PMID- 30242585 TI - Effect of alpha2-Adrenoceptor Stimulation on Functional Parameters of Langendorff Isolated Rat Heart. AB - We studied the effect of alpha2-adrenoreceptor agonist clonidine hydrochloride in concentrations of 10-9-10-6 M on inotropy, chronotropy, and coronary flow in Langendorff-isolated heart of adult rats. It was found that alpha2-adrenoreceptor agonist changed all studied parameters. Left ventricular myocardium contraction force decreased after application of all tested concentrations, the maximum effect was observed at a concentration of 10-6 M. Stimulation of alpha2 adrenergic receptors in concentrations of 10-8, 10-7, and 10-6 M produced a two phase effect (initial increase and a subsequent decrease) on the coronary flow. Clonidine hydrochloride in the maximum concentration (10-6 M) caused a decrease in HR in one group and an increase in the other. PMID- 30242584 TI - Double-decrease of the fluorescence of CdSe/ZnS quantum dots for the detection of zinc(II) dimethyldithiocarbamate (ziram) based on its interaction with gold nanoparticles. AB - A double-decrease strategy is described for ultrasensitive determination of the fungicide and vulcanization additive ziram. The assay principle is inspired by the interaction of ziram with gold nanoparticles (AuNPs). In this process, zinc ions are released, and ziram adsorption induces the aggregation of the AuNPs. The aggregated AuNPs decrease the intensity of the fluorescence of CdSe/ZnS quantum dots (QDs) capped with 3-mercaptopropionic acid via an inner filter effect. This is a result of the overlap between the absorption band of aggregated AuNPs (peaking at 680 nm) and the yellow emission of QDs (peaking at 608 nm). Zinc also exerts another decrease effect on the fluorescence of the CdSe/ZnS QDs, probably via a static quenching mechanism. Based on this double-decrease effect, ultrahigh sensitivity is achieved for ziram. The fluorescence response of the QDs (Ex / Em = 380/608 nm) is immediate. The relative fluorescence intensity is proportional to the ziram concentration within a wide range of 5 nM to 4 MUM in two consecutive linear ranges. The limit of detection is as low as ~2 nM (signal-to noise ratio of 3), which is much lower than the maximum residue limit defined by the EU pesticide database. It is also found that a similarly high sensitivity is obtained for another fungicide ferbam. Graphical abstract An ultrasensitive detection strategy for ziram was developed based on the doubledecrease effect of AuNPs and zinc ions on the fluorescence of CdSe/ZnS QDs. PMID- 30242587 TI - Development of a tool for benchmarking of clinical pharmacy activities. AB - Background Initiatives are needed to promote and evaluate clinical pharmacy. In this context, benchmarking could be useful. Objective To develop and validate a benchmarking tool for clinical pharmacy activities. Setting Six Belgian hospitals. Method A narrative literature review and two focus groups were performed to identify (1) clinical pharmacy benchmarking projects, (2) clinical pharmacy activities with a proven positive impact on the quality of care for patients, (3) quality indicators and (4) contextual factors to be included in the tool. Next, a Delphi survey and a test of the tool in practice led to content validation and usability of the benchmarking tool. Main Outcome Measure To identify quality indicators and contextual factors to be included in the tool. Results Three Delphi rounds were required (rounds 1-2: 9 participants, round 3: 8 participants). Ten quality indicators and 36 relevant contextual factors were selected. These 10 quality indicators represent 6 clinical pharmacy activities that demonstrated to improve patient outcomes: medication reconciliation at admission, patient monitoring, information provided to the health care team, patient education, discharge and transfer medication counselling, and adverse drug reaction monitoring. To collect the information needed to compose the quality indicators and to benchmark, the tool consists of three data collection instruments. An instruction manual accompanies the tool. Conclusion We have developed and validated a benchmarking tool, designed to identify and promote clinical pharmacy activities that demonstrated to improve patient outcomes. Future perspectives include the use of the tool on a national scale to identify the most efficient practices and their enablers and barriers. PMID- 30242588 TI - Prescribing omissions among elderly Brazilian patients at their hospital admission and discharge: cross-sectional study. AB - Background Potentially inappropriate prescribing for older people has become a global concern, although few researchers have analyzed potential prescribing omissions for this population. Objective This study aimed to compare the frequency of potential prescribing omissions for elderly patients at their admission to and discharge from a university hospital in northeast Brazil, using the validated and adapted Brazilian START criteria. Setting A university hospital in northeast Brazil. Methods This cross-sectional study examined data from patients who were >= 60 years old when they were admitted for > 24 h to a northeastern Brazil teaching hospital during June-December 2016. Main outcome measure Frequency of potential prescribing omissions for elderly patients at their admission to and discharge. Results Data from 227 patients were included. The mean patient age was 71 +/- 8.23 years. The patients included 131 women (57.7%), and 176 patients (77.5%) presented with a Charlson Comorbidity Index of >= 3. Based on the START criteria, the frequency of potential prescribing omissions was 44.1% (100/227) at the admission and decreased to 39.6% (90/227) at the discharge. The most common potential omissions at the admission were beta blockers in cases of stable chronic angina, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers in cases of diabetic nephropathy or renal dysfunction. Conclusion The prevalence of potential prescribing omissions among elderly patients remained relatively high at their discharge from a northeastern Brazilian university hospital. The START criteria could be a useful tool to optimize the clinical management of the elderly. PMID- 30242586 TI - The Catechol-O-Methyltransferase and Dopamine Transporter Genes Moderated the Impact of Peer Relationships on Adolescent Depressive Symptoms: A Gene-Gene Environment Study. AB - Behavioral genetics studies and new empirical evidence suggest that depression cannot simply be explained by the influence of single genes but that gene-gene environment interactions are important to better understanding the etiology of depression. The present study investigated the main and interactive effects of COMT gene Val158Met polymorphism, DAT1 gene rs27072 polymorphism, and peer relationships (i.e., peer acceptance and rejection) on adolescent depressive symptoms. In a sample of 1045 Chinese Han adolescents (Mage = 12.34 +/- 0.47 years, 50.1% girls), saliva samples, self-reported depressive symptoms and within classroom peer nominations were collected. After controlling for gender, age, and SES, the three-way interaction of COMT, DAT1, and peer acceptance significantly concurrently predicted adolescent depressive symptoms. Adolescents with ValVal genotype of COMT and CC genotype of DAT1 were more sensitive to acceptance, compared to their counterparts carrying other combined genotypes. However, a similar three-way interaction was not significant in the case of peer rejection. Additionally, the split-half validation generally replicated these findings. More importantly, this study underscores complex polygenic underpinnings of depression and lends support for the gene-gene-environment interactions implicated in the etiology of depressive symptoms. PMID- 30242589 TI - Role of pharmacists in antimicrobial stewardship programmes. AB - Antimicrobial resistance is a growing public health problem of global concern and, unless action is taken, the burden of death could reach 10 million per year by 2050. Resistance has been associated with increasing mortality, treatment failure and healthcare costs. In order to help combat this, antimicrobial stewardship programmes, have been implemented in many countries. These stewardship programmes can help, reduce inappropriate prescription and broad spectrum use of antimicrobials, improve, clinical outcomes for the population as a whole, slow down the emergence of antimicrobial resistance and conserve healthcare resources. Pharmacists are an integral part of the stewardship team and have an important role in tackling antimicrobial resistance. This article aims to review the role of pharmacists within antimicrobial stewardship programmes and the opportunities for pharmacist-driven antimicrobial stewardship strategies in hospital and community settings. PMID- 30242590 TI - Genotoxicity and Embryotoxicity Study of Bicyclol Methyl Ether, Main Impurity in Bicyclol. AB - OBJECTIVE: To assess the genotoxicity and embryotoxicity of bicyclol methyl ether (BME), the main impurity in bicyclol. METHODS: Five concentrations of BME (0.5, 5, 50, 500 and 5000 MUg/plate) were used in the Ames test to detect gene mutation. In the chromosome aberration test, Chinese hamster lung cells were used to detect chromosomal aberration of BME (15, 30, 60, 120 MUg/mL) with or without S9 mixture. Embryotoxicity test was also conducted to determine any embryotoxicity of BME (7.5, 22.5, 67.5 MUg/L) using zebrafish embryos. RESULTS: No significant differences were observed in the Ames test and the chromosome aberration test in the BME groups compared with the vehicle control group. The zebrafish embryos toxicity test also showed no embryo development toxicity of BME, including hatching rate, body length, pericardial area and yolk sac area. CONCLUSIONS: Bicyclol methyl ether has no genotoxicity in vitro and embryotoxicity in zebrafish embryos, and the impurity in bicyclol is qualified. PMID- 30242591 TI - Chinese Medicine for Alzheimer's Disease: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: To evaluate the effificacy of oral Chinese medicine (CM) in comparison with donepezil, a cholinesterase inhibitor (ChEI), for the treatment of Alzheimer's disease (AD). METHODS: Randomized controlled trials (RCTs) have been searched, and the effect of CM compared with donepezil in AD has been investigated. An electronic search of MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Library, Chinese Biological Medicine Database (CBMdisc), and China National Knowledge Infrastructure (CNKI) to identify articles in English and Chinese from the inception of the database until October 18, 2015. A modifified Jadad score (7-points) to judge the methodological quality of studies, comprehensive meta-analysis was performed with Cochrane Collaboration Revman 5.3. Dichotomous data were analyzed by relative risk (RR) with a 95% confifidence interval (CI), while continuous variables were analyzed by using mean differences (MD) with 95% CI for effect size. RESULTS: Six studies involving 596 AD patients through Jadad assessment with low bias were included in the meta-analysis. No signifificant difference was observed in cognitive improvement and daily abilities of patients using the Mini Mental State Examination (MMSE) (MD: 0.69, 95% CI:-0.17 to 1.56) and Activities of Daily Living (ADL) scale (MD: 0.94, 95% CI:-1.54 to 3.43). There were no signifificant differences in status of illness or MD for mild-moderate AD patients at 24 weeks (MD: 0.62, 95% CI:-2.99 to 4.23) and 48 weeks (MD:-0.73, 95% CI:-5.02 to 3.56). Severe AD patients were also assessed at 24 weeks (MD: 3.13, 95% CI:-6.92 to 13.18) and 48 weeks (MD: 4.23, 95% CI:-6.38 to 14.84). Furthermore, compared with donepezil, Xin (Heart) regulating CM and Shen (Kidney)-tonifying groups were observed (MD:-1.50, 95% CI: 3.08 to 0.08; MD:-1.92, 95% CI:-3.50 to-0.33; respectively). CM had fewer side effects in AD patients. CONCLUSION: Compared with donepezil, oral CM showed no signifificant difference in effectiveness in AD patients, and more evidence is needed to verify the fifindings. PMID- 30242592 TI - Pulmonoprotective Action of Zataria multiflora Ethanolic Extract on Cyclophosphamide-Induced Oxidative Lung Toxicity in Mice. AB - OBJECTIVE: To evaluate the protective effect of Zataria multiflora extract, an antioxidative medicinal plant, against cyclophosphamide (CP)-induced oxidative lung damage in mice. METHODS: Mice were intraperitoneally pre-treated with various doses of Zataria multiflora extract (50, 100, 200, and 400 mg/kg) once daily for 7 consecutive days. Animals were then injected with a single 200 mg/kg intraperitoneal dose of CP 1 h after the last administration of O. vulgare. Twenty-four hours later, mice were euthanized, the lungs were immediately removed, and biochemical and histological studies were conducted. RESULTS: A single dose of CP markedly altered the levels of several biomarkers associated with oxidative stress in lung homogenates. Pretreatment with Zataria multiflora significantly inhibited the elevation of lipid peroxidation level and the depletion in glutathione content, and superoxide dismutase and catalase activities induced by CP in lung. In addition, Zataria multiflora effectively alleviated CP-induced histopathological abnormality and pulmonary damages in mice lung tissues. CONCLUSIONS: The results reveal that Zataria multiflora protects lung tissues from CP-induced toxicity and suggest a role for oxidative stress in the pathogenesis of lung toxicity produced by CP in mice. Because Zataria multiflora has been extensively used as an additive agent and is regarded as safe, it may be used concomitantly as a good supplement for reducing organ toxicity in patients undergoing chemotherapy, besides their consolidated ethnopharmacological uses. PMID- 30242593 TI - GST transcriptional changes induced by a toxic Microcystis aeruginosa strain in two bivalve species during exposure and recovery phases. AB - Previous studies have demonstrated the modulation of glutathione transferases (GSTs) induced by microcystin (MC) alone or in combination with other cyanobacterial secondary metabolites in bivalves. However, interspecies information about which and how GST isoforms are affected by these secondary metabolites is still scarce, especially considering the dynamic process involving their uptake and elimination routes. In this context, the role of GSTs gene expression changes in response to a toxic Microcystis aeruginosa extract were examined for Mytilus galloprovincialis and Ruditapes philippinarum during exposure and recovery phases. The expression levels of sigma 1, sigma 2, pi and mu-class GST genes were analyzed in the hepatopancreas of both bivalve species during cyanobacteria extract exposure (24 h) and post-exposure (24 and 72 h). Only a significant induction of sigma 1-class GST expression was observed for R. philippinarum upon 24-hour exposure of both bivalve species to Microcystis extract. During the recovery phase, GST transcriptional changes for M. galloprovincialis were characterized by an early induction (24 h) of sigma 1 and sigma 2 transcripts. On the other hand, GST transcriptional changes for R. philippinarum during post-exposure phase were characterized by an early induction (24 h) of sigma 1 and mu transcripts and a later induction (72 h) of the four analyzed GST transcripts. Such differences reflect variable GST response mechanisms to cope with MC-producing cyanobacterial blooms exposure between these two bivalve species, revealing a higher sensitivity of R. philippinarum to Microcystis-induced stress than M. galloprovincialis. The results also suggest a much higher level of activity of the GST detoxification system during the recovery phase compared to the period of the stress exposure for both bivalve species. PMID- 30242594 TI - Fipronil (Phenylpyrazole) induces hemato-biochemical, histological and genetic damage at low doses in common carp, Cyprinus carpio (Linnaeus, 1758). AB - This study was conducted to investigate the toxic effects of fipronil on common carp (Cyprinus carpio). The trial was performed in laboratory of Department of Life Sciences at the Islamia University of Bahawalpur, Punjab, Pakistan. Total of 72 fishes, with apparently no clinical signs were purchased from local fish hatchery near Bahawalpur, Punjab, Pakistan. After 2 weeks of acclimatization fish were divided into six groups in glass aquaria (each having 100 liters of water capacity) and treated with different concentrations of fipronil for 12 days: 0 mg/L-control group (A),0.02 mg/L (B),0.04 mg/L (C),0.06 mg/L (D),0.08 mg/L (E) and 0.10 mg/L (F). Blood samples were taken every 4 days for evaluation of hemato biochemical parameters. Fish in high doses treated groups show severe abnormalities in clinical-hematological and biochemical parameters. At high dose in group E and F fish show clinical ailments such as convulsions, jerking, faintness, increase in operculum movement, body curvature and breathing difficulty. Erythrocyte count, hemoglobin, hematocrit were decreased significantly (P < 0.05) and mean corpuscular volume, total leukocyte count, neutrophils, monocytes, and lymphocytes were significantly increased. Biochemical parameters including urea, creatinine, cholesterol, triglyceride, glucose were significantly increased but albumin was significantly decreased. Nuclear and cellular abnormalities were also increased in high dose treated groups. Hence fipronil induces clinico-hematological and serum biochemical changes in common carp C. carpio. PMID- 30242596 TI - Estimation of and correction for finite motion sampling errors in small animal PET rigid motion correction. AB - Motion tracking with finite time sampling causing an associated unknown residual motion between two motion measurements is one of the factors contributing to resolution loss in small animal PET motion correction. The aim of this work is (i) to provide a means to estimate the effect of the finite motion sampling on the spatial resolution of the motion correction reconstructions and (ii) to correct for this residual motion thereby minimizing resolution loss. We calculate a tailored spatially variant deconvolution kernel from the measured motion data which is then used to deconvolve the motion corrected image using a 3D Richardson Lucy algorithm. A simulation experiment of numerical phantoms as well as a microDerenzo phantom experiment wherein the phantom was manually moved at different speeds was performed to assess the performance of our proposed method. In the motion corrected images of the microDerenzo phantom there was an average rod FWHM differences between the slow and fast motion cases of 9.7%. This difference was reduced to 5.8% after applying the residual motion deconvolution. In awake animal experiments, the proposed method can serve to mitigate the finite sampling factor degrading the spatial resolution as well as the resolution differences between fast-moving and slow-moving animals. Graphical abstract Motion correction of positron emission tomography (PET) scans of moving subjects can be performed by measuring the motion of the subject during the PET scan with an optical tracking camera. The motion tracking data obtained from the tracking camera is then used to correct the PET image reconstructions for motion. Due to finite time sampling of the motion data, the motion corrected reconstructions suffer from loss of spatial resolution. In the proposed method, a spatially variant deconvolution kernel is calculated from the motion tracking data, which is then used to correct the motion-corrected PET reconstructions for the blurring effect of the finite motion sampling through a Richardson-Lucy deconvolution. PMID- 30242595 TI - Analysis of microbial communities in heavy metals-contaminated soils using the metagenomic approach. AB - Soil pollution occurring at mining sites has adverse impacts on soil microbial diversity. New approaches, such as metagenomics approach, have become a powerful tool to investigate biodiversity of soil microbial communities. In the current study, metagenomics approach was used to investigate the microbial diversity of soils contaminated with different concentrations of lead (Pb) and zinc (Zn). The contaminated soils were collected from a Pb and Zn mine. The soil total DNA was extracted and 16S rDNA genes were amplified using universal primers. The PCR amplicons were sequenced and bioinformatic analysis of metagenomes was conducted to identify prokaryotic diversity in the Pb- and Zn-contaminated soils. The results indicated that the ten most abundant bacteria in all samples were Solirubrobacter (Actinobacteria), Geobacter (Proteobacteria), Edaphobacter (Acidobacteria), Pseudomonas (Proteobacteria), Gemmatiomonas (Gemmatimonadetes), Nitrosomonas, Xanthobacter, and Sphingomonas (Proteobacteria), Pedobacter (Bacterioidetes), and Ktedonobacter (Chloroflexi), descendingly. Archaea were also numerous, and Nitrososphaerales which are important in the nitrogen cycle had the highest abundance in the samples. Although, alpha and beta diversity showed negative effects of Pb and Zn contamination on soil microbial communities, microbial diversity of the contaminated soils was not subjected to a significant change. This study provided valuable insights into microbial composition in heavy metals-contaminated soils. PMID- 30242597 TI - To frame or not to frame? Effects of message framing and risk priming on mouth rinse use and intention in an adult population-based sample. AB - Good dental hygiene is key to public health. To promote dental hygiene behaviours, persuasive messages are key. Message framing is a popular theory that has seen mixed evidence. In this web-based experimental study, interaction effects of message frame, behavioural function, and risk priming were investigated on mouth rinse use and intentions in a representative sample of Dutch adults. Final included sample contained 549 participants (50.1% male, mean age = 47.4, SD = 16.1) and outcomes were immediate mouth rinse product choice, intentions to use mouth rinse, and mouth rinse behaviour at 2-week follow-up. Results demonstrated a theorized significant interaction between message frame and behavioural function were mouth rinse product choice. Two-week follow-up mouth rinse behaviour was affected by an interaction between message frame and risk prime. Message framing can thus be employed to promote dental health, but it requires attention to moderation effects which are inconsistent across behavioural outcomes. PMID- 30242598 TI - Daily and longitudinal associations of out-of-home time with objectively measured physical activity and sedentary behavior among middle-aged and older adults. AB - This study examined the associations of time spent out of home with physical activity and sedentary behavior among middle-aged and older adults. A diary survey was conducted for 7 days with 157 adults to measure out-of-home time and working status. Time spent in sedentary behavior and levels of physical activity were measured using an accelerometer. After a year, 137 individuals from the original sample participated in a follow-up survey. From the daily analyses of 535 non-working days and 347 working days, multilevel models revealed that on non working days, more out-of-home time was associated with less sedentary time and higher levels of physical activity at both within- and between-person levels. Longitudinal analyses of non-working days supported these results. However, on working days, similar associations were not revealed by daily or longitudinal analyses. These results suggest that increasing out-of-home time could contribute to increased physical activity and reduced sedentary behavior on non-working days. PMID- 30242599 TI - MIR4532 gene variant rs60432575 influences the expression of KCNJ11 and the sulfonylureas-stimulated insulin secretion. AB - PURPOSE: Diabetes mellitus is a major chronic disease and causes over one million deaths. KCNJ11 genetic polymorphisms influence the response of first-line oral antidiabetic agent sulfonylureas. Hsa-miR-4532 correlates with diabetic nephropathy and has a high abundance in urine. MIR4532 rs60452575 G>A variant changes the mature sequence of hsa-miR-4532. We studied whether the genetic polymorphisms of MIR4532 rs60452575 would influence KCNJ11 expression and sulfonylurea-stimulated insulin secretion or not. METHODS: To estimate the influence that rs60452575 G>A variant has on the interaction of hsa-miR-4532 and KCNJ11, we constructed a pmirGLO vector containing 3' UTR of KCNJ11 and co transfected it with wild-type and mutant hsa-miR-4532 mimics into HEK293 cells; and we overexpressed wild-type and mutant hsa-miR-4532 mimics into HEK293 cells and MIN6 cells to access its effects on KCNJ11 expression and response of sulfonylureas. RESULTS: MIR4532 rs60452575 G>A variant appeared to disrupt the repression of KCNJ11 expression in both cell lines, and reduce the sulfonylurea stimulated insulin secretion by breaking the binding of the hsa-miR-4532 to 3' UTR of KCNJ11 in MIN6 cells. CONCLUSIONS: Our study indicates that MIR4532 rs60452575 variant influences KCNJ11 expression and sulfonylurea response. It might be a potential predictive factor of sulfonylureas therapy. PMID- 30242600 TI - Insights on the phenotypic heterogenity of 11beta-hydroxylase deficiency: clinical and genetic studies in two novel families. AB - PURPOSE: 11beta-hydroxylase deficiency accounts for 5% of congenital adrenal hyperplasia cases. Diagnosis suspiction is classically based on the association between abnormal virilization, precocious puberty, and hypertension in 46XX or 46XY subjects. We investigated two families with siblings presenting with opposed clinical features, and provided a review of the mechanisms involved in mineralocorticoid-dependent phenotypic heterogeneity. METHODS: The coding region of the CYP11B1 gene of 4 patients was sequenced and familial segregation was confirmed. Clinical characterization and blood steroid profile were performed. RESULTS: Family 1 comprised a female and a male siblings who presented in middle childhood with genital ambiguity (Prader II) and precocious puberty, respectively, associated with hypertension. In the second decade of life, the woman had three full-term pregnancies, and then evolved normotensive with no treatment over a 5-year follow up. On the other hand, her brother had hypertensive end-organ damage at age 24. In family 2, a 2.9 year-old boy presented with precocious puberty and hypertension, whereas his 21 days-old sister had genital ambiguity (Prader III) and salt wasting. A homozygous exon 4 splice site mutation was identified (IVS4ds-1G > A; c.799 G > A) in family 1, while a nonsense mutation in exon 6 (p. Q356X; c.1066 C > T) was found in family 2. CONCLUSION: CYP11B1 mutations were associated with highly variable phenotypes, from mild to severe virilization, and early-onset hypertension or salt wasting. Further analysis of variants in other hypertension-related genes, steroid synthesis and metabolism compensatory pathways, and/or the investigation of chimeric CYP11B genes are needed to clarify the phenotypic heterogeneity in 11beta-hydroxylase deficiency. PMID- 30242601 TI - Impaired HPA axis function in diabetes involves adrenal apoptosis and phagocytosis. AB - PURPOSE: The aim of the present study was to analyze the involvement of oxidative stress and inflammation in the modulation of glucocorticoid production in the adrenal cortex of diabetic rats. METHODS: Male Wistar rats were treated with or without streptozotocin (STZ, an insulinopenic model of diabetes) and either alpha lipoic (90 mg/kg ip.), alpha-tocopherol (200 mg/kg po.) or with STZ and supplemented with insulin (STZ + INS: 2.5U/day) for 4 weeks. Oxidative/nitrosative stress parameters and antioxidant enzymes were determined in adrenocortical tissues. Apoptosis and macrophage activation were evaluated by immunohistochemistry (TUNEL and ED1+). Basal and ACTH-stimulated corticosterone production were assessed by RIA and plasma ACTH levels were determined by an immunometric assay. RESULTS: Diabetic rats showed a diminished response to exogenous ACTH stimulation along with higher basal corticosterone and lower plasma ACTH levels. In the adrenal cortex we determined an increase in the levels of lipoperoxides, S-nitrosothiols, nitric oxide synthase activity and nitro tyrosine modified proteins while catalase activity and heme oxygenase-1 expression levels were also elevated. Antioxidant treatments were effective in the prevention of these effects, and in the increase in the number of apoptotic and phagocytic (ED1+) cells detected in diabetic rats. No changes were observed in the STZ + INS group. CONCLUSIONS: Generation of oxidative/nitrosative stress in the adrenal cortex of diabetic rats leads to the induction of apoptosis and the activation of adrenocortical macrophages and is associated with an elevated basal corticosteronemia and the loss of the functional capacity of the gland. PMID- 30242602 TI - Intraoperative unfolding and postoperative pruning of the pituitary gland after transsphenoidal surgery for pituitary adenoma: A volumetric and endocrinological evaluation. AB - PURPOSE: To describe the volumetric changes that the pituitary gland (PG) undergoes during and after transsphenoidal surgery (TSS), and to evaluate if unfolding and/or pruning are related to endocrinological outcome measures. METHODS: Retrospective evaluation of data prospectively collected of a cohort of patients undergoing TSS for a pituitary adenoma with the adjunctive use of high field 3 Tesla intraoperative MRI. All patients underwent a full endocrinological workup preoperatively, as well as at 6 weeks and 1 year postoperatively. A decrease in PG volume >=15% between the intraoperative and 3-month, or between the 3-month and 12-month measurements, was considered early and late pruning, respectively. RESULTS: The PG unfolds significantly during TSS, and subsequently undergoes pruning up until 1 year postoperatively, in most cases returning to the preoperatively measured PG volume. A smaller baseline PG volume predicts intraoperative unfolding. Early pruning of the PG after surgery was associated with new functional deficits. Baseline pituitary compression also correlated to newly occurring deficits after surgery. A larger 1-year pituitary volume was associated with biochemical remission in secreting adenomas. CONCLUSIONS: The PG shows dynamic change during and after TSS for pituitary adenoma. Small baseline and 3-month PG volumes, as well as early pruning were independently associated with new deficits. Our findings warrant prospective validation in a larger cohort with higher statistical power. PMID- 30242603 TI - Bi2Se3 Sensitized TiO2 Nanotube Films for Photogenerated Cathodic Protection of 304 Stainless Steel Under Visible Light. AB - Titanium dioxide (TiO2) nanotube arrays coupled with a narrow gap semiconductor bismuth selenide (Bi2Se3)-exhibited remarkable enhancement in the photocathodic protection property for 304 stainless steel under visible light. Bi2Se3/TiO2 nanocomposites were successfully synthesized using a simple two-step method, including an electrochemical anodization method for preparing pure TiO2 and a chemical bath deposition method for synthesizing Bi2Se3 nanoflowers. The morphology and structure of the composite films were studied by scanning electron microscopy, energy dispersion spectroscopy, X-ray photoelectron spectroscopy and X-ray diffraction. In addition, the influence of the Bi2Se3 content on the photoelectrochemical and photocathodic protection properties of the composite films was also studied. The photocurrent density of the Bi2Se3/TiO2 nanocomposites was significantly higher than that of pure TiO2 under visible light. The sensitizer Bi2Se3 enhanced the efficient separation of the photogenerated electron-hole pairs and the photocathodic protection properties of TiO2. Under visible light illumination, Bi2Se3/TiO2 nanocomposites synthesized by the chemical bath deposition method with Bi3+ (0.5 mmol/L) exhibited the optimal photogenerated cathodic protection performance for 304 stainless steel. PMID- 30242604 TI - A focus on direct oral anticoagulants: "old" and possible new indications and efforts for a better clinical management. PMID- 30242605 TI - How long should we continue gastric cancer screening? From an epidemiological point of view. AB - BACKGROUND: In Japan, incidence of gastric cancer is expected to follow the current downward trend as the younger generation has lower incidence of Helicobacter pylori infection. In this study we aimed to estimate how long gastric cancer screening is deemed necessary in the future from epidemiologic perspectives. METHODS: Following the Japanese guidelines for gastric cancer screening 2014, recommendation of providing population-based gastric cancer screening is judged by balancing benefits and harms. Benefits and harms are estimated by number needed to screen (NNS) < 1000 and Number Needed to Recall (NNR) < 100. NNS is the number of people required to participate in a screening to prevent one death and NNR is the number of people required to undergo diagnostic examination to prevent one death. These index are estimated for 2020 2035 using future projections of gastric cancer mortality for the scenarios of relative risk (RR) of 0.5-0.9 for mortality reduction by the screening. RESULTS: The criteria of both NNS < 1000 and NNR < 100 are fulfilled for the following age groups: when RR is set as 0.6, men >= 55 and women >= 65; when RR is set as 0.7 and 0.8, men >= 65 and women >= 75; when RR is set as 0.9, men >= 75 only. CONCLUSIONS: In case of RR of 0.5 and 0.6, the gastric cancer screening are recommended for men >= 55 and women >= 65 until 2035, while it is not recommended for men and women in the 45-54 even in 2010 and 2015. PMID- 30242607 TI - Quality of Life in Thalassemia Major. PMID- 30242606 TI - Dietary Therapies: Emerging Paradigms in Therapy of Drug Resistant Epilepsy in Children : Based on 6th Dr. I. C. Verma Excellence in Research Award Oration. AB - About one-third of childhood epilepsy ultimately becomes drug resistant epilepsy. Only about one-third of drug resistant epilepsy is amenable for epilepsy surgery. Epilepsy surgery and vagal nerve stimulation is still beyond the reach of huge proportion of children with pharmacoresistant epilepsy. Ketogenic diet (KD) has been in use for almost a century now all over the world for drug resistant epilepsy, although in between there was a decline in its popularity with advent of newer antiepileptic drugs like valproate, phenytoin and carbamazepine. Again from 1990s there was resurgence of interest in KD for pharmacoresistant epilepsy and in the last two decades several randomized controlled trials and systemic reviews have proved its efficacy beyond any suspicion. Ketogenic diet is a high fat low carbohydrate and low protein diet, which has been found to reduce epileptogenesis in body most probably by production of ketone bodies. Modified Atkin's Diet (MAD) first introduced in 2003 and Low Glycemic Index Treatment (LGIT) first introduced in 2005 are another two dietary therapies, which are less restrictive, more palatable with fewer adverse effects and comparable efficacy. MAD is also a high fat, low carbohydrate diet, in which high sugar foods are discouraged and protein and fluids are unrestricted. In LGIT, only carbohydrates with Glycemic Index <50 are allowed and carbohydrate intake is restricted to 40 60 g per day. Medium Chain Triglyceride KD (MCT KD) is another alternative, in which there are more food choices as compared to classic KD, with comparable efficacy. PMID- 30242608 TI - Correction to: Laparoscopic-assisted transversus abdominis plane block as an effective analgesic in total extraperitoneal inguinal hernia repair: a double blind, randomized controlled trial. AB - In the original publication, one of the co-author 'M. Riaz' details were missed to include in the author group. The complete author group should read as A. Mughal, A. Khan, J. Rehman, H. Naseem, M. Riaz, R. Waldron, M. Duggan, W. Khan, K. Barry, I. Z. Khan. PMID- 30242609 TI - Penalized Best Linear Prediction of True Test Scores. AB - In best linear prediction (BLP), a true test score is predicted by observed item scores and by ancillary test data. If the use of BLP rather than a more direct estimate of a true score has disparate impact for different demographic groups, then a fairness issue arises. To improve population invariance but to preserve much of the efficiency of BLP, a modified approach, penalized best linear prediction, is proposed that weights both mean square error of prediction and a quadratic measure of subgroup biases. The proposed methodology is applied to three high-stakes writing assessments. PMID- 30242610 TI - Bioactive enmein-type 6,7-seco-ent-kaurane diterpenoids: natural products, synthetic derivatives and apoptosis related mechanism. AB - Diterpenoids are important and widely distributed natural compounds with various biological effects, including antitumor, anti-inflammatory and so on. Great efforts have been put in phytochemistry research on diterpenoids. A number of structural modified derivatives and pharmacophore incorporated hybrids were also designed and synthesized with promising therapeutic effects. Among the hopefuls, enmein-type 6,7-seco-ent-kaurane diterpenoids with unique ring system and stereogenic centers exhibit attractive activities. Based on their lead-like properties, enmein-type diterpenoids are suitable for further medicinal study. The derivatives were biologically evaluated and showed promising activities, which warranted in-depth research for further understanding. In this review, the natural bioactive enmein-type diterpenoids and the synthetic derivatives were comprehensively summarized. PMID- 30242611 TI - Impact of Insulin Degludec in Type 2 Diabetes: Real-World Data on Effectiveness and Safety. AB - INTRODUCTION: Real-world evidence on effectiveness and safety of insulin degludec (IDeg) in patients with diabetes is a priority. The aim of the study was to evaluate patterns of use and the long-term effectiveness and safety of IDeg in routine clinical practice. METHODS: This was an observational longitudinal study. A retrospective chart review of all patients with type 2 diabetes treated with IDeg was performed and temporal trends in clinical outcomes were assessed. All data was stratified by treatment modality: the switch group consisted of patients already treated with another basal insulin before initiating IDeg; the add-on group consisted of basal insulin-naive patients. RESULTS: Overall, 247 patients were analyzed (55 in the add-on group and 192 in the switch group), mean age 67.0 +/- 10.9 years ,and diabetes duration 16.3 +/- 8.9 years. Median (interquartile range) follow-up was 9.7 (8.0-11.9) months. In the add-on group, improvements were found in glycated hemoglobin (HbA1c) (- 1.68%; p < 0.0001), fasting blood glucose (FBG) (- 64.7 mg/dL; p < 0.0001), post-prandial glucose (PPG) (- 81.1 mg/dl; p < 0.0001), and glycemic variability (i.e., standard deviation of blood glucose) (- 11.6 mg/dl; p = 0.04). Even in the switch group, improvements were found in HbA1c (- 0.57%; p < 0.0001), FBG (- 28.1 mg/dL; p < 0.0001), and PPG (- 22.6 mg/dl; p = 0.001). Body weight increase during the follow-up was not statistically significant vs. baseline in both groups. Benefits on overall, nocturnal, and severe hypoglycemia were found in the switch group. CONCLUSION: These real-world data documented that initiating IDeg or switching to IDeg from other basal insulins in type 2 diabetes was associated with significant improvement in metabolic control without significant weight gain; a decrease in the risk of hypoglycemia was observed when switching to IDeg from another basal insulin. PMID- 30242612 TI - Pediatric Insulin Injection Technique: A Multi-Country Survey and Clinical Practice Implications. AB - INTRODUCTION: The 2015 Insulin Injection Technique Questionnaire survey involving 13,289 patients included 898 (6.8%) patients in the pediatric age range (<= 18 years). METHODS: The younger patients included in the questionnaire survey were grouped according to age: Group 1 (G1), 0-6 years, n = 85; Group 2(G2), 7-13, n = 423; Group 3 (G3), 14-18, n = 390. The injection technique was evaluated by means of a questionnaire and nurse assessment. RESULTS: Nurses found lipohypertrophy at injection sites in 41.3, 45.2, and 47.3% of patients in G1, G2, and G3, respectively. Unexpected hypoglycemia was common, ranging from 23.8 to 48.1% of patients, and glucose variability was even more common (61.0% in G1, 45.9% in G2, and 52.5% in G3); both conditions were associated with lipohypertrophy. While increasing numbers of patients were using the recommended 4-mm needles, large percentages still used longer ones (33.3% in G1, 45.9% in G2, and 61.5% in G3). The reuse of needles was also common, ranging from 21.1 to 32.5% in the three age groups. Excessive reuse, defined as using a single needle more than five times, was reported by 9.4-21.8% of patients in the three age group. The percentages of patients who had not received any injection training in the last 12 months ranged from 21.2 to 26.8% in the three groups. CONCLUSION: Implications of our study are as follows: (1) pediatric patients should use 4-mm pen needles or 6-mm syringes (inserted at a 45 degrees angle); (2) patients aged <= 6 years should always inject into a raised skin fold regardless of which device is used; (3) all patients should rotate sites and use needles only once to avoid lipohypertrophy. FUNDING: Becton-Dickinson (BD) diabetes care. PMID- 30242614 TI - Morphine Potentiates Dysbiotic Microbial and Metabolic Shifts in Acute SIV Infection. AB - Human Immunodeficiency Virus (HIV) pathogenesis has been closely linked with microbial translocation, which is believed to drive inflammation and HIV replication. Opioid drugs have been shown to worsen this symptom, leading to a faster progression of HIV infection to Acquired Immunodeficiency Syndrome (AIDS). The interaction of HIV and opioid drugs has not been studied at early stages of HIV, particularly in the gut microbiome where changes may precede translocation events. This study modeled early HIV infection by examining Simian Immunodeficiency Virus (SIV)-infected primates at 21 days or less both independently and in the context of opioid use. Fecal samples were analyzed both for 16S analysis of microbial populations as well as metabolite profiles via mass spectrometry. Our results indicate that changes are minor in SIV treated animals in the time points examined, however animals treated with morphine and SIV had significant changes in their microbial communities and metabolic profiles. This occurred in a time-independent fashion with morphine regardless of how long the animal had morphine in its system. Globally, the observed changes support that microbial dysbiosis is occurring in these animals at an early time, which likely contributes to the translocation events observed later in SIV/HIV pathogenesis. Additionally, metabolic changes were predictive of specific treatment groups, which could be further developed as a diagnostic tool or future intervention target to overcome and slow the progression of HIV infection to AIDS. PMID- 30242613 TI - Immunomodulatory Properties of Bone Marrow Mesenchymal Stem Cells from Patients with Amyotrophic Lateral Sclerosis and Healthy Donors. AB - Pathogenesis of amyotrophic lateral sclerosis (ALS) involves several mechanisms resulting in a shift from a neuroprotective to a neurotoxic immune reaction. A promising tool for ALS treatment is represented by mesenchymal stem cells (MSCs), which possess both regenerative potential and immunomodulatory properties. In this study, we aimed to compare the immunomodulatory properties of MSCs isolated from the bone marrow of patients suffering from ALS and healthy donors. Moreover, the influence of proinflammatory cytokines on the immunoregulatory functions of MSCs was also evaluated. We found that MSCs from ALS patients and healthy donors comparably affected mitogen-stimulated peripheral blood mononuclear cells and reduced the percentage of T helper (Th)1, Th17 and CD8+CD25+ lymphocytes. These MSCs also equally increased the percentage of Th2 and CD4+FOXP3+ T lymphocytes. On the other hand, MSCs from ALS patients decreased more strongly the production of tumour necrosis factor-alpha than MSCs from healthy donors, but this difference was abrogated in the case of MSCs stimulated with cytokines. Significant differences between cytokine-treated MSCs from ALS patients and healthy donors were detected in the effects on the percentage of CD8+CD25+ and CD4+FOXP3+ T lymphocytes. In general, treatment of MSCs with cytokines results in a potentiation of their effects, but in the case of MSCs from ALS patients, it causes stagnation or even restriction of some of their immunomodulatory properties. We conclude that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines. Graphical Abstract Treatment of mesenchymal stem cells (MSCs) with cytokines results in a potentiation of their effects, but in the case of MSCs from amyotrophic lateral sclerosis (ALS) patients, it causes stagnation (an equal reduction of the percentage of CD8+CD25+ T lymphocytes) or even restriction (no increase of proportion of CD4+FOXP3+ T lymphocytes) of some of their immunomodulatory properties. It means that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines. PMID- 30242615 TI - YouTube Videos as a Source of Information on Colorectal Cancer: What Do Our Patients Learn? AB - YouTube is the second most visited website in the world. No studies to date have characterized and evaluated YouTube videos on colorectal cancer (CRC) although these videos could influence patient decision-making, notably regarding screening and prevention. This study aims to report the characteristics and quality of these videos as patient education resources for CRC. YouTube's search engine was queried with different search phrases relating to CRC. The first two pages of each search result were analyzed. Two specialists devised a critical appraisal tool with a list of criteria to assess the videos. Quantitative YouTube parameter analyses and criteria assessment were performed. Inter-rater agreement was assessed between three raters. A total of 46 videos were eligible to be included in the study. The videos were on average 4:51 +/- 3:27 min long. The videos had 10 times as many likes as dislikes. Less than half the videos discussed risk factors and protective factors. Only 41% of videos mentioned screening tests and only about a quarter discussed them. Palliative care was only mentioned in 2% of videos. A single video could obtain a perfect score on the critical appraisal tool. Length was the unique parameter associated with a high score on the criteria list. There is thus a need for more authoritative and comprehensive videos easily identifiable by the patients. Video popularity is not associated with comprehensiveness. Currently, YouTube might not be an education resource for CRC suited to every patient. PMID- 30242616 TI - Co-occurrence of mycotoxins in maize food and maize-based feed from small-scale farms in Brazil: a pilot study. AB - A limited survey was conducted to assess the co-occurrence of aflatoxins (AF) B1, B2, G1, and G2; fumonisins (FB) B1 and B2; ochratoxin A (OTA); zearalenone (ZEN); and deoxynivalenol (DON) in maize food (N = 26) and animal feed (N = 45) collected from 21 small-scale farms from the states of Sao Paulo (SP) and Santa Catarina (SC), Brazil. Samples evaluated were maize meal and maize flour for human consumption available in the farm households, and maize-based feed intended for broiler chicks, laying hens, and dairy cows. Analyses of mycotoxins were performed by ultra-performance liquid chromatography coupled with tandem mass spectrometry. The median levels of mycotoxins found in maize food were 2.5 MUg/kg (total AF), 120 MUg/kg (total FB), 13 MUg/kg (ZEN), and 57 MUg/kg (DON). All values were below the Brazilian tolerance limits, except for total FB in one sample of maize flour. In feed samples, median levels of total AF, total FB, ZEN, and DON were 100 MUg/kg, 680 MUg/kg, 160 MUg/kg, and 200 MUg/kg, respectively. The co-occurrence of two or more mycotoxins was confirmed in 35% and 51% of maize food and feed, respectively. Results indicate a low human exposure to mycotoxins in the small-scale farms evaluated and a higher exposure of farm animals to mycotoxins in the feed. PMID- 30242617 TI - Impact of error structure misspecification when testing measurement invariance and latent-factor mean difference using MIMIC and multiple-group confirmatory factor analysis. AB - When multiple groups are compared, the error variance-covariance structure is not always invariant between groups. In this study we investigated the impacts of misspecified error structures on testing measurement invariance and the latent factor mean difference between groups. A Monte Carlo study was conducted to examine how measurement invariance and latent mean difference tests were affected when heterogeneous error structures were misspecified as being invariant across groups. Multiple-group confirmatory factor analysis (MGCFA) and the multiple indicator multiple-causes model (MIMIC) were employed in the present study. The rejection rates of both metric and strict invariance in measurement invariance testing, as well as the estimation accuracy and statistical inference of the factor mean difference, were investigated under error structure misspecification. In addition, sensitivity of the model fit indices to error structure misspecification was examined. Overall, misspecification of the error structure affected testing for metric but not scalar invariance. Metric invariance was often rejected, especially when error covariance in one group was ignored. In contrast, MGCFA and MIMIC performed comparatively well at detecting latent-factor mean differences between groups, with acceptable power and well-controlled Type I errors. The practical implications of these findings are discussed, as well as recommendations. PMID- 30242619 TI - Aesthetic compatibility assessment of consolidants for wall paintings by means of multivariate analysis of colorimetric data. AB - BACKGROUND AND METHODS: Wall paintings and architectural surfaces in outdoor environments are exposed to several physical, chemical and biological agents, hence they are often treated with different products to prevent or slow down their deterioration. Among the factors that have to be taken into account in the selection of the most suitable treatment for decorated surfaces, the aesthetic compatibility with the substrate is of great importance in the cultural heritage field; minimizing colour variation after treatment application is a crucial issue in particular for painted surfaces. In the framework of the European Project Nanomatch the color variation induced on wall painting mock-ups by the two innovative consolidants (calcium alkoxides) developed was evaluated using colorimetry in comparison with two traditional products. In this work these innovative consolidants have been also tested in combination with two commercial biocides and the results of colorimetric measurements discussed. Moreover, as the univariate approach didn't allow to draw clear conclusions on the relation between the different sources of data variability, multivariate analysis was performed on colorimetric data. RESULTS: Principal Component Analysis and multi way Parallel Factor Analysis (PARAFAC) were successfully applied to colorimetric data to investigate the short-term effects of the application of different consolidants on wall painting surfaces, making it possible to study at the same time the different sources of data variability, i.e. treatments, painting techniques, pigments. Finally, a ranking list of the treatments under study in terms of colour variation induced on the surface was established, in function of the painting technique and pigment, taking also in consideration the combination consolidant/biocide. In particular, given the true multi-way nature of the data, PARAFAC model turned out to be extremely useful in the study of the dependence of colour variation on pigments, a critical issue for painted surfaces, that was not clear using univariate approach. CONCLUSIONS: Multivariate approach to colorimetric data and especially 3-way PARAFAC method resulted a powerful technique to evaluate in short-term the color compatibility of consolidants for wall paintings, improving data interpretation and visualization, and thus outperforming the univariate statistical analysis. PMID- 30242620 TI - CME Instructions: Value of gated-SPECT MPI for ischemia-guided PCI of non-culprit vessels in STEMI patients with multivessel disease after primary PCI. PMID- 30242618 TI - Plasma beta-Amyloids and Tau Proteins in Patients with Vascular Cognitive Impairment. AB - Increases in plasma of beta-amyloids (Abeta) and tau proteins have been noted in patients with Alzheimer's dementia (AD). Our study investigated the associations of plasma Abeta and tau proteins with dementia in stroke patients. This cross sectional study recruited 24 controls (mean age: 67.4 +/- 7.5 years, 33.3% male), 27 stroke patients without dementia (mean age: 70.7 +/- 6.9 years, 60.7% male), 34 stroke patients with dementia (mean age: 78.3 +/- 5.3 years, 45.5% male, Clinical Dementia Ranking (CDR): 1.46 +/- 0.63), and 21 AD patients (mean age: 77.1 +/- 9.1 years, 42.9% male, CDR: 1.43 +/- 0.60) from a medical center. Dementia was defined as a CDR scale score of >= 1. The plasma levels of Abeta-40, Abeta-42, and tau were analyzed using immunomagnetic reduction. One-way analysis of variance was used to compare the differences in measured protein levels between the groups. The results indicated that plasma levels of tau and Abeta-42, but not Abeta-40, in stroke patients were significantly higher than in the controls. After adjustment for age, sex, diabetes mellitus, hypertension, and hyperlipidemia, only plasma level of Abeta-42 remained significantly higher in stroke patients with dementia than in those without dementia (OR 1.85, 1.25-2.75, p = 0.002). In summary, our results suggest that plasma Abeta-42 is a potential biomarker for dementia in stroke patients. PMID- 30242621 TI - Latest Clinical Approaches in the Ocular Management of Cystinosis: A Review of Current Practice and Opinion from the Ophthalmology Cystinosis Forum. AB - Cystinosis, a rare autosomal recessive disease caused by intracellular cystine accumulation, occurs in an estimated 1/100,000-200,000 live births. Ocular non nephropathic cystinosis is typically diagnosed during adulthood, when patients present with corneal crystal deposition and no systemic involvement. Due to the rarity of the condition, diagnosis is often delayed and can have a significant impact on the overall prognosis of the disease. Early diagnosis is therefore imperative to ensure successful treatment and improve quality of life, as most of its clinical manifestations can be prevented or delayed. Early detection strategies and practical approaches for the ocular management of cystinosis were discussed during the Ophthalmology Cystinosis Forum, a 1-day meeting held in Berlin, Germany during June 2017. Recommendations for early detection comprise ophthalmic assessment, including self- and clinician-assessed recording of photophobia, and visual acuity, slit-lamp examination and tonometry ophthalmic examinations. In vivo confocal microscopy and anterior segment optical coherence tomography were highlighted as valuable techniques in evaluating cystine crystals in the cornea, in vivo and non-invasively. The mainstay of ocular cystinosis treatment is the cystine-depleting aminothiol cysteamine. Indeed, early treatment with and strict adherence to cysteamine therapy has a considerable impact on the long-term prognosis of ocular cystinosis. In rare diseases such as ocular cystinosis, standardised guidelines and recommendations for detection, patient care and follow-up assessments are essential. Such guidelines provide a support tool for healthcare professionals caring for ocular cystinosis patients. Multidisciplinary teams (MDTs) are essential for delivering gold standard care and improving quality of life for patients and their families. This review paper highlights current early detection policies, clinical treatment strategies and practical approaches for the ocular management of cystinosis, including implementing a cystinosis MDT. Additionally, discussions of the Ophthalmology Cystinosis Forum held in 2017 are summarised. FUNDING: Orphan Europe. Plain language summary available for this article. PMID- 30242622 TI - Chemical shift assignment of the viral protein genome-linked (VPg) from potato virus Y. AB - The dysregulation of translation contributes to many pathogenic conditions in humans. Discovering new translational mechanisms is important to understanding the diversity of this process and its potential mechanisms. Such mechanisms can be initially observed in viruses. With this in mind, we studied the viral protein genome-linked VPg factor from the largest genus of plant viruses. Studies in plants show that VPg binds to the eukaryotic translation initiation factor eIF4E for translation of viral RNAs. VPg contains no known eIF4E binding motifs and no sequence homology to any known proteins. Thus, as a first step in understanding the structural basis of this interaction, we carried out NMR assignments of the VPg from the potato virus Y potyvirus protein. PMID- 30242623 TI - Backbone and side-chain resonance assignments of the methyl-CpG-binding domain of MBD6 from Arabidopsis thaliana. AB - Epigenetic regulation is essential to various biological phenomena such as cell differentiation and cancer. DNA methylation is one of the most important epigenetic signals, as it is directly involved in gene silencing of transposable elements, genomic imprinting, and chromosome X inactivation. To mediate these processes, methyl-CpG-binding domain (MBD) proteins recognize specific signals encoded in the form of DNA methylation patterns. AtMBD6, one of the 12 MBD proteins in Arabidopsis thaliana, shares a high sequential homology in the MBD domain with mammalian MBD proteins, but a detailed characterization of its structural and functional properties remains elusive. Here, we report the 1H, 13C, and 15N resonance assignments of the isolated MBD domain of AtMBD6. Analysis of the chemical shift data implied that the MBD domain of AtMBD6 has a secondary structure similar to that of mammalian MeCP2, while the beta-strands beta1 and beta3 of AtMBD6 were found to be longer than those of MeCP2. The structural differences provide insight into the different recognition mechanisms of methylated DNA by plant and mammalian MBDs. The assignments reported here will aid further analyses such as titration experiments and three-dimensional structure determination using NMR to yield a detailed characterization of the interaction between AtMBD6 and methylated DNAs. PMID- 30242624 TI - Italian Investigation on Mental Health Workers' Attitudes Regarding Personal Recovery From Mental Illness. AB - This study aimed to investigate attitudes toward personal recovery in a sample of 436 healthcare professionals and students of psychiatric rehabilitation techniques through the Italian version of the recovery knowledge inventory (RKI). The sample in our study showed a good global orientation toward recovery. Statistically significant differences were found among mental health professionals based on gender difference, professional role, and level of experience. Women seemed more inclined to accept users' decision-making processes, including therapeutic risk-taking. Nurses seemed more cautious in considering the users able to "live beyond their illness". Professionals with fewer than 15 years of experience had more favorable attitudes and expectations than the more experienced respondents. Students had more optimistic expectations regarding recovery than nurses and social workers. Academic curriculum development for students and training courses for mental health professionals could further improve the homogeneity in attitudes and skills in the support of users' "unique" recovery processes. PMID- 30242625 TI - Mutual Antagonism of PINK1/Parkin and PGC-1alpha Contributes to Maintenance of Mitochondrial Homeostasis in Rotenone-Induced Neurotoxicity. AB - Parkinson's disease (PD) is a progressive, selective, and age-related neurodegenerative disease. The pathogenic focus of PD is mitochondrial dysfunction. When mitochondrial homeostasis was damaged, it can lead to reactive oxygen species formation to further accelerate the accumulation of dysfunctional mitochondria, resulting in a vicious cycle harmful to the neuron. PINK1 and Parkin, two proteins that are linked to PD, play vital roles in mitophagy, which was very important in maintaining mitochondrial homeostasis. Thus, at present, we explored mitochondrial biogenesis, mitophagy, and fission/fusion in rotenone induced dopamine neurotoxicity. In particular, we focused on interactions between the PINK1/Parkin pathway and PGC-1alpha in the regulation of mitochondrial homeostasis impairment. The results indicated that both the autophagy and mitophagy levels increased significantly and were accompanied by altered levels of PINK1/Parkin proteins in rotenone-induced neurotoxicity. PINK1 influenced mitochondrial biogenesis by inhibiting PGC-1alpha and mtTFA protein expression as well as the mtDNA copy number. PGC-1alpha, in turn, inhibited PINK1/Parkin protein expression and the mitophagy levels. Furthermore, the results demonstrated that PINK1 influenced mitochondrial fission/fusion by regulating MFN2 and phosphorylating Drp1. In summary, mutual antagonism of the PINK1/Parkin pathway and PGC-1alpha formed a balance that regulated mitochondrial biogenesis, fission/fusion, and mitophagy. These effects contributed to the maintenance of mitochondrial homeostasis in rotenone-induced neurotoxicity. PMID- 30242626 TI - Amelioration of Aluminum Maltolate-Induced Inflammation and Endoplasmic Reticulum Stress-Mediated Apoptosis by Tannoid Principles of Emblica officinalis in Neuronal Cellular Model. AB - The neuroprotective role of tannoid principles of Emblica officinalis (EoT), an Indian and Chinese traditional medicinal plant against memory loss in aluminum chloride-induced in vivo model of Alzheimer's disease through attenuating AChE activity, oxidative stress, amyloid and tau toxicity, and apoptosis, was recently reported in our lab. However, to further elucidate the mechanism of neuroprotective effect of EoT, the current study was designed to evaluate endoplasmic reticulum stress-suppressing and anti-inflammatory role of EoT in PC 12 and SH-SY 5Y cells. These cells were divided into four groups: control (aluminum maltolate (Al(mal)3), EoT + Al(mal)3, and EoT alone based on 3-(4, 5 dimethyl 2-yl)-2, and 5-diphenyltetrazolium bromide (MTT) assay. EoT significantly reduced Al(mal)3-induced cell death and attenuated ROS, mitochondrial membrane dysfunction, and apoptosis (protein expressions of Bax; Bcl-2; cleaved caspases 3, 6, 9, 12; and cytochrome c) by regulating endoplasmic reticulum stress (PKR-like ER kinase (PERK), alpha subunit of eukaryotic initiation factor 2 (EIF2-alpha), C/EBP-homologous protein (CHOP), and high mobility group box 1 protein (HMGB1)). Moreover, inflammatory response (NF kappaB, IL-1beta, IL-6, and TNF-alpha) and Abeta toxicity (Abeta1-42) triggered by Al(mal)3 was significantly normalized by EoT. Our results suggested that EoT could be a possible/promising and novel therapeutic lead against Al-induced neurotoxicity. However, further extensive research is needed to prove its efficacy in clinical studies. PMID- 30242628 TI - Hepatoprotective effect of gastrodin against alcohol-induced liver injury in mice. AB - Alcoholic liver disease (ALD) is a common and serious threat to human health worldwide. In this study, the hepatoprotective effect of gastrodin against alcohol-induced liver injury in mice was examined. Mice with alcohol-induced hepatotoxicity were treated intragastrically with gastrodin (50, 80, or 100 mg/kg). The mice treated with gastrodin experienced better outcomes than those who received only one dose of alcohol (50%, 10 mL/kg b.w.). Gastrodin treatment reduced the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), decreased hepatic malondialdehyde (MDA) content, and increased hepatic superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities in a dose-dependent manner. Gastrodin also alleviated histopathological changes induced by alcohol. Gastrodin protected against alcohol induced increases in expression levels of the cytochrome P450 2E1 (CYP2E1) and mRNA levels of chemokine (C-X-C motif) ligand 1 (CXCL-1), interferon-gamma (IFN gamma), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), vascular cell adhesion molecule 1 (VCAM-1), nuclear factor-kappa B (NF-kappaB), Toll-like receptor 4 (TLR-4), and activator of transcription 3 (STAT-3). Moreover, gastrodin-increased nuclear transcription factor 2 (Nrf2) translocates to the nucleus and enhanced the activity of anti-oxidant enzymes, and could thereby ameliorate alcohol-induced liver injury in mice. This study demonstrated that gastrodin may be an effective therapeutic agent against alcohol-induced liver injury. PMID- 30242627 TI - Assessing Head/Neck Dynamic Response to Head Perturbation: A Systematic Review. AB - BACKGROUND: Head/neck dynamic response to perturbation has been proposed as a risk factor for sports-related concussion. OBJECTIVES: The aim of this systematic review was to compare methodologies utilised to assess head/neck dynamic response to perturbation, report on magnitude, validity and reliability of the response, and to describe modifying factors. METHODS: A systematic search of databases resulted in 19 articles that met the inclusion and exclusion criteria. RESULTS: Perturbation methods for head/neck dynamic response included load dropping, quick release and direct impact. Magnitudes of perturbation energy varied from 0.1 to 11.8 J. Head/neck response was reported as neck muscle latency (18.6-88.0 ms), neck stiffness (147.2-721.9 N/rad, 14-1145.3 Nm/rad) and head acceleration (0.2 3.8g). Reliability was only reported in two studies. Modifying factors for head/neck response included younger and older participants presenting increased responses, females showing better muscular reactivity but similar or increased head kinematics compared with males, and bracing for impact limiting muscular activity and head kinematics. DISCUSSION: Substantial differences in experimental and reporting methodologies limited comparison of results. Methodological factors such as impact magnitude should be considered in future research. CONCLUSION: Each methodology provides valuable information but their validity for anticipated and unanticipated head impacts measured in vivo needs to be addressed. Reports on head/neck response should include measurement of transmitted force, neck muscle latency, head linear and rotational accelerations, and neck stiffness. Modifying factors of anticipation, participants' age, sex, and sport are to be considered for head/neck dynamic response. PROSPERO REGISTRATION NUMBER: CRD42016051057 (last updated on 27 February 2017). PMID- 30242629 TI - Synthesis and Application of Water-Soluble Oxazine Dyes for Detection of PHAs Producing Bacteria. AB - Derivatives of oxazine dyes were synthesized on mulitigram scales via efficient synthetic strategies. One practical route was selected to prepare compounds 6, 9 and 10, especially water-soluble compound 6 was obtained in better yield than reported, and compound 10 was insoluble in aqueous media in absence of phenolic OH. Compounds 3 and 9 were found to be clear pH-dependent between pH = 4.0 and 10.0, and could be used as acid-base indicators to measure intracellular pH. Compounds 6, 9, 10 all have carboxylic acid functionalities, which could be activated and used to conjugate the dyes to biomolecules. In addition, compounds 6 and 9 with good solubility in aqueous media were used to develop a simple, quick, safe, highly sensitive staining method to detect PHAs-producing bacteria on heat-fixed smears, which was confirmed by fluorescence images of PHAs granules of bacteria. PMID- 30242630 TI - Feeding Difficulties and Orofacial Myofunctional Disorder in Patients with Hepatic Glycogen Storage Diseases. AB - : Hepatic glycogen storage diseases (GSDs) are inborn errors of metabolism whose dietary treatment involves uncooked cornstarch administration and restriction of simple carbohydrate intake. The prevalence of feeding difficulties (FDs) and orofacial myofunctional disorders (OMDs) in these patients is unknown. OBJECTIVE: To ascertain the prevalence of FDs and OMDs in GSD. METHODS: This was a cross sectional, prospective study of 36 patients (19 males; median age, 12.0 years; range, 8.0-18.7 years) with confirmed diagnoses of GSD (type Ia = 22; Ib = 8; III = 2; IXa = 3; IXc = 1). All patients were being treated by medical geneticists and dietitians. Evaluation included a questionnaire for evaluation of feeding behavior, the orofacial myofunctional evaluation (AMIOFE), olfactory and taste performance (Sniffin' Sticks and Taste Strips tests), and facial anthropometry. RESULTS: Nine (25%) patients had decreased olfactory perception, and four (11%) had decreased taste perception for all flavours. Eight patients (22.2%) had decreased perception for sour taste. Twenty-six patients (72.2%) had FD, and 18 (50%) had OMD. OMD was significantly associated with FD, tube feeding, selective intake, preference for fluid and semisolid foods, and mealtime stress (p < 0.05). Thirteen patients (36.1%) exhibited mouth or oronasal breathing, which was significantly associated with selective intake (p = 0.011) and not eating together with the rest of the family (p = 0.041). Lower swallowing and chewing scores were associated with FD and with specific issues related to eating behavior (p < 0.05). CONCLUSION: There is a high prevalence of FDs and OMDs in patients with GSD. Eating behavior, decreased taste and smell perception, and orofacial myofunctional issues are associated with GSD. PMID- 30242631 TI - Swap errors in spatial working memory are guesses. AB - In typical visual working memory tasks, participants report the color of a previously studied item at some probed location. Alternatively, in some recent studies, a color is probed and participants must report the item's location. There is a surprising difference between these tasks: in location reports participants almost never guess randomly as they do when reporting color, but often incorrectly report the locations of non-probed items. This finding has been taken as evidence for feature binding errors in memory, and evidence against discrete capacity models, which predict that pure guessing should occur. We test an alternative possibility: that non-target responses are guesses, but intelligent ones. In particular, when asked to report the location of an item for which participants have no memory, they may guess near locations where they know something was presented. Here we present false-probe trials in which a color is probed that was not actually studied, and find that the responses, which are necessarily guesses, are nonetheless centered around studied locations. Moreover, we find that the confidence ratings for non-target responses are low, and similar to confidence for uniformly distributed guesses. In a second experiment, we find that manipulating the retention interval, which is known to affect guess rates, changes the rate of these low-confidence non-target responses. These results suggest that the tendency to report locations of non-probed items reflects a good guessing strategy; not something fundamental about how features and objects are represented in working memory. PMID- 30242632 TI - Age at death, the return of an old metric whose importance is growing. PMID- 30242633 TI - Are Homeostatic States Stable? Dynamical Stability in Morphoelasticity. AB - Biological growth is often driven by mechanical cues, such as changes in external pressure or tensile loading. Moreover, it is well known that many living tissues actively maintain a preferred level of mechanical internal stress, called the mechanical homeostasis. The tissue-level feedback mechanism by which changes in the local mechanical stresses affect growth is called a growth law within the theory of morphoelasticity, a theory for understanding the coupling between mechanics and geometry in growing and evolving biological materials. This coupling between growth and mechanics occurs naturally in macroscopic tubular structures, which are common in biology (e.g., arteries, plant stems, airways). We study a continuous tubular system with spatially heterogeneous residual stress via a novel discretization approach which allows us to obtain precise results about the stability of equilibrium states of the homeostasis-driven growing dynamical system. This method allows us to show explicitly that the stability of the homeostatic state depends nontrivially on the anisotropy of the growth response. The key role of anisotropy may provide a foundation for experimental testing of homeostasis-driven growth laws. PMID- 30242634 TI - Control Strategies in Multigroup Models: The Case of the Star Network Topology. AB - In this paper, we propose control strategies for multigroup epidemic models. We use compartmental [Formula: see text] models to study the dynamics of n host groups sharing the same source of infection in addition to the transmission among members of the same group. In particular, we consider a model for infectious diseases with free-living pathogens in the environment and a metapopulation model with a central patch. We give the detailed derivation of the target reproduction number under three public health interventions and provide the corresponding biological insights. Moreover, using the next-generation approach, we calculate the basic reproduction numbers associated with subsystems of our models and determine algebraic connections to the target reproduction number of the complete model. The analysis presented here illustrates that understanding the topological structure of the infection process and partitioning it into simple cycles is useful to design and evaluate the control strategies. PMID- 30242635 TI - Adverse birth outcomes and infant mortality according to registered First Nations status and First Nations community residence across Canada. AB - OBJECTIVE: Studies of perinatal health outcomes in Canadian First Nations populations have largely focused on limited geographical areas and have been unable to examine outcomes by registered status and community residence. In this study, we compare rates of adverse birth outcomes among First Nations individuals living within vs. outside of First Nations communities and those with vs. without registered status. METHODS: Data included 13,506 singleton pregnancies from the 2006 Canadian Birth-Census Cohort. Outcomes examined included preterm birth (PTB), small- and large-for-gestational-age birth (SGA, LGA), stillbirth, overall infant mortality, and neonatal and postneonatal mortality. Risk ratios (RRs) were estimated with adjustment for maternal age, education, parity, and paternal education. RESULTS: Mothers living in First Nations communities and those with status had elevated adjusted risks of LGA (RR for First Nations community residence = 1.22, 95% CI = 1.09-1.35; RR for status = 1.50, 95% CI = 1.16-1.93). Rates of SGA were significantly lower among mothers with status (adjusted RR = 0.62, 95% CI = 0.44-0.86). Rates of PTB did not vary substantially by residence or by status. Adjusted differences in fatal outcomes could not be estimated, owing to small cell sizes. However, mothers living in First Nations communities had higher crude rates of infant mortality (10.9 vs. 7.7 per 1000), particularly for neonatal mortality (6.1 vs. 2.9). CONCLUSION: Future investigations should explore risk factors, including food security and access to health care services, that may explain disparities in SGA and LGA by status and residence within First Nations populations. PMID- 30242636 TI - Abstracts Presented at the Neurocritical Care Society (NCS) 16th Annual Meeting. PMID- 30242637 TI - Gender differences in patients with fibromyalgia: a gait analysis. AB - This study analysed the spatio-temporal parameters, asymmetry, variability and bilateral coordination of gait in women and men with fibromyalgia and healthy subjects walking at their usual velocity and at a faster walking velocity. Fifty five women and 12 men with fibromyalgia were analysed. A healthy group of 44 women and 17 men was analysed as the control group. A GAITRite system was used to obtain the spatio-temporal gait parameters for the participants when walking at their usual velocity and at a faster velocity. Coefficients of variation, bilateral coordination and gait asymmetry indexes were calculated. All groups exhibited a significant increase (p < 0.001) in spatio-temporal parameters when walking fast. The fibromyalgia groups showed increased bilateral coordination, asymmetry and variability of stance phase when walking fast. The fibromyalgia women showed significant spatio-temporal, variability and bilateral coordination of gait differences compared with the healthy women. The fibromyalgia men reported significant differences in velocity, cadence, stride length, swing time variability and stance gait asymmetry indices compared with the healthy men. No significant differences were observed between the men and women in the fibromyalgia groups. The findings of the present study did not support gender specific differences in walking variables and indices in FM patients. The differences found between both genders of FM patients and healthy subjects in walking indices at fast velocities could be a useful tool for diagnoses and evaluation of male and female patients with FM during short-term fast walking tests. PMID- 30242638 TI - Correction to: Long-term efficacy and safety of golimumab in the treatment of multirefractory Behcet's disease. AB - In the original version of this article the author name Gerardo Di Scala was originally presented incorrectly as 'Di Scala Gerardo'; this has been corrected in this article. PMID- 30242639 TI - Adverse drug events associated with 5mg versus 10mg Tofacitinib (Janus kinase inhibitor) twice daily for the treatment of autoimmune diseases: A systematic review and meta-analysis of randomized controlled trials. AB - Several recently published clinical trials have shown tofacitinib to be effective in the treatment of autoimmune diseases. This drug is commonly prescribed either in a 5-mg or in a10-mg dosage twice daily. In this review, we aimed to systematically compare the adverse drug events which were observed with 5 mg versus 10 mg tofacitinib for the treatment of autoimmune diseases. MEDLINE, EMBASE, the Cochrane library, and www.ClinicalTrials.gov were searched (from March to April 2018) for suitable English publications (published before April 2018). The inclusion criteria were as follows: randomized controlled trials, autoimmune disorders (rheumatic arthritis, psoriatic arthritis, moderate to severe psoriasis, and ankylosing spondylitis), and comparison of adverse drug events associated with 5 mg versus 10 mg tofacitinib. This study had follow-up time periods of 3 months and >= 6 months. Statistical analysis was carried out by RevMan 5.3 whereby risk ratios (RRs) and 95% confidence intervals (CIs) were generated. A total number of 4287 participants were included (2144 versus 2143 participants who received 5 mg and 10 mg tofacitinib twice daily respectively). The results showed that at 3 months, similar risks of adverse drug events, serious adverse events, and adverse events leading to drug discontinuation were observed with 5 mg versus 10 mg tofacitinib (RR 1.04, 95% CI 0.98-1.10; P = 0.17, I2 = 0%; RR 1.06, 95% CI 0.77-1.48; P = 0.71, I2 = 0%; and RR 1.06, 95% CI 0.78 1.43; P = 0.73, I2 = 32%, respectively). The other outcomes including serious infection events, adjudicated herpes zoster infection, adjudicated opportunistic infection, mild and severe neutropenia, malignancies, and adjudicated major adverse cardiovascular events were also similarly manifested. However, a decreased level of hemoglobin significantly favored 5 mg tofacitinib (RR 1.75, 95% CI 1.19-2.58; P = 0.005, I2 = 49%). Even at a follow-up time period of >= 6 months, adverse drug events, serious adverse events, adverse drug events leading to drug discontinuation, and serious infection were still similarly observed. According to this current review, both dosages of tofacitinib were safe to use. Even if similar adverse drug events were observed with 5 mg versus 10 mg tofacitinib twice daily for the treatment of autoimmune disorders, anemia was more prominent with 10 mg tofacitinib at a 3 month follow-up. Nevertheless, future studies based on a larger population size with longer follow-up time periods should further be considered. PMID- 30242640 TI - A retrospective analysis of distinguishing features of chest HRCT and clinical manifestation in primary Sjogren's syndrome-related interstitial lung disease in a Chinese population. AB - To characterize the distinctive chest high-resolution computerized tomography (HRCT) features and clinical manifestations of primary Sjogren syndrome (pSS) related interstitial lung disease (ILD). The demographic data, clinical manifestations, and laboratory and radiological findings of 527 pSS patients were retrospectively analyzed. ILD was defined based on the presences of pulmonary signs in HRCT. Two hundred six of 527 patients were diagnosed as pSS-ILD, and the prevalence was 39.1%. The three most frequent abnormalities in HRCT were reticular pattern (92.7%), ground-glass attenuation (87.4%), and bronchovascular bundle thickening (82%). One hundred twenty-four cases (60.2%) of the pSS-ILD patients had only a single HRCT pattern, which involved 86 non-specific interstitial pneumonitis (NSIP) cases (41.7%), 22 usual interstitial pneumonia (UIP) cases (10.68%), 8 organizing pneumonia (OP) cases (3.9%), and 8 lymphocytic interstitial pneumonia (LIP) cases (3.9%), respectively. Besides, the more important observation was that 82 cases had no less than two HRCT patterns, and NSIP admixed with OP (43.9%), NSIP admixed with UIP (35.4%), and NSIP admixed with LIP (19.5%) were the most frequent. HRCT of pSS-ILD patients demonstrated bilateral infiltrates (99%), with abnormalities predominantly in the lower lobes (89.3%) and subpleural areas (81.1%), and a few lesions were characterized by hilum distributed (8.7%). Pulmonary function tests (PFTs) revealed impaired diffusion capacity for carbon monoxide and total lung capacity, and the rate of small airway lesions in the pSS-ILD patients was 3.5 times higher in patients of pSS. Logistic regression analysis showed that dry cough (OR 59.05), clubbing (OR 6.26), elevated lactate dehydrogenase (OR 21.38) and positive anti-Ro (OR 7.86) were relevant factors of pSS-ILD. ILD is the common pulmonary involvement of pSS and the prevalence of pSS-ILD is 39.1%. The single pattern of NSIP and UIP in HRCT are the commonest, and about 40% of the pSS-ILD patients possess multiple patterns in HRCT. The classification of idiopathic pulmonary fibrosis cannot completely include the pulmonary imaging features of pSS-ILD. PMID- 30242641 TI - Remodeling of host membranes during herpesvirus assembly and egress. AB - Many viruses, enveloped or non-enveloped, remodel host membrane structures for their replication, assembly and escape from host cells. Herpesviruses are important human pathogens and cause many diseases. As large enveloped DNA viruses, herpesviruses undergo several complex steps to complete their life cycles and produce infectious progenies. Firstly, herpesvirus assembly initiates in the nucleus, producing nucleocapsids that are too large to cross through the nuclear pores. Nascent nucleocapsids instead bud at the inner nuclear membrane to form primary enveloped virions in the perinuclear space followed by fusion of the primary envelopes with the outer nuclear membrane, to translocate the nucleocapsids into the cytoplasm. Secondly, nucleocapsids obtain a series of tegument proteins in the cytoplasm and bud into vesicles derived from host organelles to acquire viral envelopes. The vesicles are then transported to and fuse with the plasma membrane to release the mature virions to the extracellular space. Therefore, at least two budding and fusion events take place at cellular membrane structures during herpesviruses assembly and egress, which induce membrane deformations. In this review, we describe and discuss how herpesviruses exploit and remodel host membrane structures to assemble and escape from the host cell. PMID- 30242642 TI - Cryo-EM structure of L-fucokinase/GDP-fucose pyrophosphorylase (FKP) in Bacteroides fragilis. PMID- 30242643 TI - Laparoscopic Extended Left Hemi-Hepatectomy plus Caudate Lobectomy for Caudate Lobe Hepatocellular Carcinoma. AB - BACKGROUND: Laparosopic hepatectomy for caudate lobe is classified as one of the most difficult procedures to perform.1 For malignant caudate lobe tumor which is close to hepatic veins, extended hemi-hepatectomy may be more suitable. METHODS: A 60-year-old man was diagnosed with hepatitis B virus infection-related hepatocellular carcinoma (HCC). His liver function was Child-Pugh A and ICG-15 test was 2.1%. Abdominal CT showed a 5 * 6 cm mass located in caudate lobe with middle and left hepatic vein encroached. Caudate lobectomy was not adopted because of the suspicious hepatic vein invasion by HCC. Instead, laparoscopic extended left hemi-hepatectomy plus caudate lobectomy was planned. RESULTS: The patient was placed in supine position. Three 12-mm trocars and two 5-mm trocars were used. After fully mobilization, the caudate lobe was exposed. The third porta hepatis was dissected before parenchyma transection.. The cutline was along the right side of middle hepatic vein. Pringle maneuver (15 min clamping and 5 min release, total Pringle time was 60 min with 4 times clamping) was performed during transection. The superficial tissue was divided using ultrasonic shears, while the deeper tissue was divided using LigaSure. The left pedicle was dissected and transected meticulously. The main trunk of right hepatic vein was continuously exposed from the caudal side. A linear stapler was used to transect the middle and left hepatic vein from the root. Bipolar was used for hemostasis. The specimen was removed from suprapubic incision. The operation time was 200 min and estimated blood loss was 100 ml. HCC was confirmed by postoperative pathological examination. The postoperative course was uneventful. CONCLUSIONS: Laparoscopic extended left hemi-hepatectomy plus caudate lobectomy is feasible and safe for caudate lobe HCC with suspicious hepatic veins invasion. PMID- 30242644 TI - Outcome of Patients with Borderline Resectable Pancreatic Cancer in the Contemporary Era of Neoadjuvant Chemotherapy. AB - INTRODUCTION: Approximately, 20% of patients with pancreatic ductal adenocarcinoma have resectable disease at diagnosis. Given improvements in locoregional and systemic therapies, some patients with borderline resectable pancreatic cancer (BRPC) can now undergo successful resection. The outcomes of patients with BRPC after neoadjuvant therapy remain unclear. METHODS: A prospectively maintained single-institution database was utilized to identify patients with BRPC who were managed at the Johns Hopkins Pancreas Multidisciplinary Clinic (PMDC) between 2013 and 2016. BRPC was defined as any tumor that presented with radiographic evidence of the involvement of the portal vein (PV) or superior mesenteric vein (SMV) that was deemed to be technically resectable (with or without the need for reconstruction), or the abutment (< 180 degrees involvement) of the common hepatic artery (CHA) or superior mesenteric artery (SMA), in the absence of involvement of the celiac axis (CA). We collected data on treatment, the course of the disease, resection rate, and survival. RESULTS: Of the 866 patients evaluated at the PMDC during the study period, 151 (17.5%) were staged as BRPC. Ninety-six patients (63.6%) underwent resection. Neoadjuvant chemotherapy was administered to 142 patients (94.0%), while 78 patients (51.7%) received radiation therapy in the neoadjuvant setting. The median overall survival from the date of diagnosis, of resected BRPC patients, was 28.8 months compared to 14.5 months in those who did not (p < 0.001). Factors associated with increased chance of surgical resection included lower ECOG performance status (p = 0.011) and neck location of the tumor (p = 0.001). Forty seven patients with BRPC (31.1%) demonstrated progression of disease; surgical resection was attempted and aborted in 12 patients (7.9%). Eight patients (5.3%) were unable to tolerate chemotherapy; six had disease progression and two did not want to pursue surgery. Lastly, four patients (3.3%) were conditionally unresectable due to medical comorbidities at the time of diagnosis due to comorbidities and failed to improve their status and subsequently had progression of the disease. CONCLUSION: After initial management, 31.1% of patients with BRPC have progression of disease, while 63.6% of all patients successfully undergo resection, which was associated with improved survival. Factors associated with increased likelihood of surgical resection include lower ECOG performance status and tumor location in the neck. PMID- 30242645 TI - A Preoperative Prognostic Scoring System to Predict Prognosis for Resectable Pancreatic Cancer: Who Will Benefit from Upfront Surgery? AB - BACKGROUND: Upfront surgery is recommended in patients with potentially resectable pancreatic ductal adenocarcinoma (R-PDAC) by National Comprehensive Center Network (NCCN) guidelines. However, even among R-PDACs, there is a subset that demonstrates extremely poor prognosis. The purpose of this study was to identify preoperative prognostic factors for upfront surgical resection of R PDACs. METHODS: The records of 278 consecutive patients with PDAC who underwent curative resection between 2001 and 2015 in a single institution were retrospectively reviewed. Preoperative factors to predict prognosis in patients with R-PDAC according to the NCCN guidelines were analyzed. RESULTS: Of the 278 patients who underwent resection, 153 R-PDACs received upfront surgery with a median survival time (MST) of 26.4 months. Tumor location (pancreatic head) (odds ratio [OR] 1.97, 95% confidence interval [CI] 1.14-3.40; P = 0.015), preoperative cancer antigen 19-9 (CA19-9) > 100 U/mL (OR 1.92, 1.31-2.80; P = 0.0009), and tumor size > 20 mm (OR 1.50, 1.02-2.19; P = 0.038) were identified as preoperative independent predictive risk factors for poor prognosis in patients with R-PDACs. In the patients with R-PDAC, 5-year survival was 60.7%, 21.5%, and 0% in patients with 0, 1 or 2, and 3 risk factors, respectively. There were significant differences in overall survival between the three groups (P < .0001). CONCLUSIONS: A preoperative prognostic scoring system using preoperative tumor location, tumor size, and CA19-9 enables preoperative prediction of prognosis and facilitates selection of appropriate treatment for resectable pancreatic cancer. PMID- 30242646 TI - Retrospective Study of Cystic Echinococcosis in a Recent Cohort of a Referral Center for Liver Surgery. AB - BACKGROUND: Cystic echinococcosis (CE) is a zoonosis endemic in Spain caused by the larval stage of the cestode Echinococcus granulosus and is one of the 18 neglected tropical diseases recognized by the WHO. The aim of this study was to describe the epidemiological and clinical data of CE in a surgical referral hospital. METHODS: A retrospective descriptive study of all adults' patients diagnosed with CE and followed at Vall d'Hebron University Hospital in Barcelona, Spain, between 2000 and 2015. RESULTS: We found 151 cases, 78 (51.7%) women, and median age at diagnosis was 68 (range, 15-92) years. Diagnosis was a radiological finding in 97 (64.2%) and the most frequent location was the liver [135 (89.4%) patients]. Nearly 80% of the cysts were calcified and serology was positive in 48 (51.6%). The WHO-IWGE classification was only available in 70 of the 104 (67.3%) cases of liver cysts that had an ultrasound. First therapeutic plan was "watch and wait" followed by surgery. International recommendations were not always followed, particularly in CE4 and CE5 stages, and 20% needed a change of treatment because of progression or recurrence. Patients treated surgically were younger, more symptomatic, and had larger and less calcified cysts in multiple sites. Serology was not useful for CE diagnosis and neither serology nor calcification of the cyst helped to predict viability. CONCLUSIONS: The formation of multidisciplinary teams in reference hospitals could help to improve CE diagnosis, its management, and follow-up, since international recommendations are not usually followed. PMID- 30242647 TI - Liver Resection for Neuroendocrine Tumor Liver Metastases Within Milan Criteria for Liver Transplantation. AB - BACKGROUND: The role of liver transplant (LT) for neuroendocrine liver metastasis (NELM) has not been completely defined. While international guidelines included LT as a potential treatment for highly selected patients with advanced NELM, recently, LT has been proposed as an alternative curative treatment for NELM for patients meeting restrictive criteria (Milan criteria). METHODS: Using a multi institutional cohort of patients undergoing liver resection for NELM, the long term outcomes of patients meeting Milan criteria (resected NET drained by the portal system, stable disease/response to therapies for at least 6 months, metastatic diffusion to < 50% of the total liver volume, a confirmed histology of low-grade, and <= 60 years) were investigated. RESULTS: Among the 238 patients included in the study, 28 (12%) patients met the Milan criteria for LT with a 5 year OS of 83%. Furthermore, among patients meeting Milan criteria, subsets of patients with favorable clinic-pathological characteristics had 5-year OS rates greater than 90% including G1 patients (5-year OS, 92%), patients undergoing minor liver resection (5-year OS, 94%), patients with low number of NELM (1-2 NELM), and small tumor size (< 3 cm) (for both groups of patients, 5-year OS, 100%). CONCLUSIONS: In our series, only 12% of patients met Milan criteria, and the 5-year OS after liver resection for this small selected group of patients was comparable with that reported in the literature for patients undergoing LT for NELM within Milan criteria. While LT might be the optimal treatment for patients with unresectable NELM, surgical resection should be the first option for patients with resectable NELM. PMID- 30242648 TI - Ileal Endometriosis: a Rare Cause of Enterocutaneous Fistula. PMID- 30242649 TI - Immobilization of heavy metals in two contaminated soils using a modified magnesium silicate stabilizer. AB - Heavy metal contamination is a severe environmental issue over the world. A lot of work has been done to develop effective stabilizers. In the present work, hydrothermal carbon-modified magnesium silicate (MS-C) was synthesized and used for the remediation of two heavy metal-polluted soils with different physicochemical properties. Soil samples were exposed to different doses of MS-C over 60 days (1, 3, and 5 wt%). The toxicity characteristic leaching procedure (TCLP) and the community bureau of reference sequential extraction procedure (BCR) were used to evaluate the remediation efficiency. The bioavailability of heavy metals in both soils was reduced by 20-86.7%, and the toxicity of heavy metals was reduced by 26.6-73.2% after MS-C added. Meanwhile, soil pH and water soluble organic carbon (WSOC) were increased. In addition, soil microbial biomass was increased, which indicated the improvement of soil condition. The immobilization of heavy metals was mainly caused by electrostatic attraction and cation exchange between MS-C and heavy metals. The significantly negative correlation between extractable heavy metals and pH/WSOC indicated the positive role of pH/WSOC in metal stabilization. Thus, this new stabilizer holds great application potentials for both single and multi-metal-contaminated soil remediation. ? Graphical abstract. PMID- 30242650 TI - Co-administration of glutathione alleviates the toxic effects of 2,3,7,8 TCDF on the DNA integrity of sperm and in the testes of mice. AB - This study aimed to investigate the toxic impact prompted in the testes of adult mice exposed to 2,3,7,8-tetrachlorodibenzofuran (TCDF). Four groups of 12 mice each were used in the present study. Group 1 mice were kept as control and administered corn oil only. Group 2 animals were given glutathione (GSH) in a dose of 100 mg/kg body weight by oral gavage twice a week. Group 3 was given TCDF orally twice per week, in a dose of 0.5 MUg/kg body weight for 8 weeks. Group 4 was administered GSH orally in a dosage of 100 mg/kg body weight plus TCDF twice a week for 8 weeks. Animals were sacrificed after 2, 4, and 8 weeks of exposure, serum samples were collected for estimation of testosterone hormone, the testes were dissected and one part was used for estimation of superoxide dismutase (SOD), malondialdehyde (MDA), lactate dehydrogenase (LDH), and 3beta hydroxysteroid dehydrogenase. Another portion of the testis was kept in formalin for histopathological examination. The results showed that the activities of SOD were decreased while the levels of lipid peroxidation MDA were increased in the testicular tissues of the exposed mice. The serum testosterone level and the steroidogenic enzyme 3beta-hydroxysteroid dehydrogenase activity of testicular homogenate were essentially decreased in TCDF-treated mice. A significant increment in the testicular LDH activity in testicular tissues was recorded in mice exposed to TCDF. The percentage of DNA chromatin disintegration was significantly increased in TCDF-treated mice. Histopathological changes were recorded in TCDF-exposed group as degenerative changes of the seminiferous tubules with formation of spermatid giant cells at 2 weeks in addition to exhaustion of germinal epithelium and detachment of the germ cells from the basal lamina at 4 and 8 weeks. Co-administration of GSH could reestablish MDA and LDH levels besides reduction in percentage of sperm DNA damage and improvement of the testicular tissue architecture. PMID- 30242651 TI - Mice exposure to haloxyfop-p-methyl ester at predicted environmentally relevant concentrations leads to anti-predatory response deficit. AB - Although the efficiency of haloxyfop-p-methyl ester (HPME) as selective herbicide is acknowledged, its impact on non-target organisms is poorly known. It is not known whether the short exposure of mammals to low HPME concentrations (consistent with a realistic contamination scenario) poses risks to these animals. Thus, the aim of the current study is to evaluate the effects of HPME on the anti-predatory behavior of female Swiss mice exposed to it. The animals were divided in groups: non-exposed (control) and exposed (route: i.p., for 2 days) to different herbicide concentrations (2.7 * 10-4 g/kg and 2.7 * 10-2 g/kg of body weight), which were considered environmentally relevant predicted concentrations. The animals were subjected to the open field and elevated plus-maze tests; results showed that the HPME did not lead to anxiolytic or anxiety behavior, or to locomotive changes in the tested animals, fact that was confirmed through the Basso Mouse Scale for locomotion scores. On the other hand, animals exposed to the herbicide were incapable of recognizing the snake as potential predator. Animals in the control group, exposed to a real snake (Pantherophis guttatus) remained longer in the safety zone of the test device, presented lower frequency of self-grooming behaviors for a shorter period-of-time, besides showing longer freezing time, which was not observed in animals exposed to HPME. Therefore, our study indicates the ecotoxicological potential of the herbicide, since anti predatory behavior disorders may affect preys' responses and population dynamics. PMID- 30242652 TI - Toxicological assessment of lambda-cyhalothrin and acetamiprid insecticides formulated mixture on hatchability rate, histological aspects, and protein electrophoretic pattern of Biomphalaria alexandrina (Ehrenberg, 1831) snails. AB - Several formulated mixtures of pesticides are widely used in modern agriculture. Nevertheless, the agriculture runoff causes a serious damage to the aquatic ecosystem. Therefore, the present study aims to use B. alexandrina snails as bioindicators for 30 g/l lambda-cyhalothrin and 17 g/l acetamiprid as a formulated mixture insecticide. Results showed that it has a molluscicidal activity against snails at LC50 7.9 mg/l. The hatchability percent of both treated 1-day-aged and/or 3-day-aged groups were less than that of the control group. The sublethal concentrations of the tested insecticide caused a remarkable abnormal necrosis in male and female gametogenic cells, besides a severe damage in both secretory and digestive cells. The results of SDS-PAGE protein profiles of treated snails showed that the least number of protein bands was noticed in snail groups that subjected to LC10 (6.6 mg/l) and LC25 (7.2 mg/l) concentrations when compared to control protein fractions. PMID- 30242653 TI - Decomposition of antibiotic ornidazole by gamma irradiation in aqueous solution: kinetics and its removal mechanism. AB - An efficient gamma radiolytic decomposition of one of the extensively used pharmaceutical ornidazole (ORZ) was explored under different experimental conditions by varying initial concentrations, solution pHs, and doses and concentrations of inorganic ([Formula: see text]) and organic (t-BuOH) additives. The results showed that low ORZ concentrations could be efficiently decomposed using gamma irradiation. The decomposition was followed by pseudo first-order reaction kinetics with rate constant values of 2.34, 1.48, 1.11, and 0.80 kGy-1 for the following initial concentrations: 25, 50, 75, and 100 mg L-1 with their corresponding (G(-ORZ)) values of 1.004, 1.683, 2.237, and 2.273, respectively. Decomposition rate of ORZ was remarkably improved under acidic condition when compared to neutral or alkaline medium. It was also observed that the decomposition was primarily caused by the reaction of ORZ with radiolytically generated reactive HO* radicals. The addition of H2O2 had a synergistic effect on the decomposition and mineralization extent of ORZ. However, the removal of total organic carbon (TOC) was not as effective as the decomposition of ORZ. Finally, the quantum chemical calculations were employed to optimize the geometry structure of ORZ and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) was used to identify the decomposition intermediates. On the basis of Gaussian calculations and analysis of LC-QTOF-MS, it can be inferred that ORZ radiolytic decomposition was mainly attributed to oxidative HO* radicals and the direct cleavage of ORZ molecules. Possible pathways for ORZ decomposition using gamma irradiation in aqueous medium were proposed. PMID- 30242654 TI - Determination of the phytoremediation efficiency of Ricinus communis L. and methane uptake from cadmium and nickel-contaminated soil using spent mushroom substrate. AB - Spent mushroom substrate (SMS) as an organic amendment to plant production has received increasing attention on soil phytoremediation. However, organic amendments are known to contribute to greenhouse gas (GHG) emission from soils. Castor oil plant has a high biomass production and phytoremediation potential for heavy metal-contaminated soils. In the present study, the roles of SMS on phytoremediation efficiency of castor oil plant (Ricinus communis L.) from cadmium (Cd) and nickel (Ni)-contaminated soils were investigated, and the impact of SMS application on methane emission from the contaminated soil were evaluated. Pot experiments with SMS-amended and unamended contaminated soils were conducted to investigate Cd and Ni accumulation in R. communis and CH4 emission. After growing for 3 months in soils with the addition of Cd (10 mg/kg) and Ni (at rates of 200 and 600 mg/kg), the dry biomass and the concentrations of Cd and Ni in the R. communis were measured, and the mobility factors for Cd and Ni were calculated. To assess methane emission, CH4 fluxes and potential rates of CH4 production and oxidation were measured pre- and post-incubation. SMS addition significantly improved the growth of R. communis and gave 19.15~82.46% more dry weight as compared to the single plant cultivation in the contaminated soils. SMS also increased plant Cd uptake and the total amount of Cd accumulation in R. communis increased by 28.1-152.1%, respectively, in signal Cd treatment and Cd-Ni complexation treatment, as compared to the single plant cultivation. The high values of mobility factor for Cd in single plant cultivation and co-application of SMS and R. communis pointed to the potential of R. communis to the Cd mobilization from the contaminated soils. Moreover, the addition of SMS tended to stimulate CH4 uptake that the average increases in CH4 uptake rate were 3.84-fold (in controls) and 2.91-fold (in single Cd treated soils) by the co-application of SMS and R. communis as compared to the single plant cultivation. The results suggested that the application of SMS could improve the growth of R. communis in Cd and Ni-contaminated soil, enhance heavy metal bioaccumulation, and stimulate soil CH4 uptake. Therefore, SMS might be useful for enhancing phytoremediation of heavy metals and mitigate CH4 emission from the contaminated soil. In addition, results in the study implied that implementing carefully designed management strategies (e.g., application of organic residues) during contaminated soil remediation is a promising solution for agricultural waste management and soil phytoremediation. PMID- 30242655 TI - Competitive sequestration of Ni(II) and Eu(III) on montmorillonite: role of molar Ni:Eu ratios and coexisting oxalate. AB - The competitive binding trends of Ni(II) and Eu(III) on montmorillonite in the absence/presence of Na-oxalate are explored by using batch sorption/desorption technique, speciation modeling, and X-ray diffraction (XRD) analysis. With a series of molar Ni:Eu ratios (i.e., 1:1, 5:1, 10:1, 1:5, and 1:10), the coexisting Ni(II) did not affect the sequestration behaviors and immobilization mechanisms of Eu(III). In contrast, the presence of Eu(III) obviously suppressed the sorption percentages of Ni(II) in the acidic pH range. Even though no obvious influence of Eu(III) on the macroscopic binding trends of Ni(II) was observed under alkaline conditions, the fraction of Ni(II) adsorbed by the inner-sphere complexation mechanism decreased and that of Ni(II) precipitation increased with rising molar Ni:Eu ratio. The coexisting Na-oxalate did not influence Eu(III) sorption, while inhibited the sorption of Ni(II). The XRD analysis indicated the potential formation of two Eu-oxalate precipitate phases (i.e., Eu2(C2O4)3.xH2O(s)-1 and Eu2(C2O4)3.xH2O(s)-2) at different pH values (4.0 and 6.5) and Na-oxalate concentrations (ranging from 0.5 to 5.0 mM). Interestingly, the Eu2(C2O4)3.xH2O(s)-2 phase would be transformed into the Eu2(C2O4)3.xH2O(s)-1 solid with the increase of Na-oxalate concentration. The research findings could provide essential data for evaluating the fate of coexistent Eu(III) and Ni(II) in the complicated aquatic environment. PMID- 30242657 TI - Accumulation of heavy metals in muscle, liver, and gonads of little tunny (Euthynnus alletteratus) from the western region of Algeria. AB - Cadmium, lead, zinc, and copper levels were measured in muscle, liver, and gonads of little tunny (Euthynnus alletteratus) from the western region of Algeria. Relationships between heavy metals concentrations and age, sex, sexual maturity stages, and fish size were investigated. The highest average levels of cadmium (0.2010 +/- 0.026 mg kg-1), lead (0.8069 +/- 0.09 mg kg-1), and copper (18.1135 +/- 1.34 mg kg-1) were recorded in the liver, while the highest mean zinc value of 203.1454 +/- 21.48 mg kg-1 was observed in the gonads. Significant differences (t > 1.96, p < 0.05) were found between metals levels in different tissues. The results indicated that heavy metals concentrations in muscle, liver, and gonads increase with age and fish size. However, metals analysis in gonadal tissues provides clear evidence of the transfer of heavy metals from spawners to progeny. The concentrations of Cd, Pb, Zn, and Cu measured in edible muscle flesh were lower than the maximum acceptable limit set by FAO/WHO for human consumption. PMID- 30242656 TI - Using dual isotopes and a Bayesian isotope mixing model to evaluate sources of nitrate of Tai Lake, China. AB - Identification and quantification of sources of nitrate (NO3-) in freshwater lakes provide useful information for management of eutrophication and improving water quality in lakes. Dual delta15N- and delta18O-NO3- isotopes and a Bayesian isotope mixing model were applied to identify sources of NO3- and estimate their proportional contributions to concentrations of NO3- in Tai Lake, China. In waters of Tai Lake, values for delta15N-NO3- ranged from 3.8 to 10.10/00, while values of delta18O ranged from 2.2 to 12.00/00. These results indicated that NO3- was derived primarily from agricultural and industrial sources. Stable isotope analysis in R called SIAR model was used to estimate proportional contributions from four potential NO3- sources (agricultural, industrial effluents, domestic sewage, and rainwater). SIAR output revealed that agricultural runoff provided the greatest proportion (50.8%) of NO3- to the lake, followed by industrial effluents (33.9%), rainwater (8.4%), and domestic sewage (6.8%). Contributions of those primary sources of NO3- to sub-regions of Tai Lake varied significantly (p < 0.05). For the northern region of the lake, industrial source (35.4%) contributed the greatest proportion of NO3-, followed by agricultural runoff (27.4%), domestic sewage (21.3%), and rainwater (15.9%). Whereas for the southern region, the proportion of NO3- contributed from agriculture (38.6%) was slightly greater than that contributed by industry (30.8%), which was similar to results for nearby inflow tributaries. Thus, to improve water quality by addressing eutrophication and reduce primary production of phytoplankton, NO3- from both nonpoint agricultural sources and industrial point sources should be mitigated. Graphical abstract ?. PMID- 30242658 TI - Benchmarking Toronto wastewater treatment plants using DEA window and Tobit regression analysis with a dynamic efficiency perspective. AB - The environmental-economic focus of wastewater treatment and management attracts growing attentions in recent years. The static efficiencies and their dynamic changes are helpful to systematically assess the environmental performance of the water agencies and wastewater treatment plants (WWTPs). Additionally, identifying key factors of efficiencies is critical to improve the operation of WWTPs. In this study, the window method of data envelopment analysis (DEA) was applied to estimate the annual efficiency for four Canadian WWTPs and to explore the variations of annual efficiency under different window lengths. Meanwhile, the Tobit regression analysis was developed to determine the driving forces for WWTPs' efficiency. The empirical results showed that: (i) the selected DEA window length remarkably affected both the average efficiency and the variations; however, it had no impact on the ranking of plants' efficiency; (ii) lower efficiencies were observed in plants with larger capacities due to higher infrastructure and operation investments involved; (iii) both the influent total phosphorus concentrations and influent flow rates had significant effects on the WWTPs' performance. Moreover, the staff and utility expenditures should be reduced to generate greater potential cost savings and efficiency improvement given the treatment technologies employed. PMID- 30242659 TI - Comparative transcriptome analysis of Zea mays in response to petroleum hydrocarbon stress. AB - The use of plants for the improvement of soils contaminated with hydrocarbons has been a primary research focus in phytoremediation studies. Obtaining insights regarding genes that are differentially induced by petroleum hydrocarbon stress and understanding plant response mechanisms against petroleum hydrocarbons at molecular level is essential for developing better phytoremediation strategies to remove these hazardous contaminants. The purpose of this study was to analyze the transcriptomal profile changes under hydrocarbon stress in maize plants and identify the genes associated with the phytoremediative capacity. Zea mays GeneChips were used to analyze the global transcriptome profiles of maize treated with different concentrations of petroleum hydrocarbons. In total, 883, 1281, and 2162 genes were differentially induced or suppressed in the comparisons of 0 (control) vs. 1% crude petroleum, 1 vs. 5% crude petroleum, and 0 vs. 5% crude petroleum, respectively. The differentially expressed genes were functionally associated with the osmotic stress response mechanism, likely preventing the uptake of water from the roots, and the phytoremediative capacity of plants, e.g., secretory pathway genes. The results presented here show the regulatory mechanisms in the response to petroleum hydrocarbon pollution in soil. Our study provides global gene expression data of Z. mays in response to petroleum hydrocarbon stress that could be useful for further studies investigating the biodegradation mechanism in maize and other plants. PMID- 30242660 TI - C.el Phosphatome: A Catalogue of Actual and Pseudo Phosphatases Based on In Silico Studies in Caenorhabditis elegans. AB - Phosphatases are well known to carry out important functions via counter activity of kinases and they serve as mechanism for dephosphorylating the monophosphate esters from the phosphorylated serine, threonine, tyrosine and histidine residues. The biological relevance of phosphatases could be explored further employing newer technologies and models. Caenorhabditis elegans is a powerful genetic model system that bears significant homology with humans, hence providing with a precious tool towards studying important signalling pathways. We carried out the present study to catalogue the C. elegans protein phosphatome, referred here as 'C.el phosphatome' and annotated the corresponding dataset. We further classified these phosphatases based on presence of catalytic conserved motif; GDxHG, GDxVDRG, GNHE, RxxD, DGxxG, DG, GxxDN for Ser/Thr phosphatases, HC(x)5 R for tyrosine phosphatases and DxDxT/V for aspartate based phosphatases. Bioinformatics tool DAVID was employed to decipher the biological relevance of phosphatases. Our findings show Ser/Thr phosphatases (114), Tyr phosphatases (121) and Asp phosphatases (0) in C. elegans genome based on the hallmark sequence identification. Amongst them, 34 and 57 Ser/Thr and Tyr phosphatases respectively contain the catalytic motif. This catalogue offers a precious tool for further studies towards understanding important biological processes and disease conditions. PMID- 30242661 TI - Racial and Ethnic Disparities in the Lifetime Prevalence of Homelessness in the United States. AB - Homelessness in the United States is often examined using cross-sectional, point in-time samples. Any experience of homelessness is a risk factor for adverse outcomes, so it is also useful to understand the incidence of homelessness over longer periods. We estimate the lifetime prevalence of homelessness among members of the Baby Boom cohort (n = 6,545) using the 2012 and 2014 waves of the Health and Retirement Study (HRS), a nationally representative survey of older Americans. Our analysis indicates that 6.2 % of respondents had a period of homelessness at some point in their lives. We also identify dramatic disparities in lifetime incidence of homelessness by racial and ethnic subgroups. Rates of homelessness were higher for non-Hispanic blacks (16.8 %) or Hispanics of any race (8.1 %) than for non-Hispanic whites (4.8 %; all differences significant with p < .05). The black-white gap, but not the Hispanic-white gap, remained significant after adjustment for covariates such as education, veteran status, and geographic region. PMID- 30242662 TI - Individual Uncertainty About Longevity. AB - This article presents an assessment of individual uncertainty about longevity. A survey performed on 3,331 French people enables us to record several survival probabilities per individual. On this basis, we compute subjective life expectancies (SLE) and subjective uncertainty regarding longevity (SUL), the standard deviation of each individual's subjective distribution of her or his own longevity. It is large and equal to more than 10 years for men and women. Its magnitude is comparable to the variability of longevity observed in life tables for individuals under 60, but it is smaller for those older than 60, which suggests use of private information by older respondents. Our econometric analysis confirms that individuals use private information-mainly their parents' survival and longevity-to adjust their level of uncertainty. Finally, we find that SUL has a sizable impact, in addition to SLE, on risky behaviors: more uncertainty on longevity significantly decreases the probability of unhealthy lifestyles. Given that individual uncertainty about longevity affects prevention behavior, retirement decisions, and demand for long-term care insurance, these results have important implications for public policy concerning health care and retirement. PMID- 30242663 TI - Effect of Operating Conditions and Immobilization on Butanol Enhancement in an Extractive Fermentation Using Non-ionic Surfactant. AB - The present study was undertaken in order to investigate effect of diverse parameters such as fermentation media, pH, initial concentration of biomass, different surfactant concentrations, and immobilization on increasing butanol and total solvent production. Cheng's fermentation media was successfully tested and perceived to increase final solvents concentration. Controlled pH at 12th and 24th hours had negative effect on butanol enhancement; however, it resulted in more butyric acid production which remained accumulated. Ten percent (v/v) biomass was evaluated to increase final solvents concentration and hence butanol yield compared to 20% and 30% (v/v) of initial biomass concentrations. Effect of surfactant concentration (3-20%) was studied on butanol production. Six percent (v/v) L62 resulted in 49% higher final butanol concentration compared to control. Simultaneous immobilization and fermentation showed higher butanol production (16.8 g/L with 6%) which was attributed to partial immobilization of biomass. PMID- 30242664 TI - Isolation and identification of two alkaloid structures with radical scavenging activity from Actinokineospora sp. UTMC 968, a new promising source of alkaloid compounds. AB - For decades, natural products from Actinomycetes have been recognized as one of the inestimable sources of therapeutic compounds. Presently, due to some challenges in the identification of novel compounds including the validation of novel natural products and their compatibility with the high throughput screening bioassays, evaluating new activity from known commercial ones would be an important designation. On the other hand, finding new sources of bioactive compounds from Actinomycetes can be promising in attaining pharmaceutical compounds with fewer purification steps and cost-effective production of the bioproducts. Here we describe the isolation and identification of two alkaloid compounds from a soil actinobacterium Actinokineospora sp. UTMC 968 including N acetyltyramine (1) and N-acetyltryptamine (2) with revealing a new bioactivity for these molecules. The producer is a rare actinobacterium belonging to family Pseudonocardiaceae as the first alkaloid compounds producer genus in its family. The structures of alkaloid 1 and 2 were assigned on the basis of 1D and 2D NMR spectroscopy and MS analyses. Compound 1 and 2 are used commercially for their pharmaceutical activity but their radical scavenging activity has not previously been reported. The results of 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay represented a remarkable DPPH radical scavenging capability with an IC50 value of 64.7 +/- 0.5 and 131.3 +/- 1.8 ug/mL for compound 1 and 2, respectively. PMID- 30242667 TI - Choosing the appropriate peer-reviewed journal for submission of your manuscript. PMID- 30242665 TI - Tumoricidal effect of human olfactory ensheathing cell mediated suicide gene therapy in human glioblastoma cells. AB - The potential of herpes simplex virus type 1 thymidine kinase (HSV-tk)-expressing olfactory ensheathing cells (OEC) treated with ganciclovir (GCV) to induce cell death in adjacent HSV-tk-negative cells (bystander effect) has been well demonstrated. Although it has been shown that bystander effect occurs through the delivery of phosphorylated GCV, the bystander effect mechanism and the role of gap junctions for human OECs mediated suicide gene therapy in primary astrocytes of human glioblastma remain obscure. In the present study, the efficacy of a new method for the transfer of phosphorylated GCV from OECs into primary astrocytes was evaluated. Surgical biopsy of glioblastoma was used to isolate primary astrocyte. Biopsy of olfactory mucosa was applied to isolate olfactory ensheathing cell. Expression of S100-beta antigen was confirmed immunocytochemically in astrocytes and OECs. OECs were transduced to lentiviral containing thymidine kinase gene (TK) and co-cultured with astrocytes. Fluorescent dye transfer and western blot analysis indicated the expression of connexin43 between olfactory ensheathing cells and astrocytes whereas, expression of the gap junction protein connexin43 was inhibited by the gap junction inhibitor 18alpha-glycyrrhethinic acid (AGA, 20 ug/ml). Furthermore, co-culture of astrocytes with OEC-TK in the presence of concentration of 30 ug/ml GCV led to a decrease in astrocytes survival rate. Also, apoptosis hallmarks, including DNA fragmentation in cell nuclear, expression increase of Bax to Bcl-2 ratio and increase of caspase3 activation were observed in this study. Our findings suggest that human olfactory ensheathing cells can deliver phosphorylated GCV into the glioblastoma derived astrocytes through gap junction communication for apoptosis induction. PMID- 30242666 TI - Development and characterization of 19 novel microsatellite markers in the Pacific seaweed pipefish Syngnathus schlegeli using next-generation sequencing. AB - Syngnathids (pipefishes, seahorses and seadragons) are vulnerable to human mediated habitat perturbation. The Pacific seaweed pipefish Syngnathus schlegeli has a large distribution in the northwestern Pacific, where deterioration, loss and fragmentation of its seagrass habitat are occurring through coastal development. So far, few studies have been conducted to access the genetic structure and conservation status of S. schlegeli because of the low number of genetic markers currently described. Nineteen polymorphic microsatellite markers were developed for S. schlegeli using next-generation sequencing, and characterized in 32 individuals. The mean number of alleles was 14, with 2-28 alleles per locus. The estimates of observed heterozygosity (HO) and expected heterozygosity (HE) varied depending on the locus, ranging from 0.063 to 1.000, and from 0.062 to 0.969, respectively. Seventeen of the 19 microsatellites conformed to Hardy-Weinberg equilibrium. These new microsatellite markers should provide a wealth of information for studies on conservation genetics and the behavioral ecology of S. schlegeli. PMID- 30242668 TI - Quantity discrimination in fish species: fish use non-numerical continuous quantity traits to select shoals. AB - Fish typically prefer to live in big shoals due to the associated ecological benefits. Shoaling is a behavior that depends on the ability to quantitatively discriminate. The fundamental mechanism involved in quantity discrimination determines whether fish can discriminate a shoal using numerical discrete cues (e.g., number of shoal members), non-numerical continuous traits (e.g., total body surface area) or both; however, the mechanism is currently a controversial topic. In the present study, we used a spontaneous choice experiment to test whether guppy (Poecilia reticulata), zebrafish (Danio rerio), Chinese crucian carp (Carassius auratus) and qingbo (Spinibarbus sinensis) rely on continuous (i.e., body surface area) or discrete (i.e., number of shoal members) information for shoal selection by altering the body surface area (cumulative body surface area ratio of 3:2 or 1:1) between two stimulus shoals with a different number of members (2 individuals vs 3 individuals). All four fish species preferred to shoal with the stimulus shoal with the larger cumulative surface area even if the shoal had fewer members; however, fish showed no shoal preference when the cumulative surface body areas of both stimulus shoals were equal. Furthermore, qingbo did not numerically discriminate between a shoal with 1 individual and a shoal with 3 individuals when the cumulative surface areas of both stimulus shoals were equal; however, qingbo showed a preference for the shoal with the larger cumulative surface area when the two stimulus shoals each had 3 individuals. In conclusion, the present study demonstrated that all four fish species relied only on non-numerical continuous quantity information for shoal selection, at least under a difficult task (i.e., 2 vs 3). PMID- 30242669 TI - p38 Inhibitor Protects Mitochondrial Dysfunction by Induction of DJ-1 Mitochondrial Translocation After Subarachnoid Hemorrhage. AB - p38 mitogen-activated protein kinase (MAPK) is a major player in mitochondrial dysfunction after subarachnoid hemorrhage (SAH). Moreover, DJ-1, which responds to oxidative stress and translocates to mitochondria, maintains mitochondrial homeostasis. Although a few studies have demonstrated that DJ-1 indirectly regulates p38 activation, the relationship between DJ-1 and p38 in mitochondrial dysfunction after SAH has not been delineated. Using an in vitro SAH model, alterations in p38, p-p38, DJ-1, and autophagic-related protein expression were detected. As expected, p38 inhibitor significantly blocked excessive expression of p38 and p-p38 after SAH, whereas total DJ-1 expression and mitochondrial DJ-1 were up-regulated. Further analysis showed that p38 inhibitor significantly blocked oxyhemoglobin (OxyHb) induced mitochondrial dysfunction, including mitochondrial membrane potential depolarization and reactive oxygen species (ROS) release. In addition, p38 inhibitor restored OxyHb-induced abnormal autophagic flux at the initiation and formation stage by regulating Atg5, beclin-1, the ratio of LC3-II/LC3-I, and p62 expression. This study suggested that overexpression of p38 induced the accumulation of mitochondrial dysfunction partly due to abnormal activation of autophagy, which largely relied on DJ-1 mitochondrial translocation. PMID- 30242671 TI - Effects of metformin on the PI3K/AKT/FOXO1 pathway in anaplastic thyroid Cancer cell lines. AB - BACKGROUND: The PI3K/AKT/FOXO signaling pathway plays an important role in the survival, proliferation and apoptosis of tumor cells. The aim of the present study was to explore whether metformin could affect insulin-promoting cell growth by regulation of this pathway. MATERIAL AND METHODS: Anaplastic thyroid cancer cells were treated with 0-60 mM metformin for 24, 48 and 72 h. Cell viability, morphology, apoptosis and migration were investigated by MTT assay, microscopy observation, AnexinV-PI and the wound healing assay, respectively. Expression levels of PI3K, AKT and FOXO1 were detected by RT-qPCR, and proteins phosphorylated levels were determined by ELISA. RESULTS: Metformin decreased cell viability and migration in a significant time-and dose-dependent manner, and induced apoptosis and morphological changes in the cells. RT-qPCR results showed that expression levels of PI3K, AKT and FOXO1 was inhibited by metformin (P < 0.05). However, there was no significant change in the expression level of AKT following metformin treatment for C643 cell line (P > 0.05). ELISA results showed that metformin treatment had no significant effects on the phosphorylated levels of PI3K, AKT and FOXO1 (P > 0.05). CONCLUSUION: The downregulation of FOXO1 was intensified by metformin, but no increase in cell viability was observed following FOXO1 downregulation by metformin. However, the exact molecular mechanism of metformin on inhibition of the PI3K/AKT pathway and subsequent decrease in cell viability remains unclear and further studies are required for its clarification. PMID- 30242670 TI - European research trends in nuclear medicine. AB - Written by associate editors of the Annals of Nuclear Medicine, this invited review article is intended to offer our readers a condensed global view on the high-quality research work that has been published in Europe last year. We have divided this article into five sections. The first three sections from the oncology category include "[18F]fluorodeoxyglucose (FDG) positron-emission tomography (PET) for therapy monitoring in malignant lymphoma", "[18F]fluoromisonidazole (FMISO) PET for hypoxia", and "lymphoscintigraphy update". It is followed by a section on "amyloid PET for Alzheimer's disease" using [11C]Pittsburgh Compound B (PiB) and [18F]florbetapir from the neurology category. The final section reviews three original articles in the field of "basic and translational molecular imaging" regardless of the category, which investigated new PET tracers such as L-4-borono-2-[18F]fluoro-phenylalanine (FBPA), O-(2-[18F]fluoroethyl)-L-tyrosine (FET) and 64Cu-NOTA-pertuzumab in small animals. We hope that this review article will arouse greater interest in our readers in recent European research trends in the field of nuclear medicine. PMID- 30242672 TI - Identification and anti-cancer activity in 2D and 3D cell culture evaluation of an Iranian isolated marine microalgae Picochlorum sp. RCC486. AB - PURPOSE: Cancer disease is the second cause of death in the world. Now a days, high percentage of drugs, which are involved in treatment of cancers, have natural origin. Introduction of microalgae strains as anti-cancer drugs origin is a valuable approach for cancer therapy. METHODS: In the present study we describe the isolation, characterization, and anti-proliferative activity of a new microalga strain (Picochlorum sp. RCC486) from Iran. The cytotoxic activity of four different algal extracts including methanol, ethyl acetate, chloroform, and hexane were evaluated against MDA-MB-231, MCF-7, Hep-G2, and A-549 cell liens. Cell viability was determined using MTT assay in both monolayer and spheroids 3D cultures. The apoptosis was confirmed by different methods such as AO/EB and Annexin V-FITC/PI double staining, caspase-3 colorimetric assay, ROS and MMP assay. RESULTS: The results of MTT assay and fluorescent double staining confirmed that methanol and ethyl acetate extracts showed the best cytotoxic activity against the cancer cell lines. The production of ROS, caspase-3 activity and depolarized MMP were quite significant in MDA-MB-231 cell line treated with methanol and ethyl acetate extracts. CONCLUSION: In this research we revealed that cytotoxicity and apoptotic effects of the methanol and ethyl acetate extracts in human cancer cells make them good candidates for further pharmacological studies to discover effective drugs for cancer therapy. Graphical abstract The present study describes the isolation, characterization, and anti proliferative activity of different extracts of a new microalga strain (Picochlorum sp. RCC486) from Iran. The antiproliferative and apoptosis inducing activity of ethyl acetate and methanol extracts with high content of phenol and carotenoid make them as good candidates for further pharmacological studies to discover effective drugs for cancer therapy. PMID- 30242673 TI - Determination of synthetic pharmaceutical adulterants in herbal weight gain supplements sold in herb shops, Tehran, Iran. AB - BACKGROUND: Nowadays with the growing popularity of herbal remedies across the world, large sections of population rely on herbal drug practitioners for their primary care. Therefore there is a need to ensure about the safety of herbal drugs and to detect adulteration with undeclared active pharmaceutical ingredients. Herbal drugs are used as first-line drug therapy in some instances. Unfortunately even if there are claims as to be natural, undeclared active pharmaceutical ingredients have been detected in these supplements. OBJECTIVES: The purpose of the present study was to analyse herbal weight gain drugs collected from herb shops located in Tehran, Iran to detect hidden pharmaceutical ingredients using UHPLC and GC/MS instrumentations. METHODS: Sixty herbal drugs advertised as weight gain supplements were gathered from herb shops Tehran province, Iran. All samples were analysed from analytical toxicology point of view to detect undeclared active pharmaceutical ingredients. Method was validated for quantitative analysis of cyproheptadine and dexamethasone. RESULTS: Method validity parameters showed good results for quantitative analysis of pharmaceutical ingredients. Cyproheptadine, dexamethasone, sildenafil, tramadol, caffeine and acetaminophen were detected in herbal weight gain drugs. Analysed dosage forms contained cyproheptadine and dexamethasone in concentrations higher than therapeutic doses. Quantitative analysis of contaminated drugs showed that the content of pharmacologic ingredients were 0.2-67 and 5.5-10.1 mg/tablet or capsule for cyproheptadine and dexamethasone respectively. CONCLUSIONS: Despite natural supplements producers' claim, herbal weight gain drugs were not natural at all. Undeclared active pharmaceutical ingredients can predispose patients to health problems and even life-threatening situations. Graphical Abstract ?. PMID- 30242674 TI - Measuring the time course of selection during visual search. AB - In visual search tasks, observers can guide their attention towards items in the visual field that share features with the target item. In this series of studies, we examined the time course of guidance toward a subset of items that have the same color as the target item. Landolt Cs were placed on 16 colored disks. Fifteen distractor Cs had gaps facing up or down while one target C had a gap facing left or right. Observers searched for the target C and reported which side contained the gap as quickly as possible. In the absence of other information, observers must search at random through the Cs. However, during the trial, the disks changed colors. Twelve disks were now of one color and four disks were of another color. Observers knew that the target C would always be in the smaller color set. The experimental question was how quickly observers could guide their attention to the smaller color set. Results indicate that observers could not make instantaneous use of color information to guide the search, even when they knew which two colors would be appearing on every trial. In each study, it took participants 200-300 ms to fully utilize the color information once presented. Control studies replicated the finding with more saturated colors and with colored C stimuli (rather than Cs on colored disks). We conclude that segregation of a display by color for the purposes of guidance takes 200-300 ms to fully develop. PMID- 30242675 TI - Semisupervised category learning facilitates the development of automaticity. AB - In the human category of learning, learning is studied in a supervised, an unsupervised, or a semisupervised way. The rare human semisupervised category of learning studies all focus on early learning. However, the impact of the semisupervised category learning late in learning, when automaticity develops, is unknown. Therefore, in Experiment 1, all participants were first trained on the information-integration category structure for 2 days until they reached an expert level. Afterwards, half of the participants learned in a supervised way and the other half in a semisupervised way over two successive days. Both groups received an equal number of feedback trials. Finally, all participants took part in a test day where they were asked to respond as quickly as possible. Participants were significantly faster on this test in the semisupervised group than in the supervised group. This difference was not found on day 2, implying that the no-feedback trials in the semisupervised condition facilitated automaticity. Experiment 2 was designed to test whether the higher number of trials in the semisupervised condition of Experiment 1 caused the faster response times. We therefore created an almost supervised condition where participants almost always received feedback (95%) and an almost unsupervised condition where participants almost never received feedback (5%). All conditions now contained an equal number of trials to the semisupervised condition of Experiment 1. The results show that receiving feedback almost always or almost never led to slower response times than the semisupervised condition of Experiment 1. This confirms the advantage of semisupervised learning late in learning. PMID- 30242676 TI - Transient Gene Expression in Suspension HEK293-EBNA1 Cells. AB - Transient gene expression in human embryo kidney 293 (HEK293) cells is an established approach for the rapid production of large amounts of recombinant proteins (r-proteins). Milligram to gram quantities of r-proteins can be typically obtained within less than 10 days following transfection. In this chapter, we describe a simple and robust transfection process of suspension growing human embryo kidney 293 cells using two commercially available serum-free media and polyethylenimine as the transfection reagent. This chapter provides examples for the production and purification of a his-tagged recombinant protein and two monoclonal antibodies. PMID- 30242677 TI - Transient Expression of Recombinant Membrane-eGFP Fusion Proteins in HEK293 Cells. AB - Membrane proteins play important roles in many biological processes and are a major drug target. However, only a limited number of structures of eukaryotic membrane proteins have been determined so far. Besides the challenges in crystallizing these proteins, one of the main bottlenecks in structure determination is their recombinant expression. The mammalian HEK293 cell line provides a natural environment for expression of eukaryotic membrane proteins but optimization of transfection and cultivation time is often necessary to yield amounts of protein suitable for structural studies.Here we describe a detailed protocol for expression and purification of membrane proteins from HEK293 cells with an example of the human peptide transporter, PepT2. In the first part, we focus on the expression optimization by changing transfection protocol and cultivation time. In the second part, we describe a robust protocol for large scale expression and purification of membrane proteins based on affinity chromatography and gel filtration. PMID- 30242678 TI - PEI-Mediated Transient Gene Expression in CHO Cells. AB - We describe a method for polyethyleneimine (PEI) mediated transient transfection of suspension-adapted Chinese hamster ovary (CHO-DG44) cells for protein expression applicable at scales from 2 mL to 2 L. The method involves transfection at a high cell density (5 * 106 cells/mL) by direct addition of plasmid DNA (pDNA) and PEI to the culture and subsequent incubation at 31 degrees C with agitation by orbital shaking. This method requires 0.3 mg/L of coding pDNA, 2.7 mg/L of nonspecific (filler) DNA and 15 mg/L of PEI. The production phase is performed at 31 degrees C in the presence of 0.25% N,N dimethylacetamide (DMA). We also provide information on culture vessel options, recommended working volumes, and recommended shaking speeds for transfections at scales from 2 mL to 2 L. PMID- 30242679 TI - Stable Expression by Lentiviral Transduction of Cells. AB - Lentiviral gene transfer represents a versatile and powerful method for genetic transduction of many cell lines and primary cells including "hard-to-transfect" cells. As a consequence of the integration of the recombinant lentiviral vector into the cellular genome the transgene is stably maintained and long term producing cells are established. Here, we describe the current state of the art and give details for lab scale production of lentiviral vectors as well as for infection and titration of the viral vectors. PMID- 30242680 TI - Inducible Protein Production in 293 Cells Using the piggyBac Transposon System. AB - Recombinant proteins are widely used to study various pathophysiological processes. Nevertheless, the establishment of the desired protein-producing stable mammalian cell lines using traditional methods is hampered by multiple laborious steps. In this chapter, we describe a simple and robust system that allows for the derivation of stable transgenic cell lines in 293 cells, yielding high protein expression levels, in a short time period. This methodology is based on the piggyBac transposon system and, notably, it allows for inducible production of the protein of interest. Moreover, it can easily be used in conventional laboratory cell culture settings and does not require any specialized devices. Herein, we outline all the steps of this procedure in detail and point out specific considerations. PMID- 30242681 TI - Recombinant CHO Cell Pool Generation Using piggyBac Transposon System. AB - CHO cell pools with desirable characteristics of high titer and consistent product quality are useful for rapid production of recombinant proteins. Here we describe the generation of CHO cell pools using the piggyBac transposon system for mediating gene integration. The method describes the co-transfection of cells with the donor plasmid (coding for the gene of interest) and the helper plasmid (coding for the transposase) using polyethyleneimine (PEI). This is followed by a genetic selection for the generation of a cell pool. The resulting cell pool can be used to start a batch or fed-batch culture. Alternatively it can be used for generation of clonal cell lines or generation of cell banks for future use. PMID- 30242682 TI - Genome Engineering of Hybridomas to Generate Stable Cell Lines for Antibody Expression. AB - From the perspective of academic and small research laboratories, the most common and practical strategy for recombinant expression of full-length monoclonal antibodies is to perform transient plasmid transfection of mammalian cells, resulting in small-scale and limited protein production. The generation of stable antibody producing mammalian cell lines enables larger-scale and consistent expression, however this approach is rarely pursued due to the time-consuming and expensive process of single colony screening and characterization. In order to bridge the gap between the simplicity of transient transfection and consistent production by stable cell lines, we describe a method to stably integrate antibody genes into the endogenous immunogenomic loci of hybridoma cells using CRISPR/Cas9 genome editing. Initially, the antibody variable light (VL) chain is deleted by multiplexed Cas9 cleavage; subsequently, the variable heavy (VH) chain is replaced by a fluorescent reporter gene (mRuby) by Cas9-assisted homology directed repair (HDR). This cell line is customized by replacing mRuby with a synthetic antibody (consisting of a VL, light constant region and VH) by once again using Cas9-assisted HDR. Due to hybridomas' inherent ability to surface display and secrete antibodies, they provide a suitable host for both the selection and the production process, substantially streamlining the process for stable cell line generation, and thus we refer to this platform as plug-and (dis)play (PnP) hybridomas. PMID- 30242683 TI - Protein Expression via Transient Transfection of Mammalian Cells in a WAVE Bioreactor. AB - Large culture volumes are often required when expression constructs are particularly low-yielding or when end-uses require significant amounts of material. In these cases, a single homogenous culture is usually more convenient, in terms of both consistency of expression and labour/resource requirements, than multiple parallel cultures. Using a WAVE Bioreactor culture volumes as high as 500 L may be achieved in a single vessel. Here we describe the transfection of 293-6E cells in a disposable 50 L Cellbag on a WAVE Bioreactor platform to produce recombinant protein. The methods described herein may be adapted, with suitable optimizations, for other suspension-adapted mammalian cell lines. PMID- 30242684 TI - CHO and HEK293 Cultivation and Transfection in Single-Use Orbitally Shaken Bioreactors. AB - Chinese hamster ovary (CHO) and human embryonic kidney 293 (HEK293) cells are the two most popular mammalian hosts for the production of recombinant proteins. In this chapter the suspension cultivation and transfection of these cells in small scale disposable bioreactors is described. The TubeSpin bioreactor 50 and TubeSpin bioreactor 600 are designed for the cultivation of suspension cells by orbital shaking and have maximum working volumes of about 15 mL and 400 mL, respectively. PMID- 30242685 TI - Bench-Scale Stirred-Tank Bioreactor for Recombinant Protein Production in Chinese Hamster Ovary (CHO) Cells in Suspension. AB - Most pharmaceutical biotechnology companies use stirred-tank bioreactors (STR) for recombinant protein manufacturing. These bioreactors are used at a variety of different scales ranging from bench to production scales, with working volumes from 10 mL to 25,000 L. Bench-scale STRs are commonly used to culture mammalian cells for process development, to troubleshoot production scale bioreactors using scale-down models (SDM), or to conduct fundamental research. In this chapter, we describe the operations of a bench-scale STR for the production of recombinant proteins with suspension-adapted Chinese hamster ovary (CHO-DG44) cells. These operations include bioreactor setup and configuration, batching media, inoculation of the seed cell culture, production phase, and harvest of cell-free fluids. PMID- 30242686 TI - Continuous and Integrated Expression and Purification of Recombinant Antibodies. AB - This chapter introduces the necessary concepts to design continuous expression and purification processes for monoclonal antibodies. The operation of a perfusion bioreactor is discussed containing the preparation procedures, the seeding train and the preparation and control of a long-term production run. The downstream processes exploit the benefits of countercurrent chromatography. Their design from batch experiments is presented. The CaptureSMB process is introduced for continuous capturing while for polishing applications the design of the two column MCSGP process is described. The chapter also puts these processes together in the context of their integration to an end-to-end production process. PMID- 30242687 TI - High Throughput Transfection of HEK293 Cells for Transient Protein Production. AB - Transient transfection of mammalian cells is used in the biotechnology industry to quickly supply recombinant protein for research and large molecule drug development. Here, we describe a method for high throughput transient transfection of Human Embryonic Kidney 293 (HEK293) cells in 30 mL tubespins using polyethylenimine (PEI) as a transfection reagent. An automated liquid handler can be used to perform pipetting steps for transfecting batches of 96 tubespins, and septa in the tubespin caps allow for rapid processing without decapping. The addition of valproic acid (VPA) to transfection cultures enhances recombinant protein production. The thawing and passaging operations for HEK293 cultures to source the transient transfections are also described. PMID- 30242688 TI - Microfluidic Transfection for High-Throughput Mammalian Protein Expression. AB - Mammalian synthetic biology and cell biology would greatly benefit from improved methods for highly parallel transfection, culturing, and interrogation of mammalian cells. Transfection is routinely performed on high-throughput microarrays, but this setup requires manual cell culturing and precludes precise control over the cell environment. As an alternative, microfluidic transfection devices streamline cell loading and culturing. Up to 280 transfections can be implemented on the chip at high efficiency. The culturing environment is tightly regulated and chambers physically separate the transfection reactions, preventing cross-contamination. Unlike typical biological assays that rely on end-point measurements, the microfluidic chip can be integrated with high-content imaging, enabling the evaluation of cellular behavior and protein expression dynamics over time. PMID- 30242689 TI - Genome-Wide High-Throughput RNAi Screening for Identification of Genes Involved in Protein Production. AB - With an increasing number of blockbuster drugs being recombinant mammalian proteins, protein production platforms that focus on mammalian proteins have had a profound impact in many areas of basic and applied research. Many groups, both academic and industrial, have been focusing on developing cost-effective methods to improve the production of mammalian proteins that would support potential therapeutic applications. As it stands, while a wide range of platforms have been successfully developed for laboratory use, the majority of biologicals are still produced in mammalian cell lines due to the requirement for posttranslational modification and the biosynthetic complexity of target proteins. An unbiased high throughput RNAi screening approach can be an efficient tool to identify target genes involved in recombinant protein production. Here we describe the process of optimizing the transfection conditions, performing the genome-wide siRNA screen, the activity and cell viability assays and the validation transfection to identify genes involved with protein expression. PMID- 30242690 TI - Targeting miRNAs with CRISPR/Cas9 to Improve Recombinant Protein Production of CHO Cells. AB - MicroRNAs with their unique ability to target hundreds of genes have been highlighted as powerful tools to improve bioprocess behavior of cells. The common approaches to stably deplete miRNAs are the use of sponge decoy transcripts or shRNA inhibitors, which requires the introduction and expression of extra genetic material. As an alternative, we implemented the CRISPR/Cas9 system in our laboratory to generate Chinese hamster ovary (CHO) cells which lack the expression of a specific miRNA for the purpose of functional studies. To implement the system, miR-27a/b was chosen as it has been shown to be upregulated during hypothermic conditions and therefore may be involved in controlling CHO cell growth and recombinant protein productivity. In this chapter, we present a protocol for targeting miRNAs in CHO cells using CRISPR/Cas9 and the analysis of the resulting phenotype, using miR-27 as an example. We showed that it is possible to target miRNAs in CHO cells and achieved >=80% targeting efficiency. Indel analysis and TOPO-TA cloning combined with Sanger sequencing showed a range of different indels. Furthermore, it was possible to identify clones with no detectable expression of mature miR-27b. Depletion of miR-27b led to improved viability in late stages of batch and fed-batch cultures making it a potentially interesting target to improve bioprocess performance of CHO cells. PMID- 30242691 TI - Application of the CRISPR/Cas9 Gene Editing Method for Modulating Antibody Fucosylation in CHO Cells. AB - Genetic engineering plays an essential role in the development of cell lines for biopharmaceutical manufacturing. Advanced gene editing tools can improve both the productivity of recombinant cell lines as well as the quality of therapeutic antibodies. Antibody glycosylation is a critical quality attribute for therapeutic biologics because the glycan patterns on the antibody fragment crystallizable (Fc) region can alter its clinical efficacy and safety as a therapeutic drug. As an example, recombinant antibodies derived from Chinese hamster ovary (CHO) cells are generally highly fucosylated; the absence of fucose significantly enhances antibody dependent cell-mediated cytotoxicity (ADCC) against cancer cells. This chapter describes a protocol applying clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) to disrupt the alpha-1,6-fucosyltranferase (FUT8) gene and subsequently inhibit alpha-1,6-fucosylation on antibodies expressed in CHO cells. PMID- 30242692 TI - Scalable Production and Purification of Adeno-Associated Viral Vectors (AAV). AB - Here we describe methods for the production of adeno-associated viral (AAV) vectors by transient transfection of HEK293 cells grown in serum-free medium in orbital shaken bioreactors and the subsequent purification of vector particles. The protocol for expression of AAV components is based on polyethyleneimine (PEI) mediated transfection of a 2-plasmid system and is specified for production in milliliter to liter scales. After PEI and plasmid DNA (pDNA) complex formation the diluted cell culture is transfected without a prior concentration step or medium exchange. Following a 3-day batch process, cell cultures are further processed using different methods for lysis and recovery. Methods for the purification of viral particles are described, including iodixanol gradient purification, immunoaffinity chromatography, and ultrafiltration, as well as quantitative PCR to quantify vector titer. PMID- 30242693 TI - Considerations in the Use of Codon Optimization for Recombinant Protein Expression. AB - Codon optimization is a gene engineering approach that is commonly used for enhancing recombinant protein expression. This approach is possible because (1) degeneracy of the genetic code enables most amino acids to be encoded by multiple codons and (2) different mRNAs encoding the same protein can vary dramatically in the amount of protein expressed. However, because codon optimization potentially disrupts overlapping information encoded in mRNA coding regions, protein structure and function may be altered. This chapter discusses the use of codon optimization for various applications in mammalian cells as well as potential consequences, so that informed decisions can be made on the appropriateness of using this approach in each case. PMID- 30242694 TI - Versatile Cell-Free Protein Synthesis Systems Based on Chinese Hamster Ovary Cells. AB - We present an alternative production platform for the synthesis of complex proteins. Apart from conventionally applied protein production using engineered mammalian cell lines, this protocol describes the preparation and principle of cell-free protein synthesis systems based on CHO cell lysates. The CHO cell-free system contains endogenous microsomes derived from the endoplasmic reticulum, which enables a direct integration of membrane proteins into a nature like milieu and the introduction of posttranslational modifications. Different steps of system development are described including the cultivation of CHO cells, cell harvesting and cell disruption to prepare translationally active CHO cell lysates. The requirements for DNA templates and the generation of linear DNA templates suitable for the CHO cell-free reaction is further depicted to underline the opportunity to produce different protein variants in a short period. This experimental setup provides a basis for high-throughput applications. The productivity of the CHO cell-free systems is further increased by using a non-canonical translation initiation due to the attachment of an internal ribosomal entry site of the Cricket paralysis virus (CRPV IRES) to the 5' UTR of the desired gene. In this way, a direct interaction of the IRES structure with the ribosome facilitates a translation factor independent initiation of translation. Cell-free reactions were performed in fast and efficient batch reactions leading to protein yields up to 40 MUg/mL. The reaction format was further adjusted to a continuous exchange CHO cell-free reaction (CHO CECF) to prolong reaction time and thereby increase the productivity of the cell free systems. Finally, protein yields up to 1 g/L were obtained. The CHO CECF system represents a sophisticated resource to address structural and functional aspects of difficult-to-express proteins in fundamental and applied research. PMID- 30242695 TI - The Potential Relationship Between Openness and Explicit Versus Implicit L2 Knowledge. AB - Recent studies of second language (L2) construction learning using artificial linguistic systems have begun to closely examine the role of individual differences, including personality. In such studies, adult participants learn form-meaning mappings after exposure, with scores on generalization tests as a standard criterion for learning. This paper addresses the potential role of openness in explicit versus implicit knowledge. The present research relied on a reanalysis of data from a previous study, using an extreme-groups design involving 60 participants. It was revealed that scores when using implicit versus explicit knowledge sources varied by openness. In particular, though both groups performed significantly above chance when using rules, only open learners did so when using intuition. Furthermore, learners with higher openness scores outperformed those lower in openness, based on mixed-effects regression models. This preliminary evidence for the role of openness is discussed in terms of its theoretical and methodological implications. PMID- 30242696 TI - Identification of Carassius auratus gibelio liver cell proteins interacting with the GABAA receptor gamma2 subunit using a yeast two-hybrid system. AB - The gamma-aminobutyric acid type A (GABAA) receptor is an important pentameric inhibitory neurotransmitter receptor, and the gamma2 subunit of this receptor plays a key role in potentiation of the GABAA response. We previously detected that the expression of GABAA receptor in the livers of Carassius auratus gibelio significantly increased after medication (avermectin and difloxacin treatment). In order to better understand the mechanism of action of the GABAA receptor gamma2 subunit in the livers of C. auratus gibelio, we constructed a C. auratus gibelio liver cDNA library (the titer value of 1.2 * 106 cfu/mL) and identified the proteins that interact with the GABAA receptor gamma2 subunit by using a yeast two-hybrid assay. The yeast two-hybrid screening yielded seven positive clones, namely, prelid3b, cdc42, sgk1, spg21, proteasome, chia.5, and AP-3 complex subunit beta-1, all of which have been annotated by the NCBI database. The functions of these proteins are complex; therefore, additional studies are required to determine the specific interactions of these proteins with the GABAA receptor gamma2 subunit in the liver of C. auratus gibelio. Although the interactions identified by the yeast two-hybrid system should be considered as preliminary results, the findings of this study may provide further direction and a foundation for future research focusing on the mechanisms of the GABAA receptor gamma2 subunit in C. auratus gibelio livers. PMID- 30242697 TI - Molecular, functional, and gene expression analysis of zebrafish Ror1 receptor. AB - Ror family of receptor tyrosine kinases ROR1 and ROR2 plays crucial roles in animal development by regulating cell proliferation, differentiation, and migration, as well as survival and death by acting as a receptor or co-receptor for Wnt5a and mediating Wnt5a-induced activation. Compared with our extensive understanding of ROR2, our knowledge of ROR1 is limited. In this study, we characterized the zebrafish ror1 gene and determined its temporal and spatial expression and biological activity. Sequence comparison and phylogenetic analyses indicate that its protein structure is similar to its mammalian orthologs. During embryogenesis, the ror1 mRNA levels were relatively low or undetectable at 6 and 9 h postfertilization. In adult fish, ror1 mRNA was most abundantly expressed in the ovary and testis. The levels of ror1 mRNA in non-reproductive system tissues were very low or barely detectable. Spatiotemporal distribution of ror1 and its ligand wnt5a in the ovary was then investigated. Reverse transcription PCR on isolated follicle layers and denuded oocytes demonstrated that both wnt5a and ror1 were exclusively expressed in the oocyte but not in the follicle layers. During oogenesis, the ror1 mRNA levels were relatively low from I to IV stage oocytes and increased dramatically at V stage oocyte. Unlike ror1, the wnt5a mRNA levels were increased gradually from I to V stage oocyte. When Ror1 was co transfected with Wnt5a and Wnt3a in HEK293T cells, the Wnt3a-induced Wnt reporter activity was inhibited by Ror1 in a dose-dependent manner. Taken together, these results provide new information about the structural and functional conservation, spatial and temporal expression, and biological activity of Ror1 in a fish model organism. PMID- 30242699 TI - Characterization of RING-Between-RING E3 Ubiquitin Transfer Mechanisms. AB - Protein ubiquitination is an essential posttranslational modification that regulates nearly all cellular processes. E3 ligases catalyze the final transfer of ubiquitin (Ub) onto substrates and thus are important temporal regulators of ubiquitin modifications in the cell. E3s are classified by their distinct transfer mechanisms. RING E3s act as scaffolds to facilitate the transfer of Ub from E2-conjugating enzymes directly onto substrates, while HECT E3s form an E3~Ub thioester intermediate prior to Ub transfer. A third class, RING-Between RING (RBR) E3s, are classified as RING/HECT hybrids based on their ability to engage the E2~Ub conjugate via a RING1 domain while subsequently forming an obligate E3~Ub intermediate prior to substrate modification. RBRs comprise the smallest class of E3s, consisting of only 14 family members in humans, yet their dysfunction has been associated with neurodegenerative diseases, susceptibility to infection, inflammation, and cancer. Additionally, their activity is suppressed by auto-inhibitory domains that block their catalytic activity, suggesting their regulation has important cellular consequences. Here, we identify technical hurdles faced in studying RBR E3s and provide protocols and guidelines to overcome these challenges. PMID- 30242698 TI - Proteomic variation in metamorphosing Paralichthys olivaceus induced by exogenous thyroid hormone. AB - Thyroid hormone (TH) is essential for Paralichthys olivaceus metamorphosis. Exogenous TH treatment induces premature metamorphosis in P. olivaceus larvae and a series of studies have been conducted to identify thyroid hormone-regulated functional genes and microRNAs involved in the metamorphosis of P. olivaceus; however, the proteins involved in this process remain to be fully clarified. In this study, the differential proteomic responses of P. olivaceus larvae to exogenous TH treatment were examined using tandem mass tags (TMT) for quantitation labeling followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The expression levels of 629 cellular proteins were identified to be significantly affected by TH treatment. The reliability of our TMT-labeled LC MS/MS analysis was verified by examining the mRNA and protein levels of four selected proteins using quantitative real-time reverse-transcription PCR and western blot analyses. The possible biological significance of these proteins was further investigated by Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction analyses. Notably, we identified and described five groups of proteins involved in different important life events that were significantly regulated by exogenous TH treatment. Our study provides an improved understanding of the molecular mechanisms by which TH regulates the metamorphosis of P. olivaceus. PMID- 30242700 TI - Single-Turnover RING/U-Box E3-Mediated Lysine Discharge Assays. AB - RING and U-box ubiquitin ligases promote ubiquitin (Ub) transfer by priming Ub conjugated E2 in a closed conformation to optimize the thioester bond for nucleophilic attack by substrate lysine. Here, we describe a single-turnover lysine discharge assay for direct assessment of the activity of any RING/U-box E3 E2~Ub complex. PMID- 30242701 TI - Methods for NAD-Dependent Ubiquitination Catalyzed by Legionella pneumophila Effector Proteins. AB - Ubiquitination is one of the most important posttranslational modifications in eukaryotic cells where it regulates the activity, cellular localization, and half life of proteins. Ubiquitination thus affects many essential cellular processes, including vesicle trafficking, cell cycle, DNA repair, immune response, and protein homeostasis. The ubiquitin system is exclusive to eukaryotes; however, pathogenic bacteria have developed effective strategies to influence the host ubiquitin system for their own benefit. Legionella pneumophila is the causative agent of Legionnaires' disease, a severe form of pneumonia. This bacterium utilizes a type IV secretion system to translocate more than 300 effector proteins into host cells. These virulence factors modulate a wide spectrum of host processes to support its intracellular survival and replication. Hijacking of host ubiquitin system is an important theme in Legionella virulence, and a number of L. pneumophila effector proteins have been shown to possess ubiquitin ligase or deubiquitinase activity. Among these, members of the SidE family effector proteins (SidEs) catalyze ubiquitination of several ER-associated Rab small GTPases by a mechanism that bypasses the requirement of ATP and the E1, E2 enzymes. Here, we summarize the experimental details of Rab small GTPases ubiquitination catalyzed by SdeA, a member of the SidE family. PMID- 30242702 TI - Using In Vitro Ubiquitylation Assays to Estimate the Affinities of Ubiquitin Conjugating Enzymes for Their Ubiquitin Ligase Partners. AB - Ubiquitin ligases (E3s) function by binding to both a protein substrate and to ubiquitin-conjugating enzymes (E2s) bound to ubiquitin. E3s facilitate the transfer of ubiquitin from the E2 active site to an E3-bound substrate. Thus, the affinity of the interaction of an E2 with its E3 partner is of considerable interest. The purpose of this work is to (1) provide protocols for the purification of the human E2 Cdc34, as well as for some additional protein components needed for the assays described here whose purification protocols haven't been described elsewhere in detail; (2) provide the researcher with critical information regarding the proper long-term storage of these enzymes to retain maximal activity; (3) provide a protocol to benchmark Cdc34 activity with previously described activity levels in the literature; and (4) provide a simple and rapid means of measuring E2 affinity for an E3. PMID- 30242703 TI - Competition Assay for Measuring Deubiquitinating Enzyme Substrate Affinity. AB - Assays of the affinity of a deubiquitinating enzyme for substrate, either through binding studies or determination of the Michaelis constant, KM, can shed light on substrate selectivity and the effects of mutations on substrate interactions. The difficulty in generating sufficient quantities of ubiquitinated substrate frequently presents a barrier to these studies. We describe here an alternative approach that can be used in cases where non-hydrolyzable, chemically ubiquitinated substrate analogs can be more readily generated. The substrate analog can be utilized as a competitive inhibitor in kinetics experiments monitoring cleavage of ubiquitin-AMC (Ub-AMC) by the deubiquitinating enzyme. The resulting inhibitory constant, Ki, provides a reliable approximation of the Kd for ubiquitinated substrate. We show how this approach can be used to assay the affinity of the yeast SAGA DUB module for nucleosomes containing monoubiquitinated H2B. PMID- 30242704 TI - Enzymatic Assembly of Ubiquitin Chains. AB - The availability of different polyubiquitin chains of specific linkage types has changed the appreciation of the specificity in the ubiquitin (Ub) system. Numerous E2 Ub-conjugating enzymes and E3 Ub ligases, Ub-binding domains (UBDs), and deubiquitinases (DUBs) are now known to assemble, bind, or hydrolyze individual linkage types, respectively. Biochemical and structural studies of these processes require milligram quantities of pure polyUb. Here we describe protocols that allow the enzymatic synthesis and purification of six of the eight homotypic polyUb chains through the use of chain-specific Ub ligases and DUBs. PMID- 30242705 TI - Ubiquitin-Activated Interaction Traps (UBAITs): Tools for Capturing Protein Protein Interactions. AB - UBAITs (Ubiquitin-Activated Interaction Traps) are reagents that capitalize on the biochemistry of the ubiquitin system to covalently trap transient protein protein interactions. UBAITs consist of an affinity-tagged protein of interest fused to a short linker followed by a C-terminal ubiquitin moiety. When charged in an E1- and E2-dependent manner, the C-terminal ubiquitin moiety of the UBAIT has the potential to form an amide linkage with lysine side chains of a protein that interacts transiently with the protein of interest, thereby covalently trapping the protein-protein interaction. The partner protein can then be identified by affinity-based purification of the UBAIT coupled with mass spectroscopy methods. While originally designed to identify substrates of ubiquitin ligases, UBAITs can, in principle, be used for identifying interaction partners of virtually any protein of interest. Here we describe methods for utilizing UBAITs in both cell-based and in vitro experiments. PMID- 30242706 TI - Generating Intracellular Modulators of E3 Ligases and Deubiquitinases from Phage Displayed Ubiquitin Variant Libraries. AB - Ubiquitination is a posttranslational protein modification pathway regulating diverse cellular processes that are implicated in numerous human diseases. However, targeting the enzymes in the ubiquitination cascade potently and selectively remains a major challenge. Recently we devised a methodology to generate ubiquitin-based modulators for E3 ligases and deubiquitinases, enzymes that control the specificity of protein ubiquitination and deubiquitination, respectively. Here, we describe methods to generate libraries of ubiquitin variants and perform phage display selections to isolate high-affinity binders for target proteins. Importantly, the strategy introduced here can be applied to other small protein domains mediating protein-protein interactions to engineer tools for target validation and potential therapeutic development. PMID- 30242707 TI - Integrated Proteogenomic Approach for Identifying Degradation Motifs in Eukaryotic Cells. AB - Since its discovery nearly 40 years ago, many components of the ubiquitin proteasome system (UPS) have been identified and characterized in detail. However, a key aspect of the UPS that remains largely obscure is the signals that initiate the interaction of a substrate with enzymes of the UPS machinery. Understanding these signals is of particular interest for studies that examine the mechanism of substrate recognition for proteins that have adopted a non native structure, as part of the cellular protein quality control (PQC) defense mechanism. Such studies are quite salient as the entire proteome makes up the potential battery of PQC substrates, and yet only a limited number of ubiquitination pathways are known to handle misfolded proteins. Our current research aims at understanding how a small number of PQC ubiquitin-protein ligases specifically recognize and ubiquitinate the overwhelming assortment of misfolded proteins. Here, we present a new proteogenomic approach for identifying and characterizing recognition motifs within degradation elements (degrons) in a high-throughput manner. The method utilizes yeast growth under restrictive conditions for selecting protein fragments that confer instability. The corresponding cDNA fragments are analyzed by next-generation sequencing (NGS) that provides information about each fragment's identity, reading frame, and abundance over time. This method was used by us to identify PQC-specific and compartment-specific degrons. It can readily be modified to study protein degradation signals and pathways in other organisms and in various settings, such as different strain backgrounds and under various cell conditions, all of which can be sequenced and analyzed simultaneously. PMID- 30242708 TI - A Method to Monitor Protein Turnover by Flow Cytometry and to Screen for Factors that Control Degradation by Fluorescence-Activated Cell Sorting. AB - The protein quality control network consists of multiple proteins or protein complexes that monitor proteome integrity by mediating protein folding and the removal of proteins that cannot be folded. An integral component of this network is the ubiquitin-proteasome system, which controls the degradation of thousands of cellular proteins. A number of questions remain unanswered regarding the degradation of misfolded proteins. For example, how are substrates recognized and triaged? What are the identities of the components involved? And finally, what substrates are targeted by any given component of the quality control network? Finding answers to these questions is what inspires our work in protein quality control. Further characterization of protein quality control mechanisms requires methods that can reliably quantify turnover rates of model substrates. One such method is based on flow cytometry. Here, we present protocols detailing how to assess protein stability with flow cytometry and how fluorescence-activated cell sorting (FACS) can be used to screen for factors important for protein quality control and protein turnover. PMID- 30242709 TI - E. coli-Based Selection and Expression Systems for Discovery, Characterization, and Purification of Ubiquitylated Proteins. AB - Ubiquitylation is an eukaryotic signal that regulates most cellular pathways. However, four major hurdles pose challenges to study ubiquitylation: (1) high redundancy between ubiquitin (Ub) cascades, (2) ubiquitylation is tightly regulated in the cell, (3) the transient nature of the Ub signal, and (4) difficulties to purify functional ubiquitylation apparatus for in vitro assay. Here, we present systems that express functional Ub cascades in E. coli, which lacks deubiquitylases, Ub-dependent degradations, and control mechanisms for ubiquitylation. Therefore, expression of an ubiquitylation cascade results in the accumulation of stable ubiquitylated protein that can be genetically selected or purified, thus circumventing the above challenges. Co-expression of split antibiotic resistance protein fragments tethered to Ub and ubiquitylation targets along with ubiquitylation enzymes (E1, E2, and E3) gives rise to bacterial growth on selective media. We show that ubiquitylation rate is highly correlated with growth efficiency. Hence, genetic libraries and simple manipulations in the selection system facilitate the identification and characterization of components and interfaces along Ub cascades. The bacterial expression system also facilitates the detection of ubiquitylated proteins. Furthermore, the expression system allows affinity chromatography-based purification of milligram quantities of ubiquitylated proteins for downstream biochemical, biophysical, and structural studies. PMID- 30242710 TI - Strategies to Trap Enzyme-Substrate Complexes that Mimic Michaelis Intermediates During E3-Mediated Ubiquitin-Like Protein Ligation. AB - Most cellular functions rely on pathways that catalyze posttranslational modification of cellular proteins by ubiquitin (Ub) and ubiquitin-like (Ubl) proteins. Like other posttranslational modifications that require distinct writers, readers, and erasers during signaling, Ub/Ubl pathways employ distinct enzymes that catalyze Ub/Ubl attachment, Ub/Ubl recognition, and Ub/Ubl removal. Ubl protein conjugation typically relies on parallel but distinct enzymatic cascades catalyzed by an E1-activating enzyme, an E2 carrier protein, and an E3 ubiquitin-like protein ligase. One major class of E3, with ca. 600 members, harbors RING or the RING-like SP-RING or Ubox domains. These RING/RING-like domains bind and activate the E2-Ubl thioester by stabilizing a conformation that is optimal for nucleophilic attack by the side chain residue (typically lysine) on the substrate. These RING/RING-like domains typically function together with other domains or protein complexes that often serve to recruit particular substrates. How these RING/RING-like E3 domains function to activate the E2-Ubl thioester while engaged with substrate remains poorly understood. We describe a strategy to generate and purify a unique E2Ubc9-UblSUMO thioester mimetic that can be cross-linked to the SubstratePCNA at Lys164, a conjugation site that is only observed in the presence of E3Siz1. We describe two techniques to cross-link the E2Ubc9-UblSUMO thioester mimetic active site to the site of modification on PCNA and the subsequent purification of these complexes. Finally, we describe the reconstitution and purification of the E2Ubc9-UblSUMO-PCNA complex with the E3Siz1 and purification that enabled its crystallization and structure determination. We think this technique can be extended to other E2-Ubl substrate/E3 complexes to better probe the function and specificity of RING-based E3 Ubl ligases. PMID- 30242711 TI - Small-Angle X-Ray Scattering for the Study of Proteins in the Ubiquitin Pathway. AB - Small-angle X-ray scattering (SAXS) is an invaluable complement to other biophysical methods used to interrogate the structure and dynamics of proteins. Here, we describe the standard experimental protocol used in our laboratory to analyze proteins in the ubiquitin pathway. The method addresses buffer selection, data collection using an in-house X-ray source, diagnostic tests to assess data quality, and computational approaches to interpret SAXS data. PMID- 30242712 TI - Methods for Preparing Cryo-EM Grids of Large Macromolecular Complexes. AB - The recent resolution revolution in cryo-electron microscopy has generated a huge interest in the technique for determining atomic resolution structures of large and dynamic macromolecular complexes that are intractable to crystallography and NMR. A key element of success in cryo-EM is the quality of the specimen vitrified on the cryo-EM grid. In this chapter we outline methods for cryo-EM grid sample preparation. PMID- 30242713 TI - Recombinant Expression, Unnatural Amino Acid Incorporation, and Site-Specific Labeling of 26S Proteasomal Subcomplexes. AB - The 26S proteasome is the major regulated protease in eukaryotes and is responsible for degrading ubiquitinated substrates. It consists of a barrel shaped 20S core peptidase and one or two 19S regulatory particles, which recognize, unfold, and translocate substrates into the core. The regulatory particle can be further divided into two multi-subunit complexes: the base and the lid. Here we present protocols for expressing the Saccharomyces cerevisiae base and lid recombinantly in Escherichia coli and purifying the assembled subcomplexes using a tandem affinity purification method. The purified complexes can then be reconstituted with 20S core to form fully functional proteasomes. Furthermore, we describe a method for incorporating the unnatural amino acid p azido-L-phenylalanine into the recombinant complexes at any residue position, allowing for non-disruptive site-specific modifications of these large assemblies. The use of recombinant proteins allows for complete mutational control over the proteasome regulatory particle, enabling detailed studies of the mechanism by which the proteasome processes its substrates. The ability to then specifically modify residues in the regulatory particle opens the door to a wide range of previously impossible biochemical and biophysical studies. The techniques described below for incorporating unnatural amino acids into the proteasomal subcomplexes should be widely transferable to other recombinant proteins, whether individually purified or in larger multi-subunit assemblies. PMID- 30242714 TI - Native Gel Approaches in Studying Proteasome Assembly and Chaperones. AB - Proteasomes are complex molecular machines that consist of 66 subunits. The assembly of these complexes is highly coordinated in a process that requires at least ten proteasome-specific molecular chaperones. One of the challenges in studying assembly intermediates is their relatively low abundance as compared to the proteasome holoenzyme. Therefore, superior separating techniques are crucial for analyses of proteasomal complexes in general and studies in the assembly in particular. For this reason, native gel analyses have been abundantly used in studying proteasomes, as they provide a high resolution. Native gels are very versatile and can be used in various combinatorial approaches. In this chapter, we outline two approaches to prepare samples for native gels. The first is a yeast cryogrinding method and the second a core particle (CP)-base reconstitution approach. We describe the native gel electrophoresis, as well as various downstream analyses, including 2D native-SDS-PAGE. These techniques and approaches can all be used, often in parallel, to gain a variety of information about activity and composition of the complexes separated by native gel. The potential combined approaches are discussed in this review. PMID- 30242715 TI - Measuring the Overall Rate of Protein Breakdown in Cells and the Contributions of the Ubiquitin-Proteasome and Autophagy-Lysosomal Pathways. AB - In certain physiological or pathological states (e.g., starvation, heat shock, or muscle atrophy) and upon drug treatments, the overall rate of protein degradation in cells may increase or decrease. These adaptations and pathological responses can occur through alterations in substrate flux through the ubiquitin-proteasome pathway (UPP), the autophagy-lysosomal system, or both. Therefore, it is important to precisely measure the activities of these degradation pathways in degrading cell proteins under different physiological states or upon treatment with drugs. In particular, proteasome inhibitors have become very important agents for treating multiple myeloma and very useful tools in basic research. To evaluate rigorously their efficacy and the cellular responses to other inhibitors, it is essential to know the degree of inhibition of protein breakdown. Unfortunately, commonly used assays of the activities of the UPP or autophagy rely on qualitative, indirect approaches that do not directly reflect the actual rates of protein degradation by these pathways. In this chapter, we describe isotopic pulse-chase methods to directly measure overall rates of protein degradation in cells by radiolabeling cell proteins and following their subsequent degradation to radioactive amino acids, which diffuse from cells into the medium and can be easily quantitated. While pulse-chase methods have often been used to follow degradation of specific proteins, the methods described here allow quantification of the total cellular activity in degrading either long lived proteins (the great bulk of cell constituents) or the fraction with short half-lives. Moreover, by use of specific inhibitors of proteasomes or lysosomes, it is also possible to measure precisely the total contributions of the UPP or lysosomal proteases. These approaches have already been proven very useful in defining the effects of inhibitors, growth factors, nutrients, ubiquitination, and different proteasome activators on overall proteolysis and on substrate flux through the proteasomal and lysosomal pathways. PMID- 30242716 TI - Methods to Rapidly Prepare Mammalian 26S Proteasomes for Biochemical Analysis. AB - Rapid, gentle isolation of 26S proteasomes from cells or tissues is an essential step for studies of the changes in proteasome activity and composition that can occur under different physiological or pathological conditions and in response to pharmacological agents. We present here three different approaches to affinity purify or to prepare proteasome-rich cell fractions. The first method uses affinity tags fused to proteasome subunits and has been useful in several cell lines for studies of proteasome structure by cryo-electron microscopy and composition by mass spectrometry. A second method uses the proteasome's affinity for a ubiquitin-like (UBL) domain and can be used to purify these particles from any cell or tissue. This method does not require expression of a tagged subunit and has proven to be very useful to investigate how proteasomal activity changes in different physiological states (e.g., fasting or aging), with neurodegenerative diseases, and with drugs or hormones that cause subunit phosphorylation. A third, simple method that is based on the 26S proteasome's high molecular weight (about 2.5 MDa) concentrates these particles greatly by differential centrifugation. This method maintains the association of proteasomes with ubiquitin (Ub) conjugates and many other loosely associated regulatory proteins and is useful to study changes in proteasome composition under different conditions. PMID- 30242717 TI - Measurement of the Multiple Activities of 26S Proteasomes. AB - Because proteasomes catalyze most of the protein degradation in mammalian cells, and their functioning is essential for cellular homeostasis, proteasome structure, biochemical mechanisms, and regulation in normal and disease states are now widely studied and are of major importance. In addition, inhibitors of the proteasome's peptidase activity have proven to be very valuable as research tools and in the treatment of hematologic malignancies, and a number of newer pharmacological agents that alter proteasome function are being developed. The rapid degradation of ubiquitinated proteins by the 26S proteasome involves multiple enzymatic and non-enzymatic steps, including the binding of ubiquitinated substrates to the 19S particle (Subheading 3.2), opening the gated substrate entry channel into the 20S particle (Subheading 3.3), disassembly of the Ub chain (Subheading 3.4), ATP hydrolysis (Subheading 3.5), substrate unfolding and translocation, and proteolysis within the 20S particle (Subheadings 3.3 and 3.7). Assaying each of these processes is important if we are to fully understand the physiological regulation of proteasome function and the effects of disease or drugs. Here, we describe several methods that we have found useful to measure many of these individual activities using purified proteasomes. Studies using these approaches have already provided valuable new insights into the effects of post-synthetic modifications to 26S subunits, the physiological regulation of the ubiquitin-proteasome system, and the impairment of proteasome activity in neurodegenerative disease. These advances would not have been possible if only the standard assays of peptidase activity were used. PMID- 30242718 TI - Exploring the Regulation of Proteasome Function by Subunit Phosphorylation. AB - Rates of degradation by the ubiquitin proteasome system depend not only on rates of ubiquitination, but also on the level of proteasome activity which can be regulated through phosphorylation of proteasome subunits. Many protein kinases have been proposed to influence proteasomal activity. However, for only two is there strong evidence that phosphorylation of a specific 26S subunit enhances the proteasome's capacity to degrade ubiquitinated proteins and promotes protein breakdown in cells: (1) protein kinase A (PKA), which after a rise in cAMP phosphorylates the 19S subunit Rpn6, and (2) dual tyrosine receptor kinase 2 (DYRK2), which during S through M phases of the cell cycle phosphorylates the 19S ATPase subunit Rpt3. In this chapter, we review and discuss the different methods used to assess the impact of phosphorylation by these two kinases on proteasomal activity and intracellular protein degradation. In addition, we present one method to determine if phosphorylation is responsible for an observed increase in proteasomal activity and another to evaluate by Phos-tag gel electrophoresis whether a specific proteasome subunit is modified by phosphorylation. The methods reviewed and presented here should be useful in clarifying the roles of other kinases and other posttranslational modifications of proteasome subunits. PMID- 30242719 TI - Scalable In Vitro Proteasome Activity Assay. AB - We developed a degradation assay based on fluorescent protein substrates that are efficiently recognized, unfolded, translocated, and hydrolyzed by the proteasome. The substrates consist of three components: a proteasome-binding tag, a folded domain, and an initiation region. All the components of the model substrate can be changed to modulate degradation, and the assay can be performed in parallel in 384-well plates. These properties allow the assay to be used to explore a wide range of experimental conditions and to screen proteasome modulators. PMID- 30242720 TI - Exploring the Rampant Expansion of Ubiquitin Proteomics. AB - The ubiquitin proteasome system can arguably affect all cellular proteins with few exceptions. In addition to regulating many pathways such as cell cycle progression, inflammation, gene expression, DNA repair, and vesicle trafficking to just name a few-ubiquitination can occur to any nascent or newly translated protein that misfolds. In the past years, substantial progress has been achieved in advancing our global understanding of the ubiquitinome-the ensemble of ubiquitinated proteins within a cell-using mass spectrometry-based proteomics. Notably, over 50,000 conjugation sites have now been reported. In this review, we discuss recent proteomics methods used to expand our knowledge of the ubiquitin proteasome system through the identification of ubiquitination sites, poly ubiquitin chain types, and E3 ubiquitin ligase substrates. PMID- 30242721 TI - Ubiquitin diGLY Proteomics as an Approach to Identify and Quantify the Ubiquitin Modified Proteome. AB - Protein ubiquitylation is one of the most prevalent posttranslational modifications (PTM) within cells. Ubiquitin modification of target lysine residues typically marks substrates for proteasome-dependent degradation. However, ubiquitylation can also alter protein function through modulation of protein complexes, localization, or activity, without impacting protein turnover. Taken together, ubiquitylation imparts critical regulatory control over nearly every cellular, physiological, and pathophysiological process. Affinity purification techniques coupled with quantitative mass spectrometry have been robust tools to identify PTMs on endogenous proteins. A peptide antibody-based affinity approach has been successfully utilized to enrich for and identify endogenously ubiquitylated proteins. These antibodies recognize the Lys-epsilon Gly-Gly (diGLY) remnant that is generated following trypsin digestion of ubiquitylated proteins, and these peptides can then be identified by standard mass spectrometry approaches. This technique has led to the identification of >50,000 ubiquitylation sites in human cells and quantitative information about how many of these sites are altered upon exposure to diverse proteotoxic stressors. In addition, the diGLY proteomics approach has led to the identification of specific ubiquitin ligase targets. Here we provide a detailed method to interrogate the ubiquitin-modified proteome from any eukaryotic organism or tissue. PMID- 30242722 TI - Interpreting the Language of Polyubiquitin with Linkage-Specific Antibodies and Mass Spectrometry. AB - Posttranslational modification of cellular proteins by ubiquitin serves a variety of functions. Among the multitude of ubiquitin substrates, ubiquitin itself is the most prevalent. For many years, the direct detection of polyubiquitin chains attached to cellular substrates was not practical, with cell biologists relegated to indirect approaches involving site-directed mutagenesis or in vitro biochemistry. Recent advances in two technologies-polyubiquitin linkage-specific antibodies and mass spectrometry proteomics, have overcome that limitation. Using one or both of these, the direct analysis of polyubiquitin chain linkages on cellular substrate proteins may be performed. This paper describes the complimentary nature of linkage-specific antibodies and mass spectrometry proteomics for the characterization of complex ubiquitin signals using lessons learned in early development of both technologies. PMID- 30242723 TI - Dissecting Dynamic and Heterogeneous Proteasome Complexes Using In Vivo Cross Linking-Assisted Affinity Purification and Mass Spectrometry. AB - Protein-protein interactions are essential for protein complex formation and function. Affinity purification coupled with mass spectrometry (AP-MS) is the method of choice for studying protein-protein interactions at the systems level under different physiological conditions. Although effective in capturing stable protein interactions, transient, weak, and/or dynamic interactors are often lost due to extended procedures during conventional AP-MS experiments. To circumvent this problem, we have recently developed XAP (in vivo cross-linking (X)-assisted affinity purification)-MS strategy to better preserve dynamic protein complexes under native lysis conditions. In addition, we have developed XBAP (in vivo cross linking (X)-assisted bimolecular tandem affinity purification)-MS method by incorporating XAP with bimolecular affinity purification to define dynamic and heterogeneous protein subcomplexes. Here we describe general experimental protocols of XAP- and XBAP-MS to study dynamic protein complexes and their subcomplexes, respectively. Specifically, we present their applications in capturing and identifying proteasome dynamic interactors and ubiquitin receptor (UbR)-proteasome subcomplexes. PMID- 30242724 TI - Spiritual Intelligence and Post-abortion Depression: A Coping Strategy. AB - Loss of pregnancy is a major stressor which can cause mental disorders. In stressful conditions, spiritual intelligence can be used as a coping strategy to manage and cope with the stressor. It may also produce positive outcomes in spontaneous abortion. This study aimed to assess the relationship of spiritual intelligence with depression after spontaneous abortion. This cross-sectional descriptive-correlational study was done in 2015-2016 on 185 women with spontaneous abortion who were hospitalized in the postnatal care ward of Kowsar teaching hospital, Qazvin, Iran. Data collection was performed in two steps. In the first step, a demographic and obstetric characteristics questionnaire and the Spiritual Intelligence Self-Report Inventory were completed by participants during their hospital stay. In the second step, i.e., 7 days after spontaneous abortion, the Edinburgh Postnatal Depression Scale was completed for each participant over the phone. Variables which were found in univariate analysis to have a significant correlation with depression were entered into multiple logistic regression analysis to assess their roles in predicting depression. Most women were depressed (54%). Multiple logistic regression analysis revealed that the significant predictors of depression were women's educational status (OR 0.419; CI 0.18-0.93), gestational age at the time of abortion (OR 1.121; CI 1.02 1.22), and the personal meaning production dimension of spiritual intelligence (OR 0.82; CI 0.73-0.91). Spiritual intelligence is significantly correlated with post-abortion depression. Developing and following strategies for promoting spiritual intelligence can alleviate depression, stress, and anxiety after spontaneous abortion and also help manage complicated pregnancies. PMID- 30242725 TI - Dietary Fat and Risk for Type 2 Diabetes: a Review of Recent Research. AB - PURPOSE OF REVIEW: It is estimated that over 400 million people worldwide are living with diabetes. Excess adiposity is the strongest risk factor for non insulin-dependent diabetes, type 2. Lifestyle interventions have demonstrated that diet plays a critical role in preventing the onset of type 2 diabetes. Dietary fat is not only a source of energy and nutrients, but also bioactive fatty acids. The purpose of this review was to examine data from recent prospective cohort studies and dietary interventions to determine if there are benefits to fat consumption on diabetes risk. RECENT FINDINGS: The consumption of fish and marine n-3 fatty acids among Asian populations and regular-fat dairy foods and trans-palmitoleic acid (trans-16, n-7) among Western populations may be associated with reduced risk for type 2 diabetes. Whereas some dietary fat may contribute to reduced diabetes risk, lifestyle recommendations to balance calories with physical activity are prudent at this time. PMID- 30242726 TI - The efficacy and safety of dipeptidyl peptidase-4 inhibitors for type 2 diabetes: a Bayesian network meta-analysis of 58 randomized controlled trials. AB - AIMS: The aim is to evaluate the efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP4-I: sitagliptin, saxagliptin, linagliptin, vildagliptin and alogliptin) in patients with type 2 diabetes. METHODS: We searched the Cochrane Library, PubMed, EMBASE, Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), and the Wanfang Database from inception to April, 2018. Randomized controlled trials were included if they compared the different versions of DPP4-I with each other or with placebo in treatment of type 2 diabetes. Bayesian network meta-analysis and pairwise meta-analysis were performed to evaluate the efficacy and safety of the different kinds of DPP4-I and placebo. The data were analyzed using STATA 12.0 and WinBUGS1.4 software. RESULTS: We identified 58 eligible studies (with 31356 patients) involving 14 treatment arms. Indirect comparison results showed that except for alogliptin, a decrease was found for all DPP4-I versus the placebo for hemoglobin A1c (HbA1c) with vildagliptin50 twice daily (BID) showing the highest probability. Linagliptin5 once daily (QD) decreased the level of fasting plasma glucose (FPG) the most for all DPP4-I versus the placebo; when comparing them with each other, alogliptin25QD was more effective when compared with sitagliptin100QD and vildaglipti50BID; linagliptin5qd had the highest decrease impact on body mass index (BMI). Except for hypoglycemia and upper respiratory tract infection (URTI), there are no statistical significance on incidence of adverse events and the body weight when DPP4-I are compared with each other or with placebo. CONCLUSION: Our network meta-analysis presents the associations of DPP4-I versus placebos on HbA1c, FPG, 2 h postprandial blood glucose (2HPPG), BMI, body weight and adverse events. DPP4-I have a lowering effect on the glycemic level (HbA1c, FPG), especially vildaglipti50BID and linagliptin10QD, respectively. Besides, linagliptin5QD has the greatest probabilities of reducing BMI. In addition, DPP4 I were associated with not increasing the incidence of adverse events. Among them, vildagliptin100QD and sitagliptin100QD have the lowest probability in reducing the incidence of hypoglycemia and URTI, respectively. PMID- 30242727 TI - Myelin Water Fraction Imaging Reveals Hemispheric Asymmetries in Human White Matter That Are Associated with Genetic Variation in PLP1. AB - Myelination of axons in the central nervous system is critical for human cognition and behavior. The predominant protein in myelin is proteolipid protein making PLP1, the gene that encodes for proteolipid protein, one of the primary candidate genes for white matter structure in the human brain. Here, we investigated the relation of genetic variation within PLP1 and white matter microstructure as assessed with myelin water fraction imaging, a neuroimaging technique that has the advantage over conventional diffusion tensor imaging in that it allows for a more direct assessment of myelin content. We observed significant asymmetries in myelin water fraction that were strongest and rightward in the parietal lobe. Importantly, these parietal myelin water fraction asymmetries were associated with genetic variation in PLP1. These findings support the assumption that genetic variation in PLP1 affects white matter myelination in the healthy human brain. PMID- 30242728 TI - Peer Review at JGIM. PMID- 30242729 TI - Switchable fluorescence of MoS2 quantum dots: a multifunctional probe for sensing of chromium(VI), ascorbic acid, and alkaline phosphatase activity. AB - A simple strategy for modulating the fluorescence of MoS2 quantum dots (QDs) is described. The fluorescence of MoS2 QDs was firstly switched off by the addition of Cr(VI), and the quenched fluorescence was further switched on by introducing ascorbic acid (AA) into the mixture. The fluorescence quenching of MoS2 QDs by Cr(VI) was attributed to the fluorescence inner filter effect. After the addition of AA, Cr(VI) was reduced to Cr(III), and the fluorescence was restored. This finding has been applied for the fluorescent sensing of Cr(VI) in drinking water and AA in serum samples. In addition, the present method has been extended for turn-on sensing of an important biomarker alkaline phosphatase (ALP). There is a linear relationship between the fluorescence intensity and the concentrations of ALP in the range from 2.5 to 50 U/L, and the limit of detection is 0.34 U/L. The results showed MoS2 QDs hold great potential as a multifunctional fluorescent probe for the detection of metal ions, biological small molecules, and proteins. Graphical abstract The fluorescence of MoS2 QDs can be switched off by Cr(VI), and the quenched fluorescence can be further switched on by the addition of ascorbic acid or enzymatically generated ascorbic acid. This allows the selective detection of Cr(VI), ascorbic acid, and alkaline phosphatase based on the fluorescence of MoS2 QDs. PMID- 30242730 TI - Atmospheric Deposition of Organochlorine Pesticides (OCPs): Species, Levels, Diurnal and Seasonal Fluctuations, Transfer Velocities. AB - Organochlorine pesticides (OCPs) in the persistent organic pollutants class are pollutants that can enter water reservoirs, soils, and sediments by atmospheric deposition. The aim of the present study was to determine the total atmospheric deposition fluxes of OCPs in a semi-rural area in Bursa, Turkey. Total deposition fluxes, phase distributions, dry deposition velocities and mass transfer coefficients were calculated in the samples collected during day and night periods. Ambient air OCP samples were also taken simultaneously. Samples were analyzed for 9 OCP compounds (alpha-, beta-, and gamma-hexachlorocyclohexane; heptachlor epoxide; endrin; endosulfan beta; endrin aldehyde; and methoxychlor). OCPs were found predominantly in gas and dissolved phases in all seasons for the ambient air and deposition samples, respectively. The annual maximum averages of deposition fluxes for dissolved and particulate phases for the beta-HCH compound were 200.2 ng/m2-day and 28.6 ng/m2-day, respectively. The average dry deposition velocity and mass transfer coefficient values calculated for OCPs were 4.6 +/- 5.5 cm/s and 0.46 +/- 0.37 cm/s, respectively, and these values were in line with the values in the literature. In the nighttime and daytime samples, the average deposition fluxes of OCP compounds in the dissolved phase were 1.5-10 times higher than those in the particulate phase. Although there were no great differences in daytime and nighttime samples, it was found that the flux values during daytime periods were sometimes higher. PMID- 30242731 TI - Early-onset dementia, leukoencephalopathy and brain calcifications: a clinical, imaging and pathological comparison of ALSP and PLOSL/Nasu Hakola disease. AB - Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia, and Nasu Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy are both underrecognized progressive degenerative white matter diseases that can present with young dementia, leukoencephalopathy and brain calcifications. We report and compare three cases in terms of clinical phenotype, imaging and neuropathological findings. Both cases have led to the identification of two novel causal mutations. PMID- 30242732 TI - Probable pathogenesis, diagnosis, and management of untreated arteriovenous malformation with cyst formation: case report and literature review. AB - Arteriovenous malformations (AVMs) usually manifest as headaches, seizures, focal neurological signs, and spontaneous intracerebral or subarachnoid hemorrhages. An untreated AVM with associated cyst formation is extremely rare, and the probable pathogenesis is unclear. We propose and discuss the possible pathogenesis of this condition and its diagnosis and management. A 26-year-old male presented with a generalized tonic-clonic seizure. Computed tomography showed a cystic lesion in the left frontal lobe and magnetic resonance imaging revealed a complex composition within the lesion, without a flow-voiding signal. Therefore, the initial diagnosis was oligodendroglioma and surgical treatment was performed. However, intraoperatively, engorged reddish nodule-like vessels with a cystic capsule and intra-cyst brown and sticky fluid were found. The nodule-like vessels and cystic capsule were resected completely. The patient's postoperative course was uneventful, with an excellent neurological outcome and no further seizures. Pathological examination of the surgical specimen revealed the typical microscopic appearance of an AVM, with numerous thin-walled vascular channels and deposits of hemosiderin in fibrous tissue. In conclusion, an untreated AVM with associated cyst formation is extremely rare, and the mechanism of formation is unclear. We propose a probable pathogenesis. Preoperative diagnosis, intraoperative management, and postoperative follow-up are equally crucial in dealing with this extremely rare condition. Cystic tumors associated with arteriovenous malformations (AVMs) are uncommon and are usually a complication of stereotactic radiosurgery (Ilyas et al. in J Neurosurg. https://doi.org/10.3171/2016.12.JNS162478 , 2017) or form after a hemorrhage (Daniels et al. in Radiology 133:393-394, 1979). Untreated AVMs with large cysts or cystic tumors are rare, with only five cases reported in the literature (Table 1). Here, we present a case of an untreated AVM associated with cystic formation, or a cystic tumor, in the left frontal lobe. PMID- 30242733 TI - Prediction of the very early occurrence of HCC right after DAA therapy for HCV infection. AB - BACKGROUND: Although direct-acting antiviral (DAA) developments make most of hepatitis C virus (HCV) infection curable, some HCV patients develop hepatocellular carcinoma (HCC) after curative treatment of HCV. There is much dispute whether the rapid clearance of the virus enhances the HCC development. In advance of the dispute, we should make clear the characteristics of the patients with very early occurrence and recurrence of HCC after DAA therapy because it was still unclear. METHODS: We prospectively followed consecutive patients with HCV who had received sofosbuvir (SOF)-based treatment at two hospitals. The baseline characteristics, laboratory data, and liver imaging findings were acquired. We evaluated the rate of HCC occurrence and recurrence within 1-year after DAA therapy and analyzed the associated factors of very early HCC occurrence and recurrence right after SOF therapy. RESULTS: Between July 2013 and October 2016, we studied two cohorts with HCV infection that received SOF therapy. 402 and 462 patients in Yamanashi Central Hospital and Chiba University Hospital were included in this analysis, respectively. The SVR12 rates of genotypes 1 and 2 were 98.9% (561/567) and 96.0% (285/297), respectively. 41 patients developed HCC within 1 year after SOF therapy. The cumulative HCC occurrence and recurrence rate after SOF therapy was 5.0%. The common associated factor of 1-year HCC occurrence and recurrence in all cohorts was the existence of imaging "dysplastic nodule". CONCLUSIONS: SOF regimens for HCV also have very high rates of SVR 12 in the post-market distribution. The appearance of imaging "dysplastic nodule" was an associated factor of 1-year HCC occurrence and recurrence. To investigate existence of "dysplastic nodule" by imaging surveillance before DAA treatment is useful to detect high-risk patients of very early HCC occurrence and recurrence and it should be performed. PMID- 30242735 TI - Microcystic Adenocarcinoma: An Initially Overlooked First Proposal of the Term. PMID- 30242734 TI - The metabolic alterations within the normal appearing brain in patients with Hashimoto's thyroiditis are correlated with hormonal changes. AB - Hashimoto's thyroiditis (HT) is the most common autoimmune disease in humans usually associated with subsequent hypothyroidism. The purpose of the study was to assess metabolic alterations within the normal appearing brain in subjects with HT using MR spectroscopy (MRS) and to correlate MRS measurements with hormonal concentrations. Fifty-five HT patients (mean age 43.5 yrs) and 30 healthy controls (mean age 42.5 yrs) were examined with the use of a 1.5 T MR scanner. There were no signs of central nervous system involvement in the studied group. The MRS examinations were performed using the single voxel method. The voxels were placed in the left parietal white matter (PWM) and the posterior cingulate gyrus (PCG). The NAA/Cr, Cho/Cr, and mI/Cr ratios were calculated. The correlations between metabolite ratios and hormonal concentrations (TSH, fT3, fT4) as well as anti-TG and anti-TPO levels were also assessed. We found significantly (p < 0.05) decreased NAA/Cr ratios in PCG and PWM in HT subjects compared to the control group. There were no other significant differences in metabolite ratios. We observed significant positive correlations between the NAA/Cr ratio in PCG as well as the PWM and fT3 level. There was also a significant negative correlation between the Cho/Cr ratio in the PCG and fT4 level. MRS could be a sensitive biomarker capable of depicting early cerebral metabolic disturbances associated with HT. Our findings may indicate the reduction of neuronal activity within the normal appearing brain in patients with HT as well as suggesting that there is a possible biological association between thyroid dysfunction and cerebral metabolic changes. PMID- 30242736 TI - Efficacy and Safety of Tedizolid and Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Injection Drug Users: Analysis of Two Clinical Trials. AB - INTRODUCTION: Injection drug users (IDUs) often develop acute bacterial skin and skin structure infections (ABSSSI) and use emergency departments as their primary source for medical care. METHODS: A post hoc subgroup analysis of two randomized trials examined the efficacy and safety of tedizolid in the treatment of ABSSSI in IDUs. IDUs (n = 389) were identified from two pooled phase 3 trials (NCT01170221, NCT01421511) in patients with ABSSSI (n = 1333). Patients were randomly assigned to tedizolid phosphate (200 mg once daily, 6 days) or linezolid (600 mg twice daily, 10 days). Primary endpoint was >= 20% reduction in lesion area from baseline at 48 -72 h. Secondary endpoints included investigator assessed clinical and microbiological response at the post-therapy evaluation (PTE). RESULTS: Wound infection was more common in IDUs (52.2%), while cellulitis/erysipelas was more common in non-IDUs (55.9%). Most infections were due to Staphylococcus aureus (IDUs, 75.2%; non-IDUs, 85.6%), while oral pathogens were more prevalent in IDUs. Early clinical success rates for tedizolid and linezolid were 82.5% and 79.6% in IDUs and 81.3% and 79.3% for non-IDUs, respectively; responses at PTE were similar. Microbiological response per pathogen was similar between treatment groups. Rates of treatment-emergent adverse events (AEs) in IDUs were comparable between tedizolid (46.2%) and linezolid (47.8%) arms, while lower incidence of gastrointestinal AEs was observed with tedizolid (20.3%) than with linezolid (25.1%). CONCLUSION: Efficacy and safety of tedizolid and linezolid in the treatment of ABSSSI was similar in IDUs and non-IDUs, supporting the use of oxazolidinones in treating ABSSSIs in IDUs. FUNDING: Merck & Co., Inc., Kenilworth, NJ, USA. PMID- 30242737 TI - Potential use of remote sensing techniques in evapotranspiration estimations at watershed level. AB - In hydrology, evapotranspiration (ET) is defined as phase conversion and rise of water in soils, plants, rivers, lakes, and seas under the atmospheric conditions. Investigation of water displacement through either ET or precipitations, runoffs and infiltrations may provide significant contributions for water resources management practices. In this study, daily, monthly, and seasonal ET maps were generated for Minoz Stream Watershed of Kavak town of Samsun province with the aid of energy balance-based METRIC model for the water-year of 2007. Resultant ET maps were assessed through vegetation covers, land use patterns, actual precipitations, and runoff parameters. In a previous study carried out over the same watershed, amount of water to be converted into ET was calculated as 517.0 mm for water-year of 2007. In present study, total ET for the relevant period of the same watershed was estimated as 610.0 mm. Estimated ET value was slightly greater than the total quantity of water to be converted into ET. Present ET maps were also well complied with the land use patterns. PMID- 30242738 TI - Formulation and evaluation of curcumin microsponges for oral and topical drug delivery. AB - The aim of the present study was to improve the release rate of curcumin by microsponges prepared through quasi-emulsion solvent diffusion technique using ethylcellulose and PVA as carriers. The microsponges were characterized by FTIR, DSC, XRD and SEM studies followed by determination of total drug content and entrapment efficiency. The prepared microsponges were further filled in hard gelatin capsule shell and then loaded in carbopol gel to evaluate its potential in oral and topical drug delivery. Further, it was observed from the studies on release rate that microsponges filled in hard gelatin capsule shells (batch MS4) showed 93.2% release of curcumin whereas pure curcumin filled in capsule showed only 11.7% release in 8 h study. Furthermore, the microsponges loaded in carbopol gel were evaluated for ex vivo drug deposition studies and it was found that 77.5% of the curcumin was released within 24 h. The estimated drug remained in the skin was 207.61 +/- 5.03 MUg/cm2 as determined by a Franz diffusion cell. The drug release profile data were found to be fitted best into the zero-order model with anomalous transport mechanism of drug release in both cases. PMID- 30242740 TI - Complete mitochondrial genome of a kind of snakehead fish Channa siamensis and its phylogenetic consideration. AB - The snakehead fish, Channa siamensis, belongs to the genus of Channa (perciformes: Channidae) and was first reported by Gunther in 1861. Despite it has been described approximately for 15 decades, the genetic information is limited and the taxon status of this kind of fish is still unclear. The primary objective of this study is to get more genomic data and calculate the taxon location of this kind of fish. The next generation sequencing method was used to obtain the whole mitochondrial DNA information, and bioinformatic analysis was performed to investigate the evolutionary status and taxon location of C. siamensis. The circular mitochondrial DNA was 16,570 bp in length, and which showed typical piscine structure and arrangement. The overall nucleotide composition was 29.28% A, 24.72% T, 30.71% C, 15.29% G, with 54.1% AT, respectively. Phylogenetic analyses using concatenated amino acid and nucleotide sequences of the 13 protein-coding genes with two different methods (Maximum likelihood and Bayesian analysis) both highly supported C. siamensis belongs to the genus Channa and shows a close relationship with C. micropeltes. These data will provide more useful information for a better understanding of the mitochondrial genomic diversities and evolution in fish as well as novel genetic markers for studying population genetics and species identification. PMID- 30242739 TI - Development of a PCL/gelatin/chitosan/beta-TCP electrospun composite for guided bone regeneration. AB - Many approaches have been developed to regenerate biological substitutes for repairing damaged tissues. Guided bone/tissue regeneration (GBR/GTR) that employs a barrier membrane has received much attention in recent years. Regardless of substantial efforts for treatment of damaged tissue in recent years, an effective therapeutic strategy is still a challenge for tissue engineering researchers. The aim of the current study is to fabricate a GBR membrane consisting of polycaprolactone (PCL)/gelatin/chitosan which is modified with different percentages of beta-tricalcium phosphate (beta-TCP) for improved biocompatibility, mechanical properties, and antibacterial activity. The membranes are examined for their mechanical properties, surface roughness, hydrophilicity, biodegradability and biological response. The mechanical properties, wettability and roughness of the membranes are improved with increases in beta-TCP content. An increase in the elastic modulus of the substrates is obtained as the amount of beta-TCP increases to 5% (145-200 MPa). After 5 h, the number of attached cells is enhanced by 30%, 40% and 50% on membranes having 1%, 3% and 5% beta-TCP, respectively. The cell growth on a membrane with 3% of beta-TCP is also 50% and 20% higher than those without beta TCP and 5% beta-TCP, respectively. Expression of type I collagen is increased with addition of beta-TCP by 3%, while there is no difference in ALP activity. The results indicated that a composite having (3%) beta-TCP has a potential application for guided bone tissue regeneration. PMID- 30242741 TI - Genetic analysis of roots and shoots in rice seedling by association mapping. AB - The vigorous shoots and roots help to improve drought resistance and post transplanting recovery in rice seedlings (Oryza sativa L.). Hundreds of loci related to root system have been identified recently, but little research has been done on shoot traits, and the relationship between roots and shoots development is also still unclear. The objective of this study was to identify associated loci for roots and shoots in rice seedlings as well as to screen pleiotropic QTLs involved in coordinated development of roots and shoots. Using mini core collection of 273 cultivated rice accessions and 280 simple-sequence repeat markers, we investigated six traits [root length (RL), root thickness (RT), root weight (RW), shoot length (SL), shoot weight (SW) and ratio of root-to shoot mass] in seedlings. Study was performed in hydroponic medium and genetic analysis was performed by association mapping using general linear model (GLM) with population structure (Q) and mixed linear model (MLM) involving Q and familial relatedness (K). Two subgroups indica and japonica showed significant differences in RT, RW and SW. Maximum correlation was observed between RW and SW. Using GLM 65 QTLs for root and 43 QTLs associated with shoot traits were detected. Among them, seven QTLs were present between RL and RW and five common QTLs were detected between SL and SW with high phenotypic variation effects (PVEs). Two key pleiotropic QTLs were also identified involved in collaborative development of roots and shoots in rice seedlings. Importantly, 17 and 10 QTLs were identified for root and shoot traits respectively in both studies of GLM and MLM. More common QTLs with high PVEs between root and shoot traits suggested that longitudinal growth (RL and SL) played an important role in accumulation of biomass (RW and SW). Considering the obvious phenotypic differences and fewer common QTLs between indica and japonica, we suggested that there could be different mechanisms of seedling development between both subpopulations. Key pleiotropic QTLs and QTLs identified for root and shoot traits in both studies of GLM and MLM could be preferentially used in marker-assisted breeding for strong rice seedling. PMID- 30242742 TI - Characterization of transcriptional responses mediated by benzo[a]pyrene stress in a new marine fish model of goby, Mugilogobius chulae. AB - Benzo[a]pyrene (BaP) is one of the most studied targets among polycyclic aromatic hydrocarbons (PAHs). Because of the complexity of the toxicity mechanism in BaP, little is known about the molecular mechanism at the level of transcription of BaP in marine fishes. The primary objective of this study was to investigate the molecular basis of the effects of BaP on marine fish, using Mugilogobius chulae (Smith 1932) as the model. A closed colony of M. chulae was used for the BaP toxicity test. Two fish liver samples per replicate from each group were excised and blended into one sample by pooling an equal amount of liver tissue. Total RNA of all samples was extracted separately. Equal quantities of total RNA from the three replicates of the two groups were pooled for sequencing. The sequencing cDNA libraries were sequenced using Illumina HiSeq 2000 system. Differentially expressed genes were detected with the DEGSeq R package. In total, 52,364,032 and 53,771,748 clean nucleotide reads were obtained in the control and BaP-exposed libraries, respectively, with N50 lengths of 1277 and 1288 bp, respectively. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed a significant enrichment of genes related to detoxification, transportation, and lipid metabolism. We also identified, for the first time, an association between endoplasmic reticulum dysfunction and lipid metabolism resulting from BaP exposure. Using quantitative real-time PCR, some effective molecular biomarkers for monitoring of BaP-polluted seawater were identified. The results demonstrate that BaP enhanced the expression of genes involved in detoxification in M. chulae and inhibited that of genes related to lipid metabolism, possibly by suppressing the expression of numerous ER-related genes involved in fat digestion and absorption. PMID- 30242743 TI - Cerebral small vessel disease burden and functional and radiographic outcomes in intracerebral hemorrhage. AB - OBJECTIVE: To examine the effect of individual cerebral small vessel disease (CSVD) markers and cumulative CSVD burden on functional independence, ambulation and hematoma expansion in spontaneous intracerebral hemorrhage (ICH). METHODS: Retrospective analysis of prospectively collected data from an observational study of consecutive patients with spontaneous ICH, brain MRI within 1 month from ictus, premorbid modified Rankin Scale (mRS) score <= 2, available imaging data and 90-day functional status in a tertiary academic center. Functional outcomes included 90-day functional independence (mRS <= 2) and independent ambulation; radiographic outcome was hematoma expansion (> 12.5 ml absolute or > 33% relative increase in ICH volume). We identified the presence and burden of individual CSVD markers (cerebral microbleeds (CMBs), enlarged perivascular spaces, lacunes, white matter hyperintensities) and composite CSVD burden score and explored their association with outcomes of interest in multivariable models adjusting for well established confounders. RESULTS: 111 patients were included, 65% lobar ICH, with a median volume 20.8 ml. 43 (38.7%) achieved functional independence and 71 (64%) independent ambulation. In multivariable adjusted models, there was higher total CSVD burden (OR 0.61, 95% CI 0.37-0.96, p = 0.03) and CMBs presence (OR 0.32, 95% CI 0.1-0.88, p = 0.04) remained independently inversely associated with functional independence. Individual CSVD markers or total CSVD score had no significant relation with ambulation and ICH expansion. Larger ICH volume and deep ICH location were the major determinants of lack of independent ambulation. CONCLUSIONS: Our findings suggest that in ICH patients without previous functional dependence, total CSVD burden and particularly presence of CMBs significantly affect functional recovery. The latter is a novel finding and merits further exploration. PMID- 30242744 TI - A smartphone camera reveals an 'invisible' Parkinsonian tremor: a potential pre motor biomarker? PMID- 30242745 TI - Efficacy of pregabalin in post-traumatic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase 3 trial. AB - The growing need for symptomatic treatment of post-traumatic neuropathic pain (PTNP) continues to be unmet. Studies evaluating the efficacy of pregabalin for reducing neuropathic pain following trauma and surgery yielded positive results over <= 8-week treatment. To assess the efficacy and tolerability of pregabalin over 3 months in patients with PTNP, a randomized, double-blind, placebo controlled, parallel-group trial evaluated patients with PTNP at 101 centers in 11 countries-the longest, largest such trial. Adults diagnosed with PTNP were randomly assigned (1:1) to 15 weeks of pregabalin (flexibly dosed 150-600 mg/day) or matching placebo. Primary efficacy analysis was by mixed-model repeated measures comparing change from baseline to week 15 in weekly mean pain scores between active and placebo groups. Evaluable patients included 274 in the pregabalin group and 265 in the placebo group. Trauma was surgical in 49.6% of patients, non-surgical in the remainder. The primary efficacy analysis showed no statistically significant difference between pregabalin and placebo groups in the change from baseline to week 15 [mean difference, - 0.22 points (95% confidence interval, 0.54-0.10); p = 0.1823]. However, comparisons for key secondary outcome measures yielded p values < 0.05 favoring pregabalin. Consistent with the known safety profile of pregabalin, the most common adverse events were dizziness and somnolence (14.6 and 9.9% of patients, respectively) with pregabalin (vs 4.2 and 3.4% with placebo). These findings demonstrate the feasibility of conducting a large, phase 3 registration trial in the heterogeneous PTNP study population.ClinicalTrials.gov NCT01701362. PMID- 30242746 TI - Investigating the effects of vacancies on self-diffusion in silicon clusters using classical molecular dynamics. AB - Due to recent advances in the field of microelectronics, the growth in microelectronics applications, and the exponentially increasing demand for microelectronic devices in the power sector, it is important to study the behavior of silicon at the nanoscale, given that nanoclusters of silicon could be used to design a new kind of lithium-ion batteries with strongly enhanced performance. Here, molecular dynamics was employed to calculate the self diffusion coefficients of silicon clusters at room temperature and at a temperature approaching the melting point of silicon, complementing experimental efforts in this field. Silicon clusters of the same spherical geometry and size but with different vacancy fractions were studied using molecular dynamics using the Tersoff potential in order to estimate phase changes and self-diffusion coefficients. At 300 K, the self-diffusion coefficient was found to vary non monotonically: the self-diffusion coefficient at a vacancy fraction of 7.5% is half than the vacancy at a fraction of 0%, while the self-diffusion coefficient at a vacancy fraction of 20% is two orders of magnitude larger than that at a vacancy fraction of 0%. However, there is only a marginal monotonic increase in the self-diffusion coefficient values with vacancy fraction at 2000 K. The results of this investigation of vacancy-mediated self-diffusion could aid attempts to improve diffusion control, which is crucial to nanocluster applications in various devices, and the results also provide insight into how the temperature, energy, pressure, and phase changes of the silicon clusters depend on vacancy fraction. This may ultimately allow the design and selection of materials for thermoelectric and optoelectronic devices and thermal transducers to be optimized. Our results also indicated that the findings we obtained for the clusters are independent of the particular random vacancy distribution considered and the heating rate applied to the clusters. Graphical Abstract Silicon nanoparticles (SNP) are among the best options to choose from for the design of devices for renewable energies; SNP based material performance can be effectively tailored by controling the vacancy, temperature and other properties of the SNP. PMID- 30242748 TI - IL-1beta, IL-17A and combined phototherapy predicts higher while previous systemic biologic treatment predicts lower treatment response to etanercept in psoriasis patients. AB - BACKGROUND: This study aimed to explore the correlation of circulating inflammatory cytokines' levels with treatment response to etanercept (ETN) treatment in psoriasis patients. METHODS: 97 moderate-to-severe plaque-psoriasis patients were continuously recruited in this prospective cohort study, and all patients received ETN treatment. Serum samples were collected before and at 6 months (M6) after treatment, and nine inflammatory cytokines expressions were detected by enzyme-linked immuno sorbent assay. Psoriasis Area and Severity Index (PASI) score was evaluated at baseline (M0), 1 month (M1), 3 months (M3) and M6 after treatment, and the corresponding PASI 75/90 responses' rates were calculated. RESULTS: Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL) 1beta, IL-6, IL-12, IL-17A, IL-22, IL-23, and IL-32 levels were reduced, while IL 10 level was elevated at M6 after ETN treatment compared to baseline. PASI 75/90 responses' rates to ETN were 69.1 and 38.1% at M6, respectively. IL-1beta and IL 17A levels were elevated in PASI 75-response patients compared to PASI 75 non response patients, while IL-17A level was also increased in PASI 90-response patients compared to PASI 90 non-response patients. Multivariate logistic regression revealed that IL-1beta, IL-17A and combined phototherapy during study predicted higher, while previous systemic biologic treatment predicted lower PASI 75 response to ETN independently. In addition, IL-17A independently predicted higher PASI 90 response to ETN as well. CONCLUSIONS: IL-1beta, IL-17A, and combined phototherapy predicts higher while previous systemic biologic treatment predicts lower treatment response to ETN independently in psoriasis patients. PMID- 30242749 TI - Three-Dimensional Visualization of the Lymphatic Vasculature. AB - Like the circulatory blood vessel system, the dendriform lymphatic vascular system forms a disseminated organ that is virtually indispensible for the function of most other organs. Formation and maintenance of the correct topology are essential for lymph vessel physiology and hence analysis of its three dimensional architecture provides crucial functional information.Here we describe protocols for whole-mount immunostaining of the vessel systems in various mouse tissues, mouse fetuses, and human skin biopsies. The resulting samples are suited after flat mounting for confocal microscopy or after optical tissue clearing for light sheet microscopy. Both microscopic modalities use optical sectioning to generate image stacks from which the three-dimensional vessel structure can be digitally reconstructed. We introduce the open software package Voreen, developed at the University of Munster. Voreen has been adapted and extended for the interactive visualization of large multichannel image stacks on commodity hardware, allowing for a faithful digital representation of the spatial structure of the vessel systems in whole-mount stained tissue samples. PMID- 30242750 TI - Histological and Morphological Characterization of Developing Dermal Lymphatic Vessels. AB - The capacity to visualize the lymphatic vasculature in three-dimensions has revolutionized our understanding of the morphogenetic mechanisms important for constructing the lymphatic vascular network during development. Two complementary approaches are commonly employed to assess the function of genes and signaling pathways important for development of the dermal lymphatic vasculature in the mouse embryo. The first of these is whole-mount immunostaining of embryonic skin to analyze dermal lymphatic vessel network patterning and morphology in two and three dimensions. The second is immunostaining of thin tissue sections to examine lymphatic vessel identity, lumen formation and protein localization within discrete lymphatic endothelial cells in a two-dimensional setting. Here we present detailed protocols for multicolor immunofluorescent immunostaining of embryonic dorsal skin and thin tissue cryosections. Each of these methods generates high-resolution images of the dermal lymphatic vasculature, yielding information integral to in-depth characterization of lymphatic vessel phenotypes in the developing mouse embryo. PMID- 30242751 TI - Genetic Lineage Tracing of Lymphatic Endothelial Cells in Mice. AB - Lineage tracing allows for identification of all progeny produced by a single cell or groups of cells and can thus be used to assess developmental fate of cells. Here we focus on one of the most widely used lineage tracing approaches that utilize the Cre/loxP system for site-specific genetic recombination in studying the developmental origins of lymphatic endothelial cells (LECs) in the mouse embryo. We discuss general considerations for a successful Cre/loxP based lineage tracing experiment and provide information about strains that are available for genetic lineage tracing of LECs. A protocol for lineage tracing analysis of the lymphatic vasculature by whole-mount immunofluorescence in two embryonic tissues, the skin and the mesentery, is also provided. PMID- 30242747 TI - Impact of oversedation prevention in ventilated critically ill patients: a randomized trial-the AWARE study. AB - BACKGROUND: Although oversedation has been associated with increased morbidity in ventilated critically ill patients, it is unclear whether prevention of oversedation improves mortality. We aimed to assess 90-day mortality in patients receiving a bundle of interventions to prevent oversedation as compared to usual care. METHODS: In this randomized multicentre trial, all adult patients requiring mechanical ventilation for more than 48 h were included. Two groups were compared: patients managed according to usual sedation practices (control), and patients receiving sedation according to an algorithm which provided a gradual multilevel response to pain, agitation, and ventilator dyssynchrony with no specific target to alter consciousness and no use of sedation scale and promoted the use of alternatives to continuous infusion of midazolam or propofol (intervention). RESULTS: Inclusions were stopped before reaching the planned enrolment. Between 2012 and 2014, 584 patients were included in the intervention group and 590 in the control group. Baseline characteristics were well balanced between groups. Although the use of midazolam and propofol was significantly lower in the intervention group, 90-day mortality was not significantly lower (39.4 vs. 44.2% in the control group, p = 0.09). There were no significant differences in 1-year mortality between the two groups. The time to first spontaneous breathing trial and time to successful extubation were significantly shorter in the intervention group than in the control group. These last results should be interpreted with precaution regarding the several limitations of the trial including the early termination. CONCLUSIONS: This underpowered study of severely ill patients was unable to show that a strategy to prevent oversedation could significantly reduce mortality. Trial registration NCT01617265. PMID- 30242752 TI - Visualization and Tools for Analysis of Zebrafish Lymphatic Development. AB - The accessibility and optical transparency of the zebrafish embryo offers a unique platform for live-imaging of developmental lymphangiogenesis. Transgenic lines labelling lymphatic progenitors and vessels enable researchers to visualize cellular processes and ask how they contribute to lymphatic development in genetic models. Furthermore, validated immunofluorescence staining for key signaling and cell fate markers (phosphorylated Erk and Prox1) allow single cell resolution studies of lymphatic differentiation. Here, we describe in detail how zebrafish embryos and larvae can be mounted for high resolution, staged imaging of lymphatic networks, how lymphangiogenesis can be reliably quantified and how immunofluorescence can reveal lymphatic signaling and differentiation. These methods offer researchers the opportunity to experimentally dissect developmental lymphangiogenesis with outstanding resolution. PMID- 30242753 TI - Characterization of Zebrafish Facial Lymphatics. AB - Zebrafish are well-established as a model of vascular development. The genetic tractability, external development, permeability to small molecules and optical transparency of zebrafish larvae are all attributes that make this model attractive to the vascular biologist. There are an increasing number of lymphatic reporter lines that enable the visualization of zebrafish lymphatic vessel growth in vivo; these tools, coupled with either forward or reverse genetics, have provided new insights into the process of lymphatic specification and development. Zebrafish larvae have three main lymphatic networks: the trunk lymphatics, the intestinal lymphatics, and the facial lymphatics and it is therefore possible to use zebrafish to determine network-specific roles for molecules implicated in lymphatic development. This chapter provides protocols for visualization and analysis of facial lymphatic development in the zebrafish and may be applied in developmental or drug discovery studies. PMID- 30242754 TI - Correlative Fluorescence and Scanning Electron Microscopy to Study Lymphovenous Valve Development. AB - Lymph collected from throughout the body is exclusively returned to blood circulation via two pairs of bilaterally located lymphovenous valves. Lymphovenous valves share numerous similarities with lymphatic and venous valves and are defective in multiple mouse models of lymphedema or lymphatic dysfunction. Here we describe a protocol that combines the strengths of fluorescence microscopy and scanning electron microscopy to precisely locate and analyze the topography of developing lymphovenous valves at high resolution. PMID- 30242755 TI - Characterization of Mouse Mesenteric Lymphatic Valve Structure and Function. AB - Intraluminal valves of collecting lymphatic vessels ensure unidirectional lymph transport against hydrostatic pressure gradient. Mouse mesentery harbors up to 800 valves and represents a convenient model for lymphatic valve quantification, high resolution imaging of different stages of valve development as well as for analysis of valve function. The protocol describes embryonic and postnatal mesenteric lymphatic vessel preparation for whole-mount immunofluorescent staining and visualization of valve organization, quantification of main morphological parameters such as valve size and leaflet length, and the quantitative assessment of functional properties of adult valves using back-leak and closure tests. PMID- 30242756 TI - Morphological Analysis of Lacteal Structure in the Small Intestine of Adult Mice. AB - The lacteal is a blunt-ended lymphatic capillary located at the center of a villus in the small intestine that plays multifaceted roles under both physiologic and pathologic conditions. However, studies of its biology are limited by the lack of a feasible method to visualize all the relevant components for its regulation. Here, we describe an efficient whole-mount protocol to visualize the intact structure of lacteals and surrounding cells in villi of the small intestine of adult mouse. PMID- 30242757 TI - Morphological and Functional Analysis of CNS-Associated Lymphatics. AB - The study of meningeal lymphatic vessels of the central nervous system (CNS) has recently gathered momentum, with several papers dissecting their role in draining solutes from cerebrospinal fluid and brain (Louveau et al., Nature 523(7560):337 341, 2015; Antila et al., J Exp Med 214(12):3645-3667, 2017; Aspelund et al., J Exp Med 212(7):991-999, 2015). Methodological capabilities, however, have been limited to few laboratories due to difficulties reproducibly visualizing these rare cell subsets in the meninges. To explore meningeal lymphatics fundamental role during homeostasis and how they may contribute to human pathology, the field has begun to require purification and characterization of lymphatic endothelial cells. Here, modern cell biological techniques involving a combination of histological, flow-cytometric, and functional drainage assays are applied to brain and spinal cord meninges and detailed stepwise procedures used for successful in vivo and ex vivo characterization of meningeal lymphatic vessels. PMID- 30242758 TI - Morphological Analysis of Schlemm's Canal in Mice. AB - Immunofluorescent confocal microscopy is a powerful tool for analysis of the morphology and development of vascular and lymphatic tissues. Schlemm's canal (SC) is a large, lymphatic-like vessel in the anterior chamber of the eye, which is essential for aqueous humor drainage required to maintain intraocular pressure and is sensitive to defects in blood and lymphatic vascular signaling pathways. Here, we describe a method to stain and quantify SC area and morphology in enucleated mouse eyes, providing a tool for understanding its development and function in small animal genetic or disease models. PMID- 30242759 TI - Imaging Lymphatics in Mouse Lungs. AB - Lymphatic malformations and other conditions where lymphatic function is disturbed in the respiratory tract present diagnostic and therapeutic challenges. Advances in lymphatic development, growth regulation, function, and imaging have increased the understanding of lymphatics, but the airways and lungs have not received as much attentions as many other organs. The lung presents challenges for studies of lymphatics because of the complex, densely packed three dimensional architecture of the airways and vasculature, and because it cannot readily be examined in its entirety. To address this problem, we developed methods for immunohistochemical examination of the lymphatics in mouse lungs, based on approaches we devised for lymphatic vessels and blood vessels in whole mounts of the mouse trachea. This report provides a practical guide for visualizing by fluorescence and confocal microscopy the lymphatics in mouse airways and lungs under normal conditions and in models of disease. Materials and methods are described for immunohistochemical staining of lymphatics in whole mounts of the mouse trachea and 200-MUm sections of mouse lung. Also described are mouse models in which lymphatics proliferate in the lung, blocking antibodies for preventing lymphatic growth, methods for fixing mouse lungs by vascular perfusion, and techniques for staining, visualizing, and analyzing lymphatic endothelial cells and other cells in the lung. These methods provide the opportunity to learn as much about lymphatics in the lung as in other organs. PMID- 30242760 TI - Imaging of Endothelial Cell Dynamic Behavior in Zebrafish. AB - In recent years, use of the zebrafish embryo as a model organism to study vascular development in vivo has provided valuable insights into the genetic and cellular events shaping the embryonic vasculature. In this chapter, we aim to present the methods for the measurement of some of the most commonly investigated dynamic parameters in endothelial cells during developmental angiogenesis, namely, migration speed and acceleration, filopodia extension, front-rear polarity, cell cycle progression, membrane deformations, and junctional rearrangements. We also offer suggestions on how to deal with the most common imaging and quantifications challenges faced when acquiring and quantifying endothelial cell dynamic behavior in vivo.We intend this section to serve as an experience-based imaging primer for scientists interested in endothelial cell imaging in the zebrafish embryo. PMID- 30242761 TI - Visualization and Measurement of Lymphatic Function In Vivo. AB - An increased research focus on the lymphatic system has necessitated the development of reliable in vivo assessments of lymphatic function in rodent models. Here, we provide three protocols for assays based upon near-infrared fluorescence imaging that were developed in our laboratory that can visualize and quantify different aspects of lymphatic function in mice. The first, a protocol for the tracking of the clearance of an injected intradermal bolus of a pegylated tracer, provides a measurement of lymphatic function in a specific region of the skin. The second assay allows noninvasive imaging of the contractility of collecting lymphatic vessels of the lower limb after injection of the pegylated tracer into the paw skin. This assay also enables real-time visualization of the routing of lymphatic flow from the paw to draining lymph nodes. The final protocol describes invasive imaging of the contractility and valve function of a collecting lymphatic vessel connecting the inguinal and axillary lymph nodes. This assay allows compounds to be added directly on the collecting lymphatic vessel and responses in contraction frequency and amplitude to be measured. PMID- 30242762 TI - Investigating Effects of Fluid Shear Stress on Lymphatic Endothelial Cells. AB - Recent studies using in vivo models have characterized lymph flow and demonstrated that lymph flow plays a key role in the later stages of lymphatic vascular development, including vascular remodeling, to create a hierarchical collecting vessel network and lymphatic valves (Sweet et al., J Clin Invest 125, 2995-3007, 2015). However, mechanistic insights into the response of lymphatic endothelial cells to fluid flow are difficult to obtain from in vivo studies because of the small size of lymphatic vessels and the technical challenge of lymphatic endothelial cell isolation. On the other hand, in vitro experiments can be tailored to isolate and test specific mechanotransduction pathways more cleanly than conditions in vivo. To measure in vitro the cellular response to flow, cultured primary lymphatic endothelial cells can be exposed to highly specific fluid forces like those believed to exist in vivo. Such in vitro studies have recently helped identify FOXC2 and GATA2 as important transcriptional regulators of lymphatic function during valve formation that are regulated by lymph flow dynamics. This chapter discusses the methods used to expose primary lymphatic endothelial cells (LECs) to lymph fluid dynamics and the relationship of these in vitro studies to in vivo lymphatic biology. PMID- 30242763 TI - Methods for Assessing the Contractile Function of Mouse Lymphatic Vessels Ex Vivo. AB - Lymphatic contractile dysfunction has been identified in several diseases, including lymphedema, yet a detailed molecular understanding of lymphatic muscle physiology has remained elusive. With the advent of genetic methods to manipulate gene expression in mice, a set of new tools became available for the investigation and visualization of the lymphatic vasculature. To gain insight into the molecular regulators of lymphatic contractile function, regulated primarily by the muscle cell layer encircling lymphatic collecting vessels, ex vivo approaches to allow control of hydrostatic and oncotic pressures and flow have been invaluable, complementing in vivo methods. While the original ex vivo techniques were developed for lymphatic vessels from large animals, and later adapted to rat vessels, here we describe modifications that enable the study of isolated, pressurized murine lymphatic collecting vessels. These methods, used in combination with transgenic mice, can be a powerful tool to investigate the molecular and cellular mechanisms of lymphatic function. PMID- 30242764 TI - Evaluation and Characterization of Endothelial Cell Invasion and Sprouting Behavior. AB - Here, we describe highly reproducible methods to investigate human EC invasion and sprouting behavior in 3D collagen matrices. Two assay models are presented whereby ECs are induced to sprout from a monolayer surface or from aggregated ECs suspended within a collagen gel matrix. In each case, the assays are performed using serum-free defined media containing a combination of five growth factors (Factors): FGF-2, SCF, IL-3, SDF-1alpha, and insulin. In both models, marked EC sprouting occurs with leading EC tip cells over a 12-24 h period. To illustrate their utility, we present data showing the influence of various pharmacologic inhibitors directed to membrane-type matrix metalloproteinases (MT-MMPs), protein kinase C alpha (PKCalpha), Src family kinases, and Notch-dependent signaling. Marked inhibition of sprouting is observed after blockade of MT-MMPs and PKCalpha, while strong increases in sprouting and EC tip cell number is observed following blockade of Src kinases, Notch signaling or both. Interestingly, the increased sprouting behavior observed following Src or Notch blockade directly correlates with a loss in the ability of ECs to form lumens. These defined in vitro assay models allow for a genetic and signaling dissection of EC tip cells vs. lumen forming ECs, which are both necessary for the formation of branching networks of tubes during vascular morphogenic events. PMID- 30242765 TI - Dorsal Ear Skin Window for Intravital Imaging and Functional Analysis of Lymphangiogenesis. AB - Postdevelopmental lymphangiogenesis occurs in chronic inflammation and wound healing, and here we describe a window preparation in the mouse ear in which lymphangiogenesis can be observed and manipulated. This model has many advantages, including access for intravital immunostaining and imaging to assess morphological features and regeneration kinetics, as well as functional assays such as lymphatic clearance. We describe five procedures: (1) the creation of a collagen-fibrin-filled window in the mouse ear as a model for regenerative lymphangiogenesis, (2) intravital immunostaining for live analysis of morphology and structure, (3) lymphatic clearance assay for functional quantification, (4) whole-mount imaging with tissue clearing for confocal imaging, and (5) postmortem lymphangiography. These procedures allow for identification of morphological and functional abnormalities in both preexisting and newly formed lymphatic vessels. PMID- 30242766 TI - Isolation of Human Skin Lymphatic Endothelial Cells and 3D Reconstruction of the Lymphatic Vasculature In Vitro. AB - Studies of lymphangiogenesis and lymphatic endothelial biology in vitro require pure cultures of lymphatic endothelial cells and 3D vascular constructs, which closely resemble native human lymphatic vasculature. We describe a method for the isolation of human dermal microvascular lymphatic endothelial cells and generation of a 3D lymphatic capillary network. The lymphatic vascular construct is generated by coculturing primary lymphatic endothelial cells and fibroblasts in their native matrix, without the use of synthetic scaffolds or exogenous factors. The tissue is stable over many weeks and accurately recapitulates features of human dermal lymphatic microvasculature. PMID- 30242767 TI - Stimulation and Inhibition of Lymphangiogenesis Via Adeno-Associated Viral Gene Delivery. AB - The lymphatic vessels can be selectively stimulated to grow in adult mice, rats and pigs by application of viral vectors expressing the lymphangiogenic factors VEGF-C or VEGF-D. Vice versa, lymphangiogenesis in various pathological settings can be inhibited by the blocking of the VEGF-C/VEGFR3 interaction using a ligand binding soluble form of VEGFR3. Furthermore, the recently discovered plasticity of meningeal and lacteal lymphatic vessels provides novel opportunities for their manipulation in disease. Adenoviral and adeno-associated viral vectors (AAVs) provide suitable tools for establishing short- and long-term gene expression, respectively and adenoviral vectors have already been used in clinical trials. As an example, we describe here ways to manipulate the meningeal lymphatic vasculature in the adult mice via AAV-mediated gene delivery. The possibility of stimulation and inhibition of lymphangiogenesis in adult mice has enabled the analysis of the role and function of lymphatic vessels in mouse models of disease. PMID- 30242768 TI - Isolation and Characterization of Mouse Organ-Specific Endothelial Transcriptomes. AB - Endothelial cells play an essential role in homeostasis and regeneration and their transcriptional profile has been found to be tissue specific. Here we describe the isolation of organ specific mouse endothelial cells using either magnetic beads or fluorescence-activated cell sorting. This efficient protocol should allow for the transcriptional characterization of organotypic endothelial cells. PMID- 30242769 TI - Single-Cell mRNA Sequencing of the Mouse Brain Vasculature. AB - In this chapter, we describe a method for analyzing the vasculature of the mouse brain using single-cell transcriptomics. More specifically, we focus on the use of fluorescence-activated cell sorting (FACS) for selection of the cells of interest and sorting of these cells in a 384-well format, allowing for enrichment for the cells being studied. Furthermore, we outline the Smart-Seq2 single-cell library construction method for transforming single-cell mRNA into Illumina sequencing compatible libraries. As single-cell sequencing is still a costly technology, we take special care to describe strategies to include many quality control steps. Finally, we touch upon techniques to convert the sequencing data into a meaningful biological readout. The methods reported in this chapter can be expanded toward other tissues and will prove useful also for the study of different cell types beyond adult brain vasculature. PMID- 30242770 TI - Metabolic Analysis of Lymphatic Endothelial Cells. AB - Metabolism is pivotal for formation of the lymphatic vasculature. Understanding metabolism in lymphatic endothelial cells (LECs) requires quantitative characterization of specific metabolic pathways. Here we describe methods for using radioactive tracers to assess flux rates of glycolysis, fatty acid beta oxidation, glucose oxidation, and glutamine oxidation. We also provide a detailed method for utilizing mass spectrometry (MS) to measure glycolytic intermediates and ATP. PMID- 30242771 TI - Characterizing Epigenetic Changes in Endothelial Cells. AB - Chromatin immunoprecipitation (ChIP) is an antibody-based method used to identify protein-DNA interactions and sites of protein modifications to chromatin in living cells. ChIP is a powerful method for identifying genomic sites at which epigenetic changes occur in cell types of interest because many antibodies have been developed that recognize specific epigenetic modifications of histone tails. This chapter provides detailed ChIP and subsequent polymerase chain reaction (ChIP-PCR) protocols for use in cultured endothelial cells. These protocols will allow investigators to make consistent and quantitative discoveries about epigenetic changes that occur in endothelial cells at specific genomic sites under varying treatment conditions. PMID- 30242772 TI - Selection of EMR and ESD for Laterally Spreading Lesions of the Colon. AB - INTRODUCTION: Colonic laterally spreading lesions (LSL) are increasingly managed using endoscopic methods that comprise two main techniques: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). PURPOSE OF REVIEW: In this review, we aimed to review the most recent literature on selection of the best endoscopic technique in the management of colonic LSL. RECENT FINDINGS: EMR and ESD are complimentary techniques in the management of patients with colonic LSL. EMR is safe and effective in most patients with LSL, except for cancers with submucosal invasion in whom R0 resection is favored. PMID- 30242774 TI - Can Arginase Inhibitors Be the Answer to Therapeutic Challenges in Alzheimer's Disease? AB - While the extensive hunt for therapeutics combating Alzheimer's disease (AD) has fallen short of delivering effective treatments, breakthroughs towards understanding the disease mechanisms and identifying areas for future research have nevertheless been enabled. The majority of clinical trials with beta- and gamma-secretase modulators have been suspended from additional studies or terminated due to toxicity issues and health concerns. The lack of progress in developing innovative AD therapies has also prompted a resurgence of interest in more traditional symptomatic treatments with cholinesterase inhibitors and N methyl-D-aspartate receptor antagonists, as well as in the research of immune response modulators. Recently, evidence has emerged showing that inhibitors of arginine metabolism and in particular blockers of arginase, an enzyme that catalyzes the breakdown of L-arginine, could present an effective therapeutic candidate for halting the progression of AD and boosting cognition and memory. In this commentary, we present a brief overview of reports on arginase inhibitors in AD mouse models and discuss emerging advantages and areas for careful consideration on the road to clinical translation. PMID- 30242775 TI - Trends in Lumpectomy and Oncoplastic Breast-Conserving Surgery in the US, 2011 2016. AB - BACKGROUND: Oncoplastic breast surgery aims to optimize efficacy of surgical resection and cosmesis to maximize patient satisfaction; however, despite the benefits, oncoplastic techniques have not been widely adopted in the US. This study examined trends in the incidence of lumpectomy (partial mastectomy) with or without oncoplastic techniques from 2011 to 2016. METHODS: This was a retrospective analysis of claims from the Optum Clinformatics database (January 2010-March 2017). Female patients with no history of breast surgery in the prior year were categorized into three independent cohorts: isolated lumpectomy (Lx), lumpectomy with tissue transfer (LxTT), or lumpectomy with mammaplasty and/or mastopexy (LxMM). Oncoplastic techniques (in cohorts two and three) were performed at either time of the initial lumpectomy or during 90-day follow-up. RESULTS: Overall, 19,253 patients met the inclusion criteria (91.1% Lx, 5.2% LxTT, and 3.7% LxMM). Significantly fewer patients with Lx had a family history of breast cancer compared with patients with oncoplastic techniques (26.4% vs. 33.7% and 37.9%, respectively; p < 0.001). The incidence of Lx declined significantly from 2011 (92.9%) to 2016 (88.1%), while LxTT and LxMM increased from 4.2 to 7.2% and 2.8 to 4.7%, respectively (both p < 0.001). The greatest utilization of oncoplastic techniques was observed in the Pacific census division (19.2%), while lowest utilization was in the East South Central division (3.2%; p < 0.001). CONCLUSIONS: While increased adoption of oncoplastic techniques was observed, the compound annual growth rate remained below 10% and varied significantly by region. Further adoption of oncoplastic techniques is necessary to improve cosmetic outcomes and patient satisfaction following breast-conserving surgery. PMID- 30242773 TI - Disparities in Cardiac Care of Women: Current Data and Possible Solutions. AB - PURPOSE OF REVIEW: Cardiovascular disease remains the leading cause of death in women. The goal of this review is to address known disparities in cardiovascular care with regard to diagnosis and treatment of heart disease in women. RECENT FINDINGS: Gender-specific differences in regard to the incidence, treatment, and outcomes of common cardiovascular pathology are increasingly recognized. Particular attention to ischemic heart disease, arrhythmia, congestive heart failure, and structural heart disease are reviewed in this article. There is a clear racial and ethnic discrepancy among women which is particularly concerning with a progressively diverse patient population. Medical and surgical treatment differences between men and women must be addressed by providers in order to optimize long-term outcomes among all patients. Understanding the unique cardiovascular risk profile and barriers to optimal treatment outcomes in women is imperative to eliminate the current disparities in cardiovascular disease. PMID- 30242776 TI - ASO Author Reflections: Complications in Urinary Tract Extirpation. PMID- 30242777 TI - HIPEC in the Elderly: A Meta-Analysis. PMID- 30242778 TI - Intra-Vial Heterogeneity in Physical Form of Mannitol in Colyophilized Binary Systems. AB - PURPOSE: To study spatial heterogeneity in phase composition when mannitol is co lyophilized with non-crystallizing lyoprotectant, such as sucrose or trehalose. To study the influence of formulation composition and processing conditions on the extent of mannitol hemihydrate (MHH) formation in the final lyophile. METHODS: We used synchrotron X-ray diffractometry (XRD) to spatially map and thereby comprehensively characterize mannitol phase composition in unperturbed lyophiles. Low temperature thermal analysis and XRD was used to study phase behavior of frozen systems. RESULT: When colyophilized with sucrose, trehalose or lysozyme as a second solute, mannitol crystallized partially as MHH (mannitol hemihydrate). The MHH content, based on the intensity of characteristic MHH peak (d-spacing 4.92 A), was highest in the middle region of lyophile. This heterogeneity, studied in detail in presence of sucrose, occurred irrespective of cosolute content. Annealing the frozen solution at -30 degrees C for 2 h essentially eliminated the heterogeneity, accompanied by an overall increase in MHH content. From differential scanning calorimetry it was evident that annealing caused mannitol crystallization while XRD revealed the crystallizing phase to be MHH. CONCLUSION: The intra-vial heterogeneity and total MHH content in the final lyophile is a complex interplay of formulation composition and processing conditions. Graphical Abstract Figure depicting spatial heterogeneity in mannitol hemihydrate content, when mannitol is lyophilized with a cosolute, such as sucrose, trealose or lysozyme. PMID- 30242779 TI - Factors affecting the milk yield and composition over lactation of prolific D'man ewes in Tunisian oases. AB - This work aimed to investigate milk potentiality and the influence of some non genetic factors both on milk yield production and composition in prolific D'man sheep. Observations were performed in eighty lactating D'man ewes maintained under an intensive oases system in Southern Tunisia. Daily milk yield was determined at 7-day intervals using oxytocin + hand milking method. Chemical milk composition was determined by Lactoscan. Total productions over lactation (milk, fat, and protein) were estimated using the Fleischmann method. Daily milk yield averaged 1.64 +/- 0.02 l. It increased to a plateau from the third to the fourth week of lactation, and decreased gradually to the tenth week. D'man ewes produced 128.91 +/- 3.14 l of milk, 9.23 +/- 0.26 kg of fat, and 5.26 +/- 0.12 kg of total proteins. Overall, milk contained 16.17% of total solids, 7.08% of fat, 4.04% of proteins, 4.32% of lactose, 9.09% of solids-not-fat, and 0.73% of ash. Lambing season affected the daily milk yield and milk composition, where fat and total proteins were highest in autumn. Total solids, lactose, solids-not-fat, and ash were higher in winter than in autumn and summer. Ewes reared multiple lambs produced more milk than those reared singles. Dams nursing triplets or more had the highest milk total proteins, and the lowest total solids and fat levels. Adult ewes produced more milk compared to younger and older ewes, and their milk contained higher total solids, fat, and ash levels than milk from young ewes. Ewes with asymmetric udder produced less and more concentrated milk than ewes with symmetrical udder. Daily milk yield was negatively correlated to total solids, fat, and total proteins amounts. In contrast, litter survival at weaning was positively correlated to the amounts of total milk, fat, and total proteins. PMID- 30242780 TI - 3D Brain Imaging in Vascular Segmentation of Cerebral Venous Sinuses. AB - The three-dimensional (3D) visualization of dural venous sinuses (DVS) networks is desired by surgical trainers to create a clear mental picture of the neuroanatomical orientation of the complex cerebral anatomy. Our purpose is to document those identified during routine 3D venography created through 3D models using two-dimensional axial images for teaching and learning neuroanatomy. Anatomical data were segmented and extracted from imaging of the DVS of healthy people. The digital data of the extracted anatomical surfaces was then edited and smoothed, resulting in a set of digital 3D models of the superior sagittal, inferior sagittal, transverse, and sigmoid, rectus sinuses, and internal jugular veins. A combination of 3D printing technology and casting processes led to the creation of realistic neuroanatomical models that include high-fidelity reproductions of the neuroanatomical features of DVS. The life-size DVS training models were provided good detail and representation of the spatial distances. Geometrical details between the neighboring of DVS could be easily manipulated and explored from different angles. A graspable, patient-specific, 3D-printed model of DVS geometry could provide an improved understanding of the complex brain anatomy. These models have various benefits such as the ability to adjust properties, to convert two-dimension images of the patient into three-dimension images, to have different color options, and to be economical. Neuroanatomy experts can model such as the reliability and validity of the designed models, enhance patient satisfaction with improved clinical examination, and demonstrate clinical interventions by simulation; thus, they teach neuroanatomy training with effective teaching styles. PMID- 30242781 TI - Correction to: Phlegmonous appendicitis in children is characterized by eosinophilia in white blood cell counts. AB - The original article can be found online. PMID- 30242782 TI - Factors Affecting the Management of Somatic Comorbidity in Tunisian Patients with Schizophrenia. AB - Schizophrenia is often accompanied by somatic comorbidities, which make the management challenge of such patients more difficult. In this study, we proposed to identify the sociodemographic and clinical factors correlating with somatic comorbidities in patients with schizophrenia to facilitate screening and prevention. It was a retrospective descriptive study of 78 schizophrenia patients in clinical remission and followed in outpatient psychiatry. In addition to the acquired records, other data were provided by the clinical and biological examinations performed for each patient. The evaluation of the therapeutic adherence was carried out using the Drug Attitude Inventory (DAI).Seventy-six patients (97.4%) had somatic comorbidities with a mean of 3.83 (+/- 1.81). This number increased significantly in males, older patients, couples, urban patients, and those receiving a combination therapy. According to a multivariate study, the four predictors of an increased risk of comorbidities were age, use of psychoactive substances, waist size and therapeutic adherence.Our findings focus on somatic comorbidities risk in schizophrenia patients, requiring particular vigilance in their follow-up, and suggest some modifiable clinical factors that might be a preferred target for reducing or preventing the occurrence of such disorders. PMID- 30242783 TI - Correction to: Chemotherapy and targeted therapy for breast cancer patients with hepatitis C virus infection. AB - The online version of the original article can be found. PMID- 30242784 TI - Implementing a condensed dialectical behavior therapy skills group for binge eating behaviors in adolescents. AB - PURPOSE: Subthreshold binge-eating disorder (BED) symptoms can lead to additive physical and psychological health challenges and may put youth at risk for developing BED during the early adulthood. We examined the implementation of a condensed dialectical behavior therapy (DBT) skills intervention for subthreshold binge-eating behaviors in adolescents. METHODS: Fifteen 14-18 years old participated in a 10-week DBT skills group, which experientially introduced mindfulness, distress tolerance, emotion regulation, and interpersonal effectiveness skills in the context of emotionally driven overeating behaviors. Adolescents and caregivers completed measures of emotional eating and binge eating behaviors at baseline and post-intervention, including the Eating Disorder Examination Questionnaire and Emotional Eating Scale for Children and Adolescents. Eleven participants were retained at 3-month follow-up. RESULTS: Descriptive statistics were compared at all three time points. Results suggested a reduction in emotional eating and binge-eating behaviors based on youth self report and caregiver report. Acceptability ratings of the treatment were high among participants completing the intervention. CONCLUSIONS: Using DBT skills to target emotionally driven overeating behaviors in youth may be useful in the treatment of subthreshold BED behaviors and potentially deter future development of full-criteria BED. LEVEL OF EVIDENCE: Level IV, uncontrolled pilot trial. PMID- 30242785 TI - Characterization of Senescence of Human Adipose-Derived Stem Cells After Long Term Expansion. AB - INTRODUCTION: Since the 1980s, adipose-derived stem cells (ASCs) have become a powerful and potential source for stem cell-based therapy, regenerative medicine, and even drug delivery in cancer treatment. The development of off-the-shelf mesenchymal stem cells (MSCs), including ASCs, has rapidly advanced in recent years with several clinical trials and approved products. In this technology, ASCs should be expanded long term in order to harvest higher cell number. In this study, senescence of ASCs after long-term expansion was evaluated. METHODS: Human ASCs (hASCs) were isolated and cultured continuously at a density of 103 cells/cm2 up to passage 15. The cells were assessed for aging via changes in the following: characteristics of MSCs, mitochondrial activity, accumulation of beta galactosidase, and expression of tumor suppressor genes. RESULTS: The results showed that following in vitro expansion to the 15th passage, ASCs did not show changes in immunophenotype, except for decreased expression of CD105. However, the cells increased in size and in shape and complexity (toward the "fried egg" morphology). They also almost ceased to proliferate in passage 15. Nonetheless, they maintained in vitro differentiation potential toward osteoblasts, chondrocytes, and adipocytes. Expression of tumor suppressor genes p53 and p16 did not significantly change, while p27 was significantly downregulated. Mitochondrial activities also decreased slightly in culture from passage 5 to passage 10 and remained stable to passage 15. ASCs also showed increased accumulation of beta-galactosidase in culture, but it was negligible. CONCLUSION: In conclusion, hASCs exhibited some particular characteristics of aged stem cells when the number of subculture cells increased. However, up to passage 10, ASCs also retained almost all of the characteristics of MSCs. PMID- 30242787 TI - Inhibition of Cross-Reactive Carbohydrate Determinants in Allergy Diagnostics. AB - Despite being clinically largely irrelevant, antibodies against cross-reactive carbohydrate determinants (CCD) are an important issue in the in vitro diagnostics, as they may produce false positive or falsely elevated results of the immunoglobulin E class (asIgE) in relation to the actually present level of asIgE. The present chapter demonstrates an effective resolution of this diagnostic issue by the use of a CCD inhibitor in in vitro tests. A synthetic CCD inhibitor, Polycheck(r) CCD inhibitor, was used in the laboratory diagnostics of 24 children diagnosed with allergic diseases. The anti-CCD antibody content was measured in the serum using a Polycheck(r) Atopic 30-I panel (Biocheck GmbH; Munster, Germany), a screening assay for the quantitative determination of multiple allergen-specific IgE. We found that the baseline anti-CCD antibody content, without the CCD inhibitor, ranged from 0.7 to 3.5 kU/L in the sera of the majority of 16 out of 24 children. When the CCD inhibitor was applied, the anti-CCD antibody content decreased in 16, remained unchanged in 3, and increased in 5 samples. In samples positive for plant allergens, the asIgE content dropped by an average of 72% when the CCD inhibitor was used in the assay, except the antibodies to tree and grass pollen allergens, for which the asIgE content remained above 100 kU/L. We conclude that the use of a CCD inhibitor in in vitro assays is a viable option to mitigate the influence of anti-CCD antibodies on the measured level of asIgE immunoglobulin, which increase the reliability of testing particularly in cases displaying multiple allergies. PMID- 30242786 TI - Effects of Exposure to Carbon Dioxide in Potash Miners. AB - Potash miners can become exposed to carbon dioxide (CO2) during the blasting of basalt intrusions or loading and transporting the blasted salt. In a cross-shift study, we compared physiological effects of acute exposure to elevated CO2 concentrations in miners after long-term exposure to evaluate the possible health risks. A group of 119 miners was assessed by clinical examination, lung function tests, and blood gas content directly before and after the shift. A cumulative CO2 exposure was measured using personal monitors. The miners were categorized as low (<0.1 vol.%, n = 83), medium (<0.5 vol.%, n = 26), and high (>0.5 vol.%, n = 10) CO2 exposed subjects. We found no significant differences among the three groups. Lung function testing revealed no conspicuous findings, and chronic health effects were not observed in the miners either. In conclusion, no significant adverse effects could be found in potash miners exposed to elevated CO2 concentrations. Therefore, the mining authorities allow potash mining operations for 4 h at ambient CO2 up to 1.0 vol.% and for 2 h at CO2 not exceeding 1.5 vol.% per shift. PMID- 30242788 TI - Influence of Transurethral Resection of Bladder Cancer on Sexual Function, Anxiety, and Depression. AB - The standard of care in non-muscle invasive bladder cancer consists of transurethral tumor resection. The aim of this study was to evaluate the influence of transurethral resection of bladder tumor (TURB) on the patients' self-reported depression, anxiety, sexual satisfaction, and erectile dysfunction. Psychological condition of 252 male patients who underwent TURB was prospectively evaluated. The Hospital Anxiety and Depression Scale (HADS), simplified International Index of Erectile Function (IIEF-5), and Sexual Satisfaction Questionnaires (SSQ) were administered to patients before and 10 days after tumor resection. We found that primary anxiety, depression, and erectile dysfunction were all worse in cancer patients than those in the general population, and all further worsened after tumor resection. The post-resection worsening was influenced by the operation and catheterization time, complications, and the tumor characteristics. Taxonomical analysis shows that the greatest risk of depression aggravation concerned patients who were younger, had a higher body mass index, and a medium-sized tumor. We conclude that transurethral resection of non-muscle invasive bladder cancer may adversely affect sexual function, anxiety, and depression. Patients should be informed about potential complications to prevent the abandonment of a follow-up. The findings of this study stress the role of personalized medicine pursued by a multidisciplinary medical team. PMID- 30242789 TI - Development of pemphigoid nodularis after remission of bullous lesions. PMID- 30242790 TI - High-pressure non-invasive ventilation during exercise in COPD patients with chronic hypercapnic respiratory failure: A randomized, controlled, cross-over trial. PMID- 30242791 TI - Ingenol mebutate versus imiquimod versus diclofenac for actinic cheilitis: a 6 month follow-up clinical study. PMID- 30242792 TI - Retinal Ganglion Cell Replacement: Current Status and Challenges Ahead. AB - The neurons of the retina can be affected by a wide variety of inherited or environmental degenerations that can lead to vision loss and even blindness. Retinal ganglion cell (RGC) degeneration is the hallmark of glaucoma and other optic neuropathies that affect millions of people worldwide. Numerous strategies are being trialed to replace lost neurons in different degeneration models, and in recent years, stem cell technologies have opened promising avenues to obtain donor cells for retinal repair. Stem cell-based transplantation has been most frequently used for the replacement of rod photoreceptors, but the same tools could potentially be used for other retinal cell types, including RGCs. However, RGCs are not abundant in stem cell-derived cultures, and in contrast to the short distance wiring of photoreceptors, RGC axons take a long and intricate journey to connect with numerous brain nuclei. Hence, a number of challenges still remain, such as the ability to scale up the production of RGCs and a reliable and functional integration into the adult diseased retina upon transplantation. In this review, we discuss the recent advancements in the development of replacement therapies for RGC degenerations and the challenges that we need to overcome before these technologies can be applied to the clinic. PMID- 30242793 TI - A review of environmental enrichment as treatment for problem behavior maintained by automatic reinforcement. AB - We reviewed studies that used environmental enrichment as treatment for problem behavior maintained by automatic reinforcement. A search of behavior analytic journals produced 71 publications with a total of 265 applications of environmental enrichment used alone or in conjunction with alternative behavior manipulations (e.g., prompting, reinforcement) and problem behavior manipulations (e.g., blocking, restraint). Environmental enrichment, as a sole intervention, was efficacious in 41% of the sample. Alternative behavior manipulations, problem behavior manipulations, and a combination of both improved the overall efficacy of environmental enrichment. We discuss factors that may influence the efficacy of environmental enrichment, current trends in research on this topic, and implications for both practitioners and researchers. PMID- 30242794 TI - Emerging therapies in adult and paediatric bronchiectasis. AB - Bronchiectasis is a chronic respiratory disorder characterized by persistent productive cough and recurrent chest infections secondary to permanent structural airway damage. The current treatment strategies for this debilitating disorder are limited to prompt antibiotic treatment of infective exacerbations and regular airway clearance techniques. Despite its high morbidity and associated mortality across all age groups, it has been a neglected area of research in respiratory medicine and there remain no licensed disease-modifying therapies. In this review, we have explored the numerous potential therapeutic targets to break the vicious cycle of infection and inflammation seen in these patients and the novel therapeutic agents that have been developed to target them. We have reviewed the role of novel anti-inflammatory agents designed to target the persistent neutrophilic inflammatory infiltrate seen in bronchiectatic airways, including neutrophil elastase inhibitors, CXCR2 (CXC chemokine receptor 2) antagonists, DPP 1 (dipeptidyl peptidase 1) inhibitors, PDE4 (phosphodiesterase 4) inhibitors and statins. Furthermore, we have explored novel targets to improve mucociliary clearance, namely ENaC (epithelial sodium channel) inhibitors, and discussed the potential of alternative antimicrobial strategies such as inhaled phages. Our review highlights the importance of a multi-faceted approach to bronchiectasis management, which aims not only to eradicate or suppress bronchial infection but also to break the cycle of persistent airway inflammation that results in progressive lung damage in these patients. PMID- 30242795 TI - Changes of CD90 expression and immunoreactive cell localisation in rat dental pulp after cavity preparation. AB - CD90 expression and immunoreactive cell localisation in rat dental pulp cells after cavity preparation was investigated. Cavity preparation was performed on the maxillary first molar of 8-week-old Wistar rats (n = 36), and immunohistochemistry and quantitative real-time PCR were performed. CD90 immunoreactivity was observed among subodontoblastic cells in the control group. One day after cavity preparation, the CD90-immunoreactivity disappeared under the cavity area. While CD90-immunoreactivity was faint after 3 days, the re arrangement of odontoblasts was detected in contact with dentine. After 5 days, the odontoblasts were observed beneath the dentine, and CD90-immunoreactive cells were localised under the odontoblast layer. Immunofluorescence showed co localisation of CD90 and nestin was detected after 3 days. After 5 days, CD90 immunoreactivity increased at the subodontoblastic layer. mRNA expression of CD90 and DSPP decreased after cavity preparation, and gradually recovered (P < 0.01). These results suggest that CD90-immunoreactive cells in the subodontoblastic layer contribute to regeneration of odontoblast and subodontoblastic layers following cavity preparation. PMID- 30242796 TI - The Influence of Culture on Attitudes Towards Humanoid and Animal-like Robots: An Integrative Review. AB - PURPOSE: The aim of the present review is to explore the influence of culture on attitudes towards humanoid and animal-like robots. DESIGN: An integrative review of current evidence. METHODS: Medline, CINAHL, PsycInfo, PubMed, and Google Scholar were searched from 2000 to 2017. A total of 22 articles met the inclusion criteria and were retrieved and analyzed. FINDINGS: Culture influences attitudes and preferences towards robots, but due to the limitations of the reviewed studies, concrete conclusions cannot be made. More consistent evidence was found with regard to the influence of culture on nonverbal behaviors and communication styles, with people being more accepting of a robot that behaved more closely to their own culture. CONCLUSIONS: The research field of human-robot interaction provides the current evidence on the influence that culture has on attitudes towards humanoid and animal-like robots, but more research that is guided by strong theoretical frameworks is needed. CLINICAL RELEVANCE: With the increased use of humanoid robots in the healthcare system, it is imperative that nurses and other healthcare professionals explore and understand the different factors that can affect the use of robots with patients. PMID- 30242797 TI - Comparative in vivo constituents and pharmacokinetic study in rats after oral administration of ultrafine granular powder and traditional decoction slices of Chinese Salvia. AB - Salvia miltiorrhiza, one of the most well-known herbal medicines, is commonly used for the treatment of coronary heart diseases in China. Besides traditional decoction slices (TDS), another relatively new product of S. miltiorrhiza, ultrafine granular powder (UGP; D90 < 45 MUm), is also increasingly being used. In this paper, a UHPLC-LTQ-Orbitrap MS technique was developed for a metabolite profile study after oral administration of UGP and TDS of S. miltiorrhiza. The results showed that the number of in vivo absorbed compounds from UGP was much greater than that from TDS, and different types of products from S. miltiorrhiza will have different metabolic processes in vivo. Furthermore, a UHPLC-Q-Trap MS/MS method for simultaneously determining four tanshinones (tanshinone IIA, dihydrotanshinone I, tanshinone I and cryptotanshinone) was established and applied to assess the pharmacokinetics of the two types of products. All of the analytes displayed significant higher area under the concentration-time curve and peak concentration after oral administration of UGP than after TDS, indicating that ultrafine powder product could improve the bioavailability and absorption of cryptotanshinon,tanshinone II A,dihydrotanshinonE I and tanshinone I in vivo. The present study provides scientific information for further exploration of the pharmacology of these two types of S. miltiorrhiza and offers a reference for clinical administration of S. miltiorrhiza. PMID- 30242798 TI - Molecular Detection of Mycoplasma synoviae from Backyard and commercial Turkeys in Some Parts of Iran. AB - M. synoviae (MS) is an economically important pathogen and the major cause of airsacculitis and infectious synovitis in turkeys. Infection with this pathogen may remain asymptomatic but can render infected birds susceptible to secondary infections. This study was carried out for the molecular detection of MS infection in commercial and backyard turkey flocks in Tehran, Semnan, Isfahan, Qazvin, Zanjan, East Azerbaijan, Gilan, Mazandaran, and Golestan provinces of Iran. Sixty-hundred tracheal, choanal cleft or/and infraorbital sinus samples were collected from 18 commercial and 31 backyard turkey flocks. The polymerase chain reaction (PCR) technique was performed by using primers specific for detecting the 16S rRNA and vlhA genes of MS. The results showed that 51.61% of backyard and 33.33% of commercial farms were MS-positive. These findings suggested the molecular presence of MS, especially in northern and central regions of Iran. Further, the frequency of MS-positive samples was significantly lower in commercial farms than backyard farms (P<0.05). PMID- 30242799 TI - Prevalence of Canine Monocytic Ehrlichiosis in Canine Population Across India. AB - Canine ehrlichiosis is a very important emerging disease in India. This study is the first attempt screening a large number of canines in India for the detection of canine monocytic ehrlichiosis. In the present study, 510 blood samples of dogs were screened for the presence of Ehrlichia canis and other variants of Anaplasmataceae family by serological and molecular methods.Out of the 510 serum samples, 293 (57.5%) cases were found positive for the presence of E. canis antibodies through enzyme-linked immunosorbent assay (ELISA). Furthermore, and 45 (8.8%) and 1 (0.2%) specimens were positive for E. canis and A. platys, respectively, based on the polymerase chain reaction (PCR). In the clinical samples of E. canis, the minimum detection limit for PCR was9 ng. In the immunofluorescence assay (IFA), the positive blood samples showed comparable results with those obtained from the commercially available dot ELISA kit (giving equivalent IFA titer). The results of sequencing were compared with other reported isolates in various regions of the world, and a phylogenetic relationship was established. The 16S rRNA region that was amplified and sequenced for E. canis and A. platys was highly conserved and so was another Vir B9 region. PMID- 30242800 TI - Effect of Four Chicken Carcass Transportation Methods at Selected Room Temperatures on the Bacterial Load of Staphylococcus aureus, Salmonella species, and Escherichia coli. AB - Pathogenic bacteria are responsible for a significant number of food poisonings in humans through infected poultries. The main objective of this study was to assess the effect of transportation of chicken carcasses at 18-24, 4-5, and 10-14 oC on the bacterial loads of Staphylococcus aureus, Salmonella species, and Escherichia coli. This study was conducted on 180 fresh chicken carcasses (1197.0±19.88 g) randomly collected from a commercial poultry processing plant in southern Tehran, Iran, in a hot season in 2015. The sampling was performed at two stages, namely post-chilled washing and after 4 h of transportation. In the latter stage, the samples were selected from three vehicles with three types of temperatures. These vehicles included a pickup (18 24 oC), a refrigerated car (4-5 oC), and a refrigerated vehicle with switched off refrigerator (10-14 oC). According to the results, the whole body carcass samples transported at the pickup temperature had the highest mean total count (18.63×106±2.82×106 cfu.ml-1) and was greater (P<0.05) than the standard limit (5×106). On the other hand, the samples carried by the vehicle with switched off refrigerator had the lowest total count (0.65±0.04×106 cfu.ml-1). Similar results were obtained for S. aureus; accordingly, it reached the maximum (333.0±30.73 cfu.ml-1) at 18 24 oC, which was lower than the national standard limit even after 4 h of transportation. In addition, the cfu values for the total count and S. aureus sampled from the chicken carcasses were lower than the national standard level even after 4 h of carcass transportation, with the exception of Salmonella spp. at the three vehicle temperatures and E. coli at the pickup temperature. It was suggested that the transportation temperature of less than 10-14 oC could not affect the fresh chicken carcass to be contaminated with S. aureus and E. coli. PMID- 30242801 TI - Cloning of Clostridium Perfringens Iota Toxin Gene in Escherichia Coli. AB - Iota toxin is produced by Clostridium perfringens type E. This toxin causes antibiotic-associated enterotoxemia in lambs and calves. Iota toxin is a binary toxin that has two components including Ia (the enzyme component) and Ib (the binding component). Ib binds to the surface receptor of target cells and translocate Ia into the cytosol of cells. The aim of this study was to clone toxigenic epitope of iota a gene in E. coli strain Top10. In this study, the phenol–chloroform method was used for the extraction of the whole genomic DNA. The toxigenic epitope of iota a gene was amplified by polymerase chain reaction (PCR). The PCR product was ligated into the pTZ57R/T vector cloning site. Then, based on the TA-cloning method, the product was cloned in competent E. coli strain Top10. Colony PCR was used to screen bacterial colonies transformed with recombinant plasmids. The presence of 446-bp fragment on agarose gel showed that the toxigenic epitope of iota a gene of C. perfringens has been cloned in E. coli strain Top10. PMID- 30242802 TI - Effects of Essential Oils Combination on Sporulation of Turkey (Meleagris gallopavo) Eimeria Oocysts. AB - Avian coccidiosis is the most important parasitic disease in poultry production, which inflicts numerous losses to the industry. The extensive use of anticoccidial drugs leads to parasite resistance and drug residue in poultry products. In the present study, we aimed to investigate the effects of three famous essential oils (EOs) and their combination on inactivation of mixed oocysts of Eimeria adenoides, Eimeria dispersa, Eimeria meleagrimitis, and Eimeria meleagridis. The EOs of Thymus vulgaris, Artemisia sieberi, and Mentha pulegium were prepared. After inoculation of each turkey with 7×105 sporulated oocysts, fresh unsporulated oocysts were harvested from their feces. To evaluate the sporulation inhibition effect, 5×104 oocysts were used in each treatment. Each EO was used in increasing concentrations. Half maximal inhibitory concentration (IC50) was determined for each EO and they were blended in pairs based on IC50 line. Our results showed that the IC50 values for mentha, artemisia, and thyme were 22.92, 40.5, and 53.42 mg/ml, respectively. According to our results, artemisia and thyme combination has a synergistic effect, whereas the combination of a high concentration of mentha with a low concentration of thyme had an antagonistic effect. During this study, no interactions were observed between mentha and artemisia. PMID- 30242803 TI - The Effect of Oral Administration of Zinc Oxide Nanoparticles on Quantitative and Qualitative Properties of Arabic Ram Sperm and Some Antioxidant Parameters of Seminal Plasma in the Non-Breeding Season. AB - Zinc is an essential mineral and accepted as a trace element in the animal nutrition and for its role in biological enzymatic pathways. This study aimed to investigate the effect of oral administration of zinc oxide nanoparticles (ZnONPs) on some of the antioxidant parameters of semen plasma, quantitative and qualitative properties of Arabic ram sperm in the non-breeding season. Twelve adult Arabic rams (about 3-5 years old, 70 ±2.1 kg) were randomly assigned to receive one of the three levels of dietary ZnONPs (control; 0, group 1; 40 ppm and group 2; 80 ppm). Results showed that using different levels of ZnONPs increased the activity of superoxide dismutase enzyme (SOD) and total antioxidant capacity (TAC) of semen plasma significantly compared with the control group (P<0.05). Motility (74.83%), viability (76.90%), semen volume (1.76 ml) and sperm concentration (1418×106/ml) were significantly (P<0.05) higher in ZnONPs supplemented groups compared with the control group. The sperm morphological abnormalities reduced significantly in treated groups (10.46 and 9.07%) compared with the control group (12.66%; P <0.05). Also, the results suggested that 80 ppm level of ZnONPs increased the functionality of sperm membrane (44.38%) compared with other groups (37 and 35.66%, respectively for groups 1 and control) (P<0.05). Based on the results, using 80 ppm level of ZnONPs lead to an improvement in the activity of superoxide dismutase enzyme (48.62 ml) and total antioxidant capacity of semen plasma (111.88 µg/ml) compared with other groups (P<0.05). In conclusion using 80 ppm level of ZnONPs had a positive effect on the quantitative and qualitative properties of sperm and lead to a significant betterment in the activity of some antioxidant parameters of Arabic ram semen in the non-breeding season. PMID- 30242804 TI - Distribution of Antibiotic Resistance Genes among the Phylogroups of Escherichia coli in Diarrheic Calves and Chickens Affected by Colibacillosis in Tehran, Iran. AB - Antibiotic resistance occurs in the endogenous flora of exposed population in addition to pathogenic bacteria. This study was conducted to evaluate the distribution of antibiotic resistance genes among 63 isolates of Escherichia coli of Escherichia coli (E. coli) in diarrheic calves and poultry. According to the results, B1 and B2 were the most prevalent phylogroups of E. coli in calves and poultry carcasses, respectively. Antimicrobial resistance was observed in 76% of the isolates, and 62% of the strains were multi-drug resistant. Antibiotic resistance in E. coli strains obtained from calves strains was significantly higher than those obtained from poultries. Additionally, the strains of B1 and D phylogroups had the highest and lowest antimicrobial resistance, respectively. At least one encoding gene for integrone was detected in 23 strains (36.5%) and Class I integron had the highest prevalence. Accordingly, this study gave baseline information on the magnitude of the resistance problem and its genetic background in E. coli from domesticated animals of the Tehran, Iran. Moreover, the power of oligonucleotide array technology in the discrimination of different genotypes during a short time was confirmed in this study. PMID- 30242805 TI - Detection of Mycoplasma gallisepticum and Mycoplasma synoviae among Commercial Poultry in Khouzestan Province, Iran. AB - Mycoplasmas are important avian pathogens, which can cause both respiratory disease and synovitis in poultry that result in considerable economic losses to the poultry industry all over the world. The aim of this study was to determine the prevalence of Mycoplasma gallisepticum and Mycoplasma synoviae infections among commercial poultry flocks in Khouzestan province, Iran, using the polymerase chain reaction (PCR) technique. Totally, 290 tracheal swab samples were collected from 19 broiler flocks and 4 layer-breeder flocks, with or without respiratory signs, in different areas of Khouzestan province within six months. The PCR tests were applied for the specific amplification of 16S rRNA (185 bp) and vlhA (392 bp) genes. Out of 100 swab samples obtained from the layer-breeder flocks, 1 and 72 specimens were positive for M. gallisepticum and M. synoviae, respectively. In this regard, out of the 4 layer-breeder flocks, 1 (25%) and 4 (100%) flocks were positive for M. gallisepticum and M. synoviae, respectively. However, none of the studied broiler flocks were M. gallisepticum- or M. synoviae positive. According to the results, the PCR technique could be concluded as a rapid method for the accurate identification of M. gallisepticum and M. synoviae infections in commercial poultry flocks. The results were indicative of the low prevalence of M. gallisepticum in the studied flocks in Khouzestan province. On the other hand, M. synoviae was widely distributed among layer-breeder flocks in this province. PMID- 30242806 TI - Prevalence of Haemoproteus columbae (Apicomplexa: Haemoproteidae) and Trichomonas gallinae (Metamonada: Trichomonadidae) Infections Among Pigeons (Columba livia) in West Azerbaijan Province, Iran. AB - A cross-sectional survey was performed on domestic pigeons (Columba liviadomestica) to evaluate the prevalence of Haemoproteus columbae and Trichomonas gallinae in West Azerbaijan Province, northwest of Iran between July 2015 and September 2016. Five hundred and sixty oropharyngeal swab smears were examined, 297 (53%) of which were identified to be positive for T. gallinae. Also, the results obtained from blood smears examination indicated that 115 (20.5%) cases were found to be infected with H. columbae. The rates of T. gallinae and H. columbae infection infemale pigeons (58.3% and 21.3%, respectively) were higher compared to those in males. There were 76 (26.1%) and 210 (72.4%) cases of H. columbae and T. gallinae infection in adolescent birds, respectively, which were higher than those in other age groups. We found high prevalence rates of H. columbae and T. gallinae infections in domestic pigeons. Therefore, more attention should be focused on controlling the spread of T. gallinae and H. columbae infection in domestic pigeons. PMID- 30242807 TI - Prediction of breast cancer metastasis risk using circulating tumor markers: A follow-up study. AB - Distant organ tumor dissemination is a major cause of breast cancer-related deaths. In 2010, we analyzed the prognostic importance of the circulating tumor markers (CTM) cytokeratin (CK)19, CK20, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in relation to the clinical and pathological characteristics of patients with breast cancer (BC). To assess the clinical utility of CK19, CK20 and EGFR in predicting distant metastasis and recurrence in BC, here we report 7-year follow-up results of 77 patients. The patients with at least one positive CTM were classified as CTM(+) and those negative for all CTMs were assigned to CTM(-) group. In patients who received no treatment following CTM analysis, 25.0% had metastasis in CTM(+) and 10.0% in CTM(-) group. In patients who received chemotherapy, radiotherapy or hormone therapy, or the combinations of these therapies, the rate of metastasis was 33.3% in CTM(+) and 20.0% in CTM(-) group. Disease-free time was shorter in CTM(+) patients compared to CTM(-) group (28.83 +/- 10.76 and 41.38 +/- 9.5 months, respectively). According to multivariate Cox proportional hazard regression analysis, the presence of lymph node metastasis, Ki-67 expression, higher tumor grade and CTM expression status were predictors of poor prognosis associated with the occurrence of metastasis (p < 0.05). Also, CTM positivity was a factor associated with metastasis-related poor prognosis (HR = 0.492, p = 0.026). The mean survival for CTM(+) patients was shorter than that for CTM(-) patients (90.671 +/- 2.66 and 101.23 +/- 3.92 months, respectively; p > 0.05). Our findings demonstrate that CTM positivity may indicate a high metastasis risk; however, CTM negativity does not guarantee low metastasis risk. These results may encourage further preclinical investigation of CTMs, to evaluate the possible implications of these findings to the clinical setting. PMID- 30242808 TI - Risk factors for complications and graft failure in kidney transplant patients with sepsis. AB - Immunosuppressive therapies decreased the incidence of acute kidney rejection after kidney transplantation, but also increased the risk of infections and sepsis. This study aimed to identify the risk factors associated with complications and/or graft failure in kidney transplant patients with sepsis. A total of 14,658 kidney transplant patients with sepsis, identified in the National Inpatient Sample (NIS) database (data from 2005-2014), were included in the study and classified into three groups: patients without complications or graft failure/dialysis (Group 1), patients with complications only (Group 2), and patients with complications and graft failure/dialysis (Group 3). Multinomial logistic regression analyses were conducted to evaluate factors associated with kidney transplant recipients. Multivariate analysis showed that, compared to Group 1, patients from Group 2 or Group 3 were more likely to be Black and to have cytomegalovirus infection, coagulopathy, and glomerulonephritis (p <= 0.041). Also, Group 2 was more likely to have herpes simplex virus infection, and Group 3 was more likely to have hepatitis C infection and peripheral vascular disorders, compared to Group 1 (p <= 0.002). In addition, patients from Group 3 were more likely to be Black and to have hepatitis C infection, peripheral vascular disorders, coagulopathy, and hypertension compared to Group 2 (p <= 0.039). Age and female gender were associated with lower odds of complications after kidney transplantation regardless of graft rejection/dialysis (p <= 0.049). Hyperlipidemia and diabetes decreased the chance of complications and graft failure/dialysis after kidney transplant (p < 0.001). In conclusion, the study highlights that black race, male gender, and specific comorbidities can increase the risk of complications and graft failure in kidney transplant patients with sepsis. PMID- 30242810 TI - Is It Ethical to Use Prognostic Estimates from Machine Learning to Treat Psychosis? AB - Machine learning is a method for predicting clinically relevant variables, such as opportunities for early intervention, potential treatment response, prognosis, and health outcomes. This commentary examines the following ethical questions about machine learning in a case of a patient with new onset psychosis: (1) When is clinical innovation ethically acceptable? (2) How should clinicians communicate with patients about the ethical issues raised by a machine learning predictive model? PMID- 30242809 TI - Associations Between Gene Polymorphisms and Psychological Stress in the Guangxi Minority Region of China. AB - To investigate whether there is an association between gene polymorphisms, genetic and environmental interactions, and psychological stress reactivity in Chinese subjects living in the Guangxi minority region. This cross-sectional study enrolled subjects older than 18 years, living in Nandan county, Guangxi minority region, China for at least 1 year. All participants were healthy, without any mental diseases, and were able to communicate. Eligible participants were randomly selected. The Life Event Scale Questionnaire, Simplified Coping Style Questionnaire, and Social Support Rating Scale were used to measure the physiological stress, coping style, and social support, respectively, in individuals. A total of 600 participants were recruited. A decreased risk of psychological stress was only found in TT of NPSR1 (rs324981): A allele carriers vs. TT genotype (OR 1.64, 95% CI 1.11, 2.42), and AT genotype vs. TT genotype (OR 1.76, 95% CI 1.17, 2.65). The overall coping style was positively associated with psychological stress, and no significant interactions between genetics and environment were found. We found that the NPSR1 (rs324981) T/T genotype decreased the risk of psychological stress, while the overall coping style was a risk factor for psychological stress. However, there was no interactive effects of genes and environment on psychological stress. Our findings will improve understanding of the biological basis underlying psychological stress if the results can be replicated in further research. PMID- 30242811 TI - How Should Primary Care Physicians Respond to Direct-to-Consumer Genetic Test Results? AB - In this case, a primary care physician is presented with direct-to-consumer genetic test results and asked to provide counseling and order follow-up diagnostics. In order to deal effectively with this situation, we suggest physicians need look no further than the practice principles that guide more routine clinical encounters. We examine the rationale behind 2 major clinical ethical considerations: (1) physicians have obligations to help their patients achieve reasonable health goals but are not obligated to perform procedures that are not medically indicated; and (2) primary care physicians do not need to know everything; they just need to know how to get their patients appropriate care. PMID- 30242812 TI - Should Genetic Testing for Variants Associated with Influenza Infection Be Mandatory for Health Care Employees? AB - Scientists are beginning to understand more about the role of host genetics in individuals' responses to influenza virus exposure. This fictional case addresses a situation in which a health care organization proposes requiring all health care practitioners with direct patient care responsibilities to undergo mandatory genetic testing for genetic variants used to (1) predict individuals' responses to the influenza vaccine, (2) determine individual susceptibility to influenza infection, and (3) identify individuals at increased risk for severe disease. This commentary will discuss ethical and legal issues associated with use of genetic test results to determine employee work assignments during an influenza pandemic. PMID- 30242813 TI - Justice in CRISPR/Cas9 Research and Clinical Applications. AB - CRISPR/Cas9 is a rapidly developing gene editing technology that will soon have many clinical applications. As with many other new technologies, somatic gene editing with CRISPR/Cas9 raises concerns about equitable access to therapies by historically disenfranchised racial and ethnic minorities. We describe justice concerns related to CRISPR/Cas9, including its potential impact on historically mistreated populations through underrepresentation of minorities in genomic databases and the potential for disparate access to somatic gene therapies when they become clinically available. We then describe ongoing work that aims to address these justice concerns. We conclude by highlighting important considerations to ensure equitable access to therapies going forward, including enhancing diversity in genomic sequencing efforts, improving education and transparency, and building partnerships with underserved and socially disenfranchised communities. PMID- 30242814 TI - What Precision Medicine Can Learn from Rare Genetic Disease Research and Translation. AB - The goal of this article is to examine the intersections of precision health and rare diseases. Specifically, we propose 3 lessons from the last decade of applying genomics to rare diseases: (1) precision can end one odyssey and start another; (2) precise interventions can exacerbate health disparities and create other ethical dilemmas; and (3) democratization of data will transform research and translation. By studying experiences of patients with rare diseases, researchers, clinicians, and policymakers can anticipate similar challenges in precision medicine and hopefully mitigate potential harms or injustices. PMID- 30242815 TI - Targeted Dosing as a Precision Health Approach to Pharmacotherapy in Children with Inflammatory Bowel Disease. AB - As clinicians have begun to provide targeted pharmacotherapy for children with inflammatory bowel disease (IBD), several ethical challenges have arisen. In this paper, we review 3 challenges related to applying a precision health approach to pediatric IBD populations: selection of a disease monitoring method, pharmacotherapy optimization, and economic considerations in clinical decision making. PMID- 30242816 TI - Should NASA Collect Astronauts' Genetic Information for Occupational Surveillance and Research? AB - Humans exploring beyond low-Earth orbit face environmental challenges coupled with isolation, remote operations, and extreme resource limitations in which personalized medicine, enabled by genetic research, might be necessary for mission success. With little opportunity to test personalized countermeasures broadly, the National Aeronautics and Space Administration (NASA) will likely need to rely instead on collection of significant amounts of genomic and environmental exposure data from individuals. This need appears at first to be in conflict with the statutes and regulations governing the collection and use of genetic data. In fact, under certain conditions, the Genetic Information Nondiscrimination Act (GINA) of 2008 allows for the use of genetic information in both occupational surveillance and research and in the development of countermeasures such as personalized pharmaceuticals. PMID- 30242817 TI - What Should Oversight of Clinical Decision Support Systems Look Like? AB - A learning health system provides opportunities to leverage data generated in the course of standard clinical care to improve clinical practice. One such opportunity includes a clinical decision support structure that would allow clinicians to query electronic health records (EHRs) such that responses from the EHRs could inform treatment recommendations. We argue that though using a clinical decision support system does not necessarily constitute a research activity subject to the Common Rule, it requires more ethical and regulatory oversight than activities of clinical practice are generally subjected to. In particular, we argue that the development and use of clinical decision support systems should be governed by a framework that (1) articulates appropriate conditions for their use, (2) includes processes for monitoring data quality and developing and validating algorithms, and (3) sufficiently protects patients' data. PMID- 30242818 TI - How Could Commercial Terms of Use and Privacy Policies Undermine Informed Consent in the Age of Mobile Health? AB - Granular personal data generated by mobile health (mHealth) technologies coupled with the complexity of mHealth systems creates risks to privacy that are difficult to foresee, understand, and communicate, especially for purposes of informed consent. Moreover, commercial terms of use, to which users are almost always required to agree, depart significantly from standards of informed consent. As data use scandals increasingly surface in the news, the field of mHealth must advocate for user-centered privacy and informed consent practices that motivate patients' and research participants' trust. We review the challenges and relevance of informed consent and discuss opportunities for creating new standards for user-centered informed consent processes in the age of mHealth. PMID- 30242819 TI - Should Electronic Health Record-Derived Social and Behavioral Data Be Used in Precision Medicine Research? AB - Precision medicine research initiatives aim to use participants' electronic health records (EHRs) to obtain rich longitudinal data for large-scale precision medicine studies. Although EHRs vary widely in their inclusion and formatting of social and behavioral data, these data are essential to investigating genetic and social factors in health disparities. We explore possible biases in collecting, using, and interpreting EHR-based social and behavioral data in precision medicine research and their consequences for health equity. PMID- 30242820 TI - Why Does the Shift from "Personalized Medicine" to "Precision Health" and "Wellness Genomics" Matter? AB - Efforts to conceptualize the application of human genomics to health care have displayed an evolving set of translational research goals. Under personalized genomic medicine, the aim was to individualize treatment and empower patients to take more responsibility for their own health. With the rise of interest in expert interpretation of multifactorial risk stratification, emphasis shifted to giving clinicians better tools and more authority to use them under the rubric of precision medicine. The statistical nature of risk stratification, in turn, led to the movement's importing public health goals and expanding its scope to precision prevention at the population level. Today, the confluence of precision medicine and precision prevention in precision health is leading to wellness genomics aimed at achieving goals beyond health care entirely. Each of these reorientations suggests important ethical questions for the medical community. PMID- 30242821 TI - The Precision Portrait. AB - The Precision Portrait is a mixed-media portrait illustrating the future of precision medicine and its ethical challenges. PMID- 30242822 TI - Kaleidoscope. AB - This image seeks to iteratively represent themes related to the availability of life-saving and life-threatening medications. The photograph also suggests the importance of several ethical questions. PMID- 30242823 TI - Graphic Medicine and the Limits of Biostatistics. AB - Increasing reliance on statistics for treatment and clinical risk assessment not only leads to the reductive interpretation of disease but also obscures ambiguities, distrust, and profound emotions that are important parts of a patient's lived experience of illness and that should be regarded as clinically and ethically relevant. Enabling critique of the limitations of statistics and illustrating their hegemonic impact on the patient's experience of illness, graphic medicine emerges as a democratic platform where marginalized perspectives on illness experiences are vindicated. Through a close reading of two carer narratives, Mom's Cancer (2006) and Janet & Me: An Illustrated Story of Love and Loss (2004), we illustrate how graphic pathographies represent experiential features of illness that are obscured by overreliance on statistical data. PMID- 30242824 TI - Should Artificial Intelligence Augment Medical Decision Making? The Case for an Autonomy Algorithm. AB - A significant proportion of elderly and psychiatric patients do not have the capacity to make health care decisions. We suggest that machine learning technologies could be harnessed to integrate data mined from electronic health records (EHRs) and social media in order to estimate the confidence of the prediction that a patient would consent to a given treatment. We call this process, which takes data about patients as input and derives a confidence estimate for a particular patient's predicted health care-related decision as an output, the autonomy algorithm. We suggest that the proposed algorithm would result in more accurate predictions than existing methods, which are resource intensive and consider only small patient cohorts. This algorithm could become a valuable tool in medical decision-making processes, augmenting the capacity of all people to make health care decisions in difficult situations. PMID- 30242825 TI - The effect of nebulized salbutamol on atrial electrical properties in mechanically ventilated critically ill patients - a randomized, double-blind study. AB - BACKGROUND: Salbutamol is a short acting beta-2 mimetic commonly used among intensive care unit patients. There are data suggesting that his mechanism of action can be a potential factor triggering arrhythmias. The aim of this study was to assess whether nebulized salbutamol causes systemic effects resulting in electrocardiographic alterations associated with atrial fibrillation occurrence in mechanically ventilated patients. METHODS: 50 individuals were randomly allocated to receive either 2.5 or 5 mg of nebulized salbutamol for 20 minutes. 60 minutes prior to the start of nebulization, 12 lead surface electrocardiogram has been recorded. Electrocardiographic parameters associated with atrial activity - P wave and PR interval, and their derivates: P wave dispersion and PR interval dispersion were analysed. RESULTS: Both doses of inhaled salbutamol caused changes of P wave indices - maximal, minimal and mean P wave duration, from simultaneously recorded leads, and concomitant decrease of P wave dispersion. Prolongation of P wave affected predominantly minimal P wave duration (11.93 ms [95% CI: 8.69-15.17]) comparing with maximal P wave duration (2.61 [95% CI: 021-5.43]). Atrio-ventricular conduction - PR interval was also prolonged, however minimal PR interval duration from simultaneously recorded leads was shortened in group receiving 5 mg of salbutamol. CONCLUSIONS: Nebulized salbutamol in ICU patient possess systemic effects which causes changes in P wave indices in surface ECG recordings. This electrophysiological influence may be associated with the increased risk of atrial fibrillation among this group of patients. PMID- 30242826 TI - Frailty increases mortality among patients >= 80 years old treated in Polish ICUs. AB - BACKGROUND: The increasing population of very old intensive care patients (VIPs) is a major challenge currently faced by clinicians and policymakers. Reliable indicators of VIPs' prognosis and purposefulness of their admission to the intensive care unit (ICU) are urgently needed. METHODS: This is a report from the Polish sample of the VIP1 multicentre cohort study (NCT03134807). Patients >= 80 years of age admitted to the ICU were included in the study. Information on the type and reason for admission, demographics, utilisation of ICU procedures, ICU length of stay, organ dysfunction and the decision to apply end-of-life care was collected. The primary objective was to investigate the impact of frailty syndrome on ICU and 30-day survival of VIPs. Frailty was assessed with the Clinical Frailty Scale (>= 5 points on a scale of 1-9). RESULTS: We enrolled 272 participants with a median age of 84 (81-87) years. Frailty was diagnosed in 170 (62.5%) patients. The ICU and 30-day survival rates were equal to 54.6% and 47.3% respectively. Three variables were found to significantly increase the odds of death in the ICU in a multiple logistic regression model: SOFA score (OR = 1.16; 95%CI 1.16-1.24), acute mode of admission (OR = 5.1; 95%CI 1.67-15.57) and frailty (OR = 2.25; 95%CI 1.26-4.01). CONCLUSION: Measuring frailty in critically ill older adults can facilitate making more informed clinical decisions and help avoid futile interventions. PMID- 30242828 TI - Identifying a neuroanatomical signature of schizophrenia, reproducible across sites and stages, using machine learning with structured sparsity. AB - OBJECTIVE: Structural MRI (sMRI) increasingly offers insight into abnormalities inherent to schizophrenia. Previous machine learning applications suggest that individual classification is feasible and reliable and, however, is focused on the predictive performance of the clinical status in cross-sectional designs, which has limited biological perspectives. Moreover, most studies depend on relatively small cohorts or single recruiting site. Finally, no study controlled for disease stage or medication's effect. These elements cast doubt on previous findings' reproducibility. METHOD: We propose a machine learning algorithm that provides an interpretable brain signature. Using large datasets collected from 4 sites (276 schizophrenia patients, 330 controls), we assessed cross-site prediction reproducibility and associated predictive signature. For the first time, we evaluated the predictive signature regarding medication and illness duration using an independent dataset of first-episode patients. RESULTS: Machine learning classifiers based on neuroanatomical features yield significant intersite prediction accuracies (72%) together with an excellent predictive signature stability. This signature provides a neural score significantly correlated with symptom severity and the extent of cognitive impairments. Moreover, this signature demonstrates its efficiency on first-episode psychosis patients (73% accuracy). CONCLUSION: These results highlight the existence of a common neuroanatomical signature for schizophrenia, shared by a majority of patients even from an early stage of the disorder. PMID- 30242829 TI - Hospital-Acquired Hyperkalemia Events in Older Patients Are Mostly Due to Avoidable, Multifactorial, Adverse Drug Reactions. AB - Drug-induced hyperkalemia is a frequent and severe complication in the hospital setting. Other risk factors may also induce hyperkalemia but the combination of drugs and precipitating factors has not been extensively studied. The aim was to identify drug-induced hyperkalemia events in hospitalized older patients and to describe their combinations with precipitating factors. Two experts independently analyzed retrospective data of patients aged 75 years or more. Experts identified 471 hyperkalemia events and concluded that 379 (80.5%) were induced by drugs. The cause was multifactorial (i.e., at least one drug with a precipitating factor) in 300 (79.2%) of the 379 drug-induced hyperkalemia. Most of the drug-induced hyperkalemia events were avoidable (79.9%)-mainly because of the multifactorial cause (e.g., dosage adaptation during acute kidney injury). Drug-induced hyperkalemia events are frequently combined with precipitating factors in hospitalized older patients and their prevention should focus on these combinations. PMID- 30242830 TI - History and Review of anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: From Translational Research to Treatment. AB - Objective - To briefly describe the history of and available data on anti calcitonin gene-related peptide (CGRP) therapies for headache. Background - CGRP was proposed as a target for primary headache therapies. Translational research involved moving from delineating the relationships between CGRP and primary headaches and the clinical development of anti-CGRP treatments. The first anti CGRP treatment, an intravenous CGRP-receptor antagonist or gepant, olcegepant, was described as effective in terminating migraines in humans in 2004. Methods - The author briefly reviews some of the pathophysiology and translational research that led to the development of the gepants initially and then subsequently to the anti-CGRP and anti-CGRP receptor monoclonal antibodies. All accessible randomized controlled trials, abstracts, platform presentations, and press releases on the monoclonal antibody trials are summarized. The trajectory from bench research to the approval of the first anti-CGRP receptor monoclonal antibody for clinical use in migraine prevention, erenumab, is discussed, as well as potential clinical uses of the anti-CGRP treatments. Results - The US Food and Drug Administration (FDA) approved erenumab, an anti-CGRP receptor monoclonal antibody, for prevention of migraine May 17, 2018. At the time of this writing (May 2018), 2 other anti-CGRP monoclonal antibodies have been submitted to the FDA for the indication of prevention of migraine, galcanezumab and fremanezumab. Galcanezumab has reportedly shown effectiveness in preventing episodic cluster headache as well, although has not yet been submitted to the FDA for this indication. Eptinezumab will likely be submitted to the FDA for prevention of migraine later in 2018. Two gepants, ubrogepant and rimegepant, have completed positive pivotal trials for acute treatment of migraine, but have not yet been submitted to the FDA for this indication. Conclusions - The development of anti-CGRP therapies opens a new era in the acute and preventive treatment of primary headache disorders. PMID- 30242827 TI - Long-term cognitive trajectories and heterogeneity in patients with schizophrenia and their unaffected siblings. AB - OBJECTIVE: This study aimed to assess the heterogeneity and stability of cognition in patients with a non-affective psychotic disorder and their unaffected siblings. In addition, we aimed to predict the cognitive subtypes of siblings by their probands. METHOD: Assessments were conducted at baseline, 3 and 6 years in 1119 patients, 1059 siblings and 586 controls from the Genetic Risk and Outcome of Psychosis (GROUP) study. Group-based trajectory modeling was applied to identify trajectories and clustered multinomial logistic regression analysis was used for prediction modeling. A composite score of eight neurocognitive tests was used to measure cognitive performance. RESULTS: Five stable cognitive trajectories ranging from severely altered to high cognitive performance were identified in patients. Likewise, four stable trajectories ranging from moderately altered to high performance were found in siblings. Siblings had a higher risk of cognitive alteration when patients' alteration was mild (OR = 2.21), moderate (OR = 5.70), and severe (OR = 10.07) compared with patients with intact cognitive function. The familial correlation coefficient between pairs of index patients and their siblings was 0.27 (P = 0.003). CONCLUSIONS: The cognitive profiles identified in the current study might be suitable as endophenotypes and could be used in future genetic studies and predicting functional and clinical outcomes. PMID- 30242831 TI - Effects of Nicotine Metabolic Rate on Withdrawal Symptoms and Response to Cigarette Smoking After Abstinence. AB - This study investigated the influence of the rate of nicotine metabolism, as indicated by the nicotine metabolite ratio (NMR), on tobacco dependence. We stratified 136 smokers on the basis of saliva NMR as fast (n = 65) and slow (n = 71) metabolizers. Two "loading cigarettes" were smoked after overnight, and a "reward cigarette" was smoked after 6 hours of daytime, abstinence. Blood nicotine concentrations, expired carbon monoxide, withdrawal/craving, and reward questionnaires were collected before/after smoking and during daytime abstinence. Compared with slow metabolizers, fast metabolizers had a shorter nicotine elimination half-life (P < 0.001), lower plasma nicotine concentrations (P < 0.001), and higher withdrawal/craving scores (P < 0.05) for most times during daytime abstinence, indicating that fast metabolizers are likely smoking more to relieve withdrawal symptoms (negative reinforcement). Reward/satisfaction scores were similar in fast and slow metabolizers, suggesting that faster nicotine metabolism, assessed by NMR, is not associated with greater positive reinforcement. CYP2A6 normal (n = 82) and reduced (n = 42) genotype predicted plasma nicotine concentrations but not withdrawal symptoms. PMID- 30242832 TI - Effects of repeated anaesthesia on gill and general health of Atlantic salmon, Salmo salar. AB - Fish are the second most widely utilized vertebrate group used for scientific procedures in the United Kingdom, but the development and application of 3Rs (the principles of replacement, reduction, and refinement) in aquaculture disease research lags behind methodologies in place for mammalian studies. With a need for individual monitoring and non-lethal sampling, the effect of repeat anaesthesia on experimental fish needs to be better understood. This study analyses the effect of repeat anaesthesia with MS-222, metomidate and AQUI-S upon the gill and general health of post-smolt Atlantic salmon Salmo salar. A single, lethal dose of anaesthetic was compared with seven anaesthetizing time points over 28 days, terminating in a lethal dose. No anaesthetic showed significant differences in accumulation in the muscle tissue, or changes in plasma glucose after repeated or single dosing. Fish repeatedly anaesthetized with MS-222 or AQUI-S exhibited upregulation of osmoregulatory genes in the gill and AQUI-S treated individuals showed, histologically, epithelial lifting from the lamellae capillary irrespective of whether they had a single or repeated dose history. No significant changes were seen in inflammatory or stress genes in the head kidney of fish repeatedly anaesthetized with AQUI-S or metomidate, however MS-222 treatment resulted in upregulation of tnfalpha3. Repeated anaesthesia with MS-222 and metomidate gave a significant decrease and increase in peripheral blood neutrophils, respectively. This study concludes that no increase in cumulative stress or inflammation is induced by the repeated anaesthetization of S. salar with any of the tested anaesthetics, however gill osmotic regulation and blood parameters may be affected. PMID- 30242833 TI - Nonpharmacological interventions for persistent, noncancer pain in elders residing in long-term care facilities: An integrative review of the literature. AB - Elders residing in long-term care facilities experience ongoing moderate to severe pain, relief from and increased comfort remain relevant healthcare concerns. However, persistent, noncancer pain may not have been properly addressed due to insufficient attention to research that exists to support the utilization and efficacy of nonpharmacological intervention(s) for elders in long term care facilities. Our aim of this integrated review was to evaluate the current state of the science on nonpharmacological intervention(s) for pain that are currently utilized in elders who reside in long-term care facilities. Exercise, massage, heat therapy, and relaxation/rest were identified as significant nonpharmacological interventions for persistent pain in elder residents living in long-term care facilities. PMID- 30242834 TI - The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T-cell function. AB - Tyrosine kinases are checkpoints for multiple cellular pathways and dysregulation induces malignancies, most notably chronic myeloid leukemia (CML). Inhibition of Abl-tyrosine kinases has evolved as a new concept for the treatment of CML and other malignant diseases. Due to the multiple immune-modulatory pathways controlled by tyrosine kinases, treatment with tyrosine kinase inhibitors (TKIs) will not only affect the biology of malignant cells but also modulate physiological immune functions. To understand the effects of TKIs on host defense against intracellular bacteria, we investigated the immunological impact of the dual Abl/Src TKI dasatinib on the cellular immune response to Mycobacterium tuberculosis (Mtb). Our results demonstrate that dasatinib impaired proliferation, cytokine release (IFN-gamma, TNF-alpha, GM-CSF), expression of granulysin and degranulation of cytotoxic effector molecules of human Mtb specific T-lymphocytes by inhibition of lymphocyte-specific protein tyrosine kinase (Lck) phosphorylation. Despite this profound inhibition of T-cell function, dasatinib suppressed growth of virulent Mtb in human macrophages co cultured with autologous Mtb-specific T-cells (49+/-15%). Functional analysis suggested that growth inhibition is due to dasatinib-triggered lysosomal acidification in Mtb-infected macrophages. These results highlight the significance of innate immune responses, i.e. acidification of lysosomes, which control the multiplication of intracellular bacteria despite the lack of efficient T-cell support. PMID- 30242835 TI - Thyroid cancer "epidemic" also occurs in low- and middle-income countries. AB - Thyroid cancer incidence varies greatly between and within high-income countries (HICs), and overdiagnosis likely plays a major role in these differences. Yet, little is known about the situation in low- and middle-income countries (LMICs). We compare up-to-date thyroid cancer incidence and mortality at national and subnational levels. 599,851 thyroid cancer cases in subjects aged 20-74 reported in Cancer Incidence in Five Continents volume XI from 55 countries with at least 0.5 million population, aged 20-74 years, covered by population-based cancer registration, and 22,179 deaths from the WHO Mortality Database for 36 of the selected countries, over 2008-2012, were included. Age-standardized rates were computed. National incidence rates varied 50-fold. Rates were 4 times higher among women than men, with similar patterns between countries. The highest rates (>25 cases per 100,000 women) were observed in the Republic of Korea, Israel, Canada, the United States, Italy, France, and LMICs such as Turkey, Costa Rica, Brazil, and Ecuador. Incidence rates were low (<8) in a few HICs (the Netherlands, the United Kingdom, and Denmark) and lowest (3-4) in some LMICs (such as Uganda and India). Within-country incidence rates varied up to 45-fold, with the largest differences recorded between rural and urban areas in Canada (HIC) and Brazil, India, and China (LMICs). National mortality rates were very low (<2) in all countries and in both sexes, and highest in LMICs. The very high thyroid cancer incidence and low mortality rates in some LMICs also strongly suggest a major role of overdiagnosis in these countries. PMID- 30242836 TI - Where do fish go when stranded on land? Terrestrial orientation of the mangrove rivulus Kryptolebias marmoratus. AB - The goal of the present study was to determine which sensory cues the mangrove rivulus Kryptolebias marmoratus, a quasi-amphibious, hermaphroditic fish, uses to orient in an unfamiliar terrestrial environment. In a laboratory setting, K. marmoratus were placed on a terrestrial test arena and were provided the opportunity to move toward reflective surfaces, water, dark colours v. light colours, and orange colouration. Compared with hermaphrodites, males moved more often toward an orange section of the test arena, suggesting that the response may be associated with camouflage or male-male competition, since only males display orange colouration. Younger individuals also moved more often toward the orange quadrant than older individuals, suggesting age-dependent orientation performance or behaviour. Sloped terrain also had a significant effect on orientation, with more movement downhill, suggesting the importance of the otolith-vestibular system in terrestrial orientation of K. marmoratus. By understanding the orientation of extant amphibious fishes, we may be able to infer how sensory biology and behaviour might have evolved to facilitate invasion of land by amphibious vertebrates millions of years ago. PMID- 30242837 TI - Rapid saline infusion and/or drinking enhance skin sympathetic nerve activity components reduced by hypovolaemia and hyperosmolality in hyperthermia. AB - KEY POINTS: In hyperthermia, plasma hyperosmolality suppresses both cutaneous vasodilatation and sweating responses and this suppression is removed by oropharyngeal stimulation such as drinking. Hypovolaemia suppresses only cutaneous vasodilatation, which is enhanced by rapid infusion in hyperthermia. Our recent studies suggested that skin sympathetic nerve activity (SSNA) involves components synchronized and non-synchronized with the cardiac cycle, which are associated with an active vasodilator and a sudomotor, respectively. In the present study, plasma hyperosmolality suppressed both components; drinking removed the hyperosmolality-induced suppressions, simultaneously with increases in cutaneous vasodilatation and sweating, while not altering plasma volume and osmolality. Furthermore, a rapid saline infusion increased the synchronized component and cutaneous vasodilatation in hypovolaemic and hyperthermic humans. The results support our idea that SSNA involves an active cutaneous vasodilator and a sudomotor, and that a site where osmolality signals are projected to control thermoregulation is located more superior than the medulla where signals from baroreceptors are projected. ABSTRACT: We reported that skin sympathetic nerve activity (SSNA) involved components synchronized and non-synchronized with the cardiac cycle; both components increased in hyperthermia and our results suggested that the components are associated with an active vasodilator and a sudomotor, respectively. In the present study, we examined whether the increases in the components in hyperthermia would be suppressed by plasma hyperosmolality simultaneously with suppression of cutaneous vasodilatation and sweating and whether this suppression was released by oropharyngeal stimulation (drinking). Also, effects of a rapid saline infusion on both components and responses of cutaneous vasodilatation and sweating were tested in hypovolaemic and hyperthermic subjects. We found that (1) plasma hyperosmolality suppressed both components in hyperthermia, (2) the suppression was released by drinking 200 mL of water simultaneously with enhanced cutaneous vasodilatation and sweating responses, and (3) a rapid infusion at 1.0 and 0.2 ml min-1 kg-1 for the first 10 min and the following 20 min, respectively, increased the synchronized component and cutaneous vasodilatation in diuretic-induced hypovolaemia greater than those in a time control; at 0.1 ml min-1 kg-1 for 30 min no greater increases in the non-synchronized component and sweating responses were observed during rapid infusion than in the time control. The results support the idea that SSNA involves components synchronized and non-synchronized with the cardiac cycle, associated with the active cutaneous vasodilator and sudomotor, and a site of osmolality-induced modulation for thermoregulation is located superior to the medulla where signals from baroreceptors are projected. PMID- 30242839 TI - Association between Trichomonas vaginalis and prostate cancer mortality. AB - We previously observed a positive association between seropositivity for the parasite Trichomonas vaginalis and risk of clinically significant prostate cancer at diagnosis. Here, we examined whether T. vaginalis seropositivity was associated with increased prostate cancer-specific or all-cause mortality among prostate cancer patients. We studied 736 men with prostate cancer from the Physicians' Health Study (PHS) and 749 men with prostate cancer from the Health Professionals Follow-Up Study (HPFS). We used Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between T. vaginalis serostatus and progression to death from prostate cancer and from all causes. In PHS, 423 men died of any cause during a median follow-up of 13.8 years from the date of cancer diagnosis, among whom 131 died of prostate cancer. In HPFS, there were 287 deaths, including 77 deaths from prostate cancer, during a median follow-up of 12.8 years. We found no association between T. vaginalis serostatus and either prostate cancer mortality or all-cause mortality in either the PHS or HPFS. While previous studies suggest a possible role for T. vaginalis in the development of clinically significant prostate cancer, our findings do not support the hypothesis that T. vaginalis serostatus is associated with mortality among prostate cancer patients. PMID- 30242840 TI - NHA2 promotes cyst development in an in vitro model of polycystic kidney disease. AB - KEY POINTS: Significant and selective up-regulation of the Na+ /H+ exchanger NHA2 (SLC9B2) was observed in cysts of patients with autosomal dominant polycystic kidney disease. Using the MDCK cell model of cystogenesis, it was found that NHA2 increases cyst size. Silencing or pharmacological inhibition of NHA2 inhibits cyst formation in vitro. Polycystin-1 represses NHA2 expression via Ca2+ /NFAT signalling whereas the dominant negative membrane-anchored C-terminal fragment (PC1-MAT) increased NHA2 levels. Drugs (caffeine, theophylline) and hormones (vasopressin, aldosterone) known to exacerbate cysts elicit NHA2 expression. Taken together, the findings reveal NHA2 as a potential new player in salt and water homeostasis in the kidney and in the pathogenesis of polycystic kidney disease. ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. The molecular pathways linking polycystins to cyst development in ADPKD are still unclear. Intracystic fluid secretion via ion transporters and channels plays a crucial role in cyst expansion in ADPKD. Unexpectedly, we observed significant and selective up-regulation of NHA2, a member of the SLC9B family of Na+ /H+ exchangers, that correlated with cyst size and disease severity in ADPKD patients. Using three-dimensional cultures of MDCK cells to model cystogenesis in vitro, we showed that ectopic expression of NHA2 is causal to increased cyst size. Induction of PC1 in MDCK cells inhibited NHA2 expression with concordant inhibition of Ca2+ influx through store-dependent and independent pathways, whereas reciprocal activation of Ca2+ influx by the dominant negative membrane-anchored C-terminal tail fragment of PC1 elevated NHA2. We showed that NHA2 is a target of Ca2+ /NFAT signalling and is transcriptionally induced by methylxanthine drugs such as caffeine and theophylline, which are contraindicated in ADPKD patients. Finally, we observed robust induction of NHA2 by vasopressin, which is physiologically consistent with increased levels of circulating vasopressin and up-regulation of vasopressin V2 receptors in ADPKD. Our findings have mechanistic implications on the emerging use of vasopressin V2 receptor antagonists such as tolvaptan as safe and effective therapy for polycystic kidney disease and reveal a potential new regulator of transepithelial salt and water transport in the kidney. PMID- 30242838 TI - Prss56 expression in the rodent hypothalamus: Inverse correlation with pro opiomelanocortin suggests oscillatory gene expression in adult rat tanycytes. AB - We recently reported that the number of hypothalamic tanycytes expressing pro opiomelanocortin (Pomc) is highly variable among brains of adult rats. While its cause and significance remain unknown, identifying other variably expressed genes in tanycytes may help understand this curious phenomenon. In this in situ hybridization study, we report that the Prss56 gene, which encodes a trypsin-like serine protease and is expressed in neural stem/progenitor cells, shows a similarly variable mRNA expression in tanycytes of adult rats and correlates inversely with tanycyte Pomc mRNA. Prss56 was expressed in alpha1, beta1, subsets of alpha2, and some median eminence gamma tanycytes, but virtually absent from beta2 tanycytes. Prss56 was also expressed in vimentin positive tanycyte-like cells in the parenchyma of the ventromedial and arcuate nuclei, and in thyrotropin beta subunit-expressing cells of the pars tuberalis of the pituitary. In contrast to adults, Prss56 expression was uniformly high in tanycytes in adolescent rats. In mice, Prss56-expressing tanycytes and parenchymal cells were also observed but fewer in number and without significant variations. The results identify Prss56 as a second gene that is expressed variably in tanycytes of adult rats. We propose that the variable, inversely correlating expression of Prss56 and Pomc reflect periodically oscillating gene expression in tanycytes rather than stable expression levels that vary between individual rats. A possible functional link between Prss56 and POMC, and Prss56 as a potential marker for migrating tanycytes are discussed. PMID- 30242841 TI - The validity of optimal leaf traits modelled on environmental conditions. AB - The ratio of leaf intercellular to ambient CO2 (chi) is modulated by stomatal conductance (gs ). These quantities link carbon (C) assimilation with transpiration, and along with photosynthetic capacities (Vcmax and Jmax ) are required to model terrestrial C uptake. We use optimization criteria based on the growth environment to generate predicted values of photosynthetic and water-use efficiency traits and test these against a unique dataset. Leaf gas-exchange parameters and carbon isotope discrimination were analysed in relation to local climate across a continental network of study sites. Sun-exposed leaves of 50 species at seven sites were measured in contrasting seasons. Values of chi predicted from growth temperature and vapour pressure deficit were closely correlated to ratios derived from C isotope (delta13 C) measurements. Correlations were stronger in the growing season. Predicted values of photosynthetic traits, including carboxylation capacity (Vcmax ), derived from delta13 C, growth temperature and solar radiation, showed meaningful agreement with inferred values derived from gas-exchange measurements. Between-site differences in water-use efficiency were, however, only weakly linked to the plant's growth environment and did not show seasonal variation. These results support the general hypothesis that many key parameters required by Earth system models are adaptive and predictable from plants' growth environments. PMID- 30242843 TI - A scoping review of caries risk management protocols in Australia and New Zealand. AB - To identify and map the caries risk management protocols with multiple strategies, which were used in Australia and New Zealand and reported in the existing literature, a scoping review was carried out by electronically searching PubMed, Web of Science, Scopus, Embase and Dentistry and Oral Science. Studies on caries risk management protocols, written in English, limited to Australia and New Zealand and published up to March 2018 were included in the review. There was no restriction on participants' age. Of 257 studies identified, seven were included in the review. These seven studies were reported in Australia and all but six were based on the caries management system (CMS). There were two descriptive studies, one 3-year multicentre cluster randomized controlled trial (RCT), one 2 to 4-year post-RCT follow-up and two cost-effective evaluations based on Markov decision analytic models. While concentrating on assessing individual behavioural risk factors for dental caries, studies indicated that the CMS would be more cost-effective if its protocol was properly adhered to. Future studies on caries risk management protocols are suggested to consider both the individual characteristics and the social context of different population groups in view of enhancing the effectiveness of oral care. PMID- 30242842 TI - Metformin inhibits IgE- and aryl hydrocarbon receptor-mediated mast cell activation in vitro and in vivo. AB - Metformin, an anti-diabetic drug, possesses anti-inflammatory property beyond its glucose-lowering activity, but its regulatory effect on mast cells and allergic responses remains unknown, wherein the aryl hydrocarbon receptor (AhR)-ligand axis is critical in controlling mast cell activation. Herein, we provide evidence supporting the role of metformin in modulating mast cell activation by FcepsilonR1-, AhR-mediated signaling or their combination. Metformin at relatively low doses was shown to suppress FcepsilonR1-mediated degranulation, IL 13, TNF-alpha and sphingosine-1-phosphate (S1P) secretion in murine bone marrow derived mast cells (BMMCs). In contrast, metformin at the same doses potently inhibited all parameters in mast cells stimulated with an AhR ligand, 5,11 dihydroindolo[3,2-b]carbazole-6-carbaldehyde (FICZ). Further, metformin was shown to inhibit FcepsilonR1- and AhR-mediated passive cutaneous anaphylaxis (PCA) in vivo, reversible by a S1P receptor 2 antagonist, JTE-013. Using AhR reporter cells, Huh7-DRE-Luc cells, a human mast cell line, HMC-1, and BMMCs, metformin's inhibitory effect was mediated through the suppression of FICZ-induced AhR activity, calcium mobilization and ROS generation. Notably, FICZ-mediated oxidation of S1P lyase (S1PL) and its reduced activity were reversed by metformin, resulting in decreased levels of S1P. Collectively, these results suggested the potential utility of metformin in treating allergic diseases, particularly in cases with comorbid type II diabetes mellitus. PMID- 30242844 TI - Different Upper Airway Microbiome and Their Functional Genes Associated with Asthma in Young Adults and Elderly Individuals. AB - BACKGROUND: Microbes in the airway has been shown to be associated with the pathogenesis of asthma. The upper airway microbiome influences the dysbiosis of the lower airway microbiome. However, to date, the influence of upper airway microbiome for adult and elderly asthma has not been fully elucidated. Here, the metagenome of upper airway microbiome of young adults and elderly was analyzed to identify their association with adult asthma. METHODS: Nasopharyngeal swabs were collected from young-adult and elderly asthma patients and non-asthmatic subjects. The compositions and functional genes of airway microbiome were analyzed by high-throughput sequencing. RESULTS: The composition of microbiota differed between young-adult and elderly, and it was different between asthmatics and non-asthmatics in each age group. Different bacteria were related to FEV1% predicted in each age group. Genes related to lysine degradation, N-glycan biosynthesis, caprolactam degradation, and PPAR signaling pathway, which could be related to the reduction of inflammation and degradation of air pollutants, were higher in non-asthmatics. Genes related to pentose phosphate pathway, lipopolysaccharide biosynthesis, flagella assembly, and bacterial chemotaxis - which may all be related to increased inflammation and colonization of pathogenic bacteria - were higher in young-adult asthmatic patients. However, the functional genes of airway microbiome in elderly patients were not significantly different according to asthma morbidity. CONCLUSIONS: These results suggest that the composition and function of upper airway microbiome could influence asthma pathogenesis, and the microbiome could play various roles depending on the age group. This article is protected by copyright. All rights reserved. PMID- 30242845 TI - Statistical learning in computed tomography image estimation. AB - PURPOSE: There is increasing interest in computed tomography (CT) image estimations from magnetic resonance (MR) images. The estimated CT images can be utilized for attenuation correction, patient positioning, and dose planning in diagnostic and radiotherapy workflows. This study aims to introduce a novel statistical learning approach for improving CT estimation from MR images and to compare the performance of our method with the existing model-based CT image estimation methods. METHODS: The statistical learning approach proposed here consists of two stages. At the training stage, prior knowledge about tissue types from CT images was used together with a Gaussian mixture model (GMM) to explore CT image estimations from MR images. Since the prior knowledge is not available at the prediction stage, a classifier based on RUSBoost algorithm was trained to estimate the tissue types from MR images. For a new patient, the trained classifier and GMMs were used to predict CT image from MR images. The classifier and GMMs were validated by using voxel-level tenfold cross-validation and patient level leave-one-out cross-validation, respectively. RESULTS: The proposed approach has outperformance in CT estimation quality in comparison with the existing model-based methods, especially on bone tissues. Our method improved CT image estimation by 5% and 23% on the whole brain and bone tissues, respectively. CONCLUSIONS: Evaluation of our method shows that it is a promising method to generate CT image substitutes for the implementation of fully MR-based radiotherapy and PET/MRI applications. PMID- 30242846 TI - Pharmacokinetics of florfenicol and thiamphenicol in ducks. AB - The pharmacokinetics of florfenicol (FF) and thiamphenicol (TP) after single intravenous (IV) and oral (PO) administration was investigated in Mulard ducks. Both antibiotics were administered at a dose of 30 mg/kg body weight, and their concentrations in plasma samples were assayed using high-performance liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were calculated using a noncompartmental method. After IV administration, significant differences were found for the mean residence time (2.25 +/- 0.21 hr vs. 2.83 +/- 0.50 hr for FF and TP, respectively) and the general half-life (1.56 +/- 0.15 hr vs. 1.96 +/- 0.35 hr for FF and TP, respectively) indicating slightly slower elimination of TP as compared to FF. The clearance, however, was comparable (0.30 +/- 0.07 L/hr/kg for FF and 0.26 +/- 0.04 L/hr/kg for TP). The mean volume of distribution was below 0.7 L/kg for both drugs. Pharmacokinetics after PO administration was very similar for FF and TP suggesting minor clinical importance of the differences found in the IV study. Both antimicrobials showed rapid absorption and bioavailability of more than 70% indicating that PO route should be an efficient method of FF and TP administration to ducks under field conditions. PMID- 30242847 TI - Single incision technique for implantation of subcutaneous implantable cardioverter defibrillators. AB - BACKGROUND: Subcutaneous implantable cardioverter defibrillators (S-ICDs) have gained increasing popularity because of certain advantages over transvenous ICDs. However, while conventional ICDs require a single surgical incision to implant, S ICDS need two or three incisions, making them less appealing. OBJECTIVE: This study sought out to investigate the feasibility of using a single-incision technique to implant S-ICDs. METHODS: Patients qualifying for S-ICDs were considered for a single incision. A single incision is performed by making a left inframammary incision and then the subcutaneous tissue is dissected medially toward the lower sternum. Two sutures are placed in the fascia in the xiphoid area to anchor the lead and a tunneling tool is used to dissect the tissue to place the lead parallel to the sternum. Then subcutaneous tissues are dissected down the lateral chest wall over the muscle fascia to create the pulse generator pocket in the vicinity of the fifth and sixth intercostal spaces and near the mid axillary line. RESULTS: Eleven patients (six males and five females) successfully underwent S-ICD implantation with a single incision without acute complications (64% for primary prevention). The mean age is 47.4 +/- 15.8 years. There were no lead dislodgements, inappropriate shocks, or any other issues during a median follow-up of 10 months (interquartile range 5-17). One patient had a successful appropriate shock for ventricular fibrillation about one year after device implant. CONCLUSIONS: A single incision for subcutaneous ICDs is feasible and safe in our early experience. PMID- 30242848 TI - An EPID-based method to determine mechanical deformations in a linear accelerator. AB - PURPOSE: Medical linear accelerators (linac) are delivering increasingly complex treatments using modern techniques in radiation therapy. Complete and precise mechanical QA of the linac is therefore necessary to ensure that there is no unexpected deviation from the gantry's planned course. However, state-of-the-art EPID-based mechanical QA procedures often neglect some degrees of freedom (DOF) like the in-plane rotations of the gantry and imager or the source movements inside the gantry head. Therefore, the purpose of this work is to characterize a 14 DOF method for the mechanical QA of linacs. This method seeks to measure every mechanical deformation in a linac, including source movements, in addition to relevant clinical parameters like mechanical and radiation isocenters. METHODS: A widely available commercial phantom and a custom-made accessory inserted in the linac's interface mount are imaged using the electronic portal imaging device (EPID) at multiple gantry angles. Then, simulated images are generated using the nominal geometry of the linac and digitized models of the phantoms. The nominal geometry used to generate these images can be modified using 14 DOF (3 rigid rotations and 3 translations for the imager and the gantry, and 2 in-plane translations of the source) and any change will modify the simulated image. The set of mechanical deformations that minimizes the differences between the simulated and measured image is found using a genetic algorithm coupled with a gradient-descent optimizer. Phantom mispositioning and gantry angular offset were subsequently calculated and extracted from the results. Simulations of the performances of the method for different levels of noise in the phantom models were performed to calculate the absolute uncertainty of the measured mechanical deformations. The measured source positions and the center of collimation were used to define the beam central axis and calculate the radiation isocenter position and radius. RESULTS: After the simultaneous optimization of the 14 DOF, the average distance between the center of the measured and simulated ball bearings on the imager was 0.086 mm. Over the course of a full counter-clockwise gantry rotation, all mechanical deformations were measured, showing sub millimeter translations and rotations smaller than 1 degrees along every axis. The average absolute uncertainty of the 14 DOF (1 SD) was 0.15 mm or degree. Phantom positioning errors were determined with more than 0.1 mm precision. Errors introduced in the experimental setup like phantom positioning errors, source movements or gantry angular offsets were all successfully detected by our QA method. The mechanical deformations measured are shown to be reproducible over the course of a few weeks and are not sensitive to the experimental setup. CONCLUSION: This work presents of new method for an accurate mechanical QA of the linacs. It features a 14 DOF model of the mechanical deformations that is both more complete and precise than other available methods. It has demonstrated sub millimeter accuracy through simulation and experimentation. Introduced errors were successfully detected with high precision. PMID- 30242849 TI - Complementation studies of the Arabidopsis fc1 mutant substantiate essential functions of ferrochelatase 1 during embryogenesis and salt stress. AB - Ferrochelatase (FC) is the final enzyme for haem formation in the tetrapyrrole biosynthesis pathway and encoded by two genes in higher plants. FC2 exists predominantly in green tissue, whereas FC1 is constitutively expressed. We intended to substantiate the specific roles of FC1. The embryo-lethal fc1-2 mutant was used to express the two genomic FC-encoding sequences under the FC1 and FC2 promoter and explore the complementation of the FC1 deficiency. Apart from the successful complementation with FC1, expression of FC2 under control of the FC1 promoter (pFC1::FC2) compensates for missing FC1 but not by FC2 promoter expression. The complementing lines pFC1FC2(fc1/fc1) succeeded under standard growth condition but failed under salt stress. The pFC1FC2(fc1/fc1) line exhibited symptoms of leaf senescence, including accelerated loss of haem and chlorophyll and elevated gene expression for chlorophyll catabolism. In contrast, ectopic FC1 expression (p35S::FC1) resulted in increased chlorophyll accumulation. The limited ability of FC2 to complement fc1 is explained by a faster turnover of FC2 mRNA during stress. It is suggested that FC1-produced haem is essential for embryogenesis and stress response. The pFC1::FC2 expression readily complements the fc1-2 embryo lethality, whereas higher FC1 transcript content contributes essentially to stress tolerance. PMID- 30242850 TI - Pharmacokinetics of harpagoside in horses after intragastric administration of a Devil's claw (Harpagophytum procumbens) extract. AB - Devil's claw is used for the treatment of inflammatory symptoms and degenerative disorders in horses since many years, but without the substantive pharmacokinetic data. The pharmacokinetic parameters of harpagoside, the main active constituent of Harpagophytum procumbens DC ex Meisn., were evaluated in equine plasma after administration of Harpagophytum extract FB 8858 in an open, single-dose, two treatment, two-period, randomized cross-over design. Six horses received a single dose of Harpagophytum extract, corresponding to 5 mg/kg BM harpagoside, and after 7 days washout period, 10 mg/kg BM harpagoside via nasogastric tube. Plasma samples at certain time points (before and 0-24 hr after administration) were collected, cleaned up by solid-phase extraction, and harpagoside concentrations were determined by LC-MS/MS using apigenin-7-glucoside as internal standard. Plasma concentration-time data and relevant parameters were described by noncompartmental model through PKSolver software. Harpagoside could be detected up to 9 hr after administration. Cmax was found at 25.59 and 55.46 ng/ml, t1/2 at 2.53 and 2.32 hr, respectively, and tmax at 1 hr in both trials. AUC0-inf was 70.46 and 117.85 ng hr ml-1 , respectively. A proportional relationship between dose, Cmax and AUC was observed. Distribution (Vz /F) was 259.04 and 283.83 L/kg and clearance (CL/F) 70.96 and 84.86 L hr-1 kg-1 , respectively. Treatment of horses with Harpagophytum extract did not cause any clinically detectable side effects. PMID- 30242851 TI - Pharmacokinetics and physiologic/behavioral effects of buprenorphine administered sublingually and intravenously to neonatal foals. AB - Buprenorphine is absorbed following sublingual administration, which would be a low-stress delivery route in foals. However, the pharmacokinetics/pharmacodynamics are not described in foals. Six healthy foals <21 days of age participated in a blinded, randomized, 3-period, 5-sequence, 3 treatment crossover prospective study. Foals received 0.01-0.02 mg/kg buprenorphine administered SL or IV with an equivalent volume of saline administered by the opposite route. Blood was collected from the cephalic vein for pharmacokinetic analysis. Physiologic parameters (HR, RR, body temperature, GI sounds), locomotion (pedometer), and behavioral data (activity level, nursing time, response to humans) were recorded. Plasma concentration of buprenorphine exceeded a presumed analgesic level (0.6 ng/ml) in five foals in the IV group and one in the SL group but only for a very brief time. Pharmacokinetic analysis following IV administration demonstrated a short elimination half-life (t1/2beta 1.95 +/- 0.7 hr), large volume of distribution (6.46 +/- 1.54 L/kg), and a high total clearance (55.83 +/- 23.75 ml/kg/min), which differs from adult horses. Following SL administration, maximum concentrations reached were 0.61 +/- 0.11 ng/ml and bioavailability was 25.1% +/- 10.9%. In both groups, there were minor statistical differences in HR, RR, body temperature, locomotion, and time spent nursing. However, these differences were clinically insignificant in this single dose study, and excitement, sedation, or colic did not occur. PMID- 30242852 TI - Long-term postoperative effects of administration of allogeneic blood products in 104 dogs with hemangiosarcoma. AB - OBJECTIVE: To determine the influence of administering allogeneic blood products (ABP) on the progression of hemangiosarcoma in dogs. STUDY DESIGN: Multi institutional, retrospective study. SAMPLE POPULATION: One hundred four dogs with hemangiosarcoma that survived until postoperative discharge from the hospital. METHODS: Medical records of dogs that had been operated on for hemoangiosarcoma were reviewed for signalment, presence of a hemoabdomen, presence of metastatic disease, and whether the dog had received chemotherapy or Yunnan Baiyao. Data that were collected were compared between dogs that received perioperative ABP and those that did not. Disease-free interval was compared between groups. The Kaplan-Meier method was used to obtain univariate descriptive statistics for time to clinical decline. A multivariable Cox regression model was used to analyze association or effect of potential predictor variables. RESULTS: The median disease-free interval (DFI) was shorter in the 67 dogs that received a blood transfusion (76 days; range, 1-836) than in the 37 dogs that did not receive a blood transfusion (120 days; range, 38-916). According to the multivariable Cox regression model, administration of blood products (P = .04) and the presence of gross metastatic disease at the time of surgery (P < .01) shortened the DFI, whereas administration of Yunnan Baiyao (P = .01) prolonged the DFI. CONCLUSION: Allogeneic blood product administration was associated with a shorter disease free interval in this population. However, we could not demonstrate the association between blood products and shorter DFI because of confounding factors. CLINICAL SIGNIFICANCE: Dogs that receive ABP at the time of surgical therapy for hemangiosarcoma may have accelerated disease progression compared with dogs that do not receive ABP. PMID- 30242853 TI - Responses to K deficiency and waterlogging interact via respiratory and nitrogen metabolism. AB - K deficiency and waterlogging are common stresses that can occur simultaneously and impact on crop development and yield. They are both known to affect catabolism, with rather opposite effects: inhibition of glycolysis and higher glycolytic fermentative flux, respectively. But surprisingly, the effect of their combination on plant metabolism has never been examined precisely. Here, we applied a combined treatment (K availability, waterlogging) to sunflower (Helianthus annuus L.) plants under controlled greenhouse conditions, and performed elemental quantitation, metabolomics and isotope analyses at different sampling times. While separate K deficiency and waterlogging caused well-known effects like polyamines production and sugar accumulation, respectively, waterlogging altered K-induced respiration enhancement (via the C5 -branched acid pathway) and polyamine production, and K deficiency tended to suppress waterlogging-induced accumulation of Krebs cycle intermediates in leaves. Furthermore, the natural 15 N/14 N isotope composition (delta15 N) in leaf compounds shows that there was a change in nitrate circulation, with less nitrate influx to leaves under low K availablity combined with waterlogging, and more isotopic dilution of lamina nitrates under high K. Our results show that K deficiency and waterlogging effects are not simply additive, reshape respiration as well as nitrogen metabolism and partitioning, and are associated with metabolomic and isotopic biomarkers of potential interest for crop monitoring. PMID- 30242854 TI - Reassessment of high prevalence human adenovirus detections among residents of two refugee centers in Kenya under surveillance for acute respiratory infections. AB - Human adenoviruses (HAdVs) were previously detected at high prevalence by real time reverse transcription-polymerase chain reaction (rRT-PCR) in the upper respiratory tract of residents of two Kenyan refugee camps under surveillance for acute respiratory infection (ARI) between October 2006 and April 2008. We sought to confirm this finding and characterize the HAdVs detected. Of 2148 respiratory specimens originally tested, 511 (23.8%) screened positive for HAdV and 510 were available for retesting. Of these, 421 (82.4%) were confirmed positive by repeat rRT-PCR or PCR and sequencing. Other respiratory viruses were codetected in 55.8% of confirmed HAdV-positive specimens. Species B and C viruses predominated at 82.8%, and HAdV-C1, -C2, and -B3 were the most commonly identified types. Species A, D, and F HAdVs, which are rarely associated with ARI, comprised the remainder. Viral loads were highest among species B HAdVs, particularly HAdV-B3. Species C showed the widest range of viral loads, and species A, D, and F were most often present at low loads and more often with codetections. These findings suggest that many HAdV detections were incidental and not a primary cause of ARI among camp patients. Species/type, codetections, and viral load determinations may permit more accurate HAdV disease burden estimates in these populations. PMID- 30242855 TI - Pre-emptive dengue control strategy in Pakistan. PMID- 30242856 TI - New advances in microfluidic flow cytometry. AB - In recent years, researchers are paying the increasing attention to the development of portable microfluidic diagnostic devices including microfluidic flow cytometry for the point-of-care testing. Microfluidic flow cytometry, where microfluidics and flow cytometry work together to realize novel functionalities on the microchip, provides a powerful tool for measuring the multiple characteristics of biological samples. The development of a portable, low-cost, and compact flow cytometer can benefit the health care in underserved areas such as Africa or Asia. In this article, we review recent advancements of microfluidics including sample pumping, focusing and sorting, novel detection approaches, and data analysis in the field of flow cytometry. The challenge of microfluidic flow cytometry is also examined briefly. PMID- 30242857 TI - Latest News on relationship between thunderstorms and respiratory allergy, severe asthma, and deaths for asthma. AB - Thunderstorm asthma (TA) refers to the sudden increase of acute bronchospasm following a storm during pollen seasons, necessitating primary care facilities by general practioner (GP) visits, Emergency Department (ED) admissions and hospitalizations, sometimes also endotracheal intubation for severe asthma and near fatal asthma (NFA). In the scientific literature, there are descriptions of epidemics of TA in various geographical areas of the world (1-8) and climate change scenarios indicate there will be an increase in the intensity and frequency of heavy rainfall episodes, including thunderstorms, in all the world. This article is protected by copyright. All rights reserved. PMID- 30242858 TI - Articular cartilage lesions associated with complete lateral meniscal tears in the dog. AB - OBJECTIVE: To describe articular cartilage (AC) lesions associated with complete lateral meniscal tears in dogs. STUDY DESIGN: Observational series. ANIMALS: Seventeen dogs with arthroscopic evidence of a complete lateral meniscal tear and associated AC lesions. METHODS: Medical records of dogs with arthroscopic evidence of complete lateral meniscal tear and associated AC lesions between March 2006 and December 2017 were examined for arthroscopic findings. RESULTS: The cranial cruciate ligament (CrCL) was intact in 11 of 17 dogs, partially ruptured but competent in 4 of 17 dogs, and completely ruptured in 2 of 17 dogs. All dogs had grossly normal caudal cruciate ligament, medial meniscus, and AC of the medial compartment. In each dog, a complete radial tear of the caudal body of the lateral meniscus was associated with degenerative osteoarthritis (OA) of the lateral compartment of the stifle. The Outerbridge score of the lateral tibial condyle and lateral femoral condyle was 5 of 5 in 15 dogs, 3 of 5 in 1 dog, and 4 of 5 in 1 dog. CONCLUSION: Dogs with complete tears of the lateral meniscus developed degenerative OA of the lateral compartment of the stifle leading to AC loss and clinical dysfunction. CLINICAL SIGNIFICANCE: Complete lateral meniscal tears may occur as isolated injuries in dogs with a functional CrCL. PMID- 30242859 TI - Effects of Centella asiatica extract on antioxidant status and liver metabolome of rotenone-treated rats using GC-MS. AB - Centella asiatica has been used as a culinary vegetable or medicinal herb. In this study, the hepatoprotective effect of the standardized extract of C. asiatica (ECa233) in rotenone-treated rats was examined using a GC-MS-based metabolomic approach. ECa233 contains >80% triterpenoids with a ratio of madecassoside to asiaticoside of 1.5(+/-0.5):1. Rats were randomly divided into three groups (with six rats/group): sham negative control, rotenone positive control and the ECa233 test group. Rats in the ECa233 group received 10 mg/kg ECa233 orally for 20 days, followed by 2.5 mg/kg intraperitoneal rotenone injection to induce toxicity before being sacrificed. Metabolomic analysis showed that supplementation of ECa233 protected rat liver against rotenone toxicity. Pipecolinic acid was one of the most important metabolites; its level was decreased in the rotenone group as compared with the control. Supplementation with ECa233 before administration of rotenone raised pipecolinic acid to levels intermediate between controls and rotenone alone. The metabolomics approach also helped discover a possible new genuine epimetabolite in the present work. Antioxidant tests revealed that ECa233 inhibited lipid peroxidation and increased catalase activities in liver tissue. PMID- 30242860 TI - Mechanical analysis of suture attachment methods in toggle suture constructs. AB - OBJECTIVE: To determine the effect of the method used to attach OrthoFiber #5 to a 1/8-in Securos toggle rod on the mechanical properties of the resulting construct. STUDY DESIGN: Prospective bench top mechanical analysis. SAMPLE POPULATION: One hundred twenty-eight OrthoFiber #5-toggle rod suture constructs. METHODS: Toggle-suture constructs (groups A-H) were prepared by using 8 methods to attach OrthoFiber #5 to a 1/8-in toggle rod (n = 16 constructs/group). A servohydraulic materials-testing machine was used to test each toggle-suture construct in tension. Mean load to failure, cycles to failure, construct stiffness, and suture elongation under static and cyclic loading were compared among types of constructs. RESULTS: Mean load to failure was greatest (>500 N) for constructs D (P <= .048) and G (P <= .048). Mean construct stiffness of D (53.52 N/mm) and E (53.6 N/mm) was greater than that of the 6 other constructs (P <= .040). Construct A sustained the most elongation in acute (23.47 mm; P < .001) and cyclic (18.53 mm; P < .003) loading. Cycles to failure was greater for construct C (622 cycles) compared with constructs A, B, and H (P = .008, P = .009, and P = .010, respectively). CONCLUSION: The method used to attach OrthoFiber #5 to a 1/8-in toggle rod influenced the mechanical properties of the construct. No one construct outperformed other groups in all areas of testing, but construct D was superior when mean load to failure and construct stiffness were considered. CLINICAL IMPACT: Construct D, with OrthoFiber #5, passed straight through the toggle rod eyelet, may provide superior stability and resistance to fatigue failure to toggle-in repairs of coxofemoral luxations. PMID- 30242861 TI - Cannabinoid WIN 55,212-2 induces cell cycle arrest and apoptosis, and inhibits proliferation, migration, invasion, and tumor growth in prostate cancer in a cannabinoid-receptor 2 dependent manner. AB - BACKGROUND: Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including in prostate cancer. In the present study, we explored the anti-cancer effects of the synthetic cannabinoid WIN 55,212-2 (WIN) in prostate cancer. METHODS: Established prostate cancer cells (PC3, DU145, LNCaP) were treated with varying concentrations of WIN. Cell proliferation was determined by the MTS assay. The anti-migration and anti-invasive potential of WIN was examined by the wound healing assay and the matrigel invasion assay. Cell cycle analysis was performed by flow cytometry, and mechanistic studies were performed by Western blot. Athymic mice (n = 10) were inoculated with human PC3 cells. Once tumors reached 100 mm3 , animals were randomized into two groups: saline control and WIN (5 mg/kg), delivered by intraperitoneal injection three times per week for 3 weeks. RESULTS: WIN significantly reduced prostate cancer cell proliferation, migration, invasion, induced apoptosis, and arrested cells in Go/G1 phase in a dose-dependent manner. Mechanistic studies revealed these effects were mediated through a pathway involving cell cycle regulators p27, Cdk4, and pRb. Pre-treatment with a CB2 antagonist, AM630, followed by treatment with WIN resulted in a reversal of the anti-proliferation and cell cycle arrest previously seen with WIN alone. In vivo, administration of WIN resulted in a reduction in the tumor growth rate compared to control (P < 0.05). CONCLUSIONS: The following study provides evidence supporting the use of WIN as a novel therapeutic for prostate cancer. PMID- 30242863 TI - The Effect of Social Network Size on Hashtag Adoption on Twitter. AB - Propagation of novel linguistic terms is an important aspect of language use and language change. Here, we test how social network size influences people's likelihood of adopting novel labels by examining hashtag use on Twitter. Specifically, we test whether following fewer Twitter users leads to more varied and malleable hashtag use on Twitter, because each followed user is ascribed greater weight and thus exerts greater influence on the following user. Focusing on Dutch users tweeting about the terrorist attack in Brussels in 2016, we show that people who follow fewer other users use a larger number of unique hashtags to refer to the event, reflecting greater malleability and variability in use. These results have implications for theories of language learning, language use, and language change. PMID- 30242862 TI - Evaluation of the anticancer and anti-metastasis effects of novel synthetic sodium channel blockers in prostate cancer cells in vitro and in vivo. AB - BACKGROUND: Voltage-gated sodium channels (VGSCs) are involved in several cellular processes related to cancer cell growth and metastasis, including adhesion, proliferation, apoptosis, migration, and invasion. We here in investigated the effects of S0154 and S0161, two novel synthetic sodium channel blockers (SCBs), on human prostate cancer cells (PC3, DU145, and LnCaP) and a prostate cancer xenograft model. METHODS: The MTT assay was used to assess the anticancer effects of SCBs in PC3, DU145, and LnCaP cells. Sodium indicator and glucose uptake assays were used to determine the effects of S0154 and S0161 in PC3 cells. The impact of these SCBs on the proliferation, cell cycle, apoptosis, migration, and invasion of PC3 cells were determined using a CFDA-SE cell proliferation assay, cell cycle assay, annexin V-FITC apoptosis assay, transwell cell invasion assay, and wound-healing assay, respectively. The protein expression levels of Nav1.6, Nav1.7, CDK1, cyclin B1, MMP2, MMP9 in PC3 cells were analysis by Western blotting. The in vivo anticancer activity was evaluated using a PC3 xenograft model in nude mice. RESULTS: S0154 and S0161 both showed anticancer and anti-metastatic effects against prostate cancer cells and significantly inhibited cell viability, with IC50 values in the range of 10.51 26.60 MUmol/L (S0154) and 5.07-11.92 MUmol/L (S0161). Both compounds also increased the intracellular level of sodium, inhibited the protein expression of two alpha subunits of VGSCs (Nav1.6 and Nav1.7), and caused G2/M phase cell cycle arrest, with no or minor effects on cell apoptosis. Concentrations of 5 and 10 MUmol/L of S0154 and S0161 significantly decreased the glucose uptake of PC3 cells. The compounds also inhibited the proliferation of PC3 cells and decreased their invasion in transwell assays. Furthermore, S0161 exerted antitumor activity in an in vivo PC3 xenograft model in nude mice, inhibiting the growth of the tumors by about 51% compared to the control group. CONCLUSIONS: These results suggest that S0154 and S0161 have anticancer and anti-metastasis effects in prostate cancer cells both in vitro and in vivo, supporting their further development as potential therapeutic agents for prostate cancer. PMID- 30242864 TI - Role of gram-positive bacteria in chronic pelvic pain syndrome (CPPS). AB - INTRODUCTION: Chronic pelvic pain syndrome (CPPS) is a complex disorder that affects a large proportion of all men. A limited understanding of its etiology and pathogenesis is reflected by the absence of effective therapies. Although CPPS is deemed clinically non-infectious with no well-defined etiological role for microbes, bacteria is readily isolated from both healthy and patient prostate secretion and urine samples. Our laboratory has previously demonstrated that a specific gram-negative bacterial isolate can induce CPPS-like symptoms in mice. Here we aimed to expand on these findings examining the role of gram-positive patient-derived bacteria in CPPS. METHODS: A retrospective analysis of bacterial cultures from CPPS patients from a single center was performed. Gram-positive bacteria were isolated from the expressed prostatic secretion (EPS) of three CPPS patients (pain inducers, PI) and one from a healthy volunteer (non-pain inducer, NPI). These bacteria were inoculated intra-urethrally in two mouse backgrounds and analyzed for their ability to induce tactile allodynia, voiding dysfunction, and colonize the murine prostate. Host immune responses to bacterial instillation were analyzed by flow cytometry. RESULTS: PI strains (Staphylococcus haemolyticus 2551, Enterococcus faecalis 427, and Staphylococcus epidermidis 7244) induced and maintained tactile allodynia responses (200% increase above baseline) for 28 days in NOD/ShiLtJ mice. Conversely the healthy subject derived strain (Staphylococcus epidermidis NPI) demonstrated no significant pelvic allodynia induction. Intra urethral inoculation of the four bacterial strains into C57BL/6 mice did not induce significant increases in pain responses. Infected NOD/ShiLtJ displayed significant voiding dysfunction compared to their control counterparts. Colony counts of prostate tissues from both NOD/ShiLtJ and C57BL/6 mice at day 28 demonstrated that bacterial strains colonized equally well, including NPI. We also determined that mechanistically, the patient-isolates induced prostate inflammation specifically involving T-cells and monocytes. CONCLUSIONS: Gram positive isolates from CPPS patients showed enhanced ability to induce tactile allodynia compared to a single taxonomically similar gram-positive strain isolated from a healthy control. Responses were shown to be dependent on host genetic background and not on colonization differences between strains. PMID- 30242865 TI - Multiple upstream start codons (AUG) in 5' untranslated region enhance translation efficiency of cry2Ac11 without helper protein. AB - Cry2Ac11, a 65 kDa insecticidal protein produced by Bacillus thuringiensis, shows toxicity against dipteran and lepidopteran larvae. It is encoded by cry2Ac11 gene ( orf3), which is part of an operon comprising orf1, orf2, and orf3. Orf2, a helper protein, helps in proper folding and prevents aberrant aggregation of newly produced molecules. In this study, we have elucidated the effect of different mutations in translation initiation region (TIR), particularly the ribosomal binding site and the start codon (RBS-ATG) on cry2Ac11 gene expression without helper protein. All recombinant constructs were expressed in acrystalliferous B. thuringiensis subsp israelensis 4Q7 under the control of strong chimeric promoter cyt1AP/STAB. Of all the mutants, mut/RBS2, with two consecutive AUGs after the spacer region in TIR, exhibited 89- and 2246-fold higher transcript levels compared with 4Q7-operSalI/RBS ( cry2Ac11 operon) and 4Q7-w-RBS ( cry2Ac11 gene), respectively. The analysis of mut/RBS2 messenger RNA (mRNA) structure in the RBS-AUG region showed the presence of RBS in the single stranded part of the moderately stable hairpin loop. The high expression efficiency of Cry2Ac11 mutant without helper protein is a cumulative and cooperative result of chimeric promoter cyt1AP/STAB-SD with the optimal context of RBS-AUG region provided by multiple AUGs and stabilizer sequence at 3' ends. PMID- 30242866 TI - CONDON 3.0: An Updated Software Package for Magnetochemical Analysis-All the Way to Polynuclear Actinide Complexes. AB - An update to the computational framework CONDON, introducing the ability to model and predict the magnetic and electronic properties of polynuclear exchanged coupled actinide systems, such as homonuclear and heteronuclear coordination clusters of 5f ions, is presented. The program can intuitively fit experimental magnetic and spectroscopic data from multiple sources simultaneously, under consideration of a "full model" ligand field theory Hamiltonian. CONDON accounts simultaneously for all aspects relevant to the magnetic characteristics: interelectronic repulsion, ligand field potential, spin-orbit coupling, interatomic exchange interactions, and applied magnetic field. As exemplified by several examples, CONDON represents the first program package able to accurately describe single-ion effect in exchange-coupled actinide systems, limited only by available computational resources. (c) 2018 Wiley Periodicals, Inc. PMID- 30242867 TI - Analytical calculation of pressure for confined atomic and molecular systems using the eXtreme-Pressure Polarizable Continuum Model. AB - We show that the pressure acting on atoms and molecular systems within the compression cavity of the eXtreme-Pressure Polarizable Continuum method can be expressed in terms of the electron density of the systems and of the Pauli repulsion confining potential. The analytical expression holds for spherical cavities as well as for cavities constructed from van der Waals spheres of the constituting atoms of the molecular systems. (c) 2018 Wiley Periodicals, Inc. PMID- 30242868 TI - Hemipelvic and proximal femoral limb salvage endoprosthesis with tendon ongrowth in a dog. AB - OBJECTIVE: To report the clinical application of a hemipelvic and proximal femoral endoprosthesis for limb salvage. STUDY DESIGN: Retrospective case report. ANIMAL: One 5-year-old, neutered female, flat coated retriever with a malignant neoplasia of the left coxofemoral joint. METHODS: An invasive soft tissue mass (histiocytic sarcoma) with bone lysis of the femoral head and acetabulum was noted on radiographs, computed tomography (CT), and MRI. Custom-designed hemipelvic and proximal femoral endoprostheses were produced from CT images and manufactured with hydroxyapatite coated surfaces to allow tissue integration. The proximal femoral implant allowed tendon ongrowth and muscle attachment. The pelvic implant was anchored to the ilium and ischium with screws, and the femoral implant was cemented. Chemotherapy consisted of lomustine (CCNU). RESULTS: No evidence of implant loosening or local/thoracic metastases was noted on radiographs or CT at 6 weeks and at 3, 6, 9, and 12 months after surgery. A neurapraxia resolved 14 weeks postoperatively. Intensive rehabilitation was performed. At 12 months, activity was unrestricted with minimal residual lameness. The dog was euthanized at 14 months for metastatic disease. CONCLUSION: Limb salvage with a hemipelvic and proximal femoral endoprosthesis resulted in limb function and survival for 14 months. CLINICAL SIGNIFICANCE: Neoplasia involving the bones of the coxofemoral joint traditionally requires hemipelvic resection and pelvic limb amputation. This report provides evidence that limb salvage can result in satisfactory levels of activity. PMID- 30242869 TI - Association of single nucleotide autophagy-related protein 5 gene polymorphism rs2245214 with susceptibility to non-small cell lung cancer. AB - INTRODUCTION: Autophagy is a mechanism that is involved in the regulation of cellular life, apoptosis, and stemness while its intervening genes play important functions in various cancers including lung cancer. ATG5 is one of the key genes for the regulation of the autophagy pathway. In this study, our team has investigated the potential relationship between ATG5 gene polymorphism rs2245214 with non-small cell lung cancer (NSCLC) in a subpopulation of patients from southern Iran. In this study, 34 patients with NSCLC (20 males and 14 females [mean age: 12.86 +/- 60.47 years]) and 50 healthy subjects (30 males and 20 females [mean age: 13.09 +/- 56.62 years]) were studied in terms of the genotype of the ATG5 gene. We used restriction fragment length polymorphism and analyzed the results using SPSS software (v.23). The results revealed that subjects harboring the guanine/cytosine (GC) genotype of the rs2245214 ATG5 gene polymorphism had suffered less from NSCLC, whereas the prevalence of the C-allele of this polymorphism was significantly higher in patients with NSCLC ( P < 0.05). On the basis of the results of logistic regression, the presence of this C-allele may predict the risk of lung cancer ( P value = 0.011; OR, 3.52; 95% CI, 1.33 9.26). This study concludes that the C-allele of the rs2245214 ATG5 gene polymorphism is associated with increased susceptibility to NSCLC, whereas the GC genotype of this polymorphism is associated with decreased risk and might therefore have a protective role in the development of NSCLC. PMID- 30242870 TI - Tenascin-C in brain injuries and edema after subarachnoid hemorrhage: Findings from basic and clinical studies. AB - Subarachnoid hemorrhage (SAH) by a rupture of cerebral aneurysms remains the most devastating cerebrovascular disease. Early brain injury (EBI) is increasingly recognized to be the primary determinant for poor outcomes, and also considered to cause delayed cerebral ischemia (DCI) after SAH. Both clinical and experimental literatures emphasize the impact of global cerebral edema in EBI as negative prognostic and direct pathological factors. The nature of the global cerebral edema is a mixture of cytotoxic and vasogenic edema, both of which may be caused by post-SAH induction of tenascin-C (TNC) that is an inducible, non structural, secreted and multifunctional matricellular protein. Experimental SAH induces TNC in brain parenchyma in rats and mice. TNC knockout suppressed EBI in terms of brain edema, blood-brain barrier disruption, neuronal apoptosis and neuroinflammation, associated with the inhibition of post-SAH activation of mitogen-activated protein kinases and nuclear factor-kappa B in mice. In a clinical setting, more severe SAH increases more TNC in cerebrospinal fluid and peripheral blood, which could be a surrogate marker of EBI and predict DCI development and outcomes. In addition, cilostazol, a selective inhibitor of phosphodiesterase type III that is a clinically available anti-platelet agent and is known to suppress TNC induction, dose-dependently inhibited delayed cerebral infarction and improved outcomes in a pilot clinical study. Thus, further studies may facilitate application of TNC as biomarkers for non-invasive diagnosis or assessment of EBI and DCI, and lead to development of a molecular target drug against TNC, contributing to the improvement of post-SAH outcomes. PMID- 30242871 TI - Airlie House legend. PMID- 30242872 TI - Crotalus atrox disintegrin reduces hemorrhagic transformation by attenuating matrix metalloproteinase-9 activity after middle cerebral artery occlusion in hyperglycemic male rats. AB - Hemorrhagic transformation after ischemic stroke is an independent predictor for poor outcome and is characterized by blood vessel rupture leading to brain edema. To date, no therapies for preventing hemorrhagic transformation exist. Disintegrins from the venom of Crotalus atrox have targets within the coagulation cascade, including receptors on platelets. We hypothesized that disintegrins from C. atrox venom can attenuate hemorrhagic transformation by preventing activation of matrix metalloproteinase after middle cerebral artery occlusion (MCAO) in hyperglycemic rats. We subjected 48 male Sprague-Dawley rats weighing 240-260 g to MCAO and hyperglycemia to induce hemorrhagic transformation of the infarction. At reperfusion, we administered either saline (vehicle), whole C. atrox venom (two doses were used), or fractionated C. atrox venom (HPLC Fraction 2). Rats were euthanized 24 hr post-ictus for measurement of infarction and hemoglobin volume. Reversed-phase HPLC was performed to fractionate the whole venom and peaks were combined to form Fraction 2, which contained the disintegrin Crotatroxin. Fraction 2 protected against hemorrhagic transformation after MCAO, and attenuated activation of matrix metalloproteinase-9. Administering matrix metalloproteinase antagonists prevented the protection by Fraction 2. The results of this study indicate that disintegrins found in C. atrox venom may have therapeutic potential for reducing hemorrhagic transformation after ischemic stroke. Moreover, the RP-HPLC fractions retained sufficient protein activity to suggest that gentler and less efficient orthogonal chromatographic methods may be unnecessary to isolate proteins and explore their function. PMID- 30242873 TI - CRNDE promotes cell tongue squamous cell carcinoma cell growth and invasion through suppressing miR-384. AB - Tongue squamous cell carcinoma (TSCC) is the most common type of oral cancer and is an aggressive head and neck malignancy. Increasing studies have demonstrated that long noncoding RNAs (lncRNAs) play important roles in diverse biological cell processes, such as cell development, fate decisions, cell differentiation, cell migration, and invasion. In our study, we showed that long noncoding RNA colorectal neoplasia differentially expressed (CRNDE) expression was upregulated in TSCC cell lines and tissues. Overexpression of CRNDE increased the TSCC cell proliferation, cell cycle, and cell invasion. Moreover, ectopic expression of CRNDE inhibited the miR-384 expression in the SCC1 cell and increased the Kirsten Ras (KRAS), cell division cycle 42, and insulin receptor substrate 1 expression, which were the direct target genes of miR-384. We demonstrated that the miR-384 expression was downregulated in the TSCC samples compared with the paired adjacent nontumor samples. The expression of CRNDE was negatively correlated with the expression of miR-384 in the TSCC samples. Overexpression of miR-384 suppressed TSCC cell proliferation, cell cycle, and invasion. Furthermore, we demonstrated that CRNDE promoted TSCC cell proliferation and invasion through inhibiting miR-384 expression. These results suggested that CRNDE acts as an oncogene in the development of TSCC, which partially occurs through inhibiting miR-384 expression. PMID- 30242874 TI - Optimizing methods for human testicular tissue cryopreservation and spermatogonial stem cell isolation. AB - Cryopreservation of testicular tissue before cancer therapy for fertility preservation in prepubertal boys with cancer is of great interest in reproductive medicine. Isolation of spermatogonial stem cells (SSCs) from cryopreserved tissues would be a suitable cell source to re-establish spermatogenesis after cancer therapy. We herein establish optimized protocols for cryopreservation of human testicular tissue and isolation of SSCs from cryopreserved tissue. We developed a freezing protocol that provided high testicular cell viability and supported structural integrity and tubular epithelium coherence similar to fresh tissue. Then, we established a protocol that allowed efficient isolation of functional SSCs from cryopreserved tissues. Isolated cells were found on the testicular basement membrane after xenotransplantation. Our results demonstrated the preservation of testicular tissue structure and high cell viability with efficient isolation of SSCs after testicular cryopreservation, which is promising for future therapeutic applications in fertility preservation. PMID- 30242875 TI - Esophageal cancer lymph node metastasis-associated gene signature optimizes overall survival prediction of esophageal cancer. AB - Esophageal cancer (EC) is characteristic of early regional lymph node metastasis (LNM) and most patients with metastasis have a poor prognosis. However, the current diagnostic techniques do not enable precise differentiation of EC LNM, prognostic stratification, and individual survival estimation. To identify potential molecular biomarkers for EC patients with LNM, we explored differently expressed genes in The Cancer Genome Atlas database between 77 non-LNM cases and 88 LNM cases by limma package R. Then, according to univariate and multivariate Cox regression analyses, we constructed an 8-messenger RNA (mRNA) prognostic signature model, which could predict the outcome in a more exact way. The area under the curve of the risk score is significantly higher than other clinical information, indicating that the 8-mRNA-based risk score is a good indicator for prognosis. Then, combined with other individual risk factors, such as age, sex, T stage, M stage, etc, we could precisely calculate the individual 1-, 3-, and 5 year survival rates. The Gene Set Enrichment Analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analysis indicate that the risk model is mainly associated with cancer-related pathways, such as cell division, cellular meiosis, and cell cycle regulation. In summary, the 8-mRNA-based risk score model that we developed successfully predicts the survival of EC. It is independent of clinical information and performing better than other clinical information for prognosis. PMID- 30242876 TI - Curcumin derivative L6H4 inhibits proliferation and invasion of gastric cancer cell line BGC-823. AB - Curcumin and its chalcone derivatives have well-known, explicit biological antitumor properties, such as instance antiproliferative and apoptotic effects via multiple molecular targets. In this study, we investigated the anticancer activity of curcumin derivative L6H4 (curcumin L6H4) on gastric cancer cells. Inhibitory effects of curcumin L6H4 on gastric cancer cells (BGC-823) were studied by the diphenyltetrazolium (MTT) assay, and cell apoptosis was detected by Annexin-V/propidium iodide (PI) staining and then analyzed by flow cytometry. A mouse xenotransplant gastric tumor model was established to detect the role of curcumin L6H4 in vivo. The apoptosis-related proteins p53, p21, Bax, and Bcl-2 in BGC-823 cells and mouse xenotransplant models treated with curcumin L6H4 were determined by Western blot analysis. Curcumin L6H4 can significantly inhibit the proliferation and induce the apoptosis of BGC-823 cells, thus enhancing the expression levels of p53, p21, Bax, and Bcl-2 noticeably in vivo and in vitro. Meanwhile, curcumin L6H4 can remarkably suppress the growth of tumor cells in animal models. These results suggest that curcumin derivative L6H4 has potent of antitumor properties in vitro or in vivo. PMID- 30242878 TI - Baicalin attenuates myocardial ischemia-reperfusion injury through Akt/NF-kappaB pathway. AB - BACKGROUND: Baicalin can attenuate myocardial ischemia-reperfusion (I/R) on damage. However, the mechanisms are still not fully understood. The study aimed to investigate the antiapoptosis and anti-inflammatory effects of baicalin on myocardial I/R-induced injury. METHODS: We established male rats I/R model, and baicalin was intragastric administration after ischemia onset. All experimental animals were randomly divided into five groups: group I, sham; group II, I/R; group III, 50 mg/kg; group IV, 100 mg/kg; and group V, 200 mg/kg baicalin. Postoperation, left ventricular (LV) function was recorded by transthoracic echocardiography. Myocardial infarct size, number of vessels and apoptosis were detected by histology and immunohistochemistry. Furthermore, the messenger RNA (mRNA) and protein levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), IL-6, IL-8, IL-10, Bcl2, Bax, caspase-3, phosphatidylinositol 3 kinase (PI3K), Akt, p-Akt, and nuclear factor-kappaB (NF-kappaB) p65 in myocardial tissues were measured by quantitative real-time polymerase chain reaction and Western blot analysis assays. RESULT: When compared with I/R groups, baicalin could significantly improve LV hemodynamic parameters. Myocardial infarct size and apoptosis were significantly decreased, but the vessel density was increased. The mRNA levels of TNF-alpha, IL-1beta, IL-6, and IL-8 were downregulated, but the levels of IL-10, proapoptotic genes caspase-3, and the ratio of Bax/Bcl2 were upregulated. Moreover, the protein expression of PI3K, p Akt, and Akt were upregulated but NF-kappaB p65 was downregulated in the groups III, IV, and V than in group II. CONCLUSION: Our current study suggested that baicalin attenuated myocardial I/R-induced damage, inhibited myocardial apoptosis, and inflammation by activating PI3K/Akt but suppressing NF-kappaB signaling. PMID- 30242877 TI - Neuroprotective effects of SMTP-44D in mice stroke model in relation to neurovascular unit and trophic coupling. AB - Stachybotrys microspora triprenyl phenol (SMTP)-44D has both anti-oxidative and anti-inflammatory activities, but its efficacy has not been proved in relation to the pathological changes of neurovascular unit (NVU) and neurovascular trophic coupling (NVTC) in ischemic stroke. Here, the present study was designed to assess the efficacies of SMTP-44D, moreover, compared with the standard neuroprotective reagent edaravone in ischemic brains. ICR mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min, SMTP-44D (10 mg/kg) or edaravone (3 mg/kg) was intravenously administrated through subclavian vein just after the reperfusion, and these mice were examined at 1, 3, and 7 d after reperfusion. Compared with the vehicle group, SMTP-44D treatment revealed obvious ameliorations in clinical scores and infarct volume, meanwhile, markedly suppressed the accumulations of 4-HNE, 8-OHdG, nitrotyrosine, RAGE, TNF-alpha, Iba-1, and cleaved caspase-3 after tMCAO. In addition, SMTP-44D significantly prevented the dissociation of NVU and improved the intensity of NAGO/BDNF and the number of BDNF/TrkB and BDNF/NeuN double positive cells. These effects of SMTP 44D in reducing oxidative and inflammatory stresses were similar to or stronger than those of edaravone. The present study demonstrated that SMTP-44D showed strong anti-oxidative, anti-inflammatory, and anti-apoptotic effects, moreover, the drug also significantly improved the NVU damage and NVTC in the ischemic brain. PMID- 30242879 TI - A 4-microRNA signature for survival prognosis in pediatric and adolescent acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a hematologic malignancy with significant molecular heterogeneity. MicroRNAs (miRNAs) play a critical role in AML diagnosis, pathogenesis, and prognosis of AML. Little has been done to identify a miRNA signature in pediatric and adolescent patients for predicting overall survival. This study aims to identify a panel of miRNA signature that could predict the prognosis of all younger AML patients with all subtypes of AML by analyzing data from The Cancer Genome Atlas (TCGA). A total of 229 patients under 23 years with miRNA data and corresponding clinical data from TCGA database were enrolled in this study. Through conducting multivariate analysis in the training test, it was identified that the high expression of hsa-miR-509 and hsa-miR-542 were independent poor prognostic factors, whereas that of hsa-miR-146a and hsa miR-3667 had a trend to be favorable factors. A 4-miRNA signature was constructed by these miRNAs considering the weight of each. In testing group and all 229 patients' cohort as well as 59 cytogenetically normal AML (CN-AML) patients' cohort, higher risk score was associated with shorter overall survival (OS). All results were confidential by using powerful statistical analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis were carried out to further develop leukemia-relevant mechanisms supporting the model. The results indicate that the 4-miRNA-based signature is a reliable prognostic biomarker for pediatric and adolescent AML patients. PMID- 30242880 TI - Ulinastatin protects rats from sepsis-induced acute lung injury by suppressing the JAK-STAT3 pathway. AB - Sepsis is usually accompanied by pulmonary inflammations, leading to acute lung injury. During this process, endogenous factors that play a regulatory role could be exploited to therapeutically alleviate such lethal tissue injury. Here, we showed that ulinastatin (UTI) administration could reduce lung tissue necrosis and swelling during sepsis in rats. UTI treatment also decreased the levels of inflammatory mediators both in the lung and in the serum. Mechanistically, we showed that the phosphorylation levels of JAK2 and STAT3 in the lung of UTI treated rats were lower than control rats and were correlated with the decreased levels of inflammatory mediators. Taken together, these results demonstrate the protective role of UTI in sepsis-induced acute lung injury. PMID- 30242881 TI - Improvement of membranous nephropathy by inhibition of miR-193a to affect podocytosis via targeting WT1. AB - The objective of this paper was to explore the role and molecular mechanism of miR-193a in membranous nephropathy (MN). Experimental rats and podocytes were randomly divided into four groups: control, MN, miR-NC, and miR-193a inhibitor groups. The relative mRNA level of miR-193a was determined. The mRNA level and protein expression of PODXL, NPHS1, and Notch1 were determined by real-time polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. The mRNA level and protein expression of WT1 in podocytes were also determined by RT PCR and Western blot analysis. The relative mRNA level of miR-193a in the MN group was significantly higher than that in the control group, and inhibition of miR-193a inhibited the increase successfully. Inhibition of miR-193a inhibited renal injury, podocyte injury, and tissue cell apoptosis resulting from MN. The expression of PODXL, NPHS1, and Notch1 was decreased in the MN group, while the expression was increased in the miR-193a inhibitor group. WT1 was verified as a target gene of miR-193a and the expression of WT1 increased after inhibition of miR-193a. Inhibition of miR-193a by targeting WT1 could inhibit renal function injury, renal tissue cell apoptosis, and podocytosis. PMID- 30242882 TI - Curcumin-induced autophagy and nucleophagy in Spodoptera frugiperda Sf9 insect cells occur via PI3K/AKT/TOR pathways. AB - Compounds from plants or microbes are important resources for new natural pesticides against a wide variety of pests. The growing attention on the role of autophagy (type II cell death) in regulation of insect toxicology has propelled researchers to investigate autophagic cell death pathways. Our previous study proved that the cytotoxic effect of curcumin in Spodoptera frugiperda cells is regulated by autophagy. However, the signaling pathways and molecular mechanisms had not been determined. The current study elucidates curcumin inhibition of survival signaling by blocking the activation of PI3K/AKT/TOR pathways to induce autophagy in S. frugiperda cells. The result demonstrates that nucleophagy associated with cell death following the curcumin treatment. Following the curcumin treatment, Atg8/LC3 immunostaining in both nucleus and cytoplasm was markedly increased. Further, messenger RNA expression level of Atg8 and Atg1 genes regulation by curcumin was examined using quantitative reverse transcription polymerase chain reaction, and the result exhibited increased level of expression after curcumin treatment in a time-dependent manner. Our current study provides new insights to the autophagy occurring via PI3K/AKT/TOR pathways in S. frugiperda Sf9 insect cells induced by curcumin. Taken together, our results show for the first time that curcumin induced nucleophagy in lepidopteron insect cell line. PMID- 30242883 TI - Whole transcriptome sequencing reveals biologically significant RNA markers and related regulating biological pathways in cardiomyocyte hypertrophy induced by high glucose. AB - Cardiomyocyte hypertrophy is a physiological adaptation used in an attempt to augment or preserve cardiac function for short periods. Long-term cardiomyocyte hypertrophy often progresses to heart failure. Previous studies have presented comprehensive mechanisms underlying cardiomyocyte hypertrophy, such as signaling pathways, marker genes, and marker miRNAs or lncRNAs. However, the mechanism in RNA level is still unclear. In this study, we used the whole transcriptome technology on cardiomyocety hypertrophy cells, which were cultured with a high concentration of d-glucose. Many differentially expressed markers, including genes, lncRNAs, miRNAs, and circRNAs were identified. Further quantitative real time PCR verified the highly specific expressed genes, such as Eid1, Timm8b, Mrpl50, Dusp18, Abrc1, Klf13, and Igf1. Moreover, the functional pathways were also enriched with the differentially expressed lncRNA, miRNA, and circRNA. Our study gives new insights into cardiomyocyte hypertrophy and makes great progress in comprehending its mechanism. PMID- 30242884 TI - Melatonin and inflammation-Story of a double-edged blade. AB - Melatonin is an immune modulator that displays both pro- and anti-inflammatory properties. Proinflammatory actions, which are well documented by many studies in isolated cells or leukocyte-derived cell lines, can be assumed to enhance the resistance against pathogens. However, they can be detrimental in autoimmune diseases. Anti-inflammatory actions are of particular medicinal interest, because they are observed in high-grade inflammation such as sepsis, ischemia/reperfusion, and brain injury, and also in low-grade inflammation during aging and in neurodegenerative diseases. The mechanisms contributing to anti inflammatory effects are manifold and comprise various pathways of secondary signaling. These include numerous antioxidant effects, downregulation of inducible and inhibition of neuronal NO synthases, downregulation of cyclooxygenase-2, inhibition of high-mobility group box-1 signaling and toll-like receptor-4 activation, prevention of inflammasome NLRP3 activation, inhibition of NF-kappaB activation and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). These effects are also reflected by downregulation of proinflammatory and upregulation of anti-inflammatory cytokines. Proinflammatory actions of amyloid-beta peptides are reduced by enhancing alpha-secretase and inhibition of beta- and gamma-secretases. A particular role in melatonin's actions seems to be associated with the upregulation of sirtuin-1 (SIRT1), which shares various effects known from melatonin and additionally interferes with the signaling by the mechanistic target of rapamycin (mTOR) and Notch, and reduces the expression of the proinflammatory lncRNA-CCL2. The conclusion on a partial mediation by SIRT1 is supported by repeatedly observed inhibitions of melatonin effects by sirtuin inhibitors or knockdown. PMID- 30242885 TI - CRISPR/Cas9-mediated sheep MSTN gene knockout and promote sSMSCs differentiation. AB - Myostatin (MSTN) is an important gene involved in the regulation of embryonic muscle cells and adult muscle development; it has a good application prospect in transgenic animal production by improving the yield of muscle. The purpose of this study is to construct MSTN gene knockout vector using clustered regularly interspaced short palindromic repeats ( CRISPR)/CRISPR-associated protein 9 ( Cas9). The knockout efficiency was evaluated in sheep ear fibroblasts (SEFs) by cleavage activity of transcription of guide RNA ( gRNA), luciferase-single-strand annealing assay, T7 endonuclease I assay (T7E1), and TA clone sequence (10/38); and above all, detection showed that the cleavage activity of CRISPR/Cas9 mediated MSTN reached 29%. MSTN-Cas9/gRNA4 was transfected into sheep skeletal muscle satellite cell (sSMSC) to confirm the function of MSTN in myotomes formation induced by starvation in low-serum medium. The results showed that myotubes formation efficiency were 11.2 +/- 1.3% and 19.5 +/- 2.1% in the control group and knockout group, respectively. The average length of myotomes was 22 +/- 5.3 and 47 +/- 3.6 MUm, displaying that MSTN knockout can promote sSMSC differentiation in number and length. The unlabeled MSTN-Cas9/gRNA4 was transfected into SEFs and monoclonal positive cells was obtained after 48 hours transfection. The MSTN-positive cells were used as donor cells to perform somatic cell nuclear transplantation to produce transgenic sheep. A total of 20 embryos were transplanted into surrogate mothers, four of them normally produce offspring. The genomic DNA of surviving lambs were used as a template, three positive individuals were identified by T7E1 digestion. All the results demonstrated that the CRISPR/Cas9 system has the potential to become an important and applicable gene engineering tool in animal breeding. PMID- 30242886 TI - Decreased expression of LIF mRNA in patients withmyoma uteri. AB - OBJECTIVE: The aim of this study was to evaluate endometrial receptivity by measuring HOXA-10, HOXA-11, and LIF gene expressions in women with polycystic ovary syndrome. METHODS: A total of 48 women were included in this clinical study. Thepatients were allocated to two groups: study group consisted of 28 patients with myoma uteri and control group consisted of 20 patients without myoma uteri. Endometrial sampling was performed during the proliferative phase. The biopsies obtained from the patients with myoma uteri were taken from the place where the fibroids were localized. HOXA-10, HOXA-11, and LIF expressions were measured in the endometrial sampling material. Demographic data of the patients such as age, obstetric and gynecologic history, medical conditions, medications, surgical history, last menstrual period were recorded. Also, the number, size, localization, and type of the myoma were registered. RESULTS: The mean age of the patients was 42.07 and 38.17, respectively. HOXA-11 levels in the study and control groups were 0.004 +/- 0.001 and 0.010 +/- 0.001, respectively ( P < 0.90). Paradoxically, HOXA-10 levels were found to be higher in the study group than the control group, but the difference was not statistically significant ( P < 0.25). LIF levels were significantly lower in the study group ( P < 0.05). CONCLUSION: Our results showed that myoma uteri might lead to a decrease in implantation rate by diminishing LIF gene expressions. However, there were no differences between the two groups in terms of HOXA-10 and HOXA-11 levels. PMID- 30242887 TI - Scaffolding role of TcpB in disrupting TLR4-Mal interactions: Three to tango. AB - Toll/interleukin-1 like receptors (TLRs) are membrane-spanning proteins crucially involved in innate immunity. On activation, the cytoplasmic toll/interleukin-1 receptor (TIR) domains of these receptors undergo homo- or heterodimerization. Brucella sp. are bacterial pathogens that affect the immune system by suppressing the TLR signaling pathway. They enact this by encoding a TIR domain-containing protein, TcpB, which suppresses NF-kappaB activation and proinflammatory cytokine secretion mediated by TLR4 receptors. TcpB has been shown to target the Mal mediated pathway to suppress TLR signaling. The recent identification of its mechanism of interference with TLR4 signaling involving Mal prompted us to further study the structural aspects of TcpB binding with TLR4 and Mal. Our triprotein model displays the overall scaffolding role of TcpB in anchoring TLR4 and Mal thereby inhibiting their interaction leading to the attenuation of the TLR4 pathway. PMID- 30242888 TI - Orotate phosphoribosyltransferase as a predictor of benefit from S-1 adjuvant chemotherapy for cholangiocarcinoma patients. AB - BACKGROUND AND AIM: To improve the prognosis of cholangiocarcinoma, we investigated potential biomarkers that may enable the selection of patients for whom postoperative adjuvant chemotherapy is likely effective. METHODS: The cohort of this retrospective study included 170 surgically resected cholangiocarcinoma patients, 26 with gemcitabine adjuvant chemotherapy (GEM group), 36 with S-1 adjuvant chemotherapy (S-1 group), and 103 receiving no adjuvant chemotherapy (NC group). Propensity score matching was performed to adjust patient backgrounds; 36 patients from the NC group then were selected. Immunohistochemistry of orotate phosphoribosyltransferase (OPRT) and human equilibrative nucleoside transporter 1 (hENT1) was performed to determine the correlation between their expression and disease-free survival (DFS). RESULTS: After matching, the backgrounds of these three groups were unbiased. No significant improvement of DFS by adjuvant chemotherapy was observed in the whole cohort. However, among the high-OPRT expression patients, DFS of GEM, S-1, and NC groups at 5 years was 28.8%, 53.8%, and 25.5%, respectively. The DFS of the S-1 group was significantly longer than that of the NC group (P = 0.034). On the other hand, no significant differences in DFS were observed among the low OPRT expression patients. hENT1 expression was shown to have no predictive value. Multivariate analysis of the high-OPRT expression patients demonstrated that S-1 adjuvant chemotherapy can reduce tumor recurrence (HR, 0.303; P = 0.013). CONCLUSION: Cholangiocarcinoma patients with high OPRT expression would benefit from postoperative adjuvant S-1 therapy, which increases the DFS. Assessment of OPRT expression may contribute to the optimization of adjuvant chemotherapy for cholangiocarcinoma. PMID- 30242889 TI - SMC1A is associated with radioresistance in prostate cancer and acts by regulating epithelial-mesenchymal transition and cancer stem-like properties. AB - Prostate cancer is one of the most commonly diagnosed cancers and a pressing health challenge in men worldwide. Radiation therapy (RT) is widely considered a standard therapy for advanced as well as localized prostate cancer. Although this primary therapy is associated with high cancer control rates, up to one-third of patients undergoing radiation therapy becomes radio-resistant and/or has tumor relapse/recurrence. Therefore, focus on new molecular targets and pathways is essential to develop novel radio-sensitizing agents for the effective and safe treatment of prostate cancer. Here, we describe functional studies that were performed to investigate the role of structural maintenance of chromosome-1 (SMC1A) in radioresistance of metastatic prostate cancer cells. Short hairpin RNA (shRNA) was used to suppress SMC1A in metastatic castration-resistant prostate cancer cells, DU145 and PC3. Clonogenic survival assays, Western blot, RT-PCR, and gamma-H2AX staining were used to assess the effect of SMC1A knockdown on radiation sensitivity of these prostate cancer cells. We demonstrate that SMC1A is overexpressed in human prostate tumors compared to the normal adjacent tissue. SMC1A knockdown limits the clonogenic potential, epithelial-mesenchymal transition (EMT), and cancer stem-like cell (CSC) properties of DU145 and PC3 cells and enhanced efficacy of RT in these cells. Targeted inhibition of SMC1A not only plays a critical role in overcoming radio-resistance in prostate cancer cells, but also suppresses self-renewal and the tumor-propagating potential of x irradiated cancer cells. We propose that SMC1A could be a potential molecular target for the development of novel radio-sensitizing therapeutic agents for management of radio-resistant metastatic prostate cancer. PMID- 30242890 TI - Role of angiotensin-converting enzyme insertion/deletion polymorphism in sudden cardiac arrest. AB - OBJECTIVE: This study aimed to investigate the relationship between angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and to understand sudden cardiac arrest (SCA) in the Chinese population. METHODS: In this study, 232 patients were divided into the SCA group and the coronary disease group with coronary disease, but no SCA occurred during the treatment period. After comparing the genotype frequencies of the two groups, all patients were further divided into three groups as the II homozygotes, ID heterozygotes, and DD homozygotes to investigate the relationship in ACE I/D polymorphism and other risk factors of SCA. RESULTS: The frequencies of DD genotype in the SCA group were significantly higher than the coronary disease group, as well as the D allele frequencies in the SCA group were high when compared with the coronary disease group. According to the genotypes of the ACE I/D polymorphism, the distribution of patients' characteristics had no significant differences among all the characteristics. Both, the patients who survived SCA, with II genotype and the ones who died of SCA, with DD genotype had significant higher percentages. CONCLUSION: The DD genotype was associated with a higher prevalence of SCA and might be a risk factor of survival rate in sudden cardiac death. PMID- 30242891 TI - Stabilizing proteins to prevent conformational changes required for amyloid fibril formation. AB - Amyloid fibrillation is associated with several human maladies, such as Alzheimer's, Parkinson's, Huntington's diseases, prions, amyotrophic lateral sclerosis, and type 2 diabetes diseases. Gaining insights into the mechanism of amyloid fibril formation and exploring novel approaches to fibrillation inhibition are crucial for preventing amyloid diseases. Here, we hypothesized that ligands capable of stabilizing the native state of query proteins might prevent protein unfolding, which, in turn, may reduce the propensity of proteins to form amyloid fibrils. We demonstrated the efficient inhibition of amyloid formation of the human serum albumin (HSA) (up to 85%) and human insulin (up to 80%) by a nonsteroidal anti-inflammatory drug, ibuprofen (IBFN). IBFN significantly increases the conformational stability of both HSA and insulin, as confirmed by differential scanning calorimetry (DSC). Moreover, increasing concentration of IBFN boosts its amyloid inhibitory propensity in a linear fashion by influencing the nucleation phase as assayed by thioflavin T fluorescence, transmission electron microscopy, and dynamic light scattering. Furthermore, circular dichroism analysis supported the DSC results, showing that IBFN binds to the native state of proteins and almost completely prevents their tendency to lose secondary and tertiary structures. Cell toxicity assay confirms that species formed in the presence of IBFN are less toxic to neuronal cells (SH SY5Y). These results demonstrate the feasibility of using a small molecule to stabilize the native state of proteins, thereby preventing the amyloidogenic conformational changes, which appear to be the common link in several human amyloid diseases. PMID- 30242892 TI - The lncRNA small nucleolar RNA host gene 5 regulates trophoblast cell proliferation, invasion, and migration via modulating miR-26a-5p/N-cadherin axis. AB - Pre-eclampsia (PE) is a pregnancy-specific disease characterized by the occurrence of hypertension and proteinuria after two weeks of gestation. Long noncoding RNAs (lncRNAs) are emerging as key regulators in PE development. This study aims to investigate the role of lncRNA, small nucleolar RNA host gene 5 (SNHG5), in the pathogenesis of PE. The expression of SNHG5 was significantly downregulated in placental tissues from patients with severe PE compared normal controls. Overexpression of SNHG5 promoted trophoblast (HTR-8/SVneo) cell proliferation, invasion, and migration, and flow cytometry results showed that SNHG5 overexpression inhibited apoptosis and caused a decrease of cell population at the G 0 /G 1 phase and an increase of cell population at the S phase, while knockdown of SNHG5 had the opposite effects. The interaction between SNHG5 and miR-26a-5p was predicted by bioinformatics analysis and confirmed by luciferase reporter assay and RNA immunoprecipitation, and miR-26a-5p was negatively regulated by SNHG5; miR-26a-5p expression was upregulated in PE placental tissues and was inversely correlated with SNHG5 expression. Furthermore, miR-26a-5p was predicted to target the 3' untranslated region of N-cadherin, which was confirmed by luciferase reporter assay, and miR-26a-5p overexpression suppressed N-cadherin expression in HTR-8/SVneo cells. N-cadherin mRNA expression was downregulated in PE placental tissues and was positively correlated with SNHG5 expression. Both overexpression of miR-26a-5p and knockdown of N-cadherin suppressed HTR-8/SVneo cell invasion and migration, and also attenuated the effects of SNHG5 on the cellular functions of HTR-8/SVneo cells. In conclusion, our study suggested that SNHG5 promotes trophoblast cell proliferation, invasion, and migration at least partly via regulating the miR-26a-5p/N-cadherin axis. PMID- 30242893 TI - Visualization of bacterial contamination in an apheresis platelet unit. PMID- 30242894 TI - mTOR/STAT-3 pathway mediates mesenchymal stem cell-secreted hepatocyte growth factor protective effects against lipopolysaccharide-induced vascular endothelial barrier dysfunction and apoptosis. AB - Mesenchymal stem cells (MSCs) protect the endothelial barrier complex and survival, implicated in the pathogenesis of acute lung injury (ALI) via paracrine hepatocyte growth factor (HGF). However, the mechanism of HGF in endothelial regulation remains unclear. Here, we introduced a coculture protocol of pulmonary microvascular endothelial cells (PMVECs) and overexpression of the HGF gene of MSCs (MSC-HGF). Immunofluorescence and endothelial permeability analysis revealed that MSC-HGF protected endothelial tight junction protein occludin expression and attenuated cellular permeability as well as endothelial apoptosis. To investigate the novel mechanism mammalian TOR (mTOR)/ signal transducer and activator of transcription 3 (STAT-3) signaling in HGF protective effects against endothelial barrier and apoptosis, we used recombinant mouse HGF in endothelial cells. In addition, we used mTOR inhibitor rapamycin to inhibit the mTOR pathway. Our study demonstrated that rapamycin decreased the protective effects of HGF on the endothelium by decreasing tight junction protein occludin expression and cell proliferation, and raising lipopolysaccharide (LPS)-induced endothelial permeability, endothelial cell injury factors ET-1 and vWF. Similarly, the protective effects of HGF on reducing endothelial barrier and apoptosis were weakened when PMVECs were treated with the STAT-3 inhibitor S3I-201. Moreover, mTOR/STAT-3 were activated by HGF demonstrated as raising mTOR (Ser2448) and STAT3 (Ser727) phosphorylation proteins, leading to endothelial barrier improvement and survival. Reversely, rapamycin or S3I-201 inhibited mTOR/STAT-3 activation. Taken together, our findings highlight that the activation of the mTOR/STAT-3 pathway provides novel mechanistic insights into MSC-secreted HGF protection against LPS-induced vascular endothelial permeability dysfunction and apoptosis, which contributes to decreasing microvascular loss and lung injury. PMID- 30242895 TI - Developmental exposure to silver nanoparticles at environmentally relevant concentrations alters swimming behavior in zebrafish (Danio rerio). AB - Silver nanoparticles (Ag-NPs) are ubiquitous in household and medical products because of their antimicrobial activity. A consequence of the high volume of Ag NP production and usage is increased amounts of Ag-NPs released into the environment. Their small size (1-100 nm) results in unique physiochemical properties that may increase toxicity relative to their bulk counterpart. Therefore, the goal of the present study was to assess the potential toxicity of environmentally relevant concentrations of Ag-NPs in zebrafish (Danio rerio). Wild-type tropical 5D zebrafish embryos were exposed to Ag-NPs from 4 to 120 h postfertilization at 0.03, 0.1, 0.3, 1, and 3 ppm (mg/L). Inductively coupled plasma-mass spectrometry confirmed concentration-dependent uptake of Ag into zebrafish as well as bioaccumulation over time. A morphological assessment revealed no significant hatching impairment, morphological abnormalities, or mortality at any concentration or time point examined. However, assessment of photomotor behavior at 3 d postfertilization (dpf) revealed significant hyperactivity in the 0.3, 1, and 3 ppm Ag-NP treatment groups. At 4 dpf, significant hyperactivity was observed only in the 3 ppm treatment group, whereas 5 dpf larvae exposed to Ag-NPs displayed no significant abnormalities in photomotor behavior. These findings suggest that nonteratogenic concentrations of Ag-NPs are capable of causing transient behavioral changes during development. Environ Toxicol Chem 2018;37:3018-3024. (c) 2018 SETAC. PMID- 30242896 TI - Imaging of a high concentration of iron labeled cells with positive contrast in a rat knee. AB - PURPOSE: The sweep imaging with Fourier transformation (SWIFT) imaging technique has been shown to provide positive contrast from diluted cell suspensions labeled with super-paramagnetic iron oxide (SPIO) in a tissue, as an alternative to T2* weighted imaging. Here we demonstrate a variation of the SWIFT technique that yields a hyperintense signal from a concentrated cell suspension. The proposed technique provides minimal background signal from host tissue and facilitates visualization of injected cells. METHODS: The proton resonance frequency and linewidth were determined for SPIO solutions of different concentrations. The original SWIFT sequence was modified and a dual saturation Gaussian shape RF pulse with ~200 Hz bandwidth was incorporated into the acquisition protocol to suppress host tissue and fat signals. This modification of the original acquisition protocol permits the detection of a hyperintense signal from grafted cells with minimal background signal from the host tissue. RESULTS: SPIO particles not only induce broadening of NMR line-width but also an initiate proton resonance frequency shift. This shift is linearly proportional to the concentration of the iron oxide particles and induced by the bulk magnetic susceptibility of SPIOs. The shift of the resonance frequency of iron labeled cells allowed us effectively suppress the host tissues with saturation RF pulse to improve MRI detection of grafted cells. CONCLUSIONS: Iron oxide particles increase the resonance frequency of water proton signal. This shift permitted us to add the tissue/fat saturation RF pulse into the original SWIFT acquisition protocol and detect distinct hyperintense signals from grafted cells with minimal background signal from the host tissue. PMID- 30242897 TI - Minor allele of rs1057317 polymorphism in TLR4 is associated with increased risk of Helicobacter pylori -induced gastric cancer. AB - BACKGROUND: Helicobacter pylori (HP) plays a significant role in the carcinogenesis of gastric cancer (GC), the second leading cause of cancer-related death worldwide. The aim of this study was to investigate the effect of rs1057317 polymorphism on the interaction between microRNA-034a (miR-034a) and toll-like receptor 4 (TLR4), and their involvement in the HP-associated GC. METHODS: Computation analyses, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and luciferase assays were performed to identify potential miRNAs involved in the carcinogenesis of HP-induced GC. Subsequently, the effect of miR 34a and recombinant TNFalpha-interacting protein alpha (rTip-alpha) on the expression of TLR4, interleukin (IL)-6, and tumor necrosis factor alpha (TNF alpha) was measured. RESULTS: Three hundred and twelve HP-positive GC patients (HP+ GC) and 380 HP-negative GC patients (HP- GC) were enrolled into this study. It was found that, in HP-positive patient, the AA genotype of the rs1057317 polymorphism was closely associated with the risk of GC (95% confidence interval, 1.12 to 2.70; odds ratio, 1.74; P = 0.0129). Furthermore, between the HP+ GC and HP- GC groups, miR-34a was the only miRNA showing a significantly different expression. Subsequently, TLR4 was identified as a target gene of miR-34a. Interestingly, miR-34a evidently reduced the expression of TLR4 3'-untranslated region (3'-UTR) containing the C allele of the rs1057317 polymorphism, but the TLR4 3'-UTR containing the A allele in the rs1057317 was not affected by miR-34a. In addition, the expression of IL-6 and TNF-alpha was significantly downregulated by miR-34a, but increased by rTip-alpha. Both miR-34a and rTip-alpha could enhance the viability of cells, although the effect of rTip-alpha was stronger. CONCLUSION: The data of this study suggested that the rs1057317 polymorphism in the miR-34a binding site of TLR4 may predict the risk of HP-induced GC. PMID- 30242898 TI - Estimates of age-specific diabetes incidence among men and women in China using secondary data analysis. AB - Affecting 9.5% of the population, diabetes represents a major health threat in China. Although age-specific incidence estimates are essential for the prevention and management of diabetes from the public health perspective and have been investigated among populations in several regions, there are no estimates for Chinese people in the literature. We therefore conducted a study to estimate the age-specific diabetes incidence among men and women in China using a secondary data analysis. This article is protected by copyright. All rights reserved. PMID- 30242900 TI - Copeptin, a surrogate marker for arginine vasopressin secretion, is positively associated with glucagon. AB - AIM: To explore the association of plasma copeptin, the C-terminal portion of provasopressin and a stable surrogate marker for arginine vasopressin secretion, with plasma glucagon in obese men and men of normal weight. METHODS: We measured fasting blood concentrations of copeptin and glucagon in 102 healthy obese men (mean +/- sd age 49.4 +/- 10.2 years) and a control group 27 healthy men of normal weight (mean +/- sd age 51.5 +/- 8.4 years). Differences between groups were evaluated using t-tests, and multiple linear regression analysis, adjusting for age and weight status (normal weight vs obese), was used to calculate unstandardized regression coefficients (beta) with 95% CIs between copeptin and glucagon. Copeptin was (natural) log-transformed. RESULTS: The obese men had higher [median (interquartile range)] plasma copeptin concentrations [6.6 (4.6 9.5) vs 4.9 (3.5-6.8) pmol/l; P = 0.040] and higher mean +/- sd plasma glucagon concentrations (8.5 +/- 3.8 vs 5.3 +/- 1.4 pmol/l; P < 0.001) than the normal weight men. Adjusted for age and weight status, copeptin was significantly associated with glucagon (beta = 1.35, 95% CI 0.13-2.57; P = 0.031). No significant interaction effect between copeptin and weight status on glucagon was found (P = 0.81). CONCLUSIONS: Obese men had higher concentrations of copeptin and glucagon than men of normal weight. Copeptin was positively associated with glucagon. Our data suggest that increased arginine vasopressin-stimulated glucagon secretion might contribute to higher glucagon concentrations; therefore, increased arginine vasopressin secretion, in addition to other factors, could further aggravate the hyperglucagonaemic state found in obese individuals. PMID- 30242899 TI - Multi-modal functional MRI to explore placental function over gestation. AB - PURPOSE: To investigate, visualize and quantify the physiology of the human placenta in several dimensions - functional, temporal over gestation, and spatial over the whole organ. METHODS: Bespoke MRI techniques, combining a rich diffusion protocol, anatomical data and T2* mapping together with a multi-modal pipeline including motion correction and extracted quantitative features were developed and employed on pregnant women between 22 and 38 weeks gestational age including two pregnancies diagnosed with pre-eclampsia. RESULTS: A multi-faceted assessment was demonstrated showing trends of increasing lacunarity, and decreasing T2* and diffusivity over gestation. CONCLUSIONS: The obtained multi-modal acquisition and quantification shows promising opportunities for studying evolution, adaptation and compensation processes. PMID- 30242901 TI - Physical activity is associated with lower insulin and C-peptide during glucose challenge in children and adolescents with family background of diabetes. AB - AIMS: Children and adolescents with a family history of diabetes are at increased risk of overweight, but little is known about the potentially beneficial effects of physical activity on these children. The objective of this study was to investigate the association between moderate to vigorous physical activity (MVPA) and metabolic and inflammatory risks in children and adolescents with a family background of Type 1 diabetes or gestational diabetes. METHODS: Valid MVPA measurements, made with accelerometers, were available from 234 participants (median age, 10.2 years) who had a first-degree relative with either Type 1 or gestational diabetes. Anthropometric and metabolic measurements were made and cytokines measured, and were correlated with MVPA measurements, with stepwise adjustment for confounding factors, in a cross-sectional analysis. RESULTS: MVPA was negatively associated with insulin and C-peptide during challenge with an oral glucose tolerance test. MVPA was also significantly positively associated with the insulin sensitivity index, whereas no consistently significant associations were found between MVPA and BMI, blood pressure or cytokine levels. DISCUSSION: Our findings indicate that physical activity may have beneficial effects on insulin and C-peptide metabolism in children and adolescents with a family background of diabetes, but show no evidence of a protective association with other health-related outcomes. PMID- 30242902 TI - International working group identifies need for newborn screening for mucopolysaccharidosis type I but states that existing hurdles must be overcome. AB - AIM: Mucopolysaccharidosis type I is a lysosomal storage disorder that can result in significant disease burden, disability and premature death, if left untreated. The aim of this review was to elaborate on the diagnosis of mucopolysaccharidosis type I and the pros and cons of newborn screening. METHODS: An international working group was established to discuss ways to improve the early diagnosis of mucopolysaccharidosis type I. It consisted of 13 experts in paediatrics, rare diseases and inherited metabolic diseases from Europe and the Middle East. RESULTS: It is becoming increasingly clearer that the delay between symptom onset and clinical diagnosis is considerable for mucopolysaccharidosis type I and other rare lysosomal storage disorders, despite numerous awareness campaigns since therapies became available. Diagnosis currently depends on recognising the signs and symptoms of the disease. The practice of newborn screening, which is being explored by pilot programmes around the world, enables early diagnosis and consequently early treatment. However, these studies have highlighted numerous new problems and pitfalls that must be faced before newborn screening becomes generally available. CONCLUSION: Newborn screening for mucopolysaccharidosis type I offers the potential for early diagnosis and early pre-symptomatic treatment, but existing hurdles need to be overcome. PMID- 30242903 TI - High-versus low-dose caffeine in preterm infants: a systematic review and meta analysis. AB - AIM: Though caffeine is a consolidated treatment in preterm infants, the efficacy and safety of a higher dose have not been systematically appraised. METHODS: A systematic review was conducted to compare high (loading dose >20 mg/kg and maintenance >10 mg/kg/day) versus low dose of caffeine. MEDLINE, EMBASE, Central and conference proceedings for randomised controlled trials (RCTs) and quasi-RCTs were searched. Two authors independently screened the records, extracted the data and assessed the risk of bias. RESULTS: As only six RCTs enrolling a total of 816 preterm infants were included, the required information size was not reached. The loading and maintenance doses varied between 20 and 80 mg/kg/day and 3 and 20 mg/kg/day, respectively. The use of high dose had no impact on mortality (RR: 0.85; 95% CI: 0.53-1.38; RCTs = 4) or bronchopulmonary dysplasia (RR: 0.93; 95% CI: 0.72-1.20; studies = 4); however, it resulted in fewer cases of extubation failure and apnoeas and shorter duration of mechanical ventilation. The quality of the evidence was low due to imprecision of the estimates. CONCLUSION: Due to imprecision, it is not possible to determine whether high-dose caffeine is more effective and safe than a low dose. High dose might improve short-term respiratory function without reducing bronchopulmonary dysplasia. PMID- 30242904 TI - IL-25 protects against high-fat diet-induced hepatic steatosis in mice by inducing IL-25 and M2a macrophage production. AB - Interleukin (IL)-25 is a cytokine that has previously been shown to have a protective role against nonalcoholic fatty liver disease (NAFLD), which is associated with the induction of M2 macrophage differentiation. However, the direct relationships between IL-25 expression regulation, M2 induction and NAFLD remain unknown. In this study, we demonstrate that IL-25 promotes hepatic macrophage differentiation into M2a macrophages both in vivo and in vitro via the IL-13/STAT6 pathway. M2 macrophages that were differentiated in vitro were able to ameliorate high-fat diet HFD-induced hepatic steatosis. Furthermore, we found that IL-25 treatment, both in vitro and in vivo, promotes direct binding of STAT6 to the IL-25 gene promoter region. This binding of STAT6 in response to IL-25 treatment also resulted in the increase of IL-25 expression in hepatocytes. Together, these findings identify IL-25 as a protective factor against HFD induced hepatic steatosis by inducing an increase of IL-25 expression in hepatocytes and through promotion of M2a macrophage production. PMID- 30242905 TI - Structural determination of archaeal UDP-N-acetylglucosamine 4-epimerase from Methanobrevibacter ruminantium M1 in complex with the bacterial cell wall intermediate UDP-N-acetylmuramic acid. AB - The crystal structure of UDP-N-acetylglucosamine 4-epimerase (UDP-GlcNAc 4 epimerase; WbpP; EC 5.1.3.7), from the archaeal methanogen Methanobrevibacter ruminantium strain M1, was determined to a resolution of 1.65 A. The structure, with a single monomer in the crystallographic asymmetric unit, contained a conserved N-terminal Rossmann-fold for nucleotide binding and an active site positioned in the C-terminus. UDP-GlcNAc 4-epimerase is a member of the short chain dehydrogenases/reductases superfamily, sharing sequence motifs and structural elements characteristic of this family of oxidoreductases and bacterial 4-epimerases. The protein was co-crystallized with coenzyme NADH and UDP-N-acetylmuramic acid, the latter an unintended inclusion and well known product of the bacterial enzyme MurB and a critical intermediate for bacterial cell wall synthesis. This is a non-native UDP sugar amongst archaea and was most likely incorporated from the E. coli expression host during purification of the recombinant enzyme. PMID- 30242906 TI - CCDC85B promotes non-small cell lung cancer cell proliferation and invasion. AB - Coiled-coil domain containing 85 B (CCDC85B) is involved in diverse biological processes; however, its expression patterns and functions in human cancers are yet unknown. The present study demonstrated that the expression of CCDC85B in the cytoplasm of the non-small cell lung cancer (NSCLC) tumor cells was significantly higher compared to adjacent normal lung tissues (P < 0.05). Furthermore, CCDC85B expression correlated with advanced TNM stage (P = 0.004) and positive regional lymph node metastasis (P = 0.009) of NSCLC. In addition, in A549 and H1299 lung cancer cell lines, the overexpression of CCDC85B promoted cell proliferation and invasion, while siRNA-mediated CCDC85B knockdown exhibited opposite effects. CCDC85B promoted AKT and GSK3beta phosphorylation and upregulated the levels of active beta-catenin, Wnt targets c-myc, cyclin D1, and MMP7. Besides, the CCDC85B induced upregulation of phosphorylated GSK3beta and active beta-catenin was rescued following the treatment with PI3 K inhibitor, LY294002. In conclusion, CCDC85B was associated with NSCLC progression as it promoted the proliferation and invasion of lung cancer cells through activated AKT/GSK3beta/beta-catenin oncogenic signaling pathway. Therefore, CCDC85B might serve as a novel target for NSCLC treatment. PMID- 30242907 TI - The potential for citizen science to produce reliable and useful information in ecology. AB - We examined features of citizen science that influence data quality, inferential power, and usefulness in ecology. As background context for our examination, we considered topics such as ecological sampling (probability based, purposive, opportunistic), linkage between sampling technique and statistical inference (design based, model based), and scientific paradigms (confirmatory, exploratory). We distinguished several types of citizen science investigations, from intensive research with rigorous protocols targeting clearly articulated questions to mass-participation internet-based projects with opportunistic data collection lacking sampling design, and examined overarching objectives, design, analysis, volunteer training, and performance. We identified key features that influence data quality: project objectives, design and analysis, and volunteer training and performance. Projects with good designs, trained volunteers, and professional oversight can meet statistical criteria to produce high-quality data with strong inferential power and therefore are well suited for ecological research objectives. Projects with opportunistic data collection, little or no sampling design, and minimal volunteer training are better suited for general objectives related to public education or data exploration because reliable statistical estimation can be difficult or impossible. In some cases, statistically robust analytical methods, external data, or both may increase the inferential power of certain opportunistically collected data. Ecological management, especially by government agencies, frequently requires data suitable for reliable inference. With standardized protocols, state-of-the-art analytical methods, and well-supervised programs, citizen science can make valuable contributions to conservation by increasing the scope of species monitoring efforts. Data quality can be improved by adhering to basic principles of data collection and analysis, designing studies to provide the data quality required, and including suitable statistical expertise, thereby strengthening the science aspect of citizen science and enhancing acceptance by the scientific community and decision makers. PMID- 30242908 TI - Screening for peripheral artery disease in people with diabetes: authors' reply. AB - We thank Hersant and colleagues for their interest in our work [1]. Our study was principally designed to address the utility of clinical examination and adjunctive tests to exclude peripheral artery disease (PAD) in people with diabetes-related foot ulceration. We emphasize the importance of a negative likelihood ratio (and sensitivity) throughout because a missed diagnosis has potentially more severe consequences. This article is protected by copyright. All rights reserved. PMID- 30242909 TI - Erosive lichen planus: beyond the nails. PMID- 30242910 TI - Pregnancy complications, treatment characteristics and birth outcomes in women with atopic dermatitis in Denmark. AB - BACKGROUND: The risk of prenatal, obstetric and birth complications in mothers with atopic dermatitis (AD), along with treatment use during pregnancy, is unknown. OBJECTIVES: To examine the associations between prenatal, obstetric and birth complications in mothers with AD and describe the dermatologic care received during pregnancy. METHODS: Mother-child pairs, in which the mother had a history of AD, were identified through the Danish Medical Birth Registry and matched 1 : 10 with non-AD pairs. Data on dermatologic treatment and prenatal, obstetric and birth complications were obtained through linkage via nationwide registers. Multiple logistic regression was performed. RESULTS: We identified 10 668 births from 1997 through 2014 to women with AD. Women with a hospital/ambulatory contact for AD during pregnancy had increased topical corticosteroid and ultraviolet therapy use during pregnancy compared to prior. However, overall, women with AD received decreased dermatologic therapy during pregnancy compared to prior. In adjusted analysis, maternal AD was inversely associated with gestational diabetes [OR 0.79, 95% CI (0.68-0.92)], but positively associated with premature rupture of membranes [1.15 (1.05-1.27)] and staphylococcal neonatal septicemia [2.45 (1.33-4.49)]-albeit the latter was rare. These associations did not meet statistical significance in sub-analysis where body mass index data were available. No associations were found with preeclampsia, prematurity or non-staphylococcal neonatal septicaemia. CONCLUSIONS: Women with AD during pregnancy mainly used topical corticosteroids and ultraviolet therapy to control their disease. While premature rupture of membranes and staphylococcal neonatal septicaemia were over-represented in maternal AD, no associations were found with any other significant prenatal, obstetric or birth outcome. PMID- 30242911 TI - Photoswitchable Self-Assembly/Disassembly of Near-Infrared Fluorophores. AB - A new photoswitchable near-infrared fluorophore (TDI-4DTE) with a symmetric structure exhibited reversible photo-controllable self-assembly and disassembly. The modification of pi-conjugated terrylenediimide with four dithienylethene groups not only induced photoswitchable near-infrared fluorescence, but also photoregulated reversible precipitation-dissolution with microscopic and macroscopic polymorphism. Upon 302 nm UV-light irradiation, a noticeable precipitation was observed within seconds. The precipitate was gradually dissolved again in half an hour upon visible light irradiation. Different microscopic morphologies of the precipitates, including nanoparticles, nanofibrils and nanosheets, were observed when altering the intensity of the 302 nm light irradiation, indicating the dynamic control process of self-assembly. Upon UV-light irradiation, TDI-4DTE nanosheets were also obtained as a solid polymeric film, whereas well-defined nanoribbons with molecular monolayer thickness formed at the oil/water interface with slower assembly dynamics. PMID- 30242912 TI - Interactions between fascicles and tendinous tissues in gastrocnemius medialis and vastus lateralis during drop landing. AB - Animal tendons have been shown to act as shock absorbers to protect muscle fascicles from exercise-induced damage during landing tasks. Meanwhile, the contribution of tendinous tissues to damping activities such as landing has been less explored in humans. The aim of this study was to analyze in vivo fascicle tendon interactions during drop landing to better understand their role in energy dissipation. Ultrafast ultrasound images of the gastrocnemius medialis (GM) and vastus lateralis (VL), lower limb electromyographic activity, 2-D kinematics, and ground reaction forces were collected from twelve participants during single- and double-leg drop landings from various heights. For both muscles, length changes were higher in tendinous tissues than in fascicles, demonstrating their key role in protecting fascicles from rapid active lengthening. Increasing landing height increased lengthening and peak lengthening velocity of VL fascicle and GM architectural gear ratio, whereas GM fascicle displayed similar length and velocity patterns. Single-leg landing lengthens the tendinous tissues of GM and, to a greater degree, VL muscles, without affecting the fascicles. These findings demonstrate the adjustment in fascicle-tendon interactions to withstand mechanical demand through the tendon buffer action and fascicle rotation. The higher VL fascicle contribution to negative work as the drop height increases would suggest muscle-specific damping responses during drop landing. This can originate from the distal-to-proximal sequence of joint kinetics, from differences in muscle and tendon functions (one- and two-joint muscles), architectural and morphological properties (eg, tendon stiffness), as well as from the muscle activity of the GM and VL muscles. PMID- 30242913 TI - PADI4 stimulates esophageal squamous cell carcinoma tumor growth and up-regulates CA9 expression. AB - An increasing amount of evidence indicates that peptidylarginine deiminase isoform 4 (PADI4) plays an important role in tumorigenesis. However, the effects of PADI4 on tumor-bearing mice are unknown, and no studies have investigated this tumorigenic pathway in an animal model. In the present study, ECA109 cells originating from esophageal squamous cell carcinoma (ESCC) were transfected with PADI4-expressing lentivirus and were injected into BALB/c nude mice. Tumor size and weight were significantly increased in the mouse tumors established with PADI4-overexpressing ECA109 cells. PCR array analysis revealed increased CA9 expression in ECA109 cells transfected with a PADI4-expressing plasmid, while decreased CA9 expression levels were detected in cells transfected with anti PADI4 siRNA. Furthermore, up-regulation of CA9 expression was detected in mouse tumors established with PADI4-overexpressing cells. Immunohistochemistry detected the increased expression and co-localization of PADI4 and CA9 in ESCC tissues compared with adjacent non-tumor tissues and normal tissue controls. These results were verified using Western blotting. Cell proliferation significantly increased or decreased in ECA109 and EC9706 (another ESCC-originating cell line) cells transfected with a PADI4-expressing plasmid or anti-PADI4 siRNA, respectively. The above findings suggest that increased PADI4 expression in ESCC stimulates tumor growth and up-regulates CA9 expression, which is known to promote metastatic properties in tumor cells. PMID- 30242914 TI - A banana R2R3-MYB transcription factor MaMYB3 is involved in fruit ripening through modulation of starch degradation by repressing starch degradation-related genes and MabHLH6. AB - Starch degradation is a necessary process determining banana fruit quality during ripening. Many starch degradation-related genes are well studied. However, the transcriptional regulation of starch degradation during banana fruit ripening remains poorly understood. In this study, we identified a MYB transcription factor (TF) termed MaMYB3, as a putative protein binding the promoter of MaGWD1, a member of glucan water dikinase (GWD) family which has been demonstrated as an important enzyme of starch degradation. MaMYB3 was ripening- and ethylene repressible, and its expression was negatively correlated with starch degradation. Acting as a nucleus-localized transcriptional repressor, MaMYB3 repressed the transcription of 10 starch degradation-related genes, including MaGWD1, MaSEX4, MaBAM7-MaBAM8, MaAMY2B, MaAMY3, MaAMY3A, MaAMY3C, MaMEX1, and MapGlcT2-1, by directly binding to their promoters. Interestingly, a previously identified activator of starch degradation-related genes, MabHLH6, was also suppressed by MaMYB3. The ectopic overexpression of MaMYB3 in tomato down regulated the expression of starch degradation-related genes, inhibited starch degradation and delayed fruit ripening. Based on these findings, we conclude that MaMYB3 negatively impacts starch degradation by directly repressing starch degradation-related genes and MabHLH6, and thereby delays banana fruit ripening. Collectively, our study expands our understanding of the complex transcriptional regulatory hierarchy modulating starch degradation during fruit ripening. PMID- 30242915 TI - How we treat paroxysmal nocturnal hemoglobinuria: A consensus statement of the Canadian PNH Network and review of the national registry. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by intravascular hemolysis, thrombophilia, and marrow failure. Its phenotype is due to absent or reduced expression of GPI-linked complement regulators and subsequent sensitivity of hematopoietic cells to complement mediated damage and lysis. Introduction of the terminal complement inhibitor eculizumab drastically improved outcomes in PNH patients; however, despite this improvement, there remain several challenges faced by PNH patients and physicians who care for them. One of the most important is increasing awareness of the heterogeneity with which patients can present, which can lead to significant delays in recognition. Data from the Canadian PNH Registry are presented to demonstrate the variety of presenting symptoms. In Canada, geography precludes consolidation of care to just a few centers, so management is distributed across academic hospitals, linked together as the Canadian PNH Network. The Network over the last several years has developed educational programs and clinical checklists and has worked to standardize access to diagnostics across the country. Herein, we address some of the common diagnostic and therapeutic challenges faced by PNH physicians and give our recommendations. Gaps in knowledge are also addressed, and where appropriate, consensus opinion is provided. PMID- 30242916 TI - Accuracy of tele-consultation on management decisions of lesions suspect for melanoma using reflectance confocal microscopy as a stand-alone diagnostic tool. AB - BACKGROUND: Diagnostic accuracy of reflectance confocal microscopy (RCM) as a stand-alone diagnostic tool for suspect skin lesions has not been extensively studied. OBJECTIVE: Primary aim was to measure experts' accuracy in RCM-based management decisions. Secondary aim was to identify melanoma-specific RCM features. METHODS: The study enrolled patients >=18 years that underwent biopsy of skin lesions clinically suspected to be melanoma. One hundred lesions imaged by RCM were randomly selected from 439 lesions prospectively collected at four pigmented lesion clinics. The study data set included 23 melanomas, three basal cell and two squamous cell carcinomas, 11 indeterminate melanocytic lesions and 61 benign lesions including 50 nevi. Three expert RCM evaluators were blinded to clinical or dermoscopic images, and to the final histopathological diagnosis. Evaluators independently issued a binary RCM-based management decision, 'biopsy' vs. 'observation'; these decisions were scored against histopathological diagnosis, with 'biopsy' as the correct management decision for malignant and indeterminate lesions. A subset analysis of 23 melanomas and 50 nevi with unequivocal histopathological diagnosis was performed to identify melanoma specific RCM features. RESULTS: Sensitivity, specificity and diagnostic accuracy were 74%, 67% and 70% for reader 1, 46%, 84% and 69% for reader 2, and 72%, 46% and 56% for reader 3, respectively. The overall kappa for management decisions was 0.34. Readers had unanimous agreement on management for 50 of the 100 lesions. Non-specific architecture, non-visible papillae, streaming of nuclei, coarse collagen fibres and abnormal vasculature showed a significant association with melanoma in the evaluation of at least two readers. CONCLUSIONS: Reflectance confocal microscopy tele-consultation of especially challenging lesions, based on image review without benefit of clinical or dermoscopy images, may be associated with limited diagnostic accuracy and interobserver agreement. Architectural and stromal criteria may emerge as potentially useful and reproducible criteria for melanoma diagnosis. PMID- 30242917 TI - Association of vitiligo with hospitalization for mental health disorders in US adults. AB - BACKGROUND: Vitiligo has a complex bidirectional relationship with mental health (MH) disturbances. However, little is known about the relationship between vitiligo and MH emergencies. OBJECTIVE: To examine the associations of vitiligo and MH hospitalizations in the United States. METHODS: Data from the 2002 to 2012 National Inpatient Sample were analysed, including a ~20% sample of all US hospitalizations (n = 87 053 155 children and adults). Prevalence of hospitalization for MH disorders, their length of stay (LOS) and cost of care were determined for those with vitiligo compared to those without vitiligo. RESULTS: Hospitalization for MH disorders occurred more commonly in those with vitiligo compared to those without vitiligo (4.17% vs. 2.18%). In multivariable logistic regression models, vitiligo was associated with higher odds of admission for any MH disorder [adjusted odds ratio (95% confidence interval): 1.69 (1.61 1.78)], including 14 of 15 MH disorders examined. Associated MH disorders included anxiety, schizophrenia, depression, suicidal risk, personality disorder, ADD/ADHD and conduct disorder, substance use disorder, childhood and adolescent psychiatric illnesses, alcohol-related disorders, adjustment disorders, developmental disorders, impulse control disorders, history of mental health disorders and miscellaneous mental health disorders. Vitiligo patients hospitalized with any MH disorder had higher geometric-mean (95% confidence interval) cost of inpatient care [$10 992 ($10 477-$11 507) vs. $10 082 ($9728 $10 435)] and LOS [5.6 (5.3-5.8) vs. 4.8 (4.6-4.9); P < 0.0001] compared to those without vitiligo, with $10.5 million excess annual costs from hospitalization with MH disorders in persons with vitiligo. CONCLUSIONS: Persons with vitiligo had increased hospitalization for multiple MH disorders, which were associated with a considerable cost burden. PMID- 30242918 TI - Certolizumab pegol for the treatment of patients with moderate-to-severe chronic plaque psoriasis: pooled analysis of week 16 data from three randomized controlled trials. AB - BACKGROUND: Certolizumab pegol, an Fc-free, PEGylated, anti-tumour necrosis factor (TNF) biologic, has demonstrated favourable results in three ongoing, phase 3, randomized, double-blinded, placebo-controlled trials in adults with psoriasis. OBJECTIVE: Data were pooled from the ongoing trials to investigate efficacy in selected subgroups and add precision to estimates of treatment effects during the initial 16 weeks of treatment. METHODS: In each trial, patients >=18 years with moderate-to-severe chronic plaque psoriasis for >=6 months were randomized to receive certolizumab 400 mg, certolizumab 200 mg or placebo every 2 weeks for 16 weeks. Coprimary endpoints for the pooled analysis were responder rates at Week 16, defined as >=75% reduction in psoriasis area and severity index (PASI 75) and physician global assessment (PGA) of 0/1 ('clear'/'almost clear' with >=2-category improvement). Safety was assessed by treatment-emergent adverse events. RESULTS: A total of 850 patients treated with certolizumab 400 mg (N = 342), certolizumab 200 mg (N = 351) or placebo (N = 157) were included in the pooled analysis. At Week 16, PASI 75 and PGA 0/1 responder rates were 80.1% and 63.7% in the certolizumab 400 mg group, 74.5% and 54.6% in the certolizumab 200 mg group, and 7.5% and 2.8% in the placebo group (P < 0.0001 for each dose versus placebo). In patients with and without prior biologic therapy, both doses of certolizumab resulted in substantially higher responder rates versus placebo. The incidence of adverse events was generally similar between the 400 mg and placebo groups, and somewhat lower in the 200 mg group versus placebo. No new safety signals were identified. CONCLUSION: Certolizumab pegol 400 mg or 200 mg every 2 weeks for 16 weeks was associated with statistically significant and clinically meaningful improvements in signs and symptoms of psoriasis in patients with and without prior biologic therapy, and a safety profile consistent with the anti-TNF class in psoriasis. PMID- 30242919 TI - PlantFAdb: a resource for exploring hundreds of plant fatty acid structures synthesized by thousands of plants and their phylogenetic relationships. AB - Over 450 structurally distinct fatty acids are synthesized by plants. We have developed PlantFAdb.org, an internet-based database that allows users to search and display fatty acid composition data for over 9000 plants. PlantFAdb includes more than 17 000 data tables from >3000 publications and hundreds of unpublished analyses. This unique feature allows users to easily explore chemotaxonomic relationships between fatty acid structures and plant species by displaying these relationships on dynamic phylogenetic trees. Users can navigate between order, family, genus and species by clicking on nodes in the tree. The weight percentage of a selected fatty acid is indicated on phylogenetic trees and clicking in the graph leads to underlying data tables and publications. The display of chemotaxonomy allows users to quickly explore the diversity of plant species that produce each fatty acid and that can provide insights into the evolution of biosynthetic pathways. Fatty acid compositions and other parameters from each plant species have also been compiled from multiple publications on a single page in graphical form. Links provide simple and intuitive navigation between fatty acid structures, plant species, data tables and the publications that underlie the datasets. In addition to providing an introduction to this resource, this report illustrates examples of insights that can be derived from PlantFAdb. Based on the number of plant families and orders that have not yet been surveyed we estimate that a large number of novel fatty acid structures are still to be discovered in plants. PMID- 30242920 TI - Comparison of lower limb stiffness between male and female dancers and athletes during drop jump landings. AB - Repetition of jumps in dance and sport training poses a potential injury risk; however, non-contact landing injuries are more common in athletes than dancers. This study aimed to compare the lower limb stiffness characteristics of dancers and athletes during drop landings to investigate possible mechanisms of impact related injuries. Kinematics and kinetics were recorded as 39 elite modern and ballet dancers (19 men and 20 women) and 40 college-level team sport athletes (20 men and 20 women) performed single-legged drop landings from a 30-cm platform. Vertical leg stiffness and joint stiffness of the hip, knee, and ankle were calculated using a spring-mass model. Stiffness data, joint kinematics, and moments were compared with a group-by-sex 2-way analysis of variance. Multiple linear regression was used to assess the relative contribution of hip and knee and ankle joint stiffness to variance in overall vertical leg stiffness for dancers and athletes. Dancers had lower leg (P < 0.001), knee joint (P = 0.034), and ankle joint stiffness (P = 0.043) than athletes. This was facilitated by lower knee joint moments (P = 0.012) and greater knee (P = 0.029) and ankle joint (P = 0.048) range of motion in dancers. Males had higher leg (P < 0.001) and ankle joint stiffness (P < 0.001) than females. This occurred through lower ankle range of motion (P < 0.001) and greater ankle moment (P = 0.022) compared to females. Male and female dancers demonstrated reduced lower limb stiffness compared to athletes, indicating a more pliable landing technique. Dance training techniques could potentially inform approaches to injury prevention in athletes. PMID- 30242921 TI - Treatment use and satisfaction among patients with psoriasis and psoriatic arthritis: results from the NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP). AB - BACKGROUND: There are scarce data in Scandinavia about treatment satisfaction among patients with psoriasis (PsO) and/or psoriatic arthritis (PsA). The number of patients receiving systemic treatment is unknown. OBJECTIVE: To describe patients' experience of treatments for PsO/PsA in Sweden, Denmark and Norway, addressing communication with physicians, satisfaction with treatment and concerns regarding treatment options. METHODS: The NORdic PAtient survey of Psoriasis and Psoriatic arthritis (NORPAPP) asked 22 050 adults (randomly selected from the YouGov panels in Sweden, Denmark and Norway) whether they had PsO/PsA. A total of 1264 individuals who reported physician-diagnosed PsO/PsA were invited to participate in the full survey; 96.6% responded positively. RESULTS: Systemic treatment use was reported by 14.6% (biologic: 8.1%) of respondents with PsO only and by 58.5% (biologic: 31.8%) of respondents with PsA. Biologic treatments were more frequently reported by respondents considering their disease severe (26.8% vs 6.7% non-severe) and those who were members of patient organizations (40.7% vs 6.9% non-members). Discussing systemic treatments with their physician was reported significantly more frequently by respondents with PsA, those perceiving their disease as severe (although 35.2% had never discussed systemic treatment with their physician) and those reporting being a member of a patient organization (P < 0.05). Many respondents reported health risk concerns and dissatisfaction with their treatment. Of special interest was that respondents aged 45-75 years reported less experience with biologics (8.1%) than those aged 18-44 years (21.5%). The older respondents also reported more uncertainty regarding long-term health risks related to systemic treatments (most [66.7-72.9%] responded 'do not know' when asked about the risk of systemic options). CONCLUSION: It appears likely that substantial numbers of Scandinavians suffering from severe PsO/PsA are not receiving optimal treatment from a patient perspective, particularly older patients. Also, one-third of respondents with severe symptoms had never discussed systemic treatment with a physician. PMID- 30242922 TI - The Role of N-Methyl Squaramides in a Hydrogen-Bonding Strategy to Fold Peptidomimetic Compounds. AB - Small peptides and peptomimetic compounds are valuable tools to probe and study biological systems. Small synthetic peptide analogues adopt a given secondary structure driven by structural modules that organize the compound architecture. Among them, beta- and alpha-turn mimetics are widely used. This work reports SQ4 and SQ5 squaramido-based turn modules that combine tertiary and secondary squaramide bonds in their structure to control their conformational properties. The efficacy of this combination has been evaluated to promote folding in peptide like compounds to obtain parallel and antiparallel-hairpin model compounds in hydrogen-bonding competitive media. Crystallographic structures of model compounds and conformational studies based on NMR spectroscopic analysis of the squaramido-peptides confirm that secondary-tertiary squaramides are more prone to adopt the E,Z-conformation than di-secondary squaramides, and consequently are more suitable to gain conformational control over foldable peptidomimetic compounds. PMID- 30242923 TI - Effects of pre-freeze Nigella sativa oil supplementation on cryosurvival of ovine spermatozoa. AB - The study was designed with three experiments to evaluate the effects of pre freeze supplementation of Nigella sativa oil (NSO) and thymoquinone (TQ) on total motility, progressive motility, biokinetic characteristics, acrosomal integrity and DNA integrity of cryopreserved ovine spermatozoa. Semen samples collected from three proven fertile Merino rams were diluted with a Tris-based cryomedia containing different levels of NSO (Experiment I: 0, 10, 100 and 1,000 g/ml), TQ (Experiment II: 0, 1, 10 and 20 g/ml) and their optimum levels (Experiment III: 100 g/ml of NSO, 10 g/ml of TQ and 1 mM of alpha-tocopherol and cryopreserved as pellet (200uL) and subsequently evaluated at different post-thaw incubation periods (0, 2 and 4 hr). The results revealed that the percentage of total motility, progressive motility and biokinetic characteristics such as average path velocity, curvilinear velocity and straight-line velocity were higher (p < 0.05) in the sperm aliquots cryopreserved with 100 g/ml NSO or 10 g/ml TQ than in the sperm aliquots cryopreserved without supplementation just after thawing and 2 hr of post-thaw incubation. Among the supplements, NSO (100 g/ml) showed higher values of the total motility, progressive motility, biokinetic characteristics specially, average path velocity, curvilinear velocity and straight-line velocity, acrosome integrity and DNA integrity compared with the spermatozoa frozen without supplementation. Therefore, the results suggest that NSO may be added to the cryomedium to improve the cryosurvival of ovine spermatozoa. PMID- 30242924 TI - Interfacial Asymmetric Post-Functionalization of Graphene: Amphiphilic Graphene Derivatives Self-Assembled to 3D Superstructures. AB - The interfacial asymmetric post-functionalization of graphene nanosheets and their self-assembly into superstructures is presented. By performing two sequential functionalizations, graphene nanosheets lying in the interface of a biphasic aqueous-organic system become amphiphilic, thereby generating an organophilic side and a hydrophilic side. The as-prepared Janus type amphiphilic graphene nanosheets are then self-assembled to generate different interesting superstructures, depending on the nature of the solvent in which they are dispersed. PMID- 30242925 TI - Genioglossus muscle activity during sniff and reverse sniff in healthy men. AB - NEW FINDINGS: What is the central question of this study? Maximal sniff nasal inspiratory and reverse sniff nasal expiratory pressures are measured as inspiratory and expiratory muscle strength, respectively. Is the genioglossus muscle activated during short maximal inspiratory and expiratory efforts through the nose? What is the main finding and its importance? Genioglossus muscle activity occurred with inspiratory muscle activity during a maximal sniff and with expiratory muscle activity during a maximal reverse sniff. These results indicate that genioglossus muscle activity is closely related to the generation of maximal sniff nasal inspiratory and reverse sniff nasal expiratory pressures. ABSTRACT: Maximal sniff nasal inspiratory pressure (SNIPmax ) is widely used to assess inspiratory muscle strength. The sniff nasal inspiratory pressure (SNIP) is lower in patients with neuromuscular disease with bulbar involvement compared with those without, possibly owing to impaired upper airway muscle function. However, the degree to which the genioglossus (GG) muscle, one of the upper airway muscles, is activated during inspiratory and expiratory efforts through the nose remains unclear. Therefore, we examined GG activity during short and sharp inspiratory and expiratory efforts through the nose, i.e. sniff and reverse sniff manoeuvres. In eight normal young subjects, we inserted fine wire electrodes into the GG muscle, parasternal intercostal and scalene (inspiratory) muscles and transversus abdominis (expiratory) muscle. We assessed EMG activity of each muscle and measured SNIP and reverse sniff nasal expiratory pressure (RSNEP) during sniffs and reverse sniffs from low to high intensities in the sitting position. The highest SNIP and RSNEP were analysed as SNIPmax and maximal RSNEP (RSNEPmax ), respectively. In each subject, GG EMG activity increased linearly with increasing SNIP and RSNEP. The SNIPmax and RSNEPmax were -85.1 +/- 15.9 and 83.2 +/- 24.2 cmH2 O, respectively. Genioglossus EMG activity varied with EMG activity of the parasternal intercostal and scalene muscles during generation of SNIPmax and with EMG activity of the transversus abdominis muscle during RSNEPmax . Genioglossus EMG activity during generation of SNIPmax was higher than during RSNEPmax (62.9 +/- 31.1% EMG of SNIPmax , P = 0.012). These results suggested that GG activity was closely related to the generation of both SNIPmax and RSNEPmax . PMID- 30242926 TI - Functional Conjugated Polymers for CO2 Reduction Using Visible Light. AB - The reduction of CO2 with visible light is a highly sustainable method for producing valuable chemicals. The function-led design of organic conjugated semiconductors with more chemical variety than that of inorganic semiconductors has emerged as a method for achieving carbon photofixation chemistry. Here, we report the molecular engineering of triazine-based conjugated microporous polymers to capture, activate and reduce CO2 to CO with visible light. The optical band gap of the CMPs is engineered by varying the organic electron withdrawing (benzothiadiazole) and electron-donating units (thiophene) on the skeleton of the triazine rings while creating organic donor-acceptor junctions to promote the charge separation. This engineering also provides control of the texture, surface functionality and redox potentials of CMPs for achieving the light-induced conversion of CO2 to CO ambient conditions. PMID- 30242928 TI - Disruption of glycosylphosphatidylinositol-anchored lipid transfer protein 15 affects seed coat permeability in Arabidopsis. AB - The hydrophobic biopolymer suberin, which is deposited in the root endodermis and seed coats, functions as an extracellular barrier against uncontrolled water, gas, and ion loss. Suberin monomers synthesized in the endoplasmic reticulum (ER) are exported through the plasma membrane to the apoplast. However, limited information is available about the molecular mechanisms underlying suberin monomer export and assembly. In this study, we investigated the in planta role of LTPG15 encoding a glycosylphosphatidylinositol (GPI)-anchored lipid transfer protein. LTPG15 was predominantly expressed in the root endodermis and seed coat. Fluorescent signals from LTPG15:eYFP were detected in the plasma membrane in tobacco epidermis. Disruption of LTPG15 caused a significant decrease in the levels of fatty acids (C20-C24), primary alcohols (C20 and C22), omega-hydroxy fatty acids (C22 and C24), and alpha,omega-alkanediols (C20 and C22), but an increase in the amounts of primary alcohols and hydroxy fatty acids with C16 and C18 in seed coats. The mutant phenotype was restored to that of the wild type (WT) by the expression of LTPG15 driven by its own promoter. Seed coats of ltpg15 had an increase in permeability to tetrazolium salts compared with WT seed coats. ltpg15 seeds were more sensitive than WT seeds to inhibition of germination and seedling establishment by salt and osmotic stress treatments. Taken together, our results indicate that LTPG15 is involved in suberin monomer export in seed coats, and this highlights the role of Type G non-specific lipid transfer proteins (LTPGs) in very-long-chain fatty acids and their derivatives' export for suberin polyester formation. PMID- 30242927 TI - ATP in the lateral hypothalamus/perifornical area enhances the CO2 chemoreflex control of breathing. AB - NEW FINDINGS: What is the central question of this study? ATP is known to modulate the chemosensitivity of some brain areas. However, whether the ATP contributes specifically to the mechanism of chemoreception in the lateral hypothalamus/perifornical area (LH/PFA) remains to be determined. What is the main finding and its importance? ATP, acting on the LH/PFA, enhances the hypercapnic ventilatory response in rats during wakefulness, in the dark period. Our results highlight the importance of ATP as a modulator of central chemoreception and provide new insight regarding the mechanisms involved in LH/PFA chemosensitivity and the sleep-wake differences in the CO2 /H+ -dependent drive to breathe. ABSTRACT: The lateral hypothalamus/perifornical area (LH/PFA) is a central chemoreceptor site, which acts in an arousal state-dependent manner. It has been shown that purinergic signalling through ATP influences the CO2 /H+ responsiveness of other chemosensitive regions, but it is unknown whether ATP is also involved in the mechanisms that underlie LH/PFA chemoreception. Here, we studied the effects of microdialysis of a P2X-receptor agonist [alpha,beta methylene ATP (alpha,beta-meATP), 10 mm] and a non-selective P2-receptor antagonist [pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS), 1 mm] into the LH/PFA of conscious rats on ventilation in room air and in 7% CO2 . In the dark (active) phase, but not in the light, microdialysis of alpha,beta-meATP caused an augmented hypercapnic ventilatory response during wakefulness, but not during non-REM sleep (P < 0.001). PPADS caused no change in CO2 ventilatory responses in either the dark period or the light period. Our data suggest that ATP in LH/PFA contributes to the hypercapnic ventilatory response in conscious rats during wakefulness in the dark phase of the diurnal cycle. PMID- 30242929 TI - Differential expression of heat shock proteins and activation of mitogen activated protein kinases in A549 alveolar epithelial cells exposed to cigarette smoke extract. AB - NEW FINDINGS: What is the central question of this study? What is the effect of cigarette smoke on cell death, oxidative damage, expression of heat shock proteins (HSPs) and activation of mitogen-activated protein kinases (MAPKs) in A549 alveolar epithelial cells? What is the main finding and its importance? Cigarette smoke induces cytotoxicity and oxidative damage to A549 cells, increases expression of different HSPs and activates MAPK signalling pathways. This could be related to inflammatory response and apoptosis observed in lungs of patients with smoking-related diseases. ABSTRACT: Cigarette smoking is one of the main risk factors for development of chronic obstructive pulmonary disease (COPD). We previously reported that cigarette smoke (CS) induces damage to proteins and their ineffective degradation. Here, we hypothesize that CS could induce oxidative stress and cytotoxicity in lung epithelial cells through alterations of heat shock protein (HSP) expression and mitogen-activated protein kinase (MAPK) signalling pathways. We exposed A549 alveolar epithelial cells to various concentrations of cigarette smoke extract (CSE). Higher concentrations of CSE caused apoptosis of A549 cells after 4 h, while after 24 h cell viability was decreased, and lactate dehydrogenase in cell culture medium was increased as well as the number of necrotic cells. Concentrations of malondialdehyde (MDA) were elevated, while total thiol groups were decreased. Changes in the expression of HSPs (HSP70, HSP32 and HSP27) were time-dependent. After 6 h, CSE caused an increase in the expression of HSP70 and HSP32, while after 8 h all examined HSPs were up-regulated and remained increased up to 48 h. Treatment of A549 cells with CSE stimulated phosphorylation of extracellular signal-regulated kinase and p38 in a dose-dependent manner, while c-Jun N-terminal kinase activation was not detected. By using specific inhibitors, we demonstrated that MAPKs and HSPs interplay in CSE effects. In conclusion, our results show that MAPKs and HSPs are involved in the mechanism underlying CSE-induced cytotoxicity and oxidative damage to A549 alveolar epithelial cells. These processes could be related to inflammatory response and apoptosis observed in lungs of patients with smoking related diseases, such as COPD. PMID- 30242930 TI - Accumulation of endogenous peptides triggers a pathogen stress response in Arabidopsis thaliana. AB - The stepwise degradation of peptides to amino acids in plant mitochondria and chloroplasts is catalyzed by a network of oligopeptidases (presequence protease PreP, organellar oligopeptidase OOP) and aminopeptidases. In the present report, we show that the lack of oligopeptidase activity in Arabidopsis thaliana results in the accumulation of endogenous free peptides, mostly of chloroplastic origin (targeting peptides and degradation products). Using mRNA sequencing and deep coverage proteomics, allowing for the identification of 17 000 transcripts and 11 000 proteins, respectively, we uncover a peptide-stress response occurring in plants lacking PreP and OOP oligopeptidase activity. The peptide-stress response results in the activation of the classical plant defense pathways in the absence of pathogenic challenge. The constitutive activation of the pathogen-defense pathways imposes a strong growth penalty and a reduction of the plants reproductive fitness. Our results indicate that the absence of organellar oligopeptidases PreP1/2 and OOP results in the accumulation of peptides that are perceived as pathogenic effectors and activate the signaling pathways of plant defense response. PMID- 30242931 TI - Biophysical insights into a highly selective l-arginine-binding lipoprotein of a pathogenic treponeme. AB - Biophysical and biochemical studies on the lipoproteins and other periplasmic proteins from the spirochetal species Treponema pallidum have yielded numerous insights into the functioning of the organism's peculiar membrane organization, its nutritional requirements, and intermediary metabolism. However, not all T. pallidum proteins have proven to be amenable to biophysical studies. One such recalcitrant protein is Tp0309, a putative polar-amino-acid-binding protein of an ABC transporter system. To gain further information on its possible function, a homolog of the protein from the related species T. vincentii was used as a surrogate. This protein, Tv2483, was crystallized, resulting in the determination of its crystal structure at a resolution of 1.75 A. The protein has a typical fold for a ligand-binding protein, and a single molecule of l-arginine was bound between its two lobes. Differential scanning fluorimetry and isothermal titration calorimetry experiments confirmed that l-arginine bound to the protein with unusually high selectivity. However, further comparison to Tp0309 showed differences in key amino-acid-binding residues may impart an alternate specificity for the T. pallidum protein. PMID- 30242933 TI - Human MICAL1: Activation by the small GTPase Rab8 and small-angle X-ray scattering studies on the oligomerization state of MICAL1 and its complex with Rab8. AB - Human MICAL1 is a member of a recently discovered family of multidomain proteins that couple a FAD-containing monooxygenase-like domain to typical protein interaction domains. Growing evidence implicates the NADPH oxidase reaction catalyzed by the flavoprotein domain in generation of hydrogen peroxide as a second messenger in an increasing number of cell types and as a specific modulator of actin filaments stability. Several proteins of the Rab families of small GTPases are emerging as regulators of MICAL activity by binding to its C terminal helical domain presumably shifting the equilibrium from the free - auto inhibited - conformation to the active one. We here extend the characterization of the MICAL1-Rab8 interaction and show that indeed Rab8, in the active GTP-bound state, stabilizes the active MICAL1 conformation causing a specific four-fold increase of kcat of the NADPH oxidase reaction. Kinetic data and small-angle X ray scattering (SAXS) measurements support the formation of a 1:1 complex between full-length MICAL1 and Rab8 with an apparent dissociation constant of approximately 8 MUM. This finding supports the hypothesis that Rab8 is a physiological regulator of MICAL1 activity and shows how the protein region preceding the C-terminal Rab-binding domain may mask one of the Rab-binding sites detected with the isolated C-terminal fragment. SAXS-based modeling allowed us to propose the first model of the free full-length MICAL1, which is consistent with an auto-inhibited conformation in which the C-terminal region prevents catalysis by interfering with the conformational changes that are predicted to occur during the catalytic cycle. PMID- 30242932 TI - On the damage done to the structure of the Thermoplasma acidophilum proteasome by electron radiation. AB - It has long been known that proteins are damaged when they are exposed to the electron beam in an electron microscope. Here we show that exposure to electrons under cryo-EM conditions leads to a small change in the quaternary structure of the Thermoplasma acidophilum proteasome, and that backbones atoms belonging to the alpha-helices in this molecule appear to be particular prone to chemical damage. A chemical mechanism is proposed for this damage. Both this local chemical effect and the more global quaternary structure effect appear to heterogenize samples leading to a radiation dose-dependent degradation of the resolution of the EM maps obtained from this molecule. PMID- 30242934 TI - The multidisciplinary pediatric psycho-oncology workforce: A national report on supervision for staff and training opportunities. AB - OBJECTIVE: This paper presents data on licensure/certification status, supervision of multidisciplinary pediatric psychosocial staff, and training opportunities in pediatric cancer programs in the United States, data that are critical to provide care aligned with the Standards of Psychosocial Care in Pediatric Cancer (Psychosocial Standards). METHODS: An online survey of psychosocial care consistent with the Psychosocial Standards was completed from a national sample of pediatric cancer programs (144/200). Licensure/certification status, availability and format of supervision for multidisciplinary staff (social workers, psychologists, psychiatrists, child life specialists/recreational therapists), and types and number of psychosocial trainees were reported. RESULTS: Nearly all pediatric psychosocial providers were licensed/certified. Peer consultation was the most frequently endorsed form of staff supervision although a sizeable group of centers reported no systematic ongoing supervision. Trainees in social work and child life were most common although the size of trainee cohorts is generally small. Psychosocial trainees are more prevalent in sites with pediatric hematology/oncology medical fellowship programs and in larger programs. CONCLUSIONS: A properly trained and supported psychosocial workforce is essential to providing evidence-based care consistent with the Psychosocial Standards. Psychosocial providers are appropriately licensed. However, supervision opportunities are variable and may be inadequate for the intensity of the work. It is important to address the limited opportunities for trainees in pediatric cancer programs, which may influence the pipeline for ongoing and future work in this area. PMID- 30242935 TI - Evaluation of neurological behaviour in late-preterm newborn infants using the Hammersmith Neonatal Neurological Examination. AB - AIM: We hypothesise that clinically well late-preterm infants (LPI) (34+0 -36+6 weeks) are neurologically more immature than their term counterparts, and this immaturity persists even when these infants reach term-corrected age (TCA). The primary aim of our study was to characterise and contrast the neurodevelopmental profile of well LPI with full-term infants (FTI) (39+0 -41+6 weeks) using the Hammersmith Neonatal Neurological Examination (HNNE). Our secondary aim was to obtain local reference ranges for the 34 items in the HNNE in an Asian-dominant population. METHODS: LPI were assessed at two time points: 12-72 h of life and at TCA of 39+0 -41+6 weeks, while FTI were assessed at 12-72 h of life using the HNNE. Each of the 34 items on the HNNE was assigned an optimality score (OS) of 0, 0.5 or 1, totalling up to 34. A quantitative comparison of the neurobehavioral patterns was made using two-sample t-tests. RESULTS: A total of 212 infants (79 LPI and 133 FTI) were recruited. Mean OSs for LPI and FTI at birth were (25.11 +/ 3.36)/34 and (31.19 +/- 1.50)/34, respectively, with a mean difference of 6.08 (P value <0.0001). The mean OS for LPI on reaching TCA was (28.91 +/- 2.30)/34, with a mean difference of 2.28 (P value <0.0001). Reference OSs for the 34 items on the HNNE were also obtained. CONCLUSION: LPI are more immature than their term counterparts even on reaching TCA, with discrepancies most apparent in 'tone' and 'movement'. We provide reference OSs of 34 items in the HNNE for infants in an Asian-dominant population. PMID- 30242936 TI - Metabolomics in the clinic: A review of the shared and unique features of untargeted metabolomics for clinical research and clinical testing. AB - Metabolomics is the untargeted measurement of the metabolome, which is composed of the complement of small molecules detected in a biological sample. As such, metabolomic analysis produces a global biochemical phenotype. It is a technology that has been utilized in the research setting for over a decade. The metabolome is directly linked to and is influenced by genetics, epigenetics, environmental factors, and the microbiome-all of which affect health. Metabolomics can be applied to human clinical diagnostics and to other fields such as veterinary medicine, nutrition, exercise, physiology, agriculture/plant biochemistry, and toxicology. Applications of metabolomics in clinical testing are emerging, but several aspects of its use as a clinical test differ from applications focused on research or biomarker discovery and need to be considered for metabolomics clinical test data to have optimum impact, be meaningful, and be used responsibly. In this review, we deconstruct aspects and challenges of metabolomics for clinical testing by illustrating the significance of test design, accurate and precise data acquisition, quality control, data processing, n-of-1 comparison to a reference population, and biochemical pathway analysis. We describe how metabolomics technology is integral to defining individual biochemical phenotypes, elaborates on human health and disease, and fits within the precision medicine landscape. Finally, we conclude by outlining some future steps needed to bring metabolomics into the clinical space and to be recognized by the broader medical and regulatory fields. PMID- 30242938 TI - Mechanisms shaping the mutational landscape of the FRA3B/FHIT-deficient cancer genome. AB - Genome instability is an enabling characteristic of cancer that facilitates the acquisition of oncogenic mutations that drive tumorigenesis. Underlying much of the instability in cancer is DNA replication stress, which causes both chromosome structural changes and single base-pair mutations. Common fragile sites are some of the earliest and most frequently altered loci in tumors. Notably, the fragile locus, FRA3B, lies within the fragile histidine triad (FHIT) gene, and consequently deletions within FHIT are common in cancer. We review the evidence in support of FHIT as a DNA caretaker and discuss the mechanism by which FHIT promotes genome stability. FHIT increases thymidine kinase 1 (TK1) translation to balance the deoxyribonucleotide triphosphates (dNTPs) for efficient DNA replication. Consequently, FHIT-loss causes replication stress, DNA breaks, aneuploidy, copy-number changes (CNCs), small insertions and deletions, and point mutations. Moreover, FHIT-loss-induced replication stress and DNA breaks cooperate with APOBEC3B overexpression to catalyze DNA hypermutation in cancer, as APOBEC family enzymes prefer single-stranded DNA (ssDNA) as substrates and ssDNA is enriched at sites of both replication stress and DNA breaks. Consistent with the frequent loss of FHIT across a broad spectrum of cancer types, FHIT deficiency is highly associated with the ubiquitous, clock-like mutation signature 5 occurring in all cancer types thus far examined. The ongoing destabilization of the genome caused by FHIT loss underlies recurrent inactivation of tumor suppressors and activation of oncogenes. Considering that more than 50% of cancers are FHIT-deficient, we propose that FRA3B/FHIT fragility shapes the mutational landscape of cancer genomes. PMID- 30242937 TI - Photographs of meaning: A novel social media intervention for adolescent and young adult cancer patients. PMID- 30242940 TI - Repeated switches from cooperative to selfish worker oviposition during stingless bee evolution. AB - Reproductive division of labour is a defining feature of insect societies. Stingless bees (Meliponini) are an interesting exception among the highly eusocial insects in that workers of many species contribute significantly to the production of males. Since workers remain sterile in other species of this large tropical tribe, it has been hypothesized that, in the latter species, ancestral queens have won the conflict over who produces the males. The fact that sterile workers of some species lay trophic eggs to feed the queen and display ritualized behaviours towards her during oviposition has been interpreted as an evolutionary relic of this ancient conflict. Here, I used ancestral state estimation to test whether worker reproduction is indeed the ancestral condition and worker sterility a derived state in stingless bees. Contrary to this hypothesis, data suggest that trophic egg laying was the ancestral condition, whereas selfish worker reproduction in queenright colonies evolved subsequently during stingless bee diversification. The appearance of worker reproduction in queenright conditions was tightly linked to the laying of trophic eggs, which suggests that having activated ovaries in queen presence facilitates the evolution of worker reproduction. Worker reproduction is also linked to brood cell architecture, but surprisingly not to colony size or queen-worker dimorphism. The reason for this association between brood cell architecture and worker oviposition is currently unknown. These results suggest that trophic eggs are not a relic of an ancient conflict, but a sign of overlapping interests between the queen and workers about who produces the males. PMID- 30242939 TI - Synthesis and bioactivity studies of sex pheromone analogs of the diamond back moth, Plutella xylostella. AB - BACKGROUND: Diamondback moth, Plutella xylostella L., is a very important pest of cruciferous vegetables causing excessive economic losses worldwide. Bioactivities of halo-, diazo-, and cyclopropane acetates of P. xylostella sex pheromone have been evaluated using electrophysiology and enzyme inhibition assays. RESULTS: A total of 23 sex pheromone analogs of P. xylostella were designed and synthesized and the result shows that (11Z)-hexadec-11-en-1-yl 2,2,2-trifluoroacetate, (11Z) hexadec-11-en-1-yl 2,2,3,3,3-pentafluoropropanoate, and (11Z)-hexadec-11-en-1-yl trifluoromethanesulfonate elicited potential inhibitory effects at all doses tested in the electrophysiology and enzyme inhibition assays. Interference of locating the sex pheromone source was found strongest when these three analogs were mixed with the sex pheromone at a 10:1 ratio. In addition, field test showed that the rate of mating disruption was over 90% when (11Z)-hexadec-11-en-1-yl 2,2,2-trifluoroacetate or (11Z)-hexadec-11-en-1-yl 2,2,3,3,3 pentafluoropropanoate was mixed with the sex pheromone at a 10:1 ratio. CONCLUSION: Two sex pheromone antagonists were screen out by electrophysiology, enzyme inhibition assays, wind tunnel and field tests. We believe that these antagonists could be used to establish a novel eco-friendly measure to control P. xylostella and provide evidence for clarifying the specific functions and molecular mechanisms of sex pheromone antagonists. (c) 2018 Society of Chemical Industry. PMID- 30242941 TI - Molecular imaging with neural training of identification algorithm (neural network localization identification). AB - Superresolution localization microscopy strongly relies on robust identification algorithms for accurate reconstruction of the biological systems it is used to measure. The fields of machine learning and computer vision have provided promising solutions for automated object identification, but usually rely on well represented training sets to learn object features. However, using a static training set can result in the learned identification algorithm making mistakes on data that is not well represented by the training set. Here, we present a method for training an artificial neural network without providing a training set in advance. This method uses the data to be analyzed, and the fitting algorithm to train an artificial neural network tailored to that data set. We show that the same artificial neural network can learn to identify at least two types of molecular emissions: the regular point spread functions (PSFs), and the astigmatism PSF. Simulations indicate that this method can be extremely reliable in extracting molecular emission signatures. Additionally, we implemented the artificial neural network calculation to be performed on a graphics processing unit (GPU) for massively parallelized calculation which drastically reduces the time required for the identification process. By implementing the neural identification on a GPU, we allow this method of identification to be used in a real time analysis algorithm. RESEARCH HIGHLIGHTS: Here, we present a machine learning algorithm for identifying point-spread functions without the need for an a priori training set. We show that this method can detect over 90% of molecules with less than 1% false positive identification in simulations. We further show that because this algorithm does not make assumptions of about the shape of molecular emission, it is compatible with models beyond the symmetric 2D Gaussian. PMID- 30242942 TI - Case of congenital nystagmus. PMID- 30242944 TI - Deblurring the significance of ST-elevation in aVL in anterolateral myocardial infarction. PMID- 30242943 TI - The evolution of the human foot. AB - There are 26 bones in each foot (52 in total), meaning that roughly a quarter of the human skeleton consists of foot bones. Yet, early hominin foot fossils are frustratingly rare, making it quite difficult to reconstruct the evolutionary history of the human foot. Despite the continued paucity of hominid or hominin foot fossils from the late Miocene and early Pliocene, the last decade has witnessed the discovery of an extraordinary number of early hominin foot bones, inviting a reassessment of how the human foot evolved, and providing fresh new evidence for locomotor diversity throughout hominin evolution. Here, we provide a review of our current understanding of the evolutionary history of the hominin foot. PMID- 30242945 TI - Normalization of frequency-domain parameters of heart rate variability in patients with myotonic dystrophy. PMID- 30242946 TI - Structural and functional insights into the modulation of the activity of a flax cytokinin oxidase by flax rust effector AvrL567-A. AB - During infection, plant pathogens secrete effector proteins to facilitate colonization. In comparison with our knowledge of bacterial effectors, the current understanding of how fungal effectors function is limited. In this study, we show that the effector AvrL567-A from the flax rust fungus Melampsora lini interacts with a flax cytosolic cytokinin oxidase, LuCKX1.1, using both yeast two hybrid and in planta bimolecular fluorescence assays. Purified LuCKX1.1 protein shows catalytic activity against both N6-(Delta2-isopentenyl)-adenine (2iP) and trans-zeatin (tZ) substrates. Incubation of LuCKX1.1 with AvrL567-A results in increased catalytic activity against both substrates. The crystal structure of LuCKX1.1 and docking studies with AvrL567-A indicate that the AvrL567 binding site involves a flexible surface-exposed region that surrounds the cytokinin substrate access site, which may explain its effect in modulating LuCKX1.1 activity. Expression of AvrL567-A in transgenic flax plants gave rise to an epinastic leaf phenotype consistent with hormonal effects, although no difference in overall cytokinin levels was observed. We propose that, during infection, plant pathogens may differentially modify the levels of extracellular and intracellular cytokinins. PMID- 30242947 TI - Cool storage of Queensland fruit fly eggs for increased flexibility in rearing programs. AB - BACKGROUND: The Queensland fruit fly (Q-fly) is Australia's most economically damaging insect pest of fruit crops. The Sterile Insect Technique (SIT) used to suppress outbreaks relies on supply of high-quality flies and this can be assisted by the ability to manipulate production schedules. Cool storage at temperatures that are sufficient to slow development without causing significant somatic damage can provide a valuable means of manipulating production schedules. In this study, we investigate the effect of four storage temperatures (10, 13, 16 and 19 degrees C) and three exposure times (3, 6 or 9 days) on Q-fly eggs. RESULTS: Egg storage proved effective in prolonging the developmental time of Q flies. Storage at 10 degrees C was unsuitable, resulting in a low hatching rate for all exposure times. Hatching rate was also significantly reduced when eggs were exposed to 13 degrees C for 6 or 9 days, followed by a significant reduction in the number of pupae recovered. Storage at 16 degrees C yielded promising results, prolonging the preimaginal development of Q-flies up to 6.5 days without significantly affecting egg hatching or subsequent development. CONCLUSION: Cool storage of eggs shows promise as a tool for prolonging the development of Q-flies to manipulate schedules in mass rearing programs. (c) 2018 Society of Chemical Industry. PMID- 30242948 TI - Effect of liraglutide on ambulatory blood pressure in patients with hypertension and type 2 diabetes: A randomized, double-blind, placebo-controlled trial. AB - AIMS: To assess the effect of liraglutide on 24-hour ambulatory blood pressure and heart rate in patients with hypertension (pre- and stage 1 hypertension) and inadequately controlled Type 2 diabetes (glycated haemoglobin 7%-10% [53-86 mmol/mol]). MATERIALS AND METHODS: Eligible patients for this investigator initiated, parallel-group, randomized, double-blind trial were on stable background antihyperglycaemic therapy excluding insulin, glucagon-like peptide-1 receptor agonists and dipeptidyl-peptidase-4 inhibitors. Participants were centrally randomized in a 1:1 ratio to daily liraglutide 0.6 mg, titrated to 1.2 mg after the first week, or placebo for 5 weeks. The primary outcome was change in 24-hour ambulatory systolic blood pressure (SBP), and secondary outcomes included change in ambulatory diastolic blood pressure (DBP) and heart rate. We also assessed renal sodium handling. RESULTS: Of 87 patients assessed for eligibility, 62 (66.1% men) with a mean age of 60.2 years were randomized to liraglutide (n = 31) or placebo (n = 31). All participants received background therapy with metformin, whilst 35.5% were treated concomitantly with sulphonylureas and 14.5% with pioglitazone. Compared with placebo, liraglutide reduced 24-hour SBP by -5.73 mm Hg (95% confidence interval [CI] -9.81 to -1.65) and had a neutral effect on 24-hour DBP (mean difference - 1.42 mm Hg; 95% CI 4.25 to 1.40), whilst increasing 24-hour heart rate by 6.16 beats/min (95% CI 3.25 to 9.07). Findings were consistent for daytime and night-time measurements. Liraglutide did not increase urine sodium excretion. CONCLUSION: Based on 24-hour ambulatory measurements, short-term treatment with liraglutide had a favourable effect on SBP whilst increasing heart rate. PMID- 30242949 TI - Carbon Nanotubes with Cobalt Corroles for Hydrogen and Oxygen Evolution in pH 0 14 Solutions. AB - Water splitting is promising to realize a hydrogen-based society. The practical use of molecular water-splitting catalysts relies on their integration onto electrode materials. We describe herein the immobilization of cobalt corroles on carbon nanotubes (CNTs) by four strategies and compare the performance of the resulting hybrids for H2 and O2 evolution. Co corroles can be covalently attached to CNTs with short conjugated linkers (the hybrid is denoted as H1) or with long alkane chains (H2), or can be grafted to CNTs via strong pi-pi interactions (H3) or via simple adsorption (H4). An activity trend H1?H3>H2~H4 is obtained for H2 and O2 evolution, showing the critical role of electron transfer ability on electrocatalysis. Notably, H1 is the first Janus catalyst for both H2 and O2 evolution reactions in pH 0-14 aqueous solutions. Therefore, this work is significant to show potential uses of electrode materials with well-designed molecular catalysts in electrocatalysis. PMID- 30242950 TI - Thrombogenicity assessment of Pipeline Flex, Pipeline Shield, and FRED flow diverters in an in vitro human blood physiological flow loop model. AB - Endovascular treatment of intracranial aneurysms with endoluminal flow diverters (single or multiple) has proven to be clinically safe and effective, but is associated with a risk of thromboembolic complications. Recently, a novel biomimetic surface modification with covalently bound phosphorylcholine (Shield TechnologyTM) has shown to reduce the material thrombogenicity of the Pipeline flow diverter. Thrombogenicity of Pipeline Flex, Pipeline Shield, and Flow Redirection Endoluminal Device (FRED) in the presence of human blood under physiological flow conditions-in addition to relative increase in thrombogenicity with multiple devices-remains unknown and was investigated here. Thrombin generation (mean +/- SD; MUg/mL; thrombin-antithrombin complex or TAT) was measured as FRED (30.3 +/- 2.9), Pipeline (13.9 +/- 4.4), Pipeline Shield (0.4 +/ 0.3), and negative control (no device; 0.1 +/- 0.0). Platelet activation (mean +/- SD; IU/MUL; beta-thromboglobulin or betaTG) was measured as FRED (148 +/- 45), Pipeline (92.8 +/- 41), Pipeline Shield (16.2 +/- 3.5), and negative control (2.70 +/- 0.16). FRED was significantly more thrombogenic than Pipeline and Pipeline Shield (p < 0.05) for TAT. Additionally, Pipeline Shield had significantly lower TAT and betaTG than the other devices tested (p < 0.05) and these were comparable to the negative control (p > 0.05). TAT and betaTG scaled proportionately with multiple Pipeline devices (N = 6) but was unaffected by multiple Pipeline Shield (N = 6) devices-the latter being statistically similar to negative control (p > 0.05). (c) 2018 The Authors. Journal Of Biomedical Materials Research Part A Published By Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3195-3202, 2018. PMID- 30242951 TI - The National Institute of Nursing Research: A Glance Back, andA Vision for the Future. PMID- 30242952 TI - Injectable hydrogels based on glycyrrhizin, alginate, and calcium for three dimensional cell culture in liver tissue engineering. AB - Injectable hydrogels have been paid more attentions on cell therapy and tissue regeneration resulting from the applications in minimally invasive surgical procedures with ease of handling and complete filling of defect area. Here, a biodegradable and injectable in situ hydrogel formed by glycyrrhizin (GL), alginate (Alg), and calcium (Ca) was developed for three-dimensional (3D) cell culture. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscope (SEM) and rheology analysis were performed to characterize GL-Alg-Ca hydrogel and evaluate its formation mechanism, properties, and morphology. The biocompatibility of hydrogel was investigated by cell viability, morphology, and liver specific functions. The results of DSC, XRD, and rheology suggested that hydrogel was homogenous complex with stable structure and well viscoelasticity. Human hepatoma HepG2 cells cultured in hydrogels showed well morphology. Compared with the control group, cells in hydrogels showed good biocompatibility, and could maintain the viability, proliferation and liver function for longer periods of time. Furthermore, the hydrogel improved the mRNA expression of cytochrome P450, which were key enzyme to the metabolization of hepatocytes. The GL-Alg-Ca hydrogel could be a potential 3D cells culture system for liver tissue engineering. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3292-3302, 2018. PMID- 30242953 TI - Discovery of highly insecticidal synthetic spinosyn mimics - CAMD enabled de novo design simplifying a complex natural product. AB - Simplifying complex natural products: Computer modeling-based design leads to highly insecticidal, chemically simpler synthetic mimics of the spinosyn natural products that are active in the field. (c) 2018 Society of Chemical Industry. PMID- 30242954 TI - Application of mini-clinical evaluation exercise for assessing the integrated based learning during physical diagnostic course. AB - Medical education paradigm has been questioned for the requirements of improving the quality and quantity of medical students. This study was to explore the efficiency of integrated-based learning (IBL) used mini-clinical evaluation exercise (mini-CEX) during physical diagnostics course. One hundred and eleven volunteered students were randomly divided into three groups: lecture-based learning (LBL), case-based learning (CBL), and IBL. Nephrotic syndrome was the teaching content. In the IBL group, students were provided the guideline and additional interpretation from the instructor about the basic knowledge related to disease as vertical integration curriculum. Their performance was evaluated by mini-CEX and theoretical examination, respectively. All subjects have completed the study. The difference of five factors (medical interview, physical examination, clinical judgment, organizational effectiveness, and competence) in mini-CEX between IBL, CBL, and LBL were statistically significant (p <0.05). Sample sizes of below, meets, and above the expectations of mini-CEX in different instructional groups were statistically significant (X2 =17.842, p =0.001). The final exam scores in IBL group and the CBL group were significantly higher than that of LBL group (F =41.553, p =0.000). And the relationship of final exam score only in the IBL group was positive existed with medical interview (R =0.466, p =0.004), physical examination (R =0.328, p =0.048), professional attitude (R =0.366, p =0.026), and communication skill (R =0.412, p =0.011). Therefore, our study revealed the effect of IBL on the medical students' skills. It highlights IBL could improve the physical examination, organizational effectiveness, and competence and the application of basic knowledge. (c) 2018 International Union of Biochemistry and Molecular Biology, 46(5):417-423, 2018. PMID- 30242955 TI - Vibrational mating disruption of Empoasca vitis by natural or artificial disturbance noises. AB - BACKGROUND: The green leafhopper, Empoasca vitis, is a polyphagous pest of grapevine and tea plants. To date population density is controlled primarily by insecticides and there is a demand for more sustainable controls. To develop a vibrational mating disruption method, the natural occurrence of a 'disruptive signal' was investigated. Further, the efficacy of natural and artificial 'disruptive signals' was determined. RESULTS: With behavioral trials we described male rivalry and recorded a species-specific disruptive signal (DP). The DP, a single pulse overlapping the competitor male call, interfered with the rival's ability to locate the female. Laboratory playback disruption trials revealed that the pair formation process was prevented by artificial disturbance noises that included the following features: E. vitis DP, Scaphoideus titanus disturbance noise, and a pure tone (250 Hz). Among these, the pure tone was most efficient at preventing mating. CONCLUSION: Results support development of a vibrational mating disruption method as a control strategy for E. vitis. To simultaneously disrupt the mating of E. vitis and S. titanus, the possibility of applying the S. titanus disturbance noise combined with the pure tone is discussed. (c) 2018 Society of Chemical Industry. PMID- 30242956 TI - A degradable triple temperature-, pH-, and redox-responsive drug system for cancer chemotherapy. AB - In order to achieve a precise therapeutic effect of cancer treatment and improve the utilization of drugs, a temperature-, pH-, and redox-responsive drug delivery system were synthesized. Methacrylic acid (MAA), poly(N-isopropylacrylamide) (PNIPAM), 2-hydroxyethylmethacrylate (HEMA), and N,N'-bis(acryloyl)cystamine (BACy), a disulfide bond contained cross-linker, were polymerized by a distillation-precipitation polymerization. Doxorubicin (DOX), an anti-cancer drug, can be loaded into the loose nanoparticle (NP) effectively. The prepared drug delivery remains stable during blood circulation and, when the vectors accumulated at tumor tissues, the pH-response of MMA and temperature-response of PNIPAM makes volume shrinkage of vectors which benefit the diffusion of vectors into tumor tissues. After being endocytosed into tumor cell, the disulfide bond that contained in the drug delivery can be cleaved by glutathione (GSH), causing the decomposition of NPs, and then release all of the drug. Under the influence of three trigger factors, the triple stimuli-responsive drug delivery vectors can realize tumor accumulation, tumor penetration and controlled drug release. Thus, the prepared multi-responsive NP is ideal drug carriers for developing novel drug delivery systems. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3203-3210, 2018. PMID- 30242957 TI - Practice Environment Characteristics Associated With Missed Nursing Care. AB - PURPOSE: To examine which characteristics of the practice environment were associated with missed nursing care in U.S. acute care hospital units. DESIGN: A descriptive, correlational study used secondary analysis of the 2015 National Database of Nursing Quality Indicators(r) Registered Nurse (RN) Survey data. Subscales of the Practice Environment Scale of the Nursing Work Index were used to measure practice environment characteristics. The sample included 1,583 units in 371 hospitals, containing survey responses from 31,650 RNs. METHODS: Multilevel logistic regression was performed to estimate the effects of the practice environment characteristics on missed care, controlling for hospital and unit characteristics. RESULTS: About 84.1% of unit RNs reported missing at least one of the 15 necessary care activities. Good environment units had 63.3% significantly lower odds of having RNs miss care activities than poor environment units. Units had 81.5% lower odds of having RNs miss any necessary activities with 1 point increase of the staffing and resource adequacy score; 21.9% lower odds for 1 point increase in the nurse-physician relations score; and approximately 2.1 times higher odds with 1 point increase in the nurse participation in hospital affairs score. CONCLUSIONS: Good environments were significantly associated with lower levels of missed care. The impact on missed care differed by the characteristics of the practice environment. CLINICAL RELEVANCE: Hospital and nursing administrators should maintain good practice environments for nurses to reduce missed care activities and thus potentially improve patient outcomes. Specifically, their efforts should be targeted on improving staffing and resource adequacy and nurse-physician relations and on reducing workloads on hospital affairs. PMID- 30242958 TI - Optimization of spider silk sphere formation processing conditions to obtain carriers with controlled characteristics. AB - Bioengineered spider silk is a focus of research due to its biocompatibility, biodegradability, and excellent mechanical properties. Functionalized silk can be processed into spheres and employed as selective drug delivery vehicles in targeted cancer treatment. Efficient, repeatable and controllable processing conditions are essential to drug carrier development. This study aimed to optimize the processing conditions of silk spheres formation, scale-up, and automation of the silk spheres production process. The automated micromixing system provided substantial amounts of silk spheres under repetitive production conditions. Micromixing resulted in smaller sphere sizes and narrower sphere size distributions than mixing with a pipette. Furthermore, the particle size and size distribution of silk spheres could be tailored by varying mixing process parameters, such as protein concentration, silk and salting out buffer ratio, mixing speed, and the size of the tubes and mixing zone. In addition, the implementation of ultrafiltration techniques provided a fast and efficient concentration of spheres in water. Furthermore, the shear forces introduced by micromixing did not impede the properties of the Her2 binding peptide (H2.1) since the functionalized H2.1MS1:H2.1MS2 silk spheres selectively were internalized by Her2-positive cancer cells. This study indicated that micromixing in combination with ultrafiltration enabled scale-up of the sphere production process under controllable and repeatable conditions. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3211-3221, 2018. PMID- 30242959 TI - Fitness costs of Vip3A resistance in Spodoptera frugiperda on different hosts. AB - BACKGROUND: Fall armyworm, Spodoptera frugiperda, is a major target pest of the Vip3A protein. The fitness of Bacillus thuringiensis (Bt)-resistant insects on refuges is an important factor in determining the speed of resistance development. Fitness costs associated with Bt resistance can vary among host plants. Here, we provide the first experimental evaluation of the interactions between non-Bt hosts and fitness costs of Vip3A resistance in S. frugiperda. RESULTS: Laboratory bioassays showed that survivorship, pupal weight, sex ratio, developmental time, fecundity, net reproductive rate, and intrinsic rate were not different among Vip3A-resistant (RR), -susceptible (SS) and -heterozygous (R? S? and R? S? ) strains of S. frugiperda on non-Bt corn, non-Bt cotton, and non-Bt diet. R? S? and R? S? also showed no differences on sorghum relative to SS. However, compared to SS, RR on sorghum showed significant reduction in pupal weight, and took longer time to develop to pupa and adult. CONCLUSION: These findings suggest that recessive fitness costs of reduced pupal weight and growth rate were detected at the individual level in the Vip3A resistant populations of S. frugiperda on sorghum. However, at the population level in terms of net reproductive rate and intrinsic rate, fitness costs of Vip3A resistance was not evident in S. frugiperda. (c) 2018 Society of Chemical Industry. PMID- 30242960 TI - The Role of Liver Transplantation in Propionic Acidemia. AB - Despite optimal medical treatment and strict low-protein diet, the prognosis of propionic acidemia (PA) patients is generally poor. We aim to report our experience with liver transplantation (LT) in the management of PA patients. Six patients with PA received a LT at a mean age of 5.2 years (1.3-7.5 years). The indications for LT were frequent metabolic decompensations in the first 4 patients and preventative in the last 2 patients. Two patients presented hepatic artery thromboses that were solved through an interventional radiologist approach. These patients showed a very high procoagulant state that was observed by thromboelastography. Arterial vasospasm without thrombus was observed in 2 patients during the LT surgery. In order to avoid hepatic artery thrombosis, an arterial conduit from the recipient aorta to the hepatic artery of the donor was used in the fifth patient. After LT, patients presented improvement in propionyl byproducts without complete normalization, but no decompensations have been observed. In conclusion, LT could be a good therapeutic option to improve the metabolic control and the quality of life of PA patients. Improved surgical strategies along with new techniques of interventional radiology allow us to perform the LT minimizing the complications derived from the higher risk of hepatic artery thrombosis. PMID- 30242961 TI - Fabrication of polydopamine nanoparticles knotted alginate scaffolds and their properties. AB - Polydopamine (PDA) can greatly affect polymer's properties, due to the chemical and physical interactions between the polymers and PDA. In this study, PDA was demonstrated to adjust the pore structures and increase the mechanical properties of alginate hydrogel-based cartilage tissue scaffolds. Dopamine modified alginate (Alg-DA) was firstly synthesized by modification of Alg with DA. Alg-DA interacted with preprepared PDA nanoparticles and further crosslinked with calcium ions (Ca2+ ) to form the hydrogel scaffold (Alg-DA/PDA). The Alg-DA/PDA scaffold combined multiple advantageous features, including continuous pore structure, high level of porosity, well mechanical properties, good biocompatibility and appropriate cycle life of degradation. Moreover, it could provide an optimized forming environment for hydroxyapatite (HAp) by mineralization process, thus accelerating cartilage repair. The improved performances were mainly ascribed to physical enhancement of the PDA nanoparticles and crosslinking points among the polymers and catechol groups in DA. These findings might offer a guideline for fabricating robust biocompatible cartilage tissue scaffold. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3255-3266, 2018. PMID- 30242962 TI - NYX-2925, A Novel N-methyl-D-aspartate Receptor Modulator: A First-in-Human, Randomized, Double-blind Study of Safety and Pharmacokinetics in Adults. AB - NYX-2925, a new chemical entity, acts as a co-agonist to glutamate at the N methyl-D-aspartate receptor (NMDAR). At low concentrations of endogenous agonists (glycine/D-serine), NYX-2925 partially activates NMDARs, modulating neural pathways relevant for chronic pain. NYX-2925 is being developed for the treatment of chronic pain conditions, including painful diabetic peripheral neuropathy and fibromyalgia. In this first-in-human, phase I, single-ascending dose (50-1,200 mg) and multiple-ascending dose (150-900 mg) study, the safety, tolerability, and pharmacokinetics (PKs) of NYX-2925 were evaluated in 84 healthy adult volunteers. No safety concerns emerged, including no dissociative side effects. NYX-2925 exhibited dose-proportional PKs and minimal accumulation following once-daily dosing for 7 days. Cerebrospinal fluid (CSF) measurements confirmed that NYX-2925 crosses the blood brain barrier, with maximum CSF concentrations approximating 6 9% of maximum plasma concentrations at the same dose level. NYX-2925 was safe and well-tolerated in healthy volunteers, and the study results support the continued clinical development for chronic pain conditions. PMID- 30242963 TI - Cardiomyogenic differentiation of human bone marrow-derived mesenchymal stem cell spheroids within electrospun collagen nanofiber mats. AB - Collagen is the major structural protein in myocardium and contributes to tissue strength and integrity, cellular orientation, and cell-cell and cell-matrix interactions. Significant post-myocardial infarction related loss of cardiomyocytes and cardiac tissue, and their subsequent replacement with fibrous scar tissue, negatively impacts endogenous tissue repair and regeneration capabilities. To overcome such limitations, tissue engineers are working toward developing a 3D cardiac patch which not only mimics the structural, functional, and biological hierarchy of the native cardiac tissue, but also could deliver autologous stem cells and encourage their homing and differentiation. In this study, we examined the utility of electrospun, randomly-oriented, type-I collagen nanofiber (dia = 789 +/- 162 nm) mats on the cardiomyogenic differentiation of human bone marrow-derived mesenchymal stem cells (BM-MSC) spheroids, in the presence or absence of 10 MUM 5-azacytidine (aza). Results showed that these scaffolds are biocompatible and enable time-dependent evolution of early (GATA binding protein 4: GATA4), late (cardiac troponin I: cTnI), and mature (myosin heavy chain: MHC) cardiomyogenic markers, with a simultaneous reduction in CD90 (stemness) expression, independent of aza-treatment. Aza-exposure improved connexin-4 expression and sustained sarcomeric alpha-actin expression, but provided only transient improvement in cardiac troponin T (cTnT) expression. Cell orientation and alignment significantly improved in these nanofiber scaffolds over time and with aza-exposure. Although further quantitative in vitro and in vivo studies are needed to establish the clinical applicability of such stem-cell laden collagen nanofiber mats as cardiac patches for cardiac tissue regeneration, our results underscore the benefits of 3D milieu provided by electrospun collagen nanofiber mats, aza, and spheroids on the survival, cardiac differentiation and maturation of human BM-MSCs. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3303-3312, 2018. PMID- 30242964 TI - Cytoskeletal remodeling induced by substrate rigidity regulates rheological behaviors in endothelial cells. AB - Altered microenvrionmental mechanical cues induce cytoskeletal remodeling in cells and have a profound impact on their functions as well as rheological properties. This article is aimed to characterize the viscoelastic behavior of endothelial cells, cultivated on variably compliant substrates. Synthetic tunable poly(dimethylsyloxane) substrates, with elastic moduli ranging from 1.5 MPa to 3 kPa, were used to trigger cytoskeletal remodeling of endothelial cells, verified by morphological analysis and actin fluorescent labeling. Elasticity and stress relaxation tests were conducted using an AFM, resulting in a wide range of data. To account for this heterogeneity, fuzzy c-means clustering algorithm was applied to partition elastic data into biologically meaningful groups, representative of different regions in cells. Nanocharacterization of biomechanical properties, along with cytoskeletal studies, proved a significant correlation between substrate flexibility and viscoelasticity of the cells. Regardless of the viscoelastic model applied, increasing substrate rigidity was related to an overall increase in cell stiffness and apparent viscosity (2.95 +/- 1.56 kPa and 921.45 +/- 102.46 Pa.s for the stiff substrate; 2.17 +/- 1.30 kPa and 557.37 +/- 494.11 Pa.s for the intermediate substrate), associated with an organized actin cytoskeleton. Conversely, cells on soft substrate were more deformable (1.84 +/- 1.3 kPa) and less viscous (327.13 +/- 124.25 Pa.s), exhibiting an increased actin disorganization. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 71-80, 2019. PMID- 30242965 TI - Chimeric Antigen Receptor T-Cells: Successful Translation of the First Cell and Gene Therapy From Bench to Bedside. PMID- 30242966 TI - Modeling pharmaceutical emissions and their toxicity-related effects in life cycle assessment (LCA): A review. AB - Over the last few decades, worldwide detection of active pharmaceutical ingredients (APIs) in aquatic environments and the associated toxicological effects on wildlife and human health have become a matter of public and scientific debate. While life cycle assessment (LCA) and life cycle impact assessment (LCIA) models are increasingly used to assess the potential eco- and human-toxicological effects of chemical emissions, few studies have looked into the issue of modeling pharmaceutical emissions specifically and their toxicity related effects in an LCA context. This paper reviews the state of the art to inventory and characterize API emissions in LCA with the goal to identify relevant gaps and challenges. A search for 208 environmentally relevant APIs in 2 life cycle inventory (LCI) databases revealed a meager representation of this group of chemicals. Similarly, the LCIA model USEtox was found to include characterization factors (CFs) for less than 60 APIs. First approaches to model API emissions in LCA were identified on the basis of an examination of 40 LCA case studies in the pharmaceutical sector and in the field of wastewater treatment. Moreover, CFs for 79 additional APIs, expressing their ecotoxicity and/or human toxicity potential, were gathered from literature. An analysis of the variability of API-CFs in different LCIA models showed a variation of about 2 3 orders of magnitude. Based on the review results, 3 main gaps in the modeling and characterization of API emissions in an LCA context were identified: (1) incomplete modeling of API flows and API emissions along the life cycle of human pharmaceuticals, especially during their use and end-of-life phase, (2) limited API coverage in existing LCIA toxicity models, and (3) missing pharma-specific impact pathways (e.g., endocrine disruption and antibiotic resistance) in existing LCIA models. Recommendations to tackle these gaps are provided, and priority action steps are discussed. Integr Environ Assess Manag 2018;00:000-000. (c) 2018 SETAC. PMID- 30242967 TI - Maternal aflatoxin exposure during pregnancy and adverse birth outcomes in Uganda. AB - Aflatoxins are toxic metabolites of Aspergillus moulds and are widespread in the food supply, particularly in low- and middle-income countries. Both in utero and infant exposure to aflatoxin B1 (AFB1 ) have been linked to poor child growth and development. The objective of this prospective cohort study was to investigate the association between maternal aflatoxin exposure during pregnancy and adverse birth outcomes, primarily lower birth weight, in a sample of 220 mother-infant pairs in Mukono district, Uganda. Maternal aflatoxin exposure was assessed by measuring the serum concentration of AFB1 -lysine (AFB-Lys) adduct at 17.8 +/- 3.5 (mean +/- SD)-week gestation using high-performance liquid chromatography. Anthropometry and birth outcome characteristics were obtained within 48 hr of delivery. Associations between maternal aflatoxin exposure and birth outcomes were assessed using multivariable linear regression models adjusted for confounding factors. Median maternal AFB-Lys level was 5.83 pg/mg albumin (range: 0.71-95.60 pg/mg albumin, interquartile range: 3.53-9.62 pg/mg albumin). In adjusted linear regression models, elevations in maternal AFB-Lys levels were significantly associated with lower weight (adj-beta: 0.07; 95% CI: -0.13, 0.003; p = 0.040), lower weight-for-age z-score (adj-beta: -0.16; 95% CI: -0.30, 0.01; p = 0.037), smaller head circumference (adj-beta: -0.26; 95% CI: -0.49, 0.02; p = 0.035), and lower head circumference-for-age z-score (adj-beta: -0.23; 95% CI: -0.43, -0.03; p = 0.023) in infants at birth. Overall, our data suggest an association between maternal aflatoxin exposure during pregnancy and adverse birth outcomes, particularly lower birth weight and smaller head circumference, but further research is warranted. PMID- 30242968 TI - Steroids and nonsteroidal anti-inflammatory drugs in the postoperative regime after trabeculectomy - which provides the better outcome? A systematic review and meta-analysis. AB - Surgical outcome after trabeculectomy depends on maintaining a functional bleb which requires a delicate balance between incomplete wound healing to prevent fibrosis and enough wound healing to prevent hyperfiltration. Thus, controlling the inflammatory response is essential. We conducted a systematic review and meta analysis to compare the effectiveness of different formulations of steroids (topical, systemic and depot) and nonsteroidal anti-inflammatory drugs (NSAIDs) in achieving long-term pressure control with fewer antiglaucomatous medications, preserving visual acuity and visual fields while considering surgical and postoperative complications. We used the PubMed, EMBASE and Cochrane Libraries to identify randomized controlled trials (RCTs) comparing the effect of different formulations of steroids (topical, systemic or depot) to NSAIDs. Data on prespecified outcomes from eligible references were entered into a meta-analysis using the Review Manager 5.3 program. We identified seven RCTs with a total of 342 included patients. Topical steroids were superior to placebo in controlling intraocular pressure (IOP) and reducing the risk of complications. Supplementing topical steroids with a perioperative steroid depot (subtenon or intracamerally) or systemic steroids in the early postoperative period did not provide better outcome or a change in the risk of complications. Addition of topical NSAIDs to topical steroids in patients undergoing trabeculectomy did not change the outcome or risk profile. For patients undergoing phacotrabeculectomy and topical NSAID, there was a nonsignificant trend towards better intermediate IOP control and a reduced need for antiglaucomatous medications compared to topical steroids but there was no difference in effect for patients undergoing trabeculectomy. In conclusion, there is a low level of evidence to support the clinician in deciding which postoperative regime provides a more favourable outcome because of inconsistency in the reported outcomes between studies and a low number of patients for each comparable intervention and outcome. It does seem that topical steroids are better than no anti-inflammatory treatment after glaucoma surgery, but further research is recommended. PMID- 30242969 TI - Genome-wide identification of a novel miRNA-based signature to predict recurrence in patients with gastric cancer. AB - The current tumor node metastasis (TNM) staging system is inadequate for identifying high-risk gastric cancer (GC) patients. Using a systematic and comprehensive-biomarker discovery and validation approach, we attempted to build a microRNA (miRNA)-recurrence classifier (MRC) to improve the prognostic prediction of GC. We identified 312 differentially expressed miRNAs in 446 GC tissues compared to 45 normal controls by analyzing high-throughput data from The Cancer Genome Atlas (TCGA). Using a Cox regression model, we developed an 11 miRNA signature that could successfully discriminate high-risk patients in the training set (n = 372; P < 0.0001). Quantitative real-time polymerase chain reaction-based validation in an independent clinical cohort (n = 88) of formalin fixed paraffin-embedded clinical GC samples showed that MRC-derived high-risk patients succumb to significantly poor recurrence-free survival in GC patients (P < 0.0001). Cox and stratification analysis indicated that the prognostic value of this signature was independent of clinicopathological risk factors. Time dependent receiver operating characteristic (ROC) analysis revealed that the area under the curve of this signature was significantly larger than that of TNM stage in the TCGA (0.733 vs. 0.589 at 3 years, P = 0.004; 0.802 vs. 0.635 at 5 years, P = 0.005) and validation cohort (0.835 vs. 0.689 at 3 years, P = 0.003). A nomogram was constructed for clinical use, which integrated both MRC and clinical related variables (depth of invasion, lymph node status and distance metastasis) and did well in the calibration plots. In conclusion, this novel miRNA-based signature is superior to currently used clinicopathological features for identifying high-risk GC patients. It can be readily translated into clinical practice with formalin-fixed paraffin-embedded specimens for specific decision making applications. PMID- 30242970 TI - Complete atrioventricular canal repair with a decellularized porcine small intestinal submucosa patch. AB - BACKGROUND: Congenital heart defects affect nearly 1% of all children born per year in the United States, and complete atrioventricular canal (CAVC) accounts for 2%-9%. While several patch materials have been used for septal defect closure during CAVC repair, clear superiority of one material over another has yet to be established. METHODS: A retrospective review of clinical outcomes following CAVC repair at Morgan Stanley Children's Hospital/Columbia University was performed on operations conducted from March 2010 to September 2017. Univariate and Kaplan Meir survival analyses were utilized to evaluate primary outcomes of interest following CAVC repair in the modern surgical era. RESULTS: A total of 73 patients were analyzed, with an average operative age of 22 weeks. The majority (71%) of the patients underwent a 2-patch repair. A CorMatrix patch was used for ventricular septal defect(VSD) closure in 77% of the patients, and/or in 75% of atrial septal defect closures. There was one in-hospital mortality (1.4%) due to respiratory failure. One patient required a pacemaker. At mid-term follow-up (1.6 years), a total of 7 patients required 8 reoperations due to cardiac-related indications, including 5 for left atrioventricular valve (LAVV) repair, 1 for LAVV replacement, and 2 isolated residual VSDs. CONCLUSION: A standardized repair for CAVC results in excellent outcomes in the current era, with low rates of reoperations. CorMatrix for the closure of CAVC has proven to produce good results with equivalent outcomes to other patch materials. Its ease of use and pliability make it an attractive alternative for consideration. PMID- 30242971 TI - Atrial septal defect in adults is associated with airway hyperresponsiveness. AB - OBJECTIVE: The association between secundum atrial septal defects (ASD) and asthma-like dyspnea with consequent long-term pulmonary inhalant use, is poorly understood in adult ASD patients. Airway hyperresponsiveness is suggested to be the underlying mechanism of cardiac asthma from mitral valve disease and ischemic cardiomyopathy. We hypothesized that airway hyperresponsiveness may also be found in adult ASD patients. Our aim was to study airway responsiveness in adult ASD patients before percutaneous closure and at short-and long-term postprocedural follow-up. METHODS: This prospective study included 31 ASD patients (65% female, mean age 49 +/- 15y) who underwent spirometry and bronchoprovocation testing pre and six-month postprocedurally, with additional bronchoprovocation at 2-year follow-up. Airway hyperresponsiveness was defined as >=20% fall of forced expiratory volume in 1-second (FEV1 ) following <8.0 mg/mL of inhaled methacholine. RESULTS: Airway hyperresponsiveness was found in 19/30 patients (63%[95%CI 45%-81%]; post hoc statistical power = 89%). Asthma-like symptoms wheezing, chest tightness, and cough were more frequently reported in airway hyperresponsive patients. Airway responsiveness was not influenced by successful percutaneous ASD closure, corresponding to persistence of asthma-like symptoms postclosure. Regardless of airway responsiveness, postprocedural right-sided reverse remodeling significantly improved dyspnea and pulmonary function. CONCLUSIONS: This study is the first to report a high prevalence of airway hyperresponsiveness in a cohort of unrepaired adult ASD patients, and confirms the association between asthma-like symptoms and ASD in adults. Attention to symptoms and pulmonary function should be given during clinical follow-up of adult ASD patients, both before and long after repair. PMID- 30242972 TI - Pharmacokinetic study of Sudaxine in dog plasma using novel LC-MS/MS method. AB - CONTEXT: Sudaxine is a novel respiratory stimulant that increases ventilatory drive via NO+ -thiolate signaling and is under development for reversal of opioid induced respiratory depression and other critical care indications. OBJECTIVE: This study investigates the pharmacokinetic characteristics after intravenous administration of Sudaxine by using a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. MATERIALS AND METHODS: A sensitive LC-MS/MS method was validated to determine the concentration of Sudaxine in beagle dog plasma after intravenous administration of Sudaxine at (3, 10, 30, and 100 mg/kg). Blood samples (1 mL) were collected at designated time points and SDX concentration was measured for pharmacokinetic study. RESULTS: The calibration curve was linear within the range of 50-5,000 ng/mL with the lower limit of quantification at 50 ng/mL. The CTmax for all doses was reached at 10 minutes (Tmax ). Over the dose range studied, average concentration - time curves and systemic exposure (CTmax and AUC0-t ) increased to Sudaxine dose. The terminal half-life of Sudaxine in dogs ranged from 10 to 30 minutes and about 17.3 +/- 1.0% of Sudaxine was protein-bound in dog plasma. DISCUSSION AND CONCLUSIONS: We developed a novel LC-MS/MS method of Sudaxine detection and quantification and determined its pharmacokinetic profiles after intravenous administration in canine subjects. Sudaxine followed first-order kinetics with rapid dose-dependent clearance rates and short half-life making it an ideal candidate for use in a critical care setting with intramuscular or IV administration. PMID- 30242973 TI - Anti-RNPC3 (U11/U12) antibodies in systemic sclerosis are associated with moderate to severe gastrointestinal dysmotility. AB - OBJECTIVE: We examined the association of anti-RNPC3 antibodies in systemic sclerosis (scleroderma or SSc) patients with selected gastrointestinal (GI) tract complications. METHODS: Sera from SSc patients with or without severe GI dysfunction (total parenteral nutrition-dependence) from the Johns Hopkins Scleroderma Center were screened for anti-RNPC3 antibodies. We then examined anti RNPC3-positive cases and negative SSc controls from the University of Pittsburgh and UMPC Scleroderma cohort to confirm our findings and to examine whether specific GI features were associated with anti-RNPC3 antibodies. RESULTS: In the discovery cohort, SSc patients with severe GI dysfunction (n=37) and without GI dysfunction (n=38) were screened for anti-RNPC3 antibodies. The former were more likely to have anti-RNPC3 antibodies (14% vs. 3%; p=0.11). In the Pittsburgh cohort, moderate to severe GI dysfunction (Medsger GI score >=2) was present in 36% of anti-RNPC3 positive patients vs. 15% of anti-RNPC3 negative patients (p=<0.01). Anti-RNPC3 positive patients were more likely to be male (31% vs. 15%; p =0.04), black (18% vs. 6%; p =0.02), have esophageal dysmotility (93% vs. 62%; p <0.01), and interstitial lung disease (ILD, 77% vs. 35%; p <0.01). After adjusting for relevant covariates and potential confounders, moderate to severe GI disease was associated with anti-RNPC3 antibodies (OR= 3.8; 95%CI 1.0, 14.3), and ILD trended towards significance (OR= 2.8; 95%CI 1.0, 8.2). CONCLUSION: Patients with SSc and anti-RNPC3 antibodies are more likely to be male, black and have moderate to severe GI disease and ILD. Further studies on larger patient cohorts may be helpful in further defining subsets of SSc patients at risk for severe GI involvement. This article is protected by copyright. All rights reserved. PMID- 30242974 TI - Discovery of a small molecule modulator of the Kv1.1/Kvbeta1 channel complex that reduces neuronal excitability and in vitro epileptiform activity. AB - AIMS: Kv1.1 (KCNA1) channels contribute to the control of neuronal excitability and have been associated with epilepsy. Kv1.1 channels can associate with the cytoplasmic Kvbeta1 subunit resulting in rapid inactivating A-type currents. We hypothesized that removal of channel inactivation, by modulating Kv1.1/Kvbeta1 interaction with a small molecule, would lead to decreased neuronal excitability and anticonvulsant activity. METHODS: We applied high-throughput screening to identify ligands able to modulate the Kv1.1-T1 domain/Kvbeta1 protein complex. We then selected a compound that was characterized on recombinant Kv1.1/Kvbeta1 channels by electrophysiology and further evaluated on sustained neuronal firing and on in vitro epileptiform activity using a high K+ -low Ca2+ model in hippocampal slices. RESULTS: We identified a novel compound able to modulate the interaction of the Kv1.1/Kvbeta1 complex and that produced a functional inhibition of Kv1.1/Kvbeta1 channel inactivation. We demonstrated that this compound reduced the sustained repetitive firing in hippocampal neurons and was able to abolish the development of in vitro epileptiform activity. CONCLUSIONS: This study describes a rational drug discovery approach for the identification of novel ligands that inhibit Kv1.1 channel inactivation and provides pharmacological evidence that such a mechanism translates into physiological effects by reducing in vitro epileptiform activity. PMID- 30242975 TI - Inhibition of Zinc Dendrite Growth in Zinc-Based Batteries. AB - Zinc deposition and dissolution is a significant process in zinc-based batteries. During this process, the formation of zinc dendrites is pervasive, which leads to the loss of efficiency and capacity of batteries. The continually growing dendrites will finally pierce the separator and cause the batteries to short circuit. Thus, employing effective methods to inhibit the formation and growth of zinc dendrites is vital for the practical application of zinc-based batteries. This Minireview first clarifies the formation and growth principles of zinc dendrites. Then, the research and development of methods to solve the problem of zinc dendrites are reviewed, including ways to suppress the further formation and growth of dendrites as far as possible, to minimize the adverse effects of dendrites, along with ways to produce dendrite-free deposition processes. The mechanisms, advantages, drawbacks, and perspectives of these methods are illustrated. Thus, this overview of these methods will aid understanding of the formation process of zinc dendrites and provide an extensive, comprehensive, and professional reference to resolve the problem of zinc dendrites completely. PMID- 30242976 TI - Validation of Catquest-9SF in Danish: developing a revised form of the Catquest 9SF - the Danish Catquest-7SF. AB - PURPOSE: The primary goal was to validate a Danish translated version of the Catquest-9SF by Rasch analysis. The secondary goal was to investigate whether preoperative Catquest-9SF scores, best-corrected visual acuity, comorbidity, gender, age or corneal astigmatism could predict improvements in subjective outcome. METHODS: In a prospective trial, 250 patients eligible for cataract surgery were included. Patients filled out the translated Catquest-9SF questionnaire before surgery and again 3 months after surgery. Both preoperative and postoperative questionnaires were included in the Rasch analysis. A multiple reverse stepwise regression model was used to investigate the correlation between preoperative measurements and subjective improvement. RESULTS: The preliminary Rasch analysis showed misfit of items 4 and 6. These items were removed, and the remaining seven items demonstrated a measurement precision of 2.78, a person reliability coefficient of 0.89, ordered response categories, infit of 0.69-1.22, outfit of 0.73-1.14, observed raw variance explained by measures of 70.4% and an eigenvalue of 1.7. Item 7 showed a mild DIF for gender (0.54 logits), and person mean Rasch score targeting was -1.69 logits. Preoperative Catquest score was the only parameter with a significant correlation to a gain in subjective outcome (p < 0.001). A preoperative Catquest-9SF score of 0.5 carried a 95% likelihood of an increase in subjective outcome. CONCLUSION: The Danish version of the Catquest 9SF fit the Rasch model. Only preoperative Catquest-9SF score was correlated to subjective improvement, and a cut-off value of 0.5 predicted an improvement in subjective outcome with 95% probability. PMID- 30242977 TI - The CC chemokines CCL8, CCL13 and CCL20 are local inflammatory biomarkers of HLA B27-associated uveitis. AB - PURPOSE: To determine the concentrations of the CC chemokines CCL2, CCL7, CCL8, CCL11, CCL13, CCL20, CCL24 and CCL26 in aqueous humour (AH) samples from patients with specific uveitic entities. METHODS: Aqueous humour samples from patients with active uveitis associated with Behcet's disease (BD) (n = 13), sarcoidosis (n = 8), HLA-B27-related inflammation (n = 12), Vogt-Koyanagi-Harada (VKH) disease (n = 12) and control patients (n = 9) were assayed with the use of a multiplex assay. RESULTS: When considering all uveitis patients as one group, all chemokine levels except CCL2 were significantly increased compared to controls. CCL8, CCL13 and CCL20 were the most strongly upregulated, 48-fold, 118-fold and 173-fold, respectively, above control AH levels. CCL8 and CCL13 levels were significantly higher in HLA-B27-associated uveitis than in sarcoidosis and VKH disease. CCL20 levels were significantly higher in HLA-B27-associated uveitis than in BD, sarcoidosis and VKH disease. In addition, CCL20 levels were significantly higher in BD than in VKH disease. In HLA-B27-associated uveitis, CCL8, CCL13 and CCL20 were upregulated 111-fold, 255-fold and 465-fold, respectively, compared with controls. CCL8, CCL13 and CCL20 levels were significantly higher in nongranulomatous uveitis (BD and HLA-B27-associated uveitis) than in granulomatous uveitis (sarcoidosis and VKH disease). CONCLUSIONS: Immune responses mediated by CCL8, CCL13 and CCL20 appear to be more potent in nongranulomatous uveitis, particularly in HLA-B27-associated uveitis. PMID- 30242978 TI - The geographic distribution and financial impact of canine parvovirus in Australia. AB - Canine parvovirus (CPV) is an important cause of serious and often fatal disease in dogs worldwide, however, a national survey of CPV cases in Australia has not been conducted since 1982. For this study we surveyed the entire Australian veterinary clinic population and achieved a response rate of 23.5% (534 unique veterinary clinics). Respondents reported 4,451 CPV cases in 2015 and 4,219 cases in 2016; the estimated total CPV case load across Australia was 20,661 in 2015 and 20,110 in 2016. The overall reported euthanasia rate was 41%. Geospatial analysis revealed large numbers of CPV cases in rural and remote areas of Australia. Where cases occurred in capital city areas, these were found in peri urban areas, away from the inner city. The median cost to treat CPV cases was $A1,500 per patient. A significant difference in the cost of treating cases was found between Australian states; Western Australia (median $A2,500) was the most expensive state. There was a strong correlation between cost of treatment and rate of euthanasia without treatment reflecting the important role of affordability in disease-related euthanasia. These findings highlight the considerable impact of the evolving CPV situation in Australia, particularly in regional and rural areas. This survey is the most comprehensive epidemiological investigation of canine parvoviral-related disease, to date, globally and provides a process for national disease surveillance. PMID- 30242980 TI - Establishment of 2D Cell Cultures Derived From 3D MCF-7 Spheroids Displaying a Doxorubicin Resistant Profile. AB - In vitro 3D cancer spheroids generally exhibit a drug resistance profile similar to that found in solid tumors. Due to this property, these models are an appealing for anticancer compounds screening. Nevertheless, the techniques and methods aimed for drug discovery are mostly standardized for cells cultured in 2D. The development of 2D cell culture models displaying a drug resistant profile is required to mimic the in vivo tumors, while the equipment, techniques, and methodologies established for conventional 2D cell cultures can continue to be employed in compound screening. In this work, the response of 3D-derived MCF-7 cells subsequently cultured in 2D in medium supplemented with glutathione (GSH) (antioxidant agent found in high levels in breast cancer tissues and a promoter of cancer cells resistance) to Doxorubicin (DOX) is evaluated. These cells demonstrated a resistance toward DOX closer to that displayed by 3D spheroids, which is higher than that exhibited by standard 2D cell cultures. In fact, the 50% inhibitory concentration (IC50 ) of DOX in 3D-derived MCF-7 cell cultures supplemented with GSH is about eight-times higher than that obtained for conventional 2D cell cultures (cultured without GSH), and is only about two-times lower than that attained for 3D MCF-7 spheroids (cultured without GSH). Further investigation revealed that this improved resistance of 3D-derived MCF-7 cells may result from their increased P-glycoprotein (P-gp) activity and reduced production of intracellular reactive oxygen species (ROS). PMID- 30242979 TI - Suspect and non-target screening workflows to investigate the in vitro and in vivo metabolism of the synthetic cannabinoid 5Cl-THJ-018. AB - The use of synthetic cannabinoids causes similar effects as Delta9 tetrahydrocannabinol and long-term (ab)use can lead to health hazards and fatal intoxications. As most investigated synthetic cannabinoids undergo extensive biotransformation, almost no parent compound can be detected in urine, which hampers forensic investigations. Limited information about the biotransformation products of new synthetic cannabinoids makes the detection of these drugs in various biological matrices challenging. This study aimed to identify the main in vitro biotransformation pathways of 5Cl-THJ-018 and to compare these findings with an authentic urine sample of a 5Cl-THJ-018 user. The synthetic cannabinoid was incubated with pooled human liver microsomes and cytosol to simulate phase I and phase II biotransformations. Resulting extracts were analyzed with liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-QTOF MS). Three different data analysis workflows were applied to identify biotransformation products. A suspect screening workflow used an in-house database built from literature data and in silico biotransformation predictions. Two non-target screening workflows used a commercially available software and an open-source software for mass spectrometry data processing. A total of 23 in vitro biotransformation products were identified, with hydroxylation, oxidative dechlorination, and dihydrodiol formation pathways as the main phase I reactions. Additionally, five glucuronidated and three sulfated phase II conjugates were identified. The predominant in vivo pathway was through oxidative dechlorination and in total six metabolites of 5Cl-THJ-018 were identified. Biotransformation products both in vitro and in vivo were successfully identified using complementary suspect and non-target screening workflows. PMID- 30242981 TI - Reconstruction of vocal tract geometries from biomechanical simulations. AB - Medical imaging techniques are usually utilized to acquire the vocal tract geometry in 3D, which may then be used, eg, for acoustic/fluid simulation. As an alternative, such a geometry may also be acquired from a biomechanical simulation, which allows to alter the anatomy and/or articulation to study a variety of configurations. In a biomechanical model, each physical structure is described by its geometry and its properties (such as mass, stiffness, and muscles). In such a model, the vocal tract itself does not have an explicit representation, since it is a cavity rather than a physical structure. Instead, its geometry is defined implicitly by all the structures surrounding the cavity, and such an implicit representation may not be suitable for visualization or for acoustic/fluid simulation. In this work, we propose a method to reconstruct the vocal tract geometry at each time step during the biomechanical simulation. Complexity of the problem, which arises from model alignment artifacts, is addressed by the proposed method. In addition to the main cavity, other small cavities, including the piriform fossa, the sublingual cavity, and the interdental space, can be reconstructed. These cavities may appear or disappear by the position of the larynx, the mandible, and the tongue. To illustrate our method, various static and temporal geometries of the vocal tract are reconstructed and visualized. As a proof of concept, the reconstructed geometries of three cardinal vowels are further used in an acoustic simulation, and the corresponding transfer functions are derived. PMID- 30242983 TI - Impacts of misclassification on Lyme disease surveillance. AB - In Maryland, Lyme disease (LD) is the most widely reported tickborne disease. All laboratories and healthcare providers are required to report LD cases to the local health department. Given the large volume of LD reports, the nuances of diagnosing and reporting LD, and the effort required for investigations by local health department staff, surveillance for LD is burdensome and subject to underreporting. To determine the degree to which misclassification occurs in Maryland, we reviewed medical records for a sample of LD reports from 2009. We characterized what proportion of suspected and "not a case" reports could be reclassified as confirmed or probable once additional information was obtained from medical record review, explored the reasons for misclassification, and determined multipliers for a more accurate number of LD cases. We reviewed medical records for reports originally classified as suspected (n = 44) and "not a case" (n = 92). Of these 136 records, 31 (23%) suspected cases and "not a case" reports were reclassified. We calculated multipliers and applied them to the case counts from 2009, and estimate an additional 269 confirmed and probable cases, a 13.3% increase. Reasons for misclassification fell into three general categories: lack of clinical or diagnostic information from the provider; surveillance process errors; and incomplete information provided on laboratory reports. These multipliers can be used to calculate a better approximation of the true number of LD cases in Maryland, but these multipliers only account for underreporting due to misclassification, and do not account for cases that are not reported at all (e.g., LD diagnoses based on erythema migrans alone that are not reported) or for cases that are not investigated. Knowing that misclassification of cases occurs during the existing LD surveillance process underscores the complexities of LD surveillance, which further reinforces the need to find alternative approaches to LD surveillance. PMID- 30242984 TI - Left Ventricular Systolic Myocardial Function in Ankylosing Spondylitis. AB - OBJECTIVE: Subclinical left ventricular (LV) myocardial dysfunction is associated with increased risk of cardiovascular disease (CVD), but it is not known if subclinical LV myocardial dysfunction is present in patients with ankylosing spondylitis (AS) independent of CVD risk factors. METHODS: Conventional and speckle tracking echocardiography was performed in 106 AS patients (mean age 48+/ 12 years, 59% men) and 106 matched controls (mean age 51+/-12 years, 59% men). LV systolic myocardial function was assessed by peak systolic global longitudinal strain (GLS). RESULTS: CVD risk factors were similarly distributed among AS patients and controls, but more controls used statin therapy (p=0.05). GLS was significantly lower in AS patients vs. controls (-17.7+/-2.5% vs.-18.4+/-2.3%, p=0.03). In univariable linear regression analyses in the total study population, lower GLS was associated with having AS, male sex, higher body mass index, LV mass index and lower LV ejection fraction (all p<0.05). Having AS retained an independent association with lower GLS when adjusted for these factors in multivariable analyses (beta 0.16, p=0.02). In AS patients, lower GLS was independently associated with larger aortic root diameter in multivariable analyses (beta 0.24, p=0.02), while no association with AS disease activity, disease duration or use of anti-rheumatic medication was found. CONCLUSION: Patients with AS had lower GLS than controls independent of confounders. In AS patients, lower GLS was associated with larger aortic root diameter. Whether lower GLS contributes to the observed higher CVD risk in AS patients should be tested in prospective studies. This article is protected by copyright. All rights reserved. PMID- 30242985 TI - Association of Varus Knee Thrust during Walking with Worsening WOMAC Knee Pain: The Multicenter Osteoarthritis Study. AB - OBJECTIVE: To investigate the two-year association of varus knee thrust observed during walking to the odds of worsening WOMAC knee pain in older adults with or at risk of OA. METHODS: Video recordings of self-paced walking trials of Multicenter Osteoarthritis Study (MOST) participants were assessed for the presence of varus thrust at baseline. Knee pain was assessed using the WOMAC questionnaire at baseline and at two years. Logistic regression was used to estimate the odds of worsening (defined as either any increase in WOMAC score or clinically-important worsening) knee pain, adjusting for age, sex, race, BMI, clinic site, gait speed, and static knee aligment. Analyses were repeated stratified by baseline radiographic OA status and among the subset of knees without baseline WOMAC pain. RESULTS: 1623 participants contributed 3204 knees. Varus thrust was observed in 31.5% of knees. Knees with varus thrust had 1.44 times (95% CI: 1.19, 1.73) the odds of any and 1.37 times (95% CI: 1.11, 1.69) the odds of clinically-important worsening WOMAC pain compared to knees without thrust. Knees with thrust without baseline WOMAC pain had 2.01 (95% CI: 1.47, 2.74) times the odds of incident total pain. CONCLUSION: Results indicate that varus thrust is a risk factor for worsening and incident knee pain. Targeting varus thrust through non-invasive therapies could prevent development or worsening of knee pain in older adults with or at risk for knee OA. This article is protected by copyright. All rights reserved. PMID- 30242982 TI - The European Eye Epidemiology spectral-domain optical coherence tomography classification of macular diseases for epidemiological studies. AB - PURPOSE: The aim of the European Eye Epidemiology (E3) consortium was to develop a spectral-domain optical coherence tomography (SD-OCT)-based classification for macular diseases to standardize epidemiological studies. METHODS: A European panel of vitreoretinal disease experts and epidemiologists belonging to the E3 consortium was assembled to define a classification for SD-OCT imaging of the macula. A series of meeting was organized, to develop, test and finalize the classification. First, grading methods used by the different research groups were presented and discussed, and a first version of classification was proposed. This first version was then tested on a set of 50 SD-OCT images in the Bordeaux and Rotterdam centres. Agreements were analysed and discussed with the panel of experts and a final version of the classification was produced. RESULTS: Definitions and classifications are proposed for the structure assessment of the vitreomacular interface (visibility of vitreous interface, vitreomacular adhesion, vitreomacular traction, epiretinal membrane, full-thickness macular hole, lamellar macular hole, macular pseudo-hole) and of the retina (retinoschisis, drusen, pigment epithelium detachment, hyper-reflective clumps, retinal pigment epithelium atrophy, intraretinal cystoid spaces, intraretinal tubular changes, subretinal fluid, subretinal material). Classifications according to size and location are defined. Illustrations of each item are provided, as well as the grading form. CONCLUSION: The E3 SD-OCT classification has been developed to harmonize epidemiological studies. This homogenization will allow comparing and sharing data collection between European and international studies. PMID- 30242987 TI - Do patients with skin psoriasis show subclinical axial inflammation on MRI of the sacroiliac joints and entire spine? AB - OBJECTIVE: To explore potential subclinical involvement of the axial skeleton by MRI of the sacroiliac joints (SIJ) and entire spine in patients with skin psoriasis without clinical evidence of peripheral or axial inflammation. METHODS: Twenty patients with skin psoriasis but no clinical evidence of peripheral or axial inflammation and 22 healthy controls underwent standardized dermatologic and rheumatologic clinical examination and unenhanced 1.5T MRI of the SIJ and the entire spine. Two blinded readers globally assessed the presence or absence of SIJ inflammation simultaneously on T1-weighted and STIR MRI sequences with a confidence estimate. Bone marrow edema, fat metaplasia, erosion and ankylosis of the SIJ, and vertebral corner inflammatory and fat lesions were recorded using standardized modules. The prevalence of each lesion type was calculated in both groups averaged across 2 readers. The number of subjects with >=1/2/3/4/5 lesions in the SIJ and spine as concordantly assessed by both readers was recorded. RESULTS: Median duration of skin psoriasis was 23.0 years, median age of patients 48.5 years. 25.0% of patients and 9.1% of healthy controls were concordantly classified by both readers as having SIJ inflammation (p=0.23). Prevalence of bone marrow edema and structural lesions was comparable across patients and controls both on SIJ and spine MRI. CONCLUSION: In this controlled study, patients with skin psoriasis, but no clinical arthritis or spondylitis showed limited evidence of concomitant subclinical axial involvement by SIJ and spine MRI. These findings do not support routine screening for subclinical axial inflammation in patients with longstanding skin psoriasis. This article is protected by copyright. All rights reserved. PMID- 30242986 TI - Initial intraocular pressure reduction by mono- versus multi-therapy in patients with open-angle glaucoma: results from the Glaucoma Intensive Treatment Study. AB - PURPOSE: To study newly diagnosed glaucoma patients given mono- or multi-therapy regarding differences in initial intraocular pressure (IOP) reduction, target IOP levels reached and influence of untreated baseline IOP on IOP reduction. METHODS: Patients newly diagnosed with manifest primary open-angle glaucoma and included in the Glaucoma Intensive Treatment Study (GITS) were randomized to immediate intensive treatment with any of three different IOP-lowering substances supplied in two bottles plus 360 degrees laser trabeculoplasty or to conventional stepwise treatment starting with a single-drug. Intraocular pressure reduction was analysed 1 month after initiation of treatment. RESULTS: One hundred eighteen patients (143 eyes) received mono-therapy and 122 patients (152 eyes) multi therapy. Median baseline IOP was 24.0 (min: 9.7, max: 56.0) mmHg in mono-therapy eyes and 24.0 (min: 12.3, max: 48.5) mmHg in multi-therapy eyes (p = 0.56). After 1 month in the two groups, respectively, values for median IOP reduction were 6.3 (range: -5.3-31.0) and 11.0 (range: 0.7-34.5) mmHg, and for mean relative decline 26.8 (range: -32.0-55.4) and 46.0 (range: 4.6-81.6) % (p = 0.000). A larger proportion of the multi-therapy patients reached each target IOP level (p = 0.000). The higher the baseline IOP, the larger the observed pressure reduction, considering both absolute and relative figures. The effect was more pronounced in eyes with multi-therapy than in those with mono-therapy (p = 0.000). For every mmHg higher IOP at baseline, the IOP was reduced by an additional 0.56 (mono therapy) or 0.84 (multi-therapy) mmHg. CONCLUSION: Intensive treatment led to considerably greater IOP reduction than mono-therapy. Among patients with IOP >=30 mmHg at diagnosis an IOP of <16 was reached in 2/3 of those with multi therapy but in none with mono-therapy. The IOP reduction was highly dependent on the untreated IOP level. PMID- 30242988 TI - Mental health among children of mothers with multiple sclerosis: A Danish cohort and register-based study. AB - BACKGROUND: Multiple sclerosis is associated with an increased risk of developing physical, cognitive, and mental health problems. Current studies have demonstrated variating outcomes of parental multiple sclerosis mental health problems and their children's mental health development. OBJECTIVE: The purpose of this study was to investigate whether maternal multiple sclerosis is associated with the mental health status of their child. METHODS: Data from the Danish National Birth Cohort (DNBC) were merged with information from the Danish Multiple Sclerosis Registry. Two proxies, total difficulties score and prediction of any psychiatric diagnosis based on the strengths and difficulties questionnaire, were used to measure the mental health status of the children. The two groups were compared using Mann-Whitney and logistic regression analyses. RESULTS: For the total difficulties score the control and exposed group consisted of respectively n = 42,016 and n = 40, and for the prediction of any psychiatric diagnosis respectively n = 16,829 and n = 17. We found no statistically significant association between maternal multiple sclerosis and mental health status on neither of the proxies. CONCLUSION: Maternal multiple sclerosis did not show any association with the mental health status of their children at age eleven. On the contrary, other studies conclude that there is an association between maternal multiple sclerosis and the child's mental health status, one especially mediated by the maternal mental health status. PMID- 30242989 TI - Mendelian Disease Genes More Prone to Copy Number Changes Than Previously Thought: Clinically relevant copy number variants are distinct from those that contribute to normal variation in human disease genes. PMID- 30242991 TI - USP48 May Be Potential Therapeutic Target in Fanconi Anemia: Inactivation of USP48 reduced chromosomal instability of Fanconi anemia defective cells and highlights a role for this enzyme in controlling DNA repair. PMID- 30242992 TI - Detection of flares by decrease in physical activity, collected using wearable activity trackers, in rheumatoid arthritis or axial spondyloarthritis: an application of Machine-Learning analyses in rheumatology. AB - BACKGROUND: Flares in rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) may influence physical activity. The objective was to assess longitudinally the association between patient-reported flares and activity tracker-provided steps per minute, using machine-learning. METHODS: This prospective observational study (ActConnect) included patients with definite RA or axSpA. During 3 months, physical activity was assessed continuously by number of steps/minute, using a consumer grade activity tracker, and flares were self assessed weekly. Machine-learning techniques were applied to the dataset. After intra-patient normalization of the physical activity data, using multiclass Bayesian methods, sensitivities, specificities and predictive values of the machine-generated models of physical activity to predict patient-reported flares were calculated. RESULTS: In all, 155 patients (1339 weekly flare assessments and 224,952 hours of physical activity assessment) were analyzed: for RA (N=82) and axSpA (N=73) patients respectively, mean age was 48.9+/-12.6 and 41.2+/-10.3 years; mean disease duration was 10.5+/-8.8 and 10.8+/-9.1 years; 14 (17.1%) and 41 (56.2%) were males. Disease was well-controlled (mean DAS28: 2.2+/-1.2; mean BASDAI: 3.1+/-2.0) but flares were frequent (22.7% of all weekly assessments). The model generated by machine-learning performed well against patient-reported flares (mean sensitivity: 96% [95% confidence interval 94-97%], mean specificity: 97% [96-97%], mean positive and negative predictive value: 91% [88-96and 99% [98 100%]). Sensitivity analyses were confirmatory. CONCLUSION: Although these pilot findings will have to be confirmed, the correct detection of flares by a machine learning processing of activity trackers data opens the way for future studies of remote-control monitoring of disease activity, with great precision and minimal patient burden. This article is protected by copyright. All rights reserved. PMID- 30242993 TI - Epstein Barr Virus in Patients with Nephropathy Associated with Systemic Lupus Erythematous, Pilot Study in Egyptian Patients. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease affecting young age adults especially females. Infection with Epstein Barr virus (EBV) represents a common pathogen associated with SLE activity. This study investigates the occurrence of EBV in SLE patients with renal complications by serological markers and molecular detection of EBV genome in renal biopsies and examine the association of EBV with the pathological grades in renal diseases. The study included nineteen patients with systemic lupus nephropathy and thirteen patients with non-lupus nephropathy. Renal biopsies were subjected to detection of EBV by PCR. Serum autoantibodies (anti- dsDNA, anti-Sm and anti-RNP) and EBV-IgM and IgG antibodies were detected by ELISA. The commonest autoantibody was anti- dsDNA (73.7%) followed by anti-Sm (57.8%) and anti-RNP (31.6%). The EBV-PCR revealed that 31.6% of patients with lupus nephropathy showed positive LMP1 gene expression in renal biopsies On the other hand, serological markers for EBV showed no significant difference between both groups; IgM for EBV was positive in 26.3% of patients with lupus nephropathy and 7.7% in non-lupus nephropathy, while IgG was positive in 26.3% and 15.4 % respectively. Positive LMPI-PCR was demonstrated in all (3/3) patients with severe degree of nephropathy as compared to 23.1% of patients with moderate degree of nephropathy. A significant association was found between EBV-PCR and anti-Sm, (P=0.01), anti- dsDNA (P=0.001), and IgG for EBV and anti- dsDNA (P=0.03). In conclusion, Molecular detection of EBV DNA in renal biopsies can be applied for laboratory diagnosis in SLE nephropathy. The severity of nephropathy associated with SLE seems to be aggravated by the presence of EBV. Further extended studies are required to elucidate this association. PMID- 30242994 TI - Relation of Regulatory Foxp3+ T Cells with Helicobacter pylori and Its Virulence Genes. AB - The study aimed to assess the tangled relation between various CD25 subsets (positive, negative and high) of CD4+ FoxP3+ T cells and H. pylori including its virulence genes (CagA and VacA). Diagnosis of H. pylori and its virulence genes was based on a positive culture, histopathology and/or CLO-test and PCR. Flow cytometry was used toquantifyTregs.CD4+CD25high Foxp3+ T cells were higher in patients than controls and somewhat more in H. pylori positive than negative patients. CD4+CD25high Foxp3+ T cells secreting IL10 were lower in H. pylori positive patients.CD4+CD25-Fox3+T cells were also higher in patients than controls and more in those negative for H. pylori. Moderate negative correlation was found between the presence of CagA or VacA sm genotypes and Tregs secreting IL10. CD4+CD25- Foxp3+ T cells, especially those secreting IL10, tend to be higher in patients carrying VacA m1 allele than m2 allele. In conclusion, H. pylori stimulate a regulatory T cell response, probably contributing to gastric diseases. CD25 negative subset of Fox3+CD4+T cells needs further studying to declare its potential role in immunopathogenesis of gastric diseases. Tregs are positively associated with vacA alleles. PMID- 30242995 TI - Serum IgE and Allergy Related Genotypes of IL-4R alpha and IL-13 Genes: Association with Glioma Susceptibility and Glioblastoma Prognosis. AB - Gliomas are the commonest type of primary brain tumor in adult. Glioblastoma maltiforms (GBM) is the malignant form with poor prognosis. Certain genotypes of inflammatory gene which associated with asthma and allergic conditions (IL-4R alpha and IL- 13) are inversely associated with glioma risk. We studied the relation between allergic conditions and serum level of IgE and glioma risk. We also examined the role of SNP of inflammatory genes IL-4 R alpha (rs 1801275) and IL-13 (rs 1800925) in development of glioma and to find out factors which can modify the prognosis of glioblastoma. This study included 98 Egyptian glioma cases and 98 healthy controls. Full history and clinical data were taken; total serum IgE were assayed, genotyping of IL-4 R alpha (rs 1801275) and IL-13 (rs 1800925) genes was carried out by restriction digestion after genes amplification. In cases group histopathological examination and tumor grading were done. Past history of allergic condition and elevated serum levels of IgE were more frequent in controls than in cases group (P< 0.05). Genotypes AA and AG of IL- 4R alpha were significantly frequent in cases and A allele were considered risk factor for glioma OR 2.31(1.53- 3.48), P < 0.001. We also found that C allele of IL-13 is risk factor for glioma susceptibility with p value = 0.006. Longer median survival period in glioblastoma were associated with elevated serum IgE level and who were AA genotypes of IL-4 R alpha. We conclude an inverse relation between glioma risk, and allergy biomarker IgE and allergy related (IL 4R alpha; rs 1801275) gene polymorphisms. GBM patients with IL-4Ralpha AA genotype, have longest survival. Chemotherapy and gross total resection improve GBM prognosis. PMID- 30242996 TI - Plasma Soluble Urokinase Plasminogen Activator Receptor Levels in Systemic Lupus Erythematosus Patients. AB - This study aimed to determine whether plasma soluble urokinase plasminogen activator receptor (suPAR) could serve as an activity biomarker in systemic lupus erythematosus (SLE) patients. suPAR levels were assessed in SLE patients, compared to healthy controls and correlated with disease activity. Sixty SLE patients were enrolled with assessment of disease activity using SLE Disease Activity Index (SLEDAI), C3, soluble urokinase plasminogen activator receptor level. Patients were divided according to disease activity into three groups: Patients in remission, mild to moderate activity, and high disease activity. Twenty apparently healthy individuals, age and sex matched, were included as a control group and subjected to routine laboratory tests and soluble urokinase plasminogen activator receptor level. The age range of the patients was 19 - 45 years with a mean of 29.07+/-6.84. suPAR, ESR and C3, but not CRP showed significant differences (P < 0.001), among SLE patients' subgroups. Plasma suPAR demonstrated higher levels among highly active than mild to moderately active or patients in remission, having higher discriminating ability regarding disease activity in comparison to ESR and C3 levels. It was higher in cases of nephritis. The optimum cut-off level of suPAR was >3.5 ng/ml, diagnostic validity tests for suPAR have shown to be 100% for sensitivity, specificity, positive predictive value and 74.1% for negative predictive value. These findings indicate that suPAR may be one of the valuable indicators of disease activity in SLE. PMID- 30242997 TI - Occult Hepatitis B Infection Among Blood Donors in Al Azhar University Hospital, Upper Egypt: The Current Status After 25 years of Vaccine Introduction. AB - Occult hepatitis B virus infection (OBI) is a challenging topic with much debate regarding its clinical and virological relevance. The reliance on anti HBc seropositivity for diagnosis of OBI is still controversial. We aimed to determine the frequency of OBI among Egyptian blood donors, the role of anti HBc and HBe Ag as predictors of OBI and the possible risk factors. A total of 300 randomly selected hepatitis B surface antigen (HBsAg) negative blood donors at the Blood Bank of Al Azhar University Hospital in Assiut were included. Measurement of liver enzymes and screening for HBV core antibodies (anti HBc) and Hepatitis e antigen (HbeAg) were done. Quantitative HBV DNA measurement was achieved by real time polymerase chain reaction with a detection limit of 20 IU/mL after DNA extraction from the peripheral blood mononuclear cells (PBMC). The prevalence of OBI was 3.7% (11/300) among the donors and the majority had low level viremia (63.6%). Anti HBc was detected in 20.7% (62/300) (group I). OBI was detected in 14.5% (9/62) in group I compared to 0.84% (2/238) in the anti-HBc Ab negative donors (group II). Anti HBc had a sensitivity and specificity of nearly 82% for detection of OBI with a high negative predictive value (99.16%). HBe Ag was detected in only 1.6% (1/62) of group I. There were no statistical significant differences regarding the liver enzymes, demographic data or risk factors between group I and II and even between cases of OBI and those without. We conclude that OBI exists in an alarming percentage among Egyptian blood donors. Anti HBc should be introduced in the routine blood screening. Negative anti HBc results ensures safe blood, while positive results need nucleic acid confirmation especially if given to high risk recipients. More in-depth evaluation of the immunization program is needed. PMID- 30242999 TI - Frequency of Circulating B1a and B2 B-cell Subsets in Egyptian Patients with Type 2 Diabetes Mellitus. AB - Type 2 diabetes mellitus (T2DM) is a growing health problem in Egypt. T2DM is recognized as chronic inflammatory disease with involvement of immune cells including B cells. We aimed to determine the frequency of antibody secreting B1a and B2 B cells in T2DM patients, their correlation with diabetes metabolic parameters and whether they play a role in diabetic foot infection (DFI) development. This study included 56 participants, recruited from Al-Zahraa hospital, Al-Azhar University, Egypt. Of these, 36 patients were diagnosed with T2DM, divided to two groups; (1) DM group (n=19) recently diagnosed, without foot complication; (2) DFI group (n=17); in addition to a Control group (n=20). The study assessed the frequency of circulating B1a (CD19+CD23-CD5+), and B2 (CD19+CD23+CD5-) cells by flow cytometry in diabetic patients. Comparison of the 3 studied groups revealed significant differences in frequency of studied total B cells (P=0.011), B1a (P < 0.001) and B2 subsets (P < 0.001). Comparison of B cell subsets between DFI, DM groups showed significant decrease in B1a in DFI group (P < 0.001). B1a cells % showed inverse correlation with HgA1c (r=-0.47, P < 0.001), LDL (r=-0.64, P < 0.001), and TG (r=-0.67, P < 0.001) but showed positive correlation with HDL (r=0.61, P < 0.001), while B2 cells showed opposite correlations. We concluded that imbalance of B cell subsets is seen in T2DM subjects. Beneficial role of B1a cells was spotted as they correlated inversely with glycemia and lipidemia in contrary to B2 cells. Decrease in B1a cells may predispose to DFI development. PMID- 30242998 TI - Association of sTNFR1 and BNP Levels with Diminished Estimated Glomerular Filtration Rate in Type 2 Diabetic Egyptian Patients. AB - Renal dysfunction is a key risk factor for all-cause mortality in patients with type 2 diabetes (T2D). Special attention has been raised regarding the role of soluble tumor necrosis factor receptor1 (sTNFR1) and brain natriuretic peptide (BNP) in diabetic nephropathy (DN) since they play a crucial role in the pathogenesis of T2D complications. Elevated concentrations of sTNFR1and BNP were found to be associated with progression to end stage renal disease (ESRD) in T2D. We determined serum levels of sTNFR1 and BNP in T2D patients and correlated them with various clinical variables especially kidney function and urinary albumin creatinine ratio (UACR). This study included 30 patients with T2D who were divided into two groups according to estimated glomerular filtration rate (eGFR): group 1with (eGFR < 60 mL/min/1.73m2) and group 2 with (eGFR > 60 mL/min/1.73 m2). They were compared with 15 sexes and age matched healthy individuals as a control group. Serum levels of sTNFR1 and BNP were determined using ELISA. Serum levels of sTNFR1 and BNP were significantly higher in group1when compared with group 2 (P= 0.000, P= 0.000) and they were significantly higher in both group1 and group 2 as compared with control (P= 0.000, P= 0.000); (P= 0.000, P = 0.000) respectively. Both sTNFR1 and BNP levels showed significant negative correlation with eGFR (r = - 0.58, P = 0.000); (r= - 0.77, P= 0.000) respectively, and significant positive correlation with UACR (r= 0.84, P= 0.000); (r=0.80, P= 0.000) respectively. In conclusion, increased circulating levels of sTNFR1 and BNP were associated with loss of kidney function in T2D patients. PMID- 30243000 TI - Serum Levels of Pentraxin3 and Interlukin36? in Patients with Systemic Lupus and their Relation to Disease Activity. AB - Pentraxin3 (PTX3) plays an important role in inflammation, immunity, and atherosclerosis. Serum PTX3 has drawn attention as a marker that respond to local inflammation. Interleukin 36 (IL-36) is a novel inflammatory member of the IL-1 cytokine family comprising three different isoforms IL36alpha, IL-36beta and IL 36gamma. The objective of this work was to evaluate the levels of PTX3 and IL36alpha and to determine their relationships to disease activity in patients with systemic lupus erythematosus (SLE). Forty patients with SLE diagnosed according to SLECCA/ACR2012 criteria were allocated to the study, along with 20, age and sex matched normal control subjects. SLE patients included 20 patients with active disease, each having SLEADI score over 6 points and the other 20 patients, each of them had SLEADI score less than 6 points. Levels of serum PTX3 and IL36alpha was measured by quantitative sandwich enzyme immunoassay technique. There was a significant increase in the serum pentraxin3 and IL36alpha in SLE patients (P < 0.01) compared to normal control subjects. The significance increased in serum levels of PTX3 and IL-36alpha, was noted in active (P=0.000 for both) and inactive SLE patients (P=0.003 and P=0.001, respectively), compared to normal control subjects. Moreover, the active SLE patients had significant increase in the serum levels of PTX3 and IL36alpha (P < 0.01 for both) compared to the inactive group of patients. A significant positive correlation between each of PTX3 and IL36alpha, and SLEADI score (P=0.008 and P=0.024, respectively) in SLE patients was observed. In conclusion, PTX3and IL36alpha serum levels are increased in SLE patients when compared to normal control subjects, correlated positively with SLEDAI score and thus could be used as markers of disease activity. PMID- 30243001 TI - Evaluation of Serum IFN-? and IL-5 Levels in Response to Entecavir Therapy in Patients with Chronic Hepatitis B Virus Infection. AB - Current treatment guidelines recommend the use of entecavir (ETV) as a first-line therapy for chronic HBV infection. Still little is known about its role in restoration of the exhausted HBV immune response. The aim of our study was to assess HBeAg serologic response and serum levels of IFN-gamma and IL-5 before and after one year treatment with ETV in chronic hepatitis B patients (CHB) in a trial to find possible predictors for response to ETV treatment in those patients (hepatits B viral clearance and HBeAg seroconversion). The study included 30 chronic hepatitis B patients. All patients received de novo entecavir monotherapy at a daily dose of 0.5 mg for 1 year. Virologic [HBV DNA load, HBV markers (HBsAg, HBeAg, HBeAb)], Biochemical (AST and ALT) and immunological (serum IFN-? and IL-5) assessments were done for all patients before and a year after treatment in comparison with healthy controls. Levels of AST and ALT were significantly reduced in all treated patients and normalized in 15. HBeAg seroconversion was achieved in 17 patients, HBV DNA was markedly decreased in all patients and not detectable in 10 of them. IFN- ? level increased and IL-5 levels decreased markedly reaching normal levels. Significant relations were detected between HBV DNA, IL-5, HBeAg seroconversion and virologic response (VR) to ETV. ROC curve analysis have shown good prognostic accuracy for both pretreatment HBV DNA and IL5 levels in predicting VR and HBeAg seroconversion after ETV therapy in CHB patients, with pretreatment HBV DNA having somewhat better accuracy and higher propability for the test being correct in predicting loss of HBeAg after treatment. In conclusions, ETV markedly reduced HBV DNA and ALT levels, restored IFN-? and IL-5 normal levels and HBeAg seroconversion was achieved in some patients. Both pretreatment levels of HBV DNA and IL5 can be used in predicting VR to ETV but HBV DNA is superior in predicting HBV seroconversion in HBeAg positive patients. PMID- 30243002 TI - The Effect of Breast Feeding on T-Lymphocyte Subpopulation. AB - Human milk plays an important role in the development and differentiation of the neonatal immune system. The relative immaturity of the neonatal immune system is largely compensated for by the bioactive constituents of breast milk. Yet, little is known about the effect of breast feeding on cellular immunity. This study demonstrates the effects of various milk feedings (breast, formula, mixed) on peripheral lymphocyte subsets (CD3, CD4, CD8) in normal full-term infants at the age of 4 to 8 months. It is a comparative study conducted on randomly selected 61 healthy full-term infants categorized according to the type of milk feeding. Infants were subjected to full history taking, thorough clinical examination as well as laboratory investigations including CBC, total and differential WBC count, CD3, CD4 and CD8 assessment by flowcytometry. Results showed significantly lower CD4 and higher CD8 percentages among breast-fed in comparison with artificially-fed and mixed-fed infants, while no significant difference was found regarding CD3. Comparing the artificially-fed and mixed-fed infants, no significant difference found regarding CD3, CD4 and CD8. It is concluded that Lymphocyte subset profiles in the early stages of life could be modulated by milk feeding practices. Therefore, it is recommended to encourage breast feeding for its immune-modulating effect on the developing of the immune system that minimizes risk of infection and allergy. PMID- 30243003 TI - Study of Antichromatin Antibodies As A Marker of Lupus Activity and Lupus Nephritis. AB - Systemic Lupus Erythematosus (SLE) is a chronic and potentially fatal autoimmune disorder characterized by the production of auto-antibodies that cause widespread tissue damage. Validate Antichromatin antibodies as a biomarker of renal involvement in SLE and how their titers correlate with systemic lupus activity measure (SLAM) index among a sample of Egyptian systemic lupus patients. The study was conducted on 60 patients diagnosed according to ACR criteria for diagnoses of SLE (Group I) and 25 age matched healthy controls (Group II). Group I was divided into 30 patients without nephritis group A 1 and 30 patients with nephritis group IB. (anti-dsDNA, Antinuclear antibodies ANA), rheumatoid factor (RF), Complement component C3, C4 and antichromatin antibodies were done for all patients and controls. Serum antichromatin antibodies were positive in all cases of SLE and negative in all control subjects and were higher in group1B than group IA also; there were significant positive correlation between antichromatin antibodies and SLAM score of disease activity and classes of nephropathy. In conclusion, measurement of antichromatin antibodies is a useful addition to the laboratory work up for diagnosis and monitoring of SLE and prediction of lupus nephritis. PMID- 30243004 TI - Human Leukocyte Antigen-G (HLA-G) Expression in Precancerous and Cancerous Cervical Lesions: Association with Human Papilloma Virus Infection and Host Immune Response. AB - Human leukocyte antigen-G (HLA-G) is a non-classical HLA-class Ib molecule with multiple immunoregulatory properties. Its main functions in physiological conditions are to abolish maternal immune cell activity against fetus and to establish immune tolerance at the maternal-fetal interface. Cervical tumor cells have been reported to express HLA-G which is one of the immunomodulatory molecules that is involved in every phase of cancer immunoediting. It has inhibitory functions against natural killer (NK) cells, T-lymphocytes, and antigen-presenting cells (APCs). The purpose of this study was to investigate the HLA-G expression in precancerous (squamous intraepithelial cervical lesion) and cancer cervix and determine HLA-G expression relation to HPV infection as well as host immune response. The study included 48 paraffin embedded cervical tissue sections [32 squamous intraepithelial lesion (SIL) {16 low grade lesions (LSIL) and 16 high grade lesions (HSIL)} and 16 cervical cancer tissue sections]. All tissue sections were examined for HLA-G expression by real time PCR and for host immune response by estimating the number of tumor infiltrating lymphocyte (TIL) and NK CD57+ cells. HLA-G expression increased progressively from precancerous and cancerous cervical lesions. There was an inverse relationship between HLA-G expression and estimated number of TILs and NK CD57+ cells. No significant statistical difference between HPV positive and HPV negative cervical lesions as regards HLA-G expression was detected. In conclusion, HLA-G is a potential biomarker for the diagnosis and prognosis of cervical cancer as there was a progressive increase in expression of HLA-G in precancerous and cancerous cervical lesion. It is functionally involved in tumor escape mechanisms as observed by inhibition of host immune response and more studies are needed to design strategies for blockade of HLA G expression or elimination of HLA G expressing cancer cells as this may be important to the efficacy of anticancer therapies. PMID- 30243005 TI - Relationship between Serum Level of Endocan and Severity of Childhood Asthma. AB - Endocan is an endothelial cell-associated proteoglycan that is preferentially expressed by renal and pulmonary endothe!lium. It reflects endothelial activation and dysfunction, this study aimed to investigate the role of Endocan in bronchial asthma and correlate their levels with the severity of asthma. Sixty children with mild and moderate asthma and 20 healthy controls were included in the study and subjected to full clinical examination, Anthropometric measurements, pulmonary function test, CBC and assay of serum level of Endocan using ELISA. A high significant increase in serum level of Endocan was found in all asthmatic children compared with the controls. Significant higher levels were also found in mild and moderate persistent asthma as compared to controls. In all asthmatic children, there was significant positive correlation between serum level of Endocan and PBE count and negative correlation with FEV1 and PEF, and insignificant correlation with serum IgE level. In conclusion; high Endocan level is associated with poor lung functions and severity of asthma. Further studies are needed to validate these data. PMID- 30243006 TI - Prognostic Value of Serum Antiphospholipid Antibodies in Patients with ST-Segment Elevation Myocardial Infarction. AB - Hypercoagulability in patients with primary Antiphospholipid syndrome (APS) predisposes to high rates of thromboembolic events and restenosis of the coronaries causing significant morbidity and mortality. Although the association between the APS and Acute Myocardial infraction (AMI) is very rare about 4%. Treatment of patients with APS represent a clinical challenge. Current study was designed to investigate the correlation between antiphospholipid antibodies (aPL) in prediction of the complication-associated AMI in Aswan governorate. Fifty AMI patients were compared to thirty controls. Serum aPLs was assessed using commercial ELISA kits. In patients; data revealed that mean Lupus anticoagulant was 59.2 U/mL, IgM and IgG anticardiolipin was 1.14 U/mL and 1.26 U/mL respectively. In addition the mean of antiphosphatidyl inositol (aPI) was 11.68 U/mL. On follow-up; Lupus and aCA IgM showed weak correlation with cases that showed further complications, while aCA-IgG showed protective effects (P=0.001/ r=-0.463) and aPI-IgM moderate correlation with the complications (P=0.048/ r=0.281). It's concluded that aCAs play distinct roles in the pathogenesis of AMI reduced levels of aCA-IgG has protective effects while the aCA-IgM indicate a poor prognosis, and that aPI is a good marker for prediction of recurrence of cardiovascular events among patients. PMID- 30243007 TI - Interleukin-17 Gene Expression and Serum Levels in AsthmaDegenerative Model. AB - Asthma is one of the most common chronic respiratory diseases. It is associated with significant morbidity and shows an increasing prevalence over time. Accumulating evidence suggests that interleukin (IL)-17 has a key role in severe asthma. The aim of the study was to determine quantitatively gene expression of IL-17 in peripheral blood mononuclear cells (PBMN) & the level of IL-17 in the serum of asthmatic patients, to correlate the level of IL-17 with the severity of asthma and to compare between gene expression of IL-17 and its serum level. Forty (40) asthmatic patients were enrolled and subdivided into 2 subgroups; controlled & uncontrolled asthma according to GINA, 2014. In addition, twenty (20) healthy control subjects were included. Blood samples were subjected to real time PCR assays for IL-17 mRNA gene expression and serum was tested by ELISA for estimation of IL-17 serum levels. Significant higher serum IL-17 levels were found in patients with uncontrolled asthma compared to patients with controlled asthma and healthy control group. Mean serum IL-17 value was 87.24 pg/ml in uncontrolled asthma, 75.9 pg/ml in controlled asthma and 47.0 pg/ml in healthy group (P= 0.00). IL-17 mRNA gene expression levels (DeltaDelta Ct) were also significantly elevated in uncontrolled asthma compared to patients with controlled asthma and healthy control group. Mean IL-17 mRNA gene expression levels were 33.7 units in uncontrolled asthma, 7.0 in controlled asthma and 0.30 in healthy group (P=0.00). PMID- 30243008 TI - Role of Candida Albicans Germ Tube Antibody in Diagnosis of Invasive Candidiasis in End Stage Liver Disease Patients. AB - Candida species are the leading cause of invasive fungal infections and a common cause of hospital-acquired bloodstream infections. Invasive candidiasisis a highly lethal infection associated with mortality rates between 40 and 60 %. This study was conducted with aim of assessing the role of Candida albicans germ tube antibody (CAGTA) level in the early diagnosis of invasive candidiasis and in monitoring the efficacy of antifungal drugs in patients with end stage liver disease. Sixty two end stage liver disease patients were included in this study. Candida albicans germ tube antibody (CAGTA) test was done for all cases by indirect immunofluorescence technique, and it was positive with (titre >= 1/160) in 18 cases including the 10 blood culture positive cases. Compared to positive blood culture, the sensitivity, specificity, negative predictive value, positive predictive value and accuracy of CAGTA test were 100%, 84.6 %, 55.6 %, 100 % and 73.3 % respectively. Candida albicans germ tube antibody (CAGTA) test is sensitive and specific test, that can be used for early diagnosis of invasive candidiasis and in monitoring the effect of treatment with antifungal drugs in end stage liver disease patients. PMID- 30243009 TI - Neutrophil CD64 Expression and other Laboratory Biomarkers in Discriminating Bacterial versus Non Bacterial Acute Exacerbation Chronic Obstructive Pulmonary Disease. AB - Discriminating bacterial from nonbacterial acute exacerbation chronic obstructive pulmonary disease (AE-COPD) is difficult. In this study, we evaluated T/NK-cells' subsets in peripheral blood of both stable COPD and AE-COPD patients for identifying their rule in the pathogenesis of the disease and highlighting rule of laboratory biomarkers as total and differential leukocytic count, different T/NK lymphocytes' subsets, CD64 neutrophil expression and high sensitive C reactive protein (CRP) in discriminating bacterial versus nonbacterial AE-COPD to limit overuse of antibiotics. The studied groups were divided into 30 patients with stable COPD disease (control group) and 30 patients with AE-COPD; of which 22 were classified as bacterial and 8 as non-bacterial AE-COPD groups. Total and differential leukocytic count (TLC), high sensitive-CRP and flow-cytometric immunophenotyping using monoclonal antibodies against CD3, CD4, CD8, CD16, CD56 and CD64 were analyzed for each group. Parameters that were significantly different between control and AE-COPD groups included peripheral blood CD64 percent expression, cytotoxic-T cells (Tc), T-helper (Th), NK, NK-T and total lymphocytes' percentages. Using same parameters to further differentiate between bacterial and non-bacterial AE-COPD patients; CRP and CD64% were highly significant between 2 groups (P < 0.001), with higher CRP level and CD64 expression in the bacterial group with mean value; 22.27 mg/L and 83.89%, respectively. A cutoff of 15mg/L and 59.5% for both CRP and CD64 expression were used to discriminate between bacterial and non-bacterial COPD patients. In conclusion, CD64 expression and high sensitive-CRP performed better than several leukocytes concentrations in discriminating bacterial versus non-bacterial AE COPD. The percentage of CD3CD8 (Tc), CD3CD4 (Th), CD16CD56 (NK) cells were higher in AE-COPD than stable COPD. PMID- 30243010 TI - Serum levels of Interleukins 1-Alpha & 12 as Predictors of Disease Progression in Hepatitis C Diabetic Patients. AB - This study evaluates the usefulness of interleukins 1 alpha and 12 in predicting disease progression in diabetic HCV and HCV related liver diseases compared to non-diabetics. The study included 76 hepatitis C virus-infected patients [38 diabetics, 38 none (with, without cirrhosis)]. Serum levels of IL-1alpha and IL 12 were measured by ELISA. Serum levels of IL-1alpha and IL12 were higher in cirrhotic than non -cirrhotic patients and higher in the diabetic patients. Significant correlations were detected between IL-1alpha, prothrombin time (PT), and severity scores in cirrhotic patients. Levels of both cytokines correlated with the fasting plasma glucose levels. Stronger correlations were evident between IL-12, PT and total bilirubin than IL-1alpha in diabetics. In conclusion; IL-1alpha and IL-12 are good markers for monitoring liver disease progression in cirrhotic and diabetic HCV patients. Whereas IL-1alpha is a better marker in cirrhotic patients, IL-12 is somewhat superior to IL-1alpha in diabetic patients. PMID- 30243011 TI - The adipokine Chemerin and Fetuin-A Serum Levels in Type 2 Diabetes Mellitus: Relation to Obesity and Inflammatory Markers. AB - Chemerin and fetuin-A are recently discovered as metabolic regulator hormone in obesity and type 2 diabetes mellitus. However, elevated levels of chemerin and fetuin-A have been associated with insulin resistance and systemic inflammation. The present study aimed to investigate the significance of serum chemerin and fetuin-A levels in obese diabetic patients. Also, to determine whether, chemerin and fetuin-A along with markers of inflammation (IL6 and CRP) and obesity-related parameters in T2DM patients. Serum levels of chemerin and fetuin-A were evaluated using ELISA in 71 T2DM patients and 14 apparently healthy controls. Both groups were subdivided into obese and lean. Serum chemerin and fetuin-A levels were significantly higher in T2DM patients compared to controls (P < 0.001, for both) and significantly higher in obese T2DM in comparison to obese control group (P < 0.01 & P < 0.05, respectively). Serum chemerin and fetuin-A levels correlated positively with HbA1c, HOMA-IR, FBG, IL6 and CRP. In obese patients, serum chemerin and fetuin-A levels correlated positively with BMI and waist circumference. In conclusion, the strong association of chemerin and fetuin-A with insulin resistance and some inflammatory markers may provide an interesting link between obesity, inflammation and diabetes mellitus in human. PMID- 30243012 TI - Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I). AB - NADH-quinone oxidoreductase (complex I) is the largest and most complicated enzyme complex of the mitochondrial respiratory chain. It is the entry site into the respiratory chain for most of the reducing equivalents generated during metabolism, coupling electron transfer from NADH to quinone to proton translocation, which in turn drives ATP synthesis. Dysfunction of complex I is associated with neurodegenerative diseases such as Parkinson's and Alzheimer's, and it is proposed to be involved in aging. Complex I has one non-covalently bound FMN, eight to 10 iron-sulfur clusters, and protein-associated quinone molecules as electron transport components. Electron paramagnetic resonance (EPR) has previously been the most informative technique, especially in membrane in situ analysis. The structure of complex 1 has now been resolved from a number of species, but the mechanisms by which electron transfer is coupled to transmembrane proton pumping remains unresolved. Ubiquinone-10, the terminal electron acceptor of complex I, is detectable by EPR in its one electron reduced, semiquinone (SQ) state. In the aerobic steady state of respiration the semi ubiquinone anion has been observed and studied in detail. Two distinct protein associated fast and slow relaxing, SQ signals have been resolved which were designated SQNf and SQNs. This review covers a five decade personal journey through the field leading to a focus on the unresolved questions of the role of the SQ radicals and their possible part in proton pumping. PMID- 30243013 TI - A thermometry software tool for monitoring laser-induced interstitial thermotherapy. AB - The purpose of this study was to develop a thermometry software tool for temperature monitoring during laser-induced interstitial thermotherapy (LITT). C++ programming language and several libraries including DICOM Toolkit, Grassroots DICOM library, Insight Segmentation and Registration Toolkit, Visualization Toolkit and Quasar Toolkit were used. The software's graphical user interface creates windows displaying the temperature map and the coagulation extent in the tissue, determined by the magnetic resonance imaging (MRI) thermometry with the echo planar imaging sequence and a numerical simulation based on the radiation and heat transfer in biological tissues, respectively. The software was evaluated applying the MRI-guided LITT to ex vivo pig liver and simultaneously measuring the temperature through a fiber-optic thermometer as reference. Using the software, the temperature distribution determined by the MRI method was compared with the coagulation extent simulation. An agreement was shown between the MRI temperature map and the simulated coagulation extent. Furthermore, the MRI-based and simulated temperatures agreed with the measured one - a correlation coefficient of 0.9993 and 0.9996 was obtained, respectively. The precision of the MRI temperature amounted to 2.4 degrees C. In conclusion, the software tool developed in the present study can be applied for monitoring and controlling the LITT procedure in ex vivo tissues. PMID- 30243014 TI - Optical imaging methods in medicine: how can we escape the plausibility trap? PMID- 30243015 TI - Determining qualitative effect size ratings using a likelihood ratio scatter matrix in diagnostic test accuracy systematic reviews. AB - Background Diagnostic test accuracy (DTA) systematic reviews (SRs) characterize a test's potential for diagnostic quality and safety. However, interpreting DTA measures in the context of SRs is challenging. Further, some evidence grading methods (e.g. Centers for Disease Control and Prevention, Division of Laboratory Systems Laboratory Medicine Best Practices method) require determination of qualitative effect size ratings as a contributor to practice recommendations. This paper describes a recently developed effect size rating approach for assessing a DTA evidence base. Methods A likelihood ratio scatter matrix will plot positive and negative likelihood ratio pairings for DTA studies. Pairings are graphed as single point estimates with confidence intervals, positioned in one of four quadrants derived from established thresholds for test clinical validity. These quadrants support defensible judgments on "substantial", "moderate", or "minimal" effect size ratings for each plotted study. The approach is flexible in relation to a priori determinations of the relative clinical importance of false positive and false negative test results. Results and conclusions This qualitative effect size rating approach was operationalized in a recent SR that assessed effectiveness of test practices for the diagnosis of Clostridium difficile. Relevance of this approach to other methods of grading evidence, and efforts to measure diagnostic quality and safety are described. Limitations of the approach arise from understanding that a diagnostic test is not an isolated element in the diagnostic process, but provides information in clinical context towards diagnostic quality and safety. PMID- 30243017 TI - Corrigendum to: The functional role of all postsynaptic potentials examined from a first-person frame of reference. PMID- 30243016 TI - Hypogammaglobulinemia and imaging features in a patient with infantile free sialic acid storage disease (ISSD) and a novel mutation in the SLC17A5 gene. AB - Background Infantile free sialic acid storage disease (ISSD) is a severe multisystemic disorder characterized by the accumulation of free sialic acid in lysosomes. Case presentation The patient presented prenatally with fetal ascites and large scrotal hernias, without pleural or pericardial effusion. During the infantile period, he was diagnosed with permanent isolated immunoglobulin G (IgG) hypogammaglobulinemia, which thus far has rarely been associated with ISSD. The analysis of the SLC17A5 gene revealed a novel homozygous 94 bp gene deletion. We further provide a detailed description of pre- and postnatal clinical and radiographic findings. Conclusions Fetal ascites could be the first sign of several lysosomal storage diseases (LSDs), including ISSD. The analysis of LSD gene panels is an effective approach to diagnosis in the case of non-specific symptoms and when specific biochemical tests are not easily available. PMID- 30243018 TI - CRISPR-tagging mice in aging research. PMID- 30243019 TI - Reproductive history and blood cell telomere length. AB - Telomeres are repetitive nucleotide sequences that protect against chromosomal shortening. They are replenished by telomerase, an enzyme that may be activated by estrogen. Women have longer telomeres than men; this difference might be due to estrogen exposure. We hypothesized that reproductive histories reflecting greater estrogen exposure will be associated with longer blood cell telomeres. Among women in the Sister Study (n= 1,048), we examined telomere length in relation to self-reported data on reproductive history. The difference between age at menarche and last menstrual period was used to approximate the reproductive period. Relative telomere length (rTL) was measured using qPCR. After adjustment, rTL decreased with longer reproductive period (beta= -0.019, 95% CI: -0.04, -0.00, p= 0.03). Premenopausal women had shorter rTL than postmenopausal women (beta= -0.051, 95% CI: -0.12, 0.01, p= 0.13). Longer breastfeeding duration was associated with longer rTL (beta= 0.027, 95% CI: 0.01, 0.05, p=0.01); increasing parity was associated with shorter rTL (beta = -0.016, 95% CI: -0.03, 0.00, p=0.07). Duration of exogenous hormone use was not associated with rTL. Reproductive histories reflecting greater endogenous estrogen exposure were associated with shorter rTL. Our findings suggest that longer telomeres in women are unlikely to be explained by greater estrogen exposure. PMID- 30243021 TI - Aging, cardiac repair and Smad3. PMID- 30243020 TI - Effects of N-acetyl-L-cysteine on lifespan, locomotor activity and stress resistance of 3 Drosophila species with different lifespans. AB - N-acetyl-L-cysteine (NAC) is a derivative of the sulphur-containing amino acid L cysteine with potential anti-aging properties. We studied 3 Drosophila species with contrast longevity differences (D. virilis is longest-lived, D. kikkawai is shortest-lived and D. melanogaster has moderate lifespan) to test the effects of NAC at 8 different concentrations (from 10 nM to 100 mM) on the lifespan, stress resistance and locomotor activity. Except the adverse effects of highest (10 mM and 100 mM) concentrations NAC demonstrated sexually opposite and male-biased effects on Drosophila lifespan, stress-resistance and locomotor activity and not satisfied the criteria of a geroprotector in terms of the reproducibility of lifespan extending effects in different model organisms. The concentration- and sex-dependent changes in the relative expression levels of the antioxidant genes (Cat/CG6871 and Sod1/CG11793) and genes involved in hydrogen sulfide biosynthesis (Cbs/CG1753, Eip55E/CG5345 and Nfs1/CG12264) suggest the involvement of hormetic mechanisms in the geroprotective effects of NAC. PMID- 30243022 TI - MiR-665 aggravates heart failure via suppressing CD34-mediated coronary microvessel angiogenesis. AB - BACKGROUND: Heart failure (HF) is a major public health problem worldwide. The development of HF was related to coronary microvessel dysfunction. Whether miRNAs participate in HF by regulating coronary microvessel function remain unclear. METHODS: The potential targets of miR-665 were predicted by rnahybrid software, then verified through anti-Ago2 co-immunoprecipitation, Western blotting and luciferase reporter assays. rAAV9 system was used to manipulate the expression of miR-665 in vivo. RESULTS: Significant increase of miR-665 was observed in endothelial cells of human heart with heart failure. In vitro over-expression of miR-665 in endothelial cells resulted in decreased proliferation but enhanced apoptosis. rAAV-mediated delivery of miR-665 reduced coronary microvessel angiogenesis and cardiac microvessel density, then further impaired cardiac function in vivo. Furthermore, CD34 was confirmed as one of the miR-665 targets. Consistently, re-expression of CD34 attenuated miR-665-mediated damage effects in vitro and in vivo. We also found that Sp1 regulated miR-665 expression in endothelial cells. CONCLUSION: Our findings demonstrated that miR-665 played an important role in heart failure via damaging coronary microvessel angiogenesis, and suggested that miRNA-based therapeutics may protect against coronary microvessel dysfunction and heart failure. PMID- 30243024 TI - Sirt1 enhances tau exon 10 inclusion and improves spatial memory of Htau mice. AB - Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule binding repeats, named 3R-tau and 4R-tau, respectively. Dysregulation of tau exon 10 splicing could cause neurofibrillary degeneration. Acetylation is one of the major post-translational protein modifications in the cell by attachment of the acetyl group to either the alpha-amino group of the N-terminus of proteins or to the epsilon-amino group of lysine residues. Sirt1, one member in mammalian Sirtuin family, deacetylates protein and is associated closely with age-related diseases including Alzheimer's disease. However, the role of Sirt1 in tau exon 10 splicing remains elusive. In the present study, we determined the role of Sirt1 in tau exon 10 splicing. We found that activation of Sirt1 by resveratrol enhanced tau exon 10 inclusion, leading to 4R-tau expression. Sirt1 interacted with splicing factor 9G8, deacetylated it at Lys24, and suppressed its function in promoting tau exon 10 exclusion. Moreover, resveratrol improved learning and spatial memory in Htau mice. These findings suggest that Sirt1 may serve as a new drug target for Alzheimer's Disease related tauopathies and resveratrol may be used to correct dysregulated tau exon 10 with 3R-tau > 4R-tau. PMID- 30243025 TI - Antihypertensive Therapy in the Acute Phase of Lacunar Infarcts. AB - BACKGROUND The optimal medical regimen for managing hypertension during acute phase of lacunar infarcts has not yet been clarified in real world setting. The aim of this study was to evaluate blood pressure lowering regimens on neurological progression and clinical outcomes during the acute phase of lacunar infarcts. MATERIAL AND METHODS For this study, 411 patients with first-episode lacunar infarcts and hypertension within 24 hours of symptom onset were included. All patients received antihypertension therapies, with different regimens, as well as routine medication during first 7 days after onset. There were 6 proposed antihypertensive treatments: calcium channel blockers (CCB), angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta blocker (beta-B), and diuretic drug (DD) alone or in combination. Neurological progression was defined as worsening by >=1 point in the National Institute of Health Stroke Scale (NIHSS) for motor function. The outcome was assessed using the modified Rankin Scale (mRS): favorable outcome (mRS of 0-1) or unfavorable outcome (mRS 2-5). RESULTS Logistic regression analysis showed that combination therapy with CCB, ACEI/ARB, and beta-B exhibited the lowest risk of deterioration (OR=0.48, P=0.019) and unfavorable outcomes (OR=0.50, P=0.022). Similarly, combination therapy with CCB, ACEI/ARB, and DD exhibited lower risk of deterioration (OR=0.63, P=0.033) and unfavorable outcome (OR=0.77, P=0.042) at 3 months. CONCLUSIONS Rational blood pressure lowering was beneficial to the functional outcomes of patients during acute phase of lacunar infarcts, and combination therapy was better than mono-drug therapy. PMID- 30243023 TI - A new risk score based on twelve hepatocellular carcinoma-specific gene expression can predict the patients' prognosis. AB - A large panel of molecular biomarkers have been identified to predict the prognosis of hepatocellular carcinoma (HCC), yet with limited clinical application due to difficult extrapolation. We here generated a genetic risk score system comprised of 12 HCC-specific genes to better predict the prognosis of HCC patients. Four genomics profiling datasets (GSE5851, GSE28691, GSE15765 and GSE14323) were searched to seek HCC-specific genes by comparisons between cancer samples and normal liver tissues and between different subtypes of hepatic neoplasms. Univariate survival analysis screened HCC-specific genes associated with overall survival (OS) in the training dataset for next-step risk model construction. The prognostic value of the constructed HCC risk score system was then validated in the TCGA dataset. Stratified analysis indicated this scoring system showed better performance in elderly male patients with HBV infection and preoperative lower levels of creatinine, alpha-fetoprotein and platelet and higher level of albumin. Functional annotation of this risk model in high-risk patients revealed that pathways associated with cell cycle, cell migration and inflammation were significantly enriched. In summary, our constructed HCC specific gene risk model demonstrated robustness and potentiality in predicting the prognosis of HCC patients, especially among elderly male patients with HBV infection and relatively better general conditions. PMID- 30243026 TI - Long-term exposure to neighborhood smoke from household heating and risk of respiratory and dermatological prescription medications-Growing Up in New Zealand child cohort study. PMID- 30243027 TI - Peripheral group 2 innate lymphoid cells are decreased following nasal allergen challenge in allergic rhinitis. PMID- 30243028 TI - Breathing pattern disorderin difficult asthma: characteristics and improvement in asthma control and quality of life after breathing re-training. PMID- 30243029 TI - Inhibition of Ca2+ -activated chloride channel ANO1 suppresses ovarian cancer through inactivating PI3K/Akt signaling. AB - Most common ovarian cancers are epithelial carcinoma in which the etiology for carcinogenesis remains elusive. ANO1/TMEM16A, a member of Ca2+ -activated Cl- channels (CaCCs), has been demonstrated to promote epithelium-originated cancers and whether it plays a role in the pathogenesis of ovarian cancer is unknown. In our study we found that ANO1 proteins were overexpressed in human epithelial ovarian cancer cells and tissue samples. ANO1 protein upregulation was correlated with the clinical FIGO (International Federation of Gynecology and Obstetrics) staging and poor grade in ovarian cancer tissues. Interestingly, the upregulation of ANO1 gene expression was also detected in the peripheral blood mononuclear cells (PBMCs) from pre-operative patients with ovarian tumors, and the down regulation of ANO1 in the PBMCs from post-operative patients. Silencing of ANO1 inhibited proliferation and invasion of ovarian cancer cells. Mechanistically, ANO1 knockdown attenuated phosphorylation of PI3K/Akt, and inhibition of PI3K/Akt signaling by specific inhibitor LY294002 resulted in suppression of ovarian cancer cells growth promoted by ANO1 expression. Furthermore, intratumoral injection of ANO1 siRNA suppressed subcutaneous xenograft tumor growth in nude mice implanted with ovarian cancer SKOV3 cells. Taken together, our findings demonstrate that ANO1 overexpression is involved in the pathogenesis of human epithelial ovarian cancer. Inhibition of ANO1 upregulation or inactivating PI3K/Akt signaling may have therapeutic potential for epithelial ovarian cancer, and the detection of ANO1 expression level in PBMCs from patients may also serve as a biomarker for diagnosis and prognosis of epithelial ovarian cancers. This article is protected by copyright. All rights reserved. PMID- 30243030 TI - The 2016 Melbourne thunderstorm asthma epidemic: Risk factors for severe attacks requiring hospital admission. AB - BACKGROUND: The world's most catastrophic and deadly thunderstorm asthma epidemic struck Melbourne, Australia, on November 21, 2016. OBJECTIVE: Among thunderstorm affected patients presenting to emergency rooms (ERs), we investigated risk factors predicting severe attacks requiring admission to hospital. METHODS: Thunderstorm-affected patients were identified from ER records at the eight major Melbourne health services and interviewed by telephone. Risk factors for hospital admission were analyzed. RESULTS: We interviewed 1435/2248 (64%) of thunderstorm affected patients, of whom 164 (11.4%) required hospital admission. Overall, rhinitis was present in 87%, and current asthma was present in 28%. Odds for hospital admission were higher with increasing age (odds ratio 1.010, 95% CI 1.002, 1.019) and among individuals with current asthma (adjusted odds ratio [aOR] 1.87, 95% CI 1.26, 2.78). Prior hospitalization for asthma in the previous 12 months further increased the odds for hospital admission (aOR 3.16, 95% CI 1.63, 6.12). Among patients of Asian ethnicity, the odds for hospital admission were lower than for non-Asian patients (aOR 0.59, 95% CI 0.38, 0.94), but higher if born in Australia (OR = 5.42, 95% CI 1.56, 18.83). CONCLUSIONS: In epidemic thunderstorm asthma patients who presented to the ER, higher odds for hospital admission among patients with known asthma were further amplified by recent asthma admission, highlighting the vulnerability conferred by suboptimal disease control. Odds for hospital admission were lower in Asian patients born overseas, but higher in Asian patients born locally, than in non-Asian patients; these observations suggest susceptibility to severe thunderstorm asthma may be enhanced by gene-environment interactions. PMID- 30243031 TI - Designing DNAzyme-Powered Nanomachines Simultaneously Responsive to Multiple MicroRNAs. AB - Herein, a DNAzyme-powered nanomachine responsive to multiple hepatocellular carcinoma (HCC)-related miRNAs derived from clinical samples was designed. Initially, three types of nanomachines were constructed with dye molecule [(fluorescein (FAM), tetramethylrhodamin (TMR), and Cyanine 5 (Cy5)]-labeled DNA RNA chimeric substrates and a specific recognized probe for the corresponding miRNAs target. Once the target miRNAs were captured by two recognizing probes, the DNA nanomachine was initiated, leading to the hybridization between the DNAzyme and the substrates. With the help of a cofactor, the automatic operation of the nanomachine was driven by cyclic cleavage of the DNAzyme. Meanwhile, we also explored the recognition behavior between the recognizing probe and the target miRNA. Subsequently, these DNAzyme-powered nanomachines were developed for the homogeneous and simultaneous detection of three target miRNAs at the femtomloar level. Furthermore, the potential in clinical diagnosis was proven by the successful determination of target miRNA in real clinical samples. Thus, this nanomachine-based strategy possesses significant potential to be an innovation in miRNA analysis methodology. PMID- 30243032 TI - Goji Berry Modulates Gut Microbiota and Alleviates Colitis in IL-10-Deficient Mice. AB - SCOPE: This study examines the beneficial effects of Goji berry against spontaneous colitis and its prebiotic role in IL-10-deficient mice. METHODS: IL 10-deficient mice are assigned to a standard rodent diet (control) or a control diet supplemented with Goji (1% of dry feed weight) for 10 weeks, at which point colonic tissues and fecal contents are collected. RESULTS: Goji supplementation decreases colonic pathobiological scores and mRNA expression of Il17a and Tgfb1, while it enhances Muc1 expression and fecal IgA content. Illumina MiSeq sequencing reveals that Goji supplementation increases Actinobacteria phylum, resulting in a bloom of Bifidobacteria in gut microbiota. Additionally, dietary Goji promotes butyrate-producing bacteria including Lachnospiraceae Ruminococcaceae family and Roseburia spp. under Clostridium cluster XIVa. Furthermore, butyrate-producers Clostridium leptum and its dominant constituent Fecalibacterium prazusnitzii are markedly increased in the Goji group. Moreover, the gene-encoding butyryl-coenzyme A CoA transferase, a key enzyme responsible for butyrate synthesis in butyrate-producing bacteria, is increased sixfold in the fecal samples of Goji group associated with increased fecal butyrate content. CONCLUSION: Data collectively show that dietary Goji results in the blooming of Bifidobacteria and butyrate-producing bacteria. These bacteria may cross-feed each other, conferring preventative effects against colitis in IL-10-deficient mice. PMID- 30243033 TI - Linezolid-induced thrombocytopenia increases mortality risk in intensive care unit patients, a 10 year retrospective study. AB - WHAT IS KNOWN AND OBJECTIVE: Linezolid-induced thrombocytopenia is one of the many confounding conditions in critically ill patients. It is rare but prognostic importance of linezolid-induced thrombocytopenia in ICU population has not been well investigated. The study is to assess the incidence and risk factors of linezolid-induced thrombocytopenia in ICU patients. METHODS: We conducted a retrospective study with ICU patients treated with linezolid between January 2005 and December 2015 at the adult medical, surgical, emergency, and neurological ICUs at 1500-bed tertiary university medical center. RESULTS AND DISCUSSION: There were 60 patients (mean age: 69.8 +/- 11.9), 29 (48.3%) who developed linezolid-induced thrombocytopenia determined by the Naranjo algorithm on a case by-case basis during the study period. The patients with linezolid-induced thrombocytopenia had a higher rate of any malignancy (41.4% vs 9.7%, P = 0.007), elevated baseline creatinine levels (median [interquartile range; IQR]: 1.7 mg/dL [0.9-2.5] vs 0.9 mg/dL [0.6-1.3]; P = 0.042), and lower baseline platelet counts (median [IQR] 160 * 109 /L [128-230] vs 194 * 109 /L [118-285]; P = 0.296) than patients without linezolid-induced thrombocytopenia. The patients who developed thrombocytopenia received more platelet transfusions (34.5% vs 6.5%, P = 0.009) and had higher ICU mortality rates (62.1% vs 32.3%, P = 0.037). Logistic regression analysis revealed the following significant risk factors for linezolid induced thrombocytopenia: presence of any malignancy (odds ratio; OR [95% confidence interval; CI]: 8.667 [1.986-37.831]) and an elevated baseline serum creatinine level (OR: 1.673, CI: 1.046-2.675]). WHAT IS NEW AND CONCLUSION: Critically ill patients with any malignancy or an elevated baseline creatinine level who were treated with linezolid in the ICU were more likely to develop thrombocytopenia. More importantly, mortality increased with patients who developed linezolid-induced thrombocytopenia compared to those did not. PMID- 30243034 TI - Gain-of-function mutations in STIM1 and ORAI1 causing tubular aggregate myopathy and Stormorken syndrome. AB - Calcium (Ca2+) is a key regulator for a large number of cellular functions in all kinds of cells, and small disturbances of Ca2+ homeostasis can severely compromise normal physiology in various tissues and organs. A major mechanism controlling Ca2+ homeostasis is store-operated Ca2+ entry (SOCE), which relies on the concerted action of the reticular Ca2+ sensor STIM1 and the plasma membrane Ca2+ channel ORAI1. Gain-of-function mutations in the respective genes induce excessive Ca2+ entry, and cause tubular aggregate myopathy (TAM) and Stormorken syndrome. Both disorders are part of a clinical continuum and involve muscle weakness and additional variably pronounced features including miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. Mutations in the reticular Ca2+ buffer calsequestrin (CASQ1) have moreover been associated with the mild end of the TAM/Stormorken syndrome spectrum. Here we review the clinical and histological characteristics of both disorders, provide an overview on the genetic causes, and thereby focus on the pathomechanisms leading to muscle dysfunction and the multi-systemic phenotype of tubular aggregate myopathy and Stormorken syndrome. PMID- 30243036 TI - Trauma treatment for veterans in buprenorphine maintenance treatment for opioid use disorder. AB - INTRODUCTION: Opioid use disorder (OUD) rates are high among veterans. PTSD is also prevalent among veterans; those with comorbidity have worse outcomes than those without comorbidity. This study assessed buprenorphine retention rates in veterans initiating OUD treatment, comparing veterans without PTSD to veterans with PTSD who were receiving versus not receiving concurrent trauma treatment. METHODS: This retrospective chart review examined consecutive referrals to buprenorphine maintenance (N = 140). PTSD diagnosis was identified by chart review and retention was defined as continuous buprenorphine maintenance 6-months post-admission. Logistic regression analyses compared buprenorphine retention for veterans without PTSD and PTSD-diagnosed veterans who received concurrent trauma treatment to a reference group of PTSD-diagnosed veterans who did not receive trauma treatment. Models adjusted for opioid type, age, and service-connected status. RESULTS: Sixty-seven (47.9%) buprenorphine-seeking veterans carried a PTSD diagnosis; only 31.3% (n = 21) received trauma treatment while in buprenorphine maintenance, with 11.9% (n = 8) receiving evidence-based psychotherapy for PTSD. Among PTSD-diagnosed veterans who received trauma treatment, 90.5% (n = 19/21) were in buprenorphine maintenance at 6-months, compared to 23.9% (n = 11/46) of PTSD-diagnosed veterans without trauma treatment, and 46.6% (n = 34/73) of veterans without PTSD. In the full model, veterans with trauma treatment had 43.36 times greater odds of remaining in buprenorphine treatment than the reference group. CONCLUSIONS: Most PTSD diagnosed veterans in buprenorphine treatment were not receiving trauma treatment. Those receiving concurrent trauma treatment had better retention, suggesting OUD and trauma can be simultaneously addressed. Future clinical trials should investigate trauma-focused treatment for veterans with comorbid PTSD who are seeking buprenorphine for OUD. PMID- 30243035 TI - Investigating a novel fMRI cannabis cue reactivity task in youth. AB - OBJECTIVE: Adult and adolescent studies suggest increased motivational responses to cannabis cues among regular cannabis users. However, functional magnetic resonance imaging (fMRI) studies have not explored neural activation in response to visual cannabis cues among adolescents in the United States. Gaining a better understanding of the neural circuits related to cue-elicited craving during adolescence may shed light on the neural basis for the development of problematic cannabis use that could ultimately be targeted for interventions. METHODS: 41 non treatment-seeking youth (ages 17-21; mean age = 18.83; 46.3% female) who reported regular cannabis use underwent fMRI scanning involving a visual cannabis cue task and completed self-report and biological measures. Whole-brain activation was examined for cannabis cues compared to non-cannabis cues, and for active versus passive cannabis cues. Associations between self-reported substance use and task activation were examined. RESULTS: Cannabis images were identifiable to adolescents and were rated as more rewarding than matched non-cannabis images (p < .05). Greater activation was found for the cannabis cues compared to non cannabis cues in bilateral posterior cingulate, cuneus, fusiform, precuneus, inferior temporal and parahippocampal gyri, as well as left thalamus, medial frontal and superior frontal gyri. Cue-elicited activation was not significantly associated with self-reported cannabis use (ps > 0.05). No differences were observed for the active versus passive cue contrast. CONCLUSIONS: Cannabis-using youth show more activation to cannabis cues than non-cannabis cues in brain regions underlying incentive salience, reward, and visual attention. This task could be useful for future studies examining neural underpinnings of reward processes in adolescent cannabis users. PMID- 30243037 TI - Sensitivity to pain expectations: A Bayesian model of individual differences. AB - The thoughts and feelings people have about pain (referred to as 'pain expectations') are known to alter the perception of pain. However little is known about the cognitive processes that underpin pain expectations, or what drives the differing effect that pain expectations have between individuals. This paper details the testing of a model of pain perception which formalises the response to pain in terms of a Bayesian prior-to-posterior updating process. Using data acquired from a short and deception-free predictive cue task, it was found that this Bayesian model predicted ratings of pain better than other, simpler models. At the group level, the results confirmed two core predictions of predictive coding; that expectation alters perception, and that increased uncertainty in the expectation reduces its impact on perception. The addition of parameters relating to trait differences in pain expectation improved the fit of the model, suggesting that such traits play a significant role in perception above and beyond the influence of expectations triggered by predictive cues. When the model parameters were allowed to vary by participant, the model's fit improved further. This final model produced a characterisation of each individual's sensitivity to pain expectations. This model is relevant for the understanding of the cognitive basis of pain expectations and could potentially act as a useful tool for guiding patient stratification and clinical experimentation. PMID- 30243038 TI - Sharpening the contours of positional OSA. PMID- 30243039 TI - Risk perception during urban cycling: An assessment of crowdsourced and authoritative data. AB - Subjective risk perception during urban cycling has been mostly investigated through questionnaire studies. However, newly available data sources promise extended possibilities for the investigation and understanding of the underlying factors. We validate the rationale for using both opportunistically available crowd-sourced data (i.e., volunteered geographic information or VGI) as well as more established but rarely investigated authoritative data as predictors of subjective cycling risk. We achieve this by correlating indicators of cycling risk extracted from both VGI and authoritative data for two different German cities with participants' risk estimates assessed in laboratory-based virtual reality experiments. In Case 1, 15 participants (mostly undergraduate students with a mean age of 22 years old; nine of them females) were tested as a sample representing frequent and experienced cyclists, but unfamiliar with the 19 tested locations and less likely to be affected by the virtual reality setup. In Case 2, 24 new participants (mostly undergraduate students; mean age 24 years; 13 of them females) were experienced cyclists and mostly familiar with the 40 test locations located in their city of residence. For both cases, our findings provide evidence that parameters extracted from VGI (e.g., the semantic severity of the contribution and the reception by other citizens) as well as from authoritative data sources (e.g., accident statistics or Space Syntax measures) represent valid indicators for the subjectively perceived risk of cycling at a specific location. On the basis of this validation, future research can use these data sources to investigate the sources of risk perception during urban cycling in greater detail. PMID- 30243040 TI - Adapting artificial neural networks to a specific driver enhances detection and prediction of drowsiness. AB - Monitoring car drivers for drowsiness is crucial but challenging. The high inter individual variability observed in measurements raises questions about the accuracy of the drowsiness detection process. In this study, we sought to enhance the performance of machine learning models (Artificial Neural Networks: ANNs) by training a model with a group of drivers and then adapting it to a new individual. Twenty-one participants drove a car simulator for 110 min in a monotonous environment. We measured physiological and behavioral indicators and recorded driving behavior. These measurements, in addition to driving time and personal information, served as the ANN inputs. Two ANN-based models were used, one to detect the level of drowsiness every minute, and the other to predict, every minute, how long it would take the driver to reach a specific drowsiness level (moderately drowsy). The ANNs were trained with 20 participants and subsequently adapted using the earliest part of the data recorded from a 21st participant. Then the adapted ANNs were tested with the remaining data from this 21st participant. The same procedure was run for all 21 participants. Varying amounts of data were used to adapt the ANNs, from 1 to 30 min, Model performance was enhanced for each participant. The overall drowsiness monitoring performance of the models was enhanced by roughly 40% for prediction and 80% for detection. PMID- 30243041 TI - Predicting allostery and microbial drug resistance with molecular simulations. AB - Beta-lactamase enzymes mediate the most common forms of gram-negative antibiotic resistance affecting clinical treatment. They also constitute an excellent model system for the difficult problem of understanding how allosteric mutations can augment catalytic activity of already-competent enzymes. Multiple allosteric mutations have been identified that alter catalytic activity or drug-resistance spectrum in class A beta lactamases, but predicting these in advance continues to be challenging. Here, we review computational techniques based on structure and/or molecular simulation to predict such mutations. Structure-based techniques have been particularly helpful in developing graph algorithms for analyzing critical residues in beta-lactamase function, while classical molecular simulation has recently shown the ability to prospectively predict allosteric mutations increasing beta-lactamase activity and drug resistance. These will ultimately achieve the greatest power when combined with simulation methods that model reactive chemistry to calculate activation free energies directly. PMID- 30243042 TI - Plasticity of intrinsic neuronal excitability. AB - Long-term synaptic modification is not the exclusive mode of memory storage, and persistent regulation of voltage-gated ion channels also participates in memory formation. Intrinsic plasticity is expressed in virtually all neuronal types including principal cells and interneurons. Activation of synaptic glutamate receptors initiates long-lasting changes in neuronal excitability at presynaptic and postsynaptic side. As synaptic plasticity, intrinsic plasticity is bi directional and expresses a certain level of input-specificity or cell specificity. We discuss here the nature of the learning rules shared by intrinsic and synaptic plasticity and the impact of intrinsic plasticity on temporal processing. PMID- 30243043 TI - Higher proneness to multisensory illusions is driven by reduced temporal sensitivity in people with high schizotypal traits. AB - A coherent sense of self, typically altered in schizophrenia, is accompanied by a coherent ability to integrate sensory information. According to the idea of a psychosis continuum, high schizotypal traits in the general population may be associated to higher proneness to multisensory illusions, akin to schizophrenia. We directly tested this hypothesis by means of the double-flash illusion in participants with low and high schizotypal scores. We confirmed the higher proneness to illusions in the high-schizotypal group. Crucially, such higher proneness was fully explained by a significantly reduced temporal sensitivity to integrate sensory information. We conclude that reduced temporal sensitivity accounts for enhanced proneness to illusions in people at higher risk and represents an early marker of psychosis. PMID- 30243044 TI - Acute toxicity of organic pesticides to Daphnia magna is unchanged by co-exposure to polystyrene microplastics. AB - Daphnia magna were exposed to two pesticides in the presence or absence of microplastics (300 000 particles ml-1 1 um polystyrene spheres) and to microplastics alone. The pesticides were dimethoate, an organophosphate insecticide with a low log Kow, and deltamethrin, a pyrethroid insecticide with a high log Kow. Daphnia were exposed to a nominal concentration range of 0.15, 0.31, 0.63, 1.25, 2.5, 5 mg l-1 dimethoate and 0.016, 0.08, 0.4, 2, 5 and 10 ug l 1 deltamethrin. Exposure to polystyrene microplastics alone showed no effects on Daphnia magna survival and mobility over a 72 h exposure. In the dimethoate exposures, mobility and survival were both affected from a concentration of 1.25 mg l-1, with effects were seen on mobility from 28 h and survival from 48 h, with greater effects seen with increasing concentration and exposure time. In deltamethrin exposures, survival was affected from a concentration of 0.4 ug l-1 and mobility from a concentration of 0.08 ug l-1. Effects of deltamethrin on mobility were seen from 5 h and on survival from 28 h, with greater effects on survival and mobility seen with increasing concentration and exposure time. Contrary to expectations, pesticide toxicity to Daphnia magna was not affected by the presence of microplastics, regardless of chemical binding affinity (log Kow). This therefore suggests that polystyrene microplastics are unlikely to act as a significant sink, nor as a vector for increased uptake of pesticides by aquatic organisms. CAPSULE: Polystyrene microplastics are unlikely to act as vector for increased uptake of pesticides by aquatic organisms. PMID- 30243045 TI - Simultaneous biosorption of Arsenic (III) and Arsenic (V): Application of multiple response optimizations. AB - In this work, simultaneous biosorption of As(III) and As(V) by Sargassum glaucescens was optimized using multiple response optimizations and Doehlert experimental design. The optimum condition for simultaneous biosorption of As(III) and As(V) were: biosorbent dosage 0.47 g L-1, pH 5.9 and initial concentration 120.34 mg L-1 with maximum overall desirability of 0.94. Different isotherms were fitted to biosorption equilibrium data and the Freundlich isotherm was the most suitable model. Based on thermodynamic study, the biosorption of arsenic species onto alga was endothermic and spontaneous. Kinetic results indicated that intraparticle diffusion model was the best kinetic model. Biosorption capacity of S. glaucescens and other biosorbents were also compared. PMID- 30243046 TI - Electrochemical immunosensor based on chitosan-gold nanoparticle/carbon nanotube as a platform and lactate oxidase as a label for detection of CA125 oncomarker . AB - In this work, a novel simple and sensitive electrochemical immunosensor was developed based on lactate oxidase as a single electrochemical probe for the detection of carcinoma antigen 125 (CA125). Chitosan-gold nanoparticle/multiwall carbon nanotube/graphene oxide (CS-AuNP/MWCNT/GO) was used as the electrode substrate to increase the electrode specific surface area and improve the protein immobilization and the electrochemical performance of the electrode in terms of oxidation of H2O2. Due to the peroxidase-like function of CS-AuNP, the oxidation peak of H2O2 was observed at a very low potential (0.034 V). The lactate oxidase is used, for the first time, as the single-enzyme label in a sandwich type immunosensor. In the optimum condition, the designed immunosensor exhibited two linear ranges (0.01-0.5 U/mL and 0.5-100 U/mL) by chronoamperometry (CHA). The limit of detection (LOD) was estimated to be 0.002 U/mL. The immunosensor displayed excellent reproducibility and stability with remarkable selectivity in terms of the detection of CA125 even in the human serum samples as compared to the ELISA. In conclusion, the engineered immunosensor is proposed as an ultra sensitive tool for the detection and monitoring of CA125 in the human serum. PMID- 30243047 TI - Modular microstructure design to build neuronal networks of defined functional connectivity. AB - Theoretical and in vivo neuroscience research suggests that functional information transfer within neuronal networks is influenced by circuit architecture. Due to the dynamic complexities of the brain, it remains a challenge to test the correlation between structure and function of a defined network. Engineering controlled neuronal networks in vitro offers a way to test structural motifs; however, no method has achieved small, multi-node networks with stable, unidirectional connections. Here, we screened ten different microchannel architectures within polydimethylsiloxane (PDMS) devices to test their potential for axonal guidance. The most successful design had a 92% probability of achieving strictly unidirectional connections between nodes. Networks built from this design were cultured on multielectrode arrays and recorded on days in vitro 9, 12, 15 and 18 to investigate spontaneous and evoked bursting activity. Transfer entropy between subsequent nodes showed up to 100 times more directional flow of information compared to the control. Additionally, directed networks produced a greater amount of information flow, reinforcing the importance of directional connections in the brain being critical for reliable communication. By controlling the parameters of network formation, we minimized response variability and achieved functional, directional networks. The technique provides us with a tool to probe the spatio-temporal effects of different network motifs. PMID- 30243048 TI - Morphological and molecular effects of two diluted bitumens on developing fathead minnow (Pimephales promelas). AB - Canada has experienced a significant increase in the transport of diluted bitumen (dilbit), a predominant oil sands product that combines bitumen with diluents derived from oil-gas condensates and other proprietary compounds. The toxicity of dilbit to fish embryos, which are immobile and thus at a high risk of exposure to oil in the event of a spill, remains largely unknown for most species. This study assessed the toxicity of water accommodated fractions (WAF) and chemically enhanced water accommodated fractions (CEWAF) of two winter dilbit blends, Access Western Blend (AWB) and Cold Lake Blend (CLB), to fathead minnow (Pimephales promelas) embryos. The TPH-F EC50s for malformations were 834 and 1058 MUg/L for AWB WAF and CEWAF, respectively, and 500 and 715 MUg/L for CLB WAF and CEWAF, respectively. Levels of cyp1a mRNA increased up to 46- and 69-fold, respectively, reflecting increasing exposure to polycyclic aromatic compounds (PACs) in AWB and CLB. Similarly, levels of gst mRNA were elevated up to 3.8-fold and 2.7-fold with increasing total concentrations of PACs in AWB and CLB, respectively. However, there were no significant changes in mRNA levels of p53, sod, cat, and gsr. These results suggest that the expression of cyp1a and gst may serve as biomarkers for dilbit exposure in fathead minnow, furthering our understanding of dilbit responsive indicators of toxicity in fish species native to North America. This study is important as it utilizes the same exposure methodology to examine the toxicity of two commonly used Canadian dilbits, facilitating comparison of dilbit toxicity. PMID- 30243050 TI - Global exponential synchronization of multiple coupled inertial memristive neural networks with time-varying delay via nonlinear coupling. AB - In this paper, global exponential synchronization of multiple coupled inertial memristive neural networks with time-varying delay is investigated. First, by choosing suitable variable substitution, the inertial memristive neural networks are transformed into first-order differential equations. Next, a novel coupling scheme with linear diffusive term and discontinuous sign function term depending on the first order derivative of state variables is introduced. Based on this coupling scheme, several sufficient conditions for global exponential synchronization of multiple inertial memristive neural networks are derived by using Lyapunov stability theory and some inequality techniques. Finally, several numerical examples are presented to substantiate the effectiveness of the theoretical results. PMID- 30243051 TI - Trainable spectral difference learning with spatial starting for hyperspectral image denoising. AB - Because of the limited reflected energy and incoming illumination in an individual band, the reflected energy captured by a hyperspectral sensor might be low and there is inevitable noise that significantly decreases the performance of the subsequent analysis. Denoising is therefore of first importance in hyperspectral image (HSI) analysis and interpretation. However, most HSI denoising methods remove noise with the important spectral information being severely distorted. This paper presents an HSI denoising method using trainable spectral difference learning with spatial initialization (called HDnTSDL) aimed at preserving the spectral information. In the proposed HDnTSDL model, a key band is automatically selected and denoised. The denoised key band acts as a starting point to reconstruct the rest of the non-key bands. Meanwhile, a deep convolutional neural network (CNN) with trainable non-linearity functions is proposed to learn the spectral difference mapping. Then, the rest of the non-key bands are denoised under the guidance of the learned spectral difference with the key band as a starting point. Experiments have been conducted on five databases with both indoor and outdoor scenes. Comparative analyses validate that the proposed method: (i) presents superior performance in spatial recovery and spectral preservation, and (ii) requires less computational time than state-of the-art methods. PMID- 30243052 TI - Transfer collaborative filtering from multiple sources via consensus regularization. AB - Collaborative filtering is one of the most successful approaches to build recommendation systems. Recently, transfer learning has been applied to recommendation systems for incorporating information from external sources. However, most existing transfer collaborative filtering algorithms tend to transfer knowledge from one single source domain. Rich information is available in many source domains, which can better complement the data in the target domain than that from a single source. However, it is common to get inconsistent information from different sources. To this end, we proposed a TRA nsfer collaborative filtering framework from multiple sources via C onsE nsus R egularization, called TRACER for short. The TRACER framework handles the information inconsistency with a consensus regularization, which enforces the outputs from multiple sources to converge. In addition, our algorithm is to learn and transfer knowledge at the same time while most of the traditional transfer learning algorithms are to learn knowledge first and then transfer it. Experiments conducted on two real-world data sets validate the effectiveness of the proposed algorithm. PMID- 30243049 TI - Left frontotemporal effective connectivity during semantic feature judgments in patients with chronic aphasia and age-matched healthy controls. AB - Traditional models of neural reorganization of language skills in patients with chronic stroke-induced aphasia (PWA) propose activation of reperfused or spared left hemisphere tissue results in the most favorable language outcomes. However, these models do not fully explain variable behavioral recovery patterns observed in chronic patients. Instead, investigation of connectivity patterns of critical network nodes may elucidate better-informed recovery models. In the present study, we combined fMRI and dynamic causal modeling (DCM) to examine effective connectivity of a simple three-node left hemisphere network during a semantic feature decision task in 25 PWA and 18 age-matched neurologically intact healthy controls. The DCM model space utilized in Meier, Kapse, & Kiran (2016), which was organized according to exogenous input to one of three regions (i.e., left inferior frontal gyrus, pars triangularis [LIFGtri], left posterior middle temporal gyrus [LpMTG], or left middle frontal gyrus [LMFG]) implicated in various levels of lexical-semantic processing, was interrogated. This model space included all possible combinations of uni- and bidirectional task-modulated connections between LIFGtri, LMFG and LpMTG, resulting in 72 individual models that were partitioned into three separate families (i.e., Family #1: Input to LIFGtri, Family #2: Input to LMFG, Family #3: Input to LpMTG). Family-wise Bayesian model selection revealed Family #2: Input to LMFG best fit both patient and control data at a group level. Both groups relied heavily on LMFG's modulation of the other two model regions. By contrast, between-group differences in task-modulated coupling of LIFGtri and LpMTG were observed. Within the patient group, the strength of activity in LIFGtri and connectivity of LpMTG -> LIFGtri were positively associated with lexical-semantic abilities inside and outside of the scanner, whereas greater recruitment of LpMTG was associated with poorer lexical-semantic skills. PMID- 30243053 TI - Starting university with high eating self-regulatory skills protects students against unhealthy dietary intake and substantial weight gain over 6 months. AB - BACKGROUND: There is consistent evidence that suggests first year students are at risk of weight gain, but the reasons for this vulnerability are still unclear. This study aimed to explore whether the ability to regulate eating behaviours is a predictor of weight and dietary changes in first year undergraduate students. METHODS: First year undergraduate students from universities situated in London were invited to complete a survey at the beginning of the academic year and at 6 month follow-up. Each survey included the Self-Regulation of Eating Behaviour Questionnaire, food frequency questions, socio-demographic questions and anthropometric questions. Linear and logistic regressions were performed to explore the associations between baseline eating self-regulatory skills and weight and dietary changes. RESULTS: 481 first year undergraduate students took part in the study. Students who entered university with higher eating self regulatory skills were more likely to maintain or achieve a higher fruit and vegetable (OR = 1.8, p = 0.007) and a lower sweet and salty snack (OR = 1.9, p = 0.001) intake over the course of the first 6 months in university. Higher baseline eating self-regulatory skills were also related to lower weight changes (beta = -0.15, p = 0.018) and lower likelihood of gaining 5% initial body weight (OR = 0.52, p = 0.006) at 6-month. Additionally, self-regulatory skills moderated the relationship between baseline BMI and weight changes (beta = -0.25, p <=0.001) and between baseline BMI and 5% weight gain (OR = 0.82, p = 0.008). CONCLUSIONS: Starting university with higher eating self-regulatory skills may help students to maintain or achieve a healthy diet and protect them against substantial weight gain, especially among students with overweight. PMID- 30243054 TI - Metabolic-inflammatory status as predictor of clinical outcome at 1-year follow up in patients with first episode psychosis. AB - BACKGROUND: Metabolic abnormalities and peripheral inflammation have been increasingly reported in patients at the onset of psychosis and associated with important physical health disorders and increased mortality. However, the impact of an abnormal metabolic-inflammatory status on the psychiatric outcome of these patients has not yet been investigated. OBJECTIVES: The aims of this study were 1) to explore whether, in a sample of patients at their first episode of psychosis (FEP), an overall metabolic-inflammatory status may be measured, by combining metabolic and inflammatory variables in metabolic-inflammatory factors; 2) to explore the association between these factors and clinical outcome at 1 year follow-up (FU), in terms of symptoms severity and treatment response. METHODS: In this longitudinal study we recruited 42 FEP patients and 46 healthy controls (HC) matched with patients for age, gender and ethnicity. At baseline (T1) we measured high sensitivity C-reactive protein (hsCRP) as biomarker of inflammation, and body mass index (BMI), lipid profile and gluco-metabolic parameters (glycated hemoglobin (HbA1c) and fasting glucose) as metabolic variables. A principal component analysis (PCA) was then used to reduce the dimensionality of the dataset accounting for both inflammation and metabolic status. In FEP patients, we assessed symptoms severity at T1 and at 1-year FU (T2) as well as treatment response to antipsychotics at T2. RESULTS: at T1, FEP showed higher HbA1c (p = 0.034), triglycerides (TG) (p = 0.045) and BMI (p = 0.026) than HC. PCA identified 3 factors: factor 1 accounting for hsCRP, TG and BMI, factor 2 accounting for LDL and cholesterol, and factor 3 accounting for fasting glucose and HbA1c. Factor 1 was associated with T1 negative symptoms severity (p = 0.021) and predicted T2 positive (p = 0.004) and overall symptoms severity (0.001), as well as general psychopathology (p < 0.001) and T2 treatment response (p = 0.007). CONCLUSION: In this sample of FEP patients, inflammation and metabolism, closely correlated at the onset of psychosis, proved to play a key role as predictors of the clinical course of psychosis when combined in a single factor. These findings offer an important potential target for early screening and interventions. PMID- 30243055 TI - A Q-TOF LC/MS method for identification and quantitation of Histamine in the antibiotic Gentamicin at ppm level: Validation and uncertainty evaluation. AB - Adverse reactions have been reported for antibiotics produced via fermentation with fish peptone due to Histamine contamination. Just few micrograms of Histamine can result in adverse reactions when administered intravenously. Thus in this paper a new method for identification and quantitation of Histamine at ppm levels in the antibiotic Gentamicin is described. The method is based on separation of Histamine from Gentamicin and other excipients present in the drug matrix, by hydrophilic interaction liquid chromatography (HILIC) coupled to a Q TOF/MS detector; quantitation is based on the standard addition approach. The method was validated for repeatability, inter-day precision, specificity, accuracy (relative and absolute bias) linearity, limit of detection and quantitation. Uncertainty was estimated and evaluated by comparison with values expected according to the Horwitz theory. The method showed satisfactory performances and good sensitivity, reaching a limit of quantitation of approximately 1 ppm. The method proposed can be a starting point for the development of Histamine quantitation methods in other antibiotics or even in other medicinal products which active ingredient is produced via fermentation in presence of fish peptone. PMID- 30243056 TI - Development and validation of simple step protein precipitation UHPLC-MS/MS methods for quantitation of temozolomide in cancer patient plasma samples. AB - Temozolomide (TEMODALTM) (TMZ) is an antineoplastic agent that is primarily used for the treatment of glioblastoma and anaplastic gliomas, two aggressive forms of brain cancer. Due to the poor prognosis of brain tumour patients, there is an increasing body of research into improving the stability and delivery of TMZ past the blood brain barrier using carrier molecules. These require accurate determination of TMZ levels for biodistribution and pharmacokinetic evaluation. Unfortunately, current methodologies for the determination of TMZ in human plasma suffer from low reproducibility, recovery, sensitivity or cost ineffective procedures associated with extensive sample cleaning. To surpass these disadvantages, we developed two bioanalytical methods with high sensitivity and excellent recovery for the determination of TMZ in human plasma at minimum cost. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used and both methods were validated under US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) guidelines. The two methods had minor differences in the sample pre-treatment and each method was developed and applied in separate laboratories. Theophylline was selected as internal standard (IS). Calibration curves were linear over the range of 10-500 ng/mL with extraction recovery ranging from 77.3 to 97.3% while all validation parameters met the acceptance criteria and proved the methods' reliability. The validated methods were successfully applied to plasma samples donated from cancer patient following treatment with temozolomide. PMID- 30243057 TI - Modelling aerobic granular sludge reactors through apparent half-saturation coefficients. AB - During biological wastewater treatment, substrates undergo simultaneous diffusion and reactions inside microbial aggregates, creating microscale spatial substrate gradients and limiting the macroscale reaction rates. For flocculent and anaerobic granular sludge, this rate-limiting effect of diffusion is often lumped in model parameters, like the half-saturation coefficients of Monod kinetics in activated sludge models (ASM). Yet, an explicit description of the reaction diffusion process with biofilm models is more common for aerobic granular sludge. This work investigates whether apparent half-saturation coefficients could have applications for aerobic granular sludge as well and examines the implications of this simplification. To this end, the macroscopic reaction rates predicted with a one-dimensional biofilm (1D) model were fitted with Monod kinetics. The results showed that the macroscale rates could indeed be described using apparent kinetics, at the very least over a time scale where the microbial population distribution stays fixed. However, the coefficients were sensitive to changes in the microbial population distribution, which can be affected by long-term changes in operating conditions. Also the activity of organisms that compete for the same substrates affect the parameter value. Be that as it may, apparent kinetics also depend on the operating conditions for flocculent and anaerobic granular sludge, but they have still been used successfully for design and optimization. Therefore, the last section of this work illustrates that they may also have applications for aerobic granular sludge. A simple model for ammonium removal using apparent half-saturation coefficients for oxygen and ammonium is applied to a full-scale reactor, taking advantage of the batch-wise operation and on-line monitoring data for regular recalibration. PMID- 30243058 TI - Influence of dissolved organic matter (DOM) characteristics on dissolved mercury (Hg) species composition in sediment porewater of lakes from southwest China. AB - The origin and composition of dissolved organic matter (DOM) in porewater of lake sediments is intricate and decisive for fate of pollutants including mercury (Hg). While there are many reports on the relationship between dissolved organic carbon concentration (DOC) and mercury (Hg) concentrations in aquatic systems, there are few in which DOM compositional properties, that may better explain the fate of Hg, have been the focus. In this study, porewaters from sediments of three lakes, Caihai Lake (CH), Hongfeng Lake (HF) and Wujiangdu Lake (WJD), all located in southwest China, were selected to test the hypothesis that DOM optical properties control the fate of Hg in aquatic ecosystems. Porewater DOM was extracted and characterized by UV-Vis absorption and fluorescence spectroscopy. A two end-member (autochthonous and allochthonous DOM) mixing model was used to unveil the origin of DOM in porewaters of the three lakes. Our results show a higher input of terrestrial DOM in the pristine lake CH, as compared to lakes HF and WJD lakes, which were both influenced by urban environments and enriched in autochthonous DOM. While the relationships between the concentrations of DOC and the different chemical forms of Hg forms were quite inconsistent, we found important links between specific DOM components and the fate of Hg in the three lakes. In particular, our results suggest that allochthonous, terrestrial DOM inhibits Hg(II) availability for Hg methylating micro-organisms. In contrast, autochthonous DOM seems to have been stimulated MeHg formation, likely by enhancing the activity of microbial communities. Indeed, DOM biodegradation experiments revealed that differences in the microbial activity could explain the variation in the concentration of MeHg. While relationships between concentrations of DOC and Hg vary among different sites and provide little information about Hg cycling, we conclude that the transport and transformation of Hg (e.g. the methylation process) are more strongly linked to DOM chemical composition and reactivity. PMID- 30243059 TI - A novel antifouling technique for the crossflow filtration using porous membranes: Experimental and CFD investigations of the periodic feed pressure technique. AB - Oily water production is one of the many drawbacks of petroleum and several other industries. Finding effective ways for the treatment of produced water remain one of the main areas of interest in membrane sciences. Albeit the many advantages of membrane technology, they suffer from the unavoidable problem of fouling, which results from the accumulation of dispersed materials at the surface of membranes. Membrane modification and operational optimization have been approached as a potential cure of the problem of fouling. In this work we introduce a new and novel method that minimizes the development of fouling and in the same time utilizes no chemicals (i.e., environmentally friendly). The core of this method is based on alternating the pressure in the feed channel in a periodic manner and is therefore named the periodic feed pressure technique, PFPT. The idea is to make pinned droplets at the surface of the membrane lose essential forces that keep them sticking to the surface. The drag force due to permeation flux and the capillary force due to interfacial tension represents the two forces that largely contribute to the pinning of oil droplets at the surface of the membrane. Other forces including buoyancy and lift forces are generally small to be of significant influence. The idea of the PFPT is, therefore, to eliminate the force due to permeation drag. This is done by setting the transmembrane pressure (TMP) to zero at fixed intervals allowing pinned oil droplets to dislodge the surface. When the TMP is set to zero, permeation flux stops and the force due to permeation drag vanishes. This significantly reduces the overall residence time of pinned oil droplets, minimizing the chance for other oil droplets to cluster and coalesce with pinned ones. The PFPT does not cause any damage to the support layer of the polymeric membrane, which is a drawback of back-flushing methodology. The novel PFPT displays minimal membrane fouling and very similar permeation recovery despite only half the cycle time is in filtration mode. In this work, we show how the permeation flux is recovered and provide comparisons between the PFPT and regular filtration methodology. Furthermore, we compare the overall amount of filtrate at the end of the experiments using both methods. It is interesting to note that, the amount of filtrate using the PFPT is very much comparable to that obtained using regular filtration methodology and even higher. By optimizing the frequency of the cycle and the amplitude of the pressure change, it is possible to customize the PFPT to various membrane technologies and to achieve the highest recovery of the flux. Visual inspections of the membranes post operation and post rinsing indicate that membranes undergoing filtration using the PFPT achieves a very clean surface compared with those undergoing regular filtration processes. This method is a promising solution to membrane fouling that is easy to implement without any additional use of chemicals or equipment. Computational fluid dynamics (CFD) investigation is also conducted on microfiltration processes to show why this technique works. PMID- 30243060 TI - Dynamics and determinants of amoeba community, occurrence and abundance in subtropical reservoirs and rivers. AB - Free-living amoebae are widespread in freshwater ecosystems. Although many studies have investigated changes in their communities across space, the temporal variability and the drivers of community changes across different habitat types are poorly understood. A total of 108 surface water samples were collected on a seasonal basis from four reservoirs and two rivers in Xiamen city, subtropical China. We used high throughput sequencing and qPCR methods to explore the occurrence and abundance of free-living amoebae. In total, 335 amoeba OTUs were detected, and only 32 OTUs were shared by reservoir and river habitats. The reservoirs and rivers harbored unique amoebae communities and exhibited distinct seasonal patterns in community composition. High abundance of the 18S rRNA gene of Acanthamoeba was observed in spring and summer, whereas the abundance was low in autumn and winter. In addition, the abundance of Hartmannella was significantly higher when isolated from reservoirs in summer/autumn and from river in spring/summer. Moreover, the temporal patterns of amoebae communities were significantly associated with water temperature, indicating that temperature is an important variable controlling the ecological dynamics of amoebae populations. However, our comparative analysis indicated that both environmental selection, and neutral processes, significantly contributed to amoeba community assembly. The genera detected here include pathogenic species and species that can act as vectors for microbial pathogens, which can cause human infections. PMID- 30243061 TI - Comparison of caudal epidural block with paravertebral block for renal surgeries in pediatric patients: A prospective randomised, blinded clinical trial. AB - STUDY OBJECTIVE: This study was undertaken to compare the analgesic efficacy of ultrasound-guided single-shot caudal block with ultrasound-guided single-shot paravertebral block in children undergoing renal surgeries. DESIGN: Randomised, interventional, blinded clinical trial. SETTING: Operating rooms of All India Institute of Medical Sciences, New Delhi, India. PATIENTS: 50 children aged 2-10 years, of ASA status I/II, posted for elective renal surgeries. INTERVENTIONS: The children were randomised into two groups (Group C-caudal block, Group P paravertebral block). After induction of general anesthesia, single-shot caudal or paravertebral block was performed under ultrasound guidance, with 0.2% ropivacaine with 1:200000 adrenaline. MEASUREMENTS: Time to first rescue analgesia, time to perform blocks, intraoperative and post-operative hemodynamics, post-operative FLACC scores, incidence of complications, parental satisfaction scores were recorded. MAIN RESULTS: Children in Group P had significantly longer duration of analgesia (p < 0.0004) than Group C. Post operative FLACC scores (p < 0.005) and analgesic requirements (p < 0.0004) were lower in Group P. The mean fentanyl requirement over 24 h in group P was 0.56 +/- 0.82 MUg/kg, compared to 1.8 +/- 1.2 MUg/kg in group C. Parents in Group P reported greater satisfaction (p < 0.02). No complications were seen in either of the groups. CONCLUSION: This study showed superior analgesia and parental satisfaction with single-shot paravertebral block in comparison to single-shot caudal block for renal surgeries in children. However, the block performance in children requires adequate expertise and practice. PMID- 30243062 TI - Intraoperative hypotension is not associated with postoperative cognitive dysfunction in elderly patients undergoing general anesthesia for surgery: results of a randomized controlled pilot trial. AB - STUDY OBJECTIVE: To assess the effect of different intraoperative blood pressure targets on the development of POCD and test the feasibility of a larger trial. DESIGN: Randomized controlled pilot trial. SETTING: Perioperative care in a tertiary care teaching hospital with outpatient follow-up. PATIENTS: One hundred one patients aged >=75 years with ASA physical status <4, undergoing elective, non-cardiac surgery under general anesthesia and 33 age-matched healthy controls. INTERVENTIONS: Randomization to a personalized intraoperative blood pressure target, mean arterial pressure (MAP) >= 90% of preoperative values (Target group), or to a more liberal intraoperative blood pressure management (No-Target group). Strategies to reach intraoperative blood pressure target were at discretion of anesthesiologists. MEASUREMENTS: An experienced neuropsychologist performed a validated battery of neurocognitive tests preoperatively and 3 months after surgery. Incidence of POCD at three months and postoperative delirium were assessed. Intraoperative time spent with MAP >= 90% of preoperative values, recruitment and drop-out rate at 3 months were feasibility outcomes. MAIN RESULTS: The Target group spent a higher percentage of intraoperative time with MAP >=90% of preoperative values (65 +/- 25% vs. 49 +/- 28%, p < 0.01). Incidence of POCD (11% vs. 7%, relative risk 1.52; 95% CI, 0.41 to 6.3; p = 0.56) and delirium (6% vs. 14%, relative risk, 0.44; 95% CI, 0.12 to 1.60; p = 0.21) did not differ between groups. No correlation was found between intraoperative hypotension and postoperative cognitive performance (p = 0.75) or delirium (p = 0.19). Recruitment rate was of 6 patients/month (95% confidential interval (CI), 5 to 7) and drop-out rate at 3 months was 24% (95% CI, 14 to 33%). CONCLUSIONS: Intraoperative hypotension did not correlate with postoperative cognitive dysfunction or delirium occurrence in elderly patients undergoing general anesthesia for non-cardiac surgery. A multicenter randomized controlled trial is needed in order to confirm the effect of intraoperative blood pressure on the development of POCD. TRIAL REGISTRATION NUMBER: NCT02428062www.clinicaltrials.gov. PMID- 30243063 TI - Multiple modes of action of eribulin mesylate: Emerging data and clinical implications. AB - Eribulin mesylate (eribulin) is a synthetic analogue of the marine-sponge natural product halichondrin B. Eribulin exhibits potent antiproliferative activities against a variety of human cancer cell types in vitro and in vivo, and is used for the treatment of certain patients with advanced breast cancer or liposarcoma who are refractory to other treatments. The antiproliferative effects of eribulin have long been attributed to its antimitotic activities. Unlike other microtubule targeting agents, eribulin inhibits microtubule polymerization through specific plus end binding, thus interfering with microtubule dynamic instability. Non mitotic effects of eribulin on tumor biology have also been established in laboratory settings including: tumor vasculature remodeling, increased vascular perfusion, reduced hypoxia, and phenotypic changes involving reversal of epithelial-to-mesenchymal transition (EMT), resulting in reduced capacities for migration, invasion, and seeding lung metastases in experimental models. Preclinical data suggest that increased perfusion following eribulin treatment improves delivery of subsequent drugs. Supporting evidence for eribulin's non mitotic effects in the clinical setting include increased tumor oxygen saturation, reduced hypoxia, phenotype changes consistent with EMT reversal, and genotype changes consistent with shifts from nonendocrine-responsive, luminal B, to endocrine-responsive, luminal A, breast cancer subtypes. Finally, potential biomarkers for eribulin response have been established based on tumor-phenotype and gene-expression profiles. Overall, preclinical and clinical data support both antimitotic and non-mitotic mechanisms of eribulin that may underlie the survival benefit observed in various clinical trials. PMID- 30243064 TI - The value of tumour debulking for patients with extensive multi-organ metastatic colorectal cancer. AB - Local treatment of metastases by surgical resection or other ablative therapies is technically feasible in an increasing number of patients with multi-organ metastatic cancer. This results in a growing debate on whether patients with extensive disease, that is traditionally deemed unresectable, may benefit from local treatment of metastases when added to standard palliative systemic therapy. For selected patients with oligometastatic colorectal cancer, local treatment of metastases has become the standard of care based on retrospective reports showing long-term survival rates. In addition to systemic therapy, preliminary evidence suggests that patients with extensive metastatic colorectal cancer may also benefit from local treatment. Here, we present the future perspectives based on the available literature on local treatment approaches in colorectal cancer. PMID- 30243065 TI - Anandamide inhibits FcepsilonRI-dependent degranulation and cytokine synthesis in mast cells through CB2 and GPR55 receptor activation. Possible involvement of CB2 GPR55 heteromers. AB - Activation of high affinity receptor for IgE (FcepsilonRI) by IgE/antigen complexes in mast cells (MCs) leads to the release of preformed pro-inflammatory mediators stored in granules by a Ca2+-dependent process known as anaphylactic degranulation. Degranulation inhibition has been proposed as a strategy to control allergies and chronic inflammation conditions. Cannabinoids are important inhibitors of inflammatory reactions but their effects on IgE/Ag-mediated MCs responses are not well described. In this study, we analyzed the effect of the endocannabinoid anandamide (AEA), the selective CB2 receptor agonist HU308, and the GPR55 receptor agonist lysophosphatidylinositol (LPI) on FcepsilonRI-induced activation in murine bone marrow-derived mast cells (BMMCs). Our results show that AEA, HU380 and LPI inhibited FcepsilonRI-induced degranulation in a concentration-dependent manner. This effect was mediated by CB2 and GPR55 receptor activation through a mechanism insensitive to pertussis toxin. Degranulation inhibition was prevented by CB2 and GPR55 antagonism, but not by CB1 receptor blockage. AEA also inhibited calcium-dependent cytokine mRNA synthesis induced by FcepsilonRI crosslinking, without affecting early phosphorylation events. In addition, AEA, HU308 and LPI inhibited intracellular Ca2+ rise in response to IgE/Ag. CB2 and GPR55 receptor antagonism could not prevent the inhibition produced by AEA and HU308, but partially blocked the one caused by LPI. These results indicate that AEA inhibits IgE/Ag-induced degranulation through a mechanism that includes the participation of CB2 and GPR55 receptors acting in close crosstalk, and show that CB2-GPR55 heteromers are important negative regulators of FcepsilonRI-induced responses in MCs. PMID- 30243066 TI - Pravastatin alleviates interleukin 1beta-induced cartilage degradation by restoring impaired autophagy associated with MAPK pathway inhibition. AB - BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degradation driven by proinflammatory cytokines; meanwhile, statins display anti-inflammatory effects. Here we assessed the effects of pravastatin on inflammatory rat chondrocytes and explored the underlying mechanism. METHODS: Rat articular chondrocytes were pretreated with pravastatin and subsequently stimulated with IL-1beta. Then, the expression levels of OA- and autophagy-related effectors, at the mRNA and protein levels, were examined by real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. Autophagic flux in chondrocytes in different treatment groups was monitored via GFP-mRFP-LC3 adenovirus transfection and confocal microscopy. Activation of MAPK, PI3K/Akt, and NF-kappaB pathways in chondrocytes with or without pravastatin treatment during IL-1beta stimulation was examined by Western blotting. RESULTS: Our results showed that pravastatin downregulated the degradation related genes MMP3, MMP13 and ADAMTS5, as well as extracellular matrix degeneration induced by IL-1beta. In addition, pravastatin upregulated the autophagy related genes atg7, atg12, Beclin1, and LC3 II in IL-1beta stimulated chondrocytes. GFP-mRFP-LC3 adenovirus transfection also indicated that pravastatin restored impaired autophagy in OA chondrocytes. Furthermore, we demonstrated that regulation of the MAPK signaling pathway may be responsible for autophagy regulation in the articular cartilage. CONCLUSIONS: Taken together, these findings suggested that pravastatin restores impaired autophagic flux by inhibiting MAPK activation and protects the cartilage against inflammatory responses, suggesting a potential role for autophagic flux in pravastatin mediated cartilage protection. PMID- 30243067 TI - Aromatic-turmerone ameliorates imiquimod-induced psoriasis-like inflammation of BALB/c mice. AB - Psoriasis is a usual immune-mediated inflammatory skin disease with undefined pathogenesis. Aromatic-turmerone (ATM) is a mainly constituent of essential oil from Curcuma longa L. It has been shown to exhibit strong anti-oxidant, anti tumor activities and anti-inflammatory effects. In this study, we investigated the effects of ATM on imiquimod (IMQ)-induced psoriasis-like BALB/c mice and its molecular mechanisms for anti-inflammatory effect. ATM showed inhibition of the transfer of CD8+ T cells in epidermis, and reduced expression of NF-kappaB and COX-2 as well as phosphorylation of p38 MAPK. It also decreased the level of TNF alpha and IL-6, and down-regulates IL-17 IL-22 and IL-23 mRNA synthesis. Notably, we demonstrated that topically applied ATM alleviated skin inflammation in IMQ induced mice. These results indicate that ATM, a natural active compound exhibits anti-inflammatory activity and is a promising candidate molecule to treat inflammatory skin diseases, such as psoriasis. PMID- 30243068 TI - A novel recombinant RANKL vaccine prepared by incorporation of an unnatural amino acid into RANKL and its preventive effect in a murine model of collagen-induced arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory synovitis, bone atrophy, and subsequent progressive destruction of articular tissue. Targeted inhibition of receptor activator of NF-kB ligand (RANKL) has been highly successful in preventing RA-mediated bone erosion in animal models and patients, suggesting that development of a RANKL vaccine might be of therapeutic value. Our previous study has shown that the recombinant RANKL vaccine Y234pNO2Phe, generated by replacement of a single tyrosine residue (Tyr234) in murine RANKL (mRANKL) with p-nitrophenylalanine (pNO2Phe), induces a high titer antibody response and prevents ovariectomy (OVX)-induced bone loss in mice. This aim of this study was to further evaluate the vaccine's preventive effects in a murine model of collagen-induced arthritis. The results of this study showed that Y234pNO2Phe not only induced a high titer antibody response and inhibited osteoclastogenesis but also significantly prevented bone erosion and ameliorated the severity of a collagen-induced arthritis (CIA) model in mice. Moreover, use of the vaccine improved the clinical situations of the CIA mice. These results suggest a potential application of an anti-RANKL vaccine in the treatment of RA-induced bone erosion. PMID- 30243070 TI - Lisinopril inhibits nuclear transcription factor kappa B and augments sensitivity to silymarin in experimental liver fibrosis. AB - Therapeutic interventions are still limited in the treatment of liver fibrosis even though an incredible number of publications related to silymarin are produced. This is due to the complex molecular pathogenesis. Several studies pointed to the role of renin-angiotensin system (RAS) in hepatic fibrogenesis. Therefore, the present study was designed to examine the effect of the combination of lisinopril (LIS) with silymarin (SIL) on CCl4-induced hepatic fibrosis along with an in-vitro confirmatory experiment. Rats were treated with LIS (1 mg kg-1) and SIL (30 mg kg-1) as a single agent and as combined to LIS (1 mg kg-1). Our results revealed that down-regulation of NFKBp65 mRNA expression and inhibition of phosphorylation of NFKBp65 (at Ser536) and NFKBia were implicated in the anti-fibrotic effect of both LIS and SIL. Consequently lower levels of NFkB-induced TNF-alpha, TGF-beta1, MMP-2, TIMP-1 and VEGF compared to control group. In addition, levels of alpha-SMA protein expression and hydroxyproline are decreased in association with marked improvement in liver function, oxidative stress markers and histological picture. In addition, LIS augmented the inhibitory effect of SIL on NFKB pathway at lower dose level. We concluded that LIS, via targeting NFKB pathway, increases anti-oxidant capacity of liver tissue and exhibits anti-inflammatory, anti-fibrotic and anti-angiogenic activity and augments sensitivity to SIL. Therefore, LIS is a promising candidate for further clinical investigation in the treatment of liver fibrosis. PMID- 30243069 TI - Dysfunction of natural killer cells mediated by PD-1 and Tim-3 pathway in anaplastic thyroid cancer. AB - The survival rate of anaplastic thyroid cancer (ATC) remains about 7% to 14%. The natural killer (NK) cells are a critical component of antitumor immunity, and their composition and function in thyroid cancer patients are investigated in this study. In healthy controls and early stage thyroid cancer patients, >90% of circulating NK cells were CD56loCD16hi and fewer than 10% were CD56hiCD16hi/lo. However, the frequency of the CD56hiCD16hi/lo NK subset was significantly higher in more advanced thyroid cancer patients and further increased in ATC patients. Two members of the inhibitory KIR family, CD158a and CD158b, was significantly higher in CD56hiCD16hi/lo NK cells than in CD56loCD16hi NK cells, while NKG2D, an activator of NK cells, was significantly lower in CD56hiCD16hi/lo NK cells than in CD56loCD16hi NK cells. We also found that the CD56hiCD16hi/lo NK cells presented higher PD-1, higher Tim-3, and lower cytotoxicity against the human ATC cell line CAL-62, than the CD56loCD16hi NK cells. The expression of exhaustion markers and reduction in cytotoxicity was further exacerbated in more advanced thyroid cancer patients and in ATC patients. Interestingly, PD-1 and Tim-3 blockade was effective at reinvigorating both the more impaired CD56hiCD16hi/lo NK cells and the less impaired CD56loCD16hi NK cells from ATC patients. Together, our study identified a dysfunction of NK cells in more advanced thyroid cancer patients and ATC patients, and presented actionable targets for future development of immunotherapies in thyroid cancers. PMID- 30243071 TI - Patients with intracranial aneurysms presented defects in regulatory T cells, which were associated with impairment in Tim-3 upregulation. AB - Pathogenic inflammation contributes to aneurysm formation by mediating the destruction of the endothelium and the extracellular matrix and promoting pathogenic proliferation of smooth muscle cells. In mouse models, tolerance inducing T regulatory (Treg) cells could significantly reduce the incidence and severity of aneurysms. Hence, it should be investigated why in human intracranial aneurysm (IA) patients, Treg cells failed to provide protection against aneurysm formation. In this study, the frequency and function of Treg cells in IA patients were examined. The frequency of Foxp3+ Treg cells was significantly lower in IA patients than in healthy controls. This downregulation was only specific to the Treg subset of CD4+ T cells, as the frequency of total CD4+ T cell was increased in IA patients. Subsequently, we found that the expressions of Treg-associated molecules, including Foxp3, CTLA-4, TGF-beta, and IL-10, were significantly lower in Foxp3+ Treg cells from IA patients than in Foxp3+ Treg cells from healthy controls. In both healthy controls and IA patients, Foxp3+ Treg cells were distinguished into a more potent Tim-3+ subset and a less potent Tim-3- subset. The Tim-3+ subset of Foxp3+ Treg cells was significantly reduced in IA patients. Signaling via IL-2, IL-7, IL-15 and IL-21 was shown to promote Tim-3 upregulation in CD4+ and CD8+ T cells. Interestingly, we found that Tim-3 could be upregulated in Treg cells via the same mechanism, but compared to the Treg cells from healthy controls, the Treg cells from IA patients presented defects in Tim-3 upregulation upon cytokine stimulation. Together, our results demonstrated that Foxp3+ Treg cells in IA patients presented reduced function, which was associated with a defect in Tim-3 upregulation. PMID- 30243072 TI - Oral administration of vitamin D and importance in prevention of cerebral malaria. AB - Cerebral malaria (CM) is a serious and fatal malaria-associated syndrome caused by the development of an overwhelming proinflammatory response. Vitamin D (Vit.D; cholecalciferol) has regulatory functions associated with both innate and adaptive immune responses. Prevention is better than cure, in this experiment, we evaluated prophylactic oral Vit.D as a means of preventing CM presentation before infection of C57BL/6 mice with Plasmodium berghei ANKA (PbA) by modulating the host proinflammatory response. Mice that were supplemented with oral Vit.D has reduce death rate and ameliorated the integrity of the blood brain barrier. Prophylactic oral vitamin D relieved the symptoms of brain malaria and avoided death, gained valuable time for the diagnosis and treatment post infection. The robust Th1 response was attenuated in the Vit.D + PbA group. Furthermore, T-cell trafficking to the brain was diminished before PbA infection using Vit.D. The results suggest that Vit.D supplementation mediates the development of an anti inflammatory environment that improves CM severity. In summary, the use of Vit.D as a nutritional supplement in malaria-endemic regions may help reduce the severity and mortality of CM. PMID- 30243073 TI - Suppression resource decisions are the dominant influence on containment of Australian forest and grass fires. AB - Fire agencies aim to contain wildfires before they impact on life, property and infrastructure and to reduce the risk of damage to the environment. Despite the large cost of suppression, there are few data on the success of suppression efforts under varying weather, fuel and resource scenarios. We examined over 2200 forest and 4600 grass fires in New South Wales, Australia to determine the dominant influences on the containment of wildfires. A random forest modelling approach was used to analyse the effect of a range of human and environmental factors. The number of suppression resources per area of fire were the dominant influence on the containment of both forest and grass fires. As fire weather conditions worsened the probability of containment decreased across all fires and as fuel loads and slope increased the probability of containment decreased for forest fires. Environmental controls limit the effectiveness of wildfire management. However, results suggest investment in suppression resources and strategic fuel management will increase the probability of containment. PMID- 30243074 TI - Evaluation of photocatalytic fuel cell (PFC) for electricity production and simultaneous degradation of methyl green in synthetic and real greywater effluents. AB - Recycling of alternative water sources particularly greywater and recovery of energy from wastewater are gaining momentum due to clean water scarcity and energy crisis. In this study, the photocatalytic fuel cell (PFC) employing ZnO/Zn photoanode and CuO/Cu photocathode was successfully designed for effective greywater recycling as well as energy recovery. The photoelectrodes were analyzed using X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), energy dispersive X-ray (EDX) and fourier transform infrared (FTIR) spectroscopy. The PFC performance in terms of electricity generation and parallel methyl green (MG) degradation were evaluated under operating parameters such as electrolyte type, initial MG concentration and solution pH. The results showed that the addition of Na2SO4 electrolyte, MG concentration of 40 mg L-1 and solution pH of 5.2 improved the short circuit current density (Jsc) and power density (Pmax) in the as-constructed PFC. Such a system also afforded highest MG and chemical oxygen demand (COD) removal efficiencies after 4 h of irradiation. The photoanodes used in this study demonstrated great recyclability after four repetition tests. The COD removal was reduced to some extents when the PFC treatment was tested in the real greywater under optimal conditions. Various greywater quality parameters including ammoniacal nitrogen (NH3-N), turbidity, pH and biochemical oxygen demand (BOD5) were also monitored. The phytotoxicity experiments via Vigna radiate seeds indicated a reduction in the phytotoxicity. PMID- 30243075 TI - Improving stormwater quality at source using catch basin inserts. AB - Stormwater runoff transports contaminants, including gross pollutants (GPs) accumulated on surfaces to nearby receiving water bodies. These may clog storm drainage systems, seal side entry pits and increase dissolved pollutants in receiving water bodies. Best management practices (BMPs) such as oil and grit separators, grassed swales, vegetated filter strips, retention ponds, and catch basin inserts (CBIs) are implemented to reduce stormwater pollutants in urban runoff. However, the information on physicochemical characteristics of the pollutants are still few in literature but important to improve the design of BMPs, considering qualitative aspects, and their operation. CBIs are devices used to remove GPs at source without requiring any extra land use because they are typically mounted within a catch basin (e.g. side entry pit) or existing drain. In this study, improvement of stormwater quality was investigated at two different sites (Subiaco, a residential area and Hillarys Boat Harbour, a commercial-marine-recreational area; Western Australia) where a new CBI made of non-woven polypropylene geotextile was installed in side entry pits to capture GPs at source. Influent and effluent water from the CBIs was collected and analyzed for BOD, COD, TSS and PO4-P with maximum improvements in water quality of 90%, 88%, 88% and 26% respectively. The heavy metals in influent and effluent water were found very low and below the guideline values. Analysis of particle size distribution, specific surface area of solids, SEM images and heavy metal content (Cu, Fe, Ni, Pb, Zn, Cd) in solids showed that the residential area contained more finer particles than the commercial area but that solids in the commercial area contained greater concentrations of heavy metals than those from the residential area. The specific surface area was found to be higher in the residential area and particles were thought to be largely sourced from traffic. However, these characteristics may be monitored for longer term for more CBIs installed in different locations. PMID- 30243076 TI - Changes in fluxes of carbon dioxide and methane caused by fire in Siberian boreal forest with continuous permafrost. AB - Rising air temperatures and changes in precipitation patterns in boreal ecosystems are changing the fire occurrence regimes (intervals, severity, intensity, etc.). The main impacts of fires are reported to be changes in soil physical and chemical characteristics, vegetation stress, degradation of permafrost, and increased depth of the active layer. Changes in these characteristics influence the dynamics of carbon dioxide (CO2) and methane (CH4) fluxes. We have studied the changes in CO2 and CH4 fluxes from the soil in boreal forest areas in central Siberia underlain by continuous permafrost and the possible impacts of the aforementioned environmental factors on the emissions of these greenhouse gases. We have used a fire chronosequence of areas, with the last fire occurring 1, 23, 56, and more than 100 years ago. The soils in our study acted as a source of CO2. Emissions of CO2 were lowest at the most recently burned area and increased with forest age throughout the fire chronosequence. The CO2 flux was influenced by the pH of the top 5 cm of the soil, the biomass of the birch (Betula) and alder (Duschekia) trees, and by the biomass of vascular plants in the ground vegetation. Soils were found to be a CH4 sink in all our study areas. The uptake of CH4 was highest in the most recently burned area (forest fire one year ago) and the lowest in the area burned 56 years ago, but the difference between fire chronosequence areas was not significant. According to the linear mixed effect model, none of the tested factors explained the CH4 flux. The results confirm that the impact of a forest fire on CO2 flux is long-lasting in Siberian boreal forests, continuing for more than 50 years, but the impact of forest fire on CH4 flux is minimal. PMID- 30243077 TI - Recent innovations and trends in in-conduit hydropower technologies and their applications in water distribution systems. AB - Water conduits have a large untapped potential to recapture energy for small hydroelectric generation, which can substantially reduce grid electricity consumption and/or provide renewable energy to water agencies. Over the past decade, there has been a recent technological renaissance in off-the-shelf "water to-wire" turbine technologies including reaction, impulse, and hydrokinetic turbines that target the sub 1-MW in-conduit hydroelectric market. However, adoption of small hydropower technologies remain limited in water and wastewater utility sector, possibly due to the lack of market penetration and exposure. Moreover, information about newly developed small hydropower technologies in the last 5-10 years for in-conduit applications are highly dispersed in the literature. As such, this paper is a comprehensive review on recent technological innovations and trends in hydropower generation from water conduits. Sixteen turbine technologies (eight conventional turbines and eight emerging turbines) are assessed and compared based on their potential benefits and challenges, technology readiness levels, as well as potential sites for installations in diversion structures, potable and irrigation water distribution systems, and wastewater outfalls. Although conventional turbines are considered to be more robust, the modular design of the newer turbines potentially offers a more cost effective solution and better scaling-up capability. Selected case studies on the application of conventional and new turbines for pipelines are also are also reviewed and discussed. PMID- 30243078 TI - A concise review of biochar application to agricultural soils to improve soil conditions and fight pollution. AB - Application of biochar to soil can play a significant role in the alteration of nutrients dynamics, soil contaminants as well as microbial functions. Therefore, strategic biochar application to soil may provide agronomic, environmental and economic benefits. Key environmental outcomes may include reduced availability of toxic metals and organic pollutants, reduced soil N losses and longer-term storage of carbon in soil. The use of biochar can certainly address key soil agronomic constraints to crop production including Al toxicity, low soil pH and may improve nutrient use efficiency. Biochar application has also demerits to soil properties and attention should be paid when using a specific biochar for a specific soil property improvement. This review provides a concise assessment and addresses impacts of biochar on soil properties. PMID- 30243079 TI - Visible light assisted Fenton oxidation of tartrazine using metal doped bismuth oxyhalides as novel photocatalysts. AB - This research focused on the abatement of the model food dye, tartrazine, using visible light photo-Fenton oxidation with novel bismuth oxyhalide catalysts. Bismuth-oxyhalide and metal doped bismuth oxyhalide catalysts (BiOCl, Cu-BiOCl, and Fe-BiOCl) were synthesized via the facile co-precipitation method. The catalysts were characterized by SEM-EDX, XRD, BET, and DRS analyses and the results showed that Cu-BiOCl possess a unique flower-like nanostructure with narrow band gap (2.53 eV) which enhanced its visible light photocatalytic activity remarkably which was proven by catalyst screening experiments. A detailed experimental study was carried out to investigate the effects of operating parameters on the degradation and decolorization of the dye and from this the optimum values were determined as 0.25 g/L for photocatalyst loading, 100 W for visible light power, 6 for initial pH, 6 mM for initial H2O2 concentration, and temperature of 70 degrees C. Approximately 91% degradation, 95% decolorization, and 59% TOC reduction were obtained at optimum conditions. The results for the kinetic study showed that the degradation and decolorization reactions are in the pseudo-first order and obey the simplified Langmuir Hinselwood kinetic model. The activation energies were calculated as 86.54 and 69.39 kJ/mol for degradation and decolorization, respectively. PMID- 30243080 TI - Lobaplatin suppresses proliferation and peritoneal metastasis of colorectal cancer in a preclinical model. AB - Peritoneal metastasis from colorectal cancer (CRC) is related to poor prognosis. Intraperitoneal chemotherapy is an efficient method to treat peritoneal metastasis (PM); however, the outcomes remain unsatisfactory. The present study aimed to investigate the antitumor activity of lobaplatin and its role in intraperitoneal chemotherapy. The findings showed that the proliferation of CRC was inhibited in a dose-dependent manner when DLD1 and HCT116 cells were treated with various concentrations of lobaplatin (0, 6.3, 12.5, 25, 50, and 100 MUg/mL, respectively). Flow cytometry and Western blot analysis confirmed that lobaplatin affected CRC cells by inducing apoptosis and modulating the caspase family. In the animal study, nude mice were injected with DLD1 cells and divided into three groups. Lobaplatin was injected intraperitoneally to simulate intraperitoneal chemotherapy. Group A was the control group treated with PBS. Group B was injected with DLD1 and treated with lobaplatin simultaneously, while group C was treated with lobaplatin 1 week after cell injection. The results showed that group A harbored maximal tumors on the peritoneal surface, while group B had the least number (9.2 +/- 1.3 and 0.4 +/- 0.5, respectively P < 0.01). These findings indicated that lobaplatin suppressed the tumor growth as an intraperitoneal chemotherapy agent and achieved a satisfactory therapeutic effect at an early stage. Further blood test and tissue staining did not reveal any liver and kidney toxicity that was induced by lobaplatin. In conclusion, lobaplatin could be an effective and safe agent for CRC treatment, thereby commissioning a novel strategy in intraperitoneal chemotherapy for patients with peritoneal metastasis. PMID- 30243081 TI - PNMA1, regulated by miR-33a-5p, promotes proliferation and EMT in hepatocellular carcinoma by activating the Wnt/beta-catenin pathway. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant tumors throughout the world. However, its mortality rate remains very high due to the absence of early diagnostic modalities and effective treatments, and its specific pathogenesis remains unclear. Here, we investigated the role of PNMA1 in the tumorigenesis of HCC. We found that PNMA1 was significantly upregulated in HCC. Clinically, higher expression of PNMA1 was associated with aggressive phenotypes and poor prognosis. Functionally, silencing of PNMA1 repressed proliferation in vitro and in vivo, and knockdown of PNMA1 suppressed tumor cell migration and invasion. Via GSEA analysis, we predicted that PNAM1 may be related to the epithelial-mesenchymal-transition and the Wnt signaling pathway. Both these assumptions were confirmed in our study. Furthermore, we proved that miR-33a-5p participated in the posttranscriptional regulation of PNMA1. Together, our findings suggested that PNMA1 participated in HCC progression and may be a potential biomarker and therapeutic target for HCC. PMID- 30243082 TI - Identification of oncogenic long noncoding RNA SNHG12 and DUXAP8 in human bladder cancer through a comprehensive profiling analysis. AB - Bladder cancer is a common urological malignancies world-wide. Recently, a growing number of evidence have highlighted the importance of long noncoding RNAs (lncRNAs) in multiple cancers development and progression. However, the expression pattern of lncRNAs in bladder cancer and their underlying function remain poorly understood. To identify lncRNAs profile alterations and uncover valuable lncRNA candidates for bladder cancer diagnostic, we conducted a comprehensively lncRNAs profiling analyses and explored their clinical relevance using The Cancer Genome Atlas (TCGA) data and three independent microarray profiling data from the Gene Expression Omnibus (GEO). After annotation and analyses of these data, we found that lots of lncRNAs were dysregulated in bladder specimen when compared with normal control specimen. In addition, we found that differential expression of these lncRNAs is accompanied by genomic variations, including genome loci copy number deletion or amplification. Importantly, a part of these lncRNAs are related to bladder cancer patients outcome, such as SNHG10, SNHG12 and LINC00115. Finally, we validated two of these lncRNAs' (DUXAP8 and SNHG12) function in bladder cancer cells by down-regulating their expression with siRNAs, and found that down-regulation of DUXAP8 and SNHG12 could inhibit bladder cancer cells proliferation in vitro. In summary, this study demonstrated that a lot of lncRNAs are dysregulated in bladder cancer, and might provide useful lncRNAs resource for potential prognostic or diagnostic markers for this disease. PMID- 30243083 TI - Co-expression of Akt1 and Wnt11 promotes the proliferation and cardiac differentiation of mesenchymal stem cells and attenuates hypoxia/reoxygenation induced cardiomyocyte apoptosis. AB - Mesenchymal stem cells (MSCs) transplantation has emerged as a promising therapeutic strategy for acute myocardial infarction. However, there are still limitations for this therapy, such as low survival rate and poor cardiac differentiation potential of MSCs. In this study, we genetically engineered MSCs using ex vivo adeno-associated virus (AAV) transduction to overexpress Akt1 and Wnt11, which are well-characterized genes involved in MSC proliferation and cardiac differentiation. Our results showed that infection with AAV-Akt1-Wnt11 significantly upregulated the growth and proliferation of MSCs, as compared with those infected with AAV-Akt1 or AAV-Wnt11. In addition, co-expression of Akt1 and Wnt11 markedly promoted the expression of cardiac markers including NK2 transcription factor related 5, GATA-binding protein 4, alpha-myosin MHC and brain natriuretic protein. Notably, co-expression of Akt1 and Wnt11 increased cell survival and reduced cell apoptosis of MSCs under hypoxia/reoxygenation (H/R) treatment; however, these effects were blocked by Wnt11 neutralizing antibodies or Akt1 inhibitor. Moreover, co-culture of cardiomyocytes with MSCs infected with AAV-Akt1-Wnt11, in a dual chamber system, significantly reduced H/R induced cell apoptosis compared with those co-cultured with MSCs infected with AAV-Akt1 or AAV-Wnt11. Overall, our results showed that MSCs, co-expressing Akt1 and Wnt11, showed greater survival and cardiac differentiation under H/R conditions and effectively ameliorated H/R-induced cardiomyocyte apoptosis in vitro. Our study suggests that transplantation of MSCs genetically engineered with AAV-Akt1-Wnt11 is a promising therapeutic strategy for treatment of acute myocardial infarction. PMID- 30243084 TI - Evaluating the protective effects of melatonin on di(2-ethylhexyl) phthalate induced testicular injury in adult mice. AB - OBJECTIVE: Di (2-ethylhexyl) phthalate (DEHP) is a common phthalate derivative, interfering with normal function of reproductive system. The present study evaluated effects of melatonin on DEHP-induced testicular injury in mice. DESIGN: Thirty-two adult male mice were randomly divided to four groups; group I received normal saline, group II received DEHP, group III received DEHP and melatonin, and group IV was treated with melatonin alone. Body and testes weights, total antioxidant capacity (TAC), glutathione level and superoxide dismutase, glutathione peroxidase and catalase activities were measured. Serum testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels and interleukin 1 beta (IL-1beta) and tumor necrosis factor (TNF-alpha) concentration were evaluated by ELISA assay. Also, malondialdehyde (MDA) and nitric oxide (NO) levels, sperm characteristics and histological changes of testes were analyzed. RESULTS: Body and testes weights were decreased in DEHP group. DEHP also reduced the number of spermatogonia, primary spermatocyte and sertoli cells as well as sperm vitality and progressive motility; these toxic effects were associated with alterations in serum hormone levels. Melatonin remarkably inhibited DEHP-induced reduction of body weight and antioxidant capacity. Melatonin reduced DEHP-induced elevation of NO, MDA, IL-1beta and TNF-alpha levels. Melatonin improved DEHP induced changes in hormonal levels, number of sertoli cells, spermatogonia, and sperm viability and motility. CONCLUSION: Melatonin considerably inhibits DEHP induced gonadotoxicity through reducing oxidative stress and inflammatory responses. These results suggest that melatonin may be considered as a promising agent to reduce toxic effects of endocrine disrupting chemicals such as DEHP on the male reproductive system. PMID- 30243085 TI - Usnic acid inhibits hypertrophic scarring in a rabbit ear model by suppressing scar tissue angiogenesis. AB - Hypertrophic scarring is a common condition in the Chinese population; however, there are currently no satisfactory drugs to treat the disorder. Previous studies showed that angiogenesis plays an important role in the early phase of hypertrophic scarring and inhibition of angiogenesis has been reported as an effective strategy for anti-hypertrophic scar therapy. A recent study showed that usnic acid (UA), an active compound found mainly in lichens, inhibited tumor angiogenesis both in vivo and in vitro. To investigate the therapeutic effects of UA on hypertrophic scarring and to explore the possible mechanism involved, a rabbit ear hypertrophic scar model was established. Scars were treated once a week for four weeks with UA, DMSO or triamcinolone acetonide acetate. Histological evaluation of hematoxylin and eosin staining indicated that UA significantly inhibited hypertrophic scar formation, with obvious reductions in scar height and coloration. The scar elevation index (SEI) was also evidently reduced. Masson's trichrome staining showed that UA significantly ameliorated accumulation of collagen tissue. Immunohistochemical analysis of CD31 expression showed that UA significantly inhibited scar angiogenesis. In vitro, UA inhibited endothelial cell migration and tube formation as well as the proliferation of both human umbilical vein endothelial cells and scar fibroblast cells. These results provide the first evidence of the therapeutic effectiveness of UA in hypertrophic scar formation in an animal model via a mechanism that involves suppression of scar angiogenesis. PMID- 30243086 TI - MicroRNA-143a-3p modulates preadipocyte proliferation and differentiation by targeting MAPK7. AB - Adipogenesis plays a key role in increasing fat mass, which is a main characteristic for obesity, and involves preadipocyte proliferation and differentiation. Recently, more and more evidences suggested that microRNAs (miRNAs) is an important member of the regulatory network of adipogenesis. In this study, miR-143a-3p was highly expressed in adipose tissues of obese mice, and was up-regulated at the middle and last stage of 3T3-L1 adipocyte differentiation. Using mouse 3T3-L1 cells line, which is an ideal model in vitro for the study of adipogenesis, we observed that overexpression of miR-143a-3p inhibited the preadipocyte proliferation, and enhanced the preadipocyte differentiation. In contrast, the inhibition of miR-143a-3p expression promoted the preadipocyte proliferation, and inhibited the preadipocyte differentiation. Further analysis suggested that miR-143a-3p mediating preadipocyte differentiation might be involved in fatty acid metabolism. In addition, we found that miR-143-3p and PPARgamma, an activator of miR-143a-3p transcription, could regulate each other. Compared with miR-143a-3p, MAPK7 played an opposite role in the proliferation and differentiation of adipocyte. Further analysis indicated that MAPK7 is a target gene of miR-143a-3p in 3T3-L1 cells, and inhibition of MAPK7 recede the effect of miR-143a-3p on preadipocyte proliferation and differentiation. Taken together, these results indicated that as a regulator of PPARgamma, miR-143a-3p play an important role in adipogenesis via regulating MAPK7 and fatty acid. PMID- 30243087 TI - The effect of serine phosphorylated claudin-7 on the epithelial barrier and the modulation by transient receptor potential vanilloid 4 in human colonic cells. AB - Abnormal phosphorylation of claudins changes the interaction and aggregation of tight junction proteins, affecting the intestinal epithelial barrier. Selective blockade of transient receptor potential vanilloid 4 (TRPV4) alleviated experimental colitis. Whether TRPV4 affects the intestinal epithelial barrier and the relationship to claudin-7 phosphorylation remain unknown. In the present study, we investigated the TRPV4 expression in human colonic tissues and colonic cells. Using the site-directed mutagenesis approach, we also identified the roles of claudin-7 phosphorylation in the epithelial barrier and the relationship between TRPV4 and claudin-7 phosphorylation. Increased TRPV4 expression was found in the colonic mucosa from IBD patients. In colonic cells, the mutation of claudin-7 at position 204 decreased the TRPV4 expression. Mutation of claudin-7 at position 204 significantly decreased the FD20 permeability in monolayer colonic cells, while mutations of claudin-7 at positions S206 and S207 increased the FD20 permeability. Meanwhile, mutations of claudin-7 at positions S204 and S207 increased the TER in monolayer colonic cells. TRPV4 agonist GSK1016790 A increased the FD20 permeability in the control group, cld7-wild group, cld7-S206A group and cld7-S207 A group, while the TRPV4 antagonist HC067047 decreased the FD20 permeability in the same groups. HC067047 treatment increased the TER in vector cells, cld7-wild cells and cld7-S206 A cells compared to the respective cells in GSK1016790A-treated groups. HC067047 treatment decreased the migration in vector cells, cld7-wild cells and cld7-S206 A cells compared to the respective cells in the GSK1016790A-treated groups. These results indicated that TRPV4 might be a target for the maintenance of the intestinal epithelial barrier and indicated the mechanism involved in the modulation of serine phosphorylated claudin-7. PMID- 30243088 TI - Syringic acid (SA) - A Review of Its Occurrence, Biosynthesis, Pharmacological and Industrial Importance. AB - The use of phytochemicals in control of human diseases have been considerable public and scientific interest in current days. Syringic acid (SA), a phenolic compound often found in fruits and vegetables and which is synthesized via shikimic acid pathway in plants. It shows a wide range of therapeutic applications in prevention of diabetes, CVDs, cancer, cerebral ischemia; as well as it possess anti-oxidant, antimicrobial, anti-inflammatory, antiendotoxic, neuro and hepatoprotective activities. It has an effective free radical scavenger and alleviates the oxidative stress markers. The therapeutic property of SA is attributed by the presence of methoxy groups onto the aromatic ring at positions 3 and 5. The strong antioxidant activity of SA may confer its beneficial effects for human health. SA has the potential to modulate enzyme activity, protein dynamics and diverse transcription factors involved in diabetes, inflammation, cancer and angiogenesis. In vivo experimental data and histopathological studies on SA activity has delineated its possible therapeutic mechanisms. Besides usage in biomedical field, SA has greater industrial applications in bioremediation, photocatalytic ozonation, and laccase based catalysis. The present review deals about SA natural sources, biosynthesis, bioavailability, biomedical applications (in vivo and in vito. The review addresses basic information about molecular mechanisms, therapeutic and industrial potential of SA. PMID- 30243089 TI - In vivo antifungal activity of dipyrithione against Trichophyton rubrum on guinea pig dermatophytosis models. AB - The treatment of dermatophytosis has improved considerably over the past several decades following the introduction of the oral antifungals such as azoles and amphotericin B. However, these drugs have had limited success because the treated fungi often develop drug resistance, resulting in recurrence when applied in various topical formulations. Thus, there are constant needs for new topical agents that are effective against dermatophytosis. Dipyrithione is an attractive candidate to become an antifungal agent due to its broad spectrum of antimicrobial activities. In this study, we determined that dipyrithione could potently inhibit the growth of Trichophyton rubrum, which is the most common cause of dermatophytosis. The MIC50 value of dipyrithione against T. rubrum was measured as 6.03 MUM, as compared with miconazole (MIC50: 1.38 MUM). Additionally, the compound caused morphological changes in the fungi, which was examined using the morphological interference assay. The in vivo experiment further revealed that dipyrithione had a healing effect on the skin of guinea pigs infected with T. rubrum. Our studies have demonstrated that dipyrithione had a potent antifungal activity in vitro and in vivo, suggesting that it could be formulated as a potential antifungal lead compound in search for novel therapeutic agents against dermatophytosis. PMID- 30243090 TI - Encapsulation of verapamil and doxorubicin by MPEG-PLA to reverse drug resistance in ovarian cancer. AB - PURPOSE: Ovarian cancer is usually treated with transurethral resection or systemic chemotherapy in clinic. However, the development of drug resistance in ovarian cancer is frequently observed in ovarian cancer patients, leading to failure of tumor inhibition and recurrence. In this study, we aimed to efficiently reverse the drug resistance and enhance the anticancer effects by co delivery of chemotherapeutic agents and multi-drugs resistant proteins inhibitor in ovarian cancer treatment. METHODS: The cell viability was measured by using MTT or flow cytometry (Annexin V/PI staining) under different culture conditions. Western blot was used to detect the expression of P-gp. We employed confocol to visualize the drug distribution under different culture systems. Using flow cytometry, we examined the drug absorption. MPEG-PLA was used to load chemotherapeutic drugs. We also applied mice model to evaluate the killing ability and side effects of free or methoxy poly (ethylene glycol)-poly (l-lactic acid) (MPEG-PLA) loaded drugs. RESULTS: We found that pre-treatment of verapamil, a multi-drugs resistant proteins inhibitor, could efficiently reverse the drug resistant in ovarian cancer. To further improve the pharmacokinetics profiles and avoid the systemic toxicity caused by agents, we encapsulated verapamil and doxorubicin (DOX) by polymeric nanoparticles MPEG-PLA. Co-delivery of verapamil and DOX by nano-carrier revealed reduced drug resistance and enhanced anticancer effects compared with the free drug delivery. More importantly, accumulated drugs, prolonged drug circulation and reduced systemic were observed in nanoparticles encapsulation group. CONCLUSION: Co-delivery of verapamil and chemotherapeutic drugs by MPEG-PLA efficiently reversed the drug resistance, resulting in enhanced anticancer effects along with reduced systemic toxicity, which provides potential clinical applications for drug resistant ovarian cancer treatment. PMID- 30243091 TI - miR-326 functions as a tumor suppressor in human prostatic carcinoma by targeting Mucin1. AB - Accumulating evidence suggests that microRNA-326 (miR-326) serves as a tumor suppressor in the initiation and progression of several human malignancies. However, the biological function and underlying molecular mechanism of miR-326 in prostatic carcinoma (PCa) remains largely unknown. In the present study, we found that miR-326 expression level was significantly downregulated in both primary PCa and castration-resistant PCa (CRPC) tissue samples as detected by qRT-PCR. Downregulation of miR-326 was closely associated with aggressive progression and poor prognosis of primary PCa patients. Gain- and lose- functional experiments revealed that forced expression of miR-326 significantly inhibited cell proliferation, colony formation, migration and invasion, induced G0/G1 cell cycle arrest, and promoted apoptosis in PCa cells in vitro, whereas, knockdown of miR 326 expression showed the opposite results. Overexpression of miR-326 also suppressed tumor growth in xenografted nude mice in vivo. Moreover, Luciferase reporter, qRT-PCR, and western blot assays identified that the 3'-untranslated region (3'-UTR) of Mucin1 (MUC1) was a direct target region of miR-326. Spearman's correlation analysis also confirmed an inverse relationship between miR-326 and MUC1 expressions in primary PCa tissue samples. In addition, restoration of MUC1 expression effectively abrogated the inhibitory effects of miR-326 on PCa proliferation, invasion and migration through the activation of JNK signaling pathway. Therefore, these data indicated that miR-326 functioned as a tumor suppressor in PCa by negatively regulating MUC1, and that miR-326 might serve as a potential therapeutic candidate for PCa treatment. PMID- 30243092 TI - Silencing Bmi1 expression suppresses cancer stemness and enhances chemosensitivity in endometrial cancer cells. AB - BACKGROUND: Bmi1, a polycomb group gene, is essential for self-renewal of stem cells and is frequently upregulated in various cancer cells. We aimed to investigate the effect of Bmi1 silencing on cancer stemness and chemosensitivity in endometrial cancer using targeted siRNA approach in HEC1A and Ishikawa cells. METHODS: Cell viability after treatment with Bmi1 siRNA was assessed using the MTT assay, and cell apoptosis was visualized using the TdT-mediated dUTP nick-end labeling (TUNEL) method. Western blotting, migration assays and invasion assays were performed to detect changes in the stem-like properties of cancer cells. To evaluate the anticancer effect of Bmi1 silencing, HEC1A and Ishikawa cells were treated with 100 nM Bmi1 siRNA and/or 40 MUM cisplatin. RESULTS: In the MTT assay, compared to control, viability of HEC1A and Ishikawa cells significantly decreased after Bmi1 siRNA treatment in a dose-dependent manner. Bmi1 silencing using siRNA increased the expression of cleaved caspase-3 and cleaved poly adenosine diphosphate-ribose polymerase polymerase (PARP) as observed in the western blot analysis. Apoptosis significantly increased in the HEC1A and Ishikawa cells treated with 100 nM Bmi1 siRNA for 48 h than in the control cells in TUNEL assay. SOX2 and Oct4 expression decreased in the HEC1A and Ishikawa cells treated with Bmi1 siRNA, while E-cadherin expression increased. Further, migratory and invasive properties were significantly inhibited by Bmi1 siRNA treatment in both cell lines. Notably, viability of HEC1A and Ishikawa cells decreased more when they were concurrently treated with Bmi1 siRNA and cisplatin compared to when they were treated with Bmi1 siRNA or cisplatin alone. CONCLUSION: Bmi1 silencing suppresses cancer stemness in HEC1A and Ishikawa cells. Concurrent treatment with Bmi1 siRNA and cisplatin resulted in additive anticancer effect with a cell line-specific pattern, which was higher than that shown by cisplatin treatment alone. PMID- 30243093 TI - Cancer signaling pathways with a therapeutic approach: An overview in epigenetic regulations of cancer stem cells. AB - One of the most important issues in cancer progression is caner stem cells (CSCs) which have illustrated that the bulk tumors can arise from a special combination of cells. Remarkably, it has been proposed to be a notable and strong factor in carcinogenesis and tumorogenesis and also is a key parameter of therapeutic resistance. In this way, recent findings have shown the key roles of epigenetic regulations in cancer development.Considerably, epigenetic regulations of gene expression is an active and dynamic process including histone modification, DNA methylation and chromatin remodeling with a reversible trait.Meaningly, recent and novel findings have described the significance of epigenetic regulatory proteins from divers features comprising tumorogenesis,stem cell proliferation and carcinogenesis. Evidently, abnormal epigenetic regulations is directly related with many serious disorders particularly different cancers. We here review a discussion of how the deregulation of eclectic pathways containing Sonic Hedgehog (SHH), WNT, Beta catenin and NOTCH can help to carcinogenesis specially focusing to survival and maintenance of CSCs in therapeutic approach. PMID- 30243094 TI - Dual gene deficient models of ApcMin/+ mouse in assessing molecular mechanisms of intestinal carcinogenesis. AB - The ApcMin/+ mouse, carrying an inactivated allele of the adenomatous polyposis coli (Apc) gene, is a widely used animal model of human colorectal tumorigenesis. While crossed with other gene knockout or knock-in mice, these mice possess advantages in investigation of human intestinal tumorigenesis. Intestinal tumor pathogenesis involves multiple gene alterations; thus, various double gene deficiency models could provide novel insights into molecular mechanisms of tumor biology, as well as gene-gene interactions involved in intestinal tumor development and assessment of novel strategies for preventing and treating intestinal cancer. This review discusses approximately 100 double gene deficient mice and their associated intestinal tumor development and progression phenotypes. The dual gene knockouts based on the Apc mutation background consist of inflammation and immune-related, cell cycle-related, Wnt/beta-catenin signaling-related, tumor growth factor (TGF)-signaling-related, drug metabolism related, and transcription factor genes, as well as some oncogenes and tumor suppressors. Future studies should focus on conditional or inducible dual or multiple mouse gene knockout models to investigate the molecular mechanisms underlying intestinal tumor development, as well as potential drug targets. PMID- 30243095 TI - Generation of a novel long-acting thymosin alpha1-Fc fusion protein and its efficacy for the inhibition of breast cancer in vivo. AB - Thymosin alpha1 (Talpha1) is a multifunctional polypeptide involved in immunoregulation, which universally exists in various organs. The clinical application, however, is limited because of its short half-life. The Fc domain of human IgG has functional properties, improving the affinity and serum half-life. In this study, we fused Talpha1 to Fc domain of human IgG1 for generation of a novel long-acting fusion protein, termed Talpha1-Fc. Talpha1-Fc was expressed, purified, and identified. The results showed that Talpha1-Fc was more potent than Talpha1 in inhibiting the growth of 4T1 and MCF-7 breast cancer cells in vivo. Furthermore, in the 4T1 tumor model the mice treated with Talpha1-Fc exhibited higher level of CD4 and CD8 cells compared with that of the mice Talpha1 treated. The interferon-gamma and interleukin-2 level in the Talpha1-Fc-treated mice was higher than that in the Talpha1-treated mice. Talpha1-Fc could also alleviate immunosuppression induced by hydrocortisone. In summary, Talpha1-Fc provides a novel potent strategy to recruit immune cells against tumors and enhance the antitumor activity of Talpha1. PMID- 30243096 TI - PMA treated THP-1-derived-IL-6 promotes EMT of SW48 through STAT3/ERK-dependent activation of Wnt/beta-catenin signaling pathway. AB - Colon cancer is one of the most common digestive malignant tumors that leads to high mortality worldwide, and metastasis is the primary cause of cancer-related death. It is well accepted that the epithelial-mesenchymal transition (EMT) plays a key role in the process of metastasis. As a cytokine that macrophage secretes, IL-6 is involved in the progression of tumors, including the invasion and metastasis via kinds of signaling pathways. However, the mechanism of interactions between IL-6, macrophage, EMT and colon cancer is not fully understood. Increased CD68+ macrophages and IL-6 level were found in colon tumor as compared to normal colon tissue. Metastatic lymph node showed even more CD68+ macrophages and higher IL-6 level than the primary tumor. These results suggested that macrophages and IL-6 play an important role in EMT of colon cancer. In order to investigate the effect of macrophage and IL-6 on EMT of colon cancer, we cultured human colon carcinoma cell line SW48 with conditioned medium (CM) from PMA-stimulated monocyte THP-1 cells and tested for IL-6 dependent EMT pathways. Wound healing assay and Transwell assay were used to analyze cell migration and invasion. Results showed that CM-treated SW48 cells increased IL-6 production and displayed elevated capacity of migration and invasion compared to untreated cells. Increased expressions of EMT markers (N-cadherin, Vimentin and beta catenin) and decreased expression of EMT marker(E-cadherin) were found in CM treated SW48 cells by Western Blot. The addition of an anti-IL-6 antibody significantly inhibited the increase of EMT markers (Vimentin and beta-catenin) as well as cell migration and invasion, suggesting that IL-6 played a critical role in promoting EMT of CM-treated SW48 cells. In addition, we found that the levels of p-STAT3 and p-ERK increased in CM-treated SW48 compared to untreated cells, which can be reversed by AG490, an inhibitor of JAK. In the meantime, the suppression of JAK-associated signaling pathways caused a decrease of beta catenin. In summary, our study suggested that macrophage-induced IL-6 promotes migration and invasion of colon cancer cell via Wnt/beta-catenin pathway in STAT3/ERK-dependent way. PMID- 30243097 TI - Reactive sulfur species (RSS): persulfides, polysulfides, potential, and problems. AB - Sulfur is a crucial element in biology due to its unique properties and wide range of accessible oxidation states. This reactivity gives rise to the generation of reactive sulfur species (RSS), which have emerged as a diverse class of small molecules and functional groups with important roles in chemical biology and bioinorganic chemistry. In this review, we focus on basic properties of simple RSS, highlight recent insights into the interconnectivity of RSS with reactive nitrogen species, and discuss recent advances in methods for RSS detection and measurement. Finally, we highlight key reactivity considerations that must be taken into account when working with RSS and interpreting the outcomes of labeling methods for RSS and related species. PMID- 30243098 TI - Investigation of the effects of sintering and indium-doping of zinc oxide using 67Zn magic angle spinning NMR analysis. AB - Indium-doped zinc oxide, a potential alternative material to indium tin oxide, was analyzed in powder form via 67Zn magic angle spinning nuclear magnetic resonance (MAS NMR). The 67Zn MAS NMR results show that the line shapes of zinc oxide were broadened by sintering, which was also observed for indium-doped zinc oxide, in which the broadening also depended on the sintering time. Furthermore, the line shapes of indium-doped zinc oxide were significantly broader than those of the corresponding zinc oxide, and were independent of the degree of indium doping. This indicates that indium atoms are associated into cluster-like structures in this compound. PMID- 30243099 TI - Radiocesium and 40K distribution of river sediments and floodplain deposits in the Fukushima exclusion zone. AB - In this study, radiocesium and 40K analysis were accomplished for samples of riverbed sediments and floodplain deposits collected from five rivers in the vicinity (<20 km) of the damaged Fukushima Daiichi Nuclear Power Plant after seven years of the accident. Sediment particle size distribution and major oxide content were determined also for six selected samples to understand the retention and migration process of radiocesium in river environments. The radiocesium activity concentration varied from 103 +/- 6 Bq.kg-1 to 22,000 +/- 500 Bq.kg-1 in riverbed sediments and from 92 +/- 5 Bq.kg-1 to 117,000 +/- 2000 Bq.kg-1 in floodplain deposits. The 134Cs/137Cs ratio (decay corrected to 15 March 2011) was 1.02 in the both samples. Compared to monitoring results in 2011, it was proved that the radiocesium distribution pattern had been changed remarkably during seven years. The radiocesium was primarily attached to fine clay particles but its sorption on sand and coarse sand particles was also considerable. The sorption process of radiocesium was not affected by the presence of water and moreover, after seven years of the Fukushima accident, a significant radiocesium migration cannot be expected without particle migration. Consequently, radiocesium will remain for a long time in the river environments and its redistribution is mainly affected by the erosion process of the sediments. The average 40K activity concentration of riverbed sediment and floodplain deposit samples was 640 +/- 152 Bq.kg-1 changing from 319 +/- 18 Bq.kg-1 to 916 +/- 41 Bq.kg-1. In the river estuary zones, significant activity concentration decrements were observed for both radionuclides. This suggests that seawater intrusion has a decreasing effect on both natural and artificial radionuclides via wash-out of particulate radiocesium and 40K, and desorption of these radionuclides, but to reveal the detail of this process further investigations are required. The analysis of 40K can help in a simple and easy way to reveal the mineral composition differences of sediment samples. PMID- 30243100 TI - Psychological mediators of the association between childhood adversities and psychosis: A systematic review. AB - OBJECTIVES: This is the first review to identify, summarise and critically evaluate studies that examined psychological mediators of the relationship between childhood adversities and psychosis. METHODS: A database search (PsychINFO, MEDLINE, Web of Science, CINAHL) was conducted to identify eligible studies published between January 1980 and September 2017. A narrative synthesis and appraisal of methodological quality and statistical appropriateness of the primary studies was conducted. RESULTS: We identified 37 papers, comprising 9057participants with psychotic disorders and 63,059 non-clinical participants. Despite great variation in the mediators considered and the methodological and analytic quality of the primary studies, our synthesis suggests that the relationship between childhood adversity and psychosis is mediated by several "families" of mediating variables including post-traumatic sequelae (e.g. dissociation, PTSD symptoms), affective dysfunction and dysregulation, and maladaptive cognitive factors (e.g. self-esteem and beliefs and concepts about the self and others). More tentative evidence was observed for the role played by appraisals of subsequent circumstantial factors (e.g. "life hassles"). Substance misuse was not found to be a prominent mediator of the relationship between childhood adversity and psychotic experiences, but further high quality corroborative studies are required. CONCLUSIONS: The importance of the five different (but not independent or mutually exclusive) families of mediators considered by the present evidence synthesis should be examined by future research employing appropriate modelling methods to better disentangle the contribution of these different processes. Nonetheless, they represent potentially valuable intervention targets that clinicians should consider whilst developing treatment plans for trauma survivors with distressing psychotic symptoms. PMID- 30243101 TI - Susceptibility to others' emotions moderates immediate self-reported and biological stress responses to witnessing trauma. AB - BACKGROUND: The peri-traumatic stress response is a strong predictor of symptom development after trauma exposure. Regarding witnessing trauma, the stress response might depend on the susceptibility to others' emotions (emotional contagion, EC). This study investigated whether EC moderates the immediate stress response using a trauma film paradigm. METHODS: Ninety-five healthy participants were randomly exposed to a trauma or a neutral film. Perceived stressfulness of the film and pre-to post-film changes in self-reported anxiety, heart rate and saliva cortisol levels were assessed. EC towards negative and positive emotions was measured using the emotional contagion scale and its emotion-specific subscales. RESULTS: Overall, the trauma film was perceived as distressing and elicited an increase in self-reported anxiety, heart rate and saliva cortisol levels relative to the neutral film. EC towards negative emotions was positively related to the perceived stressfulness of the film, increased anxiety and increased heart rate. The association with saliva cortisol levels was also in the expected direction, but not statistically significant. These associations were not found for EC towards positive emotions. DISCUSSION: EC towards negative emotions may be an important predictor of trauma exposure outcomes. Further research should clarify its specific contribution in witnessing and undergoing trauma. PMID- 30243102 TI - Whitefly-transmitted viruses threatening cassava production in Africa. AB - Emerging plant viruses are one of the greatest problems facing crop production worldwide, and have severe consequences in the developing world where subsistence farming is a major source of food production, and knowledge and resources for management are limited. In Africa, evolution of two viral disease complexes, cassava mosaic begomoviruses (CMBs) (Geminiviridae) and cassava brown streak viruses (CBSVs) (Potyviridae), have resulted in severe pandemics that continue to spread and threaten cassava production. Identification of genetically diverse and rapidly evolving CMBs and CBSVs, extensive genetic variation in the vector, Bemisia tabaci (Hemiptera: Aleyrodidae), and numerous secondary endosymbiont profiles that influence vector phenotypes suggest that complex local and regional vector-virus-plant-environment interactions may be driving the evolution and epidemiology of these viruses. PMID- 30243103 TI - Representation of ethnic groups in dementia trials: systematic review and meta analysis. AB - BACKGROUND: Despite the projected increase in dementia cases affecting various ethnic groups worldwide, representation of these ethnic groups in randomized controlled trials (RCTs) of treatments to improve cognitive function in persons with dementia or mild cognitive impairment (MCI) is unclear. We aimed to quantify the inclusion of various ethnicities in dementia treatment RCTs. METHODS: RCTs published between January 1, 2000 and August 1, 2017 (inclusive) were included. Participants were community-dwelling adults with a diagnosis of either dementia or MCI randomized to receive either pharmacological or non-pharmacological interventions to improve cognitive function. Analyses were performed to determine study-level characteristics associated with recruitment of various ethnic groups. Random effects meta-analyses were conducted to determine the pooled prevalence for each ethnicity. RESULTS: A total of 96 RCTs consisting of 37,278 participants (57.2% female) were included in the final analysis. Only 39 (39.4%) trials reported the ethnicity of included participants. The pooled proportion of non Caucasian trial participants was 11.4% (95% CI, 7.5 to 15.9%). Meta-regression results showed that there has been a slow increase in representation of non Caucasian ethnic groups over time (0.6% per year, P value = 0.041). CONCLUSIONS: There is an underreporting of the ethnicity of trial participants and underrepresentation of non-Caucasian ethnic groups in RCTs designed to improve cognitive function in persons with dementia or MCI. PMID- 30243104 TI - The morphology of amyloid fibrils and their impact on tissue damage in hereditary transthyretin amyloidosis: An ultrastructural study. AB - INTRODUCTION: We evaluated the morphology of amyloid fibrils in the peripheral nervous system using biopsy or autopsy specimens from hereditary transthyretin amyloidosis patients. The impact of amyloid fibril formation on neighboring tissues was also investigated. METHODS: Sural nerve biopsy specimens from 34 patients were examined using electron microscopy. Twenty-eight patients had Val30Met mutations, and the remaining 6 patients had non-Val30Met mutations (i.e., Glu54Lys, Pro24Ser, Thr49Ala, Val71Ala, Val94Gly, and Ala97Gly). The patients with the Val30Met mutation included a case from Brazil (supposedly of Portuguese origin), 6 early-onset cases from endemic foci in Japan, and 21 late onset cases from non-endemic areas in Japan. RESULTS: Long amyloid fibers were abundant in the early-onset Val30Met cases from the Japanese endemic foci and Brazil, whereas the amyloid fibrils were generally short in the late-onset Val30Met and non-Val30Met cases. The amyloid fibrils seemed to mature from dotty structures among amorphous electron-dense extracellular materials and pull surrounding tissues during the maturation process. The distortion of Schwann cells close to amyloid fibril masses was conspicuous, particularly in cases with long amyloid fibrils. Atrophy was conspicuous in non-myelinating Schwann cells and bands of Bungner (i.e., Schwann cell subunits that previously contained myelinated axons), particularly those completely surrounded by amyloid fibrils. In contrast, the myelinated fibers tended to be only partially surrounded by amyloid fibrils and morphologically preserved due to their large size. Only a few demyelinated axons were found. CONCLUSION: Pre-fibrillar amyloid precursors appear to play a pivotal role during the initial phase of amyloid fibril formation. The mechanical distortion and subsequent atrophy of Schwann cells resulting from the elongation of amyloid fibrils may be related to small-fiber predominant loss, which is a classical characteristic of amyloid neuropathy. Although rather rare, the destruction of myelin (i.e., demyelination) resulting from amyloid deposition may relate to nerve conduction abnormalities mimicking chronic inflammatory demyelinating polyneuropathy. PMID- 30243106 TI - Infrared band strengths for amorphous and crystalline methyl propionate, a candidate interstellar molecule. AB - Mid-infrared spectra of amorphous and crystalline methyl propionate, CH3CH2COOCH3, are presented for the first time from a single laboratory, along with measurements of the refractive index of each solid form. Density estimates are made and IR band strengths and absorption coefficients are calculated. Vapor pressures of crystalline methyl propionate at 140-150 K are reported along with an enthalpy of sublimation. Spectroscopic results are compared to a recent study of this compound, and the phase of methyl propionate in that work is identified. Several applications are described. PMID- 30243105 TI - A highly selective and reversible turn-off fluorescent chemosensor for Cu2+ based on electrospun nanofibrous membrane modified with pyrenecarboxaldehyde. AB - A fluorescent nanofibrous membrane (NFM) was successfully fabricated by functionalizing electrospun ethylene-vinyl alcohol copolymer (EVOH) NFM with 4 aminobenzoic acid (PABA) and 1-pyrenecarboxaldehyde (Py-CHO) for fast and selective determination of Cu2+ in aqueous solution. The effective grafting of PABA and Py-CHO on the surface of EVOH NFM was confirmed by FTIR and XPS spectra. Benefiting from the integrated merits of electrospun EVOH NFM, PABA and Py-CHO, the as-appeared EVOH-PABA-Py NFM exhibited high sensitivity and selectivity towards Cu2+ detection. The quenching efficiency was 91.7% when the concentration of Cu2+ reached 5 * 10-3 M, while the detectable fluorescence response of the NFM was still observed when the concentration of Cu2+ was 1 * 10-9 M. The fluorescence quenching caused by Cu2+ was hardly affected by other commonly co existent metal ions. More importantly, the fluorescent NFM exhibited fast response and high reversibility towards Cu2+ detection. The "off-on" fluorescence switching process via alternating addition of Cu2+ and Na2EDTA occurred in 3 min, and the quenching efficiency of the NFM kept relatively stable values within 10 cycles. This work may provide a new insight into the development of rapid, portable, stable and reusable fluorescent sensor based on electrospun nanofibers that can satisfy the requirements of practical metal ions detection. PMID- 30243107 TI - Europium(III) complex with powerful antenna ligands: Interligand interaction. AB - The luminescent properties of europium(III) trifluoroacetate [Eu(TFA)3bipy.3N2O]?bipy (I), where TFA - trifluoroacetate anion and bipy - 2,2'bipyridyl were investigated. Despite the presence of two efficient antenna ligands in complex (bipy1 in europium coordination sphere and bipy2 in the outer sphere) the complex displays weak luminescence. By employing density functional theory-based methods, the luminescence, electron structure, interligand interactions and the processes of energy transfer in I were investigated. The nature of the chemical bond in I was studied by the natural bond orbital analysis. The mechanism of luminescence weakening in the complex was ascertained: competitive energy transfer from coordinated bipy1 ligand on to outer-sphere bipy2 molecule results in appreciable weakening of the antenna effect. PMID- 30243108 TI - Pharmacophore-based virtual screening for identifying beta5 subunit inhibitor of 20S proteasome. AB - Proteasomal system plays an important role in maintaining cell homeostatis. Overexpression of proteasomes leads to several major diseases, such as cancer and autoimmune disorder. The beta5 subunit of proteasome is a crucial active site in proteolysis, and targeting proteasome beta5 subunit is essential for proteasome inhibition. In the present study, a pharmacophore-based virtual screening and molecular docking were employed to identify ligands as inhibitors of beta5 subunit of proteasome. The pharmacophore features were built with one hydrogen bond donor, two hydrogen bond acceptors, and one hydrophobic feature using native ligand of proteasome (HU10), which was then used to screen ZINC database using ZINCPharmer. The retrieved virtual hits were subjected to molecular docking analysis using iDock. The best six hits were subjected to molecular dynamics (MD) simulation and each complex was stable during 40 ns MD simulation as indicated by root-mean-square-deviation (RMSD) and root-mean-square-fluctuation (RMSF) values. The current study identifies 5 best hits having better binding potentials than HU10 as predicted by molecular mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method, i.e. Lig1540/ZINC33356240, Lig1546/ZINC33356235, Lig1522/ZINC20854878, Lig980/ZINC12391945, and Lig1119/ZINC19865241, which can be used in the development of new proteasome inhibitors. PMID- 30243109 TI - Effects of family-centered empowerment intervention on stress, anxiety, and depression among family caregivers of patients with epilepsy. AB - OBJECTIVES: Family caregivers face numerous challenges in taking care of their family members with epilepsy. The empowerment of this group of people, who can be described as forgotten patients, should always be considered through supportive interventions; therefore, this study investigated the effect of a family-centered intervention program on stress, anxiety, and depression among family caregivers of patients with epilepsy. METHODS: In 2017, a trial was conducted in Iran among subjects selected by the convenience sampling method and randomly assigned to two groups: intervention and control. After five sessions per week over a four-week period, the intervention- and control-group data were collected using the Depression Anxiety Stress Scale (DASS) in three stages: before, immediately after, and two months after the intervention. Data were analyzed with Statistical Package for the Social Sciences (SPSS) software using descriptive and analytical statistics, an independent t-test, and repeated measures Analysis of variance (ANOVA). RESULTS: In this study, the family caregivers included 61.3% women and 38.7% men, with a mean age of 37.5 years. The findings showed no significant differences in the mean scores of stress (p = 0.93), anxiety (p = 0.91), and depression (p = 0.56) before the interventional program between the intervention and control groups, but these differences were statistically significant in the mean score of stress (p = 0.003) in the immediately after the interventional program, whereas the mean scores of depression were not decreased significantly (p = 0.3). Two months after the interventional program the mean scores of stress (p = 0.001) and anxiety (p = 0.001) were significantly decreased in the intervention group, but the mean score of depression was not decreased significantly (p = 0.09). CONCLUSION: The results suggested that a family centered intervention program reduced the stress, anxiety, and depression of caregivers because of feasibility, simplicity, and utility of intervention. This program was focused on psychological issues of caregivers, and an emphasis on their empowerment helped them in managing their problems in the caregiving situation and achieved greater psychological potency in the caring process. PMID- 30243110 TI - Altered attention networks and DMN in refractory epilepsy: A resting-state functional and causal connectivity study. AB - PURPOSE: Epilepsy is considered a disorder of neural networks. Patients diagnosed with refractory epilepsy frequently experience attention impairments. Seizure activity in epilepsy may disturb brain networks and damage the brain function of attention. The aims of this study were to assess functional and causal connectivities of the attention networks and default mode network using resting state functional magnetic resonance imaging (fMRI). METHOD: Resting-state fMRI data were gathered from 19 patients with refractory epilepsy (mixed localization and aetiologies) and 21 healthy people. The fMRI data were analyzed by group independent component analysis (ICA) fMRI toolbox to extract dorsal attention network (DAN), ventral attention network (VAN), and default mode network (DMN). The components of the selected networks were compared between patients and healthy controls to explore the change in functional connectivity (FC). Granger causality analysis was performed by taking the aforementioned significant brain areas as regions of interest (ROIs) to calculate autoregression coefficients of each pair of ROIs. Comparisons were done to find the significantly different causal connectivity when FC was changed between patients and healthy controls. RESULTS: In DAN, the FC values of the bilateral frontal eye field (FEF) and left intraparietal sulcus (IPS) were decreased. In VAN, the FC values of the double side ventral prefrontal cortex (vPFC) and the temporoparietal junction (TPJ) were reduced. As for DMN, the FC values of the bilateral medial prefrontal cortices (mPFC) were decreased whereas those for the bilateral precuneus (PCUN) were increased. Granger causal connectivity values were correlated: causal influence was decreased significantly from the left IPS (in DAN) to the double side of the vPFC but remained the same for the right FEF (in DAN) to the right TPJ. The value was decreased from the left PCUN (in DMN) to the right TPJ and FEF, and the causal flow from the right PCUN to the right TPJ and bilateral vPFC was also significantly inhibited (p < 0.05). CONCLUSION: Frequent seizures in patients with refractory epilepsy may damage the cortex and disturb DAN, VAN, and DMN, leading to functional and causal connectivity alteration. In addition, epileptic activity may disrupt network interactions and further influence information communication. PMID- 30243111 TI - Temporal lobe epilepsy affects spatial organization of entorhinal cortex connectivity. AB - Evidence for structural connectivity patterns within the medial temporal lobe derives primarily from postmortem histological studies. In humans and nonhuman primates, the parahippocampal gyrus (PHg) is subdivided into parahippocampal (PHc) and perirhinal (PRc) cortices, which receive input from distinct cortical networks. Likewise, their efferent projections to the entorhinal cortex (ERc) are distinct. The PHc projects primarily to the medial ERc (M-ERc). The PRc projects primarily to the lateral portion of the ERc (L-ERc). Both M-ERc and L-ERc, via the perforant pathway, project to the dentate gyrus and hippocampal (HC) subfields. Until recently, these neural circuits could not be visualized in vivo. Diffusion tensor imaging algorithms have been developed to segment gray matter structures based on probabilistic connectivity patterns. However, these algorithms have not yet been applied to investigate connectivity in the temporal lobe or changes in connectivity architecture related to disease processes. In this study, this segmentation procedure was used to classify ERc gray matter based on PRc, ERc, and HC connectivity patterns in 7 patients with temporal lobe epilepsy (TLE) without hippocampal sclerosis (mean age, 14.86 +/- 3.34 years) and 7 healthy controls (mean age, 23.86 +/- 2.97 years). Within samples paired t tests allowed for comparison of ERc connectivity between epileptogenic and contralateral hemispheres. In healthy controls, there were no significant within group differences in surface area, volume, or cluster number of ERc connectivity defined regions (CDR). Likewise, in line with histology results, ERc CDR in the control group were well-organized, uniform, and segregated via PRc/PHc afferent and HC efferent connections. Conversely, in TLE, there were significantly more PRc and HC CDR clusters in the epileptogenic than the contralateral hemisphere. The surface area of the PRc CDR was greater, and that of the HC CDRs was smaller, in the epileptogenic hemisphere as well. Further, there was no clear delineation between M-ERc and L-ERc connectivity with PRc, PHc or HC in TLE. These results suggest a breakdown of the spatial organization of PHg-ERc-HC connectivity in TLE. Whether this breakdown is the cause or result of epileptic activity remains an exciting research question. PMID- 30243112 TI - Altered neural synchronization to pure tone stimulation in patients with mesial temporal lobe epilepsy: An MEG study. AB - OBJECTIVE: Our previous study of monaural auditory evoked magnetic fields (AEFs) demonstrated that hippocampal sclerosis significantly modulated auditory processing in patients with mesial temporal lobe epilepsy (mTLE). However, the small sample size (n = 17) and focus on the M100 response were insufficient to elucidate the lateralization of the epileptic focus. Therefore, we increased the number of patients with mTLE (n = 39) to examine whether neural synchronization induced by monaural pure tone stimulation provides useful diagnostic information about epileptic foci in patients with unilateral mTLE. METHODS: Twenty-five patients with left mTLE, 14 patients with right mTLE, and 32 healthy controls (HCs) were recruited. Auditory stimuli of 500-Hz tone burst were monaurally presented to subjects. The AEF data were analyzed with source estimation of M100 responses in bilateral auditory cortices (ACs). Neural synchronization within ACs and between ACs was evaluated with phase-locking factor (PLF) and phase-locking value (PLV), respectively. Linear discriminant analysis was performed for diagnosis and lateralization of epileptic focus. RESULTS: The M100 amplitude revealed that patients with right mTLE exhibited smaller M100 amplitude than patients with left mTLE and HCs. Interestingly, PLF was able to differentiate the groups with mTLE, with decreased PLFs in the alpha band observed in patients with right mTLE compared with those (PLFs) in patients with left mTLE. Right hemispheric predominance was confirmed in both HCs and patients with left mTLE while patients with right mTLE showed a lack of right hemispheric predominance. Functional connectivity between bilateral ACs (PLV) was reduced in both patients with right and left mTLE compared with that of HCs. The accuracy of diagnosis and lateralization was 80%-90%. CONCLUSION: Auditory cortex subnormal function was more pronounced in patients with right mTLE compared with that in patients with left mTLE as well as HCs. Monaural AEFs can be used to reveal the pathophysiology of mTLE. Overall, our results indicate that altered neural synchronization may provide useful information about possible functional deterioration in patients with unilateral mTLE. PMID- 30243113 TI - Long-term administration of fatty acid amide hydrolase inhibitor (URB597) to rats with spontaneous hypertension disturbs liver redox balance and phospholipid metabolism. AB - PURPOSE: The effect of chronic administration of [3-(3-carbamoylphenyl)phenyl] N cyclohexylcarbamate (URB597), inhibitor of fatty acid amide hydrolase (FAAH) that hydrolyzes anandamide, on cross-talk between endocannabinoid system, oxidative status and pro-inflammatory factors in the liver of spontaneously hypertensive rats (SHRs) was investigated. MATERIALS/METHODS: Experiments were conducted using SHRs and normotensive control Wistar-Kyoto rats treated by intraperitoneal injection with URB597 for 14 days. The biochemical parameters were assayed in the rat's livers. RESULTS: In the liver of SHRs an increase in endocannabinoids level, the activity of enzymes degrading them and expression of the cannabinoid receptor type 2 (CB2) receptor as well as a decrease in the expression of the CB1 and vanilloid 1 receptor (TRPV1) were shown. These changes were related to inflammatory conditions as well as oxidative stress resulting from increased reactive oxygen species (ROS) generation due to enhanced activity of enzymes generating ROS accompanied by decrease in the effectiveness of transcription activity of nuclear factor erythroid 2 and the activity of antioxidant enzymes, as well as level of glutathione and vitamins. Chronic administration of URB597 to SHRs caused a decrease in FAAH activity and an increase in anandamide and N arachidonoyl-dopamine level as well as a decrease in CB2 and an increase in TRPV1 receptor expression. The levels/activities of pro- and antioxidant and inflammatory factors tended to normalize, but phospholipid peroxidation and DNA modifications were increased. CONCLUSION: In conclusion, long-term chronic administration of URB597 to SHRs by altering interactions between endocannabinoid and redox systems enhances some liver metabolic disturbances observed in hypertension. PMID- 30243114 TI - Analysis of lipoprotein-specific lipids in patients with acute coronary syndrome by asymmetrical flow field-flow fractionation and nanoflow liquid chromatography tandem mass spectrometry. AB - A comprehensive lipid analysis was performed at the plasma lipoprotein level in patients with acute coronary syndrome (ACS) and stable coronary artery disease (CAD). Because the lipids in lipoproteins are related to the pathology of the cardiovascular system, lipoprotein-specific lipid analysis can be useful for understanding the mechanism of lipid-associated cardiovascular diseases. Lipoproteins were size-sorted into high density lipoproteins (HDL) and low density lipoproteins (LDL) using asymmetrical flow field-flow fractionation, then lipids of each lipoprotein were analysed using nanoflow ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry. A total of 365 lipids were structurally identified and quantified by selected reaction monitoring method. Two high abundance lysophosphatidylcholines (16:0 and 18:0) were significantly increased only in the HDL of the ACS group (vs. the stable CAD group). Phosphatidylethanolamines (38:5 and 40:5) significantly increased in ACS by >2-fold in both lipoproteins. (18:0, 22:6)-diacylglycerol increased in ACS by 3.5-fold only in LDL; however, most high abundance triacylglycerols decreased 2 fold in both lipoproteins. The present study revealed the usefulness of lipoprotein-specific analysis of lipids in distinguishing ACS from stable CAD, and the selected lipids analysed in this study may be useful in the development of lipid markers for the early detection of ACS. PMID- 30243115 TI - Determination of polybrominated diphenyl ethers and novel brominated flame retardants in human serum by gas chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry. AB - The accurate detection of brominated flame retardants (BFRs) in humans is an area of high scientific interest and regulatory need due to their potential toxicity. The instrumental analysis of BFRs was commonly performed on gas chromatography mass spectrometry (GC-MS) operating in electron ionization (EI) or negative chemical ionization (NCI) modes. However, soft ionization techniques, such as atmospheric pressure chemical ionization (APCI), may be more suitable for the analysis of BFRs because the BFRs show high fragmentation in EI and low selectivity in NCI. Additionally, accurate quantifications of BFRs in complex matrices is challenging due to their low concentrations and therefore, a highly sensitive technique is desperately needed. In this study, a new methodology based on gas chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (GC-APCI-MS/MS) analysis was developed for the determination of thirteen BFRs (eight usually monitored polybrominated diphenyl ethers (PBDEs) congeners and five additional novel BFRs) in human serum. The primary task was to evaluate the potential of the GC-APCI-MS/MS technique for the trace analysis of BFRs in human serum. The results of the spiked recovery test using fetal bovine serum showed that mean recoveries of the analytes ranged from 83.4% to 118% with reduced swing differential signaling (RSDs) of <=21.1%. The methodological limits of detection (mLOD) of the analytes ranged from 0.04 to 30 pg/mL, and these values were at least one order of magnitude lower than those estimated by the authors in a previous study using GC-NCI-MS or GC-EI-MS/MS, indicating that GC APCI-MS/MS is more sensitive. Specially, compared to GC-NCI-MS and GC-EI-MS/MS, when GC-APCI-MS/MS was used for the detection of highly brominated BFRs, such as BDE-209 and decabromodiphenyl ethane (DBDPE), a notable improvement in sensitivity and reliability was obtained using a deactivated capillary column connected to the analytical column as the transfer line and maintaining a high temperature to improve the chromatographic behaviors. The developed methodology was successfully used for the analysis of BFRs in human serum collected from residents living in a BFR production area and Beijing. PMID- 30243116 TI - A fast and accurate way to determine short chain fatty acids in mouse feces based on GC-MS. AB - Short-chain fatty acids (SCFAs) in the gut are mainly produced by the anaerobic microbial fermentation of unabsorbed dietary carbohydrates in the large bowel. Quantitative determinations of SCFAs in feces and colonic contents are necessary when studying the impact of fiber-rich food (such as fruits and vegetables) on health. We made the following crucial improvements to the method currently widely used: optimized the lyophilization period from 12 h to 3.5 h; disposed of the procedure for precise weight control; lowered the extraction temperature from 25 degrees C to 4 degrees C; shortened the extraction time from 45 min to 15 min; and significantly improved the extraction efficiency of acetic acid, propionic acid and butyric acid by 12.91%, 19.95% and 13.08%, respectively. Furthermore, to evaluate the applicability of this novel approach, we applied our method to determine the SCFAs in the feces and colonic contents of mice fed on different diets, and observed distinct results. PMID- 30243117 TI - Effects of dual tasking and methylphenidate on gait in children with attention deficit hyperactivity disorder. AB - Effects of dual tasking on motor processes such as gait have been mainly investigated with healthy adults and clinical older samples whereas studies with clinical samples of children with attention deficit hyperactivity disorder (ADHD) are rare. Similarly, even though methylphenidate (MPH) is the most often prescribed medication for children with ADHD, the influence of MPH on children's gait under single-task and dual-task situations remains poorly understood. In the current study, children diagnosed with ADHD (n = 26) came twice to the laboratory, once without and once with MPH medication. They were asked to walk over an electronic walkway without a concurrent task (motor single task) and while solving different cognitive tasks (motor-cognitive dual task). Gait variability and cognitive performance were measured. Children's performance was compared to an age- and sex-matched control sample of typically developing children (n = 26) who were also tested twice. Results indicated considerable effects of dual tasking on children's gait irrespective of group (ADHD vs. controls), with children diagnosed with ADHD showing more pronounced gait alterations in dual-task situations as compared to controls. Furthermore, MPH medication in children with ADHD enabled them to substantially decrease their stride time variability to a level that was comparable to the level of typically developing children. Overall, our findings support the notion that higher cognitive processes such as attention and executive functions influence gait and that MPH can positively affect cognitive and motor processes such as gait. PMID- 30243118 TI - Equilibrium studies of new bis-hydroxypyrone derivatives with Fe3+, Al3+, Cu2+ and Zn2. AB - This paper presents an easy and low cost synthesis of chelating agents for potential medical and environmental applications, and the evaluation of the stability of their complexes with Fe3+, Al3+, Cu2+ and Zn2+. In the last years, we synthesized and characterized effective iron chelators based on two kojic acid units joined by different linkers in position 6. In this study, we preserved kojic acid (a cheap and non-toxic molecule) as the basic unit but joined the two kojic acid units through ethylene diamine, propylene diamine and butylene diamine by reacting them with the OH groups in position 2. The different anchoring position of the linker, as well as the linker length, can affect both protonation and complex formation equilibria. A thorough study of the protonation and complex formation equilibria of the three ligands toward the metal ions is presented based on combined potentiometric and spectroscopic studies, and 1H NMR. The obtained results allow remarking that the orientation of the oxygen atoms in the kojic acid units, related to the anchoring position of the linker, strongly affects the protonation constants, while the chelating ability is practically unaffected. The trivalent metal ions form stable complexes with a 2:3 metal to ligand stoichiometry through the oxygen donor atoms of the ligands, whereas divalent metal ions form binuclear complexes for which the nitrogen atoms from the linker might be involved in the coordination sphere. The stability of the complexes decreases with linker length, and the selectivity of the ligands toward metal ions grows in the order Zn2+ < Cu2+ < Al3+ < Fe3+. PMID- 30243119 TI - Study on the oxidation of fibrinogen using Fe3O4 magnetic nanoparticles and its influence to the formation of fibrin. AB - Oxidative stress accompanies various diseases associated with chronic inflammation. In this work, H2O2 and H2O2-Fe3O4 magnetic nanoparticles were used as two reactive oxygen species to study the oxidative stress for the structure and polymerization behaviour of fibrinogen molecules. The alterations of secondary structure and component of fibrinogen molecule were characterized by circular dichroism spectra, ultraviolet-visible spectra and fluorescence spectra, the viscoelasticity of fibrinogen solution was studied by dynamic light scattering microrheology. Based on the molecular dynamics simulations and fluorescence properties, the possible oxidative stress sites were analyzed and confirmed by Tb3+ probe. The hydrophobicity/philicity and electrostatic net charges present on the exterior part of the fibrinogen molecules were measured with zeta potential. The height and image analysis obtained from atomic force microscope indicated that oxidative stress of fibrinogen molecules could influence the equilateral junctions of protofibrils and the different cross linking patterns between the alpha- and gamma-chains, result in the decrease of the fibre size, form a higher proportion of branching and a denser aggregation state. This study will provide insights into the misfolding and fibril formation of disease-associated fibrinogen, facilitate an increased understanding of how oxidative stress in vivo affects the formation and polymerization of fibrin, and support efforts for the improved treatment of patients suffering from the thrombotic disease. PMID- 30243121 TI - High-order self-assembly of G-quadruplex DNA: Nano-network formation under the guidance of arene ruthenium(II) complexes. PMID- 30243120 TI - Copper(II) complexes with Fusobacterium nucleatum adhesin FadA: Coordination pattern, physicochemical properties and reactivity. AB - Fusobacterium nucleatum is an anaerobic, Gram-negative bacteria linked to colon cancer. It is interesting to determine how metal ions interact with bacterial adhesin proteins. To this end, the coordination of ATDAAS-NH2 and MKKFL-NH2 fragments of Fusobacterium adhesin A (FadA) to copper(II) ions was studied by potentiometry, spectroscopic techniques (UV-Vis, CD, EPR and NMR) and the density functional theory (DFT) methods. At pH 6.8 (colon physiological pH), the metal ion in the first peptide (ATDAAS-NH2) is coordinated by one oxygen and three nitrogen donors while in the second one (MKKFL-NH2) - by sulfur and three nitrogen atoms. Both complexes form two five- and one six-membered stable chelate rings. Moreover, reactivity studies confirmed the production of reactive oxygen species such as hydroxyl radical, superoxide anion radical and singlet oxygen. Generation of reactive oxygen species (ROS) was observed during gel electrophoresis and spectroscopic assays with reporting molecules like NDMA (N,N dimethyl-p-nitrosoaniline) and NBT (Nitrotetrazolium Blue Chloride). All reactions were conducted in the presence of hydrogen peroxide as endogenous oxidant. PMID- 30243122 TI - New monofunctional platinum(II) and palladium(II) complexes: Studies of the nucleophilic substitution reactions, DNA/BSA interaction, and cytotoxic activity. AB - Four new complexes [Pd(H2LtBu)Cl]Cl (Pd1), [Pt(H2LtBu)Cl]Cl (Pt1), [Pd(Me2LtBu)Cl]Cl (Pd2) and [Pt(Me2LtBu)Cl]Cl (Pt2) (where H2LtBu = 2,6-bis(5 (tert-butyl)-1H-pyrazol-3-yl)pyridine and Me2LtBu = 2,6-bis(5-(tert-butyl)-1 methyl-1H-pyrazol-3-yl)pyridine) were synthesized and characterized by elemental microanalysis, IR, 1H NMR and ESI-MS methods. The reactivity of complexes towards thiourea (Tu), l-methionine (l-Met), l-cysteine (l-Cys) and guanosine-5' monophosphate (5'-GMP) was investigated. The obtained order was established as follows: Tu > l-Cys > l-Met > 5'-GMP. Complexes Pd1 and Pt1, that contain H2LtBu as chelator, showed higher reactivity towards biomolecules than those with Me2LtBu. The interaction of complexes with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) was studied by UV-Vis and fluorescence spectroscopy. The results have shown that complexes can bind to DNA exhibiting high binding constants (Kb = 104 M-1). Obtained results during the examination of competitive reaction with ethidium bromide (EB) showed that complexes can replace EB-bound DNA. High values of binding constants indicate good binding affinity of complexes towards BSA. We evaluated the stability differences between complexes based on terpy as well as H2LtBu/Me2LtBu by DFT calculations (B3LYP(CPCM)/LANL2DZp), showing that both tridentate ligand systems lead to complexes of similar stability. The results of biological testing showed that all complexes exert moderate to high selective cytotoxicity, inducing apoptosis and autophagy in HeLa and PANC-1 tumor cell lines. Pd1 exhibited the strongest cytotoxic effect. Finally, cell cycle analysis showed that in HeLa cells Pd1, Pd2 and Pt1 induced accumulation of cells in S phase, whereas in PANC-1 cells Pd2 and Pt1 induced G2/M cycle arrest and Pd1 induced G0/G1 arrest. PMID- 30243123 TI - Prosthesis use is associated with reduced physical self-disgust in limb amputees. AB - Self-disgust is an emotion schema negatively affecting people's body image and is triggered by bodily imperfections and deviations from the "normal" body envelope. In this study, we explore the idea that "normalising" the body in those with limb amputations via the prosthesis would be linked to reduced self-directed disgust. An international clinical community sample (N = 83) with mostly lower limb amputations completed measures about their demographics, prosthesis, adjustment, body image disturbance, psychological distress, and self-directed disgust in a survey design. Consistent with the "normalising" hypothesis, correlation and bootstrapped regression models revealed, first, that frequency of prosthesis use was significantly and negatively associated with physical self-disgust. Second, prosthesis use significantly mediated the exogenous effect of time since amputation on physical self-disgust. These results emphasise the psychological value of the prosthesis beyond its functional use, and stress its importance in normalising the body envelope in those with limb amputations, which may in turn promote psychological well-being. PMID- 30243124 TI - The effects of viewing thin, sexualized selfies on Instagram: Investigating the role of image source and awareness of photo editing practices. AB - This experiment examined how features of images shared on social media sites, such as Instagram, impact and are evaluated by young adult female users. Specifically, we examined conditions under which female viewers (N = 360, Mage = 20.34, SD = 2.74) were more or less likely to internalize the thin ideal after viewing other women's selfies (i.e., images taken of oneself by oneself) posted on Instagram that depicted the thin ideal. We also examined how female viewers evaluated women who posted these selfies. Results indicated that the more female viewers believed that the women digitally modified or altered their selfies, the less likely viewers were to internalize the thin ideal. In addition, the more female viewers believed the women digitally modified their selfies and the more they believed the women were their offline peers (vs. models), the more negatively (e.g., less intelligent, less honest) they evaluated the women. Explanations for why awareness of photo modification and different image sources (peers vs. models) influence evaluations of selfies are discussed. PMID- 30243125 TI - Age-related differences in information processing during movie watching. AB - We know how age affects the brain during lab-based tasks, but what about situations truer to everyday life, such as watching movies? We measured functional magnetic resonance imaging activity while participants (N = 577) from the Cambridge Centre for Ageing and Neuroscience (www.cam-can.com) watched a movie. Watching the same movie induces significant intersubject synchronization of brain activity across participants. These cross-subject correlations suggest that viewers are processing incoming information in a similar (or shared) way. We show that with advancing age, synchrony is preserved in some areas, including the language network, but decreased in others, including the medial prefrontal cortex, medial temporal lobe, and fronto-parietal network. Synchrony declines were driven by more idiosyncratic responding in older adults and were associated with regionally distinct temporal profiles and functional connectivity patterns, as well as declines in white matter integrity. These findings suggest that areas involved in language processing remain intact with age, while regions involved in attentional control and memory may show age-related declines, even in situations similar to daily life. PMID- 30243126 TI - Prevalence of non-psychotic disorders in ultra-high risk individuals and transition to psychosis: A systematic review. AB - Despite the growing interest in the prodromes of psychosis, the proper identification of those Ultra High Risk (UHR) subjects who will convert to psychosis remains an unresolved issue. It remains to be fully understood whether the risk of transition to psychosis is incremented by the concomitant presence of non-psychotic symptoms. We performed a systematic review in order to estimate: prevalence rates of non-psychotic disorders in UHR individuals and whether any comorbid disorder impacts on the risk of transition to frank psychosis. The review was conducted using the PRISMA guidelines by searching PubMed until August 2017. The inclusion criteria were: studies with appropriate definition of UHR/ ARMS (At Risk Mental States for psychosis); cross-sectional design (for prevalence rates) or longitudinal design (for transition rates to psychosis); adolescents and/or adults; specified instrument/interview for the diagnosis of mental disorder/symptoms. We included 46 English-language articles. We found that non-psychotic symptoms are a prevalent concern in UHR individuals, and this is true for all comorbid disorders examined. None of the mental disorder examined appear to be a marker for transition to psychosis. Our systematic review found that the great majority of UHR individuals actually has a highly prevalent clearly defined, above-the-threshold mental disorder that should constitute the primary focus of intervention. PMID- 30243127 TI - Social cognition and short-term prediction of suicidal ideation in schizophrenia. AB - Despite recent research acknowledging social cognition as an important feature of interpersonal functioning in schizophrenia, little work has evaluated the role of social cognition in suicidal ideation and behavior in psychosis. In a short-term longitudinal study, we evaluated the association between concurrent and near term suicidal ideation with social cognition, including emotion recognition and related biases (ER-40; BLERT), attribution biases (AIHQ), and evaluations of trustworthiness (trustworthiness task) in a sample of 179 outpatients with schizophrenia or schizoaffective disorder. Adjusting for severity of positive and general mental health symptoms, greater reactivity to extreme stimuli (trustworthiness measure), BLERT negative affect accuracy, and AIHQ Blame Scores were associated with suicidal ideation at baseline. AIHQ Blame Scores also longitudinally predicted the presence of ideation 2 weeks later and were highest among participants with ideation across the two time points. The present findings provide support that biased interpretations, and, concurrently with ideation, reactivity and selective accuracy to negative stimuli, are associated with suicidal ideation in schizophrenia. Further understanding the role of social cognitive ability and biases on suicidal ideation could contribute to the understanding of social cognition as a treatment target in prevention of suicidal behavior in schizophrenia. PMID- 30243128 TI - Social desirability, deceptive reporting, and awareness of problematic aggression in intermittent explosive disorder compared with non-aggressive healthy and psychiatric controls. AB - Individuals with DSM-5 Intermittent Explosive Disorder (IED) are often suspected of minimizing the nature of their recurrent, problematic, impulsive aggressive behavior due to the social undesirability of these behaviors. Our first study involved 400 study participants categorized as Healthy Controls (HC), Psychiatric Controls (PC) and as having IED and included the Crowne-Marlowe Social Desirability Scale (SDS), the Lie Scale from the Eysenck Personality Questionnaire-Revised (EPQ-R Lie), and the Readiness to Change (Anger) Questionnaire (RTC). IED study participants had lower SDS and lower EPQ-R Lie scores, while having higher RTC scores, compared with both HC and PC study participants. Thus, when studied in a clinical research setting, IED study participants do not provide socially desirable answers to questions and do not engaging in deceptive reporting; likely because they have recognized their need/interest in reducing their own impulsive aggressive behavior. The second study, part of a family study of 70 probands and their first-degree relatives revealed a very high positive (96.3%), but substantially lower negative (55.8%), predictive power for IED based on informant report. This suggests that, while interview of close informants can confirm the diagnosis of IED, informant interviews cannot rule out IED when such informants provide a negative report. PMID- 30243129 TI - Associations between negative life events and anxiety, depressive, and stress symptoms: A cross-sectional study among Chinese male senior college students. AB - The aims of this study were to explore the associations between negative life events and anxiety, depressive, and stress symptoms among male senior college students who experience negative life events in daily life. Data were obtained from 582 male senior college students recruited from universities in Chongqing China. Participants completed the Adolescent Self-rating Life Events Checklist (ASLEC), and the Depression, Anxiety, and Stress Scale-21 (DASS-21). Socio demographic information, lifestyle information, and a blood sample were acquired. 39 (6.7%), 74 (12.7%), and 39 (6.7%) subjects were depressed, anxious, and stressed, respectively. The results confirmed that negative life events were positively related to mental health problems. Different types of negative life events had their specific associations with being depressed, anxious, or stressed. With respect to different types of negative life events, subjects with more "interpersonal relationship" related problems had a higher probability of being anxious and stressed; whereas, subjects with more "change for adaptation" related problems had a higher probability of being depressed and anxious. These results indicate that more concerns over the events with both high occurrence rate and severity might be helpful to mental health prevention and promotion for senior college students. PMID- 30243130 TI - A randomized trial of low-dose gabapentin for post hospitalization relapse prevention in a Thai clinical sample of alcohol dependence. AB - Pharmacological treatments for alcohol use disorder show a modest effect, and they are unavailable in certain countries. The study's aim is to investigate the effects of gabapentin on alcohol drinking. One hundred twelve Thai individuals with alcohol dependence and very high alcohol consumption were randomly assigned to either of two groups: gabapentin treatment or placebo. Oral treatment with at least 300 mg of gabapentin per day or placebo was administered once a day for twelve weeks. The alcohol drinking pattern was assessed by means of the timeline followback method. The drinking behaviours of the two groups were compared by means of the Poisson repeated measures model and Generalized Estimating Equations (GEE) analysis. Twenty subjects (35.7%) from the gabapentin group and 14 subjects (25.0%) from the placebo group completed the study protocol. The participants in the gabapentin group did not differ from those in the placebo group with respect to demographics or baseline alcohol drinking behaviour. After follow-up, the gabapentin group showed a lower percentage of heavy drinking days per week than the placebo group (p < 0.005). GEE analysis showed treatment by time interaction on lowering drinking days within a week (p < 0.05). In conclusion, gabapentin may be used to reduce alcohol-drinking behaviours. PMID- 30243131 TI - Leukocyte telomere length in patients with bipolar disorder: An updated meta analysis and subgroup analysis by mood status. AB - The purpose of the present meta-analysis was to compare leukocyte telomere length (LTL), a proposed marker for cell aging, between patients with bipolar disorder (BD) and healthy controls and explore potential moderators for the LTL difference. We searched for the major research databases up to May 2018 for studies that examined LTL in patients with BD and healthy controls. The effect sizes (ESs) of LTL differences from the included studies were pooled using a random-effects model. Furthermore, we adopted subgroup analysis to investigate whether mood status of BD patients or methods for measuring telomere length may influence such differences. We included 10 studies, with a total of 579 patients and 551 controls, in the current meta-analysis and observed significantly shorter LTL in BD patients compared to control subjects. Such differences were found in studies with patients in all mood statuses and in studies using different methods for measuring telomere length. Late-stage BD patients demonstrated more significant LTL shortening than early-stage BD patients. Our current results support the hypothesis of accelerated aging in BD patients. In the future, further properly controlled longitudinal studies are warranted to determine whether LTL changes with disease status or medication use in BD patients. PMID- 30243132 TI - Validity and clinical utility of DSM and prototype diagnosis for depressive and anxiety spectrum disorders in predicting adaptive functioning. AB - Prototype matching, which involves comparing a patient clinical presentation with a prototype description of the disorder, addresses some of the clinical limitations of categorical approaches. Most research to-date on prototype matching has been conducted with personality disorders. Here, we examined the validity and clinical utility of prototype diagnosis for mood and anxiety disorders. We compared clinicians prototype diagnosis (based on DSM IV and empirically derived) to categorical diagnosis (based on independent SCID interview) in predicting patient global adaptive functioning rated across the clinician, patient and independent interviewer among N = 80 clinicians and N = 170 patients. Our findings show that prototype diagnosis (both one that is based on DSM criteria and empirically derived) demonstrates some incremental validity over and above the categorical DSM IV, in predicting patient's global adaptive functioning. This is particularly pronounced for mood disorders (MDD and dysthymia) as well as several anxiety disorders (OCD, social phobia) across a range of experience level of diagnosticians. Furthermore, clinicians rated the prototype matching approach as more useful in clinical practice compared with the binary categorical system. Using a dimensional approach, which is based on prototype matching that also preserves the advantages of categorical system offers a valid and efficient approach to psychiatric assessment. PMID- 30243134 TI - Challenging "privileged" stereotypes - Leukemic blasts and the central nervous system. PMID- 30243133 TI - Relationship between schizophrenia and changes in the expression of the long non coding RNAs Meg3, Miat, Neat1 and Neat2. AB - Schizophrenia (SZ) is a complex disease caused by multiple factors. The development of the disease is mediated by a number of neural growth and development factors, suggesting that extensive changes in nerve structure and abnormal expression of genes in some important signalling pathways occur. Based on accumulating evidence, long non-coding RNAs (lncRNAs) play a crucial role in regulating neural diseases, including SZ. In the current study, we used mouse models of methamphetamine (METH) - and MK801-induced SZ to investigate changes in the expression of four lncRNAs (Meg3, Miat, Neat1 and Neat2) in the prefrontal cortex (PFC). Miat and Neat2 expression was significantly decreased in the PFC of the SZ model mice, regardless of whether the disease was induced by MK801 or METH. We further measured the levels of these lncRNAs in the peripheral blood (PB) collected from treated and untreated patients with SZ and from healthy controls. Neat1 and Neat2 levels were significantly decreased in the PB of untreated patients with SZ, but the trends in the expression of these lncRNAs nearly reached a normal level in treated patients with SZ. In conclusion, Neat2 and Miat may function as important regulators of SZ. Our findings provide important clues for new targets of lncRNAs that are involved in SZ. PMID- 30243135 TI - Automated concentration of [18F]fluoride into microliter volumes. AB - Concentration of [18F]fluoride has been mentioned in literature, however, reports have lacked details about system designs, operation, and performance. Here, we describe in detail a compact, fast, fully-automated concentration system based on a micro-sized strong anion exchange cartridge. The concentration of radionuclides enables scaled-up microfluidic synthesis. Our system can also be used to provide highly concentrated [18F]fluoride with minimal water content. We demonstrate how the concentrator can produce varying concentrations of [18F]fluoride for the macroscale synthesis of N-boc-5-[18F]fluoroindole without an azeotropic drying process, while enabling high starting radioactivity. By appropriate choice of solid-phase resin, flow conditions, and eluent solution, we believe this approach can be extended beyond [18F]fluoride to other radionuclides. PMID- 30243136 TI - Hyaluronic acid-induced capacitation involves protein kinase C and tyrosine kinase activity modulation with a lower oxidative metabolism in cryopreserved bull sperm. AB - Hyaluronic acid is a glycosaminoglycan present in uterine and oviductal fluids in female ruminants, which has been used as a sperm capacitation inducer prior to in vitro fertilization in several species. CD44 is a specific hyaluronic acid receptor, present in the sperm plasma membrane, but its signaling transduction system has not been elucidated yet. Our aim was to study protein kinase C and tyrosine kinase participation in intracellular signaling and oxidative metabolism in hyaluronic acid-induced capacitation of cryopreserved bull spermatozoa. Sperm capacitation was induced with hyaluronic acid or heparin. GF-109203* and genistein were used as protein kinase C and tyrosine kinase inhibitors, respectively. Capacitation, sperm plasma membrane and acrosome integrity were studied using CTC and trypan blue - DIC, while variations in enzymatic activities were determined by spectrophotometry. The inhibition of protein kinase C and tyrosine kinase blocked hyaluronic acid and heparin induced capacitation. Metabolic enzymes such as NADP-dependent isocitrate and malate dehydrogenases participate in hyaluronic acid capacitation, in coincidence with a lower mitochondrial metabolism compared with heparin. On the other hand, NAD-dependent isocitrate and malate dehydrogenase were not modified by hyaluronic acid induction. These dehydrogenases were also modulated by protein kinase C and tyrosine kinase in the capacitation induced by heparin or hyaluronic acid. In conclusion, hyaluronic acid intracellular signal system involves protein kinase C and tyrosine kinase activities, which may modulate capacitation in cryopreserved bull sperm with a lower oxidative metabolism than heparin. PMID- 30243137 TI - The influence of experimentally induced endometritis on the PPAR expression profile in the bovine endometrium. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear receptor superfamily. The PPARs activity can be modified e.g. by arachidonic acid metabolites. Escherichia coli (E. coli) is one of the main infectious agent of endometritis in dairy cows. We hypothesized that PPAR expression profile change in the bovine endometrium under the influence of LPS or E. coli. In experiment 1, endometrial explants were obtained post mortem from heifers and incubated without (control) or with LPS for 12, 24, 48, 72 and 96 h. In experiment 2, heifers were intrauterine infused with 0.9% NaCl (control) or with E. coli suspension in 0.9% NaCl. Endometrial biopsies were performed before (0 h) and 12, 24, 48, 72, 96 h after the infusions. In experiment 1, the increase in protein expression was observed for PPARalpha 48 h, for PPARbeta/delta 24, 72 and 96 h, whereas for PPARgamma 12, 24 and 96 h after LPS treatment relative to the control groups. In experiment 2, the up-regulation in protein expression was observed for PPARalpha 48 and 72 h, for PPARbeta/delta 72 and 96 h, for PPARgamma1 and PPARgamma2 12 and 96 h after the intrauterine infusion with E. coli suspension compared to the control group. Changes in mRNA and protein PPAR expression profile in endometrial explants under the exposure of LPS indicate participation of these nuclear receptors in signal transduction during stimulation with LPS. The patterns of mRNA and protein PPAR expression in endometrial bioptates suggest that during experimentally induced endometritis in vivo, PPARs role may be connected both with enhancement of inflammation as well restoring physiological conditions in uterus. PMID- 30243138 TI - A new chicken molecular sexing assay based on the Z chromosome dose and the MHM region. AB - Birds have a ZZ and ZW sex chromosome system (male and female, respectively). On the short arm of the Z chromosome of Gallus gallus domesticus there is a repetitive region called MHM region, which is absent on the W chromosome, that causes a natural copy number difference of the MHM region between the sexes, making possible the development of a quantitative PCR (qPCR) sexing assay, based on the Z chromosome double dose. Twenty-seven samples of tissues from eight adult Gallus gallus domesticus (four males and four females) were used to establish the parameters of the MHM copy-number sexing assay. We blinded sexed 20 chicks using 140 samples from different tissues (heart, brain, gonad, kidney, lung, muscle, and blood). The success rate of the assay was 100% (140/140). It required small amounts of DNA (0.39 ng), opening the perspective to the use of the assay in studies in which the amount of available DNA is limited. PMID- 30243139 TI - Dietary quercetin maintains the semen quality in rabbits under summer heat stress. AB - This study focused to determine beneficial impact of feeding quercetin supplemented diet on semen quality in summer heat imposed rabbits. Twelve heat stressed (HS) adult rabbits bucks were either fed with basal diet (HS; n = 06) or quercetin supplemented diet (QU-HS; n = 06) for a period of 56 days. Semen samples were collected and evaluated for volume, osmolality, morphology, concentration, motility, motion kinetics, viability, acrosome integrity, mitochondrial potential, and seminal plasma MDA level. Semen volume, concentration, motility and sperm kinetics parameters were affected by diet supplementation. Diet affected the sperm mitochondrial potential and day of treatment affected the viable sperm percentage. There was an effect of diet, day of treatment and diet by day interaction on acrosome reaction rate. Sperm head abnormalities were influenced by diet provision, sperm mid-piece abnormalities were affected by diet and day of treatment, whereas, the effect of diet and diet by day of treatment interaction were observed for total sperm abnormalities. There was an effect of diet and diet by day interaction for seminal plasma MDA level. In conclusions, quercetin reduces the damaging effects of HS and maintains the semen quality by lowering the oxidative stress in rabbits. PMID- 30243140 TI - Identification and differential expression of microRNAs in the testis of chicken with high and low sperm motility. AB - Sperm motility is one of the most important indicators for evaluating roosters' fecundity. However, molecular regulation underlying chickens' sperm motility remains to be understood. MicroRNA (miRNA) plays an epigenetic role in reproduction. In this study, we compared the testicular miRNAs of Beijing-you roosters with high (HS) and low (LS) sperm motility using Illumina sequencing to try to understand the associated molecular regulation. Length distribution analysis showed that the dominant size of small RNAs detected in the testes of the chicken samples was 24-28 nt. In total, 518 known and 106 novel miRNAs were identified. A total of 23 miRNAs were found differentially expressed (P < 0.05, |log2fold change| >= 1) between the HS and LS groups, including 18 known and 5 novel miRNAs. Functional enrichment of the predicted target genes of the differentially expressed miRNAs indicated that these miRNAs were involved in the pathways of GnRH, MAPK and Wnt signaling. The miRNA-gene interaction network revealed two key candidate miRNA-gene pairs that might affect chicken sperm motility, viz, gga-miR-155/KCNA1 and gga-miR-7480-5p/AHI1. qPCR was then used to further validate their expressions. The results here provided a deep insight into the expressions of the miRNAs in the testes of chickens and suggested their roles in sperm motility regulation. PMID- 30243141 TI - Sudden unexpected death with primary adrenal lymphoma. AB - An 82-year-old man was found dead on the road near his home with unwitnessed interval of 3 h from final witness. He had been diagnosed with hypertension and mild aortic stenosis (AS) 13 years before death, and was continuously followed up with medication. Although a recent medical check-up related to cardiac function was stable and consistent with moderate AS, he sometimes complained of general fatigue, anorexia associated with intermittent mild fever and rare vomiting in the weeks before death. At autopsy, no lethal injury or drug intoxication was found, but congenital bicuspid aortic valve (BAV) with central rache was found. Although calcification was found in a restricted area of one cusp, valvular structural deformity was clearly milder than in typical severe AS cases. Moderate left ventricular hypertrophy without coronary disease was found. A brownish-red, soft nodular lesion was found in both adrenal glands, but no other tumorous focus was evident in any other organs. Immunohistochemical examination showed that B lymphocyte-derived markers (CD20, melanoma associated antigen (mutated) 1, and CD79a) were exclusively positive. Therefore, we diagnosed primary adrenal lymphoma (PAL), diffuse large B-cell lymphoma phenotype. We concluded that the cause of sudden unexpected death (SUD) was adrenal insufficiency associated with PAL, with a background of moderate AS related to BAV. PMID- 30243142 TI - Hepatitis C virus prevalence and estimated incidence among new injectors during the opioid epidemic in New York City, 2000-2017: Protective effects of non injecting drug use. AB - OBJECTIVE: Assess hepatitis C virus (HCV) prevalence and incidence among person who began injecting drugs during the opioid epidemic in New York City (NYC) and identify possible new directions for reducing HCV infection among persons who inject drugs. METHODS: 846 persons who began injecting drugs between 2000 and 2017 were recruited from persons entering Mount Sinai Beth Israel substance use treatment programs. A structured interview was administered and HCV antibody testing conducted. Protective effects of non-injecting drug use were examined among persons who "reversed transitioned" to non-injecting drug use and persons who used non-injected heroin in addition to injecting. RESULTS: Participants were 79% male, 41% White, 15% African-American, 40% Latinx, with a mean age of 35. Of those who began injecting in 2000 or later, 97 persons (11%) "reverse transitioned" back to non-injecting drug use. Reverse transitioning was strongly associated with lower HCV seroprevalence (30% versus 47% among those who continued injecting, p < 0.005). Among those who continued injecting, HCV seropositivity was inversely associated with current non-injecting heroin use (AOR = 0.72, 95%CI 0.52-0.99). HCV incidence among persons continuing to inject was estimated as 13/100 person-years. HCV seropositive persons currently injecting cocaine were particularly likely to report behavior likely to transmit HCV. CONCLUSIONS: Similar to other locations in the US, NYC is experiencing high rates of HCV infection among persons who have begun injecting since 2000. New interventions that facilitate substitution of non-injecting for injecting drug use and that reduce transmission behavior among HCV seropositives may provide additional methods for reducing HCV transmission. PMID- 30243143 TI - Polydrug use among heroin users in Cleveland, OH. AB - BACKGROUND: Since 2000, heroin use patterns have shifted within the United States. How this change may relate to polydrug use among local heroin users is unknown. Although polydrug use has been studied, user perceptions of drug use in terms of health risks, arrest risk, availability, cost, liking, and dependence have not been considered. METHODS: Data are presented from a brief, face-to-face survey conducted in 2016 of 200 non-in-treatment heroin users from Cleveland, OH. We assessed the use of and attitudes on alcohol, marijuana, methamphetamine, heroin, crack cocaine, powder cocaine, and prescription drugs. We estimated polydrug (concurrent past month) use with cluster analysis and latent profiles. Regression analysis estimated the strength of relationships between attitudes and frequency of use. RESULTS: We identified five clusters: Cluster 1 used heroin concomitantly with alcohol and occasionally crack; Cluster 2 used heroin and crack cocaine daily; Cluster 3 used heroin daily and almost exclusively; Cluster 4 used heroin and marijuana daily; and Cluster 5 were part-time drug users. Drug use frequency was associated with liking and being anxious when drugs could not be obtained. High perceived availability of heroin and cocaine and low cost facilitated polydrug use. CONCLUSIONS: Understanding polydrug use clusters among heroin users is important for addressing the larger opioid epidemic. Users' perceptions of a drug's availability and cost appeared to facilitate polydrug use and justify more detailed future research on drug access. PMID- 30243144 TI - Patterns and correlates of purchasing cigarettes on Indian reservations among daily smokers in the United States. AB - INTRODUCTION: We described the population of daily smokers purchasing cigarettes on Indian reservations (IRs), estimated the rates of cigarette purchasing on IRs for diverse populations of daily smokers in the U.S., and assessed the trends in the period from 2010-11 to 2014-15. METHODS: We used the 2010-11 and 2014-15 Tobacco Use Supplement to the Current Population Survey data for adult daily smokers as well as additional information, e.g., state excise tax on tobacco (n = 33,871). RESULTS: Daily smokers who purchased cigarettes on IRs were primarily 45+ years old, non-Hispanic (NH) White, resided in a state with an IR, paid less than $4.50 per pack, and purchased cigarettes in the state of their residency. The majority of purchases on IRs were made in New York (28%), Oklahoma (14%), Washington (10%), Arizona (9%), and Florida (6%). The rate of purchasing cigarettes on IRs decreased from 4% in 2010-11 to 3% in 2014-15 (p = 0.012). The rates were higher for females than males (OR = 1.23, CI = 1.09:1.40) and heavy than non-heavy smokers (OR = 1.35, CI = 1.17:1.55). Higher state excise tax on tobacco, on average, was associated with purchasing cigarettes on IRs. CONCLUSIONS: The rate of purchasing cigarettes on IRs is relatively low and has decreased in recent years. However, the rates differ across sociodemographic factors of daily smokers, including the state of residency and purchase. Purchasing cigarettes on IRs at lower prices can affect smokers' intentions to quit and can reduce federal and state efforts toward a tobacco-free nation. PMID- 30243145 TI - Methadone maintenance treatment among patients exposed to illicit fentanyl in Rhode Island: Safety, dose, retention, and relapse at 6 months. AB - INTRODUCTION: Illicitly manufactured fentanyl (IMF) is a potent synthetic opioid that has been contributing to overdose deaths in the United States. This study examined intake toxicology and six-month treatment outcomes for patients newly admitted to a single methadone maintenance treatment program (MMTP) in Rhode Island with a high prevalence of illicit fentanyl. METHODS: We conducted a retrospective chart review of patients admitted to a single MMTP between November 1st, 2016 and August 31st, 2017 followed for six months. Outcomes measured included: 1) retention in treatment at 6 months; 2) evidence of sustained abstinence; 3) relapse; 4) methadone dosage required to achieve sustained abstinence; and 5) the number of days required to achieve abstinence. RESULTS: We observed 154 unique intake events (representing 147 patients). 80% (n = 123) tested positive for fentanyl at intake. During the six-month follow up period, 32% (n = 49) left treatment before six months, two individuals died within five weeks of discontinuation. No deaths were seen among those remaining in treatment. The majority (89%) who remained in treatment at six months achieved abstinence. No significant difference was seen for dose or time to achieve abstinence. Relapse was common (57%). Repeated exposure to fentanyl was seen frequently (71%) while in MMT before and after achieving abstinence. CONCLUSION: While there is concern that the potency of IMF may reduce the effectiveness of MAT, this study suggests that MMT is safe, abstinence achievable, and MMT is protective against death among fentanyl-exposed patients. PMID- 30243146 TI - Loss of transforming growth factor-beta1 in epithelium cells affects enamel formation in mice. AB - OBJECTIVES: In order to understand the specific in vivo function of transforming growth factor-beta1 (TGF-beta1), we successfully established aTGF-beta1 deficient mouse model using a conditional knockout method. In the present study, we aimed to further understand the potential role of TGF-beta1 in enamel formation. DESIGN: Transgenic mice withoutTGF-beta1 in epithelial cells were generated. Scanning electron microscopy and micro-computed tomography analysis were used to detect the dental appearance, enamel microstructure and tooth density. Histological analysis was used to examine the residual organic matrix of enamel. Quantitative real-time polymerase chain reaction was used to analyze the expressions of enamel matrix proteins at the mRNA level. RESULTS: The enamel of mandibular molars and incisors inTGF-beta1 conditional knockout mice displayed severe attrition and lower density compared with the wild-type littermates. A slender microstructure of enamel rod was observed, and enamel matrix proteins were retained in the enamel space at the maturation stage in conditional knockout mice. Moreover, the expressions of enamel matrix protein-encoding genes, such as amelogenin (Amelx), ameloblastin (Ambn), Enamelin (Enam) and matrix metalloproteinase-20 (Mmp-20), were increased in enamel organs of conditional knockout mice. On the other hand, the expressions of Amelotin (Amtn), kallikrein related peptidase-4 (Klk4), C4orf26 and WD repeat-containing protein 72 (Wdr72) were dramatically decreased at the transition and maturation stages. CONCLUSIONS: TGF-beta1 played an important role in enamel mineralization through decreasing synthesis ofAmelx, Ambn and Enam and increasing synthesis of Klk4, Amtn, Corf26 and Wdr72. PMID- 30243147 TI - Characterization of Aspergilli from dried red chilies (Capsicum spp.): Insights into the etiology of aflatoxin contamination. AB - Aflatoxins are toxic carcinogens produced by several species of Aspergillus section Flavi, with some aflatoxin producers associated with specific crops. Red chilies (Capsicum spp.) are grown in warm regions that also favor aflatoxin producers. Aflatoxins in red chilies may result in serious health concerns and severe economic losses. The current study sought to gain insight on causal agents of aflatoxin contamination in red chilies. Naturally contaminated chilies from markets in Nigeria (n = 55) and the United States (US) (n = 169) were examined. The A. flavus L strain was the predominant member of Aspergillus section Flavi (84%) in chilies. Highly toxigenic fungi with S strain morphology were also detected in chilies from both countries (11%), followed by A. tamarii (4.6%) and A. parasiticus (0.4%). Fungi with L morphology produced significantly lower quantities of aflatoxins (mean = 43 MUg g-1) compared to S morphology fungi (mean = 667 MUg g-1; p < 0.01) in liquid fermentation. Eighty-one percent of S morphology fungi from chilies in US markets produced only B aflatoxins, whereas 20%, all imported from Nigeria, produced both B and G aflatoxins; all S morphology fungi from Nigerian chilies produced both B and G aflatoxins. Multi gene phylogenetic analyses of partial gene sequences for nitrate reductase (niaD, 2.1 kb) and the aflatoxin pathway transcription factor (aflR, 1.9 kb) resolved Aspergilli recovered from chilies into five highly supported distinct clades: 1) A. parasiticus; 2) A. flavus with either L or S morphology; 3) A. minisclerotigenes; 4) A. aflatoxiformans, and 5) a new lineage. Aspergillus aflatoxiformans and the new lineage produced the highest concentrations of total aflatoxins in chilies, whereas A. flavus L strains produced the least. The results suggest etiology of aflatoxin contamination of chili is complex and may vary with region. Knowledge of causal agents of aflatoxin contamination of chilies will be helpful in developing mitigation strategies to prevent human exposure. PMID- 30243148 TI - DNA methylation-based age prediction using massively parallel sequencing data and multiple machine learning models. AB - The field of DNA intelligence focuses on retrieving information from DNA evidence that can help narrow down large groups of suspects or define target groups of interest. With recent breakthroughs on the estimation of geographical ancestry and physical appearance, the estimation of chronological age comes to complete this circle of information. Recent studies have identified methylation sites in the human genome that correlate strongly with age and can be used for the development of age-estimation algorithms. In this study, 110 whole blood samples from individuals aged 11-93 years were analysed using a DNA methylation quantification assay based on bisulphite conversion and massively parallel sequencing (Illumina MiSeq) of 12 CpG sites. Using this data, 17 different statistical modelling approaches were compared based on root mean square error (RMSE) and a Support Vector Machine with polynomial function (SVMp) model was selected for further testing. For the selected model (RMSE = 4.9 years) the mean average error (MAE) of the blind test (n = 33) was calculated at 4.1 years, with 52% of the samples predicting with less than 4 years of error and 86% with less than 7 years. Furthermore, the sensitivity of the method was assessed both in terms of methylation quantification accuracy and prediction accuracy in the first validation of this kind. The described method retained its accuracy down to 10 ng of initial DNA input or ~2 ng bisulphite PCR input. Finally, 34 saliva samples were analysed and following basic normalisation, the chronological age of the donors was predicted with less than 4 years of error for 50% of the samples and with less than 7 years of error for 70%. PMID- 30243149 TI - Biodegradable hypocrellin derivative nanovesicle as a near-infrared light-driven theranostic for dually photoactive cancer imaging and therapy. AB - Photoactive agents based on natural products have attracted substantial attention in clinical applications because of their distinct biological activity, molecular structure multiformity, and low biotoxicity. Herein, we initially modify hypocrellin B (HB) with 1,2-diamino-2-methyl propane to form near-infrared (NIR) light (>700 nm)-responsive amino-substituted HB derivative (DPAHB). The DPAHB exhibit broad absorption (400-800 nm), NIR emission (maximum emission peak at 710 nm), and high singlet oxygen (1O2) quantum yield (~0.33) under NIR light (721 nm) irradiation. After self-assembly by using DPAHB with PEG-PLGA, the as-prepared nanovesicles (DPAHB NVs) retain efficient 1O2 generation, more interestingly, show high photothermal conversion efficiency (~0.24) under NIR light (721 nm) irradiation for synergistic photodynamic therapy (PDT) and photothermal therapy toward hypoxic tumor. The DPAHB NVs can not only be as a fluorescence/photoacoustic imaging agent but also exhibit an even stronger PDT efficiency than that of chlorin e6 (a widely used classic photosensitizer). In vitro and in vivo studies demonstrate that DPAHB NVs possess high photothermal stability, enhanced tumor accumulation, and suitable biodegradation rate, thus, show a highly promising clinical potential as a new photoactive agent for cancer therapy. PMID- 30243150 TI - Synthetic alpha5beta1 integrin ligand PHSRN is proangiogenic and neuroprotective in cerebral ischemic stroke. AB - Ischemic stroke is the leading cause of disability and death worldwide. An effective therapeutic approach is urgently needed. Stroke-induced angiogenesis and neurogenesis are essential mechanisms in the long-term repair. Extracellular matrix proteins are also involved in tissue self-repair. Recently, a PHSRN (Pro His-Ser-Arg-Asn) peptide from the fibronectin synergistic motif that can promote wound healing in epithelia and induce endothelial proliferation and cancer cell migration was identified. The therapeutic potential of this peptide in stroke is unknown. Here, we examined the potential of PHSRN in stroke therapy using an ischemic rat model of middle cerebral artery occlusion (MCAO). PHSRN reduced the infarct volume in MCAO rats, improved neurological function, and alleviated motor function impairment. PHSRN targeted the damaged brain region and distributed to endothelial cells after intraperitoneal injection. PHSRN significantly promoted angiogenesis and vascular endothelial growth factor secretion through activation of integrin alpha5beta1 and its downstream intracellular signals, e.g., focal adhesion kinase, Ras, cRaf, and extracellular-signal-regulated kinase. PHSRN treatment also stimulated neurogenesis in MCAO rats, and maintained neuronal survival and neuronal morphologic complexity via induction of VEGF secretion. Together, these results provide insights into the role of integrin alpha5beta1 following ischemia and support the feasibility of using PHSRN peptide in stroke therapy. PMID- 30243151 TI - Donepezil-based multi-functional cholinesterase inhibitors for treatment of Alzheimer's disease. AB - Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in elderly people. Considering the multifactorial nature of AD, the concept of multi target-directed ligands (MTDLs) has recently emerged as a new strategy for designing therapeutic agents on AD. MTDLs are confirmed to simultaneously affect diverse targets which contribute to etiology of AD. As the most potent approved drug, donepezil affects various events of AD, like inhibiting cholinesterases activities, anti-Abeta aggregation, anti-oxidative stress et al. Modifications of donepezil or hybrids with pharmacophores of donepezil in recent five years are summarized in this article. On the basis of case studies, our concerns and opinions about development of donepezil derivatives, designing of MTDLs, and perspectives for AD treatments are discussed in final part. PMID- 30243152 TI - Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library. AB - The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of HIV-1 replication and is considered an important, clinically unexploited therapeutic target. As such, small drug-like molecules that inhibit this critical HIV-1 protein have become a priority for several groups. Therefore, in this study we explore small molecule targeting of the CA protein, and in particular a very attractive inter-protomer pocket. We report the design, parallel synthesis, and anti-HIV-1 activity evaluation of a series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors synthesized via Cu(I)-catalyzed alkyne-azide 1,3 dipolar cycloaddition (CuAAC) reaction. We demonstrate robust inhibitory activity over a range of potencies against the HIV-1 NL4-3 reference strain. In particular, compound 13m exhibited the greatest potency and lowest toxicity within this new series with an EC50 value of 4.33 MUM and CC50 value of >57.74 MUM (SI > 13.33). These values are very similar to the lead compound PF-74 (EC50 = 5.95 MUM, CC50 > 70.50 MUM, SI > 11.85) in our assay, despite significant structural difference. Furthermore, we demonstrate via surface plasmon resonance (SPR) binding assays that 13m interacts robustly with recombinant HIV-1 CA and exhibits antiviral activity in both the early and late stages of HIV-1 replication. Overall, the novel parallel synthesis and structure-activity relationships (SARs) identified within this study set the foundation for further rational optimization and discovery of CA-targeting compounds with improved potency. PMID- 30243153 TI - Synthesis of scutellarein derivatives with antiproliferative activity and selectivity through the intrinsic pathway. AB - To explore antitumor agents with potent efficacy and low toxicity, scutellarein derivatives with benzoic acid mustard (10a-c, 11a-c and 13a-c) were designed and synthesized. The antiproliferative activities of the target derivatives against A549, MCF-7 and Bel-7402 cancer cell lines were tested. Compound 10a showed the strongest potency with an IC50 value of 1.50 MUM against MCF-7 cell line, and displayed low toxicity against human liver L-O2 normal cells (IC50 > 50 MUM), showing specificity between normal and malignant cells. The mechanism studies revealed that 10a could induce apoptosis in MCF-7 cells, arrest MCF-7 cell cycle at the G1 phase and cause mitochondrial dysfunction in a concentration-dependant manner. Furthermore, the enhanced expression of the pro-apoptotic proteins caspase-9, caspase-3, Bax and cytochrome c, and the reduced expression of the anti-apoptotic protein Bcl-2 confirmed that 10a induced the intrinsic apoptosis pathway in MCF-7 cells. The potent antiproliferative activity and good selectivity guaranteed 10a a lead compound for the further development into anticancer therapeutics, especially for breast cancer. PMID- 30243154 TI - Side effects of methotrexate therapy for rheumatoid arthritis: A systematic review. AB - Methotrexate (MTX) is used as an anchor disease-modifying anti-rheumatic drugs (DMARDs) in treating rheumatoid arthritis (RA) because of its potent efficacy and tolerability. MTX benefits a large number of RA patients but partially suffered from side effects. A variety of side effects can be associated with MTX when treating RA patients, from mild to severe or discontinuation of the treatment. In this report, we reviewed the possible side effects that MTX might cause from the most common gastrointestinal toxicity effects to less frequent malignant diseases. In order to achieve regimen with less side effects, the administration of MTX with appropriate dose and a careful pretreatment inspection is necessary. Further investigations are required when combining MTX with other drugs so as to enhance the efficacy and reduce side effects at the same time. The management of MTX treatment is also discussed to provide strategies for occurred side effects. Thus, this review will provide scholars with a comprehensive understanding the side effects of MTX administration by RA patients. PMID- 30243155 TI - Pd(II) and Pt(II) saccharinate complexes of bis(diphenylphosphino)propane/butane: Synthesis, structure, antiproliferative activity and mechanism of action. AB - [M(sac)2(dppp)] (1 and 2), [M(dppp)2](sac)2 (3 and 4) and [M(sac)2(dppb)] (5 and 6) complexes, where M = PdII (1, 3 and 5) and PtII (2, 4 and 6), sac = saccharinate, dppp = 1,3-bis(diphenylphosphino)propane and dppb = 1,4 bis(diphenylphosphino)butane, were synthesized and characterized by IR, NMR, ESI MS and X-ray diffraction. The anticancer activity of the complexes against human lung (A549), breast (MCF-7), prostate (DU145) and colon (HCT116) cancer cell lines showed that the cationic complexes of dppp (3 and 4) and neutral Pt complex of dppb (6) were the most active agents of series. 3 and 4 exhibited antiproliferative activity, while 6 was highly cytotoxic compared to cisplatin. These complexes were therefore subjected to further investigations to ascertain the possible role of lipophilicity, cellular uptake and DNA/HSA binding in their biological activity. Flow cytometry analysis revealed that complex 6 induced apoptotic cell death in A549 and HCT116 cells and caused the cell cycle arrest at the S phase and overproduction of reactive oxygen species (ROS), giving rise to mitochondrial depolarization and DNA damage. PMID- 30243156 TI - Four new antitumor metabolites isolated from a mutant 3-f-31 strain derived from Penicillium purpurogenum G59. AB - Penicimutanolones A (1) and B (2), penicimutanolone A methyl ether (3), and penicimumide (4), four new antitumor metabolites, were isolated from a neomycin resistant mutant of the marine-derived fungus Penicillium purpurogenum G59. The structures of the compounds were elucidated by spectroscopic methods, and the absolute configurations were determined by X-ray crystallography and calculated ECD. In MTT and SRB assays, compounds 1-3 showed strong inhibitory effects on 14 human cancer cell lines. Compounds 1 and 2 maybe induce apoptosis of cancer cells mainly due to the inhibition of the expression of survivin, a client protein of HSP90. In addition, in vivo antitumor activity was observed for compound 1 in murine sarcoma HCT116 tumor-bearing Kunming mice, using docetaxel as a positive control. PMID- 30243157 TI - DYRK1A kinase inhibition with emphasis on neurodegeneration: A comprehensive evolution story-cum-perspective. AB - Alzheimer, the fourth leading cause of death embodies a key responsible event including formation of beta-amyloid protein clustering to amyloid plaque on blood vessels. The origin of above events is Amyloid precursor protein (APP) which is an integral membrane protein known for its function in synapses formation. Modern research had proposed that the over expression of DYRK1A (Dual specificity tyrosine phosphorylation regulated kinase1A, a family of protein kinases, positioned within the Down's syndrome critical region (DSCR) on human chromosome 21causes phosphorylation of APP protein resulting in its cleavage to Abeta 40, 42 and tau proteins (regulated by beta and gamma secretase) which plays critical role in early onset of Alzheimer's disease (AD) detected in Down's syndrome (DS), leading to permanent functional and structural deformities which results ultimately into neuro-degeneration and neuronal death. Therefore, DYRK1A emerges as a potential target for prevention of neuro-degeneration and hence Alzheimer. Presently, the treatment methods for Down's syndrome, as well as Alzheimer's disease are extremely biased and represent a major deficiency for therapeutic necessities. We hereby, focus our review on the current status of the research and contributions in the development of DYRK1A inhibitors. PMID- 30243158 TI - Design and synthesis of potent dual inhibitors of JAK2 and HDAC based on fusing the pharmacophores of XL019 and vorinostat. AB - Specifically blocking more than one oncogenic pathway simultaneously in a cancer cell with a combination of different drugs is the mainstay of the majority of cancer treatments. Being able to do this via two targeted pathways without inducing side effects through a general mechanism, such as chemotherapy, could bring benefit to patients. In this work we describe a new dual inhibitor of the JAK-STAT and HDAC pathways through designing and developing two types of molecule based on the JAK2 selective inhibitor XL019 and the pan-HDAC inhibitor, vorinostat. Both series of compounds had examples with low nanomolar JAK2 and HDAC1/6 inhibition. In some cases good HDAC1 selectivity was achieved while retaining HDAC6 activity. The observed potency is explained through molecular docking studies of all three enzymes. One example, 69c had 16-25 fold selectivity against the three other JAK-family proteins JAK1, JAK3 and TYK2. A number of compounds had sub-micromolar potencies against a panel of 4 solid tumor cell lines and 4 hematological cell lines with the most potent compound, 45h, having a cellular IC50 of 70 nM against the multiple myeloma cell line KMS-12-BM. Evidence of both JAK and HDAC pathway inhibition is presented in Hela cells showing that both pathways are modulated. Evidence of apoptosis with two compounds in 4 sold tumor cell lines is also presented. PMID- 30243159 TI - Prevalence of pain in patients with breast cancer post-treatment: A systematic review. AB - PURPOSE: To evaluate the prevalence and severity of persistent pain after breast cancer treatment (PPBCT) in patients who received surgery, radiotherapy or a combination of treatments and to explore how different treatments and techniques impact pain. METHODS: Medline, Embase and Cochrane Central databases were searched for articles which evaluated the prevalence of PPBCT. Search results were limited to studies addressing chronic post-surgical pain (CPSP), persistent post-surgical pain (PPSP), post-mastectomy pain syndrome (PMPS) or radiotherapy (RT) related pain in breast cancer patients and published in the English language. The primary outcome was the incidence or severity of PPBCT. Descriptive analyses were performed. RESULTS: A total of 177 studies were included in this review. Overall, pain prevalence was 29.8% amongst 3746 patients (Group 1: 30 studies) post-surgery, 27.3% post-RT (Group 2: 41 studies, n = 15 019), and 21.8% amongst BC survivors who reported on the general prevalence of after receiving various combinations of BC treatment (Group 3: 106 studies, n = 135 437). CONCLUSION: PPBCT remains to be a prevalent and complex clinical issue, despite a variety of different techniques and treatments. Various factors such as varying definitions of pain, inconsistent use of assessment tools and differences in methodology between studies may contribute to discrepancies in reports of PPBCT. A greater understanding of BC treatments and their impact on PPBCT may help identify potential risk factors, prevention and pain management strategies. PMID- 30243160 TI - Multi-output support vector machine for regional multi-step-ahead PM2.5 forecasting. AB - Air quality deteriorates fast under urbanization in recent decades. Reliable and precise regional multi-step-ahead PM2.5 forecasts are crucial and beneficial for mitigating health risks. This work explores a novel framework (MM-SVM) that combines the Multi-output Support Vector Machine (M-SVM) and the Multi-Task Learning (MTL) algorithm for effectively increasing the accuracy of regional multi-step-ahead forecasts through tackling error accumulation and propagation that is commonly encountered in regional forecasting. The Single-output SVM (S SVM) is implemented as a benchmark. Taipei City of Taiwan is our study area, where three types of air quality monitoring stations are selected to represent areas imposed with high traffic influences, high human activities and commercial trading influences, and less human interventions close to nature situation, respectively. We consider forecasts of PM2.5 concentrations as a function of meteorological and air quality factors based on long-term (2010-2016) observational datasets. Firstly, the Kendall tau coefficient is conducted to extract key spatiotemporal factors from regional meteorological and air quality inputs. Secondly, the M-SVM model is trained by the MTL to capture non-linear relationships and share correlation information across related tasks. Lastly, the MM-SVM model is validated using hourly time series of PM2.5 concentrations as well as meteorological and air quality datasets. Regarding the applicability of regional multi-step-ahead forecasts, the results demonstrate that the MM-SVM model is much more promising than the S-SVM model because only one forecast model (MM-SVM) is required, instead of constructing a site-specific S-SVM model for each station. Moreover, the forecasts of the MM-SVM are found better consistent with observations than those of any single S-SVM in both training and testing stages. Consequently, the results clearly demonstrate that the MM-SVM model could be recommended as a novel integrative technique for improving the spatiotemporal stability and accuracy of regional multi-step-ahead PM2.5 forecasts. PMID- 30243161 TI - Geographical pattern of methanogenesis in paddy and wetland soils across eastern China. AB - Large variation of CH4 emissions from paddy and wetland ecosystems exists across different geographical locations in China. To obtain mechanistic understanding of this variation, we investigated the dynamics of methanogenesis over the course of glucose degradation in fourteen paddy field soils and five wetland soils collected from different regions of China. The results revealed that the maximal rate (2-3 mM per day) and the total amount (25-30 mM) of CH4 produced were similar across soil samples. The lag phase of methanogenesis, however, differed substantially with the shortest lag phase of 4 days in a paddy soil from north China and the longest of 32 days in a soil from south China, and this difference reflected a general geographical trend among all soils tested. Nitrate was reduced completely within 4 days in all soils. The reduction of Fe(III) and sulfate was completed after 21 days and 29 days, respectively. The depletion time of Fe(III) and sulfate were positively correlated with the lag phase of methanogenesis. Competition for common substrates between methanogens and iron and sulfate reducers, however, does not explain this coincidence because a slow production of CH4 was detected at the very beginning. It appears that the geographical variations in methanogenesis and the reduction of ferric iron and sulfate are related to the variation in soil pH but not to temperature, soil organic C and nutrient conditions in paddy and wetland soils across eastern China. PMID- 30243162 TI - Effect of Tenax addition amount and desorption time on desorption behaviour for bioavailability prediction of polycyclic aromatic hydrocarbons. AB - In this work, Tenax consecutive extractions of polycyclic aromatic hydrocarbons (PAHs) were conducted in two spiked sediments to investigate the influence of different Tenax addition amounts and desorption times on the rapidly desorbing fraction of PAHs, and to determine a reliable method for estimating PAHs bioavailability. The results indicated that a large Tenax addition amount has a positive effect on the desorption of PAHs from sediments. The desorption amounts of target PAHs compounds (3-ring phenanthrene and 4-ring fluoranthene) increased as the Tenax: sediment ratios increased from 0.25 to 2 in two spiked sediments. The highest desorption percentages of phenanthrene and fluoranthene were 48.91% and 34.70% for Jialing industrial park sediment, and 43.36% and 33.24% for Huanghuayuan bridge sediment, respectively. The results of desorption kinetics were suitably fitted with first order three-compartment model to estimate the rapidly desorbing fraction, Moreover, the Tenax: sediment ratio of 1 and desorption time of 24 h were found to be suitable for the desorption of phenanthrene and fluoranthene from sediments. The PAHs in sediments were biodegraded well by the bacterial strain J1-q. Comparing the maximum biodegraded amount of target PAHs in 30 days and the desorbed fraction over 400 h, the results showed that Tenax had better correlation with the high molecular weight fluoranthene than with the low molecular weight phenanthrene. PMID- 30243163 TI - The cost of addressing saline lake level decline and the potential for water conservation markets. AB - The world's saline lakes are shrinking and human water diversions are a significant contributor. While there is increased interest in protecting the ecosystem services provided by these lakes, the cost of protecting water levels has not been estimated. To explore this question we consider the case of Great Salt Lake (Utah, USA) where human diversions from three rivers have caused the lake level to decline during the last century. Recent work has suggested the restoration of inflows is necessary to maintain a target elevation consistent with well-functioning ecosystems. We construct cost estimates of increasing water inflows using conservation cost curves for each river basin. We then compare the cost of uniform cutbacks to cap-and-trade systems which allow intra- and inter basin trading. The cost of water to permanently implement uniform water right cutbacks to increase inflows by 20% above current levels is $37.4 million. Costs and cost-savings are sensitive to alternative allocation, inflow, and cost assumptions, and we estimate significant cost reductions from intra-basin water conservation markets (5-54% cost decrease) and inter-basin water conservation markets (22-57% cost decrease). PMID- 30243164 TI - Iron speciation at the riverbank surface in wetland and potential impact on the mobility of trace metals. AB - Fe oxyhydroxides in riverbanks and their high binding capacity can be used to hypothesize that riverbanks may act as a "biogeochemical filter" between wetlands and rivers and may constitute a major mechanism in the trapping and flux regulation of chemical elements. Until now, the properties of Fe minerals have been very poorly described in riverbanks. The goals of the present work are to identify Fe speciation in riverbanks where ferric deposits are observed and to determine their impact on the metal behavior (As, Co, Cu, Ni, Pb, Zn, etc.). At the surface, Fe speciation is mainly composed of small poorly crystalline Fe phases, i.e. ferrihydrite (~30%), Fe-OM associations (~40%) as well as crystalline Fe phases, i.e. goethite (~35%). At the subsurface, the Fe distribution is dominated by goethite (~35%) and Fe-mica (~35%), the proportion of which increases at the expense of ferrihydrite and the Fe-OM associations. At the riverbank surface, ferrihydrite and the Fe-OM associations are therefore the main Fe hosting phases in response to (i) the fast Fe(II) oxidation induced by the presence of O2 and (ii) the high amount of OM favoring the formation of nano phases bound to OM (Fe monomers, polymers and nanoparticles) and preventing mineralogical transformation (ferrihydrite into goethite). During the high-water level period (high flow), a strong erosion of the riverbank transfers these ferric deposits into the river. However, the physicochemical parameters of the river (pH 6.6-7.6 and continuous oxic conditions) do not promote the dissolution of Fe oxyhydroxides and OM. Ferric deposits and the associated trace metals are therefore maintained as colloids/particles and are exported to the outlet. All of the results presented here demonstrate that the ferric deposits trap metals on a seasonal basis and are therefore a key factor in the mobilization of metals during riverbank erosion by river flow. PMID- 30243165 TI - The impact of air pollutant deposition on solar energy system efficiency: An approach to estimate PV soiling effects with the Community Multiscale Air Quality (CMAQ) model. AB - Deposition and accumulation of aerosol particles on photovoltaics (PV) panels, which is commonly referred to as "soiling of PV panels," impacts the performance of the PV energy system. It is desirable to estimate the soiling effect at different locations and times for modeling the PV system performance and devising cost-effective mitigation. This study presents an approach to estimate the soiling effect by utilizing particulate matter (PM) dry deposition estimates from air quality model simulations. The Community Multiscale Air Quality (CMAQ) modeling system used in this study was developed by the U.S. Environmental Protection Agency (U.S. EPA) for air quality assessments, rule-making, and research. Three deposition estimates based on different surface roughness length parameters assumed in CMAQ were used to illustrate the soling effect in different land-use types. The results were analyzed for three locations in the U.S. for year 2011. One urban and one suburban location in Colorado were selected because there have been field measurements of particle deposition on solar panels and analysis on the consequent soiling effect performed at these locations. The third location is a coastal city in Texas, the City of Brownsville. These three locations have distinct ambient environments. CMAQ underestimates particle deposition by 40% to 80% when compared to the field measurements at the two sites in Colorado due to the underestimations in both the ambient PM10 concentration and deposition velocity. The estimated panel transmittance sensitivity due to the deposited particles is higher than the sensitivity obtained from the measurements in Colorado. The final soiling effect, which is transmittance loss, is estimated as 3.17 +/- 4.20% for the Texas site, 0.45 +/- 0.33%, and 0.31 +/- 0.25% for the Colorado sites. Although the numbers are lower compared to the measurements in Colorado, the results are comparable with the soiling effects observed in U.S. PMID- 30243167 TI - A random forest partition model for predicting NO2 concentrations from traffic flow and meteorological conditions. AB - High concentrations of nitrogen dioxide in the air, particularly in heavily urbanised areas, have an adverse effect on many aspects of residents' health (short-term and long-term damage, unpleasant odour and other). A method is proposed for modelling atmospheric NO2 concentrations in a conurbation, using a partition model M consisting of two separate models: ML for lower concentration values and MU for upper values. An advanced data mining technique, that of random forests, is used. This is a method based on machine learning, involving the simultaneous compilation of information from multiple random trees. Using the example of data recorded in Wroclaw (Poland) in 2015-2017, an iterative method was applied to determine the boundary concentration y~ for which the mean absolute deviation error for the partition model attained its lowest value. The resulting model had an R2 value of 0.82, compared with 0.60 for a classical random forest model. The importances of the variables in the model ML, similarly as in the classical case, indicate that the greatest influence on NO2 concentrations comes from traffic flow, followed by meteorological factors, in particular the wind direction and speed. In the model MU the importances of the variables are significantly different: while traffic flow still has the greatest impact, the effects of temperature and relative humidity are almost as great. This confirms the justifiability of constructing separate models for low and high pollution concentrations. PMID- 30243166 TI - Cyanobacteria blooms: A neglected facilitator of CH4 production in eutrophic lakes. AB - Lakes are regarded as one of the important sources of atmospheric CH4. However, the role of cyanobacteria blooms (CBBs) play in the CH4 production in eutrophic lakes is not fully clear. In this study, the spatial distribution characteristics of CH4 concentrations in surface water and sediment columns were investigated in Zhushan Bay of Taihu lake, China. Results showed that CH4 concentrations in CBBs accumulated zones were much higher than that in the open lake areas, with the highest values of 3.79 MUmol.L-1 and 2261.88 MUmol.L-1 in surface water and sediment columns, respectively. CH4 concentrations were strongly influenced by various factors. In surface water, the occurrence of CBBs greatly contributed to CH4 productions, as evidenced by the well-predicting for CH4 concentrations using Chl-a and NH4+ concentrations. In the sediments, the Ignition Loss and C:N ratio values were two indicators of CH4 contents, suggesting that the methanogenesis processes were influenced by not only the quantities, but also the qualities of organic matter. The labile substrates produced during the CBBs decomposition processes promoted the CH4 production and migration from sediments to the water column, resulting in the coherence in CH4 concentrations between the sediments and the surface water. The high-resolution determinations of CH4 concentrations in surface water and sediments clarified that the CBBs were a neglected facilitator of CH4 productions, which should be considered in the future estimation of CH4 emissions in eutrophic lakes. PMID- 30243168 TI - Effects of plastic mulching and plastic residue on agricultural production: A meta-analysis. AB - China is a large agricultural country, and food security is significantly limited by the shortage of water resources. Plastic mulching technology can effectively modify the crop growth environment and crop production due to differences in climatic conditions, spatial distribution characteristics, and cropping systems and methods. In this study, a meta-analysis was conducted to quantitatively analyze the effects of plastic film mulching and residual plastic on yield and water use efficiency (WUE) of maize, wheat, potato, and cotton in China based on 266 peer-reviewed publications. The results showed that plastic mulching significantly increased crop yield (24.32%) and WUE (27.63%). Plastic mulching had the greatest effect of potato on yield (30.62%) and WUE (30.34%) in China. At a regional scale, plastic mulching performed best in Northwest China, and crop yield and WUE were influenced by film color, mulching method, and crop type. Black film and ridge row mulching were more favorable to crop growth and increased crop yield and WUE in arid areas of China. There was no significant effect on crop yield of residual plastic between 0 and 240 kg/ha, but the yield decreased significantly with increased time and residual plastic film >240 kg/ha. In conclusion, although plastic mulching can significantly increase crop yield and WUE, especially in dryland agriculture, we should also improve the technology for recovering residual plastic film to protect the environment. PMID- 30243169 TI - Water management in the military: The SmartBlue Camp Profiling Tool. AB - Increasingly, military installations are becoming part of the ongoing discussion on environmental sustainability. Military installations, and camps in particular, often resemble small towns in terms of inhabitants and demand for resources, but are significantly different from civilian settings in terms of autonomy needs, resource management, population make up and operational requirements. In this context, what is missing is the development of a specialised and standardised framework able to assess the status of military camps in terms of water resources management and infrastructures' sustainability. To this end, we develop and present the SmartBlue Camp profiling tool. The tool comprises of 31 Performance Indicators (PI) that evaluate the sustainability of water management in a camp, covering all aspects of the "military water cycle", and 15 Context Factors (CF) that assess background characteristics of the surrounding area, enabling a deeper understanding and interpretation of PI values. We also present the implementation of the tool in six European military camps, identifying priorities and opportunities for performance improvement and short-listing specific technological interventions at a case by case basis, able to address water challenges at the camp level. PMID- 30243170 TI - Environmental availability of sulfamethoxazole and its acetylated metabolite added to soils via sludge compost or bovine manure. AB - The fate of antibiotics and their metabolites in soils after application of organic waste depends on their environmental availability, which depends on the quality and biodegradability of the added exogenous organic matter (EOM). This study aimed at better understanding the fate of sulfamethoxazole (SMX) and N acetyl-sulfamethoxazole (AcSMX) metabolite added to soils via sludge compost or cow manure application, during a 28-day incubation. Experimental results obtained for mineralized, extractable, and non-extractable fractions as well as EOM mineralization were used to couple SMX and AcSMX dynamics to the EOM evolution using the COP-Soil model. According to various mechanisms of extraction, CaCl2, EDTA and cyclodextrin solutions extracted contrasted available fractions (31-96% on day 0), resulting in different sets of parameter values in the model. CaCl2 extraction was the best method to assess the sulfonamide availability, leading to low relative root mean squared errors and best simulations of SMX and AcSMX dynamics. The decrease of SMX and AcSMX availability over time went with the formation of non-extractable residues, mostly of physicochemical origin. Using the COP-Soil model, the co-metabolism was assumed to be responsible for the formation of biogenic non-extractable residues and the low mineralization of SMX and AcSMX. PMID- 30243171 TI - Generic physiologically-based toxicokinetic modelling for fish: Integration of environmental factors and species variability. AB - One of the goals of environmental risk assessment is to protect the whole ecosystem from adverse effects resulting from exposure to chemicals. Many research efforts have aimed to improve the quantification of dose-response relationships through the integration of toxicokinetics. For this purpose, physiologically-based toxicokinetic (PBTK) models have been developed to estimate internal doses from external doses in a time-dependent manner. In this study, a generic PBTK model was developed and adapted for rainbow trout (Onchorhynchus mykiss), zebrafish (Danio rerio), fathead minnow (Pimephales promelas), and three spined stickleback (Gasterosteus aculeatus). New mechanistic approaches were proposed for including the effects of growth and temperature in the model. Physiological parameters and their inter-individual variability were estimated based on the results of extensive literature searches or specific experimental data. The PBTK model was implemented for nine environmental contaminants (with log kow from -0.9 to 6.8) to predict whole-body concentrations and concentrations in various fish's organs. Sensitivity analyses were performed for a lipophilic and a hydrophilic compound to identify which parameters have most impact on the model's outputs. Model predictions were compared with experimental data according to dataset-specific exposure scenarios and were accurate: 50% of predictions were within a 3-fold factor for six out of nine chemicals and 75% of predictions were within a 3-fold factor for three of the most lipophilic compounds studied. Our model can be used to assess the influence of physiological and environmental factors on the toxicokinetics of chemicals and provide guidance for assessing the effect of those critical factors in environmental risk assessment. PMID- 30243172 TI - Rainwater characteristics and interaction with atmospheric particle matter transportation analyzed by remote sensing around Beijing. AB - Air pollution in Beijing has attracted much more attentions, and multiple regulations have been enacted since 2013. Based on the close link between the atmospheric particle matter concentration and the deposited load in rainwater, 336 rainwater samplings with seven parameters (pH, NH4+-N, NO3--N, P, S, Cu and Cd) at five-minute intervals in 2013 and 2014 were compared. The field monitoring and the temporal patterns analysis revealed a positive development of air quality. The lesser composition of coal in the energy consumption and the effective control of traffic emission were found. The average Aerosol Optical Depth (AOD) value around the sampling point during the 7 sampling rainfall events in 2014 was 2.855, which was higher than that in 2013 (1.807). It reflected the washing effect of rain on atmospheric particulates and highlighted the urban non point source pollution effected by atmospheric deposition. AOD was demonstrated to perform well in reflecting regional air quality. A trajectory analysis conducted by HYSPLIT model in conjunction with the spatial distribution of AOD in the Beijing-Tian-Hebei (BTH) region depicted paths of air pollutants from long range transport. The dominant trace was to the south of region. Cities around BTH were provided with different emission-reducing targets. Both Inner Mongolia and Henan province were suggested to control agricultural emissions. Shanxi, Shandong and cities around Bohai Bay should supervise the energy consuming industries. Furthermore, NO3--N was introduced to be an indicator of effect of the regional joint prevention and control in the future. PMID- 30243173 TI - Defective graphene for electrocatalytic CO2 reduction. AB - The rational synthesis of earth-abundant materials with excellent electrocatalytic performances plays a critical role in electrochemical CO2 reduction (ECR) to obtain value-added chemical products or fuels. Here we demonstrate a defective graphene (DG) as such an electrocatalyst candidate via a nitrogen removal method. The graphene with a large amount of topological defects offered abundant catalytically active sites, high electronic conductivity and strong adsorption of CO2. Attributed to these features, the DG exhibited significantly higher electrocatalytic CO2 reduction performances with an excellent faradaic efficiency of ~84% at -0.6 V vs. reversible hydrogen electrode and a larger current density, compared to pristine graphene, nitrogen-doped graphene and edge-rich graphene. This work suggests a promising method for further designing efficient metal-free electrocatalysts for CO2 reduction. PMID- 30243174 TI - In situ fabrication of nanoporous BiVO4/Bi2S3 nanosheets for enhanced photoelectrochemical water splitting. AB - Nanoporous BiVO4/Bi2S3 nanosheets have been firstly fabricated through a two-step annealing followed by hydrothermal method using BiOI two-dimensional nanosheets as precursors, which could greatly improve the photoelectrochemical performances of BiVO4 due to the enhanced charge separation efficiency and the enlarged absorption range. The optimal content of Bi2S3 in the BiVO4/Bi2S3 nanocomposites has been explored by tuning the reaction time. In addition, it is found that loading co-catalysts FeOOH could further optimize the hole transfer pathway and thus enhance the photoelectrochemical water splitting ability. PMID- 30243175 TI - Noble metal-free NiS2 with rich active sites loaded g-C3N4 for highly efficient photocatalytic H2 evolution under visible light irradiation. AB - A series of noble-metal-free NiS2-loaded g-C3N4 hybrid composites were prepared via simple hydrothermal method. Benefited from the wider spectral response range and the effective separation of photoelectron-holes of g-C3N4-NiS2 heterojunction catalysts, as well as the rich unsaturated active S atoms on the NiS2 with S22-, the composite catalysts has prominent photocatalytic performance for H2 evolution. Remarkably, the optimal composite photocatalysts achieved an average hydrogen production rate as high as 715.83 MUmol/h/g in 3 h under visible-light irradiation, which is 2.75 times as high as that of precious metal Pt (259.5 MUmol/h/g) as a co-catalyst. Besides, the composite catalyst still shows prominent photocatalytic performance for H2 evolution after three continuous photocatalytic reaction cycles for 9 h. This study provided a facile method to build a low-cost but effective metal sulfide co-catalyst for hydrogen production under visible light irradiation. PMID- 30243176 TI - SILAR deposited iron phosphate as a bifunctional electrocatalyst for efficient water splitting. AB - The development of efficient and earth-abundant electrocatalysts for overall water splitting is important but still challenging. Herein, iron phosphate (FePi) electrode is synthesized using a successive ionic layer deposition and reaction (SILAR) method on a nickel foam substrate at room temperature and is used as a bifunctional electrocatalyst for water splitting. The prepared FePi electrodes show excellent electrocatalytic activity and stability for the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). The FePi electrode exhibits low overpotential of 230 mV and 157 mV towards the OER and HER, respectively, with superior long-term stability. As a result, an electrolyzer that exploits FePi as both the anode and the cathode is constructed, which requires a cell potential of 1.67 V to deliver a 10 mA cm-2 current density in 1 M KOH solution. The exceptional features of the catalyst lie in its structure and active metal sites, increasing surface area, accelerated electron transport and promoted reaction kinetics. This study may provide a facile and scalable approach to design a high-efficiency, earth-abundant electrocatalyst for water splitting. PMID- 30243177 TI - In-situ deposition of gold nanoparticles onto polydopamine-decorated g-C3N4 for highly efficient reduction of nitroaromatics in environmental water purification. AB - A green synthesized gold-catalyst (PDA-g-C3N4/Au) for highly efficient reduction of nitroaromatics by NaBH4 was proposed. Polydopamine (PDA) served as the reductant and stabilizer for AuNPs reduction, avoiding the use of chemical reductant and stabilizer that may result in secondary contamination. g-C3N4 not only acted as the support but also provided compatibility for AuNPs deposition, enhancing the stability and deposition of AuNPs, which improved the catalytic activity. Different experimental parameters including the amount of Au loading, concentration of NaBH4, and dosage of catalyst were studied. Results showed that PDA-g-C3N4/Au(3) revealed higher catalytic activity with a rate constant of 0.0514 s-1 and TOF of 545.60 h-1 for 4-NP reduction. In addition, the catalyst was highly efficient in reduction of other nitroaromatics and the reduction rates of these compounds were found as the sequence: methyl orange > 2-nitrophenol > 2, 4-dinitrophenol > Erichrome Black T > Congo red. Moreover, the PDA-g-C3N4/Au(3) catalyst kept high stability and excellent conversion efficiency over ten reduction cycles. The practical application on different real water samples suggests that this Au catalyst has promising application in environmental water purification. The simple and green synthetic Au catalyst expands the range of application and provides potential application on environmental remediation. PMID- 30243178 TI - Antireflective mesoporous silica coatings by optimization of water content in acid-catalyzed sol-gel method for application in glass covers of concentrated photovoltaic modules. AB - Porous silica layers with outstanding antireflective properties have been prepared by acid-catalyzed sol-gel process in presence of organic phases as structure directing agents (SDA) and excess water, with the aim of offering a cost-competitive, easy up-scaling and high efficiency process that contributes to reduce current levelized cost of energy (LCOE) of concentrating photovoltaics (CPV). The process has been optimized by controlling the water/alkoxide ratio, which is an important structure-regulating tool, having a strong influence in the structural properties of sol-gel synthesized materials. Hydrolysis of the inorganic precursor has been accomplished in high water/alkoxide conditions and in the presence of SDAs. Evaporation induced self-assembly (EISA) during coating deposition and the scanning of four types of SDAs have permitted to select the coating that fulfilled specific thickness and refractive index values with, in parallel, excellent results on sol stability. The final optimization has produced mesoporous coatings with ~9 nm mean pore size, leading to an enhancement in transmittance up to 7.4% over bare glass in the 300-1500 nm wavelength range. The transmittance spectra have been used as inputs for the theoretical calculation of the short-circuit current density of a commercially available multijunction solar cell for CPV applications. PMID- 30243179 TI - Intermolecular hydrogen bonding-mediated synthesis of high-quality photoluminescent carbon dots for label-free fluorometric detection of Fe3+ ions. AB - Hydrogen bonding interactions guided supramolecular self-assembly has been widely studied, which played important roles in the field of nanotechnology and nanodevices. Herein, an effective intermolecular hydrogen bonding mediated heating-up synthesis of high-quality fluorescent carbon dots (CDs) is developed based on hydrogen-bonding between trimesic acid and urea. Upon optimizing the hydrogen-bonding interaction, high quality of CDs with high monodispersity and stability could be obtained. Besides, these CDs could be used for sensitive and specific detection of ferric ions. The novel strategy may pave a new way in molecular engineering for the fabrication of high quality of CDs. PMID- 30243181 TI - Periodic limb movements in sleep: Prevalence and associated sleepiness in the Wisconsin Sleep Cohort. AB - OBJECTIVES: Periodic limb movements in sleep (PLMS) are thought to be prevalent in elderly populations, but their impact on quality of life remains unclear. We examined the prevalence of PLMS, impact of age on prevalence, and association between PLMS and sleepiness. METHODS: We identified limb movements in 2335 Wisconsin Sleep Cohort polysomnograms collected over 12 years. Prevalence of periodic limb movement index (PLMI) >=15 was calculated at baseline (n = 1084). McNemar's test assessed changes in prevalence over time. Association of sleepiness and PLMS evaluated using linear mixed modeling and generalized estimating equations. Models adjusted for confounders. RESULTS: Prevalence of PLMI >=15 at baseline was 25.3%. Longitudinal prevalence increased significantly with age (p = 2.97 * 10-14). Sleepiness did not differ significantly between PLMI groups unless stratified by restless legs syndrome (RLS) symptoms. The RLS+/PLM+ group was sleepier than the RLS+/PLM- group. Multiple Sleep Latency Test trended towards increased alertness in the RLS-/PLM+ group compared to RLS-/PLM-. CONCLUSIONS: A significant number of adults have PLMS and prevalence increased with age. No noteworthy association between PLMI category and sleepiness unless stratified by RLS symptoms. SIGNIFICANCE: Our results indicate that RLS and PLMS may have distinct clinical consequences and interactions that can help guide treatment approach. PMID- 30243180 TI - Mesoporous ZnO nanorods array with a controllable area density for enhanced photocatalytic properties. AB - Usually, a ZnO nanorods array exhibits a relatively small effective surface area due to its smooth surface and large area density (the number of ZnO nanorods per unit area). In this work, a mesoporous ZnO nanorods array with a small area density and a large effective surface area was successfully synthesized on the surface of fluorine-doped tin dioxide (FTO) glass using a facile solution process, with ethylene glycol (EG) and water serving as the mixed solvent and cadmium ions serving as an additives. The area density, aspect ratio and specific surface area of mesoporous ZnO nanorods array can be controlled by adjusting the concentration of cadmium ions in the EG-H2O mixed solution. The obtained ZnO nanorods array was applied as the photocatalyst for the photodegradation of methylene blue (MB) and showed a good catalytic performance that was dependent on the area density, rather than the specific surface area. This may be because a smaller area density of nanorods array can facilitate the diffusion of MB molecules and thus provide a larger effective surface area for MB adsorption, despite a large difference in their specific surface area. Therefore, this work can provide a guidance for synthesizing nanostructures with good photocatalytic activity on the devices. PMID- 30243182 TI - The role of oxidative stress in cardiometabolic risk related to phthalate exposure in elderly diabetic patients from Shanghai. AB - The effect of human exposure to phthalates and consequent contribution to the development of cardiometabolic health problems is unknown. However, oxidative stress has been established as playing an important role in the pathogenesis of cardiometabolic outcomes. In this study, we aimed to explore whether exposure to phthalate metabolites could induce cardiometabolic risk by increasing oxidative stress in a diabetic population from Shanghai. We collected paired blood and urine samples from a total of 300 volunteers, and measured 10 phthalate metabolites in urine and biomarkers of oxidative stress from serum including glucose and lipid levels, and liver and kidney damage. The insulin resistance (IR) risk was assessed by the surrogate indices including homeostasis model assessment-insulin resistance (HOMA-IR) and triglyceride glucose (TyG). We used multivariable linear regression to assess the association between phthalates and these physiological parameters. Mediation and modification analyses were performed to identify the role that oxidative stress played in the underlying mechanisms. The results showed that most of the determined phthalate metabolites were positively associated with HOMA-IR, 8-hydroxy-2'-deoxyguanosine (8-OHDG), and malondialdehyde (MDA). In the mediation analysis, only gamma glutamiltransferase (GGT) was found to be a significant mediator of the association between phthalates and TyG. In the modification analysis, exposure to phthalates strengthened the association between oxidative stress (MDA and 8-OHDG) and HOMA-IR. Our findings demonstrate that exposure to phthalates might be positively associated with elevated IR and oxidative stress. The direct participation (mediation effect) of GGT might play an important mechanism in promoting IR. PMID- 30243183 TI - Urinary cadmium concentrations and metabolic syndrome in U.S. adults: The National Health and Nutrition Examination Survey 2001-2014. AB - BACKGROUND: Low to moderate acute cadmium exposure has been associated with increased risk of chronic diseases, such as cardiovascular and kidney disease. Little is known about the association between urinary cadmium levels-an indicator of longer-term exposure-and metabolic syndrome (MetS). METHODS: We analysed data from 3982 participants aged 20-<80 years of the National Health and Nutrition Examination Survey 2001-2014. Urinary cadmium levels were measured and adjusted for creatinine using spot urine samples. Cadmium levels were evaluated in quintiles (Q). MetS was defined by National Cholesterol Education Program's Adult Treatment Panel III report criteria. Prevalence odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression accounting for complex survey design, while adjusting for potential confounders and stratifying by sex and smoking status. RESULTS: In the overall study population, there was a marginal inverse association between urinary cadmium and MetS (adj. OR for Q5 versus Q1: 0.7; 95% CI: 0.5-1.0). Sex stratified models were similar. When examining individual components of MetS, participants with higher levels of urinary cadmium had decreased odds of abdominal obesity (adj. OR for Q5 versus Q1 0.4; 95% CI: 0.3-0.6), but increased odds for low HDL (adj. OR for Q5 versus Q1 2.1; 95% CI: 1.4-3.1). Among current smokers, higher urinary cadmium was associated with increased odds of MetS, hypertension, and low HDL even after accounting for serum cotinine-a marker of smoking intensity. CONCLUSIONS: Higher levels of urinary cadmium, a marker of long term exposure, were not associated with an increased risk of MetS in the overall study population. However, higher urine cadmium was associated with altered MetS components. Current smokers were the most vulnerable group, with higher long-term cadmium exposure being associated with increased risk of MetS, low HDL, and hypertension. PMID- 30243185 TI - Therapeutic potentials of ginger for treatment of Multiple sclerosis: A review with emphasis on its immunomodulatory, anti-inflammatory and anti-oxidative properties. AB - Multiple sclerosis (MS) is characterized by chronic inflammatory response-induced demyelination of the neurons and degeneration of the axons within the central nervous system (CNS). A complex network of immunopathological-, inflammatory- and oxidative parameters involve in the development and advancement of MS. The anti inflammatory, immunomodulatory and anti-oxidative characteristics of the ginger and several of its components have been indicated in some of experimental and clinical investigations. The possible therapeutic potentials of ginger and its ingredients in the treatment of MS may exert mainly through the regulation of the Th1-, Th2-, Th9-, Th17-, Th22- and Treg cell-related immune responses, down regulation of the B cell-related immune responses, modulation of the macrophages related responses, modulation of the production of pro- and anti-inflammatory cytokines, down-regulation of the arachidonic acid-derived mediators, interfering with the toll like receptor-related signaling pathways, suppression of the inflammasomes, down-regulation of the oxidative stress, reduction of the adhesion molecules expression, and down-regulation of the expression of the chemokines and chemokine receptors. This review aimed to provide a comprehensive knowledge regarding the immunomodulatory-, anti-inflammatory and anti-oxidative properties of ginger and its components, and highlight novel insights into the possible therapeutic potentials of this plant for treatment of MS. The review encourages more investigations to consider the therapeutic potentials of ginger and its effective components for managing of MS. PMID- 30243184 TI - Temporal trends in serum polybrominated diphenyl ether concentrations in the Australian population, 2002-2013. AB - In Australia, systematic biomonitoring of persistent organic pollutants (POPs) in pooled serum samples stratified by age and sex has occurred every two years between 2002/03 and 2012/13. Multiple regression modeling on log10-transformed serum pool concentrations of BDEs 47, 99, 100 and 153 and on the sum of these (Sigma4PBDE) was conducted to examine trends by sex and time since baseline, stratified by age group. Temporal trends were age- and congener-specific, with the largest changes per year of observation in the 0-4 year old group, with beta (SE) = -0.098 (0.013) for log10BDE47; -0.119 (0.012) for log10BDE99; -0.084 (0.014) for log10BDE100, and -0.053 (0.013) for log10BDE153, all p < 0.001. Adults over age 16 showed much smaller decreasing temporal trends for BDE47 and BDE99, no significant changes in BDE100, and, for the oldest age groups, slight increases in BDE153. As a result, Sigma4PBDE concentrations were stable over the entire time period in adults older than 16. Concentrations of each BDE in pools from females aged 31-60 were significantly lower compared to males. Relative proportions of BDE47 declined, while BDE153 accounted for a greater share of Sigma4PBDE over time. Whereas previously we saw a large elevation in the youngest age groups compared to older children and adults, this is no longer the case. This may be due to a decline in infant and toddler exposures in the indoor environment as use of PBDEs in consumer products has been phased out, suggesting temporal changes in the relative sources of exposure for young children in Australia. PMID- 30243186 TI - The survival effect of valproic acid in glioblastoma and its current trend: a systematic review and meta-analysis. AB - Glioblastoma (GBM) can often present with seizure. Attempts have been made to associate the use of anti-epileptic medication valproic acid (VPA) in standard of care management with survival benefit in the past; however, results to date have been conflicting, and most likely subjected to historical bias. This study aimed to quantify the overall survival (OS) effect of VPA in patients with GBM based on the current literature, and identify potential trend-modifying covariates. Searches of 7 electronic databases from inception to April 2018 were conducted following the appropriate guidelines. Hazard ratios (HRs) derived from Cox proportional hazard models, and mean differences (MDs), were analyzed using the random effects model. Meta-regression was used to identify potential trend modifying covariates. Seven retrospective cohort studies satisfied selection criteria describing 2181 primary GBM diagnoses, with 534 (24%) receiving VPA in their treatment. Overall, VPA was shown to confer a statistically significant OS advantage (HR, 0.71; 95% CI, 0.56-0.91; p < 0.01) compared to the control group by up to 2.4 months (95% CI, 1.51-3.21; p < 0.01). However, upon meta-regression, this survival advantage as inferred by HRs trended towards the null in newer studies (slope, 1.15; p = 0.02) or in studies with older participants (slope, 1.13; p = 0.02). A similar result was seen with MDs. Based on the literature to date, VPA was significantly associated with better OS in GBM patients by 2.4 months when managed by current standard of care. However, this effect was particularly emphasized among older studies or studies conducted in younger participants indicating the need to exercise caution in assuming generalizability of the pooled effect. Overall, there is considerable bias risks in the current interpretation of the literature, and larger, prospective studies are required for validating our findings. PMID- 30243187 TI - Prediction of hemorrhagic transformation in patients with mild atrial fibrillation-associated stroke treated with early anticoagulation: post hoc analysis of the Triple AXEL Trial. AB - OBJECTIVES: To investigate the predictors of hemorrhagic transformation (HT) in patients with mild atrial fibrillation-related stroke who were treated with early anticoagulation. We conducted a post-hoc subgroup analysis from Acute Cerebral Infarction Patients with Non-valvular Atrial Fibrillation (Triple AXEL) study. PATIENTS AND METHODS: The Triple AXEL study was a randomized, multicenter, open label, blinded end-point evaluation, comparative phase 2 trial. To identify the relationship between the type of HT and risk factors. We analyzed various factors using data from the Triple AXEL study, such as sex, history of hypertension, diabetes, microbleeds, concomitant antiplatelet use, initial infarction volume, initial infarction location, and new intracranial hemorrhage on follow-up gradient recalled echo or susceptibility-weighted imaging. RESULTS: We analyzed various factors by dividing patients into a new HT group and a no HT group. No correlation was found between HT and risk factors that were significantly associated with HT, including age, sex, history of hypertension, diabetes, microbleeds, concomitant antiplatelet use, and initial infarction volume. When the initial infarction was classified into anterior circulation infarction (ACI) and posterior circulation infarction (PCI), the occurrence of new HT was significantly more associated with PCI than with ACI (57.6% vs 24.0%, P = 0.001). Multivariate logistic regression analysis was performed using HT as a response variable. Only the location of initial infarction according to the vascular territory contributed to the increased risk of HT (OR2.3, 95%CI1.33-3.91, P = 0.003). CONCLUSION: PCI is a very important independent risk factor for HT in patients with mild AF-related stroke treated with early anticoagulation. PMID- 30243188 TI - Transgenerational thyroid endocrine disruption induced by bisphenol S affects the early development of zebrafish offspring. AB - Maternal thyroid hormones (THs) play an essential role in the embryonic and larval development of fish. Previous studies in fish have reported that parental exposure to thyroid disrupting chemicals (TDCs) changed maternal TH levels in the offspring; however, whether this transgenerational thyroid endocrine disruption can further disturb the early development of the offspring still remains largely unknown. Bisphenol S (BPS), a substitute of bisphenol A, has been reported to be a potential TDC. In this study, zebrafish (F0) were exposed to environmentally relevant concentrations (1, 10, and 100 MUg/L) of BPS from 2 h post-fertilization to 120 days post-fertilization and then paired to spawn. Plasma levels of thyroxine (T4) were significantly decreased in F0 females while 3,5,3' triiodothyronine (T3) plasma levels were significantly increased in F0 females and males; moreover, TH content in eggs (F1) spawned by exposed F0 generation exhibited similar changes as the F0 females, with significant decreases in T4 and increases in T3, demonstrating BPS-induced maternal transfer of thyroid endocrine disruption. Further, excessive levels of maternal T3 in the offspring resulted in delayed embryonic development and hatching, swim bladder inflation defect, reduction in motility, developmental neurotoxicity, and lateral stripe hypopigmentation in non-exposed F1 embryos and larvae. These results highlight the adverse effects on the early development of offspring induced by transgenerational thyroid endocrine disruption, which have been ignored by previous studies. Therefore, these results can further improve our understanding of the ecological risks of TDCs. PMID- 30243189 TI - Azadirachtin impairs egg production in Atta sexdens leaf-cutting ant queens. AB - Leaf-cutting ants are important pests of forests and agricultural crops in the Neotropical region. Atta sexdens colonies can be composed of thousands of individuals, which form a highly complex society with a single reproductive queen. Successful control of this species is achieved only if the queen is affected. Few data are available on the lethal or sublethal effects of toxic compounds on leaf-cutting ant queens. Azadirachtin has been claimed as an effective biopesticide for insect control, but its action on leaf-cutting ants has been little explored. This study shows that azadirachtin affects oviposition in A. sexdens queens, impairing egg development by decreasing protein reserves. Azadirachtin inhibits the synthesis of vitellogenin, the major yolk protein precursor. The negative effects of azadirachtin on the reproduction of leaf cutting ant queens suggest a potential use for the control of these insects. PMID- 30243190 TI - Ambient fine particulate pollution associated with diabetes mellitus among the elderly aged 50 years and older in China. AB - The linkage between ambient air pollution exposure and occurrence of diabetes mellitus is not well defined. This study examined the association between exposure to fine particles (PM2.5) and the prevalence of diabetes among Chinese elderly people. We surveyed 11,504 adults aged >=50 years in China, estimated the annual concentrations of ambient PM2.5 using a satellite-based model of aerosol optical depth information. We employed a generalized mixed effects model to examine the association between PM2.5 and the prevalence of diabetes and explored potential effect modifiers. We estimated diabetes burden attributable to ambient PM2.5 if the observed association is indeed causal. The diabetes prevalence among the participants was 6.5% (n = 745). Our analysis found a statistically significant association between PM2.5 and diabetes. The adjusted odds ratio was 1.27 (95% confidence interval (CI), 1.12, 1.43) for each 10 MUg/m3 increment in ambient PM2.5. Stratified analyses found a lower association among the participants with higher consumption of fruit. We estimated that 22.02% (95% CI: 8.59%, 43.29%) of the diabetes cases could be ascribable to ambient PM2.5. Our finding suggests that PM2.5 exposures could increase the risk of diabetes, and if causal, could be responsible for substantial burden of diabetes among the Chinese elderly; and higher intakes of fruit might reduce the harmful effects of PM2.5, however, due to the limitation of the cross-sectional study design, more studies are warranted to confirm this observation. PMID- 30243191 TI - Transcriptional response of Mycobacterium sp. strain A1-PYR to multiple polycyclic aromatic hydrocarbon contaminations. AB - Cometabolism mechanisms of organic pollutants in environmental microbes have not been fully understood. In this study, a global analysis of Mycobacterium sp. strain A1-PYR transcriptomes on different PAH substrates (single or binary of pyrene (PYR) and phenanthrene (PHE)) was conducted. Comparative results demonstrated that expression levels of 23 PAH degradation enzymes were significantly higher in the binary substrate than in the PYR-only one. These enzymes constituted an integrated enzymatic system to actualize all transformation steps of PYR, and most of their encoded genes formed a novel gene cascade in the genome of strain A1-PYR. The roles of different genotypes of enzymes in PYR cometabolism were also discriminated even though all of their gene sequences were presented in the genome of this strain. NidAB and PdoA2B2 instead of NidA3B3 served the initial oxidization of PAHs, and PcaL replaced PcaCD to catalyze the formation of 3-oxoadipate. Novel genes associated with PYR cometabolism was also predicted by the relationships between their transcription profiles and PYR removal. The results showed that ABC-type transporters probably played important roles in the transport of PAHs and their metabolites through cell membrane, and [4Fe-4S] ferredoxin might be essential for dioxygenases (NidAB and PdoA2B2) to achieve oxidative activities. This study provided molecular insight in that microbial degrader subtly cometabolized recalcitrant PAHs with relatively more degradable ones. PMID- 30243192 TI - Developmental pathways towards mood disorders in adult life: Is there a role for sleep disturbances? AB - INTRODUCTION: Mood disorders are among the most prevalent and serious mental disorders and rank high among to the leading global burdens of disease. The developmental psychopathology framework can offer a life course perspective on them thus providing a basis for early prevention and intervention. Sleep disturbances, are considered risk factors for mood disorders across childhood, adolescence and adulthood. Assuming that sleep disturbances may play a pivotal role in the pathogenesis of mood disorders from a life course point of view, we reviewed the data on developmental pathways towards mood disorders in adult life in relation to sleep disturbances. METHOD: From February 2017, a systematic search was conducted in PubMed, PsycINFO and Embase electronic databases for literature on developmental pathways to mood disorders in adult life in relation to sleep disturbances and to 1) pre-natal stress, 2) early brain developmental processes, and 3) temperaments, character and attachment style. RESULTS: Eleven, 54 and 15 articles were respectively selected. CONCLUSIONS: Experimental and clinical studies revealed that exposure to prenatal/early life stress results in sleep disturbances such as poor sleep and altered circadian regulation phases and may predict or even precipitate mood disorders in adulthood. Chronic sleep disruption may interfere with neuronal plasticity, connectivity and the developing brain thus contributing to the development of mood disorders. In addition sleep and circadian dysregulations have been shown to be related to those temperaments, character and attachment styles which are considered precursors of mood disorders. Sleep and circadian behaviours may serve as early targets regarding mood disorders. PMID- 30243193 TI - The effects of childhood maltreatment and anxiety proneness on neuropsychological test performance in non-clinical older adolescents. AB - BACKGROUND: The effect of childhood maltreatment (CM) on neuropsychological performance is well established, but the effect of anxiety proneness (AP) on such performance has been underexplored. We assessed the predictive ability of CM and AP, and their interaction, in non-clinical adolescents, for a range of previously documented neuropsychological deficits. METHODS: Multiple linear regression models were used to assess the unique and combined influences of CM and AP on neuropsychological performance in 104 non-clinical adolescents, who underwent both neuropsychiatric and neuropsychological assessment. RESULTS: The interaction of CM and AP was associated with poorer performance in executive functioning skills, processing speed, and estimated IQ. CM and AP were uniquely associated with verbal working memory performance, while verbal and visual memory performance and learning, and visuo-spatial ability, were not associated with either CM, AP or the interaction of CM and AP. LIMITATIONS: The use of self report measures to determine participants' levels of CM, AP, and depression. The CTQ-SF, a retrospective self-report measure, may have introduced recall bias. The neuropsychological evaluation was not conducted in the Xhosa language, the first language of most African participants. Most instruments utilized have not been validated in a South African adolescent sample. The impact of important moderator variables (e.g., age of onset of maltreatment) was not assessed. CONCLUSIONS: Increased levels of CM and AP may be risk markers for poor performance in several key neuropsychological domains. Our findings underscore the importance of assessing the impact of both CM and anxiety-related temperamental traits on neuropsychological performance. PMID- 30243194 TI - Perinatal depression among a global sample of Spanish-speaking women: A sequential-process latent growth-curve analysis. AB - BACKGROUND: Despite high rates of perinatal depression among women from diverse backgrounds, the understanding of the trajectory of depressive symptoms is limited. The aim of this study was to investigate the trajectories of depressive symptoms from pregnancy to postpartum among an international sample of pregnant women. METHODS: Hispanic/Latina (79.2%), Spanish-speaking (81%) pregnant women (N = 1796; Mean age = 28.32, SD = 5.51) representing 78 unique countries/territories participated in this study. A sequential-process latent growth-curve model was estimated to examine general trajectories of depression as well as risk and protective factors that may impact depression levels throughout both the prenatal and postpartum periods. RESULTS: Overall, depression levels decreased significantly across the entire perinatal period, but this decrease slowed over time within both the prenatal and postpartum periods. Spanish-speaking women, those who were partnered, and those with no history of depression reported lower levels of depression during early pregnancy, but this buffer effect reduced over time. Depression levels at delivery best predicted postpartum depression trajectories (i.e., women with higher levels of depression at delivery were at greater risk for depression postpartum). LIMITATIONS: Given the emphasis on language and not country or culture of origin this study was limited in its ability to examine the impact of specific cultural norms and expectations on perinatal depression. CONCLUSIONS: Given these findings, it is imperative that providers pay attention to, and assess for, depressive symptoms and identified buffers for depression, especially when working with women from diverse communities. PMID- 30243195 TI - White matter - emotion processing activity relationships in youth offspring of bipolar parents. AB - BACKGROUND: Early detection of Bipolar Disorder (BD) is critical for targeting interventions to delay or prevent illness onset. Yet, the absence of objective BD biomarkers makes accurately identifying at-risk youth difficult. In this study, we examined how relationships between white matter tract (WMT) structure and activity in emotion processing neural circuitry differentiate youth at risk for BD from youth at risk for other psychiatric disorders. METHODS: Offspring (ages 8 17) of parents with BD (OBP, n = 32), offspring of comparison parents with non-BD psychopathology (OCP, n = 30), and offspring of healthy parents (OHP, n = 24) underwent diffusion tensor and functional magnetic resonance imaging while performing an emotional face processing task. Penalized and multiple regression analyses included GROUP(OBP,OCP)xWMT interactions as main independent variables, and emotion processing activity as dependent variables, to determine significant group differences in WMT-activity relationships. RESULTS: 8 GROUPxWMT interaction variables contributed to 16.5% of the variance in amygdala and prefrontal cortical activity to happy faces. Of these, significant group differences in slopes (inverse for OBP, positive for OCP) existed for the relationship between forceps minor radial diffusivity and rostral anterior cingulate activity (p = 0.014). Slopes remained significantly different in unmedicated youth without psychiatric disorders (p = 0.017) and were moderated by affective lability symptoms (F(1,29) = 5.566, p = 0.036). LIMITATIONS: Relatively small sample sizes were included. CONCLUSIONS: Forceps minor radial diffusivity-rostral anterior cingulate activity relationships may reflect underlying neuropathological processes that contribute to affectively labile youth at risk for BD and may help differentiate them from youth at risk for other psychiatric disorders. PMID- 30243196 TI - Measurement equivalence of the Social Interaction Anxiety Scale (SIAS) and Social Phobia Scale (SPS) across individuals with social anxiety disorder from Japanese and Australian sociocultural contexts. AB - BACKGROUND: Cultural factors influence both the expression of social anxiety and the interpretation and functioning of social anxiety measures. This study aimed to test the measurement equivalence of two commonly used social anxiety measures across two sociocultural contexts using individuals with social anxiety disorder (SAD) from Australia and Japan. METHODS: Scores on the straightforwardly-worded Social Interaction Anxiety Scale (S-SIAS) and the Social Phobia Scale (SPS) from two archival datasets of individual with SAD, one from Australia (n = 201) and one from Japan (n = 295), were analysed for measurement equivalence using a multigroup confirmatory factor analysis (CFA) framework. RESULTS: The best fitting factor models for the S-SIAS and SPS were not found to be measurement equivalent across the Australian and Japanese samples. Instead, only a subset of items was invariant. When this subset of invariant items was used to compare social anxiety symptoms across the Australian and Japanese samples, Japanese participants reported lower levels of fear of attracting attention, and similar levels of fear of overt evaluation, and social interaction anxiety, relative to Australian participants. LIMITATIONS: We only analysed the measurement equivalence of two social anxiety measures using a specific operationalisation of culture. Future studies will need to examine the measurement equivalence of other measures of social anxiety across other operationalisations of culture. CONCLUSIONS: When comparing social anxiety symptoms across Australian and Japanese cultures, only scores from measurement equivalent items of social anxiety measures should be used. Our study highlights the importance of culturally-informed assessment in SAD. PMID- 30243197 TI - Adolescent and adult differences in major depression symptom profiles. AB - BACKGROUND: Depression is the leading global cause of disability and often begins in adolescence. The genetic architecture and treatment response profiles for adults and adolescents differ even though identical criteria are used to diagnose depression across different age groups. There is no clear consensus on how these groups differ in their symptom profiles. METHODS: Using data from a two generation family study, we compared the presentation of DSM-IV depressive symptoms in adolescents and adults with MDD (Major Depressive Disorder). We also compared DSM-IV depressive symptom counts using latent class analysis. RESULTS: Vegetative symptoms (appetite and weight change, loss of energy and insomnia) were more common in adolescent MDD than adult MDD. Anhedonia/loss of interest and concentration problems were more common in adults with MDD. When using latent class analysis to look at depressive symptoms, a vegetative symptom profile was also seen in adolescent depression only. LIMITATIONS: Adults and adolescents were recruited in different ways. Adolescent cases were more likely to be first-onset while adult cases were recurrences. It was not possible to examine how recurrence affected adolescent depression symptom profiles. CONCLUSION: Differences in how depression presents in adolescents and adults may be consistent with different pathophysiological mechanisms. For adolescents, we found that vegetative/physical disturbances were common (loss of energy, changes in weight, appetite and sleep changes). For adults, anhedonia/loss of interest and concentration difficulties were more common. PMID- 30243198 TI - Adhering to a vegetarian diet may create a greater risk of depressive symptoms in the elderly male Chinese population. AB - BACKGROUND: A vegetarian diet may be a risk factor for depression, but this relationship was unclear in the elderly Chinese population. METHODS: Self-report data were gathered from 1051 elderly persons using the Cohort of Elderly Health and Environment Controllable Factors, which was created in West Anhui, China. The depressive symptoms were set as binary, ordinal, and continuous outcomes, respectively, whereas the dietary structures were computed as an ordinal variable and a dummy variable. Multiple logistic regression, ordinal regression, and linear regression were used to assess the relationship by adjusting the potential confounding variables with p-values of <0.1 in univariate analysis. RESULTS: The elderly participants who had a vegetable-based diet had the highest GDS scores of 8.78 +/- 6.894 (p = 0.001) and the highest rate of depression (32.9%, p = 0.003). After adjustment for the potential confounders, elderly men who had a vegetable based diet had a higher rate of depression (OR[95%CI]: 1.62[1.07-2.46], 4.71[1.38 16.03]), more severe symptoms of depression (OR[95%CI]: 8.85[2.94-34.12]), and higher GDS scores (beta[95%CI]: 1.46[0.70-2.22], 2.97[1.28-4.67]) than male participants who had a meat-based diet, but this was not the case in women. LIMITATIONS: All data were self-reported. The study lacked quantitatively evaluated dietary intake. The duration of the current dietary structures and comorbidities were not reported. The cross-sectional study made the causal role uncertain. CONCLUSIONS: Vegetarian diets may pose a greater risk of depressive symptoms among the elderly Chinese population, especially elderly men. Given the cross-sectional nature of this study, the causal role was uncertain. Further prospective studies, in particular among elderly women, are needed. PMID- 30243199 TI - The type and pain provoking nature of exercise prescribed for low back pain: A survey of Australian health professionals. AB - OBJECTIVES: To explore the type of exercise prescribed by Australian health professionals for LBP, and whether the exercises prescribed are pain-free or into pain. METHODS: A survey of physiotherapists and exercise physiologists was conducted from all states/territories in Australia. The survey contained two chronic LBP vignettes with different pain mechanisms (dominant nociceptive or central sensitisation pain) and one acute LBP vignette. Respondents were asked if they would prescribe advice to stay active and exercise. If exercise was prescribed, respondents were asked to specify the type and pain provoking nature (exercise with no pain, exercise to the start of pain, exercise with pain at a tolerable level or exercise irrespective of pain). RESULTS: The response rate was 17%(218/1276). Most respondents prescribed advice to stay active(>=95%) and exercise(>=90%) for all vignettes. Irrespective of the vignette, several exercises were prescribed [aerobic (57-85% of clinicians), motor control (62-84% of clinicians), range of motion (72-75% of clinicians)]. Strengthening exercise was prescribed more for chronic(>60%) than acute LBP(23%). Irrespective of the exercise, between 20 and 25% of respondents prescribed pain-free exercise, between 71 and 79% of respondents prescribed exercise into pain, and <=4% prescribed exercise irrespective of pain for acute and chronic LBP. CONCLUSIONS: Several exercises are prescribed for LBP, irrespective of pain mechanism or duration, with more clinicians prescribing strengthening exercise for chronic than acute LBP. Most clinicians prescribed exercise into pain for acute and chronic LBP, irrespective of the exercise. Further research should determine which exercises are beneficial based on pain mechanism and duration, and whether exercise into pain should be prescribed for LBP. PMID- 30243200 TI - High central venous pressure is associated with acute kidney injury and mortality in patients underwent cardiopulmonary bypass surgery. AB - PURPOSE: We sought to investigate the relationship between high CVP, AKI, and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. MATERIALS: All patients aged 18 years or older who underwent cardiac surgery with CPB were prospectively reviewed. Patients were excluded when renal artery were involved before and during surgery. Patients were dichotomized into high CVP group(>10 mmHg) and low CVP group(<10 mmHg). All patients were followed by telephone. RESULTS: A total of 1941 patients were included in observed study. In high CVP group, three hundred forty-seven patients (43.32%) developed AKI, while eighty-six (7.543%) in low CVP group(P <0.0001). Furthermore, in every KDIGO stage, patients of AKI in high CVP group were more than those in low CVP group(P <0.0001). The incidence of AKI increased as CVP increased, especially when CVP was higher than 10cmH2O. In a median follow-up time of 9.2 months, Crude mortality is 8.365% in the high CVP group compared to 1.929% in the low CVP group (p<0.0001). In multivariate analysis, CVP remained the independent predictor of survival. CONCLUSIONS: High CVP is associated with AKI , and it is independently related to all-cause mortality in patients underwent cardiovascular surgery with cardiopulmonary bypass. PMID- 30243201 TI - Bedside electromagnetic-guided placement of nasoenteral feeding tubes among critically Ill patients: A single-centre randomized controlled trial. AB - PURPOSE: We aimed to compare the effectiveness of EM-guided and endoscopic nasoenteral feeding tube placement among critically ill patients. MATERIALS AND METHODS: We performed a single-center, randomized controlled trial among 161 adult patients admitted to intensive care units (ICUs) requiring nasoenteral feeding. Patients were randomly assigned to EM-guided or endoscopic nasoenteral feeding tube placement (1:1). The primary end point was the total success rate of correct jejunal placement. RESULTS: This was achieved in 74/81 and 76/80 patients who underwent EM-guided and endoscopic jejunal tube placements, respectively (91.4% vs. 95%; relative risk, 0.556; [CI], 0.156-1.980; P = 0.360). The EM guided group had more placement attempts, longer placement time, and shorter inserted nasal intestinal tube length. However, they had shorter total placement procedure duration and physician's order-tube placement and order-start of feeding intervals. The EM-guided group had higher discomfort level and recommendation scores and lesser patient costs. This trial is registered at Chinese Clinical Trials Registry (ChiCTR-IOR-17011737). CONCLUSION: Bedside EM guided placement is as fast, safe, and successful as endoscopic placement and may be considered the preferred technique in critically ill patients. PMID- 30243202 TI - A multi-center evaluation of a disposable catheter to aid in correct positioning of the endotracheal tube after intubation in critically ill patients. AB - PURPOSE: To demonstrate that use of a minimally invasive catheter reduces endotracheal tube (ETT) malposition rate after intubation. MATERIALS AND METHODS: This study is a multi-center, prospective observational cohort of intubated patients in the medical intensive care unit. The catheter was inserted into the ETT immediately after intubation. The ETT was adjusted accordingly based on qualitative color markers on the catheter. A confirmatory chest radiograph was obtained to determine the ETT position. Malposition of the ETT was defined by the distal ETT not being within 2-5 cm above the carina. RESULTS: Sixty-nine patients were enrolled, age 56.2 +/- 19.5 years, body mass index 31.0 +/- 13.8 kg/m2. The catheter prompted repositioning of the ETT in 39 (56.5%) patients. Using the catheter, the rate of malposition decreased to 7.2%, with the distal ETT position at 3.7 +/- 1.2 cm above the carina. Without the catheter, the ETT malposition rate would have been 39.1%. The time for catheter use and chest radiograph completion at our institutions was 1.7 +/- 1.5 and 44.4 +/- 36.4 min, respectively. CONCLUSIONS: With use of an ETT positioning catheter after intubation, the ETT malposition rate was reduced by 82%. This catheter-based system was safe, and its use may perhaps decrease the need for the post intubation chest radiograph. PMID- 30243203 TI - Robotic technology provides objective and quantifiable metrics of neurocognitive functioning in survivors of critical illness:A feasibility study. AB - PURPOSE: To assess the feasibility of using an integrated multimodal data collection strategy to characterize the post-intensive care syndrome (PICS). MATERIALS AND METHODS: Adult patients admitted to the ICU requiring invasive mechanical ventilation for >24 h and/or requiring vasopressor support were eligible for enrollment. We assessed cognitive and sensorimotor function at 3- and 12-months after ICU discharge with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and with the KINARM robot. RESULTS: At 3- and 12-months after ICU discharge, 28/70 (40%) and 22/70 (31%) returned for follow-up testing, respectively. Prominent reasons for declining testing at 3- and 12-months included: not interested (40% and 38%) and health complications (31% and 31%). The majority of returning participants completed all tasks (96% 100%) and 100% of available data was recorded. On the RBANS, 54% (3 months) and 32% (12 months) of individuals were impaired in visuospatial/constructional skills. Similarly, the KINARM assessments demonstrated that 56% of individuals had visuospatial/executive dysfunction at 3 months, and 40% had impairment at 12 months. Individual scores indicated substantial variability. CONCLUSIONS: We demonstrated that it was feasible to quantify neurological dysfunction among participants that returned for follow-up testing. However, future investigations will need to implement multiple retention strategies. TRIAL REGISTRATION: This trial is registered on clinicaltrials.gov (Identifier: NCT02344043), retrospectively registered January 8, 2015. PMID- 30243204 TI - An automated computerized critical illness severity scoring system derived from APACHE III: modified APACHE. AB - PURPOSE: To evaluate the performance of an automated computerized ICU severity scoring derived from the APACHE III. MATERIALS AND METHODS: Within a retrospective cohort of patients admitted to Veterans Health Administration ICUs between 2009 and 2015, we created an automated illness severity score(modified APACHE or mAPACHE), that we extracted from the electronic health records, using the same scoring as the APACHE III excluding the Glasgow Coma Scale, urine output, arterial blood gas components of APACHE III. We assessed the mAPACHE discrimination by using the area under the curve(AUC), and calibration by using the Hosmer-Lemeshow test and calculating the difference between observed and expected mortality across equal-sized risk deciles for death. RESULTS: The ICU and 30-day mortality was 5.07% of 7.82%, respectively (n = 490,955 patients). The AUC of mAPACHE for ICU and 30-day mortality was 0.771 and 0.786, respectively. The Hosmer-Lemeshow test was significant for both ICU and 30-day mortality (p < .001). The absolute difference between observed and expected mortality did not exceed +/-1.53% across equal-sized deciles of risk for death. The AUC for ICU mortality was >0.7 in all admission diagnosis categories except in endocrine, respiratory, and sepsis. The AUC for 30-day mortality was >0.7 in every category. CONCLUSION: mAPACHE has adequate performance to predict mortality. PMID- 30243206 TI - Comparative copper toxicity impact and enzymatic cascade effect on Biosorption Activated Media and woodchips for nutrient removal in stormwater treatment. AB - Copper, a commonly occurring heavy metal in stormwater runoff, was tested for its inhibitory effects on key nitrogen cycle bacteria in Biosorption Activated Media (BAM) and woodchip. The information in this paper is used to show that copper can enhance the denitrification process through enzyme cascade reactions since nitrous reductase is the enzyme responsible for the last step of denitrification and is largely dependent on copper as its cofactor. However, media characteristics are critical for assessing multi-enzymatic cascade reactions from the microbial ecology point of view. Moreover, both media showed significant copper removal through various mechanisms at 30 cm depth. The bioactivity evaluation indicates that other bacteria (fermentative bacteria, etc.) can be largely depressed with the presence of copper, hence the biofilm structure would be more vulnerable under shearing effects, which may result in holistic depression on the microbial community. PMID- 30243205 TI - Femoral versus jugular access for Denali Vena Cava Filter placement: Analysis of fluoroscopic time, filter tilt and retrieval outcomes. AB - PURPOSE: To analyze relevant metrics involved in Denali Vena Cava Filter placement via different venous access sites. MATERIALS AND METHODS: Patients with Denali filters inserted between March 2017 and February 2018 were retrospectively analyzed. Pre-procedural and pre-retrieval computed tomography (CT) were reviewed. We compared inferior vena cava (IVC) diameter, filter tilt angle, filter tip IVC wall abutment, fluoroscopy time, and retrieval outcomes by venous access site. Filter tip abutment/limb penetration and procedure-related complications were investigated. RESULTS: Seventy-eight patients had successfully placed Denali filters. Seventy-one of 78 (91%) patients had both pre-procedural and pre-retrieval CT. The majority (35 [49%]) were placed via the right femoral vein (left femoral vein: 22 [31%]; right internal jugular vein: 14 [20%]). The jugular approach involved a longer fluoroscopy time (mean 117 +/- 37 s [s]) than the right and left femoral approaches (mean 64 +/- 21 s, mean 67 +/- 15 s, respectively [p < 0.05]). Filter tilt and filter tip abutment were not significantly different between the 3 access routes. Filter tip abutment and limb penetration were observed in 8/71 (11%) and 2/71 (3%) patients, respectively. Filter retrieval was attempted in 68 of 78 (87%) cases, and all filters were successfully retrieved. One filter arm fractured during advanced retrieval; no other procedure related complications were recorded. CONCLUSIONS: Both femoral venous approaches can be safely used for placement of the Denali filter. Femoral venous access involved a shorter fluoroscopy time without any differences in filter tilt and filter tip abutment compared to transjugular access. PMID- 30243207 TI - Comparison of modes of action between fish and zebrafish embryo toxicity for baseline, less inert, reactive and specifically-acting compounds. AB - The mode of action (MOA) plays a key role in the risk assessment of pollutants in water. Although fish is a key model organism used in the risk assessment of pollutants in water, the MOAs have not been compared between fish and embryo toxicity for classified compounds. In this paper, regression analysis was carried out for fish and embryo toxicities against the calculated molecular descriptors and MOAs were evaluated from toxicity ratio. The toxicity significantly related with the chemical hydrophobicity for baseline and less inert compounds, respectively, indicates that these two classes of compounds share the same MOAs between fish and embryos. Comparison of the toxicity ratios shows that reactive compounds exhibit excess toxicity to both fish and embryos. These compounds can react covalently with biologically target molecules through nucleophilic addition reactions, Michael addition oxidation, or amination. Comparing with baseline, less inert and reactive compounds, many specifically-acting compounds have strong docking capacity with protein molecules. Some specifically-acting compounds, such as fungicides, have very similar toxic effect to both fish and embryos. However, insecticides are more toxic to fish than embryos; herbicides and medications are more toxic to embryos than fish. Differences in the interactions of chemicals with target molecules or bioconcentration potentials between fish and embryos may result in the differences in toxic effects. There are some factors that influence the identification of MOAs, such as quality of toxicity data, bioavailability and ionization. These factors should be considered in the identification of MOAs in the risk assessment of organic pollutants. PMID- 30243208 TI - Developmental toxicity and biological responses of zebrafish (Danio rerio) exposed to anti-inflammatory drug ketoprofen. AB - Ketoprofen a nonsteroidal anti-inflammatory drug (NSAID) is widely used in over the-counter to treat pain, swelling and inflammation. Due to extensive application these drugs has been detected in surface waters which may create a risk to aquatic organisms. The aim of the present study is to assess the ecotoxicity of ketoprofen at different concentrations (1, 10 and 100 MUg/ml) on embryos and adult zebrafish (1, 10 and 100 MUg L-1) under laboratory conditions. In embryos, concentration dependent developmental changes such as edema, spinal curvature, slow heartbeat, delayed hatching, and mortality rate were observed. In adult zebrafish, biochemical enzymes such as AST, ALT and LDH activities were significantly (P < 0.05) increased whereas a decrease in Na+/K+-ATPase activity was noticed in all the tested concentrations of the drug ketoprofen. Similarly, exposure of ketoprofen caused a significant decrease in antioxidant levels in liver tissue (SOD, CAT, GSH, GPx, and GST). However, lipid peroxidation (LPO) level in liver tissue was found to be increased. The histopathological studies further evidenced the impact of ketoprofen in the liver tissue of zebrafish. The present result concludes that ketoprofen could have an impact on the development and biological endpoints of the zebra fish at above concentrations. The malformation in the development of the embryo and changes in the biological end points may provide integrated evaluation of the toxic effect of ketoprofen on zebrafish in a new perspective. PMID- 30243209 TI - Chlorinated and brominated bisphenol A derivatives: Synthesis, characterization and determination in water samples. AB - Bisphenol A (BPA) has been used in the plastics industry for several decades. During the treatment of drinking water with chlorine reagent, the formation of chlorinated derivatives of BPA (ClxBPA) but also bromoBPA and bromochloroBPA is to be expected. Some of these compounds are considered to have an estrogenic effect and could induce major risks for human health by targeting different organs and systems in the body. In this paper, we describe the synthesis of chloro- and bromobisphenol A (ClxBPA, BrxBPA, BrxClxBPA)and their analytical characterization. These derivatives could be used as analytical standards in LC MS/MS or evaluated in in vitro biological tests for their potential as endocrine disruptors. In this study, we evaluated the presence of BPA, ClxBPA in a pilot study from water samples. Range values found for BPA, ClxBPA were respectively 2.8-4169.3 ng/L and 0.8-11.3 ng/L. PMID- 30243210 TI - Major structural rearrangements of the canonical eukaryotic translation initiation complex. AB - Translation initiation in eukaryotes is a complex multistep process that requires the interplay of over a dozen protein factors together with the small ribosomal subunit (SSU) and the mRNA. During all these steps, the SSU serves as a platform for attachment, displacement and release of different molecules. In recent years, the great number of high-resolution X-ray and cryo-EM structures provided unprecedented insights into the molecular mechanism of this important process in eukaryotes. More specifically, cryo-EM became a leading technique in uncovering the structural details of this process due to exceptional advances in resolution and in image processing. Here, we briefly review cap-dependent eukaryotic translation initiation with an emphasis on its major conformational changes at several key steps during the process, unraveled thanks to the recent advances in the structural biology field. PMID- 30243211 TI - Measurement of volatile organic compounds and associated risk assessments through ingestion and dermal routes in Dongjiang Lake, China. AB - This study aims to investigate the occurrence, distribution and risk assessment of volatile organic compounds (VOCs) in Dongjiang Lake of China. Twenty two kinds of VOCs were detected, and the major VOCs were alkene compounds. The total concentration of VOCs (?VOCs) ranged from 2.93 to 4.69 ug/L, and none of the VOCs detected in Dongjiang Lake exceeded the concentration limits set in the National Drinking Water Quality Standards (GB5749-2006) or the National Environmental Quality Standards for Surface Water (GB3838-2002) of China. Risk quotients (RQ) model, Multimedia Environment Pollutant Assessment System (MEPAS) and value of odor hazard index (OHI) were used to assess the ecological risk, lifetime carcinogenic risk and olfactory risk of VOCs in Dongjiang Lake, respectively. The RQtotal values varied from 3.95 * 10-3 to 0.34 and the RQ values for all the 22 detected VOCs in 12 sample locations of Dongjiang Lake were below 0.01, which means negligible risk to aquatic organisms. The cancerous and non-cancerous risk indices were in the range of 2.31 * 10-9-5.16 * 10-7 and 1.68 * 10-7-1.45 * 10-2, respectively. Bromodichloromethane and 1,1-dichloroethene were associated with the highest and lowest carcinogenic risks in all 12 sample locations. Results also demonstrated that the olfactory risk in Dongjiang Lake is negligible. These data suggest that the VOCs in Dongjiang Lake may not lead great ecological and health risks for organism and human. PMID- 30243212 TI - The effects of habitual foot strike patterns on Achilles tendon loading in female runners. AB - BACKGROUND: Female runners that habitually use a forefoot/midfoot strike pattern (non-rearfoot runners) may be at greater risk for Achilles tendinopathy compared to runners that habitually use a rearfoot strike pattern. Differences in Achilles tendon loading between non-rearfoot and rearfoot strike runners may be a contributing factor. RESEARCH QUESTION: Our purpose was to determine if there were differences in Achilles tendon loading and cross-sectional area between female habitual rearfoot and non-rearfoot strike runners. METHODS: Thirty-five female runners participated in this cross-sectional study (17 rearfoot strike runners, 18 non-rearfoot strike runners). Ultrasound images of the Achilles tendon were used to measure cross-sectional area. Kinematic and kinetic data were collected at a set running speed and used in a muscloskeletal model to calculate Achilles tendon force. Achilles tendon stress was determined from specific Achilles tendon cross-sectional area. Principal components (PC) analysis was performed to identify/characterize the primary sources of variability in the Achilles tendon stress time series. The PC scores and cross-sectional area where compared using independent t-tests. RESULTS: PC 1 reflected variability in the Achilles tendon stress magnitude from 25 to 100% of stance, PC 2 reflected timing variability, and PC 3 reflected variability in the magnitude during early stance (0-25%). The non-rearfoot strike runners demonstrated higher PC scores for PC 1 and PC 3 compared to the rearfoot strike runners. This reflected greater Achilles tendon stress during mid/late stance (PC 1) and early stance (PC 3) for the non rearfoot strike runners. For PC 2, there was a trend toward higher PC scores in the non-rearfoot strike runners. Achilles tendon cross-sectional area for the rearfoot and non-rearfoot strike runners were not different. SIGNIFICANCE: Habitual non-rearfoot strike runners did not have greater cross-sectional area despite higher Achilles tendon loading, which may pose a higher risk for Achilles tendinopathy. PMID- 30243213 TI - Cognitive function impacts gait, functional mobility and falls in fragile X associated tremor/ataxia syndrome. AB - BACKGROUND: Executive function and information processing speed deficits occur in fragile X premutation carriers (PMC) with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Gait is negatively impacted by cognitive deficits in many patient populations resulting in increased morbidity and falls but these relationships have not been studied in FXTAS. RESEARCH QUESTION: We sought to investigate the associations between executive function and information processing speed and gait, turning and falls in PMC with and without FXTAS compared to healthy controls. METHODS: Global cognition and the cognitive domains of information processing speed, attention, response inhibition, working memory and verbal fluency were tested with a neuropsychological test battery in 18 PMC with FXTAS, 15 PMC without FXTAS, and 27 controls. An inertial sensor based instrumented Timed Up and Go was employed to test gait, turns and functional mobility. RESULTS: Lower information processing speed was significantly associated with shorter stride length, reflecting slower gait speed, in PMC with FXTAS (p = 0.0006) but not PMC without FXTAS or controls. Lower response inhibition was also significantly associated with slower turn-to-sit times in PMC with FXTAS (p = 0.034) but not in those without FXTAS or controls. Lower information processing speed (p = 0.012) and working memory (p = 0.004), were significantly correlated with a greater number of self-reported falls in the past year in FXTAS participants. SIGNIFICANCE: This is the first study demonstrating that worse executive function and slower information processing speed is associated with reduced gait speed and functional mobility, as well as with a higher retrospective fall history in participants with FXTAS. This information may be important in the design of cognitive and motor interventions for this neurodegenerative disorder. PMID- 30243214 TI - Perceived usefulness of the International Classification of Functioning, Disability and Health (ICF) increases after a short training: A randomized controlled trial in master of advanced nursing practice students. AB - The Master program of Advanced Nursing Practice (MANP) educates nurses to become a nurse practitioner. Nurse practitioners are health care professionals focusing on the intersection of cure and care. However, a clear model covering that area is lacking. The use of the International Classification of Functioning, Disability and Health (ICF) may be considered for incorporation in curricula due to its focus on the integration of cure and care. The purpose of this study is to test the effects of a short (= 4-h instructor-led) ICF training on perceived usefulness of the ICF. In a randomized controlled trial, 76 MANP students were randomly allocated to intervention or control group. Data were collected using an 'ICF survey and learning assessment tool'. Data of 56 students were included for analysis. Perceived usefulness of the ICF increased significantly in the intervention group immediately after training (p = 0.001) but no longer at 3 months follow-up (p = 0.388). Attitude and knowledge related to the ICF were significantly increased in the intervention group at both post-training assessments (p < 0.001 and 0.02). The positive influence of the ICF training on perceived usefulness of the ICF is relevant for including ICF in MANP curriculum. PMID- 30243215 TI - Commentary on the utility of the National Toxicology Program study on cell phone radiofrequency radiation data for assessing human health risks despite unfounded criticisms aimed at minimizing the findings of adverse health effects. AB - The National Toxicology Program (NTP) conducted two-year studies of cell phone radiation in rats and mice exposed to CDMA- or GSM-modulated radiofrequency radiation (RFR) at exposure intensities in the brain of rats that were similar to or only slightly higher than potential, localized human exposures from cell phones held next to the head. This study was designed to test the (null) hypothesis that cell phone radiation at non-thermal exposure intensities could not cause adverse health effects, and to provide dose-response data for any detected toxic or carcinogenic effects. Partial findings released from that study showed significantly increased incidences and/or trends for gliomas and glial cell hyperplasias in the brain and schwannomas and Schwann cell hyperplasias in the heart of exposed male rats. These results, as well as the findings of significantly increased DNA damage (strand breaks) in the brains of exposed rats and mice, reduced pup birth weights when pregnant dams were exposed to GSM- or CDMA-modulated RFR, and the induction of cardiomyopathy of the right ventricle in male and female rats clearly demonstrate that the null hypothesis has been disproved. The NTP findings are most important because the International Agency for Research on Cancer (IARC) classified RFR as a "possible human carcinogen" based largely on increased risks of gliomas and acoustic neuromas (which are Schwann cell tumors on the acoustic nerve) among long term users of cell phones. The concordance between rats and humans in cell type affected by RFR strengthens the animal-to-human association. This commentary addresses several unfounded criticisms about the design and results of the NTP study that have been promoted to minimize the utility of the experimental data on RFR for assessing human health risks. In contrast to those criticisms, an expert peer-review panel recently concluded that the NTP studies were well designed, and that the results demonstrated that both GSM- and CDMA-modulated RFR were carcinogenic to the heart (schwannomas) and brain (gliomas) of male rats. PMID- 30243216 TI - An EM-based semi-supervised deep learning approach for semantic segmentation of histopathological images from radical prostatectomies. AB - Automated Gleason grading is an important preliminary step for quantitative histopathological feature extraction. Different from the traditional task of classifying small pre-selected homogeneous regions, semantic segmentation provides pixel-wise Gleason predictions across an entire slide. Deep learning based segmentation models can automatically learn visual semantics from data, which alleviates the need for feature engineering. However, performance of deep learning models is limited by the scarcity of large-scale fully annotated datasets, which can be both expensive and time-consuming to create. One way to address this problem is to leverage external weakly labeled datasets to augment models trained on the limited data. In this paper, we developed an expectation maximization-based approach constrained by an approximated prior distribution in order to extract useful representations from a large number of weakly labeled images generated from low-magnification annotations. This method was utilized to improve the performance of a model trained on a limited fully annotated dataset. Our semi-supervised approach trained with 135 fully annotated and 1800 weakly annotated tiles achieved a mean Jaccard Index of 49.5% on an independent test set, which was 14% higher than the initial model trained only on the fully annotated dataset. PMID- 30243217 TI - Interference of engineered nanomaterials in flow cytometry: A case study. AB - Nanotechnology is regarded as the enabling technology of the 21st century. However, only a relatively small number of nano-enabled medical and healthcare products finally made their way to the market. There are several reasons why such innovative approaches fail in translation, with one key factor being the uncertainty surrounding their safety assessment. Although well described, interference reactions of engineered nanomaterials (ENM) with classical cytotoxicity assays remain a major source of uncertainty. Flow cytometry is a powerful, widely used, in vitro technique. Its readout is based on the detection of refracted laser light and fluorescence signals. It is therefore susceptible to ENM interference. Here we investigated possible interferences of ENM in the Annexin V/propidium iodide (PI) assay, which quantifies apoptotic and necrotic cell populations by flow cytometry. Two case studies were conducted using either silica or gold nanoparticles differing in size, specific surface area and surface chemistry. Both ENM types were found to cause distinct interference reactions at realistic concentrations. Silica particles induced false-positive signals; however only in the absence of a protein corona and in conjunction with a particular fluorophore combination (FITC/PI). In contrast, gold particles led to complex quenching effects which were only marginally influenced by the presence of proteins and occurred for both fluorophore combinations analyzed. We present a versatile spike-in approach which is applicable to all ENM and cell types. It further allows for the identification of a broad range of different interference phenomena, thereby increasing the reliability and quality of flow cytometry and ENM hazard assessment. PMID- 30243218 TI - Dual responsive gelatin-based nanoparticles for enhanced 5-fluorouracil efficiency. AB - The very slow progress in the therapeutic efficacy of the treatment of severe diseases has suggested the use of a growing need for a multidisciplinary approach to the delivery of therapeutics to targets tissues. There has been increasing effort in the design of stimuli-responsive nanomaterials that they will be developed into effective drug delivery vehicles. Most commonly, effective drug delivery is associated with nanomaterial-facilitated accumulation and/or cellular internalization. Recent studies in our lab have demonstrated that gelatin-based NPs can be considered suitable pH responsive devices for the effective intracellular delivery of drugs. Concerning cancer treatment, ligands recognizing tumour-associated antigens expressed on the surface of the tumour cells have been employed. Some of the target structures suitable for tumour targeting belong to integrins which mediate cell adhesion to extracellular matrix and other cells. Interestingly, gelatin chains contain motifs such as RGD sequences that can be recognised by integrins. In this work the inclusion of the anticancer drug 5 fluorouracil (5-FU) on these gelatin-based NPs has been projected. These NPs may provide an opportunity to increase the therapeutic effect using a dual approach by: i) targeting the therapeutic drug to the tumour cells by the action of the naturally occurring RGD-motif on gelatin and ii) minimizing the non-productive trafficking from endosomes to lysosomes by releasing the cargo using the charge reversal approach after cellular internalization. In vitro cytotoxicity experiments of NPs on tumoral and non-tumoral cell lines have reported selectivity indexes higher than 30 demonstrating a great selectivity on the mode of action as a function of the cell line and the imposed compositions. PMID- 30243219 TI - N-acetylcysteine modified hyaluronic acid-paclitaxel conjugate for efficient oral chemotherapy through mucosal bioadhesion ability. AB - N-acetylcysteine modified hyaluronic acid-paclitaxel (NAC-HA-PTX) conjugate was designed to improve the water solubility and oral bioavailability of PTX through mucosal bioadhesion ability. The average size of spherical NAC-HA-PTX micelles was 187 nm with a zeta potential of -25.38 mV. Mucin adhesion study showed that the amount of mucin adhered to NAC-HA-PTX micelles was 1.98-fold greater than that of hyaluronic acid-paclitaxel (HA-PTX) micelles. The fluorescence micrographs showed that the biodistribution sequence of coumarin 6-loaded micelles in the gastrointestinal tract was duodenum > jejunum > ileum, and NAC modified micelles significantly exhibited better mucoadhesive properties than the corresponding unmodified ones. The pharmacokinetic study showed that the area under the curve (AUC0-24h) of NAC-HA-PTX micelles was 2.32-fold and 2.56-fold higher compared to that of HA-PTX micelles and PTX solution (Taxol) after oral administration, respectively. NAC-HA-PTX micelles appear to be a promising drug delivery system to improve the bioavailability of insoluble drugs for efficient tumor therapy via oral administration. PMID- 30243220 TI - The comparison genomics analysis with glioblastoma multiforme (GBM) cells under 3D and 2D cell culture conditions. AB - GBM, the most common and aggressive malignant primary brain tumors which needs new research approach to reveal the underline molecular mechanism of tumor progression. The 3D in vitro tumor model can be a simple and effective way to study tumor characteristics with ability to replicate of the tumor milieu. In the current study, we adopted the DNA microarray to analyze the gene expression of GBM tumor cells cultured under 2D cell culture flasks and 3D PLA porous scaffolds for 4,7 and 14 days. For 14 day old cultures, 8117 and 3060 genes expression were upregulated and downregulated respectively. Further KEGG pathway analysis revealed, the upregulated genes were mainly enriched/involved in PPAR and PI3K Akt signaling pathways whereas the downregulated genes were mainly contributed in metabolism, ECM related and TGF-beta pathways. Thus, our approach of establishing 3D in vitro tumor model provides realistic results and proves itself a powerful tool for understanding the inner nature of GBM and can be considered as potential platform for drug screening. PMID- 30243221 TI - Examining the effects of dextran-based polymer-coated nanoparticles on amyloid fibrillogenesis of human insulin. AB - More than thirty human proteins and/or peptides can aggregate to form amyloid deposits that are linked to several amyloid diseases including clinical syndrome injection-localized amyloidosis, which is correlated with the aggregation of the 51-residue polypeptide insulin. While no cure is currently available toward tackling amyloid diseases, prevention or suppression of amyloid fibrillization is considered as the primary therapeutic strategy. Nanomaterials have been demonstrated to possess great potential in the fields of biomedical diagnosis and drug delivery, they are also able to affect the amyloid aggregation of proteins. This work explores the effects of three different magnetic nanoparticles coated with dextran-based polymers on the in vitro amyloid fibrillogenesis of human insulin. Surface modification of nanoparticles with dextran-based polymers was used to improve the biocompatibility of maghemite nanoparticles. We demonstrated that insulin fibrillization may be mitigated by the studied nanoparticles in a concentration-dependent fashion as verified by ThT binding assay and transmission electron microscopy. The extent of inhibitory activity against human insulin fibril formation was found to be associated with the physico-chemical properties of nanoparticles, with the highest inhibitory activity observed for diethylaminoethyl-dextran-coated nanoparticles. Using circular dichroism spectroscopy, ANS fluorescence spectroscopy, and right-angle light scattering, we probed the structural/conformational changes and investigated the aggregating behavior of insulin upon treatment with nanoparticles. This work demonstrates that nanoparticles with an appropriate surface modification can be utilized to suppress or even inhibit amyloid fibril formation of proteins. PMID- 30243222 TI - Differences in the response of the near-infrared absorbance spectra of single walled carbon nanotubes; Effects of chirality and wrapping polymers. AB - We detected antioxidant activity of catechin, one of the main components of tea, using SWNTs surface coated with two different biomolecules. Compared to coating with DNA already reported, it can hardly be detected when coated with carboxymethyl cellulose. For nanobiosensing using SWNTs, its sensitivity is not determined only by SWNTs, we found that biomolecules covering the surface are extremely important. In this experiment, we measured the near-infrared absorption spectra of SWNTs coated separately with two different water-soluble polymers; DNA (double-stranded DNA-SWNT complexes) and carboxymethyl cellulose (CMC, CMC-SWNT complexes), and uncovered the differences in their antioxidant properties against the flavonoid catechin. Each dispersion was oxidized with H2O2 at 0.03% (final concentration), following which catechin solutions were added to reduce the samples. Our results showed that the magnitude of the change in the absorbance spectra for dsDNA-SWNT complexes in response to oxidation and reduction was superior to that for CMC-SWNT complexes. The CMC-SWNT complexes exhibited almost no change in their spectra even though the same SWNT powder (produced by the high pressure carbon monoxide (HiPco) method) was used. On the other hand, when (6, 5) enriched SWNT powder produced by the ComoCat method was used, no significant change in the absorbance was observed, even though (6, 5)-enriched SWNTs are frequently used for nanobiosensing. Our results revealed that both the SWNT chirality and type of polymer for wrapping SWNTs are important factors for establishing nanobiosensing methods utilizing SWNTs. PMID- 30243223 TI - Nanostructure coated AZ31 magnesium cylindrical mesh cage for potential long bone segmental defect repair applications. AB - This current study is aimed towards the fabrication of AZ31 magnesium cylindrical mesh cage implant with circular holes for orthopedic applications. This mesh cage is coated with nanocomposite material containing polycaprolactone (PCL), pluronic F127 and nano hydroxyapatite (nHA) by electrospinning process. Morphology and composition were analyzed by various characterization techniques. Controlled degradation and weight loss of the nanocomposite coated samples in 28 days were observed when compared with uncoated samples in SBF (simulated body fluid). The nanocomposite coated material was not cytotoxic to MG63 osteosarcoma cells. The cell viability, morphology, ALP activity, calcium mineralization and collagen deposition were also better on this when compared to uncoated. Smooth and randomly deposited nanofibers on the mesh cage was observed and the contact angle indicated that the surface is hydrophilic with (initial contact angle of 55 +/- 1 degrees and after 10 s 0 degrees ) when compared to PCL (99 degrees ) coated surface. 2-5 fold higher mRNA expression levels of osteogenic genes namely ALP, BMP2, COL1 and RUNX2 was observed with nanocomposite coated scaffolds than uncoated and PCL coated samples in 14 days. These results indicate the potential use of the nanocomposite coated AZ31 cylindrical mesh cage for segmental bone defect repair and can be used as a degradable implant for orthopedic applications. PMID- 30243224 TI - Methods for describing different results obtained from different methods in accident reconstruction. AB - There is always more than one method can be employed to reconstruct a traffic accident and then more than one result can be obtained. How to describe these different results becomes an issue. Two solutions were given, the first is to fuse different results to one result, while the other is to rank different results according to their credibility. Methods based on the Ordered Weighted Averaging (OWA) operator and Uncertain Ordered Weighted Averaging (UOWA) operator were proposed to fuse different certain results and different interval results to one result, respectively. And methods based on the Combination Weight Arithmetic Average (CWAA) and OWA operators were proposed to rank different certain or interval results. Finally, a true vehicle-motorcycle accident was given to demonstrate these proposed methods, results showed that all methods work well in practice. If the calculation uncertainty was not considered, the fused result 64.56km/h and a ranked vector can be obtained; if the calculation uncertainty was considered, the fused result [62.13, 68.13]km/h and a ranked interval number set can be obtained. Because that all final results were obtained by employing widely used mature operators, they deserve to be trusted. The research provides more reliable choices to describe different results obtained from different methods in accident reconstruction. PMID- 30243225 TI - Structural analysis of the woodland strawberry COI1-JAZ1 co-receptor for the plant hormone jasmonoyl-isoleucine. AB - The phytohormone jasmonoyl-isoleucine (JA-Ile) regulates fundamental plant processes. Fragaria vesca, the woodland strawberry, is a model plant for the Rosaceae family, in which the JA-Ile perception is poorly understood at the molecular level. JA-Ile promotes binding of JAZ repressor to COI1 protein in Arabidopsis to activate jasmonate (JA)-dependent responses. The aim of this work was to understand the molecular basis of the interaction between the F. vesca COI1 (FvCOI1) and JAZ1 (FvJAZ1) promoted by JA-Ile using a computational approach. Multiple sequence alignments and phylogenetic analyses of amino acid sequences were performed for FvCOI1, FvJAZ1 and their ortholog sequences. 3D structures for FvCOI1 and FvJAZ1 proteins were built by methods of homology modeling, using AtCOI1-JA-Ile-AtJAZ1 as template and then they were further refined and validated by molecular dynamics (MD) simulation. A molecular docking approach along with MDS analysis were used to gain insights into the interaction between a putative degron-like sequence present in FvJAZ1 with the FvCOI1-JA-Ile complex. FvCOI1 and FvJAZ1 showed high and moderate sequence identity, respectively, with the corresponding ortholog proteins from other plant species including apple, grape, tomato and Arabidopsis. Moreover, the FvJAZ1 has a variant C-terminal IPMQRK sequence instead of the canonical LPIARR degron sequence located in the Jas domain of AtJAZ1. The MD simulation results showed that the FvCOI1-JA-Ile-FvJAZ1 complex was stable, and the IPMQRK peptide of FvJAZ1 directly interacted with FvCOI1 and JA-Ile. The present research provides novel insight into the molecular interactions among key JA-signaling components in the model plant F. vesca, being few examples of characterized JA-Ile receptors at a structural level in plants. PMID- 30243226 TI - Placenta-mediated pregnancy complications are not associated with fetal or paternal factor V Leiden mutation. AB - OBJECTIVE: Maternal thrombophilia is a risk factor for adverse pregnancy outcomes. The aim of this study was to elucidate the controversial role of fetal and paternal thrombophilia in the development of severe placenta-mediated pregnancy complications. STUDY DESIGN: The study group comprised 126 mothers, 72 fetuses and 58 fathers. 111 mothers, 50 fetuses and 91 fathers acted as controls. 106 couples were selected to study the thrombophilias of paternal inheritance, 58 from the study group and 48 from the control group. The prevalence of factor V Leiden mutation, prothrombin G20210 A mutation and homozygous 10 methylenetetrahydrofolate reductase C677 T mutations were compared between the study and control groups to study whether maternal, fetal or paternal thrombophilias increase the risk of severe preeclampsia, intrauterine growth restriction, placental abruption and stillbirth. RESULTS: The total prevalence of fetal thrombophilic mutations was 8.3% in the study group and 14.0% in the control group. Paternal prevalence of thrombophilic mutations was 6.8% and 4.3%, respectively. There were no statistical differences between fetal or paternal thrombophilic mutations between the study and control groups. CONCLUSION: Fetal or paternal factor V Leiden mutation is not associated with severe placenta mediated pregnancy complications. PMID- 30243227 TI - Nausea and vomiting of pregnancy: A study with pregnancy-unique quantification of emesis questionnaire. AB - OBJECTIVES: Nausea and vomiting of pregnancy (NVP) is frequent, affecting up to 70-85% of pregnant women. However, severity of NVP especially in clinical practice is often uncertainly assessed and thus both under- and overdiagnosing is probable. Furthermore, risk factors for NVP, although recognized, are not well established. The aim of our study was to evaluate the severity of NVP with a structured questionnaire and evaluate associative risk factors. STUDY DESIGN: Sample of 2411 women were recruited from maternity health care clinics. Severity of NVP was assessed with pregnancy-unique quantification of emesis (PUQE) questionnaire. Age, previous pregnancies, previous deliveries, previous miscarriages including ectopic pregnancies, previous pregnancy terminations, nationality, pre-pregnancy body mass index, smoking, marital status and employment were used as explanatory factors. RESULTS: Altogether 88.0% of the women reported some level of NVP, of which 6.4% was severe, 52.2% moderate and 29.4% mild. Daily duration of NVP was >= four hours in 12 h in 45.0%. Further, 18.8% of the women had vomiting episodes >= three times and 37.4% retching episodes >= three times in 12 h. Women with >= two previous pregnancies had increased risk for more severe NVP (OR 2.17, 95%CI; 1.34-3.51, p < 0.0001). Older women had increased daily duration of nausea (OR 1.03, 95%CI; 1.00-1.06, p = 0.004) but lower number of vomits (OR 0.93, 95%CI; 0.93-0.97, p < 0.0001) and lower number of retching (OR 0.93, 95%CI; 0.90-0.96, p < 0.0001). Smokers had shorter daily duration of nausea (OR 0.49, 95%CI; 0.33-0.73, p < 0.0001), but higher number of vomiting episodes compared to non-smokers (OR 1.83, 95%CI; 1.26 2.66, p = 0.021). CONCLUSIONS: Women suffered from NVP very frequently. The daily duration of NVP was moderately long, in nearly half of the women four hours or more. In addition, retching was more frequent than vomiting. From studied risk factors, few associations with different aspects of NVP emerged, but only multiparity was associated with the severity of NVP. As NVP affects several women during pregnancy, in future, the impact of NVP on quality of life, future family planning and health costs should be evaluated. PMID- 30243228 TI - Obstetric and cardiac outcomes in women with Marfan syndrome and an aortic root diameter <= 45mm. AB - OBJECTIVE: To assess obstetric and aortic outcomes in women with Marfan Syndrome according to aortic root diameter, in view of recommendations for caesarean delivery when the aortic root diameter is >=40 mm in the 2010 American guidelines versus >45 mm in the 2011 European guidelines. STUDY DESIGN: In this retrospective cohort study conducted at Sainte-Justine Mother and Child Tertiary Hospital, 27 pregnancies in 20 women with Marfan Syndrome as defined by the international criteria, were followed prospectively between 1994 and 2017, after excluding women with prior aortic surgery. Obstetric and aortic outcomes were compared in 2 groups according to aortic root diameter: < 40 mm (21 pregnancies) and 40-45 mm (6 pregnancies). RESULTS: 21/27 women had a vaginal delivery. The caesarean section rate was 23.8% and 16.7% in women with diameter <40 mm and 40 45 mm respectively (p-value = 1), and perinatal outcome was similar across groups. Two women with a prepregnancy aortic root diameter <40 mm developed an acute type B dissection during the third trimester. Both had a family history of aortic dissection. CONCLUSIONS: Vaginal delivery with rigorous pain control and avoidance of Valsalva maneuver may be safely considered in women with Marfan Syndrome and an aortic root diameter <=45 mm. The risk of type B aortic dissection during pregnancy is hard to predict. Other factors such as family history of dissection and descending aorta size may play an important role, and this may modify our counselling. PMID- 30243229 TI - Dietary patterns and breast cancer risk among Iranian women: A case-control study. AB - AIM: Breast cancer is the most common cancer among women worldwide. Most previous studies focused on individual nutrients or foods rather than overall dietary patterns. We aimed to assess the association between major dietary patterns and breast cancer risk. METHOD: In a hospital-based case-control study, 134 women diagnosed as breast cancer and 267 controls were recruited from referral hospitals in Tehran, Iran. Dietary intakes were evaluated by using a validated 168-item food frequency questionnaire. Dietary pattern were identified by factor analysis. Odds ratios (OR) were estimated using logistic regression. RESULTS: Two dietary patterns were extracted: healthy and unhealthy. The "Healthy" dietary pattern was loaded for high consumptions of fruits, vegetables, seeds, legume, fish and sea foods, whole grains, liquid oils, olive oils and olive and lack of salt intake. "Unhealthy" dietary pattern was characterized by high factor loadings for sweets, soft drinks, mayonnaise, solid oils, processed meat, fried and boiled potato and salt intake. In multivariate logistic regression analyses, the healthy dietary pattern was not associated with breast cancer risk (OR: 0.83; 95%CI: 0.36, 1.89; P-trend = 0.50), while women in the highest quartile of the unhealthy dietary pattern had a significantly increased breast cancer risk (OR: 2.21; 95%CI: 1.04, 4.690; P-trend = 0.009). When stratified by menopausal status, unhealthy dietary pattern showed inverse association with breast cancer risk only among post-menopausal women (OR: 3.56; 95%CI: 1.16, 10.95; P-trend = 0.008). CONCLUSIONS: Our findings showed that an unhealthy dietary pattern might be associated with higher risk of breast among Iranian women. PMID- 30243230 TI - A dual-mode sensor for colorimetric and fluorescent detection of nitrite in hams based on carbon dots-neutral red system. AB - Nitrite residue in hams was detected by a fluorescent and colorimetric sensor based on carbon dots (C-dots) and neutral red (NR). C-dots with green fluorescence was synthesized by a microwave-assisted method. This novel sensor was fabricated by C-dots as donors and NR as acceptors. The presence of nitrite led to decrease of absorbance and increase of fluorescence. Colorimetric and fluorescent methods for nitrite detection were developed with excellent correlation coefficients (R2 = 0.995 and 0.991) and low limits of detection (196 nM and 0.518 nM). Moreover, nitrite residue in seven types of ham was detected by the colorimetric and fluorescent methods which were verified by a standard method. The results obtained by the proposed method were comparable and agree with that of the Griess-based method (relative errors<5%). C-dots-NR system as a sensor has a potential application for nitrite detection in hams to monitor its quality and safety. PMID- 30243232 TI - Compensatory strategy between trunk-hip kinematics and reaction time following slip perturbation between subjects with and without chronic low back pain. AB - Compensatory trunk and hip motions following slip perturbations may compromise the control of lumbopelvic movement. However, it is unclear how postural integration of the trunk and hips can be transferred to treadmill-induced slip perturbations in subjects with chronic low back pain (LBP). The purpose of this study was to investigate trunk reaction times and three-dimensional trunk-hip angle changes following a slip perturbation (duration: 0.12 sec, velocity: 1.37 m/sec, displacement: 8.22 cm) with a handheld task between subjects with and without chronic LBP. There were 23 subjects with LBP and 33 control subjects who participated in the study. The trunk reaction time was not significantly different between groups. However, the three-dimensional trunk-hip angle changes were significantly different following the perturbation. There were significant interactions between the body regions and three-dimensional angles between groups. There was a negative correlation between reaction time and trunk flexion in the LBP group. Overall, the LBP group demonstrated significantly reduced trunk flexion, which might be associated with reduced adaptability or a possible fear of avoidance strategy. Clinicians need to consider compensatory strategies to improve trunk flexibility following slip perturbations in subjects with chronic LBP. Mini abstract: Trunk reaction time and three-dimensional trunk-hip motions were compared between subjects with and without chronic low back pain (LBP). The control group demonstrated greater trunk flexion; however, the LBP group reduced trunk flexion to protect against further injuries following the novelty of the slip perturbation. PMID- 30243231 TI - Effect of partial replacement of fat with added water and tragacanth gum (Astragalus gossypinus and Astragalus compactus) on the physicochemical, texture, oxidative stability, and sensory property of reduced fat emulsion type sausage. AB - This study aimed to investigate the effect of partial fat replacement with two species of gum tragacanth (Astragalus gossypinus and Astragalus compactus) on physicochemical, textural, oxidative stability, and acceptability of reduced fat emulsion type sausages. Increasing the concentration of both gums to 1%, minimized extractable fat and cook loss. A. gossypinus at the concentration of 1% was the most effective in retardation of TBARS formation in sausages (p < 0.05). Reduced-fat sausages with 1% A. gossypinus showed the lowest carbonyls at the end of storage (28 days) (p < 0.05). Sausages with 1% A. gossypinus or A. compactus showed the lowest shear force (~6 and ~7 N respectively) and hardness (~21 N/cm2) among all treatments (p < 0.05). The results suggested that A. gossypinus (1%) enhanced oxidative stability and textural properties. Addition of 0.5% A. gossypinus showed an acceptable sensory score of the sausage formulation and as a potential fat replacer in the reduced fat sausages. PMID- 30243233 TI - Hip-abductor fatigue influences sagittal plane ankle kinematics and shank muscle activity during a single-leg forward jump. AB - Diminished hip abductor strength decreases postural control which is a parameter that is associated with an increased risk of ankle sprains. In our study we evaluated the influence of hip abductor fatigue on sagittal plane ankle kinematics and shank muscle activity during a single-leg forward jump. Sagittal ankle plane kinematics are important in ankle sprains but less studied than frontal plane kinematics. Therefore, we evaluated differences in sagittal ankle kinematics (12-camera motion capture system) and lower limb surface electromyographic muscle activity in 20 healthy, recreationally active adults (9 females, 11 males, mean age 30.3 SD 4.0 years, mean BMI 23.6 SD 2.8 kg/m2) before and after a hip abductor fatigue protocol (200-ms prior, at and in the 250-ms following initial contact (IC)). After fatigue, the maximal ankle plantar-flexion angle decreased prior to IC (median 3.8 degrees [interquartile range 0.1, 7.2], p = 0.014), at IC (4.1 degrees [-0.3, 5.0], p = 0.027) and post IC (4.1 degrees [-1.3, 5.0] p = 0.036). Gastrocnemius activity onset was delayed (-28.0 ms [ 44.0, 0.0], p < 0.01). Average activity of the tibialis anterior increased prior to IC (pre-fatigue 19.32% [14.89, 33.45], post-fatigue 28.95% [18.49, 34.81], p < 0.05). Hip-abductor fatigue influenced sagittal ankle kinematics and shank muscle activity during single-leg landings. PMID- 30243234 TI - Pilot randomized controlled trial of functional electrical stimulation cycling exercise in people with multiple sclerosis with mobility disability. AB - BACKGROUND: Exercise training has been shown to be beneficial for persons with multiple sclerosis (MS). Adapted exercise modalities are needed to accommodate those with severe mobility impairment (Expanded Disability Status Scale [EDSS] scores 5.5-6.5). Functional electrical stimulation (FES) cycling is one such exercise modality; however, few studies have examined the feasibility and potential benefits of FES cycling for people with MS with severe mobility impairment. OBJECTIVE: Determine the feasibility of FES cycling exercise for people with MS with severe mobility impairment, and the efficacy of FES cycling exercise for improving mobility and physiological fitness. METHODS: 11 participants with MS with mobility impairment (EDSS = 5.5-6.5) were randomly allocated to FES cycling exercise (n = 6) or passive leg cycling (PLC; n = 5). Feasibility metrics included participant recruitment, retention, adherence, safety, and satisfaction. The primary mobility outcome was walking speed assessed by the Timed 25-Foot Walk (T25FW) test. The primary physiological fitness outcome was peak oxygen consumption (VO2peak), assessed using a cardiopulmonary exercise test. RESULTS: Eight participants completed the intervention (FES n = 4; PLC n = 4) with an adherence rate >=80%. Three participants (FES n = 2, PLC n = 1) withdrew due to a lack of time. Six Grade 1 (i.e., mild) adverse events were experienced by participants in the FES group. Participants in the FES cycling condition demonstrated small-to-moderate improvements on T25FW performance (Cohen's d = 0.40; 22.9%) and VO2peak (Cohen's d = 0.34; 13.8%) compared to participants in the PLC condition. CONCLUSIONS: We provide evidence that FES cycling exercise is feasible for individuals with MS with severe mobility impairment, and might have positive effects on mobility and physiological decondition. These results will inform the design of future efficacy trials of FES cycling exercise for persons with MS with mobility disability. PMID- 30243235 TI - B-cell composition in the blood and cerebrospinal fluid of multiple sclerosis patients treated with dimethyl fumarate. AB - BACKGROUND: B cells may contribute to the immunopathogenesis of multiple sclerosis (MS). Dimethyl fumarate (DMF) has recently been shown to reduce the frequency of memory B cells in blood, but it is not known whether the drug influences the cellular composition in the cerebrospinal fluid (CSF). METHODS: A cross-sectional study examining the cellular composition in blood and cerebrospinal fluid (CSF) from 10 patients treated with DMF and 18 patients receiving other disease modifying drugs or no treatment. RESULTS: Patients treated with DMF had reduced proportions of memory B cells in blood compared to other MS patients (p = 0.0007), and the reduction correlated with treatment duration (rs = -0.75, p = 0.021). In the CSF, the absolute number of mononuclear cells were significantly lower in DMF-treated patients compared to the other patients (p = 0.023), and there was a disproportionate decrease of plasmablasts (p = 0.031). CONCLUSION: The results of this exploratory study support a B-cell mediated mechanism of action for DMF in both blood and CSF. PMID- 30243236 TI - The Bayesian risk estimate at onset (BREMSO) correlates with cognitive and physical disability in patients with early multiple sclerosis. AB - BACKGROUND: Prevention of long-term disability is the goal of therapeutic intervention in Relapsing Remitting MS (RRMS). The Bayesian Risk Estimate for MS at Onset (BREMSO) gives an individual risk score predicting disease evolution into Secondary Progressive MS (SPMS). We investigated whether BREMSO correlates with physical disability, cognitive dysfunction, and regional brain atrophy early in MS. METHODS: One hundred RRMS patients with at least two years of follow-up were enrolled. BREMSO score as well as Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Severity Score (MSSS), Timed 25-Foot Walk Test (T25-FW) and 9 Hole Peg Test (9-HPT), were assessed. Intracranial volume (ICV), subcortical gray matter structures and corpus callosum (CC) were automatically segmented on MRI images and their volumes measured. RESULTS: BREMSO score correlated negatively with SDMT at visit1 (beta = -0.33, p = 0.019), visit2 (beta = -0.34, p = 0.017) and visit3 (beta = -0.34, p = 0.014), and positively with MSSS at visit1 (r = 0.38, p = 0.006), visit2 (r = 0.47, p < 0.0001) and visit3 (r = 0.42, p = 0.002), but not with T25-FW and 9-HPT. BREMSO negatively correlated with CC volume at baseline (p < 0.03). No correlations were found with ICV and subcortical gray matter. CONCLUSIONS: BREMSO score at onset correlated with physical disability (MSSS), cognitive function (SDMT) and CC volume measurements in patients with early MS. PMID- 30243238 TI - Unveiling novel 2-cyclopropyl-3-ethynyl-4-(4-fluorophenyl)quinolines as GPCR ligands via PI3-kinase/PAR-1 antagonism and platelet aggregation valuations; development of a new class of anticancer drugs with thrombolytic effects. AB - In the present study, novel 2-cyclopropyl-3-ethynyl-4-(4-fluorophenyl) quinolines (4a-l) were recognized and evaluated as G-Protein Coupled Receptor (GPCR) ligands through molecular evaluations. Thrombin mediates adhesion of mast cell, a type of cell abundantly found in connective tissue and releasing histamine and other substances during inflammatory and allergic reactions, through phosphoinositol 3 kinase pathway. With this background, as preliminary, 4a-l are resolute to be potential leads, designated from their effective phosphoinositol 3-kinase (PI3 Kinase) inhibition potentials, best-docked scores, comparative ligand efficiency, and significant structural attributes evaluated by ab initio simulations. Since thrombin is one of the main reason for various cancer invasion in association with PI3Kinase, a thrombolytic potential of the compounds also analyzed. The experimental in vitro studies confirmed the significant enhancement as PI3Kinase inhibitors and appreciable enhancement in MTT assay of breast and skin cancer cell lines. Significantly, acetophenone substituent in the quinoline scaffold could be coherent to note the significant binding affinity to all the evaluated drug targets. PMID- 30243237 TI - Characterization of a alpha-l-rhamnosidase from Bacteroides thetaiotaomicron with high catalytic efficiency of epimedin C. AB - In this study, a alpha-l-rhamnosidase gene from Bacteroides thetaiotaomicron VPI 5482 was cloned and expressed in Escherichia coli. The specific activity of rhamnosidase was 0.57 U/mg in LB medium with 0.1 mM Isopropyl beta-d Thiogalactoside (IPTG) induction at 28 degrees C for 8 h. The protein was purified by Ni-NTA affinity, which molecular weight approximately 83.3 kDa. The characterization of BtRha was determined. The optimal activity was at 55 degrees C and pH 6.5. The enzyme was stable in the pH range 5.0-8.0 for 4 h over 60%, and had a 1-h half-life at 50 degrees C. The Kcat and Km for p-nitrophenyl-alpha-l rhamnopyranoside (pNPR) were 1743.29 s-1 and 2.87 mM, respectively. The alpha-l rhamnosidase exhibited high selectivity to cleave the alpha-1,2 and alpha-1,6 glycosidic bond between rhamnoside and rhamnoside, rhamnoside and glycoside, respectively, which could hydrolyze rutin, hesperidin, epimedin C and 2"-O rhamnosyl icariside II. Under the optimal conditions, BtRha transformed epimedin C (1 g/L) to icariin by 90.5% in 4 h. This study provides the first demonstration that the alpha-l-rhamnosidase could hydrolyze alpha-1,2 glycosidic bond between rhamnoside and rhamnoside. PMID- 30243239 TI - Rational design and synthesis of new tetralin-sulfonamide derivatives as potent anti-diabetics and DPP-4 inhibitors: 2D & 3D QSAR, in vivo radiolabeling and bio distribution studies. AB - Type 2 diabetes (T2D) is a severe disease and it is one of the most raising problems worldwide. This study deals with design, synthesis and in vivo determination of a new set of tetralin-sulfonamide derivatives as anti-diabetic and dipeptidyl peptidase-IV (DPP-4) inhibiting agents. Most of the new compounds exhibited significant hypoglycemic effect alongside with DPP-4 suppression potency considering sitagliptin as a reference drug. The most promising compounds 4, 15 showed 2.80 nM DPP-4 IC50 with 20-40 folds selectivity over DPP-8 and DPP 9. 2D and 3D QSAR models were performed using auto QSAR of Schrodinger, QuaSAR of MOE and 3D Field-based QSAR of Schrodinger, respectively. The experimental results revealed that the alignment-independent descriptors, electrostatic and steric field descriptors were significantly correlated with the antidiabetic activity of the new derivatives. In addition, the new compounds were docked in the active site of DPP-4 in reference to sitagliptin to rationalize the binding modes of the compounds with the amino acid residues of the enzyme. Furthermore, 131I-compound 4 complex was selected to evaluate the pharmacokinetic behavioral profile of compound 4 and its body organs uptakes alongside its elimination pathway as a representative example for the rest of the analogues. The bio distribution pattern of the tracer proved the selective accumulation of 131I substrate in the pancreas and rapid clearance from most of the body organs. PMID- 30243240 TI - Identification of human, rat and mouse hydrolyzing enzymes bioconverting amino acid ester prodrug of ketoprofen. AB - Alkyl ester prodrugs are well known to be bioconverted by carboxylesterases, particularly in rodents' by first-pass metabolism in the systemic circulation and liver. However, the bioconversion of structurally more complex esters with polar functional groups is less well understood, especially in humans. Therefore, it is not clear if ester prodrugs can be utilized for targeted drug delivery. In the present study a brain-targeted ester prodrug (1) of ketoprofen, utilizing the l type amino acid transporter 1 (LAT1) was prepared and the enzymes involved in its metabolism in human plasma and liver S9 subcellular fraction as well as rat brain S9 fraction were identified. Furthermore, species differences among mouse, rat and human plasma and liver S9 fraction were compared. The results showed that bioconversion of the ester prodrug was much faster in mouse plasma compared to human, while it's half-life in rat plasma was closer to the one of human. Moreover, both rodent species showed more efficient bioconversion in the liver S9 fractions compared to human and relatively efficient bioconversion in the brain S9 fractions. More specifically, butyrylcholinesterase (BChE) and paraoxygenase 1 (PON1) were the main hydrolyzing enzymes of the prodrug 1 in human plasma, while carboxylesterases 1 and 2 (CES1 and CES2) as well as PONs were the main bioconverting enzymes in human liver S9 fractions. In rat brain S9 fraction, acetylcholinesterase (AChE) was hydrolyzing the prodrug 1, although also other unidentified metal-and pH-dependent enzyme(s) were recognized to be participating to the total bioconversion of the compound 1 in the brain. PMID- 30243241 TI - Thermochemical conversion of cobalt-loaded spent coffee grounds for production of energy resource and environmental catalyst. AB - Thermochemical conversion of cobalt (Co)-loaded lignin-rich spent coffee grounds (COSCG) was carried out to find the appropriate pyrolytic conditions (atmospheric gas and pyrolytic time) for syngas production (H2 and CO) and fabricate Co biochar catalyst (CBC) in one step. The use of CO2 as atmospheric gas and 110-min pyrolytic time was optimal for generation of H2 (~1.6 mol% in non-isothermal pyrolysis for 50 min) and CO (~4.7 mol% in isothermal pyrolysis for 60 min) during thermochemical process of COSCG. The physicochemical properties of CBC fabricated using optimized pyrolytic conditions for syngas production were scrutinized using various analytical instruments (FE-SEM, TEM, XRD, and XPS). The characterizations exhibited that the catalyst consisted of metallic Co and surface wrinkled carbon layers. As a case study, the catalytic capability of CBC was tested by reducing p-nitrophenol (PNP), and the reaction kinetics of PNP in the presence of CBC was measured from 0.04 to 0.12 s-1. PMID- 30243242 TI - Reduced generation time and size of carbon dioxide bubbles in a volute aerator for improving Spirulina sp. growth. AB - A novel volute aerator was proposed to generate shear force and break gas flow through water centrifugation to promote mass transfer for CO2 fixation with microalgae. The bubble evolution and gas-liquid mixing processes in volute aerator were numerically simulated. The bubble generation time and diameter were measured on a high-speed camera and assessed with level-set method. By optimizing gas inletpipe angle and water/gas inlet velocities of volute aerator, the bubble generation time decreased by 60.1% to 3.3 ms and outlet bubble diameter decreased by 50.7% to 1.8 mm, compared with traditional strip aerator. The corresponding gas-liquid mixing time reduced by 15.6% and mass transfer coefficient increased by 42.2%. The volute aerator was used as an alternative to traditional strip aerator to culture microalgae under high-purity CO2 condition, which promoted average growth rate and biomass production by 26.6% and 50.7%, respectively. PMID- 30243243 TI - Biokinetics of microbial consortia using biogenic sulfur as a novel electron donor for sustainable denitrification. AB - In this study, the biokinetics of autotrophic denitrification with biogenic S0 (ADBIOS) for the treatment of nitrogen pollution in wastewaters were investigated. The used biogenic S0, a by-product of gas desulfurization, was an elemental microcrystalline orthorhombic sulfur with a median size of 4.69 um and a specific surface area of 3.38 m2/g, which made S0 particularly reactive and bioavailable. During denitritation, the biomass enriched on nitrite (NO2-) was capable of degrading up to 240 mg/l NO2--N with a denitritation activity of 339.5 mg NO2--N/g VSS.d. The use of biogenic S0 induced a low NO2--N accumulation, hindering the NO2--N negative impact on the denitrifying consortia and resulting in a specific denitrification activity of 223.0 mg NO3--N/g VSS.d. Besides Thiobacillus being the most abundant genus, Moheibacter and Thermomonas were predominantly selected for denitrification and denitritation, respectively. PMID- 30243244 TI - Effects of phosphogypsum, superphosphate, and dicyandiamide on gaseous emission and compost quality during sewage sludge composting. AB - This study investigated the effects of phosphogypsum, superphosphate, and dicyandiamide on gaseous emission and compost quality during sewage sludge composting. Results showed that phosphogypsum reduced ammonia (NH3) and methane (CH4) emissions but increased nitrous oxide (N2O) emission. Superphosphate simultaneously reduced NH3, N2O and CH4 emissions. Dicyandiamide markedly reduced N2O emission during composting. Combination of phosphogypsum and dicyandiamide reduced CH4 and N2O emissions by 75.6% and 86.4%, while NH3 emission was increased by 22.0%. Combination of superphosphate and dicyandiamide reduced NH3, CH4 and N2O emissions by 12.3%, 81.0% and 88.2%, respectively. More importantly, with the addition of 10% initial raw materials, phosphogypsum and superphosphate conserved nitrogen and improved compost quality by introducing additional nutrients. PMID- 30243245 TI - Hydrolysis of cellulose using cellulase physically immobilized on highly stable zirconium based metal-organic frameworks. AB - Developing a new cellulase-MOF composite system with enhanced stability and reusability for cellulose hydrolysis was aimed. Physical adsorption strategy was employed to fabricate two cellulase composites, and the activity of composite was characterized by hydrolysis of carboxymethyl cellulose. The NH2 functionalized UiO-66-NH2 MOF exhibited higher protein loading than the precursor UiO-66, due to the extra anchor sites of NH2 groups. The immobilized cellulase showed enhanced thermostability, pH tolerance and lifetime. The maximum activity attained at 55 degrees C could be kept 85% when used at 80 degrees C, and the residual activities were 72% after ten cycles and 65% after 30 days storage. The abundant NH2 and COOH groups of MOF adsorb cellulase and enhance its stability, and the resulted heterogeneity offered the opportunity of recovering composite via mild centrifuge. The findings suggest the promising future of developing cellulase-MOF composite with ultrahigh activities and stabilities for practical application. PMID- 30243246 TI - Dynamic analysis of self-forming dynamic membrane (SFDM) filtration in submerged anaerobic bioreactor: Performance, characteristic, and mechanism. AB - This study attempts to provide an improved fundamental understanding of the self forming dynamic membrane (SFDM) filtration process in submerged anaerobic bioreactors. Excellent system performances were achieved in terms of high COD removal efficiency (~ 90%), fast formation/reformation of SFDM (<1 h), and sustainable low-resistance (3.92 * 1010 m-1) high-flux (10-30 L/m2.h) filtration. A typical flux-variation profile consisted of an initial abruptly fast decrease followed by a gradually slow reduction, corresponding to the formation and sustainable operation period, respectively. The increase of SFDM resistance in formation period was attributable to the fast deposition of large particles on coarse-pore support materials. After SFDM formation, the subsequent increase of SFDM resistance was controlled more by the increase of specific resistance, which was firstly mainly resulted from the increasing accumulation of small particles with higher hydrophobicity and the external deposition of eEPS but later most attributable to the increase of internal release of eEPS. PMID- 30243247 TI - Stability of aerobic granular sludge under condition of low influent C/N ratio: Correlation of sludge property and functional microorganism. AB - Aerobic granular sludge process treating domestic wastewater with low C/N ratio is necessary to be studied for rapid urbanization in China and other countries. In this study, two parallel reactors with different influent C/N ratio (15 in R1, 5 in R2) were established. Compared to the disintegrated granule in R1 with high influent C/N ratio, granules with large size (650 MUm) and compact structure (integrity coefficient <0.1) were stable in R2 along with influent C/N ratio decreased to 5. High-through sequencing illustrated the functional microbes like Thauera and Paracoccus enriched under low influent C/N ratio, and principal component analysis further showed these microbes were positive correlation with tryptophan and protein-like substances in extracellular polymeric substances (EPS) and granular strength. It was indicated that under low influent C/N ratio, several resistant microbes like Thauera (19.5%) enriched and then secreted tryptophan and protein-like substances, and stable granules with multi-functional microbes could be formed finally. PMID- 30243248 TI - Effects of amoxicillin on nitrogen transformation and bacterial community succession during aerobic composting. AB - This study systematically analyzed the effects of amoxicillin (AMX) on the nitrogen transformation and its corresponding functional bacterial communities by conducting two aerobic composting experiments, and AMX impact on bacterial community succession was also evaluated. It provides theoretical and methodological support for harmless composting treatment of large quantities of manure containing AMX in China and for the high-quality compost products. The results showed that AMX exerted several effects on basic physicochemical and biological compost parameters. Notably, temperature changes typically accompanying compost maturation were delayed in AMX compost, reflecting altered compost maturation kinetics and bacterial community structure. Moreover, relative to control, AMX inhibited growth and reproduction of dominant bacterial phyla Firmicutes and Bacteroidetes, with respective reductions of 17.8-26.1% and 0 7.76% in relative abundance (RA) and significantly increased Proteobacteria RA by 1.9-24.8%. Thus, AMX altered both compost bacterial community structure and succession. From the perspective of various nitrogen content changes, AMX has a significant effect on nitrogen conversion and release. Simultaneously, AMX may inhibit ammoniated and ammonia-oxidizing bacterial activity, while significantly increasing the RA of denitrifying bacteria. Indeed, during early composting with AMX, the RA of denitrifying bacteria was 1361.9-1435.0% of control, highlighting differences in nitrogen transformation and release between groups. PMID- 30243249 TI - Removal of multi-pollutant from flue gas utilizing ammonium persulfate solution catalyzed by Fe/ZSM-5. AB - A nano-sized iron loaded ZSM-5 zeolite (Fe/ZSM-5) catalyst was firstly used to activate (NH4)2S2O8 solution for the simultaneous removal of multi-pollutant from flue gas. The simultaneous removal efficiencies 100% of SO2, 72.6% of NO and 93.4% of Hg degrees were achieved under the condition that the catalyst dose was 0.8 g/L, concentration, pH and temperature of (NH4)2S2O8 solution were 0.03 mol/L, 5 and 65 degrees C, respectively. The stability of catalyst was checked by a continuous test, proving that the catalytic activity was maintained for 4 h and the leached iron reached low levels. Based on the catalyst characterizations, product analysis and literatures, the removal mechanism was speculated preliminarily, during which, OH and SO4- played key roles for oxidizing NO and Hg degrees into NO3- and Hg2+. PMID- 30243250 TI - Abscisic acid enhances lead translocation from the roots to the leaves and alleviates its toxicity in Populus * canescens. AB - To shed light on physiological mechanisms underlying abscisic-acid (ABA)-mediated lead (Pb) uptake, translocation and detoxification, we exposed Populus * canescens saplings to either 0 or 3 mM Pb2+ in combination with either 0 or 10 MUM exogenous ABA. Pb was taken up by the roots and accumulated mainly in the cortex. A fraction of the Pb in the roots was translocated to the leaves, thereby resulting in decreased photosynthesis and biomass. Pb accumulation caused a burst of reactive oxygen species (ROS), with higher concentrations of total thiols, glutathione, and ascorbate in the roots and/or leaves. Exogenous ABA stimulated Pb uptake, decreased Pb deposition in the cortex, and enhanced Pb vascular loading in the roots. Exogenous ABA alleviated the Pb-induced reductions in photosynthesis and root biomass, and decreased Pb-triggered ROS overproduction in the roots and/or leaves. Correspondingly, exogenous ABA stimulated the mRNA levels of a few genes involved in Pb uptake, transport, and detoxification, including NRAMP1.4, ABCG40, FRD3.1, PCS1.1, and ABCC1.1. These results suggest that exogenous ABA enhances Pb uptake and translocation, and alleviates Pb toxicity in poplars through the ABA-induced movement of Pb from the root cortex to the vascular stele, and transcriptionally regulated key genes involved in Pb tolerance. PMID- 30243251 TI - pH controlled byproduct formation in aqueous decomposition of N-chloro-alpha alanine. AB - N-chloro-amino acids are readily formed in chlorination water treatment technologies. These reactions are also important in biological systems where HOCl plays an important role in the defense mechanism against invading pathogens. The intermediates and the products formed are of primary concern because they may have significant biological activities. In order to clarify intimate details and resolve discrepancies in the literature, the decomposition kinetics of N-chloro alpha-alanine (MCA) was studied in the neutral - alkaline pH range by UV-vis spectrophotometry and 1H-NMR method. In contrast to earlier reports, the decomposition reaction proceeds via two distinct reaction paths: kobs1 = kOH[OH-] + k, where kOH = (1.38 +/- 0.02) * 10-2 M-1s-1 and k = (2.95 +/- 0.09) * 10-4 s 1. In slightly alkaline solution, the sole product is acetaldehyde. Under alkaline conditions, the main product is pyruvate ion, however, N-acetyl-alpha alanine is also formed in a subsequent reaction sequence. A detailed kinetic model is postulated which involves the rate determining dissociation of MCA into Cl- and ethanimine which produces acetaldehyde in further reaction steps. Via the OH- assisted path, first a carbanion is formed which undergoes dechlorination and produces iminopropionate ion. This species is transformed into pyruvate ion through hydration and deamination steps. PMID- 30243252 TI - Effect of heat treatment on hydrophobic silica aerogel. AB - Hydrophobic silica aerogels were heat treated under various conditions. Physical and chemical analyses were conducted to study the effect of the heat treatments on the silica aerogels. The O/Si and C/Si values in the hydrophobic silica aerogels increased and decreased, respectively, with the increase in the heating temperature. C-O, -OH, and CO were detected during pyrolysis. Pyrolysis of the silica aerogels in air could be divided into 3 steps: the hydroxylation of methyl groups, the splitting of the alcoholic hydroxyl, and the oxidisation of CO. When the heat treatment temperature was lower than 350 degrees C, the properties of the silica aerogels showed little change. With further increase in the heat treatment temperature, the variation in the relevant parameters became more prominent. The secondary particles coalesced with one another, and the mesopores were destroyed. Consequently, the thermal conductivity and bulk density rose greatly. The carbon within the silica aerogels was released after heat treatment. As a result, the heat released in the thermal gravimetry and oxygen bomb analyses dropped remarkably with the increase in the heat treatment temperature. PMID- 30243253 TI - Comparison of the structural and physical properties of nitrocellulose plasticized by N-butyl-N-(2-nitroxy-ethyl) nitramine and nitroglycerin: Computational simulation and experimental studies. AB - We performed experimental studies on the effects of N-butyl-N-(2-nitroxy-ethyl) nitramine (Bu-NENA) and nitroglycerin (NG) on the plasticization of nitrocellulose (NC). The tensile strength and elongation at break of NC/Bu-NENA measured at -40 degrees C show increments of about 23% and 33% respectively, compared with those of NC/NG, suggesting that Bu-NENA has a higher plasticizing efficiency than NG. Scanning electron microscope (SEM) observation reveals that NC shows better miscibility with Bu-NENA than NG, which was further evidenced by the mesoscopic morphologies derived from mesodynamics simulations. Furthermore, molecular dynamic simulations were conducted to explore the mechanical strengthening mechanism of plasticizers. The simulation results such as free volume (Vfree), binding energy (Ebind) and radial distribution function (RDF) were obtained. NC/Bu-NENA shows a 28% improvement in Vfree compared to NC/NG, suggesting that Bu-NENA molecules demonstrate higher mobility in NC matrix. The larger Ebind of NC/Bu-NENA than NC/NG indicates the stronger interaction between NC and Bu-NENA. Furthermore, g(r) values correlated to the atom pair interaction determined from RDF curves reveal that NC/Bu-NENA shows higher intensities of both hydrogen bond and van der waal force than those of NC/NG blend. These computational and experimental studies reveal great potential in design and fabricating low vulnerable insensitive propellants. PMID- 30243254 TI - Screening of wheat straw biochars for the remediation of soils polluted with Zn (II) and Cd (II). AB - The immobilization behaviors of Zn(II) and Cd(II) by wheat straw (WS) biochars could vary with the soil conditions. In the acidic environment, WS biochars produced at low temperature were more competent than those produced at high temperature on Zn(II) and Cd(II) immobilization; while WS biochars produced at high temperature were more effective than those produced at low temperature in the alkaline environment. The ions in the porewater could compromise the sorption capacities of Zn(II) and Cd(II) by WS biochars in acidic soils, while could enhance them in alkaline soils. For biochars produced at the same temperature, residence time had little effect on their behaviors of Zn(II) and Cd(II) immobilization. Only a small portion of immobilized Zn(II)/Cd(II) could be released from WS biochar in the simulated acid rain. Compared with Zn(II)/Cd(II) adsorbed on the acidic functional groups, Zn(II)/Cd(II) precipitates were more stable in 0.01 M CaCl2 solution. Most of the Zn(II) and Cd(II) species on biochar could be released in 1 mM citric acid solution. The immobilized Zn(II) and Cd(II) on WS biochar are likely to be released into the soil environment in the long run. PMID- 30243255 TI - Immobilization of laccase on hollow mesoporous carbon nanospheres: Noteworthy immobilization, excellent stability and efficacious for antibiotic contaminants removal. AB - In this study, the hollow mesoporous carbon spheres (HMCs) were synthesized and modified for laccase (Lac) immobilization, and the structural characteristics of HMCs materials were determined by FESEM, TEM and FTIR etc. The maximum loading of Lac on the HMCs materials could reach 835 mg/g, meanwhile, the immobilized Lac exhibited excellent thermo-stability, pH stability, storage stability and reusability. The antibiotics removal experiments indicated that the immobilized Lac possess efficient removal efficiency for both tetracycline hydrochloride (TCH) and ciprofloxacin hydrochloride (CPH) in the presence of redox mediator. The synergy of the adsorption by HMCs and the degradation by Lac could be the reasons for the high removal of antibiotics. Meanwhile, for investigating degradation mechanism, the degradation product analysis and molecular docking method had been introduced to this study. According to the degradation products, dehydroxylation and demethylation are major degradation reactions for TCH degradation, and the oxidation of the piperazinyl substituent and hydroxylation are the major degradation for CPH degradation. The docking results showed that some important residues played the key role in the degradation process. This study indicated that the immobilization of Lac on HMCs could be potentially applied in environmental remediation of antibiotics. PMID- 30243256 TI - Numerical simulation of particle migration from crushed sandstones during groundwater inrush. AB - Groundwater inrush through fault fracture zones is caused by small particle migration from fractured rocks of the faults. To investigate particle migration with the water flow, a 3D model was established for the solid-water two-phase flow. First, the simulated crushed sandstone was represented by certain different sized particles with a novel cohesive force. The discrete element method (DEM) was applied for particles considering the cohesive force, the collisions, the friction, and other conventional forces. Second, the process of particle migrating from the crushed sandstone was simulated under multiple effects accompanied by some experiments. The results indicate that the migration characteristics vary with different-sized particles, and the mass loss for different-sized particles are high at the beginning leading to stabilized conditions at different times. It can be also found that the total mass loss rate and the final mass loss all increase with the increases of initial water velocity, while the final mass loss decrease with the increases of the axial force. Moreover, selected stimulation results were compared with the experimental results and the previous simulated results, and reasonable agreements could be obtained, which would provide consults for particle migration during groundwater inrush through fault fracture zones in underground engineering. PMID- 30243257 TI - Ternary semiconductor metal oxide blends grafted Ag@AgCl hybrid as dimensionally stable anode active layer for photoelectrochemical oxidation of organic compounds: Design strategies and photoelectric synergistic mechanism. AB - The development of ultra-efficient, sustainable, and easily accessible anode with relative non-precious semiconducting metal oxides is highly significant for application in the practical treatment of organically polluted water. Herein, we report SnO2, TiO2, and Ag2O ternary semiconductor metal oxide blend grafted Ag@AgCl hybrids, prepared with the one-step sol-gel method and applied as a dimensionally stable anode (DSA)-active layer on a SnO2-Sb/Ti electrode. Factors affecting crystal formation, including the presence or absence of O2 during calcination, the calcination temperature, and Ag@AgCl additive dosage were discussed. The micromorphology, phase composition, and photoelectrochemical activity of the newly designed anode were comprehensively characterized. The optimized preparation, which yielded a solid-solution structure with flat and smooth surface and well-crystallized lattice configuration, occurred in the absence of O2 during calcination at 550 C with an Ag@AgCl additive dosage of 0.2 g in the sol-gel precursor. The newly designed DSA displayed improved electrocatalysis (EC) and photoelectrical catalysis (PEC) capacity. The phenol and its TOC removal efficiency reached 90.65% and 58.17% for 10 mA/cm2 current density with a metal halide lamp in 3 h. The lifespan was four times that of SnO2 Sb/Ti electrode. This proposed DSA construction strategy may support improved EC and PEC reactivities toward the decomposition of organic pollutants. PMID- 30243258 TI - Aerobic granular sludge and naphthenic acids treatment by varying initial concentrations and supplemental carbon concentrations. AB - Aerobic granular sludge (AGS) has previously been utilized in the treatment of toxic compounds due to its diverse and dense microbial structure. The present study subjected mature AGS to model naphthenic acids (NAs) representative of the Canadian oil sands. To this effect, three NA concentrations (10, 50 and 100 mg/L) and three supplemental carbon source concentrations (600, 1200 and 2500 mg/L) were studied in batch reactors for 5 days. The responding variables were chemical oxygen demand (COD), NA concentrations and nutrients. Cyclohexane carboxylic acid (CHCA), cyclohexane acetic acid (CHAA) and 1-adamantane carboxylic acid (ACA) were chosen to study structure-based degradation kinetics. The optimal COD according to the runs was 1200 mg/L. CHCA was removed completely with biodegradation rate constants increasing with lower NA concentrations and lower COD concentrations. CHAA was also removed completely, however, an optimal rate constant of 1.9 d-1 was achieved at NA and COD concentrations of 50 mg/L and 1200 mg/L, respectively. ACA removal trends did not follow statistically significant regressions; however, degradation and sorption helped remove ACA up to 19.9%. Pseudomonas, Acinetobacter, Hyphomonas and Brevundimonas spp. increased over time, indicating increased AGS adaptability to NAs. PMID- 30243259 TI - Arsenite and chromate sequestration onto ferrihydrite, siderite and goethite nanostructured minerals: Isotherms from flow-through reactor experiments and XAS measurements. AB - Sorption isotherms remain a major tool to describe and predict the mobility of pollutants in natural and anthropogenic environments, but they are typically determined by independent batch experiments. In the present study, the sequestration of As(III), Cr(VI) and competitive As(III)-Cr(VI) on/in 6L ferrihydrite, siderite and goethite nanostructured minerals was reinvestigated using stirred flow-through reactor experiments. Herein, sorption isotherms were particularly determined from breakthrough curves for inert and reactive tracers monitored simultaneously in a single percolation experiment. In complement, X-ray absorption spectroscopy (XAS) was used to identify As sorption sites on 6L ferrihydrite and goethite. As expected, the minerals have high potential to remove As and Cr from water (siderite = ferrihydrite (about 60 mg/g) > goethite (20 mg/g)). As and Cr sorption isotherms were modelled with a Langmuir model, and with a sigmoidal Hill model in the case of the competitive sorption. XAS measurements have revealed that As(III) was partially oxidized (up to 22%) in the competitive system with chromate oxyanion Cr(VI). As(III) sorbed on ferrihydrite and goethite adopted edge-sharing and corner sharing complex geometries. Nowadays, a new class of adsorbing phases is being developed for wastewater treatment, including engineered nanostructured materials and nanocomposites. The use of flow through reactor experiments as a high throughput method, combined with XAS, should be considered as efficient screening methods to test their sorbing properties on various contaminants. PMID- 30243260 TI - Masquelet technique for the treatment of acute osteomyelitis of the PIP joint caused by clenched-fist human bite injury: A case report. AB - INTRODUCTION: The Masquelet technique is a well-known and efficient procedure for lower limb soft tissue reconstruction after severe osteomyelitis requiring bone excision. However, this technique is rarely used in the hand. PRESENTATION OF CASE: The patient was 38-year-old man. We used this technique to reconstruct a proximal interphalangeal (PIP) joint osteochondral defect after osteomyelitis caused by clenched-fist human bite injury. The pathogen was Prevotella intermedia, which is an anaerobic pathogenic bacterium involved in periodontal infections and is a black-pigmented periodontal pathogen. Following completion of the Masquelet method, the bone remodeled at an angle at the PIP joint. DISCUSSION: Prevotella intermedia is known as Bacteroides melaninogenicus subsp. intermedius. When the infection site is black-pigmented, this pathogen is highly suspected. The Masquelet technique is rarely used in the hand, and when used, it has been in a straight fashion in the hand. We were able to reconstruct a more anatomical, bent PIP joint, and the fixed angle of the PIP joint at 40 degrees of flexion using Masquelet technique. CONCLUSION: The angled joint resulting from this technique created a relatively normal permanently bent PIP joint. PMID- 30243261 TI - Non-circumferential membranous resection of the trachea for paraganglioma: A case report. AB - INTRODUCTION: Paraganglioma is a rare neuroendocrine tumor and may sometimes be located in the membranous part of the trachea. PRESENTATION OF CASE: We report the case of a 52-year-old man presenting a paraganglioma just above the carina with obstructive symptoms. The patient successfully underwent a non circumferential tracheal membranous resection, followed by latissimus dorsi muscle flap repair, under peripheral extra-corporeal membrane oxygenation (ECMO). DISCUSSION: Complex carinal resection can be avoided for tracheal membranous tumors and replaced with non-circumferential resection and direct reconstruction with a muscle flap. In addition, ECMO support may be used for airway resection and reconstruction. CONCLUSION: Tracheal membranous tumors can be managed without circumferential resection or direct anastomosis. PMID- 30243262 TI - Case series of recurrent inguinal hernia after primary TREPP repair: re-TREPP seems feasible and safe. AB - INTRODUCTION: The Trans REctussheath PrePeritoneal (TREPP) mesh repair was introduced in 2006 to decrease the risk of postoperative inguinal pain in hernia surgery. For the repair of a recurrent inguinal hernia after a primary TREPP an alternative open anterior route (Lichtenstein) may seem the most logical option, but coincides with an increased risk of chronic postoperative inguinal pain. Therefore, this study aimed to evaluate the feasibility of a second TREPP procedure to repair a recurrent inguinal hernia after an initial TREPP repair. METHODS: Consecutive patients with a recurrent inguinal hernia after a primary TREPP, repaired by a re-TREPP were retrospectively included in the study. Data, retrieved from the electronic patient files, were combined with the clinical findings at the outpatient department where the patients were physically investigated according to a priorly written and registered protocol. RESULTS: Overall about 1800 TREPPs were performed between 2006 and 2013. Since the introduction of TREPP in 2006, 40 patients presented with a recurrence in our center. From this group 19 patients were re-operated with the TREPP technique. No intraoperative complications occurred. There was one conversion from re-TREPP to Lichtenstein and no re-recurrences occurred to date. Ten out of 19 patients could be clinically evaluated with a mean follow-up period of 37 months (range 11-95). None of these patients (n=10) complained of chronic postoperative inguinal pain. Two patients reported discomfort. One patient died non procedure related, three weeks after re-TREPP of sudden cardiac death. CONCLUSION: These first experiences with re-TREPP for secondary inguinal hernia repair are encouraging for the aspects of feasibility and safety, particularly in experienced surgical hands. PMID- 30243263 TI - Giant perianal Seborrheic keratosis: A case report. AB - INTRODUCTION: Seborrheic keratosis is one of the most common benign epidermal cutaneous lesions encountered by dermatologists and plastic surgeons in their daily practice. PRESENTATION OF THE CASE: A 66-year-old man was presented with a large verrucous mass on the sacrum and perianal area of 10 years duration. After the diagnosis of SK was confirmed, a complete excision of the lesion was done with coverage of the defect with a partial thikness skin graft, with a good outcome. DISCUSSION: Giant Seborrheic keratosis are very rare, and their location on the perianal area is rarer still, with no more than 10 published cases of genital area involvement. CONCLUSION: Giant perianal seborrheic keratoses is a very rare presentation, that may resemble many of the skin disease of that area and should be managed with excision and biopsy to confirm the diagnosis. PMID- 30243264 TI - The pedigree of baraitric surgery: A case series of revisional surgery post laparoscopic sleeve gastrectomy in 3 sisters. AB - INTRODUCTION: Obesity is a complex disease involving multiple factors that play a role in its development, including genetics. Given the high prevalence of obesity in Kuwait, this is of particular interest. CASE: This is a case of 3 sisters that presented to a single surgeon for morbid obesity with starting body mass indexes (BMI) of 46.9 kg/m2,56 kg/m2,and 51.3 kg/m2. All three elected to undergo a laparoscopic sleeve gastrectomy as an initial procedure. They presented to thier surgeon 5.5 years later with weight regain. The first patient elected to undergo a Laparoscopic Re-Sleeve Gastrectomy, the second Roux-en-Y Gastric Bypass, and the third Single-Anastomosis Gastric Bypass. The patients were followed up for 2 years post-revisional, for which the % EWL was 35.5%, 48.4% and 25.2%, respectively. CONCLUSION: Our study was also able demonstrate how effective revisional surgery is, when genetics are accounted for, with our results showing RYGB as a revisional procedure being superior to the other options. PMID- 30243265 TI - Cutaneous extra nodal lymphoma relapse: A case report and review of literature. AB - INTRODUCTION: Cutaneous lymphomas represent a unique group of lymphomas. Cutaneous lymphomas are the second most frequent extra nodal involvement; gastrointestinal involvement being the most frequent (Malkan et al. [1]). To the best of our knowledge few cases of cutaneous relapse of Non-Hodgkin Lymphoma (NHL) have been reported where there was an absence of primary cutaneous involvement. CASE PRESENTATION: A case study of a 70-year-old woman who was referred for an excisional biopsy of a lesion on her left cheek in 2017. She had previously been diagnosed with NHL in 2009; disease involved the right groin lymph nodes. The patient completed a course of chemotherapy and was in remission. An excision of the lesion on the left upper cheek confirmed low-grade follicular lymphoma. A PET scan was performed after the histology from the lesion was confirmed which demonstrated moderate fluorodeoxyglucose (FDG) uptake in left cheek, left external iliac lymph nodes and left tonsil consistent with recurrence of lymphoma. DISCUSSION: The majority of relapses of NHL occur in the first 2 years after the completion of treatment. Extra nodal lymphomas comprise 24-48 percent of cases. The reason for multifocal extra nodal lymphoma or preferential involvement of specific extra nodal sites at recurrence is not clear Extra nodal involvement involving skin accounts for 10 percent of cases. NHL typically relapses in the same involvement sites. First line treatment for solitary lesions includes surgical excision, antibiotics and radiotherapy. CONCLUSION: Disease relapse was not present in the primary involvement site. Furthermore, there was a cutaneous relapse where there was no primary cutaneous disease. Treatment involved systemic therapy for this patient given the nodal involvement found on the PET scan. PMID- 30243266 TI - Hybrid Off-pump Second-Stage Aortic Arch Repair after Type A Dissection. AB - BACKGROUND: Ascending aorta or hemi-arch repair are common in the acute phase of type A dissection. Postdissection aneurysms can develop with antegrade perfusion of the false lumen in the dissected aortic arch and require reoperation. METHODS: From 2012 to 2018, we reoperated nine patients with postdissection aneurysms using a hybrid technique without cardiopulmonary bypass. The patients had a EuroSCORE II of 13% and a logistic EuroSCORE I of 45% and were not candidates for frozen elephant trunk surgery. The median interval since the acute ascending repair was 184 (92; 528) days. All patients were treated by median resternotomy, ascending to carotid bypass on a partially clamped ascending graft, and transfemoral endovascular repair with a Relay NBS (nonbare stent) or conformable Gore C-TAG stent graft. RESULTS: Technical success was achieved in all cases. Mean follow-up was 405 (220; 672) days. There was no disabling stroke, endoleak, paraplegia, in-hospital, or late mortality. In all patients, the false lumen was completely thrombosed at the aortic arch level with a median aneurysm shrinkage of 13 mm in the distal arch. There was no bird beak or stent graft migration. Distal stent-induced new entry was observed in one case. Reinterventions were not necessary due to diameter stability. CONCLUSION: Complete debranching with transfemoral thoracic endovascular aneurysm repair showed encouraging results in patients with relevant comorbidities. The used stent grafts performed well in the mid-term follow-up period with no endoleaks or migration. PMID- 30243267 TI - [Spectrophotometric Determination of the Amount of Zinc on the Imprint Left on Hands by Zinc Coatings with 5-Br-PADAP as the Chromogenic Reagent]. AB - Spectrophotometric determination of the amount of zinc on the imprint left on hands by zinc coatings with 2-(5-Bromo-2-pyridylazo)-5-(diethylamino)-phenol (5 Br-PADAP) as a chromogenic reagent has been studied in this paper. The effect of reaction conditions including volume and pH of buffer solution as well as the volume of chromogenic reagent on the determination has also been studied. On the optimized condition, the standard curve of zinc has been established and the amount of zinc on the imprint left on hands by zinc coatings with different contact time and time elapse has been determined separately. As the results shown, the optimized reaction condition is 4 mL of boric acid and borax buffer solution(pH 8.0), 0.2 mL of 5-Br-PADAP with the concentration of 1 g.L(-1) and 1 mL of Triton-X-100 with volume fraction of 10%. Under this circumstance, high linearity of zinc is followed between 0 and 14 MUg and the regression equation of zinc is y=1.851 34x+0.002 29. The amount of zinc on the imprint left on hands by zinc coatings, ranging from 0.425 to 2.377 MUg.cm(-2), increases with contact time from 10 second to 5 min and varies insignificantly from 5 to 10 min. The amount of zinc left on hands declines sharply with time elapse from 0 h to 2 h, and then slowly from 2 to 7 h. The amount of zinc within 7 h is only 0.188 MUg.cm(-2), which is 90% lower than that of 0 h. Therefore, it is suggested that the trace metal detection should be conducted as soon as possible. Besides, the amount of zinc on the imprint left on hands by zinc coatings with different time elapse is not entirely comply with the intensity of imprint left by zinc coatings. This demonstrates that the amount of zinc on hands is not the only factor influencing the intensity of imprint on hands with different time elapse. Additionally, it also proves the hypothesis that zinc in the complex of zinc and protein can be captured and bonded by 5-Br-PADAP resorting to a stronger chelating capacity in the experiment for the first time. The application of the combined methods in a macro and micro view is useful for study in mechanism of influencing factors in trace metal detection, which lays foundations l for further researches. PMID- 30243268 TI - [Distinguish and Quality Estimation of the Leaves of Alstonia scholaris (L.) R. Br. from Different Harvest Time Based on the UV-Vis.FP and HPLC.FP]. AB - UV-Vis and HPLC fingerprint of different harvest time of the leaves of Alstonia scholaris (L.) R. Br. were establish the for identification and quality evaluation to promote the development of Dai Medicine modernization. The optimal extraction condition was used to obtain UV - vis data of different harvest time which were deducted background and eight spot smooth, were collected to make the principal component analysis in SIMCA-P(+)11.5, identifying the samples quickly with the first three principal component three-dimensional diagram. The HPLC fingerprint were obtained with Agilent ZORBAX Eclipse XDB C18 (250*4.6 mm, 5 MUm) chromatographic column with the mobile phase of acetonitrile (B) - water (contain 0.1% formic acid) (A) for gradient elution (0~5 min, 5% B; 5~35 min, 5% B->26% B; 35~40 min, 26% B->56% B). The wavelength was set at 287 nm and the column temperature was maintained at 30 C. The flow rate was 1.0 mL.min-1 and the injection volume was 7 MUL. The HPLC fingerprint of different harvest time of the leaves of Alstonia scholaris (L.) R. Br. was analysised by cluster analysis to quality evaluation. Research findings showing: (1) The UV-Vis spectrogram of different harvest time of the leaves of Alstonia scholaris (L.) R. Br. were divided into three parts according to the absorption peak position and amplitude of variation. The first was 235 to 400 nm, the second was 400 to 500 nm, and the third was 500 to 800 nm. In the first part, absorption peak were focused on 270, 287 and 325 nm, which can reflect the fingerprint character for the high absorbance and amplitude of variation. Absorption peak were distributed in 410 and 464 nm in the second part, absorbance and amplitude of variation were lower than the first part. There was a bigger absorption peak at 665 nm in the third part, but the absorbance had no difference. The UV-Vis data of different harvest time were gathered to make the principal component analysis, the result was that the samples of same month were concentrated distribution, but different month samples were dispersed distribution. (2) HPLC fingerprint were divided into three categories through hierarchical cluster analysis, 3, 4, 5 and 7 month were the first category, 6, 8, 9 month samples were second category, the others were third category. Chemical composition and content of the same category samples were similar, but the different category samples had a obvious difference, more important is that the third category samples content was the highest. Combining UV-Vis FP and HPLC FP can identify and evaluate quickly the samples of different harvest time of the leaves of Alstonia scholaris (L.) R. Br. The optimal harvest time of Alstonia scholaris (L.) R. Br. was from October to next February, which was the coldest season in the Dai calendar. PMID- 30243269 TI - [Study on Identification of Immature Corn Seed Using Hyperspectral Imaging]. AB - The seed maturity, which is one of the important factors that affect seed vigor, is an important quality index. During seed sorting, separating mature seeds from immature seeds can improve the vigor of seed lot and keep vigor consistency. Hyperspectral imaging that covered the range of 400~1 000 nm was used to find out the sensitive bands reflecting corn seed maturity, and corresponding images were employed to classify the immature corn seeds. Principal component analysis (PCA) algorithm was adopted to analyze the hyperspectral image. PC2 of PCA had the greatest difference between immature and mature areas on the seeds, therefore, the weighted coefficients of PC2 was selected to extract sensitive wavebands (501 nm). Regions of interest (ROI) from mature and immature area of 70 immature kernels was selected for mean spectra calculation. Partial least square regression (PLSR) algorithm was employed to analyze the spectra of ROI and extract wavelength related to maturity (518 nm). Band ratio algorithm and Kruskal Wallis test were used to select the best band ratio that had the biggest difference between mature and immature areas (640 nm/525 nm). 864 kernels of corn seed were analyzed by gray images of the selected wavelengths as well as band ratio images. Results showed that the light color regions of the seed crown were misidentified as immature region when the images of selected single band wavelengths were used, while the band ratio image of 640 nm/525 nm could be identified correctly. The immature seeds can be separated from the mature seeds according to the area ratio of segmented immature region to the whole kernel. The correct recognition rate was 93.9%. Using the grey images of selected band ratio can differentiate immature corn seeds from mature seeds effectively, which provide a theoretical reference for the development of seed sorting device in further work. PMID- 30243270 TI - [Study on Nondestructive Detecting Gannan Navel Pesticide Residue with Hyperspectral Imaging Technology]. AB - Hyperspectral imaging technology is a rapid, non-destructive, and non-contact technique which integrates spectroscopy and digital imaging to simultaneously obtain spectral and spatial information. Hyperspectral images are made up of hundreds of contiguous wavebands for each spatial position of a sample studied and each pixel in an image contains the spectrum for that specific position. With hyperspectral imaging, a spectrum for each pixel can be obtained and a gray scale image for each narrow band can be acquired, enabling this system to reflect componential and constructional characteristics of an object and their spatial distributions. In this study, hyperspectral image technology is used to discuss the application of hyperspectral imaging detection technology of Jiangxi navel orange surface of different concentrations of pesticide residue changes with time relationship. The pesticide was diluted to 1 : 20, 1 : 100 and 1 : 1 000 solution with distilled water. A 1*2 matrix of dilutions was applied to each of 30 cleaned samples with different density pesticide residue. After 0, 4 and 20 d respectively, hyperspectral images in the wavelength range from 900 to 1 700 nm are taken. The characteristic wavelengths are achieved by using principal component analysis (PCA) and the PC-2 image based on PCA using characteristic wavelengths (930, 980, 1 100, 1 210, 1 300, 1 400, 1 620 and 1 680 nm) as the classification and recognition of image. Based on these 8 characteristic wavelengths for a second principal component analysis, the application of PC-2 image and appropriate image processing methods for different concentrations and different days of placing pesticide residues in non-destructive testing were applied. Using hyperspectral imaging technology to detect three periods a higher dilution of the fruit surface pesticide residues are more obvious. This research shows that the technology of hyperspectral imaging can be used to effectively detect pesticide residue on Gannan navel surface. PMID- 30243271 TI - [Study of the Impact of Sample Thickness on Thin Film Method X-Ray Fluorescence Spectrum Measurement]. AB - The mixed samples of nylon film enrichment of Cr, Pb and Cd three elements and glass fiber membrane filter were as the research object. With the method of superposition of membrane filter, the XRF spectra were measured under different thin film samples thicknesses. According the changes of characteristic XRF of Cr, Pb and Cd elements in the mixed sample and Ca, As and Sr elements in glass fiber membranes, the effects of sample thickness on thin film method XRF spectrum measurement were studied. The study results showed that the effects of thin film sample thickness on the fluorescent properties of elements with characteristic spectral lines in different energy ranges were different. The energy of characteristic spectral lines was greater, the loss of element characteristic X ray fluorescence when it passed through membrane and reached detector was less. But matrix effect caused by thin film sample thickness increase was stronger with the energy of characteristic spectral lines greater. The background fluorescent intensity in corresponding characteristic spectral line location was greater. So the impact of matrix effect caused by sample thickness increase on thin film method XRF spectrum measurement sensitivity was greater. For elements with low energy characteristic spectral lines (energy<=7 keV), the way of increasing thin film sample thickness in order to increase the mass-thickness concentration of component measured, can not effectively improve the sensitivity of thin film method XRF spectrum measurement. And thin film samples thickness within 0.96 mm is conductive to the measurement and analysis of XRF spectrum. For element with higher energy characteristic spectra lines(energy>7 keV), the sensitivity of XRF spectrum measurement can be appropriately increased by the way of increase thin film sample thickness in order to increase the mass-thickness concentration of component measured. And thin film samples thickness within 0.96~2.24 mm is more conductive to the measurement and analysis of XRF spectrum. The study provides an important theoretical basis for thin sample preparation and enrichment technology of thin film method X-ray fluorescence spectrum analysis the atmosphere and water heavy metal. PMID- 30243272 TI - [Research Method and Spectral Analysis of Ancient Polychromatic Silicate Artifacts]. AB - The spectral properties, chemical compositions and phases of materials constituting the surface of 5 ancient polychromatic silicate artifacts have been analyzed non-invasively with self-built multispectral imaging system, X-ray fluorescence spectrometer (XRF) and laser Raman spectrometer (LRS). Based on spectral response in multispectral images, materials constituting the surface of 5 samples can be divided into different areas, and most of blue, green, purple areas with fluorescence behavior are also mapped. The results of XRF indicate that the chemical compositions of areas are different, but the major compositions of them are SiO(2), PbO, BaO. 5 samples mainly belong to PbO-BaO silicates. The coloring agents of all areas with fluorescence behavior are Cu ions. A variety of mineral phases including vitreous phase, Chinese blue, Chinese purple, quartz, hematite, lead carbonate, amorphous carbon and so on, are also identified by LRS. Chinese blue and Chinese purple can emit infrared radiation when excited by visible LED. The result of LRS is verified by X-ray diffraction (XRD). Combining the multispectral imaging area-measurement technique used to research paintings, and XRF, LRS which are usually used to analyze chemical composition of silicate artifacts, the present research proposes a more efficient and non-invasive research method to analyze ancient polychromatic silicate artifacts. Spectral characteristic and chemical composition of the sample are connected when spectral images, X-ray fluorescence spectra and Laser Raman spectra are combined. It has great significance for increasing efficiency of analysis, enhancing the overall understanding of silicate artifacts and decreasing risk of damage. PMID- 30243273 TI - An efficient pair natural orbital based configuration interaction scheme for the calculation of open-shell ionization potentials. AB - A spin adapted configuration interaction scheme is proposed for the evaluation of ionization potentials in alpha high spin open shell reference functions. There are three different ways to remove an electron from such a reference, including the removal of an alpha or a beta electron from doubly occupied or an alpha electron from singly occupied molecular orbitals. Ionization operators are constructed for each of these cases, and the resulting second quantized expressions are implemented using an automated code generator environment. To achieve greater computational efficiency, the virtual space is reduced using an averaged pair natural orbital machinery developed earlier and applied with great success in the calculation of X-ray absorption spectra [D. Manganas et al., J. Chem. Phys. A 122, 1215 (2018)]. Various approximate integral evaluation schemes including the resolution of identity and seminumerical techniques are also invoked to further enhance the computational efficiency. Although the resulting method is not particularly accurate in terms of predicting absolute energy values, with a simple shift in the ionization potentials, it is still possible to use it for the qualitative characterization of the basic features of X-ray photoionization spectra. While satellite intensities cannot be computed with the current method, the inclusion of vibrational effects using a path integral technique allows for the computation of vibrational transitions corresponding to main peaks. PMID- 30243274 TI - Insulin dimer dissociation in aqueous solution: A computational study of free energy landscape and evolving microscopic structure along the reaction pathway. AB - The dissociation of an insulin dimer to two monomers is an important life process. Although the monomer is the biologically active form of the hormone, it is stored in the beta-cells of the pancreas in the hexameric form. The latter, when the need comes, dissociates to dimers and the dimers in turn to monomers to maintain the endogenous delivery of the hormone. In order to understand insulin dimer dissociation at a molecular level, we perform biased molecular dynamics simulations (parallel tempering metadynamics in the well-tempered ensemble) of the dissociation of the insulin dimer in water using two order parameters and an all-atom model of the protein in explicit water. The two order parameters selected (after appropriate studies) are the distance (RMM) between the center of mass of two monomers and the number of contacts (NMM) among the backbone-Calpha atoms of the two monomers. We calculated the free energy landscape as a function of these two order parameters and determined the minimum free energy pathway of dissociation. We find that the pathway involves multiple minima and multiple barriers. In the initial stage of dissociation, the distance between the monomers does not change significantly but the NMM decreases rapidly. In the latter stage of separation, the opposite occurs, that is, the distance RMM increases at nearly a constant low value of NMM. The configurations of the two monomeric proteins so formed are found to be a bit different due to the entropic reasons. Water is seen to play a key role in the dissociation process stabilizing the intermediates along the reaction path. Our study reveals interesting molecular details during the dissociation, such as the variation in the structural and relative orientational arrangement of the amino acid residues along the minimum energy path. The conformational changes of monomeric insulin in the stable dimer and in the intermediate states during dimer dissociation have been studied in detail. PMID- 30243275 TI - Transition-path properties for folding reactions in the limit of small barriers. AB - Transition paths are of great interest because they encapsulate information about the mechanisms of barrier-crossing reactions. Analysis of experiments measuring biomolecular folding reactions has relied on expressions for properties of transition paths such as transition-path times and velocities that hold in the limit of large harmonic barriers, but real molecules often have relatively small barriers. Recent theoretical work presented more general expressions for transition-path properties. Here we extend this work, deriving expressions from the general case that can be applied to small harmonic barriers. We first compared the performance of small-barrier, large-barrier, and general solutions when applied to simulated transitions, focusing on improvements in estimates of the diffusion coefficient determined from transition times and velocities. We then applied these expressions to experimental data from force spectroscopy measurements of DNA hairpins. We found that the low-barrier approximation and exact solution reduced or resolved the small but systematic inconsistencies that had arisen from assuming large harmonic barriers, demonstrating the practical utility of the new equations for analyzing experimental data. PMID- 30243276 TI - D-carbon: Ab initio study of a novel carbon allotrope. AB - By means of ab initio computations and the global minimum structure search method, we have investigated structural, mechanical, and electronic properties of D-carbon, a crystalline orthorhombic sp3 carbon allotrope (space group Pmma [ D2h5 ] with 6 atoms per cell). Total-energy calculations demonstrate that D carbon is energetically more favorable than the previously proposed T6 structure (with 6 atoms per cell) as well as many others. This novel phase is dynamically, mechanically, and thermally stable at zero pressure and more stable than graphite beyond 63.7 GPa. D-carbon is a semiconductor with a bandgap of 4.33 eV, less than diamond's gap (5.47 eV). The simulated X-ray diffraction pattern is in satisfactory agreement with previous experimental data in chimney or detonation soot, suggesting its possible presence in the specimen. PMID- 30243277 TI - Solving the Schrodinger equation of atoms and molecules: Chemical-formula theory, free-complement chemical-formula theory, and intermediate variational theory. AB - Chemistry is governed by the principle of quantum mechanics as expressed by the Schrodinger equation (SE) and Dirac equation (DE). The exact general theory for solving these fundamental equations is therefore a key for formulating accurately predictive theory in chemical science. The free-complement (FC) theory for solving the SE of atoms and molecules proposed by one of the authors is such a general theory. On the other hand, the working theory most widely used in chemistry is the chemical formula that refers to the molecular structural formula and chemical reaction formula, collectively. There, the central concepts are the local atomic concept, transferability, and from-atoms-to-molecule concept. Since the chemical formula is the most successful working theory in chemistry ever existed, we formulate our FC theory to have the structure reflecting the chemical formula. Our basic postulate is that as far as the SE is the principle of chemistry, its solutions for chemistry should have the structure that can be related to the chemical formulas. So, in this paper, we first formulate a theory that designs the wave function to reflect the structure of the chemical formula. We call this theory chemical formula theory (CFT). In the CFT, we place the valence ground and excited states of each atom at each position of the chemical formula of the molecule and let them interact using their free valences to form the ground and excited states of the molecule. The principle there is the variational principle so that the ground and excited states obtained satisfy the orthogonality and Hamiltonian-orthogonality relations. Then, we formulate the exact FC theory starting from the initial functions produced by the CFT. This FC theory is referred to as free-complement chemical-formula theory (FC-CFT), which is expected to describe efficiently the solution of the SE by the above reason. The FC-CFT wave function is modified from that of CFT. Since this modification is done by the exact SE, its analysis may give some insights to chemists that assist their chemistry. Thus, this theory would be not only exact but also conceptually useful. Furthermore, the intermediate theory between CFT and FC-CFT would also be useful. There, we use only integratable functions and apply the variational principle so that we refer to this theory as FC-CFT-variational (FC-CFT-V). It is an advanced theory of CFT. Since the variational method is straightforward and powerful, we can do extensive chemical studies in a reasonable accuracy. After finishing such studies, if we still need an exact level of solutions, we add the remaining functions of the FC-CFT and perform the exact calculations. Furthermore, when we deal with large and even giant molecules, the inter-exchange (iExg) theory for the antisymmetry rule introduced previously leads to a large simplification. There, the inter-exchanges between distant electron pairs fade away so that only Coulombic interactions survive. Further in giant systems, even an electrostatic description becomes possible. Then, the FC-CFT for exactly solving the SE would behave essentially to order N for large and giant molecular systems, though the pre-factor should be very large and must be minimized. PMID- 30243278 TI - MonteCoffee: A programmable kinetic Monte Carlo framework. AB - Kinetic Monte Carlo (kMC) is an essential tool in heterogeneous catalysis enabling the understanding of dominant reaction mechanisms and kinetic bottlenecks. Here we present MonteCoffee, which is a general-purpose object oriented and programmable kMC application written in python. We outline the implementation and provide examples on how to perform simulations of reactions on surfaces and nanoparticles and how to simulate sorption isotherms in zeolites. By permitting flexible and fast code development, MonteCoffee is a valuable alternative to previous kMC implementations. PMID- 30243279 TI - Fourth-order vibrational perturbation theory with the Watson Hamiltonian: Report of working equations and preliminary results. AB - A derivation of fourth-order vibrational perturbation theory (VPT4) based on the Watson Hamiltonian in dimensionless rectilinear normal coordinates is presented. Terms that are linear and cubic in the (nk + 12 ), with nk being the zeroth-order harmonic oscillator quantum numbers, appear in fourth order and extend the much simpler second-order vibrational perturbation theory model. The rather involved expressions for the fourth-order terms are derived with Rayleigh-Schrodinger perturbation theory, the process of verifying their correctness is described, and a computer code to generate the VPT4 constants from the potential energy surface derivatives is provided. The paper concludes with numerical examples featuring the H2O, Si2C, and cyclic-C3H2 molecules. PMID- 30243280 TI - An efficient approach to the quantum dynamics and rates of processes induced by natural incoherent light. AB - In many important cases, the rate of excitation of a system embedded in an environment is significantly smaller than the internal system relaxation rates. An important example is that of light-induced processes under natural conditions, in which the system is excited by weak, incoherent (e.g., solar) radiation. Simulating the dynamics on the time scale of the excitation source can thus be computationally intractable. Here we describe a method for obtaining the dynamics of quantum systems without directly solving the master equation. We present an algorithm for the numerical implementation of this method and, as an example, use it to reconstruct the internal conversion dynamics of pyrazine excited by sunlight. Significantly, this approach also allows us to assess the role of quantum coherence on biological time scales, which is a topic of ongoing interest. PMID- 30243281 TI - Using fluorescence detected two-dimensional spectroscopy to investigate initial exciton delocalization between coupled chromophores. AB - Forster theory describes electronic exciton energy migration in molecular assemblies as an incoherent hopping process between donor and acceptor molecules. The rate is expressed in terms of the overlap integral between donor fluorescence and acceptor absorption spectra. Typical time scales for systems like photosynthetic antennae are on the order of a few picoseconds. Prior to transfer, it is assumed that the initially excited donor molecule has equilibrated with respect to the local environment. However, upon excitation and during the equilibration phase, the state of the system needs to be described by the full density matrix, including coherences between donor and acceptor states. While being intuitively clear, addressing this regime experimentally has been a challenge until the recently reported advances in fluorescence detected two dimensional spectroscopy. Here, we demonstrate using fourth order perturbation theory the conditions for the presence of donor-acceptor coherence induced cross peaks at zero waiting time between the first and the second pair of pulses. The approach is illustrated for a heterodimer model which facilitates an analytical solution. PMID- 30243282 TI - Mechanical and electromechanical properties of functionalized hexagonal boron nitride nanosheet: A density functional theory study. AB - Hydroxylation as a technique is mainly used to alter the chemical characteristics of hexagonal boron nitride (h-BN), affecting physical features as well as mechanical and electromechanical properties in the process, the extent of which remains unknown. In this study, effects of functionalization on the physical, mechanical, and electromechanical properties of h-BN, including the interlayer distance, Young's modulus, intrinsic strength, and bandgaps were investigated based on density functional theory. It was found that functionalized layers of h BN have an average distance of about 5.48 A. Analyzing mechanical properties of h BN revealed great dependence on the degree of functionalization. For the amorphous hydroxylated hexagonal boron nitride nanosheets (OH-BNNS), the Young's modulus moves from 436 to 284 GPa as the coverage of -OH increases. The corresponding variations in the Young's modulus of the ordered OH-BNNS with analogous coverage are bigger at 460-290 GPa. The observed intrinsic strength suggested that mechanical properties are promising even after functionalization. Moreover, the resulted bandgap reduction drastically enhanced the electrical conductivity of this structure under imposed strains. The results from this work pave the way for future endeavors in h-BN nanocomposites research. PMID- 30243283 TI - Effects of random pinning on the potential energy landscape of a supercooled liquid. AB - We use energy landscape methods to investigate the response of a supercooled liquid to random pinning. We classify the structural similarity of different energy minima using a measure of overlap. This analysis reveals a correspondence between distinct particle packings (which are characterised via the overlap) and funnels on the energy landscape (which are characterised via disconnectivity graphs). As the number of pinned particles is increased, we find a crossover from glassy behavior at low pinning to a structure-seeking landscape at high pinning, in which all thermally accessible minima are structurally similar. We discuss the consequences of these results for theories of randomly pinned liquids. We also investigate how the energy landscape depends on the fraction of pinned particles, including the degree of frustration and the evolution of distinct packings as the number of pinned particles is reduced. PMID- 30243284 TI - Solving the Schrodinger equation of atoms and molecules with the free-complement chemical-formula theory: First-row atoms and small molecules. AB - The free-complement chemical-formula theory (FC-CFT) for solving the Schrodinger equation (SE) was applied to the first-row atoms and several small molecules, limiting only to the ground state of a spin symmetry. Highly accurate results, satisfying chemical accuracy (kcal/mol accuracy for the absolute total energy), were obtained for all the cases. The local Schrodinger equation (LSE) method was applied for obtaining the solutions accurately and stably. For adapting the sampling method to quantum mechanical calculations, we developed a combined method of local sampling and Metropolis sampling. We also reported the method that leads the calculations to the accurate energies and wave functions as definite converged results with minimum ambiguities. We have also examined the possibility of the stationarity principle in the sampling method: it certainly works, though more extensive applications are necessary. From the high accuracy and the constant stability of the results, the present methodology seems to provide a useful tool for solving the SE of atoms and molecules. PMID- 30243285 TI - Uncertainty quantification confirms unreliable extrapolation toward high pressures for united-atom Mie lambda-6 force field. AB - Molecular simulation results at extreme temperatures and pressures can supplement experimental data when developing fundamental equations of state. Since most force fields are optimized to agree with vapor-liquid equilibria (VLE) properties, however, the reliability of the molecular simulation results depends on the validity/transferability of the force field at higher temperatures and pressures. As demonstrated in this study, although state-of-the-art united-atom Mie lambda-6 potentials for normal and branched alkanes provide accurate estimates for VLE, they tend to over-predict pressures for dense supercritical fluids and compressed liquids. The physical explanation for this observation is that the repulsive barrier is too steep for the "optimal" united-atom Mie lambda 6 potential parameterized with VLE properties. Bayesian inference confirms that no feasible combination of non-bonded parameters (epsilon, sigma, and lambda) is capable of simultaneously predicting saturated vapor pressures, saturated liquid densities, and pressures at high temperatures and densities. This conclusion has both practical and theoretical ramifications, as more realistic non-bonded potentials may be required for accurate extrapolation to high pressures of industrial interest. PMID- 30243286 TI - Thermoelectric efficiency in three-terminal graphene nano-junctions. AB - The thermoelectric efficiency of a thermal machine consisting of a triangular graphene nano-junction connected to three electrodes in the linear response regime is studied. Using the Onsager formalism and a combination of semi empirical tight-binding calculations as well as Green's function theory, the efficiency at maximum output power which can be written in terms of generalized figures of merit is investigated. The results for a set temperature and chemical potential parameters have shown that adding a third terminal improves the efficiency at maximum output power compared to the two-terminal setup. PMID- 30243287 TI - Dynamic formation of nanodiamond precursors from the decomposition of carbon suboxide (C3O2) under extreme conditions-A ReaxFF study. AB - We use molecular dynamics simulations with the ReaxFF-lg potential to model the high pressure pyrolysis of carbon suboxide (C3O2) in mixture with argon as a pressure bath. We show that the reactive simulations catch the experimental behavior of the low-pressure detonation of C3O2 (around 10 bars in shock tube experiments) and allow extrapolations to the high-pressure range of solid-state explosive detonation (up to 60 GPa). While at low pressure carbonaceous nanostructures are formed through the aggregation of species such as carbon dimers C2, it appears that the high pressure deeply modifies the process, with the aggregation of growing CxOy heterostructures, in which the oxygen amount is driven by the pressure and the temperature. Pressures in the order of 60 GPa lead to high oxygen ratios, which prevent carbon atoms to get four carbon neighbors (the first condition to get a diamond structure). But a pressure lowering leads to a substantial carbon enrichment through CO2/CO release and facilitates the formation of pure sp3-carbon phases where diamond precursors can form. These results give new insights on the conditions leading to nanodiamonds during the detonation of carbon-rich high explosives. PMID- 30243288 TI - Multipoint segmental repulsive potential for entangled polymer simulations with dissipative particle dynamics. AB - A model is developed for simulating entangled polymers by dissipative particle dynamics (DPD) using the segmental repulsive potential (SRP). In contrast to previous SRP models that define a single-point interaction on each bond, the proposed SRP model applies a dynamically adjustable multipoint on the bond. Previous SRP models could not reproduce the equilibrium properties of Groot and Warren's original DPD model [R. D. Groot and P. B. Warren, J. Chem. Phys. 107, 4423 (1997)] because the introduction of a single SRP induces a large excluded volume, whereas, the proposed multipoint SRP (MP-SRP) introduces a cylindrical effective excluded bond volume. We demonstrate that our MP-SRP model exhibits equilibrium properties similar to those of the original DPD polymers. The MP-SRP model parameters are determined by monitoring the number of topology violations, thermodynamic properties, and the polymer internal structure. We examine two typical DPD polymers with different bond-length distributions; one of them was used in the modified SRP model by Sirk et al. [J. Chem. Phys. 136, 134903 (2012)], whereas the other was used in the original DPD model. We demonstrate that for both polymers, the proposed MP-SRP model captures the entangled behaviors of a polymer melt naturally, by calculating the slowest relaxation time of a chain in the melt and the shear relaxation modulus. The results indicate that the proposed MP-SRP model can be applied to a variety of DPD polymers. PMID- 30243289 TI - The EXP pair-potential system. II. Fluid phase isomorphs. AB - This paper continues the investigation of the exponentially repulsive EXP pair potential system of Paper I [A. K. Bacher et al., J. Chem. Phys. 149, 114501 (2018)] with a focus on isomorphs in the low-temperature gas and liquid phases. As expected from the EXP system's strong virial potential-energy correlations, the reduced-unit structure and dynamics are isomorph invariant to a good approximation. Three methods for generating isomorphs are compared: the small step method that is exact in the limit of small density changes and two versions of the direct-isomorph-check method that allows for much larger density changes. Results from the latter two approximate methods are compared to those of the small-step method for each of the three isomorphs generated by 230 one percent density changes, covering one decade of density variation. Both approximate methods work well. PMID- 30243290 TI - Communication: Existence and control of liquid polymorphism in methanol under shear. AB - The liquid-liquid hypothesis, which states that a pure substance can exhibit two liquid forms (or polymorphs), has drawn considerable interest in recent years. The appeal of this theory is that it provides the basis for a deeper understanding of the properties of supercooled liquids. However, the study of this phenomenon is extremely challenging and a complete understanding of its impact on fluid properties has remained elusive so far, since the low-temperature liquid form is generally not stable and undergoes rapid crystallization. Using a coarse-grained model for methanol, we show that methanol under shear can exhibit, in the steady state, two liquid forms that respond differently to the applied shear. Using molecular simulations, we show that the difference in dynamical response is correlated with structural differences between the two liquid forms. This establishes the existence of liquid polymorphism for systems driven out-of equilibrium. Our findings also show how, by varying the pressure or the shear stress applied to the system, liquid-liquid transitions can be triggered and how a control of liquid polymorphism can be achieved. The resulting solid-liquid liquid nonequilibrium phase diagram leads us to identify new ways for the stabilization and study of liquid polymorphism. PMID- 30243291 TI - The EXP pair-potential system. I. Fluid phase isotherms, isochores, and quasiuniversality. AB - It was recently shown that the exponentially repulsive EXP pair potential defines a system of particles in terms of which simple liquids' quasiuniversality may be explained [A. K. Bacher et al., Nat. Commun. 5, 5424 (2014); J. C. Dyre, J. Phys.: Condens. Matter 28, 323001 (2016)]. This paper and its companion [A. K. Bacher et al., J. Chem. Phys. 149, 114502 (2018)] present a detailed simulation study of the EXP system. Here we study how structure monitored by the radial distribution function and dynamics monitored by the mean-square displacement as a function of time evolve along the system's isotherms and isochores. The focus is on the gas and liquid phases, which are distinguished pragmatically by the absence or presence of a minimum in the radial distribution function above its first maximum. A constant-potential-energy (NVU)-based proof of quasiuniversality is presented, and quasiuniversality is illustrated by showing that the structure of the Lennard-Jones system at four state points is well approximated by those of EXP pair-potential systems with the same reduced diffusion constant. Paper II studies the EXP system's isomorphs, focusing also on the gas and liquid phases. PMID- 30243293 TI - A case report: autosomal recessive Myotonia congenita caused by a novel splice mutation (c.1401 + 1G > A) in CLCN1 gene of a Chinese Han patient. AB - BACKGROUND: Autosomal recessive Myotonia congenita (Becker's disease) is caused by mutations in the CLCN1 gene. The condition is characterized by muscle stiffness during sustained muscle contraction and variable degree of muscle weakness that tends to improve with repeated contractions. CASE PRESENTATION: A 21-year-old man presented with transient muscle stiffness since the last 10 years. He had difficulty in initiating movement and experienced muscle weakness after rest, which typically improved after repeated contraction (warm-up phenomenon). There was no significant family history. Medical examination showed generalized muscle hypertrophy. Serum creatine kinase level was 2-fold higher than the normal value. Electromyogram showed myotonic discharges. DNA sequence analysis identified a novel splice mutation (c.1401 + 1G > A) and a known mutation (c.1657A > T,p.Ile553Phe). He rapidly responded to treatment with mexiletine 100 mg three times a day for 6 months. CONCLUSIONS: This case report of autosomal recessive Myotonia congenita caused by a novel compound heterozygous mutation expands the genotypic spectrum of CLCN1 gene. PMID- 30243292 TI - Recent advances in graphene-based biosensor technology with applications in life sciences. AB - Graphene's unique physical structure, as well as its chemical and electrical properties, make it ideal for use in sensor technologies. In the past years, novel sensing platforms have been proposed with pristine and modified graphene with nanoparticles and polymers. Several of these platforms were used to immobilize biomolecules, such as antibodies, DNA, and enzymes to create highly sensitive and selective biosensors. Strategies to attach these biomolecules onto the surface of graphene have been employed based on its chemical composition. These methods include covalent bonding, such as the coupling of the biomolecules via the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and N hydroxysuccinimide reactions, and physisorption. In the literature, several detection methods are employed; however, the most common is electrochemical. The main reason for researchers to use this detection approach is because this method is simple, rapid and presents good sensitivity. These biosensors can be particularly useful in life sciences and medicine since in clinical practice, biosensors with high sensitivity and specificity can significantly enhance patient care, early diagnosis of diseases and pathogen detection. In this review, we will present the research conducted with antibodies, DNA molecules and, enzymes to develop biosensors that use graphene and its derivatives as scaffolds to produce effective biosensors able to detect and identify a variety of diseases, pathogens, and biomolecules linked to diseases. PMID- 30243294 TI - Effects of propofol/remifentanil-based total intravenous anesthesia versus sevoflurane-based inhalational anesthesia on the release of VEGF-C and TGF-beta and prognosis after breast cancer surgery: a prospective, randomized and controlled study. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-beta) have been involved in tumor growth and metastasis. Sevoflurane may promote angiogenesis, whereas propofol can present an anti angiogenic effect. In this study, we compared the effects of propofol/remifentanil-based total intravenous anesthesia (TIVA) and sevoflurane based inhalational anesthesia on the release of VEGF-C and TGF-beta, as well as recurrence- free survival (RFS) rates in the patients undergoing breast cancer surgery. METHODS: Eighty female patients undergoing breast cancer resection were enrolled and randomized to receive either sevoflurane-based inhalational anesthesia (SEV group) or propofol/remifentanil-based TIVA (TIVA group). The serum concentrations of VEGF-C and TGF-beta before and 24 h after surgery were measured and RFS rates over a two-year follow-up were analyzed in both groups. The postoperative pain scores assessed using a visual analogue scale (VAS) and the use of perioperative opioids were also evaluated. RESULTS: Although VAS scores at 2 h and 24 h after surgery were comparable between the two groups, there were more patients receiving postoperative fentanyl in the TIVA group (16[40%]) compared with the SEV group (6[15%], p = 0.023). VEGF-C serum concentrations increased after surgery from 105 (87-193) pg/ml to174 (111-281) pg/ml in the SEV group (P = 0.009), but remained almost unchanged in the TIVA group with 134 (80-205) pg/ml vs.140(92-250) pg/ml(P = 0.402). The preoperative to postoperative change for VEGF-C of the SEV group (50 pg/ml) was significantly higher than that of the TIVA group (12 pg/ml) with a difference of 46 (- 11-113) pg/ml (P = 0.008). There were also no significant differences in the preoperative and postoperative TGF-beta concentrations between the two groups. The two-year RFS rates were 78% and 95% in the SEV and TIVA groups (P = 0.221), respectively. CONCLUSION: In comparison with sevoflurane-based inhalational anesthesia, propofol/remifentanil -based total intravenous anesthesia can effectively inhibit the release of VEGF-C induced by breast surgery, but didn't seem to be beneficial in the short-term recurrence rate of breast cancer. TRIAL REGISTRATION: Chictr.org.cn ChiCTR1800017910 . Retrospectively Registered (Date of registration: August 20, 2018). PMID- 30243295 TI - Triamcinolone Acetonide affects TGF-beta signaling regulation of fibrosis in idiopathic carpal tunnel syndrome. AB - BACKGROUND: Fibroblast behavior and cell-matrix interactions of cells from normal and idiopathic carpal tunnel syndrome (CTS) subsynovial connective tissue (SSCT) with and without Triamcinolone Acetonide (TA) were compared in this study. A cell seeded gel contraction model was applied to investigate the effect of steroid treatment on SSCT fibroblast gene expression and function. METHODS: SSCT cells were obtained from CTS patients and fresh cadavers. Cells were isolated by mechanical and collagenase digestion. Collagen gels (1 mg/ml) were prepared with SSCT cells (1 * 106/mL). A sterile Petri dish with a cloning ring in the center was prepared. The area between the ring and outer dish was filled with cell seeded collagen solution and gelled for 1 h. The gel was released from the outer way of the petri dish to allow gel contraction. Cell seeded gels were treated with 10 M triamcinolone acetonide (TA) or vehicle (DMSO) in modified MEM. Every 4 h for 3 days the contracting gels were photographed and areas calculated. Duplicate contraction tests were performed with each specimen, and the averages were used in the analyses, which were conducted using two-factor analysis of variance in a generalized linear model framework utilizing generalized estimating equations (GEE) to account for the correlation between samples. The contraction rate was determined by the area change over time, and the decay time constant was calculated. A customized mechanical test system was used to determine gel stiffness and tensile strength. Gene expression was assessed using Human Fibrosis and Cell Motility PCR arrays. RESULTS: TA-treated gels had a significantly higher contraction rate, tensile strength and stiffness than the untreated gels. Proteinases involved in remodeling had increased expression in TA-treated gels of the patient group. Pro-fibrotic genes and ECM regulators, such as TGF-beta, collagens and integrins, were down-regulated by TA, indicating that TA may work in part by decreasing fibrotic gene expression. CONCLUSIONS: This study showed that TA affects cell-matrix interaction and suppresses fibrotic gene expression in the SSCT cells of CTS patients. PMID- 30243296 TI - The clinical effect of an unloader brace on patients with osteoarthritis of the knee, a randomized placebo controlled trial with one year follow up. AB - BACKGROUND: Treatment of patients with knee osteoarthritis is challenging. Unloader braces have been developed with various success. Unloader One(r) Knee Brace is light, easily-fitted and shown to be effective by the unloading of the affected compartment. The aim of the study was to assess the clinical outcome of the brace vs. a placebo on patients with knee osteoarthritis. METHODS: Initially 150 patients were randomized to receive either the Unloader brace or a control placebo group look-alike brace where the active strips had been removed. The patients were followed up at 6,12,26 and 52 weeks with Knee Society Score (KSS) and Knee injury and Osteoarthritis Outcome Score (KOOS). The reason for dropout was recorded. RESULTS: A total of 149 patients were included, 74 in the study and 75 in the control group. The mean age was 59.6 vs. 60.2, BMI was 27.5 vs. 26.9, 37% vs. 44% were women in the study vs. control group. Both groups showed improvement in KSS over 52 weeks, with the study group showing higher improvement in mean scores. KSS increased from 64.3 to 84.0 for the study group and from 64.0 to 74.6 for the control group (p = 0.009). The study group improved in KSS function from 67.0 to 78.6 (p < 0.001) and KOOS for knee related symptoms increased/improved from 64.3 to 72.4 (p < 0.001). Activity of daily living increased/improved from 65.3 to 75.2 and Sports/Recreation from 24.6 to 40.2 (p > 0.001) whereas the control group did not show significant improvements in any of the scores. The dropout was higher in the control group, 40 vs. 25. CONCLUSIONS: The brace seems to be more effective and better tolerated than the placebo. TRIAL REGISTRATION: The trial was retrospectively registered with ClinicalTrials.gov ( NCT03454776 ) on March 6th 2018. PMID- 30243298 TI - The use of phoxim and bendiocarb for control of fleas in farmed mink (Mustela vison). AB - BACKGROUND: Fleas (Ceratophyllus sciurorum) are common on farmed mink in Denmark. When present, the fleas have a negative impact on the health of the farmed mink and are of nuisance for farm staff. Severe infestations of fleas cause anemia, poor growth and may result in death of mink kits. Changed behavior of the dams is also observed. Further it has been demonstrated that the fleas are vectors of Aleutian disease virus. Flea control is based on use of a few insecticides and resistance has been reported against permethrin. There is thus a need for new flea control products. In this blinded, randomized clinical trial according to GCP standard, phoxim spray and bendiocarb powder for flea control on mink farms were investigated. RESULTS: Both the phoxim spray solution and bendiocarb powder were found to be efficient for the control of C. sciurorum fleas on farmed mink. Phoxim treatments reduced the number of fleas by 98.4% and the bendiocarb treatments reduced the number of fleas by 99.0% in the mink nest boxes when compared to counts in controls. No clinical signs were observed post treatment. CONCLUSIONS: The study demonstrated that phoxim sprayed on the animals and the use of bendiocarb powder in the nest box material were highly efficient for the control of the C. sciurorum fleas on farmed mink. Both products were safe to use at the recommended dose rate. Both compounds are recommended to be integrated in a new farm management plan suggested here. PMID- 30243297 TI - Advances in redox-responsive drug delivery systems of tumor microenvironment. AB - With the improvement of nanotechnology and nanomaterials, redox-responsive delivery systems have been studied extensively in some critical areas, especially in the field of biomedicine. The system constructed by redox-responsive delivery can be much stable when in circulation. In addition, redox-responsive vectors can respond to the high intracellular level of glutathione and release the loaded cargoes rapidly, only if they reach the site of tumor tissue or targeted cells. Moreover, redox-responsive delivery systems are often applied to significantly improve drug concentrations in targeted cells, increase the therapeutic efficiency and reduce side effects or toxicity of primary drugs. In this review, we focused on the structures and types of current redox-responsive delivery systems and provided a comprehensive overview of relevant researches, in which the disulfide bond containing delivery systems are of the utmost discussion. PMID- 30243299 TI - Spermatogenesis improved by suppressing the high level of endogenous gonadotropins in idiopathic non-obstructive azoospermia: a case control pilot study. AB - BACKGROUND: Elevated plasma gonadotropins were associated with desensitization of Sertoli and Leydig cells in the male testis. Testis spermatogenesis ability would be improved via inhibiting high endogenous gonadotropin in patients with severe oligozoospermia. Whether it would be beneficial for non-obstructive azoospermia (NOA) patients was still unclear. METHODS: Goserelin, a gonadotropin releasing hormone agonist (GnRHalpha) was used to suppress endogenous gonadotropin levels (gonadotropin reset) in the NOA patients, improving the sensitization of the Sertoli and Leydig cells. Then human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG) were injected to stimulate them to ameliorate the ability of testicular spermatogenesis. The main outcome measure was the existence of spermatozoa in the semen or by testicular sperm extraction (TESE). Elevation of inhibin B and/or ameliorative expression pattern of ZO-1 was the secondary objective. RESULTS: A total of 35 NOA men who failed to retrieve sperm via TESE were enrolled. Among these, 10 patients without treatment were selected as control group and secondary TESE was performed 6 months later. Of the 25 treated men, inhibin B was elevated in 11 patients in the first 4 weeks (Response group), while only 5 patients had constant increase in the following 20 weeks (Response group 2). Of the 5 men, 2 men acquired sperm (Response group 2B), while 3 failed (Response group 2A). Immunofluorescence of mouse vasa homologue (MVH) and ZO-1 showed that both positive MVH signals and ZO-1 expression were significantly increased in the Response group 2, but only Response group 2B showed ameliorative ZO-1 distribution. CONCLUSIONS: Gonadotropin reset, a new therapeutic protocol with GnRHalpha, was able to improve the ability of testicular spermatogenesis in the NOA patients through restoring the sensitivity of Sertoli and Leydig cells, which were reflected by elevated inhibin B and ameliorative ZO-1 expression and distribution. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02544191 . PMID- 30243300 TI - The global burden of sepsis: barriers and potential solutions. AB - Sepsis is a major contributor to the global burden of disease. The majority of sepsis cases and deaths are estimated to occur in low and middle-income countries. Barriers to reducing the global burden of sepsis include difficulty quantifying attributable morbidity and mortality, low awareness, poverty and health inequity, and under-resourced and low-resilience public health and acute health care delivery systems. Important differences in the populations at risk, infecting pathogens, and clinical capacity to manage sepsis in high and low resource settings necessitate context-specific approaches to this significant problem. We review these challenges and propose strategies to overcome them. These strategies include strengthening health systems, accurately identifying and quantifying sepsis cases, conducting inclusive research, establishing data-driven and context-specific management guidelines, promoting creative clinical interventions, and advocacy. PMID- 30243302 TI - Late onset hyperornithinemia-hyperammonemia-homocitrullinuria syndrome - how web searching by the family solved unexplained unconsciousness: a case report. AB - BACKGROUND: Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a rare inherited urea cycle disorder, can remain undiagnosed for decades and suddenly turn into an acute life-threatening state. Adult presentation of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome has rarely been described, but is potentially underdiagnosed in the emergency room. In the case of acute hyperammonemia, prompt diagnosis is essential to minimize the risk of brain damage and death. CASE PRESENTATION: We present the diagnostics, clinical course, and treatment of a 48-year-old Caucasian man presenting with unexplained unconsciousness in the emergency room. A web search by a family member led to the suspicion of urea cycle disorder. Subsequent analysis of plasma ammonia and amino acids in plasma and urine demonstrated a pattern typical for hyperornithinemia hyperammonemia-homocitrullinuria syndrome. The diagnosis was confirmed by genetic analysis which revealed two heterozygous mutations in the SLC25A15 gene. The cause of the hyperammonemia crisis was acute upper gastrointestinal hemorrhage, leading to protein overload and subsequent cerebral edema. Continuous renal replacement therapy, scavenger treatment, and tightly controlled nutrition were useful in preventing hyperammonemia and recurrence of cerebral edema. CONCLUSIONS: The case emphasizes the importance of taking rare metabolic genetic disorders into consideration in patients with prolonged unexplained unconsciousness. PMID- 30243301 TI - Driving-pressure-independent protective effects of open lung approach against experimental acute respiratory distress syndrome. AB - BACKGROUND: The open lung approach (OLA) reportedly has lung-protective effects against acute respiratory distress syndrome (ARDS). Recently, lowering of the driving pressure (DeltaP), rather than improvement in lung aeration per se, has come to be considered as the primary lung-protective mechanism of OLA. However, the driving pressure-independent protective effects of OLA have never been evaluated in experimental studies. We here evaluated whether OLA shows protective effects against experimental ARDS even when the DeltaP is not lowered. METHODS: Lipopolysaccharide was intratracheally administered to rats to establish experimental ARDS. After 24 h, rats were mechanically ventilated and randomly allocated to the OLA or control group. In the OLA group, 5 cmH2O positive end expiratory pressure (PEEP) and recruitment maneuver (RM) were applied. Neither PEEP nor RM was applied to the rats in the control group. Dynamic DeltaP was kept at 15 cmH2O in both groups. After 6 h of mechanical ventilation, rats in both groups received RM to inflate reversible atelectasis of the lungs. Arterial blood gas analysis, lung computed tomography, histological evaluation, and comprehensive biochemical analysis were performed. RESULTS: OLA significantly improved lung aeration, arterial oxygenation, and gas exchange. Even after RM in both groups, the differences in these parameters between the two groups persisted, indicating that the atelectasis-induced respiratory dysfunction observed in the control group is not an easily reversible functional problem. Lung histological damage was severe in the dorsal dependent area in both groups, but was attenuated by OLA. White blood cell counts, protein concentrations, and tissue injury markers in the broncho-alveolar lavage fluid (BALF) were higher in the control than in the OLA group. Furthermore, levels of CXCL-7, a platelet derived chemokine, were higher in the BALF from the control group, indicating that OLA protects the lungs by suppressing platelet activation. CONCLUSIONS: OLA shows protective effects against experimental ARDS, even when the DeltaP is not decreased. In addition to reducing DeltaP, maintaining lung aeration seems to be important for lung protection in ARDS. PMID- 30243303 TI - Prognostic value of various subtypes of extracellular DNA in ovarian cancer patients. AB - BACKGROUND: Patients with ovarian cancer represent a heterogeneous population with a variable prognosis and response to chemotherapy. Plasma DNA has been shown to have a prognostic value in different types of cancer including ovarian carcinoma. Whether total circulating DNA, which can be assessed much easier without knowing the tumor-specific mutations, has similar informative value is currently unknown. The aim of this study was to evaluate the prognostic value of extracellular DNA in advanced ovarian cancer. METHODS: This prospective study included 67 patients (pts) with ovarian cancer treated with 1st line paclitaxel and carboplatin (25 pts) and paclitaxel, carboplatin and bevacizumab (42 pts). Thirty-five patients had optimal surgical debulking before chemotherapy. Extracellular DNA was quantified using real time PCR before administration of chemotherapy (67 pts) and after 6 cycles of chemotherapy (44 pts). RESULTS: Total extracellular DNA (ecDNA), as well as extracellular DNA of nuclear (nDNA) and mitochondrial origin (mtDNA) significantly (p < 0.05) decreased after 6 cycles of chemotherapy (by 54%, 63% and 52%, respectively. Patients with stage I disease had significantly lower mtDNA compared to patients with stage II-IV (8604 vs. 16, 984 ge/mL, p = 0.03). Patients with lower baseline nDNA had superior progression free (HR = 0.35 (0.14-0.86)) and overall survival (HR = 0.18 (0.04-0.77). The prognostic value of nDNA was confirmed independent of tumor stage and confirmed in multivariate analysis. CONCLUSIONS: Our data suggest that ecDNA of both, nuclear and mitochondrial origin could be added to prognostic markers in ovarian cancer. Analysis of ecDNA does not require the knowledge of tumor-specific mutations in contrast to the quantification of tumor-derived ecDNA. Study of the dynamics and cell type-specific source of the ecDNA could shed light on its biology in cancer and might help to direct the treatment of ovarian cancer. PMID- 30243306 TI - A new BEACON of hope for the treatment of inflammation? The endogenous metabolite itaconate as an alternative activator of the KEAP1-Nrf2 system. PMID- 30243307 TI - A novel role of renin inhibitor in the complement cascade. AB - Aberrant regulation of an alternative pathway of the complement system could be a therapeutic target of C3 glomerulopathy, including dense deposit disease. In the current issue, Bekassy and colleagues provide data on enzymatic conversion of C3 by renin in vitro and on the efficacy of a direct renin inhibitor, aliskiren, on systemic and renal complement activation in patients with dense deposit disease. PMID- 30243304 TI - Risk factors and outcomes for airway failure versus non-airway failure in the intensive care unit: a multicenter observational study of 1514 extubation procedures. AB - BACKGROUND: Patients liberated from invasive mechanical ventilation are at risk of extubation failure, including inability to breathe without a tracheal tube (airway failure) or without mechanical ventilation (non-airway failure). We sought to identify respective risk factors for airway failure and non-airway failure following extubation. METHODS: The primary endpoint of this prospective, observational, multicenter study in 26 intensive care units was extubation failure, defined as need for reintubation within 48 h following extubation. A multinomial logistic regression model was used to identify risk factors for airway failure and non-airway failure. RESULTS: Between 1 December 2013 and 1 May 2015, 1514 patients undergoing extubation were enrolled. The extubation-failure rate was 10.4% (157/1514), including 70/157 (45%) airway failures, 78/157 (50%) non-airway failures, and 9/157 (5%) mixed airway and non-airway failures. By multivariable analysis, risk factors for extubation failure were either common to airway failure and non-airway failure: intubation for coma (OR 4.979 (2.797 8.864), P < 0.0001 and OR 2.067 (1.217-3.510), P = 0.003, respectively, intubation for acute respiratory failure (OR 3.395 (1.877-6.138), P < 0.0001 and OR 2.067 (1.217-3.510), P = 0.007, respectively, absence of strong cough (OR 1.876 (1.047-3.362), P = 0.03 and OR 3.240 (1.786-5.879), P = 0.0001, respectively, or specific to each specific mechanism: female gender (OR 2.024 (1.187-3.450), P = 0.01), length of ventilation > 8 days (OR 1.956 (1.087-3.518), P = 0.025), copious secretions (OR 4.066 (2.268-7.292), P < 0.0001) were specific to airway failure, whereas non-obese status (OR 2.153 (1.052-4.408), P = 0.036) and sequential organ failure assessment (SOFA) score >= 8 (OR 1.848 (1.100 3.105), P = 0.02) were specific to non-airway failure. Both airway failure and non-airway failure were associated with ICU mortality (20% and 22%, respectively, as compared to 6% in patients with extubation success, P < 0.0001). CONCLUSIONS: Specific risk factors have been identified, allowing us to distinguish between risk of airway failure and non-airway failure. The two conditions will be managed differently, both for prevention and curative strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT 02450669 . Registered on 21 May 2015. PMID- 30243308 TI - A novel role for Tamm-Horsfall protein (uromodulin) in the renal tubule. AB - Tamm-Horsfall protein (THP)/uromodulin, the most abundant urinary protein, is produced in the thick ascending limb of the loop of Henle. Besides immunological functions, it has regulatory impact on ion transport and volume regulation. It had been debated whether the distal convoluted tubule is a source for THP as well. Novel results suggest that in its early portions, THP synthesis affects adaptive plasticity of the epithelium, stabilizes calcium homeostasis, and activates the thiazide-sensitive Na+,Cl--cotransporter. PMID- 30243309 TI - Impact of cellular phosphate handling on vascular calcification. AB - Cardiovascular calcification is still a major burden for patients with chronic kidney disease (CKD). The pathomechanism of vascular calcification is complex, involving numerous processes. In this issue, Yamada et al. describe a protective role of Pit-2 within this context by using PiT-2 heterozygous mice with CKD fed a high-phosphate diet. The mechanisms still need to be elucidated. Pit-2 could become a potential therapeutic target. PMID- 30243310 TI - C1q-binding donor-specific antibody assays help define risk and prognosis in antibody-mediated rejection. AB - Antibody-mediated rejection represents the first cause of graft loss in renal transplant recipients, and it is imperative to identify appropriate tools to enable risk stratification of such patients. Lately, the usefulness of measuring complement-binding anti-human leukocyte antigen (HLA) donor-specific antibodies (DSAs) in renal transplantation has been intensely debated. While the jury is still out, recent data suggest that monitoring complement-binding DSAs may help to recognize high-risk patients and possibly trigger more effective interventions in selected patients. PMID- 30243311 TI - Repeat kidney biopsy for lupus nephritis: an important step forward. AB - There is scant controlled data to guide the use of repeat kidney biopsies to guide therapy in glomerular disease. De Rosa et al. assessed the value of a repeat biopsy during remission in estimating the risk of subsequent relapse of lupus nephritis. They demonstrated the feasibility of a per-protocol repeat biopsy study with prespecified subsequent therapy. Their results will inform the design of future studies of repeat biopsies in lupus nephritis and other kidney diseases. PMID- 30243312 TI - Evocalcet in the management of secondary hyperparathyroidism in dialysis patients. AB - Use of calcimimetics will be influenced not only by assessment of benefits and harms in individual patients but also by cost and by national guidelines. The Japanese Society for Dialysis Therapy has a lower PTH threshold for PTH control than other countries. The current RCT, despite its limitations, provides a rationale for use of evocalcet in the management of secondary hyperPTH. PMID- 30243314 TI - The author replies. PMID- 30243315 TI - Regarding "Lipstick obsession and red urine". PMID- 30243313 TI - Executive summary of the 2018 KDIGO Hepatitis C in CKD Guideline: welcoming advances in evaluation and management. AB - Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy and in those with a kidney transplant. Since the publication of the original Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2008, major advances in HCV management, particularly with the advent of direct-acting antiviral therapies, have now made the cure of HCV possible in CKD patients. In addition, diagnostic techniques have evolved to enable the noninvasive diagnosis of liver fibrosis. Therefore, the Work Group undertook a comprehensive review and update of the KDIGO HCV in CKD Guideline. This Executive Summary highlights key aspects of the guideline recommendations. PMID- 30243316 TI - Are congenital anomalies of the kidney and urinary tract part of the SOX11 syndrome? PMID- 30243317 TI - Regarding "Combination of pediatric and adult formulas yield valid glomerular filtration rate estimates in young adults with a history of pediatric chronic kidney disease". PMID- 30243318 TI - The author replies. PMID- 30243319 TI - The authors reply. PMID- 30243320 TI - Antibodies to M-type phospholipase receptor and immunological remission in treatment-resistant and relapsing membranous nephropathy. PMID- 30243321 TI - The authors reply. PMID- 30243322 TI - Xanthine oxidase inhibitors may prevent or slow chronic kidney disease even in the absence of hyperuricemia. PMID- 30243323 TI - Acute pseudogout after cinacalcet treatment. PMID- 30243324 TI - The authors reply. PMID- 30243325 TI - Suzuki T, Abe T. Crossroads of metabolism and CKD. Kidney Int. 2018;94:242-243. PMID- 30243326 TI - Electron microscopy of urinary sediments in Fabry disease. PMID- 30243327 TI - "Highlighting" an unusual case of discolored peritoneal dialysis effluent. PMID- 30243328 TI - The Case | A 33-year-old woman with gross hematuria. PMID- 30243329 TI - How Does the Standard of Care Evolve? Anti-Vascular Endothelial Growth Factor Agents in Retinopathy of Prematurity Treatment as an Example. PMID- 30243330 TI - Lessons from Recent Phase III Trial Failures: Don't Design Phase III Trials Based on Retrospective Subgroup Analyses from Phase II Trials. PMID- 30243331 TI - Dry Eye Disease: Time to Introduce Ocular Surface Stress Tests? PMID- 30243332 TI - Isolated Conjunctival Lymphangioma. PMID- 30243333 TI - Cutaneous Amyloidosis Presenting as Bilateral Nodular Masses on the Eyelids and Cheeks. PMID- 30243334 TI - Optic Disc Hemorrhage and Glaucomatous Optic Neuropathy After Air Flight in an Eye with Intravitreal Gas. PMID- 30243335 TI - Adrenal Suppression from Topical and Subconjunctival Steroids after Pediatric Cataract Surgery. PMID- 30243336 TI - Central Retinal Vein Occlusion with Chorioretinal Folds Secondary to Active Thyroid Eye Disease. PMID- 30243337 TI - Corrigendum. PMID- 30243338 TI - Corrigendum. PMID- 30243339 TI - Re: Weakley et al.: Myopic shift 5 years after intraocular lens implantation in the infant aphakia treatment study (Ophthalmology. 2017;124:822-827). PMID- 30243340 TI - Reply. PMID- 30243341 TI - Re: Lepore et al.: Follow-up to age 4 years of treatment of type 1 retinopathy of prematurity intravitreal bevacizumab injection versus laser: fluorescein angiographic findings (Ophthalmology. 2018;125:218-226). PMID- 30243342 TI - Reply. PMID- 30243343 TI - Re: Hooshmand et al.: Ultrastructural integrity of human capsulotomies created by a thermal device (Ophthalmology. 2018;125:340-344). PMID- 30243344 TI - Reply. PMID- 30243345 TI - Re: Linden et al.: Normal-tension glaucoma has normal intracranial pressure: a prospective study of intracranial pressure and intraocular pressure in different body positions (Ophthalmology. 2018;125:361-368). PMID- 30243346 TI - Reply. PMID- 30243347 TI - Reply. PMID- 30243348 TI - Re: Lim et al.: XEN implant-related endophthalmitis (Ophthalmology. 2018;125:209). PMID- 30243349 TI - Impact of anti-PEG antibodies on PEGylated nanoparticles fate in vivo. PMID- 30243352 TI - Reply. PMID- 30243353 TI - Opioid Toxicity in Inflammatory Bowel Disease Patients Likely Includes Direct Enterocyte Effects That Exacerbate Disease. PMID- 30243354 TI - That Cursed Dyspepsia. PMID- 30243355 TI - The Association Between Consumption of Sweetened Beverages and the Risk of Inflammatory Bowel Disease. PMID- 30243356 TI - Outcomes of Endoscopic Balloon Dilation vs Surgical Resection for Primary Ileocolic Strictures in Patients With Crohn's Disease. PMID- 30243357 TI - Reply. PMID- 30243358 TI - The Journal Welcomes New Leadership Team. PMID- 30243359 TI - Use of Lean and Related Transformational Performance Improvement Systems in Hospitals in the United States: Results From a National Survey. AB - BACKGROUND: The health care system in the United States is costly with high variance in quality. There is growing interest in transformational performance improvement initiatives, such as the Lean management system, to eliminate waste and inefficiency and improve quality of care for patients. METHODS: A national survey of all 4,500 short-term acute general medical/surgical and pediatric hospitals in the United States was fielded between May and September 2017 by the Survey Data Center of the American Hospital Association. RESULTS: Responses were received from 1,222 hospitals (27.3% response rate). Sixty-nine percent (69.3%) reported use Lean or related Lean plus Six Sigma or Robust Process Improvement approaches. Not-for-profit hospitals, hospitals located in metro/urban areas, those belonging to a system/network, and those with 100-399 beds were most likely to be engaged in these activities and for an average of 5.2 years. However, only 12.6% (n = 102) of hospitals reported being at a mature hospitalwide stage of implementation. The degree of maturity, leadership commitment, daily management system use, and training were each positively associated with reported positive performance outcomes. CONCLUSION: A majority of hospitals have adopted Lean-based transformational performance improvement approaches but with wide variance in the degree of implementation. It takes time for Lean to gain traction. The length of time doing Lean is positively associated with implementation progress and reported positive performance impacts. The extent to which Lean has an organizationwide performance impact awaits further research that links the variables in this study with objective cost and quality measures. PMID- 30243360 TI - Single-stage Bilateral Tibial Tuberosity Advancement With Cranial Fixation in an English Bulldog - A Case Report. AB - This article presents a report of single-stage bilateral tibial tuberosity advancement for the treatment of cranial cruciate ligament rupture in an English bulldog. The reconstruction was performed by a new surgical technique involving tibial tuberosity advancement and fixation with two cranially placed lag screws. The patient was able to ambulate normally at a walk without lameness four days postoperatively. Except for bruising of the surgical site, no complications were observed during a six-month follow-up period. PMID- 30243361 TI - Evaluation, Description of the Technique, and Clinical Outcomes After Tibial Tuberosity Advancement With Cranial Fixation (TTA CF) for Cranial Cruciate Ligament Rupture in 22 Dogs. AB - The objective of this study is to describe a modified surgical technique for tibial tuberosity advancement with cranial fixation (TTA CF) in dogs with cranial cruciate insufficiency and to report long term clinical outcomes and complications. TTA CF was performed with a novel titanium implant. A description of the specific implant with guide, drill and saw guide, instrumentation, and template are provided, along with clinical outcomes, complications, owners' evaluation, and a 1-year postoperation follow-up. Twenty two mixed breed dogs, with a median body weight of 23 kg (range, 11-45 kg) were included. The median age at surgery was 4 years (range, 1-8 years). Clinical bone healing was seen at a mean 10 weeks (range 6-14 weeks). The minor complication rate was 27% (n = 6). No major complication occurred, and no revision surgery was required. Twenty-one (95%) dogs had a good to excellent outcome 1 year after surgery. Currently there is no accepted best treatment of the canine cranial cruciate ligament deficient stifle. Most of TTA techniques are based on fixing the implant from the medial side of tibia. We report a modified TTA technique with cranial fixation of a titanium implant and suggest that the TTA CF surgical technique may be a feasible alternative to existing surgical procedures. PMID- 30243362 TI - Hydroxyurea-induced onychomadesis in a dog with chronic myeloid leukemia: A case report. AB - A 12-year-old Rottweiler dog was presented with a history of prostration, weight loss and hyporexia for six months. Based on complete blood tests (hematological and biochemical analyses), bone marrow examination and imaging analysis, a diagnosis of chronic myeloid leukemia was made. Treatment with hydroxyurea at a dosage of 18 mg/kg twice daily was not effective in controlling the high count of white blood cells. Furthermore, after 35 days of hydroxyurea treatment, the animal developed onycholysis, with sloughing of the claws of the left pelvic and left thoracic limbs and exposure of the distal phalanx. Interruption of the medication was implemented, with clinical healing of the ungual lesions observed three months after initiation of the drug. White blood cells returned to normal after using cyclophosphamide. Currently, the animal is in complete remission, having a disease-free interval of 575 days without chemotherapy. To the authors' knowledge, this is the first report of hydroxyurea-induced onycholysis within a short-term period in a dog diagnosed with chronic myeloid leukemia. PMID- 30243363 TI - Feline Perineal Urethrostomy: A Review of Past and Present Literature. AB - Urethral obstruction is a potentially fatal condition and in cases of recurrent obstruction or an identified cause that is refractory to medical management, a urethrostomy may be performed for definitive treatment. Perineal urethrostomy is the surgical creation of a permanent stoma in the wider pelvic urethra via anastomosis to the perineal skin. Diagnosis of the underlying cause of obstruction, proper perioperative treatment, and an understanding of the anatomy and surgical technique, are imperative to the success of this procedure. This review intends to highlight these aspects, as well as the common complications and expected prognosis to aid decision making in the management of these cases. PMID- 30243364 TI - Photobiomodulation Therapy in Veterinary Medicine: A Review. AB - Laser therapy, or photobiomodulation, has rapidly grown in popularity in human and veterinary medicine. With a number of proposed indications and broad, sometimes anecdotal, use in practice, research interest has expanded aimed at providing scientific support. Recent studies have shown that laser therapy alters the inflammatory and immune response as well as promotes healing for a variety of tissue types. This review will cover the history of the modality, basic principles, proposed mechanisms of action, evidence-based clinical indications, and will guide the practitioner through its application in practice. PMID- 30243365 TI - Postamputation Orthopedic Surgery in Canine Amputees: Owner Satisfaction and Outcome. AB - Surgical management of postamputation orthopedic disease (PAOD) in canine amputees has rarely been documented, and no reports describing outcome of stifle surgery in canine amputees are available. The objective of this multisite retrospective case series was to describe cases and evaluate satisfaction with and outcome of postamputation orthopedic surgery in canine amputees. Data was obtained through medical records and owner survey responses; data included signalment, amputation cause, diagnosis, surgical treatment, timeframes, and outcome assessment. Outcome was categorized as acceptable or unacceptable, and complications were classified as catastrophic, major, or minor. Eleven thoracic limb amputees and 6 pelvic limb amputees with surgically treated PAOD were identified. Surgically treated PAOD was reported at a median of 9.7 months (range 0.5-110 months) after amputation. All 17 amputees were treated for pelvic limb disease, predominantly for cranial cruciate ligament disease that occurred in 11 of 17 dogs. Major complications following orthopedic surgeries performed in 3 thoracic limb amputees consisted of infection (n = 2) and uncontrolled pain (n = 1). No major complications were reported following orthopedic surgeries performed in pelvic limb amputees. Acceptable mid-to-long-term outcome was achieved in 16 of the 17 canine amputees. Surgical treatment of pelvic limb disease did not appear to be associated with a high number of major complications in this case series. These findings suggest that orthopedic surgery, specifically stifle surgery, in canine amputees might be considered a feasible treatment option. Although there are inherent methodological limitations of retrospective studies and owner surveys, our case series provides new information that might help guide surgical treatment decisions in canine amputees suffering from orthopedic disease. Prospective studies using objective outcome measures evaluating surgical management of PAOD are necessary to confirm the provided information. PMID- 30243366 TI - Editorial. PMID- 30243367 TI - Molecular cloning and expression analyses of immunoglobulin tau heavy chain (IgT) in turbot, Scophthalmus maximus. AB - Immunoglobulins (Igs) are humoral mediators playing the prevailing role in the innate and adaptive immunities of jawed vertebrates and provide obligatory duties to protect the organism from a wide variety of pathogens. In the present study, the membrane-bound and secretory immunoglobulin T (mIgT and sIgT) genes of turbot (Scophthalmus maximus) were cloned for the first time with the intention of better understanding the IgT functions. The mIgT cDNA is 2, 049 bp in length including a leader region, a variable region, four constant regions and a transmembrane region (TM), while the 1, 932 bp sIgT cDNA lacks the transmembrane region. In healthy turbot, the total IgT was highly expressed in gill, spleen and liver followed by peripheral blood leucocytes (PBL), skin and hindgut, and then in stomach, head kidney, trunk kidney, midgut and foregut. The expression levels of sIgT in PBL, gill, skin and spleen were much higher than mIgT. Furthermore, the expression profiles of turbot mIgT and sIgT were investigated post vaccination with formalin-inactivated Vibrio anguillarum via intraperitoneal injection and immersion, and the results showed that the expressions of mIgT and sIgT were both significantly induced by two administration routes, whereas intraperitoneal injection mostly induced mIgT expression in systematic organs including head kidney, spleen and trunk kidney, and the immersion vaccination elicited a much stronger response of sIgT in mucosa-associated tissues including gills, liver, hindgut and skin. Taken together, these results demonstrated that mIgT and sIgT were differentially expressed in different tissues and both responded positively to the vaccinations in turbot, and indicated that IgT secreting plasma cells are abundant in mucosa-associated tissues and played important roles in mucosal immunity of turbot. PMID- 30243368 TI - Use of ELISA and Western blot for serological detection of antibodies to E-S antigens of Trichinella spiralis muscle larvae in sera of swine experimentally infected with Trichinella spiralis. AB - The aim of the present study was to evaluate the detection of trichinellosis using ELISA, and to determine the degree of variation of IgG antibodies against excretory-secretory (E-S) antigens of T. spiralis muscle larvae. Ten young Polish Large White native breed pigs were experimentally inoculated with a low dose of 300 invasive Trichinella spiralis (T. spiralis) muscle larvae (ML). Pig sera were collected at 7 and 9 days prior to the experimental infection with T. spiralis and at 9, 14, 20, 23, 25, 27, 30, 33, 37, 41 and 46 days post-infection (d.p.i.). Western blotting was used as a follow-up test to detect anti-T. spiralis IgG and confirm the results provided by ELISA. The molecular weight of the E-S antigenic proteins of T. spiralis muscle larvae reacting with the sera from the infected pigs was determined. Finally, the intensity of T. spiralis infection (lpg) was determined as an average value of 16 muscles taken from each pig. The E-S antigen of T. spiralis muscle larvae in the in-house ELISA and immunoblotting assays did not demonstrate any cross-reaction with non-infected pig sera and sera from pigs naturally infected with Oesophagostomum spp. The ELISA assay did not recognize trichinellosis in pigs until 27 days after the T. spiralis infection. The anti Trichinella IgG antibodies were first detected on day 30 post-infection. The immunoblotting technique confirmed the presence of anti-Trichinella IgG antibodies in all serum samples evaluated as ELISA-positive. The Western blot detected anti-Trichinella IgG antibodies on the same day they were detected for the first time by ELISA in five pigs, whereas the immunoblot assay detected seroconversion 2, 3 or 4 days earlier than ELISA in the remaining three pigs. The swine sera reacted with a broad range of T. spiralis ML E-S antigens with molecular weights ranging from 30 to 88 kDa and the most frequently recognized proteins were 45, 49 and 60 kDa. PMID- 30243369 TI - Resveratrol administration increases phagocytosis, decreases oxidative burst, and promotes pro-inflammatory cytokine production in healthy dogs. AB - Resveratrol is a polyphenol that is safe to administer to dogs and has immunomodulating properties. Canine in vitro work indicated that resveratrol spared polymorphonuclear cell (PMN) phagocytosis but reduced the robustness of PMN oxidative burst and resulted in a pro-inflammatory leukocyte cytokine profile. The objective of this study was to determine the short-term effect of resveratrol on the healthy canine innate immune system in vivo. The hypothesis was that resveratrol would spare phagocytosis, depress the vigor of PMN oxidative burst, and result in a proinflammatory stimulated leukocyte cytokine profile in vivo. In an open-label study, whole blood was collected from 12 healthy, adult client-owned dogs on day 0 and 3. Six dogs received resveratrol, 200 mg kg-1, orally once daily for three days and six dogs served as controls with no supplement administered. Phagocytosis, oxidative burst and pathogen associated molecular pathogen stimulated leukocyte production of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-10 were measured. Results between days 0 and 3 were compared using two way repeated measures analysis of variance and Fisher least significant difference method. A P -value of < 0.05 was considered statistically significant. Resveratrol administration resulted in an increased number of Escherichia coli phagocytized by PMNs and decreased robustness of the oxidative burst reaction. Resveratrol also increased stimulated TNF and IL-6 production with no effect on IL-10. Resveratrol had differential effects on peripheral innate immune system function in dogs. Studies of resveratrol including tissue compartments and the adaptive immune system are indicated to determine if these immunologic effects may be beneficial in disease states. PMID- 30243370 TI - Blood serum acute phase proteins and iron dynamics during acute phase response of Salmonella enterica serotype Dublin experimentally infected buffalo calves. AB - The study aimed to evaluate clinical signs, blood serum acute phase proteins (APP) and iron dynamics during the acute phase response (APR) of Salmonella Dublin experimentally infected Murrah buffalo calves. Six buffalo calves constituted the control group (CNT) and six were orally inoculate with 108 CFU of S. Dublin (INF). Clinical evaluation was performed, rectal swabs to detect S. Dublin strains were collected and venous blood was sampled before and throughout seven days after inoculation. The APP fractions beta-haptoglobin, alpha haptoglobin, ceruloplasmin and transferrin were analyzed by 1-D and 2-D electrophoresis. Proteins were identified using LC/ESI-MS/MS and NCBI database. Plasma fibrinogen, serum iron and serum haptoglobin concentrations were measured. The inoculation of 108 CFU of S. Dublin was effective in inducing clinical signs of Salmonellosis, such as hyperthermia and diarrhea. 1-DE showed that beta and alpha-haptoglobin increased 204% (p = 0.008) and 184% (p = 0.022) 48 h after inoculation (HAI), respectively, with highest concentrations 120 HAI (498% increased, p = 0.012; 431% increased, p = 0.011) and 168 HAI (492% increased, p = 0.019; 523% increased, p = 0.028). 2-DE showed that the expression of two spots, identified as beta-haptoglobin, were increased 693% (p = 0.0006) and 580% (p = 0.0003) 168 HAI, respectively, while one spot, identified as alpha-haptoglobin, increased 714% (p = 0.040). Haptoglobin concentrations increased 1339% (p < 0.0001) 168 HAI. 1-DE showed that ceruloplasmin increased 42% (p = 0.034) 48 HAI, with highest concentration 120 HAI (133% increased, p = 0.022). 2-DE showed that the expression of two spots, identified as ceruloplasmin, were increased 218% (p = 0.0153) and 85% (p = 0.0143) 168 HAI, respectively. Fibrinogen increased 78% (p = 0.012) 96 HAI, with highest concentration 120 HAI (increased 114%, p = 0.002). Iron decreased 33% 24 HAI (p = 0.015) and 37% 72 HAI (p = 0.029), and began to be restored 96 HAI. 1-DE showed that transferrin decreased 23% 120 HAI (p = 0.047), and that values were restored 168 HAI. 2-DE showed that expression patterns of transferrin comparing 0 h and 168 HAI were similar, evidencing that values were restored 168 HAI. In conclusion, the inoculation of 108 CFU was effective in inducing hyperthermia and diahrrea. beta and alpha-haptoglobin, ceruloplasmin and fibrinogen worked as positive APP during the APR to S. Dublin infection and are potential biomarker candidates. Concentrations of iron and transferrin decreased during the infection, highlighting the fact that mechanisms for restricting iron availability are part of the APR triggered against S. Dublin infection in buffalo calves. PMID- 30243372 TI - Detection of anti-neutrophil cytoplasmic antibodies in dogs with immune-mediated inflammatory diseases. AB - Anti-neutrophil cytoplasmic antibody (ANCA) is a type of autoantibody against neutrophil cytoplasm. In veterinary medicine, few studies have reported the detection of ANCA in dogs, and most of these studies were performed in dogs with inflammatory bowel disease (IBD). The aim of this study was to evaluate whether ANCA is detected in dogs with immune-mediated inflammatory diseases (IMIDs) other than IBD. Serum samples were collected before treatment initiation from 40 client owned dogs with various diseases and 22 healthy beagle dogs; the dogs were classified into two groups: IMID group (n = 16) and control group (n = 46). ANCA was detected using the indirect fluorescent antibody test. Of the 16 dogs in the IMID group, 13 (81.3%) tested positive for ANCA. In contrast, of the 46 dogs in the control group, 13 (28.03%) tested positive for ANCA. Moreover, a significant association between ANCA positivity and IMIDs was identified in the IMID group than in the control group (P = 0.0003). In the control group, however, dogs with bacterial infection showed a relatively high rate of ANCA positivity. Therefore, ANCA positivity was observed in dogs with both IMIDs and bacterial infection. This suggested that ANCA positivity is associated with diseases accompanied by neutrophil activation and infiltration. PMID- 30243371 TI - Benzo(a)pyrene suppresses tracheal antimicrobial peptide gene expression in bovine tracheal epithelial cells. AB - Respiratory disease is an important cause of morbidity and mortality in cetaceans, which are also threatened by environmental degradation caused by crude oil spills. Following oil spills, cetaceans at the water surface may inhale droplets of oil containing toxic polycyclic aromatic hydrocarbons (PAHs), which could potentially alter respiratory immunity via activation of the aryl hydrocarbon receptor (AHR) and its subsequent interaction with nuclear factor kappa B (NF-kappaB). beta-defensins are antimicrobial peptides secreted by airway epithelial cells and their expression is known to be dependent on NF-kappaB. We hypothesized that PAHs may suppress the expression of beta-defensins, and thereby contribute to the pathogenesis of pneumonia. This hypothesis was modeled by measuring the in vitro effects of benzo(a)pyrene (BAP), phenanthrene, and naphthalene on tracheal antimicrobial peptide (TAP) gene expression in bovine tracheal epithelial cells. Stimulation with lipopolysaccharide (LPS) induced 20 +/- 17-fold (mean +/- SD) increased TAP gene expression. Exposure of tracheal epithelial cells to 5 MUM BAP for 4 or 8 h, followed by incubation with a combination of LPS and 5 MUM BAP for another 16 h, significantly (P = 0.002) suppressed LPS-induced TAP gene expression by 40.6 +/- 21.8% (mean +/- SD) in tracheal epithelial cells from 9 calves tested. BAP-induced suppression of TAP gene expression coincided with induction of cytochrome P450 1A1 gene expression. In contrast, phenanthrene and naphthalene had no consistent effect, and exposure to PAHs did not significantly affect constitutive TAP gene expression (i.e. without LPS). These findings characterize the suppressive effects of BAP-a toxic pollutant found in crude oil-on this respiratory innate immune response. PMID- 30243373 TI - The expression of Indoleamine 2, 3-dioxygenase (IDO) is reduced in granulomas from BCG vaccinated cattle compared to granulomas from unvaccinated controls after experimental challenge with Mycobacterium bovis. AB - Bovine tuberculosis (bTB), mainly caused by Mycobacterium bovis (M. bovis), is a major economic disease of livestock worldwide. Vaccination is considered as a potentially sustainable adjunct to the current control strategy. Cattle vaccination with the live attenuated M. bovis bacillus Calmette-Guerin (BCG) confers variable protection; the reasons for this variability are not understood. Indoleamine 2, 3-dioxygenase (IDO), through the catalysis of tryptophan, is thought to have an immunoregulatory role in the immune response to Mycobacterium tuberculosis (M. tuberculosis). In this work, we used immunohistochemistry and digital image analysis to evaluate the presence of IDO in granulomas at different stages of development in cattle that had been BCG-vaccinated or not and then challenged with M. bovis. Our results show that the expression of IDO in granulomas from non-vaccinated M. bovis challenged animals is higher than in granulomas from BCG-vaccinated M. bovis challenged animals. Thus, it is possible that vaccination with BCG prevents the induction of what are thought to be host immunosuppressive pathways by M. bovis, which contribute to pathology during the disease. PMID- 30243374 TI - Lack of cross-reactivity of human and porcine reagents to quantify manatee (Trichechus manatus) cytokines. AB - Veterinary medical examinations, including both physical examination and diagnostic tests, are important to monitor the health of both managed-care and wild marine mammals. However, limited species-specific reagents and assays are available that may contribute to a broader medical examination. This project evaluated if commercially available human and porcine antibodies and reagents would cross-react with manatee (Trichechus manatus) cytokines as the first step to validate a new diagnostic tool for manatees. Overall, as a result of limited cross-reactivity, human and porcine commercial reagents did not allow for the quantification of manatee cytokines. At this point, caution must be exercised when using human or porcine immunoassay reagents to quantify manatee cytokines if the reagents have not been fully validated. Future efforts will continue to explore and test the cross-reactivity of reagents to measure manatee cytokines as new species-specific and commercial reagents become available. PMID- 30243376 TI - Comment on "The domestic cat antibody responseto FHV-1 increases with age". PMID- 30243375 TI - Enhancing purification and plasma stability of porcine interferon-alpha/gamma by fusion to elastin-like polypeptide. AB - The clinical use of recombinant interferons (rIFNs) is limited by higher purification cost and quick clearance from circulation. Elastin-like polypeptides (ELPs) are a novel tag for recombinant protein purification and half-life extension. In this study, we evaluated the feasibility of ELP fusion for simple purification and half-life extension of recombinant porcine IFNs (rPoIFNs). After construction of five different fusion expression vectors, we optimized the conditions for soluble protein expression and purification. SDS-PAGE analysis showed that, unlike PoIFNalpha-His and PoIFNgamma-His, PoIFNalpha-ELP, ELP PoIFNalpha and PoIFNalphagamma-ELP were expressed mainly as soluble proteins at 20 C. The optimal conditions for the inverse transition cycling (ITC) of three ELP fusion proteins were 2 M NaCl at 28 C. After two rounds of ITC, the three ELP fusion proteins were purified to more than 90% purities, which were comparable to that of affinity-purified PoIFNalpha-His and PoIFNgamma-His. Cytopathic effect inhibition assay showed that the five rPoIFNs had potent but different antiviral activities against two different viruses on two different cell types. The plasma solubility assay showed that the three ELP-fused rPoIFNs remained as soluble proteins under the physical conditions. The plasma stability of three ELP-fused rPoIFNs was significantly improved in comparison with that of PoIFN-alpha. These data suggest that ELP fusion is a feasible strategy to enhance purification and plasma stability of rPoIFNs. PMID- 30243377 TI - Pharmacokinetics of human recombinant C1-esterase inhibitor and development of anti-drug antibodies in healthy dogs. AB - Complement-mediated intravascular hemolysis occurs in canine immune-mediated hemolytic anemia (IMHA). Complement inhibitors such as recombinant C1 esterase inhibitor (rC1-INH) might prevent this process and alter the disease course. This study aimed to characterize the pharmacokinetics of a single 500 IU IV dose of rC1-INH in 8 healthy beagle dogs, evaluate the dogs for any adverse effects of drug administration, and determine whether rC1-INH administration induces anti drug antibody formation. Serum rC1-INH concentrations were measured using a commercial functional ELISA at baseline and at 10, 20, 40, 60, 80, 100, 120, 240, 360, 480, 600, 720, 960, and 1440 min post drug administration. Complete blood counts were conducted at baseline, 720 and 1440 min. Western blot analysis, using rC1-INH as the target antigen was used to detect anti-drug antibodies in 14-day serum samples. No adverse clinical reactions were noted following rC1-INH administration. Pharmacokinetic modelling suggested that the peak C1-INH concentration achieved is 0.21 IU/mL and that C1-INH concentration is significantly greater than baseline for 100 min following injection. A robust antibody response was detected which suggests that rC1-INH should not be re administered after an initial course. Clinical trials of rC1-INH in dogs with intravascular IMHA are now warranted. PMID- 30243378 TI - Antibody-mediated bacterial killing of Ichthyobacterium seriolicida in Japanese amberjack. AB - Ichthyobacterium seriolicida is the causative agent of bacterial hemolytic jaundice (BHJ) in Japanese amberjack, Seriola quinqueradiata. Fish recovering from BHJ acquire protective immunity against reinfection. In this study, fish were passively immunized to determine whether serum antibody is involved in protection against BHJ. The susceptibility of I. seriolicida to the bactericidal activity of Japanese amberjack serum was also investigated. In passive immunization tests, significantly lower mortality was noted in fish that received convalescent serum. Bacteria were killed when exposed to convalescent serum but not serum from naive fish. Electron microscopic analyses showed that I. seriolicida cells were morphologically altered by reaction with convalescent serum. Naive fish serum became bactericidal upon addition of purified IgM from convalescent serum. Involvement of the classical complement pathway in the bactericidal mechanism was confirmed because bactericidal activity was lost upon heating convalescent serum or chelation treatment using EDTA. Convalescent fish serum thus protects against reinfection by I. seriolicida via humoral immunity mediated by activation of the classical complement pathway. PMID- 30243379 TI - Wind of change in pseudohypoparathyroidism and related disorders: New classification and first international management consensus. PMID- 30243380 TI - Progress in using threonine aldolases for preparative synthesis. AB - Three threonine aldolases (TAs) were cloned and overexpressed in Escherichia coli (Aeromonas jandaeil-allo-threonine aldolase, E. colil-threonine aldolase and Thermotoga maritimal-allo-threonine aldolase). A Design of Experiments strategy was used to identify optimal reaction conditions for each enzyme. These conditions were used to characterize the substrate- and stereoselectivity of each TA toward a panel of aldehyde acceptors. In general, the A. jandaei TA performed best, and six representative conversions were scaled up 10-fold in order to develop downstream steps for product isolation. One key improvement was to treat the crude reaction product with Bacillus subtilis glycine oxidase, which eliminated residual starting material and significantly simplified product isolation. NMR studies were used to identify the major and minor diastereomers from the preparative-scale reactions and the absolute configurations for three representative cases. PMID- 30243381 TI - Improved thermostability and catalytic efficiency of overexpressed catalase from B. pumilus ML 413 (KatX2) by introducing disulfide bond C286-C289. AB - Catalase catalyzes the decomposition of hydrogen peroxide to water and oxygen. The main role of this enzyme is to prevent cell damage caused by reactive oxygen species (ROS). However, endogenous catalase is sensitive to high temperature and possesses limited activity. To satisfy requirements for this critical bottleneck, in this work, we improved the thermo-stability of a heme-catalase (KatX2) from a high oxidative stress resistance Bacillus pumilus ML413 through the construction of a disulfide bond between S286C and D289C. After the site-directed mutagenesis targeting the disulfide bond between S286C and D289C into the wild-type catalase, a potential improvement of thermo-stability half-life at 60 degrees C was increased by 48 min compared to the wild-type half-life. Unexpectedly, a catalytic efficiency of KatX2 S286C/D289C mutant was increased by 40% when compared to the wild-type KatX2. More importantly, this unprecedented highly stable KatX2 recombinant mutant S286C/D289C exhibits higher catalytic efficiency and thermo-stability with no change on the catalase secondary structure. Thus, this rational design based KatX2 could be adopted as a potential biocatalyst in industry. PMID- 30243382 TI - Graphene enhanced transformation of lignin in laccase-ABTS system by accelerating electron transfer. AB - The degradation of lignin has attracted much attention since it represents approximately 30% of all non-fossil carbon sources and constitutes a sustainable bio-resource for fuels and aromatic derivatives. Here we investigated the degradation of lignin by laccase-catalysed reactions using 2,2'-Azino-bis(3 ethybenzothiazoline-6-sulfonic acid) (ABTS) as a mediator coupled with the carbon material graphene. Results indicated that there was a significant, two-fold, increase in the catalytic activity of lignin degradation in laccase-ABTS systems in the presence of graphene. Analysis suggested that the enhancement of lignin degradation could be attributed to graphene acting as an electron transfer conductor, thereby accelerating electron transfer, which facilitated the formation of intermediate oxidation states of ABTS and rendered the reactions between lignin and ABTS intermediates more efficient. This study could promote the development of novel enzymatic lignin degradation systems coupled with the carbon-based material graphene. PMID- 30243383 TI - Kinetic analysis of cellulose synthase of Gluconacetobacter hansenii in whole cells and in purified form. AB - The Gram-negative bacterium, Gluconacetobacter hansenii, has been long studied and is a model for cellulose synthesis. It produces cellulose, using the enzyme AcsA-AcsB, of exceptionally high crystallinity in comparison to the cellulose of higher plants. We determined the rate of cellulose synthesis in whole cells measured as moles of glucose incorporated into cellulose per second per mole of enzyme. This was determined by quantifying the rate of cellulose synthesis (over a short time span, such that the enzyme concentration is not changing due to cell growth) and the amount of enzyme in the whole cell by quantitative western blotting. We found that the whole cell rate of 24 s-1 is much faster than the kcat, measured from steady-state kinetic analysis, of 1.7 s-1. Our whole cell rates are consistent with previous studies using microscopy. We postulate that the rationale for this difference is the presence of an alternative in vivo priming mechanism. This in turn can increase the rate of initiation, which we previously postulated to be the rate-limiting step in catalysis. PMID- 30243384 TI - Cloning and protein expression of the sn-1(3) regioselective lipase from Cordyceps militaris. AB - In this study, the gene of a novel lipase with sn-1(3) regioselectivity (i.e., sn 1 or sn-3 specific) from Cordyceps militaris was successfully expressed by a heterologous expression system. Total RNA was extracted from C. militaris and then single-stranded cDNA was synthesized. The resulting C. militaris lipase (CML) gene was inserted in Escherichia coli expression plasmids [pET-29b(+), pET 26b, and pColdIII] to construct plasmids encoding CML, which were then transformed to E. coli strains BL21 (DE3), C43 (DE), C41 (DE3), and Origami (DE3) for protein expression. Although the recombinant CML expression level was high, it was overproduced in the form of inclusion bodies. Under a specific condition, the soluble form of the recombinant CML was detected using Western blot analysis; however, no enzyme activity was observed. To overcome the lack of post translational modifications in recombinant CML, a baculovirus-insect expression system was introduced for eukaryotic lipase expression. pDualBac was used as the transfer vector, and the CML gene was fused under the control of the polyhedrin promoter. After generating the recombinant baculovirus, the active form of CML was successfully produced and its kinetic parameters were determined. PMID- 30243385 TI - A sensitive and simple method for detecting Cu2+ in plasma using fluorescent Bacillus amyloliquefaciens containing intracellularly biosynthesized CdSe quantum dots. AB - Bacillus amyloliquefaciens containing intracellularly biosynthesized cadmium selenide (CdSe) quantum dots (QDs) was used as a fluorescent bioprobe. Several parameters in the QD biosynthesis process were systematically optimized. The optimized protocol for producing high-quality CdSe QDs in B. amyloliquefaciens features mild synthetic conditions, good reproducibility, short reaction time and high yield. This process shows promise for the mass production of QDs by bacterial matrices. The resultant fluorescent B. amyloliquefaciens containing intracellular CdSe QDs was used as a bioprobe for the simple detection of copper (II) ions in blood plasma. The selective permeability of the bacterial cell membrane along with the protection provided by a protein envelope on the QD surface prevented interference by other components of blood plasma, resulting in the accurate determination of Cu2+. Using the copper addition method, the content of Cu2+ in human blood plasma samples was determined to be 15.6-18.5 MUmol/L, consistent with atomic absorption spectroscopy results. The technique developed here shows potential for the simple determination of Cu2+ in plasma with excellent selectivity and good sensitivity. PMID- 30243386 TI - Production of (Z)-11-(heptanoyloxy)undec-9-enoic acid from ricinoleic acid by utilizing crude glycerol as sole carbon source in engineered Escherichia coli expressing BVMO-ADH-FadL. AB - Production of (Z)-11-(heptanoyloxy)undec-9-enoic acid from recinoleic acid was achieved by whole-cell biotransformation by Escherichia coli, utilizing crude glycerol as the sole carbon source. Whole-cell biotransformation resulted in ~93% conversion of the substrate ricinoleic acid to (Z)-11-(heptanoyloxy)undec-9-enoic acid. We replaced the inducer-dependent promoter system (T7 and Rhm promotors) with a constitutive promoter system. This resulted in successful expression of ADH, FadL, and E6-BVMO, without costly inducer addition. Efficacy evaluation of the whole-cell biotransformation by inducer-free system by five different E. coli strains revealed that the highest product titer was accumulated in E. coli BW25113 strain. The engineered inducer-free system using crude glycerol as the sole carbon source showed competitive performance with induction systems. Optimized conditions resulted in the accumulation of 7.38 +/- 0.42 mM (Z)-11 (heptanoyloxy)undec-9-enoic acid, and when 10 mM substrate was used as feed concentration, the product titer reached 2.35 g/L. The inducer-free construct with constitutive promoter system that this study established, which utilizes the waste by-product crude glycerol, will pave the way for the economic synthesis of many industrially important chemicals, like (Z)-11-(heptanoyloxy)undec-9-enoic acid. PMID- 30243387 TI - Altering the sensitivity of Escherichia coli pyruvate dehydrogenase complex to NADH inhibition by structure-guided design. AB - A sufficient supply of reducing equivalents is essential for obtaining the maximum yield of target products in anaerobic fermentation. The pyruvate dehydrogenase (PDH) complex controls the critical step in pyruvate conversion to acetyl-CoA and NADH. However, in anaerobic Escherichia coli, PDH residing in the dihydrolipoamide dehydrogenase (LPD) component is normally inactive due to inhibition by NADH. In this study, the protein engineering of LPD by structural analysis was explored to eliminate this inhibition. A novel IAA350/351/358VVV triple mutant was successfully verified to be more effective than other LPD mutants reported till date. Notably, PDH activity with the triple mutant at an [NADH]/[NAD+] ratio of 0.15 was still higher than that of the wild-type without NADH addition. The altered enzyme of the PDH complex was also active in the presence of such high NADH levels. This is the first study concerning protein engineering of PDH by structure-guided design. The presence and functional activity of such an NADH-insensitive PDH complex provides a useful metabolic element for fermentation products and has potential for biotechnological application. PMID- 30243388 TI - Polymerization of dopamine catalyzed by laccase: Comparison of enzymatic and conventional methods. AB - Polydopamine (PDA) films are generally produced by spontaneous oxidation of dopamine in basic medium, which is a highly convenient method for surface modification. This method is, however, not suitable for alkaline sensitive materials, which have poor stability in alkali medium and need over-long reaction time. Herein, we compared two dopamine polymerization methods: conventional method (induced by O2 at pH 8.5) and laccase-catalyzed method (at pH 5.5). The comparison showed that the polymerization of dopamine was greatly improved when catalyzed by laccase. The PDA film obtained from laccase-catalyzed method was more uniform and more stable compared with that obtained from the conventional method; the film was able to further react with amine-terminated molecules. As a result of laccase, ether bonds were found between dopamine units of PDA; while such bonds were not observed in film obtained from the conventional method. This work can be a basis for a better understanding of structure and property relationships of PDA coating. PMID- 30243389 TI - Directed evolution of a penicillin V acylase from Bacillus sphaericus to improve its catalytic efficiency for 6-APA production. AB - Penicillin acylase is commonly used to produce the medical intermediates of 6 Aminopenicillanic acid (6-APA) and 7-Aminodesacetoxycephalosporanic acid (7-ADCA) in industrial process. Nowadays, Penicillin G acylase (PGA) has been widely applied for making pharmaceutical intermediates, while penicillin V acylase (PVA) has been less used for that due to its low activity and poor conversion. In this study, a PVA from Bacillus sphaericus (BspPVA) was employed for directed evolution study with hoping to increase its catalytic efficiency. Finally, a triple mutant BspPVA-3 (T63S/N198Y/S110C) was obtained with 12.4-fold specific activity and 11.3-fold catalytic efficiency higher than BspPVA-wt (wild type of BspPVA). Moreover, the conversion yields of 6-APA catalyzed by BspPVA-3 reached 98% with 20% (w/v) penicillin V as substrate, which was significantly higher than that of the BspPVA-wt (85%). Based on the analysis of modeling, the enhancement of specific activity of mutant BspPVA-3 was probably attributed to the changes in the number of hydrogen bonds within the molecules. The triple mutant PVA developed in this study has a potential for large-scale industrial application for 6-APA production. PMID- 30243390 TI - Ocular optical aberrations. PMID- 30243391 TI - Pursuing perfection in intraocular lens calculations: IV. Rethinking astigmatism analysis for intraocular lens-based surgery: Suggested terminology, analysis, and standards for outcome reports. PMID- 30243392 TI - Comparison of effective optical zone after small-incision lenticule extraction and femtosecond laser-assisted laser in situ keratomileusis for myopia. AB - PURPOSE: To compare the effective optical zone (EOZ) after small-incision lenticule extraction (SMILE) and femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK). SETTING: Jinan Mingshui Eye Hospital, Jinan, China. DESIGN: Retrospective case series. METHODS: Myopic patients who had small incision lenticule extraction or FS-LASIK were enrolled in this retrospective study. Effective OZs were measured at 1 week, 1 month, and 3 months postoperatively, using the tangential curvature difference map of the Scheimpflug tomography system. Correlations between the changes in the EOZ and relevant parameters were analyzed 3 months postoperatively. RESULTS: The study comprised 76 patients (76 eyes). The mean EOZs at 1 week, 1 month, and 3 months postoperatively were 5.39 +/- 0.27 mm, 5.33 +/- 0.30 mm, and 5.34 +/- 0.23 mm in the small-incision lenticule extraction group and 5.06 +/- 0.36 mm, 4.98 +/- 0.39 mm, and 5.01 +/- 0.31 mm in the FS-LASIK group, when the programmed OZ was 6.5 mm. The magnitude of decreases in EOZ was significantly smaller in the small incision lenticule extraction group than in the FS-LASIK group at all timepoints after surgery (P < .01). There were significant correlations between changes in EOZ and corneal asphericity (P < .01). Epithelial thickening was positively correlated with EOZ reduction in the small-incision lenticule extraction group (r = 0.479, P < .01); however, no correlation was found between epithelial thickening and EOZ reduction in the FS-LASIK group (r = .324, P > .05). CONCLUSIONS: Both small-incision lenticule extraction and FS-LASIK resulted in EOZ reduction during correction of myopia. However, small-incision lenticule extraction resulted in less reduction than FS-LASIK and was associated with corneal asphericity changes and epithelial thickening. PMID- 30243393 TI - Effect of astigmatism on visual acuity after multifocal versus monofocal intraocular lens implantation. AB - PURPOSE: To determine whether there is a difference in how much residual astigmatism impacts uncorrected distance visual acuity (UDVA) after multifocal versus monofocal intraocular lens (IOL) implantation. SETTING: Database study. DESIGN: Retrospective data review. METHODS: An online toric IOL back-calculator allows users to input preoperative toric planning information and postoperative IOL orientation and refractive results. These data are used to determine the optimal orientation of the IOL to minimize residual refractive astigmatism. Aggregate data were extracted from this calculator to investigate factors associated with UDVA and relative magnitudes of residual astigmatic refractive error up to 2.5 diopters (D) after implantation of toric IOLs. RESULTS: Of 1919 pertinent records (455 multifocal toric IOLs and 1464 monofocal toric IOLs), a statistically significant difference by refractive cylinder category (P < .01) and a statistically significant difference by IOL type (P = .042) were noted. This difference was mostly driven by patients with residual refractive astigmatism of 1.5 D. The mean change in UDVA was 0.16 logarithm of the minimum angle of resolution per 1.0 D of astigmatism. Evaluating a more homogenous dataset with the same monofocal and multifocal IOL design, there was a statistically significant effect of refractive cylinder (P < .01) but no significant effect of IOL type (monofocal or multifocal, P = .45). The differences in UDVA at different refractive cylinder values was not statistically significantly different by orientation of the current astigmatism (P = .28). CONCLUSION: Residual astigmatism after toric IOL implantation impacts visual acuity similarly in patients who had multifocal and monofocal toric IOL implantation. PMID- 30243394 TI - Preoperative biometry data of eyes with unilateral congenital cataract. AB - PURPOSE: To investigate the differences in biometry data of eyes with unilateral congenital cataract and the contralateral normal eyes in pediatric patients. SETTING: Pediatric Ophthalmology Division, Ophthalmology Department, Semmelweis University in Budapest, Hungary. DESIGN: Retrospective case series. METHODS: Data of visually significant unilateral congenital cataract patients who had cataract surgery in the ophthalmology department at Semmelweis University between 2013 and 2016 were collected. At the time of the examinations, the mean age of the patients was 36.4 weeks +/- 25.3 (SD). Central corneal thickness (CCT), corneal refractive power (keratometry [K]), horizontal corneal diameter, and axial length (AL) measurement data were obtained from both eyes of each patient. The measurements were taken under general anesthesia using a handheld kerato refractometer (Retinomax K-plus 3) and an ultrasound instrument (Ocuscan RxP) with contact applanation method and Castroviejo straight-tip calipers at the beginning of the cataract surgery. For statistical evaluation, Originlab 7.0 software was used; paired t tests were performed for the difference analysis between the 2 sides. RESULTS: Forty-two infants (50% girls) were included. In the cases of eyes with unilateral congenital cataract, a greater CCT (P = .01330), higher average K (P = .00243), and smaller corneal diameter (P = .00010) were found, although there was no significant difference in AL when compared with the unaffected contralateral eyes. CONCLUSION: The data showed that biometric characteristics of the eyes with unilateral congenital cataract differ from the opposite normal eye before the cataract surgery. It is essential to use this biometric data in intraocular lens power calculation and to take them into account in long-term care when screening for secondary glaucoma. PMID- 30243396 TI - Progressive astigmatism post-penetrating keratoplasty: October consultation #1. PMID- 30243395 TI - October consultation #2. PMID- 30243397 TI - October consultation #3. PMID- 30243398 TI - October consultation #4. PMID- 30243399 TI - October consultation #5. PMID- 30243401 TI - October consultation #6. PMID- 30243400 TI - Editor's comment. PMID- 30243402 TI - Preoperative spectral-domain optical coherence tomography in cataract surgery. PMID- 30243403 TI - Reply. PMID- 30243405 TI - Femtosecond laser in situ keratomileusis flap creation. PMID- 30243404 TI - Changes in retinal vasculature after phacoemulsification evaluated using optical coherence tomography angiography. PMID- 30243406 TI - Multifocal intraocular lens after hyperopic laser in situ keratomileusis. PMID- 30243407 TI - Reply. PMID- 30243408 TI - Reply. PMID- 30243410 TI - Feasibility, acceptability, and preliminary effects of a brief alcohol intervention for suicidal adolescents in inpatient psychiatric treatment. AB - Alcohol use, both short-term intoxication and longer-term use, is a notable risk factor for suicide. Despite the strong relationship between alcohol use and suicidal thoughts and behaviors, providers typically treat these two problems independently. In particular, acute psychiatric care hospitalizations for adolescents are typically brief, and many only cursorily address alcohol use. Integrating a brief motivational enhancement intervention for alcohol use into an inpatient psychiatric hospitalization treatment protocol has the potential to enhance motivation to stop or reduce drinking if adolescents can more fully understand how it increases risk for suicidal behavior. This study tested the feasibility, acceptability, and preliminary effects of the Alcohol and Suicide Intervention for Suicidal Teens (ASIST), a brief motivational enhancement intervention targeting alcohol use and suicidal thoughts and behaviors for suicidal adolescents receiving inpatient psychiatric treatment. Results from a randomized pilot trial of ASIST (N = 50) revealed that the intervention was both feasible and acceptable, with 92% of those in the ASIST condition reporting that the intervention helped them to understand how their alcohol use is related to their suicidal thoughts and behaviors. Study findings suggest a larger randomized controlled trial may be warranted to test the effectiveness of ASIST with psychiatrically hospitalized adolescents. PMID- 30243409 TI - Understanding barriers to specialty substance abuse treatment among Latinos. AB - BACKGROUND: National studies have documented that Latinos are less likely to use specialty substance abuse treatment (e.g., rehabilitation programs, in/out patient services) than other racial/ethnic groups. Disparities in treatment utilization are particularly pronounced between Latinos and Whites. Few national studies have explicitly examined barriers to treatment by race/ethnicity, and current results are inconclusive. The purpose of this study was to gain a better understanding of barriers to specialty substance abuse treatment among Latinos. METHODS: In 2017-2018, in-depth qualitative interviews were conducted with 54 White, Black, and Latino participants who met eligibility criteria for a recent substance use disorder. Participants were recruited via online ads and screened for eligibility through an online survey. Interview questions were grounded in the Theory of Planned Behavior (TBP): Participants were asked about treatment related barriers in the domains of attitudes, subjective norms, and perceived control. Interviews were transcribed verbatim and coded by two independent coders. Barriers were compared across all interviews and by race/ethnicity. RESULTS: Latinos were significantly more likely to report attitudinal and subjective norm barriers than their White and Black counterparts. Within the attitudes domain, results suggested that Latinos largely avoided specialty treatment due to barriers stemming from cultural factors, perceived treatment efficacy, recovery goals, and perceived treatment need. In the area of subjective norms, stigma and perceived lack of social support from family were more pervasive among Latinos' narratives. Lastly, in terms of perceived control, a minority of Latinos reported logistical barriers to treatment. CONCLUSION: Specialty substance abuse treatment services have been found to be effective regardless of race/ethnicity. Understanding why Latinos use specialty treatment at low rates is key to reducing existing racial/ethnic disparities related to substance abuse. This study identified several malleable barriers that interventions can target to increase Latinos' utilization of treatment. These barriers may also be key to explaining Latino-White disparities in treatment utilization. PMID- 30243412 TI - How patient navigators view the use of financial incentives to influence study involvement, substance use, and HIV treatment. AB - BACKGROUND AND AIMS: While patient navigation has been shown to be an effective approach for linking persons to HIV care, and contingency management is effective at improving substance use-related outcomes, Project HOPE combined these two interventions in a novel way to engage HIV-positive patients with HIV and substance use treatment. The aims of this paper are to examine patient navigator views regarding how contingency management interacted with and affected their navigation process. DESIGN: Semi-structured qualitative interviews. PARTICIPANTS: 22 patient navigators from the original 10 Project HOPE study sites. MEASUREMENTS: Individual, semi-structured interviews lasting approximately 60 min addressed the patient navigator's professional background, descriptions of the participant population, substance use disorder versus HIV treatment entry and engagement issues, and the use of contingency management within the navigation service delivery protocol. FINDINGS: Patient navigators believed that financial incentives helped motivate participant attendance at navigation sessions, particularly early in study involvement, which helped them to establish rapport and develop relationships with participants. Patient navigators often noted that financial incentives positively influenced targeted HIV health-related behaviors, such as attending medical appointments, which provided a rapid pay-off with an escalating sum. Contingency management was more complex when used by the patient navigators for substance use-related behaviors, particularly when incentives revolved around negative urine screening. Patient navigators noted that not all participants responded the same way to the contingency management and that the incentives were particularly helpful when participants were financially strained with limited resources or when internal motivation was lacking. CONCLUSIONS: Overall patient navigators found the inclusion of contingency management to be helpful and affective at influencing participant behaviors, particularly concerning navigation session attendance and HIV healthcare-related participation. However, issues and concerns surrounding the inclusion of contingency management for drug-related behaviors as delivered in Project HOPE were noted. CLINICAL TRIALS REGISTRATION: NCT01612169. PMID- 30243411 TI - Substance use consequences, mental health problems, and readiness to change among Veterans seeking substance use treatment. AB - Individuals seeking substance use treatment who have one or more co-occurring mental health problems tend to have lower treatment engagement, higher rates of attrition, and poorer treatment outcomes. Readiness to change (RTC) is an integral construct in the recovery process, with higher RTC associated with improved treatment outcomes. However, the impact of psychiatric symptoms on RTC is not fully understood, especially among specialty subpopulations, such as military Veterans. Therefore, the aim of the present study was to examine the associations of mental health problems with RTC in a sample of Veterans initiating outpatient substance use treatment. The present sample was comprised of 278 Veterans (12% women, Mage = 48.22, SD = 14.06) who completed self-report intake measures assessing past month substance use frequency, substance-related consequences, symptoms of insomnia, depression, and anxiety, and importance and confidence to change one's substance use. Four separate canonical correlation analyses focusing on RTC alcohol, opioid, cannabis, and nicotine use were conducted. Veterans' inclusion in each analysis was not mutually exclusive. Results indicated that greater depression, anxiety, consequences, and frequency of alcohol use corresponded with greater importance to change alcohol use. Likewise, greater depression, anxiety, and insomnia symptoms along with frequency of use and consequences related to greater importance and confidence to change one's opioid use. In contrast, greater anxiety, depression, insomnia, and frequency of use were associated with less confidence in one's ability to change cannabis use. None of these variables were related to one's RTC nicotine use. Findings highlight the importance of assessing mental health problems at outset of substance use treatment, as they may be an indication of RTC and could be used as a catalyst to advance Veterans forward in the process of behavior change. PMID- 30243413 TI - Access to treatment for alcohol use disorders following Oregon's health care reforms and Medicaid expansion. AB - The study examines impacts of delivery system reforms and Medicaid expansion on treatment for alcohol use disorders within the Oregon Health Plan (Medicaid). Diagnoses, services and pharmacy claims related to alcohol use disorders were extracted from Medicaid encounter data. Logistic regression and interrupted time series analyses assessed the percent with alcohol use disorder entering care and the percent receiving pharmacotherapy before (January 2010-June 2012) and after (January 2013-June 2015) the initiation of Oregon's Coordinated Care Organization (CCO) model (July 2012-December 2012). Analyses also examined changes in access following Medicaid expansion (January 2014). Treatment entry rates increased from 35% in 2010 to 41% in 2015 following the introduction of CCOs and Medicaid expansion. The number of Medicaid enrollees with a diagnosed alcohol use disorder increased about 150% from 10,360 (2013) to 25,454 (2014) following Medicaid expansion. Individuals with an alcohol use disorder who were prescribed a medication to support recovery increased from 2.3% (2010) to 3.8% (2015). In Oregon, Medicaid expansion and health care reforms enhanced access and improved treatment initiation for alcohol use disorders. PMID- 30243414 TI - Peer navigation and take-home naloxone for opioid overdose emergency department patients: Preliminary patient outcomes. PMID- 30243415 TI - Variations in prescription drug monitoring program use by prescriber specialty. AB - BACKGROUND: Although prescription drug monitoring programs (PDMPs) have been widely implemented to potentially reduce abuse of prescription opioids, there is limited data on variations in PDMP use by prescriber specialty. Such knowledge may guide targeted interventions to improve PDMP use. METHODS: Using data from Washington state Medicaid program, we performed a retrospective cohort study of opioid prescribers and their PDMP queries between Nov 1, 2013 and Oct 31, 2014. PDMP registration was mandatory for emergency physicians, but not for other providers. The unit of analysis was the prescriber. The primary outcome was any prescriber queries of the PDMP. We used multivariate regression models to identify variations in PDMP queries by prescriber specialty, as well as to explore explanatory pathways for observed variations. RESULTS: We studied 17,390 providers who prescribed opioids, including 8718 (50%) who were not registered with PDMP, 4767 (27%) who were registered but had no recorded use of the PDMP, and 3905 (23%) PDMP users (queries/user: median 18, IQR 5-64). Compared to general medicine physicians, PDMP use was higher for emergency physicians (OR 1.4, 95%CI: 1.2-1.7), and lower for surgical specialists (OR 0.1, 95%CI: 0.08 0.1), obstetrician-gynecologists (OR 0.2, 95%CI: 0.1-0.2) and dentists (OR 0.4, 95%CI: 0.4-0.5). Higher use by emergency physicians appeared to be mediated by higher registration rates, rather than by provider level predilection to use the PDMP. CONCLUSIONS: A minority of opioid prescribers to Medicaid beneficiaries used the PDMP. We identified variations in PDMP use by prescriber specialty. Interventions to increase PDMP queries should target both PDMP registration and PDMP use after registration, as well as specialties with current low use rates. PMID- 30243416 TI - Factors associated with methadone maintenance therapy discontinuation among people who inject drugs. AB - BACKGROUND: Methadone maintenance therapy (MMT) continues to be a key treatment for opioid use disorder, although premature discontinuation of MMT can increase risk for overdose and other severe harms. We examined sociodemographic characteristics, substance use patterns and social-structural exposures associated with MMT discontinuation among a cohort of people who use drugs (PWUD) in Vancouver, Canada. METHODS: Data were derived from VIDUS and ACCESS, prospective cohorts of PWUD in Vancouver, Canada. The outcome of interest was self-reported discontinuation of MMT within the last six months. Multivariable Generalized Estimating Equations (GEE) were conducted to identify factors independently associated with MMT discontinuation. RESULTS: Between 2005 and 2015, 1301 PWUD who had accessed MMT were recruited, among whom 288 (22.1%) discontinued MMT at least once during the study period. In multivariable GEE analyses, homelessness (Adjusted Odds Ratio [AOR] = 1.46, 95% Confidence Interval [95% CI]: 1.09-1.95), daily heroin injection (AOR = 5.17, 95% CI: 3.82-6.99), daily prescription opioid use (injection or non-injection) (AOR = 2.18, 95% CI: 1.30-3.67), recent incarceration (AOR = 1.46, 95% CI: 1.01-2.12), and not being on any form of income assistance (AOR = 2.14, 95% CI: 1.33-3.46) were each independently positively associated with MMT discontinuation. Participants with more study visits on methadone (>50% vs. <=50% of visits) (AOR = 0.63, 95% CI: 0.47-0.85) and those with higher methadone dose (>100 mg vs. <60 mg per day) (AOR = 0.44, 95% CI: 0.31-0.62) were less likely to discontinue MMT. DISCUSSION AND CONCLUSIONS: Discontinuation of MMT in this urban setting was associated with recent homelessness and incarceration, not accessing social income assistance, as well as daily prescription opioid use and daily heroin injection drug use. These findings underscore a need to reduce potential barriers to MMT retention by providing access to stable housing and preventing treatment interruptions during transitions between community and custodial settings. PMID- 30243417 TI - Quality of life of individuals seeking treatment at specialist non-government alcohol and other drug treatment services: A latent class analysis. AB - Quality of Life (QOL) is increasingly being recognised as an important indicator of recovery from substance use treatment. The current study aimed to determine if there are distinct subclasses of QOL among a broad range of people attending specialist non-government alcohol and other drug treatment services, and how QOL might be associated with substance use, mental health, treatment and demographic characteristics of these individuals. The sample included 9958 individuals attending specialist non-government treatment for alcohol or other substance use in New South Wales, Australia. Cross sectional data on quality of life, drug use, treatment variables, psychological distress and substance dependence severity was collected. Latent class analysis was conducted to identify quality of life classes within the sample. Regression analyses were then performed to identify which individual, treatment and health outcomes were associated with these classes. Three distinct quality of life classes were identified, and termed low (n = 3048), moderate (n = 4211) and high quality of life (n = 2699). Classes differed across individual characteristics, substance use and psychological distress. As hypothesised, greater substance use and higher distress was evident in the lowest quality of life class. Quality of life is an important measure of an individuals' level of functioning during recovery from substance use. The identification of subgroups of individuals with substance use disorders based on their quality of life classes may help guide interventions to improve their overall global functioning and treatment outcomes. PMID- 30243418 TI - Buprenorphine treatment formulations: Preferences among persons in opioid withdrawal management. AB - BACKGROUND: In the current study, we examined factors predicting willingness to receive buprenorphine treatment and preferences for various buprenorphine formulations (oral, injection, implant) among persons in opioid withdrawal management. METHODS: Participants were three hundred thirty-eight persons entering brief inpatient opioid withdrawal management programs at two sites. We used t-tests and Pearson chi2 - tests of independence to compare participants willing and unwilling to be prescribed buprenorphine in the future. Among persons willing to receive buprenorphine, we used multinomial logistic regression to estimate the adjusted effects of potential correlates of type of buprenorphine formulation preferred. RESULTS: Participants averaged 33.9 (+/-9.5) years of age, 70.4% were male, 82.8% were White, and 11.0% were Latino/a. In all, 55.6% of participants had been prescribed buprenorphine in the past, and 54.7% were willing to use prescribed buprenorphine in the future. Those reporting past month illicit buprenorphine use and prior overdose were more willing to use prescribed buprenorphine. Of these (n = 180), most preferred daily buprenorphine formulations (tablet or film) (48.6%) over a weekly or monthly injection (23.1%) or bi-annual implant (28.3%). CONCLUSIONS: Past buprenorphine prescription does not predict future willingness to restart. Among those willing to use buprenorphine, newer formulations of buprenorphine appealed to more than half of the participants. PMID- 30243419 TI - Group therapy for women with substance use disorders: In-session affiliation predicts women's substance use treatment outcomes. AB - In-session affiliation among members is a hypothesized mechanism of action of group therapy for women with substance use disorders (SUDs). We evaluated group affiliation as an independent predictor of SUD treatment outcome in women (n = 100), 18 years or older diagnosed with substance dependence, who were randomized to the single-gender Women's Recovery Group (WRG) or mixed-gender group therapy (Group Drug Counseling; GDC). Affiliative statements made by members in both groups were measured for 39 women in each treatment arm. We studied the relationship between frequency of affiliative statements categorized in quintiles and the trajectory of days of any drug use during 3 months treatment and 6 months post-treatment using a Poisson regression model with estimation via generalized estimating equations. Furthermore, we investigated whether the effect of affiliation on substance use was moderated by group therapy type. The relationship between amount of affiliation and substance use reduction was non linear. At the end of the treatment phase (3 months), women who experienced the highest level of affiliation (>65 affiliative statements on average) were found to reduce substance use by about 1.75 days more (p-value = 0.02) than women who experienced the lowest level of affiliation (<26). The effects of affiliation persisted 6 months post-treatment and were moderated by therapy group, whereby women enrolled in the single-gender WRG appeared to benefit more from affiliation post-treatment. Training therapists to facilitate verbal affiliation may provide added therapeutic benefit to group therapy for women with SUDs. PMID- 30243420 TI - Associations between marijuana use and tobacco cessation outcomes in young adults. AB - Marijuana and tobacco co-use is common among young adults, and findings are mixed regarding the association between marijuana use and smoking cessation outcomes. This study examined the longitudinal relationships between marijuana use and smoking cessation outcomes among young adults (aged 18-25 years; N = 500) enrolled in a 3-month smoking cessation intervention on Facebook. At baseline and 3, 6, and 12 months, participants reported their marijuana use and their smoking behaviors (seven-day point prevalence abstinence from smoking, cigarettes per day, quit attempts) and readiness to quit. Longitudinal analyses controlled for experimental condition and adjusted for baseline stage of change, baseline average cigarettes per day, sex, alcohol use, and age participants began smoking regularly. Use of marijuana by young adult smokers was associated with a lower likelihood of reduced smoking (OR = 0.71, 95% CI [0.51, 0.98], p = .036) and a lower likelihood of abstaining from smoking (OR = 0.56, 95% CI [0.35, 0.90], p = .017) in the past seven days, as assessed over 12 months of follow-up. Use of marijuana was not significantly associated with perceptions of or engagement in the smoking cessation intervention, stage of change for quitting smoking, or tobacco quit attempts (all p's > 0.08). Study findings indicate that while marijuana use is unrelated to motivation to quit tobacco and engage in cessation interventions, marijuana use is associated with less success in reducing and abstaining from tobacco. Additional support and targeted tobacco cessation strategies to address challenges associated with marijuana co-use may be needed. PMID- 30243421 TI - Randomized controlled pilot trial of supportive text messaging for alcohol use disorder patients. AB - AIMS: To evaluate the effectiveness of an addiction-related supportive text messaging mobile intervention to improve treatment outcomes for patients with alcohol use disorder (AUD). METHODS: A single-rater-blinded randomized trial was conducted involving 59 AUD patients who completed a residential addiction treatment program. Patients in the intervention group (n = 29) received supportive text messages for three months following discharge. Patients in the control group (n = 30) received a text message thanking them for participating in the study. The primary outcome of this study was the three months Cumulative Abstinence Duration (CAD); secondary outcomes (units of alcohol per drinking day, numbers of days to first drink) and exploratory outcomes (health utilization) were evaluated. Subgroup analyses were also done. The enrollment rate in the study was 84%, and of those who enrolled, 73% were retained. RESULTS: When primary and secondary outcome measures were examined via effect size analysis, the number of days to first drink was longer in the intervention than control group (large effect size, although not statistically significant). The intervention group's mean first day to drink was over twice the length of the control group (e.g., approximately 60 vs. 26 days, respectively, with a mean difference of 34.97 and 95% CI of -5.87-75.81). Small to moderate effects were found for CAD and units of alcohol per drinking day. Small to negligible effects were found for health utilization. On subgroup analyses, the participants who received text messages, among those who did not attend follow-up outpatient counselling, showed a longer CAD. CONCLUSIONS: The results suggest text messaging is a feasible and effective opportunity for follow-up care in patients discharged from residential AUD treatment. PMID- 30243422 TI - Re-engineering methadone-Cost-effectiveness analysis of a patient-centered approach to methadone treatment. AB - Methadone maintenance treatment has proven effectiveness in the treatment of opioid use disorder, but significant barriers remain to treatment retention. In a randomized clinical trial, 300 newly-admitted methadone patients were randomly assigned to patient-centered methadone (PCM) v. treatment-as-usual (TAU). In PCM, participants were treated under revised program rules which permitted voluntary attendance at counseling and other changes focused on reducing involuntary discharge, and different staff roles which shifted disciplinary responsibility from the participant's counselor to the supervisor. The study found no significant differences in treatment retention, measures of opioid use, or other patient outcomes. This paper employs an activity-based costing approach to estimate the cost and cost-effectiveness of the two study conditions. We found that service use and costs were similar between PCM and TAU. Specifically, the average cost for PCM patients was $2396 compared to $2292 for standard methadone, while the average length of stay was 2 weeks longer for PCM patients. Incremental cost-effectiveness ratios (ICER) for self-reported heroin use, opioid positive urine screens, and meeting DSM-IV criteria for opioid dependence were mixed, with TAU achieving non-significantly better outcomes at lower treatment episode costs (i.e., economically dominating) for opioid positive urine screens. PCM patients reported slightly more days abstinent from heroin and fewer meet the opioid dependence criteria. While these differences are small and not statistically significant, we can still examine the cost-effectiveness implications. For days, abstinent from heroin, the ICER was $242 for one additional day of abstinence, however, there was notable uncertainty around this estimate. For opioid dependence criteria, the ICER was $1160 for a one-percentage point increase in the probability that a participant no longer met criteria for opioid dependence at follow-up. This economic study finds that patient choice concepts can be introduced into methadone treatment without significant impacts on costs or patient outcomes. PMID- 30243424 TI - Tobacco use during a clinical trial of mecamylamine for alcohol dependence: Medication effects on smoking and associations with reductions in drinking. AB - Mecamylamine is a nicotinic acetylcholine receptor (nAChR) antagonist that was recently used in a clinical trial to treat alcohol use disorder (AUD) in both smokers and non-smokers. The current manuscript reports a reanalysis of data from this clinical trial in which we examine changes in smoking that occurred over the course of the trial. We focused on examining the effects of mecamylamine on smoking and the association between reductions in alcohol use and smoking. Participants were the subgroup of smokers who participated in the clinical trial of mecamylamine (10 mg/day) to treat their AUD (n = 76). Smoking was assessed prior to randomization and tracked throughout the course of the 12-week medication treatment phase. Participants were categorized as treatment responders or non-responders based on their changes in drinking over the course of the clinical trial. Participants showed a reduction in smoking over the course of the clinical trial, but there were no significant differences in smoking outcomes between the mecamylamine and placebo groups. Among moderate/high dependence smokers, those who successfully reduced drinking showed a significant reduction in cigarettes smoked per day over the clinical trial. Mecamylamine had no detectable effect on smoking outcomes. Reductions in alcohol use predicted more favorable smoking outcomes among moderate/high tobacco dependence smokers irrespective of medication condition. The reduction in smoking among patients who decreased their alcohol use responders highlights an opportunity for patients being treated for AUD to reduce their smoking. PMID- 30243425 TI - A randomized trial of yoga for stress and substance use among people living with HIV in reentry. AB - BACKGROUND: People in reentry from prison or jail (returning citizens) living with HIV and substance use problems often experience numerous stressors and are at high risk for resumed substance use. Interventions are needed to manage stress as a pathway to reduced substance use. OBJECTIVE: This study explored the effect of a hatha yoga intervention as compared to treatment as usual on stress and substance use among returning citizens living with HIV and substance use problems. METHODS: Participants were randomized to either a 12-session, 90-minute weekly yoga intervention or treatment as usual. All participants were clients of a service provider for returning citizens that offered case management, health care, and educational classes. Outcomes included stress as measured by the Perceived Stress Scale at the completion of the yoga intervention (three-months) and substance use as measured by the Timeline Followback at one-month, two months, and three-months. RESULTS: Seventy-five people were enrolled, two of whom were withdrawn from the study because they did not have HIV. Of the 73 remaining participants, 85% participated in the three-month assessment. At three-months, yoga participants reported less stress than participants in treatment as usual [F (1,59) = 9.24, p < .05]. Yoga participants reported less substance use than participants in treatment as usual at one-month, two-months, and three-months [X2 (1) = 11.13, p < .001]. CONCLUSION: Yoga interventions for returning citizens living with HIV and substance use problems may reduce stress and substance use. This finding is tentative because the control group did not receive an intervention of equal time and intensity. PMID- 30243423 TI - Differences in tobacco use prevalence, behaviors, and cessation services by race/ethnicity: A survey of persons in addiction treatment. AB - BACKGROUND: Disparities in tobacco use prevalence, behaviors, and services have been identified among people of different racial and ethnic groups in the United States general population. Persons in addiction treatment have among the highest smoking prevalence of any population. However, little is known about racial and ethnic disparities in tobacco use prevalence, behaviors, and services among persons in addiction treatment. METHODS: Survey data were used from 1840 clients from 24 addiction treatment programs from the NIDA Clinical Trials Network. Multivariate regression analyses were conducted to assess associations between race/ethnicity (White, African American, Hispanic) and patterns of tobacco and other tobacco product use, as well as quitting behaviors and receipt of tobacco cessation services among current smokers (n = 1425) while in treatment. RESULTS: There was no difference in cigarette smoking prevalence across racial/ethnic groups. In the multivariate models, Hispanics and African Americans, compared to Whites, were less likely to be daily smokers, use smokeless tobacco, or use e cigarettes. African Americans and Hispanics reported more past-year quit attempts and higher use of menthol compared to Whites. Hispanics were more interested in quitting while in treatment than Whites. Contrary to expectations, African Americans reported receiving more tobacco cessation advice and services while in treatment than Whites. CONCLUSIONS: Some findings reflected broader population patterns (e.g., tobacco use behaviors, other tobacco product use), while others did not (e.g., no difference in tobacco use prevalence by race/ethnicity). The reasons for greater receipt of cessation services among African Americans are unclear. Findings indicate the need for continued engagement of African Americans and Hispanics in cessation services while in addiction treatment, and for addressing heavier tobacco use and lack of interest in cessation during treatment among White clients. PMID- 30243426 TI - Access to preventive services after the integration of oral health care into early childhood education and medical care. AB - BACKGROUND: The effect of Early Head Start (EHS) on receipt of preventive oral health services (POHS) from both oral and medical health care providers is not known. METHODS: The authors compared children enrolled in North Carolina EHS programs with similar children enrolled in Medicaid but not EHS on the use of POHS. They analyzed 4 dependent variables (oral assessment by medical health care provider, oral assessment by oral health care provider, fluoride application by medical health care provider, fluoride application by oral health care provider) by using multivariate logistic regression that controlled for covariates. RESULTS: Primary caregivers of children enrolled in EHS (n = 479) and Medicaid (n = 699) were interviewed when children were approximately 10 and 36 months of age. An average of 81% of EHS and non-EHS children received POHS from an oral or medical health care provider at follow-up. EHS children had greater odds of receiving an oral health assessment (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.74 to 3.13) and fluoride (OR, 1.53; 95% CI, 1.16 to 2.03) from an oral health care provider than children not enrolled. EHS children had decreased odds (OR, 0.73; 95% CI, 0.54 to 0.99) of receiving fluoride from a medical health care provider. CONCLUSIONS: Both children enrolled in EHS and community control participants had high rates of POHS, but the source of services differed. EHS children had greater odds of receiving POHS from oral health care providers than non-EHS children. EHS and non-EHS children had equal rates for fluoride overall because of the greater percentage of non-EHS children with medical fluoride visits. PRACTICAL IMPLICATIONS: The integration of POHS in early education and Medicaid medical benefits combined with existing dental resources in the community greatly improves access to POHS. PMID- 30243427 TI - A persistent swelling of the lower lip. PMID- 30243428 TI - Coordinated pediatric reconstruction and rehabilitation of maxillary central giant cell granuloma: A case report. AB - BACKGROUND AND OVERVIEW: A 9-year-old girl underwent comprehensive resection and rehabilitation of a central giant cell granuloma that required phased interprofessional collaborative care to optimize treatment decisions and outcome. CASE DESCRIPTION: The interprofessional treatment team included an oral and maxillofacial surgeon, maxillofacial prosthodontist, dentist, orthodontist, and speech-language pathologist, and treatment spanned 9 years. Treatment included surgical resection of a central giant cell granuloma and obturation with a removable interim prosthesis. After adequate growth and development, the patient then underwent a surgical free-tissue transfer reconstruction by using virtual surgical planning, followed by dental implant placement and a transitional restoration, subsequent orthodontic therapy, and eventual definitive rehabilitation with an implant-retained fixed hybrid prosthesis. CONCLUSIONS AND PRACTICAL IMPLICATIONS: The interprofessional phased and collaborative treatment facilitated an optimal functional and esthetic process in a young patient with transitional and definitive treatments that considered long-term quality-of-life implications. PMID- 30243429 TI - Irritable bowel syndrome: How to improve decision making in clinical practice. AB - Irritable bowel syndrome (IBS) is a highly prevalent functional disorder, characterised by the presence of recurrent abdominal pain associated with changes in bowel habits. Its physiopathology is complex, its clinical manifestations are diverse, and the therapeutic possibilities are multiple and not well known. In clinical practice, the diagnosis of IBS represents an important challenge; this means that in many cases the patients do not receive the proper diagnosis, which implies an absence of a targeted treatment, and therefore bad symptomatic control. In this article, the fundamental questions posed by the doctor when dealing with a patient with symptoms compatible with IBS are presented chronologically. The main objective is to provide clinical and eminently practical information that facilitates the management of patients with IBS, from both diagnostic and therapeutic points of view. PMID- 30243430 TI - Editor's Page. PMID- 30243431 TI - Molecular Identities and ATP Release Activities of Two Types of Volume-Regulatory Anion Channels, VSOR and Maxi-Cl. AB - An elaborate volume regulation system based on interplay of ion channels and transporters was evolved to cope with constant osmotic challenges caused by intensive metabolism, transport and other physiological/pathophysiological events. In animal cells, two types of anion channels are directly activated by cell swelling and involved in the regulatory volume decrease (RVD): volume sensitive outwardly rectifying anion channel (VSOR), also called volume-regulated anion channel (VRAC), and Maxi-Cl which is the most major type of maxi-anion channel (MAC). These two channels have very different biophysical profiles and exhibit opposite dependence on intracellular ATP. After several decades of verifying many false-positive candidates for VSOR and Maxi-Cl, LRRC8 family proteins emerged as major VSOR components, and SLCO2A1 protein as a core of Maxi Cl. Still, neither of these proteins alone can fully reproduce the native channel phenotypes suggesting existence of missing components. Although both VSOR and Maxi-Cl have pores wide enough to accommodate bulky ATP4- and MgATP2- anions, evidence accumulated hitherto, based on pharmacological and gene silencing experiments, suggests that Maxi-Cl, but not VSOR, serves as one of the major pathways for the release of ATP from swollen and ischemic/hypoxic cells. Relations of VSOR and Maxi-Cl with diseases and their selective pharmacology are the topics promoted by recent advance in molecular identification of the two volume-activated, volume-regulatory anion channels. PMID- 30243432 TI - Molecular Biology and Physiology of Volume-Regulated Anion Channel (VRAC). AB - The Volume-Regulated Anion Channel (VRAC) is activated by cell swelling and plays a key role in cell volume regulation. VRAC is ubiquitously expressed in vertebrate cells and also implicated in many other physiological and cellular processes including fluid secretion, glutamate release, membrane potential regulation, cell proliferation, migration, and apoptosis. Although its biophysical properties have been well characterized, the molecular identity of VRAC remained a mystery for almost three decades. The field was transformed by recent discoveries showing that the leucine-rich repeat-containing protein 8A (LRRC8A, also named SWELL1) and its four other homologs form heteromeric VRAC channels. The composition of LRRC8 subunits determines channel properties and substrate selectivity of a large variety of different VRACs. Incorporating purified SWELL1-containing protein complexes into lipid bilayers is sufficient to reconstitute channel activities, a finding that supports the decrease in intracellular ionic strength as the mechanism of VRAC activation during cell swelling. Characterization of Swell1 knockout mice uncovers the important role of VRAC in T cell development, pancreatic beta-cell glucose-stimulated insulin secretion, and adipocyte metabolic function. The ability to permeate organic osmolytes and metabolites is a major feature of VRAC. The list of VRAC substrates is expected to grow, now also including some cancer drugs and antibiotics even under non-cell swelling conditions. Therefore, a critical role of VRAC in drug resistance and cell-cell communication is emerging. This review summarizes the exciting recent progress on the structure-function relationship and physiology of VRAC and discusses key future questions to be solved. PMID- 30243433 TI - Role of WNK Kinases in the Modulation of Cell Volume. AB - Ion Transport across the cell membrane is required to maintain cell volume homeostasis. In response to changes in extracellular osmolarity, most cells activate specific metabolic or membrane-transport pathways to respond to cell swelling or shrinkage and return their volume to its normal resting state. This process involves the rapid adjustment of the activities of channels and transporters that mediate flux of K+, Na+, Cl-, and small organic osmolytes. Cation chloride cotransporters (CCCs) NKCCs and KCCs are a family of membrane proteins modulated by changes in cell volume and/or in the intracellular chloride concentration ([Cl-]i). Cell swelling triggers regulatory volume decrease (RVD), promoting solute and water efflux to restore normal cell volume. Swelling activated KCCs mediate RVD in most cell types. In contrast, cell shrinkage triggers regulatory volume increase (RVI), which involves the activation of the NKCC1 cotransporter of the CCC family. Regulation of the CCCs during RVI and RVD by protein phosphorylation is a well-characterized mechanism, where WNK kinases and their downstream kinase substrates, SPAK and OSR1 constitute the essential phospho-regulators. WNKs-SPAK/OSR1-CCCs complex is required to regulate cell shrinkage-induced RVI or cell swelling-induced RVD via activating or inhibitory phosphorylation of NKCCs or KCCs, respectively. WNK1 and WNK4 kinases have been established as [Cl-]i sensors/regulators, while a role for WNK3 kinase as a cell volume-sensing kinase has emerged and is proposed in this chapter. PMID- 30243434 TI - Intracellular Macromolecules in Cell Volume Control and Methods of Their Quantification. AB - The traditional theories of cell volume regulation focus on monovalent ions and small organic osmolytes. The main subject of this review is macromolecular content of the cell and its role in cell volume. We start by reviewing general information about cellular macromolecules and present some quantitative relationships. Next, we review a wide range of methods for measuring intracellular macromolecular concentration and related parameters; in particular, a large section is devoted to the so-called quantitative phase imaging methods based on transmission light microscopy. In the last part, we discuss three specific biological examples where quantitative analysis of macromolecular concentrations is expected to generate valuable insights into biological processes: the biology of organelles, long-term cell volume maintenance and apoptotic volume decrease. PMID- 30243435 TI - Slippery When Wet: Airway Surface Liquid Homeostasis and Mucus Hydration. AB - The ability to regulate cell volume is crucial for normal physiology; equally the regulation of extracellular fluid homeostasis is of great importance. Alteration of normal extracellular fluid homeostasis contributes to the development of several diseases including cystic fibrosis. With regard to the airway surface liquid (ASL), which lies apically on top of airway epithelia, ion content, pH, mucin and protein abundance must be tightly regulated. Furthermore, airway epithelia must be able to switch from an absorptive to a secretory state as required. A heterogeneous population of airway epithelial cells regulate ASL solute and solvent composition, and directly secrete large mucin molecules, antimicrobials, proteases and soluble mediators into the airway lumen. This review focuses on how epithelial ion transport influences ASL hydration and ASL pH, with a specific focus on the roles of anion and cation channels and exchangers. The role of ions and pH in mucin expansion is also addressed. With regard to fluid volume regulation, we discuss the roles of nucleotides, adenosine and the short palate lung and nasal epithelial clone 1 (SPLUNC1) as soluble ASL mediators. Together, these mechanisms directly influence ciliary beating and in turn mucociliary clearance to maintain sterility and to detoxify the airways. Whilst all of these components are regulated in normal airways, defective ion transport and/or mucin secretion proves detrimental to lung homeostasis as such we address how defective ion and fluid transport, and a loss of homeostatic mechanisms, contributes to the development of pathophysiologies associated with cystic fibrosis. PMID- 30243436 TI - Water Homeostasis and Cell Volume Maintenance and Regulation. AB - From early unicellular organisms that formed in salty water environments to complex organisms that live on land away from water, cells have had to protect a homeostatic internal environment favorable to the biochemical reactions necessary for life. In this chapter, we will outline what steps were necessary to conserve the water within our cells and how mechanisms have evolved to maintain and regulate our cellular and organismal volume. We will first examine whole body water homeostasis and the relationship between kidney function, regulation of blood pressure, and blood filtration in the process of producing urine. We will then discuss how the composition of the lipid-rich bilayer affects its permeability to water and salts, and how the cell uses this differential to drive physiological and biochemical cellular functions. The capacity to maintain cell volume is vital to epithelial transport, neurotransmission, cell cycle, apoptosis, and cell migration. Finally, we will wrap up the chapter by discussing in some detail specific channels, cotransporters, and exchangers that have evolved to facilitate the movement of cations and anions otherwise unable to cross the lipid-rich bilayer and that are involved in maintaining or regulating cell volume. PMID- 30243437 TI - Physiology of the Gut: Experimental Models for Investigating Intestinal Fluid and Electrolyte Transport. AB - Once thought to be exclusively an absorptive tissue, the intestine is now recognized as an important secretory tissue, playing a key role in body ion and fluid homeostasis. Given the intestine's role in fluid homeostasis, it is not surprising that important clinical pathologies arise from imbalances in fluid absorption and secretion. Perhaps the most important examples of this can be seen in enterotoxigenic secretory diarrheas with extreme fluid secretion, and Cystic Fibrosis with little or no fluid secretion. A mechanistic understanding of the cellular pathways regulating ion and fluid transport has been obtained from a variety of approaches and model systems. These have ranged from the intact intestine to a single intestinal epithelial cell type. Although for many years a reductionist approach has held sway for investigating intestinal transport, the growing realization that physiologic processes should really be examined within a physiological context has seen a marked increase in studies using models that are essentially mini-intestines in a dish. The aim of this chapter is to provide a historical context for our understanding of intestinal ion and fluid transport, and to highlight the model systems that have been used to acquire this knowledge. PMID- 30243438 TI - Cell Volume Control in Healthy Brain and Neuropathologies. AB - Regulation of cellular volume is a critical homeostatic process that is intimately linked to ionic and osmotic balance in the brain tissue. Because the brain is encased in the rigid skull and has a very complex cellular architecture, even minute changes in the volume of extracellular and intracellular compartments have a very strong impact on tissue excitability and function. The failure of cell volume control is a major feature of several neuropathologies, such as hyponatremia, stroke, epilepsy, hyperammonemia, and others. There is strong evidence that such dysregulation, especially uncontrolled cell swelling, plays a major role in adverse pathological outcomes. To protect themselves, brain cells utilize a variety of mechanisms to maintain their optimal volume, primarily by releasing or taking in ions and small organic molecules through diverse volume sensitive ion channels and transporters. In principle, the mechanisms of cell volume regulation are not unique to the brain and share many commonalities with other tissues. However, because ions and some organic osmolytes (e.g., major amino acid neurotransmitters) have a strong impact on neuronal excitability, cell volume regulation in the brain is a surprisingly treacherous process, which may cause more harm than good. This topical review covers the established and emerging information in this rapidly developing area of physiology. PMID- 30243439 TI - Cytotoxic Swelling of Sick Excitable Cells - Impaired Ion Homeostasis and Membrane Tension Homeostasis in Muscle and Neuron. AB - When they become simultaneously leaky to both Na+ and Cl-, excitable cells are vulnerable to potentially lethal cytotoxic swelling. Swelling ensues in spite of an isosmotic milieu because the entering ions add osmolytes to the cytoplasm's high concentration of impermeant anionic osmolytes. An influx of osmotically obliged water is unavoidable. A cell that cannot stanch at least one the leaks will succumb to death by Donnan effect. "Sick excitable cells" are those injured through ischemia, trauma, inflammation, hyperactivity, genetically-impaired membrane skeletons and other insults, all of which foster bleb-damage to regions of the plasma membrane. Nav channels resident in damaged membrane exhibit left shifted kinetics; the corresponding Nav window conductance constitutes a Na+ leak. In cortical neurons, sustained depolarization to ~-20mV elicits a sustained lethal gCl. Underlying Vrest in skeletal muscle is a constitutively active gCl; not surprisingly therefore, dystrophic muscle fibers, which are prone to bleb damage and which exhibit Nav-leak and Na+-overload, are prone to cytotoxic swelling. To restore viability in cytotoxically swelling neurons and muscle, the imperative of fully functional ion homeostasis is well-recognized. However, as emphasized here, in a healthy excitable cell, fully functional membrane tension homeostasis is also imperative. ATPase-pumps keep plasma membrane batteries charged, and ATPase-motor proteins maintain membrane tone. In sick excitable cells, neither condition prevails. PMID- 30243440 TI - Search for Upstream Cell Volume Sensors: The Role of Plasma Membrane and Cytoplasmic Hydrogel. AB - The plasma membrane plays a prominent role in the regulation of cell volume by mediating selective transport of extra- and intracellular osmolytes. Recent studies show that upstream sensors of cell volume changes are mainly located within the cytoplasm that displays properties of a hydrogel and not in the plasma membrane. Cell volume changes occurring in anisosmotic medium as well as in isosmotic environment affect properties of cytoplasmic hydrogel that, in turn, trigger rapid regulatory volume increase and decrease (RVI and RVD). The downstream signaling pathways include reorganization of 2D cytoskeleton and altered composition of polyphosphoinositides located on the inner surface of the plasma membrane. In addition to its action on physico-chemical properties of cytoplasmic hydrogel, cell volume changes in anisosmotic conditions affect the ionic strength of the cytoplasm and the [Na+]i/[K+]i ratio. Elevated intracellular ionic strength evoked by long term exposure of cells to hypertonic environment resulted in the activation of TonEBP and augmented expression of genes controlling intracellular organic osmolyte levels. The role of Na+i/K+i sensitive, Ca2+i -mediated and Ca2+i-independent mechanisms of excitation transcription coupling in cell volume-adjustment remains unknown. PMID- 30243441 TI - Cytoskeletal Contribution to Cell Stiffness Due to Osmotic Swelling; Extending the Donnan Equilibrium. AB - Cell volume regulation is commonly analyzed with a model of a closed semipermeable membrane filled with impermeant mobile solutes and the Donnan Equilibrium is used to predict the hydrostatic pressure. This traditional model ignores the fact that most cells are filled with a crosslinked cytoskeleton that is elastic and can be stretched or compressed like a sponge with no obvious need to move mobile solutes. However, calculations show that under osmotic stress, the elastic energy of the cytoskeleton is far greater than the elastic energy of the membrane. Here we expand the traditional Donnan model to include the elasticity of a cytoskeleton with fixed charges and show that cell stiffening happens without a membrane. PMID- 30243442 TI - Membrane Stiffening in Osmotic Swelling: Analysis of Membrane Tension and Elastic Modulus. AB - The effects of osmotic swelling on key cellular biomechanical properties are explored in this chapter. We present the governing equations and theoretical backgrounds of the models employed to estimate cell membrane tension and elastic moduli from experimental methods, and provide a summary of the prevailing experimental approaches used to obtain these biomechanical parameters. A detailed analysis of the current evidence of the effects of osmotic swelling on membrane tension and elastic moduli is provided. Briefly, due to the buffering effect of unfolding membrane reservoirs, mild hypotonic swelling does not change membrane tension or the adhesion of the membrane to the underlying cytoskeleton. Conversely, osmotic swelling causes the cell membrane envelope to stiffen, measured as an increase in the membrane elastic modulus. PMID- 30243443 TI - Preface. PMID- 30243444 TI - Evolution and Current Trends in the Management of Acute Appendicitis. AB - The treatment of appendicitis has evolved since the first appendectomy in the eighteenth century. It seems to have come full circle with nonoperative management in the era before frequent surgical interventions, to open surgical interventions, minimally invasive interventions, and now back to a renewed interest in nonoperative management of acute appendicitis. Scoring systems to help refine the diagnosis of acute appendicitis and advances in medical imaging have also changed the management of this condition. Scientific investigations into the effects the microbiome of the appendix plays in this disease process are also being considered. PMID- 30243445 TI - Emergency Presentations of Diverticulitis. AB - Acute diverticulitis is a common condition that has been increasing in incidence in the United States. It is associated with increasing age, but the pathophysiology of acute diverticulitis is still being elucidated. It is now believed to have a significant contribution from inflammatory processes rather than being a strictly infectious process. There are still many questions to be answered regarding the optimal management of acute diverticulitis because recent studies have challenged traditional practices, such as the routine use of antibiotics, surgical technique, and dietary restrictions for prevention of recurrence. PMID- 30243446 TI - The Acute Upper Gastrointestinal Bleed. AB - Upper gastrointestinal bleeding (UGIB), defined as intraluminal hemorrhage proximal to the ligament of Treitz, can range from mild and asymptomatic to massive life-threatening hemorrhage. For the purposes of this article, the authors define an acute UGIB to be one that results in new acute symptoms and is, therefore, potentially life-threatening. UGIB requires a systematic approach to evaluation and treatment, similar to the management of a trauma patient. Surgeon involvement in UGIBs remains integral despite the rare need for operative management. Endoscopy is the primary tool for diagnosis and treatment. PMID- 30243447 TI - Lower Gastrointestinal Bleeding. AB - Lower gastrointestinal bleeding entails a range of severity and a multitude of options for localization and control of bleeding. With experience in trauma, critical care, endoscopy, and definitive surgical interventions, general surgeons are equipped to manage this condition in various clinical settings. This article examines traditional and emerging options for bleeding localization and control available to general surgeons. PMID- 30243448 TI - Rapid Reversal of Novel Anticoagulant and Antiplatelet Medications in General Surgery Emergencies. AB - The reversal of the new class of nonvitamin K antagonist oral anticoagulants (NOACs) is challenging in the emergent perioperative setting. This summary focuses on the reversal of NOACs, determining the emergent nature (risk analysis), and other considerations in reversal. PMID- 30243449 TI - Acute Limb Ischemia. AB - This article details the classification of limb ischemia, outlines the numerous causes of limb ischemia, highlights the diagnosis with treatment options and describes common postoperative conditions after limb ischemia intervention. The acute limb ischemia causes in the article are divided into sections including the presentation, diagnosis, and therapy for each cause. The broad limb ischemia causes include embolism, thrombosis, venous obstruction, trauma, and upper extremity unique pathologic condition. Postoperative management is extremely important after revascularization of an acutely ischemic extremity. Reperfusion injury, myoglobinuria, and compartment syndrome are summarized in the postoperative section. PMID- 30243450 TI - Aggressive Soft Tissue Infections. AB - Necrotizing soft tissue infections (NSTI) are characterized by rapidly progressive infection that causes tissue necrosis with associated sepsis and multisystem organ failure. A rapid diagnosis is essential to decreasing the morbidity and mortality of NSTIs. There must be a high index of suspicion based on history and physical examination. There are no adjunct laboratory values or imaging that have high sensitivity and specificity in the diagnosis of NSTI. The treatment involves emergent, radical surgical debridement of involved tissues and broad spectrum antibiotics. Follow-up should include close monitoring of the wound and repeat debridements in the operating room. PMID- 30243451 TI - Acute Biliary Disease. AB - Acute biliary disease is a ubiquitous acute surgical complaint. General surgeons managing emergency surgical patients must be knowledgeable and capable of identifying and caring for common presentations. This article discusses the work up, diagnosis, and management of the varying pathologies that make up biliary disease including cholelithiasis, cholecystitis, biliary dyskinesia, choledocholithiasis, cholangitis, gallstone pancreatitis, and gallstone ileus. Also addressed are more challenging and rare presentations including pregnancy and bariatric anatomy. PMID- 30243452 TI - Pancreatitis. AB - Acute pancreatitis is an inflammation of the glandular parenchyma of the retroperitoneal organ that leads to injury with or without subsequent destruction of the pancreatic acini. This inflammatory process can either result in a self limited disease or involve life-threatening multiorgan complications. Chronic pancreatitis consists of endocrine and exocrine gland dysfunction that develops secondary to progressive inflammation and chronic fibrosis of the pancreatic acini with permanent structural damage. Recurrent attacks of acute pancreatitis can result in chronic pancreatitis; acute and chronic pancreatitis are different diseases with separate morphologic patterns. Acute pancreatitis has an increasing incidence but a decreasing mortality. PMID- 30243453 TI - Pneumoperitoneum. AB - Pneumoperitoneum has a wide differential diagnosis and presents with varying degrees of severity; however, not all etiologies require operative intervention. It is imperative that all patients with this diagnosis are evaluated by a surgeon. A thorough history, physical examination, and workup, aimed at localization of the source of pneumoperitoneum will ultimately determine the necessary treatments, including the need for operative intervention. We aim to provide the reader with a working knowledge regarding the evaluation and treatment of patients with pneumoperitoneum. PMID- 30243454 TI - Acid Peptic Disease. AB - The management of peptic ulcer disease has radically changed over the last 40 years from primarily surgical treatment to medical therapy nearly eliminating the need for elective surgery in these patients. Although there has been a decline in patients requiring acute surgical intervention for complications of peptic ulcer disease (perforation, bleeding, and obstruction), these patients still make up a significant proportion of hospital admissions every year. The modern acute care surgeon must have significant knowledge of the multiple treatment modalities used to appropriately care for these patients. PMID- 30243455 TI - Small Bowel Obstruction. AB - Identifying patients with small bowel obstruction who need operative intervention and those who will fail nonoperative management is a challenge. Without indications for urgent intervention, a computed tomography scan with/without intravenous contrast should be obtained to identify location, grade, and etiology of the obstruction. Most small bowel obstructions resolve with nonoperative management. Open and laparoscopic operative management are acceptable approaches. Malnutrition needs to be identified early and managed, especially if the patient is to undergo operative management. Confounding conditions include age greater than 65, post Roux-en-Y gastric bypass, inflammatory bowel disease, malignancy, virgin abdomen, pregnancy, hernia, and early postoperative state. PMID- 30243456 TI - Volvulus. AB - Intestinal volvulus, regardless of location, is a rare disease process, but one that requires high suspicion and timely diagnosis given the increased incidence of intestinal necrosis and potential mortality. Most patients with intestinal volvulus require some form of surgical intervention. However, over the last few decades, the work-up and management of intestinal volvulus has changed given constant advancements in technology and patient care. Most importantly, however, is recognizing the need for emergent versus more elective surgery because this influences the morbidity and mortality for the individual patient. PMID- 30243457 TI - Acute Gut Ischemia. AB - Acute mesenteric ischemia is a surgical emergency commonly caused by embolic or thrombotic occlusion of the superior mesenteric artery. Prompt diagnosis, fluid resuscitation, systemic anticoagulation, and mesenteric revascularization are key tenants to the treatment of this lethal condition. Revascularization can be performed via open thromboembolectomy or surgical bypass, endovascular techniques, or a hybrid approach of the 2. Despite technological advancements, mortalities remain high, and the plan of care and revascularization should be based on the patient's clinical status and available medical center resources. PMID- 30243460 TI - Peripheral brain-derived neurotrophic factor is reduced in stroke survivors with cognitive impairment. AB - Stroke presents a huge burden both globally and locally. Very few studies have evaluated cognitive impairment following stroke in Africa. This study evaluated cognitive impairment in stroke survivors and examined its relationship with peripheral blood levels of brain-derived neurotrophic factor (BDNF). It is hypothesized that serum BDNF levels significantly correlate with cognitive impairment. Cognition was assessed in 47 stroke survivors and 35 normal subjects using the Mini Mental State Examination (MMSE). Serum BDNF concentrations were determined using BDNF ELISA kits. Data were expressed as median (10th-90th percentiles) and analysed using non-parametric tests on SPSS statistics. The stroke survivors and controls were middle aged (in their fifties), with a median stroke duration of 10 months. The MMSE scores were significantly different between the stroke survivors and controls. The difference in serum BDNF values for the stroke survivors and controls was also statistically significant. About three quarters of the stroke survivors had mild or moderate cognitive impairment, which had a moderate positive relationship with serum BDNF levels. Our conclusion is that the very high prevalence of cognitive impairment observed during the period 10 months post stroke was associated, not with any of the socio demographic factors in the subjects studied, but rather with reduced levels of brain-derived neurotrophic factor in the peripheral blood of stroke survivors. PMID- 30243461 TI - [Focal HIFU vs robot-assisted total prostatectomy: Functionnal and oncologic outcomes at one year]. AB - OBJECTIVE: To analyse the functional and oncologic outcomes at one year of focal therapy with HIFU compared with total prostatectomy in patients with localised prostate cancer (PCa). PATIENTS AND METHODS: Retrospective and monocentric study from 2008 to 2014 comparing 2 cohorts of patients with localised PCa (T1/T2 clinical stage, Gleason score<=3+4=7 and PSA<15ng/mL), one treated by focal therapy (HIFU-F group), one by robot-assisted total prostatectomy (RATP group). Primary outcome was a trifecta defined as: absence of urinary incontinence, erectile function with sexual relations without treatment, negative PSA with negative surgical margins (RATP group) or negative biopsy cores (HIFU-F group). RESULTS: The 53 patients included in the "HIFU-F" group and the 66 patients in the "RATP" group were similar in terms of preoperative PSA, D'Amico risk group, erectile function but were different in terms of age, prostatic volume, length of cancer, Gleason score. Complication rate was not different. In multivariate analyse with propensity score, "HIFU-F" group achieved a better trifecta score than "RATP" group (OR=8,3, p=0,005). CONCLUSION: In case of low or intermediate risk localised PCa, "HIFU-F" group had better functional outcomes than initial learning curse "RATP" group, at one year. A long-term evaluation by a common endpoint is necessary to judge the oncological equivalence of both techniques. LEVEL OF EVIDENCE: 3. PMID- 30243462 TI - Electrical Triggers of Adverse Events During the Baseball World Series. PMID- 30243463 TI - Neurofibromatosis type 2: A challenge for the neurosurgical medical community. PMID- 30243464 TI - Biopsying a spinal cord lesion: A diagnostic dilemma. Case report and review of literature. AB - Spinal cord biopsy is a difficult procedure fraught with the risk of false negative results or even misdiagnosis in up to 30% of cases. Differential diagnoses of spinal cord lesions include a wide range of inflammatory, infectious and neoplastic diseases. Given the importance of correctly managing these pathologies, it is crucial to avoid delays in making the correct diagnosis in order to improve the patient's outcome. We present here the case of a 21-year-old male with rapidly progressing sphincter and lower limb motor dysfunctions up to complete paraplegia with evidence of thoracic spinal cord lesion on magnetic resonance imaging. None of the blood and cerebrospinal fluid tests pointed to a diagnosis, while a first spinal cord biopsy revealed an inflammatory necrotic process. After several weeks of empirical treatments and clinical stability, the patient started having focal structural seizures that became generalized with local progression of the lesion and diffuse leptomeningeal spread on magnetic resonance imaging. A second spinal cord biopsy found a grade IV glioblastoma with H3 K27M histone mutation. Unfortunately the patient passed away before any treatment could be initiated. In this report, the authors analyze the difficulty of making the rapid, correct diagnosis of a highly malignant intrinsic spinal cord lesion, discussing also possible strategies to avoid diagnostic delays and to improve the outcome of these difficult patients. PMID- 30243465 TI - Osteocutaneous free transfer of vascularized fibula in cervico-thoracic spinal reconstruction with filling of an esophageal fistula: A case report. AB - The case under review is a 60-year-old patient with a vertebral plasmocytoma treated by cervico-thoracic fusion 2 years previously. He presented a thoracic spinal septic non-union complicated by esophagospinal fistula. We performed vascularized fibula transplant with cutaneous pad to fill the esophageal fistula. Control CT at day 5 confirmed vascular anastomosis permeability and bone transplant position. Osseointegration was achieved at 18 months postoperatively. The patient was alive 3 years after the last procedure (5 years after tumorectomy). A systematic review of the literature on spinal reconstruction by vascularized fibula transplant showed the diversity of surgical techniques available. In view of the multiplicity of possible organ and soft tissue defects involving the spine, reminders are provided of the different approaches and recipient vessels in this type of reconstruction depending on location. PMID- 30243466 TI - Selective history of radioactive iodine in medicine: Inexactitudes no longer. PMID- 30243467 TI - Impact of ABO-incompatibility on hepatocellular carcinoma recurrence after living donor liver transplantation. AB - BACKGROUND: ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) has been reported to have acceptable outcomes in the era of rituximab-based prophylaxis. However, the outcomes of ABO-I LDLT for hepatocellular carcinoma (HCC) remain to be elucidated. This study aimed to clarify the impact of ABO Incompatibility on oncologic outcomes of LDLT for HCC. METHODS: Patients with HCC who underwent ABO-I LDLT were randomly matched by 1:2 ratio to those who underwent ABO-compatible (ABO-C) LDLT according to propensity score. HCC recurrence and patient survival were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Between January 2012 and December 2015, a total of 160 patients underwent LDLT for HCC confirmed by pathology analysis of liver explants. Thirty-nine consecutive patients underwent ABO-I LDLT for HCC, and 78 ABO-C LDLT patients were selected by propensity score matching, which made no significant difference between the two groups in baseline, perioperative, and tumor characteristics. The 1-, 3-, and 5-year recurrence-free survival rates in the ABO-I and ABO-C LDLT groups were 76.9%, 68.5%, 63.6% and 74.4%, 70.5%, 70.5%, respectively (p = 0.77). The site distribution of initial recurrence showed no significant difference between the two groups. The overall survival rates over the same period in the ABO-I and ABO-C LDLT groups were 82.1%, 73.5%, 73.5% and 92.2%, 80.3%, 80.3%, respectively (p = 0.34). CONCLUSIONS: ABO-I LDLT, having no adverse impact on oncological outcomes, can be a feasible transplant option for HCC. PMID- 30243468 TI - Use of hyperthermia versus normothermia during intraperitoneal chemoperfusion with oxaliplatin for colorectal peritoneal carcinomatosis: A propensity score matched analysis. AB - BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (OX) is increasingly used in the treatment of colorectal peritoneal carcinomatosis (PC). However, the additional benefit of hyperthermia remains clinically unproven, while it may aggravate postoperative morbidity. Here, we report the correlation of perfusion temperature with postoperative morbidity during clinical HIPEC with OX. PATIENTS AND METHODS: Patients who underwent hyperthermic (41 degrees C, HT) or normothermic (37 degrees C, NT) chemoperfusion with OX for colorectal PC were identified from a prospectively kept database of HIPEC cases and matched for baseline characteristics using propensity score (PS) analysis. The groups were compared to assess the impact of perfusion temperature on morbidity. Morbidity was graded using the Clavien-Dindo (CD) classification and the Comprehensive Complication Index (CCI). RESULTS: Out of 612 patients, 146 patients met the inclusion criteria and from these patients, 45 HT patients were matched with 45 NT patients. Baseline variables were comparable between the PS matched groups. Overall mortality was 0.7% and major morbidity (CD >= 3) occurred in 35,6% of patients. There were no significant differences between the HT and NT cohorts in mortality, major morbidity (RR 1.33, 95% CI 0.71 to 2.49, p = 0.36), anastomotic leakage (13.8% versus 11.1%, p = 1.0), hemorrhagic complications, or systemic toxicity. A trend of increased wound infections was observed in the hyperthermia group (13.3% versus 4.4%, P = 0.27). CONCLUSIONS: Compared to NT, the use of HT during HIPEC with OX does not aggravate postoperative mortality or morbidity in a high-volume center. PMID- 30243469 TI - First international database of research teams in stability and compatibility of medications: An additional function in the Stabilis(r) database. AB - A new function on the international database Stabilis(r) has been created: a database of research teams involved in stability and compatibility studies of drugs. The first part is descriptive. For each team, the list of publications and of molecules studied can be edited. A search function can extract data by using different criteria like the drug, galenic form, pharmacological class, molecule form (small molecule, monoclonal antibody), country, author and years of publications. The second part of the new function is interactive and allows Stabilis(r) users to suggest stability studies. After examination by collaborators of Stabilis(r), the suggestions are rejected, modified or accepted, published on the website and available for all research teams. The United States of America (USA) was the main country in the 1990s but today, Europe has 67 active teams which publish stability studies and 50 for USA. Europe is now the more active zone in term of number of publications. Antibiotics and cytotoxics are the main pharmacological classes studied. Monoclonal antibodies are studied by few teams due to the complexity of the methodology to study the stability of these drugs. This database can facilitate the communication between research teams and users. PMID- 30243470 TI - [Design and assessment of a outpatient living with PICC-line support program: A pilot study]. AB - The peripheral insertion central catheter (PICC-Line) is indicated for long term intravenous medication administration. Some adverse events (AE) might occur, especially for patients after hospital discharge. Therefore, patient empowerment about the side effects and precaution for use is essential to prevent potential patient harm. A multidisciplinary working group met and designed support program for outpatient living with PICC-line. Pharmacy consultations (PC) were proposed to patient before and after PICC-line insertion. A strip cartoon and card game were created to facilitate patient education. The aim of the study was to assess the comprehension of patient then secondarily to follow up AE awareness. During 10 months, 30 patients of mean age 65.9+/-14 years were included. Thirty-sixPICC Line were installed and followed on 1659days of catheterization. 4, 9 and 13patients received respectively no, at least one and two PCs before discharge from the hospital. Although the differences were not statistically significant, comprehension tends to improve when patients benefit from both PCs especially when it concerns complications. Twenty-fiveambulatory AEs were recorded including 9infections or suspicion of infection, 2 thrombosis and 2 displacements of PICC line. Among the patients who had no PC, four experienced delayed care. In comparison, it occurred in only one patient in the group who received at least one PC after PICC-line insertion. Further studies are warranted to confirm this trend. PMID- 30243471 TI - Validated RP-HPLC method for quantification of felodipine in rabbit plasma: Application in a bioequivalence study. AB - OBJECTIVE: The aim of present study was to develop a simple, rapid, selective, sensitive and robust reverse phase high performance liquid chromatographic method for quantification of felodipine in rabbit plasma at the wavelength of 360nm. METHOD: Protein was precipitated from rabbit plasma sample by addition of acetonitrile as a vehicle. An isocratic elution of samples was performed on capcell pak C8 DD S5 column (4.6mm*250mm particle size 5MUm) column with mobile phase consisting 5mM Phosphate Buffer (pH 4.8 adjusted with dilute ortho phosphoric acid solution): acetonitrile (25:75:v/v) delivered at flow rate 1.0mLmin-1. RESULT: A good linear response was achieved over the range of 0.25 20.00MUgmL-1. LODs and LOQs for felodipine were found to be 0.055 and 0.201MUgmL 1, respectively. The method was quantitatively evaluated in terms of linearity, precision, accuracy (recovery), selectivity robustness and stability study as per standard guidelines. The validated RP-HPLC method was successfully applied for the bioavailability studies of felodipine. The pharmacokinetic parameters were calculated for all the investigated drugs in rabbit after single-dose administrations of pure drug and formulation of felodipine. Finally, the obtained results for the application of the proposed RP-HPLC method proved its efficiency to be applied to the therapeutic drug monitoring (TDM) and bioequivalence (BE) studies. CONCLUSION: Thus, developed method is simple, convenient and suitable for the analysis of felodipine in bulk and pharmaceutical formulations. PMID- 30243472 TI - [Securing the distribution of patient-specific unit dose medication following the installation of a unit dose dispensing system: Cartography of risks a priori within a hospital pharmacy]. AB - INTRODUCTION: With a view to reinforcing the security of the drug distribution process, the hospital pharmacy has decided to automate the patient-specific unit dose distribution system which, up to now was performed manually, through the acquisition of a unit dose dispensing system: the ACCED S 300 (ECODEX(r)). The aim of this work is to realize a cartography of risks, focused on the dispensing stage, prior to the implementation of the automated system. MATERIALS AND METHOD: A multidisciplinary group applied the preliminary risk analysis (PRA) technique. The study was limited to the dispensing stage of unit doses within the hospital pharmacy. RESULTS: This analysis revealed 122 accident scenarii, including 18 with an initial unacceptable criticality (14.8 % of scenarii). In total, 140 risk management actions were proposed. These actions include: acquisition of equipment, communication and training of pharmacy staff, communication with services, human resources management and organization of working hours, writing and updating quality documents, programming the software and interfaces linked with the robot. CONCLUSION: The implementation of risk management actions should reduce the risk and contribute to avoiding the most critical scenarii. This will require the availability of human and financial resources and the implication of management. PMID- 30243473 TI - Bilateral adrenalectomy in Cushing's disease: Altered long-term quality of life compared to other treatment options. AB - OBJECTIVE: Bilateral adrenalectomy (BADX) has become an important treatment of Cushing's disease (CD), especially when other treatment options have failed. The aim of this study was to evaluate the long-term quality of life (QoL) of patients having undergone BADX for CD, in comparison to other therapeutic options. METHODS: Thirty-four patients with CD were identified in two French centers: 17 underwent BADX and the remaining 17 one or more of the following treatments: surgery, medical therapy or radiotherapy. Three questionnaires were filled in by each patient in order to evaluate their QoL: Short Form-36 Health Survey (SF-36), Cushing QoL questionnaire and Beck depression inventory (BDI). RESULTS: The mean age of patients was 49.3+/-15.2 years. Average time lapse between diagnosis and BADX was 6.1 years. Results from each questionnaire adjusted to age showed a lower QoL among patients who underwent BADX. These were significant in most aspects of the SF-36 questionnaire (bodily pain P<0.01, general health P<0.01, vitality P<=0.05, social functioning P<=0.05), as well as in the Cushing QoL questionnaire (P<0.05) and BDI (P<=0.05). Adrenal insufficiency appeared to be the major predictor of poor QoL whatever their initial treatment. CONCLUSIONS: Despite their clinical remission, patients who undergo BADX appear to be at a greater risk of suffering an impaired QoL due to more prolonged period of time with imperfectly controlled hypercortisolism combined with definitive adrenal insufficiency. PMID- 30243474 TI - Leptin regulates neuropeptides associated with food intake and GnRH secretion. AB - The present review focused on the most important effects of leptin on the hypothalamus and on how leptin regulates neuropeptides associated with food intake and GnRH secretion. This review of the literature suggests that a reduction in leptin serum concentrations results from lower body energy reserves or poor energy availability, leading to hypothalamic secretion of neuropeptides such as NPY/AgRP and QRFP to stimulate food intake. Under these negative metabolic conditions, GnRH secretion is reduced, impairing reproductive functions. In contrast, when metabolic status is inversed by an increase in food availability, energy reserves or both, leptin serum concentrations increase to an action threshold reversing the pattern of secretion: i.e., reducing NPY/AgRP and QRFP and increasing POMC and Kisspeptin, and thereby reducing food intake and stimulating GnRH secretion to promote reproductive function. PMID- 30243475 TI - Expression of beta-endorphin in peripheral tissues after systemic administration of lipopolysaccharide as a model of endotoxic shock in mice. AB - BACKGROUND: Endogenous beta-endorphin is delivered exclusively from the pituitary gland in various stressful conditions and plays an essential role in the nervous system. Recently, a few studies demonstrated peripheral endogenous opioid secretion from immune cells at inflammatory sites. Here, we investigated the expression of beta-endorphin, the most powerful endogenous opioid peptide, in peripheral tissues in response to systemic administration of lipopolysaccharide in mice. METHODS: Male C57BL/6N mice received intravenously administered lipopolysaccharide to induce an endotoxic shock-like condition. mRNA for proopiomelanocortin, a precursor of beta-endorphin, was quantified in peripheral blood cells, liver and spleen. beta-endorphin peptide was measured in the liver and spleen. RESULTS: Expression of proopiomelanocortin mRNA was detected in peripheral tissues after systemic administration of lipopolysaccharide. Lipopolysaccharide also induced beta-endorphin expression in the liver and spleen. CONCLUSION: Expression of proopiomelanocortin mRNA and beta-endorphin was detected in peripheral tissues after systemic administration of lipopolysaccharide. These results provide new evidence that peripheral endogenous opioids can be produced not only as a result of local inflammation but also by severe systemic stress such as endotoxic shock. Further study is required to clarify the role of peripheral beta-endorphin during endotoxic shock. PMID- 30243476 TI - [Le Bulletin du Cancer: Developing adults - children partnership]. PMID- 30243477 TI - [Minimal residual disease in chronic lymphocytic leukemia: A still current issue in 2018]. AB - Minimal residual disease (MRD) is widely used in oncohematology. In chronic lymphocytic leukemia (CLL), it can be measured by flow cytometry or polymerase chain reaction and is getting a greater place, owing to the dramatic therapeutic advances in the management this disease. As MRD decrease after chemoimmunotherapy is associated with improved progression free and overall survivals, its measure is now recommended as a surrogate marker for cytotoxic drugs licensures. This association is independent from treatment received and raises a few questions, such as sequential MRD measures to stop treatment in case of an early deep response and on the opposite, treatment continuation until reaching undetectable MRD (with the possible use of maintenance therapy). Furthermore, following MRD after a cytotoxic treatment could lead clinical trials investigators to propose pre-emptive treatments in case of MRD re-growth, to avoid overt relaspe. MRD re growth kinetics and CD4 count after treatment completion can improve MRD-based survival predictions. On the other hand, BCR inhibitors do not lead to undetectable MRD, but their association with chemoimmunotherapy increases the proportion of patients reaching that goal. Moreover, BCL2 inhibitors do lead to deep response including in the relapse/refractory setting, giving to MRD a central place in currently investigated treatments evaluation. PMID- 30243478 TI - Precision medicine and bladder cancer heterogeneity. AB - Bladder cancer is a widespread and highly heterogeneous malignancy. Moreover, bladder cancer recurrence and treatment failure are common, making this disease a challenge for genito-urinary surgeons. Precision medicine represents a new medical concept and model. It is based on personalized medicine, and employs genomics, proteomics, and other omics and cutting-edge medical technologies to classify disease at the molecular level, enabling accurate identification of its cause and therapeutic targets, ultimately offering precise, personalized medicine. The existence of heterogeneity in bladder cancer, resulting in different molecular phenotypes, constitutes a huge challenge for precision medicine. Studying phenotypic differences will be of substantial clinical significance and far-reaching research value with respect to the natural history of tumor development, reduction of drug resistance, the early diagnosis and prognosis of patients with bladder cancer, and the realization of fully developed precision medicine. This paper reviews the possible mechanisms underlying tumor heterogeneity and their impact on precision medicine. The manner in which precision medicine may be performed in the presence of bladder cancer heterogeneity and the prospects of this discipline are also discussed. PMID- 30243479 TI - [How to predict the relapse after surgery or radiofrequency of liver metastases of colorectal cancer? Interest of the serum kinetic variation of a matrix metalloproteinase cluster]. AB - INTRODUCTION: Recurrence after liver surgery or radiofrequency is a clinical and biological challenge because it worsens the colorectal cancer prognosis. To date, no biomarker is yet validated to predict the recurrence in order to intensify adjuvant therapy for patients with higher risk. Matrix metalloproteinases play a major role in the metastasis dissemination and tumoral microenvironment and could be a potential biomarker of interest. METHODS: Forty-four patients with liver metastasis treated by surgery or radiofrequency were enrolled in this study. Serum levels of MMP-1, MMP-2, MMP-7, MMP-9 and TIMP-1 were monitored in Elisa after therapy and correlated to the recurrence from January 2004 to December 2007. After the curative treatment, patients were assessed for the recurence for two years by CT-scan and examination. RESULTS: Post-operative serum level of MMP 9 was significantly higher between J0, J1 and J45 after liver surgery or radiofrequency (***P<=0.001). Level of MMP-2 was significantly increased at M3 and M6 (***P<=0.001) but does not appear to be a risk factor of liver recurrence. The level of TIMP-1 at J0 is a deleterious factor (HR=1.76, P=0.042*). CONCLUSION: This is the first study wich correlates the post-operative level of 4 MMPs and TIMP-1 with the risk of liver recurrence after surgery or radiofrequency. Serum TIMP-1 level at J0 could be helpful to identify patients with higher risk but these results need to be confirmed in a large-scale study. PMID- 30243480 TI - [Metastatic stomach cancer: Clinical trials in Asia and in Occident]. AB - Although cytotoxic chemotherapy is the main therapeutic option to treat gastric cancer in the metastatic setting, molecular targeted agents have recently been introduced in an effort to improve survival outcomes which in average do not exceed 1 year. Trastuzumab and ramucirumab, antibodies directed against HER2 and VEGFR2, respectively, may provide clinical benefit for some patients. Results of clinical studies show that Asian patients have increased survival compared to Caucasian patients. Differences between populations, and in particular the presence of polymorphisms capable of influencing the availability of fluorouracil, have been suggested as possible explanations. Other factors including histology, surgical procedures, administration of neoadjuvant chemotherapy in Western countries and screening programs in Asia have also been suggested. However, none of these elements can fully explain this phenomenon. The aim of this article is to present the main protocols used in clinical practice, the perspectives of metastatic gastric cancer treatment and the particularities observed in Asian and Caucasian patients. PMID- 30243481 TI - Understaging of clinical stage I pancreatic cancer and the impact of multimodality therapy. AB - BACKGROUND: Although current guidelines recommend multimodal therapy for all patients with pancreatic ductal adenocarcinoma, it is unclear the extent to which clinical stage I patients are accurately staged and how this may affect management. METHODS: In this retrospective cohort study of 4,404 patients aged 18 79 years with clinical stage 1 (ie, T1N0 or T2N0) pancreatic ductal adenocarcinoma treated with upfront resection in the National Cancer Database (2004-2014), understaging was ascertained by comparing pretreatment clinical stage with pathologic stage. The association between adjuvant treatment and overall risk of death among true stage I and understaged patients was evaluated using multivariable Cox regression. RESULTS: Upstaging was identified in 72.6% of patients (62.8% T3/4, 53.9% N1) of whom 69.7% received adjuvant therapy compared with 47.0% with true stage I disease. Overall survival at 5 years among those with true stage I disease was significantly higher than those who had been clinically understaged (42.9% vs 16.6%; log-rank, p < 0.001). For true stage I patients, adjuvant therapy was not associated with risk of death (hazard ratio: 1.07, 95% confidence interval: 0.89-1.29). For understaged patients, adjuvant therapy significantly decreased risk of death (hazard ratio: 0.64, 95% confidence interval: 0.55-0.74). CONCLUSION: The majority of clinical stage I pancreatic ductal adenocarcinoma patients actually have higher-stage disease and benefit from multimodal therapy; however, one third of understaged patients do not receive any adjuvant treatment. Clinicians should discuss all potential treatment strategies with patients (in the context of the acknowledged risks and benefits), including the utilization of neoadjuvant approaches in those presenting with potentially resectable disease. PMID- 30243482 TI - Amyloid angiopathy as a cause of "intracranial remote hemorrhage" in a patient treated with fibrinolysis. PMID- 30243483 TI - Perioperative Management for Colorectal Peritoneal Metastases. PMID- 30243485 TI - SCIWORA, an injury to know and diagnose. PMID- 30243484 TI - Short-Course Radiotherapy in Neoadjuvant Treatment for Rectal Cancer: A Systematic Review and Meta-analysis. AB - BACKGROUND: To assess whether preoperative short-course radiotherapy (PSRT) could be the treatment of choice compared to preoperative long-course chemoradiotherapy (PLCRT) METHODS: The PubMed, Embase, and Web of Science Databases were searched to conduct a systematic review and meta-analysis. Perioperative and survival outcomes between PSRT and PLCRT were selected as end points for our meta analysis. In addition, health-related quality-of-life outcomes were also systematically reviewed between PSRT and PLCRT. Finally, we also reviewed evidence of optimized regimens of PSRT (with delayed surgery or adding consolidation chemotherapy). RESULTS: PLCRT showed a better pathologic complete response (pCR) rate (odds ratio = 0.05, 95% confidence interval = 0.02-0.18, P < .01), but this benefit did not translate into a higher sphincter preservation rate (odds ratio = 1.62, 95% confidence interval = 0.72-3.67, P = .25) or other perioperative outcome differences. In terms of survival outcomes, adding either PLCRT or PSRT both showed obvious advantages for local control compared to surgery alone, and PSRT and PLCRT had similar long-term outcomes irrespective of pairwise or network meta-analyses. Moreover, on the basis of health-related quality-of-life scores, PSRT and PLCRT also had no overall differences. Systematic review of current evidence indicates that the insufficiency of PSRT on pCR might be improved by delayed surgery or adding consolidation chemotherapy. CONCLUSIONS: PSRT could be the treatment of choice compared to PLCRT when pCR is not the primary aim. PSRT with delayed surgery or adding consolidation may provide further possibilities for the future evolution of neoadjuvant therapies. PMID- 30243486 TI - Device-based physical activity levels among Finnish adolescents with functional limitations. AB - BACKGROUND: Monitoring physical activity among young adolescents with disabilities is a top academic priority. People with disabilities are a diverse group with various abilities in different human functioning. Therefore, we used a novel approach through functional limitations as a marker for disabilities and examined physical activity levels. OBJECTIVE: To investigate the levels and differences in light (LPA) and moderate-to-vigorous (MVPA) intensity physical activity between young adolescents with and without functional limitations. METHODS: The study included young adolescents (n = 1436) aged 11-15 years olds who attended general schools that were part of the 2016 Finnish School-aged Physical Activity (FSPA) study. PA levels were measured by hip-worn accelerometers during seven consecutive days. The data were disaggregated by the following functions related to; seeing, hearing, speaking, moving, breathing, and remembering or concentrating. Multiple general linear regression models were run to test the differences in amount of time of LPA and MVPA. RESULTS: One in six young adolescents had disabilities. Young adolescents with functional limitations had 7 min.day-1 less LPA (p = 0.021) and 8 min.day-1 less MVPA (p = 0.011) than their peers without functional limitations. After controlling for gender, age, and device wear time, the differences in LPA among young adolescents with and without functional limitations were the same, however MVPA was no longer significantly less. Results varied according to different functional limitations. CONCLUSIONS: There were significant variations in physical activity behaviours by functional limitations and activity intensity. As such, tailored approaches to physical activity promotion may be dependent on understanding functional limitations as an indicator to disabilities. PMID- 30243487 TI - Is there a standard procedure for assessing and providing assistive devices for people with neuro-disabling conditions in United Kingdom? A nation-wide survey. AB - BACKGROUND: Assistive devices are currently provided to people with neuro disabling conditions to promote or maintain independence in activities of daily living. However, it is unclear whether assessment procedures performed by health care professionals to guide the provision of assistive devices are standardized. OBJECTIVE: To explore the assessment and service-delivery processes of assistive devices for people with multiple sclerosis, cerebrovascular disease and Parkinson's disease experiencing physical disability by health care professionals in the United Kingdom. METHODS: A survey was conducted among UK health care professionals working with people with neuro-disabling conditions. Descriptive and content analyses were used to code survey data. RESULTS: In total, 231 health care professionals completed the survey: 93 occupational therapists, 136 physiotherapists and 2 assistant practitioners. Less than half of the respondents (46%) reported use of local, national, or combined guidelines when assessing a service user's suitability or need for assistive devices. When guidelines were used, they were not consistent and not specifically for assistive devices. The respondents stated that when users were allocated small and portable assistive devices, they were supplied within four weeks. This period increased for large equipment, major home adaptions or if external specialist services and/or funding was needed. CONCLUSIONS: Standardized operating procedures for assistive device provision are not being carried out within the UK. Variable access to assistive devices supplied by the state indicates inequity across regions. Future research should explore potential benefits of developing standardized assessment procedures for the provision of assistive devices and devise methods to reduce current variability in service delivery. PMID- 30243488 TI - Outcomes of Percutaneous Antegrade Intraluminal Coronary Intervention of Chronic Total Occlusion With Remote Surgical Backup. AB - Percutaneous coronary intervention (PCI) of chronic total occlusion (CTO) is not favored in facilities without on-site surgical backup. We reviewed outcomes of patients who had CTO intervention with remote surgical backup in our institution. All patients who underwent attempted antegrade intraluminal CTO PCI from January 2013 to July 2017 were analyzed. Twenty cases (18 patients, 58.1 +/- 7.0years, 70% males) were identified. Procedure was successful in 85% (17 of 20). There were 2 nonflow limiting dissections and 1 wire perforation. Two patients had post PCI myocardial infarction. There was no cardiac death, myocardial infarction, target vessel revascularization, or stroke at 30days and at mean follow-up of 19.5 +/- 13.7 months. There were 4 rehospitalizations for angina requiring repeat angiogram in 3 cases: 2 without intervention, and 1 referred for coronary artery bypass grafting. Careful attempt at antegrade intraluminal CTO intervention done at a center with remote surgical backup is feasible in selected patients. PMID- 30243489 TI - Cancer-associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p. AB - BACKGROUND: Cancer-associated fibroblasts (CAFs) play an important role in regulating tumor progression by transferring exosomes to neighboring cells. Our aim was to clarify the role of microRNA encapsulated in the exosomes derived from CAFs in oral squamous cell carcinoma (OSCC). METHODS: We examined the microRNA expression profiles of exosomes derived from CAFs and donor-matched normal fibroblasts (NFs) from patients with OSCC. We used confocal microscopy to examine the transportation of exosomal miR-34a-5p between CAFs and OSCC cells. Next, luciferase reporter and its mutant plasmids were used to confirm direct target gene of miR-34a-5p. Phenotypic assays and in vivo tumor growth experiments were used to investigate the functional significance of exosomal miR-34a-5p. FINDINGS: We found that the expression of miR-34a-5p in CAF-derived exosomes was significantly reduced, and fibroblasts could transfer exosomal miR-34a-5p to OSCC cells. In xenograft experiments, miR-34a-5p overexpression in CAFs could inhibit the tumorigenesis of OSCC cells. We further revealed that miR-34a-5p binds to its direct downstream target AXL to suppress OSCC cell proliferation and metastasis. Stable ectopic expression of AXL in OSCC cells overexpressing miR-34a-5p restored proliferation and motility abolished by the miRNA. The miR-34a-5p/AXL axis promoted OSCC progression via the AKT/GSK-3beta/beta-catenin signaling pathway, which could induce the epithelial-mesenchymal transition (EMT) to promote cancer cells metastasis. The miR-34a-5p/AXL axis enhanced nuclear translocation of beta catenin and then induced transcriptional upregulation of SNAIL, which in turn activated both MMP-2 and MMP-9. INTERPRETATION: The miR-34a-5p/AXL axis confers aggressiveness in oral cancer cells through the AKT/GSK-3beta/beta-catenin/Snail signaling cascade and might represent a therapeutic target for OSCC. FUND: National Natural Science Foundation of China. PMID- 30243490 TI - Spontaneous severe hypercholesterolemia and atherosclerosis lesions in rabbits with deficiency of low-density lipoprotein receptor (LDLR) on exon 7. AB - Rabbits (Oryctolagus cuniculus) have been the very frequently used as animal models in the study of human lipid metabolism and atherosclerosis, because they have similar lipoprotein metabolism to humans. Most of hyperlipidemia and atherosclerosis rabbit models are produced by feeding rabbits a high-cholesterol diet. Gene editing or knockout (KO) offered another means of producing rabbit models for study of the metabolism of lipids and lipoproteins. Even so, apolipoprotein (Apo)E KO rabbits must be fed a high-cholesterol diet to induce hyperlipidemia. In this study, we used the CRISPR/Cas9 system anchored exon 7 of low-density lipoprotein receptor (LDLR) in an attempt to generate KO rabbits. We designed two sgRNA sequences located in E7:g.7055-7074 and E7:g.7102-7124 of rabbit LDLR gene, respectively. Seven LDLR-KO founder rabbits were generated, and all of them contained biallelic modifications. Various mutational LDLR amino acid sequences of the 7 founder rabbits were subjected to tertiary structure modeling with SWISS-MODEL, and results showed that the structure of EGF-A domain of each protein differs from the wild-type. All the founder rabbits spontaneously developed hypercholesterolemia and atherosclerosis on a normal chow (NC) diet. Analysis of their plasma lipids and lipoproteins at the age of 12 weeks revealed that all these KO rabbits exhibited markedly increased levels of plasma TC (the highest of which was 1013.15 mg/dl, 20-fold higher than wild-type rabbits), LDL-C (the highest of which was 730.00 mg/dl, 35-fold higher than wild-type rabbits) and TG accompanied by reduced HDL-C levels. Pathological examinations of a founder rabbit showed prominent aortic atherosclerosis lesions and coronary artery atherosclerosis.In conclusion, we have reported the generation LDLR-KO rabbit model for the study of spontaneous hypercholesterolemia and atherosclerosis on a NC diet. The LDLR-KO rabbits should be a useful rabbit model of human familial hypercholesterolemia (FH) for the simulations of human primary hypercholesterolemia and such models would allow more exact research into cardio cerebrovascular disease. PMID- 30243493 TI - Can we manage without biopsy in membranous nephropathy with positive anti-PLA2R antibodies? PMID- 30243491 TI - Profiles of alternative splicing in colorectal cancer and their clinical significance: A study based on large-scale sequencing data. AB - BACKGROUND: Alternative splicing (AS), as a potent and pervasive mechanism of transcriptional regulatory, expands the genome's coding capacity and involves in the initiation and progression of cancer. Systematic analysis of alternative splicing in colorectal cancer (CRC) is lacking and greatly needed. METHODS: RNA Seq data and corresponding clinical information of CRC cohort were downloaded from the TCGA data portal. Then, a java application, known as SpliceSeq, was used to evaluate the RNA splicing patterns and calculate the Percent Spliced In (PSI) value. Differently expressed AS events (DEAS) were identified based on PSI value between paired CRC and adjacent tissues. DEAS and its splicing networks were further analyzed by bioinformatics methods. Kaplan-Meier, Cox proportional regression and unsupervised clustering analysis were used to evaluate the association between DEAS and patients' clinical features. RESULTS: After strict filtering, a total of 34,334 AS events were identified, among which 421 AS events were found expressed differently. Parent genes of these DEAS play a important role in regulating CRC-related processes such as protein kinase activity (FDR<0.0001), PI3K-Akt signaling pathway (FDR = 0.0024) and p53 signaling pathway (FDR = 0.0143). 37 DEAS events were found to be associated with OS, and 68 DEAS events were found to be associated with DFS. Stratifying patients according to the PSI value of AT in CXCL12 and RI in CSTF3 formed significant Kaplan-Meier curves in both OS and DFS survival analysis. Unsupervised clustering analysis using DEAS revealed four clusters with distinct survival patterns, and associated with consensus molecular subtypes. CONCLUSIONS: Large differences of AS events in CRC appear to exist, and these differences are likely to be important determinants of both prognosis and biological regulation. Our identified CRC related AS events and uncovered splicing networks are valuable in deciphering the underlying mechanisms of AS in CRC, and provide clues of therapeutic targets to further validations. PMID- 30243492 TI - Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational Study. PMID- 30243494 TI - Does the Kidney Donor Profile Index (KDPI) predict graft and patient survival in a Spanish population? AB - BACKGROUND AND OBJECTIVE: The Kidney Donor Profile Index (KDPI), together with other donor and recipient variables, can optimise the organ allocation process. This study aims to check the feasibility of the KDPI for a Spanish population and its predictive ability of graft and patient survival. MATERIALS AND METHODS: Data from 2,734 kidney transplants carried out in Andalusia between January 2006 and December 2015 were studied. Cases were grouped by recipient age, categorised by KDPI quartile and both graft and patient survival were compared among groups. RESULTS: The KDPI accurately discriminated optimal organs from suboptimal or marginal ones. For adult recipients (aged: 18-59years) it presents a hazard ratio of 1.013 (P<.001) for death-censored graft survival and of 1.013 (P=.007) for patient survival. For elderly recipients (aged: 60+years), KDPI presented a hazard ratio of 1.016 (P=.001) for death-censored graft survival and of 1.011 (P=.007) for patient survival. A multivariate analysis identified the KDPI, donor age, donation after circulatory death, recipient age and gender as predictive factors of graft survival. CONCLUSIONS: The results obtained show that the KDPI makes it possible to relate the donor's characteristics with the greater or lesser survival of the graft and the patient in the Spanish population. However, due to certain limitations, a new index for Spain based on Spanish or European data should be created. In this study, some predictive factors of graft survival are identified that may serve as a first step in this path. PMID- 30243496 TI - Using a cost function based on kinematics and electromyographic data to quantify muscle forces. AB - A reliable evaluation of muscle forces in the human body is highly desirable for several applications in both clinical and research contexts. Several models of muscle force distribution based on non-invasive measurements have been proposed since 1836 (Weber and Weber, 1836), amongst which Crowninshield's model (Crowninshield and Brand, 1981), which maximizes a cost-function representing the muscle fiber endurance, is the most popular. It is worth noting that Crowninshield's model is the most widely adopted notwithstanding its major limitations of physiological coherence. Forster et al. (2004) pointed out that "these (conventional) criteria however do not predict co-contraction adequately". Besides, electromyographic (EMG)-driven models have been proposed to assess individual muscle forces, which have not been broadly adopted due to their complexity and the need for a calibration before each test. In this context, a cost function based on kinematic and electromyographic data could provide the advantage of being physiologically more coherent with muscle activations compared to conventional cost-functions based on kinematics solely, and easier to use than the EMG-driven models. The objective of this study is to propose the first cost function based on kinematics and electromyographic data to quantify muscle forces. When applying this new cost-function on a database of upper limb motions data of 17 subjects, healthy or with cerebral palsy, the muscle force prediction of the proposed model was 17.74% more coherent with the EMG pattern than the prediction of Crowninshield's model. And on average, these results were more consistent whether the subjects were healthy or with cerebral palsy. In conclusion, we propose this cost-function for the quantification of muscle forces. PMID- 30243497 TI - Worm-like chain model extensions for highly stretched tropocollagen molecules. AB - Tropocollagen plays a very important role in the load bearing functionality of soft tissues. In the context of multi-scale modeling the response of tropocollagen molecules to stretch should be very carefully predicted in order to describe the mechanical behavior of soft tissues. To this end, the worm-like chain (WLC) model is often applied, although it is restricted to the entropic force regime which is essential at moderate deformations. To describe molecular forces under larger stretches several extensions of the WLC have been proposed for deoxyribonucleic acid (DNA). This contribution aims to investigate the applicability of these models in the context of tropocollagen and discusses the feasibility of their application. Finally, the models are validated in comparison to experimental data available in the literature. PMID- 30243495 TI - Erratum to "Spanish Clinical Guidelines on Vascular Access for Haemodialysis". PMID- 30243498 TI - Errors in power-law estimations of inflow rates for intracranial aneurysm CFD. AB - Patient-specific inflow rates are rarely available for computational fluid dynamics (CFD) studies of intracranial aneurysms. Instead, inflow rates are often estimated from parent artery diameters via power laws, i.e. Q ? Dn, reflecting adaptation of conduit arteries to demanded flow. The present study aimed to validate the accuracy of these power laws. Internal carotid artery (ICA) flow rates were measured from 25 ICA aneurysm patients via 2D phase contrast MRI. ICA diameters, derived from 3D segmentation of rotational angiograms, were used to estimate inflow rates via power laws from the aneurysm CFD literature assuming the same inlet wall shear stress (WSS) (n = 3), velocity (n = 2) or flow rate (n = 0) for all cases. To illustrate the potential impact of errors in flow rate estimates, pulsatile CFD was carried out for four cases having large errors for at least one power law. Flow rates estimated by n = 3 and n = 0 power laws had significant (p < 0.01) mean biases of -22% to +32%, respectively, but with individual errors ranging from -78% to +120%. The n = 2 power law had no significant bias, but had non-negligible individual errors of -58% to +71%. CFD showed similarly large errors for time-averaged sac WSS; however, these were reduced after normalizing by parent artery WSS. High frequency WSS fluctuations, evident in 2/4 aneurysms, were also sensitive to inflow rate errors. Care should therefore be exercised in the interpretation of aneurysm CFD studies that rely on power law estimates of inflow rates, especially if absolute (vs. normalized) WSS, or WSS instabilities, are of interest. PMID- 30243499 TI - Minimum time required for assessing step variability during running at submaximal velocities. AB - This study aimed to determine the minimum time required for assessing spatiotemporal variability during continuous running at different submaximal velocities and, thereby, the number of steps required. Nineteen trained endurance runners performed an incremental running protocol, with a 3-min recording period at 10, 12, 14 and 16 km/h. Spatiotemporal parameters (contact and flight times, step length and step frequency) were measured using the OptoGait system and step variability was considered for each parameter, in terms of within-participants standard deviation (SD) and coefficient of variation (CV%). Step variability was considered over six different durations at every velocity tested: 0-10 s, 0-20 s, 0-30 s, 0-60 s, 0-120 s and 0-180 s. The repeated measures ANOVA revealed no significant differences in the magnitude of the four spatiotemporal parameters between the recording intervals at each running velocity tested (p >= 0.05, ICC > 0.90). The post-hoc analysis confirmed no significant differences in step variability (SD and CV% of each spatiotemporal parameter at any velocity tested) between measurements. The Bland-Altman limits of agreement method showed that longer recording intervals yield smaller systematic bias, random errors, and narrower limits of agreement, regardless of running velocity. The results suggest that the duration of the recording period required to estimate spatiotemporal variability plays an important role in the accuracy of the measurement, regardless of running velocity (10-16 km/h). PMID- 30243500 TI - Gene expression profiling toward the next generation safety control of influenza vaccines and adjuvants in Japan. AB - Influenza becomes epidemic worldwide every year, and many individuals receive vaccination annually. Quality control relating to safety and potency of influenza vaccines is important to maintain public confidence. The safety of influenza vaccines has been assessed by clinical trials, and animal safety tests are performed to monitor the consistent quality between vaccines used for clinical trials and marketing; the biological responses in vaccinated animals are evaluated, including changes in body weight and white blood cell count. Animal safety tests have been contributing to the quality relating to the safety of influenza vaccines for decades, but improvements are needed. Although precise mechanisms involving biological changes in animal safety tests have not been fully elucidated, the application of cDNA microarray technology make it possible to reliably identify genes related to biological responses in vaccinated animals. From analysis of the expression profile of >10,000 genes of lung in animals treated with an inactivated whole virion influenza vaccine, we identified 17 marker genes whose expression patterns correlated well to changes in body weight and leukocyte count in vaccinated animals. In influenza HA vaccine-treated animals exhibiting subtle changes in biological responses, a robust expression pattern of marker genes was found. Furthermore, these marker genes could also be used in the evaluation of adjuvanted influenza vaccines. The expression profile of marker genes is expected to be an alternative indicator for safety control of various influenza vaccines conferring high sensitivity and short turnaround time. Thus, gene expression profiling may be a powerful tool for safety control of vaccines in the future. PMID- 30243501 TI - U.S. clinicians' and pharmacists' reported barriers to implementation of the Standards for Adult Immunization Practice. AB - BACKGROUND: The Standards for Adult Immunization Practice (Standards), revised in 2014, emphasize that adult-care providers assess vaccination status of adult patients at every visit, recommend vaccination, administer needed vaccines or refer to a vaccinating provider, and document vaccinations administered in state/local immunization information systems (IIS). Providers report numerous systems- and provider-level barriers to vaccinating adults, such as billing, payment issues, lower prioritization of vaccines due to competing demands, and lack of information about the use and utility of IIS. Barriers to vaccination result in missed opportunities to vaccinate adults and contribute to low vaccination coverage. Clinicians' (physicians, physician assistants, nurse practitioners) and pharmacists' reported barriers to assessment, recommendation, administration, referral, and documentation, provider vaccination practices, and perceptions regarding their adult patients' attitudes toward vaccines were evaluated. METHODS: Data from non-probability-based Internet panel surveys of U.S. clinicians (n = 1714) and pharmacists (n = 261) conducted in February-March 2017 were analyzed using SUDAAN. Weighted proportion of reported barriers to assessment, recommendation, administration, referral, and documentation in IIS were calculated. RESULTS: High percentages (70.0%-97.4%) of clinicians and pharmacists reported they routinely assessed, recommended, administered, and/or referred adults for vaccination. Among those who administered vaccines, 31.6% clinicians' and 38.4% pharmacists' submitted records to IIS. Reported barriers included: (a) assessment barriers: vaccination of adults is not within their scope of practice, inadequate reimbursement for vaccinations; (b) administration barriers: lack of staff to manage/administer vaccines, absence of necessary vaccine storage and handling equipment and provisions; and (c) documentation barriers: unaware if state/city has IIS that includes adults or not sure how their electronic system would link to IIS. CONCLUSION: Although many clinicians and pharmacists reported implementing most of the individual components of the Standards, with the exception of IIS use, there are discrepancies in providers' reported actual practices and their beliefs/perceptions, and barriers to vaccinating adults remain. PMID- 30243502 TI - Oral administration of coated PEDV-loaded microspheres elicited PEDV-specific immunity in weaned piglets. AB - Porcine epidemic diarrhea virus (PEDV) infects pigs of all ages by invading villous epithelial cells of the small intestine causing severe diarrhea with high mortality rate in suckling piglets. Mucosal immunity is believed to play an important role in PEDV control and mucosal delivery of vaccines induces mucosal immunity more efficiently than parenteral vaccination. In this study, coated PEDV loaded microspheres with the size range of 700-900 MUm in diameter were developed by centrifugal granulation-fluidized bed coating and demonstrated as an effective oral delivery system to protect PEDV antigens against the complex gastrointestinal environment by detecting the live virus particles in microspheres after the simulated gastric fluid treatment and the PEDV RNA in fecal swabs collected from all weaned piglets (100%) orally inoculated with coated PEDV-loaded microspheres. Weaned piglets orally immunized with coated PEDV loaded microspheres developed higher levels of PEDV-specific antibodies (IgG and IgA) in their sera and saliva than those negative control groups (p < 0.001 or p < 0.01). Furthermore, neutralization assays demonstrated that serum antibodies in coated PEDV-loaded microspheres groups could significantly inhibit virus infection in Vero cells, compared to PEDV only group (p < 0.05). Overall, our results indicate that the coated PEDV-loaded microspheres might serve as an effective way to induce PEDV-specific mucosal immunity in pigs against PEDV. PMID- 30243503 TI - Impact of colonic fermentation on sterols after the intake of a plant sterol enriched beverage: A randomized, double-blind crossover trial. AB - BACKGROUND: Cholesterol microbial transformation has been widely studied using in vitro fermentation assays, but less information is available on the biotransformation of plant sterols (PS). The excretion percentage of animal sterols (AS) (67-73%) is considerably greater than that of PS (27-33%) in feces from healthy humans following a Western diet. However, a lower content of AS in feces from subjects following a vegetarian, vegan or low-fat animal diet has been seen when compared to omnivorous subjects. Although only one human study has reported fecal sterol excretion after the consumption of PS-enriched food (8.6 g PS/day), it was found that the target group showed an increase in the excretion of cholesterol and a 57% decrease in its metabolites compared to the control group. OBJECTIVE: Evaluation of the impact of a PS-enriched milk based fruit beverage intake on fecal sterol excretion and the microbial conversion of sterols in postmenopausal women with mild hypercholesterolemia. METHODS: Forty postmenopausal women participated in a randomized, double-blind, crossover study with two beverages, with a PS-enriched (2 g PS/day) or without. The women were divided in two groups: 20 women consumed the PS-enriched beverage and the other 20 women consumed a placebo (without PS) beverage for 6 weeks. After a four-week washout period, the type of beverage was exchanged and consumed for another 6 weeks. Feces were collected at the start (0 and 10 weeks) and end of each intervention period (6 and 16 weeks), and fecal sterols were determined by capillary gas chromatography with mass spectrometry. RESULTS: The intake of the PS-enriched beverage modified the fecal sterol excretion profile. A significant increase mainly in PS and their metabolites versus the placebo intervention period was observed. Although the same effect was not observed in the case of AS, a tendency towards increased cholesterol and decreased coprostanol (the main metabolite of cholesterol) was recorded after PS-enriched beverage intake versus placebo. Furthermore, the PS-enriched beverage also modified the microbial conversion of sterols. In this context, an important decrease in the conversion percentage of cholesterol in 16 women (between 11% and 50%) and of sitosterol in 24 women (between 15% and 61%) was observed. CONCLUSIONS: The results obtained suggest that the microbiota could preferably use PS as a substrate, when present in a greater proportion compared with cholesterol. Besides, a lower sitosterol and cholesterol conversion trend would mean that intake of the PS-enriched beverage could modulate the metabolic activity of the gut microbiota. Therefore, further studies on the impact of PS-enriched foods upon gut microbiota modulation are needed. Clinical Trial Registry Number: NCT 02065024 listed on the NIH website: ClinicalTrials.gov. Clinical Trial Registry Name: Food Matrix and Genetic Variability as Determinants of Bioavailability and Biological Effects of Beta-cryptoxanthin and Phytosterols (foodmagenpol). The full trial protocol is available upon request to the corresponding author. PMID- 30243504 TI - Characterising the nutritional status of children with primary ciliary dyskinesia. AB - INTRODUCTION: Primary ciliary dyskinesia (PCD) is a rare, heterogeneous genetic disorder where impaired mucociliary clearance is caused by dysfunctional motile cilia leading to bronchiectasis. There is limited evidence characterising the nutritional status of children with PCD, although lower body mass index (BMI) z score has been associated with worse lung function (FEV1). METHODS: All children (n = 43) with PCD, aged <16 years, from a single tertiary centre were prospectively enrolled. Information on clinical phenotype and nutritional status including bioelectrical impedance spectroscopy (BIS) phase-angle was collected. RESULTS: There was a weak positive association between height-for-age z-score (HAZ) and FEV1 z-score (n = 28, r = 0.4, p = 0.049). Those with a low fat free mass index (<-2 z scores) had a lower BMI z score (-1.3 +/- 1.2 vs. 0.8 +/- 0.7, p = 0.0002). BIS phase angle identified more patients at nutritional risk than using moderate malnutrition cut-offs of either HAZ or BMI <= -2 z scores alone (21% vs. 4.6% vs. 6.9% respectively). PCD patients had a higher incidence of vitamin D insufficiency (<50 nmoL/L) (54%) and deficiency (<30 nmoL/L) (26%) than healthy children. CONCLUSIONS: We have characterised the nutritional phenotype of a cohort of children with PCD. Monitoring vitamin D levels is important in PCD patients. There is a weak association between lung function and nutritional status, and measures of BIS phase-angle. The use of BIS phase-angle may allow for early identification of at risk children and may therefore be of benefit for nutritional assessments in the clinical setting. These findings will help inform a future nutritional intervention strategy in children with PCD. PMID- 30243505 TI - Impact of type D personality on clinical outcomes in Asian patients with stable coronary artery disease. AB - BACKGROUND: Some personality types are associated with cardiovascular (CV) diseases and may be related to clinical outcomes in coronary artery disease (CAD). This study investigates the association between type D personality and clinical outcomes in stable CAD patients in an Asian cohort. METHODS: Stable CAD patients were enrolled and prospectively followed up for at least 1 year in Taiwan. The inclusion criteria were at least one successful percutaneous coronary intervention (PCI) and stable medical treatment for at least 1 month before enrollment. Vulnerability to psychological distress was measured by the Type D Personality Scale (DS14) after enrollment. The end point was the occurrence of total CV events. Cox regression models of CV events were used to investigate the role of type D personality in clinical outcomes. RESULTS: The study included 777 patients, among which 122 (15.77%) had type D personality. Forty-two CV events were identified: 3 cardiac deaths, 5 nonfatal myocardial infarctions, 1 stroke, 4 congestive heart failures (CHF), 6 peripheral arterial occlusive disorder cases, and 23 readmissions for angina/revascularization treatment. Patients with type D personality had significantly higher incidence of future CV events (9.84% vs. 4.58%, p = 0.018%) and admission for angina/revascularization (5.74% vs. 2.44%, p = 0.049). Patients with subsequent CV events were more likely to have type D personality (28.57% vs. 14.97%, p=0.018). After proportional Cox regression analysis, type D personality remained an independent predictor of future CV events (HR: 3.21, 95% CI: 1.06-9.69). In subgroup analyses, type D personality was especially associated with higher risk of total CV events among females, the elderly, hypertension patients, diabetes patients, and non-smokers. CONCLUSION: Type D personality was an independent predictor of CV outcomes in an Asian cohort of stable CAD patients. This personality type may be identified in risk stratification for secondary prevention after PCI. PMID- 30243506 TI - How Strongly Do Physical Examination Estimates and Ultrasonographic Measurements of Liver Size Correlate? A Prospective Study. AB - BACKGROUND: Liver size assessed by physical examination and ultrasound has long been used to gain useful clinical information. The size measurements obtained by these modalities have been difficult to compare as they are measured in 2 different axes (transaxial vs midclavicular). Our objective was to identify a measurement correlation between ultrasound and physical examination liver size findings. We aimed to develop a correction factor whereby the liver size could be translated between the measured transaxial size obtained by ultrasound and physical examination size when measured in the midclavicular line. METHODS: We conducted a prospective study including 101 adult patients with liver disease undergoing liver biopsy between April 2008 and November 2008 at Penn State Health Milton S Hershey Medical Center. Liver measurements were obtained by physical examination and ultrasound, which were performed by a single hepatologist. RESULTS: The average physical examination size using the midclavicular approach was 8.9 cm +/- 1.13. On ultrasound, the average transaxial measurement was 14.3 cm +/- 1.6. A ratio was made between measurements from the midclavicular line physical examination size and transaxial ultrasound size, and found to have a mean correction factor of 1.6 +/- 0.14. The correction factor was applied to the physical examination-determined liver size and compared with ultrasound findings, with 76% of values (77/101) falling within 10% of the ultrasound-determined liver size. CONCLUSION: This study proves that a strong correlation exists between physical examination estimates of liver size and the measured size on ultrasonography. Multiplying the percussed liver span by a correction factor consistently yields accurate predictions of the transaxial liver span. PMID- 30243507 TI - A Bad Sign: Dermatomyositis with Interstitial Lung Disease. PMID- 30243509 TI - Risk of incident atrial fibrillation after a prior critical illness: A retrospective cohort study. AB - OBJECTIVE: This investigation aimed at assessing the issue of incident atrial fibrillation (AF) associated with acute critical illness. METHODS: The study came from Taiwan and used that nation's Longitudinal Health Insurance Database 2000. Using propensity score matching, multivariable adjustment and competing risk methods, the correlations between the new-onset AF and critical illness (septicemia/septic shock, acute myocardial infarction?AMI?, hemorrhagic stroke and ischemic stroke) were investigated. RESULTS: This study consisted of 46470 patients in the critical illness cohort, 618998 persons in the general population cohort. Additionally, 37,060 critically ill patients were matched with 37060 control patients based on propensity score methods. Compared with general population cohort, patients with septicemia/septic shock were 3.12-fold more likely to develop AF (95% confidence interval ?CI? = 2.88-3.39), followed by patients with ischemic stroke (adjusted hazard ratio?aHR? = 1.96, 95% CI = 1.80 2.14), patients with AMI (aHR = 1.62, 95% CI = 1.32-2.00) and patients with hemorrhagic stroke (aHR = 1.46, 95% CI = 1.13-1.88). In addition, after controlling for the confounding factors and the competing risk of death, the critical illness cohort still exhibited a significantly higher risk of AF than the general population cohort (adjusted subhazard ratio [aSHR] = 2.66, 95% CI = 2.49-2.84). CONCLUSIONS: Our study explored incident AF among patients with critical illness in their medical history. Patients with septicemia/septic shock were at the highest risk of developing new-onset AF among these critically ill patients. PMID- 30243508 TI - Tumor-infiltrating T cells in epithelial ovarian cancer: predictors of prognosis and biological basis of immunotherapy. PMID- 30243510 TI - Aquagenic wrinkling and cystic fibrosis carriership: A dubious relationship. PMID- 30243511 TI - Lung function and outcomes in emergency medical admissions. AB - BACKGROUND: We examine the ability of pre-existing measures of Forced Expiratory Volume in 1 s (FEV1), and Diffusion Capacity for Carbon Monoxide (DLCO) to determine the subsequent 30-day mortality outcome following unselected acute medical admission. METHODS: Between 2002 and 2017, we studied all emergency medical admissions (106,586 episodes in 54,928 patients) of whom 8071 were classified as respiratory. We employed logisitic multiple variable regression models to evaluate the ability of FEV1 or DLCO to predict the 30-day hospital mortality outcome. RESULTS: The 30-day hospital episode mortality outcome demonstrated curvilinear relationships to the underlying FEV1 or DLCO values; adjusted for major outcome predictors, a higher FEV1 - OR 0.85 (95% CI: 0.82, 0.89) or DLCO OR 0.76 (95% CI: 0.73, 0.79) values predicted survival. The range of predicted mortalities was from 3.3% (95% CI: 2.5, 4.0) to 23.5% (95% CI: 20.8, 26.2); the FEV1 (Model1) and DLCO (Model2) outcome prediction was essentially equivalent (Chi2 = 2.9: p = 0.08). CONCLUSION: The 30-day mortality outcome was clearly related to the pre-admission FEV1 and DLCO value. The outcome relationship was curvilinear. Either parameter appears a useful tool to explore hospital outcomes. Previously suggested cut-points are likely an artefact and not supported by these data. PMID- 30243512 TI - Fractional order model identification using the sinusoidal input. AB - An output error optimization approach for identification of parsimonious fractional order models using multi-frequency sinusoids as input is proposed. The algorithm simultaneously estimates orders, parameters and the delay of simple models with fractional orders using the Gauss-Newton optimization approach. Optimization-based methods for fractional order model identification require evaluation of the sensitivity functions which include the logarithmic derivatives of the input signal. In the existing literature, central difference or similar methods are used to numerically calculate the Jacobian matrix due to difficulties with numerical simulation of the logarithmic derivatives. We assume deterministic input signals and provide analytical expressions for the logarithmic derivatives of single and multiple frequency sinusoids. Relevant mathematical derivations are presented and the analytical expressions are used to evaluate the Jacobian. Effects of noise to signal ratio, input frequency and sampling intervals are studied in simulation to demonstrate the efficacy of the method. Convergence and robustness of the method is also studied. In theory, the approach is applicable for models with large set of parameters; however, convergence of the optimization scheme needs to be addressed. PMID- 30243513 TI - Diagnosis of uncertain nonlinear systems using interval kernel principal components analysis: Application to a weather station. AB - The Principal Component Analysis (PCA) is one of the most known and used linear statistical methods for process monitoring. However, the PCA algorithm is not designed to handle the uncertainty of the sensor measurements that is represented by an interval type data. Including uncertainty of the sensors measurements in the analysis requires extending the PCA methodology to the Symbolic Data Analysis (SDA). The SDA refers to a paradigm where statistical units are described by interval-valued variables. In this regard, Symbolic Principal Component Analysis (SPCA), particularly Midpoints-Radii PCA (MRPCA) technique, is investigated for modeling and diagnosis of uncertain data. The aim of the present paper is to propose an extended version of the linear SPCA technique, based on midpoints and radii, to the nonlinear case of kernel PCA method (MR-KPCA). The basic idea is to construct a robust KPCA model from midpoints and radii of the nonlinear uncertain process data. Then, the robust KPCA model is used for diagnosis (FDI) purpose. In fact, the FDI decisions are improved by taking in to account the uncertainties on the nonlinear data. The MR-KPCA algorithm is applied for sensor fault detection and isolation of an automatic weather station. The results of applying this algorithm show its feasibility and advantageous performances. PMID- 30243514 TI - One for All, but Not All for One: Social Behavior during Bacterial Diseases. AB - It has been known for decades that individual cells within pathogenic bacterial populations have reduced antibiotic susceptibility, which is linked to decreased metabolic rates. A similar phenomenon occurs with virulence-associated proteins, as reduced expression is associated with increased fitness of individual cells. Non-producers within the population can benefit from the virulence proteins produced by others in the population without suffering a fitness cost, thus maintaining a genetically uniform population. Cooperative behavior has been reported for Salmonella and Yersinia, consistent with selection of social behavior to retain genes associated with pathogenesis; however, cooperation was unclear within Mycobacterium populations. This review focuses on these recent descriptions of cooperation, discusses the mechanisms driving heterogeneity, and evaluates the evidence that expression of virulence-associated proteins comes at a fitness cost. PMID- 30243515 TI - Recognizing the Molecular Multifunctionality and Interactome of TIMP-1. AB - Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a major player in preserving tissue integrity and has recently also emerged as a decisive factor in several human pathologies. This appreciation has prompted this review addressing the largely underestimated complexity of the functions executed by TIMP-1 and their mechanistic basis. In fact, the versatile impact of TIMP-1 on cellular functions stems from its two-domain structure harboring metalloproteinase-inhibitory and cytokine-like signaling activities. This feature leads to functional interactions with numerous and distinct enzymatic and cell-surface proteins that initiate an exceptionally broad range of downstream effects. We propose here that this multifunctionality and the remarkably large interactome explain the diverse biological consequences of TIMP-1 expression in health and disease. PMID- 30243516 TI - Profile on medicinal plants used by the people of North Eastern Morocco: Toxicity concerns. AB - In the North Eastern region of Morocco, many people are interested in medicinal plants and their uses. However, the rationale for the utilization of medicinal plants has remained largely underestimated with little or no scientific data on plant safety. In this paper we attempt to describe and establish a detailed list of current knowledge in relation to the toxicity of these plants and to evaluate the scientific data concerning the harmful effects of the selected natural products. Our approach consists of collecting published data from literature in specialized journals, books and website related to the toxic plants. This research revealed that 89 plant species, retrieved from 287 plants used as medicine in the North-Eastern region of Morocco, are considered toxic or present some kind of toxicity. Our data determines 55 compounds isolated from the plants which are dominated by five groups of toxic compounds: alkaloids followed by glucosides, terpenoids, protides and phenolics. The present work discusses toxicity-related issues arising from the use of medicinal plants by local people. We conclude that the database considered in this study could serve as an important source of information on the toxicity of medicinal plants used by this society. PMID- 30243517 TI - Inhibitory effect of the gut microbial linoleic acid metabolites, 10-oxo-trans-11 octadecenoic acid and 10-hydroxy-cis-12-octadecenoic acid, on BV-2 microglial cell activation. AB - 10-oxo-trans-11-octadecenoic acid (KetoC) and 10-hydroxy-cis-12-octadecenoic acid (HYA) are long-chain fatty acids generated from linoleic acid by the gut lactic acid bacterium Lactobacillus plantarum. These fatty acids have been reported to have anti-inflammatory activity in the intestine. However, little is known about their effects in the brain. In this study, we aimed to investigate the effects of these fatty acids on lipopolysaccharide (LPS)-induced inflammatory processes in mouse microglial cells (BV-2 cells). KetoC and HYA inhibited LPS-induced nitric oxide (NO) production and suppressed the expression of inducible NO synthase in BV-2 cells. NO changes in these inhibitory effects were observed with AH7614, a G protein coupled receptor 120 antagonist, or the peroxisome proliferator-activated receptors antagonists, GW6471 and GW9662. In addition, KetoC and HYA did not inhibit translocation of p65, a subunit of NF-kappaB, or IkappaB degradation. Similarly, no effect on p38 or JNK phosphorylation was observed. However, KetoC and HYA were found to inhibit ERK phosphorylation induced by LPS, suggesting that these fatty acids may exert their anti-inflammatory effects through the inhibition of ERK activation in microglial cells. PMID- 30243518 TI - How does anteroposterior cup placement affect bone coverage and range of motion in primary total hip arthroplasty for hip dysplasia? AB - BACKGROUND: Due to anterior bone defects, high and/or posterior placement of an acetabular cup is often required to achieve sufficient coverage in patients with hip dysplasia. We examined whether posterior cup placement affected the postoperative range of motion (ROM) in primary total hip arthroplasty (THA). METHODS: Using computer software, bone coverage and ROM were examined in 32 patients with unilateral osteoarthritis of the hip with Crowe type II or III hip dysplasia. We determined the cup position to satisfy cup center-edge (Cup-CE) angle >=0 degrees and the required ROM. The cup was placed at the anatomic hip center and moved in 2-mm increments anteroposteriorly and 10-mm increments vertically. RESULTS: At vertical anatomic hip center, less than 68.8% hips fulfilled Cup-CE >=0 degrees regardless of anteroposterior position. Significantly more hips at higher hip center with posterior cup placement achieved Cup-CE >=0 degrees than hips at vertical anatomic hip center, and 10 mm higher hip center was the most suitable for achieving bone coverage. However, posterior and superior cup placement significantly decreased the flexion and IR due to early bone impingement, whereas ER and extension were not affected. A smoothing spline curve demonstrated that more posterior cup placement than 4.8 mm and 3.6 mm did not satisfy the required ROM at 10 mm and 20 mm higher hip center, respectively. CONCLUSIONS: Posterosuperior cup placement gained more bone coverage but decreased the range of hip flexion and internal rotation. Consequently, posterosuperior cup placement did not satisfy the required ROM. PMID- 30243519 TI - Co-existence of ossification of the nuchal ligament is associated with severity of ossification in the whole spine in patients with cervical ossification of the posterior longitudinal ligament -A multi-center CT study. AB - BACKGROUND: Previous studies have shown that patients with cervical ossification of the posterior longitudinal ligament (OPLL) often have co-existing ossification of the nuchal ligament (ONL). However, no studies have focused on ONL and its relevance to the severity of OPLL or ossification of other spinal ligaments, such as anterior longitudinal ligament (OALL), ligamentum flavum (OLF), and supraspinous/interspinous ligament (OSIL). METHODS: In this multicenter study, we investigated ossification of the spinal ligaments in the whole spine computed tomography (CT) images of 233 cervical OPLL patients. The severity of ossification was evaluated using ossification index for each spinal ligament, calculated as the sum of the level of ossification. We compared the severity of ossification in each spinal ligament between patients with ONL and those without ONL. Furthermore, we investigated how the number of segments, where ONL exists, affects the severity of ossification in each spinal ligament. RESULTS: One hundred thirty patients (55.8%) had co-existing ONL in the cervical OPLL patients included in this study. The ONL (+) group included more male and aged patients. The cervical ossification indexes of OPLL and OALL were higher in ONL (+) patients than in ONL (-) patients. The thoracolumbar ossification indexes of OALL and OSIL were also higher in ONL (+) patients. Logistic regression analysis revealed that age, gender and cervical OA-index were independent factors correlating to the existence of ONL. In the cervical spine, both the ossification indexes of OALL and OPLL increased as the levels of ONL increased. Similarly, in the thoracolumbar spine, both the ossification indexes of OALL and OSIL were increased as the levels of cervical ONL increased. In the multiple regression analysis, cervical OA-index and thoracolumbar OSI-index showed significant correlation with the number of ONL levels. CONCLUSIONS: Co-existence of ONL in cervical OPLL patients was associated with the severity of spinal hyperostosis especially in cervical OPLL, OALL, thoracolumbar OALL and OSIL. PMID- 30243520 TI - Lumbar spinal canal stenosis leads to locomotive syndrome in elderly patients. AB - BACKGROUND: Locomotive syndrome is a condition in which the ability to lead a normal life is restricted owing to a dysfunction in one or more of the parts of the musculoskeletal system. Although lumbar spinal canal stenosis (LSS) is considered to cause locomotive syndrome, a detailed assessment of the association between two pathologies has not yet been reported. METHODS: The clinical data of patients aged > 65 years old who planned to undergo surgery for LSS at multiple institutions were prospectively collected from April 2016 to August 2017. A total of 200 participants comprising 120 men and 80 women were enrolled in this study. Association of severity of LSS evaluated by Zurich Claudication Questionnaire scores with three locomotive syndrome risk tests (Stand-up Test, the Two-step Test, and a 25-question risk assessment) and Timed Up-and-Go Test were evaluated. RESULTS: In the total assessment of locomotive syndrome, 96.5% of the participants were diagnosed as grade 2, and the remaining 3.5% were diagnosed as grade 1. When the participants were divided into 3 groups according to the LSS severity, the scores of all locomotive syndrome risk tests were significantly worse with increasing LSS severity. Logistic regression analysis revealed that LSS severity was positively correlated with the risk level of locomotive syndrome evaluated by the Two-step Test (OR = 3.45, CI = 1.33-8.96). CONCLUSIONS: All LSS patients with surgical indications were diagnosed as having locomotive syndrome. In addition, our results indicated that LSS severity is potentially associated with the progression of locomotive syndrome. The treatment of LSS may be beneficial in alleviating the risk for locomotive syndrome. PMID- 30243522 TI - How Symmetrical Are Bony Orbits in Humans? AB - PURPOSE: Establishing the symmetry of intraindividual orbital volumes is crucial for radiologic assessment, preoperative planning, and postoperative outcome evaluation. However, no reliable method exists to measure orbital volume because of problems in defining the bony boundaries of the orbit. Therefore, the purpose of this study was to propose a new approach to analyze human orbits and determine its application for quantifying bony symmetry in a cohort of patients. PATIENTS AND METHODS: Computed tomography scans of 93 patients were retrospectively collected from our institutional database. The intraindividual volume difference was quantified using a surface model derived from manual segmentations. The average shape of the orbit was calculated iteratively and nonrigidly registered to both orbits of all patients. After registration, the surface reconstructions of all orbits had an identical mesh topology and vertices at corresponding anatomic locations. The volume difference was calculated locally based on the relative position of the vertices at equivalent locations in the left orbit and right orbit. This approach was used to quantify the volume difference between the left and right orbits for all patients. Interobserver sensitivity was assessed in 5 randomly chosen patients and was measured independently by 3 specialists. RESULTS: An average difference of 600 +/- 500 MUL between the volumes of the left and right orbits was found, representing a difference of 2.1%. Although the difference in volume was small, the volumes were significantly different (P = .039). The largest asymmetries were found in the roof and floor area. CONCLUSIONS: The method proposed to measure the difference in volume between the left and right orbits is automated and does not rely on a closed orbital volume, which provides more objective volume measurements. With the help of modern computed tomography techniques and the coherent point drift method, it was possible to show that the intraindividual volume difference in the orbits is approximately 2%, not 7 to 8% as often cited in the literature. PMID- 30243521 TI - [IoNESCO trial: Immune neoajuvant therapy in early stage non-small cell lung cancer]. AB - BACKGROUND: Programmed cell death-ligand 1 (PD-L1) is a checkpoint receptor that facilitates immune evasion by tumor cells, through interaction with programmed cell death-1 (PD-1), a receptor expressed by T-cells. Durvalumab is an anti-PD-L1 monoclonal antibody that blocks PD-L1 interaction with PD-1 on T-cells, countering the tumor's immune-evading tactics. Phase I/II studies demonstrated durable responses and manageable tolerability in heavily pre-treated patients with non-small cell lung cancer (NSCLC). METHODS: This phase II study is designed to administrate three durvalumab IV infusions (10mg/kg at day 1, 15, 29) before surgery, to patients with pathologically confirmed NSCLC, clinical stage IB (>4cm) or stage II, >=18 years of age, WHO performans status 0-1, without selection on PD-L1 expression. Preoperative chemotherapy and radiation therapy are not permitted. The primary objective is feasibility of complete surgical resection. Major pathological response on surgical tissue, defined as 10% or less remaining tumor cells, will be a secondary objective. Additional secondary objectives include tolerance, adverse effects, delay between start of treatment and surgery, response rate (RECIST 1.1), metabolic response rate, postoperative adverse events, disease-free survival and overall survival. A rate of complete resection<85% (P0) is considered unacceptable. P1 hypothesis is of 95%, and with a study power of 90% and an alpha risk of 5% (two-steps Fleming's procedure), 81 patients are required. EXPECTED RESULTS: To establish whether neoadjuvant immunotherapy is feasible and could improve the survival of patients with early stage NSCLC. PMID- 30243524 TI - [Clinical and epidemiological characteristics of patients with paracoccidioidomycosis diagnosed in a hospital of Resistencia, Chaco]. AB - In order to describe the clinical and epidemiological characteristics of paracoccidioidomycosis, a descriptive study of all the cases diagnosed by the Clinical Microbiology Service at Dr. Julio C. Perrando hospital in the city of Resistencia (Chaco Province, Argentina) was conducted. Between 2011 and 2014, 46 cases were detected. In the period 2013-2014, an almost 4-fold increase in the incidence rate was detected. The chronic form of the disease was predominant with an average age of 53 years. Serological tests in 39 out of 46 patients were performed. In 15 of 39 patients, serological tests were the only diagnostic tool while in 4 patients with a microbiological diagnosis serological tests were non reactive. In patients from endemic areas with non-specific infectious syndrome it is important to include paracoccidioidomycosis in the differential diagnosis and to apply all available diagnostic tools to reach a timely diagnosis and to reduce the long-term sequelae and their socio-economic impact. PMID- 30243523 TI - Prevalence of abdominal aortic aneurysm in patients with high cardiovascular risk. AB - BACKGROUND: To determine the prevalence of abdominal aortic aneurysm (AAA) (arterial diameter >=30mm), in patients with high or very high cardiovascular risk (CVR) and to evaluate their clinical features. PATIENTS AND METHODS: Observational, cross-sectional and multicentric study conducted in Spanish Internal Medicine Services. We enrolled men with age >55years and women >65years who had a high or very high CVR. RESULTS: The study included 659 patients. The prevalence of AAA was 8% (53 patients). 76.9% were male with a mean age of 71+/ 8.7years. The multivariate analysis showed an association between AAA and age (OR: 1.06; 95%CI: 1.02-1.1; P<.01), male sex (OR: 5.6; 95%CI: 1.6-18.8; P=.01), active smoking (OR: 3.22; 95%CI: 1.16-8.93; P=.024) and peripheral arterial disease (OR: 3.51; 95%CI: 1.73-7.09; P<.01). Diabetes mellitus was an independent protective factor (OR: 0.41; 95%CI: 0.22-0.78; P=.06). Those with subaneurysmal dilatation of the abdominal aorta (diameter 25-29.9mm) presented similar features as patients with AAA. CONCLUSIONS: The prevalence of AAA in patients with high CVR is high. Ultrasound screening can be performed by general practitioners. Men >65years with elevated CVR could benefit, particularly in the presence of active smoking or peripheral arterial disease. PMID- 30243525 TI - Resistance to beta-lactams in enterococci. AB - Enterococci are intrinsically resistant to several antimicrobial classes and show a great ability to acquire new mechanisms of resistance. Resistance to beta lactam antibiotics is a major concern because these drugs either alone or in combination are commonly used for the treatment of enterococcal infections. Ampicillin resistance, which is rare in Enterococcus faecalis, occurs in most of the hospital-associated Enterococcus faecium isolates. High-level resistance to ampicillin in E. faecium is mainly due to the enhanced production of PBP5 and/or by polymorphisms in the beta subunit of this protein. The dissemination of high level ampicillin resistance can be the result of both clonal spread of strains with mutated pbp5 genes and horizontal gene transfer. PMID- 30243526 TI - [Observation of interactions between hyphae of Fusarium verticillioides, Aspergillus flavus and Talaromyces funiculosus in microcultures developed in hermetic environments]. PMID- 30243527 TI - [Helicobacter cinaedi bacteremia: Presentation of the first cases reported in Argentina]. AB - Two cases of bacteremia caused by Helicobacter cinaedi are presented. The first case was diagnosed in a 76-year-old male patient, and was secondary to a vascular access device placement; the second case corresponded to a febrile infant of 37 days of life, and was associated with acute gastroenteritis. H. cinaedi is a microorganism difficult to grow in different culture media and also to identify to species level. In both cases, the microscopic observation of blood culture bottles, the use of mass spectrometry and the subsequent sequencing of the hsp60 gene were essential. In the recent literature, H. cinaedi infections are being reported more frequently. In this report we present the first documented cases of bacteremia caused by H. cinaedi in Argentina. PMID- 30243528 TI - Loss of connexin 43 in Sertoli cells provokes postnatal spermatogonial arrest, reduced germ cell numbers and impaired spermatogenesis. AB - For the reason that adult Sertoli cell specific connexin 43 knockout (SCCx43KO) mice show arrested spermatogenesis at spermatogonial level or Sertoli cell only tubules and significantly reduced germ cell (GC) numbers, the aims of the present study were (1) to characterize the remaining GC population and (2) to elucidate possible mechanisms of their fading. Apoptosis was analyzed in both, KO and wild type (WT) male littermates during postnatal development and in adulthood using TUNEL. Although GC numbers were significantly reduced in KO at 2 and 8 days postpartum (dpp) when compared to WT, no differences were found concerning apoptotic incidence between genotypes. From 10 dpp, the substantial GC deficiency became more obvious. However, significantly higher apoptotic GC numbers were seen in WT during this period, possibly related to the first wave of spermatogenesis, a known phenomenon in normal pubertal testes associated with increased apoptosis. Characterization of residual spermatogonia in postnatal to adult KO and WT mice was performed by immunohistochemical reaction against VASA (marker of GCs in general), Lin28 and Fox01 (markers for undifferentiated spermatogonia) and Stra8 (marker for differentiating spermatogonia and early spermatocytes). During puberty, the GC component in SCCx43KO mice consisted likely of undifferentiated spermatogonia, few differentiating spermatogonia and very few early spermatocytes, which seemed to be rapidly cleared by apoptosis. In adult KOs, spermatogenesis was arrested at the level of undifferentiated spermatogonia. Overall, our data indicate that Cx43 gap junctions in SCs influence male GC development and differentiation rather than their survival. PMID- 30243529 TI - Mechanical versus electrical detachment of coils in treatment of intracranial aneurysms: Role in sickle cell disease. PMID- 30243530 TI - Gastric cancer epidemiology in tertiary healthcare in Chiapas. AB - INTRODUCTION AND AIM: Gastic cancer is the most frequent neoplasia of the digestive tract worldwide. Incidence rates vary according to the region or country analyzed. Variation in the different regions of Mexico is attributed to very specific dietary, environmental, and genetic patterns. The aim of the present work was to carry out an epidemiologic analysis of the cases of gastric cancer treated at the Hospital Regional de Alta Especialidad 'Ciudad Salud', located in Chiapas, Mexico. MATERIAL AND METHODS: A descriptive, ambispective, longitudinal study was conducted. Cases of gastric cancer were searched for in the database from the oncology service of our hospital, that were treated within the time frame of 2007 to 2014. The data obtained were analyzed using the SPSS v. 20 statistics program. RESULTS: A total of 100 cases of gastric cancer were detected, 84 of which were included in the study. Forty-one of the cases were men, 43 were women, and their mean age was 57.3 years. Incidence was 2.14 for every 100 oncology patients released from the hospital. Of the study patients, 35.71% stated they had been alcoholics, 22.61% were smokers, and 90.16% were diagnosed with adenocarcinoma. At the end of follow-up, 18 of the study patients had died. CONCLUSION: The results of the present epidemiologic analysis showed that the consumption of alcohol and tobacco played an important role in the development of gastric cancer in the patients studied, as well as having a family history of any type of cancer. Because gastric cancer is usually diagnosed in advanced stages, it would be reasonable to formulate a strategy for the prevention, early detection, and control of the disease in the State of Chiapas, Mexico. PMID- 30243531 TI - Synthesis and characterization of Ogataea thermomethanolica alcohol oxidase immobilized on barium ferrite magnetic microparticles. AB - Alcohol oxidase catalyzes the oxidation of primary alcohols into the corresponding aldehydes, making it a potential biocatalyst in the chemical industry. However, the high production cost and poor operational stability of this enzyme are limitations for industrial application. Immobilization of enzyme onto solid supports is a useful strategy for improving enzyme stability. In this work, alcohol oxidase from the thermotolerant methylotrophic yeast Ogataea thermomethanolica (OthAOX) was covalently immobilized onto barium ferrite (BaFe12O19) magnetic microparticles. Among different conditions tested, the highest immobilization efficiency of 71.0 % and catalytic activity of 34.6 U/g was obtained. Immobilization of OthAOX onto magnetic support was shown by Fourier Transformed infrared microscopy, scanning electron microscopy and X-ray diffraction. The immobilized OthAOX worked optimally at 55 degrees C and pH 8.0. Immobilization also improved thermostability, in which >65% of the initial immobilized enzyme activity was retained after 24 h pre-incubation at 45 degrees C. The immobilized enzyme showed a greater catalytic efficiency for oxidation of methanol and ethanol than free enzyme. The immobilized enzyme could be recovered by magnetization and recycled for at least three consecutive batches, after which 70% activity remained. The properties of the immobilized enzyme suggest its potential industrial application for synthesis of aldehyde. PMID- 30243532 TI - Characteristics of heterotrophic nitrification and aerobic denitrification bacterium Acinetobacter sp. T1 and its application for pig farm wastewater treatment. AB - A novel heterotrophic bacterium was isolated from activated sludge of a pig farm wastewater treatment plant and identified as Acinetobacter sp. T1. It exhibited efficient heterotrophic nitrification and aerobic denitrification capability to utilize ammonium, nitrate or nitrite as the sole nitrogen source, and their removal rates were 12.08, 5.53 and 1.69 mg/L/h, respectively. Furthermore, the optimal conditions for the heterotrophic nitrification process were sodium citrate as the carbon source, C/N mass ratio of 10, pH of 8.5 and dissolved oxygen (DO) concentration of 5.1 mg/L. Only trace amounts of nitrate and nitrite were observed during the process. When the aerobic tank of the A2O process of a pig farm wastewater treatment plant was inoculated with traditional activated sludge, the average removals of COD, NH4+- N and TN in the effluent were 30%, 15% and 16%, respectively, which was much lower than that of inoculated with strain T1, the increase was statistically significant, indicating a great potential of strain T1 for full-scale applications. PMID- 30243533 TI - Two NADH-dependent (S)-3-hydroxyacyl-CoA dehydrogenases from polyhydroxyalkanoate producing Ralstonia eutropha. AB - Ralstonia eutropha H16 contains both NADH- and NADPH-dependent reduction activities to acetoacetyl-CoA, and the NADPH-dependent activity is mediated by PhaB paralogs with (R)-stereospecificity providing (R)-3-hydroxybutyryl (3HB)-CoA monomer for poly((R)-3-hydroxybutyrate) synthesis. In contrast, the gene encoding the NADH-dependent enzyme has not been identified to date. This study focused on the NADH-dependent dehydrogenase with (S)-stereospecificity in R. eutropha, as the (S)-specific reduction of acetoacetyl-CoA potentially competed with the polyester biosynthesis via (R)-3HB-CoA. The NADH-dependent reduction activity decreased to one-half when the gene for H16_A0282 (PaaH1), one of two homologs of clostridial NADH-3HB-CoA dehydrogenase, was deleted. The enzyme responsible for the remaining activity was partially purified and identified as H16_A0602 (Had) belonging to a different family from PaaH1. Gene disruption analysis elucidated that most of the NADH-dependent activity was mediated by PaaH1 and Had. The kinetic analysis using the recombinant enzymes indicated that PaaH1 and Had were both NADH-dependent 3-hydroxyacyl-CoA dehydrogenases with rather broad substrate specificity to 3-oxoacyl-CoAs of C4 to C8. The deletion of had in the R. eutropha strain previously engineered for biosynthesis of poly((R)-3-hydroxybutyrate-co (R)-3-hydroxyhexanoate) led to decrease in the C6 composition of the copolyester synthesized from soybean oil, suggesting the role of Had in (S)-specific reduction of 3-oxohexanoyl-CoA with reverse beta-oxidation direction. Crotonase ((S)-specific enoyl-CoA hydratase) in R. eutropha H16 was also partially purified and identified as H16_A3307. PMID- 30243534 TI - Development of a Dietary Methyl Donor Food Frequency Questionnaire to Assess Folate and Vitamin B12 Status in Children with Chronic Hepatitis B Virus Infection. AB - OBJECTIVE: To develop a dietary methyl donor food frequency questionnaire (DMD FFQ) that is validated in a cohort of US children and to determine whether the consumption of folate and vitamin B12, principal DMDs, correlates with HBV DNA levels and its methylation density. STUDY DESIGN: We developed a semiquantitative DMD-FFQ to estimate intake of folate and vitamin B12 and validated this instrument against a 24-hour dietary recall and biomarkers-red blood cell folate, serum vitamin B12, and homocysteine-in 35 children with chronic HBV infection without other medical comorbidities. Estimates of DMD, as well as the serum biomarkers, were correlated with the methylation density of HBV CpG island 2 and HBV DNA levels. RESULTS: Folate per kilogram of body weight by the DMD-FFQ correlated positively with 24-hour recall (r = 0.60; P < .001) and red blood cell folate (r = 0.40; P = .02), and negatively with homocysteine (r = -0.54; P < .001). Vitamin B12 per kilogram by DMD-FFQ also correlated positively with 24 hour recall (r = 0.57; P < .001) and serum vitamin B12 (r = 0.36, P = .04), and negatively with homocysteine (r = -0.44; P = .008). Neither DMD intake (from DMD FFQ or 24-hour recall) nor serum biomarkers correlated with HBV DNA levels or its methylation density. CONCLUSIONS: Our DMD-FFQ correlates well with a 24-hour recall and circulating biomarkers. Although little evidence existed that consumption of these micronutrients correlated with HBV replication, this tool could prove useful for investigating epigenetic modification by diet for several pediatric diseases. PMID- 30243535 TI - Executive Function and Psychosocial Quality of Life in School Age Children with Congenital Heart Disease. AB - OBJECTIVE: To test a model to predict psychosocial quality of life (QOL) in children with congenital heart disease (CHD) via executive dysfunction. STUDY DESIGN: Parents of 91 children with CHD requiring surgery in the first year of life completed questionnaires by mail or as part of their cardiology clinic visit. Latent class analysis identified 2 groups of patients with different likelihoods of executive dysfunction. Select medical and demographic characteristics and executive dysfunction group membership were evaluated as predictors of QOL using structural equation modeling. RESULTS: In children with CHD, aortic obstruction, male sex, and premature birth predicted worse executive function, explaining 59% of the variance. Structural equation modeling results indicated that executive dysfunction plays an important mediating role, through which CHD with aortic obstruction, male sex, and premature birth indirectly affect psychosocial QOL. Neurologic abnormalities and single-ventricle CHD did not significantly predict executive dysfunction or QOL. CONCLUSIONS: Executive dysfunction is a strong predictor of psychosocial QOL at school age. Select medical and demographic risk factors did not directly predict QOL at school age in CHD; however, aortic obstruction, premature birth, and male sex impacted QOL indirectly by contributing to executive dysfunction. These findings suggest important risk factors for executive dysfunction that can be monitored, allowing for provision of early supports for executive skills development in an effort to improve long term psychosocial QOL in at-risk children with CHD. PMID- 30243536 TI - Adiposity in Adolescents: The Interplay of Sleep Duration and Sleep Variability. AB - OBJECTIVE: To assess whether adiposity measures differed according to joint categories of sleep duration and sleep variability in a sample of Mexican adolescents. STUDY DESIGN: A sample of 528 Mexico City adolescents aged 9-17 years wore wrist actigraphs for 6-7 days. Average sleep duration was categorized as age-specific sufficient or insufficient. Sleep variability, the standard deviation of sleep duration, was split at the median into stable versus variable. Adiposity measures-body mass index (BMI)-for-age Z score (BMIz), triceps skinfolds, waist circumference, and percent body fat-were collected by trained assistants. We regressed adiposity measures on combined sleep duration and variability categories. Log binomial models were used to estimate prevalence ratios and 95% CI for obesity (>2 BMIz) by joint categories of sleep duration and variability, adjusting for sex, age, and maternal education. RESULTS: Approximately 40% of the adolescents had insufficient sleep and 13% were obese. Relative to sufficient-stable sleepers, adolescents with insufficient-stable sleep had higher adiposity across all 4 measures (eg, adjusted difference in BMIz was 0.68; 95% CI, 0.35-1.00) and higher obesity prevalence (prevalence ratio, 2.54; 95% CI, 1.36-4.75). Insufficient-variable sleepers had slightly higher BMIz than sufficient-stable sleepers (adjusted difference, 0.30; 95% CI, 0.00-0.59). CONCLUSIONS: Adolescents with consistently insufficient sleep could be at greater risk for obesity. The finding that insufficient-variable sleepers had only slightly higher adiposity suggests that opportunities for "catch-up" sleep may be protective. PMID- 30243537 TI - Optimal Mean Arterial Blood Pressure in Extremely Preterm Infants within the First 24 Hours of Life. AB - OBJECTIVE: To define levels of mean arterial blood pressure (MABP) where cerebrovascular reactivity is strongest (MABPOPT) during the early transitional circulation in extremely preterm infants and to investigate the association between deviations above and below MABPOPT with intraventricular hemorrhage (IVH) and mortality. STUDY DESIGN: A total of 44 infants born at a median gestational age 25 (23-27) weeks with indwelling arterial catheter were studied at a median 5.5 (3.1-12.6) hours within the first 24 hours of life. Cerebrovascular reactivity (tissue oxygenation heart rate reactivity index) was estimated by the moving correlation coefficient between heart rate and near-infrared spectroscopy tissue oxygenation index. MABPOPT was defined as the MABP where tissue oxygenation heart rate reactivity index reaches minimum value. Deviations below or above MABPOPT values were calculated along with MABPOPT values during retrospective data analysis. RESULTS: MABPOPT was detected in all infants. The mean (SD) MABPOPT was 31.3 (+/-4.7) mm Hg. MABPOPT increased with increasing gestational age, R = 0.424; P = .004. Deviations below MABPOPT were greater in the IVH group (mean 2.7 mm Hg; 95% CI 2.0-3.5) compared with no-IVH (mean 1.7 mm Hg; 1.1-2.2), P = .006. In infants who died, the deviation below MABPOPT was greater (mean 3.3; 95% CI 1.9-4.8) compared with those who survived (mean 1.9 mm Hg; 95% CI 1.4-2.3), P = .015. CONCLUSIONS: Defining optimal MABP based on the strength of cerebrovascular reactivity within the first 24 hours of life is feasible and can provide an individualized approach to the care of extremely preterm infants. Deviations below MABPOPT were significantly associated with IVH and death. PMID- 30243538 TI - Lifestyle Clusters in School-Aged Youth and Longitudinal Associations with Fatness: The UP&DOWN Study. AB - OBJECTIVES: To identify lifestyle clusters in children and adolescents, to analyze associations between lifestyle clusters and body fat percentage (BFP) at baseline and 2 years later, and to examine if BFP at baseline is associated with BFP 2 years later. STUDY DESIGN: This longitudinal study involved 1634 Spanish youth (804 girls) aged 8-18 years (mean, 12.45 +/- 2.51 years). Cluster analysis was performed by including objectively measured sedentary time and physical activity and self-reported screen time and diet. The associations between cluster membership and BFP was analyzed through general linear models. All the analyses were separated by 3 age groups: older children, younger adolescents, and older adolescents. RESULTS: Four clusters were identified in the 3 age groups: (1) healthy lifestyle cluster (high moderate-to-vigorous physical activity, low screen and total sedentary time), (2) predominantly sedentary cluster, (3) mainly screen time consumers cluster, and (4) nonhealthy lifestyle cluster (predominantly low moderate-to-vigorous physical activity and unhealthy diet). Participants belonging to the healthy lifestyle cluster showed significantly lower BFP at baseline and 2 years later compared with the other profiles. These differences remained significant when adjusted by BFP at baseline within the younger adolescents. Moreover, BFP at baseline positively predicted BFP 2 years later in all groups. CONCLUSIONS: These findings identify distinct lifestyle patterns. These clusters could be useful to develop interventions to reduce overweight and obesity in children and adolescents. PMID- 30243539 TI - HIV-Associated Diffuse Intracranial Aneurysmal Arteriopathy. PMID- 30243540 TI - Reply. PMID- 30243541 TI - Reply. PMID- 30243542 TI - If You Build It, Will They Come? Getting Medical Professionals to Use the Bridge of Evidence for Improved Recognition of Physical Child Abuse. PMID- 30243543 TI - Vitamin D Status at the Time of Hospitalization for Bronchiolitis and Its Association with Disease Severity. AB - OBJECTIVE: To investigate the association between circulating 25-hydroxyvitamin D [25(OH)D] status at admission and disease severity among infants hospitalized for bronchiolitis and to determine whether the association differs by the form of 25(OH)D-total, bioavailable or free 25(OH)D. STUDY DESIGN: We conducted a 17 center prospective cohort study of 1016 US infants <12 months old hospitalized with bronchiolitis. Vitamin D status was defined by total 25(OH)D levels, and by calculated levels of bioavailable and free 25(OH)D. Bronchiolitis severity was defined by requirement for intensive care and hospital length-of-stay (LOS). Logistic and Poisson regression were used for unadjusted and multivariable analyses. RESULTS: The median age of hospitalized infants was 3.2 months (IQR 1.6 6.0). The median total 25(OH)D was 26.5 ng/mL (IQR 18.0-33.1); 298 (29%) infants had total 25(OH)D <20 ng/mL. In multivariable models, infants with total 25(OH)D <20 ng/mL had higher risk of requiring intensive care (aOR 1.72, 95% CI 1.12 2.64) and longer LOS (adjusted rate ratio 1.39, 95% CI 1.17-1.65) compared with infants with total 25(OH)D >=30 ng/mL. Infants with the lowest tertile of bioavailable 25(OH)D, compared with those with the highest tertile, had longer LOS (adjusted rate ratio 1.32, 95% CI 1.07-1.62); admission to the intensive care unit was not statistically significant in the adjusted model (aOR 1.39, 95% CI 0.96-2.64). Free 25(OH)D level was not associated with severity of bronchiolitis in either unadjusted or adjusted models. CONCLUSION: In a large, multicenter cohort of US infants hospitalized for bronchiolitis, infants with total 25(OH)D <20 ng/mL had increased risk of intensive care and longer hospital LOS. PMID- 30243544 TI - Covariation of Neonatal Intensive Care Unit-Level Patent Ductus Arteriosus Management and In-Neonatal Intensive Care Unit Outcomes Following Preterm Birth. AB - OBJECTIVE: To test the hypothesis that neonatal intensive care unit (NICU) specific changes in patent ductus arteriosus (PDA) management are associated with changes in local outcomes in preterm infants. STUDY DESIGN: This retrospective repeated-measures study of aggregated data included infants born 400-1499 g admitted within 2 days of delivery to NICUs participating in the California Perinatal Quality Care Collaborative. The period 2008-2015 was divided into four 2-year epochs. For each epoch and NICU, we calculated proportions of infants receiving cyclooxygenase inhibitor (COXI) or PDA ligation and determined NICU specific changes in these therapies between consecutive epochs. Generalized estimating equations were used to examine adjusted relationships between NICU specific changes in PDA management and contemporaneous changes in local outcomes. RESULTS: We included 642 observations of interepoch change at 119 hospitals summarizing 32 094 infants. NICU-specific changes in COXI use and ligation showed significant dose-response associations with contemporaneous changes in adjusted local outcomes. Each percentage point decrease in NICU-specific proportion treated with either COXI or ligation was associated with a 0.21 percentage point contemporaneous increase in adjusted local in-hospital mortality (95% CI 0.06, 0.33; P = .005) among infants born 400-749 g. In contrast, decreasing NICU specific ligation rate among infants 1000-1499 g was associated with decreasing adjusted local bronchopulmonary dysplasia (P = .009) and death or bronchopulmonary dysplasia (P = .01). CONCLUSIONS: NICU-specific outcomes of preterm birth co-vary with local PDA management. Treatment for PDA closure may benefit some infants born 400-749 g. Decreasing NICU-specific rates of COXI use or ligation were not associated with increases in local adjusted rates of examined adverse outcomes in larger preterm infants. PMID- 30243545 TI - High-Sensitivity Troponin: Time to Implement. PMID- 30243546 TI - Addressing New Diagnostic and Treatment Challenges Associated With a New Age of Cancer Treatment. PMID- 30243547 TI - What Is the Risk of a Venous Thromboembolic Event After a Negative Computed Tomographic Pulmonary Angiography Result? PMID- 30243548 TI - The electrocardiogram of vertebrates: Evolutionary changes from ectothermy to endothermy. AB - The electrocardiogram (ECG) reveals that heart chamber activation and repolarization are much faster in mammals and birds compared to ectothermic vertebrates of similar size. Temperature, however, affects electrophysiology of the heart and most data from ectotherms are determined at body temperatures lower than those of mammals and birds. The present manuscript is a review of the effects of temperature on intervals in the ECG of ectothermic and endothermic vertebrates rather than a hypothesis-testing original research article. However, the conclusions are supported by the inclusion of original data (Iguana iguana, N = 4; Python regius, N = 5; Alligator mississippiensis, N = 4). Most comparisons were of animals of approximately 1 kg. Compared to mammals and birds, the reptiles at 35-37 degrees C had 4 fold lower heart rates, 2 fold slower atrial and ventricular conduction (longer P- and QRS-wave durations), and 4 fold longer PR intervals (atrioventricular delay) and QT intervals (total ventricular repolarization). We conclude that the faster chamber activation in endotherms cannot be explained by temperature alone. Based on histology, we show that endotherms have a more compact myocardial architecture. In mammals, disorganization of the compact wall by fibrosis associates with conduction slowing and we suggest the compact tissue architecture allows for faster chamber activation. The short cardiac cycle that characterizes mammals and birds, however, is predominantly accommodated by shortening of the atrioventricular delay and the QT interval, which is so long in a 1 kg iguana that it compares to that of an elephant. PMID- 30243549 TI - Recent progress on gene silencing/suppression by virus-derived small interfering RNAs in rice viruses especially Rice grassy stunt virus. AB - Noncoding RNAs play essential functions during epigenetic regulation of gene expression and development in numerous organisms. Three type of small noncoding RNAs found in eukaryotes, which are small interfering RNAs (siRNAs), microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs). Small RNAs (sRNAs) originated from infecting viruses are known as virus-derived small interfering RNAs (vsiRNAs), are responsible for RNA silencing in plants. However, Virus-induced gene silencing (VIGS) is mainly dependent on RNA silencing (RNAi). Interestingly, RNA silencing happens in plants and insects during viral infections. VsiRNAs originate from dsRNA molecules which further require hosts Dicer-like (DCL) proteins, RNA dependent RNA polymerase (RdRP) proteins, and Argonaute (AGO) proteins. RdRP uses ssRNA for complete RNA amplification process as well as DCL dependent secondary vsiRNA formation. Viral Suppressors of RNA silencing (VSRs) interfere with the movement of signals during silencing mechanism. Moreover, intercellular movement of viruses is facilitated by virus-encoded movement proteins. Proteomic and Transcriptomic mechanisms regulated by specific factors like microRNAs, which has become an essential factor of gene regulation. RNAi is also involved in gene suppression by regulating the transcriptional and post transcriptional gene expression in many eukaryotes. Rice grassy stunt virus (RGSV) is a member of genus Tenuivirus. Although, there is no much work done on RGSV, but this virus has become very potent and destructive, and effects rice crop in many Asian countries, particularly in China. In this review, we have highlighted the rice viruses' biology and silencing suppressors. This work will be helpful for plant virologists in understanding the role of vsiRNAs mechanism in rice viruses especially RGSV. PMID- 30243550 TI - The fingerprint mapping and genotyping systems application on methicillin resistant Staphylococcus aureus. AB - As a typical Gram-positive microorganism, S. aureus was recognized as common foodborne pathogenic bacteria in food industry. To study their individuality and pathogenicity mechanism, thirty-three Staphylococci strains were applied to the investigation with the identification of MRSA by PCR targeting on S. aureus specific 16S rRNA and femA genes as well as methicillin-resistant mecA and orfX elements by multiplex-PCR assay. Fingerprinting mapping was then employed using three typing systems (KZ/M13, IS256 and ERIC2) to genotype 33 MRSA strains. As the result indicated, all 33 Staphylococci strains were identified as MRSA. However, diversity occurred among different fingerprinting system results. KZ/M13 system and IS256 system both typed 10 genotypes while ERIC2 system had 8 genotypes. Based on the genotyping results, a discussion was performed in typing ability, discriminatory ability and accordance ratio. Given the above studies, a novel rapid detection method for MRSA was conducted with multiplex-PCR, which possessed rapidity and accuracy. Meanwhile, three fingerprinting systems showed high sensitivity, resolution and classification ratio in MRSA typing. These methods have a broad application prospect in food safety and epidemiology in the future. PMID- 30243551 TI - Antibacterial and anticancer potential of marine endophytic actinomycetes Streptomyces coeruleorubidus GRG 4 (KY457708) compound against colistin resistant uropathogens and A549 lung cancer cells. AB - The aim of the current study is to identify bioactive compound from marine endophytic actinomycetes (MEA) isolated from Gulf of Mannar region, Southeast coast of India. Among the isolated actinomycetes, strain GRG 4 exhibited excellent ability to inhibit isolated colistin resistant (CR) Pseudomonas aeruginosa (P. aeruginosa) and Klebsiella pneumoniae (K. pneumoniae), which is a emerging threat to the world. The strain was identified as Streptomyces coeruleorubidus GRG 4 (KY457708), based on morphological, biochemical, phenotypic and genotypic characters. The bioactive metabolites present in the methanolic extract were partially purified by TLC and preparative HPLC. The active HPLC fraction 2 showed 15, 20 mm zone of inhibition against both CR P. aeruginosa and K. pneumoniae respectively. Analytical HPLC and FT-IR results of fraction 2 showed with carbonyl group. Both GC-MS and LC-MS results confirmed that the fraction 2 contained chemical constituents of Bis (2-Ethylhexyl) Phthalate (BEP). The compromised structure with loosely integrated and ruptured cell wall of BEP treated CR bacteria were observed by confocal laser scanning microscope (CLSM) and scanning electron microscope (SEM) at 75 MUg/mL of minimum inhibitory concentration (MIC) dose. Further, cytotoxic effect of BEP against A549 human lung cancer cells revealed complete inhibition by cell proliferation and apoptosis was observed at 100 MUg/mL in 24 h treatment. In addition, irreversible ROS dependent oxidative damage was clearly observed at the IC50 concentration of BEP. The toxicity of BEP was also studied against Vibrio fischeri (V. fischeri) and found to be highly toxic after 15 and 30 min of treatment. Based on the results it could be concluded that the identified compound BEP is a potent inhibitor for CR bacteria and A549 lung cancer cells. PMID- 30243553 TI - Molecular and serological data supporting the role of Q fever in abortions of sheep and goats in northern Egypt. AB - Q fever is a worldwide zoonotic disease, caused by Coxiella burnetii (C. burnetii), an obligate intracellular bacterium. The epidemiological data about the Q fever situation in Egypt is limited. The present study investigated the seroprevalence of Q fever among small ruminants in some localities in the northern Egypt and reported the shedders using specific real-time PCR (Rt-PCR). A total of 190 sera and vaginal swabs (110 sheep and 80 goats) were collected from aborted cases. Indirect ELISA was used to detect specific antibodies against C. burnetii, and Rt-PCR was used to detect DNA in the shedder animals. The study revealed that infection was significantly higher in sheep (22.7%) than in goats (12.5%) (p < 0.05). The Menoufia and Gharbia governorates had 20% seropositive animals while Qalubia and Alexandria had 15% and 17.5% seropositive animals, respectively. Using a Rt - PCR assay, C. burnetii was detected in 33.6% and 16.3% of sheep and goats, respectively. The findings of the study demonstrate that Q fever may be enzootic among small ruminants and distributed in the northern Egyptian Governorates. Further studies are needed in different regions to gain better understanding of the epidemiology of Q fever all over the country and to develop an appropriate preventive strategy for human and animals. PMID- 30243552 TI - Enterotoxigenic Escherichia coli infection promotes apoptosis in piglets. AB - Enterotoxigenic Escherichia coli (ETEC), as a universal pathogen, often causes diarrhea in animals and humans. However, whether ETEC infection induces apoptosis in host remains controversial. Herein, we use ETEC-infected piglet to investigate apoptosis in the jejunum. Apoptosis and the activation of capase-3 are observed in piglet jejunum after ETEC infection. Additionally, ETEC infection induces the activation of caspase-8 pathway, but inhibits the activation of caspase-9 pathway in piglet jejunum. These findings demonstrate that ETEC infection may inhibit the intrinsic pathway and activate the extrinsic pathway of apoptosis in piglets. PMID- 30243554 TI - Reverse vaccinology and subtractive genomics-based putative vaccine targets identification for Burkholderia pseudomallei Bp1651. AB - The Burkholderia pseudomallei is a unique bio-threat and causative agent of melioidosis. The B. pseudomallei Bp1651 strain has been isolated from a chronic cystic fibrosis patient. The genome-level DNA sequences information of this strain has recently been published. Unfortunately, there is no commercial vaccine available till date to combat B. pseudomallei infection. The genome-wide prioritization approaches are widely used for the identification of potential therapeutic candidates against pathogens. In the present study, we utilized the recently available annotated genomic information of B. pseudomallei Bp1651 through subtractive genomics and reverse-vaccinology strategies to identify its potential vaccine targets. The analyses identified more than 60 pathogen specific, human host non-homologous proteins that may prioritize in future studies to investigate therapeutic targets for B. pseudomallei Bp1651. The potential B and T-cells antigenic determinant peptides from these pathogen specific proteins were cataloged using antigenicity and epitope prediction tools. The analyses unveiled a promising antigenic peptide "FQWEFSLSV" from protein export membrane protein (SecF) of Bp1651 strain, which was predicted to interact with multiple class I and class II MHC alleles with IC50 value < 100 nM. The molecular docking analysis verified favorable molecular interaction of this lead antigenic peptide with the ligand-binding pocket residues of HLA A*02:06 human host immune cell surface receptor. This peptide is predicted to be a suitable epitope capable to elicit the cell-mediated immune response against the B. pseudomallei pathogen. The putative epitopes and proteins identified in this study may be promising vaccine targets against Bp1651 as well as other pathogenic strains of B. pseudomallei. PMID- 30243555 TI - Comparison of piezosurgery, percutaneous osteotomy, and endonasal continuous osteotomy techniques with a caprine skull model. AB - BACKGROUND: Osteotomy is a crucial step in rhinoplasty, which can have a significant impact on the outcome. In addition to previous percutaneous (external perforating) and endonasal (internal) approaches, piezosurgery has been used in rhinoplasty practice since 2007. This experimental model was planned to compare the three osteotomy techniques. MATERIALS AND METHODS: This study was performed on a caprine skull osteotomy model. Three groups were created from 12 animals, namely, endonasal continuous, external perforating, and piezosurgery groups. All the groups were evaluated for bone gaps, comminuted fractures, and nasal mucosa damage. RESULTS: There were no comminuted fractures and mucosal defects in any of the samples in the piezo osteotomy group. The average amount of bone gap at the osteotomy site and the nasal mucosa damage was lower in the piezo group than in the other groups. The time required for the osteotomy was shorter in the endonasal group, similar to that in the external and piezo groups. CONCLUSION: New techniques are constantly being developed to achieve better results in rhinoplasty. As a natural consequence to technological developments, new devices are being introduced to rhinoplasty practice. Piezo is one such device. We have found that piezo osteotomy has resulted in lower amounts of nasal mucosal damage and comminuted fractures. We believe that piezo can safely be used in rhinoplasty practice until newer and more reliable technologies are being developed. PMID- 30243556 TI - Cartilage-sparing surgery for melanoma of the external ear. AB - BACKGROUND: The excision of melanoma of the external ear poses a challenge to surgeons, who must achieve adequate oncological control while minimising impact on form and function. Cartilage-preserving surgery is an attractive option, as it leaves behind a scaffold for immediate reconstruction with a variety of techniques including full-thickness skin grafts (FTSGs) and local flaps. This manuscript will review the literature comparing cartilage-sparing surgery with composite excision of the skin and the cartilage for the treatment of auricular melanoma. We report the results of a 17 year experience of using both techniques, together with sentinel node biopsy at our centre. METHODS: A structured review of MEDLINE and EMBASE was conducted to evaluate all studies reporting local recurrence or survival rates for melanoma of the external ear treated with cartilage-preserving surgery. A retrospective review of all patients undergoing wide local excision (WLE) and sentinel lymph node biopsy (SLNB) for auricular melanoma at our centre between 2000 and 2017 was performed. RESULTS: Of 40 patients identified, 29 underwent cartilage-preserving surgery with no local recurrences or evidence of perichondral involvement. There was one local recurrence out of 11 patients who had their cartilage excised. There were no significant differences in recurrence rates or melanoma-specific survival rates when comparing cartilage-preserving and cartilage-sparing surgery. Our results are supported by the literature review, which suggests that cartilage-sparing surgery is gaining acceptance as a safe practice. PMID- 30243557 TI - Reducing Gender Disparity in Oncologists in India: An Opportunity to Address Workforce Challenges. PMID- 30243558 TI - [The serotonin syndrome: An updated literature review]. AB - The serotonin syndrome is a potentially deadly complication resulting from drug adverse effect, drug-drug interaction or overdose involving one or more serotonergic molecules, e.g., antidepressants, psychostimulants and sometimes an "ignored" serotonergic compound. The serotonin syndrome typically consists of a clinical triad including cognitive/behavioral, neurovegetative and neuromuscular features. However, this syndrome is characterized by major clinical heterogeneity, making the diagnosis difficult in practice. Moreover, many practitioners are quite unaware of this syndrome. Available scores and classifications can help physicians in their diagnosis approach. Knowing the responsible molecules, their potential interactions and mechanisms of action can help preventing this complication allowing therapeutic education among patients. This updated article reviews the clinical presentation, prevention, management, and pathophysiology of the serotonin syndrome, and addresses the most recent advances in pharmacogenetics regarding this syndrome. PMID- 30243559 TI - Ipsilateral ureteroureterostomy: does function of the obstructed moiety matter? AB - PURPOSE: Upper pole nephrectomy has been the traditional surgical management of children with poorly functioning upper pole moieties in duplex renal collecting systems having ureteral ectopia and ureterocele. However, ablative surgery confers a risk of functional loss to the remnant moiety due to vasospasm or vascular injury. It was hypothesized that ipsilateral ureteroureterostomy (IUU) is a safe and feasible approach for the management of these patients and that residual function in the obstructed upper pole does not affect surgical outcomes. MATERIALS AND METHODS: All patients with duplex systems who underwent IUU between 2010 and 2016 were retrospectively reviewed. Patients were sorted into two groups based on pre-operative imaging: those having <10% upper pole moiety function (UPMF) and those having >= 10% UPMF. Outcomes assessed were postoperative complications (Clavien-Dindo classification), need for secondary surgery, and radiological outcomes. RESULTS: The study cohort comprised 53 children with ectopia or ureterocele affecting the upper pole in a duplex system, 21 with UPMF <10% (median function 0% and median age 1.49 years) and 32 with UPMF >= 10% (median function 15% and median age 0.91 years). Median follow-up was 27.4 months and 27.6 months. In both the groups, prenatal hydronephrosis was the most common presentation (57% and 56%, respectively; p = 0.18) followed by urinary tract infection. Mann-Whitney U test comparing the two groups revealed no significant differences in any of the outcomes assessed. No patient required secondary surgery. CONCLUSION: Ipsilateral ureteroureterostomy is a safe, definitive surgical intervention that preserves the renal architecture in children with duplex collecting systems regardless of upper pole function. PMID- 30243560 TI - B cells treated with CTB-p210 acquire a regulatory phenotype in vitro and reduce atherosclerosis in apolipoprotein E deficient mice. AB - OBJECTIVE: Intranasal immunization with a fusion protein of the ApoB100-derived peptide p210 and the cholera toxin B subunit (CTB-p210) has previously been shown to induce mucosal tolerance and reduce atherosclerosis development, but the exact mode of action remains to be elucidated. Recent studies have indicated an important role for B cells in mucosal tolerance, in particular by induction of regulatory B (Bregs) and T cells (Tregs). In this study, we aimed to investigate if transfer of B cells pulsed with CTB-p210 can protect against atherosclerosis. METHOD AND RESULTS: First, we studied if CTB-p210 can induce Bregs and Tregs in vitro. After pulsing B cells from Apobtm2Sgyldlr-/- or Apoe-/- mice with CTB-p210 for 1 h and co-culturing them with naive T cells for 48 h, we observed increased expression of membrane bound TGFbeta/latency-associated peptide (mTGFbeta/LAP) on B cells and an increased proportion of CD25hiFoxP3+ Tregs. Adoptive transfer of B cells pulsed with CTB-p210 into high-fat diet-fed Apoe-/- mice at 8, 10 and 12 weeks of age, reduced the plaque area in the aorta at 20 weeks of age as compared with control-treated (CTB-pOVA treated B cells or PBS) mice. Moreover, mice receiving p210-CTB treated B cells had increased levels of anti-p210 IgG antibodies. CONCLUSION: Our observations suggest that CTB-p210 pulsed B cells acquire a regulatory phenotype and induce Tregs in vitro. Adoptive transfer of CTB-p210, but not control-treated, B cells into Apoe-/- mice decreased atherosclerosis development. PMID- 30243561 TI - The Potential for Convergence between Synthetic Biology and Bioelectronics. AB - The fields of synthetic biology, which focuses on genetic and cellular substrates, and bioelectronics, which focuses on interfacing electronics with biology, may appear to have little in common on the surface. However, we contend that there is potential for convergence between the two fields based on shared and complementary design principles from each field. We provide examples where this convergence is beginning to take place in the engineered measurement and control of cell populations, individual cells, and membrane transport. We propose that as the convergence spreads, bioelectronics will enable real-time sensing and control of synthetic biological processes through integration with conventional electronics. The increased capabilities resulting from this convergence may broaden the scope and deepen the impact of both synthetic biology and bioelectronics. PMID- 30243564 TI - The genetic code is not an optimal code in a model taking into account both the biosynthetic relationships between amino acids and their physicochemical properties. AB - We have considered a model for the origin of the genetic code that takes into account the two factors that have determined its evolution: the biosynthetic relationships between amino acids and their physicochemical properties. The model evaluates the biosynthetic relationships between amino acids considering of constraints based on the biosynthetic families of amino acids. These biosynthetic constraints are able to define six subsets of codes - that we have analyzed - in which the evolution of the genetic code might have passed. At the same time, the physicochemical properties of amino acids have been described by means of two scales of polarity, considered solely or combined with the molecular volume of amino acids. Furthermore, we have considered three cost functions. The results maintain the hypothesis that the genetic code organization is not optimal even in these subsets containing a very limited number of elements. That is to say, the genetic code is not a local or absolute minimum. For instance, only a few amino acid exchanges would have rendered the genetic code more optimized or even they would have transformed it into a completely optimized code. This would imply that the evolution of the genetic code, not considering these possibilities, has evolved through different pathways from the one that was oriented to a high optimization. Moreover, the combination of polarity and the molecular volume of amino acids results to have been more significant than when the only polarity is considered, in conditioning the evolution of the genetic code contrary to that reported in the literature. However, this is not such to produce an organization of the genetic code optimized if referred to these two properties. Nevertheless, these two properties being crucial in defining the structure of proteins, they would have affected the origin of the genetic code by means of the selective pressure directed to improve the ancestral enzymatic catalysis. As a whole these observations contradict the predictions of the physicochemical theories of the origin of the genetic code because the non-optimization of the genetic code organization - even in subsets of codes with a very low element number - would deny the absolute importance of the physicochemical properties of amino acids in its structuration, which, on the contrary, is expected from these theories. Conversely, these same observations would be in perfect agreement with the coevolution theory of the origin of the genetic code because they would explain both the not fundamental role of the physicochemical properties in organizing the genetic code and the importance of these properties in the evolution of coded catalysis - that is to say, of the genetic code - both predicted by this last theory. PMID- 30243563 TI - Hierarchical Organization Endows the Kinase Domain with Regulatory Plasticity. AB - The functional diversity of kinases enables specificity in cellular signal transduction. Yet how more than 500 members of the human kinome specifically receive regulatory inputs and convey information to appropriate substrates-all while using the common signaling output of phosphorylation-remains enigmatic. Here, we perform statistical co-evolution analysis, mutational scanning, and quantitative live-cell assays to reveal a hierarchical organization of the kinase domain that facilitates the orthogonal evolution of regulatory inputs and substrate outputs while maintaining catalytic function. We find that three quasi independent "sectors"-groups of evolutionarily coupled residues-represent functional units in the kinase domain that encode for catalytic activity, substrate specificity, and regulation. Sector positions impact both disease and pharmacology: the catalytic sector is significantly enriched for somatic cancer mutations, and residues in the regulatory sector interact with allosteric kinase inhibitors. We propose that this functional architecture endows the kinase domain with inherent regulatory plasticity. PMID- 30243562 TI - Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to Cell Variability. AB - Transcription is an episodic process characterized by probabilistic bursts, but how the transcriptional noise from these bursts is modulated by cellular physiology remains unclear. Using simulations and single-molecule RNA counting, we examined how cellular processes influence cell-to-cell variability (noise). The results show that RNA noise is higher in the cytoplasm than the nucleus in ~85% of genes across diverse promoters, genomic loci, and cell types (human and mouse). Measurements show further amplification of RNA noise in the cytoplasm, fitting a model of biphasic mRNA conversion between translation- and degradation competent states. This multi-state translation-degradation of mRNA also causes substantial noise amplification in protein levels, ultimately accounting for ~74% of intrinsic protein variability in cell populations. Overall, the results demonstrate how noise from transcriptional bursts is intrinsically amplified by mRNA processing, leading to a large super-Poissonian variability in protein levels. PMID- 30243565 TI - Exploration of synthetic multifunctional amides as new therapeutic agents for Alzheimer's disease through enzyme inhibition, chemoinformatic properties, molecular docking and dynamic simulation insights. AB - A new series of multifunctional amides has been synthesized having moderate enzyme inhibitory potentials and mild cytotoxicity. 2-Furyl(1 piperazinyl)methanone (1) was coupled with 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (2) to form {4-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-1-piperazinyl}(2 furyl)methanone (3). Different elecrophiles were synthesized by the reaction of various un/substituted anilines (4a-o) with 2-bromoacetylbromide (5), 2-bromo-N (un/substituted-phenyl)acetamides (6a-o). Further, equimolar ratios of 3 and 6a-o were allowed to react in the presence of K2CO3 in acetonitrile to form desired multifunctional amides (7a-o). The structural confirmation of all the synthesized compounds was carried out by their EI-MS, IR, 1H NMR and 13C NMR spectral data. Enzyme inhibition activity was performed against acetyl and butyrylcholinestrase enzymes, whereby 7e showed very good activity having IC50 value of 5.54 +/- 0.03 and 9.15 +/- 0.01 MUM, respectively, relative to eserine, a reference standard. Hemolytic activity of the molecules was checked to asertain their cytotoxicity towards red blood cell membrance and it was observed that most of the compounds were not toxic up to certain range. Moreover, chemoinformatic protepties and docking simulation results also showed the significance of 7e as compared to other compounds. Based on in vitro and in silico analysis 7e could be used as a template for the development of new drugs against Alzheimer's disease. PMID- 30243566 TI - Thoracic Ultrasound as an Early Predictor of Pleurodesis Success in Malignant Pleural Effusion. AB - BACKGROUND: Malignant pleural effusion (MPE) is common and imposes a significant burden on patients and health-care providers. Most patients require definitive treatment, usually drainage and chemical pleurodesis, to relieve symptoms and prevent fluid recurrence. Thoracic ultrasound (TUS) can identify the presence of pleural adhesions in other clinical scenarios, and could therefore have a role in predicting long-term pleurodesis success or failure in MPE. METHODS: Patients undergoing chest tube drainage and talc slurry pleurodesis for symptomatic MPE were recruited to a prospective observational cohort pilot study assessing whether TUS findings pre-talc and post-talc instillation predicted treatment outcome. Participants underwent TUS examination immediately before, and 24 h after talc slurry administration to derive pleural adherence scores for the affected hemithorax. The recorded TUS scans were additionally scored by two independent assessors blinded to the patient's clinical status. The primary outcome was pleurodesis success at 1-month and 3-month follow-up. RESULTS: Eighteen participants were recruited to the pilot study. Participants who suffered pleurodesis failure had a lower pleural adherence score at 24 h post talc instillation than those who were successful (difference of 6.27; 95% CI, 3.94-8.59). TUS examination was acceptable to patients, while TUS scoring was highly consistent across all assessors (intraclass correlation coefficient, 0.762; 95% CI, 0.605-0.872). CONCLUSION: A TUS-derived pleural adherence score may facilitate early prediction of long-term outcomes following chemical pleurodesis, with implications for personalized care and decision making in MPE. Further research is needed to evaluate this novel finding. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT02625675; URL: www.clinicaltrials.gov. PMID- 30243567 TI - Detection of Ehrlichia sp. strain San Luis and Candidatus Rickettsia andeanae in Amblyomma parvum ticks. AB - Owing to the sanitary importance of the tick Amblyomma parvum, this study evaluated the infection by Ehrlichia, Anaplasma and Rickettsia species of questing A. parvum collected in northwestern Argentina. Our results showed that A. parvum ticks in this region are infected with the recently reported Ehrlichia sp. strain San Luis, closely related to Ehrlichia chaffeensis. A high prevalence of Candidatus Rickettsia andeanae was observed. Most of the infected ticks presented rickettsial loads lower than those previously reported for other spotted fever group rickettsiae. The presence of Ehrlichia sp. strain San Luis in A. parvum is a potential risk for public health as the principal hosts of this tick are domestic mammals in rural areas and humans are frequently bitten by this tick species. PMID- 30243568 TI - MicroRNA-218-5p inhibit the migration and proliferation of pterygium epithelial cells by targeting EGFR via PI3K/Akt/mTOR signaling pathway. AB - Pterygium is a common ocular surface disease which could result in various ocular surface symptoms. MicroRNAs play an important role in the development of various eye diseases. However, the role of microRNAs in the pathogenesis of pterygium is rarely reported. Our research aims to analyze the relationship between miR-218-5p and Epidermal Growth Factor Receptor (EGFR) in human pterygium tissues and cultured Human Pterygium Epithelial Cells (hPECs). Furthermore, the EGFR/PI3K/Akt/mTOR signaling pathway was firstly verified in pterygium. Pterygium tissues and normal bulbar conjunctival tissues were obtained from surgery, and primary hPECs were cultured in vitro. Cell transfection, Quantitative real-time PCR (qRT-PCR), Western blotting, Luciferase reporter assay and Scratch Wound Healing Assay were performed. Our data demonstrated that miR-218-5p was decreased and EGFR was increased in pterygium tissues than normal conjunctival tissues. In transfected hPECs, our results indicated that upregulated miR-218-5p significantly suppressed the expression level of EGFR via PI3K/Akt/mTOR pathway. In addition, the migration and proliferation of hPECs was promoted by miR-218-5p inhibitor and retarded by miR-218-5p mimics. And knockdown of EGFR significantly inhibit hPECs migration. Taken together, miR-218-5p downregulated the expression of EGFR via PI3K/Akt/mTOR pathway in pterygium tissues and hPECs and inhibited hPECs migration and proliferation. The microRNA-218-5p-EGFR-PI3K/Akt/mTOR axis should be further investigated for the potential treatment of pterygium. PMID- 30243569 TI - Phomopsidione nanoparticles coated contact lenses reduce microbial keratitis causing pathogens. AB - Microbial keratitis is the infection caused by pathogenic microorganisms that commonly occurs among the contact lens users. Various antimicrobial compounds were coated on contact lenses to kill keratitis causing microorganisms, however these compounds caused several adverse side effects. Hence, the aim of this study is to develop a silicone hydrogel contact lens coated with phomopsidione nanoparticle that inhibit keratitis causing clinical isolates. Phomopsidione nanoparticles were synthesized using polyvinyl alcohol as encapsulant. The nanoparticles showed an average size of 77.45 nm, with neutral surface charge. Two drug release patterns were observed in the drug release profile, which are the initial slow release phase with extended drug release (release rate 46.65 MUg/h), and the burst release phase observed on Day 2 (release rate 2224.49 MUg/h). This well-regulated drug delivery system enables the control of drug release to meet the therapeutic requirements. On agar diffusion assay, 3 out of 5 test microorganisms were inhibited by phomopsidione nanoparticle coated contact lenses, including two Gram negative bacteria. Besides, all test microorganisms showed at least 99% of growth reduction, with the treatment of the contact lens model. The drug loaded onto the nanoparticles is sufficient to prevent the bacterial growth. In conclusion, this study provides an effective alternative to combat keratitis-causing microorganisms among contact wearers. PMID- 30243570 TI - Prognostic Nomogram for Overall Survival in Extranodal Natural Killer/T-Cell Lymphoma Patients. AB - BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare lymphoid malignancy with diverse clinical features and prognoses. The aims of this study were to explore the pretreatment prognostic factors of ENKTL and develop a new individual prognostic model. PATIENTS AND METHODS: We retrospectively enrolled 81 ENKTL patients with newly diagnosed disease between June 2006 and August 2017 at the Affiliated Cancer Hospital of Guangxi Medical University. Survival analysis was used to assess the prognostic value of various factors. A nomogram was developed to predict overall survival (OS) based on the Cox proportional hazards model. RESULTS: The median survival time of the patients was 48 months, and the 5 year OS rate was 47.5%. Cox regression analysis showed that the prognostic factors of OS for ENKTL patients included Eastern Cooperative Oncology Group performance status, Ann Arbor stage, pretreatment albumin-to-globulin ratio, and platelet count. A prognostic nomogram was developed to predict the OS rate for ENKTL patients based on these factors. The calibration curve showed that the nomogram was able to predict OS accurately. The concordance index of the nomogram for OS prediction was 0.807. CONCLUSION: Our proposed nomogram based on Eastern Cooperative Oncology Group performance status, Ann Arbor stage, albumin-to globulin ratio, and platelet count provides an individualized risk estimate of OS in patients with ENKTL. PMID- 30243571 TI - The Adverse Consequences of Initial Watchful Waiting for Patients With Follicular Lymphoma. AB - BACKGROUND: Patients with low tumor burden follicular lymphoma (FL) are commonly managed with watchful waiting (WW). The incidence of organ dysfunction and/or transformation at disease progression, and subsequent impact on outcomes is poorly understood. PATIENTS AND METHODS: Patients managed with WW during 1994 to 2011 were identified through the Alberta Lymphoma Database. Individuals receiving immediate rituximab (R)-chemotherapy were identified as a comparator group to those on WW who received R-chemotherapy at progression. Endpoints included transformation, organ dysfunction, time to progression, time to next treatment, progression-free survival (PFS) after chemotherapy, and overall survival (OS). RESULTS: We identified 238 patients managed with WW (28.9% of registry patients) during this 17-year period. The median follow up was 8.2 years. At a median of 29.9 months, 58 (24.4%) of these patients developed organ dysfunction and/or transformation. Of 169 (71%) patients who required therapy, 10-year OS was inferior for those with transformation (hazard ratio, 2.88; P = .002) and organ dysfunction (hazard ratio, 2.10; P = .028). PFS after R-chemotherapy and OS in patients without organ dysfunction and/or transformation was not affected by the initial WW period, compared with immediate R-chemotherapy. WW resulted in increased high risk FL International Prognostic Index scores at initiation of R chemotherapy (45% vs. 20%), and more frequent transformation at progression (5 year risk, 17.8% vs. 3.5%; P < .001). Baseline characteristics did not predict organ dysfunction. CONCLUSION: Patients with FL accepting initial WW should be aware of the 1 in 4 risk of organ dysfunction and/or transformation, and subsequent inferior OS. Physicians should consider surveillance for progression to consider early therapy. PMID- 30243572 TI - p53-loss mitigates early volume deficits in the brains of irradiated young mice. AB - PURPOSE: Paediatric cranial radiation therapy results in lasting changes in brain structure. Though different facets of radiation response have been characterized, the relative contributions of each to altered development is unclear. We sought to determine the role of radiation-induced programmed cell death, as mediated by the Trp53 (p53) gene, on neuroanatomical development METHODS: Mice having a conditional knockout of p53 (p53KO) or wildtype p53 (WT) were irradiated with a whole-brain dose of 7-Gy (IR, n=30) or 0-Gy (sham, n=28) at 16 days of age. In vivo magnetic resonance imaging (MRI) was performed before irradiation and at 4 time points after irradiation, until 3-months post treatment, followed by ex vivo MRI and immunohistochemistry. The role of p53 on development was assessed at 6 weeks of age in another group of untreated mice (n=37). RESULTS: Neuroanatomical development in p53KO mice was normal. After cranial irradiation, alterations in neuroanatomy were detectable in WT mice and emerged through two stages: an early volume loss within 1 week, and decreased growth through development. In many structures, the early volume loss was partially mitigated by p53KO. However, p53KO had a neutral or negative impact on growth, so that p53KO did not widely improve volume at endpoint. Partial volume recovery was observed in the dentate gyrus and olfactory bulbs of p53KO-IR mice, with corresponding increases in neurogenesis compared to WT-IR mice. CONCLUSIONS: While p53 is known to play an important role in mediating radiation-induced apoptosis, this is the first study to look at the cumulative effect of p53KO through development after cranial irradiation across the entire brain. It is clear that apoptosis plays an important role in volume loss early after radiotherapy. While this early preservation alone was insufficient to normalize brain development on the whole, regions reliant on neurogenesis exhibited a significant benefit. PMID- 30243573 TI - Tumor trailing for liver SBRT on the MR-Linac. AB - BACKGROUND: and purpose: Tumor trailing is a treatment delivery technique which continuously adjusts the beam aperture according to the last available time averaged position of the target. This study investigates whether tumor trailing on the MR-Linac can improve target coverage in liver SBRT in the case of baseline motion. MATERIAL AND METHODS: For 17 oligometastatic liver patients, mid-position SBRT treatment plans (3*20 Gy, 11-beam IMRT) were created for the ElektaUnity MR Linac. Treatment was simulated using an in-house developed delivery emulator. Respiratory motion was modelled as the superposition of periodicmotion (patient specific amplitude, 4 sec period), and the following baseline motion scenarios: a continuous linear drift (0.5 mm/min), a single shift halfway through treatment (10 mm), a periodic drift (amplitude: 5 mm, period: 5 min), or an MRI-measured baseline drifts. Delivered dose was calculated under full consideration of the patient and machine motion interplay. In addition, trailing was experimentally validated on the MR-Linac using a programmable motion phantom. RESULTS: The average simulated delivery and beam-on times were 15.9 and 8.7 min respectively. An imaging frequency of >= 1 Hz was deemed necessary for trailing. Trailing increased the median GTV D98% dose by 1.9 Gy (linear drift), 1.2 Gy (single shift), 0.7 Gy (periodic drift), and 0.5- 1.5 Gy (measured drifts) per fraction compared to a conventional delivery. In the phantom experiments, the 3%/2 mm local gamma pass rate nearly doubled to 98% when using trailing. CONCLUSION: Tumor trailing on the MR-Linac restores target dose in liver SBRT in the case of baseline motion for the presented patient cohort. PMID- 30243574 TI - The Human Cell Atlas bone marrow single-cell interactive web portal. AB - The Human Cell Atlas (HCA) is expected to facilitate the creation of reference cell profiles, marker genes, and gene regulatory networks that will provide a deeper understanding of healthy and disease cell types from clinical biospecimens. The hematopoietic system includes dozens of distinct, transcriptionally coherent cell types, including intermediate transitional populations that have not been previously described at a molecular level. Using the first data release from the HCA bone marrow tissue project, we resolved common, rare, and potentially transitional cell populations from over 100,000 hematopoietic cells spanning 35 transcriptionally coherent groups across eight healthy donors using emerging new computational approaches. These data highlight novel mixed-lineage progenitor populations and putative trajectories governing granulocytic, monocytic, lymphoid, erythroid, megakaryocytic, and eosinophil specification. Our analyses suggest significant variation in cell-type composition and gene expression among donors, including biological processes affected by donor age. To enable broad exploration of these findings, we provide an interactive website to probe intra-cell and extra-cell population differences within and between donors and reference markers for cellular classification and cellular trajectories through associated progenitor states. PMID- 30243575 TI - Utilization of prescription drug monitoring programs for prescribing and dispensing decisions: Results from a multi-site qualitative study. AB - BACKGROUND: Prescription drug monitoring programs (PDMPs) track the dispensing of prescription-controlled substances with the goal of mitigating misuse and diversion. Authorized users query the PDMP for controlled substance prescription histories at the point of care. Despite widespread implementation of PDMPs, there is much not known about how PDMPs influence prescribing and dispensing decisions. OBJECTIVES: The objective of this study was to investigate how primary care providers (PCPs) and pharmacists utilize PDMPs when making prescribing and dispensing decisions. METHODS: Data from in-depth, qualitative interviews with PCPs (n = 48) and community pharmacists (n = 60) across four states- Arkansas, Idaho, Kentucky, and Washington were analyzed for themes around PDMP use. RESULTS: Both PCPs and pharmacists reported that PDMPs are key tools for aiding prescribing and dispensing decisions. PCPs reported variable use of PDMPs with most querying the PDMP when there are "red flags" and fewer reporting having clinic policies that direct PDMP use. Primary care providers in Kentucky reported more consistent and routine use of the PDMP as a result of a state law that mandates query prior to the initial prescribing of Schedule II controlled substances. Community pharmacists practicing in chain pharmacies reported formal policies requiring PDMP query prior to dispensing opioids, while utilization of PDMPs by pharmacists practicing in independently-owned pharmacies was more variable. Pharmacists and PCPs reported barriers to PDMP use, such as having to "log in on a separate machine" and perceived that PDMP utility could be improved by integrating it within pharmacy dispensing systems and electronic health records. CONCLUSIONS: Pharmacists and PCPs reported the importance of PDMP information to aid their prescribing and dispensing decisions. Efforts to enhance state PDMP programs should consider processes that seamlessly integrate all available controlled substance prescription history for a given patient at the point of care so that PDMP utility for prescribing and dispensing decisions is maximized. PMID- 30243576 TI - Dopamine and opioid systems adaptation in alcoholism revisited: Convergent evidence from positron emission tomography and postmortem studies. AB - A major hypothesis in the addiction field suggests deficits in dopamine signaling during abstinence as a driving mechanism for the relapsing course of the disorder. Paradoxically, blockade of mu-opioid receptors (MORs) intended to suppress dopamine release and alcohol reward is a widely used treatment for preventing relapse in alcohol use disorder (AUD). To elucidate this apparent discrepancy, we systematically survey the literature on experimental studies in AUD subjects and animal models, which assessed striatal dopamine levels and D1, D2-like receptor, dopamine transporter and MOR via positron emission tomography (PET) and ex vivo receptor binding assays. The reported evidence indicates a changing dopaminergic signaling over time, which is associated with concomitant alterations in MOR, thus suggesting a highly dynamic regulation of the reward system during abstinence. Such a view can reconcile the various evidences from in vivo and postmortem studies, but makes developing an effective pharmacological intervention that specifically targets either dopamine receptors or the transporter system a daunting task. PMID- 30243577 TI - Intranasal oxytocin and OXTR genotype effects on resting state functional connectivity: A systematic review. AB - OBJECTIVE: Evaluate effects of intranasal oxytocin (IN-OT) and OXTR genotype on resting state functional connectivity in the human brain. METHODS: We searched research databases for peer-reviewed empirical studies. Of 71 unique citations, 18 articles (13 IN-OT, five OXTR) met full inclusion criteria. RESULTS: Two studies examined effects on large-scale networks; most examined acute effects on amygdala connectivity with other social and affective regions. OXTR studies identified three polymorphisms (rs2254298, rs2268498, rs53576) having allele- and sex-dependent effects on prefrontal functional connectivity, and additive effects of OXTR risk alleles on reward circuitry. Age, sex, early life stress, and psychopathology emerged as potential moderators of both IN-OT and OXTR effects. DISCUSSION: IN-OT appears to modulate resting state functional connectivity in a manner similar to its effects on task fMRI, consistent with hypothesized models of IN-OT. However, conclusions are limited by the narrow range of neuroanatomical seed regions, and methodological and experimental design heterogeneity. Future studies should take into account individual differences. Findings may provide insight into mechanisms through which IN-OT impacts human behavior. PMID- 30243578 TI - On the influence of wetting behaviour on relaxation of adsorbed liquids - A combined NMR, EPR and DNP study of aged rocks. AB - The influence of wettability modification in natural rocks has been studied by means of NMR relaxation dispersion of water and several organic liquids, employing 1H, 19F and 2H relaxometry. Berea, Bentheimer and chalk were aged with a bitumen solution, altering the samples from water-wet to mixed-wet. Relaxation measurements were supported by EPR and DNP experiments which are sensitive to bulk radicals and interfacial radicals, respectively. The effect of ageing on relaxation was found to be twofold: first, the change from water-wet to oil-wet affects the dynamics of molecules differently, in particular their immediate interaction with the surface, which is reflected in their relaxation times; second, the bitumen cover includes paramagnetic impurities which act as additional relaxation sinks to all molecules. EPR was used to confirm the amount of deposited material and the total radical content of the rock samples, whereas DNP revealed a small but significant signal enhancement due to the surface-bound bitumen containing stable radicals. The DNP enhancement is dominated by the Solid Effect despite the low viscosity of the interacting fluids. PMID- 30243579 TI - Non-destructive analysis of polymers and polymer-based materials by compact NMR. AB - Low-field nuclear magnetic resonance (NMR) based on permanent magnet technologies is currently experiencing a considerable growth of popularity in studying polymer materials. Various bulk properties can be probed with compact NMR tabletop instruments by placing the sample of interest inside the magnet. Contrary to this, compact NMR sensors with open geometries give access to depth-dependent properties of polymer samples and objects of different sizes and shapes truly non destructively by performing measurements in the inhomogeneous stray-field outside the magnet system. Some of the sensors are also portable being thus well suited for onsite measurements. The gain of both bulk and depth-dependent microscopic properties are important for establishing improved structure-property relationships needed for the rational design of new polymer formulations. Selected recent applications will be presented to illustrate this potential of compact NMR. PMID- 30243580 TI - Diffusion of water in industrial cement and concrete. AB - We propose a deuterium diffusion tracer approach to measure diffusion coefficient in the case of very short NMR relaxation times, too short for NMR pulsed field gradient sequences (T1 or T2 below 1 ms). We also treat the case of porous media containing metallic fibers (such as reinforced concrete) strongly disturbing the magnetic field, and the case of inhomogeneous porous media containing large non porous granulates. For the latter, we propose a hollow geometry maximizing the investigated volume and minimizing the experimental time. The method is a 3D diffusion technique in which samples are immersed in deuterium and the water content inside the sample is monitored as a function of time. Water diffusing outside the sample with very long relaxation times can be subtracted either from T2 relaxation time distribution or not polarizing these components using a short repeat delay. Using analytical formulations describing the concentration of a tracer diffusing out of a cylinder or a hollow cylinder, we can calculate the corresponding pore diffusion coefficient. PMID- 30243582 TI - KIR Genotyping Data of More Than 3 Million Individuals Are Available for Global Unrelated Stem Cell Donor Searches (Comment to: Weisdorf D, Cooley S, Wang T, et al. KIR donor selection: feasibility in identifying better donors. Biol Blood Marrow Transplant. 2018; doi: 10.1016/j.bbmt.2018.08.022.). PMID- 30243581 TI - Outcomes of Haploidentical Transplantation in Patients with Relapsed Multiple Myeloma: An EBMT/CIBMTR Report. AB - Allogeneic hematopoietic cell transplantation (allo-HCT) using siblings and matched donors has the potential for long-term disease control in a subset of high-risk patients with multiple myeloma (MM); however, the data on using haploidentical donors in this disease are limited. We conducted a retrospective analysis to examine the outcomes of patients with MM who underwent haploidentical allo-HCT within European Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research centers. A total of 96 patients underwent haploidentical allo-HCT between 2008 and 2016. With a median follow-up of 24.0 months (range, 13.2 to 24.9 months), 97% (95% confidence interval [CI], 93% to 100%) of patients had neutrophil engraftment by day 28, and 75% (95% CI, 66% to 84%) achieved platelet recovery by day 60. Two-year progression-free survival (PFS) was 17% (95% CI, 8% to 26%), and overall survival (OS) was 48% (95% CI, 36% to 59%). At 2 years, the cumulative risk of relapse/progression was 56% (95% CI, 45% to 67%), and 1-year nonrelapse mortality (NRM) was 21% (95% CI, 13% to 29%). The incidences of acute graft-versus-host disease (GVHD) grades II-IV by 100 days and chronic GVHD at 2 years were 39% (95% CI, 28% to 49%) and 46% (95% CI, 34% to 59%), respectively. On univariate analysis, use of post-transplantation cyclophosphamide (PT-Cy) (54% [95% CI, 41% to 68%] versus 25% [95% CI, 1% to 48%]; P =.009) and use of bone marrow as source of stem cells (72% [95% CI, 55% to 89%] versus 31% [95% CI, 17% to 46%]; P = .001) were associated with improved OS at 2 years. Disease status, patient sex, intensity of conditioning regimen, recipient/donor sex mismatch, and cytomegalovirus serostatus had no impact on OS, PFS, or NRM. Haploidentical transplantation is feasible for patients with multiply relapsed or high-risk MM, with an encouraging 2-year OS of 48% and an NRM of 21% at 1 year, supporting further investigation of haploidentical allo-HCT in suitable candidates with MM. PMID- 30243585 TI - The global burden of lower respiratory infections: making progress, but we need to do better. PMID- 30243586 TI - Old and new challenges related to global burden of diarrhoea. PMID- 30243583 TI - Estimates of the global, regional, and national morbidity, mortality, and aetiologies of diarrhoea in 195 countries: a systematic analysis for the Global Burden of Disease Study 2016. AB - BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 provides an up-to-date analysis of the burden of diarrhoea in 195 countries. This study assesses cases, deaths, and aetiologies in 1990-2016 and assesses how the burden of diarrhoea has changed in people of all ages. METHODS: We modelled diarrhoea mortality with a Bayesian hierarchical modelling platform that evaluates a wide range of covariates and model types on the basis of vital registration and verbal autopsy data. We modelled diarrhoea incidence with a compartmental meta-regression tool that enforces an association between incidence and prevalence, and relies on scientific literature, population representative surveys, and health-care data. Diarrhoea deaths and episodes were attributed to 13 pathogens by use of a counterfactual population attributable fraction approach. Diarrhoea risk factors are also based on counterfactual estimates of risk exposure and the association between the risk and diarrhoea. Each modelled estimate accounted for uncertainty. FINDINGS: In 2016, diarrhoea was the eighth leading cause of death among all ages (1 655 944 deaths, 95% uncertainty interval [UI] 1 244 073-2 366 552) and the fifth leading cause of death among children younger than 5 years (446 000 deaths, 390 894-504 613). Rotavirus was the leading aetiology for diarrhoea mortality among children younger than 5 years (128 515 deaths, 105 138-155 133) and among all ages (228 047 deaths, 183 526-292 737). Childhood wasting (low weight-for-height score), unsafe water, and unsafe sanitation were the leading risk factors for diarrhoea, responsible for 80.4% (95% UI 68.2-85.0), 72.1% (34.0-91.4), and 56.4% (49.3-62.7) of diarrhoea deaths in children younger than 5 years, respectively. Prevention of wasting in 1762 children (95% UI 1521-2170) could avert one death from diarrhoea. INTERPRETATION: Substantial progress has been made globally in reducing the burden of diarrhoeal diseases, driven by decreases in several primary risk factors. However, this reduction has not been equal across locations, and burden among adults older than 70 years requires attention. FUNDING: Bill & Melinda Gates Foundation. PMID- 30243587 TI - Current use of daptomycin and systematic therapeutic drug monitoring: clinical experience in a tertiary care institution. AB - Therapeutic drug monitoring (TDM) could optimize daptomycin use. However, no validated serum level targets have been established. We aimed to evaluate the adequacy of daptomycin doses in a real-life study, assess interpatient variability in serum levels, identify the predictive factors for non-adequate serum levels and assess their clinical impact. This is a prospective study at a tertiary center including hospitalized patients receiving daptomycin. Blood samples (Cmin and Cmax) were drawn at least 3-days post-treatment initiation. Serum daptomycin concentrations were determined with high-performance liquid chromatography. Outcome was classified as: a) favorable -if clinical improvement or cure occurred with no adverse events; b) poor -in case of no clinical response or recurrence or related mortality or if adverse events were detected. Sixty three patients [63.5% male, median age: 63.0 years] were included. Most common indications for daptomycin were bacteremia (n=29), complicated skin and soft tissue infections (n=19) and endovascular infections (n=10). Initial dosage was adequate in 43 patients (68.3%), low in 14 (22.2%) and high in 6 (9.5%). A large inter-individual variability of serum levels was observed, with median trough levels of 10.6 mg/L (range 1.28-44.68 mg/L) and median peak levels of 44 mg/L (range 3.04-93.69 mg/L). Multivariate analysis showed that values of Cmin<3.18 mg/L (OR=6.465, 95% CI=1.032-40.087, p=0.046) were independently related to poor outcome. High variability in daptomycin use and serum levels was detected. Specific serum targets were identified as risk factors for poor outcome. TDM might be useful to optimize daptomycin doses and to avoid therapeutic failure. PMID- 30243588 TI - Growth inhibition of human ovarian carcinoma by a novel AvidinOX-anchored biotinylated camptothecin derivative. AB - Oxidized form of avidin, named AvidinOX, provides stable fixation of biotinylated molecules in tissues thus representing a breakthrough in topical treatment of cancer. AvidinOX proved to be a stable receptor for radiolabeled biotin, biotinylated antibodies and cells. In order to expand applicability of the AvidinOX-based delivery platform, in the present study we investigated the possibility to hold biotinylated chemotherapeutics in AvidinOX-treated sites. A novel biotinylated gimatecan-derived camptothecin, coded ST8161AA1, was injected at suboptimal doses into human tumors xenografted in mice alone or pre-complexed to AvidinOX. Significantly higher growth inhibition was observed when the drug was anchored to AvidinOX suggesting the potential utility of this delivery modality for the local treatment of inoperable tumors. PMID- 30243589 TI - Methyl-containing pharmaceuticals: Methylation in drug design. AB - The importance of methyl groups in modulating biological activity, selectivity, solubility, metabolism and pharmacokinetic/pharmacodynamic properties of biologically active molecules is highlighted. The information compiled from selected beneficial cases, focuses mostly on marketed drugs and clinical candidates, and indicates that the methylation strategy has been successful in drug design. PMID- 30243584 TI - Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. AB - BACKGROUND: Lower respiratory infections are a leading cause of morbidity and mortality around the world. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, provides an up-to-date analysis of the burden of lower respiratory infections in 195 countries. This study assesses cases, deaths, and aetiologies spanning the past 26 years and shows how the burden of lower respiratory infection has changed in people of all ages. METHODS: We used three separate modelling strategies for lower respiratory infections in GBD 2016: a Bayesian hierarchical ensemble modelling platform (Cause of Death Ensemble model), which uses vital registration, verbal autopsy data, and surveillance system data to predict mortality due to lower respiratory infections; a compartmental meta-regression tool (DisMod-MR), which uses scientific literature, population representative surveys, and health-care data to predict incidence, prevalence, and mortality; and modelling of counterfactual estimates of the population attributable fraction of lower respiratory infection episodes due to Streptococcus pneumoniae, Haemophilus influenzae type b, influenza, and respiratory syncytial virus. We calculated each modelled estimate for each age, sex, year, and location. We modelled the exposure level in a population for a given risk factor using DisMod-MR and a spatio-temporal Gaussian process regression, and assessed the effectiveness of targeted interventions for each risk factor in children younger than 5 years. We also did a decomposition analysis of the change in LRI deaths from 2000-16 using the risk factors associated with LRI in GBD 2016. FINDINGS: In 2016, lower respiratory infections caused 652 572 deaths (95% uncertainty interval [UI] 586 475-720 612) in children younger than 5 years (under-5s), 1 080 958 deaths (943 749-1 170 638) in adults older than 70 years, and 2 377 697 deaths (2 145 584-2 512 809) in people of all ages, worldwide. Streptococcus pneumoniae was the leading cause of lower respiratory infection morbidity and mortality globally, contributing to more deaths than all other aetiologies combined in 2016 (1 189 937 deaths, 95% UI 690 445-1 770 660). Childhood wasting remains the leading risk factor for lower respiratory infection mortality among children younger than 5 years, responsible for 61.4% of lower respiratory infection deaths in 2016 (95% UI 45.7-69.6). Interventions to improve wasting, household air pollution, ambient particulate matter pollution, and expanded antibiotic use could avert one under-5 death due to lower respiratory infection for every 4000 children treated in the countries with the highest lower respiratory infection burden. INTERPRETATION: Our findings show substantial progress in the reduction of lower respiratory infection burden, but this progress has not been equal across locations, has been driven by decreases in several primary risk factors, and might require more effort among elderly adults. By highlighting regions and populations with the highest burden, and the risk factors that could have the greatest effect, funders, policy makers, and programme implementers can more effectively reduce lower respiratory infections among the world's most susceptible populations. FUNDING: Bill & Melinda Gates Foundation. PMID- 30243590 TI - 1,2,3-Triazole fused with pyridine/pyrimidine as new template for antimicrobial agents: Regioselective synthesis and identification of potent N-heteroarenes. AB - The 1,2,3-triazole ring fused with pyridine/pyrimidine was explored as new template for the identification of potential antimicrobial agents. The regioselective synthesis of these pre-designed N-heteroarenes was achieved via exploring the application of Buchwald's strategy (i.e. C-N bond formation/reduction/diazotization/cyclization sequence) to the N-heteroarene system. Two of them showed promising antibacterial (comparable to streptomycin) and several showed potent antifungal (comparable to mancozeb) activities. PMID- 30243591 TI - Synthesis of novel mono and bis nitric oxide donors with high cytocompatibility and release activity. AB - Four compounds bearing amidoxime functions were synthetized: (1) 2a,b bearing an aromatic amidoxime function, (2) 2c bearing an aliphatic amidoxime function, and (3) 2d bearing aromatic and aliphatic amidoximes functions. The ability of these compounds to release NO was evaluated in vitro using the oxidative metabolism of cytochrome P450 from rat liver microsomes. Results obtained demonstrate that all amidoximes were able to release NO with a highest amount of NO produced by the 2a aromatic amidoxime. Moreover, all amidoximes exhibit cytocompatibility with human aorta smooth muscle cells. Using intracellular S-nitrosothiol formation as a marker of NO bioavailability, compounds 2a-c were demonstrated to deliver a higher amount of NO in the intracellular environment than the reference. Considering that the concentration of the bis-amidoxime 2d was two times lower that than of 2a and 2b, we can assume that 2d is the most potent molecule among the tested compounds for NO release. PMID- 30243592 TI - Optimization of the efflux ratio and permeability of covalent irreversible BTK inhibitors. AB - Bruton's tyrosine kinase (Btk) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage (e.g. B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible Btk inhibitors targeting Cys481 within the ATP-binding pocket have been applied in the treatment of B-cell malignancies. Starting from a fragment, we discovered a novel series of potent covalent irreversible Btk inhibitors that bear N-linked groups occupying the solvent accessible pocket (SAP) of the active site of the Btk kinase domain. The hit molecules, however, displayed high P-gp mediated efflux ratio (ER) and poor A-B permeability in Caco-2 assay. By decreasing tPSA, installing steric hindrance and adjusting clogP, one top molecule 9 was discovered, which showed a 99% decrease in efflux ratio and a 90-fold increase in A-B permeability compared to hit molecule 1. PMID- 30243593 TI - Easy Access to and Applications of the Sequences of All Protein-Coding Genes of All Sequenced Mouse Strains. AB - An easily accessible and searchable overview of all protein sequences in the 36 genome-sequenced mouse strains, compared to those in the reference strain C57BL/6J, is now available, as well as an overview of the aberrant proteins in this reference strain. We provide an insight into the advantages of using these databases. PMID- 30243594 TI - Response to the letter to the editor: Urine osteopontin: A biomarker for diagnosis of nephrolithiasis? PMID- 30243595 TI - Egg desiccation leads to dehydration and enhanced innate immunity in python embryos. AB - The immune system is essential for survival and its performance can vary depending on the physiological state of the organism. Much of the current research into immune function dynamics has examined newborn to adult life stages, despite previous studies documenting physiological responses in embryos to environmental stimuli. While energy balance has been the predominant focus as the driver of changes in immune function, recent research has found a positive relationship between dehydration and innate immune performance in adult reptiles. We expanded the understanding of this relationship by examining trans generational immune effects of female dehydration as well as the effects of egg desiccation on embryonic hydration state and innate immunity using Children's pythons, Antaresia childreni. We used a 2 * 2 experiment with hydrated or dehydrated mothers and eggs either incubated under continuous optimal conditions or experiencing desiccating conditions for 24 h. Our results demonstrate that, similar to adults, embryos enhance some metrics of innate immunity when they are dehydrated. PMID- 30243596 TI - Cerebral venous thrombosis: A case series and a neuroimaging review of the literature. AB - Cerebral venous thrombosis (CVT) is a rare condition, difficult to diagnose because of its non specific clinical symptoms. In some cases CVT can mimic other conditions as subarachnoid hemorrhage, ischemia or tumor and for these reasons diagnosis is delayed or missed. CT, DSA and MRI findings help to obtain an early diagnosis and to distinguish it from other diseases. Our cases involved four patients with no signs or symptoms suspected for CVT and without risk factors associated to this disease; furthermore some early imaging findings observed in these patients could mimic other diseases. The aim of presenting these cases is to underline the importance of some findings at imaging techniques in obtaining an early diagnosis of CVT; in particular we describe the usefulness of MRI with gradient echo sequences (GRE) in detecting the venous thrombus, suggesting that GRE sequences should be included in the MRI protocol when a CVT is suspected. We also underline the role of radiologists in helping neurologists to make an early diagnosis of CVT or when in doubt to encourage further investigations in order to begin the anticoagulation therapy as soon as possible avoiding the onset of complications as permanent parenchymal damage, cerebral hemorrhage and venous infarction. PMID- 30243597 TI - The safety of post-operative elevation of mean arterial blood pressure following brain tumor resection. AB - We demonstrate the safety of artificially elevating the mean arterial blood pressure (MAP) greater than 85 mmHg or 10% above the mean MAP in patients with underlying hypertension during the acute post-operative period in patients undergoing surgery for resection of brain tumors. A retrospective review was undertaken of all patients undergoing surgery by the senior author between 2013 and 2018. Patients who underwent MAP therapy were analyzed for hemorrhagic and cardiac complications. A total of 1162 of 2270 post-operative brain tumor patients underwent MAP therapy after surgery for a minimum of 24 h post operatively. Of these, 7/1162 (0.6%) patients experienced intra-cavitary hemorrhage within 5 days of surgery. Two of 7 (29%) patients were diagnosed with venous infarction. One of 7 (14%) patients experienced post-operative, intra cavitary hemorrhage prior to the initiation of MAP therapy. The remaining 4/1162 (0.35%) patients experienced intra-cavitary hemorrhage post-operatively without clear etiology. In assessing cardiac outcomes, 2/1162 patients (0.2%) experienced elevated troponin levels. No patient demonstrated significant cardiac related morbidity or mortality within this cohort. Post-operative MAP therapy with a goal of maintaining MAP greater than 85 mmHg or 10% above the mean MAP in patients with underlying hypertension appears to be a safe intervention in brain tumor patients for at least 24 h in the post-operative period. PMID- 30243598 TI - Vertebral fracture after removing pedicle screws used for posterior lumbar interbody fusion: A case report. AB - It is uncommon to remove pedicle screws after posterolateral lumbar interbody fusion (PLIF), and there are a few case reports of vertebral fracture involving holes remaining after screw removal. We report a case of the vertebral fracture after removing pedicle screws instrumented for PLIF. A 66-year-old woman with osteopenia, who underwent PLIF at L4-S1 10 years earlier, underwent PLIF at L3-L4 to correct adjacent-segment degeneration. We removed L5 and S1 pedicle screws, and inserted L3 pedicle screws. After surgery, she presented with severe progressive low back pain. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed an L5 body fracture involving the pedicle screw holes. Revision surgery, including posterolateral fusion from L3 to S2 alar iliac and L5 vertebroplasty, was performed. One year after the revision surgery, the patient remained pain-free and returned to normal activity. Possible reasons for instrumented vertebral body fracture after pedicle screw removal are decrease of vertebral mass, increased mechanical stress caused by PLIF at the adjacent segment, stress-shielding-related osteopenia, and spinal imbalance. Vertebral body fractures associated with spinal implant removal are rare, but possible, especially in elderly patients with osteopenia and osteoporosis. PMID- 30243599 TI - Fatty infiltration of the cervical multifidus musculature and their clinical correlates in spondylotic myelopathy. AB - Cervical spondylotic myelopathy (CSM) is among the most common spinal cord disorders of the elderly. Muscle fat infiltration (MFI), a potential pathological sign of muscle adiposity, may contribute to or be associated with pain/disability/impairments in patients with CSM. We examined the relationship between MFI and CSM's clinical manifestations by enrolling nine CSM patients and five aged-matched controls to undergo MRI imaging of the cervical spine with MFI. A blinded investigator calculated MFI for each of the bilateral multifidii muscles from C3 to C7 on the MRI images. Nurick scores, Neck Disability Index, and modified Japanese Orthopedic Association scores were collected for all patients. CSM patients and controls were equivalent with respect to age, height, weight, gender, race, smoking status, and employment status. MFI was higher in patients with CSM than in controls (31.7% v. 24.6%, respectively, p = 0.0178). Higher MFI was associated with increased disability on the Nurick scale (p = 0.0371). MJOA scores correlated linearly with MFI (R = 0.542, p = 0.0453), but not NDI (p = 0.3125). Increased MFI of the multifidus muscles is associated with cervical myelopathy and a clinically significant decline in sensorimotor function as measured by mJOA and Nurick scores. Spinal injury in CSM may lead to secondary muscle loss and muscle fat infiltration. PMID- 30243600 TI - The curcuminoid, EF-24, reduces cisplatin-mediated reactive oxygen species in zebrafish inner ear auditory and vestibular tissues. AB - Cisplatin is a widely used chemotherapy drug that can damage auditory and vestibular tissue and cause hearing and balance loss through the intracellular release of reactive oxygen species (ROS). Curcumin has anticancer efficacy and can also counteract cisplatin's damaging effect against sensory tissue by scavenging intracellular ROS, but curcumin's applicability is limited due to its low bioavailability. EF-24 is a synthetic curcumin analog that is more bioavailable than curcumin and can target cancer, but its effects against cisplatin-mediated ROS in auditory and vestibular tissue is currently unknown. In this study, we employed a novel zebrafish inner ear tissue culture system to determine if EF-24 counteracted cisplatin-mediated ROS release in two sensory endorgans, the saccule and the utricle. The zebrafish saccule is associated with auditory function and the utricle with vestibular function. Trimmed endorgans were placed in tissue culture media with a fluorescent reactive oxygen species indicator dye, and intracellular ROS release was measured using a spectrophotometer. We found that cisplatin treatment significantly increased ROS compared to controls, but that EF-24 treatment did not alter or even decreased ROS. Importantly, when equimolar cisplatin and EF-24 treatments are combined, ROS did not increase compared to controls. This suggests that EF-24 may be able to prevent intracellular ROS caused by cisplatin treatment in inner ear tissue. PMID- 30243601 TI - Association of serum lipids with clinical outcome in acute ischaemic stroke: A systematic review and meta-analysis. AB - Serum lipid levels have been investigated as prognostic markers in patients with acute ischaemic stroke. However, these results remain inconsistent. This study aimed at assessing the association between serum lipid and clinical outcomes in acute ischaemic stroke. Relevant data were obtained from Cochrane Library, PubMed and Web of Science databases. The heterogeneity of pooled results was determined by the Cochran's Q test and Higgins I-squared statistic. The random-effect model was performed to calculate the pooled results if PH < 0.05 for Q-test, otherwise the fixed-effect model was applied. The primary results were death, and the secondary were recurrence, dependency, mRS score >=3, and early neurological deterioration. A total of 21 full-text studies was included in the present study. For primary results, the pooled results from 5 studies with 4119 patients showed that triglyceride (TG) was a significant predictor for death (OR = 0.65, 95%CI = 0.43-0.98, PH = 0.028). The pooled data from 11 studies with 12,486 patients for total cholesterol (TC), 4 studies with 7593 patients for low-density lipoprotein cholesterol (LDL-C), and 5 studies with 6933 patients for high-density lipoprotein cholesterol (HDL-C) suggested that TC (OR = 0.79, 95%CI = 0.56-1.13, PH < 0.001), LDL-C (OR = 1.02, 95%CI = 0.66-1.57, PH = 0.042), and HDL-C (OR = 1.18, 95%CI = 0.75-1.86, PH = 0.003) were not associated with death in acute ischaemic stroke. For secondary results, the pooled results of 2 studies with 867 patients indicated that TG was positively associated with early neurological deterioration. This study suggested that serum TG was associated with death and early neurological deterioration in acute ischaemic stroke. PMID- 30243602 TI - FET PET in the evaluation of indeterminate brain lesions on MRI: Differentiating glioma from other non-neoplastic causes - A pilot study. AB - We aimed to determine the utility of FET PET in the management of indeterminate CNS lesions found on MRI. We performed a retrospective analysis of patients with FET PET at a single tertiary institution from 2011 to 2015. FET PET images were processed using usual methods and measurements taken including SUVmax, TBRmax, and analysis of dynamic series where available (Kipeak, Vdpeak, as well as tumor:background ratio for these variables). Correlation studies were performed using ANOVA between cohorts of high-grade histology, low-grade histology, and benign histology/stable on observation. Thirty-five patients were included, of whom 34 were suitable for analysis with median follow-up of 5 months. The positive predictive value of FET PET in this cohort was 83.3%. FET SUVmax differentiated between patients with high-grade (mean SUV 3.38, 95% CI 2.21 4.55), low-grade (1.88, 95% CI 1.33-2.43) and benign/observation (1.42, 95% CI 1.13-1.71) cohorts (p = 0.0003). Similarly, tumour to brain ratio was significant (p < 0.0001). Kipeak distinguished between high grade and observation cohorts (p = 0.036), as did KiTBR (p = 0.025). Vd peak was not significantly different in these two cohorts (p = 0.057) but Vd TBR was (p = 0.041). In conclusion, FET PET demonstrated a high positive predictive value for glioma in patients with indeterminate brain lesions on MRI. The combination of negative FET and negative FDG PET scans may predict an indolent clinical course. Confirmatory trials are needed to establish the potential value of FET PET in guiding surgical management in this cohort. PMID- 30243603 TI - Challenges and controversies in the conservative management of uterine and ovarian cancer. AB - Uterine cancer is the fifth most common cancer in women worldwide with an estimated 320,000 annual diagnoses. Its most common form, endometrioid adenocarcinoma of the endometrium (endometrial adenocarcinoma [EAC]), is thought to develop through excessive proliferation of endometrial glands, and then increasing steadily in incidence. The current standard treatment for EAC is hysterectomy, which is often curative. However, it may be unacceptably expensive for women with severe medical comorbidities, those who are at risk of intra- and postoperative adverse events and those who desire fertility. Ovarian cancer is the most malignant of all gynaecological cancers, but patients with disease limited to one ovary and patients with non-epithelial tumours may expect a good prognosis. A selected group of young patients who desire fertility may be well treated with conservative surgery. This chapter reviews patient selection, diagnosis, pre-treatment evaluation, treatment options, surveillance and risk of relapse. PMID- 30243604 TI - Editorial overview: Feeding the world in a changing climate. PMID- 30243605 TI - Uterine and fetal placental Doppler indices are associated with maternal cardiovascular function. AB - BACKGROUND: The mechanism underlying fetal-placental Doppler index changes in preeclampsia and/or fetal growth restriction are unknown, although both are associated with maternal cardiovascular dysfunction. OBJECTIVE: We sought to investigate whether there was a relationship between maternal cardiac output and vascular resistance and fetoplacental Doppler findings in healthy and complicated pregnancy. STUDY DESIGN: Women with healthy pregnancies (n=62), preeclamptic pregnancies (n=13), preeclamptic pregnancies with fetal growth restriction (n=15), or fetal growth restricted pregnancies (n=17) from 24-40 weeks gestation were included. All of them underwent measurement of cardiac output with the use of an inert gas rebreathing technique and derivation of peripheral vascular resistance. Uterine and fetal Doppler indices were recorded; the latter were z scored to account for gestation. Associations were determined by polynomial regression analyses. RESULTS: Mean uterine artery pulsatility index was higher in fetal growth restriction (1.37; P=.026) and preeclampsia+fetal growth restriction (1.63; P=.001) but not preeclampsia (0.92; P=1) compared with control subjects (0.8). There was a negative relationship between uterine pulsatility index and cardiac output (r2=0.101; P=.025) and umbilical pulsatility index z score and cardiac output (r2=0.078; P=.0015), and there were positive associations between uterine pulsatility index and peripheral vascular resistance (r2=0.150; P=.003) and umbilical pulsatility index z score and peripheral vascular resistance (r2= 0.145; P=.001). There was no significant relationship between cardiac output and peripheral vascular resistance with cerebral Doppler indices. CONCLUSION: Uterine artery Doppler change is abnormally elevated in fetal growth restriction with and without preeclampsia, but not in preeclampsia, which may explain the limited sensitivity of uterine artery Doppler changes for all these complications when considered in aggregate. Furthermore, impedance within fetoplacental arterial vessels is at least, in part, associated with maternal cardiovascular function. This relationship may have important implications for fetal surveillance and would inform therapeutic options in those pathologic pregnancy conditions currently, and perhaps erroneously, attributed purely to placental maldevelopment. Uterine and fetal placental Doppler indices are associated significantly with maternal cardiovascular function. The classic description of uterine and fetal Doppler changes being initiated by placental maldevelopment is a less plausible explanation for the pathogenesis of the conditions than that relating to maternal cardiovascular changes. PMID- 30243606 TI - A clinician's concerns about motor function outcomes of fetal surgery for myelomeningocele. PMID- 30243607 TI - Reply. PMID- 30243608 TI - You can never be too prepared: ECMO for MCA. PMID- 30243609 TI - Characterization of cellular states of CHO-K1 suspension cell culture through cell cycle and RNA-sequencing profiling. AB - Chinese hamster ovary (CHO) derived cell lines are the preferred host system for the production of therapeutic proteins. The aim of this work was to explore the regulation of suspension-adapted CHO-K1 host cell line bioprocesses, especially under a temperature gradient from 37 degrees C to 31 degrees C. We analyzed cell cycle behavior through flow cytometry of propidium iodide stained cells and high throughput transcriptome dynamics by RNA sequencing. We found a cell culture state characterized by G0/G1 synchronization, mainly during the late exponential growth phase and towards the last days of the stationary phase. We successfully identified key genes and pathways connected with the particular culture states, such as response to low temperature, modulation of the cell cycle, regulation of DNA replication and repair, apoptosis, among others. The most important gene expression changes occurred throughout the stationary phase when gene up regulation markedly prevailed. Our RNA-seq data analysis enabled the identification of target genes for mechanism-based cell line engineering and bioprocess modification, an essential step to translate gene expression data from CHO-K1 host cells into bioprocess-related knowledge. Further efforts aim at increasing desirable phenotypes of CHO cells, and promoting efficient production of high quality therapeutic proteins can highly benefit from this type of studies. PMID- 30243610 TI - Chronotype, social jet lag, sleep debt and food timing in inflammatory bowel disease. AB - The preference of the sleep/wake cycle can be grouped into categories or chronotypes. Inflammatory bowel disease (IBD) has been linked to poor sleep quality which correlates with disease severity. Social jet lag (SJL) is the difference between sleep timing on work and free days and is a marker for circadian misalignment which has been linked to increased inflammation. We investigated whether chronotype, SJL, sleep debt (SD), and food timing were associated with an IBD specific complications and a lower quality of life. Overall, 191 subjects (115 IBD subjects and 76 healthy controls (HC)) completed the Pittsburgh Sleep Quality Index (PSQI), Morningness-Eveningness Questionnaire (MEQ), Munich ChronoType Questionnaire (MCTQ), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and a structured Food Timing Questionnaire. Later chronotype (by MEQ) was associated with a worse SIBDQ (r = -0.209; P < 0.05). SJL was increased in IBD at 1.32 h +/- 1.03 vs. 1.05 h +/- 0.97 in HC, P < 0.05, when adjusted for age. SJL (>2 h) was present in 40% of severe/complicated Crohn's patients (fistulizing or structuring Crohn's or history of Crohn's related surgery) compared to only 16% of uncomplicated Crohn's patients (P < 0.05). Sleep debt was increased in IBD subjects compared to HC at 21.90 m +/- 25.37 vs. 11.49 m +/- 13.58, P < 0.05. IBD subjects with inconsistent breakfast or dinner times had lower SIBDQ scores (4.78 +/- 1.28 vs. 5.49 +/- 1.02, P < 0.05; 4.95 +/- 0.31 vs. 5.42 +/- 0.32, P < 0.05 respectively). In summary, later chronotype, and markers of circadian misalignment (social jet lag, sleep debt, and inconsistent meal timing) were associated with IBD disease specific complications and/or lower quality of life. PMID- 30243611 TI - Comments on the 2018 ESC Guidelines for the Diagnosis and Management of Syncope. PMID- 30243612 TI - Gender Differences in the Professional Lives of Cardiologists in 70 Spanish Hospitals. PMID- 30243613 TI - Comment on "Clinical Practice Guidelines for the Treatment of Systemic Lupus Erythematosus by the Mexican College of Rheumatology". PMID- 30243614 TI - Intra-articular Joint Injections in Juvenile Idiopathic Arthritis: State of the Art. AB - OBJECTIVE: Intra-articular corticosteroid injections (IACI) are a fundamental part in the treatment of juvenile idiopathic arthritis. The current situation of IACI is reviewed in a population of children. METHODS: We conducted a narrative review of the literature related to IACI in children, with respect to the injection technique, use of local and general anesthesia, ultrasound guidance of the procedure, indications, special joints and type of optimal corticosteroid. RESULTS: IACI are indicated in any subcategory of juvenile idiopathic arthritis, especially in oligoarticular juvenile idiopathic arthritis. The use of local anesthetic is highly recommended, and in patients younger than 6 years or requiring multiple joint injections, conscious sedation can also be an option. Ultrasound guidance of injections is recommended in expert hands, but not in a generalized way. Triamcinolone hexacetonide is the corticosteroid of choice in large joints, whereas a more soluble corticosteroid is a better alternative in small or superficial joints (betamethasone or methylprednisolone) to avoid subcutaneous atrophy or hypopigmentation, the most frequent adverse effect of IACI. CONCLUSIONS: IACI are performed heterogeneously and scientific evidence is limited in many cases. PMID- 30243615 TI - High-intensity interval training is more effective than moderate-intensity continuous training in reducing abdominal fat mass in postmenopausal women with type 2 diabetes: A randomized crossover study. PMID- 30243616 TI - Digital diabetes: Perspectives for diabetes prevention, management and research. AB - Digital medicine, digital research and artificial intelligence (AI) have the power to transform the field of diabetes with continuous and no-burden remote monitoring of patients' symptoms, physiological data, behaviours, and social and environmental contexts through the use of wearables, sensors and smartphone technologies. Moreover, data generated online and by digital technologies - which the authors suggest be grouped under the term 'digitosome' - constitute, through the quantity and variety of information they represent, a powerful potential for identifying new digital markers and patterns of risk that, ultimately, when combined with clinical data, can improve diabetes management and quality of life, and also prevent diabetes-related complications. Moving from a world in which patients are characterized by only a few recent measurements of fasting glucose levels and glycated haemoglobin to a world where patients, healthcare professionals and research scientists can consider various key parameters at thousands of time points simultaneously will profoundly change the way diabetes is prevented, managed and characterized in patients living with diabetes, as well as how it is scientifically researched. Indeed, the present review looks at how the digitization of diabetes can impact all fields of diabetes - its prevention, management, technology and research - and how it can complement, but not replace, what is usually done in traditional clinical settings. Such a profound shift is a genuine game changer that should be embraced by all, as it can provide solid research results transferable to patients, improve general health literacy, and provide tools to facilitate the everyday decision-making process by both healthcare professionals and patients living with diabetes. PMID- 30243617 TI - Complement deposition on renal histopathology of patients with diabetic nephropathy. AB - AIMS: As the potential role of the complement system in diabetic nephropathy (DN) is increasingly reported, this study aimed to investigate C1q and C3c deposition as seen on renal histopathology, as well as its association with clinical and pathological parameters, in DN patients. METHODS: Renal biopsy specimens from 161 DN patients were investigated using direct immunofluorescence, light, and electron microscopy. For direct immunofluorescence, staining for C1q and C3c on fresh-frozen renal tissue was performed immediately after biopsy. Complement deposition was defined as the presence of C1q or C3c of at least 1 + on a 0-4 + Scale. The association between complement deposition and clinicopathological data was also analyzed. RESULTS: On direct immunofluorescence microscopy, C1q and C3c were detected in specimens from 44/161 (27.3%) and 89/161 (55.3%) patients, respectively. Regarding clinical data, patients with C1q deposition had a significantly higher level of urinary protein (7.25 +/- 4.20 g/24 h vs. 4.97 +/- 3.76 g/24 h; P < 0.01) and significantly lower estimated glomerular filtration rate (eGFR; 34.16 +/- 25.21 mL/min/1.73 m2 vs. 51.17 +/- 31.56 mL/min/1.73 m2, respectively; P < 0.01), whereas patients with vs. without C3c deposition had a significantly lower eGFR (40.09 +/- 27.97 mL/min/1.73 m2 vs. 54.48 +/- 32.49 mL/min/1.73 m2, respectively; P < 0.01). On renal histopathology, patients with C1q deposition had significantly higher Scores for interstitial fibrosis and tubular atrophy (IFTA), interstitial inflammation and vascular lesions (P < 0.01, P < 0.05 and P < 0.05, respectively), whereas patients with C3c deposition had significantly higher IFTA Scores and proportions of global sclerosis (P < 0.01 and P < 0.01, respectively). CONCLUSION: Complement deposition of C1q and C3c on renal histopathology is associated with more severe kidney damage in patients with DN. PMID- 30243618 TI - Development of Direct-acting Antiviral and Host-targeting Agents for Treatment of HBV Infection. AB - Hepatitis B virus (HBV) infection affects about 300 million people worldwide. Although antiviral therapies have improved the long-term outcomes, patients often require life-long treatment and there is no cure for HBV infection. New technologies can help us learn more about the pathogenesis of HBV infection and develop therapeutic agents to reduce its burden. We review recent advances in development of directing-acting antiviral and host-targeting agents, some of which have entered clinical trials. We also discuss strategies for unbiased high throughput screens to identify compounds that inhibit HBV and for repurposing existing drugs. PMID- 30243619 TI - Cell and Animal Models for Studying Hepatitis B Virus Infection and Drug Development. AB - Many cell culture and animal models have been used to study hepatitis B virus (HBV) replication and its effects in the liver; these have facilitated development of strategies to control and clear chronic HBV infection. We discuss the advantages and limitations of systems for studying HBV and developing antiviral agents, along with recent advances. New and improved model systems are needed. Cell culture systems should be convenient, support efficient HBV infection, and reproduce responses of hepatocytes in the human body. We also need animals that are fully permissive to HBV infection, convenient for study, and recapitulate human immune responses to HBV and effects in the liver. High throughput screening technologies could facilitate drug development based on findings from cell and animal models. PMID- 30243620 TI - Unplanned Hospital Encounters After Endoscopic Retrograde Cholangiopancreatography in 3 Large US States. AB - BACKGROUND & AIMS: We have few population-level data on the performance of endoscopic retrograde cholangiopancreatography (ERCP) in the United States. We investigated the numbers of unplanned hospital encounters (UHEs), patient and facility factors associated with UHEs, and variation in quality and outcomes in the performance of ERCP in 3 large American states. METHODS: We collected data on 68,642 ERCPs, performed at 635 facilities in California, Florida, and New York from 2009 through 2014. The primary endpoint was number of UHEs with an ERCP related event within 7 days of ERCP; secondary endpoints included number of UHEs within 30 days and mortality within 30 days. Each facility was assigned a risk standardized cohort, and variations in number of UHEs were analyzed with multivariable analysis. RESULTS: Among all ERCPs, 5.8% resulted in a UHE within 7 days and 10.2% within 30 days. Performance of sphincterotomy was significantly associated with a higher risk of UHE at 7 and 30 days (P < .001). Younger age, female sex, and more advanced comorbidity were associated with UHE. There was substantial heterogeneity in rates of UHE among facilities: 4.2% at facilities in the 5th percentile and 25.2% at facilities in the 95th percentile. Increasing facility volume and ability to perform endoscopic ultrasonography were associated inversely with risk. The median number of ERCPs performed each year was 68.7, but 69% of facilities performed 100 or fewer ERCPs per year. Risk for UHE after sphincterotomy decreased with increasing facility volume until an inflection point of 157 ERCPs per year was reached. CONCLUSIONS: In an analysis of outcomes of 68,642 ERCPs performed in 3 states, we found a higher-than-expected number of UHEs. There is substantial unexplained variation in risk for adverse events after ERCPs among facilities, and volume is the strongest predictor of risk. Annual facility volumes above approximately 150 ERCPs per year may protect against UHE. PMID- 30243621 TI - Earlier Colorectal Cancer Screening May Be Necessary In Patients With Li-Fraumeni Syndrome. PMID- 30243622 TI - Information on Genetic Variants Does Not Increase Identification of Individuals at Risk of Esophageal Adenocarcinoma Compared to Clinical Risk Factors. AB - We previously developed a tool that identified individuals who later developed esophageal adenocarcinoma (based on age, sex, body mass index, smoking status, and prior esophageal conditions) with an area under the curve of 0.80. In this study, we collected data from 329,463 individuals in the UK Biobank cohort who were tested for genetic susceptibility to esophageal adenocarcinoma (a polygenic risk score based on 18 recognized genetic variants). We found that after inclusion of this genetic information, the area under the curve for identification of individuals who developed esophageal adenocarcinoma remained at 0.80. Testing for genetic variants associated with esophageal adenocarcinoma therefore seems unlikely to improve identification of individuals at risk of esophageal adenocarcinoma. PMID- 30243623 TI - Hot topic: Management of cull dairy cows-Consensus of an expert consultation in Canada. AB - Many cull dairy cows enter the marketing system and travel to widely dispersed and specialized slaughter plants, and they may experience multiple handling events (e.g., loading, unloading, mixing), change of ownership among dealers, and feed and water deprivation during transport and at livestock markets. The objectives of this study were to describe the diverse management of cull dairy cows in Canada and establish consensus on ways to achieve improvements. A 2-day expert consultation meeting was convened, involving farmers, veterinarians, regulators, and experts in animal transport, livestock auction, and slaughter. The 15 participants, recruited from across Canada, discussed regional management practices for cull cattle, related risk factors, animal welfare problems, and recommendations. An audio recording of the meeting was used to extract descriptive data on cull cattle management and identify points of agreement. Eight consensus points were reached: (1) to assemble information on travel times and delays from farm to slaughter; (2) to increase awareness among producers and herd veterinarians of potential travel distances and delays; (3) to promote pro active culling; (4) to improve the ability of personnel to assess animal condition before loading; (5) to identify local options for slaughter of cull dairy cows; (6) to investigate different management options such as emergency slaughter and mobile slaughter; (7) to ensure that all farms and auctions have, or can access, personnel trained and equipped for euthanasia; and (8) to promote cooperation among enforcement agencies and wider adoption of beneficial regulatory options. PMID- 30243624 TI - Size, shape, and identity of surface crystals and their relationship to sensory perception of grittiness in soft smear-ripened cheeses. AB - Soft smear-ripened cheeses undergo extensive surface crystallization and radial demineralization of calcium, magnesium, and phosphorus, which likely contributes to radial softening during ripening. Furthermore, anecdotal evidence suggests that grittiness is a common characteristic of smear-ripened cheeses. The primary aims of the present study were to evaluate the intensity of perceived grittiness while assessing other key sensory attributes in US artisanal and European protected designation of origin smear-ripened cheeses, and to relate perceived grittiness to the size, shape, and identity of crystals present in the cheese surface smears. Fully ripened wheels of 24 different varieties of smear-ripened cheeses, 16 produced in the United States and 8 in the European Union, were obtained from retail sources. A trained sensory panel (n = 12) was employed to evaluate intensity of grittiness. Crystals present in the cheese smears were identified by powder X-ray diffractometry and polarized light microscopy, and further evaluated in polarized light microscopy micrographs by image analysis for size and shape characteristics. Mean sensory scores for the 24 cheeses ranged from no perceived grittiness to easily identifiable grittiness. Surface crystals included ikaite, struvite, calcite, and brushite, and mean crystal length and area ranged among cheeses from 27 to 1,096 MUm, and 533 to 213,969 MUm2, respectively. Panel threshold for grittiness occurred at a mean crystal length of about 66 MUm and mean crystal area of about 2,913 MUm2. Cheeses with mean values at or below these thresholds displayed negligible perceived grittiness. In contrast, for cheeses with mean values above these thresholds, the mean sensory scores for grittiness were highly correlated with mean crystal length and crystal area (r = 0.93 and 0.96, respectively). Results suggest that surface crystals in soft smear-ripened cheeses influence sensory perception of texture in complex ways that likely include radial softening and grittiness development. A better understanding of factors that govern surface crystal formation may lead to improved control over crystallization and more consistent cheese texture. PMID- 30243625 TI - Genome-wide association studies for tick resistance in Bos taurus * Bos indicus crossbred cattle: A deeper look into this intricate mechanism. AB - Rhipicephalus (Boophilus) microplus is the main cattle ectoparasite in tropical areas. Gir * Holstein crossbred cows are well adapted to different production systems in Brazil. In this context, we performed genome-wide association study (GWAS) and post-GWAS analyses for R. microplus resistance in an experimental Gir * Holstein F2 population. Single nucleotide polymorphisms (SNP) identified in GWAS were used to build gene networks and to investigate the breed of origin for its alleles. Tick artificial infestations were performed during the dry and rainy seasons. Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA) and single step BLUP procedure was used for GWAS. Post-GWAS analyses were performed by gene ontology terms enrichment and gene transcription factors networks, generated from enriched transcription factors, identified from the promoter sequences of selected gene sets. The genetic origin of marker alleles in the F2 population was assigned using the breed of origin of alleles approach. Heritability estimates for tick counts were 0.40 +/- 0.11 in the rainy season and 0.54 +/- 0.11 in the dry season. The top ten 0.5-Mbp windows with the highest percentage of genetic variance explained by SNP markers were found in chromosomes 10 and 23 for both the dry and rainy seasons. Gene network analyses allowed the identification of genes involved with biological processes relevant to immune system functions (TREM1, TREM2, and CD83). Gene-transcription factors network allowed the identification of genes involved with immune functions (MYO5A, TREML1, and PRSS16). In resistant animals, the average proportion of animals showing significant SNPs with paternal and maternal alleles originated from Gir breed was 44.8% whereas the proportion of animals with both paternal and maternal alleles originated from Holstein breed was 11.3%. Susceptible animals showing both paternal and maternal alleles originated from Holstein breed represented 44.6% on average, whereas both paternal and maternal alleles originated from Gir breed animals represented 9.3%. This study allowed us to identify candidate genes for tick resistance in Gir * Holstein crossbreds in both rainy and dry seasons. According to the origin of alleles analysis, we found that most animals classified as resistant showed 2 alleles from Gir breed, while the susceptible ones showed alleles from Holstein. Based on these results, the identified genes may be thoroughly investigated in additional experiments aiming to validate their effects on tick resistance phenotype in cattle. PMID- 30243626 TI - An evaluation of Molly cow model predictions of ruminal metabolism and nutrient digestion for dairy and beef diets. AB - Model evaluation, as a critical process of model advancement, is necessary to identify adequacy and consistency of model predictions. The objectives of this study were (1) to evaluate the accuracy of Molly cow model predictions of ruminal metabolism and nutrient digestion when simulating dairy and beef cattle diets; and (2) to identify deficiencies in representations of the biology that could be used to direct further model improvements. A total of 229 studies (n = 938 treatments) including dairy and beef cattle data, published from 1972 through 2016, were collected from the literature. Root mean squared errors (RMSE) and concordance correlation coefficients (CCC) were calculated to assess model accuracy and precision. Ruminal pH was very poorly represented in the model with a RMSE of 4.6% and a CCC of 0.0. Although volatile fatty acid concentrations had negligible mean (2.5% of mean squared error) and slope (6.8% of mean squared error) bias, the CCC was 0.28, implying that further modifications with respect to volatile fatty acid production and absorption are required to improve model precision. The RMSE was greater than 50% for ruminal ammonia and blood urea-N concentrations with high proportions of error as slope bias, indicating that mechanisms driving ruminal urea N recycling are not properly simulated in the model. Only slight mean and slope bias were exhibited for ruminal outflow of neutral detergent fiber, starch, lipid, total N, and nonammonia N, and for fecal output of protein, neutral detergent fiber, lipid, and starch, indicating the mechanisms encoded in the model relative to ruminal and total-tract nutrient digestion are properly represented. All variables related to ruminal metabolism and nutrient digestion were more precisely predicted for dairy cattle than for beef cattle. This difference in precision was mostly related to the model's inability to simulate low forage diets included in the beef studies. Overall, ruminal pH was poorly simulated and contributed to problems in ruminal nutrient degradation and volatile fatty acid production predictions. Residual analyses suggested ruminal ammonia concentrations need to be considered in the ruminal pH equation, and therefore the inaccuracies in predicting ruminal urea N recycling must also be addressed. These modifications to model structure will likely improve model performance across a wider array of dietary inputs and cattle type. PMID- 30243627 TI - Effects of chitosan and whole raw soybeans on ruminal fermentation and bacterial populations, and milk fatty acid profile in dairy cows. AB - The objective of this study was to evaluate whether providing chitosan (CHI) to cows fed diets supplemented with whole raw soybeans (WRS) would affect the nutrient intake and digestibility, ruminal fermentation and bacterial populations, microbial protein synthesis, N utilization, blood metabolites, and milk yield and composition of dairy cows. Twenty-four multiparous Holstein cows (141 +/- 37.1 d in milk, 38.8 +/- 6.42 kg/d of milk yield; mean +/- SD) were enrolled to a 4 * 4 Latin square design experiment with 23-d periods. Cows were blocked within Latin squares according to milk yield, days in milk, body weight, and rumen cannula (n = 8). A 2 * 2 factorial treatment arrangement was randomly assigned to cows within blocks. Treatments were composed of diets with 2 inclusion rates of WRS (0 or 14% diet dry matter) and 2 doses of CHI (0 or 4 g/kg of dry matter, Polymar Ciencia e Nutricao, Fortaleza, Brazil). In general, CHI+WRS negatively affected nutrient intake and digestibility of cows, decreasing milk yield and solids production. The CHI increased ruminal pH and decreased acetate to propionate ratio, and WRS reduced NH3-N concentration and acetate to propionate in the rumen. The CHI reduced the relative bacterial population of Butyrivibrio group, whereas WRS decreased the relative bacterial population of Butyrivibrio group, and Fibrobacter succinogenes, and increased the relative bacterial population of Streptococcus bovis. No interaction effects between CHI and WRS were observed on ruminal fermentation and bacterial populations. The CHI+WRS decreased N intake, microbial N synthesis, and N secreted in milk of cows. The WRS increased N excreted in feces and consequently decreased the N excreted in urine. The CHI had no effects on blood metabolites, but WRS decreased blood concentrations of glucose and increased blood cholesterol concentration. The CHI and WRS improved efficiency of milk yield of cows in terms of fat corrected milk, energy-corrected milk, and net energy of lactation. The CHI increased milk concentration [g/100 g of fatty acids (FA)] of 18:1 trans-11, 18:2 cis-9,cis-12, 18:3 cis-9,cis-12,cis-15, 18:1 cis-9,trans-11, total monounsaturated FA, and total polyunsaturated FA. The WRS increased total monounsaturated FA, polyunsaturated FA, and 18:0 to unsaturated FA ratio in milk of cows. Evidence indicates that supplementing diets with unsaturated fat sources along with CHI negatively affects nutrient intake and digestibility of cows, resulting in less milk production. Diet supplementation with CHI or WRS can improve feed efficiency and increases unsaturated FA concentration in milk of dairy cows. PMID- 30243628 TI - Ketoprofen affects the mammary immune response in dairy cows in vivo and in vitro. AB - Nonsteroidal anti-inflammatory drugs are commonly administered parenterally in addition to antimicrobial mastitis therapy to increase the well-being of the diseased animal. As mastitis is usually a localized infection of mammary tissue, we tested the hypothesis that a local administration of nonsteroidal anti inflammatory drugs through the teat canal could have anti-inflammatory effects on the affected area. We investigated the effects of intramammarily administered ketoprofen (KET) during an LPS-induced immune response on somatic cell count (SCC) and blood-milk barrier integrity. In addition, we investigated the effects of KET on the mRNA abundance of immune factors and their prostaglandin E2 secretion in primary bovine mammary epithelial cells in vitro. Six cows received 0.2 ug of LPS (serotype O26:B6) together with 50 mg of KET into one quarter and LPS only in the opposing quarter. The increase of SCC and of serum albumin (SA) and IgG concentrations and the increase of lactate dehydrogenase (LDH) activity in milk induced by LPS were lower in quarters that received KET in addition. In 3 cows, intramammary KET (50 mg) without additional LPS did not affect SCC, SA, IgG, and LDH in milk. Effects of KET on the immune response of mammary epithelial cells in vitro were investigated in cells from 3 cows challenged with or without LPS (0.2 ug/mL) and with or without additional KET in 2 concentrations (1.25 or 2.5 mg/mL). Ketoprofen reduced the LPS-induced increase of mRNA abundance of tumor necrosis factor alpha, IL-8, serum amyloid A, and cyclooxygenase-2. The mRNA abundance of cyclooxygenase-1 and prostaglandin E synthase was reduced in cells without LPS challenge by addition of KET at 2.5 mg/mL. Furthermore, the LPS induced secretion of prostaglandin E2 of mammary epithelial cells into the supernatant could not be detected if KET was added. The results demonstrate that intramammary KET diminishes the increase of SCC and reduces the impairment of the blood-milk barrier (based on SA and LDH in milk), leading to a reduced IgG concentration in milk during LPS-induced mastitis. In mammary epithelial cells, KET limits the expression of several immune factors that are increased during an immune response. In summary, intramammary administration of KET reduces the inflammatory response in the mammary gland. However, it remains unclear whether the inhibited transfer of immune cells and IgG from blood into milk after KET administration would reduce the success of the immune defense in infectious mastitis. PMID- 30243629 TI - Short communication: Circulating serotonin is related to the metabolic status and lactational performance at the onset of lactation in dairy cows. AB - Serotonin (5-hydroxytryptamine, 5-HT) affects many physiological functions because it is involved in glucose and lipid metabolism, calcium homeostasis, and regulation of lactation in dairy cows. This study aimed to examine physiological differences in serum 5-HT concentrations (high vs. low) and their association with metabolic status and milk production at the onset of lactation. Twelve multiparous Holstein dairy cows were milked within 4 h of calving, and blood and milk samples were collected at the first 6 subsequent milkings after parturition and at the evening milkings on d 5, 8, 10, and 14. Cows were retrospectively divided into 2 groups (6 cows/group): low serum 5-HT (LSS) and high serum 5-HT (HSS) according to their calculated areas under the curve (AUC) for serum 5-HT for the entire experimental period (cut-off: 46,000 ng/mL * 324 h). Concentrations of 5-HT, free fatty acids (FFA), beta-hydroxybutyrate (BHB), glucose, calcium, and IGF-1 were measured in blood. Milk was analyzed for fat, protein, lactose, and 5-HT concentrations. Milk yield was recorded at each milking and energy-corrected milk yield was calculated. Serum 5-HT concentrations were higher in HSS than in LSS [AUC (ng/mL * 324 h): 57,830 +/- 4,810 vs. 25,005 +/- 5,930]. The amount of energy-corrected milk was lower in HSS than in LSS. The HSS group produced less colostrum and had decreased milk yield, specifically during the first 6 milkings. Concentrations of FFA, BHB, and glucose in plasma did not differ between groups. Concentrations of IGF-1 in serum were elevated in HSS compared with LSS throughout the experiment. Total circulating calcium concentrations in serum tended to be higher in HSS than in LSS. Milk fat and protein yields were decreased in HSS compared with LSS. Milk 5-HT decreased overall during the experimental period, with LSS maintaining higher 5-HT concentrations than HSS until d 14 of lactation. In conclusion, cows with high serum 5-HT concentrations showed a reduced metabolic load at the onset of lactation, concomitantly lower milk yield, and a reduced energy output via milk. PMID- 30243631 TI - Effects of oral administration of acidogenic boluses at dry-off on performance and behavior of dairy cattle. AB - The aim of this study was to evaluate the potential of oral acidogenic mineral boluses (196 g) containing anionic salts to facilitate the transition from lactation to the dry stage by inducing a mild and temporary metabolic acidosis at dry-off. In experiment 1, 84 lactating cows were randomly allocated to 1 of 3 treatment groups consisting of an oral administration of 0, 1, or 2 boluses 5 d before dry-off to evaluate the effects on milk production. In experiment 2, 16 lactating cows were involved in a crossover study to evaluate the effects of the administration of 2 boluses on milk production, feed intake, and urine pH. In experiment 3, 152 lactating cows were allocated to 1 of 2 treatments (control: no treatment; bolus: 2 oral boluses the day before last milking) to evaluate udder pressure, incidence of milk leakage, and lying behavior during the first days following dry-off. Also, milk yield in the subsequent lactation for all enrolled cows was recorded during the first 60 DIM. In experiment 1, cows receiving 2 boluses had the greatest reduction in milk production (-2.56 kg/d of milk) compared with those receiving 1 bolus or no treatment (-1.15 and -0.23 kg/d, respectively) the second day after bolus application. In experiment 2, the application of oral boluses decreased feed intake of cows during the first 3 d following treatment, and milk production was reduced on d 2 and 3 after bolus application. Reduced urine pH at 8 and 24 h after treatment was observed in bolus cows compared with control cows. In experiment 3, bolus cows had lower udder pressure after drying off, but incidence of milk leakage did not differ between treatments. Bolus cows had an additional 85 min of lying time in the 24 h following dry-off. Serum P and beta-OH-butyrate concentrations were lower in bolus cows than in control cows after dry-off, but no other differences in blood parameters between treatments were observed. Also, no differences in milk yield in the subsequent lactation were observed between treatments. It is concluded that oral bolus application diminishes feed intake and milk production, and, if applied at dry-off, it decreases udder pressure and increases lying time during the first 24 h after dry-off. PMID- 30243630 TI - Indicators of resilience during the transition period in dairy cows: A case study. AB - The transition period is a demanding phase in the life of dairy cows. Metabolic and infectious disorders frequently occur in the first weeks after calving. To identify cows that are less able to cope with the transition period, physiologic or behavioral signals acquired with sensors might be useful. However, it is not yet clear which signals or combination of signals and which signal properties are most informative with respect to disease severity after calving. Sensor data on activity and behavior measurements as well as rumen and ear temperature data from 22 dairy cows were collected during a period starting 2 wk before expected parturition until 6 wk after parturition. During this period, the health status of each cow was clinically scored daily. A total deficit score (TDS) was calculated based on the clinical assessment, summarizing disease length and intensity for each cow. Different sensor data properties recorded during the period before calving as well as the period after calving were tested as a predictor for TDS using univariate analysis of covariance. To select the model with the best combination of signals and signal properties, we quantified the prediction accuracy for TDS in a multivariate model. Prediction accuracy for TDS increased when sensors were combined, using static and dynamic signal properties. Statistically, the most optimal linear combination of predictors consisted of average eating time, variance of daily ear temperature, and regularity of daily behavior patterns in the dry period. Our research indicates that a combination of static and dynamic sensor data properties could be used as indicators of cow resilience. PMID- 30243632 TI - Effects of ad libitum or restricted access to total mixed ration with supplemental long hay on production, intake, and rumination. AB - Limiting feeding time has been a concept used in growing and nonlactating ruminant animals with good success, especially in improving feed efficiency while maintaining normal rumen function and fiber digestibility. This study evaluated the physiological and productive responses of cows fed a total mixed ration (TMR) available for 24 or 19 h/d with or without access to additional long hay. Eight multiparous Holstein cows were used in a replicated 4 * 4 Latin square design with 21-d periods. Rations were formulated to mimic a TMR used in the Parmigiano Reggiano cheese production area of Italy, consisting of all dry and nonfermented components. Intakes were reduced by 2.49 kg/d in cows with restricted TMR access and 1.16 kg/d without supplemental hay. Rumen characteristics were similar for all groups with improvements in energy-corrected milk. The results show that once cows adapted to diet changes, few differences were observed when offering TMR continuously or with limited access. Energy-corrected milk feed efficiency was improved in cows having access to feed 19 versus 24 h/d. In addition, the presence of long hay during the TMR restriction offered the optimal conditions for ruminal function and pH stability, yet no effects were observed on body weight change. A Latin square with 21-d periods could have a carry-over effect on energy storage, and mobilization of fat reserves might be able to mask negative energy balance during restriction. Restricted feeding could be used as a strategy to manage feed availability according to cow production and metabolic condition, to maximize the use of nutrient resources, reducing the cost of milk production and improving the cows' welfare and health. PMID- 30243633 TI - Identification of objectionable flavors in purported spontaneous oxidized flavor bovine milk. AB - Spontaneous oxidized flavor (SOF) has been reported over the past 5 decades as a sporadic objectionable flavor problem in bovine milk. Parameters previously reported to influence SOF development in milk have been contradictory, limiting the ability to monitor and develop mitigation strategies. The current paper investigates the causative compounds associated with milk identified as SOF milk in the Midwest dairy region of the United States. Based on GC/MS-olfactometry analysis, endo-borneol, 2-methylisoborneol, and alpha-terpineol were identified as the off-flavor compounds. Sensory recombination studies further confirmed the sensory contribution of these compounds to the noted off-flavor attributes in the original milk, which were described as "green," "musty," and "unclean." These compounds are known microbial-derived flavor taints, indicating oxidation was not the origin of the objectionable flavor in the milk. This noted misclassification of the milk as SOF indicates the challenge of defining flavor defects without the identification of the active compounds. PMID- 30243634 TI - Genotype by environment interactions in fertility traits in New Zealand dairy cows. AB - New Zealand's seasonal dairy farming system entails a condensed calving pattern with cows required to conceive within approximately 12 wk of the planned start of calving. This has resulted in strong selection for fertility through culling of nonpregnant cows and relatively strong emphasis on fertility in Breeding Worth, the national breeding objective that drives sire selection. Despite this, average herd-level fertility is highly variable across New Zealand dairy farms. We studied genotype by environment interaction in fertility-related traits, with the goal of improving selection decisions in different fertility environments. We used data from the New Zealand national dairy database, which contains records on 3,743,862 animals. Herds were classified into high-, mid-, or low-fertility categories or environments based on herd average fertility performance, and data were analyzed in 2 different ways. First, we estimated genetic parameters when the fertility trait was defined specifically for each fertility environment to determine the extent to which genetic correlations between high- and low fertility environments differed from 1 and the extent of changes in genetic variance across environments. Second, we used simple regression to evaluate the impact of ancestral genetic merit for fertility on cow fertility phenotypes to compare the effect of changes in genetic merit on phenotypic performance between fertility environments. The genetic standard deviations of fertility-related traits were 1.5 to 3.6 times higher in low-fertility herds than in high-fertility herds, and the genetic correlations between the same fertility-related traits between the high- and low-fertility environments were moderate to high, albeit with high standard errors. The high standard errors of the correlations reflected the low heritabilities of the traits and potential problems of culling bias, particularly for traits expressed in later parities. Regression analysis revealed that the bottom 30% of herds (in terms of fertility) could achieve more than twice the benefit from selection for fertility than the top 30% of herds. Although our analyses do not support separate genetic evaluations of fertility in the different environments, they indicate that low-fertility herds could benefit more from targeted selection of sires with higher fertility estimated breeding values than from selection based solely on the multitrait national index. Conversely, high-fertility herds could focus their sire selection on traits other than fertility, provided they avoid very low fertility sires. PMID- 30243635 TI - Lactic acid bacteria with cholesterol-lowering properties for dairy applications: In vitro and in situ activity. AB - Cholesterol-lowering activity is one of the most promising properties of lactic acid bacteria with probiotic characteristics. In the present study, 58 potentially probiotic lactic acid bacteria were tested for their ability to survive in vitro digestion and reduce cholesterol in a medium containing cholesterol and bile acids. The best-performing strains (Lactobacillus casei VC199, Lactobacillus paracasei ssp. paracasei SE160 and VC213, Lactobacillus plantarum VS166 and VS513, Enterococcus faecium VC223, and Enterococcus lactis BT161) resulted in a 42 to 55% reduction of the cholesterol level in broth and were further tested in cheese manufacture. The cholesterol content in all the cheeses decreased with ripening. All the strains were present in the cheese at levels higher than 107 cfu/g until 60 d of ripening, the highest reductions (up to 23%) being obtained when Lb. paracasei ssp. paracasei VC213 and E. lactis BT161 were added during the cheese-making. The adjunct cultures had no negative effect on the sensory characteristics of the cheese. Thus, these strains with proven in vitro properties are good candidates for novel probiotic-containing formulations and could be used to functionalize foods such as dairy fermented products. PMID- 30243636 TI - Short communication: Multivariate outlier detection for routine Nordic dairy cattle genetic evaluation in the Nordic Holstein and Red population. AB - It is of practical importance to ensure the data quality from a milk-recording system before use for genetic evaluation. A procedure was developed for detection of multivariate outliers based on an approximation for Mahalanobis distance and was implemented in the Nordic Holstein and Red population. The general target of this procedure is based on the Nordic Cattle Genetic Evaluation yield model, which is a 9-trait model for milk, protein, and fat in the first 3 lactations. The procedure is based on the phenotypic correlation structure as a function of days in milk (DIM) and on computation of trait means and standard deviations within a production year, lactation, and DIM. For each record in the data, a Mahalanobis distance value was computed based on the trait mean and the covariance matrix for the actual production year, lactation, and DIM. A set of cutoff values, ranging from 10 to 100 with steps of 10, for discarding multivariate outliers was investigated. Prediction accuracy was calculated as the Pearson correlations between estimated breeding values predicted by full data set and estimated breeding values predicted by reduced data set for cows without records in the reduced data set and with 1 or more records deleted due to the editing rules on Mahalanobis distance. The results showed that, averaged over all scenarios, gains of 0.005 to 0.048 on prediction accuracy have been obtained by deleting the multivariate outliers. The improvements were more profound for progeny of young bulls compared with progeny of proven bulls. It is easy to implement this multivariate outlier-detection procedure in the routine genetic evaluation for different dairy cattle breeds; however, an optimal cutoff value for Mahalanobis distance needs to be defined to achieve an acceptable compromise between genetic evaluation accuracy and data deletion. PMID- 30243637 TI - Genome-wide association study of milk fatty acid composition in Italian Simmental and Italian Holstein cows using single nucleotide polymorphism arrays. AB - Bovine milk is important for human nutrition, but its fat content is often criticized as a risk factor in cardiovascular disease. Selective breeding programs could be used to alter the fatty acid (FA) composition of bovine milk to improve the healthiness of dairy products for human consumption. Here, we performed a genome-wide association study (GWAS) on bovine milk to identify genomic regions or specific genes associated with FA profile and to investigate genetic differences between the Italian Simmental (IS) and Italian Holstein (IH) breeds. To achieve this, we first characterized milk samples from 416 IS cows and 436 IH cows for their fat profile by gas chromatography. Subjects were genotyped with single nucleotide polymorphism array and a single-marker regression model for GWAS was performed. Our findings confirm previously reported quantitative trait loci strongly associated with bovine milk fat composition. More specifically, our GWAS results revealed significant signals on chromosomes Bos taurus autosome 19 and 26 for milk FA. Further analysis using a gene-centric approach and pathway meta-analysis identified not only some well-known genes underlying quantitative trait loci for milk FA components, such as FASN, SCD, and DGAT1, but also other significant candidate genes, including some with functional roles in pathways related to "Lipid metabolism." Highlighted genes related to FA profile include ECI2, PCYT2, DCXR, G6PC3, PYCR1, and ALG12 in IS, and CYP17A1, ACO2, PI4K2A, GOT1, GPT, NT5C2, PDE6G, POLR3H, and COX15 in IH. Overall, the breed-specific association outcomes reflect differences in the genetic backgrounds of the IS and IH breeds and their selective breeding histories. PMID- 30243638 TI - Diversity of dairy goat lactation curves in France. AB - A high level of production at the peak of lactation may be associated with animal health disorders, high feeding costs, and reduced milk supply throughout the year. The objective of this study was to typologize the lactation curves in French dairy goats and analyze the influence of environmental and genetic factors on these curves. The data set consisted of 2,231,720 monthly test-day records of 213,534 French Saanen and Alpine goats recorded between September 2008 and June 2012. First, principal component analysis classified the shape of the lactation curves into 3 principal components: the first component accounted for milk yield level throughout lactation, the second component accounted for lactation persistency, and the third component accounted for milk yield in mid-lactation. Then, from the principal component scores, the lactations were clustered into 5 different groups. Most lactations had a similar shape to the mean curve, except 30% of the lactations that fell into 3 clusters that had a high production level at the peak and then a different persistency according to cluster. Estimated breeding value for milk yield and home region of breeding were the factors most related to lactation production level. Month of kidding, breed, and gestation stage had the biggest effect on persistency. Month of kidding was the factor most strongly linked to mid-lactation production. A herd effect was observed on all 3 principal components. PMID- 30243639 TI - Pilot-scale formation of whey protein aggregates determine the stability of heat treated whey protein solutions-Effect of pH and protein concentration. AB - Denaturation and consequent aggregation in whey protein solutions is critical to product functionality during processing. Solutions of whey protein isolate (WPI) prepared at 1, 4, 8, and 12% (wt/wt) and pH 6.2, 6.7, or 7.2 were subjected to heat treatment (85 degrees C * 30 s) using a pilot-scale heat exchanger. The effects of heat treatment on whey protein denaturation and aggregation were determined by chromatography, particle size, turbidity, and rheological analyses. The influence of pH and WPI concentration during heat treatment on the thermal stability of the resulting dispersions was also investigated. Whey protein isolate solutions heated at pH 6.2 were more extensively denatured, had a greater proportion of insoluble aggregates, higher particle size and turbidity, and were significantly less heat-stable than equivalent samples prepared at pH 6.7 and 7.2. The effects of WPI concentration on denaturation/aggregation behavior were more apparent at higher pH where the stabilizing effects of charge repulsion became increasingly influential. Solutions containing 12% (wt/wt) WPI had significantly higher apparent viscosities, at each pH, compared with lower protein concentrations, with solutions prepared at pH 6.2 forming a gel. Smaller average particle size and a higher proportion of soluble aggregates in WPI solutions, pre-heated at pH 6.7 and 7.2, resulted in improved thermal stability on subsequent heating. Higher pH during secondary heating also increased thermal stability. This study offers insight into the interactive effects of pH and whey protein concentration during pilot-scale processing and demonstrates how protein functionality can be controlled through manipulation of these factors. PMID- 30243640 TI - Genetic parameters for handling and milking temperament in Danish first-parity Holstein cows. AB - The human-animal relationship in dairy cattle is reflected in the trait "temperament" in breeding programs and is mainly based on observations by farmers. However, farmers' knowledge of an individual cow's temperament decreases with an increased herd size, and this has been the case in many countries during the last decades. The aim of this study was to investigate if temperament recorded by classifiers and automatic milking systems is heritable, and estimate the genetic relationship with farmer-assessed temperament. Farmer-assessed temperament is defined as the overall assessment of the individual cows' temperament at milking and handling. Data on handling temperament were recorded by Danish classifiers from October 2016 to April 2017 on a 1 to 9 scale specially designed for this purpose. Data from automatic milking systems were recorded from January 2010 until April 2017, where connection time and number of attachments per teat were classified as milking temperament traits. Estimated heritabilities were relatively low for handling temperament (0.13) and farmer-assessed temperament (0.10). For milking temperament traits, connection time showed higher heritability than number of attachments per teat (0.36 and 0.26, respectively). The genetic correlation between farmer-assessed temperament and handling temperament was highly favorable (0.84). The genetic correlations between handling temperament and the 2 milking temperament traits, connection time and number of attachments per teat, were low (-0.02 and -0.10, respectively). Moderate genetic correlations were estimated between farmer-assessed temperament and connection time (-0.29) and between farmer-assessed temperament and number of attachments per teat (-0.37). The genetic correlations and heritabilities suggest a basis for further investigations of the possibility of including handling or milking temperament traits (or both) in the breeding program for temperament in dairy cattle. PMID- 30243641 TI - How faces (and cars) may become special. AB - Recent reports have shown that individuals from small hometowns show relatively poor face recognition ability as measured by the Cambridge Face Memory Test or CFMT (Balas & Saville, 2015, 2017), suggesting that the number of faces present in an individual's visual environment relates to that individual's face recognition ability. We replicate this finding in a sample from a different region (Nebraska) and with more variable age distribution. We extend the study by using another test of face recognition ability that does not require learning over trials, and with non-face object recognition tests that share the learning format with the CFMT. We find no hometown effect in these other tests, although more power would be required to show the CFMT effect is significantly larger. We use the same dataset to explore whether experience with more faces and cars in larger hometowns leads to specialization of these abilities. We find strong and substantial support for the hypothesis that the recognition abilities for faces and for cars are more independent from general object recognition in people from larger hometowns. This suggests that experience may be critical to the specialization of these abilities. PMID- 30243642 TI - Polygenic Scores for Neuropsychiatric Traits and White Matter Microstructure in the Pediatric Population. AB - BACKGROUND: Genome-wide association studies have identified numerous genetic variants that predispose to neuropsychiatric traits. Identification of mechanisms in the brain that underlie these associations is essential for understanding manifestations of genetic predisposition within the general population. Here, we investigated the association between polygenic scores (PGSs) for seven neuropsychiatric traits and white matter microstructure of the brain on diffusion tensor imaging in the pediatric population. METHODS: Participants from the Generation R Study who had genotype and diffusion tensor imaging data available (n = 1138, mean age = 10.2 years, range = 8.7-12.0) were included. PGSs were calculated for five psychiatric disorders (attention-deficit/hyperactivity disorder, bipolar disorder, autism, major depressive disorder, and schizophrenia) and two cognitive traits (intelligence and educational attainment) and were tested for associations with global and tract-specific fractional anisotropy (FA) and mean diffusivity. RESULTS: Significant positive associations with global FA were observed for the PGSs of intelligence (beta = .109, SE = .029, p < .001, DeltaR2 = .012) and educational attainment (beta = .118, SE = .029, p < .001, DeltaR2 = .014). No significant associations were observed with FA for the PGSs of psychiatric disorders. Tract-specific analysis showed that the PGSs for intelligence and educational attainment were associated with FA of several association and projection fibers of the brain. CONCLUSIONS: Our results show that genetic predisposition for cognition-related traits, but not for psychiatric disorders, is associated with microstructural diffusion measures of white matter tracts at an early age. These results suggest a shared genetic etiology among structural connectivity, intelligence, and educational achievement. PMID- 30243643 TI - Functional Connectivity of the Precuneus in Unmedicated Patients With Depression. AB - BACKGROUND: The precuneus has connectivity with brain systems implicated in depression. METHODS: We performed the first fully voxel-level resting-state functional connectivity (FC) neuroimaging analysis of depression of the precuneus, with 282 patients with major depressive disorder and 254 control subjects. RESULTS: In 125 unmedicated patients, voxels in the precuneus had significantly increased FC with the lateral orbitofrontal cortex, a region implicated in nonreward that is thereby implicated in depression. FC was also increased in depression between the precuneus and the dorsolateral prefrontal cortex, temporal cortex, and angular and supramarginal areas. In patients receiving medication, the FC between the lateral orbitofrontal cortex and precuneus was decreased back toward that in the control subjects. In the 254 control subjects, parcellation revealed superior anterior, superior posterior, and inferior subdivisions, with the inferior subdivision having high connectivity with the posterior cingulate cortex, parahippocampal gyrus, angular gyrus, and prefrontal cortex. It was the ventral subdivision of the precuneus that had increased connectivity in depression with the lateral orbitofrontal cortex and adjoining inferior frontal gyrus. CONCLUSIONS: The findings support the theory that the system in the lateral orbitofrontal cortex implicated in the response to nonreceipt of expected rewards has increased effects on areas in which the self is represented, such as the precuneus. This may result in low self-esteem in depression. The increased connectivity of the precuneus with the prefrontal cortex short-term memory system may contribute to the rumination about low self esteem in depression. These findings provide evidence that a target to ameliorate depression is the lateral orbitofrontal cortex. PMID- 30243644 TI - Accuracy of stridor-based diagnosis of post-intubation subglottic stenosis in pediatric patients. AB - OBJECTIVE: To assess the accuracy of stridor in comparison to endoscopic examination for diagnosis of pediatric post-intubation subglottic stenosis. METHOD: Children who required endotracheal intubation for >24h were included in this prospective cohort study. Children were monitored daily and underwent flexible fiberoptic laryngoscopy after extubation. Those with moderate-to-severe abnormalities underwent another examination 7-10 days later. If lesions persisted or symptoms developed, laryngoscopy under general anesthesia was performed. Patients were assessed daily for stridor after extubation. RESULTS: A total of 187 children were included. The incidence of post-extubation stridor was 44.38%. Stridor had a sensitivity of 77.78% (95% confidence interval [95% CI]: 51.9-92.6) and specificity of 59.18% (95% CI: 51.3-66.6) in detecting subglottic stenosis. The positive predictive value was 16.87% (95% CI: 9.8-27.1), and the negative predictive value was 96.15% (95% CI: 89.9-98.8). Stridor persisting longer than 72h or starting more than 72h post-extubation had a sensitivity of 66.67% (95% CI: 41.2-85.6), specificity of 89.1% (95% CI: 83.1-93.2), positive predictive value of 40.0% (95% CI: 23.2-59.3), and negative predictive value of 96.07% (95% CI: 91.3-98.4). The area under the receiver operating characteristic (ROC) curve was 0.78 (95% CI: 0.65-0.91). CONCLUSIONS: Absence of stridor was appropriate to rule out post-intubation subglottic stenosis. The specificity of this criterion improved when stridor persisted longer than 72h or started more than 72h post extubation. Thus, endoscopy under general anesthesia can be used to confirm subglottic stenosis only in patients who develop or persist with stridor for more than 72h following extubation. PMID- 30243645 TI - Sex difference in GPER expression does not change vascular relaxation or reactive oxygen species generation in rat mesenteric resistance arteries. AB - AIM: An imbalance between antioxidant and pro-oxidant factors, with a predominance of the latter, characterises oxidative stress and is indicative of a loss of vascular function. The beneficial vascular effects of oestrogen may be related to its ability to stimulate the G protein-coupled oestrogen receptor (GPER) and produce antioxidant activity. This study evaluated the GPER-dependent relaxation response in the mesenteric resistance arteries of female and male rats and measured the contributions of pro-oxidant and antioxidant enzymes in this response. MAIN METHODS: The relaxation response was characterised in third-order mesenteric arteries using concentration-response curves of the selective GPER agonist G-1 (1 nM-10 MUM), target protein levels were measured using Western blots, and vascular superoxide anion (O2-) and hydrogen peroxide (H2O2) levels were measured using dihydroethidium (DHE) and dichlorofluorescein (DCF) staining, respectively. KEY FINDINGS: The GPER agonist induced concentration-dependent vasorelaxation without showing differences between sexes. However, GPER expression was greater in male rats. No sex differences were detected in the expression of antioxidant proteins (catalase, SOD-1, and SOD-2). The basal vascular production of O2- and H2O2 was similar in the studied groups, and stimulation with G-1 maintained this response. SIGNIFICANCE: Together, our results show that the expression of GPER is greater in male mesenteric arteries, despite of the lack of a difference in vascular response. Nevertheless, antioxidant enzyme expression levels and the generation rates of pro-oxidants were similar between the studied groups. These results offer a new perspective for understanding GPER expression and functionality in resistance arteries. PMID- 30243646 TI - A pan-cancer study of copy number gain and up-regulation in human oncogenes. AB - AIM: There has been limited research on CNVs in oncogenes and we conducted a systematic pan-cancer analysis of CNVs and their gene expression changes. The aim of the present study was to provide an insight into the relationships between gene expression and oncogenesis. MAIN METHODS: We collected all the oncogenes from ONGene database and overlapped with CNVs TCGA tumour samples from Catalogue of Somatic Mutations in Cancer database. We further conducted an integrative analysis of CNV with gene expression using the data from the matched TCGA tumour samples. KEY FINDINGS: From our analysis, we found 637 oncogenes associated with CNVs in 5900 tumour samples. There were 204 oncogenes with frequent copy number of gain (CNG). These 204 oncogenes were enriched in cancer-related pathways including the MAPK cascade and Ras GTPases signalling pathways. By using corresponding tumour samples data to perform integrative analyses of CNVs and gene expression changes, we identified 95 oncogenes with consistent CNG occurrence and up-regulation in the tumour samples, which may represent the recurrent driving force for oncogenesis. Surprisingly, eight oncogenes shown concordant CNG and gene up-regulation in at least 250 tumour samples: INTS8 (355), ECT2 (326), LSM1 (310), DDHD2 (298), COPS5 (286), EIF3E (281), TPD52 (258) and ERBB2 (254). SIGNIFICANCE: As the first report about abundant CNGs on oncogene and concordant change of gene expression, our results may be valuable for the design of CNV-based cancer diagnostic strategy. PMID- 30243647 TI - The role of serotonin and its receptors on the anticonvulsant effect of curcumin in pentylenetetrazol-induced seizures. AB - AIM: Curcumin, derived from turmeric, has been demonstrated to be effective in controlling seizures, although the exact mechanism is yet unknown. In this study, the role of serotonin and its receptors in the anticonvulsant effect of curcumin was evaluated in mice. MAIN METHODS: Total 110 mice were randomly divided into 11 groups (n = 10). In the first to the fourth groups, the role of curcumin (150 mg/kg, i.p) and serotonin (PCPA (100 mg/kg); was used to deplete the brain serotonin levels) was investigated. The fifth group first received NAD-299 (4 mg/kg, sc), RS-102221 (5 mg/kg, i.p), SDZ205-557 Hydrochloride (1 mg/kg, i.p), and SB 26997 (10 mg/kg, i.p), then curcumin. The sixth group received NAD-299, curcumin. The animals in the seventh to ninth groups received 5-HT2C, 5-HT4, and 5-HT7 antagonists, respectively, with curcumin. The tenth group received HTR2C antagonist and the eleventh group received HTR4 antagonist. In all animals 25 min after curcumin PTZ (80 mg/kg; i.p) was injected. KEY FINDINGS: PCPA not only inhibited the anticonvulsant action of curcumin, but also reversed some of its anticonvulsant effect. The 5-HT1A, 5-HT2C and 5-HT4 antagonists diminished but 5 HT7 antagonist strengthened the anticonvulsant effect of curcumin. Evaluation of gene expression using real-time PCR confirmed that only 5-HT7 gene expression was reduced after curcumin injection. SIGNIFICANCE: According to these results, it may be suggested that curcumin exerts anticonvulsive effects by increasing the serotonin levels in the brain that influence receptors, including 5-HT1A, 5-HT2C, and 5-HT4 and likely through the reduction of 5-HT7 gene expression. PMID- 30243648 TI - Differential anticancer activities of arsenic trioxide on head and neck cancer cells with different human papillomavirus status. AB - AIMS: Approximately 20% of head and neck squamous cell carcinomas (HNSCCs) are caused by human papillomavirus (HPV) infection. The effect of arsenic trioxide (ATO) on HPV oncogene expression of HNSCC cells remains unknown. In this study, we investigated the anti-cancer activity and possible molecular pathways of ATO on the six HNSCC cell lines (three HPV-positive and three HPV-negative). METHODS: The effects of ATO on the cell proliferation, apoptosis, cell cycle of HNSCC cells were analyzed using CCK-8 assay, colony formation and flow cytometry. Transwell assay was used to examine the effect of ATO on cell migration. The transcriptional and protein expression of key genes were determined by real-time PCR and Western blot, respectively. Using a xenograft model, we assessed the effects of ATO on HNSCC cells in vivo. KEY FINDINGS: HPV-positive and -negative HNSCC cells had different expression of key genes. ATO inhibited HNSCC cell proliferation and migration and induced apoptosis and these effects were more significant in HPV-positive HNSCC cells than in HPV-negative HNSCC cells. ATO treatment reduced the expression of HPV16-E6/E7 and cyclin D1 proteins and enhanced the expression of p16, pRb, and p53 in HPV-positive HNSCC cells. By contrast, ATO treatment reduced the expression of epidermal growth factor receptor, cyclin D1 and mutant p53 and enhanced the expression of pRb in HPV negative HNSCC cells. Anti-cancer effect of ATO on HNSCCs was confirmed by inhibiting xenograft growth in vivo. SIGNIFICANCE: Our data suggest that ATO is a potential therapeutic drug for HNSCCs, especially HPV-positive HNSCCs. PMID- 30243649 TI - Proteomics, metabolomics and metagenomics for type 2 diabetes and its complications. AB - Type 2 diabetes mellitus (T2DM) is one of the most common diseases of endocrine and metabolic disorders, whose mechanism is still largely unknown. Fortunately, various "omics" tools have been employed to better understand the progression pathologies of T2DM and its complications. More specifically, proteomics, metabolomics and metagenomics have played crucial roles in advancing deeper understanding of the physiological processes and regulatory mechanisms of T2DM, such as regulation of signaling pathways perturbed by glucose levels, intestinal microorganism, and inflammation and so on. By analyzing the dynamic change and modification of proteins, proteomics has become an important tool in biology and medicine. Metabolomic analysis can amplify and quantify metabolites in living organisms to reveal the relative relationship between metabolites and physiological and pathological changes. There are also increasing evidences that the human microbiome, specifically the gastrointestinal microbiome have a potential role in the etiology and pathological outcomes of T2DM and its complications. This article summarized and discussed the recent applications of these "omics" tools in finding biomarkers for T2DM and its complications. We also reviewed employing multiple "omics" to further advance our understanding of this pathology. This review will benefit deeper understanding in new therapeutic and/or diagnostic biological target for the discovery of T2DM and its complications. PMID- 30243650 TI - Paclitaxel alleviates liver fibrosis induced by bile duct ligation in rats: Role of TGF-beta1, IL-10 and c-Myc. AB - Liver fibrosis is a global health issue that causes morbidity and mortality with no currently available treatment. It has been shown that low dose paclitaxel (PTX) can stabilize microtubules and inhibit the profibrotic transforming growth factor-beta 1 (TGF-beta1) signaling pathway. In this study the effect of treatment with low dose PTX was examined using a model of cholestatic liver fibrosis. Bile-duct ligation (BDL) was induced in rats for 2 weeks then PTX (0.3 mg/kg/ip) was administered three times a week for 2 weeks. Administration of PTX ameliorated BDL-induced elevation in biomarkers of hepatocellular damage (alanine transaminase; ALT and aspartate transaminase; AST) and obstructive cholestatic injury (total bilirubin and gamma glutamyl transferase; gamma-GT). PTX was able to correct the increase in liver weight to body weight ratio and the bile duct proliferation induced by BDL. Additionally, PTX treatment corrected the BDL induced fibrosis of portal tracts, elevation of hydroxyproline content and increased alpha smooth muscle actin (alpha-SMA) mRNA and protein expression. This antifibrotic effect of PTX was further examined through its inhibitory effect on TGF-beta1 mRNA and protein expression in addition to c-Myc mRNA expression. Furthermore, PTX rectified the BDL-induced decrease in interleukin-10 (IL-10) mRNA and protein expression. In conclusion, this study suggests that PTX at low dose has the potential to treat BDL-induced liver fibrosis in rats possibly through suppression of TGF-beta1 and c-Myc and activation of IL-10 pathways. PMID- 30243651 TI - Genotoxicity of intermediate frequency magnetic fields in vitro and in vivo. AB - We assessed genotoxic effects of intermediate frequency magnetic fields (MF) in vitro and in vivo. Rat primary astrocytes were exposed for 24 h to a 7.5 kHz MF at a magnetic flux density of 30 or 300 uT. Male C57BL/6 J mice were exposed continuously for 5 weeks to a 7.5 kHz MF at 12 or 120 MUT, and blood samples were collected for the genotoxicity assays. To evaluate possible co-genotoxicity, the in vitro experiments included combined exposure with menadione (an agent that induces mitochondrial superoxide production and DNA damage) and methyl methanesulfonate (an alkylating agent). DNA damage and DNA repair (in vitro) were measured using the alkaline Comet assay and formation of micronuclei was assessed microscopically (in vivo) or using flow cytometry (in vitro). The results did not support genotoxicity or co-genotoxicity of 7.5 kHz MFs at magnetic flux densities up to 300 uT in vitro or in vivo. On the contrary, there was some evidence that exposure to 7.5 kHz MFs might reduce the level of genetic damage. Strongest indication of any biological effects was obtained from measurements of relative cell number, which was significantly and consistently increased after MF exposure in all in vitro experiments. Health implications of this finding are unclear, but it suggests that 7.5 kHz MFs may stimulate cell proliferation or suppress cell death. PMID- 30243652 TI - Low BMD and high alcohol consumption predict a major re-operation in patients younger than 70 years of age with a displaced femoral neck fracture-A two -year follow up study in 120 patients. AB - BACKGROUND AND PURPOSE: The recommended treatment of displaced femoral neck fractures (FNF) in patients younger than 70 years of age is fracture reduction and internal fixation (IF). The incidence of re-operation due to nonunion (NU) or avascular necrosis (AVN) has been reported to be between 20-30%. Knowledge of possible predisposing factors needs to be elucidated. The primary aim of this study was to identify factors associated with a major re-operation due to NU or AVN in patients <70 years with a displaced FNF treated with IF. PATIENTS AND METHODS: 128 patients, 20-69 years with a FNF treated with IF. Follow up included radiographic and clinical examination at 4, 12 and 24 months. Logistic regression analysis was used to identify factors associated with re-operation due to NU or AVN. RESULTS: The re-operation rate due to NU or AVN was 6%, 16% and 28% at 4, 12 and 24 months respectively. Patients with low BMD was more likely to be re operated than those with normal BMD, OR 5.5, CI (95%) 1.15-26.8, and those with a high alcohol consumption had 3.2 times higher odds to be re-operated due to NU or AVN, CI (95%) 1.16-8.76. INTERPRETATION: In more than two thirds (83/120) of the patients the fracture healed after one operation. Moreover, a low BMD and high alcohol consumption were related to a major re-operation. These results suggest that only age as a sole variable for choosing the type of surgical treatment may not be rational. PMID- 30243653 TI - Histological study of the docking site after bone transport. Temporal evolution in a sheep model. AB - INTRODUCTION: Bone transport appears to be a solution for segmental bone defects; specifically, the "docking site" is where the transported segment meets the target segment at the end of the process. A lack of its consolidation is one of the major causes of failure for this technique. Many studies have been performed in order to enhance the consolidation of the docking site, but histological changes occurring in it remain unknown. The aim of this study was to determine microscopic changes present in this area, from distraction to remodeling, in order to clarify the best options to facilitate the success of this technique. MATERIALS AND METHODS: Ten adult sheep were submitted to bone transport using an Ilizarov external fixator. Histomorphometry and immunohistochemical studies were performed in the docking site to determine the main types of ossification, the evolutions of tissues and blood vessels and the distributions of collagen I and II. RESULTS: Ossification was mainly intramembranous with some areas of endochondral ossification. Fibrous tissue was predominant until 98 days after surgery. The area occupied by blood vessels increased until 50 days after surgery, when it decreased slowly until the end of the study. CONCLUSIONS: As far as the authors know, this is the first histological study performed in the docking site reporting the complete evolution of tissues until the end of remodeling, showing results contrary to those published by others authors. This could help to clarify information about its union and may be useful for future investigations about techniques for improving the consolidation of the docking site in humans. PMID- 30243654 TI - The social networks of free-roaming domestic dogs in island communities in the Torres Strait, Australia. AB - Social structure creates heterogeneity of interactions between individuals, thus influencing infectious disease spread. The objective of this study was to describe and characterise the social structure of free-roaming dog populations in three communities in the Torres Strait, Australia. Dogs in Kubin, Saibai, and Warraber communities were collared with GPS units that recorded locations at 15 s intervals for up to 1 week, and datasets were obtained from 24 (62% of the dog population), 23 (53%) and 21 (51%) dogs in each community, respectively. An association (potential contact) between dogs was defined as proximity within a spatio-temporal window of 5 m for 30 s. Networks were constructed for each dog population: 1. nodes were individual dogs, and 2. edges were weighted according to the duration of spatio-temporal association between pairs of dogs as a proportion of their simultaneous time monitored. Network statistics were calculated for each population and the robustness of networks to the duration of association between pairs of dogs was assessed in terms of efficiency, degree distribution and fragmentation (number of components). Dog social networks had 'small-world' structures, with characteristic clustering and low average shortest path length between individuals. Overall, all three networks were highly connected in terms of degree distribution and global and local efficiency, but the median tie strength (2-13.5 min) was low. Centrality and the duration of association (tie-strength) between dogs were significantly different between communities. The Kubin network was least robust to fragmentation when ties of short duration were successively removed (14 components with minimum tie strength of 2 h). In contrast, the Warraber dog network was relatively robust with 7 components at minimum tie strength of 2 h as well as high local efficiency within components. We conclude that whilst infectious disease that requires a short duration of contact for transmission is likely to spread rapidly between and within clusters in all three networks in this study, fragmentation of networks - once ties of short duration are removed - is likely to limit spread of disease that requires a longer duration of direct contact. The network information in this study is useful as a foundation for disease spread modelling and to investigate control strategies such as movement restrictions in dog populations. PMID- 30243656 TI - Research Techniques Made Simple: CAR T-Cell Therapy. AB - Chimeric antigen receptor (CAR) and chimeric autoantibody receptor T-cell therapy hold great promise in the treatment of cancer and autoimmune disease, respectively. This powerful technique involves genetically engineering T lymphocytes to enable selective destruction of disease-causing cells. In the current approach, a patient's T cells are genetically engineered to express an antigen-specific antibody fragment fused to activating cytoplasmic T-cell signaling domains. After ex vivo activation and genetic modification of a patient's own T cells, the individually tailored CAR T cells are then infused into the patient for the selective destruction of cells bearing the targeted antigen. CAR T cells directed against the CD19 antigen expressed on B lymphoma cells have shown remarkable clinical efficacy in the treatment of refractory lymphoma, with two anti-CD19 CAR-T products recently gaining approval from the US Food and Drug Administration. For dermatological disease, preliminary studies have shown efficacy of CAR T cells in targeting melanoma cells and the pathogenic B cells in pemphigus vulgaris. Despite its great promise, current clinical CAR T cell (or CAR-T) therapy carries a high risk of cytokine release syndrome, a potentially fatal systemic inflammatory response that can be manifest in cutaneous findings. For the dermatologist, the rapid clinical emergence of CAR-T therapy promises to treat and cure a variety of dermatological conditions, but it also requires an astute awareness of potential cutaneous complications in the increasing number of patients undergoing CAR-T therapy. PMID- 30243655 TI - The Amount of Bifidobacterium Genus in Colorectal Carcinoma Tissue in Relation to Tumor Characteristics and Clinical Outcome. AB - Evidence indicates a complex link between microbiota, tumor characteristics, and host immunity in the tumor microenvironment. In experimental studies, bifidobacteria appear to modulate intestinal epithelial cell differentiation. Accumulating evidence suggests that bifidobacteria may enhance the antitumor immunity and efficacy of immunotherapy. We hypothesized that the amount of bifidobacteria in colorectal carcinoma tissue might be associated with tumor differentiation and higher immune response to colorectal cancer. Using a molecular pathologic epidemiology database of 1313 rectal and colon cancers, we measured the amount of Bifidobacterium DNA in carcinoma tissue by a quantitative PCR assay. The multivariable regression model was used to adjust for potential confounders, including microsatellite instability status, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Intratumor bifidobacteria were detected in 393 cases (30%). The amount of bifidobacteria was associated with the extent of signet ring cells (P = 0.002). Compared with Bifidobacterium-negative cases, multivariable odd ratios for the extent of signet ring cells were 1.29 (95% CI, 0.74-2.24) for Bifidobacterium-low cases and 1.87 (95% CI, 1.16-3.02) for Bifidobacterium-high cases (Ptrend = 0.01). The association between intratumor bifidobacteria and signet ring cells suggests a possible role of bifidobacteria in determining distinct tumor characteristics or as an indicator of dysfunctional mucosal barrier in colorectal cancer. PMID- 30243657 TI - Advances in Cutaneous Lupus Erythematosus and Dermatomyositis: A Report from the 4th International Conference on Cutaneous Lupus Erythematosus-An Ongoing Need for International Consensus and Collaborations. PMID- 30243658 TI - Top-cited Articles in Regenerative Endodontics: A Bibliometric Analysis. AB - INTRODUCTION: Bibliometric analysis is a method for quantifying the research productivity, author performance, and manuscript impact. The citation count received by a scientific article is one of the indicators of its impact within a field. The purpose of this study was to identify the 100 top-cited articles published in regenerative endodontics and to analyze their main characteristics. METHODS: Thomson Reuters Web of Science was searched to retrieve the 100 most cited articles in "regenerative endodontics" published from January 1991 to February 2018 in the category of "Dentistry, Oral Surgery and Medicine." Among the included top-cited articles, the following parameters were recorded and analyzed: journal name, authors, institution, country, publication title and year, number of citations and average citations, type of study, collaborations, and key words. The data were analyzed using SPSS version 19.0 (IBM Corp, Armonk, NY) and VOS viewer software (version 1.6.7; Leiden University Center for Science and Technology Studies, Leiden, Netherlands). RESULTS: Among the 100 top cited articles, the highest number of citations that an article received was 309. The top cited articles appeared in 14 different journals, and the Journal of Endodontics published the greatest number of these articles (66%). The majority of articles were published in the year 2014 (n = 17). The majority of articles originated from the United States (n = 51) with the most contribution from The University of Texas Health Science Center, San Antonio, TX. The most frequent first authors were Torabinejad (n = 4), Nosrat (n = 3), and Thibodeau (n = 3). In vitro studies were the most common study design (n = 29) followed by reviews (n = 21). "Regenerative endodontics" was the most frequently used key word. CONCLUSIONS: This bibliometric analysis reveals the progress and trend of research in the field of regenerative endodontics. The in vitro articles published in the field of regenerative endodontics had the highest number of citations and average citation rates. PMID- 30243659 TI - Invasive Cervical Resorption: Clinical Management in the Anterior Zone. AB - According to the high number of articles published on invasive cervical resorption (ICR), this pathology, as commonly believed, is a more frequent form of cervical resorption. ICR is often misdiagnosed as internal resorption or caries, which leads to inappropriate treatment and even unnecessary tooth loss. Despite a correct diagnosis, the treatment of this type of hyperplastic invasive external resorption poses a challenge for the clinician. The Heithersay classification and the use of cone-beam computed tomographic imaging have increased our knowledge of the pathology and helped improve its prognosis. Nevertheless, there is no standard protocol for the treatment of this type of lesion. This article proposes a treatment protocol for ICR based on the pattern and location of resorption. Three treatment approaches (internal access, external access, and intentional replantation) are presented through 3 clinical cases. PMID- 30243660 TI - Antimicrobial Effect of Peptide DJK-5 Used Alone or Mixed with EDTA on Mono- and Multispecies Biofilms in Dentin Canals. AB - INTRODUCTION: The present study aimed to evaluate the antibacterial effect of a new peptide, DJK-5, used alone or mixed together with EDTA on mono- and multispecies biofilms in dentin canals covered by a smear layer with or without preceding sodium hypochlorite (NaOCl) irrigation. METHODS: One hundred twelve dentin blocks (224 final specimens) were prepared and divided into 56 groups, and Enterococcus faecalis or multispecies bacteria were introduced into dentinal tubules by centrifugation. After 1 week of cultivation, a uniform smear layer was created on the surface of the dentin blocks, and the samples were exposed to sterile water, 17% EDTA, 2% or 6% NaOCl, 10 MUg/mL DJK-5, or a mixture of 8.5% EDTA +10 MUg/mL DJK-5 or were combined treated with the solution in the following sequence: 2% or 6% NaOCl +10 MUg/mL DJK-5, 2% or 6% NaOCl + 8.5% EDTA +10 MUg/mL DJK-5, 2% or 6% NaOCl + 8.5% EDTA + 10 MUg/mL DJK-5. Specimens without a smear layer treated by 6% NaOCl or 10 MUg/mL DJK-5 served as the positive control. The irrigant exposure time was 3 or 10 minutes. The antibacterial efficacy was determined by live/dead staining and confocal laser scanning microscopy. RESULTS: The smear layer reduced the antibacterial capacity of 6% NaOCl and 10 MUg/mL DJK 5. The efficacy of 2% or 6% NaOCl followed by 10 MUg/mL DJK-5 was superior to 10 MUg/mL DJK-5 alone (P < .05) but inferior to 2% or 6% NaOCl + 8.5% EDTA + 10 MUg/mL DJK-5 and 2% or 6% NaOCl + 8.5% EDTA + 10 MUg/mL DJK-5 (P < .05). The mixture of 8.5% EDTA and 10 MUg/mL DJK-5 had the same disinfection effectiveness as 10 MUg/mL DJK-5 used alone (P < .05). Using 2% or 6% NaOCl before EDTA + peptide always resulted in the highest killing (P < .05). CONCLUSIONS: The smear layer inhibits the disinfectant effect in dentin. Peptide DJK-5 showed a strong antibacterial effect against mono- and multispecies biofilms in dentin canals. The highest killing was measured when 6% NaOCl was followed by a mixture of EDTA and peptide DJK-5. PMID- 30243662 TI - Comparison between Single-file Rotary Systems: Part 1-Efficiency, Effectiveness, and Adverse Effects in Endodontic Retreatment. AB - INTRODUCTION: The aim of this study was to evaluate in vitro the performance of 3 single-file systems: WaveOne Gold Primary (WOG; Dentsply Sirona, Ballaigues, Switzerland), Hyflex EDM "one file" (EDM; Coltene/Whaledent, Alstatten, Switzerland), and XP Shaper (XP; FKG, La Chaux de Fonds, Switzerland), for nonsurgical endodontic retreatment on mandibular anterior teeth in regard to the amount of remaining filling material inside the canal, debris extrusion, and operation time. METHODS: Sixty extracted standardized mandibular incisors presenting with a single oval canal were prepared to size 30.04 and obturated using warm vertical condensation. After 30 days (37 degrees C, 100% humidity), teeth were randomly divided into 3 groups (n = 20) according to the file used for retreatment (WOG, EDM, or XP operated at 3000 rpm). During the retreatment procedures, preweighed vials were used to collect apically extruded debris, and the time required to remove the filling material was recorded in seconds. Cone beam computed tomographic scans were taken before and after the retreatment to determine the amount of remaining filling material inside the root canal space. Statistical analysis was performed using the Kruskal-Wallis test, 1-way analysis of variance, and the Pearson test at a 5% significance level. RESULTS: There was a statistically significant difference among the groups regarding the instrumentation time (P < .05). XP was the fastest to remove gutta-percha from the canals (40.54 +/- 28.03 seconds) followed by EDM (55.77 +/- 19.76 seconds) and WOG (105.92 +/- 53.92 seconds). The percentage of remaining filling was significantly greater for WOG (26.65% +/- 14.63%) (P < .05). No difference was found between EDM (13.51% +/- 9.53%) and XP (8.60% +/- 7.28%). No difference was found regarding the amount of extruded debris among the 3 groups (P > .05). CONCLUSIONS: XP was the most efficient in gutta-percha removal from the canals when operated at a higher speed (3000 rpm) followed by EDM and WOG. PMID- 30243661 TI - Worldwide Analyses of Maxillary First Molar Second Mesiobuccal Prevalence: A Multicenter Cone-beam Computed Tomographic Study. AB - INTRODUCTION: Maxillary first molar second mesiobuccal (MB2) root canal prevalence may change among different populations. The aim of this study was to analyze the worldwide prevalence of the MB2 root canal and understand its possible relation with sex, age, side, and root configuration using in vivo cone beam computed tomographic (CBCT) assessment. METHODS: Observers from 21 regions were calibrated to achieve a similar CBCT assessment methodology and instructed to collect data from 250 maxillary first molars in previously existing examinations. Intra- and interrater reliability tests were performed. The sample size included 5250 molars and was defined by way of a preliminary trial. Data collected included MB2 presence, sex, age, side, number of roots per tooth, and mesiobuccal root configuration. The z test for proportions in independent groups was used to analyze the differences among subgroups. P < .05 was considered significant. RESULTS: The worldwide CBCT-assessed MB2 prevalence was 73.8%, ranging from 48.0% in Venezuela to 97.6% in Belgium. The prevalence in males and females was 76.3% and 71.8%, respectively (P < .05). Significantly higher MB2 proportions were found in younger patients and 3-rooted molar configurations. The group intraclass correlation coefficient and the percentage of agreement for the MB2 presence were 0.95 and 0.91, respectively. The intrarater Cohen kappa value was above 0.61 for all observers. CONCLUSIONS: MB2 prevalence in the analyzed regions varied widely. The differences may be associated with specificities within each region but also patient demographics. Males, younger patients, and 3 rooted configurations were associated with higher MB2 proportions. PMID- 30243663 TI - Solubility and pH Value of 3 Different Root Canal Sealers: A Long-term Investigation. AB - INTRODUCTION: The aim of this study was to compare the solubility and the change in pH of a tricalcium silicate-containing sealer (BioRoot RCS [BR]), a mineral trioxide aggregate-containing sealer (MTA Fillapex [MTA]), and an epoxy resin based sealer (AH Plus [AH]) during a longer period of time. METHODS: The solubility test was carried out in accordance with ISO6876:2012. Three hundred eighty sealer samples (n = 10 per group) were stored for 6 months in double distilled water (AD) or phosphate-buffered saline (PBS). The solubility was determined on the basis of the mass difference in percent. The pH measurement was carried out on the basis of the experimental setup of the solubility test with the aid of an electrode pH meter. The results were evaluated for significance by using analysis of variance, Student-Newman-Keuls, and t test (P < .05). RESULTS: The highest solubility was found for MTA in AD (4.65% +/- 1.17%), followed by BR in AD (3.88% +/- 0.42%) (P < .05). Also in PBS, MTA (3.24% +/- 0.7%) showed a higher solubility than BR (1.78% +/- 0.5%) (P < .05). AH was virtually insoluble during the entire period (0.5% +/- 0.5%) (P < .05). The pH decreased continuously over time for all samples. After 6 months, BR showed the highest pH in AD (pH 10.3), followed by MTA in AD (pH 8.8), BR in PBS (pH 7.5), AH in PBS (pH 7.3), MTA in PBS (pH 7.2), and AH in AD (pH 6.3). CONCLUSIONS: The solubility of MTA was significantly increased compared with BR and AH. Storage in PBS significantly reduced solubility of MTA and BR. BR showed a higher pH in both AD and PBS than MTA in AD and PBS. AH did not cause any significant pH change. PMID- 30243664 TI - Outcome of Endodontic Micro-resurgery: A Retrospective Study Based on Propensity Score-matched Survival Analysis. AB - INTRODUCTION: The purpose of this retrospective study was to evaluate and compare the outcome of endodontic micro-resurgery with that of primary endodontic microsurgery and determine prognostic factors affecting the outcome of micro resurgery. METHODS: A clinical database was searched for endodontic microsurgery cases between 2001 and 2016. Nearest neighbor 2:1 propensity score matching for the following 5 variables was performed for cases of primary microsurgery and those of micro-resurgery: age, sex, tooth type, lesion type, and postoperative restoration. For the matched cases, the outcome was categorized as success or failure according to clinical and radiographic evaluations performed at least 1 year after surgery. Kaplan-Meier survival analysis and log-rank tests were performed to compare the outcome of primary microsurgery with that of micro resurgery over time. For the micro-resurgery group, multivariate Cox proportional hazard regression analysis was performed to identify prognostic factors and estimate their effects. RESULTS: In total, 571 cases of endodontic microsurgery (498 primary microsurgery and 73 micro-resurgery cases) were identified, and 146 cases of primary microsurgery were matched to 73 cases of micro-resurgery through 2:1 propensity score matching. After matching, all covariates demonstrated an absolute standardized difference of <0.1. The estimated 5-year success rates were 91.6% and 87.6% for primary microsurgery and micro-resurgery, respectively (P = .594). The tooth type was found to be the only contributing factor for the outcome of micro-resurgery, with molars showing a higher probability of failure than anterior teeth (hazard ratio, 8.53; P = .002). CONCLUSIONS: Within the limitations, the findings of this study suggest that the outcome of endodontic micro-resurgery is comparable with that of primary endodontic microsurgery. PMID- 30243665 TI - Astaxanthin attenuates neuroinflammation contributed to the neuropathic pain and motor dysfunction following compression spinal cord injury. AB - Spinal cord injury (SCI) is a debilitating condition in which inflammatory responses in the secondary phase of injury leads to long lasting sensory-motor dysfunction. The medicinal therapy of SCI complications is still a clinical challenge. Understanding the molecular pathways underlying the progress of damage will help to find new therapeutic candidates. Astaxanthin (AST) is a ketocarotenoid which has shown anti-inflammatory effects in models of traumatic brain injury. In the present study, we examined its potential in the elimination of SCI damage through glutamatergic-phospo p38 mitogen-activated protein kinase (p-p38MAPK) signaling pathway. Inflammatory response, histopathological changes and sensory-motor function were also investigated in a severe compression model of SCI in male rats. The results of acetone drop and inclined plane tests indicated the promising role of AST in improving sensory and motor function of SCI rats. AST decreased the expression of n-methyl-d-aspartate receptor subunit 2B (NR2B) and p-p38MAPK as inflammatory signaling mediators as well as tumor necrosis factor-alpha (TNF-alpha) as an inflammatory cytokine, following compression SCI. The histopathological study culminated in preserved white mater and motor neurons beyond the injury level in rostral and caudal parts. The results show the potential of AST to inhibit glutamate-initiated signaling pathway and inflammatory reactions in the secondary phase of SCI, and suggest it as a promising candidate to enhance functional recovery after SCI. PMID- 30243666 TI - Binary colloidal crystals (BCCs): Interactions, fabrication, and applications. AB - The organization of matter into hierarchical structures is a fundamental characteristic of functional materials and living organisms. Binary colloidal crystal (BCC) systems present a diversified range of nanotopographic structures where large and small colloidal particles simultaneously self-assemble into either 2D monolayer or 3D hierarchical crystal lattices. More importantly, understanding how BCCs form opens up the possibility to fabricate more complex systems such as ternary or quaternary colloidal crystals. Monolayer BCCs can also offer the possibility to achieve surface micro- and nano-topographies with heterogeneous chemistries, which can be challenging to achieve with other traditional fabrication tools. A number of fabrication methods have been reported that enable generation of BCC structures offering high accuracy in growth with controllable stoichiometries; however, it is still a challenge to make uniform BCC structures over large surface areas. Therefore, fully understand the mechanism of binary colloidal self-assembly is crucial and new/combinational methods are needed. In this review, we summarize the recent advances in BCC fabrication using particles made of different materials, shapes, and dispersion medium. Depending on the potential application, the degree of order and efficiency of crystal formation has to be determined in order to induce variability in the intended lattice structures. The mechanisms involved in the formation of highly ordered lattice structures from binary colloidal suspensions and applications are discussed. The generation of BCCs can be controlled by manipulation of their extensive phase behavior, which facilitates a wide range potential applications in the fields of both material and biointerfacial sciences including photonics, biosensors, chromatography, antifouling surfaces, biomedical devices, and cell culture tools. PMID- 30243667 TI - Surface modified halloysite nanotubes: A flexible interface for biological, environmental and catalytic applications. AB - Halloysite Nanotubes (HNTs) are clay minerals that possess unique chemical composition and a tubular structure due to which, they have recently emerged as a potential nanomaterial for umpteen applications. Over the years, the myriad applications of HNT have been realized through the surface modification of HNT, which involves the modification of nanotube's inner lumen and the outer surface with different functional compounds. The presence of aluminum and silica groups on the inner and outer surface of HNT enhance the interfacial relationship of the nanotube with different functional agents. Compounds such as alkalis, organosilanes, polymers, compounds of biological origin, surfactants and nanomaterials have been used for the modification of the inner lumen and the outer surface of HNT. The strategies change the constitution of HNT's surface either through micro-disintegration of the surface or by introducing additional functional groups on the surface, which further enhances their potential to be used as a flexible interface for different applications. In this review, the different surface modification strategies of the outer surface and the inner lumen that have been employed over the years have been discussed. The biological, environmental and catalytic applications of these surface modified HNTs with such versatile interface in the past two years have been elaborately discussed as well. PMID- 30243668 TI - Spontaneous Giant Laryngeal Granuloma in the Absence of Laryngeal Injury. AB - The etiology of laryngeal granuloma can typically be attributed to endotracheal intubation, vocal abuse, or gastroesophageal reflux disease. There is a strong male predominance, except in cases due to intubation, where incidence is higher in women. We report a case of spontaneous development of multiple granulomas in a female with no history of intubation who presented with hoarseness and massive bilateral supraglottic masses obscuring her glottis. The disparity between the massive lesions and asymptomatic reflux highlights the need for further research in the pathophysiology of laryngeal granulomas. PMID- 30243670 TI - MRI-based automated detection of implanted low dose rate (LDR) brachytherapy seeds using quantitative susceptibility mapping (QSM) and unsupervised machine learning (ML). AB - BACKGROUND AND PURPOSE: Permanent seed brachytherapy is an established treatment option for localized prostate cancer. Currently, post-implant dosimetry is performed on CT images despite challenging target delineation due to limited soft tissue contrast. This work aims to develop an MRI-only workflow for post-implant dosimetry of prostate brachytherapy seeds. MATERIAL AND METHODS: A prostate mimicking phantom containing twenty stranded I-125 dummy seeds and calcifications was constructed. A three-dimensional gradient-echo MR sequence was employed on 3T and 1.5T MR scanners. An optimized quantitative susceptibility mapping (QSM) technique was applied to generate positive contrast for the seeds and calcifications. Seed numbers, centroids, and orientations were determined using unsupervised machine learning algorithms (K-means and K-medoids clustering). The geometrical seed positions and the resulting dose distribution were compared to the clinical CT-based approach. RESULTS: The optimized QSM-based method generated high quality positive contrast for the seeds that were significantly different from that for calcifications and could be easily differentiated by thresholding. The estimated seed centroids from both 3T and 1.5T MR data were in perfect agreement with the standard CT-based seed detection algorithm (maximum difference of 0.7 mm). The estimated seed orientations were highly correlated with the actual orientations (R > 0.98). CONCLUSIONS: The proposed MRI-based workflow enabling an accurate and robust means to localize the seeds (position and orientation) upon validation on complex seed configurations, has the potential to replace the current widely practiced CT-based workflow. PMID- 30243672 TI - Distal Urethroplasty and Glanuloplasty Procedure Can be Suitable for All Types of Glanular/Subcoronal Hypospadias. AB - OBJECTIVE: To correct all types of glanular/subcoronal hypospadias, we performed surgery named the distal urethroplasty and glanuloplasty procedure (DUG procedure). We analyzed cases that we have experienced. METHODS: A vertical incision with the meatal margin was made in the 12 o'clock direction, with the margin of the external urethral meatus as the center. By this meatoplasty according to Heineke-Mikulicz principle, we changed all type of glanular/subcoronal hypospadias to the hypospadias with wide meatus and wide glans. And then Thiersh-Duplay procedure was performed. RESULTS: Consecutive 24 underwent modified DUG procedure. The mean age at the time of surgery was 19.0 +/ 11.9 months and the mean preoperative glans width was 13 +/- 1.5 mm. The external urethral meatus was located glanular in 13 and subcoronal in 11. Hypoplastic urethra (HU) was observed in 7. Skin chordee in 10, penile torsion in 6 and meatal stenosis in 10 were observed. The mean surgical duration was 106 +/- 25.4 minutes and the mean postoperative observation period was 40.5 +/- 26.2 months. All patients with preoperative skin chordee, penile torsion, and meatal stenosis were improved postoperatively, and in all cases, apart from the patient with meatal regression with longest HU from glanular to distal penile, the slit like shape of the external urethral meatus was achieved. CONCLUSION: DUG procedure can be used for any type of glanular/subcoronal hypospadias but care should be taken not to indicate too aggressively for glanular/subcoronal hypospadias accompanying long HU to distal penile shaft. PMID- 30243673 TI - A mosaic of independent innovations involving eyes shut are critical for the evolutionary transition from fused to open rhabdoms. AB - A fundamental question in evolutionary biology is how developmental processes are modified to produce morphological innovations while abiding by functional constraints. Here we address this question by investigating the cellular mechanism responsible for the transition between fused and open rhabdoms in ommatidia of apposition compound eyes; a critical step required for the development of visual systems based on neural superposition. Utilizing Drosophila and Tribolium as representatives of fused and open rhabdom morphology in holometabolous insects respectively, we identified three changes required for this innovation to occur. First, the expression pattern of the extracellular matrix protein Eyes Shut (EYS) was co-opted and expanded from mechanosensory neurons to photoreceptor cells in taxa with open rhabdoms. Second, EYS homologs obtained a novel extension of the amino terminus leading to the internalization of a cleaved signal sequence. This amino terminus extension does not interfere with cleavage or function in mechanosensory neurons, but it does permit specific targeting of the EYS protein to the apical photoreceptor membrane. Finally, a specific interaction evolved between EYS and a subset of Prominin homologs that is required for the development of open, but not fused, rhabdoms. Together, our findings portray a case study wherein the evolution of a set of molecular novelties has precipitated the origin of an adaptive photoreceptor cell arrangement. PMID- 30243671 TI - Isodose surface volumes in cervix cancer brachytherapy: Change of practice from standard (Point A) to individualized image guided adaptive (EMBRACE I) brachytherapy. AB - PURPOSE: To investigate the isodose surface volumes (ISVs) for 85, 75 and 60 Gy EQD2 for locally advanced cervix cancer patients. MATERIALS AND METHODS: 1201 patients accrued in the EMBRACE I study were analysed. External beam radiotherapy (EBRT) with concomitant chemotherapy was followed by MR based image-guided adaptive brachytherapy (MR-IGABT). ISVs were calculated using a predictive model based on Total Reference Air Kerma and compared to Point A-standard loading systems. Influence of fractionation schemes and dose rates was evaluated through comparison of ISVs for alpha/beta 10 Gy and 3 Gy. RESULTS: Median V85 Gy, V75 Gy and V60 Gy EQD210 were 72 cm3, 100 cm3 and 233 cm3, respectively. Median V85 Gy EQD210 was 23% smaller than in standard 85 Gy prescription to Point A. For small (<25 cm3), intermediate (25-35 cm3) and large (>35 cm3) CTVHR volumes, the V85 Gy was 57 cm3, 70 cm3 and 89 cm3, respectively. In 38% of EMBRACE patients the V85 Gy was similar to standard plans with 75-85 Gy to Point A. 41% of patients had V85 Gy smaller than standard plans receiving 75 Gy at Point A, while 21% of patients had V85 Gy larger than standard plans receiving 85 Gy at Point A. CONCLUSIONS: MR-IGABT and individualized dose prescription during EMBRACE I resulted in improved target dose coverage and decreased ISVs compared to standard plans used with classical Point A based brachytherapy. The ISVs depended strongly on CTVHR volume which demonstrates that dose adaptation was performed per individual tumour size and response during EBRT. PMID- 30243674 TI - Conservative treatment of distal ulna metaphyseal fractures associated with distal radius fractures in elderly people. AB - INTRODUCTION: Although volar locking plates (VLPs) have been exclusively used for unstable distal radius fractures (DRFs), the optimal management of distal ulna fractures (DUFs) remains controversial. Internal fixation using a plate for DUFs might be challenging because of the presence of osteoporotic bone and fragile bone fragments in elderly patients. HYPOTHESIS: We hypothesized that a strategy including VLP fixation for DRFs and non-intervention for DUFs with early wrist mobilization would provide encouraging results in elderly patients. MATERIALS AND METHODS: Eighteen patients (17 women and one man, mean age 74.7 years) were included in the study. According to the Biyani classification, there were seven patients with type-1, three with type-2, five with type-3, and three with type-4 DUFs. Radiological results were analyzed in 18 patients and the clinical results could be evaluated in 10 patients who attended the necessary follow-up meetings. Ulnar angular deformity (UAD) and ulnar shortening amount (USA) were measured using anteroposterior radiographs. USA was defined as the difference in ulnar variance between just after surgery and at the final visit. Clinical results were assessed using the modified Gartland and Werley score, disability arm shoulder hand (DASH) score, range of motion, grip strength, pain, and distal radioulnar joint (DRUJ) instability. RESULTS: All ulna metaphyseal fractures united. The mean UAD just after surgery was 5.9 degrees (range, 0-22). At the final visit, the mean UAD was 6.4 degrees (range, 0-17). The mean USA was 0.35mm, and only one patient showed ulnar shortening of >2mm. The results were "excellent" in nine patients and "good" in one, according to the modified Gartland and Werley score. The mean DASH score was 4.2. Mean flexion and extension angles were 58 degrees and 71 degrees . One patient complained of ulnar-sided pain during exertion and no patients complained of DRUJ instability. DISCUSSION: All DUFs achieved good radiological results, including comminuted fractures. Functional outcomes were promising, including wide wrist ROM and no DRUJ instability. An approach including VLP fixation for DRFs and non-intervention for DUFs is a good option for elderly patients. LEVEL OF EVIDENCE: IV retrospective study. PMID- 30243675 TI - Distal femoral torsion: Differences between caucasians and asians. A multicentre computed tomography study of 515 distal femurs. AB - BACKGROUND: The posterior condylar angle (PCA) is formed by the posterior condylar line (PCL) and the clinical (or anatomic) transepicondylar line (TEL). The primary objective of this study was to compare the distribution of PCA values in Caucasians and Asians free of knee osteoarthritis. The secondary objectives were to assess PCA variability according to age, gender, and side. HYPOTHESIS: PCA values differ between Caucasians and Asians. METHODS: The study included the computed tomography scans of 515 healthy femurs, 259 from Asians in China and 256 from Caucasians in France. PCA values were determined based on four landmarks, namely, the two femoral epicondyles and the most prominent point of each condyle at the posterior aspect of the knee. The Mann-Whitney test was chosen to compare PCA values according to ethnic group, gender, and side and Spearman's correlation coefficient to assess correlations with age. Inter-observer and intra-observer variability of PCA measurements was assessed. RESULTS: Mean PCA was 6.0 degrees +/-2.5 degrees (range, 0 degrees -14 degrees ) overall, 6.4 degrees (range, 0.31 degrees -14.1 degrees ) in the Asians, and 5.5 degrees (range, 0 degrees 13.1 degrees ) in the Caucasians (p<0.0001). Chinese femurs are significantly more internally rotated. No differences in PCA values were found according to age (p=0.4307), gender (p=0.7113), or side (p=0.4304). Inter-observer and intra observer variability was limited for each of the landmarks, indicating that PCA measurement was reliable. CONCLUSION: PCA varies not only across individuals as reported previously, but also across ethnic groups. This finding further supports routine PCA measurement on imaging studies before total knee arthroplasty. LEVEL OF EVIDENCE: III, comparative retrospective study. PMID- 30243676 TI - Arthroscopic classification of chronic anterior talo-fibular ligament lesions in chronic ankle instability. AB - BACKGROUND: The surgical treatment of chronic ankle instability (CAI) relies chiefly on anterior talo-fibular ligament (ATFL) repair (with or without augmentation) or anatomical reconstruction with a tendon graft. Arthroscopy enables not only a complete assessment and the same-stage treatment of concomitant articular lesions, but also an accurate assessment of ligament lesions. Pre-operative imaging studies (MRI, CT, US) may fail to provide sufficient detail about chronic ATFL lesions to guide the decision between repair and reconstruction. The aim of this study was to develop an arthroscopic classification of chronic ATFL lesions designed to assist in selecting the optimal surgical technique. MATERIAL AND METHODS: Sixty-nine anterior ankle arthroscopy videos recorded before surgery for CAI were studied retrospectively. ATFL dissection was performed in all patients. Based on the video analysis, five ATFL grades were identified: 0, normal ATFL thickness and tension; 1, ATFL distension with normal thickness; 2, ATFL avulsion with normal thickness; 3, thin ATFL with no resistance during the hook test; and 4, no ATFL, with a bald malleolus. Intra- and interobserver reproducibility of the arthroscopic classification of chronic ATFL lesions was evaluated by computing the kappa coefficients (kappa) after assessment by two independent observers. RESULTS: All 69 ATFLs were classified as abnormal (none was grade 0). Each ATFL could be matched to a grade. Intra-observer agreement was good for both observers: kappa was 0.67 with 75% of agreement for one observer and 0.68 with 76% of agreement for the other observer. Inter-observer agreement was fair to good, with kappa values ranging from 0.59 to 0.88 and agreement from 70% to 91%. DISCUSSION: Arthroscopic ATFL dissection is a simple procedure that provides a highly accurate assessment of ATFL lesions and mechanical resistance, focussing chiefly on the superior ATFL. Grade 1 and 2 lesions can be repaired using the Brostrom Gould procedure, whereas grade 3 and 4 lesions require anatomic reconstruction with grafting. CONCLUSION: This arthroscopic classification of chronic ATFL lesions confirms the diagnostic role for arthroscopy in assessing the ligaments in patients with CAI. It is helpful for determining the best surgical technique for stabilising the ankle. These results must be confirmed in a larger study. PMID- 30243678 TI - Update on the supply and use of allografts in locomotor system pathologies in France. AB - : Allografts are increasingly used in orthopedics. The main aim of the present study was to map the use of locomotor system allografts in France between 2012 and 2016. The study hypothesis was that there are great differences in the distribution and activity of tissue banks and graft preservation procedure quality, failing to meet national requirements. MATERIAL AND METHODS: Data from activity reports of the French Biomedicine Agency (ABM) were collected for the period 2012-2016. Existing viral inactivation procedures were described. Preliminary results from a study of allograft requirements by the French Society of Arthroscopy (SFA) were reported. RESULTS: Nineteen tissue banks were located. Four dealt exclusively with cryopreserved tissue, 3 exclusively with virus inactivated bone, and 12 with both. Distribution analysis found wide disparities in geographic location and in type of activity. Viral inactivation is presently implemented only for femoral heads derived from hip replacement. Stocks of long bones, femoral heads and ligaments/tendons increased constantly over the study period, by 8.3%, 50.8% and 316.2% respectively. The SFA questionnaire confirmed a serious shortage of tissues, necessitating importation of allografts. DISCUSSION: Each tissue bank had its own specificities and specialization. They should probably be coalesced, so as to centralize both supply and demand and improve nationwide response to requirements. Locomotor system tissue harvesting also needs to be expanded to meet increasing demand. PMID- 30243677 TI - Determination of bone density in patients with sacral fractures via CT scan. AB - BACKGROUND: Gold standard to diagnose osteoporosis is standard dual-energy X-ray absorptiometry (DXA). CT is a standard diagnostic tool to detect injuries to the pelvic ring. The aim of the study was to collect information on bone density without DXA by determination of Hounsfield units (HU) in CT scans of patients with sacral fractures, to draw conclusions on the prevalence of osteoporosis in patients admitted to the investigating institution. HYPOTHESIS: Is the determination of HU in CT scans a useful method to gain more information about bone density in patients with sacral fractures? PATIENTS AND METHODS: We performed a retrospective analysis of all patients treated from 2004-2014 with sacral fractures confirmed with a CT scan. A total of 531 patients (398 female, 133 male) were included in the study. Bone density was measured with CT scans in Hounsfield units in vertebral body L5. The assessment was performed by placing a single oval over the trabecular bone in the axial view. In the sagittal plane, the correct position in the middle of the vertebral body was checked. As in previously published studies, we defined bone of less than 100 HU as osteoporotic, 100-150 HU as osteopenic and above 150 HU as normal. RESULTS: In 71.6% of the patients, bone density was reduced. Seventy-five percent of patients aged 65 or more exhibited manifest osteoporosis. With each additional year of age, bone density decreased by 2.7 Hounsfield units (p?0.001). Female patients were predominant in the patient group with osteoporotic bone (p?0.001). CONCLUSIONS: There is significant prevalence of reduced bone density in the investigated patient group. The methodology used in this study is an uncomplicated procedure to further assess bone quality in patients with fractures of the pelvic ring. Fractures of the posterior pelvic ring in women over 65 years with low-energy trauma are most probably osteoporotic. LEVEL OF EVIDENCE: III. PMID- 30243679 TI - Predictability of open superficial medial collateral ligament lengthening technique in total knee arthroplasty. Comparison of multiple needle puncturing and subperiosteal elevation: A cadaver study. AB - PURPOSE: Lengthening of superficial medial collateral ligament (sMCL) is often needed in total knee replacement for varus osteoarthritis knee. This study aimed to compare the relationship of multiple needle puncturing (MNP) and subperiosteal elevation (SE) for sMCL lengthening on the gap increment and sequential lengthening in cadaveric knees. HYPOTHESIS: MNP produces more reliable gap increment than SE technique for sMCL lengthening performed in knee flexion. METHODS: From 8 pairs of cadaveric knees, one knee from each pair was randomly assigned to undergo MNP and the others to SE. In the MNP group, an 18gauge needle was used to puncture through the sMCL, performing five punctures each time of release. For the SE group, a periosteal elevator was used to sequentially deepen distally beneath the sMCL insertion with an increment depth of 5mm each time of release. The primary outcome was the medial gap increment at knee extension and 90 degrees knee flexion after every attempt in each group. RESULTS: At each level of lengthening, the widening of flexion and extension gap were not significantly different between the two techniques except for lengthening after 4 and 6 attempts of SE that gave greater widening in extension gap. Variability (width of mid 95% of values) was significantly greater for any given number of attempts using SE than MNP (0.5 vs. 0.24mm per attempt for extension and 2.28 vs. 0.95mm per attempt for flexion; both p<0.001). CONCLUSION: The MNP technique is a reproducible technique for lengthening the sMCL in knee flexion. It has less variability in gap widening compared to the SE technique. LEVEL OF EVIDENCE: II, controlled randomized laboratory study. PMID- 30243680 TI - Antipsychotic drugs for elderly patients with schizophrenia: A systematic review and meta-analysis. AB - Elderly patients with schizophrenia are a particularly vulnerable group often excluded from clinical trials. Currently there is no evidence-synthesis about the efficacy and safety of antipsychotics in this subgroup. We reviewed all randomized-controlled-trials, about antipsychotics in elderly schizophrenics (last search Dec 12, 2017). Pairwise meta-analyses were conducted. The primary outcome was overall symptoms. Secondary outcomes included positive symptoms, negative symptoms, response, dropouts, quality of life, social functioning and side-effects. We included 29 references from 18 unique randomized-controlled trials with 1225 participants published from 1958 to 2009. The definition of "elderly" was very heterogeneous across the studies (minimum age 46-65, mean age 57-73). There were evidence gaps for most drugs in many outcomes. In terms of efficacy paliperidone was associated with fewer dropouts due to inefficacy than placebo in the only placebo-controlled-trial. Olanzapine was superior to haloperidol in overall symptoms, negative symptoms and response, and it was associated with fewer dropouts than risperidone. Risperidone and haloperidol produced more prolactin increase than olanzapine, and olanzapine was associated with less use of antiparkinson medication than haloperidol. Although we found no marked differences of the effects of these drugs in the elderly, the evidence presented was based on very few usually small studies. To examine specifically whether there are differences in efficacy and side-effects in elderly, which differs in meaningful ways from the general population, studies in patients who are defined by critiera as truly geriatric, which incorporates older age together with multimorbidity and fraility dimensions, may be more informative. PMID- 30243681 TI - Can lithium salts prevent depressive episodes in the real world? AB - To critically examine the effectiveness of lithium in preventing depressive symptoms (mixed and depressive episodes) in real life settings, taking into account adherence to drug treatment and its implications for the clinical costs of the disease. Overall, 72 patients with bipolar disorder initially treated with lithium carbonate were included and followed-up for 10 years. Patients were assessed every 8 weeks for morbidity and alcohol/drug consumption. Patients with good adherence to lithium had fewer episodes with depressive features than poor adherers (B = 2.405, p = 0.046) and also fewer manic and hypomanic episodes (B = 2.572; p < 0.001), after controlling for confounders. Time to relapse into a depressive or mixed episode and into a manic or hypomanic episode was shorter in patients with poor adherence. The costs of the 1.95 +/- 2.38 (mean +/- standard deviation) admissions of adherent patients through the 10 years of follow-up were ?10,349, while the costs of the 6.25 +/- 4.92 admissions of non-adherent patients were ?44,547. In clinical practice settings, long-term lithium salts seem to have a preventive effect on depressive symptoms. PMID- 30243682 TI - Schizophrenia dimension-specific antipsychotic drug action and failure in amphetamine-sensitized psychotic-like rats. AB - Schizophrenic patients suffer from various disruptions in their psyche, mood and cognition, most of which cannot be effectively treated with the available antipsychotic drugs. Some dimensions of the schizophrenia syndrome in man can be mimicked in animals by the amphetamine (AMPH)-sensitization-induced psychosis model. Using such a sensitization procedure, we induced a psychosis-like syndrome in rats, measured as a deficit in sensory information processing and memory deficits. We then investigated the possible restorative effects of continuous treatment with haloperidol (HAL), a typical antipsychotic drug, on distinct dimensions of the syndrome. We found that, continuous infusion of a clinically relevant dose of HAL (0.5 mg/kg/day) effectively ameliorated AMPH-sensitization induced sensorimotor gating disruptions after seven days of treatment. However, the sensory information processing deficit reappeared after prolonged HAL treatment, suggesting a treatment failure in this dimension of the syndrome. HAL had at this dose little beneficial effects on the cognitive deficits. In contrast, a continuously administered low dose of HAL (0.05 mg/kg/day) successfully attenuated cognitive deficits, but aggravated the sensorimotor gating deficit under both short- or long-term treatment conditions. Post mortem neurochemical analysis revealed that the psychotic-like behavior induced by our manipulations might be explained by altered monoamine levels in distinct brain regions. These findings provide evidence for dissociating and dose-dependent HAL treatment action and failure at different dimensions of schizophrenia. PMID- 30243683 TI - An fMRI study of decision-making under sunk costs in gambling disorder. AB - The sunk cost effect is the tendency to continue an investment, or take an action, even though it has higher future costs than benefits, if costs of time, money, or effort were previously incurred. This type of decision bias is pervasive in real life and has been studied in various disciplines. Previous studies and clinical observations suggest that decision-making under sunk costs is altered in gambling disorder (GD). However, the neural mechanisms of decision making under sunk costs in GD remain largely unknown, and so is their association with the clinical characteristics of this patient group. Here, by combining functional magnetic resonance imaging and the task that demonstrated a clear example of the sunk cost effect, we investigated the neural correlates during decision-making under sunk costs in GD. We found no significant differences in the strength of the sunk cost effect between the GD and healthy control (HC) groups. However, the strength of the sunk cost effect in patients with GD showed a significant negative correlation with abstinence period and a marginally significant positive correlation with the duration of illness. We also found a reduction in the neural activation in the dorsal medial prefrontal cortex during decision-making under sunk costs for the GD group compared with the HC group. Furthermore, in patients with GD, the levels of activation in this area negatively correlated with the duration of illness. These findings have important clinical implications. This study will contribute to a better understanding of the mechanisms underlying altered decision-making abilities in GD. PMID- 30243684 TI - Cesarean Scar Pregnancies: Incidence and Factors Associated with Conversion to Surgery from Medical Management. AB - STUDY OBJECTIVE: To describe the incidence, management, and complications of cesarean scar pregnancy (CSP) and define risk factors for conversion from medical to surgical treatment of CSP. DESIGN: Retrospective clinical study (Canadian Task Force classification II-3). SETTING: Tertiary medical center. PATIENTS: All patients who were admitted and treated for CSP between 2008 and 2016. INTERVENTIONS: The cohort was divided according to management, and demographic, clinical, and sonographic data were collected. Rates of conversion were compared between groups, and risk factors necessitating conversion were sought. MEASUREMENTS AND MAIN RESULTS: Forty-six cases of CSP were identified. The incidence of CSP has increased from 0.05% to 0.09% of all deliveries. A regression model for absolute numbers of CSP predicted an additional 0.47 CSP each year (p = .03). The most common treatment modalities were systemic treatment with methotrexate (28.2%) and ultrasound-guided intrasac injection of KCl with systemic treatment of methotrexate (58.7%). The mean sac diameter (MSD) of cases that were converted was 11.2 mm larger than in cases that were not converted (p < .001). No patients with an MSD <10 mm or a trophoblastic mass <20 mm3 were converted to surgical management. Maximal levels of beta human chorionic gonadotropin (beta-hCG) were significantly associated with the risk of conversion. Only 6.3% of patients with a beta-hCG level <10,000 IU at presentation were converted from medical to surgical management. There was no significant association between fetal cardiac activity and conversion from medical to surgical management. CONCLUSIONS: CSP has emerged as an important phenomenon in modern obstetrics and gynecology, and its frequency appears to be on the rise. The preferred method of treatment remains unclear; however, it is possible that a large MSD and trophoblastic mass at presentation should prompt surgical treatment. PMID- 30243685 TI - Surgeon Volume in Benign Gynecologic Surgery: Review of Outcomes, Impact on Training, and Ethical Contexts. AB - It is becoming increasingly clear that surgeon volume affects surgical outcomes. High-volume surgeons demonstrate reduced perioperative complications, shorter operative times, and reduced blood loss during multiple modalities of benign gynecologic surgery. Furthermore, high-volume surgeons consistently demonstrate higher rates of minimally invasive approaches, low rates of conversion to laparotomy, and lower per-procedure case costs. It is suggested that surgeons who have completed postresidency training have improved surgical outcomes, although these data are limited. Surgical exposure in obstetrics and gynecology residency is varied and does not consistently meet demonstrated surgical learning curves. Deficiencies in residency surgical training may be related to the volume-outcome relationship. We suggest reforming residency surgical training and tracking postresidency practice to provide optimal surgical care. Additionally, surgeons may have an ethical obligation to inform patients of their surgical volume and outcomes, with options for referrals if needed. PMID- 30243686 TI - Laparoscopic Management of Cervical Ectopic Pregnancy with Devascularization. PMID- 30243687 TI - Laparoscopic management of an intrauterine fallopian tube incarceration after curettage for a non- progressing pregnancy. AB - STUDY OBJECTIVE: To report a case of a laparoscopic repair of an intrauterine fallopian tube incarceration as complication of curettage DESIGN: A step-by-step explanation of the surgery using video (instructive video), approved the local Institutional Review Board (Canadian Task Force III) SETTING: University Hospital Estaing, Clermont-Ferrand, France PATIENT: A 29-year-old woman experiencing a non evolving pregnancy at 8 weeks underwent a curettage. After nine months, she complained from abnormal vaginal discharge. Ultrasound evaluation showed a right para-uterine mass. She reported a maternal medical history of ovarian cancer in a context of Lynch syndrome. A MRI described a right hydrosalpinx of 12mm diameter, with a suspect fimbriae lesion of the tuba and a 7mm endometriosis nodule of the uterine torus. INTERVENTION: We decided to explore the tuba by laparoscopy and to perform an hysteroscopy. A fallopian tube incarceration was suspected during hysteroscopy: a defect of the uterine wall was observed, through which there was protrusion of a tubal fimbriae. The laparoscopic view of the pelvis confirmed the incarceration of the right fallopian tube through the uterine wall. It was carefully extracted out of the uterine defect. The uterine wall defect was repaired with an X point with Monocryl 1. MEASUREMENTS AND MAIN RESULTS: A tubal patency test was performed, which was positive on both sides. As phimosis responsible for the hydrosalpinx had been treated, salpingectomy was not performed. CONCLUSION: Curettage for miscarriage or undesired pregnancy is not exempt from complications (as hemorrhage, simple perforation, or infection) Intrauterine fallopian tube incarceration is uncommon but can affect fertility. This diagnosis is important to avoid destruction of the fimbriae, necrosis of the tube and also to reduce the risk for ectopic pregnancy. PMID- 30243688 TI - Higher Education - Is the Value Worth the Cost? PMID- 30243689 TI - Tailoring NCLEX-RN Indicator Assessments for Historically Black Colleges and Universities: Literature Review. AB - A review of the literature was undertaken as the foundation for developing an assessment tool for Blacks/African Americans, other racial/ethnic minorities, and low-income students attending historically Black colleges and universities. Findings revealed a variety of academic and nonacademic indicators were used to evaluate likelihood of success. Course specific grades, grade point average (GPA), standardized comprehensive exams and standardized course specific exams were the most commonly used predictor variables that showed significant outcomes. Indicators more accurately predicted which students would pass NCLEX-RN rather than those who would fail. The type of pre-licensure program may influence best outcome indicators. Increased attention to and reporting of demographic information would increase the usefulness of findings in relation to developing a tailored assessment strategy for students enrolled in nursing programs at historically Black colleges and universities. PMID- 30243690 TI - African American nurses describe pre-licensure education experiences: A qualitative study. AB - Greater diversity in the healthcare workforce enhances cross-cultural communication, diminishes bias and stereotyping, thereby improving health outcomes for African Americans. Diversifying the nursing profession has been a persistent challenge and the experiences of African American nursing students in not yet well understood. The aims of this study were to describe the experiences of pre-licensure nursing school, and the meaning of those experiences, retrospectively for African American nurses. The sample for this qualitative descriptive study included 14 African American nurses who reflected on their nursing school experiences. A salient theme of standing out emerged from the data with subthemes of being watched and being ignored. Laying low and being noticed emerged as success strategies for nursing school. African American student experiences are complex and at times appear dichotomous. Improving African American nursing student success necessitates the creation of a more hospitable learning environment to mitigate the effects of standing out. PMID- 30243691 TI - Predicting student attrition using social determinants: Implications for a diverse nursing workforce. AB - BACKGROUND: Attrition of academically qualified nursing students affects the size of the nursing workforce. A better understanding of the multifaceted predictive factors of attrition is needed to inform targeted interventions to promote program progression and maintain an adequate nursing workforce. PURPOSE: The purpose of this study was to identify demographic, academic, and social determinant factors associated with attrition at the end of the first semester in an upper-division baccalaureate nursing program. METHOD: Students' demographic and academic data from an administrative database were combined with social determinants data collected via a web-based survey. RESULTS: Among this cohort (n=164), social determinants were significantly associated with attrition. A significantly greater percentage of students who failed were born outside the United States (U.S.), had one or both parents born outside the U.S., reported English was not the primary language spoken in the home, and were racially/ethnically diverse. CONCLUSIONS: Attrition was primarily among students with diverse racial, ethnic, and/or cultural backgrounds, which has implications for achieving a diverse nursing workforce. Proactive strategies to support success should be especially targeted on diverse students. PMID- 30243692 TI - Visual intelligence education as an innovative interdisciplinary approach for advancing communication and collaboration skills in nursing practice. AB - BACKGROUND: Recognizing the relationship of keen observation to communication, critical thinking, and leadership in evidence-based literature, educators have expanded the use of art museums to augment visual intelligence skills. The purpose of this pilot intervention was to evaluate an innovative, interdisciplinary approach for integrating visual intelligence skills into an advanced communications and collaboration course. METHOD: Collaborating with museum educators, the intervention for doctoral students was conducted at the National Gallery of Art. The aims were to explore and evaluate observation skills, use of intentional language in communication, impact of visual intelligence on perception, and role of visual intelligence with empathy. RESULTS: Descriptive and nonparametric statistics highlighted significant differences in pre- to post-assessment scores related to the expansiveness of intentional visual observation, alternate views, perception and empathy, suggesting that visual intelligence training's impact can be identified and evaluated. CONCLUSION: Healthcare providers' ability to communicate effectively, including observing, listening, explaining, and empathizing, significantly impacts healthcare outcomes and patient perceptions of satisfaction. All educators have access to a variety of two-dimensional art and the opportunity to implement interdisciplinary learning experiences to enhance visual intelligence. The intervention was considered a successful new learning modality for advanced communications skills and was integrated into the curriculum. PMID- 30243693 TI - The I Will Help You mental health initiative: A pedagogy for nursing leadership and a call to action for nurses. AB - Mental illness is a major cause of morbidity and mortality in society. Undergraduate nursing students designed and implemented a mental health awareness campaign called the I Will Help You initiative as part of their senior leadership nursing course. The aims of the initiative were to: spread awareness on mental illness; give the general public the skills and resources needed to identify and assist individuals who are struggling with mental illness; and decrease the stigma surrounding mental illness. A website, four online educational modules, four social media accounts, and two videos were designed by the students in order to promote the initiative. One month following the initiative's launch, the website had over 4000 page views, the videos had over 20,000 views, there were over 200 pledges, and the educational modules had 60 users. The initiative received substantial media attention and was featured via a variety of platforms including: a local news story, numerous health blogs, the state nurses' website and across the university campus. The I Will Help You initiative provided real life application of nursing leadership to an undergraduate student population while building a sustainable, evidence-based tool that can be used as a public health resource for mental illness. PMID- 30243694 TI - Nurses Preparation for Advanced Directives: An Integrative Review. AB - Although nurses have a legal and ethical responsibility to educate and help patients complete advance directives, few nurses have a clear understanding of their role. This review integrates 19 studies published between 1990 and 2018 of the knowledge or confidence of nurses and nursing students regarding advance directives or of education on advance directives in nursing curricula. Fewer than half of working nurses demonstrated knowledge, confidence, or both regarding advance directives, and nursing programs which cover advance directives at all typically devote only 1.5 h or less to this legal document which potentially has impact on patient care and outcomes. Nurses with greater confidence regarding advance directives did not always have accurate knowledge about them. Nursing programs need more education specifically about advance directives, and more research is needed to determine what education methods can successfully address nurses' knowledge and confidence deficits. PMID- 30243695 TI - Collaborative Learning in Higher Nursing Education: A Systematic Review. AB - BACKGROUND: Collaborative learning has been used in nursing education for more than two decades. However, little is known about its relationship to quality of nursing education, its implementation process as well as what factors likely influence the effectiveness of the teaching approach. METHODS: Previous relevant literature had been searched and located from three electronic databases including CINAIL, PubMed, and Google Scholar. RESULTS: Collaborative learning had been employed in classroom teaching, clinical education and online course teaching. The strategy of instruction was found useful for improving nursing knowledge and skill performance, improving student clinical competency, as well as promote student group skills and learning behavior (e.g., Class engagement, motivation for learning, self-confidence). CONCLUSIONS: It was recommended to integrate collaborative learning into nursing education due to positive influences on student learning. PMID- 30243696 TI - Job satisfaction and the factors affecting satisfaction in nurse educators: A systematic review. AB - OBJECTIVES: The present study seeks to answer the following two questions: Are nurse educators satisfied with their job? What are the factors affecting job satisfaction in nurse educators? BACKGROUND: Nurse educators' job satisfaction has a significant role in the efficiency and performance of nursing schools. Identifying the factors affecting job satisfaction in nurse educators is essential to improving their quality of work and ultimately training efficient students and nurses. EVALUATION: The present systematic review searched databases including PubMed, Medline, Cochrane Library, Scopus, Web of Science, Science Direct, ProQuest, Google Scholar and SID for articles published up to April 24, 2018, using keywords including Nurse Teachers, Nurse Faculty, Academic Nurses, Nurse Educators, Dis/Satisfaction, Work, Career, Professional, Practice and Job. Of the total of 971 articles extracted, only 74 remained for the final analysis after the qualitative assessment. KEY ISSUE: The articles included in the analysis investigated the relationship between job satisfaction and its contributing factors rather than providing an accurate report on job satisfaction. Nonetheless, a number of the articles had reported fairly to very favorable levels of job satisfaction. The factors affecting nurse educators' job satisfaction were categorized into six levels, including personal, organizational, managerial, academic, professional and economic levels. CONCLUSION: Although job satisfaction was reported relatively well in the nurse educators, this condition depends on several indices. The lack of positive steps toward job satisfaction in nurse educators leads to destructive behaviors and turnover intentions; meanwhile, it is satisfied educators who can train competent nurses. PMID- 30243697 TI - Nursing Competence in Geriatric/Long Term Care Curriculum Development for Baccalaureate Nursing Programs: A Systematic Review. AB - BACKGROUND: As facing the rapid growth of the elderly population, the demands for geriatric and long-term care are drastically increasing. Since one of the important strategies in preparation for long-term care system is to focus on the engagement of health care professionals, this paper applies a systematic approach to review the current geriatric and long term care courses in Bachelor of Science in Nursing (BSN) programs. This review assessed the impact of Geriatric Nursing (GN) and/or Long Term Care (LTC) courses on nursing students' knowledge, care intention and competence of Geriatric Long Term Care (GLTC) care to enable their nursing competence before graduation. METHOD: Data related to the purpose of the study, research design, sample, curriculum content, teaching strategies, evaluation measurements and results were extracted. The methodological quality of all publications was included in the review. RESULTS: Eighteen articles were eligible for analysis, including 16 quantitative and 2 qualitative studies. The review revealed that including geriatric and long term care content in undergraduate nursing curriculum could effectively enhance students' nursing competence. CONCLUSION: GN and LTC curriculum development should offer established content on geriatric and long term care as a foundation to implement early learning experiences in the curriculum. Both theory and clinical practice of GLTC course can be developed to increase the nursing students' knowing on the elders and the disabled through the clinical placement. PMID- 30243699 TI - Perceptions, Experiences, and Needs of Nursing Preceptors and Their Preceptees on Preceptorship: An Integrative Review. AB - Preceptorship is a commonly used clinical teaching method for new nurses, and perceptions regarding it are varied and come from many sources. The aim of this integrative review is to explore the perceptions of preceptorship from preceptors and newly graduated nurses. Three electronic databases were searched for relevant articles and the Joanna Briggs Institute's critical appraisal tools were used to assess for suitability before inclusion in the review. Twenty articles were included eventually. A total of six focus areas were identified: (a) role of the preceptor, (b) preceptor preparation and support, (c) challenges of being a preceptor, (d) preceptorship significance for newly graduated nurses, (e) needs of newly graduated nurses, and (f) factors affecting the preceptor-preceptee relationship. The impact of preceptorship is significant and especially so on newly graduated nurses who are going through a transition as they enter the workforce. The preceptor functions to teach and additionally provide psychosocial support to the preceptee. Preceptors need to receive preceptor education to effectively carry out their role. Awareness of the preceptor's role by nursing managers can aid in optimizing preceptorship outcomes. Preceptorship helps to ease the stressful transition that new graduates experience. Preceptorship has a potential in nursing retention when utilized in nursing with newly graduated nurses. Hence, perceptions of preceptorship from preceptor-preceptee pairs of varying ethnic backgrounds, nationalities, educational qualifications, and generations can be further explored. PMID- 30243698 TI - An Innovative Evaluation in Fundamental Nursing Curriculum for Novice Nursing Students: An Observational Research. AB - BACKGROUND: is the first specialized curriculum for nursing students, laying a foundation for nursing education. includes many important basic nursing skills, which suggests the traditional examination could not evaluate how well students learn. Since the OSCE (objective structured clinical examination) developed, it has been used among newly graduated nurses, postgraduate nursing students and achieved some success. OSCE might be a better way to evaluate and reflect students' fundamental nursing skills and comprehensive abilities, although few studies have put it into practice. OBJECTIVES: To build an examination model relating to based on OSCE, and put this examination model into practice, and then evaluate the reliability and validity of this examination model. DESIGN: This study is to design an examination model based on literature and teaching purposes of . A quantitative descriptive survey methodology was used to obtain the students' outcome and the views of the students on the process and outcome. SETTINGS: This study was conducted in the nursing school of one comprehensive university in Beijing, China. PARTICIPANTS: 99 undergraduate nursing students in second year participated in this study. METHODS: The OSCE consisted of 4 interactive simulated patient stations, 2 operating stations without standard patients, 2 theoretical stations. We designed 4 standardized process-based case scenarios and corresponding scripts pertinent to each station. 4 standard patients and 8 teachers of were recruited, trained and evaluated before the implementation of objective structured clinical examination. RESULTS: The average score of overall fundamental nursing skills was 90.51 +/- 4.00. The Cronbach alpha was 0.665, demonstrating the OSCE is reliable. The content validity of each station varies from 0.90-1, and the criterion validity was promising (R = 0.661, p = 0.000). Also, most students were in favor of OSCE to evaluate in . CONCLUSIONS: The OSCE is a reliable and valid assessment tool in . Meanwhile, it could inspire students' critical thinking and promote students' communication skills. Through successive application of OSCE in nursing education from the very beginning, it might also have some potential effect on the clinical performance. PMID- 30243700 TI - VTE ought to be divided not only in DVT and PTE, but also in subacute/chronic forms. PMID- 30243701 TI - Ultrasonography assessment of spermatic vein thrombosis. AB - There are few clinical problem of spermatic vein thrombosis were reported. Spontaneous spermatic vein thrombosis is a particularly rare diseases which can lead to acute or chronic testicular pain and testicular swelling. We report a case in which ultrasonography (US) discovered hypoechoic mass of left spermatic vein and contrast-enhanced ultrasonography (CEUS) revealed thrombus formation of left spermatic vein in a patient who had underwent a continuous driving for eight hours twenty days ago. PMID- 30243702 TI - Molecular hydrogen reduces acute exercise-induced inflammatory and oxidative stress status. AB - Physical exercise induces inflammatory and oxidative markers production in the skeletal muscle and this process is under the control of both endogenous and exogenous modulators. Recently, molecular hydrogen (H2) has been described as a therapeutic gas able to reduced oxidative stress in a number of conditions. However, nothing is known about its putative role in the inflammatory and oxidative status during a session of acute physical exercise in sedentary rats. Therefore, we tested the hypothesis that H2 attenuates both inflammation and oxidative stress induced by acute physical exercise. Rats ran at 80% of their maximum running velocity on a closed treadmill inhaling either the H2 gas (2% H2, 21% O2, balanced with N2) or the control gas (0% H2, 21% O2, balanced with N2) and were euthanized immediately or 3 h after exercise. We assessed plasma levels of inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6] and oxidative markers [superoxide dismutase (SOD), thiobarbituric acid reactive species (TBARS) and nitrite/nitrate (NOx)]. In addition, we evaluated the phosphorylation status of intracellular signaling proteins [glycogen synthase kinase type 3 (GSK3alpha/beta) and the cAMP responsive element binding protein (CREB)] that modulate several processes in the skeletal muscle during exercise, including changes in exercise-induced reactive oxygen species (ROS) production. As expected, physical exercise increased virtually all the analyzed parameters. In the running rats, H2 blunted exercise induced plasma inflammatory cytokines (TNF-alpha and IL-6) surges. Regarding the oxidative stress markers, H2 caused further increases in exercise-induced SOD activity and attenuated the exercise-induced increases in TBARS 3 h after exercise. Moreover, GSK3alpha/beta phosphorylation was not affected by exercise or H2 inhalation. Otherwise, exercise caused an increased CREB phosphorylation which was attenuated by H2. These data are consistent with the notion that H2 plays a key role in decreasing exercise-induced inflammation, oxidative stress, and cellular stress. PMID- 30243703 TI - The role of chelating agents and amino acids in preventing free radical formation in bleaching systems. AB - The control of bleaching reaction is important in hair bleaching and laundry detergents to ensure quality of the final product. A better understanding of the reaction mechanisms is needed to minimize product failures. 31P NMR-spectroscopy based spin trap technique was employed to detect and quantify the free radical species that were generated in different bleaching solutions. These solutions contained the key actives in an alkaline hair colorant/bleaching product, an ammonium salt and hydrogen peroxide at pH = 10. Generally, the main radical species detected in hair oxidative coloring or bleaching processes, were hydroperoxyl/superoxide radicals HO2./O2.-, amino radicals .NH2 and hydroxyl radicals .OH. Their amounts showed a variation based on the chemical composition of the bleaching systems and the metal ion content. The generation of free radicals from reactions between transition metal ions, such as copper, and hydrogen peroxide at pH = 10 was evaluated. In the absence of chelating agents, the copper ions generated a significant level of hydroxyl radicals in a Fenton like reaction with hydrogen peroxide at pH = 10. Besides that, an increase in copper ion content led to an increase of amino radical .NH2, whereas the concentration of superoxide radical O2.- decreased which was not yet well reported in the previous literature. The effect of chelating agents like ethylenediaminetetraacetic acid (EDTA), tetrasodium-iminodisuccinate (IDS), a mixture of basic amino acids and dicarboxylic acid on free radical formation was investigated in the presence of binary Cu2+-Ca2+ bleaching systems. As expected, in the binary Cu2+-Ca2+ ion system EDTA did not suppress hydroxyl radical formation effectively, but the mixture containing sodium succinate, lysine and arginine reduced hydroxyl radical formation, whereas IDS (nearly) completely inhibited hydroxyl radical formation. The results indicated that each bleaching solution has its characteristic performance and damage profile. Whereas the reactivity can be controlled by the usage of chelating agents. PMID- 30243704 TI - A Simple Way to Measure Glucose and Lactate Values During Free Flap Head and Neck Reconstruction Surgery. AB - PURPOSE: Evaluation of flap blood flow is necessary to detect flap blood flow abnormalities and perform salvage surgery. This study determined whether intra flap blood glucose and lactate values measured with a simple instrument could detect impaired blood flow during head and neck reconstruction. MATERIALS AND METHODS: We prospectively analyzed 82 cases of head and neck cancer reconstruction (62 men and 20 women; mean age, 64.0 years [range, 20 to 88 years]), of which 74 had impeded blood flow. Glucose and lactate levels were regularly measured over a period of 48 hours, from the time of flap elevation, as predictor variables. Blood flow obstruction was the outcome variable. Other study variables included primary site, flap type, gender, age at operation, height, weight, body mass index, presence or absence of diabetes, ischemia time, and operative time. Logistic analysis, using glucose and lactate values at the time of blood flow failure, was performed. Cutoff values were calculated using a receiver operating characteristic analysis. RESULTS: The breakdown of the flaps was as follows: 20 free jejunum, 19 anterolateral thigh, 12 fibular, 11 radial forearm, 8 rectus abdominis myocutaneous, and 4 other flaps. Congestion was observed in 8 of the 82 flaps, including 3 anterolateral thigh flaps, 3 radial forearm flaps, 1 free jejunum flap, and 1 rectus abdominis myocutaneous flap. The intra-flap blood glucose values in the normally progressing cases gradually decreased until 16 hours postoperatively and thereafter recovered to normal levels. Intra-flap blood lactate values increased until 8 hours postoperatively and subsequently decreased. The odds ratio during congestion was only significantly different for lactate (odds ratio, 2.55, P = .014), and the cutoff values for sensitivity and specificity were 4.2 mmol/L and 6.7 mmol/L, respectively. CONCLUSIONS: Intra-flap blood glucose and lactate values may reflect the transition of the postoperative circulation of free flaps. During congestion, lactate values change more sensitively than blood glucose values. PMID- 30243705 TI - What Is the Most Effective Rehabilitation Method for Posterior Maxillas With 4 to 8 mm of Residual Alveolar Bone Height Below the Maxillary Sinus With Implant Supported Prostheses? A Frequentist Network Meta-Analysis. AB - PURPOSE: The most effective rehabilitation method for patients with edentulous posterior maxillas with an intermediate (4 to 8 mm) residual bone height (RBH) below the maxillary sinus is unclear. Evidence derived from conventional meta analysis is limited because of the lack of head-to-head studies. This network meta-analysis (NMA) was performed to identify the most effective method to treat patients with intermediate posterior RBH. MATERIALS AND METHODS: An NMA of randomized controlled clinical trials (RCTs) was conducted to assess various rehabilitation methods using implant-supported prostheses for patients with intermediate posterior maxillary RBH (4 to 8 mm). Publications from 1970 through March 2018 in 3 major databases were searched. Parallel and split-mouth RCTs that reported the outcomes of interest with follow-up of at least 6 months from initial loading were included. Predictor variables were short implants (SIs; <=8 mm) alone, SIs in conjunction with osteotome sinus floor elevation (OSFE) with or without bone grafting, long implants (LIs) in conjunction with OSFE with and without bone grafting, and LIs combined with lateral sinus floor elevation (LSFE) with bone grafting. Outcome variables were implant and prosthesis failure rates, marginal bone loss, and complications. Frequentist NMA was performed using STATA software. RESULTS: Twenty RCTs involving 770 patients with intermediate posterior maxillary RBH and 837 concerned maxillary sinuses who received 1,486 implants using any of the 4 rehabilitation methods were included. There were no statistically significant differences among the 4 groups for implant and prosthesis failure rates and marginal bone loss at follow-up (range, 6 months to 5 years after loading). There was a marked decrease in complications for SIs alone compared with LIs combined with LSFE. For implant and prosthesis survival rates, SIs in conjunction with OSFE with or without bone grafting ranked first as the most effective option (77.1%) followed by LIs plus OSFE with or without bone grafting (62%), LIs plus LSFE with bone grafting (43.9%), and SIs alone (24.8%). CONCLUSION: There is moderate-quality evidence derived from this NMA showing that OSFE combined with SI or LI placement with or without bone grafting or SI placement alone is superior to LI placement combined with LSFE and bone grafting when used for patients with intermediate maxillary RBH (4 to 8 mm). Furthermore, the results of this study show that LSFE for patients with intermediate RBH is not a suitable treatment option because of unjustified high cost and rate of complications. PMID- 30243706 TI - Unplanned Reoperations in Oral and Maxillofacial Surgery. AB - PURPOSE: The purpose of this study was to determine the incidence of and reasons for unplanned reoperations in oral and maxillofacial surgery. MATERIALS AND METHODS: During a 4-year period, a total of 169 patients undergoing reoperations were encountered. The clinical characteristics and causes were reviewed. RESULTS: There were 11,151 patients who underwent surgery, and the incidence of unplanned reoperations was 1.52%. The male-to-female ratio was 2.45:1. The average age in this cohort was 51.5 years. Among the common causes of an unplanned return to the operating room, the most common were reoperations performed for postoperative bleeding, diagnostic issues, and vascular crisis (32.54%, 28.40%, and 29.59%, respectively). CONCLUSIONS: The unplanned reoperation rate was 1.52%. The main causes were postoperative bleeding, diagnostic issues, and vascular crisis. Patients with malignant tumors or microvascular flaps were more likely to undergo unplanned reoperations. Improving perioperative management and diagnostic capability might reduce the incidence of unplanned reoperations. PMID- 30243707 TI - Negative Pressure Wound Therapy in Necrotizing Fasciitis of the Head and Neck. AB - PURPOSE: Necrotizing fasciitis is a severe soft tissue infection that is uncommon in the head and neck region. Despite the advancement of care over the past few decades, the mortality rate remains high. Negative pressure wound therapy (NPWT), an advanced wound-healing technique, has become increasingly popular for a wide variety of complicated wounds. Since December 2015, we have used this technique in the management of necrotizing fasciitis of the head and neck. We report a consecutive case series treated with NPWT as the initial surgical procedure. MATERIALS AND METHODS: Seven patients who received a surgical diagnosis of necrotizing fasciitis of the head and neck underwent surgery under general anesthesia. After complete debridement, an NPWT device was applied for positive drainage of the involved areas. The drainage tube was connected to a central negative pressure system. The device was not replaced or removed until the infection was controlled. Then, a conventional drainage approach was used. RESULTS: Of the 7 patients, 6 underwent the surgical procedure and NPWT once; the remaining patient underwent these procedures twice. The infectious cavities showed a clean wound covered with healthy granulation formation during the removal of the NPWT device. The following course was uneventful. The mean time for wound healing was 17.3 +/- 6.1 days. CONCLUSIONS: NPWT provides various advantages compared with conventional debridement and drainage, resulting in excellent clinical outcomes. This method could be recommended as an alternative approach in the management of necrotizing fasciitis in the head and neck region. PMID- 30243709 TI - Coordinate regulation by transcription factors and DNA methylation in the core promoter region of SIRT6 in bovine adipocytes. AB - Sirtuin6 (SIRT6) is an ADP-ribosyltransferase and NAD+-dependent deacylase of acetyl groups and long-chain fatty acyl groups, and has been shown as a regulator of insulin secretion, glucose metabolism, lipid metabolism, and cancer. In this study, we determined that the bovine SIRT6 showed higher levels of mRNA expression in the testis, longissimus thoracis, and subcutaneous fat tissue. To elucidate the molecular regulation mechanism of bovine SIRT6 expression, we obtained a 2-kb fragment containing the 5'-regulatory region, and the functional proximal minimal promoter of bovine SIRT6 was identified in the -472/-73 bp region. The CCAAT enhancer binding protein beta (CEBPbeta), paired box 6 (PAX6), Kruppel-like factor 2 (KLF2), myb proto-oncogene protein (CMYB), nuclear respiratory factor 1 (NRF1), and E2F transcription factor 1 (E2F1) binding sites, as transcriptional activators or repressors in the core promoter region of SIRT6, were determined by electrophoretic mobility shift assay (EMSA) experiments and luciferase reporter assays. In addition, the results from methylation assay and luciferase report assay showed that the bovine SIRT6 promoter activity was coordinately regulated by methylation and NRF1 or E2F1 during bovine adipocyte differentiation. Taken together, this study illuminated the underlying mechanism of methylation and transcription regulation of SIRT6 expression in bovine adipocytes. PMID- 30243708 TI - PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer. AB - Anaplastic thyroid cancer (ATC) is among the most lethal malignancies. The mitotic kinase PLK1 is overexpressed in the majority of ATCs and PLK1 inhibitors have shown preclinical efficacy. However, they also cause mitotic slippage and endoreduplication, leading to the generation of tetraploid, genetically unstable cell populations. We hypothesized that PI3K activity may facilitate mitotic slippage upon PLK1 inhibition, and thus tested the effect of combining PLK1 and PI3K inhibitors in ATC models, in vitro and in vivo. Treatment with BI6727 and BKM120 resulted in a significant synergistic effect in ATC cells, independent of the levels of AKT activity. Combination of the two drugs enhanced growth suppression at doses for which the single drugs showed no effect, and led to a massive reduction of the tetraploid cells population. Furthermore, combined treatment in PI3Khigh cell lines showed a significant induction of apoptosis. Finally, combined inhibition of PI3K and PLK1 was extremely effective in vivo, in an immunocompetent allograft model of ATC. Our results demonstrate a clear therapeutic potential of combining PLK1 and PI3K inhibitors in anaplastic thyroid tumors. PMID- 30243710 TI - Peptaibols as a model for the insertions of chemical modifications. AB - Peptaibols are linear non ribosomal peptides which have been the object of intense research efforts regarding their synthesis and the elucidation of the mechanism allowing their insertion in biological membranes. Forty years after their discovery they are still considered as model compounds and suitable probes for the investigation of new approaches aiming to test the efficacy of new coupling reagents, to physically and spectroscopically investigate the way by which they interact with the lipid bilayer and to develop artificial membrane pores. The stable helical secondary structure adopted by the peptaibols turn to be an adequate platform for gaining insight on the structural modifications induced by the substitution of the amide bond by 1,2,3-triazoles, but also for monitoring the impact of newly designed alpha,alpha-dialkyl glycine with fluorinated and silylated side chains as 2-aminoisobutyric acid mimic. Peptaibols secondary structure dictated by Aib high content has inspired the development of foldamers. Challenges and investigations on the above mentioned topics are discussed in this brief review. PMID- 30243711 TI - Conformational changes in a multidrug resistance ABC transporter DrrAB: Fluorescence-based approaches to study substrate binding. AB - Bacterial multidrug transporter DrrAB exhibits overlapping substrate specificity with mammalian P-glycoprotein. DrrA hydrolyzes ATP, and the energy is transduced to carrier DrrB resulting in export of drugs. Previous studies suggested that DrrB contains a large and flexible drug-binding pocket made of aromatic residues contributed by several transmembrane helices with different drugs binding to both specific and shared residues in this pocket. However, direct binding of drugs to DrrAB or the mechanism of substrate-induced conformational changes between DrrA and DrrB has so far not been investigated. We used two fluorescence-based approaches to determine substrate binding to purified DrrAB. Our analysis shows that DrrB binds drugs with variable affinities and contains multiple drug binding sites. This work also provides evidence for two asymmetric nucleotide binding sites in DrrA with strikingly different binding affinities. Using targeted fluorescence labeling, we provide clear evidence of long-range conformational changes occurring between DrrA and DrrB. It is proposed that the transduction pathway from the nucleotide-binding DrrA subunit to the substrate binding DrrB subunit includes Q-loop and CREEM motifs in DrrA and EAA-like motif in DrrB. This study lays a solid groundwork for examining roles of various conserved regions of DrrA and DrrB in transduction of conformational changes. PMID- 30243712 TI - Dysregulation of KCNQ1OT1 promotes cholangiocarcinoma progression via miR-140 5p/SOX4 axis. AB - It is commonly recognized that aberrant expression of long non-coding RNAs (lncRNAs) is an important cause of cancer progression. The oncogenic property of KCNQ1OT1 has been identified in several malignant tumors. Here, we decided to explore the biological function and molecular mechanism of KCNQ1OT1 in cholangiocarcinoma (CCA). The expression conditions of KCNQ1OT1 in different tissues and cell lines were examined with qRT-PCR analysis. As expected, KCNQ1OT1 was highly expressed in CCA tissues and cell lines. Results of functional assays revealed the oncogenic function of KCNQ1OT in cholangiocarcinoma progression. The positive effect of KCNQ1OT1 on cell proliferation, invasion and epithelial mesenchymal transition was identified by performing MTT assay, colony formation assay, transwell invasion assay and western blotting. Whereas, the negative effect of KCNQ1OT1 on the cell apoptosis was tested with flow cytometry analysis. Mechanism investigation revealed that KCNQ1OT1 can act as a ceRNA to improve CCA progression by regulating miR-140-5p/SOX4 axis. Recue assays were conducted to demonstrate the actual effects of KCNQ1OT1-miR-140-5p-SOX4 pathway on CCA progression. PMID- 30243713 TI - Coding of coronary arterial origin and branching in congenital heart disease: The modified Leiden Convention. AB - OBJECTIVES: Variations in coronary anatomy are common and may relate to the position of the coronary ostium relative to the aortic sinus, the angle of coronary take-off, or the course of the coronary arterial branches. Several classification systems have been proposed. However, they all lack a simple rationale that is applicable irrespective of the relative position of the great arteries, as well as in bicuspid aortic valves. We present a modification of a relatively simple system introduced in the early 1980s, designated the "Leiden Convention." METHODS: The first step of the Leiden Convention is that the clinician takes position in the nonfacing sinus of the aorta looking toward the pulmonary orifice. The right-hand facing sinus is sinus 1, and the left-hand facing sinus is sinus 2. The coronary branches arising from sinus 1 are annotated proceeding in a counterclockwise fashion toward sinus 2. "Usual" (normal) coronary anatomy would be 1R-2LCx. Given their clinical relevance, single sinus coronary arteries are discussed separately. RESULTS: This system was originally designed and highly applicable in hearts with an altered great artery relationship, such as in the variable and complicated patterns seen in transposition of the great arteries and double outlet right ventricle. The modified system also can be used in cases with normally related great arteries, cases with single sinus coronary arteries, and cases with bicuspid aortic valves. CONCLUSIONS: The modified Leiden Convention is not a strict classification but a simple coronary coding system that is broadly applicable. PMID- 30243714 TI - The circular RNA circ-ITCH suppresses ovarian carcinoma progression through targeting miR-145/RASA1 signaling. AB - As the leading cause of death for gynecological cancers, ovarian cancer (OC) ranks fifth overall for cancer-related death among women. Emerging evidence has indicated that circular RNA (circRNA), recognized as functional non-coding transcripts in eukaryotic cells, may be involved in many physiological or pathological processes. It was reported that circ-ITCH is downregulated in multi cancers and serves as a powerful tumor suppressor among through a competing endogenous RNA (ceRNA) pathway. However, the existence and the role of circ-ITCH in OC was not reported. Here, we found a broad down-regulation of circ-ITCH in OC tissues and cells, which correlates with a worse prognosis in OC patients. Functional studies suggest that circ-ITCH overexpression inhibits the cell viability and motility by CCK8, cell cycle, wound healing assay and invasion assay. It also inhibits the tumorigenesis ability in xenograft NOD mice in vivo. Mechanically, we demonstrated that circ-TCH acts as a ceRNA to sponge miR-145, increases the level of RASA1, and inhibits the malignant progression of OC cells via the circ-ITCH-miR-145-RASA1 axis in vitro and in vivo. Taken together, our findings provide a novel tumor suppressive role regarding circ-ITCH function in the malignant progression of OC. PMID- 30243715 TI - B-family subunits of protein phosphatase 2A are necessary for pollen development but not for female gametophyte development in Arabidopsis. AB - Protein phosphatase 2A (PP2A) is a heterotrimeric protein complex conserved among eukaryotes. The B subunit of PP2A determines the substrate specificity of the PP2A holoenzyme, and is classified into the B, B', B" and B''' families. Arabidopsis thaliana has two isoforms of the B-family subunit (ATBA and ATBB). A double knockout of their genes is lethal, but which developmental process is primarily impaired by the double knockout is unclear. Identifying such a process helps understand PP2A-mediated signaling more deeply. Here, genetic characterization of new knockout mutants for these genes shows that they are necessary for pollen development but not for female gametophyte development. Compared to wild-type pollen grains, the mutant pollen grains exhibited lower enzyme activities, germinated less frequently on stigmas, and exhibited the aberrant numbers of sperm cell nuclei, suggesting that ATBA and ATBB play pleiotropic roles in pollen development. The amino acids stabilizing the interaction between the human PP2A A and B-family subunits are conserved in an Arabidopsis A subunit (AtPP2AA2), ATBA and ATBB. His-tagged AtPP2AA2 co immunoprecipitated with either Myc-tagged ATBA or Myc-tagged ATBB in vitro, confirming their interactions. Proteins that regulate pollen development and that undergo dephosphorylation are likely primary targets of ATBA and ATBB. PMID- 30243716 TI - Production and characterization of monoclonal antibody against a triple negative breast cancer cell line. AB - Breast cancer is the most prevalent malignancy among women around the world such that more than 1,400,000 new cases are being diagnosed each year. Despite immense studies over many years on diagnosis and treatment of breast cancer, about 30% of treated patients will relapse and require subsequent therapy. By development of hybridoma technology, murine monoclonal antibodies (MAbs) against several human tumor-associated antigens have been produced and characterized in many laboratories. The purpose of these studies is to generate effective monoclonal antibodies that could be useful in tumor diagnosis and therapy. In this study, splenic lymphocytes of immunized BALB/c mouse with a new established breast cancer cell line (Pari-ICR cell line, established in Shiraz Institute for Cancer Research) were fused with the mouse myeloma cell line SP2/0 in the presence of polyethylene glycol. We generated a panel of monoclonal antibodies against the newly established cell line. The hybrid cultures were screened by flow cytometry. Hybridomas that produced antibody to surface antigens of immunizing cell line but not to Human Gingival Fibroblasts, adipose stem cells, and leucocytes isolated from peripheral blood were selected and cloned by limiting dilution method. The 1E3 clone (IgG2a type) that displayed clonal stability was further analyzed for specificity by flow cytometry. MAb 1E3 showed weak to strong reactivity to other cell lines compared with Pari-ICR cell line. Antigen identification was performed by a workflow consisting of immunoaffinity purification, SDS-PAGE, Western blotting, and mass spectrometry analysis. The target of 1E3 mAb was identified as NCAM1. In conclusion, using the antibody-based strategy we identified NCAM1 as a potential therapeutic target and biomarker for breast cancer. PMID- 30243717 TI - Induction of apoptosis by morusin in human non-small cell lung cancer cells by suppression of EGFR/STAT3 activation. AB - This study was designed to validate the anticancer effects of morusin in human non-small cell lung cancer (NSCLC) cells. Morusin suppressed the cell growth and colony formation in a concentration-dependent manner in H1299, H460 and H292 cells. These anticancer activities were related with apoptosis induction proved by the accumulation of chromatin condensation, PARP cleavage, increase of sub-G1 phage and annexin V-positive cell population. Interestingly, signal transducer and activator of transcription 3 (STAT3) was dephosphorylated by morusin. Morusin suppressed the transcriptional activity of STAT3 and down-regulated the expression of STAT3 target genes. In addition, morusin inhibited the phosphorylation of epithelial growth factor receptor (EGFR), an upstream regulator of STAT3. The docking study showed that morusin directly binds to the tyrosine kinase domain of EGFR. Furthermore, the anticancer effects of morusin were consistently observed in erlotinib-resistant H1975 cells expressing L858R and T790 M mutant EGFR, suggesting that morusin can be used for the advanced NSCLC with acquired resistance to EGFR TKI. Taken together, our results demonstrate that morusin induced apoptosis in human NSCLC cells regardless of EGFR mutation status through inhibition of EGFR/STAT3 activation. PMID- 30243718 TI - Fibroblast growth factor 19 improves cardiac function and mitochondrial energy homoeostasis in the diabetic heart. AB - In diabetic cardiomyopathy, mitochondrial fatty acid oxidation dominates over mitochondrial glucose oxidation, leading to metabolic disturbances. Fibroblast growth factor 19 (FGF19) acts as a metabolic regulator and may have a cardioprotective role on diabetic cardiomyopathy. In this study, we investigated the effects of FGF19 on energy metabolism. FGF19 treatment of diabetic hearts exhibited higher glucose uptake and lower lipid profiles, suggesting changes in energy metabolism. The protective effects of FGF19 prevented ventricular dysfunction in diabetic hearts and improved mitochondrial function by the upregulation of PGC-1alpha expression. On the other side, knockdown of PGC-1alpha by siRNA attenuated the effects of FGF19 on the enhancement of mitochondrial function and energy efficiency. Taken together, these results show that FGF19 exhibited improved mitochondrial efficiency, which might be associated with higher cardiac contractility in diabetic hearts. It is also of note that modulation of PGC-1alpha, which is responsible for the activation by FGF19, may be a therapeutic target for diabetic cardiomyopathy. PMID- 30243719 TI - Nop-7-associated 2 (NSA2) is required for ribosome biogenesis and protein synthesis. AB - Ribosome biogenesis is a fundamental cellular process and occurs mainly in the nucleolus in eukaryotes. The process is exceptionally complex and highly regulated by numerous ribosomal and non-ribosomal factors. A recent discovery strengthened the link between ribosome biogenesis and malignant transformation. Here, we determined that Nop-7-associated 2 (NSA2) is a nucleolar protein required for ribosome biogenesis. NSA2 knockdown reduced the rate of rRNA synthesis, diminishing the 60S ribosomal subunit. Moreover, we demonstrated that depletion of NSA2 suppressed protein synthesis. To investigate the signaling pathway affected by NSA2, NSA2 was depleted, which triggered the inactivation of the mTOR signaling pathway. Taken together, our findings reveal a novel function of NSA2 and provide insight into the regulation of ribosome biogenesis by NSA2. PMID- 30243720 TI - Unique methionine-aromatic interactions govern the calmodulin redox sensor. AB - Calmodulin contains multiple redox sensitive methionines whose oxidation alters the regulation of numerous targets. Molecular dynamics simulations were used to define the molecular principles that govern how calmodulin is structurally poised to detect and respond to methionine oxidation. We found that calmodulin's open and closed states were preferentially stabilized by unique, redox sensitive, methionine-aromatic interactions. Key methionine-aromatic interactions were coupled to reorientation of EF hand helices. Methionine to glutamine substitutions designed to mimic methionine oxidation strongly altered conformational transitions by modulating the strength of methionine-aromatic interactions. Together, these results suggest a broadly applicable redox sensing mechanism though which methionine oxidation by cellular oxidants alters the strength of methionine-aromatic interactions critical for functional protein dynamics. PMID- 30243721 TI - Integrin beta1 promotes gemcitabine resistance in pancreatic cancer through Cdc42 activation of PI3K p110beta signaling. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignancies with very poor prognosis due to its broad resistance to chemotherapy. Our previous study showed that integrin beta1 expression is upregulated in PDAC and confers gemcitabine resistance in PDAC cells via the signaling pathway including Cdc42 and AKT activation. But the accurate signal transductions are not clear. Here, we aimed to illuminate the signal transductions of integrin beta1 in the acquisition of gemcitabine resistance in PDAC. Drug-resistance (DR) cells from AsPC-1 parent cell line (PCL) were selected. Integrin beta1 expression was determined using western blot assay. Changes in drug response and the activity of phosphatidylinositol 3-kinase (PI3K) signaling after knockdown of integrin beta1, Cdc42 or p110beta were evaluated using MTT, cleaved caspase-3 immunofluorescence and western blot assay. Western blot assays also detected the variations in Cdc42 activity and p110beta expression after integrin beta1 knockdown. The interaction between Cdc42 and p110beta was determined by Glutathione S-transferase (GST) pull down assay. The results showed that integrin beta1 expression was upregulated in DR-AsPC-1 cells, and integrin beta1 knockdown significantly decreased the activity of Cdc42, a target molecule of integrin beta1, and p110beta expression. Knockdown of anyone of integrin beta1, Cdc42 and p110beta inhibited the activity of PI3K signaling, and sensitized DR-AsPC-1 cells to gemcitabine. GST pull-down assay showed that GTP-Cdc42 interacted with p110beta. Collectively, these data indicated that integrin beta1 promoted gemcitabine resistance in PDAC through Cdc42 activation of PI3K p110beta signaling. In vivo experiments also confirmed this conclusion. These findings contribute to a better understanding the molecular mechanism of chemoresistance and facilitate the development of more targeted and effective treatment strategy for PDAC. PMID- 30243722 TI - DNA-binding activity of STAT3 increased in hypothalamus of DIO mice; the reduction of STAT3 phosphorylation may facilitate leptin signaling. AB - Leptin-mediated DNA-binding activity of STAT3 in hypothalamus plays crucial roles in the maintenance of energy homeostasis in lean mice; however its effects still remains unclear in case of leptin resistance in mice with diet induced obesity (DIO). In this study significant elevation of both basal and exogenously leptin treated DNA-binding activity of STAT3 was detected using EMSA in the hypothalamus of male C57BL/6J mice fed high-fat diet for 10 wks, in concomitant with hyperleptinemia, high body weight, high fat mass, and hyperphagia as well as decreased POMC expression. The studies in vitro showed that both DNA binding activity and the proximal SBE of POMC promoter was essential to leptin-mediated POMC expression. However, the diminution of STAT3 phosphorylation, achieved by S3I-201 or a FoxO1 mutant, facilitated leptin-mediated POMC expression. The findings here demonstrated excess STAT3 activity negatively regulated POMC expression in hypothalamus of DIO mice, and suggested the limitation of STAT3 activity may promote leptin signaling. PMID- 30243723 TI - Phosphoproteomic analysis reveals PAK2 as a therapeutic target for lapatinib resistance in HER2-positive breast cancer cells. AB - The human epidermal growth factor receptor 2 (HER2)-positive breast cancer with overexpression of HER2 accounts for approximately 25% of breast cancers and is more aggressive than other types of breast cancer. Lapatinib has been widely used as a HER2-targeted therapy, however, a number of patients develop lapatinib resistance and still suffer from poor prognosis. Therefore, it is essential to identify novel therapeutic targets that could overcome lapatinib resistance. In this study, we carried out phosphoproteomic analysis of lapatinib sensitive and resistant cell lines (SKBR3 and SKBR3-LR) using stable isotope labeling with amino acids in cell culture (SILAC). We identified 3808 phosphopeptides from 1807 proteins and then analyzed signaling pathways, Gene Ontology, and protein-protein interaction networks. Finally, we identified PAK2 as a therapeutic target from the network analysis and validated that PAK2 knockdown and PAK inhibitor treatment resensitize the lapatinib resistant cells to lapatinib. This results suggest that PAK2 is a potent therapeutic target to overcome acquired lapatinib resistance in HER2-positive breast cancer cells. PMID- 30243724 TI - Elucidation of the crystal structure of FabD from the multidrug-resistant bacterium Acinetobacter baumannii. AB - Bacterial fatty acid synthesis (FAS) has been extensively studied as a potential target of antimicrobials. In FAS, FabD mediates transacylation of the malonyl group from malonyl-CoA to acyl-carrier protein (ACP). The mounting threat of nosocomial infection by multidrug-resistant Acinetobacter baumannii warrants a deeper understanding of its essential cellular mechanisms, which could lead to effective control of this highly competent pathogen. The molecular mechanisms involved in A. baumannii FAS are poorly understood, and recent research has suggested that Pseudomonas aeruginosa, a closely related nosocomial pathogen of A. baumannii, utilizes FAS to produce virulence factors. In this study, we solved the crystal structure of A. baumannii FabD (AbFabD) to provide a platform for the development of new antibacterial agents. Analysis of the structure of AbFabD confirmed the presence of highly conserved active site residues among bacterial homologs. Binding constants between AbFabD variants and A. baumannii ACP (AbACP) revealed critical conserved residues Lys195 and Lys200 involved in AbACP binding. Computational docking of a potential inhibitor, trifluoperazine, revealed a unique inhibitor-binding pocket near the substrate-binding site. The structural study presented herein will be useful for the structure-based design of potent AbFabD inhibitors. PMID- 30243725 TI - Orexin-A signaling in the paraventricular nucleus modulates spontaneous firing of glucose-sensitive neurons and promotes food intake via the NPY pathway in rats. AB - Understanding the mechanisms regulating feeding is crucial to unraveling the pathogenesis of obesity. The study primary explored the effects of orexin-A and neuropeptide Y (NPY) signaling in the hypothalamic paraventricular nucleus (PVN) on feeding and glucose-sensitive (GS) neuron activity in rats. Microinjection of orexin-A into the PVN promoted feeding and modulated the spontaneous firing of GS neurons. Those effects were eliminated by pre-injection of the orexin-A receptor 1 (OX1R) antagonist SB-334867 and weaken by the NPY-1 receptor (NPY-1R) antagonist BMS-193885. After orexin-A administration into the PVN, the number of c-fos cells in the arcuate nucleus (ARC) was significantly higher than that in the group receiving normal saline. Furthermore, most cells exhibited co expression of NPY and c-fos, indicating activation of NPY neurons in the ARC by PVN-administered orexin-A, which might be involved in feeding regulation. These findings indicate that orexin-A and NPY signaling in the PVN are essential to regulating GS neuronal excitability and feeding in rats. PMID- 30243726 TI - In vitro large scale production of megakaryocytes to functional platelets from human hematopoietic stem cells. AB - Megakaryocytopoiesis results in the formation of platelets, which are essential for hemostasis. Decreased production or increased destruction of platelets can cause thrombocytopenia, in which platelet transfusion is the mode of treatment. The present study is aimed in generation of megakaryocytes (MKs) and platelet from human hematopoietic stem cells (HSCs). The purity of HSCs was assessed through Flow cytometry and immunocytochemistry (ICC) studies. These pure HSCs were induced with thrombopoietin (TPO), similarly with Andrographis paniculata extract (APE) for 21 days to generate MKs. The APE is mainly composed of andrographolide which stimulates TPO from the liver, and this binds to CD110 present on the surface of HSCs and triggers the proliferation of HSCs and initiate higher MKs population subsequently, a large number of platelets. The results of the present study showed increased proliferation of HSCs grown in the presence of APE and revealed a high population of CD41a and CD42b positive MKs as enumerated by Flow cytometry compared with TPO induced MKs. These results also concurred with qRT-PCR and western blot analysis. The scanning electron microscopy (SEM) revealed the morphology of differentiated MKs and platelets were similar to human blood platelets. The differentiated MKs in APE exhibited polyploidy up to 32 N while TPO induced MKs showed polyploidy of 8 N, these results corroborated with colony forming unit assay. On thrombin stimulation, high expression of P-selectin (CD62p) and fibrinogen binding were detected in APE induced platelets. Autologous transplantation of platelets generated from APE may be a useful option in thrombocytopenia condition. PMID- 30243727 TI - Corrigendum to 'The C-terminus of ubiquitin plays a critical role in deamidase Lpg2148 recognition.' [Biochem. Biophys. Res. Commun. 503(4), 18 September 2018, 2943-2948]. PMID- 30243728 TI - The signaling pathways underlying BDNF-induced Nrf2 hippocampal nuclear translocation involve ROS, RyR-Mediated Ca2+ signals, ERK and PI3K. AB - The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) induces complex neuronal signaling cascades that are critical for the cellular changes underlying synaptic plasticity. These pathways include activation of Ca2+ entry via N-methyl D-aspartate receptors and sequential activation of nitric oxide synthase and NADPH oxidase, which via generation of reactive nitrogen/oxygen species stimulate Ca2+-induced Ca2+ release mediated by Ryanodine Receptor (RyR) channels. These sequential events underlie BDNF-induced spine remodeling and type-2 RyR up regulation. In addition, BDNF induces the nuclear translocation of the transcription factor Nrf2, a master regulator of antioxidant protein expression that protects cells against the oxidative damage caused by injury and inflammation. To investigate the possible BDNF-induced signaling cascades that mediate Nrf2 nuclear translocation in primary hippocampal cultures, we tested here whether reactive oxygen species, RyR-mediated Ca2+ release, ERK or PI3K contribute to this response. We found that pre-incubation of cultures with inhibitory ryanodine to suppress RyR-mediated Ca2+ release, with the reducing agent N-acetylcysteine or with inhibitors of ERK or PI3K activity, prevented the nuclear translocation of Nrf2 induced by incubation for 6 h with BFNF. Based on these combined results, we propose that the key role played by BDNF as an inducer of neuronal antioxidant responses, characterized by BDNF-induced Nfr2 nuclear translocation, entails crosstalk between reactive oxygen species and RyR-mediated Ca2+ release, and the participation of ERK and PI3K activities. PMID- 30243729 TI - IMM-H004, a Novel Coumarin Derivative Compound, Inhibits H2O2-Induced Neurotoxicity via Antioxidant and Antiapoptosis in PC12 Cells. AB - IMM-H004 [7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin] is a novel derivative of coumarin, which played neuroprotective roles in brain ischemia in rats in previous studies. Although antiapoptosis and improving synapsis structure were proved, the effects and mechanisms of IMM-H004 in brain ischemia need further study. In this paper, the effect of IMM-H004 on H2O2 induced neurotoxicity in pheochromocytoma (PC12) cells was researched. Morphological observation, MTT method and PI/Hoechst staining were used to indicate cell viability and apoptosis. JC-1 and DCFH-DA were used to test mitochondrial membrane potential (MMP) and reactive oxygen species (ROS), respectively. The antioxidative activity was detected by Glutathione (GSH) and Total Antioxidant Capacity (TAC) Assay kits. Western blot was used to test apoptosis related proteins. Our results showed that treatment with 1-10 MUM IMM H004 markedly increased cell viability and decreased cell apoptosis induced by H2O2. Moreover, 1-10 MUM IMM-H004 could enhance MMP and protect mitochondrial function. 1-10 MUM IMM-H004 also could lower the ROS and raise the GSH and TAC level. Furthermore, 1-10 MUM IMM-H004 could decrease the ratio of Bax/Bcl-2 and increase the ratio of p-AKT/AKT, which were related to apoptosis and survival. All these indicated that IMM-H004 protects PC12 cells against H2O2-induced neurotoxicity. Antioxidative and antiapoptosis may be the mechanisms of IMM-H004 in brain ischemia. These studies indicate that IMM-H004 might be a potential drug for treatment brain ischemia. PMID- 30243730 TI - The organophosphorus pesticide dimethoate decreases cell viability and induces changes in different biochemical parameters of rat pancreatic stellate cells. AB - In the present study we employed cultured pancreatic stellate cells to study the effect of the organophosphorus insecticide dimethoate on pancreatic cell physiology. Esterase activity, cell viability, reactive oxygen species generation and Ca2+ mobilization were examined. Our results show that dimethoate (0.1, 1 and 10 MUM) induced a concentration-dependent inhibition of cholinesterase enzymatic activity at all concentrations tested. A drop in carboxylesterase activity was noted in the presence of 10 MUM dimethoate. In the presence of the pesticide a decrease in cell viability was detected. The clearer effect could be observed when the cells had been incubated during 96 h in the presence of dimethoate. The pesticide induced a slight but statistically significant increase in the production of reactive oxygen species in the mitochondria. Incubation of cells with dimethoate, in the presence of Ca2+ in the extracellular medium, led to a slow and progressive increase in [Ca2+]c towards an elevated value over the prestimulation level. A similar behavior was observed in the absence of extracellular Ca2+, indicating that dimethoate releases Ca2+ from the intracellular stores. Our results suggest that dimethoate might alter intracellular pathways that are critical for pancreatic physiology, creating a situation potentially leading to dysfunction in the exocrine pancreas. PMID- 30243731 TI - Butyl benzyl phthalate promotes prostate cancer cell proliferation through miR 34a downregulation. AB - Prostate cancer is the most common malignancy in men. Phthalate esters are a class of environmental endocrine disruptors and were reported to be cancer promoting agents, however the potential role of phthalate esters in prostate cancer has been rarely reported. Mounting evidence has shown that miR-34a is a master tumor suppressor miRNA in cancer. The aim of this study was to investigate the role of butyl benzyl phthalate (BBP), one of the typical phthalate esters, in cell proliferation of prostate cancer cells. Human prostate cancer LNCaP and PC-3 cells were exposed to low dose of BBP for 6 days. The results showed that 10-6 and 10-7 mol/L BBP increased the expression of cyclinD1 and PCNA, decreased p21 expression, and induced cell growth in both LNCaP and PC-3 cells. Furthermore, we found that BBP significantly downregulated the expression of miR-34a, along with upregulation of miR-34a target gene c-myc. Using cell tranfection of miR-34a mimic and inhibitor, we demonstrated that BBP promoted cell proliferation through miR-34a/c-myc axis in prostate cancer cells. Findings from this study could provide new insight into the involvement and the molecular mechanism of phthalate esters on prostate cancer. PMID- 30243732 TI - Leveraging proteomics to compare submerged versus air-liquid interface carbon nanotube exposure to a 3D lung cell model. AB - With the emerging concern over the potential toxicity associated with carbon nanotube inhalation exposure, several in vitro methods have been developed to evaluate cellular responses. Since the major concern for adverse effects by carbon nanotubes is inhalation, various lung cell culture models have been established for toxicity testing, thus creating a wide variation of methodology. Limited studies have conducted side-by-side comparisons of common methods used for carbon nanotube hazard testing. The aim of this work was to use proteomics to evaluate global cellular response, including pro-inflammatory and pro-fibrotic mediators, of a 3D lung model composed of macrophages, epithelial cells, and fibroblasts which mimics the human alveolar epithelial tissue barrier. The cells were exposed to Mitsui 7 (M-7) multi-walled carbon nanotubes (MWCNT) under submerged and air-liquid interface (ALI) conditions and discovery proteomics identified 3500 proteins. The M-7 ALI exposure compared to control was found to increase expression in proteins related to oxidative stress that were not found to be enriched in submerged exposure. Comparison of MWCNT exposure methods, M-7 ALI exposure versus M-7 submerged exposure, yielded protein enrichment in pathways known to be associated with carbon nanotube exposure stress response, such as acute phase response signaling and NRF2-mediated oxidative stress response. This study demonstrates a comparison of commonly deployed carbon nanotube exposure methods. These data should be considered by the nanotoxicology community when interpreting or cross comparing in vitro exposure results. PMID- 30243733 TI - Degeneration of cholinergic basal forebrain nuclei after focally evoked status epilepticus. AB - Status epilepticus (SE) of limbic onset might cause degenerative phenomena in different brain structures, and may be associated with chronic cognitive and EEG effects. In the present study SE was evoked focally by microinfusing picomolar doses of cyclothiazide+bicuculline into the anterior extent of the piriform cortex (APC) in rats, the so-called area tempestas, an approach which allows to evaluate selectively the effects of seizure spreading through the natural anatomical circuitries up to secondary generalization. In the brain of rats submitted to SE we analyzed neuronal density, occurrence of degenerative phenomena (by Fluoro-Jade B-FJB- staining) and expression of heat shock protein 70 (HSP-70) in the piriform cortex, the hippocampus and ventromedial thalamus. We further analyzed in detail, the loss of cholinergic neurons, and the presence of FJB- and HSP-70 positive neurons in basal forebrain cholinergic areas, i.e. the medial septal nucleus (MSN, Ch1), the diagonal band of Broca (DBB, Ch2 and Ch3) and the Nucleus basalis of Meynert (NBM, Ch4). In fact, these nuclei are strictly connected with limbic structures, and play a key pivotal role in different cognitive functions and vigilance. Although recent studies begun to investigate these nuclei in experimental epilepsy and in persons with epilepsy, conflicting results were obtained so far. We showed that after severe and long-lasting, focally induced limbic SE there is a significant cell loss within all of the abovementioned cholinergic nuclei ipsi- and contra-laterally to the infusion site. In parallel, these nuclei show also FJB and heat shock protein-70 expression. Those effects vary depending on the single nucleus assessed and on the severity of the SE seizure score. We also showed the occurrence of cell loss and degenerative phenomena in limbic cortex, hippocampus and limbic thalamic areas. These novel findings show direct evidence of SE-induced neuronal damage which is solely due to seizure activity ruling out potential confounding effects produced by systemic pro-convulsant neurotoxins. A damage to basal forebrain cholinergic nuclei, which may underlie cognitive alterations, is documented for the first time in a model of SE triggered focally. PMID- 30243734 TI - Masqueraders of central serous chorioretinopathy. AB - Central serous chorioretinopathy (CSCR) is one of the most common chorioretinal pathologies affecting middle-aged men worldwide. Although it has a self-limited course, a significant number of patients suffer from chronic and recurrent episodes. This often leaves the patient with various degrees of visual impairment. The situation is further aggravated by the fact that it is one of the most common conditions to be misdiagnosed. Because of overlapping features with other diseases or the atypical presentation of the disease itself, CSCR is a great mimicker and is one of the commonest causes of referral. We describe some of the conditions which can masquerade as CSCR. PMID- 30243736 TI - Interfacing nanoliter liquid chromatography and inductively coupled plasma mass spectrometry with an in-column high-pressure nebulizer for mercury speciation. AB - Metal speciation analysis of microsamples in the clinical, biological and forensic fields is important for elucidating the metals' toxicity, mobility and metabolic behaviors of metals. Such analysis may be achieved by nanoliter high performance liquid chromatography (nanoHPLC) hyphenated with inductively coupled plasma mass spectrometry (ICP-MS). In this work, an in-column high-pressure nebulizer (ICHPN) was developed to enhance the sensitivity and the separation efficiency of the sheathless nanoHPLC-ICP-MS coupling. The ICHPN consists of two concentric fused-silica capillaries with tapered tips connected via a PEEK tee, where C18 silica particles with a size of 5 MUm were packed in the tapered inner capillary based on the keystone effect. Combining a heated single pass spray chamber with a makeup gas, the ICHPN was capable of independently optimizing the nebulization efficiency and the transport efficiency. The ICHPN offered high sensitivities, low detection limits and good precision at nanoflow rates. Compared with commercial nebulizers, the ICHPN fabrication was simple, rapid, reproducible and inexpensive. By implementing the ICHPN, we achieved rapid separation of four mercury species, i.e., Hg2+ and methyl-, ethyl- and phenylmercuric chloride, within 8.0 min with good resolution (2.0-13.9). Detection limits of 0.044-0.13 MUg L-1 were obtained with precisions of peak heights and areas ranging from 1.5 to 3.5% for a 50 MUg L-1 standard solution. Good agreement between the determined and certified values of mercury species in a certified reference material of caprine blood (SRM 955c) together with good recoveries (93-101%) validated the accuracy of the method. PMID- 30243735 TI - Dealing with overlapped and unaligned chromatographic peaks by second-order multivariate calibration for complex sample analysis: Fast and green quantification of eight selected preservatives in facial masks. AB - The quantification of preservatives in cosmetics has attracted great attentions for their controversial and widespread use. HPLC is a prevailing method for preservatives determination among various analytical methods. However, it takes long time to fully separate these compounds because of the complexity of cosmetic matrices. In this study, a fast and green HPLC-DAD strategy assisted with second order multivariate calibration methods based on alternating trilinear decomposition (ATLD) and multivariate curve resolution-alternating least squares (MCR-ALS) was developed for the simultaneous determination of eight selected preservatives in complex facial mask samples. This appealing strategy proved to be a useful tool for eliminating unknown interferences in complex matrices without complete separation, which benefited from the "second-order advantages" and thus made the determination of the eight analytes in facial mask samples shorten to 8.2 min under a fast elution program. In particular, for the first time, we focused on the applicability of ATLD method for modeling of HPLC-DAD data with severe signal overlapping and slight time shifts. The spiked recovery values were in the range of 71.4-124.6%, and the RMSEP and REP values ranged from 0.07 to 2.4 MUg mL-1 and 1.3-14.5%, respectively, indicating that the ATLD method could provide satisfactory prediction. The resolved spectral profiles and concentration values were compared with those obtained by the MCR-ALS method, an excellent tool for modeling of data deviating from trilinearity. Both qualitative and quantitative results from the two methods were consistent with each other, which evidenced the competence of ATLD method in handling HPLC-DAD data with severe signal overlapping and slight time shifts. PMID- 30243737 TI - Transserosal migration of enteric neural stem cells: Developing an avian colon model. AB - BACKGROUND: Stem cell transplantation is a potential therapy for enteric neuropathies, including Hirschsprung disease. Proof-of-principle has been obtained using focal transplants into neonatal mouse colon. The challenge now is to deliver stem cells to a large surface area to reconstruct an enteric nerve plexus. One proposed method is serosal application using a polymer membrane. However, transserosal migration of stem cells has not been demonstrated in mature colon. This study aimed to develop an avian model to demonstrate stem cell migration across the intact serosa of mature colon. METHODS: Hindguts were obtained from E14 quail embryos, transplanted onto E8 chicken chorioallantoic membranes and harvested after 2 and 8 days. Tissues were assessed immunohistologically for apoptosis (caspase-3), maturity (alpha-SMA), preservation of mucosa (E-cadherin), and preservation of serosa (cytokeratin). RESULTS: Transient necrosis of the central mucosa was observed over the first two days, followed by recovery. Twenty-three grafts were assessed immunohistologically at day 8. Nineteen grafts demonstrated progressive maturation and an intact mucosa. Circumferential serosal preservation was observed in 9 grafts. No apoptosis was seen. CONCLUSION: Avian colon may be successfully harvested with an intact serosa. Large chorioallantoic membrane grafts remain viable for at least 8 days, and the serosa can be preserved throughout. This provides an economical platform for assessing transserosal migration of stem cells in mature colon. PMID- 30243738 TI - The effects of Kasai procedure on living donor liver transplantation for children with biliary atresia. AB - OBJECTIVE: To evaluate the effects of Kasai procedure (hepatic portoenterostomy) on living donor liver transplantation (LDLT) for children with biliary atresia (BA). METHODS: From January 2006 to January 2014, 150 children with BA were treated with LDLT in China. The children were categorized into pre-Kasai and non Kasai groups, based on whether they had previously undergone Kasai procedure. Clinical data were retrospectively analyzed, and the difference in postoperative survival was compared between the groups. Preoperative data, including height, weight, serum bilirubin, and pediatric end-stage liver disease score, and perioperative blood loss, operation duration, incidence of postoperative surgical complications including vascular complications, bile duct complications, lymphatic fluid leakage, and digestive tract fistula were compared between the groups. RESULTS: In total, 89 and 61 children were categorized in the pre-Kasai and non-Kasai groups, respectively. The 1-, 6-, and 12-month survival was 97.8%, 95.4%, and 95.4% for the Kasai group, and 98.4%, 96.7%, and 96.7% for the non Kasai group, respectively (P > 0.05). The differences in mean operation duration and mean blood loss, and the incidences of outflow tract obstruction, portal vein stenosis, hepatic artery thrombosis, bile duct complications, lymphatic fluid leakage, and digestive tract fistula were not statistically significant between the groups (P > 0.05). CONCLUSION: Kasai procedure could effectively delay the requirement of liver transplantation. In light of previous findings that Kasai procedure could significantly improve the liver transplantation-free survival of children with BA, we suggest that Kasai procedure should be used as a first-line treatment method for this condition. TYPE OF STUDY: Treatment Study. LEVEL OF EVIDENCE: Level III. PMID- 30243739 TI - Oridonin prevents epithelial-mesenchymal transition and TGF-beta1-induced epithelial-mesenchymal transition by inhibiting TGF-beta1/Smad2/3 in osteosarcoma. AB - Osteosarcoma is the most common primary bone tumor with highly invasive characteristic and low long-term survival. Recently, epithelial-mesenchymal transition (EMT) is reported as a key event in cancer invasion and metastasis. Oridonin, a bioactive diterpenoid, has been proved to possess anti-cancer effects. However, the effect of oridonin on EMT and metastasis of osteosarcoma is unclear. In this study, we investigated the underlying mechanism of oridonin on EMT and metastasis of osteosarcoma. We found that oridonin inhibited migration and invasion of MG-63 and 143B cells. Moreover, oridonin increased the protein expression of E-cadherin and decreased that of N-cadherin and Vimentin. Oridonin upregulated the transcription of E-cadherin and downregulated N-cadherin and Vimentin. Oridonin inhibited the protein and mRNA levels of Snail and Slug. Furthermore, oridonin inhibited TGF-beta-induced phosphorylation of Smad 2/3, prevented Smad dimer translocation into the nucleus. Finally, we established metastatic models of osteosarcoma 143B cells, and found that oridonin inhibited lung metastasis in vivo. Oridonin increased the protein expression of E-cadherin and reduced N-cadherin and Vimentin. Oridonin inhibited the protein expression of Snail and Slug as well as Smad 2/3 activation. In conclusion, our study demonstrated that oridonin inhibited EMT and TGF-beta1-induced EMT by inhibiting TGF-beta1/Smad2/3 signaling pathway in osteosarcoma. PMID- 30243740 TI - Tissue oxidative damage mediates impairment on phosphotransfer network during thymol intake: Effects on hepatic and renal bioenergetics. AB - Recent evidences demonstrated that ingestion of several monoterpenes cause hepatic and renal damage due to impairment on mitochondrial energy production, eliciting a collapse on adenosine triphosphate (ATP) synthesis and consequently impairment on bioenergetic homeostasis. Thus, the aim of this study was to evaluate whether phosphotransfer network, catalyzed by creatine kinase (CK), adenylate kinase (AK), and pyruvate kinase (PK), can be a pathway to explain hepatic and renal bioenergetics homeostasis impairment due to thymol ingestion. Daily intake of thymol (40 mg/kg) significantly cause a decreased kidney weight and relative kidney weight compared to control group. The same dose of thymol inhibited renal cytosolic and mitochondrial CK activity as well as renal PK activity compared to control group. Finally, thymol (40 mg/kg) elicited a significant increase on renal reactive oxygen species and lipid damage levels, as well as an inhibition on antioxidant capacity against peroxyl radicals and non protein thiol levels, which did not occur liver. Doses of 10 and 20 mg/kg of thymol administered orally for 30 consecutive days non-changed these variables. Based on these evidence, the data supported that intake of a high dose of thymol severely inhibits cytosolic and mitochondrial CK activity, a crucial enzyme to maintain cellular energy homeostasis. Moreover, high dietary thymol intake impaired communication between CK isoenzymes, which inhibits the attempts to regenerate ATP or to facilitate the CK/PCr shuttle to improve the intracellular ATP utilization and consumption. Moreover, the inhibition of renal CK and PK activities appears to be mediated by the renal oxidation of lipids and thiol groups, as well as by the reduction of the renal antioxidant capacity. PMID- 30243741 TI - Inhibition of microRNA-30d attenuates the apoptosis and extracellular matrix degradation of degenerative human nucleus pulposus cells by up-regulating SOX9. AB - Accumulating evidence has suggested that microRNAs are critical regulators of intervertebral disc degeneration (IDD). The excessive apoptosis and extracellular matrix degradation of nucleus pulposus (NP) cells contribute to the initiation of IDD. However, the precise regulatory role of miRNAs in NP cell apoptosis and extracellular matrix degradation remains largely unknown. MicroRNA-30d (miR-30d) has been reported to be involved in regulating apoptosis and bone homeostasis. In this study, we aimed to investigate the role of miR-30d in regulating apoptosis and the extracellular matrix degradation of NP cells, along with the potential underlying molecular mechanism. Herein, our results showed that miR-30d was significantly increased in degenerative NP tissues compared with normal controls. Functional experiments showed that the inhibition of miR-30d promoted the viability and reduced the apoptosis of NP cells in vitro. Moreover, miR-30d inhibition increased the expression of type II collagen and aggrecan and inhibited the expression of matrix metalloproteinase. In contrast, the overexpression of miR-30d showed the opposite effects. Bioinformatics analysis, the dual-luciferase reporter assay, real-time quantitative PCR and western blot analysis showed that miR-30d directly targeted the 3'-untranslated region of SRY related high mobility group box 9 (SOX9) and negatively regulated SOX9 expression. Correlation analysis showed that miR-30d expression was inversely correlated with SOX9 expression in degenerative NP tissues. Moreover, siRNA mediated silencing of SOX9 expression significantly blocked the protective effects of miR-30d inhibition against NP cell apoptosis and extracellular matrix degradation. Overall, these results demonstrate that the inhibition of miR-30d attenuates the apoptosis and extracellular matrix degradation of degenerative human NP cells by up-regulating SOX9, suggesting a potential therapeutic target for IDD. PMID- 30243742 TI - RIFM fragrance ingredient safety assessment, 4,4a,6,7,8,8a-hexahydro-1,4 methanonaphthalen-5(1H)-one, CAS Registry Number: 51519-65-4. PMID- 30243743 TI - RIFM fragrance ingredient safety assessment, 1-methoxyhexane, CAS Registry Number 4747-07-3. PMID- 30243745 TI - RIFM fragrance ingredient safety assessment, terpinyl acetate (isomer mixture), CAS Registry number 8007-35-0. PMID- 30243744 TI - RIFM fragrance ingredient safety assessment, octahydro-4,7-methano-1H indenemethyl acetate, CAS Registry Number 30772-69-1. PMID- 30243746 TI - RIFM fragrance ingredient safety assessment, isobutyl benzoate, CAS registry number 120-50-3. PMID- 30243747 TI - Brazil nut improves the oxidative metabolism of superoxide-hydrogen peroxide chemically-imbalanced human fibroblasts in a nutrigenomic manner. AB - There are some genes associated to the risk of chronic diseases that present potential nutrigenetic response, such as the human manganese-dependent superoxide dismutase gene (Val16Ala-SOD2, rs4880) for which homozygous genotypes (VV and AA) are associated with higher basal superoxide (S) and hydrogen peroxide (HP) levels, respectively. It is possible that the VV- and AA-imbalance could be attenuated by selenium(Se)-rich foods such as Brazil nut (BN). To test this hypothesis, we conducted an in vitro protocol triggering a chemical S-HP imbalance by exposure of dermal fibroblast cells (HFF-1) to paraquat, which generates high S levels (VV-like treatment) and porphyrin (MnTBAP), which generates high HP levels (AA-like treatment). Modulation of cell growth and pro oxidative and antioxidant markers were evaluated. BN aqueous extract (BNAE) most effective concentration which increased cell growth and decreased oxidative metabolism indicators of imbalanced cells was 75 ng Se/mL. However, this effect was not directly affected by the S-HP imbalance: in AA-SOD2-like cells, thioredoxin reductase (TrxR-1) gene was upregulated and in VV-SOD2-like cells an upregulation of glutathione peroxidase (GPx-1) gene expression was observed, however, this regulation occured in a homeostatic manner. These results suggest that BNAE was able to minimize negative effects in both directions of the S-HP imbalance, by modulation of different oxidative-metabolic pathways. PMID- 30243748 TI - Evaluation of the new Sebia free light chain assay using the AP22 ELITE instrument. AB - BACKGROUND: Serum kappa and lambda free light chains (FLC) are useful in the diagnosis, prognosis and monitoring of patients with monoclonal gammopathies. The Binding Site and Siemens were the only suppliers of kits for these analyses until recently, when Sebia introduced an enzyme-linked immunosorbent assay (ELISA) on an automated instrument, DAS AP22 ELITE. METHOD: Samples from routine analysis, controls and chronic kidney disease (CKD) patients were tested using the automated version of Sebia FLC ELISA with the AP22 ELITE and results were compared with Freelite on the SPA PLUS (The Binding Site). RESULTS: Sebia FLC ELISA showed a good performance using the AP22 ELITE. A concordance of 82% was found with the results obtained with Freelite. Sebia FLC is a reproducible assay, requiring less retesting than Freelite thanks to a broader range. Earlier findings that the results obtained are closer to the FLC monoclonal band measured by electrophoresis were confirmed. Higher kappa and lambda values obtained in CKD individuals were also shown, confirming that a kappa/lambda FLC ratio should be introduced by Sebia for CKD patients, as with The Binding Site. CONCLUSIONS: Sebia put forward new technology that automatically measures free light chains. This technique is suitable for routine use; however, the results cannot be used interchangeably with Freelite kits. PMID- 30243749 TI - Unilateral retinitis pigmentosa in children. AB - BACKGROUND: Retinitis pigmentosa (RP) is a group of rare inherited retinal disorders characterized by diffuse progressive degeneration of the retina that typically presents bilaterally. Unilateral RP has not often been reported in children. We present a series of cases that illustrate discrimination between unilateral and asymmetric disease and between dystrophy and acquired degeneration. METHODS: Four patients (9-15 years of age; 3 females) were referred to our institution for possible unilateral RP based on fundus appearance and unilateral symptoms. All underwent full-field electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT), widefield and color fundus photography, and fundus autofluorescence (FAF) imaging. Genetic testing and a vitamin and essential fatty acids panel were also conducted in 1 patient. RESULTS: Unilateral retinal degeneration was confirmed in 2 patients, whose fellow eyes showed no abnormalities on ERG or imaging. The other 2 patients were found to have highly asymmetric retinal degeneration based on ERG, wide-angle images, and repeated examinations (range, 0.3-9.8 years). Genetic testing and blood testing in 1 unilateral case were negative. CONCLUSIONS: Childhood-onset "unilateral RP" remains a difficult and uncertain diagnosis. ERG testing and longitudinal and widefield fundus examination are necessary to exclude asymmetrical disease. Although unilateral degeneration may exist in some children, its inherited or acquired etiology remains poorly understood. PMID- 30243750 TI - Anterior superior oblique tuck: an alternate treatment for excyclotorsion. AB - Excyclotorsion is typically treated with surgical procedures such as the Harada Ito, rectus muscle transposition, and inferior oblique weakening. We describe an alternative technique, the anterior superior oblique tuck. This procedure is technically simpler than the Harada-Ito and provides similar results. PMID- 30243751 TI - Effects of a cardiorespiratory synchronization training mobile application on heart rate variability and electroencephalography in healthy adults. AB - Cardiorespiratory synchronization training (CRST) uses diaphragmatic breathing to increase balance in the autonomic nervous system and reduce negative emotions. CRST integrated with high-technology mobile applications affords innovative and convenient home-based training. This study examined the effects of a CRST mobile application on heart rate variability (HRV) and electroencephalography (EEG) parameters in healthy adults. Ninety-six participants were randomly assigned to the CRST, relaxation training (RT; active control group), and control (C) groups. The CRST group received paced breathing training using a wearable device connected to a mobile application and received feedback on the HRV indices. The RT group received muscle relaxation training using a wearable device connected to a mobile application and received feedback on heart rate (HR). The training program was conducted for 1 h per week for 4 weeks. The C group did not receive any wearable device, mobile application, or psychological intervention. Psychological questionnaires on depression and anxiety and physiological measurements of the breathing rates, electrocardiography (ECG), and EEG were measured at the pretest and posttest. The CRST group showed significantly higher HRV indices and lower breathing rates at the posttest than the RT and C groups. There were no significant interaction effects on EEG parameters at pretest and posttest among the three groups. Use of a CRST mobile application increased balance in the autonomic nervous system at the resting state. This clinical evidence-based technologically advanced mobile application could be implemented in future clinical practice. PMID- 30243752 TI - Respiratory sinus arrhythmia and adaptive emotion regulation as predictors of nonsuicidal self-injury in young adults. AB - Research suggests that both respiratory sinus arrhythmia (RSA) and emotion regulation are related to maladaptive outcomes. However, little is known about how these factors jointly contribute to nonsuicidal self-injury (NSSI). We examined how resting RSA and RSA withdrawal to stress predicted NSSI among young adults, and whether adaptive emotion regulation strategies moderated this effect. We examined this relation in a sample of 70 young adults (Mage = 19.25, SDage = 0.92, 94% female), 35 with a recent history of NSSI and 35 who had never engaged in NSSI. Participants completed a baseline questionnaire and lab visit where physiological responses to a social stressor were collected. Results indicated that resting RSA did not predict recent NSSI engagement. However, greater RSA withdrawal to social stress significantly predicted recent NSSI (beta = 1.35 [0.57], Wald chi2 = 5.52 p = 0.02). Further, problem-solving moderated the relation between RSA withdrawal and recent NSSI such that individuals with greater levels of RSA withdrawal were significantly more likely to engage in NSSI if they also reported low problem-solving (beta = -1.44 [0.64], Wald chi2 = 5.16, p = 0.02). In contrast, the effect of greater RSA withdrawal on NSSI was buffered by high problem-solving. Cognitive reappraisal did not moderate the relation between RSA withdrawal and NSSI. These findings suggest that problem-solving may be an important moderator in the relation between physiological reactivity and NSSI. Interventions should help clients with poor self-regulation develop adaptive problem-solving strategies. PMID- 30243753 TI - JESREC score and mucosal eosinophilia can predict endotypes of chronic rhinosinusitis with nasal polyps. AB - OBJECTIVE: Recently, JESREC score and mucosal eosinophil count have been used to diagnose eosinophilic chronic rhinosinusitis (ECRS) in Japan. However, it remains unknown whether the subtypes of CRS diagnosed by these criteria have different endotypes. In the present study, we investigated whether JESREC score and mucosal eosinophil count were appropriate for classification of CRS subgroups into endotypes. METHODS: A cross-sectional study involving 71 consecutive patients with CRS with nasal polyps (CRSwNP) and 13 control patients was performed. Nasal polyp tissues from CRSwNP patients and uncinate process tissues from control patients were collected for analysis of inflammatory cells by immunohistochemistry and measurement of cytokines and chemokines by ELISA and quantitative real-time PCR. We compared the differences between subtypes according to JESREC score and mucosal eosinophil count and investigated the subgroups with different endotypes by cluster analysis and principal component analysis. RESULTS: In the 71 CRSwNP patients, 9 patients had JESREC score <11 and mucosal eosinophil count <70/HPF (Group A), 20 patients had JESREC score >=11 and mucosal eosinophil count <70/HPF (Group C), and 42 patients had JESREC score >=11 and mucosal eosinophil count >=70/high-power field (HPF) (Group D). Semiquantitative analysis of inflammatory cells showed that eosinophils, neutrophils, macrophages, mast cells, and basophils differed significantly between the subgroups. At the mRNA level, CLC, IL5, IL13, CCL11, CCL24, CCL26, POSTN, CSF3, and IL8 showed significant differences. At the protein level, eotaxin-2/CCL24, eotaxin-3/CCL26, and G-CSF had significant differences. Cluster analysis using gene expression levels in 55 CRS patients and 11 control patients revealed that the patients could be classified into five clusters. Cluster 1 (n=27) contained all patients with Group D. Cluster 2 (n=11) comprised all control patients. Cluster 3 (n=4) included mixed subtypes: one with Group A and three with Group D. Cluster 4 (n=7) and Cluster 5 (n=17) contained all patients with Groups A and C, respectively. Furthermore, the principal component analysis revealed that the subtypes had different characteristics. CONCLUSION: CRS subtypes based on JESREC score and mucosal eosinophil count showed different inflammatory patterns, and unsupervised statistical analyses supported the classification that can predict endotypes. From these results, we concluded that the classification based on JESREC score and mucosal eosinophil count was useful for predicting CRS endotypes. PMID- 30243754 TI - Optimal control to develop therapeutic strategies for metastatic castrate resistant prostate cancer. AB - In metastatic castrate resistant prostate cancer (mCRPC), abiraterone is conventionally administered continuously at maximal tolerated dose until treatment failure. The majority of patients initially respond well to abiraterone but the cancer cells evolve resistance and the cancer progresses within a median time of 16 months. Incorporating techniques that attempt to delay or prevent the growth of the resistant cancer cell phenotype responsible for disease progression have only recently entered the clinical setting. Here we use evolutionary game theory to model the evolutionary dynamics of patients with mCRPC subject to abiraterone therapy. In evaluating therapy options, we adopt an optimal control theory approach and seek the best treatment schedule using nonlinear constrained optimization. We compare patient outcomes from standard clinical treatments to those with other treatment objectives, such as maintaining a constant total tumor volume or minimizing the fraction of resistant cancer cells within the tumor. Our model predicts that continuous high doses of abiraterone as well as other therapies aimed at curing the patient result in accelerated competitive release of the resistant phenotype and rapid subsequent tumor progression. We find that long term control is achievable using optimized therapy through the restrained and judicious application of abiraterone, maintaining its effectiveness while providing acceptable patient quality of life. Implementing this strategy will require overcoming psychological and emotional barriers in patients and physicians as well as acquisition of a new class of clinical data designed to accurately estimate intratumoral eco-evolutionary dynamics during therapy. PMID- 30243755 TI - A comparison of stable and fluctuating resources with respect to evolutionary adaptation and life-history traits using individual-based modeling and machine learning. AB - There are three non-mutually-exclusive key strategies evolved by gene pools to cope with fluctuating food resource availability, including evolutionary adaptation, phenotypic plasticity, and migration. We focus primarily on evolutionary adaptation and behavioral plasticity, which is a type of phenotypic plasticity, resulting in life-history changes as ways of dealing with fluctuations in food resource availability. Using EcoSim, a predator-prey individual-based model, we compare individuals with stable food resources with those in environments where there are fluctuating food resources in terms of adaptation through behavioral plasticity and evolution. The purpose of our study is to determine whether evolution and behavioral plasticity truly play a role in adapting to an environment with fluctuating food resources, as well as to determine whether there are specific gene divergences between gene pools in fluctuating food resource environments versus gene pools where food resources are relatively stable. An important result of our study is that individuals in environments that are unstable with respect to food resource availability exhibited significant differences in behaviors versus those in environments with stable food resources. Although behavioral plasticity facilitates a rapid response to unstable food conditions, our study revealed the evolution of perceptual traits such as vision range in reaction to fluctuating food resources, indicating the importance of evolution in adapting to unstable resource environments in the long run. Moreover, using decision trees, we found that there were significant behavioral gene divergences between individuals in environments with fluctuating food resources as opposed to individuals in environments with stable food resources. PMID- 30243756 TI - Responsive neurostimulation: Review of clinical trials and insights into focal epilepsy. AB - The responsive neurostimulator (RNS (r), NeuroPace Inc.) has been available clinically since 2013 for the treatment of medically refractory partial epilepsy. Using intracranial electrodes and a cranially implanted device, RNS (r) provides on-demand electrical cortical stimulation to reduce seizures. A randomized, multicenter, double-blind clinical trial demonstrated seizure reduction compared with sham stimulation. Seizure reduction was improved and sustained over years in a long-term treatment trial. The RNS (r) provides chronic ambulatory electrographic monitoring over years giving unprecedented insight into epilepsy dynamics. Studies to date have looked at the length of time to detecting bilateral seizure onsets in mesial temporal lobe epilepsy (MTLE), demonstrated biorhythms in interictal epileptiform activity over varied time scales, and shown promise in early detection of benefits of adding a new antiepileptic drug. Questions remain as to the boundaries of patient selection and lead placement. This article is part of the Special issue "Neurostimulation for Epilepsy." PMID- 30243757 TI - Mineralocorticoid receptor function and cognition in health and disease. AB - The steroid hormone cortisol is released in response to stress and exerts its effects in the brain via two different receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). This review - dedicated to Dirk Hellhammer - focusses on the role of MR on cognitive and emotional function in healthy individuals and in stress-associated disorders such as major depressive disorder (MDD) or borderline personality disorder (BPD). Animal data and studies from healthy individuals converge such that MR play an important role in the appraisal of new situations and the following response selection. Decision-making and empathy are important determinants of this response selection and both are affected by MR function. Furthermore, MR are crucially involved in visuospatial navigation and memory in young and elderly healthy individuals whereas the exact physiological role of MR in verbal learning and verbal memory needs to be further characterized. In contrast to studies in healthy participants, age played a moderating role on the effects of MR stimulation on cognition in depressed patients. In young depressed patients, MR stimulation exerted beneficial effects on verbal memory and executive function, whereas in elderly depressed patients MR stimulation led to impaired verbal learning and visuospatial memory. Similar to healthy controls, BPD patients showed enhanced emotional empathy but not cognitive empathy after MR stimulation. Accordingly, this make MR an interesting target for potential pharmacological augmentation of psychotherapy in BPD. Given the important role MR play in cognitive and emotional function in health and disease, further studies should examine whether MR modulation can alleviate cognitive and emotional problems in patients with stress-associated disorders. PMID- 30243758 TI - Late onset psoriatic arthritis in a longitudinal cohort: Disease presentation, activity over time and prognosis. AB - AIMS: To evaluate disease activity of late onset psoriatic arthritis (LoPsA) patients at presentation, during follow-up, and after 5years of follow-up, compared to young onset PsA patients (YoPsA). METHODS: The study included patients with PsA followed prospectively within 2years from diagnosis. Patients were divided into two groups: (1) LoPsA - defined as disease onset >= 50 years, (2) YoPsA - defined as disease onset < 50 years. Descriptive statistics are provided and multivariable logistic regression models were developed to compare these groups. RESULTS: Five hundred and sixty-six patients were included at presentation. Regression analysis showed that the LoPsA group at presentation was characterized by: less males (OR 0.4, p = 0.001), less HLA-C*06 (OR 0.3, p = 0.005), longer psoriasis duration (OR 1.04, p = 0.0005), higher BMI (OR 1.1, p = 0.005) and higher modified Steinbrocker score (mSS) (OR 1.1, p = 0.005). Regression analysis adjusted for gender, BMI, psoriasis duration, HLA and treatments after 5years of follow-up revealed a trend toward higher adjusted mean active joint count (OR 7.98, p = 0.052) and higher mean mSS score (OR 13.39, p = 0.007) in the LoSpA group compared to the YoPsA group. During 5years of follow up, the YoPsA patients were treated with more NSAIDs (96% vs. 88%, p = 0.04), while there were no significant differences in the DMARDs and biologic drugs. CONCLUSION: The LoPsA patients at presentation are characterized by female predominance, higher BMI, more damage and less HLA-C*06. After 5years of follow up the LoPsA patients have worse prognosis manifested by a trend toward higher disease activity burden and significantly more damage. PMID- 30243759 TI - Colonic Schistosoma Granulomas: An Unusual Cause of Colonic Subepithelial Lesions. PMID- 30243760 TI - Monitoring and Treatment of Patients Undergoing Immunotherapy With Anti-CD20 Who are Exposed to HBV. AB - Reactivation of hepatitis B virus (HBV) is a potentially fatal complication of immunosuppressive therapy, and can occur in individuals who are hepatitis B surface antigen (HBsAg) negative but positive for hepatitis B core antibody (anti HBc). While anti-HBc positivity indicates prior HBV exposure, it may also reflect clearance of HBsAg, but with viral persistence at low intrahepatic replicative and transcriptional levels.1 HBV reactivation can still occur during intense immunosuppression, including B cell-depleting therapy with anti-CD20 antibodies2 and hematopoietic stem cell transplantation.3 While prevention via antiviral prophylaxis is recommended, it remains uncertain, from a global perspective, if this is an ideal and cost-effective strategy. An alternative is regular HBV DNA monitoring.4 However, this approach is problematic in resource-constrained regions, where the logistics of sample collection, transportation, and molecular analysis in dedicated facilities poses challenges.5 We aimed to evaluate the effectiveness of simple monitoring strategies using routine liver biochemistry and serum HBsAg in preventing HBV-related complications during anti-CD20 therapy. PMID- 30243761 TI - Primary Localized Gastric Amyloidosis Mimicking a Submucosal Tumor-Like Gastrointestinal Tumor. PMID- 30243762 TI - How Quickly Do Inflammatory Bowel Disease Medications Really Work? PMID- 30243764 TI - No one should be left behind - IDF initiative to improve diabetes care in humanitarian settings. PMID- 30243765 TI - Ex vivo liver resection and autotransplantation: An emerging option in selected indications. PMID- 30243763 TI - A Resource for Inactivation of MicroRNAs Using Short Tandem Target Mimic Technology in Model and Crop Plants. AB - microRNAs (miRNAs) are endogenous small non-coding RNAs that bind to mRNAs and target them for cleavage and/or translational repression, leading to gene silencing. We previously developed short tandem target mimic (STTM) technology to deactivate endogenous miRNAs in Arabidopsis. Here, we created hundreds of STTMs that target both conserved and species-specific miRNAs in Arabidopsis, tomato, rice, and maize, providing a resource for the functional interrogation of miRNAs. We not only revealed the functions of several miRNAs in plant development, but also demonstrated that tissue-specific inactivation of a few miRNAs in rice leads to an increase in grain size without adversely affecting overall plant growth and development. RNA-seq and small RNA-seq analyses of STTM156/157 and STTM165/166 transgenic plants revealed the roles of these miRNAs in plant hormone biosynthesis and activation, secondary metabolism, and ion-channel activity associated electrophysiology, demonstrating that STTM technology is an effective approach for studying miRNA functions. To facilitate the study and application of STTM transgenic plants and to provide a useful platform for storing and sharing of information about miRNA-regulated gene networks, we have established an online Genome Browser (https://blossom.ffr.mtu.edu/designindex2.php) to display the transcriptomic and miRNAomic changes in STTM-induced miRNA knockdown plants. PMID- 30243766 TI - Aptamer-based fluorometric assay for direct identification of methicillin resistant Staphylococcus aureus from clinical samples. AB - Accurate and rapid identification of methicillin-resistant Staphylococcus aureus (MRSA) is of important clinical significance. In this study, a novel aptamer based fluorometric assay was developed for detection of MRSA in clinical samples by coupling with immunomagnetic separation. The S. aureus cells in clinical specimens were enriched by magnetic separation. Following lysis by staphylococcal lysin, the PBP2a proteins were released from S. aureus cells and detected by the aptamer-based fluorometric assay. Without lengthy period of bacteria cultivation in the traditional susceptibility testing, this test has an overall testing time of only 2 h with the detection limit of 2.63 * 103 and 1.38 * 103 CFU/mL in PBS and spiked nasal swab, respectively. Since it is simple, rapid and sensitive, this method could be used for the detection of MRSA in various clinical samples. PMID- 30243767 TI - Behavioral response to fiber feedingis cohort-dependent and associated with gut microbiota composition in mice. AB - Recent data has supported a role for the gut microbiota in improving cognition and shaping behavior. Here, we assessed whether pectin, a soluble, fermentable fiber, could enhance learning and memory in mice. Two cohorts of young male C57Bl/6 J mice, C1 (n = 20) and C2 (n = 20), were obtained from Jackson Laboratory and randomized to semi-purified AIN-93 M diets containing 5% pectin (n = 10) or cellulose (n = 10). After 16 weeks, learning and memory was assessed by Morris Water Maze (MWM) and microbiota composition was analyzed by 16S rRNA sequencing. Despite identical treatment, we observed differences in learning and memory abilities between cohorts, along with distinct microbiotas. In C1, pectin fed mice spent a higher percentage of time in the target quadrant at the 24-h probe trial of the MWM versus cellulose-fed mice; in C2, no effect of pectin was observed. In both cohorts, UniFrac distance revealed significant differences in gut microbial communities between cellulose-fed and pectin-fed mice. UniFrac analysis also revealed significantly different bacterial communities between cohorts. Further analysis demonstrated that the microbial genera Oscillospira, Bilophila, and Peptostreptococcoceae were more abundant in C1 versus C2, and positively associated with distance from the platform during the 24-h probe test. These data support previous findings that differences in the gut microbiota may play a role in host response to a dietary intervention and could partly explain irreproducibility in psychological and behavioral experiments. Further research is needed to determine if a causal relationship exists. PMID- 30243768 TI - A Cost-effectiveness Analysis of Rabbit Antithymocyte Globulin Versus Antithymocyte Globulin-fresenius as Induction Therapy for Patients With Kidney Transplantation From Donation After Cardiac Death in China. AB - PURPOSE: Induction immunosuppression therapy is used to support optimal outcomes in kidney transplantation. This study was to assess the cost-effectiveness of rabbit antithymocyte globulin (r-ATG) versus ATG-Fresenius (ATG-F) in kidney transplantation in the Chinese setting from the perspective of the health care payer. METHODS: A 2-part survival model was developed, consisting of a short-term part and a long-term part. The short-term part analyzed the first year, using the decision tree, and consisted of the functioning transplant, acute rejection (AR), delayed graft function (DGF), dialysis, and death health states. The long-term part analyzed 2 to 5 years, using Markov model, and consisted of the functioning transplant, chronic dysfunction, recurring primary disease, dialysis, and death health states, with capture of the association between DGF and graft loss. Costs, including drug acquisition and other direct medical costs, were derived from China IQVIA database (formerly known as IMS) hospitaldatabase, chart review, and physician interviews. Clinical outcomes and utility were retrieved from published literature. The model calculated quality-adjusted life-years (QALYs) and total costs per patient. Costs and QALYs were discounted at an annual rate of 3.5%. Univariate sensitivity analysis and probability sensitivity analysis (PSA) were conducted to assess the impact of uncertainty of the variables on the results. FINDINGS: Patients who received r-ATG had more clinical effectiveness than patients who received ATG-F mainly because of less AR, DGF, and dialysis. The incremental QALY was 0.01 over a 1-year time horizon and 0.0496 over a 5-year time horizon. R-ATG and ATG-F drug costs were Y10,783 and Y8409, respectively. However, the total treatment costs of the r-ATG arm were lower than the ATG-F arm because of lower costs related to DGF, AR, dialysis, and adverse events. In total, r-ATG saved Y5423 over the 1-year and Y7042 over the 5-year time horizon. R-ATG was dominant with lower total direct medical costs and higher QALYs compared with ATG-F. Both univariate sensitivity analysis and PSA found the robustness of the model results. PSA results indicated that r-ATG was cost effective compared with ATG-F in 86.81% of the simulations, considering <3 times the gross domestic product per capita as the threshold. IMPLICATIONS: From the perspective of the health care payer, r-ATG should be considered as the preferred treatment agent for induction therapy for Chinese patients undergoing kidney transplantation because of its lower overall medical costs and greater QALYs gained compared with ATG-F. The study was limited by lack of long-term efficacy data among the Chinese population and lack of comprehensive real-world higher quality costs data. PMID- 30243769 TI - Breast Milk: A Postnatal Link Between Maternal Life Choices and the Prevention of Childhood Obesity. AB - The prevention of diabetes and obesity in the young starts with the prevention and treatment of modifiable maternal risk factors encompassing the period from before conception until weaning. Major modifiable variables are characteristics and behaviors that include prepregnancy weight, gestational weight gain, glycemia, and intensity and duration of breastfeeding. Much of the early programming of resistance or vulnerability to age-related diseases is influenced by the integrated balance of maternal hormones transferred to the offspring by milk. This whole-body programming/reprogramming of milk recipient (infant) and milk donor (mother) may be involved in the dose effect of human milk on a healthier body composition and metabolic function in the mother-infant pair following the period of exposure. The pattern and trajectory of weight and metabolic characteristics vary between the active period of exposure and postexposure. In addition, the optimal hormone ranges in maternal circulation and milk need to be determined beyond the observation that extremely high and extremely low concentrations may be detrimental for the mother-infant pair. This commentary discusses the metabolic implications of breastfeeding for this pair. PMID- 30243770 TI - Rethinking Childhood Obesity: Novel Preventive and TreatmentStrategies. PMID- 30243771 TI - Explaining all without causing unnecessary harm: Is there scope for positively framing medical risk information? AB - Clinicians in the United Kingdom are now legally obliged to tell patients about every risk involved in prescribed medical treatments. Although important for informed consent, warning patients of risks such as side-effects can increase the incidence of these very side-effects, through the nocebo effect. Positively framing risk information could be a potential solution to this dilemma, and preliminary data has shown it is effective in healthy volunteers receiving a sham drug. Future research is needed to test its effectiveness in a clinical population. PMID- 30243772 TI - Racial and ethnic estimates of Alzheimer's disease and related dementias in the United States (2015-2060) in adults aged >=65 years. AB - INTRODUCTION: Alzheimer's disease and related dementias (ADRD) cause a high burden of morbidity and mortality in the United States. Age, race, and ethnicity are important risk factors for ADRD. METHODS: We estimated the future US burden of ADRD by age, sex, and race and ethnicity by applying subgroup-specific prevalence among Medicare Fee-for-Service beneficiaries aged >=65 years in 2014 to subgroup-specific population estimates for 2014 and population projection data from the US Census Bureau for 2015 to 2060. RESULTS: The burden of ADRD in 2014 was an estimated 5.0 million adults aged >=65 years or 1.6% of the population, and there are significant disparities in ADRD prevalence among population subgroups defined by race and ethnicity. ADRD burden will double to 3.3% by 2060 when 13.9 million Americans are projected to have the disease. DISCUSSION: These estimates can be used to guide planning and interventions related to caring for the ADRD population and supporting caregivers. PMID- 30243773 TI - An Evolutionary Perspective on the Obesity Epidemic. AB - An evolutionary approach to obesity involves a genomic/anthropological dimension. For 1.8 Myr the lifestyle of hunter-gatherers (HGs) comprised intense physical activity and a high-protein/low-carbohydrate diet. Genomes of HGs were adapted to low insulin sensitivity. When the agrarian epoch began a new 'farmer diet' high in carbohydrates (CHO) emerged. Owing to periodic famines, the genome may not have adapted; they preserved a HG genome. Ever since the industrial revolution our genome is adapting rapidly to a CHO-rich diet. Individuals with preserved HG genome develop obesity at age 4-8 years and need a low-CHO diet. By contrast, those with a farmer genome become obese in infancy; they need a low-calorie diet. This knowledge prompts exploration of the two genomes and their clinical presentations. PMID- 30243774 TI - Antiviral effect of 7-(4-benzimidazole-butoxy)-coumarin on rhabdoviral clearance via Nrf2 activation regulated by PKCalpha/beta phosphorylation. AB - Coumarin forms an elite class of naturally occurring compounds that possess promising antiviral therapeutic perspectives. In the previous study, we designed and synthesized a coumarin derivative, 7-(4-benzimidazole-butoxy)-coumarin (BBC), to evaluate its antiviral activity on spring viraemia of carp virus (SVCV). In this study, our results show that BBC does not affect viral adhesion and delivery from endosomes to the cytosol, indicating BBC has no inhibitory activity in the early stage of viral infection. Further data are determined that BBC significantly declines SVCV-infected apoptosis and recovers caspase-3/8/9 activity. To reveal the pathway that affects Nrf2 translocation by BBC, we examine changes in protein kinase C (PKC) in EPC cells treated with BBC. We observe that BBC results in a higher phosphorylation of PKCalpha/beta that is involved in the activation of erythroid 2-related factor 2 (Nrf2) phosphorylation to favor Nrf2 translocation to nucleus at 24 and 48 h. In addition, the results show that BBC also up-regulates both antiviral responses, heme oxygenase-1 (HO-1) expression and cellular IFN response. Overall, this mechanism of action provides a new therapeutic target for the treatment of SVCV infection, and these results suggest that treatment with BBC is effective in reducing SVCV infection and differently regulates SVCV-induced undesirable conditions. PMID- 30243775 TI - Preface to the special issue 'targeting fish vaccination'. PMID- 30243776 TI - Identification of a Bcl-xL homolog from orange-spotted grouper (Epinephelus coioides) involved in SGIV-induced nonapoptotic cell death. AB - Bcl-2 family proteins play essential roles in modulating immune response and controlling cells' fate. Bcl-xL is one of anti-apoptotic protein in this family. In this study, a new Bcl-xL homolog (EcBcl-xL) was identified and characterized from orange-spotted grouper, Epinephelus coioides. EcBcl-xL encoded a 221 amino acid peptides that shared 86% identity to Larimichthys crocea Bcl-xL protein, contained four conserved BH domains and one transmembrane region. The predicted three-dimensional structure of EcBcl-xL was similar with Homo sapiens Bcl-xL. EcBcl-xL widely expressed in all tested tissues with highest expression in head kidney. Its expression level was significantly up-regulated after SGIV infection in vivo. Furthermore, overexpression of EcBcl-xL could inhibit SGIV-induced nonapoptotic cell death and suppressed viral genes transcriptions in GS cells. Our findings suggested that EcBcl-xL might play a role during virus infection through modulating SGIV-induced nonapoptotic cell death. PMID- 30243777 TI - Hall Pass. PMID- 30243778 TI - Cytotoxic and antibacterial aspidofractinine alkaloids from Kopsia hainanensis. AB - The ethanol extract of the twigs and leaves of Kopsia hainanensis afforded six new aspidofractinine alkaloids, kopsiahainanins A-F (1-6), among which alkaloids 1 and 2 possessed a lactone bridge with novel regiochemistry. The structures of the isolated compounds were established based on 1D and 2D (1H1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated compounds were tested in vitro for cytotoxic activity against seven tumor cell lines and antibacterial activities against two Gram-positive bacteria and five Gram-negative bacteria. As a result, alkaloids 1 and 2 exhibited cytotoxic activities (IC50 values <20 MUM) against all tested tumor cell lines and significant antibacterial properties (MIC values from 0.12 to 0.26 mM). PMID- 30243780 TI - [What would a person in a medical uniform know about communities? Dialogue on community health and its many varied forms. SESPAS Report 2018]. AB - Terms such as community or community health are used more and more frequently and in multiple contexts. As healthcare workers, we acknowledge the need to reflect upon these concepts in order to shed light on the different meanings we bestow on community health. This dialogue approaches the notion of the community examining its relationships with other notions; for example, we examine how the notion of territory could trigger both communitarian networks and exclusionary practices. On the other hand, the practices that identify and help in building what is "communal" are perceived as more inclusive and as a starting point to think about what communities mean. Far from a naive vision of the community as a non hierarchical structure, this dialogue exposes the risks of reproducing inequalities within the communities we work with. Therefore, we propose maintaining an active dialogue within the communities to collectively rename the real experienced conditions that need to be transformed. Finally, this dialogue reflects upon the professional roles arising from the different approaches to community health and the sociopolitical implications that this diversity entails. PMID- 30243779 TI - LC-MS guided isolation of gracilistones A and B, a pair of diastereomeric sesquiterpenoids with an unusual tetrahydrofuran-fused tricyclic skeleton from Acanthopanax gracilistylus and their potential anti-inflammatory activities. AB - Gracilistones A (1) and B (2), two new eudesmane-type sesquiterpenoids with an unusual tetrahydrofuran-fused 6/6/5 tricyclic ring system, were obtained from Acanthopanax gracilistylus under the guidance of LC-MS investigation. Their structures and absolute configurations were assigned by extensive spectroscopic analyses and quantum calculation methods. Compounds 1 and 2 showed potent inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages, compared with the positive control L-NMMA. In addition, compounds 1 and 2 were also evaluated for their antioxidant (DPPH* and ABTS*+) and xanthine oxidase (XO) inhibitory activities, and they exhibited weak inhibitory effects at 100 MUM. PMID- 30243781 TI - Adverse consequences of low-dose methotrexate medication errors: data from French poison control and pharmacovigilance centers. AB - OBJECTIVE: The objectives of this study are to carefully describe the context of methotrexate medication errors, to details medical consequences and management approaches, and to determine the rate of fatal outcome. METHODS: Data on methotrexate medication errors were obtained from the French network of poison control and pharmacovigilance centres, which collected and documented reported drug-induced adverse effects. Cases were included if the intake was more than 2 fold the intended weekly dose or a weekly cumulative dose >= 30 mg and a follow up of at least 4 days after the last dose. Data were analysed for demographics, treatment indication, prescribed dose, drug interactions, clinical complications and medical outcomes. RESULTS: Seventy four patients were included. The causes of methotrexate errors resulted from an erroneous prescription renewal (23.3%), incomprehensiveness of the weekly schedule by patients or at-home caregivers (56.2%) and administration of a wrong dose by a health care professional (20.5%). Of the 70 patients who took methotrexate daily, the mean daily dose received over the whole duration of the error was 9.6 +/- 4.1 mg (range 2.5-22.5) with a mean duration of the error of 11.7 +/- 12.2 days (range 2 to 90). Thirteen (18%) patients remained asymptomatic and 61 (82%) developed complications of which 46 (62.2%) were severe. Nine (14.8%) patients died within 11 to 45 days after the first dosing error. Compared to patients with no or mild symptoms, those with severe symptoms were more likely to be older (75.6 +/- 10.8 vs. 69.5 +/- 12.9 years) and to be exposed to a higher cumulative dose (94.8 +/- 46.2 vs. 68.0 +/- 45.7 mg). CONCLUSIONS: This study confirms that dosing errors with methotrexate can be lethal and persisted despite several warnings from drug agencies. Further measures are awaited from the European Medicine Agency. PMID- 30243782 TI - Recommendations for the assessment and optimization of adherence to disease modifying drugs in chronic inflammatory rheumatic diseases: A process based on literature reviews and expert consensus. AB - BACKGROUND: Adherence to treatment is a key issue in chronic inflammatory rheumatic diseases (CIRDs). OBJECTIVE: To develop recommendations to facilitate in daily practice, the management of non-adherence to disease-modifying drugs in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, connective tissue diseases or other CIRDs. METHODS: The process comprised (a) systematic literature reviews of methods (including questionnaires) to measure non-adherence, risk factors for non-adherence and efficacy of targeted interventions; (b) development of recommendations through consensus of 104 rheumatologist and nurse experts; (c) assessment of agreement and ease of applicability (1-5 where 5 is highest) by the 104 experts. RESULTS: (a) Overall, 274 publications were analysed. (b) The consensus process led to 5 overarching principles and 10 recommendations regarding adherence. Key points include that adherence should be assessed at each outpatient visit, at least using an open question; questionnaires and hydroxychloroquine blood level assessments may also be useful. Risk factors associated to non-adherence were listed. Patient information and education, and patient/physician shared decision, are key to optimize adherence. Other techniques such as formalized education sessions, motivational interviewing and cognitive behavioral therapy may be useful. All health professionals can get involved and e-health may be a support. (c) The agreement with the recommendations was high (range of means, 3.9-4.5) but ease of applicability was lower (2.7-4.4). CONCLUSIONS: Using an evidence-based approach followed by expert consensus, this initiative should improve the assessment and optimization of adherence in chronic inflammatory rheumatic disorders. PMID- 30243783 TI - Identification of cartilage oligomeric matrix protein as biomarker predicting abatacept response in rheumatoid arthritis patients with insufficient response to a first anti-TNFalpha treatment. PMID- 30243784 TI - Advances in the treatment of systemic lupus erythematosus: From back to the future, to the future and beyond. AB - There have been many advances in the diagnosis and therapeutic management of systemic lupus erythematosus (SLE) over the past decades. Following more than eleven centuries of therapeutic uncertainty, the discovery of the therapeutic properties of glucocorticoids is without any doubt one of the most significant advance in the field of autoimmune diseases. The many progresses made by rapidly growing chemical industry of the 19th century chemistry have allowed the identification of valuable therapeutic compounds such as anti-malarials, cyclophosphamide, azathioprine, cyclosporine and later mycophenolate mofetil, which have all profoundly changed the face of the disease. A very visible consequence of this is the profound improvement in the prognosis of the disease, with 10-year survival rates of more than 90% in most dedicated centres. Following the development of biotherapies in rheumatoid arthritis, the late 20th century has slowly opened a new era for the treatment of SLE, that of targeted therapies. With the approval of belimumab in 2011 and 74 targeted therapies in clinical development, we may expect great changes in the therapeutic management of SLE. Those molecules target inflammatory cytokines or chemokines and their receptors, B cells or plasma cells, intracellular signalling pathways, B/T cells co stimulation molecules, interferons, plasmacytoid dendritic cells, as well as various other targets of interest. Current challenges are now slowly shifting from whether some new drugs will be available to how to select the most adequate drug (or drug combination) at the patient-level. PMID- 30243785 TI - Tendon thickening in dialysis-related joint arthritis is due to amyloid deposits at the surface of the tendon. AB - OBJECTIVES: Beta-2-microglobulin (beta2M) dialysis-related amyloidosis (DRA), a disabiliting joint disease, has been initially reported in patients under long term dialysis. The incidence and prevalence has significantly decreased with the improvement in dialysis techniques. Here, we attempted to clarify the clinical and MRI features to improve the diagnosis. METHODS: We retrospectively reviewed the files of 19 patients under dialysis treatment referred for suspicion of beta2M DRA. The diagnosis was based on MRI criteria (low signal intensity on both T1- and T2-weighted MR sequences). MRI analysis included a scoring of the several joint lesions. Scores were quantified according to a severity scale (0 to 3). RESULTS: Patients had a mean age of 66.0 +/- 10.5 years and mean dialysis duration of 23.7 +/- 10.5 years. DRA affected mainly large joints (shoulder in 73.7%, hip in 47.3%) and spine (36.8%). MRI images for 8 shoulders, 8 hips, and 3 spines were analysed. Amyloid synovitis was present in all cases, with high mean scores in the three sites. In all joints, the most common lesions were tendon thickening (68.4%) and bone erosions (68.4%). The mean tendon thickening score was high, particularly at the shoulders and also at the spine. Bone erosions were most frequent in the shoulder and pelvis. CONCLUSION: In patients under long-term dialysis, beta2M DRA involves large joints but also the spine. Special awareness should be drawn by the thickening of the tendon. MRI is required to characterize the pattern of the lesions and to achieve the diagnosis. PMID- 30243786 TI - Arthroscopic Repair of Anterior Talofibular Ligament Using the Pull-Out Technique for Chronic Ankle Instability: Case Report. AB - Arthroscopic repair of the lateral ankle ligament using the anchor system has been increasingly reported. We treated a 39-year-old woman who suffered from pain and instability in her left ankle joint. She was diagnosed with chronic ankle instability and an osteochondral lesion of the talar dome. For this patient, arthroscopic repair of the anterior talofibular ligament (ATFL) was performed. Standard anteromedial and anterolateral portals were placed, and excision of the osteochondral fragment and microfracture were performed. Then, an accessory anterolateral (AAL) portal was placed. No. 2 nylon sutures were inserted into the ATFL remnant through the AAL portal. Two bone tunnels were created at the footprint of the fibula attachment toward the posterior edge of the lateral malleolus using a passing pin, and nylon sutures anchored in the ATFL were retrieved toward the posterior fibula. The foot was held in neutral position with eversion, and nylon sutures were tied at the posterior fibula. At 1 year after surgery, the Japanese Society for Surgery of the Foot scale was improved from the preoperative value of 48 points to a postoperative value of 100 points. Stress radiography showed no difference of talar tilt angle between the involved and noninvolved ankles. Joint position sense was also improved at 3 and 6 months after surgery. This arthroscopic repair of the ATFL using the pull-out technique enabled achievement of an improved clinical score and stability of the ankle and proprioception, and there was no concern about complications of the anchor system. PMID- 30243787 TI - Efficacy of Ponseti Technique in Virgin and Relapsed Clubfeet: A Comparative Study. AB - Doubts still loom over the effectiveness of Ponseti casting in treating children with recurrent clubfeet. We have undertaken this study to confirm whether excellent results obtained in treating virgin clubfeet by Ponseti casting can be reproduced with equal success in relapsed clubfeet. The patients were divided into 2 groups; Group I was untreated children with congenital clubfeet younger than 1 year of age (21 feet) and Group II was children with relapsed congenital clubfeet younger than 2 years of age (21 feet). The Ponseti method was applied with equal success in both groups. Groups I (virgin) and II (recurrent) were similar in terms of number of casts, period of immobilization, and successful initial correction. We did not find statistically significant differences (p value = .75) when comparing the number of casts required for correcting deformity in virgin (mean 6.3) and relapsed group (mean 5.5). The Pirani score improved significantly after treatment from 4.3 to a post-treatment value of 0.4 (p < .001) in recurrent clubfeet and from 5.4 to 0.31 (p < .001) in virgin clubfeet. The results of our study suggest that excellent initial correction of deformity can be achieved without the need for an extensive soft tissue release in more than 95% of children with recurrent clubfeet. PMID- 30243788 TI - Combined Medial Column Arthrodesis with Open Reduction Internal Fixation of Central Column for Treatment of Lisfranc Fracture-Dislocation: A Review of Consecutive Cases. AB - Lisfranc fracture-dislocations can be devastating injuries with significant long term sequelae with or without surgical intervention. The main goal of treatment is to minimize the common long-term complications including pain, progressive arch collapse, degenerative joint disease, hardware failure, and reoperation. Partial primary fusion involving the first, second, and third tarsometatarsal joints has become a common approach for primarily dislocation injuries, with open reduction and internal fixation (ORIF) favored for Lisfranc injuries involving fracture. ORIF commonly requires revision surgery for hardware removal or delayed fusion. Major revision creates hardship for the patient due to the prolonged recovery required, and even "simple" hardware removal can be traumatic to local nerve, artery, and tendon structures. A common injury pattern includes the findings of primary dislocation and instability of the first tarsometatarsal joint with oftentimes comminuted fracture to the second and third tarsometatarsal joints, which does not fit the standard surgical approach. We report a review of our preferred surgical approach consisting of medial column primary arthrodesis combined with central column ORIF and lateral column temporary pinning. We undertook an institutional review board-approved review of 35 consecutive Lisfranc injuries treated with this hybrid approach. Mean follow-up time was 22.14 +/- 22.39 (range 2.5 to 84) months. All but 2 (5.71%) patients had radiographic evidence of union at 10 weeks. Complications included 3 with neuritis, 1 with medial column nonunion that was treated with a bone stimulator, and 1 with revision of second metatarsal nonunion. The present retrospective series highlights our experience with isolated primary fusion of the medial column in both subtle and obvious Lisfranc injuries. PMID- 30243789 TI - Postoperative Reoperations and Complications in 32,307 Ankle Fractures With and Without Concurrent Ankle Arthroscopic Procedures in a 5-Year Period Based on a Large U.S. Healthcare Database. AB - Residual symptoms often persist even after successful operative reduction and internal fixation (ORIF) of ankle fractures. Concurrent ankle arthroscopic procedures (CAAPs) have been proposed to improve clinical outcomes; however, a dearth of evidence is available supporting this practice. The purpose of the present study was to investigate the reoperation and complication rates after ORIF of ankle fractures with and without CAAPs. Reoperations and complications after ORIF of ankle fractures were identified using the PearlDiver database from January 2007 to December 2011. The CAAPs included bone marrow stimulation, debridement, synovectomy, and unspecified cartilage procedures. Reoperation procedures consisted of ankle fracture repeat fixation, arthroscopic procedures, osteochondral autograft transfers, and ankle arthrodesis. Of the 32,307 patients who underwent ankle fracture fixation, 248 received CAAP and 32,059 did not. No significant difference was found in the reoperation rate between the 2 groups (7.7% versus 8.6%; odds ratio 0.89; 95% confidence interval 0.55 to 1.42; p = .61). Of the 248 patients in the CAAP group, 19 (7.7%) underwent reoperation, of which 13 (68.4%) were arthroscopic debridement and 6 were either ankle refixation or osteochondral autograft transfer. For the non-CAAP group, 3021 reoperation procedures were performed, consisting of ankle refixation in 83.2%, arthroscopic procedures in 14.3%, and ankle arthrodesis in 2.5%. The complication rate in the non-CAAP group included wound dehiscence in 2.4%, wound surgery in 0.4%, deep vein thrombosis in 0.8%, and pulmonary embolism in 0.4%. No complications were detected in the CAAP group. Ankle fracture fixation with CAAPs did not increase the postoperative reoperation rate compared with ankle fracture fixation without CAAPs. PMID- 30243790 TI - Mild-to-Moderate Hallux Valgus Does Not Decrease Ankle Muscle Strength in Middle Aged Japanese Women: A Comparative Study. AB - Extreme hallux valgus has been documented to be related to lower functional ability and health-related quality of life. It also has a negative effect on foot structure and biomechanical characteristics, which in turn may affect muscle strength in the foot and ankle. Thus, the purposes of this study were to determine whether there is a difference of ankle muscle strength in varied hallux valgus deformities and to investigate correlations between hallux valgus angles and ankle muscle strength. Hallux valgus angles and ankle muscle strength data were collected from 31 middle-aged Japanese women. The hallux valgus angle was measured with a 3-dimensional foot scanner; ankle muscle strength was measured with a dynamometer. Results showed no differences in ankle muscle strength between normal and mild-to-moderate hallux valgus at both 60o/second and 120o/second (p > .05). Unexpectedly, women with mild-to-moderate hallux valgus had a greater value for inversion peak torque per body weight and eversion-to inversion ratio than those with normal hallux valgus (p = .019 and p = .022) at 120o/second. Furthermore, hallux valgus was correlated with inversion peak torque and peak torque per body weight (r = 0.47; p = .012 and r = 0.50; p = .007) and associated with eversion-to-inversion strength ratio (r = -0.47; p = .012). The findings indicated that mild-to-moderate hallux valgus did not result in a decrease in ankle muscle strength. Conversely, mild-to-moderate hallux valgus had greater ankle inversion strength in middle-aged Japanese women. Further studies are needed to investigate ankle muscle strength in severe hallux valgus deformities. PMID- 30243791 TI - Successful non-operative management of intraabdominal hypertension and abdominal compartment syndrome after complex ventral hernia repair: a case series. AB - BACKGROUND: Intraabdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are devastating complications of surgery. Patients who undergo complex ventral hernia repair (CVHR) may be at risk for IAH and ACS. METHODS: We performed a retrospective review of 175 patients who underwent CVHR by a single surgeon. Body mass index (BMI), prior hernia repair, operative time, bladder pressure, serum creatinine, sedation, paralytic therapy, and ventilator support were reviewed. RESULTS: IAH was identified in 33 patients; 11 patients developed ACS. Paralytic therapy was employed in 29 patients for an average of 1.4 days. Elevated BMI was independently associated with an increased risk of IAH (p = 0.006) and ACS (p = 0.02). CONCLUSION: Patients who undergo CVHR are at risk of developing IAH and ACS in the postoperative period. Elevated BMI and longer operative time are independent risk factors for the development of IAH. IAH and ACS can be successfully managed with surgical critical care. PMID- 30243792 TI - Pyrrolo[2,1-c][1,4] benzodiazepine-3,11-diones protect SHSY-5Y cells from Cd induced apoptosis involving suppression of endoplasmic reticulum stress. AB - Cadmium (Cd) is a potent toxic heavy metal, some studies showed that Cd-induced apoptosis is through ER stress pathway. Compounds of pyrrolo[2,1 c][1,4]benzodiazepine (PBD)-3,11-diones were discovered as potent neuroprotective agents against Cd-induced toxicity in SH-SY5Y cells for the first time. In this study, twenty-six PBD-3,11-dione derivatives were synthesized and evaluated for their neuroprotective activity against Cd-induced toxicity by CCK-8 assay. Their preliminary SARs studies indicated that various substituents were tolerated on the benzene ring, and alkyl heterocycles groups at the N10-position of the PBD 3,11-dione scaffold were important for the activities. Among them, compound 13c exhibited the best activity (cell viability = 68.6%, 25 MUM). Furthermore, we found that the compound 13c could inhibit cadmium-induced cell apoptosis with the downregulation of the ER stress markers GRP78, CHOP, cleaved-caspase12 and cleaved-caspase3 through western blotting. The results of in silico evaluation of ADME/T properties showed that 13c exhibited medium BBB penetration level and promising toxicity profiles. These results proved the potential of 13c as a promising lead compound against Cd-induced neurotoxicity. PMID- 30243793 TI - There is no evidence that organochlorine pesticides, such as DDT, cause chronic kidney disease of unknown etiology. PMID- 30243794 TI - Conopeptides promote itch through human itch receptor hMgprX1. AB - Members of Mas related G-protein coupled receptors (Mrgpr) are known to mediate itch. To date, several compounds have been shown to activate these receptors, including chloroquine, a common antimalarial drug, and peptides of the RF-amide family. However, specific ligands for these receptors are still lacking and there is a need for novel compounds that can be used to modulate the receptors in order to understand the cellular and molecular mechanism in which they mediate itch. Some cone snail venoms were previously shown to induce itch in mice. Here, we show that the venom of Conus textile induces itch through activation of itch sensing sensory neurons, marked by their sensitivity to chloroquine. Two RF-amide peptides, CNF-Tx1 and CNF-Tx2, were identified in a C. textile venom gland transcriptome. These belong to the conorfamide family of peptides which includes previously described peptides from the venoms of Conus victoriae (CNF-Vc1) and Conus spurius (CNF-Sr1 and CNF-Sr2). We show that CNF-Vc1 and CNF-Sr1 activate MrgprC11 whereas CNF-Vc1 and CNF-Tx2 activate the human MrgprX1 (hMrgprX1). The peptides CNF-Tx1 and CNF-Sr2 do not activate MrgprC11 or hMrgprX1. Intradermal injection of CNF-Vc1 and CNF-Tx2 into the cheek of a transgenic mouse expressing hMrgprX1 instead of endogenous mouse Mrgprs resulted in itch-related scratching thus demonstrating the in vivo activity of these peptides. Using truncated analogues of CNF-Vc1, we identified amino acids at positions 7-14 as important for activity against hMrgprX1. The conopeptides reported here are tools that can be used to advance our understanding of the cellular and molecular mechanism of itch mediated by Mrgprs. PMID- 30243796 TI - Spinal cord astrocytomas: progresses in experimental and clinical investigations for developing recovery neurobiology-based novel therapies. AB - Spinal cord astrocytomas (SCAs) have discernibly unique signatures in regards to epidemiology, clinical oncological features, genetic markers, pathophysiology, and research and therapeutic challenges. Overall, there are presently very limited clinical management options for high grade SCAs despite progresses made in validating key molecular markers and standardizing tumor classification. The endeavors were aimed to improve diagnosis, therapy design and prognosis assessment, as well as to define more effective oncolytic targets. Efficacious treatment for high grade SCAs still remains an unmet medical demand. This review is therefore focused on research state updates that have been made upon analyzing clinical characteristics, diagnostic classification, genetic and molecular features, tumor initiation cell biology, and current management options for SCAs. Particular emphasis was given to basic and translational research endeavors targeting SCAs, including establishment of experimental models, exploration of unique profiles of SCA stem cell-like tumor survival cells, characterization of special requirements for effective therapeutic delivery into the spinal cord, and development of donor stem cell-based gene-directed enzyme prodrug therapy. We concluded that precise understanding of molecular oncology, tumor survival mechanisms (e.g., drug resistance, metastasis, and cancer stem cells/tumor survival cells), and principles of Recovery Neurobiology can help to create clinically meaningful experimental models of SCAs. Establishment of such systems will expedite the discovery of efficacious therapies that not only kill tumor cells but simultaneously preserve and improve residual neural function. PMID- 30243795 TI - Screening of cyanobacterial cultures originating from different environments for cyanotoxicity and cyanotoxins. AB - Eighty cultures from the Novi Sad Cyanobacterial Culture Collection (NSCCC) were screened for toxicity with Artemia salina bioassay and for common cyanobacterial toxins, microcystins/nodularin (MCs/NOD) and saxitoxin (STX), with ELISA assays. The results show that 22.5% (11) of the investigated cyanobacterial cultures in exponential phase exhibited toxicity in the A. salina bioassay and 38.7% (31) produced MCs/NOD and/or STX. However, the findings in the two methods applied were contradictory. Therefore, A. salina bioassay was repeated on 28 cultures in stationary growth phase, which were positive in ELISA assays but not in the initial A. salina bioassay. Seven more cultures exhibited cell-bound toxicity, and only one extracellular toxicity. The observed difference in the toxicity indicates that cyanobacterial growth phase could affect the screening results. The findings also varied depending on the environment from which the cultures originated. In the initial screening via bioassay, 11.8% (6 cultures out of 51) from terrestrial and 17.2% (5 out of 29) from aquatic environment showed cell bound toxicity. Furthermore, based on the ELISA assay, 31.4% (16) of the cultures from terrestrial ecosystems were positive for the presence of the investigated cyanotoxins, and 51.7% (15) from aquatic ecosystems. Based on all results, more frequent toxin production was observed in cultures originating from aquatic environments. Furthermore, the group of terrestrial cultures that originated from biological loess crusts were basically non-toxic. The discrepancies in the results by two different methods indicates that the use of several complementary methods would help to improve the assessment of cyanobacterial toxicity and cyanotoxin analyses. PMID- 30243797 TI - Characterization of T cell immunophenotypes in intestinal transplantation: A pilot study. AB - Immunophenotyping of peripheral blood mononuclear cells has been shown to be a useful, non-invasive method of predicting acute cellular rejection (ACR) following intestinal transplantation (ITx). Our objectives were to characterize differences in the T cell immunophenotype of ITx recipients in peripheral blood samples (1) collected late versus early after ITx and (1) associated with episodes of ACR and infectious enteritis. An IRB-approved, cross-sectional study of ITx recipients was performed. Peripheral blood samples were collected during normal visits and episodes of allograft dysfunction. A total of 38 patients were included in the analysis: 31 ITx recipients (87% liver-inclusive allografts) and 7 intestinal failure control patients. Of the ITx patients, 26 patients were pediatric patients (<21 years). A total of 70 samples were analyzed from ITx recipients, including 51 during normal visits and 19 during episodes of allograft dysfunction (median of 2 samples per patient; range of 1-6 samples per patient). In the late (n = 32) versus early post-ITx (n = 19) normal samples, there was a significantly higher percentage of central memory CD4 T cells (p = .001). In the ACR (n = 5) versus infectious enteritis (n = 14) samples, there was a higher percentage of CD8 T cells expressing HLA-DR (p = .002), CD57 (p < .001), and KLRG1 (p < .001) and a higher percentage of CD4 T cells expressing CD57 (p = .03). Additional studies are needed with larger cohorts to validate these changes in the T cell immunophenotype. Further elucidating T cell immunophenotypes in ITx will lead to a better understanding of immune mechanisms of allograft dysfunction, identification of potential biomarkers in ITx, and optimized selection of immunosuppressive therapies. PMID- 30243798 TI - The Learning Curve for Robot-assisted Partial Nephrectomy: Impact of Surgical Experience on Perioperative Outcomes. AB - Robot-assisted partial nephrectomy (RAPN) outcomes might be importantly affected by increasing surgical experience (EXP). The aim of the study is to investigate the effect of EXP on warm ischemia time (WIT), presence of at least one Clavien Dindo >=2 postoperative complication (CD >= 2), and positive surgical margins (PSMs) to define the learning curve for RAPN. We evaluated 457 consecutive patients diagnosed with a cT1-T2 renal mass were evaluated. EXP was defined as the total number of RAPNs performed by each surgeon before each patient's operation. Median WIT was 14min and the rate of CD >= 2 and PSMs was 15% and 4%, respectively. At multivariable regression analyses adjusted for case mix, EXP resulted associated with shorter WIT (p<0.0001) and higher probability of CD >= 2 free postoperative course (p=0.001), but not with PSMs (p=0.7). The relationship between EXP and WIT emerged as nonlinear, with a steep slope reduction within the first 100 cases and a plateau observed after 150 cases. Conversely, the relationship between EXP and CD >= 2-free course resulted linear, without reaching a plateau, even after 300 cases. Patient summary: Perioperative outcomes after robot-assisted partial nephrectomy (RAPN) are importantly and individually affected by surgeon's experience. After 150 RAPNs, no further improvement is observed with respect to ischemia time, but the learning curve appears endless with respect to complications. PMID- 30243799 TI - Epidemiology of Renal Cell Carcinoma. AB - CONTEXT: Despite the improvement in renal cell carcinoma (RCC) diagnosis and management observed during the last 2 decades, RCC remains one of the most lethal urological malignancies. With the expansion of routine imaging for many disorders, an increasing number of patients who harbour RCC are identified incidentally. OBJECTIVE: To summarise and compare RCC incidence and mortality rates, analyse the magnitude of risk factors, and interpret these epidemiological observations in the context of screening and disease management. EVIDENCE ACQUISITION: The primary objective of the current review was to retrieve and describe worldwide RCC incidence/mortality rates. Secondly, a narrative literature review about the magnitude of the known risk factors was performed. Finally, data retrieved from the first two steps were elaborated to define the clinical implications for RCC screening. EVIDENCE SYNTHESIS: RCC incidence and mortality significantly differ among individual countries and world regions. Potential RCC risk factors include behavioural and environmental factors, comorbidities, and analgesics. Smoking, obesity, hypertension, and chronic kidney disease represent established risk factors. Other factors have been associated with an increased RCC risk, although selection biases may be present and controversial results have been reported. CONCLUSIONS: Incidence of RCC varies worldwide. Within the several RCC risk factors identified, smoking, obesity, and hypertension are most strongly associated with RCC. In individuals at a higher risk of RCC, the cost effectiveness of a screening programme needs to be assessed on a country-specific level due to geographic heterogeneity in incidence and mortality rates, costs, and management implications. Owing to the low rates of RCC, implementation of accurate biomarkers appears to be mandatory. PATIENT SUMMARY: The probability of harbouring kidney cancer is higher in developed countries and among smokers, obese individuals, and individuals with hypertension. PMID- 30243800 TI - An Open-label Randomized Phase 2 study of Durvalumab Alone or in Combination with Tremelimumab in Patients with Advanced Germ Cell Tumors (APACHE): Results from the First Planned Interim Analysis. PMID- 30243801 TI - RNAi targeting of rootworm Troponin I transcripts confers root protection in maize. AB - Western corn rootworm, Diabrotica virgifera virgifera, is the major agronomically important pest of maize in the US Corn Belt. To augment the repertoire of the available dsRNA-based traits that control rootworm, we explored a potentially haplolethal gene target, wings up A (wupA), which encodes Troponin I. Troponin I, a component of the Troponin-Tropomyosin complex, is an inhibitory protein involved in muscle contraction. In situ hybridization showed that feeding on wupA targeted dsRNAs caused systemic transcript knockdown in D. v. virgifera larvae. The knockdown of wupA transcript, and by extension Troponin I protein, led to deterioration of the striated banding pattern in larval body muscle and decreased muscle integrity. Additionally, the loss of function of the circular muscles surrounding the alimentary system led to significant accumulation of food material in the hind gut, which is consistent with a loss of peristaltic motion of the alimentary canal. In this study, we demonstrate that wupA dsRNA is lethal in D. v. virgifera larvae when fed via artificial diet, with growth inhibition of up to 50% within two days of application. Further, wupA hairpins can be stably expressed and detected in maize. Maize expressing wupA hairpins exhibit robust root protection in greenhouse bioassays, with several maize transgene integration events showing root protection equivalent to commercial insecticidal protein expressing maize. PMID- 30243802 TI - Mountain pine beetle (Dendroctonus ponderosae) CYP4Gs convert long and short chain alcohols and aldehydes to hydrocarbons. AB - Hydrocarbon biosynthesis in insects involves the elongation of fatty acyl-CoAs to very-long chain fatty acyl-CoAs that are then reduced and converted to hydrocarbon, with the last step involving the oxidative decarbonylation of an aldehyde to hydrocarbon and carbon dioxide. Cytochromes P450 in the 4G family decarbonylate aldehydes to hydrocarbon. All insect acyl-CoA reductases studied to date reduce fatty acyl-CoAs to alcohols. The results of the work reported herein demonstrate that CYP4G55 and CYP4G56 from the mountain pine beetle, Dendroctonus ponderosae, expressed as fusion proteins with house fly cytochrome P450 reductase (CPR), convert both long chain aldehydes and long chain alcohols to hydrocarbons. CYP4G55 and CYP4G56 appear to prefer primary alcohols to aldehydes as substrates. These data strongly suggest that hydrocarbon biosynthesis in insects occurs by the two-step reduction of very long chain fatty acyl-CoAs to alcohols, which are then oxidized to aldehydes and then oxidatively decarbonylated to hydrocarbon by CYP4G enzymes. In addition, both CYP4G55 and CYP4G56 fusion proteins convert C10 alcohols and aldehydes to hydrocarbons, including the conversion of (Z)-7 decenal, a putative intermediate in the exo-brevicomin pheromone biosynthetic pathway, to (Z)-3-nonene. These data demonstrate that the highly conserved CYP4G enzymes accept a broad range of carbon chain lengths, including C10 and C18, and have evolved to function in cuticular hydrocarbon biosynthesis and pheromone production. PMID- 30243804 TI - A renaissance in diabetic foot care: new evidence-based treatments. PMID- 30243803 TI - LeucoPatch system for the management of hard-to-heal diabetic foot ulcers in the UK, Denmark, and Sweden: an observer-masked, randomised controlled trial. AB - BACKGROUND: The LeucoPatch device uses bedside centrifugation without additional reagents to generate a disc comprising autologous leucocytes, platelets, and fibrin, which is applied to the surface of the wound. We aimed to test the effectiveness of LeucoPatch on the healing of hard-to-heal foot ulcers in people with diabetes. METHODS: This was a multicentre, international, observer-masked, randomised controlled trial of people with diabetes and a hard-to-heal foot ulcer done in 32 specialist diabetic foot clinics in three countries (UK, Denmark, and Sweden). After a 4-week run-in period, those with a reduction in ulcer area of less than 50% were randomly allocated (1:1) by computer-generated, web-based randomisation (block sizes of two, four, and six) to either prespecified good standard care alone or care plus weekly application of LeucoPatch. The primary outcome was the proportion of ulcers that healed within 20 weeks assessed in the intention-to-treat population (all participants with post-randomisation data collected), defined as complete epithelialisation (confirmed by an observer who was masked to randomisation group), and remained healed for 4 weeks. This trial is registered with the ISRCTN registry, number 27665670, and ClinicalTrials.gov, number NCT02224742. FINDINGS: Between Aug 30, 2013, and May 3, 2017, 269 participants were randomly allocated to receive treatment (137 to receive standard care and 132 to receive LeucoPatch). The mean age was 61.9 years (SD 11.6), 217 (82%) were men, and 222 (83%) had type 2 diabetes. In the LeucoPatch group, 45 (34%) of 132 ulcers healed within 20 weeks versus 29 (22%) of 134 ulcers in the standard care group (odds ratio 1.58, 96% CI 1.04-2.40; p=0.0235) by intention-to-treat analysis. Time to healing was shorter in the LeucoPatch group (p=0.0246) than in the standard care group. No difference in adverse events was seen between the groups. The most common serious adverse event (SAE) was diabetic foot infection (24 events in the LeucoPatch group [24% of all SAEs] and 20 in the standard care group [27% of all SAEs]. There were no device-related adverse events. INTERPRETATION: The use of LeucoPatch is associated with significant enhancement of healing of hard-to-heal foot ulcers in people with diabetes. FUNDING: Reapplix ApS. PMID- 30243805 TI - Should hyperthermic intraperitoneal chemotherapy be the new standard of care in ovarian cancer? PMID- 30243806 TI - Comparing once-weekly semaglutide to incretin-based therapies in patients with type 2 diabetes: a systematic review and meta-analysis. AB - AIMS: Our aim was to compare once-weekly semaglutide to incretin-based therapies defined as either dipeptidyl peptidase-4 inhibitors (DPP-4i) or other glucagon like peptide-1 receptor agonist (GLP-1RA) - in patients with type 2 diabetes. METHODS: We searched for randomized trials comparing once-weekly semaglutide to other incretin-based therapies in patients with type 2 diabetes. We pooled trials that compared semaglutide to other GLP-1RA together, and those comparing semaglutide to DPP-4i together. The primary outcome was the change in haemoglobin A1c over time. RESULTS: Five trials met our inclusion criteria. There was a significantly greater reduction in haemoglobin A1c favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = -0.38% (-0.62, -0.15) and 1.14% (-1.53, -0.75) respectively]. There was a significantly greater weight loss favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = 2.50 kg (-3.91, -1.09) and -3.19 kg (-3.66, -2.72) respectively]. The proportion of patients achieving glycaemic goals and goal weight loss was greater in semaglutide-treated patients when compared to either other GLP-1RA or DPP-4i. However, semaglutide-treated patients had a significantly higher incidence of gastrointestinal side effects. CONCLUSIONS: While both once-weekly semaglutide and other incretin-based therapies can reduce haemoglobin A1c, semaglutide causes a more potent haemoglobin A1c reduction and greater weight loss when compared to other incretin-based therapies. However, this potent effect of semaglutide was associated with a higher incidence of gastrointestinal side effects. Additional studies are needed to determine whether this marked reduction in both haemoglobin A1c and body weight may translate into improved cardiovascular outcomes. PMID- 30243807 TI - The expression and biological information analysis of miR-375-3p in head and neck squamous cell carcinoma based on 1825 samples from GEO, TCGA, and peer-reviewed publications. AB - BACKGROUND: The specific expression level and clinical significance of miR-375-3p in HNSCC had not been fully stated, as well as the overall biological function and molecular mechanisms. Therefore, we purpose to carry out a comprehensive meta analysis to further explore the clinical significance and potential function mechanism of miR-375-3p in HNSCC. METHODS: HNSCC-related data was gained from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and peer-reviewed journals. A meta-analysis was carried out to comprehensively explore the relationship between miR-375-3p expression level and clinicopathological features of HNSCC. And summary receiver operating characteristic (SROC) curve analysis was applied for evaluating disease diagnosis value of miR-375-3p. In addition, a biological pathway analysis was also performed to assess the possible molecular mechanism of miR-375-3p in HNSCC. RESULTS: A total of 24 available records and references were added into analysis. The overall pooled meta-analysis outcome revealed a relatively lower expression level of miR-375-3p in HNSCC specimens than that in non-cancerous controls (P < 0.001). And SROC curve analysis showed that the pooled area under the SROC curve (AUC) was 0.90 (95%CI: 0.88-0.93). In addition, biological pathway analysis indicated that LAMC1, EDIL3, FN1, VEGFA, IGF2BP2, and IGF2BP3 maybe the latent target genes of miR-375-3p, which were greatly enriched in the pathways of beta3 integrin cell surface interactions and the binding of RNA via the insulin-like growth factor-2 mRNA-binding protein (IGF2BPs/IMPs/VICKZs). CONCLUSION: MiR-375-3p expression clearly decreased in HNSCC samples compared with non-cancerous controls. Meanwhile, miR-375-3p may serve as a tumor suppressor via regulating tumor-related genes LAMC1, EDIL3, FN1, VEGFA, IGF2BP2, and IGF2BP3 in HNSCC. PMID- 30243808 TI - MiR-124-3p suppresses glioma aggressiveness via targeting of Fra-2. AB - Malignant glioma is the most common and deadly primary brain tumor in adults. However, the mechanisms underlying the malignancy of glioma remain unclear. In the present study, we found that Fos-related antigen-2 (Fra-2) was overexpressed in most glioma cells, and knockdown of Fra-2 prevented cell proliferation, migration, and invasion. Mechanistically, Fra-2 silencing led to a significant reduction in cell-cycle drivers (Cyclin D1 and Cyclin E1), one invasion associated gene (MMP9), the mesenchymal marker (Vimentin), and induction of the epithelial marker (E-cadherin). Further study confirmed that miR-124-3p decreased the expression of Fra-2 via directly targeting the 3'-UTR, and transfection with miR-124-3p in glioma cells inhibited expression of the above cell-cycle and EMT promoters. Phenotypic experiments also showed that overexpression of Fra-2 weakened the inhibitory effects of miR-124-3p on the proliferation, migration, and invasion of glioma cells. In addition, Fra-2 knockdown impaired the malignant phenotypes enhanced by miR-124-3p inhibition, which suggested a crucial role for the miR-124-3p/Fra-2 pathway in glioma development. Consistently, high expression of Fra-2 was closely associated with low miR-124-3p level and indicated a poor prognosis in patients with glioma. In conclusion, this study indicates the existence of an aberrant miR-124-3p/Fra-2 pathway that results in glioma aggressiveness, which suggests novel therapeutic opportunities for this fatal disease. PMID- 30243809 TI - Multimodal general anesthesia approach for Ex Utero Intrapartum Therapy (EXIT) procedures: two case reports. AB - High-dose volatile anesthesia is the most common method of achieving uterine relaxation for Ex Utero Intrapartum Therapy (EXIT) procedures. Other methods employ nitroglycerin for additional uterine relaxation with or without remifentanil for additional fetal analgesia. We report a combination approach including one minimum alveolar concentration of volatile anesthetic plus nitroglycerin and remifentanil infusions, to provide timely uterine relaxation under general anesthesia for both mother and fetus, during two EXIT procedures. PMID- 30243810 TI - Optimal treatment for women with a persisting pregnancy of unknown location, a randomized controlled trial: The ACT-or-NOT trial. AB - OBJECTIVE: Pregnancy of unknown location (PUL) is not a diagnosis but a transient state used to classify a woman when she has a positive pregnancy test without definitive evidence of an intra-uterine or extra-uterine pregnancy on transvaginal ultrasonography. Management of a persisting PUL varies substantially, including expectant or active management. Active management can include uterine cavity evacuation or systemic administration of methotrexate. To date, no consensus has been reached on whether either management strategy is superior or non-inferior to the other. DESIGN: Randomized controlled trial. SETTING: Academic medical centers. PATIENTS: We plan to randomize 276 persisting PUL-diagnosed women who are 18 years or older from Reproductive Medicine Network clinics and additional interested sites, all patients will be followed for 2 years for fertility and patient satisfaction outcomes. INTERVENTIONS: Randomization will be 1:1:1 ratio between expectant management, uterine evacuation and empiric use of methotrexate. After randomization to initial management plan, all patients will be followed by their clinicians until resolution of the PUL. The clinician will determine whether there is a change in management, based on clinical symptoms, and/or serial human chorionic gonadotropin (hCG) concentrations and/or additional ultrasonography. MAIN OUTCOME: The primary outcome measure in each of the 3 treatment arms is the uneventful clinical resolution of a persistent PUL without change from the initial management strategy. Secondary outcome measures include: number of ruptured ectopic pregnancies, number and type of re-interventions (additional methotrexate injections or surgical procedures), treatment complications, adverse events, number of visits, time to resolution, patient satisfaction, and future fertility. CONCLUSION: This multicenter randomized controlled trial will provide guidance for evidence-based management for women who have persisting pregnancy of unknown location. PMID- 30243811 TI - Home-based, square-stepping exercise program among older adults with multiple sclerosis: results of a feasibility randomized controlled study. AB - There is very little known about exercise rehabilitation approaches for older adults with multiple sclerosis (MS), yet this growing segment of the MS population experiences declines in cognition and mobility associated with disease progression and aging. We conducted a RCT examining the feasibility of a 12-week, home-based Square-Stepping Exercise (SSE) program in older adults with MS. Older adults with MS (N = 26) with mild-to-moderate levels of disability were recruited and randomized into the intervention (i.e., SSE) or a minimal activity, attention control conditions. Participants in the SSE condition received a mat for home based practice of the step patterns, an instruction manual, and a logbook along with a pedometer for monitoring compliance. Both conditions received weekly SkypeTM calls and had biweekly meetings with an exercise trainer. Feasibility was assessed based on process, resource, management and scientific outcomes. Regarding scientific outcomes, participants in both conditions completed in-lab assessments before and after the 12-week period. Twenty-five participants completed the study (96%) and the total cost of the study was $13,387.00 USD. Pedometer data demonstrated good compliance with the SSE intervention condition. Effect sizes calculated for all treatment outcomes ranged from small-to-moderate for both mobility and cognitive variables between the intervention and attention control conditions, thereby providing preliminary evidence that participation in the SSE program may improve cognition and mobility function. The results support the feasibility, acceptability, and possible efficacy of a home-based SSE intervention for older adults with MS. PMID- 30243813 TI - Editorial Comment. PMID- 30243812 TI - Rationale and development of a randomized pragmatic trial to improve diabetes outcomes in patient-centered medical homes serving rural patients. AB - Proper diabetes self-care requires patients to have considerable knowledge, a range of skills, and to sustain multiple health behaviors. Self-management interventions are needed that can be readily implemented and sustained in rural clinics with limited resources that disproportionately care for patients with limited literacy. Researchers on our team developed an evidence-based, patient centered, low literacy intervention promoting diabetes self-care that includes: 1) the American College of Physicians (ACP) Diabetes Guide that uses plain language and descriptive photographs to teach core diabetes concepts and empower patients to initiate behavior change; 2) a brief counseling strategy to assist patients in developing short-term, explicit and attainable goals for behavior change ('action plans'); and 3) a training module for health coaches that prepares them to assume educator/counselor roles with the Diabetes Guide as a teaching tool. While the intervention has previously been field tested and found to significantly improve patient knowledge, self-efficacy, and engagement in related health behaviors, its optimal implementation is not known. This project took advantage of a unique opportunity to modify and disseminate the ACP health literacy intervention among patients with type 2 diabetes cared for at rural clinics in Arkansas that are Patient-Centered Medical Homes (PCMH). These practices all had health coaches that could be leveraged to provide chronic disease self-management mostly via phone, but also at the point-of-care. Hence we conducted a patient-randomized, pragmatic clinical trial in 6 rural PCMHs in Arkansas, targeting individuals with uncontrolled type 2 diabetes. PMID- 30243814 TI - Editorial Comment. PMID- 30243815 TI - Reply by Authors. PMID- 30243816 TI - Re: Correlations between Sonographic and Urodynamic Findings after Mid Urethral Sling Surgery: L. Wen, K. L. Shek, N. Subramaniam, T. Friedman and H. P. Dietz J Urol 2018;199:1571-1576. PMID- 30243817 TI - All-night functional magnetic resonance imaging sleep studies. AB - BACKGROUND: Previous functional magnetic resonance imaging (fMRI) sleep studies have been hampered by the difficulty of obtaining extended amounts of sleep in the sleep-adverse environment of the scanner and often have resorted to manipulations such as sleep depriving subjects before scanning. These manipulations limit the generalizability of the results. NEW METHOD: The current study is a methodological validation of procedures aimed at obtaining all-night fMRI data in sleeping subjects with minimal exposure to experimentally induced sleep deprivation. Specifically, subjects slept in the scanner on two consecutive nights, allowing the first night to serve as an adaptation night. RESULTS/COMPARISON WITH EXISTING METHOD(S): Sleep scoring results from simultaneously acquired electroencephalography data on Night 2 indicate that subjects (n = 12) reached the full spectrum of sleep stages including slow-wave (M = 52.1 min, SD = 26.5 min) and rapid eye movement (REM, M = 45.2 min, SD = 27.9 min) sleep and exhibited a mean of 2.1 (SD = 1.1) nonREM-REM sleep cycles. CONCLUSIONS: It was found that by diligently applying fundamental principles and methodologies of sleep and neuroimaging science, performing all-night fMRI sleep studies is feasible. However, because the two nights of the study were performed consecutively, some sleep deprivation from Night 1 as a cause of the Night 2 results is likely, so consideration should be given to replicating the current study with a washout period. It is envisioned that other laboratories can adopt the core features of this protocol to obtain similar results. PMID- 30243818 TI - Questions of Stochasticity and Control in Immune Repertoires. PMID- 30243819 TI - [Beyond actinic keratoses: Field cancerization of the skin]. AB - Lesions occurring in actinic keratoses (AK) form erythematous, squamous, crusty and keratotic papules that appear on skin chronically exposed to the sun due to ultraviolet radiation. They are formed by the proliferation of atypical keratinocytes limited to the epidermis and may progress to squamous cell carcinoma in situ and to cutaneous squamous cell carcinoma (CEC). Although low, the metastatic risk associated with the CEC is not negligible. The concept of field cancerization was introduced in 1953 following studies of neoplastic lesions of the oral mucosa. A cancer field is a normal-looking pre-tumoral zone with subclinical, multifocal anomalies, which may constitute a base for new neoplastic lesions. Such fields are frequently seen in areas of photo-exposed skin and around the edges of AK and CEC. In this event, treatment should not be limited to visible or palpable AK lesions, and if a cancer field is suspected, treatment involving the physical destruction or elimination of atypical keratinocytes from the entire area should be considered. Such an approach may improve the long-term prognosis, reduce treatment costs and ensure optimal cosmetic outcome. PMID- 30243820 TI - Differential Motivations for Pursuing Interventional Radiology: Implications for Residency Recruitment. AB - PURPOSE: The purpose of this study is to compare the motivations of interventional radiology (IR) residency, IR fellowship, and diagnostic radiology (DR) applicants. MATERIALS AND METHODS: A questionnaire was distributed to IR integrated residency and IR fellowship applicants for the 2018 National Resident Matching Program (NRMP) Match. Survey respondents scored the influence of 13 aspects of IR on their career decision. These results were combined with a previously published survey of DR residency applicants from 2016 who were asked the same questions. Pairwise comparisons to survey responses were made between IR residency and IR fellowship as well as IR residency and DR residency respondents. RESULTS: There were 202 of 657 DR residency respondents (response rate 30.7%), 114 of 295 IR residency respondents (response rate 38.6%), and 70 of 169 IR fellowship respondents (response rate 41.4%). Compared with DR respondents, IR residency respondents rated the following factors more positively: influence of a mentor (P = .030), perceived job satisfaction (P < .001), job market (P < .001), salary (P < .001), intellectual stimulation (P = .030), the use of emerging or advanced technology (P < .001), and the visual nature of the field (P < .001). In contrast, DR residency respondents rated flexible work hours (P < .001), physics (P < .001), and competitiveness of the application process (P < .001) more positively than IR respondents. Compared with IR fellowship respondents, IR residency respondents rated flexible work hours (P = .002), the job market (P = .020), physics (P < .001), and salary (P < .001) more positively, and competitiveness (P = .002) was felt to be more negative for residency applicants. CONCLUSION: The motivations for pursuing IR residency differ from both DR residency and IR fellowship. Understanding these motivations can help to recruit top quality IR residency applicants. PMID- 30243821 TI - AMPK breathing and oxygen supply. AB - Regulation of breathing is critical to our capacity to accommodate deficits in oxygen availability and demand during, for example, sleep and ascent to altitude. Key to this are two reflex responses, hypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching at the lungs, and the hypoxic ventilatory response (HVR) which accelerates ventilation. In 2004 I proposed that HPV might be mediated by the AMP-activated protein kinase, which governs cell autonomous metabolic homeostasis. Pharmacological evidence was presented in support of this view, and the hypothesis extended to incorporate a role for AMPK in regulating carotid body afferent input responses during hypoxia and thus the HVR. The present article reviews our subsequent findings on these matters and those of others, which provide strong support for the view that AMPK mediates HPV. AMPK is also critical to the HVR, but against our expectations it is not required for carotid body activation during hypoxia. Contrary to current consensus in this respect, our findings suggest that AMPK deficiency blocks the HVR at the level of the brainstem, even when afferent input responses from the carotid body are normal. We have therefore revised our hypothesis on the HVR, now proposing that AMPK integrates local hypoxic stress at defined loci within the brainstem respiratory network with an index of peripheral hypoxic status, namely afferent chemosensory inputs. Nevertheless, in general outcomes are consistent with the original hypothesis, that the role of AMPK has evolved, through natural selection, to extend to the regulation of breathing, and thus oxygen and energy (ATP) supply to the whole body. PMID- 30243822 TI - Mycophenolate mofetil contributes to downregulation of the hippocampal interleukin type 2 and 1beta mediated PI3K/AKT/mTOR pathway hyperactivation and attenuates neurobehavioral comorbidities in a rat model of temporal lobe epilepsy. AB - The role of neuroinflammatory mediators has been well established in the pathogenesis of temporal lobe epilepsy (TLE) and associated neurobehavioral comorbidities. Mycophenolate mofetil (MMF) is commonly used as an immunosuppressant in organ transplantations. Its neuroprotective effect is well explored in different preclinical and clinical studies. The present study was designed to investigate the effect of MMF in rat model of lithium pilocarpine (LiPc)-induced spontaneous recurrent seizures and its associated neurobehavioral comorbidities. MMF treatment showed a dose-dependent decrease in seizure severity and reduced aggression in epileptic rats. There was marked improvement in spatial and recognition memory functions, along with substantial decrease in depression like behavior in MMF treated epileptic rats. There was considerable decrease in mossy fiber sprouting in the dentate gyrus and the cornu ammonis 3 regions of the hippocampus, along with reduction in neuronal death in the treated groups. Furthermore, the hippocampal mRNA level of IL-1beta, IL-2, PI3K, AKT, HIF-1alpha, RAPTOR, mTOR, Rps6kb1 and Rps6 was found to be decreased in MMF treated animals. mTOR, S6, pS6 and GFAP protein expression was decreased, whereas NeuN was increased in the rat hippocampus of the treated animals. The results concluded that MMF suppress recurrent seizures, and improves its associated behavioral impairments and cognitive deficit in rat model of TLE. The observed effects of MMF be correlated with the inhibition of IL-2 and IL-1beta linked PI3K/AKT/mTOR signaling pathway hyperactivation. PMID- 30243823 TI - Cell-permeable NF-kappaB inhibitor-conjugated liposomes for treatment of glioma. AB - Application of liposomes-based drug delivery in treatment of glioma has been hampered by the poor permeability of blood-brain barrier and the low uptake efficiency by glioma tissues. Moreover, many chemotherapy drugs promote the activation of the NF-kappaB, which plays a role in the development and progression of cancer and chemoresistance. In this report, CB5005 peptide, designed for its dual function in cell membrane penetration and NF-kappaB inhibition, was conjugated to PEGylated liposomes loaded with doxorubicin (CB5005 LS/DOX) or a fluorescent dye (CB5005-LS/dye). These CB5005-modified liposomes were utilized for targeting and penetrating glioma. Both qualitative and quantitative evaluations of CB5005-LS/dye showed that modification by CB5005 significantly increased cellular uptake of the liposomes by glioma cells, and substantially improved permeability of the liposomes into tumor spheroids. Intracellular localization studies demonstrated that CB5005-modified liposomes could not only penetrate into glioma cells but also deliver DOX into the nucleus. Cytotoxicity assay indicated that compared with the unmodified DOX liposomes (LS/DOX), CB5005-LS/DOX increased the efficiency of killing glioma cells by more than fivefold. In vivo imaging illustrated that CB5005-modified liposomes, via intravenous injection, distributed fluorescence into the brain and accumulated at tumor xenograft and intracranial glioblastoma in different animal models. More importantly, CB5005-LS/DOX treatment significantly prolonged the survival time of nude mice bearing intracranial glioblastoma. In summary, CB5005-modified liposomes represent a promising drug delivery system for cancer treatment attributing to its unique ability not only to transfer drugs to the tumor sites but also to function as a synergist for chemotherapy of glioma and other human tumors. PMID- 30243824 TI - A filter-free blood-brain barrier model to quantitatively study transendothelial delivery of nanoparticles by fluorescence spectroscopy. AB - The delivery of therapeutics to the brain is greatly hampered by the blood-brain barrier (BBB). The use of nanoparticles that can cross the BBB via the process of receptor-mediated transcytosis at blood-brain barrier endothelial cells seems a promising strategy to transport therapeutics into the brain. To screen for suitable nanocarriers, and to study the process of transcytosis, a cultured polarized monolayer of brain microvascular endothelial cells on an extracellular matrix-coated porous membrane filter is widely used as an in vitro BBB model. However, due to the adhesion of numerous types of nanoparticles to the membrane filter and within the filter pores, such a model is unsuitable for the quantification of transendothelial delivery of nanoparticles. Hence, there is a pressing need for a filter-free in vitro BBB model. Ideally, the model is inexpensive and easy to use, in order to allow for its wide use in nanomedicine and biology laboratories around the world. Here, we developed a filter-free in vitro BBB model that consists of a collagen gel covered with a monolayer of brain microvascular endothelial (hCMEC/D3) cells. The paracellular leakage of differently sized dextrans and the transcellular transport of LDL were measured to demonstrate the validity of the filter-free model. Finally, the transendothelial delivery of fluorescently-labelled PEG-P(CL-g-TMC) polymersomes that were functionalized with GM1-targeting peptides was assessed by fluorescence spectroscopy measurement of the luminal, cellular, and abluminal parts of the filter-free BBB model. Our data confirm the effectiveness of the G23 peptide to mediate transport of polymersomes across the BBB and the suitability of this filter-free in vitro model for quantification of nanoparticle transcytosis. PMID- 30243825 TI - Astragali radix and its main bioactive compounds activate the Nrf2-mediated signaling pathway to induce P-glycoprotein and breast cancer resistance protein. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Astragali radix (Huang Qi, HQ), a well-known Chinese herbal medicine, is widely coadministered with many other drugs for treating diseases. The potential herb-drug interactions (HDIs) possibly occur during the combination therapy. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are the crucial targets that mediate the production of HDIs. We previously observed that HQ and its three main bioactive compounds, including Astragaloside IV (AS-IV), calycosin (CS) and formononetin (FMNT), could significantly induce the expression of P-gp and BCRP in HepG2 cells in vitro. However, their modulations on the function of P-gp and BCRP remain unknown; their impact on these two proteins expression in vivo is not clear; the exact regulatory mechanism has also not yet been explored. AIM OF THE STUDY: This study aimed to investigate the impact of HQ, AS-IV, CS and FMNT on P-gp and BCRP in vivo, and the exact regulatory mechanism involved. The effects of HQ and these compounds on the function of P-gp and BCRP were also studied. MATERIALS AND METHODS: Wild-type C57BL/6 mice and nuclear factor E2-related factor-2 knockout (Nrf2-/-) C57BL/6 mice were orally treated with HQ, AS-IV, CS or FMNT. The protein levels of P-gp and BCRP in the liver of mice were measured by using Western blot and immunohistochemistry. The mRNA levels were measured by using real-time PCR. The activation of the drugs on the antioxidant response element (ARE)-luciferin activity was studied by using reporter assay in a stably transfected HepG2-C8 cells. The efflux activity of P-gp and BCRP in HepG2 cells were tested by using flow cytometer with typical probes. RESULTS: HQ, AS-IV, CS and FMNT significantly upregulated the P-gp and BCRP expression in the liver of wild-type mice. The induction was significantly reversed in the Nrf2-/- mice. HQ and these compounds significantly increased the Nrf2 expression in wild-type mice. HQ and these compounds also markedly enhanced the ARE-luciferin activity and promoted the nuclear translocation of Nrf2 in cells. Besides, HQ and these compounds significantly enhanced the efflux activity of P-gp and BCRP, and increased the intracellular ATP levels. CONCLUSIONS: Our results proved that HQ and its main bioactive compounds could induce the P-gp and BCRP expression through the activation of the Nrf2-mediated signaling pathway. HQ and these compounds also significantly enhanced the efflux activity of P-gp and BCRP, and the increased intracellular ATP levels were likely involved in the increased P-gp and BCRP function. These results suggested that potentially HDIs likely occurred when HQ was used concomitantly with other drugs that are substrates of P-gp and BCRP. PMID- 30243826 TI - Astragali Radix and its compound formononetin ameliorate diesel particulate matter-induced skin barrier disruption by regulation of keratinocyte proliferation and apoptosis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Astragali Radix (AR), the root of Astragalus mongholicus Bunge, is widely applied in traditional medicine to promote skin health and tissue regeneration. AIM OF THE STUDY: This study investigated the effects of AR and its active compound, formononetin (FMT), on skin barrier defects in keratinocytes exposed to diesel particulate matter (PM). MATERIALS AND METHODS: HaCaT cells and three-dimensional (3D) human skin reconstructed model were pre-treated with AR (50, 100 MUg/ml) and FMT (30, 50 MUM), then treated with PM (200 MUg/ml). RESULTS: AR and FMT significantly enhanced the expression of Keratin (KRT) 16 in PM stimulated HaCaT cells. PM increased p53 and Bax expression as well as the subsequent cleavage of caspase 3 and PARP in HaCaT cells, while this was inhibited by AR and FMT treatment. In vitro studies using the PM stimulated 3D human skin reconstructed model revealed that AR and FMT increased the expression of KRT 16 and KRT 17. Histological examination of the 3D human skin reconstructed model showed that AR and FMT up-regulated the expression of Ki67, but down-regulated the expression of cleaved caspase 3. Both AR and FMT significantly inhibited phosphorylation of ERK, but not JNK and p38 MAPK in PM stimulated HaCaT cells. CONCLUSIONS: These results suggest that AR and FMT act as anti-pollution agents and alleviate PM induced skin barrier defects through regulation of apoptosis and proliferation in keratinocytes. PMID- 30243827 TI - Clinical efficacy and safety of Aidi injection plus paclitaxel-based chemotherapy for advanced non-small cell lung cancer: A meta-analysis of 31 randomized controlled trials following the PRISMA guidelines. AB - ETHNOPHARMACOLOGICAL RELEVANCE: As an important Chinese herb injection, Aidi injection is composed of the extracts from Astragalus, Eleutherococcus senticosus, Ginseng, and Cantharis. Aidi injection plus paclitaxel-based chemotherapy is often used to in the treatment of non-small cell lung cancer (NSCLC) in China. AIM OF THE STUDY: The objective of this study is to further confirm whether Aidi injection can improve the tumor responses and survivals, and reveal its safety, optimal usage and combination with paclitaxel. MATERIALS AND METHODS: A meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All randomized controlled trials (RCTs) concerning the Aidi injection plus paclitaxel-based chemotherapy for NSCLC were selected. Main outcomes were objective response rate (ORR), disease control rate (DCR), survivals, quality of life (QOL) and adverse drug reactions (ADRs). All data were extracted by using a standard data extraction form and synthesized through meta-analysis. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used for rating the quality of evidence. RESULTS: Thirty-one RCTs involving 2058 patients were included, and most trials had an unclear methodological bias risk. The risk ratio (RR) and 95% confidence intervals (CI) of ORR, DCR, QOL, neutropenia, thrombocytopenia, gastrointestinal toxicity and liver injury were as following: 1.32 (1.20-1.46), 1.14 (1.09-1.20), 1.89 (1.66-2.16), 0.61 (0.51 0.74), 0.62 (0.45-0.87), 0.59 (0.49-0.72) and 0.52 (0.36-0.75). Compared to chemotherapy alone, all differences were statistically significant. Subgroup analysis showed that only with the TP, Aidi injection could increase the ORR and DCR. Treatment with 100 ml, 80 ml or 50 ml/time, and 14 days/2 cycles or 21 days/2-4 cycles, Aidi injection could increase the ORR and DCR, respectively. Sensitivity analysis showed that the results had good robustness. None of the trials reported the overall survivals (OS), progression free survival (PFS). The quality of evidences was moderate. CONCLUSIONS: Current moderate evidence revealed that Aidi injection plus paclitaxel-based chemotherapy, especially TP can significantly improve the clinical efficacy and QOL for patients with stage III/IV NSCLC. Aidi injection can relieve the risk of hematotoxicity, gastrointestinal toxicity and liver injury in patient with NSCLC receiving paclitaxel-based chemotherapy. The optimal usage may be 50 ml/time and 14 days/2 cycles. PMID- 30243828 TI - Treatment of skeletal open bite using a navigation system: CAD/CAM osteotomy and drilling guides combined with pre-bent titanium plates. AB - Severe skeletal open bite associated with posterior vertical maxillary excess and mandibular deformity is considered a difficult problem in orthodontic and surgical treatment. This study used a navigation system for the correction of severe skeletal open bite in order to accurately transfer the virtual plan to the actual operation and achieve precise rigid internal fixation in bimaxillary osteotomies of the jaws. Twelve patients with a severe skeletal open bite associated with vertical maxillary excess and mandibular deformity were recruited. All patients underwent Le Fort I osteotomy and bilateral sagittal split ramus osteotomy with the guidance of this navigation system. Computed tomography and cephalometric examinations were performed to evaluate the correction of the deformity. Deviations between the simulated plan and actual postoperative outcome were measured to determine the precision of the surgery. Satisfactory and stable results were achieved in all patients postoperatively, without complications or relapse during follow-up. Photographs and cephalometric evaluations showed that the facial profile and occlusion were improved. Assessment of the deviations between the simulated plan and actual postoperative outcome showed that the navigation system can precisely transfer the virtual plan to the actual operation. The results suggest that the navigation system can accurately transfer the virtual plan to the actual operation during bimaxillary jaw osteotomies, without relapse, in patients with a severe skeletal open bite. PMID- 30243829 TI - Management of nasopharyngeal teratomas associated with cleft palate. AB - Nasopharyngeal teratomas are rare tumours, responsible for a high birth mortality rate from acute respiratory distress. Palatine localization can lead to an embryopathogenic mechanical obstacle responsible for a cleft palate. The aim of this study was to update current knowledge concerning the management of this rare pathological association. We conducted a multicentre, retrospective study by case analysis. The inclusion criteria were patients of any age under care for a nasopharyngeal teratoma associated with a velopalatine cleft. The diagnosis of the teratoma was confirmed by histological analysis. Seven cases were included in the study: three cases from the University Hospital of Lille, one from the University Hospital of Caen, one from of the University Hospital of Toulouse, and two from of the University Hospital of Amiens. Approximately 30% of patients experienced acute respiratory distress at birth, necessitating oro- or nasotracheal intubation. The surgical excision was performed in the first 5 months of life for all patients and in a single operative time for 70%. There was no recurrence. Therapeutic management of nasopharyngeal teratomas associated with cleft palate at birth is multidisciplinary and is based on surgical excision. In the absence of other associated pathologies, the prognosis is favourable. PMID- 30243830 TI - Impact of postoperative radiotherapy on survival and loco-regional control in node-negative oral cavity tumours classified as T3 using the AJCC Cancer Staging Manual eighth edition. AB - According to the eighth edition of the AJCC Cancer Staging Manual (AJCC8), a depth of invasion (DOI) >10mm is classified as pT3, representing a locally advanced tumour requiring postoperative radiotherapy (PORT). When node-negative, however, evidence regarding whether PORT improves loco-regional control or survival is unclear. To clarify this, two cohorts of patients were studied: (1) patients classified as pT3N0 by the seventh edition of the AJCC manual (AJCC7), with DOI >10mm and a tumour diameter >4cm (17 patients who received PORT), and (2) patients classified as pT1N0 and pT2N0 by AJCC7, with DOI >10mm and a tumour diameter <4cm (55 patients who did not receive PORT). Loco-regional control and survival were analysed. PORT was found not to impact overall survival or disease free survival. It was also found not to impact local, regional, or distant recurrence. Although the two subsets of patients considered here (DOI >10mm with tumour diameter below or above 4cm) were previously distinct, they are both considered pT3 in AJCC8. Data from this study indicate that the routine administration of PORT to patients with a DOI >10mm may not be warranted in the absence of other risk features such as nodal disease or close margins. PMID- 30243831 TI - Microglia polarization by mitochondrial metabolism modulation: A therapeutic opportunity in neurodegenerative diseases. PMID- 30243832 TI - HASAN: Highly accurate sensitivity for auto-contrast-corrected pMRI reconstruction. AB - A novel method for highly accurate coil sensitivity-map estimation, based on a constrained image-domain multi-channel LMS (c-iMCLMS) algorithm, is proposed for image reconstruction using self-calibrating SENSE. The sensitivity information is extracted by developing an image-domain cross-relation equation using the low resolution images constructed from the fully sampled central region of the variable density MR data. Then this formulation is solved in an iterative way using a novel sum-of-squares (SOS) constraint. The improvement of the convergence speed of the c-iMCLMS algorithm is accomplished by SOS normalization of the low resolution image data and using a variable step-size in the update equation. The salient feature of the proposed technique is that it does not require any prior selection of the basis function and/or simultaneous estimation of the object image and the coil sensitivity-map. Only the low resolution images are re filtered for the compensation of the data truncation effect to improve the consistency of the estimated coil maps. Besides, the application of the novel SOS constraint, estimated using the pixel position-wise variance of the coil maps, gives closest to the true sensitivity-map. As a result, true object image with auto-corrected contrast is reconstructed without adopting any traditional post contrast correction techniques. For minimization of the process noise, regularized conjugate gradient (CG) based SENSE reconstruction algorithm is used for image reconstruction using the estimated coil sensitivity-map. The proposed technique is tested on various simulation, synthetic and in-vivo datasets and significant signal-to-artifact-noise-ratio (SANR) improvement closest to the theoretical limit set by coil geometric factor is obtained as compared to some noted techniques in the literature both visually and numerically. PMID- 30243833 TI - Overview of Biochemical Assays in Lipidic Cubic Phase. AB - The development of novel biochemical methods to efficiently characterize membrane protein (MP) properties in lipidic cubic phase (LCP) is important for studying complicated MPs and their multimeric complexes. Here, we summarize recent LCP related assays and provide an outlook on their applications in structure and function studies of MPs. PMID- 30243834 TI - Expanding the Role of Targets in Conservation Policy. AB - Conservation targets perform beneficial auxiliary functions that are rarely acknowledged, including raising awareness, building partnerships, promoting investment, and developing new knowledge. Building on these auxiliary functions could enable more rapid progress towards current targets and inform the design of future targets. PMID- 30243835 TI - Comparison of freeze-dried tibialis anterior allograft and four-strand hamstring autograft in anterior cruciate ligament reconstruction. AB - PURPOSE: The aim of this retrospective study was to evaluate the clinical outcomes of the patients who underwent primary anterior cruciate ligament (ACL) reconstruction surgery with either hamstring autograft or freeze-dried tibialis anterior allograft, which performed by the same surgeon using the same fixation technique. METHODS: In this retrospective study, patients who had primary ACL reconstruction using either four-strand hamstring autograft (FSH) or freeze-dried irradiated tibialis anterior allograft (FDT) between 2012 and 2015 were evaluated. Patients who were skeletally mature with a minimum follow-up of 24 months and who had no previous surgery from the affected knee were included; patients who had multiple ligament injuries or chondral lesions over Outerbridge grade 2 were excluded from the study. Patients were grouped according to the graft type used in ACL reconstruction. Tegner activity scale and Lysholm knee scoring scale were used to assess patients' activity levels and functional status preoperatively and at the final follow-up. KT-2000 arthrometer measurements were done at the final follow-up to evaluate anterior laxity. RESULTS: There were 27 patients (mean age 27 +/- 8.9 years) in the FSH group and 36 patients (mean age 27.1 +/- 6.7 years) in the FDT group. The mean follow-up time was 38.2 +/- 3.5 months for the FSH group and 41 +/- 6.1 months for the FDT group. There were no statistically significant differences between the groups when preoperative and postoperative Tegner-Lysholm scores were compared (Tegner P = 0.583, 0.742; Lysholm P = 0.592, 0.249). The mean anteroposterior laxity and side-to-side differences measured by KT-2000 were 4.1 mm and 2.1 mm for the FSH group, respectively; 4.2 mm and 2.2 mm for the FDT group, respectively. There was not a statistically significant difference (P = 0.745, 0.562 respectively). CONCLUSIONS: Primary ACL reconstruction with a single loop freeze-dried irradiated tibialis anterior allograft revealed comparable results with four strand hamstring autograft in non-athlete patients. LEVEL OF EVIDENCE: Level III, Therapeutic study. PMID- 30243836 TI - Interaction Analyses of 14-3-3zeta, Dok1, and Phosphorylated Integrin beta Cytoplasmic Tails Reveal a Bi-molecular Switch in Integrin Regulation. AB - Integrins are hetero-dimeric (alpha and beta subunits) type I transmembrane proteins that facilitate cell adhesion and migration. The cytoplasmic tails (CTs) of integrins interact with a plethora of intra-cellular proteins that are required for integrin bidirectional signaling. In particular, the beta CTs of integrins are known to recruit a variety of cytosolic proteins that often have overlapping recognition sites. However, the chronological sequence of beta CTs/cytosolic proteins interactions remains to be fully characterized. Previous studies have shown that the scaffold protein 14-3-3zeta binds to phosphorylated beta CTs in activated integrins, whereas interactions of Dok-1 with phosphorylated beta CTs maintained integrins in the resting state. In this study, we examined the binding interactions between 14-3-3zeta, Dok1, and phosphorylated integrin beta2 and beta3 CTs. We show that the scaffold protein 14-3-3zeta interacts with the phosphotyrosine binding (PTB) domain of Dok1 even in the absence of the phosphorylated integrin beta CTs. The interactions were mapped onto the beta-sheet region of the PTB domain of Dok1. Furthermore, we provide evidence that the 14-3-3zeta/Dok1 binary complex is able to bind to their cognate phosphorylated sequence motifs in the integrin beta CTs. We demonstrate that Thr phosphorylated pTTT beta2 CT or pTST beta3 CT can bind to 14-3-3zeta that is in complex with the Dok1 PTB domain, whereas Ser phosphorylated beta2 CT or Tyr phosphorylated beta3 CT interacted with Dok1 in 14-3-3zeta/Dok1 complex. Based on these data, we propose that 14-3-3zeta/Dok1 complex could serve as a molecular switch providing novel molecular insights into the regulating integrin activation. PMID- 30243837 TI - The Selenium Transport Protein, Selenoprotein P, Requires Coding Sequence Determinants to Promote Efficient Selenocysteine Incorporation. AB - Selenoproteins are an essential and unique group of proteins in which selenocysteine (Sec) is incorporated in response to a stop codon (UGA). Reprograming of UGA for Sec insertion in eukaryotes requires a cis-acting stem loop structure in the 3' untranslated region of selenoprotein mRNA and several trans-acting factors. Together these factors are sufficient for Sec incorporation in vitro, but the process is highly inefficient. An additional challenge is the synthesis of selenoprotein P (SELENOP), which uniquely contains multiple UGA codons. Full-length SELENOP expression requires processive Sec incorporation, the mechanism for which is not understood. In this study, we identify core coding region sequence determinants within the SELENOP mRNA that govern SELENOP synthesis. Using 75Se labeling in cells, we determined that the N-terminal coding sequence (upstream of the second UGA) and C-terminal coding sequence context are two independent determinants for efficient synthesis of full-length SELENOP. In addition, the distance between the first UGA and the consensus signal peptide is also critical for efficiency. PMID- 30243838 TI - Left ventricular remodeling in patients with acute type B aortic dissection after thoracic endovascular aortic repair: Short- and mid-term outcomes. AB - BACKGROUND: Left ventricular (LV) remodeling remains unknown in patients with acute Type B aortic dissection (aTBAD) after thoracic endovascular aortic repair (TEVAR) during follow-up. METHODS: Between May 2004 and January 2016, 163 consecutive patients (136 males, mean preoperative age: 51.06 +/- 10.79 years) with aTBAD underwent TEVAR. A linear mixed model was used to evaluate risk factor influencing on LV remodeling and investigate longitudinal changes in LV thickness, diameter, volume, function and mass at preoperation, postoperation, short- and mid-term follow-up. RESULTS: Median follow-up time was 48.0 months (quartiles 1-3, 31-84 months, maximum 147 months). LV thickness and mass followed a continuous downward trend over time. Interventricular septal thickness at end diastole significantly decreased at mid-term follow-up (time, p < 0.001: preoperative 11.59 +/- 0.14 mm vs mid-term 10.82 +/- 0.15 mm, p < 0.001; postoperative 11.40 +/- 0.14 mm vs mid-term 10.82 +/- 0.15 mm, p = 0.006). LV posterior wall thickness at end-diastole was markedly reduced at mid-term follow up (time, p < 0.001: preoperative 10.89 +/- 0.11 mm vs mid-term 10.02 +/- 0.11 mm, p < 0.001; postoperative 10.78 +/- 0.13 mm vs mid-term 10.02 +/- 0.11 mm, p < 0.001; short-term 10.56 +/- 0.15 mm vs mid-term 10.02 +/- 0.11 mm, p = 0.021). LV mass index markedly decreased during follow-up (time, p = 0.001: preoperative 129.60 +/- 3.55 g/m2 vs short-term 119.26 +/- 3.19 g/m2, p = 0.009; preoperative 129.60 +/- 3.55 g/m2 vs mid-term 115.79 +/- 3.62 g/m2, p = 0.003). LV function was improved, but not significantly so, during follow-up. Strict blood pressure control had no influence on LV remodeling. True lumen followed a continuous enlargement trend in terms of proximal thoracic aorta and celiac trunk level during follow-up. CONCLUSIONS: TEVAR can reverse LV remodeling and LV hypertrophy in patients with aTBAD during follow-up. PMID- 30243839 TI - The effects of nasal decongestion on obstructive sleep apnoea. AB - BACKGROUND: Many studies have indicated associations between impaired nasal breathing and sleep disorders. However, the precise nature of the relationship between nasal patency and sleep remains unclear. PURPOSE: We analysed the effects of nasal patency on sleep architecture and breath in nasal obstruction predominant obstructive sleep apnoea (NO-OSA) patients by applying nasal decongestant. MATERIAL AND METHODS: A randomized, placebo-controlled double-blind crossover study was performed in OSA patients with chronic nasal obstruction and without obvious pharyngeal narrowing. All OSA patients (confirmed by polysomnography) were recruited and completed 2 overnight studies (randomly applying oxymetazoline or placebo). Data collected after oxymetazoline or placebo treatments were compared. The ClinicalTrials.gov identifier is NCT03506178. RESULTS: Compared with placebo, oxymetazoline resulted in significant increase in rapid eye movement sleep (p = 0.027) and reduction of stage 1 sleep (p = 0.004), as well as arousal index (p = 0.002). Moreover, great improvements in apnoea/hypopnea index (AHI) were observed (p < 0.001); AHI in the supine position was significantly reduced (p = 0.001). Oxygen saturation during sleep was increased significantly [mean oxygen saturation (p = 0.005) and lowest oxygen saturation (p = 0.024)]. Oxygen desaturation index was significantly reduced (p < 0.001). CONCLUSIONS: Improving nasal patency by decongestant could improve sleep quality, AHI, and oxygen saturation level during sleep. PMID- 30243840 TI - The clinical value of a thorough diagnostic evaluation for neurotologic complaints. AB - PURPOSE: Determine the clinical efficacy of comprehensive neurotologic testing in patients presenting with complaints of hearing loss, tinnitus and/or dizziness. METHODS: This is a retrospective analysis of 1170 consecutive charts of patients who presented between 1980 and 2013 with neurotologic complaints. Demographic data, chief complaint, diagnostic imaging, audiograms, and blood tests were evaluated. RESULTS: Retrospective analysis of 1170 patient charts was performed. 762/1170 (65%) patients presented with subjective hearing loss, 575/1170 (49%) with dizziness, and 657/1170 (56%) with tinnitus. Audiometric testing revealed hearing loss in 1059/1169 (91%) patients. 536/1120 (48%) patients had abnormalities on Magnetic Resonance Imaging, and 343/1087 (32%) on Computed Tomography imaging. Endocrine and immunologic testing revealed 108/1135 (9.5%) patients were hyperglycemic; 125/1124 (11%) patients had elevated TSH; 149/1141 (13%) patients had a positive ANA; and 82/1133 (7.2%) patients were positive for RF. 198/1083 (18%) of patients were positive for HLA-B35, 246/1083 (23%) for HLA Cw4, 454/1083 (42%) for HLA-Cw7, and 747/1060 (70%) of patients had absent HLA DR4. 112/1085 (10%) of patients were positive for anti-68kD antibodies and 154/936 (17%) for protein 0. Many patients were diagnosed with previously unrecognized medical conditions. CONCLUSION: Comprehensive neurotological workup results in diagnoses that would go unrecognized otherwise, allowing patients to receive prompt treatment for medically important conditions, some of which may be causally related to their neurotologic complaints. However, the value of each study for routine testing of patients with neurotologic complaints remains controversial; and the evidence presented herein should help practitioners determine what studies should be included in their patient assessments. PMID- 30243841 TI - The intrinsically disordered C-terminal F domain of the ecdysteroid receptor from Aedes aegypti exhibits metal ion-binding ability. AB - The dominant vector of dengue and Zika diseases is a female Aedes aegypti mosquito. Its reproduction is controlled by the formation of an active heterodimer complex of the 20-hydroxyecdysone receptor (EcR) and Ultraspiracle protein (Usp). Although EcR exhibits a structural and functional organization typical of nuclear receptors (NRs), the EcR C-terminus has an additional F domain (AaFEcR) that is rarely present in the NRs superfamily. The presence of F domains is evolutionarily not well conserved in the NRs. The structure-function relationship of EcR F domains in arthropods is unclear and enigmatic. To date, there have been no data concerning the structure and function of AaFEcR. Our results showed that AaFEcR belongs to a family of intrinsically disordered proteins (IDPs) and possesses putative pre-molten globule (PMG) characteristics. Unexpectedly, additional amino acid composition in silico analyses revealed the presence of short unique repeated Pro-His clusters forming an HGPHPHPHG motif, which is similar to those responsible for Zn2+ and Cu2+ binding in histidine proline-rich glycoproteins (HPRGs). Using SEC, SV-AUC and ESI-TOF MS, we showed that the intrinsically disordered AaFEcR is able to bind metal ions and form complexes with these ions. Our studies provide new insight into the structural organization and activities of the F domains of NRs. This unique for the F domains of NRs ion-binding propensity demonstrated by the AaFEcR domain may be a part of the ecdysteroid receptor's mechanism for regulating the expression of genes encoding oxidative stress-protecting proteins. PMID- 30243842 TI - Palmatine ameliorated murine colitis by suppressing tryptophan metabolism and regulating gut microbiota. AB - Inflammatory bowel disease (IBD), majorly include Crohn's disease (CD) and ulcerative colitis (UC), is chronic and relapsing inflammatory disorders of the gastrointestinal tract, which treatment options remain limited. Here we examined the therapeutic effects of an isoquinoline alkaloid, Palmatine (Pal), on mice experimental colitis induced by dextran sulfate sodium (DSS) and explored underlying mechanisms. Colitis was induced in BALB/c mice by administering 3% DSS in drinking water for 7 days. Pal (50 and 100 mg kg-1) and the positive drug Sulfasalazine (SASP, 200 mg kg-1) were orally administered for 7 days. Disease activity index (DAI) was evaluated on day 8, and colonic tissues were collected for biochemistry analysis. The fecal microbiota was characterized by high throughput Illumina MiSeq sequencing. And plasma metabolic changes were detected by UPLC-MS. Our results showed that Pal treatment significantly reduced DAI scores and ameliorated colonic injury in mice with DSS-induced colitis. Mucosal integrity was improved and cell apoptosis was inhibited. Moreover, gut microbiota analysis showed that mice received Pal-treatment have higher relative abundance of Bacteroidetes and Firmicutes, but reduced amount of Proteobacteria. Moreover, Pal not only suppressed tryptophan catabolism in plasma, but also decreased the protein expression of indoleamine 2,3-dioxygenase 1 (IDO-1, the rate-limiting enzyme of tryptophan catabolism) in colon tissue. This is consolidated by molecular docking, which suggested that Pal is a potent IDO-1 inhibitor. Taken together, our findings demonstrate that Pal ameliorated DSS-induced colitis by mitigating colonic injury, preventing gut microbiota dysbiosis, and regulating tryptophan catabolism, which indicated that Pal has great therapeutic potential for colitis. PMID- 30243843 TI - Genome-wide identification and analysis of Nrf2 binding sites - Antioxidant response elements in zebrafish. AB - In the post-genomic era, deciphering the Nrf2 binding sites - antioxidant response elements (AREs) is an essential task that underlies and governs the Keap1-Nrf2-ARE pathway - a cell survival response pathway to environmental stresses in the vertebrate model system. AREs regulate the transcription of a repertoire of phase II detoxifying and/or oxidative-stress responsive genes, offering protection against toxic chemicals, carcinogens, and xenobiotics. In order to identify and analyze AREs in zebrafish, a pattern search algorithm was developed to identify AREs and computational tools available online were utilized to analyze the identified AREs in zebrafish. This study identified the AREs within 30 kb upstream from the transcription start site of antioxidant genes and mitochondrial genes. We report for the first time the AREs of all the known protein coding genes in the zebrafish genome. Western blotting, RT2 profiler array PCR, and qRT-PCR were performed to test whether AREs influence the Nrf2 target genes expression in the zebrafish larvae using sulforaphane. This study reveals unique AREs that have not been previously reported in the cytoprotective genes. Nine TGAG/CNNNTC and six TGAG/CNNNGC AREs were observed significantly. Our findings suggest that AREs drive the dynamic transcriptional events of Nrf2 target genes in the zebrafish larvae on exposure to sulforaphane. The identified abundant putative AREs will define the Keap1-Nrf2-ARE network and elucidate the precise regulation of Nrf2-ARE pathway in not only diseases but also in embryonic development, inflammation, and aerobic respiration. Our results help to understand the dynamic complexity of the Nrf2-ARE system in zebrafish. PMID- 30243844 TI - Physiologically-based pharmacokinetic modeling suggests similar bioavailability of Mn from diet and drinking water. AB - Due to concerns for enhanced absorption of manganese (Mn) from drinking water compared to diet, bioavailability of Mn from drinking water remains a major data gap in understanding Mn kinetics. In this study, PBPK models for adult rats and humans were updated with a drinking water exposure route and were used to assess the homeostatic control of Mn uptake, excretion and tissue kinetics between the two different ingestion modes. Drinking water model parameters were estimated from tissue kinetic data from a drinking water study in rats. The published study included a 10 ppm-Mn diet with additional Mn added to drinking water to give a total ingested Mn dose equivalent to that from a 200 ppm diet. The 200 ppm diet and equivalent mixed drinking water/diet exposures provided Mn concentrations for brain (striatum, olfactory bulb, and cerebellum), liver and bone after 7 and 61 days of Mn exposure. Modeling of these data sets indicated that (1) the oral Mn bioavailability is similar for diet or drinking water and (2) homeostatic control of gut uptake of Mn occurs with either drinking water or dietary ingestion. This updated description for absorption and distribution of Mn from gut was added to a human Mn-PBPK model to simulate Mn exposure from multiple routes of exposure (i.e. dietary intake, drinking water, and inhalation). This increases the utility of the Mn PBPK model by allowing for the simulation of multiple Mn exposure scenarios, including variable daily food and drinking water exposures in a human population. PMID- 30243845 TI - Maintaining Professional Boundaries in the Practitioner-Patient/Client Relationship. PMID- 30243846 TI - Recognition of protein biomarkers using epitope-mediated molecularly imprinted films: Histidine or cysteine modified epitopes? AB - This research aims to engineer molecularly imprinted polymer (MIP)-based synthetic receptors for the molecular recognition of neuron specific enolase (NSE) biomarker. The synthetic peptide derived from the NSE was synthesized along with its cysteine and histidine modified versions. The modified peptides were utilized as templates for molecular imprinting, which was achieved by combination of epitope- and electrochemical surface imprinting strategy. The subsequently generated imprinted cavities were used for the detection of the NSE derived peptide and NSE. The imprints created with cysteine (CME) and histidine modified epitopes (HME) could detect the peptide in a concentration range of 2-128 uM and 15.6 nM to 128 uM, respectively. The recognition of NSE was achieved by the same imprints in a linear range of 1-64 ng mL-1 (CME) and 0.25-64 ng mL-1 (HME), respectively. The target molecules bound to the control polymer very weakly, confirming the high selectivity of the MIP cavities. Selectivity studies resulted in imprinting factors of 8.8 and 11 for the CME and HME imprints, respectively. The affinity analyses provided dissociation constants of 2.3 * 10-10 M and 3 * 10 11 M for NSE recognition using the corresponding epitope imprints. Cross reactivity studies with non-specific molecules proved high specificity of the artificial receptors for the targets. PMID- 30243847 TI - A PNA-based Lab-on-PCB diagnostic platform for rapid and high sensitivity DNA quantification. AB - We report the development of a Lab-on-PCB DNA diagnostic platform, exploiting peptide nucleic acid (PNA) sequences as probes. The study demonstrates the optimization and characterization of two commercial PCB manufacturing gold electroplating processes for biosensing applications. Using an optimized ratio of PNA with a spacer molecule (MCH), the lowest limit of detection (LoD) to date for PCB-based DNA biosensors of 57 fM is reported. The study also showcases a fully integrated Lab-on-PCB microsystem designed for rapid detection, which employs PCB integrated sample delivery, achieving DNA quantification in the 0.1-100 pM range for 5 MUL samples analyzed within 5 min under continuous flow. The demonstrated biosensor proves the capability of PCB-based DNA biosensors for high sensitivity and paves the way for their integration in Lab-on-PCB DNA diagnostic microsystems. PMID- 30243848 TI - Pre-weaning paternal deprivation impairs social recognition and alters hippocampal neurogenesis and spine density in adult mandarin voles. AB - Disruption of the early social environment, such as maternal separation or early deprivation, can impair cognitive function, alter offspring neurogenesis and restrict dendritic architecture in the hippocampus. However, whether paternal deprivation during the pre-weaning period affects adult neurogenesis, synaptogenesis and social recognition remains unclear in monogamous species. In the present study, mandarin vole (Microtus mandarinus) pups were deprived of fathers during postnatal day 14-21. Then social recognition, hippocampal neurogenesis and spine density, basal levels of corticosterone (CORT) and oxytocin (OT) were examined at adulthood. We found that paternal deprivation impaired social recognition at adulthood. In addition, paternal deprivation significantly reduced 5-bromo-2-deoxyuidine (BrdU) immunoreactive cells (p < 0.01) and Brdu/Neun-labeled cells (p < 0.05) in the dentate gyrus compared to those of biparental care group in females, but not in males (p > 0.05). Meanwhile, paternal deprivation group had fewer double-staining cells with BrdU and the immature neuron marker doublecortin than biparental care group both in male (p < 0.01) and female (p < 0.05) voles. Paternal deprivation also decreased the number of dendritic spines in the dentate gyrus at adulthood. Paternal deprivation reduced circulating levels of OT and increased CORT only in females. These results demonstrated that impaired social recognition induced by paternal deprivation may be linked with alterations in neurogenesis and spine densityof the dentate gyrus and levels of OT and CORT, especially in females. PMID- 30243849 TI - Inferring action-dependent outcome representations depends on anterior but not posterior medial orbitofrontal cortex. AB - Although studies examining orbitofrontal cortex (OFC) often treat it as though it were functionally homogeneous, recent evidence has questioned this assumption. Not only are the various subregions of OFC (lateral, ventral, and medial) hetereogeneous, but there is further evidence of heterogeneity within those subregions. For example, several studies in both humans and monkeys have revealed a functional subdivision along the anterior-posterior gradient of the medial OFC (mOFC). Given our previous findings suggesting that, in rats, the mOFC is responsible for inferring the likelihood of unobservable action outcomes (Bradfield, Dezfouli, van Holstein, Chieng, & Balleine, 2015), and given the anterior nature of the placements of our prior manipulations, we decided to assess whether the rat mOFC also differs in connection and function along its anteroposterior axis. We first used retrograde tracing to compare the density of efferents from mOFC to several structures known to contribute to goal-directed action: the mediodorsal thalamus, basolateral amygdala, posterior dorsomedial striatum, nucleus accumbens core and ventral tegmental area. We then compared the functional effects of anterior versus posterior mOFC excitotoxic lesions on tests of Pavlovian-instrumental transfer, instrumental outcome devaluation and outcome specific reinstatement. We found evidence that the anterior mOFC had greater connectivity with the accumbens core and greater functional involvement in goal directed action than the posterior mOFC. Consistent with previous findings across species, therefore, these results suggest that the anterior and posterior mOFC of the rat are indeed functionally distinct, and that it is the anterior mOFC that is particularly critical for inferring unobservable action outcomes. PMID- 30243850 TI - Transcriptional changes before and after forgetting of a long-term sensitization memory in Aplysia californica. AB - Most long-term memories are forgotten, becoming progressively less likely to be recalled. Still, some memory fragments may persist, as savings memory (easier relearning) can be detected long after recall has become impossible. What happens to a memory trace during forgetting that makes it inaccessible for recall and yet still effective to spark easier re-learning? We are addressing this question by tracking the transcriptional changes that accompany learning and then forgetting of a long-term sensitization memory in the tail-elicited siphon withdrawal reflex of Aplysia californica. First, we tracked savings memory. We found that even though recall of sensitization fades completely within 1 week of training, savings memory is still detectable at 2 weeks post training. Next, we tracked the time-course of regulation of 11 transcripts we previously identified as potentially being regulated after recall has become impossible. Remarkably, 3 transcripts still show strong regulation 2 weeks after training and an additional 4 are regulated for at least 1 week. These long-lasting changes in gene expression always begin early in the memory process, within 1 day of training. We present a synthesis of our results tracking gene expression changes accompanying sensitization and provide a testable model of how sensitization memory is forgotten. PMID- 30243851 TI - Manipulation of hippocampal CA3 firing via luminopsins modulates spatial and episodic short-term memory, especially working memory, but not long-term memory. AB - The CA3 subregion of the hippocampus is important for rapid encoding, storage and retrieval of associative memories. Lesions and pharmacological inhibitions of hippocampal CA3 suggest that it is essential for different memories. However, how CA3 functions in spatial and episodic memory in different time scales (i.e. short term versus long term) without permanent lesions has not been systematically investigated yet. Taking advantage of the chemogenetic access to opsins, this study used luminopsins, fusion proteins of luciferase and optogenetic elements, to manipulate neuronal activity in CA3 during memory tasks over a range of spatial and temporal scales. In this study, we found that excitation or inhibition of CA3 neurons had no significant effects on long-term spatial or episodic memory, but had remarkable effects on spatial working memory, spatial short-term memory as well as episodic short-term memory. In addition, stimulation of CA3 neurons altered the expression levels of NR2A. Intracerebral injection of receptor inhibitors further confirmed that NR2A is crucial to spatial working memory, which is consistent with the luminopsins experiments. These findings indicate that CA3 maintains a specific role on spatial and episodic memory over a short period of time. PMID- 30243852 TI - Loneliness in psychotic illness and its association with cardiometabolic disorders. AB - Loneliness is an established risk factor for poor cardiometabolic health. People with psychotic disorders experience high rates of both cardiometabolic disease and loneliness, but how these factors are associated is poorly understood. Thus, using data from the second Australian National Survey of Psychosis we examined whether loneliness is associated with the likelihood of cardiometabolic disorder in psychotic illness. Loneliness was assessed using a single-item measure, with a 4-point scale (not lonely; lonely occasionally; some friends but lonely for company; socially isolated and lonely) whilst cardiometabolic status was assessed in terms of the criteria used to determine metabolic syndrome (elevated waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose). Logistic regression was employed to examine whether loneliness was associated with metabolic syndrome status, and its individual components, with and without adjustment for confounding variables. Increased loneliness was associated with an increased risk of metabolic syndrome in people with psychosis (OR 1.21, 95% CI 1.08-1.36, p < .001) and to the risk of elevated waist circumference (p < .01), elevated triglycerides (p < .05) and reduced high-density lipoprotein cholesterol (p < .05). Notably, these associations largely persisted when controlling for a range of covariates. Feeling lonely is significantly associated with metabolic syndrome, and dyslipidemia specifically, in people with psychotic disorders. These data suggest that the potential benefits of interventions to reduce loneliness in psychosis may extend to cardiovascular as well as psychosocial functioning, and should be explored in future research. PMID- 30243853 TI - Effects of oxytocin on empathy, introspective accuracy, and social symptoms in schizophrenia: A 12-week twice-daily randomized controlled trial. AB - The effects of intranasal oxytocin, a neuropeptide involved in prosocial behavior and modulation of neural networks underlying social cognition and emotion regulation, have been studied in schizophrenia. We tested the hypothesis that twice-daily intranasal oxytocin administered for 12-weeks would improve tertiary and exploratory outcomes of self-reported social symptoms, empathy and introspective accuracy from the Jarskog et al. (2017) randomized controlled trial. Sixty-eight stable outpatients with schizophrenia or schizoaffective disorder were randomized to receive oxytocin (24 IU twice daily) or placebo. Introspective accuracy was assessed with the Specific Level of Functioning Scale and the Interpersonal Perception Task. Empathy was assessed with the Interpersonal Reactivity Index (IRI), and social symptoms were assessed with the Liebowitz Social Anxiety Scale and the Green et al. Paranoid Thoughts Scales. Outcomes were assessed at baseline, six, and twelve weeks. Results demonstrated limited effect of oxytocin with some improvement on the IRI Perspective-Taking Subscale. No additional between-group differences emerged on self-reported symptoms, empathy, or introspective accuracy. PMID- 30243854 TI - Oral health in psychosis: An unmet need. PMID- 30243855 TI - GLP-1 agonists for metabolic disorders in schizophrenia. PMID- 30243856 TI - The dark side of ventricular arrhythmias in athletes. PMID- 30243857 TI - Topological linkage disequilibrium calculated from coalescent genealogies. AB - We revisit the classical, and introduce a novel, concept of two-locus linkage disequilibrium (LD). In contrast to defining haplotypes as allele combinations at two marker loci, we concentrate on the clustering of a sample of chromosomes induced by their coalescent genealogy. The root of a binary coalescent tree defines two clusters of chromosomes, each one of them containing the left and right descendants of the root. At two different loci this assignment may be different as a result of recombination. We show that the proportion of shared chromosomes among clusters at two different loci, measured by the squared correlation, constitutes a natural measure of LD. We call this topological LD (tLD) since it is induced by the topology of the coalescent tree. We find that it is, on average, larger than classical LD for any given distance between loci. Furthermore, tLD has a smaller coefficient of variation, which should provide an advantage, compared to the use of classical LD, for any kind of mapping purposes. We conclude with a practical application to the LCT region in human populations. PMID- 30243858 TI - Damaged cardiovascular autonomic control in wheelchair-using children and adolescents with myelomeningocele: a case-control study. AB - BACKGROUND: Cardiovascular autonomic dysfunction is associated with the development of cardiovascular diseases, but little is known about it in children and adolescents with myelomeningocele. OBJECTIVE: This study investigated the cardiovascular autonomic function in wheelchair-using children and adolescents with myelomeningocele. METHODS: Twenty-two participants were assigned to one of two groups: myelomeningocele group (n=11) and Control group (n=11). Heart rate variability and systolic blood pressure variability were collected in supine resting position using spectral analyses. Spontaneous baroreflex sensitivity was collected by time-domain through the sequence method. RESULTS: At rest, heart rate was higher in myelomeningocele group when compared to Control group (mean difference 22.1, 95% CI 4.82-39.40; p=0.01). The heart rate and systolic blood pressure variability parameters did not show differences between groups. However, myelomeningocele showed lower gain mean in baroreflex sensitivity (mean difference -4.5, 95% CI -8.47 to -0.60; p=0.02), when compared to Control. CONCLUSION: Wheelchair-using children and adolescents with myelomeningocele presented differences in the autonomic cardiovascular function. This may be associated with hypomobility due to wheelchair dependence, and venous muscle pump insufficiency due to paraplegia. PMID- 30243859 TI - Patients' experience with opioid tapering: A conceptual model with recommendations for clinicians. AB - : Clinical guidelines discourage prescribing opioids for chronic pain but give minimal advice about how to discuss opioid tapering with patients. We conducted focus groups and interviews involving 21 adults with chronic back or neck pain in different stages of opioid tapering. Transcripts were qualitatively analyzed to characterize patients' tapering experiences, build a conceptual model of these experiences, and identify strategies for promoting productive discussions of opioid tapering. Analyses revealed 3 major themes. First, due to dynamic changes in patients' social relationships, emotional state, and health status, patients' pain and perceived need for opioids fluctuate daily; this may conflict with recommendations to taper by a certain amount each month. Second, tapering requires substantial patient effort across multiple domains of patients' everyday lives; patients discuss this effort superficially, if at all, with clinicians. Third, patients use a variety of strategies to manage the tapering process (e.g., keeping an opioid "stash," timing opioid consumption based on planned activities). Recommendations for promoting productive tapering discussions include understanding the social and emotional dynamics likely to impact patients' tapering, addressing patient fears, focusing on patients' best interests, providing anticipatory guidance about tapering, and developing an individualized tapering plan that can be adjusted based on patient response. PERSPECTIVE: This study used interview and focus group data to characterize patients' experiences with opioid tapering and identify communication strategies that are likely to foster productive, patient-centered discussions of opioid tapering. Findings will inform further research on tapering and help primary care clinicians to address this important, often challenging topic. PMID- 30243860 TI - Mesothelial-mesenchymal transitions in embryogenesis. AB - Most animals develop coelomic cavities lined by an epithelial cell layer called the mesothelium. Embryonic mesothelial cells have the ability to transform into mesenchymal cells which populate many developing organs contributing to their connective and vascular tissues, and also to organ-specific cell types. Furthermore, embryonic mesothelium and mesothelial-derived cells produce essential signals for visceral morphogenesis. We review the most relevant literature about the mechanisms regulating the embryonic mesothelial-mesenchymal transition, the developmental fate of the mesothelial-derived cells and other functions of the embryonic mesothelium, such as its contribution to the establishment of left-right visceral asymmetries or its role in limb morphogenesis. PMID- 30243862 TI - Corrections. PMID- 30243861 TI - Biological and clinical manifestations of juvenile Huntington's disease: a retrospective analysis. AB - BACKGROUND: Huntington's disease is a rare, neurodegenerative disease caused by an expanded CAG repeat mutation in the huntingtin gene. Compared with adult-onset Huntington's disease, juvenile Huntington's disease (onset <=20 years) is even rarer and has not been studied extensively. We aimed to further characterise juvenile Huntington's disease by examining the effect of CAG repeat size on disease presentation, progression, and survival. METHODS: We did a retrospective analysis of patients with juvenile Huntington's disease aged 20 years or younger, according to the length of their CAG repeat and who had disabling psychiatric symptoms (with motor symptoms) or motor symptoms alone, and of patients with adult-onset Huntington's disease manifesting aged 30-60 years with 40 or more CAG repeats, from the REGISTRY and ENROLL-HD platforms and from two institutional databases (Lega Italiana Ricerca Huntington Foundation and the Instituto Neurociencias de Buenos Aires and the Sanatorio de la Trinidad Mitre). Patients with psychiatric but no motor symptoms were excluded. We compared symptoms at onset and longitudinally in patients with juvenile Huntington's disease with highly expanded (HE subgroup) or low expansion (LE subgroup) mutations, grouped by hierarchical clustering analysis. We also compared disease progression (longitudinal change in Unified Huntington's Disease Rating Scale-Total Motor Score) and survival of patients with juvenile and adult-onset Huntington's disease. FINDINGS: We extracted medical records from 580 patients entered into the studies or databases between June 23, 2004, and March 31, 2018, of whom 36 patients met our definition of juvenile Huntington's disease and 197 for adult onset Huntington's disease. According to caregiver reports, gait disturbance was more often a first presenting symptom in the HE subgroup (eight [80%] of 10 patients) than in the LE subgroup (seven [27%] of 26 patients; p=0.0071), whereas loss of hand dexterity was more common in the LE subgroup (11 [42%] of 26 patients) than in the HE subgroup (0 [0%] of 10 patients; p=0.0160). Compared with the LE subgroup, development delay (0 [0%] in the LE subgroup vs nine [90%] in the HE subgroup; p<0.0001), severe gait impairment (nine [35%] in the LE subgroup vs nine [90%] in the HE subgroup; p=0.0072), and seizures (three [11%] in the LE subgroup vs eight [80%] in the HE subgroup; p<0.0001) prevailed over time in the HE subgroup. Disease progression was more rapid in juvenile Huntington's disease (n=14) than in adult-onset Huntington's disease (n=52; generalised estimating equation model, p=0.0003). Of 121 deceased patients, median survival was shorter in the juvenile Huntington's disease (n=17) cohort than in adult-onset Huntington's disease (n=104) cohort (hazard ratio 2.18 [95% CI 1.08-4.40]; p=0.002). INTERPRETATION: Patients with HE juvenile Huntington's disease differ clinically from patients with LE juvenile Huntington's disease or adult-onset Huntington's disease, suggesting reclassification of this particularly aggressive form of Huntington's disease might be required. FUNDING: Lega Italiana Ricerca Huntington Foundation and IRCCS Ospedale Casa Sollievo della Sofferenza. PMID- 30243863 TI - Juvenile Huntington's disease: left behind? PMID- 30243864 TI - Nidogen-2: Location and expression during corneal wound healing. AB - Nidogen-2 is a basement membrane (BM) glycoprotein that could be a key to understanding why defects in BM regeneration occur after severe trauma to the cornea. We monitored the location and expression of nidogen-2 during corneal repair after alkali burn in rabbits. In rabbits that received both general and ocular topical anaesthesia, the central cornea of the left eye was burned by placing an 8-mm diameter filter paper soaked in 0.5 N NaOH for 60 s. Right corneas were used as controls. The eyes were evaluated at 2, 7, 15, and 30 days after burning and analysed by immunohistochemistry for nidogen-2 and alpha-smooth muscle actin, a myofibroblast marker. Nidogen-2 mRNA expression levels were determined by quantitative real-time polymerase chain reaction. In control corneas, nidogen-2-positive cells were in all epithelial layers, the endothelium, and the anterior and posterior stromal regions. At Day 2 after the alkali burn, the wound area epithelium and the peripheral epithelium were made up of only 1 to 2 cell layers, all of them nidogen-2 positive. At Day 7 in the wound area, the epithelium consisted of two cell layers, and the basally located cells were mostly nidogen-2 positive. The greatest change was observed at Day 30. At this time, the ulcer prevalence in the alkali-burned corneas was approximately 50% and the central epithelial defects remained. In unepithelialized corneas, frequent epithelial detachments were present, in which almost of the epithelial cells were nidogen-2 negative. The injured stroma was repopulated by activated stromal cells that synthesized nidogen-2. The nidogen-2 was retained in the newly secreted, but disordered, matrix produced mainly by the myofibroblasts localized in the stroma at 7, 15, and 30 days after burning. Thus, even though nidogen-2 was present, it was unable to contribute to the effective regeneration of the BM. PMID- 30243865 TI - Management of Intra-Aortic Balloon Rupture and Entrapment. PMID- 30243866 TI - Renal Angina Is a Sensitive, but Nonspecific Identifier of Postcardiac Surgery Acute Kidney Injury. AB - OBJECTIVES: Acute kidney injury (AKI) is a common complication of cardiac surgery, and early detection is difficult. This study was performed to determine the sensitivity, specificity, positive predictive value, negative predictive value, and statistical performance of renal angina (RA) as an early predictor of AKI in an adult cardiac surgical patient population. DESIGN: Retrospective, nonrandomized, observational study. SETTING: A single, university-affiliated, quaternary medical center. PARTICIPANTS: The study comprised 324 consecutive patients undergoing coronary artery bypass grafting or cardiac valvular surgery from February 1 through July 30, 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred-seven patients at moderate or high risk of developing postoperative renal injury were identified, 82 of whom met criteria for RA. The occurrence of RA was found to have an 80.9% sensitivity and 30.8% specificity for the prediction of AKI using Acute Kidney Injury Network criteria and 89.3% sensitivity and 27.8% specificity when paired with the Risk, Injury, Failure, Loss, End Stage Renal Disease criteria. A receiver operating characteristic area under the curve analysis revealed a nonsignificant predictive ability of 55.8% (95% confidence interval 0.47-0.65) when RA was paired with Acute Kidney Injury Network criteria; however, the receiver operating characteristic area under the curve was significant when paired with Risk, Injury, Failure, Loss, End Stage Renal Disease criteria, with a predictive ability of 0.586 (0.509-0.662). CONCLUSIONS: RA is a sensitive, but nonspecific, predictor of postcardiac surgery AKI, with clinical utility most suited as a screening tool. PMID- 30243867 TI - Perioperative Anxiety and Stress in Children Undergoing Congenital Cardiac Surgery and Their Parents: Effect of Brief Intervention-A Randomized Control Trial. AB - OBJECTIVE: To know the effects of psychological preparation on perioperative stress, anxiety, and mood in children undergoing cardiac surgery and their parents. DESIGN: Prospective randomized control nonblinded trial. SETTING: Single center tertiary teaching hospital. PARTICIPANTS: A total of 60 children aged 5 to 15 years undergoing cardiac surgery were included in the study. One of the parents, preferably the father, was selected from the respective children. INTERVENTIONS: Subjects were randomized into 2 groups: noninterventional (group 1) and interventional (group 2). Intervention was in the form of toys and video games in children, and counseling and information in parents. Preoperative and postoperative anxiety in parents was measured using the State-Trait Anxiety Inventory (STAI), stress using the Index of Clinical Stress (ICS) scale by Abell, and the Ottawa mood scale. In children, the STAI-C (child version of STAI), Ottawa mood and Ottawa stress scales, and Wong-Baker faces pain scale were applied and serum cortisol was measured. MEASUREMENTS AND MAIN RESULTS: Group 2 children had significantly less (p < 0.001) stress, anxiety, and pain and improved mood. Group 2 parents had a significant reduction in state anxiety (42 +/- 4.4 v 54.5 +/- 7.8; p < 0.001) and ICS score (68.1+/-9.6 v 84.2 +/- 9.2; p < 0.001) and an improvement in mood (7.5 +/- 0.7 v 5.9 +/- 1; p < 0.001) compared with group 1. Postoperatively, cortisol levels in group 2 were lower than group 1 (571.3 nmol/L [123.3 -1247.14] v 718.9 nmol/L [53-1642.0]). CONCLUSION: Providing video games and toys preoperatively reduced postoperative stress and anxiety and improved mood in children undergoing congenital cardiac surgery. Parents were relieved of anxiety and stress with proper counseling and information. PMID- 30243868 TI - A Perspective in Critical Care Medicine: To Be a Mature Specialty We Must Move Our Focus Beyond Mortality. PMID- 30243869 TI - Pulmonary-Systemic Pressure Ratio Correlates with Morbidity in Cardiac Valve Surgery. AB - OBJECTIVES: Pulmonary hypertension portends worse outcomes in cardiac valve surgery; however, isolated pulmonary artery pressures may not reflect patients' global cardiac function accurately. To better account for the interventricular relationship, the authors hypothesized that patients with greater pulmonary systemic ratios (mean pulmonary arterial pressure)/(mean systemic arterial pressure) would correlate with worse outcomes after valve surgery. DESIGN: Retrospective cohort study. SETTING: Single academic hospital. PARTICIPANTS: The study comprised 314 patients undergoing valve surgery with or without coronary artery bypass grafting (2004-2016) with Society of Thoracic Surgeons predicted risk scores and preoperative right heart catheterization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The pulmonary-systemic ratio was calculated as follows: mean pulmonary arterial pressure/mean systemic arterial pressure. Patients were stratified by pulmonary-systemic ratio quartile. Logistic regression was used to assess the risk-adjusted association between pulmonary systemic ratio or mean pulmonary arterial pressure. Median pulmonary-systemic ratio was 0.33 (Q1-Q3: 0.23-0.65); median pulmonary arterial pressure was 29 (21 30) mmHg. Patients with the highest pulmonary-systemic ratio had the highest rates of morbidity and mortality (p < 0.0001). A high pulmonary-systemic ratio was associated with longer duration in the intensive care unit (p < 0.0001) and hospital (p < 0.0001). After risk-adjustment, pulmonary-systemic ratio and pulmonary arterial pressure were independently associated with morbidity and mortality, but the pulmonary-systemic ratio (odds ratio 23.88, p = 0.008, Wald 7.1) was more strongly associated than the pulmonary arterial pressure (odds ratio 1.035, p = 0.011, Wald 6.5). CONCLUSIONS: The pulmonary-systemic ratio is more strongly associated with risk-adjusted morbidity and mortality in valve surgery than pulmonary arterial pressure. By integrating ventricular interactions, this metric may better characterize the risk of valve surgery. PMID- 30243870 TI - The Use of Regional or Local Anesthesia for Carotid Endarterectomies May Reduce Blood Loss and Pulmonary Complications. AB - OBJECTIVE: Over 150,000 carotid endarterectomy (CEA) procedures are performed each year. Perioperative anesthetic management may be complex due to multiple patient and procedure-related risk factors. The authorsaimed to determine whether the use of general anesthesia (GA), when compared with regional anesthesia (RA), would be associated with reduced perioperative morbidity and mortality in patients undergoing a CEA. DESIGN: Retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. SETTING: The authorsevaluated patients undergoing a CEA at multiple university- and community-based settings. PARTICIPANTS: A total of 43,463 patients were identified; 22,845 patients were propensity matched after excluding for missing data. INTERVENTIONS: The study population was divided into 2 groups: patients undergoing RA or GA. The RA group included regional anesthesia performed by the anesthesiologist or surgeon, monitored anesthesia care, and local infiltration. METHODS: The primary endpoint was 30-day mortality. Secondary endpoints included surgical site infection, pulmonary complications, return to the operating room, acute kidney injury, cardiac arrest, urinary tract infection, myocardial infarction, thromboembolism, perioperative transfusion, sepsis, and days to discharge. MEASUREMENTS AND MAIN RESULTS: Younger age, Hispanic ethnicity, body mass index <18.5, dyspnea, chronic obstructive pulmonary disease, and smoking history were associated with receiving GA. Patients with low hematocrit and low platelets were more likely to get RA. There was no mortality difference. GA was associated with a significantly higher rate of perioperative transfusions (p = 0.037) and perioperative pneumonia (p = 0.027). CONCLUSION: The use of RA over GA in CEA is associated with decreased risk of postoperative pneumonia and a reduced need for perioperative blood transfusions. PMID- 30243871 TI - Type-A Aortic Dissection-More Than a Surgical Disease? PMID- 30243872 TI - Fellowship Training in Pediatric Cardiac Anesthesia: History, Maturation, and Current Status. AB - Pediatric cardiac anesthesia as a discipline has evolved over the years to become a well recognized sub-specialty. Education and training in the field has also continued to change and develop. In this review, the author outline the changes in the field over the years and suggest a structure for an organized fellowship training process. PMID- 30243873 TI - Serratus Anterior Plane Block Versus Thoracic Epidural Analgesia for Post Thoracotomy Pain Relief. PMID- 30243874 TI - Miniaturized Echocardiography in the Cardiac Intensive Care Unit. AB - Miniaturized transesophageal echocardiography has become more common in cardiac intensive care units. There are potential benefits to this mode of technology, many of which have been described in the literature. However, image acquisition and quality have been cited as being less optimal when compared to traditional transesophageal echocardiography. This review will discuss the current options available for miniaturized transesophageal echocardiography along with a literature review of this emerging assessment modality. PMID- 30243875 TI - Experimental study of the effects of soil pH and ionic species on the electro osmotic consolidation of kaolin. AB - The application of an electric field on soil mass induces both electro-osmotic flow and electro-migration, which has been used for the dewatering of soft soils and remediation of contaminated soils. The physical and chemical properties of soft soils are influenced by the soil pH as well as ionic species and their concentrations, which subsequently influence the dewatering and remediation efficiency. In the present study, one-dimensional column experiments were conducted to investigate the influence of soil pH and ionic species on the electro-osmotic consolidation process of kaolin. The initial drainage rate, total volume of the discharged water and the voltage loss near the anode increased with the increase in the initial soil pH. After electro-osmosis, the water content was lower near the anode and higher near the cathode for sample with higher initial soil pH. The addition of copper ions reduced the dewatering efficiency while the addition of sodium ions increased the drainage rate and total volume of discharged water. Moreover, the precipitation of copper ions increased the voltage loss near the cathode. PMID- 30243876 TI - Impact of postoperative intravenous fluid administration on complications following elective hepato-pancreato-biliary surgery. AB - BACKGROUND: The impact of perioperative intravenous fluid administration on surgical outcomes has been documented in literature, but not specifically studied in the context of hepato-pancreato-biliary (HPB) surgery. This study aimed to investigate the impact of postoperative intravenous fluid administration on intensive care unit (ICU), in this subgroup of patients. METHODS: A single-center retrospective cohort of 241 HPB patients was assessed, focusing on intravenous fluid administration in ICU, during the first 24 h. Intravenous fluid variables were compared to hospital stay and postoperative complications. Data were assessed using Spearman's correlation test for bivariate correlations and logistic regression for multivariate analysis. RESULTS: The median volume of intravenous fluid administered in the first 24 h postoperatively was 4380 mL, of which 2200 mL was crystalloid, 1500 mL colloid and 680 mL "other" fluid. Patients with one or more complications had a higher median total intravenous fluid input (4790 vs. 4300 mL), higher colloid volume (2000 vs. 1500 mL), lower urine output (1595 vs. 1900 mL) and greater overall fluid balance (+3040 vs.+2553 mL) than those without complications. There were correlations between total intravenous fluid volume administered (r = 0.278, P < 0.001), intravenous colloid input (r = 0.278, P < 0.001), urine output (r = -0.295, P < 0.001), positive fluid balance (r = 0.344, P < 0.001) and length of hospital stay. Logistic regression model was constructed to predict the occurrence of one or more complications; total intravenous fluid volume and overall fluid balance were both independent significant predictors (OR = 2.463, P = 0.007; OR = 1.001, P = 0.011; respectively). CONCLUSIONS: Administration of high volumes of intravenous fluids in the first 24 hours post-HPB surgery, along with higher positive fluid balance is associated with a higher rate of complications and longer hospital stay. Moreover, lower urine output is associated with longer hospital stay. Whether these are the cause of complications or the result of them remains unclear. PMID- 30243877 TI - Liver transplantation benefits selected patients with hilar cholangiocarcinoma and colorectal liver metastases. PMID- 30243878 TI - Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic fibrosis via the regulation of MMPs/TIMPs in mice. AB - BACKGROUND: Previous research suggested that insulin-like growth factor binding protein related protein 1 (IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) play an essential role in hepatic fibrogenesis by regulating homeostasis and remodeling of the extracellular matrix (ECM). However, the interaction between IGFBPrP1 and MMP/TIMP is not clear. The present study was to knockdown IGFBPrP1 to investigate the correlation between IGFBPrP1 and MMP/TIMP in hepatic fibrosis. METHODS: Hepatic fibrosis was induced by thioacetamide (TAA) in mice. Knockdown of IGFBPrP1 expression by ultrasound targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhibition of the Hedgehog (Hh) pathway by cyclopamine treatment, was performed in TAA-induced liver fibrosis mice. Hepatic fibrosis was determined by hematoxylin and eosin and Sirius red staining. Hepatic expression of IGFBPrP1, alpha-smooth muscle actin (alpha-SMA), transforming growth factor beta 1 (TGFbeta1), collagen I, MMPs/TIMPs, Sonic Hedgehog (Shh), and glioblastoma family transcription factors (Gli1) were investigated by immunohistochemical staining and Western blotting analysis. RESULTS: We found that hepatic expression of IGFBPrP1, TGFbeta1, alpha-SMA, and collagen I were increased longitudinally in mice with TAA-induced hepatic fibrosis, concomitant with MMP2/TIMP2 and MMP9/TIMP1 imbalance and Hh pathway activation. Knockdown of IGFBPrP1 expression, or inhibition of the Hh pathway, reduced the hepatic expression of IGFBPrP1, TGFbeta1, alpha-SMA, and collagen I and re-established MMP2/TIMP2 and MMP9/TIMP1 balance. CONCLUSIONS: Our findings suggest that IGFBPrP1 knockdown attenuates liver fibrosis by re-establishing MMP2/TIMP2 and MMP9/TIMP1 balance, concomitant with the inhibition of hepatic stellate cell activation, down-regulation of TGFbeta1 expression, and degradation of the ECM. Furthermore, the Hh pathway mediates IGFBPrP1 knockdown-induced attenuation of hepatic fibrosis through the regulation of MMPs/TIMPs balance. PMID- 30243879 TI - Tumor-stromal cross-talk modulating the therapeutic response in pancreatic cancer. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor's high chemoresistance. Cancer associated fibroblasts (CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor-stromal interactions when exposed to three well-known chemotherapeutic agents. METHODS: Monocultures, indirect and direct co-cultures of two PDAC cell lines (AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the gamma-secretase-inhibitor (GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed. RESULTS: On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma (CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co cultures of cancer cells with CAFs. A change in the morphology of direct co cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor-stromal interaction more complex. CONCLUSIONS: CAFs are highly chemoresistant. Direct cell-cell contact and high levels of IL-6 correlate with a high chemoresistance. PMID- 30243880 TI - Food Protein-Induced Enterocolitis Syndrome Food Challenges: Experience from a Large Referral Center. AB - BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE mediated food allergy that is diagnosed based on clinical findings, but can be confirmed with oral food challenge (OFC). OFC is more often performed to assess the development of tolerance. Most studies describing OFCs in FPIES are limited in size. OBJECTIVE: We sought to describe our experience with OFCs using our FPIES protocol. Patients were given one-third of serving size with a 4-hour observation period, followed by home titration to full dose. METHODS: We conducted a retrospective chart review of patients who underwent OFC via the FPIES protocol from 2014 to 2017. Data regarding the history of reaction, age at the time of challenge, and reactions during challenge or with home introduction were collected. RESULTS: A total of 169 OFCs were completed under the FPIES protocol, in 119 patients to 19 different foods. Thirty challenges (18%) were positive, with 17 challenges (10%) during initial challenge and 13 (7.7%) during home dosing. Most reactions during initial challenge required intravenous fluids (IVF), but hypotension was uncommon. One hundred thirty-nine (82%) OFCs were negative with home introduction, indicating tolerance to the challenged foods. The mean age of passing a challenge to milk, soy, and grain was earlier than that of other solid foods. CONCLUSIONS: Our data suggest that our FPIES OFC protocol is safe. Early administration of IVF may prevent the development of hypotension. It is difficult to stratify the risk of severe or delayed reaction based on patient characteristics, and more data are needed to identify those appropriate for home introduction. PMID- 30243881 TI - The Utilization of Metal Augments Allows Better Biomechanical Reconstruction of the Hip in Revision Total Hip Arthroplasty With Severe Acetabular Defects: A Comparative Study. AB - BACKGROUND: Reconstructing the normal hip biomechanics is important for a successful revision total hip arthroplasty (THA). Little is known about whether using metal augments in revision THA is biomechanically superior to traditional techniques. METHODS: A retrospective review was conducted on 74 consecutive THAs revised using metal augments with a cementless hemispherical cup and 77 consecutive THAs revised using the jumbo cup, all with a minimum 2-year follow up. Biomechanical parameters were measured before and immediately after the revision. Radiological and clinical outcomes at follow-ups were also evaluated. RESULTS: The metal augment group had a reconstructed center of rotation (COR) that was 6.5 mm closer to the anatomic COR in height (P < .001), had 3.6 m smaller cup size (P < .001), and had 5.7 mm less head-cup difference (P < .001). Moreover, there was a reconstructed COR that was much closer to the anatomic COR (vertical distance: 1.8 vs 14.1 mm, P < .001; horizontal distance: -2.1 vs 7.9 mm, P = .013), had 4.1 mm greater femoral offset (P = .006), and had 8 mm less leg length discrepancy (P = .035) in the subgroup of Paprosky type III bone defects when compared to the jumbo cup group. All cup-augment constructs were radiologically stable with a higher mean postoperative Harris Hip Score (P = .012). One jumbo cup was radiologically unstable. CONCLUSION: In revision THA, utilizing metal augments helps to restore the COR position more precisely, avoid using a larger cup, reduce head-cup difference, rebuild femoral offset, and decrease leg length discrepancy, particularly with Paprosky type III bone defects. Moreover, it provides satisfactory radiological and clinical outcomes in the short term. PMID- 30243882 TI - Machine Learning and Primary Total Knee Arthroplasty: Patient Forecasting for a Patient-Specific Payment Model. AB - BACKGROUND: Value-based and patient-specific care represent 2 critical areas of focus that have yet to be fully reconciled by today's bundled care model. Using a predictive naive Bayesian model, the objectives of this study were (1) to develop a machine-learning algorithm using preoperative big data to predict length of stay (LOS) and inpatient costs after primary total knee arthroplasty (TKA) and (2) to propose a tiered patient-specific payment model that reflects patient complexity for reimbursement. METHODS: Using 141,446 patients undergoing primary TKA from an administrative database from 2009 to 2016, a Bayesian model was created and trained to forecast LOS and cost. Algorithm performance was determined using the area under the receiver operating characteristic curve and the percent accuracy. A proposed risk-based patient-specific payment model was derived based on outputs. RESULTS: The machine-learning algorithm required age, race, gender, and comorbidity scores ("risk of illness" and "risk of morbidity") to demonstrate a high degree of validity with an area under the receiver operating characteristic curve of 0.7822 and 0.7382 for LOS and cost. As patient complexity increased, cost add-ons increased in tiers of 3%, 10%, and 15% for moderate, major, and extreme mortality risks, respectively. CONCLUSION: Our machine-learning algorithm derived from an administrative database demonstrated excellent validity in predicting LOS and costs before primary TKA and has broad value-based applications, including a risk-based patient-specific payment model. PMID- 30243883 TI - Inhibitory and facilitatory connections from dorsolateral prefrontal to primary motor cortex in healthy humans at rest-An rTMS study. AB - BACKGROUND: The human motor system consists of several divisions in the frontal lobes. The physiological function of projections from the dorsolateral prefrontal cortex (DLPFC) to the primary motor cortex (M1) remains elusive. Here, we introduce theta burst stimulation (TBS)-based protocols to target inhibitory and facilitatory connections in the DLPFC-M1 network. METHODS: Intermittent and continuous TBS with 600 pulses (iTBS600/cTBS600) were applied to the left DLPFC. Resting motor threshold (RMT), motor-evoked potential (MEP), and short-interval intracortical inhibition (SICI) were measured with transcranial magnetic stimulation to the ipsilateral M1. RESULTS: iTBS600 to the DLPFC decreased MEP amplitude in M1. Conversely, cTBS600 to the DLPFC increased MEP amplitude in M1. The peak decrease in MEP amplitude after iTBS600 was negatively correlated with the peak increase in MEP amplitude after cTBS600. There were no significant effects in the control group with the sham stimulation. DISCUSSION: These results provide insight into the regulation of inhibitory and facilitatory balance from the local DLPFC to M1. TBS modulation in one brain region will induce interactions within other remote cortical areas. Our results enable better understanding of how cognitive resources are allocated to achieve optimal control of motor output. PMID- 30243884 TI - Elevated microRNA-520d-5p in the serum of patients with Parkinson's disease, possibly through regulation of cereloplasmin expression. AB - Iron metabolism dysfunction and redox-active iron-induced oxidative stress in the brain may contribute to the pathogenesis of Parkinson's disease. We have previously demonstrated that reduced serum ceruloplasmin level exacerbates nigral iron deposition in Parkinson's disease, although the underlying cause of the low serum ceruloplasmin level in Parkinson's disease remains unknown. Fluorescent quantitative real-time polymerase chain reaction analysis revealed that patients with Parkinson's disease had higher serum levels of microRNA (miR)-520d-5p than controls (p = 0.0011). Patients with Alzheimer's disease or multiple system atrophy did not have significantly elevated miR-520d-5p levels. Expression of miR 520d-5p did not correlate with disease severity or the motor phenotype of Parkinson's disease. Luciferase assays confirmed that miR-520d-5p was associated with ceruloplasmin gene expression, as predicted by the TargetScan tool and miRBase. In vitro experiments showed that miR-520d-5p reduced ceruloplasmin gene expression in the U251 astrocyte cell line. Our data suggest that miR-520d-5p may be a potential regulator of ceruloplasmin gene expression in vitro. PMID- 30243885 TI - Distinct microRNA and mRNA responses elicited by ecdysone, diapause hormone and a diapause hormone analog at diapause termination in pupae of the corn earworm, Helicoverpa zea. AB - Ecdysone, diapause hormone and a diapause hormone analog are all capable of breaking pupal diapause and prompting initiation of adult development in the cotton earworm, Helicoverpa zea. In this study we asked whether these three chemically-distinct diapause terminators elicit the same effect on expression of a collection of microRNAs and transcripts encoding components of the ecdysone signaling pathway. Injection of all three endocrine agents resulted in downregulation of one miRNA, miR-277-3p, a miRNA previously linked to the insulin/FOXO signaling pathway, and all three agents promoted upregulation of spook, a member of the ecdysone biosynthesis pathway, and iswi, an ecdysone responsive transcript. Other miRNA and mRNA responses varied depending on the agent used to terminate diapause, thus suggesting that different endocrine pathways and mechanisms can lead to the same final developmental response. PMID- 30243886 TI - Age-related nomograms of serum anti-Mullerian hormone levels in female monkeys: Comparison of rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys. AB - AMH is regarded as a promising predictor for ovarian reserve in humans and non human primate, and widely used in human medicine to predict ovarian response to gonadotropin, menopause and premature ovarian failure. However, large data set on the range of AMH levels in nonhuman primates is still scarce, which limited its applications largely. In this study, age-related AMH nomograms of rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) were produced and compared. 219 rhesus and 529 cynomolgus monkeys ranging from infancy to adult were included. In total, the mean serum AMH levels in cynomolgus monkeys were higher than that of rhesus monkeys (14.6 +/- 5.3 ng/ml vs 9.5 +/- 6.0 ng/ml, P < 0.001). AMH was inversely correlated with age (r = -0.371, P < 0.001) in rhesus, while the negative correlation did not reach statistical significance in cynomolgus monkeys (r = -0.044, P = 0.156). The maximum mean AMH levels were attained at the subgroup of 4-11 yr and the lowest AMH levels were obtained at the subgroup of ?12 yr in both primates, corresponding to their fertility potential. In rhesus monkeys, from 1 to 11 years old, AMH level remained stable (1-3 yr: beta = 2.784, P = 0.340; 4-11 yr: r = 0.100, P = 0.110) whereas from 12 yr onward, an inverse correlation between AMH and age (r = -0.450, P = 0.02) was observed. Similarly, AMH appeared stable from 1 to 3 yr (beta = -2.289, P = 0.429) and showed an inverse correlation with age (r = -0.521, P < 0.001) from 12 yr onward in cynomolgus monkeys, while a positive correlation was observed (r = 0.156, P = 0.001) from 4 to 11 yr. AMH levels were relatively stable across the menstrual cycle in both primates and no seasonal difference for AMH levels was observed in rhesus monkeys. Body mass index did not affect serum AMH levels in both primates. Our nomograms of serum AMH provide a reference guide on AMH longitudinal distribution by age for Macaca monkeys and might facilitate its applications. PMID- 30243887 TI - Hydrogen ameliorates chronic intermittent hypoxia-induced neurocognitive impairment via inhibiting oxidative stress. AB - Obstructive sleep apnea (OSA) is a very common breathing and sleep disorder characterized by intermittent hypoxia (IH), which is often associated with behavioral and neurocognitive functions impairment. Hydrogen (H2), as a novel and effective antioxidant, is reported to be a potential neuroprotective agent. The aim of this study is to investigate whether H2 could improve CIH-induced neurocognitive impairment and the related mechanism. Rats were exposed to IH for 5 weeks (8 h/day) and/or inhalation of H2 gas 2 h/day. Morris Water Maze test was used to appraise the spatial reference and working memory. The oxidative stress was evaluated through the level of MDA and SOD and apoptosis of hippocampal neurons was assayed with Bcl-2/Bax ratio and TUNEL staining. Our results showed that H2 treatment improved the CIH-induced spatial learning and memory impairments. Moreover, inhalation of H2 gas reduced the level of MDA and increased in the activity of SOD, indicating suppressed CIH-induced oxidative stress. In addition, H2 could increase expression of Bcl-2/Bax ratio and inhibited neurons apoptosis in hippocampus. In conclusion, these results suggest that inhalation of H2 could attenuate the CIH-induced neurocognitive functions impairment via anti-oxidant and anti-apoptosis effect. Additional, our findings may provide a potential therapeutic for neurocognitive diseases in patients with OSA. PMID- 30243888 TI - Variability in strain distribution in the mice tibia loading model: A preliminary study using digital volume correlation. AB - It is well known that bone has an enormous adaptive capacity to mechanical loadings, and to this extent, several in vivo studies on mouse tibia use established cyclic compressive loading protocols to investigate the effects of mechanical stimuli. In these experiments, the applied axial load is well controlled but the positioning of the hind-limb between the loading endcaps may dramatically affect the strain distribution induced on the tibia. In this study, the full field strain distribution induced by a typical in vivo setup on mouse tibiae was investigated through a combination of in situ compressive testing, uCT scanning and a global digital volume correlation (DVC) approach. The precision of the DVC method and the effect of repositioning on the strain distributions were evaluated. Acceptable uncertainties of the DVC approach for the analysis of loaded tibiae (411 +/- 58uE) were found for nodal spacing of approximately 50 voxels (520 um). When pairs of in situ preloaded and loaded images were registered, low variability of the strain distributions within the tibia were seen (range of mean differences in principal strains: 585-1800uE). On contrary, larger differences were seen after repositioning (range of mean differences in principal strains: 2500-5500uE). To conclude, these preliminary results on thee specimens showed that the DVC approach applied to the mouse tibia can be precise enough to evaluate local strain distributions under loads, and that repositioning of the hind-limb within the testing machine can induce large differences in the strain distributions that should be accounted for when modelling this system. PMID- 30243889 TI - Multiple Biomarker Testing Tissue Consumption and Completion Rates With Single gene Tests and Investigational Use of Oncomine Dx Target Test for Advanced Non Small-cell Lung Cancer: A Single-center Analysis. AB - INTRODUCTION: First-line targeted therapies have been developed for advanced non small-cell lung cancer (NSCLC). However, small biopsy samples pose a challenge to testing all relevant biomarkers. The present study characterized clinician ordered single-gene lung cancer testing and evaluated tissue stewardship and the ability to successfully determine mutation status with single-gene testing or investigational use of the Oncomine Dx Target Test. MATERIALS AND METHODS: Clinician-submitted orders for 3659 single-gene tests (EGFR, ALK, ROS1, BRAF, KRAS, ERBB2, MET, RET, FGFR1) across 1402 samples at a large US-based commercial reference laboratory and 169 investigational Oncomine Dx Target Tests were retrospectively evaluated. The testing success rates and tissue consumption were evaluated by sample type, test type, and number of single-gene tests per sample. RESULTS: The large majority of lung tissue samples submitted for clinical testing were small (70.5% core needle biopsies; 10.0% fine needle aspirations). With single-gene testing, mutation status was successfully reported for >= 1 biomarker for 88.4% of the clinical samples. The success rates decreased and tissue consumption increased with testing of additional biomarkers. Investigational Oncomine Dx Target Tests were permitted 1 tissue slide each and demonstrated success rates similar to single-gene testing for >= 5 biomarkers on core needle biopsies, >= 4 biomarkers on fine needle aspirations, and >= 2 biomarkers on surgical resection specimens. CONCLUSION: Tissue stewardship is important to enable successful completion of genetic testing and informed NSCLC treatment decisions. Preliminary assessment of the investigational Oncomine Dx Target Test suggests it could facilitate access to multiple biomarker testing using small tissue samples to support therapy decisions for patients with advanced NSCLC. PMID- 30243890 TI - Full-length next-generation sequencing of HLA class I and II genes in a cohort from Thailand. AB - The human leukocyte antigen (HLA) genes are highly variable and are known to play an important role in disease outcomes, including infectious diseases. Prior knowledge of HLA polymorphisms in a population usually forms the basis for an effective case-control study design. As a prelude to future disease association analyses, we report HLA class I and II diversity in 334 unrelated donors from a Dengue vaccine efficacy trial conducted in Thailand. Long-range PCR amplification of six HLA loci was performed on DNA extracted from saliva samples. HLA-A, -B, C, -DPB1, -DQB1 and -DRB1 were genotyped using a next-generation sequencing method presented at the 17th International HLA and Immunogenetics Workshop. In total, we identified 201 HLA alleles, including 35 HLA-A, 57 HLA-B, 28 HLA-C, 24 HLA-DPB1, 21 HLA-DQB1 and 36 HLA-DRB1 alleles. Very common HLA alleles with frequencies greater than 10 percent were A*11:01:01, A*33:03:01, A*24:02:01, B*46:01:01, C*07:02:01, C*01:02:01, C*08:01:01, DPB1*05:01:01, DPB1*13:01:01, DPB1*04:01:01, DPB1*02:01:02, DQB1*03:01:01, DQB1*05:02:01, DQB1*03:03:02, DRB1*12:02:01, DRB1*09:01:02, and DRB1*15:02:01. A novel HLA allele, B*15:450, had a non-synonymous substitution and occurred in more than one donor. Population based full-length NGS HLA typing is more conclusive and provides a sound foundation for exploring disease association in a given population. PMID- 30243891 TI - Why Radiology Residents Experience Burnout and How to Fix It. PMID- 30243892 TI - Design and Validation of a Peer-Teacher-Based Musculoskeletal Ultrasound Curriculum. AB - RATIONALE AND OBJECTIVES: To design and validate a peer-teacher based musculoskeletal ultrasound curriculum for radiology residents. MATERIALS AND METHODS: A musculoskeletal ultrasound curriculum with hands-on scanning workshops was designed for radiology residents. Prior to the workshops, several residents received 3 hours of hands-on training in ultrasound scanning technique which was overseen by an attending musculoskeletal radiologist; these "peer teachers" then led small-group hands-on scanning during the workshops. Participants performed diagnostic ultrasound examinations at the conclusion of the workshops to assess skill acquisition and 2 months following the workshops to quantify skill retention. Participants also completed surveys to determine confidence in performing musculoskeletal ultrasound examinations. Median scores and interquartile range (25-75%) were calculated, and t test was used to compare results. RESULTS: Thirty seven residents from all years of training and six senior resident or fellow peer teachers participated in four workshops. Diagnostic ultrasound images were obtained in 100% at the conclusion of the workshop and in 79% 2 months later. Prior to the workshops, residents reported low level of musculoskeletal ultrasound knowledge (median 2, interquartile ranges 1-2), and low confidence in performing (1, 1-2) and interpreting (1, 1-2) musculoskeletal ultrasound examinations. There was a significant increase in knowledge (3, 3-4) and confidence performing (3, 3-4) and interpreting (3, 3-4) studies following the workshops (p < 0.001 for all comparisons). CONCLUSION: Hands-on musculoskeletal ultrasound workshops, utilizing a peer teacher led small group format is an effective method of teaching scanning skills to residents. There was excellent skill acquisition, good skill retention, and significant increase in confidence performing and interpreting these studies following completion of the curriculum. PMID- 30243893 TI - Motor improvement requires an increase in presynaptic protein expression and depends on exercise type and age. AB - The aging process is associated with structural and functional changes in the nervous system. Considering that exercise can improve the quality of life of the elderly, the aim of this study was to evaluate the effects of exercise protocols with different motor demands on synaptic protein expression (i.e., synapsin-I and synaptophysin). Cognitive and motor brain areas and the motor performance of adult and aged animals were analyzed. Adult (7 months old) and aged (18 months old) male Wistar rats were used. Animals were divided into the following groups: treadmill exercise (TE, rhythmic motor activity), acrobatic exercise (AE, complex motor activity) and sedentary (SED, control). The animals were exposed to exercise 3 times per week for 8 weeks. The brains were collected for immunohistochemistry and immunoblotting assays. Our results showed that both types of exercise induced changes in motor performance and synaptic protein expression in adult and aged animals. However, acrobatic exercise promoted a greater number of changes, mainly in the aged animals. In addition, protein expression changes occurred in a greater number of brain areas in the aged animals than in adult animals. There were clear increases in synapsin-I expression in all areas analyzed of aged animals only after acrobatic exercises. On the other hand, synaptophysin increased in the same areas but with both types of exercise. Thus, in general, our data suggest that even at advanced ages, when the aging process is already in progress, initiating physical training may be beneficial to generate neuroplasticity that can improve motor performance. PMID- 30243894 TI - Analysis of aging-dependent changes in taste sensitivities of the senescence accelerated mouse SAMP1. AB - To investigate aging-dependent changes in taste sensitivities, we performed behavioral tests regarding taste sensitivity among young and old SAMP1 mice. In this senescence-accelerated mice model, dramatic changes in taste sensitivities were observed at least 70 weeks old. As for in a brief access test, old mice showed significantly increased taste sensitivity to bitter, salty, sweet, and umami tastes. On the other hand, in a two-bottle test, avoidance of bitter and salty tastes increased, while preference for umami decreased with aging. To investigate the participation of peripheral taste detection systems in the observed changes, we analyzed both the expression of representative taste-related molecules and also turnover rates of taste bud cells. The mRNA expressions of the bitter taste receptor Tas2r105 and its coupled G protein gustducin were significantly decreased with aging. However, the majority of molecules tested did not show significant expression changes. In addition, no significant differences in the turnover rates of taste bud cells were observed between the two age groups. These results suggest that the changes in taste sensitivity of SAMP1 mice due to aging are caused by factors other than the deterioration of taste detection systems in the oral cavity. PMID- 30243895 TI - Corrigendum to "Mid- to long-term survivorship of oxidised zirconium total knee replacements performed in patients under 50 years of age" [Knee 25 (2018) 617 622]. PMID- 30243896 TI - Giant duodenal Brunner's gland hamartoma successfully treated via endoscopic mucosal resection. AB - We describe a patient with a giant Brunner's gland hamartoma in the duodenum who was safely treated by endoscopic mucosal resection (EMR). A 64-year-old woman visited our hospital for a workup of severe anaemia (haemoglobin level: 5 g/dL). Oesophagogastroduodenoscopy revealed a large pedunculated and elongated polypoid lesion measuring approximately 70 mm in longitudinal diameter, located at the anterior wall of the duodenal bulb. We diagnosed her as having gastrointestinal bleeding originating from this lesion. Although we considered surgical intervention initially, en bloc EMR, a less invasive treatment, was finally accomplished safely by placing endoclips before resection. The histological examination of the specimen revealed a hamartomatous lesion consisting of Brunner's glands with cystic change and adipose tissue separated by the septa of smooth muscle fibers. Ultimately, we diagnosed her as having Brunner's gland hamartoma. Notably, there were tiny foci of heterotopic pancreatic tissue containing islets and duct epithelium. Although this type of lesion is benign, a larger one may cause clinical symptoms such as obstruction or bleeding, and thus, local resection is preferable. PMID- 30243897 TI - Expression of epidermal growth factor receptor (EGFR) in colorectal cancer: An immunohistochemical study. AB - BACKGROUND AND STUDY AIM: The epidermal growth factor receptor (EGFR) plays an important role in tumourigenesis and tumour progression of colorectal cancer (CRC) and leads to the activation of intracellular signaling pathways. The use of anti-EGFR-targeted therapy has increased for patients with metastatic CRC. Today, the clinical utility of immunohistochemistry has remained somewhat inconclusive. It is based on EGFR screening methods using paraffin-embedded tumour specimen to select patients eligible for treatment. There is still lack of agreement on reproducible scoring criteria for EGFR immunohistochemistry has in various clinical trials. PATIENTS AND METHODS: We retrospectively reviewed 36 CRC patients who underwent surgeries during 2011 in Habib Thameur hospital in Tunis. We analyzed the immunohistochemical overexpression of EGFR using a score based on immunostaining intensity. In addition, we analyzed the correlation between this overexpression and patients' clinicopathologic parameters. RESULTS: The positive expression rate of EGFR was 78% (28/36). Using the immunoreactivity score, 21 cases were considered low grade expression and 15 tumours were high grade. Immunohistochemical expression of EGFR showed a significant difference with tumour's location (p = 0.034) and vascular invasion (p = 0.03). This expression was not significantly associated with age, gender, tumour size, histological type, grade, TNM staging and perineural invasion. CONCLUSIONS: EGFR expression by immunohistochemistry in CRC is variably correlated with clinicopathological parameters. Its assessment by this method has still not proved its predictive value. PMID- 30243898 TI - Effects of 8-week kettlebell training on body composition, muscle strength, pulmonary function, and chronic low-grade inflammation in elderly women with sarcopenia. AB - OBJECTIVES: To examine the effect of kettlebell training on body composition, muscle strength, pulmonary function, and chronic low-grade inflammatory markers among elderly people with sarcopenia. DESIGN: Randomized controlled trial. SETTING: Community center and research center. PARTICIPANTS: A total of 33 elderly women with sarcopenia (aged 65-75 years) were recruited. INTERVENTION: The participants were randomly assigned to a kettlebell training (KT) group or a control (CON) group. The KT group received an 8-week training intervention involving 60-min sessions twice a week, whereas the CON group members continued their daily lifestyles without participating in any exercise training. Four weeks of detraining were organized to observe the retention effect of the training program on the KT group. MEASUREMENTS: The participants' body composition, muscle strength, pulmonary function, and chronic low-grade inflammatory markers were measured and analyzed before training (at Week 0, W0), after 8 weeks of training (at Week 8, W8), and after 4 weeks of detraining (at Week 12, W12). RESULTS: In the KT group, appendicular skeletal muscle mass (ASM) and the sarcopenia index measured at W8 and W12 were significantly higher than those at W0(p = .004; p = .005). At W8 and W12, the sarcopenia index was significantly higher in the KT group than the CON group(p = .020; p = .019). In the CON group, the skeletal muscle mass levels measured at W8 and W12 were significantly lower than that at W0(p = .029; p = .005), and the ASM and the sarcopenia index measured at W8 were significantly lower than those at W0(p = .037; p = .036). Additionally, the measured left handgrip strength(p = .006), back strength(p = .011; p = .018), and peak expiratory flow (PEF) (p = .008; p = .006) were significantly higher in the KT group than the CON group at W8 and W12. At W8, the measured right handgrip strength was significantly higher in the KT group than the CON group(p = .043). In the KT group, the back strength and PEF levels measured at W8 and W12 were significantly higher than those at W0(p = .000; p = .004), and the left and right handgrip strength levels at W8 were significantly higher than those at W0(p = .004; p = .013). By contrast, in the CON group, the left(p = .004; p = .006)and right(p = .002; p = .004)handgrip strength levels and PEF(p = .018; p = .012) measured at W8 and W12 were significantly lower than those at W0. Moreover, compared with the high-sensitivity C-reactive protein (hs-CRP) levels measured at W0, those measured at W8 and W12 were significantly lower in the KT group(p = .006; p = .013)but significantly higher in the CON group(p = .005; p = .009). There was no significant difference in hs-CRP, IL-6, TNF-alpha between the KT and CON group. CONCLUSION: For elderly people with sarcopenia, participating in kettlebell training significantly increases the sarcopenia index, grip strength, back strength, and PEF. In addition, the retention effect of the training program continued after 4 weeks of detraining. PMID- 30243899 TI - Progesterone improves functional outcomes after transient focal cerebral ischemia in both aged male and female rats. AB - Progesterone hormone (P4) is a promising agent against strokes because post ischemic administration of P4 exerts neuroprotective effects in several young and aged animal models of stroke. However, in contrast to a majority of the studies using male animals, female animals remain underrepresented. In addition, we do not know whether the same administration way of P4 is effective in both male and female animals because there are gender different responses to steroid hormones and stroke. In this study, we thus evaluated long-term histological and functional outcomes in the same treatment with P4 in both 18-month old male and age-matched female rats subjected to transient middle cerebral artery occlusion (MCAO). MCAO aged male and female rats were given a subcutaneous injection of P4 (4 mg/kg) 6 h after MCAO followed by once daily for successive 7 days. The post ischemic administration of P4 significantly improved the impairments of spatial working memory and motor coordination 28-29 days after MCAO in both aged male and age-matched female rats. However, the P4 administration slightly but not significantly reduced infarct sizes 30 days after MCAO in aged female rats, in contrast to significant better histological outcome in P4-treated aged males. On the other hand, these histological and behavioral analyses showed no adverse effects of P4 in aged rats of both sexes. Collectively, our study provides preclinical evidence to prompt further preclinical studies for post-stroke treatment with P4 and the translation of its clinical trials in old stroke patients of both sexes. PMID- 30243900 TI - Comparison between local and national epidemiology of antimicrobial resistance using the JANIS data. AB - The Japanese Ministry of Health, Labor and Welfare established the Japanese Nosocomial Infection Surveillance (JANIS) system in July 2000 to provide nationwide epidemiological information. The data of all clinically isolated bacteria at participating hospitals were collected, treated according to a protocol, and analyzed by the JANIS office. Nationwide and individual hospital data were reported to participating hospitals monthly and yearly. In this study, we surveyed local antimicrobial resistance of clinically isolated bacteria in Kawasaki City between 2014 and 2016 using JANIS data. There were 8, 14, and 16 major hospitals in Kawasaki City that participated in the surveillance in 2014, 2015, and 2016, respectively. The data were returned to each hospital monthly from JANIS, totaled for Kawasaki City, and compared with the nationwide data. The Kawasaki City data were approximately the same as the nationwide data, and most resistant bacteria decreased gradually over the three years examined. The incidence of methicillin-resistant Staphylococcus aureus (MRSA) in S. aureus (Kawasaki City, Japan) was (56.6%, 48.8%), (50.5%, 47.9%), and (51.6%, 46.9%), the incidence of penicillin-resistant Streptococcus pneumoniae (PRSP) in S. pneumoniae, was (43.4%, 37.5%), (34.3%, 38.0%), and (31.4%, 36.9%) in 2014, 2015, and 2016, respectively. Therefore, in Kawasaki City the incidence of MRSA was relatively higher and that of PRSP was relatively lower than the nationwide incidences. Both continuous local and national surveillance are important for monitoring antimicrobial resistance in clinical isolates. The JANIS database is a powerful tool for the epidemiology of nosocomial infections in Japanese hospitals. PMID- 30243901 TI - Fungal endocarditis after transcatheter aortic valve replacement (TAVR): Case report and review of literature. AB - The reported number of transcatheter aortic valve replacement-associated infective endocarditis (TAVR-IE) cases has been increasing worldwide, but information about the incidence and clinical features of fungal TAVR-IE is quite limited. We present a patient who acquired TAVR-IE caused by Candida parapsilosis four month after TAVR, who was successfully treated redo-aortic valve replacement and prolonged antifungal therapy. PMID- 30243903 TI - Increased co-contraction of arm adductors is associated with a favorable course in subacromial pain syndrome. AB - BACKGROUND: Enhancement of arm adductor activity during abduction (ie, adductor co-contraction), may be effective in the treatment of subacromial pain syndrome (SAPS). We assessed whether an increase of adductor co-contraction is associated with a favorable course of SAPS. METHODS: At baseline and after nearly 4 years of follow-up, electromyography of the latissimus dorsi (LD), teres major (TM), pectoralis major, and deltoid muscle was obtained during isometric abduction and adduction tasks in 26 patients with SAPS. Changes in co-contraction were assessed with change in the activation ratio (DeltaAR). The AR ranges between -1 and 1, where lower values indicate more co-contraction. Clinical course was determined from an anchor question (reduced, persistent, or increased complaints), the visual analog scale for pain (VAS), and the Western Ontario Rotator Cuff score (WORC). RESULTS: In patients indicating persistent complaints (31%), the VAS and WORC remained stable. In patients who indicated reduced complaints (69%), the VAS reduced (z score, -3.4; P = .001) and WORC increased (z score, 3.6; P < .001). Unchanged ARs associated with complaints persistence, whereas decreased AR of the LD (DeltaARLD, -0.21; 95% confidence interval [CI], -0.36 to -0.06) and TM (DeltaARTM, -0.17; 95% CI, -0.34 to -0.00) coincided with reduced complaints. There was a significant between-group difference in DeltaARLD (-0.35; 95% CI, 0.60 to 0.10) and DeltaARTM (-0.36; 95% CI, -0.66 to -0.05). CONCLUSIONS: Increased co-contraction of the LD and TM is associated with a favorable course of SAPS. This may be explained by widening of the subacromial space accomplished by adductor co-contraction. PMID- 30243902 TI - The functional potency of natural killer cells in response to IL-2/IL-15/IL-21 stimulation is limited by a concurrent upregulation of Tim-3 in bladder cancer. AB - For reasons not completely clear, natural killer (NK) cells from tumor patients displayed multiple exhaustion features and could not be completely restored even when the inhibitory signals from the intratumoral environment had ceased to exist. Here, we found that the circulating NK cells from bladder cancer patients presented significantly reduced cytotoxicity than the circulating NK cells from healthy volunteers. This impairment in cytotoxicity resulted in part from an overrepresentation of Tim-3+ NK cells in bladder cancer patients. Interestingly, patients with higher frequency of Tim-3+ NK cells tended to present higher frequency of Gal-9+ cells in tumor. Exogenous Gal-9 significantly reduced the cytotoxicity of Tim-3+, but not Tim-3-, NK cells. Patients with better prognosis presented lower levels of Tim-3+ NK cells and Gal-9+ tumor cells. We then attempted to improve the cytotoxicity of NK cells using a combination of exogenous cytokines. IL-2 + IL-15 and IL-2 + IL-21 significantly enhanced, but could not completely restore, the cytotoxicity of NK cells in bladder cancer patients. Notably, when the cytokine concentration increased from intermediate levels to high levels, the cytotoxicity of NK cells from healthy volunteers significantly increased with a strong upward trend, whereas the cytotoxicity of NK cells from bladder cancer patients plateaued at intermediate levels. Further examination revealed that high cytokine concentration significantly increased the Tim-3 expression in NK cells from bladder cancer patients. Blocking Tim-3 not only improved the cytotoxicity of NK cells from bladder cancer patients, but also eliminated the plateauing effect when the NK cells were stimulated with high concentrations of cytokines. Together, these data suggested that proinflammatory cytokines could moderately improve NK cell cytotoxicity in bladder cancer patients. However, the effect was limited due to a concurrent upregulation of Tim 3. PMID- 30243904 TI - Aneurysmal bone cyst of the clavicle: a series of 13 cases. AB - BACKGROUND: Aneurysmal bone cyst (ABC) is a benign but locally aggressive bone tumor occurring most commonly in the first 2 decades of life. The clavicle is a rare location for tumors, and ABCs of the clavicle have been sparsely described in the literature. We present the largest known series of ABCs of the clavicle to describe this rare condition. METHODS: Patients were identified retrospectively from an orthopedic oncology database to obtain demographic, diagnostic, and treatment information. A literature search was performed to identify all English language reports of ABC of the clavicle. RESULTS: We identified 13 patients with ABC of the clavicle, 77% of which were in the acromial end. Most patients (77%) presented with pain or swelling or both. The initial treatment in 11 patients was by curettage, with or without allograft bone packing, and 1 underwent resection/reconstruction of the lateral clavicle. Seven patients (58%) had 1 or more recurrences at an average of 6 months, for which 2 were treated with partial resection of the clavicle. CONCLUSIONS: ABC of the clavicle is a rare condition that we found to occur most frequently in the acromial end of the bone. Most patients were initially treated with curettage and showed a higher rate of recurrence than in other locations. The unique anatomy of the clavicle makes resection a feasible and very functional option, especially if the coracoclavicular ligaments can be preserved. However, the potential resulting deformity may cause patients to opt for a less aggressive and, consequently, less effective treatment method. PMID- 30243905 TI - Ischemic stroke in atrial fibrillation patients: don't put the blame always on heart. PMID- 30243906 TI - The organization of tyrosine hydroxylase-immunopositive cells in the sparrow retina. AB - The purpose of this study was to identify tyrosine hydroxylase-immunopositive (TH+) cells in the sparrow retina using immunocytochemistry and quantitative analysis. All TH+ cells were conventional amacrine cells. Based on dendritic morphology, at least two types were observed. The first type had a single thick primary process that descended from the cell body and many densely beaded processes in substrata (s) 1, less beaded processes in s3, and spiny processes in s4/5 of the inner plexiform layer. The dendrites of the second type appeared similar in each layer, but it displayed several primary processes that spread laterally away from the soma before descending to the inner plexiform layer. The average density of TH+ cells was 37.48 +/- 1.97 cells/mm2 (mean +/- standard deviation; n = 4), and the estimated total number of TH+ cells was 3,061.25 +/- 192.79. The highest and lowest densities of TH+ cells were located in the central dorsotemporal retina and periphery of the ventronasal retina, respectively. TH+ cells did not express calbindin-D28 K, calretinin, or parvalbumin. These results suggest that all TH+ cells in specific amacrine cell subpopulations are involved in retinal information processing in both the ON and OFF sublaminae in sparrow retina. PMID- 30243907 TI - Stages and transitions in dendrite arbor differentiation. AB - Neurons connect through dendrite arbors to receive inputs from their appropriate partners. The branching pattern, size, and input distribution in the arbor determine neuron function. Complex nervous system activity depends on creating and wiring a wide diversity of neuron types, each with a characteristic arbor organization. Here we discuss how, by tracking arbor differentiation in vivo, a mature dendrite arbor pattern is derived from the compound outcome of a series of different stages of arbor elaboration. We highlight core stages of elaboration shared between different model systems, and how regulating the transformation between these stages controls the dendrite arbor differentiation process. Finally, we discuss how control over these transformations creates neuron type specific dendrite arbor morphologies, contributes to nervous system evolution, and is perturbed in disease. PMID- 30243908 TI - GABAergic inhibition reduces the impact of synaptic excitation on somatic excitation. AB - The effect of excitatory synaptic input on the excitation of the cell body is believed to vary depending on where and when the synaptic activation occurs in dendritic trees and the spatiotemporal modulation by inhibitory synaptic input. However, few studies have examined how individual synaptic inputs influence the excitability of the cell body in spontaneously active neuronal networks mainly because of the lack of an appropriate method. We developed a calcium imaging technique that monitors synaptic inputs to hundreds of spines from a single neuron with millisecond resolution in combination with whole-cell patch-clamp recordings of somatic excitation. In rat hippocampal CA3 pyramidal neurons ex vivo, a fraction of the excitatory synaptic inputs were not detectable in the cell body against background noise. These synaptic inputs partially restored their somatic impact when a GABAA receptor blocker was intracellularly perfused. Thus, GABAergic inhibition reduces the influence of some excitatory synaptic inputs on the somatic excitability. Numerical simulation using a single neuron model demonstrates that the timing and locus of a dendritic GABAergic input are critical to exert this effect. Moreover, logistic regression analyses suggest that the GABAergic inputs sectionalize spine activity; that is, only some subsets of synchronous synaptic activity seemed to be preferably passed to the cell body. Thus, dendrites actively sift inputs from specific presynaptic cell assemblies. PMID- 30243910 TI - Fatal Balamuthia mandrillaris brain infection associated with improper nasal lavage. AB - We report the case of a 69-year-old female who presented with a chronic nasal skin rash, new onset focal seizure, and a cerebral ring-enhancing lesion after a year of improper nasal irrigation. Despite aggressive and novel anti-amoebic treatment, she died as a result of a Balamuthia mandrillaris brain infection. PMID- 30243909 TI - aPKC-Mediated Persistent Increase in AMPA/NMDA Ratio in the VTA Participates in the Neuroadaptive Signal Necessary to Induce NAc Synaptic Plasticity After Cocaine Administration. AB - Chronic cocaine exposure produces enduring neuroadaptations in the brain's reward system. Persistence of early cocaine-evoked neuroadaptations in the ventral tegmental area (VTA) is necessary for later synaptic alterations in the nucleus accumbens (NAc), suggesting a temporal sequence of neuroplastic changes between these two areas. However, the molecular nature of the signal that mediates this sequential event is unknown. Here we used the behavioral sensitization model and the aPKC inhibitor of late-phase LTP maintenance, ZIP, to investigate if a persistent increase in AMPA/NMDA ratio plays a role in the molecular mechanism that allows VTA neuroadaptations to induce changes in the NAc. Results showed that intra-VTA ZIP microinfusion successfully blocked cocaine-evoked synaptic enhancement in the VTA and the expected AMPA/NMDA ratio decrease in the NAc following cocaine sensitization. ZIP microinfusions also blocked the expected AMPA/NMDA ratio increase in the NAc following cocaine withdrawal. These results suggest that a persistent increase in AMPA/NMDA ratio, mediated by aPKCs, could be the molecular signal that enables the VTA to elicit synaptic alterations in the NAc following cocaine administration. PMID- 30243911 TI - Specific cholecystitis: An unusual presentation of extrapulmonary tuberculosis. PMID- 30243912 TI - Comparison of the preventive effect of urethral cleaning versus disinfection for catheter-associated urinary tract infections in adults: A network meta-analysis. AB - BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) are the main cause of infectious complications in patients with indwelling urinary catheters (IDCs). However, the best cleaning methods for the prevention of CAUTIs have not been evaluated clearly in previous studies. METHODS: An electronic database search was performed, from inception to December 2017. Randomized controlled trials and quasi-experimental trials using different methods of urethral cleaning versus disinfection to prevent CAUTIs were considered. The study selection and data collection were performed independently by two reviewers. The risk of bias assessment was performed using the Cochrane risk of bias scale. The primary outcome was the incidence rates of CAUTIs. A network meta-analysis was conducted to compare the effect among the different methods of urethral cleaning versus disinfection to prevent CAUTIs. RESULTS: Thirty-three studies (6490 patients) with seven different methods of urethral cleaning versus disinfection were eligible for inclusion, and the data were summarized in the network meta analysis. No evidence of heterogeneity (P>0.05) was observed among the studies. The network meta-analysis showed that there was no difference in the incidence of CAUTIs when comparing the different urethral cleaning methods versus disinfection (P>0.05 for all). However, chlorhexidine ranked first in the results of the Bayesian analysis and is recommended for preventing CAUTIs. CONCLUSIONS: Current evidence suggests that there are no significant differences among different urethral cleaning versus disinfection methods with regard to CAUTI incidence rates. PMID- 30243913 TI - Alcoholism in internally displaced people of Colombia: An ecological study. PMID- 30243914 TI - The 5-HT3 receptor antagonist ondansetron potentiates the effects of the acetylcholinesterase inhibitor donepezil on neuronal network oscillations in the rat dorsal hippocampus. AB - Cognitive impairments in Alzheimer's disease (AD) have been associated with alterations in neuronal oscillatory activity, of which hippocampal theta and gamma oscillations are essential for the coordination of neuronal networks during cognitive functions. Cognitive deterioration in AD is delayed by symptomatic treatment with donepezil and other acetylcholinesterase inhibitors (AChEIs). However, the efficacy of symptomatic monotherapy is insufficient. Combining 5-HT receptor antagonists with AChEIs represents a promising new approach for symptomatic treatment of AD. The selective 5-HT3 receptor antagonist ondansetron decreases the activity of interneurons with a concomitant increase in the activity of pyramidal neurons in the hippocampus of freely moving rats. Additionally, 5-HT3 receptor antagonism modulates acetylcholine release in rat cortex and hippocampus. We investigated the effects of ondansetron alone and in combination with donepezil on hippocampal oscillations using in vivo electrophysiology. Neuronal network oscillations were recorded in the dorsal hippocampus during electrical stimulation of the brainstem pedunculopontine tegmental nucleus in urethane-anaesthetised rats. In addition, potential pharmacokinetic interactions between donepezil and ondansetron were assessed. Ondansetron alone did not affect hippocampal network oscillations. Donepezil dose dependently increased hippocampal theta and gamma power during PPT stimulation. Ondansetron (0.3 mg/kg, i.v.) potentiated theta and gamma responses to 0.2 mg/kg donepezil and prolonged theta and gamma responses to 0.3 mg/kg donepezil. These effects could not be attributed to pharmacokinetic interactions between the compounds. This study demonstrates that ondansetron potentiates the effects of donepezil on elicited neuronal oscillations and suggests that 5-HT3 receptor antagonists may be beneficial as adjunctive therapy to AChEIs for the symptomatic treatment of cognitive deficits in AD. PMID- 30243915 TI - Mechanism underlying NMDA blockade-induced inhibition of aggression in post weaning socially isolated mice. AB - When faced with stressful conditions, people with a tendency toward impulsive aggression may suddenly hurt others. We have previously shown that the blockade of NMDA receptors (NMDARs) within the ventral hippocampus (VH) produces anti aggressive effects. However, little is known about the mechanism for tamping down stress-provoked attack behavior. Here, we report that expression of brain-derived neurotrophic factor (BDNF) after inhibition of NMDARs in the VH is required for blunting stress-provoked attack behavior in post-weaning socially isolated mice. Administration of NMDAR antagonist MK-801 decreased the phosphorylated eukaryotic elongation factor 2 (p-eEF2) and increased BDNF expression in the VH. Infusion of eEF2 kinase inhibitor NH125 to the VH decreased attack behavior and increased BDNF expression. Knockdown of BDNF in the VH blocked the anti-aggressive effect of MK-801 and NH125. Furthermore, MK-801 rapidly increased the activity of protein phosphatase 2A (PP2A). Intra-VH infusion of PP2A inhibitor okadaic acid blocked the anti-aggressive effects of MK-801. These results suggest that blockade of NMDAR reduces attack behavior through increasing PP2A activity leading to dephosphorylation of eEF2 and an increase in BDNF expression. Our findings indicate that the enhancement of BDNF expression is beneficial for preventing impulsive aggression in at-risk beings. PMID- 30243916 TI - Head and neck cancer, quality of life, and determinant factors: a novel approach using decision tree analysis. AB - OBJECTIVE: The goal of the present study was to investigate health-related quality of life (HRQoL) and oral health-related quality of life (OHRQoL) in patients under treatment for head and neck cancer and to identify the associated factors. STUDY DESIGN: A cross-sectional study was conducted with 102 patients undergoing treatment for head and neck cancer at 2 medical centers. Participants answered a sociodemographic questionnaire and the Brazilian versions of the Medical Outcomes Study 36 (SF-36) and the Oral Health Impact Profile (OHIP-14) questionnaires to assess HRQoL and OHRQoL, respectively. Clinical aspects, cancer staging, and treatment approach were also investigated. Descriptive and multivariate analyses were performed by using decision tree analysis with the Chi square Automatic Interaction Detector (CHAID) algorithm. RESULTS: The decision tree revealed that reduced quality of life is associated with the clinical staging (adjusted P value = .035), patient's gender (adjusted P value = .028), and treatment approach (adjusted P value = .032). Female patients who are diagnosed with advanced head and neck cancer and undergo radiotherapy or chemotherapy are more likely to exhibit lower rates of quality of life. CONCLUSIONS: The results suggested that sociodemographic characteristics, clinical staging, and treatment approach can exert a significant influence on the quality of life of patients with head and neck cancer. PMID- 30243917 TI - Glomus tumor: a comprehensive review of the clinical and histopathologic features with report of two intraoral cases. AB - BACKGROUND: Glomus tumors are benign neoplasms that most commonly present in the subungual region. Their occurrence in the oral cavity is exceedingly rare. Here, we present 2 cases from the oral cavity, detail their clinical and histopathologic features, and review the literature for solitary cases involving the oral regions. STUDY DESIGN: The English language literature was queried for cases of benign glomus tumors in/around the oral cavity. Additional citations were cross-referenced from the identified sources. RESULTS: Thirty-one cases of solitary glomus tumor in the oral and paraoral regions have been described, including the present cases. Patient age ranged from 10 to 85years, with an average age of 47years. In 12 of the 31 cases, the tumors occurred in the lips, 5 in the palate, 4 in the tongue, 4 in the buccal mucosa, 3 in the gingiva, and 1 each in the parotid, pterygoid fossa, and oropharynx. Only 18 of these cases had accompanying immunohistochemical stains, with 14 expressing positivity for muscle cell markers. CONCLUSIONS: Although glomus tumors have distinct histopathologic features, diagnostic confusion may exist with regard to extradigital locations. Detailed documentation and discussion of the clinical and histopathologic features of rare tumors like these are vital to understanding them. PMID- 30243918 TI - Mycobacterium abscessus infection in a boy with X-linked anhidrotic ectodermal dysplasia, immunodeficiency. PMID- 30243920 TI - Prebiotic chemistry and origins of life research with atomistic computer simulations. AB - Research in origins of life is an intrinsically multi-disciplinary field, aimed at finding answers to the formidably complex problem of understanding the emergence of life from the modern versions of Charles Darwin's celebrated "primordial soup". In the last few years, thanks to the increasing computational power and the development of sophisticated theoretical and numerical methods, several computational chemistry and physics groups have invested this field, providing new microscopic insights on fundamental prebiotic chemistry phenomena possibly occurring in the early Earth and outer space. This review presents the most successful and powerful approaches in computational chemistry, and the main results thus obtained in prebiotic chemistry and origins of life. The aim of this work is both to describe the state-of-the-art in computational prebiotic chemistry, possibly useful both to theorists and experimentalists in origins of life research, and to suggest future directions and new perspectives offered by modern simulation tools. PMID- 30243919 TI - Description of pharmacist-led quality improvement huddles in the patient-centered medical home model. AB - OBJECTIVES: This case study describes the implementation of pharmacist-led quality improvement team huddles in the patient-centered medical home clinic model. The purpose of these huddles is to have an impact on clinic-based quality metrics. SETTING: Pharmacists embedded into primary care clinics at 2 separate health centers, within a large academic medical center, were funded by the clinics to lead their quality improvement (QI) team huddles. PRACTICE DESCRIPTION: Huddle team members vary depending on the practice sites and can include physicians, pharmacists, advanced practice providers, nurses, administrative managers, social workers, and medical assistants. These huddles are typically held every 1-2 weeks for 15-20 minutes. Small rapid plan-do-check act cycles allow the process to be quickly assessed and altered if needed. The quality metric that the team focused on changed based on clinic goals. Two case studies showcase successful examples of quality improvement initiatives that had a significant impact on the individual clinic-based metrics. INNOVATION: The 2 case studies focus on pharmacist-led quality team huddles for controlled substance and asthma action plan metrics. The clinical pharmacists involved were pivotal to organizing and helping incorporate new processes within their clinics sites. RESULTS: The work of the team huddles brought the clinics from a nonreimbursable status to reimbursable for these metrics. DISCUSSION: Because pharmacists in the ambulatory care setting focus on chronic care disease management and QI, they are in an excellent position to lead team huddles focused on QI and registry management. By establishing interdisciplinary QI team huddles led by clinical pharmacists, these clinics were able to increase revenue for the clinic in the way of increasing pay-for-performance measures. CONCLUSION: Pharmacist-led quality improvement team huddles can have a positive impact on quality metrics, population health, and reimbursement. PMID- 30243921 TI - Interrater Reliability of a Field-Based Preschool Movement Skills Assessment. AB - OBJECTIVE: To determine the interrater reliability of the Preschool Movement Assessment (PMA), a unique field-based assessment tool for use by early childhood professionals in preschool settings. METHODS: A total of 123 preschool children, aged 3-5years, were assessed by 6 trained raters using the PMA tool in an intervention. Interrater agreement on individual items of the PMA was determined using the kappa (kappa) and intraclass correlation coefficient statistics. RESULTS: Weighted kappa values were 0.82-0.96, indicating excellent agreement for all constructs of the PMA. The 95% confidence intervals indicated that all weighted kappa's were statistically significant. The intraclass correlation coefficient for the PMA total score was 0.97. CONCLUSIONS AND IMPLICATIONS: After additional developmental research, the tool might serve to establish and support a minimum level of functional movements that should be attained before a child enters grade school. PMID- 30243922 TI - Psychometric Analyses of the Motivation to Prepare Healthy Foods Questionnaire Used With Adult College Students. AB - OBJECTIVE: To develop and validate a questionnaire to measure adult college students' motivation to prepare healthy foods based on the psychosocial needs identified by Self-determination Theory. DESIGN: This study used a cross sectional design. SETTING: A major southeastern public university. SUBJECTS: A total of 1,027 free-living adults, aged 18-30years, were recruited. Data from 997 were analyzed. VARIABLES MEASURED: The 5 constructs of Self-determination Theory were validated. ANALYSIS: Descriptive statistics, exploratory factor analysis, internal consistency, test-retest reliability, confirmatory factor analysis, and respecification analysis were performed. RESULTS: The exploratory factor analysis returned 5 factors with acceptable internal structure. Cronbach alpha values were .94 for perceived competence, .85 for autonomy support, .87 for intrinsic motivation, .78 for relatedness, and .77 for autonomy. Test-retest reliability coefficients were 0.66-0.79. Confirmatory factor and respecification analyses revealed that the 5-factor structure was an appropriate fit for the data. CONCLUSIONS AND IMPLICATIONS: More research is needed to test the questionnaire's use in a culinary classroom setting to reaffirm these findings. Future research includes testing the instrument's convergent and discriminant validity, performing differential analyses to generalize its use in a wider adult population, and using it to assess change in motivation as a result of participating in a classroom-based culinary skills-building intervention. Additional confirmatory studies are needed to determine whether using nutrition and kinesiology students in the current study affected construct validity. PMID- 30243923 TI - The antimicrobial peptides casocidins I and II: Solution structural studies in water and different membrane-mimetic environments. AB - Antimicrobial peptides (AMPs) represent crucial components of the natural immune defense machinery of different organisms. Generally, they are short and positively charged, and bind to and destabilize bacterial cytoplasmic membranes, ultimately leading to cell death. Natural proteolytic cleavage of alphas2-casein in bovine milk generates the antimicrobial peptides casocidin I and II. In the current study, we report for the first time on a detailed structure characterization of casocidins in solution by means of Nuclear Magnetic Resonance spectroscopy (NMR). Structural studies were conducted in H2O and different membrane mimetic environments, including 2,2,2-trifluoroethanol (TFE) and lipid anionic and zwitterionic vesicles. For both peptides, results indicate a mainly disordered conformation in H2O, with a few residues in a partial helical structure. No wide increase of order occurs upon interaction with lipid vesicles. Conversely, peptide conformation becomes highly ordered in presence of TFE, with both casocidins presenting a large helical content. Our data point out a preference of casocidins to interact with model anionic membranes. These results are compatible with possible mechanisms of action underlying the antimicrobial activity of casocidins that ultimately may affect membrane bilayer stability. PMID- 30243924 TI - An updated Alzheimer hypothesis: Complement C3 and risk of Alzheimer's disease-A cohort study of 95,442 individuals. AB - INTRODUCTION: We tested the hypothesis that low plasma complement C3 is observationally and genetically associated with high risk of Alzheimer's disease (AD). METHODS: We studied 95,442 individuals enrolled in the Copenhagen General Population Study. In genetic analyses, we further included 8367 individuals from the Copenhagen City Heart Study. In the two studies, 1189 and 35 developed AD during median 8 years follow-up. RESULTS: The multifactorially adjusted hazard ratio for risk of AD for a one standard deviation lower levels of complement C3 was 1.11 (95% confidence interval: 1.04-1.19) in all individuals and 1.66 (1.33 2.07) in APOE epsilon44 carriers. In Mendelian randomization, the corresponding genetic estimates were 1.66 (1.05-2.63) overall and 1.99 (0.52-7.65) in APOE epsilon44 carriers. DISCUSSION: Low baseline levels of complement C3 were associated with high risk of AD. The risk was amplified in APOE epsilon44 highly susceptible individuals, and these findings were substantiated by a Mendelian randomization approach, potentially implying causality. Based on these findings, we present and thoroughly discuss an updated Alzheimer hypothesis incorporating low complement C3 levels. PMID- 30243925 TI - The potential role of exosomes in the diagnosis and therapy of ischemic diseases. AB - In the past, exosomes have been thought of as cellular dust. Today, they are thought to be carriers of real biomarkers and intercellular biological information. The composition of exosomes differs according to their source, and the subsequent information they carry, such as protein, microRNA or mRNA, may also be different. Recent studies have demonstrated that exosomes in ischemic diseases can help to make an early diagnosis, and in cellular experiments and animal models, exosomes promote angiogenesis, restrain cell apoptosis and reduce inflammation, among other actions, to protect ischemic organs. There is evidence that these protective effects are related to microRNAs in exosomes. In this review, we discuss the use of exosomes for early diagnosis of ischemic diseases and recent advances in the therapeutic use of exosomes in cell and mammalian models of ischemic diseases. PMID- 30243927 TI - Spontaneous eyeblinks are sensitive to sequential learning. AB - Although sequential learning and spontaneous eyeblink rate (EBR) have both been shown to be tightly related to cerebral dopaminergic activity, they have never been investigated at the same time. In the present study, EBR, taken as an indirect marker of dopaminergic activity, was investigated in two resting state conditions, both before and after visuomotor sequence learning in a serial reaction time task (SRT) and during task practice. Participants' abilities to produce and manipulate their knowledge about the sequential material were probed in a generation task. We hypothesized that the time course of spontaneous EBR might follow the progressive decrease of RTs during the SRT session. Additionally, we manipulated the structure of the transfer blocks as well as their respective order, assuming that (1) fully random trials might generate a larger psychophysiological response than an unlearned but structured material, and (2) a second (final) block of transfer might give rise to larger effects given that the sequential material was better consolidated after further practice. Finally, we tentatively hypothesized that, in addition to their online version, spontaneous EBR recorded during the pre- and post-learning resting sessions might be predictive of (1) the SRT learning curve, (2) the magnitude of the transfer effects, and (3) performance in the generation task. Results showed successful sequence learning with decreased accuracy and increased reaction times (RTs) in transfer blocks featuring a different material (random trials or a structured, novel sequence). In line with our hypothesis that EBR reflects dopaminergic activity associated with sequential learning, we observed increased EBR in random trials as well as when the second transfer block occurred at the end of the learning session. There was a positive relationship between the learning curve (RTs) and the slope of EBR during the SRT session. Additionally, inter-individual differences in resting and real-time EBR predicted the magnitude of accuracy and RTs transfer effects, respectively, but they were not related to participants' performances during the generation task. Notwithstanding, our results suggest that the degree of explicit sequential knowledge modulates the association between the magnitude of the transfer effect in EBR and SRT performance. Overall, the present study provides evidence that EBR may represent a valid indirect psychophysiological correlate of dopaminergic activity coupled to sequential learning. PMID- 30243928 TI - Identifying and Addressing High Priority Issues in General Surgery Training and Education. AB - BACKGROUND: Complex problems are often easier to address when multiple entities collaborate. The Procedural Learning and Safety Collaborative (PLSC) was established to address complex problems in general surgery residency training by connectively engaging multiple residency programs in addressing progressive research questions. STUDY DESIGN: Recently, PLSC members held a national symposium which included leadership from several leading surgical societies to come to a consensus on what are the most critical issues in general surgery education. RESULTS: This paper describes the process used and the end result of this process. This paper describes the process used and the end result of this process. PMID- 30243929 TI - Social Belonging as a Predictor of Surgical Resident Well-being and Attrition. AB - OBJECTIVE: In light of the predicted shortage of surgeons, attrition from surgical residency is a significant problem. Prior data have shown that those who are happier are more productive, and those who are less well have higher rates of absenteeism. This study sought to identify the role of social belonging and its relationship to well-being and risk of attrition. DESIGN: Surgical residents were invited to participate in an online survey containing measures of social belonging (a 10-item scale adapted from previous studies), well-being (the Dupuy Psychological General Well-Being Scale, Beck Depression Inventory Short Form, and Maslach Burnout Inventory), and risk of attrition (indicated by frequency of thoughts of leaving the program). SETTING: We surveyed residents at 2 tertiary care centers, Stanford Health Care (2010, 2011, and 2015) and Washington University in St. Louis (2017). PARTICIPANTS: Categorical general surgery residents, designated preliminary residents going into 7 surgical subspecialties, and nondesignated preliminary residents were included. RESULTS: One hundred sixty nine residents responded to the survey for a response rate of 66%. Belonging was positively correlated with general psychological well-being (r = 0.56, p < 0.0001) and negatively correlated with depression (r = -0.57, p < 0.0001), emotional exhaustion (r = -0.58, p < 0.0001), and depersonalization (r = -0.36, p < 0.0001). Further, belonging was negatively correlated with frequency of thoughts of leaving residency (r = -0.45, p < 0.0001). In regression analysis controlling for demographic variables, belonging was a significant positive predictor of psychological well-being (B = 0.95, t = 8.18, p < 0.0001) and a significant negative predictor of thoughts of leaving (B = -1.04, t = -5.44, p < 0.0001). CONCLUSIONS: Social belonging has a significant positive correlation with well-being and negative correlation with thoughts of leaving surgical training. Lack of social belonging appears to be a significant predictor of risk of attrition in surgical residency. Efforts to enhance social belonging may protect against resident attrition. ACGME COMPETENCY: Interpersonal and Communication Skills. PMID- 30243930 TI - Sarcoidosis related uveitis: Clinical presentations, disease course and rates of systemic disease progression after uveitis diagnosis. AB - OBJECTIVE: To document the clinical presentation, treatment and visual outcome of sarcoid uveitis and to determine the timing and potential risk factors of sarcoidosis progression to symptomatic systemic disease from the time of sarcoid uveitis diagnosis. DESIGN: Retrospective, interventional case series SUBJECTS: Patients with dual diagnoses of uveitis and presumed/biopsy-proven sarcoidosis. METHOD: Retrospective review of 143 patient records from the Royal Victorian Eye and Ear Hospital and Eye Surgery Associates in Melbourne, Australia between October 1990 and April 2014 coded with the dual diagnoses of uveitis and sarcoidosis. Only patients with uveitis, and presumed or biopsy-proven sarcoidosis (N=113) were included. MAIN OUTCOME MEASURES: Ascertain rate and time (months) to the development of symptomatic systemic sarcoidosis from uveitis onset. Compare and contrast the patient demographics, characteristics of uveitis, treatment and visual outcome between those who developed systemic sarcoidosis and those who remained systemically asymptomatic. RESULTS: Uveitis was the initial presenting complaint of sarcoidosis in 78.8% (n=89). Twenty-three patients had concurrent undiagnosed systemic disease at presentation and 29 subsequently developed symptomatic sarcoidosis in an organ uninvolved at uveitis onset. The median time to the development of symptomatic systemic sarcoidosis was 12 months. No statistically significant association was ascertained between any particular uveitis characteristic and extra-ocular sarcoidosis progression. CONCLUSION: Uveitis was the initial presentation of sarcoidosis in the vast majority of our subjects. Concurrent undiagnosed systemic sarcoidosis was common at the time of uveitis onset. A high index of suspicion for subsequent systemic progression should also be maintained, especially within the first 5 years of the uveitis diagnosis. PMID- 30243926 TI - A robust dissociation among the language, multiple demand, and default mode networks: Evidence from inter-region correlations in effect size. AB - Complex cognitive processes, including language, rely on multiple mental operations that are carried out by several large-scale functional networks in the frontal, temporal, and parietal association cortices of the human brain. The central division of cognitive labor is between two fronto-parietal bilateral networks: (a) the multiple demand (MD) network, which supports executive processes, such as working memory and cognitive control, and is engaged by diverse task domains, including language, especially when comprehension gets difficult; and (b) the default mode network (DMN), which supports introspective processes, such as mind wandering, and is active when we are not engaged in processing external stimuli. These two networks are strongly dissociated in both their functional profiles and their patterns of activity fluctuations during naturalistic cognition. Here, we focus on the functional relationship between these two networks and a third network: (c) the fronto-temporal left-lateralized "core" language network, which is selectively recruited by linguistic processing. Is the language network distinct and dissociated from both the MD network and the DMN, or is it synchronized and integrated with one or both of them? Recent work has provided evidence for a dissociation between the language network and the MD network. However, the relationship between the language network and the DMN is less clear, with some evidence for coordinated activity patterns and similar response profiles, perhaps due to the role of both in semantic processing. Here we use a novel fMRI approach to examine the relationship among the three networks: we measure the strength of activations in different language, MD, and DMN regions to functional contrasts typically used to identify each network, and then test which regions co-vary in their contrast effect sizes across 60 individuals. We find that effect sizes correlate strongly within each network (e.g., one language region and another language region, or one DMN region and another DMN region), but show little or no correlation for region pairs across networks (e.g., a language region and a DMN region). Thus, using our novel method, we replicate the language/MD network dissociation discovered previously with other approaches, and also show that the language network is robustly dissociated from the DMN, overall suggesting that these three networks contribute to high-level cognition in different ways and, perhaps, support distinct computations. Inter-individual differences in effect sizes therefore do not simply reflect general differences in vascularization or attention, but exhibit sensitivity to the functional architecture of the brain. The strength of activation in each network can thus be probed separately in studies that attempt to link neural variability to behavioral or genetic variability. PMID- 30243931 TI - No detection of Zika virus infection in asymptomatic Dutch military personnel after deployment in high endemic areas (Belize, Curacao, Saint Martin) from December 2016 to December 2017. PMID- 30243932 TI - Association between congenital nasolacrimal duct obstruction and mode of delivery at birth. AB - PURPOSE: To investigate the association between mode of delivery, incidence of congenital nasolacrimal duct obstruction (CNLDO), and treatment outcomes. METHODS: The medical records of children diagnosed with CNLDO at a tertiary referral center between 2012 and 2017 were analyzed retrospectively. Patient demographics, pregnancy and birth history, clinical characteristics of CNLDO, and treatment outcomes were compared in patients delivered via Cesarean section (CS) versus vaginal delivery (VD). The rates of CS, as well as full-term and premature births, were also compared to Miami-Dade County normative values to eliminate the confounding effects of prematurity. RESULTS: A total of 104 patients were included. A significantly higher percentage of patients with CNLDO (61%) were delivered via CS (P < 0.0001). Among full-term babies, there was 55% greater risk (OR = 1.55; 95% CI, 0.98-2.43; P = 0.067) of CNLDO for CS birth compared to all other babies. Among preterm babies, there were no significantly greater odds of CNLDO for CS compared to VD births (P = 0.575). CNLDO did not resolve spontaneously in 50 patients, including 37 CS (74%) and 13 VD (26%) patients (P = 0.007). Among those patients who failed first-line probing, 86.2% were born via CS, whereas 13.8% were born via VD (P = 0.0009). CONCLUSIONS: CS is a risk factor for CNLDO, independent of gestational age. Children born via CS also tend to have a more complicated clinical course requiring additional surgical interventions. PMID- 30243933 TI - Patient-derived questionnaire items for patient-reported outcome measures in pediatric eye conditions. AB - PURPOSE: To identify specific health-related quality of life (HRQOL) and functional vision concerns of children with eye conditions, and create comprehensive lists of potential questionnaire items as a first step in developing patient-reported outcome measures. METHODS: Children experiencing a range of pediatric eye conditions, along with one of their parents, were interviewed to identify specific concerns. Transcribed interviews were reviewed, and specific HRQOL and functional vision concerns were coded independently by two reviewers. Coded concerns were reviewed to formulate questions to address specific child concerns (derived from child and parent interviews) and specific parent concerns. Questions were grouped into bins of like questions. Two comprehensive lists of questions were formulated, one addressing child-related concerns and one addressing parent-related concerns. RESULTS: This study included 180 children and 328 parents. A total of 614 individual child questions were grouped into 36 bins (eg, appearance, coordination, glasses, learning), and 589 parent questions were formulated and grouped into 61 bins (eg, having to assist the child, worry about deterioration, time off work, safety). CONCLUSIONS: Using rigorous methods based on individual interviews, we identified a comprehensive list of patient- and parent-derived questionnaire items that address functional vision and HRQOL concerns of children with eye conditions and of their parents. We plan to use this large pool of potential questionnaire items to develop a formal set of pediatric outcome measures, and this pool of questions may also be a resource for future research. PMID- 30243934 TI - Bile acids down-regulate the expression of Augmenter of Liver Regeneration (ALR) via SHP/HNF4alpha1 and independent of Egr-1. AB - Bile acids (BA) are signaling molecules that activate nuclear factors and g protein coupled receptors signaling to maintain metabolic homeostasis. However, accumulation of toxic BA promotes liver injury by initiating inflammation, inducing apoptosis and causing oxidative stress leading to cirrhosis and liver failure. Augmenter of Liver Regeneration (ALR) is a hepatotrophic growth factor with anti-apoptotic and anti-oxidative properties that has been shown to improve mitochondrial and hepatic functions in rats after bile duct ligation. In the current study we aimed to analyze the regulation of the pro-survival protein, ALR, under conditions of cytotoxic concentrations of BA. Promoter studies of ALR (-733/+527 bp) revealed potential binding sites for various transcription factors like Egr-1, HNF4alpha and two bile acid response elements (BARE). Using a full length and several truncated promoter constructs for ALR we analyzed promoter activity and showed that BA reduce ALR promoter activity whereas Egr-1 transfection induces it. EMSA and supershift analysis confirmed the specific binding of Egr-1 to its response element within ALR promoter and this binding was reduced upon simultaneous stimulation with BA. We also showed that ALR promoter activity and protein expression are induced by HNF4alpha1 and repressed by SHP. In conclusion, these results indicate that BA negatively regulate ALR expression by SHP activation. PMID- 30243935 TI - Long non-coding RNA 319 facilitates nasopharyngeal carcinoma carcinogenesis through regulation of miR-1207-5p/KLF12 axis. AB - Long non-coding RNAs (lncRNAs) have been wildly verified to modulate multiple tumorigeneses, especially nasopharyngeal carcinoma (NPC). In present study, we aim to investigate the role of LINC00319 in the NPC carcinogenesis. It was indicated that LINC00319 was markedly increased in NPC tissues and cells in comparison to their corresponding controls. Moreover, the aberrant overexpression of LINC00319 indicated the poor prognosis of NPC patients. Silence of LINC00319 was able to suppress NPC cell growth in vitro while overexpression of LINC00319 inversed this process. Moreover, in vivo tumor xenografts were established using CNE-1/SUNE-1 cells to investigate the function of LINC00319 in NSCLC tumorigenesis. Rescue assay was performed to further confirm that LINC00319 contributed to NPC progression by regulating miR-1207-5p/KLF12 signal pathway. Taken together, our study discovered the oncogenic role of LINC00319 in clinical specimens and cellular experiments, showing the potential LINC00319/miR-1207 5p/KLF12 pathway. This results and findings provide a novel insight for NPC tumorigenesis. PMID- 30243937 TI - Prenatal mold exposure is associated with development of atopic dermatitis in infants through allergic inflammation. AB - OBJECTIVE: Mold exposure in early life may be associated with development of atopic dermatitis; however, studies of this link are inconclusive and evidence for the underlying mechanism(s) is lacking. This study identified the association between the time of mold exposure and development of atopic dermatitis and investigated the underlying mechanisms. METHOD: The association between atopic dermatitis and mold exposure was examined in the Cohort for Childhood Origin of Asthma and Allergic Diseases birth cohort study (n=1446). Atopic dermatitis was diagnosed at 1 year of age by pediatric allergists. Exposure to mold was assessed by questionnaire. The Illumina MiSeq platform was used to examine the environmental mycobiome in 20 randomly selected healthy infants and 20 infants with atopic dermatitis at 36 weeks of gestation. RESULTS: Prenatal, but not postnatal, mold exposure was significantly associated with atopic dermatitis (adjusted odds ratio, 1.36; 95% confidence interval, 1.01-1.83). Levels of total serum IgE at 1 year of age were higher in infants with atopic dermatitis exposed to mold during pregnancy than in healthy infants not exposed to mold during pregnancy (p=0.021). The relative abundance of uncultured Ascomycota was higher in infants with atopic dermatitis than in healthy infants. The relative abundance of uncultured Ascomycota correlated with total serum IgE levels at 1 year of age (r=0.613, p<0.001). CONCLUSION: Indoor mold exposure during the fetal period is associated with development of atopic dermatitis via IgE-mediated allergic inflammation. Avoidance of mold exposure during this critical period might prevent the development of atopic dermatitis. PMID- 30243936 TI - The mechanisms and clinical significance of PDCD4 in colorectal cancer. AB - In recent years, the incidence and mortality of colorectal cancer (CRC) have been on a global upward trend. There is an urgent need for effective tools to prevent and treat CRC and reduce morbidity and mortality of CRC patients. Recent evidence suggests that programmed cell death 4 (PDCD4), a novel tumor suppressor gene, inhibits tumor progression at transcriptional and translational levels and regulates multiple signal transduction pathways. However, little is known about the precise mechanisms regulating PDCD4 expression in CRC. In addition, several studies have demonstrated that the expression of in CRC is down-regulated or even absent. PDCD4 is therefore considered to be an independent prognostic factor in CRC and may be a potential support diagnostic tool for distinguishing in normal colon tissue, benign adenoma and CRC. This review will focus on the expression of PDCD4 in CRC and the relevant molecular mechanisms. PMID- 30243938 TI - Unlocking the secrets of banded coral snake (Calliophis intestinalis, Malaysia): A venom with proteome novelty, low toxicity and distinct antigenicity. AB - : The Asiatic coral snakes are basal in the phylogeny of coral snakes. Although envenoming by the Asiatic coral snakes is rarely fatal, little is known about their venom properties and variability from the American coral snakes. Integrating reverse-phase high performance liquid chromatography and nano-liquid chromatography-tandem mass spectrometry, we showed that the venom proteome of the Malaysian banded or striped coral snake (Calliophis intestinalis) was composed of mainly phospholipases A2 (PLA2, 43.4%) and three-finger toxins (3FTx, 20.1%). Within 3FTx, the cytotoxins or cardiotoxins (CTX) dominated while the neurotoxins' content was much lower. Its subproteomic details contrasted with the 3FTx profile of most Micrurus sp., illustrating a unique dichotomy of venom phenotype between the Old and the New World coral snakes. Calliophis intestinalis venom proteome was correlated with measured enzymatic activities, and in vivo it was myotoxic but non-lethal to mice, frogs and geckos at high doses (5-10 MUg/g). The venom contains species-specific toxins with distinct sequences and antigenicity, and the antibodies raised against PLA2 and CTX of other elapids showed poor binding toward its venom antigens. The unique venom proteome of C. intestinalis unveiled a repertoire of novel toxins, and the toxicity test supported the need for post-bite monitoring of myotoxic complication. SIGNIFICANCE: Malaysian banded or striped coral snake (Calliophis intestinalis) has a cytotoxin (CTX)-predominating venom proteome, a characteristic shared by its congener, the Malayan blue coral snake (Calliophis bivirgata). With little neurotoxins (NTX), it illustrates a CTX/NTX dichotomy of venom phenotype between the Old World and the New World coral snakes. The low toxicity of the venom imply that C. intestinalis bite envenoming can be managed via symptomatic relief of the mild to moderate pain with appropriate analgesia. Systemically, the serum creatine kinase level of patients should be monitored serially for potential complication of myotoxicity. The distinct antigenicity of the venom proteins implies that the empirical use of heterologous antivenom is mostly inappropriate and not recommended. PMID- 30243939 TI - Dehydration-induced proteomic landscape of mitochondria in chickpea reveals large scale coordination of key biological processes. AB - : Mitochondria play crucial roles in regulating multiple biological processes particularly electron transfer and energy metabolism in eukaryotic cells. Exposure to water-deficit or dehydration may affect mitochondrial function, and dehydration response may dictate cell fate decisions. iTRAQ-based quantitative proteome of a winter legume, chickpea, demonstrated the central metabolic alterations in mitochondria, presumably involved in dehydration adaptation. Three week-old chickpea seedlings were subjected to progressive dehydration and the magnitude of dehydration-induced compensatory physiological responses was monitored in terms of physicochemical characteristics and mitochondrial architecture. The proteomics analysis led to the identification of 40 dehydration responsive proteins whose expressions were significantly modulated by dehydration. The differentially expressed proteins were implicated in different metabolic processes, with obvious functional tendencies toward purine-thiamine metabolic network, pathways of carbon fixation and oxidative phosphorylation. The linearity of dehydration-induced proteome alteration was examined with transcript abundance of randomly selected candidates under multivariate stress conditions. The differentially regulated proteins were validated through sequence analysis. An extensive sequence based localization prediction revealed >62.5% proteins to be mitochondrial resident by, at least, one prediction algorithm. The results altogether provide intriguing insights into the dehydration-responsive metabolic pathways and useful clues to identify crucial proteins linked to stress tolerance. BIOLOGICAL SIGNIFICANCE: Investigation on plant mitochondrial proteome is of significance because it would allow a better understanding of mitochondrial function in plant adaptation to stress. Mitochondria are the unique organelles, which play a crucial role in energy metabolism and cellular homeostasis, particularly when exposed to stress conditions. Chickpea is one of the cultivated winter legumes, which enriches soil nitrogen and has very low water footprint and thus contributes to fortification of sustainable agriculture. We therefore examined the dehydration-responsive mitochondrial proteome landscape of chickpea and queried whether molecular interplay of mitochondrial proteins modulate dehydration tolerance. A total of 40 dehydration-induced mitochondrial proteins were identified, predicted to be involved in key metabolic processes. Our future efforts would focus on understanding both posttranslational modification and processing for comprehensive characterization of mitochondrial protein function. This approach will facilitate mining of more biomarkers linked to the tolerance trait and contribute to crop adaptation to climate change. PMID- 30243940 TI - Factors Affecting Symptom Onset to First-Medical-Contact in Egyptian STEMI Patients. PMID- 30243941 TI - [PALB2, a major susceptibility gene for breast cancer]. AB - OBJECTIVES: About 5% of breast cancers are linked to an inherited predisposition, the two most known susceptibility genes being BRCA1 and BRCA2. Recently, new susceptibility genes, including PALB2, have been identified. The risk of breast cancer associated with a deleterious mutation of PALB2, the age of onset of these cancers, their prognosis and associated cancers have so far been the subject of controversy. Our objective was to clarify these different questions from an updated review of the literature. METHODS: The analyzed articles were taken from the PUBMED database between January 2008 and December 2015. The keywords used were "breast cancer" and "PALB2". RESULTS: Women with PALB2 mutations have a higher risk than the general population of developing breast cancer. The relative risk is significant, varying according to the different studies between 3,4 (IC 95%: 2,4-5,9) and 9,47 (IC 95%: 5,72-14,39). The different mutations as well as environmental and geographical factors should be taking into account when interpreting these results. There is currently no proven link between a PALB2 mutation and the occurrence of ovarian or pancreas cancer. CONCLUSION: PALB2 must be considered as a high-penetrance breast cancer predisposing gene. Women with a PALB2 mutation face an increased risk of triple negative breast cancer and higher risk of death from breast cancer. PMID- 30243942 TI - [How do I do ... a lumpectomy with an external oncoplasty]. PMID- 30243943 TI - Direct imaging of the dissolution of salt forms of a carboxylic acid drug. AB - The optimisation of the pharmaceutical properties of carboxylic acid drugs is often conducted by salt formation. Often, the salt with the best solubility is not chosen due to other factors such as stability, solubility, dissolution and bioavailability that are taken into consideration during the preformulation stage. This work uses advanced imaging techniques to give insights into the preformulation properties that can aid in the empirical approach often used in industry for the selection of salts. Gemfibrozil (GEM) was used as a model poorly soluble drug. Four salts of GEM were made using cyclopropylamine (CPROP), cyclobutylamine (CBUT), cyclopentylamine (CPENT) and cyclohexylamine (CHEX) as counterions. DSC, XRD and SEM were used to confirm and characterise salt formation. IDR obtained using UV-imaging up to 10 min for all the salts showed that an increase in the chain length of the counterion caused a decrease in the IDR. Past the 10 min mark, there was an increase in the IDR value for the CPROP salt, which was visualised using UV-imaging. The developed interfacial (surface) area ratio (Sdr) showed significant surface gains for the compacts. Full dosage form (capsule) imaging showed an improvement over the GEM for all the salts with an increase in chain length of the counterion bringing about a decrease in dissolution which correlated with the obtained UV-imaging IDR data. PMID- 30243944 TI - A study on the role of cholesterol and phosphatidylcholine in various features of liposomal doxorubicin: From liposomal preparation to therapy. AB - The lipid membrane composition defines the physical and pharmacological characteristics of liposomal drugs, and it can be tailored to meet the desired drug delivery needs. The current study is aimed to provide a sharper understanding of the lipid composition effect on doxorubicin (DOX) delivery kinetics, using cholesterol and phosphatidylcholine lipids (PCs) with different acyl chains in liposomal DOX formulations. The PCs were distearoyl (DSPC), dipalmitoyl (DPPC), dimyristoyl (DMPC) and egg-derived PC (EPC), either alone or in combination with cholesterol. Several characteristics were monitored, including DOX loading capacity of liposomes, DOX release in phosphate buffered saline (PBS), PBS/human plasma including buffy coat and human blood, cell uptake, as well as in vivo distribution and therapeutic effects in BALB/c mice bearing C26 colon carcinoma. Addition of cholesterol to liposomal formulation enhanced the particle size stability of the liposomes and the DOX-to-lipid ratio. EPC liposomes and EPC/Cholesterol-liposomes showed few distinctive features. Overall, cholesterol decreased DOX release from the liposomes, and longer saturated fatty acyl chains in PC decreased DOX release and side-effects and increased the anti tumor effects of liposomal DOX. PMID- 30243945 TI - Opinion: Virtual memory CD8 T cells and lymphopenia-induced memory CD8 T cells represent a single subset: Homeostatic memory T cells. AB - It is well established that lymphopenia induces the formation of the memory phenotype T cells without the exposure to foreign antigens. More recently, the memory-phenotype antigen-inexperienced memory T cells were described in lymphoreplete mice and called virtual memory T cells. In this review, we compare multiple aspects of the biology of lymphopenia-induced memory T cells and virtual memory T cells, including cytokine requirements, the role of T-cell receptor specificity in the differentiation process, gene expression signature, and the immune response. Based on this comparison, we conclude that lymphopenia-induced memory T cells and virtual memory T cells most likely represent a single T-cell subset, for which we propose a term 'homeostatic memory T cells'. PMID- 30243946 TI - Mechanisms of endogenous repair failure during intervertebral disc degeneration. AB - Intervertebral disc (IVD) degeneration is frequently associated with Low back pain (LBP), which can severely reduce the quality of human life and cause enormous economic loss. However, there is a lack of long-lasting and effective therapies for IVD degeneration at present. Recently, stem cell based tissue engineering techniques have provided novel and promising treatment for the repair of degenerative IVDs. Numerous studies showed that stem/progenitor cells exist naturally in IVDs and could migrate from their niche to the IVD to maintain the quantity of nucleus pulposus (NP) cells. Unfortunately, these endogenous repair processes cannot prevent IVD degeneration as effectively as expected. Therefore, theoretical basis for regeneration of the NP in situ can be obtained from studying the mechanisms of endogenous repair failure during IVD degeneration. Although there have been few researches to study the mechanism of cell death and migration of stem/progenitor cells in IVD so far, studies demonstrated that the major inducing factors (compression and hypoxia) of IVD degeneration could decrease the number of NP cells by regulating apoptosis, autophagy, and necroptosis, and the particular chemokines and their receptors played a vital role in the migration of mesenchymal stem cells (MSCs). These studies provide a clue for revealing the mechanisms of endogenous repair failure during IVD degeneration. This article reviewed the current research situation and progress of the mechanisms through which IVD stem/progenitor cells failed to repair IVD tissues during IVD degeneration. Such studies provide an innovative research direction for endogenous repair and a new potential treatment strategy for IVD degeneration. PMID- 30243947 TI - Pre-operative pressure pain thresholds do not meaningfully explain satisfaction or improvement in pain after knee replacement: a cohort study. AB - OBJECTIVES: Pain sensitization could be a risk factor for poor outcomes after knee replacement surgery (KR) for knee osteoarthritis (KOA). We aimed to evaluate the association between pre-operative central and peripheral pain sensitization measured using a digital pressure algometer and KR outcomes. METHODS: Consecutive patients with severe KOA listed for KR were recruited. Sociodemographic and symptoms data were collected prior to surgery. Pre-operative pressure pain thresholds (PPTs) were measured using a digital pressure algometer at the index knee and forearm. Patient satisfaction at 6 and 12 months after KR was assessed using a 4-point Likert scale, and dichotomized to satisfied and dissatisfied to KR. Western Ontario and McMaster Universities Index (WOMAC) Pain and function was assessed. The associations between pre-operative PPTs with KR outcomes at 6 and 12 months were evaluated. RESULTS: Of the 243 patients recruited, response rate at 6 and 12 months were 95.5% and 96.7%. The dissatisfaction rates were 8.2% and 5.1% at 6 and 12 months. There was no statistically significant association between pre-operative index knee or forearm PPTs and patient satisfaction. PPTs measured at the knee, but not the forearm, were weakly associated with change in the WOMAC pain score at 12 months, after adjustment for confounding factors. CONCLUSION: Pre-operative central sensitization, measured by handheld digital algometry, was not statistically significantly associated with satisfaction or change in pain after KR. Pre-operative peripheral sensitization was associated with change in pain symptoms after KR; however, this association was weak and unlikely to be a meaningful predictor of KR outcome in clinical practice. PMID- 30243948 TI - Ethics in musculoskeletal regenerative medicine; guidance in choosing the appropriate comparator in clinical trials. AB - BACKGROUND: Regenerative Medicine (RM) techniques aimed at the musculoskeletal system are increasingly translated to clinical trials and patient care. This revolutionary era in science raises novel ethical challenges. One of these challenges concerns the appropriate choice of the comparator in (randomized controlled) trials, including the ethically contentious use of sham procedures. To date, only general guidelines regarding the choice of the comparator exist. OBJECTIVE: To provide specific guidelines for clinical trial comparator choice in musculoskeletal RM. METHODS: In this manuscript, we discuss the ethics of comparator selection in RM trials. First, we make a classification of RM interventions according to different health states from disease prevention, return to normal health, postponing RM treatment, supplementing RM treatment, substituting RM treatment, improving RM outcome, and slowing progression. Subsequently, per objective, the accompanying ethical points to consider are evaluated with support from the available literature. RESULTS: a sham procedure is demonstrated to be an ethically acceptable comparator in RM trials with certain objectives, but less appropriate for musculoskeletal RM interventions that aim at preventing disease or substituting a surgical treatment. The latter may be compared to 'standard of care'. CONCLUSION: From a scientific perspective, choosing the correct comparator based on ethical guidelines is a step forward in the success of musculoskeletal RM. PMID- 30243949 TI - A Randomized Trial of a Group-Based Integrative Medicine Approach Compared to Waitlist Control on Irritable Bowel Syndrome Symptoms in Adults. AB - INTRODUCTION: Irritable bowel syndrome (IBS) is a chronic debilitating functional gastrointestinal disorder that affects a large proportion of the general population. Dietary and mind-body approaches have shown some effectiveness in reducing IBS symptoms. OBJECTIVES: The purpose of this project was to test the feasibility of a low cost, group-oriented integrative medicine approach to IBS, and to explore whether such an approach improves participant outcomes. METHODS: This was a randomized-controlled trial involving a 4-week group-oriented treatment intervention combining dietary intervention and mind-body therapies followed by 8-weeks of telephonic health coaching. Differences between the intervention and control groups on IBS-specific measures were examined at baseline, 4, 8, and 12-week. RESULTS: Fifty-two participants completed the study, 30 in the control group and 22 in the intervention group. On the IBS Symptom Severity Score, at 4 weeks the intervention group showed statistically significant improvement compared to the control group (p < .02), which was sustained at the 8 and 12-week data points as well, with the proportion of the intervention group experiencing moderate to severe symptoms decreasing from 81.3% at baseline to 45% at week 4 and 54.5% at week 12. A statistically significant improvement was also seen on the CES-D measure of depression between baseline and week 12 in the intervention group compared to controls. On the IBS Quality of Life measure we did not observe a statistically significant difference between the groups. CONCLUSIONS: This low-cost, group-oriented intervention approach offers a strategy to address the challenge of access to this type of integrative approach for patients of low socioeconomic status or limited means. PMID- 30243950 TI - Effect of Integrative Medicine Services on Pain for Hospitalized Patients at an Academic Health Center. AB - BACKGROUND: Pharmaceuticals such as opioids have routinely been prescribed for pain management. However, there has been an increasing epidemic of prescription opioid abuse, causing demand for nonpharmacologic complementary and integrative therapies for pain management. OBJECTIVE: To determine if integrative medicine services provided to inpatients could help reduce pain posttreatment. In addition, this study aimed to track total services requested and performed over the fourth quarter of 2017. DESIGN, SETTING, AND PARTICIPANTS: This prospective study analyzed documented integrative medicine services requested, indications for the requests, and pre- and posttreatment pain scores. A paired t test was used to determine significance. The study population was inpatients, from October 1, 2017, through December 31, 2017, at Mayo Clinic's Methodist and St. Mary's Hospitals in Rochester, Minnesota. RESULTS: During the study period, 1220 integrative services were provided with a majority being massage therapy (1,064; 87.2%), followed by acupuncture (112; 9.1%). Massage therapy and acupuncture were highly significant (P < 0.00) at reducing pain scores posttreatment to inpatients. Over one-third of patients fell asleep during their therapy service time. CONCLUSION AND RELEVANCE: Integrative therapies are appropriate modalities to help alleviate pain and other symptoms for the inpatient population. Due to the effectiveness of these modalities, integrative therapies may be a complement to opioids prescribed for pain. In addition, with over one-third of the patients falling asleep during therapy, our results suggest that integrative therapies can promote a state of relaxation. Future studies are warranted to determine the impact of integrative medicine therapies on sleep deprivation and other common symptoms of hospitalized patients. PMID- 30243951 TI - Shifting Food Systems: Increasing Well-being Through Plant-Based Approaches. AB - Growing evidence reveals food production systems and consumption practices contradict goals for environmental well-being and population health. This interdisciplinary paper reviews research for impacts from diets on non communicable human diseases, climate change, and animal well-being. With increasing pressures to innovate and reduce economic as well as emotional costs associated with ill-health, our recommendations could positively impact policy. PMID- 30243952 TI - Biosynthesized silver nanoparticles: Decoding their mechanism of action in Staphylococcus aureus and Escherichia coli. AB - The oxidative stress generation in bacteria by the presence of antibiotics (in this case silver nanoparticles (AgNPs)) is already widely known. Previously, we demonstrated that AgNPs generate oxidative stress in Staphylococcus aureus and Escherichia coli mediated by the increase of reactive oxygen species (ROS). In this work we are demonstrating the consequences of the oxidative stress by the presence of AgNPs; these bacterial strains increased the levels of oxidized proteins and lipids. In addition, it was possible to determine which reactive oxygen species are mainly responsible for the oxidative damage to macromolecules. Also, we found that the bacterial DNA was fragmented and the membrane potential was modified. This increase in the levels of ROS found in both, S. aureus and E. coli, was associated with the oxidation of different types of important macromolecules for the normal functioning of cell, so the oxidative stress would be one of the mechanisms by which the AgNPs would exert their toxicity in both strains, one Gram positive and the other Gram negative of great clinical relevance. PMID- 30243953 TI - Knockdown of LncRNA MALAT1 contributes to cell apoptosis via regulating NF kappaB/CD80 axis in neonatal respiratory distress syndrome. AB - Neonatal respiratory distress syndrome (NRDS) is a leading cause of morbidity in premature newborns and is a common reason for admission to the neonatal intensive care unit (NICU). Recent studies found that the pathogenesis of NRDS is not simply lung immaturity. Apoptosis is an essential process for the development and maturation of the lungs. In this study, we report a critical role of lncRNA MALAT1 in regulating CD80 transcription in the NRDS-associated apoptosis via binding with NF-kappaB. We first showed MALAT1 and CD80 were highly expressed in the peripheral blood mononuclear cells of NRDS with infection exposure. Then we found MALAT1 expressions were significantly increased by the treatment of LPS. We confirmed knockdown of MALAT1 promoted cell viability by CCK-8 assays, cell apoptosis by flow cytometric assays and cytoskeleton destruction by immunocytochemistry. We confirmed CD80 expression level was associated with cell apoptosis by affecting PARP and caspase-3. Then we demonstrated knockdown of MALAT1 promoted CD80 transcription in A549 cells. Furthermore, we confirmed that MALAT1 downregulated transcriptional expression of CD80 by interfering with NF kappaB activation and disrupting its binding efficiency with the CD80 promoter in the cell nucleus. In conclusion, we first identified lncRNA MALAT1 as an important prognosis maker for NRDS patients. Most significantly, this study then demonstrated a novel regulatory function of knocked-down MALAT1 on the transcriptional level of CD80 by enhancing the binding of NF-kappaB to CD80 promoter. Since the interaction between MALAT1 and CD80 plays an essential role in the cell apoptosis of NRDS, our findings demonstrate the possibility of using MALAT1 as therapeutic target for treatment of NRDS, and extend existing knowledge about the molecular mechanism that underlies NRDS pathogensis. PMID- 30243954 TI - The pyrethroid insecticides permethrin and esfenvalerate do not disrupt testicular steroidogenesis in the rat fetus. AB - The present study investigated the effects of maternal exposure to the widely used pyrethroid insecticides, permethrin and esfenvalerate, on fetal testicular steroidogenesis. Pregnant Sprague-Dawley rats were administered permethrin at doses of 1, 10, 50, or 100 mg/kg/day, or esfenvalerate at 0.1, 1, 7.5 or 15 mg/kg/day, by gavage, from gestation day (GD) 13 to 19. Testicular testosterone production and the expression of several key genes necessary for cholesterol and androgen synthesis and transport were assessed in GD 19 male fetuses. Dams treated with 100 mg/kg/day of permethrin or 15 mg/kg/day of esfenvalerate showed clinical signs of neurotoxicity. The highest dose of esfenvalerate also resulted in reduced maternal body weight gain throughout the treatment period. In the fetal testes, mRNA expressions of HMG-CoA synthase and reductase, SR-B1, StAR, P450scc, 3betaHSD, P450 17A1, and 17betaHSD were not affected by exposure to either pyrethroid. No significant change was observed in ex vivo testosterone production. In conclusion, in utero exposure to permethrin or esfenvalerate has no effect on the testosterone biosynthesis pathway in the fetal rat testis up to maternal toxic doses. PMID- 30243955 TI - Simultaneous and inherent correction of B0 and eddy-current induced distortions in high-resolution diffusion MRI using reversed polarity gradients and multiplexed sensitivity encoding (RPG-MUSE). AB - In diffusion MRI (dMRI), static magnetic field (B0) inhomogeneity and time varying gradient eddy currents induce spatial distortions in reconstructed images. These distortions are exacerbated when high spatial resolutions are used, and many field-mapping based correction techniques often only acquire maps of static B0 distortion, which are not adequate for correcting eddy current induced image distortions. This report presents a novel technique, termed RPG-MUSE, for achieving distortion-free high-resolution diffusion MRI by integrating reversed polarity gradients (RPG) into the multi-shot echo planar imaging acquisition scheme used in multiplexed sensitivity encoding (MUSE). By alternating the phase encoding direction between shots in both baseline and diffusion-weighted acquisitions, maps of both static B0 and eddy current induced field inhomogeneities can be inherently derived, without the need for additional data acquisition. Through both 2D and 3D encoded dMRI acquisitions, it is shown that an RPG-MUSE reconstruction can simultaneously achieve high spatial resolution, high spatial fidelity, and subsequently, high accuracy in diffusion metrics. PMID- 30243956 TI - Eccentricity-dependent temporal contrast tuning in human visual cortex measured with fMRI. AB - Cells in the peripheral retina tend to have higher contrast sensitivity and respond at higher flicker frequencies than those closer to the fovea. Although this predicts increased behavioural temporal contrast sensitivity in the peripheral visual field, this effect is rarely observed in psychophysical experiments. It is unknown how temporal contrast sensitivity is represented across eccentricity within cortical visual field maps and whether such sensitivities reflect the response properties of retinal cells or psychophysical sensitivities. Here, we used functional magnetic resonance imaging (fMRI) to measure contrast sensitivity profiles at four temporal frequencies in five retinotopically-defined visual areas. We also measured population receptive field (pRF) parameters (polar angle, eccentricity, and size) in the same areas. Overall contrast sensitivity, independent of pRF parameters, peaked at 10 Hz in all visual areas. In V1, V2, V3, and V3a, peripherally-tuned voxels had higher contrast sensitivity at a high temporal frequency (20 Hz), while hV4 more closely reflected behavioural sensitivity profiles. We conclude that our data reflect a cortical representation of the increased peripheral temporal contrast sensitivity that is already present in the retina and that this bias must be compensated later in the cortical visual pathway. PMID- 30243957 TI - Altered temporal variance and functional connectivity of BOLD signal is associated with state anxiety during acute systemic inflammation. AB - Systemic inflammation is accompanied by complex behavioral changes and disturbed emotion regulation that have been related to the pathophysiology of mood disorders including depression and anxiety. However, the causal role of systemic inflammation on mood disorders is still unclear. We herein investigated neural resting state patterns of temporal variance of the amygdala and functional connectivity within the salience network underlying changes in state anxiety during experimentally-induced systemic inflammation. In this randomized, double blind study, N = 43 healthy men received an intravenous injection of either low dose lipopolysaccharide (LPS, 0.4 ng/kg body weight) or saline. Resting state functional magnetic resonance imaging was assessed before and 3.5 h after injection. State anxiety, assessed with a standardized questionnaire, and plasma cytokine concentrations were repeatedly measured. LPS administration induced a transient systemic inflammatory response reflected in increases in plasma Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-alpha concentration. Compared to placebo, state anxiety and temporal variance in the amygdala significantly increased while functional connectivity in the salience network decreased during LPS-induced systemic inflammation. Together, these data indicate that acute systemic inflammation alters temporal variance of the BOLD signal as well as functional connectivity in brain regions and networks implicated in emotion processing and regulation. These results are of translational importance to encourage further research on the role of inflammatory pathways in the pathophysiology of neuropsychiatric conditions including anxiety disorders. PMID- 30243958 TI - Increased responses of the reward circuitry to positive task feedback following acute stress in healthy controls but not in siblings of schizophrenia patients. AB - Acute stress is known to affect the way we process rewards. For example, during, or directly after stress, activity within key brain areas of the reward circuitry is reduced when a reward is presented. Generally, the effects of stress on the brain are time-dependent, changing neural and cognitive processing in the aftermath of stress to aid recovery. Such a dynamic response to stress is important for resilience on the longer term. However, relatively little is known about reward processing during the recovery phase of stress and whether this is changed in individuals at increased risk for stress-related psychopathology. Healthy male individuals (N = 40) and unaffected siblings of schizophrenia patients (N = 40) were randomized to either an acute stress task (Trier Social Stress Test) or a no-stress task. Neural responses during reward anticipation and reward feedback (monetary gain or no gain) were examined 50 min later using an fMRI monetary incentive delay task. The ventral striatum and orbitofrontal cortex (OFC) were used as predefined hypothesis-driven regions of interest. Neural responses following stress differed between controls and siblings during reward feedback (group * stress interaction OFC p = 0.003, ventral striatum p = 0.031), showing increased ventral striatum and OFC responses following stress in healthy controls only. Exploratory analyses revealed that this effect was most pronounced during hit trials (compared to when a reward was omitted), and independent of monetary value. Stress did not affect subsequent reward processing in siblings of schizophrenia patients. We found no significant differences between controls and siblings in ventral striatum and OFC responses during reward anticipation following stress. This study shows that ventral striatum and OFC responses to positive task feedback are increased in the aftermath of stress in healthy male controls, regardless of monetary value. This indicates a dynamic shift from previously reported reduced responses in the striatum and OFC to reward feedback directly after stress to increased responses to both reward and non-reward feedback during the recovery phase of stress. These increased neural responses following stress were absent in siblings of schizophrenia patients. Together, these findings indicate that stress recovery is affected in this at-risk group, particularly in responses to positive feedback following stress. PMID- 30243959 TI - Neural representations of aversive value encoding in pain catastrophizers. AB - Chronic pain is exacerbated by maladaptive cognition such as pain catastrophizing (PC). Biomarkers of PC mechanisms may aid precision medicine for chronic pain. Here, we investigate EEG biomarkers using mass univariate and multivariate (machine learning) approaches. We test theoretical notions that PC results from a combination of augmented aversive-value encoding ("magnification") and persistent expectations of pain ("rumination"). Healthy individuals with high or low levels of PC underwent an experimental pain model involving nociceptive laser stimuli preceded by cues predicting forthcoming pain intensity. Analysis of EEG acquired during the cue and laser stimulation provided event-related potentials (ERPs) identifying spatially and temporally-extended neural representations associated with pain catastrophizing. Specifically, differential neural responses to cues predicting high vs. low intensity pain (i.e. aversive value encoding) were larger in the high PC group, largely originating from mid-cingulate and superior parietal cortex. Multivariate spatiotemporal EEG patterns evoked from cues with high aversive value selectively and significantly differentiated the high PC from low PC group (64.6% classification accuracy). Regression analyses revealed that neural patterns classifying groups could be partially predicted (R2 = 28%) from those neural patterns classifying the aversive value of cues. In contrast, behavioural and EEG analyses did not provide evidence that PC modifies more persistent effects of prior expectation on pain perception and nociceptive responses. These findings support the hypothesis of magnification of aversive value encoding but not persistent expression of expectation in pain catastrophizers. Multivariate patterns of aversive value encoding provide promising biomarkers of maladaptive cognitive responses to chronic pain that have future potential for psychological treatment development and clinical stratification. PMID- 30243960 TI - Mass isotopomer-guided decluttering of metabolomic data to visualize endogenous biomarkers of drug toxicity. AB - Metabolomics offers the opportunity to uncover endogenous biomarkers that can lead to metabolic pathways and networks and that underpin drug toxicity mechanisms. A novel protocol is presented and discussed that is applicable to drugs which generate urinary metabolites when administered to mice sensitive to its toxicity. The protocol would not apply to drugs that are not metabolized or eliminated by a different route. Separate stable isotope-labeled and unlabeled drug administration to mice is made together with collection of urines from control animals. Untargeted mass spectrometry-based metabolomic analysis of these three urine groups is conducted in addition to principal components analysis (PCA). In the case of unlabeled acetaminophen and [acetyl-2H3]acetaminophen, each given at a hepatotoxic dose (400 mg/kg i.p.) to the sensitive mouse strain (wild type 129), the PCA loadings plot showed a distribution of ions in the shape of a "fallen-Y" with the deuterated metabolites in one arm and the paired nondeuterated metabolites in the other arm of the fallen-Y. Ions corresponding to the endogenous toxicity biomarkers sat in the mouth of the fallen-Y. This protocol represents an innovative means to separate endogenous biomarkers from drug metabolites, thereby aiding the identification of biomarkers of drug toxicity. For acetaminophen, increased hepatic oxidative stress, mitochondrial damage, Ca2+ signaling, heme catabolism, and saturation of glucuronidation, together with decreased fatty acid beta-oxidation and cellular energy dysregulation were all implied from the discovered biomarkers. The protocol can be applied to other drugs and may now be translated to clinical studies. PMID- 30243961 TI - Comparison of clinical outcomes between very long stents and overlapping stents for the treatment of diffuse coronary disease in real clinical practice. AB - BACKGROUND: The stent length as well as the stent overlap for the percutaneous treatment of diffuse coronary disease have been considered predictors of adverse events. However, there are no comparative data on the use of very long stents or overlapping stents in this scenario. OBJECTIVE: To compare the clinical results of very long stents (>=40 mm) or overlapping stents in real clinical practice. METHODS: We included 643 lesions in 628 consecutive patients treated with a single very long stent (>=40 mm) (251 lesions) or >=2 overlapped stents (392 lesions). We analyzed the procedural characteristics and the presentation of the combined endpoint [cardiovascular death, non-fatal myocardial infarction, need for target lesion revascularization or stent thrombosis] after a follow-up of 20 months. RESULTS: Total stent length was 54 +/- 18 mm and minimum diameter was 2.9 +/- 1.2 mm. At the end of follow-up, the rate of adverse events was 8.3% (cardiac death: 4.9%, myocardial infarction: 1.7%, target lesion revascularization: 3.1%, stent thrombosis: 0.7%). There were no significant differences between both groups in the presentation of the combined endpoint. Procedures with overlapping stents had more contrast volume (309 +/- 115 vs 273 +/- 127 ml; p = 0.002), longer duration (47 +/- 22 vs 39 +/- 18 min; p < 0.0001), higher fluoroscopy time (20 +/- 13 vs 16 +/- 9 min; p < 0.0001) and higher number of stents to treat the index lesion (2.2 +/- 0.5 vs 1; p < 0.0001). CONCLUSIONS: New designs of very long stents allow not only treating increasingly complex lesions, but also simplifying the procedure and decreasing the number of stents with very favorable results similar to those obtained with stent overlap. PMID- 30243962 TI - Effect of hemostatic device on radial artery occlusion: A randomized comparison of compression devices in the radial hemostasis study. AB - BACKGROUND: Asymptomatic radial artery occlusion (RAO) is a major limitation of transradial catheterization (TRC). Two radial compression hemostatic devices are compared for their respective effects on RAO. METHODS: In a prospective, randomized, single center, blinded trial, 320 patients were randomly treated with a TR band (Terumo Corporation) or Safeguard Radial (Merit Medical). Institution wide protocols consisting of anticoagulation, patent hemostasis, duration of compression, and use of 6 French slender sheaths (Terumo Corporation) were observed. Patient discomfort related to the device was recorded using the universal pain scale. Radial artery patency was evaluated by reverse Barbeau's test prior to discharge (1-hour post-diagnostic catheterization or 6-24 hour post intervention) and at 30-days. RESULTS: Of the 320 patients, 155 were randomized to the TR group (TRG) and 159 to the Safeguard group (SGG). 6 patients were excluded due to the inability to insert 6 Fr slender sheaths or patient withdrawing consent. Demographic and procedural characteristics were similar with the exception of the type of coronary procedure performed. Both bands were equally effective in achieving patent hemostasis. Despite having a higher rate of post-procedure hematoma (1.29% TRG vs. 3.1% SGG, p = 0.04) and acute RAO (3.8% TRG vs. 6.28% SGG, p = 0.05) with the Safeguard band, at 30 days RAO was similar in both groups (1.9% TRG vs. 2.5% SGG; p = 0.21). Patients in the SGG reported significantly less band discomfort and were found to require less air to achieve patent hemostasis. CONCLUSION: Evidence-based contemporary TRC protocols of using smaller diameter access, anticoagulation, and use of just enough pressure for the shortest duration of time to achieve hemostasis is associated with very low RAO rate at 30 days irrespective of the radial compression device used. PMID- 30243963 TI - The impact of in-hospital P2Y12 inhibitor switch in patients with acute coronary syndrome. AB - BACKGROUND/PURPOSE: Dual antiplatelet therapy (DAPT) varies after placement of drug-eluting stents (DES) in patients presenting with acute coronary syndromes (ACS). Our aim was to study patient characteristics and predictors of switching, in-hospital or at discharge, from clopidogrel (CLO) to ticagrelor (TIC) or vice versa. METHODS/MATERIALS: The study population included patients with ACS who had DES and initially received either CLO or TIC between January 2011 and December 2017. Patients were divided into 4 groups based on initial DAPT choice and whether DAPT was switched in-hospital or during discharge. Clinical outcomes of interest were bleeding events, need for anticoagulation, and need for in-hospital coronary artery bypass graft (CABG). RESULTS: We identified 2837 patients who received DES and started on DAPT. DAPT switch from 1 P2Y12 inhibitor to another occurred in 9%, either in-hospital or at discharge. Of 1834 patients started on CLO, 112 were switched to TIC. Of 1003 patients started on TIC, 142 were switched to CLO. The need for in-hospital CABG was 7.8% in the TIC-CLO group compared to none in the CLO-TIC group (p = 0.002). Adjusted for covariates, the TIC-CLO group was 3 times more likely to need anticoagulation with warfarin than the CLO-CLO group (p < 0.001) and over 5 times more likely than the CLO-TIC group and the TIC TIC group (p < 0.005 for both). CONCLUSIONS: Switching from 1 generation P2Y12 inhibitor to another does occur in ACS patients. Clinical needs such as in hospital CABG or oral anticoagulation upon discharge are real and dictate the switch from TIC to CLO. SUMMARY: A single-center observational study of 2837 patients with acute coronary syndromes treated with drug-eluting stents found that some do get switched from one generation P2Y12 inhibitor to another. The switch from clopidogrel to ticagrelor is driven by clinical needs such as in hospital coronary artery bypass grafting or the need for oral anticoagulation upon discharge. PMID- 30243964 TI - Procedural and long-term ischemic outcomes of tight subtotal occlusions treated with orbital atherectomy: An ORBIT II subanalysis. AB - BACKGROUND/PURPOSE: Orbital atherectomy is an effective treatment strategy to modify severely calcified coronary lesions prior to stent placement. Traversing a severely calcified subtotal occlusion with the crown may be more challenging compared with a less severely stenotic lesion. The purpose of this ORBIT II subanalysis was to evaluate outcomes post-orbital atherectomy (OA) treatment of lesions with >=95% stenosis. METHODS/MATERIALS: ORBIT II, a single-arm, prospective, multicenter trial, enrolled 443 subjects with severely calcified coronary lesions. Patients with chronic total occlusions were excluded from the trial. Subjects with the OA device activated were stratified based on pre procedure percent stenosis: >=95% stenosis (N = 91) and <95% stenosis (N = 341). Procedural success and 3-year major adverse cardiac event (MACE) rates were compared. RESULTS: The severe angiographic complications rates were 6.6% and 6.7% in the >=95% and <95% stenosis groups, respectively. There was no significant difference in procedural success (94.5% vs. 88.3%, p = 0.120). 3-year MACE rates were similar (27.1% vs. 22.5%, p = 0.548), as were the rates of cardiac death (5.7% vs. 7.1%, p = 0.665) and MI (7.9% vs. 12.1%, p = 0.244). The TVR rate was higher in the >=95% stenosis group (19.1% vs. 7.5%, p = 0.004). CONCLUSIONS: In ORBIT II, OA treatment of lesions with >=95% stenosis resulted in a high rate of procedural success. Although the 3-year revascularization rate was higher in the >=95% stenosis group, it is not unexpected given the challenge of treating such complex lesions. The results of this analysis suggest that OA may be a reasonable treatment strategy for tight, severely calcified subtotal occlusions. SUMMARY: The purpose of this ORBIT II subanalysis was to evaluate outcomes post-orbital atherectomy (OA) treatment of lesions with >=95% stenosis. In ORBIT II, OA treatment of lesions with >=95% stenosis resulted in a high rate of procedural success. Although the 3-year revascularization rate was higher in the >=95% stenosis group, it is not unexpected given the challenge of treating such complex lesions. The results of this analysis suggest that OA may be a reasonable treatment strategy for tight, severely calcified subtotal occlusions. PMID- 30243965 TI - Apoptotic cell death induced by Z-Ligustilidein human ovarian cancer cells and role of NRF2. AB - Z-Ligustilide is the most potent bioactive component of Angelica sinensis, which is widely used in Chinese traditional medicine. Z-Ligustilide selectively affected ovarian cancer cell survival in a dose dependent manner. Z-Ligustilide induced apoptotic cell death was determined by flow cytometry. We also demonstrated that apoptotic cell death was triggered by Z-Ligustilideinduced oxidative stress and mitochondria played an active role. Mitochondrial polarization was reduced by Z-Ligustilidewhereas mitochondrial superoxide formation was increased. NRF2 was induced by Z-Ligustilide in OVCAR-3 cells at epigenetic level and its downstream antioxidant defense genesHeme oxygenase 1,NAD(P)H Quinone Dehydrogenase 1, UDP Glucuronosyltransferase Family 1 Member A1and Glutamate-Cysteine Ligase. NRF2 knockdown by siRNA resulted increased cell death by Z-Ligustilide in ovarian cancer cells. Our result demonstrated the pro survival role of NRF2 in Z-Ligustilide induced ovarian cancer cell death. PMID- 30243966 TI - RIFM fragrance ingredient safety assessment, octyl butyrate, CAS Registry Number 110-39-4. PMID- 30243968 TI - Review article: Role of satiety hormones in anorexia induction by Trichothecene mycotoxins. AB - The trichothecenes, produced by Fusarium, contaminate animal feed and human food in all stages of production and lead to a large spectrum of adverse effects for animal and human health. An hallmark of trichothecenes toxicity is the onset of emesis followed by anorexia and food intake reduction in different animal species (mink, mice and pig). The modulation of emesis and anorexia can result from a direct action of trichothecenes in the brain or from an indirect action in the gastrointestinal tract. The direct action of trichothecenes involved specific brain areas such as nucleate tractus solitarius in the brainstem and the arcuate nuclei in the hypothalamus. Activation of these areas in the brain leads to the activation of specific neuronal populations containing anorexigenic factors (POMC and CART). The indirect action of trichothecenes in the gastrointestinal tract involved, by enteroendocrine cells, the secretion of several gut hormones such as cholecystokinin (CCK) and peptide YY (PYY) but also glucagon-like peptide 1 (GLP 1), gastric inhibitory peptide (GIP) and 5-hydroxytryptamine (5-HT), which transmitted signals to the brain via the gut-brain axis. This review summarizes current knowledge on the effects of trichothecenes, especially deoxynivalenol, on emesis and anorexia and discusses the mechanisms underlying trichothecenes induced food reduction. PMID- 30243967 TI - RIFM fragrance ingredient safety assessment, octahydro-4,7-methano-1h-indene-5 ol, CAS Registry Number 13380-89-7. PMID- 30243969 TI - Editorial Comment. PMID- 30243970 TI - Editorial Comment. PMID- 30243971 TI - Editorial Comment. PMID- 30243972 TI - Low-frequency alternating current stimulation rhythmically suppresses gamma-band oscillations and impairs perceptual performance. AB - Low frequency oscillations such as alpha (8-12 Hz) are hypothesized to rhythmically gate sensory processing, reflected by 40-100 Hz gamma band activity, via the mechanism of pulsed inhibition. We applied transcranial alternating current stimulation (TACS) at individual alpha frequency (IAF) and flanking frequencies (IAF-4 Hz, IAF+4 Hz) to the occipital cortex of healthy human volunteers during concurrent magnetoencephalography (MEG), while participants performed a visual detection task inducing strong gamma-band responses. Occipital (but not retinal) TACS phasically suppressed stimulus-induced gamma oscillations in the visual cortex and impaired target detection, with stronger phase-to amplitude coupling predicting behavioral impairments. Retinal control TACS ruled out retino-thalamo-cortical entrainment resulting from (subthreshold) retinal stimulation. All TACS frequencies tested were effective, suggesting that visual gamma-band responses can be modulated by a range of low frequency oscillations. We propose that TACS-induced membrane potential modulations mimic the rhythmic change in cortical excitability by which spontaneous low frequency oscillations may eventually exert their impact when gating sensory processing via pulsed inhibition. PMID- 30243973 TI - RF-induced heating in tissue near bilateral DBS implants during MRI at 1.5 T and 3T: The role of surgical lead management. AB - Access to MRI is limited for patients with deep brain stimulation (DBS) implants due to safety hazards, including radiofrequency (RF) heating of tissue surrounding the leads. Computational models provide an exquisite tool to explore the multi-variate problem of RF heating and help better understand the interaction of electromagnetic fields and biological tissues. This paper presents a computational approach to assess RF-induced heating, in terms of specific absorption rate (SAR) in the tissue, around the tip of bilateral DBS leads during MRI at 64MHz/1.5 T and 127 MHz/3T. Patient-specific realistic lead models were constructed from post-operative CT images of nine patients operated for sub thalamic nucleus DBS. Finite element method was applied to calculate the SAR at the tip of left and right DBS contact electrodes. Both transmit head coils and transmit body coils were analyzed. We found a substantial difference between the SAR and temperature rise at the tip of right and left DBS leads, with the lead contralateral to the implanted pulse generator (IPG) exhibiting up to 7 times higher SAR in simulations, and up to 10 times higher temperature rise during measurements. The orientation of incident electric field with respect to lead trajectories was explored and a metric to predict local SAR amplification was introduced. Modification of the lead trajectory was shown to substantially reduce the heating in phantom experiments using both conductive wires and commercially available DBS leads. Finally, the surgical feasibility of implementing the modified trajectories was demonstrated in a patient operated for bilateral DBS. PMID- 30243974 TI - Whole-slice mapping of GABA and GABA+ at 7T via adiabatic MEGA-editing, real-time instability correction, and concentric circle readout. AB - An adiabatic MEscher-GArwood (MEGA)-editing scheme, using asymmetric hyperbolic secant editing pulses, was developed and implemented in a B1+-insensitive, 1D semiLASER (Localization by Adiabatic SElective Refocusing) MR spectroscopic imaging (MRSI) sequence for the non-invasive mapping of gamma-aminobutyric acid (GABA) over a whole brain slice. Our approach exploits the advantages of edited MRSI at 7T while tackling challenges that arise with ultra-high-field-scans. Spatial-spectral encoding, using density-weighted, concentric circle echo planar trajectory readout, enabled substantial MRSI acceleration and an improved point spread-function, thereby reducing extracranial lipid signals. Subject motion and scanner instabilities were corrected in real-time using volumetric navigators optimized for 7T, in combination with selective reacquisition of corrupted data to ensure robust subtraction-based MEGA-editing. Simulations and phantom measurements of the adiabatic MEGA-editing scheme demonstrated stable editing efficiency even in the presence of +/-0.15 ppm editing frequency offsets and B1+ variations of up to +/-30% (as typically encountered in vivo at 7T), in contrast to conventional Gaussian editing pulses. Volunteer measurements were performed with and without global inversion recovery (IR) to study regional GABA levels and their underlying, co-edited, macromolecular (MM) signals at 2.99 ppm. High quality in vivo spectra allowed mapping of pure GABA and MM-contaminated GABA+ (GABA + MM) along with Glx (Glu + Gln), with high-resolution (eff. voxel size: 1.4 cm3) and whole-slice coverage in 24 min scan time. Metabolic ratio maps of GABA/tNAA, GABA+/tNAA, and Glx/tNAA were correlated linearly with the gray matter fraction of each voxel. A 2.15-fold increase in gray matter to white matter contrast was observed for GABA when enabling IR, which we attribute to the higher abundance of macromolecules at 2.99 ppm in the white matter than in the gray matter. In conclusion, adiabatic MEGA-editing with 1D-semiLASER selection is as a promising approach for edited-MRSI at 7T. Our sequence capitalizes on the benefits of ultra-high-field MRSI while successfully mitigating the challenges related to B0/B1+ inhomogeneities, prolonged scan times, and motion/scanner instability artifacts. Robust and accurate 2D mapping has been shown for the neurotransmitters GABA and Glx. PMID- 30243975 TI - A representative template of the neonatal cerebellum. AB - The cerebellum plays an important role in human brain development. To improve the spatial specificity of the analysis of human cerebellar magnetic resonance imaging (MRI) data, we present a new template of the neonatal human cerebellum and brainstem based on the anatomy of 20 full-term healthy neonates. The template is spatially unbiased, which means that the location of each structure is not biased by the anatomy of the individuals used to create the template. In comparison to current whole-brain templates, it allows for an improved voxel-by voxel normalization for MRI analysis. To align the cerebellum to the template, it needs to be isolated from the surrounding tissue, a process for which an automated algorithm has been developed. Our methodology outperforms normalization to a whole-brain neonatal template, using either linear or nonlinear transformations. Our algorithm reduces the spatial variability of the infratentorial area, while simultaneously increasing the overlap of the cerebellum. The template and the related software are freely available as part of SUIT v3.3 SPM toolbox. PMID- 30243976 TI - Detecting and typing target DNA with a novel CRISPR-typing PCR (ctPCR) technique. AB - This study develops a new method for detecting and typing the interested DNAs based on CRISPR, which was named as ctPCR3.0, representing CRISPR- or Cas9/sgRNA typing PCR, version 3.0. This technique detects target DNA in just one homogeneous step: quantitative PCR (qPCR) amplifying the Cas9/sgRNA-cleaved DNA samples. By directly adding Cas9 and sgRNA into the qPCR reaction and giving an additional isothermal incubation before qPCR program, the target DNA can be homogeneously detected in as few as 2 h. Without opening the detecting tube in the whole detection process, ctPCR3.0 can be used to detect target DNA as the traditional qPCR detection. The technique was fully verified by detecting the cloned HPV L1 genes of 10 high-risk human papillomavirus (HPV) subtypes. The technique also successfully detected the L1 and E6-E7 genes of two highest-risk HPVs, HPV16 and HPV18, in the genomic DNA of two HPV-positive cervical carcinoma cells, HeLa and SiHa. Finally, the ctPCR3.0 method was validated by successfully detecting HPVs in many clinical samples. By performing these detections, this study thus provides a new CRISPR-based DNA detection and typing platform and a ready-to-use HPV clinical detection technique. The platform has wide application in clinical diagnosis. PMID- 30243977 TI - Spectroscopic methods for assessing the molecular origins of macroscopic solution properties of highly concentrated liquid protein solutions. AB - In cases of subcutaneous injection of therapeutic monoclonal antibodies, high protein concentrations (>50 mg/ml) are often required. During the development of these high concentration liquid formulations (HCLF), challenges such as aggregation, gelation, opalescence, phase separation, and high solution viscosities are more prone compared to low concentrated protein formulations. These properties can impair manufacturing processes, as well as protein stability and shelf life. To avoid such unfavourable solution properties, a detailed understanding about the nature of these properties and their driving forces are required. However, the fundamental mechanisms that lead to macroscopic solution properties, as above mentioned, are complex and not fully understood, yet. Established analytical methods for assessing the colloidal stability, i.e. the ability of a native protein to remain dispersed in solution, are restricted to dilute conditions and provide parameters such as the second osmotic virial coefficient, B22, and the diffusion interaction coefficient, kD. These parameters are routinely applied for qualitative estimations and identifications of proteins with challenging solution behaviours, such as high viscosities and aggregation, although the assays are prepared for low protein concentration conditions, typically between 0.1 and 20 mg/ml ("ideal" solution conditions). Quantitative analysis of samples of high protein concentration is difficult and it is hard to obtain information about the driving forces of such solution properties and corresponding protein-protein self-interactions. An advantage of using specific spectroscopic methods is the potential of directly analysing highly concentrated protein solutions at different solution conditions. This allows for collecting/gaining valuable information about the fundamental mechanisms of solution properties of the high protein concentration regime. In addition, the derived parameters might be more predictive as compared to the parameters originating from assays which are optimized for the low protein concentration range. The provided information includes structural data, molecular dynamics at various timescales and protein-solvent interactions, which can be obtained at molecular resolution. Herein, we provide an overview about spectroscopic techniques for analysing the origins of macroscopic solution behaviours in general, with a specific focus on pharmaceutically relevant high protein concentration and formulation conditions. PMID- 30243978 TI - Sleep Apnea Increases the Risk of New Hospitalized Atrial Fibrillation: A Historical Cohort Study. AB - OBJECTIVES: This study examined the relationship between newly diagnosed OSA and incident hospitalized atrial fibrillation (AF) over the subsequent 10 years in a large arrhythmia-free cohort. METHODS: Adults referred between 1994 and 2010 to a large academic hospital with suspected OSA who were arrhythmia-free at the time of the first diagnostic sleep study were included. Clinical data were linked to provincial health administrative data to define outcome. Cox regressions were used to investigate the relationship between severity of OSA as measured by the apnea-hypopnea index (AHI) and degree of nocturnal hypoxemia, and incident hospitalized AF. RESULTS: In total, 8,256 subjects were included in this study. Their median age was 47 years, 62% were men; 28% had an AHI > 30 events per hour, and 6% spent > 30% of sleep time with oxygen saturation < 90%. Over a median follow-up of 10 years (interquartile range, 7-13 years), 173 participants (2.1%) were hospitalized with AF. Controlling for age, sex, alcohol consumption, smoking status, previous heart failure, COPD, and pulmonary embolism, nocturnal hypoxemia (but not AHI) was a significant predictor of incident AF: hazard ratio, 2.47 (95% CI, 1.64-3.71). After further controlling for BMI and hypertension, this association was attenuated but remained significant (hazard ratio, 1.77 [95% CI, 1.15-2.74]). CONCLUSIONS: In a large arrhythmia-free clinical cohort with suspected OSA, nocturnal hypoxemia was independently associated with a 77% increased hazard of incident hospitalized AF. These findings further support a relationship between OSA, nocturnal hypoxemia, and new-onset AF, and they may be used to enhance AF prevention in patients with OSA and severe nocturnal hypoxemia. PMID- 30243979 TI - Hypersensitivity Pneumonitis: Radiologic Phenotypes Are Associated With Distinct Survival Time and Pulmonary Function Trajectory. AB - BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease with a better prognosis, on average, than idiopathic pulmonary fibrosis (IPF). We compare survival time and pulmonary function trajectory in patients with HP and IPF by radiologic phenotype. METHODS: HP (n = 117) was diagnosed if surgical/transbronchial lung biopsy, BAL, and exposure history results suggested this diagnosis. IPF (n = 161) was clinically and histopathologically diagnosed. All participants had a baseline high-resolution CT (HRCT) scan and FVC % predicted. Three thoracic radiologists documented radiologic features. Survival time is from HRCT scan to death or lung transplant. Cox proportional hazards models identify variables associated with survival time. Linear mixed models compare post-HRCT scan FVC % predicted trajectories. RESULTS: Subjects were grouped by clinical diagnosis and three mutually exclusive radiologic phenotypes: honeycomb present, non-honeycomb fibrosis (traction bronchiectasis and reticulation) present, and nonfibrotic. Nonfibrotic HP had the longest event-free median survival (> 14.73 years) and improving FVC % predicted (1.92%; 95% CI, 0.49-3.35; P = .009). HP with non-honeycomb fibrosis had longer survival than IPF (> 7.95 vs 5.20 years), and both groups experienced a significant decline in FVC % predicted. Subjects with HP and IPF with honeycombing had poor survival (2.76 and 2.81 years, respectively) and significant decline in FVC % predicted. CONCLUSIONS: Three prognostically distinct, radiologically defined phenotypes are identified among patients with HP. The importance of pursuing a specific diagnosis (eg, HP vs IPF) among patients with non-honeycomb fibrosis is highlighted. When radiologic honeycombing is present, invasive diagnostic testing directed at determining the diagnosis may be of limited value given a uniformly poor prognosis. PMID- 30243980 TI - Molecular identification of bovine trypanosomes in relation to cattle sources in southwest Nigeria. AB - Bovine trypanosomosis is a problem in the livestock industry in Nigeria. A longitudinal survey of cattle sampled during the wet and dry seasons was conducted from April 2016 to March 2017. Blood samples were collected by random sampling from 745 cattle in southwest Nigeria and screened for trypanosomes by internal transcribed spacer-polymerase chain reaction (ITS-PCR). Cattle positive for Trypanozoon DNA were further screened with the Rode Trypanozoon antigen type (RoTat) 1.2 PCR and Trypanosoma brucei gambiense glycoprotein (TgsGP) genes for T. evansi and T. b. gambiense respectively. Trypanosome DNA was amplified in 23.8% (95%CI: 20.8-26.9) of cattle with significantly higher prevalence in wet season (95%CI: 22.9-30.8) when compared to the dry season (95%CI: 14.3-23.6). A high prevalence was observed in Fulani cattle farms 54.1% (95%CI: 42.78-64.93%) while the prevalence was lower in institutional farms 14.7% (95%CI: 10.10 20.97%). Trypanosoma vivax was the most prevalent trypanosome observed (11.54% (95%CI: 9.44-14.04%)), followed by T. congolense 8.5% (95%CI: 6.67-10.67%) T. b. brucei 4.8% (95%CI: 3.51-6.62%) and T. evansi 1.74% (95%CI: 1.02-2.96%). Mixed infections were observed in 2.8% (95%CI: 1.85-4.27%) of cattle. Seasonal variation revealed a predominance of T. congolense and T. vivax in wet and dry season, respectively. The high prevalence of Trypanosoma species in cattle indicates a need for expanded surveillance for AAT in southwest Nigeria. Migration, settlement patterns, increased marketing and management types were some of the risk factors identified for AAT. PMID- 30243981 TI - One-step real-time PCR assay for detection and quantification of RNA HCV to monitor patients under treatment in Brazil. AB - The Brazilian Public Health Service provides pegylated alfa-interferon free-of charge to treat patients infected with HCV. The primary goal of HCV therapy is the long-term elimination of HCV from the blood to reduce the risk of HCV associated complications and death. Patient viremia affects treatment duration and response, thus influencing clinical decisions. We developed a high-throughput method to perform the quantification of RNA hepatitis C virus virus load in plasma samples to monitor patients under treatment. The method is based on a duplex detection, in a one-step real-time RT-PCR assay which has been validated according to the rules established by the official Brazilian regulatory agency (ANVISA). This new method was compared to a commercial kit (Cobas/Taqman HCV Test v2.0 - Roche), showing virus load results with significant correlation between them (p=0.012) using commercial and clinical panels. In addition, 611 samples from patients treated with alphaPEG-IFN from different regions of Brazil were analyzed. Our one-step real-time RT-PCR assay demonstrated good performance in viral load measurement and in treatment course monitoring, with acceptable sensitivity and specificity values. PMID- 30243982 TI - CMV specific T cell immunity predicts early viremia after liver transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) infection is one of the most important factors affecting liver transplant with direct and indirect effects. However, CMV disease after transplant remains poorly predicted. OBJECTIVE: In this study, preoperative CMV-specific cell-mediated immunity was evaluated in recipients of liver transplant in Korea, where most people are seropositive. METHODS: A total of 32 patients were enrolled in a prospective study, and blood samples were collected before liver transplant to determine CMV-specific cell-mediated immunity. Testing using ELiSpot IFN-gamma (CMVspot) and CMV serology were performed simultaneously. RESULTS: CMVspot results showed that 30 recipients had CMV-specific cell-mediated immunity, of which 29 were positive for phosphoprotein 65 and 14 for immediate early protein 1 (IE-1). All patients were positive for CMV IgG before transplantation, and 17 patients had a CMV viremia episode after transplantation. CMVspot showed 100% specificity and positive predictive value, and 11.76% sensitivity to predict CMV viremia. Patients with positive or borderline results for IE-1 did not show viremia two months after transplantation (p = .041). CONCLUSION: CMVspot may be helpful in establishing a treatment strategy that includes regular monitoring for risk stratification of CMV reactivation. PMID- 30243983 TI - Plasmid-mediated resistance is going wild. AB - Multidrug resistant (MDR) Gram-negative bacteria have been increasingly reported in humans, companion animals and farm animals. The growing trend of plasmid mediated resistance to antimicrobial classes of critical importance is attributed to the emergence of epidemic plasmids, rapidly disseminating resistance genes among the members of Enterobacteriaceae family. The use of antibiotics to treat humans and animals has had a significant impact on the environment and on wild animals living and feeding in human-influenced habitats. Wildlife can acquire MDR bacteria selected in hospitals, community or livestock from diverse sources, including wastewater, sewage systems, landfills, farm facilities or agriculture fields. Therefore, wild animals are considered indicators of environmental pollution by antibiotic resistant bacteria, but they can also act as reservoirs and vectors spreading antibiotic resistance across the globe. The level of resistance and reported plasmid-mediated resistance mechanisms observed in bacteria of wildlife origin seem to correlate well with the situation described in humans and domestic animals. Additionaly, the identification of epidemic plasmids in samples from different human, animal and wildlife sources underlines the role of horizontal gene transfer in the dissemination of resistance genes. The present review focuses on reports of plasmid-mediated resistance to critically important antimicrobial classes such as broad-spectrum beta-lactams and colistin in Enterobacteriaceae isolates from samples of wildlife origin. The role of plasmids in the dissemination of ESBL-, AmpC- and carbapenemase-encoding genes as well as plasmid-mediated colistin resistance determinants in wildlife are discussed, and their similarities to plasmids previously identified in samples of human clinical or livestock origin are highlighted. Furthermore, we present features of completely sequenced plasmids reported from wildlife Enterobacteriaceae isolates, with special focus on genes that could be associated with the plasticity and stable maintenance of these molecules in antibiotic-free environments. PMID- 30243984 TI - Regulation of tumor cell - Microenvironment interaction by the autotaxin lysophosphatidic acid receptor axis. AB - The lipid mediator lysophosphatidic acid (LPA) in biological fluids is primarily produced by cleavage of lysophospholipids by the lysophospholipase D enzyme Autotaxin (ATX). LPA has been identified and abundantly detected in the culture medium of various cancer cell types, tumor effusates, and ascites fluid of cancer patients. Our current understanding of the physiological role of LPA established its role in fundamental biological responses that include cell proliferation, metabolism, neuronal differentiation, angiogenesis, cell migration, hematopoiesis, inflammation, immunity, wound healing, regulation of cell excitability, and the promotion of cell survival by protecting against apoptotic death. These essential biological responses elicited by LPA are seemingly hijacked by cancer cells in many ways; transcriptional upregulation of ATX leading to increased LPA levels, enhanced expression of multiple LPA GPCR subtypes, and the downregulation of its metabolic breakdown. Recent studies have shown that overexpression of ATX and LPA GPCR can lead to malignant transformation, enhanced proliferation of cancer stem cells, increased invasion and metastasis, reprogramming of the tumor microenvironment and the metastatic niche, and development of resistance to chemo-, immuno-, and radiation-therapy of cancer. The fundamental role of LPA in cancer progression and the therapeutic inhibition of the ATX-LPA axis, although highly appealing, remains unexploited as drug development to these targets has not reached into the clinic yet. The purpose of this brief review is to highlight some unique signaling mechanisms engaged by the ATX-LPA axis and emphasize the therapeutic potential that lies in blocking the molecular targets of the LPA system. PMID- 30243985 TI - Mitogen and stress- activated protein kinase regulated gene expression in cancer cells. AB - The mitogen- and stress-activated protein kinases activated by the extracellular signal-regulated kinase 1/2 and/or stress-activated protein kinase 2/p38 mitogen activated protein kinase pathways are recruited to the regulatory region of a subset of genes termed immediate-early genes, often leading to their induction. These genes, many of which code for transcription factors, have been directly linked to the phenotypic events in carcinogenesis. In this paper, we focus on the mitogen- and stress-activated protein kinases; their discovery, activation, H3 phosphorylation and recent discoveries in their roles in cancer. PMID- 30243986 TI - Early intrathecal infusion of everolimus restores cognitive function and mood in a murine model of Alzheimer's disease. AB - The discovery that mammalian target of rapamycin (mTOR) inhibition increases lifespan in mice and restores/delays many aging phenotypes has led to the identification of a novel potential therapeutic target for the treatment of Alzheimer's disease (AD). Among mTOR inhibitors, everolimus, which has been developed to improve the pharmacokinetic characteristics of rapamycin, has been extensively profiled in preclinical and clinical studies as anticancer and immunosuppressive agent, but no information is available about its potential effects on neurodegenerative disorders. Using a reliable mouse model of AD (3 * Tg-AD mice), we explored whether short-term treatment with everolimus injected directly into the brain by osmotic pumps was able to modify AD-like pathology with low impact on peripheral organs. We first established in non-transgenic mice the stability of everolimus at 37 degrees C in comparison with rapamycin and, then, evaluated its pharmacokinetics and pharmacodynamics profiles through either a single peripheral (i.p.) or central (i.c.v.) route of administration. Finally, 6-month-old (symptomatic phase) 3 * Tg-AD mice were treated with continuous infusion of either vehicle or everolimus (0.167 MUg/MUl/day, i.c.v.) using the osmotic pumps. Four weeks after the beginning of infusion, we tested our hypothesis following an integrated approach, including behavioral (tests for cognitive and depressive-like alterations), biochemical and immunohistochemical analyses. Everolimus (i) showed higher stability than rapamycin at 37 degrees C, (ii) poorly crossed the blood-brain barrier after i.p. injection, (iii) was slowly metabolized in the brain due to a longer t1/2 in the brain compared to blood, and (iv) was more effective in the CNS when administered centrally compared to a peripheral route. Moreover, the everolimus-induced mTOR inhibition reduced human APP/Abeta and human tau levels and improved cognitive function and depressive-like phenotype in the 3 * Tg-AD mice. The intrathecal infusion of everolimus may be effective to treat early stages of AD-pathology through a short and cyclic administration regimen, with short-term outcomes and a low impact on peripheral organs. PMID- 30243987 TI - Inhibition of sphingomyelin synthase 1 ameliorates alzheimer-like pathology in APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1. AB - Sphingolipids emerge as essential modulators in the etiology of Alzheimer's disease (AD) with unclear mechanisms. Elevated levels of SM synthase 1 (SMS1), which catalyzes the synthesis of SM from ceramide and phosphatidylcholine, have been observed in the brains of Alzheimer's disease (AD), where expression of beta site APP cleaving enzyme 1 (BACE1), a rate limiting enzyme in amyloid-beta (Abeta) generation, are upregulated. In the present study, we show knockdown of SMS1 via andeno associated virus (serotype 8, AAV8) in the hippocampus of APP/PS1 transgenic mice, attenuates the densities of Abeta plaques, neuroinflammation, synaptic loss and thus rescuing cognitive deficits of these transgenic mice. We further describe that knockdown or inhibition of SMS1 decreases BACE1 stability, which is accompanied with decreased BACE1 levels in the Golgi, whereas enhanced BACE1 levels in the early endosomes and the lysosomes. The reduction of BACE1 levels induced by knockdown or inhibition of SMS1 is prevented by inhibition of lysosomes. Therefore, knockdown or inhibition of SMS1 promotes lysosomal degradation of BACE1 via modulating the intracellular trafficking of BACE1. Knockdown of SMS1 attenuates AD-like pathology through promoting lysosomal degradation of BACE1. PMID- 30243988 TI - Post-stroke neovascularization and functional outcomes differ in diabetes depending on severity of injury and sex: Potential link to hemorrhagic transformation. AB - Diabetes is associated with increased risk and worsened outcome of stroke. Previous studies showed that male diabetic animals had greater hemorrhagic transformation (HT), profound loss of cerebral vasculature, and poor behavioral outcomes after ischemic stroke induced by suture or embolic middle cerebral artery occlusion (MCAO). Females are protected from stroke until reaching the menopause age, but young females with diabetes have a higher risk of stroke and women account for the majority of stroke mortality. The current study postulated that diabetes is associated with greater vascular injury and exacerbated sensorimotor and cognitive outcome after stroke even in young female animals. Male and female control and diabetic animals were subjected to transient MCAO and followed for 3 or 14 days to assess the neurovascular injury and repair. The vascularization indices after stroke were lower in male diabetic animals with 90 min but not 60-min ischemia/reperfusion injury, while there was no change in female groups. Cognitive deficits were exacerbated in both male and female groups regardless of the injury period, while the sensorimotor dysfunction was worsened in male diabetic animals with longer ischemia time. These results suggest that diabetes negates the protection afforded by sex in young female animals, and post stroke vascularization pattern is influenced by the degree of injury and correlates with functional outcome in both sexes. Vasculoprotection after acute ischemic stroke may provide a novel therapeutic strategy in diabetes. PMID- 30243989 TI - Omalizumab as single-dose therapy for vernal keratoconjunctivitis. PMID- 30243990 TI - Increasing interest in the field of allergy and immunology in medical students and residents: A critical need. PMID- 30243991 TI - Comparative hepatic transcriptome analyses revealed possible pathogenic mechanisms of fasiglifam (TAK-875)-induced acute liver injury in mice. AB - Fasiglifam (TAK-875), a G protein-coupled receptor 40 (GPR40) agonist, was a drug candidate for type 2 diabetes. However, its development was terminated in phase 3 trials due to liver safety concerns. Although TAK-875 was reported to inhibit hepatobiliary transporters and disturb bile acid disposition, pathogenic mechanisms of TAK-875-induced liver injury are not fully understood. In this study, we sought to identify the mechanisms with a hepatic genome-wide transcriptomic analysis in a murine model. We demonstrated that, among the three GPR40 agonists, TAK-875, AMG-837, and TUG-770, only TAK-875 induced acute liver injury in mice. Transcriptome profiles of TAK-875-exposed liver was compared with those of non-hepatotoxic analogues AMG-837 and TUG-770 as negative controls and those of classical hepatotoxicants concanavalin A and carbon tetrachloride as positive controls. The comparative hepatic transcriptome analyses revealed the enrichment of genes involved in inflammation, endoplasmic reticulum (ER) stress, apoptosis, and hepatic lipid accumulation, suggesting that these events play pathophysiologic roles in the development of TAK-875-induced liver injury. These results were validated by quantitative PCR with significant changes in chemokines, danger signals, ER stress mediators, proapoptotic factors, and hepatic steatosis markers only in TAK-875-exposed liver. Pretreatment of TAK-875 administered mice with an ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated the liver injury. Consistent with the in vivo study, pretreatment of HepG2 cells with 4-PBA significantly improved the decrease of cell viability induced by TAK-875. In conclusion, by a comprehensive transcriptomic analysis, we found multiple possible processes that contribute to TAK-875-induced acute liver injury in mice. PMID- 30243992 TI - Advances in the treatment of hypoparathyroidism with PTH 1-34. AB - Hypoparathyroidism is a rare disorder of calcium metabolism which is treated with calcium and vitamin D analogs. Although conventional therapy effectively raises serum calcium, it bypasses the potent calcium reabsorption effects of PTH on the kidney which leads to hypercalciuria and an increased risk of nephrocalcinosis and renal insufficiency. Twenty-five years ago, we launched the first systematic investigation into synthetic human PTH 1-34 replacement therapy in both adults and children. These studies led to our current understanding of the complex nature of PTH 1-34 therapy and to the challenges we still face in our pursuit of a safe and effective physiologic replacement therapy for hypoparathyroidism. The normalization and minimal fluctuation of serum and urine calcium levels were the primary management goals. As the frequency of PTH 1-34 injections increased, the total daily dose required to normalize calcium homeostasis decreased and episodes of hypercalcemia and hypercalciuria diminished, producing a more physiologic biochemical profile. Twice-daily injections achieved simultaneous normalization of serum and urine calcium levels in many patients but the persistent elevation of bone markers and the difficulty in reducing urine calcium to normal levels in the more severe cases, suggested an alternative to PTH 1-34 injections was needed. The studies with PTH 1-34 delivered by insulin pump represent an important advance in the management of hypoparathyroidism. PTH 1-34 delivered by insulin pump normalized serum and urine calcium and markers of bone turnover. Additionally, pump delivery of PTH 1-34 produced stable magnesium values within the normal range and reduced magnesium excretion. Currently, PTH 1-34 delivery by pump is the only alternative to PTH injections that has been tested in both adults and children and proven to achieve a physiologic biochemical profile. PMID- 30243994 TI - Validation of a precision tremor measurement system for multiple sclerosis. AB - BACKGROUND: Tremor is a debilitating symptom of Multiple Sclerosis (MS). Little is known about its pathophysiology and treatments are limited. Clinical trials investigating new interventions often rely on subjective clinical rating scales to provide supporting evidence of efficacy. NEW METHOD: We present a novel instrument (TREMBAL) which uses electromagnetic motion capture technology to quantify MS tremor. We aim to validate TREMBAL by comparison to clinical ratings using regression modelling with 310 samples of tremor captured from 13 MS participants who performed five different hand exercises during several follow-up visits. Minimum detectable change (MDC) and test-retest reliability were calculated and comparisons were made between MS tremor and data from 12 healthy volunteers. RESULTS: Velocity of the index finger was most congruent with clinical observation. Regression modelling combining different features, sensor configurations, and labelling exercises did not improve results. TREMBAL MDC was 84% of its initial measurement compared to 91% for the clinical rating. Intra class correlations for test-retest reliability were 0.781 for TREMBAL and 0.703 for clinical ratings. Tremor was lower (p = 0.002) in healthy subjects. COMPARISON WITH EXISTING METHODS: Subjective scales have low sensitivity, suffer from ceiling effects, and mitigation against inter-rater variability is challenging. Inertial sensors are ubiquitous, however, their output is nonlinearly related to tremor frequency, compensation is required for gravitational artefacts, and their raw data cannot be intuitively comprehended. CONCLUSIONS: TREMBAL, compared with clinical ratings, gave measures in agreement with clinical observation, had marginally lower MDC, and similar test-retest reliability. PMID- 30243995 TI - Application of identity vectors for EEG classification. AB - BACKGROUND: Finding an optimal EEG subject verification algorithm is a long standing goal within the EEG community. For every advancement made, another feature set, classifier, or dataset is often introduced; tracking improvements in classification without a consistent benchmark, such as a classifier-feature pairing tested on a publicly available dataset, makes it difficult to understand how and why these improvements occur. NEW METHOD: Following on previous biometric experiments, I-Vectors and Gaussian Mixture Model-Universal Background Models are compared to an established Mahalanobis classifier. A second experiment then addresses the impact of epoch duration as a function of classification performance across all three classifiers. RESULTS: The experimental classification results indicate that I-Vectors are more robust than the other classifiers displaying less sensitivity to epoch duration, data composition, and feature selection. COMPARISON WITH EXISTING METHODS: This I-Vector based approach is compared against commonly used EEG classifiers, such as Mahalanobis and Gaussian mixture models. These classifiers are benchmarked using the publicly available PhysioNet database converted into three feature sets, spectral coherence, power spectral density, and cepstral coefficients. CONCLUSIONS: The experimental results suggests I-Vectors provide reliable baseline performance by leveling the field between feature set and datasets making them well suited for EEG signal processing tasks. PMID- 30243996 TI - Supportive and palliative care in people with cirrhosis: International systematic review of the perspective of patients, family members and health professionals. AB - BACKGROUND & AIMS: People with cirrhosis have unmet needs, which could benefit from a palliative care approach. Developing effective services needs to be based on evidence from those with personal experience. This review aims to explore; patient and family perspectives of perceived needs including communication; health professionals' perspectives on delivery of care and improving palliative care between specialities. METHODS: A literature search was conducted in Medline, Embase and CINAHL using key words reporting on the perspectives of patients with liver cirrhosis (18 years and over), family members or health professionals on the provision of care in liver cirrhosis. Study quality was assessed using the Mixed Methods Appraisal Tool. Qualitative and quantitative findings were grouped together according to the main relevant themes identified. RESULTS: Nineteen research studies predominantly from high-income Western countries were identified, with a total sample consisting of 1,413 patients, 31 family carers and 733 health professionals. Patients and family members had limited understanding of cirrhosis or its impact. They wanted better information about their disease, its treatment and help with psychological and practical needs. Health professionals had difficulty communicating about these issues to patients and their families. General practitioners left care predominantly to the liver clinicians, who lacked confidence to have discussions about prognosis or future care preferences. The role of palliative care was recognised as important in caring for this group through earlier integration with liver and community services. CONCLUSIONS: Health professionals need support to improve their communication with patients, to address patients' broader needs beyond medical treatment and to develop new models to improve palliative care coordination between different medical specialities. Future research should focus on developing communication aides, testing existing tools to identify suitable patients for supportive care and exploring robust ways of evaluating supportive care interventions, with more studies needed from middle- and low-income countries. Registration number: PROSPERO CRD42017064770. LAY SUMMARY: Patients and their families had a poor understanding of advanced liver disease and its impact on them. They need more information about the treatments they receive and how to get practical and psychological support. Liver specialists and GPs found it difficult to talk to patients and their families about the seriousness of advanced liver disease and the lack of healthcare options available to them if their condition gets worse. All doctors and nurses involved in the care of patients with advanced liver disease recognise that palliative and supportive care have an important role in improving patient care. PMID- 30243997 TI - Upregulation of DAPK2 ameliorates oxidative damage and apoptosis of placental cells in hypertensive disorder complicating pregnancy by suppressing human placental microvascular endothelial cell autophagy through the mTOR signaling pathway. AB - Death-associated protein kinase 2 (DAPK2) has indicated functional roles in cellular processes, including survival, apoptosis, and autophagy. This study is aimed to identify the effect of DAPK2 on oxidative damage and apoptosis of placental cells in hypertensive disorder complicating pregnancy (HDCP) through mTOR pathway. Microarray-based gene expression analysis was performed to predict the differentially expressed genes related to HDCP. To investigate the specific mechanism of DAPK2 in HDCP cells, placental microvascular endothelial cells were treated with mimic or siRNA of DAPK2 and mTOR to detect the expression of related genes, cell autophagy and apoptosis and oxidative damage. Finally, rats were modeled with HDCP to verify the cell experiment results. DAPK2 was downregulated in HDCP, and could activate mTOR. Besides, DAPK2 overexpression led to decreases in autophagy in HPVECs as well as apoptosis and oxidative damage in placental cells indicated by a substantial decrease in Beclin-1, LC3 II/LC3 I and Bax along with an increase in Bcl-2, 4EBP1 and p70S6K. It also ameliorates blood pressure elevation in HDCP rats. The study defined remission effect of DAPK2 on placental cell oxidative damage and apoptosis in HDCP via mTOR activation. Together, DAPK2 regulating mTOR pathway presents a promising therapy for HDCP treatment. PMID- 30243998 TI - Phosphorylation compromises FAD binding and intracellular stability of wild-type and cancer-associated NQO1: Insights into flavo-proteome stability. AB - Over a quarter million of protein phosphorylation sites have been identified so far, although the effects of site-specific phosphorylation on protein function and stability, as well as their possible impact in the phenotypic manifestation in genetic diseases are vastly unknown. We investigated here the effects of phosphorylating S82 in human NADP(H):quinone oxidoreductase 1, a representative example of disease-associated flavoprotein in which protein stability is coupled to the intracellular flavin levels. Additionally, the cancer-associated P187S polymorphism causes inactivation and destabilization of the enzyme. By using extensive in vitro and in silico characterization of phosphomimetic S82D mutations, we showed that S82D locally affected the flavin binding site of the wild-type (WT) and P187S proteins thus altering flavin binding affinity, conformational stability and aggregation propensity. Consequently, the phosphomimetic S82D may destabilize the WT protein intracellularly by promoting the formation of the degradation-prone apo-protein. Noteworthy, WT and P187S proteins respond differently to the phosphomimetic mutation in terms of intracellular stability, further supporting differences in molecular recognition of these two variants by the proteasomal degradation pathway. We propose that phosphorylation could have critical consequences on stability and function of human flavoproteins, important for our understanding of genotype-phenotype relationships in their related genetic diseases. PMID- 30243993 TI - Elevated Syndecan-1 after Trauma and Risk of Sepsis: A Secondary Analysis of Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial. AB - BACKGROUND: Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx. Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) >= 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality. We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis. STUDY DESIGN: We analyzed a subset of patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial who survived at least 72 hours after hospital admission, and we determined elevated Synd-1 levels (>= 40 ng/mL) 4 hours after hospital arrival. Sepsis was defined a priori as meeting systemic inflammatory response criteria and having a known or suspected infection. Univariate analysis was performed to identify variables associated with elevated Synd-1 levels and sepsis. Significant variables at a value of p < 0.2 in the univariate analysis were chosen by purposeful selection and analyzed in a mixed effects multivariate logistic regression model to account for the 12 different study sites. RESULTS: We included 512 patients. Of these, 402 (79%) had elevated Synd-1 levels, and 180 (35%) developed sepsis. Median Synd-1 levels at 4 hours after admission were 70 ng/dL (interquartile range [IQR] 36 to 157 ng/dL) in patients who did not develop sepsis, and 165 ng/dL [IQR 67 to 336 ng/dL] in those who did (p < 0.001). Adjusting for treatment arm and site, multivariable analyses revealed that elevated Synd-1 status, Injury Severity Score (ISS), and total blood transfused were significantly associated with an increased likelihood of developing sepsis. CONCLUSIONS: Elevated Synd-1 levels 4 hours after admission in severely injured adult trauma patients who survived the initial 72 hours after hospital admission are associated with subsequent sepsis. PMID- 30243999 TI - Concomitant use of opioids and benzodiazepines in the outpatient setting: A retrospective study. AB - BACKGROUND: Benzodiazepines have been identified as a concurrent factor in opioid related deaths. Although the dangers of concomitant administration of opioids and benzodiazepines are well documented, implementation of this knowledge into practice may be lagging behind. OBJECTIVE: To examine the concomitant use of opioids and benzodiazepines in the outpatient setting. DESIGN: Retrospective study. SETTING: Academic outpatient multispecialty practice. PARTICIPANTS: Over 2000 outpatient clinic visits from January 2018 to April 2018 among 4 Physiatrists were analyzed. METHODS: All patients were reviewed in the Prescription Drug Monitoring Program (PDMP) website to identify if they have filled either opioid or benzodiazepine prescription(s) in the last 12 months. MAIN OUTCOME MEASUREMENTS: Number of opioid and benzodiazepine prescriptions, discrepancies in reporting of medications, providers prescribing medications, and cigarette/alcohol use. RESULTS: 353 patients were identified to have filled either opioid or benzodiazepine prescription(s) in last 12 months. 49.4% of patients prescribed opioids were found to be on benzodiazepines concurrently. Reporting discrepancies were noted between the outpatient electronic medical record and PDMP in 17.2% of patients. Among patients on both opioids and benzodiazepines, 38.9% had multiple providers prescribing these medications, 41.9% were over 65 years old, and 11.9% were daily cigarette/alcohol users. Patients on both types of drugs (opioids and benzodiazepines) were significantly more likely to use different providers (38.9%) compared to patients on one type of drug (9.8%, p<.001). The former group was also noted to fill significantly more prescriptions than the latter group (p<.001). CONCLUSION: The study results emphasize clinicians may not be aware that some of their patients are concurrently taking both opioids and benzodiazepines, hence highlights the importance of routinely checking the PDMP and utilizing that information to make fully informed decisions regarding the safest possible way to prescribe these controlled substances. LEVEL OF EVIDENCE: III. PMID- 30244000 TI - How occupational status influences the processing of faces: an EEG study. AB - This study examines the influence of social hierarchy on the neural electrophysiological responses to faces. In contrast with earlier EEG studies that typically manipulate social rank through competitive situations, we implemented hierarchy through occupational status and thus contrasted faces associated with high- vs. low-status (e.g. lawyer vs. waiter). Since social hierarchies are largely intertwined with gender, both female and male faces were used as stimuli, and both female and male participants were tested. The procedure consisted in presenting a status label before the face it was associated with. The analyses focused mainly on two components that have been shown to be modulated by competitive hierarchies and other social contexts, namely the N170 and the Late Positive Potential (LPP). The results indicated that gender, but not status, modulated the N170 amplitude. Moreover, high-status faces elicited larger LPP amplitude than low-status faces but this difference was driven by female participants. This gender effect is discussed in line with research showing that women and men are sensitive to different kinds of hierarchy. Methodological differences are considered to account for the discrepancy between studies that find an effect of hierarchy on the N170 and those that do not. PMID- 30244001 TI - Deontological morality can be experimentally enhanced by increasing disgust: A transcranial direct current stimulation study. AB - Previous studies empirically support the existence of a distinctive association between deontological (but not altruistic) guilt and both disgust and obsessive compulsive (OC) symptoms. Given that the neural substrate underlying deontological guilt comprises brain regions strictly implicated in the emotion of disgust (i.e. the insula), the present study aimed to test the hypothesis that indirect stimulation of the insula via transcranial direct current stimulation (tDCS) would enhance disgust and morality in the deontological domain. A randomized, sham-controlled, within-subject design was used. Thirty-seven healthy individuals (25 women) underwent 15-min anodal and sham tDCS over T3 in two different days, while their heart rate (HR) was recorded to derive measures of parasympathetic nervous system activity (HR variability; HRV). After the first 10 min of sham or active tDCS stimulation, participants were asked to 1) complete a series of 6-item words that could be completed with either a disgust-related word (cleaning/dirtiness) or neutral alternatives; 2) rate how much a series of vignettes, each depicting a behavior that violated a specific moral foundation, were morally wrong. Levels of trait anxiety, depression, disgust sensitivity, scrupulosity, and altruism as well as pre- and post- stimulation momentary emotional states were assessed. Compared to the sham condition, after active stimulation of T3 a) HRV significantly increased and participants b) completed more words in terms of cleaning/dirtiness and c) reported greater subjective levels of disgust, all suggesting the elicitation of the emotion of disgust. Although the results are only marginally significant, they point to the absence of difference between the two experimental conditions for moral vignettes in the altruistic domain (i.e., animal care, emotional and physical human care), but not in the deontological domain (i.e., authority, fairness, liberty, and sacrality), where vignettes were judged as more morally wrong in the active compared to the sham condition. Moreover, scores on the OCI-R correlated with how much vignettes were evaluated as morally wrong in the deontological domain only. Results preliminarily support the association between disgust and morality in the deontological domain, with important implications for OC disorder (OCD). Future studies should explore the possibility of decreasing both disgust and morality in patients with OCD by the use of non-invasive brain stimulation techniques. PMID- 30244002 TI - Residual effects of cannabis use on attentional bias towards fearful faces. AB - Cannabis use has increased since legalization in various states within the United States of America. Although much of the research on the neurological and psychological effects of cannabis has been on non-human animals, the current research suggests that it can have anxiolytic effects and also decrease some cognitive functioning (e.g. memory, emotional processing, etc.). Individuals with high anxiety have been suggested to have increased attentional bias towards threat-related stimuli. The current study measured event-related potential (ERP) during a dot-probe task with fearful and neutral facial expression to examine the residual effects of cannabis use on attentional bias. The results indicated that there was reduced attentional bias, as measured by the P1 component in cannabis users, which is similar to low anxious individuals. Additionally, there was no difference between users and non-users in N170, indicating that the residual effects of cannabis did not interfere with face processing. However, an exploratory correlation indicated that higher cannabis use was associated with reduced N170 towards fearful faces. Cannabis use was associated with enhanced N2pc, which would indicate greater spatial orientation of attention. These results suggest that cannabis use did have an effect on attentional bias towards fearful faces. PMID- 30244003 TI - Neural correlates of risk perception as a function of risk level: An approach to the study of risk through a daily life task. AB - We are often required to make decisions that can have safe or risky consequences. Evaluating the risk of each possible alternative is an important step before making our final decision. The main goal of the present research was to explore the neural basis of risk perception in a naturalistic context (driving). Twenty two drivers evaluated the perceived risk in 72 traffic situations (previously categorized by driving instructors) while brain activity was recorded using fMRI. A neural network involving attentional factors, emotional processing, stimulus response associations, and risk aversion was related to the perception of risks. Given the nature of our task, a more prominent role was played by emotional factors (evaluation of the consequences) than cognitive factors (e.g. probabilistic calculations). Moreover, activation in the insula, inferior frontal gyrus, precentral/postcentral gyrus, inferior parietal gyrus, and temporal and occipital regions linearly increased as a function of risk level. Our findings provide a new step towards understanding the neural processing underlying risk behavior in daily life tasks, which is particularly relevant given the study context and its important practical implications for our society. PMID- 30244004 TI - Odd-skipped related transcription factor 1 (OSR1) suppresses tongue squamous cell carcinoma migration and invasion through inhibiting NF-kappaB pathway. AB - Tongue squamous cell carcinoma (TSCC) is the most common cancers of oral, owing to the high invasive and metastatic ability, patients with TSCC have poor prognosis, it's important to explore the regulatory mechanism of TSCC invasion and metastasis. Previous studies suggest OSR1 suppresses the progression of gastric cancer and renal cell carcinoma, but its role in TSCC hasn't been studied. Here, we found OSR1 was downregulated in TSCC cells and specimens, Transwell and 3D spheroid invasion assay suggested OSR1 overexpression inhibited TSCC cell migration and invasion, while its knockdown promoted TSCC cell migration and invasion. Mechanism analysis found OSR1 expression was negatively correlated with NF-kappaB pathway and its targets. Western blot and NF-kappaB activity analysis suggested OSR1 inhibited NF-kappaB activity. Double inhibition of OSR1 and NF-kappaB significantly inhibited TSCC cell migration and invasion. These findings suggested OSR1 inhibited TSCC cell migration and invasion through inhibiting NF-kappaB pathway. PMID- 30244006 TI - Structural modulation of a periplasmic sugar-binding protein probes into its evolutionary ancestry. AB - Substrate-binding proteins (SBPs) are periplasmic proteins consisting of two alpha/beta domains joined by a hinge region with specificity towards cognate ligands. Based on three-dimensional fold, sugar-specific SBPs have been classified into cluster B and cluster D-I. The analysis of sequences and structures of sugar-binding pocket of cluster D-I SBPs revealed the presence of extra residues on two loops (L1, L2) and a helix (H1) in few members of this family, that binds specifically to monosaccharides. Presence of conserved histidine in L2 and tryptophan in H1 can be considered as the identity marks for the cluster D-I monosaccharide-binding SBPs. A glucose binding protein (ppGBP) from Pseudomonas putida CSV86 was found to contain a structural fold similar to oligosaccharide-binding cluster D-I SBPs, but functionally binds to only glucose due to constriction of its binding pocket mainly by L2 (375-382). ppGBP with partial deletion of L2 (ppGBPDeltaL2) was created, crystallized and biochemical characterization was performed. Compared to wild type ppGBP, the ppGBPDeltaL2 structure showed widening of the glucose-binding pocket with ~80% lower glucose binding. Our results show that the substrate specificity of SBPs can be altered by modulating the size of the binding pocket. Based on this, we propose a sub classification of cluster D-I SBPs into (i) cluster D-I(a)-monosaccharide-binding SBPs and (ii) cluster D-I(b)-oligosaccharide-binding SBPs. This study also provides the direct structural and functional correlation indicating that divergence of proteins may occur through insertions or deletions of sequences in the already existing SBPs leading to evolution at the functional level. PMID- 30244007 TI - In Vitro and In Vivo Correlation of Hepatic Fraction of Metabolism by P450 in Dogs. AB - 1-Aminobenzotriazole (ABT) has been widely used as a nonspecific mechanism-based inhibitor of cytochrome P450 (P450) enzymes. It is extensively used in preclinical studies to determine the relative contribution of oxidative metabolism mediated by P450 in vitro and in vivo. The aim of present study was to understand the translation of fraction metabolized by P450 in dog hepatocytes to in vivo using ABT, for canagliflozin, known to be cleared by P450-mediated oxidation and UDP-glucuronosyltransferases-mediated glucuronidation, and three drug discovery project compounds mainly cleared by hepatic metabolism. In a dog hepatocyte, intrinsic clearance assay with and without preincubation of ABT, three Lilly (LY) compounds exhibited a wide range of fraction metabolized by P450. Subsequent metabolite profiling in dog hepatocytes demonstrated a combination of metabolism by P450 and UDP-glucuronosyltransferases. In vivo, dogs were pretreated with 50 mg/kg ABT or vehicle at 2 h before intravenous administration of canagliflozin and LY compounds. The areas under the concentration-time curve (AUC) were compared for the ABT-pretreated and vehicle pretreated groups. The measured AUCABT/AUCveh ratios were correlated to fraction of metabolism by P450 in dog hepatocytes, suggesting that in vitro ABT inhibition in hepatocytes is useful to rank order compounds for in vivo fraction of metabolism assessment. PMID- 30244008 TI - Impact of Different Dry and Wet Granulation Techniques on Granule and Tablet Properties: A Comparative Study. AB - Four granulation techniques were compared evaluating their impact on granule properties and the tablet tensile strength. A common formulation was chosen to be processed with both wet and dry granulation techniques: roll compaction/dry granulation, high-shear granulation, twin-screw granulation, and fluidized-bed granulation. The produced granules were characterized in terms of granule size distribution, X-ray powder diffraction, scanning electron microscopy, porosity, and strength. Granules were tableted, and the tablets were evaluated in terms of tensile strength and mass variation. A particular focus was given to granule strength measurements. Granule strength showed to be strongly affected by the used granulation technique. Moreover, a nonlinear inverse correlation was identified between granule strength and tablet tensile strength. High-shear granulation produced the densest and strongest granules, which presented the lowest tablet tensile strength. Granules manufactured by roll compaction/dry granulation showed no loss in tabletability with the used formulation even for the more compacted and strong granules. Tablets produced by the fluidized-bed granulation showed the best properties in terms of tensile strength and mass variation. However, twin-screw granulation presented comparable results for the specific formulation evaluated in the study, thus revealing a great potential of this technique. PMID- 30244009 TI - A Composite Model for the Transport of Hydrophilic and Lipophilic Compounds Across the Skin: Steady-State Behavior. AB - A porous pathway feature has been added to an existing skin diffusion model to extend the range of applicability to highly polar solutes that do not readily diffuse across the stratum corneum (SC) lipid/corneocyte matrix. The porous pathway consists of 2 components: Pathway A is appendageal and is implemented as an array of aqueous shunts (the macropores), which themselves have microporous walls with transient aqueous pores (the micropores). Two varieties of shunts are discussed, one representing a terminal hair follicle and the other representing an eccrine sweat duct; however, the focus here is on the hair follicle. Pathway B is transcellular, with lipid-phase transport accomplished through defects or breaks in the bilayer lipid structure. The composite model admits polar solutes into the skin in a size-selective manner with an effective micropore radius of 1.6 nm. Steady-state permeabilities, desorption rates from isolated SC, and SC/water partition coefficients of both polar and lipophilic solutes are effectively explained. PMID- 30244010 TI - Lactulose: A Model System to Investigate Solid State Amorphization Induced by Milling. AB - In this article, we show that crystalline lactulose can be amorphized directly in the solid state by mechanical milling. Moreover, compared to similar materials, the amorphization kinetics of lactulose is found to be very rapid and the amorphous state thus obtained appears to be very stable against recrystallization on heating. These features make lactulose a model compound for this type of solid state transformation. The ease of crystalline lactulose to be amorphized on milling is explained by comparing elastic constants of lactulose with those of several other disaccharides. These constants have been determined by molecular dynamics simulations. The article also shows how isothermal dissolution calorimetry can be used effectively for the determination of amorphization kinetics during grinding when the usual characterization techniques (differential scanning calorimetry and powder X-ray diffraction) fail. PMID- 30244011 TI - Commentary on Fit-For-Purpose Models for Regulatory Applications. AB - Model-based analyses have been applied to influence various drug development and regulatory decisions in the last 2 decades. Applied models range from empirical models to highly complex mechanistic models. "Fit-for-purpose" has been the principle to determine the level of model complexity. While numerous case studies have been published to highlight the impact and value of model-based analyses, more experience and lessons are being accumulated to address new challenges and create more opportunities. The inclusion of Model-Informed Drug Development in the Prescription Drug User Fee Act (PDUFA) VI represents a new landmark for the field of quantitative clinical pharmacology. PMID- 30244005 TI - Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection. AB - The functional significance of the selective enrichment of the omega-3 essential fatty acid docosahexaenoic acid (DHA; 22C and 6 double bonds) in cellular membrane phospholipids of the nervous system is being clarified by defining its specific roles on membrane protein function and by the uncovering of the bioactive mediators, docosanoids and elovanoids (ELVs). Here, we describe the preferential uptake and DHA metabolism in photoreceptors and brain as well as the significance of the Adiponectin receptor 1 in DHA retention and photoreceptor cell (PRC) survival. We now know that this integral membrane protein is engaged in DHA retention as a necessary event for the function of PRCs and retinal pigment epithelial (RPE) cells. We present an overview of how a) NPD1 selectively mediates preconditioning rescue of RPE and PR cells; b) NPD1 restores aberrant neuronal networks in experimental epileptogenesis; c) the decreased ability to biosynthesize NPD1 in memory hippocampal areas of early stages of Alzheimer's disease takes place; d) NPD1 protection of dopaminergic circuits in an in vitro model using neurotoxins; and e) bioactivity elicited by DHA and NPD1 activate a neuroprotective gene-expression program that includes the expression of Bcl-2 family members affected by Abeta42, DHA, or NPD1. In addition, we highlight ELOVL4 (ELOngation of Very Long chain fatty acids-4), specifically the neurological and ophthalmological consequences of its mutations, and their role in providing precursors for the biosynthesis of ELVs. Then we outline evidence of ELVs ability to protect RPE cells, which sustain PRC integrity. In the last section, we present a summary of the protective bioactivity of docosanoids and ELVs in experimental ischemic stroke. The identification of early mechanisms of neural cell survival mediated by DHA-synthesized ELVs and docosanoids contributes to the understanding of cell function, pro-homeostatic cellular modulation, inflammatory responses, and innate immunity, opening avenues for prevention and therapeutic applications in neurotrauma, stroke and neurodegenerative diseases. PMID- 30244012 TI - Formulation Optimization of Chitosan-Stabilized Silver Nanoparticles Using In Vitro Antimicrobial Assay. AB - Antimicrobial resistance at the infected site is a serious medical issue that increases patient morbidity and mortality. Silver has antibacterial activity associated with some dose-dependent toxicity. Silver nanoparticles, due to larger surface area, have antibacterial properties, which make them useful in the treatment of infections. Chitosan-stabilized silver nanoparticles (CH-AgNP) were formulated and evaluated for minimal inhibitory concentration and minimal bactericidal concentration testing against Staphylococcus aureus ATCC 29213, S aureus ATCC 25923, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, and 20 methicillin-resistant S aureus isolates. Minimum biofilm eradication concentration study was used to evaluate the biofilm reduction, and in vitro antimicrobial checkerboard assays were performed. The effective optimum ratio of AgNP:chitosan solution was 1:4. Minimal inhibitory concentration and minimal bactericidal concentration ranges of CH-AgNP were 4 to 14 times lower compared to AgNP alone against methicillin-resistant S aureus isolates. Minimum biofilm eradication concentration values of CH-AgNP for ATCC PA-01, P aeruginosa isolate 1, and P aeruginosa isolate 2 were found to be >84.59 MUg/mL, 42.29 MUg/mL, and 21.15 MUg/mL, respectively. Thus, CH-AgNP is a potential formulation for wound treatment and management of infected sites associated with antimicrobial resistance. PMID- 30244013 TI - Impact of method of preparation of Amorphous Solid Dispersions on Mechanical Properties: Comparison of co-precipitation and spray drying. AB - Usage of the amorphous phase of compounds has become the method of choice to overcome oral bioavailability problems related to poor solubility. Due to the unstable nature of glasses, it is clear that the method preparation of the amorphous glass will have an impact on physical/chemical stability and in turn in vivo performance. The method of preparation can also have a profound impact on the mechanical properties of the amorphous phase. We have explored the impact of preparation method on the mechanical properties of an amorphous solid dispersion using a development compound, GDC-0810. Three methods were used to generate amorphous solid dispersions (ASD) of 50% GDC-0810 with HPMC-as: (i) Spray drying (SDD), (ii) Co-precipitation using overhead mixing (OHM), and (iii) Co precipitation using resonant acoustic mixing (RAM). All three methods were found to generate ASDs with good phase mixing and similar glass transition temperatures. Coprecipitated ASD powders (OHM and RAM) demonstrated superior tabletability and flow properties when compared to the SDD powder. Careful choice of manufacturing process can be used to tune material properties of ASDs to make them more amenable for downstream operations like tableting. Acoustic mixing has been demonstrated as a scalable new method to make ASDs through co-precipitation. PMID- 30244014 TI - Drug Repurposing for Ebola Virus Disease: Principles of Consideration and the Animal Rule. AB - There are no approved drugs or biologics to treat Ebola virus disease (EVD). Literature reviews identified a list of 141 drugs with reports of preliminary in vitro potency and/or in vivo effectiveness in animals or with reports of clinical use/trials in EVD patients. The majority of these drugs have been individually approved by the U.S. Food and Drug Administration for treating various non-EVD diseases. The anti-Ebola potency data of these drugs were curated from literature and publicly accessible databases, along with their individual biopharmaceutical and pharmacokinetic characteristics. To facilitate the development of antiviral drugs including anti-EVD drugs, highlights include optimization of the exposure response relationship, design of a safe and effective clinical dosing regimen to achieve an adequate high ratio of clinical Cmin to a plasma protein binding adjusted EC95, and the pharmacokinetic studies needed in animal models (healthy and affected) and in healthy volunteers. The exposure/response relationship for human dose selection is summarized, as described in the U.S. Food and Drug Administration "Animal Rule'' guidance when human efficacy studies are not ethical or feasible. PMID- 30244015 TI - Stochastic hybrid models of gene regulatory networks - A PDE approach. AB - A widely used approach to describe the dynamics of gene regulatory networks is based on the chemical master equation, which considers probability distributions over all possible combinations of molecular counts. The analysis of such models is extremely challenging due to their large discrete state space. We therefore propose a hybrid approximation approach based on a system of partial differential equations, where we assume a continuous-deterministic evolution for the protein counts. We discuss efficient analysis methods for both modeling approaches and compare their performance. We show that the hybrid approach yields accurate results for sufficiently large molecule counts, while reducing the computational effort from one ordinary differential equation for each state to one partial differential equation for each mode of the system. Furthermore, we give an analytical steady-state solution of the hybrid model for the case of a self regulatory gene. PMID- 30244016 TI - Impact of glutathione modulation on the toxicity of the Fusarium mycotoxins deoxynivalenol (DON), NX-3 and butenolide in human liver cells. AB - DON, NX-3 and butenolide (BUT) are secondary metabolites formed by Fusarium graminearum. Evidence for formation of DON-glutathione adducts exists in plants, and also in human liver (HepG2) cells mass spectrometric evidence for GSH-adduct formation was reported. NX-3 is a DON derivative lacking structural features for Thiol-Michael addition, while BUT has the structural requirements (conjugated double bond and keto group). In the present study, we addressed whether these structural differences affect levels of intracellular reactive oxygen species in HepG2 cells, and if intracellular GSH levels influence toxic effects induced by DON, NX-3 and BUT. Pre-treatment with an inhibitor of GSH bio-synthesis, L buthionine-[S,R]-sulfoximine, aggravated substantially BUT-induced cytotoxicity (>=50 MUM, 24 h), but only marginally affected the cytotoxicity of DON and NX-3 indicating that GSH-mediated detoxification is of minor importance in HepG2 cells. We further investigated whether BUT, a compound inducing alone low oral toxicity, might affect the toxicity of DON. Under different experimental designs with respect to pre- and/or co-incubations, BUT was found to contribute to the combinatorial cytotoxicity, exceeding the toxic effect of DON alone. The observed combinatorial effects underline the potential contribution of secondary metabolites like BUT, considered to be alone of low toxicological relevance, to the toxicity of DON or structurally related trichothecenes, arguing for further studies on the toxicological relevance of naturally occurring mixtures. PMID- 30244017 TI - Outcomes and Durability of Endovascular Aneurysm Repair in Octogenarians. AB - BACKGROUND: Endovascular aneurysm repair (EVAR) accounts for the majority of all abdominal aortic aneurysm (AAA) repairs in the United States. EVAR utilization in the aging population is increasing due to the minimally invasive nature of the procedure, the low associated perioperative morbidity, and early survival benefit over open repair. The objective of this study is to compare the outcomes of octogenarians after elective EVAR to their younger counterparts, a question that can be answered by a long-term, institutional data set. METHODS: This was a retrospective series of 255 patients, who underwent elective EVAR within our institution from 2008 to 2015. A comparative analysis of patients aged 80 years and older and less than 80 years was performed. Outcomes measured included perioperative death and myocardial infarction (MI), length of stay, and readmission within 30 days. Aneurysm reintervention, long-term surveillance imaging, and aneurysm-related deaths were also evaluated. In addition, subset analyses of octogenarians were compared for survival at 24 months. RESULTS: Overall, 255 patients were included in our analysis. Fifty-nine patients were octogenarians, and 196 patients were nonoctogenarians. The mean age difference between the two groups was significant (84.5 years [SD, +/-3.44] vs. 69.6 years [SD, +/-6.13] in the >=80 and <80 groups, respectively; P < 0.0001). There was no significant difference in the mean aneurysm size (6.03 cm [SD, +/-1.12] vs. 5.535 cm [SD, +/-0.9]; P < 0.06) between the >=80 and < 80 groups. Octogenarians had higher rates of perioperative MI (5% vs. 1%, P < 0.04), thirty-day mortality (7% vs. 0%, P < 0.003), a higher number of perioperative complications (0.64 incidence per patient [SD, +/-1.11] vs. 0.31 [SD, +/-0.69], P < 0.005), and a longer mean hospital stay (5.34 [SD, +/-5.75] days vs. 3.16 [SD, +/-3.23] days, P < 0.0003), and they were also less likely to be discharged home after surgery (75% vs. 91%, P < 0.002). In the evaluated long-term outcomes, the two groups were similar with regard to aneurysm reintervention (10% vs. 9%, P < 0.06) and the stability of aneurysm sac size on imaging at last follow-up (71% vs. 80%, P < 0.27). The overall aortic related cause of death was different between the groups (8% vs. 1%, P < 0.003); however, the long-term aortic related mortality was not different between the two groups (2% vs. 1%, P < 0.4). Finally, a subset analysis of the octogenarian group was performed comparing patients based on survival status at 24 months. Higher preoperative creatinine (1.73 mg/dL [SD, +/-1.54] vs. 1.15 mg/dL [SD, +/-0.46]) and lower preoperative hematocrit (33.9% [SD, +/-3.43] vs. 37.2% [SD, +/-4.9]) along with number of perioperative complications (1.2 incidence per patient [SD, +/-1.74] vs. 0.45 [SD, +/-0.73]) were associated with death at 24 months after the index operation. CONCLUSIONS: Elective endovascular repair of AAA in octogenarians carries a higher risk of perioperative mortality but acceptable long-term outcomes. Appropriateness of elective EVAR in octogenarians should be answered based on this potential short-lived survival benefit, taking into account that advanced age should not be the sole basis of exclusion for otherwise suitable candidates for elective EVAR. PMID- 30244018 TI - Experience-dependent c-Fos expression in the primary chemosensory cortices of the rat. AB - Eating a new food is a unique event that guides future food choices. A key element for these choices is the perception of flavor (odor-taste associations), a multisensory process dependent upon taste and smell. The two primary cortical areas for taste and smell, gustatory cortex and piriform cortex, are thought to be crucial regions for processing and responding to odor-taste mixtures. To determine how previous experience impacts the primary chemosensory cortices, we compared the expression of the immediate early gene, c-Fos, between rats presented with a taste, an odor, or an odor-taste mixture for the first-time with rats that had many days of prior experience. Compared to rats with prior experience, we found that first-time sampling of all three chemosensory stimuli led to significantly greater c-Fos expression in gustatory cortex. In piriform cortex, only the novel chemosensory stimuli containing odors showed greater c-Fos expression. These results indicate that prior experience with taste, odor, or odor-taste stimuli habituates responses in the primary chemosensory cortices and adds further evidence supporting gustatory cortex as a fundamental node for the integration of gustatory and olfactory signals. PMID- 30244019 TI - Nestorone exerts long-term neuroprotective effects against transient focal cerebral ischemia in adult male rats. AB - Progesterone (P4) exerts long-term neuroprotective effects in animal models of stroke, and P4 receptors play a crucial role in this neuroprotection. However, it currently remains unclear whether the activation of P4 receptors alone is sufficient to exert long-term neuroprotection because P4 exhibits other steroidogenic and GABAergic activities via several of its metabolites. Nestorone is a potent selective P4 receptor agonist without other steroidogenic and GABAergic activities. Therefore, we examined the effects of nestorone in adult male rats subjected to transient middle cerebral artery occlusion (MCAO). The dose-response relationship of nestorone showed that the 6-h post-ischemic administration of 10 MUg/kg nestorone resulted in greater reductions in infarct sizes 48 h after MCAO than the other two doses tested (5 and 80 MUg/kg), and this dose of nestorone significantly decreased astrocyte activation in the peri infarct cortical region. Moreover, 10 MUg/kg nestorone significantly prevented functional impairments on the 28th and 29th days and slightly reduced infarct size on the 30th day after MCAO. The present results suggest that the activation of P4 receptors alone is sufficient to exert neuroprotection against transient cerebral ischemia in adult male rats; therefore, nestorone is a promising agent in post-stroke treatment due to its potent progestational effects without other steroid-related activities. PMID- 30244020 TI - Macromolecule-suppressed GABA measurements correlate more strongly with behavior than macromolecule-contaminated GABA+ measurements. AB - The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is known to be fundamental to the neuronal processes underlying visual orientation and vibrotactile frequency and amplitude discrimination. Previous studies have demonstrated that performance on visual and vibrotactile psychophysics tasks is associated with in vivo measurements of "GABA+" levels - a measure of GABA substantially contaminated by a macromolecular (MM) signal. Here, we establish that these prior findings are indeed driven by the GABA fraction of that signal. Edited magnetic resonance spectroscopy (MRS) was used to measure GABA with and without MM suppression in the sensorimotor (SM1) and occipital cortices in 14 healthy male adults. Volunteers also underwent psychophysical experiments to assess their performance on visual orientation discrimination and vibrotactile amplitude and frequency discrimination. We show that MM-suppressed GABA levels correlate more strongly with individual differences in vibrotactile (in the case of SM1 GABA; amplitude: r = -0.63, p = 0.03; frequency: r = -0.62, p = 0.02) and visual orientation (in the case of occipital GABA; r = -0.59, p = 0.05) discrimination thresholds than GABA levels contaminated by MM (vibrotactile amplitude: r = -0.36, p = 0.30; vibrotactile frequency: r = -0.53, p = 0.09; visual orientation: r = 0.21, p = 0.55). These findings further support the view that measurements of endogenous GABA acquired with edited MRS can usefully probe neurochemical-behavioral relationships in humans. Moreover, the more specific measurement of GABA used in this study provides increased statistical power to observe these regionally specific relationships. PMID- 30244021 TI - Breathing stimulation mediated by 5-HT1A and 5-HT3 receptors within the preBotzinger Complex of the adult rabbit. AB - Serotonin (5-HT) has been reported to play excitatory effects on respiration by acting on preBotzinger complex (preBotC) neurons in neonatal or juvenile rodents. However, whether its action is circumscribed to the preBotC and present in other animal species, particularly in adult preparations, is unknown. We investigated the respiratory role of 5-HT within the preBotC and neighbouring respiration related regions. Experiments were performed on alpha-chloralose-urethane anesthetized, vagotomized, paralyzed and artificially ventilated rabbits making use of bilateral microinjections (30-50 nl). 5-HT caused excitatory effects on respiratory activity only when applied to the preBotC. These effects were mediated by 5-HT1A and 5-HT3 receptors as shown by microinjections of specific agonists of the different types of 5-HT receptors. Unexpectedly, the blockade of 5-HT1A receptors by methysergide or the specific antagonist (S)-WAY 100135 induced excitatory respiratory effects. Microinjections of the 5-HT3 receptor antagonist ondansetron did not influence respiration, but prevented (S)-WAY 100135-induced responses. The blockade of GABAA receptors by bicuculline within the preBotC prevented the effects of the 5-HT1A receptor agonist 8-OH-DPAT. The involvement of GABAergic inhibition and 5-HT1A receptor-mediated disinhibition is also corroborated by immunohistochemical data. The results show for the first time in an adult animal preparation that 5-HT plays a pivotal role in the modulation of the preBotC activity probably via both presynaptic and postsynaptic mechanisms and highlight the importance of disinhibition phenomena. Present findings may be relevant to some respiratory disorders in which an impairment of central 5-HT mechanisms has been reported, such as sleep apnoea and sudden infant death syndrome. PMID- 30244022 TI - Dynorphin/kappa-opioid receptor control of dopamine dynamics: Implications for negative affective states and psychiatric disorders. AB - Negative affective states are prevalent symptoms in a plethora of neuropsychiatric disorders, including depression and drug addiction. Dysfunction of mesocorticolimbic dopamine systems has been implicated in negative affective states in neuropsychiatric disorders. The dynorphin/kappa-opioid receptor system is a powerful effector of stress-related behavior and is highly enriched within the mesocorticolimbic dopamine system. Dysfunction of dynorphin/KOR signaling within the mesocorticolimbic dopamine system is implicated in promoting symptoms in neuropsychiatric disorders. As such, the kappa-opioid receptor system provides an important therapeutic target to treat negative affective states associated with psychiatric disorders. In this review, we provide a comprehensive overview of the dynorphin/kappa-opioid receptor system and its role in regulating the mesocorticolimbic dopamine system, motivation, and emotional behavior. Furthermore, we highlight unresolved issues in the field and offer some insights for future research. PMID- 30244023 TI - Characterizing drug-induced capillary leak syndromes using the World Health Organization VigiBase. PMID- 30244024 TI - Food protein-induced enterocolitis syndrome: Increased prevalence of this great unknown-results of the PREVALE study. PMID- 30244025 TI - GM-CSF intrinsically controls eosinophil accumulation in the setting of allergic airway inflammation. AB - BACKGROUND: Eosinophils are a therapeutic target in asthmatic patients, and GM CSF has been suggested to control various aspects of eosinophil biology, including development, function, and survival. However, to date, the role of GM CSF signaling in eosinophils in vivo is largely unclear. OBJECTIVE: We sought to elucidate the role of GM-CSF signaling in asthmatic inflammation. METHODS: Wild type and GM-CSF receptor alpha (Csf2ra)-deficient mice reconstituted with Csf2ra proficient alveolar macrophages were subjected to different models of airway inflammation to evaluate the effect of GM-CSF signaling deficiency on asthmatic inflammation in general and on eosinophils in particular. RESULTS: We demonstrate that GM-CSF signaling, although being largely dispensable for eosinophil development at steady state, intrinsically promotes accumulation of eosinophils in the lung during allergic airway inflammation. In contrast, chitin-induced eosinophil accumulation in the peritoneal cavity occurs independent of GM-CSF, indicating organ specificity. We show that GM-CSF induces chemokinesis and promotes eosinophil survival in vitro, which likely contribute to eosinophil accumulation in the airways in vivo. CONCLUSION: GM-CSF intrinsically promotes eosinophil accumulation in the setting of pulmonary allergic inflammation. PMID- 30244026 TI - Applying a Novel Population-Based Model Approach to Estimating Breath Alcohol Concentration (BrAC) from Transdermal Alcohol Concentration (TAC) Biosensor Data. AB - Alcohol biosensor devices have been developed to unobtrusively measure transdermal alcohol concentration (TAC), the amount of ethanol diffusing through the skin, in nearly continuous fashion in naturalistic settings. Because TAC data are affected by physiological and environmental factors that vary across individuals and drinking episodes, there is not an elementary formula to convert TAC into easily-interpretable metrics like blood and breath alcohol concentrations (BAC/BrAC). In our prior work, we addressed this conversion problem in a deterministic way by developing physics/physiological-based models to convert TAC to estimated BrAC (eBRAC), in which the model parameter values were individually determined for each person wearing a specific transdermal sensor using simultaneously collected TAC (via a biosensor) and BrAC (via a breath analyzer) during a calibration episode. We found these individualized parameter values produced relatively good eBrAC curves for subsequent drinking episodes, but our results also indicated the models were not fully capturing the dynamics of the system and variations across drinking episodes. Here, we report on a novel mathematical framework to improve our ability to model eBrAC from TAC data that uses aggregate population data instead of individualized calibration data to determine model parameter values via a random diffusion equation. We first provide the theoretical mathematical basis for our approach, and then test the efficacy of this method using datasets of contemporaneous BrAC/TAC measurements obtained by a) a single subject during multiple drinking episodes and b) multiple subjects during single drinking episodes. For each dataset, we used a set of drinking episodes to construct the population model, and then ran the model with another set of randomly-selected test episodes. We compared raw TAC data to model-simulated TAC curve, breath analyzer BrAC data to model eBrAC curves with 75% credible bands, episode summary scores of peak BrAC, times of peak BrAC, and area under the drinking curve also with 75% credible intervals, and report the percent of the raw BrAC captured within the eBrAC curve credible bands. We also display results when stratifying the data based on the relationship between the raw BrAC and TAC data. Results indicate the population based model is promising, with better fit within a single participant when stratifying episodes. This study provides initial proof-of-concept for constructing, fitting, and using a population-based model to obtain estimates and error bands for BrAC from TAC. The advancements in this study, including new applications of math, the development of a population-based model with error bars, and the production of corresponding Matlab codes, represent a major step forward in our ability to produce quantitatively- and temporally-accurate estimates of BrAC from TAC biosensor data. PMID- 30244027 TI - Bio-inspired and optimized interlocking features for strengthening metal/polymer interfaces in additively manufactured prostheses. AB - Biomedical and dental prostheses combining polymers with metals often suffer failure at the interface. The weak chemical bond between these two dissimilar materials can cause debonding and mechanical failure. This manuscript introduces a new mechanical interlocking technique to strengthen metal/polymer interfaces through optimized additively manufactured features on the metal surface. To reach an optimized design of interlocking features, we started with the bio-mimetic stress-induced material transformation (SMT) optimization method. The considered polymer and metal materials were cold-cured Poly(methyl methacrylate) (PMMA) and laser-sintered Cobalt-Chromium (Co-Cr), respectively. Optimal dimensions of the bio-inspired interlocking features were then determined by mesh adaptive direct search (MADS) algorithm combined with finite element analysis (FEA) and tensile experiments such that they provide the maximum interfacial tensile strength and stiffness while minimizing the stress in PMMA and the displacement of PMMA at the Co-Cr/PMMA interface. The SMT optimization process suggested a Y-shape as a more favorable design, which was similar to mangrove tree roots. Experiments confirmed that our optimized interlocking features increased the strength of the Co-Cr/PMMA interface from 2.3 MPa (flat interface) to 34.4 +/- 1 MPa, which constitutes 85% of the tensile failure strength of PMMA (40.2 +/- 1 MPa). STATEMENT OF SIGNIFICANCE: The objective of this study was to improve metal/polymer interfacial strength in dental and orthopedic prostheses. This was achieved by additive manufacturing of optimized interlocking features on metallic surfaces using laser-sintering. The interlocking design of the features, which was a Y shape similar to the roots of mangrove trees, was inspired by a bio-memetic optimization algorithm. This interlocking design lowered the PMMA displacement at the Co-Cr/PMMA interface by 70%, enhanced the interfacial strength by more than 12%, and increased the stiffness by 18% compared with a conventional bead design, meanwhile no significant difference was found in the toughness of both designs. PMID- 30244028 TI - Indicator of RNA oxidation in urine for the prediction of mortality in patients with type 2 diabetes and microalbuminuria: A post-hoc analysis of the Steno-2 trial. AB - OBJECTIVE: The RNA oxidation product, 8-oxo-7,8-dihydroguanosine (8-oxoGuo), has been associated with mortality in patients with type 2 diabetes (T2D). However, the identification and the potential effect of approved treatments decreasing urine 8-oxoGuo level remain unraveled. In the Steno-2 study intensified multifactorial treatment compared with conventional multifactorial treatment reduced mortality in T2D patients with microalbuminuria by 45%. We assessed association between 8-oxoGuo at advanced baseline and total mortality with up to 19.9 years follow-up and from end of intervention to end of follow-up up to (up to 13.9 years). MATERIALS AND METHODS: In 1993, 160 T2D patients with microalbuminuria were included in the Steno-2 trial. Urine samples from baseline were not available, but samples were available from 155 patients (97%) in 1995 (advanced baseline) and from 125 patients (96%) in 2001 (end of intervention). Hazard ratios (HR) for log2-transformed 8-oxoGuo and dichotomized (cut-off at median; low vs. high RNA oxidation) were estimated using Cox regressions. RESULTS: During follow-up of 19.9 years after advanced baseline, 89 died and no association between 8-oxoGuo and mortality was found (p = 0.40). From the end of 7.8 years of intervention and during remaining 13.9 years of observation, 61 died and doubling the urine 8-oxoGuo level was associated with mortality with a HR 3.08 (95% CI [1.86 -5.12]; p < 0.001) after multiple adjustments. Patients with low 8-oxoGuo in the intensified-treatment had the lowest risk of dying compared with high 8-oxoGuo in the conventional-treatment both from advanced baseline onwards, adjusted HR 0.40 (95% CI [0.21 -0.75]; p = 0.004), and from end of intervention onwards, adjusted HR 0.28 (95% CI [0.13 -0.61]; p = 0.001). CONCLUSIONS: In T2D patients with microalbuminuria, high levels of urine 8-oxoGuo after 7.8 years of multifactorial intervention was associated with higher mortality during 13.9 years of post-trial follow-up. Patients with low 8-oxoGuo in the intensified treatment group had the lowest risk of dying. PMID- 30244029 TI - Oxytocin promotes action prediction. AB - The neuropeptide oxytocin (OT) has been suggested to facilitate social cognition and behavior. As predicting others' behavior is at the core of human social cognitive abilities and is indispensable for successful social interaction, we hypothesized that OT would increase action prediction. To test this hypothesis, 61 male and female healthy participants self-administered OT or placebo intranasally and their anticipatory eye-movements were recorded using eye tracking techniques. We found that the ability to predict others' future actions was enhanced following OT treatment. This effect was mediated by the time to the first anticipatory eye-movement suggesting that improved action prediction might operate by increased attention to social cues. These findings provide direct evidence for the role of OT in promoting perception and processing of social cues. PMID- 30244030 TI - Light as a modulator of emotion and cognition: Lessons learned from studying a diurnal rodent. AB - Light profoundly affects the behavior and physiology of almost all animals, including humans. One such effect in humans is that the level of illumination during the day positively contributes to affective well-being and cognitive function. However, the neural mechanisms underlying the effects of daytime light intensity on affect and cognition are poorly understood. One barrier for progress in this area is that almost all laboratory animal models studied are nocturnal. There are substantial differences in how light affects nocturnal and diurnal species, e.g., light induces sleep in nocturnal mammals but wakefulness in diurnal ones, like humans. Therefore, the mechanisms through which light modulates affect and cognition must differ between the chronotypes. To further understand the neural pathways mediating how ambient light modulates affect and cognition, our recent work has developed a diurnal rodent model, the Nile grass rat (Arvicanthis niloticus), in which daytime light intensity is chronically manipulated in grass rats housed under the same 12:12 hour light/dark cycle. This simulates lighting conditions during summer-like bright sunny days vs. winter like dim cloudy days. Our work has revealed that chronic dim daylight intensity results in higher depression- and anxiety-like behaviors, as well as impaired spatial learning and memory. Furthermore, we have found that hypothalamic orexin is a mediator of these effects. A better understanding of how changes in daytime light intensity impinge upon the neural substrates involved in affect and cognition will lead to novel preventive and therapeutic strategies for seasonal affective disorder, as well as for non-seasonal emotional or cognitive impairments associated with light deficiency. PMID- 30244031 TI - Rationale and Efficacy of Sound Therapies for Tinnitus and Hyperacusis. AB - Sound therapies are a common component of treatments for tinnitus and hyperacusis. The original idea was to partially or completely mask tinnitus with broadband noise delivered by sound generators or hearing aids, for a few hours each day. Over several months, many patients reported that their tinnitus became quieter or easier to bear, and that loud sounds became less aversive. However, it wasn't always clear that these benefits could be attributed to sound therapy rather than to other aspects of treatment, such as counseling or hearing aid use, and not all patients reported benefits. During the past few decades, many other sound stimuli have been tried, including narrower bands of noise and tone bursts, music, and nature sounds. These sounds have been filtered in relation to the tinnitus pitch, adjusted for hearing loss, amplitude-modulated, and recently paired with electrical nerve stimulation. Many of our ideas about the neural underpinnings of tinnitus and hyperacusis come from animal models. However, studies of sound treatments in animals with putative tinnitus or hyperacusis have been rare. Clinical sound therapy trials are emerging, but outcomes typically remain modest, and few patients achieve complete remission of tinnitus or hyperacusis, unless the underlying hearing loss is treated with hearing aids or implants, in which case success rates are higher. More studies are needed, on both animal models and human subjects, to further explore the rationales for the various sound therapy options reviewed here, and to optimally tailor sounds and treatment approaches to individual patients, so that maximum benefits can be obtained. PMID- 30244032 TI - Modulation of Motor Learning Capacity by Transcranial Alternating Current Stimulation. AB - Motor function can be modulated by transcranial alternating current stimulation (tACS) in alpha, beta, and high-gamma frequencies. However, few studies have investigated tACS-induced behavioral changes in combination with endogenous oscillatory neural activity in detail. Herein, we investigated the effect of tACS on motor learning capacity and endogenous oscillatory neural activity. Fifty-two healthy volunteers were randomly assigned to four stimulation groups (10 Hz, 20 Hz, 70 Hz, or sham) and performed a visually cued button press motor learning task before and after tACS, which was delivered at the left primary motor area. Oscillatory neural activities during the motor learning task were measured using magnetoencephalography (MEG). Following tACS, the capacity for motor learning was significantly increased for 70 Hz tACS compared to sham stimulation. Oscillation analysis revealed a significant increase in beta-band power after 70-Hz tACS but not in the other stimulation groups. Our finding that capacity for motor learning and endogenous oscillatory beta activity were modulated in parallel after 70-Hz tACS suggests that 70-Hz tACS may increase the motor learning capacity by cross modulating beta oscillatory activity. Because high gamma and beta oscillatory activity have been shown to reflect the activity of excitatory and inhibitory interneuron, our results may derive from the modulation of excitatory and inhibitory interneurons in M1 by 70-Hz tACS. PMID- 30244033 TI - Ent-abietanes from the Godavari mangrove, Ceriops decandra: Absolute configuration and NF-kappaB inhibitory activity. AB - Nine new ent-abietanes, named decandrols A-I (1-9), which could be categorized into three groups (1, 2-6, 7-9), were isolated from the roots of an Indian mangrove, Ceriops decandra, collected in the swamp of Godavari estuary, Andhra Pradesh, together with six previously reported abietanes (10-15), of which the absolute configurations were first determined. The relative and absolute configurations of these compounds were unambiguously established by HR-ESIMS, extensive 1D and 2D NMR investigations, single-crystal X-ray diffraction analysis with Cu Kalpha radiation, and quantum-chemical electronic circular dichroism (ECD) calculations. Decandrol A (1) is a rare C9-spirofused 7,8-seco-ent abietane, whereas 2-15 are typically tricyclic ent-abietanes. Decandrols C (3) and E (5) exhibited significant NF-kappaB inhibitory activity at the concentration of 100 MUM. PMID- 30244034 TI - Indirect ELISA using a multi-epitope recombinant protein to detect antibodies against foot-and-mouth disease virus serotype O in pigs. AB - Foot-and-mouth disease (FMD) is a devastating animal disease. A previously developed multi-epitope protein B4 vaccine of the FMD virus (FMDV) serotype O provides safety advantages over inactivated vaccines and could be used to prevent and control FMD in pigs. Commercial enzyme-linked immunosorbent assay (ELISA) kits for assessing vaccine efficacy are available for the inactivated vaccines but not for the multi-epitope protein vaccine. In this study, multi-epitope protein B4 was expressed in Escherichia coli, and an indirect ELISA (I-ELISA) was developed to detect antibodies against FMDV serotype O in pigs. The specificity and sensitivity were 96.7% and 95.9%, respectively. B4-vaccinated pigs yielded B4 I-ELISA serum values that were positively correlated with clinical protection against challenge with FMDV serotype O. The I-ELISA's ability to detect antibodies from animals vaccinated with the inactivated vaccine was also evaluated, and the B4 I-ELISA values were significantly positively correlated with liquid-phase blocking ELISA (LPBE) titers (r = 0.6708, p < 0.0001); thus, the I-ELISA was also suitable for detection of antibodies from swine vaccinated with the inactivated vaccine. PMID- 30244035 TI - LPS-induced histone H3 phospho(Ser10)-acetylation(Lys14) regulates neuronal and microglial neuroinflammatory response. AB - Epigenetic modifications of DNA and histone proteins are emerging as fundamental mechanisms by which neural cells adapt their transcriptional response to environmental cues, such as, immune stimuli or stress. In particular, histone H3 phospho(Ser10)-acetylation(Lys14) (H3S10phK14ac) has been linked to activation of specific gene expression. The purpose of this study was to investigate the role of H3S10phK14ac in a neuroinflammatory condition. Adult male rats received a intraperitoneal injection of lipopolysaccharide (LPS) (830 MUg/Kg/i.p., n = 6) or vehicle (saline 1 mL/kg/i.p., n = 6) and were sacrificed 2 or 6 h later. We showed marked region- and time-specific increases in H3S10phK14ac in the hypothalamus and hippocampus, two principal target regions of LPS. These changes were accompanied by a marked transcriptional activation of interleukin (IL) 1beta, IL-6, Tumour Necrosis Factor (TNF) alpha, the inducible nitric oxide synthase (iNOS) and the immediate early gene c-Fos. By means of chromatin immunoprecipitation, we demonstrated an increased region- and time-specific association of H3S10phK14ac with the promoters of IL-6, c-Fos and iNOS genes, suggesting that part of the LPS-induced transcriptional activation of these genes is regulated by H3S10phK14ac. Finally, by means of multiple immunofluorescence approach, we showed that increased H3S10phK14ac is cell type-specific, being neurons and reactive microglia, the principal histological types involved in this response. Present data point to H3S10phK14ac as a principal epigenetic regulator of neural cell response to systemic LPS and underline the importance of distinct time-, region- and cell-specific epigenetic mechanisms that regulate gene transcription to understand the mechanistic complexity of neuroinflammatory response to immune challenges. PMID- 30244036 TI - Postoperative stroke after anterior cervical discectomy and fusion in patients with carotid artery stenosis: a statewide database analysis. AB - BACKGROUND: Carotid artery injury and stroke secondary to prolonged retraction remains an extremely rare complication in anterior cervical discectomy and fusion (ACDF). However, multiple studies have demonstrated that carotid artery retraction during the surgical approach may alter the normal blood flow, leading to a significant reduction in the cross-sectional area of the vessel. Others have suggested that dislodgment of atherosclerotic plaques following manipulation of the carotid artery can be a potential risk for intracranial embolus and stroke. PURPOSE: We aimed to evaluate: (1) the incidence of postoperative stroke following ACDF and (2) incidence of other postoperative complications in a cohort of patients who had a diagnosis of carotid artery stenosis (CAS) versus those who did not. PATIENT SAMPLE: This study utilized the Statewide Planning and Research Cooperative System database from January 1, 2009 to December 31, 2013. All patients who underwent (ACDF) and had a preoperative diagnosis of CAS were identified using the International Classification of Disease, ninth revision codes. Those who had a previous history of stroke were excluded. Patients who had CAS were propensity score matched to patients without history of CAS for demographics and Charlson/Deyo comorbidity scores. OUTCOME MEASURES: Incidence of postoperative stroke and other complications were compared between the cohorts. The threshold for statistical significance was set at a p<.05. This study received no funding. The authors report no conflict of interests relevant to this study. RESULTS: There were 34,975 patients who underwent an ACDF in the study time period. After excluding those under the age of 18 and with history of previous stroke, there were 61 patients who had CAS that were compared with a propensity-matched cohort. The CAS cohort had a significantly higher incidence of postoperative stroke during their hospitalization (6.6% vs 0%, p<.042). The CAS cohort also had higher rates of acute renal failure (27.9% vs 4.9%, p = .01) and sepsis (18% vs 4.9%, p = .023). There were no stroke related deaths. CONCLUSIONS: Patients with CAS who underwent ACDF had a statistically significant greater incidence of developing a postoperative stroke. To the best of our knowledge, no previous study has evaluated the development of postoperative stroke in patients with CAS undergoing ACDF. Larger, multicenter studies are needed to estimate the true incidence of stroke in this specific patient population. However, our results may illustrate the importance of preoperative optimization, approach selection, and postoperative stroke surveillance in patients with a history of CAS who undergoes ACDF. PMID- 30244037 TI - Resistance of bacterial pathogens to calcium hypochlorite disinfectant and evaluate the usability of treated-filter paper impregnated in Nano-silver composite for drinking water purification. AB - : Objectives To control the bacterial contaminants in drinking water sources, new techniques are urgently demanded to remove pathogenic bacteria using an innovative method achieving the target of purified water. Therefore, this study was aimed to evaluate the biocidal activity of calcium hypochlorite Ca(OCl)2, silver nanoparticles (AgNPs) and its loaded forms (Ca(OCl)2/AgNPs composite) against isolated bacteria from drinking water supplies (tap and hand pump water), then implemented a field trial to evaluate a biocidal filter paper containing Ca(OCl)2/Nano-silver composite against existing bacteria and indicator coliforms bacteria. METHODS: One hundred water samples were collected from the main source and water troughs used for cattle drinking and examined for the presence of pathogenic bacteria. The sensitivity of sixty strains of isolated bacteria were evaluated against Ca(OCl)2, AgNPs and Ca(OCl)2/AgNPs using broth macro dilution method. Thereafter, a field trial was applied through examination of different water samples collected from both water supplies (pre and post-treatment) using filter paper impregnated in Ca(OCl)2/AgNPs. RESULTS: Ca (OCl)2 loaded on AgNPs at a concentration of 1.5mg/L showed the lethal effect on E. Coli, S. aureus and K. pneumoniae (100% each) on exposure to 180minutes. Furthermore, Ca(OCl)2/AgNPs filter paper exhibited a biocidal effect (100%) against the existing bacteria, total viable bacterial count (TVC) CFU/ml, total coliforms (TCC) and fecal coliforms bacteria (FCC) CFU/100ml. CONCLUSIONS: the use of the disinfectant, Ca(OCl)2, against isolated bacteria exhibited the existence of bacterial resistance profile. Therefore, a new trend for enhancement of the biocidal effect of tested disinfectant using Nano-silver particles was reliable proving that Ca(OCl)2/AgNPs had a biocidal effect (100%) against isolated bacteria at 1.5mg/L as well as inactivation of coliforms and pathogenic bacteria during percolation through the bactericidal filter paper. PMID- 30244038 TI - Carbapenem-resistant Pseudomonas aeruginosa carrying blaVIM-36 assigned as ST308: indicated non-virulence in G. mellonella model. AB - OBJECTIVES: Based on pulsed field gel electrophoresis profile, whole genome sequencing (WGS) of 8 CarbR P. aeruginosa strains from a bone marrow transplant unit, in Sao Paulo, Brazil, was carried out to investigate which resistance and virulence genes are present as well as determine the multilocus sequence types (ST). METHODS: Initial susceptible pattern was obtained by Vitek 2. Minimal inhibitory concentrations (MICs) were determined by broth microdilution for amikacin, meropenem and colistin. WGS was performed using Illumina MiSeq. The Galleria mellonella infection model was used to evaluate the virulence of the strains. RESULTS: WGS demonstrated that mutations in the genes that encode outer membrane proteins and efflux pumps in the isolate harboring blaVIM-36 (ST308) differ from those in the isolates harboring blaSPM (ST277). The mexT gene possessed a mutation resulting in a frameshift in all isolates; in addition, the oprD gene of the isolate carrying blaVIM-36 had an insertion that led to a frameshift. The virulence genes did not differ between ST277 and ST308. Moreover, only two isolates harboring blaSPM indicated virulence in the G. mellonella model, killing 100% of larvae after 18-24hours. CONCLUSIONS: P. aeruginosa carrying blaVIM-36 gene belonging to ST308 was identified for the first time in our hospital. Although, the virulence genes profiles were similar in isolates carrying blaSPM and the isolate carrying blaVIM-36, only two isolates harboring blaSPM indicated virulence in the G. mellonella model. PMID- 30244039 TI - Potent in vitro antileishmanial activity of nanoformulation of cisplatin with carbon nanotubes against Leishmania major. AB - OBJECTIVES: The aim of this study was to evaluate the cytotoxicity and antileishmanial activities of carbon nanotube-bounded cisplatin (CP-CNTs) against both promastigotes and amastigotes of L. major in vitro. METHODS: Cisplatin bounded to single- (CP-SWCNTs) and multi-walled carbon nanotubes (CP-MWCNTs) were considered as test compounds. In addition, SWCNT, MWCNT, cisplatin, and Glucantime(r) were considered as controls. The effect of each compound was evaluated on both promastigote and amastigote stages and the results were compared with each other. RESULTS: There was a statistically significant difference between IC50 of CP-SWCNT and each of the controls, including SWCNT, cisplatin, and Glucantime(r) for both promastigote and amastigote (P <0.05). In addition, for both promastigote and amastigote, the comparison between IC50 of CP MWCNT and each of the controls, including MWCNT, cisplatin, and Glucantime(r) was statistically significant (P <0.05). Nevertheless, the selectivity index (SI) of CP-SWCNT was lower than 10 (5.23), meaning that this compound is not completely safe. However, SI of CP-MWCNT (12.54) and Glucantime(r) (16.28) were higher than 10, indicating the selective effect of these two compounds on the parasite. Moreover, IC50 of CP-MWCNT (0.11+/-0.09MUM) for amastigote was 0.02-fold lower than that of Glucantime(r) (4.52+/-1.31MUM), suggesting that a lower dose of CP MWCNT in comparison with Glucantime(r) is required to kill 50% of amastigotes. CONCLUSIONS: According to the potent antileishmanial activity of CP-MWCNT in low concentration against L. major, it is suggested to be evaluated on the animal model. PMID- 30244040 TI - Detection of chromosomal and plasmid mediated mechanisms conferring colistin resistance in Escherichia coli and Klebsiella pneumoniae from Indian food samples. AB - OBJECTIVES: Multiple earlier publications on detection of mcr-1 in animals and human isolates, strongly suggested an underlying route of food chain transmission of colistin resistance (Col-R). Aim of our study was to investigate the presence of Col-R bacteria in Indian food samples and to identify the underlying mechanisms conferring colistin resistance. METHODS: Raw food materials including poultry meat, mutton meat, fish and vegetables collected from food outlets of Chennai, India, were processed to identify Col-R bacteria using Eosin Methylene Blue agar supplemented with colistin. Colistin MIC (Minimum Inhibitory Concentration) was determined by broth micro dilution method. mcr-1 and mcr-3 PCR were done on Col-R E.coli and K. pneumoniae isolates. Mutations in mgrB were determined in K. pneumoniae isolates. One representative mcr-1 positive E. coli was subjected to Whole Genome Sequencing. RESULTS: Out of 110 food samples tested, 51(46%) were positive for non-intrinsic Col-R Gram negative bacteria. Three E. coli isolates were found to harbour mcr-1 and none positive for mcr-3. Ten K. pneumoniae isolates had alterations in mgrB gene, with mutations in four and insertional inactivation in six. CONCLUSIONS: The presence of Col-R bacteria and mcr-1gene in raw food samples further complicates the antimicrobial resistance scenario in India. To the best of our knowledge, this is the first report in the global literature on mgrB mutation and its insertional inactivation conferring Col-R in K. pneumoniae in food samples. PMID- 30244041 TI - Accurate measurement of main aerosol constituents from heated tobacco products (HTPs): Implications for a fundamentally different aerosol. AB - ISO 4387 Standard determines the main aerosol constituents (total particulate matter, water, nicotine, and nicotine-free-dry-particulate matter, referred to as "tar") in cigarette mainstream smoke (ISO, 2000). Heated Tobacco Products (also called Tobacco Heating Products or Heat-not-Burn Products) are designed to form aerosol by heating tobacco rather than burning like in combustible cigarettes. In this study we have evaluated the suitability of ISO 4387 Standard to be adapted for quantifying main aerosol constituents for HTP aerosol. HTP emissions have much higher levels of water and humectants (e.g., glycerol) in dynamic equilibria between gaseous and particulate phases. Several modifications to ISO 4387 Standard on aerosol collection were tested to improve the accuracy and reliability of aerosol capturing, with minimal deviation to the standard method. The proposed modifications are readily adoptable by laboratories already practicing the Standard for cigarette smoke analyses. Taking collectively with other available aerosol chemistry and biological results on HTPs in the literature, they show a fundamentally different aerosol in HTPs and call for category-specific product standards and terminology. PMID- 30244042 TI - Preclinical safety evaluation of the human-identical milk oligosaccharide lacto-N tetraose. AB - Lacto-N-tetraose (LNT) is one of the most abundant oligosaccharides that are endogenously present in human breast milk. To simulate the composition of human breast milk more closely, commercial infant formula can be supplemented with human-identical milk oligosaccharides, which are manufactured structurally identical versions of their naturally occurring counterparts. As part of the safety evaluation of LNT, in vitro genotoxicity tests and a subchronic oral gavage toxicity study (in neonatal Sprague-Dawley rats) were conducted. In the subchronic study, LNT was administered at dose levels of 0, 1,000, 2500 or 4000 mg/kg body weight (bw)/day, once daily for at least 90 days, followed by a 4-week treatment-free period. An identically comprised reference control group received fructooligosaccharides powder (a non-digestible oligosaccharide used in infant formula) at 4000 mg/kg bw/day, to allow for direct comparison against the high dose LNT group. LNT was non-genotoxic in the in vitro tests. There were no compound-related adverse effects in the 90-day study; therefore, 4000 mg/kg bw/day (the highest feasible dose) was established as the no-observed-adverse effect-level. These results support the safe use of LNT in infant formula and as a food ingredient, at levels not exceeding those found naturally in human breast milk. PMID- 30244043 TI - Dose related effects of buspirone on pain, learning / memory and food intake. AB - The present study concerned extending the therapeutic use of buspirone for treating pain and improving cognition. Effects of single and repeated administration of buspirone were therefore monitored on pain threshold in the hot plate test and on spatial memory in the water maze test in rats. Effects on cumulative food intake were also monitored. The drug was administered intraperitoneally in doses of 0.1, 0.3, 1.0 and 2.0 mg/kg. We found that single and repeated administration of buspirone in doses of 0.1 mg/kg decreased pain threshold in the hot plate test, while doses of 1.0 and 2.0 mg/kg increased it. Effects of single and repeated administration were not different. A dose of 0.3 mg/kg had no effect. Food intake increased following single as well as repeated administration of 0.1 mg/kg buspirone; higher doses had no effect. Low doses (0.1 and 0.3 mg/kg) improved acquisition and retention of memory in the water maze test, while memory extinction was reduced. Higher doses had either no effect (1.0 mg/kg) or impaired (2.0 mg/kg) performance in this test. The results suggest potential therapeutic use of selected doses of buspirone as an analgesic and nootropic drug. PMID- 30244044 TI - Photodynamic therapy as an alternative therapeutic option for pediatric condyloma acuminata: A case series. PMID- 30244046 TI - Emergency department use of a mechanical chest compression device frequently causes unanticipated interruptions in cardiopulmonary resuscitation. PMID- 30244045 TI - Brain imaging in comatose survivors of cardiac arrest: Pathophysiological correlates and prognostic properties. AB - INTRODUCTION: Hypoxic-ischemic brain injury is the main cause of death and disability of comatose patients after cardiac arrest. Early and reliable prognostication is challenging. Common prognostic tools include clinical neurological examination and electrophysiological measures. Brain imaging is well established for diagnosis of focal cerebral ischemia but has so far not found worldwide application in this patient group. OBJECTIVE: To review the value of Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET) for early prediction of neurological outcome of comatose survivors of cardiac arrest. METHODS: A literature search was performed to identify publications on CT, MRI or PET in comatose patients after cardiac arrest. RESULTS: We included evidence from 51 articles, 21 on CT, 27 on MRI, 1 on CT and MRI, and 2 on PET imaging. Studies varied regarding timing of measurements, choice of determinants, and cut-off values predicting poor outcome. Most studies were small (n = 6-398) and retrospective (60%). In general, cytotoxic oedema, defined by a grey-white matter ratio <1.10, derived from CT, or MRI-diffusion weighted imaging <650 * 10-6 mm2/s in >10% of the brain could differentiate between patients with favourable and unfavourable outcomes on a group level within 1-3 days after cardiac arrest. Advanced imaging techniques such as functional MRI or diffusion tensor imaging show promising results, but need further evaluation. CONCLUSION: CT derived grey-white matter ratio and MRI based measures of diffusivity and connectivity hold promise to improve outcome prediction after cardiac arrest. Prospective validation studies in a multivariable approach are needed to determine the additional value for the individual patient. PMID- 30244047 TI - Synthesis of 19-norcalcitriol analogs with pegylated alkylidene chains at C-2. AB - The results presented in this paper constitute an extension of our synthetic efforts focused on 19-norvitamin D compounds possessing elongated 2-alkylidene substituents. Based on our previous results, molecular modeling studies, and docking experiments, we selected a novel 19-norcalcitriol analog with long chain at C-2 containing several ether moieties and terminated by 2-(pyridin-2' yl)ethylamino fragment. It was expected that such structural modification might allow binding of transition metal by the ligand, increase solubility of the formed complexes as well as improve their affinity to the VDR. For comparison, a 19-norcalcitriol analog was also obtained with the terminal hydroxyl group at its pegylated 2-alkylidene substituent. The synthesis of the target vitamin D compounds described in this work was performed using the Wittig-Horner approach. The respective A-ring phosphine oxide was obtained starting from the D-(-)-quinic acid and then coupled with the known Grundmann ketone. PMID- 30244048 TI - Synthesis of 28,28,28-trideutero-25-hydroxydihydrotachysterol2. AB - As part of our program on synthesis of labeled vitamin D metabolites and analogs, we describe here an efficient and versatile synthetic approach to 28,28,28 trideutero- 25-hydroxydihydrotachysterol2 where isotopic labeling was incorporated stereoselectively in the last step of the synthesis. This deuterated compound will allow the study this analog in vitro or in vivo and to measure AT10 like compounds in serum by LC-MS/MS. PMID- 30244049 TI - Presbyopia: Effectiveness of correction strategies. AB - Presbyopia is a global problem affecting over a billion people worldwide. The prevalence of unmanaged presbyopia is as high as 50% of those over 50 years of age in developing world populations, due to a lack of awareness and accessibility to affordable treatment, and is even as high as 34% in developed countries. Definitions of presbyopia are inconsistent and varied, so we propose a redefinition that states "presbyopia occurs when the physiologically normal age related reduction in the eye's focusing range reaches a point, when optimally corrected for distance vision, that the clarity of vision at near is insufficient to satisfy an individual's requirements". Strategies for correcting presbyopia include separate optical devices located in front of the visual system (reading glasses) or a change in the direction of gaze to view through optical zones of different optical powers (bifocal, trifocal or progressive addition spectacle lenses), monovision (with contact lenses, intraocular lenses, laser refractive surgery and corneal collagen shrinkage), simultaneous images (with contact lenses, intraocular lenses and corneal inlays), pinhole depth of focus expansion (with intraocular lenses, corneal inlays and pharmaceuticals), crystalline lens softening (with lasers or pharmaceuticals) or restored dynamics (with 'accommodating' intraocular lenses, scleral expansion techniques and ciliary muscle electrostimulation); these strategies may be applied differently to the two eyes to optimise the range of clear focus for an individual's task requirements and minimise adverse visual effects. However, none fully overcome presbyopia in all patients. While the restoration of natural accommodation or an equivalent remains elusive, guidance is given on presbyopic correction evaluation techniques. PMID- 30244050 TI - Early screening and treatment of gestational diabetes in high-risk women improves maternal and neonatal outcomes: A retrospective clinical audit. AB - AIMS: Evidence suggests that screening for gestational diabetes (GDM) occurs too late in pregnancy, when changes in glucose metabolism and fetal growth rates can already be detected. In August 2016 NHS Lothian began screening women with risk factors for GDM during early pregnancy (11-13 weeks). We hypothesised that an earlier identification and treatment of dysglycaemia would improve pregnancy outcomes compared to previous standard care. METHODS: We compared management and outcomes for singleton pregnancies with GDM delivering at Royal Infirmary Edinburgh, UK, diagnosed through routine or early screening from 01/01/2015 31/10/2017 (routine screening n = 335, early screening n = 241). RESULTS: Early screening increased the proportion of women diagnosed before 24 weeks' gestation (n = 59/335, 17.6% vs n = 103/241, 42.7%, p < 0.001) but did not change the average monthly rate of diagnosis. Early screening increased the median duration of GDM during pregnancy (71 vs 93 days of gestation, p < 0.001) with no significant changes in the pharmacological management. Early screening improved the primary composite outcome (emergency caesarean section, neonatal hypoglycaemia and macrosomia; n = 138/335, 41.2% vs n = 73/241, 30.3%, adjusted Odds Ratio [95% confidence interval] 0.62 [0.43-0.91]. CONCLUSIONS: There is a role for early screening and management of GDM however it is unclear whether this represents a cost-effective intervention. PMID- 30244052 TI - Ethnic differences in the prevalence of diabetes in underweight and normal weight individuals: The CARRS and NHANES studies. AB - AIMS: Type 2 diabetes in lean individuals has recently come to attention. We assessed type 2 diabetes prevalence and the associated risk factors in underweight and normal weight individuals in two ethnic populations. METHODS: We conducted cross-sectional analyses, using representative samples of 4930 Asian Indians from the CARRS-Chennai Study and 2868 Whites from the NHANES Survey. Diabetes was defined as use of glucose lowering medication, fasting glucose >=126 mg/dl, or 2 h glucose >=200 mg/dl. Body mass index (BMI) was classified using WHO standard criteria. RESULTS: Prevalence of type 2 diabetes by BMI varied by ethnicity and sex. In men, type 2 diabetes prevalence was 5.4% and 23.5% in underweight and normal weight Asian Indians and 0.0% and 6.1% in underweight and normal weight Whites. In women, the prevalence was 5.6% and 13.6% in underweight and normal weight Asian Indians and 2.3% and 2.8% in underweight and normal weight Whites. Adjustment for waist circumference, insulin resistance, and insulin secretion did not explain the increased prevalence in Asian Indians. CONCLUSIONS: These findings suggest significant ethnic differences in type 2 diabetes prevalence without overweight or obesity. Future studies should examine the pathophysiology of type 2 diabetes development in lean individuals. PMID- 30244053 TI - Relations of Vitamin D Status With B-Type Natriuretic Peptide Levels and the Risk of Cardiac Events in Japanese Subjects With Heart Failure. PMID- 30244054 TI - Socially regulated estrogen in an eavesdropping brood parasite. AB - Social regulation of reproductive hormones is a means by which conspecific males and females orchestrate successful reproductive efforts. We investigate whether social cues modify activity within the hypothalamic-pituitary-gonadal (HPG) axis and the specificity of this response in a social parasite that is known to eavesdrop on the communication signals of other species: the brown-headed cowbird (Molothrus ater). Brown-headed cowbirds are obligate brood parasites that do not build nests or care for their own young. Instead, obligate brood parasites leave their eggs in the nest of a host species and therefore must coordinate their breeding attempts with conspecifics as well as potential heterospecific hosts. Here, we explore whether the vocal signals of potential host species can also be used as a social cue that modifies the HPG axis of female brown-headed cowbirds. Results reveal that both conspecific and heterospecific song-exposed females exhibit significantly greater circulating estradiol concentrations as compared to silence-exposed females. While conspecific song induces the greatest elevation in circulating estradiol, there is no significant difference in circulating estradiol levels in females exposed to either conspecific or heterospecific songs. This pattern suggests both song types are effective at evoking a reproductive physiological response. On the other hand, circulating progesterone concentrations did not differ among the song- and silence-exposed groups nor did the size of the female's ovarian follicles. These results indicate that heterospecific vocal communication signals can effectively be used as a social cue that simultaneously provides necessary information regarding breeding status of hosts and modifies breeding condition of the eavesdropper. PMID- 30244055 TI - Insights from zebrafish deficiency models to understand the impact of local thyroid hormone regulator action on early development. AB - Thyroid hormones (THs) stimulate and coordinate a wide range of processes to ensure normal development, mainly by binding of the most active TH 3,5,3' triiodothyronine (T3) to nuclear receptors resulting in changes in gene transcription. Local TH action is monitored at three distinct levels by different types of regulators: transmembrane transporters (TH influx and efflux), deiodinases (TH activation and inactivation) and nuclear receptors (TH signalling). Since TH regulators are strongly conserved among vertebrate species, the externally and rapidly developing zebrafish (Danio rerio) has become one of the favourite models to study their role in TH-dependent development. Most regulators are expressed in zebrafish from early stages in development in a dynamic and tissue-specific pattern. Transient or permanent disruption of a given regulator severely perturbs development of multiple organs. These zebrafish deficiency models help to explain why, next to overall hypo-/hyperthyroidism, inactivating mutations in the genes encoding TH regulators such as MCT8 and THRA/B have irreversible adverse effects on human development. Zebrafish are also increasingly used as a high-throughput model to assess the toxicity of various xenobiotics and their impact on development. While adverse effects on TH metabolism and gene expression have been shown, information on direct interaction with TH regulators is scarce, albeit essential to fully understand their mechanism of action. For the future, the combination of novel gene silencing tools, fluorescent reporter lines and (single-cell) transcriptomics holds promise for new zebrafish models to further elucidate the role of each TH regulator in vertebrate development. PMID- 30244056 TI - Physiological relevance of nitric oxide in ovarian functions: An overview. AB - Nitric oxide (NO, nitrogen monoxide), a short-lived, free radical carrying an unpaired electron, is one of the smallest molecules synthesized in the biological system. In addition to its role in angiogenesis, neuronal function and inflammatory response, NO has wide-spread significance in regulation of ovarian function in vertebrates. Based on tissue-specific expression, three different nitric oxide synthase (NOS) isoforms, neuronal (nNOS) or NOS1, inducible (iNOS) or NOS2 and endothelial (eNOS) or NOS3 have been identified. While expression of both inducible (iNOS) and constitutive NOS (eNOS) isoforms varies considerably in the ovary at various stages of follicular growth and development, selective binding of NO with proteins containing heme moieties have significant influence on ovarian steroidogenesis. Besides, NO modulation of ovulatory response suggests physiological significance of NO/NOS system in mammalian ovary. Compared to the duality of NO action on follicular development, steroidogenesis and meiotic maturation in mammalian models, participation of NO/NOS system in teleost ovary is less investigated. Genes encoding nos1 and nos2 have been identified in fish; however, presence of nos3 is still ambiguous. Interestingly, two distinct nos2 genes, nos2a and nos2b in zebrafish, possibly arose through whole genome duplication. Differential expression of major NOS isoforms in catfish ovary, NO inhibition of meiosis resumption in Anabas testudineus follicle-enclosed oocytes and NO/sGC/cGMP modulation of oocyte maturation in zebrafish are some of the recent advancements. The present overview is an update on the advancements made and shortfalls still remaining in NO/NOS modulation of intercellular communication in teleost vis-a-vis mammalian ovary. PMID- 30244051 TI - Turkish nationwide survEy of glycemic and other Metabolic parameters of patients with Diabetes mellitus (TEMD study). AB - AIMS: Turkey has the highest prevalence of diabetes in Europe. It is therefore essential to know the overall cardiovascular risk and reveal the predictors of metabolic control in Turkish adults with diabetes mellitus. METHODS: A nationwide, multicenter survey consecutively enrolled patients who were under follow up for at least a year. Optimal control was defined as HbA1c < 7%, home arterial blood pressure (ABP) < 135/85 mmHg, or LDL-C < 100 mg/dL. Achieving all parameters indicated triple metabolic control. RESULTS: HbA1c levels of patients (n = 5211) were 8.6 +/- 1.9% (71 +/- 22 mmol/mol) and 7.7 +/- 1.7% (61 +/- 19 mmol/mol), in Type 1 and Type 2 diabetes, respectively. Glycemic control was achieved in 15.3% and 40.2%, and triple metabolic control was achieved in 5.5% and 10.1%, respectively. Only 1.5% of patients met all the criteria of being non obese, non-smoker, exercising, and under triple metabolic control. Low education level was a significant predictor of poor glycemic control in both groups. CONCLUSIONS: Few patients with Type 2, and even fewer with Type 1 diabetes have optimal metabolic control in Turkey. TEMD study will provide evidence-based information to policy makers to focus more on the quality and sustainability of diabetes care in order to reduce the national burden of the disease. PMID- 30244057 TI - Bisphenol A induced abnormal DNA methylation of ovarian steroidogenic genes in rare minnow Gobiocypris rarus. AB - Bisphenol A (BPA), an ubiquitous environmental endocrine disruptor chemical, disturbs the mRNA expressions of steroidogenic genes and subsequently steroid hormone synthesis in mammals and aquatic species. However, the underlying regulation mechanisms are barely understood, especially in fish. To explore the regulation mechanism, we exposed female rare minnow Gobiocypris rarus (G. rarus) to BPA at a nominal concentration of 15 MUg/L for 7 and 14 days in the present study. Results showed significant increase of gonad somatic index (GSI) and serum estradiol (E2) levels in response to BPA at day 14. The 7-day BPA exposure notably repressed the expression of two ovarian steroidogenic genes (star and hsd11b2) and suppressed their capacity of estrogen response elements (ERE) to recruit estrogen receptor (ER), while the 14-day BPA treatment remarkably induced transcript of hsd3b and enhanced the capacity of ERE to recruitment ER in ovaries. Furthermore, the 7-day BPA exposure caused DNA hypermethylation of star (CpGs: -742 bp and -719 bp) and hsd11b2 (CpG: -1788 bp). However, 14-day BPA exposure resulted in DNA hypomethylation of hsd3b (CpG: -181 bp). Correlation analysis revealed that the DNA methylation levels at specific CpGs in star, hsd3b and hsd11b2 were significantly correlated to their mRNA levels and ER-EREs interactions. These findings suggest that the disturbed steroidogenesis and the transcripts of ovarian steroidogenic genes might attribute to the altered DNA methylation status of these ovarian steroidogenic genes in response to BPA. PMID- 30244058 TI - A Provider Global Assessment Quality Measure for Clinical Practice for Inflammatory Skin Disorders. AB - In our evolving healthcare system, dermatologists are increasingly being asked to prove the value of care they provide to patients with severe skin diseases. Current quality measures for inflammatory dermatoses have limited validity and feasibility. Through collaboration and a modified Delphi process, the International Dermatology Outcome Measures (IDEOM) group and American Academy of Dermatology (AAD) sought to reach consensus on a valid and feasible provider assessed global disease severity metric to be incorporated into a quality measure for inflammatory dermatoses. To inform the modified Delphi process, a review of the literature was performed, and data was collected on current provider-assessed global disease severity metrics. Following literature review, 36 members of IDEOM and the AAD participated in the modified Delphi process to reach consensus on features of the metric. Psoriasis, atopic dermatitis, and acne achieved overwhelming consensus for inflammatory dermatoses that could be measured in a global disease severity metric. Consensus was also reached on the utilization of a 5-point ordinal scale with descriptors provided through referenced electronic platforms. Expert development of quality measures incorporating this metric and its inclusion in data collection platforms are critical to enabling dermatologists to prove the value of care provided to patients with severe inflammatory dermatoses. PMID- 30244059 TI - Validated Patient-Reported Outcome Measurements for Psoriasis may not Reflect Patients' Current Preferences. PMID- 30244060 TI - Dermoscopy of Pityrosporum Folliculitis. PMID- 30244061 TI - A population-based registry study on relative survival from melanoma in Germany stratified by tumor thickness for each histological subtype. AB - BACKGROUND: Differences in melanoma relative survival (RS) between histologies were discussed to be mainly caused by tumor thickness. OBJECTIVE: To investigate RS from melanoma, stratified by tumor thickness for each histological subtype, and identify survival trends. METHODS: Using cancer registry data on melanoma cases (ICD-10: C43.0-C43.9) diagnosed in Germany in 1997-2013, 5- and 10-year age standardized RS stratified by histology and stratified or standardized by T-stage was estimated using standard and modelled period analyses. We restricted 10-year RS analyses to patients younger than 75 years. RESULTS: We analyzed 82,901 cases. Overall, 5- and 10-year RS was 91.7% and 90.8%, respectively. Prognosis worsened with increasing T-stage for all histologies but T-stage distribution varied substantially. Survival differences by histology were strongly alleviated after adjustment for T-stage, but remained significant. Overall, 5-year RS increased significantly by 3.8 percentage points between 2002-2005 and 2010-2013. This increase was no longer seen after adjustment for T-stage. LIMITATIONS: Exclusion of cases due to missing information on T-stages, changes in the definition of T stages, and lack of information on screening and treatment limit our analyses. CONCLUSION: Differences in RS between histologies were strongly mediated by tumor thickness. Over time, melanoma RS increased due to changes in T-stage distribution. PMID- 30244063 TI - Platelet rich plasma as an adjunctive treatment in Lichen Plano pilaris. PMID- 30244062 TI - Clinical and dermoscopic features of cutaneous BAP1 inactivated melanocytic tumors: results of a multicenter case-control study by the International Dermoscopy Society (IDS). AB - BACKGROUND: Multiple BAP-1 inactivated melanocytic tumors (BIMTs) have been associated with a familial cancer-syndrome involving germline mutations in BAP1. OBJECTIVES: We sought to describe the clinical and dermoscopic features of BIMTs. METHODS: Retrospective, multicenter, case-control study. Participating centers clinical data, dermoscopic images, and histopathological data of biopsy-proven BIMTs. We compared the dermoscopic features between BIMTs and controls. RESULTS: The dataset consisted of 48 BIMTs from 31 patients (22 females, median age=37 years), and 80 controls. Eleven patients had a BAP1 germline mutation. Clinically, most BIMTs presented as pink, dome-shaped papules (n=24). Dermoscopically, we identified 5 patterns: structureless pink-to-tan with irregular eccentric dots/globules (n=14, 29.8%); structureless pink-to-tan with a peripheral vessels (n=10, 21.3%); structureless pink-to-tan (n=7, 14.9%); network with raised, structureless, pink-to-tan areas (n=7, 14.9%); and globular pattern (n=4, 8.5%). The structureless with eccentric dots/globules pattern and network with raised structureless areas pattern were only identified in BIMT and were more common in patients with BAP1 germline mutations (p<0.0001 and p=0.001, respectively) LIMITATIONS: Small sample size, retrospective design, absence of germline genetic testing in all patients, inclusion bias towards more atypical looking BIMTs. CONCLUSION: Dome-shaped papules with pink-to-tan structureless areas and peripheral irregular dots/globules or network should raise suspicion for BIMT. PMID- 30244064 TI - Clinical outcomes in high-risk squamous cell carcinoma patients treated with Mohs micrographic surgery alone. AB - BACKGROUND: There is little evidence to predict patient outcomes following the treatment of high risk cutaneous SCC (hrSCC) using Mohs micrographic surgery (MMS). OBJECTIVE: To report the rates of poor outcomes in patients with hrSCC treated by MMS alone, and determine if any specific clinical factors may be more predictive of these outcomes. METHODS: We conducted a retrospective chart review of all hrSCC patients treated in our clinic from October 2011 to December 2015. RESULTS: We identified 647 hrSCC tumors that met inclusion criteria. During the follow-up period, there were 19 local recurrences(LR) (2.9%), 31 nodal metastases(NM) (4.8%), 7 distant metastases(DM) (1.1%), and 7 disease-specific deaths(DSD) (1.1%). Two factors, poor differentiation and invasion beyond the subcutaneous fat, were positively associated with local recurrence, nodal metastasis, and disease-specific death through multivariate analysis. CONCLUSIONS: Invasion beyond subcutaneous fat and poor histologic differentiation may carry a greater risk of poor outcomes than other factors in hrSCC. Mohs surgery alone provides excellent marginal control with low rates of local recurrence, nodal metastasis and disease-specific death. PMID- 30244065 TI - Rethinking the classification of alopecia areata. PMID- 30244066 TI - Lack of an FDA indication should not limit access to appropriate treatment. PMID- 30244067 TI - Reflectance confocal microscopy as novel tool for pre-surgical identification of basal cell carcinoma biopsy site. PMID- 30244068 TI - Comment on Okhovat et al "The first 30 years of the American Academy of Dermatology skin cancer screening program: 1985-2014". PMID- 30244069 TI - Effects of glucocorticoid on the eye development in guinea pigs. AB - Glucocorticoid (GC) has been widely used in clinic. However, the effect of GC on normal and myopic development of eyes is still unknown. In this study, 3-week-old guinea pigs were randomly divided into four groups: No-Lens (control), GC+No Lens, negative lens-induced myopia (LIM), and GC+LIM. To induce myopia, right eyes were covered with a -10 D lens in GC+LIM and LIM groups. GC+No-Lens and GC+LIM groups received intraperitoneal injections of hydrocortisone (10 mg/kg) once daily for 2 weeks, and then received intragastric hydrocortisone (32.5 mg/kg) every other day for the next 4 weeks, while No-Lens (control) and LIM groups were injected intraperitoneally with saline for 2 weeks, and then given saline by intragastric administertion for the next 4 weeks. Several parameters were assessed: ocular axial length and refractive error, sclera thickness, matrix metalloprotein-2 (MMP-2) and tissue inhibitor metalloprotease-2 (TIMP-2) expressions and localization of the posterior sclera, plasma concentrations of free triiodothyronine (FT3), free thyroxine (FT4), testosterone (T), and oestradiol (E2). Results indicated that: (1) in normal eye development, hydrocortisone could inhibit both the axial elongation and the myopic shift; whereas (2) in LIM eye development, hydrocortisone (a) enhanced the axial elongation, myopic shift and sclera thinning; (b) enhanced the MMP-2 expression and decreased TIMP-2 expression, and (c) elevated the plasma concentration of E2 but decreased the levels of FT3, FT4, and T. In conclusion, glucocorticoid may influence both normal and LIM eye development. The balance of the hormones is fundamental for the eye development. PMID- 30244070 TI - Lobectomy Is Associated with Better Outcomes than Sublobar Resection in Spread through Air Spaces (STAS)-Positive T1 Lung Adenocarcinoma: A Propensity Score Matched Analysis. AB - INTRODUCTION: Spread through air spaces (STAS) is a form of invasion wherein tumor cells extend beyond the tumor edge within the lung parenchyma. In lung adenocarcinoma (ADC), we investigated the (1) association between STAS and procedure-specific outcomes (sublobar resection and lobectomy), (2) effect of surgical margin-to-tumor diameter ratio in STAS-positive patients, and (3) potential utility of frozen sections (FSs) for detecting STAS intraoperatively. METHODS: We investigated 1497 patients who underwent lobectomy (n = 970) or sublobar resection (n = 527) for T1N0M0 lung ADC after propensity score matching. Outcomes were analyzed by using a competing risks approach. The effect of margin to-tumor ratio on recurrence pattern (locoregional and distant) was investigated in patients who underwent sublobar resection. Five pathologists evaluated the feasibility of intraoperatively identifying STAS by using FSs (sensitivity, specificity, and interrater reliability). RESULTS: On multivariable analysis after propensity score matching (349 pairs/procedure), sublobar resection was significantly associated with recurrence (subhazard ratio = 2.84 [p < 0.001]) and lung cancer-specific death (subhazard ratio = 2.63 [p = 0.021]) in patients with STAS but not in those without STAS. Patients with STAS who underwent sublobar resection had a higher risk of locoregional recurrence regardless of margin-to tumor ratio (for a margin-to-tumor ratio of >=1 versus <1, the 5-year cumulative incidence of recurrence rates were 16% and 25%, respectively); among patients without STAS, locoregional recurrences occurred in patients with margin-to-tumor ratio lower than 1 (a 5-year cumulative incidence of recurrence rate of 7%). The sensitivity and specificity for detecting STAS by use of FSs were 71% and 92%, with substantial interrater reliability (Gwet's AC1, 0.67). CONCLUSIONS: In patients with T1 lung ADC with STAS, lobectomy was associated with better outcomes than sublobar resection was. Pathologists can recognize STAS on FSs. PMID- 30244071 TI - Revisiting the binding kinetics and inhibitory potency of cardiac glycosides on Na+,K+-ATPase (alpha1beta1): Methodological considerations. AB - INTRODUCTION: Ouabain and digoxin are classical inhibitors of the Na+,K+-ATPase. In addition to their conventional uses as therapeutic agents or experimental tools there is renewed interest due to evidence suggesting they could be endogenous hormones. Somewhat surprisingly, different publications show large discrepancies in potency for inhibiting Na+,K+-ATPase activity (IC50), particularly for the slow binding inhibitors, ouabain and digoxin. METHODS: Using purified pig kidney Na+,K+-ATPase (alpha1beta1FXYD2) and purified detergent soluble recombinant human Na+,K+-ATPase (alpha1beta1FXYD1) we have re-evaluated binding and inhibition kinetics and effects of K+ concentration for ouabain, digoxin, ouabagenin and digoxigenin. RESULTS: We demonstrate unequivocally that for slow binding inhibitors, ouabain and digoxin, long incubation times (>=60 min at 37 degrees C) are required to avoid under-estimation of potency and correctly determine inhibition (IC50 around 100-200 nM at 5 mM K+) contrary to what occurs when pre-incubation of the drugs without ATP is followed by a short incubation time. By contrast, for the rapidly bound inhibitors, ouabagenin and digoxigenin, short incubation times suffice (<10 min). The strong reduction of inhibitory potency observed at high un-physiological K+ concentrations (>=5 mM) also explained the low potency reported by some authors. DISCUSSION: The data resolve discrepancies in the literature attributable to sub-optimal assay conditions. Similar IC50 values are obtained for pig kidney and recombinant human Na+,K+ ATPase, showing that inhibitory potencies are not determined by the species difference (pig versus human) or environment (membrane-bound versus detergent soluble) of the Na+,K+-ATPase. The present methodological considerations are especially relevant for drug development of slow binding inhibitors. PMID- 30244072 TI - Oncogenic human papillomavirus infection and genotypes characterization among sexually active women in Tenkodogo at Burkina Faso, West Africa. AB - OBJECTIVE: This study was conducted to determine the prevalence and distribution of high-risk human papillomavirus (HR-HPV) genotypes among sexually active women in Tenkodogo, Burkina Faso. METHODS: Among 131 sexually active women attending the Tenkodogo Urban Medical Center, endocervical samples were collected prior to screening for precancerous lesions. After viral DNA extraction, fourteen HR-HPV genotypes were characterized by real-time multiplex PCR in these cervical samples. RESULTS: The mean age was 35.5 +/- 9.5 years. Of the 131 women, 45 were infected with at least one HR-HPV genotype. The prevalence of HR-HPV infection among these women was 34.4%. Among the 45 oncogenic HPV-infected women, single HR HPV genotype was found in 55.6% while 44.4% were infected with more than one HR HPV genotype. The most frequent genotypes were HPV56 (36.5%), HPV66 (36.5%). CONCLUSION: Tenkodogo women included in this study had a higher prevalence of HPV 56, HPV 66. A larger study with a more representative sample would therefore be needed to determine predominant oncogenic genotypes in the subregion and especially in cancer cases. PMID- 30244073 TI - Association of Cardioembolism and Intracranial Arterial Stenosis with Outcomes of Mechanical Thrombectomy in Acute Ischemic Stroke. AB - OBJECTIVE: To estimate the association of different etiologies of cardioembolism (CE), intracranial arterial stenosis (ICAS), or the combination of these conditions with outcomes of mechanical thrombectomy in acute ischemic stroke. METHODS: Data from the intervention group of the Endovascular therapy for Acute ischemic Stroke Trial (EAST) were analyzed. In 140 patients, the presence of CE, ICAS, neither CE nor ICAS, or both conditions was assessed. The primary outcome was a favorable outcome at 90 days (modified Rankin Scale score 0-2); secondary outcomes included successful reperfusion (modified Thrombolysis In Cerebral Infarction grade 2b-3), symptomatic intracerebral hemorrhage, and 90-day mortality. RESULTS: Of 140 patients, 47 had neither CE nor ICAS, 35 had ICAS but not CE, 46 had CE but not ICAS, and 12 had both CE and ICAS. The rate of favorable outcome was 67.1% in the no CE and no ICAS group, 74.3% in the ICAS without CE group, 41.3% in the CE without ICAS group, and 33.3% in the CE and ICAS group. The CE and ICAS group had poor outcomes (odds ratio = 0.20 after adjusting for age, sex, and National Institutes of Health Stroke Scale score; 95% confidence interval, 0.04-0.95; P = 0.043). No significant differences were observed in secondary outcomes. CONCLUSIONS: The presence of both CE and ICAS was associated with poor outcome in patients with anterior circulation large-vessel occlusion treated with endovascular thrombectomy. Future studies are warranted to further explore this association. PMID- 30244075 TI - Bloodstream infections in oncology patients at Red Cross War Memorial Children's Hospital, Cape Town, from 2012 to 2014. AB - OBJECTIVES: This study was performed to investigate the epidemiology of bloodstream infection (BSI) in oncology patients at Red Cross War Memorial Children's Hospital (RCWMCH), Cape Town, with focus placed on the most common causes, complications, and antimicrobial susceptibilities in BSI. METHODS: A retrospective cross-sectional study was conducted in the Haematology-Oncology Unit of RCWMCH. All positive blood cultures from RCWMCH oncology patients obtained in 2012 to 2014 were retrieved to identify cases of BSI. RESULTS: Three hundred and forty-three positive cultures were identified, for 150 BSI episodes among 89 patients; 49.1% of the culture isolates were Gram-positive bacteria, 41.6% were Gram-negative bacteria, and 9.3% were fungal. Coagulase-negative Staphylococcus and viridans group Streptococcus were the most common Gram positive isolates. Escherichia coli and Klebsiella species were the most common Gram-negative isolates. The majority of BSI episodes occurred in patients with haematological malignancies (74%), in the presence of severe neutropenia (76.4%), and were associated with chemotherapy (88%). Complications occurred in 14% of BSI. Fungal infections had the highest prevalence of complications (21.4%). Three children died during BSI, giving a case-fatality rate of 2%. CONCLUSIONS: BSI in these patients was caused mainly by Gram-positive bacteria and was associated with a low case-fatality rate. These results are consistent with worldwide experience of BSI in paediatric oncology. PMID- 30244074 TI - Surgical Treatment for Primary Brainstem Hemorrhage to Improve Postoperative Functional Outcomes. AB - BACKGROUND: It remains controversial whether primary brainstem hemorrhage (PBH) should be managed conservatively or treated promptly by surgical evacuation of the hematoma. In the present study, we discuss 5 cases of PBH that were treated surgically and the ability of surgical management to improve postoperative functional outcomes. METHODS: The 4 patients with pontine and medullary hemorrhage underwent surgery via the lateral or midline suboccipital and trans rhomboid fossa approach in the half-sitting position. The patient with a midbrain hemorrhage underwent surgery via the subtemporal approach in the supine lateral position. We analyzed the postoperative functional outcomes 1 week after surgery and the modified Rankin scale scores 6 months after discharge. RESULTS: Three patients with disturbance of consciousness experienced improvement in their level of consciousness. Four patients with hemiparesis improved in motor function. Oculomotor nerve function improved in 2 of 3 cases. Facial nerve function improved in 2 of 2 cases. Spontaneous respiration improved in 1 patient. The postoperative modified Rankin scale scores improved in all 5 cases. CONCLUSIONS: Because of the good results with these 5 patients with PBH, this surgical strategy could be encouraged with exclusion criteria for early initiation of rehabilitation strategies. We hope to increase our number of patients to accumulate further evidence. PMID- 30244076 TI - The use of bedaquiline to treat patients with multidrug-resistant tuberculosis and end-stage renal disease: A case report. AB - The use of bedaquiline to treat patients with multidrug-resistant tuberculosis (MDR-TB) and end-stage renal disease (ESRD) may raise safety concerns. Currently, no clinical information is available on the use of bedaquiline to treat MDR-TB patients with ESRD. We report the use of bedaquiline to treat two patients with MDR-TB and ESRD. This report highlights the safety and tolerability of bedaquiline as well as the treatment outcome. The use of bedaquiline in patients with ESRD is also discussed. PMID- 30244077 TI - Results of the effectiveness of two piperacillin-tazobactam molecules in the real world. AB - OBJECTIVE: The objective was to determine the effectiveness of two piperacillin tazobactam molecules in terms of all-cause mortality, mortality by infection, and hospital stay. METHODS: A cohort study was performed involving patients treated with piperacillin-tazobactam at a clinic in Colombia. The patients were divided into those who received the innovator piperacillin-tazobactam (from July to December 2014) and those who received the generic piperacillin-tazobactam (from January to June 2015). Socio-demographic, clinical (all-cause mortality, death by infection, days of hospitalization), microbiological, pharmacological, and comorbidity variables were evaluated. Multivariate analyses were performed. RESULTS: A total of 279 patients were included: 140 treated with the innovator piperacillin-tazobactam and 139 with the generic piperacillin-tazobactam. The median age was 63 years, and 56% of the patients were male. There was no statistically significant difference in death from all causes (22.9% vs. 14.4%, p=0.069), death by infection (7.9 vs. 10.8%, p=0.399), or hospital stay (18.1+/ 16.2 vs. 15.7+/-11.6 days, p=0.178) between the innovator and generic piperacillin-tazobactam, respectively. CONCLUSIONS: The generic piperacillin tazobactam was equivalent to the innovator piperacillin-tazobactam with regards to all-cause mortality, mortality by infection, hospital stay, and safety, and at a lower cost, which may be useful for decision-makers in hospitals. PMID- 30244078 TI - The historic and unprecedented United Nations General Assembly High Level Meeting on Tuberculosis (UNGA-HLM-TB)-'United to End TB: An Urgent Global Response to a Global Epidemic'. PMID- 30244079 TI - Bile acid homeostasis paradigm and its connotation with cholestatic liver diseases. AB - Bile acid (BA) has an important role in signal transduction, and has clinical applicability as an early biomarker for the diagnosis and prevention of cholestatic liver disease, which has a close relationship with BA homeostasis. Understanding the regulatory factors, function, and regulation of BA homeostasis under physiological conditions and in cholestatic liver diseases could provide novel therapeutic approaches for treating cholestatic liver injury. Here, we review potential biomarkers of BA, and new therapeutic approaches and the latest therapeutic drugs for cholestasis. We believe that the molecular mechanisms of cholestasis and the identification of key regulatory mechanisms of the enterohepatic circulation of BA could be pharmacologically targeted to cholestatic liver diseases. PMID- 30244080 TI - Functionalizing bioinks for 3D bioprinting applications. AB - 3D bioprinting has emerged as the intersection between chemistry, biology and technology. Through its integration of cells, biocompatible materials and robotic controlled dispensing systems, the process enables the production of structures that are biomimetic and functional, thus revolutionizing the concept of tissue engineering. One of the biggest limitations of 3D bioprinting for tissue engineering is the lack of printable materials (bioinks) with all-inclusive properties desirable for the construction of engineered 'bio-physico-functional' tissues and organs. Thus, bioinks are required to be functionalized or altered to produce the most desirable bioarchetypes. Functionalization methods vary across chemical, mechanical, physical and biological methods, and common methods include blending of materials, coatings, crosslinking and exploiting functional groups. In this short review, a description and critical comparison of reported functionalization methods, focusing on their effects and contributions toward bioinks, have been presented. PMID- 30244081 TI - Safety differentiation: emerging competitive edge in drug development. AB - With increasing expectations to provide evidence of drug efficacy, safety, and cost-effectiveness, best-in-class drugs are a major value driver for the pharmaceutical industry. Superior safety is a key differentiation criterion that could be achieved through better risk:benefit profiles, safety margins, fewer contraindications, and improved patient compliance. To accomplish this, comparative safety assessments using innovative and adaptive nonclinical and clinical outcome-based approaches should be undertaken, and continuous strategic adjustments must be made as the risk:benefit profiles evolve. Key success criteria include scientific expertise and integration between all disciplines during the full extent of the drug development process. PMID- 30244082 TI - Biosimilar medicines used for cancer therapy in Europe: a review. AB - This article provides an updated review of the biosimilar medicines approved for cancer therapy in the European Union (EU). First we discuss the most relevant aspects for the development and approval of biosimilar medicines. We then present the oncological biosimilar drugs currently used, which include epoetins (alpha and zeta), filgrastim, and monoclonal antibodies (rituximab, trastuzumab and bevacizumab). Among the clinical applications of biosimilar medicines, cancer therapy remains the main target area and more approved biosimilars are expected over the next few years, providing cost-effective drugs to more patients. Furthermore, comprehensive pharmacovigilance studies are going on, monitoring the marketed biosimilars, and providing more feasible information to clinicians regarding the safety and efficacy of these medications. PMID- 30244083 TI - High-content analysis for mitophagy response to nanoparticles: A potential sensitive biomarker for nanosafety assessment. AB - Mitophagy, a selective autophagy of mitochondria, clears up damaged mitochondria to maintain cell homeostasis. We performed high-content analysis (HCA) to detect the increase of PINK1, an essential protein controlling mitophagy, in hepatic cells treated with several nanoparticles (NPs). PINK1 immunofluorescence-based HCA was more sensitive than assays and detections for cell viability and mitochondrial functions. Of which, superparamagnetic iron oxide (SPIO)-NPs or graphene oxide-quantum dots (GO-QDs) was selected as representatives for positive or negative inducer of mitophagy. SPIO-NPs, but not GO-QDs, activated PINK1 dependent mitophagy as demonstrated by recruitment of PARKIN to mitochondria and degradation of injured mitochondria. SPIO-NPs caused the loss of mitochondrial membrane potential, decrease in ATP, and increase in mitochondrial reactive oxide species and Ca2+. Blocking mitophagy with PARKIN siRNA aggravated the cytotoxicity of SPIO-NPs. Taken together, PINK1 immunofluorescence-based HCA is considered to be an early, sensitive, and reliable approach to evaluate the bioimpacts of NPs. PMID- 30244084 TI - Rotary jet-spun porous microfibers as scaffolds for stem cells delivery to central nervous system injury. AB - Stem cell transplantation is a promising strategy to treat brain injuries. However, cell-based therapies are limited because poor local cell engraftment. Here, we present a polylactic acid (PLA) scaffold to support mesenchymal stem cells (MSCs) delivery in stroke. We isolated bone marrow MSCs from adult C57/Bl6 mice, cultured them on PLA polymeric rough microfibrous (PRM) scaffolds obtained by rotary jet spinning, and transplanted over the brains of adult C57/Bl6 mice, carrying thermocoagulation-induced cortical stroke. No inflammatory response to PRM was found. MSCs transplantation significantly reduced the area of the lesion and PRM delivery increased MSCs retention at the injury site. In addition, PRM upregulated alpha6-integrin and CXCL12 production, which may be the cause for greater cell retention at the lesion site and may provide additional benefit to MSCs transplantation procedures. We conclude that PRM scaffolds offer a promising new system to deliver stem cells to injured areas of the brain. PMID- 30244085 TI - Galactosylated chitosan triptolide nanoparticles for overcoming hepatocellular carcinoma: Enhanced therapeutic efficacy, low toxicity, and validated network regulatory mechanisms. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Current therapies present significant limitations. Triptolide (TP) is highly effective against multiple cancers including HCC. However, high toxicity, low water solubility, and unknown therapeutic targets limit its clinical application. Herein, we designed galactosylated-chitosan-TP nanoparticles (GC-TP-NPs) with high drug loading capacities for targeted delivery to HCC. In addition to a sustained release pattern, an efficient asialoglycoprotein receptor mediated cellular uptake in vitro, and high liver tumor accumulation in vivo, GC-TP-NPs showed lower systemic and male reproductive toxicities than free TP. Importantly, GC-TP-NPs retained the anti-cancer activities of the free TP, exerting the same pro-apoptotic and anti-proliferative effects on HCC cells in vitro, and displayed higher efficacies in reducing tumor sizes in vivo. Further investigation revealed that GC-TP-NPs induced cancer cell apoptosis via blocking TNF/NF-kappaB/BCL2 signaling. Collectively, GC-TP-NP represents a promising candidate in halting liver cancer progression while minimizing systemic toxicity. PMID- 30244086 TI - Increase of viral hemorrhagic septicemia virus growth by knockout of IRF9 gene in Epithelioma papulosum cyprini cells. AB - Viral hemorrhagic septicemia virus (VHSV) has been a notorious pathogen in freshwater and marine fish. Due to the lack of effective treatment measures against VHSV disease, the development of prophylactic vaccines has been required, and methods that can produce high-titered viruses would be advantageous in producing cost-effective vaccines. Type I interferon (IFN) responses are the key elements of vertebrates' antiviral activities, and IFN-stimulated gene factor 3 (ISGF3) complex formed through type I IFNs up-regulates the expression of IFN stimulated genes (ISGs). IFN regulatory factor 9 (IRF9) is a key component of ISGF3, so the inhibition of IRF9 would compromise host's type I IFN responses, which would weaken host antiviral activity. In this study, to increase the replication of VHSV, we generated IRF9 knockout Epithelioma papulosum cyprini (EPC) cells using a CRISPR/Cas9 vector that contains an EPC cell's U6 promoter driven guide RNA cassette (targeting IRF9 gene) and a Cas9 expressing cassette. In the clones of IRF9 knockout EPC cells, there were no increase in ISG15 gene by poly I:C, and in Mx1 gene by both poly I:C and VHSV. Interestingly, although the increased folds were conspicuously lower than control EPC cells, the expression of ISG 15 gene in all the IRF9 knockout clones was significantly increased by VHSV infection. Control EPC cells pre-treated with poly I:C did not show any CPE when infected with VHSV, however, IRF9 knockout EPC cells showed CPE by VHSV infection in spite of being pretreated with poly I:C. The replication of VHSV in IRF9 knockout EPC cells was significantly faster and higher than that in control EPC cells indicating that the IRF9 knockout-mediated decrease of type I IFN responses allowed VHSV to replicate efficiently. Considering an economical aspect for the production of fish vaccines, the present IRF9 knockout EPC cells can be used to get higher-titered VHSV. PMID- 30244087 TI - Comparative transcriptome analysis of red swamp crayfish (Procambarus clarkia) hepatopancreas in response to WSSV and Aeromonas hydrophila infection. AB - To better study the immune system of shrimp and understand the similarities and differences between the host's immune defense against viral and bacterial infections, this study used a comparative transcriptomics method to systematically analyze the hepatopancreas of the crayfish Procambarus clarkia in response to WSSV and A. hydrophila infection. After assembly, there was an average of 24,404,837 clean reads were obtained after filtering out low-quality reads. Unigenes were annotated by comparing against nr, Swiss Prot?KEGG?COG?KOG?GO and Pfam databases, and 17,954 unigenes were annotated in at least one database. 2600 and 2073 differentially expressed genes (DEGs) in the hepatopancreas in response to WSSV and A. hydrophila infections were identified respectively. The GO and KEGG enrichment analyses of DEGs were conducted to further explore their functions. The pathways like PI3K-Akt signaling pathway, mTOR signaling pathway, Jak-STAT signaling pathway, NF-kappaB signaling pathway, VEGF signaling pathway, Ras signaling pathway, were the most prominent for immunity-related DEGs in C-/W-Groups, while Endocytosis, Lysozyme, Focal adhesion, Phagosome, Peroxisome, MAPK signaling pathway were observed in C-/A Groups. Furthermore, the expression levels of nine selected immune-related DEGs were validated by qRT-PCR, substantiating the reliability of RNA-Seq results. This study not only provides effective data support to reveal the different immune defense strategies by P. clarkia to cope with bacterial and WSSV infections, but also to provide new information about the immune system and defense mechanisms of shrimp. PMID- 30244088 TI - Cardiac effects of cigarette tobacco smoking in rat model of diabetes. AB - AIMS: Tobacco smoking is considered a global health issue, contributing to increased risk of cardiovascular disease (CVD) and diabetes (DM). We aimed to assess effects of cigarette smoking on cardiac inflammation, oxidative stress and fibrosis in rat model of streptozotocin (STZ)-induced diabetes. MAIN METHODS: Adults Wistar rats were assigned into control (fresh air, intraperitoneal injection (i.p) of citrate buffer), cigarette smoking (1 h daily for 4 weeks, i.p citrate buffer), DM (35 STZ mg/kg single i.p, fresh air), and DM + Smoking groups for 4 weeks. Cardiac biomarkers of oxidative stress, inflammation, and fibrosis were evaluated. KEY FINDINGS: STZ-induced diabetes as documented by the persistent increase in blood glucose. Relative to control, a significant decrease in body weight was observed in diabetic groups paralleled with increased heart to body weight ratio and systolic blood pressure in all groups. Levels of total nitrite, thiobarbituric acid substances, endothelin -1, interleukin-6 and myeloperoxidase were increased in the DM, Smoking and DM + Smoking groups without changes in C-reactive protein. Cardiac levels of GSH were increased in Smoking groups whereas activities of catalase and superoxide dismutase increased in DM, Smoking and DM + Smoking groups. DM but not smoking increased cardiac fibrosis with a parallel increase in transforming growth factor beta. Cardiac levels of matrix metalloproteinase-2 were elevated in Smoking groups and decreased in DM. SIGNIFICANCE: Exposure to cigarette smoke may increase risk of CVD in DM by increased cardiac oxidative stress and inflammation. Smoking was associated with increased oxidant enzymes and metalloproteinase-2 probably to prevent cardiac fibrosis. PMID- 30244089 TI - Numerical analysis of steele et al. (2018): "Cause of Cambrian explosion - Terrestrial or cosmic?" PMID- 30244090 TI - Helicobacter pylori CagA EPIYA-C motifs and gastric diseases in Moroccan patients. AB - BACKGROUND: The pathogenicity of cagA-positive H. pylori strains is associated with the number and type of repeated sequences named EPIYA located in the C terminal region of the CagA protein. The aim of this study is to determine the polymorphism of the H. pylori cagA 3' region circulating in Morocco and its association with different gastric pathologies. METHODS: A total of 1353 consenting patients, were recruited in this study. The gastric biopsies performed during endoscopy were used for histological examination and for molecular characterization of H. pylori. The study of the type and number of "EPIYA" motif was identified by PCR directly on H. pylori positive biopsies. RESULTS: Of all the biopsies, the infection rate was 61.1%. The cagA gene was amplified in 68.9% of the cases and the analysis of the 3' region of cagA showed the exclusive presence of the "Western CagA" type with a predominance of the EPIYA-ABC motif (71.4%). The number of EPIYA-C motif varies from 0 to 2. The multinomial analysis shows that the infection with strains of H. pylori having two EPIYA-C motifs is a factor that increases the risk of developing gastric cancer compared to gastritis cases with strains lacking this motif (OR = 11.64; CI: 3.34-45.15), whereas this risk is 6 fold higher in comparison with duodenal ulcer cases (OR = 6, CI: 1.29 27.76). CONCLUSIONS: The results of this study suggest that the number of EPIYA-C motifs might be useful as a predictive marker of the infection evolution and will help in the identification of patients at high risk of developing gastric cancer. PMID- 30244091 TI - Genetic characteristics and geographic segregation of Giardia duodenalis in dairy cattle from Guangdong Province, southern China. AB - Giardia duodenalis is a gastrointestinal parasitic protozoan with important veterinary and public health implications worldwide. In this study, a total of 1440 fecal specimens were collected from dairy calves in Guangdong Province, China. The overall prevalence of G. duodenalis was 2.2% (31/1440) by polymerase chain reaction (PCR). The prevalence was 8.4% and 1.1% in pre- and post-weaned calves, respectively. Both assemblages A (6.5%, 2/31) and E (93.5%, 29/31) were found based on sequence analysis of the SSU rRNA gene. All G. duodenalis-positive samples were assayed with PCR followed by sequencing the beta giardin (bg), glutamate dehydrogenase (gdh), and triosephosphate isomerase (tpi) genes, and 20, 23, and 18 sequences were obtained, respectively. Multilocus genotyping yielded 10 assemblage E multilocus genotypes (MLGs). All assemblage E MLGs were genetically distinct from those obtained in cattle from Henan, Xinjiang, Shanghai, and Shaanxi in China. This finding was also supported by FST, Nm, and median-joining network analysis. Results of this study indicated that G. duodenalis was found in low prevalence in dairy calves in Guangdong Province, southern China; nevertheless, the infected calves might represent a public health risk in this region. Additionally, the differences in assemblage E MLGs from the five analyzed regions revealed significant geographic segregation of G. duodenalis in China. PMID- 30244092 TI - Genetic diversity of avian infectious bronchitis virus in China in recent years. AB - In this study, 213 infectious bronchitis viruses (IBVs) were isolated from samples collected from 801 flocks suspected to be infected with IBV from January 2016 to December 2017 in China. By using complete nucleotide sequences of S1 gene we determined the phylogeny of these IBV isolates, which in turn allowed us to define six lineages/genotypes, a number of recombinants and a novel variant. The GI-19 lineage was the most frequently isolated type in China in recent years. Although scattered mutations in the S1 gene among the GI-19 lineage viruses were observed, we also noted different sublineages in the GI-19 lineage with unique mutations, suggesting a high degree of S1 gene variation since they were first isolated in the mid-1990s. We also isolated a number of vaccine-like viruses from vaccinated diseased chickens, although more work is needed to differentiate the reisolation of vaccine strains from field strains of the same serotype. One of the important findings in this study is that the prevalence of the TW I type viruses in GI-7 lineage has been increasing in recent years in China. Another important finding is that recombination events occurred between the predominant GI-19 lineage and the commonly used 4/91 vaccine, which gave rise to distinct IBV isolates. In addition, a novel IBV isolate, together with a reference strain in GenBank database, were found to form a novel lineage/genotype that was remarkably distinct from established lineages. The characteristics of the antigenicity, tissue tropism, pathogenicity and complete genome were required for further investigation for the recombinants and the viruses in different sublineages and novel lineages. Meanwhile, permanent monitoring of circulating strains was needed to monitor the emerging viruses and rationally modify vaccination strategies in the field situation. PMID- 30244093 TI - Identification and localization of SAS-6 in the microsporidium Nosema bombycis. AB - The centriole in eukaryotes functions as the cell's microtubule-organizing center (MTOC) to nucleate spindle assembly. The evolutionarily conserved protein SAS-6 constitutes the center of the cartwheel assembly that scaffolds centrioles early in their biogenesis. Microsporidia possess the spindle plaque instead of centriole as their MTOC to nucleate spindle assembly. However, little is known about the components of spindle plaques in microsporidia. In our present study, we identified a SAS-6 protein in the microsporidium Nosema bombycis and named it as NSAS-6. The NSAS-6 gene contains a complete ORF of 1104 bp in length that encodes a 367-amino acid polypeptide. NSAS-6 consists of a conserved N-terminal domain and a coiled-coil domain. The high identity of SAS-6 homologous sequences from microsporidia indicates that SAS-6 is a conserved protein in microsporidia. Immunolocalization in sporoplasms, intracellular stages and mature spores showed that NSAS-6 probably localizes to the nucleus of N. bombycis and exists throughout the life cycle of N. bombycis. These results suggest that NSAS-6 is required in cell morphogenesis and division in N. bombycis. The function and structure of NSAS-6 should be the focus for further studies, which is essential to elucidate the role of SAS-6 in spindle plaque assembly. PMID- 30244094 TI - Defining Optimal Comorbidity Measures for Patients With Early-Stage Non-Small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy. AB - PURPOSE: Comparison of overall survival (OS) between stereotactic body radiation therapy (SBRT) and other treatments for early-stage non-small cell lung cancer is confounded by differences in age, performance status, and medical comorbidity. We sought to define the most robust measurement for this population among 5 indices: age, Eastern Cooperative Oncology Group performance status, Adult Comorbidity Evaluation 27, Charlson Comorbidity Index (CCI), and age-adjusted CCI (CCIa). METHODS AND MATERIALS: A total of 548 patients with stage I non-small cell lung cancer treated with SBRT were analyzed. Patients were divided into high- and low risk groups for OS for each index using the log-rank test. Continuous and dichotomized models were compared via Akaike information criterion and the Vuong test. Multivariate Cox regression modeling was used with demographic information to determine the independent prognostic value of the continuous and dichotomized versions of the indices. The best was used to stratify the patients into as many significantly different cohorts as possible. RESULTS: Optimal cut-points between high-risk and low-risk OS groups for age, Eastern Cooperative Oncology Group status, Adult Comorbidity Evaluation 27, CCI, and CCIa were >=75 years, >=1, >=3, >=3, and >=6 with hazard ratios for death of 1.23 (95% confidence interval, 1.00 1.50), 1.66 (1.28-2.15), 1.37 (1.12-1.67), 1.43 (1.17-1.76), and 1.47 (1.20 1.80), respectively. Dichotomizing did not result in a significant loss of prognostic power. Although there was no significant difference in prognostic power among the indices, CCIa best predicted OS. CCIa divided the patients into 3 cohorts with median OS of 42 months, 33 months, and 23 months for scores of <=5, 6 to 7, and >=8, respectively. CONCLUSIONS: CCIa was the best indicator of OS in every model employed with no loss of prognostic power with dichotomization. Dichotomization of CCIa (>=6) could be implemented in future comparisons of SBRT with OS. No cohort could be identified with a median survival of less than a year, for which treatment could be deemed futile. PMID- 30244095 TI - The discriminative stimulus effects of nicotine & ethanol with two distinct olfactory contexts in male and female rats. AB - Odor cues and interoceptive cues can combine in promoting drug seeking behavior. Drug discrimination methodology was combined with odor-context conditioning in 8 male and 8 female rats. One drug (nicotine or EtOH) plus odorant (peppermint or anise) compound functioned as setting the occasion for sessions of food reinforced nose poke responses (i.e., the SD) that were maintained on a variable interval 30 s schedule (VI-30), whereas the opposite drug (EtOH or nicotine) plus odorant (anise or peppermint) compound predicted intermixed sessions of non reinforcement of nose poking (i.e., the SDelta). During brief non-reinforcement tests conducted with each condition there was significantly greater responding under the SD drug plus odor compound compared to the SDelta drug plus odor compound. Discriminative control was evident and there was a sex by stimulus role interaction with greater SDelta responding in females. The odor contexts and drug contexts alone also sustained strong stimulus control but to a lesser extent compared to the full drug-odor compounds. These data suggest configural learning among drug and odor cues. PMID- 30244096 TI - Personality in the longsnout seahorse, Hippocampus reidi Ginsburg, 1933: Are males shyer than females? AB - Individual responses, particularly based on personality, can have important consequences for individual fitness, based upon success in exploring new habitats, feeding on novel foods, and aggressiveness in competitive interactions. We conducted laboratory experiments to analyze individual responses to different artificial conditions that could suit specific male and female personalities in the endangered seahorse, Hippocampus reidi. Our experiments with H. reidi evaluated individual responses to a new habitat, novel objects, level of inactivity and social interactions. We demonstrate that approximately half of the seahorses have a bold personality, readily inspecting new habitats and objects and sporadically presenting social approaches. The remaining shy individuals had high levels of inactivity and did not check novelties in their habitats. Although we expected that males would have shyer personalities when compared with females, due to their ecological role in the provision of parental care, we found no statistical difference between the sexes in terms of these aspects of personality. The similar frequency of both types of personality in males and females suggests that these features may be balanced and evolutionarily stable in the sampled population. PMID- 30244097 TI - A Reduction in Inflammatory Macrophages May Contribute to Skin Cancer Chemoprevention by Nicotinamide. PMID- 30244098 TI - Collection, Cryostorage, Transplantation, and Disposal of Hematopoietic Stem Cell Products. AB - Many transplantation centers routinely collect 1 or more autologous peripheral blood stem cell (PBSC) grafts in patients with hemato-oncologic and autoimmune disorders. However, subsequent high-dose chemotherapy and autologous blood stem cell transplantation (ABSCT) are often not performed, for various reasons. Currently, little is known about the actual utilization rate of stored PBSCs. We retrospectively analyzed the collection, storage, and disposal practices of PBSC products from a large cohort of patients (n = 1020) with hematologic, oncologic, and autoimmune disorders at our institution over a 12-year period. Patients with multiple myeloma were excluded. Based on our institution-specific charges, we estimated the costs for PBSC collection/processing and storage. The median number of sufficient PBSC collections per patient in the whole cohort was 2 (range, 1 to 6). We could demonstrate that only 67% of all patients who had collected sufficient PBSCs for transplantation actually underwent ABSCT, and only a small minority of all patients (4%) underwent multiple ABSCTs. The actual use of the stored PBSC grafts varied among disease entities from >80% to 0%. From a retrospective standpoint, the collected and discarded (definitively not used) or stored (potentially not used) cryostored PBSCs were associated with considerable costs of collection, cryopreservation, and long-term cryostorage. Although keeping open the therapeutic option for future transplantations may be important, there is currently a huge discrepancy between collection/storage practices and actual utilization of the cryopreserved PBSCs, at a considerable cost and strain on patients. Our study provides a rationale for reevaluating the present standards. PMID- 30244099 TI - Cognitive Function and Quality of Life in Vorinostat-Treated Patients after Matched Unrelated Donor Myeloablative Conditioning Hematopoietic Cell Transplantation. AB - Myeloablative conditioning allogeneic hematopoietic cell transplantation (HCT) puts patients at greater risk for significant cognitive and quality of life decline compared with recipients of reduced-intensity conditioning or autologous HCT. Vorinostat, a histone deacetylase inhibitor, has been shown to have neuroprotective and neurorestorative effects in preclinical models of neurologic diseases. Thus, within the context of a myeloablative conditioning phase II clinical trial of vorinostat combined with tacrolimus and methotrexate for graft versus-host disease prophylaxis, we conducted an ancillary study to evaluate feasibility of assessing associations between vorinostat and neurocognitive function and quality of life (ClinicalTrials.gov NCT02409134). Nine patients (mean age, 53 years; range, 36 to 66) underwent computerized neuropsychological testing (Cogstate) and completed surveys of mood (Patient Health Questionnaire 9), anxiety (General Anxiety Disorder-7), and quality of life (Functional Assessment of Cancer Therapy-General). Control cohorts from a separate concurrent longitudinal study (19 autologous and 18 allogeneic HCT patients, who matched the vorinostat patients on relevant medical and demographic variables) completed the same test battery. All allogeneic patients received busulfan-based myeloablative conditioning and were transplanted with HLA-matched unrelated donors. The total neurocognitive performance score of vorinostat patients did not change significantly across the study duration (ie, baseline, day 30, day 100, and day 160). Depression, anxiety, and quality of life also did not differ significantly across time. In univariate analyses (analysis of variance), vorinostat-treated patients showed no difference in neurocognitive function or quality of life compared with autologous and allogeneic control subjects. However, when medical variables were accounted for in a linear mixed effects regression model, the total neurocognitive performance of vorinostat-treated patients was comparable with autologous control subjects. Notably, autologous control subjects performed significantly better than allogeneic control subjects (estimate, .64; standard error, .23; P <= .01). Moreover, a smaller percentage of vorinostat-treated patients were classified as mildly, moderately, or severely impaired across neurocognitive domains as well as time points compared with both control cohorts. Thus, vorinostat may have neurorestorative or neuroprotective effects in the HCT setting. Accordingly, we recognize the need for a future, full-scale randomized controlled trial to further examine this hypothesis. PMID- 30244100 TI - Ten Things to Know About Primary Mediastinal B Cell Lymphoma. PMID- 30244101 TI - High-Dose Chemotherapy with Early Autologous Stem Cell Transplantation Compared to Standard Dose Chemotherapy or Delayed Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis. AB - Autologous stem cell transplantation (SCT) is the standard of care for all transplantation-eligible patients diagnosed with multiple myeloma (MM). Various studies have compared clinical outcomes with frontline SCT ("early SCT") versus standard-dose therapy (SDT) alone, with or without salvage SCT ("SDT/late SCT"). In this meta-analysis, we compare overall survival (OS) and progression-free survival (PFS) outcomes between these 2 treatment approaches. Twelve studies were identified, including a total of 3633 patients, of whom 1811 received early SCT and 1822 received SDT/late SCT. In our analysis of all 12 studies, OS was not significantly different between the 2 groups (hazard ratio [HR], .86; 95% confidence interval [CI], .70 to 1.04), but PFS was better with early SCT (HR, .67; 95% CI, .54 to .82). In a subgroup analysis of 3 studies in which novel agents were used for induction, OS again was similar in the 2 groups, and PFS was favorable with early SCT (HR, .50; 95% CI, .36 to .70). This analysis shows that over the years, early SCT has been associated with prolonged PFS, but this did not consequently translate into prolonged OS in patients with newly diagnosed MM. The benefit of early SCT in terms of OS is less clear in the era of novel agents, given the limited follow-up of these studies. PMID- 30244102 TI - Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation. AB - Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK) guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015. A weight-based test dose of 0.8 mg/kg was used with PK assessments to predict area under the curve (AUCpred) achieved with weight-based dosing, with a target AUC of 4800 uM*minute (AUCtarget). PK from the test dose was then used to calculate a PK guided first myeloablative busulfan dose. PK assessments were also done after the first dose to assess if the goal area under the curve (AUC) had been achieved (AUCfirst). A PK-guided first dose resulted in achievement of target AUC with target ranges of +/-10% in 50% of patients, +/-15% in 75%, and +/-20% in 94%. This was an improved rate of target achievement compared with the 33%, 44%, and 63% of patients who achieved the desired AUC for these respective target ranges when using weight-based dosing (P = .12, .004, and <.001, respectively). The PK guided strategy also decreased the variability of AUC from 3.6-fold in AUCpred from the weight-based test doses (2700.8 to 9631 uM*minute; SD, 1211.6 uM*minute) to 1.8-fold in AUCfirst from the PK-guided first doses (3672.1 to 6609.8 uM*minute; SD, 574.7 uM*minute). This reflects a 2-fold improvement in AUC variability with a PK-guided dosing strategy. This is also improved from the 3 fold variability in AUC reported in other studies. Weight and body surface area were significantly associated with the likelihood of AUCfirst being within the +/ 10% target range (P = .04 for both associations). There was no significant association between AUCfirst and death, relapse, or a composite of the two. These results demonstrate a significant improvement in target AUC attainment and less interpatient variability with PK-guided dosing using a test dose strategy compared with weight-based dosing. PMID- 30244103 TI - Outcomes after Second Hematopoietic Cell Transplantation in Children and Young Adults with Relapsed Acute Leukemia. AB - Children with acute leukemia who relapse after hematopoietic cell transplantation (HCT) have few therapeutic options. We studied 251 children and young adults with acute myelogenous or lymphoblastic leukemia who underwent a second HCT for relapse after their first HCT. The median age at second HCT was 11 years, and the median interval between first and second HCT was 17 months. Most of the patients (n = 187; 75%) were in remission, received a myeloablative conditioning regimen (n = 157; 63%), and underwent unrelated donor HCT (n = 230; 92%). The 2-year probability of leukemia-free survival (LFS) was 33% after transplantation in patients in remission, compared with 19% after transplantation in patients not in remission (P = .02). The corresponding 8-year probabilities were 24% and 10% (P = .003). A higher rate of relapse contributed to the difference in LFS. The 2-year probability of relapse after transplantation was 42% in patients in remission and 56% in those in relapse (P = .05). The corresponding 8-year probabilities were 49% and 64% (P = .04). These data extend the findings of others showing that patients with a low disease burden are more likely to benefit from a second transplantation. Late relapse led to a 10% decrement in LFS beyond the second year after second HCT. This differs from first HCT, in which most relapses occur within 2 years after HCT. PMID- 30244104 TI - Characterization of Late Acute and Chronic Graft-Versus-Host Disease according to the 2014 National Institutes of Health Consensus Criteria in Japanese Patients. AB - To characterize the incidences and outcomes of late acute (LA) and chronic graft versus-host disease (GVHD) in East Asians according to the 2014 National Institutes of Health criteria, we retrospectively analyzed 506 consecutive Japanese patients who had a first allogeneic hematopoietic cell transplantation (HCT) at our center between 2006 and 2013. According to manifestations at onset 91 patients (60%) had LA GVHD and 60 (40%) had chronic GVHD. The cumulative incidences of LA and chronic GVHD were 20% and 17%, respectively, at 48 months after HCT. The involved sites at the onset of LA GVHD included the skin (71%), gut (13%), and liver (8%). The cumulative incidences of relapse, nonrelapse mortality (NRM), transition to chronic GVHD, and discontinued systemic treatment were 11%, 6%, 22%, and 46%, respectively, at 48 months after onset of LA GVHD. Cox models showed that prior acute GVHD was associated with NRM, and HCT from a female donor to a male patient, myeloablative conditioning, and low Karnofsky performance status were associated with a longer duration of systemic treatment after LA GVHD. The most frequently involved sites at the onset of chronic GVHD included the mouth (83%), liver (75%), skin (69%), and eyes (62%). Cox models showed that use of antithymocyte globulin in conditioning regimens was associated with a higher risk of discontinued systemic treatment after the onset of chronic GVHD. The cumulative incidences of relapse, NRM, and discontinued systemic treatment were 16%, 11%, and 41%, respectively, at 48months after the onset of chronic GVHD. Our results suggested several potential differences between Japanese patients and those of other ethnicities. A direct comparison is needed to formally investigate ethnic differences. PMID- 30244105 TI - Impact of Obesity on Clinical Outcomes of Elderly Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myeloid Malignancies. AB - Allogeneic hematopoietic cell transplantation (allo-HCT) is a high-risk treatment option for patients with hematologic malignancies. Advanced age and obesity can impact outcomes after allo-HCT. Previous registry studies of all age groups found that obesity does not affect outcomes. However, obesity can accelerate age related decline in physical function and exacerbate comorbid conditions in older patients. Studies evaluating the effect of obesity on elderly patients undergoing allo-HCT are lacking. We performed a retrospective analysis of 86 nonobese (body mass index [BMI] <30) and obese (BMI >=30) patients age >=60 years who underwent allo-HCT for myeloid malignancies between January 2010 and June 2015. We found no significant between-group differences in mean age, sex, comorbid conditions, cytogenetic risk, disease indication for transplantation, or donor type. The median overall survival (OS) was 36 months for the BMI <30 group and 24 months for the BMI >=30 group (P = .55). The median progression-free survival (PFS) was 10.1 months in the BMI <30 group and 13.6 months in the BMI >=30 group (P = .93). There were no significant between-group differences in acute graft-versus-host disease (GVHD) and cumulative incidence of chronic GVHD at 1 year post transplantation. Among patients admitted for transplantation, the mean length of stay was 25 days in the BMI <30 group and 26 days in the BMI >=30 group (P = .64). The rate of readmission within 30 days of discharge was significantly higher in the BMI >=30 group (34% versus 16%; P = .045). Our data reveal that in these elderly patients with myeloid malignancies undergoing allo-HCT, clinical outcomes, including OS, PFS, and GVHD, were not affected by obesity. Thus, in elderly patients, obesity should not preclude consideration for curative allo-HCT and does not portend worse outcomes after allo-HCT. PMID- 30244106 TI - Turn off the Tap! The Need for Induction Therapy for AL Amyloidosis Before Transplantation. PMID- 30244107 TI - Unique Challenges of Hematopoietic Cell Transplantation in Adolescent and Young Adults with Hematologic Malignancies. AB - Slow but definite progress has been made in recognizing the differences in disease biology, host factors, and psychosocial issues related to management of hematologic malignancies, including hematopoietic cell transplantation (HCT), in the adolescent and young adult (AYA) population. Improvement in survival rates among AYAs undergoing HCT for hematologic malignancies have paralleled those seen among children and older adults in the contemporary era. However, overall outcomes remain inferior compared with those in children owing largely to higher rates of treatment related mortality and late relapses in AYA HCT recipients. We review the unique issues and challenges facing AYAs with hematologic malignancies undergoing HCT, identify unmet needs and gaps in care, and describe potential strategies to address them. A patient-centric and multidisciplinary approach to AYA HCT care with lifelong follow-up is necessary to ensure long-term health. PMID- 30244108 TI - Double-Negative T Cell Levels Correlate with Chronic Graft-versus-Host Disease Severity. AB - Chronic graft-versus-host disease (cGVHD) is a major complication, affecting 50% to 80% of long-term survivors of allogeneic hematopoietic stem cell transplantation. Current cGVHD therapies are neither specific nor curative, and patients are typically maintained for several months to years under immunosuppressive regimens that are associated with important side effects and increased susceptibility to life-threatening infections. As a result, continued investigation into the pathology of the disease and the search for novel diagnostic and therapeutic strategies to treat cGVHD remains a high priority. We report that the cellular dynamics of various immune cell subsets are related to cGVHD onset and severity in a cohort of allogeneic hematopoietic stem cell transplantation recipients. We document a decrease in the proportion of CD45RO+ CD4-CD8- (double-negative [DN]) T cells at the onset of cGVHD, a time at which serum levels of B cell activating factor and B cells are increased. We also find that DN T cell levels are correlated with cGVHD severity. Our present findings are in line with the view that activated DN T cells exhibit their immunoregulatory potential by eliminating B cells in vivo. Taken together, these findings suggest that maintaining elevated DN T cell numbers before the onset of cGVHD may prevent pathological B cell responses. PMID- 30244109 TI - The Dilemma of Conditioning Intensity: When Does Myeloablative Conditioning Improve Outcomes for Allogeneic Hematopoietic Cell Transplantation. AB - The impact of conditioning intensity on different disease risk index (DRI) groups has not been evaluated. We retrospectively analyzed acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) hematopoietic cell transplantation (HCT) recipients in 2 groups based on DRI, to assess the impact of conditioning intensity on overall survival (OS), disease free survival (DFS), relapse, and nonrelapse mortality (NRM). A total of 380 patients with either high/very high (n = 148) or low/intermediate DRI (n = 232) myeloid malignancy (AML, n = 278; MDS, n = 102) were included in the analysis. Median follow-up for survivors was 35 months. Median age was 58 years (range, 18 to 75). Patient and transplant-related characteristics were 41% reduced-intensity conditioning (RIC), 59% myeloablative conditioning (MAC), 13% bone marrow graft, 29% matched related donor, 49% matched unrelated donor, 22% haploidentical donor, and 52% HCT-specific comorbidity index >= 3. Among patients with high/very high DRI, there was no difference in OS, DFS, relapse, and NRM between RIC and MAC conditioning groups. For low/intermediate risk DRI recipients of MAC had better 3-year OS estimate (69% versus 57%, P = .001), DFS (65% versus 51%, P = .003), and lower relapse (3-year cumulative incidence, 17% versus 32%; P = .01) but similar NRM (19% versus 17%, P = .04) to RIC recipients. On multivariable analysis MAC was associated with better DFS (hazard ratio [HR], .58; 95% confidence interval [CI], .39-.88; P = .01), lower relapse (HR, .56; 95% CI, .32 to .97; P = .038), and similar NRM (HR, 1.11; 95% CI, .54 to 2.26; P = .781) compared with RIC in the low/intermediate DRI group. Intensity had no impact on HCT outcomes in the high/very high DRI group. MAC improves DFS and relapse compared with RIC among AML/MDS patients with low/intermediate DRI. The finding of no such benefit in high/very high DRI needs to be further explored in a larger cohort with a longer follow-up. PMID- 30244110 TI - Pregabalin increases food intake through dopaminergic systems in the hypothalamus. AB - Pregabalin is useful for treating neuropathic pain, but known to increase body weight as a side effect. To investigate the mechanism of this increase in body weight, we focused on dopamine in the lateral hypothalamus (LH) and examined the effects of pregabalin on dopamine levels in the LH and food intake. The dopamine levels in the LH was gradually decreased during fasting. When the animals were fed, dopamine levels in the LH was significantly increased, indicating that dopamine levels in the LH reflects energy state. The systemic injection of pregabalin tended to decrease dopamine levels in the LH after feeding. The dopamine levels in the LH was also significantly increased by glucose injection, which was inhibited by pregabalin. These results suggest that pregabalin inhibits dopaminergic function in the LH, which might increase food intake. To make these points clear, we examined the effects of pregabalin on food intake and blood glucose levels. Pregabalin significantly increased food intake, whereas pregabalin did not affect blood glucose levels. These results indicate that pregabalin stimulates feeding behavior, but not glucose metabolism. Moreover, the non-selective dopamine receptor antagonist cis-(Z)-flupenthixol injected into the LH significantly increased food intake, though neither the dopamine D1 receptor antagonist SCH 23390 nor the D2 receptor antagonist l-sulpiride injected into the LH affected food intake. These results indicate that the inhibition of dopaminergic function in the LH increases food intake. In conclusion, the present results suggest that pregabalin increases food intake through the inhibition of dopaminergic functions in the LH. PMID- 30244111 TI - CT perfusion imaging of cerebral microcirculatory changes following subarachnoid hemorrhage in rabbits: Specific role of endothelin-1 receptor antagonist. AB - BACKGROUND: Cerebral vasospasm may lead to delayed ischemic neurological deficits following subarachnoid hemorrhage (SAH). Endothelin (ET-1) is an important factor participating in cerebral vasospasm underlying SAH. We used a specific endothelin receptor antagonist, BQ123 to assess the specific role of endothelin-1 receptor antagonist in cerebral vasospasm in a rabbit model of SAH by examining plasma ET 1 levels and the principal CT perfusion (CTP) parameters pertinent to the hemodynamic status of microcirculation following SAH. METHODS: 102 male New Zealand white rabbits were divided into control, SAH and SAH + BQ123 intervention group (BQ123 group). Rabbit SAH model was established by double hemorrhage injection of autologous blood into the cisterna magna; Aquilion ONE was used to collect cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) which were used to evaluate cerebral microcirculation hemodynamics; Elisa was used to assess plasma ET-1 levels. Data were collected on days 1, 4, 7 and 14 following SAH, respectively. RESULTS: Compared with the control group, the CBF in the SAH group was significantly lower, while the MTT was significantly higher. The CBF decreased on the 4th day and reached the lowest on the 7th day. The MTT began to rise on the 4th day and peaked on the 7th day. While in the BQ123 intervention group, the CBF significantly increased while the MTT significantly decreased on the 1st and the 4th days, respectively. Compared with SAH group, plasma ET-1 levels in BQ123 group significantly increased on the earlier (1st and 4th days) but not later days (between the 7th and 14th days). In addition, the inflammatory infiltration of brain tissues in rabbits treated with BQ123 post-SAH was significantly reduced compared with SAH group. CONCLUSION: CTP can quantify the therapeutic effect of BQ123 after SAH; Selective blockade of ET 1 endothelin receptor, BQ123 significantly improved microcirculatory perfusion along with a reduction in resultant vasogenic inflammatory responses. The effect of BQ123 on the cerebral microcirculation was lobe dependent. PMID- 30244112 TI - Dopamine D1 receptor in the medial prefrontal cortex mediates anxiety-like behaviors induced by blocking glutamatergic activity of the ventral hippocampus in rats. AB - The medial prefrontal cortex (mPFC) receives direct and indirect projections from the ventral hippocampus (VH) and plays an important role in the regulation of anxiety. However, the effect of the mPFC dopamine D1 receptor on anxiety-like behaviors induced by inhibition of glutamatergic activity in the VH has not been described. Here, we examined the effects of SKF38393, a selective dopamine D1 receptor agonist, on anxiety-like behaviors induced by NMDA receptor inhibition in the VH and neuron firing activity of mPFC. Injection of MK-801 (6 MUg/0.5 MUl) into the VH produced anxiety-like behaviors in the elevated plus maze and open field tests, increased the firing activity of pyramidal neurons in the mPFC, and decreased the level of dopamine in the mPFC. Injection of SKF38393 (0.5 MUg/0.5 MUl) into the mPFC produced anxiolytic effects, and normalized the hyperactive firing activity of mPFC pyramidal neurons induced by MK-801, whereas in both normal and anxiety-like rats caused by MK-801, injection of SKF38393 into the mPFC decreased the firing activity of mPFC interneurons but did not affect the dopamine content in the mPFC. The present data demonstrate that decreased D1 receptor activation in the mPFC may mediate anxiety-like behaviors induced by inhibition of glutamatergic activity in the VH. The balance of D1 receptor activity between pyramidal neurons and interneurons is a crucial factor in maintaining normal conditions, and inhibitory glutamatergic activity in the VH induces hyperactivity of mPFC pyramidal neurons through decreases in dopamine release and in the amount of D1 receptor activation on mPFC pyramidal neurons, which may be a critical factor for anxiety disorders. PMID- 30244113 TI - Resveratrol and dimethyl fumarate ameliorate depression-like behaviour in a rat model of chronic unpredictable mild stress. AB - Chronic stress occurs in everyday life and induces depression. Emerging evidence shows that oxidative stress, inflammation and apoptosis are main contributing pathophysiologic mechanisms of depression. Resveratrol and dimethyl fumarate (DMF) are natural antioxidants that have diverse biological activities. Our study aimed to determine whether resveratrol and DMF affected these systems in rats exposed to chronic unpredictable mild stress (CUMS)-induced depression-like behaviours. Rats were submitted to 8 weeks of CUMS to induce depressive-like behaviour. The depressive-like behaviour of rats induced by CUMS was revealed by an elevated serum corticosterone level and decreased serum and hippocampal serotonin levels. Our results showed that CUMS significantly-induced behavioural abnormalities (reduced sucrose preference and increased immobility time) in stressed rats. CUMS exposure significantly decreased BDNF and beta-catenin expression levels as well as increased GSK-3beta expression level in hippocampus. Furthermore, CUMS exposure resulted in a significant increase in expression levels of NF-kappaB, TNF-alpha and IL-Ibeta accompanied by decreased Bcl-2 expression level. CUMS increased hippocampal MDA level and significantly decreased hippocampal GSH and serum total antioxidant capacity levels compared to the control group. Histopathological examinations provided evidence for the biochemical and molecular analysis. All of these effects were significantly ameliorated by administration of resveratrol and DMF. In conclusion, our study revealed that resveratrol and DMF exerted promising antidepressant-like effects in CUMS rats that are mediated in part by suppressing the neuroinflammation, oxidative stress, apoptosis and up-regulating hippocampal BDNF and beta-catenin levels. Serum serotonin analysis may be a reliable indicator for monitoring depression. PMID- 30244114 TI - Acute hypoxic exposure and prolyl-hydroxylase inhibition improves synaptic transmission recovery time from a subsequent hypoxic insult in rat hippocampus. AB - In the CNS short episodes of acute hypoxia can result in a decrease in synaptic transmission which may be fully reversible upon re-oxygenation. Stabilization of hypoxia-inducible factor (HIF) by inhibition of prolyl hydroxylase domain (PHD) enzymes has been shown to regulate the cellular response to hypoxia and confer neuroprotection both in vivo and in vitro. Hypoxic preconditioning has become a novel therapeutic target to induce neuroprotection during hypoxic insults. However, there is little understanding of the effects of repeated hypoxic insults or pharmacological PHD inhibition on synaptic signaling. In this study we have assessed the effects of hypoxic exposure and PHD inhibition on synaptic transmission in the rat CA1 hippocampus. Field excitatory postsynaptic potentials (fEPSPs) were elicited by stimulation of the Schaffer collateral pathway. 30 min hypoxia (gas mixture 95% N2/5% CO2) resulted in a significant and fully reversible decrease in fEPSP slope associated with decreases in partial pressures of tissue oxygen. 15-30 min of hypoxia was sufficient to induce stabilization of HIF in hippocampal slices. Exposure to a second hypoxic insult after 60 min resulted in a similar depression of fEPSP slope but with a significantly greater rate of recovery of the fEPSP. Prior single treatment of slices with the PHD inhibitor, dimethyloxalylglycine (DMOG) also resulted in a significantly greater rate of recovery of fEPSP post hypoxia. These results suggest that hypoxia and 'pseudohypoxia' preconditioning may improve the rate of recovery of hippocampal neurons to a subsequent acute hypoxia. PMID- 30244115 TI - Reply by the Authors: Shock-wave Lithotripsy for Pediatric Patients: Which Nomogram Can Better Predict Postoperative Outcomes? PMID- 30244116 TI - Testosterone therapy for high-risk prostate cancer survivors: a systematic review and meta-analysis. AB - A systematic review and meta-analysis was performed to determine the relationship between testosterone therapy and risk of recurrence in testosterone-deficient survivors of curatively treated high-risk prostate cancer. Primary outcome was the risk of biochemical recurrence (BCR) in 109 high-risk patients in 13 included studies (1997-2017). Biochemical and symptomatic effects of therapy were also reviewed. The BCR rate was 0.00 (0.00-0.05), lower than the expected rate for high-risk prostate cancer survivors, suggesting that testosterone therapy may not increase their BCR risk. However, this is uncertain as the available evidence is of very low quality. Testosterone therapy remains investigational in this group. PMID- 30244117 TI - Comparison of Postradical Cystectomy Ileus Rates Using GIA-80 Versus GIA-60 Intestinal Stapler Device. AB - OBJECTIVE: To assess the impact on recovery of bowel function using an 80 mm versus 60 mm gastrointestinal anastomosis (GIA) stapler following radical cystectomy and urinary diversion (RC/UD) for bladder cancer. METHODS: We identified 696 patients using a prospectively maintained RC/UD database from January 2006 to November 2010. Two nonrandomized consecutive cohorts were compared. Patients between January 2006- and December 2007 (n = 180) were treated using a 60 mm GIA stapler, and 331 patients between January 2008 and December 2010 were subject to an 80 mm GIA stapler. All patients were treated on the same standardized postoperative recovery pathway. After accounting for baseline patient and perioperative characteristics, using a multivariable logistic regression model, we directly compared rates of postoperative ileus using a standardized definition. RESULTS: Of 511 evaluable patients, ileus was observed in 32% (57/180) for 60 mm GIA versus 33% (110/331) for the 80 mm GIA. Preoperative renal function, age, gender, body mass index, and type of diversion were comparable between cohorts. On multivariate analysis, stapler size was not significantly associated with the development of ileus (GIA-60 vs GIA-80: OR 1.11; 95% CI 0.75, 1.66; P = .6). Positive fluid balance was associated with an increased risk (P = .019) and female sex a decreased risk (P = .008) of developing ileus compared to patients with negative fluid balance. CONCLUSION: The size of the intestinal bowel anastomosis (GIA 80 mm vs 60 mm) does not independently impact the time to bowel recovery following RC/UD. PMID- 30244118 TI - Re: Shock-wave Lithotripsy for Pediatric Patients: Which Nomogram Can Better Predict Postoperative Outcomes? From Yanaral F, Ozgor F, Savun M, Agbas A, Akbulut F, Sarilar O. PMID- 30244119 TI - TRPV1 mediates capsaicin-stimulated metabolic activity but not cell death or inhibition of interleukin-1beta release in human THP-1 monocytes. AB - Human monocytes and dendritic cells express transient receptor potential vanilloid 1 (TRPV1) which may play a role in mediating the inflammatory, immune and cancer surveillance responses of these cells. The aim of the present study was to investigate TRPV1 expression and function in THP-1 monocytic cells. RT-PCR and Western blot were used to detect TRPV1. The metabolic activity and viability of THP-1 cells following exposure to vanilloids was assessed using resorufin production from rezazurin. Cytokine release was measured using ELISA. TRPV1 was expressed in cultured THP-1 monocytic cells and naive monocytes. Lower concentrations (<250 MUM) of capsaicin, but not other putative TRPV1 agonists, were shown to stimulate cell metabolic activity, whereas at concentrations >250 MUM, all agonists decreased metabolic activity. Capsaicin-stimulated THP-1 metabolic activity was blocked by the TRPV1 antagonist, 5-iodo-resiniferatoxin (5'-IRTX), whereas the decline in resorufin production by THP-1 cells at higher capsaicin concentrations (due to cell death), was not affected by 5'-IRTX. Finally, capsaicin (<=125 MUM) significantly increased lipopolysaccharide stimulated IL-6 and TNF-alpha release from THP-1 cells, whereas phytohaemagglutinin-stimulated IL-1beta, TNF-alpha, MCP-1 and IL-6 release were concentration-dependently inhibited by capsaicin. Modulation of IL-1beta release was not TRPV1 mediated. Overall, these results show that functional TRPV1 channels are present in naive monocytes and THP-1 cells, and when activated, increase cell metabolic activity. In addition, capsaicin modifies cytokine release from THP-1 cells and induces cell death, most likely by a mechanism that is independent of TRPV1 activation. PMID- 30244120 TI - The toxic effects of monosodium glutamate (MSG) - The involvement of nitric oxide, prostanoids and potassium channels in the reactivity of thoracic arteries in MSG-obese rats. AB - We investigated the potential effects of monosodium glutamate (MSG)-induced obesity with regards to nitric oxide and prostanoid production, as well as potassium channel function, in rat thoracic arteries. Newborn male Wistar rats were injected intraperitoneally with typically reported MSG (4.0 mg/g) once daily for 4 consecutive days. At 90 days postnatal, the rats were sacrificed and the thoracic aortas were evaluated for vascular responses and for prostanoid production. Nitric oxide was studied with calcium ionophore (A23187), acetylcholine (ACh) and sodium nitroprusside (SNP). The release of prostanoids was measured under basal and ACh-stimulated conditions, and the vasomotor effect of exogenous thromboxane A2 mimetic, U46619 was assessed. Potassium channel activities were analyzed using an NS1619 opener for BKCa channels and pinacidil for KATP channels. Arteries from MSG-obese rats exhibited a reduced maximal contraction to potassium chloride and hyper-responsiveness to U46619, suggesting that MSG also alters the responsiveness of vascular smooth muscles. The endothelium-dependent relaxation to ACh and A23817 was attenuated, suggesting low nitric oxide bioavailability. The hypersensitivity of arteries to an exogenous nitric oxide donor, SNP, occurred. The secondary contraction to A23817 was augmented, suggesting increased activation of the prostanoid receptor. The prostanoid release was increased in both basal- and acetylcholine-stimulated rings. In addition, down-regulation of KATP and BKCa channels influenced hyperpolarizing mechanisms. Our findings suggest that increased prostanoid production and hypersensitivity to thromboxane A2 together with down-regulation of potassium channels and low nitric oxide bioavailability may contribute to the increase in blood pressure found in adult MSG-obese male rats. PMID- 30244121 TI - Knockdown of lncRNA H19 restores chemo-sensitivity in paclitaxel-resistant triple negative breast cancer through triggering apoptosis and regulating Akt signaling pathway. AB - Triple negative breast cancer (TNBC) is associated with poor prognosis and systemic chemotherapy is the only treatment for TNBC. However, development of chemo-resistance remains a major obstacle for TNBC treatment. Paclitaxel resistance is mainly related to the activation of the Akt signaling pathway and deregulation of apoptotic regulatory proteins. LncRNAs are frequently dysregulated in various malignancies, including breast cancer, facilitating cell proliferation, metastasis and drug resistance. LncRNA H19 is overexpressed in approximately 70% of breast cancer patients, and has been reported to confer chemo-resistance in breast cancer. In the present study, we investigated the expression level of lncRNA H19 in paclitaxel-resistant and paclitaxel-sensitive cell lines. The results showed that the level of lncRNA H19 expression in paclitaxel-resistant cells was significantly higher than that in paclitaxel sensitive cells, and knockdown of lncRNA H19 might restore chemo-sensitivity in paclitaxel-resistant TNBC by mediating the AKT signaling pathway. Thus, lncRNA H19 might be an efficient therapeutic target in paclitaxel-resistant TNBC treatment. PMID- 30244122 TI - Integration of transcriptomic data and metabolic networks in cancer samples reveals highly significant prognostic power. AB - Effective stratification of cancer patients on the basis of their molecular make up is a key open challenge. Given the altered and heterogenous nature of cancer metabolism, we here propose to use the overall expression of central carbon metabolism as biomarker to characterize groups of patients with important characteristics, such as response to ad-hoc therapeutic strategies and survival expectancy. To this end, we here introduce the data integration framework named Metabolic Reaction Enrichment Analysis (MaREA), which strives to characterize the metabolic deregulations that distinguish cancer phenotypes, by projecting RNA-seq data onto metabolic networks, without requiring metabolic measurements. MaREA computes a score for each network reaction, based on the expression of the set of genes encoding for the associated enzyme(s). The scores are first used as features for cluster analysis and then to rank and visualize in an organized fashion the metabolic deregulations that distinguish cancer sub-types. We applied our method to recent lung and breast cancer RNA-seq datasets from The Cancer Genome Atlas and we were able to identify subgroups of patients with significant differences in survival expectancy. We show how the prognostic power of MaREA improves when an extracted and further curated core model focusing on central carbon metabolism is used rather than the genome-wide reference network. The visualization of the metabolic differences between the groups with best and worst prognosis allowed to identify and analyze key metabolic properties related to cancer aggressiveness. Some of these properties are shared across different cancer (sub) types, e.g., the up-regulation of nucleic acid and amino acid synthesis, whereas some other appear to be tumor-specific, such as the up- or down-regulation of the phosphoenolpyruvate carboxykinase reaction, which display different patterns in distinct tumor (sub)types. These results might be soon employed to deliver highly automated diagnostic and prognostic strategies for cancer patients. PMID- 30244123 TI - An electro-conductive plane heating element for rapid thermal lysis of bacterial cells. AB - In the process of developing a point-of-care testing device, we fabricated a plane heating element using carbon paste capable of thermal lysis. The plane heating element can generate heat of 150 degrees C within 60 s at 0.4 A power supply within 8 W. The developed plane heating element was very effective in the extraction of DNA from both Gram-negative and Gram-positive bacteria which was further confirmed by agarose gel electrophoresis. In this approach, we aimed to eliminate expensive, time-consuming and labor-intensive procedures for the lysis of bacterial cells to extract nucleic acids to detect pathogenic bacteria accurately and swiftly. PMID- 30244124 TI - Conidia-based fluorescence quantification of Streptomyces. AB - Determination of cell numbers in filamentous bacteria, such as Streptomyces, is challenging due to the tangled and twisted structure of the filaments and formation of cell clumps in liquid cultures. Here, we developed a conidia-based approach, in which fluorescence of conidia, after staining with the DNA-binding stain SYBR Green 1, was related to SYBR Green 1 fluorescence of DNA in Streptomyces. When cell number in Streptomyces filaments, determined by the conidia assay, was compared to number obtained by a qPCR assay, 34 to 62% of cells in the Streptomyces filaments were recovered. The difference in numbers probably reflects an insufficient extraction of DNA from the Gram-positive bacteria, rather than underestimation of the actual cell number by the conidia based determination. The conidia-based approach appears to be a fast and reliable procedure for counting cell numbers in Streptomyces filaments but it can also be used for other filamentous bacteria, if proper standard curves can be made. PMID- 30244125 TI - Switch to a biosimilar: Whatever the cost? PMID- 30244126 TI - Exploring the DNA interactions, FGF growth receptor interaction and biological screening of metal(II) complexes of NNN donor ligand derived from 2 (aminomethyl)benzimidazole. AB - This work deals with a series of biologically important novel transition metal(II) Schiff base chelates containing terpyridine. Benzimidazole, a moiety found in broad spectrum of drugs is espoused in a Schiff base ligand system. Eight such metal(II) complexes are designed, synthesized and characterized. An octahedral geometry has been envisaged for all the complexes. DNA-binding behaviours are studied by absorption titration, electrochemical, viscosity, fluorescence and circular dichroism methods. The DNA cleavage ability is also evaluated by agarose gel electrophoresis method. These studies reveal that the complexes show an intercalative mode of binding to CT-DNA and also effectively cleave the supercoiled pBR322 DNA. The molecular docking studies of the complexes against FGF growth receptors indicate that they bind through electrostatic, van der Waals, hydrogen bonding and pi-pi interactions. The ligand and its complexes are screened for in vitro antimicrobial activities against a few microorganisms. The data exhibit that they are better antimicrobial agents than the ligand. The cytotoxic activity of the complexes is probed in four cell lines wherein the complex 5 has good cytotoxic activity and is partial to MCF-7 cell line which is comparable with the cisplatin drug which can be attributed to the presence of planar terpyridine co-ligand. PMID- 30244127 TI - Effect of SiO2 nanoparticle on the physical and chemical properties of eco friendly agar/sodium alginate nanocomposite film. AB - Agar/sodium alginate (AG/SA) nanocomposite films were prepared using solution casting method in presence of various concentrations of nano-SiO2 (2.5, 5, 7.5, and 10 wt%). The effect of nano-SiO2 concentration on the nanocomposite film was investigated. The result of Fourier transform infrared (FTIR) illustrated the formation of hydrogen bonding between nano-SiO2 and polysaccharide. As nano-SiO2 concentration rose from 0 to 10 wt%, the tensile strength and elongation at break all increased up to maximum, respectively. The tensile strength and elongation at break of film containing 10 wt% nano-SiO2 increased by 65.29% and 60.38% respectively when compared to those of film prepared without nano-SiO2. The reason for enhancing in tensile strength might be related to the formation of molecular interaction. The film containing 2.5 wt% nano-SiO2 had maximum water contact angle and minimum water vapor permeability among those of all films prepared in this work. However, the film containing 10 wt% nano-SiO2 had minimum swelling degree and water solubility, further demonstrating the formation of strong interaction. The addition of nano-SiO2 improved the properties of film against UV light and thermal stability. Overall, the addition of nano-SiO2 enhanced the mechanical properties, water resistance and thermal stability of polysaccharide film. PMID- 30244128 TI - Silencing of FTS increases radiosensitivity by blocking radiation-induced Notch1 activation and spheroid formation in cervical cancer cells. AB - Increasing evidence(s) suggests that cancer stem cells (CSC) in tumours contribute to radio-resistance and recurrence. Notch plays an important role in the maintenance of CSC in many cancers including cervical cancer. Previously, we have reported the role of Fused Toes Homolog (FTS) in conferring radioresistance in cervical cancer cells in vitro and human subjects. The present study investigated the regulatory role of FTS in Notch signaling and maintenance of CSC upon irradiation of cervical cancer cells. The expression of Notch1, 2, 3, cleaved Notch1 and its downstream target Hes1, and spheroid formation was increased by irradiation. Silencing of FTS prevented the radiation-induced increase in the expression of Notch signaling molecules and spheroid formation. Immunoprecipitation showed FTS binds Notch1 and Hes1. Also in silico structural analysis identified putative residues responsible for the binding between FTS and Notch1. Spheroid formation and the expression of CSC markers, Nanog, Oct4A and Sox2 were greatly reduced by combining silencing of FTS and radiation. Taken together, these results suggest that FTS is involved in the regulation of irradiation-induced Notch signaling and CSC activation and can be used as a target to increase radiosensitivity in cervical cancer. PMID- 30244129 TI - Lignins isolated from Prickly pear cladodes of the species Opuntia ficus-indica (Linnaeus) Miller and Opuntia cochenillifera (Linnaeus) Miller induces mice splenocytes activation, proliferation and cytokines production. AB - Opuntia ficus-indica and Opuntia cochenillifera are species of Cactaceae, found in the arid regions of the planet. They present water, cellulose, hemicellulose, pectins, extractives, ashes and lignins. Here we aimed to study the immunomodulatory action of lignins from these two species against mice splenocytes, since no study for this purpose has yet been reported. The antioxidant activities of these lignins were evaluated by the DPPH, ABTS, NO assays and total antioxidant activity. Cytotoxicity was evaluated through Annexin V-FITC and propidium iodide-PE probs and cell proliferation was determined by CFSE. Immunomodulation studies with Opuntia lignins obtained were performed through investigation of ROS levels, cytosolic calcium release, changes on mitochondrial membrane potential, cytokine production and NO release. Results showed that Opuntia cochenillifera lignin presented more phenolic amount and antioxidant activities than Opuntia ficius-indica. Both lignins showed high cell viability (>96%) and cell proliferation. Activation signal was observed for both lignins with increase of ROS and cytosolic calcium levels, and changes in mitochondrial membrane potential. In addition, lignins induced high TNF-alpha, IL 6 and IL-10 production and reduced NO release. Therefore, these lignins present great potential to be used as molecules with a proinflammatory profile, being shown as a promising therapeutic agent. PMID- 30244130 TI - Experimental and theoretical study of IBC domain from human IP3R2; molecular cloning, bacterial expression and protein purification. AB - IP3 is a ubiquitous second messenger in eukaryotic cells that triggers Ca2+ release from intracellular stores. IP3 binds to intracellular IP3-receptor (IP3R) and induces conformational change within the ligand-binding domain which regulates Ca2+-release; hence, both IP3 and IP3R are key components of the signal transduction mechanism. Here we present cDNA cloning of IP3-binding core (IBC) domain encoding only residues 224-604 of human IP3R type 2 that binds to IP3 with high affinity. RNA extraction, RT-PCR, PCR and cloning were carried out, and then the cloned DNA was checked by sequencing. Thereafter, expression vector pET-28a harboring the correct gene was transformed into different E. coli (DE3) strains and investigated its protein expression under various conditions. Finally, the IBC expression was induced at 20 degrees C for 20 h into BL21 strain at LB medium with 4 mM lactose and 0.5 mM IPTG, and then confirmed by western blotting. After protein purification, structural study was recorded in absence and presence of its ligand. Far-CD and intrinsic fluorescence spectra analysis of the purified protein with and without IP3 ligand showed change in secondary and tertiary IBC structure. Moreover, bioinformatics study demonstrated that the ligand binding site residues R269, K508 and R511 are conserved. PMID- 30244131 TI - Inhibition of aggregation of physically modified rice proteins by isoconcentration of l-Arg and l-Glu. AB - Unwelcome protein aggregation plays a negative role in food sensory properties. In this study, the aggregation tendency of a typical hydrophobic protein (rice proteins) was effectively inhibited by addition of equimolar l-arginine (l-Arg) and l-glutamine (l-Glu). Soluble rice proteins were prepared by freeze-milling treatment (FM-RPs), and their spontaneous aggregation during buffer storage was characterized. Studies from confocal laser scanning microscopy, atomic force microscopy and scanning electron microscopy indicated that spherical FM-RPs were disintegrated into irregular structures that then spontaneously reorganized into amorphous aggregates during storage. Kinetics studies manifested a sigmoidal growth of the aggregation. Examinations of amide I region of aggregates confirmed that FM-RPs were rich in antiparallel and intermolecular beta-sheets, and the hydrophobic bonding of which gave rise to the formation of insoluble agglomerates. Importantly, simultaneous addition of equimolar l-Arg and l-Glu at an isoconcentration of 10 mM reduced the plateau aggregation of FM-RPs from 25.74 to 7.96%. Conformational measurements and zeta-potential studies demonstrated sheet-turn transformations of FM-RPs during aggregation, which lead to stabilization of proteins in solutions. PMID- 30244132 TI - Synthesis and structure characterization of sulfated galactomannan from fenugreek gum. AB - Sulfated derivatives of the galactomannan family have multiple biological activities. In the present study, sulfated galactomannan from fenugreek gum (SFG) were prepared by chlorosulfuric acid/pyridine (CSA/Py) method. In order to acquire the derivatives with the highest degree of substitution (DS), the experiment optimum conditions of the sulfation were determined by Box-Behnken design (BBD). The quadratic regression model analysis confirmed that reaction time was the most significant parameter for the impact of DS. Under the selected conditions, maximum DS was obtained as 0.490. Results of FT-IR and X-ray photoelectron spectroscopy (XPS) indicated the present of SO3- group. In 13C NMR spectroscopy, the original C-6 peaks did not disappear completely and the newly peaks appeared at delta 63.2 and 64.0 illustrating the incomplete substitution were predominantly on C-6 position. After sulfation, size exclusion chromatography combined with multi-angle laser light scattering (SEC-MALLS) detected all the weight average molecular mass (MW) of sulfated derivatives decrease rapidly. The introduction of the electrostatic interaction of negatively charged SO3- groups and the decrease in MW could have a significant effect on its biological activity. PMID- 30244133 TI - Seroprevalence of dengue fever and the associated sociodemographic, clinical, and environmental factors in Makkah, Madinah, Jeddah, and Jizan, Kingdom of Saudi Arabia. AB - This study aimed to estimate the seroprevalence of anti-dengue IgG antibodies in Makkah, Al Madinah, Jeddah, and Jizan; and to identify the associated demographic, clinical, and environmental independent risk factors. A community based household serosurvey conducted between September 20, 2016 and January 31, 2017. A multi-stage stratified cluster sampling was used to select 6596 participants from Makkah, Madinah, Jeddah, and Jizan. Blood samples were drawn from all participants to detect anti-dengue IgG antibodies. A semi-structured questionnaire was used to collect information on demographic, clinical, and environmental data. Multivariate logistic regression was carried out to identify independent risk factors of dengue seropositivity. The dengue seroprevalence (95% confidence intervalI) was 26.7% (25.6%, 27.8%), with the highest (33.6%) and lowest (14.8%) rates in Jizan and Madinah, respectively, and reaching 50% or more in several districts of the four cities. Demographic predictors of seroprevalence included: dwelling in Makkah (odds ratio [OR] = 2.19, p < 0.001) or Jizan (OR = 2.17, p < 0.001); older age (OR = 3.91, p < 0.001 for age>30 years); housing type (OR = 1.84 and 1.82, p < 0.001 for popular and social houses, respectively); and number of household occupants (OR = 0.86 and 0.71 for 6-10 [p = 0.042] and 11-20 [p = 0.002] occupants, respectively). Environmental predictors included the absence of pest control works in residency area (OR = 1.39, p = 0.002), presence of mosquitoes in the home (OR = 1.39, p = 0.001), and absence of awareness campaigns (OR = 1.97, p < 0.001). One in four inhabitants of the Western region of Saudi Arabia was seropositive for the dengue virus. Implementation of behavior based educational programs is recommended, involving the population in the identification and eradication of vector sources and promoting appropriate behaviors that prevent the spread. PMID- 30244134 TI - Insulinotropic activity of the host-defense peptide frenatin 2D: Conformational, structure-function and mechanistic studies. AB - Of four naturally occurring frenatin peptides tested, frenatin 2D (DLLGTLGNLPLPFI.NH2) from Discoglossus sardus was the most potent and effective in producing concentration-dependent stimulation of insulin release from BRIN BD11 rat clonal beta-cells without displaying cytotoxicity. The peptide also stimulated insulin release from 1.1B4 human-derived clonal beta-cells and isolated mouse islets and improved glucose tolerance concomitant with increased circulating insulin concentrations in mice following intraperitoneal administration. The insulinotropic activity of frenatin 2D was not associated with membrane depolarization or an increase in intracellular [Ca2+] but incubation of the peptide (1 MUM) with BRIN-BD11 cells produced a modest, but significant (P < 0.05), increase in cAMP production. Stimulation of insulin release was abolished in protein kinase A-downregulated cells but maintained in protein kinase C-downregulated cells. Circular dichroism studies showed that, in the presence of dodecylphosphocholine micelles, frenatin 2D exhibited a helical content of 35% and a turn content of 28%. Substitution of the Thr5, Asn8, Pro10, and Ile14 residues in frenatin-2D by Trp and interchange of Pro12 and Phe13 led to loss of insulinotropic activity but the [D1W] and [G7W] analogues were as potent and effective as the native peptide. Frenatin 2D (1 MUM) also stimulated proliferation of BRIN-BD11 cells and provided significant protection of the cells against cytokine-induced apoptosis. It is concluded that the insulinotropic activity of frenatin 2D is mediated predominantly, if not exclusively, by the KATP channel-independent pathway. PMID- 30244135 TI - Nucleic acid aptamers in diagnosis of colorectal cancer. AB - Nucleic acid aptamers are promising recognition ligands for diagnostic applications. They are short DNA or RNA molecules isolated from large random libraries through the Systematic Evolution of Ligands by EXponential enrichment (SELEX) procedure. These molecules, with a particular three-dimensional shape, bind to a wide range of targets from small molecules to whole cells with high affinity and specificity. The unique properties of nucleic acid aptamers including high binding affinity and specificity, thermostability, ease of chemical production, ease of chemical modification, target adaptability, simple storage, resistance to denaturation, low immunogenicity, and low cost make them potential diagnostic tools for clinical use. Colorectal cancer is one of the most common types of cancer in humans and the third leading cause of cancer deaths in the world. Due to low response rate to current therapies in advanced stages of the disease, early detection of CRC can be useful in disease management. This review highlights recent advances in the development of nucleic acid aptamer based methods for diagnosis, prognosis, and theranosis of colorectal cancer. PMID- 30244136 TI - Thermodynamics of the fourU RNA thermal switch derived from molecular dynamics simulations and spectroscopic techniques. AB - Bacterial 5' untranslated regions of mRNA, termed thermal switches or thermometers, change their structure in response to temperature change. This structural change provides for the regulation of gene expression. One of such thermal switches, called fourU, is present in the Salmonella species. Mutations of fourU were found to abrogate its regulatory properties. We investigated the thermodynamics of the fourU fragment responsible for its structural changes. All atom molecular dynamics simulations at various temperatures and spectroscopic experiments in solution were performed for the wild-type fourU and its mutants. We found that the U11C and A8C mutations stabilize the fourU structure in comparison to the wild-type fourU, and the double-point G14A/C25U mutant has the most destabilizing effect on the fourU hairpin 2 responsible for temperature sensing. The G14A/C25U mutant is also the easiest to strand-invade by a complementary oligonucleotide as indicated by fluorescence spectroscopy experiments. PMID- 30244137 TI - PLGA: From a classic drug carrier to a novel therapeutic activity contributor. AB - Poly(lactic-co-glycolic acid) (PLGA) is well known for its biocompatibility and minimal toxicity. It is one of the most promising biodegradable polymeric drug delivery systems able to get endorsement from regulatory bodies to enter market. For many decades, PLGA has been functioning as an excipient, which by definition is pharmaceutically inert at a given dose of formulation. Lactate (one of the hydrolysis products of PLGA) has a key role in biochemical pathways and could improve physiological activities in certain illnesses by exerting therapeutic effects such as angiogenesis and promotion of healing. These activities, however, depend on the released amounts and metabolic clearance of lactate and route of formulation delivery. In the current commentary, along with several key notes on the lactate interactions, we would like to inform the PLGA research community that lactate (resulting from local delivery of physiologically significant amount of PLGA) may positively or negatively affect therapeutic efficacy of certain drugs. Hence, the excipient role of PLGA may be investigated for its potential pharmacological contributions in some biomedical applications. PMID- 30244139 TI - From Eye Wash to Cardiac Modeling. PMID- 30244138 TI - Huachansu suppresses TRPV1 up-regulation and spinal astrocyte activation to prevent oxaliplatin-induced peripheral neuropathic pain in rats. AB - Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a major dose- and therapy-limiting side effect that is particularly difficult to treat. Huachansu, an aqueous extract from toad skin, is a widely used anti-cancer natural product in China. Clinical findings have established the safety and effectiveness of Huachansu in combination with chemotherapy to promote the therapeutic efficacy while alleviate the side effects, especially cancer-related pain symptoms. Unfortunately, experimental data on the effects and mechanisms of Huachansu in combination with chemotherapy is not available. In this study, the effects of Huachansu were tested in vivo on a rat model of oxaliplatin-induced CIPNP. The results show, a single injection of Huachansu 2.5 g/kg produced a short-term analgesic effect on pre-established oxaliplatin-induced CIPNP after 60 min, as indicated by decreased mechanical and thermal hypersensitivity in comparison to oxaliplatin-treated rats. Repeated doses of Huachansu, given during CIPNP induction, prevented the development of oxaliplatin-induced CIPNP. This prophylactic effect of Huachansu was associated with suppressed oxaliplatin induced TRPV1 up-regulation in the dorsal root ganglia and spinal astrocyte activation. These findings reveal Huachansu therapeutic potential in treating and preventing CIPNP. PMID- 30244140 TI - The comparison of the performance of 3 T and 7 T T2 mapping for untreated low grade cartilage lesions. AB - OBJECTIVE: To investigate T2 mapping as a possible marker for low-grade human articular cartilage lesions during a one-year follow-up, possible changes during the follow-up and compare the reliability and sensitivity of these measurements on high-field (3 T) and ultra-high-field (7 T) MRI scanners. DESIGN: Twenty-one patients with femoral, tibial and patellar cartilage defect in the knee joint participated in the study. The MRI protocol consisted of morphological, as well as three-dimensional triple-echo steady-state (3D-TESS) T2 mapping sequences with similar parameters at 3T and 7T. Patients were scanned at five time-points up to 12 months. T2 values were evaluated in the lesion and healthy-appearing regions for superficial and deep cartilage zone. The repeated ANOVA was used to determine differences in T2 values at various time points. RESULTS: A significant decrease in T2 values was observed between baseline and six months in the superficial layer of the lesion in patients at 3 T (decrease from 41.89 +/- 9.3 ms to 31.21 +/- 7.2 ms, which is a difference of -5.67 +/- 2.2 ms (p = 0.031)), and at 12 months in the superficial layer of the lesion in patients at 3 T (decrease from 41.89 +/- 9.3 ms to 35.28 +/- 4.9 ms, which is a difference of -6.60 +/- 4.4 ms (p = 0.044). No significant differences were recorded at 7 T. CONCLUSION: The change in T2 values acquired with 3 T 3D-TESS appears to be reflecting subtle changes of cartilage composition in the course of low-grade lesion development. 7 T T2 mapping does not reflect these changes probably due to completely decayed short T2 component. PMID- 30244141 TI - Characterization and function of the T-box 1 gene in Chinese giant salamander Andrias davidianus. AB - We characterized the Andrias davidianus T-box 1 (Tbx1) gene. Tbx1 expression was high in testis and low in other examined tissues. Immunohistochemistry detected tbx1 expression in somatic and germ cells 62 days post-hatching (dph), prior to gonad differentiation. At 210 dph, after gonad differentiation, tbx1 was expressed in spermatogonia and testis somatic cells and in granulosa cells in ovary. Tbx1 expression was up-regulated in ovary after high temperature treatment. In the neomale, tbx1 expression showed a similar profile to normal males, and vice-versa for genetic male. Over-expression of tbx1 in females after injection of TBX1 protein down-regulated the female-biased genes cyp19a and foxl2 and up-regulated the male-biased amh gene. When tbx1 was knocked down by tbx1/siRNA, cyp19a and foxl2 expression was up-regulated, and expression of amh, cyp26a, dmrt1, and wt1 was down-regulated. Results suggest that tbx1 influenced sex-related gene expression and participates in regulation of A. davidianus testis development. PMID- 30244142 TI - Identification and expression analysis of phosphatidy ethanolamine-binding protein (PEBP) gene family in cotton. AB - The phosphatidy ethanolamine-binding proteins (PEBP) play an important role in controlling flower development and phase change. Here, a total of 61 PEBP genes were identified, in which 20, 21, 10, and 10 were from tetraploid Gossypium hirsutum (AD1) and G. barbadense (AD2), and diploid G. raimondii (D5) and G. arboreum (A2), respectively. In G. hirsutum, 20 identified PEBP genes were unevenly distributed on 12 chromosomes. The identified PEBP genes were classified into four groups (TFL1, MFT, FT and FT-like). Among those, FT-like group are unique to cotton. The majority of PEBP genes had similar intron/exon distribution, whereas the divergence of PEBP genes suggests the possibility of functional diversification. The expression of PEBP genes varied among different tissues. This study brings new insights into the integrated genome-wide identification of PEBP genes in cotton and provides a foundation for breeding cotton cultivars with early maturation. PMID- 30244143 TI - Editorial Reply concerning prospective randomized clinical trail of iStent inject. PMID- 30244145 TI - Non-viral vectors based on cationic niosomes as efficient gene delivery vehicles to central nervous system cells into the brain. AB - Development of safe and efficient non-viral vectors to deliver DNA into the CNS represents a huge challenge to face many neurological disorders. We elaborated niosomes based on DOTMA cationic lipid, lycopene "helper" lipid and polysorbate 60 as non-ionic surfactants for gene delivery to the CNS. Niosomes, and their corresponding nioplexes obtained after the addition of the pCMS-EGFP plasmid, were characterized in terms of size, charge, morphology and capacity to condense, release and protect DNA. In vitro experiments were performed in NT2 cells to evaluate transfection efficiency, viability, cellular uptake and intracellular distribution. Additionally, transfection in primary cortex cells were performed prior to brain administration into rat cerebral cortex. Data obtained showed that nioplexes exhibited not only adequate physicochemical properties for gene delivery applications, but also relevant transfection efficiencies (17%), without hampering viability (90%). Interestingly, In vivo experiments depicted promising protein expression in both cortical glial cells and blood vessels. PMID- 30244144 TI - Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration: The LEAD Randomized Controlled Clinical Trial. AB - PURPOSE: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. DESIGN: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. METHODS: Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT(r); Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. MAIN OUTCOME MEASURES: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. RESULTS: Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. CONCLUSIONS: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT(r) laser, but they should not be extrapolated to other short-pulse lasers. PMID- 30244146 TI - Using two-fluid nozzle for spray freeze drying to produce porous powder formulation of naked siRNA for inhalation. AB - Spray freeze drying is an attractive technology to produce powder formulation for inhalation. It can be used to generate large porous particles which tend to aerosolize efficiently and do not aggregate readily. It also avoids material to be exposed to elevated temperature. In this study, we reported the use of two fluid nozzle to produce spray freeze dried powder of small interfering RNA (siRNA). The effect of atomization gas flow rate and liquid feed rate were inspected initially using herring sperm DNA (hsDNA) as nucleic acid model. The atomization gas flow rate was found to have a major impact on the aerosol properties. The higher the atomization gas flow rate, the smaller the particle size, the higher the fine particle fraction (FPF). In contrast, the liquid feed rate had very minor effect. Subsequently, spray freeze dried siRNA powder was produced at various atomization gas flow rates. The particles produced were highly porous as examined with the scanning electron microscopy, and the structural integrity of the siRNA was demonstrated with gel electrophoresis. The gene-silencing effect of the siRNA was also successfully preserved in vitro. The best performing siRNA formulation was prepared at the highest atomization gas flow rate investigated with a moderate FPF of 30%. However, this was significantly lower than that obtained with the corresponding hsDNA counterparts (FPF ~57%). A direct comparison between the hsDNA and siRNA formulations revealed that the former exhibited a lower density, hence a smaller aerodynamic diameter despite similar geometric size. PMID- 30244147 TI - 3D printing and coating to fabricate a hollow bullet-shaped implant with porous surface for controlled cytoxan release. AB - Intratumoral implants have aroused great interests for local chemotherapy of cancer, however, how to efficiently control drug release from implants is still a great challenge. Herein, we designed and prepared a new hollow bullet-shaped implant with porous surface by 3D printing, loaded chemotherapeutic agent cytoxan (CTX) with tetradecyl alcohol or lecithin as matrix and coated it with poly (lactic acid) to obtain a CTX implant, which has a highly tuned drug release property with a drug release time from 4 h to more than 1 month. The drug release from the implant can be easily controlled by changing pore sizes, kinds of matrices, and coating thickness. PMID- 30244148 TI - Theranostic polymeric nanoparticles for NIR imaging and photodynamic therapy. AB - Near-Infrared (NIR) dyes forming some of the photosensitizer agents show imaging and therapy features by themselves. NIR dyes show photodynamic therapy by formation of reactive oxygen species and imaging by NIR Fluorescence light. Photodynamic therapy occurs from irradiation of laser or light to photosensitizer matters and following by the formation of reactive oxygen species diseased tissues or cells can be killed effectively. NIR dyes have advantages such as stability, high specificity and sensitivity when compared with the other photosensitizer and imaging agents. Drug delivery systems are getting attention for either diagnosis or therapy of almost all of the diseases. Theranostic nanoparticles comprise the substances which shows the imaging and treatment features together. Besides, the combination of active substance and the imaging agent can also be encapsulated in theranostic nanoparticles. Many researchs are performed to evaluate the efficacy of theranostic drug delivery systems particularly polymeric nanoparticles in order to enhance targeting properties, specificity and bioavailability. Polymeric nanoparticles give advantages because of easier degradation properties when compared with the others. Theranostic polymeric nanoparticles can be used for NIR imaging and photodynamic therapy of several diseases especially cancers. PMID- 30244149 TI - Mechanistic study of the adjuvant effect of chitosan-aluminum nanoparticles. AB - The use of tailored particle-based adjuvants constitutes a promising way to enhance antigen-specific humoral and cellular immune responses. However, a thorough understanding of the mechanisms underlying their adjuvanticity is crucial to generate more effective vaccines. We studied the ability of chitosan aluminum nanoparticles (CH-Al NPs), which combine the immunostimulatory effects of chitosan and aluminum salts, to promote dendritic cell activation, assess their impact on innate and adaptive immune responses, and compare the results to those reported for conventional chitosan particles (CH-Na NPs). All tested CH-NP formulations were capable of modulating cytokine secretion by dendritic cells. CH Al NPs promoted NLRP3 inflammasome activation, enhancing the release of IL-1beta without significantly inhibiting Th1 and Th17 cell-polarizing cytokines, IL-12p70 or IL-23, and induced DC maturation, but did not promote pro-inflammatory cytokine production on their own. In vivo results showed that mice injected with CH-Al NPs generated a local inflammatory response comparable to that elicited by the vaccine adjuvant alum. Importantly, after subcutaneous immunization with CH Al NPs combined with the hepatitis B surface antigen (HBsAg), mice developed antigen-specific IgG titers in serum, nasal and vaginal washes. Overall, our results established CH-Al NPs as a potential adjuvant to enhance both innate and adaptive immune responses. PMID- 30244150 TI - A rare case of pleural effusion due to Prevotella dentalis. AB - Prevotella dentalis is a Gram-negative anaerobic rod involved in various human diseases, especially oral infections. We report a rare case of a pleural effusion due to this microorganism in an elderly patient. An 88-year-old man with chronic respiratory disease presented with a left pleural effusion for more than 1 month. Culture of drained pleural fluid resulted in isolation of P. dentalis. Resistance to penicillin and moxifloxacin was documented. Treatment with drainage and clindamycin was established, but the patient developed cognitive impairment and died after a worsening of his general condition. PMID- 30244151 TI - Novel Cardinium strains in non-marine ostracod (Crustacea) hosts from natural populations. AB - Endosymbiotic bacteria are known from many metazoan taxa, where they manipulate host biology and reproduction. Here, we used classic PCR amplification and direct DNA sequencing with universal primers for four different endosymbionts to test for their presence in more than 300 specimens of three recent non-marine ostracod superfamilies from different geographic areas and aquatic habitats. We verified these results with "high throughput" amplicon sequencing of 16S of nine selected specimens and evolutionary placement algorithms. The phylogenetic position of endosymbionts detected in ostracod hosts was compared to known endosymbionts from other metazoans. While Wolbachia, Spiroplasma and Rickettsia are absent, we find evidence for the general presence of Cardinium bacteria in natural populations of various non-marine ostracod species. Phylogenetic reconstructions based on Cardinium 16S data and estimates of genetic distances both indicate that Cardinium from ostracods are distantly related to Cardinium from Diptera and Nematoda but represent novel strains with a monophyletic origin. Cardinium bacteria from different ostracod hosts have genetic distances of up to 3.8%, providing evidence against recent and frequent horizontal transmissions amongst the three ostracod superfamilies. High throughput sequencing reveals more than 400 different 16S amplicon sequence variants in the investigated ostracods as well as the presence of different Cardinium strains within individual Eucypris virens and Heterocypris hosts. These results call for future, more in-depth investigations. Mapping Cardinium infections on COI trees of non-marine ostracod hosts shows that the occurrence of these endosymbionts is not linked to genetic species identity or phylogenetic host groups and, except for one ostracod morphospecies, prevalence never reaches 100%. PMID- 30244152 TI - Norovirus-specific mucosal antibodies correlate to systemic antibodies and block norovirus virus-like particles binding to histo-blood group antigens. AB - The best acknowledged correlate of protection from norovirus (NoV) infection is the ability of serum antibodies to block binding of NoV virus-like particles (VLPs) to histo-blood group antigens (HBGAs). We investigated mucosal NoV specific antibody levels in adult volunteers and used saliva from a single donor to determine whether purified saliva antibodies confer blocking. NoV-specific IgG and IgA levels in saliva and plasma samples were measured against four NoV genotype VLPs. NoV-specific IgG and IgA titers in saliva and plasma samples correlated significantly. Antibodies were detected against all VLPs with the highest level of antibodies directed against ancestral GII.4 99 genotype. Affinity chromatography purified salivary IgA and IgG blocked binding of GII.4 99 VLPs to HBGAs. Saliva sampling is a non-invasive alternative to blood drawing and an excellent biological fluid to study NoV-specific immune responses. Mucosal anti-NoV antibodies block binding of NoV VLPs to HBGAs, and may therefore be protective. PMID- 30244153 TI - Surgery for Endometriosis Improves Major Domains of Quality of Life: A Systematic Review and Meta-Analysis. AB - Because surgery for endometriosis can involve severe complications, it is important to determine if the patient's quality of life (QOL) is indeed improved after surgery. A systematic review and meta-analysis, when appropriate, was conducted and included 38 studies that assessed the QOL using validated questionnaires administered before and after surgery. Results were grouped according to the type of endometriosis reported: all types endometriosis, deep infiltrative endometriosis (DIE), and bowel endometriosis. Quantitative analysis was performed on 17 homogeneous studies. Pooled response mean differences between the 36-Item and 12-Item Short Form Survey (SF-36 and SF-12) showed significant improvement in Mental Component Score (MCS) after surgery for all types of endometriosis (.21; 95% confidence interval [CI], .04-.38); significant improvement after surgical treatment for DIE in Vitality (.67; 95% CI, .41-.94), Social Functioning (.59; 95% CI, .18-.99), Role Emotional .49; 95% CI, .02-.97), Mental Health (.39; 95% CI, .03-.74), Physical Functioning (.93; 95% CI, .49 1.38), Bodily Pain (1.23; 95% CI, .47-1.99), General Health (.57; 95% CI, .02 1.12), MCS (.55; 95% CI, .10-1.00), and Physical Component Score (PCS; .73; 95% CI, .27-1.18); and significant improvement after surgery for bowel endometriosis for all 8 domains (Vitality [1.00; 95% CI, .56-1.43], Social Functioning [.97; 95% CI, .57-1.37], Role Emotional [1.17; 95% CI, .7-1.63], Mental Health [.94; 95% CI, .5-1.38], Physical Functioning [.74; 95% CI, .3-1.18], Role Physical [1.25; 95% CI, .75-1.76], Bodily Pain [1.39; 95% CI, .79-1.98], General Health [.84; 95% CI, 1.46-1.22]), MCS (.93; 95% CI, .47-1.40), PCS (.82; 95% CI, .40 1.23), and total score (1.15; 95% CI, .48-1.83). Only 1 study assessed patients with minimal disease and showed significant improvement in PCS (p = .002) and MCS (p <.001). This systematic review reveals that surgery for endometriosis resulted in overall improvement in most health domains of health-related QOL, with the greatest improvement found in the Bodily Pain domain. PMID- 30244154 TI - Fellowship in Minimally Invasive Gynecologic Surgery: The Evolving Field Behind the Name. PMID- 30244155 TI - A new species of Haliotrema (Monogenea: Ancyrocephalidae (sensu lato) Bychowsky & Nagibina, 1968) from holocentrids off Langkawi Island, Malaysia with notes on the phylogeny of related Haliotrema species. AB - Haliotrema susanae sp. nov. is described from the gills of the pinecone soldierfish, Myripristis murdjan off Langkawi Island, Malaysia. This species is differentiated from other Haliotrema species especially those from holocentrids in having a male copulatory organ with bract-like extensions at the initial of the copulatory tube, grooved dorsal anchors and ventral anchors with longer shafts. The maximum likelihood (ML) analysis based on partial 28S rDNA sequences of H. susanae sp. nov. and 47 closely related monogeneans showed that H. susanae sp. nov. is recovered within a monophyletic clade consisting of only species from the genus Haliotrema. It is also observed that H. susanae sp. nov. forms a clade with H. cromileptis and H. epinepheli which coincides with a similar grouping by Young based on solely morphological characteristics. The morphological and molecular results validate the identity of H. susanae sp. nov. as belonging to the genus Haliotrema. PMID- 30244156 TI - Long term prognosis of Scheuermann's disease: The association with fragility fracture - The MINOS cohort. AB - The aim was to assess the association of Scheuermann's disease (SCD) with fracture risk (vertebral, peripheral) and bone mineral density (BMD) in older men. SCD was assessed on the baseline lateral spine radiographs using the Berlin criteria in 766 men aged 50-85. We evaluated the association of SCD and its diagnostic criteria with incident fracture (vertebral over 7.5 years, peripheral over 10 years) and BMD (baseline). SCD prevalence was 25.2%. SCD and its criteria showed inconsistent associations with BMD at different skeletal sites. Eighty four men had incident fractures. After adjustment for age, weight, spine BMD, prevalent vertebral fractures, prior falls and score of disc space narrowing due to osteoarthritis (DSN-OA), SCD was not associated with vertebral fracture risk. Vertebral endplate irregularities (EI), one of its diagnostic criteria, were associated with higher vertebral fracture risk (OR = 3.26, 95% CI: 1.34-7.94, p < 0.01). Vertebral fracture risk was higher in men with EI and low spine BMD vs. men without these characteristics (OR = 12.84, 95% CI: 3.12-52.83, p < 0.005). EI was associated with higher vertebral fracture risk in men without severe DSN-OA and without prevalent vertebral fractures. Peripheral fracture risk was lower in men with SCD (HR = 0.39, 95% CI: 0.18-0.83, p < 0.02) and EI. Peripheral fracture risk was higher in men without SCD who had low femoral neck BMD vs. men with SCD and normal BMD (HR = 4.68, 95% CI: 1.09-20.03, p < 0.05). In conclusion, EI were associated with high vertebral fracture risk. SCD and EI were associated with lower peripheral fracture risk. The associations of SCD and its criteria with BMD were inconsistent. PMID- 30244157 TI - FRAX is a robust predictor of baseline vertebral fractures in multiple myeloma patients. AB - FRAX is a commonly used tool to evaluate patient fracture risk based on individual patient models that integrate the risks associated with clinical risk factors with or without bone mineral density (BMD) at the femoral neck. Retrospectively, factors identified by the FRAX scoring algorithm were used to predict the risk for vertebral compression fractures at baseline in newly diagnosed multiple myeloma patients. The data were derived from myeloma patients enrolled in Total Therapy Protocols (TT4 & TT5) between 8/2008 and 9/2017. FRAX scores were calculated and baseline PET and MRI imaging obtained. Univariate and multivariate logistic regression analyses determined the association between FRAX components and the existence of vertebral compression fractures, both pathologic and osteoporotic. The patient population had a median age of 61 years (43-76), 37% female, and 87% white. The median major osteoporotic score (MOS) and Hip fracture scores (HFS) for TT4 patients (low-risk myeloma) were 5.6 and 0.5, respectively, while median MOS and HFS for TT5 (high risk myeloma) patients were 6.2 and 0.7, respectively. The odds ratio for fracture at diagnosis in patients with elevated MOS (>2), and HFS (>4.5) was significant OR (1.48, 95% confidence interval (1.35,1.62)) and OR (1.61, 95% confidence interval (1.42, 1.81)), respectively. In sum, an elevated baseline FRAX score was highly predictive of baseline vertebral fractures in MM patients at presentation. In addition, patients with higher FRAX scores had significantly shorter survival in the low risk (TT4) group but this survival effect was not seen in the high-risk (TT5) group. These findings suggest that FRAX assessment of baseline fracture risk is beneficial in MM patients to identify an individual patients' risk of vertebral fracture. PMID- 30244158 TI - Adjuvant Chemotherapy in Rectal Cancer Patients Treated with Preoperative Chemoradiation and Total Mesorectal Excision: A Multicenter and Retrospective Propensity-Score Matching Study. AB - PURPOSE: The role of adjuvant chemotherapy after preoperative chemoradiotherapy (CRT) and curative surgery in rectal cancer has not to be definitely determined yet. We performed a retrospective and multicenter study to evaluate whether adjuvant chemotherapy (AC) could reduce recurrence and improve survival in locally advanced rectal cancer. METHODS AND MATERIALS: We analyzed 1,442 patients with rectal cancer from 8 tertiary institutions who underwent preoperative CRT and total mesorectal excision. Patients were classified into two groups; the AC group consisted of patients who received chemotherapy after surgery while the observation group consisted of those who did not. Propensity-score matching was used to assess the exact role of AC. The AC group was then subdivided to investigate the impact of adding oxaliplatin to 5-fluorouracil. Group I was treated with 5-FU/folinic acid or capecitabine without oxaliplatin and group II received 5-FU/folinic acid or capecitabine with oxaliplatin. RESULTS: The 3-year relapse-free survival (RFS) rates in the AC and observation groups were 85.9% and 84.3%, respectively (P = 0.532). The 3-year overall survival (OS) rates in the AC and observation groups were 94.9% and 89.9%, respectively (P = 0.123). The rates of locoregional recurrence (2.2% vs. 3.2%, P = 0.294) and distant metastasis (12.4% vs. 12.9%, P = 0.927) at 3 years were not significantly different between the two groups. The 3-year RFS rates of group I and group II were 71.5% and 74.8%, respectively (P = 0.426). The 3-year OS rates of group I and group II were 89.9% and 96.5%, respectively (P = 0.102). CONCLUSION: This multicenter study found an insufficient evidence to support the use of 5-FU-based AC after preoperative CRT and curative surgery in rectal cancer. PMID- 30244160 TI - Predictors of early recurrence prior to planned post-operative radiation therapy for oral cavity squamous cell carcinoma and outcomes following salvage intensified radiation therapy. AB - PURPOSE: To determine predictors and outcomes for oral squamous cell carcinoma (OSCC) patients who had early recurrence before commencement of postoperative radiotherapy (PORT). METHODS: Retrospective review was performed for OSCC patients treated with PORT between 2003-2015 following curative-intent surgery. Early recurrence was defined as tumor recurrence following surgical resection and before initiating planned PORT. Patients were classified into: 1) adjuvant-PORT group (no early recurrence), 2) salvage-PORT group (had locoregional early recurrence), and palliative-PORT group (had locoregional and distant early recurrence). For the whole cohort, multivariable analysis (MVA) was applied to identify predictors of early recurrence. In the salvage-group, the post-PORT recurrence-free rate was estimated, and MVA was used to identify predictors of recurrence-free rate, disease free- (DFS) and overall- survival (OS). RESULTS: A total of 601 patients were identified, of whom 513 (85%) were treated with adjuvant-PORT, while 88 (15%) had early recurrence (28/88, 32% were biopsy proven) before PORT (70 in salvage-group and 18 in palliative-group). On MVA, oral tongue subsite, microscopic positive resection margin, pT3-4, and pN2-3 were associated with development of early recurrence (p<0.05 for all). The 3-year OS for OSCC patients treated with adjuvant and salvage PORT were 71% (95%CI:67%-75%) and 41% (95%CI:30%-56%) respectively (p<0.001) [median follow-up was 3.4 and 2.9 years respectively]. Following salvage-PORT, the 3-year recurrence-free rate was 36% (95%CI:23%-47%). On MVA, extranodal extension and volume of early recurrent gross disease were associated with poor recurrence-free rate, DFS and OS (p<0.05 for all). CONCLUSION: Early recurrences are not uncommon in patients with high risk features.. Future studies are required to improve prediction and outcomes of this very high risk group. PMID- 30244161 TI - Intended pregnancy after receiving vs. being denied a wanted abortion. AB - OBJECTIVES: To understand how having or being denied an abortion affects the likelihood of trying to become pregnant, overall pregnancy rates, and the rate and timing of an intended pregnancy in the future. STUDY DESIGN: The Turnaway Study is a prospective cohort study of women who received or were denied a wanted abortion. Women were recruited from one of 30 US abortion facilities. We examined subsequent intended pregnancy among those who presented just under the facility's gestational limit and received an abortion (Near-Limit Abortion Group, n=413) and those who presented for abortion just beyond the facility's gestational limit, were denied an abortion and went on to parent the child (Parenting Turnaways, n=146). First, we modeled the probability of trying to become pregnant using multivariable mixed-effects logistic regression. We then used Cox proportional hazards models to compare overall pregnancy rates and intended pregnancy rates over 5 years. RESULTS: Parenting Turnaways had lower predicted probabilities of reporting trying to become pregnant in the first 1.5 years after birth/abortion than the Near-Limit Abortion Group. They also had lower pregnancy rates overall [40.4 per 100 woman-years vs. 53.5 per 100 woman-years, adjusted hazards ratio (aHR)=0.69, 95% confidence interval (CI): 0.54-0.89]. The 5-year intended pregnancy rate was low among both groups, but compared to the Near-Limit Abortion Group, Parenting Turnaways had a lower intended pregnancy rate (2.2 per 100 woman years vs. 7.5 per 100 woman-years, aHR=0.29, 95% CI: 0.10-0.85). CONCLUSION: Being able to obtain a wanted abortion may enable women to have an intended pregnancy later. IMPLICATIONS: Ensuring that women can obtain an abortion for an unwanted pregnancy may enable them to have a subsequent pregnancy when they are ready to have a baby. PMID- 30244159 TI - Late Sequelae of Childhood and Adolescent Nasopharyngeal Carcinoma Survivors after Radiotherapy. AB - PURPOSE: The objective of this study was to reveal the long-term sequelae in survivors of childhood and adolescent nasopharyngeal carcinoma (NPC) after radiotherapy. METHODS AND MATERIALS: We reviewed the medical records of NPC patients younger than 18 years old who were treated at XXX from February 1991 to October 2010. Data concerning clinical characteristics, treatment, outcomes, and late morbidities were extracted. Chi-squared tests and binary regression analysis were used to compare the cumulative incidence (CI) of treatment comorbidities between different groups of survivors. RESULTS: A total of 94 patients survived. They had a median follow-up time of 10 years (5~27 years). When compared with that of the survivors treated with convention radiotherapy treatment (CRT), the CI of xerostomia, dysphagia and chronic otitis media was significantly decreased in the survivors treated with intensity-modulated radiotherapy treatment (IMRT). The CI of blurred vision in patients younger than 10 years old and in patients 10~18 years old were 33.3% and 2.3%, respectively (P = 0.006). Survivors who received a nasopharynx dose > 72 Gray (Gy), compared with a nasopharynx dose = 60~72 Gy, had a significantly higher CI of hearing loss (P = 0.008), lalopathy (P = 0.013) and cranial nerve injury (CNI) (P = 0.029). We also had records of height, weight, education level, annual income, marital and fertility status, and menstruation state for 59 of the survivors. 22% of the survivors had a body mass index (BMI) lower than 18.5. 62.5% (11/16) of the female survivors had menstrual or fertility problems. CONCLUSION: Compared with CRT, IMRT can potentially ameliorate xerostomia, dysphagia and chronic otitis media. In addition, patients younger than 10 years old had a higher CI of blurred vision. Moreover, a dose of more than 72 Gy to primary tumor increased the CI of hearing loss, lalopathy and CNI. PMID- 30244162 TI - Reduced phenotypic expression in genetic hemochromatosis with time: Role of exposure to non-genetic modifiers. AB - BACKGROUND & AIMS: Genetic hemochromatosis is mainly related to the homozygous p.Cys282Tyr (C282Y) mutation in the HFE gene, which causes hepcidin deficiency. Its low penetrance suggests the involvement of cofactors that modulate its expression. We aimed to describe the evolution of disease presentation and of non genetic factors liable to impact hepcidin production in the long term. METHODS: Clinical symptoms, markers of iron load, and risk factors according to the year of diagnosis were recorded over 30 years in a cohort of adult C282Y homozygotes. A total of 2,050 patients (1,460 probands [804 males and 656 females] and 542 relatives [244 males and 346 females]) were studied. RESULTS: Over time: (i) the proband-to-relative ratio remained roughly stable; (ii) the gender ratio tended towards equilibrium among probands; (iii) age at diagnosis did not change among males and increased among females; (iv) the frequency of diabetes and hepatic fibrosis steadily decreased while that of chronic fatigue and distal joint symptoms remained stable; (v) transferrin saturation, serum ferritin and the amount of iron removed decreased; and (vi) the prevalence of excessive alcohol consumption decreased while that of patients who were overweight increased. Tobacco smoking was associated with increased transferrin saturation. CONCLUSION: Genetic testing did not alter the age at diagnosis, which contrasts with the dramatic decrease in iron load in both genders. Tobacco smoking could be involved in the extent of iron loading. Besides HFE testing, which enables the diagnosis of minor forms of the disease, the reduction of alcohol consumption and the increased frequency of overweight patients may have played a role in the decreased long-term iron load, as these factors are likely to improve hepcidin production. LAY SUMMARY: Genetic hemochromatosis is an inherited disorder that leads to progressive iron overload in the body. It results in chronic fatigue and in potential liver (cirrhosis), pancreas (diabetes) and joint (arthritis) damage in adulthood. The present study showed that tobacco smoking may aggravate iron loading, but that hemochromatosis has become less and less severe over the last 30 years despite patients being older at diagnosis, likely because of the protective effects of lower alcohol consumption and of increased weight in the French population. PMID- 30244164 TI - Reply to Abbas et al. "Infection prevention: Is copper the new gold?" PMID- 30244163 TI - Social brain, social dysfunction and social withdrawal. AB - The human social brain is complex. Current knowledge fails to define the neurobiological processes underlying social behaviour involving the (patho-) physiological mechanisms that link system-level phenomena to the multiple hierarchies of brain function. Unfortunately, such a high complexity may also be associated with a high susceptibility to several pathogenic interventions. Consistently, social deficits sometimes represent the first signs of a number of neuropsychiatric disorders including schizophrenia (SCZ), Alzheimer's disease (AD) and major depressive disorder (MDD) which leads to a progressive social dysfunction. In the present review we summarize present knowledge linking neurobiological substrates sustaining social functioning, social dysfunction and social withdrawal in major psychiatric disorders. Interestingly, AD, SCZ, and MDD affect the social brain in similar ways. Thus, social dysfunction and its most evident clinical expression (i.e., social withdrawal) may represent an innovative transdiagnostic domain, with the potential of being an independent entity in terms of biological roots, with the perspective of targeted interventions. PMID- 30244165 TI - Diagnostic performance of knee physical exam and participant-reported symptoms for MRI-detected effusion-synovitis among participants with early or late stage knee osteoarthritis: data from the Osteoarthritis Initiative. AB - OBJECTIVE: Evaluate the diagnostic performance of knee physical exam findings and participant-reported symptoms for MRI-detected effusion-synovitis (ES) among knees with early and late-stage osteoarthritis (OA). DESIGN: The Osteoarthritis Initiative (OAI) is a longitudinal study of participants with or at risk for knee OA. Two samples with MRI readings were available: 344 knees with early OA (312 participants) and 216 with late-stage OA (186 participants). Trained examiners performed bulge sign (BS) and patellar tap (PT) exams, and participants reported on knee swelling and pain with leg straightening. Effusion-synovitis on 3T non contrast MRI was scored using the MRI Osteoarthritis Knee Score (MOAKS). Diagnostic performance of physical exam findings and symptoms was estimated with bootstrapped confidence intervals. RESULTS: For the early OA sample, the highest sensitivity for medium/large effusion-synovitis was achieved with a positive finding for any of the physical exam maneuvers and/or participant-reported symptoms (81.0 [95% CI: 70.0, 91.3]). Both knee symptoms in combination had a prevalence of 11.7% and yielded the highest estimated positive predictive value (PPV) (50.0 [95% CI: 34.2, 66.7]) and likelihood ratio positive (LR+) (5.2 [95% CI: 2.9, 9.7]). In late-stage OA knees, exam findings and symptoms provided minimal information beyond the prevalence. CONCLUSION: Patient report of both symptoms, or at least one positive exam finding and at least one symptom, could be used to identify knees at increased risk of effusion-synovitis in knees with early stage OA, either for screening purposes in clinical evaluation, or for study sample enrichment with an inflammatory phenotype; diagnostic performance was not sufficiently high for clinical diagnostic purposes. PMID- 30244166 TI - Andrographolide prevented toluene diisocyanate-induced occupational asthma and aberrant airway E-cadherin distribution via p38 MAPK-dependent Nrf2 induction. AB - Toluene diisocyanate (TDI) is a major cause of chemical-induced occupational asthma, which contributes about 15% of global asthma burden. Resistance and compounded side effects associated with the use of corticosteroid in asthma necessitate the search for alternative drugs. Andrographolide (AGP), a naturally occurring diterpene lactone is known to exhibit various bioactivities. Its ability to ameliorate cardinal features of allergic asthma was previously suggested in an eosinophilic asthma endotype. However, its potential antiasthma activity and mechanism of action in a neutrophilic occupational asthma model, as well as its effect on epithelial dysfunction remain unknown. BALB/c mice were dermally sensitised with 0.3% TDI or acetone olive oil (AOO) vehicle on day 1 and 8, followed by 0.1% TDI intranasal challenge on days 15, 18 and 21. Endpoints were evaluated via bronchoalveolar lavage fluid (BALF) cell analysis, 2',7' dichlorofluorescein diacetate (DCFDA) assays, immunoblotting, immunohistochemistry and methacholine challenge test. Decreases in total and differential leukocyte counts of BALF were recorded in AGP-treated animals. The compound dose-dependently reduced intracellular de-esterification of DCFDA, thus suggesting AGP's potential to inhibit intracellular reactive oxygen species (ROS). Mechanistically, the treatment prevented TDI-induced aberrant E-cadherin distribution and restored airway epithelial beta-catenin at cell to cell contact site. Furthermore, AGP ameliorated TDI induced pulmonary collagen deposition. In addition, the treatment significantly upregulated pulmonary HO-1, Nrf2 and phospho-p38 levels. Airway hyperresponsiveness was markedly suppressed among AGP treated animals. Collectively, these findings suggest AGP's protective function against TDI-induced airway epithelial barrier dysfunction and oxidative lung damage possibly through the upregulation of adherence junction proteins and the activation of p38/Nrf2 signalling. This study elucidates the therapeutic potential of AGP in the control and management of chemical-induced allergic asthma. To the best of our knowledge, the potential anti-asthma activity of AGP in TDI-induced occupational asthma has not been reported previously. PMID- 30244167 TI - Design of multifunctional peptide collaborated and docetaxel loaded lipid nanoparticles for antiglioma therapy. AB - Glioblastoma multiforme (GBM) is one of the most encountered gliomas of the central nervous system. The chemotherapeutic drugs used in the treatment of GBM suffer from poor blood brain barrier penetration, severe systemic toxicities and lack of specificity towards tumor cells. There is an urgent need to explore novel drug delivery systems specifically designed for targeting GBM. Solid lipid nanoparticles (SLN) are biocompatible vehicle with less toxicity issues compared to other drug delivery systems and serve the purpose of obviating the limitations posed by existing anti-cancer drugs for GBM. In this study, angiopep-2, a ligand for the lipoprotein receptor related protein 1 (LRP 1) receptor over expressed in endothelial cells of both brain and glioma, was grafted on the surface of solid lipid nanoparticles for the delivery of docetaxel. The peptide grafted nanoparticles (A-SLN) showed increased cytotoxicity, enhanced cellular internalization and prominent apoptosis than that of unconjugated nanoparticles against U87MG human glioblastoma and GL261 mouse glioma cells. A significant dual targeting effect of A-SLN (p < 0.0001) was confirmed in in-vivo studies by real time fluorescence imaging studies in glioblastoma induced C57BL/6 mice model. Pharmacokinetic and tissue distribution studies showed selective targeting with higher accumulation of A-SLN in brain compared to Taxtotere, a marketed formulation of docetaxel. After treatment with A-SLN, the mean animal survival time of the animals was significantly enhanced to 39 days from 24 days of plain docetaxel. Collectively, this study indicated that solid lipid nanoparticles decorated with angiopep-2 can be an excellent option as targeted drug delivery system for antiglioma therapy. PMID- 30244169 TI - USF2 inhibits the transcriptional activity of Smurf1 and Smurf2 to promote breast cancer tumorigenesis. AB - Smurf1 (Smad ubiquitylation regulatory factor 1) and Smurf2 are negative regulators of the TGF-beta (transforming growth factor-beta) pathway. The protein stability and ubiquitin E3 activity regulation of Smurfs have been well studied. However, the mechanism of Smurfs expression at the transcriptional level remains uncharacterized. Here, we reported that USF2 (upstream stimulatory factor 2), a basic helix-loop-helix-leucine-zip transcription factor, is necessary for the transcriptional activity of Smurf1 and Smurf2. The 5'-flanking sequences of the Smurfs gene have more than one E-box motifs, and USF2 bounds the Smurfs promoter in vitro and in vivo. Over-expression USF2 inhibited the transcriptional activity of the Smurfs, and Smurfs mRNA was markedly decreased. Therefore, the activity of TGF-beta was distinctly enhanced. Furthermore, in human breast cancers, USF2 was abnormally high expressed and correlated with cancer progression. USF2 was specifically inversely correlated with Smurfs in Luminal A subtype breast cancer patients. These findings suggest the mechanism regulation of Smurfs transcriptional activity, and shed new light on the cancer-promoting role of USF2. PMID- 30244168 TI - BAFF inhibits autophagy promoting cell proliferation and survival by activating Ca2+-CaMKII-dependent Akt/mTOR signaling pathway in normal and neoplastic B lymphoid cells. AB - B cell activating factor from the TNF family (BAFF) is implicated in not only the physiology of normal B cells, but also the pathophysiology of aggressive B cells related to malignant and autoimmune diseases. Autophagy plays a crucial role in balancing the beneficial and detrimental effects of immunity and inflammation. However, little is known about whether and how excessive BAFF mediates autophagy contributing to B-cell proliferation and survival. Here, we show that excessive human soluble BAFF (hsBAFF) inhibited autophagy with a concomitant reduction of LC3-II in normal and B-lymphoid (Raji) cells. Knockdown of LC3 not only potentiated hsBAFF inhibition of autophagy, but also attenuated hsBAFF activation of Akt/mTOR pathway, thereby diminishing hsBAFF-induced B-cell proliferation/viability. Further, we found that hsBAFF inhibition of autophagy was Akt/mTOR-dependent. This is supported by the findings that hsBAFF increased mTORC1-mediated phosphorylation of ULK1 (Ser757); Akt inhibitor X, mTORC1 inhibitor rapamycin, mTORC1/2 inhibitor PP242, expression of dominant negative Akt, or knockdown of mTOR attenuated hsBAFF-induced phosphorylation of ULK1, decrease of LC3-II level, and increase of cell proliferation/viability. Chelating intracellular free Ca2+ ([Ca2+]i) with BAPTA/AM or preventing [Ca2+]i elevation using EGTA or 2-APB profoundly blocked hsBAFF-induced activation of Akt/mTOR, phosphorylation of ULK1 and decrease of LC3-II, as well as increase of cell proliferation/viability. Similar effects were observed in the cells where CaMKII was inhibited by KN93 or knocked down by CaMKII shRNA. Collectively, these results indicate that hsBAFF inhibits autophagy promoting cell proliferation and survival through activating Ca2+-CaMKII-dependent Akt/mTOR signaling pathway in normal and neoplastic B-lymphoid cells. Our findings suggest that manipulation of intracellular Ca2+ level or CaMKII, Akt, or mTOR activity to promote autophagy may be exploited for prevention of excessive BAFF-induced aggressive B lymphocyte disorders and autoimmune diseases. PMID- 30244170 TI - Protectin DX prevents H2O2-mediated oxidative stress in vascular endothelial cells via an AMPK-dependent mechanism. AB - Protectin DX (PDX), which is a novel regulator of 5' adenosine monophosphate activated protein kinase (AMPK), has recently gained attention for its ability to improve several metabolic diseases. However, the function of PDX in vascular endothelial cells remains unclear. To confirm the protective effects of PDX on endothelial oxidative stress, human umbilical vein endothelial cells (HUVECs) were treated with hydroperoxide (H2O2) and PDX. PDX treatment significantly increased the level of AMPK phosphorylation, and this elevation was attenuated after treatment with G-protein coupled receptor 120 (GPR120) antagonist or GPR120 knockdown. Expressions and activities of antioxidant proteins, including catalase and superoxide dismutase 2 (SOD2), were elevated by PDX and were inhibited by treatment with AMPK inhibitor or with GPR120 antagonist. Production of H2O2 induced reactive oxygen species (ROS), the Bax/Bcl-2 ratio, and the loss of mitochondrial membrane potential were all reversed by PDX, leading to improved cell viability and reduced release of lactate dehydrogenase (LDH). Using flow cytometry, we also found that PDX significantly reduced the H2O2-induced apoptotic population of cells. These protective effects of PDX were all reversed after treatment with AMPK inhibitor or GRP120 antagonist. These results show that the PDX-AMPK axis has a protective role against H2O2-induced oxidative stress in vascular endothelial cells. PMID- 30244171 TI - Jab1/Cops5 contributes to chemoresistance in breast cancer by regulating Rad51. AB - Jab1 overexpression correlates with poor prognosis in breast cancer patients, suggestting that targeting the aberrant Jab1 signaling in breast cancer could be a promising strategy. In the current study, we investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, the cellular response of breast cancer to chemotherapy with adriamycin and cisplatin. High throughput mRNA sequencing (RNA-Seq) data from 113 normal and 1109 tumor tissues (obtained from TCGA) were integrated to our analysis to give further support to our findings. We found that Jab1 was overexpressed in adriamycin-resistant breast cancer cell MCF-7R compared with parental MCF-7 cells, and that knockdown of Jab1 expression conferred cellular sensitivity to adriamycin and cisplatin both in vivo and in vitro. By contrast, exogenous Jab1 expression enhanced the resistance of breast cancer cells to adriamycin and cisplatin. Moreover, we discovered that Jab1 positively regulated Rad51 in p53-dependent manner and that overexpression of Rad51 conferred cellular resistance to adriamycin and cisplatin in Jab1 deficient cells. Data from TCGA further validated an correlation between Jab1 and Rad51 in breast cancer, and elevated Jab1 and Rad51 associated with poor survival in breast cancer patients. Our findings indicate that Jab1 association with Rad51 plays an important role in cellular response to chemotherapy in breast cancer. PMID- 30244172 TI - Elucidating the microRNA-203 specific biological processes in glioblastoma cells from comprehensive RNA-sequencing transcriptome profiling. AB - Glioblastoma (GBM) is the most common primary malignant intracranial adult brain tumor. Allelic deletion on chromosome 14q plays an essential role in GBM pathogenesis, and this chromosome 14q site was thought to harbor multiple tumor suppressor genes associated with GBM, a region that also encodes microRNA-203 (miR-203). This study was conducted to identify whole transcriptome profile changes associated with miR-203 expression by high-throughput RNA sequencing. Enrichment analyses for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that miR-203 expression had a strong, negative effect on a number of fundamental and interconnected biological processes involved in cell growth and proliferation. The biological processes mostly influenced were p53 signaling pathway, FoxO signaling pathway, DNA replication, cell cycle, MAPK signaling pathway, and apoptosis. In total, 847 upregulated and 345 downregulated differentially expressed genes were identified in control versus miR-203 expressing glioma cells. After GO enrichment, the downregulated differentially expressed genes such as BCL2, SPARC were found to be mainly enriched in cell cycle regulation and apoptosis processes, whereas the upregulated differentially expressed genes such as CCND1, E2F1 were involved in the DNA replication and cell cycle regulation. We also performed miR-203 target analysis and found BCL2, AKT, SPARC, ROBO1, c-JUN, PDGFA, and CREB were predicted target of miR-203 and miR-203 expression suppressed the protein and mRNA levels of these target genes by western blotting and qRT-PCR analysis. Moreover, co transfection experiments using a luciferase-based reporter assay demonstrated that miR-203 directly regulated BCL-2 expression and BCL-2 overexpression suppressed miR-203 mediated glioma cell apoptosis. These results indicate that overexpression of miR-203 coordinately regulates several oncogenic pathways in GBM. PMID- 30244173 TI - Socket-shield technique: the influence of the length of the remaining buccal segment of healthy tooth structure on peri-implant bone and socket preservation. A study in dogs. AB - OBJECTIVE: The aim of this study was to evaluate the influence of the location and length of root pieces on buccal peri-implant bone width and socket preservation in socket shield technique. MATERIAL AND METHODS: Forty-eight dental implants (24 narrow and 24 regular platform internal hex implants) were placed in six dogs. The clinical crowns of teeth P2, P3, P4 and M1 were detached horizontally and removed from the underlying roots. Then the mesial root of each tooth was extracted and the distal root was degraded using a high-speed hand piece with round bur, creating a concave shell of dentin cementum and periodontal ligament (PDL) connected to the buccal aspect of the socket. Remaining root fragments of different lengths were created: coronal (1/3); middle and coronal (2/3); full length (3/3). These were positioned all around the bone crest. Implants were placed at the center of the root sockets, 1-3mm deeper than the original root apex. RFA and histological evaluations were made at 4 and 12 weeks. Data underwent statistical analysis (p<0.05). RESULTS: All 48 implants osseointegrated satisfactorily. On both buccal and lingual sides, the coronal (1/3) radicular fragment was attached to the buccal bone plate by physiologic periodontal ligament with less crestal bone resorption compared with middle (2/3) and whole root (3/3) groups for narrow and standard implants. CONCLUSIONS: Within the limitations of this study, the results demonstrate that a small piece of root in the coronal part of the alveolus can protect the buccal, mesial and distal bone crest following the immediate placement of NeO narrow or NeO Standard Internal Hex implants. The thickness of peri-implant bone and the remaining root fragment together will provide a total thickness of >2mm. The technique would appear to be highly predictable, maintaining bone volume and reducing the risk of crestal bone resorption. PMID- 30244174 TI - Alarming decline in recognition of anatomical structures amongst medical students and physicians. AB - BACKGROUND: Insufficient anatomical training can put patients' safety at risk. The aim of this study was to assess the proficiency of medical students and physicians in identifying labeled anatomical structures. The second aim of the study was to evaluate factors that can affect this recognition. METHODS: An internet-based survey where participants had to correctly identify labeled anatomical structures on cadaveric specimens was designed. RESULTS: The study group included 1186 participants (58.7% females): 931 medical students and 255 medical graduates from all twelve Polish medical schools. The mean total survey score for the entire study group was 65.6%. Students gained significantly higher results than graduates (total: 67.3% vs. 59.5%, P<0.001); 331 (27.9%) participants did not pass the test (<60). There was a correlation observed between points gained in this survey and grade obtained in the gross anatomy course (P<0.001). Multivariable logistic regression found that participation in cadaver laboratory classes most strongly increases anatomical competencies (OR=5.30, 95%CI=1.20-23.40, P=0.03). Other significant factors boosting anatomical proficiency were membership in students' scientific clubs, being male, and having a high grade (>=80%) in initial gross anatomy course. The time since anatomy course completion was negatively correlated with the total survey score (OR=0.86, 95%CI=0.81-0.92, P<0.001). CONCLUSIONS: Anatomical knowledge of Polish medical students is moderate (<70%) and it significantly decreases with time. Anatomical structure recognition can be up to 25% lower in highly trained physicians when compared to pre-clinical medical students. This trend may be reversed by replacing subject-based anatomy courses with system-based (integrated) curricula at the undergraduate level or introducing short refresher anatomical courses during postgraduate training. PMID- 30244175 TI - PTMD: A Database of Human Disease-associated Post-translational Modifications. AB - Various posttranslational modifications (PTMs) participate in nearly all aspects of biological processes by regulating protein functions, and aberrant states of PTMs are frequently implicated in human diseases. Therefore, an integral resource of PTM-disease associations (PDAs) would be a great help for both academic research and clinical use. In this work, we reported PTMD, a well-curated database containing PTMs that are associated with human diseases. We manually collected 1950 known PDAs in 749 proteins for 23 types of PTMs and 275 types of diseases from the literature. Database analyses show that phosphorylation has the largest number of disease associations, whereas neurologic diseases have the largest number of PTM associations. We classified all known PDAs into six classes according to the PTM status in diseases and demonstrated that the upregulation and presence of PTM events account for a predominant proportion of disease associated PTM events. By reconstructing a disease-gene network, we observed that breast cancers have the largest number of associated PTMs and AKT1 has the largest number of PTMs connected to diseases. Finally, the PTMD database was developed with detailed annotations and can be a useful resource for further analyzing the relations between PTMs and human diseases. PTMD is freely accessible at http://ptmd.biocuckoo.org. PMID- 30244176 TI - Biallelic TOR1A mutations cause severe arthrogryposis: A case requiring reverse phenotyping. AB - Heterozygous mutations in TOR1A gene are known to be responsible for DYT1 dystonia with incomplete penetrance. Autosomal recessive TOR1A disease is a very recently described syndrome characterized by severe arthrogryposis, developmental delay, strabismus and tremor. A 2 month-old boy with severe arthrogryposis and developmental delay was referred to our department for genetic counseling. Dystonic movements were observed on physical examination. Whole exome sequencing revealed a homozygous nonsense variant in exon 5 of TOR1A (c.862C > T, p.Arg288*). Our results expand the phenotypic and mutational spectrum of biallelic TOR1A disease, while emphasizing the importance of reverse phenotyping in the diagnosis of rare genetic disorders. PMID- 30244177 TI - Raf kinase inhibitor protein protects microglial cells against 1-methyl-4 phenylpyridinium-induced neuroinflammation in vitro. AB - The Raf kinase inhibitor protein (RKIP), belonging to a member of the phosphatidylethanolamine-binding protein (PEBP) family, is involved in regulating neural development. However, the role of RKIP in microglial cells stimulated with 1-methyl-4-phenylpyridinium (MPP+) has not been determined. Thus, in the present study, we investigated the role of RKIP and its underlying mechanism in Parkinson's disease (PD). Our results showed that the expression of RKIP was significantly reduced in BV-2 cells treated with MPP+. Overexpression of RKIP markedly rescued cell viability and inhibited cell apoptosis in BV-2 cells exposed to MPP+. In addition, overexpression of RKIP inhibited MPP+-induced the production of pro-inflammatory molecules in BV-2 cells. Similar results were observed in primary microglial cells isolated from neonatal mice. Exploration of the underlying mechanisms of its action indicated that overexpression of RKIP prevented the activation of NF-kappaB and MEK/ERK pathways in MPP+-stimulated BV 2 cells. Taken together, these findings indicated that RKIP suppresses apoptosis and inflammation in MPP+-treated microglial cells through the inactivation of NF kappaB and MEK/ERK signaling pathways. Thus, RKIP may be a promising target molecular involving in the pathogenesis of PD. PMID- 30244179 TI - Self-complementary and tyrosine-mutant rAAV vectors enhance transduction in cystic fibrosis bronchial epithelial cells. AB - Recombinant adeno-associated virus (rAAV) vector platforms have shown considerable therapeutic success in gene therapy for inherited disorders. In cystic fibrosis (CF), administration of first-generation rAAV2 was safe, but clinical benefits were not clearly demonstrated. Therefore, next-generation vectors that overcome rate-limiting steps in rAAV transduction are needed to obtain successful gene therapy for this devastating disease. In this study, we evaluated the effects of single-strand or self-complementary (sc) rAAV vectors containing single or multiple tyrosine-to-phenylalanine (Y-F) mutations in capsid surface-exposed residues on serotypes 2, 8 or 9. For this purpose, CF bronchial epithelial (CFBE) cells were transduced with rAAV vectors, and the transgene expression of enhanced green fluorescence protein (eGFP) was analyzed at different time points. The effects of vectors on the cell viability, host cell cycle and in association with co-adjuvant drugs that modulate intracellular vector trafficking were also investigated. Six rAAV vectors demonstrated greater percentage of eGFP+ cells compared to their counterparts at days 4, 7 and 10 post transduction: rAAV2 Y(272,444,500,730)F, with 1.95-, 3.5- and 3.06-fold increases; rAAV2 Y(252,272,444,500,704,730)F, with 1.65-, 2.12-, and 2-fold increases; scrAAV2 WT, with 1.69-, 2.68-, and 2.32-fold increases; scrAAV8 Y773F, with 57-, 6.06-, and 7-fold increases; scrAAV9 WT, with 7.47-, 4.64-, and 3.66 fold increases; and scrAAV9 Y446F, with 8.39-, 4.62-, and 4.4-fold increases. At days 15, 20, and 30 post-transduction, these vectors still demonstrated higher transgene expression than transfected cells. Although the percentage of eGFP+ cells reduced during the time-course analysis, the delta mean fluorescence intensity increased. These vectors also led to increased percentage of cells in G1-phase without eliciting any cytotoxicity. Prior administration of bortezomib or genistein did not increase eGFP expression in cells transduced with either rAAV2 Y(272,444,500,730)F or rAAV2 Y(252,272,444,500,704,730)F. In conclusion, self-complementary and tyrosine capsid mutations on rAAV serotypes 2, 8, and 9 led to more efficient transduction than their counterparts in CFBE cells by overcoming the intracellular trafficking and second-strand DNA synthesis limitations. PMID- 30244178 TI - L-plastin phosphorylation regulates the early phase of sealing ring formation by actin bundling process in mouse osteoclasts. AB - The process of sealing ring formation requires major actin filament reorganization. We previously demonstrated that an actin-bundling protein L plastin has a role in the cross-linking of actin filaments into tight bundles and forms actin aggregates (denoted as nascent sealing zones). These nascent sealing zones mature into fully functional sealing rings. We have shown here that TNF alpha signaling regulates the phosphorylation of serine-5 and -7 in L-plastin which increases the actin bundling capacity of L-plastin and hence the formation of nascent sealing zones in mouse osteoclasts. Using the TAT-mediated transduction method, we confirmed the role of L-plastin in nascent sealing zones formation at the early phase of the sealing ring assembly. Transduction of TAT fused full-length L-plastin peptide significantly increases the number of nascent sealing zones and therefore sealing rings. But, transduction of amino-terminal L plastin peptides consisting of the serine-5 and -7 reduces the formation of both nascent sealing zones and sealing rings. Therefore, bone resorption in vitro was reduced considerably. The decrease was associated with the selective inhibition of cellular L-plastin phosphorylation by the transduced peptides. Neither the formation of podosomes nor the migration was affected in these osteoclasts. Phosphorylation of L- plastin on serine 5 and -7 residues increases the F-actin bundling capacity. The significance of our studies stands on laying the groundwork for a better understanding of L-plastin as a potential regulator at the early phase of sealing ring formation and could be a new therapeutic target to treat bone loss. PMID- 30244180 TI - The Impella Microaxial Flow Catheter Is Safe and Effective for Treatment of Myocarditis Complicated by Cardiogenic Shock: An Analysis From the Global cVAD Registry. AB - BACKGROUND: Myocarditis complicated by cardiogenic shock remains a complex problem. The use of acute mechanical circulatory support devices for cardiogenic shock is growing. We explored the utility of Impella transvalvular microaxial flow catheters in the setting of myocarditis with cardiogenic shock. METHODS AND RESULTS: We retrospectively analyzed data from 21 sites within the cVAD registry, an ongoing multicenter voluntary registry at sites in North America and Europe that have used Impella in patients with myocarditis. Myocarditis was defined by endomyocardial biopsy (n = 11) or by clinical history without angiographic evidence of coronary disease (n = 23). A total of 34 patients received an Impella 2.5, CP, 5.0, or RP device for cardiogenic shock complicating myocarditis. Baseline characteristics included age 42 +/- 17 years, left ventricular ejection fraction (LVEF) 18% +/- 10%, cardiac index 1.82 +/- 0.46 L.min-1.m-2, pulmonary capillary wedge pressure 25 +/- 7 mm Hg, and lactate 27 +/- 31 mg/dL. Before Impella placement, 32% (n = 11) of patients required intra-aortic balloon pump. Mean duration of Impella support was 91 +/- 74 hours; 21 of 34 patients (62%) survived the index hospitalization and were discharged with an improved mean LVEF of 37.32% +/- 20.31% (P = .001); 15 patients recovered with successful support, 5 patients were transferred to another hospital on initial Impella support, 1 patient underwent orthotopic heart transplantation. Ten patients required transition to another mechanical circulatory support device. CONCLUSIONS: This is the largest analysis of Impella-supported myocarditis cases to date. The use of Impella appears to be safe and effective in the settings of myocarditis complicated by cardiogenic shock. PMID- 30244181 TI - Effects of Oral Supplementation With Nitrate-Rich Beetroot Juice in Patients With Pulmonary Arterial Hypertension-Results From BEET-PAH, an Exploratory Randomized, Double-Blind, Placebo-Controlled, Crossover Study. AB - BACKGROUND: The nitrate-nitrite-nitric oxide (NO) pathway may represent a potential therapeutic target in patients with pulmonary arterial hypertension (PAH). We explored the effects of dietary nitrate supplementation, with the use of nitrate-rich beetroot juice (BRJ), in patients with PAH. METHODS AND RESULTS: We prospectively studied 15 patients with PAH in an exploratory randomized, double-blind, placebo-controlled, crossover trial. The patients received nitrate rich beetroot juice (~16 mmol nitrate per day) and placebo in 2 treatment periods of 7 days each. The assessments included; exhaled NO and NO flow-independent parameters (alveolar NO and bronchial NO flux), plasma and salivary nitrate and nitrite, biomarkers and metabolites of the NO-system, N-terminal pro-B-type natriuretic peptide, echocardiography, ergospirometry, diffusing capacity of the lung for carbon monoxide, and the 6-minute walk test. Compared with placebo ingestion of BRJ resulted in increases in; fractional exhaled NO at all flow rates, alveolar NO concentrations and bronchial NO flux, and plasma and salivary levels of nitrate and nitrite. Plasma ornithine levels decreased and indices of relative arginine availability increased after BRJ compared to placebo. A decrease in breathing frequency was observed during ergospirometry after BRJ. A tendency for an improvement in right ventricular function was observed after ingestion of BRJ. In addition a tendency for an increase in the peak power output to peak oxygen consumption ratio (W peak/VO2 peak) was observed, which became significant in patients reaching an increase of plasma nitrite >30% (responders). CONCLUSIONS: BRJ administered for 1 week increases pulmonary NO production and the relative arginine bioavailability in patients with PAH, compared with placebo. An increase in the W peak/VO2 peak ratio was observed after BRJ ingestion in plasma nitrite responders. These findings indicate that supplementation with inorganic nitrate increase NO synthase-independent NO production from the nitrate-nitrite-NO pathway. PMID- 30244182 TI - Pupillary Light Reflex as a New Prognostic Marker in Patients With Heart Failure. AB - BACKGROUND: Autonomic function can be evaluated based on the pupillary light reflex (PLR). However, the relationship between PLR and prognosis in patients with heart failure (HF) remains unclear. This study was performed to examine whether PLR could be used as a prognostic indicator in patients with HF. METHODS AND RESULTS: A retrospective review was performed in 535 consecutive Japanese patients hospitalized for acute HF (mean age 66.1 +/- 13.7 y). PLR was recorded at least 7 days after hospitalization for HF with the use of a pupilometer. Fifty three patients died over a median follow-up period of 1.3 years (interquartile range 0.6-2.3 y). After adjustment for several preexisting prognostic factors, including Seattle Heart Failure Score (SHFS), PLR as assessed by recovery time (time to 63% redilation) was independently associated with all-cause mortality (hazard ratio 0.50, 95% confidence interval 0.35-0.73; P < .001). The addition of recovery time to SHFS resulted in a significant increase in the area under the curve on receiver-operating characteristic curve analysis (0.69 vs 0.77; P < .001). CONCLUSIONS: PLR assessed by recovery time was an independent predictor of mortality and added prognostic information to the SHFS in patients with HF. Our results suggest that PLR may be useful as a new prognostic marker in HF patients. PMID- 30244183 TI - Quality of Life After Treatment of Unruptured Intracranial Aneurysms. AB - OBJECTIVE: Quality of life is an important factor in the decision making for the treatment of unruptured intracranial aneurysms (UIA). The data dealing with QoL in patients after the treatment are spare. We have evaluated QoL of patients after endovascular or surgical treatment of incidental intracranial aneurysm. METHODS: We performed a prospective analysis of retrospectively collected data. All patients received 36-Item Short Form Health Survey (SF-36), Hospital Anxiety and Depression Scale (HADS), German questionnaire for self-perceived deficits in attention (FEDA) and not standardized questionnaire analyzing personal job related situation, family circumstances and chronic illnesses. RESULTS: 177 patients were treated during the evaluated period. 79 (44.6%) patients responded. In this cohort, 62.03% of patients underwent coiling. Complications were noted in 13.9% of patients. Stroke was the most common complication (7.6%). All SF-36 related data except for pain showed significant lower mean, if compared to the standard German population (p < 0.01). For both genders, anxiety (males, P = 0.003 and females, P = 0.002) but not depression was more common than in the standard population. According to the FEDA test, treated patients showed significant difference only for fatigue in comparison to healthy population (P < 0.001). 54.4% of patients suffered from chronic illnesses, and among them only 1 patient (1.3%) had aneurysm associated chronic disease. No significant differences were found between treatment modalities. CONCLUSIONS: The risk for depression and pain is not significantly increased after elective treatment of UIA. According to our results, decreased QoL is common in this cohort of patients but often related to factors not associated with aneurysm treatment. PMID- 30244184 TI - Magnetic Resonance-Guided Laser Interstitial Thermal Therapy Versus Stereotactic Radiosurgery for Medically Intractable Temporal Lobe Epilepsy: A Systematic Review and Meta-Analysis of Seizure Outcomes and Complications. AB - INTRODUCTION: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) and stereotactic radiosurgery (SRS) are 2 emerging minimally invasive procedures being increasingly used for surgical intervention in cases of medically intractable temporal lobe epilepsy (TLE). To date, no comparative analyses of these 2 procedures have been made. In the current study, we synthesized pooled data from existing studies in an attempt to present a systematic review and meta-analysis of seizure and clinical outcomes of the 2 procedures in patients with TLE. METHODS: The Population, Intervention, Comparator, and Outcome (PICO) approach and Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed to perform an indirect meta-analysis of seizure and clinical outcomes between MRgLITT and SRS. Only studies reporting outcomes for patients with TLE were included in the current review. RESULTS: A total of 19 studies were included in the final analysis, giving a total of 415 TLE patients. Of those studies, 9 were on MRgLITT, with a total of 250 patients (60%), and 10 were on SRS, with a total of 165 patients (40%). We found that the overall seizure freedom rate was comparable between the 2 procedures (MRgLITT 50%, 95% confidence interval [CI] 44% to 56%, vs. SRS 42%, 95% CI 27% to 59%, P = 0.39). Similarly, among patients with lesional pathologic conditions only, the seizure freedom rate was comparable between the 2 procedures (MRgLITT 62%, 95% CI 48% to 74%, vs. SRS 50%, 95% CI 37% to 64%, P = 0.23). Compared with SRS, MRgLITT was associated with lower complication rates (MRgLITT 20%, 95% CI 14% to 26% vs. SRS 32%, 95% CI 20% to 46%, P = 0.06) but similar reoperation rates (15%, 95% CI 9% to 22% vs. 27%, 95% CI 12% to 46%, P = 0.31). CONCLUSIONS: As minimally invasive procedures continue to gain popularity for use in surgery for epilepsy, it is imperative to evaluate their efficacy and safety outcomes. In this study we pooled the data from existing studies to compare the seizure and clinical outcomes in patients with TLE undergoing MRgLITT and SRS. We found similar outcomes and complications between the 2 procedures. PMID- 30244185 TI - No Disparity in Outcomes Between Surgical Clipping and Endovascular Coiling After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) can be treated with either endovascular coiling or surgical clipping. The International Subarachnoid Aneurysm Trial (ISAT) found that endovascular coiling provided lower mortality rates at 1-year follow-up, starting a trend toward the endovascular treatment approach for SAH. Subsequently, specific procedural indications have driven an approach to SAH management involving a patient-specific procedural choice. The present study evaluates whether specific indications for these procedures have eliminated the differences in risk-adjusted mortality and in-hospital complications from SAH in a large nationally representative set of hospitalizations from 2013 to 2014. METHODS: All cases of nontraumatic subarachnoid hemorrhage were queried from the National Inpatient Sample using codes from the International Classification of Diseases, 9th edition. These patients were assigned to cohorts based on whether they were treated by surgical clipping or by endovascular coiling. Subsequent univariate and multivariate analyses were used to characterize and compare demographics, in-hospital complications, and total charges between the 2 groups. RESULTS: In 2013 to 2014, 6555 patients hospitalized for SAH underwent surgical clipping and 15,350 underwent endovascular coiling. The patients undergoing coiling were older (55.3 vs. 54.1, P = 0.02) and had lower severity scores (3.24 vs. 3.44, P < 0.0001); however, they had higher average risk of mortality scores (2.96 vs. 2.44, P < 0.0001) and longer lengths of stay (19.0 vs. 17.8 days, P = 0.009) than did those undergoing surgical clipping. Multivariate logistic regression analysis comparing clipping to coiling showed no differences in rates of complication (odds ratio [OR]: 0.87; 95% confidence interval [CI]: 0.67-1.13), death (OR: 0.78; 95% CI: 0.57-1.05), or total charges (-$3282, 95% CI: -$8376-$14,941) between both cohorts. CONCLUSIONS: Concerns about overzealous use of endovascular coiling in treating SAH after the ISAT stemmed from a lag in condition-specific indications. The allure of endovascular coiling stems from its noninvasiveness and initial results; however, in the years after ISAT, evaluation of SAH conditions led to more patient-specific indications for SAH. The results presented here suggest that more rigorous procedural selection has allowed for an optimization of outcomes for the 2 procedures. PMID- 30244186 TI - Two-Micron Continuous-Wave Laser-Assisted Neuroendoscopy: Clinical Experience of Two Institutions in 524 Procedures. AB - OBJECTIVE: To present the clinical experience of 2 neurosurgical centers with the use of a 2-micron continuous-wave laser (2MU-cwL) system as standard tool in neuroendoscopic procedures and to discuss the safety and efficacy of this system. METHODS: In total, 469 patients underwent neuroendoscopic procedures using 2MU cwL between September 2009 and January 2015. All patient data were retrospectively reviewed. In total, 241 (51%) patients were children and 228 (49%) adults. Mean age was 27.5 years (range: 3 days to 83 years). Intraoperative ultrasonography or neuronavigation were used to guide ventricular or cyst puncture and for intraventricular or intracystic orientation if necessary. RESULTS: A total of 524 neuroendoscopic procedures using 2MU-cwL were performed. Laser-assisted endoscopic third ventriculostomy was the most common procedure in 302 (64%) patients. Cyst fenestration was performed in 124 (26%), septostomy in 45, tumor biopsy in 41, tumor resection in 8, and choroid plexus coagulation in 3 patients. There was no intraoperative complication directly attributable to the use of laser and an overall procedural complication rate of 4.8%. CONCLUSIONS: This large series of 2MU-cwL as a routine tool in neuroendoscopic procedures demonstrates that 2MU-cwL is safe for endoscopic third ventriculostomy, septostomy, cyst fenestration, and intraventricular tumor biopsy or resection. As a cutting and coagulation tool, it combines the action of mechanical tools like forceps, balloons, and scissors plus those of electric tools. It therefore renders neuroendoscopic procedures more straightforward with a minimum need to change tools. PMID- 30244187 TI - The Value of Computed Tomography Imaging of the Head After Ventriculoperitoneal Shunt Surgery in Adults. AB - BACKGROUND: Patients with a ventriculoperitoneal shunt for hydrocephalus often undergo multiple follow-up computed tomography (CT) scans of the head, increasing the risk for long-term effects of ionizing radiation. The purpose of our study was to evaluate the necessity as a routine diagnostic procedure and cost analysis of routine postoperative CT scan of the head after ventriculoperitoneal shunt surgery. METHODS: In this study, we comprised adults with ventriculoperitoneal shunt operations who underwent early CT scans within 48 hours postoperatively. We reviewed the correlation between revision surgery rate and the experience of surgeons who performed surgery and provided a cost analysis. RESULTS: In total, 479 surgeries were performed in 439 patients. Early revision surgery was performed in 11 (2.3%) patients. Reason for revision surgery was malposition in 9 cases and intracerebral hemorrhage in 2 patients. There was no significant correlation between the surgeon's experience and the rate of revision surgery. Placement of the ventricular catheter via an approach other than a standard right or left frontal burr hole resulted in risk of need for surgical shunt revision (P >= 0.002, odds ratio 54, confidence interval 13.5-223). A total of 468 CT scans of the head revealed a normal finding; thus, ~$562,000 could be saved by omitting postoperative head CT scans. CONCLUSIONS: Routine postoperative head CT scans after fentriculoperitoneal shunting are not necessary in all cases. The reduction of exposure to ionization radiation and the beneficial economic factor are main advantages. PMID- 30244188 TI - Efficacy of Carotid Endarterectomy for Mild (<50%) Symptomatic Carotid Stenosis with Unstable Plaque. AB - BACKGROUND: Carotid endarterectomy (CEA) is known to reduce stroke risk in patients with symptomatic, moderate to severe carotid stenosis but has no apparent impact in patients with symptomatic, mild (less than 50%) carotid stenosis. However, recent development of noninvasive imaging modalities has shown that a certain subgroup of patients are at high risk for further ischemic events despite antiplatelet therapy. This study, therefore, aimed to clarify the patients' clinical features and explore the impact of CEA for them. METHODS: This prospective cohort study included 74 patients who underwent CEA for symptomatic carotid stenosis between April 2012 and December 2016. Of these, 16 (22%) had mild (less than 50%) carotid stenosis. Their demographic, radiologic, intraoperative, and pathologic findings were precisely analyzed, and their outcome after CEA was examined for 38.5 +/- 13.3 months. RESULTS: Of these 16 patients, 12 had already been treated with antiplatelets against previous ischemic cerebrovascular or coronary artery diseases. Plaque magnetic resonance imaging revealed that all patients had vulnerable plaque, including lipid-rich plaque (n = 6) and intraplaque hemorrhage (n = 10). Intraoperative observations confirmed this. Histologic analysis revealed that inflammatory cells and fragile angiogenesis were widely found in the specimens. Only 1 patient experienced transient (less than 30 days) neurologic deficit after CEA, and none of them repeated cerebrovascular events during the follow-up period. CONCLUSIONS: It is not rare the patients who are at high risk for subsequent ischemic events because of vulnerable plaque despite mild (less than 50%) carotid stenosis. Magnetic resonance imaging is quite useful to noninvasively detect such vulnerable plaque. CEA is a promising procedure to treat these patients. PMID- 30244190 TI - Outcome of conscious survivors of out-of-hospital cardiac arrest. AB - AIM: Only up to 20% of patients with out-of-hospital cardiac arrest (OHCA) receive immediate and optimal initial cardiac resuscitation and consequently regain consciousness soon after return of spontaneous circulation (ROSC). In the present study, we compared the outcome of conscious survivors of OHCA presenting with ST-elevation myocardial infarction (STEMI) in post-resuscitation electrocardiogram undergoing immediate invasive coronary strategy with randomly selected STEMI patients without preceding OHCA undergoing primary PCI. METHODS: We conducted a single-centre registry-based analysis of all conscious OHCA survivors with STEMI over the last 10 year period. We gathered clinical and angiographic data and compared them with a randomly selected cohort of non-OHCA patients with STEMI within the same period. Patients were matched by sex, age and STEMI location. RESULTS: 86 conscious survivors of OHCA were admitted between 2006 and 2016. OHCA was witnessed in all patients (85% EMS witnessed), and all patients presented with initial shockable rhythm. Clinical and angiographic features were well matched with randomly selected STEMI patients without OHCA presenting to our department within the same study period. Delay from symptoms to EMS arrival but not delay from EMS to PCI was significantly shorter in conscious OHCA survivors (1.2 +/- 1.3 h vs 3.1 +/- 3.8 h, p < 0.001), yielding decreased total myocardial ischemic time (2.6 +/- 1.3 h vs 4.6 +/- 4.0 h, p < 0.001). Hospital and 1-year survival with normal neurological condition in conscious survivors of OHCA (cerebral performance category 1) was excellent and numerically even better than survival of STEMI patients without OHCA. CONCLUSION: Conscious survivors of OHCA with STEMI have excellent survival if they undergo immediate invasive coronary strategy. Since there is no obvious post-resuscitation brain injury in this subgroup of OHCA patients, it is probably shorter duration of myocardial ischemia driven by shorter delay from symptoms to EMS arrival that contributes to the good outcome, which is at least similar to STEMI patients without OHCA. PMID- 30244189 TI - Low versus standard-blood-flow reperfusion strategy in a pig model of refractory cardiac arrest resuscitated with Extra Corporeal Membrane Oxygenation. AB - OBJECTIVE: This study was designed to assess the effect of two veno-arterial ExtraCorporeal Membrane Oxygenation (ECMO) blood-flow strategies in an experimental model of Extracorporeal Cardio-Pulmonary Resuscitation (ECPR) on macrocirculatory, metabolic and microcirculatory parameters in the first six hours of ECMO initiation. METHODS: Cardiac arrest was induced in 18 pigs by surgical ligature of the left descending coronary artery followed by a low-flow time of 40 min using internal cardiac massage. ECPR was initiated in normothermia with an ECMO blood flow of 30-35 ml.kg-1. min-1 (low-blood-flow group, LBF) or 65 70 ml.kg-1. min-1 (standard-blood-flow group, SBF), with the same mean arterial pressure target of 65 mmHg adjusted with norepinephrine. Macrocirculatory and metabolic parameters were assessed by lactate clearance and carotid blood flow. Microcirculatory parameters were assessed by sublingual microcirculation with Sidestream Dark Field (SDF) imaging and peripheral Near-InfraRed Spectrometry (NIRS). Inflammatory cytokine levels were measured with a multicomplexed ELISA based array platform. RESULTS: There were no between-group differences at baseline and at ECMO initiation (H0). Lactate clearance at H6 was lower in LBF compared to SBF (6.67[-10.43-18.78] vs. 47.41[19.54-70.69] %, p = 0.04). Carotid blood flow was significantly lower (p<0.005) during the last four hours despite similar mean arterial pressure levels. For microvascular parameters, SDF and NIRS parameters were transitorily impaired at H3 in LBF. IL-6 cytokine level was significantly higher in LBF at the end of the experiment. CONCLUSION: In an experimental porcine model of refractory cardiac arrest treated by ECMO, a low blood-flow strategy during the first six hours of resuscitation was associated with lower lactate clearance and lower cerebral blood flow with no benefits on ischemia-reperfusion parameters. PMID- 30244191 TI - Maternal Placentophagy as a Possible Cause of Breast Budding and Vaginal Bleeding in a Breast-Fed 3-Month-Old Infant. AB - BACKGROUND: Placentophagy, or the practice of placental consumption, has grown in popularity over the past decade. Although advocates endorse prevention of postpartum depression, increased breast milk production, reduction in postpartum bleeding, and provision of nutrients postpartum, scientific studies have failed to show benefit. No studies have explored the effect of placental hormone consumption on the hypothalamic-pituitary-ovarian axis of the offspring. CASE: We present a case of vaginal bleeding and breast budding in a 3-month-old infant whose mother was exclusively breastfeeding. Maternal history was notable for placentophagy. Upon discontinuation of consuming encapsulated placenta, the infant's vaginal bleeding resolved. SUMMARY AND CONCLUSION: Our case raises concerns regarding placentophagy and infant endocrine function. More research is needed to assess maternal and infant exogenous estrogen exposure with maternal placental consumption. PMID- 30244192 TI - Cushing Syndrome Induced by Topical Corticosteroids for the Treatment of Lichen Sclerosus. AB - BACKGROUND: Lichen sclerosus is a chronic inflammatory dermatological condition with a predilection for the anogenital area. CASE: We describe a case of iatrogenic Cushing syndrome from the administration of high-potency topical steroids for vulvar lichen sclerosus in a 6-year-old girl. Her symptoms resolved after the cessation of topical steroid treatment. SUMMARY AND CONCLUSION: This case brings attention to iatrogenic Cushing syndrome as a potential complication when using high-potency topical corticosteroids in the anogenital region. PMID- 30244193 TI - A Study of Adolescent Female Genitalia: What is Normal? AB - STUDY OBJECTIVE: Female adolescents often present to health care providers with concerns about the appearance of their external genitalia. These patients might experience significant distress about their genital appearance and might request surgery to correct a perceived abnormality. Accurate descriptions of normal adolescent female genital anatomy are lacking in the literature. The purpose of this study was to examine a small sample of normal female adolescents to obtain measurements and descriptors of the external genital structures, with a focus on the size and morphology of the labia minora. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Participants were female adolescent patients, ages 10-19 years, who underwent routine surgical procedures in the operating room. RESULTS: Forty-four patients were examined. The mean age was 14.4 years (range 10-19 years). Mean height was 159.6 cm and mean weight was 60.8 kg. Most were non-Hispanic ethnicity (n = 32/44; 72%) and were Caucasian race (n = 38/44; 86%). Right and left labia minora lengths were different in n = 19/44 patients (43%). Right and left labia minora widths also differed, in stretched (n = 20/33; 61%) and unstretched (n = 24/44; 55%) labia, with a difference ranging from 1 to 22 mm. There was no correlation between size and shape of labia minora and patient age, height, weight, or race. CONCLUSION: Wide variability exists in female adolescent genital anatomy with no established normal range. This study provides a resource for physicians who care for adolescent girls, who need normative data to describe female genital anatomy. We propose that the role of labiaplasty in adolescents should be considered with extreme caution because of the wide range in size and morphology and paucity of data in this population. PMID- 30244194 TI - Sputum exosomes: promising biomarkers for idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown aetiology which leads rapidly to death. As diagnosis of IPF is complex, we aimed to characterise microRNA (miRNA) content of exosomes from sputum of patients with IPF. Using miRNA quantitative PCR array, we found a substantial dysregulation of sputum exosomal miRNA levels between patients with IPF and healthy subjects and identified a unique signature of three miRNAs. Interestingly, we found a negative correlation between miR-142-3p and diffusing capacity of the lungs for carbon monoxide/alveolar volume. This is the first characterisation of miRNA content of sputum-derived exosomes in IPF that identified promising biomarkers for diagnosis and disease severity. PMID- 30244196 TI - New MS diagnostic criteria in practice. PMID- 30244195 TI - Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in Hereditary Haemorrhagic Telangiectasia. AB - INTRODUCTION: Hereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder caused by mutations in the genes ENG, ACVRL1, and SMAD4. Yet the genetic cause remains unknown for some families even after exhaustive exome analysis. We hypothesised that non-coding regions of the known HHT genes may harbour variants that disrupt splicing in these cases. METHODS: DNA from 35 individuals with clinical findings of HHT and 2 healthy controls from 13 families underwent whole genome sequencing. Additionally, 87 unrelated cases suspected to have HHT were evaluated using a custom designed next-generation sequencing panel to capture the coding and non-coding regions of ENG, ACVRL1 and SMAD4. Individuals from both groups had tested negative previously for a mutation in the coding region of known HHT genes. Samples were sequenced on a HiSeq2500 instrument and data were analysed to identify novel and rare variants. RESULTS: Eight cases had a novel non-coding ACVRL1 variant that disrupted splicing. One family had an ACVRL1intron 9:chromosome 3 translocation, the first reported case of a translocation causing HHT. The other seven cases had a variant located within a ~300 bp CT-rich 'hotspot' region of ACVRL1intron 9 that disrupted splicing. CONCLUSIONS: Despite the difficulty of interpreting deep intronic variants, our study highlights the importance of non-coding regions in the disease mechanism of HHT, particularly the CT-rich hotspot region of ACVRL1intron 9. The addition of this region to HHT molecular diagnostic testing algorithms will improve clinical sensitivity. PMID- 30244197 TI - Exploring gendered leadership stereotypes in a shared leadership model in healthcare: a case study. AB - The existing literature on leadership often describes it within fairly rigid gender roles. Entire models of leadership have been ascribed gendered labels. Shared leadership is, in traditional leadership theory, a feminine model. After observing a National Health Service (NHS) department enacting a shared leadership model, and using ethnography, grounded theory and comics-based research, we decided to explore the relationship between shared leadership and gender stereotypes. We realised our hope was to see a subversion of traditional stereotypes. Our data showed shared leadership overall as a feminine model, with its focus on distribution and compassion. Within the group, a range of gender roles were performed, meaning that the group could represent itself to the outside world as either more masculine or more feminine as required. This was beneficial, as conflict with outsiders was minimised and hence anxiety reduced. However, we noted that within the group, traditional gender roles were not subverted and were probably reinforced. Despite our view that shared leadership has not been an opportunity to resist gender stereotyping within this department, the success of this feminine model may represent a challenge to the prevailing masculine model of leadership within the NHS. PMID- 30244198 TI - Tele-echocardiography: enhancing quality at the point-of-care. PMID- 30244199 TI - Evaluating ventricular assist device outcomes internationally with a focus on neurological events. PMID- 30244200 TI - Potential utility of the Genedrive point-of-care test for HCV RNA detection. PMID- 30244201 TI - Efficacy of glutamine in postinfection IBS. PMID- 30244202 TI - Archaeology and modern reflections on death. PMID- 30244203 TI - Overall survival in older patients with cancer. AB - OBJECTIVES: A growing number of patients with cancer are older adults. We sought to identify the predictors for overall survival (OS) in older adults with solid tumour and haematological malignancies between January 2013 and December 2016. METHODS: Retrospective cohort study. A comprehensive geriatric assessment was performed, with a median follow-up of 12.8 months. ANALYSIS: univariate and multivariate Cox proportional hazards regression analysis. RESULTS: In this study, among the 455 patients with last follow-up date or date of death, 152 (33.4%) died during the follow-up. The median follow-up is 12.8 months (range 0.2 51.1 months) and the median OS is 20.5 months (range 0.3-44.5 months). Among all older patients with cancer, predictors of OS included male gender, cancer stage, malnutrition, history of smoking, heavy alcohol use, frailty, weight loss, major depression, low body weight and nursing home residence. Traditional performance scores (Eastern Cooperative Oncology Group (ECOG) and Karnofsky Performance Scale (KPS)) were predictors of OS. Independent predictors included age >85 years and haematological malignancies. Among solid tumours (n=311) in addition to the above predictors, comorbidity, gait speed and vitamin D deficiency were associated with OS. CONCLUSIONS: We identified specific geriatric factors associated with OS in older patients with cancer, and comparable in predictive ability to traditional performance scores such as KPS and ECOG. Prospective studies will be necessary to confirm our findings. PMID- 30244205 TI - The association between mentoring and training outcomes in junior doctors in medicine: an observational study. AB - OBJECTIVE: To determine quantitatively if a positive association exists between the mentoring of junior doctors and better training outcomes in postgraduate medical training within the UK. DESIGN: Observational study. PARTICIPANTS: 117 trainees from the East of England Deanery (non-mentored group) and the recently established Royal College of Physicians (RCP) Mentoring scheme (mentored group) who were core medical trainees (CMTs) between 2015 and 2017 completed an online survey. Trainees who received mentoring at the start of higher specialty training, incomplete responses and trainees who were a part of both the East of England deanery and RCP Mentoring scheme were excluded leaving 85 trainees in the non-mentored arm and 25 trainees in the mentored arm. Responses from a total of 110 trainees were analysed. MAIN OUTCOME MEASURES: Pass rates of the various components of the Membership of the Royal College of Physicians (MRCP) (UK) examination (MRCP Part 1, MRCP Part 2 Written and MRCP Part 2 PACES), pass rates at the Annual Review of Competency Progression (ARCP), trainee involvement in significant events, clinical incidents or complaints and trainee feedback on career progression and confidence. RESULTS: Mentored trainees reported higher pass rates of the MRCP Part 1 exam versus non-mentored trainees (84.0% vs 42.4%, p<0.01). Mentored international medical graduates (IMGs) reported higher pass rates than non-mentored IMGs in the MRCP Part 2 Written exam (71.4% vs 24.0%, p<0.05). ARCP pass rates in mentored trainees were observed to be higher than non mentored trainees (95.8% vs 69.9%, p<0.05). Rates of involvement in significant events, clinical incidents and complaints in both groups did not show any statistical difference. Mentored trainees reported higher confidence and career progression. CONCLUSIONS: A positive association is observed between the mentoring of CMTs and better training outcomes. Further studies are needed to investigate the causative effects of mentoring in postgraduate medical training within the UK. PMID- 30244204 TI - Strategies to improve the implementation of policies, practices or programmes in sporting organisations targeting poor diet, physical inactivity, obesity, risky alcohol use or tobacco use: a systematic review. AB - OBJECTIVES: The primary aim for this review is to determine the effectiveness of strategies to improve the implementation of policies, practices or programmes in sporting organisations. The secondary aims are to describe the cost or cost effectiveness and adverse effects of such strategies and to examine the effects of those implementation strategies on individual's diet, physical activity, obesity, alcohol use or tobacco use. METHODS: We conducted searches of academic databases (eg, MEDLINE, EMBASE and CENTRAL), trial registers and hand searches of selected journals. Studies were included if they were conducted at a sporting venue; described a strategy to improve implementation of policies, practices or programmes focusing on one or more health risks (diet, physical inactivity, obesity, alcohol or tobacco use), and included a parallel control group. Two authors independently screened citations and extracted data. The results of included studies were synthesised narratively. RESULTS: Of the 5926 citations screened three studies met the inclusion criteria. Two studies were randomised controlled trials. Two studies sought to improve the implementation of nutrition related policy and practices and one study sought to improve implementation of alcohol-related policy and practices. Each study reported improvement in at least one measure of policy or practice implementation. Two studies reported individual level outcomes and found a reduction in excessive alcohol consumption and an increase in purchase of fruits and vegetables at the sports club ground. Two studies assessed club revenue as a potential adverse effect, neither reported significant between-group differences on these measures. CONCLUSION: There is a sparse evidence base regarding the effectiveness of strategies to improve the implementation of policies, practices or programmes targeting chronic disease risk factors in sporting clubs. While all studies reported some improvements in implementation, for some multistrategic implementation strategies it is difficult to determine the extent to which such effects are generalisable. PROSPERO REGISTRATION NUMBER: CRD42016039490. PMID- 30244206 TI - Integration of academic and health education for the prevention of physical aggression and violence in young people: systematic review, narrative synthesis and intervention components analysis. AB - OBJECTIVES: To systematically review evidence on the effectiveness of interventions including integration of academic and health education for reducing physical aggression and violence, and describe the content of these interventions. DATA SOURCES: Between November and December 2015, we searched 19 databases and 32 websites and consulted key experts in the field. We updated our search in February 2018. ELIGIBILITY CRITERIA: We included randomised trials of school-based interventions integrating academic and health education in students aged 4-18 and not targeted at health-related subpopulations (eg, learning or developmental difficulties). We included evaluations reporting a measure of interpersonal violence or aggression. DATA EXTRACTION AND ANALYSIS: Data were extracted independently in duplicate, interventions were analysed to understand similarities and differences and outcomes were narratively synthesised by key stage (KS). RESULTS: We included 13 evaluations of 10 interventions reported in 20 papers. Interventions included either full or partial integration, incorporated a variety of domains beyond the classroom, and used literature, local development or linking of study skills and health promoting skills. Evidence was concentrated in KS2, with few evaluations in KS3 or KS4, and evaluations had few consistent effects; evaluations in KS3 and KS4 did not suggest effectiveness. DISCUSSION: Integration of academic and health education may be a promising approach, but more evidence is needed. Future research should consider the 'lifecourse' aspects of these interventions; that is, do they have a longitudinal effect? Evaluations did not shed light on the value of different approaches to integration. PMID- 30244207 TI - Perceptions of French general practitioners and patients regarding dextropropoxyphene withdrawal: a qualitative study. AB - OBJECTIVES: Dextropropoxyphene (DXP), a step 2 analgesic commonly prescribed in France, was withdrawn from the French market in 2011 following a European decision due to its poor risk-benefit ratio. The purpose of this study was to explore the perceptions of French general practitioners (GPs) and patients regarding DXP withdrawal. DESIGN: Qualitative study based on 26 individual semi structured interviews. SETTING: Rhone-Alpes region of France. PARTICIPANTS: Thirteen patients and 13 GPs. METHODS: Interviews were conducted to collect data concerning the status of DXP, its efficacy and safety, the conditions of DXP's withdrawal and its potential impact. The transcripts were analysed using NVivo software. RESULTS: DXP was a very popular drug among both patients and GPs. Its withdrawal was a bad experience for patients and many GPs; these misunderstood the reasons for its withdrawal and several contested them. They generally recognised more benefits than risks of DXP and considered alternative drugs unsatisfactory. In the same period, a French court case regarding another drug led to distrust towards the pharmaceutical industry and healthcare institutions, which contributed to the negative feelings reported. However, the experience was positive for the GPs who had been alerted to the poor DXP risk-benefit ratio well before its withdrawal. CONCLUSIONS: Apart from physicians who were previously informed of its poor risk-benefit ratio, DXP withdrawal was not a good experience for patients and GPs. Better anticipation by the health authorities, in terms of pharmacoepidemiological surveillance and communication to healthcare professionals as well as the general public, should provide better acceptance of such a decision in the future. PMID- 30244208 TI - Are short-stem prostheses superior to conventional stem prostheses in primary total hip arthroplasty? A systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVE: Cementless total hip arthroplasty (THA) is associated with reliable clinical results and high patient satisfaction. Short-stem prostheses (SS) were designed to achieve superior preservation of proximal bone stock and stability compared with those of conventional-stem prostheses (CS). This meta-analysis was conducted to determine the proximal bone remodelling, revision rate, Harris Hip Score, radiolucent line and maximum total point motion values of both SS and CS for primary THA. METHOD: Relevant randomised controlled trials (RCTs) involving SS and CS in primary THA were identified from electronic databases, such as EMBASE, PubMed and the Cochrane Library. RESULT: Ultimately, 12 RCTs involving 1130 patients (1387 hips) were included. The results showed that compared with CS, SS resulted in less bone mineral density (BMD) changes in Gruen zone 7 at 1 year and 2 years postoperatively (mean difference (MD)=5.11; 95% CI, 1.61, 8.61; P=0.30; and MD=4.90; 95% CI, 1.01, 8.79; P=0.17, respectively). No difference in BMD changes was found for Gruen zone 1 (MD=2.66; 95% CI, -3.31, 8.64; P<0.00001), and no differences were observed for the revision rate (relative risk (RR)=1.52; 95% CI, 0.71, 3.26; P=0.94), Harris Hip Score (MD=-0.38; 95% CI, -1.02, 0.26; P=0.89) or stem migration (MD=0.02; 95% CI, -0.07, 0.11; P=0.04). CONCLUSION: Our results suggest that compared with CS, SS may provide superior bone remodelling and similar survival rates and clinical outcomes. However, the short-term follow up of the included studies was inadequate to determine the long-term performance of SS. PMID- 30244210 TI - Physical activity-related injuries among university students: a multicentre cross sectional study in China. AB - OBJECTIVES: This study aimed to investigate the epidemiological characteristics and preliminarily explore possible risk factors of physical activity-related injury (PARI) occurrences among Chinese university students via a multicentre mixed survey. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 4758 undergraduates graded 1-3 in nine universities in three Chinese cities were enrolled via cluster random sampling and completed the self-administered online questionnaires during March and April 2017. MAIN OUTCOME MEASURES: PARI in the past 12 months. RESULTS: Of the 4758 participants, 1081 sustained PARI in the past 12 months, with an overall PARI incidence rate of 22.7% (27.3% (367/1343) in males and 20.9%(714/3415) in females). Around one-quarter of the injured (26.4%) suffered from PARI over at least three episodes. More than half of the injured subjects experienced physical activity (PA) absenteeism and sought medical attention. All PA indicators were significantly and positively associated with PARI, with a frequency of sports and leisure-time vigorous-intensity PA (VPA) participation being the strongest (adjusted OR: 1.079, 95% CI: 1.018 to 1.144). Moreover, males (OR=1.199), Shantou students (OR=4.239), year 1 students (OR=1.287), university and other sports team members (OR=1.717-2.360) and those with insufficient sleep time (OR=1.262-1.333) were also at a higher risk of PARI. CONCLUSIONS: PARI is prevalent among university students in China. The frequency of sports and leisure-time VPA participation was most strongly associated with PARI among all PA indicators. These data can inform future programmes for injury intervention among university students. Safety issues should also be emphasised when promoting PA among the public to reduce PARI. PMID- 30244209 TI - Development of the individualised Comparative Effectiveness of Models Optimizing Patient Safety and Resident Education (iCOMPARE) trial: a protocol summary of a national cluster-randomised trial of resident duty hour policies in internal medicine. AB - INTRODUCTION: Medical trainees' duty hours have received attention globally; restrictions in Europe, New Zealand and some Canadian provinces are much lower than the 80 hours per week enforced in USA. In USA, resident duty hours have been implemented without evidence simultaneously reflecting competing concerns about patient safety and physician education. The objective is to prospectively evaluate the implications of alternative resident duty hour rules for patient safety, trainee education and intern sleep and alertness. METHODS AND ANALYSIS: 63 US internal medicine training programmes were randomly assigned 1:1 to the 2011 Accreditation Council for Graduate Medical Education resident duty hour rules or to rules more flexible in intern shift length and number of hours off between shifts for academic year 2015-2016. The primary outcome is calculated for each programme as the difference in 30-day mortality rate among Medicare beneficiaries with any of several prespecified principal diagnoses in the intervention year minus 30-day mortality in the preintervention year among Medicare beneficiaries with any of several prespecified principal diagnoses. Additional safety outcomes include readmission rates, prolonged length of stay and costs. Measures derived from trainees' and faculty responses to surveys and from time-motion studies of interns compare the educational experiences of residents. Measures derived from wrist actigraphy, subjective ratings and psychomotor vigilance testing compare the sleep and alertness of interns. Differences between duty hour groups in outcomes will be assessed by intention-to treat analyses. ETHICS AND DISSEMINATION: The University of Pennsylvania Institutional Review Board (IRB) approved the protocol and served as the IRB of record for 40 programmes that agreed to sign an Institutional Affiliation Agreement. Twenty-three programmes opted for a local review process. TRIAL REGISTRATION NUMBER: NCT02274818; Pre-results. PMID- 30244212 TI - Impact of group practices on patients, physicians and healthcare systems: protocol for a scoping review. AB - INTRODUCTION: Group practices have potential benefits for patients, physicians and healthcare systems. Although group practices have been around for many years, research in this area is lacking and generally is centred around the economic benefits that may be realised from group practice. The aim of this scoping review is to identify the impact that group practices have on patients, physicians and healthcare systems to guide further research in this area. METHODS AND ANALYSIS: A scoping review will be performed based on the methodology proposed by Arksey and O'Malley and refined by Levac and colleagues. MEDLINE, EMBASE, Cochrane Central and Cochrane Economic Database will be searched from inception to present day to identify relevant studies that assess the impact of group practices on patient care, satisfaction and outcomes; physician quality of life, satisfaction and income and healthcare systems. Titles and abstracts will be screened by two members and the abstraction results charted and verified. Qualitative and quantitative analyses will be performed to identify key themes. ETHICS AND DISSEMINATION: Research ethics board approval is not required for this scoping review. A consultation phase will be used to discuss the results with key stakeholders followed by dissemination at local and national levels. We will also publish the results in a peer-reviewed journal. PMID- 30244211 TI - Impact of fatigue and insufficient sleep on physician and patient outcomes: a systematic review. AB - OBJECTIVES: For physicians in independent practice, we synthesised evidence on the (1) impacts of insufficient sleep and fatigue on health and performance, and patient safety and (2) effectiveness of interventions targeting insufficient sleep and fatigue. DESIGN: We systematically reviewed online literature. After piloting, one reviewer selected studies by title and abstract; full texts were then reviewed in duplicate. One reviewer extracted data; another verified a random 10% sample. Two reviewers assessed risk of bias. We pooled findings via meta-analysis when appropriate or narratively. DATA SOURCES: We searched Medline, Embase, PsycINFO, CINAHL and PubMed for published studies in April 2016; Medline was updated in November 2017. We searched Embase for conference proceedings, and hand-searched meeting abstracts, association and foundation websites. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: English or French language primary research studies published from 2000 to 2017 examining the effect of fatigue-related or sleep-related exposures or interventions on any outcome among physicians in independent practice and their patients. RESULTS: Of 16 154 records identified, we included 47 quantitative studies of variable quality. 28 studies showed associations between fatigue or insufficient sleep and physician health and well being outcomes. 21 studies showed no association with surgical performance, and mixed findings for psychomotor performance, work performance and medical errors. We pooled data from six cohort studies for patient outcomes. For sleep deprived versus non-sleep deprived surgeons, we found no difference in patient mortality (n=60 436, relative risk (RR) 0.98, 95% CI 0.84 to 1.15, I2=0% (p=0.87)) nor postoperative complications (n=60 201, RR 0.99, 95% CI 0.95 to 1.03, I2=0% (p=0.45)). The findings for intraoperative complications and length of stay were considerably heterogeneous. CONCLUSIONS: Fatigue and insufficient sleep may be associated with negative physician health outcomes. Current evidence is inadequate to inform practice recommendations. PMID- 30244213 TI - Increased risk of aortic aneurysm and dissection in patients with Sjogren's syndrome: a nationwide population-based cohort study in Taiwan. AB - OBJECTIVES: Sjogren's syndrome (SS) is a systemic autoimmune disorder. Several molecular pathways and the activation of matrix metalloproteinases associated with the pathogenesis of SS participate in the initiation and progression of aortic aneurysm (AA) and aortic dissection (AD). In this study, we aimed to evaluate whether patients with SS exhibit an increased risk of AA or AD. METHODS: We conducted a retrospective cohort study using a database extracted from Taiwan's National Health Insurance Research Database. All medical conditions for each case and control were categorised using the International Classification of Diseases, Ninth Revision. HRs and 95% CIs for associations between SS and AA/AD were estimated using Cox regression and adjusted for comorbidities. RESULTS: Our analyses included 10 941 SS cases and 43 764 propensity score-matched controls. Compared with the controls, the patients with SS exhibited a significantly increased risk of developing an AA or AD (adjusted HR=3.642, p<0.001). Subgroup analysis revealed that compared with patients without SS, patients with primary and secondary SS both exhibited a significantly increased risk of developing AA or AD (adjusted HR=1.753, p=0.042; adjusted HR=3.693, p<0.001). CONCLUSION: Patients with SS exhibit increased risks of developing AA or AD, and healthcare professionals should be aware of this risk when treating patients with SS. Increased aortic surveillance may be required for patients with SS. PMID- 30244214 TI - Multicentred randomised controlled trial of an augmented exercise referral scheme using web-based behavioural support in individuals with metabolic, musculoskeletal and mental health conditions: protocol for the e-coachER trial. AB - INTRODUCTION: Physical activity is recommended for improving health among people with common chronic conditions such as obesity, diabetes, hypertension, osteoarthritis and low mood. One approach to promote physical activity is via primary care exercise referral schemes (ERS). However, there is limited support for the effectiveness of ERS for increasing long-term physical activity and additional interventions are needed to help patients overcome barriers to ERS uptake and adherence.This study aims to determine whether augmenting usual ERS with web-based behavioural support, based on the LifeGuide platform, will increase long-term physical activity for patients with chronic physical and mental health conditions, and is cost-effective. METHODS AND ANALYSIS: A multicentre parallel two-group randomised controlled trial with 1:1 individual allocation to usual ERS alone (control) or usual ERS plus web-based behavioural support (intervention) with parallel economic and mixed methods process evaluations. Participants are low active adults with obesity, diabetes, hypertension, osteoarthritis or a history of depression, referred to an ERS from primary care in the UK.The primary outcome measure is the number of minutes of moderate-to-vigorous physical activity (MVPA) in >=10 min bouts measured by accelerometer over 1 week at 12 months.We plan to recruit 413 participants, with 88% power at a two-sided alpha of 5%, assuming 20% attrition, to demonstrate a between-group difference of 36-39 min of MVPA per week at 12 months. An improvement of this magnitude represents an important change in physical activity, particularly for inactive participants with chronic conditions. ETHICS AND DISSEMINATION: Approved by North West Preston NHS Research Ethics Committee (15/NW/0347). Dissemination will include publication of findings for the stated outcomes, parallel process evaluation and economic evaluation in peer-reviewed journals.Results will be disseminated to ERS services, primary healthcare providers and trial participants. TRIAL REGISTRATION NUMBER: ISRCTN15644451; Pre results. PMID- 30244215 TI - Hepatitis B virus contact disclosure and testing in Lusaka, Zambia: a mixed methods study. AB - OBJECTIVES: The aim of this study was to estimate the frequency of disclosure to and testing of contacts of patients with hepatitis B virus (HBV) in Zambia. DESIGN: We used a convergent parallel mixed-method research design including a quantitative survey and focus group discussions with patients with HBV. SETTING: A university hospital in Lusaka, Zambia. PARTICIPANTS: 79 hepatitis B surface antigen (HBsAg)-positive, HIV-negative, adults (18+ years) receiving HBV care completed a quantitative survey and 32 also participated in a focus group discussion. OUTCOMES AND ANALYSIS: Contacts of patients with HBV were enumerated and patient-reported disclosure, contact testing and contact HBV test results were used to develop a testing cascade. Using multivariable logistic regression, we identified factors associated with disclosure of HBV status. In focus groups, we explored how index patient knowledge and awareness of their condition shaped perspectives on contact disclosure and testing. Focus groups coding and analysis followed a thematic analysis approach. RESULTS: Among 79 patients with HBV (median age 35 years; 26.6% women), the majority reported disclosure to >=1 contact. According to the index patients' knowledge, of 776 contacts enumerated, 326 (42.1%) were disclosed to, 77 (9.9%) were tested, 67 (8.6%) received results and 8 (11.9%) were HBsAg-positive. Increased stigma score was associated with reduced disclosure. In focus groups, HBV awareness, knowledge and stigma emerged as barriers to disclosure and referral of contacts for testing. Association of HBV with HIV-related stigma was also reported as a strong barrier to contact disclosure and testing and to taking antivirals for HBV monoinfection. CONCLUSIONS: HBV contact disclosure and testing were feasible and yielded new diagnoses in Zambia. A better understanding of barriers to seeking HBV testing and treatment is needed to scale-up this important intervention in Africa. TRIALS REGISTRATION NUMBER: NCT03158818. PMID- 30244216 TI - Education, sex and risk of stroke: a prospective cohort study in New South Wales, Australia. AB - OBJECTIVE: To determine whether the association between highest educational attainment and stroke differed by sex and age; and whether potential mediators of observed associations differ by sex. DESIGN: Prospective cohort study. SETTING: Population based, New South Wales, Australia. PARTICIPANTS: 253 657 stroke-free participants from the New South Wales 45 and Up Study. OUTCOME MEASURES: First ever stroke events, identified through linkage to hospital and mortality records. RESULTS: During mean follow-up of 4.7 years, 2031 and 1528 strokes occurred among men and women, respectively. Age-standardised stroke rate was inversely associated with education level, with the absolute risk difference between the lowest and highest education group greater among women than men. In relative terms, stroke risk was slightly more pronounced in women than men when comparing low versus high education (age-adjusted HRs: 1.41, 95% CI 1.16 to 1.71 and 1.25, 95% CI 1.07 to 1.46, respectively), but there was no clear evidence of statistical interaction. This association persisted into older age, but attenuated. Much of the increased stroke risk was explained by modifiable lifestyle factors, in both men and women. CONCLUSION: Low education is associated with increased stroke risk in men and women, and may be marginally steeper in women than men. This disadvantage attenuates but persists into older age, particularly for women. Modifiable risk factors account for much of the excess risk from low education level. Public health policy and governmental decision making should reflect the importance of education, for both men and women, for positive health throughout the life course. PMID- 30244218 TI - Corrections: Impact of patient characteristics on the Canadian Patient Experiences Survey-Inpatient Care: survey analysis from an academic tertiary care centre. PMID- 30244217 TI - Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation. AB - INTRODUCTION: Observational studies indicate a potentially causal role for interleukin 6 (IL-6), a proinflammatory cytokine, in pathogenesis of depression, but interventional studies based on patients with depression have not been conducted. Tocilizumab, anti-inflammatory drug, is a humanised monoclonal antibody that inhibits IL-6 signalling and is licensed in the UK for treatment of rheumatoid arthritis. The main objectives of this study are to test whether IL-6 contributes to the pathogenesis of depression and to examine potential mechanisms by which IL-6 affects mood and cognition. A secondary objective is to compare depressed participants with and without evidence of low-grade systemic inflammation. METHODS AND ANALYSIS: This is a proof-of-concept, randomised, parallel-group, double-blind, placebo-controlled clinical trial. Approximately 50 participants with International Classification of Diseases 10th revision (ICD-10) diagnosis of depression who have evidence of low-grade inflammation, defined as serum high-sensitivity C reactive protein (hs-CRP) level >=3 mg/L, will receive either a single intravenous infusion of tocilizumab or normal saline. Blood samples, behavioural and cognitive measures will be collected at baseline and after infusion around day 7, 14 and 28. The primary outcome is somatic symptoms score around day 14 postinfusion. In addition, approximately, 50 depressed participants without low-grade inflammation (serum hs-CRP level <3 mg/L) will complete the same baseline assessments as the randomised cohort. ETHICS AND DISSEMINATION: The study has been approved by the South Central-Oxford B Research Ethics Committee (REC) (Reference: 18/SC/0118). Study findings will be published in peer-review journals. Findings will be also disseminated by conference/departmental presentations and by social and traditional media. TRIAL REGISTRATION NUMBER: ISRCTN16942542; Pre-results. PMID- 30244219 TI - Medicaid work requirements: a really bad idea for increasing employment. PMID- 30244220 TI - Case of colonic mucosal Schwann cell hamartoma and review of literature on unusual colonic polyps. AB - Mucosal Schwann cell hamartomas (MSCH) are benign mesenchymal tumours rarely seen in the gastrointestinal tract. They occasionally present as incidental sessile polyps during colonoscopy. A 55-year-old asymptomatic female patient with a medical history of multiple sclerosis presented for a screening colonoscopy. A 5 mm low-risk tubular adenoma was noted in the caecum, and a second 5 mm polyp was found in the ascending colon. Histopathology of the ascending colon polyp showed proliferation of spindle cells without ganglion cells in the lamina propria. Immunohistochemical findings are compatible with an MSCH. Surveillance colonoscopy was scheduled in 5 years based on the presence of a single low-risk tubular adenoma. PMID- 30244221 TI - Intrahepatic sarcomatoid cholangiocarcinoma. AB - Sarcomatoid carcinoma is a rare tumour composed of intermingled malignant epithelial and mesenchymal cells, and it has been reported in various organs including the liver. Sarcomatoid cholangiocarcinoma (CCC) is an extremely rare liver primary tumour. Here, we report a case of an elderly man who was admitted to our hospital after head trauma. He performed a head CT that diagnosed cerebral metastasis. On abdominal CT, he presented a 10*8*9 cm-sized hypodense liver mass in the VII and VIII segments, with peripheral enhancement. Histological and immunohistochemical examination of the tumour showed a malignant neoplasm with both carcinomatous and sarcomatous components and positive expression of cytokeratin and vimentin antibodies. The patient was diagnosed with intrahepatic sarcomatoid CCC at an advanced stage and died 45 days after the diagnosis. We emphasise the importance of immunohistochemistry which may provide a clue to proper diagnosis. PMID- 30244222 TI - Primary renal angiosarcoma: a diagnostic and therapeutic challenge. AB - Primary renal angiosarcoma is an exceedingly rare and aggressive neoplasm. Although it may occur in youth, this tumour is frequently reported in the sixth and seventh decades of life. The clinical presentation is frequently varied. Pathogenesis remains largely unknown and it has overlapping features with other tumours of the kidney. Current treatment options include variable combinations of surgery, chemotherapy and radiotherapy. Reports regarding the disease prognosis and natural history are limited. In this article, we chronicle the case of a patient with primary renal angiosarcoma presenting at an advanced stage as a widely metastasised tumour. Additionally, we undertake here a brief literature review highlighting the rarity and aggressiveness of this condition, its poor prognosis, and the lack of specific management guidelines. PMID- 30244223 TI - Intestinal obstruction with a twist: a rare case of congenital portal vein aneurysm causing intestinal obstruction. AB - Bilious vomiting is often a presenting feature of upper intestinal obstruction in newborn. We present a case of intestinal obstruction in a newborn baby caused by abnormal vascular band arising from portal vein aneurysm in association with a midgut volvulus. Congenital anomalies of portovenous system are very rare, and it usually presents with portal hypertension in late infancy or childhood. In this particular child, the portal vein aneurysm contributed to intestinal obstruction due to both a failure of intestinal rotation and a mechanical band over the transverse colon. PMID- 30244224 TI - Significant cephalad lead migration with use of externally powered spinal cord stimulator. AB - Spinal cord stimulation has been an effective therapy for treatment of chronic low back pain over the last four decades. Over the years, there have been significant technological advances in the neuromodulation devices. Externally powered neuromodulation devices, that do not require an internal pulse generator (IPG) implantation, have recently been approved for treatment of chronic pain and the data on potential pitfalls and unforeseen complications with these devices is minimal. Here, we report a case of a 60-year-old woman with chronic back pain who underwent the implantation of one of such devices and developed complication that required neurosurgical intervention. The epidural stimulator leads in the patient migrated cranially to the T2 level that required extensive neurosurgical exploration. We believe this is the first reported case of such significant cranial epidural lead migration with the use of neurostimulation devices and demands more research into the safety of externally powered neurostimulation devices. PMID- 30244226 TI - Naclerio's V sign and continuous diaphragm sign after endoscopy. PMID- 30244225 TI - Rare case of Propionibacterium acnes-related splenic abscess. AB - A 64-year-old woman with a medical history of morbid obesity, chronic hepatitis C, essential hypertension, multiple episodes of abdominal cellulitis, diabetes mellitus type 2 on insulin, intravenous and subcutaneous drug abuse presented to the emergency department complaining of left lower chest pain for 6 weeks along with multiple episodes of vomiting. Initial laboratory data revealed leucocytosis of 17 200*103/MUL with left shift. She reported multiple episodes of fever spikes. Abdominal and pelvic CT showed a splenic hypodense lesion. Specimens from interventional radiology aspiration and splenectomy grew Propionibacterium acnes Following splenectomy, patient's symptoms resolved. To the best of our knowledge, this would represent the fifth reported case of P. acnes splenic abscess. PMID- 30244227 TI - Hypertrophic pyloric stenosis following repair of oesophageal atresia and tracheo oesophageal fistula in a neonate. AB - Development of hypertrophic pyloric stenosis (HPS) after a few weeks of repair of an oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) is a rare condition in early infancy. Although vomiting or feeding intolerance in operated cases of OA+TOF are attributed to oesophageal stricture, gastro-oesophageal reflux and oesophageal dysmotility, it may also be caused by HPS. Herein, we report a newborn infant who had OA and TOF operation on day 2 of life and diagnosed to have HPS at 15th day of age. Even though it is a rare anomaly, HPS should be kept on mind in the presence of persistent vomiting following repair of OA. PMID- 30244228 TI - Haemorrhagic cholecystitis: a rare entity not to be forgotten. AB - Haemorrhagic cholecystitis is a rare entity of acute cholecystitis that carries a high morbidity and mortality rate if management is delayed. Its clinical course can mirror that of acute cholecystitis. Characteristic findings on ultrasound or CT scan are useful clues to early diagnosis. Urgent cholecystectomy is required prior to progressing to perforation of gallbladder. Most of the literature are case reports with causes associated with anticoagulation. Herein, we described a morbidly obese patient with poorly controlled diabetes presenting with non specific right upper quadrant pain and was subsequently diagnosed with haemorrhagic cholecystitis. A review of the literature was also performed to summarise the potential clinical presentations, distinctive imaging findings and management options available for this rare condition. PMID- 30244229 TI - Alpha-2 antiplasmin-associated aortic valve thrombus presenting as a STEMI in a patient with Graves disease. PMID- 30244230 TI - Pneumomediastinum: a complication of reinserting a dislodged tracheostomy. PMID- 30244231 TI - LED for hyperspectral imaging - a new selection method. AB - Hyperspectral imaging (HSI) has become a sophisticated technique in modern applications such as food analyses, recycling technology, medicine, pharmacy and forensic science. It allows one to analyse both spatial and spectral information from an object. But hyperspectral cameras are still expensive due to their extended wavelength range. The development of new light-emitting diodes (LED) in the recent past enables another approach to HSI using a monochrome camera in combination with a LED-based illumination. However, such a system has a lower spectral resolution. Additionally, the growing supply of LED on the market complicates the selection of LED. In this paper, we propose a new time efficient selection method for the design process of an illumination. It chooses an optimised LED combination from an existing database to match a predefined spectral power distribution. Therefore, an algorithm is used to evaluate various LED combinations. Furthermore, the method considers the spectral behaviour of each LED in dependence of forward current and temperature of the solder point. Our method has already shown promise during the selection process for even spectral distributions which is demonstrated in the study. Additionally, we will show its potential for HSI illuminations. PMID- 30244232 TI - Values and stability of serum (or plasma) indices in uncentrifuged serum and lithium-heparin plasma. PMID- 30244233 TI - Glucose intolerance in children with cystic fibrosis: a developing country's perspective. AB - Background Cystic fibrosis-related diabetes (CFRD) is a common comorbidity reported in patients with cystic fibrosis (CF). There is a dearth of data on glucose intolerance or CFRD in children with CF from developing countries. So, we planned to study the prevalence of abnormal glucose tolerance (AGT) in children with CF and its relation with the duration and severity of CF. Methods We performed an oral glucose tolerance test (OGTT) on children (2-18 years old) having CF for at least 6 months. Two-hour plasma glucose levels on OGTT were correlated with various disease-related factors. Results Out of the 25 children enrolled, there were 18 boys and seven girls. The mean age and duration of CF were 7.9+/-4.3 and 3.16+/-2.5 years, respectively. AGT was observed in 16 (64%) children with CF including three (12%) children with CFRD. Children with a duration of CF of 3 years had significantly higher prevalence (81.8%) of AGT when compared with duration <=3 years (p-value<0.05). Twelve out of 17 (70.6%) children were colonized with Pseudomonas and 12 out of 15 (80%) children >6 years of age had AGT. There was a positive correlation of 2-h glucose value on OGTT with duration of CF and number of hospitalizations with acute pulmonary exacerbations. Conclusions The majority of children having CF for >3 years and/or age >6 years developed AGT. In our clinical setting, an annual screening with OGTT to detect AGT may be required at an early age and duration of CF. PMID- 30244234 TI - Locoregional disease control after external beam radiotherapy in 91 patients with differentiated thyroid carcinoma and pT4 tumor stage - a single institution experience. AB - Background Locoregional recurrence is common in patients with locally advanced differentiated thyroid carcinoma (DTC). Our aim was to find out the rate of locoregional control of the disease after external beam radiotherapy (EBRT) of the neck and mediastinum in patients with DTC and pT4 tumor. Patients and methods Altogether 91 patients (47 males, 44 females, median age 61 years) with DTC had EBRT of the neck and mediastinum as part of the multimodal treatment of pT4 tumor (63 cases pT4a, 28 cases pT4b) from the year 1973 to 2015. Data on clinical factors, histopathology and recurrence were collected. Disease-free, disease specific and overall survival was calculated. Results Median tumor size was 5 cm (range 1-30 cm). Out of 91 patients, 23 had distant and 38 regional metastases. A total or near-total thyroidectomy, lobectomy, subtotal thyroidectomy and lymph node dissection was performed in 70%, 14%, 2% and 30% of cases, respectively. Thirteen percent of patients were not treated with surgery. All patients had EBRT and 39 had chemotherapy. Radioiodine (RAI) ablation of thyroid remnant and RAI therapy was applied in 90% and 40% of cases, respectively. Recurrence was diagnosed in 29/64 patients without a persistent disease: locoregional and distant in 16 and 13 cases, respectively. Five-year and ten-year disease-free survival rate was 64% and 48%, respectively. Conclusions The majority of patients with DTC and pT4 tumors who were treated with EBRT of the neck and mediastinum region as part of multimodal treatment have long-lasting locoregional control of the disease. PMID- 30244235 TI - A possible key role of vision in the development of schizophrenia. AB - Based on a brief overview of the various aspects of schizophrenia reported by numerous studies, here we hypothesize that schizophrenia may originate (and in part be performed) from visual areas. In other words, it seems that a normal visual system or at least an evanescent visual perception may be an essential prerequisite for the development of schizophrenia as well as of various types of hallucinations. Our study focuses on auditory and visual hallucinations, as they are the most prominent features of schizophrenic hallucinations (and also the most studied types of hallucinations). Here, we evaluate the possible key role of the visual system in the development of schizophrenia. PMID- 30244236 TI - Pecha Kucha presentations by medical students in Spain. PMID- 30244237 TI - The relationship between empathy and emotional intelligence among Iranian nursing students. AB - Objectives: To determine the relationship between empathy and emotional intelligence among Iranian nursing students. Methods: This is a cross-sectional, descriptive-correlational study that was conducted on three hundred and twenty eligible students, selected using stratified random sampling. Participants were mainly nursing students at Tehran University of Medical Sciences. Data gathering was done using The Jefferson Scale of Empathy and The Schutte Self Report Emotional Intelligence Test. Data were analyzed using SPSS. Results: The results showed a strong positive correlation between empathy and emotional intelligence (r=0.499, p <.001). Students in their fourth year had the highest score for empathy (M=109.16, SD=10.16), while first-year students had the highest scores for emotional intelligence (M= 151.68, SD= 17.47). Female students got higher empathy scores than male students (t(318)= 2.524, p= .012). Age had a strong inverse correlation with emotional intelligence (r= 0.143, p= .010). Conclusions: The results of this study show a correlation between emotional intelligence and empathy among nursing students. Nurses with higher emotional intelligence tend to be better in establishing productive relationships with patients and their families, and if nurses possess empathetic skills, they manage their emotions more effectively. In addition to imparting knowledge and clinical experience, nursing curricula should provide students with opportunities to develop their communication and emotional skills. PMID- 30244238 TI - The Arteriovenous Loop: Engineering of Axially Vascularized Tissue. AB - BACKGROUND: Most of the current treatment options for large-scale tissue defects represent a serious burden for the patients, are often not satisfying, and can be associated with significant side effects. Although major achievements have already been made in the field of tissue engineering, the clinical translation in case of extensive tissue defects is only in its early stages. The main challenge and reason for the failure of most tissue engineering approaches is the missing vascularization within large-scale transplants. SUMMARY: The arteriovenous (AV) loop model is an in vivo tissue engineering strategy for generating axially vascularized tissues using the own body as a bioreactor. A superficial artery and vein are anastomosed to create an AV loop. This AV loop is placed into an implantation chamber for prevascularization of the chamber inside, e.g., a scaffold, cells, and growth factors. Subsequently, the generated tissue can be transplanted with its vascular axis into the defect site and anastomosed to the local vasculature. Since the blood supply of the growing tissue is based on the AV loop, it will be immediately perfused with blood in the recipient site leading to optimal healing conditions even in the case of poorly vascularized defects. Using this tissue engineering approach, a multitude of different axially vascularized tissues could be generated, such as bone, skeletal or heart muscle, or lymphatic tissues. Upscaling from the small animal AV loop model into a preclinical large animal model could pave the way for the first successful attempt in clinical application. Key Messages: The AV loop model is a powerful tool for the generation of different axially vascularized replacement tissues. Due to minimal donor site morbidity and the possibility to generate patient specific tissues variable in type and size, this in vivo tissue engineering approach can be considered as a promising alternative therapy to current treatment options of large-scale defects. PMID- 30244239 TI - Utility of Rapid On-Site Cytologic Evaluation during Endobronchial Ultrasound Guided Transbronchial Needle Aspiration in Malignant and Nonmalignant Disease. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an accurate procedure to sample mediastinal tissue. Rapid on-site cytologic evaluation (ROSE) has been advocated to improve the performance of this procedure, but its benefit remains controversial. Our objective is to assess the utility of ROSE for EBUS-TBNA diagnostic accuracy among unselected patients. METHODS: We prospectively collected data from all consecutive EBUS-TBNA procedures performed between 2008 and 2014. ROSE was introduced since 2011 in our daily practice. The accuracy of EBUS-TBNA with and without ROSE was compared in a univariate and multivariate model accounting for confounding factors. The impact of ROSE was then analyzed according to the etiology and size of the lesions. RESULTS: Among 348 EBUS-TBNA procedures analyzed, 213 were performed with ROSE. The overall accuracy tended to be better with ROSE than without (90.6 vs. 84.4%; p = 0.082). After adjustment in a multivariate model, the benefit of ROSE still did not reach statistical significance (adjusted odds ratio 1.86; 95% confidence interval 0.79-4.41). Similar results were obtained in subgroups of patients with malignant disease or sarcoidosis. The size of the lesion did not influence the impact of ROSE on accuracy. CONCLUSIONS: ROSE was associated with a moderate increase in the accuracy of EBUS-TBNA, but the difference was not statistically significant. The same effect of ROSE was observed in malignant and nonmalignant lesions and this effect was not influenced by the lesion's size. PMID- 30244240 TI - Common Rodent Flap Models in Experimental Surgery. AB - BACKGROUND: Flap procedures are widely used in clinical reconstructive surgery. Since ische-mia-associated complications, e.g., wound breakdown or tissue necrosis, are still a great challenge in flap surgery, experimental flap models are widely used to study flap physiology and to evaluate treatment strategies to prevent these complications. SUMMARY: Since rodents in general, and mice and rats in particular, are widely used in experimental flap models, we give an overview of the most common flap models in rodents, including the cremaster flap, the osteomyocutaneous flap, the McFarlane flap, the ear flap, and the dorsal skinfold chamber. Key Messages: Rodent flap models in experimental surgery are manifold and have a long history. These models play an important role in training surgical techniques, understanding flap physiology, defining flap anatomy and vascularity, and developing treatment regimens to prevent the necrosis of ischemically challenged tissue. However, it is important to be aware of the advantages and disadvantages of the single flap models concerning the possible time span of the experiment, the degree of difficulty, and the reproducibility and the translation of the results in humans. PMID- 30244241 TI - Glandular Cell Abnormalities on SurePath Preparations: A Retrospective Review with Cytology-Histology Correlations. AB - OBJECTIVE: Detecting glandular lesions is challenging by all Pap test methodologies. As the availability of data on identifying glandular abnormalities by SurePath is scarce, we investigated the detection rates and the correlation with histology follow-up. STUDY DESIGN: A total of 105,927 cases (SurePath and conventional) were searched for the diagnosis of atypical glandular cells or higher glandular abnormalities (AGC+) with the corresponding histologic diagnosis. The associations between the Pap test methods and diagnostic categories were assessed by chi2 test. RESULTS: Overall, 0.32% of SurePath (159/49,375) and 0.29% of conventional (164/56,552) cases showed AGC+ (p = 0.38). Histology confirmed significant abnormalities in 42 versus 53.5% of the cases, respectively (p = 0.064); 72.7% (SurePath) versus 65.2% (conventional) of these were glandular in nature (p = 0.37). The diagnosis of neoplasia (favored or definitive) showed malignancy on follow-up in 100% of SurePath cases (12/12). In contrast, 82.1% of these conventional cases disclosed premalignant or malignant lesions by histology (p = 0.12). CONCLUSIONS: AGC+ cases showed higher prevalence on SurePath preparations. Conventional cases had more abnormalities on follow-up, while glandular lesions represented a higher proportion of abnormal histologies following SurePath AGC+s. The positive predictive value of favored or definite neoplasia was higher in SurePath cases. Overall, these differences were not statistically significant. PMID- 30244242 TI - Allergen Immunization Induces Major Changes in Microbiota Composition and Short Chain Fatty Acid Production in Different Gut Segments in a Mouse Model of Lupine Food Allergy. AB - BACKGROUND: The incidence of food allergies in western countries has increased in recent decades. OBJECTIVES: To study the association between gut bacterial microbiota composition, short-chain fatty acids (SCFAs) and food allergy in a mouse model. METHODS: After oral immunizations with the human food allergen lupine with the adjuvant cholera toxin (CT) (or buffer in controls), sensitization and anaphylactic responses were determined. Gastrointestinal content was collected from the distal ileum, cecum, colon, and fecal pellets, and the bacterial diversity and composition was determined by deep sequencing of the 16S rRNA gene. SCFAs in gastrointestinal content supernatants were determined by gas chromatography. RESULTS: The microbiota signatures were profoundly affected by allergen immunization. Ten operational taxonomic units (OTUs) were significantly different between immunized and control animals for at least one of the intestinal segments; eight of these OTUs belonged to the Clostridia class. Although consistent across all four gut segments, the colon showed the highest number of OTUs significantly associated with allergic immunization. SCFA levels in the cecum were also altered by immunization. CONCLUSIONS: Allergen immunization with CT in the present food allergy model induced profound changes in the microbiome composition and SCFA production. The result suggests that the colon may be the most sensitive gut segment for investigating changes in the gut microbiome. PMID- 30244243 TI - Vascularization, Regeneration and Tissue Engineering. PMID- 30244244 TI - Ligustrazine Inhibits Growth, Migration and Invasion of Medulloblastoma Daoy Cells by Up-Regulation of miR-211. AB - BACKGROUND/AIMS: Ligustrazine (LSZ) has been identified as an antitumor agent against some types of cancers. Nevertheless, its ability to inhibit growth, migration and invasion of medulloblastoma cells is still unclear. This study aimed to explore the effect of LSZ on Daoy cells. METHODS: The effects of LSZ on viability, proliferation, apoptosis, migration, and invasion of Daoy cells were analyzed by CCK-8, BrdU, flow cytometry and Transwell assays, respectively. The effect of LSZ on miR-211 expression was analyzed by qRT-PCR. miR-211 inhibitor transfection was performed to suppress miR-211 expression. The effects of LSZ on apoptosis-related factors, MMP-2, MMP-9, and Vimentin (Vim), as well as main factors of PI3K/AKT and mTOR pathways were analyzed by Western blot. RESULTS: LSZ inhibited viability but promoted apoptosis of Daoy cells. Additionally, the proliferative, migratory and invasive abilities of Daoy cells were decreased by LSZ. Meanwhile, LSZ promoted the activations of Caspase-3 and Caspase-9, increased Bax level, decreased Bcl-2 level, as well as inhibited the expressions of MMP-2, MMP-9 and Vim. Additionally, we found that LSZ enhanced miR-211 expression and exerted its anti-medulloblastoma effect by up-regulation of miR 211. Furthermore, LSZ inhibited PI3K/AKT and mTOR signaling pathways by up regulating miR-211. CONCLUSION: LSZ suppressed medulloblastoma Daoy cells by up regulating miR-211 and further modulating the activations of PI3K/AKT and mTOR signaling pathways. PMID- 30244245 TI - Platelet-Rich Plasma in Tissue Engineering: Hype and Hope. AB - BACKGROUND: Platelet-rich plasma (PRP) refers to an enriched platelet suspension in plasma. In addition to the clinical application of PRP in the context of various orthopedic diseases and beyond, PRP and platelet lysate (PL) have been in focus in the field of tissue engineering. In this review, we discuss the application of PRP as a cell culture supplement and as part of tissue engineering strategies, particularly emphasizing current hurdles and ambiguities regarding the efficacy of PRP in these approaches. SUMMARY: As a putative autologous replacement for animal-derived supplements such as fetal calf serum (FCS), PRP has been applied as cell culture supplement for the expansion of stem and progenitor cells for tissue engineering applications and cell therapies. Attributed to the high content of growth factors in platelets, PRP has been shown to promote cell growth, which was mostly superior to standard cultures supplemented with FCS, while the differentiation capacity of progenitor cells seems not to be affected. However, it was also suggested that cultivation of cells with PRP significantly alters the protein expression profile in cells in comparison to FCS, indicating that the influence of PRP on cell behavior should be thoroughly investigated. Moreover, different PRP preparation methods and donor variations have to be considered for the use of PRP under good manufacturing practice conditions. PRP has been used for various tissue engineering applications in the context of bone, cartilage, skin, and soft tissue repair, where most studies were conducted in the field of bone tissue engineering. These approaches take either advantage of the release of chemoattractive, angiogenic, proliferative, and putatively pro-regenerative growth factors from PRP, and/or the hydrogel properties of activated PRP, making it suitable as a cell delivery vehicle. In many of these studies, PRP is combined with biomaterials, cells, and in some cases recombinant growth factors. Although the experimental design often does not allow conclusions on the pro-regenerative effect of PRP itself, most publications report beneficial effects if PRP is added to the tissue-engineered construct. Furthermore, it was demonstrated that the release of growth factors from PRP may be tailored and controlled when PRP is combined with materials able to capture growth factors. Key Messages: Platelet-derived preparations such as PRP and PL represent a promising source of autologous growth factors, which may be applied as cell culture supplement or to promote regeneration in tissue engineered constructs. Furthermore, activated PRP is a promising candidate as an autologous cell carrier. However, the studies investigating PRP in these contexts often show conflicting results, which most likely can be attributed to the lack of standardized preparation methods, particularly with regard to the platelet content and donor variation of PRP. Ultimately, the use of PRP has to be tailored for the individual application. PMID- 30244246 TI - Role of miR-148a in Mitigating Hepatic Ischemia-Reperfusion Injury by Repressing the TLR4 Signaling Pathway via Targeting CaMKIIalpha in Vivo and in Vitro. AB - BACKGROUND/AIMS: Hepatic ischemia-reperfusion (I/R) injury, which is mainly induced by inflammation and unstable intracellular ions, is a major negative consequence of surgery that compromises hepatic function. However, the exact mechanisms of liver I/R injury have not been determined. Positive crosstalk with the Ca2+/CaMKII pathway is required for complete activation of the TLR4 pathway and inflammation. We previously found that miR-148a, which decreased in abundance with increasing reperfusion time, targeted and repressed the expression of CaMKIIalpha. In the present study, we examined the role of the miR-148a machinery in I/R-induced Ca2+/CaMKII and TLR4 signaling changes, inflammation, and liver dysfunction in vivo and in vitro. METHODS: Liver function was evaluated by serum aminotransferase levels and hematoxylin-eosin (HE) staining. Inflammatory factors were detected by enzyme-linked immunosorbent assay. Gene and protein expression were assessed by RT-PCR and western blot. Small interfering RNA was used to silence target gene expression. HE staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling were used to measure hepatic tissue apoptosis. These assays were performed to identify factors upregulated in hepatic I/R injury and downregulated by miR-148a. RESULTS: We manifested that expression of CaMKIIalpha and phosphorylation of TAK1 and IRF3 were elevated in hypoxia/reoxygenation (H/R)-treated primary Kupffer cells (KCs) and liver tissue of I/R-treated mice, but these effects were attenuated by treatment with miR-148a mimic and were accompanied by the alleviation of liver dysfunction and hepatocellular apoptosis. Luciferase reporter experiments showed that miR148a suppressed luciferase activity by almost 60%. Moreover, knockdown of CaMKIIalpha in H/R KCs led to significant deficiencies in p-TAK1, P-IRF3, IL-6, and TNF alpha, which was consistent with the effects of miR-148a overexpression. Otherwise, the same trend of activation of TAK1 and IRF3 and inflammatory factors in vitro was observed in the siTAK1 + siIRF3 group compared with the siCaMKIIalpha group. CONCLUSION: Taken together, we conclude that miR-148a may mitigate hepatic I/R injury by ameliorating TLR4-mediated inflammation via targeting CaMKIIalpha in vitro and in vivo. PMID- 30244247 TI - Smad Ubiquitination Regulatory Factor 1 (Smurf1) Promotes Thyroid Cancer Cell Proliferation and Migration via Ubiquitin-Dependent Degradation of Kisspeptin-1. AB - BACKGROUND/AIMS: Thyroid cancer is the most common malignancy in human endocrine system. Smad ubiquitination regulatory factor 1 (Smurf1) is an E3 ubiquitin protein ligase in ubiquitin-proteasome pathway (UPP) system. This study aimed to investigate the effects of Smurf1 on thyroid cancer proliferation and metastasis, as well as underlying potential mechanism. METHODS: The expression levels of Smurf1 in thyroid tumor tissues and thyroid cancer cells were detected by western blotting and qRT-PCR. Then, the effects of up-regulation or down-regulation of Smurf1 on thyroid cancer cell viability, migration, invasion, proliferation and apoptosis were measured using trypan blue exclusion assay, two-chamber migration (invasion) assay, cell colony formation assay and Guava Nexin assay, respectively. The ubiquitination of kisspeptin-1 (KISS-1) was assessed by protein ubiquitination assay. Finally, the effects of KISS-1 overexpression on activity of nuclear factor-kappa B (NF-kappaB) signaling pathway, as well as thyroid cancer cell viability, migration, invasion, proliferation and apoptosis were also detected, respectively. RESULTS: Smurf1 was highly expressed in thyroid tumor tissues and thyroid cancer cells. Up-regulation of Smurf1 promoted the viability, migration, invasion and proliferation of thyroid cancer cells. Knockdown of Smurf1 had opposite effects. Moreover, smurf1 promoted the ubiquitination of KISS 1. Overexpression of KISS-1 inactivated NF-kappaB pathway, suppressed thyroid cancer cell viability, migration, invasion and proliferation, and induced cell apoptosis. CONCLUSION: Up-regulation of Smurf1 exerted important roles in thyroid cancer formation and development by promoting thyroid cancer proliferation and metastasis. The ubiquitin-dependent degradation of KISS-1 induced by Smurf1 and the activation of NF-kappaB signaling pathway might be involved in this process. Smurf1 could be an effective therapy target and biomarker for thyroid cancer treatment. PMID- 30244248 TI - Efficacy of Dexamethasone Implants in Uveitic Macular Edema in Cases with Behcet Disease. AB - PURPOSE: Investigation of the efficacy of intravitreal dexamethasone implants (0.7 mg) in patients with Behcet disease (BD) who had cystoid macular edema (CME) despite immunomodulatory treatment. MATERIALS AND METHODS: Twenty-seven eyes of 20 patients who had intravitreal dexameth-asone implant injections and follow-up for more than 6 months were included in this study. Best corrected visual acuities (BCVA), intraocular pressures (IOP), and central macular thicknesses (CMT) were recorded. Systemic immunomodulatory treatment was noted. Injection related complications and the need for recurrent injections were recorded. RESULTS: Statistically significant anatomical and functional success was achieved with a single injection. BCVA increased from 0.85 +/- 0.72 to 0.45 +/- 0.52 logMAR, while the mean CMT decreased from 406 +/- 190 to 243 +/- 101 um at the sixth month. The peak of visual acuity gain was reached within the first 2 months and a substantial proportion of the patients gained 3 or more lines. There was no complication other than transient IOP elevation in 4 eyes and cataract surgery in 2 eyes. CONCLUSION: Adjuvant intravitreal dexamethasone implant injections offer promising results in cases of BD with CME. It is effective in preserving the macular anatomy and vision particularly in transition to biological agents. PMID- 30244249 TI - Parkin Modulates ERRalpha/eNOS Signaling Pathway in Endothelial Cells. AB - BACKGROUND/AIMS: Although a number of reports documented the important role of parkin in mitophagy, emerging evidence also indicated additional functions of parkin besides mitophagy. The present study was undertaken to investigate the role of parkin in the regulation of ERRalpha/eNOS pathway in endothelial cells (ECs). METHODS: Mouse aortic endothelial cells (MAECs) and cardiac muscle HL-1 cells were transfected with parkin plasmid or siRNA. ERRalpha inhibitor XCT-790, autophagy inhibitor 3-MA and Bafilomycin A1, and caspase inhibitor Z-VAD-FMK were used to block autophagy or apoptosis. Western blotting was performed to examine the protein levels. Flow cytometry was applied to determine the cell apoptosis and ROS production. Mitochondrial membrane potential was measured using JC-1 and TMRM. Immunoprecipitation was performed to confirm the parkin effect on ERRalpha ubiquitination. RESULTS: Overexpression of parkin resulted in a significant reduction of total-eNOS and p-eNOS in parallel with the downregulation of ERRalpha (a regulator of eNOS) protein and the enhancement of ERRalpha ubiquitination. To test the role of ERRalpha in regulating eNOS in this experimental setting, we treated ECs with ERRalpha inhibitor and found a decrement of total-eNOS and p-eNOS. On the contrary, overexpression of ERRalpha increased the levels of total-eNOS and p-eNOS. Meanwhile, parkin overexpression induced mitochondrial dysfunction and cell apoptosis in both ECs and HL-1 cells. Finally, we confirmed that the parkin effect on the regulation of eNOS was independent of the autophagy and apoptosis. CONCLUSION: These findings suggested that parkin overexpression downregulated eNOS possibly through the ubiquitination of ERRalpha in endothelial cells. PMID- 30244250 TI - Baicalein Inhibits Proliferation Activity of Human Colorectal Cancer Cells HCT116 Through Downregulation of Ezrin. AB - BACKGROUND/AIMS: The present study was aimed at examining Ezrin expression in human colorectal cancer (CRC) tissues and elucidating the influence of baicalein on the proliferation of HCT116 cells. METHODS: The expression of Ezrin was determined by qRT-PCR and immunohistochemistry. HCT116 cells were divided into four groups- baicalein groups with various concentrations, pcDNA3.1-Ezrin group, si-Ezrin group and dual inhibitory group (baicalein + si-Ezrin). CCK-8 assay and flow cytometry (FCM) were employed to assess cell proliferation and to detect the distribution of cell cycle respectively. The expression levels of Ezrin protein and cell cycle-associated proteins were detected by using western blot. The proliferation ability of CRC cells was also evaluated in vivo. RESULTS: Ezrin expression in CRC tissues was observably higher than that in adjacent colorectal tissues. With drug concentration and action time of baicalein increasing, the cell propagation capacity of HCT116 cells was decreased and the cell cycle progression was arrested. Ezrin expression was inhibited by the administration of baicalein in a dose-dependent way. The levels of CyclinD1 and CDK4 were also significantly decreased, but the expression of P53 pathway proteins P53 and P21 was markedly upregulated. CONCLUSION: Baicalein repressed proliferation of human colorectal cancer cells HCT116 and blocked cell cycle through downregulating Ezrin and upregulating P53 pathway-related proteins. PMID- 30244251 TI - Cell Sheet-Based Vascularized Myocardial Tissue Fabrication. AB - BACKGROUND: The development of regenerative medicine in recent years has been remarkable as tissue engineering technology and stem cell research have advanced. The ultimate goal of regenerative medicine is to fabricate human organs artificially. If fabricated organs can be transplanted medically, it will be the innovative treatment of diseases for which only donor organ transplantation is the definitive therapeutic method at present. SUMMARY: Our group has reported successful fabrication of thick functional myocardial tissue in vivo and in vitro by using cell sheet engineering technology which requires no scaffolds. Thick myocardial tissue can be fabricated by stacking cardiomyocyte sheets on the vascular bed every 24 h, so that a vascular network can be formed within the myocardial graft. We call this procedure a multi-step transplantation procedure. After human-induced pluripotent stem cells were discovered and human cardiomyocytes became available, a thick, macroscopically pulsate human myocardial tissue was successfully constructed by using a multi-step transplantation procedure. Furthermore, our group succeeded in fabricating functional human myocardial tissue which can generate pressure. Here, we present our way of fabricating human myocardial tissue by means of cell sheet engineering technology. Key Messages: Our group succeeded in fabricating thick, functional human myocardium which can generate pulse pressure. However, there are still a few problems to be solved until clinically functional human cardiac tissue or a whole heart can be fabricated. Research on myocardial regeneration progresses at such a pace that we believe the products of this research will save many lives in the near future. PMID- 30244252 TI - No Evidence for Benefits of the Depression Coach. PMID- 30244253 TI - Downregulation of MicroRNA-4463 Attenuates High-Glucose- and Hypoxia-Induced Endothelial Cell Injury by Targeting PNUTS. AB - BACKGROUND/AIMS: Vascular complications are the main reasons for disability and mortality associated with type 2 diabetes mellitus (T2DM) and numerous microRNAs (miRNAs) are involved in this process. Our previous study demonstrated that miR 4463 was increased in the plasma of T2DM patients combined with arteriosclerosis of low extremity artery (ASO). However, the role of miR-4463 remains unclear. METHODS: miR-4463 expression in the vascular tissues of patients with ASO and T2DM and in human umbilical vein endothelial cells (HUVECs) was detected by qPCR. Cell survival and apoptosis was analyzed via Cell Counting Kit-8 and flow cytometry assays, respectively. Protein expression was determined by Western blot and protein subcellular localization was detected with immunofluorescence. A dual luciferase assay was used to elucidate the target gene of miR-4463. RESULTS: miR 4463 was elevated in the vascular tissues of patients with T2DM and ASO. In HUVECs, both 25 mmol/L glucose (high glucose, HG) and hypoxia induced miR-4463 expression. Downregulation of miR-4463 promoted HUVEC survival and reduced cell apoptosis under HG and/or hypoxic conditions by facilitating the expression of protein phosphatase-1 nuclear targeting subunit (PNUTS), X-linked inhibitor of apoptosis protein (XIAP), p-AKT, p-Bad, increased the Bcl-2/Bax ratio, as well as downregulated cleaved caspase 3 expression. Mechanistically, we identified PNUTS as a direct target gene of miR-4463. Both the inhibition of AKT phosphorylation and silencing of PNUTS diminished the effect of miR-4463 on HUVEC apoptosis. Moreover, downregulation of miR-4463 enhanced PNUTS to enable PTEN nuclear localization, which resulted in AKT phosphorylation. CONCLUSION: Our results suggest that downregulation of miR-4463 attenuates cell apoptosis by directly enhancing PNUTS expression to promote PTEN nuclear localization, subsequently activating AKT signaling pathway in HUVECs under HG and/ or hypoxic conditions. PMID- 30244254 TI - Panta Rhei: Neovascularization, Angiogenesis and Nutritive Perfusion in Wound Healing. AB - BACKGROUND: In response to tissue damage, angiogenesis is an extremely dynamic process that is finely regulated by signals from cells, the surrounding extracellular matrix (ECM), and derived mediators. As the only process, angiogenesis remains of decisive importance in the context of the entire wound healing process and is subject to constant change. The dissolution of the endothelial basement membrane, the migration of endothelial cells, and the development of new capillary vessels during wound healing depend not only on the cells and cytokines present, but also on the production and organization of ECM components in the immediate wound. SUMMARY: Angiogenesis in wound healing can be divided into two main phases. During the pro-angiogenic phase at the beginning of wound healing, excessive neo-formation of blood vessels, some of which are poorly differentiated, occurs, which restore blood flow and thus nutritive perfusion as quickly as possible. This is followed by an anti-angiogenic phase in which the initially established vascular network undergoes a maturing process, which, however, is accompanied by a significant reduction in the number of vessels. Key Messages: Although many mechanisms and specific cell functions in wound healing have already been described, many underlying pathophysiological processes remain unknown. Because angiogenesis and its maturation is a very fast but also very long-lasting process, the understanding of the underlying mechanisms is of crucial importance. This article will give an overview of the current understanding and controversy in this sub-step of wound healing. PMID- 30244255 TI - Lung Carcinoids: long-term surgical results and the lack of prognostic value of somatostatin receptors and other novel IHC markers.
. AB - BACKGROUND/AIMS: Lung carcinoids (LCs) are often diagnosed at an early stage and are then eligible for surgical intervention. To date, there is a lack of long term follow-up data after surgery and prognostication based on WHO classification criteria and evolving prognostic markers, particularly the expression of somatostatin receptors (SSR).

Methods: We included 102 consecutive patients (72 women; age at baseline 51+/-16 years [mean +/- SD]) with LCs, who underwent thoracic surgery (n=99) and/or laser treatment (n=8). Hospital charts were reviewed for clinico-pathological parameters. Immunohistochemical (IHC) expression of SSR1-5 and other novel markers were studied with regards to their prognostic value.

Results: Five- and 10-year overall survival (OS) was 96% and 83% respectively; relative survival (RS) 101% and 93% respectively; and event-free survival (EFS) 80% and 67% respectively. Independent prognostic factors for OS, RS and/or EFS were age at diagnosis, histopathological type and the presence of ipsilateral mediastinal subcarinal lymph node metastases. Macro radicality of resective surgery and the extent of it were associated with increased OS and EFS. The IHC expression of SSR1-5 and other novel markers was not associated with OS or EFS.

Conclusion: The long-term outcome of surgical treated patients with LCs is favourable. Age, histopathological type and ipsilateral mediastinal subcarinal lymph node status at baseline were independent prognostic factors for survival and disease recurrence or progression. The extent of surgery and operative macro-radicality also had an impact on prognosis. None of the IHC markers tested appeared to be associated with disease prognosis.

. PMID- 30244256 TI - The Crucial Role of Vascularization and Lymphangiogenesis in Skin Reconstruction. AB - BACKGROUND: The treatment of extensive skin defects and bradytrophic wounds remains a challenge in clinical practice. Despite emerging tissue engineering approaches, skin grafts and dermal substitutes are still the routine procedure for the majority of skin defects. Here, we review the role of vascularization and lymphangiogenesis for skin grafting and dermal substitutes from the clinician's perspective. SUMMARY: Graft revascularization is a dynamic combination of inosculation, angiogenesis, and vasculogenesis. The majority of a graft's microvasculature regresses and is replaced by ingrowing microvessels from the wound bed, finally resulting in a chimeric microvascular network. After inosculation within 48-72 h, the graft is re-oxygenated. In contrast to skin grafts, the vascularization of dermal substitutes is slow and dependent on the ingrowth of vessel-forming angiogenic cells. Preclinical angiogenic strategies with adipose tissue-derived isolates are appealing for the treatment of difficult wounds and may markedly accelerate skin reconstruction in the future. However, their translation from bench to bedside is still restricted by major regulatory restrictions. Finally, the lymphatic system contributes to edema reduction and the removal of local wound debris. Therapeutic lymphangiogenesis is an emerging field of research in skin reconstruction. Key Messages: For the successful engraftment of skin grafts and dermal substitutes, the rapid formation of a microvascular network is of pivotal importance. Hence, to understand the biological processes behind revascularization of skin substitutes and to implement this knowledge into clinical practice is a prerequisite when treating skin defects. Furthermore, a functional lymphatic drainage crucially contributes to the engraftment of skin substitutes. PMID- 30244257 TI - Ghrelin Alleviates Angiotensin II-Induced H9c2 Apoptosis: Impact of the miR-208 Family. AB - BACKGROUND Ghrelin is a novel peptide with abundant cardioprotective effects. The miR-208 family, consisting of cardiac-specifically expressed microRNAs, are not only involved in hypertrophy and fibrosis, but are also closely related with myocyte apoptosis. This study explored the role of the miR-208 family in the protective effect of ghrelin on angiotensin II (Ang II)-induced apoptosis. MATERIAL AND METHODS H9c2 cells were exposed to Ang II with or without ghrelin. Cell viability was detected by MTT assay and the percentage of apoptotic cells was confirmed by flow cytometry. miRNAs expression levels were measured by qRT PCR. Then, cells transfected with miR-208 negative control, mimics, and inhibitors were treated with Ang II and ghrelin, followed by flow cytometry. PCR array was performed to explore the pathways affected by miR-208. RESULTS The miR 208 level was reduced in Ang II-treated H9c2 cells, accompanied with increased cell apoptosis, which were both reversed by ghrelin administration. Flow cytometry revealed that miR-208 inhibitors clearly upregulated the apoptotic percentage, whereas miR-208 mimics showed the opposite effects in the Ang II group. miR-208a further alleviated apoptosis when treated with ghrelin. miR-208 mainly affected caspase, inflammatory-related genes, and several signaling pathways. CONCLUSIONS We provide new evidence that the miR-208 family is regulated by Ang II and ghrelin. Overexpression of miR-208 family alleviated Ang II-induced cell apoptosis and miR-208a assisted in the protective effect of ghrelin. Several apoptosis pathways affected by miR-208 family were found. These findings suggest the pathogenesis of cardiomyocyte apoptosis and the protective mechanism of ghrelin. PMID- 30244258 TI - Interleukin-33 (IL-33) Increases Hyperoxia-Induced Bronchopulmonary Dysplasia in Newborn Mice by Regulation of Inflammatory Mediators. AB - BACKGROUND Interleukin-33 (IL-33) has been reported to affect chronic inflammation of the lungs, but its impact on hyperoxia-injured lungs in newborns remains obscure. This study aimed to investigate the role of IL-33 in the lungs of neonatal mice with hyperoxia-induced bronchopulmonary dysplasia (BPD). MATERIAL AND METHODS Twenty-four C57BL/6 baby mice were randomly separated into three groups: the on-air group (N=16); the O2 group (N=8); and the O2 + anti-IL 33 group (N=8). Forced mechanical ventilation with oxygen-rich air (MV-O2) was used in 16 mouse pups. The mouse pups were incubated in containers with either air or 85% O2 for 1, 3, 7, 14, 21, and 28 days after birth. At the end of the treatment period, the mouse lungs were studied by histology, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) to examine the expression of the pro-inflammatory mediators, including interleukin (IL)-1beta, chemokine (CC motif) ligand 1 (CXCL-1), and monocyte chemoattractant protein-1 (MCP-1). RESULTS Following forced MV-O2, increased levels of IL-33 in whole mouse lungs were associated with impaired alveolar growth and with changes consistent with BPD, including reduced numbers of enlarged alveoli, increased apoptosis, and increased expression of IL-1beta, CXCL-1, and MCP-1. IL-33 inhibition improved alveolar development in hyperoxia-impaired lungs and suppressed IL-1beta and MCP 1 expression and was associated with increased transforming growth factor-beta (TGF-beta) signaling, reduced pulmonary NF-kappaB activity and decreased expression of the TGF-beta inhibitor SMAD-7 in forced MV-O2 exposed mouse pups. CONCLUSIONS IL-33 increased hyperoxia-induced BPD in newborn mice by regulation of the expression of inflammatory mediators. PMID- 30244259 TI - Icariin Reduces Cartilage Degeneration in a Mouse Model of Osteoarthritis and is Associated with the Changes in Expression of Indian Hedgehog and Parathyroid Hormone-Related Protein. AB - BACKGROUND The aim of this study was to determine the role of icariin, a Chinese traditional herbal medicine extracted from Epimedium, in osteoarthritis (OA), using the murine anterior cruciate ligament transection (ACLT)-induced model of OA and micromass culture of murine chondrocytes. MATERIAL AND METHODS Twenty-four three-month-old C57/6J mice were randomly divided into three groups: the sham group (no surgery and joint injection with normal saline) (N=8); the ACLT + ICA group (ACLT surgery and icariin treatment) (N=8); and the ACLT group (ACLT surgery and joint injection with normal saline) (N=8). At 12 weeks after ACLT surgery, murine articular cartilage was harvested from all mice for histological evaluation of any differences in cartilage degeneration. In vitro micromass culture of mouse chondrocytes was used to study the effects of icariin on chondrocyte differentiation and growth from the three mouse groups. RESULTS Icariin treatment (mice in the ACLT + ICA group) significantly reduced degeneration of cartilage in OA with increased cartilage thickness, associated with increased expression of collagen type II alpha 1 (COL2A1), decreased chondrocyte hypertrophy, and decreased expression of collagen type X (ColX) and matrix metalloproteinase 13 (MMP13). In vitro, icariin promoted chondrocyte differentiation by upregulating the expression of agrrecan, Sox9 and parathyroid hormone-related protein (PHrP) and down-regulation of Indian hedgehog (Ihh) and genes regulated by Ihh. CONCLUSIONS In a mouse model of OA icariin treatment reduced destruction of cartilage, promoted chondrocyte differentiation, upregulated expression of PHrP and down-regulated the expression of Ihh. PMID- 30244260 TI - Arguments for a national questionnaire-based screening for hidradenitis suppurativa in Denmark. AB - INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic inflammatory disease. HS patients develop painful subcutaneous nodules, primarily in the intertriginous regions. Early diagnosis is crucial to initiate appropriate treatment, which may prevent disease progression. The cost of treatment increases with disease severity. Studies have found a considerable diagnostic delay in HS. Screening programs may reduce diagnostic delay and allow for better utilization of resources. METHODS: Arguments for implementing an HS screening program were explored based on the 10 WHO criteria for implementing screening programs. RESULTS: HS is an important health problem due to its prevalence and the adverse effects of the disease. Facilities for treatment and diagnosis exist, and the validated screening questionnaire is considered acceptable to the population. HS patients should be seen by a dermatologist and treated accordingly. Medical expenses increase with disease severity, and finding patients with early-stage HS is considered cost-effective. CONCLUSIONS: We consider a screening program as valuable for public healthcare. Patients can avoid extensive surgery or treatment with biologics if disease progression is prevented, and this will reduce medical expenses for the public healthcare system. Politicians should consider implementing a screening program for HS. PMID- 30244261 TI - The efficacy and safety of omalizumab in refractory chronic spontaneous urticaria: real-life experience in Turkey. AB - INTRODUCTION: This study used real-world data to evaluate the effectiveness and reliability of omalizumab in treating recalcitrant chronic spontaneous urticaria in Turkish patients. METHODS: Study data were collected retrospectively from eight tertiary-care hospitals in Turkey. This study included 132 patients with chronic spontaneous urticaria that were resistant to H1 antihistamine treatment in a dose up to four times the licensed dose and were treated with 300 mg/month of omalizumab for 6 months. RESULTS: The mean weekly urticarial activity score (UAS7) after omalizumab treatment improved significantly compared to the pre treatment score (p < 0.001). Treatment response was detected primarily in the 1st and 2nd months after treatment. No significant association was observed between omalizumab's treatment effectiveness and disease-related parameters or laboratory data. The mean dermatology life quality index was 23.12 +/- 6.15 before treatment and decreased to 3.55 +/- 3.60 6 months after treatment (p < 0.001). No side effects were reported in 89.4% (118) of the patients. CONCLUSIONS: This study showed that UAS7 decreased significantly and quality of life improved in omalizumab-treated patients. Moreover, treatment effectiveness was mainly observed in the first 2 months after treatment. However, no association was observed between omalizumab treatment effectiveness and disease-related parameters or laboratory data. PMID- 30244262 TI - A systematic literature review of studies reporting human papillomavirus (HPV) prevalence in esophageal carcinoma over 36 years (1982-2017). AB - A total of 203 reports published between 1982 and 2017 on the association between human papillomaviruses (HPV) and esophageal squamous cell carcinoma (ESCC), originating from 187 studies performed in 32 countries from six continents, were selected and reviewed. The selected studies included a total of 14,788 ESCC cases; the presence of HPV infection was detected in 30.9% of cases (95% CI 30.1 31.6%) and was the highest in regions with the highest incidence of ESCC. Across studies published in the last 6 years, Alphapapillomavirus species were detected in 31.1% of ESCCs (1,464/4,708, 95% CI 29.8-32.4%), of which 73.8% (1,080/1,464, 95% CI 71.5-76.0%) were positive for the presence of HPV16/18. HPV16 was by far the most common HPV type detected, accounting for 21.0% (799.5/3,803, 95% CI 19.8 22.4%) of the total number of ESCC cases investigated. Our results are in line with previously published studies, suggesting the etiological role of HPV in the development of a subset of ESCC cases. Although the association between HPV and esophageal adenocarcinoma (EAC) has been studied to a far lesser extent, some studies also suggest a potential etiological role of HPV in a subset of EAC cases. PMID- 30244263 TI - Clinical presentation, diagnostic approach, and treatment of hand lipomas: a review. AB - Lipomas are the most common soft tissue tumors of mesenchymal origin. They can appear anywhere on the body, and in rare cases they may present on the hands. Lipomas represent approximately 1% to 3.8% of all benign tumors in the hands. Typically, lipomas present in the fifth or sixth decade of life, occurring in both men and women. Lipomas may appear anywhere on the hand, often presenting as painless, slow-growing, and mobile masses. Symptoms may develop if local neurovascular structures are compressed. Differential diagnosis includes liposarcoma and fibrolipomatous hamartoma. To assist with clinical diagnosis, ultrasound, computed tomography, or magnetic resonance imaging may be utilized. The best way to confirm diagnosis is with histopathology. The main treatment for hand lipomas is surgical excision. Postoperative recurrence is rare. PMID- 30244264 TI - Distribution of hepatitis B virus genotypes in Europe and clinical implications: a review. AB - With an estimated 15 million infected persons in Europe, hepatitis B virus (HBV) infection is still one of the leading causes of chronic liver disease and associated mortality. The HBV infection prevalence in the general population depends on the region and ranges from 0.01% in Scandinavia to 10.3% in Kyrgyzstan. The prevalence of the 10 HBV genotypes (A-J) varies among different parts of the world, with genotypes A and D being most prevalent in Europe. Other HBV genotypes are mainly imported into Europe from other parts of the world and are rarely detected. HBV genotypes influence the clinical outcome of HBV infection, HBeAg seroconversion rates, and the frequency of mutations in the pre core and core promoter regions. In addition, response rates to treatment with pegylated interferon alpha vary among HBV genotypes, whereas there is no influence of HBV genotypes on treatment response when using nucleoside/nucleotide analogues. Due to recent large-scale immigration to Europe, a change in HBV genotype distribution and the consequent clinical outcome of chronic hepatitis B may be expected in the near future. PMID- 30244265 TI - Dermoscopy of early non-ulcerated livedoid vasculopathy. AB - Livedoid vasculopathy is a rare disease related to a hypercoagulable state. It can lead to painful and chronic relapsing ulcerations. We report dermoscopic findings of early, non-ulcerated livedoid vasculopathy in five patients. A mixture of ivory-white atrophic areas with multiple erythematous papules in the center of the lesions is characteristic. With dermoscopy, these papules correspond to glomerular vessels. In the periphery of the lesions some telangiectatic linear vessels complete the picture, although they could be absent in some patients. PMID- 30244266 TI - Sparfloxacin-induced photo-onycholysis and photosensitivity characteristically sparing lepromatous skin lesions: an interesting observation. AB - Sparfloxacin is an antibiotic in the quinolone group of antibacterial agents, which often induce photosensitive skin reactions, more often phototoxic reactions than photoallergic ones, and sometimes associated photo-onycholysis. We present a case of phototoxic dermatitis with photo-onycholysis in a 38-year-old man probably induced by sparfloxacin, which was prescribed to him along with rifampicin and clofazimine because he was suffering from borderline lepromatous leprosy. He developed exaggerated sunburn-like eruptions mainly on sun-exposed sites along with painful onycholysis of the fingernails. Interestingly, the hypopigmented patches of leprosy were spared, which is a very rare phenomenon. Withdrawal of sparfloxacin along with administration of systemic steroids and other supportive measures helped heal the skin eruptions with hyperpigmentation, but the photo-onycholysis was slow to resolve. PMID- 30244267 TI - Multiorgan involvement of Behcet's disease in a young woman. AB - Behcet's disease is a rare disorder of unknown etiology that is classified as a systemic vasculitis. The prevalence of the disease is high in countries in the Far East, Mediterranean Basin, and East Asia. Thus, it is also known as the Silk Road Disease. Behcet's disease is characterized by recurrent oral aphthous ulcers, genital sores, and ocular lesions. However, it can present with severe clinical manifestations as a result of cardiovascular system, central nervous system, and gastrointestinal tract involvement. The disease causes serious complications, morbidity, and mortality, especially in male patients with early age onset. Here we present a rare case of Behcet's disease exhibiting multiple organ involvement in a 26-year-old Caucasian female. PMID- 30244268 TI - Rapunzel syndrome: a rare form of trichobezoar in the stomach with some extension into the small intestine. AB - Trichobezoars are gastric foreign bodies rarely found in children. They are mainly composed of swallowed hair. Rapunzel syndrome is a very rare form of trichobezoar characterized by extension of the ingested hair from the stomach into the small intestine or even beyond. Clinical presentation can range from an asymptomatic abdominal mass to severe symptoms: gastric outlet obstruction, perforation of the stomach, and acute pancreatitis. Trichobezoars are usually treated with surgical removal. Here we present the case of an 8-year-old girl in whom a firm non-tender mass in the epigastric region was palpated during a regular outpatient clinic visit. The girl reported some slight abdominal discomfort and early satiety during meals. Subsequently, focal alopecia was detected. A trichobezoar in the stomach with some extension into the duodenum was diagnosed by ultrasound, and later confirmed by a barium swallow study and CT scan. The trichobezoar was successfully surgically removed. PMID- 30244269 TI - Mycobacterium abscessus infection in a spa worker. AB - Mycobacterium abscessus (M. abscessus) is a non-tuberculous mycobacterium widely present in the natural environment and is now being increasingly identified as a cause of human disease. However, it can cause skin and soft tissue infection following trauma or surgery. We report a case of a skin ulcer associated with M. abscessus in a spa worker. Frequently, contamination with atypical mycobacteria occurs through tap water. However, in most outbreaks the infection source remains unknown. For an early diagnosis, it is important to perform biopsies and mycobacterium cultures. No specific treatment for skin infection with M. abscessus has been established; it depends on the immune status of the host and the extent of disease. Although it is rare, non-tuberculous mycobacterial infection should be part of the differential diagnosis of cutaneous ulcers, especially on trauma-prone areas. PMID- 30244270 TI - Acute febrile neutrophilic dermatosis in a patient with Crohn's disease: case report and review of the literature. AB - Crohn's disease is a chronic inflammatory bowel disease. The disease is characterized by acute exacerbations with diarrhea, abdominal pain, fever, anorexia, intestinal bleeding, and weight loss. Immune-mediated diseases that are frequently associated with Crohn's disease include arthritis, ankylosing spondylitis, sacroiliitis, episcleritis, uveitis, and skin lesions, such as erythema nodosum and pyoderma gangrenosum. The authors present the case of a 22 year-old female patient that was admitted to their hospital due to diarrhea, fever, arthralgias, and diffuse erythematous papules and plaques with vesicles and pustules affecting the patient's face, lips, arms, trunk, and legs. Six months prior to onset, the patient was diagnosed with terminal ileitis and Crohn's disease of the sigmoid colon. Treatment with mesalazine and budesonide had been introduced. In the diagnostic procedure, a skin biopsy was taken from the patient. Histology confirmed dense infiltration of neutrophilic polymorphonuclear leukocytes, or Sweet's syndrome. This condition is a rare manifestation of chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. This syndrome is thought to be a hypersensitivity reaction and may be associated with various inflammatory, infectious, or neoplastic diseases. The patient was treated with high doses of methylprednisolone (60 mg IV), which resulted in rapid improvement of Crohn's disease and skin lesions. PMID- 30244271 TI - An adverse reaction after hyaluronic acid filler application: a case report. AB - Among several skin fillers developed in recent decades, hyaluronic acid (HA) fillers have become the material of choice. They are safe, long-lasting, not immunogenic, and cost effective, and they can be removed with hyaluronidase. Unfortunately, early and delayed complications can also occur following HA filler injection. Here we report the case of a hyaluronic filler-related complication in a 50-year-old female patient. The locations affected were the forehead, glabella, and nose. Three days after HA filler application in the upper lip, glabellar region, and nasal root, with no immediate diverse reaction at the time of application, an erythematous, livedoid rash with a well-defined border occurred at the site of the injection in the glabellar region, including the area from the nasal root to the scalp and left upper eyelid. Because an infection or allergy was suspected, she was first given an antibiotic for 6 days p.o. and later also a corticosteroid systemically with good results. Two years later (in 2017) the patient decided to repeat the treatment with HA injections in the glabellar region and experienced no adverse reactions. PMID- 30244272 TI - The role of formation of pyrrole-ATP synthase subunit beta adduct in pyrrolizidine alkaloid-induced hepatotoxicity. AB - Pyrrolizidine alkaloids (PAs) are one of the most significant groups of hepatotoxic phytotoxins. It is well-studied that metabolic activation of PAs generates reactive pyrrolic metabolites that rapidly bind to cellular proteins to form pyrrole-protein adducts leading to hepatotoxicity. Pyrrole-protein adducts all contain an identical core pyrrole moiety regardless of structures of the different PAs; however, the proteins forming pyrrole-protein adducts are largely unknown. The present study revealed that ATP synthase subunit beta (ATP5B), a critical subunit of mitochondrial ATP synthase, was a protein bound to the reactive pyrrolic metabolites forming pyrrole-ATP5B adduct. Using both anti-ATP5B antibody and our prepared anti-pyrrole-protein antibody, pyrrole-ATP5B adduct was identified in the liver of rats, hepatic sinusoidal endothelial cells, and HepaRG hepatocytes treated with retrorsine, a well-studied representative hepatotoxic PA. HepaRG cells were then used to further explore the consequence of pyrrole ATP5B adduct formation. After treatment with retrorsine, significant amounts of pyrrole-ATP5B adduct were formed in HepaRG cells, resulting in remarkably reduced ATP synthase activity and intracellular ATP level. Subsequently, mitochondrial membrane potential and respiration were reduced, leading to mitochondria-mediated apoptotic cell death. Moreover, pre-treatment of HepaRG cells with a mitochondrial membrane permeability transition pore inhibitor significantly reduced retrorsine-induced toxicity, further revealing that mitochondrial dysfunction caused by pyrrole-ATP5B adduct formation significantly contributed to PA intoxication. Our findings for the first time identified ATP5B as a protein covalently bound to the reactive pyrrolic metabolites of PAs to form pyrrole ATP5B adduct, which impairs mitochondrial function and significantly contributes to PA-induced hepatotoxicity. PMID- 30244273 TI - Contemporary trends in toxicological research on arsenic. PMID- 30244274 TI - The Effects of an Herbicide and Antibiotic Mixture on Aquatic Primary Producers and Grazers. AB - Widespread use of agrochemicals increases their likelihood of entering aquatic systems in mixture. Despite different modes of action, atrazine (herbicide) and tetracycline (antibiotic) adversely affect non-target photosynthetic organisms individually, but the effects of simultaneous exposure to both contaminants are untested. We created microcosms containing microalgae (Chlorella sp.), floating macrophytes (Lemna minor), and a zooplankton grazer (Daphnia magna). Microcosms were exposed to environmentally relevant concentrations of atrazine and tetracycline, alone and together, for 10 days. Atrazine decreased Chlorella sp. abundance, but not enough to reduce food availability to D. magna whose reproduction and mortality were unaffected. In contrast, tetracycline and atrazine appeared to have additive effects on L. minor abundance and growth inhibition. These additive adverse effects suggest increased potential for L. minor population decline over the long term, and potential for altered species interactions in aquatic systems receiving agricultural runoff. PMID- 30244275 TI - Remediation of Toxic Metal Contaminated Sediment Using Three Types of nZVI Supported Materials. AB - Due to nZVI effectiveness in the removal of toxic metals as well as low-cost regarding its production, kaolinite, bentonite and carboxymethyl cellulose supported nZVI were chosen for in-situ remediation of river sediment. Small-scale laboratory studies have shown that the percentage of removed metal (Ni, Zn and Pb) ranged up to 80% depending on the nanomaterial used. The metal mobility in sediments was investigated using single extraction, which is proved to be better for quick estimation of metal mobility, and for highly contaminated sites both single and sequential extraction needs to be used. Risk assessment code indicated medium risk for Ni and high risk for Pb and Zn in untreated sediment. In-situ treatment in laboratory proved to be very effective, providing the choice of optimal doses of three different nanomaterials used towards the concentration of toxic metals in the sediment. PMID- 30244276 TI - Synthesis of a New Nitrate-Fertilizer Form with a Controlled Release Behavior via an Incorporation Technique into a Clay Material. AB - The current study shows an advanced synesthetic technique of a nitrate-fertilizer with a controlled release behavior into different soils (normal and acidic agriculture soils solutions) at different climate temperatures. The environmentally friendly and the biocompatible layered double hydroxide (LDH) clay material was used as a host to accommodate the nitrate anion into its interlayer gallery by applying a reconstruction-incorporation technique (the memory effect property of LDH that allows calcined LDH to memorize its original structure). The prepared materials were characterized by different spectroscopic techniques including; X-ray powder spectroscopy, IR, SEM, TEM, and TGA analyses. A remarkable loading ratio of the nitrate anion fertilizer was recorded into the LDH structure. Around 90 wt% of the intercalated nitrate anion was released in a sustained controlled behavior over around 24 days, while the same amount of nitrate was released over 10 days in the acidic soil. Accordingly, the present study offers a new passway for the formulation of controlled release fertilizers by using the hosting anionic clay LDH materials. PMID- 30244277 TI - High-Throughput Quantitative Measurement of Bacterial Attachment Kinetics on Seconds Time Scale. AB - Surface attachment is an important factor in the life of many microbial species. Late stages of attachment (i.e., mature biofilms) are rigorously studied, but data on the very early stages is scarce. The lack of robust research methods may go a long way in explaining this situation. We have developed a method that allows the rapid kinetic measurement of bacterial attachment, with seconds to minute's temporal resolution, in a high-throughput setting. The method requires the use of a commercially available microtiter plate reader capable of fluorescence measurement from the bottom, standard microtiter plates, fluorescently tagged bacteria, and a common dye. The high temporal resolution reveals nuanced, fast, and dynamic behaviors in the very early phases of attachment. To demonstrate potential applications, we tested the effect of various conditions on attachment kinetics-specie, substratum, salt concentration, and culture density. Results are in good agreement with crystal violet staining (correlation R2 > 0.95 in all cases) and reproducing published data but show much greater detail and fidelity. PMID- 30244278 TI - Dimethylformamide is a novel nitrilase inducer in Rhodococcus rhodochrous. AB - Nitrilases are of commercial interest in the selective synthesis of carboxylic acids from nitriles. Nitrilase induction was achieved here in three bacterial strains through the incorporation of a previously unrecognised and inexpensive nitrilase inducer, dimethylformamide (DMF), during cultivation of two Rhodococcus rhodochrous strains (ATCC BAA-870 and PPPPB BD-1780), as well as a closely related organism (Pimelobacter simplex PPPPB BD-1781). Benzonitrile, a known nitrilase inducer, was ineffective in these strains. Biocatalytic product profiling, enzyme inhibition studies and protein sequencing were performed to distinguish the nitrilase activity from that of sequential nitrile hydratase amidase activity. The expressed enzyme, a 40-kDa protein with high sequence similarity to nitrilase protein Uniprot Q-03217, hydrolyzed 3-cyanopyridine to produce nicotinic acid exclusively in strains BD-1780 and BD-1781. These strains were capable of synthesising both the vitamin nicotinic acid as well as beta amino acids, a compound class of pharmaceutical interest. The induced nitrilase demonstrated high enantioselectivity (> 99%) in the hydrolysis of 3-amino-3 phenylpropanenitrile to the corresponding carboxylic acid. PMID- 30244279 TI - Bioproduction, purification, and application of polysialic acid. AB - Polysialic acid (PSA) is a negatively charged linear homopolymer linked by N acetylneuraminic acid and widely present in vertebrates and some pathogens. PSA, commonly found on cell surfaces as glycoproteins and glycolipids, plays important roles in intercellular adhesion, cell migration, and formation and remodeling of the neural system by regulating the adhesive property of nerve cell adhesion molecules. PSA with a molecular weight that can reach as high as 260 kDa also belongs to the group II capsule polysaccharide of neonatal meningitis-causing Escherichia coli K1. To date, much effort has been devoted to developing the biotechnological production of PSA. As a non-glycosaminoglycan, PSA is a non immunogenic and biodegradable polysaccharide that can be used as a biomaterial in protein polysialylation, tissue engineering, and drug delivery. PSA can also combine with other macromolecules to form multifunctional composites. In this mini-review, the production, purification, and application of PSA are summarized to provide a basis for further PSA applications. PMID- 30244280 TI - Gene overexpression screen for chromosome instability in yeast primarily identifies cell cycle progression genes. AB - Loss of heterozygosity (LOH) in a vegetatively growing diploid cell signals irregularity of mitosis. Therefore, assays of LOH serve to discover pathways critical for proper replication and segregation of chromosomes. We screened for enhanced LOH in a whole-genome collection of diploid yeast strains in which a single gene was strongly overexpressed. We found 39 overexpression strains with substantially increased LOH caused either by recombination or by chromosome instability. Most of them, 32 in total, belonged to the category of "cell division", a broadly defined biological process. Of those, only one, TOP3, coded for an enzyme that uses DNA as a substrate. The rest related to establishment and maintenance of cell polarity, chromosome segregation, and cell cycle checkpoints. Former studies, in which gene deletions were used, showed that an absence of a protein participating in the DNA processing machinery is a potent stimulator of genome instability. As our results suggest, overexpression of such proteins is not comparably damaging as the absence of them. It may mean that the harmful effect of overexpression is more likely to occur in more complex and multistage processes, such as chromosome segregation. We also report a side finding, resulting from the fact that we worked with the yeast strains bearing a 2-micron plasmid. We noted that intense transcription from such a plasmid led to an enhanced rate of an entire chromosome loss (as opposed to LOH produced by recombination). This observation may support models linking segregation of 2 micron plasmids to segregation of chromosomes. PMID- 30244281 TI - Intricate regulation on epigenetic stability of the subtelomeric heterochromatin and the centromeric chromatin in fission yeast. AB - In eukaryotes, the integrity of chromatin structure and organization is crucial to diverse key cellular processes from development to disease avoidance. To maintain the cell identity through mitotic cell generations, the genome (the genomic DNA sequence) as well as the epigenome (pertaining various forms of epigenetic information carriers, such as histone modifications, nucleosome positioning and the chromatin organization) is inherited with high fidelity. In comparison to the wealth of knowledge on genetic stability, we know much less on what may control the accuracy of epigenetic inheritance. In our recent work in the fission yeast Schizosaccharomyces pombe, by quantifying the epigenetic fidelity of CENP-A/Cnp1 or H3K9me2 nucleosome inheritance through cell divisions, we demonstrated that Ccp1, a homolog of histone chaperone Vps75 in budding yeast, participates in the modulation of centromeric nucleosomal epigenetic stability as well as proper heterochromatin organization. In this essay, we focus on discussing the uniquely high dynamicity of the subtelomeric heterochromatin regions and the complex mechanisms regulating epigenetic stability of centromeric chromatin. PMID- 30244282 TI - Corpus luteum with ovarian stromal edema is associated with pelvic pain and confusion for ovarian torsion. AB - PURPOSE: To distinguish the corpus luteum with adjacent ovarian stromal edema as an entity associated with pelvic pain, with confounding ultrasound features that may lead to false-positive diagnosis of ovarian torsion. METHODS: This is a blinded, retrospective study of 243 corpora lutea on transvaginal ultrasound. Imaging parameters included ovarian and corpus luteum volumes, central cystic space within the corpus luteum, vascularity around the corpus luteum, peripherally displaced follicles, and complex free fluid. Residual volume (ovarian volume minus corpus luteum volume) was used as a surrogate for ovarian stromal edema. Clinical parameters included age, pregnancy, and location/acuity of pain if present. Concern for ovarian torsion in radiology reports was documented. RESULTS: 51.0% (124/243) of patients presented with pain. Multivariate regression analysis of factors significantly associated with pain (including age, p = 0.001; larger corpus luteum volume, p = 0.002; larger residual volume, p < 0.001; complex free fluid, p = 0.002; and peripherally displaced follicles, p < 0.001) left only increased residual volume as significantly associated with pain [OR 1.02-1.16; p = 0.01]. False-positive concern for ovarian torsion on ultrasound was present in 12.9% (16/124) of patients with pain, associated with enlarged ovaries (p < 0.001) and peripherally displaced follicles (p < 0.001). High correlation between location of pain and side of the corpus luteum was demonstrated in patients with pain < 14 days duration (p < 0.001). CONCLUSION: Corpus luteum with ovarian stromal edema is associated with pelvic pain and can mimic ovarian torsion on ultrasound. Further research should explore diagnostically useful differences between cases of ovarian torsion and cases of ovarian edema related to corpora lutea. PMID- 30244283 TI - Post-auricular lump: CT diagnosis. PMID- 30244285 TI - Reappraising cognitive control: normal reactive adjustments following conflict processing are abolished by proactive emotion regulation. AB - The congruency sequence effect (CSE) reflected by the influence of the congruency of the previous trial on the current one translates improved cognitive control (CC). Yet, it remains debated whether reactive or proactive control processes mostly contribute to this effect. To address this question, we administered a Stroop task controlling for effects of feature repetition and contingency learning to a large group of participants, where we manipulated the frequency of incongruent trials in a block-wise fashion to induce either proactive (high conflict frequency) or reactive (low-conflict frequency) control. Moreover, as the presentation of trial-by-trial evaluative feedback could influence control processes operating at a local level, we compared effect of evaluative vs. neutral feedback on the CSE, for each control mode separately. We tested the prediction that CSE should be influenced by conflict frequency and feedback type concurrently. Results showed that when evaluative feedback was used, the CSE was increased if conflict frequency was low, confirming that the CSE stemmed from reactive control mainly. If conflict frequency was high, a different sequence effect was observed. The use of neutral feedback abolished the modulation of the CSE by conflict frequency. Moreover, correlation results showed that reappraisal, corresponding to a proactive emotion regulation strategy, was negatively related to the CSE in this condition, suggesting that proactive control can alleviate the reactive dominance of the CSE. Altogether, these results suggest that CC is flexible, and its expression depends on the subtle balance between proactive and reactive control processes. PMID- 30244286 TI - Sleep and mindfulness meditation as they relate to false memory. AB - By a systematic analysis of the current literature, we compare two states of sleep and meditation in terms of their role in the formation or suppression of Deese-Roediger-McDermott (DRM) false memory. We aim to suggest that the occurrence of false memory under these two states is a result of reinforcing some abilities and changes in cognitive systems which can ultimately improve some aspects of cognitive functions. In our analogy, we propose that: (1) both sleep and meditation may improve source monitoring ability whose failure is one of the most important mechanisms in producing false memories, and (2) despite improvement in source monitoring ability, adaptive cognitive processes, as mechanisms which are common in sleep and meditation, can still produce false memories. In conclusion, we propose that in spite of their contribution to false memory through adaptive processes, the beneficial role of sleep and meditation in cognition may be more prominent than their harmful role. PMID- 30244284 TI - Probability discounting of treatment decisions in multiple sclerosis: associations with disease knowledge, neuropsychiatric status, and adherence. AB - RATIONALE: Patients weigh risks and benefits when making treatment decisions. Despite this, relatively few studies examine the behavioral patterns underpinning these decisions. Moreover, individual differences in these patterns remain largely unexplored. OBJECTIVES: The purpose of this study was to test a probability discounting model to explain the independent influences of risks and benefits when patients make hypothetical treatment decisions. Furthermore, we examine how individual differences in this probability discounting function are associated with patient demographics, clinical characteristics, disease knowledge, neuropsychiatric status, and adherence. METHODS: Two hundred eight participants with relapsing-remitting multiple sclerosis (MS) indicated their likelihood (0-100%) of taking a hypothetical medication as the probability of mild side effects (11 values from .1 to 99.9%) and reported medication efficacies (11 values from .1 to 99.9%) varied systematically. They also completed a series of questionnaires and cognitive tests. RESULTS: Individual components of medication treatment decision making were successfully described with a probability discounting model. High rates of discounting based on risks were associated with poor treatment adherence and less disease-specific knowledge. In contrast, high rates of discounting of benefits was associated with poorer cognitive functioning. Regression models indicated that risk discounting predicted unique variance in treatment adherence. CONCLUSIONS: Insights gained from the present study represent an important early step in understanding individual differences associated with medical decision making in MS. Future research may wish to use this knowledge to inform the development of empirically supported adherence interventions. PMID- 30244287 TI - Radiation Exposure to Staff and Patient During Videofluoroscopic Swallowing Studies and Recommended Protection Strategies. AB - Videofluoroscopic swallowing studies expose both the patients and the staff to ionising radiation. Although the radiation exposure is considered low compared to other diagnostic procedures, it is still prudent to keep the radiation dose as low as reasonably achievable. This review aims to summarise the latest literature pertaining to staff and patient radiation dose, as well as to make evidence-based recommendations on dose optimisation strategies. The evidence shows that patient radiation dose is low; nonetheless, care must be taken for patients that require multiple examinations. There are limited studies measuring the staff dose during videofluoroscopic swallowing procedures. However, the operator may receive radiation doses approaching 1 mSv per year. Recommendations for radiation protection strategies are summarised. PMID- 30244288 TI - The systemic myokine response of decorin, interleukin-6 (IL-6) and interleukin-15 (IL-15) to an acute bout of blood flow restricted exercise. AB - PURPOSE: Blood flow restricted resistance exercise (BFR-RE) is an emerging hypertrophy training modality. A complete profile of its mechanisms of action has yet to be elucidated. Cytokines are universal intercellular messengers. Recent research has implicated certain cytokines (termed "myokines") in skeletal muscle hypertrophy pathways; however, little research has been conducted on the systemic myokine response to BFR-RE as potential hypertrophic biomarkers. Therefore, this project was conducted to determine any differences in the systemic myokine response between BFR-RE and control conditions. METHODS: The appearance of systemic myokines interleukin-6 (IL-6), interleukin-15 (IL-15), and decorin were measured following acute bouts of low-load resistance exercise, BFR-RE, and high load resistance exercise in physically active young males to determine if BFR-RE modifies the exercise-induced systemic myokine response. RESULTS: No measurable levels of IL-6 were observed during the project. No significant effects were observed for IL-15. A significant time (11.91% increase pre to post exercise; p < 0.05) but no condition or condition by time effect was observed for decorin. CONCLUSION: These findings suggest that BFR-RE does not modify the systemic myokine appearance of IL-6, IL-15, or decorin when compared to control conditions. PMID- 30244289 TI - Host range and molecular characterization of a lytic Pradovirus-like Ralstonia phage RsoP1IDN isolated from Indonesia. AB - A lytic Ralstonia solanacearum-infecting phage designated Ralstonia phage RsoP1IDN was isolated from soil in Indonesia. The phage has a linear double stranded DNA genome of 41,135 bp with 413-bp terminal repeats, and contains 41 annotated open reading frames. The phage is most closely related to Ralstonia phage RSB1, but different from RSB1 mainly in containing a putative HNH homing endonuclease and having a narrower host range. Our phylogenetic and genomic analyses revealed that both phages RsoP1IDN and RSB1 belong to the genus Pradovirus or a new genus, and not Phikmvvirus as previously reported for phage RSB1. RsoP1IDN is the first sequenced and characterized R. solanacearum-infecting phage isolated from Indonesia in the proposed species Ralstonia virus RsoP1IDN. PMID- 30244290 TI - SERS based monitoring of toluene vapors at ambient and elevated temperatures by using a ruffled silver nanolayer as a substrate. AB - The authors describe a Surface enhanced Raman spectroscopy (SERS)-based method for the detection of gaseous toluene at different temperature regimes using 3D ruffled silver SERS substrates and a commercially available handheld Raman system equipped with a 785 nm laser. The 3D silver SERS substrates were synthesized via electroless deposition of silver on the ruffled sandpaper and HF-etched silicon wafers. The morphological characterization of the silver SERS substrates was carried out by atomic force microscopy and scanning electron microscopy. UV-Vis spectroscopy absorption spectra of the silver nanostructures showed plasmonic peaks at 522 nm and 731 nm. Toluene vapors were collected with a syringe at ambient temperature and at 100 degrees C, while SERS detection was always performed at room temperature. Toluene detection was based on the measurement of the Raman bands at 787 cm-1 and 1003 cm-1 (in the fingerprint region). The method allow gaseous toluene to be detected at its vapor concentrations of 522 ppm (mg/L), 261 ppm (mg/L) and 26 ppm (mg/L). Graphical abstract Schematic presentation of an original method for the detection of toluene vapors by SERS technique. The collection of toluene vapors was carried out at room and at high temperatures. The vapors were transferred to methanol by bubbling. The SERS measurements were carried out at room temperature. PMID- 30244291 TI - Comparing fertility preservation resources and policies between NCCN member and non-member institutions. AB - PURPOSE: The National Comprehensive Cancer Network (NCCN) created guidelines to facilitate implementation of fertility preservation (FP) discussions and referrals for adolescent and young adult patients. We assessed if availability of workplace FP resources and referral policies differed among learners in the Educating Nurses about Reproductive Health in Cancer Healthcare (ENRICH) training program based on NCCN membership. METHODS: Learners completed a baseline application, including demographic information and the availability of FP resources and referral policies. Learners were categorized as either NCCN members or non-members and chi-square tests compared resources between the two groups. RESULTS: Learners from NCCN institutions reported the highest rates of established FP referral guidelines (p < .01), reproductive endocrinologist and infertility specialist (REI) on staff (p < .01), partnerships with REI, educational materials for staff (p < .05), and patients (p < .01). CONCLUSION: FP resources and referral policies were highest among learners from NCCN member institutions, but areas for development with fertility issues still exist and learners from non-member institutions may assist their workplaces in improving rates of discussions and referrals based on their ENRICH training. PRACTICE IMPLICATIONS: The variation of available resources and referral policies between groups suggests more FP education and training; focusing on implementation programs is needed to make steps towards impactful institutional level resources and policies. PMID- 30244293 TI - Correction to: Blocking of opioid receptors in experimental formaline-inactivated respiratory syncytial virus (FI-RSV) immunopathogenesis: from beneficial to harmful impacts. AB - In the original publication, seventh author's name was incorrectly published as 'Maryam Golaram'. PMID- 30244292 TI - Intracerebroventricular streptozotocin induces impaired Barnes maze spatial memory and reduces astrocyte branching in the CA1 and CA3 hippocampal regions. AB - Sporadic Alzheimer's disease (SAD) is the most common form of dementia; therefore, there is an urgent need for a model that recapitulates the main pathologic hallmarks of this disease. The intracerebroventricular (icv) injection of streptozotocin (icv-STZ) in rats constitutes a promising model, and thus, icv STZ rats develop insulin-resistant brain state and cognitive impairments. Even though a great piece of studies has hitherto described this system as a model for SAD, further behavioral and morphometric studies are still needed to fully characterize it. In this study, using Sprague Dawley rats, we evaluated short term effects on behavior and hippocampus morphometry of the icv-STZ injection at two doses: 1 (STZ1) and 3 mg/kg (STZ3). We found that, following icv-STZ injection, STZ3 animals, but not STZ1, exhibited impairments in spatial reference learning and memory (Barnes maze test) and in recognition memory (object recognition test). Furthermore, the results from behavioral and morpho histochemical data are compatible. STZ3 rats displayed Stratum Radiatum volume reduction and a decreased NeuN immunoreactivity (neuron loss) in hippocampal CA1 region, together with an increased immunoreactivity for microglial (Iba1) and astroglial (GFAP) markers (neuroinflammation). Sholl analysis revealed the vulnerability of hippocampal astrocytes to STZ in CA1 and CA3. Thus, both doses induced a reduction in process length and in the number of main processes, accompanied by a frank decrease in branching complexity. The present study provides important knowledge of this AD rat model. Overall, we found that the only high STZ dose induced severe and acute neurodegenerative lesions, associated with an inflammation process. PMID- 30244295 TI - The effects of the economic recession on spending on private health insurance in Spain. AB - The paper seeks to analyse the evolution of expenditure on private health insurance (PHI) in Spain. We consider the factors that influence PHI demand and level of spending before and during the economic recession, along with identifying the effect of the recession on these factors. The data is obtained from the Spanish Family Budget Survey (SFBS) for 2006 and 2012. Due to the data structure and the demand function, the analysis is performed using a sample selection model in order to avoid sample selection bias. We estimate three models: a pre-recession model (2006), a model for the recession period (2012) and a third one covering both periods (2006 and 2012) and where we include a dummy variable that establishes the effect of the economic recession. The results show that the effect of the economic recession on PHI demand is not significant, but it is on the level of spending. PMID- 30244294 TI - The Cholegas trial: long-term results of prophylactic cholecystectomy during gastrectomy for cancer-a randomized-controlled trial. AB - BACKGROUND: The incidence of cholelithiasis has been shown to be higher for patients after gastrectomy than for the general population, due to vagal branch damage and gastrointestinal reconstruction. The aim of this trial was to evaluate the need for routine concomitant prophylactic cholecystectomy (PC) during gastrectomy for cancer. METHODS: A multicenter, randomized, controlled trial was conducted between November 2008 and March 2017. Of the total 130 included patients, 65 underwent PC and 65 underwent standard gastric surgery only for curable cancers. The primary endpoint was cholelithiasis-free survival after gastrectomy for gastric adenocarcinoma. Cholelithiasis was detected by ultrasound exam. RESULTS: After a median follow-up of 62 months, eight patients (12.3%) in the control group developed biliary abnormalities (four cases of gallbladder calculi and four cases of biliary sludge), with only three (4.6%) being clinically relevant (two cholecystectomies needed, one acute pancreatitis). One patient in the PC group had asymptomatic biliary dilatation during sonography after surgery. The cholelithiasis-free survival did not show statistical significance between the two groups (P = 0.267). The number needed to treat with PC to avoid reoperation for cholelithiasis was 1:32.5. CONCLUSIONS: Concomitant PC during gastric surgery for malignancies, although reducing the absolute number of biliary abnormalities, has no significant impact on the natural course of patients. PMID- 30244296 TI - Ponicidin inhibits pro-inflammatory cytokine TNF-alpha-induced epithelial mesenchymal transition and metastasis of colorectal cancer cells via suppressing the AKT/GSK-3beta/Snail pathway. AB - Ponicidin (PON), a natural diterpenoid compound, has been shown to exhibit potent anticancer activities in a wide variety of cancers, including colorectal cancer (CRC). Nevertheless, the precise mechanisms underlying the anti-metastasis effect of PON have not yet been completely defined. The present study was designed to uncover the inhibitory effect of PON on epithelial-mesenchymal transition (EMT), migration and invasion of HCT116 cells induced by pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in vitro, and liver metastasis in vivo. Briefly, cell proliferation was assessed by Cell Counting Kit-8 assay, followed by wound healing and transwell assays to evaluate cell migration and invasion. The EMT-related molecular markers were determined through quantitative real-time polymerase chain reaction (qPCR), immunofluorescence (IF), western blot (WB), and immunohistochemistry (IHC). Additionally, WB was used to assess the expression of AKT, phosphorylated AKT (p-AKT), GSK-3beta, and phosphorylated GSK-3beta (p-GSK 3beta). As a result, PON could effectively suppress EMT, migration, and invasion in HCT116 cells in vitro, and liver metastasis of HCT116 cells in vivo. Additionally, PON administration also dramatically altered the expression of EMT associated markers such as E-cadherin, N-cadherin, and Vimentin, and suppressed the expression of p-AKT, p-GSK-3beta and transcription factor, Snail in a dose dependent manner. Moreover, the incidence of liver metastasis in the control group was 100% and although the incidence of liver metastasis did not decrease, the number of metastatic nodules in the livers of each PON dose group decreased by (34 +/- 4.2)%, (64 +/- 3.6)%, and (76 +/- 5.3)%, respectively, compared to the control group. Collectively, these findings indicated that targeting the AKT/GSK 3beta/Snail pathway by PON might be a promising treatment for TNF-alpha-induced EMT and metastasis of CRC. PMID- 30244298 TI - Use of Antidepressants in Patients with Co-occurring Depression and Substance Use Disorders. AB - This chapter reviews antidepressant treatment considerations and recommendations for patients with co-occurring depression and substance use disorders. Depression and substance use disorders are highly comorbid conditions. Substance use disorders are chronic disorders that result in a cluster of symptoms indicating that an individual continues to use a substance despite significant problems resulting from their use. About 17 million Americans have an alcohol use disorder, and another approximately 7 million individuals have other drug use disorders (not including alcohol) in the United States. The rate of any substance use disorder (including alcohol) in individuals with major depressive disorder is 32% based on a national survey. Evidence suggests that the best outcome for individual with co-occurring conditions is treating both conditions simultaneously. Therefore, practitioners should know the following before prescribing antidepressants for patients with co-occurring substance use disorders: (1) treatment recommendations for patients with co-occurring depression and substance use disorders, (2) potential antidepressant interactions with alcohol and drugs of abuse, and (3) do antidepressants have a risk of misuse? Finally, we will summarize antidepressant treatment recommendations for patients with co-occurring depression and substance use disorders. PMID- 30244297 TI - Risk of colon cancer recurrence in relation to diabetes. AB - PURPOSE: To describe the association between diabetes and colon cancer recurrence. METHODS: We conducted a cohort study at two integrated health care delivery systems in the United States. Using tumor registry data, we identified patients aged >= 18 years when diagnosed with stage I-IIIA adenocarcinomas of the colon during 1995-2014. Pre-existing diabetes was ascertained via diagnosis codes. Medical records were reviewed for eligibility and to abstract recurrence and covariate information. Recurrence was ascertained beginning 90 days after the end of colon cancer treatment (i.e., cohort entry). Recurrence of any cancer or a new primary cancer at any site was a secondary outcome. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for the associations between diabetes at cohort entry and study outcomes. RESULTS: Among the 1,923 eligible patients, 393 (16.7%) had diabetes at cohort entry. Diabetes was not associated with recurrence (HR 0.87; 95% CI 0.56 1.33) or with any subsequent cancer (HR 1.09; 95% CI 0.85-1.40). When the definition of recurrence included second primary colorectal cancer, risk was non significantly higher in patients with diabetes than without diabetes. CONCLUSIONS: The risk of colon cancer recurrence appears to be similar in patients with and without diabetes at diagnosis. IMPACT: Future studies should evaluate the association between diabetes and colorectal cancer outcomes, especially second primary colon cancers, in larger populations. PMID- 30244299 TI - Psychometric properties of the Berg balance scale in idiopathic Parkinson' disease in the drug off-phase. AB - BACKGROUND: Having an appropriate tool for assessment of the balance status during the drug off-phase in idiopathic Parkinson's disease (PD) is relevant for clinical and research settings. Our objective was to assess the clinimetric properties of the Berg balance scale (BBS) during drug off-phase in PD. METHOD: Balance of 98 PD patients (mean age +/- SD, 59.19 +/- 10.88 years) was evaluated with the BBS. Other assessments in the study included the Fall Efficacy Scale International (FES-I), Functional Reach Test (FRT), Section II of the Unified Parkinson's Disease Rating Scale-3.0, Parkinson's Disease Questionnaire-39 (PDQ 39), and Schwab and England Activities of Daily Living Scale. All evaluations took place during the drug off-phase. Internal consistency and inter- and intra rater reliability were evaluated by Cronbach's alpha coefficient and intraclass correlation coefficient, respectively. Dimensionality was explored by factor analysis. Discriminative validity was tested by comparing BBS score between PD patients with and without a history of falling. RESULTS: Internal consistency was high (alpha = 0.98), as were intra- and inter-rater reliability (ICC = 0.98 and 0.95, respectively). Factor analysis identified only one dimension for the BBS, whose convergent validity with FES-I, FRT, and domain mobility of the PDQ-39 were moderate or high (rS = |0.60-0.74|). Correlation of BBS with functional scales and PDQ-39 Summary Index was moderate (rS = |0.45-0.62|). Finally, the BBS showed a moderate strength to discriminate between PD patients with and without a history of falling. CONCLUSION: Our study suggests that BBS has satisfactory internal consistency, reliability, and construct validity for measuring functional balance in people with PD during the drug off-phase. PMID- 30244300 TI - Risk Assessment of Processes and Products in Industrial Biotechnology. AB - Risk assessment has been used extensively as the main approach to prevent accidents in the chemical and process industry. Industrial biotechnology has many of the same hazards as chemical technology, but also encounters biological hazards related to biological agents. Employees in the biotechnology industry are susceptible to health risks because of different types of exposure to harmful agents. The external environment may also be affected by these agents in cases of accidental release. This chapter first presents several traditional risk assessment methods that may be used in industrial biotechnology after comparing differences between industrial biotechnology and chemical technology. Hazard identification in industrial biotechnology is then discussed, for biological as well as traditional hazards. Furthermore, risk assessment of occupational health and safety related to biological hazards is examined using exposure analysis and risk characterization. A two-stage risk assessment method is recommended to assess environmental and ecological risks in industrial biotechnology. Risk analysis of traditional accidents (fire, explosions, and toxic releases) in industrial biotechnology is also described. Graphical Abstract. PMID- 30244301 TI - MEDNIK syndrome with a frame shift causing mutation in AP1S1 gene and literature review of the clinical features. AB - MEDNIK syndrome is an autosomal recessive rare disease as one of the most recently described copper metabolism disorder characterized by intellectual disability, ichthyosis, hearing loss, peripheral neuropathy, enteropathy and keratodermia. Here in, we reported a case presented with ichthyosis and intellectual disability with MEDNIK syndrome that confirmed by mutation analysis in a Turkish child. She was finally diagnosed with MEDNIK syndrome by clinical findings, which were confirmed by molecular genetic testing. Sequencing of AP1S1 gene showed a homozygous insertion c.364dupG (NM_001283.4), which is predicted to cause a frameshift of the reading frame (p.D122Gfs*18). To our knowledge, this is the first case of MEDNIK syndrome from Turkey. Diagnosis of MEDNIK syndrome is still challenging and we hope that this case will contribute to further understanding. PMID- 30244302 TI - Insights into the introduction history and population genetic dynamics of the Argentine black-and-white tegu (Salvator merianae) in Florida. AB - Invasive species are a major threat to global biodiversity. The US state of Florida is especially susceptible to the spread of exotic reptiles due to its subtropical climate, disturbed habitats, and robust pet trade. The Argentine black-and-white tegu (Salvator merianae) is a large, omnivorous lizard currently established in two different regions of Southern Florida. These two populations pose potential threats to sensitive ground nesting species such as gopher tortoises, American crocodiles, and migratory birds. At present, the introduction histories of these populations and the degree to which they are connected by gene flow are largely unknown. To address these issues, we genotyped S. merianae from Hillsborough and Miami-Dade Counties at ten microsatellite loci to assess intrapopulation genetic diversity, the degree of gene flow between populations, and compare the plausibilities of several potential introduction scenarios. Our results indicate that both populations have low genetic diversity [mean number of effective alleles across loci in both populations = 2.09 and are highly differentiated from each other (GST = 0.170; G"ST = 0.545)]. In addition, our results suggest that these populations underwent a bottleneck event prior to their divergence. We discuss what our results suggest about the histories of Florida's invasive tegu populations, as well as how they inform ongoing management strategies. PMID- 30244303 TI - Elevated carbon dioxide and drought modulate physiology and storage-root development in sweet potato by regulating microRNAs. AB - Elevated CO2 along with drought is a serious global threat to crop productivity. Therefore, understanding the molecular mechanisms plants use to protect these stresses is the key for plant growth and development. In this study, we mimicked natural stress conditions under a controlled Soil-Plant-Atmosphere-Research (SPAR) system and provided the evidence for how miRNAs regulate target genes under elevated CO2 and drought conditions. Significant physiological and biomass data supported the effective utilization of source-sink (leaf to root) under elevated CO2. Additionally, elevated CO2 partially rescued the effect of drought on total biomass. We identified both known and novel miRNAs differentially expressed during drought, CO2, and combined stress, along with putative targets. A total of 32 conserved miRNAs belonged to 23 miRNA families, and 25 novel miRNAs were identified by deep sequencing. Using the existing sweet potato genome database and stringent analyses, a total of 42 and 22 potential target genes were predicted for the conserved and novel miRNAs, respectively. These target genes are involved in drought response, hormone signaling, photosynthesis, carbon fixation, sucrose and starch metabolism, etc. Gene ontology and KEGG ontology functional enrichment revealed that these miRNAs might target transcription factors (MYB, TCP, NAC), hormone signaling regulators (ARF, AP2/ERF), cold and drought factors (corA), carbon metabolism (ATP synthase, fructose-1,6 bisphosphate), and photosynthesis (photosystem I and II complex units). Our study is the first report identifying targets of miRNAs under elevated CO2 levels and could support the molecular mechanisms under elevated CO2 in sweet potato and other crops in the future. PMID- 30244304 TI - The Transjugular Approach: An Alternative Route to Improve Ablation Success in Right Anteriorly and Anterolaterally-Located Supraventricular Tachycardia Substrates in Children. AB - Catheter ablation via the femoral vein has been widely used in children. However, in certain conditions, an alternative vascular access is required for a successful ablation. Herein we reported that, accessory pathways (APs) and ectopic foci which reside right anterior and anterolateral to tricuspid valve orifice can be safely and effectively ablated with transjugular venous approach. Eleven procedures performed via the transjugular venous approach were reviewed retrospectively from the 355 electrophysiological procedures performed between March 2016 and November 2017. EnSite 3D electro-anatomic mapping and limited flouroscopy was used in all patients. The mean age of patients was 14.4 +/- 2.9 years (12-18) and 6/11 (54.5%) were males. Seven of the patients had previous ablation procedures via the femoral vein approach and due to failure or recurrence the procedures had to be repeated. In these patients mean procedure time shortened from 196 +/- 80 (105-280) to 111 +/- 13 (96-125) min with the transjugular approach. 10/11 patients had APs, and one patient had focal atrial tachycardia. One of the APs was a Mahaim pathway. Ablation localisations were right anterior and right anterolateral in 8/11 and 3/11 patients respectively. The average fluoroscopy time was 3.38 +/- 6.5 (0-15) min. All of the RF ablations via transjugular approach were successful (100%, 11/11). The mean follow-up period was 10.6 +/- 1.1 (9-12) months. So far no recurrence has been observed. Right anterior and anterolateral regions are the most challenging areas in terms of catheter stabilization even when long sheaths are used during femoral route ablation. Ablation attempts in these regions have partial success, frequent recurrence, and high complication rates. This study revealed that transjugular approach seems as an effective alternative for those cases where transfemoral approach is unsuccessful for the ablation targets located in the right anterior and antero-lateral regions. PMID- 30244305 TI - Organohalogenated Contaminants (OHCs) in Surface Sediments and Water of East Dongting Lake and Hong Lake, China. AB - East Dongting Lake and Hong Lake are two typical lakes in the middle watershed of the Yangtze River, China. The differences in the hydrological condition and human activities of the region may result in the differences in concentrations, distribution, and sources of contaminants. The levels, sources, distribution, and ecological risk of OHCs, including 15 OCPs, 7 PCBs, and 7 PBDEs in surface sediments and water from this region, were investigated. OCPs and PCBs were the predominant pollutants in water and sediments samples, respectively. Source analysis showed that HCHs, PBDEs, and PCBs were mainly from the historical input of commercial products, but there were recent discharges of DDT into the water. The spatial distribution of OHCs showed that higher levels of OHCs in sediments and water were found in the sampling sites far away from the estuary of Hong Lake, but such obvious distribution characteristic was not found in East Dongting Lake. TOC played a crucial role in the retention of OCPs in the sediments of Hong Lake, but significant correlation between TOC and OCPs for East Dongting Lake, TOC and PCBs or PBDEs for both lakes were not found. The possible adverse biological effects could be caused by OCPs residues in sediments of both lakes, and it was worse for Hong Lake. The noncarcinogenic and carcinogenic risk assessment of HCHs and DDTs indicated the water quality of both lakes was safe for bathing and drinking. The potential ecotoxicological risks of PBDEs and PCBs of both lakes were rather low. PMID- 30244306 TI - 3D modelling of non-intestinal colorectal anatomy. AB - PURPOSE: There is a paucity of methods to model soft anatomical tissues. Accurate modelling of these tissues can be difficult with current medical imaging technology. METHODS: The aim of this research was to develop a methodology to model non-intestinal colorectal tissues that are not readily identifiable radiologically to enhance contextual understanding of these tissues and inform medical device design. The models created were used to inform the design of a novel medical device to separate the mesocolon from the retroperitoneum during resection of the colon. We modelled the peritoneum and the mesentery. The mesentery was used to indicate the location of Toldt's fascia. RESULTS: We generated a point cloud dataset using cryosection images as the target anatomy is more visible than in CT or MRI images. The thickness of the mesentery could not be accurately determined as point cloud data do not have thickness. A denser point cloud detailing the mesenteric boundaries could be used to address this. CONCLUSIONS: Expert anatomical and surgical insight and point cloud data modelling methods can be used to model soft tissues. This research enhances the overall understanding of the mesentery and Toldt's fascia in the human specimen which is necessary for medical device innovations for colorectal surgical procedures. PMID- 30244307 TI - Automatic estimation of the aortic lumen geometry by ellipse tracking. AB - PURPOSE: The shape and size of the aortic lumen can be associated with several aortic diseases. Automated computer segmentation can provide a mechanism for extracting the main features of the aorta that may be used as a diagnostic aid for physicians. This article presents a new fully automated algorithm to extract the aorta geometry for either normal (with and without contrast) or abnormal computed tomography (CT) cases. METHODS: The algorithm we propose is a fast incremental technique that computes the 3D geometry of the aortic lumen from an initial contour located inside it. Our approach is based on the optimization of the 3D orientation of the cross sections of the aorta. The method uses a robust ellipse estimation algorithm and an energy-based optimization technique to automatically track the centerline and the cross sections. The optimization involves the size and eccentricity of the ellipse which best fits the aorta contour on each cross-sectional plane. The method works directly on the original CT and does not require a prior segmentation of the aortic lumen. We present experimental results to show the accuracy of the method and its ability to cope with challenging CT cases where the aortic lumen may have low contrast, different kinds of pathologies, artifacts, and even significant angulations due to severe elongations. RESULTS: The algorithm correctly tracked the aorta geometry in 380 of 385 CT cases. The mean of the dice similarity coefficient was 0.951 for aorta cross sections that were randomly selected from the whole database. The mean distance to a manually delineated segmentation of the aortic lumen was 0.9 mm for sixteen selected cases. CONCLUSIONS: The results achieved after the evaluation demonstrate that the proposed algorithm is robust and accurate for the automatic extraction of the aorta geometry for both normal (with and without contrast) and abnormal CT volumes. PMID- 30244308 TI - 1H, 13C and 15N backbone and side-chain assignment of a carbohydrate binding module from a xylanase from Roseburia intestinalis. AB - The N-terminal domain (residues 28-165) from the glycoside hydrolase family 10 from Roseburia intestinalis (RiCBMx), has been isotopically labeled and recombinantly expressed in Escherichia coli. Here we report 1H, 13C and 15N NMR chemical shift assignments for this carbohydrate binding module (CBM). PMID- 30244309 TI - Correction to: Controlled delivery of pirfenidone through vitamin E-loaded contact lens ameliorates corneal inflammation. AB - In the original article the typesetter made several errors. Figures 7 and 9 are incorrect. Following are the correct figures. PMID- 30244310 TI - A case of unique endoscopic findings of intestinal endometriosis exposed to the mucosa: aggregation of papillary protruded bulges from the submucosal elevation of the rectum. AB - Intestinal endometriosis exposed to the mucosa is relatively rare. Therefore, its endoscopic findings with pit pattern and magnifying endoscopy with narrow-band imaging and clinicopathological features of intestinal endometriosis exposed to the mucosa have not been well documented until now. A 44-year-old woman was suspected to have gastrointestinal bleeding by positive fecal occult blood test. Colonoscopy revealed a hemicircular submucosal tumor whose surface was covered with easy-bleeding papillary bulges in the rectum. Pit pattern analysis and magnifying endoscopy with narrow-band imaging revealed straight microvessels among the straight pits arranged in a radial manner, and the avascular area with no pit pattern of the top of the bulge. These findings were different from those of polyps or cancer. Biopsy specimens from the protruded lesions were diagnosed as rectal mucosal endometriosis by hematoxylin-eosin staining and immunohistochemical examination. Surgical resection was suggested to the patient, but the patient did not favor surgical treatment. After the diagnosis dienogest treatment started and successfully relieved her abdominal pain. Malignant transformation of the endometriotic lesion has not arisen to this date. PMID- 30244312 TI - Developmental Change in Adolescent Delinquency: Modeling Time-Varying Effects of a Preventative Intervention and GABRA2 Halpotype Linked to Alcohol Use. AB - Better integrating human developmental factors in genomic research is part of a set of next steps for testing gene-by-environment interaction hypotheses. This study adds to this work by extending prior research using time-varying effect modeling (TVEM) to evaluate the longitudinal associations between the PROSPER preventive intervention delivery system, a GABRA2 haplotype linked to alcohol use, and their interaction on adolescent delinquency. Logistic and Poisson analyses on eight waves of data spanning ages 11 to 19 (60% female, 90% Caucasian) showed the intervention reduced delinquency from ages 13 to 16. Moreover, interaction analysis revealed that the effect of the multicomponent intervention was significantly greater for T-allele carriers of the GABRA2 SNP rs279845, but only during the 13 to 16 age period. The results are discussed in terms of adolescent delinquency normativeness, implications for preventive intervention research, and the utility of incorporating development in GxE research. PMID- 30244311 TI - The intact postsynaptic protein neurogranin is reduced in brain tissue from patients with familial and sporadic Alzheimer's disease. AB - Synaptic degeneration and neuronal loss are early events in Alzheimer's disease (AD), occurring long before symptom onset, thus making synaptic biomarkers relevant for enabling early diagnosis. The postsynaptic protein neurogranin (Ng) is a cerebrospinal fluid (CSF) biomarker for AD, also in the prodromal phase. Here we tested the hypothesis that during AD neurodegeneration, processing of full-length Ng into endogenous peptides in the brain is increased. We characterized Ng in post-mortem brain tissue and investigated the levels of endogenous Ng peptides in relation to full-length protein in brain tissue of patients with sporadic (sAD) and familial Alzheimer's disease (fAD), healthy controls and individuals who were cognitively unaffected but amyloid-positive (CU AP) in two different brain regions. Brain tissue from parietal cortex [sAD (n = 10) and age-matched controls (n = 10)] and temporal cortex [sAD (n = 9), fAD (n = 10), CU-AP (n = 13) and controls (n = 9)] were included and all the samples were analyzed by three different methods. Using high-resolution mass spectrometry, 39 endogenous Ng peptides were identified while full-length Ng was found to be modified including disulfide bridges or glutathione. In sAD parietal cortex, the ratio of peptide-to-total full-length Ng was significantly increased for eight endogenous Ng peptides compared to controls. In the temporal cortex, several of the peptide-to-total full-length Ng ratios were increased in both sAD and fAD cases compared to controls and CU-AP. This finding was confirmed by western blot, which mainly detects full-length Ng, and enzyme-linked immunosorbent assay, most likely detecting a mix of peptides and full-length Ng. In addition, Ng was significantly associated with the degree of amyloid and tau pathology. These results suggest that processing of Ng into peptides is increased in AD brain tissue, which may reflect the ongoing synaptic degeneration, and which is also mirrored as increased levels of Ng peptides in CSF. PMID- 30244314 TI - Verification of modified receiver-operating characteristic software using simulated rating data. AB - ROCKIT, which is a receiver-operating characteristic (ROC) curve-fitting software package, was developed by Metz et al. In the early 1990s, it is a very frequently used ROC software throughout the world. In addition to ROCKIT, DBM-MRMC software was developed for multi-reader multi-case analysis of the difference in average area under ROC curves (AUCs). Because this old software cannot run on a PC with Windows 7 or a more recent operating system, we developed new software that employs the same basic algorithms with minor modifications. In this study, we verified our modified software and tested the differences between the index of diagnostic accuracies using simulated rating data. In our simulation model, all data were generated using target AUCs and a binormal parameter b. In ROC curve fitting with simulated rating data, we varied four factors: the total number of case samples, the ratio of positive-to-negative cases, a binormal parameter b, and the preset AUC. To investigate the differences between the statistical test results obtained from our software and the existing software, we generated simulated rating data sets with three levels of case difficulty and three degrees of difference in AUCs obtained from two modalities. As a result of the simulation, the AUCs estimated by the new and existing software were highly correlated (R > 0.98), and there were high agreements (85% or more) in the statistical test results. In conclusion, we believe that our modified software is as capable as the existing software. PMID- 30244315 TI - Ecological processes determining the distribution dynamics of vole populations during forest succession. AB - The size and distribution of animal populations may vary drastically over time following a disturbance event. While both competition and predation can control the size of animal populations, changes in the relative importance of these two density-dependent processes remain poorly documented during ecological succession. Here, we combined habitat selection and optimal foraging theory to identify the processes that can explain the increase in red-backed voles (Myodes gapperi) during post-logging forest succession in boreal ecosystems. Specifically, we assessed the extent to which changes in intra- and interspecific competition and in predation risk can explain variation in abundance and distribution of voles during post-harvest forest succession. We estimated the abundances of the red-backed vole and of its main competitor, the deer mouse (Peromyscus maniculatus), in adjacent pairs of logged (5-66 years old) forest stands and uncut stands (> 120 years old). We found that voles increased their preference for uncut stands with increasing conspecific density. Foraging experiments revealed that in early-seral forest stands, voles increased their feeding effort in the presence of deer mice, particularly in safer food patches. This behaviour is expected from foraging theory when interspecific competitors increase predation risk. Apparent competition would thus limit the density of red backed voles, and changes in the relative strength of this process during forest succession would control patterns of distribution and abundance of the species. PMID- 30244316 TI - Expanding neuropeptide signalling by multiplying receptor functional states and sub-cellular locations. AB - Neuropeptide signalling is primarily based on activation of G protein-coupled receptors (GPCRs), the largest family of membrane receptors. GPCRs are involved in multiple physiological processes and are important drug targets for many human diseases. In this at a glance review, we focus on the recent advances in GPCR signalling related to the different structural and functional features of complexes involved in G protein- and arrestin-mediated signalling, receptor dimerization and oligomerization, modulation and transactivation of other signalling proteins and receptor compartimentalization. Our goal is to highlight the astonishingly complex and diverse network of signal transduction events that could arise from the activation of neuropeptide receptors. PMID- 30244317 TI - Enrichment of cancer stem cells by agarose multi-well dishes and 3D spheroid culture. AB - As the theory of cancer stem cells (CSCs) is maturing, CSC-targeted therapy is emerging as an important therapeutic strategy and seeking the ideal method for rapid enrichment and purification of CSCs has become crucial. So far, based on the known CSC phenotypes and biological characteristics, the methods for enrichment CSCs mainly include low adhesion culture, low oxygen culture, chemotherapy drug stimulation and side population (SP) sorting but these methods cannot realize quick enrichment of the desired CSCs. Herein, we adopt a novel method that efficiently enriches a certain amount of CSCs through agarose multi well dishes using rubber micro-molds to make cancer cells into cell spheroids (3D). These 3D cancer cell spheroids in the proportions of expression of CSC biomarkers (single stain of CD44, CD44v6 and CD133 or double stain of both CD44 and CD133) were significantly higher than those of the conventional adherent culture (2D) using flow cytometry analysis. In addition, the expression levels of stemness transcription factors such as OCT4, NANOG and SOX2 in 3D were also significantly higher than that in 2D through Western blot (WB) and quantitative polymerase chain reaction (qPCR) assays. In addition, the CSCs in 3D could form colonies with different sizes in soft agar. In conclusion, we developed a new method to enrich some kinds of CSCs, which might be a benefit for future CSC targeted therapy studies and anti-CSC drug screening applications. PMID- 30244318 TI - Exposure-response analysis and simulation of lenvatinib safety and efficacy in patients with radioiodine-refractory differentiated thyroid cancer. AB - PURPOSE: Once-daily lenvatinib 24 mg is the approved dose for radioiodine refractory differentiated thyroid cancer. In a phase 3 trial with lenvatinib, the starting dose of 24 mg was associated with a relatively high incidence of adverse events that required dose reductions. We used an exposure-response model to investigate the risk-benefit of different dosing regimens for lenvatinib. METHODS: A population pharmacokinetics/pharmacodynamics modeling analysis was used to simulate the potential benefit of lower starting doses to retain efficacy with improved safety. The seven lenvatinib regimens tested were: 24 mg; and 20 mg, 18 mg, and 14 mg, all with or without up-titration to 24 mg. Exposure response models for efficacy and safety were created using a 24-week time course. RESULTS: The approved dose of lenvatinib at 24 mg, predicted the best efficacy. However, the lenvatinib dosing regimens of 14 mg with up-titration or 18 mg without up-titration potentially provides comparable efficacy (objective response rate at 24 weeks) and a better safety profile. CONCLUSIONS: Treatment with lenvatinib at starting doses lower than the approved once-daily 24 mg dose could provide comparable antitumor efficacy and a similar or better safety profile. Based on the results from this modeling and simulation study, a comparator dose of lenvatinib 18 mg without up-titration was selected for evaluation in a clinical trial. PMID- 30244319 TI - Comparison of Efficacy and Economic Value of Prandilin 25 and Humalog Mix 25 in Patients with Newly Diagnosed Type 2 Diabetes by a Continuous Glucose Monitoring System. AB - INTRODUCTION: To determine the clinical efficacy and economic value of insulin lispro 25-Prandilin 25 vs. insulin lispro 25-Humalog mix 25 in treatment of newly diagnosed type 2 diabetes mellitus (T2DM) by a continuous glucose monitoring system (CGMS). METHODS: This was a single-center, randomized, case-crossover clinical trial. Participants were randomly allocated to two groups and underwent two kinds of insulin lispro 25 treatment separated by a 1-day washout period. In total, 81 patients with newly diagnosed T2DM with hemoglobin A1c (HbA1c) above 9% were hospitalized and randomly divided to receive Prandilin 25/Humalog mix 25 or Humalog mix 25/Prandilin 25 treatment. All participants were subjected to metformin therapy simultaneously. Glycemic control was reached after 7-8 days Prandilin 25 or Humalog mix 25 treatment; each patient received continuous glucose monitoring (CGM) for 5 consecutive days (from day 1 to day 5). On day 3 of CGM performance, Prandilin 25 treatment was switched to Humalog mix 25 treatment at the same dosage or vice versa. Parameters representing glycemic variability (GV) and postprandial glucose excursions, including 24-h mean blood glucose (24hMBG), 24-h standard deviation of blood glucose (24hSDBG), 24-h mean amplitude of glycemic excursion (24hMAGE), large amplitude of glycemic excursion (LAGE), incremental area under the curve (AUC) for different glucose levels, and postmeal relative areas under the CGM curve (AUCpp) for 1-4 h of each meal, were calculated for each patient. RESULTS: No significant differences were found in the 24hMAGE, 24hMBG, 24hSDBG, LAGE, mean 1-h preprandial blood glucose and the incidence of hypoglycemia between the Prandilin 25 treatment group and Humalog mix 25 treatment group. Similarly, there were no between-treatment differences for AUC and time when blood glucose was below 3.9 mmol/l, between 3.9 mmol/l and 10.0 mmol/l, or above 10.0 mmol/l. Further analysis showed the AUCpp for 1-4 h of each meal for two kinds of treatments were similar. However, the mean estimated cost of Prandilin 25 was only 85% of Humalog mix 25 in one treatment course. CONCLUSION: Prandilin 25 is non-inferior in clinical efficacy compared with Humalog mix 25. In view of the significant difference in the cost of the two kinds of insulin lispro 25, Prandilin 25 is a much more cost-effective anti diabetes drug for management of T2DM. TRIAL REGISTRATION: Chinese Clinical Trial Register identifier, ChiCTR1800015829. PMID- 30244321 TI - Thermoregulatory response to outdoor heat stress of hair sheep females at different physiological state. AB - Forty Dorper * Pelibuey sheep females were used to evaluate the effects of physiological state on physiological variables and serum concentrations of metabolites, thyroid hormones, and electrolytes under outdoor heat stress conditions. Females were selected as follows (n = 10 per group): weaning ewe lambs (WEL; 3 months old), replacement nulliparous ewes (RNE; 8 months old), non pregnant and non-lactating multiparous ewes (NME; 3-4 years old) and lactating multiparous ewes (LME; 3-4 years old). While physiological variables were measured both morning and afternoon, blood samples were collected before feeding in the morning to determine all blood components. Three contrasts were constructed: (1) WEL vs. older ewes, (2) RNE vs. multiparous ewes, and (3) NME vs. LME. Compared with older ewes, WEL had higher (P < 0.01) rectal temperature (RT) and hair coat temperatures through the day, and also higher (P < 0.01) respiratory rate (RR) only in the afternoon. Serum levels of glucose and cholesterol were lower (P <= 0.02) in WEL than in older ewes. Nulliparous ewes compared with multiparous had always similar RT but higher (P <= 0.05) hair coat temperatures in most of the body regions by the morning and higher (P < 0.01) RR, without difference for hair coat temperatures in the afternoon. Only serum glucose (P = 0.07) and urea nitrogen (P < 0.01) levels were affected by parturition number, being lower in multiparous ewes. Regarding the effect of lactation, while RR was unaffected, afternoon RT and hair coat temperatures in most of the body regions through the day were higher (P <= 0.03) in lactating ewes. In addition, LME had lower (P < 0.01) serum levels of glucose, cholesterol, and urea nitrogen, but higher (P = 0.02) triiodothyronine levels than NME. In conclusion, ewe lambs and lactating ewes were less tolerant to heat stress, while nulliparous and multiparous ewes showed similar thermoregulatory ability. PMID- 30244320 TI - Grain development and endogenous hormones in summer maize (Zea mays L.) submitted to different light conditions. AB - Low light is a type of abiotic stress that seriously affects plant growth and production efficiency. We investigated the response mechanisms of summer maize to low light by measuring the changes in endogenous hormones in the grains and during grain filling in summer maize at different light intensities to provide a theoretical basis for the production and management of summer maize under light stress. We applied different light treatments in a field experiment as follows: S, shading from tassel stage (VT) to maturity stage (R6); CK, natural lighting in the field; and L, increasing light from VT to R6. The shading level was 60%, and the maximum illumination intensity of the increasing light treatment on cloudy days was 1600-1800 MUmol m-2 s-1. Compared with the control, shading significantly increased the grain abscisic acid (ABA) content at 5-20 days after pollination and decreased the indole acetic acid (IAA), zeatin riboside (ZR), and gibberellin (GA) contents (P < 0.05). The grain-filling rate decreased under shading conditions. Meanwhile, the grain volume, grain weight, and yield all decreased; the yields in 2013 and 2014 decreased by 61 and 60%, respectively. The grain IAA, ZR, and GA contents were increased by increasing light. The grain ABA content at 5-20 days after pollination did not significantly differ from that of CK (P < 0.05). After 20 days after pollination, the ABA content decreased, the grain-filling rate and the filling duration increased, and the yield increased. However, shading after anthesis increased the grain ABA content and reduced the IAA, ZR, and GA contents. Grain growth and development were inhibited, and the yield decreased. The grain ABA content decreased; the IAA, ZR, and GA contents increased; and the yield increased after increasing light. The results indicate that different light intensities regulated the levels of grains endogenous hormones, which influenced the grain-filling rate and duration, and consequently, regulated grain weight and yield. PMID- 30244322 TI - Effects of climate change-related heat stress on labor productivity in South Korea. AB - This study assessed the potential impact of heat stress on labor productivity in South Korea; as such, stress is expected to increase due to climate change. To quantify the future loss of labor productivity, we used the relationship between the wet-bulb globe temperature and work-rest cycles with representative concentration pathways (RCPs) 4.5 and 8.5 as the climate change scenarios. If only climate factors are considered, then future labor productivity is expected to decline in most regions from the middle of the twenty-first century onwards (2041-2070). From the late twenty-first century onwards, the productivity of heavy outdoor work could decline by 26.1% from current levels under the RCP 8.5 climate scenario. Further analysis showed that regional differences in labor characteristics and the working population had noteworthy impacts on future labor productivity losses. The heat stress caused by climate change thus has a potentially substantial negative impact on outdoor labor productivity in South Korea. PMID- 30244323 TI - ABPP and Host-Virus Interactions. AB - Successful viral infection, as well as any resultant antiviral response, relies on numerous sequential interactions between host and viral factors. These interactions can take the form of affinity-based interactions between viral and host macromolecules or active, enzyme-based interactions, consisting both of direct enzyme activity performed by viral enzymes and indirect modulation of the activity of the host cell's enzymes via viral interference. This activity has the potential to transform the local microenvironment to the benefit or detriment of both the virus and the host, favouring either the continuation of the viral life cycle or the host's antiviral response. Comprehensive characterisation of enzymatic activity during viral infection is therefore necessary for the understanding of virally induced diseases. Activity-based protein profiling techniques have been established as effective and practicable tools with which to interrogate the regulation of enzymes' catalytic activity and the roles played by these enzymes in various cell processes. This paper will review the contributions of these techniques in characterising the roles of both host and viral enzymes during viral infection in humans. PMID- 30244324 TI - Recent Advances in Activity-Based Protein Profiling of Proteases. AB - The activity of proteases is tightly regulated, and dysregulation is linked to a variety of human diseases. For this reason, ABPP is a well-suited method to study protease biology and the design of protease probes has pushed the boundaries of ABPP. The development of highly selective protease probes is still a challenging task. After an introduction, the first section of this chapter discusses several strategies to enable detection of a single active protease species. These range from the usage of non-natural amino acids, combination of probes with antibodies, and engineering of the target proteases. A next section describes the different types of detection tags that facilitate the read-out possibilities including various types of imaging methods and mass spectrometry-based target identification. The power of protease ABPP is illustrated by examples for a selected number of proteases. It is expected that some protease probes that have been evaluated in animal models of human disease will find translation into clinical application in the near future. PMID- 30244325 TI - Spermidine application alleviates salinity damage to antioxidant enzyme activity and gene expression in alfalfa. AB - We investigated whether spermidine (Spd) application alleviates salinity-induced damage in alfalfa (Medicago sativa L), and explored defence mechanisms associated with stress-related ion balance, antioxidant metabolism, and gene expression. We examined the response of 30-day-old alfalfa maintained in hydroponic culture tests for 7 days and subjected to one of six treatments: half-strength Hoagland solution (control); 1% NaCl; 10 MUM Spd + 1% NaCl; 20 MUM Spd + 1% NaCl; 40 MUM Spd + 1% NaCl; and 60 MUM Spd + 1% NaCl. In salinity-stressed plants, chlorophyll b, chlorophyll a + b, and total protein showed significant decreases, while marked increases were detected in relative electrolyte leakage, H2O2 content, glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), glutathione reductase (GR) activity, the Na+/K+ ratio, and APX1, APX2, GR, and SOD gene expression levels. Chlorophyll a and total protein content markedly increased under exogenous application of 20 MUM Spd, while H2O2 content, GSH, SOD, CAT, POD, GR activity, the Na+/K+ ratio, and APX2, GR, and SOD expression levels all decreased. These results indicated that exogenous application of 20 MUM spermidine effectively alleviates salinity-induced damage in alfalfa. These findings could benefit alfalfa cultivation and promote the development and utilization of saline-alkali soil. PMID- 30244326 TI - Female masculinization and reproductive success in Cnesterodon decemmaculatus (Jenyns, 1842) (Cyprinodontiforme: Poeciliidae) under anthropogenic impact. AB - Aquatic organisms are exposed to a myriad of chemical compounds, with particular concerns focused on endocrine disruptors. Growing scientific evidence indicates that these compounds interfere with normal endocrine function and could affect the reproductive system of humans and wildlife. We analyzed the proportion of masculinized females, defined by elongation and fusion of the anal fin rays, and the extent of masculinization, masculinization index, defined by anal fin length divided by the standard length, of Cnesterodon decemmaculatus resident to areas of agricultural and urban-industrial activities in the Arroyo Colorado basin. Additionally, a bioassay was carried out to assess the potential effects of masculinization on reproductive success, measured as the number of viable progenies, using pregnant females from the site downstream of the urban industrial zone. Masculinized females were observed in all sampling sites, particularly downstream of the urban-industrial area, where over 80% of females presented abnormal sexual characteristics and the highest masculinization index was registered. In the laboratory, masculinized adult females showed male mating behavior, and survival of their progeny was lower than those of normal females. To our knowledge, this is the first report of endocrine disruption in field collected C. decemmaculatus, and the first evaluation of the reproductive success of masculinized females. Finally, our results support C. decemmaculatus as an excellent sentinel species due to its wide distribution, easy culture in laboratory conditions, and its potential capability to respond to sources of pollution, particularly endocrine disruptors. PMID- 30244327 TI - Cardiovascular risk factors are important determinants of platelet-dependent thrombin generation in adult survivors of childhood cancer. AB - Cardiovascular disease is the most frequent non-malignant cause of morbidity and mortality in adult survivors of childhood or adolescent cancer. Thrombin generation (TG) analysis gives insight in hypercoagulability as an important mechanism linked to cardiovascular risk factors (CVRFs). In 200 individuals, from the cardiac and vascular late sequelae in long-term survivors of childhood cancer study, TG in platelet-rich plasma (PRP) and platelet-free plasma (PFP) at 1pM tissue factor was investigated. Endogenous thrombin potential (ETP) and peak height were the analysed parameters of a TG curve. Sex-specific multivariable linear regression analysis adjusted for age and CVRFs was used to assess the clinical determinants of TG. Females presented with higher ETP and peak height compared to males, both in PRP and PFP. Hypertension (beta estimate, beta: 184.8 [90.7; 278.8]), obesity (beta: 161.9 [63.9; 259.5]), and HbA1c (beta: 715.6 [97.4; 1333.8]) were associated with higher ETP in PRP only. ETP in PRP was positively associated with obesity and HbA1c in both males and females and with dyslipidemia (beta: 253.07 [72.92; 433.22]) and systolic hypertension (beta: 436.7 [119.02; 754.39]) in females only. CVRFs showed no association with TG variables in PFP. In conclusion, this study presents an important relation between traditional CVRFs and TG in the presence of platelets only. Sex-specific differences in TG with females presenting with higher TG, particularly those with dyslipidemia and systolic hypertension, were demonstrated. These results highlight the potential of the platelet-coagulant function in identifying cancer survivors at higher risk for adverse cardiovascular events. PMID- 30244329 TI - Health and Healthcare Needs of Koreans in San Francisco Bay Area: The Korean Needs Assessment (KoNA) Project. AB - Korean Americans (KA) face a significant burden of health disparities. However, limited data are available on their health needs. This health needs assessment includes a community-based sample of 342 KA from the San Francisco Bay Area. The assessment investigated participants' sociodemographic characteristics, health status, and their healthcare needs. Nearly half of the survey participants rated their health as fair or poor, > 30% did not have a usual place for healthcare, and chronic conditions were prevalent. Limited English Proficiency (LEP) was significantly associated with low self-rated health and having no usual source of care, after adjusting for other sociodemographic factors. Older, LEP KA faced the highest health and health care burden. In addition, females were less likely to be physically active. Males were more likely to smoke. The findings provide guidance in identifying major KA health needs and supports local programming and policy development for KA. PMID- 30244328 TI - Utility of multiplex polymerase chain reaction (PCR) in diarrhea-An Indian perspective. AB - BACKGROUND: Infective diarrhea causes morbidity worldwide. Polymerase chain reaction (PCR)-based pathogen diagnostics of diarrheal stool specimens are shown to be highly sensitive and rapid as opposed to conventional diagnostics. METHODS: We analyzed the performance of FilmArray gastrointestinal (GI) panel, one such multiplex PCR test, on stool specimens in patients presenting with diarrhea to our hospital from March 2016 to September 2017 and compared the results with conventional diagnostic tests. RESULTS: A total of 106 patients were included. The panel detected at least one target in 54 out of 106 patients (50.9%) with results available on the same day. Multiple targets were detected in 26 out of 54 patients who tested positive (48.1%). Bacteria as an isolated etiology for diarrhea was present in 34 patients (62.9%), viruses (16.7%, nine patients), parasites (7.4%, four patients), and multiple pathogens in seven patients (12.9%). Enteroaggregative Escherichia coli (EAEC) was the commonest pathogen detected (in 23, 24% patients). Conventional diagnostic investigations, undertaken in 68/106 (64.1%) patients were positive in 12 (17.65%) as compared to 54/106 (50.9%) (p < 0.0001). Conventional investigations detected a pathogen not included in the study panel in 11 of 52 patients (21.1%). CONCLUSION: FilmArray multiplex PCR panel detects a wide array of GI pathogens including viruses and co infections at a shorter time with more sensitivity compared to conventional diagnostics. Henceforth, it may facilitate treatment decisions, isolation policy, and antimicrobial stewardship in patients with diarrhea requiring hospitalization. PMID- 30244330 TI - Trauma, Post-Migration Stress, and Mental Health: A Comparative Analysis of Refugees and Immigrants in the United States. AB - Numerous studies describe mental health effects of pre-migration trauma and post resettlement stress among refugees, yet less research examines these associations with non-refugee immigrants. Additionally, few studies assess the prevalence and impact of traumatic experiences after settlement in a new country. Using a U.S. based representative sample of Asian (n = 1637) and Latino (n = 1620) refugees and immigrants, we investigated how traumatic events prior to and after migration, and post-migration stressors, are associated with mental illness and distress. Pre-migration trauma posed risk across a broad range of psychological outcomes for Asian refugees and Latino immigrants. Deleterious effects of post migration trauma were notable for both groups of refugees and immigrants. Discrimination, acculturative stress, and family conflict increased risk for disorder and distress across groups in complex ways. Findings highlight the importance of examining trauma and stress at pre- and post-migration phases across migrant populations, including those not labeled as refugees. PMID- 30244331 TI - Actinomycosis Presenting as Macroglossia: Case Report and Review of Literature. AB - Cervicofacial actinomycosis is a common form of Actinomyces infection. However, the latter seldom occurs in the tongue. We present a case of a 66 year-old man with macroglossia caused by actinomycosis of the tongue. Radiographic features were compatible with a chronic inflammatory disease. Biopsies revealed granulomas containing giant cells and Gram positive bacterial clusters consistent with actinomycosis. The patient was treated with a 22 week course of antibiotics. Imaging showed a notable improvement in the extent of the lesions 1 year later. The patient was asymptomatic and in good condition during his second year follow up. Diagnosis of actinomycosis of the tongue can prove to be challenging because of the non-specific nature of its symptoms, clinical signs, and radiographic features. Isolation of Actinomyces sp. is an added diagnostic hurdle, because of its fastidious nature. PMID- 30244332 TI - Endoscopic Dilation of Bariatric RNY Anastomotic Strictures: a Systematic Review and Meta-analysis. AB - Gastrojejunostomy anastomotic strictures are a complication of Roux-en-Y gastric bypass surgery without an established treatment guideline. A systematic review and meta-analysis were performed to determine the safety and efficacy of endoscopic dilation in their management. PubMed, Web of Science, and Cochrane Central (1994-2017) were searched. Data was analyzed with random effects meta analysis and mixed effects meta-regression. Twenty-one observational studies (896 patients) were included. The stricture rate for laparoscopic patients was 6% (95% CI, 5-9%). Only 38% (95% CI, 30-47%) required greater than one dilation. Symptom improvement occurred in 97% (95% CI, 94-98%). The complication rate was 4% (95% CI, 3-6%). Endoscopic dilation of GJA strictures is safe, effective, and sustaining. This study can guide endoscopists in the treatment of a common bariatric surgical complication. PMID- 30244333 TI - Circulating Endocannabinoids Are Reduced Following Bariatric Surgery and Associated with Improved Metabolic Homeostasis in Humans. AB - BACKGROUND: The endocannabinoid (eCB) system plays a key role in the development of obesity and its comorbidities. Limited information exists on the changes in circulating eCBs following bariatric surgery. OBJECTIVES: This study aims to (i) assess the circulating levels of eCBs and related molecules and (ii) examine the association between their levels and numerous clinical/metabolic features pre- and post-operatively. METHODS: Sixty-five morbidly obese patients (age 42.78 +/- 9.27 years; BMI 42.00 +/- 5.01 kg/m2) underwent laparoscopic sleeve gastrectomy (LSG) surgery, and were followed up for 12 months. Data collected included anthropometrics and metabolic parameters. The serum levels of the eCBs, 2 arachidonoylglycerol (2-AG), anandamide (AEA); and their related molecules, arachidonic acid (AA) and oleoylethanolamine (OEA) were measured by liquid chromatography-mass spectrometry. RESULTS: Levels of 2-AG, AEA, and AA were reduced post operatively with no differences in serum OEA levels. The delta changes in eCB levels between pre- and post-operation were correlated with the delta of different metabolic parameters. Positive correlations were found between delta AA and waist circumference (WC) (r = 0.28, P < 0.05), free fat mass (r = 0.26, P < 0.05), SteatoTest score (r = 0.45, P < 0.05), and ALT (r = 0.32, P < 0.05). Delta AEA levels positively correlated with WC (r = 0.30, P < 0.05). Delta 2-AG levels positively correlated with total cholesterol (r = 0.27, P < 0.05), triglycerides (r = 0.55, P < 0.05), and SteatoTest score (r = 0.27, P < 0.05). Delta OEA levels negatively correlated with fasting glucose levels (r = - 0.27, P < 0.05). CONCLUSIONS: This study provides compelling evidence that LSG surgery induces reductions in the circulating 2-AG, AEA, and AA levels, and that these changes are associated with clinical benefits related to the surgery including reduced fat mass, hepatic steatosis, glucose, and improved lipid profile. PMID- 30244335 TI - New study suggests patients with advanced prostate cancer on androgen deprivation therapy need more dialogue with health care provider, especially around cardiovascular risk. AB - PURPOSE: To study the current level of patients' awareness, and patient-health care provider (HCP) dialogue with respect to treatment-related risks, especially cardiovascular risk (CVR) associated with advanced prostate cancer (PCa) treatment. METHODS: This 10-min online survey summarised data by treatment, region, and CVR (high or low). RESULTS: Of the 411 patients, 83% were at high CVR while only 8% patients were aware of CVR associated with PCa treatment, majority of which (80%) were informed about this risk by HCPs. No significant difference in treatment approach was reported, regardless of patient's CVR status. Compared to other potential risks, patients were more likely to initiate discussion about heart problems with HCPs (38% patients). When prompted, 26% patients rated heart problems as the most concerning risk factor, and this concern was twice in patients with high CVR (28%) versus low CVR (14%). Lifestyle modifications were made by 64% patients, of which 45% patients reported an improvement in overall well-being. Improved diet was the most adopted lifestyle modification. CONCLUSION: There is a need to enhance a constant patient-HCP dialogue, and both groups need to make a conscious effort in that direction. This would help in increasing patients' awareness of risks, having better treatment choice and acceptance, and reducing side-effects. PMID- 30244334 TI - Treatment of NASH with Gastric Bypass. AB - PURPOSE OF REVIEW: Nonalcoholic steatohepatitis (NASH) is a spectrum of nonalcoholic fatty liver disease (NAFLD). It is defined as the presence of fatty liver along with inflammation and hepatocyte injury. To date, weight loss achieved via lifestyle intervention remains the mainstay of NASH treatment. However, given the known benefit of weight loss on NASH and the known effect of bariatric surgery on weight loss, several studies have explored the potential role of bariatric surgery on the treatment of NASH. RECENT FINDINGS: This review article summarizes the evidence on the effect of Roux-en-Y gastric bypass (RYGB), a common bariatric surgery, on NASH therapy. Specifically, studies show that RYGB is associated with an improvement of all NASH histologic features at 1 year. Compared to adjustable gastric band, RYGB appears to be superior at treating NASH. Randomized controlled trials and long-term studies are underway to better clarify the role of these procedures specifically for NASH therapy. PMID- 30244336 TI - Paclitaxel resistance and the role of miRNAs in prostate cancer cell lines. AB - PURPOSE: To investigate the expression profiles of 86 miRNAs in paclitaxel resistant prostate cancer cell lines and to identify the genes that have a role in the development of drug resistance. METHODS: Three prostate cancer cell lines, androgen-dependent VCaP, androgen-independent PC-3 and DU-145, were used to obtain paclitaxel-resistant cells by progressively increasing the concentration of paclitaxel in the culture medium. Viability assays with 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium and sulforhodamine B were used to assess the cell resistance level and cytotoxic effects of paclitaxel treatment. Total RNA was isolated from both prostate cancer cell lines and their resistant versions, and cDNA samples were reverse transcribed from total RNA. Selected target genes of miRNAs that showed differences in expression and were estimated to be effective on drug resistance mechanism were analyzed with western blot analysis. RESULTS: Expression study of 86 miRNAs by RT-PCR demonstrated that several of the miRNAs were expressed at different levels in paclitaxel-resistant cells compared to wild type cells. Moreover, the expression profiles of these miRNAs varied among different prostate cancer cell line types, with 13 miRNAs being up-regulated in the resistant cells. Among these, miR-200b-3p, miR-34b-3p and miR-375 exhibited a marked up-regulation. Further, miR-100-5p showed a prominent increase in paclitaxel-resistant VCaP-R and DU145-R cells. Western blot and RT-PCR studies showed that only the LARP1 and CCND1 genes were over-expressed up to 2-5 times in all paclitaxel-resistant cell lines compared to the other investigated genes. CONCLUSIONS: In this study, the three paclitaxel-resistant prostate cancer cell lines examined showed remarkably different miRNA expression profiles. PMID- 30244337 TI - Ultrasound-guided versus fluoroscopy-guided percutaneous nephrolithotomy: a systematic review and meta-analysis. AB - PURPOSE: To evaluate the efficacy and safety of ultrasound-guided (UG) versus fluoroscopy-guided (FG) percutaneous nephrolithotomy (PCNL). METHODS: A systematic search of PubMed (MEDLINE), Embase, and the Cochrane Library was conducted to identify randomized controlled trials that compared UG-PCNL with FG PCNL, and a meta-analysis of those studies was completed. The primary outcomes assessed were stone-free rate (SFR) and complication rate. Secondary outcomes assessed were the successful access-creation rate, time necessary for entrance into the target calyx, auxiliary procedure rate, transfusion rate, hemoglobin decrease after surgery, surgery duration, and hospital stay. RESULTS: Eight studies comprising 966 patients were included in the meta-analysis. Compared with FG-PCNL, UG-PCNL had comparable stone-free rates [odds ratio (OR) 0.95; 95% confidence interval (CI) 0.67-1.35; p = 0.79] irrespective of the patient's position, and a favorable safety profile resulting in a lower complication rate (OR 0.56; 95% CI 0.36-0.86; p = 0.009). No statistical difference was found between UG and FG groups in secondary outcomes. CONCLUSIONS: UG-PCNL is as effective as FG-PCNL and has the advantage of lower complication rates. In addition, UG-PCNL could be performed with patients in the supine position without compromising its efficacy. PMID- 30244338 TI - Health Care Costs Associated With Muscle Weakness: A UK Population-Based Estimate. AB - Sarcopenia and muscle weakness are responsible for considerable health care expenditure but little is known about these costs in the UK. To address this, we estimated the excess economic burden for individuals with muscle weakness regarding the provision of health and social care among 442 men and women (aged 71-80 years) who participated in the Hertfordshire Cohort Study (UK). Muscle weakness, characterised by low grip strength, was defined according to the Foundation for the National Institutes of Health criteria (men < 26 kg, women < 16 kg). Costs associated with primary care consultations and visits, outpatient and inpatient secondary care, medications, and formal (paid) as well as informal care for each participant were calculated. Mean total costs per person and their corresponding components were compared between groups with and without muscle weakness. Prevalence of muscle weakness in the sample was 11%. Mean total annual costs for participants with muscle weakness were L4592 (CI L2962-L6221), with informal care, inpatient secondary care and primary care accounting for the majority of total costs (38%, 23% and 19%, respectively). For participants without muscle weakness, total annual costs were L1885 (CI L1542-L2228) and their three highest cost categories were informal care (26%), primary care (23%) and formal care (20%). Total excess costs associated with muscle weakness were L2707 per person per year, with informal care costs accounting for 46% of this difference. This results in an estimated annual excess cost in the UK of L2.5 billion. PMID- 30244339 TI - Large Bone not Necessarily High Bone Mineral Density: Evidence from a National Survey. AB - There is scarcity of population-level data on the bone areal size (BA) that produces the highest bone mineral density (BMD), and how BA relates to BMD among racial groups. We use population-level data to estimate the BA that coincide with the highest BMD among racial groups in the United States. A total of 7425 participants, age 18-75 years, whose BA and BMD were measured in the United States National Health and Nutrition Examination Survey (NHANES) 2009-2014, were assessed in this study. Multiple regression models were used to estimate race specific relationships between BA and BMD. The critical BA that associates with the highest (peak) BMD among racial groups adjusted for confounders was estimated. Results showed a curvilinear relationship between BA and BMD at the population level such that BMD increases with BA at lower values and then decreases after a peak value. Races combined, BA of about 45 cm2 seems to correspond to a peak femur BMD in this sample. The peak BMD was different among racial groups. The BA at which BMD peaks was lower among blacks and Mexicans compared to whites. We conclude that femur BMD increases up to a critical femur BA and then decreases thereafter. Persons with femur BA at or close to the critical value may tend to have higher than average BMD. PMID- 30244340 TI - Modern cemented total knee arthroplasty design shows a higher incidence of radiolucent lines compared to its predecessor. AB - PURPOSE: To prevent early failure it is necessary to evaluate modern TKA system for possible shortcomings during implantation. The aim of this study was to evaluate the radiographic outcome and short-term survival of a modern cemented primary TKA system compared to its predecessor. METHODS: The authors reviewed 529 primary cemented TKAs [276 Attune (ATT) and 253 PFC Sigma (PFC)], which were implanted between 2014 and 2017 concerning the radiographic outcome and short term survival. Radiographs were taken before discharge, 6 weeks, 6 months and 12 months postoperatively. Radiographic analysis was performed by two independent assessors using the Modern Knee Society Radiographic Evaluation System. RESULTS: The incidence of radiolucent lines was significantly higher in the ATT group compared with the PFC group 12 months postoperatively (35.1%; n = 97 TKAs vs. 7.5%; n = 19 TKAs; p < 0.001). Survival analysis could not show any differences in revision-free survival or revision rate. CONCLUSION: The modern primary TKA system shows an increased number of radiolucent lines, especially on the tibial component in this short-term analysis and may mostly be due to technique-related issues. Patients with those radiolucent lines even though they show no clinical evidence for loosening should be closely monitored at regular intervals. These findings are of vital clinical importance because surgeons should be aware of particular challenges in preparation and cementing technique once they are using this TKA-system. LEVEL OF EVIDENCE: Retrospective cohort study, Level III. PMID- 30244341 TI - Obstructive sleep apnea affects complication rates following knee arthroscopy but use of continuous positive airway pressure is not protective against complications. AB - PURPOSE: Obstructive sleep apnea (OSA) has not been studied as a risk factor for complications following knee arthroscopy. The goals of this study were to: (1) compare complication rates after knee arthroscopy between patients with and without OSA and (2) evaluate whether continuous positive airway pressure (CPAP) mitigated complication rates. METHODS: A national private insurance database was queried for patients undergoing simple knee arthroscopy from 2007 to 2016. Patients with a diagnosis of OSA were then identified using ICD-9/10 codes. Patients with OSA were then subdivided into cohorts with and without a billing code for a CPAP device. Adverse events within 30 days postoperatively related to OSA were then assessed in all groups: (1) emergency room (ER) visit, (2) hospital admission, (3) pulmonary embolism (PE), (4) myocardial infarction, (5) respiratory arrest and (6) in-hospital mortality within 6 months postoperatively. Adverse event rates were compared between the control and study groups using a multivariable regression analysis. RESULTS: 97,036 patients underwent simple knee arthroscopy with 8656 patients having a diagnosis of OSA. Of these, 3820 (44%) had orders for CPAP machines. After controlling for confounders, patients with OSA had significantly higher risk of ER visits, PE and respiratory arrest compared to controls (p < 0.05). The majority of these significant findings persisted regardless of CPAP use. There were no significant differences in complication rates between OSA patients with and without CPAP orders. CONCLUSIONS: OSA appears to be independently associated with a higher risk for ER visits, PE and respiratory arrest following knee arthroscopy after controlling for demographic and comorbidity confounders. An order for CPAP was not associated with a significant reduction the risk for these complications. CPAP noncompliance may not be as important a factor when risk stratifying patients undergoing ambulatory knee arthroscopy compared to more significant medical comorbidities. LEVEL OF EVIDENCE: III. PMID- 30244342 TI - A threshold value of 3.5 mm of passive anterior tibial subluxation on MRI is highly specific for complete ACL tears. AB - PURPOSE: To identify and quantify passive anterior tibial subluxation on MRI using a standardized measurement protocol and determine the diagnostic threshold of subluxation for complete anterior cruciate ligament tears. METHODS: A retrospective case-control study was performed. Patients who underwent surgery for a complete isolated ACL tear between 2009 and 2015 were matched for age and gender to controls with an intact ligament on knee MRI. All subjects underwent 1.5 T closed field MR imaging with the same protocol. Measurements were performed on axial sequences to evaluate translation of the medial and lateral condyles compared to the tibial plateau. Each compartment was measured between the vertical tangent to the posterior femoral condyles and the most posterior part of the tibial plateau. The main criterion was global passive subluxation measurements on MRI, corresponding to mean medial and lateral compartment subluxation. The reproducibility and diagnostic value of passive subluxation were calculated. RESULTS: Sixty (30/30) subjects were included, mean age 27.1 +/- 1.7 years, 20 women and 40 men. Patients had a significantly higher global passive subluxation than controls (3.3 +/- 0.6 mm vs 0.6 +/- 0.2 mm, respectively p < 0.00001). Reproducibility was excellent and the diagnostic value of passive subluxation for a complete ACL tear was fair. A passive subluxation threshold of 3.5 mm had a sensitivity of 55.2%, a specificity of 100% and 77.6% of well classified subjects. CONCLUSION: The calculated cutoff value for global passive subluxation to identify patients with a complete ACL tear was 3.5 mm, with excellent specificity and a high positive likelihood ratio. Suboptimal clinical results following ACL reconstruction could be partially due to failure to restore an anatomical femorotibial relationship. LEVEL OF EVIDENCE: III. PMID- 30244343 TI - Reoperation for inguinal hernia recurrence in Ontario: a population-based study. AB - PURPOSE: Despite the frequency with which inguinal hernia repairs (IHR) are performed, the real-world comparative effectiveness of laparoscopic versus open repairs is not well established. We compared the rate of recurrent inguinal hernia after laparoscopic and open mesh procedures. METHODS: We designed a population-based retrospective cohort study using linked administrative databases including adult patients in Ontario, Canada, who underwent primary IHR from April 1, 2003 to December 31, 2012. Patients were followed to August 31, 2014. Our primary outcome was reoperation for recurrent IHR, with covariate adjustment using Cox proportional hazards modeling. We constructed separate models to evaluate the effect of surgeon caseload on recurrence rates. RESULTS: We identified 93,501 adults undergoing primary IHR (85.4% open with mesh and 14.6% laparoscopic) with a median follow-up of 5.5 years. The 5-year cumulative risk of recurrent IHR was 2.0% in the open group and 3.4% in the laparoscopic group. After adjusting for patient and surgeon factors, we found that patients who underwent laparoscopic repair had a higher risk of recurrent IHR than those who underwent open repair when annual surgeon volume in the preceding year was <=25 technique-specific cases (HR 1.76; 95% CI 1.45-2.13) or 26-50 technique-specific cases (HR 1.78; 95% CI 1.08-2.93). Few high-volume laparoscopic surgeons (> 50 cases/year) could be identified. Laparoscopic IHR did not carry a higher risk of recurrence for patients whose surgeons had performed > 50 technique-specific cases in the preceding year (HR 1.21; 95% CI 0.45-3.26). CONCLUSION: Laparoscopic IHR is generally associated with a higher risk of recurrence than open IHR. Though high-volume surgeons may be able to achieve equivalent results with laparoscopic and open techniques, few surgeons in our study population met this volume criterion for laparoscopic repairs. PMID- 30244345 TI - An 11-year analysis of reoperated groins after endoscopic totally extraperitoneal (TEP) inguinal hernia repair in a high volume hernia center. AB - BACKGROUND: Developments in inguinal hernia surgery have substantially lowered recurrence rates, yet recurrences remain an important outcome parameter of inguinal hernia repair. The aim of this study was to analyze the characteristics of all reoperated groins after endoscopic totally extraperitoneal (TEP) inguinal hernia repair in a high-volume hernia clinic in the Netherlands. METHODS: All groins with recurrence-like symptoms reoperated after previous TEP inguinal hernia repair between January 2006 and December 2016 were analyzed. Patient characteristics, imaging findings, primary hernia type, time to recurrence and recurrence type were assessed. RESULTS: A total of 137 groins were reoperated in 130 patients. The median age at the TEP procedure was 55 years [interquartile range (IQR) 45-64 years]. Fifty-seven groins were initially part of a bilateral procedure (42%). Median time until recurrence was 9 months (IQR 4-26 months). Reoperation findings were a hernia recurrence in 76%, an isolated lipoma in 18%, and no recurrence or lipoma in 6%. The majority of hernias recurred at their initial site (70%), of which the greatest part involved direct hernias. Isolated lipomas were more frequently seen after indirect hernia repair. CONCLUSIONS: Inguinal hernia recurrences were still observed in this high-volume hernia clinic. Recurrences were most frequently seen at their initial hernia site, the majority involving direct hernias. Isolated lipomas presenting as a pseudorecurrence were most frequently seen after correction of indirect hernias. In accordance with the current guidelines, reducing recurrence rates can be achieved by mesh fixation in bilateral, large and direct defects and by thoroughly reducing lipomas. PMID- 30244344 TI - Robotic transabdominal retromuscular umbilical prosthetic hernia repair (TARUP): observational study on the operative time during the learning curve. AB - PURPOSE: The use of extraperitoneal mesh in place of intra-peritoneal mesh is gaining popularity in laparoscopic ventral hernia repair. We have adopted a robotic assisted laparoscopic technique using a lateral single-dock robotic access with retromuscular mesh placement after opening the ipsilateral posterior rectus fascia. In this study, we wanted to evaluate the changes in operative times during the initial experience with this novel technique. METHODS: The initial consecutive patients undergoing robotic assisted transabdominal retromuscular umbilical prosthetic repair (r-TARUP) using a 15 * 15 cm self fixating mesh were prospectively entered in the study and the operative times during the separate steps of the surgical procedure were recorded. Complications were reported up to 4 week post operatively and quality of life was assessed using the EuraHS-QoL score. RESULTS: Over a 5 month inclusion period, 41 patients with either a primary (n = 34) or a trocar site hernia (n = 7) at the umbilicus were identified. All hernias had a mean diameter of less than 4 cm. The total OR time decreased significantly during the learning curve (tertile 1: 126 min versus tertile 3: 102 min; p = 0.002) due to a decrease in the skin-to-skin operating time (tertile 1: 81 min versus tertile 3:61 min; p = 0.002). The decrease in the retromuscular dissection time was the most significant of all the steps that comprised the console time (p = 0.004). The non-surgical time did not decrease (p = 0.15). The operation was performed on an outpatient basis in 68% of patients and with a one-night-stay in 29%. No complications related to the introduction of the robotic technique for this approach were observed and the early outcome is promising, with favorable quality-of-life evaluation at 4 weeks. CONCLUSIONS: The decrease in operative time during the adoption of r-TARUP was mainly related to the improved efficiency in the dissection phase of the procedure. The technique is reproducible and safe and the operative time compares favorably to published operative times for laparoscopic and open retromuscular umbilical hernia repair. PMID- 30244346 TI - Structures, intermolecular interactions, and chemical hardness of binary water organic solvents: a molecular dynamics study. AB - The evolution of structural properties, thermodynamics and averaged (dynamic) total hardness values as a function of the composition of binary water-organic solvents, was rationalized in view of the intermolecular interactions. The organic solvents considered were ethanol, acetonitrile, and isopropanol at 0.25, 0.5, 0.75, and 1 mass fractions, and the results were obtained using molecular dynamics simulations. The site-to-site radial distribution functions reveal a well-defined peak for the first coordination shell in all solvents. A characteristic peak of the second coordination shell exists in aqueous mixtures of acetonitrile, whereas in the water-alcohol solvents, a second peak develops with the increase in alcohol content. From the computed coordination numbers, averaged hydrogen bonds and their lifetimes, we found that water mixed with acetonitrile largely preserves its structural features and promotes the acetonitrile structuring. Both the water and alcohol structures in their mixtures are disturbed and form hydrogen bonds between molecules of different kinds. The dynamic hardness values are obtained as the average over the total hardness values of 1200 snapshots per solvent type, extracted from the equilibrium dynamics. The dynamic hardness profile has a non-linear evolution with the liquid compositions, similarly to the thermodynamic properties of these non-ideal solvents. Graphical abstract Computed dynamic total hardness, as a function of the cosolvent mass fraction for water-ethanol (EtOH), water-isopropanol (2PrOH) and water-acetonitrile (AN). PMID- 30244347 TI - Expectant management surveillance for patients at risk for invasive squamous cell carcinoma of the anus: a large US healthcare system experience. AB - PURPOSE: To determine the impact of expectant management surveillance for patients at risk for squamous cell carcinoma of the anus (SCCA). METHODS: Adult patients at risk for anal cancer, specifically those with human immunodeficiency virus (HIV) or known human papilloma virus (HPV) infections (anal dysplasia, anogenital warts, cervical dysplasia, or cervical cancer), underwent expectant management surveillance with targeted therapy of only grossly abnormal or symptomatic anoderm lesions. A retrospective analysis investigated the SCCA incidence in these surveilled populations and in the general population patients without known HIV or HPV infection. RESULTS: There were 452 incident SCCA in a population of 5,978,510 patients (mean follow-up per patient of 5.4 years). Four hundred ten cancers (90.7%) developed in 5,750,501 HIV-negative patients without documented history of HPV infection (cumulative incidence 0.007%). In at-risk patient populations, the cumulative incidence was 0.69% in patients with anal dysplasia (6 out of 872 patients), 0.14% in HIV+ patients (8 out of 5626 patients), and less than 0.1% in the remaining at-risk groups: cervical cancer (1 out of 1168 patients), cervical dysplasia (14 out of 125,604 patients), and genital warts (14 out of 94,739 patients). CONCLUSIONS: Expectant management surveillance, with targeted treatment for symptomatic or abnormal lesions, is an effective strategy for the diagnosis of anal cancer in at-risk patient populations. In this study, most patients who developed anal cancer had no known risk factors. A screening strategy for the general population needs to be further delineated. PMID- 30244348 TI - Effects of replacing maize offal with high levels of yam peels on the performance and nutrient digestibility of red Sokoto bucks. AB - Sixteen red Sokoto (RS) bucks having an average weight of 9.11 kg and aged 5-8 months were used to determine the performance and digestibility of diets containing graded levels of yam peel meal in a completely randomized design. Four diets were compounded to replace maize offal with yam peel meal (YPM) at 0% (T1), 50% (T2), 75% (T2), and 100% (T4) levels and fed to the red Sokoto bucks for 105 days. Results show that there was no effect of treatment on all the performance parameters measured. There was also no effect of treatment on dry matter, organic matter, crude protein, nitrogen free extract, and ether extract digestibility of RS bucks. The cell wall constituents showed treatment effects on acid detergent fiber, acid detergent lignin, and cellulose. The nutrient intake values for the proximate composition were similar across the treatments. However, ether extract (EE) values decreased significantly (P < 0.05) from T1 to T4 as the levels of YPM increased in the diets. Ash values on the other hand increased significantly (P < 0.05) from T1 to T4 with increasing levels of YPM. The neutral detergent fiber (NDF) intake value for the control (T1) was significantly higher (P < 0.05) than the other treatments, but there was no significant difference between T2, T3, and T4. The study has shown that YPM can be used to replace maize offal up to 100% without adverse effect on the growth performance and digestibility of red Sokoto goats. PMID- 30244350 TI - Effects of combined menaquinone-4 and PTH1-34 treatment on osetogenesis and angiogenesis in calvarial defect in osteopenic rats. AB - PURPOSE: The aim of this study was to evaluate the effect of combining human parathyroid hormone (1-34) (PTH1-34; PTH) and menaquinone-4 (MK-4) on calvarial bone defect repair in osteopenic rats. METHODS: Fourteen week olds were subject to craniotomy for the establishment of osteopenic animal models fed through a chronically low-protein diet. After that, critical calvarial defect model was established and all rats were randomly divided into four groups: sham, MK-4, PTH, and PTH + MK-4. The animals received MK-4 (30 mg/kg/day), PTH1-34 (60 MUg/kg, three times a week), or PTH1-34 (60 MUg/kg, three times a week) plus MK-4 (30 mg/kg/day) for 8 weeks, respectively. Serum gamma-carboxylated osteocalcin (Gla OC) levels, histological and immunofluorescent labeling were employed to evaluate the bone formation and mineralization in calvarial bone defect. In addition, Microfil perfusion, immunohistochemical, and micro-CT suggested enhanced angiogenesis and bone formation in calvarial bone healing. RESULTS: In this study, treatment with either PTH1-34 or MK-4 promoted bone formation and vascular formation in calvarial bone defects compared with the sham group. In addition, combined treatment of PTH1-34 plus MK-4 increased serum level of Gla-OC, improved vascular number and vascular density, and enhanced bone formation in calvarial bone defect in osteopenic conditions as compared with monotherapy. CONCLUSIONS: In summary, this study indicated that PTH1-34 plus MK-4 combination therapy accelerated bone formation and angiogenesis in calvarial bone defects in presence of osteopenia. PMID- 30244351 TI - Denoising Brain Images with the Aid of Discrete Wavelet Transform and Monarch Butterfly Optimization with Different Noises. AB - The aim of this paper is to denoise the high noise density image proficiently with minimal computation cost using various techniques. This paper proposes an approach for image denoising based on Discrete Wavelet Transform (DWT) in association with Monarch Butterfly Optimization (MBO) technique. Along with Gaussian noise, salt & pepper and speckle noise are added to the image and DWT is applied on the noisy image. The Haar wavelet is used to segregate the sub bands and threshold operation is carried out in three bands. The wavelet coefficient optimization process is performed for optimizing the coefficient value with the assistance of MBO technique. In this wavelet-optimized parameter, the inverse DWT (IDWT) is applied. The proposed method decreases the noise from images more efficiently. The result exhibits that MBO technique is better than the existing and other traditional techniques as it minimize the mean square error (MSE). This process is validated with PSNR value and implemented in MATLAB. PMID- 30244352 TI - Paraoxonase 1 Gene L55M Polymorphism and Paraoxonase 1 Activity in Obstructive Sleep Apnea Patients. AB - The antioxidant enzyme paraoxonase-1 (PON1) may limit oxidative stress in the development of cardiovascular diseases (CVD) and obstructive sleep apnea (OSA). The aim of the study was to determine PON1 gene L55M polymorphism in OSA-positive and OSA-negative subjects, along with paraoxonase activity of the enzyme (PON1 act). Caucasians aged 25-75, with BMI 19.0-53.0 kg/m2 and no acute or severe chronic disorder underwent polysomnography, and OSA-negative (n = 44) and OSA positive (n = 57) groups were established. The following parameters were assessed: arterial blood pressure and serum glucose, lipids, C-reactive protein, and homocysteine. Genomic DNA was extracted and amplified, and automatic sequencing was used to confirm the LL, LM, MM genotypes. PON1-act was measured spectrophotometrically using paraoxon as a substrate. We found that frequency of polymorphisms differed significantly between the OSA-negative and OSA-positive patients (p < 0.05). Increased PON1-act was observed in the LL-genotype versus the LM + MM-genotype in the study population (p < 0.05). PON1-act was higher in the OSA-negative compared with OSA-positive patients (p < 0.001); in general and in the subgroups presenting the LL or LM genotype. In addition, there was an inverse relationship between PON1-act and LDL-cholesterol in the entire study population. The OSA-positive group presented an inverse relationship between PON1 act and fasting glucose. We conclude that patients could benefit from the LL genotype related with higher activity of PON1. OSA pathology might decrease the enzyme activity, despite the presence of L allele. PMID- 30244353 TI - Mitigation of drought-induced oxidative damage by enhanced carbon assimilation and an efficient antioxidative metabolism under high CO2 environment in pigeonpea (Cajanus cajan L.). AB - In the current study, pigeonpea (Cajanus cajan L.), a promising legume food crop was assessed for its photosynthetic physiology, antioxidative system as well as C and N metabolism under elevated CO2 and combined drought stress (DS). Pigeonpea was grown in open top chambers under elevated CO2 (600 umol mol-1) and ambient CO2 (390 +/- 20 umol mol-1) concentrations, later subjected to DS by complete water withholding. The DS plants were re-watered and recovered (R) to gain normal physiological growth and assessed the recoverable capacity in both elevated and ambient CO2 concentrations. The elevated CO2 grown pigeonpea showed greater gas exchange physiology, nodule mass and total dry biomass over ambient CO2 grown plants under well-watered (WW) and DS conditions albeit a decrease in leaf relative water content (LRWC). Glucose, fructose and sucrose levels were measured to understand the role of hexose to sucrose ratios (H:S) in mediating the drought responses. Free amino acid levels as indicative of N assimilation provided insights into C and N balance under DS and CO2 interactions. The enzymatic and non-enzymatic antioxidants showed significant upregulation in elevated CO2 grown plants under DS thereby protecting the plant from oxidative damage caused by the reactive oxygen species. Our results clearly demonstrated the protective role of elevated CO2 under DS at lower LRWC and gained comparative advantage of mitigating the DS-induced damage over ambient CO2 grown pigeonpea. PMID- 30244354 TI - Response to "On the appropriate use of QCA in environmental management research: A comment on Hossu et al." by Ide. PMID- 30244355 TI - Probing into farmers' perceptions of a globally endangered ecosystem service provider. AB - Society's perception of ecosystem services is a key issue in conservation, particularly for endangered species providing services linked to human activities. Misperceptions may lead to wildlife-human conflicts with the risk of disappearance of the species involved. We contrasted farmers' perceptions with highly accurate quantitative data of an endangered vulture species, which provide ecosystem services. We combined surveys of 59 farmers with data from 48 GPS tagged Canarian Egyptian vultures (Neophron percnopterus majorensis endemic to the Spanish Canary Islands) to disentangle factors influencing consistency between farmers' awareness of vulture occurrence on their properties and vulture behavior. Egyptian vultures were perceived as the main providers of scavenging services and the most beneficial avian scavenger. Consistency between farmers' perceptions (surveys) and vulture use of their farms (GPS data) was higher in the morning, in older males, and at farms with lower livestock numbers, located near vulture communal roosts, and visited more frequently by vultures. Our results underline the potential influence of modern livestock husbandry in disconnecting people from ecosystems, and how appreciation could be even lower for scarce or threatened ecosystem service providers. PMID- 30244356 TI - Mind the mind: How to effectively communicate about cognition in social ecological systems research. AB - Social-ecological systems (SES) research underlines the tremendous impact of human behaviour on planet Earth. To enable a sustainable course of humanity, the integration of human cognition in SES research is crucial for better understanding the processes leading to and involved in human behaviour. However, this integration is proving a challenge, not only in terms of diverging ontological and epistemological perspectives, but also-and this has received little attention in SES research-in terms of (lacking) precision of communication regarding cognition. SES scholars often implicitly disagree on the meaning of this broad concept due to unexpressed underlying assumptions and perspectives. This paper raises awareness for the need to communicate clearly and mindfully about human cognition by exemplifying common communication pitfalls and ways of preventing them. We focus on the concept of cognition itself and provide aspects of cognition that need to be communicated explicitly, i.e. different objects of investigation and levels of description. Lastly, we illustrate means of overcoming communication pitfalls by the example of rationality. PMID- 30244357 TI - Risk of Myocardial Infarction After Carbon Monoxide Poisoning: A Nationwide Population-Based Cohort Study. AB - Carbon monoxide poisoning (COP) may lead to ischemic changes in organs, and heart is one of the most susceptible targets to ischemic condition. The objective of this study is to evaluate the risk of myocardial infarction following COP. Using a nationwide database of insurance claims in Taiwan, we conducted a population based cohort study to identify COP patients diagnosed between 1999 and 2012. At a ratio of 3:1, we identified non-COP patients who were matched by the index date and age and compared the risk of myocardial infarction between the two cohorts by time after the index dates of the COP patients, until 2013. We identified 22,258 COP patients and 66,774 non-COP patients. COP patients had an increased risk of myocardial infarction, with an incidence rate ratio of 1.45 (95% confidence interval 1.06-1.98) in comparison with the non-COP patients after adjusting for other independent predictors, including older age, male sex, and underlying comorbidity of hypertension, diabetes, and renal disease. Stratified analyses showed that the increased risk was more prominent in patients with a young age (< 34 years), female sex, and liver disease, and occurred only in the first month of follow-up. We concluded that COP increased the risk of myocardial infarction, but the increased risk was only observed in the first month after COP, which indicated that the impact of COP on the heart was mainly acute. Patients who were younger than 34 years, female, and with liver diseases were more prone to myocardial infarction after COP. PMID- 30244358 TI - An autopsy case of TAFRO syndrome with membranoproliferative glomerulonephritis like lesions. AB - TAFRO syndrome (thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly) is an atypical manifestation of multicentric Castleman's disease. Although overproduction of interleukin-6, vascular endothelial growth factor, and other cytokines may partially explain the pathophysiology of this rare syndrome, the precise mechanisms underlying the renal dysfunction associated with the condition remain unclear. Here, we describe a case of a 69-year-old male with TAFRO syndrome. He was treated with immunosuppressive agents and his renal function improved. Tapering of immunosuppressive agents resulted in a deterioration of renal function and an elevation of C-reactive protein. After 20 months of treatment, the patient died from tuberculous peritonitis and gastrointestinal bleeding. An autopsy revealed miliary tuberculosis, mediastinal lymphadenopathy, and gastric ulcers. Renal histopathology showed a membranoproliferative glomerulonephritis-like appearance. Almost all glomeruli showed lobular formations with mesangial proliferation and duplication of glomerular capillary walls on light microscopy. Immunofluorescence showed deposition of C1q and IgM along the glomerular capillary walls. Electron microscopy showed mesangial expansion and widening of the subendothelial space with a large number of electron-dense deposits. The glomerular lesions might be characteristic of TAFRO syndrome, and were regarded as the main cause of the patient's renal dysfunction. PMID- 30244359 TI - Illness perceptions, depression and anxiety in informal carers of persons with depression: a cross-sectional survey. AB - PURPOSE: To examine the illness perceptions of informal carers of persons with depression, using the theoretical framework of Leventhal's Common-Sense Model (CSM) and to determine whether these illness perceptions are predictors of anxiety and depression, as measures of psychological well-being. METHODS: A cross sectional survey was conducted with 94 Maltese individuals caring for a person with depression within a community setting. The informal carers completed the modified Illness Perception Questionnaire (IPQS-Relatives version) and the Hospital Anxiety and Depression Scale (HADS). Data were analysed using descriptive statistics, Spearman's rank order correlations and ANCOVA regression models, to identify predictors of anxiety and depression respectively in the informal carers. RESULTS: The informal carers perceived depression as a cyclical condition, having negative consequences on both the patient and on themselves. Participants perceived the causes of depression to be mainly psychosocial in nature and generally viewed the treatment as effective. Caring for a person with depression was perceived as having a considerable negative emotional impact on them. Years of caring was identified as a predictor of anxiety accounting for 20.4% of the variance, and timeline chronicity beliefs, consequences (relative) and illness coherence were identified as predictors of depression, accounting for 56.8% of the variance. CONCLUSION: Illness cognitions are significant predictors of depression, thereby suggesting that cognition-based interventions may be effective in targeting depression in these informal carers. Thus, health professionals should explore the carers' personal understanding of the disease, their timeline beliefs and the perceived consequences of providing care, as they relate to their psychological well-being. PMID- 30244360 TI - Psychosocial predictors of quality of life among South Africa adolescents receiving antiretroviral therapy. AB - PURPOSE: Minimal research has been conducted to understand how fatigue influences quality of life (QOL) among adolescents living with HIV. The purpose of the study was to examine the relationship between fatigue, sleep disturbance, depression, anxiety, pain and QOL among adolescents receiving antiretroviral therapy (ART). METHODS: Using a cross-sectional survey design, we studied 134 South African adolescents receiving an ART at community clinics. RESULTS: Participants in general reported low levels of fatigue, insomnia, distress and pain and non problematic levels of QOL. In the regression model, the linear combination of these variables explained 49% of the variance in QOL, a large effect size. Insomnia, anxiety, and depression significantly predicted QOL but surprisingly fatigue and pain did not. CONCLUSIONS: Many members of the sample experienced non clinical levels of sleep disturbance, fatigue and psychosocial distress. Similarly, QOL was within the normal range. These findings are surprising as the commonly held assumption is that adolescents living with HIV, especially those of poorer socio-economic backgrounds, would experience lower QOL than the norm. Even though scores on the instruments measuring these variables fell in the non clinical range, they were still robustly predictive of poor QOL. Future research may address the relationship between self-reported adherence and QOL, possibly by examining the role of viral load as a mediating variable. Further research may also focus on non-adherent adolescents to understand the ways in which fatigue and other factors such as school functioning and social interaction influence QOL. PMID- 30244361 TI - Personal and environmental contextual factors as mediators between functional disability and quality of life in adults with serious mental illness: a cross sectional analysis. AB - PURPOSE: To examine personal and environmental contextual factors as mediators of functional disability on quality of life (QOL) in a sample of individuals with serious mental illness (SMI). METHODS: A cross-sectional analysis of 194 individuals with SMI (major depressive disorder = 38.1%; bipolar disorder = 35.6%; schizophrenia spectrum disorder = 25.8%) recruited from four psychosocial rehabilitation clubhouses was undertaken to test a multiple regression model assuming that personal (i.e., resilience, social competence, and disability acceptance) contextual factors and environmental (i.e., family support, support from friends, and support from significant others) contextual factors would mediate the relationship of functional disability on QOL. The bootstrap test for multiple mediators was then used to test for the significance of the indirect effects functional disability on QOL through the mediators. RESULTS: In the simple regression model, functional disability had a strong relationship with QOL; however, after introducing the potential mediators, its effect was significantly reduced indicating partial mediation effects. The final regression model yielded a large effect, accounting for 44% of the variance in QOL. Controlling for all other potential mediating factors, social competence, disability acceptance, family support, and support from friends were found to partially mediate the relationship between functional disability and QOL. Bias corrected bootstrap procedure results further supported the mediation model. CONCLUSIONS: The findings from the study provide good support for the inclusion of person-environment contextual factors in conceptualizing the relationship between functional disability and QOL for individuals with SMI. PMID- 30244362 TI - Development of a Risk-Scoring Tool to Determine Appropriate Level of Care in Acute Bacterial Skin and Skin Structure Infections in an Acute Healthcare Setting. AB - INTRODUCTION: Acute bacterial skin and skin structure infections (ABSSSIs) represent a large burden to the US healthcare system. There is little evidence based guidance regarding the appropriate level of care for ABSSSIs. This study aimed to develop a prediction model and risk-scoring tool to determine appropriate levels of care. METHODS: This was a single-center observational cohort study of adult patients treated for ABSSSIs from 2012 to 2015 at the Detroit Medical Center. The predictive model used to create a novel risk-scoring tool was derived using multinomial regression analysis. The overall accuracy of this tool was compared to the Clinical Resource Efficacy Support Team (CREST) Classification and Standardized Early Warning Score (SEWS) using area-under-the- receiver-operator-curve (AUROC) analysis and Z-statistic. RESULTS: Final patient disposition was 230 (45.5%) home from the emergency department (ED), 65 (12.8%) observation unit (OU), and 211 (41.7%) initial inpatient. IV antibiotic therapy was used in 358 (70.8%) patients. CREST and SEWS were not accurate in the determination of ED versus OU disposition [AUROC CREST 0.0.682 (95% CI 0.640 0.724), AUROC SEWS 0.686 (95% CI 0.641-0.731)], but performed better in determining ED/OU versus inpatient [AUROC CREST = 0.678 (95% CI 0.630-0.725), AUROC SEWS 0.693 (95% CI 0.645-0.740)]. These scores were also not accurate in determining IV versus PO antibiotic therapy [AUROC CREST = 0.586 (95% CI 0.530 0.624), AUROC SEWS = 0.630 (95% CI 0.576-0.684)]. A risk-scoring tool ranging from 0 to 10 points was derived incorporating WBC, temperature, site of infection, and past medical history of diabetes, liver disease, PVD, AKI, and/or CKD. The AUROC of the new model was 0.675 (95% CI 0.611-0.739) ED versus OU, 0.789 (95% CI 0.748-0.829) ED/OU versus inpatient, and 0.742 (95% CI 0.694-0.789) IV versus oral antibiotics. The new score had a significantly higher AUROC compared to both the CREST and SEWS for determining ED/OU versus inpatient (p < 0.001). CONCLUSION: Prediction models based on patient risk may be useful for determining appropriate level of care during for ABSSSIs. While the prediction model demonstrated moderate to high levels of correlation with patient level of care, further validation of a prospective cohort of patients is warranted. PMID- 30244363 TI - Vaginal Ureaplasma species increase chorioamnionitis in very preterm infants with preterm premature rupture of the membranes at < 28 weeks of gestation. AB - Our aim was to investigate the association between vaginal Ureaplasma species (spp.) and the subsequent occurrence of chorioamnionitis (CAM), perinatal death, neonatal morbidity, and long-term neurodevelopmental impairments (NDIs) at 3 years of age. We analyzed 55 pregnant women with singleton pregnancy who had preterm premature rupture of the membranes (pPROM) at < 28+0 weeks of gestation, and delivered between 22+0 and 31+6 weeks at our tertiary hospital in 2007-2016. NDIs were defined as either cerebral palsy or developmental delay evaluated at 1.5 and/or 3 years old. The presence of Ureaplasma spp. and Mycoplasma hominis were evaluated using urea-arginine broth and Mycoplasma PPLO Agar. The presence of Ureaplasma spp. in the vagina was positive in 41%. Vaginal Ureaplasma spp. was a significant risk factor for CAM; however, it was not significantly associated with the occurrence of perinatal death, pulmonary hypoplasia, respiratory distress syndrome, transient tachypnea of the newborn, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia defined as oxygen required and occasional ventilatory assistance required at week 36 as modified (BPD36), or NDIs. The crude odds ratio (95% confidence interval) of Ureaplasma spp. for the occurrence of CAM was 9.5 (1.10-82) (p = 0.041). In very preterm birth infants with pPROM, CAM, BPD36, and NDIs occurred in 78, 60, and 36%, respectively. Vaginal Ureaplasma spp. was a significant risk factor for CAM in very preterm birth infants with pPROM. The incidences of BPD36 and NDIs in such infants were very high, nearing 3/5 and 1/3, respectively. PMID- 30244364 TI - Coadministration of cytotoxic chemotherapeutic agents with irinotecan is a risk factor for irinotecan-induced cholinergic syndrome in Japanese patients with cancer. AB - BACKGROUND: Cholinergic syndrome is an acute adverse event frequently observed in patients administered irinotecan, and can sometimes negatively affect their quality of life. In some manifestations of the syndrome such as bradycardia, careful monitoring of patients is advised. In this study, we retrospectively investigated the risk factors associated with irinotecan-induced cholinergic syndrome in Japanese patients with cancer. METHODS: Patients who received irinotecan-based chemotherapy between April 2014 and June 2018 were examined. Patient backgrounds and clinical data during the first cycle of an irinotecan containing regimen, including cholinergic syndrome manifestation within 24 h after the start of treatment, were collected from medical records. Univariate and multivariate analyses were performed to assess the risk of irinotecan-induced cholinergic syndrome. RESULTS: Among 179 patients administered an irinotecan containing regimen, 51 experienced cholinergic syndrome after the initiation of treatment. The most common symptom was sweating followed by diarrhea, abdominal pain, lacrimation, and nasal discharge. 42 patients developed symptoms of cholinergic syndrome during their first treatment with irinotecan. Multivariate analyses revealed that the incidences of cholinergic syndrome in patients administered 2 or 3 chemotherapeutic agents; i.e., irinotecan plus 1 or 2 other cytotoxic anticancer drug(s), were significantly higher than that in patients administered irinotecan alone [odds ratio (OR) 4.35, 95% confidence interval (CI) 1.5-12, p = 0.0053 and OR 4.50, 95% CI 1.5-14, p = 0.0093, respectively]. The addition of a molecularly targeted drug did not affect the incidence of cholinergic syndrome. CONCLUSION: The incidence rate of irinotecan-induced cholinergic syndrome increased concomitantly with the addition of cytotoxic chemotherapeutic agents administered. PMID- 30244365 TI - Flutter sensitivity in FM bats. Part I: delay modulation. AB - Echolocating bats measure target distance by the time delay between call and echo. Target movement such as the flutter of insect wings induces delay modulations. Perception of delay modulations has been studied extensively in bats, but only concerning how well bats discriminate flutter frequencies, never with regard to flutter magnitude. We used an auditory virtual reality approach to generate changes in echo delay that were independent of call repetition rate, mimicking fluttering insect wings. We show that in the frequency-modulating (FM) bat Phyllostomus discolor, the sensitivity for modulations in echo delay depends on the rate of the modulation, with bats being most sensitive at modulation rates below 20 Hz and above 50 Hz. The very short duration of their calls compels FM bats to evaluate slow modulations (< about 100 Hz) across entire echo sequences. This makes them susceptible to interference between their own call repetition rate and the modulation rate. We propose that this phenomenon constitutes an echo acoustic wagon-wheel effect. We further demonstrate how at high modulation rates, flutter sensitivity could be rescued by using spectral and temporal cues introduced by Doppler distortions. Thus, Doppler distortions may play a crucial role in flutter sensitivity in the hundreds of FM species worldwide. PMID- 30244366 TI - Descending aortic banding for re-rupture of retrograde aortic dissection after emergency thoracic endovascular aortic repair. AB - Conversion to open repair after thoracic endovascular aortic repair (TEVAR) for acute type B aortic dissection is rare, but inevitable. We present a case of an 86-year-old man with ruptured type B aortic dissection after TEVAR. He received a successful stent-graft implantation of the descending aorta without any type of endoleak. After the patient was transferred to the intensive care unit, he went into a shock state. Contrast-enhanced CT revealed a re-rupture of acute retrograde type B aortic dissection. The false lumen was patent and perforated to the left thorax. Left thoracotomy and descending aortic banding was performed. Descending aorta was encircled with a woven Dacron graft at the distal part of the rupture site to compress the patent false lumen. The bleeding was stopped, and the follow-up CT showed false lumen thrombosis. Descending aortic banding is one of the quick and effective open conversion techniques. PMID- 30244367 TI - Idiopathic osteosclerosis in the maxillomandibular area. AB - OBJECTIVES: To test a more complete set of morphometric radiographic parameters to evaluate the idiopathic osteosclerosis (IO) lesions located in the maxillomandibular area and to know their features during routine radiographic evaluation. MATERIALS AND METHODS: Radiographs from patients attending the oral diagnosis clinic of our institution were reviewed. Evaluated parameters were gender and age of the patients, size, side, homogeneity, morphology, radiodensity, mineralization, borders, relation to roots, affected tooth or teeth and location of the analyzed lesions. RESULTS: Of the 6340 assessed patients, 354 (5.6%) harbored 362 lesions. IOs were more common during 2nd to 4th decades (mean age = 39 years). IO frequency rose from 1st to 3rd decades and then decreased. Size varied from 0.1 to 5.8 cm, and its frequency increased from 7 to 30 years age and then decreased too. The mandible and molar region were more commonly affected. Radiopaque image, radicular location, round shape, homogeneous core and well-defined boundaries were the more frequent IO features. CONCLUSIONS: Our method allows to analyze IO lesions with precise parameters. Analysis of the results does not support the previously suggested theories to explain their origin, and these figures suggest that the so-called IOs are developmental alterations of the bone. PMID- 30244368 TI - A computer-aided diagnosis system for the assessment and characterization of low to-high suspicion thyroid nodules on ultrasound. AB - AIM OF THE STUDY: To compare the diagnostic performance of a commercially available computer-aided diagnosis (CAD) system for thyroid ultrasound (US) with that of a non-computer-aided radiologist in the characterization of low-to-high suspicion thyroid nodules. METHODS: This retrospective study included a consecutive series of adult patients referred for US-guided fine-needle aspiration biopsy (FNAB) of a thyroid nodule. All patients were eligible for thyroid nodule FNAB according to the current international guidelines. An interventional radiologist experienced in thyroid imaging acquired the US images subsequently used for post-processing, performed FNAB and provided the US features of each nodule. A radiology resident and an endocrinology resident in consensus performed post-processing using the CAD system to assess the same nodule characteristics. The diagnostic performance and agreement of US features between the CAD system and the radiologist were compared. RESULTS: Sixty-two patients (50 F; age 60 +/- 12 years) were enrolled: 77.4% (48/62) of thyroid nodules were benign, 22.6% (14/62) were undetermined to malignant and required follow-up or surgery. Interobserver agreement between the CAD system and the radiologist was substantial for orientation (K = 0.69), fair for composition (K = 0.36), echogenicity (K = 0.36), K-TIRADS (K = 0.29), and slight for margins (K = 0.03). The radiologist demonstrated a significantly higher sensitivity than the CAD system (78.6% vs. 21.4%; P = 0.008), while there was no statistical difference in specificity (66.7% vs. 81.3%; P = 0.065). CONCLUSION: This CAD system is less sensitive than an experienced radiologist and showed slight-to substantial agreement with the radiologist for the characterization of thyroid nodules. Although it is an innovative tool with good potential, additional efforts are needed to improve its diagnostic performance. PMID- 30244369 TI - The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies. AB - : This post-hoc analysis queried whether women experiencing fracture on denosumab indicates inadequate treatment response or whether the risk of subsequent fracture remains low with continuing denosumab. Results showed that denosumab decreases the risk of subsequent fracture and fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response. INTRODUCTION: This analysis assessed whether a fracture sustained during denosumab therapy indicates inadequate treatment response and if the risk of a subsequent fracture decreases with continuing denosumab treatment. METHODS: In FREEDOM, a clinical trial to evaluate the efficacy and safety of denosumab, postmenopausal women with osteoporosis were randomized to placebo or denosumab for 3 years. In the 7-year FREEDOM Extension, all participants were allocated to receive denosumab. Here we compare subsequent osteoporotic fracture rates between denosumab-treated subjects during FREEDOM or the Extension and placebo-treated subjects in FREEDOM. RESULTS: During FREEDOM, 438 placebo- and 272 denosumab treated subjects had an osteoporotic fracture. Exposure-adjusted subject incidence per 100 subject-years was lower for denosumab (6.7) vs placebo (10.1). Combining all subjects on denosumab from FREEDOM and the Extension for up to 10 years (combined denosumab), 794 (13.7%) had an osteoporotic fracture while on denosumab. Of these, one or more subsequent fractures occurred in 144 (18.1%) subjects, with an exposure-adjusted incidence of 5.8 per 100 subject-years, similar to FREEDOM denosumab (6.7 per 100 subject-years) and lower than FREEDOM placebo (10.1 per 100 subject-years). Adjusting for prior fracture, the risk of having a subsequent on-study osteoporotic fracture was lower in the combined denosumab group vs placebo (hazard ratio [95% CI]: 0.59 [0.43-0.81]; P = 0.0012). CONCLUSIONS: These data demonstrate that denosumab decreases the risk of subsequent fracture and a fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response. PMID- 30244370 TI - Reservoir water quality: a case from Jordan. AB - Jordan relies heavily on reservoirs building and development to cope with water supply challenges, where monitoring and assessment of reservoir water quality are critically important for the sustainable use of these water supplies. Mujib Dam is an important water supply source in central western Jordan. Evaluation of water quality parameters and their spatial distributions (vertical and horizontal) showed near-neutral pH values with nearly similar values from surface to bottom. The vertical profile of DO and TDS in the dammed reservoir showed slight decreasing trends with increasing depth. Although Ca, Mg, Na, and K concentrations varied slightly with depths, their variations showed no trends. Similarly, the vertical and horizontal distribution patterns of Cl, SO4, HCO3, NO3, and PO4 in Mujib reservoir water showed insignificant variations in surface water layer and relatively unchanged values or decreasing trends through the water column. Higher values of TN have been observed, especially in the western part, suggesting that agricultural activities and livestock farming in the upstream catchment are impacting water quality. Results revealed that weathering and dissolution of rocks are the major source of water chemistry. The majority of trace metal levels (Cd, Cr, Cu, Fe, Mn, Pb, Zn, Co, Ni, Sr, and B) in water showed relatively similar surface and bottom values. The concentrations of COD and BOD5 in surface water were relatively low with higher concentrations observed in the northwestern corner, coincided with higher levels of chlorophyll a. The average ratio of TN to TP in surface water suggests that phosphorus is the limiting factor for the algal blooms, whereas the average chlorophyll a level in surface water indicates oligo-mesotrophic water. PMID- 30244371 TI - Presentations to the emergency department with non-medical use of benzodiazepines and Z-drugs: profiling and relation to sales data. AB - BACKGROUND: Non-medical use of benzodiazepines and Z-drugs is common; however, there is limited information available on the extent of harm related to this in Europe, as well as the relationship between misuse and availability. AIM: To describe presentations to the emergency department in Europe related to the recreational use of benzodiazepines and Z-drugs and compare regional differences in these presentations with legal drug sales of benzodiazepines and Z-drugs within each country. METHODS: Emergency department presentations with recreational misuse of benzodiazepines and Z-drugs were obtained from the Euro DEN dataset for the period from October 2013 to September 2015; data extracted included demographics, clinical features, reported coused drugs, and outcome data. Sales figures obtained by QuintilesIMSTM (Atlanta, Georgia) were used to compare regional differences in the proportion of benzodiazepines and Z-drugs in the emergency department presentations and legal drug sales across Europe. RESULTS: Over the 2 years, there were 2119 presentations to the Euro-DEN project associated with recreational use of benzodiazepines and/or Z-drugs (19.3% of all Euro-DEN presentations). Presentations with 25 different benzodiazepines and Z drugs were registered in all countries, most (1809/2340 registered benzodiazepines and Z-drugs, 77.3%) of which were prescription drugs. In 24.9%, the benzodiazepine was not specified. Where the benzodiazepine/Z-drug was known, the most frequently used benzodiazepines and Z-drugs were respectively clonazepam (29.5% of presentations), diazepam (19.9%), alprazolam (11.7%), and zopiclone (9.4%). The proportions of types of benzodiazepines/Z-drugs related to ED presentations varied between countries. There was a moderate (Spain, UK, Switzerland) to high (France, Ireland, Norway) positive correlation between ED presentations and sales data (Spearman Row's correlation 0.66-0.80, p < 0.005), with higher correlation in countries with higher ED presentation rates. CONCLUSION: Presentations to the emergency department associated with the non medical use of benzodiazepines and/or Z-drugs are common, with variation in the benzodiazepines and/or Z-drugs between countries. There was a moderate to high correlation with sales data, with higher correlation in countries with higher ED presentation rates. However, this is not the only explanation for the variation in non-medical use and in the harm associated with the non-medical use of benzodiazepines/Z-drugs. PMID- 30244372 TI - Adoption of Sustainable Agriculture Practices among Farmers in Kentucky, USA. AB - Promoting the sustainable agricultural practices at an individual farm level is essential to ensure agricultural sustainability. This study analyzed whether and how various factors related to farm or farmers' characteristics influence the adoption intensity of sustainable agriculture practices. We used a negative binomial regression model to fit the data collected from a mail survey of farmers in Kentucky, USA. Our results showed that the adoption intensity of sustainable agriculture practices varied significantly among agricultural districts in Kentucky. Farmers who grew row crops, had irrigation facilities, and were in favor of crop diversification were significantly more likely than their respective counterparts to adopt more sustainable agriculture practices. Similarly, having a college education and participating in the Tobacco Buyout Program also positively and significantly affected the intensity of adopting sustainable agriculture practices among Kentucky farmers. In contrast, a lack of adequate knowledge about sustainable farming and an unfamiliarity with technology significantly and negatively related to less adoption of sustainable agriculture practices. PMID- 30244373 TI - The Relationship Between Volunteer Motivations and Variation in Frequency of Participation in Conservation Activities. AB - Environmental conservation activities such as biodiversity and natural resource management are supported by many eager volunteers in many countries. Because it takes a great deal of time and effort to train new members, volunteer programs are important for preventing the burnout of volunteers and maintaining their motivations to participate. This study explored whether motivations that inspire the future frequency of participation, which volunteers prefer, differ depending on the previous frequency of participation in conservation activities. Online surveys were chosen as the primary social research method to collect the relevant data, and 1500 responses were obtained from Japanese citizens who had participated in conservation activities. The findings suggest that improvement of personal physical well-being can have an influence on the variation in frequency of participation in the episodic group that participates only about once a year. The results also indicate that improvement of personal mental well-being and well being for a local community can have an influence on the variation in frequency of participation in the irregular group that participates about every 2 months. Additionally, this study shows that interaction with other people and enjoyment of cultural services from ecosystems can have an influence on the variation in frequency of participation in many groups including the regular group that participates every month. These results represent valuable information that can be used as a reference for conducting conservation programs aimed at encouraging people to learn about nature conservation and interact with others to improve their local community. PMID- 30244374 TI - Incidence and treatment of femur fractures in adults with osteogenesis imperfecta: an analysis of an expert clinic of 216 patients. AB - PURPOSE: Osteogenesis imperfecta (OI) is characterized by increased bone fragility and susceptibility for fractures. A few studies described and compared treatment modalities for femur fractures in children with OI. However, no cohort studies on adults with OI have been published. This study on adult OI patients aims to give insight into the incidence of femur fractures and non-unions and its best treatment options to avert non-union. METHODS: In this retrospective, descriptive study of the OI expert clinic in The Netherlands, all medical charts of patients 16 years or older were analyzed for femur fracture incidence, non union rate and treatment modality. RESULTS: Of 216 OI patients, 34 patients suffered a femur fracture with 12 patients having more than 1 femur fracture. For all types of femur fractures, the incidence was 651 fractures per 100,000 person years annually. In 49 total fractures, 10 fractures resulted in a non-union, mostly shaft fractures of type 4 OI patients. Surgically treated shaft fractures had the best outcomes for non-union. CONCLUSIONS: OI adults were prone to developing femur fractures and non-unions. Especially type 4 OI adults, with conservatively treated shaft fractures, were at high risk for non-unions. PMID- 30244375 TI - The molecular mechanism of SLC34 proteins: insights from two decades of transport assays and structure-function studies. AB - The expression cloning some 25 years ago of the first member of SLC34 solute carrier family, the renal sodium-coupled inorganic phosphate cotransporter (NaPi IIa) from rat and human tissue, heralded a new era of research into renal phosphate handling by focussing on the carrier proteins that mediate phosphate transport. The cloning of NaPi-IIa was followed by that of the intestinal NaPi IIb and renal NaPi-IIc isoforms. These three proteins constitute the main secondary-active Na+-driven pathways for apical entry of inorganic phosphate (Pi) across renal and intestinal epithelial, as well as other epithelial-like organs. The key role these proteins play in mammalian Pi homeostasis was revealed in the intervening decades by numerous in vitro and animal studies, including the development of knockout animals for each gene and the detection of naturally occurring mutations that can lead to Pi-handling dysfunction in humans. In addition to characterising their physiological regulation, research has also focused on understanding the underlying transport mechanism and identifying structure-function relationships. Over the past two decades, this research effort has used real-time electrophysiological and fluorometric assays together with novel computational biology strategies to develop a detailed, but still incomplete, understanding of the transport mechanism of SLC34 proteins at the molecular level. This review will focus on how our present understanding of their molecular mechanism has evolved in this period by highlighting the key experimental findings. PMID- 30244376 TI - A Meta-analysis of Prophylaxis of Surgical Site Infections with Topical Application of Povidone Iodine Before Primary Closure. AB - BACKGROUND: Povidone iodine (PVI) is a widely used antiseptic solution among surgeons. A meta-analysis based on randomized controlled trials (RCTs) was conducted to establish whether application of PVI before wound closure could reduce surgical site infection (SSI) rates. METHODS: Systematic review of MEDLINE/PubMed, Scopus, CINAHL, and Web of Science databases from inception to September 2017, with no language restrictions. Only RCTs were retrieved. The primary outcome was the SSI rate. Meta-analysis was complemented with trial sequential analysis (TSA). RESULTS: A total of 7601 patients collected from 16 RCTs were analyzed. A reduction in overall SSI rate was found (RR 0.64, 95% CI 0.48-0.85, P = 0.002, I2 = 65%), which was attributed to patients undergoing elective operations (n = 2358) and mixed elective/urgent operations (n = 2019). When RCTs of uncertain quality (n = 9) were excluded, the use of PVI before wound closure (n = 4322 patients) was not associated with a significant reduction of SSI (RR 0.81, 95% CI 0.55-1.20, P = 0.29, I2 = 51%) and was only significant in clean wounds (RR 0.25, 95% CI 0.09-0.70, P = 0.008, I2 = 0%). For the primary outcome, the TSA calculation using a relative risk reduction of 19% and an 11% proportion of control event rate (CER) with 51% of I2, the accrued information size (n = 4322) was 32.8% of the estimated optimal information size (n = 13,148). CONCLUSIONS: There is no conclusive evidence for a strong recommendation of topical PVI before wound closure to prevent SSI. PMID- 30244377 TI - Role of mesial temporal lobe structures in sensory processing in humans: a prepulse modulation study in temporal lobe epilepsy. AB - Prepulse modulation (PPM) is an electrophysiological method which enables to assess sensory processing in vivo. Reflex responses may be facilitated or inhibited (prepulse inhibition, PPI) after a weak stimulus. Theoretically, in animal studies, the generator of PPI involves pedunculopontine nucleus which is modulated by various structures, including amygdala. We aimed to investigate whether or not there was a role of limbic structures in the generation of PPM in humans. For this purpose, we studied PPM of the blink reflex (BR) in 10 patients with mesial temporal lobe epilepsy (MTLE group) and in nine patients who had previously undergone amygdala resection for medically resistant MTLE (surgery group). A control group including 19 healthy volunteers was formed. Blink reflex, BR-PPM and BR excitability recovery were recorded in all participants. Two components of BR, first early ipsilateral component (R1) and second late bilateral components (R2 and R2c) were identified. All BR parameters after single stimulation were normal in all groups. Compared to healthy subjects, R2-PPI was more pronounced in the surgery group whereas there was a R2-PPI deficit in the MTLE group. R2-PPI deficit in the MTLE group was more prominent on the lesion side. Ipsilesional R1 facilitation was more evident at ISI of 100 ms in both MTLE and surgery groups compared to healthy subjects. BR excitability recovery was not different between groups. MTLE in humans leads to a PPI deficit. Interestingly, removal of amygdala in humans with MTLE probably provides more efficient functioning of PPI network. Amygdala and hippocampus play roles in the human R2 PPI circuit. Modulation of R1 facilitation is unilateral whereas the modulation of R2-PPI is bilateral, though asymmetric. PMID- 30244378 TI - Learning a specific, individual and generalizable coordination function: evaluating the variability of practice hypothesis in motor learning. AB - Constant and variable practice conditions have been hypothesized to lead to different learning outcomes between them but similar within. However, experiments have found that within a constant practice condition, participants can show highly individual outcomes (i.e., coordination functions). Considering the contradictory evidence on the effects of variable practice, we tested the idea that measures of the individual learned outcome would be required to provide a full explanation for results in transfer tests rather than or in addition to the group task-related conditions on which individuals practiced. Twenty-four participants were divided into three groups with different practice conditions (constant, varied distance of the target, and varied angle of the target) and for 5 days performed a task of throwing for precision to a target. Pre-, post-, and transfer tests were used to evaluate our hypothesis. The results showed that although the group measures could predict certain aspects of the transfer tests, the coordination function characteristics were required to show higher levels of explanatory power. This finding supports the view that learning involves a specific, individual and generalizable solution although there are aspects of learning that are specific to the condition of practice. PMID- 30244379 TI - Comparative effects of different whole grains and brans on blood lipid: a network meta-analysis. AB - PURPOSE: The comparative effects of different whole grains and brans on blood lipid are still not totally elucidated. We aimed to estimate and rank the effects of different whole grains and brans on the control of blood lipid. METHODS: We performed a strategic literature search of PubMed, EMBASE and the Cochrane Library for relevant trials. Both pairwise meta-analyses and network meta analyses were conducted to compare and rank the intervention strategies of whole grains and brans for the control of total cholesterol (TC), LDL cholesterol (LDL C), HDL cholesterol (HDL-C), and triglycerides (TG). RESULTS: Fifty-five eligible trials with a total of 3900 participants were included. Cumulative ranking analyses showed that oat bran was the most effective intervention strategy for TC and LDL-C improvements, with significant decreases of - 0.35 mmol/L (95% CI - 0.47, - 0.23 mmol/L) and - 0.32 mmol/L (95% CI - 0.44, - 0.19 mmol/L) in TC and LDL-C compared with control, respectively. In comparison with control, oat was associated with significant reductions in TC by - 0.26 mmol/L (95% CI - 0.36, - 0.15 mmol/L) and LDL-C by - 0.17 mmol/L (95% CI - 0.28, - 0.07 mmol/L), which was ranked as the second best treatment. Barley, brown rice, wheat and wheat bran were shown to be ineffective in improving blood lipid compared with control. CONCLUSIONS: This network meta-analysis suggests that oat bran and oat are ranked higher than any other treatments for the regulations of TC and LDL-C, indicating that increasing oat sources of whole grain may be recommended for lipid control. PMID- 30244380 TI - Echocardiographic surrogates of right atrial pressure in pulmonary hypertension. AB - Right atrial pressure (RAP), a representative parameter of right heart failure, is very important for prognostic evaluation and risk assessment in pulmonary hypertension. However, its measurement requires invasive cardiac catheterization. In this study, we determined the most accurate echocardiographic surrogate of catheterization-based RAP. In 23 patients with pulmonary hypertension, a total of 66 cardiac catheterization procedures were performed along with 2-dimensional echocardiography. We evaluated tricuspid E/A, E', A' and E/E', and estimated RAP by the respirophasic variation of the inferior vena cava diameter (eRAP-IVCd) as possible surrogates of catheterization-based RAP. In simple linear regression analysis, E/A (R = 0.452, P = 0.0001) and eRAP-IVCd (R = 0.505, P < 0.0001) were positively correlated with catheterization-based RAP, whereas A' (R = - 0.512, P < 0.0001) was negatively correlated with RAP. In multiple regression analysis, A' was the most significant independent predictor of catheterization-based RAP (R = 0.375, P = 0.0007). In 16 patients who had multiple measurements, there were a total of 43 measurements before and after medication changes. The absolute change in catheterization-based RAP was negatively correlated with the percent change in A'. Receiver operating characteristic curve analysis indicated that the optimal cut-off value of A' to predict a catheterization-based RAP > 10 mmHg was 11.3 cm/s (area under the curve = 0.782, sensitivity = 0.70, specificity = 0.78). In 20 measurements of 20 patients with left heart failure, catheterization-based RAP was not correlated with any of 5 echocardiographic parameters. However, it was closely correlated with catheterization-based pulmonary capillary wedge pressure. The echocardiographic parameter, A', was the best surrogate of catheterization based RAP in patients with pulmonary hypertension. PMID- 30244381 TI - The interrelation of endothelial function and microvascular reactivity in different vascular beds, and risk assessment in hypertension: results from the Doxazosin-ramipril study. AB - : There are several non-invasive methods to study endothelial function, but their interrelation and association to cardiovascular risk have not been well evaluated. We studied macrovascular and microvascular endothelial function simultaneously in different vascular beds in relation to cardiovascular mortality risk (Systematic Coronary Risk Evaluation, SCORE) and hypertension induced cardiac organ damage, and their interrelationship. The study investigated 71 hypertensive patients by forearm post-ischemic flow-mediated vasodilation, pulse wave analysis (applanation tonometry) and beta 2-adrenoceptor agonist stimulation for changes in reflection index, skin microvascular reactivity by laser Doppler fluxmetry with iontophoresis and heat-induced hyperaemia, and coronary microvascular function by subendocardial viability ratio (derived from pulse wave analysis). Flow mediated vasodilation related inversely to SCORE (r = 0.34, P = 0.011). Adding microalbuminuria and pulse wave velocity strengthened the associations. Pulse wave reflection changes did not relate to SCORE. Skin microvascular reactivity related inversely to SCORE (peak flux change to sodium nitroprusside r = 0.29, P = 0.033, and to heating r = 0.31, P = 0.018). Subendocardial viability ratio did not relate to SCORE. Endothelial function indices showed no consistent relation to cardiac target organ damage. The agreement between the different methods for evaluating indices of macrovascular and microvascular endothelial function was weak. In conclusion, indices of macrovascular and microvascular endothelial function relate to cardiovascular mortality risk. Their use may improve cardiovascular risk prediction in hypertension. However, methods representing different vascular beds show little interrelationship and are not interchangeable, which may depend on different pathogenetic mechanisms representing different aspects of future cardiovascular risk. TRIAL REGISTRY: NCT02901977. PMID- 30244382 TI - Melatonin enhances thermotolerance of maize seedlings (Zea mays L.) by modulating antioxidant defense, methylglyoxal detoxification, and osmoregulation systems. AB - Melatonin (MT), derived from tryptophan, is an amazing signaling molecule with multiple functions in plants. Heat stress (HS) induced by high temperature is a major stress factor that limits metabolism, growth, development, and productivity of plants. However, whether MT could enhance the thermotolerance of maize seedlings and the underlying mechanisms is not completely known. In this study, treatment of maize seedlings with MT enhanced the survival percentage of maize seedlings under HS conditions, mitigated an increase in malondialdehyde (MDA, product of membrane lipid peroxidation) and electrolyte leakage, and improved tissue vitality compared with the control without MT treatment, indicating that MT treatment could enhance the theromotolerance of maize seedlings. To understand the mechanisms underlying MT-enhanced thermotolerance of maize seedlings, the antioxidant defense (guaiacol peroxidease: GPX; glutathione reductase: GR; catalase: CAT; ascorbic acid: AsA; and glutathione: GSH), methylglyoxal (MG) detoxification (glyoxalase I: Gly I; and glyoxalase II: Gly II), and osmoregulation (proline: Pro; trehalose: Tre; and total soluble sugar: TSS) systems were assayed. The results showed that MT treatment stimulated the activities of antioxidant enzymes (GPX, GR, and CAT) and MG detoxification enzymes (Gly I and Gly II), increased the contents of nonenzyme antioxidants (AsA and GSH) and osmolytes (Pro, Tre, and TSS) in maize seedlings under normal culture conditions, and maintained a higher abovementioned enzyme activity and antioxidant and osmolyte contents under HS conditions compared with the control. This work reported that MT could enhance the thermotolerance of maize seedlings by modulating the antioxidant defense, MG detoxification, and osmoregulation systems. PMID- 30244383 TI - Cyclic fatigue of Reciproc Blue and Reciproc instruments exposed to intracanal temperature in simulated severe apical curvature. AB - OBJECTIVE: The aim of this study was to evaluate the cyclic fatigue resistance of Reciproc and Reciproc Blue by testing in a severe apical curvature at intracanal temperature. MATERIALS AND METHODS: Eighteen Reciproc R25 (25.08) and Reciproc Blue (25.08) instruments were tested in a cyclic fatigue device at body temperature (37 degrees C) using a stainless steel block with an artificial canal with a curvature angle of 90 degrees and radius of curvature of 2 mm. The number of cycles to fracture (NCF) was calculated. The instruments were examined by differential scanning calorimetry (DSC). The data were analyzed using both Student's t tests and Weibull analysis. RESULTS: The NCF values of Reciproc R25 were significantly lower than Reciproc Blue R25 (P < 0.05). There was no significant difference between the instruments regarding the length of fractured fragments (P > 0.05). CONCLUSIONS: Reciproc Blue R25 instruments displayed significantly higher NCF than Reciproc R25. CLINICAL RELEVANCE: This study reported that novel reciprocating blue wire instruments exhibited higher cyclic fatigue resistance than its precedence M-wire instrument when tested in severely curvatured canals. PMID- 30244384 TI - Validation study of using the free volume approximation to confined thermotropic and lyotropic liquid-crystalline fluids. AB - We examined the accuracy of the free volume approximation (FVA) to calculate the isotropic-nematic (IN) transition properties of thermotropic and lyotropic rods between two parallel hard walls. This approximation has been proposed to ease the calculation of the confined systems. It approximates the free energy of the confined particles with a bulk free energy. It predicts a special point for these two types of liquid crystals where the first-order IN transition changes to the second one by decreasing either the temperature, the density or the pore width. This prediction is in contradiction (in spite of some qualitative agreement) with those of the other publications where the authors note that the discontinuous transition terminates at the critical point when the walls are completely impenetrable. PMID- 30244385 TI - Medical Image Security Using Dual Encryption with Oppositional Based Optimization Algorithm. AB - Security is the most critical issue amid transmission of medical images because it contains sensitive information of patients. Medical image security is an essential method for secure the sensitive data when computerized images and their relevant patient data are transmitted across public networks. In this paper, the dual encryption procedure is utilized to encrypt the medical images. Initially Blowfish Encryption is considered and then signcryption algorithm is utilized to confirm the encryption model. After that, the Opposition based Flower Pollination (OFP) is utilized to upgrade the private and public keys. The performance of the proposed strategy is evaluated using performance measures such as Peak Signal to Noise Ratio (PSNR), entropy, Mean Square Error (MSE), and Correlation Coefficient (CC). PMID- 30244386 TI - Comparison of 18F-GE-180 and dynamic 18F-FET PET in high grade glioma: a double tracer pilot study. AB - BACKGROUND: PET represents a valuable tool for glioma imaging. In addition to amino acid tracers such as 18F-FET, PET targeting the 18-kDa mitochondrial translocator-protein (TSPO) is of high interest for high-grade glioma (HGG) imaging due to its upregulation in HGG cells. 18F-GE-180, a novel TSPO ligand, has shown a high target-to-background contrast in HGG. Therefore, we intra individually compared its uptake characteristics to dynamic 18F-FET PET and contrast-enhanced MRI in patients with HGG. METHODS: Twenty HGG patients (nine IDH-wildtype, 11 IDH-mutant) at initial diagnosis (n = 8) or recurrence (n = 12) were consecutively included and underwent 18F-GE-180 PET, dynamic 18F-FET PET, and MRI. The maximal tumour-to-background ratios (TBRmax) and biological tumour volumes (BTV) were evaluated in 18F-GE-180 and 18F-FET PET. Dynamic 18F-FET PET analysis included the evaluation of minimal time-to-peak (TTPmin). In MRI, the volume of contrast-enhancement was delineated (VOLCE). Volumes were spatially correlated using the Sorensen-Dice coefficient. RESULTS: The median TBRmax tended to be higher in 18F-GE-180 PET compared to 18F-FET PET [4.58 (2.33-8.95) vs 3.89 (1.56-7.15); p = 0.062] in the overall group. In subgroup analyses, IDH-wildtype gliomas showed a significantly higher median TBRmax in 18F-GE-180 PET compared to 18F-FET PET [5.45 (2.56-8.95) vs 4.06 (1.56-4.48); p = 0.008]; by contrast, no significant difference was observed in IDH-mutant gliomas [3.97 (2.33-6.81) vs 3.79 (2.01-7.15) p = 1.000]. Only 5/20 cases showed higher TBRmax in 18F-FET PET compared to 18F-GE-180 PET, all of them being IDH-mutant gliomas. No parameter in 18F-GE-180 PET correlated with TTPmin (p > 0.05 each). There was a tendency towards higher median BTVGE-180 [32.1 (0.4-236.0) ml] compared to BTVFET [19.3 (0.7-150.2) ml; p = 0.062] with a moderate spatial overlap [median Sorensen-Dice coefficient 0.55 (0.07-0.85)]. In MRI, median VOLCE [9.7 (0.1-72.5) ml] was significantly smaller than both BTVFET and BTVGE180 (p < 0.001 each), leading to a poor spatial correlation with BTVGE-180 [0.29 (0.01-0.48)] and BTVFET [0.38 (0.01-0.68)]. CONCLUSION: PET with 18F-GE-180 and 18F-FET provides differing imaging information in HGG dependent on the IDH-mutational status, with diverging spatial overlap and vast exceedance of contrast-enhancement in MRI. Combined PET imaging might reveal new insights regarding non-invasive characterization of tumour heterogeneity and might influence patients' management. PMID- 30244387 TI - Amyloid burden identifies neuropsychological phenotypes at increased risk of progression to Alzheimer's disease in mild cognitive impairment patients. AB - PURPOSE: The extent of amyloid burden associated with cognitive impairment in amnestic mild cognitive impairment is unknown. The primary aim of the study was to determine the extent to which amyloid burden is associated to the cognitive impairment. The secondary objective was to test the relationship between amyloid accumulation and memory or cognitive impairment. MATERIALS AND METHODS: In this prospective study 66 participants with amnestic mild cognitive impairment underwent clinical, neuropsychological and PET amyloid imaging tests. Composite scores assessing memory and non-memory domains were used to identify two clinical classes of neuropsychological phenotypes expressing different degree of cognitive impairment. Detection of amyloid status and definition of optimal amyloid +/- cutoff for discrimination relied on unsupervised k-means clustering method. RESULTS: Threshold for identifying low and high amyloid retention groups was of SUVr = 1.3. Abeta + participants showed poorer global cognitive and episodic memory performance than subjects with low amyloid deposition. Abeta positivity significantly identified individuals with episodic memory impairment with a sensitivity and specificity of 80 and 79%, (chi2 = 21.48; P < 0.00001). Positive and negative predictive values were 82 and 76%, respectively. Amyloid deposition increased linearly as function of memory impairment with a rate of 0.13/ point of composite memory score (R = -44, P = 0.0003). CONCLUSION: The amyloid burden of SUVr = 1.3 allows early identification of subjects with episodic memory impairment which might predict progression from MCI to Alzheimer's disease. TRIAL REGISTRATION: EudraCT 2015-001184-39. PMID- 30244388 TI - Surgical intervention for paediatric blepharoptosis: a 6-year case series. AB - PURPOSE: To present our experience of paediatric blepharoptosis in a tertiary referral centre and evaluate the effectiveness of surgical intervention. METHODS: A retrospective cohort study of all children receiving surgical blepharoptosis correction between 1/1/10 and 29/2/16. Children with pre-operative levator function (LF) >= 7 mm received levator resection, those with LF <= 4 mm received brow suspension, and in those children with LF of 5-6 mm, either levator resection or brow suspension was chosen depending on the degree of frontalis recruitment. RESULTS: Ninety-five children (109 eyes, 64 boys) underwent blepharoptosis surgery within the study period. Mean (range) age at surgery was 5.9 (1.2-12.5) years. Seventy-nine (83.2%) had simple levator maldevelopment. Fifteen children were excluded due to inadequate follow-up. Of the remaining 80 children, 41 (51.2%) underwent levator resection, 27 (33.8%) underwent fascia lata brow suspension, and twelve (15.0%) underwent mersilene mesh brow suspension. Margin reflex distance-1 was greatest at 6-week follow-up with a small "lid drop" by 6-month follow-up in both the levator resection (0.9 mm pre operatively, 3.1 mm at 6-week follow-up, 2.6 mm at 6-month follow-up) and fascia lata brow suspension (0.3 mm, 2.5 mm, 2.2 mm) groups. No immediate complications, and only two serious post-operative complications, were noted. One case of residual blepharoptosis was re-operated (fascia lata brow suspension). CONCLUSIONS: Surgical correction of paediatric blepharoptosis is safe and, after an observed lid drop between 6-week and 6-month follow-up (not seen in the mersilene mesh brow suspension group), effect appears to be maintained to 6 months and beyond. Readily accessible orthoptic assessment would help identify children at risk of amblyopia, both pre-operatively and post-operatively. PMID- 30244389 TI - Efficacy and safety analysis of the German expanded access program of osimertinib in patients with advanced, T790M-positive non-small cell lung cancer. AB - PURPOSE: Osimertinib, a third-generation irreversible mutant-selective inhibitor of EGFR kinase activity was clinically evaluated in the AURA trials, where it showed high clinical efficacy and a favorable toxicity profile in patients with acquired exon 20-EGFR pT790M mutation. We provide the clinical data of the German expanded access program that further characterizes the efficacy and safety of osimertinib in a heterogeneous patient population outside clinical trials. METHODS: We performed a retrospective data analysis on patients who were included into the German osimertinib EAP. RESULTS: Of 81 patients enrolled, 51 patients (62.9%) with sufficient case report form data were available for efficacy and safety analysis. Unconfirmed overall response rate was 80.0% with 2 patients (3.9%) achieving a complete remission and 37 patients (72.5%) having a partial remission. Disease control rate was 95.9% and only two patients showed refractory disease. Disease control rate did not correlate with clinical characteristics and was independent of number as well as type of the previous therapy line(s). Estimated progression-free survival was 10.1 months (95% CI 9.2-11.0 months). Osimertinib showed a favorable toxicity profile with no dose reductions in our observation period, even in patients with low performance status. Median survival from first diagnosis to data cut-off was 47.3 months (95% CI 43.3-51.9 months). Repeated tissue/liquid biopsy of three patients in our cohort who showed disease progression revealed an amplification of MET. CONCLUSIONS: We confirm safety and efficacy of osimertinib with high response rates among all subgroups, including patients with poor performance status and multiple prior therapy lines. Amplification of MET might mediate acquired resistance to osimertinib. PMID- 30244391 TI - Measuring Autism Traits in the Adult General Population with the Brief Autism Spectrum Quotient, AQ-10: Findings from the Stockholm Public Health Cohort. AB - BACKGROUND: The autism-spectrum quotient scale was developed to study autism as a spectrum. Few studies have examined the psychometric properties of the 10 item AQ (AQ-10). We examine the AQ-10 measurement ability and convergent validity in a population health survey (n = 44,722). METHODS: The item severity and item discrimination was assessed using item response theory. Convergent validity was assessed by regressing on ADHD, psychological distress (PD) and having an education in the sciences. RESULTS: Whilst unidimensional, the AQ-10 had some poorly fitting items. Item discrimination ranged from very low to very high. The scale correlated as hypothesised with the regress expected when factoring in ADHD, PD and possessing an eduction in the sciences. CONCLUSION: The AQ-10 has adequate validity in the present sample and may be used in s as a measure of autistic traits. In Conclusion, The AQ-10 has adequate validity to be used in health surveys as a measure of autistic traits, although some items may perform poorly. PMID- 30244390 TI - The ambiguous role of microRNA-205 and its clinical potential in pancreatic ductal adenocarcinoma. AB - PURPOSE: Early treatment of pancreatic ductal adenocarcinoma (PDAC) is significantly delayed due to the lack of liquid biopsy markers for early diagnosis at surgically resectable tumor stages. Recent studies suggest that microRNA-205 (miR-205) is involved in PDAC progression by post-transcriptional regulation of epithelial-to-mesenchymal transition (EMT). However, the clinical potential of miR-205 as diagnostic and prognostic marker remains undefined and its exact role in PDAC is still ambiguous. This retrospective study is a substantial contribution to this on-going scientific discussion. METHODS: Expression analysis of miR-205 and its molecular targets in PDAC cell lines (n = 5), human tissue (n = 73), and blood serum samples (n = 85) by qRT-PCR, tissue microarray immunohistochemistry, and western blot. Descriptive and explorative statistical analysis of miR-205's clinical potential for diagnosis and prognosis of PDAC. RESULTS: The expression of miR-205 differs more than 2000-fold (p < 0.001) between epithelial and mesenchymal-like human PDAC cell lines correlating with EMT-marker expression of E-cadherin, vimentin, fibronectin, and ZEB-1. Expression of miR-205 is significantly upregulated in carcinoma tissue (eightfold, p = 0.028) and serum (2.3-fold, p = 0.023) of PDAC patients compared to age-matched healthy controls. In our patient collective circulating miR-205 in combination with CA.19-9 outperforms the diagnostic accuracy of CA.19-9 alone with an AUC of 0.890 (p < 0.001), sensitivity of 0.867, and specificity of 0.933. Though non-significant, low expression of circulating miR-205 is more frequent in advanced tumor stages combined with a worse overall survival (6.9 vs. 11.9 months, p = 0.176). CONCLUSION: Besides its controversial role in carcinogenesis, miR-205 shows high potential as a solid and liquid biopsy marker in PDAC. This result is an urgent call for larger confirmatory multi-center studies. PMID- 30244392 TI - Contrasting the Effects of Task Difficulty and Perceptual Load on Auditory Detection Sensitivity in Individuals with Autism. AB - To test a central assumption of the increased perceptual capacity account in individuals with Autism Spectrum Disorder (ASD), the effects of perceptual load and target-stimulus degradation on auditory detection sensitivity were contrasted. Fourteen adolescents with ASD and 16 neurotypical controls performed a visual letter search task under three conditions: low perceptual load, high perceptual load and low perceptual load with a degraded target while simultaneously detecting an auditory tone in noise. For both participants with ASD and neurotypical controls, increasing perceptual load and target degradation increased task difficulty as indexed by reaction times and accuracy. However, only increasing perceptual load reduced subsequent auditory detection sensitivity. The study confirms that perceptual load, and not task difficulty, modulates selective attention in ASD. PMID- 30244393 TI - Fine mapping and candidate gene screening of the downy mildew resistance gene RPF1 in Spinach. AB - KEY MESSAGE: A SLAF-BSA approach was used to locate the RPF1 locus. The three most likely candidate genes were identified which provide a basic for cloning the resistance gene at the RPF1 locus. Spinach downy mildew is a globally devastating oomycete disease. The use of downy mildew resistance genes constitutes the most effective approach for disease management. Hence, the objective of the present study was to fine map the first-reported resistance locus RPF1. The resistance allele at this resistance locus was effective against races 1-7, 9, 11, 13, and 15 of Peronospora farinosa f. sp. spinaciae (P. effusa). The approach fine mapped RPF1 using specific-locus amplified fragment sequencing (SLAF-Seq) technology combined with bulked segregant analysis. A 1.72 Mb region localized on chromosome 3 was found to contain RPF1 based on association analysis. After screening recombinants with the SLAF markers within the region, the region was narrowed down to 0.89 Mb. Within this region, 14 R genes were identified based on the annotation information. To identify the genes involved in resistance, resequencing of two resistant inbred lines (12S2 and 12S3) and three susceptible inbred lines (12S1, 12S4, and 10S2) was performed. The three most likely candidate genes were identified via amino acid sequence analysis and conserved domain analysis between resistant and susceptible inbred lines. These included Spo12729, encoding a receptor-like protein, and Spo12784 and Spo12903, encoding a nucleotide-binding site and leucine-rich repeat domains. Additionally, based on the sequence variation in the three genes between the resistant and susceptible lines, molecular markers were developed for marker-assisted selection. The results could be valuable in cloning the RPF1 alleles and improving our understanding of the interaction between the host and pathogen. PMID- 30244394 TI - Carbon isotope composition, water use efficiency, and drought sensitivity are controlled by a common genomic segment in maize. AB - KEY MESSAGE: A genomic segment on maize chromosome 7 influences carbon isotope composition, water use efficiency, and leaf growth sensitivity to drought, possibly by affecting stomatal properties. Climate change is expected to decrease water availability in many agricultural production areas around the globe. Therefore, plants with improved ability to grow under water deficit are urgently needed. We combined genetic, phenomic, and physiological approaches to understand the relationship between growth, stomatal conductance, water use efficiency, and carbon isotope composition in maize (Zea mays L.). Using near-isogenic lines derived from a maize introgression library, we analysed the effects of a genomic region previously identified as affecting carbon isotope composition. We show stability of trait expression over several years of field trials and demonstrate in the phenotyping platform Phenodyn that the same genomic region also influences the sensitivity of leaf growth to evaporative demand and soil water potential. Our results suggest that the studied genomic region affecting carbon isotope discrimination also harbours quantitative trait loci playing a role in maize drought sensitivity possibly via stomatal behaviour and development. We propose that the observed phenotypes collectively originate from altered stomatal conductance, presumably via abscisic acid. PMID- 30244395 TI - Genetic analysis and identification of a candidate gene associated with in vitro regeneration ability of cucumber. AB - KEY MESSAGE: Candidate genes associated with in vitro regeneration were identified in cucumber. The ability to regenerate shoots or whole plants from differentiated plant tissues is essential for plant transformation. In cucumber (Cucumis sativus L.), regeneration ability varies considerably across accessions, but the genetic mechanism has not yet been demonstrated. In the present study, 148 recombinant inbred lines and a core collection were examined to identify candidate genes involved in cucumber regeneration. Four QTL for cotyledon regeneration that explained 9.7-16.6% of the phenotypic variation in regeneration were identified on cucumber chromosomes 1, 3, and 6. The loci Fcrms1.1 and Fcrms+1.1 were consistently detected in the same genetic interval on two regeneration media. A genome-wide association study revealed 18 SNPs (- log(p) > 5) significantly associated with cotyledon regeneration. Three candidate genes in this region were identified. RT-PCR analyses revealed that Csa1G642540 was significantly more highly expressed in genotypes with high cotyledon regeneration rates than in those with low regeneration. The Csa1G642540 CDS driven by its native promoter was transformed into cucumber line 9110Gt; molecular analyses showed that the T-DNA had integrated into the genomes of 8.6% of regenerated plantlets. The seeds from T0 plants expressing Csa1G642540 were tested for regeneration from cotyledon explants, and the segregate ratio in regeneration frequency is 3:1. The AT3G44110.1, the homologue gene of Csa1G642540 in Arabidopsis, has been reported as PM H+-ATPase activity regulation, integrating flowering signals and enlarging meristem function. These results demonstrate that Csa1G642540 might play an important role in regeneration in cucumber and could serve as a selectable marker for regeneration from cotyledons. PMID- 30244396 TI - Constructing and transient expression of a gene cassette containing edible vaccine elements and shigellosis, anthrax and cholera recombinant antigens in tomato. AB - Shigella dysenteriae causing shigellosis is one of the diseases that threaten the health of human society in the developing countries. In Shigella, IpaD gene is one of the key pathogenic genes causing strong mucosal immune system reactions. Anthrax disease is caused by Bacillus anthracis. PA protective antigen is one of the subunits in anthrax toxin complex responsible for the transfer of other subunits into the cytosol of host cells. The 20 kDa subunit of PA (PA20) has the property of immunogenicity. CTxB or B subunit of Vibrio cholerae toxin (CT) is a non-toxic protein and has the function to transfer toxic subunit into cytosol of the host cells by binding to GM1 receptor. The aim of this study was to fuse PA20, ipaD and CTxB and transform tomato plants by this cassette in order to produce an oral vaccine against shigellosis, anthrax and cholera. CTxB was used for these two antigens as an immune adjuvant. IpaD and PA20 genes were cloned in pBI121 containing the CTxB gene and Extensin signal peptide. In order to evaluate the transient expression of Shigellosis, Anthrax and Cholera antigens, agro infiltrated tomato tissues were inoculated with Agrobacterium tumefaciens containing the gene cassette. Cloning was confirmed by PCR, enzymatic digestion and sequencing techniques. Expression of the antigens was examined by SDS-PAGE, dot blot and ELISA. Maturate green fruits demonstrated the highest expression of the recombinant proteins. The first phase of this study was carried out for cloning and expressing of CtxB, ipaD and PA20 antigens in tomato. In the next phase, we aim to analyze the immunogenicity of this vaccine candidate in laboratory animals. PMID- 30244398 TI - Anti-tumor necrosis factor therapy decreases the risk of initial intestinal surgery after diagnosis of Crohn's disease of inflammatory type. AB - BACKGROUND: Anti-tumor necrosis factor (TNF) therapy induces and maintains clinical remission in patients with Crohn's disease (CD). However, the effect of anti-TNF therapy on the natural course of CD remains controversial. We aimed to investigate the effect of anti-TNF therapy on the initial intestinal surgery for CD. METHODS: In this single-center retrospective cohort study, clinical course of 199 CD patients of inflammatory type at the initial diagnosis (the period between 1973 and 2014) was precisely reviewed until the end of 2016. Patients were divided into TNF and non-TNF groups based on anti-TNF agent use. After comparisons of clinical characteristics and medical treatments, propensity scores were calculated for covariates. Risk of intestinal surgery was compared by a Cox proportional hazards model using the propensity scores. The effect of immunomodulators on initial intestinal surgery was assessed in the TNF group. RESULTS: During the study period, 108 patients received anti-TNF therapy. The patients in the TNF group were diagnosed more recently, and more frequently had isolated colonic involvement, and perianal disease. Immunomodulators were more frequently used in the TNF group. Cumulative probability of initial intestinal surgery was significantly lower in the TNF group (P < 0.0001). The hazard ratio in the TNF group was 0.32 (95% CI 0.13-0.74). Immunomodulators did not decrease the risk of initial intestinal surgery. CONCLUSIONS: Anti-TNF therapy can decrease the risk of intestinal surgery among patients with inflammatory-type CD at the initial diagnosis. Further studies should be necessary to determine the additive effect of immunomodulators on the risk of intestinal surgery. PMID- 30244399 TI - Progress in characterizing the linkage between Fusobacterium nucleatum and gastrointestinal cancer. AB - Microbiome research is a rapidly advancing field in human cancers. Fusobacterium nucleatum is an oral bacterium, indigenous to the human oral cavity, that plays a role in periodontal disease. Recent studies have found that F. nucleatum can promote gastrointestinal tumor progression and affect the prognosis of the disease. In addition, F. nucleatum may contribute to the chemo-resistance of gastrointestinal cancers. This review summarizes recent progress in the pathogenesis of F. nucleatum and its impact on gastrointestinal cancer. PMID- 30244397 TI - Bio and phyto-chemical effect of Amphora coffeaeformis extract against hepatic injury induced by paracetamol in rats. AB - Paracetamol is the most commonly used analgesic-antipyretic drugs. Its excess use causes an acute hepatotoxicity. It is well known that the Bacillariophyta alga Amphora coffeaeformis is rich in many photosynthetic pigments with antioxidant activities as well as a series of biologically active substances. The current work has been designed to study the phytochemical composition of different A. coffeaeformis algal extracts to select the most effective one. It was verified that acetone A. coffeaeformis algal extract is rich in various pigments and polyphenolic compounds (beta-carotene (9.31 +/- 0.06 mg.g-1), gallic acid (28.31 ug.g-1), catechin (38.08 ug.g-1) and p-coumaric acid (38.69 ug.g-1)). The pigments and phenolic profiles in acetone extract were determined in addition to isolation of beta-carotene and fucoxanthin which exhibited free radical scavenging activity by 74.80% and 69.40%, respectively. Therefore, the highest total antioxidant capacity and free radical scavenging activity were noticed with this extract. Consequently, efficiency of this algal extract was evaluated against hepatic intoxication induced by paracetamol in rats. The biochemical measurements (liver functions and markers of oxidative stress) were assayed. Moreover, the native protein, lipid and calcium moieties of native protein patterns in addition to catalase (CAT); peroxidases (POX); alpha- and beta esterase (EST) isoenzymes and genomic DNA patterns were electrophoretically detected in liver tissues. It was found that paracetamol caused significant (P < 0.05) elevation in serum liver functions associated with decline in activities of the antioxidant enzymes in that tissues. Also, it caused alterations represented electrophoretically at qualitative level from variations in the bands number and arrangement. So that, the paracetamol treated group was noticed with the lowest similarity index (SI). In addition, it caused abnormalities at the quantitative level through variations in quantity of normal bands. Algal extract restored all the biochemical functions to normal levels in the algal extract simult-treated and pre-treated groups. Furthermore, it exhibited ameliorative effect against the electrophoretic alterations through restoring the absent normal bands and hiding the abnormal ones and hence increasing the SI values especially in the extract simult-treated group. Algal extract exhibited antagonistic effect against the hepatic injury and the deleterious effects induced by paracetamol in the extract simult-treated group. PMID- 30244400 TI - Biochemical changes in injured sciatic nerve of rats after low-level laser therapy (660 nm and 808 nm) evaluated by Raman spectroscopy. AB - The aim of this study was to identify biochemical changes in sciatic nerve (SN) after crush injury and low-level laser therapy (LLLT) with 660 nm and 808 nm by Raman spectroscopy (RS) analysis. A number of 32 Wistar rats were used, divided into four groups (control 1, control 2, LASER 660 nm, and LASER 808 nm). All animals underwent surgical procedure of the SN and groups control 2, LASER 660 nm, and LASER 808 nm were submitted to SN crush damage (axonotmesis). The LLLT in the groups LASER 660 nm and LASER 808 nm was applied daily for 21 consecutive days (100 mW, 30 s, 133 J/cm2 fluence). The hind paw was removed and the SN was dissected and positioned on an aluminum support to collect dispersive Raman spectra (830 nm excitation, 30 s accumulation). To estimate the biochemical changes in the SN associated with LLLT, the principal component analysis (PCA) was applied. The Raman spectra of the sciatic nerve fragments showed peaks of the major biochemical components of the nerve, especially sphingolipids, phospholipids, glycoproteins, and collagen. The spectral features identified in some of the principal component loading vectors are referred to the biochemical elements present on the SN and were increased in the groups treated with LLLT, mainly lipids (sphingo and phospholipids) and proteins (collagen)-constituents of the myelin sheath. The RS was effective in identifying the biochemical differences in the SN after the crush injury, and LASER 660 nm was more efficient than the LASER 808 nm in cell proliferation and repair of the injured SN. PMID- 30244401 TI - Wound-healing effects of 635-nm low-level laser therapy on primary human vocal fold epithelial cells: an in vitro study. AB - Low-level laser therapy (LLLT) has been promoted for its beneficial effects on tissue healing and pain relief for skin and oral applications. However, there is no corresponding literature reporting on vocal fold wound healing. Our purpose was to assess the potential wound-healing effects of LLLT on primary human vocal fold epithelial cells (VFECs). In this study, normal vocal fold tissue was obtained from a 58-year-old male patient who was diagnosed with postcricoid carcinoma without involvement of the vocal folds and underwent total laryngectomy. Primary VFECs were then cultured. Cells were irradiated at a wavelength of 635 nm with fluences of 1, 4, 8, 12, 16, and 20 J/cm2 (50 mW/cm2), which correspond to irradiation times of 20, 80, 160, 240, 320, and 400 s, respectively. Cell viability of VFECs in response to varying doses of LLLT was investigated by the Cell Counting Kit-8 (CCK-8) method. The most effective irradiation dose was selected to evaluate the cell migration capacity by using the scratch wound-healing assay. Real-time polymerase chain reaction (RT-PCR) was used to detect the gene expression of TGF-beta1, TGF-beta3, EGF, IL-6, and IL-10. Irradiation with doses of 8 J/cm2 resulted in 4% increases in cell proliferation differing significantly from the control group (p < 0.05). With subsequent doses at 48 and 72 h after irradiation, the differences between the experimental and the control groups became greater, up to 9.8% (p < 0.001) and 19.5% (p < 0.001), respectively. It also increased cell migration and the expression of some genes, such as EGF, TGF-beta1, TGF-beta3, and IL-10, involved in the tissue healing process. This study concludes that LLLT at the preset parameters was capable of stimulating the proliferation and migration of human vocal fold epithelial cells in culture as well as increase the expression of some genes involved in tissue healing process. Additionally, successive laser treatments at 24 h intervals have an additive beneficial effect on the healing of injured tissues. PMID- 30244402 TI - The role of Wnt/beta-catenin signaling in the restoration of induced pluripotent stem cell-derived retinal pigment epithelium after laser photocoagulation. AB - To investigate the role of Wnt/beta-catenin signaling pathway in the restoration of induced pluripotent stem cell-derived retinal pigment epithelium (hiPSC-RPE) after laser photocoagulation. After differentiation of RPE cells from hiPSCs, laser photocoagulation was performed. Activation of Wnt/beta-catenin signaling at days 1 and 5 after laser photocoagulation was evaluated by expression of beta catenin. Cell proliferation and alteration in cell-to-cell contact at day 5 after laser photocoagulation with or without Dickkopf-1 (Dkk-1) treatment were studied using ethynyl-2'-deoxyuridine (EdU) assay and zonula occludens-1 (ZO-1) expression analysis, respectively. The mRNA levels of Wnt genes at day 5 after laser photocoagulation were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Activation of Wnt/beta-catenin signaling at days 1 and 5 after laser photocoagulation was confirmed by beta-catenin accumulation in the cytoplasm and nucleus of hiPSC-RPE. Many EdU-positive cells also expressed beta catenin, and the number of EdU-positive cells was decreased at day 5 after laser photocoagulation after Dkk-1 treatment, indicating that Wnt/beta-catenin signaling mediated hiPSC-RPE proliferation. ZO-1 expression was not decreased with Dkk-1 treatment at day 5 after laser photocoagulation, indicating that Wnt/beta-catenin signaling mediated hiPSC-RPE restoration. At day 5, after laser photocoagulation, mRNA levels of Wnt2b, Wnt3, Wnt5a, Wnt7a, and Wnt10b were increased. Wnt/beta-catenin signaling has a crucial role in restoration of hiPSC RPE proliferation after laser photocoagulation. Manipulation of Wnt/beta-catenin signaling while elucidating the underlying mechanisms of RPE restoration might have a therapeutic potential in retinal degenerative diseases. PMID- 30244403 TI - Effect of Educational Intervention Based on the Health Belief Model and Self Efficacy in Promoting Preventive Behaviors in a Cholangiocarcinoma Screening Group. AB - Cholangiocarcinoma (CCA) is a neoplasm known as one of the most common causes of cancer-related deaths in Southeast Asia, particularly in Thailand, Laos, and Cambodia. Prevention and health education are required. Therefore, this study aimed to determine the effectiveness of an educational intervention to prevent CCA among a rural population in Thailand based on the health belief model (HBM) and self-efficacy frameworks. In this quasi-experimental study, 60 participants (30 participants in the experimental group and 30 participants in the control group) were selected in 2017. The educational intervention for the experimental group consisted of seven training sessions (introduction to CCA, risk factors, complications, benefits and barriers to proper consumption of cooked fish, carcinogenic agents, behavioral protection, and self-efficacy in applying preventive behaviors). A questionnaire that consisted of demographic information, knowledge, and HBM constructs (perceived susceptibility, severity, benefits, barriers, cues to action, and self-efficacy) was used to measure CCA preventive behaviors before and 3 months after the intervention. Data were analyzed using SPSS-22 via chi-squared, paired t-tests, and independent samples t tests at a significance level of 0.5. Three months after the intervention, the experimental group showed a significant increase in the knowledge, perceived susceptibility, perceived severity, perceived benefits, perceived barriers, cues to action, self efficacy, and CCA preventive behaviors compared to the control group. This study showed the effectiveness of the intervention based on the HBM constructs and self efficacy in the adoption of CCA preventive behaviors 3 months post intervention in the risk group. Thus, these models may serve as a framework for designing and implementing educational interventions for the prevention of CCA. PMID- 30244404 TI - Is prolactin a negative neuroendocrine regulator of human skin re-epithelisation after wounding? AB - Chronic wounds remain a major unmet healthcare challenge, associated with substantial morbidity and economic costs. Therefore, novel treatment strategies and therapeutic approaches need to be urgently developed. Yet, despite the increasingly recognized importance of neurohormonal signaling in skin physiology, the neuroendocrine regulation of cutaneous wound healing has received surprisingly little attention. Human skin, and its appendages, locally express the pleiotropic neurohormone prolactin (PRL), which not only regulates lactation but also hair follicle cycling, angiogenesis, keratinocyte proliferation, and epithelial stem cell functions. Therefore, we examined the effects of PRL in experimentally wounded female human skin organ culture. Overall, this revealed that PRL slightly, but significantly, inhibited epidermal regeneration (reepithelialisation), cytokeratin 6 protein expression and intraepidermal mitochondrial activity (MTCO1 expression), while it promoted keratinocyte terminal differentiation (i.e. involucrin expression) ex vivo. If the current pilot data are confirmed by further studies, PRL may serve as one of the-rarely studied-negative regulators of cutaneous wound healing that control excessive reepithelialisation. This raises the intriguing and clinically relevant question of whether PRL receptor antagonists could actually promote epidermal repair after human skin wounding. PMID- 30244405 TI - Application of Deacetylated Poly-N-Acetyl Glucosamine Nanoparticles for the Delivery of miR-126 for the Treatment of Cecal Ligation and Puncture-Induced Sepsis. AB - Sepsis is an acute inflammatory syndrome in response to infection. In some cases, excessive inflammation from sepsis results in endothelial dysfunction and subsequent increased vascular permeability leading to organ failure. We previously showed that treatment with endothelial progenitor cells, which highly express microRNA-126 (miR-126), improved survival in mice subjected to cecal ligation and puncture (CLP) sepsis. miRNAs are important regulators of gene expression and cell function, play a major role in endothelial homeostasis, and may represent an emerging therapeutic modality. However, delivery of miRNAs to cells in vitro and in vivo is challenging due to rapid degradation by ubiquitous RNases. Herein, we developed a nanoparticle delivery system separately combining deacetylated poly-N-acetyl glucosamine (DEAC-pGlcNAc) polymers with miRNA-126-3p and miRNA-126-5p and testing these combinations in vitro and in vivo. Our results demonstrate that DEAC-pGlcNAc polymers have an appropriate size and zeta potential for cellular uptake and when complexed, DEAC-pGlcNAc protects miRNA from RNase A degradation. Further, DEAC-pGlcNAc efficiently encapsulates miRNAs as evidenced by preventing their migration in an agarose gel. The DEAC-pGlcNAc miRNA complexes were taken up by multiple cell types and the delivered miRNAs had biological effects on their targets in vitro including pERK and DLK-1. In addition, we found that delivery of DEAC-pGlcNAc alone or DEAC-pGlcNAc:miRNA-126 5p nanoparticles to septic animals significantly improved survival, preserved vascular integrity, and modulated cytokine production. These composite studies support the concept that DEAC-pGlcNAc nanoparticles are an effective platform for delivering miRNAs and that they may provide therapeutic benefit in sepsis. PMID- 30244406 TI - Correction to: Improvement in Cognitive Function as Measured by NeuroTrax in Patients with Relapsing Multiple Sclerosis Treated with Natalizumab: A 2-Year Retrospective Analysis. AB - An Online First version of this article was made available online at http://link.springer.com/journal/40263/onlineFirst/page/1 on 24 August 2018. An error was subsequently identified in the article, and the following correction should be noted. PMID- 30244407 TI - Identification novel LQT syndrome-associated variants in Polish population and genotype-phenotype correlations in eight families. AB - Congenital long QT syndrome (LQTS) is a primary cardiac channelopathy. Genetic testing has not only diagnostic but also prognostic and therapeutic implications. At present, 15 genes have been associated with the disease, with most mutations located in 3 major LQTS-susceptibility genes. During a routine genetic screening for KCNQ1, KCNH2 and SCN5A genes in index cases with LQTS, seven novel variants in KCNH2 and SCN5A genes were found. Genotype-phenotype correlations were analysed in these patients and their families. An open reading frame and splice site analysis of the exons was conducted using next-generation sequencing. In novel variants, phenotypes of carriers and their affected relatives were analysed. In 39 unrelated patients, 40 pathogenic/putative pathogenic mutations were found. Thirty-three of them, predominantly missense, were reported previously: 11 were in the KCNQ, 17 in the KCNH2 and 5 in the SCN5A gene. Seven novel missense variants were found in eight families. Among them, four variants were in typical for LQTS location. Two variants in the KCNH2 gene (p.D803Y and p.D46F) and one in the SCN5A gene (G1391R) were in amino acid (AA) position which up to present has not been reported in LQTS. Phenotype analysis showed the life threatening course of the disease in index cases with a history of sudden cardiac death in six families. Mutation carriers presented with ECG abnormalities and some of them received beta-blocker therapy. We report three novel variants (KCNQ1 p.46, KCNH2 p.D803Y, SCN5A p.G1391R) which have never been reported for this AA location in LQTS; the phenotype-genotype correlation suggests their pathogenicity. PMID- 30244409 TI - Coexistence of regulatory B cells and regulatory T cells in tumor-infiltrating lymphocyte aggregates is a prognostic factor in patients with breast cancer. AB - BACKGROUND: Tumors can acquire tolerance to tumor immunity and develop enhanced proliferation. Regulatory B cells (Bregs), whose role in immune tolerance is similar to that of regulatory T cells (Tregs), appear to be involved in tumor immunity. Recently, Bregs were found to induce Tregs against tumor immunity. However, the platform for the coexistence of Bregs and Tregs in cancer patients and its clinical significance remain unclear; thus, they were evaluated in breast cancer patients. METHODS: In 489 breast cancer patients, CD25- and IL10-positive Bregs and Foxp3-positive Tregs were immunohistochemically evaluated in tumor infiltrating lymphocyte aggregates (TIL aggregates) that consisted of CD19 positive B-cell follicles and CD3-positive T-cell parafollicles. Then the correlations of the localization and existence of these cells with metastasis free survival (MFS) were evaluated in breast cancer patients. RESULTS: TIL aggregates were observed in marginal regions of tumors in breast cancer patients. In the TIL aggregates, the existence of Bregs was closely related to that of Tregs (p < 0.0001). On multivariate analysis, the coexistence of Bregs and Tregs in TIL aggregates was correlated with MFS in breast cancer patients (p = 0.007). Furthermore, MFS was significantly shorter for patients with the coexistence of Tregs and Bregs in TIL aggregates than in those with Tregs alone without Bregs (p = 0.0475). CONCLUSIONS: The present results suggest that Bregs are related to the induction of Tregs in TIL aggregates and the development of metastasis of breast cancer cells. Bregs are expected to be a new diagnostic and therapeutic target in breast cancer patients. PMID- 30244408 TI - Evolutionary divergence of the rye Pm17 and Pm8 resistance genes reveals ancient diversity. AB - KEY MESSAGE: We have isolated a novel powdery mildew resistance gene in wheat that was originally introgressed from rye. Further analysis revealed evolutionary divergent history of wheat and rye orthologous resistance genes. Wheat production is under constant threat from a number of fungal pathogens, among them is wheat powdery mildew (Blumeria graminis f. sp. tritici). Deployment of resistance genes is the most economical and sustainable method for mildew control. However, domestication and selective breeding have narrowed genetic diversity of modern wheat germplasm, and breeders have relied on wheat relatives for enriching its gene pool through introgression. Translocations where the 1RS chromosome arm was introgressed from rye to wheat have improved yield and resistance against various pathogens. Here, we isolated the Pm17 mildew resistance gene located on the 1RS introgression in wheat cultivar 'Amigo' and found that it is an allele or a close paralog of the Pm8 gene isolated earlier from 'Petkus' rye. Functional validation using transient and stable transformation confirmed the identity of Pm17. Analysis of Pm17 and Pm8 coding regions revealed an overall identity of 82.9% at the protein level, with the LRR domains being most divergent. Our analysis also showed that the two rye genes are much more diverse compared to the variants encoded by the Pm3 gene in wheat, which is orthologous to Pm17/Pm8 as concluded from highly conserved upstream sequences in all these genes. Thus, the evolutionary history of these orthologous loci differs in the cereal species rye and wheat and demonstrates that orthologous resistance genes can take different routes towards functionally active genes. These findings suggest that the isolation of Pm3/Pm8/Pm17 orthologs from other grass species, additional alleles from the rye germplasm as well as possibly synthetic variants will result in novel resistance genes useful in wheat breeding. PMID- 30244410 TI - S100P and Ezrin promote trans-endothelial migration of triple negative breast cancer cells. AB - PURPOSE: Triple negative breast cancer (TNBC) patients generally have an adverse clinical outcome because their tumors often recur and metastasize to distant sites in the first 3 years after surgery. Therefore, it has become pivotal to identify potential factors associated with metastasis. Here, we focused on the effects of S100P and Ezrin on the trans-endothelial migration (TEM) of TNBC cells, as they have both been suggested to play a role in this process in other malignancies. METHODS: The expression of S100P and Ezrin was examined by immunohistochemistry in 58 primary TNBC samples. The mRNA and protein levels of S100P and Ezrin were assessed in breast cancer-derived cell lines using qRT-PCR and Western blotting, respectively. Proliferation and migration assays were performed using TNBC-derived MFM-223 and SUM-185-PE cells transfected with S100P and Ezrin siRNAs. Two different timeframes were employed for TEM assays using TNBC-derived cells and human umbilical vein endothelial-derived cells, respectively. Correlations between the status of EzrinThr-567 expression and various clinicopathological features were analyzed by immunohistochemistry. RESULTS: We found that S100P and Ezrin double negative TNBC cases were significantly associated with a better disease-free survival. We also found that single and double siRNA-mediated knockdown of S100P and Ezrin in TNBC-derived cells significantly inhibited their TEM and destabilized the intercellular junctions of endothelial cells. In addition, we found that EzrinThr-567 immunoreactivity significantly correlated with vascular invasion in TNBC patients. CONCLUSIONS: From our data we conclude that S100P, Ezrin and EzrinThr 567 are involved in the trans-endothelial migration of TNBC cells and that they may serve as potential targets in TNBC patients. PMID- 30244411 TI - Barry Davis Fletcher, MDCM (1935-2018). PMID- 30244412 TI - Validation of cardiac magnetic-resonance-derived left ventricular strain measurements from free-breathing motion-corrected cine imaging. AB - BACKGROUND: Myocardial strain is an important measure of cardiac function and can be assessed on cardiac magnetic resonance (MR) through the current gold standard of breath-held segmented steady-state free precession (SSFP) cine imaging. Novel free-breathing techniques have been validated for volumetry and systolic function, allowing for evaluation of sicker and younger children who cannot reliably hold their breath. It is unclear whether strain measurements can be reliably performed on free-breathing, motion-corrected, re-binning cine images. OBJECTIVE: To compare strain analysis from motion-corrected retrospective re binning images to the breath-held SSFP cine images to explore their validity. MATERIALS AND METHODS: Twenty-five children and young adults, ages (2.1-18.6 years) underwent breath-held and motion-corrected retrospective re-binning cine techniques during the same MR examination on a 1.5-tesla magnet. We measured endocardial end-systolic global circumferential strain and endocardial averaged segmental strain using commercial software (MEDIS QStrain 2.1). We used Pearson correlation coefficients to test agreement across techniques. RESULTS: Analysis was possible in all 25 breath-held and motion-corrected retrospective re-binning studies. Global circumferential strain and endocardial averaged segmental strain obtained by motion-corrected retrospective re-binning compared favorably to breath-held studies. Global circumferential strain linear regression models demonstrated acceptable agreement, with coefficients of determination of 0.75 for breath-held compared to motion-corrected retrospective re-binning (P<0.001) and for endocardial averaged segmental strain comparisons yielded 0.77 for breath held vs. motion-corrected retrospective re-binning (P<0.001). Bland-Altman assessment demonstrated minimal bias for breath-held compared to motion-corrected retrospective re-binning (mean 2.4 and 1.9, respectively, for global circumferential strain and endocardial averaged segmental strain). CONCLUSION: Free-breathing imaging by motion-corrected retrospective re-binning cine imaging provides adequate spatial and temporal resolution to measure myocardial deformation when compared to the gold-standard breath-held SSFP cine imaging in children with normal or borderline systolic function. PMID- 30244413 TI - Gray-to-white matter ratio predicts long-term recovery potential of patients with aneurysmal subarachnoid hemorrhage. AB - Predicting recovery potential of patients with aneurysmal subarachnoid hemorrhage (aSAH) is challenging. We investigated whether the gray-to-white matter ratio (GWR) predicts recovery of cognitive function (CF) and quality of life (QOL) of these patients. We analyzed data of 69 patients with aSAH. Patients' demographics, comorbidities, and neurological status were recorded. One year after aSAH, Montreal Cognitive Assessment (MoCA) and Short Form-36 (SF-36) tests were administered to the patients, and brain volumes of patients were examined using MRI. Three years after aSAH, MoCA and SF-36 tests were conducted again. Differences between the test scores 1 and 3 years after aSAH were evaluated (DeltaMoCA and DeltaSF-36). Patients with DeltaMoCA >= 4 points and those with DeltaSF-36 >= 8 points were referred to as good MoCA and SF-36 recovery, respectively. DeltaMoCA correlated with GWR in male and female patients (females: p < 0.001, R2 = 0.581; males: p < 0.001, R2 = 0.481). In female patients, GWR > 1.34 predicted good MoCA recovery with 82.3% sensitivity and 80% specificity, and in male patients, GWR > 1.36 predicted good MoCA recovery with 80% sensitivity and 95% specificity. DeltaSF-36 correlated with GWR in male and female patients (females: p < 0.001, R2 = 0.479; males: p < 0.001, R2 = 0.627). In female patients, GWR > 1.35 predicted good SF-36 recovery with 74% sensitivity and 84% specificity, and in male patients, GWR > 1.38 predicted good SF-36 recovery with 72% sensitivity and 92% specificity. GWR is a good predictor of the recovery of CF and QOL in patients with aSAH and, thus, can help physicians to better organize rehabilitation of patients. PMID- 30244414 TI - Improved visualization of superficial temporal artery using segmented time-of flight MR angiography with venous suppression at 7T. AB - PURPOSE: To evaluate the quality of time-of-flight MR angiography (TOF-MRA) with venous suppression at 7T on imaging superficial temporal artery (STA). METHODS: A recently developed segmented TOF technique with reduced specific absorption rate (SAR) of venous suppression (VS) module was employed to achieve high-resolution arterial angiography without the contamination of venous signal. Images of segmented TOF with VS at 7T, TOF without VS at 7T, and TOF with VS at 3T were collected on 17 healthy volunteers. The number of STA branches and their local contrast achieved by the three methods were quantified and compared using paired t test. RESULTS: Segmented TOF with VS at 7T successfully suppressed venous signal without reducing the contrast of arterial angiography. The numbers of STA branches in 7T images were significantly higher than that in 3T images (5.79 vs. 4.50, p < 0.001). The contrast of 7T segmented TOF was significantly higher than 3T TOF (7.21 vs. 5.56, p = 0.006). CONCLUSION: Segmented TOF with VS at 7T displayed more branches of STA, while eliminating the signal of superficial temporal vein (STV). The improved visualization of STA will potentially facilitate the pre-operative assessment of STA in STA-MCA bypass surgery. PMID- 30244416 TI - ASO Author Reflections: Survival Impact of N2 in Non-small Cell Lung Cancer. PMID- 30244417 TI - ASO Author Reflections: Elimination of Breast Cancer Surgery in Complete Responders After Neoadjuvant Chemotherapy: Imaging Perspective. PMID- 30244415 TI - Patterns of striatal and cerebellar functional connectivity in early-stage drug naive patients with Parkinson's disease subtypes. AB - PURPOSE: Both the striatal-thalamo-cortical (STC) circuit and cerebello-thalamo cortical (CTC) circuit play a critical role in Parkinson's disease (PD). METHODS: Resting-state functional MRI was used to assess functional connectivity (FC) focusing on the basal ganglia (BG) and cerebellum among early-stage drug-naive PD patients with tremor-dominant (TD) PD patients with postural instability and gait dysfunction (PIGD) and healthy controls (HCs). RESULTS: Compared to HCs, both PD subgroups had higher FC between the cerebellum and paracentral lobule, sensorimotor areas; lower FC between the BG and superior frontal gyrus, and within the BG circuit; PD-TD patients showed higher FC between the BG and fusiform, paracentral lobule, cerebellum Lobule VI, and between the cerebellum and supplementary motor areas (SMA), insula; lower FC between the BG and rectus, sensorimotor areas, and within the cerebellum circuit; PD-PIGD patients showed higher FC between the cerebellum and middle frontal gyrus, precuneus; lower FC between the BG and cerebellum Crus II. Besides, compared to PD-PIGD patients and HCs, PD-TD patients had higher FC between the BG and calcarine region. In all PD patients, FC in paracentral lobule, SMA, and cerebellum Lobule VI positively correlated with tremor scores, and FC in calcarine area positively correlated with tremor scores, but negatively correlated with PIGD scores. CONCLUSION: Our findings mainly suggested that the BG and cerebellum had hyper-connectivity with the cortical motor cortex, and the BG had prominent hyper-connectivity with the visual cortex in early-stage PD-TD patients. These findings may be helpful for facilitating the further understanding of potential mechanisms in the early-stage PD-TD. However, our results are preliminary, and further investigations are needed. PMID- 30244419 TI - Current Practice and Future Directions for Metaplastic Breast Cancer. PMID- 30244418 TI - Long-Term Survival in Octogenarians After Surgical Treatment for Colorectal Cancer: Prevention of Postoperative Complications is Key. AB - BACKGROUND: Whether to treat octogenarians with colorectal cancer (CRC) in the same manner as younger patients remains a challenging issue. The purpose of this study was to analyse postoperative complications and long-term survival in a consecutive cohort of octogenarians who were surgically treated for CRC. METHODS: Octogenarians with primary CRC suitable for curative surgery between January 2008 and December 2011 were included. Data about comorbidities, tumour stage, and complications were retrospectively collected from patient files. Data about survival were retrieved with use of the Dutch database for persons and addresses. To identify factors associated with severe postoperative complications and postoperative survival, logistic regression analyses, and Cox regression analyses were performed. Odds ratios and hazard ratios (HR) with 95% confidence intervals (CI) were estimated. RESULTS: In a series of 108 octogenarians, median age was 83 years (range 80-94 years). Median follow-up was 47 (range 1-107) months. Major postoperative complications occurred in 25% of the patients. No risk factors for development of severe postoperative complications could be identified. The 30-day mortality was 7%; 1- and 5-year mortality was 19% and 56%, respectively. Overall median survival was 48 months: 66 months in patients without complications versus 13 months in patients with postoperative complications. Postoperative complications were most predictive of decreased survival (HR 3.16; 95% CI 1.79 5.59), even including tumour characteristics, comorbidity, and emergency surgery. CONCLUSIONS: Long-term survival in octogenarians deemed fit for surgery is reasonably good. Prevention of major postoperative complications could further improve clinical outcome. PMID- 30244420 TI - Sarcopenia After Resection of Early Non-small Cell Lung Cancer: Is Postoperative Skeletal Muscle Loss a Risk Factor for Poor Outcomes? PMID- 30244421 TI - Recurrence Patterns After Anatomic or Parenchyma-Sparing Liver Resection for Hepatocarcinoma in a Western Population of Cirrhotic Patients. AB - BACKGROUND: The optimal surgical strategy to lessen the risk of hepatocarcinoma (HCC) recurrence is debated. This study aimed to investigate the role of anatomic resection (AR) and parenchyma-sparing resection (PSR) in HCC recurrence patterns. METHODS: The study analyzed 384 cirrhotic patients with a first diagnosis of HCC. Of these patients, 142 underwent AR, and 242 underwent PSR. The two groups were unbalanced at the univariate analysis. To minimize this bias, a 1:1 propensity score-matching analysis (PSA) was used. Disease-free survival (DFS) curves were analyzed by the Kaplan-Maier method. RESULTS: The PSA allowed pairing of 200 patients (100 for AR and 100 for PSR). In this study, 59 patients (62.8%) had recurrence after AR compared with 58 patients (63.7%) after PSR (p = 0.891). The rates of local recurrence were respectively 15.3% and 15.5% (p = 0.968). When microvascular invasion was considered, the median DFS was 10.7 months for AR and 9.4 months for PSR (p = 0.607). In comparisons of AR and PSR, DFS did not differ significantly between subgroups with high histologic grading (p = 0.520), multiple nodules (p = 0.307), and Child-Pugh B (p = 0.679). CONCLUSION: Excision of the anatomic segment did not seem to reduce the rate of relapse or recurrence patterns significantly, even in high-risk subgroups. PMID- 30244422 TI - ASO Author Reflections: Equitable High-Quality Cancer Surgery Care: Optimism, Pessimism, and Realism. PMID- 30244423 TI - Enzymatic synthesis of cefazolin using immobilized recombinant cephalosporin-acid synthetase as the biocatalyst. AB - A method for the synthesis of beta-lactam antibiotic cefazolin (CEZ) by enzymatic acylation of 7-amino-3-(5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4 carboxylic acid (TDA) using immobilized cephalosporin-acid synthetase (IECASA) from recombinant E. coli strain VKPM B-12316 has been developed. A stepwise pH gradient designed on the basis of investigations on the solubility of components was applied for synthesis. This helped in avoiding the precipitation of TDA in the reaction when its initial concentration was high (150-200 mM). Thus, under optimal conditions a high yield of CEZ (relative to TDA) of 92-95% was obtained. Where the final reaction mixture contained 65-85 mg/mL of CEZ, 4-5 mg/mL of unreacted TDA, and 40-60 mg/mL of the by-product, 1(H)-tetrazolylacetic acid (TzAA). Testing of optimized CEZ synthesis using IECASA in a batch reactor has proved sufficiently high operational stability of the biocatalyst, with its residual activity after the 25th cycle accounting for about 83 +/- 2% of its starting value. The half-inactivation period of IECASA was estimated as 85 cycles of CEZ synthesis. PMID- 30244424 TI - Ethanol production from xylose is highly increased by the Kluyveromyces marxianus mutant 17694-DH1. AB - Directed evolutionary approach and random mutagenesis were performed on thermotolerant yeast Kluyveromyces marxianus KCTC17694 for isolating a yeast strain producing ethanol from xylose efficiently. The isolated mutant strain, K. marxianus 17694-DH1, showed 290% and 131% improvement in ethanol concentration and ethanol production yield from xylose, respectively, as compared with the parental strain. Sequencing of the KmXYL1 gene of K. marxianus 17694-DH1 revealed substitutions of arginine and tryptophan with lysine and leucine at positions 25 and 202, respectively, as compared to the parental strain. In addition, sequencing of the KmXYL2 gene uncovered a substitution of glutamate with leucine at position 232. When enzymatic assays of xylose reductase (XR) and xylitol dehydrogenase (XDH) from the parental strain and K. marxianus 17694-DH1 were performed, XR activities were not significantly different whereas XDH activities were significantly improved in the mutant strain up to 50 degrees C of reaction temperatures. RNA-Seq based transcriptome analysis showed that alcohol dehydrogenases and glucose transporters were up-regulated while TCA cycle involved enzymes were down-regulated in K. marxianus 17694-DH1. PMID- 30244425 TI - A button battery in the nose. PMID- 30244426 TI - Fluid intake and chronic kidney disease: effect of coaching an increase in fluid intake on kidney function decline. PMID- 30244427 TI - Molecular evidence of infection with air sac nematodes in the great tit (Parus major) and the captive-bred gyrfalcon (Falco rusticolus). AB - Serratospiculiasis is a parasitic disease caused by filariid nematodes of the genus Serratospiculum that parasitise the air sacs of various species of falcons, bald eagles and Cooper's hawks around the world. An infection with Serratospiculum was recently confirmed in a nonspecific host, the great tit, in Slovakia. Parasitic material from this host was fixed for molecular analysis. Nematode found in the air sacs from a captive-bred gyrfalcon was also stored. Analysis of small subunit (18S) ribosomal DNA (18S rDNA) gene indicated that sequences from Serratospiculum sp. and Serratospiculoides amaculata were closely related to a reference sequence from Serratospiculum tendo, in agreement with morphology. This study is the first to generate molecular data and infer the phylogenetic position of S. amaculata as the first representative of the genus Serratospiculoides. PMID- 30244428 TI - Distribution and morphology of baroreceptors in the rat carotid sinus as revealed by immunohistochemistry for P2X3 purinoceptors. AB - The morphological characteristics of baroreceptors in the rat carotid sinus were reevaluated by whole-mount preparations with immunohistochemistry for P2X3 purinoceptors using confocal scanning laser microscopy. Immunoreactive nerve endings for P2X3 were distributed in the internal carotid artery proximal to the carotid bifurcation, particularly in the region opposite the carotid body. Some pre-terminal axons in nerve endings were ensheathed by myelin sheaths immunoreactive for myelin basic protein. Pre-terminal axons ramified into several branches that extended two-dimensionally in every direction. The axon terminals of P2X3-immunoreactive nerve endings were flat and leaf-like in shape, and extended hederiform- or knob-like protrusions in the adventitial layer. Some axons and axon terminals with P2X3 immunoreactivity were also immunoreactive for P2X2, and axon terminals were closely surrounded by terminal Schwann cells with S100 or S100B immunoreactivity. These results revealed the detailed morphology of P2X3-immunoreactive nerve endings and suggested that these endings respond to a mechanical deformation of the carotid sinus wall with their flat leaf-like terminals. PMID- 30244429 TI - Generation of Cas9 transgenic zebrafish and their application in establishing an ERV-deficient animal model. AB - OBJECTIVES: To investigate the effect of endogenous Cas9 on genome editing efficiency in transgenic zebrafish. RESULTS: Here we have constructed a transgenic zebrafish strain that can be screened by pigment deficiency. Compared with the traditional CRISPR injection method, the transgenic zebrafish can improve the efficiency of genome editing significantly. At the same time, we first observed that the phenotype of vertebral malformation in early embryonic development of zebrafish after ZFERV knockout. CONCLUSIONS: The transgenic zebrafish with expressed Cas9, is more efficient in genome editing. And the results of ZFERV knockout indicated that ERV may affect the vertebral development by Notch1/Delta D signal pathway. PMID- 30244430 TI - Factors Associated with Community-Partnered School Behavioral Health Clinicians' Adoption and Implementation of Evidence-Based Practices. AB - Community-partnered school behavioral health (CP-SBH) is a model whereby schools partner with local community agencies to deliver services. This mixed-methods study examined 80 CP-SBH clinicians' adoption and implementation of evidence based practice (EBP) approaches following mandated training. Forty-four clinicians were randomly assigned to one of two training conditions for a modular common elements approach to EBPs; 36 clinicians were preselected for training in a non-modular EBP. EBP knowledge improved for all training conditions at 8-month follow-up and practice element familiarity improved for modular approach training conditions, but the modular condition including ongoing consultation did not yield better results. Qualitative interviews (N = 17) highlighted multi-level influences of the CP-SBH service system and individual clinician characteristics on adoption and implementation. PMID- 30244431 TI - International position paper on the appropriate use of uricosurics with the introduction of lesinurad. AB - Over the last 70 years, pharmacotherapy in gout with urate-lowering drugs has consisted of four drugs only: In 1952, a mild uricosuric probenecid became available, the xanthine oxidase inhibitor Allopurinol in 1964, and the latter became the most frequently used urate-lowering drug worldwide; in the Eurozone, the uricosuric benzbromarone was welcomed in 1977. Only in 2002, the potent non purine xanthine oxidase inhibitor febuxostat was introduced. In many countries, uricosurics such as probenecid and benzbromarone have not been available up to now, and these days, the new uricosuric lesinurad is the first uricosuric that may be introduced in these countries, which is the reason for describing the position this novel uricosuric deserves in treating gout. Recent literature will be shortly reviewed, and the current proposed position for lesinurad will be given as an aid for clinicians. PMID- 30244432 TI - Active tuberculosis in patients with systemic lupus erythematosus from Southern China: a retrospective study. AB - To investigate the characteristics and associated factors for Mycobacterium tuberculosis (TB) infection in patients with systemic lupus erythematosus (SLE) from Southern China. A retrospective study of 1108 patients admitted to the First Affiliated Hospital of Sun Yat-Sen University from January 2007 to December 2017 was performed. Demographic and clinical characteristics, laboratory data, and radiographic manifestations were recorded. A total of 59 (5.3%) lupus patients with active TB were included. Pulmonary TB occurred in 41 (69.5%) patients. Single lobe involvement was showed in 14 (34.1%) patients. Multi-lobar involvement, including miliary TB (36.6%), was presented in 27 (65.8%) patients. Lower lobe involvement accounted for 31 (75.6%) of the cases. Extrapulmonary TB occurred in 18 (30.5%) patients. Nearly one-third (35.6%) of the patients developed disseminated TB. T-SPOT.TB assay was performed in 23 patients and positive in 18 patients (78.3%). Nineteen patients (32.2%) had co-infection with TB and other pathogens, most of which were bacterial-associated (52.6%). Lymphopenia was predominant in TB-infected patients, especially in those with disseminated TB. Multivariate logistic regression analysis found that lymphopenia [odds ratio (OR) = 2.19, 95% confidence interval (CI) 1.03-4.63, P = 0.04] and the accumulated doses of glucocorticoid (GC) (OR = 2.32, 95% CI 1.69-3.20, P < 0.001) were associated with TB. TB infection is a common comorbidity in patients with SLE. Manifestations of pulmonary computed tomography (CT) scan are relatively atypical. Co-infection with TB and other pathogens is not rare. Lymphopenia and the accumulated doses of GC are associated with TB infection in lupus patients. PMID- 30244433 TI - Mononuclear-cell-derived microparticles attenuate endothelial inflammation by transfer of miR-142-3p in a CD39 dependent manner. AB - Plasma microparticles (MP) bear functional active ectonucleotidases of the CD39 family with implications in vascular inflammation. MP appear to be able to fuse with cells and transfer genetic information. Here, we tested whether levels of different immunomodulatory microRNAs (miRs) in plasma MP are modulated by CD39 after experimental hepatectomy. We further investigated whether horizontal transfer of miR-142-3p between mononuclear (MNC) and endothelial cells via MP is regulated by purinergic signaling. Partial hepatectomy was performed in C57BL/6 wild type and Cd39 null mice. MP were collected via ultracentrifugation. MNC were stimulated with nucleotides and nucleosides, in vitro, and tested for miR-142-3p levels. Fusion of MNC-derived MP and endothelial cells with subsequent transfer of miR-142-3p was imaged by flow cytometry and confocal microscopy. Endothelial inflammation and apoptosis were quantified after transfection with miR-142-3p. Significantly lower miR-142-3p levels were observed in plasma MP of Cd39 null mice after partial hepatectomy, when compared to C57BL/6 wild types (p < 0.05). In contrast to extracellular nucleotides, anti-inflammatory adenosine significantly increased miR-142-3p levels in MNC-derived MP, in vitro (p < 0.05). MNC-derived MP are able to transfer miR-142-3p to endothelial cells by fusion. Transfection of endothelial cells with miR-142-3p decreased TNF-alpha levels (p < 0.05) and endothelial apoptosis (p < 0.05). MiR-142-3p levels in MNC-derived MP are modulated by nucleoside signaling and might reflect compensatory responses in vascular inflammation. Our data suggest the transfer of genetic information via shed MP as a putative mechanism of intercellular communication-with implications in organ regeneration. PMID- 30244434 TI - Evaluation of Nutritional and Mineral-Heavy Metal Contents of Horse Mackerel (Trachurus trachurus) in the Middle Black Sea in terms of Human Health. AB - In this study, the effects of seasonal and sexual differences on the nutritional composition, macro (Na, Mg, P, K, Ca), trace element (Mn, Fe, Co, Cu, Zn, Mo, Ni, Se) and potential toxic metal levels (Cd, Pb, As) of horse mackerel (Trachurus trachurus) caught in the middle Black Sea coast during all seasons were investigated. The metal levels of muscle tissues of the examined specimens were determined using ICP-MS instrument. The results showed that horse mackerel had a high nutritional value in terms of protein and lipid levels. Metal levels were found to be different in terms of sexual and seasonal factors. With regard to macro element levels, horse mackerel muscle was found to be rich. Zn and Cu levels of the trace elements were below the legal limits specified by the codex. It was also observed that the levels of Cd and Pb in horse mackerel muscle tissue were below the FAO (Food Agriculture Organ U N 464:5-10, 1983) limit values and above the TFC (Turkish Food Codex 2011) limit values. In terms of EWI and EDI values, horse mackerel was found to be non-toxic. This study suggests that horse mackerel is beneficial seafood for human health and nutrition. PMID- 30244435 TI - Factors Affecting the Tailing of Blunt End DNA with Fluorescent Pyrimidine dNTPs. AB - The transferase activity of non-proofreading DNA polymerases is a well-known phenomenon that has been utilized in cloning and sequencing applications. The non templated addition of modified nucleotides at DNA blunt ends is a potentially useful feature of DNA polymerases that can be used for selective transformation of DNA 3' ends. In this paper, we characterized the tailing reaction at perfectly matched and mismatched duplex ends with Cy3- and Cy5-modified pyrimidine nucleotides. It was shown that the best DNA tailing substrate does not have a perfect Watson-Crick base pair at the end. Mismatched duplexes with a 3' dC were the most efficient in the Taq DNA polymerase-catalysed tailing reaction with a Cy5-modified dUTP. We further demonstrated that the arrangement of the dye residue relative to the nucleobase notably affects the outcome of the tailing reaction. A comparative study of labelled deoxycytidine and deoxyuridine nucleotides showed higher efficiency for dUTP derivatives. The non-templated addition of modified nucleotides by Taq polymerase at a duplex blunt end was generally complicated by the pyrophosphorolysis and 5' exonuclease activity of the enzyme. PMID- 30244437 TI - Isolation of Extracellular Vesicles from Subventricular Zone Neural Stem Cells. AB - The neonatal subventricular zone (SVZ) is a neurogenic niche that contains neural stem cells (NSCs). NSCs release particles called extracellular vesicles (EVs) that contain biological material. EVs are transferred to cells, including immune cells in the brain called microglia. A standard approach to identify EV functions is to isolate and transplant EVs. Here, a detailed protocol is provided that will allow one to culture neonatal SVZ NSCs and to isolate, label, and transplant EVs. The protocol will permit careful and thorough examination of EVs in a wide range of physiological and pathophysiological conditions. PMID- 30244438 TI - 3D Culture of Mesenchymal Stem Cells in Alginate Hydrogels. AB - Three-dimensional (3D) cell culture systems have gained increasing interest among the scientific community, as they are more biologically relevant than traditional two-dimensional (2D) monolayer cultures. Alginate hydrogels can be formed under cytocompatibility conditions, being among the most widely used cell-entrapment 3D matrices. They recapitulate key structural features of the natural extracellular matrix and can be bio-functionalized with bioactive moieties, such as peptides, to specifically modulate cell behavior. Moreover, alginate viscoelastic properties can be tuned to match those of different types of native tissues. Ionic alginate hydrogels are transparent, allowing routine monitoring of entrapped cells, and crosslinking can be reverted using chelating agents for easy cell recovery. In this chapter, we describe some key steps to establish and characterize 3D cultures of mesenchymal stem cells using alginate hydrogels. PMID- 30244436 TI - Molecular and Functional Diversity of RNA Editing in Plant Mitochondria. AB - RNA editing is a fundamental biochemical process relating to the modification of nucleotides in messenger RNAs of functional genes in cells. RNA editing leads to re-establishment of conserved amino acid residues for functional proteins in nuclei, chloroplasts, and mitochondria. Identification of RNA editing factors that contributes to target site recognition increases our understanding of RNA editing mechanisms. Significant progress has been made in recent years in RNA editing studies for both animal and plant cells. RNA editing in nuclei and mitochondria of animal cells and in chloroplast of plant cells has been extensively documented and reviewed. RNA editing has been also extensively documented on plant mitochondria. However, functional diversity of RNA editing factors in plant mitochondria is not overviewed. Here, we review the biological significance of RNA editing, recent progress on the molecular mechanisms of RNA editing process, and function diversity of editing factors in plant mitochondrial research. We will focus on: (1) pentatricopeptide repeat proteins in Arabidopsis and in crop plants; (2) the progress of RNA editing process in plant mitochondria; (3) RNA editing-related RNA splicing; (4) RNA editing associated flower development; (5) RNA editing modulated male sterile; (6) RNA editing regulated cell signaling; and (7) RNA editing involving abiotic stress. Advances described in this review will be valuable in expanding our understanding in RNA editing. The diverse functions of RNA editing in plant mitochondria will shed light on the investigation of molecular mechanisms that underlies plant development and abiotic stress tolerance. PMID- 30244440 TI - Cleaner emissions from a DI-diesel engine fueled with mahua oil and low carbon ethanol-hydrogen in dual fuel mode. AB - This work is all about utilization of more than two low carbon fuels in a diesel engine with a main objective of reducing harmful emissions. Initially, test engine was tested with a non-petroleum-based fuel namely mahua oil, under different load conditions. In the second phase of the work, test engine was modified into dual fuel mode with slight modification in the intake manifold for the admission of a low carbon high octane primary fuel namely ethanol. The engine was tested by varying the ethanol energy share (EES) from 5% to the point at which engine tends to knock at 100% and 40% of the maximum engine power output. Finally, an attempt was made to induct a zero carbon high octane fuel (i.e., hydrogen) in the intake manifold of the dual fuel engine operated with mahua and ethanol and tested for the behavior. Experimental results claimed that inclusion of ethanol improved the brake thermal efficiency (BTE) only at the higher loads. Optimized EES at 100% load conditions was identified as 15%. It is found that injection of ethanol significantly reduced the harmful emissions like smoke and oxides of nitrogen at the price of increased hydrocarbon and carbon monoxide emissions. It is also inferenced that BTE was improved further with the increases of hydrogen flow rate at peak load. Interestingly all the carbon-based emissions were drastically reduced with the inclusion of hydrogen. However, the oxides of nitrogen emission were found to be increased with increase of hydrogen flow rate. PMID- 30244439 TI - Enzyme activity modification in adult beetles (Agelastica coerulea) inhabiting birch trees in an ozone-enriched atmosphere. AB - Tropospheric ozone (O3) is a naturally occurring gas in the atmosphere. However, the concentration of O3 increased in the twentieth century. Although the effects of O3 on vegetation have been extensively studied since the 1950s, limited information exists regarding the effects of O3 on insect herbivores. In particular, evidence is lacking regarding the effects of O3 on the biology of insect herbivores. Agelastica coerulea Baly (1874) is a coleopteran species that grazes on Betulaceae plants. In this study, to investigate the effects of O3 on A. coerulea biology for the first time, female adult insects were collected from Japanese white birch trees grown in a Free Air Controlled Exposure System (FACE) in Sapporo, Japan. These beetles inhabited trees exposed either to ambient or to elevated O3 for 23 days. After collection, the enzyme activities in the beetles were measured. Elevated O3 led to a greater total antioxidant activity and lower alpha- and beta-esterase activities, a phenomenon that may suggest an increased resistance of the beetles to stress. Our results are further discussed with regard to biological and toxicological aspects. Collectively, our findings indicate that total antioxidants and alpha- and beta-esterase activities can serve as effective O3 biomarker systems in this beetle species. This adaptive response of the beetle, which was induced by moderate O3 exposure, should be further tested across generations and for its protection against greater exposure. PMID- 30244441 TI - Distribution of virulence factors, determinants of antibiotic resistance and molecular fingerprinting of Salmonella species isolated from cattle and beef samples: suggestive evidence of animal-to-meat contamination. AB - In this study, three hundred presumptive Salmonella strains isolated from cattle faeces and raw beef samples were subjected to both preliminary and confirmatory tests specific for Salmonella. PCR assays revealed that 100%, 20% and 26.7% of the isolates were positive for 16S rRNA, fliC and fljB gene fragments, respectively. Large proportions (62.4 to 94.3%) of these isolates were multiple antibiotic resistant (MAR) strains that were resistant to three or more antibiotics belonging to different classes. MAR phenotypes Ab1, Ab2, Ab3, Ab7, Ab8, Ab9, Ab26 and Ab27 were dominant among the isolates. Cluster analysis of antibiotic inhibition zone diameter data revealed two major clusters (clusters 1 and 2), and each cluster contained two sub-clusters (1A, 1B, 2A and 2B). PCR data revealed that 27.1% and 30.7% of the isolates possessed the spvC and invA virulent genes, respectively. There was a significant correlation between the possession of MAR phenotypes and virulent gene determinants. Analysis of restriction fragment length polymorphism (RFLP) of 16S rRNA gene fragments using EcoRI and HaeIII showed that large proportions of isolates from beef and cattle faeces produced similar genetic fingerprints. From these results, it is suggested that Salmonella species in cattle are transmitted to beef and, therefore, the consumption of undercooked beef could pose severe health complications on consumers. These findings provide baseline data that could be of great epidemiological importance and, thus, the need to utilise more sensitive typing tools in determining the genetic relatedness of isolates from different sources. PMID- 30244442 TI - Air quality improvement and health benefit of PM2.5 reduction from the coal cap policy in the Beijing-Tianjin-Hebei (BTH) region, China. AB - Large amounts of air pollutants emitted from massive coal combustion result in the air quality deterioration and threaten public health in China. To improve air quality, the Chinese government released the coal cap policy to reduce coal consumption. So it is important and necessary to understand the possible environmental impact and relevant health benefits from the coal cap policy. The purpose of this paper is to quantify the air quality improvement and to evaluate the health benefits from the implementation of the coal cap policy, with the Beijing-Tianjin-Hebei (BTH) region as the study area. The results showed that the emissions of SO2, NOx, CO, VOCs, PM10, and PM2.5 could be reduced by 20-40% in the BTH region in 2020 and all pollutants from industrial boilers notably decreased. Under the coal cap policy, the PM2.5 concentration in the whole region would fall by 11.27%, and the total economic benefit from health impacts could achieve 26.61 (13.29 to 39.14) billion RMB (3.9 billion USD) in the BTH region in 2020, accounting for 0.43% (0.21 to 0.63%) of regional GDP in 2013. This study demonstrated the quantification of environmental effect and health benefit from the coal cap policy, which could be used for the complete cost-benefit analysis and provide the sufficient support for policy makers to implement the coal cap policy in the BTH region and other areas of China. PMID- 30244443 TI - Characterization and application of microalgae hydrochar as a low-cost adsorbent for Cu(II) ion removal from aqueous solutions. AB - Hydrochar prepared from the hydrothermal liquefaction of microalgae is characterized and investigated for copper removal from aqueous solution. Two hydrochars were prepared at 210 degrees C (HD210) and 250 degrees C (HD250). The effect of the initial solution pH, the initial Cu(II) concentration, the contact time, and the temperature will be investigated. According to the elemental analysis, the volatile matter in the hydrochars was lower and ash content was higher than those of microalgae. Also, pore characteristic analysis revealed that the surface area of the HD250 was higher than that of the HD210 suggesting a higher potential for the adsorption process. FTIR analysis and Boehm titration showed that both hydrochars contained oxygen-containing functional groups (OFG) on the surface which were effective for the copper removal. The adsorption experiments indicated that the amount of copper adsorbed reached a maximum value at the pH of 5 which was considered as the optimum solution pH. In addition, HD250 had a higher amount of copper adsorption than that of HD210 at all values of the solution pH. The adsorption data at the optimum solution pH was well fitted by the Langmuir's isotherm model and the adsorption process could be well described by the pseudo-2nd order kinetic model. Moreover, thermodynamic analysis revealed that copper adsorption onto the hydrochar was a physical endothermic process. PMID- 30244444 TI - Effects of high ammonium enrichment in water column on the clonal growth of submerged macrophyte Vallisneria natans. AB - As we know, the survival of young ramets and stolons is essential for the clonal growth of many aquatic plants. However, few NH4+ enrichment experiments on clonal growth of submerged macrophytes have been conducted to provide possible evidences for their declines in eutrophic lakes. Here, the growth and physiological responses of V. natans to the enrichment of NH4+-N were examined under six inorganic nitrogen (IN, i.e., the sum of nitrate nitrogen (NO3--N) and ammonium nitrogen (NH4+-N)) concentrations (control, 2.5, 4.5, 6.5, 8.5, and 10.5 mg L-1). When NH4+-N concentration increased over 0.5 mg L-1, free amino acid (FAA) contents in leaves and stolons increased while soluble carbohydrate (SC) and starch contents decreased, and major growth indices (total biomass of plants, number of ramets, and stolon dry weight (DW)) also showed a degressive tendency. Remarkably, the stolon DW significantly declined with increasing FAA, but significantly positively related to SC and starch. These results indicated that clonal growth of V. natans was inhibited by high NH4+-N concentration, and imbalance of C-N metabolism of stolons partly explained the decline of submerged clonal macrophytes. In this study, the leaves of new and small (NS) ramets contained significantly more FAA and less SC than that of mature and mother (MM) plants, indicating that the C-N metabolism of young ramets was easier to be disrupted, consequently inhibiting the clonal growth of aquatic plants. Furthermore, under the condition of high NH4+-N concentration, FAA may be a useful indicator of both macrophyte growth and physiological stress of plants. PMID- 30244445 TI - Antioxidative response in leaves and allelochemical changes in root exudates of Ricinus communis under Cu, Zn, and Cd stress. AB - We have previously reported that Ricinus communis is a good candidate for the phytoremediation of Cd- and Zn-contaminated soil and for fuel production. In this study, changes in the activity of antioxidant enzymes (superoxide dismutase, SOD; catalase, CAT; and guaiacol peroxidase, POD) and the contents of chlorophyll and malondialdehyde (MDA) in R. communis leaves under Cu, Zn, and Cd stress were examined. Compounds from the exudate of R. communis roots were collected and analyzed using GC-MS chromatograms. The results of enzyme activity showed that Cd treatment significantly increased the SOD content of R. communis leaves and slightly elevated the CAT content, whereas the POD content increased markedly at low Cd treatment concentrations and decreased as Cd concentrations increased. Zn treatment distinctly elevated SOD and POD content in R. communis leaves but had no great influence on CAT content. Cu treatment slightly increased CAT activity, while Cu did not evidently change SOD and POD activity. We found 17, 29, 18, 18, and 33 different compounds in the R. communis root exudates from the control group and Cd, Cu, Zn, and Cd+Cu+Zn treatment groups, respectively. The root exudates mainly included ester, alcohol, ether, amide, acid, phenol, alkanes, ketone, aromatic hydrocarbon, and nitrile compounds. However, the root exudates of R. communis grown in uncontaminated soils were dominated by esters, alcohols, and ethers. Single Cu or Zn treatment slightly changed the root exudates, which were dominated by esters, alcohols, and amides. In the Cd and Cd+Cu+Zn treatment groups, the compositions of root exudates apparently increased, with alkanes as the major species (> 88%). PMID- 30244447 TI - Evaluation of aromatic hydrocarbon decomposition catalyzed by the dioxygenase system and substitution of ferredoxin and ferredoxin reductase. AB - In this study, the catalytic activity and kinetic characteristics of the aromatic hydrocarbon dioxygenase system and the possibility of substituting its ferredoxin and ferredoxin reductase components were evaluated. The genes encoding toluene dioxygenase and toluene dihydrodiol dehydrogenase were cloned from Pseudomonas putida F1, and the corresponding enzymes were overexpressed and purified to homogeneity. Oxidative hydroxylation of toluene to cis-toluene dihydrodiol was catalyzed by toluene dioxygenase, and its subsequent dehydrogenation to 3 methylcatechol was catalyzed by toluene dihydrodiol dehydrogenase. The specific activity of the dioxygenase was 2.82 U/mg-protein, which is highly remarkable compared with the values obtained in previous researches conducted with crude extracts or insoluble forms of enzymes. Kinetic parameters, as characterized by the Hill equation, were vmax = 497.2 MUM/min, KM = 542.4 MUM, and nH = 2.2, suggesting that toluene dioxygenase has at least three cooperative binding sites for toluene. In addition, the use of alternative ferredoxins and reductases was examined. Ferredoxin cloned from CYP153 could transfer electrons to the iron sulfur protein component of toluene dioxygenase. The ferredoxin could be reduced by ferredoxin, rubredoxin, and putidaredoxin reductases of CYP153, alkane-1 monooxygenase, and camphor 5-monooxygenase, respectively. The results provide useful information regarding the effective enzymatic biotreatment of hazardous aromatic hydrocarbon contaminants. PMID- 30244446 TI - Independent and interactive effects of reduced seawater pH and oil contamination on subsurface sediment bacterial communities. AB - Ocean acidification may exacerbate the environmental impact of oil hydrocarbon pollution by disrupting the core composition of the superficial (0-1 cm) benthic bacterial communities. However, at the subsurface sediments (approximately 5 cm below sea floor), the local biochemical characteristics and the superjacent sediment barrier may buffer these environmental changes. In this study, we used a microcosm experimental approach to access the independent and interactive effects of reduced seawater pH and oil contamination on the composition of subsurface benthic bacterial communities, at two time points, by 16S rRNA gene-based high throughput sequencing. An in-depth taxa-specific variance analysis revealed that the independent effects of reduced seawater pH and oil contamination were significant predictors of changes in the relative abundance of some specific bacterial groups (e.g., Firmicutes, Rhizobiales, and Desulfobulbaceae). However, our results indicated that the overall microbial community structure was not affected by independent and interactive effects of reduced pH and oil contamination. This study provides evidence that bacterial communities inhabiting subsurface sediment may be less susceptible to the effects of oil contamination in a scenario of reduced seawater pH. PMID- 30244448 TI - Collagen-Induced Arthritis Models. AB - Due to limitations of using patient-derived samples for systemic kinetic studies in rheumatoid arthritis (RA) research, animal models are helpful for further understanding the pathophysiology of RA and seeking potential therapeutic targets or strategies. The collagen-induced arthritis (CIA) model is one of the standard RA models used in preclinical research. The CIA model shares several pathological features with RA, such as breach of tolerance and generation of autoantibodies targeting collagen, synovial inflammatory cell infiltration, synovial hyperplasia, cartilage destruction, and bone erosion. In this chapter, a protocol for successful induction of CIA in mice is described. In this protocol, CIA is induced by active immunization by inoculation with type II heterologous collagen in Freund's adjuvant in susceptible DBA/1 mice. PMID- 30244449 TI - Human Xenograft Model. AB - Human-SCID grafting is a commonly used technique for the long-term investigation of rheumatoid arthritis (RA) explants. To establish a chimeric immunological system in NOD/SCID mice, RA patient-derived pannus tissue from the synovial membrane, articular cartilage, and bone can be transplanted subcutaneously. The same patient-derived peripheral blood mononuclear cell chimerism can be successfully achieved by intraperitoneal engraftment. This xenograft model is able to be used for initial screening of human target-specified biologics. PMID- 30244450 TI - Long-Term Constant Subcutaneous Drug Administration. AB - In this chapter, a long-term drug delivery system for preclinical therapeutic research is introduced. By using a subcutaneously implanted ALZET(r) osmotic pump, continuous zero-order delivery of drugs under investigation that need repeated oral or intravenous dosing is realizable. Compared to traditional delivery systems, implanted osmotic pumps present several advantages such as that no external connections or researcher intervention is required during infusion and that it is possible to save time by eliminating the need for frequent animal handling and repetitive injection schedules. Most importantly, a stable peripheral concentration of drug is able to be obtained using this constant drug delivery system, which would benefit researchers to verify the efficiency of antirheumatoid drugs and establish safety profiles in preclinical studies. PMID- 30244451 TI - Clinical Scoring of Disease Activity in Animal Models. AB - Disease severity in murine arthritis models, such as collagen-induced arthritis (CIA), is commonly assessed by clinical scoring of paw swelling and histological examination of joints. Clinical scoring using a qualitative scoring system of paw inflammation (paw thickness, width, or volume) over time is the standard method used for subjective quantification of arthritis activity. To evaluate paw swelling status, a quantitative method using three-dimensional T2-weighted flash sequence magnetic resonance imaging (MRI) is introduced. The efficacy of a therapeutic approach can be semiologically quantified using a clinical scoring system and an index of paw inflammation in CIA mice. PMID- 30244452 TI - Histological Analysis of Arthritic Joints. AB - Histological analysis is a morphological technique and an effective method for understanding the pathology of rheumatoid arthritis (RA). Here, we describe the processes of paraffin samples, including fixation, decalcifying, embedding, sectioning, and staining (hematoxylin and eosin, tartrate-resistant acid phosphatase, and immunohistochemistry) for an RA model mouse. PMID- 30244453 TI - Preparation of Joint Extracts. AB - Since mice are widely used to establish rheumatoid arthritis models, assessment of the pathogenesis of local arthritis is fundamental. Proteins are the most diverse group of biologically important molecules and are essential for cellular structure and function. The first step in pathogenesis-related protein analysis is joint tissue extraction. Unlike other large rodents, obtaining synovium from model mice is challenging, since it is so small and fragile. In this chapter, methods for harvesting synovium through a quadriceps approach and preparing protein extracts are introduced. PMID- 30244454 TI - Production of Immunizing Antigen Proteoliposome Using Cell-Free Protein Synthesis System. AB - Antibodies specifically recognizing integral membrane protein are essential tool for functional analysis, diagnosis, and therapeutics targeting membrane proteins. However, development of antibodies against membrane protein remains a big challenge, because mass production of membrane protein is difficult. Recently, we developed a highly efficient cell-free production method of proteoliposome antigen using cell-free protein synthesis method with liposome and dialysis cup. Here we introduce practical and efficient integrated procedures to produce large amount of proteoliposome antigen for anti-membrane protein antibody development. PMID- 30244455 TI - Reconstruction of Protein/Liposome Complex. AB - Most ion channels and receptors are distributed in cell membranes and are known as membrane proteins. These membrane proteins are folded in the cell membrane and become functional proteins. Here, we demonstrate a method of reconstructing membrane proteins into liposome membranes which are commonly used as artificial cell membranes. PMID- 30244456 TI - Production of Neutralizing Antibody. AB - Techniques employing monoclonal antibodies (mAbs) are widely used in the initial development phase of biologics. The usefulness of mAbs in basic RA research has been established based on their characteristics, including specificity of binding, homogeneity, and ability to be produced on a large scale. MAb immunoglobulins are the starting material for the generation of smaller antibody fragments and other engineered immunomodulatory antibodies. In this chapter, the basic hybridoma technique, which is a well-established and feasible method for the production of mAbs involving animal immunization, cell fusion, hybridoma screening, expanding positive hybridomas, and purification, is introduced. Aiming at specific affinity to a membrane protein, synthetic proteoliposomes are used in the immunization and screening steps. PMID- 30244457 TI - Autoantibody Profiling Using Human Autoantigen Protein Array and AlphaScreen. AB - Autoantibodies that recognize self-antigens are believed to have close relationship diseases such as autoimmune diseases, cancer, and lifestyle diseases. Analysis of autoantibodies is essential for investigating pathology mechanisms, diagnosis, and therapeutics of these diseases. We developed autoantibody profiling assay using cell-free synthesized protein array and high throughput screening technology. Our assay system can sensitively detect interaction between recombinant antigen protein and autoantibody and efficiently analyze autoantibody profiling in patients' sera. PMID- 30244458 TI - Generation of Specific Aptamers. AB - Nucleic acid aptamers are therapeutic agents consisting of short single-strand DNA or RNA oligonucleotides, which have the ability to bind to target therapeutic molecules with high affinity and specificity, and have been developed as potent drugs for the treatment of rheumatoid arthritis. Aptamers have unique and advantageous features over antibodies, such as superior affinity with nano- or pico-molar dissociation constants, and ease of chemical synthesis, modification, and inactivation by designing antisense sequences. In this chapter, using a DNA oligonucleotide pool, the technology of proteoliposome-systematic evolution of ligands by exponential enrichment (SELEX) is introduced. By using this technique, potential therapeutic agents with high affinity and specificity could be obtained. PMID- 30244459 TI - Production of Lentiviral Particles. AB - Lentiviral-mediated transfection technique is a powerful tool for gene modification in preclinical studies. By using this technique, the desired gene modification can be achieved easily in immune cells, nondividing and terminally differentiated cells, including hematopoietic stem cells, neurons, and even tumor cells, which other viral vectors cannot do. The main considerations of therapeutic gene delivery using a lentiviral system are the risk of insertional mutagenesis and the immune reaction elicited by infected cells. Although some biosafety concerns need to be addressed before clinical trials in rheumatoid arthritis, the lentiviral system targeting therapeutic targets has been widely used for in vivo gene transfer in animal models. In this chapter, the protocols for production of viral particles and viral concentration are provided. PMID- 30244460 TI - RNA Interference Ex Vivo. AB - RNA interference (RNAi) is a widely used technique to regulate the expression of genes and proteins with a high degree of specificity that is not easily accessed by traditional pharmacological approaches. For preclinical research on rheumatoid arthritis (RA), silencing of target genes in primary immune cells can be easily achieved by application of small interfering RNA (siRNA) and synthetic short hairpin RNA (shRNA). Cellular and systemic administration of siRNA or shRNA has been a significant advance in preclinical research on RA. In this chapter, the basic techniques for gene silencing in human-derived peripheral T cells using liposome-dependent siRNA transfection and lentiviral-mediated shRNA delivery, aiming at gene silencing of therapeutic targets, are introduced. PMID- 30244461 TI - Lentiviral-Mediated Systemic RNA Interference In Vivo. AB - The shRNA-encoding lentivirus has been widely used for gene manipulation in preclinical studies. It is a powerful tool for gene transfer and shows promise in its ability to efficiently transduce immune cells and hematopoietic stem cells, which are the initial therapeutic target of autoimmune diseases, considering that gene manipulation of these cells is usually difficult to achieve using other techniques. In previous chapters, we have described how to produce concentrated shRNA-encoding lentiviral particles. Here, systemic in vivo application of lentivirus, including viral quantification prior to injection, intraperitoneal injection, and quantification of integrated provirus, is introduced. PMID- 30244462 TI - Mesenchymal Stem Cell Engineering. AB - Mesenchymal stem cells (MSC) are multipotent stem cells that display the capacity to generate the tissue in which they reside. MSC have been used as progenitor cells to engineer cartilage implants that can be used to repair chondral and osteochondral lesions, or as trophic producers of bioactive factors to initiate endogenous regenerative activities in the arthritic joint. Targeted gene therapy might further enhance the capacity of MSC for chondrogenesis. By using a clustered regularly interspaced short palindromic repeats/CRISPR-associated protein genomic manipulation technique, target-gene-modified MSC would be a promising therapeutic option for regeneration of diseased joints in the treatment of RA. PMID- 30244463 TI - Screening of Ca2+ Influx in Lymphocytes. AB - The Ca2+ ion is an important second messenger in lymphocytes, similarly to its function in other mammalian cells. The generation of long-lasting intracellular Ca2+ elevations is essential for Ca2+-dependent gene transcription, proliferation, differentiation, and cytokine production in lymphocytes. Since store-operated Ca2+ entry (SOCE) is considered the predominant mode of Ca2+ influx in lymphocytes, the activation and function of lymphocytes can be generally predicted by monitoring SOCE. A method suitable for dynamic monitoring of Ca2+ influx using fura-2 labeling in lymphocytes is introduced in this chapter. Using this technique, large-scale screening of the activation status of primary or cultured lymphocytes can be realized. PMID- 30244464 TI - Single-Cell Ca2+ Imaging. AB - In rheumatological studies, visualization of Ca2+ dynamics in intact cells as direct experimental evidence of Ca2+-dependent signal pathways is generally used to monitor the function of immune cells at first glance. Ability to monitor Ca2+ signaling in living cells would greatly facilitate advances in the functional dissection of immune cells. In this chapter, we describe a basic technique and methods of data analysis for single-cell real-time Ca2+ monitoring using Fluo-4 labeling, which is a single-wavelength Ca2+ indicator. PMID- 30244465 TI - Electrophysiological Methods to Measure Ca2+ Current. AB - To achieve the most accurate assessment of functional Ca2+ channel or modulator properties and their regulation, a patch clamp technique to record membrane currents is required. This technique has wide applications ranging from recording the activity of native channels in their natural environment to that of recombinant channels expressed in heterologous cells. This chapter introduces the methods that have been used for the detection of calcium release-activated calcium (CRAC) currents, one of the store-operated calcium entry pathways, in human primary T cells. This standard protocol is for laboratories already equipped with a full patch clamp setup or for investigators collaborating with laboratories experienced in patch clamp. PMID- 30244466 TI - The Functional Assessment of T cells. AB - It is important to know what kind of T cell populations is involved in various disease states and to know the state of T cell functions involved in the disease. When T cell antigen receptors (TCR) recognize a specific antigen, the cell transmits a signal by a transduction mechanism within the T cell's cytoplasm. This signal initiates gene transcription essential for differentiation and activation of T cells. In this chapter, we will describe the methods of analyzing the transcribed mRNA and detecting the translated product in order to know the activation state of T cells. PMID- 30244467 TI - Release of Antibodies and Cytokines from B Cells. AB - Autoreactive B cells play a critical role in rheumatoid arthritis. These cells differentiate into long-living memory B cells and autoantibody-producing plasma cells and also present autoantigens to T cells to amplify misdirected immune responses. The therapeutic benefit of B-cell-deleting therapies suggests that B cells are emerging as important factors in the pathogenesis of RA. Aiming at evaluation of the function of B cells, which are usually derived from peripheral blood of RA patients and healthy donors, it is possible to conduct a series of experiments, such as in vitro assessment of antibody production and BCR-mediated cytokine release. These techniques can also be applied for in vivo application. PMID- 30244468 TI - Evaluation of Autoreactive Responses. AB - Loss of tolerance to self-antigens is considered to be one of the initial reasons for the onset of rheumatoid arthritis (RA). Identification of self-antigens and evaluation of autoreactive antibodies can foster understanding of the pathogenesis of the disease and the development of new therapeutics. By detection of responses to a particular self-antigen, such as alpha-enolase, keratin, fibrinogen, fibronectin, collagen, or vimentin, in patient- and animal model derived samples, high-affinity T-cell receptor-dependent activation of autoreactive T cells to self-antigens can be elucidated. This chapter introduces a simple method to estimate T-cell autoreactive responses to CII in a murine CIA model. A limiting dilution system is established in order to assess CII-dependent T-cell responses, which are reflected by the level of cytokine release. PMID- 30244469 TI - Bone Resorption Activity in Mature Osteoclasts. AB - Bone homeostasis depends on balanced bone deposition and bone resorption, which are mediated by osteoblasts and osteoclasts, respectively. As one therapeutic strategy, the blockage of osteoclast activity reduces subsequent bone erosion. Morphological analysis of bone resorption pits formed by osteoclasts by using scanning electron microscope is an effective method for understanding rheumatoid arthritis. Here we describe methods for observing surface microstructure of pits formed by osteoclasts on hard tissue sections. PMID- 30244470 TI - Animal Models of Vasculitis. AB - The diagnosis of vasculitis in rheumatoid arthritis (RV) is associated with considerable mortality; therefore, understanding the basic mechanisms underlying the pathogenesis of vasculitis is very important. Animal models of vasculitis have contributed to elucidating such mechanisms. We here introduce a Candida albicans water-soluble (CAWS) glycoprotein-induced vasculitis model and the methodological approach to evaluate inflammatory vascular change. PMID- 30244471 TI - Design an Intervention Study. AB - Randomized controlled trials are commonly designed to compare the effectiveness of treatments in rheumatoid arthritis (RA). In a clinical trial (intervention study), researchers apply interventions or preventive services to patients and examine outcomes. Clinical trial design consists of the following categories: choice of intervention, selection of patients, informed consent, baseline measurement, bank specimens, randomized allocation and blinding, and outcome measurements. Here, we discuss the design of clinical trials for RA. PMID- 30244472 TI - Assessment of Disease Activity, Structural Damage, and Function in Rheumatoid Arthritis. AB - The primary goal in the treatment of rheumatoid arthritis (RA) should be achieving control of disease activity, prevention of structural damage in joints, and normalization of function. Therefore, reliable tools are necessary to evaluate RA. Here, we describe methods recently used to assess RA. PMID- 30244473 TI - Source method biases as implicit personality theory at the domain and facet levels. AB - OBJECTIVE: We tested predictions about the structure and magnitude of method biases in single-source personality trait assessments. We expected a large number of distinct biases that would parallel the observed structure of traits, at both facet and item levels. METHOD: We analyzed multimethod ratings on the Estonian NEO Personality Inventory-3 in a sample of 3,214 adults. By subtracting informant ratings from self-reports, we eliminated true score variance and analyzed the size and structure of the residual method biases. We replicated analyses using data (N = 709) from the Czech Revised NEO Personality Inventory. RESULTS: The magnitude of method biases was consistent with predictions by McCrae (, Psychological Assessment). Factor analyses at the facet level showed a clear replication of the normative Five-Factor Model structure in both samples. Item factor analyses within domains showed that facet-level method biases mimicked the facet structure of the instrument. CONCLUSIONS: Method biases apparently reflect implicit personality theory (IPT)-beliefs about how traits and trait indicators covary. We discuss the (collective) accuracy and possible origins of IPT. Because method biases limit the accuracy of single-source assessments, we recommend assessments that combine information from two or more informants. PMID- 30244474 TI - Evaluation of Fetal Left Ventricular Size and Function Using Speckle-Tracking and the Simpson Rule. AB - OBJECTIVES: This study was conducted to evaluate left ventricular (LV) size and function in healthy fetuses and to test a cohort of fetuses at risk for abnormal function using speckle-tracking software. METHODS: Two hundred control fetuses were examined between 20 and 40 weeks' gestation. With the use of offline speckle tracking software, the end-diastolic and end-systolic volumes were measured and the following computed: stroke volume (SV), SV per kilogram, cardiac output (CO), CO per kilogram, and ejection fraction. These were regressed against 7 independent variables related to the size, weight, and age of the fetuses. Five fetuses with risk factors for LV dysfunction were examined to sample the validity of the data from the control group. RESULTS: The R2 values for measurements of the end-diastolic volume, SV, and CO correlated with the 7 independent variables of fetal size and age (0.7-0.78), whereas the SV/kg, CO/kg, and ejection fraction had lower R2 values (0.02-0.1). The measurements were normally distributed (Shapiro-Wilke > 0.5). The 5 fetuses at risk for abnormal LV function had measurements of LV size and function that were consistent with the expected pathologic condition. CONCLUSIONS: Speckle tracking can provide a comprehensive evaluation of the size and function of the fetal LV. PMID- 30244475 TI - Design, graph theoretical analysis, density functionality theories, Insilico modeling, synthesis, characterization and biological activities of novel thiazole fused quinazolinone derivatives. AB - Hit, Lead & Candidate Discovery A series of 2-(2-substituted benzylidenehydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolo din-3 yl]phenyl)quinazolin-4(3H)-one 7a-7l were synthesized and characterized by IR, 1 H-NMR, 13 C-NMR, mass spectroscopy and elemental analyses. In this present study, the density functionality theory was performed to identify drug stability. Further we introduced graph theoretical analysis by utilised Kyoto Encyclopedia of Genes and Genomes (KEGG) database and Cytoscape software to identify drug target. Based on the observed drug target insilico modeling was executed to know effective drug. The antiepileptic effects of title compounds were evaluated by using MES and subcutaneous pentylenetetrazole (scPTZ) test. Acute neurological toxicity of title compounds was studied by using standardized rotorod test. After 0.5 hr of period many of the compounds showed anticonvulsant activity at MES or scPTZ test. Comparison of the biological activity of test compounds with its chemical structures indicates that, compounds possessing electron donating group exhibited superior activity than the analogs having electron withdrawing moieties. Among the electron donating group tested, amino derivative exhibited good activity than rest of derivatives. From the study it was concluded that, the compound 7j was established as very potent compared with rest of the compounds and standard drugs subjected to biological studies. Thus the compound 2-(2-[4 aminobenzylidene]hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3 yl]phenyl) quinazolin-4(3H)-one (7j) came out as pilot derivative without any neurotoxicity with a wide spectrum of antiepileptic activity. HIGHLIGHTS: The performed work is having great significance in terms of Graph theoretical analysis used to identify drug target In silico modeling used to identify designed drug interaction with identify target Density functionality studies used to identify synthesized compound energy band gap which is correlate with enhancement of its biological activity Antiepileptic effects of entire synthesized quinazolinone scaffolds were evaluated by MES and scPTZ test 2-(2-[4 aminobenzylidene]hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3 yl]phenyl) quinazolin-4(3H)-one (7j) was established as very potent compared to the rest of the compounds and standard drugs which were subjected to biological studies. PMID- 30244476 TI - The Hadlock Method Is Superior to Newer Methods for the Prediction of the Birth Weight Percentile. AB - OBJECTIVES: To compare a traditional ultrasound (US) method for estimated fetal weight (EFW) calculation and fetal growth restriction diagnosis with 2 newer methods for the prediction of small for gestational age (SGA) at birth. METHODS: We reviewed deliveries at our institution from January 1, 2013, to March 31, 2017. Singleton, nonanomalous, well-dated fetuses with a US examination within 2 weeks of delivery were included. Estimated fetal weights and percentiles were calculated by a traditional method (Hadlock et al; Radiology 1991; 181:129-133) and 2 newer methods: Intergrowth-21st (INTG; Ultrasound Obstet Gynecol 2017; 49:478-486) and Salomon et al (Ultrasound Obstet Gynecol 2007; 29:550-555). We calculated each method's test characteristics to predict SGA (birth weight < 10th percentile) using both traditional (EFW < 10th percentile) and receiver operating characteristic (ROC)-derived fetal growth restriction cutoffs. Mean percentile discrepancies between EFW and birth weight measurements were calculated to compare method accuracy. We hypothesized that the INTG and Salomon methods would have superior SGA prediction compared with the Hadlock method. RESULTS: Of 831 pregnancies with a US examination within 2 weeks of delivery, 138 (16.7%) were SGA at birth. Hadlock had the smallest US-birth weight percentile discrepancy (P < .001 versus both INTG and Salomon). When comparing ROC curves, the Hadlock and INTG methods performed comparably, with areas under the curve of 0.91 and 0.90 (P = .08) and optimal EFW cutoffs of the 15th and 22nd percentiles, respectively. The Salomon method performed less well, with an area under the curve of 0.82 (P < .001 versus both Hadlock and INTG methods). CONCLUSIONS: In our study cohort, the Hadlock method predicted the birth weight percentile more accurately than the INTG or Salomon methods and performed comparably with INTG to predict SGA when ROC-derived cutoffs were used. PMID- 30244477 TI - Prediction of Clinical Prognosis according to Intermetatarsal Distance and Neuroma Size on Ultrasonography in Morton Neuroma: A Prospective Observational Study. AB - OBJECTIVES: This study aims to evaluate the clinical importance of intermetatarsal distance, size of neuroma, and proportion of neuroma in the intermetatarsal space in examinations of Morton neuroma using ultrasonography. METHODS: Clinical prognosis was observed prospectively after corticosteroid injections in 136 patients with Morton neuroma, and the results were compared with ultrasonographic parameters of intermetatarsal distance, size of neuroma, and proportion of neuroma in the intermetatarsal space. RESULTS: Twenty-one patients (15%) did not respond to corticosteroid injections and underwent surgical treatment for Morton neuroma. Logistic regression analysis and receiver operating characteristic curve analysis showed that the size of the neuroma was the sole predictor of failure of corticosteroid injections (P = .002). No other factors were significant for the prediction of clinical prognosis (P > .05). CONCLUSIONS: The size of the neuroma on ultrasonography is the sole predictor of corticosteroid injection failure, while intermetatarsal distance and proportion of neuroma in the intermetatarsal space are not significant when predicting clinical prognosis of Morton neuroma. PMID- 30244478 TI - The polyploid state restricts hepatocyte proliferation and liver regeneration. AB - : The liver contains a mixture of hepatocytes with diploid or polyploid (tetraploid, octaploid, etc.) nuclear content. Polyploid hepatocytes are commonly found in adult mammals, representing ~90% of the entire hepatic pool in rodents. The cellular and molecular mechanisms that regulate polyploidization have been well-characterized; however, it is unclear if diploid and polyploid hepatocytes function similarly in multiple contexts. Answering this question has been challenging because proliferating hepatocytes can increase or decrease ploidy, and animal models with healthy diploid-only livers have not been available. Mice lacking E2f7 and E2f8 in the liver (LKO) were recently reported to have a polyploidization defect but were otherwise healthy. Herein, livers from LKO mice were rigorously characterized, demonstrating a 20-fold increase in diploid hepatocytes and maintenance of the diploid state even after extensive proliferation. Livers from LKO mice maintained normal function but became highly tumorigenic when challenged with tumor-promoting stimuli, suggesting that tumors in LKO mice were driven, at least in part, by diploid hepatocytes capable of rapid proliferation. Indeed, hepatocytes from LKO mice proliferate faster and out compete control hepatocytes, especially in competitive repopulation studies. In addition, diploid or polyploid hepatocytes from wild-type mice were examined to eliminate potentially confounding effects associated with E2f7/E2f8 deficiency. The wild-type diploid cells also showed a proliferative advantage, entering and progressing through the cell cycle faster than polyploid cells, both in vitro and during liver regeneration. Diploid and polyploid hepatocytes responded similarly to hepatic mitogens, indicating that proliferation kinetics are unrelated to differential response to growth stimuli. CONCLUSION: Diploid hepatocytes proliferate faster than polyploids, suggesting that the polyploid state functions as a growth suppressor to restrict proliferation by the majority of hepatocytes. This article is protected by copyright. All rights reserved. PMID- 30244479 TI - Methotrexate Administration to Patients With Presumed Ectopic Pregnancy Leads to Methotrexate Exposure of Intrauterine Pregnancies. AB - OBJECTIVE: To report clinical experience with methotrexate (MTX) treatment for suspected but not definite ectopic pregnancy (EP). METHODS: This was a retrospective cohort study. All patients treated with MTX for presumed EP between 2000 and 2016 were included. Demographic, clinical, sonographic, and outcome data were collected and analyzed. RESULTS: A total of 820 patients were treated with MTX, 692 (84.4%) of which were lacking definitive features of EP; 155 (22.4%) failed to follow up until complete resolution and were excluded. Retrospective sonographic categorization was applied to 537 patients; of those patients, 393 (73.2%) were categorized as probable EPs, 136 (25.3%) pregnancies of unknown location (PULs), and 8 (1.5%) probable intrauterine pregnancies (IUPs). Sixteen were eventually diagnosed with IUP: 6 from the probable EPs, 9 from the PULs, and 1 from the probable IUP group. Patients with final diagnosis of IUP had higher values of beta-human chorionic gonadotropin as well as lower prevalence of adnexal mass (38% versus 74%; P = .003), higher prevalence of intracavitary fluid (44% versus 9%; P = .0004) and thicker endometrium (17.1 +/- 11.8 versus 9.7 +/- 5.6; P = .04). None of the sonographic parameters were able to distinguish patients with IUP. One patient of the 16 with IUP was diagnosed with a viable pregnancy, and 7 additional patients had a possible viable pregnancy. None of them elected to continue the pregnancy. CONCLUSIONS: Most patients with suspected EP who are eligible for medical treatment lack definitive sonographic features of EP. Treatment with MTX in such cases should be delayed, as clinically reasonable, to improve the diagnosis and prevent inadvertent administration of MTX to patients with a viable IUP. PMID- 30244480 TI - Systematic review of rituximab for autoimmune diseases: a potential alternative to intravenous immune globulin. AB - BACKGROUND: The anti-CD20 monoclonal antibody rituximab has immune-modulatory effects similar to intravenous immunoglobulin (IVIG). We performed a systematic review and meta-analysis to determine the efficacy and safety of rituximab in autoimmune diseases that are also treated with IVIG. STUDY DESIGN AND METHODS: The most common indications for immune modulation with IVIG, as identified from a 2012 regional audit in Canada, were chronic inflammatory demyelinating polyneuropathy (CIDP), immune thrombocytopenia (ITP), myasthenia gravis, multifocal motor neuropathy, Guillain-Barre syndrome, systemic lupus erythematosus (SLE), Sjogren's syndrome, and pemphigus vulgaris. We searched MEDLINE, EMBASE, and the Cochrane Library until July 2016 for studies evaluating rituximab in each of these conditions. The primary outcome in our meta-analysis was clinical response at 6 months as defined by disease-specific criteria in randomized trials. We also calculated pooled proportions of responders within disease types from observational studies. RESULTS: Ninety-five rituximab studies were identified: 86 were observational studies in patients with ITP (n = 1746), SLE (n = 1047), pemphigus vulgaris (n = 564), Sjogren's syndrome (n = 138), myasthenia gravis (n = 66), and CIDP (n = 31) and nine were randomized controlled trials (n = 992) in patients with ITP, SLE, and Sjogren's syndrome that compared rituximab with placebo plus standard of care. Among randomized trials, response rates were higher with rituximab (relative risk, 1.38; 95% confidence interval [CI], 1.05-1.83). The pooled proportion of rituximab responses ranged from 94% (95% CI, 88%-98%) for pemphigus vulgaris to 48% (95% CI, 30%-66%) for CIDP. Rituximab was generally well tolerated in observational studies although in the randomized trials, adverse events were more common in the rituximab group. CONCLUSION: Rituximab is an immune-modulating agent with biologic activity across many autoimmune conditions. Our data support the use of comparative trials with broad eligibility criteria to evaluate rituximab as an alternative to IVIG in autoimmune diseases. PMID- 30244481 TI - Local recurrence and quality of life after adjuvant radiation therapy in high risk squamous cell carcinoma. PMID- 30244482 TI - Intravascular Ultrasound for Evaluation of Left Gonadal Vein Anatomic Variations During Coil Embolization. AB - We illustrate the intravascular ultrasound (US) findings in the evaluation of left gonadal vein anatomic variations. During a 2-year period, 4 consecutive patients (mean age, 37 years; range, 28-45 years) with left-sided varicocele underwent embolization. Intravascular US examinations and retrograde venography were performed to assess varicocele anatomy. Anatomic variants were recorded and categorized. A comparison between intravascular US and fluoroscopic findings was performed. The Fisher exact test was used for statistical analysis (P < .05). Technical success was achieved in all cases. There was a statistically significant difference in the maximum gonadal vein diameter between venography and intravascular US (P = .0087). Intravascular US showed left gonadal vein anatomic variations and better ability in the evaluation of the vein diameter. PMID- 30244483 TI - Limited Added Value of Magnetic Resonance Imaging After Dynamic Transvaginal Ultrasound for Preoperative Staging of Endometriosis in Daily Practice: A Prospective Cohort Study. AB - OBJECTIVES: To assess the added value of magnetic resonance imaging (MRI) after dynamic transvaginal ultrasound (TVUS) in the diagnostic pathway for preoperative staging of pelvic endometriosis. METHODS: A prospective observational study was conducted between April 22, 2014, and May 1, 2015. During that period, 363 patients with a clinical suspicion of endometriosis were included. All patients underwent a history, clinical examination, and dynamic TVUS examination. Most of the patients (n = 274) underwent conservative treatment according to the European Society of Human Reproduction and Embryology guidelines. Eighty-nine patients were selected for surgery, of whom 72 patients underwent the complete diagnostic pathway: ie, history, clinical examination, dynamic TVUS, and MRI. All data were analyzed by the nonparametric McNemar test for comparing each step in the diagnostic algorithm. RESULTS: The sensitivity and specificity for the history, pelvic examination, and dynamic TVUS were 93.7% and 55.6% (P < .001), respectively; when MRI findings were included, the sensitivity and specificity were 85.9% and 62.5%. Adding MRI routinely to the diagnostic procedure of endometriosis did not significantly improve the sensitivity or specificity. CONCLUSIONS: There is no significant added value of routine MRI after dynamic TVUS for the preoperative staging of endometriosis. PMID- 30244484 TI - Secondary Imaging Findings Aid in Prenatal Diagnosis and Characterization of Congenital Diaphragmatic Hernia: Role of an Abnormal Orientation of Vascular Structures and Gallbladder Position. AB - OBJECTIVES: To determine whether an abnormal orientation of the abdominal or hepatic vasculature and an abnormal gallbladder position on prenatal ultrasound (US) imaging are associated with intrathoracic liver herniation and postnatal outcomes in cases of congenital diaphragmatic hernia (CDH). METHODS: Children who underwent prenatal US examinations and postnatal CDH repair at our institution were eligible. Prenatal US images were reviewed, and the orientation of the superior mesenteric artery (SMA) and hepatic veins as well as gallbladder position were recorded. Findings were correlated with prenatal US measurements (lung-to-head ratio and calculated observed-to-expected lung-to-head ratio) and postnatal outcomes, including intrathoracic liver herniation, an extracorporeal membrane oxygenation (ECMO) requirement, and mortality. RESULTS: A total of 175 patients met inclusion criteria. The SMA was shown in 168 cases and had a cephalad orientation in 95.4% (161 of 168), which was not associated with outcome measures and represented bowel herniation. A cephalad orientation of the hepatic veins was identified in 52.6% (90 of 171) and was associated with intrathoracic liver herniation, an ECMO requirement, and mortality (P < .01). In right-sided CDH, the gallbladder was intrathoracic in 91.3% (21 of 23). In left-sided CDH, an abnormal gallbladder position was seen in 51.3% (76/152) and was associated with intrathoracic liver herniation, an ECMO requirement, mortality, and lower lung-to head ratio and observed-to-expected lung-to-head ratio values. When combined, abnormal hepatic vein and gallbladder positions showed good sensitivity and specificity in predicting intrathoracic liver herniation (area under the curve, 0.93). CONCLUSIONS: Abnormal SMA, hepatic vein, and gallbladder positions can be used to improve prenatal characterization of CDH. Accurate depiction of these structures on prenatal US images may aid in patient counseling and postnatal management. PMID- 30244485 TI - Rapid Assessment of the Neonate With Sonography (RANS) Scan. AB - The use of point-of-care sonography in clinical settings such as emergency medicine and intensive care units has increased, but adoption in neonatology has been slow. Unlike the focused assessment with sonography for trauma scan used in adults, a quick bedside scan to rapidly evaluate an acutely deteriorating neonate does not exist. The objective of our article is to introduce a focused bedside ultrasound scan that is easy to learn, rapidly performed, and relatively inexpensive.(c) 2018 by the American Institute of Ultrasound in Medicine. PMID- 30244486 TI - Legends of Allergology/Immunology: Gunnar Johansson. PMID- 30244487 TI - Subacute cutaneous lupus erythematosus and dermatomyositis associated with anti programmed cell death (PD)-1 therapy. AB - Programmed cell death 1 (PD-1) blockade has rapidly emerged as an effective therapy for a wide variety of metastatic malignancies. It has been associated with multiple immune related adverse effects, including cutaneous eruptions. We describe two patients who developed clinical and histologic findings consistent with subacute cutaneous lupus erythematosus (SCLE) after receiving PD-1 inhibitor therapy for metastatic lung cancer. We successfully treated our first one patient with systemic and topical steroids, photoprotection, and hydroxychloroquine. However, he subsequently developed dermatomyositis after continuing PD-1 inhibitor therapy. Our second patient presented with a protracted course of her cutaneous eruption in spite of discontinuation of anti-PD-1 therapy and treatment with systemic corticosteroids and infliximab. Her SCLE resolved after the addition of topical steroids and photoprotection and discontinuation of anti-TNF therapy. She and her oncology team decided to pursue non-PD-1 inhibitor treatment for her lung cancer due to lack of response of her tumour. We add to SCLE and dermatomyositis to the growing list of autoimmune complications of PD-1 blockade. Our cases raise a number of questions including the viability of continuing anti PD-1 therapy after developing SCLE, as well as the role of immunosuppressive therapy in patients with PD-1 inhibitor associated connective tissue disease. This article is protected by copyright. All rights reserved. PMID- 30244488 TI - Fetal Tachycardia Is an Independent Risk Factor for Chromosomal Anomalies in First-Trimester Genetic Screening. AB - OBJECTIVES: The association of an abnormal fetal heart rate (FHR) and chromosomal anomalies in the first trimester of pregnancy remains unclear, probably because of the lack of control for known confounding factors. This study was designed to determine whether an increased FHR is an independent risk factor for chromosomal anomalies between 11 and 14 weeks' gestation. METHODS: This cohort study included women who underwent first-trimester genetic screening between 2011 and 2014 at a single institution. A multivariable logistic regression analysis was performed to determine whether an FHR of 170 beats per minute (bpm) or higher, derived from a receiver operating characteristic curve, is an independent risk factor for all chromosomal anomalies while controlling for known confounding factors. P < .05 was considered significant. RESULTS: An FHR of 170 bpm or higher was observed in 7% (228 of 3254), and chromosomal anomalies were present in 1.0% (31 of 3254) of the population. A higher proportion of fetuses with an FHR of 170 bpm or higher had chromosomal anomalies compared to those with an FHR lower than 170 bpm. An FHR of 170 bpm or higher was an independent risk factor for chromosomal anomalies after controlling for known confounding factors. Of note, in the group of fetuses with a nuchal translucency above the 95th percentile, the frequency of chromosomal anomalies was significantly higher among fetuses with an FHR of 170 bpm or higher compared to those with an FHR lower than 170 bpm. CONCLUSIONS: Fetal tachycardia is a risk factor for chromosomal anomalies during first trimester genetic screening, independent of increased nuchal translucency, nuchal septations, and maternal age. PMID- 30244489 TI - Effect of Ultrasound-Guided Intercostal Nerve Block Versus Fluoroscopy-Guided Epidural Nerve Block in Patients With Thoracic Herpes Zoster: A Comparative Study. AB - OBJECTIVES: To compare the efficacy of a conventional fluoroscopy-guided epidural nerve block and an ultrasound (US)-guided intercostal nerve block in patients with thoracic herpes zoster (HZ). METHODS: This work was a comparative study of 38 patients with thoracic HZ pain and a chest wall herpetic eruption, aged 18 years or older, with pain intensity of 5 or greater on a numeric rating scale (NRS) for less than a 1-month duration. Patients were consecutively enrolled and assigned to 2 groups in which the intervention was either the US-guided intercostal nerve block or the fluoroscopy-guided epidural nerve block approach with the addition of a 5-mL mix of 2.5 mg of dexamethasone plus 0.5% lidocaine. The primary outcome measure was the NRS score reduction for the pain. Secondary outcomes included the duration of treatment, number of repeated injections until the final visit, and proportion of patients with pain relief after the first and final visits. RESULTS: All patients within both intervention groups showed significant pain relief on the NRS at the final follow-up point (P < .05). There was no significant difference in the mean value of NRS improvement based on the intervention type. There was also no statistically significant difference in the duration of treatment and the frequency of injection for pain relief. CONCLUSIONS: These findings showed that both the US-guided intercostal nerve block and the fluoroscopy-guided epidural nerve block were effective in patients with thoracic HZ. Compared data showed no significant differences in the pain reduction, duration of treatment, and frequency of injection. The US-guided intercostal nerve block, which is more accessible than the fluoroscopy-guided epidural nerve block, might be an alternative option for thoracic HZ. PMID- 30244490 TI - Ultrasound Features of the Normal and Pathologic Periosteum. AB - Thickening and elevation of the periosteum from the underlying bone cortex, defined as a periosteal reaction, can be associated with several bone disorders. Although ultrasound (US) has limited possibilities in assessing bones, it can depict a periosteal reaction earlier than plain radiography, thus indicating underlying bone disorders. This pictorial essay aims to illustrate the normal and pathologic US appearances of the periosteum in both children and adults. Several disorders are discussed, such as pediatric bone trauma, infections and tumors, as well as trauma, overuse, including medial tibial stress syndrome, and finally certain seronegative spondyloarthropathies in adults. Whenever US depicts a periosteal reaction, a correlation with clinical and laboratory data is mandatory to differentiate different bone disorders. Computed tomography or magnetic resonance imaging must be performed when an infection or a tumor is suspected based on both US and the clinical presentation. PMID- 30244491 TI - Reproducibility of Liver-to-Thorax Area Ratio Ultrasound Measurements in Congenital Diaphragmatic Hernia. AB - OBJECTIVES: The aim of this study was to investigate the reproducibility of a standardized method to assess the ultrasound liver-to-thoracic area ratio in fetuses with congenital diaphragmatic hernia. METHODS: We selected 24 images of 9 fetuses diagnosed with left-sided at our institution between January 2010 and December 2017. Eight operators (1 maternal-fetal medicine specialist and 7 sonographers) reviewed the selected images and assessed the ultrasound liver-to thoracic area ratio according to a standardized protocol. We evaluated the correlation between operators using the intraclass correlation coefficient and compared agreement between the sonographers and a physician with experience in measuring the ultrasound liver-to-thoracic area ratio using a Bland-Altman analysis. RESULTS: Good intraoperator reproducibility was observed for the standardized ultrasound liver-to-thoracic area ratio (intraclass correlation coefficient, 0.78). Good agreement among sonographers and the physician was also observed for the standardized measurements (bias, 0.01; precision, 0.03; limits of agreement, -0.05 to + 0.07). CONCLUSIONS: We demonstrated that good intraoperator and interoperator reproducibility of ultrasound liver-to-thoracic area ratio assessment is feasible after standardizing the method in our center. PMID- 30244492 TI - Limited Ultrasound Protocol for Upper Extremity Peripherally Inserted Central Catheter Monitoring: A Pilot Study in the Neonatal Intensive Care Unit. AB - OBJECTIVES: To assess whether a limited ultrasound (US) scanning protocol to monitor the upper extremity peripherally inserted central catheter (PICC) location in neonates is feasible for experienced US operators. METHODS: A radiologist, who was blinded to the PICC location on chest radiography, performed 14 US scans on 11 neonates with upper extremity PICCs. A US machine with 13-6-MHz linear and 8-4-MHz phased array transducers was used for the examinations. RESULTS: The study population included 54% (n = 6) preterm infants, with 72% (n = 8) weighing less than 1500 g. The US location of the PICC was the same as the chest radiographic report in all 14 scans. A subclavicular long-axis view of the anterior chest visualized all PICCs in the subclavian or brachiocephalic veins. A parasternal long-axis right ventricular inflow view was able to visualize PICCs in the superior vena cava (SVC), and a subcostal long-axis view evaluated PICCs in the lower SVC and heart. The scanning time was location dependent: less than 5 minutes for PICCs in the brachiocephalic or subclavian vein and 5 to 10 minutes for PICCs in the SVC or heart. There were no desaturations below 90%, increases in the fraction of inspired oxygen need, or hypotension episodes during scanning. CONCLUSIONS: A limited US scanning protocol to determine the upper extremity PICC location is feasible. Our protocol needs to be tested in neonatal providers before further dissemination. PMID- 30244493 TI - Antinociceptive, anti-inflammatory, and central nervous system (CNS) effects of the natural coumarin soulattrolide. AB - Soulattrolide is a natural coumarin synthesized by the leaves of species of Calophyllum (Calophyllaceae) rain forest trees, including the American C. brasiliense, and the Asian C. teysmanii. Soulattrolide is a potent inhibitor of the reverse transcriptase from HIV-1 (RT-HIV-1), and active against Mycobacterium tuberculosis. However, the effects of this coumarins on other systems, remains to be evaluated. C. brasiliense is used in traditional medicine for the treatment of pain and inflammation. Therefore, we decided to explore the antinociceptive, anti inflammatory activity of soulattrolide in mice, as well as, some of its possible effects on the CNS. Soulattrolide showed antinociceptive effects in the writhing test (ED50 = 33.8 mg/kg), as well as, in the formalin test with an ED50 = 7.9, and 22.1 mg/kg for Phases 1 and 2, respectively. The highest dose of soulattrolide (50 mg/kg) induced 40% of antinociception in the hot plate test. Regarding to anti-inflammatory activity, in the 12-O-Tetradecanoylphorbol-13 acetate (TPA) test, soulattrolide showed an IC50 = 1.81 MUmol/ear, whereas in the myeloperoxidase assay, it showed an inhibition of 87% (1 MUmol/ear). Soulattrolide showed sedative effects on the pentobarbital-induced sleeping time test, and the rotarod test, but lacked antidepressant activity on the tail suspension test. In conclusion, we report for the first time, the antinociceptive effects of soulattrolide in mice, like those of naproxen; soulattrolide also showed mild anti-inflammatory activity, as well as mild sedative and anxiolytic properties, therefore, it has also activity on the CNS. PMID- 30244494 TI - Dynamic Changes of the Aspartate Aminotransferase-to-Platelet Ratio and Transient Elastography in Predicting a Histologic Response in Patients With Chronic Hepatitis B After Entecavir Treatment. AB - OBJECTIVES: To evaluate the dynamic changes of the aspartate aminotransferase (AST)-to-platelet ratio and transient elastography (FibroScan; Echosens, Paris, France) in predicting a histologic response in patients with chronic hepatitis B (CHB) after entecavir treatment. METHODS: A total of 148 patients with CHB were enrolled. Patient information was collected. All patients received liver biopsy and FibroScan before and after 96 weeks of entecavir treatment. RESULTS: Baseline liver biopsy results showed that there were 7 patients without liver fibrosis (fibrosis stage F0; 4.7%), 51 patients with mild liver fibrosis (F1; 34.5%), and 90 patients with advanced liver fibrosis (>F1; 60.9%). The liver stiffness value and AST-to-platelet ratio increased significantly as the METAVIR score of the patients increased from F0 to F4 (P < .001). After antiviral therapy for 96 weeks, the average liver stiffness value measured by FibroScan and the AST-to platelet ratio showed a significant decrease. When we use a decreased liver stiffness value to predict a histologic response, the area under the receiver operating characteristic curve was 0.70 (95% confidence interval, 0.61-0.79; P < .001), and the sensitivity and specificity were 74.3% and 68.8%, respectively. The decrease of the AST-to-platelet ratio also could predict the histologic response of patients with CHB; the area under the receiver operating characteristic curve was 0.77 (95% confidence interval, 0.69-0.86; P < .001) with sensitivity of 76.2% and specificity of 70.2%. A multivariate analysis indicated that a high hepatitis B virus DNA viral load (odds ratio, 1.44; P = .04) and high METAVIR score (odds ratio, 1.38; P = .02) were independent risk factors for the histologic response. CONCLUSIONS: Both the AST-to-platelet ratio and FibroScan value can effectively predict a histologic response in patients with CHB during entecavir treatment. Therefore, they can be used to monitor these patients during antiviral treatment to avoid multiple liver biopsies. PMID- 30244495 TI - Legends of Allergology: Alfred William (Bill) Frankland. PMID- 30244496 TI - Involvement of SRF coactivator MKL2 in BDNF-mediated activation of the synaptic activity-responsive element in the Arc gene. AB - The expression of immediate early genes (IEGs) is thought to be an essential molecular basis of neuronal plasticity for higher brain function. Many IEGs contain serum response element in their transcriptional regulatory regions and their expression is controlled by serum response factor (SRF). SRF is known to play a role in concert with transcriptional cofactors. However, little is known about how SRF cofactors regulate IEG expression during the process of neuronal plasticity. We hypothesized that one of the SRF-regulated neuronal IEGs, activity regulated cytoskeleton-associated protein (Arc; also termed Arg3.1), is regulated by an SRF coactivator, megakaryoblastic leukemia (MKL). To test this hypothesis, we initially investigated which binding site of the transcription factor or SRF cofactor contributes to brain-derived neurotrophic factor (BDNF)-induced Arc gene transcription in cultured cortical neurons using transfection and reporter assays. We found that BDNF caused robust induction of Arc gene transcription through a cAMP response element, binding site of myocyte enhancer factor 2, and binding site of SRF in an Arc enhancer, the synaptic activity-responsive element (SARE). Regardless of the requirement for the SRF-binding site, the binding site of a ternary complex factor, another SRF cofactor, did not affect BDNF-mediated Arc gene transcription. In contrast, chromatin immunoprecipitation revealed occupation of MKL at the SARE. Furthermore, knockdown of MKL2, but not MKL1, significantly decreased BDNF-mediated activation of the SARE. Taken together, these findings suggest a novel mechanism by which MKL2 controls the Arc SARE in response to BDNF stimulation. PMID- 30244497 TI - Update on pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity. AB - Anthracycline chemotherapy has a prominent role in treating many forms of cancer. Unfortunately, cardiotoxic side effects represent a serious limitation to their use, with doxorubicin being the leading drug of the group. Indeed, anthracycline induced cardiomyopathy is an important public health concern because it may not be detected for many years and remains a lifelong threat. Even after decades of investigation, neither the exact mode of action of anthracyclines nor the pathways leading to their side effect are fully understood. It is increasingly important to establish collaboration between oncologists and cardiologists to improve the management of cancer patient receiving anthracyclines. This article reviews the clinical course, pathogenesis, cardiac monitoring and new concepts in diagnosing and preventing anthracycline-induced cardiotoxicity. PMID- 30244498 TI - Direct and transdentinal biostimulatory effects of grape seed extract rich in proanthocyanidin on pulp cells. AB - AIM: To evaluate the potential biostimulatory effects of grape seed extract (GSE) on a primary culture of human pulp cells. METHODOLOGY: Human molars were used to obtain the primary pulp cell culture and 0.5-mm dentine discs. For GSE direct exposure, dose-response (0.0065-6.5%) and time response (1-60 min of contact) were examined. For transdentinal exposure, 0.65% of GSE was tested for 24 h. Cellular metabolism, nitric oxide and collagen production, and cell morphology alterations were assessed at periods of 24 and 72 h. After cell differentiation and direct exposure to GSE, the total protein production (TP), alkaline phosphatase activity (ALP) and formation of mineralization nodules (MN) were assessed. The results were analysed by parametric tests or non-parametric tests (alpha = 0.05). RESULTS: The lower concentration of GSE tested (0.0065%) was associated with an increase in cellular metabolism, a reduction in the production of nitric oxide and an increase in extracellular matrix synthesis (collagen). Distinct behaviours were observed for the different concentrations, without a reduction of cellular metabolism >10% compared with the control, either when applied directly or transdentinally. SEM revealed no significant change in cell morphology, except for the positive control (H2 O2 ). There was no difference in TP, ALP or MN between the control group and the group exposed to GSE. CONCLUSIONS: Treatment with grape seed extract, even at the highest concentration and longest period, caused neither direct nor transdentinal cytotoxic effects on human pulp cells. Grape seed extract components may play a biostimulatory role and protect dental pulp cells when in direct contact. PMID- 30244499 TI - What's the problem with patient experience feedback? A macro and micro understanding, based on findings from a three-site UK qualitative study. AB - CONTEXT: Collecting feedback from patients about their experiences of health care is an important activity. However, improvement based on this feedback rarely materializes. In this study, we focus on answering the question-"what is impeding the use of patient experience feedback?" METHODS: We conducted a qualitative study in 2016 across three NHS hospital Trusts in the North of England. Focus groups were undertaken with ward-based staff, and hospital managers were interviewed in-depth (50 participants). We conducted a conceptual-level analysis. FINDINGS: On a macro level, we found that the intense focus on the collection of patient experience feedback has developed into its own self-perpetuating industry with a significant allocation of resource, effort and time being expended on this task. This is often at the expense of pan-organizational learning or improvements being made. On a micro level, ward staff struggled to interact with feedback due to its complexity with questions raised about the value, validity and timeliness of data sources. CONCLUSIONS: Macro and micro prohibiting factors come together in a perfect storm which provides a substantial impediment to improvements being made. Recommendations for policy change are put forward alongside recognition that high-level organizational culture/systems are currently too sluggish to allow fruitful learning and action to occur from the feedback that patients give. PMID- 30244500 TI - Are thyroid nodules with spongiform morphology always benign? AB - OBJECTIVE: Fine needle aspiration (FNA) biopsy for evaluation of spongiform nodules >=20 mm or observation without FNA was recommended by American Thyroid Association. However, this was a weak recommendation supported by moderate quality evidence. We aimed to assess malignancy risk in spongiform nodules. METHODS: From January 2015 to June 2016, an experienced endocrinologist performed B-mode greyscale ultrasonography and observed 96 spongiform nodules among 3748 ultrasound procedures. Power Doppler ultrasonography and ultrasound-guided FNA were performed to 96 spongiform nodules. Both colour elastography and strain ratio measurements of dominantly solid areas were performed. RESULTS: All spongiform nodules had benign cytology. Fifty-two (54.2%) nodules were >=20 mm and 44 (45.8%) were smaller than 20 mm in maximum diameter. Presence of ultrasonography features related to malignancy was rare; 2% (n = 2) microcalcification, 9.4% (n = 9) taller than wide shape and 2% (n = 2) marked central blood flow were noted. None of the nodules had two or more suspicious features. Ultrasound elastography findings revealed that dominantly solid components of nodules were usually soft as 66.7% had an elasticity score 1 according to colour scale and mean strain ratio was 1.39 +/- 0.99. CONCLUSIONS: Follow-up with ultrasonography seems to be an efficacious method even for spongiform nodules larger than 2 cm. Determination of soft appearance according to colour map on ultrasound elastography and low strain ratio values of dominantly solid areas may be useful to avoid unnecessary biopsies. PMID- 30244501 TI - Key characteristics of foods with an elevated risk for viral enteropathogen contamination. AB - Viral enteropathogens are one of the leading causative agents of foodborne illnesses in both the United States and the European Union. While human noroviruses and hepatitis A virus cause the vast majority of outbreaks and illnesses, there are handful of human enteric viruses that contribute to sporadic outbreaks worldwide including astrovirus, sapovirus, rotavirus, enterovirus and Aichi virus. In addition, hepatitis E virus is increasingly being recognized as an emerging zoonotic threat within the food supply. This review aims to briefly describe the primary human enteric viruses of concern with respect to foodborne transmission. Next, we focus on the contamination and persistence of these viruses within three high-risk food commodities-leafy greens, soft red fruits and bivalve mollusks. As opposed to detailing the specific routes by which these foods can be contaminated with enteric viruses, we have chosen to focus on their persistence and specific interactions within the food itself. Therefore, the processes of attachment and internalization of the viruses in foods have been emphasized. Looking forward, the implications of these specific interactions of human enteric viruses with leafy greens, soft red fruits and bivalve mollusks are briefly considered within the context of future prevention and control strategies. PMID- 30244502 TI - Fracture in drug-eluting stents increases focal intimal hyperplasia in the atherosclerosed rabbit iliac artery. AB - OBJECTIVES: Drug-eluting stent (DES) strut fracture (SF) is associated with higher incidence of In-stent restenosis (ISR)-return of blockage in a diseased artery post stenting-than seen with bare metal stents (BMS). We hypothesize that concomitance of drug and SF leads to greater neointimal response. BACKGROUND: Controlled release of therapeutic agents, such as sirolimus and its analogs, or paclitaxel from has reduced tissue based DES failure modes compared to BMS. ISR is dramatically reduced and yet the implications of mechanical device failure is magnified. METHODS: Bilateral Xience Everolimus-eluting stents (EES) were implanted in 20 New Zealand White rabbits on normal (n = 7) or high fat (HF)/high cholesterol (HC) (n = 13) diets. Implanted stents were intact or mechanically fractured. Everolimus concentration was as packaged or pre-eluted. After 21 days, stented vessels were explanted, resin embedded, MicroCT scanned, and analyzed histomorphometrically. RESULTS: Fractured EES were associated with significant (P < 0.05) increases in arterial stenosis and neointimal formation and lower lumen to-artery area ratios compared to intact EES. Hyperlipidemic animals receiving pre-eluted EES revealed no significant difference between intact and fracture groups. CONCLUSIONS: SF increases intimal hyperplasia, post EES implant, and worse with more advanced disease. Pre-eluted groups, reflective of BMS, did not show significant differences, suggesting a synergistic effect of everolimus and mechanical injury, potentially explaining the lack of SF reports for BMS. Here, we report that ISR has a higher incidence with SF in EES, the clinical implication is that patients with SF after DES implantation merit careful follow up. PMID- 30244503 TI - Pathogens, faecal indicators and human-specific microbial source-tracking markers in sewage. AB - The objective of this review is to assess the current state of knowledge of pathogens, general faecal indicators and human-specific microbial source tracking markers in sewage. Most of the microbes present in sewage are from the microbiota of the human gut, including pathogens. Bacteria and viruses are the most abundant groups of microbes in the human gut microbiota. Most reports of this topic show that raw sewage microbiological profiles reflect the human gut microbiota. Human and animal faeces share many commensal microbes as well as pathogens. Faecal orally transmitted pathogens constitute a serious public health problem that can be minimized through sanitation. Assessing both the sanitation processes and the contribution of sewage to the faecal contamination of water bodies requires knowledge of the content of pathogens in sewage, microbes indicating general faecal contamination and microbes that are only present in human faecal remains, which are known as the human-specific microbial source-tracking (MST) markers. Detection of pathogens would be the ideal option for managing sanitation and determining the microbiological quality of waters contaminated by sewage; but at present, this is neither practical nor feasible in routine testing. Traditionally, faecal indicator bacteria have been used as surrogate indicators of general faecal residues. However, in many water management circumstances, it becomes necessary to detect both the origin of faecal contamination, for which, MST is paramount; and live microorganisms, for which, molecular methods are not suitable. The presence and concentrations of pathogens, general faecal indicators and human-specific MST markers most frequently reported in different areas of the world are summarized in this review. This article is protected by copyright. All rights reserved. PMID- 30244504 TI - Twelve-month outcomes of patients unsuitable for prolonged DAPT presenting with an acute coronary syndrome and treated with polymer-free biolimus A9 drug-coated stents. AB - INTRODUCTION: Prolonged dual anti-platelet therapy (DAPT) is undesirable in certain patients. The biolimus-A9 drug-coated stent (BA9-DCS) has a rapid drug elution profile allowing shortened DAPT. METHODS: The demographics, procedural data, and clinical outcomes for 505 patients presenting with an ACS to three UK centres and treated with a BA9-DCS stent (PCI-DCS) were collected, and compared to a consecutive ACS cohort of unselected patients treated in the same period with drug-eluting stents (PCI-DES). RESULTS: PCI-DCS patients were older, more often female with hypertension, chronic kidney disease, severe LV dysfunction, and peripheral vascular disease more frequent than the PCI-DES cohort. PCI-DCS patients had a much higher Mehran bleed risk score (21.5 +/- 7.7 vs. 15.9 +/- 7.7, P < 0.0001). Baseline disease burden was greater in the PCI-DCS cohort with more left main and three vessel disease. During PCI, more stents (1.91 +/- 1.1 vs. 1.57 +/- 0.94, P < 0.0001), total stent length (38.2 +/- 20.8 vs. 31.4 +/- 20.3, P < 0.0001) and longer stents (38.2 +/- 20.8 vs. 31.4 +/- 20.3 mm, P < 0.0001) were used in the PCI-DCS cohort with rotational atherectomy also used more frequently. Physician-recommended DAPT duration was 2.9 +/- 3.9 months for PCI-DCS patients and 11.3 +/- 2.4 months for PCI-DES patients (P < 0.0001). At 12 month follow-up, definite stent thrombosis (0.6% vs. 1.1%) and TLR (3.2% vs. 2.7%) rates were similar between the two groups. After adjustment for baseline differences, there were no statistically significant differences in death and combined MACE rates at 12 months. CONCLUSIONS: The outcomes of patients treated with polymer-free BA9 drug-coated stent who present with an ACS and who were deemed unsuitable for prolonged DAPT are encouraging. Further studies are warranted. PMID- 30244505 TI - Ligation of intersphincteric fistula tract procedure for the treatment of fistula in ano - a video vignette. PMID- 30244506 TI - Coronary bifurcation bench test using multimodality imaging: Impact of stent strut link location on stent deformity and jailed side-branch orifices during re proximal optimizing technique. AB - OBJECTIVES: The purpose of this study was to compare the stent deformation, obstruction of stent struts at a jailed side branch (SB) ostium, and stent strut malapposition after a repetitive proximal optimizing technique (re-POT) sequence between bifurcation lesions with and without stent links at SB ostia in ex vivo experimental setting. METHODS: A flexible urethane coronary bifurcation bench model was used, and crossover single stent implantation was performed from main branch (MB) with re-POT sequence. Under videoscope observation, presence (link group, n = 12) or absence (no-link group, n = 12) of stent link at distal semicircle of SB ostium was intentionally set, and rewiring was performed through distal cell in four different stent platforms. RESULTS: There were no significant differences in the rate of malapposed struts and in SB jailing ratio after the re POT sequence between the link and no-link groups. SB jailing ratio increased significantly from 8.0% to 9.6% during the second POT procedure (P < 0.001). SB jailing ratio after the second POT procedure differed among stent platforms. CONCLUSIONS: The presence of a stent link at an SB ostium was not associated with a rate of malapposed struts and SB jailing ratio after the re-POT sequence. SB jailing ratio was significantly increased after second POT procedure, but was different among stent platforms. The Xience stent might minimize the change of SB jailing ratio and be suitable for coronary bifurcation stenting using re-POT sequence. PMID- 30244507 TI - In utero exposure to cigarette smoke and effects across generations: A conference of animals on asthma. AB - BACKGROUND: The prevalence of asthma and chronic obstructive pulmonary disease (COPD) has risen markedly over the last decades and is reaching epidemic proportions. However, underlying molecular mechanisms are not fully understood, hampering the urgently needed development of approaches to prevent these diseases. It is well established from epidemiological studies that prenatal exposure to cigarette smoke is one of the main risk factors for aberrant lung function development or reduced fetal growth, but also for the development of asthma and possibly COPD later in life. Of note, recent evidence suggests that the disease risk can be transferred across generations, that is, from grandparents to their grandchildren. While initial studies in mouse models on in utero smoke exposure have provided important mechanistic insights, there are still knowledge gaps that need to be filled. OBJECTIVE: Thus, in this review, we summarize current knowledge on this topic derived from mouse models, while also introducing two other relevant animal models: the fruit fly Drosophila melanogaster and the zebrafish Danio rerio. METHODS: This review is based on an intensive review of PubMed-listed transgenerational animal studies from 1902 to 2018 and focuses in detail on selected literature due to space limitations. RESULTS: This review gives a comprehensive overview of mechanistic insights obtained in studies with the three species, while highlighting the remaining knowledge gaps. We will further discuss potential (dis)advantages of all three animal models. CONCLUSION/CLINICAL RELEVANCE: Many studies have already addressed transgenerational inheritance of disease risk in mouse, zebrafish or fly models. We here propose a novel strategy for how these three model organisms can be synergistically combined to achieve a more detailed understanding of in utero cigarette smoke-induced transgenerational inheritance of disease risk. PMID- 30244508 TI - Extracellular vesicle microRNA cargo is correlated with HPV status in oropharyngeal carcinoma. AB - BACKGROUND: The incidence of human papilloma virus positive (HPV+ ) oropharyngeal squamous cell carcinoma (OPSCC) has increased rapidly in recent decades. These tumours have a favourable outcome compared to HPV-negative (HPV- ) OPSCC. However, HPV+ tumours are more likely to metastasise to distant sites, suggesting a difference in how these tumour subtypes interact with the metastatic niche. Extracellular vesicles (EVs) have emerged as important players in cell-to-cell communication and are a potential source of biomarkers for cancer diagnosis. This study aims to characterise the microRNA cargo of small EVs released by HPV+ and HPV- OPSCC cell lines. METHODS: Extracellular vesicles produced by HPV+ (SCC2 and SCC90) and HPV- (SCC72 an SCC89) OPSCC cells were characterised by tunable resistive pulse sensing (TRPS) and western blotting. RNA was extracted from EVs and analysed by small RNA sequencing. A bioinformatics approach was used to identify EV miRNA signatures associated with HPV status. RESULTS: HPV- OPSCC cells produced more EVs than HPV+ OPSCC cells. EVs were positive for the common EV markers CD63, CD9 and TSG101. Unbiased hierarchical clustering analysis of EV miRNA cargo revealed that samples clustered based on HPV status. 14 miRNA were enriched in HPV+ cell-derived EVs, whereas 19 miRNA were enriched in EVs derived from HPV- cell lines. CONCLUSIONS: Here, we identify EV miRNA signatures indicative of the HPV status of the parent cell. This may provide a platform from which to validate salivary or blood-based biomarkers with utility for early detection and stratifying risk in OPSCC patients. PMID- 30244509 TI - Glycoprotein IIb/IIIa inhibitor use in patients with acute myocardial infarction undergoing PCI: Insights from the TRANSLATE ACS study. AB - INTRODUCTION: Concomitant use of glycoprotein IIb/IIIa inhibitors (GPI) and P2Y12 inhibitors increases bleeding risk. How GPIs are being used with faster onset, higher potency P2Y12 inhibitors are unclear. METHODS AND RESULTS: We studied 11,781 myocardial infarction (MI) patients treated with percutaneous coronary intervention (PCI) at 233 hospitals in the TRANSLATE ACS study (2010-2012). We used propensity matching to compare 6-week major adverse cardiac events (MACE: death, recurrent MI, stroke, or unplanned revascularization) and BARC 2+ bleeding events between patients who did and did not receive planned GPI. Planned and bailout GPI were used in 4,983 (42.2%) and 229 (4.4%) MI patients undergoing PCI, respectively. Patients receiving planned GPI were younger (58 vs. 61 years), more likely to present with STEMI (62.6% vs. 45.4%) or have stent thrombosis (4.2% vs. 2.1%, all P < 0.001) than those without planned GPI use. Planned GPI was used less often with prasugrel/ticagrelor versus clopidogrel (37.1% vs. 43.3%), or when any P2Y12 inhibitor was given >6 hr prior to PCI versus earlier (27.8% vs. 44.4%, both P < 0.01). After propensity matching, planned GPI use was not associated with any difference in MACE (6.4% vs. 5.5% OR 1.18; 95% CI: 0.99 1.57), however, the risk of BARC 2+ bleeding was higher in patients who received planned GPI (11.3% vs. 8.7%; OR 1.34; 95% CI: 1.13-1.59). CONCLUSION: Planned GPI use as reported by practicing physicians was prevalent between 2010 and 2012 and was associated with increased risk of bleeding but not lower MACE. PMID- 30244510 TI - Autologous blood reinfusion during iatrogenic acute hemorrhagic cardiac tamponade: Safety and feasibility in a cohort of 30 patients. AB - BACKGROUND: Iatrogenic hemorrhagic pericardial tamponade (IHPT) represents a life threating condition requiring emergency pericardiocentesis. In this clinical context, reinfusion of pericardial blood can stabilize the patient and sustain hemodynamic conditions. AIMS AND METHODS: We reviewed all cases of IHPT occurred at our hospital over a 10 years span. In all patient autologous blood reinfusion through a femoral vein was performed. RESULTS: In our clinical experience of 30 consecutive patients with hemorrhagic cardiac tamponade, this technique was successful to limit blood transfusions, to prevent further clinical worsening and bridge patients with intractable bleeding, to cardiac surgery. No major adverse reactions were directly related to blood autotransfusion. CONCLUSION: In the complex clinical scenario of acute tamponade occurring during catheter-based cardiac procedures, autotransfusion of pericardial blood through a femoral vein is safe and effective. It can be a useful trick up the sleeve of the interventional cardiologist. PMID- 30244511 TI - Open sesame technique in percutaneous coronary intervention for ST-elevation myocardial infarction. AB - In patients with ST-elevation myocardial infarction (STEMI), delays in reperfusion attenuate the benefit of primary percutaneous coronary intervention (PCI) and associate with higher mortality rates. Although PCI operators are making their best effort in time saving for reperfusion, it is sometimes challenging and takes time to pass the guide wire across the target lesions. A totally occluded lesion in which a side branch was bifurcating at the proximal end of the occluded segment is one of the most technically challenging anatomies of the target lesion because it is difficult to identify the entry point of the occluded segment. A side branch technique, termed "Open Sesame Technique" (OST), has been previously introduced for chronic total occlusion (CTO) lesion in which a side branch was bifurcating at the proximal end of the occluded segment. We herein present two cases applying this technique in STEMI with totally occluded lesions at bifurcation as a culprit lesion, in which the entry point was not identified on the initial angiography. PCI were performed successfully using the OST in both cases, which resulted in saving procedural time and contrast volume without any complications. This technique can be effective not only in PCI for CTO lesions but also in primary PCI for STEMI cases with occluded bifurcation lesions. PMID- 30244512 TI - Excision release of 5?hydroxycytosine oxidatively induced DNA base lesions from the lung genome by cat dander extract challenge stimulates allergic airway inflammation. AB - BACKGROUND: Ragweed pollen extract (RWPE) induces TLR4-NFkappaB-CXCL-dependent recruitment of ROS-generating neutrophils to the airway and OGG1 DNA glycosylase dependent excision of oxidatively induced 8-OH-Gua DNA base lesions from the airway epithelial cell genome. Administration of free 8-OH-Gua base stimulates RWPE-induced allergic lung inflammation. These studies suggest that stimulation of innate receptors and their adaptor by allergenic extracts initiates excision of a set of DNA base lesions that facilitate innate/allergic lung inflammation. OBJECTIVE: To test the hypothesis that stimulation of a conserved innate receptor/adaptor pathway by allergenic extracts induces excision of a set of pro inflammatory oxidatively induced DNA base lesions from the lung genome that stimulate allergic airway inflammation. METHODS: Wild-type (WT), Tlr4KO, Tlr2KO, Myd88KO, and TrifKO mice were intranasally challenged once or repeatedly with cat dander extract (CDE), and innate or allergic inflammation and gene expression were quantified. We utilized GC-MS/MS to quantify a set of oxidatively induced DNA base lesions after challenge of naive mice with CDE. RESULTS: A single CDE challenge stimulated innate neutrophil recruitment that was partially dependent on TLR4 and TLR2, and completely on Myd88, but not TRIF. A single CDE challenge stimulated MyD88-dependent excision of DNA base lesions 5-OH-Cyt, FapyAde, and FapyGua from the lung genome. A single challenge of naive WT mice with 5-OH-Cyt stimulated neutrophilic lung inflammation. Multiple CDE instillations stimulated MyD88-dependent allergic airway inflammation. Multiple administrations of 5-OH Cyt with CDE stimulated allergic sensitization and allergic airway inflammation. CONCLUSIONS AND CLINICAL RELEVANCE: We show for the first time that CDE challenge stimulates MyD88-dependent excision of DNA base lesions. Our data suggest that the resultant-free base(s) contribute to CDE-induced innate/allergic lung inflammation. We suggest that blocking the MyD88 pathway in the airways with specific inhibitors may be a novel targeted strategy of inhibiting amplification of innate and adaptive immune inflammation in allergic diseases by oxidatively induced DNA base lesions. PMID- 30244513 TI - Left atrial hemodynamics and left ventricular remodeling -predictors of outcomes after Transcatheter mitral valve repair with the MitraClip device. AB - BACKGROUND: Increased afterload and reduced left ventricular (LV) performance are sequela of mitral valve repair. However, hemodynamic left atrial and ventricular parameters that can predict outcome following mitral valve repair remain elusive. METHODS: One hundred and two consecutive patients undergoing MitraClip procedure from 2014 to 2017 at Banner University Medical Center were enrolled in this study. All patients underwent pre-procedure echocardiograms and intra-procedure invasive left atrial (LA) pressure monitoring. Clinical, laboratory, and procedural parameters were collected. The primary end-point was the composite outcome of all-cause mortality and repeat hospitalization within 90 days. RESULTS: The mean age was 77 +/-10 years, the majority were Caucasians (93, 91.2%) and 47 (46.1%) were males. Thirty-two patients (31.4%) had diabetes, 39 (38.2%) had renal insufficiency, and 38 (37.3%) had a history of congestive heart failure. The median society of thoracic surgeons score was 6.7% (Interquartile range [IQR]: 3.9, 10.2). Immediately post-procedure there was a significant reduction in the LA pressure (Mean 12.0 vs. 18.6 mmHg, P < 0.001) and pulmonary artery systolic pressure (43.5 vs. 53.2 mmHg, P = 0.001) compared to baseline. LA pressure was an independent predictor of the composite outcome in an unadjusted (OR = 1.07, 95% CI: 1.00-1.13, P = 0.03) and adjusted (OR = 1.07, 95% CI: 1.00 1.14, P = 0.03) analysis respectively. CONCLUSION: LA pressure drop is an independent predictor of outcome after the MitraClip procedure. This finding has implications for early identification of patients at risk of poor outcomes and instituting aggressive medical therapy and close follow-up for avoiding hospitalizations for heart failure decompensation. PMID- 30244514 TI - How does it feel to be a problem? Patients' experiences of self-management support in New Zealand and Canada. AB - BACKGROUND: The impact of long-term conditions is the "healthcare equivalent to climate change." People with long-term conditions often feel they are a problem, a burden to themselves, their family and friends. Providers struggle to support patients to self-manage. The Practical Reviews in Self-Management Support (PRISMS) taxonomy lists what provider actions might support patient self management. OBJECTIVE: To offer providers advice on how to support patient self management. DESIGN: Semi-structured interviews with 40 patient-participants. SETTING AND PARTICIPANTS: Three case studies of primary health-care organizations in New Zealand and Canada serving diverse populations. Participants were older adults with long-term conditions who needed support to live in the community. MAIN OUTCOME MEASURES: Qualitative description to classify patient narratives of self-management support according to the PRISMS taxonomy with thematic analysis to explore how support was acceptable and effective. RESULTS: Patients identified a relationship-in-action as the mechanism, the how by which providers supported them to self-manage. When providers acted upon knowledge of patient lives and priorities, these patients were often willing to try activities or medications they had resisted in the past. Effective self-management support saw PRISMS components delivered in patient-specific combinations by individual providers or teams. DISCUSSION AND CONCLUSIONS: Providers who establish relationships with patients can support them to self-manage and improve health outcomes. Delivery of taxonomy components, in the absence of a relationship, is unlikely to be either acceptable or effective. Providers need to be aware that social determinants of health can constrain patients' options to self-manage. PMID- 30244515 TI - Molecular cloning and characterisation of an isotocin paralogue ([V8] isotocin) in catfishes (superorder Ostariophysi): Origin traced likely to the fish-specific whole genome duplication. AB - The present study reports the molecular cloning of a previously uncharacterised neurohypophyseal nonapeptide precursor cDNA in two catfish species: Heteropneustes fossilis and Clarias batrachus. The deduced nonapeptide is CYISNCPVG ([V8] isotocin), which has not been reported in any vertebrate till date. Phylogenetic and conserved synteny analyses showed the gene to have originated from the isotocin precursor (pro-it) gene by fish-specific whole genome duplication (3R). The two isotocin lineages have been designated as pro ita (new gene) and pro-itb (conventional it gene). All teleost groups may not possess both pro-ita and pro-itb and the pattern of losses/retention was found to be lineage-specific. Quantitative reverse transcriptase-polymerase chain reaction studies showed the expression of the pro-ita gene in the brain and ovary of H. fossilis. In situ hybridisation studies localised the pro-ita transcripts in the nucleus preopticus of the hypothalamus and the follicular layer (theca-granulosa) of oocytes, comprising tissues in which pro-itb and vasotocin precursor (pro-vt) mRNA expression was previously reported. The transcript levels varied with the reproductive stage and a high abundance was found in both brain and ovary during the breeding phase. The substitution of valine in place of isoleucine at the eighth position in Ita may have modified the ligand-receptor interaction, leading to sub-functionalisation and the retention of the gene in catfishes. PMID- 30244516 TI - Day-case percutaneous left atrial appendage occlusion-Safety and efficacy. AB - OBJECTIVES: We evaluated the safety and efficacy of percutaneous left atrial appendage (LAA) occlusion performed as a day case procedure. BACKGROUND: LAA occlusion has been shown to be safe and effective for stroke prevention in patients with atrial fibrillation. It has not been shown if the procedure can safely be performed on a day-case basis. METHODS: Retrospective analysis was made of 117 LAA occlusion procedures in a single large teaching hospital in the UK. Procedural success, procedural complications, length of stay, and readmission data were examined. RESULTS: Successful deployment of a device was possible in all but one patient (whose appendage was too large). Major in-hospital complications occurred in 1.7% of patients (both femoral vascular). Same-day discharge was made in 66% of patients overall. Since January 2016, only 3 of 59 patients (5%) have remained in hospital overnight following LAAO. Echocardiography 2-4 hr postprocedure was undertaken prior to discharge. One patient was readmitted within 7 days but this readmission would not have been prevented by overnight stay. CONCLUSIONS: LAA occlusion can be safely performed as a day case procedure with acceptable complication rates and no increment of complications related to the lack of routine overnight stay. PMID- 30244518 TI - Valvuloplasty balloon entrapment in a self-expanding aortic valve stent frame after inadvertent wire passage through the outflow struts. AB - Transcatheter aortic valve replacement (TAVR) is a leading-edge therapy option for patients with severe aortic stenosis (AS) and high surgical risk. However, this minimally invasive procedure is associated with specific complications that may be life-threatening. Valvuloplasty balloon entrapment during postdilatation in transcatheter self-expanding aortic valve stent frames has not yet been a focus of interest in this context. Although it is a rare event, it may critically influence outcome, and different management strategies can be considered. Hereafter, we present the case of a 67-year-old male who underwent transfemoral TAVR and subsequent postdilatation. The valvuloplasty balloon was entrapped in the self-expanding aortic valve stent frame after inadvertent wire passage through the outflow struts. Since surgical risk was high, we preferred a percutaneous approach and extracted the entrapped balloon with high traction force under rapid pacing after valve stabilization with another balloon, which was placed in the annular position. PMID- 30244517 TI - Impact of left atrial compliance improvement on functional status after percutaneous mitral valvuloplasty. AB - BACKGROUND: Conventional hemodynamic parameters may not accurately predict symptomatic improvement after percutaneous mitral valvuloplasty (PMV). Changes in left heart chamber compliance following adequate relief o0066 mitral stenosis (MS) may be useful in determining functional capacity after PMV. This study aims to determine the acute effects of PMV on compliance of the left heart and whether its changes relate to the patient's functional capacity. METHODS: One-hundred thirty-seven patients with severe MS undergoing PMV were enrolled. Left atrial (Ca ) and left ventricular (Cv ) compliance were invasively estimated and net atrioventricular compliance (Cav ) was calculated before and immediately after the procedure. B-type natriuretic peptide (BNP) levels were obtained before and 24 hr after the procedure. The primary endpoint was functional status at 6-month follow-up, and the secondary endpoint was a composite of death, mitral valve (MV) replacement, repeat PMV, new onset of atrial fibrillation, or stroke in patients in whom PMV was successful. RESULTS: The mean age was 43 +/- 12 years, and 119 patients were female (87%). After PMV, Ca and Cav improved significantly from 5.3 [IQR 3.2-8.2] mL/mmHg to 8.7 [5.3-19.2] mL/mmHg (P < 0.001) and 2.2 [1.6-3.4] to 2.8 [2.1-4.1] mL/mmHg (P < 0.001), respectively, whereas Cv did not change (4.6 [3.2-6.8] to 4.4 [3.1-5.6]; P = 0.637). Plasma BNP levels significantly decreased after PMV, with no correlation between its variation and changes in left chamber compliance. At 6-month follow-up, NYHA functional class remained unchanged in 32 patients (23%). By multivariable analyses, changes in Ca immediately after PMV (adjusted OR 1.42; 95% CI 95% 1.02 to 1.97; P = 0.037) and younger age (adjusted OR 0.95; CI 95% 0.92-0.98; P = 0.004), predicted improvement in functional capacity at 6-month follow-up, independent of postprocedural data. The secondary endpoint were predicted by post-PMV mean gradient (adjusted HR 1.363; 95% CI 95% 1.027-1.809; P = 0.032), and lack of functional improvement at 6-month follow-up (adjusted HR 4.959; 95% 1.708-14.403; P = 0.003). CONCLUSIONS: Ca and Cav increase significantly after PMV with no change in Cv . The improvement of Ca is an important predictor of functional status at 6-month follow up, independently of other hemodynamic data. Postprocedural mean gradient and lack of short-term symptomatic improvement were predictors of adverse outcome. PMID- 30244519 TI - The relevance of donor satisfaction after living kidney donation-a plea for a routine psychosocial follow-up. PMID- 30244520 TI - Acute and long-term outcomes after polytetrafluoroethylene or pericardium covered stenting for grade 3 coronary artery perforations: Insights from G3-CAP registry. AB - BACKGROUND: Covered stent (CS) implantation is considered a useful device in the setting of Grade III Coronary Perforation (G3CP), one of the most harmful PCI complication. However, data regarding efficacy of this device and clinical outcomes are still limited. METHODS AND RESULTS: From 1993 to 2015, among 97,779 patients from 9 European centres undergoing PCI, 224 patients had G3CP (0.23%), and 102 patients were managed with CS implantation (96 with PTFE, 6 with pericardium). Device oriented composite endpoint (DOCE), a composite of cardiac death, target lesion revascularization, and stent thrombosis (ST) in-hospital and at long term follow-up were evaluated. G3-CP perforations were successfully sealed with CS in 88 patients (86.3%) with need of intraprocedural pericardiocentesis in one-third of cases. Protamine as heparin reversal agent was administered in 36 (35%) of cases. The cumulative incidence of in-hospital DOCE were 16.6% (17/102): death 14.7%, TLR 2.9%, ST 3.9%. At long-term follow-up (mean 42 +/- 38 months), DOCE rates occurred in 19.7%: death 7.4%, TLR 11%, and ST 6.2%. Indication to Dual Antiplatelet Therapy (DAPT) was lifelong in 20% of cases, 1 to 6 months in 22.5% and 12-months in 57.5% without differences in long term DOCE before and after DAPT interruption (8.0 vs. 6.6%, respectively, P = 0.20). CONCLUSIONS: Use of CS was successful in sealing grade 3 coronary artery perforations in the majority of cases. Beside the high rate of clinical events at short and long-term, ST remains the leading cause of device failure. PMID- 30244521 TI - Chronic immunosuppressant use in colorectal cancer patients worsens postoperative morbidity and mortality through septic complications in a propensity-matched analysis. AB - AIM: Chronic immunosuppressant use increases the risk of septic complications after colectomy; however, adverse effects on other organ systems remain poorly understood. The aim of this study was to evaluate the multisystem organ effect(s) of chronic immunosuppressant(s) in colorectal cancer patients. METHODS: This was a retrospective study. The American College of Surgeons National Surgical Quality Improvement database (2005-2012) was queried. The primary end-points were 30-day mortality and 30-day morbidity after colectomy in patients on chronic immunosuppressant(s) compared to a non-immunosuppressant cohort. RESULTS: In total, 50 766 patients were identified, with 1203 (2.4%) taking chronic immunosuppressant(s). After propensity matching, 1197 patients in each cohort were evaluated with no differences seen in age, body mass index, male sex, wound classification, emergency case status, the presence of preoperative sepsis or operative time. On outcome analysis, 30-day mortality (5.7% vs 3.4%, P < 0.001) and 30-day overall morbidity (35.4% vs 29.0%, P = 0.001) were higher in patients on chronic immunosuppressant(s). Septic complications (10.6% vs 7.9%, P = 0.02) and surgical site infections (15.3% vs 12.3%, P = 0.03) were elevated with chronic immunosuppressant(s). There were no differences in cardiovascular, pulmonary, renal or neurological complications. Chronic immunosuppressant patients demonstrated longer total hospital stay (11.4 +/- 11.7 vs 9.5 +/- 9.4 days, P < 0.001) and postoperative length of stay (9.4 +/- 9.2 vs 8.1 +/- 7.6 days, P < 0.001). The limitation was that this was a retrospective study using a clinical dataset. CONCLUSION: In this study, immunosuppressant use is associated with worsened infective complications, without contributing to organ-specific complications following colectomy. Significant thought should be given to anastomosis vs stoma creation to possibly prevent worsened morbidity and mortality. Future study is required to determine specific pathways for risk reduction. PMID- 30244522 TI - Bronchoscopic mucosal cryobiopsies as a method for studying airway disease. AB - BACKGROUND: Investigating disease mechanisms and treatment responses in obstructive airway diseases with invasive sampling are hampered by the small size and mechanical artefacts that conventional forceps biopsies suffer from. Endoscopic cryobiopsies are larger and more intact and are being increasingly used. However, the technique has not yet been explored for obtaining mucosa biopsies. OBJECTIVE: To investigate differences in size and quality of endobronchial mucosal biopsies obtained with cryotechnique and forceps. Further, to check for eligibility of cryobiopsies to be evaluated with immunohistochemistry and in situ hybridization and to investigate tolerability and safety of the technique. METHODS: Endobronchial mucosal biopsies were obtained with cryotechnique and forceps from patients with haemoptysis undergoing bronchoscopy and evaluated by quantitative morphometry, automated immunohistochemistry and in situ hybridization. RESULTS: A total of 40 biopsies were obtained from 10 patients. Cross-sectional areas were threefold larger in cryobiopsies (median: 3.08 mm2 (IQR: 1.79) vs 1.03 mm2 (IQR: 1.10), P < 0.001). Stretches of intact epithelium were 8-fold longer (median: 4.61 mm (IQR: 4.50) vs 0.55 mm (IQR: 1.23), P = 0.001). Content of glands (median: 0.095 mm2 (IQR: 0.30) vs 0.00 mm2 (IQR: 0.01), P = 0.002) and airway smooth muscle (median: 0.25 mm2 (IQR: 0.30) vs 0.060 mm2 (IQR: 0.11), P = 0.02) was higher in the cryobiopsies compared with forceps biopsies. Further, the cryobiopsies had well-preserved protein antigens and mRNA. Mild to moderate bleeding was the only complication observed. CONCLUSION AND CLINICAL RELEVANCE: By yielding significantly larger and more intact biopsies, the cryotechnique represents a valuable new research tool to explore the bronchi in airway disease. Ultimately with the potential to create better understanding of underlying disease mechanisms and improvement of treatments. PMID- 30244524 TI - The use of cytological material in melanoma for programmed death ligand 1 immunostaining. AB - OBJECTIVE: Interest in immune therapies has exploded since the 2014 approval of first-generation programmed cell death 1 blocking antibodies for use in advanced melanoma. Clinical trials have focused primarily on histological material as the gold standard for evaluating programmed death ligand 1 (PD-L1) by immunoperoxidase (IPOX) studies. Studies validating the use of cytological specimens in the assessment of PD-L1 by IPOX staining are needed to optimise tissue utilisation in complementary diagnostic testing. METHODS: Twenty-three melanoma surgical biopsies (SBx) with an IPOX stain for PD-L1 clone 28-8, and a corresponding cytological specimen from the same patient, adequate for PD-L1 evaluation, were selected. Cell-transfer cell blocks (CBs) and conventional CBs were used to perform PD-L1 testing. Tumour proportion scores (TPS) were generated and the results were correlated with the corresponding SBx. RESULTS: Overall agreement (OA) using a >=1% TPS cut-off for SBx compared to CB was 88.9%, positive percent agreement (PPA) was 87.5%, and negative percent agreement (NPA) was 100%, OA using a >=5% TPS cut-off was 55.6%, PPA was 42.9%, and NPA was 100%. SBx compared to cell-transfer CB using a >=1% TPS cut-off had an OA of 65.2%, a PPA of 55.6%, and a NPA of 100%, while a >=5% TPS cut-off generated an OA of 52.2%, a PPA of 35.7%, and a NPA of 77.8%. CONCLUSION: Our results demonstrate that cytological material, particularly conventional CB, is a viable alternative for evaluating PD-L1 in melanoma cases and suggest that a lower threshold (>=1%) may be beneficial when evaluating cytological material. PMID- 30244523 TI - Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts. AB - Cells that had undergone telomere dysfunction-induced senescence secrete numerous cytokines and other molecules, collectively called the senescence-associated secretory phenotype (SASP). Although certain SASP factors have been demonstrated to promote cellular senescence in neighboring cells in a paracrine manner, the mechanisms leading to bystander senescence and the functional significance of these effects are currently unclear. Here, we demonstrate that TGF-beta1, a component of the SASP, causes telomere dysfunction in normal somatic human fibroblasts in a Smad3/NOX4/ROS-dependent manner. Surprisingly, instead of activating cellular senescence, TGF-beta1-induced telomere dysfunction caused fibroblasts to transdifferentiate into alpha-SMA-expressing myofibroblasts, a mesenchymal and contractile cell type that is critical for wound healing and tissue repair. Despite the presence of dysfunctional telomeres, transdifferentiated cells acquired the ability to contract collagen lattices and displayed a gene expression signature characteristic of functional myofibroblasts. Significantly, the formation of dysfunctional telomeres and downstream p53 signaling was necessary for myofibroblast transdifferentiation, as suppressing telomere dysfunction by expression of hTERT, inhibiting the signaling pathways that lead to stochastic telomere dysfunction, and suppressing p53 function prevented the generation of myofibroblasts in response to TGF-beta1 signaling. Furthermore, inducing telomere dysfunction using shRNA against TRF2 also caused cells to develop features that are characteristic of myofibroblasts, even in the absence of exogenous TGF-beta1. Overall, our data demonstrate that telomere dysfunction is not only compatible with cell functionality, but they also demonstrate that the generation of dysfunctional telomeres is an essential step for transdifferentiation of human fibroblasts into myofibroblasts. PMID- 30244525 TI - Potential cofactors in accidental food allergic reactions are frequently present but may not influence severity and occurrence. AB - BACKGROUND: Cofactors, such as physical exercise and alcohol intake, might be associated with the severity or occurrence of food allergic reactions. OBJECTIVE: To gain insight into the frequency of presence of potential cofactors in accidental food allergic reactions in adults and to what extent these factors influence the severity and occurrence of allergic reactions. METHODS: A prospective cohort study was conducted, with a 1-year follow-up in adult patients with a physician-diagnosed food allergy. Patients were required to fill in a questionnaire after every accidental allergic reactions to food over a 1-year period. The primary outcome measure was the frequency that potential cofactors were present in these allergic reactions. RESULTS: A total of 157 patients were included, of which 46% reported a total of 153 reactions during a 1-year follow up period. In 74% of the reactions, >=1 potential cofactor was reported to be present: tiredness (38%), alcohol intake (16%), stress (14%), symptoms of pollinosis (16%), symptoms of asthma (9%), sickness/flu (3%), physical exercise (3%) and use of analgesics (2%). More than one potential cofactor was reported in almost half of all reactions (47%). There was no significant difference in the presence of these factors between mild, moderate and severe reactions (P = 0.522). In the total study population, 9% of the patients used medication that might act as cofactor (antacids, angiotensin receptor blockers [ARBs], beta blockers and angiotensin-converting enzyme inhibitors [ACEIs]) on a daily basis, which however did not influence the occurrence of reactions. Furthermore, 38% daily used allergy-suppressing medication. CONCLUSIONS: Although factors suggested to be cofactors were frequently present during accidental food allergic reactions, we found no evidence for an association between the potential cofactors examined and reaction severity, in a population where most reactions were of mild to moderate severity. PMID- 30244526 TI - Identification of novel PIEZO1 variants using prenatal exome sequencing and correlation to ultrasound and autopsy findings of recurrent hydrops fetalis. AB - Nonimmune hydrops fetalis (NIHF) is a rare disorder with a high perinatal mortality of at least 50%. One cause of NIHF is generalized lymphatic dysplasia (GLD), a rare form of primary lymphedema of the extremities and systemic involvement including chylothoraces and pericardial effusions. An autosomal recessive form of GLD has been described, caused by variants in the PIEZO1 gene. It has been reported clinically to cause NIHF and childhood onset of facial and limb lymphedema, most of which were diagnosed postnatally. We present a case of a woman with recurrent pregnancies affected by NIHF because of novel compound heterozygous variants in the PIEZO1 gene diagnosed prenatally using exome sequencing (ES). Two variants in PIEZO1 (c.3206G>A and c.6208A>C) were identified that were inherited from the father and mother, and are predicted to cause a nonsense and missense change, respectively, in the PIEZO1 subunits. Ultrasound demonstrated severe bilateral pleural effusions, whole body edema and polyhydramnios. Histopathology revealed an increased number of lymphatic channels, many of which showed failure of luminal canalization. Sanger sequencing confirmed the same variants in a prior fetal demise. We provide phenotypic correlation with ultrasound and autopsy finding, review PIEZO1 variants as a cause of GLD and discuss the uses of prenatal ES to date. PMID- 30244527 TI - Simultaneous transfemoral transcatheter aortic valve replacement and trans-septal mitral valve-in-ring implantation after partial laceration of an Alfieri stitch. AB - In patients with an Alfieri Stitch transcatheter mitral valve replacement (TMVR) may be difficult due to the double orifice configuration of the mitral valve. We report a case of simultaneous and completely percutaneous TAVR and TMVR using LAMPOON-related techniques prior to TMVR to allow for optimal valve deployment. PMID- 30244528 TI - 22q and two: 22q11.2 deletion syndrome and coexisting conditions. AB - 22q11.2 deletion syndrome (DS) is the most frequent copy number variant (CNV) affecting ~1/1,000 fetuses and ~1/2,000-4,000 children, resulting in recognizable but variable findings across multiple organ systems. Patients with atypical features should prompt consideration of coexisting diagnoses due to additional genome-wide mutations, CNVs, or mutations/CNVs on the other allele, unmasking autosomal recessive conditions. Importantly, a dual diagnosis compounds symptoms and impacts management. We previously reported seven patients with 22q11.2DS and: SCID, Trisomy 8 mosaicism, Bernard-Soulier, and CEDNIK syndromes. Here we present six additional unreported patients with 22q11.2DS and concurrent diagnoses. Records on 1,422 patients with 22q11.2DS, identified via FISH, microarray, or MLPA, followed in our 22q and You Center at the Children's Hospital of Philadelphia (CHOP) were reviewed to identify a dual diagnosis. In addition to our seven previously reported cases, we identified an additional six with 22q11.2DS and another coexisting condition identified via: molecular/cytogenetic studies, newborn screening, coagulation factor studies, or enzyme testing; these include CHARGE syndrome (CHD7 mutation), cystic fibrosis, a maternally inherited 17q12 deletion, G6PD deficiency, von Willebrand disease, and 1q21.1 deletion, resulting in an incidence of dual diagnoses at our center of 0.9%. The range of dual diagnoses identified in our cohort is notable, medically actionable, and may alter long-term outcome and recurrence risk counseling. Thus, our findings may support testing patients with 22q11.2DS using a combination of microarray, mutational analysis of the other allele/WES, to ensure appropriate personalized care, as formulating medical management decisions hinges on establishing the correct diagnoses in their entirety. PMID- 30244529 TI - Extending the ALDH18A1 clinical spectrum to severe autosomal recessive fetal cutis laxa with corpus callosum agenesis. PMID- 30244530 TI - Small 4p16.3 deletions: Three additional patients and review of the literature. AB - Wolf-Hirschhorn syndrome is a well-defined disorder due to 4p16.3 deletion, characterized by distinct facial features, intellectual disability, prenatal and postnatal growth retardation, and seizures. Genotype-phenotype correlations based on differently sized deletions have been attempted, and some candidate genes have been suggested. We report on clinical characteristics of three patients with pure interstitial submicroscopic 4p16.3 deletions, ranging in size from 68 to 166 kb, involving WHSCR1 and/or part of WHSCR2, and review published cases with overlapping 4p16.3 losses. The present study highlights a major role of NSD2 gene in the pathogenesis of the WHS main features and predicts that loss-of-function mutations affecting NSD2 gene could result in microcephaly, prenatal and postnatal growth retardation, psychomotor and language delay, and craniofacial features. Absent seizures in all subjects corroborate the suggestion that this specific feature is causally linked with at least one additional causative gene. Finally, we suggest that mir-943 could play a role in the pathogenesis of CHD in some of these patients. PMID- 30244531 TI - Methodology for evaluating and comparing flow cytometers: A multisite study of 23 instruments. AB - We demonstrate improved methods for making valid and accurate comparisons of fluorescence measurement capabilities among instruments tested at different sites and times. We designed a suite of measurements and automated data processing methods to obtain consistent objective results and applied them to a selection of 23 instruments at nine sites to provide a range of instruments as well as multiple instances of similar instruments. As far as we know, this study represents the most accurate methods and results so far demonstrated for this purpose. The first component of the study reporting improved methods for photoelectron scale (Spe) evaluations, which was published previously (Parks, El Khettabi, Chase, Hoffman, Perfetto, Spidlen, Wood, Moore, and Brinkman: Cytometry A 91 (2017) 232-249). Those results which were within themselves are not sufficient for instrument comparisons, so here, we use the Spe scale results for the 23 cytometers and combine them with additional information from the analysis suite to obtain the metrics actually needed for instrument evaluations and comparisons. We adopted what we call the 2+2SD limit of resolution as a maximally informative metric, for evaluating and comparing dye measurement sensitivity among different instruments and measurement channels. Our results demonstrate substantial differences among different classes of instruments in both dye response and detection sensitivity and some surprisingly large differences among similar instruments, even among instruments with nominally identical configurations. On some instruments, we detected defective measurement channels needing service. The system can be applied in shared resource laboratories and other facilities as an aspect of quality assurance, and accurate instrument comparisons can be valuable for selecting instruments for particular purposes and for making informed instrument acquisition decisions. An institutionally supported program could serve the cytometry community by facilitating access to materials, and analysis and maintaining an archive of results. (c) 2018 International Society for Advancement of Cytometry. PMID- 30244532 TI - Discovery of restless legs syndrome plasmatic biomarkers by proteomic analysis. AB - OBJECTIVES: Restless legs syndrome (RLS) can lead to severe clinical consequences, thus negatively impacts on patients' overall health and quality of life. Nevertheless, the pathophysiology of RLS is still unclear, resulting in underestimate, incorrect, or ignored diagnosis and in limited management and treatment. The aim of this study was to compare the plasma proteome of RLS patients and healthy controls, in the search of diagnostic biomarkers related to the disease severity. MATERIALS AND METHODS: Two-dimensional gel electrophoresis coupled with liquid chromatography-mass spectrometry was employed to analyze plasma samples of 34 patients with primary RLS, divided into two subgroups according to the disease severity: MMS group (mild-moderate symptoms) and HS group (severe and very severe symptoms), and 17 age- and sex-matched control subjects. Sleep quality, daytime sleepiness, and the level of depression were also evaluated. RESULTS: We identified eight upregulated spots, corresponding to five unique proteins, in both RLS group vs. controls (alpha-1B-glycoprotein, alpha-1-acid glycoprotein 1, haptoglobin, complement C4-A, and immunoglobulin kappa constant); five increased spots, consistent with three unique proteins, only in HS-RLS (kininogen-1, immunoglobulin heavy constant alpha 1, and immunoglobulin lambda constant 2); one downregulated spot in both patient's groups (complement C3) and another one only in HS-RLS (alpha-1-antitrypsin). CONCLUSIONS: The significantly different plasma proteins detected in RLS were mainly associated with inflammation, immune response, and cardiovascular disorders. Particularly, the gradual increasing in immunoglobulins could be indicative of the disease severity and evolution. Accordingly, these proteins may represent a valid set of useful biomarkers for RLS diagnosis, progression and treatment. PMID- 30244533 TI - Impact of diabetes on clinical outcomes after revascularization with sirolimus eluting and biolimus-eluting stents with biodegradable polymer from the SORT OUT VII trial. AB - OBJECTIVES: In this substudy of the SORT OUT VII trial, the clinical outcomes among patient with diabetes mellitus treated with Orsiro sirolimus-eluting stent (O-SES; Biotronik, Bulach, Switzerland) or Nobori biolimus-eluting stent (N-BES; Terumo, Tokyo, Japan) were compared. BACKGROUND: Diabetes is associated with increased risk of target lesion failure (TLF) after percutaneous coronary intervention. METHODS: In total, 2525 patients were randomized to stent implantation with O-SES (n = 1261, diabetes: n = 236) or N-BES (n = 1264, diabetes: n = 235). The primary endpoint, TLF, was a composite of cardiac death, target-lesion myocardial infarction (MI), or target lesion revascularization (TLR) within 2 years. RESULTS: At 2 year, TLF did not differ between O-SES vs N BES in diabetic (9.3% vs 9.4%; RR 0.98, 95% CI 0.54-1.78) patients. The individual components of the primary endpoint did not differ among stent type. In diabetics, cardiac death occurred in 3% of O-SES-treated and in 3.8% of N-BES treated patients (RR 0.77, 95% CI 0.29-2.08), MI occurred in 3.0% of O-SES treated and in 3.8% of N-BES-treated patients (RR 0.76, 95% CI 0.28-2.06) and TLR occurred in 5,5% of O-SES-treated and in 6.0% of N-BES-treated patients (RR 0.91, 95% CI 0.43-1.95). CONCLUSION: TLF did not differ between O-SES- and N-BES treated diabetic patients. PMID- 30244535 TI - Early restenosis of resorbable magnesium scaffolds: Optical coherence tomography findings. AB - Resorbable Magnesium Scaffolds (RMS) represent an interesting alternative to current drug-eluting stents. Current data from clinical trials seems to confirm good performance of these new devices with low rates of late device failure. Little is known about mechanisms leading to RMS failure. Herein, we present the first description of an early RMS in-scaffold restenosis. Optical coherence tomography (OCT) analysis at implantation detected acute non-severe malapposition and underexpansion as main promoters of RMS failure. OCT during in-scaffold restenosis intervention confirmed early severe neointimal proliferation and RMS late recoil and dismantling as the main mechanisms of device failure. We hypothesize that the fast resorption process of RMS may lead to an early loss of radial strength, that could favor late recoil, acquired underexpansion, device dismantling and might interact with distribution of sirolimus. This case also illustrates that OCT is pivotal to unravel both acute and acquired mechanisms related to RMS failure. PMID- 30244534 TI - Further delineation of the clinical spectrum of de novo TRIM8 truncating mutations. AB - De novo mutations of the TRIM8 gene, which codes for a tripartite motif protein, have been identified using whole exome sequencing (WES) in two patients with epileptic encephalopathy (EE), but these reports were not sufficient to conclude that TRIM8 was a novel gene responsible for EE. Here we report four additional patients presenting with EE and de novo truncating mutations of TRIM8 detected by WES, and give further details of the patient previously reported by the Epi4K consortium. Epilepsy of variable severity was diagnosed in children aged 2 months to 3.5 years of age. All patients had developmental delay of variable severity with no or very limited language, often associated with behavioral anomalies and unspecific facial features or MRI brain abnormalities. The phenotypic variability observed in these patients appeared related to the severity of the epilepsy. One patient presented pharmacoresistant EE with regression, recurrent infections and nephrotic syndrome, compatible with the brain and kidney expression of TRIM8. Interestingly, all mutations were located at the highly conserved C-terminus section of TRIM8. This collaborative study confirms that TRIM8 is a novel gene responsible for EE, possibly associated with nephrotic syndrome. This report brings new evidence on the pathogenicity of TRIM8 mutations and highlights the value of data-sharing to delineate the phenotypic characteristics and biological basis of extremely rare disorders. PMID- 30244537 TI - Is PNPT1-related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1-related disorders. AB - PNPT1 is a mitochondrial RNA transport protein that has been linked to two discrete phenotypes, namely isolated sensorineural hearing loss (OMIM 614934) and combined oxidative phosphorylation deficiency (OMIM 614932). The latter has been described in multiple families presenting with complex neurologic manifestations in childhood. We describe adult siblings with biallelic PNPT1 variants identified through WES who presented with isolated severe congenital sensorineural hearing loss (SNHL). In their 40s, they each developed and then followed a nearly identical neurodegenerative course with ataxia, dystonia, and cognitive decline. Now in their 50s and 60s, all have developed the additional features of optic nerve atrophy, spasticity, and incontinence. The natural history of the condition in this family may suggest that the individuals previously reported as having isolated SNHL may be at risk of developing multisystem disease in late adulthood, and that PNPT1-related disorders may constitute a spectrum rather than distinct phenotypes. PMID- 30244536 TI - A mosaic intragenic microduplication of LAMA1 and a constitutional 18p11.32 microduplication in a patient with keratosis pilaris and intellectual disability. AB - The application of array-based comparative genomic hybridization and next generation sequencing has identified many chromosomal microdeletions and microduplications in patients with different pathological phenotypes. Different copy number variations are described within the short arm of chromosome 18 in patients with skin diseases. In particular, full or partial monosomy 18p has also been associated with keratosis pilaris. Here, for the first time, we report a young male patient with intellectual disability, diabetes mellitus (type I), and keratosis pilaris, who exhibited a de novo 45-kb microduplication of exons 4-22 of LAMA1, located at 18p11.31, and a 432-kb 18p11.32 microduplication of paternal origin containing the genes METTL4, NDC80, and CBX3P2 and exons 1-15 of the SMCHD1 gene. The microduplication of LAMA1 was identified in skin fibroblasts but not in lymphocytes, whereas the larger microduplication was present in both tissues. We propose LAMA1 as a novel candidate gene for keratosis pilaris. Although inherited from a healthy father, the 18p11.32 microduplication, which included relevant genes, could also contribute to phenotype manifestation. PMID- 30244538 TI - Percutaneous melody valve implantation in a native tricuspid valve following failed surgical repair. AB - Transcatheter valve-in-valve and valve-in-ring implantation has become a common approach to treating patients with failed bioprosthetic tricuspid valves as well as failed surgical repairs of the tricuspid valve where an annuloplasty ring has been utilized. We describe a case where a Melody valve was percutaneously implanted in a native tricuspid valve with severe stenosis following surgical repair without a supporting annuloplasty ring. PMID- 30244539 TI - Outcome of staged percutaneous coronary intervention within two weeks from admission in patients with ST-segment elevation myocardial infarction with multivessel disease. AB - BACKGROUND: The optimum timing of revascularization strategy for stenoses in nonculprit vessels in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD) remains unclear. At present, there is no evidence investigating the outcome of staged percutaneous coronary intervention (PCI) within two weeks from admission among STEMI patients with MVD. METHODS: A total of 210 STEMI patients with MVD who underwent primary PCI were analyzed. We compared the all-cause mortality and major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, heart failure, unstable angina, and stroke) with median follow-up of 1200 days among the patients who underwent staged PCI within two weeks from admission (staged PCI <=2 W) (n = 75), staged PCI after two weeks from admission (staged PCI >2 W) (n = 37) and culprit-only PCI (n = 98) in patients with STEMI and MVD. RESULTS: The staged PCI <=2 W showed lower all-cause mortality than culprit-only PCI (4.0 vs 29.6%, log-rank P = 0.001), and lower incidence of MACE than the staged PCI >2 W group (1.3 vs 18.9%, log-rank P = 0.001) and culprit-only PCI group (1.3 vs 22.5%, log-rank P = 0.001). In the multivariable Cox regression analysis, the staged PCI <=2 W was a predictor of lower all-cause mortality (hazard ratio [HR], 0.176; 95% confidence interval [CI], 0.049-0.630; P = 0.008) and lower incidence of MACE (HR, 0.068; 95% CI, 0.009-0.533; P = 0.011), but staged PCI >2 W was not. CONCLUSION: In conclusion, staged PCI within two weeks after admission showed more favorable outcomes compared with staged PCI after two weeks from admission or culprit-only PCI in STEMI patients with MVD. PMID- 30244540 TI - Radial vs femoral access for the prevention of acute kidney injury (AKI) after coronary angiography or intervention: A systematic review and meta-analysis. AB - OBJECTIVES: We sought to investigate the impact of radial vs femoral access on the incidence of acute kidney injury (AKI) after coronary angiography or intervention. BACKGROUND: There is a growing recognition of the importance of access site selection as an adjudicative measure to mitigate the risk of renal impairment for patients with coronary artery disease undergoing angiography with or without percutaneous coronary intervention. METHODS: We conducted a systematic review of the literature and meta-analyzed available evidence comparing the rates of AKI with radial vs femoral access in patients undergoing coronary angiography or intervention. Studies reporting the incidence of AKI as a primary or secondary outcome were pooled in fixed- and random-effects meta-analyses and meta regression techniques were used to account for across-study heterogeneity. RESULTS: Across data pooled from nine studies (n = 32 181), radial access was significantly associated with a reduction in the incidence of AKI (OR 0.57, 95% CI 0.50 to 0.66, P < 0.0001 with fixed-effects model, OR 0.55, 95% CI 0.45 to 0.67, P < 0.0001 with random-effects model) as compared to femoral. In the meta regression model, the effect size of radial access effect was related to the number of centers in which studies were conducted. CONCLUSIONS: Compared with the femoral approach, radial access was associated with a lower incidence of AKI after coronary angiography or intervention, although this benefit was less pronounced in multicenter than in single-center studies. PMID- 30244541 TI - Buddy-wire technique during rotational Atherectomy: Simple and effective solution to achieve strong back-up support. AB - A 52-year-old male underwent percutaneous coronary intervention (PCI) using rotational atherectomy (RA: 1.5-mm burr) for a severely calcified lesion in the proximal to mid obtuse marginal (OM) branch. Even with 7 Fr extra back-up guiding catheter via femoral access, the burr could not cross the lesion due to insufficient back-up support. In order to achieve stronger back-up support, we kept the burr at the position in the OM branch and placed a supportive wire in left anterior descending artery through the side of drive-shaft sheath of the Rotablator, which sufficiently stabilized the guiding catheter during the ablation and the burr crossed the lesion. This case demonstrates that a simple technique of placing additional supportive wire in the other vessel during RA could be an effective and safe solution to facilitate improved back-up support without necessity to change the PCI system used already. PMID- 30244543 TI - A hybrid technique for treatment of commissural primary mitral regurgitation. AB - BACKGROUND: MitraClip is an effective transcatheter therapy for mitral regurgitation (MR). However, MitraClip is challenging in commissural MR and the optimal therapeutic approach is unclear. METHODS: We describe a case series of six consecutive patients with severe commissural primary mitral regurgitation who underwent MitraClip insertion followed by an Amplatzer Vascular Plug (AVP) II occluder between the commissure and the MitraClip. RESULTS: The procedure was successful in all patients. MR was reduced from severe to mild/trivial in 50% and moderate in 50% of cases. On 30-day follow-up, NYHA class had improved from III (6 patients) to I (2 patients), II (2 patients), and III (2 patients). The mean transmitral gradient was 2.5 +/- 1.8 mmHg at baseline and 4.8 +/- 2.6 mmHg following the procedure. One patient developed hemolysis immediately post procedure. The other five patients remained well during a median follow-up of 20 months (range 5-50 months) with no reported device dislodgement. CONCLUSIONS: Elective treatment of severe commissural MR with a laterally or medially placed MitraClip coupled with an AVP II occluder between the clip and the commissure is feasible and safe. This approach may provide a useful management alternative in selected patients. PMID- 30244542 TI - Phenotypic and molecular insights into PQBP1-related intellectual disability. AB - We report two discordant clinical and imaging features in four male patients from two unrelated families of Egyptian descent with hemizygous pathogenic variants in PQBP1. The three patients of the first family displayed the typical features underlying PQBP1 such as the long triangular face, bulbous nose, hypoplastic malar region, and micrognathia, which were subsequently confirmed using targeted sequence analysis that showed a previously reported nonsense mutation c.586C>T p.R196*. Whole exome sequencing identified a novel missense PQBP1 variant c.530G>A:p.R177H in the second family, in which the index patient presented with intellectual disability and dysmorphic facial features reminiscent of Kabuki-like syndrome and his brain magnetic resonance imaging revealed partial agenesis of corpus callosum, mild vermis, and brainstem hypoplasia. These imaging features are distinct from the previously described with a well-known phenotype that is already known for PQBP1. This report expands the phenotypic spectrum of PQBP1 related disorders and is the second reported missense PQBP1 variant. Further, it highlights the possible role of PQBP1 in hindbrain development. PMID- 30244544 TI - The association between Cytomegalovirus co-infection with Pneumocystis pneumonia and mortality in immunocompromised non-HIV patients. AB - INTRODUCTION: Impact of Cytomegalovirus (CMV) co-infection pneumonia in non-HIV patients with Pneumocystis jirovecii pneumonia (PCP) is unclear. OBJECTIVES: The aim of our study was to determine whether CMV co-infection is associated with an increased risk of mortality. METHODS: Our study was conducted at Ege University Hospital, Turkey. We used molecular assays to diagnose Pneumocystis jirovecii in respiratory samples, and CMV in both respiratory and blood samples. We compared morbidity and mortality stratified by CMV co-infection status. RESULTS: Between 2009 and 2015, 43 patients (mean age: 56.7 +/- 15.3 years) were diagnosed with PCP. Only 3 of 43 patients had received PCP prophylaxis. We microbiologically confirmed CMV co-infection in 28 of 43 (65.1%) patients. Acute respiratory distress syndrome (ARDS) and requirement of mechanical ventilation were more common in the CMV co-infection group (P = .019 and P = .031 respectively), and duration of intensive care unit was also longer (P = .006). In univariate analyses, mortality at 30 days was higher in the CMV co-infection group as compared to the group with PCP alone (78.6% and 46.7% respectively; P = .046). In multivariate analyses, mortality was independently associated only with the presence of ARDS [OR: 6.22 95% CI 1.3-29.32] and the association with CMV co infection was no longer significant [OR: 2.6 95% CI 0.49-13.72, P = .257]. CONCLUSION: The risk of mortality appears to be increased in the setting of CMV and PCP co-infection in HIV-uninfected immunocompromised patients. PCP prophylaxis use was lower than expected, suggesting low physician awareness of the risks of PCP in this population. PMID- 30244545 TI - Thrombocytopenia after transcatheter aortic valve implantation. A comparison between balloon-expandable and self-expanding valves. AB - BACKGROUND: Thrombocytopenia after transcatheter aortic valve implantation (TAVI) is common and has been related to higher mortality and major complications. No comparison between balloon-expandable (BEV) and self-expanding valves (SEV) regarding drop platelet count (DPC) has been reported to date. The objectives of this study were to analyze the differences in DPC between BEVs or SEVs and their prognostic implications in clinical outcomes. METHODS: We retrospectively analyzed patients undergoing TAVI. Platelet counts after TAVI were collected. Two groups were created: DPC <= 30% and DPC > 30%. VARC-2 criteria were used to define outcomes. RESULTS: Study population was composed of 195 patients (age 77.5 +/- 6.7, 57.4% males). All of them but one experienced DPC (mean DPC 31.9 +/- 15.3%). DPC was significantly higher among the patients treated with BEV compared to those treated with SEV (36.3 +/- 15.1% vs 27.7 +/- 14.4, P < 0.001). After multivariate analysis, the use of BEV was independently associated with a higher rate of DPC > 30% (67.4% vs 36.0%; OR 3.4; 95% CI, 1.42-8.16). At 30 days, the DPC > 30% was associated with a higher rate of life-threatening/major bleeding, major vascular complications, in-hospital sepsis and mortality. At one year, there were no statistically significant differences in the mortality rate between groups (6.35% vs 10.0%, HR 1.54; 95% CI, 0.56-4.25). CONCLUSIONS: In this study, the use of BEV was associated with a higher risk of DPC after TAVI. A DPC rate > 30% was associated with an increased risk of major complications at 30 days. PMID- 30244546 TI - Comparison of 3-year clinical outcomes after endovascular therapy for aortoiliac artery occlusive disease between patients with and without hemodialysis: Subanalysis of the REAL-AI registry. AB - PURPOSE: The impact of hemodialysis (HD) on aortoiliac (AI) occlusive lesions remains unknown. Here, we report the 3-year clinical outcomes of endovascular treatment (EVT) for AI occlusive lesions in propensity-matched populations of patients who did and did not undergo HD. METHODS: The cohort of this large-scale, multicenter, retrospective registry study included 574 consecutive patients with AI occlusive disease. Propensity score-matched analysis was performed to compare AI occlusive lesions between patients who did and did not undergo HD. The endpoints were primary patency, assisted primary patency, and secondary patency as well as overall survival and major adverse limb events (MALEs). RESULTS: A total of 57 matched pairs of patients who did and did not undergo HD were analyzed after propensity score-matched analysis. No significant difference was observed in primary patency, assisted primary patency, secondary patency, and MALEs at 3 years. The survival rate was significantly lower in the HD group than in the without-HD group (68% vs. 93%, P = 0.03). CONCLUSIONS: Although the survival rate of HD patients was poor, the results of EVT for AI occlusive lesions were reasonable in these patients. PMID- 30244547 TI - Dermal fiber structures and photoaging. AB - The use of multiphoton imaging has become a standard technique to visualize the dermis fibers as it requires no specific staining. The density and organization of collagen and elastin are common markers of skin intrinsic aging and photoaging; thus, there is a need of grading this skin aging with quantitative indicators able to provide a robust evaluation of the dermis fibers' state. We propose a systematic analysis of multiphoton images of skin biopsies taken on the buttock and the forearm of patients of different ages. The intensity histograms of images were analyzed through their moments, a wavelet decomposition was done, and the wavelet coefficients distribution was fitted by a generalized Gaussian distribution. Different parameters relative to the collagen or elastin densities, organizations, and structures were calculated and exhibit phenomena specific to intrinsic or extrinsic aging. Those indicators could become a standard method to analyze the degree of skin aging (intrinsic or extrinsic) through multiphoton imaging. PMID- 30244548 TI - Doctor, my armpit hair has turned yellow! Malodorous yellowish axillary hair in an adolescent patient. PMID- 30244550 TI - Neurology. PMID- 30244549 TI - Primary care and neurological disorders. PMID- 30244551 TI - Multidisciplinary management of motor neurone disease. AB - BACKGROUND: Motor neurone disease (MND) is the term for a group of progressive, debilitating, neurodegenerative disorders that affect various aspects of a patient's life, including speech, swallowing, breathing and limb function. OBJECTIVE: This review outlines the common symptoms and issues in MND and the latest available treatment options. A multidisciplinary approach to MND, involving the general practitioner (GP) and rehabilitation, palliative care and allied health services, is discussed. DISCUSSION: The complexity of care for patients with MND and their families is best managed using a multidisciplinary team approach, with the GP as an important member of that team. The biopsychosocial care model discussed can improve the quality of life for patients and carers, as well as the life expectancy of patients with MND. PMID- 30244552 TI - Workforce issues of general practice in a developing country: Pakistan. AB - BACKGROUND: Pakistan is a developing country that has a double burden of communicable and non-communicable disease. Healthcare reform is required to combat these prevailing healthcare issues with the 'family medicine approach' to primary care. Developing a workforce of trained general practitioners (GPs) to implement this approach is essential but challenging, yet there are success stories not only from developed countries but also from a few developing countries. OBJECTIVE: General practice is a specialty that has been recognised only recently in Pakistan. This article reviews the challenges of developing a workforce of trained GPs for primary care and proposes solutions to address the gap. DISCUSSION: Involving all stakeholders and organisations related to the specialty of general practice, integrating the subject of family medicine at an undergraduate level and encouraging postgraduate training and capacity-building through on-the-job training of GPs working in rural and urban primary care are all essential to develop a workforce of trained GPs in Pakistan. At the same time, standardisation and accreditation of primary care sites for training and research through public-private partnership are recommended. PMID- 30244555 TI - A GP primer on incisional hernia. AB - BACKGROUND: Incisional hernias are often overlooked as a source of morbidity in post-surgical patients. OBJECTIVE: Drawing on evidence-based literature and personal clinical experience, this article seeks to provide information relevant to general practitioners (GPs) encountering patients with incisional hernias. DISCUSSION: Drawing on evidence-based literature and personal clinical experience, this article seeks to provide information relevant to GPs encountering patients with incisional hernias. PMID- 30244553 TI - Insights into the management of chronic hepatitis C in primary care using MedicineInsight. AB - BACKGROUND AND OBJECTIVES: Direct-acting antivirals (DAAs) became available for patients with chronic hepatitis C (CHC) in primary care in March 2016, yet not all patients will have undergone pre-treatment assessment. The aim of this study was to assess where patients with CHC are situated in the diagnosis and care continuum, to encourage general practitioners (GPs) to improve pretreatment assessment and increase DAA treatment uptake. METHOD: This was a cross-sectional study of 4025 adult patients with CHC first recorded between 2013 and 2017, using the general practice data program MedicineInsight. RESULTS: Only half of all patients with confirmed CHC had a hepatitis C virus qualitative RNA recorded, and few patients had all recommended pretreatment assessments. The majority had low aspartate aminotransferase to platelet ratio index (APRI) scores. DISCUSSION: Incomplete pretreatment assessment is likely to be a reflection of the recent shift in management of CHC to primary care. The majority of patients have APRI results that suggest cirrhosis is unlikely, and they are potentially suitable for treatment in primary care. This highlights a substantial opportunity for GPs to recall patients for further assessment and treatment. PMID- 30244556 TI - Low back pain: Can we mitigate the inadvertent psycho-behavioural harms of spinal imaging? AB - BACKGROUND: Low back pain is responsible for significant personal and societal burden, particularly when it becomes persistent. Despite international consensus regarding the judicious use of diagnostic spinal imaging, patients continue to be over-referred. OBJECTIVE: The aim of this article is to highlight the critical need for primary care clinicians to engage in thoughtful use of imaging procedures, and to consider alternative or adjunct methods for providing reassurance, in order to avoid or mitigate the potential negative impact of 'anomalous' findings. DISCUSSION: While imaging is frequently requested with the goal of reassuring patients, it can paradoxically have a negative impact on patient attitudes and beliefs and can influence pain behaviours. For improved patient outcomes we recommend contextualisation of radiological findings within age-related norms, use of reassuring and non-threatening language when communicating results, and educating patients on non-pathoanatomical contributors to pain. PMID- 30244557 TI - Improving early detection of developmental dysplasia of the hip through general practitioner assessment and surveillance. AB - BACKGROUND: Cases of late diagnosed developmental dysplasia of the hip (DDH) have increased in Australia in recent years despite an ongoing clinical screening program and increasing use of selective ultrasonography screening. OBJECTIVE: The aim of this paper is to discuss an evidence-based approach that involves prevention and early detection of DDH using assessment and surveillance that is suitable for general practitioners (GPs) who see young children in their practices. DISCUSSION: Repeated, carefully performed clinical examinations of the paediatric hip from newborn to walking age remain the best method for early detection of DDH. GPs are ideally placed to conduct regular assessments to maximise detection of dislocated hips in early infancy and lower the age at detection for children who develop progressive signs of DDH outside the newborn period. PMID- 30244558 TI - Botulinum neurotoxin for the treatment of movement disorders. AB - BACKGROUND: Botulinum neurotoxin (BoNT) is an exotoxin that causes neuromuscular weakness. BoNT serotypes A and B have been used for decades for the safe and effective treatment of various movement disorders, including some forms of focal dystonia. These conditions, such as cervical dystonia, hemifacial spasm, blepharospasm and spasmodic dysphonia, can have a substantial impact on patients' quality of life, but are often under-recognised. OBJECTIVE: The aim of this article is to describe the usefulness of BoNT for the treatment of movement disorders, including a description of its mechanism of action, mode of administration, indications and evidence of benefit. DISCUSSION: General practitioners have a vital role in the identification of patients with potentially treatable movement disorders such as cervical dystonia. Treatment with BoNT can improve patients' function, reduce pain and improve workforce participation. Patients require ongoing periodic injections by a trained neurologist to obtain long-term benefits with minimal side effects. PMID- 30244560 TI - September correspondence. PMID- 30244559 TI - Office-based assessment of cognitive impairment. AB - BACKGROUND: Dementia is an increasingly prevalent condition, currently affecting over 400,000 Australians, and this is expected to rise to over one million by 2056. Diagnosis of dementia is a clinical one, as there is no single well-defined blood test, imaging or cognitive function test that validly diagnoses dementia. There are also many causes of cognitive impairment other than dementia, which need to be identified or excluded. General practitioners (GPs) are on the frontline of presentation and will therefore play an increasingly important role in identification and management. OBJECTIVE: This article reviews what the GP can do in relation to office-based assessment for cognitive impairment. DISCUSSION: Dementia is an increasingly common condition, and it is important that GPs become familiar with its assessment and management in order to optimise access to care services, advance care planning and management of other conditions for their patients. PMID- 30244561 TI - Achieving optimal self-management in hereditary haemochromatosis: Results from a community questionnaire. AB - BACKGROUND AND OBJECTIVES: Hereditary haemochromatosis is a chronic inherited iron overload disorder that is primarily treated with venesection. The aim of this study was to investigate factors associated with optimal haemochromatosis self-management. METHOD: A national online questionnaire was developed. Questions covered demographics, and individual haemochromatosis history and management. The theory of planned behaviour also guided question development. Two logistic regression models were developed for the binary outcomes of serum ferritin within target range and intention to continue venesection. RESULTS: There were 378 complete responses collected. Questions measuring factors of importance (P = 0.022; odds ratio [OR]: 2.284; 95% confidence interval [CI]: 1.125, 4.637), preventing complications (P = 0.017; OR: 2.967; 95% CI: 1.211, 7.265), feeling involved with doctors' decisions (P = 0.006; OR: 1.482; 95% CI: 1.121, 1.958) and control of iron levels (P <0.001; OR: 1.868; 95% CI: 1.399, 2.493) were positively associated with dependent variables. Significant factors related to having a positive attitude and perceived control over haemochromatosis management. DISCUSSION: A positive attitude and sense of behavioural control contribute to successful self-management. Doctors are in an important position to provide self-management support and education. PMID- 30244562 TI - Incidence of allergic rhinitis in children with residual snoring and sleep symptoms after adenotonsillectomy. AB - BACKGROUND AND OBJECTIVES: Allergic rhinitis may contribute to sleep disordered breathing (SDB) in children. Although adenotonsillectomy is commonly performed to treat SDB, some patients will return to their primary practitioners with residual sleep symptoms. The aim of this study was to assess the incidence of allergic rhinitis via radioallergosorbent testing (RAST) in children undergoing adenotonsillectomy who had residual snoring or sleep symptoms. METHOD: A retrospective analysis of 500 patients post-adenotonsillectomy was undertaken. The incidence of residual snoring, residual sleep symptoms and results of RAST, as well as total immunoglobulin E (IgE) after surgical intervention, were documented. RESULTS: Children with positive RAST results or elevated total IgE had a significantly greater incidence of residual snoring post-adenotonsillectomy (P = 0.049) and residual sleep symptoms after surgery (P <0.0001). DISCUSSION: A positive RAST or elevated IgE in children with SDB was associated with incomplete resolution of snoring and residual sleep symptoms after adenotonsillectomy. Thus, there should be raised suspicion of allergic rhinitis in this population. PMID- 30244563 TI - The influence of therapeutic alliance on adult obesity interventions in primary care: A systematic review protocol. AB - BACKGROUND AND OBJECTIVES: Obesity is a common chronic condition, and general practitioners are seeking more effective strategies for assisting their patients. The therapeutic relationship between patients and practitioners is increasingly recognised as a fundamental part of intervention effectiveness. The influence of therapeutic relationships in obesity interventions in primary care has not been systematically studied. We plan to undertake a systematic review and meta analysis to identify the influence of the therapeutic alliance on the effectiveness of obesity interventions in primary healthcare. The aim of this article is to outline the study protocol. METHOD: A systematic review of primary care interventions for patients with obesity will be undertaken. Using Bordin's framework for the therapeutic alliance, interventions will be categorised as to whether they incorporate the alliance or not. A meta-analysis will be performed if studies of sufficiently homogenous primary outcome data are found. DISCUSSION: Understanding the role of the therapeutic alliance on interventions for obesity management will have implications for both future intervention development and the translation of current interventions from trial settings to the real world. PMID- 30244564 TI - Current approaches to the pharmacological treatment of Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease is the most common form of dementia and is a major contributor to morbidity and mortality in older Australians. OBJECTIVE: The aim of this article is to provide an overview of available pharmacological therapies for the symptomatic treatment of Alzheimer's disease. DISCUSSION: Acetylcholinesterase inhibitors (AChEIs) or memantine may be trialled in people with Alzheimer's disease to delay symptoms of cognitive and functional decline. The choice of pharmacological agent is based on the stage of Alzheimer's disease, tolerability, adverse effect profile, ease of use and cost. People should be monitored for efficacy, side effects and possible treatment discontinuation. Strategies should be used to optimise medication management and adherence. Evidence for other pharmacological therapies is mixed or lacking. Behavioural and psychological symptoms of dementia (BPSD) are common in people with Alzheimer's disease and may respond to symptomatic pharmacological and non-pharmacological treatment. PMID- 30244565 TI - Discovery of a Photoinduced Dark Catalytic Cycle Using in Situ LED-NMR Spectroscopy. AB - We report the use of LED-NMR spectroscopy to study the reaction mechanism of a newly discovered photoinduced iron-catalyzed cycloisomerization of alkynols to cyclic enol ethers. By understanding on/off ligand binding to the catalyst, we were able to appropriately design reaction conditions to balance catalyst activity and stability. LED-NMR was demonstrated to be a powerful tool in elucidating reaction mechanisms of photochemical reactions. Temporal NMR spectroscopic data under visible light illumination (1) revealed the pre-catalyst activation mechanism, (2) proved that photon flux provides a unique external control of the equilibrium distribution between the pre-catalyst and active catalyst, and ultimately the rate of reaction, (3) provided information about the reaction driving forces and the turnover-limiting step, and (4) enabled both real time structural and kinetic insights into elusive species (e.g., dissolved gases). PMID- 30244567 TI - Mechanistically Guided Design of Ligands That Significantly Improve the Efficiency of CuH-Catalyzed Hydroamination Reactions. AB - Using a mechanically guided ligand design approach, a new ligand (SEGFAST) for the CuH-catalyzed hydroamination reaction of unactivated terminal olefins has been developed, providing a 62-fold rate increase over reactions compared to DTBM SEGPHOS, the previous optimal ligand. Combining the respective strengths of computational chemistry and experimental kinetic measurements, we were able to quickly identify potential modifications that lead to more effective ligands, thus avoiding synthesizing and testing a large library of ligands. By optimizing the combination of attractive, noncovalent ligand-substrate interactions and the stability of the catalyst under the reaction conditions, we were able to identify a finely tuned hybrid ligand that greatly enables accelerated hydrocupration rates with unactivated alkenes. Moreover, a modular and robust synthetic sequence was devised, which allowed for the practical, gram-scale synthesis of these novel hybrid ligand structures. PMID- 30244566 TI - Electrocatalytic Nanoparticles That Mimic the Three-Dimensional Geometric Architecture of Enzymes: Nanozymes. AB - Enzymes are characterized by an active site that is typically embedded deeply within the protein shell thus creating a nanoconfined reaction volume in which high turnover rates occur. We propose nanoparticles with etched substrate channels as a simplified enzyme mimic, denominated nanozymes, for electrocatalysis. We demonstrate increased electrocatalytic activity for the oxygen reduction reaction using PtNi nanoparticles with isolated substrate channels. The PtNi nanoparticles comprise an oleylamine capping layer that blocks the external surface of the nanoparticles participating in the catalytic reaction. Oxygen reduction mainly occurs within the etched channels providing a nanoconfined reaction volume different from the bulk electrolyte conditions. The oxygen reduction reaction activity normalized by the electrochemically active surface area is enhanced by a factor of 3.3 for the nanozymes compared to the unetched nanoparticles and a factor of 2.1 compared to mesoporous PtNi nanoparticles that possess interconnecting pores. PMID- 30244568 TI - Using Polyurethane Foam-Based Passive Air Sampling Technique to Monitor Monosaccharides at a Regional Scale. AB - Monosaccharides are important tracers of pollution aerosol from biomass burning. Air sampling of monosaccharides is often conducted using active samplers. However, applicability of sampling monosaccharides using polyurethane foam passive air samplers (PUF-PASs) has not been investigated, since passive air samplers are often applied to monitor semivolatile organic contaminants in large scale and remote area. Our study successfully collected atmospheric monosaccharides using PUF-PASs, providing a valuable tool for monosaccharides sampling. PUF-PAS sampling rates for individual monosaccharides were calibrated using an active sampler for 92 days, and were 1.1, 1.5, and 1.1 m3/d for levoglucosan, mannosan, and galactosan, respectively. Degradation of monosaccharides in PUF-PAS was demonstrated to be negligible by spike test of 13C labeled levoglucosan. Furthermore, passive sampling was carried out at 11 sites in the Pearl River Delta of Southern China from January to April and July to September of 2015. Monosaccharide concentrations derived from PUF-PASs were comparable with the reported data obtained by active sampling, demonstrating that the PUF-PAS approach is valid for monosaccharides monitoring. On the basis of our approach, we found that there is a clear correlation between the monosaccharide concentrations and the MODIS fire activities during January-April. PMID- 30244569 TI - Molecular Recognition of Hydrophilic Molecules in Water by Combining the Hydrophobic Effect with Hydrogen Bonding. AB - During the last half a century, great achievements have been made in molecular recognition in parallel with the invention of numerous synthetic receptors. However, the selective recognition of hydrophilic molecules in water remains a generally accepted challenge in supramolecular chemistry but is commonplace in nature. In an earlier Communication [ Huang et al. J. Am. Chem. Soc. 2016 , 138 , 14550 ], we reported a pair of endo-functionalized molecular tubes that surprisingly prefer highly hydrophilic molecules over hydrophobic molecules of a similar size and shape. The hydrophobic effect and hydrogen bonding were proposed to be responsible, but their exact roles were not fully elucidated. In this Article, we present a thorough study on the binding behavior of these molecular tubes toward 44 hydrophilic molecules in water. Principal component analysis reveals that the binding strength is weakly correlated to the hydrophobicity, volume, surface area, and dipole moment of guests. Furthermore, molecular dynamics simulations show the hydrophobic effect through releasing the poorly hydrogen-bonded cavity water contributes to the binding of all the hydrophilic molecules, while hydrogen bonding differentiates these molecules and is thus the key to achieve a high selectivity toward certain hydrophilic molecules over other molecules with a similar size and shape. Therefore, a good guest for these molecular tubes should meet the following criteria: the hydrogen-bonding sites should be complementary, and the molecular volume should be large enough to expel all the cavity water but not too large to cause steric hindrance. This rule of thumb may also be used to design a selective receptor for certain hydrophilic molecules. Following these guidelines, a "best-fit" guest was found for the syn configured molecular tube with a binding constant as high as 106 M-1. PMID- 30244570 TI - Exploring Ferredoxin-Dependent Glutamate Synthase as an Enzymatic Bioelectrocatalyst. AB - Ferredoxin-dependent glutamate synthase (Fd-GltS) is reported as an enzymatic bioelectrocatalyst for the first time. By configuring mediated electrochemical interfaces with mediators of different redox potentials, we realize bioelectrosynthesis or bioelectrooxidation of glutamate with recombinant Fd-GltS from cyanobacteria. Particularly, bioelectrocatalytic oxidation of glutamate by Fd-GltS is demonstrated to be oxygen independent. This study reinforces a new catalytic option for developing enzymatic bioelectronic devices for powering, sensing or synthesis. PMID- 30244571 TI - Fast and Highly Sensitive Detection of Pathogens Wreathed with Magnetic Nanoparticles Using Dark-Field Microscopy. AB - Cryptosporidium parvum ( C. parvum) is a highly potent zoonotic pathogen, which can do significant harm to both human beings and livestock. However, existing technologies or methods are deficient for rapid on-site detection of water contaminated with C. parvum. Better detection approaches are needed to allow water management agencies to stop major breakouts of the pathogen. Herein, we present a novel detection method for cryptosporidium in a tiny drop of sample using a magnetic nanoparticle (MNP) probe combined with dark-field microscopy in 30 min. The designed MNP probes bind with high affinity to C. parvum, resulting in the formation of a golden garland-like structure under dark-field microscopy. This MNP-based dark-field counting strategy yields an amazing PCR-like sensitivity of 8 attomolar (aM) (5 pathogens in 1 MUL). Importantly, the assay is very rapid (~30 min) and is very simple to perform as it involves only one step of mixing and magnetic separation, followed by dropping on a slide for counting under dark-field microscope. By combining the advantages of the specific light scattering characteristic of MNP probe under dark field and the selective magnetic separation ability of functionalized MNP, the proposed MNP-based dark field enumeration method offers low cost and significant translational potential. PMID- 30244572 TI - In Situ Fabrication of a Nickel/Molybdenum Carbide-Anchored N-Doped Graphene/CNT Hybrid: An Efficient (Pre)catalyst for OER and HER. AB - Despite the recent promise of transition metal carbides as nonprecious catalysts for the hydrogen evolution reaction (HER), their extension to the oxygen evolution reaction (OER) to achieve the goal of overall water splitting remains a significant challenge. Herein, a new Ni/Mo xC (MoC, Mo2C) nanoparticle-supported N-doped graphene/carbon nanotube hybrid (NC) catalyst is developed via a facile, one-step integrated strategy, which can catalyze both the HER and OER in an efficient and robust manner. The catalyst affords low overpotentials of 162 and 328 mV to achieve a current density of 10 mA/cm2 for HER and OER, respectively, in alkaline medium, which either compares favorably or exceeds most of the Mo based catalysts documented in the literature. It is believed that there is an electronic synergistic effect among Mo xC, Ni, and NC, wherein a tandem electron transfer process (Ni -> Mo xC -> NC) may be responsible for promoting the HER as well as OER activity. This work opens a new avenue toward the development of multicomponent, highly efficient but inexpensive electrocatalysts for overall water splitting. PMID- 30244574 TI - Site-Selective Ni-Catalyzed Reductive Coupling of alpha-Haloboranes with Unactivated Olefins. AB - A mild, chemo- and site-selective catalytic protocol that allows for incorporating an alkylboron fragment into unactivated olefins is described. The use of internal olefins enables C-C bond-formation at remote sp3 C-H sites, constituting a complementary and conceptually different approach to existing borylation techniques that are currently available at sp3 centers. PMID- 30244573 TI - Black Sesame Seeds Ethanol Extract Ameliorates Hepatic Lipid Accumulation, Oxidative Stress, and Insulin Resistance in Fructose-Induced Nonalcoholic Fatty Liver Disease. AB - The aim of the present study was to investigate the effect of black sesame seeds ethanol extract (BSSEE) against nonalcoholic fatty liver disease (NAFLD) in fructose-fed mice. Mice were fed a standard diet without or with 30% fructose in drinking water for 8 consecutive weeks, while mice in three BSSEE tested groups received different doses of BSSEE (0.5, 1, and 2 mL/kg) once a day from the fifth week to the eighth week. Administration of BSSEE dose-dependently exerted antiobesity and protective effect against metabolism disorder in fructose-fed mice. Histological examinations indicated that administration of BSSEE obviously reduced hepatic lipid accumulation. Insulin tolerance test (ITT) and glucose tolerance test (GTT) along with decreases of serum insulin and glucose levels by BSSEE treatment suggested the improvement of body insulin resistance, and administration of 1 and 2 mL/kg BSSEE mitigated liver insulin resistance as the evidence of downregulated expression of phospho-JNK1/2/3, phospho-NF-kappaB p65, phospho-IRS1, and phospho-IKK alpha/beta, up-regulated XBP1 expression, and reductions of TNF-alpha and IL-6 levels. In addition, BSSEE treatment ameliorated hepatic oxidative stress through increasing GSH, vitamin C, and Nrf2 levels, decreasing MDA and NO levels, and enhancing SOD, CAT, and GSH-Px activities. These results demonstrated that BSSEE showed protective effects against NAFLD related metabolic diseases in fructose-fed mice. Therefore, BSSEE may be a potent dietary supplement to ameliorate the diseases. PMID- 30244575 TI - Field Evaluation and In-Situ Stress-Testing of the Organic-Diffusive Gradients in Thin-Films Passive Sampler. AB - The organic-diffusive gradients in thin-films (o-DGT) technique has emerged as a promising aquatic passive sampler that addresses many of the challenges associated with current sampling tools used for measurement of polar organic contaminants. This study represents the first comprehensive field evaluation of the o-DGT in natural surface waters, across a wide suite of polar pharmaceuticals and pesticides. We explore the utility and limitations of o-DGT as a quantitative measurement tool compared to grab sampling and the polar organic chemical integrative sampler (POCIS) across four connected agricultural and wastewater influenced freshwater systems spanning 600 km from the U.S. border to northern Manitoba, Canada. Overall, the suite of analytes detected with o-DGT and POCIS were similar. Concentrations in water estimated using o-DGT were greater than concentrations estimated from POCIS in 71 of 80 paired observations, and on average, the estimates from o-DGT were 2.3-fold higher than estimates from POCIS. Grab sample concentrations suggested that the systematic underestimation with POCIS were largely a result of sampling rate variation related to flow-rate and boundary-layer effects, an issue reported consistently in the POCIS literature. These comprehensive measurements in an agriculturally-influenced fast-flowing river, long-term sampling (>40 days) in a large dilute lake system, deployments in wastewaters, and under-ice at near-freezing temperatures represent effective stress-testing of o-DGT under representative and challenging conditions. Overall, its strong performance and improved accuracy over POCIS supports its use as a robust, quantitative, and sensitive measurement tool for polar organic chemicals in aquatic systems. PMID- 30244577 TI - Mechanisms of Antioxidant Activities of Fullerenols from First-Principles Calculation. AB - Fullerenols possess excellent antioxidant activity, in which they can scavenge all of the major physiologically relevant reactive oxygen species (ROS). However, the underlying ROS-scavenging mechanisms of C60 fullerenols are not completely understood. Using density functional theory calculations, we investigated *OH-, O2*--, and H2O2-scavenging mechanisms of C60 fullerenols and the correlations between hydroxyl distributions and radical-scavenging ability. For scavenging *OH and O2*-, H* donation and electron transfer via hydrogen bonds, respectively, are the dominant mechanisms for C60 fullerenols. Although the obtained fullerenols simultaneously contain radicals and anions, there is an isolated OH anion which possesses the activity of eliminating H2O2. The *OH-scavenging activity depends on the distribution of hydroxyls according to the calculations for ten C60(OH)24 isomers. Fullerenols, in which the distribution of hydroxyls leads to low redox potential (epsilon) values, possess high scavenging activity. For the nonmagnetic fullerenols, activity relies on the number of sp2 substructures, in which the greater their number is, the lower the activity of the fullerenols. The results will be of fundamental importance in understanding the antioxidant activities of fullerenols. PMID- 30244576 TI - Lipid-Lowering Effects of Medium-Chain Triglyceride-Enriched Coconut Oil in Combination with Licorice Extracts in Experimental Hyperlipidemic Mice. AB - Coconut oil has gained in popularity over recent years as a healthy oil due to its potential cardiovascular benefits. Coconut oil contains medium chain triglycerides (MCT) including lauric acid and capric acid that display beneficial properties in human health. Licorice ( Glycyrrhiza uralensis) is used as a sweetener and in traditional Chinese medicine with anti-inflammatory, antimicrobial, and antioxidant activities. This study investigated the in vivo effects of medium chain-triglycerides (MCT)-coconut oil (MCO) and its combination with licorice extract (LE-MCO) on serum lipid profile, hepatic steatosis, and local fat pad proteins in diet-induced obese mice. No liver toxicity was observed in 45% fat diet (HFD)-fed mice orally treated with LE, MCO, and LE-MCO for 12 weeks. Their supplementation reduced HFD-enhanced body weight, blood glucose, and insulin in mice. Plasma levels of both PLTP and LCAT were boosted in LE-MCO administered mice. Supplementation of LE-MCO diminished plasma levels of TG and TC with concomitant reduction of the LDL-C level and tended to raise blood HDL-C level compared to that of HFD alone-mice. Treatment of LE-MCO encumbered the hepatic induction of hepatosteatosis-related proteins of SREBP2, SREBP1c, FAS, ACC, and CD36 in HFD-fed mice. Substantial suppression of this induction was also observed in the liver of mice treated with MCO. Oral administration of LE-MCO to HFD mice boosted hepatic activation of AMPK and the induction of UCP-1 and FATP1 in brown fat. Conversely, LE-MCO disturbed hepatic PPAR-LXR-RXR signaling in HFD fed animals and reversed HFD-elevated epididymal PPARgamma. Collectively, oral administration of LE-MCO may impede hyperlipidemia and hepatosteatosis through curtailing hepatic lipid synthesis. PMID- 30244578 TI - Silica-Supported Sterically Hindered Amines for CO2 Capture. AB - Most studies exploring the capture of CO2 on solid-supported amines have focused on unhindered amines or alkylimine polymers. It has been observed in extensive solution studies that another class of amines, namely sterically hindered amines, can exhibit enhanced CO2 capacity when compared to their unhindered counterparts. In contrast to solution studies, there has been limited research conducted on sterically hindered amines on solid supports. In this work, one hindered primary amine and two hindered secondary amines are grafted onto mesoporous silica at similar amine coverages, and their adsorption performances are investigated through fixed bed breakthrough experiments and thermogravimetric analysis. Furthermore, chemisorbed CO2 species formed on the sorbents under dry and humid conditions are elucidated using in situ Fourier-transform infrared spectroscopy. Ammonium bicarbonate formation and enhancement of CO2 adsorption capacity is observed for all supported hindered amines under humid conditions. Our experiments in this study also suggest that chemisorbed CO2 species formed on supported hindered amines are weakly bound, which may lead to reduced energy costs associated with regeneration if such materials were deployed in a practical separation process. However, overall CO2 uptake capacities of the solid supported hindered amines are modest compared to their solution counterparts. The oxidative and thermal stabilities of the supported hindered amine sorbents are also assessed to give insight into their operational lifetimes. PMID- 30244579 TI - Mechanistic Insights into Electrochemical Nitrogen Reduction Reaction on Vanadium Nitride Nanoparticles. AB - Renewable production of ammonia, a building block for most fertilizers, via the electrochemical nitrogen reduction reaction (ENRR) is desirable; however, a selective electrocatalyst is lacking. Here we show that vanadium nitride (VN) nanoparticles are active, selective, and stable ENRR catalysts with an ENRR rate and a Faradaic efficiency (FE) of 3.3 * 10-10 mol s-1 cm-2 and 6.0% at -0.1 V within 1 h, respectively. ENRR with 15N2 as the feed produces both 14NH3 and 15NH3, which indicates that the reaction follows a Mars-van Krevelen mechanism. Ex situ X-ray photoelectron spectroscopy characterization of fresh and spent catalysts reveals that multiple vanadium oxide, oxynitride, and nitride species are present on the surface and identified VN0.7O0.45 as the active phase in the ENRR. Operando X-ray absorption spectroscopy and catalyst durability test results corroborate this hypothesis and indicate that the conversion of VN0.7O0.45 to the VN phase leads to catalyst deactivation. We hypothesize that only the surface N sites adjacent to a surface O are active in the ENRR. An ammonia production rate of 1.1 * 10-10 mol s-1 cm-2 can be maintained for 116 h, with a steady-state turnover number of 431. PMID- 30244580 TI - Nature of the Electronic and Optical Excitations of Ruddlesden-Popper Hybrid Organic-Inorganic Perovskites: The Role of the Many-Body Interactions. AB - The knowledge of the exact nature of the electronic and optical excitations of Ruddlesden-Popper organic-inorganic halide perovskites (RPPs) is particularly relevant in view of their usage in optoelectronic devices. By means of parameter free quantum-mechanical simulations, we unambiguously demonstrate the dominant role of many-body Coulomb interaction, as recently proposed by Blancon et al. Indeed, focusing on the first two terms ( n = 1,2) of the Pb-based buthylammonium series, in the form of both isolated nanosheet and repeated bulk-like quantum well, we observe large band gap renormalization and strongly bound excitons with binding energies up to ~1 eV in the thinnest isolated nanosheet. Notably, taking into account electronic correlation beyond density functional theory, we obtain exciton reduced masses similar to the corresponding 3D bulk counterpart and large Rashba splitting of the same order of the value reported by Zhai et al. in a recent experimental work. PMID- 30244581 TI - Direct Measurement of the Magnitude of the van der Waals Interaction of Single and Multilayer Graphene. AB - Vertical stacking of monolayers via van der Waals (vdW) assembly is an emerging field that opens promising routes toward engineering physical properties of two dimensional materials. Industrial exploitation of these engineering heterostructures as robust functional materials still requires bounding their measured properties so as to enhance theoretical tractability and assist in experimental designs. Specifically, the short-range attractive vdW forces are responsible for the adhesion of chemically inert components and are recognized to play a dominant role in the functionality of these structures. Here, we reliably quantify the strength of ambient vdW forces in terms of an effective Hamaker coefficient for chemical vapor deposition-grown graphene and show how it scales by a factor of two or three from single to multiple layers on standard supporting surfaces such as copper or silicon oxide. Furthermore, direct measurements on freestanding graphene provide the means to discern the interplay between the vdW potential of graphene and its supporting substrate. Our results demonstrated that the underlying substrates could be controllably exploited to enhance or reduce the vdW force of graphene surfaces. We interpret the physical phenomena in terms of a Lifshitz theory-based analytical model. PMID- 30244582 TI - Semiconductor Nanoplatelet Excimers. AB - Excimers, a portmanteau of "excited dimer", are transient species that are formed from the electronic interaction of a fluorophore in the excited state with a neighbor in the ground state, which have found extensive use as laser gain media. Although common in molecular fluorophores, this work presents evidence for the formation of excimers in a new class of materials: atomically precise two dimensional semiconductor nanoplatelets. Colloidal nanoplatelets of CdSe display two-color photoluminescence resolved at low temperatures with one band attributed to band-edge fluorescence and a second, red band attributed to excimer fluorescence. Previously reasonable explanations for two-color fluorescence, such as charging, are shown to be inconsistent with additional evidence. As with excimers in other materials systems, excimer emission is increased by increasing nanoplatelet concentration and the degree of cofacial stacking. Consistent with their promise as low-threshold gain media, amplified spontaneous emission emerges from the excimer emission line. PMID- 30244584 TI - A new paradigm for mental-health quality and safety: are we ready? AB - OBJECTIVE: Development of a Mental Health Quality and Safety Framework with co designed priority areas for improvement. METHOD: A qualitative and inductive approach was utilised, including a literature search, consultations with staff and focus groups with consumers and carers. RESULTS: Thematic analysis resulted in 32 categories, grouped into seven key themes. Combined with the evidence base, these were distilled into component parts of the Framework. CONCLUSIONS: A change in strategy and culture is required, balancing a traditionally centralised top down approach to health care governance and improvement, with a complementary localised bottom-up model that embeds improvement science principles involving frontline staff, consumers and carers. This Framework, that centres on patient safety and quality improvement, in combination with a corresponding cultural change, can enhance clinical outcomes, service efficiency, staff morale and staff retention rates. PMID- 30244583 TI - Three-Dimensional Volumetric Evaluation of the Maxillary Sinuses in Chronic Rhinosinusitis Surgery. AB - INTRODUCTION:: The objective of this study was to ascertain whether the 3 dimensional volumetric measurement method could be used for the evaluation of operative treatment results in patients with chronic rhinosinusitis. METHODS:: A total of 61 adult patients with chronic rhinosinusitis were analyzed. Cone-beam computed tomographic images of the paranasal sinuses were examined preoperatively and at 12 months postoperatively. The results were compared using the Sino-Nasal Outcome Test (SNOT-22) and the Lund-Mackay (LM) and Zinreich modified staging systems. RESULTS:: The mean change in pneumatized volumes in the maxillary sinuses after operative treatment per patient was 2.0 +/- 7.5 cm3 ( P = .146). The median for volumetric change was 0.97 cm3 (range, -11.6 to 33.6 cm3). Both the LM and Zinreich modified LM staging systems showed no change in 32 of 61 patients (53%). The alterations in patients' maxillary sinuses measured using the volumetric measurement method correlated well with changes in Zinreich's modified LM staging (-0.77, P < .01). CONCLUSIONS:: The 3D volumetric method is more sensitive in detecting small alterations in pneumatized volumes of the maxillary sinuses than Zinreich's modified LM staging and LM staging. The method correlates better with Zinreich's modified LM staging than with LM staging. PMID- 30244585 TI - Sensory hypersensitivity predicts repetitive behaviours in autistic and typically developing children. AB - The objective of this study was to examine the relationship between sensory hypersensitivity and restricted interests and repetitive behaviours associated with autism spectrum disorder and their typically-developing peers. Furthermore, the aims included the examination of the relationship across sensory modalities and various types of restricted interests and repetitive behaviours. Data were collected from the parents of 114 children: 49 of whom were diagnosed with autism spectrum disorder and 65 typically-developing children. Parents completed the Sensory Profile 2 - Child Version and the Repetitive Behaviours Questionnaire, Second Edition. The results suggested that sensory hypersensitivity is strongly related to the core autism spectrum disorder symptom of repetitive behaviours. This relationship was not specific to autism spectrum disorder; repetitive behaviours significantly increased with sensory hypersensitivity in typically developing individuals as well. This effect was consistent across all modalities in both autism spectrum disorder and typically developing groups; group differences were observed in the oral and tactile modalities. Furthermore, sensory hypersensitivity was significantly predictive of repetitive behaviours in all participants, autism spectrum disorder and typically-developing, and importantly, autism spectrum disorder diagnosis did not add any predictive influence above and beyond sensory hypersensitivity. Finally, sensory hypersensitivity was significantly predictive of all subdomains of repetitive behaviours, including repetitive motor movements, rigidity and adherence to routine, preoccupation with restricted patterns of interest and unusual sensory interests, and diagnosis added no predictive ability beyond sensory hypersensitivity. PMID- 30244586 TI - Hepatitis B Prevalence and Risk Factors in a Foreign-Born Asian and Pacific Islander Population at a Community Health Center in Hawai'i. AB - Hawai'i has one of the highest rates of liver cancer in the United States. This is in large part due to undiagnosed chronic hepatitis B (CHB) infection among foreign-born Asian and Pacific Islanders (APIs). In order to estimate the prevalence of CHB infection among foreign-born APIs in Hawai'i, the Hawai'i State Department of Health conducted a cross-sectional study from August 2013 through August 2015 of patients of a federally qualified health center serving the largest population of medically underserved APIs in the state. Among 1261 patients surveyed, the prevalence of CHB infection (based on HBsAg seropositivity) was 5.6% (71/1259). No significant differences were detected by place of birth, age, or gender; however, the adjusted prevalence ratio of CHB infection was 6.0 times higher among persons reporting household contact with hepatitis B virus compared with those without such contact. Our findings underscore the need for targeted screening of at-risk individuals and their household contacts. PMID- 30244587 TI - "Girls don't have big tummies": The experiences of weight-related discussions for children with autism spectrum disorders. AB - Children with autism spectrum disorders appear to be at a higher risk of having obesity than their typically developing peers. Although it has been recommended that healthcare providers speak to children with autism spectrum disorders about the potential health risks of unhealthy weight, no previous research has explored how healthcare providers communicate with them about this topic. The purpose of this study was to explore children's perspectives and experiences of discussing weight-related topics in healthcare consultations. Eight children were interviewed, and an interpretive phenomenological analysis informed the research approach and analysis of the data. Results indicated that weight-related discussions with healthcare providers were often met with trepidation, anxiety, anger, and frustration. Children also expressed that they experienced weight stigma in clinical visits and everyday interactions. Weight stigma was often (unwittingly) projected by healthcare providers during appointments and had debilitating effects on children. Finally, higher weights emerged as a repetitive/restricted interest, and children reported body image challenges regarding their higher weights. Frameworks and tools that are specific to the needs and abilities of children with autism spectrum disorders are needed for healthcare providers to foster positive conversations about weight-related topics in an effort to promote lifelong wellness. PMID- 30244588 TI - The National Health Service, Alma Ata, and the Great Western China Earthquake: Important Public Health Anniversaries to Remember. PMID- 30244589 TI - Intravoxel incoherent motion imaging in monitoring the function of kidney allograft. AB - Background Non-invasive alternatives to percutaneous renal biopsy are sought for follow-up of renal allografts. Purpose To evaluate the feasibility of intravoxel incoherent motion (IVIM) imaging in monitoring and predicting the function of renal allografts. Material and Methods Thirty-five kidney recipients were examined on a 1.5-T MR unit approximately three and 18 months after transplantation. Based on estimated glomerular filtration rate (eGFR), patients were divided into three groups: improved; declined; and stable graft function. Diffusion parameters were calculated with the use of monoexponential (total apparent diffusion coefficient [ADCT]) and biexponential (pure diffusion coefficient [D], perfusion fraction [Fp]) model and compared among and within study groups using Kruskal-Wallis, Mann-Whitney, and Wilcoxon matched pairs tests. Diffusion parameters were correlated with eGFR using Spearman's rank correlation coefficients. Results of tests with P values < 0.05 were considered statistically significant. Results Values of diffusion parameters, especially Fp, were lower in patients with a declined graft function; however, statistically significant intergroup differences were observed only in a limited number of parameters at the time of follow-up magnetic resonance imaging (MRI). None of the diffusion parameters from the baseline MRI correlated with the change in eGFR over time. Flow-related diffusion parameters calculated with the IVIM model showed high variability. Conclusion We observed a trend toward a decrease in values of diffusion parameters in patients with a declined graft function. Further research is needed to verify a clinical usefulness of this observation. PMID- 30244590 TI - Intergrating conventional MRI, texture analysis of dynamic contrast-enhanced MRI, and susceptibility weighted imaging for glioma grading. AB - Background The application of conventional magnetic resonance imaging (MRI) in glioma grading is limited and non-specific. Purpose To investigate the application values of MRI, texture analysis (TA) of dynamic contrast-enhanced MRI (DCE-MRI) and intratumoral susceptibility signal (ITSS) on susceptibility weighted imaging (SWI), alone and in combination, for glioma grading. Material and Methods Fifty-two patients with pathologically confirmed gliomas who underwent DCE-MRI and SWI were enrolled in this retrospective study. Conventional MRIs were evaluated by the VASARI scoring system. TA of DCE-MRI-derived parameters and the degree of ITSS were compared between low-grade gliomas (LGGs) and high-grade gliomas (HGGs). The diagnostic ability of each parameter and their combination for glioma grading were analyzed. Results Significant statistical differences in VASARI features were observed between LGGs and HGGs ( P < 0.05), of which the enhancement quality had the highest area under the curve (AUC) (0.873) with 93.3% sensitivity and 80% specificity. The TA of DCE-MRI derived parameters were significantly different between LGGs and HGGs ( P < 0.05), of which the uniformity of Ktrans had the highest AUC (0.917) with 93.3% sensitivity and 90% specificity. The degree of ITSS was significantly different between LGGs and HGGs ( P < 0.001). The AUC of the ITSS was 0.925 with 93.3% sensitivity and 90% specificity. The best discriminative power was obtained from a combination of enhancement quality, Ktrans- uniformity, and ITSS, resulting in 96.7% sensitivity, 100.0% specificity, and AUC of 0.993. Conclusion Combining conventional MRI, TA of DCE-MRI, and ITSS on SWI may help to improve the differentiation between LGGs and HGGs. PMID- 30244592 TI - Do guidelines provide evidence-based guidance to health professionals on promoting developmentally appropriate chronic condition self-management in children? A systematic review. AB - Objectives To determine whether evidence-based practice guidelines promote developmentally appropriate chronic condition self-management for children with asthma, type 1 diabetes mellitus, and cystic fibrosis. Methods Systematic review of clinical guidelines current as at 22 September 2017, including assessment of quality of each guideline using the iCAHE 'Guideline Quality Checklist', and mapping of the supporting evidence. Results Fifteen guidelines were identified: asthma ( n=7) and type 1 diabetes mellitus ( n=7), CF ( n=1). Guideline quality was variable, and 11 different grading systems were used. In total, there were 28 recommendations promoting age/developmental considerations. Recommendations focused on: collaboration ( n=15), chronic condition self-management education ( n= 17), clinicians' skills ( n= 4); personalized action plans ( n=3), problem solving ( n=2); and the assessment of children's chronic condition self management needs ( n=3). Developmental transitions are highlighted as important time points in some guidelines: preschool ( n=2), and adolescence ( n=3). All guidelines encouraged triadic partnerships between children, adult caregivers and clinicians. Evidence supporting the developmental aspects of the guidelines' recommendations was poor; only 14 out of 57 journals listed as evidence were concordant. Discussion Current guidelines articulate that developmentally appropriate chronic condition self-management is important; however, more work needs to be done to translate the concept into practical clinical tools. PMID- 30244591 TI - The Role of Non-Echoplanar Diffusion-Weighted Magnetic Resonance Imaging in Diagnosis of Primary Cholesteatoma and Cholesteatoma Recidivism as an Adjunct to Clinical Evaluation. AB - INTRODUCTION:: The aim of this study was to analyze the sensitivity and specificity of non-echoplanar (non-EPI) diffusion-weighted (DW) magnetic resonance imaging (MRI) for the detection of cholesteatoma, with a focus on its value as an adjunct to clinical examination. METHODS:: In a prospective cohort study, 92 cases were divided into 2 groups: "clinically cholesteatoma" ( n = 79) and "clinically no cholesteatoma" ( n = 13). Non-EPI DW MRI was performed preoperatively in all cases. The presence of a cholesteatoma was assessed by clinicians otoscopically, by neuroradiologists on non-EPI DW MRI, by the surgeon intraoperatively, and finally by the pathologist postoperatively. Data analysis was performed for specificity, sensitivity, positive predictive value, negative predictive value, and interrater variability. RESULTS:: The sensitivity and specificity were 89.3% and 75%, respectively, in the "clinically cholesteatoma" group and 0% and 100% in the "clinically no cholesteatoma" group. Non-EPI DW MRI had a positive predictive value of 98.5% when cholesteatoma was suspected clinically and a negative predictive value of 84.6% when cholesteatoma was not suspected clinically. CONCLUSION:: If cholesteatoma is suspected clinically, non EPI DW MRI is not necessary. If there is no clinical suspicion of cholesteatoma in second-look situations, sensitivity is low and serial follow-up MRI with long intervals is advised. PMID- 30244593 TI - Best Practices for Avoiding Paper Backup When Implementing Electronic Approaches to Patient-Reported Outcome Data Collection in Clinical Trials. AB - Electronic data capture is fast becoming the preferred method of collecting patient-reported outcome (PRO) data in clinical trials. Data collection can be site-based (clinical study site), and typically collected on a tablet, or field based (subject's typical environment such as home, school, or workplace), and most often accomplished with handheld devices, such as a smartphone. While site and study subject compliance with protocol-specific data collection procedures using these devices is critical to trial success, so is the robustness of the device hardware and the software these devices use to capture the trial data. Technology failures and/or site or subject resistance to the electronic data capture protocol may lead a subject to record data on paper, which can result in undesirable data challenges. As such, both site and subject compliance issues and technology-related factors must be anticipated to adhere to the ePRO data collection plan. The objective of this paper is to provide the technology industry's best practice recommendations for optimizing ePRO data collection in clinical trials by proposing the inclusion of a planned approach to data collection that includes viable electronic backup strategies so that defaulting to a paper-based backup becomes unnecessary. PMID- 30244594 TI - A Retrospective Review Demonstrating the Feasibility of Discharging Patients Without Opioids After Ureteroscopy and Ureteral Stent Placement. AB - PURPOSE: Efforts have begun to implement nonopioid protocols for outpatient urologic surgery. In this study, we report a retrospective review of the feasibility of implementing a nonopioid protocol to manage postoperative pain after ureteroscopy with stent placement. METHODS: Between November 2016 and March 2018, 210 patients underwent ureteroscopy with stent placement by a single surgeon at an academic medical center. A treatment algorithm was used to determine the eligibility and appropriately select patients for the nonopioid pathway. Frequency of postoperative events was reviewed and included visits to the emergency department (ED), telephone calls to the clinic, and requests for prescription refills. RESULTS: Two hundred six of 210 patients met the inclusion criteria. Of these 206 patients, 151 were discharged without opioid medications (73%) and 55 received opioids (27%). Both patients receiving opioids and nonopioids had a low number of postoperative visits to the ED for genitourinary related concerns (7 patients receiving opioids [13%] and 15 patients without opioids [10%]). Telephone calls made to the urology clinic for concerning symptoms were made by 25 patients receiving opioids (45%) and 32 patients without opioids (21%). The number of pain medication refill requests was low for both groups: 13 patients receiving opioids (24%) and 11 patients without opioids (7%). CONCLUSIONS: Our experience using a nonopioid pathway after ureteroscopy and stent placement reveals that approximately three-fourths of patients can be discharged without opioids. Patients had a low number of visits to the ED for postoperative genitourinary symptoms, a low number of telephone calls to the clinic, and requested few prescription pain medication refills regardless of whether or not they received opioids on discharge. PMID- 30244595 TI - Anticoagulation for the Treatment of Cancer-Associated Thrombosis: A Systematic Review and Network Meta-Analysis of Randomized Trials. AB - To perform a systematic review and network meta-analysis evaluating the efficacy and safety of low-molecular-weight heparins (LMWHs), vitamin K antagonists (VKAs), and direct-acting oral anticoagulants (DOACs) for the treatment of cancer associated thrombosis (CAT). We searched MEDLINE, Cochrane Central Register of Controlled Trials, and conference abstracts through March 2018. Randomized controlled trials (RCTs) enrolling adults with CAT comparing 2 or more full-dose anticoagulants (LMWH, VKA, and DOAC) and evaluating recurrent venous thromboembolism (VTE), major bleeding, and/or all-cause mortality were included. Reviewers identified studies, extracted data, and assessed the quality of the evidence in duplicate. A frequentist network meta-analysis, which uses direct and indirect evidence to simultaneously compare multiple interventions, was performed using a random-effects approach. Results are reported as pooled relative risks (RRs) with 95% confidence intervals (CIs). We included 13 RCTs (n = 6292): 7 compared LMWHs with VKAs, 4 compared DOACs with VKAs, and 2 compared DOACs with LMWHs. The risk of recurrent VTE was significantly reduced by 28% and 54% with a DOAC compared to an LMWH and a VKA, respectively. Low-molecular-weight heparins significantly reduced the risk of recurrent VTE by 36% versus VKAs. The risk of major bleeding was 14% higher with DOACs compared to LMWHs and 15% and 25% lower with DOACs and LMWHs versus VKAs, although 95% CIs included unity for each. The risk of all-cause mortality appeared similar for all 3 comparisons (RR = 1.0 for each comparison). Direct-acting oral anticoagulants appeared superior in reducing recurrent VTE in patients with CAT compared to LMWH and VKAs, but an increased risk of major bleeding versus LMWH cannot be ruled out. PMID- 30244596 TI - Laparoscopic Bilateral Cervicosacropexy and Vaginosacropexy: New Surgical Treatment Option in Women with Pelvic Organ Prolapse and Urinary Incontinence. AB - OBJECTIVE: Sacrocolpopexy (SCP) is the gold standard for apical prolapse treatment. However, the technical performance of each SCP is strongly dependent on the surgeon's own discretion and comparison of clinical outcomes with respect to urinary incontinence (UI) is difficult. We developed a comprehensible laparoscopic surgical technique for the treatment of apical prolapse with UI. METHODS: A total of 120 women with UI underwent laparoscopic bilateral SCP for apical prolapse. Thereby, the uterosacral ligaments (USLs) were bilaterally replaced by polyvinylidene fluoride (PVDF) tapes of identical length and shape, which were fixed at defined anatomical landmarks (cervix/vaginal vault and S1). RESULTS: The restoration of apical vaginal support was achieved in 116 patients (97%); restoration failed in the first 4 patients owing to the use of fast absorbable sutures. Seventy-eight patients (65%) with mixed and urgency UI symptoms before surgery achieved continence. The mean hospitalization was 3 days; no major complications were observed intraoperatively. CONCLUSION: The advantage of laparoscopic cervicosacropexy (laCESA) and laparoscopic vaginosacropexy (laVASA) lies in the comprehensible surgical technique (clearly defined technique) and the minimal amount of material used (no polypropylenes). The possibility of a short operating time and short hospitalization depicts this laparoscopic bilateral USL replacement as one treatment alternative in patients with apical prolapse suffering from UI. PMID- 30244597 TI - Can extra care housing support the changing needs of older people living with dementia? AB - With over two-thirds of people with dementia living in the community and one third of those living alone, it is important to consider the future housing needs of this population, particularly as symptoms of cognitive impairment increase. Policy in England has focused on enabling people living with dementia to remain in their own homes for as long as possible, often with the support of a family carer. However, many people struggle to maintain an acceptable quality of life in their own homes as their dementia advances, often due to the design limitations of mainstream housing and the challenge of finding specialist domiciliary care that is affordable and of sufficient quality. Extra care housing offers a model that aims to support older people living in their own apartments, whilst also offering specialist person-centred care as and when it is needed. This paper reports on a longitudinal project that explored how extra care housing can respond to the changing social care needs of residents, including those living with dementia. Participants included residents and staff from four extra care housing schemes, one of which was a specialist dementia scheme, in two regions of England. Interviews were carried with 51 residents across 4 rounds at 5 month intervals between October 2015 and June 2017. Interviews were also carried out with 7 managers, 20 care staff and 2 local authority commissioners of housing for older people. Key factors included person-centred care and support, flexible commissioning and staffing, appropriate design of the environment and suitable location of the scheme within the wider community. The challenge of delivering services that addresses these issues during a period of reduced public spending is acknowledged. Further research is suggested to compare different approaches to supporting people with dementia, including integrated and separated accommodation, and different stages of dementia. PMID- 30244598 TI - Factors That Determine the Prothrombin Time in Patients With Atrial Fibrillation Receiving Rivaroxaban. AB - Rivaroxaban, a direct factor Xa inhibitor, is widely used to reduce the chance of stroke in patients with atrial fibrillation (AF). It is not clear why the prothrombin time (PT) of the international normalized ratio (INR) fails to correlate with treatment using rivaroxaban in patients with AF. In this study, patient characteristics, the rivaroxaban dosage, AF type, drug history, biochemical properties, and hematological profiles were assessed in patients treated with rivaroxaban. In 69 patients with AF receiving rivaroxaban, 27 (39.1%) patients had a normal INR (<=1.1, group 1), 27 (39.1%) patients had a slightly prolonged INR (1.1~1.5, group 2), and 15 (21.7%) patients had a significantly prolonged INR (>1.5, group 3). Group 1 patients had a higher incidence of a stroke history than did patients in group 2 ( P = .026) and group 3 ( P = .032). We scored patients with a persistent AF pattern (1 point), paroxysmal AF pattern (0 point), renal function (ie, the creatinine clearance rate in mL/min/1.73 m2 of >60 as 0 points, of 30~60 as 1 point, and of <30 as 2 points), and no history of stroke (1 point), and we found that group 3 had a higher score than groups 2 or 1 (2.9 +/- 0.8, 2.4 +/- 0.7, and 2 +/- 0.7, respectively; P < .05). There were similar incidences of bleeding, stroke, and unexpected hospitalizations among the 3 groups. The PT of the INR is determined by multiple variables in patients with AF receiving rivaroxaban. Rivaroxaban treated patients with AF having different INR values may have similar clinical outcomes. PMID- 30244599 TI - Effect of ramp slope on different methods to determine lactate threshold in semi professional soccer players. AB - The present study aimed to investigate the effect of stage duration in incremental protocols on lactate threshold (LT), determined by different methods. Sixteen semi-professional soccer-players performed a 4-min stage incremental discontinuous (DP) and two maximal incremental running continuous (1 km h-1. min 1, CP1; and 1 km h-1.2 min-1 CP2) protocols. Blood-lactate concentration [La-] was measured at baseline and during the protocols. LT was determined using DMAX, DMAX-MOD, 4-mM?L-1, Delta1-mM?L-1 and Log-Log methods. Log-Log showed no difference in LT between CP1, CP2 and DP. Conversely, LT was determined at higher velocity in CP1 than CP2 for DMAX (15.2 +/- 0.5 vs 14.4 +/- 1.2 km?h-1, P = 0.002), DMAX-MOD (16.0 +/- 0.5 vs 14.7 +/- 1.3 km?h-1, P < 0.001), 4-mM?L-1 (15.5 +/- 1.4 vs 14.4 +/- 1.2 km?h-1, P < 0.001), Delta1-mM?L-1 (15.5 +/- 1.3 vs 14.4 +/- 1.2 km?h-1, P < 0.001). Higher LT in CP1 than DP for DMAX (15.2 +/- 0.5 vs 13.0 +/- 1.0 km?h-1, P < 0.001) and DMAX-MOD (16.0 +/- 0.5 vs 13.6 +/- 1.6 km?h 1, P < 0.001) was found (P < 0.001). Log-Log resulted in shorter but accurate protocols to determine LT. PMID- 30244600 TI - Should the last be first? Questions and dilemmas regarding early short-term insulin treatment in Type 2 Diabetes Mellitus. AB - INTRODUCTION: Early short-term insulin treatment (STIT), defined as insulin administration shortly after diabetes diagnosis for only a brief period of time, is an alternative concept, aiming to entirely revise the perspective of type 2 diabetes (T2DM) management. Areas covered: The present review intends to summarize what is already known regarding early STIT in T2DM and highlight questions and dilemmas from the clinician's point of view, with a discourse on future research agenda. Expert opinion: STIT has the potential to modify the natural history of T2DM, resulting in improved drug-free remission rates by favorably affecting the underlying pathophysiology of the disease. Existing data in the field manifest significant weaknesses, mainly being the small number of trials and patients included, the lack of control groups in most studies and the wide heterogeneity between study designs and explored outcomes, which limit definitive conclusions. Therefore, before such a therapeutic strategy is incorporated into daily practice, important issues require further clarification by future trials. These issues include the optimal time point for the intervention, the ideal insulin type, the identification of patients being most likely to benefit, the STIT effects on cardiovascular and other clinical outcomes and the cost-effectiveness evaluation of this therapeutic strategy. ABBREVIATIONS: T2DM: Type 2 Diabetes Mellitus; HbA1C: Hemoglobin A1c; OHA: Oral Hypoglycemic Agents; STIT: Short-term Insulin Treatment; CSII: Continuous Subcutaneous Insulin Infusion; MDI: Multiple Daily Injections; PPG: Postprandial Plasma Glucose; FPG: Fasting Plasma Glucose; HOMA-b: Homeostasis Model Assessment of beta-cell function; TDD: Total Daily Insulin Dose; DI: Disposition Index; HOMA IR: Homeostasis Model Assessment of Insulin Resistance; ROS: Reactive Oxygen Species; TNF: Tumor Necrosis Factor; GLP-1: Glucagon-like peptide-1; GIP: Glucose dependent Insulinotropic Polypeptide; BMI: Body Mass Index; CV: Cardiovascular; DR: Diabetic Retinopathy; SU: Sulfonylurea; IGI: Insulinogenic Index. PMID- 30244601 TI - Exploring barriers to consistent condom use among sub-Saharan African young immigrants in Switzerland. AB - No study to date has focused on barriers to condom use specifically among young immigrants to Europe from sub-Saharan Africa. Based on a qualitative study in sociology, this paper explores generational differences in barriers to condom use between first-generation immigrants (born in Africa and arrived in Switzerland after age 10) and second-generation immigrants (born in Switzerland to two native parents or arrived in Switzerland before age 10). Results are based on in-depth, semistructured individual interviews conducted with 47 young women and men aged 18 to 25 to understand how individual, relational, and cultural dimensions influence sexual socialization and practices. Six main barriers to consistent condom use were identified: reduced pleasure perception, commitment and trust, family-transmitted sexual norms and parental control, lack of accurate knowledge on HIV transmission, lack of awareness about HIV in Switzerland, and gender inequalities. The three first barriers concerned both generations of immigrants, whereas the three last revealed generational differences. These findings can help sexual health providers identify social causes for young sub-Saharan immigrants not using condoms. The findings also highlight the necessity of offering accurate, accessible, and adapted information to all young immigrants, as well as the particular importance of addressing families' lack of discussions about sex, understanding the sexual norms transmitted by parents, and taking into consideration cultural differences among young people born in immigration countries. PMID- 30244602 TI - Remote Injuries and Outcomes After Distal Radius Fracture Management. AB - BACKGROUND: Distal radius fracture (DRF) is a common fracture of the upper extremity. The role of concurrent injuries in patients treated for DRFs is poorly elucidated. The authors sought to determine whether remote injuries were associated with worse outcomes after management of DRFs. METHODS: A retrospective cohort study including all consecutively seen patients by a university hospital hand service between 2010 and 2015. Preoperative radiographs were analyzed, and patients were managed by surgeon preference and evaluated postoperatively using pain scores. Remote injury was defined as any other injury sustained at the time of fracture not localized to affected extremity. Univariate analysis was performed to identify factors associated with risk of complication. A multivariate logistic regression analysis was performed, controlling for confounding factors. RESULTS: A total of 181 DRFs in 176 patients were treated over the 5-year period of the study. Forty-eight (26.5%) of the fractures were managed nonoperatively with casting, 12 (6.6%) with closed reduction and pinning, and 119 (65.7%) with open reduction and plating. The mean follow-up was 5.2 months. The complication rate was 18.2%. The most common complication was persistent pain in 5 patients, followed by median neuropathy, loss of reduction, arthritis, and distal radioulnar joint instability. After controlling for age, body mass index, hand surgeon, and other confounders, remote injury was associated with a significantly increased risk of complications ( P = .04, odds ratio: 6.03, 95% confidence interval: 1.05-34.70). CONCLUSIONS: Patients with remote injuries have a 6-fold increased risk of complications after DRF treatment. The additional risk in these patients should be considered during patient/family counseling and clinical decision-making in DRF management. PMID- 30244603 TI - Five-Fold Variation Among Surgeons and Hospitals in the Use of Secondary Palate Surgery. AB - OBJECTIVE: To identify child-, surgeon- and hospital-specific factors at the time of primary cleft palate repair that are associated with the use of secondary palate surgery. DESIGN: Retrospective cohort study. SETTING: Forty-nine pediatric hospitals. PARTICIPANTS: Children who underwent cleft palate repair between 1998 and 2015. MAIN OUTCOME MEASURE: Time from primary cleft palate repair to secondary palate surgery. RESULTS: By 5 years after the primary palate repair, 27.5% of children had undergone secondary palate surgery. In multivariable analysis, cleft type and age at primary palate repair were both associated with secondary surgery ( P < .01). Children with unilateral cleft lip and palate had a 1.69-fold increased hazard of secondary surgery (95% confidence interval [CI]: 1.54-1.85) compared to children with cleft palate alone. Primary palate repair before 9 months had a 3.99-fold increased hazard of secondary surgery (95% CI: 3.39-4.07) compared to repair at 16 to 24 months of age. After adjusting for cleft type, age at repair, and procedure volume, there remained substantial variation in secondary surgery use among surgeons and hospitals ( P < .01). For children with isolated cleft palate, the predicted proportion of children undergoing secondary surgery within 5 years of primary repair ranged from 8.5% to 46.0% across surgeons and 9.1% to 49.4% across hospitals. CONCLUSIONS: There are substantial differences among surgeons and hospitals in the rates of secondary palate surgery. Further work is needed to identify causes for this variation among providers and develop interventions to reduce the need for secondary surgery. PMID- 30244604 TI - Delayed autism spectrum disorder recognition in children and adolescents previously diagnosed with attention-deficit/hyperactivity disorder. AB - Phenotypic elements of autism spectrum disorder can be masked by attention deficit/hyperactivity disorder symptoms, potentially leading to a misdiagnosis or delaying an autism spectrum disorder diagnosis. This study explored differences in the age of autism spectrum disorder diagnosis between participants with previously diagnosed attention-deficit/hyperactivity disorder versus autism spectrum disorder-only respondents. Children and adolescents, but not adults, initially diagnosed with attention-deficit/hyperactivity disorder received an autism spectrum disorder diagnosis an average of 1.8 years later than autism spectrum disorder-only children, although the findings regarding the adult sample should be interpreted with caution. Gender differences were also explored, revealing that the delay in receiving an autism diagnosis was 1.5 years in boys and 2.6 years in girls with pre-existing attention-deficit/hyperactivity disorder, compared with boys and girls without prior attention deficit/hyperactivity disorder. No significant gender differences were observed in the adult sample. We argue that overlapping symptoms between autism spectrum disorder and attention-deficit/hyperactivity disorder might delay a formal diagnosis of autism either by leading to a misdiagnosis of attention deficit/hyperactivity disorder or by making it difficult to identify the presence of co-occurring autism spectrum disorder conditions once an initial diagnosis of attention-deficit/hyperactivity disorder has been obtained. Current findings highlight the need to recruit multidimensional and multidisciplinary screening procedures to assess for potential emerging autism spectrum disorder hallmarks in children and adolescents diagnosed or presenting with attention deficit/hyperactivity disorder symptoms. PMID- 30244605 TI - Expert opinion on emerging urate-lowering therapies. AB - INTRODUCTION: There has been a resurgence in gout therapeutics in the last decade, not only for the management of gout flares, but also for the treatment of hyperuricemia. This editorial summarizes new, emerging therapies for people with gout. Areas covered: We review several new therapies for gout, including those that are focused on lowering serum urate (levotofisopam, ulodesine, verinurad, merbarone, KUX-1151, UR-1102, FYU-981, SEL-212), or treating gout flares (canakinumab, bucillamine) or both (arhalofenate, diacerein). Expert opinion: Among therapies with both urate lowering and anti-inflammatory action, arhalofenate seems promising, but more data are needed. Examining therapies aimed at treating gout flares [anti-inflammatory action], bucillamine has some potential, but more data and Phase III studies are needed, to better understand its efficacy and safety. Among the urate-lowering therapies (ULTs), verinurad seems to be the most promising, while levotofisopam and ulodesine require more data. A uricase-replacement therapy with improved immune reaction (SLE-212) is in a Phase II trial. A number of ULTs including KUX-1151, UR-1102 and FYU-981 are in early development and more will be known once initial data and studies are published. PMID- 30244606 TI - Evaluating an AAC training for special education teachers in Sri Lanka,a low- and middle-income country. AB - A majority of people with disabilities live in low- and middle-income countries where communication services for individuals with complex communication needs are scarce. It is essential that communication partners of individuals who have complex communication needs receive training to support communication. To address this issue, the current study evaluated an augmentative and alternative communication training for special education teachers living in a low- and middle income country, Sri Lanka. The training was based on four key practices identified when training in low- and middle-income countries: investigate learner needs, provide contextually relevant instructional content, use engaging instructional activities, and assess the impact of instructional activities. This investigation implemented an interrupted time-series design with nine teacher student dyads. Special education teachers were taught to provide evocative communication opportunities. Following the training, all nine special education teachers significantly increased the number of evocative communication opportunities provided to students with complex communication needs. Additionally, all nine students with complex communication needs significantly increased their number of communication turns. PMID- 30244607 TI - The current data on the 3-month paliperidone palmitate formulation for the treatment of schizophrenia. AB - INTRODUCTION: A three-month injection of paliperidone palmitate (PP3M) has been gradually introduced in the market since 2015. Recently, and due to different reasons, there is an increase in the LAIAs prescription rates, including patients in early phases of psychotic disorders. Areas covered: The following article provides an overview of the antipsychotic market before providing the reader with an overview of the efficacy and tolerability data of the 3-month paliperidone palmitate formulation for the treatment of schizophrenia. The authors take into account the current state of knowledge, as well as the needs not covered by other therapeutic tools at our disposal at this time. Expert opinion: PP3M offers a substantially longer dosing interval than other options, which may be a potential advancement to reduce nonadherence in some patients. Future research, both from randomized controlled trials and large pragmatic studies in real-world settings, will identify which subpopulation and disease stages may obtain greater benefit from this new formulation. PMID- 30244608 TI - High one-year mortality following hospitalization for severe hypoglycemia among patients with diabetes mellitus: findings of a retrospective cohort study at an acute tertiary care hospital in Singapore. AB - OBJECTIVES: Little is known about the 1-year short-term mortality rate following hospital admissions with severe hypoglycemia. This study aimed to determine the factors associated with increased 1-year mortality rate following hospitalization in diabetes patients admitted with severe hypoglycemia to the Singapore General Hospital. METHODS: Clinical, biochemical, and 1-year mortality data from diabetes patients who were admitted with severe hypoglycemia in the year 2014 were extracted from institutional medical records. Patients who passed away during the episode of admissions with severe hypoglycemia were excluded from the analysis. The clinical and biochemical factors between patients who survived and those who did not survive within 1 year following admission were compared using logistic regression analysis. RESULTS: Three hundred and four patients (181 female and 123 male) were admitted with severe hypoglycemia in 2014, and the mean capillary blood glucose on admission was 2.3 +/- 0.7 mmol/L. Sixty-three (20.7%) patients died within 1-year post-discharge from the hospital. Compared with patients who survived 1-year post-discharge from the hospital, non-survivors were older (69.3 +/- 11.0 vs 75.5 +/- 11.2 years, p < .001), had longer lengths of stay (LOS) (5.0 +/- 7.4 vs 9.0 +/- 12.8 days, p = .02), and had a higher Charlson Comorbidity Index (CCI) (4.1 +/- 1.9 vs 5.9 +/- 2.4, p < .001). Factors associated with increased 1-year mortality risk were age (odds ratio [OR] = 1.06; 95% confidence interval [CI] = 1.03-1.09, p < .01), LOS in hospital (OR = 1.01; 95% CI = 1.01 1.08, p < .01), and CCI (OR = 1.51; 95% CI = 1.31-1.75, p < .01), respectively. CONCLUSIONS: Older diabetes patients with more comorbidities and longer LOS were at increased risk of dying within a year of discharge after hospitalization with severe hypoglycemia. Admission with severe hypoglycemia has important prognostic implications. Healthcare professionals should address hypoglycemia and other health issues during the hospital admissions. PMID- 30244609 TI - High-protein diets in trained individuals. AB - The United States (US) recommended dietary allowance (RDA) for protein is 0.8 grams per kilogram body weight per day (g/kg/d). The International Society of Sports Nutrition (ISSN) recently recommended an intake of 1.4-2.0 g/kg/d whereas the United States and Canadian Dietetic Association typically recommend a lower range of 1.2 to 1.7 g/kg/d. It is clear that the US RDA for protein is grossly inadequate for exercising individuals; thus, athletes are typically advised to consume twice the RDA. This falls within the range commonly recommended by academic societies. The effect of protein consumption that exceeds these aforementioned guidelines is not entirely known. This review examines the current literature as it pertains to the influence of very high protein intakes in trained individuals (i.e., humans). It is the scientific opinion of the author that athletes should consume at least 2.2 g/kg/d of protein. PMID- 30244610 TI - Synthesis and characterisation of (Z)-styrylbenzene derivatives as potential selective anticancer agents. AB - To identify anticancer agents with high potency and low toxicity, a series of (Z) styrylbenzene derivatives were synthesised and evaluated for anticancer activities using a panel of nine cancer cell lines and two noncancerous cell lines. Most derivatives exhibited significant anti-proliferative activities against five cancer cell lines, including MGC-803 and BEL-7402. (Z)-3-(p-Tolyl)-2 (3,4,5-trimethoxyphenyl)acrylonitrile (6h) showed a strong inhibitory effect on MGC-803 cells (IC50 < 0.01 uM) and exhibited stronger anti-proliferative activity than taxol (IC50 < 0.06 +/- 0.01 uM). The IC50 value of 6h in L-02 cells was 10,000-fold higher than in MGC-803 cells. Compound 6h inhibited proliferation of BEL-7402 cells by arresting at the G2/M phase through up-regulation of cyclin B1 expression, down-regulation of cyclin A and D1 expression, and induction of apoptosis. In addition, 6h inhibited the migration of BEL-7402 cells and the formation of cell colonies. PMID- 30244611 TI - An evaluation of memantine ER + donepezil for the treatment of Alzheimer's disease. AB - INTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide and carries an immense societal burden. Unfortunately, no curative or disease-modifying treatment has yet been discovered. The currently approved medications are symptomatic. They include two classes: the cholinesterase inhibitors, such as donepezil, and the NMDA receptor antagonist memantine. Most evidence has shown that combining both classes is superior to monotherapy but may complicate the treatment regimen for patients and families. Namzaric(r), a fixed dose combination of donepezil and memantine extended-release (ER) (FDC memantine ER/donepezil), was recently approved by the U.S. Food and Drug Administration (FDA) for patients with moderate to severe AD and warrants further consideration as a clinically useful and advantageous pharmacotherapy in AD. Areas covered: This review discusses the pharmacological properties, efficacy, and safety/tolerability data of this FDC memantine ER/donepezil as well as its benefits and disadvantages for patients and families. A literature search using PubMed was conducted using Namzaric, donepezil, memantine, AD, and medication adherence as keywords. Expert opinion: Aside from its cost, FDC memantine ER/donepezil improves adherence to medication and reduces caregiver burden. It allows patients to benefit from combination therapy as the disease progresses, especially in those with dysphagia, poor adherence and limited caregiver support. PMID- 30244612 TI - What lies beneath? Experiencing emotions and caring in oncology. AB - Medical encounters - while often viewed as centred on conveying clinical knowledge - are also sites of emotion and for exerting emotional labour by healthcare professionals. The temptation to view these encounters as largely 'technical' - an exchange of knowledge or information - can marginalise the complex emotions often experienced by healthcare professionals, and negates the critical work done in these encounters. Drawing on in-depth interviews with 22 Australian medical oncologists, this article explores the experience and meaning of (their) emotions in medical encounters, and the manner in which emotional labour is performed by medical oncologists. Emotions, as it emerges, are central to the 'management' of encounters, ensuring professional sustainability and in 'achieving' clinical outcomes. Here, we broaden understandings of emotionality in oncological work, focusing on emotions as central to the production and enactment of professionalism, relationships and identities across professional careers. We illustrate how the performance of emotional labour reflects a dialectic between notions of 'professionalism' and 'feelings' - which in practice are co-existing and intermingling dimensions of oncology relations - manifested in the practice of 'bounded caring'. PMID- 30244613 TI - Brexpiprazole: a step forward for precision medicine in resistant depression. AB - INTRODUCTION: Resistant depression is still a common and burdensome issue and there is an urgent need for new and effective adjunctive treatments. Areas covered: In this paper, the author discusses the background, trial design, results and implications of a recent study (NCT02196506, Sirius study) which confirmed the possible benefit of brexpiprazole as adjunctive treatment in depressed subjects with inadequate benefit from first line treatments. As secondary aims, the study confirmed the effects in subjects with minimal benefit from standard treatments and in subjects with anxious distress. Despite some reported side effects such as akathisia, restlessness, and increased weight, the treatment was well tolerated. Expert opinion: The unique pharmacodynamic profile of brexpiprazole, in terms of reduced dopamine intrinsic stimulation and a range of other more anxiolytic receptor effects, suggests that brexpiprazole should be preferred in specific subpopulations, particularly where a more sedative profile is needed. Indeed, this study suggests another step in the direction of precision medicine. PMID- 30244614 TI - The effect of aspirin on antibiotic susceptibility. AB - INTRODUCTION: Aspirin (acetylsalicylic acid, ASA) is often co-administered during the treatment of infections. Salicylic acid (SAL), the active metabolite of ASA, has significant effects on bacteria that might improve or (more likely) compromise the effectiveness of antibiotics. Areas covered: In this review, we summarize the interactions between SAL and antibiotics, and describe the underlying mechanisms involved. Expert opinion: In an era of rapidly increasing antibiotic resistance and lack of new antibiotic development, it is important to explore ways to optimize the effectiveness of antimicrobial treatment. This includes a better understanding of the interactions between commonly co administered drugs. SAL might compromise the effectiveness of antibiotic treatment by inducing phenotypic resistance in bacteria. It can induce phenotypic resistance by up- or downregulating outer membrane proteins or efflux pumps, by upregulating antibiotic targets and by inducing enzymes with degrading activity. Moreover, SAL can increase the frequency of mutations leading to antibiotic resistance. PMID- 30244615 TI - Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging. AB - INTRODUCTION: Glycogen synthase kinase 3 (GSK3) is at the center of cellular signaling and controls various aspects of brain functions, including development of the nervous system, neuronal plasticity and onset of neurodegenerative disorders. Areas covered: In this review, recent efforts in elucidating the roles of GSK3 in neuronal plasticity and development of brain pathologies; Alzheimer's and Parkinson's disease, schizophrenia, and age-related neurodegeneration are described. The effect of microglia and astrocytes on development of the pathological states is also discussed. Expert opinion: GSK3beta and its signaling pathway partners hold great promise as therapeutic target(s) for a multitude of neurological disorders. Activity of the kinase is often elevated in brain disorders. However, due to the wide range of GSK3 cellular targets, global inhibition of the kinase leads to severe side-effects and GSK3 inhibitors rarely reach Phase-2 clinical trials. Thus, a selective modulation of a specific cellular pool of GSK3 or specific down- or upstream partners of the kinase might provide more efficient anti-neurodegenerative therapies. PMID- 30244617 TI - POC-LUS guiding pleural puncture drainage to treat neonatal pulmonary atelectasis caused by congenital massive effusion. AB - Point of care lung ultrasound (POC-LUS) has played important roles in diagnosing neonatal lung diseases and assisting in their treatment. A newborn infant with severe respiratory distress diagnosed as pulmonary atelectasis caused by congenital massive pleural effusion, whose consolidated lung recruitment after pleural puncture drainage under POC-LUS guidance. Lung ultrasound can be performed easily and timely at bed-side with free of radiation exposure, thus it should be used extensively in the neonatal department. PMID- 30244616 TI - Is probiotic use beneficial for skin lesions in patients with inflammatory bowel disease? AB - BACKGROUND: Inflammatory bowel diseases (IBDs) are associated with extraintestinal manifestations including skin lesions. The intestinal microflora plays a key role in the development and course of IBD. AIM: To examine the efficacy of probiotics and the occurrence of skin lesions in patients with IBD. METHODS: The occurrence of cutaneous lesions in IBD patients from Northern Sardinia was analyzed according to demographic, anthropometrics, clinical features, treatments, and probiotic use expressed as the ratio of disease duration under probiotic treatment and the total disease duration. RESULTS: In 170 IBD patients (59.4% women; UC: 61.2%) at least one skin lesion was present (8.2%) at diagnosis and in 30.6% developed during the follow-up. Psoriasis, erythema nodosum, and pyoderma gangrenosum were the most frequent. An inverse trend was observed between probiotics use and skin lesions occurrence after adjusting for confounders, including conventional treatment for IBD. The risk of developing at least one skin lesion was 1.40 for probiotic use between 5-19% of disease duration and 0.3 for probiotic use > 50%. Body mass index, Crohn phenotype, marriage, and potency of IBD-treatment were significant predictors for developing skin lesions. CONCLUSION: These findings suggest that probiotics may be an additional tool in the treatment of IBD. PMID- 30244618 TI - Treatment of patients with plaque psoriasis with secukinumab in a real-life setting: a 52-week, multicenter, retrospective study in Spain. AB - BACKGROUND: The efficacy and safety of secukinumab in patients with plaque psoriasis (PsO) has been demonstrated in randomized clinical trials (RCTs). However, data regarding its efficacy and safety in real-life settings are scarce. OBJECTIVES: To evaluate the efficacy and safety of secukinumab in clinical practice in patients with PsO attending 10 dermatology centres in Spain. METHODS: Data from 136 patients consecutively treated with secukinumab for at least 52 weeks were collected in a retrospective observational study. RESULTS: After 52 weeks of treatment, 69% and 46% of patients achieved a PASI-75, PASI-90, respectively. PASI-score <= 5 was achieved in 83% of patients, PASI-score <= 3 in 73% and PASI-score <= 1 in 47%. Response rates were found significantly lower in patients with obesity and non-naive to biologics (p< 0.05). The most common adverse event (AE) was candidiasis (5/136). Thirty-six patients (26.5%) discontinued treatment by week 52 due to lack or loss of response (n = 29), AEs (n = 2) or other causes (n = 5). CONCLUSION: These findings complement the efficacy and safety profiles of secukinumab in PsO outlined in RCTs. The effectiveness in clinical practice may be lower in patients whit a BMI >= 30 and those previously treated with other biologic agents. PMID- 30244620 TI - The role of orthoses in knee osteoarthritis. AB - OBJECTIVES: Taking into account that the role of orthoses in patients with knee osteoarthritis (OA) is unclear and controversial, the purpose of this article is to review recent literature with the aim of answering the following question: What is the current role of orthoses in the treatment of knee OA? METHODS: A Cochrane Library and PubMed (MEDLINE) search related to the role of orthoses in knee OA was performed. RESULTS: Unloader braces decrease the adduction moment of the knee. In patients with varus medial compartment knee OA bracing is beneficial for pain, stiffness, function and quality of life (low grade of evidence). Lateral wedge arch support insoles seem not to decrease knee load. Lateral wedge insoles appear inefficacious at attenuating structural changes in patients with medial knee OA. CONCLUSIONS: The ideal option for an orthosis in patients with knee OA keeps on indeterminate, and long-run inferences are lacking. PMID- 30244619 TI - Treatment of Rosai-Dorfman disease with oral bexarotene: a case series. AB - BACKGROUND: Rosai-Dorfman disease (RDD) is a rare histiocytic proliferative disorder of unknown etiology. The skin is the most frequent extranodal site of RDD involvement and may be the only organ involved. While RDD is an indolent self limited disease, treatment is needed in patients with extensive, persistent or progressive disease, or if cosmetic disfigurement or physical impairment significantly affects the patient. There is no specific treatment for RDD, and multiple therapeutic approaches have been described with variable success rates. Ojective: To demonstrate the clinical efficacy of oral bexarotene for RDD. MATERIALS AND METHODS: Descriptive retrospective case series of three patients with RDD receiving oral bexarotene. RESULTS: Two patients had excellent response and regression of their skin lesions was achieved with long-term therapy. In the other patient, pruritus was promptly controlled while the lesions did not seem to regress and treatment was discontinued after five months. CONCLUSIONS: Our case series is the first report in the literature of the use of oral bexarotene as an effective and safe treatment for RDD. PMID- 30244621 TI - Does Axl have potential as a therapeutic target in pancreatic cancer? AB - INTRODUCTION: Pancreatic cancer is a leading cause of cancer-related death. Metastasis, therapy resistance, and immunosuppression are dominant characteristics of pancreatic tumors. Strategies that enhance the efficacy of standard of care and/or immune therapy are likely the most efficient route to improve overall survival in this disease. Areas covered: Axl, a member of the TAM (Tyro3, Axl, MerTK) family of receptor tyrosine kinases, is involved in cell plasticity, chemoresistance, immune suppression, and metastasis in various cancers, including pancreatic cancer. This review provides an overview of Axl and its function in normal conditions, summarizes the regulation and function of Axl in cancer, and highlights the contribution of Axl to pancreatic cancer as well as its potential as a therapeutic target. Expert opinion: Axl is an attractive therapeutic target in pancreatic cancer because it contributes to many of the roadblocks that hamper therapeutic efficacy. Clinical evidence supporting Axl inhibition in pancreatic cancer is currently limited; however, multiple clinical trials have been initiated or are in the planning phase to test the effect of inhibiting Axl in conjunction with standard therapy in pancreatic cancer patients. We anticipate that these studies will provide robust validation of Axl as a therapeutic target in pancreatic cancer. PMID- 30244622 TI - Treatment of phantom shocks: A case report. AB - Implantable cardioverter-defibrillators have become standard preventive treatment for patients with ventricular arrhythmias and other life-threatening cardiac conditions. The advantages and efficiency of the device are supported by multiple clinical trials and outcome studies, leading to its popularity among cardiologists. Implantation of the device is not without adverse outcomes. Implantable cardioverter-defibrillator placement has been found to lead to negative psychological and psychosocial sequelae such as apprehension to engage in physical activity, chronic anxiety, decreased physical and social functioning, a nagging fear of being shocked by the device, and the development of "phantom shocks." Defined as patient-reported shocks in the absence of evidence that the implantable cardioverter-defibrillator device has discharged, phantom shocks could impact the mental health of those affected. This article reviews the case of Mr. L, a 47-year-old man with ischemic cardiomyopathy who was seen by the psychiatry consultation team while under cardiologic care because he reported that his implantable cardioverter-defibrillator device had been shocking him despite no objective evidence after interrogating the device. A literature review of phantom shocks, their associated symptomatology, and psychological consequences are outlined and discussed. PMID- 30244623 TI - Comparative study of adjuvants for allergen-specific immunotherapy in a murine model. AB - AIM: To compare the immunological and clinical changes induced by allergen specific immunotherapy (AIT) using different adjuvants. MATERIALS & METHODS: Olea europaea pollen-sensitized mice were treated with olea plus aluminum hydroxide, calcium phosphate, monophosphoryl lipid A (MPL) or immunostimulatory sequences (ISS). RESULTS: Aluminum hydroxide seems to drive initially to a Th2-type response. Bacteria-derived adjuvants (MPL and ISS) skew the immune response toward Th1 and Treg pathways. Specific-IgE production was lower after AIT with MPL and ISS. Moreover, IgG2a production significantly increased in ISS-treated mice. Bacteria-derived adjuvants also improved the Th1 cytokine response due to IFN-gamma higher secretion. In addition, they improved bronchial hyper-reactivity and lung inflammation. CONCLUSION: Bacteria-derived adjuvants may enhance the efficacy of AIT. PMID- 30244624 TI - Beyond the new blood pressure guidelines: the beat goes on. AB - The scope of hypertension (HTN) even for those involved in the field is staggering with numbers close to 60 million Americans and more than 1 billion individuals across the globe. It is the most common reason to seek medical attention and according to the World Health Organization, the number one cause of mortality in the world. Yet, we still don't know what is normal or abnormal. Even though the most recent 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults has created quite a commotion, new questions could be raised. The purpose of this Editorial not only to fuel more interest on this topic but also to create the notion that HTN needs to be considered a dynamic clinical entity rather than a static blood pressure reading. PMID- 30244625 TI - Interventions to improve diagnostic decision making: A systematic review and meta analysis on reflective strategies. AB - AIMS: To identify, appraise and describe studies of cognitive interventions to improve diagnostic decision making (DDM) amongst medical professionals, assess their effectiveness and identify methodological limitations in existing studies. METHODS: We systematically searched for studies (publication date 2000-2016) in multiple databases including Cochrane Controlled Trials, EMBASE, ERIC, Medline, PubMed and PsycINFO, and used additional strategies such as hand searching and snowballing. Included studies evaluated cognitive interventions to enhance DDM amongst medical professionals, using defined outcomes such as diagnostic accuracy. A meta-analysis assessed the impact of "reflection". RESULTS: Forty four studies out of 10,114 screened citations, involving 4380 medical professionals, were included. Studies evaluated reasoning workshops/curricula, de biasing workshops, checklists, reflection, feedback, and instructions to induce analytical thinking. Guided reflection was demonstrated to improve DDM [effect size 0.38(95%CI 0.23-0.52), p < 0.001]. Immediate feedback and modeling reflection using contrasting examples also appeared to improve diagnostic accuracy, however underlying methodological issues prevented a quantitative assessment of any strategies other than reflection. CONCLUSIONS: Educational interventions incorporating practising deliberate reflection on a formulated diagnosis, modeled reflection on contrasting examples and immediate feedback are promising strategies for improving DDM. The effectiveness of other strategies is unknown, with more methodological refinements required in future research. PMID- 30244626 TI - Spontaneous resolution of direct carotid-cavernous fistulas: case series and literature review. AB - Spontaneous regression of direct carotid-cavernous fistulas (CCFs) is extremely rare. Most of the patients with direct CCFs are usually treated using endovascular techniques. Spontaneous obliteration of the direct fistulas probably results from thrombosis of the venous drainage and/or cavernous sinus. We report spontaneous closure of nine direct CCFs in nine patients. From literature review, we found another 37 patients with 43 fistulas due to spontaneous obliteration of bilateral lesions in six cases. There was no spontaneous closure in large-sized fistula. The factors associated with spontaneous thrombosis of the fistulas may be low-flow and small-sized fistula, hypotension, severe ocular manifestations, dissections or spasm of carotid artery, and increased intracranial pressure. Spontaneous healing of direct traumatic CCFs should be confirmed with cerebral angiography. Conservative treatment of direct CCFs should be carefully restricted in patients with normal vision or minimal visual impairment, and the patients must be monitored closely for any changes in visual function. Prompt endovascular treatment for complete obliteration of the fistula should be performed in patients with rapidly progressive visual loss. Venous thrombosis can still effect vision and rerouting towards cortical veins remains a concern. Because spontaneous resolution cannot be reliably predicted, the fistula then should be treated rather than waiting for spontaneous thrombosis. PMID- 30244627 TI - Determinants associated with making prenatal screening decisions in a national study. AB - This study sought to evaluate the associations between background exposures and psychological determinants, among postpartum Jewish and Arab women, relative to actual prenatal test endorsement. The independent and aggregative effects of contextual features and the subjective opinions and attitudes relative to a prenatal testing were evaluated, using logistic regressions. After accounting for contextual features, Jews with positive vs. negative opinions on screening were significantly more likely to undergo a prenatal screening. Specifically, having more favourable ideas on pregnancy termination, among Jews, was associated with a greater likelihood of triple test, nuchal translucency and ultrasound uptake as compared with those that refused. Similarly, Arabs who were more inclined to abort the pregnancy had a greater chance of using nuchal translucency and ultrasound vs. those that declined testing. As the preferences for prenatal test outcomes are multifaceted and vary according to population group, a better understanding of the factors involved in making testing choices could help ease the decision-making process. Impact Statement What is already known on this subject? The choice to undergo prenatal screening tests is influenced by various determinants, which include: social, demographic and emotional factors that vary by cultural preferences. Indeed, women integrate (subjective) beliefs and values that extend beyond rational (objective) reasoning when estimating whether or not to undergo testing. It may then be that, prenatal test choices might be, influenced less by actual risk status and more so by emotional factors. And while, the latter are more likely to be amendable, and thus influence changes in perception, the effect of psychological exposures on the decision making process in the genetic testing context, especially among Israeli Jews and Arabs, has been understudied. What the results of this study add? The current study extends the focus by addressing the role of evaluative beliefs and emotional factors involved with formulating prenatal screening judgments relative to actual testing among individuals with diverse profiles (Israeli Jews and Arabs). What was clarified was that background factors and psychological perceptions, such as having supportive attitudes on screening and a willingness to undergo abortion were, for the most part, related to prenatal test uptake. Concomitantly, these involve dense decision-making practices that can be difficult to approximate, as cultural settings and individual preferences often have an impact on intention-to-test. What the implications are of these findings for clinical practice and/or further research? Culturally appropriate counselling that would account for personal preferences alongside actual risk appraisals could enable pregnant women to make informed and autonomous prenatal testing choices. The integration of socio demographics, psychological correlates and other contextual factors into a theoretical framework, studied uniquely by sub-populations, could enrich future research. Such research can, in turn, provide a clearer picture of the social need for genetic counselling, help customise local interventions, and on a broader scale inform national policy. PMID- 30244628 TI - Pregnancy complicated by ovarian planoepithelial carcinoma arising in mature cystic teratoma. PMID- 30244629 TI - Gluteus medius tears of the hip: a comprehensive approach. AB - Greater trochanteric pain syndrome (GTPS) is a common clinical condition that can affect a wide range of patients. Historically, the condition has been associated with trochanteric bursitis. More recently, however, a growing body of literature has demonstrated gluteus medius tendinopathy and tearing is present in many cases of GTPS. Pathology of the gluteus medius can result in significant hip pain, loss of motion, and decreased function. Affected patients characteristically have symptoms including lateral hip pain and a Trendelenburg gait, which may be refractory to conservative management such as non-steroidal anti-inflammatory drugs (NSAIDs), physical therapy, and injections. In these cases, both open and arthroscopic repair techniques have been described, with recent literature demonstrating excellent patient-reported outcomes. We present a comprehensive review of gluteus medius tears including relevant anatomy, clinical evaluation, diagnosis, and treatment options. PMID- 30244630 TI - NIRS improves hemodynamic monitoring and detection of risk for cerebral injury: cases in the neonatal intensive care nursery. AB - Near-infrared spectroscopy (NIRS) monitoring provides a noninvasive, bedside measure of cerebral and somatic oxygenation in neonates at risk for hemodynamic instability and brain injury. This technology has been increasingly utilized in the neonatal intensive care unit, however, clinicians perceive a lack of evidence for the added value of NIRS monitoring. We present six clinical scenarios illustrating the value of NIRS monitoring for the diagnosis and management of critically ill newborns. PMID- 30244631 TI - Multidimensional Care Burden in Parkinson-Related Dementia. AB - BACKGROUND AND OBJECTIVE:: Providing care to people with Parkinson-related dementia (PwPRD) may result in significant stress, strain, and burden for life partners. A common measurement of life partner burden is the Zarit Burden Interview (ZBI), which considers "burden" as a unitary concept; however, burden is highly complex and most likely comprises several dimensions. This study aimed to explore the factor structure of the ZBI in life partners of PwPRD and to examine the relationships among the emerging factors and the demographic and clinical features. METHODS:: Life partners of PwPRD participated in home-based quantitative assessments and self-completed postal questionnaires. The assessment battery included ZBI, measures of relationship satisfaction, mood, stress, resilience, health, quality of life, feelings related to care provision, and sociodemographic questions. Data on PwPRDs' motor and neuropsychiatric symptom severity were also elicited in home-based assessments. RESULTS:: An exploratory factor analysis (principal axis factoring) of ZBI, conducted with 127 life partners, revealed five burden dimensions: social and psychological constraints, personal strain, interference with personal life, concerns about future, and guilt. These burden factors were associated with lower relationship satisfaction, mental health, and resilience, and higher stress, anxiety, depression, resentment, negative strain, and PwPRD motor severity. In multiple linear regression analyses, where each factor score was the dependent variable, stress, negative strain, and resentment emerged as significant predictors of specific burden dimensions. CONCLUSIONS:: Burden is a complex and multidimensional construct. Interventions should address specific types of burden among life partners of PwPRD to support couples' relationships and maintain quality of life. PMID- 30244632 TI - "Not Everything That Shakes Is a Seizure": Making the Determination of Test Article-Induced Convulsions in Toxicology Studies. AB - Spontaneous unexpected events occasionally develop during the course of rodent preclinical toxicology studies. The presentation of serious adverse events on animal studies may require notification of these events to the Food and Drug Administration if the events are most likely the direct result of test article administration. Classical conditioning of emotional responses may occur over the course of a repeat-dose study and clinical observation calls of "convulsions" are reported to the study director and/or staff veterinarians. In the current heightened environment of most research laboratories related to general animal welfare issues, it is imperative to have an action plan that will help to elucidate the potential origins of these motor events. We provide 10 factors that should be considered to help the study director determine the most likely cause of these motor attacks as being organic or psychogenic in origin. PMID- 30244633 TI - Late preterms: are they all the same? AB - Very preterm infants (VPT) and, especially extreme low gestational age (ELGA) preterms, often on the threshold of viability, make the headlines of both, the scientific as well as the popular press. However, all together they represent between 1 and 2% of all livebirths. Late preterms (LPT) those born between 34/07 and 36/06 weeks, on the other hand, may account for up to 80% of all preterms and for some 5-8% of all births. Although mortality is low they are prone to increasing neonatal morbidities posing a considerable medical, financial and psychosocial burden. In the last years, for many reasons, LPT appear to have increased considerably throughout the western world. But are LPT neonates all the same? In spite of overlapping gestational ages (GA) LPT may behave quite differently depending on circumstances surrounding their pre- and postnatal events. We can identify three different classes of LPT neonates: spontaneous late preterms (SpLPT) born in the absence of previous maternal illnesses and/or pregnancy related disorders; Induced LPT (IdLPT) due to maternal/fetal complications and those babies being born after 34-week gestation from postponed delivery at an earlier GA (PtLPT) - and they are quite different babies, with different behavior, despite a common and same gestational age. PMID- 30244634 TI - MicroRNA-146b-3p promotes cell metastasis by directly targeting NF2 in human papillary thyroid cancer. AB - BACKGROUND: MiR-146b has been reported to be over-expressed in papillary thyroid cancer (PTC) tissues and showed association with aggressive PTC. MiR-146b-5p has been confirmed to increase cell proliferation by repressing SMAD4, however as the other expression of miR-146b, detailed functional analysis of miR-146b-3p has not been carried out. In this study, we aimed to identify miR-146b-5p and miR-146b-3p differentially expressed in PTC with more aggression, such as lymph node metastasis and further elucidate the contribution and mechanism of miR-146b-3p in the process of PTC metastasis. METHODS: Expression of miR-146b-5p and miR-146b-3p was assessed in formalin-fixed paraffin-embedded (FFPE) tissues samples of PTC patients and the relationship with lymph node metastasis was analyzed.. A variety of PTC cells including BHP10-3 and K1 cells were cultured and miR-146b-5p or miR 146b-3p were over-expressed with microRNA mimics. The cell abilities of migration and invasion were detected by RTCA assay and transwell assay. PTC xenograft models were used to examine the effect of miR-146b-3p on PTC metastasis ability in vivo. Direct downstream target of miR-146b-3p was analyzed by luciferase reporter assay and western blot. The mechanism of miR-146b-3p on cell metastasis was further determined by co-transfected with merlin (the protein product of NF2 gene). RESULTS: MiR-146b-5p and miR-146b-3p expression was significantly higher in thyroid cancer tissues and cell lines compared to normal thyroid tissue and cells. Moreover, expression of miR-146b-5p and miR-146b-3p was further higher in thyroid metastatic nodes than thyroid cancer. After overexpression of miR-146b-5p or miR-146b-3p in BHP10-3, papillary thyroid cancer migration and invasion were increased. Notably, miR-146b-3p increased cell migration and invasion more obviously than miR-146b-5p. Overexpression of miR-146b-3p also significantly promoted PTC tumor metastasis in vivo. Luciferase reporter assay revealed that NF2 was a downstream target of miR-146b-3p in PTC cells as miR-146b-3p bound directly to the 3' untranslated region of NF2, thus reducing protein levels of NF2. Over-expression of merlin reversed the enhanced aggressive effects of miR 146b-3p. CONCLUSIONS: Over-expression of miR-146b-5p and miR-146b-3p was associated with PTC metastasis. MiR-146b-3p could enhance cell invasion and metastasis more obviously than miR-146b-5p through the suppression of gene NF2. These findings suggest a diagnosis and therapeutic benefit in PTC metastasis. PMID- 30244635 TI - Bronchoscope-Guided Percutaneous Endoscopic Gastrostomy Tube Placement by Interventional Pulmonologists: A Feasibility and Safety Study. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) tube placement is a procedure frequently done in the intensive care unit. The use of a traditional endoscope can be difficult in cases of esophageal stenosis and theoretically confers an increased risk of infection due to its complex architecture. We describe a technique using the bronchoscope, which allows navigation through stenotic esophageal lesions and also minimizes the risk of endoscopy-associated infections. METHODS: Prospective series of patients who had PEG tube placement guided by a bronchoscope. Procedural outcomes including successful placement, duration of the entire procedure, time needed for passage of the bronchoscope from the oropharynx to the major curvature, PEG tube removal rate, and mortality were collected. Procedural adverse events, including infections and long-term PEG related complications, were recorded. RESULTS: A total of 84 patients underwent bronchoscope-guided PEG tube placement. Percutaneous endoscopic gastrostomy tube insertion was completed successfully in 82 (97.6%) patients. Percutaneous endoscopic gastrostomy tube placement was performed immediately following percutaneous tracheostomy in 82.1%. Thirty-day mortality and 1-year mortality were 11.9% and 31%, respectively. Overall, minor complications occurred in 2.4% of patients, while there were no major complications. No serious infectious complications were identified and no endoscope-associated hospital acquired infections were documented. CONCLUSIONS: The use of the bronchoscope can be safely and effectively used for PEG tube placement. The use of bronchoscope rather than a gastroscope has several advantages, which include the ease of navigating through complex aerodigestive disorders such as strictures and fistulas as well as decreased health-care utilization. In addition, it may have a theoretical advantage of minimizing infections related to complex endoscopes. PMID- 30244636 TI - In situ use of the King-Devick eye tracking test and changes seen with sport related concussion: saccadic and blinks counts. AB - OBJECTIVES: Sport-related concussion (SRC) can result in impaired oculomotor function. Oculomotor performance, measured utilizing the King-Devick/Eye Tracking test (K-D/ET), is reported to be able to identify sub-optimal brain function. The objectives of the study were to determine the diagnostic accuracy of the K-D/ET in identifying SRC occurring from game participation and to perform a comparative analysis on saccade and blink counts for each K-D card individually and total counts between baseline and post-concussion. METHODS: Nineteen male Australian Football players were assessed on the K-D/ET test. Those suspected of having SRC secondary to a head impact were also tested. RESULTS: Participants recorded a slower time on the third (20.2 +/- 4.6 s) screen when compared with the first (p = 0.0424) and second (p = 0.0150) screens. The number of blinks was higher on the third (2.9 +/- 2.9) when compared with the second (p = 0.0057) screen. There was decrease of the K-D/ET total times between pre- and post-game (p = 0.1769). Participants who sustained a head impact recorded slower mean total K-D time (p = 0.7322), fewer mean total saccades (p = 0.0112), and more mean blinks (p = 0.8678) compared with their baseline scores. The assessment of blinks was the most sensitive measure for potential SRC (0.67). The K-D/ET duration was the most specific measure for potential SRC (0.88). An increase in the number of blinks had a fair specificity of 0.69. CONCLUSION: The rapid number-naming component of the K-D test is an assessment tool which quantifies impairment to oculomotor function and has been validated as a diagnostic tool for SRC. The clinical usefulness of the eye tracking component of the K-D/ET test is that it may be an effective method to assess concussions with the eye tracking component serving as a measure of progression and return to play. However, more research is required at the adult and youth level. PMID- 30244637 TI - Molecular regulation of miR-378 on the development of mouse follicle and the maturation of oocyte in vivo. AB - MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs which can bind to completely or partially complementary sequences in the 3'UTR of target mRNAs, therefore degrading the mRNA or repressing translation. We previously reported that miR-378 played a role in estradiol production via suppression of aromatase translation in porcine granulosa cells and could affect oocyte maturation in vitro by inhibiting cumulus cell expansion. However, the role of miR-378 on ovary development in vivo is unknown. The current study aimed to uncover the molecular mechanism of miR-378 in regulating mouse follicular development via micro injection of CMV-miR-378 lentivirus into the bursa of mouse ovary. The results showed that CMV-miR-378 lentivirus transduction in the mouse ovaries resulted in reduced ovary size, extended oestrous cycle (6-7 d in miR-378 overexpression group and 4-5 dyas in GFP control group) due to continuous oestrum, decreased percentage of oocytes in vitro maturation rate (IVM 60.8% vs. 89.4% in GFP control), increased apoptosis rate (Bax/Bcl2 in mRNA and protein level), decreased expression of genes associated with gap junction, such as connexin 43 (Cx-43) and connexin (Cx-37) and decreased expression of genes associated with follicular development, such as BMP15 and GDF9. Moreover, the number of pups/litter was consistently lower in the miR-378 group in each batch of the paired breeding. Our data suggest that miR-378 alters gene expression in cumulus cells and indirectly influences oocyte maturation competency, possibly via inhibition of oocyte-cumulus interaction or induction of apoptosis. PMID- 30244638 TI - Evaluation of the Use of Low-Dose 4-Factor Prothrombin Complex Concentrate in the Reversal of Direct Oral Anticoagulants in Bleeding Patients. AB - OBJECTIVE: This study investigated the percentage of patients who achieved hemostasis with 4-factor prothrombin complex concentrate (4-factor PCC) 35 U/kg. The primary end point was to determine the effect of 4-factor PCC 35 U/kg on bleeding progression, assessed using computed tomography. METHODS: This was a retrospective, observational, single-center study conducted in patients with a major bleed admitted to a level 1 trauma center from May 1, 2013, to June 15, 2015, who received 4-factor PCC 35 U/kg for reversal of a direct factor Xa inhibitor taken prior to admission. RESULTS: Thirty-three patients were included in the study, with 31 patients in the final analysis. The mean (standard deviation) age was 73 (14.8) years; 54.5% of patients were female. Of the 33 patients, 13 presented with a traumatic brain injury, 9 with an aneurysmal subarachnoid hemorrhage, 8 with an intracerebral hemorrhage, 1 with a gastrointestinal bleed, 1 with a hematoma with active extravasation, and 1 with an intra-abdominal bleed. The most frequently used direct factor Xa inhibitor was rivaroxaban (81.8%). Overall, 83.8% of patients achieved hemostasis with 4-factor PCC 35 U/kg. Progression of hemorrhage was observed in 4 patients on repeat computed tomography scan and 1 patient had continued surgical bleeding. No thromboembolic events were reported. CONCLUSIONS: Low-dose, 4-factor PCC 35 U/kg appeared to produce hemostasis in a majority of the patients. This may be an effective dosing regimen for anticoagulant reversal of factor Xa inhibitors in clinically bleeding patients. PMID- 30244640 TI - Back to basics. PMID- 30244641 TI - Tales from the menopause clinic. PMID- 30244639 TI - Early Surgical Decompression Improves Neurological Outcome after Complete Traumatic Cervical Spinal Cord Injury: A Meta-Analysis. AB - In patients with traumatic spinal cord injury (tSCI) a distinction in surgical urgency is made on the basis of the severity of the initial neurological injury. The optimal timing of surgical decompression, as well as its impact on neurological recovery, is as of yet undetermined. This study addresses neurological improvement after early and late surgery for complete and incomplete cervical tSCI. A systematic search retrieved 15 publications of observational studies reporting outcome measurements after surgery in 1126 patients with cervical tSCI from PubMed and Embase databases. Surgery was considered early within 24 h, and late thereafter. An improvement of at least two grades on the American Spinal Injury Association (ASIA) scale was considered clinically meaningful. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Improvement rates were summarized using individual patient data in a Bayesian random effects model and compared for those with complete and incomplete tSCI after early and late surgery. In patients with complete cervical tSCI (n = 422), improvement was more frequent after early surgery than after late surgery (respectively, 22.6%, 95% credibility interval [CI]: 16.6-28.7% and 10.4%, 95% CI: 5.6-15.8%; odds ratio [OR] 2.6 [95% CI: 1.4 5.1]). Whereas in patients with incomplete cervical tSCI (n = 636), improvement was similar between early and late surgery (respectively 30.4%, 95% CI: 19.8 41.6% and 32.5%, 95% CI: 21.4-45.8%; OR 0.9 [95% CI: 0.4-1.9]). These data suggest a paradigm shift in the treatment of patients with complete cervical tSCI, as surgical decompression within 24 h is more frequently associated with clinically meaningful improvement. In incomplete cervical tSCI, neurological outcome is similar between early and late surgery. PMID- 30244642 TI - Report on the 28th BMS annual conference - Royal College of Physicians, 5 and 6 July 2018. PMID- 30244644 TI - BMS - Consensus statement. AB - Urogenital atrophy is more common than it would first appear and women do not always seek advice and guidance. Confusion still exists between systemic hormone replacement therapy (HRT) and local estrogen preparations but new treatment modalities have emerged that extend the range of options beyond lubricants, moisturisers and vaginal estrogen preparations. PMID- 30244645 TI - GLNMDA: a novel method for miRNA-disease association prediction based on global linear neighborhoods. AB - Recently, increasing studies have shown that miRNAs are involved in the development and progression of various complex diseases. Consequently, predicting potential miRNA-disease associations makes an important contribution to understanding the pathogenesis of diseases, developing new drugs as well as designing individualized diagnostic and therapeutic approaches for different human diseases. Nonetheless, the inherent noise and incompleteness in the existing biological datasets have limited the prediction accuracy of current computational models. To solve this issue, in this paper, we propose a novel method for miRNA-disease association prediction based on global linear neighborhoods (GLNMDA). Specifically, our method obtains a new miRNA/disease similarity matrix by linearly reconstructing each miRNA/disease according to the known experimentally verified miRNA-disease associations. We then adopt label propagation to infer the potential associations between miRNAs and diseases. As a result, GLNMDA achieved reliable performance in the frameworks of both local and global LOOCV (AUCs of 0.867 and 0.929, respectively) and 5-fold cross validation (average AUC of 0.926). Case studies on five common human diseases further confirmed the utility of our method in discovering latent miRNA-disease pairs. Taken together, GLNMDA could serve as a reliable computational tool for miRNA disease association prediction. PMID- 30244646 TI - Comparison of biomechanical characteristics between male and female elite fast bowlers. AB - This study investigated ball release speed and performance kinematics between elite male and female cricket fast bowlers. Fifty-five kinematic parameters were collected for 20 male and 20 female elite fast bowlers. Group means were analysed statistically using an independent samples approach to identify differences. Significant differences were found between: ball release speed; run-up speed; the kinematics at back foot contact (BFC), front foot contact (FFC), and ball release (BR); and the timings between these key instants. These results indicate that the female bowlers generated less whole body linear momentum during the run-up than the males. The male bowlers also utilised a technique between BFC and FFC which more efficiently maintained linear momentum compared to the females. As a consequence of this difference in linear momentum at FFC, the females typically adopted a technique more akin to throwing where ball release speed was contributed to by both the whole body angular momentum and the large rotator muscles used to rotate the pelvis and torso segments about the longitudinal axis. This knowledge is likely to be useful in the coaching of female fast bowlers although future studies are required to understand the effects of anthropometric and strength constraints on fast bowling performance. PMID- 30244647 TI - Impact of meteorological conditions on the incidence of acute aortic dissection. AB - BACKGROUND:: There is still much controversy about whether meteorological conditions influence the occurrence of acute aortic dissection (AAD). The aim of the present study was to investigate the possible correlation between atmospheric pressure, temperature, lunar cycle and the event of aortic dissection in our patient population. METHODS:: The clinical data for 348 patients with AAD (73% type Stanford A) were confronted with the meteorological data provided by the Cologne weather station over the same period. RESULTS:: There were no statistically significant differences between meteorological parameters on days of AAD events compared with control days. A logistic regression model showed that air pressure (odds ratio [OR] 1.004, 95% confidence interval [CI] 0.991-1.017, p = 0.542), air temperature (OR 0.978, 95% CI 0.949-1.008, p = 0.145), season ( p = 0.918) and month of the event ( p = 0.175) as well as presence of full moon (OR 1.579, 95% CI 0.763-3.270, p = 0.219) were not able to predict AAD events. Also, no predictive power of meteorological data and season was found on analysing their impact on different types of AAD events. CONCLUSIONS:: Our study did not reveal any dependence of atmospheric pressure, air temperature or the presence of full moon on the incidence of different types of AAD. PMID- 30244648 TI - A Generalized Deep Learning-Based Diagnostic System for Early Diagnosis of Various Types of Pulmonary Nodules. AB - A novel framework for the classification of lung nodules using computed tomography scans is proposed in this article. To get an accurate diagnosis of the detected lung nodules, the proposed framework integrates the following 2 groups of features: (1) appearance features modeled using the higher order Markov Gibbs random field model that has the ability to describe the spatial inhomogeneities inside the lung nodule and (2) geometric features that describe the shape geometry of the lung nodules. The novelty of this article is to accurately model the appearance of the detected lung nodules using a new developed seventh-order Markov Gibbs random field model that has the ability to model the existing spatial inhomogeneities for both small and large detected lung nodules, in addition to the integration with the extracted geometric features. Finally, a deep autoencoder classifier is fed by the above 2 feature groups to distinguish between the malignant and benign nodules. To evaluate the proposed framework, we used the publicly available data from the Lung Image Database Consortium. We used a total of 727 nodules that were collected from 467 patients. The proposed system demonstrates the promise to be a valuable tool for the detection of lung cancer evidenced by achieving a nodule classification accuracy of 91.20%. PMID- 30244649 TI - How Do Professionals Assess Sexual Recidivism Risk? An Updated Survey of Practices. AB - Forensic evaluators may be assisted by comparing their use of instruments with that of their peers. This article reports the results of a 2017 survey of instrument use by forensic evaluators carrying out sexual recidivism risk assessments. Results are compared with a similar survey carried out in 2013. Analysis focuses primarily on adoption of more recently developed instruments and norms, and on assessment of criminogenic needs and protective factors, and secondarily, on exploring factors related to differences in evaluator practice. Findings indicate that most evaluators have now adopted modern actuarial instruments, with the Static-99R and Static-2002R being the most commonly used. Assessment of criminogenic needs is now common, with the STABLE-2007 being the most frequently used instrument. Evaluators are also increasingly likely to consider protective factors. While a majority of evaluators uses actuarial instruments, a substantial minority employs Structured Professional Judgment (SPJ) instruments. Few factors discriminated patterns of instrument use. PMID- 30244650 TI - The Dark Side of Luxury: Social Costs of Luxury Consumption. AB - Extant research demonstrates that luxury goods are beneficial signals that bestow upon individuals social benefits that range from positive evaluations to compliance. In contrast to this perspective, the current work explores the idea that luxury goods can carry significant negative social costs for actors. Across four experiments, the social cost of luxury is examined. Although individuals who display luxury goods are ascribed higher status, they can pay a hefty tax when it comes to warmth. The social costs of luxury consumption appear to be driven by impression management concerns rather than envy. Consequently, whether the consumption of luxury goods yields positive or negative social consequences for an actor critically depends both on whether status or warmth is relevant for a decision and observers' own lay beliefs about luxury consumption. Overall, this work reveals the more complex psychology of individuals' interpretation and response to actors' use of luxury goods. PMID- 30244651 TI - Efficacy of Percutaneous Thermal Ablation Combined With Transarterial Embolization for Recurrent Hepatocellular Carcinoma After Hepatectomy and a Prognostic Nomogram to Predict Survival. AB - AIM: This study aimed to evaluate the efficacy of percutaneous thermal ablation combined with transarterial embolization for recurrent hepatocellular carcinoma after hepatectomy and establish a prognostic nomogram to predict survival. METHODS: One hundred seventeen patients with recurrent hepatocellular carcinoma receiving ablation from 2009 to 2014 were included in primary cohort to establish a prognostic nomogram. Between 2014 and 2016, 51 patients with recurrent hepatocellular carcinoma treated by ablation were enrolled in the validation cohort to validate the predictive accuracy of the nomogram. All patients underwent locoregional ablation. Overall survival was the primary end point, and progression-free survival was the second end point. The performance of the nomogram was assessed through concordance index and calibration curve and compared with 5 conventional hepatocellular carcinoma staging systems. RESULTS: The 1-, 3-, and 5-year overall survival rates of primary cohort were 88.4%, 70.7%, and 64.1%, respectively. The 1-, 3-, and 5-year progression-free survival rates of primary cohort were 44%, 14%, and 8.7%, respectively. The results of multivariate analysis showed that tumor size ( P = .0469; hazard ratio, 1.020; 95% confidence interval, 1.0004-1.040), preoperative extrahepatic disease ( P = .0675; hazard ratio, 2.604; 95% confidence interval, 0.933-7.264), and close to hepatic hilum <2 cm ( P = .0053; hazard ratio, 3.691; 95% confidence interval, 1.474-9.240) were predictive factors for overall survival. The study established a nomogram to predict survival (concordance index, 0.752; 95% confidence interval, 0.656-0.849). According to the predicted overall survival, patients with recurrent hepatocellular carcinoma were divided into 3 risk classes ( P < .05): low-risk group (total score <55; predicted 5-year overall survival rate, 82.9%), intermediate-risk group (55 <= total score < 99; predicted 5-year overall survival rate, 52.8%), and high-risk group (hazard ratio, total score >=99; predicted 5-year overall survival rate, not available). CONCLUSION: Percutaneous thermal ablation appears to be an effective procedure for the treatment of recurrent hepatocellular carcinoma after hepatectomy. The proposed nomogram provides a mechanism to accurately predict survival and could stratify risk among patients with recurrent hepatocellular carcinoma treated by ablation therapy. PMID- 30244652 TI - Liquid Biopsy Promotes Non-Small Cell Lung Cancer Precision Therapy. AB - The range of potential applications of liquid biopsies for non-small cell lung cancer management is expanded by the use of circulating tumor deoxyribonucleic acid and circulating tumor cells. Principal studies have demonstrated the predictive accuracy of droplet digital polymerase chain reaction detection, next generation sequencing, and circulating tumor cells detection in patients with non small cell lung cancer. The translational potential of these liquid biopsy technologies promotes the improvement of sensitivity and specificity in genomic and molecular methods. Here, we highlight the realities and challenges associated with the use of liquid biopsies for the detection of non-small cell lung cancer in patients. However, liquid biopsy technologies including circulating tumor cells detection, droplet digital polymerase chain reaction detection, and next generation sequencing detection for precision therapy in non-small cell lung cancer will show substantive clinical applications in the future. PMID- 30244653 TI - Cytomegalovirus-Associated Glomerulonephritis in a Kidney Transplant Recipient. PMID- 30244654 TI - Development of Decellularized Cornea by Organic Acid Treatment for Corneal Regeneration. AB - IMPACT STATEMENT: This study successfully developed decellularized corneal scaffolds that were prepared by organic acid, which safely exist in animal tissues and plants. The results showed the highly efficient removal of cell debris from porcine corneas, and excellent preservation of optical properties, extracellular matrix (ECM) architecture, and biomolecules. In addition, decellularized corneal scaffolds revealed excellent biocompatibility and recellularization potential in vitro. In an animal model, the transplanted corneas were completely epithelialized, clear, showed no signs of immune response, and effectively supported stromal keratocytes growth. Hence, this could be a promising scaffold material for corneal tissue engineering applications. PMID- 30244655 TI - Further Evidence for Hypercoagulability in Women With Ovarian Endometriomas. AB - Our previous studies have shown that platelets play a crucial role in the development of endometriosis, and women with endometriosis appear to be in a state of hypercoagulability. However, a recent study could only replicate part of our previous finding, casting doubts on this notion. We further investigated this question through a cross-sectional study by measuring additional coagulation factors in women with and without endometriosis. To this end, we conducted a cross-sectional study of 100 women with laparoscopically and pathologically diagnosed ovarian endometriomas (OMA) and another 100 women without endometriosis. The platelet count; platelet activation rate; maximum platelet aggregation rate; plasma levels of D-dimer, fibrinogen, fibrin degradation products (FDPs), plasma soluble P-selectin (sP-sel), and prothrombin fragment 1+2 (F1+2); prothrombin time; thrombin time (TT); and activated partial thromboplastin time were measured before surgery and 3 months after surgery, and their clinical data were recorded. These measurements were also performed in control patients. We found that, compared with controls, women with OMA had a significantly higher platelet activation rate and platelet aggregation rate, elevated plasma D-dimer, fibrinogen, FDPs, sP-sel, and F1+2 levels as well as shortened TT. Remarkably, TT was prolonged, and all the other coagulation measurements, except plasma fibrinogen level, were significantly reduced 3 months after surgical removal of endometriotic lesions. Thus, our study provides another piece of evidence that endometriosis is a hypercoagulable disease, and anticoagulation therapy may hold promises in treating endometriosis. PMID- 30244656 TI - The Benefit of Supplemental Nutrition Education for Severely Malnourished Patients Awaiting Liver Transplant. AB - INTRODUCTION:: Nutritional interventions improve patient outcomes and reduce mortality in patients with cirrhosis by reducing infection risk, ascites, length of stay in hospital and intensive care unit, and mortality. Follow-up phone calls have been found to be useful in improving patient adherence to therapy. PROBLEM:: The purpose of this quality improvement project was to determine whether supplemental nutrition education would improve nutrition and outcomes among patients with cirrhosis who are undergoing a liver transplant evaluation. In addition, we sought to measure patient adherence with nutritional recommendations and whether patients perceived this additional education improved their nutrition status. METHODS:: The Plan-Do-Study-Ask methodology was used. PROCESSES:: Addressed 8 patients were enrolled to participate in the supplemental nutrition education, after which they received 3 follow-up phone calls. A retrospective review of data from 10 patients meeting project inclusion criteria were identified by the nutrition specialist and were used as a comparison group. Data were analyzed using descriptive statistics; comparing data from before and after implementation of the supplemental nutrition education was done. OUTCOMES:: At the end of the 8-week project period, 4 (66.7%) patients reported weight loss since the time of enrollment (nutrition education class), and the median patient generated subjective global assessment score increased by 4 points, rather than decreasing as expected. However, all patients reported they believed the phone calls improved their nutrition status. IMPLICATIONS:: With a multidisciplinary approach, this additional patient education may improve patient care and outcomes. PMID- 30244657 TI - Fear of Recurrence and View of Life Affect Health-Related Quality of Life in Patients with Differentiated Thyroid Carcinoma: A Prospective Swedish Population Based Study. AB - BACKGROUND: Differentiated thyroid cancer (DTC) has a good prognosis but a remaining risk of recurrence and need for lifelong follow-up. The aim was to study changes in health-related quality of life (HRQoL) from diagnosis to one year of follow-up. METHODS: In this prospective population-based study, patients were identified from all the Swedish departments of oncology treating DTC. In total, 487 patients diagnosed with DTC between 2012 and 2017 were invited to answer the Swedish version of the Short Form-36 Health Survey (SF-36) and a study specific questionnaire at diagnosis and after one year. RESULTS: In total, 349 (72%) patients responded. Of these, 235 (67%) had reached one year of follow-up and also answered the questionnaire after one year. Of those, 23% had a negative view of life, and 75% had a fear of recurrence at diagnosis. These patients had a significantly lower HRQoL on eight and five of the SF-36 domains, respectively (p < 0.05). A negative view of life and a fear of recurrence also affected HRQoL negatively after one year of follow-up, with a significantly lower HRQoL on seven SF-36 domains for those reporting a negative view of life or fear of recurrence often (p < 0.05). Thyrotropin suppression did not affect HRQoL negatively. In regression models, HRQoL at diagnosis was the most important predictive factor for HRQoL at the one-year follow-up. CONCLUSIONS: Despite a good prognosis, HRQoL was substantially affected at the time of diagnosis, with some improvements after one year. As fear of recurrence and a negative view of life substantially affect HRQoL, these patients should be given additional attention. PMID- 30244658 TI - Tumor Thickness and Modified Clark Level in Canine Cutaneous Melanocytic Tumors. AB - Breslow thickness and Clark level are prognostic factors for human cutaneous melanomas. Breslow thickness is measured with an ocular micrometer from the top of the granular layer of the epidermis to the deepest invasive cell across the broad base of the tumor, while Clark level is based on the anatomical level of invasion through the layers of the dermis. Because of the anatomical differences between humans and dogs, we evaluated the tumor thickness and a modified Clark level in 77 canine primary cutaneous melanocytic tumors. Tumor thickness (using both a traditional and a more convenient system) and modified Clark level were measured and associated with histological diagnosis and clinical outcome. Tumor thickness was a prognostic factor, being greater in animals with shorter overall survival and disease-free time. Cutoffs of 0.95 cm and 0.75 cm defined a higher hazard for an unfavorable outcome and to develop recurrence/metastasis, respectively. Because of an excellent agreement between the 2 methods, it was concluded that tumor thickness could be measured with a ruler when an ocular micrometer is not available. Modified Clark level was not found to be relevant for prognosis. However, we suggest that both tumor thickness and a modified Clark level can be valid additional parameters when histological diagnosis is uncertain. Further studies, including a wider sample population, would be worthwhile to confirm the prognostic significance of these 2 parameters. PMID- 30244659 TI - Belongingness: a commentary. AB - Vivekananda-Schmidt and Sandars have carried out a scoping review of the literature in health professions education on belongingness. Whereas the literature suggests a strong role for this concept in student motivation and learning identity formation and in facilitating positive mental health, their work reveals a dearth of research in medical, and particularly in primary care education. We know that embedded contact with primary care learning environments increases the proportion of medical graduates who enter general practice training and it is likely this association is mediated, at least in part, by the opportunity to develop a sense of belonging in the primary care world. By looking closely at belongingness, might we derive practical applications for enhanced primary care teaching? Using the social learning model proposed by Wenger who developed a concept of 'modes of belonging' and the connection with learning, this commentary identifies ways in which primary care educators might think about belonging as they develop learning opportunities. PMID- 30244660 TI - Zygomatic Arch Parosteal Osteosarcoma in Dogs and a Cat. AB - Parosteal osteosarcoma is a rare, slow-growing tumor most commonly arising from the surface of long bones. Tissue or histological sections from 5 dogs and 1 cat with zygomatic arch masses were examined. Clinical presentations varied from chronic sneezing to facial swelling. Imaging consistently demonstrated osseous proliferation in the area of the zygomatic arch. Histologically, the masses were characterized by well-differentiated fibro-osseous and chondroid components that radiated outward from the periosteum of the zygomatic bone. Cellular atypia and mitotic figures were uncommon. Parosteal osteosarcomas have previously been reported in the skulls of dogs and cats, but only 1 has been reported on the zygomatic arch. Initially, these tumors are of low histologic low grade, but with time, they can show more aggressive behavior and invade the underlying bone. PMID- 30244661 TI - Treponeme-Associated Hoof Disease of Free-Ranging Elk ( Cervus elaphus) in Southwestern Washington State, USA. AB - A novel foot disease in free-ranging elk ( Cervus elaphus) in southwestern Washington State emerged in 2008 and spread throughout the region. Initial studies showed adult elk had chronic hoof overgrowth, sole ulcers, and sloughed hoof capsules, but no cause was determined. To identify possible causes and characterize the earliest lesions, 9-, 7-, and 3-month-old elk were collected. Nine-month-old elk had sole ulcers (3/9 elk) and sloughed/overgrown hoof capsules (4/9 elk) similar to adults. Histologically, lesions consisted of coronary, heel bulb, and interdigital ulcers with suppurative inflammation, epithelial hyperplasia, deeply invasive spirochetes, and underrunning of the hoof capsule and heel-sole junction. Spirochetes were identified as Treponema via immunohistochemistry and polymerase chain reaction (PCR). Seven-month-old elk had similar underrunning foot ulcers (6/8 elk) with Treponema identified in all lesions but no chronic overgrowth or sloughed hoof capsules. Three-month-old calves had superficial coronary erosions with no inflammation or identifiable spirochetes (3/5 elk) but were culture/PCR positive for Treponema, suggesting possible early lesions. Lesions from 9- and 7-month-old elk included aerobic and anaerobic bacteria, many of which are associated with infectious foot disease in livestock. Antibody enzyme-linked immunosorbent assay of 7- and 3-month-old elk from the enzootic region showed a trend toward increased Treponema antibody titers compared to normal control elk from outside the region, further supporting the significance of Treponema in the pathogenesis of foot disease. Treponeme associated hoof disease (TAHD) in elk, a debilitating and progressive condition, shares similarities to bovine digital dermatitis and contagious ovine digital dermatitis. PMID- 30244663 TI - Fetal Pathology in an Aborted Holstein Fetus Infected With Bovine Parainfluenza Virus-3 Genotype A. AB - Bovine parainfluenza virus-3 (BPIV-3) is a recognized respiratory pathogen of cattle, and it has also been identified in aborted fetuses. However, little is known of this agent as a reproductive pathogen and detailed descriptions of fetal pathology on natural cases are lacking in the scientific literature. This article describes and illustrates lesions in a fetus spontaneously aborted by a first calving Holstein heifer, naturally infected with BPIV-3 genotype A, broadening the current knowledge on fetal pathology by this virus. Fetal autopsy revealed diffusely reddened, rubbery and unexpanded lungs. Histologically, there was necrotizing bronchiolitis/alveolitis with intraluminal fibrin exudate and syncytial cells in the bronchiolar/alveolar spaces, and non-suppurative peribronchiolitis and perivascular interstitial pneumonia. In the small intestine there was multifocal necrotizing cryptitis and occasional necrotic syncytial enterocytes. Intralesional and extralesional BPIV-3 antigen was detected by immunohistochemistry in the lung and small intestine, and BPIV-3a was identified in fetal tissues by RT-PCR and sequencing. PMID- 30244662 TI - The Study of MDM2 rs937283 Variant and Cancer Susceptibility in a Central Chinese Population. AB - The rs937283 variant, locating in murine double minute 2 promoter region, has been previously reported to potentially alter the promoter activity and to influence cancer susceptibility. In this study, we investigated the association of murine double minute 2 rs937283 variant and cancer susceptibility in a central Chinese population, followed by a meta-analysis. A total of 1058 healthy controls, 480 patients with breast cancer, 384 patients with cervical cancer, 480 patients with liver cancer, 426 patients with colon cancer, and 361 patients with rectal cancer were recruited in this case-control study. The murine double minute 2 rs937283 was genotyped by polymerase chain reaction restriction fragment length polymorphism and confirmed by sequencing. Our case-control analysis revealed that rs937283 was associated with the susceptibility to breast and liver cancer, but not cervical, colon, or rectal cancer. Specifically, the G allele of rs937283 conferred a significantly increased risk of breast and liver cancer. Moreover, results of meta-analysis demonstrated that rs937283 was significantly associated with cancer susceptibility, and this significant association remained in Asian (Chinese) population, but not in Caucasian population. Collectively, the murine double minute 2 rs937283 variant may serve as a potential biomarker for cancer predisposition in Chinese population. PMID- 30244664 TI - Using leading and lagging indicators to select safe contractors at the prequalification stage of construction projects. AB - The contractor-selection decision at the prequalification stage is critical to the project success. An insufficient prediction of contractors' safety capacities using only lagging indicators may hinder the continuous improvement of safety performance in the construction industry. This research enhanced construction management and practices by proposing a comprehensive safe contractor selection model which integrated both leading and lagging indicators. First, a set of leading and lagging safety indicators were identified based on literature review and expert opinions. Then, the grey correlation analysis (GCA) was utilized to assign weights to individual indicators. We found that management commitment, safety training and education, safety risk management, and safety rules and procedures were four most influential factors to the safety performance of contractors. In addition, the fuzzy technique of ordering preference by similarity to ideal solution (Fuzzy TOPSIS) was used to condense individual indicators and create a composite safety performance indicator (c-SPI). Finally, the feasibility of the decision support tool for safe contractor selection was verified using a real-case railway construction project. PMID- 30244665 TI - Lipid-Related Lesions in Quaker Parrots ( Myiopsitta monachus). AB - The Quaker parrot has been used as a psittacine model to study clinical lipidology and lipid-related disorders. However, while Quaker parrots appear to be anecdotally susceptible to a variety of spontaneous dyslipidemic disorders and lesions caused by excess lipid accumulation, epidemiologic data are lacking. A multicenter retrospective study on 652 pathology submissions (411 necropsies and 243 biopsies) from Quaker parrots was performed by recording the final pathological diagnoses, age, and sex for each bird. The prevalence of lesions associated with lipid metabolism, such as hepatic lipidosis, atherosclerosis, xanthomas, adipose tumors, coelomic steatitis/steatonecrosis, endogenous lipid pneumonia, and acute pancreatic necrosis/pancreatitis, was reported. Multiple logistic regression models were used to characterize the effects of sex and age on these lesions, and the prevalence of hepatic lipidosis and atherosclerosis was compared to those in a random sample of control psittacine birds. The raw prevalence of atherosclerosis and hepatic lipidosis was 5.6% (95% confidence interval [CI], 3.4%-7.8%) and 21.2% (95% CI, 17.2%-25.1%), respectively. While the prevalence of atherosclerosis was similar to other psittacine species, hepatic lipidosis was more common in Quaker parrots. Quaker parrots also showed a unique susceptibility to acute pancreatic necrosis with a prevalence of 12.9% (95% CI, 9.7%-16.1%). Male parrots were found to be more susceptible than females to lipid accumulation lesions ( P = .0024), including atherosclerosis ( P = .018) and hepatic lipidosis ( P < .001). This retrospective study confirms the high susceptibility of Quaker parrots to lipid-related disorders and presents epidemiological data that may be useful to avian clinicians, pathologists, and researchers using Quaker parrots. PMID- 30244666 TI - Grading Cutaneous Mast Cell Tumors in Cats. AB - Cutaneous mast cell tumors (cMCTs) account for approximately 20% of skin neoplasms in cats. As there is no grading system for these tumors, prognosis is difficult to estimate. Although the typical presentation is a benign tumor that can be cured by surgical excision, a small but important proportion of feline cMCTs is biologically aggressive and can spread to local lymph nodes, precede the onset of disseminated cutaneous disease, or be associated with visceral involvement. A number of macroscopic and histologic features were retrospectively evaluated in cases of feline cMCTs treated with surgical excision with or without medical therapy. Cats were divided into 2 groups based on the clinical outcome. Group 1 included cats alive with no mast cell tumor-related disease at 1000 days from surgery; group 2 included cats developing histologically confirmed metastatic or cutaneous disseminated disease. The criteria allowing the best differentiation between the groups were used to develop a grading scheme. Groups 1 and 2 were composed by 48 (76%) and 15 (24%) cases, respectively. Tumors were classified as high grade if there were >5 mitotic figures in 10 fields (400*) and at least 2 of the following criteria: tumor diameter >1.5 cm, irregular nuclear shape, and nucleolar prominence/chromatin clusters. According to this scheme, the 15 (24%) high-grade cMCTs had significantly reduced survival time (median, 349 days; 95% CI, 0-739 days) as compared with the 48 low-grade tumors (median not reached; P < .001). Further studies are warranted to validate this grading system and test reproducibility on a larger case series. PMID- 30244667 TI - Patient-Centred IVF - Bioethics and Care in a Dutch Clinic. PMID- 30244668 TI - Exploring the relative importance of work-organizational burnout risk factors in Belgian residents. AB - Previous research has shown that residents are at risk for developing burnout. Most burnout measures focus on individual risk factors, although work organizational-focused measures might be beneficial as well. This study analyzed the relative importance of positive and negative work-organizational stressors, according to residents themselves, with NVivo11. Eleven work-organizational themes were found with deductive reasoning and two themes, recognition and success experiences, were found inductively. Main positive stressors are professional development, receiving feedback, experiencing success, autonomy and social support. Main negative stressors are high workloads, role conflicts/ambiguity, long work hours, and a lack of feedback, a lack of social support, and a lack of professional development. Measures to improve residents' well-being should not only focus on reducing workload and work hours. Our results suggest to allocate resources to improve supervisors' skills, such as providing social support, feedback, and recognition. A better match between internship obligations and residents' studies could also contribute positively to this purpose. PMID- 30244669 TI - Can the severity of orofacial myofunctional conditions interfere with the response of analgesia promoted by active or placebo low-level laser therapy? AB - OBJECTIVE: To analyze the influence of orofacial myofunctional condition (OMC) on pain perception, temporomandibular disorders (TMD) severity, and the response to low-level laser therapy (LLLT) in women with painful TMD. METHODS: Seventy-eight women, 59 with TMD, received active laser (30) or placebo (29), with 19 controls. OMC, TMD severity, pain intensity, and pressure pain threshold (PPT) were assessed at different times during the masticatory test: before treatment (LLLT dose: 780nm), during, and after 30 days. RESULTS: No correlation was found between OMC and pain perception or TMD severity (p > 0.05). The active and placebo LLLT showed reduction of pain during chewing and better recovery levels during the rest period (p > 0.05), without differences between OMC groups. DISCUSSION: The perception of pain and severity of TMD are not correlated with the OMC, and the response of analgesia promoted by active LLLT or placebo is not associated with OMC. PMID- 30244670 TI - Open questions: CRISPR biology. AB - CRISPR-Cas systems, the purveyors of adaptive immunity in archaea and bacteria and sources of the new generation of genome engineering tools, have been studied in exquisite molecular detail. However, when it comes to biological functions, ecology, and evolution of CRISPR-Cas, many more intriguing questions remain than there are answers. PMID- 30244672 TI - Gendered norms of responsibility: reflections on accountability politics in maternal health care in Malawi. AB - BACKGROUND: This paper aims to provide insights into the role of traditional authorities in two maternal health programmes in Northern Malawi. Among strategies to improve maternal health, these authorities issue by-laws: local rules to increase the uptake of antenatal and delivery care. The study uses a framework of gendered institutions to critically assess the by-law content, process and effects and to understand how responsibilities and accountabilities are constructed, negotiated and reversed. METHODS: Findings are based on a qualitative study in five health centre catchment areas in Northern Malawi. Data were collected using meeting observations and document search, 36 semi-structured individual interviews and 19 focus group discussions with female maternal health service users, male community members, health workers, traditional leaders, local officials and health committee members. A gender and power sensitive thematic analysis was performed focusing on the formulation, interpretation and implementation process of the by-laws as well as its effects on women and men. RESULTS: In the study district, traditional leaders introduced three by-laws that oblige pregnant women to attend antenatal care; bring their husbands along and; and to give birth in a health centre. If women fail to comply with these rules, they risk being fined or denied access to maternal health services. The findings show that responsibilities and accountabilities are negotiated and that by-laws are not uniformly applied. Whereas local officials support the by-laws, lower level health cadres' and some community members contest them, in particular, the principles of individual responsibility and universality. CONCLUSIONS: The study adds new evidence on the understudied phenomenon of by-laws. From a gender perspective, the by-laws are problematic as they individualise the responsibility for maternal health care and discriminate against women in the definition and application of sanctions. Through the by-laws, supported by national policies and international institutions, women bear the full responsibility for failures in maternal health care, suggesting a form of 'reversed accountability' of women towards global maternal health goals. This can negatively impact on women's reproductive health rights and obstruct ambitions to achieve gender inequality and health equity. Contextualised gender and power analysis in health policymaking and programming as well as in accountability reforms could help to identify these challenges and potential unintended effects. PMID- 30244671 TI - Inflammation and micronutrient biomarkers predict clinical HIV treatment failure and incident active TB in HIV-infected adults: a case-control study. AB - BACKGROUND: Various individual biomarkers of inflammation and micronutrient status, often correlated with each other, are associated with adverse treatment outcomes in human immunodeficiency virus (HIV)-infected adults. The objective of this study was to conduct exploratory factor analysis (EFA) on multiple inflammation and micronutrient biomarkers to identify biomarker groupings (factors) and determine their association with HIV clinical treatment failure (CTF) and incident active tuberculosis (TB). METHODS: Within a multicountry randomized trial of antiretroviral therapy (ART) efficacy (PEARLS) among HIV infected adults, we nested a case-control study (n = 290; 124 cases, 166 controls) to identify underlying factors, based on EFA of 23 baseline (pre-ART) biomarkers of inflammation and micronutrient status. The EFA biomarker groupings results were used in Cox proportional hazards models to study the association with CTF (primary analysis where cases were incident World Health Organization stage 3, 4 or death by 96 weeks of ART) or incident active TB (secondary analysis). RESULTS: In the primary analysis, based on eigenvalues> 1 in the EFA, three factors were extracted: (1) carotenoids), (2) other nutrients, and (3) inflammation. In multivariable-adjusted models, there was an increased hazard of CTF (adjusted hazard ratio (aHR) 1.47, 95% confidence interval (CI)1.17-1.84) per unit increase of inflammation factor score. In the secondary incident active TB case-control analysis, higher scores of the high carotenoids and low interleukin 18 factor was protective against incident active TB (aHR 0.48, 95% CI 0.26-0.87). CONCLUSION: Factors identified through EFA were associated with adverse outcomes in HIV-infected individuals. Strategies focused on reducing adverse HIV outcomes through therapeutic interventions that target the underlying factor (e.g., inflammation) rather than focusing on an individual observed biomarker might be more effective and warrant further investigation. PMID- 30244673 TI - Cardiovascular magnetic resonance imaging in the prospective, population-based, Hamburg City Health cohort study: objectives and design. AB - BACKGROUND: The purpose of this work is to describe the objectives and design of cardiovascular magnetic resonance (CMR) imaging in the single center, prospective, population-based Hamburg City Health study (HCHS). The HCHS aims at improving risk stratification for coronary artery disease (CAD), atrial fibrillation (AF) and heart failure (HF). METHODS: The HCHS will finally include 45,000 inhabitants of the city of Hamburg (Germany) between 45 and 74 years who undergo an extensive cardiovascular evaluation and collection of biomaterials. Risk-scores for CAD, AF and HF are used to create enriched subpopulations who are invited for CMR. A total number of approximately 12,362 subjects will undergo CMR and incident CAD, AF and HF will be assessed after 6 years follow-up. The standard CMR protocol includes cine-CMR, T1 and T2 mapping, aortic/mitral valve flow measurements, Late gadolinium enhancement, angiographies and measurements of aortic distensibility. A stress-perfusion scan is added in individuals at risk for CAD. The workflow of CMR data acquisition and analyses was evaluated in a pilot cohort of 200 unselected subjects. RESULTS: The obtained CMR findings in the pilot cohort agree with current reference values and demonstrate the ability of the established workflow to accomplish the objectives of HCHS. CONCLUSIONS: CMR in HCHS promises novel insights into major cardiovascular diseases, their subclinical precursors and the prognostic value of novel imaging biomarkers. The HCHS database will facilitate combined analyses of imaging, clinical and molecular data ("Radiomics"). PMID- 30244675 TI - Are we entering a new era for qualitative research? Using qualitative evidence to support guidance and guideline development by the World Health Organization. AB - Qualitative approaches are one of several methodologies utilised within the social sciences. New developments within qualitative methods are widening the opportunities for using qualitative evidence to inform health policy and systems decisions. In this commentary, we discuss how, in our work with the World Health Organization (WHO), we have explored ways of broadening the types of evidence used to develop evidence-informed guidance for health systems.Health systems decisions are commonly informed by evidence on the effectiveness of health system interventions. However, decision makers and other stakeholders also typically have additional questions, including how different stakeholders value different outcomes, the acceptability and feasibility of different interventions and the impacts of these interventions on equity and human rights. Evidence from qualitative research can help address these questions, and a number of WHO guidelines are now using qualitative evidence in this way. This growing use of qualitative evidence to inform decision making has been facilitated by recent methodological developments, including robust methods for qualitative evidence syntheses and approaches for assessing how much confidence to place in findings from such syntheses. For research evidence to contribute optimally to improving and sustaining the performance of health systems, it needs to be transferred easily between different elements of what has been termed the 'evidence ecosystem'. This ecosystem includes primary and secondary evidence producers, guidance developers and those implementing and evaluating interventions to strengthen health systems. We argue that most of the elements of an ecosystem for qualitative evidence are now in place - an important milestone that suggests that we are entering a new era for qualitative research. However, a number of challenges and constraints remain. These include how to build stronger links between the communities involved in the different parts of the qualitative evidence ecosystem and the need to strengthen capacity, particularly in low and middle income countries, to produce and utilise qualitative evidence and decision products informed by such evidence. We invite others who want to support the wider use of qualitative evidence in decision processes to look for opportunities in their settings to put this into practice. PMID- 30244676 TI - Showcasing the contribution of social sciences to health policy and systems research. AB - BACKGROUND: This Special Issue represents a critical response to the frequent silencing of qualitative social science research approaches in mainstream public health journals, particularly in those that inform the field of health policy and systems research (HPSR), and the study of equity in health. METHODS: This collection of articles is presented by SHAPES, the thematic working group of Health Systems Global focused on social science approaches to research and engagement in health policy and systems. The issue aims to showcase how qualitative and theory-driven approaches can contribute to better promoting equity in health within the field of HPSR. RESULTS: This issue builds on growing recognition of the complex social nature of health systems. The articles in this collection underscore the importance of employing methods that can uncover and help explain health system complexities by exploring the dynamic relationships and decision-making processes of the human actors within. Articles seek to highlight the contribution that qualitative, interpretivist, critical, emancipatory, and other relational methods have made to understanding health systems, health policies and health interventions from the perspective of those involved. By foregrounding actor perspectives, these methods allow us to explore the impact of vital but difficult-to-measure concepts such as power, culture and norms. CONCLUSION: This special issue aims to highlight the critical contribution of social science approaches. Through the application of qualitative methods and, in some cases, development of theory, the articles presented here build broader and deeper understanding of the way health systems function, and simultaneously inform a more people-centred approach to collective efforts to build and strengthen those systems. PMID- 30244677 TI - Blood-brain and blood-cerebrospinal fluid barrier permeability in spontaneously hypertensive rats. AB - BACKGROUND: Hypertension is an important risk factor for cerebrovascular disease, including stroke and dementia. Both in humans and animal models of hypertension, neuropathological features such as brain atrophy and oedema have been reported. We hypothesised that cerebrovascular damage resulting from chronic hypertension would manifest itself in a more permeable blood-brain barrier and blood cerebrospinal fluid barrier. In addition, more leaky barriers could potentially contribute to an enhanced interstitial fluid and cerebrospinal fluid formation, which could, in turn, lead to an elevated intracranial pressure. METHODS: To study this, we monitored intracranial pressure and estimated the cerebrospinal fluid production rate in spontaneously hypertensive (SHR) and normotensive rats (Wistar Kyoto, WKY) at 10 months of age. Blood-brain barrier and blood cerebrospinal fluid barrier integrity was determined by measuring the leakage of fluorescein from the circulation into the brain and cerebrospinal fluid compartment. Prior to sacrifice, a fluorescently labelled lectin was injected into the bloodstream to visualise the vasculature and subsequently study a number of specific vascular characteristics in six different brain regions. RESULTS: Blood and brain fluorescein levels were not different between the two strains. However, cerebrospinal fluid fluorescein levels were significantly lower in SHR. This could not be explained by a difference in cerebrospinal fluid turnover, as cerebrospinal fluid production rates were similar in SHR and WKY, but may relate to a larger ventricular volume in the hypertensive strain. Also, intracranial pressure was not different between SHR and WKY. Morphometric analysis of capillary volume fraction, number of branches, capillary diameter, and total length did not reveal differences between SHR and WKY. CONCLUSION: In conclusion, we found no evidence for blood-brain barrier or blood-cerebrospinal fluid barrier leakage to a small solute, fluorescein, in rats with established hypertension. PMID- 30244679 TI - What have the social sciences ever done for equity in health policy and health systems? AB - BACKGROUND: The social sciences can be defined as the scientific study of human society and social relationships. MAIN TEXT: A number of underpinning disciplines within the social sciences, notably sociology, social psychology and anthropology, as well as interdisciplinary fields like science and technology studies and migration studies, offer both theoretical insights and methodological approaches which can productively enhance the study of equity in health systems and policy research. In particular, qualitative research in general and the use of narrative methods in particular can help illuminate individual experience and the interaction of multiple structural influences on that experience. CONCLUSION: This article sets the theoretical scene for a special issue of the journal on social sciences and equity. PMID- 30244678 TI - Net ultrafiltration intensity and mortality in critically ill patients with fluid overload. AB - BACKGROUND: Although net ultrafiltration (UFNET) is frequently used for treatment of fluid overload in critically ill patients with acute kidney injury, the optimal intensity of UFNET is unclear. Among critically ill patients with fluid overload receiving renal replacement therapy (RRT), we examined the association between UFNET intensity and risk-adjusted 1-year mortality. METHODS: We selected patients with fluid overload >= 5% of body weight prior to initiation of RRT from a large academic medical center ICU dataset. UFNET intensity was calculated as the net volume of fluid ultrafiltered per day from initiation of either continuous or intermittent RRT until the end of ICU stay adjusted for patient hospital admission body weight. We stratified UFNET as low (<= 20 ml/kg/day), moderate (> 20 to <= 25 ml/kg/day) or high (> 25 ml/kg/day) intensity. We adjusted for age, sex, body mass index, race, surgery, baseline estimated glomerular filtration rate, oliguria, first RRT modality, pre-RRT fluid balance, duration of RRT, time to RRT initiation from ICU admission, APACHE III score, mechanical ventilation use, suspected sepsis, mean arterial pressure on day 1 of RRT, cumulative fluid balance during RRT and cumulative vasopressor dose during RRT. We fitted logistic regression for 1-year mortality, Gray's survival model and propensity matching to account for indication bias. RESULTS: Of 1075 patients, the distribution of high, moderate and low-intensity UFNET groups was 40.4%, 15.2% and 44.2% and 1-year mortality was 59.4% vs 60.2% vs 69.7%, respectively (p = 0.003). Using logistic regression, high-intensity compared with low-intensity UFNET was associated with lower mortality (adjusted odds ratio 0.61, 95% CI 0.41-0.93, p = 0.02). Using Gray's model, high UFNET was associated with decreased mortality up to 39 days after ICU admission (adjusted hazard ratio range 0.50-0.73). After combining low and moderate-intensity UFNET groups (n = 258) and propensity matching with the high-intensity group (n = 258), UFNET intensity > 25 ml/kg/day compared with <= 25 ml/kg/day was associated with lower mortality (57% vs 67.8%, p = 0.01). Findings were robust to several sensitivity analyses. CONCLUSIONS: Among critically ill patients with >= 5% fluid overload and receiving RRT, UFNET intensity > 25 ml/kg/day compared with <= 20 ml/kg/day was associated with lower 1-year risk-adjusted mortality. Whether tolerating intensive UFNET is just a marker for recovery or a mediator requires further research. PMID- 30244674 TI - Pharmacokinetics-pharmacodynamics issues relevant for the clinical use of beta lactam antibiotics in critically ill patients. AB - Antimicrobials are among the most important and commonly prescribed drugs in the management of critically ill patients and beta-lactams are the most common antibiotic class used. Critically ill patient's pathophysiological factors lead to altered pharmacokinetics and pharmacodynamics of beta-lactams.A comprehensive bibliographic search in PubMed database of all English language articles published from January 2000 to December 2017 was performed, allowing the selection of articles addressing the pharmacokinetics or pharmacodynamics of beta lactam antibiotics in critically ill patients.In critically ill patients, several factors may increase volume of distribution and enhance renal clearance, inducing high intra- and inter-patient variability in beta-lactam concentration and promoting the risk of antibiotic underdosing. The duration of infusion of beta lactams has been shown to influence the fT > minimal inhibitory concentration and an improved beta-lactam pharmacodynamics profile may be obtained by longer exposure with more frequent dosing, extended infusions, or continuous infusions.The use of extracorporeal support techniques in the critically ill may further contribute to this problem and we recommend not reducing standard antibiotic dosage since no drug accumulation was found in the available literature and to maintain continuous or prolonged infusion, especially for the treatment of infections caused by multidrug-resistant bacteria.Prediction of outcome based on concentrations in plasma results in overestimation of antimicrobial activity at the site of infection, namely in cerebrospinal fluid and the lung. Therefore, although no studies have assessed clinical outcome, we recommend using higher than standard dosing, preferably with continuous or prolonged infusions, especially when treating less susceptible bacterial strains at these sites, as the pharmacodynamics profile may improve with no apparent increase in toxicity.A therapeutic drug monitoring-guided approach could be particularly useful in critically ill patients in whom achieving target concentrations is more difficult, such as obese patients, immunocompromised patients, those infected by highly resistant bacterial strains, patients with augmented renal clearance, and those undergoing extracorporeal support techniques. PMID- 30244680 TI - Socialization, legitimation and the transfer of biomedical knowledge to low- and middle-income countries: analyzing the case of emergency medicine in India. AB - BACKGROUND: Medical specialization is a key feature of biomedicine, and is a growing, but weakly understood aspect of health systems in many low- and middle income countries (LMICs), including India. Emergency medicine is an example of a medical specialty that has been promoted in India by several high-income country stakeholders, including the Indian diaspora, through transnational and institutional partnerships. Despite the rapid evolution of emergency medicine in comparison to other specialties, this specialty has seen fragmentation in the stakeholder network and divergent training and policy objectives. Few empirical studies have examined the influence of stakeholders from high-income countries broadly, or of diasporas specifically, in transferring knowledge of medical specialization to LMICs. Using the concepts of socialization and legitimation, our goal is to examine the transfer of medical knowledge from high-income countries to LMICs through domestic, diasporic and foreign stakeholders, and the perceived impact of this knowledge on shaping health priorities in India. METHODS: This analysis was conducted as part of a broader study on the development of emergency medicine in India. We designed a qualitative case study focused on the early 1990s until 2015, analyzing data from in-depth interviewing (n = 87), document review (n = 248), and non-participant observation of conferences and meetings (n = 6). RESULTS: From the early 1990s, domestic stakeholders with exposure to emergency medicine in high-income countries began to establish Emergency Departments and initiate specialist training in the field. Their efforts were amplified by the active legitimation of emergency medicine by diasporic and foreign stakeholders, who formed transnational partnerships with domestic stakeholders and organized conferences, training programs and other activities to promote the field in India. However, despite a broad commitment to expanding specialist training, the network of domestic, diasporic and foreign stakeholders was highly fragmented, resulting in myriad unstandardized postgraduate training programs and duplicative policy agendas. Further, the focus in this time period was largely on training specialists, resulting in more emphasis on a medicalized, tertiary-level form of care. CONCLUSIONS: This analysis reveals the complexities of the roles and dynamics of domestic, diasporic and foreign stakeholders in the evolution of emergency medicine in India. More research and critical analyses are required to explore the transfer of medical knowledge, such as other medical specialties, models of clinical care, and medical technologies, from high-income countries to India. PMID- 30244681 TI - Goblet cell carcinoid of the appendix - diagnostic challenges and treatment updates: a case report and review of the literature. AB - BACKGROUND: Goblet cell carcinoid is a rare but distinct entity of appendiceal tumors which is a hybrid or mixed tumor consisting of both epithelial (glandular) and neuroendocrine elements containing goblet cells. This entity is important to recognize and appropriately grade as it tends to be more aggressive than typical carcinoid tumors, often presenting with metastatic disease. As a result, the 5 year overall survival is 14-22% in stage III-IV disease. GCC therefore warrants more aggressive surgical and medical (chemotherapy) interventions than typical carcinoid tumors. Through this case report we give a brief update on GCC pathological features, staging, surgical management, and review the literature as a guide to indications for chemotherapy and choice of agents. CASE PRESENTATION: We present the case of a 77-year-old Caucasian man with a history of stage I adenocarcinoma of transverse colon status post transverse colectomy who was incidentally found on surveillance colonoscopy to have an abnormal appendiceal orifice lesion. A biopsy revealed an appendiceal goblet cell carcinoid and he underwent a right hemicolectomy which revealed a pathologic stage III GCC for which he received eight cycles of adjuvant chemotherapy with capecitabine. CONCLUSIONS: It is essential that patients who have tumors > 2 cm, are pT3 or pT4, have higher grade histology with signet ring (Tang grade B or grade C), locally advanced, or with positive surgical margins on appendectomy undergo a right hemicolectomy. Although there is no category 1 evidence, consensus recommendations are that patients with stage II (particularly Tang B and C) and stage III GCC be offered adjuvant chemotherapy with a regimen based on 5 fluorouracil, as these patients are known to have high rates of relapse. PMID- 30244682 TI - Examining intersectional inequalities in access to health (enabling) resources in disadvantaged communities in Scotland: advancing the participatory paradigm. AB - BACKGROUND: Multiple structural, contextual and individual factors determine social disadvantage and affect health experience. There is limited understanding, however, of how this complex system works to shape access to health enabling resources (HER), especially for most marginalised or hard-to-reach populations. As a result, planning continues to be bereft of voices and lived realities of those in the margins. This paper reports on key findings and experience of a participatory action research (PAR) that aimed to deepen understanding of how multiple disadvantages (and structures of oppression) interact to produce difference in access to resources affecting well-being in disadvantaged communities in Edinburgh. METHODS: An innovative approach combining intersectionality and PAR was adopted and operationalised in three overlapping phases. A preparatory phase helped establish relationships with participant groups and policy stakeholders, and challenge assumptions underlying the study design. Field-work and analysis was conducted iteratively in two phases: with a range of participants working in policy and community roles (or 'bridge' populations), followed by residents of one Edinburgh locality with relatively high levels of deprivation (As measured by the Scottish Index of Multiple Deprivation, a geographically-based indicator. See http://www.gov.scot/Topics/Statistics/SIMD/DataAnalysis/SPconstituencyprofile/Edi burghNorthern-Leith ). Traditional qualitative methods (interviews, focus groups) alongside participatory methods (health resource mapping, spider-grams, photovoice) were employed to facilitate action-oriented knowledge production among multiply disadvantaged groups. RESULTS: There was considerable agreement across groups and communities as to what healthful living (in general) means. This entailed a combination of material, environmental, socio-cultural and affective resources including: a sense of belonging and of purpose, feeling valued, self-esteem, safe/secure housing, reliable income, and access to responsive and sensitive health care when needed. Differences emerge in the value placed by people at different social locations on these resources. The conditions/aspects of their living environment that affected their access to and ability to translate these resources into improved health also appeared to vary with social location. CONCLUSION: Integrating intersectionality with PAR enables the generation of a fuller understanding of disparities in the distribution of, and access to, HER, notably from the standpoint of those excluded from mainstream policy and planning processes. Employing an intersectionality lens helped illuminate links between individual subjectivities and wider social structures and power relations. PAR on the other hand offered the potential to engage multiply disadvantaged groups in a process to collectively build local knowledge for action to develop healthier communities and towards positive community-led social change. PMID- 30244683 TI - Beyond the template: the needs of tribal women and their experiences with maternity services in Odisha, India. AB - BACKGROUND: Over the past 15 years, several efforts have been made by the Government of India to improve maternal health, primarily through providing cash incentives to increase institutional child birth and strengthen services in the public health system. The result has been a definite but unequal increase in the proportion of institutional deliveries, across geographical areas and social groups. Tribal (indigenous) communities are one such group in which the proportion of institutional deliveries is low. The persistence of these inequities indicates that a different approach is required to address the maternal health challenges in these communities. METHODS: This paper describes an exploratory study in Rayagada District of Odisha which aimed to understand tribal women's experiences with pregnancy and childbirth and their interactions with the formal health system. Methods included in-depth interviews with women, traditional healers and formal health care providers and outreach workers, observations in the community and health facilities. RESULTS: The exploration of traditional practices shows that in this community, pregnancy and childbirth is treated as part of a natural process, not requiring external intervention. There is a well-established practice of birthing in the community which also recognizes the need for health system interventions in case of high-risk births or complications. However, there has been no effort by the health system to build on this traditional understanding of safety of woman and child. Instead, the system continues to rely on incentives and disincentives to motivate women. Traditional health providers who are important stakeholders have not been integrated into the health system. Despite the immense difficulties that women face, however, they do access health facilities, but barriers of distance, language, cultural inappropriateness of services, and experiences of gross violations have further compounded their distrust. CONCLUSIONS: The results of the study suggest a re examining of the very approach to addressing maternal health in this community. The study calls for reorienting maternal health services, to be responsive to the requirements of tribal women, cater to their cultural needs, provide support to domiciliary deliveries, invest in building trust with the community, and preserve beneficial traditional practices. PMID- 30244684 TI - The health system accountability impact of prison health committees in Zambia. AB - BACKGROUND: From 2013, the Zambian Corrections Service (ZCS) worked with partners to strengthen prison health systems and services. One component of that work led to the establishment of facility-based Prison Health Committees (PrHCs) comprising of both inmates and officers. We present findings from a nested evaluation of the impact of eight PrHCs 18 months after programme initiation. METHODS: In-depth-interviews were conducted with 11 government ministry and Zambia Corrections Service officials and 6 facility managers. Sixteen focus group discussions were convened separately with PrHC members (21 females and 51 males) and non-members (23 females and 46 males) in 8 facilities. Memos were generated from participant observation in workshops and meetings preceding and after implementation. We sought evidence of PrHC impact, refined with reference to Joshi's three domains of impact for social accountability interventions - state (represented by facility-based prison officials), society (represented here by inmates), and state-society relations (represented by inmate-prison official relations). Further analysis considered how project outcomes influenced structural dimensions of power, ability and justice relating to accountability. RESULTS: Data pointed to a compelling series of short- and mid-term outcomes, with positive impact on access to, and provision of, health services across most facilities. Inmates (members and non-members) reported being empowered via a combination of improved health literacy and committee members' newly-given authority to seek official redress for complaints and concerns. Inmates and officers described committees as improving inmate-officer relations by providing a forum for information exchange and shared decision making. Contributing factors included more consistent inmate-officer communications through committee meetings, which in turn enhanced trust and co-production of solutions to health problems. Nonetheless, long-term sustainability of accountability impacts may be undermined by permanently skewed power relations, high rates of inmate (and thus committee member) turnover, variable commitment from some officers in-charge, and the anticipated need for more oversight and resources to maintain members' skills and morale. CONCLUSION: Our study shows that PrHCs do have potential to facilitate improved social accountability in both state and societal domains and at their intersection, for an extremely vulnerable population. However, sustained and meaningful change will depend on a longer-term strategy that integrates structural reform and is delivered through meaningful cross-sectoral partnership. PMID- 30244685 TI - The unintended consequences of combining equity measures with performance-based financing in Burkina Faso. AB - BACKGROUND: User fees and poor quality of care contribute to low use of healthcare services in Burkina Faso. The government implemented an innovative intervention that combines equity measures with performance-based financing (PBF). These health equity measures included a community-based selection of indigents to receive user fee exemptions and paying healthcare centres higher purchase prices for services provided to indigents. Research suggests complex interventions can trigger changes not targeted by program planners. To date, however, there is a knowledge gap regarding the unintended consequences that can emerge from combining PBF with health equity measures. Our objective is to document unintended consequences of the equity measures in this complex intervention. METHODS: We developed a conceptual framework using the diffusion of innovations theory. For the design, we conducted a multiple case study. The cases were four healthcare facilities in one district. We collected data through 93 semi-structured interviews, informal discussions, observation, as well as intervention documents. We conducted thematic analysis using a hybrid deductive inductive approach. We also used secondary data to describe the monthly evolution of services provided to indigent and non-indigent patients before and after indigent cards were distributed. Time series graphs were used to validate some results. RESULTS: Local actors, including members of indigent selection committees and healthcare workers, re-invented elements of the PBF equity measures over which they had control to increase their relative advantage or to adapt to implementation challenges and context. Some individuals who did not meet the local conceptualization of indigents were selected to the detriment of others who did. Healthcare providers believed that distributing free medications led to financial difficulties and drug shortages, especially given the low purchase prices and long payment delays. Healthcare workers adopted measures to limit free services delivered to indigents, which led to conflicts between indigents and providers. Ultimately, selected indigents received uncertain and unequal coverage. CONCLUSIONS: The severity of unintended consequences undermined the effectiveness and equity of the intervention. If the intervention is prolonged and expanded, decision-makers and implementers will have to address these unintended consequences to reduce inequities in accessing care. PMID- 30244687 TI - Conducting clinical studies targeting cognition in psychiatry: guiding principles and design. AB - Cognitive dysfunction is common in many psychiatric disorders. While it has long been described as a core feature in schizophrenia, more recent data suggest qualitatively similar impairments in patients with bipolar disorder and major depressive disorder. There is compelling evidence to suggest that cognitive impairment contributes directly to functional disability and reduced quality of like across these disorders. As current treatments focus heavily on "primary" symptoms of mood and psychosis, the standard of care typically leaves cognitive deficits unmanaged. With this in mind, the field has recently begun to consider intervening directly on this important symptom domain, with several ongoing trials in schizophrenia. Fewer studies have targeted cognition in bipolar disorder and still fewer in MDD. With progress toward considering this domain as a target for treatment comes the need for consensus guidelines and methodological recommendations on cognitive trial design. In this manuscript, we first summarize the work conducted to date in this area for schizophrenia and for bipolar disorder. We then begin to address these same issues in MDD and emphasize the need for additional work in this area. PMID- 30244688 TI - Interventions for hearing and vision impairment to improve outcomes for people with dementia: a scoping review. AB - : ABSTRACTBackground:Age-related hearing and vision problems are common among people with dementia and are associated with poorer function, reduced quality of life and increased caregiver burden. Addressing sensory impairments may offer an opportunity to improve various aspects of life for people with dementia. METHODS: Electronic databases were searched using key terms dementia, hearing impairment, vision impairment, intervention, and management. Database searches were supplemented by hand searching bibliographies of papers and via consultation with a network of health professional experts. Studies were eligible for inclusion if they included adults aged over 50 with dementia with adult-onset hearing or vision impairment who had received a hearing or vision intervention in relation to cognitive function, rate of decline, psychiatric symptoms, hearing/vision related disability, quality of life, and/or caregiver burden outcomes. A range of study designs were included. Results were summarized descriptively according to level of evidence and effect sizes calculated where possible. Risk of bias was assessed using Downs and Black's (1998) checklist. The development of the intervention was summarized according to the CReDECI2 scheme. PROSPERO review registration number 2016:CRD42016039737. RESULTS: Twelve papers describing hearing interventions and five papers describing vision interventions were included. Most were of low to moderate quality. One high quality randomized controlled trial of a hearing aid intervention was identified. Hearing interventions included provision of hearing aids, assistive listening devices, communication strategies, hearing aid trouble shooting, and cochlear implantation. Vision interventions included prism lenses, rehabilitation training, and cataract surgery. There was no consistent evidence for the positive impact of hearing/vision interventions on cognitive function, rate of cognitive decline, quality of life, or caregiver burden. CONCLUSION: Sensory interventions may promote better outcomes, but there is a need for properly powered, controlled trials of hearing and vision interventions on outcomes relevant to people living with dementia. PMID- 30244689 TI - National survey of attitudes towards pregnancy termination procedures among anaesthesiology residents in the US. AB - Anaesthesiologists are vital to abortion access in the US. An online survey of 215 anaesthesiology residents assessed attitudes towards abortion. Among the surveyed residents, first-trimester abortion was more acceptable than second trimester abortion (P < 0.001). Few respondents objected to abortion in cases of fetal anomalies or maternal health indications. Further, 77.3% of surveyed residents reported past participation in abortion procedures, including 77.8% of residents with objections to abortion in some circumstances. Anaesthesiology residents who are female, childless and non-religious were more likely to find first-trimester abortion acceptable. PMID- 30244690 TI - Simulation of health care and related costs in people with dementia in Australia. AB - Objectives The aim of this study was to develop a validated model to predict current and future Australian costs for people with dementia to help guide decision makers allocate scarce resources in the presence of capacity constraints.Methods A hybrid discrete event simulation was developed to predict costs borne in Australia for people with dementia from 2015 to 2050. The costs captured included community-based care, permanent and respite residential aged care, hospitalisation, transitional care, pharmaceuticals, aged care assessments, out of hospital medical services and other programs.Results The costs borne for people with dementia in Australia are predicted to increase from A$11.8 billion in 2015 to A$33.6 billion in 2050 at 2013-14 prices, ceteris paribus. If real per capita health and social expenditure increased by 1.0% annually, these costs are predicted to increase by around A$14.2 billion to a total of around A$47.8 billion by 2050.Conclusions This simulation provides useful estimates of the potential future costs that will be borne for people with dementia and allows the exploration of the effects of capacity constraints on these costs. The model demonstrates that the level of real annual per capita growth in health and social expenditure has significant implications for the future sustainability of dementia care in Australia.What is known about the topic? With the aging of the Australian population, the number of people living with dementia is predicted to rise markedly in the next four decades. As the number of people living with dementia increases, so too will the financial burden these debilitating and degenerative diseases place on private and public resources. These increases are likely to challenge the efficiency and sustainability of many health systems in the developed world.What does this paper add? This research provides a validated model to predict current and future Australian costs for people with dementia to help guide decision makers allocate scarce resources in the presence of capacity constraints (i.e. where the supply of resources does not meet demand). The model predicts an increase in costs for people with dementia from A$11.8 billion in 2015 to A$33.6 billion in 2050 at 2013-14 prices. If real per capita health and social expenditure increased by 1.0% annually, these costs are predicted to increase by around A$14.2 billion to a total of around A$47.8 billion by 2050.What are the implications for practitioners? This simulation provides useful estimates of the potential future costs that will be borne for people with dementia and allows the exploration of the effects of capacity constraints on these costs. The model demonstrates that the level of real annual per capita growth in health and social expenditure has significant implications for the future sustainability of dementia care in Australia. PMID- 30244691 TI - Facilitators of and barriers to high-resolution anoscopy adherence among men who have sex with men: a qualitative study. AB - Background: Anal cancer is a rare malignancy that disproportionately affects men who have sex with men (MSM) and HIV-infected people. Anal cancer is associated with human papillomavirus (HPV) in upward of 90% of cases and is preceded by pre cancerous changes in cells of the anal canal. High-resolution anoscopy (HRA) is used for the detection, treatment and continued monitoring of anal dysplasia. Practice guidelines regarding anal cancer prevention vary by jurisdiction and institution, and patient engagement is low for high-risk populations such as MSM. The purpose of this study is to characterise perceptions among MSM of barriers to and facilitators of their adherence to HRA follow-up recommendations. Methods: Surveys and in-person focus groups with MSM who were either adherent or non adherent to HRA follow-up recommendations at a Federally Qualified Health Centre in Boston, MA, which specialises in sexual and gender minority care, were conducted. Facilitators of and barriers to follow-up were identified by deductive content analysis. Results: Focus group participants identified the following barriers to and facilitators of HRA follow up: (1) patient-level beliefs about HPV-related disease or HRA, ability to engage in care, internalised stigma and physical discomfort; (2) provider-level knowledge and expertise, communication skills and relationship-building with patient; and (3) systems-level societal stigma and healthcare system inefficiencies. Conclusions: Reinforcing facilitators of and reducing barriers to HRA follow up may improve adherence among MSM. This includes improvements to: patient education, provider training to increase knowledge and cultural sensitivity, public awareness about HPV-related anal cancer, physical discomfort associated with HRA and systems inefficiencies. PMID- 30244693 TI - A broader filtration of UVA1 wavelengths improves skin photoprotection. PMID- 30244694 TI - Untangling Mesoamerican Nephropathy. PMID- 30244686 TI - Enteral nutrition feeding in Chinese intensive care units: a cross-sectional study involving 116 hospitals. AB - BACKGROUND: There is a lack of large-scale epidemiological data on the clinical practice of enteral nutrition (EN) feeding in China. This study aimed to provide such data on Chinese hospitals and to investigate factors associated with EN delivery. METHODS: This cross-sectional study was launched in 118 intensive care units (ICUs) of 116 mainland hospitals and conducted on April 26, 2017. At 00:00 on April 26, all patients in these ICUs were included. Demographic and clinical variables of patients on April 25 were obtained. The dates of hospitalization, ICU admission and nutrition initiation were reviewed. The outcome status 28 days after the day of investigation was obtained. RESULTS: A total of 1953 patients were included for analysis, including 1483 survivors and 312 nonsurvivors. The median study day was day 7 (IQR 2-19 days) after ICU entry. The proportions of subjects starting EN within 24, 48 and 72 h after ICU entry was 24.8% (84/352), 32.7% (150/459) and 40.0% (200/541), respectively. The proportion of subjects receiving > 80% estimated energy target within 24, 48, 72 h and 7 days after ICU entry was 10.5% (37/352), 10.9% (50/459), 11.8% (64/541) and 17.8% (162/910), respectively. Using acute gastrointestinal injury (AGI) 1 as the reference in a Cox model, patients with AGI 2-3 were associated with reduced likelihood of EN initiation (HR 0.46, 95% CI 0.353-0.599; p < 0.001). AGI 4 was significantly associated with lower hazard of EN administration (HR 0.056; 95% CI 0.008-0.398; p = 0.004). In a linear regression model, greater Sequential Organ Failure Assessment scores (coefficient - 0.002, 95% CI - 0.008 to - 0.001; p = 0.024) and male gender (coefficient - 0.144, 95% CI - 0.203 to - 0.085; p < 0.001) were found to be associated with lower EN proportion. As compared with AGI 1, AGI 2-3 was associated with lower EN proportion (coefficient - 0.206, 95% CI - 0.273 to - 0.139; p < 0.001). CONCLUSIONS: The study showed that EN delivery was suboptimal in Chinese ICUs. More attention should be paid to EN use in the early days after ICU admission. PMID- 30244692 TI - Aim for the core: suitability of the ubiquitin-independent 20S proteasome as a drug target in neurodegeneration. AB - Neurodegenerative diseases are a class of age-associated proteopathies characterized by the accumulation of misfolded and/or aggregation-prone proteins. This imbalance has been attributed, in part, to an age-dependent decay in the capacity of protein turnover. Most proteins are degraded by the ubiquitin proteasome system (UPS), which is composed of ubiquitin ligases and regulatory particles, such as the 19S, that deliver cargo to the proteolytically active 20S proteasome (20S) core. However, a subset of clients, especially intrinsically disordered proteins (IDPs), are also removed by the action of the ubiquitin independent proteasome system (UIPS). What are the specific contributions of the UPS and UIPS in the context of neurodegeneration? Here, we explore how age associated changes in the relative contribution of the UPS and UIPS, combined with the IDP-like structure of many neurodegenerative disease-associated proteins, might contribute. Strikingly, the 20S has been shown to predominate in older neurons and to preferentially act on relevant substrates, such as synuclein and tau. Moreover, pharmacological activation of the 20S has been shown to accelerate removal of aggregation-prone proteins in some models. Together, these recent studies are turning attention to the 20S and the UIPS as potential therapeutic targets in neurodegeneration. PMID- 30244695 TI - The Evaluation of Living Kidney Donors: How Long Is Too Long? PMID- 30244696 TI - Fever and Gross Hematuria in Kidney Transplant Recipient. PMID- 30244697 TI - Synthetic Biology Ethics at iGEM: iGEMer Perspectives. AB - The Human Practice (HP) work of the international Genetically Engineered Machine (iGEM) competition can serve as a great example of integrating ethical considerations into synthetic biology research. By highlighting three independent perspectives from those involved in various aspects of iGEM, here we aim to provide an informative picture of how ethical issues are approached within the iGEM competition. PMID- 30244698 TI - An improved method for vitrification of in vitro matured ovine oocytes; beneficial effects of Ethylene Glycol Tetraacetic acid, an intracellular calcium chelator. AB - Vitrification affects fertilization ability and developmental competence of mammalian oocytes. This effect may be more closely associated with an intracellular calcium rise induced by cryoprotectants. The present study aimed to assess whether addition of Ethylene Glycol Tetraacetic acid (EGTA) to vitrification solution could improve quality and developmental competence of in vitro matured ovine oocytes. Vitrified groups were designed according to the presence or absence of EGTA and/or calcium in base media, including: mPB1+ (modified PBS with Ca2+), mPB1- (modified PBS without Ca2+), mPB1+/EGTA (mPB1+ containing EGTA), mPB1-/EGTA (mPB1- containing EGTA). In vitro development, numerical chromosome abnormalities, hardening of zona pellucida, mitochondrial distribution and function of viable oocytes were evaluated and compared between groups. Quality of blastocysts was assessed by differential and TUNEL staining. Also, mRNA expression levels of six candidate genes (KIF11, KIF2C, CENP-E, KIF20A, KIF4A and KIF2A), were quantitatively evaluated by RT-PCR. Our results showed that calcium-free vitrification and EGTA supplementation can significantly increase the percentage of normal haploid oocytes and maintain normal distribution and function of mitochondria in vitrified ovine oocytes, consequently improving developmental rate after in vitro fertilization. qRT-PCR analysis showed no significant difference in mRNA expression levels of kinesin genes between vitrified and fresh oocytes. Also, the presence of calcium in vitrification solution significantly increased zona hardening. In conclusion, we have shown for the first time that supplementation of vitrification solution with EGTA, as a calcium chelator, improved the ability of vitrified ovine oocytes to preserve mitochondrial distribution and function, as well as normal chromosome segregation. PMID- 30244699 TI - Metformin as a modulator of myocardial fibrosis postmyocardial infarction via regulation of cardiomyocyte-fibroblast crosstalk. PMID- 30244701 TI - Systemic leptin administration alters callus VEGF levels and enhances bone fracture healing in wildtype and ob/ob mice. AB - INTRODUCTION: Leptin's role in bone formation has been reported, however, its mechanism of affecting bone metabolism is remaining unclear. In this study, we aimed to test whether leptin has a positive effect on fracture healing through the possible mechanism of increasing vascular endothelial growth factor (VEGF) expression in callus tissue. METHODS: Standardized femur fractures were created in leptin-deficient ob/ob and wildtype C57BL/6J mice, and recombinant mouse leptin or its vehicle (physiological saline) was administered intraperitoneally during the study. Body weight, radiological, histologic and immunoblotting analyses were performed at different stages of fracture healing. KEY FINDINGS: The results showed that leptin treatment led to lower rate of body weight change in both mice genotypes. Radiological and histological analyses showed that the experimental groups had better fracture healing at 14, 21 and 28 days compared to the control groups. Leptin-treated groups had significantly higher VEGF expression in callus compared with the control groups at 2 and 3 weeks post fracture except normal mice at 2 weeks, and leptin-deficient mice had higher VEGF levels in calluses than normal mice at the same timepoint. CONCLUSION: Low-dose systemically-administered leptin has a positive effect on promoting fracture healing during the latter stages in a clinically-relevant mouse bone fracture model, and increase callus VEGF levels. PMID- 30244700 TI - Influence of the induced membrane filled with syngeneic bone and regenerative cells on bone healing in a critical size defect model of the rat's femur. AB - INTRODUCTION: The induced membrane technique for the treatment of large bone defects consists of a 2-stage procedure. In the first stage, a polymethylmethacrylate (PMMA) cement spacer is inserted into the bony defect of a rat's femur and over a period of 2-4 weeks a membrane forms that encapsulates the defect/spacer. In a second operation the membrane is opened, the PMMA spacer is removed and the resulting cavity is filled with autologous bone. Since little effort has been made to replace the need for autologous bone this study was performed to elucidate the influence of different stem cells and the membrane itself on bone healing in a critical size femur defect model in rats. Especially the question should be addressed whether the use of stem cells seeded on a beta TCP scaffold is equivalent to syngeneic bone as defect filling in combination with the induced membrane technique. MATERIALS AND METHODS: A total of 96 male Sprague-Dawley (SD) rats received a 10 mm critical size defect of the femur, which was stabilized by a plate osteosynthesis and filled with PMMA cement. In a second step the spacer was extracted and the defects were filled with syngeneic bone, beta-TCP with MSC + EPC or BM-MNC. In order to elucidate the influence of the induced membrane on bone defect healing the induced membrane was removed in half of the operated femurs. The defect area was analysed 8 weeks later for bone formation (osteocalcin staining), bone mineral density (BMD) and bone strength (3 point bending test). RESULTS: New bone formation, bone mineral density and bone stiffness increased significantly, if the membrane was kept. The transplantation of biologically active material (syngeneic bone, stem cells on b-TCP) into the bone defect mostly led to a further increase of bone healing. Syngeneic bone had the greatest impact on bone healing however defects treated with stem cells were oftentimes comparable. CONCLUSION: For the first time we demonstrated the effect of the induced membrane itself and different stem cells on critical size defect healing. This could be a promising approach to reduce the need for autologous bone transplantation with its' limited availability and donor site morbidity. PMID- 30244702 TI - Patella fractures are not associated with an increased risk of mortality in elderly patients. AB - INTRODUCTION: The modern literature includes only limited information regarding mortality rates and cumulative survival following patella fractures. The aim was to report the 30-day, six-month, and one-year mortality of patients with patella fractures and compare this to the mortality of a matched reference population. METHODS: All patients who sustained a patella fracture in Denmark between 1996 and 2000 were included in the study. The survival status of these patients was monitored until 2015. We compare the mortality with a ten-fold reference population matched on age and gender without a prior patella fracture. RESULTS: 6096 patients were treated for 6114 patella fractures. The mean age of patients was 48.9 years. The overall mortality rates at 30 days, six months, and one year were 0.7%, 1.8%, and 2.8%. The mortality rates for patients > 65 years at 30 days, six months, and one year were 1.3%, 3.9%, and 6.2%. The mortality rates for patients at <= 65 years at 30 days, six months, and one year were 0.4%, 0.9%, and 1.3%. Compared to the matched reference population, the relative risk of mortality in patients > 65 years at 30 days, six months, and one year were 1.9 (95% CI 1.2-2.9), 1.0 (95% CI 0.8-1.3), and 0.9 (95% CI 0.7-1.1). CONCLUSION: The overall one-year mortality rate of patella fractures was 2.8% and this was increased to 6.2% in patients older than 65 years. In elderly patients above 65 years, the relative risk of death was 0.9, indicating that patella fractures in elderly patients were not associated with an increased mortality rate. PMID- 30244704 TI - Reply. PMID- 30244703 TI - The Incremental Value of Three or More Arterial Grafts in CABG: The Effect of Native Vessel Disease. AB - BACKGROUND: We investigated whether extended arterial grafting with three or more arterial grafts in patients with a left internal thoracic artery to left anterior descending artery graft improves survival in coronary artery bypass graft surgery patients and whether its effects will depend on the extent of coronary artery disease; specifically three-vessel disease (3VD) versus two-vessel disease (2VD). METHODS: Fifteen-year mortality was analyzed in 11,931 patients with multivessel disease and primary isolated left internal thoracic artery to left anterior descending artery coronary artery bypass graft surgery with 2 or more grafts. Patients were aged 64.3 +/- 10.5 years; 3,484 (29.2%) were women; 2,532 (21.2%) had 2VD and 9,399 (78.8%) had 3VD. Patients were grouped into one single-artery group (n = 6,782, 56.9%; reference group), and two multiple artery groups: two arteries (n = 3,678, 30.8%) and three arteries (n = 1,471, 12.3%). Long-term survival was compared by Kaplan-Meier estimates. Risk-adjusted mortality hazard ratio (HR) with 95% confidence interval (CI) were derived by covariate adjusted Cox regression to quantify multiple artery effects versus one artery in the overall cohort and separately among patients with 2VD and 3VD. RESULTS: Radial artery (94%) and right internal thoracic artery (6%) conduits were used for additional arterial grafts. For the entire multivessel cohort, increasing number of arterial grafts was associated with incrementally improved 15-year survival (two arteries HR 0.85, 95% CI: 0.78 to 0.92; three arteries HR 0.75, 95% CI: 0.65 to 0.85). The three arteries versus two arteries comparison was consistent, even if not significant (HR 0.89, 95% CI: 0.77 to 1.03). The benefits derived from additional arterial grafts were more pronounced in case of 3VD (two arteries HR 0.84 95% CI: 0.76 to 0.92; three arteries HR 0.73, 95% CI: 0.63 to 0.84), without survival benefit with 2VD. CONCLUSIONS: Our results support the use of extended arterial grafting to maximize long-term coronary artery bypass graft surgery patient survival, especially for 3VD patients. PMID- 30244705 TI - Preoperative STOP-BANG Scores and Postoperative Delirium and Coma in Thoracic Surgery Patients. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with higher rates of postoperative delirium. The relationship between preoperative OSA risk and postoperative delirium and coma in thoracic surgery patients hospitalized in the intensive care unit (ICU) is not well understood. This study tests the hypothesis that thoracic surgery patients hospitalized in ICU with a higher preoperative risk for OSA are more likely to develop postoperative delirium and coma, resulting in longer hospital stays. METHODS: Preoperative OSA risk was measured using the STOP-BANG questionnaire. STOP-BANG scores of greater than or equal to 3 were defined as intermediate-high risk for OSA; 128 patients who underwent major thoracic surgery completed the STOP-BANG questionnaire preoperatively. The Richmond Agitation and Sedation Scale was used to assess level of consciousness. The Confusion Assessment Method for the ICU was used to assess for delirium. Linear regression was used to assess the relationship between risk of OSA and outcome measures. Results were adjusted for age, sex, body mass index, Charlson Comorbidity Index, instrumental activities of daily living, and surgery type. RESULTS: A total of 96 of 128 patients (76%) were in the intermediate-high-risk OSA group. Adjusted analyses showed that the intermediate-high-risk OSA group had a longer duration of postoperative ICU delirium and coma compared with the low risk OSA group (1.4 +/- 1.3 days versus 0.9 +/- 1.4 days; P = 0.04). Total number of hospital days was not significantly different. CONCLUSIONS: Higher preoperative risk for OSA in thoracic surgery patients was associated with a longer duration of postoperative delirium and coma. PMID- 30244707 TI - Long-distance care of face transplant recipients in the United States. AB - Promising aesthetic and functional outcomes in facial transplantation have fueled the interest of patients and providers alike. However, there are currently only 11 active face transplant centers in the United States, and only five have accumulated operative experience to date, resulting in an extremely unbalanced geographical distribution of providers. Since face transplant recipients must receive life-long follow-up, this presents unique challenges for face transplant candidates and provider teams, as long-distance travel may add considerable difficulty to pre- and post-transplant care. Furthermore, by compromising follow up, this burden of travel may impact the ability of experienced face transplant centers to collect data, share knowledge as these patients are followed, and continue to advance the field. This article highlights the unique logistical and ethical implications of the highly probable long-distance nature of face transplant care in the United States, a challenging aspect of management that has not been previously discussed in the literature. Furthermore, we review current strategies in the long-distance management of solid organ transplantation (SOT) recipients, and propose several possibilities to help address these challenges in facial transplantation based on SOT experience. PMID- 30244708 TI - Immediate breast reconstruction with a wise pattern mastectomy and NAC-sparing McKissock vertical bipedicle dermal flap. AB - Preservation of the nipple-areola complex (NAC) in immediate reconstruction of ptotic and large breasts is surgically challenging. This article presents a modification of the inferior dermal flap ("dermal sling") to a vertical bipedicle flap with NAC preservation. This flap is well described in breast reductions but has never been described in a mastectomy setting. The study reviews data for a case series of 17 breasts in 11 women who underwent breast reconstruction with the new technique. The complication rate was 12%, thus indicating that the vertical bipedicle NAC-sparing flap should be considered a feasible option for breast reconstruction in women with ptotic and/or large breasts. PMID- 30244709 TI - Concomitant injuries affect prognosis in patients with central slip tear. AB - Central slip tears often occur with concomitant hand injuries. However, the outcome of a central slip tear and the effect of concomitant injuries are rarely reported. We evaluated 67 fingers in 63 patients with central slip tears who underwent primary surgery in our hospital between April 2009 and June 2017. We performed multivariate analyses, with proximal interphalangeal (PIP) joint active range of motion (AROM) and existing extension lag greater than 10 degrees as dependent variables and age, existence of concomitant fractures, skin defects, collateral ligament injuries, ruptured lateral bands, ruptured flexor tendons or vascular injury in the injured finger as independent variables. Concomitant injuries of tendons in the adjacent fingers were also independent variables. The average AROM of the PIP joint was 62 degrees , and extension lag occurred in 34 fingers (51%). Patients aged > 40 years with fractures of the injured finger or flexor tendon injuries in an adjacent finger had low decreases in AROM (partial regression coefficient [95% confidence interval, CI]: -13.7 [43-66], -31.6 [30 57], -34.5 [32-60] and -33.5 [10-43]). Extensor tendon injuries in an adjacent finger caused significantly more extension lag in the PIP joint (odds ratio [95% CI]: 3.2 [1.0-9.6]). The present study indicated the negative impact of a tendon injury on adjacent fingers, a circumstance widely known as the quadriga phenomenon. Ultimately, we can use these prognostic factors in surgical repair planning, particularly when comparing treatments such as central slip reconstruction and primary arthrodesis. PMID- 30244710 TI - Clinical features affecting the patient-based outcome after minimal medial epicondylectomy for cubital tunnel syndrome. AB - BACKGROUND: Little information is currently available to analyze unsatisfactory surgical outcomes for cubital tunnel syndrome (CuTS). The aim of this study was to analyze the clinical features influencing patient-reported outcomes of minimal medial epicondylectomy for CuTS. METHODS: We evaluated 91 patients who underwent minimal medial epicondylectomy for CuTS using the grip strength; two-point discrimination; Disability of the Arm, Shoulder and Hand (DASH) questionnaire; and a satisfaction with treatment questionnaire for one year, postoperatively. The clinical features evaluated as prognostic indicators included age, gender, body mass index (BMI), smoking, alcohol consumption, comorbidities, hand dominance, work level, history of elbow trauma, elbow arthritis, elbow flexion contracture, duration of symptoms, and severity of disease. RESULTS: Grip strength, two-point discrimination, and DASH scores exhibited significant clinical improvements, with 77% (70/91) of patients satisfied with treatment. In terms of patient-reported disability, heavy smoking, elbow flexion contracture, and preoperative disease severity increased DASH scores at 1-year follow-up. However, only heavy smoking and elbow flexion contracture were associated with a higher likelihood of dissatisfaction with treatment. CONCLUSIONS: Heavy smoking, elbow flexion contracture, and preoperative disease severity are associated with persistently increased disability after minimal medial epicondylectomy for CuTS. However, only heavy smoking and elbow flexion contracture were associated with a higher likelihood of dissatisfaction with the treatment. PMID- 30244711 TI - Feasibility of using computer simulation to predict the postoperative outcome of the minimally invasive Nuss procedure: Simulation prediction vs. postoperative clinical observation. AB - The Nuss procedure is the most minimally invasive and commonly used surgical correction for pectus excavatum (PE) by using a prebent pectus bar to elevate the deformed chest wall. However, there are some complications associated with this procedure such as postoperative pain as well as surgical uncertainties because of human judgment. It is therefore important to understand the biomechanical effect of the pectus bar on PE thoraces undergoing an operation to alleviate the postoperative pain as well as to improve surgical outcome. The current study incorporated the finite element method (FEM) to simulate the entire Nuss procedure including the flipping process of the pectus bar on a preoperative PE patient-specific thorax model, in conjunction with comparison against the postoperative CT scans. The mid-sagittal sternovertebral elevation was found to be within 5.32 mm, whereas the transverse sternal deviations ranged from 1.59 to 3.02 mm. The average discrepancy between the predicted contour and postoperative CT contour was approximately 3%. On a different note, the stress and strain distributions largely concurred with reported findings. High bilateral stress was seen to occur at the back of ribs near the vertebral column, and particularly over the second to fifth ribs, whereas the greatest strain was found to be confined to the regions of costal cartilages. It is evident that the FEM is a feasible and robust approach in predicting the outcome of the mechanical surgical procedure. This contributes to the future development of a predictive tool incorporated in surgical planning to enhance surgical management of PE. PMID- 30244712 TI - Status of blood transfusion in World Health Organization-Eastern Mediterranean Region (WHO-EMR): Successes and challenges. PMID- 30244713 TI - Intravenous immunoglobulin as an adjunct therapy in persisting heparin-induced thrombocytopenia. AB - Heparin induced thrombocytopenia (HIT) is a serious adverse drug reaction caused by transient antibodies against platelet factor 4 (PF4)/heparin complexes, resulting in platelet activation and potentially fatal arterial and/or venous thrombosis. Most cases of HIT respond to cessation of heparin and administration of an alternative non-heparin anticoagulant, but there are cases of persisting HIT, defined as thrombocytopenia due to platelet activation/consumption for greater than seven days despite standard therapy. These patients remain at high risk for thrombotic events, which may result in limb-loss and mortality. Intravenous immunoglobulin (IVIg) has been proposed as an adjunct therapy for these refractory cases based on its ability to saturate FcgammaRIIa receptors on platelets, thus preventing HIT antibody binding and platelet activation. We describe 2 cases of persisting HIT (strongly positive antigen and functional assays, and persisting thrombocytopenia >7 days) with rapid clinical response to IVIg. We performed in-vitro experiments to support IVIg response. Healthy donor platelets (1 * 10e6) were treated with PF4 (3.75 MUg/mL) for 20 min followed by 1 hour incubation with patients' sera. Platelet activation with and without addition of IVIg (levels equivalent to those reached in a patient after treatment with 2 gm/Kg) was evaluated in the PF4-dependent P-selectin expression assay (PEA). A significantly decreased platelet activation was demonstrated after the addition of IVIg to both patient samples, which correlated well with the rapid clinical response that each patient experienced. Thus, our study supports the use of IVIg as an adjunct therapy for persisting HIT. PMID- 30244714 TI - Are future doctors ready to donate blood and encourage blood donation? AB - BACKGROUND: Blood donation is the most common method of supplying blood. For maintaining the reliability of the blood supply through donation, the blood should be provided by voluntary, non-profit and regularly donating individuals. It is critical to be aware of the attitudes, behaviors and knowledge levels of the doctors about this issue who will inform and lead people to donate blood. The aim of this study was to determine the current knowledge levels, attitudes, and behaviors of the medical faculty students, who will be future doctors, on blood donation and to investigate whether a change occurs in the these parameters with the initiation of clinical education and training. METHOD: This descriptive study was conducted by using a questionnaire including a total of 40 questions about blood donation. Chi-square and Mann-Whitney U tests were performed. RESULTS: The study included 120 students in the third year of the faculty, which is the last preclinical year, and 100 students in the fifth year, which is the second year of clinical education. Of the students, 44.1% were trained for blood donation. The rates of blood donation and promoting people to donate blood were significantly higher in students who had received blood donation training compared to those who had not received such training. Willingness to donate blood and the knowledge levels regarding blood donation were significantly greater among the fifth year students. CONCLUSION: Efforts for raising the awareness of blood donation together with its training should be increased and popularized in medical faculties. PMID- 30244715 TI - Building on a Solid Foundation. PMID- 30244716 TI - Research Techniques Are Not Simple. PMID- 30244717 TI - The Value and Process of Authoring a "Research Techniques Made Simple" Article. PMID- 30244718 TI - Research Techniques Made Simple: Animal Models of Wound Healing. AB - Animal models have been developed to study the complex cellular and biochemical processes of wound repair and to evaluate the efficacy and safety of potential therapeutic agents. Several factors can influence wound healing. These include aging, infection, medications, nutrition, obesity, diabetes, venous insufficiency, and peripheral arterial disease. Lack of optimal preclinical models that are capable of properly recapitulating human wounds remains a significant translational challenge. Animal models should strive for reproducibility, quantitative interpretation, clinical relevance, and successful translation into clinical use. In this concise review, we discuss animal models used in wound experiments including mouse, rat, rabbit, pig, and zebrafish, with a special emphasis on impaired wound healing models. PMID- 30244719 TI - Topical Antiseptics and the Skin Microbiota. AB - The impact of antiseptics on the skin microbiota is poorly understood. SanMiguel et al. (2018) use a sequencing-based approach to compare treatment effects and find that they are dependent on interpersonal and body site-specific community differences. While treatment results in an immediate depletion of the skin microbiota, not all bacterial families are affected equally. PMID- 30244720 TI - Automated Classification of Skin Lesions: From Pixels to Practice. AB - The letters "Interpretation of the Outputs of Deep Learning Model trained with Skin Cancer Dataset" and "Automated Dermatological Diagnosis: Hype or Reality?" highlight the opportunities, hurdles, and possible pitfalls with the development of tools that allow for automated skin lesion classification. The potential clinical impact of these advances relies on their scalability, accuracy, and generalizability across a range of diagnostic scenarios. PMID- 30244721 TI - SnapshotDx Quiz: October 2018. PMID- 30244723 TI - It's hard to swallow-which test is best? PMID- 30244722 TI - Cells to Surgery Quiz: October 2018. PMID- 30244724 TI - Follow-up of low birth weight newborns into adolescence-a focus on social competencies. PMID- 30244725 TI - 50 Years Ago in The Journal of Pediatrics: Maternal Phenylketonuria: Implications for Growth and Development. PMID- 30244727 TI - Complementary medicines are not always complimentary in Down syndrome. PMID- 30244726 TI - 50 Years Ago in The Journal of Pediatrics: Abnormally Small Head Size and Intellect in Children. PMID- 30244728 TI - Do you have patients treated with adalimumab? Know the safety profile. PMID- 30244729 TI - 50 Years Ago in The Journal of Pediatrics: Phenylketonuria and Scleroderma. PMID- 30244730 TI - Decline in otitis media associated ambulatory visits in the US. PMID- 30244731 TI - Growth effects of combined psychotropic regimens. PMID- 30244732 TI - Corrigendum. PMID- 30244733 TI - 50 Years Ago in The Journal of Pediatrics: Comparison of Intramuscular and Oral Ampicillin Therapy for Shigellosis. PMID- 30244734 TI - Post Kawasaki disease exercise capacity. PMID- 30244735 TI - 50 Years Ago in The Journal of Pediatrics: Uric Acid Levels in Full-Term and Low Birth-Weight Infants. PMID- 30244736 TI - Prevalent fecal contamination in drinking water resources and potential health risks in Swat, Pakistan. AB - Fecal bacteria contaminate water resources and result in associated waterborne diseases. This study assessed drinking water quality and evaluated their potential health risks in Swat, Pakistan. Ground and surface drinking water were randomly collected from upstream to downstream in the River Swat watershed and analyzed for fecal contamination using fecal indicator bacteria (Escherichia coli) and physiochemical parameters (potential of hydrogen, turbidity, temperature, electrical conductivity, total dissolved solid, color, odor and taste). The physiochemical parameters were within their safe limits except in a few locations, whereas, the fecal contaminations in drinking water resources exceeded the drinking water quality standards of Pakistan Environmental Protection Agency (Pak-EPA), 2008 and World Health Organization (WHO), 2011. Multivariate and univariate analyses revealed that downstream urbanization trend, minimum distance between water sources and pit latrines/sewerage systems, raw sewage deep well injection and amplified urban, pastures and agricultural runoffs having human and animal excreta were the possible sources of contamination. The questionnaire survey revealed that majority of the local people using 10-20years old drinking water supply schemes at the rate of 73% well supply, 13% hand pump supply, 11% spring supply and 3% river/streams supply, which spreads high prevalence of water borne diseases including hepatitis, intestinal infections and diarrhea, dysentery, cholera, typhoid fever, jaundice and skin diseases in children followed by older and younger adults. PMID- 30244737 TI - Soot reduction by addition of dimethyl carbonate in normal and inverse ethylene diffusion flames: Nanostructural evidence. AB - Oxygenated fuel represents an attractive alternative as an additive for reducing soot emissions. Dimethyl carbonate (DMC) is an oxygenated compound which is a good option to reduce soot, but the detailed characteristics of soot produced from combustion of hydrocarbon fuels blended with DMC are still lacking. The present research studied the nanostructure and reactivity of soot particles in ethylene/DMC normal and inverse diffusion flames. High resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), and thermogravimetric analysis (TGA) were used to analyze the nanostructure and reactivity of soot. It was found that DMC addition was effective in decreasing the average weights of soot formed in flames. The results of HRTEM images showed that soot particles obtained with DMC addition showed liquid-like material and tight bonding, and exhibited more highly disorganized layers, which give it higher reactivity than soot obtained without DMC addition. Furthermore, HRTEM was used to analyze soot fringe characteristics consisting of fringe tortuosity, fringe length, and fringe separation. XRD was used to crosscheck the results for fringe separation, and was consistent with HRTEM results. In addition, the mass loss curve of TGA experiments showed that DMC addition could enhance the reactivity of soot particles. PMID- 30244739 TI - Fabrication and photocatalytic activity of TiO2 composite membranes via simultaneous electrospinning and electrospraying process. AB - In present study, a simultaneous electrospinning and electrospraying (SEE) process was employed to produce microclusters of TiO2 nanoparticles and interlock them in nanofibrous network. The photocatalytic composite membranes (PCMs) were fabricated by electrospraying TiO2 nanoparticle suspension into microcluster form that dispersed and entrapped within nylon-6 electrospun fiber membrane. Three PCMs membrane with TiO2 content of 52.0, 83.6, and 91.7wt.% were successfully fabricated. The membrane consisted of TiO2 microclusters, ranging in sizes from around 0.3 to 10MUm, distributed uniformly within the nylon-6 nanofibrous network. PCMs photocatalytic activity against Methylene Blue (MB) in aqueous solution showed more than 98% MB removal efficiency after 120min of photocatalytic oxidation (PCO) for all PCMs. For PCM with the highest TiO2 content tested for 5 PCO cycles, it was found that most of their TiO2 content remained incorporated within the nanofibrous structure. The concept of nanoparticles clusters entrapment with SEE fabrication employed here provide a simple and effective method for reducing detachment of nanostructure phase from nanocomposite membrane. PMID- 30244738 TI - Insights into the formation of secondary organic carbon in the summertime in urban Shanghai. AB - To investigate formation mechanisms of secondary organic carbon (SOC) in Eastern China, measurements were conducted in an urban site in Shanghai in the summer of 2015. A period of high O3 concentrations (daily peak > 120 ppb) was observed, during which daily maximum SOC concentrations exceeding 9.0 MUg/(C.m3). Diurnal variations of SOC concentration and SOC/organic carbon (OC) ratio exhibited both daytime and nighttime peaks. The SOC concentrations correlated well with Ox (= O3 + NO2) and relative humidity in the daytime and nighttime, respectively, suggesting that secondary organic aerosol formation in Shanghai is driven by both photochemical production and aqueous phase reactions. Single particle mass spectrometry was used to examine the formation pathways of SOC. Along with the daytime increase of SOC, the number fraction of elemental carbon (EC) particles coated with OC quickly increased from 38.1% to 61.9% in the size range of 250 2000 nm, which was likely due to gas-to-particle partitioning of photochemically generated semi-volatile organic compounds onto EC particles. In the nighttime, particles rich in OC components were highly hygroscopic, and number fraction of these particles correlated well with relative humidity and SOC/OC nocturnal peaks. Meanwhile, as an aqueous-phase SOC tracer, particles that contained oxalate-Fe(III) complex also peaked at night. These observations suggested that aqueous-phase processes had an important contribution to the SOC nighttime formation. The influence of aerosol acidity on SOC formation was studied by both bulk and single particle level measurements, suggesting that the aqueous-phase formation of SOC was enhanced by particle acidity. PMID- 30244740 TI - Effects of Asian dust events on atmospheric bacterial communities at different distances downwind of the source region. AB - Aeolian dust particles arising from arid and semiarid zones are known to carry microbes by air currents. The effect of wind-borne bacteria on atmospheric bacterial population at various downwind distances from the dust source regions must be clarified, but has not yet been reported. This study monitored the bacterial abundance and community composition in outdoor aerosol samples in Beijing, China, which is close to the Asian dust source regions, and compared them with the results obtained in a distant region (Osaka, Japan). The Asian dust collected in Beijing contained (4+/-3)*104bacterial cells/m3, approximately 4 times higher than in Osaka. On 15 April 2015, Beijing experienced severe Asian dust events with a 1000-fold increase in bacterial abundance, relative to non Asian dust days. Dominant bacterial phyla and classes in Asian dust collected in Beijing were Actinobacteria, Bacilli and Acidobacteria, and the bacterial community composition varied more widely than in Osaka. The bacterial community compositions differed between the Beijing and Osaka dusts, even for the same Asian dust events. These results indicated that aerosol bacterial communities nearer the dust source are more affected by eolian dust than their distant counterparts. PMID- 30244741 TI - Toxicity evaluation of ZnO and TiO2 nanomaterials in hydroponic red bean (Vigna angularis) plant: Physiology, biochemistry and kinetic transport. AB - The toxicity and kinetic uptake potential of zinc oxide (ZnO) and titanium dioxide (TiO2) nanomaterials into the red bean (Vigna angularis) plant were investigated. The results obtained revealed that ZnO, due to its high dissolution and strong binding capacity, readily accumulated in the root tissues and significantly inhibited the physiological activity of the plant. However, TiO2 had a positive effect on plant physiology, resulting in promoted growth. The results of biochemical experiments implied that ZnO, through the generation of oxidative stress, significantly reduced the chlorophyll content, carotenoids and activity of stress-controlling enzymes. On the contrary, no negative biochemical impact was observed in plants treated with TiO2. For the kinetic uptake and transport study, we designed two exposure systems in which ZnO and TiO2 were exposed to red bean seedlings individually or in a mixture approach. The results showed that in single metal oxide treatments, the uptake and transport increased with increasing exposure period from one week to three weeks. However, in the metal oxide co-exposure treatment, due to complexation and competition among the particles, the uptake and transport were remarkably decreased. This suggested that the kinetic transport pattern of the metal oxide mixtures varied compared to those of its individual constituents. PMID- 30244742 TI - Hollow TiO2 spheres with improved visible light photocatalytic activity synergistically enhanced by multi-stimulative: Morphology advantage, carbonate doping and the induced Ti3. AB - Great efforts have been devoted to improve the photocatalytic activity of TiO2 in the visible light region. Rational design of the external structure and adjustment of intrinsic electronic status by impurity doping are two main effective ways to achieve this purpose. A facile one-pot synthetic approach was developed to prepare C-doped hollow TiO2 spheres, which simultaneously realized these advantages. The synthesized TiO2 exhibits a mesoporous hollow spherical structure composed of fine nanocrystals, leading to high specific surface area (~180m2/g) and versatile porous texture. Carbonate-doping was achieved by a post thermal treatment at a relatively low temperature (200 degrees C), which makes the absorption edge red-shifted to the visible region of the solar spectrum. Concomitantly, Ti3+ induced by C-doping also functions in improving the visible light photocatalytic activity by reducing the band gap. There exists a synergistic effect from multiple stimulatives to enhance the photocatalytic effect of the prepared TiO2 catalyst. It is not out of expectation that the as prepared C-doped hollow TiO2 spheres exhibits an improved photocatalytic activity under visible light irradiation in organic pollutant degradation. PMID- 30244743 TI - Heavy metals and their source identification in particulate matter (PM2.5) in Isfahan City, Iran. AB - The presence of heavy metals (HMs) in particulate matters (PMs) particularly fine particles such as PM2.5 poses potential risk to the health of human being. The purpose of this study was to analyze the contents of HMs in PM2.5 in the atmospheric monitoring stations in Isfahan city, Iran, in different seasons between March 2014 and March 2015 and their source identification using principle component analysis (PCA). The samples of PM2.5 were taken using a high volume sampler in 7 monitoring stations located throughout the city and industrial zones since March 2014 to March 2015. The HMs content of the samples was measured using ICP-MS. The results showed that the concentrations of As, Cd and Ni were in a range of 23-36, 1-12, and 5-76ng/m3 at all the stations which exceeded the US-EPA standards. Furthermore, the concentrations of Cr and Cu reached to 153 and 167ng/m3 in some stations which were also higher than the standard levels. Depending on the potential sources of HMs, their concentration in PM2.5 through the various seasons was different. PCA illustrated that the different potential sources of HMs in the atmosphere, showing that the most important sources of HMs originated from fossil fuel combustion, abrasion of vehicle tires, industrial activities (e.g., iron and steel industries) and dust storms. Management and control of air pollution of industrial plants and vehicles are suggested for decreasing the risk of the HMs in the region. PMID- 30244744 TI - Roles of membrane and organic fouling layers on the removal of endocrine disrupting chemicals in microfiltration. AB - To understand the adsorption behavior of endocrine disrupting chemicals (EDCs) is important for enhancing the treatment performance and preventing potential secondary pollution caused by EDCs desorption in a microfiltration system. The dynamic adsorption of four representative EDCs, namely estriol (E3), 17beta estradiol (E2), 17alpha-ethynylestradiol (EE2), and 4-nonylphenol (4-NP) in a microfiltration system was investigated using the Thomas' model. The product of the equilibrium constant and the total adsorption capacity of the membrane, Ka, for E3, E2, EE2, and 4-NP were 4.91, 9.78, 15.6, and 826, respectively, strongly correlating with the compound octanol-water partition coefficient (KOW). Adsorption appeared to be enhanced when organic fouling formed on the surface of membrane, indicating the role of an additional adsorption column for EDCs acted by a fouling layer in microfiltration. Results of a comparison between the Ka values for clean membrane and fouled membrane illustrated that the significant contribution made by fouling layers may be attributed to the foulant layer's hydrophobicity (in the case of calcium humate layer) and thickness (in the case of calcium alginate layer). This study provided a novel perspective to quantitatively analyze the dynamic adsorption behavior of trace pollutants in membrane process. PMID- 30244745 TI - Seasonal and spatial distributions of euphotic zone and long-term variations in water transparency in a clear oligotrophic Lake Fuxian, China. AB - To assess the seasonal and spatial variations and long-term trends in water optical properties in Lake Fuxian, investigations based on field work in four seasons and a long-term analysis of data from 1980 to 2014 were conducted. The results show that there was no significant variation in the euphotic depth (Zeu) across the four seasons, and no significant correlations between Zeu and potential influencing factors in seasons other than summer, suggesting that the water itself may be a major factor regulating the Zeu in general. Nevertheless, significant differences in Zeu between the north region (NR) and the south region (SR) were observed in all seasonal tests except spring. This finding relates to a higher abundance of chromophoric dissolved organic matter (CDOM) in the NR due to runoff, especially in the rainy seasons (summer and autumn). CDOM and its terrigenous component had an important impact on Zeu in summer, with the highest precipitation, and impacts from suspended solids and non-algal particles were also found in the NR in summer. The Secchi disk depth in the lake decreased clearly over the years, with significantly negative correlations with the increasing permanganate index and air temperature, implying that organic contaminants (CDOM and/or phytoplankton) are important regulators of water transparency. We estimate that the combined effects of climate warming and changes in land use and land cover are also indirect regulating factors. These findings should be considered in the protection of Lake Fuxian, owing to the importance of light penetration in aquatic ecosystems. PMID- 30244746 TI - Characterization of aircraft emissions and air quality impacts of an international airport. AB - Beijing Capital International Airport (ZBAA) is the world's second busiest airport. In this study, the emissions of air pollutants from aircraft and other sources at ZBAA in 2015 were estimated using an improved method, which considered the mixing layer height calculated based on aircraft meteorological data relay (AMDAR), instead of using the height (915m) recommended by ICAO. The yearly emissions of NOx, CO, VOCs, SO2, and PM2.5 at the airport were 8.76*103, 4.43*103, 5.43*102, 4.80*102, and 1.49*102ton/year, respectively. The spatial temporal distribution of aircraft emissions was systematically analyzed to understand the emission characteristics of aircraft. The results indicated that NOx was mainly emitted during the take-off and climb phases, accounting for 20.5% and 55.5% of the total emissions. CO and HC were mainly emitted during the taxi phase, accounting for 91.6% and 92.2% of the total emissions. Because the mixing layer height was high in summer, the emissions of aircraft were at the highest level throughout the year. Based on the detailed emissions inventory, four seasons simulation using WRF-CMAQ model was performed over the domain surrounding the airport. The results indicated that the contribution to PM2.5 was relatively high in winter; the average impact was about 1.15MUg/m3 within a radius of 1km around the airport. Meanwhile, the near surroundings and southwest areas of the airport are the most sensitive to PM2.5. PMID- 30244747 TI - Distribution of polychlorinated naphthalenes (PCNs) in the whole blood of typical meat animals. AB - The concentrations and distribution of polychlorinated naphthalenes (PCNs) in the whole blood of eight typical terrestrial meat animals (chicken, duck, rabbit, pig, cattle, sheep, horse and donkey) consumed daily in our life were investigated. The total concentrations (on a liquid volume basis) of PCNs were in a range from 305 to 987pg/L. Donkey blood contained the highest PCN concentrations. Mono-CNs were the dominant homolog group, accounting for 38%-71% PCNs. Apart from the mono-CNs and tri-CNs homolog groups, two hepta-CNs (mean: 9.5%) contributed most, followed by tetra-CNs (mean: 6.5%). The congeners CN1, 5/7, 24/14, 27/30, 52/60, 66/67, and 73 were the most abundant congeners or congener groups. The highest toxicity equivalencies (TEQs) were observed in cattle blood (117.4fg TEQ/L) then chicken blood (117.1fg TEQ/L). CN73 contributed 65% to total TEQs, followed by CN70 (20%) and CN66/67 (14%). The dietary intakes of PCNs were also estimated. Chicken meat, which forms the second largest component of meat product consumption in China, contributed most to the total TEQs (61%), followed by beef (27%) and pork (5.9%). The consumption of chicken might pose the highest risk from exposure to PCNs than other types of meat to populations who prefer to eat chicken meat. PMID- 30244748 TI - Evaluation of sulfur trioxide detection with online isopropanol absorption method. AB - Measurement of the SO3 concentration in flue gas is important to estimate the acid dew point and to control corrosion of downstream equipment. SO3 measurement is a difficult question since SO3 is a highly reactive gas, and its concentration is generally two orders of magnitude lower than the SO2 concentration. The SO3 concentration can be measured online by the isopropanol absorption method; however, the reliability of the test results is relatively low. This work aims to find the error sources and to evaluate the extent of influence of each factor on the measurement results. The test results from a SO3 analyzer showed that the measuring errors are mainly caused by the gas-liquid flow ratio, SO2 oxidation, and the side reactions of SO3. The error in the gas sampling rate is generally less than 13%. The isopropanol solution flow rate decreases 3% to 30% due to the volatilization of isopropanol, and accordingly, this will increase the apparent SO3 concentration. The amount of SO2 oxidation is linearly related to the SO2 concentration. The side reactions of SO3 reduce the selectivity of SO42- to nearly 73%. As sampling temperature increases from 180 to 300 degrees C, the selectivity of SO42- decreases from 73% to 50%. The presence of H2O in the sample gas helps to reduce the measurement error by inhibiting the volatilization of the isopropanol and weakening side reactions. A formula was established to modify the displayed value, and the measurement error was reduced from 25%-54% to less than 15%. PMID- 30244749 TI - Particles and porous tablets based on Fe0/ZSM-5 composites prepared by ball milling for heavy metals removal: Dissolved Fe2+, pH, and mechanism. AB - Novel, low-cost Fe0/ZSM-5-based particles and porous tablets were prepared by a ball-milling method and used for the removal of Pb2+ in solution. Solid-phase characterization by scanning electron microscopy coupled with energy-dispersive X ray spectroscopy (SEM-EDS) and transmission electron microscopy (TEM) revealed that the Fe0 microparticles were evenly loaded and tightly immobilized on the surface of ZSM-5 because of the extrusion/welding impact during ball-milling. For different Pb2+ concentrations, batch experiments indicated that the removal of Pb2+ increased with the decline of dissolved Fe2+ and pH value in the solution for particles; opposite results were obtained for the tablets. The differences in the contact between both materials and Pb2+ were the main factor controlling Pb2+ removal in the solution. Investigation into the effect of initial pH value revealed that high pH reduced the number of electrons released from Fe corrosion. Consequently, low levels of removed Pb2+ and dissolved Fe2+ were synchronously observed. Also, simulated electroplating wastewater was treated using the prepared particles and porous tablets, and the removal order of Pb2+>Cr6+>Cu2+~Cd2+ was observed. The Fe0/ZSM-5 particles and tablets prepared through ball-milling show potential as materials for treatment of Pb2+ and other toxic metals. PMID- 30244750 TI - Engineering of responsive polymer based nano-reactors for facile mass transport and enhanced catalytic degradation of 4-nitrophenol. AB - Silver nanoparticles with average diameter of 10+/-3nm were synthesized within the sieves of poly(N-isopropylacrylamide-2-hydroxyethylmethacrylate-acrylic acid) (p(NIPAAm-HEMA-AAc)) polymer microgels. Free radial emulsion polymerization was employed for synthesis of p(NIPAAm-HEMA-AAc) polymer microgels. Silver nanoparticles were introduced within the microgels sphere by in situ reduction method. Microgels and hybrid microgels were characterized by Fourier transform infrared spectroscopy, ultra violet-visible spectroscopy, transmission electron microscopy and dynamic light scattering measurements. Catalytic activity of Ag p(NIPAAm-HEMA-AAc) hybrid microgels was studied using catalytic reduction of 4 nitrophenol (4-NP) as a model reaction in aqueous media. The influence of sodium borohydride (NaBH4) concentration, catalyst dose and 4-NP concentration on catalytic reduction of 4-NP was investigated. A linear relationship was found between catalyst dose and apparent rate constant (kapp). The mechanism of catalysis by hybrid microgels was explored for further development in this area. The deep analysis of catalytic process reveals that the unique combination of NIPAAm, HEMA and AAc does not only stabilize silver nanoparticles in polymer network but it also enhances the mass transport of hydrophilic substrate like 4 NP from outside to inside the polymer network. PMID- 30244751 TI - Quantification of multi-antibiotic resistant opportunistic pathogenic bacteria in bioaerosols in and around a pharmaceutical wastewater treatment plant. AB - Pharmaceutical wastewater treatment plants (WWTPs) are thought to be a "seedbed" and reservoirs for multi-antibiotic resistant pathogenic bacteria which can be transmitted to the air environment through aeration. We quantified airborne multi antibiotic resistance in a full-scale plant to treat antibiotics-producing wastewater by collecting bioaerosol samples from December 2014 to July 2015. Gram negative opportunistic pathogenic bacteria (GNOPB) were isolated, and antibiotic susceptibility tests against 18 commonly used antibiotics, including 11 beta lactam antibiotics, 3 aminoglycosides, 2 fluoroquinolones, 1 furan and 1 sulfonamide, were conducted. More than 45% of airborne bacteria isolated from the pharmaceutical WWTP were resistant to three or more antibiotics, and some opportunistic pathogenic strains were resistant to 16 antibiotics, whereas 45.3% and 50.3% of the strains isolated from residential community and municipal WWTP showed resistance to three or more antibiotics. The calculation of the multiple antibiotic resistance (MAR) index demonstrated that the air environment in the pharmaceutical WWTP was highly impacted by antibiotic resistance, while the residential community and municipal WWTP was less impacted by antibiotic resistance. In addition, we determined that the dominant genera of opportunistic pathogenic bacteria isolated from all bioaerosol samples were Acinetobacter, Alcaligenes, Citrobacter, Enterobacter, Escherichia, Klebsiella, Pantoea, Pseudomonas and Sphingomonas. Collectively, these results indicate the proliferations and spread of antibiotic resistance through bioaerosols in WWTP treating cephalosporin-producing wastewater, which imposed a potential health risk for the staff and residents in the neighborhood, calling for administrative measures to minimize the air-transmission hazard. PMID- 30244752 TI - Highly time-resolved aerosol characteristics during springtime in Weizhou Island. AB - A single particle aerosol mass spectrometer was deployed to measure the changes of single particle species and sizes during March 2015 in Weizhou Island of the Beibu Gulf, Guangxi province, South China. In this campaign, a total of 3,100,597 particles were sized, and 25.8% particles with both positive and negative mass spectrum were collected and 24.8% characterized in combination with the ART-2a neural network algorithm. The distribution of sized particles was mainly in from 520 to 600nm, and the diameters ranging from 340 to 1000nm accounted for above 90%. Eight types of particles were classified: Elemental Carbon containing (EC), Organic Carbon containing (OC), EC and OC combined containing particles, Na containing particles, K containing particles (K), Levoglucosan containing particles, mineral containing particles, and Heavy Metal containing particles (HM). EC, OC and K were the major containing particles, which accounted for 84.3% in the eight types particles. The relative ratio and size distribution of the three types were EC (48.1%, 620nm), OC (12.7%, 440nm), and K (23.5%, 600nm), respectively. The three types of particles were a bit increasing ratios compared with those in clean periods during haze pollution periods. Combined with the back trajectory results from the Hysplit-4 model and local pollution sources revealed that the ambient air quality on the Weizhou Island may be influenced by biomass burning in the Indochina Peninsula (biomass burning in the Indochina Peninsula) from the transportation on higher level atmospheric layer and by mainland of south China located northeast of Weizhou Island on the ground. PMID- 30244753 TI - Occupational exposure assessment of phthalate esters in indoor and outdoor microenvironments. AB - Phthalate esters (PAEs) are widely used as plasticizers in consumer products. PAEs are a group of environmental hormone which disrupts human and animals' endocrine systems. Different occupational groups are exposed to various levels of PAEs. In the present study, four typical occupational groups were chosen, including doctors, college teachers, college students, and drivers who worked in public traffic system. In order to understand the exposure levels to PAEs via inhalation, air samples were collected from multiple microenvironments including indoor and outdoor in Hangzhou to measure the gas and particle concentrations of six PAEs, together with time spent in different microenvironments of these four groups. A comprehensive PAEs exposure model was built to estimate the daily PAEs exposure through inhalation, oral and dermal pathways. The Monte Carlo simulation results show that doctors were exposed to the highest level of PAEs, and consequently had the highest health risk among these four occupational groups. In contrast, college students had the lowest health risk. By setting the exposure level of staying in residences as the baseline, doctors and drivers were two occupations exposed to high PAEs health risk. Di-(2-ethylhexyl) phthalate (DEHP) was the largest contributor among the six phthalates, posing moderate health risk (10-5-10-6) to every occupation. For traffic microenvironments alone, the total exposure levels for different transportation modes were in the descending order of busses, cars, cabs, tubes, motor bikes, and walking. PMID- 30244754 TI - Structural characteristic and ammonium and manganese catalytic activity of two types of filter media in groundwater treatment. AB - Two types of filter media in groundwater treatment were conducted for a comparative study of surface structure and catalytic performance. Natural filter media was adopted from a conventional aeration-filtration groundwater treatment plant, and active filter media as a novel and promising filter media was also adopted. The physicochemical properties of these two kinds of filter media were characterized using numerous analytical techniques, such as X-Ray diffraction (XRD), scanning electron microscope (SEM), energy dispersive X-ray (EDX), X-ray photoelectron spectroscopy (XPS) and Zeta potential. The catalytic activities of these filter media were evaluated for ammonium and manganese oxidation. XRD data showed that both active filter media and natural filter media belonged to birnessite family. A new manganese dioxide (MnO2) phase (PDF#72-1982) was found in the structure of natural filter media. The SEM micrograph of natural filter media showed honeycomb structures and the active filter media presented plate structures and consisted of stacked particle. These natural filter media presented lower level of some trace elements such as calcium and magnesium, lower degree of crystallinity, lower Mn(III) content and lattice oxygen content than that of active filter media, which were associated with its poor ammonium and manganese catalytic activities. In addition, some gamma-Fe2O3 and MnCO3 were found in the coating which may hinder the ammonium and manganese catalytic oxidation. This study provides a thorough and comprehensive understanding about the most commonly used filter media in water treatment, which can provide a theoretical guide to practical applications. PMID- 30244755 TI - Characterization particulate matter from several Chinese cooking dishes and implications in health effects. AB - Cooking fume produced by oil and food at a high temperature releases large amount of fine particulate matter (PM) which have a potential hazard to human health. This chamber study investigated particle emission characteristics originated from using four types of oil (soybean oil, olive oil, peanut oil and lard) and different kinds of food materials (meat and vegetable). The corresponding emission factors (EFs) of number, mass, surface area and volume for particles were discussed. Temporal variation of size-fractionated particle concentration showed that olive oil produced the highest number PM concentration for the entire cooking process. Multiple path particle dosimetry (MPPD) model was performed to predict deposition in the human respiratory tract. Results showed that the pulmonary airway deposition fraction was the largest. It was also found that particles produced from olive oil led to the highest deposition. We strongly recommend minimizing the moisture content of ingredients before cooking and giving priority to the use of peanut oil instead of olive oil to reduce human exposure to PM. PMID- 30244756 TI - Letter From the Guest Editor: Emergencies in Neuroradiology I: The Brain. PMID- 30244757 TI - Role of Imaging in Acute Ischemic Stroke. AB - Rapid multimodal imaging is essential in the workup and management of acute ischemic stroke. Early parenchymal findings on noncontrast computed tomography or standard magnetic resonance imaging are used to triage patients for intravenous thrombolysis and to provide insight on prognosis. In the wake of recent endovascular stroke trials, advanced techniques including perfusion imaging and noninvasive vascular imaging are becoming important tools to guide potential endovascular treatment or expand therapy windows. Advanced imaging is also important in pediatric ischemic stroke which requires a slightly different workflow and treatment approach. Here, we will discuss key imaging findings in acute ischemic stroke, as well as the present and future of neuroimaging in light of recent and ongoing clinical trials. PMID- 30244758 TI - Stroke Mimics: The Quest for Leptomeningeal Anastomoses and Isolated Diffusion Weigthed MR Signal. AB - Stroke is caused by occlusion of a medium- or large-sized vessel in the brain. The treatment with either intravenous or intra-arterial thrombolysis is based on an accurate and time-sensitive diagnosis. On clinical and imaging grounds a number of entities-seizures, toxic-metabolic, infectious, or demyelinating diseases-can mimic stroke. Identifying them is paramount as the treatment differs significantly. Prior imaging reviews have focused on the nonterritorial distribution of these mimics. However, some important questions arise here. Are the vascular territories and their boundaries invariable in the human brain? Where should we draw the lines separating arterial territories? van der Zwan and colleagues addressed these questions decades ago. For him and others, the leptomeningeal anastomoses-a contentious concept for some but increasingly linked to collateral flow in stroke-is an important anatomic structure with significant variations in their distribution and pathophysiology. Variations in blood supply appear larger that traditionally taught. We revisit this concept and entertained their implications in cases of stroke mimics. For instance, the distribution of abnormalities in some toxic-metabolic processes appear to correlate with areas where rich leptomeningeal anastomoses are expected. We will also explore the concept of hyperintense signal on diffusion weighted-imaging with no correlated changes on apparent diffusion coefficient maps. We name this finding as "isolated DWI signal" and lay-out its importance in the recognition of many entities mimicking stroke. Taking together, the discussed anatomic and imaging concepts will help radiologists and clinicians to recognize not only the common but the unusual entities imitating stroke in the emergency room. PMID- 30244759 TI - Intracranial Hemorrhage Imaging. AB - Intracranial hemorrhage is a medical event frequently encountered in the clinical practice of radiology that has significant potential for patient morbidity and mortality. The expedient and accurate identification of intracranial hemorrhage as well as elucidation of the underlying cause can assist in optimizing the care of these patients. In this review, we attempt to familiarize the reader with the imaging appearance of multiple types of intracranial hemorrhage, both intra-axial and extra-axial and utilizing both computed tomography and magnetic resonance imaging, as well as to provide a framework for assessment of the underlying cause of the hemorrhage. PMID- 30244760 TI - Pitfalls in the Imaging Interpretation of Intracranial Hemorrhage. AB - Intracranial hemorrhage (ICH) is one of the most common pathologic findings in the emergent computed tomography (CT) imaging. ICH presents as hyperattenuation in parenchymal, subarachnoid, subdural, or epidural location. However, the initial interpretation of areas of hyperattenuation can be challenging as other pathologic or nonpathologic processes (eg, calcifications, vascular malformations, highly cellular tumors, iodinated contrast, or beam-hardening artifacts) can have similar appearance. ICH can also present as isoattenuation on CT, being difficult to distinguish from the brain parenchyma. Dual-energy CT can separate hemorrhage from other causes of hyperattenuation. Albeit, this type of technology has limited availability. Pitfalls on magnetic resonance imaging (MRI) are possible but less common. The characterization of hemorrhage on conventional MR sequences, and particularly on gradient recall echo or susceptibility-weighted imaging is improved. Thus, MRI is considered a problem-solving technique. Radiologists have a prominent role in the interpretation of the initial head CT, recognizing potential pitfalls or alternative diagnosis and if necessary recommending additional work-up. Key imaging findings and technical considerations in common and uncommon pitfalls of ICH are reviewed here. PMID- 30244761 TI - Essentials of Head Trauma Imaging. AB - Head trauma is a common indication for neuroimaging in the emergency room. CT is the modality of first choice, as it is quick, safe, and effective in evaluating for life-threatening intracranial hemorrhage and mass effect. CT is also best for evaluating for skull fractures, which may alter management and lead to further imaging studies. MRI is reserved for selected patients, particularly when the clinical exam does not match the CT imaging findings, such as in diffuse axonal injury. Emergency room physicians and radiologists, particularly those in training, would benefit from a consistent approach and search pattern for evaluating head trauma. We offer a comprehensive "outside-to-inside" approach to head trauma imaging, discussing not only common findings but also subtle "should not miss" findings and their clinical correlation. PMID- 30244762 TI - Hypoxic, Toxic, and Acquired Metabolic Encephalopathies at the Emergency Room: The Role of Magnetic Resonance Imaging. AB - Our purpose is to describe typical computed tomography and magnetic resonance imaging findings in encephalopathies in the emergency. The focus of this article are the most frequent toxic and acquired metabolic diseases and their preferential sites of involvement, such as hepatic encephalopathy, hypoglicemia, nonketotic hyperglycemia, osmotic demyelination, posterior reversible encephalopathy syndrome, uremia, illegal drug abuse, carbon monoxide poisoning, and hypoxic-ischemic encephalopathy. The radiologist must be able to identify the most usual patterns of lesion in computed tomography and magnetic resonance imaging in these settings. PMID- 30244763 TI - Pediatric Emergencies: Imaging of Pediatric Head Trauma. AB - Pediatric head trauma is an important cause of morbidity and mortality in children and may be seen in the setting of accidental or abusive injuries. Although many of the patterns of head injury are similar to adults, the imaging manifestations of head injury in children are more complex due to the developing brain and calvarium. Additionally, there are unique considerations for mechanisms of injury in children, to include abusive head trauma and birth-related injuries. The primary role of the radiologist is to identify and characterize the type and severity of head injury to help guide appropriate patient management. PMID- 30244764 TI - Brain Death: Diagnosis and Imaging Techniques. AB - Brain death (BD) is an irreversible cessation of functions of the entire brain, including the brainstem. The diagnosis of BD is made on clinical grounds and neurologic examination. In the United States, clinical criteria set by the American Academy of Neurology (AAN) emphasize 3 specific clinical findings to confirm BD, which include coma, absence of brainstem reflexes and apnea. Ancillary tests are needed when neurologic examination or apnea test cannot be performed. AAN recommended ancillary tests include electroencephalogram, which confirms electrical activity loss; catheter cerebral angiogram, which confirms loss of cerebral blood flow; as well as transcranial Doppler and nuclear scintigraphy. Digital subtraction angiography remains the gold standard for confirmation of lack of cerebral blood flow. On 99m Techentium hexa methyl propylene amine oxime or 99mTechnetium-ethylene cysteine diethyl ester (99mTc ethylene cysteine diethyl ester) Nuclear scintigraphy, lack of intracranial radiotracer uptake, correlates with BD. Although imaging studies like computed tomography angiogram (CTA), MR angiogram, CT perfusion, and MR perfusion are frequently used, they are currently not recommended by AAN. However, they hold tremendous promise in future as imaging tools in the armamentarium of a radiologist investigating BD as adjunct imaging to clinical findings. Imaging markers for BD on CTA include nonopacification of the cortical middle cerebral arteries and internal cerebral veins. On CT perfusion, there is lack of cerebral blood flow and blood volume in brainstem. Residual brain perfusion can occur with reduced intracranial pressure as in decompressive craniectomy, ventricular drainage and multiple skull fractures leading to false-negative results. On magnetic resonance imaging, there can be massive brain edema with herniations, poor gray or white matter differentiation, diffuse diffusion restriction, and nonvisualization of intracranial vessels on MR angiogram. On transcranial Doppler, cerebral circulatory arrest is indicated by flow patterns without forward flow progress, progressing from decrease in diastolic flow to disappearance of diastolic flow to oscillating pattern with retrograde flow in diastole, short systolic spikes, and finally absence of Doppler signal. AAN has included neuroimaging explaining coma as one of their prerequisite to be checked before evaluation for BD. Thus, a radiologist can play a critical role by recognizing the initial extensive hypoxic or ischemic damage to the central nervous system including the brainstem on imaging; guiding a neurologist evaluating a potential BD, as well as ruling out other pitfalls. In many cases, the radiologist is often the first person to appreciate the devastating findings of irreversible brain damage. Three most common mimics of BD are hypothermia, locked-in syndrome, and drug intoxication. By judicious usage of the available ancillary tests, cautiously interpreting the findings with awareness of their limitations and pitfalls, a radiologist can provide the support needed to confirm BD. PMID- 30244765 TI - Expert document on management of acromegaly. AB - OBJECTIVES: To seek a consensus on issues that may generate doubts in management of acromegaly in Spain. METHOD: Nominal groups and Delphi. Four experts defined relevant issues in management of acromegaly and generated different assertions and recommendations. Subsequently, a group of 30 additional experts was selected to test agreement with the assertions through two Delphi rounds. The following response categories were established: 1) Totally disagree; 2) Basically disagree; 3) Basically agree; 4) Totally agree. Agreement was defined as >=70% of answers in categories 1 and 2 (consensus with the disagreement) or 3 and 4 (consensus with the agreement) in the second Delphi round. RESULTS: Assertions covers various aspects of clinical practice, including: 1) Useful instruments in individualization of treatment (response predictive markers, imaging techniques, etc.); 2) Clinical profiles and relevant comorbidities in treatment individualization; 3) Role of patient in treatment decision-making; 4) Access to treatments (accessibility and equity). The first Delphi round included 35 assertions. Consensus was reached on six of these assertions, two were eliminated, and two were reformulated. Of the 27 assertions included in the second round, consensus was reached on 24 (22 in the agreement, two in the disagreement) and three were eliminated. CONCLUSIONS: This document is intended to solve some common clinical questions and to facilitate decision making in the management of patients with acromegaly. PMID- 30244766 TI - A tribute to the visionaries. PMID- 30244767 TI - Gold nanoparticle biosensors, a novel application in gene transformation and expression. AB - The conventional techniques of PCR, Southern blot, northern blot, in situ hybridization, and RNase protection assay have long been used to investigate transformation and expression of genes, but most of them are time-consuming and have relatively low sensitivity. In recent years, applying biosensors for molecular identification of biomolecules has been expanding significantly. Hence in this study, Zabol melon was used as a model plant to introduce new DNA and RNA based biosensors for confirming gene transformation and expression. First, the melon seeds were grown in vivo and Agrobacterium tumefaciens LBA4404 was used to introduce GUS reporter gene to the plant. In order to analyze GUS gene transformation and expression, probes were designed based on DNA, RNA, and cDNA of GUS gene sequence. Then, the analysis was performed using probes attached to gold nanoparticles to observe color change of the solution in presence of the target biomolecules. Hybridization of the probes with target molecules was evaluated at a wavelength of 400-700 nm and maximum change was observed in the wavelength range of 550-650 nm. In addition, lower detection limit of the assay was 0.25 ng/MUL and linear regression showed the relationship between different concentrations of the genomic DNA and absorbance. Consequently, results showed that application of detectors attached to gold nanoparticles for investigation on gene transformation and expression is more rapid, specific and economic compared to the biochemical and molecular techniques. These tests can be carried out with initial optimization at research centers using the least facilities; hence there will be no need for special equipment. PMID- 30244768 TI - Visceral adiposity index for the diagnosis of nonalcoholic fatty liver disease in premenopausal women with and without polycystic ovary syndrome. AB - OBJECTIVE: Visceral adiposity index (VAI), initially developed for the assessment of cardiometabolic risk, has been also proposed for the detection of nonalcoholic fatty liver disease (NAFLD); however, its diagnostic performance for NAFLD is still under investigation. We evaluated VAI as a marker of NAFLD and compared its diagnostic performance with that of three other NAFLD indices - fatty liver index (FLI), lipid accumulation product (LAP) and hepatic steatosis index (HSI) - in premenopausal women with and without polycystic ovary syndrome (PCOS) assessed for NAFLD by ultrasonography. DESIGN: Cross-sectional case-control study. METHODS: Anthropometric measurements, biochemical testing and abdominal ultrasonography after excluding causes of secondary liver disease were performed in 145 premenopausal women with PCOS (Rotterdam criteria) and 145 healthy control women within the same age range and matched for body mass index (BMI). The diagnostic performance of the four indices was assessed with receiver operating characteristic (ROC) analysis. RESULTS: NAFLD by ultrasonography was detected in 132 of the total sample of 290 women (45.5%). VAI, FLI, LAP and HSI values were significantly higher in women with NAFLD than those without. The areas under the curve (AUROCs) for VAI, FLI, LAP and HSI were 0.77 +/- 0.03, 0.87 +/- 0.02, 0.84 +/- 0.02 and 0.83 +/- 0.02, respectively, in the whole group, showing an adequate discriminatory ability for NAFLD of the four indices. AUROCs of the four indices calculated separately for PCOS and control women showed a similar performance of all indices in the two groups. CONCLUSIONS: These data show that VAI is useful for detecting NAFLD in premenopausal women with and without PCOS. However, VAI had a lower diagnostic performance in this cohort than FLI, LAP and HSI. PMID- 30244769 TI - Sedentary behavior and perceived stress among adults aged >=50 years in six low- and middle-income countries. AB - BACKGROUND: Sedentary behavior and perceived stress are both negatively associated with physical and mental health. Little is known about the association between sedentary behavior and perceived stress, and there is a particular paucity of data on people aged >=50 years from low- and middle-income countries (LMICs). METHODS: We analyzed cross-sectional, community-based data from 34,129 individuals aged >=50 years [mean age 62.4 (SD = 16.0) years, 52% females] from six LMICs. Perceived stress was assessed using the Perceived Stress Scale and time spent sedentary per day was self-reported. Multivariable linear regression analyses were conducted, adjusting for important socio-economic and physical and mental health-related confounders. RESULTS: The mean perceived stress score increased with greater sedentary time (38.4 for 0-<4 h/day to 54.2 for >=11 h/day). In the fully adjusted model, 4-8, 8-11, and >=11 h/day of sedentary behavior (SB) were associated with 1.97 (95%CI = 0.57-3.36), 7.11 (95%CI = 4.96 9.27), and 9.02 (95%CI = 5.45-12.59) times higher mean perceived stress scores, compared with 0-<4 h/day. Greater time spent sedentary was associated with higher perceived stress scores in all six countries, although the association in Mexico fell short of statistical significance. CONCLUSION: This is the first multinational analysis to show that a greater amount of sedentary behavior is associated with higher levels of perceived stress among older adults in LMICs. Future research may examine the types and contexts of sedentary behavior, and explore the underlying mechanisms of the relationship. PMID- 30244770 TI - Temporal trends in sitting time by domain in a cohort of mid-age Australian men and women. AB - There are few prospective data on temporal trends in overall sitting time for different domains of sitting. This study examined time trends over 6 years in total and domain-specific sitting time in mid-age Australian men and women. Self report data from 5246 participants in four survey waves (2007, 2009, 2011, 2013) of the HABITAT study in Brisbane, Australia, were analysed. Overall trends in 'high' total sitting time (>8 h/day sitting) and five domains were examined: a) >5 h/day for TV; b) >2 h/day for travel; c) >2 h/day for home computer use; d) >2 h/day for leisure; and e) >6 h/day for work. Sitting to watch TV and sitting at work accounted for more than half of total sitting time. The proportions who reported high sitting for computer use at home increased from 25% in 2007 to 37% in 2013 in men and from 19% to 29% over the same period in women. High TV sitting time was reported by 11.8% of men and 10.2% of women. These estimates increased to 16.5% and 13.2% respectively over the six years. In conclusion, although overall total sitting time remained fairly stable, there were significant increases in sitting time in some domains (home computer use and TV viewing) and in some sub-groups (such as women, and the employed). These increases were countered by declines in work-related sitting due to retirement. PMID- 30244771 TI - Therapeutic applications of polarized light: Tissue healing and immunomodulatory effects. AB - As the population grows and ages, non-pharmaceutical options for the treatment and management of wounds, disease and injury are required to ensure adequate care. Polarized light therapy (PLT) utilizes visible-spectrum polarized light for a number of clinical applications. The advantage of polarized light is that it is able to penetrate the skin to a depth of up to 5 cm, reaching deeper tissues involved in wound healing. PLT has been shown to accelerate the healing process for ulcers, surgical wounds and dermal burns as well as a small number of musculoskeletal injuries. As research into the histological and physiological effects of PLT is largely absent, studies related to other light therapy modalities, largely low-level laser therapy, may pave the way to identify putative mechanisms by which PLT might exert its effects. Changes to cell signalling and secretion of substances required for wound healing have been identified in response to phototherapies. The reviewed literature suggests that PLT may be efficacious in some wound and injury healing contexts, though a gap in the literature exists regarding its mechanisms of action. Future studies should fully explain the therapeutic effects of PLT and the physiological mechanisms underpinning them. PMID- 30244772 TI - Expectations for future care provision in a population-based cohort of baby boomers. AB - OBJECTIVE: We describe sources expected to provide for future care needs among baby-boomers in their late sixties and examine how expectations vary according to earlier health and social experiences. We hypothesised that greater integration in social relationships across adulthood is associated with greater expectation of informal care, and that greater morbidity over a longer time period is associated with greater expectation of formal care. METHOD: The MRC National Survey of Health and Development, a population-based birth cohort study set in mainland Britain, provided data on care expectations for 2135 participants aged 68-69. The outcome was who, besides the partner or spouse, is expected to provide for the future care needs, coded as adult children, other relatives, friends/neighbours, paid/professional care, or no one. Adult children were taken as the reference category and the latter two categories were combined as 'formal care' in the multiple regression analysis. RESULTS: 91% had an adult child, of whom 74% expected them to provide care if needed, and 11% expected formal care. The latter rose to 33% of those with no adult children. Geographical distance to adult children (over 25 miles) was strongly correlated with expectations but, independently of this, lack of someone to help in a crisis from midlife onwards and low social contact were associated with expecting formal care. Expectations did not differ by number of chronic conditions, functional limitations or longstanding illness from age 60 + . CONCLUSION: Those lacking social relationships in midlife onwards and those living further from adult children are more likely to expect formal help with their future care needs. As personal care needs are projected to rise with population ageing and families are increasingly expected to provide for these needs, initiatives to remove barriers to smaller distances between ageing parents and their children and to support and maintain high-quality family relationships across the life course should be considered. PMID- 30244773 TI - Managing nocturia: The multidisciplinary approach. AB - Nocturia, defined as waking at night to pass urine, is a common condition which increases with age. Whilst nocturia is known to have an important effect on quality of life, more recent evidence has linked the symptom with significant morbidity and mortality due to the effects of sleep deprivation on glucose metabolism and the immune system. The causes of nocturia are multifactorial and may be related to urine overproduction, storage disorders and primary sleep disorders. The commonest underlying pathology, however, is nocturnal polyuria, which may be associated with a number of medical conditions. This review explores the underlying causes of nocturia and nocturnal polyuria and, by doing so, describes a multidisciplinary approach to managing patients effectively. PMID- 30244774 TI - Postural control and posture-unrelated attention control in advanced age-An exploratory study. AB - OBJECTIVES: The link between postural control and cognition is under-studied, especially in healthy older adults. In the present study, we examined the link between postural control and posture-unrelated attention control. STUDY DESIGN AND OUTCOME MEASURES: Healthy individuals (n = 112) - men aged 77.2 +/- 5.5, and two groups of women, aged 78.6 +/- 3.5 and 68.9 +/- 3.7 - participated in this cross-sectional study. Postural control was assessed by static balance (SB) posturography in eight standing positions, and by two measures of dynamic balance (DB): the Timed Up-and-Go (TUG) test, and the Functional Reach Test (FRT). Attention control (inhibition) was assessed by the Continuous Performance Test (CPT) measuring Go/NoGo tasks with and without visual and audio distractors. RESULTS: Men tended to perform better on DB and women on SB. In the men, significant correlations were observed between Go/NoGo tasks and DB (r range: 0.373 to 0.653 for TUG, and -0.342 to -0.530 for FRT). In the younger women, Go/NoGo tasks were correlated with SB (r range: 0.323 to 0.572), and no correlations were observed in the older women. Go/NoGo tasks without distractions followed by tasks with audio distractors explained postural control measures. CONCLUSIONS: Posture-unrelated attention inhibition was associated with SB in the women and with DB in the men. Tasks with no distractions explained the variability in postural control in both genders. It is recommended to examine the effect of balance exercises on postural control and posture-unrelated attention control in both genders, and the contribution of the relationship between postural control and posture-unrelated attention control to falls in old age. PMID- 30244775 TI - Types of urinary incontinence in Bangladeshi women at midlife: Prevalence and risk factors. AB - OBJECTIVE: To determine the prevalence of, and risk factors for, sub-types of urinary incontinence (UI) in a nationally representative sample of midlife Bangladeshi women. METHODS: Bangladeshi women, aged 30-59, recruited by multi stage cluster sampling, completed the Questionnaire for the Diagnosis of Urinary Incontinence. The prevalence and the factors associated with each form of UI were explored using multivariable weighted logistic regression. RESULTS: 59.3% of the women were premenopausal, 8.4% perimenopausal and 32.3% postmenopausal. 83.2% had a BMI < 28 kg/m2 and none were using menopausal hormone therapy. The prevalence of stress UI was 5.4% (95% CI 4.4-6.6%), urgency UI 11.3% (9.8-12.9%), and mixed UI 7.0% (5.8-8.3%). Urgency UI was the most prevalent form of UI at each decade of age. Postmenopausal women were significantly more likely to have urgency UI (AOR 2.41, 95%CI 1.38-4.20; p = 0.002) and mixed UI (AOR 2.35, 95%CI 1.22-4.50; p = 0.010). Having more than 2 children was significantly associated with stress UI (AOR 2.79, 95%CI 1.30-6.00; p = 0.009) and urgency UI (AOR 2.34, 95%CI 1.28-4.30; p = 0.006), pelvic organ prolapse with stress UI (AOR 2.46, 95%CI 1.34-4.52; p = 0.004) and mixed UI (AOR 3.40, 95%CI 2.00-5.80; p < 0.0001), and diabetes with mixed UI (AOR 3.16, 95%CI 1.67-5.97; p < 0.0001). The women in the highest wealth quintile (AOR 0.27, 95%CI 0.10-0.72; p = 0.009) and underweight women had a lower risk of urgency UI (AOR 0.21, 95%CI 0.06-0.77; p = 0.018), while urgency UI was associated with working outside the home (AOR 3.11, 95%CI 1.36-7.15; p = 0.007) and obesity (AOR 3.00, 95%CI 1.57-5.74; p = 0.001). CONCLUSIONS: The overall prevalence of UI amongst Bangladeshi midlife women is low, with urgency UI the most common form, in contrast to developed countries, where stress UI predominates. Being postmenopausal, having more than two children, being obese and working outside the home increase the likelihood of urgency UI, whereas higher socio-economic status and lower weight appear to be protective. Menopausal hormone therapy use was not reported by any study participants. PMID- 30244776 TI - Effect of exercise alone or combined with dietary supplements on anthropometric and physical performance measures in community-dwelling elderly people with sarcopenic obesity: A meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the effect of exercise (EXE) alone or exercise combined with dietary supplements (EXE-SUPPL) on body composition and physical performance in subjects 60 years and older with sarcopenic obesity. METHODS: A systematic review was carried out of studies identified through five search engines up to April 15, 2018. We searched for randomized controlled trials (RCTs) evaluating EXE or EXE-SUPPL in elderly individuals with sarcopenic obesity for at least six weeks. Primary outcomes were percentage of body fat mass, appendicular skeletal muscle mass, and hand grip strength. Random effects meta-analyses with the inverse variance method were used to evaluate the effects of interventions on outcomes. Effects were expressed as mean differences (MD) and their 95% confidence intervals (CI). Risk of bias was assessed with the Cochrane tool. RESULTS: Nine papers reporting seven RCTs (with a total of 558 participants) were included in the review. EXE alone and EXE-SUPPL increased grip strength (MD 1.30 kg; 95% CI 0.58-2.01), gait speed (MD 0.05 m/s; 95% CI 0.03-0.07) and appendicular skeletal muscle mass (MD 0.40 kg; 95% CI 0.18-0.63). EXE alone and EXE-SUPPL reduced waist circumference (MD -1,40 cm; 95% CI -1.99 to -0.81), total fat mass (MD -1,77 kg; 95% CI -2.49 to -1.04), and trunk fat mass (MD -0.82 kg; 95% CI -1.22 to -0.42). CONCLUSION: EXE alone and EXE-SUPPL improved muscle related outcomes and reduced fat-related outcomes in subjects with sarcopenic obesity. There is a need for better-designed RCTs with systematic assessment of both different exercise regimes and dietary supplements in sarcopenic obese subjects. PMID- 30244777 TI - A qualitative assessment of health behaviors and experiences during menopause: A cross-sectional, observational study. AB - OBJECTIVES: A qualitative research study was performed to assess the health and lifestyle behaviors of middle-aged women during the menopause transition, as well as to inform the development of interventions designed to combat menopause symptoms and improve quality of life during and after menopause. STUDY DESIGN: Data were collected from 1611 women via a 21-item questionnaire distributed electronically. Only women who self-reported age >=40 years and who were either peri-menopausal or post-menopausal were included in the analyses. OUTCOME MEASURES: Women responded to questions about their health behaviors and experiences during menopause, including use of hormone replacement therapy (HRT), symptom ratings, and use of diet/lifestyle, exercise, and holistic remedies to relieve menopause symptoms. RESULTS: More than 80% of women were interested in a structured lifestyle program to alleviate menopause symptoms, with 72% of these women wanting targeted strategies for weight loss or weight maintenance. Insomnia and hot flashes were the most severe symptoms reported. Although HRT is a well established treatment of menopausal symptoms, more than 60% of women denied use of HRT, stating that they 'never considered HRT' as a treatment option or 'preferred to not take HRT'. Most women (65%) did not feel prepared for menopause. CONCLUSIONS: Women do not feel prepared for menopause and report interest in a structured lifestyle program containing weight-loss and weight maintenance strategies to combat menopause symptoms. PMID- 30244778 TI - Influence of gender and menopausal status on gut microbiota. AB - OBJECTIVES: We explore the differences in the gut microbiota associated with gender and hormonal status. STUDY DESIGN: We included 76 individuals in this study: 17 pre-menopausal women, 19 men matched by age, as a control group for the pre-menopausal women, 20 post-menopausal women and 20 men matched by age as a control group for the post-menopausal women; all 4 groups were also matched by body mass index (BMI) and nutritional background. MAIN MEASUREMENTS: We analyzed the differences in the gut microbiota, endotoxemia, intestinal incretins, pro inflammatory cytokines, and plasma levels of energy homeostasis regulatory hormones between pre- and post-menopausal women and compared them with their respective male control groups. RESULTS: We found a higher Firmicutes/Bacteroidetes ratio, a higher relative abundance of Lachnospira and Roseburia, and higher GLP-1 plasma levels in pre-menopausal women than in post menopausal women, who had similar levels to men. In contrast, we observed a lower relative abundance of the Prevotella, Parabacteroides and Bilophila genera, and IL-6 and MCP-1 plasma levels in pre-menopausal women than in post-menopausal women, who had similar levels to the men. We also found higher GiP and leptin plasma levels in women than in men, irrespective of the menopausal status of the women. In addition, adiponectin levels were higher in pre-menopausal women than in their corresponding age-matched male control group. CONCLUSIONS: Our results suggest that the differences in the composition of gut microbiota between genders and between women of different hormonal status may be related to the sexual dimorphism observed in the incidence of metabolic diseases and their co morbidities. PMID- 30244779 TI - A panel of multibiomarkers of inflammation, fibrosis, and catabolism is normal in healthy centenarians but has high values in young patients with myocardial infarction. AB - OBJECTIVES: Frailty confers a poor prognosis as it portends an increased risk of disability, dependence, and mortality. Although frailty is generally associated with aging, a marked interindividual variability exists. We compared a range of serum biomarkers of inflammation, fibrosis, and catabolism in three distinct cohorts, consisting of young patients with myocardial infarction, age-matched healthy volunteers, and disease-free centenarians. STUDY DESIGN: Prospective observational registry study. MAIN OUTCOME MEASURES: Serum levels of five biomarkers were measured in the three study groups. RESULTS: Disease-free centenarians had significantly lower (all p < 0.01) serum biomarker levels than young patients with myocardial infarction (growth differentiation factor 15: 877 +/- 299 vs. 1062 +/- 358 pg/mL; matrix metalloproteinase (MMP)-1: 1.7 +/- 0.9 vs. 3.2 +/- 1.2 ng/mL; MMP-2 174 +/- 38 vs. 214 +/- 44 ng/mL; MMP-9 325 +/- 73 vs. 407 +/- 54 ng/mL; and carboxy-terminal telopeptide of collagen type I: 3.3 +/- 1 vs. 4.2 +/- 1.3 ng/mL). No significant differences in biomarker concentrations between healthy controls and centenarians were identified. CONCLUSIONS: Disease free centenarians had significantly lower levels of inflammation, fibrosis, and catabolism biomarkers than young patients with myocardial infarction. Advanced aging per se is not invariably associated with these biomarkers. PMID- 30244780 TI - Dietary patterns and cardiovascular risk in postmenopausal women: Protocol of a cross-sectional and prospective study. AB - OBJECTIVE: Aging and menopause are associated with an adverse cardiometabolic profile, predisposing to cardiovascular disease. Diet may also affect their cardiometabolic risk. The aim of this study is to assess dietary habits and patterns of postmenopausal women and their association with adiposity measures, cardiometabolic parameters and subclinical atherosclerosis. STUDY PROTOCOL: The study will include two parts. The first part consists of cross-sectional evaluation of 750 postmenopausal women recruited consecutively from the Menopause Unit of an academic hospital. Dietary intake will be assessed by a food frequency questionnaire. Nutrient and food group intake will be calculated and adherence to the Mediterranean diet and other dietary patterns will be evaluated. A-priori and a-posteriori defined dietary patterns will be tested for associations with major and minor outcome measures. The second part consists of a prospective follow-up of all women recruited at baseline and re-assessment of the same variables after 3 years. Adherence to predefined or a-posteriori defined dietary patterns over these 3 years will be evaluated in association with changes in obesity indices and lipid levels, as well as in the progression of subclinical atherosclerosis. MAJOR OUTCOME MEASURES: Body mass index, lipid profile, carotid and femoral artery intima-media thickness and plaques. MINOR OUTCOME MEASURES: Waist circumference, waist-to-hip ratio, abdominal fat layers, incident hypertension and diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), c reactive protein and markers of subclinical arterial disease, including flow mediated dilation, pulse wave velocity, augmentation index and ankle-brachial index. RESULTS: The study is expected to complete baseline enrolment by the end of 2018 and follow-up assessment by the end of 2021. The results of the study will address the question of whether dietary patterns and eating habits are associated with cardiometabolic risk as well as with accelerated subclinical arterial disease and arterial aging in postmenopausal women. PMID- 30244782 TI - Examining factors that influence a woman's search for information about menopause using the socio-ecological model of health promotion. AB - Recognizing that increased knowledge of the perimenopause transition, in advance of experiencing symptoms, can make a positive impact on a woman's menopause experience, this study investigated whether women engage in self-directed learning to inform themselves about menopause, and if they do initiate self directed learning, what socio-ecological issues may help or hinder their search. Two hundred twenty-seven responses to an online survey were analyzed from women aged 35-55 years. Fewer than half (48%) indicated that they had engaged in any kind of learning action regarding menopause. For the women who initiated a search to know more about their bodies at menopause, factors influencing their self directed learning actions were found at every level of the socio-ecological model (SEM) of health promotion: intrapersonal, interpersonal, institutional, community, and policy factors. In general, women indicate they need more information than they receive. However, in this study the interpersonal level was the only level whose factors provided respondents with more help than hindrance. At all other levels, women were hindered from gaining the knowledge they need. From feelings of embarrassment to feelings of neglect by health care providers, women struggled to gain the information they sought. Understanding that education is one of the key determinants of health, the most important implication of the results of this study is that there is a need to connect adult education with health promotion, at every level of the socio-ecological model of health promotion. PMID- 30244781 TI - Physical activity and breast cancer survivors: Importance of adherence, motivational interviewing and psychological health. AB - Behavioral change theories have been used to support interventions that increase both motivation for and adherence to physical activity programs for breast cancer survivors. Most of the programs can improve psychological health-related quality of life. Depressive and anxious symptoms seem to be associated with some stressors, such as the perception of breast cancer, prognosis, long-term treatment-related side-effects and fear of cancer recurrence. Beyond physical fitness, several physical activity programs for breast cancer survivors have been reported to improve psychosocial wellness and life satisfaction. However, many physical activity programs have failed to motivate breast cancer survivors due to barriers such as general health issues and lack of time. More specifically, women may have little confidence in the benefits of physical activity and breast cancer outcomes. Therefore, engaging breast cancer survivors in physical activity is challenging for health care professionals. Herein, we identify cancer-related mental distress, coping style and behavioral theories applied to physical activity programs in breast cancer survivors. More specifically, we discuss the effectiveness and limitations of 3 psychological theories and 2 concepts related to behavioral change, including the theory of planned behavior, social cognitive theory, self-determination theory, transtheoretical model and motivational interviewing for physical activity adherence in breast cancer survivors. PMID- 30244783 TI - Efficacy of intravaginal dehydroepiandrosterone (DHEA) for symptomatic women in the peri- or postmenopausal phase. AB - OBJECTIVE: There is uncertainty whether treatment with dehydroepiandrosterone (DHEA) decreases menopausal symptoms for women in the peri- or postmenopausal phase. A previous systematic review considering this subject suggested that DHEA may slightly improve sexual function compared with placebo (CS. Scheffers, S. Armstrong, AEP. Cantineau, C. Farquhar, V. Jordan Dehydroepiandrosterone for women in the peri- or postmenopausal phase. Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD011066. DOI: https://doi.org/10.1002/14651858.CD011066.pub2). The purpose of this article is to review recent research investigating whether the use of DHEA, and in particular intravaginal DHEA (Prasterone(r)), improves sexual function. METHODS: We conducted an online search using Medline OVID for recent articles related to DHEA and menopause. We found 48 relevant publications, out of which 14 papers were original research, all related to the development and licensing of intravaginal DHEA. We critically analysed these 14 articles in relation to sexual function. RESULTS: All the randomised controlled trials assessed the efficacy of vaginal DHEA in women with vulvovaginal atrophy and showed that sexual dysfunction improved with treatment regardless of the level of dyspareunia at baseline. Treatment with DHEA was found to be superior to placebo and at least as efficacious as vaginal oestrogens in improving symptoms. CONCLUSION: Intravaginal DHEA appears to be a safe and effective treatment for menopausal vulvovaginal atrophy and dyspareunia in most women. Further studies are required before it can be recommended for women with a history of thrombosis, cardiovascular disease or hormone-sensitive neoplasms. PMID- 30244784 TI - Prescribing antipsychotics in older people: A mini-review. AB - Antipsychotic medications are widely prescribed in elderly populations for a range of psychiatric symptoms. Evidence for their efficacy in this population is limited, and such individuals are at increased risk of numerous side-effects, including stroke and death, particularly in those with dementia. There appears to be a mismatch between the current evidence base and what is occurring in clinical practice, especially in the use of antipsychotics to treat delirium and behavioural and psychological disturbance in dementia. We advise caution in the prescription of antipsychotics in older people and seeking specialist advice. PMID- 30244785 TI - Vitamin D levels in Mediterranean breast cancer patients compared with those in healthy women. AB - OBJECTIVES: To evaluate the vitamin D status of postmenopausal women with early estrogen-receptor-positive breast cancer and to compare it with that of healthy postmenopausal women from the same Mediterranean region. STUDY DESIGN AND OUTCOME MEASURES: Data from 691 breast cancer (BC) patients in the B-ABLE cohort were analyzed after recent cancer intervention (recent-BC) or after a minimum of two years since this intervention (long-term-BC). Patients were also stratified by previous chemotherapy exposure (ChT+ and ChT-). Plasma levels of 25 hydroxyvitamin D [25(OH)D] (25(OH)D) were compared with data from 294 healthy women (non-BC) by linear regression to estimate beta-coefficients using non-BC participants as the reference group. Age, body mass index and season of blood extraction were selected as potential confounders. RESULTS: Of the recent-BC patients, 23.7% had 25(OH)D deficiency, compared with 17.7% of the long-term-BC group, and just 1.4% of the non-BC participants. Most of the women were located in the insufficient 25(OH)D category regardless of study group. BC patients had significantly lower 25(OH)D levels than non-BC participants (adjusted beta coefficients: -4.84 [95%CI -6.56 to -3.12] in recent-BC, and -2.05 [95%CI -4.96 to -0.14] in long-term-BC). Among BC patients, the lowest 25(OH)D levels were found in the recent-BC (ChT+) group (p < 0.001). No differences were found between the long-term-BC (ChT-), long-term-BC (ChT+) and recent-BC (ChT-) groups. Among the BC ChT+ patients, the recent-BC group had significantly lower 25(OH)D levels than the long-term-BC group (p < 0.001). CONCLUSION: Severely reduced 25(OH)D levels were detected in patients with breast cancer, particularly after recent chemotherapy. These 25(OH)D levels had partially recovered over the long term, but still remained much lower than in the healthy population. PMID- 30244786 TI - Interventions targeting sedentary behavior in non-working older adults: a systematic review. AB - Sedentary behavior has been found to be associated with negative health outcomes independently of physical activity in older adults. This systematic review collates interventions to reduce sedentary behavior in non-working older adults, assessing whether they are effective, feasible, and safe. A systematic search identified 2560 studies across five databases. Studies were included where participants were >=60 years on average with none younger than 45, and participants did not work >2 days per week. A total of six studies were identified, three of which included control groups, while the other three were repeated-measures pre-post designs. Only one study randomised participants. The overall level of quality of included studies was poor. A narrative synthesis was conducted, as the level of heterogeneity in outcomes and outcome reporting were too high for a meta-analysis to be performed. The narrative synthesis suggested that interventions have the potential to reduce sitting time in non-working older adults. Included studies reported feasible and safe implementations of their interventions in most samples, except for one subsample from a study of people in sheltered housing. Objectively measured reductions in sitting time were between 3.2% and 5.3% of waking time, or up to 53.9 min per day. Future studies should employ more rigorous designs to assess the effects of reducing sedentary behavior on health and physical function, and should include follow-ups to measure the duration of behavior change. PMID- 30244787 TI - Interlocking Enzymes in Graphene-Coated Cellulose Paper for Increased Enzymatic Efficiency. AB - A simple method for interlocking glucose oxidase and horseradish peroxidase in a network of cellulose fibers coated with bovine serum albumin (BSA)-exfoliated graphene (biographene) is reported here. The resulting paper reactor is inexpensive and stable. Biographene is expected to function as an electron shuttle, making the reaction between the enzyme and the substrate more efficient, and this hypothesis is examined here. The BSA used to separate the sheets of graphene provides extra carboxylic acid groups and primary amines to help interlock the enzymes and the graphene in between the fibers. The decrease in entropy associated with interlocking the enzymes on a solid support is likely responsible for the increase in enzymatic stability/activity observed. Each cellulose disk contained 5.2mg of enzyme per gram of paper and 93% of the enzyme is retained after washing for 0.5-2h. This simple methodology provides a low cost, effective approach for achieving high enzymatic activity and good loadings on a benign, versatile support. PMID- 30244788 TI - PAMAM Dendrimer Modified Reduced Graphene Oxide Postfunctionalized by Horseradish Peroxidase for Biosensing H2O2. AB - In this chapter, we describe the tethering of horseradish peroxidase (HRP) to reduced graphene oxide (RGO) for sensing H2O2 in serum. To accomplish this, RGO was synthesized through a green route by reducing graphene oxide (GO) prepared by Hummers method with carrot extract. The RGO was then covalently functionalized by electrochemical amination using fourth generation, amine-terminated PAMAM dendrimers. Subsequently, HRP was postfunctionalized through glutaraldehyde linkage. The synthesized RGO and the functionalization steps were well characterized by spectroscopic, microscopic, and electrochemical techniques. The application of HRP tethered RGO was demonstrated for H2O2 sensing in blood serum. This work provides scope for extending this functionalization strategy for other carbonaceous materials as well. PMID- 30244789 TI - Preparation, Characterization, and Application of Enzyme Nanoparticles. AB - Enzymes are fundamental biocatalysts, which regulate various metabolic reactions. They exhibit high substrate specificity, sensitivity, and exceptional catalytic activity under ideal conditions and, hence, have been used as industrial catalysts. Enzyme nanoparticles have attracted the scientific community as they can be used for environment protection, biochemical engineering, and biomedicine. It is necessary to understand the nature of enzyme nanoparticles interactions with their analyte. Various types of enzyme/protein nanoparticles have been immobilized onto a matrix (electrode or membrane) for the fabrication of biosensors. Among the various nanoparticles and nanomaterials, organic nanoparticles have received more attention due to their fascinating properties. Therefore, the future research should be focused to develop advanced biosensors based on enzyme nanoparticles that could be used for early diagnosis and management of chronic diseases. This chapter explains various enzyme nanoparticles-based biosensors, such as GOX, HRP, uricase, cholesterol oxidase, hemoglobin, and their biomedical applications. PMID- 30244790 TI - Encapsulation of Microorganisms, Enzymes, and Redox Mediators in Graphene Oxide and Reduced Graphene Oxide. AB - Graphene oxide (GO) and reduced graphene oxide (rGO) were demonstrated in the past decade as biocompatible carbon-based materials that could be efficiently used in bioelectrochemical systems (BESs). Specifically, for redox enzyme encapsulation in order to improve electron communication between enzymes and electrodes. The addition of GO to different solvents was shown to cause gelation while still allowing small molecule diffusion through its gel-like matrix. Taking the combination of these traits together, we decided to use GO hydrogels for the encapsulation of enzymes displayed on the surface of yeast in anodes of microbial fuel cells. During our studies we have followed the changes in the physical characteristics of GO upon encapsulation of yeast cells displaying glucose oxidase in the presence of glucose and noted that GO is being rapidly reduced to rGO as a function of glucose concentrations. GO reduction under these conditions served as a proof of electron communication between the surface-displayed enzymes and GO. Hence, we set out to study this phenomenon by the encapsulation of a purified glucose dehydrogenase (in the absence of microbial cells) in rGO where improved electron transfer to the electrode could be observed in the presence of phenothiazone. In this chapter, we describe how these systems were technically constructed and characterized and how a very affordable matrix such as GO could be used to electrically wire enzymes as a good replacement for expensive mediator containing redox active polymers commonly used in BESs. PMID- 30244791 TI - Chemical and Biochemical Approach to Make a Perfect Biocatalytic System on Carbonaceous Matrices. AB - Enzymatic processes are widely used in food industry, pharmacy, cosmetic and household chemistry, and medicine. However, the common and efficient application of the biological catalysts is limited by a number of factors that influence enzymes activity. One of the most frequent methods to improve the biocatalysts' properties is immobilization. This chapter presents a recent overview of our attempts to obtain the perfect biocatalytic system. The experimental approach, proposed in this chapter, includes the critical points like: the choice of adequate immobilization method, most suitable carrier, determination of enzyme kinetic parameters, stability, and toxicity of obtained systems. As carbon materials including graphene-derived materials offer unique properties and a plenty of different modifications, these parameters seem to be of decisive importance to understand chemistry of complex systems. Consideration of all the mentioned requirements lead us to the conclusion that graphene oxide could be the best candidate for support in perfect biocatalytic systems. PMID- 30244792 TI - Enzyme Multilayers on Graphene-Based FETs for Biosensing Applications. AB - Electrochemical sensors represent a powerful tool for real-time measurement of a variety of analytes of much significance to different areas, ranging from clinical diagnostics to food technology. Point-of-care devices which can be used at patient bedside or for online monitoring of critical parameters are of great importance in clinical daily routine. In this work, portable, low-cost electrochemical sensors for a fast and reliable detection of the clinically relevant analyte urea have been developed. The intrinsic pH sensitivity of reduced graphene oxide (rGO)-based field-effect transistors (FETs) was exploited to monitor the enzymatic hydrolysis of urea. The functionalization of the sensor platform using the layer-by-layer technique is especially advantageous for the immobilization of the biorecognition element provided that this approach preserves the enzyme integrity as well as the rGO surface. The great selectivity of the enzyme (urease) combined with the high sensitivity of rGO-based FETs result in the construction of urea biosensors with a limit of detection (LOD) of 1MUM and a linear range up to 1mM. Quantification of Cu2+ with a LOD down to 10nM was performed by taking advantage of the specific inhibition of urease in the presence of heavy metals. These versatile biosensors offer great possibilities for further development of highly sensitive enzyme-based FETs for real-time, label-free detection of a wide variety of clinically relevant analytes. PMID- 30244793 TI - Immobilization of a Mesophilic Lipase on Graphene Oxide: Stability, Activity, and Reusability Insights. AB - Catalyst-mediated bioprocessing at an industrial scale is dependent on the sustained stability and activity of the biocatalyst. Here, we demonstrate that strategy employed to increase the stability and activity of a mesophilic lipase immobilized on graphene oxide (GO). The protein adsorption capacity of GO is much higher than of other large surface area carbonaceous materials. Its structure and physicochemical properties are reported beneficial for enzymatic activity modifications. A purified lipase from Brevibacillus borstelensis NLIP05 immobilized on GO showed remarkable increase in thermostability (at 95 degrees C) over a broad alkaline pH range (pH 7-12) compared to the free enzyme. Thermodynamic analysis of the GO-lip showed decreases in Km and activation energy (Ea) with increased Vmax and deactivation energy (Ed) at both 45 and 95 degrees C. The decrease in decay constant (k) coupled with the increase in t1/2 value with temperature increase were salient features of the GO-lip system. This implies that GO-based immobilization conferred structural stability to the enzyme at higher temperature indicating chaperone like activity. Our findings support suitability of immobilized lipase on GO nanosupport for possible production of value-added materials with varied biological applications in the form of active pharmaceutical substances, synthetic building blocks, and effective synthesis of surfactants. The enhanced stability and activity of lipase indicate major application of GO on an industrial scale. PMID- 30244794 TI - A Simple Flow Reactor for Continuous Synthesis of Biographene for Enzymology Studies. AB - The unique properties of graphene make it an intriguing platform for the attachment and enhancement of biological molecules, but it has yet to achieve its full potential in terms of biological applications. Single-layer graphene is expensive, making alternatives to this material highly desired for applications that require high-quality graphene in large quantities. In this context, we report a simple, environmentally friendly, nonlabor-intensive method for the synthesis of colloidal graphene suspensions of 3-5 layers, stabilized by bovine serum albumin, in water. The method involves a flow reactor designed to continually yield high-quality graphene colloids, synthesized, purified, and optimized all in one setup. The flow reactor is able to produce colloidal graphene sheets on a multigram scale, and these colloids were characterized by Raman spectroscopy, electron microscopy, and zeta potential studies. The average size of the sheets is 0.16MUm2, each consisting of 3-5 layers of graphene with little or no sp3 defects. These graphene colloids stabilized by the protein were successfully used in protein kinetic studies as well as in surface plasmon resonance protein binding studies. The ease of synthesis of these high-quality graphene colloidal suspensions in water provides an exciting opportunity for biographene to be used on an industrial scale for electronic, thermal, and enzymology applications. PMID- 30244795 TI - Enzyme-Graphene Platforms for Electrochemical Biosensor Design With Biomedical Applications. AB - Due to the growing need for sensitive, reliable, reusable, fast, and cheap devices for the detection of analytes which have an important role in diagnosis of different diseases, in metabolic disorders, in monitoring treatment of serious diseases such as cancers, the sensing field has attracted huge interest from the scientists. The majority of the traditional methods that are currently in use are invasive, expensive, and laborious. Moreover, highly specialized operators and sophisticated instrumentations are usually required. Taking these into account, the introduction of electrochemical sensors and biosensors avoid a lot of the disadvantages associated with most of the used analytical techniques. The biggest contribution to this development was the use of different nanomaterials as transducers of the analytical signal. The properties, such as high mechanical strength, good electrical conductivity, and ability to serve as efficient signal transducers, make carbon-based nanomaterials, including graphene, ideal materials for biosensor applications. Furthermore, graphene presents high surface area that can be easily modified in different ways to be adapted for the immobilization of various biocompounds for the construction of biosensors. Recent advances regarding the use of graphene and graphene materials for the immobilization of several enzymes for biosensor development and their applications for the detection of chemical and biological species are presented with focus on different enzymes immobilization techniques. In the end, the future trends for the development of graphene-based biosensors in biomedical field are also discussed. PMID- 30244796 TI - Graphene Quantum Dots: Synthesis and Applications. AB - Graphene and its derivatives having at least one dimension in nanoscale range have attracted tremendous attention in recent years due to their unique electronic, optical, chemical, and mechanical properties. This chapter is about graphene quantum dots (GQDs) that are zero-dimensional graphene derivatives with one to few layers of graphene sheet having size range less than 20nm. This chapter is an overview of synthesis of GQDs by top-down and bottom-up approaches, as well as detailed methods of synthesis of GQDs by acidic oxidation of carbon fibers. Owing to their extremely small size, quantum confinement, edge effect, biocompatibility, low toxicity, photostability as well as water solubility they are excellent candidates for understanding biological systems and cellular processes at the molecular scale. These are also suitable nanomaterials to replace inorganic semiconducting nanoparticles (e.g., CdS, CdSe, ZnS, and Si) which are toxic to biological systems. PMID- 30244797 TI - Shielding of Enzymes on the Surface of Graphene-Based Composite Cellular Foams Through Bioinspired Mineralization. AB - Immobilization of enzyme on the surface of graphene-based composite cellular foams (GCCFs) is commonly prone to acquire stable and ultrahigh loading of enzymes and fast transport of substrates during the catalytic process. In this chapter, we reported a method of preparing GCCFs through combination of redox assembly and biomimetic mineralization with in situ enzyme immobilization. Briefly, GCCFs were first prepared through redox assembly of graphene oxide (GO) nanosheets enabled by polyethyleneimine (PEI). The cationic PEI in the resultant reduced GO/PEI (rGO/PEI) cellular foams acted as the mineralization-inducing agent could catalyze the condensation of silicate to form silica (biomimetic silicification) on the reduced graphene oxide (rGO) surface, where enzyme (with penicillin G acylase as model enzyme) is in situ entrapped and shielded within the silica network. Enzymes could be stably resided on the surface of GCCFs without any leaching against a broad range of pH values (3.5-10.0). GCCFs show a three-dimensional (3D) porous structure, which facilitates the fast transfer of substrate and, thereby, leads to desirable catalytic activity. Combined with the monolithic feature, GCCFs exhibit ease of recyclability and superior thermal/recycling stabilities during the catalytic synthesis of 6 aminopenicillanic acid (6-APA, an important pharmaceutical intermediate) compared to free enzyme and enzyme adsorbed on rGO/PEI cellular foams. PMID- 30244798 TI - Enzyme Immobilization on Functionalized Graphene Oxide Nanosheets: Efficient and Robust Biocatalysts. AB - Enzymes are used as biocatalysts for analytical purposes in diagnostics and preparative purposes in large-scale industrial processes. Despite perfect catalytic properties of enzymes, their industrial applications are limited due to the drawbacks regarding the lack of long-term stability under process conditions. The difficulties associated with recycling have to be resolved before enzyme implementation at industrial scale. Enzyme immobilization, as a novel approach, can improve the half-life, stability, catalytic activity, and reusability of enzymes. Graphene-based nanomaterials, as nanoscaled and thermostable inorganic carriers, are nontoxic materials and selective modulators for enzyme activity. Herein, we have concentrated on strategies for preparing graphene-based nanocomposites for enzyme immobilization. Nanostructures of graphene, hybrid graphene, and their derivatives with adjustable surface chemistry, caused them to be excellent candidates for immobilization of enzymes. For instance, the synthesis and functionalization of Fe3O4-graphene oxide (GO) hybrids were improved recently, in our research group, using cyanuric chloride and polyethylene glycol bis-amine for the immobilization of xylanase and glucoamylase enzymes, via physical and covalent attachments. Decorating GO nanosheets with Fe3O4 nanoparticles has facilitated the reusability of enzymes and increased the surface area for enzyme loading. The use of these hydrophilic crosslinkers may change the microenvironment of the immobilized enzymes that could result in the enhancement of their catalytic activity. As a result of the fascinating properties of graphene-based nanocarriers, with respect to structures that can be oriented and surfaces that can be modified, in our opinion, they offer some important advantages for biotechnological applications, especially in the areas of enzyme immobilization and medicine. PMID- 30244799 TI - Stabilization of Laccase Through Immobilization on Functionalized GO-Derivatives. AB - This chapter deals with the use of functionalized derivatives of graphene oxide as nanoscaffolds for the immobilization and stabilization of laccase from Trametes versicolor. Covalent and noncovalent immobilization approaches are described, while a novel method for the development of laccase-based multilayer nanoassemblies is also presented. Various biochemical, spectroscopic, and microscopic techniques were applied to characterize the nanobiocatalytic systems in respect to their microstructure and catalytic performance. Laccase-GO nanosystems were characterized with FTIR spectroscopy in order to confirm the functionalization of the nanomaterials, as well as to interpret the nanomaterial enzyme interactions, while the multilayer structure of laccase-based multilayer nanoassemblies was confirmed by atomic force microscopy. The nanobiocatalytic systems presented here demonstrated exceptional stability and reusability compared with the free enzyme form, leading to robust biocatalytic systems appropriate for various applications of industrial interest. PMID- 30244800 TI - Synthesis, Characterization, and Applications of Nanographene-Armored Enzymes. AB - The unexpected discovery of graphene and especially the follow-up explosion of interest in its properties and applications marked the beginning of a new carbon era. Graphene-based nanostructured materials are highly useful because they show great promise in the field of biotechnology and biomedicine. Owing to their unique structural features, exceptional chemical, electrical, and mechanical properties, and their ability to affect the microenvironment of biomolecules, graphene-armored nanomaterials are suitable for use in various applications, such as immobilization of enzymes, field-effect transistors, photovoltaic devices, and biosensors, which in turn is extremely vital to the development of biomedical instruments, clinical diagnosis, and disease treatment. In this chapter, we present our recently reported work to armor hydrolytic enzymes on graphene-based nanomaterial in order to develop novel scaffolds to build robust nanobiocatalysts. Synthesized graphene-Fe3O4 and polyaniline-coated silver graphene nanocomposite have been used to immobilize beta-galactosidase and lipase, using noncovalent and covalent strategies, respectively. Herein, the methodologies of both techniques have been discussed in detail. Owing to the large surface area offered by the honeycomb like structure of graphene, very high amount of enzyme has been loaded on small amounts of the nanocomposite. The stability and reusability of the fabricated nanobiocatalysts have been compared with their free forms. Nanographene-armored enzymes demonstrated high catalytic stability and easy recovery from the reaction medium and can be applied in various biotechnological applications. Lastly, future prospects and possible challenges in this rapidly developing area have also been discussed. PMID- 30244801 TI - Preface. PMID- 30244802 TI - Overview of Studies Regarding Mesoporous Silica Nanomaterials and Their Biomedical Application. AB - Synthesis of mesoporous silica nanomaterials occurred in the late 1980s and early 1990s. Since then, we have seen dramatic increase in the number of publication dealing with this nanomaterial. In particular, there have been a large number of publications regarding biomedical application of mesoporous silica nanoparticles including their use in cancer therapy and diagnosis. Various surface modification strategies have been explored to enhance drug loading and to target them to tumor. In addition, the nanoparticles have been armed with controlled release capability. In this review, we point out some crucial issues regarding the material, which will be discussed in more detail in chapters of this volume. PMID- 30244803 TI - Controlled Release With Emphasis on Ultrasound-Induced Release. AB - Mesoporous silica nanoparticles (MSNs) represent a promising approach to be used as nanocarriers because they fulfill some basic criteria: biocompatibility, high loading capacity and possibility of easy surface modifications. As a consequence, MSNs have been employed to design sophisticated stimuli-responsive nanocarriers able to release the entrapped cargo on demand. Among those stimuli ultrasound (US) is considered as one of the most promising triggers for drug delivery systems due to the high tissue-penetrating capability and non-invasiveness. Recently, we employed US as a stimulus to control the drug release from MSNs for the first time, and found that acoustic cavitation played a key role in triggering the release. Those US-responsive MSNs were transported using cellular vehicles toward disease areas where they demonstrated their capacity to kill cancer cells when exposed to US. Light is also an excellent trigger because of the high biocompatibility and the capacity to focus to very small regions. However, its poor penetration in living tissues compromises its use in a clinical scenario. An alternative could be the use of near infrared (NIR) as trigger, as it would be described in this chapter. Other option could be the use of magnetic fields as stimulus because it can reach deep areas into the living tissue without damaging the surrounding tissues. MSNs have been combined with magnetic fields in a many different approaches and a quick overview is here provided. This chapter will show how some of these external stimuli represent a valuable tool for fighting complex diseases such as cancer. PMID- 30244804 TI - Structure Characterization of Mesoporous Materials by Electron Microscopy. AB - The structural analysis of silica mesoporous crystals (SMCs) is a key step for understanding their properties, especially toward drug delivery. Although various techniques can be applied, electron crystallography has been proved the most powerful method in the structure solution of mesoporous materials. In this chapter, we will begin with introducing basic crystallography and extend to the 3D structure solution using a set of HRTEM images. Typical examples will also be given to show the structure features of 2D, 3D, cage-type, and hyperbolic surface type mesostructures. A drug delivery system using SMCs as a reservoir will be given at the end. PMID- 30244805 TI - The Bioimaging Applications of Mesoporous Silica Nanoparticles. AB - The unique features of Mesoporous Silica Nanoparticles (MSNs) provide a suitable platform to carry fluorescence dyes for various bioimaging applications. Several strategies have been developed to conjugate a variety of dyes either in the pores or on the surfaces of MSNs to form the fluorescence MSNs (FMSNs). In this chapter, we will discuss recent research progress and future development of FMSNs for living system imaging. We will first describe different strategies for the fabrications of FMSNs. Then, we will discuss the recent developments of cellular and intracellular imaging including self-probe for the interactions of FMSNs with the cells, receptor and organelle labeling, sensing and tracking of biological system, and monitoring the drug delivery and release processes. Moreover, we will include the applications of FMSNs as contrast agents for in vivo imaging. Finally, we will conclude and highlight the challenges and opportunities for MSNs in medical applications. PMID- 30244806 TI - Biodistribution and Excretion of Intravenously Injected Mesoporous Silica Nanoparticles: Implications for Drug Delivery Efficiency and Safety. AB - Mesoporous silica nanoparticles (MSNs) are currently attracting a high interest for use as drug carriers in vivo. To date only data on the biodistribution in small animals are available. As any nanoparticle system, the MSNs typically accumulate in the RES organs lung, liver, and spleen upon intravenous (i.v.) administration. However, the literature data are partly inconclusive, which can be connected to the wide variability of the experimental designs, differing for example in particle size and shape, mesopore size, and surface functionalization, as well as the animal models used, the amount administered, and the means for particle detection. The present review is an attempt to summarize the literature to date with main focus on the increasing number of studies related to quantitative full body distributions. Whenever possible, attempts are also made to discuss differences in experimental observations between studies. Finally, an outlook is given listing some open issues, and highlighting the need for more standardized experimental designs in order to allow for a faster identification of optimal particle characteristics for drug delivery applications of MSNs. PMID- 30244807 TI - Biodegradable Silica-Based Nanoparticles: Dissolution Kinetics and Selective Bond Cleavage. AB - Silica-based nanomaterials are extensively used in industrial applications and academic biomedical research, thus properly assessing their toxicity and biodegradability is essential for their safe and effective formulation and use. Unfortunately, there is often a lot of confusion in the literature with respect to the toxicity and biodegradability of silica since various studies have yielded contradictory results. In this contribution, we first endeavor to underscore that the simplistic model of silica should be discarded in favor of a more realistic model recognizing that all silicas are not created equal and should thus be considered in the plural as silicas and silica hybrids, which indeed hold various biocompatibility and biodegradability profiles. We then demonstrated that all silicas are-as displayed in Nature-degradable in water by dissolution, as governed by the laws of kinetics. Lastly, we explore the vast potential of tuning the degradability of silica by materials design using various silica hybrids for redox-, pH-, enzymatic-, and biochelation-mediated lysis mechanisms. PMID- 30244808 TI - Stimuli-Responsive Nanomachines and Caps for Drug Delivery. AB - In this review we focus on methods that are used to trap and release on command therapeutic drugs from mesoporous silica nanoparticles (MSNs). The pores in the MSNs are large enough to accommodate a wide range of cargo molecules such as anticancer and antibiotic drugs and yet small enough to be blocked by a variety of bulky molecules that act as caps. The caps are designed to be tightly attached to the pore openings and trap the cargo molecules without leakage, but upon application of a designed stimulus detach from the nanoparticles and release the cargo. Of special emphasis in this review are nanomachines that respond to stimuli administered from external sources such as light or magnetic fields, or from chemical stimuli produced by the biological system such as a general change in pH or redox potential, or a highly specific chemical produced by a cancer cell or infectious bacterium. The goal is to release a high local concentration of the cargo only where and when it is needed, thus minimizing off-target side effects. We discuss sophisticated reversible nanomachines but also discuss some useful caps that simply break off from the nanoparticles in response to the selected stimulus. Many ingenious systems have been and are being designed; we primarily highlight those that have been demonstrated to operate in vitro and/or in vivo. In most cases the closed MSNs are endocytosed by diseased or infected cells and opened inside the cells to release the drugs. We begin with an overview of the nanoparticles and nanomachines and then present examples of drug release triggered by internal chemical stimuli from the organism and finally by external light and magnetic field stimuli. PMID- 30244809 TI - Mesoporous Silica-Based Nanoparticles for Light-Actuated Biomedical Applications via Near-Infrared Two-Photon Absorption. AB - In this review, we highlight the design of nanomaterials for two-photon excitation, in order to treat tumors with a high accuracy. Indeed two-photon excitation allows remote control of the nanoparticles with a spatio-temporal resolution. The nanomaterials are based on mesoporous silica-organosilica nanoparticles including core-shell systems. The therapeutic treatments include drug delivery, photodynamic therapy, gene silencing, and their combinations. At first, the nanosystems designed for two-photon-triggered cytotoxic drug delivery are reviewed. Then the nanomaterials prepared for two-photon photodynamic therapy and reactive oxygen species delivery are discussed. Finally, the nanosystems combining drug delivery or gene silencing with two-photon photodynamic therapy are presented. Due to the rapid progresses concerning two-photon-excited nanomaterials and the interest of near-infrared light to treat deep tumors, we believe this technology could be of high interest for the personalized medicine of the future. PMID- 30244810 TI - Preface. PMID- 30244811 TI - A Before and After Analysis of Health Care Utilization by Patients Enrolled in Opioid Controlled Substance Agreements for Chronic Noncancer Pain. AB - OBJECTIVE: To evaluate the impact of opioid controlled substance agreements (CSAs) enrollment on health care utilization. PATIENTS AND METHODS: We retrospectively evaluated health care utilization changes among 772 patients receiving long-term opioid therapy for chronic noncancer pain enrolled in a CSA between July 1, 2015, and December 31, 2015. We ascertained patient characteristics and utilization 12 months before and after CSA enrollment. Decreased utilization was defined as a decrease of 1 or more hospitalizations or emergency department visits and 3 or more outpatient primary and specialty care visits. Multivariate modeling assessed demographic characteristics associated with utilization changes. RESULTS: The 772 patients enrolled in an opioid CSA during the study period had a mean +/- SD age of 63.5+/-14.9 years and were predominantly female, white, and married. The CSA enrollment was associated with decreased outpatient primary care visits (odds ratio [OR], 0.16; 95% CI, 0.14 0.19) and increased diagnostic radiology services (OR, 1.22; 95% CI, 1.02-1.47). After CSA enrollment, patients with greater comorbidity (Charlson Comorbidity Index score >3) were more likely to have reduced hospitalizations (adjusted OR, 2.8; 95% CI, 1.3-6.0; P=.008), reduced outpatient primary care visits (adjusted OR, 2.0; 95% CI, 1.2-3.2; P=.005), and reduced specialty care visits (adjusted OR, 2.0; 95% CI, 1.2-3.3; P=.006). CONCLUSION: For patients receiving long-term opioid therapy for chronic noncancer pain, CSA enrollment is associated with reductions in primary care visits and increased radiologic service utilization. Patients with greater comorbidity were more likely to have reductions in hospitalizations, outpatient primary care visits, and outpatient specialty clinic visits after CSA enrollment. The observational nature of the study does not allow the conclusion that CSA implementation is the primary reason for these observed changes. PMID- 30244812 TI - Association of Low Urinary Sodium Excretion With Increased Risk of Stroke. AB - The positive relationship between sodium intake and blood pressure is well established. However, results of observational studies on dietary sodium intake and risk of stroke are inconsistent. Moreover, prospective studies with multiple 24-hour urine samples for accurate estimation of habitual sodium intake are scarce. We examined the association of urinary sodium excretion (UNaV) as an accurate estimate of intake with risk of stroke. We studied 7330 individuals free of cardiovascular events at baseline in the Prevention of Renal and Vascular End stage Disease (PREVEND) study, a prospective, population-based cohort of Dutch men and women. The UNaV was measured in two 24-hour urine specimens at baseline (1997-1998) and two specimens during follow-up (2001-2003). Baseline median UNaV was 137 mmol/24 h (interquartile range, 106-171 mmol/24 h). During a median follow-up of 12.5 years (interquartile range, 11.9-12.9 years), a total of 183 stroke events occurred. An inverse association between UNaV and risk of stroke was observed after adjustment for age and sex (hazard ratio [HR] per 1-SD [51 mmol/24 h] decrement, 1.36; 95% CI, 1.11-1.65), which remained independent of additional adjustment for anthropometric, dietary, lifestyle, and other potential confounding factors (HR, 1.44; 95% CI, 1.14-1.82). After adjustment for potential mediators (systolic blood pressure and antihypertensive medication, plasma renin, aldosterone, and sodium levels), the association of UNaV with risk of stroke remained unchanged, with HRs (95% CIs) of 1.44 (1.14-1.82), 1.50 (1.18-1.90), 1.54 (1.21-1.97), and 1.49 (1.17-1.90), respectively. This prospective study revealed an association of low UNaV with an increased risk of stroke. PMID- 30244813 TI - Tocopherol suppresses 24(S)-hydroxycholesterol-induced cell death via inhibition of CaMKII phosphorylation. AB - Although 24(S)-hydroxycholesterol (24S-OHC) plays an important role to maintain homeostasis of cholesterol in the brain, it induces neuronal cell death at high concentrations. 24S-OHC-induced cell death was suppressed by gamma-tocopherol (gamma-Toc) but not by gamma-tocotrienol (gamma-Toc3) in a similar way to alpha tocopherol (alpha-Toc) and alpha-tocotrienol (alpha-Toc3) in human neuroblastoma SH-SY5Y cells. Both gamma-Toc and gamma-Toc3 significantly inhibited cumene hydroperoxide-induced cell death, as previously shown in the case of alpha-Toc and alpha-Toc3. Lipid droplet-like structure formation induced by 24S-OHC was suppressed by neither gamma-Toc nor gamma-Toc3. The phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) was induced by 24S-OHC, which was suppressed by CaMKII phosphorylation-site inhibitor mM3 but not by calmodulin-binding-site inhibitor KN62. A calcium chelator, BAPTA-AM, inhibited calcium ionophore A23187-induced CaMKII phosphorylation but not 24S-OHC-induced CaMKII phosphorylation. Receptor-interacting protein kinase 1 (RIPK1) phosphorylation induced by 24S-OHC was not inhibited by either mM3 or KN62, suggesting that CaMKII activation does not affect RIPK1 phosphorylation. Knockdown of RIPK1 using siRNA induced not only inhibition of CaMKII phosphorylation but also reduction of total CaMKII protein levels, suggesting that RIPK1 may regulate CaMKII signalling. 24S-OHC-induced RIPK1 phosphorylation was inhibited by neither alpha-Toc nor alpha-Toc3. In contrast, CaMKII phosphorylation induced by 24S-OHC was significantly suppressed by alpha-Toc but not by alpha-Toc3. These results suggest that CaMKII activation is involved in the mechanism of 24S-OHC-induced cell death and that Toc inhibits the cell death via inhibition of CaMKII activation through a RIPK1 phosphorylation-independent pathway. PMID- 30244814 TI - Diagnostic Error Categorization at Abdominal Imaging Peer Learning Conference. AB - Recognizing and preventing diagnostic errors is an increasingly emphasized topic across medicine, and abdominal imaging is no exception. Peer-learning strives for quality improvement through understanding why errors occur and identifying opportunities to prevent errors from recurring. In an effort to learn from mistakes, our abdominal imaging section initiated a Peer Learning Conference, where errors are discussed and compartmentalized into oneor more of the following categories: Observation, Interpretation, Communication, and Inadequate Data Gathering. In this manuscript, the structure of our Peer Learning Conference is introduced and the components of each discrepancy category are described in detail. Images are included to highlight learning points through exemplary cases from the conference. PMID- 30244815 TI - Recognizing the CT Manifestations of Gynecologic Conditions Encountered in the Emergency Department. AB - Women commonly present to the emergency room with subacute or acute symptoms of gynecologic origin. Although a pelvic exam and ultrasound (US) are the preferred initial diagnostic tools for gynecologic entities, a CT is often the first line imaging modality in the emergency department. We will provide a review of normal uterine enhancement and normal pregnancy related findings, and then familiarize radiologists with the CT appearances of gynecologic entities classically described on ultrasound that may present to the emergency department. PMID- 30244816 TI - Ductal carcinoma in situ current trends, controversies, and review of literature. AB - Ductal carcinoma in situ (DCIS) is a non-obligate precursor, non-invasive malignancy confined within the basement membrane of the breast ductal system. There is a wide variation in the natural history of DCIS with an estimated incidence of progression to invasive ductal carcinoma being at least 13%-50% over a range of 10 or more years after initial diagnosis. Regardless of the treatment strategy, long-term survival is excellent. The controversy surrounding DCIS relates to preventing under-treatment, while also avoiding unnecessary treatments. In this article, we review the incidence, presentation, management options and surveillance of DCIS. Furthermore, we address several current controversies related to the management of DCIS, including margin status, sentinel node biopsy, hormonal therapy, the role of radiation in breast conservation surgery, and various risk stratification schemes. PMID- 30244817 TI - A 15-year residency program report card: Differences between the creme of the crop and the bottom of the barrel on the American Board of Surgery examinations. AB - BACKGROUND: American Board of Surgery examination performance represents an important residency metric. The hypothesis is that demographic differences exist between the most and least successful programs. METHODS: This was a retrospective fifteen-year study. Data focused on program Examination Index (EI). The first and tenth decile programs were compared across demographics, using an alpha = 0.05. RESULTS: The first decile had a higher EI than the tenth decile (91.0% +/- 2 .6% vs 51.4% +/- 5.4% [p < 0.001]). The first decile programs were larger (p = 0.001). The first decile had more military and academic programs, with fewer community programs (p = 0.01). More first decile programs were in the West with fewer in the Northeast (p = 0.02). CONCLUSION: There are clear differences in ABS examination performance based on program size, type, and location. These results essentially perform a national needs-assessment, and may evoke a spirit of competition and collaboration. PMID- 30244818 TI - Celebrating 60 years of the Midwest Surgical Association (MSA): Reflections on 'testa dura', old men, football and la famiglia! PMID- 30244819 TI - Partnerships with the alcohol industry: opportunities and risks. PMID- 30244820 TI - Department of Error. PMID- 30244821 TI - In reply to Mengis et al. PMID- 30244822 TI - Microenvironmental Influences on Extracellular Vesicle-Mediated Communication in the Lung. AB - Extracellular vesicles (EVs) are increasingly appreciated as important vectors of information transmission between cells. Most research on EVs has emphasized their roles in inflammatory and pathologic conditions, and in the airways and alveoli, EV secretion by various cell types is implicated in various forms of lung disease. However, recent evidence also demonstrates a homeostatic role for lung EVs by mediating transmission of anti-inflammatory signals between alveolar macrophages and lung epithelial cells. Nevertheless, our understanding of the mechanisms responsible for EV cargo packaging, stability in the extracellular milieu, and acquisition by recipient cells remains limited. Here, we review the current understanding of these mechanistic aspects of vesicular communication and their potential modulation by constituents of the unique microenvironment of the lung. PMID- 30244823 TI - The relationship between dual practice, intention to work abroad and job satisfaction: A population-based study in the Serbian public healthcare sector. AB - Increasing dual practice and emigration of health workers threatens the effectiveness of the healthcare system. Insufficient information exists about these phenomena in the transitional countries of South-East Europe. Serbia, a European Union candidate, permits dual practice and there is a high intention to work abroad among its prospective healthcare professionals. A population-based, cross-sectional study was conducted to determine the prevalence and predictors of job satisfaction, dual practice, and intention to work abroad of all workers in the Serbian public healthcare sector (73,940 employees, a response rate of 83.8%). This study observed that 22.6% of the respondents were dissatisfied with their jobs, 11.7% reported dual practice, and 14.3% had an intention to work abroad. Physicians and nurses younger than 55 years of age employed in a tertiary healthcare institution, and males were more likely to be dissatisfied than other workers. Poor management and working conditions increased job dissatisfaction, with a subsequent increased odds for dual practice and intention to work abroad by 1.5 and 3.6 times, respectively. The national and institutional framework for health workforce policy and management must be powerful and efficient when taking advantage of the positive effects and managing the negative aspects of dual practice and the intention to work abroad. PMID- 30244824 TI - Does loss of hormonal receptors influence the pathophysiological characteristics of the HER-2 breast cancer phenotype? AB - BACKGROUND: Some breast carcinomas (BC) of the HER-2 type respond poorly to endocrine therapy, indicating that hormonal receptor (HR) status possibly impacts the biological criteria of this tumor class. The aim of this study was to compare the clinicopathological characteristics of HR-positive and HR-negative tumors occurring in HER-2 and non-HER-2 BC. METHODS: Tissue microarray sections from 336 primary invasive BC specimens were stained immunohistochemically with antibodies against HER-2, ER, and PR. Proliferation was assessed using Ki67 and the P53 status was identified. RESULTS: The HER-2 phenotype was identified in 42/336 (12.5%) specimens, while 293/336 (87.5%) were of the non-HER-2 phenotype. In the non-HER-2 group, 103/293 (35%) were HR-negative tumors. HR negativity was significantly associated with higher tumor grades (P < 0.0001), higher proliferation rates (P < 0.0001), presence of necrosis (P < 0.0001), and with a higher P53 expression (P < 0.0001). There were no differences in patient age, tumor size, LN status, or presence of vascular invasion (VI) between the HR negative and HR-positive groups. In the HER-2 group, 16/42 (38%) had HR-negative tumors. No significant difference in clinicopathological characteristics, except for tumor grade, was detected between the HR-positive and HR-negative tumors in this group. CONCLUSION: Loss of HR does not influence the biological features of HER-2 BC. This finding may indicate that some tumors will 'biologically' move from being HER-2-positive/HR-positive tumors to behaving more like HER-2 positive/HR-negative tumors even when ER are present on the cell surface. Further studies are needed to explore this hypothesis and to identify the subset of tumors that will benefit from endocrine therapy. PMID- 30244825 TI - Multiscale bioprinting of vascularized models. AB - A basic prerequisite for the survival and function of three-dimensional (3D) engineered tissue constructs is the establishment of blood vessels. 3D bioprinting of vascular networks with hierarchical structures that resemble in vivo structures has allowed blood circulation within thick tissue constructs to accelerate vascularization and enhance tissue regeneration. Successful rapid vascularization of tissue constructs requires synergy between fabrication of perfusable channels and functional bioinks that induce angiogenesis and capillary formation within constructs. Combinations of 3D bioprinting techniques and four dimensional (4D) printing concepts through patterning proangiogenic factors may offer novel solutions for implantation of thick constructs. In this review, we cover current bioprinting techniques for vascularized tissue constructs with vasculatures ranging from capillaries to large blood vessels and discuss how to implement these approaches for patterning proangiogenic factors to maintain long term, stimuli-controlled formation of new capillaries. PMID- 30244826 TI - Comment on: primary care provider (PCP) management of patients with obesity at an integrated health network (IHN): a survey of practices, views and knowledge. PMID- 30244828 TI - Comorbidities, treatment, and pathophysiology in restless legs syndrome. AB - Restless legs syndrome, also known as Willis-Ekbom disease, is a common neurological condition whose manifestation is affected by complex environmental and genetic interactions. Restless legs syndrome can occur on its own, mostly at a young age, or with comorbidities such as cardiovascular disease, diabetes, and arterial hypertension, making it a difficult condition to properly diagnose. However, the concept of restless legs syndrome as being two entities, primary or secondary to another condition, has been challenged with genetic data providing further insight into the pathophysiology of the condition. Although dopaminergic treatment was formerly the first-line therapy, prolonged use can result in a serious worsening of symptoms known as augmentation. Clinical studies on pregabalin, gabapentin enacarbil, oxycodone-naloxone, and iron preparations have provided new treatment options, but most patients still report inadequate long term management of symptoms. Studies of the hypoxic pathway activation and iron deficiency have provided valuable information about the pathophysiology of restless legs syndrome that should now be translated into new, more effective treatments for restless legs syndrome. PMID- 30244829 TI - Nutrition and prevention of cognitive impairment. AB - Nutrition is an important lifestyle factor that can modify the risk of future cognitive impairment and dementia. Some, but not conclusive, evidence (mostly from observational studies and infrequently from clinical trials) exists of a protective association between certain nutrients (eg, folate, flavonoids, vitamin D, and certain lipids) or food groups (eg, seafood, vegetables, and fruits, and potentially moderate alcohol and caffeine consumption) and cognitive outcomes in older people. For some nutrients and food groups, protection might be greater in individuals with either deficiencies in certain nutrients or a genetic predisposition to cognitive impairment. Identification of potentially different associations between such subgroups should be a priority for future research. At present, evidence of an association between nutrition and cognitive outcomes is somehow stronger for healthy dietary patterns, such as the Mediterranean-type diet, than for individual nutrients and food groups, possibly because of the cumulative beneficial effects of the many ingredients in these diets. Multidomain interventions (including a nutrition component) might also hold some promise for the prevention of cognitive impairment and dementia, but their effectiveness is still uncertain. Use of advanced technologies for nutrition assessment (eg, metabolomics and innovative methods of dietary intake assessment) and recently identified biomarkers of nutrition and neurobiological outcomes will be important to achieve this goal. PMID- 30244830 TI - Magnetic Resonance Imaging only Workflow for Radiotherapy Simulation and Planning in Prostate Cancer. AB - Magnetic resonance imaging (MRI) is often combined with computed tomography (CT) in prostate radiotherapy to optimise delineation of the target and organs-at-risk (OAR) while maintaining accurate dose calculation. Such a dual-modality workflow requires two separate imaging sessions, and it has some fundamental and logistical drawbacks. Due to the availability of new MRI hardware and software solutions, CT examinations can be omitted for prostate radiotherapy simulations. All information for treatment planning, including electron density maps and bony anatomy, can nowadays be obtained with MRI. Such an MRI-only simulation workflow reduces delineation ambiguities, eases planning logistics, and improves patient comfort; however, careful validation of the complete MRI-only workflow is warranted. The first institutes are now adopting this MRI-only workflow for prostate radiotherapy. In this article, we will review technology and workflow requirements for an MRI-only prostate simulation workflow. PMID- 30244831 TI - Release of Ubiquitinated and Non-ubiquitinated Nascent Chains from Stalled Mammalian Ribosomal Complexes by ANKZF1 and Ptrh1. AB - The ribosome-associated quality control (RQC) pathway degrades nascent chains (NCs) arising from interrupted translation. First, recycling factors split stalled ribosomes, yielding NC-tRNA/60S ribosome-nascent chain complexes (60S RNCs). 60S RNCs associate with NEMF, which recruits the E3 ubiquitin ligase Listerin that ubiquitinates NCs. The mechanism of subsequent ribosomal release of Ub-NCs remains obscure. We found that, in non-ubiquitinated 60S RNCs and 80S RNCs formed on non-stop mRNAs, tRNA is not firmly fixed in the P site, which allows peptidyl-tRNA hydrolase Ptrh1 to cleave NC-tRNA, suggesting the existence of a pathway involving release of non-ubiquitinated NCs. Association with NEMF and Listerin and ubiquitination of NCs results in accommodation of NC-tRNA, rendering 60S RNCs resistant to Ptrh1 but susceptible to ANKZF1, which induces specific cleavage in the tRNA acceptor arm, releasing proteasome-degradable Ub-NCs linked to four 3'-terminal tRNA nucleotides. We also found that TCF25, a poorly characterized RQC component, ensures preferential formation of the K48-ubiquitin linkage. PMID- 30244832 TI - A Loss of Epigenetic Control Can Promote Cell Death through Reversing the Balance of Pathways in a Signaling Network. AB - Epigenetic control of regulatory networks is only partially understood. Expression of Insulin-like growth factor-II (IGF2) is controlled by genomic imprinting, mediated by silencing of the maternal allele. Loss of imprinting of IGF2 (LOI) is linked to intestinal and colorectal cancers, causally in murine models and epidemiologically in humans. However, the molecular underpinnings of the LOI phenotype are not clear. Surprisingly, in LOI cells, we find a reversal of the relative activities of two canonical signaling pathways triggered by IGF2, causing further rebalancing between pro- and anti-apoptotic signaling. A predictive mathematical model shows that this network rebalancing quantitatively accounts for the effect of receptor tyrosine kinase inhibition in both WT and LOI cells. This mechanism also quantitatively explains both the stable LOI phenotype and the therapeutic window for selective killing of LOI cells, and thus prevention of epigenetically controlled cancers. These findings suggest a framework for understanding epigenetically modified cell signaling. PMID- 30244833 TI - Examining the Roles of H3K4 Methylation States with Systematically Characterized Antibodies. AB - Histone post-translational modifications (PTMs) are important genomic regulators often studied by chromatin immunoprecipitation (ChIP), whereby their locations and relative abundance are inferred by antibody capture of nucleosomes and associated DNA. However, the specificity of antibodies within these experiments has not been systematically studied. Here, we use histone peptide arrays and internally calibrated ChIP (ICeChIP) to characterize 52 commercial antibodies purported to distinguish the H3K4 methylforms (me1, me2, and me3, with each ascribed distinct biological functions). We find that many widely used antibodies poorly distinguish the methylforms and that high- and low-specificity reagents can yield dramatically different biological interpretations, resulting in substantial divergence from the literature for numerous H3K4 methylform paradigms. Using ICeChIP, we also discern quantitative relationships between enhancer H3K4 methylation and promoter transcriptional output and can measure global PTM abundance changes. Our results illustrate how poor antibody specificity contributes to the "reproducibility crisis," demonstrating the need for rigorous, platform-appropriate validation. PMID- 30244834 TI - The Mcm2-Ctf4-Polalpha Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands. AB - Although essential for epigenetic inheritance, the transfer of parental histone (H3-H4)2 tetramers that contain epigenetic modifications to replicating DNA strands is poorly understood. Here, we show that the Mcm2-Ctf4-Polalpha axis facilitates the transfer of parental (H3-H4)2 tetramers to lagging-strand DNA at replication forks. Mutating the conserved histone-binding domain of the Mcm2 subunit of the CMG (Cdc45-MCM-GINS) DNA helicase, which translocates along the leading-strand template, results in a marked enrichment of parental (H3-H4)2 on leading strand, due to the impairment of the transfer of parental (H3-H4)2 to lagging strands. Similar effects are observed in Ctf4 and Polalpha primase mutants that disrupt the connection of the CMG helicase to Polalpha that resides on lagging-strand template. Our results support a model whereby parental (H3-H4)2 complexes displaced from nucleosomes by DNA unwinding at replication forks are transferred by the CMG-Ctf4-Polalpha complex to lagging-strand DNA for nucleosome assembly at the original location. PMID- 30244835 TI - Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis. AB - Antibiotic-resistant bacterial pathogens pose an urgent healthcare threat, prompting a demand for new medicines. We report the mode of action of the natural ansamycin antibiotic kanglemycin A (KglA). KglA binds bacterial RNA polymerase at the rifampicin-binding pocket but maintains potency against RNA polymerases containing rifampicin-resistant mutations. KglA has antibiotic activity against rifampicin-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis (MDR-M. tuberculosis). The X-ray crystal structures of KglA with the Escherichia coli RNA polymerase holoenzyme and Thermus thermophilus RNA polymerase-promoter complex reveal an altered-compared with rifampicin conformation of KglA within the rifampicin-binding pocket. Unique deoxysugar and succinate ansa bridge substituents make additional contacts with a separate, hydrophobic pocket of RNA polymerase and preclude the formation of initial dinucleotides, respectively. Previous ansa-chain modifications in the rifamycin series have proven unsuccessful. Thus, KglA represents a key starting point for the development of a new class of ansa-chain derivatized ansamycins to tackle rifampicin resistance. PMID- 30244837 TI - The BRCT Domains of the BRCA1 and BARD1 Tumor Suppressors Differentially Regulate Homology-Directed Repair and Stalled Fork Protection. AB - The BRCA1 tumor suppressor preserves genome integrity through both homology directed repair (HDR) and stalled fork protection (SFP). In vivo, BRCA1 exists as a heterodimer with the BARD1 tumor suppressor, and both proteins harbor a phosphate-binding BRCT domain. Here, we compare mice with mutations that ablate BRCT phospho-recognition by Bard1 (Bard1S563F and Bard1K607A) or Brca1 (Brca1S1598F). Brca1S1598F abrogates both HDR and SFP, suggesting that both pathways are likely impaired in most BRCA1 mutant tumors. Although not affecting HDR, the Bard1 mutations ablate poly(ADP-ribose)-dependent recruitment of BRCA1/BARD1 to stalled replication forks, resulting in fork degradation and chromosome instability. Nonetheless, Bard1S563F/S563F and Bard1K607A/K607A mice, unlike Brca1S1598F/S1598F mice, are not tumor prone, indicating that HDR alone is sufficient to suppress tumor formation in the absence of SFP. Nevertheless, because SFP, unlike HDR, is also impaired in heterozygous Brca1/Bard1 mutant cells, SFP and HDR may contribute to distinct stages of tumorigenesis in BRCA1/BARD1 mutation carriers. PMID- 30244838 TI - Water immersion policies and guidelines: How are they informed? AB - BACKGROUND: Water immersion for labour and birth is consistently challenged as a practice lacking support from high quality evidence. Despite this, the option is available to Australian women. Practitioners are guided by policies and guidelines however, given the research paucity, questions surround the way in which water immersion policies and guidelines are informed. AIMS: The aims of the study were to determine how water immersion policies and/or guidelines are informed and to what extent the policy/guideline facilitates the option of water immersion for labour and birth with respect to women's choice and autonomy. METHODS: Phase two of a three phase mixed methods study used critical, post structural interpretive interactionism to examine the process of development and implementation of water immersion policies and guidelines from informant's experience. Semi-structured interviews were conducted with 12 Australian participants. FINDINGS: Participants highlighted that the lack of randomised controlled trials had resulted in other forms of evidence being drawn upon to inform water immersion policies and guidelines. This was influenced in part by individual interpretations of evidence with medical views taking precedence. This sometimes resulted in policy and guideline documents that were restrictive with this impacting on women's ability to access the option. CONCLUSION: Perceived limitations of research and the subsequent translation of this perceived paucity of evidence into policies and guidelines, has impacted on women's ability to exercise choice and autonomy with respect to water immersion and indeed, on the professional autonomy of practitioners who wish to facilitate it. PMID- 30244839 TI - [Smart wristbands to help in the deprescription of hypnotics]. PMID- 30244836 TI - Cancer Mutations of the Tumor Suppressor SPOP Disrupt the Formation of Active, Phase-Separated Compartments. AB - Mutations in the tumor suppressor SPOP (speckle-type POZ protein) cause prostate, breast, and other solid tumors. SPOP is a substrate adaptor of the cullin3-RING ubiquitin ligase and localizes to nuclear speckles. Although cancer-associated mutations in SPOP interfere with substrate recruitment to the ligase, mechanisms underlying assembly of SPOP with its substrates in liquid nuclear bodies and effects of SPOP mutations on assembly are poorly understood. Here, we show that substrates trigger phase separation of SPOP in vitro and co-localization in membraneless organelles in cells. Enzymatic activity correlates with cellular co localization and in vitro mesoscale assembly formation. Disease-associated SPOP mutations that lead to the accumulation of proto-oncogenic proteins interfere with phase separation and co-localization in membraneless organelles, suggesting that substrate-directed phase separation of this E3 ligase underlies the regulation of ubiquitin-dependent proteostasis. PMID- 30244840 TI - Frictional coefficient during flossing of teeth. AB - OBJECTIVE: This in-vitro study aimed to develop a technique to measure the frictional forces and determine the frictional coefficient (MU) associated with the rubbing of dental floss against teeth. Incorrect flossing technique and the etiology of grooves at the cementoenamel junction (CEJ) of proximal area of teeth has long been a controversial topic. We hypothesized that the MU between teeth surfaces and dental floss is affected by contact angulation. MATERIALS AND METHODS: Tests were conducted using two different types of dental floss (waxed and unwaxed nylon) on different surfaces (enamel, dentine, smooth and rough glass rods) under different moisture conditions (dry and wet). The MU generated by performing C-shape flossing was measured, using the Capstan equation, at constant load (100g) over different flossing contact sliding angulations. In addition, the surface characteristics of intact and used nylon flosses were compared using a scanning electron microscope (SEM). RESULTS: The mean MU was highest with a smooth glass rod (0.42+/-0.11), followed by rough glass rods (0.30+/-0.07), dry enamel (0.27+/-0.08), wet enamel (0.23+/-0.06), then dentine (0.18+/-0.04). Moreover, higher MU was associated with waxed floss when used against dry enamel, smooth and rough glass rods (P<0.001). At different moisture conditions, waxed floss demonstrated greater MU with dry surfaces (P<0.03). No association was found between MU and dental floss contact angulation. Both floss types showed deterioration after usage; although waxed type exhibited markedly greater deterioration when used on dry surfaces. In conclusion, the magnitude of the MU was found to be influenced by surface roughness, moisture condition, and independent of the contact angulation area during sliding of dental floss. SIGNIFICANCE: It is important to consider the potential side effects of frictional forces on both tooth surface and dental floss during clinical application. PMID- 30244841 TI - Successful treatment of painful Hashimoto's thyroiditis with intrathyroidal injection of glucocorticoid in two patients. PMID- 30244842 TI - [Lysozyme amyloidosis]. AB - Lysozyme amyloidosis is a non-neuropathic hereditary amyloidosis identified in 1993. About fifty cases of this rare, probably under-diagnosed disease are reported. Lysozyme amyloidosis has a very broad spectrum of clinical manifestations. Sicca syndrome is often the first symptom, preceding the diagnosis by several years. Every part of the digestive tract can be involved with different grades of severity. The hallmark of this amyloidosis is the usually life-threatening spontaneous hepatic rupture. Renal involvement is frequent and progresses towards end-stage renal failure and dialysis. Skin, lymph nodes, and spleen can also be affected. More recently, cardiac and pulmonary involvement was reported. Phenotypic heterogeneity and incomplete penetrance make the clinical diagnosis difficult. Amyloid deposits are revealed by Congo red staining with birefringence under polarized light. They can be limited or diffuse and lead to the progressive destruction of the architecture of an organ and its failure. Immunohistochemistry reveals the nature of the amyloid variant by identifying antilysozyme antibodies in the deposit. Up to know, eight pathologic mutations and one polymorphism involving exons 2, 3, and 4 of the lysozyme gene have been identified. The transmission is autosomal dominant, without any genotype-phenotype correlation. The therapeutic options are limited and based on symptomatic or supportive treatment. Renal and hepatic transplant has proved its benefits with a prolonged graft survival. A long term regular and multidisciplinary follow-up is required. PMID- 30244843 TI - Long-term Outcomes After Endovascular Recanalization in Patients with Chronic Carotid Artery Occlusion. AB - Successful carotid artery stenting may correct ipsilateral hemisphere hypoperfusion and improve neurocognitive function in patients with chronic internal carotid artery occlusion (ICAO). Its effect on long-term outcomes, however, has never been studied. From May 2004 to April 2015, endovascular recanalization for chronic ICAO was attempted in 118 consecutive patients (119 lesions; 98 men; 67 +/- 10 years old) with either recurrent neurologic events or objectively impaired ipsilateral hemisphere perfusion. Technical success in recanalization was achieved in 70 lesions (59%, 70/119). 3-months cumulative any stroke or death rate was 5% (6/119; 4 in recanalized group, 2 in failure group), including 2 periprocedural ischemic stroke, 2 intracranial hemorrhage, and 2 subarachnoid hemorrhage. In recanalized patients without periprocedural complication, 1-year reocclusion rate was 15% (10/65). Up to 7 years after procedure, cumulative events of transient ischemic attack (TIA), or any stroke, or death were 17 in recanalized group, compared with 23 in failure group (hazard ratio 0.51, 95% confidence interval 0.27 to 0.97; p = 0.04). The difference became more significant after excluding patients with periprocedure events (hazard ratio 0.41, 95% confidence interval 0.20 to 0.84, p = 0.015). In conclusions, the technical success and periprocedural complication rates of endovascular recanalization for chronic ICAO were acceptable. The cumulative event rates of any stroke or death up to 7 years were more favorable in patients after successful recanalization, compared to those in patients after failed procedure. PMID- 30244844 TI - Usefulness of Canakinumab to Improve Exercise Capacity in Patients With Long-Term Systolic Heart Failure and Elevated C-Reactive Protein. AB - Interleukin-1beta (IL-1beta) is a cytokine involved in atherothrombosis and is known to depress cardiac function. We hypothesized that blocking IL-1beta in patients with symptomatic systolic heart failure (HF) would improve their cardiorespiratory fitness. The purpose of the study was to measure changes in peak oxygen consumption (VO2) in 30 patients with prior myocardial infarction, high-sensitivity C-reactive protein >= 2 mg/l and HF with left ventricular ejection fraction (LVEF) < 50% enrolled in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) in an independent single center substudy. We measured peak VO2 before and after 3 and 12 months of treatment with Canakinumab every 3 months (50, 150, or 300mg subcutaneously) or placebo, and measured LVEF before and after 12 months. In December 2013, the CANTOS study announced early termination of enrollment, halting enrollment for this substudy after only 15 patients, of which 3 were assigned to placebo and 12 to Canakinumab (50mg [1; 7%], 150mg [5; 33%], 300mg [6; 40%]). Patients treated with Canakinumab had a significant improvement in peak VO2, from 19.2 to 22.8 ml/kg/min at 3 months (p = 0.023 within-group changes, p = 0.026 for time_x_group interaction versus placebo [primary end point]), and an improvement in LVEF 38% (33-43) to 44% (38-52) at 12 months (p = 0.012 for within-group changes). No significant changes were seen in the placebo group. In conclusion, the findings of this small prespecified secondary analysis of the CANTOS trial support the positive results of the overall study, and confirm IL-1 as a potential therapeutic target in HF. https://clinicaltrials.gov/ct2/show/NCT01900600. PMID- 30244845 TI - Usefulness of Epicardial Adipose Tissue Volume to Predict Recurrent Atrial Fibrillation After Radiofrequency Catheter Ablation. AB - Although increasing evidence suggests that epicardial adipose tissue volume (EATV) is associated with post-ablation atrial fibrillation (AF), ranges of EATV predictive of post-ablation recurrence of AF remain unclear. In this study, we evaluated: (1) relationships between EATV and characteristics of AF, (2) impact of EATV on recurrent AF after radiofrequency ablation; , and (3) cut-off point for recurrent AF using a receiver operating characteristic curve. In 218 consecutive symptomatic patients undergoing who underwent ablation for AF (143 paroxysmal AF; 78 persistent AF), the EATV index (EATVI: EATV/body surface area, mL/m2) was measured using 320-row multidetector computed tomography. The high EATV group showed specific cardiometabolic derangements as well as left atrial dilatation and left ventricular dysfunction. Multivariate regression analysis showed that the EATVI was an independent predictor of recurrent AF after catheter ablation. High EATV (EATVI >= 85 mL/m2) or EATVI cutoff >=116 mL/m2 can predict recurrent AF after catheter ablation, independent of other risk factors. In conclusion, EATVI was an independent predictor of recurrent AF after catheter ablation; a high EATV tertile or EATVI cutoff may be useful for prediction of recurrent AF after catheter ablation. Future studies should determine the utility of the EATVI in the clinical setting of AF ablation. PMID- 30244846 TI - Usefulness of Heart Rate Control in Atrial Fibrillation Patients With Obstructive Sleep Apnea. AB - In patients without atrial fibrillation and flutter (AF), obstructive sleep apnea (OSA) is associated with cyclic and often marked changes in heart rate (HR). We aimed to assess whether presence of OSA impacts optimal HR control in patients in AF. We retrospectively correlated diurnal HR patterns (recorded by 24-hour Holter monitoring) in patients with AF who independently also underwent diagnostic polysomnography. Exclusion criteria were paced rhythm or inadequate recordings from polysomnography and Holter monitoring. The relationship between the presence and severity of OSA and the mean, minimum, maximum HR, as well as pauses (>2 seconds) and their diurnal variation were studied. Of the 494 studied patients (age 69 +/- 10 years; 26% women) mild-moderate OSA (apnea hypoxia index >=5 and <20) was present in 171 (34%) and severe OSA (apnea hypoxia index >=20) in 254 (51%). Mean 24-hour HR in patients with severe OSA and mild-moderate OSA was similar to those without OSA (78 vs 80 vs 79 beats per minute; p = 0.39), and there was no significant difference observed in minimum and maximum HR of these groups. However, the frequency of short pauses was greater in OSA patients (p = 0.009), with a prominent nocturnal distribution. In conclusion, OSA was not associated with increased HR in patients with AF suggesting that adequate HR control was similarly achievable in patients with and without OSA. The increased frequency of nocturnal pauses in OSA patients may function as a clinical hallmark, and the timing of pauses (during sleep vs wakefulness) should be noted before making therapeutic decisions regarding HR control. PMID- 30244848 TI - Recognizing the Challenges of Oncogene Fusion Detection: A Critical Step toward Optimal Selection of Lung Cancer Patients for Targeted Therapies. PMID- 30244847 TI - Provider continuity and reasons for not having a provider among persons with and without disabilities. AB - BACKGROUND: Persons with disabilities experience health disparities while having usual providers more frequently than persons without disabilities. Provider discontinuity may help to explain these paradoxical findings, but research on the topic is nascent. OBJECTIVE: To provide initial insight into whether persons with disabilities more frequently experience provider discontinuity than persons without disabilities. METHODS: Pooled 2-year data from panels 14-16 (2009-2012) of the Medical Expenditure Panel Survey were examined. Working-age adults (18-64) were categorized as having no disability, basic disabilities, or complex disabilities. Persons were categorized having provider continuity (provider throughout the period) or discontinuity (gaining or losing providers during the period). chi2 and multinomial logistic regressions were used to examine outcomes by disability status. RESULTS: Persons with complex disabilities more frequently experienced continuity (83.7%) than persons without disabilities and those with basic disabilities (60.7% and 65.6%, respectively, p < 0.001). Seldom or never being sick was the most frequently reported reason for not having a usual provider; more persons without disabilities (64%) reported this reason than persons with disabilities (basic: 41.9%, p < 0.001; complex: 26.6%, p = 0.001). Persons with disabilities more frequently reported visiting different providers for different needs and not having a usual provider due to the costs of medical care than persons without disabilities. CONCLUSIONS: Future research needs to examine the influence of continuity on healthcare disparities among persons with complex disabilities. Policies and practice must be attentive to how proposed changes to the healthcare system potentially reduce access to care among persons with disabilities. PMID- 30244849 TI - Programmed Death 1 Blockade With Nivolumab in Patients With Recurrent Malignant Pleural Mesothelioma. PMID- 30244850 TI - How Should We Treat Alectinib-Refractory ALK-Positive Non-Small Cell Lung Cancer? PMID- 30244851 TI - Are We Ready for Histology-Driven Stereotactic Ablative Radiotherapy? PMID- 30244852 TI - A Case of Primary Pulmonary Combined Small Cell Carcinoma With Adenocarcinoma Harboring the Same KLC1-ALK Fusion in Both Histologic Components. PMID- 30244853 TI - Favorable Outcome With Pemetrexed Treatment for Advanced BRAF-V600E-Positive Lung Adenocarcinoma in a Patient Followed up Over 8 Years. PMID- 30244854 TI - MET-UBE2H Fusion as a Novel Mechanism of Acquired EGFR Resistance in Lung Adenocarcinoma. PMID- 30244855 TI - Response to Osimertinib in an EGFR Exon 20 Insertion-Positive Lung Adenocarcinoma. PMID- 30244856 TI - Gefitinib-Induced Cardiomyopathy in Epidermal Growth Receptor-Mutated NSCLC. PMID- 30244857 TI - Pseudoprogression and Rapid Response to Pembrolizumab in a Patient with Advanced Lung Adenocarcinoma with Loss of Epidermal Growth Factor Receptor Gene Mutation after Tyrosine Kinase Inhibitor Therapy. PMID- 30244858 TI - A Case of Small Cell Lung Cancer Transformation from EGFR-Mutant Lung Adenocarcinoma with Primary Resistance to Gefitinib. PMID- 30244859 TI - Robotic tracheobronchoplasty is feasible, but which patients truly benefit? PMID- 30244860 TI - Following the guidelines: Life in the real world. PMID- 30244861 TI - Centers for Disease Control "increased-risk" organ donor: Not so risky? PMID- 30244862 TI - Infective endocarditis: Finding the right time for the right side. PMID- 30244863 TI - Non-A, non-B aortic dissections: Unresolved issues. PMID- 30244864 TI - When will we learn from using donor hearts with decreased ventricular function? PMID- 30244865 TI - National Heart, Lung, and Blood Institute and American Association for Thoracic Surgery Workshop Report: Identifying collaborative clinical research priorities in lung transplantation. PMID- 30244866 TI - A survey of dental journal methodological practices: Reporting guidelines and ethical policies. AB - BACKGROUND: The authors evaluated instructions for author norms among existing dental journals and analyzed whether these journals address the practice of reporting guidelines and ethics policies. METHODS: The authors evaluated 87 journals indexed in Journal Citation Reports (Thomson Reuters). The authors extracted information regarding the journals from the Journal Citation Reports database and from the instructions for authors of each journal. The authors conducted bivariate analysis to compare the methodological policy issues of journals with higher and those with lower impact factors (>= 1.452 and <= 1.436, respectively). RESULTS: Among journals, 44 (50.6%) required the use of Consolidated Standards of Reporting Trials, 22 (25.3%) Preferred Reporting Items for Systematic Reviews and Meta-Analyses, 21 (24.1%) Animal Research: Reporting of In Vivo Experiments, 17 (19.5%) STrengthening the Reporting of OBservational Studies in Epidemiology, 6 (6.9%) Standards for Reporting of Diagnostic Accuracy Studies, 3 (3.4%) Meta-analysis of Observational Studies in Epidemiology, and 1 (1.1%) Standard Protocol Items: Recommendations for Interventional Trials. No journals required STrengthening the REporting of Genetic Association Studies. Journals with higher impact factors had more instructions related to the peer review process (P = .027), redundant publication (P < .001), authorship policy (P = .024), contributorship policy (P < .001), ethical conduct of biomedical research with human participants (P = .021), ethical conduct of biomedical research with nonhuman participants (P = .001), registration of clinical trials (P = .004), and conflicts involving editors as authors in their own journals (P < .001) than did journals with lower impact factors. The submission of clinical case studies was significantly more prevalent in journals with lower impact factors (P = .008). CONCLUSIONS: Journals with higher impact factors have more rules regarding publication policies. PRACTICAL IMPLICATIONS: Journals with higher impact factors are stricter regarding publication policies than are journals with lower impact factors. Authors should be careful with the instructions for authors and plan studies with high methodological quality to publish their studies in a scientific journal. PMID- 30244868 TI - PGC-1alpha Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ. PMID- 30244867 TI - Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells. AB - The decline of tissue regenerative potential with age correlates with impaired stem cell function. However, limited strategies are available for therapeutic modulation of stem cell function during aging. Using skeletal muscle stem cells (MuSCs) as a model system, we identify cell death by mitotic catastrophe as a cause of impaired stem cell proliferative expansion in aged animals. The mitotic cell death is caused by a deficiency in Notch activators in the microenvironment. We discover that ligand-dependent stimulation of Notch activates p53 in MuSCs via inhibition of Mdm2 expression through Hey transcription factors during normal muscle regeneration and that this pathway is impaired in aged animals. Pharmacologic activation of p53 promotes the expansion of aged MuSCs in vivo. Altogether, these findings illuminate a Notch-p53 signaling axis that plays an important role in MuSC survival during activation and is dysregulated during aging, contributing to the age-related decline in muscle regenerative potential. PMID- 30244869 TI - Esophageal Organoids from Human Pluripotent Stem Cells Delineate Sox2 Functions during Esophageal Specification. AB - Tracheal and esophageal disorders are prevalent in humans and difficult to accurately model in mice. We therefore established a three-dimensional organoid model of esophageal development through directed differentiation of human pluripotent stem cells. Sequential manipulation of bone morphogenic protein (BMP), Wnt, and RA signaling pathways was required to pattern definitive endoderm into foregut, anterior foregut (AFG), and dorsal AFG spheroids. Dorsal AFG spheroids grown in a 3D matrix formed human esophageal organoids (HEOs), and HEO cells could be transitioned into two-dimensional cultures and grown as esophageal organotypic rafts. In both configurations, esophageal tissues had proliferative basal progenitors and a differentiated stratified squamous epithelium. Using HEO cultures to model human esophageal birth defects, we identified that Sox2 promotes esophageal specification in part through repressing Wnt signaling in dorsal AFG and promoting survival. Consistently, Sox2 ablation in mice causes esophageal agenesis. Thus, HEOs present a powerful platform for modeling human pathologies and tissue engineering. PMID- 30244871 TI - Corrigendum to "One or two doses of live varicella virus-containing vaccines: Efficacy, persistence of immune responses, and safety six years after administration in healthy children during their second year of life" [Vaccine 36 (2018) 381-387]. PMID- 30244870 TI - 3D Modeling of Esophageal Development using Human PSC-Derived Basal Progenitors Reveals a Critical Role for Notch Signaling. AB - Pluripotent stem cells (PSCs) could provide a powerful system to model development of the human esophagus, whose distinct tissue organization compared to rodent esophagus suggests that developmental mechanisms may not be conserved between species. We therefore established an efficient protocol for generating esophageal progenitor cells (EPCs) from human PSCs. We found that inhibition of TGF-beta and BMP signaling is required for sequential specification of EPCs, which can be further purified using cell-surface markers. These EPCs resemble their human fetal counterparts and can recapitulate normal development of esophageal stratified squamous epithelium during in vitro 3D cultures and in vivo. Importantly, combining hPSC differentiation strategies with mouse genetics elucidated a critical role for Notch signaling in the formation of this epithelium. These studies therefore not only provide an efficient approach to generate EPCs, but also offer a model system to study the regulatory mechanisms underlying development of the human esophagus. PMID- 30244872 TI - Dynamic changes of circulating miRNAs induced by the Ebola virus vaccine VSV EBOV. AB - VSV-EBOV is a replication-competent Ebola virus (EBOV) vaccine, which was tested in clinical trials as response to the Ebola virus disease (EVD) outbreak 2013 2016. It is the most advanced EBOV candidate currently in the licensure process. The experimental vaccine was again administered as response to outbreaks in the Democratic Republic of Congo. However, underlying molecular mechanisms that convey protection remain incompletely understood. MicroRNAs (miRNAs) are known key regulators that influence gene expression on a post-transcriptional level. The miRNA-mediated control has emerged as a critical regulatory principle in the immune system, which strongly influences the balance of innate and adaptive immune responses by modulation of signaling pathways critical for differentiation of immune cells. We investigated expression levels of circulating miRNAs (c miRNAs) in plasma from healthy vaccinees, as they may reflect cellular dynamics following VSV-EBOV immunization and additionally may serve as potential biomarkers for vaccine efficacy. As part of the WHO-led VEBCON consortium, we investigated safety and immunogenicity of VSV-EBOV in a phase I trial. A comprehensive analysis of expression levels on c-miRNAs from plasma samples following VSV-EBOV immunization (day 0, 1, 3 post vaccination) was conducted using RT-qPCR assays. Potential biological relevance was assessed using in silico analyses. Additionally, we correlated dynamics of miRNA expressions with our previously reported data on vaccine-induced antibody and cytokine responses and finally evaluated the prognostic power by generating ROC curves. We identified four promising miRNAs (hsa-miR-146a, hsa-miR-126, hsa-miR-199a, hsa-miR-484), showing a strong association with adaptive immune responses, exhibited favourable prognostic performance and are implicated in immunology-related functions. Our results provide evidence that miRNAs may serve as useful biomarkers for prediction of vaccine-induced immunogenicity. Furthermore, our unique data set provides insight into molecular mechanisms that underlie VSV-EBOV-mediated protective immune responses, which may help to decipher VSV-EBOV immune signature and accelerate strategic vaccine design or personalized approaches. PMID- 30244874 TI - Tuberous Sclerosis Complex Associated with Hemihypertrophy and Combined Vascular Malformations. PMID- 30244873 TI - Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) in healthy infants. AB - BACKGROUND: Pediatric use of pneumococcal conjugate vaccines (PCV) has been associated with significant decrease in disease burden. However, disease caused by non-vaccine serotypes has increased. Safety and immunogenicity of 15-valent PCV (PCV15) containing serotypes included in 13-valent PCV (PCV13) plus serotypes 22F and 33F were evaluated in infants (NCT01215188). METHODS: Infants received adjuvanted PCV15, nonadjuvanted PCV15, or PCV13 at 2, 4, 6, and 12-15 months of age. Safety was monitored for 14 days after each dose. Serotype-specific IgG geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured at postdose-3, predose-4, and postdose 4. RESULTS: Safety profiles were comparable across vaccination groups. At postdose-3, both PCV15 formulations were non-inferior to PCV13 for 10 of 13 shared serotypes but failed non-inferiority for 3 serotypes (6A, 6B, and 19A) based on proportion of subjects achieving IgG GMC >=0.35 ug/mL. Adjuvanted PCV15 and nonadjuvanted PCV15 were non-inferior to PCV13 for 11 and 8 shared serotypes, respectively, based on postdose 3 comparisons of GMC ratios. PCV15 induced higher antibodies to serotypes 3, 22F, and 33F than PCV13. CONCLUSIONS: PCV15 displayed acceptable safety profile and induced IgG and OPA to all 15 vaccine serotypes at levels comparable to PCV13 for 10 of 13 shared serotypes. Study identification: V114-003. CLINICALTRIALS.GOV identifier: NCT01215188. PMID- 30244875 TI - Drivers of hospitalisation trends for non-valvular atrial fibrillation in Western Australia, 2000-2013. AB - OBJECTIVE: To determine if increasing hospitalisations for non-valvular atrial fibrillation (NVAF) in Western Australia (WA) was due to incident (first-ever) or repeat hospitalisations, an ageing population structure, changing procedural practice or a combination of these factors. METHODS: We conducted a longitudinal retrospective population study on all WA residents aged 25-94 years between 2000 and 2013, with a principal hospital discharge diagnosis of NVAF. Person-linked hospital morbidity and mortality records were used to measure annual rate ratios (RRs) and 95% confidence intervals (CIs) in the total and incident NVAF (25-94 years) hospitalisations, further stratified by sex and by age-specific standardised groups (25-44, 45-64, 65-75, 75-84, 85-94 years). RESULTS: There were 55,532 total hospitalisations for NVAF between 2000 and 2013, patient mean age 68.3 years, and 58% male. Annual age- and sex- standardised rates for total NVAF hospitalisation increased by 3.0%/year (RR 1.030; 95%CI; 1.028, 1.038), and in both men and women. The largest absolute increase in hospitalisation rate occurred in those aged 85-94 years (?613/100,000 men and women combined). Incident NVAF hospitalisations showed a borderline decline of 0.5%/year (RR 0.99; 95%CI; 0.99, 1.0) with a statistically significant trend in women but not men. The rate of AF admissions associated with a catheter ablation increased by 13%/year (95%CI; 13.1%, 15.3%). CONCLUSION: The increasing rates of total hospitalisation for NVAF is driven more by repeat than incident admissions, escalating hospitalisations in the very elderly, and more frequent interventional procedures. These drivers have major economic and healthcare planning implications. PMID- 30244876 TI - High altitude exposure during pregnancy enhances the vulnerability of fetal heart dysfunction to ischemic stress: Epigenetic mechanisms. PMID- 30244878 TI - Focal Salvage High Dose-Rate Brachytherapy for Locally Recurrent Prostate Cancer After Primary Radiation Therapy Failure: Results From a Prospective Clinical Trial. AB - PURPOSE: Although increasing data support whole-gland salvage therapy for recurrent prostate cancer, toxicity remains a significant concern. We hypothesized that focal therapy, treating only a portion of the prostate containing recurrent disease, might be equally effective and associated with less toxicity. The objectives of this prospective study were to explore the toxicities, quality of life, and efficacy of focal salvage high-dose-rate (HDR) brachytherapy in patients with multiparametric magnetic resonance imaging (MRI) visible, biopsy-confirmed local recurrence after previous definitive external beam radiation therapy. MATERIALS AND METHODS: Fifteen patients with locally recurrent prostate cancer after external beam radiation therapy were enrolled in this prospective study. Patients were treated with ultrasound-based HDR brachytherapy with a prescription dose of 27 Gy divided in 2 implants, separated by 1 week, to the clinical target volume, which was defined as the quadrant of the prostate where the MRI-visible recurrent lesion was located. Toxicity, quality of life, and biochemical outcomes were analyzed. Postsalvage MRI was performed to assess radiation therapy response. RESULTS: Median follow-up was 36 months. The median size of the recurrence on MRI was 9 mm (range, 7-20 mm), and clinical target volume at the time of HDR was 6.1 mL (range, 2.2-16.1 mL). Only one grade 3 genitourinary toxicity event was observed. No urinary retention was observed. Three-year prostate-specific antigen failure-free rate was 61%. There was no significant change in Expanded Prostate Cancer Index Composite urinary or bowel domains over time. Of the 14 patients who had a post-HDR MRI, 12 had a treatment response. CONCLUSIONS: Our results suggest that focal salvage HDR brachytherapy is well tolerated and promising. External validation is needed. PMID- 30244879 TI - Impact of Whole Lung Irradiation on Survival Outcome in Patients With Lung Relapsed Ewing Sarcoma. AB - PURPOSE: There is no standard treatment procedure for relapsed Ewing sarcoma (EwS). This retrospective analysis evaluates the survival outcome in patients with an isolated pulmonary relapse of EwS treated with whole lung irradiation (WLI) in addition to second line chemotherapy (Ctx). METHODS AND MATERIALS: In our study, 136 patients with pulmonary relapsed EwS who were registered in the relapse register of the Cooperative Ewing Sarcoma Study group or the Sarcoma Relapse Registry for relapsed sarcoma of bone and soft tissues were analyzed. All patients received relapse Ctx or an additional total resection of lung metastasis. Of these patients, 88 (median age, 21 years; range, 7-52 years) achieved a second remission by the relapse treatment. Of these 88 patients, 48 patients received an additional WLI. The 3-year progression-free survival (PFS) and 3-year overall survival (OS) were analyzed (median follow-up, 3 years; range, 7 months to 11 years and 9 months). Additional prognostic factors for survival outcomes, including the response of lung metastases to Ctx, were also estimated. RESULTS: The survival outcome was significantly improved after WLI when analyzing the entire group of pulmonary relapsed patients: 3-year PFS 36% (+WLI) versus 14% (-WLI) (P = .001); 3- year OS 47% (+WLI) versus 33% (-WLI) (P = .007). The 3-year PFS in patients with complete remission of lung relapse receiving WLI (n = 48) compared with those without WLI (n = 40), was 37% (+WLI) versus 21% (-WLI) (P = .18). The site of the primary tumor and the response of pulmonary lesions to Ctx were significant prognostic indicators for survival in patients treated with WLI. No severe pulmonary function disorders or lung toxicities were observed after WLI treatment in both pediatric and adult patients. CONCLUSIONS: The WLI does not correlate with improved OS in patients with pulmonary relapsed EwS. However, a marginal trend toward superior PFS and improved local control of pulmonary disease suggests the application of WLI in patients with EwS with isolated lung relapse and second clinical remission. PMID- 30244877 TI - Circulating Tumor Cell Assessment in Presumed Early Stage Non-Small Cell Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy: A Prospective Pilot Study. AB - PURPOSE: In patients treated with stereotactic body radiation therapy (SBRT) for presumed early stage non-small cell lung cancer (NSCLC), detection and monitoring of circulating tumor cells (CTCs) may be useful for assessing treatment response safely and noninvasively. No published reports of CTC trends in this patient population exist to date. METHODS AND MATERIALS: Patients with clinically diagnosed stage I NSCLC treated with SBRT were eligible for this institutional review board-approved prospective clinical trial. Peripheral blood samples were assayed for CTCs via a green fluorescent protein-expressing adenoviral probe. CTC positivity was defined as 1.3 green fluorescent protein-positive cells/mL of collected blood. Samples were obtained before (pre-radiation therapy [RT]), during, and after SBRT (post-RT; months 1, 3, 6, 12, 18, and 24). SBRT was delivered in <=5 fractions (median dose of 50 Gy in 12.5 Gy fractions) to a biological equivalent dose of >=100 Gy in all cases. RESULTS: Forty-eight consecutive patients (T1a [73%], T1b [21%], and T2a [6%]) were enrolled. Median follow-up was 14.2 months. Twenty patients (42%) had a positive CTC level pre-RT, with a median CTC count of 4.2 CTCs per mL (interquartile range [IQR], 2.2-18.7). Of these 20 patients, 17 had evaluable post-RT CTC evaluations showing reduced CTC counts at 1 month (median, 0.2; IQR, 0.1-0.8) and 3 months (median, 0.6; IQR, 0-1.1). Three of these 17 patients experienced disease progression at a median of 19.9 months; all 3 experienced >=1 positive post-RT CTC test predating clinical progression by a median of 16 months (range, 2-17 months). In contrast, among patients presenting with CTC-detectable disease and for whom all post-RT CTC tests were negative, none experienced recurrence or progression. CONCLUSIONS: CTC monitoring after SBRT for presumed early stage NSCLC may give lead-time notice of disease recurrence or progression. Conversely, negative CTC counts after treatment may provide reassurance of disease control. CTC analysis is thus potentially useful in enhancing clinical diagnosis and follow-up in this population. PMID- 30244880 TI - A Bayesian Approach for Prediction of Patient Radiosensitivity. AB - PURPOSE: A priori identification of the small proportion of radiation therapy patients who prove to be severely radiosensitive is a long-held goal in radiation oncology. A number of published studies indicate that analysis of the DNA damage response after ex vivo irradiation of peripheral blood lymphocytes, using the gamma-H2AX assay to detect DNA damage, provides a basis for a functional assay for identification of the small proportion of severely radiosensitive cancer patients undergoing radiotherapy. METHODS AND MATERIALS: We introduce a new, more rigorous, integrated approach to analysis of radiation-induced gamma-H2AX response, using Bayesian statistics. RESULTS: This approach shows excellent discrimination between radiosensitive and non-radiosensitive patient groups described in a previously reported data set. CONCLUSIONS: Bayesian statistical analysis provides a more appropriate and reliable methodology for future prospective studies. PMID- 30244881 TI - Establishing a New Clinical Role for Medical Physicists: A Prospective Phase II Trial. AB - PURPOSE: To investigate a new clinical role for medical physicists in direct patient care with a prospective phase 2 clinical trial. MATERIALS AND METHODS: Medical physicists participated in the Physics Direct Patient Care (PDPC) protocol, establishing independent professional relationships with radiation oncology patients. After attending a dedicated patient communication training program, medical physicists routinely met with patients for 2 physicist-patient consults to explain the treatment planning and delivery process, review the patient's treatment plan, and answer all technical questions. The first physicist patient consult took place immediately before the computed tomography simulation, and the second took place immediately before the first treatment. Questionnaires were administered to each patient on the PDPC protocol at 3 time points to assess both anxiety and satisfaction. The first questionnaire was given shortly after the first physicist-patient consult, the second questionnaire was given shortly after the second physicist-patient consult, and the third questionnaire was given after the last treatment appointment, with no associated physicist-patient consult. RESULTS: The mean patient anxiety score was considered to be low at all questionnaire time points. There was a statistically significant decrease (P < .0001) in anxiety from the simulation time point to the first treatment time point. The mean patient technical satisfaction score was considered to be high at all measurement time points. There was a statistically significant increase (P = .0012) in technical satisfaction from the simulation time point to the first treatment time point. There was a statistically significant decrease (P < .023) in technical satisfaction from the first treatment time point to the last treatment time point. CONCLUSIONS: Establishing a new clinical role for medical physicists and investigating its effects on patient anxiety and satisfaction have created the foundation for future studies. Based on the results of this trial, the PDPC protocol will be expanded to a larger group of medical physicists, radiation oncologists, and patient disease sites and investigated with a randomized phase 3 clinical trial. PMID- 30244882 TI - Radiation-Induced Lung Density Changes on CT Scan for NSCLC: No Impact of Dose Escalation Level or Volume. AB - PURPOSE: Dose-escalation for patients with non-small cell lung cancer (NSCLC) in the positron emission tomography (PET)-boost trial (NCT01024829) exposes portions of normal lung tissue to high radiation doses. The relationship between lung parenchyma dose and density changes on computed tomography (CT) was analyzed. MATERIALS AND METHODS: The CT scans of 59 patients with stage IB to III NSCLC, randomized between a boost to the whole primary tumor and an integrated boost to its 50% SUVmax (maximum standardized uptake value) volume. Patients were treated with concurrent or sequential chemoradiation or radiation only. Deformable registration mapped the 3-month follow-up CT to the planning CT. Hounsfield unit differences (DeltaHU) were extracted to assess lung parenchyma density changes. Equivalent dose in 2 Gy fractions (EQD2)-DeltaHU response was described sigmoidally, and regional response variation was studied by polar analysis. Prognostic factors of DeltaHU were obtained through generalized linear modeling. RESULTS: Saturation of DeltaHU was observed above 60 Gy. No interaction was found between boost dose distribution (D1cc and V70Gy) and DeltaHU at lower doses. DeltaHU was lowest peripherally from the tumor and peaked posteriorly at 3 cm from the tumor border (3.1 HU/Gy). Right lung location was an independent risk factor for DeltaHU (P = .02). CONCLUSIONS: No apparent increase of lung density changes at 3-month follow-up was observed above 60 Gy EQD2 for patients with NSCLC treated with (concurrent or sequential chemo) radiation. The mild response observed peripherally in the lung parenchyma might be exploited in plan optimization routines minimizing lung damage. PMID- 30244883 TI - Single Neurons in the Human Brain Encode Numbers. AB - Our human-specific symbolic number skills that underpin science and technology spring from nonsymbolic set size representations. Despite the significance of numerical competence, its single-neuron mechanisms in the human brain are unknown. We therefore recorded from single neurons in the medial temporal lobe of neurosurgical patients that performed a calculation task. We found that distinct groups of neurons represented either nonsymbolic or symbolic number, but not both number formats simultaneously. Numerical information could be decoded robustly from the population of neurons tuned to nonsymbolic number and with lower accuracy also from the population of neurons selective to number symbols. The tuning characteristics of selective neurons may explain why set size is represented only approximately in behavior, whereas number symbols allow exact assessments of numerical values. Our results suggest number neurons as neuronal basis of human number representations that ultimately give rise to number theory and mathematics. PMID- 30244884 TI - Probing Sensory Readout via Combined Choice-Correlation Measures and Microstimulation Perturbation. AB - It is controversial whether covariation between neuronal activity and perceptual choice (i.e., choice correlation) reflects the functional readout of sensory signals. Here, we combined choice-correlation measures and electrical microstimulation on a site-to-site basis in the medial superior temporal area (MST), middle temporal area (MT), and ventral intraparietal area (VIP) when macaques discriminated between motion directions in both fine and coarse tasks. Microstimulation generated comparable effects between tasks but heterogeneous effects across and within brain regions. Within the MST and MT, microstimulation significantly biased an animal's choice toward the sensory preference instead of choice-related signals of the stimulated units. This was particularly evident for sites with conflict preference of sensory and choice-related signals. In the VIP, microstimulation failed to produce significant effects in either task despite strong choice correlations presented in this area. Our results suggest that sensory readout may not be inferred from choice-related signals during perceptual decision-making tasks. PMID- 30244886 TI - Circuit Robustness to Temperature Perturbation Is Altered by Neuromodulators. AB - In the ocean, the crab Cancer borealis is subject to daily and seasonal temperature changes. Previous work, done in the presence of descending modulatory inputs, had shown that the pyloric rhythm of the crab increases in frequency as temperature increases but maintains its characteristic phase relationships until it "crashes" at extremely high temperatures. To study the interaction between neuromodulators and temperature perturbations, we studied the effects of temperature on preparations from which the descending modulatory inputs were removed. Under these conditions, the pyloric rhythm was destabilized. We then studied the effects of temperature on preparations in the presence of oxotremorine, proctolin, and serotonin. Oxotremorine and proctolin enhanced the robustness of the pyloric rhythm, whereas serotonin made the rhythm less robust. These experiments reveal considerable animal-to-animal diversity in their crash stability, consistent with the interpretation that cryptic differences in many cell and network parameters are revealed by extreme perturbations. PMID- 30244885 TI - Communication from Learned to Innate Olfactory Processing Centers Is Required for Memory Retrieval in Drosophila. AB - The behavioral response to a sensory stimulus may depend on both learned and innate neuronal representations. How these circuits interact to produce appropriate behavior is unknown. In Drosophila, the lateral horn (LH) and mushroom body (MB) are thought to mediate innate and learned olfactory behavior, respectively, although LH function has not been tested directly. Here we identify two LH cell types (PD2a1 and PD2b1) that receive input from an MB output neuron required for recall of aversive olfactory memories. These neurons are required for aversive memory retrieval and modulated by training. Connectomics data demonstrate that PD2a1 and PD2b1 neurons also receive direct input from food odor encoding neurons. Consistent with this, PD2a1 and PD2b1 are also necessary for unlearned attraction to some odors, indicating that these neurons have a dual behavioral role. This provides a circuit mechanism by which learned and innate olfactory information can interact in identified neurons to produce appropriate behavior. VIDEO ABSTRACT. PMID- 30244887 TI - Biomimetic Intraneural Sensory Feedback Enhances Sensation Naturalness, Tactile Sensitivity, and Manual Dexterity in a Bidirectional Prosthesis. AB - Peripheral intraneural stimulation can provide tactile information to amputees. However, efforts are still necessary to identify encoding strategy eliciting percepts that are felt as both natural and effective for prosthesis control. Here we compared the naturalness and efficacy of different encoding strategies to deliver neural stimulation to trans-radial amputees implanted with intraneural electrodes. Biomimetic frequency modulation was perceived as more natural, while amplitude modulation enabled better performance in tasks requiring fine identification of the applied force. Notably, the optimal combination of naturalness and sensitivity of the tactile feedback can be achieved with "hybrid" encoding strategies based on simultaneous biomimetic frequency and amplitude neuromodulation. These strategies improved the gross manual dexterity of the subjects during functional task while maintaining high levels of manual accuracy. They also improved prosthesis embodiment, reducing abnormal phantom limb perceptions ("telescoping effect"). Hybrid strategies are able to provide highly sensitive and natural percepts and should be preferred. VIDEO ABSTRACT. PMID- 30244889 TI - Discussion. PMID- 30244888 TI - Discussion. PMID- 30244890 TI - Discussion. PMID- 30244891 TI - Discussion. PMID- 30244892 TI - Discussion. PMID- 30244894 TI - Discussion. PMID- 30244893 TI - Discussion. PMID- 30244895 TI - Discussion. PMID- 30244896 TI - Discussion. PMID- 30244897 TI - Discussion. PMID- 30244898 TI - Discussion. PMID- 30244899 TI - Discussion. PMID- 30244900 TI - Discussion. PMID- 30244901 TI - Discussion. PMID- 30244902 TI - Discussion. PMID- 30244903 TI - Discussion. PMID- 30244905 TI - Discussion. PMID- 30244904 TI - Discussion. PMID- 30244907 TI - Discussion. PMID- 30244906 TI - Discussion. PMID- 30244908 TI - Discussion. PMID- 30244909 TI - Discussion. PMID- 30244910 TI - Discussion. PMID- 30244912 TI - Discussion. PMID- 30244911 TI - Discussion. PMID- 30244913 TI - Discussion. PMID- 30244914 TI - Discussion. PMID- 30244915 TI - DISCUSSION. PMID- 30244916 TI - Discussion. PMID- 30244917 TI - Discussion. PMID- 30244918 TI - Discussion. PMID- 30244919 TI - Discussion. PMID- 30244920 TI - Lentiviral-mediated let-7d microRNA overexpression induced anxiolytic- and anti depressant-like behaviors and impaired dopamine D3 receptor expression. AB - Generalized anxiety and major depression disorders (MDD) are severe debilitating mood disorders whose etiology are not fully understood, but growing evidence indicates that microRNAs (miRNAs) might play a key role in their neuropathophysiological mechanisms. In the current study, we investigate the role of Lethal-7 (let-7d) miRNA, and its direct target dopamine D3 receptor (D3R) gain of-function, in the hippocampus, in preclinical models of anxiety and depression in mice. For this purpose, we have constructed a lentiviral vector carrying let 7d miRNA and its anxiolytic effect was investigated by employing the open-field (OF) and the elevated plus maze (EPM) tests. The anti-depressant activity was evaluated using the tail suspension and the forced-swim tests (TST & FST). Our results show that let-7d overexpression significantly improved the measures of anxiety in the OF and EPM tests. In addition, let-7d increased the mobility time in the TST and FST. Interestingly, gene expression interaction analysis shows that the D3R mRNA negatively correlates with let-7d expression. In a different set of experiments, we used a tetracycline-inducible (tet-off) lentiviral vector to overexpress D3R to assess its gain-of-function in the hippocampus on anxiety- and depression-like behaviors. In line, we found that in the absence of doxycycline, D3R produced a significant anxiogenic and depressant-like response. Most importantly, these effects were abrogated when mice were fed doxycycline in drinking water. Our results provide the first evidence for an anxiolytic and anti depressant-like action of let-7d through a potential D3R target-mediated mechanism which might open new avenues for anxiolytic and anti-depressant therapies. PMID- 30244921 TI - Reply to Hua Liu, HaiCun Shi and PingLei Pan: Coordinate based meta-analyses in a medium sized literature: Considerations, limitations and road ahead. PMID- 30244922 TI - B cells from patients with multiple sclerosis have a pathogenic phenotype and increased LTalpha and TGFbeta1 response. AB - The contribution of B cells to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS) is currently of great interest due to the positive outcomes of treatment with B cell-depleting monoclonal antibodies. In this exploratory study we examined the phenotype and cytokine response of B cells from untreated patients with RRMS and healthy controls. The CNS migration potential of the individual blood B cell subpopulations was evaluated according to the expression of CD49d, ALCAM, CXCR3, and CCR7, and cerebrospinal fluid (CSF) samples were analyzed to establish the phenotype of migrated B cells. The frequency of the individual blood B cell subsets expressing CD5, CD43, CD69, CD80, CD83, DC-SIGN and CD138 was similar in patients with RRMS and healthy controls. However, a higher percentage of CD27-IgD-IgM+ memory B cells were found in the blood of patients with RRMS, a population also identified in the CSF samples. We also observed an increased percentage of B cells producing LTalpha and a higher level of TGFbeta1 in patients with RRMS. Altogether, we found that patients with RRMS have an increased frequency of blood CD27-IgD-IgM+ memory B cells that are recruited to the CSF together with other memory B cell populations. Furthermore, we report an increased B cell production of LTalpha and TGFbeta1 in patients with RRMS. PMID- 30244923 TI - Invited commentary. PMID- 30244924 TI - Utilization, patency, and complications associated with vascular access for hemodialysis in the United States. AB - BACKGROUND: This study examines the utilization and outcomes of vascular access for long-term hemodialysis in the United States and describes the impact of temporizing catheter use on outcomes. We aimed to evaluate the prevalence, patency, and associated patient survival for pre-emptively placed autogenous fistulas and prosthetic grafts; for autogenous fistulas and prosthetic grafts placed after a temporizing catheter; and for hemodialysis catheters that remained in use. METHODS: We performed a retrospective study of all patients who initiated hemodialysis in the United States during a 5-year period (2007-2011). The United States Renal Data System-Medicare matched national database was used to compare outcomes after pre-emptive autogenous fistulas, preemptive prosthetic grafts, autogenous fistula after temporizing catheter, prosthetic graft after temporizing catheter, and persistent catheter use. Outcomes were primary patency, primary assisted patency, secondary patency, maturation, catheter-free dialysis, severe access infection, and mortality. RESULTS: There were 73,884 (16%) patients who initiated hemodialysis with autogenous fistula, 16,533 (3%) who initiated hemodialysis with prosthetic grafts, 106,797 (22%) who temporized with hemodialysis catheter prior to autogenous fistula use, 32,890 (7%) who temporized with catheter prior to prosthetic graft use, and 246,822 (52%) patients who remained on the catheter. Maturation rate and median time to maturation were 79% vs 84% and 47 days vs 29 days for pre-emptively placed autogenous fistulas vs prosthetic grafts. Primary patency (adjusted hazard ratio [aHR], 1.26; 95% confidence interval [CI], 1.25-1.28; P < .001) and primary assisted patency (aHR, 1.36; 95% CI, 1.35-1.38; P < .001) were significantly higher for autogenous fistula compared with prosthetic grafts. Secondary patency was higher for autogenous fistulas beyond 2 months (aHR, 1.36; 95% CI, 1.32-1.40; P < .001). Severe infection (aHR, 9.6; 95% CI, 8.86-10.36; P < .001) and mortality (aHR, 1.29; 95% CI, 1.27-1.31; P < .001) were higher for prosthetic grafts compared with autogenous fistulas. Temporizing with a catheter was associated with a 51% increase in mortality (aHR, 1.51; 95% CI, 1.48-1.53; P < .001), 69% decrease in primary patency (aHR, 0.31; 95% CI, 0.31-0.32; P < .001), and 130% increase in severe infection (aHR, 2.3; 95% CI, 2.2-2.5; P < .001) compared to initiation with autogenous fistulas or prosthetic grafts. Mortality was 2.2 times higher for patients who remained on catheters compared to those who initiated hemodialysis with autogenous fistulas (aHR, 2.25; 95% CI, 2.21-2.28; P < .001). CONCLUSIONS: Temporizing catheter use was associated with higher mortality, higher infection, and lower patency, thus undermining the highly prevalent approach of electively using catheters as a bridge to permanent access. Autogenous fistulas are associated with longer time to catheter-free dialysis but better patency, lower infection risk, and lower mortality compared with prosthetic grafts in the general population. PMID- 30244925 TI - Invited commentary. PMID- 30244926 TI - Invited commentary. PMID- 30244927 TI - Sequential aneurysms of the internal carotid artery with fibromuscular dysplasia. PMID- 30244928 TI - A meta-analysis of randomized trials comparing bovine pericardium and other patch materials for carotid endarterectomy. AB - OBJECTIVE: Patch angioplasty during carotid endarterectomy is commonly used to treat symptomatic and asymptomatic carotid artery stenosis. The objective of the present study was to compare the different patch materials that are currently available (synthetic vs venous vs bovine pericardium) in terms of short- and long term outcomes. METHODS: This study was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and eligible randomized control trials were identified through a comprehensive search of PubMed, Scopus, and Cochrane Central published until September 2017. A meta analysis was conducted with the use of a random effects model. The I2 statistic was used to assess for heterogeneity. The primary study end point was the incidence of long-term restenosis. Secondary study end points were 30-day stroke, transient ischemic attack (TIA), myocardial infarction, neck wound infection, local hematoma, carotid artery thrombosis, cranial nerve injury, long-term stroke incidence, and death. RESULTS: Eighteen studies and 3234 patients were included. The risk of 30-day stroke (relative risk [RR], 1.00; 95% confidence interval [CI], 0.45-2.19; I2 = 0%), TIA (RR, 1.14; 95% CI, 0.41-3.19; I2 = 0%), myocardial infarction (odds ratio, 0.75; 95% CI, 0.14-3.97; I2 = 0%), death (RR, 0.53; 95% CI, 0.21-1.34; I2 = 0%), wound infection (RR, 1.84; 95% CI, 0.43-7.81; I2 = 0%), carotid artery thrombosis (RR, 1.47; 95% CI, 0.44-4.97; I2 = 0%), cranial nerve palsy (RR, 1.21; 95% CI, 0.53-2.77; I2 = 0%), and long-term stroke (RR, 2.33; 95% CI, 0.76-7.10; I2 = 0%), death (RR, 1.09; 95% CI, 0.65-1.83; I2 = 0%) and restenosis of greater than 50% (RR, 0.48; 95% CI, 0.19-1.20; I2 = 0%) were similar between the synthetic vs venous patch groups. Also, no differences in terms of 30-day stroke (RR, 0.31; 95% CI, 0.02-5.16; I2 = 63.1%), TIA (RR, 0.49; 95% CI, 0.14-1.76; I2 = 0%), death (RR, 0.74; 95% CI, 0.05-10.51; I2 = 31.7%), carotid artery thrombosis (RR, 0.13; 95% CI, 0.02-1.07; I2 = 0%), and long-term restenosis of greater than 70% (RR, 0.15; 95% CI, 0.01-2.29; I2 = 70.9%) were detected between the synthetic polytetrafluoroethylene and Dacron patch groups. The comparison between the bovine pericardium vs synthetic patch did not yield any statistically significant results in terms of 30-day stroke (RR, 1.44; 95% CI, 0.19-10.79; I2 = 12.7%), TIA (RR, 1.05; 95% CI, 0.11-10.27; I2 = 0%), local neck hematoma (RR, 4.01; 95% CI, 0.46-34.85; I2 = 0%), and death (RR, 4.01; 95% CI, 0.46-34.85; I2 = 0%). CONCLUSIONS: Closure of the carotid arteriotomy with any of the studied patch materials seems to be similar in terms of short- and long-term end points. However, additional randomized trials with adequate follow up periods are needed to compare bovine pericardium patches with other patch materials. PMID- 30244929 TI - Treatment of thoracoabdominal aortic disease in patients with connective tissue disorders. AB - OBJECTIVE: Aneurysmal degeneration of the entire aorta is common in patients with connective tissue disorders (CTDs). Potential treatment options of these aneurysms include open repair and endovascular repair. Our objective herein was to review available evidence for different approaches to treatment of thoracoabdominal aortic disease in patients with CTDs. METHODS: We performed a systematic literature review using PubMed and referenced manuscripts on open and endovascular treatment of thoracoabdominal aortic aneurysms and dissections in patients with CTDs. RESULTS: A total of 28 studies were identified for inclusion in this review, 8 reporting on outcomes after open thoracoabdominal aortic aneurysm repair in patients with CTD, 8 on open branched graft use, and 12 on endovascular aortic repair in this population of patients. Reported outcomes were characterized by low perioperative morbidity and mortality, good branch patency, and low rate of reintervention for open repair and significant rates of endograft related complications and substantial need for secondary endovascular interventions and open conversions for endovascular repair. CONCLUSIONS: There is a lack of high-quality evidence to support any particular approach to aortic repair in patients with CTD and a dearth of comparative data between open repair and endovascular repair. There are distinct differences in the published lengths of follow-up between the two repair approaches as well as in the prevalence of their use in an acute vs elective setting. It is evident that endovascular interventions for aortic disease in patients with CTDs are associated with many device- and aorta-related complications both in the short term and in the long term. Despite the lack of level 1 evidence, open repair currently remains the standard approach to treatment of aortic disease due to CTDs. Open branched graft repair in particular is the preferred technique. Endovascular interventions may be cautiously used in patients with CTDs in selective circumstances. PMID- 30244931 TI - MACRA for the community practice vascular surgeon. PMID- 30244932 TI - The imperative need to identify stroke risk stratification models for patients with asymptomatic carotid artery stenosis. PMID- 30244933 TI - Alarmingly high stroke and death rates after carotid artery stenting. PMID- 30244934 TI - Neurogenic thoracic outlet syndrome: Bringing order to chaos. PMID- 30244935 TI - Invited commentary. PMID- 30244936 TI - Invited commentary. PMID- 30244937 TI - Predictors of early lobectomy after birth in prenatally diagnosed congenital pulmonary airway malformation. AB - PURPOSE: The purpose of this study was to clarify the relationship between congenital pulmonary airway malformation volume ratio (CVR) of bronchial atresia (BA), CVR of congenital cystic adenomatoid malformations (CCAM), and time of surgery after birth. METHOD: We retrospectively analyzed data of 36 BA and CCAM cases, prenatally diagnosed as CPAM from 2009 through 2014. RESULTS: Within 2 h after birth, 12 neonatal patients underwent emergent (EMG) lobectomy. Five cases of lobectomy were performed urgently (UG) from 12 to 48 h after birth. Four cases of lobectomy were required within 30 days after birth (early = EAG). We performed lobectomy in 15 other patients at 11 months after birth (late = LG). Of the EMG cases, 11 were macrotype CCAM (maximal CVR >2.0), and 4 of 5 UG cases were microtype CCAM (CVR >2.0). Of the EAG cases, 3 of 4 were macrotype CCAM with CVR of <1.5. Of 15 LG, 13 were BA and showed a CVR of 0.13-3.0 (median, 0.78). The CVR of the cases operated on within 48 h after birth was significantly larger than that of the cases operated on after 2 weeks (p = 0.001). CONCLUSION: EMG or UG lobectomy was usually required after birth in CCAM, indicating maximal CVR >2.0. By contrast, elective surgery was performed in most BA cases. LEVEL OF EVIDENCE: IV. PMID- 30244938 TI - The burden of surgery and postoperative complications in children with inflammatory bowel disease. AB - BACKGROUND: Pediatric inflammatory bowel disease (IBD) may be associated with a higher burden of surgery and postoperative complications. This study aimed to measure the burden in pediatric IBD over a 20-year period in a large tertiary referral center. METHODS: A retrospective review was conducted of children diagnosed with IBD between 1996 and 2015, with a focus upon operative intervention (excluding endoscopy) and postoperative outcomes. RESULTS: Of 786 IBD patients, 121/581 (20.8%) with Crohn's disease (CD) and 22/205 (10.7%) with ulcerative colitis (UC) underwent surgery during the study period. When comparing 10-year epochs for CD, median time from diagnosis to intervention decreased from 34 months to 3 months (P < 0.0001). Postoperative complications occurred in 16/121 (13%) CD patients (bowel obstruction: 10, anastomotic stricture: 4, stomal issues: 4, anastomotic leak: 1). Within the UC cohort, the median time from diagnosis to intervention decreased from 62 months to 6 months (P = 0.0019). Postoperative complications occurred in 9/22 (41%) UC patients (bowel obstruction: 7, stomal issues: 3, anastomotic stricture: 1). Compared with CD, complications were more frequent in UC patients (P = 0.004). CONCLUSION: Surgery and postoperative complications are common in pediatric IBD. The timing of intervention has trended towards earlier operations in both CD and UC. LEVEL OF EVIDENCE: Treatment study-level III (retrospective comparative study). PMID- 30244939 TI - Resting energy expenditure in infants with congenital diaphragmatic hernia without respiratory support at time of neonatal hospital discharge. AB - BACKGROUND: Infants with congenital diaphragmatic hernia (CDH) are at risk for growth failure because of inadequate caloric intake and high catabolic stress. There is limited data on resting energy expenditure (REE) in infants with CDH. AIMS: To assess REE via indirect calorimetry (IC) in term infants with CDH who are no longer on respiratory support and nearing hospital discharge with advancing post-conceptional age and to assess measured-to-predicted REE using predictive equations. METHODS: A prospective cohort study of term infants with CDH who were no longer on respiratory support and nearing hospital discharge was conducted to assess REE via IC and caloric intake. Baseline characteristics and hospital course data were collected. Three day average caloric intake around time of IC testing was calculated. Change in REE with advancing post-conceptional age and advancing post-natal age was assessed. The average measured-to-predicted REE was calculated for the cohort using predictive equations [22]. RESULTS: Eighteen infants with CDH underwent IC. REE in infants with CDH increased with advancing postconceptional age (r2 = 0.3, p < 0.02). The mean REE for the entire group was 53.2 +/- 10.9 kcal/kg/day while the mean caloric intake was 101.2 +/- 17.4 kcal/kg/day. The mean measured-to-predicted ratio for the cohort was in the normal metabolic range (1.10 +/- 0.17) with 50% of infants considered hypermetabolic and 11% of infants considered hypo-metabolic. CONCLUSIONS: Infant survivors of CDH repair who are without respiratory support at time of neonatal hospital discharge have REE, as measured by indirect calorimetry, that increases with advancing post-conceptional age and that is within the normal metabolic range when compared to predictive equations. LEVEL OF EVIDENCE: III. PMID- 30244940 TI - Combined application of Indocyanine green (ICG) and laser lead to targeted tumor cell destruction. AB - PURPOSE: Precise excision of neuroblastoma is challenging, especially when tumors adhere to vital structures. Indocyanine green (ICG), an FDA-approved dye with absorption peaking at 800 nm, can absorb the near IR laser energy and release heat in the dyed tissue. We hypothesize that by injecting ICG at tumor sites followed by precise laser application, tumor cell death can be selectively targeted. METHODS: Orthotopic neuroblastoma tumors were created in the adrenal gland of immunocompromised mice. Tumor, liver, kidney, and muscle tissues were chosen for ICG injection. Intervention variables included presence of tumor capsule, continuous vs. pulsed laser treatment and total energy delivered. Control groups included laser or ICG only. Tissues were stained with hematoxylin/eosin. RESULTS: Continuous wave laser generated excessive heat, causing damage in all tissues. When using pulsed laser treatment, liver, kidney, muscle, and intact tumor tissues showed no cell death when treated with laser alone or laser plus ICG. Tumor tissue with the capsule removed, however, showed cell death on histology. CONCLUSIONS: Pulsed laser treatment combined with ICG causes targeted tumor cell death in neuroblastoma tumor without capsule. No cell death was observed when tumor capsule was present, when only laser was used, or when applied over non-tumor tissues. PMID- 30244941 TI - The long-term quality of life outcomes in adolescents with Hirschsprung disease. AB - BACKGROUND: Postoperative outcomes for Hirschsprung disease (HD) remain variable, with many patients affected by constipation and/or fecal incontinence. The long term impact upon quality of life (QoL) for HD patients is unclear. We measured long-term QoL outcomes in adolescents with HD using validated questionnaires. METHODS: Patients with HD, managed at a large tertiary pediatric institution between 1997 and 2004, were identified. Patients and/or their proxy completed validated questionnaires. Results were compared with published healthy population controls. Two questionnaires assessed QoL: Pediatric Quality of Life Inventory (PedsQL) and Fecal Incontinence and Constipation Quality of Life (FICQOL). Three measures assessed functional outcomes: Baylor Continence Scale, Cleveland Clinic Constipation Scoring System, and Vancouver Dysfunctional Elimination Symptom Survey. RESULTS: Interviews were completed for 58 (70% response rate) patients [M:F, 49:9; median age, 14.5 years (11.1-18.7)]. No significant differences were found in general QoL scores between patients and healthy controls (84.84 versus 81.49, p = 0.28). Disease-specific questionnaires revealed reduced QoL in patients and families, with 17% of parents reporting the bowel dysfunction stopped their child from socializing and 47% of parents experiencing some degree of anxiety/depression regarding their child's bowel condition. Fecal incontinence (r = -0.59, p < 0.01), constipation (r = -0.36, p = 0.01), and dysfunctional elimination (r = -0.59, p < 0.01) all negatively correlated with QoL scores. CONCLUSIONS: In this study, generic QoL in the adolescent HD population was comparable to healthy populations. However, children with HD have ongoing bowel dysfunction which negatively impacts upon their QoL. LEVEL OF EVIDENCE: Prognosis study:- level II (prospective cohort study). PMID- 30244942 TI - Long-term follow-up of tracheal cartilage growth promotion by intratracheal injection of basic fibroblast growth factor. AB - BACKGROUND: Intratracheal injection of basic fibroblast growth factor (b-FGF) has been shown to enlarge the tracheal lumen 4 weeks after treatment. The objective of this study was to investigate the long-term effect of tracheal cartilage growth promotion by intratracheal injection of b-FGF. MATERIALS AND METHODS: New Zealand white rabbits were classified into four groups to receive either distilled water alone (Group 1; n = 16; control), 40 MUg (Group 2; n = 10), 100 MUg (Group 3; n = 13), or 200 MUg (Group 4; n = 16) of b-FGF dissolved in water. The treatment was injected into the posterior wall of the cervical trachea using a tracheoscope. The animals were sacrificed 4 or 12 weeks later. RESULTS: Four weeks after treatment, the mean luminal areas of tracheas for Groups 1, 2, 3, and 4 were 27.2, 25.6, 32.2, and 36.2 mm2, respectively. At 12 weeks, these were 29.3, 37.9, 42.5, and 56.0 mm2, respectively. The levels of glycosaminoglycan at 12 weeks were 93.9, 152.5, 123.2, and 210.6 MUg/mg, respectively. At 12 weeks, the levels of type II collagen were 77.2, 133.1, 99.2, and 148.9 MUg/mg, respectively. CONCLUSION: Twelve weeks after a single injection of b-FGF, the mean luminal area of the trachea continued to increase. PMID- 30244943 TI - Feasibility of a plasma bioassay to assess oxidative protection of low-density lipoproteins by high-density lipoproteins. AB - BACKGROUND: Traditionally, the impact of lipoproteins on vascular disease has been evaluated in light of their quantity, that is, cholesterol content, in plasma. However, recent studies of high-density lipoproteins (HDLs) have focused on functionality with regard to atheroprotection. For example, bioassays have emerged to assess the ability of HDL, in its near native plasma environment, to promote cholesterol removal (efflux) from cells. As a result, attention has focused on developing plasma-based assays for other putative HDL protective functions including protecting low-density lipoproteins (LDLs) from oxidative damage. OBJECTIVE: To determine the feasibility of such an assay in a complex sample such as plasma, we evaluated the contribution of HDL vs other plasma factors in preventing LDL oxidation. METHODS: We separated normolipidemic human plasma by gel filtration chromatography and assessed each fraction for its ability to prevent LDL modification by water soluble radical and copper-initiated oxidation mechanisms. RESULTS: Using proteomics and selective precipitation methods, we identified major antioxidative contributions for fibrinogen, immunoglobulin G, albumin, and small soluble molecules like uric acid and ascorbate, with albumin being especially dominant in copper-initiated mechanisms. HDL particles were minor contributors (~1%-2%) to the antioxidant capacity of plasma, irrespective of oxidation mechanism. CONCLUSIONS: Given the overwhelming background of antioxidant capacity inherent to highly abundant plasma proteins, specific bioassays of HDL antioxidative function will likely require its complete separation from plasma. PMID- 30244944 TI - Abdominal etiologies of pleural effusion. PMID- 30244945 TI - The future of population medicine: Investigating the role of advanced practice providers and simulation education in special patient populations. PMID- 30244946 TI - Cytoplasmic Pin1 expression is correlated with poor prognosis in colorectal cancer. AB - OBJECTIVE: The aim of this study was to determine the clinicopathological significance and prognostic role of Pin1 expression and subcellular localization in colorectal cancer (CRC). METHODS: The Pin1 expression, as well as cytoplasmic and nuclear localization, was investigated using immunohistochemistry in 265 human CRC tissues. The impact of subcellular localization of Pin1 on clinicopathological significance and prognosis in CRC was evaluated. RESULTS: Pin1 was expressed in 164 of 265 CRCs (61.9%). Pin1 expression was not significantly correlated with any clinicopathological parameters. However, Pin1 expression was significantly correlated with worse overall and recurrence-free survivals (P = 0.002 and P = 0.001, respectively). CRCs with only nuclear Pin1 expression showed no difference in survival compared to CRCs with no Pin1 expression. Over half (51.7%, 137/265) of the CRCs had any cytoplasmic Pin1 expression, and 26.8% (71/265) had both cytoplasmic and nuclear expression. Cytoplasmic Pin1 expression was more frequent than only nuclear or no Pin1 expression in cases with vascular invasion and distant metastasis. Cytoplasmic Pin1 expression was significantly correlated with worse overall and recurrence free survivals (P < 0.001 and P < 0.001, respectively). CONCLUSION: Taken together, our results indicated different prognostic roles of subcellular Pin1expression in CRC. Cytoplasmic expression of Pin1, with or without nuclear expression, is an important factor in predicting aggressive tumor behavior and worse prognosis. PMID- 30244947 TI - Progress in studies of necroptosis and its relationship to disease processes. AB - This review briefly introduces the mechanism and detection methods of necroptosis in recent years. The most significant points of this review focus on the involvement of necroptotic proteins in disease progression. The following aspects are summarized: 1) RIPs, MLKL, and the upstream and downstream molecules that mediate necroptosis; 2) The development of detection methods for necroptosis; 3) The involvement of related necroptotic proteins in diverse diseases etiology; and 4) The application of necroptotic proteins in disease diagnosis. PMID- 30244948 TI - Identification of potential drugs for diffuse large b-cell lymphoma based on bioinformatics and Connectivity Map database. AB - Diffuse large B-cell lymphoma (DLBCL) is the most main subtype in non-Hodgkin lymphoma. After chemotherapy, about 30% of patients with DLBCL develop resistance and relapse. This study was to identify potential therapeutic drugs for DLBCL using the bioinformatics method. The differentially expressed genes (DEGs) between DLBCL and non-cancer samples were downloaded from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs were analyzed using the Database for Annotation, Visualization, and Integrated Discovery. The R software package (SubpathwayMiner) was used to perform pathway analysis on DEGs affected by drugs found in the Connectivity Map (CMap) database. Protein-protein interaction (PPI) networks of DEGs were constructed using the Search Tool for the Retrieval of Interacting Genes online database and Cytoscape software. In order to identify potential novel drugs for DLBCL, the DLBCL-related pathways and drug affected pathways were integrated. The results showed that 1927 DEGs were identified from TCGA and GEO. We found 54 significant pathways of DLBCL using KEGG pathway analysis. By integrating pathways, we identified five overlapping pathways and 47 drugs that affected these pathways. The PPI network analysis results showed that the CDK2 is closely associated with three overlapping pathways (cell cycle, p53 signaling pathway, and small cell lung cancer). The further literature verification results showed that etoposide, rinotecan, methotrexate, resveratrol, and irinotecan have been used as classic clinical drugs for DLBCL. Anisomycin, naproxen, gossypol, vorinostat, emetine, mycophenolic acid and daunorubicin also act on DLBCL. It was found through bioinformatics analysis that paclitaxel in the drug-pathway network can be used as a potential novel drug for DLBCL. PMID- 30244949 TI - ? PMID- 30244950 TI - [Caregivers and their emotions in their day-to-day work]. AB - Faced with difficult situations, caregivers experience emotions which can sometimes overwhelm them. They need to adopt strategies to prevent an overflow of emotions without falling into avoidance. PMID- 30244951 TI - [Compassion fatigue and vicarious trauma in caregivers]. AB - While the concept of burnout is in the media spotlight, other disorders can also affect caregivers. Vicarious trauma evokes a state of post-traumatic stress in caregivers confronted with the trauma endured by a patient. Compassion fatigue is manifested by a gradual erosion of empathy, optimism and compassion. Both disorders require immediate and adapted support. PMID- 30244952 TI - [Facets of caregivers' suffering and grief]. AB - Caregivers' grief and emotions are often considered to be inappropriate and unjustified. This suffering is not often addressed in the care environment, as if its presence signalled a lack of professionalism. However, whether it is linked to fantasies of immortality or omnipotence, to an ideal of care or to personal injuries, this grief testifies unanimously to the ordeals endured collectively by the caregiving teams. A work of verbalisation and symbolisation is essential in this context. PMID- 30244953 TI - [The impact of difficult situations on caregivers]. AB - Caregivers are confronted with disease and death, sometimes regularly. Faced with these difficult situations, the emotions they feel affect every aspect of their lives: physical, intellectual, spiritual and social. It is important to take into account these emotions and to identify the resources which can be offered to caregivers. Solidarity between caregivers and team cohesion are also essential. PMID- 30244954 TI - [Resources to support caregivers]. AB - For caregivers, managing their emotions is a complex, daily practice. It initially requires awareness of their own experience, followed by individual and collective work to adjust their positioning and develop their reflexive capacities. There are various tools available to support caregivers in difficult situations, notably opportunities for dialogue, formal or otherwise, team meetings, feedback sessions and practice analyses. These moments are essential for allowing everyone to express themselves freely and to draw up individual or collective strategies. PMID- 30244955 TI - [Listening to the suffering of caregivers]. AB - Health professionals are confronted with suffering, disease and death. All these situations are distressing on a human level. They are also faced with budget constraints which are changing their working conditions. So as not to lose the meaning of their mission, they can notably draw on their psychological resources and on space and time in the workplace for exchange, in order to symbolise and transform their emotions into a positive force. PMID- 30244956 TI - [Caregivers faced with painful events, testimonials]. AB - Whatever the profession of caregivers, their activity involves supporting patients and families who are suffering. Doctors and nurses, in particular, talk of the strong emotions which they feel but which they find difficult to express. Being aware of them is essential for being able to accept them and limit their consequences. This article shares different insights. PMID- 30244957 TI - [Remaining a caregiver despite the inconceivable]. AB - A children's nurse assistant and a children's nurse, both working in the child welfare protection sector, were confronted with the death, in dramatic circumstances, of a young girl monitored by their unit. This situation provoked considerable suffering in these professionals. In this article they share their experience. PMID- 30244958 TI - [Management of minors returning from regions controlled by Islamic State]. AB - Certain children's welfare accommodation facilities have, since the end of 2015, taken in minors returning from regions controlled by Islamic State. These complex situations challenge professionals and involve political, media-related and religious issues. They require understanding of the process of radicalisation in order to be able to support the children and their families. In this context, training and team work are essential. PMID- 30244959 TI - ? PMID- 30244960 TI - Uterine leiomyosarcoma: A review of the literature and update on management options. AB - Uterine leiomyosarcoma is the most common type of uterine sarcoma. It is an extremely aggressive malignancy associated with a poor overall prognosis. Women affected may vary in age, but are most often diagnosed in their perimenopausal years. Presenting symptoms may be vague and mimic other benign uterine conditions. Preoperative diagnosis of leiomyosarcoma is difficult and often only made at time of surgical resection. These rare mesenchymal tumors are characterized by cytologic atypia, a high mitotic index, and tumor necrosis on histologic inspection. Management of early stage disease entails hysterectomy and complete surgical resection of gross tumor, though routine oophorectomy or lymph node dissection do not appear to confer much clinical benefit. Adjuvant therapy for early stage disease remains controversial as multiple clinical trials have failed to demonstrate benefit on overall survival. Recently, progress has been made in regards to therapy for advanced and recurrent disease. Novel chemotherapeutics, targeted therapies such as olaratumab and pazopanib, and new immunotherapies such as nivolumab and pembrolizumab have demonstrated promise in these previously difficult drug-resistant patients. In this article, we provide a detailed review of uterine leiomyosarcoma including epidemiology, clinical presentation, diagnosis, and pathologic characteristics. We then go on detail management strategies, including options for adjuvant therapy, and highlight new and developing regimens in the field. PMID- 30244961 TI - Impact of enhanced recovery after surgery (ERAS) protocol on gastrointestinal function in gynecologic oncology patients undergoing laparotomy. AB - OBJECTIVE: To evaluate the impact of enhanced recovery after surgery (ERAS) on postoperative gastrointestinal function in gynecologic oncology patients. METHODS: This retrospective cohort study compared gynecology oncology patients undergoing non-emergent laparotomy from 10/2016 to 6/2017 managed on an ERAS protocol to a control cohort from the year prior to ERAS implementation. Major changes to postoperative care after ERAS implementation included multimodal analgesia, early feeding, goal-directed fluid resuscitation, and early ambulation. The primary outcome was rate of postoperative ileus, defined as nausea and vomiting requiring nothing-per-mouth status or nasogastric tube (NGT) placement. Secondary outcomes included length of stay (LOS) and 30-day readmission. RESULTS: 376 patients met inclusion criteria; 197 in the control group and 179 in the ERAS group. Patient demographics were similar between groups. Ileus rate was significantly lower in the ERAS group (2.8% vs. 15.7%; p < 0.001), and fewer patients in the ERAS group required NGT placement (2.2% vs. 7.1%; p = 0.06). ERAS remained independently associated with decreased ileus rates when controlling for other patient and surgical factors (OR 0.2; p = 0.01). Epidural use was correlated with a significant increase in ileus risk (OR 2.6; p = 0.03), as was increased Charlson Comorbidity Index (OR 1.2; p < 0.01). LOS was significantly decreased in the ERAS group (2.9 vs. 4.0 days; p = 0.04), while 30 day readmission rates were similar (10.1% vs. 10.7%; p = 0.62). CONCLUSIONS: Implementation of an ERAS protocol significantly decreases the risk of postoperative ileus in gynecologic oncology patients undergoing laparotomy. ERAS also reduced LOS compared to pre-ERAS controls. PMID- 30244962 TI - Structural comparison of hemifacial microsomia mandible in different age groups by three-dimensional skeletal unit analysis. AB - PURPOSE: The goal of this study was to understand the three-dimensional (3D) structural characteristics of hemifacial microsomia (HFM) mandible in terms of skeletal units, especially to locate the underdeveloped skeletal regions for treatment. Another goal was to compare the HFM structure of different age groups to understand growth potential relevant to treatment scheduling. MATERIALS AND METHODS: We reconstructed 3D mandibles from computed tomographic images of French and Korean patients with HFM (N = 28; group II) and normal subjects (N = 27; group I). Each mandible was classified by Pruzansky's HFM types I, II and III, and by age group (child, adolescent, and adult). The mandible was divided into skeletal units, and geometrical representation by skeletal unit line was performed, including the condylar, body, coronoid, and angular units. Their length and angulations were measured and statistically analyzed. RESULTS: The results showed that the affected condylar unit in type II HFM and the condylar/coronoid unit in type III were smaller in young age groups than were other units. The angulation between the skeletal units in type II, though not type III, tended toward normalcy with age, but not to the normal degree of angulations in group I. CONCLUSION: Our study shows the major involvement of condylar unit and minor involvement of body unit for HFM, improving with age in type II. The mandibular skeletal unit analysis seems to be a useful tool for individualized diagnosis, allowing identification of the major etiopathogenic area and treatment planning, including a simulation to set up a regimen for successful reconstruction of HFM. PMID- 30244963 TI - Long term effectiveness of electrochemotherapy for the treatment of lower lip squamous cell carcinoma. AB - PURPOSE: Electrochemotherapy (ECT) is a therapeutic approach based on the local application of electrical pulses that permeabilize cell membranes to enhance the uptake of low-permeant chemotherapeutic agents, thus increasing their cytotoxic effects. MATERIALS AND METHODS: Twenty-one patients with SCC of the lower lip were treated according to the European Standard Operating Procedures of Electrochemotherapy. Bleomycin (15,000 IU/m2 body surface area) was administered intravenously over a 1-min period. Eight electrical pulses (amplitude, 1000 V/cm; duration, 100 MUs) were generated and delivered at a repetition frequency of 5 kHz. Changes in tumor volume were used to assess treatment response. RESULTS: Objective response (OR), complete response (CR), and partial response (PR) rates of 100%, 71.4%, and 28.6% respectively were demonstrated following a single session of ECT. ECT was well tolerated, and no adverse events occurred. CONCLUSIONS: Intravenous bleomycin-based ECT is a safe and effective therapy for SCC of the lower lip. ECT improves the quality-of-life of patients by preserving the function and the aesthetic appearance of the affected area. ECT provides a therapeutic option for elderly and frail patients who, due to their state of health, are not suitable for, or refuse surgical interventions. PMID- 30244964 TI - [Klinefelter'syndrome: A predisposition to sexual crime?] AB - BACKGROUND: Several studies have reported over-representation of psychiatric disorders among patients with Klinefelter' Syndrome (KS), with forensic complications. OBJECTIVE: Consider determinants of sexual assault in patient with KS. REVIEW: In this work, we present the case of Jules, 23 years old, with KS, benefiting from steroid replacement therapy, convicted of rape of a minor and evaluated in this context. We question here the role of his genetic pathology and of his hormonal treatment in this sexual assault. FINDINGS: According to evidence from the literature, it is not possible to determine with certainty the fair value of each factor and their impact on the occurrence of the sexual criminal act. Indeed, although the crime rate among KS subjects is higher than in the general population, the majority of them have never been in trouble with the law; moreover, these subjects were no more likely to commit violent sexual acts than were criminals without KS. As for hormonal treatment, it seems that testosterone is better viewed as a facilitator of initiating an aggressive response than as a primary inductor. CONCLUSION: In conclusion, the onset of sexual violence that accompanied the introduction of hormonal treatment into a patient with KS suggests an effective involvement of steroid replacement therapy, even small, in the criminal act. This must incite clinicians to extreme prudence and to take account of multidisciplinary expertise (psychiatrist, endocrinologist) in order to reconsider the continuation of the treatment in this particular forensic context. Finally, we discuss other factors that can precipitate such a violent act. PMID- 30244965 TI - [Networking: discussing community health and networks. SESPAS Report 2018]. AB - Four voices from around Spain discuss community health and networks. These voices understand that the networks are systems formed by interconnected people, with a common interest, that provide support. Networks require a common place and time, in order to generate trust and respect for horizontal work. Thus, networks are appropriate structures for health promotion, facilitating the exchange of knowledge, collaboration and innovation through the participation of those who form them. It is important that networks are evaluated by analysing their autonomy, leadership, quality of links, training, network projection, capacity for integrating groups and synergy. PMID- 30244967 TI - Light-Driven Domain Mechanics of a Minimal Phytochrome Photosensory Module Studied by EPR. AB - Light-exposed organisms developed photoreceptors to transduce light signals for environmental adaptation. Phytochromes, found in bacteria, fungi, and plants, can discriminate the ratio of red and far-red light using the isomerization of a bilin chromophore bound to a photosensory module to trigger downstream conformational changes in the protein. Here, we investigated by hydrogen/deuterium exchange mass spectrometry and electron paramagnetic resonance spectroscopy the light-driven domain mechanics of a minimal monomeric photosensory module from the group II phytochrome Cph2 from Synechocystis sp. PCC 6803. We could unambiguously trace the light-driven secondary structural rearrangement of its tongue region, and we found a translational motion of the PHY domain that is related to what was found before by X-ray studies in a group I module. Our analysis demonstrates a common light response in the photosensory modules of phytochromes, orchestrated solely by the GAF-PHY bidomain independent of further quaternary interactions or the nature of downstream effector domains. PMID- 30244966 TI - Structural Basis of TRPV4 N Terminus Interaction with Syndapin/PACSIN1-3 and PIP2. AB - Transient receptor potential (TRP) channels are polymodally regulated ion channels. TRPV4 (vanilloid 4) is sensitized by PIP2 and desensitized by Syndapin3/PACSIN3, which bind to the structurally uncharacterized TRPV4 N terminus. We determined the nuclear magnetic resonance structure of the Syndapin3/PACSIN3 SH3 domain in complex with the TRPV4 N-terminal proline-rich region (PRR), which binds as a class I polyproline II (PPII) helix. This PPII conformation is broken by a conserved proline in a cis conformation. Beyond the PPII, we find that the proximal TRPV4 N terminus is unstructured, a feature conserved across species thus explaining the difficulties in resolving it in previous structural studies. Syndapin/PACSIN SH3 domain binding leads to rigidification of both the PRR and the adjacent PIP2 binding site. We determined the affinities of the TRPV4 N terminus for PACSIN1, 2, and 3 SH3 domains and PIP2 and deduce a hierarchical interaction network where Syndapin/PACSIN binding influences the PIP2 binding site but not vice versa. PMID- 30244968 TI - Salmonella Phage S16 Tail Fiber Adhesin Features a Rare Polyglycine Rich Domain for Host Recognition. AB - The ability of phages to infect specific bacteria has led to their exploitation as bio-tools for bacterial remediation and detection. Many phages recognize bacterial hosts via adhesin tips of their long tail fibers (LTFs). Adhesin sequence plasticity modulates receptor specificity, and thus primarily defines a phage's host range. Here we present the crystal structure of an adhesin (gp38) attached to a trimeric beta-helical tip (gp37) from the Salmonella phage S16 LTF. Gp38 contains rare polyglycine type II helices folded into a packed lattice, herein designated "PGII sandwich." Sequence variability within the domain is limited to surface-exposed helices and distal loops that form putative receptor binding sites. In silico analyses revealed a prevalence of the adhesin architecture among T-even phages, excluding the archetypal T4 phage. Overall, S16 LTF provides a valuable model for understanding binding mechanisms of phage adhesins, and for engineering of phage adhesins with expandable or modulated host ranges. PMID- 30244970 TI - On the Complexity of PAHSA Research. AB - Reporting in Cell Metabolism, Pflimlin et al. recently found no beneficial effect of PAHSAs on glucose control in mice on several high-fat diets. Kuda cautions that due to methodological differences, the data must be carefully reinterpreted, emphasizing that olive oil contains high amounts of FAHFAs, potentially masking the effects of PAHSAs in studies utilizing this vehicle. PMID- 30244969 TI - Temperature-Induced Replacement of Phosphate Proton with Metal Ion Captured in Neutron Structures of A-DNA. AB - Nucleic acids can fold into well-defined 3D structures that help determine their function. Knowing precise nucleic acid structures can also be used for the design of nucleic acid-based therapeutics. However, locations of hydrogen atoms, which are key players of nucleic acid function, are normally not determined with X-ray crystallography. Accurate determination of hydrogen atom positions can provide indispensable information on protonation states, hydrogen bonding, and water architecture in nucleic acids. Here, we used neutron crystallography in combination with X-ray diffraction to obtain joint X-ray/neutron structures at both room and cryo temperatures of a self-complementary A-DNA oligonucleotide d[GTGG(CSe)CAC]2 containing 2'-SeCH3 modification on Cyt5 (CSe) at pH 5.6. We directly observed protonation of a backbone phosphate oxygen of Ade7 at room temperature. The proton is replaced with hydrated Mg2+ upon cooling the crystal to 100 K, indicating that metal binding is favored at low temperature, whereas proton binding is dominant at room temperature. PMID- 30244971 TI - Translational and HIF-1alpha-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides. AB - There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine, and serine synthesis by modulating mRNA translation, while ablation of 4E-BP1/2 substantially decreases sensitivity of breast cancer and melanoma cells to KI/biguanide combinations. Efficacy of the KI/biguanide combinations is also determined by HIF-1alpha-dependent perturbations in glutamine metabolism, which were observed in VHL-deficient renal cancer cells. This suggests that cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms, which allows them to survive therapeutic insults that target cancer metabolism. PMID- 30244972 TI - Inhibition of Acetyl-CoA Carboxylase by Phosphorylation or the Inhibitor ND-654 Suppresses Lipogenesis and Hepatocellular Carcinoma. AB - The incidence of hepatocellular carcinoma (HCC) is rapidly increasing due to the prevalence of obesity and non-alcoholic fatty liver disease, but the molecular triggers that initiate disease development are not fully understood. We demonstrate that mice with targeted loss-of-function point mutations within the AMP-activated protein kinase (AMPK) phosphorylation sites on acetyl-CoA carboxylase 1 (ACC1 Ser79Ala) and ACC2 (ACC2 Ser212Ala) have increased liver de novo lipogenesis (DNL) and liver lesions. The same mutation in ACC1 also increases DNL and proliferation in human liver cancer cells. Consistent with these findings, a novel, liver-specific ACC inhibitor (ND-654) that mimics the effects of ACC phosphorylation inhibits hepatic DNL and the development of HCC, improving survival of tumor-bearing rats when used alone and in combination with the multi-kinase inhibitor sorafenib. These studies highlight the importance of DNL and dysregulation of AMPK-mediated ACC phosphorylation in accelerating HCC and the potential of ACC inhibitors for treatment. PMID- 30244974 TI - Methodological Issues in Studying PAHSA Biology: Masking PAHSA Effects. AB - PAHSAs are anti-diabetic and anti-inflammatory lipids. Syed et al. identify numerous experimental differences that likely account for the failure of Pflimlin et al. to observe PAHSA beneficial effects. The differences include different HFDs resulting in minimal/no glucose intolerance, different assay conditions, an LC-MS protocol that was not validated, and use of olive oil, a bioactive nutrient that improves glucose tolerance, as a vehicle. PMID- 30244973 TI - PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers. AB - High-grade serous ovarian cancer (HGSOC) remains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogeneity in HGSOC. By combining proteomic, metabolomic, and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS. While low-OXPHOS exhibit a glycolytic metabolism, high-OXPHOS HGSOCs rely on oxidative phosphorylation, supported by glutamine and fatty acid oxidation, and show chronic oxidative stress. We identify an important role for the PML-PGC-1alpha axis in the metabolic features of high-OXPHOS HGSOC. In high-OXPHOS tumors, chronic oxidative stress promotes aggregation of PML-nuclear bodies, resulting in activation of the transcriptional co-activator PGC-1alpha. Active PGC-1alpha increases synthesis of electron transport chain complexes, thereby promoting mitochondrial respiration. Importantly, high-OXPHOS HGSOCs exhibit increased response to conventional chemotherapies, in which increased oxidative stress, PML, and potentially ferroptosis play key functions. Collectively, our data establish a stress mediated PML-PGC-1alpha-dependent mechanism that promotes OXPHOS metabolism and chemosensitivity in ovarian cancer. PMID- 30244976 TI - Unidirectional porous beta-tricalcium phosphate induces bony fusion in lateral lumbar interbody fusion. AB - Lateral lumbar interbody fusion (LLIF) often requires the use of allograft or artificial bone. We used beta-tricalcium phosphate artificial bone with a porosity of 57% consisting of a novel unidirectional porous structure (Affinos(r)) in patients (5 male and 9 female) who underwent LLIF from August 2015 as a substitute for autologous bone. We evaluated 60 graft windows in the cages at 30 intervertebral levels. To evaluate interbody bony fusion, CT multi planar reconstruction coronal and sagittal images obtained 1 year after surgery were assessed. Intra-cage bony fusion was observed in 39 of 60 graft windows and so total bony fusion rate was 65%. Intra-cage bony fusion was confirmed in 17 of 29 (58.6%) graft windows with autologous bone and 22 of 31 (70.9%) graft windows with Affinos(r). There was no significant difference in the rate of bony fusion between autologous bone and Affinos(r) (p = 0.418). In conclusion, the rate of bony fusion using Affinos(r) in LLIF cages was not inferior to that using autologous bone graft. Affinos(r) is a candidate for graft material in LLIF surgery and further exploration is warranted. PMID- 30244977 TI - Evaluation of different ulegyria patterns with magnetic resonance imaging. AB - Ulegyria is a parenchymal sequel of hypoxic ischemic encephalopathy causing mushroom-like appearance in gyri. Aim of the present study was to evaluate clinico-radiological findings of patients who applied with different clinical features, predominantly epilepsy, and who were found to have ulegyria formations in MRI examinations. The study included a total of 30 patients (12 female and 18 male) who applied with different types of seizures in February 2011-August 2016 period and had brain MRI examinations using 1.5T MRI scanner. Mushroom-shaped gyri accompanied by gliosis and atrophy in subcortical white matter were considered ulegyria. Locations, MRI features and accompanying pathologies of ulegyria formations were studied. Age of the patients ranged from 4 to 62 (mean 26.0 +/- 13.8). Both cerebral lobes were involved in 18 patients. In terms of involved area, symmetrical or asymmetrical involvements were observed in occipital lobes in 26 patients, parietal lobes in 19, frontal lobes in 12 and temporal lobes in 4. The most common involvement type was bilateral occipital and bilateral parieto-occipital lobe involvements with five patients each. Lesions were symmetrical in 11 patients. Six patients had cingulate gyrus atrophy. Nineteen patients had different levels of symmetrical or asymmetrical ventricular dilatation. Cranial asymmetry was observed in six patients with unilateral involvement and in one patient with generalized involvement. Although ulegyria predominantly involves parasagittal watershed areas in MRI examinations of patients applying with epilepsy, clinical manifestations and appearance of lesions could vary depending upon the size of involved area and level of injury. PMID- 30244978 TI - Does breast size affect how women participate in physical activity? AB - OBJECTIVES: Research has shown that women with large breasts experience increased breast motion, which can act as a barrier to participating in physical activity. Despite this evidence, limited research has investigated the effect of breast size on physical activity participation. DESIGN: Cross-sectional study. METHODS: 355 Australian women (aged 18-75years) who volunteered as participants were divided into four breast size groups (small, medium, large and hypertrophic). All participants completed the Active Australia Survey to assess their participation in physical activity in the previous week, and were asked to indicate whether they agreed or disagreed that their breast size affected their participation in physical activity. Participant responses to time spent in each type of activity were compared across the four breast size groups using an ANCOVA design, controlling for age. RESULTS: Participants with hypertrophic breasts participated in significantly less total physical activity per week, particularly less vigorous-intensity physical activity, compared to their counterparts with smaller breasts. Participants with large breasts also participated in less vigorous intensity physical activity compared to participants with small and with medium breasts, and a high percentage of women with large and with hypertrophic breasts perceived their breast size to affect the amount and intensity of physical activity they performed. CONCLUSIONS: Breast size should be acknowledged as a potential barrier to women participating in physical activity. Strategies to assist women with large and hypertrophic breasts participate in all types and intensities of physical activity are needed so women can enjoy the health benefits associated with an active lifestyle. PMID- 30244975 TI - Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer. AB - Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect. PMID- 30244979 TI - The effect of sensory-targeted ankle rehabilitation strategies on single-leg center of pressure elements in those with chronic ankle instability: A randomized clinical trial. AB - OBJECTIVES: To determine the effects of sensory-targeted ankle rehabilitation strategies on laboratory-oriented measures of single-leg balance in those with chronic ankle instability. DESIGN: Non-inferiority randomized controlled trial. METHODS: Seventy-seven participants with self-reported chronic ankle instability were randomized into 4 treatment groups: Ankle joint mobilization, plantar massage, triceps surae stretching, and a control group. All participants performed 3 trials of single-leg balance on a force plate with eyes open and closed at 3 time points (baseline, immediately after the first treatment, and following 6 treatments over 2 weeks). The spatial (standard deviation), temporal (velocity), and spatiotemporal (time-to-boundary) elements of center of pressure excursions in single-leg balance were evaluated with eyes open and eyes closed at each time point. Immediate and final change scores were calculated for each group from the baseline values on these variables. RESULTS: Joint mobilization produced immediate improvements in the temporal elements with eyes open and closed that exceeded the minimum detectable changes for these measures. Plantar massage and triceps surae stretching also enhanced the temporal element after a single treatment, but only with eyes closed. No substantial benefit of any of the interventions were found after 2-weeks of treatment, regardless of treatment group. CONCLUSIONS: Sensory-targeted ankle rehabilitation strategies substantially improve single-leg postural control after one treatment, but these changes are short-lived. Future research is needed to determine whether combinations of sensory-targeted ankle rehabilitation strategies with other therapeutic interventions potentially improve single-leg balance stability in those with CAI compared to use in isolation. CLINICAL TRIAL REGISTRATION NUMBER: NCT01541657. PMID- 30244980 TI - [Chemotherapy-induced peripheral neuropathy: Symptomatology and epidemiology]. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is common with specific semiological characteristics. When CIPN appears, there are many difficulties in guaranteeing sustained treatment, especially with optimal protocol. Moreover, CIPN have bad repercussions on quality of life after cancer disease. In this article, we have achieved a current state of CIPN and try to report details about semiological characteristics and topography. We have also produced some epidemiological data. Nonetheless, we have not voluntarily introduced treatment because it will be the topic of further work. PMID- 30244981 TI - [Physiopathological mechanisms of immune-related adverse events induced by anti CTLA-4, anti-PD-1 and anti-PD-L1 antibodies in cancer treatment]. AB - Recently, the emergence of anti-CTLA-4 and anti-PD-1/PD-L1 antibodies called immune check-point inhibitors (ICPI) has modified the landscape of anti-cancer treatments. These therapeutics are associated with immune related adverse events that affect many organs, most commonly skin, digestive tract, endocrine glands and lungs. This review summarizes the main physiopathological hypotheses on the mechanisms of these toxicities. In most cases, the T lymphocytes hyperactivation induced by ICPI generates a specific response directed against tumor antigens, leading to anti-tumor activity in tumor tissues but also side effects in normal tisues called "on-target". The CD8+ cytotoxic T lymphocytes-mediated cell lysis induces the release of neoantigens, tumor antigens and auto-antigens from normal tissues, respectively. This phenomenon called "epitope spreading" leads to diversification of the T cell repertoire and thus to reduced immune tolerance, which is exacerbated by inhibition of regulator T lymphocytes. Furthermore, the predominant activation of Th1 and Th17T lymphocytes mediated by ICPI induced an increased production of pro-inflammatory cytokines such as interferon-gamma (IFNgamma) and interleukine-17 (IL-17). These two mechanisms are responsible for the so called "off-target" toxicities. The roles of cross-reactivity with the intestinal microbiota, hypersensitivity and the specific effect of PD-L2 remain to be determined. Better knowledge of these mechanisms will improve patient care and help predict patients at risk of developing severe toxicities to ICPIs. PMID- 30244983 TI - Parental Perspectives on Diagnosis and Prognosis of Neonatal Intensive Care Unit Graduates with Cerebral Palsy. AB - OBJECTIVES: To describe how parents of neonatal intensive care unit (NICU) graduates with cerebral palsy (CP) perceive both the accuracy of prognoses provided in the NICU and the timing of their child's diagnosis of CP, and to assess the influence of functional outcome on these perceptions. STUDY DESIGN: We surveyed parents of NICU graduates with CP about timing and benefit of diagnosis, accuracy of prognosis, and functional abilities of their children. After piloting and validation, CP parent support groups circulated the survey on social media, websites, and email lists. Bivariate relationships between categorical responses to survey questions were assessed with the chi2 test, and multivariable logistic regression was performed to identify independent factors associated with perceptions about the timing of diagnosis. RESULTS: Parents of 463 children were included. Two-thirds (67%) of the children were diagnosed with CP before age 2 years, yet 40% of the respondents felt that diagnosis was made late, and only 11% categorized diagnosis as early. More than one-half (59%) perceived a benefit to diagnosis. There was a significant association between earlier age at diagnosis and greater functional limitations; 24% of parents who recalled being given a prognosis reported that their child functioned as predicted, and 46% reported that their child exceeded expectations. Parents were more likely to believe that children with fewer functional limitations had exceeded expectations. CONCLUSION: Parents remember prognostic discussions about children who develop CP as underestimating functional outcome. Diagnosis is rarely seen as early and is associated with benefits. These observations suggest that clinicians should aim to diagnose CP early and to maintain guarded optimism about future outcomes. Tools for improved communication are urgently needed. PMID- 30244982 TI - [Medico-economic benefits of subcutaneous formulations of trastuzumab and rituximab in day hospitalisation (SCuBA Study)]. AB - INTRODUCTION: New pharmaceutical forms of trastuzumab and rituximab which can be administered by the subcutaneous route have been developed recently. For day hospitalisation units, these can be used in simpler treatment protocols than previous intravenous formulations. The objective of this study was to evaluate the medical and economic consequences of switching to subcutaneous formulations of trastuzumab and rituximab. METHODS: Thirty-six day care units in 30 hospitals or clinics participated in this observational study. Data were collected on the capacity of the units, the number of chemotherapy sessions implemented, the duration of occupation of a chair and the production capacity of the unit pharmacy. The number of additional sessions made possible by the use of subcutaneous forms in 2016 was determined and the associated gain in earnings calculated using national tariffs. RESULTS: Compared to the intravenous route, the mean duration of occupation of a chair was reduced by 56.1 % for a session of subcutaneous trastuzumab and by 73.8 % for a session of subcutaneous rituximab. The mean number of additional sessions made possible by the use of subcutaneous treatments was 242 [168-316] sessions by year by unit, corresponding to 2.7 % [1.9 %-3.4 %] of the total number of chemotherapy sessions in the unit. The corresponding gain in annual earnings was ? 111 388. DISCUSSION: Switching the route of administration from the intravenous to the subcutaneous route is a useful strategy to address the increase in activity of day hospitalisation units. This allows an increase of 2.7 % in the total number of chemotherapy sessions in the unit. In most of the participating units, there was room for further optimization of activity, potentially to reach 4.2 % of the total number of sessions. PMID- 30244984 TI - Hepatitis B Virus Infection and the Progress toward its Elimination. PMID- 30244985 TI - Associations of Neighborhood-Level Social Determinants of Health with Bacterial Infections in Young, Febrile Infants. AB - OBJECTIVE: To examine the sociodemographic characteristics of one population of young, febrile infants and identify associations between neighborhood-level social determinants of health (SDHs) with bacterial infections. STUDY DESIGN: This was a retrospective cross sectional study of all infants <=90 days old with a temperature of >=38 degrees C who presented in 2014 to the emergency department of an urban children's hospital in a large east coast city. The primary outcome was the presence of a bacterial infection, defined as a positive urine, blood, or cerebrospinal fluid culture that was treated clinically as a pathogen. The home address of each infant was geocoded and linked to neighborhood data based on census tract. Neighborhood-level SDHs included deprivation index, median household income, poverty, childhood poverty, social capital, and crowded housing. Associations were estimated using generalized estimating equations and negative binomial regression analysis. Models were adjusted for age, prematurity, and race/ethnicity. RESULTS: Of 232 febrile infants, the median age was 54 days, 58% were male, 49% were Hispanic, and 88% had public health insurance; 31 infants (13.4%) had a bacterial infection. In the adjusted analyses, the risk of bacterial infection among infants from neighborhoods with high rates of childhood poverty was >3 times higher (relative risk, 3.16; 95% CI, 1.04-9.6) compared with infants from neighborhoods with low rates of childhood poverty. CONCLUSIONS: Our findings suggest that SDHs may be associated with bacterial infections in young, febrile infants. If confirmed in subsequent studies, the inclusion of SDHs in predictive tools may improve accuracy in detecting bacterial infections among young, febrile infants. PMID- 30244986 TI - Social Adversity and Cognitive, Language, and Motor Development of Very Preterm Children from 2 to 5 Years of Age. AB - OBJECTIVE: To assess the extent to which social and family factors explain variability in cognitive, language, and motor development among very preterm (<30 weeks of gestation) children from 2 to 5 years of age. STUDY DESIGN: As part of a longitudinal study, very preterm children recruited as neonates were assessed at 2 (n = 87) and 5 (n = 83) years of age using standardized tests of cognitive, language, and motor ability alongside demographically matched full term (FT) children (n = 63). For very preterm children, developmental change scores were calculated for each domain to assess within-individual variability to 5 years of age. Multivariate regression and mixed-effect models examined social risk index, parenting stress, family functioning, and maternal intellectual ability as predictors of developmental variation among very preterm children. RESULTS: Very preterm children demonstrated poorer cognitive, language, and motor abilities than FT children at 2 (P <= .001) and 5 (P < .002) years of age. Social adversity was associated with cognitive (P < .001) and language (P < .001) outcomes at both ages, with parenting stress also related to cognitive outcomes (P = .03). Infant medical risk was associated with motor outcome at 5 years (P=.01). Very preterm children showed considerable within-individual variation between assessments. Among very preterm children, neonatal white matter abnormalities predicted worsening cognitive (P=.04) and motor development (P = .01). Social risk index predicted worsening language development (P = .04), but this association was subsequently explained by dysfunctional maternal affective involvement (P = .01) and lower maternal intellectual ability (P = .05). CONCLUSIONS: Both clinical and socioenvironmental factors are associated with cognitive, language, and motor developmental variation among very preterm children from infancy to early school age. PMID- 30244987 TI - Echocardiographic Measurements of Right Ventricular Mechanics in Infants with Bronchopulmonary Dysplasia at 36 Weeks Postmenstrual Age. AB - OBJECTIVE: To test the hypothesis that specific echocardiographic measurements of right ventricular (RV) mechanics at 36 weeks postmenstrual age (PMA) are associated with the severity of bronchopulmonary dysplasia (BPD). STUDY DESIGN: A subset of 93 preterm infants (born between 27 and 29 weeks of gestation) was selected retrospectively from a prospectively enrolled cohort. BPD was defined using the National Institutes of Health workshop definition, with modifications for oxygen reduction testing and altitude. The cohort was divided into no-BPD and BPD groups using previously published methodology for analyses. Echocardiographic measurements of RV function (ie, tricuspid annular plane systolic excursion, fractional area of change, systolic-to-diastolic ratio, tissue Doppler myocardial performance index, and RV strain), RV remodeling/morphology (end-systolic left ventricular eccentricity index), and RV afterload (pulmonary artery acceleration time measure) were evaluated at 36 weeks PMA. Multivariable logistic regression determined associations between RV measurements and BPD severity. RESULTS: Compared with the no-BPD cohort, the BPD group had lower birth weight z-scores (P = .04) and trended toward a male predominance (P = .08). After adjusting for birth weight z-score, gestational age, and sex, there were no between-group differences in echocardiographic measurements except for the eccentricity index (scaled OR [0.1-unit increase], 1.49; 95% CI, 1.13-2.12; P = .01). CONCLUSIONS: Among conventional and emerging echocardiographic measurements of RV mechanics, eccentricity index was the sole variable independently associated with BPD severity in this study. The eccentricity index may be a useful echocardiographic measurement for characterizing RV mechanics in patients with BPD at 36 weeks PMA. PMID- 30244989 TI - Use of Audio Computer-Assisted Self-Interviews to Gather Information on Risk Behaviors in a Population of Pregnant Adolescents. AB - In a prospective study comparing the use of the Audio Computer-Assisted Self Interview (ACASI) with a traditional clinical interview in 40 pregnant adolescents, there was significantly greater disclosure of violence with the ACASI method. Better identification of high-risk behaviors may help to optimize care and programing for pregnant adolescents. PMID- 30244990 TI - Major Depressive Disorder Screening Remains Low Even Among Privately Insured Adolescents. AB - OBJECTIVE: To determine if screening for major depressive disorder (MDD) increased in a national sample of privately insured adolescents following the US Preventive Services Task Force 2009 endorsement of universal screening for adolescent MDD. STUDY DESIGN: This was a retrospective cohort study of 12- to 14 year-old adolescents, continuously insured from 2010 to 2014 based on the MarketScan database. The primary outcome was the frequency of MDD screening, defined by International Classification of Diseases, Ninth Revision or Current Procedural Terminology code within the context of a well-visit. Multivariable analysis identified factors associated with MDD screening. RESULTS: Adolescents (n = 413 080) were 49% female and 89% urban, and 21% had a family history of depression. Adolescents averaged 2.9 +/- 1.6 well-visits during the 5-year study period. Of the cohort, 1.8% had MDD screening coded. Coding for MDD screening was more likely for urban residents (OR, 1.95; 95% CI, 1.69-2.25; P < .001), those with conduct disorder (OR, 1.37; 95% CI, 1.14-1.64; P < .001), and adolescents with more well visits (OR, 1.25; 95% CI, 1.21-1.31; P < .001). Coding for MDD screening was 96% less likely for those switching between multiple provider types for well-visits compared with pediatric providers. A family history of depression did not influence coding for MDD screening. CONCLUSIONS: MDD screening remains insufficient to address the youth mental health crisis. Furthermore, this study captures those adolescents most able to receive such services, given their continuous enrollment in private insurance. Disparities persist, with adolescents who are rural, less frequently seen, and with poor continuity of care less likely to receive screening. PMID- 30244988 TI - Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial. AB - OBJECTIVE: To investigate the impact of corticosteroid therapy on the growth of participants in the Steroids in Biliary Atresia Randomized Trial (START) conducted through the Childhood Liver Disease Research Network. The primary analysis in START indicated that steroids did not have a beneficial effect on drainage in a cohort of infants with biliary atresia. We hypothesized that steroids would have a detrimental effect on growth in these infants. STUDY DESIGN: A total of 140 infants were enrolled in START, with 70 randomized to each treatment arm: steroid and placebo. Length, weight, and head circumference were obtained at baseline and follow-up visits to 24 months of age. RESULTS: Patients treated with steroids had significantly lower length and head circumference z scores during the first 3 months post-hepatoportoenterostomy (HPE), and significantly lower weight until 12 months. Growth trajectories in the steroid and placebo arms differed significantly for length (P < .0001), weight (P = .009), and head circumference (P < .0001) with the largest impact noted for those with successful HPE. Growth trajectory for head circumference was significantly lower in patients treated with steroids irrespective of HPE status, but recovered during the second 6 months of life. CONCLUSIONS: Steroid therapy following HPE in patients with biliary atresia is associated with impaired length, weight, and head circumference growth trajectories for at least 6 months post-HPE, especially impacting infants with successful bile drainage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00294684. PMID- 30244992 TI - Staphylococcus aureus Bacteremia in Children Aged 5-18 Years-Risk Factors in the New Millennium. AB - OBJECTIVES: To assess the association between comorbidities and Staphylococcus aureus bacteremia in children aged 5-18 years, thus, in children with a matured immune system. Further, we aimed to identify presumably healthy children acquiring bacteremia. STUDY DESIGN: By cross-linking nationwide registries, we consecutively included all children born from 1995 onward at their 5-year birthday or date of immigration during 2000-2015. We examined incidence rate ratios (IRR) between preselected exposures and microbiologically verified S aureus bacteremia (reference = children without exposure) using Poisson regression models. RESULTS: We followed 1 109 169 children in 2000-2015 during which 307 children (incidence rate: 3.7 per 100 000 person-years) acquired S aureus bacteremia (methicillin-resistant S aureus = 8; 2.6%). Children without known comorbidities or recent contact with the healthcare system comprised 37.1% of infected children. The highest IRRs were observed in children undergoing dialysis or plasmapheresis (IRR = 367.2 [95% CI) = 188.5-715.3]), children with organ transplantation (IRR = 149.5 [95% CI = 73.9-302.2]), and children with cancer (IRR = 102.9 [95% CI = 74.4-142.2]). Positive associations also were observed in children with chromosomal anomalies (IRR = 7.16 [95% CI = 2.96 17.34]), atopic dermatitis (IRR = 4.89 [95% CI = 3.11-7.69]), congenital heart disease (IRR = 3.14 [95% CI = 1.92-5.11]), and in children undergoing surgery (IRR = 3.34 [95% CI = 2.59-4.28]). Neither premature birth nor parental socioeconomic status was associated with increased disease rates. CONCLUSIONS: S aureus bacteremia is uncommon in children between 5 and 18 years of age. Risk factors known from the adult population, such as dialysis, plasmapheresis, organ transplantation, and cancer, were associated with the highest relative rates. However, prematurity and parental socioeconomic status were not associated with increased rates. Approximately one-third of infected children were presumably healthy. PMID- 30244991 TI - Evaluation of Gentamicin Exposure in the Neonatal Intensive Care Unit and Hearing Function at Discharge. AB - OBJECTIVE: To characterize the association between gentamicin dosing, duration of treatment, and ototoxicity in hospitalized infants. STUDY DESIGN: This retrospective cohort study conducted at 330 neonatal intensive care units (2002 2014) included inborn infants exposed to gentamicin with available hearing screen results, and excluded infants with incomplete dosing data and major congenital anomalies. Our primary outcome was the final hearing screen result performed during hospitalization: abnormal (failed or referred for further testing in one or both ears) or normal (bilateral passed). The 4 measures of gentamicin exposure were highest daily dose, average daily dose, cumulative dose, and cumulative duration of exposure. We fitted separate multivariable logistic regression models adjusted for demographics, comorbidities, and other clinical events. RESULTS: A total of 84 808 infants met inclusion/exclusion criteria; median (25th, 75th percentile) gestational age and birth weight were 35 weeks (33, 38) and 2480 g (1890, 3184), respectively. Failed hearing screens occurred in 3238 (3.8%) infants; failed screens were more likely in infants of lower gestational age and birth weight, who had longer hospital lengths of stay, higher rates of morbidities, and were small for gestational age. Median highest daily dose, average daily dose, and cumulative dose were 4.0 mg/kg/day (3.0, 4.0), 3.8 mg/kg/day (3.0, 4.0), and 12.1 mg/kg (9.1, 20.5), respectively. Median cumulative duration of exposure was 3 days (3, 6). In adjusted analysis, gentamicin dose and duration of therapy were not associated with hearing screen failure. CONCLUSIONS: Gentamicin dosing and duration of treatment were not associated with increased odds of failed hearing screen at the time of discharge from initial neonatal intensive care unit stay. PMID- 30244993 TI - Guidance Document for Hepatic Hemangioma (Infantile and Congenital) Evaluation and Monitoring. AB - OBJECTIVE: To define the types of hepatic hemangiomas using the updated International Society for the Study of Vascular Anomalies classification and to create a set of guidelines for their diagnostic evaluation and monitoring. STUDY DESIGN: We used a rigorous, transparent consensus protocol defined by an approved methodology, with input from multiple pediatric experts in vascular anomalies from hematology-oncology, surgery, pathology, radiology, and gastroenterology. RESULTS: In the first section, we define the subtypes of hepatic hemangiomas based on the clinical course, histology, and radiologic characteristics. We recommend against using the term "hemangioma" for any vascular malformations affecting the liver or any hypervascular tumors that are not characterized by the approved definitions. We recommend against using the term "hemangioendothelioma" for infantile or congenital hemangioma. The following 2 sections dedicated to infantile hepatic hemangioma and to congenital hepatic hemangioma individually describe these subtypes in further detail, including complications to be considered during monitoring and respectively recommended screening evaluations. CONCLUSIONS: Although institutional variations may exist for specific clinical details, a clear understanding of the diagnosis of hepatic hemangiomas affecting children and the possible complications that require screening during the monitoring period should be standard. As children with hepatic hemangiomas are managed by different medical and surgical specialties, we offer an expert opinion multidisciplinary consensus based on current literature and on data extracted from the liver hemangioma registry. PMID- 30244994 TI - [Hypertensive urgencies: Description of clinical characteristics, management, variables associated with re-entry and short-term prognosis]. AB - OBJECTIVES: To describe the characteristics of hypertensive urgencies at the emergency department, as well as the variables associated with early re-admission (<7 days) and re-admission at one month (<30 days). METHODS: We conducted a descriptive, retrospective study of all patients who were admitted to the emergency department of a third level hospital during 2013. Subsequently, a case control analysis was performed to analyze the group of patients with readmission. RESULTS: A total of 398 hypertensive urgencies were collected (32.4% men, mean age 67.75 years), which led to an incidence of 3.28/1000 visits. Eighty point nine percent had a previous history of hypertension, and the mean Charlson Index was 2.23. Headache was the most frequent symptom (49.1%), followed by dizziness/instability (29.5%) and nausea/vomiting (17.1%). Eighty point seven percent of the patients were prescribed pharmacological treatment. The rates of cardiovascular events or mortality at one month were low (2.26% and 0.25% respectively). Despite this, 7.53% and 11.31% of patients were readmitted in under 7 days or 30 days, respectively. The variables associated with readmission in the multivariate analysis were elevated systolic blood pressure in the first determination, previous hypertension and the presence of palpitations. CONCLUSIONS: Hypertensive emergencies are high-incidence conditions in the Emergency Department. In our study, patients with a prior diagnosis of hypertension and elevated systolic blood pressure at the first determination had a higher risk of re-entry and would be candidates for closer follow-up on discharge. PMID- 30244995 TI - The role of bile leak testing in liver resection: a systematic review and meta analysis. AB - BACKGROUND: Bile leak following liver resection can be associated with significant morbidity. This systematic review and meta-analysis aims to evaluate the effect of intraoperative bile leak testing on postoperative bile leak rate and other complications after liver resection without biliary reconstruction for any cause. METHODS: PubMed, MEDLINE, Embase, Cochrane Library and grey literature databases were searched for articles between 1960 and 2017 comparing bile leak rates with or without bile leak testing. Standard meta-analysis methods were used. The primary outcome was bile leak rate, and secondary outcomes were overall morbidity, reintervention rate and length of stay. RESULTS: 8 articles met inclusion criteria. Intraoperative bile leak testing after resection was associated with lower postoperative bile leak rate (4.1% vs 12.3%, OR 0.36, 95% CI 0.23-0.55, p < 0.001), overall morbidity (OR 0.67, 95% CI 0.47-0.96, p = 0.030), need for reintervention (OR 0.11, 95% CI 0.03-0.36, p < 0.001) and a shorter duration of hospital stay (2.21 days, 95% CI 0.69-3.73, p = 0.004). CONCLUSION: The routine use of intraoperative bile leak testing during liver resection results in a significant reduction in postoperative bile leak rate, overall morbidity, length of hospital stay and need for re-intervention. Bile leak testing should be performed after liver resection without biliary reconstruction. PMID- 30244996 TI - Corrigendum to "Silicone-water partition coefficients determined by cosolvent method for chlorinated pesticides, musks, organo phosphates, phthalates and more" [Chemosphere 210 (2018) 662-671]. PMID- 30244997 TI - Anemia in Pregnancy Presenting as Acute Glossitis. PMID- 30244998 TI - Anemie gravidique se manifestant par une glossite aigue. PMID- 30244999 TI - Further evidence for the association between CMYA5 rs7714250 and schizophrenia in a Han Chinese population. PMID- 30245000 TI - Differences in overall survival and cancer-specific survival in high-risk prostate cancer patients according to the primary treatment. AB - INTRODUCTION AND OBJECTIVES: There is no high-level evidence as to which primary treatment provides an overall survival (OS) or cancer-specific survival (CSS) advantage in high-risk localised prostate cancer (HRLPC). Our aim was to analyse the differences in survival and predictive factors in this group of patients, according to their primary treatment (radical prostatectomy (RP) or radiotherapy and androgen blockade (RT+HT)). MATERIAL AND METHODS: A retrospective study of 286 HRLPC patients diagnosed between 1996-2008, treated by RP (n=145) or RT+HT(n=141). Survival was assessed using the Kaplan-Meier method. Significant differences between the different variables were analysed using the log-rank test. A uni and multivariate Cox regression analysis was performed to identify risk factors. RESULTS: the median follow-up was 117.5 (IQR 87-158) months. The OS was longer (p=.04) in the RP patients, while there were no differences (P=.44) in CSS between either group. The type of primary treatment was not related to OS or CSS. Age (P=.002), the onset during follow-up of a 2nd tumour (P=.0001), and stage cT3a (P=.009) behaved as independent predictive variables of OS. None of the variables behaved as an independent predictive variable of CSS, although biochemical recurrence after rescue treatment (P=.058), and the onset of a 2nd tumour during follow-up showed a significant trend to statistical significance, the latter reducing specific cancer mortality (HR .16, 95%CI .02-1.18, P=.07). CONCLUSIONS: Primary treatment did not relate to OS or CSS in patients with HRPC. PMID- 30245002 TI - Second primary cancer in people with HIV. PMID- 30245001 TI - Anaerobic biodegradation of pharmaceutical compounds coupled to dissimilatory manganese (IV) or iron (III) reduction. AB - Pharmaceuticals in water have adverse effects on aquatic environment. Anaerobic pharmaceutical biodegradation coupled to dissimilatory manganese(Mn) (IV)- or iron(Fe) (III)-oxides reduction is potentially efficient but unexplored. In this study, batch experiments were performed using different Mn(IV) and Fe(III) species with a microbial inoculum pre-cultivated with 15 mM chemically synthesized Mn(IV) and 10 mg L-1 metoprolol. Results show 26% caffeine and 52% naproxen are degraded with Mn(IV) as terminal electron acceptor and insignificant biodegradation for other pharmaceuticals tested. Reduction of Mn(IV) from drinking water treatment is coupled to anaerobic biodegradation of metoprolol and propranolol, resulting in removal efficiencies of 96% and 31%, respectively. The results indicate that adsorption contributes to the pharmaceutical removal during the first 10 days of incubation, while biodegradation is the main removal mechanism in the whole period. Fe(III) can also be used as electron acceptor in anaerobic pharmaceutical biodegradation. Over half of the added metoprolol is degraded with both chemically-synthesized Fe(III) and Fe(III)-citrate as terminal electron acceptors. However, this process did not occur when using Fe(III) from drinking water treatment or Fe(III)-based sorbents. This study indicates that anaerobic pharmaceutical biodegradation coupled to dissimilatory Mn(IV) or Fe(III) reduction is possible, and promising for application to cleaning wastewater treatment plant effluents. PMID- 30245003 TI - Preventive and therapeutic features of broadly neutralising monoclonal antibodies against HIV-1. AB - The viral plasticity and the vast diversity of HIV-1 circulating strains necessitates the identification of new approaches to control this global pandemic. New generation broadly neutralising monoclonal antibodies (bnMAbs) against the HIV-1 viral envelope protein (Env) can prevent virus acquisition, reduce viraemia, enhance immunity, and induce the killing of infected cells in animal models of HIV-1 infection. Most importantly, passively administered bnMAbs are effective at decreasing viraemia and delaying viral rebound in people chronically infected with HIV-1. Single antibody treatment is associated with the emergence of viral escape mutants, and virus suppression is not maintained in the long term. However, a combination of bnMAbs and bioengineered multivalent antibodies that target different sites on Env might increase the efficacy of immunotherapy, adding a new relevant tool for clinical use. The aim of this Review is to highlight the potential benefits of this novel prophylactic and therapeutic approach to fight HIV-1. PMID- 30245004 TI - Incidence of first and second primary cancers diagnosed among people with HIV, 1985-2013: a population-based, registry linkage study. AB - BACKGROUND: Cancer survivors are at increased risk for subsequent primary cancers. People living with HIV are at increased risk for AIDS-defining and non AIDS-defining cancers, but little is known about their risk of first versus second primary cancers. We identified first and second primary cancers that occurred in above population expected numbers among people diagnosed with HIV in San Francisco, and compared first and second cancer incidence across five time periods that corresponded to important advances in antiretroviral therapy. METHODS: In this population-based study, we used the San Francisco HIV/AIDS case registry to identify people aged 16 years and older who were diagnosed with HIV/AIDS in San Francisco (CA, USA) between Jan 1, 1990, and Dec 31, 2010. We computer-matched records from the registry with the California Cancer Registry to identify primary cancers diagnosed between Jan 1, 1985, and Dec 31, 2013. We calculated year, age, sex, and race adjusted standardised incidence ratios with exact 95% CIs and trends in incidence of first and second AIDS-defining and non AIDS-defining cancers from 1985 to 2013. FINDINGS: Of the 22 623 people diagnosed with HIV between Jan 1, 1990, and Dec 31, 2010, we identified 5655 incident primary cancers. We excluded 48 cancers with invalid cancer sequence numbers and 1062 in-situ anal cancers, leaving 4545 incident primary cancers, comprising 4144 first primary cancers, 372 second primary cancers, 26 third primary cancers, and three fourth or later primary cancers. First primary cancer standardised incidence ratios were elevated for Kaposi sarcoma (127, 95% CI 121-132), non Hodgkin lymphoma (17.2, 16.1-18.4), invasive cervical cancer (8.0, 4.1-11.9), anal cancer (46.7, 39.7-53.6), vulvar cancer (13.3, 6.1-20.6), Hodgkin's lymphoma (10.4, 8.4-12.5), eye and orbit cancer (4.2, 1.4-6.9), lip cancer (3.8, 1.3-6.2), penile cancer (3.8, 1.4-6.1), liver cancer (3.0, 2.3-3.7), miscellaneous cancer (2.3, 1.7-3.0), testicular cancer (2.0, 1.4-2.6), tongue cancer (1.9, 1.1-2.7), and lung cancer (1.3, 95% CI 1.1-1.6). Second primary cancer risks were increased for Kaposi sarcoma (28.0, 95% CI 20.2-35.9), anal cancer (17.0, 10.2-23.8), non Hodgkin lymphoma (11.1, 9.3-12.8), Hodgkin's lymphoma (5.4, 1.1-9.7), and liver cancer (3.6, 1.4-5.8). We observed lower first primary cancer standardised incidence ratios for prostate cancer (0.6, 95% CI 0.5-0.7), colon cancer (0.6, 0.4-0.8), and pancreatic cancer (0.6, 0.3-1.0), and lower second primary cancer standardised incidence ratios for testicular cancer (0.3, 0.0-0.9), kidney cancer (0.4, 0.0-0.9), and prostate cancer (0.6, 0.2-0.9). First and second primary AIDS defining cancer incidence declined, and second primary non-AIDS-defining cancer incidence increased over time. INTERPRETATION: Because of an increased risk for both first and second primary cancers, enhanced cancer prevention, screening, and treatment efforts are needed for people living with HIV both before and after initial cancer diagnosis. FUNDING: University of California San Francisco and US Centers for Disease Control and Prevention. PMID- 30245006 TI - Design, synthesis, and biological evaluation of novel selective peptide inhibitors of 11beta-hydroxysteroid dehydrogenase 1. AB - The enzyme 11beta-HSD1 plays a crucial role in the tissue-specific regulation of cortisol levels and it has been associated with various diseases. Inhibition of 11beta-HSD1 is an attractive intervention strategy and the discovery of novel selective 11beta-HSD1 inhibitors is of high relevance. In this study, we identified and evaluated a new series of selective peptide 11beta-HSD1 inhibitors with potential for skin care applications. This novel scaffold was designed with the aid of molecular modeling and two previously reported inhibitors. SAR optimization yielded highly active peptides (IC50 below 400 nM) that were inactive at 1 uM concentration against structurally related enzymes (11beta-HSD2, 17beta-HSD1 and 17beta-HSD2). The best performing peptides inhibited the conversion of cortisone into cortisol in primary human keratinocytes and the most active compound, 5d, was further shown to reverse cortisone-induced collagen damage in human ex-vivo tissue. PMID- 30245005 TI - Management of Acute Contrast Reactions-Understanding Radiologists' Preparedness and the Efficacy of Simulation-Based Training in Canada. AB - PURPOSE: Acute radiologic emergencies, primarily severe contrast reactions, are rare but life-threatening events. Given a generalized paucity of formalized or mandated training, studies have shown that radiologists and trainees perform poorly when acutely managing such events. Moreover, skill base, knowledge, and comfort levels precipitously decline over time given the infrequent occurrence of these events during one's daily practice. The primary aim of this study was to assess radiologists' preparedness for managing acute radiologic emergencies and to determine the efficacy of a high-fidelity simulation based training model in an effort to provide a rationale for similar programs to be implemented on a provincial or national level. METHODS: This was a prospective, observational study of radiology residents and attending radiologists throughout the province who were recruited to attend a full-day simulation-based course presenting various cases of acute radiologic emergencies. Participant demographics were collected at the time of commencement of the workshop. Course materials were disseminated 4 weeks prior to the workshop, and a 17-question knowledge quiz was administered before and after the workshop. Likert-type questionnaires were also distributed to survey comfort levels and equipment familiarity. The knowledge quiz and questionnaire were redistributed at 3- and 6-month intervals for acquisition of follow-up data. RESULTS: A total of 14 attending radiologists and 7 residents attended the workshop, with all participants completing the preworkshop questionnaire and 90.5% (19 of 21) completing the post-workshop questionnaire. Participants' principle locations of practice were as follows: academic institutions (50%), community hospitals (36.9%), and private clinics (13.1%). A significant increase in knowledge was demonstrated, with average scores of 10 out of 17 (59%) and 14.5 out of 17 (85%) (P < .001) before and after the workshop, respectively. A significant increase in participants' comfort levels in recognizing acute anaphylactic reactions (3.5; 4.7, P < .001), commencing initial management for acute radiologic emergencies (3.3; 5.0, P < .001), and administering the correct dose for anaphylactic reactions (2.5; 4.8, P < .001) was also demonstrated. Moreover, participants became increasingly familiar with the contents and equipment found within contrast reaction kits (2.8; 3.8, P < .01). Repeat evaluations at 3 and 6 months found an average knowledge test score of 13.8 out of 17 (81%) and 10.8 out of 17 (64%), respectively. Comfort levels were also reassessed in recognizing acute anaphylactic reactions (4.5; 4.1), commencing initial management (4.0; 3.9) and administering the correct dose of medication (4.0; 3.7) at 3- and 6-month intervals. CONCLUSIONS: Acute radiologic emergencies are rare but life threatening events that require rapid diagnosis and treatment to mitigate associated morbidity and mortality. Simulation-based workshops are a highly efficacious training model to increase knowledge, comfort levels, and equipment familiarity for radiologists and trainees alike; however, retraining at regular intervals is required. PMID- 30245007 TI - Dietary, immunological, surgical, and other emerging treatments for pediatric refractory status epilepticus. AB - PURPOSE: To summarize the evidence regarding dietary, immunological, surgical, and other emerging treatments for refractory status epilepticus (RSE)/super-RSE (SRSE). METHODS: Narrative literature review including relevant human studies. RESULTS: Hypothermia and brenaxolone were tested in randomized controlled trials for RSE/SRSE management, while other interventions have only limited evidence for their efficacy and safety. Clinical trials including the HYBERNATUS study found the efficacy of therapeutic hypothermia to be no better than placebo for RSE/SRSE, and raised concerns about its safety. Ketogenic diet has shown possible efficacy in RSE/SRSE in several case series, with electrographic seizure resolution within 7 days in 20%-90% patients in larger (n = 8-17) reports. A review of 37 pediatric patients reported seizure control with immunotherapy in only 7 patients. A phase 3 double-blind trial showed that brexanolone was no better than placebo for successful wean of 3rd line anesthetic agent(s) and freedom from RSE for >=24 hours. Epilepsy surgery has been reported to successfully control seizures in small series; however, pre-surgical evaluation is confounded by ongoing ictal activity and anesthetic infusions. Vagus nerve stimulation was reported to be associated with cessation of RSE/SRSE in 21/28 patients in a review of anecdotal reports. There is no evidence for use of pyridoxine and magnesium outside of specific indications. CONCLUSIONS: There is only anecdotal evidence for dietary, immunological, surgical, and other treatments for RSE/SRSE, often confounded by multiple concurrent treatments, and heterogeneity in their use and assessment of outcomes. Clinical trials for therapeutic hypothermia and brexanolone have not shown a significant advantage over comparators. PMID- 30245008 TI - LC3-Associated Phagocytosis in Myeloid Cells Promotes Tumor Immune Tolerance. AB - Targeting autophagy in cancer cells and in the tumor microenvironment are current goals of cancer therapy. However, components of canonical autophagy play roles in other biological processes, adding complexity to this goal. One such alternative function of autophagy proteins is LC3-associated phagocytosis (LAP), which functions in phagosome maturation and subsequent signaling events. Here, we show that impairment of LAP in the myeloid compartment, rather than canonical autophagy, induces control of tumor growth by tumor-associated macrophages (TAM) upon phagocytosis of dying tumor cells. Single-cell RNA sequencing (RNA-seq) analysis revealed that defects in LAP induce pro-inflammatory gene expression and trigger STING-mediated type I interferon responses in TAM. We found that the anti tumor effects of LAP impairment require tumor-infiltrating T cells, dependent upon STING and the type I interferon response. Therefore, autophagy proteins in the myeloid cells of the tumor microenvironment contribute to immune suppression of T lymphocytes by effecting LAP. PMID- 30245009 TI - Acetate Production from Glucose and Coupling to Mitochondrial Metabolism in Mammals. AB - Acetate is a major nutrient that supports acetyl-coenzyme A (Ac-CoA) metabolism and thus lipogenesis and protein acetylation. However, its source is unclear. Here, we report that pyruvate, the end product of glycolysis and key node in central carbon metabolism, quantitatively generates acetate in mammals. This phenomenon becomes more pronounced in the context of nutritional excess, such as during hyperactive glucose metabolism. Conversion of pyruvate to acetate occurs through two mechanisms: (1) coupling to reactive oxygen species (ROS) and (2) neomorphic enzyme activity from keto acid dehydrogenases that enable function as pyruvate decarboxylases. Further, we demonstrate that de novo acetate production sustains Ac-CoA pools and cell proliferation in limited metabolic environments, such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. By virtue of de novo acetate production being coupled to mitochondrial metabolism, there are numerous possible regulatory mechanisms and links to pathophysiology. PMID- 30245011 TI - Human Rad52 Promotes XPG-Mediated R-loop Processing to Initiate Transcription Associated Homologous Recombination Repair. AB - Given that genomic DNA exerts its function by being transcribed, it is critical for the maintenance of homeostasis that DNA damage, such as double-strand breaks (DSBs), within transcriptionally active regions undergoes accurate repair. However, it remains unclear how this is achieved. Here, we describe a mechanism for transcription-associated homologous recombination repair (TA-HRR) in human cells. The process is initiated by R-loops formed upon DSB induction. We identify Rad52, which is recruited to the DSB site in a DNA-RNA-hybrid-dependent manner, as playing pivotal roles in promoting XPG-mediated R-loop processing and initiating subsequent repair by HRR. Importantly, dysfunction of TA-HRR promotes DSB repair via non-homologous end joining, leading to a striking increase in genomic aberrations. Thus, our data suggest that the presence of R-loops around DSBs within transcriptionally active regions promotes accurate repair of DSBs via processing by Rad52 and XPG to protect genomic information in these critical regions from gene alterations. PMID- 30245010 TI - Integration of Parallel Opposing Memories Underlies Memory Extinction. AB - Accurately predicting an outcome requires that animals learn supporting and conflicting evidence from sequential experience. In mammals and invertebrates, learned fear responses can be suppressed by experiencing predictive cues without punishment, a process called memory extinction. Here, we show that extinction of aversive memories in Drosophila requires specific dopaminergic neurons, which indicate that omission of punishment is remembered as a positive experience. Functional imaging revealed co-existence of intracellular calcium traces in different places in the mushroom body output neuron network for both the original aversive memory and a new appetitive extinction memory. Light and ultrastructural anatomy are consistent with parallel competing memories being combined within mushroom body output neurons that direct avoidance. Indeed, extinction-evoked plasticity in a pair of these neurons neutralizes the potentiated odor response imposed in the network by aversive learning. Therefore, flies track the accuracy of learned expectations by accumulating and integrating memories of conflicting events. PMID- 30245013 TI - Functional Genetic Variants Revealed by Massively Parallel Precise Genome Editing. AB - A major challenge in genetics is to identify genetic variants driving natural phenotypic variation. However, current methods of genetic mapping have limited resolution. To address this challenge, we developed a CRISPR-Cas9-based high throughput genome editing approach that can introduce thousands of specific genetic variants in a single experiment. This enabled us to study the fitness consequences of 16,006 natural genetic variants in yeast. We identified 572 variants with significant fitness differences in glucose media; these are highly enriched in promoters, particularly in transcription factor binding sites, while only 19.2% affect amino acid sequences. Strikingly, nearby variants nearly always favor the same parent's alleles, suggesting that lineage-specific selection is often driven by multiple clustered variants. In sum, our genome editing approach reveals the genetic architecture of fitness variation at single-base resolution and could be adapted to measure the effects of genome-wide genetic variation in any screen for cell survival or cell-sortable markers. PMID- 30245012 TI - A Neural Circuit for Gut-Induced Reward. AB - The gut is now recognized as a major regulator of motivational and emotional states. However, the relevant gut-brain neuronal circuitry remains unknown. We show that optical activation of gut-innervating vagal sensory neurons recapitulates the hallmark effects of stimulating brain reward neurons. Specifically, right, but not left, vagal sensory ganglion activation sustained self-stimulation behavior, conditioned both flavor and place preferences, and induced dopamine release from Substantia nigra. Cell-specific transneuronal tracing revealed asymmetric ascending pathways of vagal origin throughout the CNS. In particular, transneuronal labeling identified the glutamatergic neurons of the dorsolateral parabrachial region as the obligatory relay linking the right vagal sensory ganglion to dopamine cells in Substantia nigra. Consistently, optical activation of parabrachio-nigral projections replicated the rewarding effects of right vagus excitation. Our findings establish the vagal gut-to-brain axis as an integral component of the neuronal reward pathway. They also suggest novel vagal stimulation approaches to affective disorders. PMID- 30245014 TI - Evolutionary Pressure against MHC Class II Binding Cancer Mutations. AB - The anti-cancer immune response against mutated peptides of potential immunological relevance (neoantigens) is primarily attributed to MHC-I-restricted cytotoxic CD8+ T cell responses. MHC-II-restricted CD4+ T cells also drive anti tumor responses, but their relation to neoantigen selection and tumor evolution has not been systematically studied. Modeling the potential of an individual's MHC-II genotype to present 1,018 driver mutations in 5,942 tumors, we demonstrate that the MHC-II genotype constrains the mutational landscape during tumorigenesis in a manner complementary to MHC-I. Mutations poorly bound to MHC-II are positively selected during tumorigenesis, even more than mutations poorly bound to MHC-I. This emphasizes the importance of CD4+ T cells in anti-tumor immunity. In addition, we observed less inter-patient variation in mutation presentation for MHC-II than for MHC-I. These differences were reflected by age at diagnosis, which was correlated with presentation by MHC-I only. Collectively, our results emphasize the central role of MHC-II presentation in tumor evolution. PMID- 30245015 TI - New technical method to correct secondary vermilion deformities with cleft lip. AB - Various techniques for correcting whistling deformities that occurred after primary surgery for cleft lip have been reported. These techniques are mainly intended to correct the lack of volume of the red lip. However, irregularity of the dry-wet lip junction (mucocutaneous junction) in the red lip has rarely been mentioned. If the wet lip is located in an exposed area, not only is the aesthetic appearance poor but also uncomfortable complications such as a crusted or bleeding lip repeatedly occur under a dry condition. A new technique for correcting the irregular line of the dry-wet lip junction is described in this report. The technique is simple. After removal of the exposed wet lip, flaps are designed on both dry lip sides of the defect as M-W-M plasty and are transposed toward the defect. The dog-ears are small; the scar is inconspicuous because it is incorporated with the wrinkle line, and scar contracture is prevented. In addition, more soft tissues may be included to correct a mild whistling deformity. PMID- 30245016 TI - Shear-wave elastography in the diagnosis of ulnar tunnel syndrome. AB - An interesting alternative to traditional diagnostic techniques of the upper extremity nerve entrapments might be an ultrasound elastography that has started to gain attention in recent research. The aim of this preliminary study was to verify whether a quantitative analysis of the ulnar nerve stiffness by shear-wave elastography can be used to diagnose ulnar tunnel syndrome (UTS), an ulnar nerve neuropathy at Guyon's canal. The study included 46 patients (39 women) and 39 healthy controls (34 women). All diagnoses in patients and controls were confirmed with nerve conduction studies. Measurements of nerve stiffness were taken at three levels: Guyon's canal (G), distal forearm (DF), and mid forearm (MF). Additionally, the ulnar nerve cross-sectional area at the canal's level was determined by ultrasonography. Patients with UTS presented with significantly greater nerve stiffness than the controls (mean, 99.41 kPa vs. 49.08 kPa, P < 0.001). No significant intergroup differences were found in the nerve elasticity at DF and MF levels (P < 0.836 and P < 0.881, respectively). An ulnar nerve stiffness value of 80 kPa and G:DF and G:MF ratios equal to 1.5 provided 100% sensitivity, specificity, and positive and negative predictive values in the detection of the syndrome. The mean nerve cross-sectional area in the Guyon's canal was significantly greater in patients than in the controls (4.63 mm2, range, 2-7 mm2 vs. 3.23 mm2, range, 2-5 mm2, P < 0.001). In conclusion, we believe that shear-wave elastography has the potential to become a useful adjunct diagnostic test for UTS. PMID- 30245017 TI - Consensus research priorities for facial palsy: A Delphi survey of patients, carers, clinicians and researchers. AB - Despite the potential negative impact of facial palsy, major gaps in understanding persist surrounding the treatment and care of those affected. This collaborative three-round Delphi process aimed to identify priorities for future facial palsy research, from the perspective of clinicians, researchers, patients and carers. It also determined whether the research priorities of patients and carers aligned with those of health professionals and researchers. In Round 1, participants (n = 85) were asked to generate research questions by focus groups or an online or postal survey. In Rounds 2 (n = 72) and 3 (n = 78), participants were asked to rate the priorities identified on a 5-point ordinal scale. Thirty six questions reached the definition of 'high priority' consensus. Seven of each groups' top ten research priorities were shared. Prioritised questions included the provision and pathways of care, the psychosocial impact of living with facial palsy and the effective management of side effects. Establishing the research priorities in the field of facial palsy is a significant first step in ensuring that the future research agenda is focussed on topics that are considered important by both patients and health professionals. PMID- 30245018 TI - Upper blepharoplasty revision technique: Correction of the high eyelid fold using the pretarsal orbicularis oculi flap. AB - PURPOSE: With the growing popularity of upper lid blepharoplasty, there have been increasing reports of unsatisfactory outcomes that have necessitated a revision surgery. This study aimed to evaluate aesthetic outcomes of surgical correction of the high eyelid fold using a pretarsal orbicularis oculi flap and to highlight the key practice points of this surgical procedure in secondary blepharoplasty. METHODS: A retrospective study of 31 consecutive Chinese patients who underwent revision surgeries between January 2013 and December 2015 was undertaken through a review of medical records. All these patients underwent surgical correction of high eyelid folds using a pretarsal orbicularis oculi flap, with postoperative follow-up ranging from 6 months to 4 years. Postoperative outcomes were reviewed, evaluated, and analyzed. RESULTS: In this study of 31 women who underwent secondary revision procedure of the high eyelid fold using a pretarsal orbicularis oculi muscle flap, mean follow-up time was 8.2 (range 6-48) months. All flaps survived without significant complications. There was no reported incidence of hematoma or infection in early postoperative complications. Clinical effectiveness was satisfactory in most of the patients who underwent fold repair (26/31, 83.9%). However, five patients (16.1%) expressed dissatisfaction with postoperative outcomes; of them, four patients (12.9%) had mild asymmetry, whereas surgical revision was required in only one patient (3.2%). CONCLUSION: Secondary blepharoplasty to correct the high eyelid fold is a challenging procedure for plastic surgeons. Use of the pretarsal orbicularis oculi muscle flap for correction of the high eyelid fold is safe and effective, with better biomechanics and a satisfying aesthetic outcome. This provides a novel treatment option in limited secondary revision techniques. PMID- 30245019 TI - Efficacy of breast reconstruction with fat grafting: A systematic review and meta analysis. AB - BACKGROUND: Breast reconstruction with fat grafting is a new alternative to prosthetic implants and flaps for women with breast cancer. In this study, we investigate the efficacy of fat grafting for breast reconstruction in a meta analysis. METHODS: The study followed the PRISMA and MOOSE guidelines for systematic reviews and meta-analyses. Studies were included if the patients underwent complete breast reconstruction with fat grafting as the only treatment modality. The number of fat grafting treatments needed to complete a breast reconstruction was modeled in a meta-analysis for five treatment categories: modified radical mastectomy, skin-sparing mastectomy, and breast-conserving surgery; the two mastectomy groups were subdivided into nonirradiated and irradiated. RESULTS: Twenty-one studies were included in the meta-analysis. The studies comprised 1011 breast reconstructions in 834 patients. The estimated numbers of treatments to complete a reconstruction were 2.84-4.66 in the mastectomy groups and 1.72 in the breast-conserving surgery group. The number of fat grafting sessions needed to complete a breast reconstruction was significantly higher for the irradiated patients than for the nonirradiated patients (p < 0.05). There was no significant difference in the number of fat grafting sessions needed to complete a breast reconstruction after a modified radical mastectomy versus a skin-sparing mastectomy. CONCLUSIONS: This study provides an evidence-based foundation for several practical issues related to breast reconstruction with fat grafting. The analysis showed that radiotherapy is the most important factor associated with the number of treatment sessions needed to complete a breast reconstruction and with the rate of complications. PMID- 30245020 TI - The surgical anatomy of the superficial and deep palmar arches: A Meta-analysis. AB - INTRODUCTION: The following study aimed to find the pooled prevalence estimate of anatomical variations in the palmar vasculature, namely the superficial palmar arch (SPA) and the deep palmar arch (DPA). The importance of understanding the vasculature of the hand has become critical with the increasing use of hand microsurgery. METHODS: Major online medical databases (PubMed, EMBASE, ScienceDirect, and Web of Science) were extensively searched for terms pertaining to the SPA, the DPA, and their anatomy and variations. Articles reporting data on the SPA and/or the DPA were collected and their data extracted. Furthermore, a reference search was performed, allowing to pinpoint any articles that were not previously found. The collected data were analyzed using MetaXL 5.3. RESULTS: The analysis included 36 studies (n = 4841 palmar arches). The SPA was found to be complete in 81.3% of cases, with the radioulnar anastomosis being the most common variant (72.0%). The incomplete SPA was present in 18.7% of cases, with the ulnar artery supplying the third finger from both radial and ulnar side as the most prevalent in 34.8%. The DPA was found to be complete in 95.2% of cases. CONCLUSION: In this study, the SPA was predominantly complete, with the anastomosis between the radial and the ulnar artery being most prevalent. Furthermore, the DPA was also complete in the vast majority of cases. The palmar arches and their variations should be kept in mind when considering the use of palmar vasculature for cardiac catheterization and other medical procedures, due to the risk of iatrogenic ischemic hand complications. PMID- 30245021 TI - Indirect calorimetry in critically ill mechanically ventilated patients: Comparison of E-sCOVX with the deltatrac. AB - BACKGROUND & AIMS: Indirect calorimetry is recommended to measure energy expenditure (EE) in critically ill, mechanically ventilated patients. The most validated system, the Deltatrac(r) (Datex-Ohmeda, Helsinki, Finland) is no longer in production. We tested the agreement of a new breath-by-breath metabolic monitor E-sCOVX(r) (GE healthcare, Helsinki, Finland), with the Deltatrac. We also compared the performance of the E-sCOVX to commonly used predictive equations. METHODS: We included mechanically ventilated patients eligible to undergo indirect calorimetry. After a stabilization period, EE was measured simultaneously with the Deltatrac and the E-sCOVX for 2 h. Agreement and precision of the E-sCOVX was tested by determining bias, limits of agreement and agreement rates compared to the Deltatrac. Performance of the E-sCOVX was also compared to four predictive equations: the 25 kcal/kg, Penn State University 2003b, Faisy, and Harris-Benedict equation. RESULTS: We performed 29 measurements in 16 patients. Mean EE-Deltatrac was 1942 +/- 274 kcal/day, and mean EE-E-sCOVX was 2177 +/- 319 kcal/day (p < 0.001). E-sCOVX overestimated EE with a bias of 235 +/- 149 kcal/day, being 12.1% of EE-Deltatrac. Limits of agreement were -63 to +532 kcal/day. The 10% and 15% agreement rates of EE-E-sCOVX compared to the Deltatrac were 34% and 72% respectively. The bias of E-sCOVX was lower than the bias of the 25 kcal/kg-equation, but higher than bias of the other equations. Agreement rates for E-sCOVX were similar to the equations. The Faisy-equation had the highest 15% agreement rate. CONCLUSION: The E-sCOVX metabolic monitor is not accurate in estimating EE in critically ill mechanically ventilated patients when compared to the Deltatrac, the present reference method. The E-sCOVX overestimates EE with a bias and precision that are clinically unacceptable. PMID- 30245022 TI - Coital Incontinence in Women With Urinary Incontinence: An International Study. AB - INTRODUCTION: Coital urinary incontinence (CUI) is not much explored during clinical history, and this could lead to an underestimation of the problem. AIM: To evaluate the prevalence and clinical risk factors of CUI in women with urinary incontinence (UI), and to measure the impact of CUI on women's sexuality and quality of life. METHODS: This was a multicenter international study, conducted in Italy, Greece, the United States, and Egypt. Inclusion criteria were: sexually active women with UI and in a stable relationship for at least 6 months. Exclusion criteria were: age <18 years and unstable relationship. The UI was classified as stress UI (SUI), urgency UI (UUI), and mixed UI (MUI). Women completed a questionnaire on demographics and medical history, in particular on UI and possible CUI and the timing of its occurrence, and the impact of CUI on quality and frequency of their sexual life. MAIN OUTCOME MEASURES: To evaluate the CUI and its impact on sexual life we used the open questions on CUI as well as the International Consultation on Incontinence questionnaire and Patient Perception of Bladder Condition questionnaire. RESULTS: In this study 1,041 women (age 52.4 +/- 10.7 years) were included. In all, 53.8% of women had CUI: 8% at penetration, 35% during intercourse, 9% at orgasm, and 48% during a combination of these. Women with CUI at penetration had a higher prevalence of SUI, women with CUI during intercourse had higher prevalence of MUI with predominant SUI, and women with CUI at orgasm had higher prevalence of UUI and MUI with predominant UUI component. Previous hysterectomy was a risk factor for CUI during any phase, while cesarean delivery was a protective factor. Previous failed anti UI surgery was a risk factor for CUI during penetration and intercourse, and body mass index >25 kg/m2 was a risk factor for CUI at intercourse. According to International Consultation on Incontinence questionnaire scores, increased severity of UI positively correlated with CUI, and had a negative impact on the quality and frequency of sexual activity. CLINICAL IMPLICATIONS: This study should encourage physicians to evaluate the CUI; in fact, it is an underestimated clinical problem, but with a negative impact on quality of life. STRENGTHS & LIMITATIONS: The strength of this study is the large number of women enrolled, while the limitation is its observational design. CONCLUSION: CUI is a symptom that can affect sexual life and should be investigated during counseling in all patients who are referred to urogynecological centers. Illiano E, Mahfouz W, Giannitsas K, et al. Coital Incontinence in Women With Urinary Incontinence: An International Study. J Sex Med 2018;15:1456-1462. PMID- 30245023 TI - The Mediating Role of Sexual Behavior in Event-Level Associations Between Sexual Difficulties and Sexual Satisfaction in Newlywed Mixed-Sex Couples. AB - INTRODUCTION: Many sexual difficulties encountered by couples in their day-to-day lives, although of insufficient intensity and persistence to warrant a clinical diagnosis of sexual disorder, are nevertheless frequent and a source of individual and relational distress. AIM: The aim of this study was to assess the event-level associations between couples' everyday, subclinical sexual difficulties (specifically, low subjective sexual arousal, low physiological sexual arousal, and genito-pelvic pain), the range of sexual behaviors that these couples engage in, and their sexual satisfaction. METHODS: 70 Newlywed participants (35 couples, average age = 25.6 years, SD = 3.2 years; average duration of relationship = 5.4 years, SD = 3.4 years) individually completed daily diaries about sexual difficulties, range of activities performed during sex, and sexual satisfaction over the course of 5 weeks. Analyses were guided by the actor-partner interdependence model. MAIN OUTCOME MEASURE: The main outcome was sexual satisfaction, measured at the event-level on a 5-point Likert scale using a single-item question. RESULTS: On days of sexual activity, men and women's difficulties with subjective sexual arousal were associated with lower sexual satisfaction in both partners (actor and partner effects). This association was mediated by the range of couples' sexual behaviors, such that lower subjective arousal was associated with a more restricted range of sexual activities, which in turn was associated with lower sexual satisfaction. Men's and women's difficulties with physiological sexual arousal, and women's genito pelvic pain, were each associated with their own lower sexual satisfaction. No partner effects were observed for these sexual difficulties, nor were they mediated by the range of couples' sexual activities. CLINICAL IMPLICATIONS: The study's results highlight how couples' sexual difficulties can interfere with same-day sexual satisfaction, and how for subjective sexual arousal, this interference is reflected by a more restricted range of sexual behaviors. STRENGTH & LIMITATIONS: Strengths of the study include the daily diary methodology, which allowed a focus on event-level sexual activities with minimal retrospective bias. Further, the dyadic analyses allowed both intra-individual and inter-individual effects to be assessed. Limitations include the lack of a more general measure of sexual desire and of a more diverse sample, in terms of age, race, and sexual orientation. CONCLUSION: These findings underscore the importance of treatments that include both partners, and that target the types as well as range of sexual activities in which couples engage. Jodouin J-F, Bergeron S, Janssen E. The Mediating Role of Sexual Behavior in Event-Level Associations Between Sexual Difficulties and Sexual Satisfaction in Newlywed Mixed-Sex Couples. J Sex Med 2018;15:1384-1392. PMID- 30245024 TI - Successful Aging and Changes in Sexual Interest and Enjoyment Among Older European Men and Women. AB - INTRODUCTION: Despite the popularity and analytical relevance of the concept of successful aging, little efforts have been made to address its relationship to sexuality in older individuals. AIM: To explore the relationship between successful aging and the (retrospectively assessed) change in sexual interest and enjoyment in the past 10 years, using a new multidimensional model of successful aging. METHODS: The data for this study was collected in 2016 using national probability-based surveys in four European countries (Norway, Denmark, Belgium and Portugal). In total, information from 2,461 sexually active and inactive participants aged 60-75 years was used for analyses. Multigroup structural equation analysis was employed to address the associations between key constructs. MAIN OUTCOME MEASURE: The dependent variable was a composite (two item) indicator of change in sexual interest and enjoyment in the past 10 years; a multifaceted model of successful aging predicted the change by country and gender. RESULTS: Tested cross-culturally, the proposed model of successful aging demonstrated a good fit to the data. Furthermore, its metric characteristics enabled direct comparisons across gender and national cultures. Controlling for sociodemographic characteristics, higher successful aging scores were consistently related to lower reduction in sexual interest/enjoyment among men and women across the 4 countries. CLINICAL IMPLICATIONS: Given an increased life expectancy and focus on healthy aging in many countries, the findings about the associations between sexual expression, quality of life and aging well are valuable to professionals working in the area of healthy sexual aging. STRENGTH & LIMITATIONS: This is the first study to systematically address the relationship between successful aging and sexuality. Furthermore, it provides a multidimensional measure of successful aging for a wide range of sexologic studies. Among limitations, possible self-selection bias (toward more sexually permissive and sexually active participants) and the fact that the findings are restricted to older heterosexual individuals, should be considered. CONCLUSION: Without stigmatizing the absence of sexual expression in aging individuals, the findings from this cross-cultural study point out that sustained sexual interest and sexual enjoyment are linked to successful aging in both genders. Stulhofer A, Hinchliff S, Jurin T, Hald GM, Traeen B. Successful Aging and Changes in Sexual Interest and Enjoyment Among Older European Men and Women. J Sex Med 2018;15:1393 1402. PMID- 30245025 TI - Sildenafil 25 mg ODT + Collagenase Clostridium hystoliticum vs Collagenase Clostridium hystoliticum Alone for the Management of Peyronie's Disease: A Matched-Pair Comparison Analysis. AB - INTRODUCTION: The effectiveness of phosphodiesterase type 5 (PDE5) inhibitors over the conservative management of Peyronie's disease (PD) has been widely questioned. AIM: To determine the role of sildenafil 25 mg film formulation twice a day (S25 b.i.d.) in the improvement of curvature after treatment of collagenase of Clostridium hystoliticum (CCH) in penile curvature owing to PD. METHODS: From April 2017 to April 2018, 161 consecutive patients were treated with S25 b.i.d. + CCH or CCH alone. Adjustment variables consisted of age, penile curvature, and the 15-question International Index of Erectile Function (IIEF-15) questionnaire at baseline using 1:1 propensity-score matching. Overall, 50 patients were considered subdivided into the following: 25 patients who received S25 b.i.d. + CCH (group A) and 25 who received CCH alone (group B). Patients received CCH injection using a shortened protocol and vacuum device in both groups. MAIN OUTCOME MEASURE: The primary outcome of the study was the change in penile curvature after treatment, and secondary outcomes were the change in sexual function (IIEF-15) and in the Peyronie's Disease Questionnaire (PDQ) and its subscores, PDQ-PS (psychosexual symptoms), PDQ-PP (penile pain), and PDQ-SB (symptom bother). RESULTS: Overall, mean penile curvature was 47.0 degrees (SD 21.88), the mean IIEF-EF (erectile function) was 23.56 (SD 4.10), and the mean PDQ was 27.06 (SD 13.55). After the treatment, we observed a mean change for penile curvature of 25.6 (SD 9.05) in group A and -25.6 (SD 9.7) in group B (P < .01), for IIEF-EF of 2.28 (SD 2.33) in group A and 1.36 (SD 1.77) in group B (P = .03), for PDQ-PS of -3.04 (SD 2.95) in group A and of -2.12 (SD 2.06) in group B (P = .11), for PDQ-PP of -1.0 (SD 4.48) in group A and of -0.88 (SD 2.04) in group B (P = .60), for PDQ-SB of -5.84 (SD 4.58) in group A and of -4.16 (SD 4.45) in group B (P = .60), and for Female Sexual Function Index of 3.8 (SD 2.45) in group A and of 2.72 (SD 2.28) in group B (P = .14). We found a rate of global satisfaction of 70.83% in group A and of 84.0% in group B (P = .27). CLINICAL IMPLICATIONS: Addition of S25 b.i.d. to CCH is superior to CCH alone for improving penile curvature and erectile function. STRENGTH & LIMITATIONS: This is the first study comparing sildenafil + CCH vs CCH alone for the treatment of PD. Lack of randomization and direct verification of appropriate use of penile modeling could be considered limitations. CONCLUSION: In this study, combination therapy was superior in terms of penile curvature and erectile dysfunction improvement. Cocci A, Cito G, Urzi D, et al. Sildenafil 25 mg ODT + collagenase Clostridium hystoliticum vs collagenase Clostridium hystoliticum alone for the management of Peyronie's disease: A matched-pair comparison analysis. J Sex Med 2018;15:1472-1477. PMID- 30245026 TI - CRL4DCAF2 is required for mature T-cell expansion via Aurora B-regulated proteasome activity. AB - The proliferation of T cells in peripheral lymphoid tissues requires T cell receptor (TCR)-mediated cell cycle entry. However, the underlying mechanism regulating cell cycle progression in mature T cells is incompletely understood. Here, we have identified an E3 ubiquitin ligase, CRL4DCAF2, as a critical mediator controlling M phase exit in activated T cells. DCAF2 expression is induced upon TCR stimulation and its deficiency attenuates T cell expansion. Additionally, DCAF2 T cell-specific knockout mice display impaired peripheral T cell maintenance and reduced severity of various autoimmune diseases. Continuous H4K20me1 modification caused by DCAF2 deficiency inhibits the induction of Aurkb expression, which regulates 26S proteasome activity during G2/M phase. CRL4DCAF2 deficiency causes M phase arrest through proteasome-dependent mechanisms in peripheral T cells. Our findings establish DCAF2 as a novel target for T cell mediated autoimmunity or inflammatory diseases. PMID- 30245027 TI - GPR15+ T cells are Th17 like, increased in smokers and associated with multiple sclerosis. AB - Smoking is a risk factor for the development and progression of multiple sclerosis (MS); however, the pathogenic effects of smoking are poorly understood. We studied the smoking-associated chemokine receptor-like molecule GPR15 in relation to relapsing-remitting MS (RRMS). Using microarray analyses and qPCR we found elevated GPR15 in blood cells from smokers, and increased GPR15 expression in RRMS. By flow cytometry we detected increased frequencies of GPR15 expressing T and B cells in smokers, but no difference between patients with RRMS and healthy controls. However, after cell culture with the autoantigens myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein, frequencies of MBP reactive and non-proliferating GPR15+CD4+ T cells were increased in patients with RRMS compared with healthy controls. GPR15+CD4+ T cells produced IL-17 and were enriched in the cerebrospinal fluid (CSF). Furthermore, in the CSF of patients with RRMS, GPR15+ T cells were associated with CCR6+CXCR3+/CCR6-CXCR3+ phenotypes and correlated positively with concentrations of the newly identified GPR15 ligand (GPR15L), myelin degradation and disability. In conclusion, we have identified a proinflammatory cell type linking smoking with pathogenic immune cell functions in RRMS. PMID- 30245028 TI - An Ancient Fecundability-Associated Polymorphism Creates a GATA2 Binding Site in a Distal Enhancer of HLA-F. AB - Variation in female reproductive traits, such as fertility, fecundity, and fecundability, are heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits have been challenging. Here, we explore the functional significance and evolutionary history of a G/A polymorphism at SNP rs2523393, which is an eQTL for HLA-F and is significantly associated with fecundability (the probability of being pregnant within a single menstrual cycle). We replicated the association between the rs2523393 genotype and HLA-F expression by using GTEx data and demonstrate that HLA-F is upregulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells. Next, we show that the rs2523393 A allele creates a GATA2 binding site in a progesterone-responsive distal enhancer that loops to the HLA-F promoter. Remarkably, we found that the A allele is derived in the human lineage and that the G/A polymorphism arose before the divergence of modern and archaic humans and segregates at intermediate to high frequencies across human populations. Remarkably, the derived A allele is has also been identified in a GWAS as a risk allele for multiple sclerosis. These data suggest that the polymorphism is maintained by antagonistic pleiotropy and a reproduction health tradeoff in human evolution. PMID- 30245029 TI - Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. AB - The classification of genetic variants represents a major challenge in the post genome era by virtue of their extraordinary number and the complexities associated with ascribing a clinical impact, especially for disorders exhibiting exceptional phenotypic, genetic, and allelic heterogeneity. To address this challenge for hearing loss, we have developed the Deafness Variation Database (DVD), a comprehensive, open-access resource that integrates all available genetic, genomic, and clinical data together with expert curation to generate a single classification for each variant in 152 genes implicated in syndromic and non-syndromic deafness. We evaluate 876,139 variants and classify them as pathogenic or likely pathogenic (more than 8,100 variants), benign or likely benign (more than 172,000 variants), or of uncertain significance (more than 695,000 variants); 1,270 variants are re-categorized based on expert curation and in 300 instances, the change is of medical significance and impacts clinical care. We show that more than 96% of coding variants are rare and novel and that pathogenicity is driven by minor allele frequency thresholds, variant effect, and protein domain. The mutational landscape we define shows complex gene-specific variability, making an understanding of these nuances foundational for improved accuracy in variant interpretation in order to enhance clinical decision making and improve our understanding of deafness biology. PMID- 30245031 TI - Progress in preventing child maltreatment in Europe. PMID- 30245032 TI - Periprocedural Considerations for Anticoagulated Atrial Fibrillation Patients. AB - Periprocedural patient instruction and coordination is an important piece in achieving safe outcomes for patients needing procedures and receiving anticoagulants for atrial fibrillation. Balancing the needs for anticoagulation versus bleeding during the procedure requires clinical reasoning and preparation. In this article, the current guidelines for use of anticoagulants with atrial fibrillation, the relevant pharmacology, and the use of standardized tools to quantify the risks of thrombus or bleeding in the procedures will be discussed. In addition, resources for examining the optimal practice for these case types will be provided. Perianesthesia health care providers are pivotal to lead relevant stakeholders in the perianesthesia setting work together to create protocols and individual plans of care for this patient population. PMID- 30245033 TI - The Effect of Education on the Anxiety Level of Patients Before Thyroidectomy. AB - PURPOSE: The present study aims to evaluate the effect of preoperative education on the level of anxiety provided to patients scheduled for thyroidectomy using education brochures on the level of anxiety. DESIGN: The study design was quasi experimental. METHODS: The study data were collected using the Patient Information Form and the Turkish version of the Anxiety Specific to Surgery Questionnaire (ASSQ). Study group patients were informed by brochure before 24 hours. Control group patients were informed verbally during routine preoperative preparation or 1 day before surgery. Test and control group patients were resubjected to the ASSQ before being transported from their unit beds to the operating room. FINDINGS: There was no significant difference in the mean scores of the pretest and final test ASSQ scores for the test and control groups (P > .05). CONCLUSIONS: Our study results showed that education provided to the patients scheduled for thyroid surgery using written materials did not affect anxiety. PMID- 30245030 TI - Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency. AB - Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ~65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects' fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects' fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ~830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis. PMID- 30245035 TI - Comment on: Roux-En-Y gastric bypass, sleeve gastrectomy, or one-anastomosis gastric bypass as rescue therapy after failed adjustable gastric banding: a multicenter comparative study. PMID- 30245034 TI - [Quality control of mixtures for pediatric parenteral nutrition: Validation of sodium and potassium assay method]. AB - OBJECTIVES: Control of electrolyte concentration in mixtures for parenteral nutrition (MPN) for newborns is crucial before the release of the final product. We aimed to assess the validation of the electrolytes assay in MPN. METHODS: Electrolytes assay was performed with Ilyte Analyzer(r). Validation of method was realized in accordance with ICH (International Conference on Harmonization) guideline Q2(R1) and the commission report of the French society of pharmaceutical science and technology. Linearity test solutions were prepared in triplicate using five levels of concentrations for sodium and potassium (60-140% of theoretical concentrations). Accuracy of the method was deducted from the same results of linearity. The intermediate precision was ensured by dosing the main electrolyte in six MPN, during three successive days. RESULTS: Linearity was assessed with correlation coefficients greater than 0.996 for both electrolytes. A non-significant result of comparison test of the intercept with zero (Student test) was obtained. A highly significant result of the test of existence of slopes (Fisher test) proved a linear regression for the 2 electrolytes (P<0.1%). Inter-day precision values were 2.68% and 2.65% respectively for sodium and potassium. CONCLUSION: The validation of sodium and potassium assay method was successfully performed with Ilyte Analyzer(r) allowing routine quality control in MPN. PMID- 30245036 TI - Clinical significance of perioperative hyperglycemia in bariatric surgery: evidence for better perioperative glucose management. AB - BACKGROUND: Uncontrolled hyperglycemia in patients undergoing surgery has been shown to be a risk factor for postoperative complications. OBJECTIVE: To assess the clinical significance of perioperative hyperglycemia on infectious complications and clinical outcomes in patients undergoing bariatric surgery. SETTING: Single academic center. METHODS: Retrospective chart review of all patients who underwent primary laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy between 2013 and 2016 was performed. The association between any elevated perioperative glucose value (hyperglycemia: >=126 mg/dL) and level of elevation (>=126 or >=200 mg/dL) with 30-day infectious complications, reoperation, length of hospital stay, and readmission was assessed. Patients who developed early complications (within 3 d of surgery), which could potentially lead to immediate postoperative hyperglycemia, were not included in the analysis. Outcomes of patients with and without diabetes were separately analyzed. RESULTS: A cohort of 1981 patients was studied, including Roux-en-Y gastric bypass (n = 1171, 59%) and sleeve gastrectomy (n = 810, 41%) patients. In patients with diabetes (n = 751, 38%), perioperative hyperglycemia was independently associated with higher composite infectious complications (defined as presence of any of 6 infectious complications; odds ratio [OR] 3.1, 95% confidence interval [CI] 1.2 8.2, P = .018) and higher readmission rate (OR 2.2, 95% CI 1.1-4.6, P = .027). In patients without diabetes (n = 1230, 62%), 19.2% had perioperative hyperglycemia (>=126 mg/dL). Perioperative hyperglycemia in patients without diabetes was associated with higher composite infectious complications (OR 2.6, 95% CI 1.1 5.5, P = .018) and prolonged length of stay (OR 3.0, 95% CI 1.5-5.9, P = .001). CONCLUSIONS: An elevated perioperative glucose value is adversely associated with infectious complications and key clinical outcomes after bariatric surgery. The increased risk is correlated with the extent of glucose elevation (dose-response relationship). Our findings highlight the importance of glucose control during the perioperative period in bariatric surgical patients. PMID- 30245037 TI - Comparison of butterfly volumetric modulated arc therapy to full arc with or without deep inspiration breath hold for the treatment of mediastinal lymphoma. AB - PURPOSE: Radiotherapy is an effective treatment for mediastinal lymphoma but induces late effects including cardiac toxicity and secondary breast and lung cancer. Therefore reducing the dose to these organs is vital. We compared full arc volumetric modulated arc therapy (F-VMAT) against limited angle 'Butterfly' VMAT (B-VMAT) on free breathing (FB) and deep inspiration breath-hold (DIBH) computed tomography scans. The aim was to assess the benefits of B-VMAT over F VMAT and to establish if the addition of DIBH results is a cumulative benefit. MATERIALS AND METHODS: F-VMAT and B-VMAT plans were calculated for 20 consecutive patients (15 females) with mediastinal lymphoma on both FB and DIBH scans. The planning target volume V95% was kept comparable between all plans while reducing organ doses as much as possible. RESULTS: B-VMAT significantly reduced low lung doses (V5-10), while F-VMAT was better for higher lung doses (V20-30). DIBH further improved lung doses for both types of plans. DIBH B-VMAT produced the lowest mean lung dose. With FB, heart doses were slightly higher for B-VMAT but the maximum difference was small (0.8% for V20) and only statistically significant for V10-20. The mean heart dose increased by only 0.1 Gy. The addition of DIBH however significantly reduced heart doses. While DIBH F-VMAT had the lowest heart doses, the difference was small compared with DIBH B-VMAT. B VMAT significantly reduced breast V4 while DIBH reduced the V10. CONCLUSION: B VMAT and DIBH are both effective in reducing organ doses and the dosimetric benefit is additive for some parameters and complementary for others. PMID- 30245038 TI - Systems Science: A Primer on High Reliability. AB - In the 21st century, most medical care is not delivered by a single physician but rather, by a team. A team is a type of system, a set of people and things interacting together for a defined aim. The discipline of systems science concerns itself with how complex teams or organizations function. The application of systems science has had a major positive impact on safety and quality in such diverse disciplines as auto manufacturing, airline safety, and nuclear power generation. A modest understanding of how systems science applies to medical care can help improve safety and quality of care. PMID- 30245039 TI - Device Safety. AB - Medical devices are essential in the diagnosis and treatment of otolaryngologic disease. The US Food and Drug Administration (FDA) is tasked with assuring the safety and effectiveness of these devices. Otolaryngologists, in turn, are often responsible for helping patients understand risks, benefits, and alternatives when deciding whether to rely on devices in their care. To best counsel patients, otolaryngologists should be aware of the strengths and limitations of device regulation by the FDA. This article reviews the FDA regulatory framework for medical devices, premarket evidentiary standards for marketing devices, and postmarket methods of safety surveillance. PMID- 30245040 TI - The Impact of Cognitive and Implicit Bias on Patient Safety and Quality. AB - Humans use cognitive shortcuts, or heuristics, to quickly assess and respond to situations and data. When applied inappropriately, heuristics have the potential to redirect analysis of available information in consistent ways, creating systematic biases resulting in decision errors. Heuristics have greater effect in high-pressure, high-stakes decisions, particularly when dealing with incomplete information, in other words, daily medical and surgical practice. This article discusses 2 major categories: cognitive biases, which affect how we perceive and interpret clinical data; and implicit biases, which affect how we perceive and respond to other individuals, and also discusses approaches to recognize and alleviate bias effects. PMID- 30245041 TI - Interprofessional education for health science students' attitudes and readiness to work interprofessionally: a prospective cohort study. AB - BACKGROUND: Interprofessional education of healthcare providers is necessary to foster collaborative practice and improve patient outcomes. OBJECTIVE: To examine the effectiveness of the single-session interprofessional education in improving interprofessional attitudes, increasing knowledge of healthcare professions, and improving perceived-readiness for working interprofessionally and with older adults in students in occupational therapy, physical therapy, and physician assistant graduate programs. METHODS: We used a prospective, pre-post cohort design. Fall risk evaluation for older adults was selected as the topic of the 4 hour interprofessional education session. Graduate students from three professional programs including occupational therapy (n=20), physical therapy (n=26), and physician assistant studies (n=35) participated in the study, and 17 older adults aged 65 years or older volunteered for the session. Our primary outcome measure was the Interprofessional Attitudes Scale measuring interprofessional attitudes, and our secondary outcome measure was the study specific questionnaire measuring the direct effect of our interprofessional education session. RESULTS: Graduate students showed significant improvements in the subscale of teamwork, roles, and responsibilities in the Interprofessional Attitudes Scale. Students also showed significant improvements in "understanding of other professions," "perceived-readiness to work interprofessionally," and "perceived-readiness to work with older adults" in the study-specific questionnaire. Ceiling effects were observed in most of the subscales in the Interprofessional Attitudes Scale. CONCLUSION: This study demonstrates that a single 4-hour interprofessional education session can improve interprofessional attitudes, knowledge of other professions, and perceived-readiness of health science graduate students to work interprofessionally and to work with older adults. PMID- 30245042 TI - Current evidence does not support whole body vibration in clinical practice in children and adolescents with disabilities: a systematic review of randomized controlled trial. AB - BACKGROUND: Whole body vibration has been used alone or combined with other interventions in rehabilitation of children and adolescents with disabilities; however, there is limited evidence to support this approach. OBJECTIVES: To review the strength, quality, and conclusiveness of evidence supporting the use of whole body vibration in children and adolescents with disabilities. METHODS: Electronic database search included Medline, AMED, Embase, Cochrane, SportDiscus, CINAHL and PEDro from the inception to June 2018. Studies investigating the effects of whole body vibration, alone or combined with other interventions, compared to minimal intervention or other interventions were included. The outcomes measured were: body structure and function (lean body mass, bone mineral density, knee muscle strength and overall stability) and activity and participation (gait speed, walking distance, gross motor function, self-care and mobility). RESULTS: Fifteen randomized trials involving 403 participants were included. Methodological quality of eligible trials was moderate (mean of 5.5 points on the 10-point PEDro scale). Overall, whole body vibration was no better than minimal intervention. In all comparisons where additional effect of whole body vibration was better than other interventions, the effect size ranged from low to high in the trials, but ranged from very-low to low quality at short and medium-term follow-up. Sensitivity analysis for health condition and low-quality studies showed impact on trunk bone mineral density of additional effect of whole body vibration at medium-term compared to other interventions. CONCLUSION: The low to very-low quality of evidence suggests caution in recommending the use of this approach. New studies could change the findings of this review. PROSPERO registration: CRD42017060704. PMID- 30245043 TI - Prevalence of dyspnea after stroke: a telephone-based survey. AB - OBJECTIVE: Dyspnea is a relevant outcome to be taken into consideration during stroke rehabilitation. Prevalence, severity, and effects of this condition on individuals with stroke remain uncertain. This study investigated the prevalence and severity of dyspnea after a stroke, as well the associations between dyspnea, activity limitations, and participation restrictions. METHODS: A telephone-based survey was conducted with 285 individuals with stroke. The survey included information regarding the onset and severity of the dyspnea, activity limitations, and participation restrictions. Prevalence of dyspnea was reported as percentage of individuals who had the symptom. Chi-square tests were used to investigate the associations between dyspnea, activity limitations, and participation restrictions. Relative risks and respective 95% confidence intervals were calculated. RESULTS: Out of the 285 participants, 124 (44%) reported having dyspnea after stroke. Severe symptoms were reported by 51% of the participants with dyspnea. In addition, dyspnea limited activity and restricted social participation in 85% and 49% of the participants, respectively. Dyspnea was significantly correlated with activity limitations (r=0.87; 95% CI 0.82-0.92; p<0.01) and participation restrictions (r=0.53; 95% CI 0.46-0.62; p<0.01). The analyses indicated that individuals with dyspnea were more likely to report that it limited their activities (RR: 6.5; 95% CI 4.3-9.9) and restricted social participation (RR: 1.7; 95% CI 1.5-2.0). CONCLUSIONS: Dyspnea is an important symptom after stroke and showed to be associated with activity limitations and restrictions in community participation. Earlier detection of dyspnea in people with stroke, followed by appropriate management, is strongly recommended and has the potential to improve activity and social participation. PMID- 30245044 TI - Tuberculosis (TB) outbreak in a closed Aotus monkey breeding colony: Epidemiology, diagnosis and TB screening using antibody and interferon-gamma release testing. AB - : Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is a devastating and terminal disease in non-human primates (NHPs). Regular TB screenings using the intradermal tuberculin test (TST) have been the mainstay of TB surveillance and control in NHPs. Historically, Aotus monkeys have been considered less susceptible to TB than other NHPs. Here we present the diagnosis and epidemiology of a TB outbreak at The Gorgas Memorial Institute Aotus colony in Panama, and the results of two cross-sectional randomized TB screening studies, using antibody (Ab) and IFN-gamma release assay testing. RESULTS: Epidemiological and spatial analysis confirmed that the outbreak was the result of a continuing intermittent exposure, with human to monkey transmission as the most likely source. During the outbreak that lasted five months (January-June 2015), Mycobacterium kansassi and MTB were isolated from lung caseous granulomas in 1/7 and 3/7 TB suspicious animals respectively. Furthermore, MTB was detected by qRT-PCR in formalin fixed lung and liver granulomas in 2/7 and 1/6 monkeys respectively, suggesting an aerosol route of infection. Likewise, a random sample that included 63 / 313 adult (>2 year-old) monkeys, screened for latent TB with the Primagam(r) IFN gamma release assay, between March-May, 2016, were all non-reactors; indicating that the outbreak was self-limiting and the colony was likely free or latent TB infection. Control measures included, quarantine, disinfection and TST screening of all personnel. In conclusion, this study demonstrates that Aotus are highly susceptible to TB, therefore, TB prevention measures should be strictly enforced in Aotus monkey colonies. PMID- 30245045 TI - Detection of hepatitis E virus genotype 3 in pigs from subsistence farms in the state of Mato Grosso, Brazil. AB - Hepatitis E is a zoonotic disease, recognized as an important global public health concern. In this study, molecular detection of the ORF1 and ORF2 genomic regions of the hepatitis E virus (HEV) was carried out in fecal and serum samples from pigs in subsistence farms of Mato Grosso, Brazil. Fragments of the ORF2 region were amplified in 8% (12/150) of fecal samples, with 53.3% (8/15) of farms having positive results. Of the 12 positive samples, fragments of the ORF1 region were amplified in 33.3% (4/12) of these. Molecular characterization confirmed the phylogenetic groupings as HEV subtypes 3d, 3 h, and 3i. The results revealed that meat from pigs that was originally meant for personal consumption is being traded in marketplaces in metropolitan Cuiaba, thereby creating a source of transmission to consumers in Mato Grosso. The environmental conditions must be taken into account when investigating the presence and transmission of HEV. PMID- 30245046 TI - Identification of rickettsial immunoreactive proteins using a proximity ligation assay Western blotting and the traditional immunoproteomic approach. AB - The closely related species Rickettsia conorii and R. africae are both etiological agents of rickettsiosis, a tick-borne serious infective disease. The laboratory diagnosis is based on serology, but remains not enough specific to provide the diagnosis at the species level. Here, we attempted to identify specific proteins that would enable the discrimination of R. africae sp from R. conorii sp infections. We screened 22 R. africae- and 24 R. conorii-infected sera at different course of infection using a traditional immunoproteomic approach. In parallel, we focused on the technical development of a "relatively new technique" named a proximity ligation assay coupled to two-dimensional Western blotting. The top range markers of R. africae early infection were rpoA, atpD, and acnA, ORF0029, R. africae active infection were rOmpB beta-peptide, OmpA, groEL and ORF1174, early R. conorii infection was prsA, RC0031, pepA, R. conorii active infection were ftsZ, cycM and rpoA. They are candidates for serodiagnosis of rickettsioses. PMID- 30245047 TI - Infections with Bartonella spp. in free-ranging cervids and deer keds (Lipoptena cervi) in Norway. AB - Bartonella bacteria are arthropod-borne and can cause long-term bacteremia in humans and animals. The predominant arthropod vectors and the mode of transmission for many novel Bartonella species remain elusive or essentially unstudied. The aim of this study was to investigate the prevalence of Bartonella spp. in Norwegian cervids and deer keds (Lipoptena cervi) and to characterise the bacteria by sequencing of the partial gltA gene and 16 S-23 S rRNA intergenic spacer region (ITS) in order to evaluate a possible transmission route. A total of 260 spleen samples and 118 deer keds were collected from cervids by hunters in the Southern part of Norway. Bartonella DNA was detected in 10.5% of spleen samples of roe deer (n = 67), in 35.1% red deer (n = 37), in 35.9% moose (n = 156), and in 85% pools of adult wingless deer ked (n = 59). Two Bartonella lineages were identified based on phylogenetic analysis of the gltA gene and ITS region sequences. PMID- 30245048 TI - Protein profile of FAdV-4 based on SDS-PAGE and Western blot isolated from chickens in India. AB - Fowl adenovirus-4 (FAdV-4) causes hydropericardium syndrome (HPS) in poultry worldwide. An understanding of viral structural protein composition is important for developing novel immunodiagnostics and immunoprophylactics. Here we report isolation, culture, molecular and protein profile of FAdV-4 isolates recovered from HPS outbreaks in chicken in the states of Himachal Pradesh and Tamil Nadu in India. We performed a sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting-based protein profiling of FAdV-4 isolates against a reference FAdV-1 or Chicken Embryo Lethal Orphan (CELO) virus. SDS-PAGE analysis showed that seven protein bands in FAdV-4 isolates were similar to CELO expect an additional band of 110 kDa in CELO virus. On Western blotting, two protein fractions of 43 kDa and 78 kDa size were observed in FAdV-4 isolates. Overall, results show that FAdV-4 isolates recovered from different regions of the country had similar protein profile and possibly a common source of origin. PMID- 30245049 TI - Mamastrovirus 5 detected in a crab-eating fox (Cerdocyon thous): Expanding wildlife host range of astroviruses. AB - Astroviruses are a common cause of gastroenteritis in children worldwide and can also cause infection in a range of domestic and wild animal species. Canine astrovirus (formally named as Mamastrovirus 5, MAstV5) has been reported worldwide, and its role as an enteric pathogen is still controversial. Herein, we describe the genomic characterization of a MAstV5 (strain crab-eating fox/2016/BRA) identified in a wild canid (Cerdocyon thous) diagnosed with canine distemper virus (CDV) as causa mortis. The nearly complete genome comprised 6579 nt in length and displayed the archetypal organization of astroviruses. The present report is the first evidence of MAstV5 infection in an animal species other than the dog and highlights a possible natural astrovirus spillover between domestic and wild canids. Moreover, these results show the first evidence of extra-intestinal MAstV5, suggesting a virus systemic spread. This work is expected to contribute to a better understanding of the astroviruses biology and their interactions with the wildlife health. PMID- 30245050 TI - F18+Escherichia coli flagellin expression in Salmonella has immunoadjuvant effects in a ghost vaccine candidate containing E. coli Stx2eB, FedF and FedA against porcine edema disease. AB - Flagellin, a major structural component of bacteria flagella, is responsible for facilitating motility and invading host cells. The binding capacity of flagellin to toll-like receptor 5 (TLR5) and its trigger action for innate immunity make it an attractive vaccine adjuvant. In this work, we explored the efficacy of F18+STEC flagellin as an adjuvant in a ghost vaccine candidate against porcine edema disease (ED). TLR5-stimulating activity and IL-8 cytokine expression produced via downstream signaling following ligand exposure was detected in HEK BlueTM-hTLR5 cells stimulated with flagellin expressed in the Salmonella Typhimurium (ST) ghost, JOL1485. Mice immunized with JOL1485 mixed with the vaccine candidate showed significantly increased secretory IgA specific to flagellin during the study period. JOL1485 efficiently induced maturation of naive dendritic cells, resulting in production of immunomodulatory cytokines associated with Th1 and Th2 immunity. Particularly, marked increases in IL-6 inducing B-cell differentiation and IL-12 associated with Th1 immunity were observed in CD4 + T-cells stimulated with JOL1485 primed DCs. Furthermore, all mice immunized with JOL1485 mixed with the vaccine candidate showed higher protection efficacy against challenge and significantly enhanced clearance of the challenge strain, compared to mice immunized with only the vaccine candidate. Collectively, these results indicated that flagellin expression in JOL1485 may have immunostimulatory properties that serve as a potent adjuvant for the vaccines against ED. PMID- 30245051 TI - Genetic analysis of bovine respiratory syncytial virus in Croatia. AB - Bovine respiratory syncytial virus (BRSV) represents an important causative agent of respiratory tract disease in cattle. This study describes the genetic diversity of BRSV strains detected in beef cattle herds in Croatia during four consecutive years, from the end of 2011 to April 2016. Genetic diversity of circulating Croatian strains is reflected in their clustering within three different genetic subgroups. Analysis of representative BRSV G gene sequences revealed that infections in Croatia were caused by BRSV strains belonging to two new subgroups (VII and VIII identified herein for the first time). In 2014-2016, the subgroup VII strains were replaced with BRSV strains clustered in the previously unidentified subgroup VIII. Furthermore, co-circulation of subgroup II and new subgroup VIII strains in Croatia was recorded in the same time period. Sequences of Croatian BRSV strains within subgroups II and VII revealed unique mutations within an essential immunodominant region, demonstrating continuous evolution of viral mechanisms for immune escape. PMID- 30245052 TI - Role of a combination dietary supplement containing mucopolysaccharides, vitamin C, and collagen on tendon healing in rats. AB - OBJECTIVE: The aim of this study was to investigate the effect of mucopolysaccharide, vitamin C, and collagen supplementation on the healing of Achilles tendon in rats. METHODS: Sixteen rats were separated into 2 groups. Both Achilles tendons of all rats were transected 5 mm above the insertion and repaired using a Kessler suture. After the surgical repair, the study group received the daily recommended amount of the supplement by gastric gavage, while the control group received a placebo. At the end of the third week, the animals were sacrificed. The biomechanical properties of the groups were compared with ultimate tensile strength and stiffness tests. The biological properties of the 2 groups were assessed with a histomorphometric comparison to determine the amount of collagen type I (COL1), proliferating cell nuclear antigen (PCNA), and transforming growth factor beta1 (TGF-beta1) expression in 3 different tissue subgroups (collagen matrix, tenocytes, and endotenon fibroblasts). RESULTS: Analysis of histomorphometric results revealed that the rats receiving dietary supplements demonstrated a significant increase in PCNA (mean value of 86 in the control group and 168.85 in the trial group; p < 0.05) and TGF-beta1 (mean value of 87.57 in the control group and 161.85 in the trial group; p < 0.05) in the endotenon fibroblasts of the repair site. However, there was no difference between the groups in PCNA or TGF-beta1 when the collagen matrix and the tenocytes of the repair site were examined. Furthermore, no significant difference could be found between groups in COL1 in any of the 3 tissue subgroups (collagen matrix, tenocytes, and endotenon fibroblasts). The statistical analysis also indicated that the rats receiving supplements did not demonstrate a significant increase in the ultimate tendon tensile strength or stiffness. CONCLUSION: The results of this study revealed no advantage to the oral administration of the trial supplement in collagen synthesis or biomechanical properties in rats after 3 weeks using the presented study design. However, the increased expression of PCNA and TGFbeta1 seen in the endotenon fibroblasts of the repair site might play a role in the continuum of tendon healing. PMID- 30245053 TI - State-level diabetes-attributable mortality and years of life lost in the United States. AB - PURPOSE: To estimate state-level diabetes-attributable deaths and years of life lost (YLL) in the Unites States. METHODS: We estimated diabetes-attributable all cause and cardiovascular disease (CVD) deaths by age, sex, and state, using the attributable fraction approach. Data on diabetes prevalence were collected from Behavioral Risk Factor Surveillance System. Relative risks for people with and without diabetes were estimated using the National Health Interview Survey. State sex-age-specific deaths were obtained from CDC WONDER. YLL were calculated by multiplying the number of people with diabetes by the difference in life expectancy between people with and without diabetes using the life table approach. RESULTS: Nationally, estimated diabetes-attributable all-cause deaths and CVD deaths were 293,224 and 90,953, respectively. Diabetes resulted in a total of 109,707,000 YLL with an average 4.4 years of life lost per person with diabetes. Most state variation in total deaths was explained by state population size and diabetes prevalence. All-cause deaths ranged from 415 in Alaska to 28,538 in California, and CVD deaths ranged from 113 in Alaska to 8908 in California. Across all states, the average diabetes-attributable death rate per 100,000 was 125 for males and 105 for females for all-cause deaths and 40 for males and 31 for females for CVD deaths. CONCLUSIONS: Mortality attributable to diabetes is greatly underestimated when looking only at diabetes listed as an underlying cause of death. These results can be used to track state differences in deaths due to diabetes and to monitor the success of public health activities. PMID- 30245055 TI - Atezolizumab for metastatic triple-negative breast cancer. PMID- 30245054 TI - Alectinib shows CNS efficacy in ALK-positive NSCLC. PMID- 30245057 TI - Long-term results using a transanal irrigation system (Peristeen(r)) for treatment of stool incontinence in children with myelomeningocele. AB - INTRODUCTION: Faecal incontinence due to constipation associated with myelomeningocele (MMC) is a frustrating problem. It could have a bad impact on patients and their families' quality of life. Conservative measures could be a starting point. In case of failure, Malone antegrade continence enema (MACE) is commonly considered. However, it is associated with higher complications. Peristeen transanal irrigation (TAI) depends on the injection of water into the colon through a rectal catheter with an inflatable balloon to promote a controlled evacuation of large quantities of faecal contents. Transanal irrigation could be an alternative in these patients to avoid surgery. OBJECTIVE: The objective of this study was to evaluate the long-term effectiveness and satisfaction of TAI management (Peristeen(r), Coloplast, Denmark) in children with MMC who failed to respond to conservative measures for stool incontinence. STUDY DESIGN: All patients with MMC who did not respond to conservative measures for stool incontinence and were using TAI with the last follow-up 6 months before the end date were included. Data were collected retrospectively from January 2008 till January 2016. The data collected included the age of starting Peristeen, duration of using the Peristeen, acceptance and compliance of the patient's family with the TAI. Success was defined as stool continence. RESULTS: A total of 109 patients (55 males and 54 females) diagnosed as having MMC were started on TAI Peristeen. With a mean follow-up of 48 months (24-108), 101 patients (90.4%) achieved complete stool continence and 8 patients were considered failures. DISCUSSION: The study results are comparable with those of previously reported publications. The main limitation of Peristeen TAI is that it cannot be performed by the patient himself/herself. This may present a problem with later independence. CONCLUSION: Transanal irrigation with Peristeen(r) system is a safe and good alternative option for stool incontinence when other conservative measures fail. PMID- 30245058 TI - The design and psychometric evaluation of the emergency medical services resilience scale (EMSRS). AB - INTRODUCTION: The nature of pre-hospital emergency medical care can expose healthcare workers to significant stresses that might lead to psychological problems such as job burnout and impaired resilience. A valid and reliable tool is, therefore, needed to investigate resilience in emergency medical services (EMS) personnel. This study was conducted to design a tool for assessing the resilience of emergency medical personnel in Iran and to examine the psychometric properties of the designed tool. METHODS: This methodological study was conducted in two phases: A qualitative stage with individual interviews and a review of literature to generate items, and a quantitative stage of psychometric evaluations that assessed the face, content, and construct validity of the tool. The reliability of the tool was also assessed using the internal consistency and test-retest methods. RESULTS: Exploratory factor analysis was used to design a 31 item scale with a six-factor structure. These six factors, i.e. job motivation, communication challenges, social support, remaining calm, self-management, and consequences of stress, explained 51.8% of the variance. The scale's Cronbach's alpha coefficient and intraclass correlation coefficient were calculated as 0.91 and 0.85, respectively. CONCLUSION: The scale developed on the resilience of EMS personnel can be used as a valid and reliable tool for assessing resilience in EMS personnel. It can also assist emergency service managers to plan courses to improve their staff's resilience. PMID- 30245056 TI - Smartphone-based pathogen diagnosis in urinary sepsis patients. AB - BACKGROUND: There is an urgent need for rapid, sensitive, and affordable diagnostics for microbial infections at the point-of-care. Although a number of innovative systems have been reported that transform mobile phones into potential diagnostic tools, the translational challenge to clinical diagnostics remains a significant hurdle to overcome. METHODS: A smartphone-based real-time loop mediated isothermal amplification (smaRT-LAMP) system was developed for pathogen ID in urinary sepsis patients. The free, custom-built mobile phone app allows the phone to serve as a stand-alone device for quantitative diagnostics, allowing the determination of genome copy-number of bacterial pathogens in real time. FINDINGS: A head-to-head comparative bacterial analysis of urine from sepsis patients revealed that the performance of smaRT-LAMP matched that of clinical diagnostics at the admitting hospital in a fraction of the time (~1 h vs. 18-28 h). Among patients with bacteremic complications of their urinary sepsis, pathogen ID from the urine matched that from the blood - potentially allowing pathogen diagnosis shortly after hospital admission. Additionally, smaRT-LAMP did not exhibit false positives in sepsis patients with clinically negative urine cultures. INTERPRETATION: The smaRT-LAMP system is effective against diverse Gram negative and -positive pathogens and biological specimens, costs less than $100 US to fabricate (in addition to the smartphone), and is configurable for the simultaneous detection of multiple pathogens. SmaRT-LAMP thus offers the potential to deliver rapid diagnosis and treatment of urinary tract infections and urinary sepsis with a simple test that can be performed at low cost at the point-of-care. FUND: National Institutes of Health, Chan-Zuckerberg Biohub, Bill and Melinda Gates Foundation. PMID- 30245059 TI - Medical Student Perceptions of 24-Hour Call. AB - OBJECTIVE: To assess the medical student perception and experience of a 24-hour call requirement, and to learn if improvements can be made to improve the 24-hour call requirement. DESIGN: Medical students completing their required surgical clerkship over 1 academic year at our institution were surveyed prior to their clerkship and on the last week of clerkship regarding their perceptions and experience with 24-hour call. SETTING: This study was performed at the University of Minnesota, in Minneapolis, Minnesota, a medical school and tertiary medical center. PARTICIPANTS: Two hundred one medical students were given the option to complete an anonymous survey before and after their required surgical clerkship. RESULTS: Response rate for the preclerkship survey was 70% (n = 140) and 58% (n = 117) for the postclerkship survey. The mean age of respondents was 26years, and the majority of students were in their third year of medical school. After completing the clerkship, students interested in surgery more often agreed the 24 hour call requirement should remain (51% versus 31%, p = 0.01). Students rotating at a Level I Trauma Center were also more likely to agree the call requirement should remain (59% versus 33%, p = 0.008). Medical students generally had less concerns (mental health, fatigue, mistakes, and grade performance) related to 24 hour call after completion of the clerkship. Concerns about the effect of 24-hour call on study schedule remained high in both pre and postclerkship groups. CONCLUSIONS: Medical students have concerns about the experience prior to the clerkship that diminished by its completion. To improve medical student perceptions and overall experience of 24-hour call, frequency of shifts could be limited and the 24-hour call requirement sites could be shifted to Level I Trauma Centers. PMID- 30245060 TI - Global Collaboration to Modernize Advanced Trauma Life Support Training. AB - BACKGROUND: Each year, thousands of surgeons and other trauma health care providers participate in the American College of Surgeon's Advanced Trauma Life Support (ATLS) program, which historically has allowed trainees to practice cricothyroidotomy, chest tube insertion, pericardiocentesis, venous cutdown, and diagnostic peritoneal lavage on live dogs, pigs, sheep, and goats. However, more than 99% of ATLS programs in the United States and Canada have now ended animal use, driven primarily by simulation technology advancements. OBJECTIVE: This review details an international survey of animal versus simulation use in ATLS programs and summarizes the surgical training impact of a novel collaboration between the industry manufacturer of the TraumaMan human simulator, Simulab Corporation (Seattle, Washington), and an animal protection nongovernmental organization (NGO) based in Norfolk, Virginia, to replace animal use in ATLS programs with human simulators. METHODS: From 2012 through 2017, the NGO e-mailed formal surveys concerning program statistics and animal use practices to ATLS officials in various countries (N = 64). The survey response rate was 87.5% and included pre- and post-comparison surveys relative to the industry-NGO simulation collaboration. RESULTS: Eighteen ATLS programs (32.1%) initially replied that they use nonanimal training methods, whereas 38 ATLS programs (67.8%) replied that they use animals for surgical skills training and cited financial constraints as the primary barrier to adopting human simulation methods. Through the industry-NGO collaboration, the NGO donated 119 TraumaMan models valued at nearly $3million (USD) to ATLS programs in 22 countries, such that 75% of those ATLS programs surveyed by the NGO now use exclusively nonanimal simulation models. CONCLUSIONS: The industry-NGO collaboration successfully transformed the surgical skills laboratories of 22 international ATLS programs to replace animal use with nonanimal simulation models that are more anatomically realistic, cost less, and allow trainees to repeat surgical skills until proficiency. PMID- 30245061 TI - The Relationship Between Self-Efficacy and Well-Being Among Surgical Residents. AB - OBJECTIVE: Residency is a challenging time in the lives of physicians. In this study, we examined the relationship between general self-efficacy, defined as the belief in one's own capabilities in a variety of situations, and burnout and psychological well-being in a sample of surgical residents. DESIGN: In the context of a larger study, a cross-sectional survey was administered to residents. The survey included measures of general self-efficacy, the emotional exhaustion and personal accomplishment domains of burnout, and general psychological well-being. We examined correlations between self-efficacy and these well-being outcomes and used multivariable linear regression models that controlled for age, gender, postgraduate year, ethnicity, and the interaction between gender and self-efficacy. SETTING: We surveyed residents at Stanford Health Care, a tertiary care center, between the fall of 2010 and the spring of 2013. PARTICIPANTS: One hundred and seventy nine residents from 9 surgical subspecialties responded to the survey for a response rate of 76%. RESULTS: Residents reported high levels of self-efficacy, and over a third reported high emotional exhaustion. Eighty-nine percent of residents had average or high personal accomplishment. In adjusted regression analyses, general self-efficacy was negatively predictive of emotional exhaustion (B = -0.43, p = 0.0127) and positively predictive of personal accomplishment (B = 0.33, p = 0.0185) and general psychological well-being (B = 0.34, p = 0.0010). There was no interaction between gender and general self-efficacy in regression analyses (ps >= 0.6776). CONCLUSIONS: Among other factors, self-efficacy appears to be significantly predictive of resident well-being. High self-efficacy suggests that residents feel prepared and capable. Interventions to improve residents' general self efficacy should be explored as a possible mechanism to improve well-being. PMID- 30245062 TI - Factors that Predict an Intern's First ABSITE Score are Known by September. AB - BACKGROUND: Previous studies offer conflicting relevance of a variety of factors to predict resident performance on the The American Board of Surgery In-Training Exam (ABSITE). With numerous stellar applicants scoring poorly on their first ABSITE, we sought to identify key factors that might allow us to tailor pre emptive study efforts in the fall and early winter to enhance scores. METHODS: General Surgery residents in our program from 2009 through 2016 were included in our cohort study. Specific trainee data (sex, prelim vs categorical, United States Medical Licensing Examination (USMLE) Step 1 and 2 scores, ABSITE scores, clinical rotations, biannual objective structured clinical examination OSCE-type scores, and in-house prep test [IHPT], etc.) were collected retrospectively. The data were analyzed using JMP pro 10 and MedCalc. RESULTS: ABSITE scores of our 110 trainees did not vary by sex or by categorical vs preliminary residents. USMLE step 1 and 2, IHPT and one objective structured clinical examination (OSCE) station (Sim-Based Trauma Exam) scores were positively correlated with ABSITE scores (p < 0.05; correlation coefficient (CC) = 0.6 [strong] for IHPT, 0.5 [moderate] for step 1 and 2 and [weak] 0.3 for Sim-Based Trauma Exam). The mean (standard deviation) ABSITE %tile score for residents scoring above 230 (USMLE 1 or 2) vs <230 were different: 81 (3) vs 56 (4) (p < 000.1). Of residents scoring lower than 230 in USMLE 1 or 2, their ABSITE performance had a strong positive linear correlation with their performance in the IHPT (CC = 0.7) and SBTA (CC = 0.5). Residents rotating twice on the Acute Care Surgery services before the ABSITE scored higher than those with 1 or zero rotations (p < 0.05). CONCLUSIONS: USMLE steps 1 and 2 are useful parameters in our program to predict subsequent resident ABSITE performance. An in-house 60-minute preparation test in September, a 6-minute simulation-based trauma assessment in July, and rotation schedule with 2 stints on Acute Care Surgery were surprisingly useful early intern year tools to predict ABSITE scores. PMID- 30245063 TI - HCV treatment for people with recent drug use: time for new measures of success? PMID- 30245064 TI - Direct-acting antiviral treatment for hepatitis C among people who use or inject drugs: a systematic review and meta-analysis. AB - BACKGROUND: There are concerns around poorer response to direct-acting antiviral (DAA) therapy for hepatitis C virus infection among people who use drugs. This systematic review assessed DAA treatment outcomes among people with recent drug use and those receiving opioid substitution therapy. METHODS: Bibliographic databases and conference presentations were searched for observational studies and clinical trials assessing DAA treatment completion, sustained virological response (SVR), and loss to follow-up among people with recent drug use (injecting or non-injecting) and those receiving opioid substitution therapy. Meta-analysis was used to pool estimates and meta-regression to explore heterogeneity. FINDINGS: 38 eligible studies, with 3634 participants, were included. The definition of recent drug use varied across studies, with drug use in the past 6 months and at the initiation of or during DAA therapy most commonly used. Among individuals with recent injecting or non-injecting drug use (21 studies; 1408 participants), treatment completion was 97.5% (95% CI 96.6-98.3) and SVR was 87.7% (95% CI 84.2-91.3). Among individuals receiving opioid substitution therapy (36 studies; 2987 participants), treatment completion was 97.4% (95% CI 96.5-98.3) and SVR was 90.7% (95% CI 88.5-93.0). Among individuals with recent injecting drug use (eight studies; 670 participants), treatment completion was 96.9% (95% CI 95.6-98.2) and SVR was 87.4% (95% CI 82.0-92.8). In meta-regression analysis, clinical trials (vs observational studies; adjusted odd ratio 2.18, 95% CI 1.27-3.75; p=0.006) and higher mean or median age (1.07, 1.02 1.12; p=0.008) were significantly associated with higher SVR. Clinical trials (0.45, 0.22-0.94; p=0.033) and older age (0.94, 0.88-0.99; p=0.034) were also significantly associated with a lower proportion of participants lost to follow up. INTERPRETATION: Response to DAA therapy was favourable among people with recent drug use (including those who inject) and those receiving opioid substitution therapy, supporting broadening access in these populations. FUNDING: The Kirby Institute, UNSW Sydney, and National Health and Medical Research Council of Australia. PMID- 30245065 TI - Differentially methylated CpG regions analyzed by PCR-high resolution melting for monozygotic twin pair discrimination. AB - Discrimination between monozygotic (MZ) twins is a forensic limitation when using conventional DNA profiling techniques for human identification. Recent works based on epigenetics seem to open a new way to solve this issue due to methylation status of MZ twins change during their lifetime. Methylation analysis through BeadChip platforms allows the study up to 850 K CpG sites revealing that numerous differential methylation regions exist between MZ twins. However, this methodology is difficult to implement in forensic laboratories. On the contrary, PCR-HRM (High Resolution Melting) technology is one of the easiest methods for analyzing DNA methylation and it has been capable to discriminate between MZ twins. The purpose of this study is to contribute with new differential methylation regions in MZ twins to those that have been previously studied through PCR-HRM. Here, we have selected 6 CpG regions located at the ITGA2B, ASPA, PDE4C, ZIC5, USP11 and NOP14 loci that have shown methylation status variation during lifetime. The study has been carried out from saliva-derived DNA of 18 MZ twin pairs. The most discriminating regions were those located at ITGA2B, ASPA and ZIC5 loci showing significant within-pair differences in 44.4% of the cases. Non evidences of relation between age and significant differences between MZ twins were found, although the 50% of MZ twin pairs were discrimnated in the oldest age range (59-66 years old). These results support the use of these regions to increase the number of epigenetics age-related markers available to discriminate between MZ twins in a pair by PCR-HRM in forensic laboratories. PMID- 30245066 TI - Arthroscopic treatment of chronic ankle instability: Prospective study of outcomes in 286 patients. AB - BACKGROUND: Chronic ankle instability (CAI) is the main complication of ankle sprains and requires surgery if non-operative treatment fails. Surgical ankle stabilisation techniques can be roughly classified into two groups, namely, repair involving retensioning and suturing of the anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) and reconstruction using a tendon graft. Arthroscopic repair and reconstruction techniques for CAI have been introduced recently. The objective of this prospective multicentre study was to assess the feasibility, morbidity, and short-term outcomes of these arthroscopic ankle-stabilisation techniques. MATERIAL AND METHODS: Consecutive patients scheduled for arthroscopic treatment of CAI were included prospectively. Of the 286 included patients, 115 underwent ligament repair and 171 ligament reconstruction. Mean follow-up was 9.6 months (range, 6-43 months). We recorded the AOFAS and Karlsson scores, patient satisfaction, complications, and time to return to sports. RESULTS: The overall patient satisfaction score was 8.5/10. The AOFAS and Karlsson scores improved significantly between the pre- and postoperative assessments, from 62.1 to 89.2 and from 55 to 87.1, respectively. These scores were not significantly different between the groups treated by repair and by reconstruction. Neurological complications occurred in 10% of patients and consisted chiefly in transient dysesthesia (with neuroma in 3.5% of patients). Cutaneous or infectious complications requiring surgical revision developed in 4.2% of patients. DISCUSSION: Arthroscopic treatment is becoming a method of choice for patients with CAI, as it allows a comprehensive assessment of the ligament lesions, the detection and treatment of associated lesions, and repair or reconstruction of the damaged ligaments. These simple, reliable, and reproducible arthroscopic techniques seem as effective as conventional surgical techniques. The rate of cutaneous complications is at least halved compared to open surgery. CONCLUSION: Arthroscopic ankle stabilisation repair and reconstruction techniques hold considerable promise but require further evaluation to better determine the indications of repair versus reconstruction and to obtain information on long-term outcomes. PMID- 30245067 TI - Tranexamic acid is effective for blood management in open-wedge high tibial osteotomy. AB - INTRODUCTION: There has been paucity in literature regarding the blood-sparing effect of TXA after high tibial osteotomy (HTO). The purpose of this study is to determine the efficacy of tranexamic acid (TXA) with regard to its blood-sparing effects in open-wedge HTO, and to assess thromboembolic complications in patients undergoing open-wedge HTO with or without the use of TXA. HYPOTHESIS: The intravenous TXA would reduce postoperative blood loss and transfusion requirements without increasing thromboembolic complications in open-wedge HTO. MATERIALS AND METHODS: From March 2011 to December 2016, medial open-wedge HTO was performed in 150 consecutive knees with varus gonarthrosis. The mean age at the time of surgery was 55.3+/-5.0 years. TXA was intravenously used in the latter 75 knees (TXA group), and the group was retrospectively compared with the former 75 knees without use of TXA (control group). Outcome measures were postoperative hemoglobin drop, drain amount, total estimated blood loss, transfusion requirements, and incidence of thromboembolic complications. RESULTS: The use of TXA led to a significant decrease in hemoglobin drop (p<0.001) and drain amount (p=0.025). Total estimated blood loss was lower in the TXA group than in the control group (p<0.001). Two knees in the control group had postoperative blood transfusion, compared to none in the TXA group (p>0.05). There were no thromboembolic complications such as symptomatic deep vein thrombosis and pulmonary embolism in both groups. CONCLUSION: The use of TXA reduced perioperative hemoglobin drop, drain amount, and total estimated blood loss without thromboembolic complications in patients undergoing open-wedge HTO. Therefore, the use of TXA is a safe and viable option for perioperative blood management in open-wedge HTO. LEVEL OF EVIDENCE: III, Case control study. PMID- 30245068 TI - The respiratory delivery of high dose dry powders. PMID- 30245069 TI - Integrating quantitative morphological and intratumoural textural characteristics in FDG-PET for the prediction of prognosis in pharynx squamous cell carcinoma patients. AB - AIM: To assess potential prognostic factors in pharynx squamous cell carcinoma (SCC) patients by quantitative morphological and intratumoural characteristics obtained by 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography/computed tomography (FDG-PET/CT). MATERIALS AND METHODS: The cases of 54 patients with pharynx SCC who underwent chemoradiation therapy were analysed retrospectively. Using their FDG-PET data, the quantitative morphological and intratumoural characteristics of 14 parameters were calculated. The progression free survival (PFS) and overall survival (OS) information was obtained from patient medical records. Univariate and multivariate analyses were performed to assess the 14 quantitative parameters as well as the T-stage, N-stage, and tumour location data for their relation to PFS and OS. When an independent predictor was suggested in the multivariate analysis, the parameter was further assessed using the Kaplan-Meier method. RESULTS: In the assessment of PFS, the univariate and multivariate analyses indicated the following as independent predictors: the texture parameter of homogeneity and the morphological parameter of sphericity. In the Kaplan-Meier analysis, the PFS rate was significantly improved in the patients who had both a higher value of homogeneity (p=0.01) and a higher value of sphericity (p=0.002). With the combined use of homogeneity and sphericity, the patients with different PFS rates could be divided more clearly. CONCLUSION: The quantitative parameters of homogeneity and sphericity obtained by FDG-PET can be useful for the prediction of the PFS of pharynx SCC patients, especially when used in combination. PMID- 30245070 TI - Can acoustic radiation force imaging of the liver and spleen predict the presence of gastroesophageal varices? AB - AIM: To determine whether acoustic radiation force imaging (ARFI) of the liver/spleen could be used in patients with cirrhosis to predict the presence of gastroesophageal varices (GOVs). MATERIALS AND METHODS: Fifty-eight patients with cirrhosis who were undergoing 6-monthly ultrasound examinations for hepatoma surveillance and who were due to have oesophagogastroduodenoscopy (OGD) within 6 months of their ultrasound were recruited. During routine ultrasound, the patient's liver and spleen were also assessed using ARFI. Other clinical parameters (platelet count, spleen size, and transient elastography measurements) were also collected. Logistic regression was used to determine which variables were significantly associated with presence or absence of varices univariably and multivariably RESULTS: Fourteen patients (24%) had GOVs. Patients with GOVs had higher ARFI measurements in the liver and spleen than patients without GOVs (liver: 2.39 versus 2.13, spleen: 2.89 versus 2.82), but these results were not statistically significant (odds ratio=1.75, 95% confidence interval [CI]=0.82, 3.91 and odds ratio=1.12, 95% CI=0.33, 3.97, respectively). The platelet/splenic ratio, in comparison, was associated with the presence or absence of GOVs in multivariate analysis (odds ratio=0.32, 95% CI=0.008, 0.91). CONCLUSION: Although patients with GOVs had overall higher ARFI liver and spleen results, this was not statistically significant. As such, ARFI cannot yet replace OGD in predicting GOVs in this patient group. PMID- 30245071 TI - Integrated comprehensive two-dimensional gas-chromatographic and spectroscopic characterization of vetiveryl acetates: Molecular identifications, quantification of constituents, regulatory and olfactory considerations. AB - Vetiveryl acetate is a common ingredient of the perfume industry highly prized by perfumers for its crisp vetiver note and thus often used in high-end perfume compositions. Vetiveryl acetate is currently manufactured from vetiver oil by means of various industrial processes that result in the conversion of the main vetiver alcohols into their corresponding acetates. Despite being used for decades as perfume ingredient, vetiveryl acetate has barely been studied in the past, therefore its chemical composition is poorly documented. While vetiveryl acetate is currently under investigation by regulation authorities, it was crucial to fill this gap of knowledge. We report here the first detailed investigation of different types of vetiveryl acetates, covering analytical, regulatory, and olfactory aspects. This study is based upon an integrated analytical methodology involving a full array of gas chromatographic techniques and spectroscopic/spectrometric methods. The principal objective was the identification of the main ester constituents contained in different samples of vetiveryl acetate, as well as linking their chemical composition with their manufacture process. Among the major esters detected in all samples, 23 ester constituents were either isolated by capillary preparative-gas chromatography or synthesized in order to provide their complete spectral characterization. The quantification of constituents in both commercial and laboratory-made vetiveryl acetates was carried out by internal calibration using comprehensive two dimensional-gas chromatography and predicted relative response factors. The generated set of analytical data permitted to explore both the regulatory aspects and the olfactory properties associated with the substance. The manufacture of vetiveryl acetate modulates the initial scent of vetiver essential oil by suppressing the notes brought by the main fragrant alcohols. While the impact of undesired odorant molecules such as phenol derivatives and geosmin is lowered, the major odour-active ketones such as khusimone, ziza-6(13)-en-3-ones, and the two vetivones develop their own odor characters in vetiveryl acetate. PMID- 30245072 TI - A efficient method to identify cardioprotective components of Astragali Radix using a combination of molecularly imprinted polymers-based knockout extract and activity evaluation. AB - Although herb medicines have become the major source for new drug discovery, many of them are largely under-explored due to the purity-activity relationship. Efficient identification of bioactive compounds in conventional stepwise separation and isolation has not yet been elucidated. Therefore, we proposed a new separation strategy for holism understanding of herb pharmacology using molecularly imprinted polymers (MIPs). Astragali Radix (AR), important in traditional Chinese medicine, was chosen in this study for multicomponent knockout followed by bioactivity evaluation. We prepared calycosin molecularly imprinted polymers (calycosin-MIPs) which could selectively recognize flavonoid aglycons in AR. The molecular selectivity of calycosin-MIPs as a critical parameter was evaluated using the template and other high content compounds in AR. Based on it, using the calycosin-MIPs material via solid-phase extraction procedures was applied for the knockout of flavonoid aglycons in AR. Finally, hypoxia/reoxygenation model in H9c2 cells was used to evaluate the activity of the AR extract before and after knockout. The results showed that calycosin-MIPs as recognition materials for flavonoid aglycons in AR are applied in one-step separation with high selectivity and tunability. The subextract in the absence of flavonoid aglycons has been demonstrated to clarify the cardio-protective components of AR. In conclusion, this proof-of-principle study is the first one showing that molecular imprinting technology coupled with a bioassay can be used to explore the bioactive variability from the perspective of multicomponent separation of herbal medicine. PMID- 30245073 TI - Influence of charged aerosol detector instrument settings on the ultra-high performance liquid chromatography analysis of fatty acids in polysorbate 80. AB - The analysis of polysorbate 80 is a challenge because all components lack a chromophore. Here, an ultra-high-performance liquid chromatography system equipped with a charged aerosol detector (UHPLC-CAD) was used to study the effect of systematic variation of the CAD settings, namely evaporation temperature, filter constant and power function value (PFV), on the detector response of fatty acid standards and manufacturing batches of polysorbate. Evaporation temperature and filter constant strongly affect the detection limits described by signal-to noise (S/N) ratios. Although evaporation temperature can be increased to improve signal to noise ratios, analyte volatility at higher temperatures is an important limiting factor. The PFV was found to be a strong tool for optimizing response linearity, but the optimal PFV differed depending on analyte volatility. Because PFV optimization required some additional measurement time and because double logarithmic transformation at the default PFV of 1.0 yielded satisfying universal results with less measurement time over a range of two orders of magnitude for every homologue fatty acid from C14 to C18, use of the log-log transformation is the favored linearization strategy. Possible optimization procedures for semi volatile substances are presented. Overall, this new UHPLC method method offers improved detection limits, as well as time savings of over 75% and eluent savings of more than 40% compared to the previously published HPLC-CAD method for polysorbate analysis. PMID- 30245074 TI - Analysis of calystegines in tomato-based products by liquid chromatography Orbitrap mass spectrometry. AB - Taking into account the high consumption of tomato and tomato-based products, a study of the occurrence of 7 nortropane alkaloids (calystegines A3, A5, B1, B2, B3, B4 and C1) in this type of matrix has been performed. For that purpose, a simple and fast solid-liquid extraction with methanol/water (50/50, v/v) has been developed, and then liquid chromatography, using a HILIC-A as stationary phase, coupled to high resolution mass spectrometry (LC-HRMS-Orbitrap) has been used for their determination. The developed method was validated and recoveries ranged from 96 to 121%, and relative standard deviations lower than or equal to 16% were obtained. Limits of quantification (LOQ) were established at 0.1 (B4), 0.25 (B3) and 0.5 (A3, A5, B1, B2 and C1) mg/kg. Twelve different samples were analyzed, comprising 4 crushed tomatoes, 4 fried tomatoes and 4 jam tomatoes. Calystegines A3 and B2 were identified in all the analyzed samples, while calystegine B3 was determined in all the fried tomatoes as well as in two crushed tomatoes and one jam tomato at concentrations ranging from 0.4 mg/kg (calystegine B2) to 19.0 mg/kg (calystegine A3). Although calystegine A5 was also detected in all the samples, only 3 of them gave concentrations higher than LOQ. Additionally, calystegine B1 was found in one jam tomato at 1.9 mg/kg. PMID- 30245075 TI - A Paradigm Shift in the Trophic Importance of Jellyfish? AB - The past 30 years have seen several paradigm shifts in our understanding of how ocean ecosystems function. Now recent technological advances add to an overwhelming body of evidence for another paradigm shift in terms of the role of gelatinous plankton (jellyfish) in marine food webs. Traditionally viewed as trophic dead ends, stable isotope analysis of predator tissues, animal-borne cameras, and DNA analysis of fecal and gut samples (metabarcoding) are all indicating that many taxa routinely consume jellyfish. Despite their low energy density, the contribution of jellyfish to the energy budgets of predators may be much greater than assumed because of rapid digestion, low capture costs, availability, and selective feeding on the more energy-rich components. Feeding on jellyfish may make marine predators susceptible to ingestion of plastics. PMID- 30245077 TI - Unsupervised toothbrushing: Risk of airway injury in young children. PMID- 30245076 TI - Clinical practice guideline. Diagnosis and prevention of colorectal cancer. 2018 Update. AB - This document updates the recommendations made by the Spanish Society of Family and Community Medicine and the Spanish Association of Gastroenterology for the diagnosis and prevention of colorectal cancer (CRC). In order to evaluate the quality of the evidence and determine the recommendation levels of the interventions, we used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. This document establishes optimal delay intervals based on symptoms and the faecal immunochemical test (FIT) and recommends reducing the barriers for diagnostic confirmation in symptomatic subjects. With regard to CRC screening in the average-risk population, we propose strategies to achieve the universal implementation of organised CRC screening programmes based on biennial FIT and to increase the participation of the target population, including the involvement of Primary Healthcare. This Clinical Practice Guideline recommends universal screening for Lynch syndrome with mismatch repair proteins immunohistochemistry or microsatellite instability in incident CRCs and the use of gene panels in patients with adenomatous polyposis. It also updates the strategies to reduce the incidence and mortality of both CRC and other tumours associated with hereditary syndromes. Regarding non-hereditary familial CRC and surveillance after resection of adenomas, serrated lesions or CRC, we established the recommendations based on the attributable risk and the risk reduction of the proposed intervention. Finally, the document includes recommendations regarding surveillance intervals in inflammatory bowel disease and the attitude towards dysplasia. PMID- 30245078 TI - Relationship between serum Pentraxin 3 and pro-adrenomedullin levels with acute cholecystitis. AB - OBJECTIVES: The perforation of the gallbladder (GP) is one of the most significant complications of acute cholecystitis. A biochemical marker indicating the GP has not been determined fully to date. Pentraxin 3 and pro-adrenomedullin (Pro-ADM) proteins are novel acute phase reactants. We aimed to investigate the relationship between serum Pentraxin 3 and Pro-ADM and the GP in patients with acute cholecystitis. METHODS: This prospective cross-sectional study was conducted on patients with acute cholecystitis in a tertiary care emergency department during the six-month period. The acute cholecystitis patients were divided into two groups as with GP, and without GP. Additionally, patients with GP were evaluated according to pericholecystic fluid and gallbladder wall thickness. Serum levels of pro-ADM and pentraxin 3, WBC, CRP and sedimentation rate were measured in all patients. RESULTS: A total of 60 patients with acute cholecystitis were included in the study. Pro-ADM and pentraxin 3 levels were significantly higher in patients with GP and the with pericholecystic free fluid (p < 0.0001). There was no significant relationship between serum pentraxin 3 and pro-ADM with gallbladder wall thickness (p > 0.05) According to the ROC analysis, serum Pentraxin 3 levels of >=4.9 ng/mL could predict GP with a sensitivity of 75% and a specificity of 85% and serum pro-ADM levels of >=97 nmol/L with sensitivity and specificity of 100% and 95%. CONCLUSION: Our study results reveal that serum Pentraxin 3 and pro-ADM may be novel biochemical parameters in the detection of GP in acute cholecystitis cases. PMID- 30245079 TI - Derivation of a screen to identify severe sepsis and septic shock in the Emergency Department-BOMBARD vs. SIRS and qSOFA. AB - STUDY OBJECTIVE: To predict severe sepsis/septic shock in ED patients. METHODS: We conducted a retrospective case-control study of patients >=18 admitted to two urban hospitals with a combined ED census of 162,000. Study cases included patients with severe sepsis/septic shock admitted via the ED. Controls comprised admissions without severe sepsis/septic shock. Using multivariate logistic regression, a prediction rule was constructed. The model's AUROC was internally validated using 1000 bootstrap samples. RESULTS: 143 study and 286 control patients were evaluated. Features predictive of severe sepsis/septic shock included: SBP <= 110 mm Hg, shock index/SI >= 0.86, abnormal mental status or GCS < 15, respirations >= 22, temperature >= 38C, assisted living facility residency, disabled immunity. Two points were assigned to SI and temperature with other features assigned one point (mnemonic: BOMBARD). BOMBARD was superior to SIRS criteria (AUROC 0.860 vs. 0.798, 0.062 difference, 95% CI 0.022-0.102) and qSOFA scores (0.860 vs. 0.742, 0.118 difference, 95% CI 0.081-0.155) at predicting severe sepsis/septic shock. A BOMBARD score >= 3 was more sensitive than SIRS >= 2 (74.8% vs. 49%, 25.9% difference, 95% CI 18.7-33.1) and qSOFA >= 2 (74.8% vs. 33.6%, 41.2% difference, 95% CI 33.2-49.3) at predicting severe sepsis/septic shock. A BOMBARD score >= 3 was superior to SIRS >= 2 (76% vs. 45%, 32% difference, 95% CI 10-50) and qSOFA >= 2 (76% vs. 29%, 47% difference, 95% CI 25 63) at predicting sepsis mortality. CONCLUSION: BOMBARD was more accurate than SIRS and qSOFA at predicting severe sepsis/septic shock and sepsis mortality. PMID- 30245080 TI - Corrigendum to "Ventilation distribution and lung recruitment with speaking valve use in tracheostomised patient weaning from mechanical ventilation in intensive care" [Journal of Critical Care 40 (2017) 164-170]. PMID- 30245081 TI - Proposed Title X Regulatory Changes: Silencing Health Care Providers and Undermining Quality of Care. PMID- 30245082 TI - Temporary placements: A crisis-management strategy for physically abused children? AB - A large majority of children who are placed outside the family home experience temporary placements (between 1 to 60 days) at some point in time. Yet, information on the use of temporary placements remains fragmentary, with only occasional indirect references. This scant information does, however, suggests a particular link between physical abuse and temporary placements. The objective of the present study is to describe the context in which temporary placements are used by children's services in Quebec (Canada) while analyzing the associative link between temporary placements and physical abuse as the reason for the placement. Our study is based on a population cohort of 10,181 children placed in Quebec who have been followed for four years. Propensity-weighted multinomial regression analysis was used to assess the relative importance of the various individual pre-placement factors that may be associated with physical abuse. Results show that children investigated for physical abuse alone are 6.335 times more likely to have temporary placement trajectories compared to children investigated for other reasons. Cases that involved physical abuse combined with other reasons, were between 33.4% and 41% more likely to involve trajectories with temporary placements, than cases that were investigated for reasons other than physical abuse. Sex, age, and history of services have been used as covariates. In conclusion, the use of temporary placements is discussed with regards to the mandate of child-protection services and of certain etiological profiles of physical abuse. PMID- 30245083 TI - Prospective Isolation and Characterization of Genetically and Functionally Distinct AML Subclones. AB - Intra-tumor heterogeneity caused by clonal evolution is a major problem in cancer treatment. To address this problem, we performed label-free quantitative proteomics on primary acute myeloid leukemia (AML) samples. We identified 50 leukemia-enriched plasma membrane proteins enabling the prospective isolation of genetically distinct subclones from individual AML patients. Subclones differed in their regulatory phenotype, drug sensitivity, growth, and engraftment behavior, as determined by RNA sequencing, DNase I hypersensitive site mapping, transcription factor occupancy analysis, in vitro culture, and xenograft transplantation. Finally, we show that these markers can be used to identify and longitudinally track distinct leukemic clones in patients in routine diagnostics. Our study describes a strategy for a major improvement in stratifying cancer diagnosis and treatment. PMID- 30245084 TI - [Indications for breast reconstruction after mastectomy according to the oncological situation]. AB - Breast reconstruction is an integral part of breast cancer treatment. It must be systematically mentioned when the disease is announced and proposed at an optimal time during cancer management. In case of ductal carcinoma in situ, reconstruction should be proposed at the same time as mastectomy, which generally preserves the skin. The conservation of the nipple-areolar complex should be further evaluated. In the case of invasive breast carcinoma, breast reconstruction is generally proposed at a distance from the oncological time, except for patients requiring neither chemotherapy nor postoperative radiotherapy for whom reconstruction can be immediate. Finally, in the case of prophylactic synchronous contralateral mastectomy, reconstruction should never delay the overall management of breast cancer. PMID- 30245085 TI - Mutational Profile of Aggressive, Localised Prostate Cancer from African Caribbean Men Versus European Ancestry Men. AB - Causes of high mortality of prostate cancer in men of African ancestry living in the French West Indies are still debated, between suspicions of environmental factors and genetic susceptibility. We report an integrated genomic study of 25 tumour tissues from radical prostatectomy of aggressive (defined by International Society of Urological Pathology >=3) prostate cancer patients (10 African Caribbean and 15 French Caucasian) using single nucleotide polymorphism arrays, whole-genome sequencing, and RNA sequencing. The results show that African Caribbean tumours are characterised by a more frequent deletion at 1q41-43 encompassing the DNA repair gene PARP1, and a higher proportion of intrachromosomal rearrangements including duplications associated with CDK12 truncating mutations. Transcriptome analyses show an overexpression of genes related to androgen receptor activity in African Caribbean tumours, and of PVT1, a long non-coding RNA located at 8q24 that confirms the strong involvement of this region in prostate tumours from men of African ancestry. Patient summary: Mortality of prostate cancer is higher in African Caribbean men than in French Caucasian men. Specificities of the former could be explained by genomic events linked with key genes such as DNA damage pathway genes PARP1, CDK12, and the oncogenic long non-coding RNA gene PVT1 at the 8q24 prostate cancer susceptibility locus. PMID- 30245086 TI - The Combination of Enzalutamide and Opioids: A Painful Pitfall? PMID- 30245087 TI - Clinical, morphological, and molecular characterization of an undetermined Babesia species in a maned wolf (Chrysocyon brachyurus). AB - A possible novel Babesia species infection of a maned wolf (Chrysocyon brachyurus) was first reported in 2012. The current case details a confirmed report of a maned wolf with infection by an undetermined species of Babesia. As the mortality and morbidity of babesiosis is high, this may become a significant concern to captive maned wolves, which are considered a near-threatened species by the World Association of Zoos and Aquariums. The aim of this study is to report the clinical, morphological and molecular characterization of this Babesia species. A 2.5-year-old, intact female maned wolf was found laterally recumbent with pale mucous membranes and jaundice the morning of presentation. Hematological and serum biochemical data were consistent with babesiosis and showed a regenerative severe anemia, leukocytosis, thrombocytopenia, hyperbilirubinemia, azotemia, increased creatine phosphokinase and increase alanine aminotransferase. On blood film review, inclusion bodies were seen in the red blood cells with cytomorphological features that were most consistent with a small form Babesia species. A blood sample was sent for polymerase chain reaction (PCR) testing and multi-locus sequence analyses. These findings suggested a unique Babesia species that is most closely related to a Babesia species (Babesia sp. AJB-2006) that has been found to infect raccoons (Procyon lotor) in North America. Although the cytomorphological features of the piroplasms and the clinical presentation were similar in both the current and 2012 case, when comparing the 18S melt curve temperature of the two Babesia isolates, the peak temperature was different. Unfortunately, genetic material from the 2012 case was not available so comparison of multi-locus gene sequences could not be performed, excluding the possibility to definitively state if the Babesia spp. from both cases were distinct from each other. The maned wolf was treated with a whole blood transfusion, dexamethazone (0.28 mg/kg IM), azithromycin (10 mg/kg in NaCl SC), atavaquone (1.5 cc PO), and 2 imidocarb (6.6 mg/kg IM) injections, and clinically improved. These findings demonstrate the need to further characterize the molecular and epidemiological differences of the Babesia species in this case report and the Babesia species known to infect raccoons. PMID- 30245088 TI - Continued expansion of tick-borne pathogens: Tick-borne encephalitis virus complex and Anaplasma phagocytophilum in Denmark. AB - Tick-borne encephalitis virus (TBEV) is a tick-transmitted flavivirus within the tick-borne encephalitis (TBE) complex. The TBE complex is represented by both TBEV and louping ill virus (LIV) in Denmark. Anaplasma phagocytophilum is also transmitted by ticks and is believed to play an essential role in facilitating and aggravating LIV infection in sheep. This study aimed to describe the distribution of TBE complex viruses in Denmark, to establish the possible emergence of new foci and their association with the distribution of A. phagocytophilum. We performed a nationwide seroprevalence study of TBE complex viruses using roe deer (Capreolus capreolus) as sentinels and determined the prevalence of A. phagocytophilum in roe deer. Danish hunters obtained blood samples from roe deer during the hunting season of 2013-14. The samples were examined for TBEV-specific antibodies by virus neutralization tests (NT). A. phagocytophilum infection was assessed by specific real-time-PCR. The overall seroprevalence of the TBE complex viruses in roe deer was 6.9% (51/736). The positive samples were primarily obtained from a known TBE endemic foci and risk areas identified in previous sentinel studies. However, new TBE complex risk areas were also identified. The overall prevalence of A. phagocytophilum was 94.0% (173 PCR-positive of 184 roe deer), which is twice the rate observed ten years ago. These results point to an expansion of these tick-borne diseases geographically and within reservoir populations and, therefore, rationalize the use of sentinel models to monitor changes in transmission of tick-borne diseases and development of new risk areas. We found no association between TBE complex positive roe deer and the prevalence of A. phagocytophilum, as almost all roe deer were infected. Based on our findings we encourage health care providers to be attentive to tick-borne illnesses such as TBE when treating patients with compatible symptoms. PMID- 30245089 TI - Usefulness of CT-based measurement of volar prominence for evaluation of risk of flexor tendon injury following fixation of a distal radius fracture. AB - BACKGROUND: Although some radiographic evaluations of the risk of flexor tendon injury following fixation of a distal radius fracture are useful, these radiographic measurements are limited because of their inability to obtain three dimensional measurements. We hypothesized that CT-based measurements would be more sensitive indicators for risk estimation than radiography. METHODS: We retrospectively evaluated the relationship between plate positioning and the incidence of flexor tendon symptoms based on postoperative radiographic and CT based measurements in 99 hands that were followed up for more than 12 months. We also compared the reproducibility, diagnostic accuracy, and ability to detect the plate-bone gap between radiographic and CT-based measurements. We also assessed the correlation between the volar prominence and plate-bone gap using CT. Multivariable analysis using stepwise logistic regression was performed to identify factors independently associated with tendon rupture or irritation. RESULTS: In single variable analysis, we found that the volar tilt was significantly smaller and the radiographic plate-to-critical line distance (PCL), CT-PCL, and CT-gap were significantly greater in the group with tendon irritation or rupture. Multivariable logistic regression analysis indicated that the CT based measurement of the volar prominence is a significantly positive independent predictor of tendon rupture or irritation. CONCLUSION: CT-based measurement of the volar prominence may be one of the best radiographic predictors of the risk of flexor tendon injury following fixation of a distal radius fracture regardless of the plate type and distal prominence and the extent of rotation. This measurement may assist surgeons when deciding on the need for removal of hardware to decrease the long-term risk of flexor tendon rupture. PMID- 30245090 TI - Surgical management for middle or lower thoracic spinal tuberculosis (T5-T12) in elderly patients: Posterior versus anterior approach. AB - BACKGROUND: Spinal tuberculosis accounts for more than 50% of bone tuberculosis cases. This study compared clinical, radiological and functional outcomes between anterior and posterior approaches for treatment of middle or lower thoracic spinal tuberculosis in elderly patients. METHODS: We retrospectively examined middle or lower thoracic spinal tuberculosis (T5-T12) in patients over 65 years. All procedures included debridement, decompression, autologous bone graft and fixation. Surgical procedure, surgical duration, estimated blood loss during surgery and laboratory results were recorded. Pleural effusion volume, thoracic cavity volume, Oswestry Disability Index score, neurological status, radiological parameters and complication rate were evaluated. RESULTS: No significant difference was found in surgical duration, blood loss, kyphosis angle correction, loss of correction, thoracic cavity volume, or complication rate between the two groups (P > 0.05). Average postoperative pleural effusion volumes were 605.9 +/- 209.5 mL (377-1074 mL) and 262.9 +/- 228.1 mL (0-702.4 mL) in the anterior and posterior groups, respectively (P = 0.004). Average hospitalization durations were 26.4 +/- 10.5 days (17-53 days) and 19.2 +/- 5.0 days (14-30 days) (P = 0.04). Average postoperative serum albumin levels were 24.19 +/- 3.84 g/L (19 29.5 g/L) and 28.24 +/- 2.52 g/L (24.4-31.6 g/L) (P = 0.01). No relapse or reinfection was observed in either group at the final follow-up. Surgical revision was not required in either group. CONCLUSIONS: Both anterior and posterior surgeries can be used to treat middle or lower thoracic spinal (T5-T12) tuberculosis in elderly patients. In general, the posterior approach might be superior, especially for patients with poor general health. PMID- 30245091 TI - New radiographic standards for age at appearance of the ossification center of the femoral head in Japanese: Appearance at <=12 months of age is normal in Japanese infants. AB - BACKGROUND: The ossification center of the femoral head reportedly appears at 7-8 months in 95% infants in the radiographs, but its appearance often delays in Japanese normal infants. The purpose of this study was to survey the age at appearance of the femoral head in the radiographs, evaluate the normal standards of its appearance in Japanese infants, and determine whether the acetabular state affects the time of its appearance. MATERIALS AND METHODS: The patients comprised 436 infants consulted with our institution because of a limitation of abduction in flexion (LA), acetabular dysplasia, or suspected developmental dysplasia of the hip (DDH). Among these patients, 111 infants (222 hips) without radiographic appearance of the femoral head at the first visit were reviewed. The 222 hips were classified into three groups: alpha angle >=30 degrees (DDH + group), <30 degrees with LA (DDH-/LA + group), or < 30 degrees without LA (DDH-/LA-group). The age at appearance of the femoral head was investigated in the radiograph in each group. RESULTS: The 50th percentile of the age at appearance of the femoral head was 6 months in the DDH-/LA- and DDH-/LA + groups and 8 months in the DDH + group. The femoral head significantly appeared earlier in the DDH-/LA- and DDH /LA + groups than in the DDH + group (P < 0.01). The 95th percentile was 12 months in all groups. CONCLUSIONS: Radiographic appearance of the ossification center of the femoral head by 12 months of age is normal in Japanese infants. When the alpha angle is >= 30 degrees , the age at appearance of the femoral head is sometimes delayed. PMID- 30245092 TI - The clinical outcomes and the ability to sit straight in the Japanese style following high tibial osteotomy combined with osteochondral autologous transfer for osteonecrosis of the medial femoral condyle. AB - BACKGROUND: There have been some reports of high tibial osteotomy combined with osteochondral autograft transfer for osteonecrosis of the medial femoral condyle of the knee. However, few of them have focused on the deep knee flexion needed to sit straight in the Japanese style. PURPOSE: To evaluate the clinical outcomes and the knee flexion of HTO combined with OAT for osteonecrosis of the medial femoral condyle of the knee, especially the ability to sit straight in the Japanese style. METHODS: Between 1998 and 2012, valgus HTO combined with OAT was performed in 23 patients for stage IV osteonecrosis according to Koshino's radiological classification of the medial femoral condyle. The follow-up period was more than 2 years in all cases. The mean age at the time of the surgery was 65.8 years, and the mean follow-up period was 72.2 months. The function of the knee and the ability to sitting straight in the Japanese style were examined. Twenty-one knees were examined with second-look arthroscopy to assess the recipient and donor sites. RESULTS: The JOA scale and IKDC subjective scores were significantly improved. Twelve patients were able to sit straight in the Japanese style after the surgery, compared to 3 patients who were able to do so before surgery. On second-look arthroscopy of 21 knees, the average ICRS score was 10.5 points. No patient needed additional surgery except for removal of the implants. CONCLUSION: Valgus HTO combined with OAT is one treatment option for osteonecrosis of the medial femoral condyle with osteoarthritis. In the present study, many of the patients regained good knee function, and 50% of the patients were able to sit straight in the Japanese style after surgery, which is a higher rate than after total knee arthroplasty and unilateral knee arthroplasty. PMID- 30245093 TI - Predictors for progression of two different types of cervical lesions in rheumatoid arthritis treated with biologic agents. AB - BACKGROUND: Biologic agents (BAs) enabled not only a reduction of disease activity but also a slowing down of structural damage to the joints in patients with rheumatoid arthritis (RA). However, the incidence of cervical lesions in patients with RA is still high. PURPOSE: To elucidate the predictors for the progression of two different cervical lesions in patients with RA under BA treatment. METHODS: Of 151 subjects who received more than two years of continuous BA treatment, 101 subjects who had cervical X-ray images taken at baseline and final visit were enrolled. The mean disease duration and mean radiography interval were 10.6 years and 4.4 years, respectively. The existence and progression of cervical lesions (atlanto-axial subluxation [AAS], vertical subluxation [VS], and subaxial subluxation [SS]) were investigated. And predictors for the AAS or VS progression were analyzed by multivariate logistic regression analysis. RESULTS: The incidence of cervical lesions at baseline were no pre-existing cervical lesion (none) in 50 cases (50%), AAS only in 32 (32%), both AAS and VS in 12 (12%), and VS only in 7 cases (7%). In the none group, only 4 cases of AAS progression (8%) was observed during the follow-up. In contrast, in the groups with pre-existing cervical lesions, a high incidence of VS progression was observed (63% in the AAS only group, 58% in the AAS + VS group, and 71% in the VS only group). Multivariate regression analysis demonstrated that the DAS-CRP value at baseline (odds ratio [OR] = 9.23) and matrix metaloprotease 3 level at baseline (OR = 1.01) were significant predictors for the progression of AAS, and pre-existing AAS (OR = 18.38) was a sole significant predictor for the progression of VS. CONCLUSIONS: Cervical lesions progressed irrespective of disease activity after AAS development. Strict disease control before the development of AAS is crucial for preventing further progression and development of cervical lesions. PMID- 30245094 TI - Modified distal tibial oblique osteotomy for osteoarthritis of the ankle: Operative procedure and preliminary results. AB - BACKGROUND: Low tibial osteotomy is an effective joint-preserving surgery for ankle arthritis. However, poor postoperative wound healing, infection, and delayed or non-union of bones remain significant concerns. We describe a modified distal tibial oblique osteotomy procedure and report preliminary results for varus ankle arthritis. METHODS: The osteotomy path consisted of an oblique doglegged line from the lateral end of the distal tibia to a proximal point about one-third from the lateral edge and continuing along an arc defined by virtual coronal-plane rotation of the doglegged line to the medial edge. After osteotomy, the distal tibial fragment was rotated distally in the coronal plane for realignment while maintaining contact with the proximal tibia and the distal tibial fragment. The resulting wedge-shaped gap was filled with artificial bone blocks and tibial bone projecting medially from rotation. A locking plate was then applied for stabilization. We evaluated 7 ankles from 6 osteoarthritis patients both clinically and radiographically following this procedure. RESULTS: Bone union was achieved within 3 months for all patients. The Japanese Society for Surgery of the Foot ankle-hindfoot scale improved from a mean of 38.4 points preoperatively to 85.7 points at the latest follow-up. No wound healing problems, infections, or nerve disturbances were observed. Multiple radiographic parameters were also improved following the operation. CONCLUSIONS: This procedure maintains close bone contact for better postoperative union, obviates the need for iliac bone harvesting, and reduces tension on medial soft tissue. We believe these modifications are potential advantages for achieving stable results in patients with ankle osteoarthritis. PMID- 30245095 TI - Comparison of three approaches for femoral tunnel during double-bundle anterior cruciate ligament reconstruction: A case controlled study. AB - BACKGROUND: It is still controversial whether which femoral tunnel creation technique is best during anterior cruciate ligament reconstruction (ACLR). We aimed to clarify the features of three different techniques based on the femoral tunnel position created with the same tunnel-creating concept and the measurement data. METHODS: The femoral tunnel of double-bundle (DB) ACLR was created using the behind-remnant approach in a remnant preserved manner following the policy of our institute. The trans-tibial approach (TT) was applied for all primary ACL injured cases until December 2012. The trans-portal approach (TP) was applied from January to September 2013, and the outside-in approach (OI) was indicated from October 2013 to March 2014. We compared the femoral tunnel aperture positions with the postoperative three-dimensional computed tomography (3D-CT). Additionally, the femoral tunnel length and the septum distance of each anteromedial (AM) and posterolateral (PL) tunnel were analyzed. RESULTS: The AM tunnel aperture position of TT was significantly higher and shallower than that of TP in knee flexion position. The femoral tunnel length of TP was significantly shorter than that of TT and OI. The septum between each tunnel of OI trended wider than that of TT and TP. CONCLUSIONS: The AM tunnel aperture position of TT runs the risk of a high and shallow position. TP runs the risk of insufficiently short tunnel length. It is important to apply each method flexibly to each case because no single best approach was found. PMID- 30245096 TI - [Ultrasound guided airway access]. AB - Ultrasound has increasingly growing applications in anesthesia. This procedure has proven to be a novel, non-invasive and simple technique for the upper airway management, proving to be a useful tool, not only in the operating room but also in the intensive care unit and emergency department. Indeed, over the years mounting evidence has showed an increasing role of ultrasound in airway management. In this review, the authors will discuss the importance of ultrasound in the airway preoperative assessment as a way of detecting signs of difficult intubation or to define the type and/or size of the endotracheal tube as well as to help airway procedures such as endotracheal intubation, cricothyrotomy, percutaneous tracheal intubation, retrograde intubation as well as the criteria for extubation. PMID- 30245097 TI - Cytokine levels in persistent skin lesions of adult-onset Still disease. PMID- 30245098 TI - The gastrointestinal symptoms present in patients with postural tachycardia syndrome: A review of the literature and overview of treatment. AB - Orthostatic intolerance, including postural tachycardia syndrome, is often associated with gastrointestinal symptoms. In the vast majority of the cases, the gastrointestinal symptoms are not secondary to the orthostatic disorder, but rather just a comorbid condition. This concept is critical, since treatment aimed at the orthostatic condition will not improve the gastrointestinal symptoms. Only when the gastrointestinal symptoms develop in the upright position and improve or resolve in the supine position, they may be related to the orthostatic stress. The most common symptoms associated with orthostatic intolerance include nausea, dyspepsia, bloating and constipation. The majority of subjects do not have gastroparesis. The chapter discusses available treatments of these conditions. PMID- 30245099 TI - Differences in expectations of passing standards in communication skills for pre clinical and clinical medical students. AB - OBJECTIVE: Communication and interpersonal skills (CIS) are essential elements of competency-based education. We examined defensible CIS passing levels for medical students completing basic sciences (second-year students) and clinical training (fourth-year students), using five standard setting methods. METHODS: A 14-item CIS scale was used. Data from second-year (n = 190) and fourth-year (n = 170) students were analyzed using descriptive statistics and generalizability studies. Fifteen judges defined borderline CIS performance. Cut scores and fail rates from five standard setting methods (Angoff, Borderline-Group, Borderline-Regression, Contrasting-Groups, and Normative methods) were examined. RESULTS: CIS performance was similar during second-year (Mean = 74%, SD = 6%) and fourth-year (Mean = 72%, SD = 5%) students. Judges using the Angoff method expected greater competence at the fourth-year level, as reflected in the Angoff cut scores (second-year = 53% with 0% fail, fourth-year = 66% with 10% fail). Cut scores from the remaining methods did not differentiate between training levels. We found evidence of case specificity. CONCLUSION: Performance on CIS may be case specific. Passing standards for communication skills may require employing approaches such as the Angoff method that are sensitive to expectations of learner performance for different levels of training, competencies, and milestone levels. PRACTICE IMPLICATIONS: Institutions that want to encourage continued growth in CIS should apply appropriate standard setting methods. PMID- 30245100 TI - Clinical and Disease Characteristics From REVEAL at Time of Enrollment (Baseline): Prospective Observational Study of Patients With Polycythemia Vera in the United States. AB - BACKGROUND: Polycythemia vera (PV) has a prevalence of 44 to 57 per 100,000 people in the United States. Prospective data concerning the demographics, clinical characteristics, and treatment patterns of patients with PV in the United States are lacking. PATIENTS AND METHODS: The ongoing, prospective, observational REVEAL study evaluates demographics, disease burden, clinical management, patient-reported outcomes, and health care resource utilization of adult patients with PV in the United States. This report summarizes the demographics and clinical characteristics of patients at enrollment (baseline). RESULTS: Patients (n = 2510) were a median age of 67.0 years, 54.2% were male, and 89.1% were white. The median time from PV diagnosis to study enrollment was 4.0 (range, 0-56.3) years. Most patients (89.7%) were diagnosed after an abnormal blood test. Less than half (49.2%) underwent JAK2 mutation analysis, of whom 95.8% were JAK2 V617F mutation positive; < 1% were positive for JAK2 exon 12 mutations. At enrollment, 47.7% of patients had elevated hematocrit (> 45%), 35.8% had elevated platelets (> 400 * 109/L), and 37.0% had elevated leukocytes (> 10 * 109/L). Most patients (94.5%) were receiving active PV treatment, predominantly therapeutic phlebotomy alone (33.6%), hydroxyurea monotherapy (29.0%), or hydroxyurea plus phlebotomy (23.7%). Thrombotic events occurred in 11.9% of patients before PV diagnosis (venous, 6.7%; arterial, 5.7%), and 8.3% between diagnosis and enrollment. Hypertension (70.6%) was the most common previous medical condition. CONCLUSION: REVEAL enrollment data inform our understanding of the baseline demographics, diagnostic approach, disease characteristics, and treatment patterns of patients with PV in the United States. Longitudinal real-world data collected in this study will complement information collected during randomized controlled clinical trials. PMID- 30245101 TI - A Conserved Role for Serotonergic Neurotransmission in Mediating Social Behavior in Octopus. AB - Human and octopus lineages are separated by over 500 million years of evolution [1, 2] and show divergent anatomical patterns of brain organization [3, 4]. Despite these differences, growing evidence suggests that ancient neurotransmitter systems are shared across vertebrate and invertebrate species and in many cases enable overlapping functions [5]. Sociality is widespread across the animal kingdom, with numerous examples in both invertebrate (e.g., bees, ants, termites, and shrimps) and vertebrate (e.g., fishes, birds, rodents, and primates) lineages [6]. Serotonin is an evolutionarily ancient molecule [7] that has been implicated in regulating both invertebrate [8] and vertebrate [9] social behaviors, raising the possibility that this neurotransmitter's prosocial functions may be conserved across evolution. Members of the order Octopoda are predominantly asocial and solitary [10]. Although at this time it is unknown whether serotonergic signaling systems are functionally conserved in octopuses, ethological studies indicate that agonistic behaviors are suspended during mating [11-13], suggesting that neural mechanisms subserving social behaviors exist in octopuses but are suppressed outside the reproductive period. Here we provide evidence that, as in humans, the phenethylamine (+/-)-3,4 methylendioxymethamphetamine (MDMA) enhances acute prosocial behaviors in Octopus bimaculoides. This finding is paralleled by the evolutionary conservation of the serotonin transporter (SERT, encoded by the Slc6A4 gene) binding site of MDMA in the O. bimaculoides genome. Taken together, these data provide evidence that the neural mechanisms subserving social behaviors exist in O. bimaculoides and indicate that the role of serotonergic neurotransmission in regulating social behaviors is evolutionarily conserved. PMID- 30245102 TI - A Plausible Microtubule-Based Mechanism for Cell Division Orientation in Plant Embryogenesis. AB - Oriented cell divisions are significant in plant morphogenesis because plant cells are embedded in cell walls and cannot relocate. Cell divisions follow various regular orientations, but the underlying mechanisms have not been clarified. We propose that cell-shape-dependent self-organization of cortical microtubule arrays is able to provide a mechanism for determining planes of early tissue-generating divisions and may form the basis for robust control of cell division orientation in the embryo. To show this, we simulate microtubules on actual cell surface shapes, from which we derive a minimal set of three rules for proper array orientation. The first rule captures the effects of cell shape alone on microtubule organization, the second rule describes the regulation of microtubule stability at cell edges, and the third rule includes the differential effect of auxin on local microtubule stability. These rules generate early embryonic division plane orientations and potentially offer a framework for understanding patterned cell divisions in plant morphogenesis. PMID- 30245103 TI - Robust Sensorimotor Learning during Variable Sentence-Level Speech. AB - Sensorimotor learning has been studied by altering the sound of the voice in real time as speech is produced. In response to voice alterations, learned changes in production reduce the perceived auditory error and persist for some time after the alteration is removed [1-5]. The results of such experiments have led to the development of prominent models of speech production. This work proposes that the control of speech relies on forward models to predict sensory outcomes of movements, and errors in these predictions drive sensorimotor learning [5-7]. However, sensorimotor learning in speech has only been observed following intensive training on a handful of discrete words or perceptually similar sentences. Stereotyped production does not capture the complex sensorimotor demands of fluid, real-world speech [8-11]. It remains unknown whether talkers predict the sensory consequences of variable sentence production to allow rapid and precise updating of speech motor plans when sensory prediction errors are encountered. Here, we used real-time alterations of speech feedback to test for sensorimotor learning during the production of 50 sentences that varied markedly in length, vocabulary, and grammar. Following baseline production, all vowels were simultaneously altered and played back through headphones in near real time. Robust feedforward changes in sentence production were observed that, on average, precisely countered the direction of the alteration. These changes occurred in every participant and transferred to the production of single words with varying vowel sounds. The results show that to maintain accurate sentence production, the brain actively predicts the auditory consequences of variable sentence-level speech. PMID- 30245104 TI - SHOU4 Proteins Regulate Trafficking of Cellulose Synthase Complexes to the Plasma Membrane. AB - Cell walls play critical roles in plants, regulating tissue mechanics, defining the extent and orientation of cell expansion, and providing a physical barrier against pathogen attack [1]. Cellulose microfibrils, which are synthesized by plasma membrane-localized cellulose synthase (CESA) complexes, are the primary load-bearing elements of plant cell walls [2]. Cell walls are dynamic structures that are regulated in part by cell wall integrity (CWI)-monitoring systems that feed back to modulate wall properties and the synthesis of new wall components [3]. Several receptor-like kinases have been implicated as sensors of CWI [3-5], including the FEI1/FEI2 receptor-like kinases [4]. Here, we characterize two genes encoding novel plant-specific plasma membrane proteins (SHOU4 and SHOU4L) that were identified in a suppressor screen of the cellulose-deficient fei1 fei2 mutant. shou4 shou4l double mutants display phenotypes consistent with elevated levels of cellulose, and elevated levels of non-crystalline cellulose are present in this mutant. Disruption of SHOU4 and SHOU4L increases the abundance of CESA proteins at the plasma membrane as a result of enhanced exocytosis. The SHOU4/4L N-terminal cytosolic domains directly interact with CESAs. Our results suggest that the SHOU4 proteins regulate cellulose synthesis in plants by influencing the trafficking of CESA complexes to the cell surface. PMID- 30245105 TI - Understanding the Molecular Basis of Salt Sequestration in Epidermal Bladder Cells of Chenopodium quinoa. AB - Soil salinity is destroying arable land and is considered to be one of the major threats to global food security in the 21st century. Therefore, the ability of naturally salt-tolerant halophyte plants to sequester large quantities of salt in external structures, such as epidermal bladder cells (EBCs), is of great interest. Using Chenopodium quinoa, a pseudo-cereal halophyte of great economic potential, we have shown previously that, upon removal of salt bladders, quinoa becomes salt sensitive. In this work, we analyzed the molecular mechanism underlying the unique salt dumping capabilities of bladder cells in quinoa. The transporters differentially expressed in the EBC transcriptome and functional electrophysiological testing of key EBC transporters in Xenopus oocytes revealed that loading of Na+ and Cl- into EBCs is mediated by a set of tailored plasma and vacuole membrane-based sodium-selective channel and chloride-permeable transporter. PMID- 30245106 TI - Hunter-Gatherers Maintain Assortativity in Cooperation despite High Levels of Residential Change and Mixing. AB - Widespread cooperation is a defining feature of human societies from hunter gatherer bands to nation states [1, 2], but explaining its evolution remains a challenge. Although positive assortment of cooperators is recognized as a basic requirement for the evolution of cooperation, the mechanisms governing assortment are debated. Moreover, the social structure of modern hunter-gatherers, characterized by high mobility, residential mixing, and low genetic relatedness [3], undermines assortment and adds to the puzzle of how cooperation evolved. Here, we analyze four years of data (2010, 2013, 2014, 2016) tracking residence and levels of cooperation elicited from a public goods game in Hadza hunter gatherers of Tanzania. Data were collected from 56 camps, comprising 383 unique individuals, 137 of whom we have data for two or more years. Despite significant residential mixing, we observe a robust pattern of assortment that is necessary for cooperation to evolve; in every year, Hadza camps exhibit high between-camp and low within-camp variation in cooperation. We find little evidence that cooperative behavior within individuals is stable over time or that similarity in cooperation between dyads predicts their future cohabitation. Both sets of findings are inconsistent with models that assume stable cooperative and selfish types, including partner choice models. Consistent with social norms, culture, and reciprocity theories, the strongest predictor of an individual's level of cooperation is the mean cooperation of their current campmates. These findings underscore the adaptive nature of human cooperation-particularly its responsiveness to social contexts-as a feature that is important in generating the assortment necessary for cooperation to evolve. PMID- 30245107 TI - Conserved SUN-KASH Interfaces Mediate LINC Complex-Dependent Nuclear Movement and Positioning. AB - Many nuclear positioning events involve linker of nucleoskeleton and cytoskeleton (LINC) complexes, which transmit forces generated by the cytoskeleton across the nuclear envelope. LINC complexes are formed by trans-luminal interactions between inner nuclear membrane SUN proteins and outer nuclear membrane KASH proteins, but how these interactions are regulated is poorly understood. We combine in vivo C. elegans genetics, in vitro wounded fibroblast polarization, and in silico molecular dynamics simulations to elucidate mechanisms of LINC complexes. The extension of the KASH domain by a single alanine residue or the mutation of the conserved tyrosine at -7 completely blocked the nuclear migration function of C. elegans UNC-83. Analogous mutations at -7 of mouse nesprin-2 disrupted rearward nuclear movements in NIH 3T3 cells, but did not disrupt ANC-1 in nuclear anchorage. Furthermore, conserved cysteines predicted to form a disulfide bond between SUN and KASH proteins are important for the function of certain LINC complexes, and might promote a developmental switch between nuclear migration and nuclear anchorage. Mutations of conserved cysteines in SUN or KASH disrupted ANC 1-dependent nuclear anchorage in C. elegans and Nesprin-2G-dependent nuclear movements in polarizing fibroblasts. However, the SUN cysteine mutation did not disrupt nuclear migration. Moreover, molecular dynamics simulations showed that a disulfide bond is necessary for the maximal transmission of cytoskeleton generated forces by LINC complexes in silico. Thus, we have demonstrated functions for SUN-KASH binding interfaces, including a predicted intermolecular disulfide bond, as mechanistic determinants of nuclear positioning that may represent targets for regulation. PMID- 30245109 TI - Phylotranscriptomics of Pristionchus Nematodes Reveals Parallel Gene Loss in Six Hermaphroditic Lineages. AB - Mutation and recombination are main drivers of phenotypic diversity, but the ability to create new allelic combinations is strongly dependent on the mode of reproduction. While most animals are dioecious (i.e., separated male and female sexes), in a number of evolutionary lineages females have gained the ability to self-fertilize [1, 2], with drastic consequences on effective recombination rate, genetic diversity, and the efficacy of selection [3]. In the genus Caenorhabditis, such hermaphroditic or androdioecious lineages, including C. briggsae and C. tropicalis, display a genome shrinkage relative to their dioecious sister species C. nigoni and C. brenneri, respectively [4, 5]. However, common consequences of reproductive modes on nematode genomes remain unknown, because most taxa contain single or few androdioecious species. One exception is the genus Pristionchus, with seven androdioecious species. Pristionchus worms are found in association with scarab beetles in worldwide samplings, resulting in deep taxon sampling and currently 39 culturable and available species. Here, we use phylotranscriptomics of all 39 Pristionchus species to provide a robust phylogeny based on an alignment of more than 2,000 orthologous clusters, which indicates that the seven androdioecious species represent six independent lineages. We show that gene loss is more prevalent in all hermaphroditic lineages than in dioecious relatives and that the majority of lost genes evolved recently in the Pristionchus genus. Further, we provide evidence that genes with male biased expression are preferentially lost in hermaphroditic lineages. This supports a contribution of adaptive gene loss to shaping nematode genomes following the evolution of hermaphroditism. PMID- 30245110 TI - Patient Demographics and Extracorporeal Membranous Oxygenation (ECMO)-Related Complications Associated With Survival to Discharge or 30-Day Survival in Adult Patients Receiving Venoarterial (VA) and Venovenous (VV) ECMO in a Quaternary Care Urban Center. AB - OBJECTIVE: Investigate how a multitude of patient demographics and extracorporeal membranous oxygenation (ECMO)-related complications affect 30-day survival or survival to discharge. DESIGN: Retrospective observational study. SETTING: Urban university hospital, quaternary care center. PARTICIPANTS: Patients who underwent ECMO circulatory support from January 2012 to May 2016. INTERVENTIONS: Date-based data extraction, univariate and multivariate regression analysis. MEASUREMENTS AND MAIN RESULTS: The hospital database contained complete data for 235 adult patients who received venoarterial ECMO (74.04 %) and venovenous ECMO (25.96 %); 106 patients (45.11%) survived. The independent predictors significant in the odds of in-hospital mortality in a multiregression model were age (odds ratio [OR] = 1.028, p = 0.008), extracorporeal cardiopulmonary resuscitation (ECPR) after unsuccessful high-quality CPR (OR = 7.93, p =0.002), cardiogenic shock as the primary indication for circulatory support (OR = 2.58, p = 0.02), acute kidney injury (AKI) before ECMO initiation (OR = 7.53, p < 0.001), time spent on ECMO in days (OR = 1.08, p = 0.03), and limb ischemia (OR = 3.18, p = 0.047). CONCLUSION: The most significant findings of advancing age, time spent on ECMO, AKI, ECMO use in the setting of cardiogenic shock, ECPR, and limb ischemia as a complication of ECMO all independently increase the odds of in-hospital and 30 day mortality. To the best of the authors' knowledge, this study is the first to demonstrate a significant relationship between limb ischemia and mortality. PMID- 30245108 TI - Inactivation of Medial Frontal Cortex Changes Risk Preference. AB - Humans and other animals need to make decisions under varying degrees of uncertainty. These decisions are strongly influenced by an individual's risk preference; however, the neuronal circuitry by which risk preference shapes choice is still unclear [1]. Supplementary eye field (SEF), an oculomotor area within primate medial frontal cortex, is thought to be an essential part of the neuronal circuit underlying oculomotor decision making, including decisions under risk [2-5]. Consistent with this view, risk-related action value and monitoring signals have been observed in SEF [6-8]. However, such activity has also been observed in other frontal areas, including orbitofrontal [9-11], cingulate [12 14], and dorsal-lateral frontal cortex [15]. It is thus unknown whether the activity in SEF causally contributes to risky decisions, or whether it is merely a reflection of neural processes in other cortical regions. Here, we tested a causal role of SEF in risky oculomotor choices. We found that SEF inactivation strongly reduced the frequency of risky choices. This reduction was largely due to a reduced attraction to reward uncertainty and high reward gain, but not due to changes in the subjective estimation of reward probability or average expected reward. Moreover, SEF inactivation also led to increased sensitivity to differences between expected and actual reward during free choice. Nevertheless, it did not affect adjustments of decisions based on reward history. PMID- 30245111 TI - Impact of Sex on the Outcome of Isolated Aortic Valve Replacement and the Role of Different Preoperative Profiles. AB - OBJECTIVE: The aim of this study was to compare the patient profiles and outcomes of men and women undergoing isolated aortic valve replacement. DESIGN: Patient data were analyzed retrospectively. SETTING: This single-center study was performed at Catharina Hospital in Eindhoven, the Netherlands. PARTICIPANTS: The study comprised 2,362 patients, of whom 1,040 (44%) were women and 1,322 were men (56%). INTERVENTIONS: Isolated aortic valve replacement was performed between January 1998 and December 2016. MEASUREMENTS AND MAIN RESULTS: The mean follow-up was 8.3 +/- 5.1 years. Women were relatively older (69.9 years v 64.6 years; p < 0.001); more of them were underweight, obese, and diabetic; and they had lower hemoglobin values and worse renal function than did men. However, fewer women than men experienced chronic obstructive pulmonary disease, aortic regurgitation, left ventricular dysfunction, and endocarditis. Early mortality did not differ significantly between men and women (p = 0.238). Overall survival was worse in women (p < 0.001). After correction for potential risk factors, female sex was not associated with worse survival. During the study period, the mean age of patients undergoing aortic valve replacement increased. In addition, the mean age at the time of death increased, following the trend of national statistics. CONCLUSIONS: Although women undergoing aortic valve replacement have relatively more risk factors than do men, early mortality in women is not significantly higher than in men. Overall survival is worse in women than in men; however, after adjustment for preoperative risk factors, there is no difference in overall survival between women and men. PMID- 30245112 TI - The Long QT Conundrum. PMID- 30245113 TI - A Peculiar Radial Artery Pressure Waveform After Aortic Valve Replacement. PMID- 30245114 TI - Establishment of Predictive Models for Nonocclusive Mesenteric Ischemia Comparing 8,296 Control with 452 Study Patients. AB - OBJECTIVE: The aim of this study was to develop clinical preoperative, intraoperative, and postoperative scores for early identification of patients who are at risk of nonocclusive mesenteric ischemia (NOMI). DESIGN: A retrospective analysis. SETTING: Single center. PARTICIPANTS: From January 2008 to December 2014, all patients from the Department of Thoracic and Cardiovascular Surgery were included on the basis of the hospital database. INTERVENTIONS: All mesenteric angiographically identified NOMI patients were compared with non-NOMI patients. MEASUREMENTS AND MAIN RESULTS: The study population of 8,748 patients was randomized into a cohort for developing the scores (non-NOMI 4,214 and NOMI 235) and a cohort for control (non-NOMI 4,082 and NOMI 217). Risk factors were identified using forward and backward Wald test and were included in the predictive scores for the occurrence of NOMI. C statistic showed that the scores had a high discrimination for the prediction of NOMI preoperatively (C statistic 0.79; p < 0.001), intraoperatively (C statistic 0.68; p < 0.001), and postoperatively (C statistic 0.85; p < 0.001). A combination of the preoperative, intraoperative, and postoperative risk scores demonstrated the highest discrimination (C statistic 0.87; p < 0.001). The combined score included the following risk factors: renal insufficiency (preoperative); use of cardiopulmonary bypass and intra-aortic balloon pump support (intraoperative); and reexploration for bleeding, renal replacement therapy, and packed red blood cells >= 4 units (postoperative). The results were similar in the control group. CONCLUSIONS: These scores could be useful to identify patients at risk for NOMI and promote a rapid diagnosis and therapy. PMID- 30245115 TI - Endometriosis and infertility: Insights into the causal link and management strategies. AB - When evaluating the correlation between endometriosis and infertility with application of the evidence-based guidelines to establish causality in medicine, it becomes apparent that endometriosis causes infertility. This is supported by a strong and consistent association between the two in various settings (prevalence, natural conception, intrauterine insemination (IUI), and assisted reproductive technologies (ARTs)), evidence for a temporal relation, arguments for a dose-response gradient, and proven effects of the removal of lesions on infertility. Next to surgical treatment of endometriosis lesions, medically assisted reproduction treatments such as IUI and ART such as in vitro fertilization are cornerstones of the management of endometriosis-related infertility. Because the revised American Society for Reproductive Medicine (rASRM) staging system is poorly correlated with pregnancy rates as opposed to the Endometriosis Fertility Index (EFI), the latter should be used as the preferred clinical tool to counsel patients on their postoperative fertility management options. PMID- 30245116 TI - Occult hepatitis C virus infection among haemodialysis patients. AB - BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) infection is a severe problem among patients on maintenance haemodialysis who are at particular risk for blood borne infections because of prolonged vascular access and potential for exposure to contaminated equipment. Occult hepatitis C virus infection (OCI) is defined as the presence of HCV RNA in liver or peripheral blood mononuclear cells (PBMCs) in the absence of detectable HCV antibody or HCV RNA in the serum. In this study, we aimed to investigate the existence of occult hepatitis C virus infection in PBMCs of haemodialysis (HD) patients in one center. Moreover, we tried to link the condition to risk factors associated with HCV infection in those patients. PATIENTS AND METHODS: We included 40 patients with renal diseases undergoing regular haemodialysis who were repeatedly anti-HCV negative. HCV RNA detection was tested by Quantitative Real time PCR in serum and PBMCs. RESULTS: The results of this study revealed that 23% of our haemodialysis patients have occult hepatitis C virus infection. There was a highly significant increase in ALT levels in patients with OCI versus the negative group. Also, there is a significant increase of history of blood transfusion in patients with occult HCV (p = 0.03) while the duration of haemodialysis showed no statistical significant difference between both groups. The viral load of the occult hepatitis C virus infection subjects ranged from 581to 74,307 copies/ml. CONCLUSION: These results highlight the potential risk of hepatitis C virus transmission from patients within haemodialysis units in Egypt. Isolation of patients on dialysis machines depending on the results of hepatitis serological markers is not enough. Testing for hepatitis C virus -RNA in peripheral blood mononuclear cells is more reliable in identifying patients with an OCI when a liver biopsy is not available. PMID- 30245117 TI - Two novel SNPs in the promoter region of PKR gene in hepatitis C patients and their impact on disease outcome and response to treatment. AB - BACKGROUND AND STUDY AIMS: The double-stranded RNA dependent protein kinase (PKR) plays a vital role in the immune system. During HCV infection, PKR has antiviral effect by inhibition of protein synthesis of the HCV. The functional single nucleotide polymorphisms (SNPs) in PKR promoter region might have a relation to HCV disease outcome and response to treatment. The objective of the present work was threefold. First, it proposed an optimized protocol for PCR amplification of PKR promoter. Second, it screened the promoter region of PKR gene in HCV Egyptian patients to detect the possible SNPs' function. Third, to study the association between the detected SNPs and the response to treatment. PATIENTS AND METHODS: The functional SNPs in PKR promoter region were detected using DNA sequencing in 40 HCV infected patients; 20 sustained virologic response (SVR) patients and 20 nonresponse (NR) patients after combined interferon/ribavirin therapy. Twenty healthy subjects were included as a control. RESULTS: Two functional SNPs were detected: rs62133148T>G and rs12992188C>T within our target PKR promoter region. In rs62133148 polymorphism, there is a significant difference between patients and control subjects for TT and TG genotypes (p < 0.0001). In addition, the G allele is more predominant in HCV patients. In rs12992188 polymorphism, the CC genotype is significantly different between patients and healthy control subjects (OR/95% CI: 0.033/0.006-0.172, p < 0.0001). The presence of C allele was significantly associated with the NR patients (OR/95%CI: 0.25/0.097-0.643, p = 0.006). The TT genotype is significantly different between SVR and NR (OR/95%CI: 8.5/1.54-46.871, p = 0.014). CONCLUSION: This study is a pioneer clinical study on these two functional SNPs (rs62133148T>G and rs12992188 C>T). The rs62133148 polymorphism does not show any association with response to treatment. The TT genotype in rs12992188 polymorphism shows association with response to treatment. Therefore, patients with TT genotypes were more likely to achieve SVR. PMID- 30245118 TI - Correction to Lancet Glob Health 2018; 6: e1132-38. PMID- 30245119 TI - Comments on "Enhanced removal of organic contaminants in water by the combination of peroxymonsulfate and carbonate", Science of the Total Environment, 647, 734 743 (2019). AB - This correspondence refers to the Science of the Total Environment article by Nie et al. entitled "Enhanced removal of organic contaminants in water by the combination of peroxymonsulfate and carbonate". Authors of this paper argue that it was CO32- that activated PMS oxidation of organic pollutants. However, the removal of pollutants was observed at pH <10 where CO32- was not a dominant species. Also, the concentration of carbonate in a solution open to atmosphere is not determined by the quantity of Na2CO3 or NaHCO3 added, but dictated by pH. These factors should not be ignored in the data interpretation. PMID- 30245120 TI - PARAMEDIC2 study: Ethical issues. PMID- 30245121 TI - A machine learning-based model for 1-year mortality prediction in patients admitted to an Intensive Care Unit with a diagnosis of sepsis. AB - INTRODUCTION: Sepsis is associated to a high mortality rate, and its severity must be evaluated quickly. The severity of illness scores used are intended to be applicable to all patient populations, and generally evaluate in-hospital mortality. However, patients with sepsis continue to be at risk of death after hospital discharge. OBJECTIVE: To develop a model for predicting 1-year mortality in critical patients diagnosed with sepsis. PATIENTS: The data corresponding to 5650 admissions of patients with sepsis from the Medical Information Mart for Intensive Care (MIMIC-III) database were evaluated, randomly divided as follows: 70% for training and 30% for validation. DESIGN: A retrospective register-based cohort study was carried out. The clinical information of the first 24h after admission was used to develop a 1-year mortality prediction model based on Stochastic Gradient Boosting (SGB) methodology. Variable selection was addressed using Least Absolute Shrinkage and Selection Operator (LASSO) and SGB variable importance methodologies. The predictive power was evaluated using the area under the ROC curve (AUROC). RESULTS: An AUROC of 0.8039 (95% confidence interval (CI): [0.8033 0.8045]) was obtained in the validation subset. The model exceeded the predictive performances obtained with traditional severity of disease scores in the same subset. CONCLUSION: The use of assembly algorithms, such as SGB, for the generation of a customized model for sepsis yields more accurate 1-year mortality prediction than the traditional scoring systems such as SAPS II, SOFA or OASIS. PMID- 30245122 TI - Arrhythmia detection using deep convolutional neural network with long duration ECG signals. AB - This article presents a new deep learning approach for cardiac arrhythmia (17 classes) detection based on long-duration electrocardiography (ECG) signal analysis. Cardiovascular disease prevention is one of the most important tasks of any health care system as about 50 million people are at risk of heart disease in the world. Although automatic analysis of ECG signal is very popular, current methods are not satisfactory. The goal of our research was to design a new method based on deep learning to efficiently and quickly classify cardiac arrhythmias. Described research are based on 1000 ECG signal fragments from the MIT - BIH Arrhythmia database for one lead (MLII) from 45 persons. Approach based on the analysis of 10-s ECG signal fragments (not a single QRS complex) is applied (on average, 13 times less classifications/analysis). A complete end-to-end structure was designed instead of the hand-crafted feature extraction and selection used in traditional methods. Our main contribution is to design a new 1D-Convolutional Neural Network model (1D-CNN). The proposed method is 1) efficient, 2) fast (real time classification) 3) non-complex and 4) simple to use (combined feature extraction and selection, and classification in one stage). Deep 1D-CNN achieved a recognition overall accuracy of 17 cardiac arrhythmia disorders (classes) at a level of 91.33% and classification time per single sample of 0.015 s. Compared to the current research, our results are one of the best results to date, and our solution can be implemented in mobile devices and cloud computing. PMID- 30245123 TI - Utilizing the Time Trade-Off, Standard Gamble, and Willingness to Pay Utility Measures to Evaluate Health-Related Quality of Life Prior to Knee or Hip Arthroplasty. AB - BACKGROUND: Time trade-off, standard gamble, and willingness to pay assess the number of years, risk of death, and income a patient would give up for perfect health. These questions were used to evaluate the impact knee arthritis, hip arthritis, or failed total knee (TKA) or hip arthroplasty (THA) has on patients' health-related quality of life prior to surgery. METHODS: Three hundred sixty patients including 176 undergoing primary TKA, 127 undergoing primary THA, 31 undergoing revision TKA, and 26 undergoing revision THA were assessed. Time trade off and standard gamble were converted to utility scores with 1.0 suggesting perfect health and 0 suggesting preference for death rather than living in current state. Willingness to pay is the percentage of yearly income that a patient would pay for perfect health. RESULTS: The mean time trade-off, standard gamble, and willingness to pay scores were 0.74, 0.83, and 0.32 without significant difference between procedures with the numbers available for study (P = .16, .31, and 0.41, respectively). Increasing body mass index was correlated with decreasing time trade-off scores (P = .014). CONCLUSION: Patients scheduled for primary or revision THA and TKA would accept an average 17% risk of death, lose 2.6 years of an additional 10-year life expectancy, and pay 32% of their income for perfect health. The time trade-off (0.74) was similar to patients with history of acute myocardial infarction (0.74) or minor stroke (0.72) and worse than those with chronic hepatitis C (0.83) or human immunodeficiency virus/acquired immunodeficiency syndrome infection (0.86). These data highlight the high value that patients place on adult reconstructive procedures. PMID- 30245124 TI - Persistent Wound Drainage After Total Joint Arthroplasty: A Narrative Review. AB - BACKGROUND: Persistent wound drainage after total joint arthroplasty (TJA) is an important complication with potential substantial adverse consequences, in particular periprosthetic joint infection. METHODS: This review evaluated the available literature regarding several issues in the field of persistent wound drainage after TJA and offers a classification of persistent wound drainage and an algorithmic approach to the decision-making process. RESULTS: Available literature addressing the diagnosis and treatment of persistent wound drainage after TJA is scarce and an evidence-based clinical guideline is lacking. This is partially caused by the absence of a universally accepted definition of persistent wound drainage. In patients with persistent wound drainage, clinical signs and serological tests can be helpful in the diagnosis of a developing infection. Regarding the treatment of persistent wound drainage, nonsurgical treatment consists of absorbent dressings, pressure bandages, and temporary joint immobilization. Surgical treatment is advised when wound drainage persists for more than 5-7 days and consists of open debridement with irrigation and exchange of modular components and antimicrobial treatment. CONCLUSION: Based on this literature review, we proposed a classification and algorithmic approach for the management of patients with persistent wound drainage after TJA. Hopefully, this offers the orthopedic surgeon a practical clinical guideline by finding the right balance between overtreatment and undertreatment, weighing the risks and benefits. However, this classification and algorithmic approach should first be evaluated in a prospective trial. PMID- 30245125 TI - Financial implications of telemedicine visits in an academic endocrine surgery program. AB - BACKGROUND: Telemedicine is an emerging medium for the delivery of ambulatory care, but the reimbursement profile of telemedicine visits in the surgical setting has not been well studied. METHODS: A retrospective assessment of telemedicine encounters for thyroid and parathyroid conditions occurring from April 2015 to April 2017 was performed. Financial reimbursement from commercial payers for new and established patient visits were compared between telemedicine visits and in-person visits. Patient "savings" in terms of travel distance and drive time were calculated. RESULTS: A total of 290 telemedicine encounters were conducted; 7% were initial consultations, 47% were postoperative visits, and 45% were follow-up visits. The median patient age was 57 years. The median round-trip travel distance saved was 123.6 miles with estimated drive time of 2.4 hours per encounter. In 2% of cases, a second in-person visit within the 90-day global period occurred after a postoperative telemedicine encounter. Charges were filed for 67 encounters. The initial unpaid claims rate was 6%, which was consistent with the unpaid claims rate for in-person visits. The charge-to-collection ratio was comparable to that of in-person visits. There was a higher ratio of level 2 visits in the telemedicine encounters. Over the study period, 70 clinic hours were liberated via the use of telemedicine. CONCLUSION: Endocrine surgery telemedicine visits have the same level for level reimbursement profile as in person visits. Down-coding and elimination of components of in-office physical examinations may lead to modest decreases in overall reimbursement. Other advantages include reallocation of clinic resources and decreased travel burden for patients. PMID- 30245126 TI - RESPONSE TO REVIEWERS. PMID- 30245127 TI - Editors' Note. PMID- 30245128 TI - Iron attenuates erythropoietin production by decreasing hypoxia-inducible transcription factor 2alpha concentrations in renal interstitial fibroblasts. AB - Iron is an essential mineral for oxygen delivery and for a variety of enzymatic activities, but excessive iron results in oxidative cytotoxicity. Because iron is primarily used in red blood cells, defective erythropoiesis caused by loss of the erythroid growth factor erythropoietin (Epo) elevates iron storage levels in serum and tissues. Here, we investigated the effects of iron in a mouse model of Epo-deficiency anemia, in which serum iron concentration was significantly elevated. We found that intraperitoneal injection of iron-dextran caused severe iron deposition in renal interstitial fibroblasts, the site of Epo production. Iron overload induced by either intraperitoneal injection or feeding decreased activity of endogenous Epo gene expression by reducing levels of hypoxia inducible transcription factor 2alpha (HIF2alpha), the major transcriptional activator of the Epo gene. Administration of an iron-deficient diet to the anemic mice reduced serum iron to normal concentration and enhanced the ability of renal Epo production. These results demonstrate that iron overload due to Epo deficiency attenuates endogenous Epo gene expression in the kidneys. Thus, iron suppresses Epo production by reducing HIF2alpha concentration in renal interstitial fibroblasts. PMID- 30245129 TI - Effect of Acyl Activating Enzyme (AAE) 3 on the growth and development of Medicago truncatula. AB - The Acyl-Activating Enzyme (AAE) 3 gene encodes an oxalyl-CoA synthetase that catalyzes the conversion of oxalate to oxalyl-CoA in a CoA and ATP-dependent manner. Although the biochemical activity of AAE3 has been established, its biological role in plant growth and development remains unclear. To advance our understanding of the role of AAE3 in plant growth and development, we report here the characterization of two Medicago truncatula AAE3 (Mtaae3) mutants. Characterization of a Mtaae3 RNAi mutant revealed an accumulation of calcium oxalate crystals and increased seed permeability. These phenotypes were also exhibited in the Arabidopsis aae3 (Ataae3) mutants. Unlike the Ataae3 mutants, the Mtaae3 RNAi mutant did not show a reduction in vegetative growth, decreased seed germination, or increased seed calcium concentration. In an effort to clarify these phenotypic differences, a Mtaae3 Tnt1 mutant was identified and characterized. This Mtaae3 Tnt1 mutant displayed reduced vegetative growth, decreased seed germination, and increased seed calcium concentration as well as an accumulation of calcium oxalate crystals and increased seed permeability as found in Ataae3. Overall, the results presented here show the importance of AAE3 in the growth and development of plants. In addition, this study highlights the ability to separate specific growth and development phenotypes based on the level of AAE3 gene expression. PMID- 30245130 TI - Toosendanin induces caspase-dependent apoptosis through the p38 MAPK pathway in human gastric cancer cells. AB - Although many advances have been made in the treatment of gastric cancer (GC), numerous difficulties, such as the emergence of chemo-drug resistance, continue to lead to disappointing GC prognoses. Thus, novel alternative strategies are urgently needed. The use of natural products could be a viable option to treat GC. Toosendanin (TSN) is a triterpenoid derived from the bark of Melia toosendanin Sieb. et Zucc that has been shown to be highly cytotoxic to multiple cancer cells. As the underlying impact of TSN on GC and its molecular mechanism remain poorly understood, in this study, we performed a series of experiments involving the use of TSN to treat GC cells. In the present study, we showed that TSN suppressed cell viability, inhibited cell proliferation by causing G1/S arrest and induced caspase-dependent apoptosis in AGS and HGC-27 cells. The possible mechanism of TSN-induced apoptosis may be associated with the activation of the p38 MAPK pathway. These results demonstrated the potential of TSN as a promising therapeutic compound to treat gastric cancer. PMID- 30245131 TI - Quantitative proteome analysis identifies MAP2K6 as potential regulator of LIFR induced radioresistance in nasopharyngeal carcinoma cells. AB - Using Tandem Mass Tags (TMT) labeling and LC-MS/MS analysis of peptides from two cell lines (CNE2 and its radioresistant subclone CNE2-IR), we identified 754 proteins differentially expressed in CNE2-IR compared to CNE2. MAP2K6 was identified as a candidate radioresistance-related protein kinase. In vitro functional analysis revealed that over-expression of MAP2K6 significantly enhanced cell survival and colony formation following irradiation in NPC cells. Further, knockdown of MAP2K6 in radioresistant NPC cells led to decreased colony formation and increased apoptotic cells following irradiation. However, the effect of MAP2K6 in regulating the radioresistance in NPC cells did not seem to depend on p38/MAPK activity. Importantly, MAP2K6 might be required for leukemia inhibitory factor receptor (LIFR)-regulated radioresistance, as the expression levels of MAP2K6 affected LIFR/p70S6K signaling activation in NPC cells. Further, MAP2K6 kinase activity is required to activate LIFR/p70S6K signaling and to confer pro-survival effect on NPC cells. In conclusion, MAP2K6 might be an important regulator of LIFR-induced radioresistance in NPC. PMID- 30245132 TI - Engineering of Escherichia coli beta-lactamase TEM-1 variants showing higher activity under acidic conditions than at the neutral pH. AB - Escherichia coli beta-lactamase TEM-1 is potentially useful in the antibody directed enzyme/prodrug therapy (ADEPT), converting nontoxic prodrugs to toxic agents. The produced toxin would kill cancer cells, when the enzyme is attached to a tumor-antigen-specific antibody. However, the off-site reaction possibly occurring in the blood or normal tissues raises safety concern. In the present study, we engineered TEM-1 variants preferentially active at pH 5.8-6.2, near the pH of the acidic microenvironment of tumor. A library of randomly mutagenized variants was screened for the ability to confer an antibiotic resistance on E. coli cells in acidic growth media and not in neutral media, to isolate a variant with a Thr-to-Ile substitution at position 160. An extensive mutagenesis study was then conducted in the proximity of this position, to show that a Leu162Glu mutation also causes the acid preference. Kinetic analyses indicated that the overall activity of the wild-type TEM-1 hardly changes over a pH range from 5.8 to 7.0, whereas TEM-1(T160I) is 1.5-times as active at pH 6.2 than pH 7.0, and TEM-1(T160I) is 3.1-fold as active at pH 5.8 than pH 7.0. A further mutagenesis study suggested that a change in the overall structure of the enzyme underlies the pH dependency of the variants. PMID- 30245133 TI - miR-423-5p suppresses high-glucose-induced podocyte injury by targeting Nox4. AB - Podocyte injury plays crucial roles in the pathogenesis of diabetic nephropathy (DN). Aberrant microRNAs (miRNAs) have been suggested to contribute to podocyte injury. However, whether miR-423-5p could alleviate high glucose (HG)-mediated podocyte injury and the underlying mechanisms remains unclear. In this study, we found that patients with DN have reduced miR-423-5p and elevated Nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) expressions in clinical renal tissues, and HG induced Nox4 but suppressed miR-423-5p expressions in cultured podocytes in a time-dependent manner. Moreover, overexpression of miR-423-5p antagonized HG-stimulated podocyte injury by enhancing cell viability, inhibiting reactive oxygen species (ROS) production, suppressing cell apoptosis, reducing inflammatory activity, and repressing cytoskeleton damage accompanied with alternations of podocyte specific proteins. Furthermore, functional assays substantiated that Nox4 was a direct target and negatively regulated by miR-423 5p. Additionally, restoration of Nox4 impeded the protective effect of miR-423-5p on podocyte injury via activation of p38 MAPK pathway. Therefore, this study manifested that miR-423-5p overexpression protected HG-induced podocyte damage by inhibiting ROS generation via targeting Nox4, providing a potential therapeutic strategy against DN. PMID- 30245135 TI - Corrigendum to "Reactive oxygen species promotes cellular senescence in normal human epidermal keratinocytes through epigenetic regulation of p16(INK4a)" [Biochem. Biophys. Res. Commun. 452 (2014) 622-628]. PMID- 30245134 TI - Visualization of specific collagen-producing cells by Col1-GFP transgenic mice revealed novel type I collagen-producing cells other than fibroblasts in systemic organs/tissues. AB - Type I collagen is one of the most abundant proteins in mammals and plays important roles in maintaining the integrity of many tissues. Although fibroblasts are the main source of type I collagen, other cells also produce it; however, these cells are not well-defined owing to the lack of a specific marker. A transgenic (Tg) mouse line has been generated in which type I collagen producing cells are labeled with enhanced green fluorescent protein (EGFP), which enables the monitoring of these cells without requiring an additional cell marker. This Tg mouse line has since been widely used to study type I collagen producing cells and fibrosis; one study revealed that podocytes, which were not previously considered to produce type I collagen, expressed EGFP. This raises a question regarding the specificity of EGFP expression in this Tg mouse line. To exclude the possibility of non-specific EGFP expression in the existing Tg mouse line and specifically monitor type I collagen-producing cells, we generated a new Tg mouse line and histologically confirmed the specificity of EGFP expression throughout the body. Moreover, we explored type I collagen-producing cells other than fibroblasts and revealed for the first time that Leydig cells have the ability to produce type I collagen. Because of its highly specific and physiologically accurate expression, our new Tg mouse line will help to accurately elucidate not only type I collagen-producing cells in normal tissues but also the potential cells in fibrotic tissues, providing new insights into the pathology of fibrosis. PMID- 30245136 TI - Alleviation of A disintegrin and metalloprotease 10 (ADAM10) on thromboangiitis obliterans involves the HMGB1/RAGE/ NF-kappaB pathway. AB - Thromboangiitis obliterans (TAO), also known as Buerger's disease, is a nonatherosclerotic inflammatory disease that influences medium- and small-sized blood vessels of extremities. However, mechanisms underlying TAO are still unclear. As a mediator associated with inflammation, A disintegrin and metalloprotease 10 (ADAM10) was hypothesized to play inhibitory roles in the development of TAO. Thus, the objective of this study is to investigate the effects of ADAM10 in a sodium laurate-induced TAO rat model and elucidate underlying mechanisms. Male Wistar rats were randomly divided into four groups (n = 6) for treatment: sham-operated (SHAM), TAO model (TAO), ADAM10 low dose injection (3 mg/kg; ADAM10-LD) and ADAM10 high dose injection (6 mg/kg; ADAM10 HD). After 14-day treatment, color Doppler ultrasound and hematology analysis indicated TAO rats displayed higher whole blood viscosity and blood platelet count compared with those in the SHAM group. Histologic evaluation and transmission electron microscopy revealed that the ultrastructural damages of vascular smooth muscle and endothelial cells were observed in TAO rats, such as fractured endoplasmic reticulum, decreased cell counts, and fibrillation. On the other hand, the typical signs and symptoms of TAO rats were significantly alleviated via ADAM10 treatment with a dose-dependent pattern. Real-time PCR and western blot results revealed that the expression of high-mobility-group box 1 (HMGB1), receptor for advanced glycation end-products (RAGE) and nuclear factor kappa B (NF-kappaB) increased in TAO rats whereas decreased by ADAM10 treatment in both mRNA and protein levels. In conclusion, the results suggest ADAM10 alleviates symptoms of sodium laurate-induced TAO in rats via the RAGE/NF-kappaB signaling pathway and provides insight into the molecular basis and a potential therapeutic strategy for TAO. PMID- 30245137 TI - Evaluation of photodynamic therapy with methylene blue, by the Fourier Transform Infrared Spectroscopy (FT-IR) in Leishmania major - in vitro. PMID- 30245138 TI - Cu (II)-based metal-organic xerogels as a novel nanozyme for colorimetric detection of dopamine. AB - Cu (II)-based metal-organic gels (Cu-MOGs), which are formed by 4-[2,2':6',2" terpyridine]-4'-ylbenzoic acid (Hcptpy) and Cu (II) through ionic interactions, pi-pi stacking, van der Waals and hydrogen bonding, have been simply synthesized and used for the preparation of Cu (II)-based metal-organic xerogels (Cu-MOXs). Owing to the metal active sites in Cu-MOXs, Cu-MOXs were successfully applied to chromogenic experiment. The peroxidase substrate 3,3',5,5'-tetramethylbenzidine (TMB), which could be catalyzed by Cu-MOXs from TMB to the oxidation state of TMB (oxTMB) and the color of TMB could be changed from colorless to blue with maximum absorbance at 657 nm, was selected as chromogenic agent. Thus, the Cu-MOXs-TMB H2O2 system based on MOXs was established. Due to the inhibitory effect of dopamine (DA) on oxidation process of TMB, the characteristic absorption peak intensity of oxTMB decreased when the DA was added into the mixed solution. Subsequently, the Cu-MOXs-TMB- H2O2 system was used for DA detection. The linear range for DA was 0.5 MUM-20 MUM and the detection limit was 85.76 nM. Our work has helped to develop the promising application of Cu-MOGs material in the field of nanozymes property. PMID- 30245139 TI - Prolonged Activated partial thromboplastin time without coagulopathy in peritoneal dialysis. PMID- 30245140 TI - Well-being and volunteering: Evidence from aging societies in Asia. AB - This study examines whether and how volunteering is associated with the well being of older people in rapidly aging Asian societies; this topic has received remarkably little attention in the literature. Based on the severity of their population aging problem, five Asian societies are selected for an empirical study, namely Hong Kong, Japan, Singapore, South Korea, and Taiwan. We conduct analysis of the latest World Values Survey data set collected from 2011 to 2012 and the effect of volunteering on four aspects of well-being, namely self reported life satisfaction, happiness, health, and life mastery. Given the ordinal nature of well-being, we establish ordered probit models that focus on voluntary work type, volunteer age, and the level of immersion in volunteer work. The findings indicate a significant positive relationship between active volunteering and well-being, which is valid for all well-being aspects. Active volunteering may have a more significant effect on well-being than inactive volunteering. Age is also a relevant factor affecting volunteering effect. No significant volunteering benefits are found for people younger than 54 years old. Voluntary work in charitable, humanitarian, and religious organizations is the most closely associated with higher well-being for relatively younger people. For people aged 65 and above, volunteering in self-help and cultural organizations is also associated with higher well-being. Moreover, immersion in volunteer work is crucial, particularly for retired people and people aged more than 65 in South Korea, Japan, and Taiwan. The results suggest people should be encouraged to engage in longer hours (or longer duration) of voluntary service. This study identifies the types of volunteer work that most effectively enhance the well being of older people, which might help older adults transition to retirement and age with higher well-being and help aging societies alleviate their labor shortage problems by involving productive older people. PMID- 30245141 TI - The genetic landscape of Parkinson's disease. AB - The cause of Parkinson's disease (PD) remains unknown in most patients. Since 1997, with the first genetic mutation known to cause PD described in SNCA gene, many other genes with Mendelian inheritance have been identified. We summarize genetic, clinical and neuropathological findings related to the 27 genes reported in the literature since 1997, associated either with autosomal dominant (AD): LRRK2, SNCA, VPS35, GCH1, ATXN2, DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, CHCHD2, and GBA; or autosomal recessive (AR) inheritance: PRKN, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, SPG11, VPS13C, PODXL, and PTRHD1; or an X-linked transmission: RAB39B. Clinical and neuropathological variability among genes is great. LRRK2 mutation carriers present a phenotype similar to those with idiopathic PD whereas, depending on the SNCA mutations, the phenotype ranges from early onset typical PD to dementia with Lewy bodies, including many other atypical forms. DNAJC6 nonsense mutations lead to a very severe phenotype whereas DNAJC6 missense mutations cause a more typical form. PRKN, PINK1 and DJ1 cases present with typical early onset PD with slow progression, whereas other AR genes present severe atypical Parkinsonism. RAB39B is responsible for a typical phenotype in women and a variable phenotype in men. GBA is a major PD risk factor often associated with dementia. A growing number of reported genes described as causal genes (DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, and CHCHD2) are still awaiting replication or indeed have not been replicated, thus raising questions as to their pathogenicity. Phenotypic data collection and next generation sequencing of large numbers of cases and controls are needed to differentiate pathogenic dominant mutations with incomplete penetrance from rare, non-pathogenic variants. Although known genes cause a minority of PD cases, their identification will lead to a better understanding their pathological mechanisms, and may contribute to patient care, genetic counselling, prognosis determination and finding new therapeutic targets. PMID- 30245142 TI - [Coronary spasm a diagnostic and therapeutic challenge]. AB - Vasospastic angina is a clinical and physio-pathological entity, which has been documented for many years, but its diagnosis is under-estimated despite the fact that though inadequately considered and investigated. This condition is potentially serious and can sometimes trigger severe arrhythmia resulting in ventricular fibrillation and sudden death. This pathology has a higher incidence in Asia, where it is, therefore, better documented with provocative testing being carried out more frequently, while in France, these tests are not sufficiently performed probably due to the fact that they often produce negative findings. Provocative tests with Ergonovine injection should be performed via intra coronary to improve its sensibility. Should this test become more sensitive and more routinely performed, this condition, which often responds well to medical treatment, could regain appropriate recognition as a coronary disease. PMID- 30245143 TI - Calycosin-7-O-beta-D-glucoside reduces myocardial injury in heat stroke rats. AB - BACKGROUND/PURPOSE: Calycosin-7-O-beta-D-glucoside (CG), a calycosin derivative compound derived from Astragali Radix, has protective effect against ischemia/reperfusion injury as well as bacterial endotoxin-induced vascular cell injury. In the present study, we ascertained whether CG could reduce myocardial injury in heatstroke rats. METHODS: Heat stroke was induced by exposing anaesthetized rats to heat stress (43 degrees C for 70 min). Rats were given an i.p. dose of CG (26.8 mg/ml/kg) or vehicle solution (ml/kg) 15 min before the start of heat stress and immediately after termination of heat stress. Left ventricular performance, myocardial injury markers in the blood, and myocardial damage scores were assessed in heat stroke rats treated with or without CG. Additionally, cardiac levels of oxidative stress and inflammatory status were estimated simultaneously. RESULTS: At the time point of heat stroke onset, compared with normothermic controls, group rats with vehicle solution had significantly decreased survival rate, increased hyperthermia, decreased left ventricular stress markers, and increased cardiac damage scores. Compared with group rats with vehicle solution, group rats with CG had significantly improved survival rate, decreased hyperthermia, decreased cardiac ischemic, inflammatory, and oxidative damage. CONCLUSION: We thus conclude that myocardial injury can be a pressing need for the design of diagnostic and therapeutic modalities for heat stroke. In particular, our data indicate that CG protects against heat stroke in rats by mitigating myocardial injury. PMID- 30245144 TI - Comparison of tunneled central venous catheters and native arteriovenous fistulae by evaluating the mortality and morbidity of patients with prevalent hemodialysis. AB - PURPOSE: We examined the association between catheter use for maintenance hemodialysis (HD) and mortality/hospitalization in a cohort of patients with prevalent HD. METHODS: In this study, 70 HD patients with tunneled cuffed central venous catheters (TCVCs) from a Taiwanese HD center during 2014-2016 were enrolled and compared with 70 matched HD patients with native arteriovenous fistulae (AVF). The compared variables included demographic parameters and laboratory and dialysis-related indices. Cox regression analysis was used to assess the risk of mortality/hospitalization within a year. RESULTS: Low baseline serum albumin levels were found in patients with TCVCs (3.64 g/dL vs 3.79 g/dL, p = 0.030). The mortality rates of patients with AVF and TCVCs were 14 per 1000 patients and 171 per 1000 patients, respectively. Infection was the leading cause of mortality/hospitalization in patients with TCVCs. Using multivariate analyses, the risk of death was found to be significantly higher in patients with TCVCs than in those with AVF (Hazard ratio [HR] 12.15, 95% CI 1.16-127.17; p = 0.037). Patients with TCVC also had a higher hospitalization rate (HR 1.33, 95% CI 0.71 2.49; p = 0.369) (not statistically significant). CONCLUSION: Catheter use for maintenance HD was associated with increased all-cause mortality. PMID- 30245145 TI - Social Dimensions of Sexual Consent Among Cisgender Heterosexual College Students: Insights From Ethnographic Research. AB - PURPOSE: Nonconsensual sexual experiences on college campuses represent a serious public health problem. The preponderance of existing research on students' actual consent practices is quantitative, lab based, or focused on how single dimensions of social context shape consent practices. Filling those gaps and illustrating ethnography's potential to lay the groundwork for innovative prevention, this paper draws on research conducted with undergraduates on two interconnected campuses to examine multiple social dimensions of sexual consent practices. METHODS: Data include in-depth interviews with over 150 students, 16 months of participant observation, 17 focus groups, and key informant interviews. Research conducted for this study took place between September 2015 and January 2017 at Columbia University and Barnard College. RESULTS: Although sexual consent is often approached as an individual or interpersonal practice, this research highlights potentially modifiable social dimensions of consent. These seven dimensions of sexual consent practices are as follows: (1) gendered heterosexual scripts; (2) sexual citizenship; (3) intersectionality; (4) men's fear of "doing" consent wrong; (5) "drunk sex"; (6) peer groups; and (7) spatial/temporal factors shaping when consent is assumed. CONCLUSIONS: Effective promotion of consensual sex, as a strategy to prevent assault, will likely require understanding and modifying the social structures that shape consent practices, rather than just legislation that mandates the promotion of affirmative consent. We describe seven potential modifiable social contextual dimensions of consent practices, along with related strategies to promote consensual sex and prevent sexual assault. PMID- 30245146 TI - Laparoscopic versus robotic hysterectomy in obese and extremely obese patients with endometrial cancer: A multi-institutional analysis. AB - OBJECTIVE: The aim of this study was to evaluate the surgical and oncological outcome of robotic surgical staging with hysterectomy (RH) plus or less pelvic and aortic lymphadenectomy, compared to the same procedures performed by laparoscopic surgery (LH) in obese patients (BMI>=30 kg/m2) with endometrial cancer. MATERIAL AND METHODS: From October 2001 to April 2017, obese patients (BMI > 30 kg/m2) with primary, histologically confirmed endometrial carcinoma who underwent LH or RH using the Da Vinci Si or Xi Surgical System(r) (Intuitive Surgical Inc(r), 1266 Kifer Road, Building 101 Sunnyvale, CA) were eligible for the study. RESULTS: We identified 655 women with endometrial cancer and BMI >30 kg/m2. Out of 655 patients, 249 (38%) underwent RH and 406 (62%) underwent LH plus or less pelvic and aortic lymphadenectomy. Our study showed that, compared to the 406 patients treated in LPS, 249 patients treated in robotics have a statistically significant difference in terms of increased operating time and a decreased conversion rate. In addition, the rate of pelvic lymphadenectomies in robotic surgeries is twice the one reported in LPS surgeries. Furthermore, a reduction in hospital stay was observed in the robotic group. We observed that the oncological outcomes do not vary according to the surgical approach and BMI variation. CONCLUSIONS: robotic surgery in severely obese women with endometrial cancer is feasible, safe, and reproducible and could be a valid alternative to laparoscopy in the treatment of these patients. Prospective studies could confirm our results. PMID- 30245147 TI - Prevention of meconium obstruction in very low birth weight preterm infants. AB - INTRODUCTION: Delayed meconium expulsion is a cause of bowel obstruction in the extremely premature newborn (<28 WGE) weighing less than 1500g at birth. OBJECTIVE: To evaluate the efficacy of conservative treatment in the prevention of meconium obstruction in very-low-birt- weight preterm infants. METHOD: Descriptive and retrospective study performed at the Neonatal Intensive Care Unit of a tertiary level hospital. All very-low-birth-weight preterm infants who were born during the study period, from August 2016 to January 2017, and who had meconium obstruction were included. RESULTS: A sample of 42 newborn infants was obtained. Regarding the expulsion of meconium, 57.1% of the sample spontaneously ejected meconium, while 42.9% received different treatments. Of these, 72.2% were treated with saline enemas, 16% with acetylcysteine enemas, 16% with Gastrografin(r) and none required surgical treatment. CONCLUSION: Conservative treatment seems to be an effective therapeutic measure for the prevention of meconium obstruction in very-low-birth-weight preterm infants since it achieved the expulsion of meconium without having to apply surgical treatment. PMID- 30245148 TI - A Randomized Phase II Study of Eribulin/Cyclophosphamide or Docetaxel/Cyclophosphamide as Neoadjuvant Therapy in Operable HER2-negative Breast Cancer. AB - BACKGROUND: Eribulin mesylate is a non-taxane microtubule inhibitor effective in the treatment of metastatic breast cancer refractory to anthracyclines and taxanes. In preclinical studies, additional mechanisms of eribulin included reversal of epithelial mesenchymal transition and tumor vascular remodeling. The present study compared the safety and efficacy of eribulin plus cyclophosphamide (ErC) to docetaxel plus cyclophosphamide (TC) as neoadjuvant therapy for operable HER2- breast cancer. PATIENTS AND METHODS: Women with invasive HER2- breast adenocarcinoma with no distant metastases were eligible. After a 10-patient safety lead-in, the patients were randomized 2:1 to receive either ErC (eribulin 1.4 mg/m2 on days 1 and 8 plus cyclophosphamide 600 mg/m2 on day 1) or TC (docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1) administered every 21 days for 6 cycles, followed by surgery. The pathologic complete response (pCR) rate was the primary endpoint. Tumor samples collected at baseline and at surgery were assayed for select epithelial mesenchymal transition and vascular density markers: E-cadherin, vimentin, and CD31 expression. RESULTS: A total of 76 patients were enrolled. Of the 76 patients, 10 received ErC in the lead-in phase and 66 were randomized to ErC (n = 44) or TC (n = 22). The pCR rates with ErC and TC were 13% and 9%, respectively. Both regimens produced frequent neutropenia and peripheral neuropathy. Both regimens increased vascular density as measured by CD31 staining. CONCLUSION: The neoadjuvant regimens of ErC and TC resulted in relatively low pCR rates in this patient population. No unexpected toxicities were observed. Our results also provided no suggestion that ErC is a neoadjuvant treatment with greater efficacy than that of standard regimens. PMID- 30245149 TI - When REVEAL meets AMBITION, does it reveal more? PMID- 30245150 TI - A tale of the twist in the outflow graft: An analysis from the MOMENTUM 3 trial. PMID- 30245152 TI - Corrigendum to "Correlation of pesticide exposure from dietary intake and bio monitoring: The different sex and socio-economic study of children" [Ecotoxicol. Environ. Saf. 162 (2018) 170-177]. PMID- 30245151 TI - Ward visits- one essential step in intensive care follow-up. An interview study with critical care nurses' and ward nurses'. AB - OBJECTIVE: The aim of this study was to describe critical care nurses' and ward nurses' perceptions of the benefits and challenges with a nurse-led follow-up service for intensive care-survivors at general wards. BACKGROUND: Patients recently transferred from intensive care to the general ward are still vulnerable and require complex care. There are different models of intensive care follow-up services and some include ward visits after transfer from intensive care. Research methodology/design: This study had a qualitative design. Data from 13 semi-structured interviews with Swedish critical care nurses and ward nurses were analysed using qualitative content analysis. FINDINGS: The findings consisted of one theme, namely, "Being a part of an intra-organisational collaboration for improved quality of care", and four subthemes: "Provides additional care for the vulnerable patients, "Strengthens ward-based critical care", "Requires coordination and information", and "Creates an exchange of knowledge". The nurse led follow-up service detected signs of deterioration and led to better quality of care. However, shortage of time, lack of interaction, feedback and information about the function of the follow-up service led to problems. CONCLUSION: The findings indicate that ward visits should be included in the intensive care follow-up service. Furthermore, intra-organisational collaboration seems to be essential for intensive care survivors' quality of care. PMID- 30245153 TI - The predictors of post-procedural arm pain after transradial approach in 1706 patients underwent transradial catheterization. AB - BACKGROUND: Although patients prefer radial over femoral approach, some develop post-procedural arm pain after transradial procedures. This complication has been poorly defined in prior studies. We evaluated the extent of non-ischemic arm pain after transradial arterial access and identify variables that may be associated with this complication. METHODS: We performed a retrospective analysis of a 1706 patient database on patients who underwent transradial catheterization at three experienced radial centers. Arm pain was assessed by adult visual analogue scale (score > 4) defined as moderate to severe pain at the accessed forearm not related to hand ischemia and was evaluated at one day after the procedure. Logistic regression was used to identify the predictors of post-procedural arm pain. RESULTS: The overall incidence of post-procedural arm pain one day after a transradial procedure was 4.5%. Covariate associated with post-procedural arm pain were hemostasis compression >4 h (odds ratio (OR) = 29.47, p < 0.001), radial artery occlusion by Doppler evaluation (OR = 3.35, p < 0.001), radial artery diameter < 2.8 mm (OR = 2.66, p = 0.01), and multiple puncture attempts (OR = 2.31, p = 0.03). CONCLUSION: Approximately 1 in 20 patients undergoing transradial procedure have post-procedural arm pain one day after the procedure. Predictors of this complication relate to radial hemostasis, radial artery occlusion, radial artery diameter, and number of access attempts. PMID- 30245154 TI - Chromosomal Instability Induces Cellular Invasion in Epithelial Tissues. AB - Most sporadic carcinomas with high metastatic activity show an increased rate of changes in chromosome structure and number, known as chromosomal instability (CIN). However, the role of CIN in driving invasiveness remains unclear. Using an epithelial model in Drosophila, we present evidence that CIN promotes a rapid and general invasive behavior. Cells with an abnormal number of chromosomes delaminate from the epithelium, extend actin-based cellular protrusions, form membrane blebs, and invade neighboring tissues. This behavior is governed by the activation of non-muscle Myosin II by Rho kinase and by the expression of the secreted EGF/Spitz ligand. We unravel fundamental roles of the mitogen-activated protein kinase pathways mediated by the Fos proto-oncogene and the Capicua tumor suppressor gene in the invasive behavior of CIN-induced aneuploid cells. Our results support the proposal that the simple production of unbalanced karyotypes contributes to CIN-induced metastatic progression. PMID- 30245155 TI - Somatic and Germline MicroRNAs Form Distinct Silencing Complexes to Regulate Their Target mRNAs Differently. AB - Animal germ cells possess a specific post-transcriptional regulatory context allowing the storage of maternal transcripts in the oocyte until their translation at a specific point in early development. As key regulators of gene expression, miRNAs repress translation mainly through mRNA destabilization. Thus, germline miRNAs likely use distinct ways to regulate their targets. Here, we use C. elegans to compare miRNA function within germline and somatic tissues. We show that the same miRNA displays tissue-specific gene regulatory mechanisms. While translational repression occurs in both tissues, targeted mRNAs are instead stabilized in the germline. Comparative analyses of miRNA silencing complexes (miRISC) demonstrate that their composition differs from germline to soma. We show that germline miRNA targets preferentially localize to perinuclear regions adjacent to P granules, and their repression is dependent on the core P granule component GLH-1. Together, our findings reveal the existence of different miRISC in animals that affect targeted mRNAs distinctively. PMID- 30245156 TI - Human beta-Tubulin Isotypes Can Regulate Microtubule Protofilament Number and Stability. AB - Cell biological studies have shown that protofilament number, a fundamental feature of microtubules, can correlate with the expression of different tubulin isotypes. However, it is not known if tubulin isotypes directly control this basic microtubule property. Here, we report high-resolution cryo-EM reconstructions (3.5-3.65 A) of purified human alpha1B/beta3 and alpha1B/beta2B microtubules and find that the beta-tubulin isotype can determine protofilament number. Comparisons of atomic models of 13- and 14-protofilament microtubules reveal how tubulin subunit plasticity, manifested in "accordion-like" distributed structural changes, can accommodate distinct lattice organizations. Furthermore, compared to alpha1B/beta3 microtubules, alpha1B/beta2B filaments are more stable to passive disassembly and against depolymerization by MCAK or chTOG, microtubule associated proteins with distinct mechanisms of action. Mixing tubulin isotypes in different proportions results in microtubules with protofilament numbers and stabilities intermediate to those of isotypically pure filaments. Together, our findings indicate that microtubule protofilament number and stability can be controlled through beta-tubulin isotype composition. PMID- 30245157 TI - The Structure and Dynamics of C. elegans Tubulin Reveals the Mechanistic Basis of Microtubule Growth. AB - The dynamic instability of microtubules is a conserved and fundamental mechanism in eukaryotes. Yet microtubules from different species diverge in their growth rates, lattice structures, and responses to GTP hydrolysis. Therefore, we do not know what limits microtubule growth, what determines microtubule structure, or whether the mechanisms of dynamic instability are universal. Here, we studied microtubules from the nematode C. elegans, which have strikingly fast growth rates and non-canonical lattices in vivo. Using a reconstitution approach, we discovered that C. elegans microtubules combine intrinsically fast growth with very frequent catastrophes. We solved the structure of C. elegans microtubules to 4.8 A and discovered sequence divergence in the lateral contact loops, one of which is ordered in C. elegans but unresolved in other species. We provide direct evidence that C. elegans tubulin has a higher free energy in solution and propose a model wherein the ordering of lateral contact loops activates tubulin for growth. PMID- 30245158 TI - Public knowledge and behaviours relating to antibiotic use in Gulf Cooperation Council countries: A systematic review. AB - The aim of this review was to assess public knowledge and behaviours in relation to antibiotic use in GCC countries. A systematic review was performed using MEDLINE, EMBASE and other relevant databases. Cross-sectional studies published from January 2000 to June 2017 relating to public knowledge and behaviours towards antibiotic use were included. Overall nine studies met the inclusion criteria for this systematic review. Nearly half of general public respondents in the GCC region reported a lack of knowledge about antibiotic use and showed negative attitudes towards antibiotic utilisation. Penicillin was the most frequently misused antibiotic, particularly for self-medication. Most respondents declared that they obtained information on antibiotics from pharmacists. Pharmacies were the major source of antibiotics used for self-medication. A multi disciplinary approach must be put in place to educate the public on appropriate antibiotic use, to improve policies regarding the rational prescription of antimicrobials and to increase regulation enforcement. PMID- 30245159 TI - Lack of RAC. PMID- 30245160 TI - Accurate Identification of Predictive Biomarkers of Response to Targeted Therapies in Lung Cancer With Next Generation Sequencing. PMID- 30245161 TI - Rate of inadvertently induced seizures with deep repetitive transcranial magnetic stimulation. PMID- 30245162 TI - Intermittent theta burst stimulation induced seizure in a child with schizophrenia: A case report. PMID- 30245163 TI - Long-term results after deep brain stimulation of nucleus accumbens and the anterior limb of the internal capsule for preventing heroin relapse: An open label pilot study. AB - BACKGROUND: Deep brain stimulation (DBS) is currently used to treat addiction, with the nucleus accumbens (NAc) as one promising target. The anterior limb of the internal capsule (ALIC) is also a potential target, as it carries fiber tracts connecting the mesocorticolimbic circuits that are crucially involved in several psychiatric disorders, including addiction. Stimulating the NAc and ALIC simultaneously may have a synergistic effect against addiction. METHODS: Eight patients with a long history of heroin use and multiple relapses, despite optimal conventional treatments, were enrolled. Customized electrodes were implanted through the ALIC into the NAc, and deep brain stimulation (DBS) treatment began two weeks after surgery. The patients were followed for at least 24 months. The duration of drug-free time, severity of drug cravings, psychometric evaluations, and PET studies of glucose metabolism before and after DBS were conducted. All adverse events were recorded. RESULTS: With DBS, five patients were abstinent for more than three years, two relapsed after abstaining for six months, and one was lost of follow-up at three months. The degree of cravings for drug use after DBS was reduced if the patients remained abstinent (p < 0.001). Simultaneous DBS of the NAc and ALIC also improved the quality of life, alleviated psychiatric symptoms, and increased glucose metabolism in addiction-related brain regions. Moreover, stimulation-related adverse events were few and reversible. CONCLUSIONS: Simultaneous DBS of the NAc and ALIC appears to be safe, with few side effects, and may prevent long-term heroin relapse after detoxification in certain patients. (This trial was registered at ClinicalTrials.gov, NCT01274988). PMID- 30245164 TI - Corrigendum to "Cosupplementation with a synthetic, lipid-soluble polyphenol and vitamin C inhibits oxidative damage and improves vascular function yet does not inhibit acute renal injury in an animal model of rhabdomyolysis" [Free Radic. Biol. Med. 52(9) (2012) 1918-1928]. PMID- 30245165 TI - Spondylocarpotarsal synostosis syndrome: "Bat wings" spinal fusions and "ladybug" carpal coalitions. PMID- 30245166 TI - Electrochemiluminescence on smartphone with silica nanopores membrane modified electrodes for nitroaromatic explosives detection. AB - Silica nanopores have electron channels and ion channels interpenetrating each other, which prompt the use of this structure for creating efficient electronic devices. In this study, silica nanopores membrane modified screen printed electrodes were applied in a smartphone-based electrochemiluminescence system for nitroaromatic explosives detection. Universal serial bus-on the go (USB-OTG) and camera on smartphone were used as the electrical stimulation and luminescence capture, respectively. ?Multimode methods including (red-green-blue) RGB, (hue saturation-brightness) HSB, and Gray were proposed for luminescence analysis. Specific polypeptides were immobilized on the nanopores modified electrodes for nitroaromatic explosives sensing. With positive-charged tris(2,2' bipyridyl)ruthenium(II) (Ru(bpy)32+) as electrochemiluminescence label, the increase in luminescence was associated with the selective ion channels and the well-conductive electron channels in the negative-charged nanopores. Besides, on account of the large specific surface area, nanopores modified screen printed electrodes showed stable and uniform luminescence. Results showed that the nanopores-enhanced electrochemiluminescence on smartphone covered a linear dynamic range from 10-7 mg/mL to 10-3 mg/mL for nitroaromatic explosives detection with the detection limit of 2.3 * 10-9 mg/mL. Therefore, high-efficient photo-electricity conversion capabilities of nanopores made it a kind of promising platform for sensitive and stable electrochemiluminescence. Furthermore, smartphone-based electrochemiluminescence with disposable screen printed electrodes could facilitate the mobile monitoring of biochemical analytes in the fields of environment, security, and health. PMID- 30245167 TI - Microcomputed tomography (microCT) and histology of the mandibular canal in human and laboratory animals. AB - The inferior alveolar nerve (IAN) is a sensitive branch of the trigeminal nerve. It has an intra-bone path in the mandible, inside the mandibular canal, where it is accompanied by lymph, venous and arterial vessels. We have studied the mandibular canal in human mandibles and in some laboratory animals (mice, rats, rabbits and cats). Microcomputed tomography evidenced that the walls of the canal are made with thin plates of trabecular bone with numerous fenestrations. This aspect is evidenced in dentate subjects and become more evident in edentulous subjects with atrophy of the alveolar bone. In rats and mice, the wall of the canal is also clearly composed of trabecular plates coming from the surrounding alveolar bone of the mandible. In the rabbit, similar findings are also observed but the trajectory of the canal is more difficult to identify. In the cat, the floor of the canal is composed of the cortical bone from the basilar cortex of the mandible and the roof has a trabecular nature. Vascular injections of gelatin barium evidenced the arterial trajectories inside the bone in rats and humans. Undecalcified bone sections in human evidenced the histological aspect of the IAN and its connective sheets. Some nervous bundles can be observed outside the epineurium. Bone remodeling is observed on the wall of the mandibular canal. These descriptive findings have a clinical relevance in dental implantology or mandibular surgery. PMID- 30245168 TI - Reply. PMID- 30245169 TI - Using a surgical prostate-specific antigen threshold of >0.2 ng/mL to define biochemical failure for intermediate- and high-risk prostate cancer patients treated with definitive radiation therapy in the ASCENDE-RT randomized control trial. AB - PURPOSE: To compare biochemical failure using a prostate-specific antigen (PSA) threshold of >0.2 ng/mL to that using Phoenix threshold (nadir+2 ng/mL). METHODS AND MATERIALS: Androgen suppression combined with elective nodal and dose escalated radiation therapy (the ASCENDE-RT trial) is a randomized control trial in which 276 high-risk and 122 intermediate-risk patients were randomized to (1) a standard arm with 12 months of androgen deprivation therapy, pelvic external beam radiation therapy (EBRT) to 46 Gy, and an EBRT boost (dose-escalated EBRT [DE-EBRT]) to 78 Gy, or (2) an experimental arm which substituted a low-dose-rate prostate brachytherapy boost (LDR-PB). The primary endpoint was biochemical progression-free survival (b-PFS) using the Phoenix threshold. In this reanalysis of ASCENDE-RT, the b-PFS using phoenix is compared to the surgical PSA threshold of >0.2 ng/mL. RESULTS: Compared to nadir+2 ng/mL, the >0.2 ng/mL PSA threshold doubled the number of relapse events from 69 to 139. However, the increase was confined to the DE-EBRT subjects. The 7-year Kaplan-Meier b-PFS after DE-EBRT declined from 76% using nadir+2 ng/mL to 38% using the >0.2 ng/mL threshold (p < 0.001). Among the LDR-PB subset, there was no significant difference in b-PFS; the 7-year Kaplan-Meier b-PFS was 85% (>0.2 ng/mL) versus 88% (nadir+2 ng/mL) (p = 0.319). CONCLUSIONS: Replacing Phoenix with a surgical threshold greatly increased biochemical failure after DE-EBRT boost but had no effect after LDR-PB. As a result of this finding, PSA outcomes after surgery or brachytherapy can be directly compared by using the surgical definition of PSA failure. In this context, a brachytherapy boost appears to produce superior b-PFS compared to contemporary surgical series. PMID- 30245171 TI - Central nervous system microbleeds in the acute phase are associated with structural integrity by DTI one year after mild traumatic brain injury: A longitudinal study. AB - INTRODUCTION: Several imaging modalities are under investigation to unravel the pathophysiological mystery of delayed performance deficits in patients after mild traumatic brain injury (mTBI). Although both imaging and neuropsychological studies have been conducted, only few data on longitudinal correlations of diffusion tensor imaging (DTI), susceptibility weighted imaging (SWI) and extensive neuropsychological testing exist. METHODS: MRI with T1- and T2 weighted, SWI and DTI sequences at baseline and 12 months of 30 mTBI patients were compared with 20 healthy controls. Multiparametric assessment included neuropsychological testing of cognitive performance and post-concussion syndrome (PCS) at baseline, 3 and 12 months post-injury. Data analysis encompassed assessment of cerebral microbleeds (Mb) in SWI, tract-based spatial statistics (TBSS) and voxel-based morphometry (VBM) of DTI (VBM-DTI). Imaging markers were correlated with neuropsychological testing to evaluate sensitivity to cognitive performance and post-concussive symptoms. RESULTS: Patients with Mb in SWI in the acute phase showed worse performance in several cognitive tests at baseline and in the follow-ups during the chronic phase and higher symptom severity in the post concussion symptom scale (PCSS) at twelve months post-injury. In the acute phase there was no statistical difference in structural integrity as measured with DTI between mTBI patients and healthy controls. At twelve months post injury, loss of structural integrity in mTBI patients was found in nearly all DTI indices compared to healthy controls. CONCLUSIONS: Presence of Mb detected by SWI was associated with worse cognitive outcome and persistent PCS in mTBI patients, while DTI did not prove to predict neuropsychological outcome in the acute phase. PMID- 30245170 TI - Selection of patients who would not require long-term prostate-specific antigen monitoring after low-dose-rate brachytherapy. AB - PURPOSE: To identify patients at extremely low risk of biochemical recurrence (BCR) of prostate cancer after low-dose-rate brachytherapy (LDR-BT) to determine when prostate-specific antigen (PSA) monitoring can be stopped. METHODS AND MATERIALS: We retrospectively reviewed clinicopathologic data of patients with prostate cancer who underwent LDR-BT between 2003 and 2011. Of 1569 patients reviewed, 689 (43.9%) received combination external beam radiotherapy, and 970 (61.8%) had neoadjuvant hormonal therapy. We stratified patients according to risk factors identified by multivariate analysis and assessed the factors for an association with BCR (defined as >=2 ng/mL higher than the nadir). RESULTS: The median followup was 96 months. Of 1531 patients who were BCR-free at 3 years after treatment, 76 subsequently developed BCR; of 1500 who were BCR-free at 5 years, 45 eventually had BCR. On multivariate analysis, independent risk factors for BCR were the National Comprehensive Cancer Network risk group at diagnosis and PSA levels at 3 or 5 years after radiotherapy. In the low-risk group, no patient with a PSA level <=0.2 ng/mL at 3 years after radiotherapy subsequently developed BCR. In the intermediate-risk group, no patients with a PSA level <=0.2 ng/mL at 5 years subsequently developed BCR. CONCLUSIONS: The National Comprehensive Cancer Network risk group at diagnosis and PSA values at 3 and 5 years after LDR-BT are independently associated with a risk of later BCR. Using these two factors may help to select patients for whom PSA monitoring could be stopped because they have an extremely low risk of later BCR. PMID- 30245172 TI - Life expectancy and mortality in chorea-acanthocytosis and McLeod syndrome. AB - OBJECTIVE: To document life expectancy and causes of death in chorea acanthocytosis (ChAc) and McLeod syndrome (MLS). METHODS: We reviewed our personal databases and the published literature to identify cases of ChAc and MLS for whom adequate information was available regarding ages of disease onset and death, cause of death, and other clinical information. RESULTS: Adequate information was obtained on 52 patients with ChAc and 34 with MLS. Causes of death included pneumonia, cardiac disease, seizure, suicide, and sepsis. Mean disease duration from diagnosis was 11 years for ChAc, while for MLS it was 21 years. CONCLUSIONS: Given the current data, causes of death in ChAc and MLS are similar to those for the phenotypically similar Huntington's disease, with additional risks due to the presence of seizures and cardiac disease. Suicidality was seen in 10% of patients with ChAc. Identifying causes of mortality is valuable for disease management and ultimately for clinical trials. In the absence of disease-modifying agents, disease management should focus upon treating symptoms which may contribute to morbidity. PMID- 30245173 TI - Skin nerve alpha-synuclein deposits in a parkinsonian patient with heterozygous parkin mutation. PMID- 30245174 TI - Use and perceived effectiveness of complementary therapies in Parkinson's disease. AB - INTRODUCTION: Complementary therapies are commonly used by people with Parkinson's disease to relieve symptoms not fully addressed by pharmacologic and rehabilitation therapies currently available through medical clinics and programs. Three prior surveys in the US have shown that 40-85% of patients have used complementary therapies. We were interested in understanding what complementary therapies (CTs) our patients had used, to treat what symptoms, and whether they felt that the treatments were effective. METHODS: Patients scheduled for a return visit to a center neurologist were mailed a survey and instructed to bring the completed survey to their clinic visit. The survey contained questions on CTs used, effectiveness, and for what symptoms was the CT helpful. Willingness to participate in CT research was also included in the survey. RESULTS: 272 of 435 people with Parkinson's disease who completed the survey (62.5%) had tried some kind of CT, including a higher proportion of women than men (75.7% vs 53.8%; p < 0.01). Massage was the most frequently used therapy followed by yoga, Tai Chi, meditation and acupuncture. A high proportion of patients found the CT to be effective, for instance meditation was viewed as helpful by 85% of patients. Almost 2/3 of patients said they would be willing to participate in a research study of a CT. CONCLUSIONS: Complementary therapies are frequently used by people with Parkinson's disease coming to our center, and are viewed to be helpful for both motor and non-motor symptoms. Formal research assessments of therapies such as meditation are warranted. PMID- 30245175 TI - Perforated gastric diffuse large B-cell lymphoma: A case report and literature review. PMID- 30245176 TI - Access to Antihypertensive Medicines at the Household Level: A Study From 8 Counties of Kenya. AB - BACKGROUND: Estimates of hypertension prevalence in Kenya range from 12.3% to 50.1% nationally. Of those diagnosed, only 1 in 5 were taking medication. OBJECTIVES: This study aims to describe the access to antihypertensive medicines at the household level in 8 counties of Kenya, including factors associated with the location of purchase. METHODS: A household survey was conducted asking individuals with a diagnosis and prescription of antihypertensive medicines about the location of diagnosis and purchase of medicines, the availability of medicines at home, and the costs of medicines per month. A logistic regression model explores the relationship between patient characteristics and the probability that patients bought medicines at a public facility. RESULTS: Of 445 individuals diagnosed and prescribed medicines for hypertension, 20.9% were also diagnosed with another noncommunicable disease, including diabetes or asthma. The majority of study subjects received their diagnosis at a public hospital (67.5%) but the most common place of medicine purchase was a retail pharmacy (33.6%). Some study subjects bought their medicines at a public hospital (21.1%). The most frequent answer for not having medicines at home was that they could not afford their medicines (50.0%). Purchase in the public sector was associated with being less wealthy, having >1 noncommunicable disease, and living in urban areas. CONCLUSIONS: Affordability remains an important barrier to hypertension treatment access in Kenya. Programs to promote access to affordable treatment need to take into account that diagnosis of disease and choice of medicines takes place largely in the public sector, whereas the private sector is the gatekeeper for purchase of medicines. PMID- 30245178 TI - Losartan treatment significantly attenuates the fibrotic changes in the corpus cavernosum of castrated rats. AB - INTRODUCTION AND OBJECTIVES: The aim of this study is to evaluate the effects of castration and subsequent losartan administration on the fibrosis-related parameters in the corpora cavernosa of castrated rats. MATERIAL AND METHODS: Twenty-four male rats were divided into four equal groups. Group 1:sham surgery plus vehicle (0.9% NaCl) (control:con), group 2:sham surgery plus losartan (con+los), group 3: castration plus vehicle (castration:cast) and group 4:castration plus losartan (cast+los). After four weeks of oral losartan treatment, corporal levels of transforming growth factor-beta (TGF-beta), thrombospondin-1 (TSP-1), alpha-actin, beta-actin and fibronectin were investigated by ELISA kits. Changes in the collagen and smooth muscle content were evaluated by histological analysis with Masson trichrome staining. RESULTS: Initial and post-treatment body weights of rats were similar among groups. Castration significantly increased the expression of TGF-beta, TSP-1 and fibronectin and resulted in a significant decrease in alpha-actin levels in the corpora cavernosa. Administration of losartan reduced the levels of TGF-beta, TSP 1 and fibronectin in castrated rats. Alpha actin levels also increased after losartan treatment. Beta-actin levels were not significantly different among 4 groups. The levels of all markers were similar in group 1 and 2. Rate of fibrosis was significantly higher in castrated rats and treatment with losartan reduced this rate. CONCLUSION: Castration increased the expression of fibrosis-related markers in the corpora cavernosa of rats. Administration of losartan significantly attenuated those changes and exerted an antifibrotic effect. PMID- 30245177 TI - Global Unmet Needs in Cardiac Surgery. AB - More than 6 billion people live outside industrialized countries and have insufficient access to cardiac surgery. Given the recently confirmed high prevailing mortality for rheumatic heart disease in many of these countries together with increasing numbers of patients needing interventions for lifestyle diseases due to an accelerating epidemiological transition, a significant need for cardiac surgery could be assumed. Yet, need estimates were largely based on extrapolated screening studies while true service levels remained unknown. A multi-author effort representing 16 high-, middle-, and low-income countries was undertaken to narrow the need assessment for cardiac surgery including rheumatic and lifestyle cardiac diseases as well as congenital heart disease on the basis of existing data deduction. Actual levels of cardiac surgery were determined in each of these countries on the basis of questionnaires, national databases, or annual reports of national societies. Need estimates range from 200 operations per million in low-income countries that are nonendemic for rheumatic heart disease to >1,000 operations per million in high-income countries representing the end of the epidemiological transition. Actually provided levels of cardiac surgery range from 0.5 per million in the assessed low- and lower-middle income countries (average 107 +/- 113 per million; representing a population of 1.6 billion) to 500 in the upper-middle-income countries (average 270 +/- 163 per million representing a population of 1.9 billion). By combining need estimates with the assessment of de facto provided levels of cardiac surgery, it emerged that a significant degree of underdelivery of often lifesaving open heart surgery does not only prevail in low-income countries but is also disturbingly high in middle-income countries. PMID- 30245179 TI - [Urological and psychological approach of secondary complications to penile aesthetic modifications]. AB - OBJECTIVES: Due to the scarcity of scientific articles that review the technical alternatives available for aesthetic modifications in the penis that are the cause of subsequent uro-andrological problems, the existing literature is reviewed after the assistance of a penile infection by injection of subcutaneous hyaluronic acid with aesthetic purposes. MATERIAL AND METHODS: A 38-year-old male patient with no medical or psychiatric remarkable reports who came to the emergency room due to inflammation and abscess in penile skin after injection of hyaluronic acid. Surgical treatment was required and degloving and excision of affected skin was performed, with subsequent satisfactory evolution. The psychological analysis showed a narcissistic personality possibly secondary to traumas in childhood. We have reviewed the literature present in medical databases as well as information available on-line. RESULTS: Enlargement of the penis is an important cultural and social concern, so that there are different devices in the market to meet this demand, among them: herbal medicine, stretching exercises, weights, vacuum pumps or extensor devices. Among the surgical techniques, there have been described the pubic liposuction, the section of the suspensory ligament of the penis or the injection of autologous material or synthetic substances among others. As for the aesthetic modifications of the penis, there is a wide variety of genital piercings, tattoos and subcutaneous implants also called "pocketing" or "3D implants". All of these techniques or modifications are described in this article along with their possible associated more frequent urological complications. CONCLUSIONS: Aesthetic manipulations in the penis are becoming increasingly popular, and both its terminology and its medical implications should be known by urologists and andrologists. community. PMID- 30245180 TI - Interventions involving repetitive practice improve strength after stroke: a systematic review. AB - QUESTIONS: Do interventions involving repetitive practice improve strength after stroke? Are any improvements in strength accompanied by improvements in activity? DESIGN: Systematic review of randomised trials with meta-analysis. PARTICIPANTS: Adults who have had a stroke. INTERVENTION: Any intervention involving repetitive practice compared with no intervention or a sham intervention. OUTCOME MEASURES: The primary outcome was voluntary strength in muscles trained as part of the intervention. The secondary outcomes were measures of lower limb and upper limb activity. RESULTS: Fifty-two studies were included. The overall SMD of repetitive practice on strength was examined by pooling post-intervention scores from 46 studies involving 1928 participants. The SMD of repetitive practice on strength when the upper and lower limb studies were combined was 0.25 (95% CI 0.16 to 0.34, I2=44%) in favour of repetitive practice. Twenty-four studies with a total of 912 participants investigated the effects of repetitive practice on upper limb activity after stroke. The SMD was 0.15 (95% CI 0.02 to 0.29, I2=50%) in favour of repetitive practice on upper limb activity. Twenty studies with a total of 952 participants investigated the effects of repetitive practice on lower limb activity after stroke. The SMD was 0.25 (95% CI 0.12 to 0.38, I2=36%) in favour of repetitive practice on lower limb activity. CONCLUSION: Interventions involving repetitive practice improve strength after stroke, and these improvements are accompanied by improvements in activity. REVIEW REGISTRATION: PROSPERO CRD42017068658. [de Sousa DG, Harvey LA, Dorsch S, Glinsky JV (2018) Interventions involving repetitive practice improve strength after stroke: a systematic review. Journal of Physiotherapy 64: 210-221]. PMID- 30245181 TI - The co-administration of proanthocyanidins and an obesogenic diet prevents the increase in intestinal permeability and metabolic endotoxemia derived to the diet. AB - The consumption of Westernized diets leads to hyperphagia and obesity, as well as intestinal alterations. In the present study, we evaluated the effect of the administration of a grape seed proanthocyanidin extract (GSPE) at different time points on the modulation of intestinal barrier function (intestinal permeability and metabolic endotoxemia), in rats with high-fat/high-carbohydrate diet-induced obesity. Animals were fed a cafeteria diet (CAF) supplemented with a preventive (PRE-CAF) or simultaneously intermittent (SIT-CAF) GSPE treatment (500 mg/kg bw). Changes in the plasma levels of an orally administered marker of intestinal permeability (ovalbumin, OVA), lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF-alpha) were analyzed after animals were fed the obesogenic diet for 8, 12 and 17 weeks. In addition, ex vivo variations in transepithelial electrical resistance (TEER), the expression of tight junction (TJ) genes and the activity of myeloperoxidase (MPO) in the small and large intestines were monitored at the end of the experiment. The CAF diet increased OVA, LPS, MPO and TNF-alpha levels, accompanied by decreased TEER values in the small and large intestines. Interestingly, both GSPE treatments prevented these detrimental effects of the CAF diet, being the SIT-CAF group the most effective after 17 weeks of diet intervention. For the first time, this study provides evidence of the ameliorative effect of a proanthocyanidin extract, administered before or together with an obesogenic diet, on barrier dysfunction, as measured by intestinal permeability and metabolic endotoxemia. PMID- 30245182 TI - Dietary grape seed procyanidin extract protects against lead-induced heart injury in rats involving endoplasmic reticulum stress inhibition and AKT activation. AB - To investigate the protective role of grape seed procyanidin extract (GSPE) against lead-induced heart injury and the possible molecular mechanism associated with this event, Wistar rats were orally given GSPE (200 mg/kg) daily with or without lead acetate (PbA) (0.5 g/L) in drinking water for 56 d. GSPE attenuated oxidative stress, heart dysfunction, and lead accumulation in lead-exposed rat hearts. Meanwhile, GSPE inhibited the protein kinase RNA-like endoplasmic reticulum (ER) kinase/eukaryotic initiation factor 2alpha signaling pathway, and promoted protein kinase B (AKT) and glycogen synthase kinase 3beta phosphorylation altered by lead, and regulated lead-activated apoptosis and its related signaling pathway. This study suggests that dietary GSPE ameliorates lead induced heart injury associated with ER stress inhibition and AKT activation. Dietary GSPE may be a protector against lead-induced heart injury and a novel therapy for lead exposure. PMID- 30245183 TI - Soy genistein administered in soluble chitosan microcapsules maintains antioxidant activity and limits intestinal inflammation. AB - We used water-soluble Chitosan obtained by Maillard reaction with glucosamine to microencapsulate soy genistein (Ge) and preserve its biological activity for oral administration. Release of Ge was pH dependent with a super Case II mechanism at pH 1.2 and an anomalous transport with non-Fickian kinetics at pH 6.8. Microencapsulated Ge retained its antioxidant properties in vitro and its daily administration to mice attenuated clinical signs of acute colitis, limited inflammatory reaction and reduced oxidative stress and tissue injury as well. Remarkably, after feeding microencapsulated Ge the production of IL-10 in colonic tissue was restored to levels of untreated controls. According to statistical multivariate analysis, this cytokine was the parameter with the highest influence on the inflammatory/oxidative status. Microencapsulation of Ge with derivatized Chitosan becomes an interesting alternative to develop therapeutic approaches for oxidative inflammatory diseases; our findings suggest that the soy isoflavone could be incorporated into any functional food for application in intestinal inflammation. PMID- 30245184 TI - Physical activity and mental health - Author's reply. PMID- 30245185 TI - Physical activity and mental health. PMID- 30245186 TI - Shared genetic factors, fetal programming, and the transmission of depression. PMID- 30245187 TI - Maternal prenatal depressive symptoms and risk for early-life psychopathology in offspring: genetic analyses in the Norwegian Mother and Child Birth Cohort Study. AB - BACKGROUND: Maternal prenatal depression is a known risk factor for early-life psychopathology among offspring; however, potential risk transmission mechanisms need to be distinguished. We aimed to test the relative importance of passive genetic transmission, direct exposure, and indirect exposure in the association between maternal prenatal depressive symptoms and early-life internalising and externalising psychopathology in offspring. METHODS: We used structural equation modelling of phenotypic data and genetically informative relationships from the families of participants in the Norwegian Mother and Child Birth Cohort Study (MoBa). The analytic subsample of MoBa used in the current study comprises 22 195 mothers and 35 299 children. We used mothers' self-reported depressive symptoms during pregnancy, as captured by the Symptom Checklist, and their reports of symptoms of psychopathology in their offspring during the first few years of life (measured at 18, 36, and 60 months using the Child Behavior Checklist). FINDINGS: Maternal prenatal depressive symptoms were found to be associated with early-life psychopathology primarily via intergenerationally shared genetic factors, which explained 41% (95% CI 36-46) of variance in children's internalising problems and 37% (30-44) of variance in children's externalising problems. For internalising problems, phenotypic transmission also contributed significantly, accounting for 14% (95% CI 5-19) of the association, but this contribution was found to be explained by exposure to concurrent maternal depressive symptoms, rather than by direct exposure in utero. INTERPRETATION: Associations between maternal prenatal depressive symptoms and offspring behavioural outcomes in early childhood are likely to be at least partially explained by shared genes. This genetic confounding should be considered when attempting to quantify risks posed by in utero exposure to maternal depressive symptoms. FUNDING: UK Economic and Social Research Council, Norwegian Research Council, Norwegian Ministries of Health and Care Services, and Education & Research, Wellcome Trust, Royal Society, and National Institute for Health Research. PMID- 30245188 TI - Visual perceptions of ageing; A longitudinal mixed methods study of UK undergraduate student nurses' attitudes and perceptions towards older people. AB - Ageism and negative attitudes are said to be institutionally embedded in healthcare during a time when there are unprecedented increases in older population numbers. As nurses' care for older people in a range of environments it is important to examine attitudes and perceptions of undergraduate nurses towards older people. A longitudinal mixed methods study in conjunction with a three-year undergraduate UK nursing programme 2009-2012 was conducted with 310 undergraduate nurses. A questionnaire incorporating Kogan's attitude towards older people scale and a drawing of a person aged 75 years was completed three times, once each year. Thurstone scale and photo elicitation were also employed. Comparisons were made between individual participant's attitude score and drawing. The study established 75% of participants had moderately positive attitudes towards older people when the programme began, at the programme end this had increased to 98%. Age, gender, educational qualifications, practice learning, nursing field and contact with older people influenced participants' overall attitude score. Drawings provided a visual narrative of participants' perceptions of older people, appearance was a dominant discourse and the images were socially constructed. The study established the undergraduate nursing programme influenced attitudes and perceptions towards older people and suggests nurse education can influence changing attitudes. To date there is no known study that has advanced this understanding. PMID- 30245189 TI - Phase I study of ruxolitinib in previously treated patients with low or intermediate-1 risk myelodysplastic syndrome with evidence of NF-kB activation. AB - Therapeutic options for patients with lower-risk myelodysplastic syndrome (MDS) who have failed prior therapies are limited particularly after hypomethylating agent. Several studies have indicated that deregulation of innate immunity signaling is critical in the pathogenesis of MDS. This process involves Toll-like receptor stimulation, cytokine overexpression, and nuclear factor-kB (NF-kB) activation. Since ruxolitinib, a JAK1/JAK2 inhibitor, suppresses NF-kB expression, we conducted a phase 1 dose-escalation study to determine the safety and efficacy of ruxolitinib in previously treated lower-risk MDS patients with evidence of NF-kB activation. Nineteen patients, 8 with chronic myelomonocytic leukemia and 11 with MDS, were enrolled. No dose limiting toxicity was observed and the maximum tolerated dose was 20 mg twice daily. Responses were restricted to MDS patients with an overall response rate of 22% [hematological improvement in platelets (HI-P) = 2, hematological improvement in erythrocytes (HI-E) = 1, partial cytogenetic response (PCyR) = 1]. Of these patients, 2 relapsed (HI-P and PCyR) and 2 continue to be in HI-P and HI-E, respectively, with ongoing therapy. Meaningful improvement in bone marrow dysplasia was only seen in a patient who achieved HI-E. Phosphorylated p65 (pp65) decreased in 6 of 15 patients (40%) including the 2 patients with continued response to treatment and increased in a patient who relapsed after a short-lived HI-P. This suggests potential correlation between reduction in pp65 expression and response duration. In conclusion, ruxolitinib was well-tolerated in previously treated lower-risk MDS patients with evidence of NF-kB activation and resulted in low but significant frequency of responses. (NCT01895842). PMID- 30245190 TI - Baroreflex sensitivity and heart rate variability are predictors of mortality in patients with aneurysmal subarachnoid haemorrhage. AB - OBJECT: We aimed to investigate the link between the autonomic nervous system (ANS) impairment, assessed using baroreflex sensitivity (BRS) and heart rate variability (HRV) indices, and mortality after aneurysmal subarachnoid haemorrhage (aSAH). METHODS: A total of 57 patients (56 +/- 18 years) diagnosed with aSAH were retrospectively enrolled in the study, where 25% of patients died in the hospital. BRS was calculated using a modified cross-correlation method. Time- and frequency-domain HRV indices were calculated from a time-series of systolic peak intervals of arterial blood pressure signals. Additionally, cerebral autoregulation (CA) was assessed using the mean velocity index (Mxa), where Mxa > 0 indicates impaired CA. RESULTS: Both BRS and HRV indices were lower in non-survivors than in survivors. The patients with disturbed BRS and HRV had more extensive haemorrhage in the H-H scale (p = .040) and were more likely to die (p = .013) when compared to patients with the intact ANS. The logistic regression model for mortality included: the APACHE II score (p = .002; OR 0.794) and the normalised high frequency power of the HRV (p < <.001; OR 0.636). A positive relationship was found between the Mxa and BRS (R = 0.48, p = .003), which suggests that increasing BRS is moderately strongly associated with worsening CA. CONCLUSION: Our results indicated that lower values of HRV indices and BRS correlate with mortality and that there is a link between cerebral dysautoregulation and the analysed estimates of the ANS in aSAH patients. PMID- 30245191 TI - Dabigatran - Idarucizumab-facilitated intravenous thrombolysis - Hemorrhagic transformation. PMID- 30245192 TI - Supporting decision-making of adults with cognitive disabilities: The role of Law Reform Agencies - Recommendations, rationales and influence. AB - Article 12 of the UNCRPD on equal recognition before the law, places an obligation on member states to 'provide access by persons with disabilities to the support they may require in exercising their legal capacity'. This has resulted in an increased focus on the concept and practice of supported decision making, as opposed to substitute decision-making, for those with cognitive disabilities. To date, translation of this concept into law has been limited. However, Law Reform Agencies, tasked with reviewing legal decision-making schemes are increasingly recommending incorporation of legally recognised supported decision-making measures. This paper identifies the contribution of Law Reform Agencies' reports and recommendations to the evolving body of knowledge in relation to supported decision-making. In particular, it analyses the rationales for recommendations favouring the introduction of forms of legally recognised supported decision-making and the types of legal models of supported decision making being recommended by Law Reform Agencies. PMID- 30245193 TI - Macroscopic whole-mounts of the developing human fetal urogenital-genital tract: Indifferent stage to male and female differentiation. AB - We present a detailed review of fetal development of the male and female human urogenital tract from 8 to 22 weeks gestation at the macroscopic and morphometric levels. Human fetal specimens were sexed based on macroscopic identification of fetal testes or ovaries, Wolffian or Mullerian structures and the presence of the SRY gene in the specimens at or near the indifferent stage (8-9 weeks). Specimens were photographed using a dissecting microscope with transmitted and reflected light. Morphometric measurements were taken of each urogenital organ. During this time period, development of the male and female urogenital tracts proceeded from the indifferent stage to differentiated organs. The kidneys, ureters, and bladder developed identically, irrespective of sex with the same physical dimensions and morphologic appearance. The penis, prostate and testis developed in males and the clitoris, uterus and ovary in females. Androgen-dependent growth certainly influenced size and morphology of the penile urethra and prostate, however, androgen-independent growth also accounted for substantial growth in the fetal urogenital tract including the clitoris. PMID- 30245194 TI - Human glans and preputial development. AB - The urethra within the human penile shaft develops via (1) an "Opening Zipper" that facilitates distal canalization of the solid urethral plate to form a wide urethral groove and (2) a "Closing Zipper" that facilitates fusion of the epithelial surfaces of the urethral folds. Herein, we extend our knowledge by describing formation of the human urethra within the glans penis as well as development of the prepuce. Forty-eight normal human fetal penile specimens were examined using scanning electron microscopy and optical projection tomography. Serial histologic sections were evaluated for morphology and immunohistochemical localization for epithelial differentiation markers: Cytokeratins 6, 7, 10, FoxA1, uroplakin and the androgen receptor. As the closing zipper completes fusion of the urethral folds within the penile shaft to form a tubular urethra (~ 13 weeks), canalization of the urethral plate continues in proximal to distal fashion into the glans penis to directly form the urethra within the glans without forming an open urethral groove. Initially, the urethral plate is attached ventrally to the epidermis via an epithelial seam, which is remodeled and eliminated, thus establishing mesenchymal confluence ventral to the glanular urethra. The morphogenetic remodeling involves the strategic expression of cytokeratin 7, FoxA1 and uroplakin in endodermal epithelial cells as the tubular glanular urethra forms. The most ventral epithelial cells of the urethral plate are pinched off from the glanular urethra and are reabsorbed into the epidermis ultimately losing expression of their markers, a process undoubtedly regulated by androgens. The prepuce initially forms on the dorsal aspect of the glans at approximately 12 weeks of gestation. After sequential proximal to distal remodeling of the ventral urethral plate along the ventral aspect of glans, the prepuce of epidermal origin fuses in the ventral midline. PMID- 30245195 TI - Multiple divergent picobirnaviruses with functional prokaryotic Shine-Dalgarno ribosome binding sites present in cloacal sample of a diarrheic chicken. AB - Picobirnaviruses (PBVs) of family Picobirnaviridae have bisegmented (S1 and S2 segments), double-stranded RNA genomes. In this study a total of N = 12 complete chicken PBVs (ChPBV) segments (N = 5 of S1 and N = 7 of S2, Acc. Nos.: MH425579 90) were determined using viral metagenomic and RT-PCR techniques from a single cloacal sample of a diarrheic chicken. The identified ChPBV segments are unrelated to each other and distant from all of the currently known PBVs. In silico sequence analyses revealed the presence of conserved prokaryotic Shine Dalgarno-like (SD-like) sequences upstream of the three presumed open reading frames (ORFs) of the S1 and a single presumed ORF of the S2 segments. According to the results of expression analyses in E. coli using 6xHis-tagged recombinant ChPBV segment 1 construct and Western blot these SD-like sequences are functional in vivo suggesting that S1 of study PBVs can contain three ORFs and supporting the bacteriophage-nature of PBVs. PMID- 30245196 TI - Resource recovery from wastewater by anaerobic membrane bioreactors: Opportunities and challenges. AB - This review examines the potential of anaerobic membrane bioreactor (AnMBR) to serve as the core technology for simultaneous recovery of clean water, energy, and nutrient from wastewater. The potential is significant as AnMBR treatment can remove a board range of trace organic contaminants relevant to water reuse, convert organics in wastewater to biogas for subsequent energy production, and liberate nutrients to soluble forms (e.g. ammonia and phosphorus) for subsequent recovery for fertilizer production. Yet, there remain several significant challenges to the further development of AnMBR. These challenges evolve around the dilute nature of municipal wastewater, which entails the need for pre concentrating wastewater prior to AnMBR, and hence, issues related to salinity build-up, accumulation of substances, membrane fouling, and membrane stability. Strategies to address these challenges are proposed and discussed. A road map for further research is also provided to guide future AnMBR development toward resource recovery. PMID- 30245197 TI - Current state and challenges of full-scale membrane bioreactor applications: A critical review. AB - Membrane bioreactor (MBR) technology for wastewater treatment has been developed for over three decades. Our latest survey shows that MBR applications for wastewater treatment are still in rapid growth today. This review summarizes the pros, cons and progress in full-scale MBR applications. Critical statistics on the capital cost, operating cost, footprint, energy consumption and chemical consumption of full-scale MBRs are provided, and are compared to those of conventional activated sludge (CAS) processes with/without tertiary treatment. The efficiencies in full-scale treatment of ordinary pollutants (C, N and P), pathogens (bacteria and viruses) and emerging pollutants (e.g., trace organic pollutants) are reviewed. The long-term operation stability of full-scale MBRs is also discussed with several examples provided, with special attention placed on the seasonal variation of membrane fouling. Finally, the future challenges of MBR application are outlined from the perspectives of fouling control, pollutant removal, cost-effectiveness and competitiveness in specific fields of application. PMID- 30245198 TI - Refining understanding of working memory buffers through the construct of binding: Evidence from a single case informs theory and clinical practise. AB - Binding operations carried out in working memory enable the integration of information from different sources during online performance. While available evidence suggests that working memory may involve distinct binding functions, whether or not they all involve the episodic buffer as a cognitive substrate remains unclear. Similarly, knowledge about the neural underpinnings of working memory buffers is limited, more specifically regarding the involvement of medial temporal lobe structures. In the present study, we report on the case of patient KA, with developmental amnesia and selective damage to the whole hippocampal system. We found that KA was unable to hold shape-colours associations (relational binding) in working memory. In contrast, he could hold integrated coloured shapes (conjunctive binding) in two different tasks. Otherwise, and as expected, KA was impaired on three relational memory tasks thought to depend on the hippocampus that are widely used in the early detection of Alzheimer's disease. Our results emphasize a dissociation between two binding processes within working memory, suggesting that the visuo-spatial sketchpad could support conjunctive binding, and may rely upon a large cortical network including sub hippocampal structures. By contrast, we found evidence for a selective impairment of relational binding in working memory when the hippocampal system is compromised, suggesting that the long-term memory deficit observed in amnesic patients may be related to impaired short-term relational binding at encoding. Finally, these findings may inform research on the early detection of Alzheimer's disease as the preservation of conjunctive binding in KA is in sharp contrast with the impaired performance demonstrated very early in this disease. PMID- 30245199 TI - Alpha oscillations reveal implicit visual processing of motion in hemianopia. AB - After lesion or deafferentation of the primary visual cortex, hemianopic patients experience loss of conscious vision in their blind field. However, due to the spared colliculo-extrastriate pathway, they might retain the ability to implicitly process motion stimuli through the activation of spared dorsal extrastriate areas, despite the absence of awareness. To test this hypothesis, Electroencephalogram (EEG) was recorded from a group of hemianopic patients without blindsight (i.e., who performed at chance in different forced-choice tasks), while motion stimuli, static stimuli or no stimuli (i.e., blank condition) were presented either in their intact or in their blind visual field. EEG analyses were performed in the time-frequency domain. The presentation of both motion and static stimuli in the intact field induced synchronization in the theta band and desynchronization both in the alpha and the beta band. In contrast, for stimuli presented in the blind field, significantly greater desynchronization in the alpha range was observed only after the presentation of motion stimuli, compared to the blank condition, over posterior parietal occipital electrodes in the lesioned hemisphere, at a late time window (500-800 msec). No alpha desynchronization was elicited by static stimuli. These results show that hemianopic patients can process only visual signals relying on the activation of the dorsal pathway (i.e., motion stimuli) in the absence of awareness and suggest different patterns of electrophysiological activity for conscious and unconscious visual processing. Specifically, visual processing in the absence of awareness elicits an activity limited to the alpha range, most likely reflecting a "local" process, occurring within the extrastriate areas and not participating in inter-areal communication. This also suggests a response specificity in this frequency band for implicit visual processing. In contrast, visual awareness evokes changes in different frequency bands, suggesting a "global" process, accomplished by activity in a wide range of frequencies, probably within and across cortical areas. PMID- 30245200 TI - No evidence for enhanced distractor template representation in early visual cortex. PMID- 30245201 TI - Rehabilitating the brain through meditation and electrical stimulation. AB - This paper is a review of our recent studies and ideas related to the neuropsychological issues that Robert Rafal and I worked together to understand attention and hopefully improve it in a variety of patients. Rehabilitation is also a goal of my current research to determine if non invasive stimuli can improve white matter in humans. We have found that fractional anisotropy (FA) is improved in pathways surrounding the anterior cingulate cortex (ACC) following two week to four weeks of meditation training. We hypothesized that the frontal theta increased following meditation training might be a cause of the improved connectivity. This was confirmed by a mouse study using optogenetics to impose theta rhythms in the ACC. We have evidence that electrical stimulation while performing a task that activates the ACC can also increase theta. We plan studies to determine whether two to four weeks of stimulation can improve FA in pathways surrounding the anterior cingulate. PMID- 30245202 TI - Ultrasound assisted synthesis of Mg-Mn-Zr impregnated activated carbon for effective fluoride adsorption from water. AB - High fluoride content in the natural water sources is a serious matter of concern and adsorption is recommended as one of the most convenient, affordable and widely applied defluorination technologies. In this study, a novel composite was synthesized by impregnating magnesium (Mg), manganese (Mn) and zirconium (Zr) on powdered activated carbon (AC) for effective fluoride adsorption and the synthesis was made using sonochemical method. The characterization of the prepared adsorbent AC-Mg-Mn-Zr along with individual metal composites AC-Zr, AC Mg and AC-Mn were done by SEM, EDX, FTIR, XRD and BET analysis to understand the major functional bonds, and changes in surface chemistry after adsorption. The mechanism of the process was discussed through major reactions involved for individual metals. Due to high point of zero charge (pHPZC = 11.9), the adsorbent was able to remove more than 96% of fluoride consistently with only 1 g/L of optimum adsorbent dosage for a wide pH range (2 to 10). The maximum adsorption capacity obtained was 26.27 mg/g within an equilibrium time of 3 h. More than 96% energy saving was achieved in the sonochemical synthesis route compared to conventional precipitation method of synthesis. PMID- 30245203 TI - The sonochemical synthesis of vertically aligned ZnO nanorods and their UV photodetection properties: Effect of ZnO buffer layer. AB - Vertically aligned Zinc oxide nanorods (ZnO NRs) were successfully synthesized in this study using the sonochemical method to improve the intrinsic properties of UV photodetector (PD). Three different thin films: Ti/Zn, Ti/ZnO, and Ti/ZnO/Zn, with the thicknesses of 10 nm/55 nm, 10 nm/85 nm, and 10 nm/85 nm/55 nm respectively, were deposited on glass substrates using the RF-sputtering technique. The synthesized ZnO NRs were investigated using XRD, FESEM and Raman spectroscopy to determine the effect of Zn and ZnO as seed layers, and ZnO as a buffer layer on the surface morphology, crystal structure, optical properties of ZnO NRs. The ZnO NRs grown on Zn/Ti, ZnO/Ti, and Zn/ZnO/Ti are characterized by hexagonal crystal structure with preferential growth in the c-axis direction. The ZnO NRs grown on Zn/ZnO/Ti displayed the highest density, uniform size distribution, vertically aligned rods and aspect ratio. The UV device fabricated from the ZnO NRs grown on Zn /ZnO/Ti also showed the highest photocurrent (360 uA) and responsivity of (878 mA/W). ZnO NRs grown on Zn/ZnO/Ti were also observed to be highly stable and exhibited a relatively rapid response and recovery times for different time intervals when exposed to the UV light of 365 nm wavelength. Thus, the inclusion of the ZnO as a buffer layer (Zn as a seed layer/ZnO as buffer layer/Ti as a buffer layer) improve the properties of the ZnO NRs. In addition, the current gain of ZnO NRs grown on Zn (55 nm)/ZnO (85 nm)/Ti (10 nm) based ultraviolet (UV) photodetector (PD) is about two times higher than that of conventional Zn (55 nm)/ZnO (85 nm)/Ti (10 nm) thin-films UV PD, which is due to the higher surface-to-volume ratio of ZnO nanorods (NRs) compared with their thin films. This study confirms the possibility of sonochemically fabricating vertically aligned ZnO nanorods as well as its applicability as a viable UV photodetector. PMID- 30245204 TI - Effects of the ultrasound-assisted pretreatments using borax and sodium hydroxide on the physicochemical properties of Chinese fir. AB - This work investigated the physicochemical properties of Chinese fir after ultrasound-assisted pretreatments with borax and sodium hydroxide additives in an aqueous solution. TGA, FTIR, and XRD were used to analyze the thermal degradation processes, changes in chemical structures, and crystallinity of the treated samples, respectively. Additionally, the release of volatiles from wood pyrolysis was measured on-line by the TG-FTIR apparatus. In thermal analysis, all samples showed main degradation stages at 220-500 degrees C, and alkaline compounds could efficiently shift the process to lower temperatures with lower maximum weight loss rate (MWLR) and more residues. From TG-FTIR, it was observed that CO2 was the primary gas product from pyrolysis in the alkaline-treated samples, while there were more carbonyl compounds released in the control and deionized water groups. Due to the destruction and removal of hemicellulose and lignin after alkaline treatments, the related peaks changed greatly. Changes in the ester groups caused by saponification also accounted for one of the most significant differences between samples. Moreover, except for the deionized water group without sonication, the crystallinity of the samples increased from 6.34% to 11.29%. Overall, comparing the samples treated with or without ultrasound, the results showed that the ultrasound treatment did influence the samples' physicochemical properties, and its' effects varied by the basicity of the solution. This in-depth investigation offers a better understanding of ultrasound assisted and alkaline pretreatments of wood materials. PMID- 30245205 TI - Impact of prior pulmonary tuberculosis in treatment outcomes of HCAP and CAP patients in intensive care units. AB - BACKGROUND/PURPOSE: It is controversial whether healthcare-associated pneumonia (HCAP) belongs to a unique clinical entity or it shares common characteristics with community-acquired pneumonia (CAP). The impact of prior pulmonary tuberculosis (PTB) in clinical presentation and treatment outcome of ICU-admitted CAP and HCAP patients also remains unknown. METHODS: We report a nationwide, multi-center, retrospective study. ICU-admitted CAP and HCAP patients from six medical centers in Taiwan were enrolled for analysis. Patients were defined as either CAP or HCAP cases, and with and without prior PTB, according to the database of Taiwan CDC. The disease severity, microbiologic characteristics, and treatment outcomes between CAP and HCAP patients with or without prior PTB were compared and analyzed. RESULTS: A total of 414 ICU-admitted patients, including 176 CAP cases and 238 HCAP cases were included for analysis during the study period. In both CAP and HCAP subgroups, the pneumonia severities, proportions of organ dysfunction, and microbiologic characteristics were similar between patients with and without prior PTB. In survival analysis, patients with prior PTB had higher 30-day mortality than those without prior PTB (38.9% vs. 16.5%, p = 0.021) in the CAP population. Multivariate analysis revealed that a history of prior PTB was an independent clinical factor associated with higher 30-day mortality rate in CAP patients (HR = 4.45, 95% CI: 1.81-10.98, P = 0.001). CONCLUSION: History of prior PTB is an independent clinical factor for increased 30-day mortality rate in ICU-admitted CAP patients, but not in ICU-admitted HCAP patients. PMID- 30245206 TI - [Traditional Chinesse medicine on skin]. PMID- 30245207 TI - [Review through a clinical case of pretibial injuries]. PMID- 30245208 TI - Hsp83/Hsp90 Physically Associates with Insulin Receptor to Promote Neural Stem Cell Reactivation. AB - Neural stem cells (NSCs) have the ability to exit quiescence and reactivate in response to physiological stimuli. In the Drosophila brain, insulin receptor (InR)/phosphatidylinositol 3-kinase (PI3K)/Akt pathway triggers NSC reactivation. However, intrinsic mechanisms that control the InR/PI3K/Akt pathway during reactivation remain unknown. Here, we have identified heat shock protein 83 (Hsp83/Hsp90), a molecular chaperone, as an intrinsic regulator of NSC reactivation. Hsp83 is both necessary and sufficient for NSC reactivation by promoting the activation of InR pathway in larval brains in the presence of dietary amino acids. Both Hsp83 and its co-chaperone Cdc37 physically associate with InR. Finally, reactivation defects observed in brains depleted of hsp83 were rescued by over-activation of the InR/PI3K/Akt pathway, suggesting that Hsp83 functions upstream of the InR/PI3K/Akt pathway during NSC reactivation. Given the conservation of Hsp83 and the InR pathway, our finding may provide insights into the molecular mechanisms underlying mammalian NSC reactivation. PMID- 30245209 TI - Targeting the Extracellular Signal-Regulated Kinase 5 Pathway to Suppress Human Chronic Myeloid Leukemia Stem Cells. AB - Tyrosine kinase inhibitors (TKi) are effective against chronic myeloid leukemia (CML), but their inefficacy on leukemia stem cells (LSCs) may lead to relapse. To identify new druggable targets alternative to BCR/ABL, we investigated the role of the MEK5/ERK5 pathway in LSC maintenance in low oxygen, a feature of bone marrow stem cell niches. We found that MEK5/ERK5 pathway inhibition reduced the growth of CML patient-derived cells and cell lines in vitro and the number of leukemic cells in vivo. Treatment in vitro of primary CML cells with MEK5/ERK5 inhibitors, but not TKi, strikingly reduced culture repopulation ability (CRA), serial colony formation ability, long-term culture-initiating cells (LTC-ICs), and CD26-expressing cells. Importantly, MEK5/ERK5 inhibition was effective on CML cells regardless of the presence or absence of imatinib, and did not reduce CRA or LTC-ICs of normal CD34+ cells. Thus, targeting MEK/ERK5 may represent an innovative therapeutic approach to suppress CML progenitor/stem cells. PMID- 30245210 TI - Crosstalk between BPA and FXRalpha Signaling Pathways Lead to Alterations of Undifferentiated Germ Cell Homeostasis and Male Fertility Disorders. AB - Several studies have reported an association between the farnesoid X receptor alpha (FXRalpha) and estrogenic signaling pathways. Fxralpha could thus be involved in the reprotoxic effects of endocrine disruptors such as bisphenol-A (BPA). To test this hypothesis, mice were exposed to BPA and/or stigmasterol (S), an FXRalpha antagonist. Following the exposure to both molecules, wild-type animals showed impaired fertility and lower sperm cell production associated with the alteration of the establishment and maintenance of the undifferentiated germ cell pool. The crosstalk between BPA and FXRalpha is further supported by the lower impact of BPA in mice genetically ablated for Fxralpha and the fact that BPA counteracted the effects of FXRalpha agonists. These effects might result from the downregulation of Fxralpha expression following BPA exposure. BPA and S act additively in human testis. Our data demonstrate that FXRalpha activity modulates the impact of BPA on male gonads and on undifferentiated germ cell population. PMID- 30245211 TI - Generation of Vascular Endothelial Cells and Hematopoietic Cells by Blastocyst Complementation. AB - In the case of organ transplantation accompanied by vascular anastomosis, major histocompatibility complex mismatched vascular endothelial cells become a target for graft rejection. Production of a rejection-free, transplantable organ, therefore, requires simultaneous generation of vascular endothelial cells within the organ. To generate pluripotent stem cell (PSC)-derived vascular endothelial cells, we performed blastocyst complementation with a vascular endothelial growth factor receptor-2 homozygous mutant blastocyst. This mutation is embryonic lethal at embryonic (E) day 8.5-9.5 due to an early defect in endothelial and hematopoietic cells. The Flk-1 homozygous knockout chimeric mice survived to adulthood for over 1 year without any abnormality, and all vascular endothelial cells and hematopoietic cells were derived from the injected PSCs. This approach could be used in conjunction with other gene knockouts which induce organ deficiency to produce a rejection-free, transplantable organ in which all the organ's cells and vasculature are PSC derived. PMID- 30245212 TI - Reproducibility of Molecular Phenotypes after Long-Term Differentiation to Human iPSC-Derived Neurons: A Multi-Site Omics Study. AB - Reproducibility in molecular and cellular studies is fundamental to scientific discovery. To establish the reproducibility of a well-defined long-term neuronal differentiation protocol, we repeated the cellular and molecular comparison of the same two iPSC lines across five distinct laboratories. Despite uncovering acceptable variability within individual laboratories, we detect poor cross-site reproducibility of the differential gene expression signature between these two lines. Factor analysis identifies the laboratory as the largest source of variation along with several variation-inflating confounders such as passaging effects and progenitor storage. Single-cell transcriptomics shows substantial cellular heterogeneity underlying inter-laboratory variability and being responsible for biases in differential gene expression inference. Factor analysis based normalization of the combined dataset can remove the nuisance technical effects, enabling the execution of robust hypothesis-generating studies. Our study shows that multi-center collaborations can expose systematic biases and identify critical factors to be standardized when publishing novel protocols, contributing to increased cross-site reproducibility. PMID- 30245213 TI - The Cricothyroid Joint: A Practical Guide for Distinguishing Between Different Joint Types. AB - OBJECTIVE: Type A cricothyroid joint (CTJ) leads to a higher elongation of the vocal folds than Type B/C CTJ. Therefore, the determination for the CTJ type is important whether to perform a cricoid-thyroid approximation for a pitch elevation in transwomen with gender dysphoria. This study aimed to develop a tool for clinicians and radiologists for distinguishing between Type A (cricoid cartilage protuberance) and Type B/C (flat surface with/without cartilage of the cricoid) CTJs on high-resolution computed tomography (HRCT). STUDY DESIGN: This was a prospective study. METHODS: Analysis of 60 male HRCTs and 60 female HRCTs of the larynx/CTJs. Three-dimensional reconstruction of the laryngeal cartilages, based on visualization of the CTJ in HRCT scans. The intercartilaginous distances (nearest distance between the inner side of the Thyroid and outer side of the cricoid of the CTJ) were measured to compare different types of CTJs. RESULTS: In all HRCT scans, three-dimensional reconstructions of the CTJ were feasible. All Type A CTJs showed the typical cricoid cartilage protuberance (like a volcano) in biplanar images and three-dimensional reconstructions. All Type B/C CTJs showed a flat cricoid joint cartilage in biplanar images and three-dimensional reconstructions. The type distribution was Type A: 61% in male and female larynges; Type B/C: 39% in male and female larynges. The intercartilaginous distances were Type A: 0.71mm [0.42-0.98] in male larynges and 0.75mm [0.44-1.40] in female larynges; Type B/C: 1.13mm [0.36-1.24] in male larynges and 1.32mm [0.76-2.47] in female larynges. CONCLUSIONS: In HRCT scans, the Type A CTJ showed an intercartilaginous space less than 1mm. In contrast, the Type B/C CTJ showed an intercartilaginous distance exceeded 1mm. PMID- 30245214 TI - Insect cuticular proteins and their role in transmission of phytoviruses. AB - Many viruses of agricultural importance are transmitted to host plants via insect vectors. Characterizing virus-vector interactions at the molecular level is essential if we are to fully understand the transmission mechanisms involved and develop new strategies to control viral spread. Hitherto, insect proteins involved in virus transmission have been characterized only poorly. Recent advances in this topic, however, have significantly filled this knowledge gap. Among the vector molecules identified, cuticular proteins have emerged as key molecules for plant virus transmission, regardless of transmission mode or vector considered. Here, we review recent evidence highlighting that the CPR family, and particularly RR-1 proteins, undoubtedly deserves special attention. PMID- 30245215 TI - Residents' Views on Tobacco Cessation in Radiation Oncology. PMID- 30245216 TI - Validation of Adult Relative Radiation Levels Using the ACR Dose Index Registry: Report of the ACR Appropriateness Criteria Radiation Exposure Subcommittee. AB - The ACR Dose Index Registry (DIR) provides a new source of clinical radiation exposure data that has not been used previously to establish or update the relative radiation level (RRL) values in the ACR Appropriateness Criteria (AC). The results of a recent review of DIR data for 10 common CT examinations were compared with current ACR AC RRL values for the same procedures. The AC RRL values were previously determined by consensus of members of the AC Radiation Exposure Subcommittee based on reference radiation dose values from the literature (when available) and anecdotal information from individual members' clinical practices and experiences. For 7 of the 10 examination types reviewed, DIR data agreed with existing RRL values. For 3 of 10 examination types, DIR data reflected lower dose values than currently rated in the AC. The Radiation Exposure Subcommittee will revise these RRL assignments in a forthcoming update to the AC (in October 2018) and will continue to monitor the DIR and associated reviews and analyses to refine RRL assignments for additional examination types. Given recent attention and efforts to reduce radiation exposure in CT and other imaging modalities, it is likely that other examination types will require revision of RRL assignments once information from the DIR database is considered. PMID- 30245217 TI - The Influence of North American Radiology Institutions in Advancing Mexican Radiology. PMID- 30245219 TI - Radiologists as Co-Authors in Case Reports Containing Radiological Images: Does Their Presence Influence Quality? PMID- 30245218 TI - The State of Medical Student Teaching of Interventional Radiology: Implications for the Future. AB - INTRODUCTION: The formation of integrated interventional radiology (IR) residency programs has changed the training paradigm. This change mandates the need to provide adequate exposure to allow students to explore IR as a career option and to allow programs to sufficiently evaluate students. This study aims to highlight the availability of medical student education in IR and proposes a basic framework for clinical rotations. MATERIALS AND METHODS: The Liaison Committee on Medical Education (LCME) website was utilized to generate a list of accredited medical schools in the United States. School websites and course listings were searched for availability of IR and diagnostic radiology rotations. The curricula of several well-established IR rotations were examined to identify and categorize course content. RESULTS: In all, 140 LCME-accredited medical schools had course information available. Of those schools, 70.5% offered an IR rotation; 84.6% were only available to senior medical students and only 2% were offered for preclinical students; and 8.1% of courses were listed as subinternships. Well established IR clerkships included a variety of clinical settings, including preprocedure evaluation, experience performing procedures, postprocedure management, and discharge planning. CONCLUSION: Medical student exposure to IR is crucial to the success of integrated IR residency programs. Current research shows few institutions with formal IR subinternship rotations. Although 70.5% of institutions have some form of nonstandardized IR course, 84.6% are available only to fourth-year students, and 2% are offered to preclinical students. This suggests there is a significant opportunity for additional formal exposure to IR through increasing availability of IR rotations and exposure during the clinical and preclinical years. PMID- 30245220 TI - Statistical methods for detecting admixture. AB - The increasing availability of large-scale autosomal genetic variation data sampled from world-wide geographic areas, coupled with advances in the statistical methodology to analyse these data, is showcasing the power of DNA as a major tool to gain insights into the demographic history of humans and other organisms. Here we review statistical techniques that shed light on a specific aspect of demography: the detection and description of admixture events where two or more genetically distinct groups intermixed at one or more times in the past. In particular we give an overview of some of the widely used methods to identify and describe admixture events using autosomal DNA from unrelated individuals, with a particular focus on analysing biallelic Single-Nucleotide-Polymorphsim (SNP) markers. PMID- 30245221 TI - Enantioselective bioaccumulation and metabolism of lactofen in zebrafish Danio rerio and combined effects with its metabolites. AB - Pesticide residue in agricultural land might led to contamination of fresh waters, creating potential risks to organisms. The environmental behavior of herbicide lactofen may be enantioselective and the metabolites may have high toxic effects in individual or in combination. In this work, the enantioselective bioaccumulation, metabolism and toxic effects of lactofen and three metabolites (desethyl lactofen, acifluorfene, and amino acifluorfene) in zebrafish were investigated. The antioxidase activity (superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase), lipid peroxidation content were measured after exposure, and genetic toxicity was evaluated by a micronucleus test. The integrated biomarker response (IBR) method was used to determine the effects of the lactofen and its metabolites as well as their combinations. The metabolites were found to have higher toxic effects, and enantioselective toxic effects of lactofen and desethyl lactofen were observed, with the S-enantiomer more toxic. Based on IBR values, synergistic effects existed in combination of lactofen and desethyl lactofen, while antagonistic effects of lactofen with acifluorfene or amino acifluorfene were observed. Zebrafish were exposed to 0.5 mg L-1 lactofen and the bioaccumulation were measured during a 15 d period followed by a 7 d elimination. The half-lives of the metabolites varied between 0.66 and 5.21 d, with bioconcentration factors (BCFs) in the range of 39-120. The metabolic pathways of R- and S-lactofen were found to be significantly different. The results supported our hypothesis. Therefore, the assessment of enantiomers and metabolites in individual or in combination should be taken into consideration in evaluating chiral pesticide risks. PMID- 30245222 TI - A molecular-scale study on the hydration of sulfuric acid-amide complexes and the atmospheric implication. AB - Amides are ubiquitous in atmosphere. However, the role of amides in new particle formation (NPF) is poorly understood. Herein, the interaction of urea and formamide with sulfuric acid (SA) and up to four water (W) molecules has been studied at the M06-2X/6-311++G(3df,3pd) level of theory. The structures and properties of (Formamide)(SA)(W)n (n = 0-4) and (Urea)(SA)(W)n (n = 0-4) clusters were investigated. Results show that the interaction of SA with the CO group of amides plays a more important role in amide clusters compared with the NH2 group. Proton transfer to water molecule become dominant in highly hydrated amide clusters at lower temperatures. There is no proton transfer to CO group in formamide clusters. The Rayleigh light scattering intensities of amide clusters are comparable to that of amine and oxalic acid clusters reported previously. Moreover, unhydrated (Amide)(SA) clusters have similar or even higher ability than hydrated SA clusters to participate in ion-induced nucleation. In comparison with formamide, urea has more interacting sites and its clusters have higher Rayleigh light scattering intensities, larger dipole moment, stronger interaction with SA and lower water affinity. The intermolecular interaction in (Formamide)(SA) is slightly weaker than that of SA dimer, which may be compensated by the high concentration of formamide, thus enabling formamide to participate in initial steps of NPF. This study may bring new insight into the role of amides in initial steps of NPF from molecular scale and could help better understand the properties of amide-containing organic aerosol. PMID- 30245223 TI - Characterization of airborne antibiotic resistance genes from typical bioaerosol emission sources in the urban environment using metagenomic approach. AB - The wide spread of antibiotic resistance genes (ARGs) has attracted increasing concern. However, the occurrence and diversity of ARGs in airborne particles remains to be understood. In this study, total suspended particles (TSP) in the atmosphere were collected from typical sources of ARG pollution, including animal farms and wastewater treatment plant (WWTP), as well as the downtown area in Zhuhai, China. Metagenomic profiling demonstrated that ARGs were abundant and diverse in the TSP from animal farms and WWTP, but significant differences in ARG composition pattern between these samples were observed. ARGs associated with the resistance to aminoglycoside, macrolide-lincosamide-streptogramin (MLS) and tetracycline were dominant over other ARGs in the TSP of the animal farms, whereas multidrug and bacitracin resistance genes were more abundant than other ARGs in the TSP of the WWTP. In the animal farms, ARG profiles of the TSP were consistent with those of animal feces, indicating that animal feces could be one of the most contributing sources of airborne ARGs in animal farms. In contrast to representative sources of ARG pollution, ARG abundance and diversity in the TSP collected from the downtown area was relatively low, with multidrug resistance genes being predominant. This study suggests that metagenomic profiling of the ARGs in airborne TSP could enhance our comprehensive understanding of ARGs dissemination in the environment and their potential health threats. PMID- 30245224 TI - Diffusion of organic anions in clay-rich media: Retardation and effect of anion exclusion. AB - The transport of emerging organic contaminants through the geosphere is often an environmental issue. The sorption of organic compounds slows their transport in soils and porous rocks and retardation is often assessed by extrapolation of batch experiments. However, transport experiments are preferable to strengthen migration data and modelling. In this context, we evaluated the adsorption of various organic acids by means of through-diffusion experiments in a sedimentary clay-rich rock (Callovo-Oxfordian, East of Paris Basin, France). A low diffusivity of organic anions was quantified with effective diffusion coefficients, De, ranged between 0.5 and 7 10-12 m2 s-1. These values indicated an organic anion exclusion. As for chloride, the porosity accessible to organic anions was lower than that of water: epsilona(organic anions) < epsilon(water). The partial exclusion of organic anions from rock porosity was linked to both charge and size effects. A significant retardation was observed for organic anions such as oxalate, citrate or alpha-isosaccharinate. Yet, retardation measured by diffusion experiments was significantly lower than expected from batch experiments on crushed samples. An empirical correction factor is proposed to account for a possible decrease of retardation with accessible porosity of diffusing solute. This feature has significant implications for the estimation of migration parameters of organic compounds in the environment. PMID- 30245226 TI - Synergistic inhibition of anaerobic ammonium oxidation (anammox) activity by phenol and thiocyanate. AB - Coke-oven wastewater discharged from the steel-manufacturing process is phenol and thiocyanate (SCN)-rich wastewater, which inhibits microbial activities in biological wastewater treatment processes. In the present study, synergistic inhibition of anaerobic ammonium oxidation (anammox) activity by phenol and SCN was examined by batch incubation and continuous operation of an anammox reactor. The comparison of anammox activities determined in the batch incubation, in which the anammox biomass was anoxically incubated with 10-250 mg L-1 of i) phenol, ii) SCN, or iii) both phenol and SCN, showed that synergistic inhibition by phenol and SCN was greater than the inhibitions by phenol or SCN alone. The synergistic inhibition by phenol and SCN was further investigated by operating an up-flow column anammox reactor for 262 d. The removal efficiencies of NH4+ and NO2- deteriorated when phenol and SCN concentrations in the influent increased to 16 and 32 mg L-1, respectively, and the inhibition of anammox activity was further investigated by a15NO2- tracer experiment. Addition of phenol and SCN resulted in a population shift of anammox bacteria, and the dominant species changed from "Candidatus Kuenenia stuttgartiensis" to "Ca. Brocadia sinica". The relative abundance of Azoarcus and Thiobacillus 16S rRNA gene reads increased during the operation, suggesting that they were responsible for the anaerobic phenol and SCN degradation. The present study is the first to document the synergistic inhibition of anammox activity by phenol and SCN and the microbial consortia involved in the nitrogen removal as well as the phenol and SCN degradations. PMID- 30245225 TI - Visible light driven photo-degradation of Congo red by TiO2ZnO/Ag: DFT approach on synergetic effect on band gap energy. AB - In this paper, we report the combination of two metal oxides (TiO2ZnO) that allows mixed density of states to reduce band gap energy, facilitating the photo oxidation of Congo red dye under visible light. For the oxidation, a possible mechanism is proposed after analyzing the intermediates by GC-MS, and it is consistent with Density Functional Theory (DFT). The nanohybrids were characterized comprehensibly by several analytical techniques such as X-Ray diffraction (XRD), Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM), and X-ray Photoelectron Spectroscopy (XPS). For the addition of ZnO to TiO2, a dominance of anatase phase was found rather than other phases (rutile or brookite). A broad band (~550 nm) is observed in UV-Visible spectra for TiO2ZnO/Ag NPs nm because of Surface Plasmon properties of Ag NPs. The band gap energy was calculated for TiO2ZnO/Ag system, and then it has been further studied by DFT in order to show why the convergence of two semiconductors allows a mixed density of states, facilitating the reduction of the energy gap between occupied and unoccupied bands; ultimately, it improves the performance of catalysts under visible light. Significantly, the interaction of crystal planes (0 0 I) of TiO2 anatase and (0 0 1) of ZnO crucially plays as an important role for the reduction of energy band-gap. Additionally, TiO2ZnOAg NPs were used recognize Saccharomyces cerevisiae cells by con-focal fluorescence microscope, showing that it develops bright bio-images for the cells; while for TiO2 or ZnO or TiO2ZnO NPs, no fluorescent response was seen within the cells. PMID- 30245227 TI - Possible case of pressure resorption associated with osteoarthritis in human skeletal remains from ancient China. AB - Osteoarthritis, one of the most common pathological conditions observed in human skeletal remains, is traditionally thought to only affect the structures within the joint capsule. We examined the osteoarthritic distal femora of an individual from Ancient North China, ca. 475-221 BCE. The standard signs of osteoarthritis, marginal lipping and extensive eburnation, were observed in the patellofemoral compartment of the knee joint. In addition however were bilateral pressure-caused fossae on the extra-articular anterior surfaces of the distal femora 10 mm proximal to the large osteophytes at the apex of the patellar surfaces. Anatomy and possible pathogenesis of knee arthritis are explored in order to come to a tentative aetiology of the extra-articular lesions. These lesions are suggested to be a new criterion for identifying severe knee arthritis. The osteological phenomenon is then placed into archaeological context of the Warring States period of ancient China. PMID- 30245228 TI - A circular depression at the spinoglenoid notch of a prehistoric Andean scapula: Plausible evidence of suprascapular nerve entrapment by a paralabral cyst. AB - While intraosseous cysts have been described in the paleopathological literature, it is rare to find reports concerning effects of soft tissue cysts, although they are relatively common in clinical contexts. Here we present plausible evidence of an extraosseous paralabral cyst, seen in an adult scapula from a Late Intermediate period commingled tomb (ca. AD 1200) at the northern highland site of Marcajirca, Ancash, Peru. The scapula demonstrated a smooth-sided concave depression at the spinoglenoid notch. The depression was notable for its regular appearance, with no bone deposition or destruction. Rather than reflect an intraosseous pathology, the defect likely resulted from pressure erosion from a space-occupying mass. A narrow strip of flattened bone connected the depression to the posterior-superior aspect of the glenoid. The location and morphology of the depression and its connection with the glenoid are consistent with the effects of a paralabral cyst that arose secondary to a tear of the posterior superior glenoid labrum. A labral tear may act as a one-way valve permitting fluid to flow along a path of least resistance, often to the spinoglenoid notch. A cyst at the spinoglenoid notch would compress the suprascapular nerve, causing weakened function of infraspinatus and its eventual atrophy. PMID- 30245229 TI - A possible case of mycosis in a post-classical burial from La Selvicciola (Italy). AB - An examination of an adult male buried from the post-classical necropolis of La Selvicciola (Viterbo, Latium, Italy; 4th-6th centuries AD) revealed a series of skeletal lesions. The lesions, both proliferative and lytic, ranging in size from small (around 0.01 mm) to extensive (up to 16.00 mm) pits, occurred at multiple sites. A holistic approach assessed lesion type, frequency and location in a differential diagnosis, which included myeloma, metastatic carcinoma, tuberculosis, leukemia, osteomyelitis, and mycoses. It was concluded that a mycosis, specifically Cryptococcosis, was the most likely cause of these lesions. Both macroscopic analyses and X-ray scans support our diagnosis. We also provide a methodological scheme as a model for examining unknown lesion patterns. PMID- 30245230 TI - Time after time: individuals with multiple fractures and injury recidivists in long eighteenth-century (c. 1666-1837) London. AB - Investigating injury recidivism and individuals with multiple injuries is an area of growing interest in bioarchaeology. Differentiating between whether an individual sustained multiple injuries, represented by antemortem healed fractures, in one incident or in multiple incidents over the life course, is a major challenge. This research analyzed the skeletal remains of 721 adults (402 males, 319 females) from five post-medieval cemeteries from London, UK, known to include working class individuals for evidence of skeletal trauma - fractures, myositis ossificans, subluxations/dislocations, blunt force trauma, and sharp force trauma. A total of 164 individuals had more than two fractures; males were significantly more likely to have multiple (2+) fractures than females. An investigation of fracture recidivism incorporating a relative timeline of fracture events was possible because 14 individuals (12 males, two females) were identified as injury recidivists, meaning they had a combination of antemortem healed, antemortem healing, and/or perimortem fractures. This paper examines the distribution and relative timing of these fractures, incorporating contemporary clinical as well as social and historical context, noting that the majority of the fractures were likely to be caused by accidental mechanisms. PMID- 30245232 TI - The azatryptophan-based fluorescent platform for in vitro rapid screening of inhibitors disrupting IKKbeta-NEMO interaction. AB - The nuclear factor-kappaB (NF-kappaB) plays an important role in inflammatory and immune responses. Aberrant NF-kappaB signaling is implicated in multiple disorders, including cancer. Targeting the regulatory scaffold subunit IkappaB kinase gamma (IKKgamma/NEMO) as therapeutic interventions could be promising due to its specific involvement in canonical NF-kappaB activation without interfering with non-canonical signaling. In this study, the use of unnatural amino acid substituted IKKbeta with unique photophysical activity to sense water environment changes upon interaction with NEMO provides a powerful in vitro screening platform that would greatly facilitate the identification of compounds having the potential to disrupt IKKbeta-NEMO interaction, and thus specifically modulate the canonical NF-kappaB pathway. We then utilized a competitive binding platform to screen the binding ability of a number of potential molecules being synthesized. Our results suggest that a lead compound (-)-PDC-099 is a potent agent with ascertained potency to disrupt IKKbeta-NEMO complex for modulating NF-kappaB canonical pathway. PMID- 30245231 TI - Drug resistance in multiple myeloma. AB - Multiple myeloma (MM, plasma cell myeloma) is a malignant hematologic disease characterized by the clonal proliferation of malignant plasma cells. The treatment of MM has changed dramatically in recent years, with the introduction of new drugs into therapeutic strategies, both in the front line setting and in relapsed refractory disease. However, most patients eventually relapse and often demonstrate multiple drug resistance. Therefore there is still an urgent and unmet need to define the molecular mechanisms of resistance for available drugs in order to enhance the use of existing treatments and design more effective therapies. Genetic abnormalities are well known to play a central role in MM resistance to available drugs, and epigenetic aberrations mainly affecting the patterns of DNA methylation and histone modifications of genes, especially tumor suppressors, can be involved in the resistance mechanism. Moreover, defects in the mechanisms of apoptosis, senescence and DNA repair could also contribute to drug resistance. In addition, mutations or alterations in the expression of the drug target can influence response to therapy. Achieving a better understanding of the pathways and protein expression involved in MM drug resistance and the development of novel therapeutic strategies are important goals for further progress in the treatment of MM. This review gives a critical overview of the role of cellular, microenvironmental and molecular mechanisms of drug resistance in MM. PMID- 30245234 TI - Identification and characterization of a highly S-enantioselective halohydrin dehalogenase from Tsukamurella sp. 1534 for kinetic resolution of halohydrins. AB - Halohydrin dehalogenases are remarkable enzymes which possess promiscuous catalytic activity and serve as potential biocatalysts for the synthesis of chiral halohydrins, epoxides and beta-substituted alcohols. The enzyme HheC exhibits a highly R enantioselectivity in the processes of dehalogenation of vicinal halohydrins and ring-opening of epoxides, which attracts more attentions in organic synthesis. Recently dozens of novel potential halohydrin dehalogenases have been identified by gene mining, however, most of the characterized enzymes showed low stereoselectivity. In this study, a novel halohydrin dehalogenase of HheA10 from Tsukamurella sp. 1534 has been heterologously expressed, purified and characterized. Substrate spectrum and kinetic resolution studies indicated the HheA10 was a highly S enantioselective enzyme toward several halohydrins, which produced the corresponding epoxides with the ee (enantiomeric excess) and E values up to >99% and >200 respectively. Our results revealed the HheA10 was a promising biocatalyst for the synthesis of enantiopure aromatic halohydrins and epoxides via enzymatic kinetic resolution of racemic halohydrins. What's more important, the HheA10 as the first individual halohydrin dehalogenase with the highly S enantioselectivity provides a complementary enantioselectivity to the HheC. PMID- 30245233 TI - Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation. AB - A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068 MUM and 0.0089 MUM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 uM for hAChE; 0.101 uM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold. PMID- 30245235 TI - Chemically induced degradation of CK2 by proteolysis targeting chimeras based on a ubiquitin-proteasome pathway. AB - As a ubiquitous, highly pleiotropic and constitutively active serine/threonine protein kinase, casein kinase 2 (CK2) is closely associated with tumorigenesis by its overexpression in cancer cells. Here we report several proteolysis targeting chimeras (PROTACs) via "click reaction" to connect a CK2 inhibitor (CX-4945) and pomalidomide for degradation of CK2 protein. Among them, compound 2 degraded CK2 in a dose and time-dependent manner, and kept CK2 at a low basal level by recruiting ubiquitin-proteasome system. The degradation of CK2 resulted in the reduced phosphorylation of Akt and the up-regulation of p53. As a CK2 protein degrader, 2 showed the analogous cytotoxicity to CX-4945 but with a quite different mechanism of action from the CK2 inhibitor, hinting that degradation of CK2 proteins by PROTACs is a potential way for cancer treatments. PMID- 30245237 TI - Impaired motor inhibition in developmental coordination disorder. AB - This study aimed to evaluate the 'inhibitory deficit' hypothesis of developmental coordination disorder (DCD). We adopted a multifaceted approach, investigating two distinct, yet complimentary facets of motor inhibition: action restraint and action cancellation. This was achieved using carefully constructed versions of the 'Go/No-go' and 'Stop-signal' tasks, respectively. The sample comprised 11 young adults with DCD aged between 18 and 30 years of age and 11 typically developing, age-matched controls. Participants completed both the 'Go/No-go' and 'Stop-signal' tasks to assess action restraint and action cancellation respectively. Individuals with DCD were less efficient than their typically developing peers at performing both action restraint and action cancellation, indicated by significantly reduced action restraint efficiency index scores on the 'Go/No-go' task and a trend towards longer stop-signal reaction times on the 'Stop-signal' task. This work clarifies disparate evidence speaking to the integrity of action restraint in DCD and provides the first account of action cancellation in DCD using a purpose-built measure. In support of the inhibitory deficit hypothesis of DCD, our results suggest that young adults with DCD experience broad difficulties with engaging inhibitory mechanisms during motor behaviour. PMID- 30245236 TI - alpha-Glucosidase inhibitory effects of polyphenols from Geranium asphodeloides: Inhibition kinetics and mechanistic insights through in vitro and in silico studies. AB - Some Geranium species have been used to treat diabetes. To evaluate the scientific basis of this ethnopharmacological use, we aimed to isolate potent alpha-glucosidase inhibitory metabolites of Geranium asphodeloides Burm. through in vitro bioactivity-guided fractionation. All the tested extracts showed high alpha-glucosidase inhibitory effect compared to acarbose. Among the tested extracts, the ethyl acetate subextract showed the highest activity with an IC50 value of 0.85 +/- 0.01 uM. A hydrolysable tannin, 1,2,4-tri-O-galloyl-beta-d glucopyranose (1), and five flavonoid glycosides, kaempferol-3-O-alpha rhamnopyranoside (2), kaempferol-3-O-alpha-arabinofuranoside (3), quercetin-3-O beta-glucopyranoside (4), quercetin-3-O-alpha-rhamnopyranoside (5), and quercetin 3-O-alpha-rhamnofuranoside (6), were isolated from the ethyl acetate subextract. Their structures were identified by 1D- and 2D-NMR experiments. 1 exhibited the highest alpha-glucosidase inhibitory effect, approximately 61 times more potent than positive control, acarbose, with an IC50 value of 0.95 +/- 0.07 uM. Also, 2 was more potent than acarbose. An enzyme kinetics analysis revealed that compounds 2, 3 and 4 were competitive, whereas 1 and 6 uncompetitive inhibitors. Molecular docking studies were performed to get insights into inhibition mechanisms of the isolated compounds in the light of the enzyme kinetic studies using various binding sites of the enzyme model. PMID- 30245238 TI - Comparison of chronological changes in blood characteristics in the atrium and peripheral vessels after the development of non-valvular atrial fibrillation. AB - INTRODUCTION: Changes in blood characteristics in the atrium and peripheral vessels in patients with non-valvular atrial fibrillation (NVAF) are unclear. We investigated chronological changes in blood characteristics in the atrium and peripheral vessels in a dog model of NVAF by using a total thrombus-formation analysis system (T-TAS). MATERIALS AND METHODS: In NVAF model dogs (n = 8, 390 bpm rapid atrial pacing), atrial and peripheral blood samples were collected. Using this blood, T-TAS was performed before and 1, 2, and 3 weeks after the onset of rapid atrial pacing. RESULTS: Occlusion time (OT: time to +80 and +60 kPa in the AR and PL chips, respectively) and area under the flow pressure curve (AUC) were measured using the AR chip (for mixed white thrombus analysis) and PL chip (for platelet thrombus analysis). OT of the AR chip showed shortening as early as 1 week after NVAF onset, which continued for 3 weeks. OT of the PL chip showed significant shortening in atrium blood only 3 weeks after NVAF onset. By contrast, peripheral blood showed no significant changes in OT or AUC with both AR and PL chips. CONCLUSIONS: In our dog model of NVAF, thrombus formation accelerated in the atrium as early as 1 week after NVAF onset and continued for 3 weeks, but no significant changes were found in peripheral blood. We conclude that antithrombotic therapy should be started early after NVAF onset even if no changes in coagulation activity are observed in peripheral blood. PMID- 30245239 TI - Coordination and variability during anticipated and unanticipated sidestepping. AB - BACKGROUND: Numerous investigations have attempted to link the incidence and risk of non-contact anterior cruciate ligament injuries to specific intrinsic and extrinsic mechanisms. However, these are often measured in isolation. RESEARCH QUESTION: This study utilizes a dynamical systems approach to investigate differences in coordination and coordination variability between segments and joints in anticipated and unanticipated sidestepping, a task linked to a high risk of non-contact anterior cruciate ligament injuries. METHODS: Full body, three-dimensional kinematics and knee kinetic data were collected on 22 male collegiate soccer players during anticipated and unanticipated sidestepping tasks. A modified vector coding technique was used to quantify coordination and coordination variability of the trunk and pelvis segments and the hip and knee joints. RESULTS: Sagittal and frontal plane trunk-pelvis coordination were more in-phase during unanticipated sidestepping. Sagittal plane hip-knee and hip (rotation)-knee (flexion/extension) coordination were more in-phase with the knee dominating the movement during unanticipated sidestepping (P < 0.05). Coordination variability was greater in unanticipated sidestepping for trunk (flexion)-pelvis (tilt), trunk (lateral flexion)-pelvis (obliquity), hip (flexion/extension)-knee (flexion/extension) and hip (rotation)-knee (flexion/extension) (P < 0.05). In unanticipated sidestepping where there is limited time to pre-plan the movement, multiple kinematic solutions and high coordinative variability is required to achieve the task. SIGNIFICANCE: Our results suggest that coordination becomes more in-phase and the variability of this coordination increases as a function of task complexity and reduced planning time as that which occurs in unanticipated sporting task scenarios. Consequently, injury prevention programs must incorporate perceptual components in order to optimise planning time and coordinate appropriate postural adjustments to reduce external knee joint loading and subsequent injury risk in sport. PMID- 30245240 TI - Children with Autism Spectrum Disorder, Developmental Coordination Disorder, and typical development differ in characteristics of dynamic postural control: A preliminary study. AB - BACKGROUND: Autism Spectrum Disorder (ASD) and Developmental Coordination Disorder (DCD) are developmental disorders with distinct definitions and symptoms. However, both conditions share difficulties with motor skills, including impairments in postural control. While studies have explored postural sway variables in children with DCD and ASD as compared to typical development (TD), few have used kinematic data to assess the magnitude of differences between these two neurodevelopmental conditions. There are few sensitive and specific measures available to assess balance impairment severity in these populations. RESEARCH QUESTION: Do individuals with ASD, DCD, and TD differ in dynamic postural control? METHODS: We quantified postural control differences between ASD, DCD, and TD during a dynamic balance task. 10 ASD, 10 DCD, and 8 TD agematched children completed a dynamic postural control task in a virtual environment. They leaned to shift their center of pressure (CoP) to match a user controlled object to an oscillating target (0.1 Hz-0.8 Hz). RESULTS: The DCD group had higher CoP accelerations compared to ASD or TD. While the DCD and TD groups did not differ in their medial-lateral velocity, the ASD group had low medial-lateral velocity and acceleration as compared to DCD and TD. ASD group velocity and acceleration did not differ from that of the TD group in the anterior-posterior direction. Higher accelerations in the DCD group reflected non fluid movements; by contrast, the ASD group had slower, more fluid movements. Results may reflect differences in how children with ASD and DCD plan, execute, and modify motor actions. SIGNIFICANCE: This study demonstrates the potential utility of CoP acceleration and velocity as a sensitive and specific means of differentiating between ASD, DCD, and TD. Results indicating group differences between ASD and DCD in velocity and acceleration profiles represent an important step toward understanding how these populations modify motor plans during dynamic tasks. PMID- 30245241 TI - Emerging areas for therapeutic discovery in SLE. AB - Recent advances in the field of autoimmunity have identified numerous dysfunctional pathways in Systemic Lupus Erythematosus (SLE), including aberrant clearance of nucleic-acid-containing debris and immune complexes, excessive innate immune activation leading to overactive type I IFN signalling, and abnormal B and T cell activation. On the background of genetic polymorphisms that reset thresholds for immune responses, multiple immune cells contribute to inflammatory amplification circuits. Neutrophils activated by immune complexes are a rich source of immunogenic nucleic acids. Identification of new B subsets suggests several mechanisms for induction of autoantibody producing effector cells. Disordered T cell regulation involves both CD4 and CD8 cells. An imbalance in immunometabolism in immune cells amplifies autoimmunity and inflammation. These new advances in understanding of disease pathogenesis provide fertile ground for therapeutic development. PMID- 30245243 TI - Effects of aging on executive functioning and mesocorticolimbic dopamine markers in male Fischer 344 * brown Norway rats. AB - Aging is associated with changes in executive functioning and the mesocorticolimbic dopamine system. However, the effects of aging on different forms of behavioral flexibility are not fully characterized. In young (~5 months) and aged (~22 months) male Fischer 344 * brown Norway rats, we assessed spatial working memory and different forms of behavioral flexibility using operant tasks: strategy set-shifting (study 1) or probabilistic reversal learning (study 2). We also assessed dopaminergic markers using immunohistochemistry. Compared with young rats, aged rats displayed impairments in working memory. Aged rats also showed nonperseverative impairments in set-shifting, with a subset also showing impairments in initial discrimination learning. In probabilistic reversal learning, aged rats completed more reversals, driven by an increased sensitivity to recent reward and negative feedback. Tyrosine hydroxylase (TH) showed region specific changes with aging and was correlated with several measures of behavioral flexibility. These data suggest that age-related changes prefrontal cortical function and dopamine synthesis contribute to changes in executive functioning during aging. PMID- 30245242 TI - Hydroxyurea attenuates oxidative, metabolic, and excitotoxic stress in rat hippocampal neurons and improves spatial memory in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by accumulation of amyloid beta-peptide (Abeta) plaques in the brain and decreased cognitive function leading to dementia. We tested if hydroxyurea (HU), a ribonucleotide reductase inhibitor known to activate adaptive cellular stress responses and ameliorate abnormalities associated with several genetic disorders, could protect rat hippocampal neurons against oxidative-, excitatory-, mitochondrial-, and Abeta-induced stress and if HU treatment could improve learning and memory in the APP/PS1 mouse model of AD. HU treatment attenuated the loss of cell viability induced by treatment of hippocampal neurons with hydrogen peroxide, glutamate, rotenone, and Abeta1-42. HU treatment attenuated reductions of mitochondrial reserve capacity, maximal respiration, and cellular adenosine triphosphate content induced by hydrogen peroxide treatment. In vivo, treatment of APP/PS1 mice with HU (45 mg/kg/d) improved spatial memory performance in the hippocampus-dependent Morris water maze task without reducing Abeta levels. HU provides neuroprotection against toxic insults including Abeta, improves mitochondrial bioenergetics, and improves spatial memory in an AD mouse model. HU may offer a new therapeutic approach to delay cognitive decline in AD. PMID- 30245244 TI - The influence of social networks and the built environment on physical inactivity: A longitudinal study of urban-dwelling adults. AB - Policies targeting the built environment to increase physical activity may be ineffective without considering personal social networks. Physical activity and social network data came from the Montreal Neighborhood Networks and Healthy Aging Panel; built environment measures were from geolocation data on Montreal parks and businesses. Using multilevel logistic regression with repeated physical inactivity measures, we showed that adults with more favorable social network characteristics had lower odds of physical inactivity. Having more physical activity facilities nearby also lowered physical inactivity, but not in socially isolated adults. Community programs that address social isolation may also benefit efforts to increase physical activity. PMID- 30245245 TI - State dream acts and education, health and mental health of Mexican young adults in the U.S. AB - We investigate the education, health and mental health effects of state policies that allowed or explicitly banned tuition subsidy and financial aid to undocumented college students using the National Health Interview Survey (NHIS) for 1998-2013. Our analysis suggests that an explicit ban on tuition subsidy or enrollment in public colleges lowered college education of non-citizen Mexican young adults by 5.4-11.6 percentage points. We find some evidence that in-state tuition and access to financial aid improved self-reported health and reduced mental health distress, and ban on in-state-tuition/enrollment increased mental health distress among non-citizen Mexican young adults: estimated effects are generally significant in first-difference models and models that include state specific cubic trends, and often insignificant in difference-in-difference models. PMID- 30245246 TI - Tuning of a dead-time compensator focusing on industrial processes. AB - This paper proposes tuning rules for the Simplified Dead-Time Compensator (SDTC), which is intended to deal with stable, unstable and integrative dead-time processes. The main contribution is the proposal of new guidelines for the tuning of the robustness filter. The new set of rules allow for the use of lower order filters which are able to simultaneously account for closed-loop robustness and noise attenuation. Through illustrative examples, it is shown that the proposed approach provides enhanced disturbance rejection and noise attenuation in the control of industrial processes when compared with other recently published works. Furthermore, the internal temperature of an in-house thermal chamber is controlled to evaluate the applicability of the strategy on real processes. PMID- 30245247 TI - Tracking control of an underactuated ship by modified dynamic inversion. AB - The tracking control problem of an underactuated ship is investigated. We intend to use the underactuated ship as an example to extend the traditional dynamic inversion control method to underactuated systems. The difficulty lies in the fact that the system has no relative degree, which prevents the application of standard dynamic inversion. Three modified dynamic inversion methods are proposed that are applicable to this system. The first is the well-known dynamic extension based dynamic inversion (DEDI), which treats an input as a state and takes dynamic extension to achieve a relative degree. The second is virtual input-based dynamic inversion (VIDI), which treats a state as a virtual input to achieve a relative degree. The third is output redefinition-based dynamic inversion (ORDI), which selects a particular variable as a new output to achieve a relative degree. The three methods are generalizations of dynamic inversion control and remove some of its inherent limitations, making it applicable to a wide variety of underactuated systems. The effectiveness of the proposed methods is verified by numerical simulations. PMID- 30245248 TI - Severe allergic reaction during angioplasty culminating to fatal acute stent thrombosis: An association with Kounis syndrome. AB - BACKGROUND: Kounis syndrome is a systemic complication following an allergic reaction, presenting with coronary artery spasm or thrombosis and occasionally with stent thrombosis that can have fatal outcome. OBJECTIVES: Heparins can induce allergic reactions via tissue antigenicity, heparin induced thrombocytopenia and contact system-activating effects of contaminants but allergy bivalirudin has not been reported so far. METHODS: Herein, we describe a patient with fatal acute coronary in-stent thrombosis following an allergic reaction soon after an intra-arterial heparin dose and intravenous administration of bivalirudin during angioplasty. RESULTS: The patient received intense myocardial infarction protocol treatment including angioplasty and defibillation together with antiallergic therapy but despite all of these efforts and measures, he succumbed 2 h later. CONCLUSIONS: Significant suspicion should be raised that life saving drugs such as heparin and bivalirudin could join forces with concurrent medication acting as antigens and induce fulminant and fatal stent thrombosis as a manifestation of Kounis syndrome. PMID- 30245249 TI - Pretreatment brain connectivity during positive emotion upregulation predicts decreased anhedonia following behavioral activation therapy for depression. AB - BACKGROUND: Neurobiological predictors of antidepressant response may help guide treatment selection and improve response rates to available treatments for major depressive disorder (MDD). Behavioral activation therapy for depression (BATD) is an evidence-based intervention designed to ameliorate core symptoms of MDD by promoting sustained engagement with value-guided, positively-reinforcing activities. The present study examined pre-treatment task-based functional brain connectivity as a predictor of antidepressant response to BATD. METHODS: Thirty three outpatients with MDD and 20 nondepressed controls completed a positive emotion regulation task during fMRI after which participants with MDD received up to 15 sessions of BATD. We used generalized psychophysiological interaction analyses to examine group differences in pre-treatment functional brain connectivity during intentional upregulation of positive emotion to positive images. Hierarchical linear models were used to examine whether group differences in functional connectivity predicted changes in depression and anhedonia over the course of BATD. RESULTS: Compared to controls, participants with MDD exhibited decreased connectivity between the left middle frontal gyrus and right temporoparietal regions during upregulation of positive emotion. Within the MDD group, decreased connectivity of these regions predicted greater declines in anhedonia symptoms over treatment. LIMITATIONS: Future studies should include comparison treatments and longitudinal follow-up to clarify the unique effects of BATD on neural function and antidepressant response. CONCLUSIONS: Results are consistent with previous work showing BATD may be particularly effective for individuals with greater disturbances in brain reward network function, but extend these findings to highlight the importance of frontotemporoparietal connectivity in targeting symptoms of low motivation and engagement. PMID- 30245250 TI - Biased neurocognitive self-perception in depression - What is the reason for the discrepancy? Reply to Dehn & Beblo (2018). PMID- 30245251 TI - Identifying and differentiating melancholic depression in a non-clinical sample. AB - BACKGROUND: Differentiating melancholic and non-melancholic depressive disorders and evaluating whether they differ categorically or dimensionally has had a lengthy history, but has not previously been evaluated in a non-clinical adolescent sample. METHODS: We studied a sample of 1579 senior high school students and evaluated the capacity of the Sydney Melancholia Prototype Index (SMPI) to differentiate melancholic from non-melancholic depression, both using a 'top down' strategy of imposing a pre-established cut-off score and a 'bottom up' strategy of employing latent class analyses. RESULTS: The two strategies respectively generated prevalence figures of 3.4% and 8.1% of the students having experienced a melancholic depressive episode and with the difference reflecting the LCA assigning some students who did not reach the pre-established cut-off score for the SMPI in the putative melancholic class. The principal latent class analysis failed to generate pristine melancholic and non-melancholic depressive classes, in that it also generated an 'intermediate' as well as a non-clinical depressive class. Both SMPI strategies identified similar symptoms-such as anhedonia and anergia-and several illness correlates that best differentiated those assigned melancholia status, and both strategies confirmed melancholia assignment being associated with factors indicative of more severe depressive disorders and of likely melancholic depression. LIMITATIONS: Data were assessed by self-report only, only lifetime depression was assessed, and no other depressive diagnostic validating measure was administered. CONCLUSIONS: The SMPI appears capable of identifying and differentiating melancholic from non melancholic depression in a non-clinical adolescent sample. PMID- 30245252 TI - Prenatal and postnatal maternal depression and infant hospitalization and mortality in the first year of life: A systematic review and meta-analysis. AB - BACKGROUND: Prenatal and postnatal depression have been well studied in recent decades, but few studies address their relationship with hospitalization and mortality in one-year-old children. OBJECTIVE: Review the literature about the effects of maternal depression on hospitalization and mortality of the child from birth to one year of age and conduct a meta-analysis. METHODS: A systematic search was performed in the PubMed and LILACS databases. We included original studies that evaluated the effect of prenatal and/or postnatal depressive symptoms on child hospitalization or mortality up to one year of age. Meta analyses were conducted according to the outcome and stratified by prenatal and postnatal depression, using random effects models. RESULTS: Six studies were included in this review (170,371). Children of mothers with prenatal and postnatal depressive symptoms or depression had 1.44 (CI95% 1.10 - 1.89) greater risk of hospitalization, and children of mothers with postnatal depressive symptoms or depression had 1.93 (CI95% 1.02-3.64) greater risk of death before one year of age than those whose mothers did not have the disorder. LIMITATIONS: Small number of studies (n < 10), different instrument and cut points were used to evaluate maternal depressive symptoms or diagnose depression. CONCLUSION: Maternal depressive symptoms or depression have an unfavorable effect on hospitalization and mortality in children up to one year of age. This finding is relevant to public health and should stimulate the systematic screening of prenatal and postnatal depressive symptoms, so that adequate care can be provided for women and their children. PMID- 30245253 TI - Temperament and self-esteem in high-risk offspring of bipolar parents: Vulnerability and scar effects. AB - BACKGROUND: The nature of the temporal relationship between psychological factors and mood episodes is unclear. The objectives of this study were to determine if temperament and self-esteem predict the onset of mood episodes, and if prior mood episodes influence the stability of these factors over time in high-risk offspring of bipolar parents. METHODS: Offspring of a parent with bipolar disorder participating in the Flourish Prospective Offspring Study were clinically assessed repeatedly using semi-structured KSADS-PL/SADS-L format interviews, and completed repeated measures of self-esteem, and temperament. Shared frailty survival models and mixed effects regression models were used to determine if psychological factors predicted incident mood episodes, and whether these factors change over time after the incident mood episode, respectively. RESULTS: Emotionality, shyness and self-esteem were not associated with the hazard of incident major depression; however, increased activity reduced the hazard of this outcome (hazard ratio [HR]: 0.51; 95% CI: 0.27, 0.98). Emotionality and shyness scores increased, while sociability, activity and self esteem scores decreased after the incident major depressive episode (emotionality: mean change [MC]: 0.35, p = 0.0289; shyness: MC: 0.40, p = 0.0196; sociability: MC: -0.49, p = 0.0001, activity: MC: -0.32, p = 0.0001; self-esteem: MC: -0.79, p = 0.001). LIMITATIONS: Psychological measures were based on self report and some models had low numbers limiting the numbers of covariates included as potential confounders. DISCUSSION: Among the assessed temperamental dimensions, activity showed a protective effect for major depressive episode onset suggesting this temperamental characteristic could serve as a protective target in high risk youth. Conversely, all assessed psychological factors shifted towards increased vulnerability after the first depressive episode. PMID- 30245254 TI - Facile defluoridation of drinking water by forming shell@fluorapatite nanoarray during boiling egg shell. AB - High fluoride water is one of the major problems against drinking water and are affecting millions of people all over the world. Refined adsorbents and water treatment plants aim at massive water supply but can't meet scattered household requirements, especially in the developing areas. Here, we developed a facile defluoridation method in which F- can be removed by boiling eggs or shell assisted by phosphate. 0.4 L of high fluoride water (10 mg/L) can be transformed to safe drinking water with F- concentration lower than 1.5 mg/L by boiling one egg at 80 degrees C for 10 min with the addition of 0.3 g/L of NaH2PO4 and 0.05 v% acetic acid. The mechanism study shows that F- is adsorbed onto the egg shell outer surface forming nanorod arrays of fluorapatite and/or F- substituted hydroxyapatite. Higher F- adsorption capacity can be obtained (Langmuir adsorption capacity, 47.9 mg/g) if using egg shell powder instead of whole eggs. Pilot scale defluoridation (2.5 L, 10 times) was successfully realized by boiling egg shell in the presence of phosphate and acetic acid. The boiling shell defluoridation technology has potential household applications by common people with little professional backgrounds. PMID- 30245255 TI - Host-guest supramolecular assembly directing beta-cyclodextrin based nanocrystals towards their robust performances. AB - Fluorescent CdTe nanocrystals (NCs) capped with beta-cyclodextrin (beta-CD) are successfully synthesized by host-guest supramolecular assembly of the hydrophobic alkyl chains of N-acetyl-l-cysteine (NAC) on the surface of CdTe NCs and eco friendly beta-CD via the promising simple hydrothermal method in our experiments. The as-prepared NCs display better stability and lower toxicity compared with traditional those only capped with NAC. Specially, cytotoxicity experiments to human umbilical vein endothelial cells in vitro and zebrafish embryo toxicological tests in vivo are performed to determine the toxicity of CdTe NCs. For their practical applications, the promising red-luminescent NCs are employed as stable and low poison red phosphors to fabricate white light-emitting diodes (WLEDs) with remarkable color-rendering index (CRI) being 91.6. This research offers significance for solving the difficulty in toxicity and instability of heavy metal based NCs, which has potential applications in future optoelectronic devices and biomarkers. PMID- 30245256 TI - Characteristics of nursing students with high levels of academic resilience: A cross-sectional study. AB - BACKGROUND: Academic resilience is an important characteristic that helps nursing students, who must engage in intensive learning and clinical practice, to overcome academic stress and adapt to their school and the clinical field. OBJECTIVES: To determine the characteristics of nursing students with high academic resilience. DESIGN: This study used a cross-sectional design. SETTING: Three universities in South Korea. SUBJECTS: We recruited a convenience sample of 254 nursing students. METHODS: Academic resilience, general characteristics, clinical practice stress, clinical practice satisfaction, and social-affective capability were assessed via self-reported questionnaires. The collected data were analyzed using descriptive statistics, chi-squared test, and analysis of variance with Tukey's post hoc test. RESULTS: The mean academic resilience score was 3.79. A greater proportion of respondents with high levels of academic resilience had good interpersonal relationships (chi2 = 35.175, p < .001), high academic grades (chi2 = 30.968, p < .001), a role model (chi2 = 9.770, p = .033), and high satisfaction with their major (chi2 = 20.214, p = .001). Significant differences in the subscale scores for clinical practice stress, including burden of clinical tasks (F = 4.727, p = .010), conflict of interpersonal relations (F = 4.889, p = .008), and conflict with patients (F = 7.023, p = .001), were found among the academic resilience groups. We also observed differences in the subscale scores of clinical practice satisfaction, including practice content (F = 4.894, p = .008) and practice environment (F = 8.301, p < .001). Respondents in the high resilience group had higher social-affective capability scores than did those with lower resilience (F = 43.994, p < .001). CONCLUSION: Based on our results, students with high academic resilience are more likely to continue their studies and benefit from programs that strengthen their social-affective capability. We therefore propose that nursing school curriculum focus on enhancing social-affective capability. PMID- 30245257 TI - Registered nurses' provision of end-of-life care to hospitalised adults: A mixed studies review. AB - OBJECTIVES: To describe, critically appraise and synthesise research regarding nurses' perceptions of their knowledge, skills or experiences in providing end-of life care to hospitalised adults to help inform both future educational and practice initiatives. DESIGN: Mixed studies review. DATA SOURCES: MEDLINE, CINAHL, Cochrane Library, Web of Science and SCOPUS databases were searched for the years 2004-June 2018, along with journal hand-searching and reference list searching. REVIEW METHODS: Two independent reviewers screened the titles and abstracts of studies. Data extraction and quality assessment using the Mixed Methods Appraisal Tool was conducted independently by two reviewers. Disagreements were adjudicated by a third reviewer. Study findings were synthesised thematically. RESULTS: Nineteen studies met the inclusion criteria. Of them, ten were quantitative, eight qualitative and one mixed-method. All but one quantitative study were conducted in the United States and all but one used some form of survey. The qualitative studies were conducted in a variety of countries and all but one used some form of interview for data collection. Five themes were identified including nurse as a protecting provider, nurse as an advocate, nurse as a reflective practitioner, obstacles to providing quality end of-life care and aids to providing quality end-of-life care. CONCLUSIONS: Registered Nurses have aligned their end-of-life care with practice with the profession's expectations and are enacting a patient centred approach to their practice. They rely on reflective practices and on the support of others to overcome organisational, educational and emotional the challenges they to providing quality end-of-life care. PMID- 30245258 TI - Epidemiology of acute kidney injury and the role of urinary [TIMP-2].[IGFBP7]: a prospective cohort study in critically ill obstetric patients. AB - BACKGROUND: There are few data regarding acute kidney injury in critically-ill obstetric patients. A combination of urinary cell cycle arrest markers, tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein7 (IGFBP7), is validated for the early prediction of acute kidney injury in non-obstetric patients. METHODS: We evaluated the epidemiology of acute kidney injury in critically-ill obstetric patients and the role of the biomarker combination in predicting acute kidney injury and mortality. Acute kidney injury, its severity and risk factors, were assessed using Kidney Disease: Improving Global Outcomes (KDIGO) guidelines during the intensive care unit stay. An ELISA technique measured TIMP-2 and IGFBP7 in urine samples collected at the time of admission there. RESULTS: Results for 66 patients showed an overall incidence of acute kidney injury of 40/66 (61%), with 50%, 10% and 40% being in stage 1, 2 and 3 respectively. Patients with acute kidney injury showed significantly greater sepsis and shock; longer stay and higher mortality during intensive care (33% vs 0%) and in hospital (38% vs 0%) compared to those without (P <0.05). The area under-the receiver operating characteristics curve was <0.5 for urinary [TIMP 2].[IGFBP7] as a predictor of kidney injury and mortality (P >0.05). CONCLUSIONS: Acute kidney injury is common in critically-ill obstetric patients, increasing mortality and duration of hospitalization. It was significantly more common in patients with septic shock. Previously validated results of urinary [TIMP 2].[IGFBP7] that successfully predict early acute kidney injury or mortality are not applicable to obstetric patients. PMID- 30245259 TI - Insertion of an intrathecal catheter following a recognised accidental dural puncture reduces the need for an epidural blood patch in parturients: an Australian retrospective study. AB - BACKGROUND: There is no clear consensus about how best to prevent post-dural puncture headache (PDPH) following an accidental dural puncture in parturients. Our primary objective was to investigate whether the insertion of an intrathecal catheter following accidental dural puncture reduces the incidence of PDPH and therapeutic epidural blood patch. METHODS: Anaesthetic records from January 2009 to December 2015 were reviewed retrospectively and parturients who had an accidental dural puncture and/or PDPH were identified. Data from those with a recognised dural puncture in whom an intrathecal catheter was inserted at the time of accidental dural puncture (ITC group) were compared to those without an intrathecal catheter (non-ITC group), as were outcomes of patients with an intrathecal catheter for >=24 hours compared to <24 hours. RESULTS: Of 94 recognised accidental dural punctures, 66 were in the ITC group (37 for >=24 h) and 28 in the non-ITC group. In the ITC group, 22 (33.3%) required an epidural blood patch in comparison to 19 (67.9%) in the non-ITC group (P <0.01, 95% CI 12.5 to 52.0). In the ITC group, 62 (93.9%) developed PDPH in comparison to 28 (100%) in the non-ITC group (P=0.186, 95% CI -6.55 to 14.57). Intrathecal catheter insertion for >=24 h obviated the need for an epidural blood patch in 28 (75.7%) parturients, compared to 13 (59.1%) if <24 h (P=0.184, 95% CI -7.08 to 39.72). CONCLUSION: Inserting an intrathecal catheter after a recognised accidental dural puncture significantly reduced the need for an epidural blood patch. PMID- 30245260 TI - Retrospective study to investigate fresh frozen plasma and packed cell ratios when administered for women with postpartum hemorrhage, before and after introduction of a massive transfusion protocol. AB - BACKGROUND: Administration of packed red blood cells (PRBC) and fresh frozen plasma (FFP) to women with postpartum hemorrhage (PPH) before and after introduction of a massive transfusion protocol. METHODS: The retrospective PPH study cohort of two tertiary centers was identified using blood bank records, verified by patient electronic medical records. We identified women transfused with >=3 units PRBC in a short time period within 24 hours of delivery. Since 2010, both centers have used a protocol using 1:1 FFP:PRBC ratios. Demographic, obstetric, and blood management data were retrieved from medical records. Outcome measures included estimated blood loss, blood product administration, and hematologic variables. RESULTS: 273 women were included, 112 (41.0%) prior to introduction of the protocol (2004-2009) and 161 (59.0%) afterwards (2010-2014). The frequency of women managed with 1:1 FFP:PRBC ratios was similar before 55/112 (49.1%) and after 83/161 (51.6%) introduction of the protocol (P=0.69). There was strong correlation between PRBC units transfused and the FFP:PRBC transfusion ratio (R-square 0.866, P <0.0001), demonstrating that as the number of transfused PRBC units increased, FFP:PRBC ratios became closer to 1:1. There were no outcome differences between women managed before and after introduction of the protocol. CONCLUSIONS: Among women with PPH receiving >=3 PRBC units within a short period of time, it appears that factors other than the existence of our massive transfusion protocol influence the number and ratio of PRBC and FFP units transfused. Blood products were not transfused according to exact ratios, even when guided by a protocol. PMID- 30245261 TI - Interprofessional provider attitudes toward the initiation of epidural analgesia in the laboring patient: are we all on the same page? AB - BACKGROUND: The timing of initiation of neuraxial labor analgesia should ultimately depend on patient preference although obstetricians, anesthesiologists and nurses may influence decision-making. We hypothesized that provider groups would have similar attitudes toward the timing of epidural placement, but some identifiable differences could be used to improve understanding and communication among providers. METHODS: Anesthesiologists, nurses and obstetricians completed a survey assessing their knowledge and attitudes on the timing of epidural placement in specified clinical circumstances. RESULTS: Anesthesiologists (100%) and nurses (86.2%) reported being more familiar with epidural management than obstetricians (43.3%, P <0.01). The willingness of providers to advocate epidural placement based on the magnitude of cervical dilation was similar, although at 10 cm dilatation obstetricians (73.3%) were significantly more likely to advocate neuraxial block compared to both nurses (27.6%, P <0.01) and anesthesiologists (36.7%, P <0.01). The impact of patient factors and clinical circumstances on the timing of neuraxial block placement showed significant differences among provider groups in five of 24 areas assessed, including patient desire for an epidural, primigravid patients without membrane rupture, oxytocin infusion initiated, labor epidural in a previous pregnancy, and a difficult airway. CONCLUSIONS: There were differences between providers in factors that may impact the timing of epidural placement and in their self-perceived familiarity with epidural management. These present an opportunity for furthering interprofessional education and collaboration. PMID- 30245262 TI - Magnetic resonance elastography demonstrates elevated liver stiffness in cystic fibrosis patients. PMID- 30245263 TI - Role of FABP7 in tumor cell signaling. AB - Lipids are major molecules for the function of organisms and are involved in the pathophysiology of various diseases. Fatty acids (FAs) signaling and their metabolism are some of the most important pathways in tumor development, as lipids serve as energetic sources during carcinogenesis. Fatty acid binding proteins (FABPs) facilitate FAs transport to different cell organelles, modulating their metabolism along with mediating other physiological activities. FABP7, brain-typed FABP, is thought to be an important molecule for cell proliferation in healthy as well as diseased organisms. Several studies on human tumors and tumor-derived cell lines put FABP7 in the center of tumorigenesis, and its high expression level has been reported to correlate with poor prognosis in different tumor types. Several types of FABP7-expressing tumors have shown an up regulation of cell signaling activity, but molecular mechanisms of FABP7 involvement in tumorigenesis still remain elusive. In this review, we focus on the expression and function of FABP7 in different tumors, and possible mechanisms of FABP7 in tumor proliferation and migration. PMID- 30245264 TI - Galectins as regulators of cell survival in the leukemia niche. AB - The microenvironment within the bone marrow (BM) contains support cells that promote leukemia cell survival and suppress host anti-tumor defenses. Galectins are a family of beta-galactoside binding proteins that are critical components in the tumor microenvironment. Galectin 1 (LGALS1) and Galectin 3 (LGALS3) as regulators of RAS signaling intracellularly and as inhibitors of immune cells extracellularly are perhaps the best studied members for their role in leukemia biology. Interest in Galectin 9 (LGALS9) is growing as this galectin has been identified as an immune checkpoint molecule. LGALS9 also supports leukemia stem cells (LSCs) though a mechanism of action is not clear. LGALS1 and LGALS3 each participate in a diverse number of survival pathways that promote drug resistance by supporting pro-tumor molecules such BCL2, MCL-1, and MYC and blocking tumor suppressors like p53. Acute myeloid leukemia (AML) BM mesenchymal stromal cells (MSC) have protein signatures that differ from healthy donor MSC. Elevated LGALS3 protein in AML MSC is associated with refractory disease/relapse demonstrating that MSC derived galectin impacts patient survival. LGALS3 is a critical determining factor whether MSC differentiate into adipocytes or osteoblasts so the galectin influences the cellular composition of the leukemia niche. Both LGALS3 and LGALS1 when secreted can suppress immune function. Both galectins can induce apoptosis of T cells. LGALS3 also modulates T cell receptor endocytosis and impairs interferon mediated chemokine production by binding glycosylated interferon. LGALS3 as a TIM3 binding partner acts to suppress T cell function. Galectins also impact leukemia cell mobilization and may participate in homing mechanisms. LGALS3 participates in transport mechanism of integrins, receptors, and other molecules that control cell adhesion and cell:cell interactions. The diversity of these various functions demonstrate the importance of these galectins in the leukemia niche. This review will cover the role of LGALS1, LGALS3, and LGALS9 in the various processes that are critical for maintaining leukemia cells in the tumor microenvironment. PMID- 30245265 TI - Characterization of cDNA clones encoding major histocompatibility class II receptors from walleye (Sander vitreus). AB - The teleost major histocompatibility (MH) class II receptor presents peptides from exogenous sources to CD4+ T cells, leading to the initiation of the adaptive immune response. The genes encoding MH class II have been identified in a number of teleost species, but not in walleye, an important recreational fish and commercial fishery in North America. In this study, we cloned and characterized the sequences encoding walleye MH class II alpha and beta chains. These sequences contained all of the domains typical for functional MH class II alpha and beta chain proteins, and aligned with other teleost sequences of MH class II. The walleye MH class II alpha amino acid sequence, along with other members of the Supraorder Percomorpharia, contains a high concentration of methionine residues in the beginning of the leader peptide. Southern blotting indicated that there is more than one gene copy for both MH class II alpha and beta, while northern blotting analysis of both genes showed that expression of these genes is greatest in lymphoid tissues and at potential entry points for pathogens. These results help to further the understanding of MH class II receptors in teleosts, and could prove useful in the study of disease issues in walleye such as dermal sarcoma virus. PMID- 30245266 TI - Omentin-1 protects against bleomycin-induced acute lung injury. AB - Acute lung injury (ALI) is characterized by inflammatory cell infiltration, macrophage activation, and excessive pro-inflammatory cytokine production. Bleomycin (BLM) is widely used to induce acute lung injury (ALI) and fibrosis in murine models. Intratracheally administration of BLM leads to the early stage of inflammatory response and the late stage of collagen deposition. Omentin-1 exerts an anti-inflammatory role in reducing tumor necrosis factor alpha (TNF-alpha) induced cyclooxygenase-2 expression in endothelial cells and attenuating lipopolysaccharide (LPS)-induced ALI. However, the role of omentin-1 in BLM induced ALI remains unclear. The aim of this study is to examine the effects of omentin-1 on BLM-induced ALI. We found that omentin-1 was decreased in lungs of BLM-induced ALI mice. Omentin-1 overexpression mediated by adenovirus alleviated lung injury and maintained the integrity of the alveolar septa. Omentin-1 overexpression also remarkably decreased the aggregation of neutrophil and macrophages activation, the expression of monocyte chemotactic protein 1 (MCP-1), and down-regulated expression of interleukin 1beta (IL-1beta) in lungs of BLM induced ALI mice. Furthermore, we observed that omentin-1 reduced oxidative stress and suppressed the activation of NF-kappaB pathway in BLM-induced ALI and LPS-induced macrophages activation. Together, our findings indicated that omentin 1 protected mice from BLM-induced ALI may through reducing inflammatory cells recruitment and macrophages activation via alleviation of oxidative stress and NF kappaB pathway. Thus, therapeutic strategies aiming to restore omentin-1 levels may be valuable for the prevention of BLM-induced ALI. PMID- 30245268 TI - Effect of graphene on setting and mechanical behaviour of tricalcium phosphate bioactive cements. AB - The potential reinforcing effect of graphene on calcium phosphate cements (CPCs) for injectable bone substitutes and scaffolds is presented. The influence of graphene (0-3.84 vol%) on the microstructural development during setting and the resultant mechanical properties of CPCs constituted by alpha + beta-tricalcium phosphate is analysed. Optimum setting conditions were established using uniaxial compression strength of CPC and composites with pristine and functionalized graphene and liquid/solid ratios (L/S = 0.5-0.6 mL/g) that allowed the mixing and spatulation of the powders. Tensile strength of optimised materials has been determined using the Diametric Compression of Discs Test (DCDT). X-ray diffraction, Raman spectroscopy and FE-SEM-EDS on fracture surfaces were used to investigate phase composition and morphological changes in set specimens. Strengthening occurs for functionalized graphene additions up to 1.96 vol% due to different toughening mechanisms. Crack deflection, bridging and branching by graphene and, finally, the pull-out of the unbroken graphene sheets have been identified. Interlayer sliding between the graphene before pulling-out is an additional toughening process. Main effect of graphene on strength is the increase of reliability. PMID- 30245267 TI - Identifying trippers and non-trippers based on knee kinematics during obstacle free walking. AB - Trips are a major cause of falls. Sagittal-plane kinematics affect clearance between the foot and obstacles, however, it is unclear which kinematic measures during obstacle-free walking are associated with avoiding a trip when encountering an obstacle. The purpose of this study was to determine kinematic factors during obstacle-free walking that are related to obstacle avoidance ability. It was expected that successful obstacle avoidance would be associated with greater peak flexion/dorsiflexion and range of motion (ROM), and differences in timing of peak flexion/dorsiflexion during swing of obstacle-free walking for the hip, knee and ankle. Three-dimensional kinematics were recorded as 35 participants (young adults age 18-45 (N = 10), older adults age 65+ without a history of falls (N = 10), older adults age 65+ who had fallen in the last six months (N = 10), and individuals who had experienced a stroke more than six months earlier (N = 5)) walked on a treadmill, under obstacle-free walking conditions with kinematic features calculated for each stride. A separate obstacle avoidance task identified trippers (multiple obstacle contact) and non trippers. Linear discriminant analysis with sequential feature selection classified trippers and non-trippers based on kinematics during obstacle-free walking. Differences in classification performance and selected features (knee ROM and timing of peak knee flexion during swing) were evaluated between trippers and non-trippers. Non-trippers had greater knee ROM (P = .001). There was no significant difference in classification performance (P = .193). Individuals with reduced knee ROM during obstacle-free walking may have greater difficulty avoiding obstacles. PMID- 30245269 TI - Glyphosate and aminomethylphosphonic acid degradation in biomixtures based on alfalfa straw, wheat stubble and river waste. AB - The aim of the work was to evaluate novel biomixtures for their use on biopurification systems (BPS) in Argentina also called biobeds. Glyphosate and aminomethylphosphonic acid (AMPA) degradation was evaluated on biomixtures containing local materials: alfalfa straw (As), wheat stubble (Ws), river waste (Rw) and soil. Glyphosate, AMPA concentrations and biological activity were followed with time. Soil was used as control. Glyphosate initial concentration was 1000 mg kg-1. Glyphosate disappeared almost completely after 63 days in all tested biomixtures. For Ws, WsRw and AsRw glyphosate degradation was around 99% and for As 85%. The biomixture Ws showed the highest glyphosate degradation rate. In all cases AMPA was formed and degraded to concentrations between 60 and 100 mg kg-1. In the control with only soil, glyphosate was degraded 53% and AMPA concentration at the end of the test was 438 mg kg-1. We conclude that alfalfa straw, wheat stubble and river waste are local materials that can be used in the preparation of biomixtures since they showed higher glyphosate degradation capacity and less AMPA accumulation compared to the soil alone. Also, the presence of river waste did enhance the water retention capacity. PMID- 30245270 TI - Evaluation of antibiotic resistant lactose fermentative opportunistic pathogenic Enterobacteriaceae bacteria and blaTEM-2 gene in cephalosporin wastewater and its discharge receiving river. AB - This study investigated the concentration of cephalosporin, the resistant levels of lactose fermentative opportunistic pathogenic Enterobacteriaceae bacteria (LFOPEB) against seven antibiotics and one cephalosporin-resistant gene in cephalosporin wastewater (CPWW) treatment plant and its discharge receiving river. Although large numbers of bacteria have been removed during the CPWW treatment process, the antibiotic resistant rates of the isolates to beta-lactam antibiotics significantly increased (p = 0.032) after treatment, while the percentage of resistant LFOPEB to non-beta-lactam antibiotics did not change dramatically. Furthermore, the discharge of the effluent of CPWW treatment plant (CPWWeff) led to an obvious increase in the percentages of beta-lactam antibiotic resistant LFOPEB and relative abundance of the blaTEM-2 gene in the downstream receiving river (RWdown) in comparison with those in the upstream receiving river (RWup). The antibiotic resistant phenotypes of isolates in the influent of CPWW treatment plant (CPWWin), CPWWeff and RWdown appeared to be seriously affected by the cephalosporin residues, which suggested that main antibiotic resistance phenotypes in antibiotic contaminated water were closely associated with its antibiotic composition. Therefore, CPWW treatment process has been proved to result in selective growth of ARB and proliferation of ARG. Besides, CPWWeff was also proved to be an important supplier of ARB and ARG to the receiving river. PMID- 30245271 TI - Nitrogen removal efficiencies and pathways from unsaturated and saturated zones in a laboratory-scale vertical flow constructed wetland. AB - A laboratory-scale vertical flow constructed wetland system was designed and monitored to compare nitrogen removal rates and pathways from both saturated and unsaturated zones under a hydraulic loading rate and influent total nitrogen concentration of 1.5 m3/m2.d and 508 mg/L respectively. Weekly measurements of the concentrations of nitrogen compounds, chemical oxygen demand, temperature, dissolved oxygen, oxidation-reduction potential, and hydrogen ion concentration were taken throughout the study. At the end of the experiments, PCR analysis of 16S rRNA gene sequencing was performed to identify microbial communities in the unsaturated and saturated parts of the system. The nitrogen compounds were removed from the system after 182 days, with similar total nitrogen removal efficiencies (94% and 93%) for the unsaturated and saturated zones respectively. Heterotrophic nitrification/aerobic denitrification was the major pathway responsible for the removal of nitrogen compounds. Adsorption into the gravel bed also contributed to ammonium removal. Proteobacteria were the dominant bacterial strains involved in nitrogen transformation and accounted for 80% of the total bacteria in the unsaturated zone and 60% in the saturated zone. With little difference in the concentration removal efficiencies of the unsaturated and saturated zones, a more effective design would be an entirely saturated wetland as the total mass removal of nitrogen depends on the water volume stored, which at full saturation in this design was seven times greater per unit wetland volume than the unsaturated zone. PMID- 30245272 TI - Liquid-liquid extraction of phenolic compounds from water using ionic liquids: Literature review and new experimental data using [C2mim]FSI. AB - In this work, the capability of the ionic liquid, 1-ethyl-3-methylimidazolium bis(fluorosulfonyl)imide, [C2mim]FSI, to extract o-cresol, 2-chlorophenol, resorcinol and phenol from water, reaching the legal limit of 1 mg L-1 was analyzed. The extraction process was carried out for each one of these phenolic compounds varying the initial concentration in water from 3 mg L-1 to 1000 mg L 1, and for aqueous mixtures of the four phenolic compounds in the same concentration range. Because of the scarcity of physical properties of the [C2mim]FSI, density, speed of sound, dynamic viscosity and refractive index were measured from 293.15 to 343.15 K at atmospheric pressure. From the experimental data, the thermal expansion coefficient and the isentropic compressibility for the pure ionic liquid were calculated. Even though [C2mim]FSI is hydrophobic, it can solve small quantities of water that can hinder the recovery of the ionic liquid, consequently the solubility of water in the ionic liquid was determined at several temperatures and atmospheric pressure. In addition to experimental data, a literature review on the use of ionic liquids to extract phenolic compounds from water was performed. PMID- 30245273 TI - Interaction of isolated silymarin flavonolignans with iron and copper. AB - Silymarin, the standardized extract from the milk thistle (Silybum marianum), is composed mostly of flavonolignans and is approved in the EU for the adjuvant therapy of alcoholic liver disease. It is also used for other purported effects in miscellaneous nutraceuticals. Due to polyhydroxylated structures and low systemic bioavailability, these flavonolignans are likely to interact with transition metals in the gastrointestinal tract. The aim of this study was to analyze the interactions of pure silymarin flavonolignans with copper and iron. Both competitive and non-competitive methods at various physiologically relevant pH levels ranging from 4.5 to 7.5 were tested. Only 2,3-dehydrosilybin was found to be a potent or moderately active iron and copper chelator. Silybin A, silybin B and silychristin A were less potent or inactive chelators. Both 2,3 dehydrosilybin enantiomers (A and B) were equally active iron and copper chelators, and the preferred stoichiometries were mainly 2:1 and 3:1 (2,3 dehydrosilybin:metal). Additional experiments showed that silychristin was the most potent iron and copper reductant. Comparison with their structural precursors taxifolin and quercetin is included as well. Based on these results, silymarin administration most probably affects the kinetics of copper and iron in the gastrointestinal tract, however, due to the different interactions of individual components of silymarin with these transition metals, the biological effects need to be evaluated in the future in a much more complex study. PMID- 30245274 TI - Pt-induced crosslinks promote target enrichment and protection from serum nucleases. AB - Identifying the interactions of small molecules with biomolecules in complex cellular environments is a significant challenge. As one important example, despite being widely used for decades, much is still not understood regarding the cellular targets of Pt(II)-based anticancer drugs. In this study we introduce a novel method for isolation of Pt(II)-bound biomolecules using a DNA hybridization pull-down approach. Using a modified Pt reagent, click-ligation of a DNA oligonucleotide to both a Pt(II)-bound DNA hairpin and bovine serum albumin (BSA) are demonstrated. Subsequent hybridization to a biotin-labeled oligonucleotide allows for efficient isolation of Pt(II)-bound species by streptavidin pulldown. We also find that platinated bovine serum albumin readily crosslinks to DNA in the absence of click ligation, and that a fraction of BSA-bound Pt(II) can transfer to DNA over time. Interestingly, in in vitro studies, fragmented mammalian DNA that is crosslinked to BSA through Pt(II) exhibits significantly increased protection from degradation by serum nucleases. PMID- 30245275 TI - Predicting conversion from MCI to AD by integrating rs-fMRI and structural MRI. AB - Structural MRI (sMRI) and resting-state functional MRI (rs-fMRI) have provided promising results in the diagnosis of Alzheimer's disease (AD), though the utility of integrating sMRI with rs-fMRI has not been explored thoroughly. We investigated the performances of rs-fMRI and sMRI in single modality and multi modality approaches for classifying patients with mild cognitive impairment (MCI) who progress to probable AD-MCI converter (MCI-C) from those with MCI who do not progress to probable AD-MCI non-converter (MCI-NC). The cortical and subcortical measurements, e.g. cortical thickness, extracted from sMRI and graph measures extracted from rs-fMRI functional connectivity were used as features in our algorithm. We trained and tested a support vector machine to classify MCI-C from MCI-NC using rs-fMRI and sMRI features. Our algorithm for classifying MCI-C and MCI-NC utilized a small number of optimal features and achieved accuracies of 89% for sMRI, 93% for rs-fMRI, and 97% for the combination of sMRI with rs-fMRI. To our knowledge, this is the first study that investigated integration of rs-fMRI and sMRI for identification of the early stage of AD. Our findings shed light on integration of sMRI with rs-fMRI for identification of the early stages of AD. PMID- 30245276 TI - Examining mesh independence for flow dynamics in the human nasal cavity. AB - Increased computational resources provide new opportunities to explore sophisticated respiratory modelling. A survey of recent publications showed a steady increase in the number of mesh elements used in computational models over time. Complex geometries such as the nasal cavity exhibit sharp gradients and irregular curvatures, leading to abnormal flow development across their surfaces. As such, a robust method for examining the near-wall mesh resolution is required. The non-dimensional wall unit y+ (often used in turbulent flows) was used as a parameter to evaluate the near-wall mesh in laminar flows. Mesh independence analysis from line profiles showed that the line location had a significant influence on the result. Furthermore, using a single line profile as a measure for mesh convergence was unsuitable for representing the entire flow field. To improve this, a two-dimensional (2D) cross-sectional plane subtraction method where scalar values (such as the velocity magnitude) on a cross-sectional plane were interpolated onto a regularly spaced grid was proposed. The new interpolated grid values from any two meshed models could then be compared for changes caused by the different meshed models. The application of this method to three dimensional (3D) volume subtraction was also demonstrated. The results showed that if the near-wall mesh was sufficiently refined, then narrow passages were less reliant on the overall mesh size. However, in wider passages, velocity magnitudes were sensitive to mesh size, requiring a more refined mesh. PMID- 30245277 TI - Multi-scale representation of proteomic data exhibits distinct microRNA regulatory modules in non-smoking female patients with lung adenocarcinoma. AB - Adenocarcinoma in female non-smokers is an under-explored subgroup of non-small cell lung cancer (NSCLC), in which the molecular mechanism and genetic risk factors remain unclear. We analyzed the protein profiles of plasma samples of 45 patients in this subgroup and 60 non-cancer subjects using surface-enhanced laser desorption/ionization time-of- flight mass spectrometry. Among 85 peaks of mass spectra, the differential expression analysis identified 15 markers based on False Discovery Rate control and the Discrete Wavelet Transforms further selected a cluster of 6 markers that were consistently observed at multiple scales of mass charge ratios. This marker cluster, corresponding to 7 unique proteins, was able to distinguish the female non-smokers with adenocarcinoma from non-cancer subjects with a value of accuracy of 87.6%. We also predicted the role of competing endogenous RNAs (ceRNAs) in 3 out of these 7 proteins. Other studies reported that these ceRNAs and their targeting microRNAs, miR-206 and miR-613, were significantly associated with NSCLC. This study paves a crucial path for further investigating the genetic markers and molecular mechanism of this special NSCLC subgroup. PMID- 30245278 TI - Frequency and associated factor of atypical periprosthetic femoral fracture after hip arthroplasty. AB - BACKGROUND: Atypical femoral fracture (AFF) is a serious complication after the use of bisphosphonates, and periprosthetic femoral fracture (PFF) appeared as a common complication after hip arthroplasty, especially in senile patients. Although American Society for Bone and Mineral Research has excluded PFFs from the definition of AFFs, several case reports found PFF patients undergoing bisphosphonate treatment, have fractures resembling AFF and the authors suggested that AFF can also occur in operated femurs after hip arthroplasty. To date, the frequency and risk factors of atypical PFF are unknown. The purpose of our study was (1) to evaluate the proportion of atypical PFF among Vancouver type B PFFs, and (2) to determine the association between occurrence of atypical PFF and use of bisphosphonate. METHODS: We reviewed medical records and radiographs of 67 Vancouver type B PFFs (67 patients) due to low-energy trauma and classified them into atypical PFF group and ordinary PFF group. We calculated the proportion of atypical PFFs among PFFs and identified risk factors for atypical PFF. RESULTS: Among the 67 PFFs, 7 fractures (10.4%) were classified as atypical PFF. Longer duration of bisphosphonate use was an independent risk factor of atypical PFF. (Odds ratio 2.600, 95% CI 1.184-5.709, p = 0.017). CONCLUSION: In accordance with wide use of bisphosphonate, atypical PFFs after hip arthroplasty are not rare anymore. Physicians should suspect the atypical PFF, when they meet low-energy fracture in bisphosphonate users, and radiographs show features of AFF. PMID- 30245279 TI - Radiographic predictors of symptomatic locking screw removal after treatment of tibial fractures with intramedullary nails. AB - INTRODUCTION: The purpose of this study was to determine the radiographic parameters associated with symptomatic locking screw removal after intramedullary tibial nail insertion. Our hypothesis was that locking screws located closer to joints and those extending longer than the width of the bone result in more symptomatic implant removal. METHODS: We conducted a retrospective cohort study at our Level I trauma center. Seventy-five patients underwent surgical removal of symptomatic locking screws from 2007 to 2014 and were compared with a control group of 122 patients from the same time period who did not undergo symptomatic locking screw removal. Our main outcome measures were radiographic and demographic factors associated with implant removal. RESULTS: Multivariable regression indicated that a proximal locking screw that started anterolateral and was directed posteromedial was the strongest radiographic predictor of symptomatic removal (odds ratio [OR], 2.83; p = 0.03). An Injury Severity Score <11 (OR, 3.10; p < 0.001) and a body mass index <25 kg/m2 (OR, 2.15; p = 0.02) were also associated with locking screw removal. The final prediction model discriminated patients requiring symptomatic locking screw removal with moderate accuracy (area under the receiver operating characteristic curve = 0.73). CONCLUSIONS: The strongest radiographic predictor for symptomatic locking screw removal after tibial nail insertion was the direction of the most proximal locking screw. In contrast to previous research on retrograde femoral nails, tibial locking screws that were closer to the joints were not associated with an increased likelihood of symptomatic screw removal. Clinicians can use these data to help counsel patients regarding the likelihood of symptomatic screws and perhaps to help guide screw placement in cases with multiple options. PMID- 30245280 TI - Assessing the impact of blood alcohol concentration on the rate of in-hospital mortality following traumatic motor vehicle crash injury: A matched analysis of the National Trauma Data Bank. AB - BACKGROUND: The purpose of this study was to compare the outcomes of trauma patients who were injured in a motor vehicle crash and tested positive for alcohol upon hospital arrival versus those who tested negative. METHODS: Study data came from the US National Trauma Data Bank (2007-2010). Any blood alcohol concentration (BAC) found at or above the legal limit (>=0.08 g/dL) was considered "alcohol positive", and if no alcohol was identified through testing, the patient was considered "alcohol negative". Patients' demographics including age > = 14, race, gender, drug test results, systolic blood pressure, heart rate, injury severity score (ISS), and Glasgow Coma Scale (GCS) were included in the study. Propensity score and exact pair matching were performed between the groups using baseline characteristics. RESULTS: From a total of 88,794 patients, 30.9% tested positive and 69.1% tested negative for alcohol. There were significant differences found between the groups regarding age, gender, race, and GCS (all p < 0.001) as well as a significantly higher in-hospital mortality rate (3.5% vs. 2.7%, p < 0.001) and median time to patient expiration (4 vs. 3 days, p < 0.001) in the alcohol negative group. After running both matching scenarios, there was no evidence of a significant difference seen in the rates of in-hospital mortality or the median time to patient expiration between the alcohol groups in either matched comparison. CONCLUSION: Patients who tested positive for alcohol following a traumatic motor vehicle crash showed no significant increase in in hospital mortality or time to expiration when compared to propensity score and exact matched patients who tested negative for alcohol. PMID- 30245281 TI - Analgesic Efficacy of an Acetaminophen/Ibuprofen Fixed-dose Combination in Moderate to Severe Postoperative Dental Pain: A Randomized, Double-blind, Parallel-group, Placebo-controlled Trial. AB - PURPOSE: Acute pain is a significant burden to the individual and to society. There is a clear need for a pain medication that provides improved analgesia over common analgesics, without compromising tolerability. The goal of this study was to determine the efficacy of a new fixed-dose combination of acetaminophen 975 mg and ibuprofen 292.5 mg (FDC 975/292.5) relative to acetaminophen or ibuprofen monotherapy, or placebo. METHODS: This prospective, multicenter, randomized, double-blind, placebo-controlled, Phase III trial included 408 adult volunteers aged 18 to 60 years experiencing moderate to severe pain after surgical removal of at least 2 impacted third molars. Subjects were randomized in a 3:3:3:2 ratio to the following interventions: FDC 975/292.5, acetaminophen 975 mg, ibuprofen 292.5 mg, and placebo. Self-reported pain intensity scores were recorded over a 48-hour double-blind treatment period using a 100-mm visual analog scale. In addition, time to perceptible and meaningful pain relief was assessed by using the two-stopwatch method; use of rescue medication (oxycodone) was recorded; and patients rated their pain relief on a 5-point categorical scale. All adverse events during the 30-day study period were assessed. FINDINGS: The majority of participants were female (67.4%) and white (90.0%), with a mean age of 24.8 years. Demographic and baseline characteristics were balanced across treatment groups, with a mean baseline pain score of 56.4 mm. The primary end point was the time-adjusted sum of pain intensity differences over 48 hours, which was found to be significantly greater for FDC 975/292.5 than for both monotherapies and placebo (all, P < 0.001). The robustness of the procedures used in the calculation of the primary end point was confirmed in a series of sensitivity analyses. Statistical superiority of the combination was evident in all secondary end points (time to meaningful pain relief, maximum pain score, response rate, participants using supplementary analgesia, time to rescue, oxycodone consumption, and categorical pain relief score) with the exception of time to perceptible pain relief versus monotherapies and the time to peak response versus ibuprofen. The percentage of patients reporting adverse events was 37.3% in the FDC 975/292.5 group, with no significant differences between treatment groups. Nausea was the most common adverse event across all groups. IMPLICATIONS: Overall, the fixed-dose combination of acetaminophen and ibuprofen provided greater and more rapid analgesia than comparable doses of either agent alone or placebo in adults after removal of impacted third molars. ClinicalTrials.gov identifier: NCT01420653. PMID- 30245282 TI - The Effect of Puerarin on Carotid Intima-media Thickness in Patients With Active Rheumatoid Arthritis: ARandomized Controlled Trial. AB - PURPOSE: Cardiovascular and diabetic complications are the main causes of death in patients with rheumatoid arthritis (RA). Puerarin has potential protective effects against subclinical atherosclerosis and insulin resistance, but the clinical evidence is still not sufficient to draw definitive conclusions. Therefore, we performed the clinical trial to assess the effect of puerarin on carotid intima-media thickness (CIMT) in RA. METHODS: This is an open, controlled, randomized, and parallel-group comparison study of 119 patients with a definite diagnose of active RA. All 119 consecutive patients with RA receiving routine antirheumatic care were randomized to receive treatment with (n = 60; 16 males and 44 females; mean age, 52.97 years; 95% CI, 49.78-56.15 years) or without (n = 59; 17 males and 42 females; mean age, 54.05 years; 95% CI, 50.03 58.07 years) 400mg of puerarin. The effects of both interventions on CIMT, homeostasis model assessment of insulin resistance (HOMA-IR) value, and possible adverse events were assessed and compared at entry, 12 weeks, and 24 weeks. The collected data were processed and assessed using ANCOVA, paired t test, repeated measure ANOVA, one-way ANOVA, Pearson's chi2 test, Fisher exact test, Kaplan Meier survival analysis, Pearson correlation, and LOESS (locally weighted smoothing) regression analysis. FINDINGS: No significant adverse effects occurred concerning the use of puerarin, and both interventions were generally well tolerated in all the patients. A tiny but significant decrease of CIMT was observed in puerarin-treated patients at 24 weeks (-0.003 mm; 95% CI, -0.005 to 0.001vs 0.019 mm; 95% CI, -0.002 to 0.040; P < 0.001). At 24 weeks, insulin resistance was indicated with more pronounced improvement in the puerarin group versus the control group (homeostasis model assessment, -0.40; 95% CI, -0.47 to 0.33vs -0.05; 95% CI, -0.08 to -0.01; P < 0.001). Correlation analysis indicated an interaction between the parallel reductions in CIMT and insulin resistance in the puerarin group (r = 0.878, P < 0.001) but not in the control group. IMPLICATIONS: In the study, 24 weeks of treatment with 400mg of puerarin exerted a significant effect against CIMT progression in patients with active RA, which may be associated with the improvement of insulin resistance. Puerarin holds promise as a drug candidate for the prevention and treatment of cardiometabolic comorbidities in patients with active RA. However, more strictly designed trials, such as double-blind and placebo-controlled trials, are still required. ClinicalTrials.gov identifier: NCT02254655. PMID- 30245284 TI - Benefit of sugammadex in a morbidly obese patient with multiple sclerosis and severe respiratory dysfunction. PMID- 30245285 TI - Prevalence of self-reported drug hypersensitivity reactions among Lithuanian children and adults. AB - INTRODUCTION AND OBJECTIVES: Drug hypersensitivity reactions (DHRs) are the adverse effects of drugs that, when taken at doses generally tolerated by normal subjects, clinically resemble allergy. We aimed to assess the prevalence of self reported DHRs among Lithuanian children and adults and to identify possible risk factors. MATERIALS AND METHODS: A cross-sectional survey of a population visiting their general practitioners in Vilnius and Kaunas regions of Lithuania was performed. Thirty-five questions on drug allergy symptoms, in addition, food, pollen allergy and family history were included. RESULTS: 3222 (60.0%) children and 2148 (40.0%) adults were included in the study. 7.9% of children and 13.8% of adults reported a DHR for at least one drug (p<0.001). 69.8% of children and 47.3% of adults, who indicated DHRs, had skin symptoms. Rate of anaphylaxis was similar in both groups (about 10%). 4.5% of children and 7.3% of adults had DHRs induced by antibiotics and this was the most implicated group of drugs. Significant self-reported risk factors for DHRs were family history of DHRs (OR=6.007, 95%CI 4.756-7.587), pollen allergy (OR=2.0, 95%CI 1.573-2.544), food allergy (OR=1.92, 95%CI 1.505-2.448), female gender (OR=1.439, 95%CI 1.187-1.744) and age (OR=1.017 in favour of adults, 95%CI 1.013-1.021). CONCLUSIONS: The prevalence of self-reported DHRs in Lithuania is higher among adults than children. Drug-induced skin reactions were the predominant symptom in both groups. Besides female gender and age, a positive family history of DHR and presence of pollen or food allergy may be associated with DHR. PMID- 30245283 TI - Rapamycin but not acarbose decreases age-related loss of outer hair cells in the mouse Cochlea. AB - Adding rapamycin or acarbose to diet at 9-10 months of age has been shown to significantly increase life span in both male and female UM-HET3 mice. The current study examined cochleae of male and female UM-HET3 mice at 22 months of age to determine if either treatment also influenced age-related loss of cochlear hair cells. A large loss of cochlear outer hair cells was observed at 22 months of age in untreated mice in both apical and basal halves of the cochlear spiral. Addition of acarbose to diet had no significant effect on the amount of outer hair cell loss at 22 months of age or in its pattern, with large loss in both apical and basal halves. The addition of rapamycin to diet, however, significantly reduced outer hair cell loss in the basal half of the cochlea at 22 months of age when compared to untreated mice. There was no significant difference between male and female mice in any of the conditions. Age-related outer hair cell loss in the apical cochlea precedes outer hair cell loss in the base in many mouse strains. The results of the present study suggest that rapamycin but not acarbose treatment can delay age-related loss of outer hair cells at doses at which each drug increases life span. PMID- 30245286 TI - Molecular diagnostics improves diagnosis and treatment of respiratory allergy and food allergy with economic optimization and cost saving. AB - BACKGROUND: Component resolved diagnosis (CRD) allows to precisely identify the sensitization to specific molecules of a given allergenic source, resulting in an important improvement in clinical management, particularly of polysensitized subjects. This will end in the correct prescription of allergen immunotherapy (AIT) for respiratory allergy and in adequate avoidance diets or prescription of self-injectable adrenaline in food allergy. OBJECTIVE: The aim of this multicenter, real life study is to evaluate the percentage change of the diagnostic-therapeutic choice in polysensitized patients with respiratory allergy and in patients with food allergy, after using CRD compared to a first level diagnosis, along with an economic analysis of the patient's overall management according to the two different approaches. METHODS: An overall number of 462 polysensitized patients, as suggested by skin prick tests (SPT), and with clinical symptoms related to a respiratory (275 pts) or food (187 pts) allergy, were recruited. All patients underwent CRD for specific IgE against food or inhalant recombinant molecules, which were chosen according to medical history and positivity to SPT. The first diagnostic-therapeutic hypothesis, based only on medical history and SPT, was recorded for each patient while the final diagnostic therapeutic choice was based on the results from CRD. The rate of change of the diagnostic-therapeutic choice from the first hypothesis to the final choice was statistically evaluated. The economic impact of CRD on the overall management of the allergic patients was analyzed to evaluate whether the increase in the diagnostic costs would be compensated and eventually exceeded by savings coming from the improved diagnostic-therapeutic appropriateness. RESULTS: An approximate 50% change (k index 0.54) in the prescription of AIT for respiratory allergy as well as a change in the prescription of self-injectable adrenaline (k index 0.56) was measured; an overall saving of financial resources along with a higher diagnostic-therapeutic appropriateness was also detected. CONCLUSION: There is moderate agreement concerning prescription of AIT and self-injectable adrenaline before and after performing CRD: this highlights the usefulness of CRD, at least in polysensitized patients, in indicating the risk assessment and therefore the correct therapy of respiratory and food allergy, which results in a cost-saving approach. PMID- 30245287 TI - Polydatin alleviated alcoholic liver injury in zebrafish larvae through ameliorating lipid metabolism and oxidative stress. AB - Hepatic steatosis is the early stage of alcoholic liver disease (ALD), may progress to steatohepatitis, fibrosis even cirrhosis. Polydatin, the primary active component of Polygonum cuspidatum Sieb. et Zucc, has been recognized to possess hepatoprotective and anti-inflammatory properties. To investigate whether polydatin alleviates ethanol induced liver injury and to elucidate the underlying molecular mechanisms, zebrafish larvae at 4 days post-fertilization (dpf) were exposed to 350 mmol/L of ethanol for 32 h, then treated with polydatin for 48 h. Oil red O, Nile Red and H&E staining were used to analyze the pathological changes in liver. The mRNA levels were measured by quantitative PCR and the antioxidant capacity was detected using H2O2-specific fluorescent probe. Here, polydatin strongly alleviated hepatic steatosis and decreased the expression levels of alcohol and lipid metabolism-related genes, including CYP2Y3, CYP3A65, HMGCRa, HMGCRb and FASN. Additionally, polydatin inhibited oxidative stress in the liver according to fluorescent probe. Moreover, significantly up-regulated expression of DNA damage-related genes (CHOP, GADD45alphaa) revealed that polydatin attenuated hepatic apoptosis in larvae. In conclusion, polydatin may improve the liver function of zebrafish with acute alcoholic liver injury through attenuating hepatic fat accumulation, ameliorating lipid and ethanol metabolism and reducing oxidative stress and DNA damage. PMID- 30245288 TI - Yeast distribution in Grignolino grapes growing in a new vineyard in Piedmont and the technological characterization of indigenous Saccharomyces spp. strains. AB - The aim of this study was to characterize the yeast consortium isolated from Grignolino grapes in a newly planted vineyard in Piedmont (Italy) via analysis of the intra-vineyard yeast distribution of grape samples from single rows. A two phase approach allowed the identification of culturable yeasts present on grape skins and, through an enriching procedure via grape fermentation, the isolation of low frequency non-Saccharomyces and Saccharomyces spp. fermentative species, including S. paradoxus, which is highly unusual during grape fermentation, along with the intra-specific characterization of S. cerevisiae isolates. Culture-based molecular techniques revealed a grape yeast microbiota formed by (in order of abundance) Hanseniaspora uvarum, the yeast-like fungus Aerobasidium pullulans, Candida zemplinina, Pichia kluyveri, Candida californica, Curvibasidium cygneicollum, Meyerozima caribbica, Rhodotorula babjevae, Metschnikowia pulcherrima and Cryptococcus flavescens. Technological properties of isolated Saccharomyces spp. strains were analysed, identifying strains, including S. paradoxus, potentially suitable as an ecotypical starter for territorial wines. PMID- 30245289 TI - ESbetaL E. coli isolated in pig's chain: Genetic analysis associated to the phenotype and biofilm synthesis evaluation. AB - Resistance to new generation cephalosporins is an important public health problem globally, in terms of economic and social costs, morbidity and mortality. Betaeta lactamase enzymes are mainly responsible for the antibiotic resistance of Gram negative bacteria and extended-spectrum-beta-lactamases (ESbetaLs) are one of the major determinants of resistance against oxymino-cephalosporins in Enterobacteriaceae. Food-producing animals represent one of the sources of antibiotic resistant bacteria, including pigs. Here we analysed the presence of E. coli resistant to III generation cephalosporins isolated from different matrices collected from intensively bred pigs. A total of 498 E. coli were isolated from faeces and carcasses of pigs at slaughterhouse as well as from pork meat and sausages. Among these, 73 were phenotypically confirmed to be ESbetaL producers. Genetic analysis revealed that all except two harboured at least one of the three selected genes: blaCTX-M, blaTEM, and blaSHV. Furthermore, six of the E. coli ESbetaL isolated from faeces and carcasses swabs, were also able to produce biofilm, highlighting the virulence potential of these strains. The presence of Multi-Drug-Resistance patterns (MDR) recorded by the 73 ESbetaL E. coli was significant (60% of the strains were resistant to more than six antibiotics in MIC test). Results from the present study show that the transmission of resistant bacteria is possible along the food chain, including production of pork, one the most highly consumed meats around the world. Transmission is possible through the ingestion of raw meat products, and following cross-contamination between raw and cooked foods during preparation. The potential risk for human health demonstrated here, associated with the consumption of pork contaminated with bacterial strains characterized by multidrug resistance patterns, and the ability to produce ESbetaL and biofilm, is cause for concern. It is imperative to study future control strategies to avoid or limit as much as possible the transmission of these highly pathogenic strains through food consumption and/or contact with the environment. PMID- 30245290 TI - MiR-139-5p regulates VEGFR and downstream signaling pathways to inhibit the development of esophageal cancer. AB - BACKGROUND: MiR-139-5p plays a significant role in tumorigenesis, metastasis and recurrence, suggesting that it may potentially be used as a promising biomarker for esophageal cancer diagnosis, prognosis and therapy. This study aimed to investigate the role and the mechanism of miRNA-139-5p in esophageal cancer. METHODS: This study included 11 patients from an area with a high incidence of esophageal cancer. The expression levels of miRNA-139-5p in esophageal cancer tissues and para-carcinoma tissues of 11 patients were measured. We examined the expression of miR-139-5p in serum obtained from 92 consecutive patients from Cixian, which is a region in Hebei Province with a high rate of histologically confirmed esophageal cancer. The expression of miR-139-5p in esophageal cancer cell lines was detected. In the KYSE150 cell line with the lowest expression level of miR-139-5p, we transfected a plasmid to upregulate the expression level and examined the role of miR-139-5p in esophageal squamous cell carcinoma proliferation, migration and invasion. We conducted a gene profiling study using miR-139-5p cell lines to detect the expression of significant genes related to tumor progression, including cyclinD1, E-cadherin and VEGFR-1. We then constructed luciferase reporters containing miR-139-5p, which contained wild-type (WT) or mutated-type (Mut) VEGFR-1 binding sites to investigate the target. RESULTS: MiRNA-139-5p expression levels in esophageal cancer tissues from 11 patients were significantly higher than those in para-carcinoma tissues. MiR-139 5p expression in the serum of 92 patients with esophageal cancer was associated with gender (P = 0.039) and TNM stage (P = 0.015). Factors that were not correlated with miR-139-5p expression were age (P = 0.293), smoking history (P = 0.397), length of tumor (P = 0.309), width of tumor (P = 0.296), depth of tumor (P = 0.724), lymphoma metastasis (P = 0.531) and postoperative therapy (P = 0.884). MiR-139-5p (P = 0.013) correlated significantly with observed survival rates. The lymphoma metastasis (P = 0.005) and TNM stage (P = 0.000) were significantly associated with observed survival rates. However, no significant relationships were found between the miR-139-5p and patient characteristics including gender, age, smoking history, tumor size and postoperative therapy. In the KYSE150 cell line, the expression level of miR-139-5p was the lowest. We transfected a plasmid to upregulate the expression level and found that the cell proliferation, metastasis and invasion abilities decreased. Upregulation of miR 139-5p inhibited the expression of Cyclin D1 and VEGFR-1 and increased the expression of E-cadherin. For further confirmation, we constructed luciferase reporters containing miR-139-5p, which contained wild-type (WT) or mutated-type (Mut) VEGFR-1 binding sites for target investigation. The results show that the corresponding VEGFR-1-Mut construct no longer suppressed miR-139-5p. CONCLUSIONS: MiR-139-5p may be a novel therapeutic target and prognostic biomarker of esophageal cancer. PMID- 30245291 TI - TEMPORARY REMOVAL: Controversies in Drug Allergy: Beta-Lactam Hypersensitivity Testing. AB - Available online September 20, 2018. The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 30245292 TI - Queen bee acceptance under threat: Neurotoxic insecticides provoke deep damage in queen-worker relationships. AB - Virgin queens (gynes) exhibit a range of behaviors in order to be accepted as the leader of colony. However, environmental neurotoxic insecticides as neonicotinoids may affect the social performance of the bees. Here, we evaluated the sublethal effects of neonicotinoid imidacloprid on the larval food of queens from Plebeia droryana, a species of neotropical stingless bee. Several behaviors were analyzed as multivariate response variables in a Hotelling test, as well as generalized additive mixed models. Our findings demonstrate that treated queens perform less wing vibration and trophallaxis with their workers. Furthermore, the treated gynes encounter more harassment (aggression) from their workers, suggesting that workers can differentiate nontreated queens from treated queens most likely by chemical signals. Our data indicate that the behavioral repertoire underlying the queen selection process by the stingless bee P. droryana may be seriously affected by residual doses of imidacloprid in larval food. As a result, such queens are rather undernourished and aggressed by workers, which most likely compromises the viability and permanence of colonies in the long term. PMID- 30245293 TI - Subacute intoxication with sodium nitrate induces hematological and biochemical alterations and liver injury in male Wistar rats. AB - Nitrate pollution has emerged as a problem of great importance because in recent years, the levels of nitrate in soil and groundwater have increased, mainly through anthropogenic activities, such as the use of fertilizers in agriculture, domestic wastewater and septic tanks, industrial waste and deforestation. In animals, nitrate reduction to nitrite (NO2) and nitric oxide (NO) promote the formation of methemoglobin in the blood and the generation of highly reactive intermediates that induce oxidative stress in target organs. Exposition to nitrates has been associated with methemoglobinemia, reproductive toxicity, metabolic and endocrine alterations and cancer. This study analyzed acute intoxication with sodium nitrate (NaNO3) in male Wistar rats, aged 12-16 weeks. Four groups with n = 10 rats each were formed: group 1 was the control, and group 2, group 3 and group 4 were treated for 10 days with intragastric doses of 19, 66 and 150 mg/kg/d NaNO3, respectively. Hematological, metabolic and histological biomarkers in the liver were analyzed. The results showed high percentages of methemoglobin, an increase in NO2 in the plasma and an accumulation in the liver. Moreover, there were high counts of white blood cells and platelets in all treated groups. Additionally, there was an increase in the spleen weight in group 4. High levels of glucose, triglycerides, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were observed and were significantly increased in groups 3 and 4. For oxidative stress biomarkers, there were increases in Thiobarbituric Acid Reactive Substances (TBARS), total GSH and SOD activity, mainly in group 4. Changes in mitochondrial activity were not significant. Histopathological analyses of the liver showed inflammation, infiltration of mononuclear cells, steatosis, ischemia and necrosis, and these findings were more evident at high doses of NaNO3 in which high of S nitrosylation were found. In conclusion, NaNO3 was reduced to NO2, thereby inducing methemoglobinemia, whereas other reactive species generated oxidative stress, causing hematological and metabolic alterations and injury to the liver. PMID- 30245294 TI - Toxicity evaluation of textile dyeing effluent and its possible relationship with chemical oxygen demand. AB - Textile dyeing wastewater was the focus of much research because of its adverse effect on aquatic biota. In the present research, textile dyeing influent and effluent samples were collected from four textile dyeing wastewater treatment plants (TDPs) in Guangdong province, China, and their conventional indicators and toxicity were examined to reveal relationships. The relationship between toxicity and chemical oxygen demand (COD) was clearly established at individual TDPs. Results indicated the highest removal efficiencies of 94.4%, 90.6%, 91.9%, 94.6%, 92.8% and 97.5% for TOC, mixed-liquor volatile suspended solids (MLVSS), COD, ammonia nitrogen (NH3-N), total phosphorus (TP) and colour, respectively. The primary clarifier used in TDP3 and TDP4 was beneficial for removing macromolecular organic substances, and membrane filtration and sedimentation basin employed at TDP1 and TDP2, respectively, helped to remove toxic substances. Toxicity to V. fischeri or D. subspicatus was found to be related to certain conventional indicators such as TOC, COD, TP, colour, and MLVSS, and was positively correlated with COD in different textile dyeing effluents (R2 > 0.84). It was recommended that the relationship between toxicity and COD in wastewater should be established individually at each plant. Therefore, this study could be useful in providing suggestions for guiding effluent management when no toxicity experiments were conducted. PMID- 30245295 TI - Design and characterization of immobilized biocatalyst with lipase activity onto magnetic magnesium spinel nanoparticles: A novel platform for biocatalysis. AB - Lipases (EC 3.1.1.3) are very used industrial enzymes but presents drawbacks such as lack of stability, and poor recyclability. Most of these obstacles can be solved by lipase immobilization. The objective of this work was evaluated to magnetic magnesium spinel nanoparticles as support for lipase immobilization by covalent bound. The techniques used for nanoparticles synthesis presented advantages in the size selection of the nanoparticles obtained (60-100 nm). The immobilization of Candida rugosa lipase (CRL) was optimized. The optimal conditions were determined to be pH 3.7, enzyme concentration of 1.1 mg/mL at 4 degrees C and an ionic strength of 100 mM. The CRL@MgFe2O4 activity obtained was 3.2 times over the starting conditions (4.03 U/mL). The immobilization of the lipase on Fe3O4 was evaluated and compared. The activity of the CRL@MgFe2O4 was 61% higher than CRL@Fe3O4 and 22% higher than free enzyme. CRL@MgFe2O4 improved the lipase stability at alkaline pH, hydrophilic solvent and high temperatures. The thermogravimetric analysis showed that this new biocatalyst was more stable compared to the free enzyme. Additionally, the immobilized lipase was recycled by magnetic force and used in ten catalysis cycles. The performance of the recycle was improved using butanol or Triton X 100 during washing. Finally, CRL@FeMg2O4 showed hydrolysis and synthesis activity. Thus, CRL@FeMg2O4 as a novel biocatalyst generation presents interesting properties for industrial applications. PMID- 30245296 TI - Fluorescent magnetic PEI-PLGA nanoparticles loaded with paclitaxel for concurrent cell imaging, enhanced apoptosis and autophagy in human brain cancer. AB - Magnetic nanoparticles are regarded as a promising drug delivery vehicle with the improved efficacy and lowered side effects for antitumor therapy. Herein, the poly lactic-co-glycolic acid (PLGA) modified magnetic nanoplatform was synthesized using superparamagnetic gamma-Fe2O3 nanoparticles (MNPs) as a core, and then labelled with polyethylenimine (PEI)-conjugated fluorescein isothiocyanate (FITC), and simultaneously loaded with antitumor drug paclitaxel (PTX) for theranostic analysis of antitumor effects investigated in human brain glioblastoma U251 cells. As a result, the prepared PEI-PLGA-MNPs showed a relatively round sphere with an average size of 80 nm approximately, and the FITC labeling PEI-PLGA-MNPs were efficiently endocytosed by the U251 cells for cellular imaging. Moreover, the fabricated PEI-PLGA-PTX-MNPs also demonstrated an inhibition of the targeted cell proliferation and migration, and a programmed cell death, via both apoptosis modulating by a burst of reactive oxygen species (ROS) and autophagy with accumulation of autophagosomes and LC3-II signals detected in the treated glioblastoma U251 cells after uptaking. Therefore, the constructed nanoplatform could be effectively applied for simultaneous cellular imaging and drug delivery in human brain glioblastoma treatment in future. PMID- 30245298 TI - Nanoscaled ultrasound contrast agents for enhanced sonothrombolysis. AB - Sonothrombolysis, the enhancement of thrombolysis with ultrasound (US), is widely used in clinical practice. The use of an ultrasound contrast agent can lead to a further reduced recanalization time of the occluded blood vessel and thus to better outcome for the patient. In this study the sonothrombolytic efficacy of our new nanoscaled ultrasound contrast agent (NUSCA) was investigated. This new contrast agent has a size of less than 100 nm and should thus be able to penetrate the thrombus and achieve a thrombolysis from inside out. In this study human whole blood clots were exposed to US, US and NUSCA, US and recombinant tissue plasminogen activator (rt-Pa) or urokinase (UK), or a combination of US, NUSCA and thrombolytic drug in a closed-loop flow model. We sonicated with diagnostic US at a frequency of 2.85 MHz for 30 min. Clot mass loss of 50.6 +/- 6.0% for the combination of US, NUSCA and rt-PA was found. Using UK as thrombolytic drug 57.7 +/- 9.0% clot mass loss could be seen. Thus the weight loss exceeded the conventional values of up to 30%. Scanning electron microscopy (SEM) images revealed changes of the fibrin network on the thrombus surface. The NUSCA was able to loosen the network and induce large pores in the thrombus surface. The high rates of clot mass loss and the obvious changings of fibrin structure make our NUSCA a promising tool for sonothrombolytic therapy. PMID- 30245297 TI - Novel electrospun polycaprolactone/graphene oxide/Fe3O4 nanocomposites for biomedical applications. AB - In this study, one of the most promising methods of tailoring a composite scaffold material in nano sized diameters, electrospinning method were used to produce Polycaprolactone (PCL)/Graphene Oxide (GO)/Iron(II, III) Oxide (Fe3O4) nanocomposite fibers as biocompatible scaffolds for biomedical applications. Products were analyzed by scanning electron microscopy (SEM) for morphological analysis of the electrospun nanocomposites and Fourier Transform Infrared Spectroscopy (FTIR) was used to determine functional groups of the PCL, GO, and Fe3O4 materials in the electrospun nanocomposites. For physical properties, viscosity, density, permittivity, dielectric loss and liquid and solid state alternating current conductivity, measurements were done for each nanocomposite fibers. Effects of concentration percentage of GO on permittivity, dielectric loss and AC conductivity have been analyzed by using measured and calculated data. Trend lines have been drawn for permittivity, dielectric loss and conductivity via concentration percentage of GO. The relation between ac conductivity and frequency have been studied for each concentration percentage of GO and interpretations have been done by using the obtained results. PMID- 30245299 TI - Morphophysiological responses and tolerance mechanisms of Xanthium strumarium to manganese stress. AB - Effective phytoremediation of manganese (Mn) requires the careful selection of a species that has a relatively high manganese tolerance. Exploring the physiological mechanisms related to Mn stress responses is crucial for identifying and employing species for Mn phytoremediation. Xanthium strumarium is a species that can accumulate high levels of Mn, thus it is a candidate species for Mn-phytoremediation. To reveal the tolerance mechanisms of this species to manage Mn stress, the morphological, physiological, and biochemical responses of seedlings grown in water cultures under six different Mn concentrations were analyzed. The results showed that X. strumarium can accumulate high levels of Mn, even as plant growth was inhibited by rising Mn concentrations. Malondialdehyde (MDA) content increased and catalase (CAT) activity decreased along with the increased Mn concentrations, while soluble protein and proline content, as well as the superoxide dismutase (SOD) and peroxidase (POD) enzymes, all increased initially and then declined. The highest value of POD, SOD, soluble protein and proline all occurred at 5000 uM of Mn stress, which means that X. strumarium can adapt to low concentration of Mn stress. The net photosynthetic rate (Pn), stomatal conductance (Gs), intercellular CO2 concentration (Ci) and transpiration rate (Tr) decreased, and the stomatal limitation (Ls) increased in response to Mn stress. Furthermore, water use efficiency (WUE) and intrinsic water use efficiency (WUEi) increased first under low concentration of Mn, and then reduced as the concentration of Mn increased. The maximum quantum efficiency of PSII photochemistry (Fv/Fm), efficiency of excitation capture by open PSII reaction centers (Fv'/Fm'), electron transport rate (ETR) declined as Mn concentration increased. In conclusion, the above results showed that X. strumarium can be effectively used for phytoremediation of Mn-contaminated soils. PMID- 30245300 TI - Response of the freshwater mussel, Dreissena polymorpha to sub-lethal concentrations of samarium and yttrium after chronic exposure. AB - Samarium (Sm) and yttrium (Y) are commonly used rare earth elements (REEs) but there is a scarcity of information concerning their biological effects in non target aquatic organisms. The purpose of this study was to determine the bioavailability of those REEs and their toxicity on Dreissena polymorpha after exposure to increasing concentration of Sm and Y for 28 days at 15 degrees C. At the end of the exposure period, the gene expression of superoxide dismutase (SOD), catalase (CAT), metallothionein (MT), glutathione-S-transferase (GST), cytochrome c oxidase 1 (CO1) and cyclin D (Cyc D) were analysed. In addition, we examined lipid peroxidation (LPO), DNA strand breaks (DSB), GST and prostaglandin cyclooxygenase (COX) activities. Results showed a concentration dependent increase in the level of the REEs accumulated in the soft tissue of mussels. Both REEs decreased CAT but did not significantly modulated SOD and MT expressions. Furthermore, Sm3+ up-regulated GST, CO1 and Cyc D, while Y3+ increased and decreased GST and CO1 transcripts levels, respectively. Biomarker activities showed no oxidative damage as evidenced by LPO, while COX activity was decreased and DNA strand breaks levels were changed suggesting that Sm and Y exhibit anti inflammatory and genotoxic effects. Factorial analysis revealed that the major impacted biomarkers by Sm were LPO, CAT, CO1 and COX, while GST gene expression, COX, Cyc D and CAT as the major biomarkers affected by Y. We conclude that these REEs display different mode of action but further investigations are required in order to define the exact mechanism involved in their toxicity. PMID- 30245301 TI - The past is prologue? The long arc of childhood trauma in a multigenerational study of teen mothering. AB - The purpose of this interpretive phenomenological study was to describe intergenerational patterns in adverse childhood experiences (ACE) and protective childhood experiences among teen mothers, their parents and children, and to include social disadvantage as a source of ACE. At the seventh wave of a study that has followed teen mothers and families beginning in 1988 for 28 years, 42 family members were reinterviewed in 2016. Adult participants also completed two tools that identify ACE and childhood family strengths. After narrative data were coded inductively, Interpretive Family Profiles were created to facilitate case and cross-case analysis. Of the 9 participating teen mothers at Time 7, 4 reported few ACE and many family strengths; their parents and children reported similar scores. Of the 5 mothers reporting high ACE, children's scores improved with one exception. Findings suggest that mothers' aspirations to shield their children from trauma was a fragile endeavor for mothers who faced ongoing trauma and economic hardships. Clinicians may facilitate intergenerational repair by capitalizing on mothers' aspirations with trauma-informed care and referrals to community resources. Trauma assessment should also include poverty-related ACE and experiences related to stigma and discrimination. PMID- 30245302 TI - Constraints to healthcare access among commercial fishers. AB - Fishing is a challenging occupation, in which physical and mental health risks may be exacerbated by environmental, socio-economic and policy change. While anecdotal information suggests that compared to other groups fishers are less likely to access healthcare, the reasons for this are poorly understood. Constraints to accessing healthcare were assessed through a mixed methods approach, using a holistic framework of access. A self-administered questionnaire was completed by 119 commercial fishers in Cornwall, UK, and complemented by qualitative focus groups with women from fishing communities. Health issues experienced and perceived constraints to healthcare access differed among fishers. Organisational factors and social norms were the most commonly perceived constraints, and stronger perception of these was associated with greater likelihood of leaving a health concern untreated in the past year. The findings suggest that proactive steps are needed to enhance supply and utilisation of available healthcare services, to ensure fishers' needs are met. PMID- 30245303 TI - Equity of a government subsidised exercise referral scheme: A population study. AB - BACKGROUND: Health inequities could increase if utilisation of physical activity interventions is lower among socioeconomically disadvantaged groups. We examined associations between area level socioeconomic disadvantage and utilisation of Australian government-subsidised, general practitioner (GP)-referred, accredited exercise physiologist (AEPs) services. METHODS: We conducted a cross-sectional analysis of Australian Medical Benefits Scheme (MBS) data (N = 228,771 AEP services) for the 2015-2016 financial year and aggregated publicly available data from several sources. Spearman's correlations examined associations between utilisation of AEP services and area-level socioeconomic disadvantage, indicated by Index of Relative Socioeconomic Disadvantage (IRSD) decile scores. Lower IRSD scores indicate greater levels of socioeconomic disadvantage. RESULTS: Significant correlations between IRSD score and study variables were as follows: Out-of-pocket expenses/service (rs = 0.52); number of patients/AEP provider (rs = -0.42); number of patients/1000 population (rs = -0.24); AEP services/1000 population (rs = -0.18); average services/patient (rs = 0.24); and AEP provider/1000 population (rs = 0.14). CONCLUSION: Patients living in areas of greater disadvantage utilised government-subsidised, GP-referred AEP services at a higher rate and paid lower out-of-pocket fees than those living in more affluent areas. Thus, AEP services are equitably distributed, from a utilisation perspective, and acceptable to patients living in areas of disadvantage. However, the higher caseloads and lower fees that characterise AEP services in areas of greater disadvantage may result in shorter consultation times. Further research on exercise referral schemes is warranted, particularly whether socioeconomic disadvantage is associated with adherence to exercise sessions and health outcomes. PMID- 30245305 TI - Action-related dynamic changes in inferior frontal cortex effective connectivity: A TMS/EEG coregistration study. AB - Humans show exquisite abilities to perform versatile finger movements. The inferior frontal cortex (IFC) plays a pivotal role in the visual control of such movements through connections with other sensorimotor regions. Yet, the dynamics of IFC effective connectivity during action execution are still poorly understood. Using single-pulse TMS and simultaneous EEG recording (i.e., TMS-EEG coregistration), we stimulated the left posterior IFC at rest and during a visuomotor task. We recorded TMS-evoked potentials (TEPs) to assess action related changes in IFC connectivity and localized their sources using sLORETA. We found two key time windows at ~60 and ~80 msec after IFC stimulation in which TEPs were modulated by task conditions in remote electrodes. In the first time window (~60 msec), action-related changes in TEP amplitudes were observed over frontal and temporo-parietal electrodes, reflecting increased IFC connectivity with fronto-parietal motor areas and decreased IFC connectivity with visual occipito-temporal areas. In the second time window (~80 msec), action-related TEP increases were observed in frontal, temporal and parietal regions partially overlapping with the default-mode network. No similar effects were observed when TMS was administered over a non-motor control area (the left posterior superior temporal sulcus, STS). These findings highlight dynamic changes in IFC connectivity with motor, sensory and default-mode networks. They suggest sequential stages of task-related changes in IFC connectivity possibly related to controlling and sensing actions and inhibiting default-mode brain activity during motor performance. PMID- 30245304 TI - SERPINB7 Expression Predicts Poor Pancreatic Cancer Survival Upon Gemcitabine Treatment. AB - Stratification of patients with pancreatic ductal adenocarcinoma (PDAC) remains a key challenge in the field of clinical oncology. No predictive biomarkers have yet been found for any available treatment options. Previously, we identified SERPINB7 as a putative biomarker for PDAC and thus, herein, we aimed to validate our previous findings and assessed the predictive value of SERPINB7. Patients who underwent surgery and received gemcitabine (gem) or gemcitabine plus nab paclitaxel (gem/nab) as adjuvant therapy, between 2011 and 2017, were included in this study (n = 57). Expression level of SERPINB7 was assessed in tumor tissue by immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH). Its association with disease-free survival (DFS) and overall survival (OS) was investigated. While IHC did not show any correlation between survival and the protein level of SERPINB7, RNA ISH revealed that expression of SERPINB7 was associated with a poor DFS (P = .01) and OS (P = .002) in the gem group but not in the gem/nab. Adjusted Cox-regression analysis confirmed the independent predictive value of SERPINB7 on OS (P = .006, HR: 3.47; 95% CI: 1.49-8.09) in the gem group. In conclusion, SERPINB7 was identified as the first predictive RNA biomarker for PDAC. This study suggests that patients who expressed SERPINB7 might receive another treatment than gem alone. PMID- 30245306 TI - Association between tumor necrosis factor-alpha-308G/A gene polymorphism and susceptibility to pre-eclampsia: An updated meta-analysis. AB - AIMS: Although two meta-analysis have reported no association between the tumor necrosis factor-alpha (TNF-alpha)-308G/A polymorphism and susceptibility to pre eclampsia (PE), recent studies showed the association was still controversial. Thus, we conduct an updated meta-analysis to elucidate this association. METHODS: Studies related to TNF-alpha-308G/A and PE risk were retrieved from PubMed, the Web of Science, Embase, Cochrane Library, CNKI, Wanfang, CBM, VIP Database. The odds ratios (OR) and 95% confidence intervals (CIs) were calculated to estimate the association between the TNF-alpha-308G/A polymorphism and susceptibility to PE under the models of allelic contrast (A vs. G), recessive (AA vs. AG+GG), dominant (AA+AG vs. GG), and co-dominant (AA vs. GG). RESULTS: 22 studies (including 2459 cases and 4246 controls) were included in the meta-analysis. The overall analysis indicated that the significant association between TNF-alpha 308G/A polymorphism and susceptibility to pre-eclampsia existed in allele model (A vs. G: OR = 1.37, 95%CI: 1.06-1.77), but not in dominant model, recessive model, and co-dominant model. In subgroup analysis by ethnicity, pre-pregnancy BMI and pregnancy parity, the results showed the significant association between TNF-alpha-308G/A polymorphism and the risk of PE was obvious in Caucasian (A vs. G: OR = 1.36, 95%CI: 1.13-1.64; AA vs. GG: OR = 1.71, 95%CI: 1.03-2.86; AA+AG vs. GG: OR = 1.32, 95%CI: 1.03-1.71), Iranian (A vs. G: OR = 4.28, 95%CI: 2.01-9.11), and primipara (A vs. G: OR = 1.49, 95%CI: 1.15-1.92; AA vs. GG: OR = 2.15, 95%CI: 1.10-4.21). CONCLUSION: Current evidence demonstrates that carriers of TNF-alpha (308A) allele would increase the susceptibility to PE, especially among Caucasian, Iranian and primipara. PMID- 30245307 TI - Shielding and relaxation in multitasking: Prospect of reward counteracts relaxation of task shielding in multitasking. AB - Performing two similar tasks at the same time requires the shielding of the prioritized Task 1 from interference of additional Task 2 processing (between task interference). In the present study we tested how motivational factors such as prospect of reward might drive shifts between increased proactive control, enabling task shielding, and reduced proactive control resulting in relaxed task shielding. In Experiment 1 an instruction-induced prioritization of Task 1 over Task 2 resulted in initially reduced between-task interference. With increasing time on task, however, between-task interference continuously increased, presumably because participants engaged less in proactive control resulting in reduced task shielding. In Experiment 2 the prospect of reward activated proactive control as indicated by reduced between-task interference in the Reward than in the No reward condition. In Experiment 3, we directly compared the performance of a Reward and a No reward group in a between-subject design. Whereas between-task interference again continuously increased over time in the No reward group, indicating a relaxed mode of task shielding, the Reward group displayed constant small between-task interference over time, suggesting maintained high levels of task shielding. Together these findings speak in favor of an impressive flexibility in regulating cognitive control engagement in multitasking situations. This not only shows the capacity for optimization of multitasking performance by motivational incentives but also further supports assumptions of the strategic nature of assumed processing limitations (bottlenecks) in dual-task performance. PMID- 30245308 TI - Solvent-free membrane extraction of volatile fatty acids from acidogenic fermentation. AB - Diversification of anaerobic digestion into higher value products, namely volatile fatty acids (VFAs), is receiving interest. One of the biggest challenges with this is recovery of the VFAs. Membrane extraction can be used, and a novel process configuration using a non-porous silicone membrane and water for an extractant is proposed here. This process would enable the reduction in the number of downstream unit operations compared to other membrane extraction processes. Selective recovery in favour of longer chain VFAs was demonstrated. Testing with a synthetic solution resulted in an overall mass transfer coefficient of 0.088 MUm s-1 for butyric acid, and 0.157 MUm s-1 when fermentation broth was used. This indicates this process is not hindered by fouling, but improved somehow. Although the preliminary economic analysis showed this process to require a larger membrane area compared to porous membrane alternatives, it also has a significantly reduced cost associated with the extractant. PMID- 30245309 TI - Influence of volatile fatty acids in different inoculum to substrate ratio and enhancement of biogas production using water hyacinth and salvinia. AB - The aim of the study was to explore the role of volatile fatty acids in batch scale anaerobic digestion of two potential aquatic weeds (water hyacinth and salvinia), as substrates for anaerobic digestion. Inoculum (cow dung) to biomass (aquatic weeds) ratio of 0.25:1, 0.5:1, 1:1 and 3:1 were taken and monitored in a 2 L digester for 30 days. The maximum amount of biogas produced for was 406 L kg 1 VS for water hyacinth in 0.5:1 and 330 L kg-1 VS for salvinia in 1:1 and 3:1 ratio for both. The total VFA for water hyacinth and salvinia were 410 mgL-1 & 365 mg L-1, 424 mg L-1 & 316 mg L-1, 272 mg L-1 & 234 mg L-1 and 158 mg L-1 & 94 mg L-1 in 0.25:1, 0.5:1, 1:1 and 3:1 ratios respectively. Multiple linear regression was performed to find the relationship between the methane from biogas, total VFA, acetic acid and propionic acid for enhanced biogas production. It was observed that total VFA significantly influenced methane content in 1:1 (SC) and 3:1 (WC). PMID- 30245310 TI - Influence of coal ash on potassium retention and ash melting characteristics during gasification of corn stalk coke. AB - This study experimentally investigated the potassium fixation ability and ash fusion characteristics during the gasification of corn stalk coke blended with coal ash in CO2 atmosphere. The ash samples were analyzed by X-ray diffraction (XRD) and scanning electron microscopy (SEM). FactSage was also employed to calculate the components and quantities of solid and liquid phase. The results show that the ratio of potassium retained in the biomass ash decreases with the increase in the gasification temperature. In addition, the retention ratio increases with more coal ash added. The improvement of potassium retention ratio is due to the reaction of potassium with alumina/silica to form the solid/slag phase of the potassium aluminosilicates. On the other hand, the ash fusion temperatures of the blended ash are increased by adding the coal ash, compared with the biomass ash. The study confirms that coal ash is a potential additive for not only fixing potassium, but also increasing the ash fusion temperatures of easy-to-slagging biomass. PMID- 30245312 TI - Enhancement of sucrose metabolism in Clostridium saccharoperbutylacetonicum N1-4 through metabolic engineering for improved acetone-butanol-ethanol (ABE) fermentation. AB - This work investigated sucrose metabolism in C. saccharoperbutylacetonicum. Inactivation of sucrose catabolism operon resulted in 28.9% decrease in sucrose consumption and 44.1% decrease in ABE production with sucrose as sole carbon source. Interestingly, a large amount of colloid-like polysaccharides were generated in the mutant, which might be due to inefficient intracellular sucrose metabolism. Deletion of transcriptional repressor gene successfully alleviated CCR and enhanced ABE production by 24.7%. Additional overexpression of endogenous sucrose pathway further elevated sucrose consumption and enhanced ABE production by 17.2%, 45.7%, or 22.5% compared to wild type with sucrose, mixed sugars or sugarcane juice as substrate, respectively. The engineered strain could be a robust platform for efficient biofuel production from inexpensive sucrose-based carbon sources. PMID- 30245311 TI - Evaluation of microbial p-chloroaniline degradation in bioelectrochemical reactors in the presence of easily-biodegrading cosubstrates: Degradation efficiency and bacterial community structure. AB - This study aimed to illustrate p-Chloroaniline (p-CIA) biodegradation efficiencies in bioelectrochemical reactors under stimulation by a low-voltage electric field (0.2 V versus Ag/AgCl) in the presence of easily-degrading cosubstrates including glucose and acetate. The biodegradation efficiencies of closed-circuit bioreactors were compared with those of open-circuit reactors. Experimental results showed that the six different bioreactors provided different p-CIA biodegradation efficiencies. The highest biodegradation efficiency of 38.5 +/- 10.3 mg/l was obtained in a closed-circuit bioreactor with acetate and the lowest biodegradation efficiency of 15.7 +/- 9.4 mg/l was obtained in an open circuit bioreactor. This difference may be attributed to the presence of electrical stimulation and acetate. The results for generated current and biodegradation efficiency indicated that acetate is a better cosubstrate than glucose. High-throughput sequencing technologies were used to characterise the bacterial community structure of the six bioreactors and revealed that different bacterial communities resulted in different treatment efficiencies. PMID- 30245313 TI - Isolation and characterization of biosurfactant producing and oil degrading Bacillus subtilis MG495086 from formation water of Assam oil reservoir and its suitability for enhanced oil recovery. AB - The strains isolated from the formation water were characterized and screened considering their crude oil degradation capability and biosurfactant production ability. The growth kinetics study of isolated Bacillus subtilis MG495086 was carried out by varying growth parameters i.e. carbon source, temperature, pH and salinity. The biosurfactant production was optimized adopting RSM-CCD considering carbon source (1-5%), pH (3-11) and temperature (25-65 degrees C) as matrix parameters. The optimum biosurfactant production (6.3 +/- 0.1 g/L) and the minimum surface tension 29.85 mN/m were obtained after 96 h of incubation under optimal conditions i.e. 3.8% (v/v) of light-paraffin oil as sole carbon source at 62.4 degrees C and pH 7.7 with the maximum oil degradation capability of 91.3 +/ 5%. Critical micelle concentration value of crude biosurfactant was found to be 40 mg/L with high emulsification activity of 72.45 +/- 0.85%. The produced biosurfactant was identified as lipopeptide (Surfactin) and characterized using various analytical techniques to establish its suitability for microbial enhanced oil recovery. PMID- 30245314 TI - Pre-treatment of corn stover, Cynara cardunculus L. stems and wheat straw by ethanol-water and diluted sulfuric acid: Comparison under different energy input conditions. AB - Ethanol-water (EW) and diluted sulfuric acid (DSA) pre-treatment have been studied for lignocellulosic biomass (corn stover, Cynara cardunculus L. stems and wheat straw). Both pre-treatments have been compared taken into account: solids recovery, glucans recovery, xylans removed, delignification and glucose yield. In all cases, the amount of energy involved has been taken as a criterion for sustainability. In general terms, EW is more efficient to remove lignin and DSA more appropriate to hydrolysate xylans. The combined effect of delignification and xylans removal is responsible for the improvement in the enzymatic cellulose hydrolysis. Under conditions of moderate-low energy inputs, EW pre-treatment yields better results than DSA with glucose yields in the range of 50-60% for EW pre-treated corn stover and cardoon stems; while wheat straw pulps reach up to 80%. So, multiple raw materials biorefinery needs a previous study to fit the type and conditions of the pre-treatment to each feedstock. PMID- 30245315 TI - Effects of ambient temperature and aeration frequency on emissions of ammonia and greenhouse gases from a sewage sludge aerobic composting plant. AB - This study analyzed emissions characteristics of NH3 and greenhouse gases (i.e. N2O, CH4, and CO2) from a municipal sewage sludge aerobic composting plant. Samples were collected during different seasons in which ambient temperatures and aeration frequencies varied. Results revealed (1) the maximum gas emissions occurred during the mesophilic phase for N2O (22%-56%) and CH4 (65%-95%), and in the thermophilic phase for NH3 (84%-86%) and CO2 (65%-74%); (2) raising ambient temperatures promoted emissions of NH3 and greenhouse gases, while improved aeration frequency increased NH3 but decreased greenhouse gas emissions; (3) CO2 and N2O were found to be the key greenhouse gases emitted during aerobic composting according to assessment of the CO2 equivalent. The results obtained from this study suggest that adjusting ambient temperature to -3 to 5 degrees C and aeration frequency in composting workshops can be useful approaches for the reduction of NH3 and greenhouse gas emissions from municipal sewage sludge composting plants. PMID- 30245316 TI - Comparative evaluation of the use of acidic additives on sewage sludge composting quality improvement, nitrogen conservation, and greenhouse gas reduction. AB - The aim of this study was investigated the effects of acidic additives apple pomace (AP), citric acid (CA), elemental sulphur (ES), phosphoric acid (PA), magnesium hydrogen phosphate (PM), and calcium superphosphate (CP)) on N conservation and greenhouse gas (GHG) emissions during sewage sludge composting. Results showed that adding the additives have no negative effects on compost hygienisation, but could improve the N conservation. Treatments with additives showed 2.56-5.48% N loss of initial N, which is lower than the control (9.73%). Compared to other compost products, ES- and PA-treatments had the lower NH3 volatilizations (0.80% and 0.98% of initial N, respectively) and germination index values (0.52 and 0.74, respectively), while the higher N2O emissions (2.48% and 2.29% of initial N, respectively) and salinities. Comprehensive evolution of N loss, GHG emissions and compost maturity in this study, the feasibility of using AP, CA, and PM in high-quality compost production is promising. PMID- 30245317 TI - Advanced treatment of the low concentration petrochemical wastewater by Tribonema sp. microalgae grown in the open photobioreactors coupled with the traditional Anaerobic/Oxic process. AB - In this paper, the filamentous microalgae Tribonema sp. grown in the open photobioreactors (PBRs) was directly integrated with the traditional Anaerobic/Oxic (A/O) process for the advanced treatment of low concentration petrochemical wastewater. The COD removal rate was only 71.7% after direct treatment of wastewater effluent from the primary clarifier in the open PBRs, while in-depth purification could be achieved in the secondary clarifier with COD removal rates reached to 97.8% in the open PBRs. The NH3-N and P of the two effluents were almost completely removed after 5-7 days in the open PBRs. The biomass concentration, productivity and the oil content in the open PBRs with the secondary clarifier effluent were all higher than those in the primary clarifier group. The filamentous microalgae Tribonema sp. as a post-treatment step for the A/O process can achieve deep removal of the pollutants and accumulate higher biomass concentration and oil content. PMID- 30245319 TI - Sodium chloride incites reactive oxygen species in green algae Chlorococcum humicola and Chlorella vulgaris: Implication on lipid synthesis, mineral nutrients and antioxidant system. AB - In the present study, microalgae Chlorococcum humicola and Chlorella vulgaris were grown in different concentrations of NaCl (25-1000 mM) to elucidate its impact on morphology, lipid synthesis, minerals status and antioxidative responses. Scanning Electron microscopy showed distorted cell morphology and increased cell size by 33.52% (C. humicola) and 27.79% (C. vulgaris) at 100 mM NaCl. Energy Dispersive Spectroscopy data revealed reduction in mineral contents (C, S, Fe, Mg, Si, Mn and Zn) by 14-54% in both algae. Further, C. humicola was found to have high lipid content than C. vulgaris under NaCl regime. The activities of superoxide dismutase, catalase and glutathione reductase were increased by 2.5-5 folds in both algae as compared to control. The increased level of ascorbate, cysteine and proline in both algae indicated tolerance against salinity. Thus, C. humicola and C. vulgaris may exhibit dual benefits viz., high lipid production and reclamation of sodic soil. PMID- 30245318 TI - Biodegradation of oxytetracycline and electricity generation in microbial fuel cell with in situ dual graphene modified bioelectrode. AB - A three-step method to prepare dual graphene modified bioelectrode (D-GM-BE) in microbial fuel cell (MFC) in previous studies. This study explored the biodegradation of oxytetracycline (OTC) and electricity generation in O-D-GM-BE MFC. The OTC removal efficiency of graphene modified biocathode and bioanode (O GM-BC, O-GM-BA) was 95.0% and 91.8% in eight days. The maximum power density generated by O-D-GM-BE MFC was 86.6 +/- 5.1 mW m-2, which was 2.1 times of that in OTC control bioelectrode (O-C-BE) MFC. The Rct of O-GM-BA and O-GM-BC were decreased significantly by 78.3% and 76.3%. OTC was biodegraded to monocyclic benzene compounds by bacteria. O-GM-BA was affected strongly by OTC, and Salmonella and Trabulsiella were accounted for 83.0%, while typical exoelectrogens (Geobacter) were still enriched after the maturity of biofilm. In O-GM-BC, bacteria related with OTC biodegradation (Comamonas, Ensifer, Sphingopyxis, Pseudomonas, Dechloromonas, etc.) were enriched, which contributed to the high removal efficiency of OTC. PMID- 30245320 TI - New coculture system of Clostridium spp. and Megasphaera hexanoica using submerged hollow-fiber membrane bioreactors for caproic acid production. AB - In this study, a coculture bioprocess was developed with Clostridium strains producing butyric acid and Megasphaera hexanoica producing caproic acid from the butyric acid. The two bacterial strains were each cultivated in two submerged hollow-fiber membrane bioreactors (s-HF/MBRs), separately. Each fermentation broth was filtered through the membrane modules, and the filtered broth was either interchanged on another reactor or obtained sequentially through. Using s HF/MBRs, the caproic acid concentration increased to 10.08 g L-1, with the fastest productivity of 0.69 g L-1 h-1, which higher than that previously reported. PMID- 30245321 TI - Enhancement of biomass, lipids, and polyunsaturated fatty acid (PUFA) production in Nannochloropsis oceanica with a combination of single wavelength light emitting diodes (LEDs) and low temperature in a three-phase culture system. AB - A three-phase culture system combining blue (465 nm) light-emitting diode (LED) wavelength as the first phase, green (550 nm) as the second phase, and temperature stress as the third phase was applied to a Nannochloropsis oceanica culture in 14-L photobioreactors. Microalgal growth promotion parameters were optimized in the first phase, followed by green LED stress for lipid production in the second phase. Maximum biomass and lipid production values of 0.75 gdcw L-1 and 57.6% (w/w) were obtained at an aeration rate of 0.50 vvm, with a light intensity of 250 umol m-2 s-1 and 24:0 h light/dark cycle. Culture temperatures of 15, 10 and 5 degrees C were applied in the third phase, where temperature stress induced the production of monounsaturated and polyunsaturated fatty acid synthesis in N. oceanica. The production of alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid increased by 52% (w/w), 96% (w/w), and 77% (w/w), respectively, at 5 degrees C in the third phase. PMID- 30245322 TI - An integrated microfluidic platform to perform uninterrupted SELEX cycles to screen affinity reagents specific to cardiovascular biomarkers. AB - As cardiovascular diseases (CVD) are responsible for millions of deaths annually, there is a need for rapid and sensitive diagnosis of CVD at earlier stages. Aptamers generated by systematic evolution of ligands by exponential enrichment (SELEX) processes have been shown to be superior to conventional antibody-based cardiac biomarker detection. However, SELEX is a complicated, lengthy procedure requiring multiple rounds of extraction/amplification and well-trained personnel. To circumvent such issue, we designed an automated, miniaturized SELEX platform for the screening of aptamers towards three protein biomarkers associated with CVDs: N-terminal pro-peptide of B-type natriuretic peptide, human cardiac troponin I, and fibrinogen. The developed microfluidic platform was equipped with microfluidic devices capable of sample transport and mixing along with an on-chip nucleic acid amplification module such that the entire screening process (5 rounds of selection in 8 h.) could be performed consecutively on a single chip while consuming only 35 uL of reagents in each cycle. This system may therefore serve as a promising, sensitive, cost-effective platform for the selection of aptamers specific for CVD biomarkers. PMID- 30245323 TI - Oxygen reduction reaction activity and the microbial community in response to magnetite coordinating nitrogen-doped carbon catalysts in bioelectrochemical systems. AB - A Fe-N-C catalyst is supposed to drive commercialization of microbial fuel cells (MFCs) because of its remarkable catalytic performance on oxygen reduction reaction (ORR). However, the catalyst suffers from unclear active site structure and unknown responses of the cathodic microbial community. Here, we prepared a mesoporous core-shell structure catalyst with a nitrogen doped matrix carbon shell, and a Fe3O4 core (Fe3O4@N-mC) as efficient cathode catalysts for the oxygen reduction reaction (ORR). The resulting hybrid electrocatalyst (Fe3O4@N mC) showed higher limiting current density (2.94 mA cm-2), lower H2O2 yield (7.2 12.7%), and a higher electron transfer number (3.74-3.85) for ORR activity than its intermediates, including Fe3O4, polyaniline (PANI), nitrogen doped carbon (N C), and magnetic polyaniline composite (Fe3O4@PANI). In MFC tests, Fe3O4@N-mC produced a power density of 0.73 W m-2, which was 2.14 times of N-C (0.34 W m-2), 3.84 times of Fe3O4@PANI (0.19 W m-2), and more than four times of Fe3O4 (4.29, 0.17 W m-2) and PANI (4.87, 0.15 W m-2). Illumina sequencing of 16S rRNA gene amplicons and non-metric multi-dimensional scaling (NMDS) indicated distinct separation of the cathode biofilm bacterial communities between MFCs with different cathodic catalysts. MFCs with the Fe3O4@N-mC cathode facilitated the enrichment of putative exoelectrogenic Dietzia. Our findings suggest that enhancing ORR performance of Fe3O4@N-mC in MFCs can be attributed to the co effects of Fe and N, the core-mesoporous shell structure, and various nitrogen functionalities. PMID- 30245324 TI - Aptamer functionalized MoS2-rGO nanocomposite based biosensor for the detection of Vi antigen. AB - We report a novel aptamer functionalized MoS2-rGO based electrochemical method for Vi polysaccharide antigen mediated detection of enteric fever. Herein, highly selective anti-Vi aptamers were screened from a pool of oligonucleotides using a microtitre based SELEX approach and characterized for its specificity and stability. The MoS2-rGO nanocomposite was synthesized using a liquid assisted exfoliation by taking optimum ratio of MoS2 and rGO. The nanocomposite presented synergistic effect owing to easy biomolecular functionalization and enhanced conductivity. The screened anti-Vi aptamers were embedded on the MoS2-rGO nanocomposite via thiol linkage to give a stable biointerface. The developed aptasensor was characterized and further evaluated for its performance with different concentrations of Vi antigen using ferrocene labeled boronic acid as an electroactive probe. The aptasensor responded linearly in the range between 0.1 ng mL-1 to 1000 ng mL-1with a detection limit of 100 pg mL-1, and did not show any cross-reactivity with other bacterial polysaccharides indicating high specificity. The applicability of the developed aptasensor was further validated in urine and sera specimens spiked with Vi antigen. PMID- 30245325 TI - Melanin-based electronics: From proton conductors to photovoltaics and beyond. AB - The successful interfacing of electronics with biology is the next frontier for microelectronics and nanotechnology. Melanin, a naturally occurring conjugated polymer composed of different structural subunits, may be an ideal candidate for such interfacing. In the solid-state, the large broadband molar attenuation coefficient of melanin over the visible spectrum implicates potential applications as a semiconductor for light harvesting and light detection. Additionally, the conductance of melanin has been shown to increase with hydration, making this irregular polymer a hybrid electronic-protonic conductor. While the precise mechanism of charge transfer in melanin is not well understood, the hydration dependence of conductance has been tapped to utilize melanin-based devices in a variety of roles, such as humidity sensors and pH detectors. The applications of melanin active layers in OLEDs, OPVs and OFETs have been explored. The viability of this polymer has also been validated inside biological systems, showing the potential for creating electronic devices that are biocompatible. This paper reviews the status of melanin towards achieving biocompatible electronics. PMID- 30245326 TI - An integrated portable system for single chip simultaneous measurement of multiple disease associated metabolites. AB - Metabolites, the small molecules that underpin life, can act as indicators of the physiological state of the body when their abundance varies, offering routes to diagnosis of many diseases. The ability to assay for multiple metabolites simultaneously will underpin a new generation of precision diagnostic tools. Here, we report the development of a handheld device based on complementary metal oxide semiconductor (CMOS) technology with multiple isolated micro-well reaction zones and integrated optical sensing allowing simultaneous enzyme-based assays of multiple metabolites (choline, xanthine, sarcosine and cholesterol) associated with multiple diseases. These metabolites were measured in clinically relevant concentration range with minimum concentrations measured: 25 MUM for choline, 100 MUM for xanthine, 1.25 MUM for sarcosine and 50 MUM for cholesterol. Linking the device to an Android-based user interface allows for quantification of metabolites in serum and urine within 2 min of applying samples to the device. The quantitative performance of the device was validated by comparison to accredited tests for cholesterol and glucose. PMID- 30245327 TI - Impedimetric biosensor for detection of cancer cells employing carbohydrate targeting ability of Concanavalin A. AB - The successful development of selective detection of cancer cells from normal cells is a highly demanded but challenging task. Herein, we have developed a rapid and label-free impedimetric biosensor for quantitative determination of cancer cells with high glycoprotein expression. Homogenously distributed 2-9 nm graphene quantum dots (GQDs) was anchored on the surface Fe3O4 through covalent bonding. Concovalin A (ConA) was then adhered onto GQDs by physical mixing to fabricate ConA-GQD@Fe3O4 nanosensing probe. A good dynamic range in the cell concentration of 5 * 102-1 * 105 cells mL-1 with LOD values of 246 and 367 cells mL-1 for HeLa and MCF-7, respectively, is obtained. The impedimetric responses to the cancerous HeLa and MCF-7 cells are 16.7 and 13.1 times higher than those of their original sensor electrodes. However, the interaction between sensing probe and normal MCF-10 and bEnd.3 cells is negligible, confirming the specific selectivity toward cancer cells. Cellular uptake images as well as in-vitro cytotoxicity corroborates the electrochemical results. In addition, the successful detection of cancer cells in human serum and circulating tumor cells in blood sample envisions the feasibility of using ConA-GQD@Fe3O4 as the nanosensing probe for clinically early diagnosis of cancer cells with high glycoprotein expression. PMID- 30245328 TI - The corticosteroid prednisolone increases amygdala and insula reactivity to food approach signals in healthy young men. AB - Short- and long-term treatment with glucocorticoids is widely used in clinical practice and frequently induces features of iatrogenic Cushing syndrome, such as abdominally centered weight gain. Despite decades of glucocorticoids usage, the mechanisms underlying these side effects are still only partly understood. One possibility is that glucocorticoids impact subcortical (hypothalamus, amygdala, insula) and cortical (orbitofrontal and cingulate cortex) brain regions involved in appetite regulation and reward processing. In the present study, we used functional magnetic resonance imaging (fMRI) to study the acute effects of a prednisolone infusion on reactivity of brain reward systems to food stimuli. Twenty healthy normal-weight men were tested in a randomized, double-blind, cross over study. After an overnight fast and infusion of either 250 mg prednisolone or placebo (always administered between 8 and 9 A M), fMRI scans were taken while presenting food and object pictures in a Go/NoGo (GNG) task. At home, participants were asked to register what they had eaten. On the following morning they came back to the lab and had a supervised ad libitum breakfast at a standardized buffet. Food-Go in contrast to Object-Go pictures yielded increased blood oxygen level dependent (BOLD) activity in hippocampus, amygdala, orbitofrontal cortex, insula and anterior cingulate cortex. Prednisolone increased activation in the bilateral amygdala and right insula for approach associated food pictures. The buffet test did not reveal significant differences in calorie consumption or preferences of different macronutrients. However, prednisolone-induced insula reactivity to Food-Go images was associated with greater caloric intake, both at home and in the standardized buffet. In sum, we observed a specific effect of prednisolone on the BOLD response of the amygdala and insula to approach-associated food stimuli. As these brain areas have previously been implicated in hedonic eating, the present pattern of results may reflect an increased anticipated reward value of food modulated by glucocorticoids. These effects might potentially drive increased food intake and weight gain under prolonged glucocorticoid treatment. PMID- 30245330 TI - Post-exposure cortisol administration does not augment the success of exposure therapy: A randomized placebo-controlled study. AB - Cortisol administration prior to treatment can promote the efficacy of exposure based treatments in specific phobia: cortisol has been proposed to reduce fear retrieval at the beginning of exposure and to enhance the acquisition and consolidation of corrective information learned during exposure. Whether cortisol exerts a beneficial therapeutic effect when given after exposure, e.g., by targeting the consolidation of new corrective information, has not been addressed so far to date. Here, we examined whether post-exposure cortisol administration promotes fear reduction and reduces return of fear following contextual change in specific phobia. Furthermore, the effect of cortisol on return of fear following contextual change (i.e., contextual renewal) was assessed. Patients with spider phobia (N = 43) were treated with a single session of in-vivo exposure, followed by cortisol administration (20 mg hydrocortisone) in a double-blind, placebo controlled study design. Return of fear was assessed with behavioral approach tests (BATs) in the familiar therapy context (versus a novel unfamiliar context) at one-month and seven-month follow-up assessment. Exposure was effective in reducing fear from pre-treatment to post-treatment (i.e., 24 h after exposure) on fear-related behavioral (approach behavior during the BAT), psychophysiological (heart rate during the BAT) and subjective (fear during the BAT, spider-fear related questionnaires) measures of therapeutic outcome, with no add-on benefit of cortisol administration. Cortisol had no effect on contextual renewal at one month follow-up. However, in a subsample (N = 21) that returned to the seven month follow-up, an adverse effect of cortisol on fear renewal was found, with cortisol-treated patients showing an increase in subjective fear at the final approach distance of the BAT from post-treatment to seven-month follow-up. These and previous findings underline the importance of considering the exact timing of cortisol application when used as an add-on treatment for extinction-based psychotherapy: post-exposure cortisol administration does not seem to be effective, but might promote fear renewal at the subjective level. PMID- 30245329 TI - Pregnancy anxiety predicts shorter gestation in Latina and non-Latina white women: The role of placental corticotrophin-releasing hormone. AB - OBJECTIVE: Previous research has shown that a woman's anxiety about her pregnancy predicts gestational length. Placental corticotrophin-releasing hormone (CRH) is a stress-responsive peptide proposed as a mechanism. We examined placental CRH as a physiological mediator of the association between pregnancy anxiety and gestational length in Latina and non-Latina White women to replicate evidence of associations between pregnancy anxiety, placental CRH and gestational length; to test whether placental CRH levels or changes mediate effects of pregnancy anxiety on gestational length; to examine ethnic differences in pregnancy anxiety, placental CRH, and gestational length; and to explore whether the effects of pregnancy anxiety on gestational length as mediated by placental CRH vary by ethnicity. METHODS: In a prospective study of 337 pregnant Latina and non-Latina White women, participants completed in-person interviews that included a 10-item measure of pregnancy anxiety and provided blood samples assayed using radioimmunoassay at three timepoints (19, 25, and 31 weeks gestation). RESULTS: Pregnancy anxiety at 19 and 31 weeks and levels of placental CRH at 31 weeks predicted gestational length. Tests of indirect effects were consistent with mediation such that both pregnancy anxiety at 19 weeks and increases from 19 to 31 weeks predicted placental CRH at 31 weeks, which in turn predicted gestational length. Tests of moderated mediation by ethnicity showed that the mediated effect of placental CRH at 31 weeks was significant for Latinas only. CONCLUSIONS: These findings add to growing evidence of the involvement of pregnancy anxiety in the timing of birth, address mechanisms, and suggest possible ethnic differences. PMID- 30245331 TI - Analysis of clinical and pathological findings in inflammatory fibroid polyps of the gastrointestinal system: A series of 69 cases. PMID- 30245332 TI - Evaluation of factors involved in the failure of ovum capture in superovulated buffaloes. AB - The aim of this work was to evaluate factors affecting ovum capture in superovulated buffaloes, by comparing the morphological features of pre-ovulatory follicles and oocytes, the intrafollicular and plasmatic steroid profile, as well as the expression of genes involved in cumulus expansion and steroid cascade in granulosa cells (GCs) and that of genes involved in contraction-relaxation of the oviduct between superovulated and synchronized buffaloes. Italian Mediterranean Buffalo cows were either synchronized by Ovsynch (n = 25) and superovulated (n = 10) with conventional FSH protocol and sacrificed 18 h after last GnRH. Antral follicular count, recovery rate and oocyte quality were recorded, and plasma and follicular fluid were collected for steroid profile determination. In addition, in 10 animals (5/group), GCs were collected to analyse the mRNA expression of gonadotropin receptors (LHR and FSHR) and genes involved in steroid synthesis, as the cytochrome P450 family 19 (CYP19A1) and the steroidogenic acute regulatory protein (STAR). Moreover, oviducts were collected to evaluate the mRNA expression of estrogen receptor 1 (ER1) and the progesterone receptor (PGR), the vascular endothelial growth factor (VEGF) and the VEGF receptors, i.e. the kinase insert domain receptor (FLK1) and the fms related tyrosine kinase 1 (FLT1). No differences were recorded in steroids plasma concentration between synchronized and superovulated animals whereas intrafollicular E2 and P4 concentrations decreased in superovulated group (63.2 +/- 10.6 vs 30.3 +/- 5.9 ng/mL of E2 and 130.1 +/- 19.8 vs 71.6 +/- 8.5 ng/mL of P4, respectively in synchronized and superovulated animals; P < 0.05). Interestingly, both the recovery rate (85.7% vs 56.6%, respectively in synchronized and in superovulated animals; P < 0.05) and the percentage of oocytes exhibiting proper cumulus expansion (75% vs 28.1%, respectively in synchronized and in superovulated animals; P < 0.01) decreased in superovulated animals. In addition, the expression of FSHR and CYP19A1 increased while the expression of STAR in GCs decreased (P < 0.05). Finally, in superovulated buffaloes a decreased expression of PGR, ER1, VEGF and its receptor FLK1 in the oviduct was observed. The results suggest that the exogenous FSH treatment impairs steroidogenesis, affecting both the oviduct and the ovarian function, accounting for the failure of ovum capture in superovulated buffaloes. PMID- 30245333 TI - Distribution of DNA damage in the sperm nucleus: A study of zebrafish as a model of histone-packaged chromatin. AB - Reproductive defects can occur when the integrity of the male gamete genome is affected. Sperm chromatin is not homogeneous, having relaxed regions which are more accessible to the transcription machinery in the embryo, and thought to be specially sensitive to DNA damage. The level of damage in specific genes located in these sensitive regions could represent an early biomarker of damage. Our objective is to test the hypothesis that these more relaxed regions show greater susceptibility to damage in zebrafish, a species lacking protamines and whose sperm chromatin is compacted with histones. After sperm UV irradiation, treatment with H2O2 and cryopreservation, global chromatin fragmentation was evaluated using the TUNEL assay, and the number of lesions per 10 Kb in specific genes (hoxa3a, hoxb5b, sox2, accessible for early transcription and rDNA 18S and rDNA 28S) was quantified by using a qPCR approach. Additionally, oxidative damage within the sperm nucleus and the potential colocalization of this injury with histone H3 and TOPO IIalpha+beta were located by using immunofluorescence. UV irradiation produced the highest degree of fragmentation (p = 0.041) and the highest number of lesions per 10 Kb in all the genes, but no differences were observed in sensitivity to damage in the studied genes (ranging from 14.93 to 8.03 lesions per 10 Kb in hoxb5b and 28S, respectively). In contrast, H2O2 and cryopreservation caused varying levels of damage in the analyzed genes which was not related to their accessibility, ranging from 0.00 to 1.65 lesions per 10 Kb in 28S and hoxb5b, respectively, after H2O2 treatment, and from 0.073 to 5.51 in 28S and sox2, respectively, after cryopreservation. Immunodetection near oxidative lesions also revealed different spatial patterns depending on the treatments used, these being mostly homogeneous with UV irradiation or cryopreservation, and peripherally located around the nucleus after H2O2 treatment. Oxidative lesions did not colocalize with histone H3 or TOPO IIalpha+beta, thus demonstrating that the relaxed DNA regions associated with these proteins were not more vulnerable to oxidative damage. Results suggest that accessibility of each agent to the nucleus could be the main factor responsible for the distribution of sperm DNA damage rather than the organization of the chromatin. Lesions in these genes important to early embryo development assayed in this study cannot be used as biomarkers of global DNA damage. PMID- 30245334 TI - Effect of metritis on endometrium tissue transcriptome during puerperium in Holstein lactating cows. AB - The objective of this prospective cohort study was to evaluate the effect of parity and uterine health status postpartum on the gene expression profile of the endometrium early post-partum. Twenty-four Holstein cows were randomly selected (16 multiparous (MP) and 8 primiparous (PP)) and endometrium biopsies were collected on days 1, 3, and 6 after calving and clinically monitored for metritis. Rectal temperature was measured twice and fever was defined as a temperature >=39.5 degrees C. A case of metritis was diagnosed with the presence of red-brown watery, foul-smelling uterine discharge or a purulent discharge with more than 50% pus and fever between days 1 and 6 postpartum. Cows were then retrospectively selected (cows diagnosed with metritis were paired with healthy ones) to analyze the expression of 66 genes measured on the NanoString nCounter Analysis System. The genes selected were related with adhesion, immune system, steroid and prostaglandin biosynthesis regulation, insulin metabolism and transcription factors, and nutrient transporters. The results indicated a different pattern on genes related to immune function by parity. PTX3, involved in antigen presentation, was increased in healthy MP compared with healthy PP whereas inflammatory cytokine TNFalpha and complement-related protein SERPING1 was upregulated in MP compared with PP (P < 0.05). As expected, presence of a metritis condition affected the expression of genes related to immune function. There was an increased expression of the antiviral factor MX2 and MYH10 gene, which is involved in macrophages recruitment, in metritic compared with healthy cows (P < 0.05). Differences in uterine involution from cows diagnosed with metritis were reflected by the downregulation of IGF1 (P < 0.10), involved in endometrium remodeling, and a possible compensatory upregulation of its receptor IGFR1 (P < 0.05). A greater expression of prostaglandins and oxytocin receptors (PGR and OXTR), involved in the involution process, were observed in metritic PP compared with healthy PP (P < 0.05). Overall, it seems that metritis significantly modulate processes closely tied with the physical involution of the uterus early post-partum (IGF1, IGFR1, PGR, OXTR), whereas both metritis and multiparous cows tended to upregulate genes related to immune response (PTX3, TNFalpha, SERPING1, MX2, MYH10). PMID- 30245335 TI - Western diet given to healthy rats mimics the human phenotype of diabetic cardiomyopathy. AB - Diabetes mellitus (DM) is a major problem worldwide. Within this patient group, cardiovascular diseases are the biggest cause of morbidity and mortality. Diabetic cardiomyopathy (DCM) is defined as diabetes-associated structural and functional changes in the myocardium, not directly attributable to other confounding factors such as coronary artery disease or hypertension. Pathophysiology of DCM remains unclear due to a lack of adequate animal models reflecting the current pandemic of diabetes, associated with a high increased sugar intake and the 'Western' lifestyle. The aim of this study was to develop an animal model mimicking this 'Western' lifestyle causing a human-like phenotype of DCM. Twenty-four Sprague-Dawley rats were randomly assigned into a normal or a 'Western' diet group for 18 weeks. Glucose and insulin levels were measured with an OGTT. Heart function was assessed by echocardiography and hemodynamic measurements in vivo. Cardiac fibrosis and inflammation were investigated in vitro. 'Western' diet given to healthy rats for 18 weeks induced hyperglycemia together with increased AGEs levels, insulin levels and hypertriglyceridemia. Heart function was altered with increased end-diastolic pressure, left ventricle hypertrophy. Changes in vivo were associated with increased collagen deposition and increased PAI-1 levels in the heart. High-sugar diet or 'Western' diet causes T2DM and the hallmarks of DCM in rats, reflecting the phenotype of the disease seen in patients. Using this new model of T2DM with DCM might open new insight in understanding the pathophysiology of DCM and on a long term, test targeted therapies for T2DM with DCM patients. PMID- 30245336 TI - M1 macrophage subtypes activation and adipocyte dysfunction worsen during prolonged consumption of a fructose-rich diet. AB - Fructose-rich diet (FRD) has been associated with obesity development, which is characterized by adipocytes hypertrophy and chronic low-grade inflammation. Interaction of adipocytes and immune cells plays a key role in adipose tissue (AT) alterations in obesity. We assessed the metabolic and immune impairments in AT in a murine obesity model induced by FRD at different periods. Adult Swiss mice were divided into groups of 6 and 10 weeks of fructose (FRD 6wk, FRD 10wk) or water intake (CTR 6wk, CTR 10wk). FRD induced increased in body weight, epidydimal AT mass, and plasmatic and liver Tg, and impaired insulin sensitivity. Also, hypertrophic adipocytes from FRD 6wk-10wk mice showed higher IL-6 when stimulated with LPS and leptin secretion. Several of these alterations worsened in FRD 10wk. Regarding AT inflammation, FRD mice have increased TNFalpha, IL-6 and IL1beta, and decrease in IL-10 and CD206 mRNA levels. Using CD11b, LY6C, CD11c and CD206 as macrophages markers, we identified for first time in AT M1 (M1a: Ly6C+/-CD11c+CD206- and M1b: Ly6C+/-CD11c+CD206+) and M2 subtypes (Ly6C+/ CD11c-CD206+). M1a phenotype increased from 6 weeks onward, while Ly6C+/- M1b phenotype increased only after 10 weeks. Finally, co-culture of RAW264.7 (monocytes cell line) and CTR or FRD adipocytes showed that FRD 10wk adipocytes increased IL-6 expression in non- or LPS-stimulated monocytes. Our results showed that AT dysfunction got worse as the period of fructose consumption was longer. Inflammatory macrophage subtypes increased depending on the period of FRD intake, and hypertrophic adipocytes were able to create an environment that favored M1 phenotype in vitro. PMID- 30245337 TI - Deuterated phytantriol - A versatile compound for probing material distribution in liquid crystalline lipid phases using neutron scattering. AB - Phytantriol is an interfacially-active lipid that is chemically robust, non digestible and forms particles with internal bicontinuous cubic phase structures (cubosomes) when dispersed with non-ionic surfactants at ambient and physiological temperatures. The liquid crystalline internal structure of phytantriol-based cubosomes can be changed to alter the interfacial contact area/topology with the aqueous dispersant to trigger bioactive payload release or to alter the local membrane curvature around bound or embedded proteins. To enable the study of payload distribution, structure and transformation kinetics within phytantriol particles by neutron scattering techniques it is desirable to have access to a deuterated version of this molecule but to date a synthetic route has not been available. The first successful synthesis of phytantriol-d39 is presented here alongside a preliminary physical characterisation of related particle structures when phytantriol-d39 is dispersed using two non-ionic surfactants, Tween(r) 80 and Pluronic(r) F127. Synchrotron small angle X-ray scattering (SAXS) was used to confirm that phytantriol-d39-based nanoparticles in D2O form similar liquid crystalline structures to those of their natural isotopic abundance (phytantriol/H2O) counterparts as a function of temperature. Finally, small angle neutron scattering (SANS) with solvent contrast to match out the phytantriol-d39 structuring was used to show that the spatial correlations between the Tween(r) and Pluronic(r) non-ionic surfactant molecules are different within dispersed phytantriol-d39 particles with different liquid crystalline structures in D2O. The surfactant molecules in phytantriol-d39/Tween(r) 80 particles with Im3m cubic structures were found to follow a self-avoiding walk, whereas in phytantriol-d39/Pluronic(r) F127 particles with Pn3m cubic structures they were found to follow a more rod-like packing arrangement. PMID- 30245338 TI - Enhancing adsorption capacity of Egyptian diatomaceous earth by thermo-chemical purification: Methylene blue uptake. AB - In the current study, calcination and thermo-chemical methods were applied in treatment of the processed diatomite fraction (<45 MUm), which containing nearly 82.6 wt.% of the raw Egyptian diatomaceous earth. The untreated and modified diatomite fractions were characterized by optical microscopy (OM), X-ray fluorescence (XRF), X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT-IR). Thermo-chemical purification produced the highest concentration of diatom frustules (>92% SiO2) without blocking impurities and created SiOSi active sites. These fractions were tested for Methylene blue (MB) adsorption at different pH solutions (2.0-10.0). The purified diatomite via thermo-chemical treatment (PD) gave the greatest adsorption capacity for MB compared to the untreated (UD) and calcinated (CUD) diatomite fractions. Effects of experimental parameters such as MB concentration (60-200 mg L-1), contact time (5-480 min), adsorbent mass (50-250 mg) and temperature (30-55 degrees C) on MB uptake were investigated. Linear and non linear forms of Langmuir, Freundlich and Dubinin-Radushkevich (D-R) models indicated that Langmuir model with a maximum adsorption capacity (qmax=105.03mgg 1) fitted well the adsorption data. The chemical nature of MB uptake was revealed by the values of mean free energy E=8.655kJ/moland correlation coefficient of the pseudo-second-order model (R2=0.9997). The calculated thermodynamic parameters (DeltaH0, DeltaG0 and DeltaS0) indicated that the removal of MB is spontaneous and endothermic. PMID- 30245339 TI - High molecular weight block copolymer lithography for nanofabrication of hard mask and photonic nanostructures. AB - An unusual dot pattern was realized via self-assembly of high molecular weight polystyrene-block-polydimethylsiloxane (PS-b-PDMS) copolymer by a simple one-step solvent annealing process, optimized based on Hansen solubility parameters. Annealing PS-b-PDMS under neutral solvent vapors at room temperature produces an ordered arrangement of dots with ~112 nm spacing and ~54 nm diameter. The template is highly resistant to dry etching with chlorine-based plasma, enabling its utilization on a variety of hard masks and substrates. The self-assembled PDMS dots were further exploited as a template for direct patterning of silicon, metal, and dielectric materials. This nanopatterning methodology circumvents expensive and time-consuming atomic layer deposition, wet processes, and sequential infiltration techniques. Application-wise, we show a process to fabricate nanostructured antireflection surfaces (nanocones) on a 2 in. silicon wafer, reducing the reflectance of planar silicon from 35% to below 0.5% over a broad wavelength range. Alternatively, nanocones made of TiO2 on silicon exhibit low reflectance (<3%) and improved transmittance into the substrate at the visible wavelength range. The measured optical properties concur with the simulation results. The versatility of the PS-b-PDMS templates was further utilized for nanopatterning materials such as silicon-on-insulator substrates, gallium arsenide, aluminum indium phosphide, and gallium nitride, which are important in electronics and photonics. PMID- 30245340 TI - Aggregation behavior of surfactants with cationic and anionic dendronic head groups. AB - HYPOTHESIS: Ionic dendronic head groups possess very different structural features than simple surfactant head groups. Accordingly, their self-assembly behavior is expected to differ from that of conventional surfactants. The number of generations of the headgroup should play a particularly relevant role. EXPERIMENTS: A novel type of surfactants with different dendronic head groups (cationic and anionic) was studied in this work. A systematic variation of the number of generations of the head group (n = 1, 2, and 3), of the head group charge (cationic and anionic), and of the length of the hydrophobic chain (hexanoyl and hexadecanoyl chains) was performed and the self-assembly behavior probed by means of small-angle neutron scattering (SANS) in order to obtain detailed structural insights. FINDINGS: The analysis of the scattering data shows that the general packing parameter concept applies also to dendrimeric surfactants and a larger head group results in smaller aggregates. However, in contrast to conventional surfactants, increasing the head group size results in a stronger tendency to self-aggregate, as a consequence of the head group's partly hydrophobic character. Another peculiarity of the self-assembled aggregates, is the low aggregation numbers and the high water content within the micelle, as a result of the highly branched head group. PMID- 30245341 TI - Effect of anion co-existence on ionic organic pollutants removal over Ca based layered double hydroxide. AB - The effects of co-existing anions (NO3- or SO42-) on the removal of sodium dodecylsulfate (SDS), representing anionic organic pollutants, by Ca-based layered double hydroxide (CaAl-LDH-Cl) are investigated to provide fundamental insights on the ionic surfactant removal in the presence of co-existing anions, and facilitate the establishment of a practical and advanced water treatment for environmental remediation. The SO42- system shows higher adsorption capacity (4.43 mmol.g-1) and larger d-spacing of adsorption resultant (3.4 nm) than the control system with no co-existing anion (3.64 mmol.g-1, 3.25 nm) and the NO3- system (3.82 mmol.g-1, 3.27 nm). The macroscopic and microscopic analyses reveal that, NO3- had a little influence on the SDS removal due to strong electrolysis, while SO42- could significantly promote the SDS removal. Moreover, the reaction mechanism varies under different molar ratios of DS-/SO42-. PMID- 30245342 TI - Genome-wide identification and characterization of the CsSnRK2 family in Camellia sinensis. AB - The sucrose nonfermenting 1 (SNF1)-related protein kinase 2 (SnRK2) genes play central roles in plant stress signal transduction. In this study, 8 SnRK2 genes were identified from the tea plant genome database and named CsSnRK2.1-8. Phylogenetic analysis showed that the CsSnRK2 genes were classifiable into three groups, similar to those of Arabidopsis thaliana, Oryza sativa and maize. The coding sequences (CDSs) of all CsSnRK2s were separated by eight introns, and their exon-intron organizations exhibited high similarity to those of other plants. The fluorescence of GFP fused with CsSnRK2.3 was detected in only the cytoplasm, while the rest of the proteins showed GFP signal in both the nucleus and the cytoplasm. The results of the expression patterns of the CsSnRK2 genes showed that CsSnRK2s were differentially induced by salt, polyethylene glycol (PEG) and abscisic acid (ABA) stress. Interestingly, The expression of CsSnRK2.3 was inhibited by ABA, suggesting the complicated roles of CsSnRK2s in the ABA signal transduction pathway. Some CsSnRK2 gene pairs showed significant expression change correlations under stresses, indicating that CsSnRK2s might exhibit synergistic effects of signal regulation in response to various stresses. In summary, this comprehensive analysis will facilitate further studies of the SnRK2 family of Camellia sinensis and provide useful information for the functional validation of CsSnRK2s. PMID- 30245343 TI - Arbuscular mycorrhizal fungi mitigate negative effects of combined drought and heat stress on tomato plants. AB - Arbuscular mycorrhizal (AM) symbiosis can alleviate drought and temperature stresses in plants, but it is unknown whether the benefits can be maintained when the plants are exposed to combined drought and heat stress. In this study, the impacts of AM fungi, Septoglomus deserticola and Septoglomus constrictum on tomato plant tolerance to combined drought and heat stress were investigated. No substantial differences in physiological parameters were found in all plants under non-stress conditions, except a higher expression of SlLOXD and SlPIP2.7 in plants + S. constrictum. Under drought, heat and drought + heat stress, both fungal symbionts could moderate oxidative stress by decreasing the lipid peroxidation, hydrogen peroxide level and improving leaf and root antioxidant enzyme activities, however better performance in plants + S. constrictum. Under drought and the combined stress, inoculation with S. constrictum enhanced stomatal conductance, leaf water potential and relative water content, elevated Fv/Fm and biomass production of the hosts as compared to non-inoculated plants whilst these improvements in plants + S. deserticola were not obvious. Under the combined stress inoculation of S. constrictum did not change the expression of SlNCED and SlPIP2.7 in roots as under heat stress. Expression of SlLOXD in root were upregulated in plants + S. contrictum under drought + heat stress as in mycorrhizal roots under drought stress. Altogether, our results indicated that AM inoculation, particularly with S. constrictum had a positive influence on the tomato plant tolerance to drought + heat stress. Further studies are essential to add some light on molecular mechanisms of mycorrhizal plant tolerance to this combined stress. PMID- 30245344 TI - A temporal high-resolution investigation of the Ah-receptor pathway during early development of zebrafish (Danio rerio). AB - In order to contribute to a comprehensive understanding of the regulating mechanisms of the aryl-hydrocarbon-receptor (AHR) in zebrafish embryos, we aimed to elucidate the interaction of proteins taking part in this signaling pathway during early development of the zebrafish (Danio rerio) after chemical exposure. We managed to illustrate initial transcription processes of the implemented proteins after exposure to two environmentally relevant chemicals: polychlorinated biphenyl 126 (PCB126) and beta-Naphthoflavone (BNF). Using qPCR, we quantified mRNA every 4 h until 118 h post fertilization and found the expression of biotransformation enzymes (cyp1 family) and the repressor of the AHR (ahr-r) to be dependent on the duration of chemical exposure and the biodegradability of the compounds. PCB126 induced persistently increased amounts of transcripts as it is not metabolized, whereas activation by BNF was limited to the initial period of exposure. We did not find a clear relation between the amount of transcripts and activity of the induced CYP-proteins, so posttranscriptional mechanisms are likely to regulate biotransformation of BNF. With regard to zebrafish embryos and their application in risk assessment of hazardous chemicals, our examination of the AHR pathway especially supports the relevance of the time point or period of exposure that is used for bioanalytical investigations and consideration of chemical properties determining biodegradability. PMID- 30245345 TI - Effects of imidacloprid and a neonicotinoid mixture on aquatic invertebrate communities under Mediterranean conditions. AB - Neonicotinoid insecticides are considered contaminants of concern due to their high toxicity potential to non-target terrestrial and aquatic organisms. In this study we evaluated the sensitivity of aquatic invertebrates to a single application of imidacloprid and an equimolar mixture of five neonicotinoids (imidacloprid, acetamiprid, thiacloprid, thiamethoxam, clothianidin) using mesocosms under Mediterranean conditions. Cyclopoida, Cloeon dipterum and Chironomini showed the highest sensitivity to neonicotinoids, with calculated NOECs below 0.2 MUg/L. The sensitivity of these taxa was found to be higher than that reported in previous studies performed under less warm conditions, proving the high influence of temperature on neonicotinoid toxicity. The short-term responses of the zooplankton and the macroinvertebrate communities to similar imidacloprid and neonicotinoid mixture concentrations were very similar, suggesting that the concentration addition model can be used as a plausible hyphotesis to assess neonicotinoid mixture effects in aquatic ecosystems. Long term mixture toxicity assessments, however, should consider the fate of the evaluated substances in the environment of concern. As part of this study, we also demonstrated that Species Sensitivity Distributions constructed with chronic laboratory toxicity data and calculated (multi-substance) Potentially Affected Fractions provide an accurate estimation to asssess the ecotoxicologial risks of imidacloprid and neonicotinoid mixtures to aquatic invertebrate species assemblages. PMID- 30245346 TI - Transmission of Lamb waves across a partially closed crack: Numerical analysis and experiment. AB - The transmission characteristics of Lamb waves across a partially closed through thickness crack in a plate are investigated numerically and experimentally. In the numerical analysis, the spectral element method is used to simulate the transmission of the lowest-order symmetric (S0) and antisymmetric (A0) Lamb modes across a crack in a low-frequency range. The analysis is carried out for an open crack with traction-free surfaces as well as for a partially closed crack modeled as a spring-type interface characterized by normal and tangential stiffnesses. The transmission ratios of both modes are obtained from the spectral amplitude of the simulated transmission waveforms for different crack lengths and interfacial stiffnesses. The numerical results show that the transmission ratio of the S0 mode increases monotonically with the interfacial stiffness, but that of the A0 mode depends on the interfacial stiffness in a non-monotonic manner depending on the frequency. The Lamb wave transmission measurements are carried out for aluminum alloy plates with artificial slits or a fatigue crack. The experimental results for the plates with slits show reasonable agreement with the numerical results for open cracks. The measured transmission ratio of the S0 mode is shown to decrease with the tensile load applied to the plate, but that of the A0 mode shows different load dependence for different frequencies. The qualitative features of the experimental results for the fatigue crack are discussed based on the numerical simulation for closed cracks. PMID- 30245347 TI - Immunomodulatory effects of rhesus monkey bone marrow-derived mesenchymal stem cells in serum-free conditions. AB - Mesenchymal stem cells (MSCs) have generated tremendous interest for treating various diseases due to their self-renewal and differentiation capacities. Many studies have demonstrated the immunoregulatory capability of MSCs; however, most of these studies were conducted with fetal bovine serum (FBS), which has an uncertain composition. In this study, we established a serum-free, xeno-free, completely chemically defined medium for the proliferation and expansion of rhesus monkey bone marrow (BM)-derived MSCs (rBMSCs) in vitro. The growth kinetics, characteristics, immunophenotype, and immunosuppressive abilities of rBMSCs grown in serum-free media (SFM) were evaluated and compared with those of cells grown in serum-containing media (SCM). Moreover, we employed RNA sequencing to evaluate the expression pattern of genes related to immune responses in both culture conditions. Compared to cells grown in SCM, rBMSCs grown in SFM exhibited better biological characteristics regarding cell proliferation and immunosuppressive abilities. Cells from both media types exhibited similar immunophenotypic expression patterns for CD29, CD34, CD45, HLA-DR, CD73, CD90, and CD105. Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Gene Set Enrichment Analysis (GSEA) revealed that CXCL8 was downregulated by 4.1 fold in SFM-cultured rBMSCs compared with those in SCM. Furthermore, the mixed lymphocyte culture revealed that the proliferation activity and the expression levels of inflammatory factors of peripheral blood mononuclear cells (PBMCs) were significantly decreased after the addition of the CXCL8 neutralizing antibody, which was related to the elevated immunosuppressive abilities of SFM-suspended rBMSCs. These results suggest a possible cell culture method as well as immunoregulatory mechanisms for clinical cell therapies requiring nonanimal-derived components. PMID- 30245348 TI - Activity of rutin, a potent flavonoid against SSG-sensitive and -resistant Leishmania donovani parasites in experimental leishmaniasis. AB - The current treatment approach for leishmaniasis has been questioned in terms of development of the resistance and life threatening side-effects. The utility of the drug can only be confirmed by inspecting its safety window along with its impact against different strains of parasite including the resistant ones. The aim of this study was to evaluate the therapeutic effects of a flavonoid, rutin (RTN) against sodium stibogluconate (SSG) sensitive (S-) and resistant (R-) strain of L. donovani. RTN exhibited its anti-promastigote activity via arresting the cells at sub G0/G1 phase. Further RTN resulted in decline of splenic parasite burden. The parasiticidal activity was associated with the elicitation of cell mediated immune response in terms of increased DTH response, augmented levels of T cells (CD4+, CD8+), Th1 cytokines, NO and ROS. RTN also up-regulated the expression of NF-KB and iNOS gene in S- as well as R- strain infected mice. Where no therapeutic effect of SSG was seen in the R-strain infected mice, the RTN treatment was able to control the disease in even R-strain infected mice. Moreover RTN was found to be devoid of any hepatic or renal toxicity. RTN could control the infection and it even had the capacity to counteract the resistant parasite by restoring the ability of host to produce protective immune response and microbicidal NO via up-regulating NF-KB and iNOS gene. This finding elucidates RTN to be a strong candidate in the antileishmanial drug pipeline not only against the sensitive but resistant strains also. PMID- 30245349 TI - 2-Furoic piperazide derivatives as promising drug candidates of type 2 diabetes and Alzheimer's diseases: In vitro and in silico studies. AB - The heterocyclic compounds have been extensively reported for their bioactivity potential. The current research work reports the synthesis of some new multi functional derivatives of 2-furoic piperazide (1; 1-(2-furoyl)piperazine). The synthesis was initiated by reacting the starting compound 1 with 3,5-dichloro-2 hydroxybenzenesulfonyl chloride (2) in a basic, polar and protic medium to obtain the parent sulfonamide 3 which was then treated with different electrophiles, 4a g, in a polar and aprotic medium to acquire the designed molecules, 5a-g. These convergent derivatives were evaluated for their inhibitory potential against alpha-glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Acarbose was used as a reference standard for alpha-glucosidase inhibition while eserine for AChE and BChE inhibition. Some of the synthesized compounds were identified as promising inhibitors of these three enzymes and their bioactivity potentials were also supported by molecular docking study. The most active compounds among the synthetic analogues might be helpful in drug discovery and development for the treatment of type 2 diabetes and Alzhiemer's diseases. PMID- 30245350 TI - Computational insight into the phthalocyanine-DNA binding via docking and molecular dynamics simulations. AB - Phthalocyanines are considered as good DNA binders, which makes them promising anti-tumor drug leads. The purpose of this study is to investigate the interactions between DNA and quaternary metallophthalocyanine derivatives (Q-MPc) possessing varying metals (M = Zn, Ni, Cu, Fe, Mg and Ca) by molecular docking since there seems to be a lack of information in the literature regarding this issue. In this direction, Autodock Vina and Molegro Virtual Docker programs were employed. Autodock Vina results reveal that each Q-MPc derivative binds to DNA strongly with similar binding energies and almost identical binding modes. They bind to the grooves of DNA by constituting favorable interactions between phosphate groups of DNA and Q-MPcs. Although changing the metal has no significant effect on binding, presence of quaternary amine substituents increases the binding constant Kb by about 2-fold comparing to the core Pc (ZnPc). Contrary to Autodock Vina, the calculated Molegro Virtual Docker binding scores have been more diverse indicating that the scoring function of Molegro is better in differentiating these metals. Despite the fact that Molegro is superior to Autodock Vina in terms of metal characterization, Autodock Vina and Molegro exhibit similar binding sites for the studied metallophthalocyanines. We propose that Q-MPc derivatives designed in this study are promising anti-tumor lead compounds since they tightly bind to DNA with considerably high Kb values. Cationic substituents and presence of metal have both positive effects on DNA binding which is critical for designing DNA-active drugs. Additional calculations employing molecular dynamics (MD) simulations verified the stability of Q-MPc-DNA complexes which remained in contact after 20 ns via attractive interactions mainly between DNA backbone and the Pc metal center. PMID- 30245351 TI - Bohr effect and oxygen affinity of carp, eel and human hemoglobin: Quantitative analyses provide rationale for the Root effect. AB - The functional properties of most fish hemoglobins are more complex than those of human hemoglobin. This complexity arises in the form of the Root effect, in which the oxygen affinity of such fish hemoglobins decreases rapidly with pH relative to that of human hemoglobin. Cooperative ligand binding is also diminished below pH ~ 6.5. The Bohr effect, determined by acid-base titration, has been reported for the Root effect carp and anodic eel hemoglobins. Unlike for mammalian hemoglobins, the Wyman equation for the Bohr effect fails to account quantitatively for these Bohr data. We present a successful quantitative accounting for these data based on evidence for multiple T states in various fish hemoglobins and on their lack of sixhistidine Bohr groups, with pKoxy > pKdeoxy. On the same bases we also provide a rationale for the higher pH sensitivity of the oxygen affinity of carp compared to human hemoglobin. PMID- 30245352 TI - Giant symptomatic gastric lipoma: A case report and literature review. AB - INTRODUCTION: Lipomas are uncommon tumors of the gastrointestinal tract; gastric lipomas account for <1% of all gastric tumors encountered (Nickloes and Sutphin [1]). Giant gastric lipomas, defined as >=10 cm, are exceedingly rare with only 6 cases reported since 1980 (Cappell et al., Termos et al., Singh et al., Ramaraj et al., Rao et al., Priyadarshi et al., Neto et al. [3-9]). We hereby present a case of a giant gastric lipoma that became symptomatic seven years after its initial identification and was excised preserving gastric continuity. CASE PRESENTATION: Our patient is a 58-year-old African American male with a 3 cm gastric mass incidentally found on CT in 2010. In September of 2017, the patient presented with severe epigastric pain, nausea, and vomiting. Abdominal CT scan revealed an increase in size of the patient's gastric lesion to 7.2 * 10.3 * 7.3 cm. He underwent an exploratory laparotomy with transverse anterior gastrotomy and primary closure. Pathologic examination revealed a 12 cm submucosal, well circumscribed, non-encapsulated mass comprised of mature adipose tissue without atypia or mitotic figures, consistent with lipoma. DISCUSSION: The majority of gastric lipomas are asymptomatic, identified on CT scan as round/ovoid masses with low attenuation and homogenous appearance, measuring -80 to -120 Hounsfield units. These findings are nearly pathognomonic. Due to the benign nature of gastric lipomas, circumferential excision with a clear margin of normal tissue is adequate for symptomatic resection. This is the second report of giant gastric lipoma excised with continuity preserving partial gastrectomy, avoiding gastrojejunostomy complications. CONCLUSION: Fatty tumors are rare in the gastrointestinal tract, yet lipomas must be on the differential when masses are found with Hounsfield units similar to peripheral fat. PMID- 30245353 TI - Case report of maxillofacial fracture in a patient under bisphosphonates in the absence of ONJ disease: Guidelines? AB - INTRODUCTION: Inspired by the presented case, this paper investigates treatment options for patients under active bisphosphonate therapy, suffering from a traumatic fracture in the absence of MRONJ (patients classified as 'at risk'). We review literature in search of standardized protocols and in combination. PRESENTATION OF CASE: A 75-year-old woman, suffering from osteoporosis for over a decade and being treated with alendronate for about 10 years, stumbled and fell and ended up with a displaced fracture on the right side of her extremely atrophied mandible. Under general anesthesia, using a limited submandibular approach with minimal reflecting of the periosteum, an external fixation device was placed. The patient recovered well from surgery and was discharged after 2 days. Long term follow-up shows good healing with a mouth opening of 46 mm in the absence of any sensory of functional deficits. DISCUSSION: We conclude from our literature review that there are no clear guidelines regarding fixation of traumatic (non-pathologic) maxillofacial fractures in patients under active antiresorptive therapy. Literature suggests that damaging the periosteum needs to be avoided since this would endanger the already fragile blood supply in the area. This could make an intra-oral approach unfavourable. CONCLUSION: We prefer an extra-oral approach whenever possible. The choice between the use of supraperiostally placed locking reconstruction plates or external fixation should be based on the overall medical condition of the patient, the regional osseous anatomy and the specific fracture morphology. PMID- 30245354 TI - Combined laparoscopic and robotic surgery for synchronous colorectal and genitourinary cancer: A case series. AB - INTRODUCTION: Advances in diagnostic techniques and treatment have resulted in an increase in patients with synchronous cancer. Surgical reports of combined laparoscopic and robotic resection for synchronous colorectal and genitourinary cancer are rare. MATERIALS AND METHODS: Between August 2015 and November 2017, three patients underwent combined laparoscopic and robotic surgery for synchronous colorectal and genitourinary cancer in our hospital. RESULTS: Case 1 was a 59-year-old man with synchronous rectal and prostate cancer treated by combined laparoscopic anterior resection and robotic-assisted prostatectomy. Case 2 was a 77-year-old man with synchronous cancer of transverse colon and left kidney treated by combined laparoscopic transverse colectomy and robotic-assisted partial nephrectomy. Case 3 was a 74-year-old man with synchronous adenocarcinoma of descending colon and prostate treated by combined laparoscopic left hemicolectomy and robotic-assisted prostatectomy. DISCUSSION: In simultaneous endoscopic surgery, it is necessary to consider sequence of resection, intraoperative position of patient and port arrangement. Simultaneous surgery allows promptly for postoperative adjuvant chemotherapy. CONCLUSION: Combined laparoscopic and robotic surgery for synchronous colorectal and genitourinary cancer is suitable for advanced cancer cases requiring multidisciplinary treatment. PMID- 30245355 TI - Brown tumor of the cervical spine in a patient with secondary hyperparathyroidism: A case report. AB - INTRODUCTION: Brown tumors are non-neoplastic, expansive bone lesions that occur only in the setting of hyperparathyroidism. The most usual localization of brown tumors is in mandible, ribs and large bones. In cervical spine, to date, there are only 11 cases reported. The aim of this work is to report the case of a patient with Wegener's granulomatosis with secondary end stage renal failure who developed a brown tumor in C4 vertebra. PRESENTATION OF CASE: A 25-year-old woman with an history of 2 months of worsening cervicalgia without history of trauma. She complained about progressive neck pain with irradiation to both shoulders and right arm paresthesias, spontaneous fracture or brown spinal cord tumor were suspected. She presented cervical spine instability, was managed with corpectomy of C4 and biopsy. DISCUSSION: The initial suspicion of this disease must be since the first clinician contact of the patient and with the past medical history of end stage renal failure plus recent neurologic manifestations. The aim of neurosurgical management of these patients is to promote spinal stability and release spinal cord and nerve roots to eliminate risk of neurological deficits. CONCLUSION: The importance of the prompt diagnosis of the brown tumor is to establish a multidisciplinary management to prevent progression, neurologic complications and sequelae despite its benign behavior. PMID- 30245356 TI - Bowel perforation secondary to metastatic lung cancer: Report of two cases with literature review. AB - INTRODUCTION: Gastrointestinal metastases from pulmonary neoplasm represent a rare but potentially fatal pathology that can complicate the disease in most advanced stages; this is a rare but well-known phenomenon in Literature and small intestine is the most common metastatic site. Generally these are patients with a known or surgically treated pulmonary neoplasm; the onset of pulmonary neoplastic disease with a symptomatic intestinal metastasis is to be considered extremely rare. PRESENTATION OF CASES: We report two cases of small intestine perforation from pulmonary metastasis; diagnosis was made at the time of exploratory laparotomy and the operation was in one patient the resection of the perforated bowel and in the second a resection and an intestinal bypass to overcome the stenosis caused by the metastatic masses. In the postoperative period, a patient died of pulmonary complications, the second was dismissed, but survival was only three months. DISCUSSION: Intestinal metastasis of a pulmonary tumor is a rare occurrence but must be suspected in acute abdominal syndrome in a patient with a diagnosed pulmonary neoplasia. CONCLUSION: Emergency surgical treatment of abdominal metastases of a lung cancer is mandatory but prognosis is extremely unfavorable. PMID- 30245357 TI - Treatment of hypocalcemia in hungry bone syndrome: A case report. AB - INTRODUCTION: Hungry bone syndrome (HBS) is rapid, intense and prolonged hypocalcemia that follows parathyroidectomy. The focus of this paper is HBS in patients with secondary hyperparathyroidism (SHPT) due to end stage renal disease (ESRD). Various risk factors are correlated with developing HBS post parathyroidectomy due to SHPT which include: old age (>60 years); the preoperative level of parathyroid hormone (PTH); increased osteoclasts; and evidence of bone disease before surgery. PRESENTATION OF CASE: A 25-year-old woman, who underwent parathyroidectomy of all four parathyroid glands due to SHPT caused by ESRD. Her calcium deficit was prolonged, as expected in patients who undergo parathyroidectomy, however her calcium levels remained low despite unprecedented supplementation of elemental calcium and calcitriol. DISCUSSION: Unfortunately, there is not enough data-based evidence to help prevent or minimize severe complications of hypocalcemia prior to parathyroidectomy. The main goal of treatment is replenishing the calcium deficiency through supplementation with calcium salts, high doses of active metabolites of vitamin D, and electrolytes. CONCLUSION: The ultimate goal of reviewing and analyzing this particular case is to obtain a better understanding for the treatment of Hungry bone syndrome. Although, there are very few cases as severe as this patient, hopefully this case study will result in greater insight and lead to improvement in the overall treatment of hypocalcemia. PMID- 30245359 TI - Urinary excretion of phenols, parabens and benzophenones in young men: Associations to reproductive hormones and semen quality are modified by mutations in the Filaggrin gene. AB - BACKGROUND: The filaggrin gene (FLG) encodes an epidermal protein, filaggrin, which is important for normal skin barrier functions. We previously showed that FLG loss-of-function mutation carriers have a higher internal exposure to some non-persistent chemicals such as certain phthalates and parabens, suggesting increased trans-epidermal penetration. Several groups of non-persistent chemicals are suspected endocrine disrupters with potential to affect testicular function. OBJECTIVES: To investigate associations between exposure to non-persistent chemicals and testicular function in young Danish men with and without FLG mutations. METHODS: We measured urinary concentrations of bisphenol A (BPA) and other simple phenols, parabens, and UV filters including benzophenones (BP-1, BP 3 and 4-HBP) in men genotyped for FLG R501X, 2282del4, and R2447X loss-of function mutations; in total 65 mutation carriers and 130 non-carriers (controls) were included. Outcomes were markers of testicular function, assessed by serum reproductive hormones and semen quality. RESULTS: We found that associations between urinary chemical concentrations and outcomes were different in cases and controls. Within the group of FLG mutation carriers, higher urinary concentrations of BPA, BP-1 and BP-3 were associated with higher testosterone and estradiol serum levels and lower FSH. Similar trends in hormone levels were observed for FLG mutation carriers with measurable levels of 4-HBP compared to those who had no detectable levels of urinary 4-HBP. Furthermore, those in the highest urinary BPA quartile had lower sperm motility than those in the lower quartiles. None of these associations were evident in the control group. In the control group, however, lower sperm motility and sperm concentration were observed in the men with detectable urinary 4-HBP compared to the men non detectable urinary 4-HBP. We found no association between any parabens and outcomes, nor for the other measured phenols or UV filters. CONCLUSIONS: Associations between male reproductive health parameters and urinary levels of BPA and benzophenones such as BP-3, BP-1 and 4-HBP were observed in FLG mutation carriers but not in controls from the same study population. This difference between FLG mutation carriers and non-carriers is not explained solely by differences in exposure levels of the examined compounds as e.g. BPA and 4-HBP urinary levels did not differ between the two groups. We hypothesise that effects of exposure to these compounds may be modulated in FLG mutation carriers by either different levels of co-exposures or by route of uptake, with a higher fraction of the uptake by dermal uptake. PMID- 30245358 TI - Bradycardias are associated with more severe effects on cerebral oxygenation in very preterm infants than in late preterm infants. AB - BACKGROUND: Commonly the magnitude and frequency of bradycardia is underestimated in the neonatal unit due to the long averaging time used in bedside oximeters. We aimed to assess the frequency and severity of bradycardia in preterm infants using the lowest averaging time (2 s) available on a clinical oximeter, compared with bradycardia detected using electrocardiogram (ECG), and whether bradycardia severity and postmenstrual age affected cerebral oxygenation. METHODS: Preterm infants (10 M/9F) were studied longitudinally at 26-31 (very preterm) and 32-38 weeks (late preterm) postmenstrual age. Heart rate falls calculated from ECG were used to determine mild or moderate/severe (MS) bradycardias. Cerebral tissue oxygenation index (TOI, %) was recorded and fractional tissue oxygen extraction (FTOE) calculated. RESULTS: Of the 615 bradycardias scored using ECG criteria, 10% were not detected by oximetry. TOI falls associated with bradycardias were greater for MS bradycardias compared with Mild for both groups (p < 0.001 for both). The FTOE associated with MS bradycardias was higher for the very preterm compared with the late preterm group (p < 0.001). In very preterm infants 61% of MS and 35% Mild bradycardias were associated with TOI nadirs below 55%. CONCLUSION: Even the most sensitive oximeter setting underestimates bradycardias. The cerebral effect from bradycardias in very preterm infants is more severe than in late preterm infants. Even the mild bradycardias are associated with falls in cerebral oxygenation. Routine NIRS monitoring of cerebral oxygenation in NICUs may increase staff awareness for interventions to reduce the repetitive falls in cerebral oxygenation in preterm infants. PMID- 30245360 TI - Exposure to chromium during pregnancy and longitudinally assessed fetal growth: Findings from a prospective cohort. AB - BACKGROUND: Prenatal exposure to chromium may be associated with reduced birth weight; however, critical windows of such exposure for fetal growth are unclear. OBJECTIVE: Our study was aimed to assess trimester-specific associations of chromium exposure with fetal growth parameters measured repeatedly by ultrasound and birth size, and to see whether these associations were modified by fetal sex. METHODS: We conducted a prospective cohort of 3041 women in Wuhan, China, from 2013 to 2016. Chromium concentrations were measured in maternal urine samples collected in the 1st, 2nd, and 3rd trimesters using an inductively coupled plasma mass spectrometry. We calculated standard deviation scores for ultrasound measured head circumference, abdominal circumference (AC), femur length, and estimated fetal weight (EFW) at 16, 24, and 31 weeks of gestation. Linear regressions with generalized estimating equations were used to estimate the associations of specific gravity-adjusted urinary chromium concentrations in each trimester with fetal growth parameters and birth weight, birth length, and ponderal index. RESULTS: Inverse associations of chromium exposure in the 1st trimester with fetal growth parameters at 31 weeks of gestation were observed, resulting in significant reductions in AC of -5.4% (95% confidence interval [CI]: -9.6%, -1.2%) and EFW of -5.6% (95% CI: -9.8%, -1.4%) per unit increase in natural logarithm transformed urinary chromium concentration. Urinary chromium concentration in the 2nd trimester was also associated with reductions in AC of 7.0% (95% CI: -12.5%, -1.4%) and in EFW of -5.0% (95% CI: -10.6%, 0.6%) at 31 weeks, and these inverse associations were evident in boys (reduction in AC of 13.9% [95% CI: -21.1%, -6.7%]; EFW of -9.5% [95% CI: -16.9%, -2.0%]) but not in girls (increase in AC of 2.9% [95% CI: -5.7%, 11.5%]; EFW of 1.5% [95% CI: -6.8%, 9.8%]) (both pineraction < 0.05). Moreover, one-unit increase in urinary chromium concentrations in the 1st and 2nd trimesters were both associated with significant reductions in ponderal index of -0.11 kg/m3 (95% CI: -0.19, -0.03 kg/m3) and -0.15 kg/m3 (95% CI: -0.27, -0.03 kg/m3), respectively. CONCLUSION: Our findings suggest that chromium may be a toxic metal for fetal growth. Early and mid-pregnancy seem to be the most vulnerable period for fetal exposure to chromium, but these results need further confirmation. PMID- 30245361 TI - Ambient air pollution exposure and risk of migraine: Synergistic effect with high temperature. AB - BACKGROUND: Migraine is a chronic and agonizing neurological disorder prevalent worldwide. Although its pathogenesis remains unclear, limited evidence exists on the role of air pollution. OBJECTIVE: We aimed to assess the association of short term air pollution exposure with migraine in conjunction with the synergistic effect of temperature. METHODS: We identified 18,921 patients who visited emergency departments (EDs) for migraine as a primary disease in Seoul from the national emergency database between 2008 and 2014. We conducted a time stratified, case-crossover analysis to compare levels of particles <2.5 MUm (PM2.5), particles <10 MUm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO) on ED visit days and those on the control days matched to day of the week, month, and year. We evaluated the synergistic effects of air pollution and temperature using an interaction term. RESULTS: Higher air pollution levels were significantly associated with risk of migraine over various lag structures. In the best fitting lags, the odds ratio (OR) associated with an interquartile range increase of PM2.5, PM10, NO2, O3, and CO was 1.031 (95% CI: 1.010-1.053), 1.032 (95% CI: 1.007-1.057), 1.053 (95% CI: 1.022-1.085), 1.034 (95% CI: 1.001-1.067), and 1.029 (95% CI: 1.005-1.053), respectively. The SO2 effect was positive but not significant (OR 1.019 [95% CI: 0.991-1.047]). The PM effect was significantly stronger on high-temperature days (above the 75th percentile) than on low-temperature days (PM2.5, high: OR 1.068, low: OR 1.021, Pinteract = 0.03; PM10, high: OR 1.066, low: OR 1.014, Pinteract = 0.02). CONCLUSION: Our study provides new evidence that air pollution exposure may trigger migraine especially on high-temperature days, and this finding may contribute in establishing preventive measures against migraine. PMID- 30245362 TI - PM2.5-related health and economic loss assessment for 338 Chinese cities. AB - China is in a critical stage of ambient air quality management after global attention on pollution in its cities. Industrial development and urbanization have led to alarming levels of air pollution with serious health hazards in densely populated cities. The quantification of cause-specific PM2.5-related health impacts and corresponding economic loss estimation is crucial for control policies on ambient PM2.5 levels. Based on ground-level direct measurements of PM2.5 concentrations in 338 Chinese cities for the year 2016, this study estimates cause-specific mortality using integrated exposure-response (IER) model, non-linear power law (NLP) model and log-linear (LL) model followed by morbidity assessment using log-linear model. The willingness to pay (WTP) and cost of illness (COI) methods have been used for PM2.5-attributed economic loss assessment. In 2016 in China, the annual PM2.5 concentration ranged between 10 and 157 MUg/m3 and 78.79% of the total population was exposed to >35 MUg/m3 PM2.5 concentration. Subsequently, the national PM2.5-attributable mortality was 0.964 (95% CI: 0.447, 1.355) million (LL: 1.258 million and NPL: 0.770 million), about 9.98% of total reported deaths in China. Additionally, the total respiratory disease and cardiovascular disease-specific hospital admission morbidity were 0.605 million and 0.364 million. Estimated chronic bronchitis, asthma and emergency hospital admission morbidity were 0.986, 1.0 and 0.117 million respectively. Simultaneously, the PM2.5 exposure caused the economic loss of 101.39 billion US$, which is 0.91% of the national GDP in 2016. This study, for the first time, highlights the discrepancies associated with the three commonly used methodologies applied for cause-specific mortality assessment. Mortality and morbidity results of this study would provide a measurable assessment of 338 cities to the provincial and national policymakers of China for intensifying their efforts on air quality improvement. PMID- 30245363 TI - Food and Alcohol Disturbance (FAD) in the U.S. and France: Nationality and gender effects and relations to drive for thinness and alcohol use. AB - OBJECTIVE: Food and Alcohol Disturbance (FAD), colloquially coined "drunkorexia," is a set of behaviors that encompasses restriction of calories, over-exercise, and other compensatory behaviors before, during, or after alcohol use to offset caloric intake or maximize intoxication. To date, this phenomenon has not been compared in a cross-cultural sample. METHOD: The Compensatory Eating and Behaviors Related to Alcohol Consumption Scale (CEBRACS), Eating Disorder Inventory - Drive for Thinness Subscale (EDI-DT) and Alcohol Use Disorders Identification Test of Consumption (AUDIT-C) were completed by 502 American (73% female) and 365 French (68% female) college students. RESULTS: Just over half (56.70%) of French and American (55.83%) participants engaged in FAD. Nationality was found to be a significant moderator of the relationship between alcohol use and FAD for both compensatory (p = .013) and intoxication (p = .01) purposes, such that Americans who drank more engaged in more FAD. Further, nationality moderated the relationship between drive for thinness and FAD for compensatory purposes (p = .005), but not for intoxication purposes (p = .10). At higher levels of drive for thinness French participants were more likely to engage in FAD for compenatory purposes. DISCUSSION: There is growing concern around how maladaptive eating and drinking behaviors intersect within the college population. These findings suggest that FAD is present cross-culturally, but that the relationships between predictors vary across culture. Thus, culture should be taken into consideration in the development of interventions for FAD. PMID- 30245364 TI - Analytical and field evaluation of the Biocentric Generic HCV assay on open polyvalent PCR platforms in France and Cambodia. AB - BACKGROUND: Implementation of affordable methods for HCV viremia is a key priority for identifying individuals who need treatment among persons screened positive for HCV antibodies. Different HCV PCR assays for use on open polyvalent PCR platforms are currently commercially available but studies evaluating the performances of these nucleic acid tests are needed. OBJECTIVES: In the present study, we evaluated the analytical and clinical performances of a recently developed HCV RNA PCR assay for detection and quantification of HCV viremia. STUDY DESIGN: In this study the Biocentric Generic HCV PCR was compared to the Roche Cobas AmpliPrep/Cobas TaqMan HCV RNA assay. Analytical and clinical performances was evaluated on reference materials and HCV plasma samples collected in 141 patients attending at the Montpellier University Hospital in France. Field evaluation was performed on samples collected in 185 patients attending at Medical Laboratory, Institut Pasteur in Cambodia. RESULTS: The lower limit of detection ranged from 50 HCV RNA IU/ml to 300 HCV RNA IU/ml using four different Diasorin and Qiagen automated or manual extraction methods. The specificity (CI) and sensitivity of the assay were 100% (92.5-100), and 98.7% (92.3-99.9), respectively, in France, and 100% (95.5-100), and 100% (94.4-100%), respectively, in Cambodia. Bland-Altman analysis shown good agreement between the two assays including for genotypes 6 HCV, which represent the majority of HCV isolates in Cambodia. CONCLUSIONS: The Biocentric Generic HCV assay has shown overall satisfactory analytical performances and a close agreement to the Cobas HCV assay on clinical specimens collected in France and Cambodia. There is an urgent need to further evaluate commercial assays dedicated to HCV detection and quantification using open polyvalent PCR platforms in different settings. PMID- 30245365 TI - Factors associated with the progression of conservatively managed acute traumatic subdural hemorrhage. AB - PURPOSE: Traumatic subdural hemorrhage (SDH) is associated with high mortality, yet many patients are not managed surgically. We sought to understand what factors might be associated with SDH enlargement to contribute to the triage of these conservatively managed patients. MATERIALS AND METHODS: A consecutive series of 117 patients admitted to our institution's level 1 trauma center for SDH between January 1, 2010 and December 31, 2010 were evaluated. Volumetric measurement of SDHs was performed on initial and follow-up head computed tomography (CT) scans with recording of initial midline shift and classification by location. Multimodel analysis quantified associations with change in SDH volume. RESULTS: Systolic blood pressure, presence of subarachnoid hemorrhage, and initial SDH volume demonstrated positive associations with change in SDH volume, while initial midline shift and transfusion of platelets demonstrated negative associations. Initial convexity SDH volume demonstrated positive association with change in convexity SDH volume, while initial midline shift and transfusion of platelets demonstrated negative associations. Anticoagulant/antiplatelet use demonstrated positive association with change in tentorial SDH volume, while time between CT scans demonstrated negative association. CONCLUSIONS: Platelet transfusion, anticoagulation, and hypertension have significant associations with expansion in non-surgical cases of SDH. Monitoring these factors may assist triaging these patients. PMID- 30245367 TI - Not all organ dysfunctions are created equal - Prevalence and mortality in sepsis. AB - PURPOSE: While organ dysfunctions within sepsis have been widely studied, interaction between measures of organ dysfunction remains an understudied area. The objective of this study is to quantify the impact of organ dysfunction on in hospital mortality in infected population. MATERIALS AND METHODS: Descriptive and multivariate analyses of retrospective data including patients (age >= 18 years) hospitalized at the study hospital from July 2013 to April 2016 who met the criteria for an infection visit (62,057 unique visits). RESULTS: The multivariate logistic regression model had an area under the curve of 0.9. Highest odds ratio (OR) associated with increased mortality risk was identified as fraction of inspired oxygen (FiO2) > 21% (OR = 5.8 and 95% Confidence Interval (CI) 1.8 35.6), and elevated lactate >2.0 mmol/L (OR = 2.45 (95% CI = 2.1-2.8)). Most commonly observed measures of organ dysfunction within mortality visits included elevated lactate (> 2.0 mmol/L), mechanical ventilation, and oxygen saturation (SpO2)/FiO2 ratio (< 421) at least once within 48 h prior to or 24 h after anti infective administration. CONCLUSION: There exist differences in measures of organ dysfunction occurrence and their association with mortality. These findings support increased clinical efforts to identify sepsis patients to inform diagnostic decisions. PMID- 30245366 TI - Patient and family engagement in the ICU: Report from the task force of the World Federation of Societies of Intensive and Critical Care Medicine. AB - PURPOSE: Patient and family engagement plays an important role in the intensive care unit (ICU), however the degree to which practices are being implemented globally is not known. MATERIALS: To provide insights, a task force of the World Federation of Societies of Intensive and Critical Care Medicine conducted a cross sectional survey. RESULTS: A total of 345 responses were received from 40 countries. Varying practices with respect to patient and family engagement were reported. Majority of those responding to individual survey questions (n=109, 61.2%) provided written materials on the ICU to family members. Just over half (n=184, 53.8%) of respondents identified that structured patient and family care conferences were held to review goals of care. Practices such as open visitation were reported by 39.6% (n=136), and family presence during resuscitation were reported to be fully (12%, n=41) or somewhat adopted (33%, n=113) by less than half of respondents. ICU diaries, music or pet therapy, or the use of a patient and family advisory group were reported by less than half of respondents. CONCLUSIONS: We document and hence provide successful implementation techniques, tactics, and strategies that could help clinicians to address barriers to implementing patient and family engagement in the ICU. PMID- 30245368 TI - Caregivers' perceptions towards communication with mechanically ventilated patients: The results of a multicenter survey. AB - PURPOSE: The purpose of this study was to investigate ICU health care providers' perception towards communication and associated problems with mechanically ventilated (MV) patients. The primary aim was to quantify the extent of the problem and to determine its effect on patient care and job satisfaction. METHODS: A multicenter survey study was conducted among nurses, residents and intensivists of 15 ICUs in the Netherlands using an online questionnaire. RESULTS: Out of 1740 caregivers, 457 responses were received. Communication difficulties were experienced in half of the interactions with MV patients. Over 75% of participants indicated that patient care was negatively affected. Job satisfaction was negatively affected in 43% of the participants, primarily with feelings of unfulfillment (76%) and frustration (72%). Patient factors considered relevant to communication difficulties were delirium, disease severity and anxiety, among others. To facilitate communication, the use of basic gestures remained the most preferred method. CONCLUSIONS: In half of the interactions with MV patients, health care professionals experience significant communication difficulties. The respondents indicated that these difficulties frequently lead to negative effects on patient care and job satisfaction. These results emphasize the need for improvements such as the development of communication protocols, skills training and continued research into new communication methods. PMID- 30245370 TI - The global three: A Malaysian lens on the challenges and opportunities facing restorative justice planning and implementation. AB - From the rise of restorative justice to evidence-based approaches to reducing recidivism, the intellectual landscape of criminal justice has seen considerable change in recent decades. The result is that an increasing number of countries have tackled the task of shifting preexisting political institutions to confirm with these new understandings. This is, of course, no easy feat. A great number of challenges confront willing policymakers, a reality that often puts philosophy at loggerheads with practicality. Moreover, the political process of change is subject to the influence of cultural and institutional norms. In this paper, we look at one particular case study - that of Malaysia's juvenile justice system - to understand the challenges faced in changing criminal justice policy. We identify three primary categories of challenges and elucidate their shape and impact through the Malaysian example. We also briefly analyze potential opportunities to mitigate and overcome these challenges. Furthermore, we also conclude with several implications for future research that we deem are important to be taken place. In sum, we argue that criminal justice reform must be undertaken with an eye toward important societal and institutional norms, each requiring thoughtful analysis of complex local cases. PMID- 30245369 TI - Genotyping of Multiple Clinical Samples with a Combined Direct PCR and Magnetic Lateral Flow Assay. AB - Developing a sensitive, low-cost, and easy-to-use point-of-care testing system for genotyping is important for informing treatment decisions and predicting the risk of underlying diseases. Conventional methods normally require complex operational procedures as well as expensive and sophisticated instruments. Here, we report a general approach that enables us to detect the genotype of multiple sample types directly without DNA purification. Moreover, the PCR results can be further quantitatively analyzed based on a magnetic lateral flow assay (MLFA) system, which avoids multiple steps needed for conventional nucleic acid biosensors. As a demonstration, we show that three genotypes of aldehyde dehydrogenase 2 (ALDH2) can be identified using a small volume of sample with an accuracy of 100% and a sensitivity of 1.0 * 102 cells/MUL, which are better than those of the gold standard methods. We believe that the direct PCR-MLFA system represents a significant advance toward the development of portable, sensitive biomedical platforms. PMID- 30245371 TI - An assessment of child protection in Bangladesh: How effective is NGO-led Child Friendly Space? AB - Many underprivileged Bangladeshi children are vulnerable to child trafficking, abuse, and exploitation. Child-Friendly Space (CFS) is a semi-permanent house space where vulnerable children are given the support to have a safe environment to survive and thrive. The purpose of this study is to evaluate the role of CFS in providing a protective environment for the children in Bangladesh. A set of secondary and primary data was used to review child protection situation in Bangladesh, and to evaluate the effectiveness of the CFS within a community. An evaluation of child development among the children who attend in the CFS and who do not attend in the CFS was conducted. CFS was found to benefit vulnerable children and communities in terms of protective environment and child development. Children attending in the CFS had better performance at almost every child development indicator. At the community level, child labor decreased in the areas where CFS exists. To respond to the continuing threats of child insecurity, this study presents a set of recommendations for the sustainability of the CFS in the community. PMID- 30245373 TI - Hormonal Contraception, depression, and Academic Performance among females attending college in the United States. AB - Associations between Hormonal Contraception (HC) and Depression have been previously reported, and indicate increased risk to younger women. These relationships need be explored and expanded to include measures of impact on Academic Performance (AP). Data was acquired from the National College Health Assessment (NCHA), administered from Fall 2008 to Spring 2015 across 370 schools nationwide. The most popular HC method was oral, followed by an IUD, and vaginal ring. HC use increased across all ages groups 18-29, and then decreased in the 30 34 age group. HC use significantly increased the odds of ever being diagnosed with depression in all age groups. HC use was found to have significantly increased odds of reporting AP issues in the 18-19 age group and to have significantly decreased odds of reporting AP issues in the 25-29 age group. Adding depression as a moderator, HC use continued to significantly increase the odds of AP issues. Women and their providers should balance the risks and benefits of initiating HC. Specifically, younger women, and be advised of the risks that HC presents in terms of a potential association with depression. Efforts to develop standardized protocols for discussing the risk-benefits for HC therapy should be pursued. PMID- 30245372 TI - Hypovitaminosis D is associated with depression and anxiety in schizophrenia: Results from the national FACE-SZ cohort. AB - OBJECTIVE: Hypovitaminosis D has been associated with respectively major depressive disorder, schizophrenia (SZ) and cognitive disorders in the general population, and with positive and negative symptoms and metabolic syndrome in schizophrenia. The objectives were (i) to determine the prevalence of hypovitaminosis D and associated factors (with a focus on depression and cognition) in a national non-selected multicentric sample of community-dwelling SZ subjects (ii) to determine the rate of SZ patients being administered vitamin D supplementation and associated factors. METHODS: A comprehensive 2 daylong clinical and neuropsychological battery was administered in 140 SZ subjects included between 2015 and 2017 in the national FondaMental Expert Center (FACE SZ) Cohort. Hypovitaminosis D was defined by blood vitamin D level <25 nM. Depressive symptoms were assessed by the Positive and Negative Syndrome Scale depressive subscore and current anxiety disorder by the Structured Clinical Interview for Mental Disorders. RESULTS: Hypovitaminosis D has been found in 21.4% of the subjects and none of them had received vitamin D supplementation in the previous 12 months. In multivariate analysis, hypovitaminosis D has been significantly associated with respectively higher depressive symptoms (aOR = 1.18 [1.03-1.35], p = 0.02) and current anxiety disorder (aOR = 6.18 [2.15-17.75], p = 0.001), independently of age and gender. No association of hypovitaminosis D with respectively positive and negative symptoms, cognitive scores or other biological variables has been found (all p > 0.05), however, a trend toward significance has been found for metabolic syndrome (p = 0.06). Vitamin D supplementation has been administered during the previous 12 months in only 8.5% of the subjects but was associated with lower depressive symptoms (aOR = 0.67 [0.46-0.98], p = 0.04) and lower rate of current anxiety disorder (aOR = 0.06 [0.01-0.66], p = 0.02) compared to patients with hypovitaminosis D. CONCLUSION: Hypovitaminosis D is frequent and associated with depressive symptoms and anxiety disorders in schizophrenia. Vitamin D supplementation is associated with lower depressive and anxiety symptoms, however patients with hypovitaminosis D remain insufficiently treated. PMID- 30245374 TI - Theory of mind and emotion regulation difficulties in children with ADHD. AB - Social cognition deficits and emotion dysregulation (ED) are frequently separately studied in relation to ADHD. This study aimed to examine the link between theory of mind (ToM) abilities and ED in children with ADHD. Participants were 200 children aged 11-17 years (study group, n = 100; healthy controls, n = 100). Emotion regulation skills were quantified by using the Difficulties in Emotion Regulation Scale (DERS). ToM was quantified by three different tasks. Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) Disruptive Behavior Disorders Rating Scale - parents form was used for determination of ADHD symptom severity (ADHD-SS). Children in the study group had more overall difficulties regulating their emotions than healthy controls. Within the study group, a significant correlation was found between the scores of DERS-total and ADHD-SS; and between the scores of DERS-total and gender. The linear regression showed that the predictor variables accounted for 56% of the variation in DERS-total. Unexpected Outcomes Test (UOT) scores significantly improved the accountability of the total variance when added to the linear regression. Our findings show that theory of mind deficits may partly explain ED in children with ADHD. PMID- 30245375 TI - Association of vitamin B12 mediated hyperhomocysteinemia and methylenetetrafolate reductase (C677T) gene polymorphism with cognitive impairment: A population based study from North India. AB - The present study attempts to understand the association of homocysteine, vitamin B12, folate, and MTHFR C677T gene polymorphism with cognitive impairment (CI) among 808 individuals of either sex (aged 30-70 years) from a largely vegetarian, mendelian population of North India. Biochemical and genetic analyses were done using standard protocols. Results indicate that 34.3% of the subjects had mild CI, 28.7% moderate CI and 0.2% were having severe CI. Hyperhomocysteinemia was found to be a significant risk factor for moderate/severe CI. Both CT genotype and T allele of MTHFR C677T gene polymorphism were found to pose significant decreased risk for CI. PMID- 30245376 TI - Seasonal variation of spontaneous blink rate and beta EEG activity. AB - Seasonal variations of the photoperiod have been shown to regulate biological and behavioral functions, with also effects on clinical symptom and course of several psychiatric conditions. Although melatonin is considered the principal signal used to transmit informations about the light and dark cycle, a dopamine (DA) role in regulating seasonal changes has been suggested. Few studies have addressed a seasonal pattern of dopamine, and human studies have been conducted on inter-subject differences, comparing measures obtained during fall-winter with those of spring-summer. We studied within-subject seasonal changes of blink rate (BR), a indirect marker of central DA activity, in 26 normal subjects (15 females and 11 males, mean age: 24.7 +/- 4.0) during winter, spring, summer and fall. Occipital EEG activity and subjective measures of vigilance and mood were also assessed to account for variations on arousal and fatigue. A significant seasonal effect was found for BR, with higher rate in summer, and for EEG beta activity, with higher activity in spring and summer. Subjective fatigue was found higher in winter. According to our data, it is possible that higher BR and increased EEG beta activity result by an arousal activation sustained by dopamine systems during the months with a long photoperiod. PMID- 30245377 TI - Testing the psychometric properties of the self-harm and suicide disclosure scale. AB - Suicide-related disclosure is an important component of identifying individuals at risk for suicide. However, no standardized measures exist to assess the degree to which individuals have disclosed suicide-related experiences. Therefore, the present study tested the psychometric properties of the Self-Harm and Suicide Disclosure Scale. A sample of 142 individuals, predominantly female and Caucasian, with ages ranging from 18-77 who had experienced suicidal ideation or behavior in their lifetime completed online surveys. A Rasch model analysis was used to test the item and individual separation and reliability and model fit of the instrument's use for disclosure to both family and nonfamily members. Analyses indicated strong item separation and reliability. Items were removed to improve model fit, resulting in two revised instruments. Findings indicate the Revised Suicide and Self-Harm Disclosure Scales are appropriate measures for assessing the depth of suicide-related disclosure. Future studies should attempt to replicate these findings with a more diverse sample. PMID- 30245378 TI - Pharmacological interventions in social cognition deficits: A systematic mapping review. AB - Social cognition is an important research field in psychiatry due to its relevance in the functioning and quality of life of patients. The objective of this work is to conduct a systematic mapping review of pharmacological strategies for improving social cognition deficits. Publications from 2006 to 2016 were reviewed in Scopus, PsycINFO, PubMed, and Embase. From the initial 1059 publications obtained, a final number of 110 were selected. The results show an increasing interest in pharmacological approaches in different medical fields (especially psychiatry, pharmacology, and endocrinology, with schizophrenia and autism as the most studied disorders), as can be observed in the progressive increase in the number of publications, the high degree of scientific evidence, and the high impact factor of publications. However, it is also observed that most studies were conducted with oxytocin, psychostimulants, and antipsychotics (mainly risperidone and olanzapine), with few studies using other drugs. In the different social cognition domains, the majority of publications were focused on emotional processing or theory of mind, with few studies in other domains. Thus, this systematic mapping review shows that, even though there are increasing research activities, there are some important gaps to cover in future investigation. PMID- 30245379 TI - Psychopathic personality factor "Fearless dominance" is related to low self reported stress-levels, fewer psychiatric symptoms, and more adaptive stress coping in psychiatric disorders. AB - The aim of this cross-sectional study was to test the idea that the psychopathic trait "Fearless dominance" (FD) may be associated with reduced psychological stress symptoms and better stress coping strategies in psychiatric patients, whereas the factor "Self-centered impulsivity" (SCI) may be associated with more stress and maladaptive stress coping. The investigation included 626 individuals with psychiatric disorders treated in a psychiatric rehabilitation program. The participants were tested with the Psychopathic Personality Inventory Revised (PPI R) and completed several clinical scales measuring stress experience and stress coping (Symptom-Checklist Revised, Trier Inventory for Chronic Stress, The Stress Coping Style Questionnaire 78). Consistent with the hypothesis, structural equation modeling results showed that self-reported stress levels and adaptive stress coping strategies might be explained by psychopathic FD traits in the psychiatric sample. Supplemental subscale analyses showed that especially the PPI R scales Stress Immunity and Social Influence were positively related to adaptive stress coping. The second model of SCI did not fit our data well. In conclusion, individuals with psychopathic FD traits may experience less stress symptoms during residential care. Well-designed prospective trials may ultimately answer the question whether psychopathic traits could be viewed as serving a buffer function in the development of depression. PMID- 30245380 TI - Links between sensory processing, adaptive behaviours, and attention in children with autism spectrum disorder: A systematic review. AB - Atypical sensory processing has been described in autism spectrum disorder. The goal of this systematic review is to investigate the links between sensory processing, adaptive behaviours, and attention skills in children with autism spectrum disorder. The PRISMA guidelines were followed and a search was conducted using electronic databases: Medline, PsychInfo and Eric. Among the 11 studies about sensory processing that were selected, 7 investigated the association with adaptive behaviours and 5 with attention. Atypical sensory processing was reported in 82% to 97% of the participants with ASD, depending on the study. This review found a significant impact of sensory abnormalities on adaptive behaviour. In addition, we found interrelations between sensory processing and attention skills. However, the current literature is too limited to definitively conclude the direction of these interactions and the theories concerning perceptive functioning are conflicting. PMID- 30245381 TI - Depressive symptoms among first-year Chinese undergraduates: The roles of socio demographics, coping style, and social support. AB - The prevalence of depressive symptoms among Chinese university students seems to be increasing. However, little research has been conducted in order to examine whether and how socioeconomic factors, coping style and social support affect depressive symptoms among university freshmen. The present study aimed to explore these effects on a sample of freshmen from single- and multi-child households in urban and rural environments. A total of 2,563 university freshmen (883 women, 1,680 men; mean age, 18.27 yr) from three universities in China completed a demographic questionnaire, Patient Health Questionnaire-9, Social Support Rating Scale, and Coping Style Questionnaire. Pearson correlation coefficients suggested that gender and place of origin affected students' coping styles, social support, and depression. Depression was negatively associated with problem-solving and help-seeking, but positively associated with self-blaming, fantasizing, avoidance, and rationalization. Logistic regression showed that depression was predicted by engaging in self-blame and fantasizing, being female, coming from a rural area, being an only child, lacking subjective and social support, having low skills at problem-solving and help-seeking. These findings may help psychological service providers identify first-year students at risk of depressive symptoms and provide them with systematic, gender-specific interventions that pay specific attention to self-blaming and fantasizing coping style. PMID- 30245382 TI - The relationship between problematic smartphone use and psychiatric symptoms among adolescents who applied to psychiatry clinics. AB - Problematic mobile phone use is an important problem which has increasing prevalence among adolescents. We should address risk factors to create intervention frameworks related to this problem. In this study, we aimed to determine the prevalence of problematic smartphone use among adolescents who were referred to clinics, its relationship to sociodemographic characteristics, psychiatric symptoms and emotion regulation problems. We included 150 adolescents aged 12-18 years who own smartphones. All participants filled out the Sociodemographic Information Form, Brief Symptom Inventory (BSI), Difficulties in Emotion Regulation Scale (DERS) and Problematic Mobile Phone Use Scale (PMPUS). Problematic smart phone use was detected in 50.6% of the sample. Adolescents with problematic use were found to be older than the others, with lower levels of maternal education and self-achievement. Regression analysis revealed that the factors predicting the risk of problematic smartphone use are somatization, interpersonal sensitivity and hostility symptoms. According to our results, we suggest psychiatrists consider the high prevalence of problematic smartphone use, address the relationship between hostility, somatic symptoms and interpersonal sensitivity (susceptibility) and the effects of this current problem on social academic functioning while evaluating and treating adolescents. PMID- 30245383 TI - Primary progressive multiple sclerosis in Iran: A consensus recommendation for diagnosis and management. PMID- 30245384 TI - Extreme delta brush and distinctive imaging in a pediatric patient with autoimmune GFAP astrocytopathy. AB - Autoimmune encephalitis has been increasingly recognized within the pediatric population, and the number of implicated autoantibodies continues to grow. The identification of characteristic clinical and paraclinical features helps direct the evaluation and increases the likelihood of making a definitive diagnosis of a specific antibody-mediated encephalitis. The finding of extreme delta brush on electroencephalogram (EEG) has been suggested to serve as a clinical clue to the diagnosis of anti-NMDA-R encephalitis. Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a recently described antibody-mediated meningoencephalomyelitis, reported almost exclusively in adult patients. We report a case of autoimmune GFAP astrocytopathy in a pediatric patient with extreme delta brush pattern on EEG, negative anti-NMDA-R antibodies, and distinctive MRI findings. The findings reported herein should prompt clinicians to consider the diagnosis of autoimmune GFAP astrocytopathy in patients with suspected autoimmune encephalitis. PMID- 30245385 TI - Bioinstructive microparticles for self-assembly of mesenchymal stem Cell-3D tumor spheroids. AB - 3D multicellular tumor spheroids (3D-MCTS) that closely mimic in vitro the complex lung tumor microenvironment (TME) are highly desirable for screening innovative anti-cancer therapeutics. Despite significant improvements in mimicking lung TME, few models have combined tumor-infiltrating mesenchymal stem cells from bone marrow (hBM-MSCs) with heterotypic 3D tumor spheroid models containing ECM mimetic components. Herein, we engineered hybrid 3D-MCTS that combine, for the first time, A549:fibroblasts:hBM-MSCs in heterotypic tri culture, with bioinstructive hyaluronan microparticles that act as tumor-ECM mimetics and as cell-anchoring hotspots. The obtained results indicated that 3D microspheres provided proper support for cells to self-assemble into compact 3D microtissues and promoted an increase in CD44 expression, emulating the presence of native-ECM hyaluronan. 3D-MCTS size and sphere-like morphology was reproducible and tri-culture models presented the characteristic solid tumors necrotic core. Mesenchymal stem cells tracking demonstrated that hBM-MSCs migrate to different regions in 3D microtumors mass exhibiting dynamic interactions with cancer cells and stromal fibroblasts, alike in human tumors. Importantly, doxorubicin administration revealed hBM-MSCs effect on cytotoxic responses in 3D tri-culture models and in dual cultures of hBM-MSCs:A549 at 10:1 ratio. Such findings evidence the relevance of including hBM-MSCs in combination with cancer stromal fibroblasts in 3D in vitro tumor models and the importance to test different cell-to-cell ratios to mimic tumor heterogeneity. In addition, bioinstructive hyaluronan-microparticles were also effective as cell agglomerating scaffolds and showed potential to be used as an enabling technology for including different ECM components in 3D in vitro models in the future. PMID- 30245386 TI - Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities. AB - Antiretroviral therapy (ART) has changed the outcome of human immunodeficiency virus type one (HIV-1) infection from certain death to a life free of disease co morbidities. However, infected people must remain on life-long daily ART. ART reduces but fails to eliminate the viral reservoir. In order to improve upon current treatment regimens, our laboratory created long acting slow effective release (LASER) ART nanoformulated prodrugs from native medicines. LASER ART enables antiretroviral drugs (ARVs) to better reach target sites of HIV-1 infection while, at the same time, improve ART's half-life and potency. However, novel ARV design has been slowed by prolonged pharmacokinetic testing requirements. To such ends, tri-modal theranostic nanoparticles were created with single-photon emission computed tomography (SPECT/CT), magnetic resonance imaging (MRI) and fluorescence capabilities to predict LASER ART biodistribution. The created theranostic ARV probes were then employed to monitor drug tissue distribution and potency. Intrinsically 111Indium (111In) radiolabeled, europium doped cobalt-ferrite particles and rilpivirine were encased in a polycaprolactone core surrounded by a lipid shell (111InEuCF-RPV). Particle cell and tissue distribution, and antiretroviral activities were sustained in macrophage tissue depots. 111InEuCF-PCL/RPV particles injected into mice demonstrated co registration of MRI and SPECT/CT tissue signals with RPV and cobalt. Cell and animal particle biodistribution paralleled ARV activities. We posit that particle selection can predict RPV distribution and potency facilitated by multifunctional theranostic nanoparticles. PMID- 30245388 TI - Immune lipoprotein nanostructures inspired relay drug delivery for amplifying antitumor efficiency. AB - Chemo-immunotherapy represents an appealing approach to improving cancer treatment. Simultaneously administrating chemotherapeutics with immunoadjuvants can elicit potent tumor death and immune responses. Herein, high density lipoprotein (HDL) inspired immune lipoprotein was proposed for relay drug delivery and amplifying antitumor therapy. Lipophilic AS1411 aptamer immunoadjuvant CpG fused sequences (Apt-CpG-DSPE) were conjugated to facilitate decoration onto HDLs; and doxorubicin (Dox) was successively intercalated into the consecutive base pairs of Apt-CpG to complete immune HDL nanodrug imHDL/Apt CpG-Dox. For relay drug delivery, imHDL/Apt-CpG-Dox underwent site-specific structure collapse in tumor intercellular substances inspired from HDL biofunctions (sequential module I); subsequently, dissociated Apt-CpG-Dox was endocytosed into tumor cells mediated by the recognition of AS1411 and nucleolin (sequential module II), translocating Dox to nucleus and enabling tumor ablation and antigens release. The liberated CpG motif further evoked antigen recognition, induced vast secretion of pro-inflammatory cytokines and potentiated host antitumor immunity. Our studies demonstrated that HDL biomimetic platform based relay drug delivery strategy outperformed the monotherapy counterparts in malignant tumor models, eventually generating an augmented antitumor efficacy. PMID- 30245387 TI - Improved in situ seeding of 3D printed scaffolds using cell-releasing hydrogels. AB - The design of tissue engineered scaffolds based on polymerized high internal phase emulsions (polyHIPEs) has emerged as a promising bone grafting strategy. We previously reported the ability to 3D print emulsion inks to better mimic the structure and mechanical properties of native bone while precisely matching defect geometry. In the current study, redox-initiated hydrogel carriers were investigated for in situ delivery of human mesenchymal stem cells (hMSCs) utilizing the biodegradable macromer, poly(ethylene glycol)-dithiothreitol. Hydrogel carrier properties including network formation time, sol-gel fraction, and swelling ratio were modulated to achieve rapid cure without external stimuli and a target cell-release period of 5-7 days. These in situ carriers enabled improved distribution of hMSCs in 3D printed polyHIPE grafts over standard suspension seeding. Additionally, carrier-loaded polyHIPEs supported sustained cell viability and osteogenic differentiation of hMSCs post-release. In summary, these findings demonstrate the potential of this in situ curing hydrogel carrier to enhance the cell distribution and retention of hMSCs in bone grafts. Although initially focused on improving bone regeneration, the ability to encapsulate cells in a hydrogel carrier without relying on external stimuli that can be attenuated in large grafts or tissues is expected to have a wide range of applications in tissue engineering. PMID- 30245389 TI - Young adult cardiovascular diseases: a single center coronary computed tomography angiography study. AB - PURPOSE AND BACKGROUND: Cardiovascular disease (CVD) is one of the leading causes of death. However, the prevalence of CVD in young adults (<40 years of age) has not been well documented. We conducted this study to determine the proportion of CVD in both symptomatic and asymptomatic young adults. MATERIALS AND METHODS: Coronary CT angiography images obtained from April 2015 to July 2017 in our institution was retrospectively reviewed. Young adults were separated into two groups according to whether they had experienced chest discomfort. The diagnosis was classified as normal, coronary artery disease (CAD), myocardial bridging (MB), congenital coronary anomaly, congenital cardiac anomaly, cardiomyopathy, and aortic anomaly. The proportion of different diagnoses in two groups and cardiovascular risk factors were analyzed. RESULTS: Totally 107 patients (mean age, 35.6 +/- 3.55 years) were grouped into 36 cases of symptomatic group and 71 patients of asymptomatic group. Cardiovascular anomalies were found in 61 cases (41%). No significant difference in the occurrence rates of CAD (14% vs 11%, p = 0.53), MB (31% vs 42%, p = 0.51), and congenital coronary anomaly (7% vs 3%, p = 0.26) between groups. Mild arterial stenosis was implied in most CAD cases. Hypertension was the only risk factor significantly correlated with CAD. CONCLUSIONS: Although young adults are conventionally identified as low-risk, more than 60% of the cases in our cohort were proved to present cardiovascular anomalies, with no significant relation to cardiac symptoms. Early interventions should be conducted for aggressive CVD subtypes to prevent future acute events. PMID- 30245390 TI - MR imaging features and tumor biomarkers of screen-detected and non-screen detected breast cancers: preliminary results of a comparative study. AB - PURPOSE: To investigate differences in clinical features, MRI findings and tumor biomarker characteristics in screen-detected (SCD) and non-screendetected (NSCD) cancers. MATERIAL AND METHODS: A total of 62 women (mean age, 48.4 years; range, 33-68 years) with biopsy confirmed breast cancer who underwent preoperative breast MRI were retrospectively evaluated by two expert radiologists. The women were divided into two groups according to the mode of cancer detection (Group A: screen- detected, Group B: non-screen/symptomatic cancer) and clinical, histopathological, MRI characteristics and biomarker features in each group were evaluated. RESULTS: NSCD tumors had significantly greater size (3.5 cm vs. 2.1 cm) and Ki-67 expression (68.4% vs. 41.7%) in comparison to SCD cancers. NSCD cancers were less likely to have strongly positive progesterone receptors (Pr) and more likely to have Ki-67 > 15% or positive nodal status (47.4% vs. 8.3%). Increased breast density (ACR C and D: 78.9% vs. 50%ACR A and B) and intense background parenchymal enhancement (BPE, moderate/marked: 42.1% vs. 8.3% minimal/mild) were significantly more frequent in NSCD cases. CONCLUSION: NSCD cancers had higher prevalence of poor prognostic characteristics in comparison to SCD tumors, including larger tumor size, higher Ki-67 index, and positive nodes. Increased fibroglandular tissue and intense BPE were both strongly associated with NSCD cancers, supporting their use as potential MR biomarkers in breast cancer risk models. PMID- 30245391 TI - Anatomy and pathology of the nail and subungual space: Imaging evaluation of benign lesions. AB - The lesions of the ungual and subungual space include various etiologies, which may be similar in clinical presentation, almost always with nail deformity. Imaging evaluation is helpful in the characterization of these lesions, narrowing the differential diagnosis and leading to appropriate treatment. This review aims to outline the anatomy and terminology used to describe the alterations of the nail unit and the main imaging characteristics of some of the most common benign lesions of the nail. PMID- 30245392 TI - Recent advancements in fungal-derived fuel and chemical production and commercialization. AB - Due to unsustainable petroleum supply and poor yields from plant and animal sources, there is an increased effort to engineer microbial hosts for renewable chemical production. When compared to microbes such as Escherichia coli, fungal hosts show advantages due to their natural robust tolerance for industrial fermentation. Synthetic biology has focused on implementing heterologous pathways and manipulating native flux towards downstream products to achieve industrial productivity, titers, and yields. This review highlights recent advances in the engineering of yeasts for fuels and other molecules. As the field progresses, strains with improved productivities will begin to compete with the traditional chemical-based industrial approaches. PMID- 30245393 TI - Novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 antagonists and PDE4/7 inhibitors: A new approach for the treatment of pain. AB - A series of novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl alkylcarboxylic acids designed using a structure-based computational approach was synthesized and assayed to evaluate their ability to block human TRPA1 channel and inhibit PDE4B/7A activity. We identified compounds 16 and 27 which showed higher potency against TRPA1 compared to HC-030031. In turn, compound 36 was the most promising multifunctional TRPA1 antagonist and PDE4B/7A dual inhibitor with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Compound 36 as a combined TRPA1/PDE4B/PDE7A ligand was characterized by a distinct binding mode in comparison to 16 and 27, in the given protein targets. The inhibition of both cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-alpha effect of 36in vivo. Moreover, the potent anti inflammatory and analgesic efficacy of 36 was observed in animal models of pain and inflammation (formalin test in mice and carrageenan-induced paw edema in rats). This compound also displayed significant antiallodynic properties in the early phase of chemotherapy-induced peripheral neuropathy in mice. In turn, the pure TRPA1 antagonists 16 and 27 revealed a statistically significant antiallodynic effect in the formalin test and in the von Frey test performed in both phases of oxaliplatin-induced allodynia. Antiallodynic activity of the test compounds 16, 27 and 36 was observed at a dose range comparable to that of the reference drug - pregabalin. In conclusion, the proposed approach of pain treatment based on the concomitant blocking of TRPA1 channel and PDE4B/7A inhibitory activity appears to be interesting research direction for the future search for novel analgesics. PMID- 30245394 TI - HDAC as onco target: Reviewing the synthetic approaches with SAR study of their inhibitors. AB - Even though one is moving towards the success in the discovery of efficient anti cancer molecules, the drugs used in the treatment of various malignancies are found to possess toxicity and adverse reactivity in the human body that limit their use. The scientists all over the world are engaged in bringing up strategies that aim to develop small molecules that target the abnormal epigenetic factors. The discovery of the role of Histone deacetylases (HDACs) has promised to be a turning point in the treatment of various malignancies. Thus, the invention of potent and safe anticancer therapeutics agents with minimal adverse and side effects are still a major topic of concern and a huge number of research works have been reported in the past few years. This review has been written to discuss on the influence of Histone Deacetylases in cancer malignancies. We have tried to embrace majority of the developments made till date in the field of HDAC and its inhibitors herein. The drugs that are clinically applied, synthesis and SAR study that highlight the chemical groups responsible for evoking the HDAC inhibition and potential of various new classes of HDAC inhibitors (synthetic, hybrid and natural) have also been included. PMID- 30245395 TI - Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3Kalpha H1047R mutant inhibitors. AB - Phosphatidylinositol 3-kinase alpha (PI3Kalpha) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel PI3Kalpha H1047R mutant inhibitor Hit-02 (EC50 = 115.3 MUM), which was identified from a high-throughput screening campaign. Structure-activity relationship analysis enabled us to discover compound 7h, which strongly inhibited PI3Kalpha H1047R mutant with an EC50 value of 0.55 MUM, over 200-fold more potent than Hit-02, while having little effect on other PI3K isoforms. Western blotting assay suggested that 7h decreased the phosphorylation level of AKT, another proof that 7h inhibited PI3Kalpha H1047R mutant function. Cell viability assay revealed that 7h inhibited HCT-116 cancer cell growth with an IC50 value of 10.9 MUM. In addition, 7h was found to arrest cell cycle at G2 phase but did not show any cell apoptosis effect. Furthermore, 7h obviously induced cell autophagy, which might contribute to its anti proliferation effect in cancer cell. Collectively, all these data demonstrated that 7h could be a promising lead for the development of structurally novel PI3Kalpha inhibitor. PMID- 30245396 TI - Activity of oxygen-versus sulfur-containing analogs of the Flex-Het anticancer agent SHetA2. AB - Five series of chromans with urea and thiourea linkers connecting a chroman unit (ring A) and a 4-substituted benzene unit (ring B) have been prepared and evaluated relative to SHetA2 (NSC 721689) for activity against the human A2780 ovarian cancer cell line. The lead compound SHetA2 had a sulfur in place of the oxygen in ring A and a thiourea linker to ring B. The 2-Me-4-Me series (two sets of geminal dimethyl groups at C2 and at C4 on the ring A unit) permitted direct comparison with SHetA2. Ring B in this series was evaluated with specific functional groups at C4 on the ring, including NO2, CO2Et, CF3, OCF3, CN and SO2NH2. The 2-H-4-Me series (only one geminal dimethyl group at the C4 position on ring A) permitted structure-activity relationship analysis to assess the importance of the hydrophobic geminal dimethyl groups on ring A to the activity of SHetA2. The remaining three series 2-Et-4-Me, 2-Me-4-Et and 2-Et-4-Et (ring A methyl groups replaced with ethyls at C2, at C4 and at both C2 and C4, respectively) offered the opportunity to modulate the hydrophobicity of the chroman moiety. Additionally, in all these series, the influence of a urea versus a thiourea linker was also investigated. The results of these modifications are summarized below. The exact analog of SHetA2 with oxygen substituted for sulfur in ring A (2a) showed comparable efficacy but a significantly lower IC50 against the ovarian cancer cell line. The urea linked analogs bearing CN, CF3 and OCF3 at C4 of ring B (3c,d and f) showed greater efficacy than SHetA2, but also had lower IC50 values. Removing the geminal dimethyl group at C2 (4a-c, 5a-c) caused a significant lowering of the efficacy and percent growth inhibition, indicating that the hydrophobic geminal dimethyl group at C2 in ring A is crucial for activity. Finally, replacing the geminal dimethyl groups with geminal diethyls on ring A in the urea derivatives gave 6b-c, 7c-d and 8b, all of which outperformed SHetA2 with respect to efficacy and IC50. The results for compounds 4-8 are in concurrence with modeling studies, which predicted that greater hydrophobicity in ring A would be beneficial. Binding energies were determined for compounds docked in silico to mortalin, the protein identified as a receptor of SHetA2. The urea linker promoted activity comparable to or, in some cases, greater than compounds with a thiourea linker. Several compounds achieved 94% efficacy and an IC50 of 2 MUM, which were better than SHetA2 (84%, 3 MUM). PMID- 30245397 TI - Conformation impacts on the bioactivities of SMART analogues. AB - As promising colchicine binding site inhibitors, SMART and its analogues have attracted many research efforts in recent years. A large number of SMART analogues with different B-rings have been reported; however, the effects of B ring on the bioactivity are still unclear so far. Herein, we speculated that the conformational preference caused by B-rings was crucial for active SMART analogues. Our assumption was supported by the molecular docking studies, molecular dynamic simulation and DFT computations of SMART and its analogues reported by other and our research groups. Moreover, several novel SMART analogues with different conformational preferences were designed and synthesized to disclose the conformation impacts, and the preliminary biological evaluation was in accordance with our assumption. PMID- 30245398 TI - A cardiac glycoside HTF-1 isolated from Helleborus thibetanus Franch displays potent in vitro anti-cancer activity via caspase-9, MAPK and PI3K-Akt-mTOR pathways. AB - Experiments have been undertaken and for the first time, we have identified that a new cardiac glycoside (CG) isolated from Helleborus thibetanus Franch. a plant endemic to China, bears potent anti-cancer activity. We have named it as HTF-1. By using in vitro cell models, we have found that HTF-1 induces apoptosis against several types of cancer cells in a concentration- and time-dependent manner. It is able to inhibit cancer cell in proliferation, migration and invasion. HTF-1 causes S cell cycle arrest. Further-on, we have identified that HTF-1 triggers caspase-9 dependent apoptosis pathway and double strand DNA breaks (DSBs). Additionally, HTF-1 activates JNK, but suppresses ERK and PI3K-Akt-mTOR pathways. Collectively, the above-mentioned mechanisms contribute to the anti-cancer activity of HTF-1. It is rare to discover novel anti-cancer CG during the past couple of decades. We believe that our work will enrich the understanding of CGs; also, pave the way for natural product-based anti-cancer drug development. PMID- 30245399 TI - Design, synthesis and biological evaluation of 2-substituted 3-hydroxy-6-methyl 4H-pyran-4-one derivatives as Pseudomonas aeruginosa biofilm inhibitors. AB - Drug-resistant bacteria associated with biofilm formation are rapidly on the rise, requiring novel therapeutic options to combat biofilm induced drug resistance. In this study, a class of 3-hydroxy-2-(phenylhydroxy-methyl)-6-methyl 4H-pyran-4-one derivatives (1a-1e) were found by screening of an in-house compound library to be potential Pseudomonas aeruginosa biofilm inhibitors. Thirty one novel 2-substituted 3-hydroxy-6-methyl-4H-pyran-4-one derivatives were synthesized and assayed for their biofilm inhibitory activity. A promising biofilm inhibitor 6a was identified, and showed an obvious biofilm inhibitory effect even at a concentration of 2.5 MUM. Further mechanism studies revealed that 6a only shows inhibitory effects on the expression of pqsA-gfp in a fluorescent reporter strain, and the production of a PQS- regulated virulence factor, pyocyanin. This indicates that this type of compound exercises its anti biofilm activity specifically through the PQS pathway. Novel chemical biofilm inhibitors are described here and guard against biofilm formation associated with Pseudomonas aeruginosa infections. PMID- 30245400 TI - Discovery of furyl/thienyl beta-carboline derivatives as potent and selective PDE5 inhibitors with excellent vasorelaxant effect. AB - Based on our previous studies and predictive docking results, furans and thiophenes were introduced to the privileged tetrahydro-beta-carboline scaffold to generate more potent and selective PDE5 inhibitors. A total of 66 novel furyl/thienyl tetrahydro-beta-carboline derivatives were designed, synthesized and evaluated for PDE5 inhibition. Tetrahydro-beta-carboline-piperazinedione 19f and tetrahydro-beta-carboline-hydantoin 26b with optimized pendant 5-ethylfuran/5 ethylthiophene were identified as the most potent PDE5 inhibitors, and showed high selectivity towards PDE5 versus other PDE isozymes, especially PDE6 and PDE11. Further vasorelaxant activity assessments revealed that these PDE5 inhibitors also exhibited significant angiectasis on the norepinephrine precontracted 3rd-order mesenteric arteries (110-150 MUm) via NO-sGC-cGMP pathway, implying their further application for the treatment of vascular diseases. PMID- 30245401 TI - Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone based monoamine oxidase/cholinesterase inhibitors. AB - There has been a substantial research effort to design multi-target ligands for the treatment of Alzheimer's disease (AD), an approach that is moved by the knowledge that AD is a complex and multifactorial disease affecting many linked to pathological pathways. Accordingly, we have devoted efforts to develop multi target ligands based on the chromone scaffold. As a result, a small library of chromone derivatives was synthesized and screened towards human cholinesterases and monoamine oxidases. Compounds 2-(dimethylamino)ethyl (E)-3-(4-oxo-2-(p methylphenlcarbamoyl)-4H-chromen-6-yl)acrylate (9a) and 2-(dimethylamino)ethyl (E)-3-(4-oxo-3-(phenylcarbamoyl)-4H-chromen-6-yl)acrylate (23a) were identified as the most promising multi-target inhibitors of the series. Compound 9a acted as a potent, selective and bifunctional AChEI (IC50 = 0.21 MUM, Ki = 0.19 MUM) and displayed dual hMAO inhibitory activity (hMAO-A IC50 = 0.94 MUM, Ki = 0.057 MUM and hMAO-B IC50 = 3.81 MUM, Ki = 0.48 MUM). Compound 23a acted as a selective IMAO-B (IC50 = 0.63 MUM, Ki = 0.34 MUM) while still displaying hChE inhibitory and bifunctional activity in the low micromolar range. Overall, these two compounds stand out as reversible multi-target inhibitors with favourable permeability, toxicological and drug-like profiles, thus being valid candidates for subsequent optimization and pre-clinical studies. PMID- 30245404 TI - Wet chemical processing for nuclear waste glass to retrieve radionuclides. AB - Here, we show unexpected and significant elution behavior of various elements from simulated nuclear waste glass (NWG) in ~10 degrees mol dm-3 acidic solutions below 100 degrees C, where a borosilicate-based glass matrix has been believed to be chemically durable. Most elements like glass main components (Li, B, Na, Ca, Al, and Zn, but except for Si) and simulated radionuclides (Rb, Cs, Sr, Ba, Se, Te, Mn, Pd, Mo, rare earths, Cr, Fe, and Ni) were remarkably eluted from the simulated NWG in ~10 degrees M HNO3 aq with Cl- at 90 degrees C. Especially, the elution of Pd is governed by its coordination chemistry including a redox reaction, because Pd(0) present in the simulated NWG has to be oxidized to Pd2+ which forms [PdCl4]2- for its dissolution. While Zr in simulated NWG is sparingly eluted even in this treatment, its elution actually proceeds in 1-3 M H2SO4 aq at 90 degrees C thanks to strong coordination of Zr(IV) with SO42-. Through design and optimization of the leaching conditions, a protocol of the wet chemical process to retrieve the radionuclides from simulated NWG has been proposed and demonstrated. PMID- 30245403 TI - Genetic and Epigenetic Perturbations by DNMT3A-R882 Mutants Impaired Apoptosis through Augmentation of PRDX2 in Myeloid Leukemia Cells. AB - DNA methyltransferase 3A (DNMT3A) is mutated in various myeloid neoplasms including acute myeloid leukemia (AML), especially at the Arg882 and associated with inferior outcomes. Here, we report that the DNMT3A-Arg882His/Cys (R882H/C) mutations led to inactivation of apoptosis through DNA damage signaling following the impairment of differentiation of myeloid leukemia cells. Gene expression profiling analysis revealed aberrant expression of several cell-cycle and apoptosis-related genes, and the DNA methylation assay identified both hypo- and hypermethylation features in different regions throughout the whole genome of DNMT3A mutants-transduced myeloid cells. We found that DNMT3A-R882H/C mutations upregulated the expression of an antioxidant protein, pyroxiredoxin-2 (PRDX2), at the mRNA and protein levels with decreased accumulation of reactive oxygen species (ROS). Augmentation of ROS generation by ROS accumulating agent or by knockdown of PRDX2 from myeloid cells effectively increased drug sensitivity and apoptosis as a consequence of reduced cell proliferation. DNMT3A-R882C/H mutations decreased apoptosis induction in part by increasing the antioxidant capacity of the cell owing to upregulation of PRDX2. Molecularly, both DNMT3A-WT and R882H/C mutants interacted with PRDX2; and R882C/H mutation-induced hypomethylation increased PRDX2 expression which enhanced cell proliferation and growth with impairment of apoptosis, thereby contributing to leukemogenesis. PMID- 30245402 TI - One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites. AB - Malaria drug discovery has shifted from a focus on targeting asexual blood stage parasites, to the development of drugs that can also target exo-erythrocytic forms and/or gametocytes in order to prevent malaria and/or parasite transmission. In this work, we aimed to develop parasite-selective histone deacetylase inhibitors (HDACi) with activity against the disease-causing asexual blood stages of Plasmodium malaria parasites as well as with causal prophylactic and/or transmission blocking properties. An optimized one-pot, multi-component protocol via a sequential Ugi four-component reaction and hydroxylaminolysis was used for the preparation of a panel of peptoid-based HDACi. Several compounds displayed potent activity against drug-sensitive and drug-resistant P. falciparum asexual blood stages, high parasite-selectivity and submicromolar activity against exo-erythrocytic forms of P. berghei. Our optimization study resulted in the discovery of the hit compound 1u which combines high activity against asexual blood stage parasites (Pf 3D7 IC50: 4 nM; Pf Dd2 IC50: 1 nM) and P. berghei exo erythrocytic forms (Pb EEF IC50: 25 nM) with promising parasite-specific activity (SIPf3D7/HepG2: 2496, SIPfDd2/HepG2: 9990, and SIPbEEF/HepG2: 400). PMID- 30245405 TI - Bio-inspired ultrasensitive colorimetric detection of methyl isothiocyanate on nylon-6 nanofibrous membrane: A comparison of biological thiol reactivities. AB - Living organisms, including human beings, rapidly show skin color changes after chemical poisonings, a result of toxicological or detoxification reactions caused by biological thiol compounds. On the other side, quick and portable detection of highly-volatile toxicants is an urgent need for improving human safety and personal protection, especially real-time monitoring of fumigants at low level for protection of farm workers and residents from overexposure of fumigants, vaporous pesticides. Here, we designed a rapid and portable detection method for methyl isothiocyanate (MITC) vapor by mimicking detoxification reactions of biological thiols in human bodies with MITC. The detection reaction was implemented on a nylon-6 nanofibrous membrane with ultrahigh surface areas to show color signals with the addition of Ellman's reagent. The reactivities of glutathione, N-acetyl-L-cysteine, L-homocysteine, cysteamine, and thioglycolic acid toward MITC were experimentally explored and theoretically discussed. The detection sensitivity is tunable in different biological thiol systems, which broadens the sensor applications in detection of trace amount of MITC in ambient environment and improves the protection of human safety. The new sensor system reduced the sensor operation time to 15 min and achieved the detection limit of 99 ppb, much lower than its permissible exposure limit (220 ppb). PMID- 30245406 TI - Oryza sativa class III peroxidase (OsPRX38) overexpression in Arabidopsis thaliana reduces arsenic accumulation due to apoplastic lignification. AB - ClassIII peroxidases are multigene family of plant-specific peroxidase enzyme. They are involved in various physiological and developmental processes like auxin catabolism, cell metabolism, various biotic, abiotic stresses and cell elongation. In the present study, we identified a class III peroxidase (OsPRX38) from rice which is upregulated several folds in both arsenate (AsV) and arsenite (AsIII) stresses. The overexpression of OsPRX38 in Arabidopsis thaliana significantly enhances Arsenic (As) tolerance by increasing SOD, PRX GST activity and exhibited low H2O2, electrolyte leakage and malondialdehyde content. OsPRX38 overexpression also affect the plant growth by increasing total biomass and seeds production in transgenics than WT under As stress condition. Confocal microscopy revealed that the OsPRX38-YFP fusion protein was localized to the apoplast of the onion epidermal cells. In addition, lignification was positively correlated with an increase in cell-wall-associated peroxidase activities in transgenic plants. This study indicates the role of OsPRX38 in lignin biosynthesis, where lignin act as an apoplastic barrier for As entry in root cells leading to reduction of As accumulation in transgenic. Overall the study suggests that overexpression of OsPRX38 in Arabidopsis thaliana activates the signaling network of different antioxidant systems under As stress condition, enhancing the plant tolerance by reducing As accumulation due to high lignification. PMID- 30245407 TI - Epidemiology of hallucinogen use in the U.S. results from the National epidemiologic survey on alcohol and related conditions III. AB - BACKGROUND: Population-based data regarding the epidemiology of hallucinogen use and co-occurring psychiatric disorders is largely absent from the literature. We aim to present findings on the prevalence, sociodemographic correlates, psychiatric comorbidity, treatment utilization, social support and associated disability of hallucinogen use using nationally representative data. METHOD: We analyzed data from the National Epidemiologic Study on Alcohol and Related Conditions-III (2011-2012, N = 36,309). We conducted multivariate logistic regression analyses in unadjusted and adjusted models in order to explore the odds of psychiatric disorders and associated disability among hallucinogen users. RESULTS: Prevalence of twelve-month and lifetime hallucinogen use was 0.62% and 9.32%, respectively. Hallucinogen use was found to be significantly associated with mood disorders, anxiety disorders, eating disorders, personality disorders and substance use disorders. Following adjustment, significant associations were retained with several substance use disorders (adjusted odds ratio (AOR) for heroin use disorder = 4.89 (95% CI, 1.90-12.58), personality disorders (AOR = 2.10 (95% CI, 1.81-2.44)), Post-Traumatic Stress Disorder (AOR = 1.86, 95% CI 1.00-3.45) and past suicide attempts (AOR = 1.49, 95% CI 1.21-1.85). CONCLUSIONS: Lifetime hallucinogen use in the US is prevalent and highly comorbid with other substance use and psychiatric disorders. Hallucinogen Use Disorder is relatively uncommon, with a low risk of development following exposure to hallucinogens. There are significant associations between hallucinogen use and substance use disorders, personality disorders, PTSD and past suicide attempts. The evolving therapeutic utility of this class of substances requires further assessment of short- and long-term risks of use, before large scale clinical application is pursued. PMID- 30245408 TI - Elastoplastic behavior of highly cross-linked and vitamin E-stabilized polyethylene - A biomechanical study. AB - BACKGROUND: Vitamin E-stabilized cross-linked polyethylene has been touted to alleviate the negative effects of oxidation. Although it has demonstrated significant improvements in wear resistance, bio-tribology, and oxidative resistance, little is known about the effect of antioxidants and dosage of cross linking on the mechanical strength. This study aimed to evaluate the mechanical properties of these novel materials, which are commonly used in orthopedic implants. METHODS: Samples of different polymers were prepared with various levels of cross-linking and with or without vitamin E-stabilization and then tested according to ASTM D695 and D638. The elastoplastic characteristics under compression and tension were compared between the groups. FINDINGS: Vitamin E stabilized cross-linked polyethylene showed a significant increase in elastic modulus over other groups, with a maximum increase of 26% in compression and 40% in tension when compared to the highly cross-linked group without vitamin E stabilization. The elastoplastic behavior under compression differed to that in tension for all polymers, demonstrating the anisotropic characteristics of these polymers. INTERPRETATION: The lower mechanical strength of highly cross-linked polyethylene has been a complication with the use of this polymer in orthopedic liners. This current study suggests that vitamin E-stabilized cross-linked polyethylene could be a suitable alternative material for knee implants because of its improved strength in resisting external forces. PMID- 30245409 TI - An investigation of global-local processing bias in a large sample of typical individuals varying in autism traits. AB - Although individuals with an autism spectrum disorder display impaired function across several social and behavioral domains, they possess intact, and often superior visual processing abilities for local relative to global aspects of their visual environment. To address whether differences in visual processing similarly vary within typical individuals as a function of their level of social competence, using the Navon hierarchical figures task, here we examined the relationship between global-local visual processing style and the number of autism-like traits in a large sample of 434 typically developed persons. In line with the existing literature, our data indicated an overall global processing bias. However, this overall visual processing style did not vary with participants' number of autism-like traits. These results suggest that the visual processing of Navon figures may be different in typical individuals vs. those with an autism spectrum disorder, with those differences potentially reflecting specific stimulus and task settings. PMID- 30245410 TI - Designing a network of green infrastructure to enhance the conservation value of protected areas and maintain ecosystem services. AB - There is a growing demand for holistic landscape planning to enhance sustainable use of ecosystem services (ESS) and maintenance of the biodiversity that supports them. In this context, the EU is developing policy to regulate the maintenance of ESS and enhance connectivity among protected areas (PAs). This is known as the network of Green Infrastructure (GI). However, there is not a working framework defined to plan the spatial design of such network of GI. Here, we use the software Marxan with Zones, to prioritize the spatial distribution of different management zones that accommodate the needs of a network of GI. These zones included a conservation zone, mainly devoted to protecting biodiversity, a GI zone, that aimed at connecting PAs and maintaining regulating and cultural ESS; and a management zone devoted to exploiting provisioning ESS. We performed four planning scenarios that distribute the targets for ESS and biodiversity in different ways across management zones. We also conducted a sensitivity analysis by increasing ESS targets to explore trade-offs that may occur when managing together biodiversity and ESS. We use Catalonia (northeastern Spain) as a case study. We found that the representation of ESS could be achieved for intermediate targets in all scenarios. There was, however, a threshold on these targets over which trade-offs appeared between maintaining regulating and cultural ESS and biodiversity versus getting access to provisioning ESS. These "thresholds values" were displaced towards higher ESS targets when we moved from more strict to more flexible planning scenarios (i.e., scenarios that allowed mixing representation of objectives for biodiversity and ESS within the same zone). This methodological approach could help design a framework to integrate biodiversity and ESS management in holistic plans and decision making and, at the same time, meeting European mandates concerning the design of GI networks, or similar needs elsewhere. PMID- 30245411 TI - Optimization and toxicity assessment of a combined electrocoagulation, H2O2/Fe2+/UV and activated carbon adsorption for textile wastewater treatment. AB - In this study, the potential application of sequential Electrocoagulation + Fenton (F) or Photo-Fenton (PF) + Active carbon adsorption (EC + F/PF + AC) processes were analyzed as alternatives for the treatment of an industrial textile wastewater resulting from an industrial facility located in Medellin (Colombia). In order to maximize the organic matter degradation, each step of the treatment was optimized using the Response Surface Methodology. At first, the optimal performance of EC was achieved with Fe electrodes operating at pH = 7, jEC = 10 mA/cm2 and 60 rpm, during 10 min of electrolysis. At these conditions, EC let to remove 94% of the dye's color, 56% of the COD and 54% of the TOC. Next, sequentially applied Fenton or photo-Fenton process (i.e., EC + F/PF), operating at the optimized conditions (pH = 4.3, [Fe2+] = 1.1 mM, [H2O2] = 9.7 mM, stirring velocity = 100 rpm and reaction time = 60 min.), improved the quality of the treated effluent. The EC + F let to achieve total color reduction, as well as COD and TOC removals of 72 and 75%, respectively. The EC + PF reached 100% of color, 76% of COD and 78% of TOC reductions. The EC + F/PF processes were more efficient than EC in elimination of low molecular weight (<5 kDa) compounds from wastewater. Moreover, the BOD5/COD ratio increased from 0.21 to 0.42 and from 0.21 to 0.46 using EC + F and EC + PF processes, respectively. However, EC + F/PF were not fully effective for the removal of acute toxicity to Artemia salina: 20% and 60% of reduction in toxicity using EC + F and EC + PF, respectively, comparing to very toxic (100%) raw textile wastewater. Thus, activated carbon adsorption was applied as an additional step to complete the treatment. After AC adsorption, the acute toxicity decreased to 10% and 0% using EC + F and EC + PF, respectively. The total operational costs, including chemical reagents, electrodes, energy consumption and sludge disposal, were of 1.65 USD/m3 and 2.3 USD/m3 for EC + F and EC + PF, respectively. PMID- 30245412 TI - A deeper look at plant uptake of environmental contaminants using intelligent approaches. AB - Uptake of contaminants from the groundwater is one pathway of interest, and efforts have been made to relate root exposure to transloation throughout the plant, termed the transpiration stream concentration factor (TSCF). This work utilized machine learning techniques and statistcal analysis to improve the understanding of plant uptake and translocation of emerging contaminants. Neural network (NN) was used to develop a reliable model for predicting TSCF using physicochemical properties of compounds. Fuzzy logic was as a technique to examine the simultaneous impact of properties on TSCF, and interactions between compound properties. The significant and effective compound properties were determined using stepwise and forward regression as two widely used statiscal techniques. Clustering was used for detecting the hidden structures in the plant uptake data set. The NN predicted the TSCF with improved accuracy compared to mechanistic models. We also delivered new insight to compound properteis and their importance in transmembrane migration. The sensitivity analysis indicated that log Kow, molecular weight, hydrogen bond donor, and rotatable bonds are the most important properties. The results of fuzzy logic demonstrated that the relationship between molecular weight and log Kow with TSCF are both bell-shape and sigmoidal. The employed clustering algorithms all discovered two major distinct clusters in the data set. PMID- 30245413 TI - Growth inhibition and oxidative stress caused by four ionic liquids in Scenedesmus obliquus: Role of cations and anions. AB - Ionic liquids (ILs) are widely used in various industrial applications. However, they are considered potential toxins in aquatic environments because of their physical stability and solubility. The growth inhibition and oxidative stress induced by four ionic liquids with different cations and anions on the green algae Scenedesmus obliquus was investigated in this study. The order of growth inhibition was 1-hexyl-3-methylimidazolium nitrate ([HMIM]NO3) > 1-hexyl-3 methylimidazolium chloride ([HMIM]Cl) > N-hexyl-3-metylpyridinium bromide ([HMPy]Br) > N-hexyl-3-metylpyridinium chloride ([HMPy]Cl). Imidazolium IL had a higher growth inhibition effect than pyridinium IL, nitrate IL and bromide IL had a higher effect than chloride IL. Reactive oxygen species (ROS) level in S. obliquus increased with increasing IL concentrations. Green fluorescence in [HMIM]Cl treated algae showed increased brightness compared to the [HMPy]Cl treatment, and [HMIM]NO3 treatment produced increased brightness compared to the [HMPy]Br treatment, suggesting that higher ROS levels were induced by [HMIM]Cl and [HMIM]NO3. Soluble protein, catalase (CAT), and superoxide dismutase (SOD) activities were stimulated at lower concentrations but were inhibited at higher concentrations. Regression analysis suggested that ROS level is the main index responsible for oxidative stress induced by the four ILs. The ILs induced oxidative damage on S. obliquus, and ROS in high concentration treatments could not be effectively removed by the antioxidant system, leading to oxidative damage and ultimately resulting in growth inhibition and cell death. PMID- 30245414 TI - The residual tetracycline in pharmaceutical wastewater was effectively removed by using MnO2/graphene nanocomposite. AB - The object of this study was to remove the tetracycline (TC) residue in pharmaceutical wastewater after flocculation treatment. MnO2/graphene nanocomposite was synthesized by an in situ hydrothermal method and its TC removal rate was up to 99.4%. This nanocomposite had excellent water solubility. More importantly, the introduction of MnO2 nanorods allowed the avoidance of excessive stacking of treated graphene sheets during the adsorption process, which made the TC molecules to have more opportunities to make contact with the adsorbents. In order to eliminate the interference factors, the adsorption isotherm, kinetics, thermodynamics and mechanism were all studied in TC aqueous solution. The influence of solution pH, contact time, MnO2 loading amount, temperature and solution concentration on the adsorption process were also assessed. The main adsorption mechanism contributed to the complexation of Mn(IV) and pi-pi interactions of the benzene ring structure on treated graphene sheets with TC molecules. PMID- 30245415 TI - Impact of agricultural fertilization practices on organo-mineral associations in four long-term field experiments: Implications for soil C sequestration. AB - Soil organic carbon (SOC) associated with minerals is considered to be one of the most fundamental long-term SOC storage strategies, but little research has integrated the organo-mineral complexes regulated by long-term fertilization. Here, soil samples under three fertilization treatments (Control, no fertilization; NPK, chemical nitrogen, phosphorus and potassium fertilization; NPKM, NPK plus manure) from four 23-34 years long-term field experiment sites across China were examined. Chemical analyses indicated that vigorous iron (Fe) mobilization could be regulated by long-term fertilization regimes. Meanwhile, Fe K-edge X-ray absorption near-edge fine structure (XANES) demonstrated that compared to NPK treated soils, NPKM treated soils contained significantly higher concentration of poorly crystalline ferrihydrite. Results from both the Fourier transform infrared combined with two-dimensional correlation spectroscopy analyses (FTIR-2DCOS) and C 1 s X-ray photoelectron spectroscopy (XPS) revealed that aliphatic carbohydrate might play an important role in binding exogenous Fe(III) in all tested four soils. In addition, greater amounts of aromatic C (the most resistant soil C fraction) were under long-term treated NPKM than NPK soils. Furthermore, multiple regression analyses showed a significantly positive relationship between poorly crystalline Fe minerals and SOC or aromatic C. Such relationships indicated that aromatic functional groups had been attached to the poorly crystalline Fe minerals, which could also be protected from being transformed to the crystalline counterpart. In conclusion, results from our integrated spectroscopic analyses have evidenced greater improvement of both poorly crystalline Fe minerals and aromatic C in organically fertilized than in chemically fertilized soils. PMID- 30245416 TI - A comprehensive city-level GHGs inventory accounting quantitative estimation with an empirical case of Baoding. AB - Cities represent a critical source and primary unit of Greenhouse Gas (GHG) emissions. The accurate emission accounts of cities provide robust and solid data support for further emission analysis as well as the local low-carbon policy making. Restricted by the data and method lacking, there is a relative lag in city-level emission accounts. Thus, this study attempts to build an investigation based GHG emission inventory framework for cities. We include CO2, CH4, N2O, and SF6 emissions from five sources: energy activity, industrial processes/product use, agriculture, land use change/forestry, and waste disposal. This study then uses Baoding as a case study to analyse its emission characteristics. Baoding is a low-carbon pilot city in China, which is a core and crucial city in Jing-Jin-Ji area. It is also the origin of the recently established Xiongan New Area, which has great strategic development significance. The results show that energy activity is the highest emission source followed by waste disposal processes in Baoding. Emissions induced by electricity input that brought from other provinces or cities account for another considerable emission proportion as well. Moreover, agricultural activity, which is a pillar industry in Baoding, contributes the most to methane emissions. Several emissions reduction policy recommendations are provided. PMID- 30245417 TI - Thermal stratification dynamics in a large and deep subtropical reservoir revealed by high-frequency buoy data. AB - We measure the thermal stratification dynamics in Lake Qiandaohu, China, a deep subtropical reservoir, to better understand the mixing mechanism and its response to lake warming. A high-frequency monitoring buoy dataset from February 2016 to October 2017 is used to evaluate variations in the water temperature profile, Schmidt stability (SS) and thermocline parameters, such as the thermocline depth (TD), bottom depth (TB), thickness (TT), and strength (TS), and elucidate the potential effects of thermal stratification on the lake's ecosystem. High frequency observation data demonstrate that the lake's thermal-stratification cycle can be divided into three stages: formation, stationary and weakening periods. Consequently, a significant positive correlation between the TB and TT during the formation period and a significant negative correlation between the TD and TT are found during the stationary and weakening periods. Additionally, strong positive correlations exist among the TS, TT and SS for all the data. Our data indicated that an increase in the air temperature caused the surface water temperature, TT, TS and SS to increase. Furthermore, thermal stratification affected the vertical distribution of dissolved oxygen and expanded the area of the hypoxic-anoxic zone. The incomplete mixing of the water from December 2016 to February 2017 because of the high air temperature, which was 2.49 degrees C higher than the mean air temperature of 1966-2015 (6.44 degrees C), created the hypoxia hypolimnion from March to May 2017. Under the background of global warming, the thermal stratification of Lake Qiandaohu will likely intensify and further significantly affect the lake's ecosystem. PMID- 30245418 TI - C:N ratio shaped both taxonomic and functional structure of microbial communities in livestock and poultry breeding wastewater treatment reactor. AB - C:N ratios play critical roles in determining the stability and performance of the wastewater treatment reactor. Here, we investigated bacterial and archaeal community composition, diversity, association networks, and functional profiles in livestock and poultry breeding wastewater (LPBW) with C:N gradients from 7.8 to 18.9 using 16S rRNA gene amplicon sequencing. Highest total nitrogen (TN) and total phosphorous (TP) removal rates were detected in the wastewater with high C:N ratios, while bacterial and archaeal communities in the wastewater varied across the four C:N ratios. Proteobacteria, Acidobacteria, and Bacteroides were generally the dominant phyla in the wastewater across treatments, with Candidatus Saccharibacteria being more enriched in the wastewater with high C:N ratios. Association network analysis showed that specific bacterial and archaeal taxa likely have similar metabolic activities allowing them to respond similarly to different C:N ratios. Bacteroidetes, Actinobacteria, Verrucomicrobia, Candidatus Saccharibacteria, and Proteobacteria were the keystone species found in the networks. Most dominant bacterial functions in the wastewater were chemoheterotrophy and aerobic chemoheterotrophy. Nitrite respiration, nitrous oxide denitrification, nitrate denitrification and nitrite denitrification were up-regulated with increased C:N ratios. Our findings provide new insights into our understanding of the compositions, potential associations, and predicted functional profiles of the microbial community in LPBW treated with different C:N ratios. PMID- 30245419 TI - The safety of tattoo inks: Possible options for a common regulatory framework. AB - Tattoo prevalence has been increasing in the last 25 years, but specific regulations on tattoo inks are still missing. In the European Union, no supranational regulation is available and only few national provisions cover them. In the United States, tattoo inks are classified as cosmetics but are not approved for injection into the dermis. Health risks for consumers may derive from microbiological contamination and the presence of toxic substances or nanomaterials. However, current regulations and non-binding recommendations, where present, only address the microbiological and chemical risks, completely overlooking nanotoxicity. The aim of this paper is to promote awareness of the risks associated with tattoo inks and the nanomaterials contained therein. In particular, the need for a harmonised regulation or, at least, a set of minimal requirements is highlighted to improve the safety of tattoo inks and market surveillance by regulatory authorities. PMID- 30245421 TI - Does short-term salinization of freshwater alter the behaviour of the Iberian barbel (Luciobarbus bocagei, Steindachner 1864)? AB - Stream salinization is a great environmental hazard being aggravated by anthropogenic disturbances. Harmful conditions, as increasing salinity in freshwater systems, may negatively affect river fish fauna and possibly influence fish behaviour, such as boldness and/or cerebral lateralization. Salinity has been proven to affect behavioural expression, despite the tolerance of some species. It is thus relevant to study these behaviours, as the salinity exposure effects could represent greater environmental consequences. The impact of salinity stress was evaluated by exposing Iberian barbels, Luciobarbus bocagei (Steindachner, 1864) (Cypriniformes, Cyprinidae), to three levels of salinity (0.9, 9 and 19 mS/cm, using NaCl) and by conducting boldness and lateralization experiments, regarding population trends. Results show that, with increased salinity, fish diverged to the extremes of the shy-bold gradient, the population was slightly lateralized to the left, and seemed to become more lateralized with increasing salinity. However, there were no statistical differences between the treatments. Fish living in a Mediterranean climate are especially resilient to various stressors, which may confer them additional tolerance, and in this case, acute punctual exposure to increased salinity may not be detrimental for behaviour maintenance. We encourage the expansion of the research to different freshwater fish species that would help to recognise salinity thresholds and use them to implement effective conservation measures and appropriate ecological restoration actions for these sensible systems. PMID- 30245420 TI - Impact of emissions from the Ports of Los Angeles and Long Beach on the oxidative potential of ambient PM0.25 measured across the Los Angeles County. AB - In this study, weekly samples of ambient PM0.25 (particulate matter with an aerodynamic diameter <0.25 MUm) were collected in three contrasting locations, including central Los Angeles (USC), north Long Beach (NLB), and the Port of Long Beach (PRT), during June and July of 2017 to evaluate the chemical composition of ambient PM0.25 and identify the sources that contribute to the oxidative potential of ambient PM0.25 in these locations. Special focus was given in exploring the impact of emissions from the Ports of Los Angeles and Long Beach on the oxidative potential of ambient PM0.25 measured across these sites. The oxidative potential of the collected samples was quantified by means of an in vitro cell-based alveolar macrophage (AM) assay. We used multiple linear regression (MLR) analysis to link individual measured species, used as source markers, to the oxidative potential of the ambient PM0.25 across the monitoring sites. Results from the MLR analysis indicated that vehicular emissions and secondary organic aerosols (SOA) were the major contributors to the oxidative potential of ambient PM0.25 across the three sites, with corresponding contributions of 40 +/- 2% and 39 +/- 3%, respectively. Emissions of PM0.25 related to port activities, including emissions from ships, locomotives, and heavy-duty vehicles (HDVs) operating at the port, accounted for 16 +/- 3% of the overall oxidative potential of the ambient PM0.25 samples. The concentrations of the marker species at the three different sites suggested that the contributions of port-related emissions to the oxidative potential of PM0.25 decreased from the port area to central Los Angeles, underscoring the greater impact of these emissions on the PM0.25 toxicity in the communities near the Ports of Los Angeles and Long Beach, whereas we observed larger impact of SOA formation and vehicular emissions on the oxidative potential of ambient PM0.25 in the receptor sites located further inland. PMID- 30245422 TI - Spatial diversity of Cr distribution in soil and groundwater sites in relation with land use management in a Mediterranean region: The case of C. Evia and Assopos-Thiva Basins, Greece. AB - The present study compiles new and literature data in a GIS platform aiming to (a) evaluate the extent and magnitude of Cr contamination in a Mediterranean region (Assopos-Thiva and Central Evia (Euboea) Basins, Greece); (b) combine spatial distribution of Cr in soil and groundwater with land use maps; (c) determine geochemical constraints on contamination by Cr; and (d) provide information that will be useful for better management of land use in a Mediterranean type ecosystem in order to prevent further degradation of natural resources. The spatial diversity of Cr distribution in soils and groundwater throughout the C. Evia and Assopos-Thiva Basins is considered. It is attributed to both natural Cr sources (Cr-bearing peridotites, affecting primarily soil) and human (industrial) activities (the dominant source of groundwater contamination). A combination of the spatial distribution of metals in soil and land use maps was used to define the specific areas of agricultural land use with elevated heavy metal contents. Furthermore, the combination of the spatial distribution of Cr in groundwater and land use maps allows for definition of specific areas of industrial land use with elevated Cr concentrations (Inofita, south Assopos-Thiva Basin). Despite the good correlation (r = 0.75) between Cr(VI) and the strong oxidant NO3- in C. Evia, the lower standard potential (E0) values for NO3- compared to those for Cr2O72- (the latter is a stronger oxidant than the former) suggest that NO3- is not an oxidant of Cr. This detailed assessment and presentation of the available analytical data for soil and groundwater in Assopos Thiva and C. Evia Basins on a land use map provides information for land management decision makers. PMID- 30245423 TI - Hydrodynamics of salt flat basins: The Salar de Atacama example. AB - The Salar de Atacama is one of the most well-known saline endorheic basins in the world. It accumulates the world main lithium reserves and contains very sensitive ecosystems. The objective of this work is to characterize the hydrodynamics of the Salar de Atacama, and to quantify its complex water balance prior to the intense brine extraction. The methodology and results can be extrapolated to the groundwater flow and recharge of other salt flats. A three-dimensional groundwater flow model using low computational effort was calibrated against hundreds of hydraulic head measurements. The water infiltrated from the mountains ascends as a vertical flux through the saline interface (mixing zone) produced by the density contrast between the recharged freshwater and the evaporated brine of the salt flat nucleus. This water discharges and is largely evaporated from lakes or directly from the shallow water table. On the other hand, the very low hydraulic gradients, coupled with the presence of the mixing zone that operates as barrier, leads the salt flat nucleus to act as a hydrodynamically quasi isolated area. The computed water table shows the lowest hydraulic head in the salt flat nucleus near the discharge at the mixing zone. The groundwater balance of the Salar de Atacama in its natural regime was quantified resulting in an inflow/outflow of 14.9 m3.s-1. This balance considers the basin as an endorheic system. The very low infiltration values that are generally assumed for hyperarid basins are not consistent with the hydrogeology of the Salar de Atacama. Indeed, very high infiltration rates (up to 85% of rainfall) occur because of the high degree of fracturing of rocks and the scarce vegetation. This high infiltration is consistent with the light isotopic composition of the water from the recharge area (Altiplano). Therefore, the existence of additional inflows outside the basin is unlikely. PMID- 30245424 TI - Combination of passive and grab sampling strategies improves the assessment of pesticide occurrence and contamination levels in a large-scale watershed. AB - Fifty-one monitoring stations from the Water Framework Directive network (2000/60/CE) were selected in the Adour-Garonne basin (117,650 km2, SW France). These stations were characterized by a diversity of land use, implying different water pesticide contamination profiles. In each, Polar Organic Chemical Integrative Sampler (POCIS) deployment (14 days) and grab water samples (1 per period) were performed 6 times in 2016 in order to obtain contamination levels (29 pesticides monitored). The large amount of data collected during this 1-year monitoring required specific graphical and map processing to compare the information provided by POCIS and grab samples. Graphical projections demonstrated that with POCIS the number of quantified pesticides and the quantification frequencies were higher than with grab samples. Additionally, projections showed that POCIS provided better temporal representativeness of monthly contamination levels. Indeed, the POCIS data showed seasonal trends which were directly linked with the use of each pesticide (application period) and the land use of each sampling site, that was not visible with the grab samples data. Map projections of the measured concentrations, using a common scale for the two sampling strategies, clearly showed the strengths of the POCIS deployment and the link between measured contamination levels, quantified pesticides and land use. Finally, this study shows that the combination of grab sample data (magnitude of contamination peaks) and POCIS data (average concentration over a given period) provided more complete and reliable knowledge of the contamination levels in the Basin than either method alone. PMID- 30245425 TI - Microbial assessments of soil with a 40-year history of reclaimed wastewater irrigation. AB - The long-term effects on soil microorganisms from 40 years of irrigating soil with reclaimed wastewater was investigated by determining the quantity, composition, and inter-species connection of microorganisms. No significant difference in microbial quantity and composition were identified in the reclaimed wastewater- and groundwater-irrigated soils. The dominant bacterial phylum in both irrigation water sources and soils was Proteobacteria, which commonly exists in soil. From the analysis of four (4) alpha diversity metrics, including the observed number of operational taxonomic units (OTUs), Chao1, and the Shannon and Simpson diversity, there was no significant difference between the reclaimed wastewater- and groundwater-irrigated soils. Three zones (shallow, medium and deep) were identified in the reclaimed wastewater- and groundwater-irrigated soils based on the taxonomic networks and clusters generated by graphical lasso and random walk algorithm. The cluster profiles (shallow, medium and deep zones) appear to be different in the reclaimed wastewater- and groundwater-irrigated soils. Soil irrigated with reclaimed wastewater showed less depth of clustered profile in medium zone than that in soil irrigated with groundwater (20-60 cm of reclaimed wastewater-irrigated soil compared to 20-100 cm of groundwater irrigated soil), although the significance of such a variance (the depth of medium zone of reclaimed wastewater-irrigated soil decreased 40 cm than that of groundwater-irrigated soil) is not clear at this time. Positive influence has been identified in the growth and yield of eggplant, tomato and cucumber between the reclaimed wastewater- and groundwater-irrigated soils, suggesting that reclaimed wastewater irrigation can potentially substitute groundwater irrigation, despite the variance in inter-species clustering profiles in soil microbes in certain soil zones. Nevertheless, the possible negative influence of pathogens, organic compounds and pharmaceuticals should be seriously considered during the reclaimed wastewater irrigation. PMID- 30245426 TI - Effects of arginine on the growth and microcystin-LR production of Microcystis aeruginosa in culture. AB - Although toxic cyanobacterial blooms and their toxins threaten drinking water and ecology and are promoted by nutrient loading, the precise nutrient regime that increases cyanobacterial populations and toxin production is poorly understood. Here, the influences of arginine (Arg), as a common amino acid with high nitrogen content, on the growth and microcystins (MCs) production of Microcystis aeruginosa (M. aeruginosa) were investigated by an isotope method (15N). The results showed that the biomass and production of microcystin-LR (MC-LR) increased with an increase in initial Arg concentrations in the range of 0.3-1.4 mmol-N L-1, whereas a higher Arg concentration (3.6 mmol-N L-1) inhibited the growth. MC-LR on different days (days 0, 6, 12, and 18) was detected by liquid chromatography with tandem mass spectrometry (LC-MS/MS) after incubation with 15N Arg. The MC-LR molecular weight increased from 995 to 1004 with 100% relative abundance with 10 15N atoms bound by the Adda, Arg (4 15N), Glu, Mdha, Ala, Leu, and MeAsp residues on day 18. It seems that there was a sequential order when M. aeruginosa assimilated Arg to synthesize MC-LR. The Arg residue in the molecule of MC-LR was the last one to be labeled by 15N from 15N-arginine. This study not only presents a deeper insight into the biosynthesis of free amino acids that are incorporated into MCs but also reminds us of the potential risk caused by Arg, which should arouse concerns. PMID- 30245427 TI - Short-term effects of thinning on soil CO2, N2O and CH4 fluxes in Mediterranean forest ecosystems. AB - In Mediterranean ecosystems an increasing demand for in situ trace gas exchange data is emerging to enhance the adaptation and mitigation strategies under forest degradation. Field-chamber green-house gas fluxes and site characteristics were analysed in two Mediterranean peri-urban pine forests showing degradation symptoms. We examined the effect of different thinning interventions on soil CO2, CH4 and N2O fluxes, addressing the relationships with the environmental variables and C and N contents along forest floor-soil layers. Soil temperature resulted as the main driving variable for CO2 efflux and CH4 uptake. Soil moisture content and organic matter availability affected CO2 emission patterns in the two sites. N2O fluxes showed a positive correlation with soil moisture under wetter climatic conditions only. GHG fluxes showed significant correlations with C and N content of both forest floor and mineral soil, especially in the deepest layers, suggesting that it should be considered, together with environmental variables when accounting GHG fluxes in degraded forests. Short-term effects of thinning on CO2 emissions were dependent on disturbance induced by logging operations and organic matter inputs. After thinning CH4 uptake increased significantly under selective treatment, independently from specific site-induced effects. N2O fluxes were characterized by low emissions in both sites and were not affected by treatments. Soil CO2 efflux was the largest component of global warming potential (GWP) from both sites (11,553 kg ha-1 y-1 on average). Although it has a large global warming potential, N2O contribution to GWP was about 131 kg CO2eq ha-1 y 1. The contribution of CH4-CO2 equivalent to total GWP showed a clear and significant CH4 sink behaviour under selective treatment (36 kg ha-1 y-1 on average). However, in the short-term both thinning approaches produced a weak effect on total GWP. PMID- 30245428 TI - An uncertain future for the endemic Galliformes of the Caucasus. AB - Impacts of climate change are already evident in ecosystems worldwide. High latitude and altitude regions are at greatest risk because the effects of climate change are greater in these regions, and species from these areas have limited ability to track their climate envelopes. The Caucasian snowcock (Tetraogallus caucasicus) and the Caucasian grouse (Lyrurus mlokosiewiczi) are both high altitude specialists that are endemic to a restricted range in the Caucasus mountains of Europe. Little research has been performed to determine the status of the populations or the potential impacts of climate change. We investigated how climate and land use change may impact both species in future and determined whether their life history traits may increase their vulnerability using a combined exposure and trait-based index. We compared several climate models, and in all instances, both species showed drastic range contractions although the extent of the contraction varied with each model. Traits like habitat specialism, ground nesting and incubation period meant that both species may be considered "most vulnerable" in the exposure and trait-based index. Given that both species already occur near the maximum elevations of the Caucasus, and that they lack any dispersal capabilities due to the isolation from alternative mountainous areas, research efforts need to be prioritized to improve our knowledge about their population status, to monitor future trends and to begin developing species action plans that conserve these endemic and iconic species of Europe. Both species are flagship and umbrella species and may serve as indicator species, their protection may therefore benefit a whole range of other species inhabiting this vulnerable Alpine ecosystem. Especially the Caucasian grouse has a high aesthetic value and is favoured by hunters in the region. The potential demise of this species may therefore also be negative for local communities. PMID- 30245429 TI - A novel approach for examining downstream thermal responses of streams to contemporary forestry. AB - Temperature is a fundamental driver of aquatic environments. Changes in thermal regimes due to timber harvest may be detrimental for cold-water instream biota. Although it is understood that stream temperature may increase immediately below timber harvest operations, the understanding of how thermal responses propagate downstream is less clear. Here, we examine the effects of timber harvest on stream temperature pre- (2-3 years) and post-harvest (5 years) at 16 sites (average annual streamflow rates <0.283 m3 s-1) located in the Coast Range, Oregon, USA. At each site, an array of temperature sensors were deployed on the extremes of three consecutive reaches: an upstream unharvested reference reach, a treatment reach, and a downstream unharvested reach. We used several metrics to describe and evaluate changes over time and space focusing on the responses of downstream reaches. Primarily, we evaluated the differences over time in daily maximum temperature between the two sensors located at the downstream unharvested reach. Furthermore, using a statistical ordination technique, we examined the spatial and temporal variability of an array of sensors for daily maximum temperature. Moreover, we assessed distributional shifts (statistical moments) of hourly temperature differences between the two sensors at the downstream unharvested reach over time. Lastly, we used a combination of statistical moments and the ordination technique to provide an index that describes the behavior of site-specific thermal disturbance over time. We found that stream reaches responded differently to upstream timber harvest operations between pre and post harvest summer seasons. In addition, we showed distinct patterns of longitudinal variability of temperature across sites and summer seasons with increases, decreases or mixed responses including no change downstream. Overall, the net change of daily maximum temperature at the downstream reach revealed that the highest difference occurred during the first and second year post-harvest and, in some cases, a distinctive shift in stream warming and cooling occurred between the day and the night. Observed temperature patterns in downstream reaches were most similar to the pre-harvest conditions at the fifth year post-harvest. Collectively, we offer a novel approach for assessing stream temperature regime change using multiple metrics that can improve our understanding of thermal effects downstream of timber harvest, taking in consideration idiosyncratic responses across sites and time. PMID- 30245430 TI - Kinetics and reaction pathway of Aroclor 1254 removal by novel bimetallic catalysts supported on activated carbon. AB - Bimetallic catalysts supported on activated carbon (AC) with high metal loadings were prepared by an ion-exchange method. AC-supported Ni-Cu, Ni-Zn and Ni-Pd bimetallic catalysts were used to decompose Aroclor 1254, which is one of the most commonly used commercial mix of polychlorinated biphenyls. Characterization by scanning electron microscopy and energy-dispersive X-ray analysis showed that the metals were uniformly distributed on the surfaces and inside the catalysts. The efficiencies of Aroclor 1254 decomposition were measured at different reaction temperatures and times. With increasing temperature, the catalytic activities increased and the activation energies of the reactions decreased, resulting in higher decomposition efficiencies. At 300 degrees C in a nitrogen atmosphere, Aroclor 1254 decomposition efficiencies of 99.3%, 99.4% and 99.5% were achieved for reactions with Ni-Cu/C, Ni-Zn/C and Ni-Pd/C, respectively. The kinetics and pathway of the decomposition reaction were discussed, and we concluded that the reactivity of the chlorine atoms located on the benzene rings followed the order para-position > meta-position > ortho-position. The PCBs were dechlorinated stepwise to form the final biphenyl product. The design concept and synthetic strategy developed in this study are of great significance in the disposal of chlorinated organic compounds, for use with the existing adsorption technology of AC. PMID- 30245431 TI - Optimal approximation of piecewise smooth functions using deep ReLU neural networks. AB - We study the necessary and sufficient complexity of ReLU neural networks - in terms of depth and number of weights - which is required for approximating classifier functions in an Lp-sense. As a model class, we consider the set Ebeta(Rd) of possibly discontinuous piecewise Cbeta functions f:[-12,12]d->R, where the different "smooth regions" of f are separated by Cbeta hypersurfaces. For given dimension d>=2, regularity beta>0, and accuracy epsilon>0, we construct artificial neural networks with ReLU activation function that approximate functions from Ebeta(Rd) up to an L2 error of epsilon. The constructed networks have a fixed number of layers, depending only on d and beta, and they have O(epsilon-2(d-1)/beta) many nonzero weights, which we prove to be optimal. For the proof of optimality, we establish a lower bound on the description complexity of the class Ebeta(Rd). By showing that a family of approximating neural networks gives rise to an encoder for Ebeta(Rd), we then prove that one cannot approximate a general function f?Ebeta(Rd) using neural networks that are less complex than those produced by our construction. In addition to the optimality in terms of the number of weights, we show that in order to achieve this optimal approximation rate, one needs ReLU networks of a certain minimal depth. Precisely, for piecewise Cbeta(Rd) functions, this minimal depth is given - up to a multiplicative constant - by beta/d. Up to a log factor, our constructed networks match this bound. This partly explains the benefits of depth for ReLU networks by showing that deep networks are necessary to achieve efficient approximation of (piecewise) smooth functions. Finally, we analyze approximation in high dimensional spaces where the function f to be approximated can be factorized into a smooth dimension reducing feature map tau and classifier function g - defined on a low-dimensional feature space - as f=g?tau. We show that in this case the approximation rate depends only on the dimension of the feature space and not the input dimension. PMID- 30245432 TI - A novel training method to preserve generalization of RBPNN classifiers applied to ECG signals diagnosis. AB - In this paper a novel training technique is proposed to offer an efficient solution for neural network training in non-trivial and critical applications such as the diagnosis of health threatening illness. The presented technique aims to enhance the generalization capability of a neural network while preserving its sensitivity and precision. The implemented method has been devised in order to slowly increase, during training, the generalization capabilities of a Radial Basis Probabilistic Neural Network classifier, as well as preventing it from over generalization and the consequent lack of resulting classification performances. The developed method was tested on Electrocardiograms. These latter are generally considered non-trivial both due to the difficulty to recognize some anomalous heart activities, and due to the intermittent nature of abnormal beat occurrences. The implemented training method obtained satisfactory performances, sensitivity and precision while showing high generalization capabilities. PMID- 30245433 TI - An improved robust heteroscedastic probabilistic neural network based trust prediction approach for cloud service selection. AB - Trustworthiness is a comprehensive quality metric which is used to assess the quality of the services in service-oriented environments. However, trust prediction of cloud services based on the multi-faceted Quality of Service (QoS) attributes is a challenging task due to the complicated and non-linear relationships between the QoS values and the corresponding trust result. Recent research works reveal the significance of Artificial Neural Network (ANN) and its variants in providing a reasonable degree of success in trust prediction problems. However, the challenges with respect to weight assignment, training time and kernel functions make ANN and its variants under continuous advancements. Hence, this work presents a novel multi-level Hypergraph Coarsening based Robust Heteroscedastic Probabilistic Neural Network (HC-RHRPNN) to predict trustworthiness of cloud services to build high-quality service applications. HC RHRPNN employs hypergraph coarsening to identify the informative samples, which were then used to train HRPNN to improve its prediction accuracy and minimize the runtime. The performance of HC-RHRPNN was evaluated using Quality of Web Service (QWS) dataset, a public QoS dataset in terms of classifier accuracy, precision, recall, and F-Score. PMID- 30245434 TI - Efficacy of platelet transfusion in the management of acute subdural hematoma. AB - OBJECTIVE: Oral Antithrombotic Therapy has become a well documented predisposing risk factor in the development of traumatic intracranial hemorrhage. Currently, a reversal protocol for antiplatelet therapy remains ill-defined in the management of non-surgical traumatic subdural hematoma and there is no evidence to suggest a clear benefit of platelet transfusion to mitigate the effect of antiplatelet agents. This study aims to establish parameters in which platelet transfusion would be of benefit in patients with non-surgical traumatic subdural hematoma with preinjury antiplatelet therapy. PATIENTS AND METHODS: This study is a retrospective chart review of patents from 2015 to 2018 at two Level II trauma centers identifying consecutive patients with non-surgical acute traumatic subdural hematomas. Patients with use of aspirin and/or clopidogrel were categorized into subgroups based on transfusion of platelets for antiplatelet reversal therapy, and were compared to a control group. The primary outcome measure was the presence of subdural hematoma expansion. RESULTS: A total of 72 patients met the criteria for inclusion in this study. The average age of the cohort was 75.4 with a median of 77.5. There were 40 males and 32 females. Chi square analysis was performed which demonstrated statistical significance for difference between the aspirin and clopidogrel group for percent of hematoma expansion (p = 0.0284). Patients on antiplatelet therapy (n = 36) were grouped together and compared to patients without antiplatelet therapy (n = 36), this demonstrated that the transfusion of platelets for patients on antiplatelet agents (n = 19/36) still resulted in a significant hematoma expansion in (n = 7/19, 36.8%) compared to patients not on antiplatelet therapy (n = 3/36, 8.3%) (p = 0.0001). CONCLUSION: The results of this study suggest that patients with non surgical traumatic subdural hematomas on presentation are less likely to expand, however the risk of expansion is greater when the patient is on antiplatelet therapy. There is no clear benefit in the use of platelet transfusion as a reversal agent to mitigate the effects of antiplatelet therapy in the setting of non-surgical traumatic subdural hematomas. PMID- 30245435 TI - White matter diffusion abnormalities in migraine and medication overuse headache: A 1.5-T tract-based spatial statistics study. AB - OBJECTIVES: Migraine and medication overuse headache are common, but its pathophysiology remains unclear. Differential diagnosis of chronic headache is still challenging. Conventional brain imaging techniques exclude secondary causes of headache but cannot produce a proper diagnosis. Accordingly, more sensitive diagnostic methods are needed for certain diagnosis. In the present study, we performed voxel-wise tract-based spatial statistics of 1.5-T diffusion tensor imaging in migraine patients and healthy volunteers. PATIENTS AND METHODS: One hundred and three migraine patents and 46 healthy volunteers were registered. The fractional anisotropy values in the white matter of each group compared to age matched healthy volunteers. RESULTS: Compared to the controls, the migraine without aura with medication overuse headache had remarkable fractional anisotropy decrease in the white matter in several regions. The migraine with aura without medication overuse headache also had significant fractional anisotropy decrease compared to the controls. The disease duration and frequency of migraine attack were not correlated with fractional anisotropy values of the corpus callosum. CONCLUSION: Our 1.5-T DTI study demonstrated significantly lower fractional anisotropy in the white matter in the MoA with medication overuse headache and MwA without medication overuse headache groups, suggesting that fractional anisotropy abnormalities may be useful biomarkers in headache patients. PMID- 30245436 TI - Use of Genie 2000 and Excel VBA to correct for gamma-ray interference in the determination of NORM building material activity concentrations. AB - The gamma-radiation emitted by building materials is calculated from the activity indices for 232Th, 226Ra and 40K and expressed as the activity concentration index (ACI). Gamma spectroscopy is a non-destructive technique frequently used to simultaneously determine the indices for several radionuclides. Spectral interpretation poses a number of challenges, including identification of gamma lines subject to summing-in effects, interference from other gamma-ray emitting radionuclides and the time required to reach secular equilibrium. These challenges are not fully addressed by Canberra Industries' Genie 2000, the software used by many laboratories to analyse samples. This article describes a Microsoft Excel workbook that exploits Genie 2000 flexibility to program applications with Visual Basic using Canberra's Nuclear Data Access Library and batch procedure tools. The workbook determines 40K activity concentration after correcting for 228Ac interference and 226Ra activity directly from the gamma-peak at 186.5 keV. The method proposed was tested by participating in 13 national and international scale inter-comparison exercises. The results were statistically indistinguishable from the reference values at a coverage factor of k = 3 and no statistically significant differences were identified between the respective means by a Student's t pairwise comparison. PMID- 30245437 TI - The influence of core power distribution on neutron flux density behind a pressure vessel of a VVER-1000 Mock Up in LR-0 reactor. AB - The neutron flux distribution behind a reactor pressure vessel (RPV) is an important parameter that is monitored to determine neutron fluence in the RPV. Together with mechanical testing of surveillance specimens, these are the most important parts of in-service inspection programs that are essential for a realistic and reliable assessment of the RPV residual lifetime. The fast neutron fluence values are determined by a calculation. These calculation results are accompanied by measurements of induced activities of the activation foils placed in the capsules behind the RPV at selected locations, namely in azimuthal profile. In case of discrepancies between the measured and calculated activities of the activation foils placed behind the pressure vessel, it is difficult to determine the source of the deviation. During such analysis, there arises a question on the influence of power peaking near core boundary on neutron profile behind the RPV. This paper compares the calculated and measured increase of the neutron flux density distribution behind the reactor pressure vessel in the azimuthal profile that has arisen from the replacement of 164 fuel pins located close to reactor internals by pins with the higher enrichment. This work can be understood as the first step in the characterization of the effect of incorrectly calculated pin power or burn-up in the fuel assembly at the core boundary relative to the neutron flux distribution behind reactor pressure vessel. Based on a good agreement between the calculated and experimental values, it can be concluded that the mathematical model used to evaluate the power increase is correct. PMID- 30245438 TI - Optimization design of betavoltaic battery based on titanium tritide and silicon using Monte Carlo code. AB - This article presents the optimization design and simulation of a betavoltaic battery composed of a silicon p-n junction converter and a titanium tritide film as an isotope source. The self-absorption of beta particles emitted from the tritium radioisotope in the titanium tritide film and the energy deposition of beta particles in the silicon converter are investigated by the Monte Carlo simulation with the Geant4 radiation transport toolkit. The relationships between doping concentrations and basic parameters such as depletion region width, minority carrier diffusion length and leakage current of the PN junction are discussed through the calculation formulas. By optimizing the doping concentrations in the P-type and N-type regions, the optimized betavoltaic battery can maximize the output power and the conversion efficiency based on the energy deposition in the silicon. The results show that the optimal thickness of the titanium tritide film is about 0.7 um and the optimal doping concentrations of the battery with a PN junction depth of 50 nm are Na=5.75*1019cm 3,Nd=2.95*1018cm-3. Under these parameters, the size 1mm*1mm proposed battery with 2.9 mCi/mm2 3H can achieve the output power 0.902 nW and the conversion efficiency 0.91%. The open circuit voltage, short circuit current and fill factor of the battery are 0.389 V, 3.03 nA and 0.766, respectively. PMID- 30245439 TI - Simplified and automatable radiochemical separation strategy for the production of radiopharmaceutical quality 86Y using single column extraction chromatography. AB - We present a simplified, automatable single-column radiochemical separation method using the extraction chromatographic branched-DGA resin for the production of no-carrier-added 86Y with a radiochemical yield higher than 95%, an apparent molar activity of 1.4 +/- 0.4 Ci/MUmol (DOTA) and 2.3 +/- 0.7 Ci/MUmol (DTPA), and a run-to-run recycling efficiency of the isotopically-enriched target of 98 +/- 1%. These results enable the preparation of 86Y radiopharmaceuticals for 86Y/90Y-based cancer theranostic applications. PMID- 30245440 TI - Development, validation and implementation of radio-HPLC methods for the P2X7 receptor-targeted [11C]GSK1482160 radiopharmaceutical. AB - A radio-analytical RP-HPLC method was developed and validated to support production of the P2X7-receptor-targeted [11C]GSK1482160 radiopharmaceutical. Method validation included characterization of retention times, peak shapes, linearity, accuracy, precision, selectivity, limits of detection and quantitation (UV signal), radiochemical stability, as well as analytical method range and robustness. The validated radio-HPLC method is suitable for the definition of [11C]GSK1482160 radiochemical identity, radiochemical purity, as well as molar activity, and is being employed in support of human studies with [11C]GSK1482160. PMID- 30245441 TI - Distinguishing the progression of an endometrioma: Benign or malignant? AB - OBJECTIVE: To elucidate the immunohistochemical (IHC) differences of endometrioma tissues that may have the potential to progress to ovarian clear cell carcinoma (OCCC) by using KRAS, HNF1beta, PIK3CA, PPP2R1A, and ARID1A as biomarkers. STUDY DESIGN: This is a retrospective clinical study, which was conducted in an university hospital. The groups comprised 14 patients with endometrioma resection who later developed OCCC (non-healthy endometrioma-case group) and 66 patients with endometrioma resection who did not develop ovarian cancer in subsequent follow-ups (healthy endometrium-control group). IHC staining with KRAS, HNF1beta, PIK3CA, PPP2R1A, and ARID1A antibodies was performed in paraffin blocks of endometriomas obtained in both groups. For KRAS, PIK3CA, PPP2R1A, and ARID1A, cell staining intensity on a scale from 0 (negative) to 3 (strongly positive), and for HNF1beta, the percentage of stained cells (0-5) and the intensity of staining (0-3) were scored. RESULTS: KRAS, HNF1beta, PIK3CA, PPP2R1A, and ARID1A were overexpressed in the case group samples compared with the endometrioma samples in the epithelial cells, and ARID1A and KRAS in the stroma were overexpressed in the case group samples compared with the matched control samples. CONCLUSIONS: KRAS, HNF1beta, PIK3CA, PPP2R1A, and ARID1A immunostaining scores in endometriomas previous to OCCC were significantly different than in endometriomas with no malignancy occurring in subsequent follow-ups, and were single predictors of OCCC. Hence, immunostaining with these biomarkers may be a method of identifying patients with endometrioma who have the potential to develop OCCC. PMID- 30245442 TI - Unexpected uterine sarcomas in 4478 patients with electric power morcellation for leiomyomas. AB - OBJECTIVES: Our objective is to investigate the prevalence, pathology and prognosis of uterine sarcomas in laparoscopic hysterectomy/myomectomy with electric power morcellation for presumed leiomyomas. STUDY DESIGN: We retrospectively reviewed patients with laparoscopic power morcellation (LPM) for presumed leiomyomas in a Chinese tertiary institution by chart review from September 1, 2013 to December 31, 2016. RESULTS: Twenty-four in 4478 patients (0.54%) with LPM for presumed leiomyomas had unexpected cancers. The patients showed the highest frequency of occult cancers (10/375, 2.6%) at 51-60 years and lowest (0/255) before 30 years. The pathology included 14 endometrial stromal sarcomas (ESS) (low-grade 12 and high-grade 2), 9 leiomyosarcomas, and 1 malignant mixed mesodermal tumor. The patients underwent abdominal re-exploration including total hysterectomy with bilateral salpingo-oophorectomy and staging surgery. Three patients were at advanced FIGO stage (IIIb-IVb) and 21 at stage I. Seven patients recurred within 1-25 (mean 6.29) months including 5 leiomyosarcomas, 1 high-grade and 1 low-grade ESS. Four recurrent patients with leiomyosarcomas and one with high-grade ESS died of disease in 1-3 months. Seventeen patients had no relapse and were alive for 6-41 (mean 24) months. CONCLUSIONS: Our study suggests that patients with LPM for presumed leiomyomas appear to have a considerable risk of unexpected cancers. Moreover, morcellation is potentially associated with adverse prognosis in patients with high-grade sarcomas. Informed consent on unexpected cancers that should be discussed before morcellation. PMID- 30245443 TI - Thromboprophylaxis in gynecologic cancer surgery: Is extended prophylaxis with low molecular weight heparin justified? AB - OBJECTIVE: Evidence on the optimal duration of thromboprophylaxis with low molecular weight heparin after gynecologic cancer surgery is scarce and the benefits of extended prophylaxis have not been validated specifically in these patients. The aim of this study is to assess the efficacy and safety of postoperative venous thromboembolism (VTE) prophylaxis with enoxaparin 40 mg for 28 days, as recommended by international guidelines, compared to 7 days in patients undergoing surgery for gynecologic cancer. STUDY DESIGN: Prospective cohort study compared to a historic cohort of women who underwent surgery for gynecologic cancer in our center between 2004 and 2014. Pre- and postoperative screening with a routine duplex scan was done in the prospective cohort. Comparative analysis of comorbidity, surgical technique and incidence of VTE, as well as prognostic factors of events and mortality. RESULTS: N:571 patients (28 days: 207, 7 days: 364). No significant differences were identified between groups in regard to the factors related to VTE in our series. There were no differences in VTE incidence between groups after one month (1.9% vs 1.4%; p = 0.729), 90 days (2.4% vs 2.5%; p > 0.99) or during follow-up (Breslow p = 0.156). No deaths due to VTE at 90 days were recorded. Only one case of asymptomatic DVT was identified in the screening with duplex. The incidence of postoperative bleeding was similar in both groups (0.5% vs 2.2%; p = 0.166). The presence of a history of VTE was the only independent risk factor for VTE after one month (OR 14.31 CI 95% 2.67-76.87; p = 0.002) and 90 days (OR 8.27 CI 95% 1.65-41.45; p = 0.010). No differences were identified regarding age, other comorbidities, type of tumor, stage, surgical approach, reintervention or adjuvant therapy in the multivariate analysis. CONCLUSION: Extended prophylaxis for 28 days with enoxaparin did not improve the rates of VTE following gynecologic oncological surgery in our series compared to the 7-day therapy, although neither was this extended duration associated with adverse events or mortality. PMID- 30245444 TI - Zona pellucida birefringence and meiotic spindle visualization are not related to the time-lapse detected embryo morphokinetics in women with polycystic ovarian syndrome. AB - OBJECTIVES: Oocyte parameters as well as embryo developmental kinetics can be applied as non-invasive predictors for selection of viable embryos and clinical outcomes. Time-lapse morphokinetic events in conjunction with zona pellucida birefringence (ZPB) and meiotic spindle visualization (MSV) have been evaluated for predicting pregnancy outcome. STUDY DESIGN: We assessed a total of 547 embryos from 100 intra cytoplasmic sperm injection cycles in women with polycystic ovary syndrome (PCOS) and tubal factor infertility. ZPB and MSV were evaluated in 100 oocytes using polarized microscope. Time-lapse archives were noted for time to pronuclear fading (tPNf), time to 2-8 cells (t2-t8), direct cleavage, reverse cleavage and also for the presence of multinucleation. RESULTS: The mean timings of embryo morphokinetics were not significantly different between high and low ZPB and visible and not-visible meiotic spindle oocytes in the PCOS group (P > 0.05). Furthermore implantation rate was 4.6 fold higher in embryos derived from oocytes with visible meiotic spindles compared to those without visible meiotic spindle in PCOS patients (P < 0.05). We observed that chemical and clinical pregnancy rates as well as live birth were higher in transferred embryos which formed from oocytes with visible meiotic spindle (27.6% vs.16.7%),(24.1% vs. 8.3%) and (24.1% vs. 8.3%) respectively. According to logistic regression analysis, only tPNf significantly influenced clinical pregnancy and live birth (P < 0.05). CONCLUSION: Time-lapse embryo parameters are not related to oocyte ZPB and MSV status. However, clinical pregnancy and live birth have been affected by the presence of meiotic spindle. PMID- 30245445 TI - Effects of glyphosate on the ovarian function of pregnant mice, the secretion of hormones and the sex ratio of their fetuses. AB - Glyphosate is the active ingredient of the commercial formulation Roundup(r), which is used worldwide. This study aimed to investigate the toxic effects of pure glyphosate or Roundup(r) on pregnant mice and their fetuses during pregnancy. From gestation days (GDs) 1-19, ICR mice were orally administered distilled water, 0.5% glyphosate solution or 0.5%-glyphosate Roundup(r) solution. The ovaries and serum were collected at GD19. The results showed decreases in body weight gain and, ovary and liver weight in glyphosate-treated mice. Additionally, histopathological alterations in the ovary including increased atretic follicles, interstitial fibrosis and decreased mature follicles were observed in the groups treated with glyphosate. The serum concentrations of both progesterone and estrogen were markedly altered after glyphosate exposure, and there were also changes in the expression of GnRH, LHR, FSHR, 3beta-HSD and Cyp19a1 genes at the hypothalamic-pituitary-ovarian axis. Furthermore, oxidative stress was observed in the treated mice, increasing the activity of T-AOC, CAT and GSH-Px, as well as the MDA content in both the serum and ovary. With regard to litters, the sex ratio was significantly altered by pure glyphosate. These results show that glyphosate is able to cause several effects on pregnant mice, such as ovarian failure, interference with hormone secretion by affecting the steroidogenesis-related gene expression, and oxidative stress. The sex ratio of litters was also influenced by prenatal exposure to pure glyphosate. PMID- 30245446 TI - Optimal-combined model for air quality index forecasting: 5 cities in North China. AB - Air pollution forecasting is significant for public health and controlling pollution, and statistical methods are important air pollution forecasting techniques. Nevertheless, the research of AQI (air quality index) forecasting is very rare. So an accurate and stable AQI forecasting model is very urgent and necessary. For the high complex, volatile and nonlinear AQI series, this research presents a novel optimal-combined model based on CEEMD (complementary ensemble empirical mode decomposition), PSOGSA (particle swarm optimization and gravitational search algorithm), PSO (particle swarm optimization) and combined forecasting method. The proposed model effectively solves the blind combined forecasting. AQI series forecasts of five cities in North China show that the proposed model has the highest correct rate of forecasting classifications compared with the candidates. Totally, the presented model has the following advantages compared with the candidates: more robust forecasting performance, smaller forecasting error and better generalization ability. PMID- 30245447 TI - PM2.5 exposure during pregnancy induces hypermethylation of estrogen receptor promoter region in rat uterus and declines offspring birth weights. AB - Particulate matter 2.5 (PM2.5) exposures during pregnancy could lead to declined birth weight, intrauterine developmental restriction, and premature delivery, however, the underlying mechanisms are still not elucidated. There are few studies concerning the effects of PM2.5 exposure on maternal and child health in Xi'an (one of the cities with severe air pollution of PM2.5 in North China). Then, this study aimed to investigate the effect of PM2.5 exposure in Xi'an on the offspring birth weights and the possibly associated epigenetic mechanisms. We found the Low and High groups: the offspring with declined birth weights; the decreased mRNA and protein expression of the estrogen receptor (ERs) and eNOs in the uterus; the decreased endometria vascular diameter maximum (EVDM); the increased mRNA and protein expressions of the DNMT1 and 3b in the uterus; the elevated methylation levels of the CpG sites in the CpG island of ERalpha promoter region in the uterus. However, no differences were observed in the mRNA or protein expressions of ERbeta and DNMT3a between the Clean and PM2.5 exposure groups, as well as endometriavascular density (EVD). Additionally, PM2.5 level was negatively correlated with the ERalpha protein expression, EVDM and offspring birth weight, as well as the methylation level of the CpG sites in the CpG island of ERalpha promoter region and the ERalpha protein expression in the uterus; whereas the ERalpha protein expression was positively correlated with the offspring birth weight, as well as PM2.5 level and the methylation level of the CpG sites in the CpG island of ERalpha promoter region in the uterus. Taken together, elevated methylation level of the CpG sites in the CpG island of ERalpha promoter region reduces ERalpha expression in the uterus, which could be one of the epigenetic mechanisms that pregnant PM2.5 exposure reduces the offspring birth weights. PMID- 30245448 TI - Field and laboratory evaluation of DGT for predicting metal bioaccumulation and toxicity in the freshwater bivalve Hyridella australis exposed to contaminated sediments. AB - The diffusive gradients in thin films (DGT) technique has shown to be a useful tool for predicting metal bioavailability and toxicity in sediments, however, links between DGT measurements and biological responses have often relied on laboratory-based exposures and further field evaluations are required. In this study, DGT probes were deployed in metal-contaminated (Cd, Pb, Zn) sediments to evaluate relationships between bioaccumulation by the freshwater bivalve Hyridella australis and DGT-metal fluxes under both laboratory and field conditions. The DGT-metal flux measured across the sediment/water interface (+/-1 cm) was useful for predicting significant cadmium and zinc bioaccumulation, irrespective of the type of sediment and exposure. A greater DGT-Zn flux measured in the field was consistent with significantly higher zinc bioaccumulation, highlighting the importance of performing metal bioavailability assessments in situ. In addition, DGT fluxes were useful for predicting the potential risk of sub-lethal toxicity (i.e., lipid peroxidation and lysosomal membrane damage). Due to its ability to account for multiple metal exposures, DGT better predicted bioaccumulation and toxicity than particulate metal concentrations in sediments. These results provide further evidence supporting the applicability of the DGT technique as a monitoring tool for sediment quality assessment. PMID- 30245449 TI - Impact of manganese ferrite (MnFe2O4) nanoparticles on growth and magnetic character of barley (Hordeum vulgare L.). AB - The main objective of this study was to assess the uptake and translocation of MnFe2O4 magnetic nanoparticles (MNPs) in hydroponically grown barley (Hordeum vulgare L.). Hydrothermally synthesized and well characterized MNPs (average crystallite size of 14.5 +/- 0.5 nm) with varied doses (62.5, 125, 250, 500, and 1000 mg L-1) were subjected to the plants at germination and early growing stages (three weeks). The tissues analyzed by vibrating-sample magnetometer (VSM) and transmission electron microscopy (TEM) revealed the uptake and translocation of MNPs, as well as their internalization in the leaf cells. Also, elemental analysis proved that manganese (Mn) and iron (Fe) contents were ~7-9 times and ~4 7 times higher in the leaves of MNPs-treated plants than the ones for non-treated control, respectively. 250 mg L-1 of MNPs significantly (at least p < 0.05) promoted the fresh weight (FW, %10.25). However, higher concentrations (500 and 1000 mg L-1) remarkably reduced the increase to %8 and %5, respectively, possibly due to the restricted water uptake. Also, catalase activity was increased from 91 (MUM H2O2 min-1 mg-1) to 138 in leaves, and decreased to 66 in roots upon 1000 mg L-1 of MNPs application. Chlorophyll and carotenoid contents were not significantly changed, except chlorophyll a (%6 increase at 1000 mg L-1, p < 0.05). Overall, MnFe2O4 NPs were up-taken from the roots and migrated to the leaves which promoted the growth parameters of barley. Hence, MNPs can be suggested for barley breeding programs and can be proposed as effective delivery system for agrochemicals. However, the possible negative effect of MNPs due to its potential horizontal transfer from plants to animals via the food chain must be also considered. PMID- 30245450 TI - The influence of three e-cigarette models on indoor fine and ultrafine particulate matter concentrations under real-world conditions. AB - Electronic cigarette (e-cigarette) use has steadily increased since 2010. Indoor e-cigarette use exposes bystanders to a new source of particulate matter (PM) air pollution. Elevated short-term exposures to PM with a lower measuremented aerodynamic diameter (<=2.5 MUm), PM2.5 and ultrafine particles (UFPs) have been linked to increased risk of adverse respiratory and cardiac events. This exposure study estimated concentrations of PM2.5 and UFPs from indoor e-cigarette use at 0.5 meters (m) and 1 m away from an e-cigarette user and investigated whether these indoor concentrations varied across three common e-cigarette models. One e cigarette user tested three different e-cigarettes containing the same nicotine solution on three separate occasions and measured concentrations on PM2.5 and UFPs at 0.5 and 1 m in a ~38 m3 office. Continuous measures of PM2.5 and UFPs were taken for 5.5 min before e-cigarette use, then the user puffed seven times for 6.5 min (exposure), and for 10 min after ceasing e-cigarette use. Following the initiation of e-cigarette use, levels of PM2.5 increased 160-fold at a distance of 0.5 m, and 103-fold at 1 m. The corresponding increases in UFP counts were 5.2, and 3.0-fold higher, respectively. The PM2.5 concentrations and UFP counts between e-cigarette models were statistically significantly different at 1 m, but not at 0.5 m. There was substantial variability between distances, e cigarettes, and replicates. This study indicates that e-cigarette vapors influence PM2.5 and UFPs concentrations/counts at close proximity distances indoors; additional research is needed to characterize the composition of those particles and evaluate the impacts of other e-cigarette solutions on indoor air quality. PMID- 30245451 TI - Does sea-dyke construction affect the spatial distribution of pesticides in agricultural soils? - A case study from the Red River Delta, Vietnam. AB - The Red River Delta is a major agricultural production area of Vietnam with year round use of pesticides for paddy rice cultivation and other production systems. The delta is protected from flooding, storm surges and saline water intrusion by a sophisticated river and sea-dyke system. Little is known about the effects of such a dyke system on pesticide pollution in the enclosed landscape. Our aim was to address this gap by i) determining pesticide prevalence in soils and sediments within a dyked agricultural area, and by ii) assessing whether and to which degree this dyke system might affect the spatial distribution of pesticides. After sampling paddy rice fields (topsoil) and irrigation ditches (sediment) perpendicular to the dyke in Giao Thuy district, we analysed 12 of the most commonly used pesticides in this area. In soils, we detected most frequently isoprothiolane (100% detection frequency), chlorpyrifos (85%) and propiconazole (41%) while in sediments isoprothiolane (71%) and propiconazole (71%) were most frequently found. Maximum concentrations reached 42.6 MUg isoprotiolane kg-1 in soil, and 35.1 MUg azoxystrobin kg-1 in sediment. Our results supported the assumption that the dyke system influenced residue distribution of selected pesticides. More polar substances increasingly accumulated in fields closer to the sea-dyke (R2 = 0.92 for chlorpyrifos and 0.51 for isoprothiolane). We can thus support initiatives from local authorities to use the distance to dykes as a mean for deliniating zones of different environmental pollution; yet, the degree at which dykes influence pesticide accumulation appear to be compound specific. PMID- 30245452 TI - Field-realistic exposure to the androgenic endocrine disruptor 17beta-trenbolone alters ecologically important behaviours in female fish across multiple contexts. AB - The capacity of pharmaceutical pollution to alter behaviour in wildlife is of increasing environmental concern. A major pathway of these pollutants into the environment is the treatment of livestock with hormonal growth promotants (HGPs), which are highly potent veterinary pharmaceuticals that enter aquatic ecosystems via effluent runoff. Hormonal growth promotants are designed to exert biological effects at low doses, can act on physiological pathways that are evolutionarily conserved across taxa, and have been detected in ecosystems worldwide. However, despite being shown to alter key fitness-related processes (e.g., development, reproduction) in various non-target species, relatively little is known about the potential for HGPs to alter ecologically important behaviours, especially across multiple contexts. Here, we investigated the effects of exposure to a field realistic level of the androgenic HGP metabolite 17beta-trenbolone-an endocrine disrupting chemical that has repeatedly been detected in freshwater systems-on a suite of ecologically important behaviours in wild-caught female eastern mosquitofish (Gambusia holbrooki). First, we found that 17beta-trenbolone-exposed fish were more active and exploratory in a novel environment (i.e., maze arena), while boldness (i.e., refuge use) was not significantly affected. Second, when tested for sociability, exposed fish spent less time in close proximity to a shoal of stimulus (i.e., unexposed) conspecific females and were, again, found to be more active. Third, when assayed for foraging behaviour, exposed fish were faster to reach a foraging zone containing prey items (chironomid larvae), quicker to commence feeding, spent more time foraging, and consumed a greater number of prey items, although the effect of exposure on certain foraging behaviours was dependent on fish size. Taken together, these findings highlight the potential for exposure to sub-lethal levels of veterinary pharmaceuticals to alter sensitive behavioural processes in wildlife across multiple contexts, with potential ecological and evolutionary implications for exposed populations. PMID- 30245453 TI - Effects of a glyphosate-based herbicide on Fucus virsoides (Fucales, Ochrophyta) photosynthetic efficiency. AB - Herbicides are increasingly recognised as sources of water pollution. Glyphosate based herbicides (GBHs) are widely used because of their low cost and high effectiveness. By measuring the photosynthetic efficiency of Fucus virsoides fronds exposed to a GBH (Roundup(r) Power 2.0), we investigated the effect of a continuous exposure (6 days) and the potential of recovery after a short exposure (24 h). Both experiments were carried out combining GBH with and without nutrient enrichment, simulating a runoff event. A factorial experimental design allowed us to assess the potential of interactions between GBH and nutrients, which are likely to co-occur in coastal areas. Our results show deleterious effects of GBH at low concentration on F. virsoides, independently from the duration of exposure and the presence of nutrients. PMID- 30245454 TI - The organic molecular composition, diurnal variation, and stable carbon isotope ratios of PM2.5 in Beijing during the 2014 APEC summit. AB - Organic tracers are useful for investigating the sources of carbonaceous aerosols but there are still no adequate studies in China. To obtain insights into the diurnal variations, properties, and the influence of regional emission controls on carbonaceous aerosols in Beijing, day-/nighttime PM2.5 samples were collected before (Oct. 15th - Nov. 2nd) and during (Nov. 3rd - Nov. 12th) the 2014 Asia Pacific Economic Cooperation (APEC) summit. Eleven organic compound classes were analysed using gas chromatography/mass spectrometry (GC/MS). In addition, the stable carbon isotope ratios (delta13CTC) of total carbon (TC) were detected using an elemental analyser/isotope ratio mass spectrometry (EA/irMS). Most of the organic compounds were more abundant during the night than in the daytime, and their concentrations generally decreased during the APEC. These features were associated with the strict regional emission controls and meteorological conditions. The day/night variations of delta13CTC were smaller during the APEC than those before the APEC the summit, suggesting that regionally transported aerosols are potentially played an important role in the loading of organic aerosols in Beijing before the APEC summit. The source apportionment based on the organic tracers suggested that biomass burning, plastic and microbial emissions, and fossil fuel combustion were important sources of organic aerosols in Beijing. Furthermore, a similar contribution of biomass burning to OC before and during the APEC suggests biomass burning was a persistent contributor to PM2.5 in Beijing and its surroundings. PMID- 30245455 TI - Graphite particle electrodes that enhance the detoxification of municipal solid waste incineration fly ashes in a three-dimensional electrokinetic platform and its mechanisms. AB - This paper investigated the application of graphite particle electrodes to the removal of Zn, Pb, Cu, and Cd from municipal solid waste incineration (MSWI) fly ashes in a three-dimensional (3D) electrokinetic reactor. The influences of the voltage gradient, mass ratio of graphite powers to fly ashes, nitric acid concentrations, proposing times, and liquid-solid (L-M) ratios on the remedial efficiencies of MSWI fly ashes were comprehensively studied in an orthogonal deign and a sequential double-factor setup. Significant analysis showed that changes in the mass ratios and nitric acid concentrations both had a statistically significant effect on the removals of Zn and Pb. Proposing times and L-M ratios both remarkably affected the removals of heavy metals (HMs) in a 3D electrochemical system. The graphite powers had a narrower distribution interval and slightly larger surface areas compared with MSWI fly ashes, which relented pH gradients over the time in the electrochemical experiments and minimized the bubble barricade caused by the hydrolysis. The particle electrode had increased the residue factions of Zn, Pb, Cu, and Cd in S1 region by approximately 216%, 136%, 309%, and 950%, respectively, compared with the raw MSWI fly ashes. The addition of graphite powders to a two-dimensional (2D) electrochemical process strengthened hydrolysis reactions, shortened time for the redistribution of pH balance, decreased the tortuosity of migration path, and increased the desorption concentrations of HMs in the sample area. PMID- 30245456 TI - Impact of soil clay minerals on growth, biofilm formation, and virulence gene expression of Escherichia coli O157:H7. AB - Soil, composed mainly of minerals, plays a central role in the circulation of microbial pathogens in the environment. Herein, the growth, biofilm formation, and virulence gene expression of the pathogenic bacteria Escherichia coli O157:H7 were monitored following exposure to montmorillonite, kaolinite, and goethite, three common soil minerals in the clay size fraction. E. coli O157:H7 growth was notably promoted (P < 0.05), while biofilm formation was inhibited in the presence of montmorillonite (P < 0.05), which is attributed to the suppression of colanic acid (CA) production and an increase in bacterial motility. Kaolinite not only promoted bacterial growth (P < 0.05), but also contributed to biofilm formation upon stimulating CA production. Upon exposure to goethite, notably slower bacterial growth and higher biomass of biofilm were observed as compared to the control (P < 0.05). Goethite stimulated the synthesis of CA to encase cells in a protective biofilm in response to the tight association between bacteria and goethite, which could cause bacterial death. Additionally, the transcription of virulence factors (stxA-1 and stxA-2) was significantly decreased in goethite or kaolinite system (P < 0.05). These findings indicate that minerals play important roles in the physiological state of bacteria and ultimately govern the fate of this pathogen in soils. PMID- 30245457 TI - Outcome and predictive factors in post-stroke seizures: A retrospective case control study. AB - PURPOSE: To evaluate clinical, radiographic, and electrophysiological features in the development and prognosis of ischemic post-stroke seizures (PSS). METHOD: A retrospective study of 1119 patient records was performed between January 2006 and December 2016. After selection, 42 patients with seizures due to ischemic stroke were matched to a control group of 60 patients where seizures were absent. Stroke size and severity were analyzed using ASPECTS and NIHSS, respectively. Hemorrhagic transformation graded by ECASS III classification. Outcomes were assessed using the modified Rankin Scale. Fisher's exact test assessed categorical variables, and Mann-Whitney tested continuous variables. RESULTS: Forty-two patients experienced PSS (22 females; median age 72.5 years) and were matched with 60 control subjects that had ischemic stroke without seizures. Focal seizures were present in 42.9% (18/42), and focal to bilateral convulsions in 57.1% (24/42). Stroke localization and severity did not differ (p = 0.6 and 0.21, respectively). Stroke size in anterior circulation was larger in PSS patients (median ASPECTS 6 vs 8 [p = 0.01]). Posterior circulation stroke size was similar in both groups. The presence of hemorrhage was the primary risk factor for PSS (61.9%) compared to controls (36.7%), p = 0.01. The presence of laminar necrosis (LN) (47.6% vs 21.6%, p = 0.005) and hemosiderin deposition (38.1% vs 18.3%, p = 0.02) were most predictive. PSS patients demonstrated worse outcomes than the controls (median mRS 3 vs 2, [p=<0.001]) with a median follow up of 14.8 and 20.7 months, respectively. CONCLUSIONS: The size of anterior infarction, presence of blood products within the infarct bed, and especially LN predicted PSS. PMID- 30245458 TI - Subfield-specific tractography of the hippocampus in epilepsy patients at 7 Tesla. AB - PURPOSE: MRI-negative epilepsy patients could benefit from advanced imaging techniques such as high-resolution diffusion magnetic resonance imaging (dMRI). Our aim was to perform hippocampal subfield-specific tractography and quantify connectivity of the subfields in MRI-negative patients. Abnormal connectivity of the hippocampal subfields may help inform seizure focus hypothesis and provide information to guide surgical intervention. METHODS: Hippocampal structural imaging and dMRI was acquired in 25 drug resistant MRI-negative patients and 25 healthy volunteers. The hippocampi of each subject was segmented on high resolution structural images and dMRI-based probabilistic tractography was performed in each subfield. The degrees of connectivity and fiber densities of the hippocampal subfields were quantified and compared between epilepsy patients and healthy volunteers. RESULTS: We were able to perform subfield-specific hippocampal tractography in each subject that participated in this study. These methods identified some hippocampal subfields that are abnormally connected in MRI-negative patients. In particular patients suspected of left temporal seizure focus exhibited increased connectivity of certain ipsilateral subfields, especially the subiculum, presubiculum, and parasubiculum, and reduced connectivity of some contralateral subfields, such as CA1 and subiculum. CONCLUSIONS: Our data suggest that the hippocampal subfields are connected in distinct ways in different types of epilepsy. These results may provide important information that could help inform seizure focus hypothesis and in the surgical treatment of MRI-negative patients. These observations suggest that high resolution dMRI-based tractography of the hippocampal subfields can detect subtle abnormalities in otherwise normal-appearing MRI-negative patients. PMID- 30245459 TI - Regular MDMA use is associated with decreased risk of drug injection among street involved youth who use illicit drugs. AB - OBJECTIVES: Childhood trauma is common among street-involved youth and is associated with injection drug use. Illicit 3,4-Methylenedioxymethamphetamine (MDMA) use is also common among street-involved youth, and data suggest this substance has clinical utility in management of post-traumatic stress disorder (PTSD) and associated harms. Despite this, little is known about co-occurring patterns of MDMA use and injection drug use. METHODS: Data were derived from a prospective cohort of street-involved youth using illicit drugs in Vancouver, Canada. Using multivariable generalized estimating equation logistic regression, we examined the association between MDMA use and the use of injection drugs, adjusting for confounders such as polysubstance use and sociodemographic factors. RESULTS: 4941 surveys from 1208 participants between September 2005 and May 2015 were included. Of these, 829 (68.6%) were male, 815 (67.5%) reported white ethnicity, and median age was 21.7 years. Overall, 599 (49.6%) participants reported MDMA use, 544 (45.0%) reported injection drug use, and 244 (20.2%) reported concurrent MDMA and injection drug use at least once during the study period. In multivariable analyses, regular MDMA use was significantly negatively associated with injection drug use (Adjusted Odds Ratio [AOR] = 0.57, 95% CI: 0.46-0.69). DISCUSSION: After accounting for socio-demographic factors and polysubstance use, periods of reported regular MDMA use were negatively associated with reported injection drug use among this cohort. These findings suggest that, unlike the use of most other non-injection drugs, illicit MDMA use does not appear to promote injection drug use but rather is associated with a reduced likelihood of injection drug use. PMID- 30245460 TI - Usage of low dead space syringes and association with hepatitis C prevalence amongst people who inject drugs in the UK. AB - INTRODUCTION: Syringes with attached needles (low dead space syringes [LDSS]) retain far less blood following injection than syringes with detachable needles (high dead space syringes [HDSS]). People who inject drugs (PWID) who share needles/syringes may be less likely to acquire Hepatitis C virus (HCV) infection using LDSS, compared with HDSS, but data are limited. METHODS: Utilizing drug behavior and HCV antibody testing data from the UK 2014/2015 Unlinked Anonymous Monitoring Survey of PWID, we calculated the percentage of syringes used in the past month that were LDSS. We investigated which injecting characteristics and demographic factors were associated with 100% LDSS (against 0-99%) usage, and whether 100% LDSS use was associated with antibody HCV-status, after adjusting for confounders. RESULT: Of 2174 participants, 55% always used LDSS, 27% always used HDSS, and 17% used both LDSS and HDSS. PWID that had injected into their groin during the past month were unlikely to use LDSS, adjusted odds ratio (aOR) 0.14 (95% confidence interval 0.11-0.17), compared to those not using the groin. Those injecting crack were less likely to use LDSS than those not, aOR 0.79 (0.63 0.98). Polydrug use was negatively associated with LDSS use, aOR 0.88 (0.79-0.98) per additional drug. LDSS use was associated with lower prevalent HCV among all PWID (aOR 0.77, [0.64-0.93]), which was stronger among recent initiates (aOR 0.53 [0.30-0.94]) than among experienced PWID (aOR 0.81 [0.66-0.99]). DISCUSSION: People who inject into their groin were less likely to use LDSS. Exclusive LDSS use was associated with lower prevalence of HCV amongst PWID that started injecting recently, suggesting LDSS use is protective against HCV. PMID- 30245461 TI - E-cigarettes-An unintended illicit drug delivery system. AB - Since the introduction of electronic cigarettes (e-cigarettes) in 2003, the technology has advanced allowing for greater user modifications, with users now able to control voltage, battery power, and constituents of the e-cigarette liquid. E-cigarettes have been the subject of a growing body of research with most research justifiably focused on the chemical makeup and risk analysis of chemicals, metals, and particulates found in e-cigarette liquids and vapor. Little research to date has focused on assessing the risks associated with the drug delivery unit itself and its potential for use as an illicit drug delivery system. In light of this, a range of illicit drugs was researched focusing on pharmacodynamics, usual method of administration, the dosage required for toxicity, toxic effects, and evidence of existing use in e-cigarettes in both literature and online illicit drug forums. A systematic literature search found evidence of current use of e-cigarettes to vape almost all illicit drug types analyzed. This presents both a potential population health risk and a management issue for clinicians. It also raises the issue of policing illicit drugs due to potential altered characteristic smells and storage within e-cigarette fluids. E cigarettes are a viable illicit drug delivery system with evidence both inside and outside of the formal medical literature detailing their potential use for drug delivery of a wide range of illicit and legal drugs. PMID- 30245462 TI - Protective effect of syringaldehyde on biomolecular oxidation, inflammation and histopathological alterations in isoproterenol induced cardiotoxicity in rats. AB - BACKGROUND: Ischemic injury during myocardial infarction (MI) is responsible for increased deaths among patients with cardiovascular disorders. Recently, research has been directed for finding treatment using natural compounds. This study was performed to investigate the effects of syrigaldehyde (SYD), a phytochemical against isoproterenol (ISO) induced cardiotoxicity model. METHODS: For induction of MI, rats were intoxicated with two doses of ISO and were treated with SYD at three different concentrations (12.5, 25 & 50 mg/kg) both prior and simultaneous to ISO administration. RESULTS: ISO group revealed amplified activity of marker enzymes (CKMB, LDH, AST, ALT), increased oxidation of proteins and lipid molecules. Moreover, augmentation in pro-inflammatory markers was also found. The same group also displayed marked changes in histopathology and erythrocyte (RBCs) morphology. SYD treated groups showed diminished levels of serum markers enzymes, lipid peroxidation and protein carbonyl (PC) with increment in antioxidant defense in cardiac tissues of ISO administered rats. Our findings also revealed the modulatory effect of SYD on membrane bound ATPases, showing that SYD significantly improved the ISO induced changes in membrane fluidity. Furthermore, decline in infarct size, alleviation of structural RBC damage and improved myocardial histopathological outcome were observed in treated groups. In addition, mitigation of biochemical and histopathological changes by SYD was found to be dependent on its concentration. CONCLUSION: SYD had cardioprotective efficacy owing to its antioxidative and anti-inflammatory properties. Our results support incorporation of SYD in regular diet for prevention of MI. PMID- 30245463 TI - Protective effect of wax apple (Syzygium samarangense (Blume) Merr. & L.M. Perry) against streptozotocin-induced pancreatic beta-cell damage in diabetic rats. AB - The purpose of this study was to investigate the protective properties and mechanisms of wax apple (Syzygium samarangense (Blume)) against streptozotocin (STZ)-induced pancreatic beta-cell apoptosis in diabetic rats. Diabetes was induced by STZ (65 mg/kg; i.p.) injection and wax apple (100 mg/kg) was orally administered to diabetic rats for a period of 30 days. During this time, fasting blood glucose (FBG) and body weight were measured weekly. At the end of the experiment, serum insulin, HOMA-B, and pancreatic insulin expression were assessed. The expression of apoptosis-related proteins along with the nitrotyrosine level, antioxidant activities, and pro-inflammatory cytokine TNF alpha in the pancreas were also determined. STZ-induced diabetic rats exhibited an increase in FBG, and a decrease in body weight, serum and pancreatic insulin, as well as HOMA-B. Pancreatic apoptosis was noted in diabetic rats and indicated by enhancing the expression of cleaved caspase-3 and Bax proteins and downregulating the expression of Bcl-2 and Bcl-xl proteins. The activities of antioxidant CAT and SOD in the pancreas of the diabetic rats was also reduced. Importantly, wax apple treatment resulted in a significant reduction of FBG and increased body weight in diabetic rats. Wax apple also improved pancreatic beta cell function, this was clearly evidenced by increased HOMA-B and pancreatic and serum insulin levels in diabetic rats. Moreover, pancreatic beta-cell apoptosis was alleviated with significantly down-regulated cleaved caspase-3 and Bax protein expression, and upregulated Bcl-2 and Bcl-xl protein expression in wax apple treated diabetic rats. These were related to the induction of CAT and SOD activities, and reduction of nitrotyrosine and TNF-alpha levels in wax apple administration. Overall, these results provide evidence that wax apple protects against STZ-induced pancreatic beta-apoptosis and dysfunction in diabetic rats, possibly through inhibiting oxidative stress and pro-inflammatory cytokine, and activating anti-apoptotic proteins. PMID- 30245464 TI - Transcription factor 7-like 2 controls matrix degradation through nuclear factor kappaB signaling and is repressed by microRNA-155 in nucleus pulposus cells. AB - AIM: TCF7L2, a key transcription factor in the canonical Wnt pathway, plays a vital role in the matrix degradation of chondrocytes. However, it is unknown whether TCF7L2 is important in the matrix metabolism of inner gel-like nucleus pulposus (NP) cells; thus, the aim of this study was to explore the effect and mechanism of TCF7L2 in this process. METHODS: Western blotting and immunofluorescence analyses were used to observe TCF7L2 expression in rat and human NP tissues. Real-time PCR and western blotting were performed to detect the expression of TCF7L2 stimulated by inflammatory cytokines. Dual luciferase reporter assay, real-time PCR, western blotting and knockdown experiments were performed to demonstrate the role of NF-kappaB signaling in matrix regulation by TCF7L2 and the regulation of TCF7L2 by miR-155 in intervertebral disc degeneration. KEY FINDINGS: TCF7L2 is present in rat and human NP tissues and is expressed in the nucleus of NP cells. TCF7L2 is refractory to stimulation of rat and human NP cells with the inflammatory cytokines TNF-alpha and IL-1beta, in contrast to the results in other cell types. Loss-of-function experiments using TCF7L2 siRNA or lentiviral shTCF7L2 showed that TCF7L2 knockdown suppresses matrix degradation through p65/NF-kappaB signaling in the absence and presence of TNF-alpha. In addition, TCF7L2 expression is repressed by miR-155 overexpression and promoted by miR-155 inhibition. SIGNIFICANCE: Overall, these results demonstrate that the suppression of TCF7L2, which is modulated by miR-155, inhibits matrix degradation through p65/NF-kappaB signaling. TCF7L2 suppression may have therapeutic potential in intervertebral disc degeneration. PMID- 30245465 TI - Molecular pathways associated with oxidative stress in diabetes mellitus. AB - The role of oxidative stress in the occurrence and development of diabetes mellitus is both critical and pivotal. Several molecular event cascade in different metabolic pathways such as glycolytic, hexosamine, protein kinase C, polyol and advanced glycation end-product (AGE) pathways have been identified as pro-oxidative processes and are usually up-regulated in the diabetics. Inhibition of glyceraldehyde-3-P dehydrogenase by poly-ADP-ribose polymerase 1 and subsequent accumulation of the enzyme substrate (glyceraldehyde-3-P) appears to be central to diabetes-associated oxidative stress. Increased level of glyceraldehyde-3-P activates two major pro-oxidative pathways in diabetes: (i) It activates the AGE pathway, precisely the synthesis of methylglyoxal from non enzymatic dephosphorylation of the triose phosphates (ii) It activates protein kinase C (PKC) pathway by promoting the synthesis of diacylglycerol. In addition, it causes the accumulation of glycolytic metabolites upstream, and this leads to excessive stimulation of other pro-oxidative pathways such as hexosamine and polyol pathways. This review tends to highlight the main oxidative processes associated with diabetes mellitus. PMID- 30245466 TI - Icariin and mesenchymal stem cells synergistically promote angiogenesis and neurogenesis after cerebral ischemia via PI3K and ERK1/2 pathways. AB - Mesenchymal stem cells (MSCs) are one promising candidate for regenerative therapy of ischaemic stroke through transdifferetiation and paracrine actions. Icariin (ICA) has shown great potential in improving cell activity and VEGF, BDNF secretion in vitro. Whether they will synergistically improve therapy effect on cerebral ischemia is unknown. In this study, male SD rats were subjected to transient middle cerebral artery occlusion (MCAO) followed by reperfusion and ICA/MSC treatment. Results showed that ICA and MSCs combined treatment greatly reduced brain infarction volume, improved neurologic deficits of motor and somatosensory function and neurobehavioral outcomes. The combined therapy increased expression of VEGF and BDNF to a maximum through activating PI3K and ERK1/2 pathways in the hippocampus and frontal cortex in response to transient MCAO. They notably promoted angiogenesis and neurogenesis in vivo. Thus, ICA and MSCs combined treatment may represent a feasible approach for improving the beneficial effects of stem cell therapy for cerebral ischemia. PMID- 30245467 TI - Design, synthesis, in vitro, in vivo and in silico pharmacological characterization of antidiabetic N-Boc-l-tyrosine-based compounds. AB - In this study, we synthesized five N-Boc-L-tyrosine-based analogues to glitazars. The in vitro effects of compounds 1-5 on protein tyrosine phosphatase 1B (PTP 1B), peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma), glucose transporter type-4 (GLUT-4) and fatty acid transport protein-1 (FATP-1) activation are reported in this paper. Compounds 1 and 3 were the most active in the in vitro PTP-1B inhibition assay, showing IC50s of approximately 44 MUM. Treatment of adipocytes with compound 1 increased the mRNA expression of PPARgamma and GLUT-4 by 8- and 3-fold, respectively. Moreover, both compounds (1 and 3) also increased the relative mRNA expression of PPARalpha (by 8-fold) and FATP-1 (by 15-fold). Molecular docking studies were performed in order to elucidate the polypharmacological binding mode of the most active compounds on these targets. Finally, a murine model of hyperglycemia was used to evaluate the in vivo effectiveness of compounds 1 and 3. We found that both compounds are orally active using an exploratory dose of 100 mg/kg, decreasing the blood glucose concentration in an oral glucose tolerance test and a non insulin-dependent diabetes mellitus murine model. In conclusion, we demonstrated that both molecules showed strong in vitro and in vivo effects and can be considered polypharmacological antidiabetic candidates. PMID- 30245468 TI - Astragalosides IV protected the renal tubular epithelial cells from free fatty acids-induced injury by reducing oxidative stress and apoptosis. AB - Renal tubular injury is associated with the development of diabetic nephropathy (DN) and the end-stage renal disease (ESRD). Free fatty acids (FFAs)-associated lipotoxicity contributes to injury of proximal renal tubular epithelial (HK-2) cells in diabetes. Palmitic acid (PA) which is the most abundant saturated fatty acid in FFAs is closely associated with the gradual decline of renal function. Astragalosides IV (AS-IV) has a variety of pharmacological effects such as anti inflammation and anti-oxidation. In the current study, we investigated the effects of AS-IV on PA-induced apoptosis of HK-2 cells and the underlying mechanisms. The results showed that AS-IV (10, 20, 40 MUmol/L) could alleviate PA induced apoptosis of HK-2 cells. We found that AS-IV reduced the expression of Bax and cleaved-caspase3, but increased the expression of Bcl-2 and phosphorylated Nrf2 in HK-2 cells. Moreover, AS-IV reduced the level of reactive oxygen species (ROS) in the cells. Our study suggests that AS-IV could protect against PA-induced apoptosis in HK-2 cells by inhibiting ROS generation and apoptotic protein expression. This study may provide a new theoretical option for the patients with type 2 diabetes. PMID- 30245469 TI - Melatonin improves vascular cognitive impairment induced by ischemic stroke by remyelination via activation of ERK1/2 signaling and restoration of glutamatergic synapses in the gerbil hippocampus. AB - Vascular dementia affects cognition by damaging axons and myelin. Melatonin is pharmacologically associated with various neurological disorders. In this study, effects of melatonin on cognitive impairment and related mechanisms were investigated in an animal model of ischemic vascular dementia (IVD). Melatonin was intraperitoneally administered to adult gerbils after transient global cerebral ischemia (tGCI) for 25 days beginning 5 days after tGCI. Cognitive impairment was examined using a passive avoidance test and the Barnes maze test. To investigate mechanisms of restorative effects by melatonin, neuronal damage/death, myelin basic protein (MBP, a marker for myelin), Rip (a marker for oligodendrocyte), extracellular signal-regulated protein kinase1/2 (ERK1/2) and phospho-ERK1/2 (p-ERK1/2), and vesicular glutamate transporter (VGLUT)-1 (a glutamatergic synaptic marker) in the hippocampal Cornu Ammonis 1 area (CA1) were evaluated using immunohistochemistry. Melatonin treatment significantly improved tGCI-induced cognitive impairment. Death of CA1 pyramidal neurons after tGCI was not affected by melatonin treatment. However, melatonin treatment significantly increased MBP immunoreactivity and numbers of Rip-immunoreactive oligodendrocytes in the ischemic CA1. In addition, melatonin treatment significantly increased ERK1/2 and p-ERK1/2 immunoreactivities in oligodendrocytes in the ischemic CA1. Furthermore, melatonin treatment significantly increased VGLUT-1 immunoreactive structures in the ischemic CA1. These results indicate that long-term melatonin treatment after tGCI improves cognitive deficit via restoration of myelin, increase of oligodendrocytes which is closely related to the activation of ERK1/2 signaling, and increase of glutamatergic synapses in the ischemic brain area. PMID- 30245470 TI - MicroRNA199a-Based Post-transcriptional Detargeting of Gene Vectors for Hepatocellular Carcinoma. AB - A gene therapeutic platform needs to be both efficient and safe. The criterion of safety is particularly important for diseases like hepatocellular carcinoma (HCC), which develop in a background of an already compromised liver. Gene vectors can be constructed either by targeting HCC or by detargeting liver and/or other major organs. miRNA-based negative detargeting has gained considerable attention in recent times due to its effectiveness and the ease with which it can be adapted into current gene delivery vectors. In this study, we provide a proof of-concept using miRNA199a as a negative targeting agent. We introduced vectors harboring reporters with miRNA199a binding sites in cells expressing high endogenous levels of miRNA199a and compared the reporter expression in HCC cells with low endogenous miRNA199a. We observed that the expression of reporters with miRNA199a binding sites is significantly inhibited in miRNA199a-positive cells, whereas minimal effect was observed in miRNA199a-negative HCC cells. In addition, we created a post-transcriptionally regulated suicide gene therapeutic system based on cytosine deaminase (CD)/5-fluorocytosine (5-FC) exploiting miRNA199a binding sites and observed significantly lower cell death for miRNA199a-positive cells. Furthermore, we observed a decrease in the levels of miRNA199 in 3D tumorspheres of miRNA199a-positive Hepa1-6 cells and a reduction in the inhibition of reporter expression after transfection in these 3D models when compared with 2D Hepa1-6 cells. In summary, we provide evidence of miRNA199a based post-transcriptional detargeting with relevance to HCC gene therapy. PMID- 30245471 TI - Tissue-Dependent Expression and Translation of Circular RNAs with Recombinant AAV Vectors In Vivo. AB - Circular RNAs (circRNAs) are long-lived, covalently closed RNAs that are abundantly expressed and evolutionarily conserved across eukaryotes. Possible functions ranging from microRNA (miRNA) and RNA binding protein sponges to regulators of transcription and translation have been proposed. Here we describe the design and characterization of recombinant adeno-associated viral (AAV) vectors packaging transgene cassettes containing intronic sequences that promote backsplicing to generate circularized RNA transcripts. Using a split GFP transgene, we demonstrate the capacity of vectors containing different flanking intronic sequences to efficiently drive persistent circRNA formation in vitro. Further, translation from circRNA is efficiently driven by an internal ribosomal entry site (IRES). Upon injecting AAV vectors encoding circRNA in mice, we observed robust transgene expression in the heart, but low transduction in the liver for the intronic elements tested. Expression in the murine brain was restricted to astrocytes following systemic or intracranial administration, while intravitreal injection in the eye yielded robust transgene expression across multiple retinal cell layers. These results highlight the potential for exploiting AAV-based circRNA expression to study circRNA function and tissue specific regulation in animal models, as well as development of therapeutic platforms using this approach. PMID- 30245473 TI - Targeting protein misfolding to protect pancreatic beta-cells in type 2 diabetes. AB - The islet in type 2 diabetes is characterized by beta-cell dysfunction and deficit, increased beta-cell apoptosis and amyloid deposits that derived from islet amyloid polypeptide (IAPP). In species such as humans that are vulnerable to developing type 2 diabetes, IAPP has the propensity to form toxic oligomers that contribute to beta-cell dysfunction and apoptosis, defining type 2 diabetes as a protein misfolding disorder. In this report, we review mechanisms known to contribute to protein misfolding and formation of toxic oligomers, and the deleterious consequences of these oligomers on beta-cell function and survival. Finally, we will consider approaches to prevent protein misfolding and formation of toxic oligomers as potential novel therapeutic targets for type 2 diabetes and other protein misfolding diseases. PMID- 30245472 TI - G-Quadruplex-Forming DNA Aptamers Inhibit the DNA-Binding Function of HupB and Mycobacteriumtuberculosis Entry into Host Cells. AB - The entry and survival of Mycobacterium tuberculosis (Mtb) within host cells is orchestrated partly by an essential histone-like protein HupB (Rv2986c). Despite being an essential drug target, the lack of structural information has impeded the development of inhibitors targeting the indispensable and multifunctional C terminal domain (CTD) of HupB. To bypass the requirement for structural information in the classical drug discovery route, we generated a panel of DNA aptamers against HupB protein through systemic evolution of ligands by exponential (SELEX) enrichment. Two G-quadruplex-forming high-affinity aptamers (HupB-4T and HupB-13T) were identified, each of which bound two distinct sites on full-length HupB, with an estimated KD of ~1.72 MUM and ~0.17 MUM, respectively, for the high-affinity sites. While HupB-4T robustly inhibited DNA-binding activity of HupB in vitro, both the aptamers recognized surface-located HupB and significantly blocked Mtb entry into THP-1 monocytic cells (p < 0.0001). In summary, DNA aptamers generated in this study block DNA-binding activity of HupB, inhibit virulent Mtb infection in host cells, and demonstrate aptamers to be inhibitors of HupB functions. This study also illustrates the utility of SELEX in developing inhibitors against essential targets for whom structural information is not available. PMID- 30245474 TI - New developments in the treatment of gastroparesis and functional dyspepsia. AB - Functional dyspepsia (FD) and gastroparesis are frequent causes of upper gastrointestinal symptoms such as postprandial fullness, early satiation, epigastric pain or burning, upper abdominal bloating, bothersome belching, nausea and vomiting. The underlying pathophysiological mechanisms are heterogeneous and involved mechanisms such as abnormal gastric motility (accommodation, emptying), visceral hypersensitivity, low grade mucosal inflammation and cellular changes in enteric nerves, muscle or interstitial cells of Cajal. Patient-reported outcomes for evaluating treatment efficacy in these conditions were recently developed and validated. Prokinetic agents, which enhance gastric motility, are used for treating both gastroparesis and FD. In FD, besides acid suppressive therapy and Helicobacter pylori eradication, neuromodulators and drugs that enhance gastric accommodation can be applied. In gastroparesis, anti-emetics may also provide symptom relief. Novel approaches under evaluation in these conditions are the fundus relaxing agents acotiamide and buspirone and the antidepressant mirtazapine in FD. For gastroparesis, recently studied agents include the prokinetic ghrelin agonist relamorelin, the prokinetic serotonergic agents velusetrag and prucalopride, the anti-emetic aprepitant and per-endoscopic pyloric myotomy procedures. PMID- 30245475 TI - Accuracy of phase-contrast velocimetry in systems with skewed intravoxel velocity distributions. AB - Phase contrast velocimetry (PCV) has been widely used to investigate flow properties in numerous systems. Several authors have reported errors in velocity measurements and have speculated on the sources, which have ranged from eddy current effects to acceleration artefacts. An often overlooked assumption in the theory of PCV, which may not be met in complex or unsteady flows, is that the intravoxel displacement distributions (propagators) are symmetric. Here, the effect of the higher moments of the displacement distribution (variance, skewness and kurtosis) on the accuracy of PCV is investigated experimentally and theoretically. Phase and propagator measurements are performed on tailored intravoxel distributions, achieved using a simple phantom combined with a single large voxel. Asymmetric distributions (Skewness ? 0) are shown to generate important phase measurement errors that lead to significant velocimetry errors. Simulations of the phase of the spin vector sum, based on experimentally measured propagators, are shown to quantitatively reproduce the relationship between measured phase and experimental parameters. These allow relating the observed velocimetry errors to a discrepancy between the average phase of intravoxel spins considered in PCV theory and the vector phase actually measured by a PFG experiment. A theoretical expression is derived for PCV velocimetry errors as a function of the moments of the displacement distribution. Positively skewed distributions result in an underestimation of the true mean velocity, while negatively skewed distributions result in an overestimation. The magnitude of these errors is shown to increase with the variance and decrease with the kurtosis of the intravoxel displacement distribution. PMID- 30245476 TI - Comparing road safety performance across countries: Do data source and type of mortality indicator matter? AB - This study examined the impact of data source estimates (World Health Organization (WHO) versus Global Burden of Disease (GBD)) and the type of mortality indicator (population-based versus exposure-based mortality) on road safety performance evaluation. Data were derived from WHO publications and the GBD results tool, and we calculated mortality rate ratio (MRR) and differences in country ranking between the two data sources, plus differences in country rankings and in mortality changes between 2010 and 2013 for population-based and vehicle-based mortality. Of 172 countries in both datasets, 32 countries (19%) had low consistency across the two data sources (MRR <= 0.49 or >=1.51). Using population-based mortality data to rank the 172 countries, 77 (45%) had >= 20 position difference between the two data sources. Population-based vs. vehicle based mortality data yielded >= 20 position difference in 33 countries for WHO estimates and 42 for GBD estimates. Among the 80 countries having comparable population-based and vehicle-based GBD mortality rates over time, 9 countries displayed opposite changing directions - that is, the change increased in one mortality indicator but decreased in the other indicator between 2010 and 2013. Data source and type of mortality indicators yield a substantial impact on ranking road safety performance across countries, as they are widely used for decision-making by global and national policy-makers and injury researchers. The differences between WHO and GBD estimates may arise from inconsistencies in data input and estimation models. Exposure-based indicators should be preferred in road safety evaluation when data are available. Advanced research is needed to interpret large country variations in road traffic mortality and mortality progress and to develop strategies to narrow the gaps across countries. PMID- 30245477 TI - Modelling driver acceptance of driver support systems. AB - Driver support systems are intended to enhance driver performance and improve transportation safety. Even though these systems afford safety advantages, they challenge the traditional role of drivers in operating vehicles. Driver acceptance, therefore, is essential for the adoption of new in-vehicle technologies into the transportation system. In this study, a model of driver acceptance of driver support systems was developed. A conceptual driver acceptance model, including several components, was proposed based on a review of current literature. An empirical study was subsequently carried out using an online survey approach. The study collected data on participants' perceptions of two driver support systems (a fatigue monitoring system and an adaptive cruise control system combined with a lane-keeping system) in terms of attitude, perceived usefulness, and other components of driver acceptance. Results identified five components of driver acceptance (attitude, perceived usefulness, endorsement, compatibility, and affordability). The results also confirmed several mediating effects. The developed model was able to explain 85% of the variability in driver acceptance. The model provides an improved understanding how driver acceptance is formed, including which factors affect driver acceptance and how they affect it. The model can also help automakers and researchers to assess the design and estimate the potential use of a driver support system. The model could also be highly beneficial in developing a questionnaire to assess driver acceptance. PMID- 30245479 TI - Infographics and digital resources: an international consensus on golf and health. PMID- 30245480 TI - Depression and anxiety among university students in Hong Kong. AB - INTRODUCTION: Entry into tertiary education is a critical juncture where adolescents proceed to adulthood. This study aimed to determine the prevalence of depression and anxiety, and factors associated with such symptoms, among university undergraduate students in Hong Kong. METHODS: A cross-sectional questionnaire study was employed. A total of 1200 undergraduate students from eight University Grants Committee-funded universities were invited to complete three sets of questionnaires, including the 9-item patient health questionnaire for screening of depressive symptoms, the 7-item generalised anxiety disorder scale for screening of anxiety symptoms, and a socio-demographic questionnaire. RESULTS: Among the valid responses (n=1119) analysed, 767 (68.5%) respondents indicated mild to severe depressive symptoms, which were associated with mild to severe anxiety symptoms. Several lifestyle and psychosocial variables, including regular exercise, self-confidence, satisfaction with academic performance, and optimism towards the future were inversely related with mild to severe depressive symptoms. A total of 599 (54.4%) respondents indicated mild to severe anxiety symptoms, which were associated with level of academic difficulty. Satisfaction with friendship, sleep quality, and self-confidence were inversely associated with mild to severe anxiety symptoms. CONCLUSION: More than 50% of respondents expressed some degree of depressive and anxiety symptoms (68.5% and 54.4%, respectively). Approximately 9% of respondents exhibited moderately severe to severe depressive symptoms; 5.8% exhibited severe anxiety symptoms. Respondents reporting regular exercise, higher self-confidence, and better satisfaction with both friendship and academic performance had fewer depressive and anxiety symptoms. PMID- 30245478 TI - 2018 International Consensus Statement on Golf and Health to guide action by people, policymakers and the golf industry. AB - Scientific and public interest relating to golf and health has increased recently. Players, potential players, the golf industry and facilities, and decision makers will benefit from a better understanding of how to realise potential health benefits and minimise health issues related to golf. We outline an International Consensus on Golf and Health. A systematic literature review informed the development of a survey. Utilising modified Delphi methods, an expert panel of 25 persons including public health and golf industry leaders, took part in serial surveys providing feedback on suggested items, and proposing new items. Predefined criteria for agreement determined whether each item was included within each survey round and in the final consensus. The working group identified 79 scientifically supportable statement items from literature review and discussions. Twenty-five experts (100%) completed all three rounds of surveys, rating each item, and suggesting modifications and/or new items for inclusion in subsequent surveys. After three rounds, 83 items achieved consensus with each with >75% agreement and <10% disagreement. These items are included in the final International Consensus on Golf and Health. The final consensus presented here can inform scientific knowledge, and action plans for (1) golfers and potential golfers, (2) golf facilities and the golf industry, and (3) policy and decision makers external to golf. These outputs, if widely adopted, will contribute to an improved understanding of golf and health, and aid these groups in making evidence-informed decisions to improve health and well-being. PMID- 30245481 TI - Measles: a disease often forgotten but not gone. AB - Measles (rubeola) is a highly contagious vaccine-preventable disease caused by the measles virus-a virus of the Paramyxoviridae family. The illness typically begins with fever, runny nose, cough, and pathognomonic enanthem (Koplik spots) followed by a characteristic erythematous, maculopapular rash. The rash classically begins on the face and becomes more confluent as it spreads cephalocaudally. Laboratory confirmation of measles virus infection can be based on a positive serological test for measles-specific immunoglobulin M antibody, a four-fold or greater increase in measles-specific immunoglobulin G between acute and convalescent sera, isolation of measles virus in culture, or detection of measles virus ribonucleic acid by reverse transcriptase-polymerase chain reaction. Complications occur in 10% to 40% of patients, and treatment is mainly symptomatic. Bacterial superinfections, if present, should be properly treated with antibiotics. To eradicate measles, universal childhood immunisation and vaccination of all susceptible individuals with measles vaccine would be ideal. In developed countries, routine immunisation with measles-containing vaccine is recommended, with the first and second doses at ages 12 to 15 months and 4 to 6 years, respectively. The World Health Organization recommends that the first and second doses of measles-containing vaccine be given at ages 9 months and 15 to 18 months, respectively, in countries with high rates of measles transmission. PMID- 30245482 TI - Biomimetic encoding model for restoring touch in bionic hands through a nerve interface. AB - OBJECTIVE: Hand function can be restored in upper-limb amputees by equipping them with anthropomorphic prostheses controlled with signals from residual muscles. The dexterity of these bionic hands is severely limited in large part by the absence of tactile feedback about interactions with objects. We propose that, to the extent that artificial touch mimics its natural counterpart, these sensory signals will be more easily integrated into the motor plan for object manipulation. APPROACH: We describe an approach to convey tactile feedback through electrical stimulation of the residual somatosensory nerves that mimics the aggregate activity of tactile fibers that would be produced in the nerve of a native hand during object interactions. Specifically, we build a parsimonious model that maps the stimulus-described as time-varying indentation depth, indentation rate, and acceleration-into continuous estimates of the time-varying population firing rate and of the size of the recruited afferent population. MAIN RESULTS: The simple model can reconstruct aggregate afferent responses to a wide range of stimuli, including those experienced during activities of daily living. SIGNIFICANCE: We discuss how the proposed model can be implemented with a peripheral nerve interface and anticipate it will lead to improved dexterity for prosthetic hands. PMID- 30245483 TI - The Origen of Pico's Kabbalah: Esoteric Wisdom and the Dignity of Man. AB - The importance of Origen of Alexandria's legacy for Giovanni Pico della Mirandola has been widely debated for its role in Pico's trial, its possible reverberations on the entire "Apology," and its assonance with the Pichian idea of the dignity of man. This article aims instead to show the substantial role of Origen in shaping the Pichian construction of the Christian Kabbalah's tradition. This scrutiny, by clarifying the extent of the Origenian influence as well as Pico's rhetorial strategies, helps to put the Pichian idea of the freedom of man in a new framework. PMID- 30245484 TI - Immaterial Spirits and the Reform of First Philosophy: The Compatibility of Kant's pre-Critical Metaphysics with the Arguments in Dreams of a Spirit Seer. AB - This article argues that Kant's early metaphysics (1755-1764) remains unscathed by the arguments found in the 1766 work, Dreams of a Spirit-Seer. I expose the errors of the standard approaches to Dreams, which take the text to be either entirely opposed to metaphysics or at least critical of all present forms of metaphysics, Kant's own early work included. Through a close reading of the text of Dreams, I show that Kant's early metaphysics remains the standard of how metaphysics should be done, how it avoids any commitment to immaterial spirits, and what some of its actual conclusions are. PMID- 30245485 TI - Revisiting Hempel's 1942 Contribution to the Philosophy of History. AB - This paper situates Carl Hempel's 1942 paper "The Function of General Laws in History" within a broader debate over the philosophy of history in American academia between 1935 and 1943. I argue that Hempel's paper was directed against German neo-Kantianism, and show how the German debate over historiography continued between 1939 and 1943 in the context of New York through the contributions of German philosophers who operated in the same intellectual network as Hempel, namely Paul Oskar Kristeller and Edgar Zilsel. Whereas this debate still witnessed many different philosophical approaches, Hempel's logico analytic methodology would come to dominate analytic philosophy of history. PMID- 30245486 TI - Introduction: Special Forum on Christianity and Human Rights. PMID- 30245487 TI - Christian Human Rights in the French Revolution. AB - This essay explores the early Catholic response to the concept of human rights. It is widely assumed that the Catholic Church opposed human rights talk in the wake of the French Revolution, and only slowly came around to accepting it in the twentieth century. However, a more systematic analysis of Pius VI's stance toward the French Revolution reveals that he approved of human rights, but had a more Thomistic understanding of them than what was found in the French Declaration. The Vatican's embrace of human rights in the 1930s should accordingly be seen as a continuity of more long-standing practices. PMID- 30245488 TI - American Protestants and the Era of Anti-racist Human Rights. AB - How Christian conceptions of human rights became associated with anti-racism is the subject of this article. Protestants rooted human rights in a philosophical doctrine called "personalism," whose language of "dignity," the "human family," and the "human person" was first developed in the Methodist-run philosophy department at Boston University at the turn of the century. Personalism, evoked in interwar discussions of racism and colonialism, transformed into the political language of human rights during World War II, a moment when Protestant intellectuals were seeking to defend liberal freedoms. PMID- 30245489 TI - Theology and the Politics of Christian Human Rights. AB - This article provides a rejoinder to recent historical accounts which trace the origins of international human rights to the work of conservative Christians writing in the 1930s and 1940s. Focusing on the French Catholics usually identified as the architects of Christian human rights theory, I argue that this was neither a unified project, nor an unambiguously conservative one. Instead, I stress the political ambivalence of Christian human rights discourse-the way it defied distinctions between right and left, or liberal and conservative. PMID- 30245490 TI - Catholics, Protestants, and the Tortured Path to Religious Liberty. AB - This essay explores the transformation of Catholic thinking about the right to religious freedom. Throughout the first half of the twentieth century, Catholics vehemently opposed this right (Pope Gregory XVI called it "absurd and erroneous"). Church leaders claimed that in order to protect Catholic Church teachings on marriage, education, and worship, states had to enshrine them in law, even if that meant severely limiting the rights of Protestants, Jews, and others. The 1950s and 1960s, however, witnessed a sea change, as a growing chorus of thinkers and theologians called on Catholics to embrace a pluralist and tolerant attitude. PMID- 30245491 TI - An Anti-totalitarian Saint: The Canonization of Edith Stein. AB - This essay explores the intellectual origins of Edith Stein's canonization. In the years of the early Cold War, when Christians on both sides of the Atlantic proclaimed "Judeo-Christian civilization" to be the greatest bulwark against totalitarianism in both its Nazi and Soviet guises, Stein became a powerful anti totalitarian symbol. During the 1980s, a new Pope, John Paul II, revived the memory of Stein and linked it to his own rich understanding of Judeo-Christian civilization as a set of values opposed to both Nazism and Communism. Thus, Edith Stein became an icon of anti-totalitarianism in an age of Holocaust memory. PMID- 30245494 TI - Innovation in Indian Handloom Weaving. AB - Handloom weaving is the second most important livelihood in rural India after farming. Improving handloom technologies and practices thus will directly affect the lives of millions of Indians, and this is similar for many other communities in the global South and East. By analyzing hand-loom weaving as a socio technology, we will show how weaving communities are constantly innovating their technologies, designs, markets, and social organization-often without calling it innovation. This demonstration of innovation in handloom contradicts the received image of handloom as a pre-modern and traditional craft that is unsustainable in current societies and that one should strive to eliminate: by mechanization and/or by putting it into a museum. PMID- 30245495 TI - Research, Invent, Improve: A Dictionnaire Technologique for Non-elites (1822-35). AB - After nearly a quarter century of war, France faced the challenge of retooling for peace. From 1822 to 1835 a team of five savant-technologists challenged elitism through the twenty-six-volume Dictionnaire Technologique. They promoted research and innovation by redistributing technological knowledge to the general public through an accessible, comprehensive, up-to-date publication. This study illustrates the Dictionnaire's approach by focusing on innovative products made by tinsmiths and how the authors' synthesis of theory and practice promoted the acceleration of industrial change via a consumer-oriented alternative to a war economy. This study thus challenges the dominant historical narrative that has framed French technology as focused on theory against a British emphasis on practice, instead of integrated theory and practice; a French lag behind Britain, instead of a unique French artisanal path of innovation; and a repressive aristocratic political regime, instead of the pragmatic opposition of politics through dissemination of technology to non-elites. PMID- 30245496 TI - Island in the Air: Powered Aircraft and the Early Formation of British Airspace. AB - In this article, I explore the formation of airspace in Britain from 1910 to 1913. The technology of flight challenged the "flat discourse" of nationalized geography, drawing up instead a volumetric space in the sky as airplanes flew from the Continent to England. The drive to control aerial mobility and convert the sky into a sovereign territory was especially pronounced in Britain. But the challenge of creating a sovereign space out of mobile and transparent air was an intricate problem both in legal and practical terms. This article shows how geopolitical interests called for an upward extension of the Island Kingdom, extrapolating its coastal borders into the sky. However, even as Parliament passed the Aerial Navigation Act in 1913, this legal construction of an island in the air could not endure the agency of airplanes. The formation of airspace, I argue, is a history particularly well suited to showing the dynamic processes by which spaces are assembled, enacted, and co-produced by mobile technologies. PMID- 30245497 TI - Alvin Weinberg and the Promotion of the Technological Fix. AB - The term technological fix, coined by technologist/administrator Alvin Weinberg in 1965, vaunted engineering innovation as a generic tool for circumventing problems commonly conceived as social, political, or cultural. A longtime Director of Oak Ridge National Laboratory, government consultant, and essayist, Weinberg also popularized the term big science to describe national goals and the competitive funding environment after the Second World War. Big science reoriented towards technological fixes, he argued, could provide a new "Apollo project" to address social problems of the future. His ideas-most recently echoed in "solutionism"-have channeled confidence and controversy ever since. This article traces the genesis and promotion of the concept by Weinberg and his contemporaries. It argues that, through the concept, the marginal politics and technological confidences of interwar scientists and technocrats were repositioned as mainstream notions closer to the heart of big science policy. PMID- 30245498 TI - Systems of Power: A Spatial Envirotechnical Approach to Water Power and Industrialization in the Po Valley of Italy, ca.1880-1970. AB - Fossil fuels, more than water, are immediately associated with the industrial energy transition. Preindustrial energy sources, however, continued to play a role in industrial energy regimes. This was the case in the industrializing Po Valley, where water power remained crucial until the 1960s. The article analyzes the ways in which the technological and spatial features of mechanical hydropower and hydroelectricity combined with the spatial and environmental features of the Po watershed, as well as the different envirotechnical regimes associated with these configurations. Through this approach, it sheds lights on the radical change that hydropower underwent during industrialization: from discontinuous to continuous energy production, from diffusion to concentration of access to water resources, and from small- to large-scale, basin-wide system building and interdependency. Concentration, continuity, and large-scale interdependency transformed profoundly the social distribution of access to hydropower, and scaled up, without eliminating, the influence of environmental factors on water power production. PMID- 30245499 TI - Technology's Cutting Edge: Futurism and Research in the Red Army, 1917-1937. AB - Seeking to defend the new Soviet Union with a devastated economic base and a vast technical gap with the West, Soviet military planners sought in new technology and the language of science the possibility of self-defense. Within that context, a group of young officers emerged as military futurists. Specifically, they theorized that technology was the decisive factor in war, and that technology had changed so fundamentally after 1918 that the operational lessons of the First World War were limited in usefulness. As a result of their leadership, the Red Army invested tremendous sums in new and exotic military technologies. This paper explores the military futurists' unique understanding of technology through an examination of two of the technological systems that they patronized: robotic tanks and a particle beam designed by Nikola Tesla. PMID- 30245501 TI - History and the Art of Hand-pump Maintenance: Reflections on My Working Life. PMID- 30245500 TI - Display of Arms: A Roundtable Discussion about the Public Exhibition of Firearms and Their History. PMID- 30245502 TI - The Canada Science and Technology Museum. PMID- 30245503 TI - Diabetes Mellitus is a Risk Factor for Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Virus Infection in China. AB - BACKGROUND This study aimed to investigate whether diabetes mellitus (DM) increased the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. MATERIAL AND METHODS Individuals with a confirmed diagnosis of HCC and chronic HBV infection (n=112), and non-diabetic individuals with both chronic HBV infection and HCC (n=210), were matched by age, sex, and degree of liver cirrhosis. Demographic, lifestyle, and clinical data were reviewed. Data were analyzed by univariate and multiple logistic regression analysis to identify the risk factors for HCC. RESULTS Of the 112 patients with HCC (median age, 52.0 years; range, 46.3-56.0 years), 18.8% were men, and the prevalence of cirrhosis was 90.2%. Of the 210 patients without HCC (median age, 51.0 years; range, 47.0-58.0 years), 26.2% were men, and the prevalence of cirrhosis was 91.9%. Diabetes mellitus was more prevalent among individuals with HCC (16.1%) compared with those without HCC (7.6%) and increased the risk for HCC by two-fold to three-fold (adjusted odds ratio [AOR]: 2.402; 95% confidence interval [CI], 1.150-5.018). Multivariate analysis showed that cigarette smoking significantly increased the risk of HBV-related HCC (AOR: 1.665; 95% CI, 1.031 2.690), as did increased levels of HBV DNA (>=103 IU/mL) (AOR: 1.753; 95% CI, 1.079-2.849). CONCLUSIONS In a Chinese population with chronic HBV infection, DM increased the risk of HCC, as did cigarette smoking and high levels of HBV DNA. Screening patients with known risk factors for HCC might improve early detection rates and treatment to prevent tumor progression. PMID- 30245504 TI - A Small Jejunal Angioleiomyoma Detected by Double-Balloon Enteroscopy: A Case Report. AB - BACKGROUND Angioleiomyoma in the small intestine is a rare cause of gastrointestinal bleeding. Only 7 cases of angioleiomyoma in the small intestine were reported in the English literature, with 4 of them causing gastrointestinal bleeding. The diagnosis of angioleiomyomas in the small intestine before surgery is difficult. CASE REPORT We report the case of a 42-year-old man with recurrent melena who underwent repeated esophagogastroduodenoscopy and colonoscopy, without positive finding. During a double-balloon enteroscopy, an elevated lesion with a diameter of 6 mm was found in the jejunum. The lesion was resected laparoscopically assisted with double-balloon enteroscpy. A microscopic examination showed fibric membrane of the mass and numerous vascular channels surrounded by proliferated smooth muscle. There were exudative fibrin and many thrombi formed by red blood cells. Immunohistochemistry was positive for SMA and CD34. A pathological diagnosis of jejunal angioleiomyoma with thrombus was established. During a 5-year follow-up, there was no further gastrointestinal bleeding. CONCLUSIONS The gastroenterologists should consider angioleiomyoma in the small intestine when assessing obscure gastrointestinal bleeding. PMID- 30245505 TI - [Ethnicity and health policy: Building equitable solutions in the face of ethnic inequalities]. AB - BACKGROUND: The evidence highlights the importance of working with ethnicity in relation to the social determinants of health for the progressive achievement of universal access to health and universal health coverage. This implies that all people and communities have access, without any kind of discrimination, to comprehensive, appropriate and timely, quality health services, while ensuring that the use of these services does not expose users to financial hardship. The Pan American Health Organization (PAHO / WHO) recognized the need for a political commitment and a consensual strategic framework to advance towards equity in health. As a result, in a participatory way, the first policy on ethnicity and health was elaborated and approved by the Ministries of Health in September 2017 during the 29th Pan American Sanitary Conference. This policy, promoted by PAHO / WHO, includes ethnicity as one of its four cross cutting themes for work, aligned with important global commitments, including the 2030 Agenda for Sustainable Development. This article presents the way in which this political proposal was elaborated, and the challenges for its implementation. This policy takes into account the need to work together and reorient health services with an intercultural approach in order to improve the health conditions of indigenous peoples, afro-descendants, Roma people and other ethnic groups that coexist in the Americas region, who present health results more unfavorable than the rest of the population. CONCLUSIONS: With the approval of the policy, the Americas becomes the first region of WHO to respond to the need to adopt an intercultural approach in the context of the social determinants of health. This is done by taking into account the gender and ethnic inequalities that interact, the differences in access to health throughout the life course, as well as the promotion and respect of individual rights and, in the case of indigenous peoples, collective rights. PMID- 30245506 TI - [Use of the theory of the social representations to understand discriminatory attitudes towards HIV/AIDS]. AB - OBJECTIVE: The Theory of Social Representation (TSR) is a widely used approach to understanding attitudes towards HIV/AIDS in diverse cultures and contexts. However, there are few studies that offer a articulate view of the problem, and that also focus on the role of future educators. This research aimed to understand the extent to which knowledge and social representations about HIV/AIDS determine attitudes towards HIV/AIDS in a population of educators in training. METHODS: This research is based on the contribution of 613 university students from Huelva, Spain. For that, TRS has been used and the hypothesis has been formulated according to its assumptions. A test about HIV, representation scales and attitude scales towards HIV are the instruments that have used for data collection. These help to obtain information about some social representations and exclusive attitudes. As an analythical method, the reproduction of structural equations was into use. RESULTS: The data have proved that the knowledge degree about HIV has a negative (beta=-0,36) influence on negative representations. And these have a positive effect (beta=0,80) on exclusive attitudes. Similarly, the knowledge degree determined both in an indirect and negative (beta=-0,26) way the discriminatory attitudes. CONCLUSIONS: The results show that student teachers'attitudes, whether discriminatory or tolerant towards people with HIV/AIDS, are determined by their social representations, and these by the level of knowledge about HIV/AIDS, highlighting the importance of education. PMID- 30245507 TI - Polymorphism of FCGR3A gene in chronic beryllium disease. AB - Previously we showed that alveolar macrophages (AMs) from patients with chronic beryllium disease (CBD) and beryllium sensitization (BeS) demonstrated significantly greater cell surface CD16 (encoded by the FCGR3A gene) than controls. We hypothesized that these differences were related to polymorphisms in the FCGR3A gene. This study was to determine the association between FCGR3A polymorphisms in CBD, BeS versus controls as well as clinical data, providing potential information about disease pathogenesis, risk, and activity. A total of 189 CBD/154 BeS/150 controls (92 Be-exposed non-diseased and 58 healthy controls) were included in this study. Sequence-specific primers polymerase chain reaction (PCR-SSP) was used to determine FCGR3A 158V/F polymorphisms. We found significantly higher frequencies of the 158V allele (OR: 1.60 (CI: 1.17-2.19), p = 0.004) and 158VV homozygotes (OR: 2.97 (CI: 1.48-5.97) p = 0.007) in CBD versus controls. No differences were found in the frequencies of FCGR3A alleles or genotypes between BeS versus controls and CBD versus BeS. Average changes in exercise testing maximum workload (Wlm), maximum oxygen consumption (VO2m), and diffusion capacity of carbon monoxide (DLCO) demonstrated greater decline over time in those CBD cases with the 158VV gene, modeled between 10 and 40 years from first beryllium exposure. The FCGR3A V158F polymorphism is associated with CBD compared to BeS and controls and may impact lung function in CBD. PMID- 30245508 TI - System network analysis of genomics and transcriptomics data identified type 1 diabetes-associated pathway and genes. AB - Genome-wide association studies (GWASs) have discovered >50 risk loci for type 1 diabetes (T1D). However, those variations only have modest effects on the genetic risk of T1D. In recent years, accumulated studies have suggested that gene-gene interactions might explain part of the missing heritability. The purpose of our research was to identify potential and novel risk genes for T1D by systematically considering the gene-gene interactions through network analyses. We carried out a novel system network analysis of summary GWAS statistics jointly with transcriptomic gene expression data to identify some of the missing heritability for T1D using weighted gene co-expression network analysis (WGCNA). Using WGCNA, seven modules for 1852 nominally significant (P <= 0.05) GWAS genes were identified by analyzing microarray data for gene expression profile. One module (tagged as green module) showed significant association (P <= 0.05) between the module eigengenes and the trait. This module also displayed a high correlation (r = 0.45, P <= 0.05) between module membership (MM) and gene significant (GS), which indicated that the green module of co-expressed genes is of significant biological importance for T1D status. By further describing the module content and topology, the green module revealed a significant enrichment in the "regulation of immune response" (GO:0050776), which is a crucially important pathway in T1D development. Our findings demonstrated a module and several core genes that act as essential components in the etiology of T1D possibly via the regulation of immune response, which may enhance our fundamental knowledge of the underlying molecular mechanisms for T1D. PMID- 30245509 TI - TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants. AB - PURPOSE: TANGO2-related disorders were first described in 2016 and prior to this publication, only 15 individuals with TANGO2-related disorder were described in the literature. Primary features include metabolic crisis with rhabdomyolysis, encephalopathy, intellectual disability, seizures, and cardiac arrhythmias. We assess whether genotype and phenotype of TANGO2-related disorder has expanded since the initial discovery and determine the efficacy of exome sequencing (ES) as a diagnostic tool for detecting variants. METHODS: We present a series of 14 individuals from 11 unrelated families with complex medical and developmental histories, in whom ES or microarray identified compound heterozygous or homozygous variants in TANGO2. RESULTS: The initial presentation of patients with TANGO2-related disorders can be variable, including primarily neurological presentations. We expand the phenotype and genotype for TANGO2, highlighting the variability of the disorder. CONCLUSION: TANGO2-related disorders can have a more diverse clinical presentation than previously anticipated. We illustrate the utility of routine ES data reanalysis whereby discovery of novel disease genes can lead to a diagnosis in previously unsolved cases and the need for additional copy-number variation analysis when ES is performed. PMID- 30245510 TI - A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay. AB - PURPOSE: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. METHODS: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. RESULTS: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. CONCLUSIONS: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy. PMID- 30245511 TI - A new clinical screening strategy and prevalence estimation for glucokinase variant-induced diabetes in an adult Chinese population. AB - PURPOSE: To estimate the prevalence of glucokinase variant-induced diabetes (GCK DM) in a general population and to establish a clinical strategy for identifying GCK-DM from type 2 diabetes (T2DM). METHODS: A population-based study of diabetes in a rural region of Beijing, China, was conducted using two-stage stratified random cluster sampling. The glucokinase exons were sequenced in patients with diabetes. RESULTS: A total of 3345 subjects, including 545 patients with diabetes, participated in this study. Seven patients with GCK-DM were identified. The estimated prevalence rates of GCK-DM were 0.21% and 1.3% in the whole population and the diabetic patients, respectively. In the newly diagnosed diabetic patients (New-DM), a triglyceride cutoff <=1.43 mmol/L (126.55 mg/dl) could discriminate GCK-DM from T2DM with 100% sensitivity and 68.4% specificity. Its effectiveness was confirmed in an additional 134 early-onset young patients with T2DM and mild hyperglycemia. A clinical criterion based on triglyceride and mild hyperglycemia could differentiate GCK-DM from T2DM in New-DM and was shown to be effective in identifying GCK-DM from 559 early-onset young patients with T2DM in the hospital. CONCLUSIONS: The prevalence of GCK-DM is approximately 1.3% in the Chinese population with diabetes, and the new clinical screening strategy is helpful for identifying GCK-DM. PMID- 30245512 TI - Direct health-care costs for children diagnosed with genetic diseases are significantly higher than for children with other chronic diseases. AB - PURPOSE: We aimed to estimate direct health-care costs and physician utilization for a cohort of children diagnosed with genetic diseases. METHODS: Retrospective cohort study using population-based provincial health administrative data for children with genetic diseases (n = 255) compared with three matched cohorts (asthma n = 1275, diabetes n = 255, general population n = 1275). We estimated direct health-care costs and resource use 5 years after diagnosis in five categories: physician billing, same day surgery, emergency, inpatient hospitalizations, and home care. RESULTS: During the postdiagnostic period, annual mean total costs for the genetic disease cohort were significantly higher than all other cohorts. Annual mean total costs for all cohorts were highest in the year after diagnosis with costs for the genetic disease cohort between 4.54 and 19.76 times higher during the 5 years. Inpatient hospitalizations and physician billing accounted for the majority of costs. The genetic disease cohort received more care from specialists, whereas the chronic disease cohorts received more care from general practitioners. CONCLUSION: Direct health-care costs for children with genetic diseases are significantly higher than children with/without a chronic disease, particularly in the year after diagnosis. These findings are important when considering resource allocation and funding prioritization for children with genetic diseases. PMID- 30245514 TI - Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37. AB - PURPOSE: The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family. METHODS: Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family. RESULTS: Affected individuals presented with early-onset progressive mild hearing impairment with a fairly flat, gently downsloping or U-shaped audiogram configuration. Detailed clinical examination excluded any additional symptoms. Linkage analysis detected an interval on chromosome 1p21 with a logarithm of the odds (LOD) score of 8.29: designated locus DFNA37. Exome sequencing identified a novel canonical acceptor splice-site variant c.652-2A>C in the COL11A1 gene within the DFNA37 locus. Genotyping of all 48 family members confirmed segregation of this variant with the deafness phenotype in the extended family. The c.652-2A>C variant is novel, highly conserved, and confirmed in vitro to alter RNA splicing. CONCLUSION: We have identified COL11A1 as the gene responsible for deafness at the DFNA37 locus. Previously, COL11A1 was solely associated with Marshall and Stickler syndromes. This study expands its phenotypic spectrum to include nonsyndromic deafness. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with COL11A1 pathogenic variants. PMID- 30245515 TI - Secondary findings on virtual panels: opportunities, challenges, and potential for preventive medicine. PMID- 30245516 TI - The evolving landscape of expanded carrier screening: challenges and opportunities. AB - Carrier screening allows individuals to learn their chance of passing on an autosomal or X-linked condition to their offspring. Initially introduced as single-disease, ancestry-based screening, technological advances now allow for the possibility of multi-disease, pan-ethnic carrier screening, which we refer to as "expanded carrier screening." There are numerous potential benefits to expanded carrier screening, including maximizing the opportunity for couples to make autonomous reproductive decisions, and efficiency and marginal additional costs of including more conditions if the test is already being offered. While numerous laboratories currently offer expanded carrier screening services, it is not yet commonly used in clinical practice, and there is a lack of consensus among experts about the service, including whether this should be offered to individuals and couples, whether this should be offered preconception or prenatally, and what conditions to include in screening programs. Challenges for expanded carrier screening programs include a lack of demand from the public, low prioritization by health systems, the potential for pressure to undergo screening, the possibility of disability-based discrimination, needed adaptations to pre- and post-test counseling, technical limitations, and the evolving technological and socio-political landscape. PMID- 30245513 TI - KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants. AB - PURPOSE: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. METHODS: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. RESULTS: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. CONCLUSION: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management. PMID- 30245517 TI - Primary prevention of cardiovascular disease: an umbrella review. AB - BACKGROUND: The aim of this study is to determine the effectiveness of non pharmacological interventions for prevention of cardiovascular disease (CVD) events and mortality in healthy adults or those at high risk of CVD. METHODS: An umbrella review about primary prevention of non-pharmacological interventions was undertaken in key databases as PubMed Health, Effective Health Care Program AHRQ, McMaster University and the Cochrane Plus until July 2017. The primary outcomes were the relative risk of fatal and non-fatal CVD events, and mortality. Secondary outcomes were adverse events. RESULTS: Twenty-four reviews were included of which thirteen reported outcomes of interest. Four of these found a pooled statistically significant risk reduction: dietary supplements of vitamin D, increased consumption of omega 3 fatty acids, Qigong, and counselling or education to modify more than one cardiovascular risk factor. Seven studies reported adverse events but minor or insignificant with respect to the control group. CONCLUSIONS: Four non-pharmacological interventions have been shown to provide a statistically significant reduction in risk of CVD events or overall mortality, with minor adverse events if any. Further research should aim for higher methodological quality and longer follow-up of interventions to establish if these interventions, alone or in combination, translate into definite long term health benefits. PMID- 30245518 TI - [Occupational diseases among healthcare and social workers in 2009-2016]. AB - BACKGROUND: The aim of the paper is to present statistical data on the occurrence of occupational diseases among healthcare and social workers in Poland in 2009 2016. MATERIAL AND METHODS: All cards certifying that a case of occupational disease had been diagnosed in a patient belonging to this occupational group, received by the Central Register of Occupational Diseases, served as the basis of the study. Data is presented in absolute numbers and incidence rates. In the analysis, disease categories, voivodships and occupations were taken into account. RESULTS: In 2009-2016, as many as 1462 cases of occupational diseases were diagnosed for healthcare workers. In 2016, the number of cases was 42.6% lower than in 2009. Mean annual incidence rate in these years was 26.3 cases per 100 thousand workers. The most frequent were: infectious and parasitic diseases (64.8% of cases), peripheral nervous system diseases (9.6%), dermal diseases (8.9%), locomotor (8.3%), and chronic vocal organ disorders (3.2%). Among infectious or parasitic diseases, the most cases were viral hepatitis (56%) and tuberculosis (39%). Almost every second case of occupational disease in healthcare workers was detected in the nurses (47.8%). CONCLUSIONS: The incidence of occupational diseases in total and in the most frequent categories continued to decrease. One of the reasons for the decline is the improvement of working conditions resulting from the application of more modern instruments and apparatus as well as greater knowledge of the risks and the use of appropriate procedures. Med Pr 2018;69(5). PMID- 30245519 TI - Electromagnetic fields exposure assessment among workers at broadcast centers in Poland. AB - BACKGROUND: In the studies investigating the potential health effects of occupational exposure to electromagnetic fields (EMF), the key problem is the assessment of workers' exposure. Electromagnetic fields exposure assessment requires determining maximum EMF levels, for the acute effect, and the dose absorbed, for the cumulative effect. A study was undertaken to determine EMF exposure in workers at broadcasting centers (BCs) in Poland. It was the first part of a comprehensive project on health effects of occupational exposure to EMF. MATERIAL AND METHODS: The study was conducted in 4 selected BCs. Spot measurements of electric field strength (E), and the results of E measurements that were made in the past for occupational hygiene assessments, were used for determining workers' exposure to electric field. The parameters considered were the maximum E value (Emax), the weighted average E value (Eavg) and the E lifetime dose (Elifetime dose). RESULTS: In the group of workers examined, the E values did not exceed 16.7 V/m for Emax (the occupational exposure limit (OEL) for work shift in Poland is 20 V/m), 2.9 V/m for Eavg and 1 500 000 (V/m)2*h for Elifetime dose. CONCLUSIONS: In view of the lack of dosimetry data, a retrospective assessment of BC workers' exposure to very high frequency and ultra-high frequency EMF was conducted, which made it possible to estimate EMF lifetime dose for the workers. Since the EMF exposure levels at BCs did not exceed the admissible values, they can be considered safe to the workers' health, according to the approach used for developing OELs for EMF exposure. Med Pr 2018;69(5):477 482. PMID- 30245520 TI - [Risk of occupational exposures to blood-borne pathogens in paramedics]. AB - Paramedics constitute a group of professionals who are constantly exposed to potentially infectious biological material through frequent and close contact with patients, possibly resulting in occupationally acquired infections. The paper's objective has been to assess the occupational risk regarding blood-borne infections and identify preventive measures used among paramedics worldwide, on the basis of the related literature review. The literature search, covering the period 1987-2017, was performed using PubMed, Elsevier, Springer and Google Scholar databases. A comparative analysis of blood exposure was conducted and the report of such events and the use of personal protective equipment among paramedics in Poland and other countries worldwide was developed. The data on occupational blood exposures among paramedics is sparse. The resulting comparisons obtained in various scientific studies are difficult due to diverse data collection methods, influencing the resulting consistency. Additionally, there were some methodological errors found in previously published studies, such as selection bias. The percentage rate of paramedics exposed to blood in the last 12 months varies from 22% in the USA to 63% in Thailand; in Poland that rate fluctuates widely, ranging between 14-78%. Paramedics are frequently exposed to blood while performing their duties, but almost 50% of paramedics do not report any exposure which is mitigated by the systematic use of personal protective equipment: gloves are regularly used by 53-98% of paramedics, masks and goggles are worn by 33-62% of them. This fact puts the paramedics group at risk of blood borne infections. Therefore, there is an urgent need to conduct further, methodologically correct, multi-center studies to accurately assess occupational blood exposure in paramedics. Med Pr 2018;69(6). PMID- 30245521 TI - [Relationship between PM2.5 concentration in the ambient air and daily exacerbation of respiratory diseases in the population of Silesian voivodeship during winter smog]. AB - BACKGROUND: Recurring winter smog episodes, recently observed in Poland, have inspired the researches to assess the epidemiological situation concerning the registered exacerbations of respiratory diseases related to worsening of the ambient air quality. MATERIAL AND METHODS: The model comprising the ecological study results and secondary epidemiological data on registered outpatient visits and hospitalizations in the Silesian voivodeship was used. We assessed the effect of smog observed in January 2017 on the number of acute respiratory disorders registered in that month. Aerosanitary situation was obtained from the Provincial Inspectorate for Environmental Protection in Katowice database. RESULTS: It was documented that the increase in PM2.5 concentration (with simultaneously observed unfavorable meteorological parameters) was related to a higher number of acute respiratory disorders registered daily. Moreover, the increase in the number of outpatient visits due to asthma exacerbation or bronchitis was observed on the first day of episode, and hospitalizations took place with delay of 1-2 days. CONCLUSIONS: The preliminary results indicate the relationship between worsening of ambient air quality during the winter smog and the increase in daily number of registered outpatient visits and hospitalizations due to acute respiratory diseases. Med Pr 2018;69(5):523-530. PMID- 30245522 TI - Effects of Temperature and Spatial Scale on Rio Grande Cutthroat Trout Growth and Abundance. AB - Diversity in habitat and life-history strategies promote a species' long-term persistence. However, life-history strategies are most commonly studied at broad spatial and temporal scales. We applied longevity growth models and closed N mixture models to examine within- versus between stream variability in life history characteristics of Rio Grande Cutthroat Trout in northern New Mexico streams. We developed a von Bertalanffy growth model and a closed N-mixture model in a hierarchical Bayesian framework to examine the importance of fine-scale variability in temperature and density-dependence on growth and abundance. The model indicated that accumulation of degree days likely positively influenced instantaneous growth rates and, to a lesser extent, negatively affected asymptotic body length. A nonlinear response of abundance to temperature was also observed, suggesting that Cutthroat Trout productivity along the temperature continuum was affected by physiological limitations (e.g., optimal growth temperatures). Parameter variability was greatest at the segment level for asymptotic size and abundance, but greatest at the stream level for the rate at which asymptotic size is reached. In total, the results suggest that fine-scale habitat heterogeneity (i.e., temperature) may play important roles in the continued persistence of Rio Grande Cutthroat Trout. Management actions should, therefore, consider the role of fine-scale processes for improving the likelihood of future population persistence. PMID- 30245523 TI - Key Issues for Seamless Integrated Chemistry-Meteorology Modeling. AB - Online coupled meteorology-atmospheric chemistry models have greatly evolved in recent years. Although mainly developed by the air quality modeling community, these integrated models are also of interest for numerical weather prediction and climate modeling, as they can consider both the effects of meteorology on air quality and the potentially important effects of atmospheric composition on weather. This paper summarizes the main conclusions from the "Symposium on Coupled Chemistry-Meteorology/Climate Modelling: Status and Relevance for Numerical Weather Prediction, Air Quality and Climate Research," which was initiated by the European COST Action ES1004 "European Framework for Online Integrated Air Quality and Meteorology Modelling (EuMetChem)." It offers a brief review of the current status of online coupled meteorology and atmospheric chemistry modeling and a survey of processes relevant to the interactions between atmospheric physics, dynamics, and composition. In addition, it highlights scientific issues and emerging challenges that require proper consideration to improve the reliability and usability of these models for three main application areas: air quality, meteorology (including weather prediction), and climate modeling. It presents a synthesis of scientific progress in the form of answers to nine key questions, and provides recommendations for future research directions and priorities in the development, application, and evaluation of online coupled models. PMID- 30245524 TI - Voltammetric Application of Polypyrrole-Modified Microelectrode Array for the Characterization of DNA Methylation in Glutathione S-Transferase Pi 1. AB - Direct and efficient label-free voltammetric detection of Glutathione S Transferase Pi 1 (GSTP1) hypermethylation is reported using a custom developed 16 channel Microelectrode Array chip. The microelectrode array chip is used in a dipstick configuration allowing detection of DNA hybridization in a solution volume of only 0.35 mL. Platinum microelectrode disks (n = 16) 30 um in diameter have been modified with a polypyrrole bilayer before any contact with the oligonucleotides. The attachment of the 15-mer Probe DNA to the bilayer is random but controlled by the presence of aliphatic tether groups allowing it to form a bidentate complex with the probe DNA. The voltammetric detection procedure of methylated GSTP1-specific target DNA is combined with bisulfite treatment of target DNA. Changes at the interface of the modified microelectrodes in an array configuration are used to record simultaneously cyclic voltammetry on all of the devices. The detection of the hybridization is evaluated statistically for a yes or no event by comparing the changes in recorded cyclic voltammograms before and after exposure to the Target DNA. All cyclic voltammograms of the methylated target show a greater percentage change than those with the non-methylated target exposure and show a greater change in cyclic voltammogram area after methylated target exposure. We observe an average percentage difference of 25.6% +/- 4.9 with a variation of 19.1%. These results demonstrate that the fast sensing strategy possesses sensitivity and good specificity. Furthermore, this technology can potentially support rapid, accurate diagnosis and risk assessment of patients with prostate cancer. PMID- 30245525 TI - No task specialization among helpers in Damaraland mole-rats. AB - The specialization of individuals in specific behavioural tasks is often attributed either to irreversible differences in development, which generate functionally divergent cooperative phenotypes, or to age-related changes in the relative frequency with which individuals perform different cooperative activities; both of which are common in many insect caste systems. However, contrasts in cooperative behaviour can take other forms and, to date, few studies of cooperative behaviour in vertebrates have explored the effects of age, adult phenotype and early development on individual differences in cooperative behaviour in sufficient detail to discriminate between these alternatives. Here, we used multinomial models to quantify the extent of behavioural specialization within nonreproductive Damaraland mole-rats, Fukomys damarensis, at different ages. We showed that, although there were large differences between individuals in their contribution to cooperative activities, there was no evidence of individual specialization in cooperative activities that resembled the differences found in insect societies with distinct castes where individual contributions to different activities are negatively related to each other. Instead, individual differences in helping behaviour appeared to be the result of age-related changes in the extent to which individuals committed to all forms of helping. A similar pattern is observed in cooperatively breeding meerkats, Suricata suricatta, and there is no unequivocal evidence of caste differentiation in any cooperative vertebrate. The multinomial models we employed offer a powerful heuristic tool to explore task specialization and developmental divergence across social taxa and provide an analytical approach that may be useful in exploring the distribution of different forms of helping behaviour in other cooperative species. PMID- 30245526 TI - Assessing threats of non-native species to native freshwater biodiversity: Conservation priorities for the United States. AB - Non-native species pose one of the greatest threats to native biodiversity, and can have severe negative impacts in freshwater ecosystems. Identifying regions of spatial overlap between high freshwater biodiversity and high invasion pressure may thus better inform the prioritization of freshwater conservation efforts. We employ geospatial analysis of species distribution data to investigate the potential threat of non-native species to aquatic animal taxa across the continental United States. We mapped non-native aquatic plant and animal species richness and cumulative invasion pressure to estimate overall negative impact associated with species introductions. These distributions were compared to distributions of native aquatic animal taxa derived from the International Union for the Conservation of Nature (IUCN) database. To identify hotspots of native biodiversity we mapped total species richness, number of threatened and endangered species, and a community index of species rarity calculated at the watershed scale. An overall priority index allowed identification of watersheds experiencing high pressure from non-native species and also exhibiting high native biodiversity conservation value. While priority regions are roughly consistent with previously reported prioritization maps for the US, we also recognize novel priority areas characterized by moderate-to-high native diversity but extremely high invasion pressure. We further compared priority areas with existing conservation protections as well as projected future threats associated with land use change. Our findings suggest that many regions of elevated freshwater biodiversity value are compromised by high invasion pressure, and are poorly safeguarded by existing conservation mechanisms and are likely to experience significant additional stresses in the future. PMID- 30245527 TI - Uptake of nickel by synthetic mackinawite. AB - The uptake of aqueous Ni(II) by synthetic mackinawite (FeS) was examined in anaerobic batch experiments at near-neutral pH (5.2 to 8.4). Initial molar ratios of Ni(II) to FeS ranged from 0.008 to 0.83 and maximum Ni concentrations in mackinawite, expressed as the cation mol fraction, were as high as XNi = 0.56 (Fe1 - x Ni x S; 0 <= x <= 1). Greater than 99% Ni removal from solution occurred when Ni loading remained below 0.13 +/- 0.03 (1sigma) mol Ni per mol FeS due to sorption of Ni at the mackinawite surface. Characterization of experimental solids using X-ray diffraction and Raman spectroscopy showed patterns characteristic of nanocrystalline mackinawite; no evidence of nickel monosulfide (alpha-NiS or millerite), polydymite (Ni3S4), or godlevskite [(Ni,Fe)9S8] formation was indicated regardless of the amount of Ni loading. Slight expansion of the c-axis correlated with increasing Ni content in synthetic mackinawite, from c = 5.07 +/- 0.01 A at XNi = 0.02 to c = 5.10 +/- 0.01 A at XNi = 0.38. Ni K edge extended X-ray absorption fine structure (EXAFS) spectra of synthetic Ni bearing mackinawite are similar in phase and amplitude to the Fe K-edge EXAFS spectrum of Ni-free mackinawite, indicating that the molecular environment of Ni2+ in Ni-bearing mackinawite is similar to that of Fe2+ in Ni-free mackinawite. EXAFS data fitting of Ni-bearing mackinawite with XNi = 0.42 indicated a coordination number of 4.04 +/- 0.30 and an average Ni_S bond distance of 2.28 A, in good agreement with the Fe_S bond distance of 2.26 A in mackinawite, tetrahedral Fe coordination, and slight lattice expansion along the c-axis. At lower Ni loadings (XNi = 0.05-0.11), EXAFS analysis showed a decrease in Ni_S coordination towards CN = 3, which reflects the influence of sorbed Ni. Continued Ni uptake, past the maximum amount of sorption, was accompanied by proportional molar release of Fe to solution. Interstitial occupancy of Ni within the mackinawite interlayer may be transitional to structural substitution of Fe. The Ni-mackinawite solid-solution is described by a one-site binary mixing model: LnKd=lnKe-(W/RT)(1-2XNi) where Kd is the distribution coefficient, Ke is the ratio of equilibrium constants for Ni-mackinawite and mackinawite (14.4 +/- 1.3), W is an ion interaction parameter, and XNi is the mole fraction of end-member NiS in the solid solution. The experimentally determined value of W is 17.74 +/- 1.15 kJ/mol and indicates significant non-ideality of the solid solution. Transformation processes were evaluated by aging Ni-mackinawite with polysulfides and solutions saturated with air. Reaction of Ni-mackinawite with polysulfides led to the formation of pyrite (FeS2) and Ni retention in the solid phase. When Ni-mackinawite was aged in the presence of dissolved oxygen, transformation to goethite (FeOOH) and violarite (FeNi2S4) was observed. PMID- 30245528 TI - Illuminating for Safety: Investigating the Role of Lighting Appraisals on the Perception of Safety in the Urban Environment. AB - In two studies, we took a prospect-refuge based perspective to investigate how lighting and other physical attributes (i.e., prospect, concealment, and entrapment) affect people's judgments of the safety of urban streets during nighttime. Both studies complement existing research, which predominantly use factorial designs, with more ecologically valid correlational research using a large and representative sample of urban streets as stimulus materials. Results from Study 1 corroborate existing research demonstrating that differences in prospect, concealment, and entrapment predicted, to a large extent, variation in the perceived safety of urban streets-thus demonstrating the utility of such environmental information for making safety judgments in real-life settings. Results from a mediation analysis conducted in Study 2 showed that the relation between appraisals of lighting quality and safety judgments was completely accounted for by co-occurring variation in appraisals of prospect and entrapment. Implications for theory and methodology are discussed. PMID- 30245529 TI - Riparian proper functioning condition assessment to improve watershed management for water quality. AB - Pollutants can be reduced, ameliorated, or assimilated when riparian ecosystems have the vegetation, water, and soil/landform needed for riparian functions. Loss of physical form and ecological function unravels assimilation processes, increasing supply and transport of pollutants. Water quality and aquatic organisms are response measures of accumulated upstream discharges, and ultimately of changes in riparian functions. Thus, water quality monitoring often fails to identify or lags behind many causes of pollution or remediation from riparian degradation. This paper reviews the interagency riparian proper functioning condition (PFC) assessment for lotic (running water) riparian ecosystems and outlines connections between PFC and water quality attributes (sediment, nutrients, temperature, and dissolved oxygen [DO]). The PFC interaction of hydrology, vegetation, and soils/landforms influences water quality by dissipating energy associated with high waterflow, thereby reducing vertical instability and lateral erosion while developing floodplains with captured sediment and nutrients. Slowing flood water enables aquifer recharge, deposition, and plant nutrient uptake. Water-loving, densely rooted streambank stabilizing vegetation and/or wood helps integrate riparian functions to maintain channel pattern, profile, and dimension with characteristics for a diversity of habitats. A complex food web helps slow the nutrient spiral with uptake and storage. Temperature fluctuations are dampened by delayed discharges, narrower and deeper active channels, coarser substrates that enhance hyporheic interchange, and shade from riparian vegetation. After assessment and implementation, monitoring recovery of impaired riparian function attributes (e.g., streambank plant species) naturally focuses on persistent drivers of water quality and aquatic habitat. This provides timely environmental indicators of stream ecological health and water quality remediation projects or land management. PMID- 30245530 TI - Sequential coprecipitation and matrix removal for determination of cadmium impurities from multivitamin supplements by inductively coupled plasma mass spectrometry and method validation by isotope dilution analysis of SRM 3280 multivitamin/multielement tablets. AB - In this paper, we examined three different sequential coprecipitation schemes based on Mg(OH)2 and CaF2 precipitation using triethylamine (TEA) and hydrofluoric acid (HF), respectively, for determination of cadmium (Cd) impurities from multivitamin/mineral (MVM) supplements by isotope dilution (ID) inductively coupled plasma mass spectrometry (ICP-MS). The schemes involved three step coprecipitation with either TEA alone or in combination with HF and are designated as Scheme 1 (TEA-TEA-TEA), Scheme 2 (TEA-HF-TEA) and Scheme 3 (HF-TEA TEA) according to the addition sequence of each reagent. Experiments were carried out with MVM solutions spiked with 60 MUg L-1 Cd from a multielement standard solution. All schemes provided quantitative separation of Cd from MVM matrix. Scheme 1 was the least effective in removal of interfering concomitant elements, molybdenum (Mo) and tin (Sn). Scheme 2 performed better for Sn, but failed in eliminating Mo. Scheme 3 was the most effective in eliminating both Mo and Sn. Mo levels in test MVM solutions reduced from 4.3 MUg mL-1 to as low as 0.014 MUg mL 1 while that for Sn decreased from 0.5 MUg mL-1 to 0.018 MUg mL-1 allowing interference-free determination of Cd to be achieved. Salt-matrix due to Mg, Ca, P and K along with the essential elements (Mn, Fe, Cu and Zn) levels was also reduced significantly. Reagent blanks from HF and TEA were insignificant (0.008 MUg L-1) allowing a limit of detection of 0.004 MUg L-1 or 0.26 ng g-1 Cd to be achieved (3sigma, n = 6). The performance of the coprecipitation method (Scheme 3) was validated by determination of Cd in multivitamin/multielement tablets certified reference material (SRM 3280) by ID-ICP-MS. Experimental results (ng g 1) and recoveries were 78.8 +/- 4.7 (98.5%), 77.9 +/- 5.2 (97.4%) and 76.5 +/- 4.8 (95.6%) for 110Cd, 111Cd and 114Cd isotopes, respectively. Several commercial MVM supplements were analyzed using the method. Mean Cd concentration ranged from 21.4 ng g-1 to 93.3 ng g-1. These values are much lower than those reported to date for various MVM supplements by ICP-MS determinations without chemical separation. PMID- 30245531 TI - Bereaved mothers' attitudes regarding autopsy of their stillborn baby. AB - Background: Here we present additional information from the Safe Passage Study, where the effect of alcohol exposure during pregnancy on sudden infant death syndrome and stillbirth was investigated. Objective: To explore bereaved mothers' attitudes toward obtaining an autopsy on their stillborn baby, and the future implications of consenting or non-consenting to autopsy in retrospect. Methods: Demographic data was obtained by a questionnaire. A largely qualitative mixed methods approach was used to meet the aims of the study, using an exploratory and descriptive research design to provide a detailed description of maternal attitudes. A semi-structured questionnaire based on information from literature and reflections on practice was administered during individual interviews. Results: We interviewed 25 women who had had a recent stillbirth. The time interval between the time of consenting to autopsy and completing this study ranged from 6 to 18 months. Most participants reported that autopsy results provided peace of mind and helped alleviate their feelings of blame. Participants who were unable to comprehend the results reported negative reactions to receiving autopsy results. The majority of participants were of the opinion that they benefited from consenting to autopsy. Conclusion: Autopsy and the disclosure of its results generally contribute positively to coping following stillbirth. PMID- 30245532 TI - A photocaged, cyclopropene-containing analog of the amino acid neurotransmitter glutamate. AB - Substituted cyclopropenes serve as compact biorthogonal appendages that enable analysis of biomolecules in complex systems. Neurotransmitters, a chemically diverse group of biomolecules that control neuron excitation and inhibition, are not among the systems that have been studied using biorthogonal chemistry. Here we describe the synthesis of cyclopropene-containing analogs of the excitatory amino acid neurotransmitter glutamate starting from a Garner's aldehyde-derived alkyne. The deprotected cyclopropene glutamate was stable in solution but decomposed upon concentration. Appending a light-cleavable group improved the stability of the cyclopropene while simultaneously caging the neurotransmitter. This strategy has the potential to permit deployment of cyclopropene-modified glutamate as a bioorthogonal probe of the neurotransmitter glutamate in vivo with spatiotemporal precision. PMID- 30245533 TI - A possible link between winter Arctic sea ice decline and a collapse of the Beaufort High? AB - A new study by Moore et al., (2018, this issue) highlights a collapse of the anticyclonic 'Beaufort High' atmospheric circulation over the western Arctic Ocean in the winter of 2017 and an associated reversal of the sea ice drift through the southern Beaufort Sea (eastward instead of the predominantly westward circulation). The authors linked this to the loss of sea ice in the Barents Sea, anomalous warming over the region, and the intrusion of low-pressure cyclones along the eastern Arctic. In this commentary we discuss the significance of this observation, the challenges associated with understanding these possible linkages, and some of the alternative hypotheses surrounding the impacts of winter Arctic sea ice loss. PMID- 30245534 TI - On the Collisionless Asymmetric Magnetic Reconnection Rate. AB - : A prediction of the steady state reconnection electric field in asymmetric reconnection is obtained by maximizing the reconnection rate as a function of the opening angle made by the upstream magnetic field on the weak magnetic field (magnetosheath) side. The prediction is within a factor of 2 of the widely examined asymmetric reconnection model (Cassak & Shay, 2007, https://doi.org/10.1063/1.2795630) in the collisionless limit, and they scale the same over a wide parameter regime. The previous model had the effective aspect ratio of the diffusion region as a free parameter, which simulations and observations suggest is on the order of 0.1, but the present model has no free parameters. In conjunction with the symmetric case (Liu et al., 2017, https://doi.org/10.1103/PhysRevLett.118.085101), this work further suggests that this nearly universal number 0.1, essentially the normalized fast-reconnection rate, is a geometrical factor arising from maximizing the reconnection rate within magnetohydrodynamic-scale constraints. Plain Language Summary: To understand the evolution of many space and astrophysical plasmas, it is imperative to know how fast magnetic reconnection processes the magnetic flux. Researchers found that reconnection in both symmetric and asymmetric geometries exhibits a normalized reconnection rate of order 0.1. In this work, we show that this nearly universal value in asymmetric geometry is also the maximal rate allowed in the magnetohydrodynamic scale. This result has applications to the transport process at plasma boundary layers like Earth's magnetopause. PMID- 30245535 TI - The Effect of a Pressure-Containing Correlation Model on Near-Wall Flow Simulations with RST Models. AB - It is accustomed to think that turbulence models based on solving the Reynolds Averaged Navier-Stokes equations require empirical functions to accurately reproduce the behavior of flow characteristics of interest, particularly near a wall. The current paper analyzes how choosing a model for pressure-strain correlations in second-order closures affects the need for introducing empirical functions in model equations to reproduce the flow behavior near a wall correctly. An axially-rotating pipe flow is used as a test flow for the analysis. Results of simulations demonstrate that by using more physics-based models to represent pressure-strain correlations, one can eliminate wall functions associated with such models. The higher the Reynolds number or the strength of imposed rotation on a flow, the less need there is for empirical functions regardless of the choice of a pressure-strain correlation model. PMID- 30245536 TI - The Development and Evaluation of a High-Resolution Above Ground Biomass Product for the Commonwealth of Puerto Rico (2000). AB - This study details the development of a U.S. Commonwealth of Puerto Rico above ground forest biomass (agb) product (baseline 2000) developed by the United States Environmental, Protection Agency (epa) that was compared to another AGB product developed by the U.S. Forest Service (usfs) for the same area. The USEPA product tended to over-predict in areas of low biomass and under-predict in high biomass areas when compared to observed plot data, but compared favorably to a Forest Inventory Analysis (fia) assessment of structure and condition of Puerto Rico forests (72.6 Mg/ha versus 80.0 Mg/ ha, respectively). AGB estimates were highly correlated with reference FIA biomass for both maps at their native spatial resolutions (USEPA: r =0.93, USFS: r = 0.92). AGB mean difference between both products was 33.5 Mg/ha (USFS mean = 106.1 Mg/ha; USEPA mean = 72.6 Mg/ha), a difference not out-of- scope when compared to other biomass comparative studies. PMID- 30245537 TI - Suburbanization and Segregation in the United States: 1970-2010. AB - Analysis of trends in the suburbanization of whites, blacks, Asians, and Hispanics reveal that all groups are becoming more suburbanized, though the gap between whites and minorities remains large. Although central cities have made the transition to a majority-minority configuration, suburbs are still overwhelmingly white. Levels of minority-white segregation are nonetheless lower in suburbs than cities. Blacks remain the most segregated group at both locations. Black segregation and isolation levels are declining in cities and suburbs, however, while Hispanic and Asian segregation levels have remained stable and spatial isolation levels have risen. Multivariate analyses suggest that Hispanics achieve desegregation indirectly by using socioeconomic achievements to gain access to less-segregated suburban communities and directly by translating r status attainments into residence in white neighborhoods. Blacks do not achieve desegregation indirectly through suburbanization and they are much less able than Hispanics to use their socioeconomic attainments directly to enter white neighborhoods. PMID- 30245538 TI - Planning for community resilience to future United States domestic water demand. AB - Costs of repairing and expanding aging infrastructure and competing demands for water from other sectors such as industry and agriculture are stretching water managers' abilities to meet essential domestic drinking water needs for future generations. Using Bayesian statistical modeling on past and present water use, we project domestic water demand in the context of four climate scenarios developed by the Intergovernmental Panel on Climate Change as part of the their Special Report on Emission Scenarios (SRES). We compare 2010 demand to projections of domestic water demand for the years 2030, 2060 and 2090 for the four SRES scenarios. Results indicate that the number of counties exceeding fifty percent or greater demand over 2010 levels increases through 2090 for two of the scenarios and plateaus around 2050 for the other two. Counties experiencing the largest increases in water demand are concentrated in the states of California, Texas, and isolated portions of the Mid-West, Southeast, and Mid-Atlantic. Closer examination of the spatial distribution of high demand counties reveals that they are typically found near or adjacent to metropolitan centers, potentially placing greater stress on already taxed systems. Identifying these counties allows for targeted adaptive management and policies, economic incentives, and legislation to be focused towards locations that are potentially the most vulnerable. PMID- 30245539 TI - Stream channel erosion in a rapidly urbanizing region of the US-Mexico border: documenting the importance of channel hardpoints with Structure-from-Motion photogrammetry. AB - Urbanization can lead to accelerated stream channel erosion, especially in areas experiencing rapid population growth, unregulated urban development on erodible soils, and variable enforcement of environmental regulations. A combination of field surveys and Structure-from-Motion (SfM) photogrammetry techniques was used to document spatial patterns in stream channel geometry in a rapidly urbanizing watershed, Los Laureles Canyon (LLCW), in Tijuana, Mexico. Ground-based SfM photogrammetry was used to map channel dimensions with 1 to 2 cm vertical mean error for four stream reaches (100-300 m long) that were highly variable and difficult to survey with a differential GPS. Regional channel geometry curves for LLCW had statistically larger slopes and intercepts compared with regional curves developed for comparable, undisturbed reference channels. Cross-sectional areas of channels downstream of hardpoints, such as concrete reaches or culverts, were up to 64 times greater than reference channels, with enlargement persisting, in some cases, up to 230 m downstream. Percentage impervious cover was not a good predictor of channel enlargement. Proximity to upstream hardpoint, and lack of riparian and bank vegetation paired with highly erodible bed and bank materials may account for the instability of the highly enlarged and unstable cross sections. Channel erosion due to urbanization accounts for approximately 25-40% of the total sediment budget for the watershed, and channel erosion downstream of hardpoints accounts for one-third of all channel erosion. Channels downstream of hardpoints should be stabilized to prevent increased inputs of sediment to the Tijuana Estuary and local hazards near the structures, especially in areas with urban settlements near the stream channel. PMID- 30245540 TI - Tumor Margin Classification of Head and Neck Cancer Using Hyperspectral Imaging and Convolutional Neural Networks. AB - One of the largest factors affecting disease recurrence after surgical cancer resection is negative surgical margins. Hyperspectral imaging (HSI) is an optical imaging technique with potential to serve as a computer aided diagnostic tool for identifying cancer in gross ex-vivo specimens. We developed a tissue classifier using three distinct convolutional neural network (CNN) architectures on HSI data to investigate the ability to classify the cancer margins from ex-vivo human surgical specimens, collected from 20 patients undergoing surgical cancer resection as a preliminary validation group. A new approach for generating the HSI ground truth using a registered histological cancer margin is applied in order to create a validation dataset. The CNN-based method classifies the tumor normal margin of squamous cell carcinoma (SCCa) versus normal oral tissue with an area under the curve (AUC) of 0.86 for inter-patient validation, performing with 81% accuracy, 84% sensitivity, and 77% specificity. Thyroid carcinoma cancer normal margins are classified with an AUC of 0.94 for inter-patient validation, performing with 90% accuracy, 91% sensitivity, and 88% specificity. Our preliminary results on a limited patient dataset demonstrate the predictive ability of HSI-based cancer margin detection, which warrants further investigation with more patient data and additional processing techniques to optimize the proposed deep learning method. PMID- 30245541 TI - A semiautomatic algorithm for three-dimensional segmentation of the prostate on CT images using shape and local texture characteristics. AB - Prostate segmentation in computed tomography (CT) images is useful for planning and guidance of the diagnostic and therapeutic procedures. However, the low soft tissue contrast of CT images makes the manual prostate segmentation a time consuming task with high inter-observer variation. We developed a semi-automatic, three-dimensional (3D) prostate segmentation algorithm using shape and texture analysis and have evaluated the method against manual reference segmentations. In a training data set we defined an inter-subject correspondence between surface points in the spherical coordinate system. We applied this correspondence to model the globular and smoothly curved shape of the prostate with 86, well distributed surface points using a point distribution model that captures prostate shape variation. We also studied the local texture difference between prostate and non-prostate tissues close to the prostate surface. For segmentation, we used the learned shape and texture characteristics of the prostate in CT images and we used a set of user inputs for prostate localization. We trained our algorithm using 23 CT images and tested it on 10 images. We evaluated the results compared with those of two experts' manual reference segmentations using different error metrics. The average measured Dice similarity coefficient (DSC) and mean absolute distance (MAD) were 88 +/- 2% and 1.9 +/- 0.5 mm, respectively. The averaged inter-expert difference measured on the same dataset was 91 +/- 4% (DSC) and 1.3 +/- 0.6 mm (MAD). With no prior intra-patient information, the proposed algorithm showed a fast, robust and accurate performance for 3D CT segmentation. PMID- 30245542 TI - Evaluating drywells for stormwater management and enhanced aquifer recharge. AB - Drywells are increasingly used for stormwater management and enhanced aquifer recharge, but only limited research has quantitatively determined the performance of drywells. Numerical and field scale experiments were, therefore, conducted to improve our understanding and ability to characterize the drywell behavior. In particular, HYDRUS (2D/3D) was modified to simulate transient head boundary conditions for the complex geometry of the Maxwell Type IV drywell; i.e., a sediment chamber, an overflow pipe, and the variable geometry and storage of the drywell system with depth. Falling-head infiltration experiments were conducted on drywells located at the National Training Center in Fort Irwin, California (CA) and a commercial complex in Torrance, CA to determine in situ soil hydraulic properties (the saturated hydraulic conductivity, Ks , and the retention curve shape parameter, alpha) for an equivalent uniform soil profile by inverse parameter optimization. A good agreement between the observed and simulated water heights in wells was obtained for both sites as indicated by the coefficient of determination 0.95-0.99-%, unique parameter fits, and small standard errors. Fort Irwin and Torrance drywells had very distinctive soil hydraulic characteristics. The fitted value of Ks =1.01 * 10-3 m min-1 at the Torrance drywell was consistent with the sandy soil texture at this site and the default value for sand in the HYDRUS soil catalog. The drywell with this Ks = 1.01 * 10-3 m min-1 could easily infiltrate predicted surface runoff from a design rain event (~51.3 m3) within 5760 min (4 d). In contrast, the fitted value of Ks=2.25 * 10-6 m min 1 at Fort Irwin was very low compared to the Torrance drywell and more than an order of magnitude smaller than the default value reported in the HYDRUS soil catalog for sandy clay loam at this site, likely due to clogging. These experiments and simulations provide useful information to characterize effective soil hydraulic properties in situ, and to improve the design of drywells for enhanced recharge. PMID- 30245543 TI - Barley lys3 mutants are unique amongst shrunken-endosperm mutants in having abnormally large embryos. AB - Many shrunken endosperm mutants of barley (Hordeum vulgare L.) have been described and several of these are known to have lesions in starch biosynthesis genes. Here we confirm that one type of shrunken endosperm mutant, lys3 (so called because it was first identified as a high-lysine mutant) has an additional phenotype: as well as shrunken endosperm it also has enlarged embryos. The lys3 embryos have a dry weight that is 50-150% larger than normal. Observations of developing lys3 embryos suggest that they undergo a form of premature germination and the mature lys3 grains show reduced dormancy. In many respects, the phenotype of barley lys3 is similar to that of rice GIANT EMBRYO mutants (affected in the OsGE gene). However, the barley orthologue of OsGE is located on a different chromosome from Lys3. Together these results suggest that the gene underlying Lys3 is unlikely to encode a starch biosynthesis protein but rather a protein influencing grain development. PMID- 30245544 TI - The Reliability and Reciprocity of a Social Network Measure. AB - There have been few efforts to systematically develop reliable and valid measures of social networks, particularly in studies dealing with individuals having substance use disorders. In the current study, individuals living in recovery homes called Oxford Houses completed a 6-item measure of social networks. The Cronbach's alpha was .85 and a confirmatory factor analysis found excellent fit statistics with all items having substantial (> .70) load factors. In addition, the measure was independent of age, sex, and ethnicity and significantly related to length of stay in the recovery homes and quality of life. The authors have found that this instrument works well as an ego network with adequate psychometric properties and empirical relations to other recovery variables. PMID- 30245545 TI - Assessing metal mobilization from industrial lead-contaminated soils in an urban site. AB - A series of leaching and partitioning tests (Toxicity Characteristic Leaching Procedure (TCLP), Synthetic Precipitation Leaching Procedure (SPLP), Controlled Acidity Leaching Protocol (CALP), Acid Neutralization Capacity (ANC), and sequential extraction) were applied to three different soils to study the potential mobility of metals into groundwater. Two of these soils were lead (Pb) contaminated soils (Hotspot 1 and Hotspot 2) collected from an urban site associated with lead smelting and other industrial operations. The third sample (Stockpile) was soil affected by previous contamination in the area, removed from residential properties, stockpiled, and selected to be used as fill material in the studied site. The TCLP and CALP showed that Pb could be released from both hotspots, but were not released in the acidic rainfall extraction fluid of the SPLP. The sequential extraction showed that Pb in the hotspot soils was associated with the carbonate fraction, while As was associated with the Fe and Mn oxides. The stockpile released traces of Pb or As in the TCLP and CALP, but the ANC only released Pb under acidic conditions and the SPLP did not release Pb or As. Overall, the projected repository with Stockpile would not pose imminent danger to groundwater because, under the expected environmental conditions, Pb and As tend to remain in the solid phase. PMID- 30245547 TI - Feasibility Assessment of a New Surveillance Tool for Respiratory Protective Devices Used in U.S. Healthcare. AB - Background: Respiratory protective devices (RPDs) are used for infection prevention in healthcare settings during routine patient care and public health emergencies. In recent years, healthcare systems have experienced shortages of RPDs during outbreaks of infectious diseases, in part due to a lack of information about their availability. New tools to track RPD inventories may improve accessibility during an emergency. Investigators at Vanderbilt University have identified four major themes that influence RPD use for infection prevention: hospital preparedness, responsiveness to airborne pathogens, potential exposure outcomes, and infection control practices related to respirator effectiveness. Based on these findings, an RPD surveillance tool (RST) was developed to collect and share near real-time data about RPD supplies in healthcare facilities. The objective of this study was to conduct a feasibility assessment of this RST. Methods: The new online surveillance tool was implemented at four large, urban, acute care U.S. hospitals in January 2014; data was collected about RPD inventory, tracking systems, hospital characteristics, and utility of gathered information. Results: The RST was implemented successfully and without difficulty at hospitals that had 78 to 90 percent occupancy rates. Participating hospitals reported that the RST (1) provided value for benchmarking their RPD supply, (2) promoted understanding about RPD accessibility among hospital systems engaged in infection control, and (3) served as a means to assess RPD program quality. Conclusion: Implementation of this newly developed RST is feasible and appears to have utility in U.S. hospitals for tracking and understanding RPD use for routine healthcare delivery and public health emergencies. PMID- 30245546 TI - Polycyclic Aromatic Hydrocarbons in Fine Particulate Matter Emitted from Burning Kerosene, Liquid Petroleum Gas, and Wood Fuels in Household Cookstoves. AB - This study measures polycyclic aromatic hydrocarbon (PAH) compositions in particulate matter emissions from residential cookstoves. A variety of fuel and cookstove combinations are investigated, including: (i) liquid petroleum gas (LPG), (ii) kerosene in a wick stove, (iii) wood (10 and 30% moisture content on a wet basis) in a forced-draft fan stove, and (iv) wood in a natural-draft rocket cookstove. The wood burning in the natural-draft stove had the highest PAH emissions followed by the wood combustion in the forced-draft stove and kerosene burning. LPG combustion has the highest thermal efficiency (~57%) and the lowest PAH emissions per unit fuel energy, resulting in the lowest PAH emissions per useful energy delivered (in the unit of megajoule delivered, MJd). Compared with the wood combustion emissions, LPG burning also emits a lower fraction of higher molecular weight PAHs. In rural regions where LPG and kerosene are unavailable or unaffordable, the forced-draft fan stove is expected to be an alternative because its benzo[a]pyrene (B[a]P) emission factor (5.17-8.24 MUg B[a]P/MJd) and emission rate (0.522-0.583 MUg B[a]P/min) are similar to those of kerosene burning (5.36 MUg B[a]P/MJd and 0.452 MUg B[a]P/min). Relatively large PAH emission variability for LPG suggests a need for additional future tests to identify the major factors influencing these combustion emissions. These future tests should also account for different LPG fuel formulations and stove burner types. PMID- 30245549 TI - Mono- and Multilayer Silicene-Type Honeycomb Lattices by Oriented Attachment of PbSe Nanocrystals: Synthesis, Structural Characterization, and Analysis of the Disorder. AB - Nanocrystal (NC) solids are commonly prepared from nonpolar organic NC suspensions. In many cases, the capping on the NC surface is preserved and forms a barrier between the NCs. More recently, superstructures with crystalline connections between the NCs, implying the removal of the capping, have been reported, too. Here, we present large-scale uniform superstructures of attached PbSe NCs with a silicene-type honeycomb geometry, resulting from solvent evaporation under nearly reversible conditions. We also prepared multilayered silicene honeycomb structures by using larger amounts of PbSe NCs. We show that the two-dimensional silicene superstructures can be seen as a crystallographic slice from a 3-D simple cubic structure. We describe the disorder in the silicene lattices in terms of the nanocrystals position and their atomic alignment. The silicene honeycomb sheets are large enough to be used in transistors and optoelectronic devices. PMID- 30245550 TI - Dynamic parallelism for synaptic updating in GPU-accelerated spiking neural network simulations. AB - Graphical processing units (GPUs) can significantly accelerate spiking neural network (SNN) simulations by exploiting parallelism for independent computations. Both the changes in membrane potential at each time-step, and checking for spiking threshold crossings for each neuron, can be calculated independently. However, because synaptic transmission requires communication between many different neurons, efficient parallel processing may be hindered, either by data transfers between GPU and CPU at each time-step or, alternatively, by running many parallel computations for neurons that do not elicit any spikes. This, in turn, would lower the effective throughput of the simulations. Traditionally, a central processing unit (CPU, host) administers the execution of parallel processes on the GPU (device), such as memory initialization on the device, data transfer between host and device, and starting and synchronizing parallel processes. The parallel computing platform CUDA 5.0 introduced dynamic parallelism, which allows the initiation of new parallel applications within an ongoing parallel kernel. Here, we apply dynamic parallelism for synaptic updating in SNN simulations on a GPU. Our algorithm eliminates the need to start many parallel applications at each time-step, and the associated lags of data transfer between CPU and GPU memories. We report a significant speed-up of SNN simulations, when compared to former accelerated parallelization strategies for SNNs on a GPU. PMID- 30245548 TI - Extracting quantal properties of transmission at central synapses. AB - Chemical synapses enable neurons to communicate rapidly, process and filter signals and to store information. However, studying their functional properties is difficult because synaptic connections typically consist of multiple synaptic contacts that release vesicles stochastically and exhibit time-dependent behavior. Moreover, most central synapses are small and inaccessible to direct measurements. Estimation of synaptic properties from responses recorded at the soma is complicated by the presence of nonuniform release probability and nonuniform quantal properties. The presence of multivesicular release and postsynaptic receptor saturation at some synapses can also complicate the interpretation of quantal parameters. Multiple-probability fluctuation analysis (MPFA; also known as variance-mean analysis) is a method that has been developed for estimating synaptic parameters from the variance and mean amplitude of synaptic responses recorded at different release probabilities. This statistical approach, which incorporates nonuniform synaptic properties, has become widely used for studying synaptic transmission. In this chapter, we describe the statistical models used to extract quantal parameters and discuss their interpretation when applying MPFA. PMID- 30245551 TI - Cumulative global forest carbon implications of regional bioenergy expansion policies. AB - Several previous studies have evaluated the potential greenhouse gas (GHG) benefits of forest biomass energy relative to fossil fuel equivalents over different spatial scales and time frames and applying a variety of methodologies. This paper contributes to this literature through an analysis of multiple projected sources of biomass demand growth in different regions of the world using a detailed intertemporal optimization model of the global forest sector. Given the range of current policies incentivizing bioenergy expansion globally, evaluating the combined global implications of regional bioenergy expansion efforts is critical for understanding the extent to which renewable energy supplied from forest biomass can contribute to various policy goals (including GHG emissions mitigation). Unlike previous studies that have been more regionally focused, this study provides a global perspective, illustrating how large potential demand increases for forest biomass in one or multiple regions can alter future forest management trends, markets, and forest carbon sequestration in key timber supply regions. Results show that potential near term (2015-2030) biomass demand growth in the U.S., Europe, and elsewhere can drive forest resource investment at the intensive and extensive margins, resulting in a net increase in forest carbon stocks for most regions of the world. When the reallocation of biomass away from traditional pulp and sawtimber markets is accounted for, net forest carbon sequestration increases (that stored on the land and in wood products) by 9.4 billion tons CO2 over the near term and 15.4 billion tons CO2 by 2095. Even if most of the increased forest biomass demand arises from one region (e.g., Europe) due to a particularly strong promotion of forest bioenergy expansion, changes in forest management globally in anticipation of this demand increase could result in carbon beneficial outcomes that can be shared by most regions. PMID- 30245552 TI - Mysticism in the courtroom in 19th-century Europe. AB - This article examines how and why criminal proceedings were brought against alleged cases of Catholic mysticism in several European countries during modernity. In particular, it explores how criminal charges were derived from mystical experiences and shows how these charges were examined inside the courtroom. To bring a lawsuit against supposed mystics, justice systems had to reduce their mysticism to 'facts' or actions involving a breach of the law, usually fraud. Such accusations were not the main reason why alleged mystics were taken to court, however. Focusing on three representative examples, in Spain, France and Germany, I argue that 'mystic trials' had more to do with specific conflicts between the defendant and the ecclesiastical or secular authorities than with public concern regarding pretence of the supernatural. Criminal courts in Europe approached such cases in a similar way. Just as in ecclesiastical inquiries, during the trials, judges called upon expert testimony to debunk the allegedly supernatural. Once a mystic entered the courtroom, his or her reputation was profoundly affected. Criminal lawsuits had a certain 'demystifying power' and were effective in stifling the fervour surrounding the alleged mystics. All in all, mystic trials offer a rich example of the ways in which modern criminal justice dealt with increasing enthusiasm for the supernatural during the 19th century. PMID- 30245553 TI - Emergy Analysis for the Sustainable Utilization of Biosolids Generated in a Municipal Wastewater Treatment Plant. AB - This contribution describes the application of an emergy-based methodology for comparing two management alternatives of biosolids produced in a wastewater treatment plant. The current management practice of using biosolids as soil fertilizers was evaluated and compared to another alternative, the recovery of energy from the biosolid gasification process. This emergy assessment and comparison approach identifies more sustainable processes which achieve economic and social benefits with a minimal environmental impact. In addition, emergy based sustainability indicators and the GREENSCOPE methodology were used to compare the two biosolid management alternatives. According to the sustainability assessment results, the energy production from biosolid gasification is energetically profitable, economically viable, and environmentally suitable. Furthermore, it was found that the current use of biosolids as soil fertilizer does not generate any considerable environmental stress, has the potential to achieve more economic benefits, and a post-processing of biosolids prior to its use as soil fertilizer improves its sustainability performance. In conclusion, this emergy analysis provides a sustainability assessment of both alternatives of biosolid management and helps decision-makers to identify opportunities for improvement during the current process of biosolid management. PMID- 30245554 TI - Life cycle cost and environmental assessment for resource-oriented toilet systems. AB - The rich content of nutrients in human waste provides an outlook for turning it from pollutants to potential resources. The pilot-scale resource-oriented toilet with forward osmosis technology was demonstrated to have advantages to recover clean water, nitrogen, phosphorus, potassium, biogas, and heat from urine and feces. For the possibility of further full-scale implementation in different scenarios, six resource-oriented toilet systems and one conventional toilet system were designed in this study. The methodology of cost-benefit analysis and life cycle assessment were applied to analyze the life cycle economic feasibility and environmental sustainability of these systems. As results indicated, resource oriented toilets with forward osmosis technology concentrating urine proved to have both economic and environmental benefit. The economic net present value results of new resource-oriented toilets were much better than conventional toilet. The energy consumption in resource-oriented toilets contributes a lot to the environmental impacts while resource recovery such as the fertilizer production and fresh water harvest in resource-oriented toilet systems offsets a lot. Taking both life cycle economic feasibility and environmental sustainability into consideration, the partial resource-oriented toilet (only recovering nutrients from urine) is the best choice, and the totally independent resource oriented toilet could be applied to replace conventional toilets in areas without any external facilities such as sewer and water supply system etc. PMID- 30245556 TI - A Novel Dynamic Hyper-Graph Inference Framework for Computer Assisted Diagnosis of Neuro-Diseases. AB - Recently hyper-graph learning gains increasing attention in medical imaging area since the hyper-graph, a generalization of a graph, opts to characterize the complex subject-wise relationship behind multi-modal neuroimaging data. However, current hyper-graph methods are re-strained with two major limitations: (1) The data representation encoded in the hyper-graph is learned only from the observed imaging features for each modality separately. Therefore, the learned subject wise relation-ships are neither consistent across modalities nor fully consensus with the clinical labels or clinical scores. (2) The learning procedure of data representation is completely independent to the subsequent classification step. Since the data representation optimized in the feature domain is not exactly aligned with the clinical labels, such independent step-by-step workflow might result in sub-optimal classification. To overcome these limitations, we propose a novel dynamic hyper-graph inference frame-work. Working in a semi-supervised manner, it iteratively estimates and adjusts the subject-wise relationship from multi-modal neuroimaging data until the learned data representation (encoded in the hyper-graph) achieves the largest consensus with the observed clinical labels and scores. It is worth noting that our inference framework is also flexible to integrate classification (identifying individuals with neuro-disease) and regression (predicting the clinical scores). We have demonstrated that the performance of our proposed dynamic hyper-graph inference framework renders more accurate diagnosis result in identifying MCI (Mild Cognition Impairment) subjects and the fine-grained recognition of different progression stage of MCI compared to conventional counterpart methods. PMID- 30245555 TI - The BDNF gene val66met polymorphism and behavioral inhibition in early childhood. AB - Stably elevated behavioural inhibition (BI) is an established risk factor for internalizing disorders. This stability may be related to genetic factors, including a valine-to-methionine substitution on codon 66 (val66met) of the brain derived neurotrophic factor (BDNF) gene. Past work on the BDNF met variant has inconsistently linked it to vulnerability to internalizing problems; some of this inconsistency may stem from the failure to consider gene-trait interactions in shaping the course of early BI. Toward elucidating early pathways to anxiety vulnerability, we examined gene-by-trait interactions in predicting the course of BI over time in 476 children, assessed for BI using standardized laboratory methods. We found that children with the met allele showed lower stability of BI between ages 3 and 6 than those without this allele. While the mechanisms that underlie this effect are unclear, our findings are consistent with the notion that the met variant, in the context of early BI, influences the stability of this trait in early development. PMID- 30245558 TI - The Opposition. AB - Although social workers have an ethical and professional mandate to address inequity, theoretical and treatment approaches usually fail to address historical and structural contexts. In opposition, radical social work bridges individual and community practice by acknowledging that macro forces have micro consequences; micro practices are reflective of macro socio-political processes; and, by opposing the socio-structural forces underlying individual problems. By adopting transformative, anti-oppressive frameworks and practices, radical social workers make visible the invisible social-ecological factors that hurt people, including institutionalized white privilege; transform systems to help individuals rather than helping individuals cope with oppressive systems by reinforcing marginalized roles in accordance with inferior treatment; and develop transformative potential in self and others. PMID- 30245557 TI - Sleep duration moderates the association between children's temperament and academic achievement. AB - The primary goal of this study was to determine whether sleep duration moderated the relations of two dimensions of children's temperament, shyness and negative emotion, to academic achievement. In the autumn, parents and teachers reported on kindergarteners' and first graders' (N = 103) shyness and negative emotion and research assistants observed negative emotion in the classroom. In the spring, children wore actigraphs that measured their sleep for five consecutive school nights, and they completed the Woodcock Johnson-III standardized tests of achievement. Interactions between temperament and sleep duration predicting academic achievement were computed. Interactions of sleep duration with parent reported shyness, teacher-reported negative emotion, and observed negative emotion indicated that the negative relations of shyness or negative emotion to academic achievement were strongest when children slept less. Results suggest that sleep duration may be an important bio-regulatory factor to consider in young children's early academic achievement. PMID- 30245559 TI - Experimental Study on Potential Heat Treatment Issues of Large Bi-2212 Coils. AB - The route to 30 T NMR endorsed by a recent National Academy report clearly still has many challenges to achieve high stability and homogeneous high temperature superconducting (HTS) magnet. As the only HTS conductor with round wire (RW) geometry, Bi2Sr2CaCu2O8-x (Bi-2212) RW conductor is very attractive for NMR magnet applications. At present, an NMR quality demonstration magnet with Bi-2212 RW wound insert coils is under development at the National High Magnetic Field Laboratory (NHMFL). The target of this demonstration magnet is to generate a total field of 23+ T with ppm level homogeneity. Since Bi-2212 coils require Wind and-React (W&R) technology, our initial major concern was that large Bi-2212 coils might deform during the typical partial melt Bi-2212 heat treatment (HT) due to their large self-weight. To experimentally mimic the HT of large Bi-2212 coil, several small test coils were heat treated under deadweight loads. After 1 bar Bi-2212 full reaction, these coils were characterized in terms of coil geometry, transport critical current properties, oxygenation status and insulation performance. Coil geometry and individual wire shape was in fact not distorted, nor was transport properties degradation was induced by mechanical loading. Uniform oxygen equilibration was achieved in these coils even though they were coated with dense oxide insulation. However, although the TiO2-based insulation coating was well preserved on the wire surface, several coils developed electrical shorts. PMID- 30245561 TI - Naltrexone Maintenance: Effect on Morphine Sensitivity in Normal Volunteers. PMID- 30245562 TI - An 85-Year-Old Man With Recurrent Fever and Multiple Splenic Infarcts. PMID- 30245560 TI - Insomnia among Cancer Caregivers: A Proposal for Tailored Cognitive Behavioral Therapy. AB - Caregivers are relatives, friends, or partners who have a significant relationship with and provide assistance (i.e., physical, emotional) to a patient with often life-threatening, serious illnesses. Between 40 and 76 percent of caregivers for people with cancer experience sleep disturbance. This is thought to be due, in part, to the unique responsibilities, stressors, and compensatory behaviors endemic to caregiving that serve as precipitating and perpetuating factors of insomnia. Sleep disturbances are associated with significant alterations in one's mental and physical health. Once chronic, insomnia does not remit naturally. Cognitive-behavioral therapy for insomnia (CBT-I) is well-suited to address the multifaceted contributing factors unique to caregivers' sleep disturbance, yet only one intervention has tested a CBT-I informed intervention among cancer caregivers. Toward the goal of developing effective, tailored treatments for insomnia in caregivers, we address the distinct presentation of insomnia among cancer caregivers and describe key modifications to standard CBT-I that address these specific needs and enhance sensitivity and feasibility, modeled in a demonstrative case vignette. Future research must seek to provide a wide range of effective treatment options for this population, including internet based, dyadic, and alternative integrative medicine treatments. Applicability of key modifications for caregivers of patients with other chronic illnesses is discussed. Establishing empirically-supported interventions for insomnia among cancer caregivers has the potential to enhance their quality of life and care provided, lead to improved bereavement outcomes, and attenuate the notable mental and physical health disparities present in this vulnerable population. PMID- 30245563 TI - Carbapenem-resistant Klebsiella pneumoniae in a Febrile Neutropenia Patient With Acute Myelogenous Leukemia After Hematopoietic Stem Cell Transplantation. PMID- 30245564 TI - Arsenic Exposure and Cancer Risk Reduction with Local Ordinance Requiring Whole House Dual-Tank Water Treatment Systems. AB - Arsenic, a known human carcinogen, occurs naturally in groundwater in New Jersey and many other states and countries. A number of municipalities in the Piedmont, Highlands, and Valley and Ridge Physiographic Provinces of New Jersey have a high proportion of wells that exceed the New Jersey maximum contaminant level (MCL) of 5 ug/L. Hopewell Township, located in Mercer County and the Piedmont Province, has a progressive local ordinance which requires the installation of dual-tank, point-of-entry treatment systems on affected wells.Thisprovided a unique study opportunity. Of the 55 homes with dual-tank POE treatment systems recruited into this study, 51 homes (93%) had arsenic levels under the MCL at the kitchen sink, regardless of years in service and/or maintenance schedule adherence. Based on the study participants' water consumption and arsenic concentrations, we estimate that Hopewell's arsenic water treatment ordinance, requiring POE dual-tank arsenic treatment, reduced the incidence of excess lifetime (70-year) bladder and lung cancers from 121 (1.7 cancer cases/year) to 16 (0.2 cancer cases/year) preventing 105 lifetime cancer cases (1.5 cases/year). Because the high risk of cancer from arsenic can be mitigated with effective arsenic water treatment systems, this ordinance should be considered a model for other municipalities. PMID- 30245565 TI - Measuring ephemeral gully erosion rates and topographical thresholds in an urban watershed using unmanned aerial systems and structure from motion photogrammetric techniques. AB - Both rural and urban development can lead to accelerated gully erosion. Quantifying gully erosion is challenging in environments where gullies are rapidly repaired, and in urban areas where microtopographic complexity complicates the delineation of contributing areas. This study used unmanned aerial vehicles (UAVs) and Structure-from-Motion (SfM) photogrammetric techniques to quantify gully erosion in the Los Laureles Canyon watershed, a rapidly urbanizing watershed in Tijuana, Mexico. Following a storm event, the gully network extent was mapped using an orthomosaic (0.038 m pixel size); the local slope and watershed area contributing to each gully head were mapped with a Digital Surface Model (0.3 m pixel size). Gullies formed almost exclusively on unpaved roads which had erodible soils and concentrated flow. Management practices (e.g. road maintenance that fill gullies after large storms) contributed to total sediment production at the watershed scale. Sediment production from gully erosion was higher and threshold values of slope and drainage area for gully incision were lower than ephemeral gullies reported for agricultural settings. This indicates high vulnerability of unpaved roads to gully erosion which is consistent with high soil erodibility and low critical shear stress measured in the laboratory with a mini jet-erosion-test device. Future studies that evaluate effects of different soil types on gully erosion rates for unpaved roads, as well as those that model effects of management practices such as road paving and their impact on runoff, soil erosion, and sediment loads are needed to advance sediment management and planning in urban watersheds. PMID- 30245566 TI - PHYSICAL AND CHEMICAL CONNECTIVITY OF STREAMS AND RIPARIAN WETLANDS TO DOWNSTREAM WATERS: A SYNTHESIS. AB - Streams, riparian areas, floodplains, alluvial aquifers and downstream waters (e.g., large rivers, lakes, oceans) are interconnected by longitudinal, lateral, and vertical fluxes of water, other materials and energy. Collectively, these interconnected waters are called fluvial hydrosystems. Physical and chemical connectivity within fluvial hydrosystems is created by the transport of nonliving materials (e.g., water, sediment, nutrients, contaminants) which either do or do not chemically change (chemical and physical connections, respectively). A substantial body of evidence unequivocally demonstrates physical and chemical connectivity between streams and riparian wetlands and downstream waters. Streams and riparian wetlands are structurally connected to downstream waters through the network of continuous channels and floodplain form that make these systems physically contiguous, and the very existence of these structures provides strong geomorphologic evidence for connectivity. Functional connections between streams and riparian wetlands and their downstream waters vary geographically and over time, based on proximity, relative size, environmental setting, material disparity, and intervening units. Because of the complexity and dynamic nature of connections among fluvial hydrosystem units, a complete accounting of the physical and chemical connections and their consequences to downstream waters should aggregate over multiple years to decades. PMID- 30245568 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/1176935118786260.]. PMID- 30245567 TI - S-plot2: Rapid Visual and Statistical Analysis of Genomic Sequences. AB - With the daily release of data from whole genome sequencing projects, tools to facilitate comparative studies are hard-pressed to keep pace. Graphical software solutions can readily recognize synteny by measuring similarities between sequences. Nevertheless, regions of dissimilarity can prove to be equally informative; these regions may harbor genes acquired via lateral gene transfer (LGT), signify gene loss or gain, or include coding regions under strong selection. Previously, we developed the software S-plot. This tool employed an alignment-free approach for comparing bacterial genomes and generated a heatmap representing the genomes' similarities and dissimilarities in nucleotide usage. In prior studies, this tool proved valuable in identifying genome rearrangements as well as exogenous sequences acquired via LGT in several bacterial species. Herein, we present the next generation of this tool, S-plot2. Similar to its predecessor, S-plot2 creates an interactive, 2-dimensional heatmap capturing the similarities and dissimilarities in nucleotide usage between genomic sequences (partial or complete). This new version, however, includes additional metrics for analysis, new reporting options, and integrated BLAST query functionality for the user to interrogate regions of interest. Furthermore, S-plot2 can evaluate larger sequences, including whole eukaryotic chromosomes. To illustrate some of the applications of the tool, 2 case studies are presented. The first examines strain specific variation across the Pseudomonas aeruginosa genome and strain-specific LGT events. In the second case study, corresponding human, chimpanzee, and rhesus macaque autosomes were studied and lineage specific contributions to divergence were estimated. S-plot2 provides a means to both visually and quantitatively compare nucleotide sequences, from microbial genomes to eukaryotic chromosomes. The case studies presented illustrate just 2 potential applications of the tool, highlighting its capability to identify and investigate the variation in molecular divergence rates across sequences. S-plot2 is freely available through https://bitbucket.org/lkalesinskas/splot and is supported on the Linux and MS Windows operating systems. PMID- 30245569 TI - Opioids and the Internet: Convergence of Technology and Policy to Address the Illicit Online Sales of Opioids. AB - The United States is in the midst of an opioid public health emergency, one that is also influenced by a convergence of Internet-based technology, health policy, and the need for stakeholder collaboration and action around the need to combat the illicit online sales of opioids by illegal online pharmacies and digital drug dealers. This risk is not new, however, with calls to actively reduce online opioid availability as online pharmacies use a growing array of digital channels, including search engines, social media platforms, and the dark Web. In response, the US Food and Drug Administration convened a special June 2018 summit bringing together technology companies, government agencies, researchers, and advocacy groups with the goal of collaboratively developing and implementing solutions to tackle the problem. Yet after this meeting, stakeholders remain fragmented in approaches despite the availability of technology that can detect, classify, and report illicit sellers who are in direct violation of Federal law. Despite ongoing challenges, advances in data science and the resources and expertise technology companies can contribute will be a key factor in ensuring that the Internet helps end and not fuel the public health emergency of opioid abuse. PMID- 30245570 TI - Functional Outcome Measures of Recombinant Tissue Plasminogen Activator-Treated Stroke Patients in the Telestroke Technology. AB - The efficiency of telestroke programs in improving the rates of recombinant tissue plasminogen activator (rtPA) in stroke patients has been reported. Previous studies have reported favorable treatment outcomes with the use of telestroke programs to improve the use of rtPA, but functional outcomes are not fully understood. This study investigated the effect of telestroke technology in the administration of rtPA and related functional outcomes associated with baseline clinical variables. Retrospective data of a telestroke registry were analyzed. Univariate analysis was used to compare demographic and clinical variables in the rtPA group and the no rtPA group and between the improved functional ambulation group and the no improvement group. A stepwise binary logistic regression identified factors associated with improved functional outcome in the total telestroke population and in the subset of the telestroke population who received rtPA. In adjusted analysis and elimination of any multicollinearity for patients who received rtPA in the telestroke setting, obesity (odds ratio [OR] = 2.138, 95% confidence interval [CI], 1.164-3.928, P < .05), higher systolic blood pressure at the time of presentation (OR = 1.015, 95% CI, 1.003-1.027, P < .05), and baseline high-density lipoprotein at the time of admission (OR = 1.032, 95% CI, 1.005-1.059, P < .05) were associated with improved functional outcomes. Increasing age (OR = 0.940, 95% CI, 0.916-0.965, P < .0001) and higher calculated National Institutes of Health Stroke Scale (OR = 0.903, 95% CI, 0.869-0.937) were associated with a poorer outcome in rtPA-treated patients. Telestroke technology improves functional outcomes at spoke stations where neurological expertise is unavailable. Further studies are necessary to determine how telestroke technology can be optimized, especially to improve contraindications and increase eligibility for thrombolysis therapy. PMID- 30245571 TI - Behavioral Mechanisms That Depend on Dopamine and Serotonin in Caenorhabditis elegans Interact With the Antipsychotics Risperidone and Aripiprazole. AB - The neurotransmitters dopamine and serotonin participate in specific behavioral neuromuscular mechanisms in the nematode Caenorhabditis elegans. Dopamine is involved in the gentle touch response and serotonin in the pharyngeal pumping rate. In its genome, the worm presents genes encoding dopamine and serotonin receptors orthologous to those of human genes. Risperidone and aripiprazole are a class of drugs known as atypical antipsychotics commonly used to treat schizophrenia, bipolar disorder, and irritability associated with autism. Risperidone is an antagonist of the dopamine D2 and serotonin 5-HT2A receptors. Aripiprazole functions as a partial agonist of the dopamine D2 receptor and as a partial agonist and antagonist of 5-HT1A and 5-HT2A serotonin receptors, respectively. Our results show that risperidone and aripiprazole alter the touch response and pharyngeal pumping in wild-type worm animals. Furthermore, in the presence of the drugs, both behaviors change to varying degrees in dopamine (dop 1, dop-2, and dop-3), serotonin (ser-1), and tyramine (ser-2) receptor-deficient mutants. This variation in response reveals specific targets for these antipsychotics in the nematode. Interestingly, their effect on behavior persisted to some extent in successive generations, indicating that they might induce epigenetic changes throughout development. Sodium butyrate, a histone deacetylase inhibitor, eliminated the consecutive generation effect of both drugs. In addition, these transgenerational effects were also abolished after the dauer stage. These observations suggest that risperidone and aripiprazole, in addition to interacting with specific receptors impairing the function of the nervous system of the nematode, may lead to the deposition of long-lasting epigenetic marks. PMID- 30245573 TI - A Reduced Form Model for Ozone Based on Two Decades of CMAQ Simulations for the Continental United States. AB - A Reduced Form Model (RFM) is a mathematical relationship between the inputs and outputs of an air quality model, permitting estimation of additional modeling without costly new regional-scale simulations. A 21-year Community Multiscale Air Quality (CMAQ) simulation for the continental United States provided the basis for the RFM developed in this study. Predictors included the principal component scores (PCS) of emissions and meteorological variables, while the predictand was the monthly mean of daily maximum 8-hour CMAQ ozone for the ozone season at each model grid. The PCS form an orthogonal basis for RFM inputs. A few PCS incorporate most of the variability of emissions and meteorology, thereby reducing the dimensionality of the source-receptor problem. Stochastic kriging was used to estimate the model. The RFM was used to separate the effects of emissions and meteorology on ozone concentrations. by running the RFM with emissions constant (ozone dependent on meteorology), or constant meteorology (ozone dependent on emissions). Years with ozone-conducive meteorology were identified, and meteorological variables best explaining meteorology-dependent ozone were identified. Meteorology accounted for 19% to 55% of ozone variability in the eastern US, and 39% to 92% in the western US. Temporal trends estimated for original CMAQ ozone data and emission-dependent ozone were mostly negative, but the confidence intervals for emission-dependent ozone are much narrower. Emission-driven changes in monthly mean ozone levels for the period 2000-2010 ranged from 6.4 to 10.9 ppb for the eastern US and from 1.4 to 2.5 ppb for the western US. PMID- 30245572 TI - Obesity and Weaning from Mechanical Ventilation-An Exploratory Study. AB - Introduction: Obesity is associated with increased risk of hypercapnic respiratory failure, prolonged duration on mechanical ventilation, and extended weaning periods. Objective: Pilot study to determine whether morbidly obese adult tracheotomized subjects (body mass index [BMI] ? 40) can be more efficiently weaned from the ventilator by optimizing their positive end-expiratory pressure (PEEP) using either an esophageal balloon or the best achieved static effective compliance. Methods: We randomly assigned 25 morbidly obese adult tracheotomized subjects (median [interquartile range] BMI 53.4 [26.4]; range 40.4-113.8) to 1 of 2 methods of setting PEEP; using either titration guided by esophageal balloon to overcome negative transpulmonary pressure (Ptp) (goal Ptp 0-5 cmH2O) (ESO group) or titration to maximize static effective lung compliance (Cstat group). Our outcomes of interest were number of subjects weaned by day 30 and time to wean. Results: At day 30, there was no significant difference in percentage of subjects weaned. 8/13 subjects (62%) in the ESO Group were weaned vs. 9/12(75%) in the Cstat Group (P = 0.67). Among the 17 subjects who weaned, median time to ventilator liberation was significantly shorter in the ESO group: 3.5 days vs Cstat group 14 days (P = .01). Optimal PEEP in the ESO and Cstat groups was similar (ESO mean +/- SD = 26.5 +/- 5.7 cmH2O and Cstat 24.2 +/- 7 cmH2O (P = .38). Conclusions: Optimization of PEEP using esophageal balloon to achieve positive transpulmonary pressure did not change the proportion of patients weaned. Among patients who weaned, use of the esophageal balloon resulted in faster liberation from mechanical ventilation. There were no adverse consequences of the high PEEP (mean 25.4; range 13-37 cmH2O) used in our study. The study was approved by the Institutional Review Board at our institution (UMCIRB#10-0343) and registered with clinicaltrials.gov (NCT02323009). PMID- 30245574 TI - The effects of minimum wages on the health of working teenagers. AB - This article examines the effect of minimum wage increases on the self-reported health of teenage workers. We use a difference-in-differences estimation strategy and data from the Current Population Survey, and disaggregate the sample by race/ethnicity and gender to uncover the differential effects of changes in the minimum wage on health. We find that white women are more likely to report better health with a minimum wage increase while Hispanic men report worse health. PMID- 30245575 TI - Enhancements to AERMOD's Building Downwash Algorithms based on Wind-Tunnel and Embedded-LES Modeling. AB - Knowing the fate of effluent from an industrial stack is important for assessing its impact on human health. AERMOD is one of several Gaussian plume models containing algorithms to evaluate the effect of buildings on the movement of the effluent from a stack. The goal of this study is to improve AERMOD's ability to accurately model important and complex building downwash scenarios by incorporating knowledge gained from a recently completed series of wind tunnel studies and complementary large eddy simulations of flow and dispersion around simple structures for a variety of building dimensions, stack locations, stack heights, and wind angles. This study presents three modifications to the building downwash algorithm in AERMOD that improve the physical basis and internal consistency of the model, and one modification to AERMOD's building pre-processor to better represent elongated buildings in oblique winds. These modifications are demonstrated to improve the ability of AERMOD to model observed ground-level concentrations in the vicinity of a building for the variety of conditions examined in the wind tunnel and numerical studies. PMID- 30245576 TI - The social construction of the value of wildlife: A green cultural criminological perspective. AB - The trade in wildlife is not a new phenomenon. The earliest civilizations were linked to the trade in live animals and parts thereof, from the Egyptian pharaohs to aristocrats in the modern era. This article focuses on the history of the wildlife trade in order to understand the social construction of the value of wildlife. In dynamic social and cultural contexts, the meaning of wildlife changes. Historically, exotic animals and the products thereof were associated with social elites, but today, wildlife attracts people from all walks of life and a wide variety of live animals and products thereof are traded for functional, symbolic and social purposes. Increasing ecocentric and biocentric values in contemporary western society, however, may influence constructed demand patterns for wildlife in the near future. By integrating cultural criminological concepts with the social construction of green crimes, this article aims to understand constructed wildlife consumerism through the ages. PMID- 30245577 TI - Migrant Women's Economic Success in Russia: Objective Reality and Subjective Assessment. AB - This study contributes to the growing body of literature on the outcomes of labor migration by focusing on the effects of migrant legal status on the economic and perceptual measures of migration success. To study the effects of legal status, we use a sample of Central Asian migrant women who work in Russia and of their native counterparts who occupy the same positions on the labor market. Similar to the studies in the developed settings, we find that a temporary legal status is associated with an earnings penalty and that permanent legal status corrects this earning disparity. We also find that both temporary and permanent migrant status is positively associated with perceptions of pay inequality but that, irrespective of these perceptions, both types of migrants are more likely to be satisfied with their jobs than natives. We interpret these findings within the legal and social context of migrant economic incorporation in Russia and relate them to the findings from other migrant-receiving settings. PMID- 30245578 TI - Use of Selected Scavengers for the Determination of NF-TiO2 Reactive Oxygen Species during the Degradation of Microcystin-LR under Visible Light Irradiation. AB - Although UV-induced TiO2 photocatalysis involves the generation of several reactive oxygen species (ROS), the formation of hydroxyl radicals are generally associated with the degradation of persistent organic contaminants in water. In this study, a variety of radical scavengers were employed to discriminate the roles of different ROS during visible light activated (VLA) photocatalysis using nitrogen and fluorine doped TiO2 (NF-TiO2) in the degradation of the hepatotoxin, microcystin-LR (MC-LR) in water. The addition of hydroxyl radical scavengers, methanol and tert-butyl alcohol to the reaction mixture resulted in negligible inhibition of VLA NF-TiO2 photocatalytic degradation of MCLR at pH 3.0 and only partial inhibition at pH 5.7. While hydroxyl radicals generally play the primary role in UV TiO2 photocatalysis, the minimal influence of MeOH and t-BuOH on the degradation process under these experimental conditions indicates hydroxyl radicals (*OH) do not play the primary role in VLA NF-TiO2 photocatalysis. However, strong inhibition was observed in VLA NF-TiO2 photocatalytic degradation of MC-LR in the presence of superoxide dismutase, benzoquinone and catalase at pH 3.0 and 5.7 indicating O2*- and H2O2 play critical roles in the degradation process. Similar degradation rates were observed in the presence of singlet oxygen scavenger, deuterium oxide, which enhances singlet oxygen mediated processes further suggesting singlet oxygen does not play a key role in the degradation of MCLR in these system. Formic acid and cupric nitrate were added to probe the roles of the valence band holes and conduction band electrons, respectively. Under UV+vis light irradiation, almost complete inhibition of MC-LR removal is observed with NF-TiO2 in the presence of *OH scavengers at pH 5.7. These results demonstrate that solution pH plays a major role in the formation and reactivities of ROS during VLA NF-TiO2 photocatalysis. The adsorption strength of the scavengers and MCLR onto NF-TiO2 as well as the speciation of the ROS as a function of pH need to be carefully considered since they also play a key role in the efficiency of the process. These results indicate the reduction of molecular oxygen by photo-generated electrons rather than hydroxyl radicals produced by oxidative reactions of photo-generated holes play a key role in the of VLA NF-TiO2 photocatalytic degradation of MC-LR. PMID- 30245579 TI - Mechanisms and effectivity of sulfate reducing bioreactors using a chitinous substrate in treating mining influenced water. AB - Mining-influenced water (MIW) is one of the main environmental challenges associated with the mining industry. Passive MIW remediation can be achieved through microbial activity in sulfate-reducing bioreactors (SRBRs), but their actual removal rates depend on different factors, one of which is the substrate composition. Chitinous materials have demonstrated high metal removal rates, particularly for the two recalcitrant MIW contaminants Zn and Mn, but their removal mechanisms need further study. We studied Cd, Fe, Zn, and Mn removal in bioactive and abiotic SRBRs to elucidate the metal removal mechanisms and the differences in metal and sulfate removal rates using a chitinous material as substrate. We found that sulfate-reducing bacteria are effective in increasing metal and sulfate removal rates and the duration of operation in SRBRs, and that the main mechanism involved was metal precipitation as sulfides. The solid residues provided evidence of the presence of sulfides in the bioactive column, more specifically ZnS, according to XPS analysis. The feasibility of passive treatments with a chitinous substrate could be an important option for MIW remediation. PMID- 30245580 TI - Resurveying historical vegetation data - opportunities and challenges. AB - Background: Resurveying historical vegetation plots has become more and more popular in recent years as it provides a unique opportunity to estimate vegetation and environmental changes over the past decades. Most historical plots, however, are not permanently marked and uncertainty in plot location, in addition to observer bias and seasonal bias, may add significant error to temporal change. These errors may have major implications for the reliability of studies on long-term environmental change and deserve closer attention of vegetation ecologists. Material & Methods: Vegetation data obtained from the resurveying of non-permanently marked plots are assessed for their potential to study environmental-change effects on plant communities and the challenges the use of such data have to meet. We describe the properties of vegetation resurveys distinguishing basic types of plots according to relocation error, and we highlight the potential of such data types for studying vegetation dynamics and their drivers. Finally, we summarise the challenges and limitations of resurveying non-permanently marked vegetation plots for different purposes in environmental change research. Results and Conclusions: Resampling error is caused by three main independent sources of error: error caused by plot relocation, observer bias, and seasonality bias. For relocation error, vegetation plots can be divided into permanent and non-permanent plots, while the latter are further divided into quasi-permanent (with approximate relocation) and non traceable (with random relocation within a sampled area) plots. To reduce the inherent sources of error in resurvey data, the following precautions should be followed: (i) resurvey historical vegetation plots whose approximate plot location within a study area is known; (ii) consider all information available from historical studies in order to keep plot relocation errors low; (iii) resurvey at times of the year when vegetation development is comparable to the historical survey to control for seasonal variability in vegetation; (iv) keep a high level of experience of the observers to keep observer bias low; and (v) edit and standardise datasets before analyses. PMID- 30245581 TI - Human virus and microbial indicator occurrence in public-supply groundwater systems: meta-analysis of 12 international studies. AB - Groundwater quality is often evaluated using microbial indicators. This study examines data from 12 international groundwater studies (conducted 1992-2013) of 718 public drinking-water systems located in a range of hydrogeological settings. Focus was on testing the value of indicator organisms for identifying virus contaminated wells. One or more indicators and viruses were present in 37 and 15% of 2,273 samples and 44 and 27% of 746 wells, respectively. Escherichia coli (E. coli) and somatic coliphage are 7-9 times more likely to be associated with culturable virus-positive samples when the indicator is present versus when it is absent, while F-specific and somatic coliphages are 8-9 times more likely to be associated with culturable virus-positive wells. However, single indicators are only marginally associated with viruses detected by molecular methods, and all microbial indicators have low sensitivity and positive predictive values for virus occurrence, whether by culturable or molecular assays, i.e., indicators are often absent when viruses are present and the indicators have a high false positive rate. Wells were divided into three susceptibility subsets based on presence of (1) total coliform bacteria or (2) multiple indicators, or (3) location of wells in karst, fractured bedrock, or gravel/cobble settings. Better associations of some indicators with viruses were observed for (1) and (3). Findings indicate the best indicators are E. coli or somatic coliphage, although both indicators may underestimate virus occurrence. Repeat sampling for indicators improves evaluation of the potential for viral contamination in a well. PMID- 30245582 TI - Alternating Gaussian Process Modulated Renewal Processes for Modeling Threshold Exceedances and Durations. AB - It is often of interest to model the incidence and duration of threshold exceedance events for an environmental variable over a set of monitoring locations. Such data arrive over continuous time and can be considered as observations of a two-state process yielding, sequentially, a length of time in the below threshold state followed by a length of time in the above threshold state, then returning to the below threshold state, etc. We have a two-state continuous time Markov process, often referred to as an alternating renewal process. The process is observed over a truncated time window and, within this window, time in each state is modeled using a distinct cumulative intensity specification. Initially, we model each intensity over the window using a parametric regression specification. We extend the regression specification adding temporal random effects to enrich the model, using a realization of a log Gaussian process over time. With only one type of renewal, this specification is referred to as a Gaussian process modulated renewal process. Here, we introduce Gaussian process modulation to the intensity for each state. Model fitting is done within a Bayesian framework. We clarify that fitting with a customary log Gaussian process specification over a lengthy time window is computationally infeasible. The nearest neighbor Gaussian process (NNGP), which supplies sparse covariance structure, is adopted to enable tractable computation. We also propose methods for both generating data under our models and for conducting model comparison. The model is applied to hourly ozone data for four monitoring sites in different locations across the United States for the ozone season of 2014. For each site, we obtain estimated profiles of up-crossing and down-crossing intensity functions through time. In addition, we obtain inference regarding the number of exceedances, the distribution of the duration of exceedance events, and the proportion of time in the above and below threshold state for any time interval. PMID- 30245583 TI - Social structures, power and resistance in monist sociology: (New) materialist insights. AB - Though mainstream sociological theory has been founded within dualisms such as structure/agency, nature/culture, and mind/matter, a thread within sociology dating back to Spencer and Tarde favoured a monist ontology that cut across such dualistic categories. This thread has been reinvigorated by recent developments in social theory, including the new materialisms, posthumanism and affect theories. Here we assess what a monist or 'flat' ontology means for sociological understanding of key concepts such as structures and systems, power and resistance. We examine two monistic sociologies: Bruno Latour's 'sociology of associations' and DeLanda's ontology of assemblages. Understandings of social processes in terms of structures, systems or mechanisms are replaced with a focus upon the micropolitics of events and interactions. Power is a flux of forces or 'affects' fully immanent within events, while resistance is similarly an affective flow in events producing micropolitical effects contrary to power or control. PMID- 30245584 TI - Social media platforms as a photo-elicitation tool in research on alcohol intoxication and gender. AB - This methodological paper aims to describe the use of comparative social media platforms within a Photo Elicitation (PE) activity as part of a multi-method interview-based study on the gendered meanings of alcohol intoxication among young adults (age 18-25, n = 200). Early interviews revealed social media as a particularly engaging topic for participants, and discussions of social media exposed relevant issues that often were not discussed in other sections of the interview guide. By embedding photos of young people drinking within three social media platforms with photo-sharing capabilities - Instagram, Snapchat and Facebook - we elicited narrative data revealing important aspects of the meanings of intoxication and providing information on how participants manage and judge drinking behaviours shared through online Social Networking Systems (SNS). Given that social media use and photo-sharing are so common, familiar, and endemic among young people, to ignore this feature of contemporary social interaction would have limited our exploration of meanings of intoxication. We suggest that embedding existing methods, like photo-elicitation, to social media contexts that are salient for youth may be a valuable strategy for providing a more comprehensive approach for investigating contemporary social issues. PMID- 30245585 TI - Similes We Cure By: The Poetics of Late Medieval Medical Texts. PMID- 30245586 TI - Dexmedetomidine Inhibits Voltage-Gated Sodium Channels via alpha2-Adrenoceptors in Trigeminal Ganglion Neurons. AB - Dexmedetomidine, an alpha2-adrenoceptor agonist, is widely used as a sedative and analgesic agent in a number of clinical applications. However, little is known about the mechanism by which it exerts its analgesic effects on the trigeminal system. Two types of voltage-gated sodium channels, Nav1.7 and Nav1.8, as well as alpha2-adrenoceptors are expressed in primary sensory neurons of the trigeminal ganglion (TG). Using whole-cell patch-clamp recordings, we investigated the effects of dexmedetomidine on voltage-gated sodium channel currents (INa) via alpha2-adrenoceptors in dissociated, small-sized TG neurons. Dexmedetomidine caused a concentration-dependent inhibition of INa in small-sized TG neurons. INa inhibition by dexmedetomidine was blocked by yohimbine, a competitive alpha2 adrenoceptor antagonist. Dexmedetomidine-induced inhibition of INa was mediated by G protein-coupled receptors (GPCRs) as this effect was blocked by intracellular perfusion with the G protein inhibitor GDPbeta-S. Our results suggest that the INa inhibition in small-sized TG neurons, mediated by the activation of Gi/o protein-coupled alpha2-adrenoceptors, might contribute to the analgesic effects of dexmedetomidine in the trigeminal system. Therefore, these new findings highlight a potential novel target for analgesic drugs in the orofacial region. PMID- 30245587 TI - Intra-Articular Cytokine Levels in Adolescent Patients after Anterior Cruciate Ligament Tear. AB - The treatment of anterior cruciate ligament (ACL) injuries in children and adolescents is challenging. Preclinical and clinical studies investigated ACL repairing techniques in skeletally immature subjects. However, intra-articular bioenvironment following ACL tear has not yet been defined in skeletally immature patients. The aim of this study was to measure cytokine concentrations in the synovial fluid in adolescent population. Synovial levels of IL-1beta, IL-1ra, IL 6, IL-8, IL-10, and TNF-alpha were measured in 17 adolescent patients (15 boys) with ACL tears who underwent ACL reconstruction including acute (5), subacute (7), and chronic (5) phases. Femoral growth plates were classified as "open" in three patients, "closing" in eight, and "closed" in six. Eleven patients presented an ACL tear associated with a meniscal tear. The mean Tegner and Lysholm scores (mean +/- SD) of all patients were 8 +/- 1 and 50.76 +/- 26, respectively. IL-8, TNF-alpha, and IL-1beta levels were significantly greater in patients with "open" physes. IL-1ra and IL-1beta levels were significantly higher in patients with ACL tear associated with a meniscal tear. Poor Lysholm scores were associated with elevated IL-6 and IL-10 levels. IL-10 levels positively correlated with IL-6 and IL-8 levels, whereas TNF-alpha concentration negatively correlated with IL-6 levels. Skeletally immature patients with meniscal tears and open growth plates have a characteristic cytokine profile with particularly elevated levels of proinflammatory cytokines including IL-8, TNF-alpha, and IL 1beta. This picture suggests that the ACL tear could promote an intra-articular catabolic response in adolescent patients greater than that generally reported for adult subjects. The study lacks the comparison with synovial samples from healthy skeletally immature knees due to ethical reasons. Overall, these data contribute to a better knowledge of adolescent intra-articular bioenvironment following ACL injuries. PMID- 30245588 TI - Overexpression of Tear Inflammatory Cytokines as Additional Finding in Keratoconus Patients and Their First Degree Family Members. AB - Keratoconus is a progressive corneal ectasia that may lead to severe visual impairment due to the irregular astigmatism caused by corneal thinning. In addition to its association with atopy, eye rubbing, or genetic component, late reports suggest the involvement of inflammation in the pathogenesis of the disease. Our aim was to determine the concentration of IL-4, IL-6, IL-10, RANTES, IFN gamma, and TNF alpha in the tear film of patients with keratoconus and their first degree family members. We analyzed forty-eight participants in an observational cross-sectional study. The diagnosis of keratoconus had to be confirmed in addition to a minimum of 47 D corneal refractive power by corneal topography readings provided by a Placido-based topography system and analysis of the pattern: irregular astigmatism with an asymmetric "bow-tie." As for the other groups, the most important diagnosis criteria were a normal topographic pattern with a regular astigmatism. 17 keratoconus patients, 16 relatives, and 15 controls were recruited after clinical assessment as part of the research. The cytokine's mean values were similar in the keratoconus group and the relatives' samples but significantly higher compared to the controls. Important differences were found in IL-4 levels between keratoconus patients and relatives and between relatives and controls (mean difference of 302.42, p < 0.0016 and 219.16, p < 0.033, Tukey's HSD procedure). In the keratoconus group, using the CORR procedure, we found statistically strong correlations of IL-6 lacrimal concentrations with the disease stage (r = 0.56, p < 0.01), keratometry (r = 0.55, p < 0.02), pachymetry (r = -0.64, p < 0.048), and corneal hysteresis (r = 0.53, p < 0.02). Cytokine overexpression may be relevant for the inflammatory etiology of keratoconus. In conclusion, in the case of some first degree family members, the elevated tear biomarkers may represent a supplementary risk factor. PMID- 30245589 TI - Satellite monitoring of cyanobacterial harmful algal bloom frequency in recreational waters and drinking source waters. AB - Cyanobacterial harmful algal blooms (cyanoHAB) cause extensive problems in lakes worldwide, including human and ecological health risks, anoxia and fish kills, and taste and odor problems. CyanoHABs are a particular concern in both recreational waters and drinking source waters because of their dense biomass and the risk of exposure to toxins. Successful cyanoHAB assessment using satellites may provide an indicator for human and ecological health protection, In this study, methods were developed to assess the utility of satellite technology for detecting cyanoHAB frequency of occurrence at locations of potential management interest. The European Space Agency's MEdium Resolution Imaging Spectrometer (MERIS) was evaluated to prepare for the equivalent series of Sentine1-3 Ocean and Land Colour Imagers (OLCI) launched in 2016 as part of the Copernicus program. Based on the 2012 National Lakes Assessment site evaluation guidelines and National Hydrography Dataset, the continental United States contains 275,897 lakes and reservoirs >1 hectare in area. Results from this study show that 5.6 % of waterbodies were resolvable by satellites with 300 m single-pixel resolution and 0.7 % of waterbodies were resolvable when a three by three pixel (3*3-pixel) array was applied based on minimum Euclidian distance from shore. Satellite data were spatially joined to U.S. public water surface intake (PWSI) locations, where single-pixel resolution resolved 57% of the PWSI locations and a 3*3-pixel array resolved 33% of the PWSI locations. Recreational and drinking water sources in Florida and Ohio were ranked from 2008 through 2011 by cyanoHAB frequency above the World Health Organization's (WHO) high threshold for risk of 100,000 cells mL 1. The ranking identified waterbodies with values above the WHO high threshold, where Lake Apopka, FL (99.1 %) and Grand Lake St. Marys, OH (83 %) had the highest observed bloom frequencies per region. The method presented here may indicate locations with high exposure to cyanoHABs and therefore can be used to assist in prioritizing management resources and actions for recreational and drinking water sources. PMID- 30245590 TI - Enhancement of Organic Matter Removal in an Integrated Biofilm-Membrane Bioreactor Treating High-Salinity Wastewater. AB - High salinity can strongly inhibit microbial activity and decrease the sedimentation ability of activated sludge. The combination of biofilm and membrane bioreactor is a practical approach towards effective removal of pollutants and low fouling rate. An integrated biofilm-membrane bioreactor (BMBR) treating mustard tuber wastewater was investigated. An average COD removal efficiency of 94.81% and ammonium removal efficiency of 96.84% were achieved at an organic load of 0.5 kg COD/(m3.d). However, the reactor showed a relatively low efficiency in total nitrogen and soluble phosphorus removal due to the lack of anaerobic environment. The increase of influent organic load resulted in a performance degradation because a balance between the degradation ability and pollution has been reached. Images of scanning electron microscopy revealed that halophilic bacteria were the dominant microbe in the system that leads to a loose sludge structure and declined settling properties. It was found that membrane fouling was the consequence of the interaction of microbial activities and NaCl crystallization. PMID- 30245591 TI - DNA methylation biomarkers for hepatocellular carcinoma. AB - Background: Aberrant methylation of DNA is a key driver of hepatocellular carcinoma (HCC). In this study, we sought to integrate four cohorts profile datasets to identify such abnormally methylated genes and pathways associated with HCC. Methods: To this end, we downloaded microarray datasets examining gene expression (GSE84402, GSE46408) and gene methylation (GSE73003, GSE57956) from the GEO database. Abnormally methylated differentially expressed genes (DEGs) were sorted and pathways were analyzed. The String database was then used to perform enrichment and functional analysis of identified pathways and genes. Cytoscape software was used to create a protein-protein interaction network, and MCODE was used for module analysis. Finally, overall survival analysis of hub genes was performed by the OncoLnc online tool. Results: In total, we identified 19 hypomethylated highly expressed genes and 14 hypermethylated lowly expressed genes at the screening step, and finally found six mostly changed hub genes including MAD2L1, CDC20, CCNB1, CCND1, AR and ESR1. Pathway analysis showed that aberrantly methylated-DEGs mainly associated with the cell cycle process, p53 signaling, and MAPK signaling in HCC. After validation in TCGA database, the methylation and expression status of hub genes was significantly altered and same with our results. Patients with high expression of MAD2L1, CDC20 and CCNB1 and low expression of CCND1, AR, and ESR1 was associated with shorter overall survival. Conclusions: Taken together, we have identified novel aberrantly methylated genes and pathways linked to HCC, potentially offering novel insights into the molecular mechanisms governing HCC progression and serving as novel biomarkers for precision diagnosis and disease treatment. PMID- 30245592 TI - Re-experiencing 9/11-Related PTSD Symptoms Following Exposure to Hurricane Sandy. AB - Background: Understanding Pre-Existing Posttraumatic Stress Disorder (PTSD) symptoms and risk of PTSD following Hurricane Sandy (Sandy) has important implications for PTSD screening of persons exposed to multiple traumas. This study assessed the association between Sandy exposure and a subset of PTSD symptoms related to re-experiencing trauma from the events of the September 11, 2001 (9/11). Methods: We studied 4,220 respondents from a random 8,870 person sample of adult World Trade Center Health Registry enrollees who completed a post Sandy survey between March 28 and November 7, 2013. The symptom cluster of re experiencing 9/11 was defined using 3 out of 5 questions in the intrusion domain of the PTSD Checklist. Multivariable logistic regression, adjusting for socio demographics, social support and any post-9/11 life threatening events prior to Sandy, was performed separately in those symptomatic and non-symptomatic of re experiencing 9/11 prior to Sandy. Results: A total of 688 enrollees (16.3%) reported re-experiencing 9/11 symptoms after Sandy (58.8% in those symptomatic prior to Sandy, and 8.7% in those non-symptomatic). A significant association between Sandy exposure and re-experiencing 9/11 was observed only among those non symptomatic prior to Sandy (adjusted odds ratio (AOR)=1.7, 95% confidence interval=1.2-2.3 for moderate Sandy exposure; AOR=2.8, 2.0-4.0 for high Sandy exposure). Conclusions: Individuals with a history of trauma should be considered for early screening and counseling for mental health after a subsequent traumatic event, regardless of PTSD status, especially in 9/11 exposed populations. PMID- 30245593 TI - A Range Condition for Polyconvex Variational Regularization. AB - In the context of convex variational regularization, it is a known result that, under suitable differentiability assumptions, source conditions in the form of variational inequalities imply range conditions, while the converse implication only holds under an additional restriction on the operator. In this article, we prove the analogous result for polyconvex regularization. More precisely, we show that the variational inequality derived by the authors in 2017 implies that the derivative of the regularization functional must lie in the range of the dual adjoint of the derivative of the operator. In addition, we show how to adapt the restriction on the operator in order to obtain the converse implication. PMID- 30245594 TI - Healthcare worker feedback on a prototype smartphone-based point-of-care test platform for use in episodic care. AB - With a growing list of new platforms, end-user acceptability is an evolving topic in point-of-care (POC) test development. While technical reports of new experimental POC tests are common, it is rare to find reports which evaluate the end-user acceptability of such innovations. This work illustrates an example of bridging that gap by evaluating the end-user acceptability of an experimental POC test platform with novel technical features. A prototype smartphone-based STI tests was evaluated by ED technicians, followed by a survey of acceptability factors. Our findings suggest that the end-user acceptability of some design features implemented in the prototype. PMID- 30245595 TI - Point-of-Care Diagnosis of Acute Myocardial Infarction in Central Vietnam: International Exchange, Needs Assessment, and Spatial Care Paths. AB - Objectives: Objectives were to (a) advance point-of-care (POC) education, international exchange, and culture; (b) report needs assessment survey results from Thua Thien Hue Province, Central Vietnam; (c) determine diagnostic capabilities in regional health care districts of the small-world network of Hue University Medical Center; and (d) recommend Spatial Care Paths that accelerate the care of acute myocardial infarction (AMI) patients. Methods: We organized progressively focused, intensive, and interactive lectures, workshops, and investigative teamwork over a 2-year period. We surveyed hospital staff in person to determine the status of diagnostic testing at 15 hospitals in 7 districts. Questions focused on cardiac rapid response, prediabetes/diabetes, infectious diseases, and other serious challenges, including epidemic preparedness. Results: Educational exchange revealed a nationwide shortage of POC coordinators. Throughout the province, ambulances transfer patients primarily between hospitals, rarely picking up from homes. No helicopter rescue was available. Ambulance travel times from distant sites to referral hospitals were excessive, longer in costal and mountainous areas. Most hospitals (92.3%) used electrocardiogram and creatine phosphokinase-MB isoenzyme to diagnose AMI. Cardiac troponin I/T testing was performed only at large referral hospitals. Conclusions: Central Vietnam must improve rapid diagnosis and treatment of AMI patients. Early upstream POC cardiac troponin testing on Spatial Care Paths will expedite transfers directly to hospitals capable of intervening, improving outcomes following coronary occlusion. Point-of-care coordinator certification and financial support will enhance standards of care cost-effectively. Training young physicians pivots on high-value evidence-based learning when POC cardiac troponin T/cardiac troponin I biomarkers are in place for rapid decision making, especially in emergency rooms. PMID- 30245596 TI - Timing of housing crises: Impacts on maternal depression. AB - Housing problems threaten maternal mental health, but the nature of the relationship between housing and depression across time is not fully understood. Drawing upon the literatures of household shocks and depressive illness, the present study leveraged longitudinal data from the Fragile Families and Child Well-Being Study to probe the relationship between a housingrelated crisis and depression among at-risk mothers (N = 2,503). Binary logistic regression tested whether a housing crisis predicted an episode of depression across up to one-, three-, and seven-year time lags. The sample was then balanced on key predictors of housing crises using greedy matching with propensity scores; regression models were replicated on the new matched samples. Results showed a housing crisis significantly elevated risk for depression within one year, but effects were attenuated across three and seven years; findings were consistent in the matched samples. Implications include the need to develop new conceptualizations of depression in the context of housing instability. Brief interventions may be most effective for addressing distress associated with housing crises and improving treatment access. Policies and programs addressing the lack of affordable housing in the United States may be effective means of reducing the burden of mental disorder on families with children. PMID- 30245597 TI - Role of Mitochondrial DNA in Aging Processes. PMID- 30245598 TI - Mitochondrial Genes in Degenerative Disease and Aging. PMID- 30245599 TI - The International Editorship of Freshwater Systems. AB - It is my pleasure to announce that two distinguished internationalscientists have joined the editorship of the FreshwaterSystems domain of TheScientificWorldJOURNAL - Professor BrijGopal of Jawaharlal Nehru University (India) and Dr. Manual Graca of the Universityof Coimbra (Portugal). Professor Gopal is the Secretary General of the NationalInstitute of Ecology, Editor of the InternationalJournal of Ecology & Environmental Science,and Chairman of the SIL (International Association of Theoretical and AppliedLimnology) Committee on Limnology in Developing Countries. His research interestsinclude the ecology, biogeochemistry and biodiversity of wetland ecosystems,the management of wetlands as an integral part of the watershed, and wetlandwater policy-related issues. Dr. Graca is a stream ecologist whose researchinterests include the two general areas of organic matter decomposition andbiological monitoring. His specific areas of research focus include quantificationof organic matter and other chemical changes in decomposing leaves, the ecologyof aquatic hyphomycetes, and the ecology of animals feeding on detritus. Hisresearch dealing with biological monitoring is carried out in close cooperationwith the paper and mining industries, facilitating the practical applicationof his work. PMID- 30245600 TI - Corrigendum to "Erbium-Based Perfusion Contrast Agent for Small-Animal Microvessel Imaging". AB - [This corrects the article DOI: 10.1155/2017/7368384.]. PMID- 30245601 TI - Sensory Overresponsivity, Loneliness, and Anxiety in Taiwanese Adults with Autism Spectrum Disorder. AB - Purpose: Sensory overresponsiveness is highly prevalent in individuals with autism spectrum disorders (ASD) and typically persist into adulthood. However, the role of sensory processing difficulties in influencing emotional well-being among adults with ASD remains unclear. Additionally, the associations between sensory overresponsiveness, anxiety, and loneliness are yet to be examined among adults with ASD. Therefore, to address these critical gaps in the literature, we aimed to investigate the relationships among sensory avoiding, anxiety, and loneliness in a sample of adults with ASD. Participants: Seventy adults (age, 20 39 years) completed three self-reported measures. All participants had a documented diagnosis of ASD and had normal IQ. Methods: Sensory processing, loneliness, and anxiety were assessed with the Adult Sensory Profile, short-form UCLA loneliness scale, and Beck Anxiety Inventory, respectively. Results: Autism spectrum traits and sensory avoiding were associated with anxiety and loneliness. Participants who experienced sensory avoiding more frequently reported higher anxiety and feelings of loneliness, with loneliness mediating the relationship between sensory avoiding and anxiety. More anxiety symptoms in participants with greater sensory avoiding were associated with their higher level of loneliness. Conclusion: This study demonstrates that the relationships existed between sensory processing difficulties, loneliness, and anxiety among adults with ASD. Interventions regarding sensory processing difficulties and emotional well-being are substantial need for adults with ASD, and our results highlight the importance of sensory overresponsiveness and anxiety in evaluating and improving the psychological well-being of adults with ASD. PMID- 30245603 TI - Biological Consequences of Exposure to Mechanical Vibration. AB - A special issue of the journal Dose-Response entitled "Biological Consequences of Exposure to Mechanical Vibration" is proposed. When there is the interaction of physical agents, such as mechanical vibration to a body, physiological stress can be generated leading to expected and unexpected consequences. The aim is to describe effects due to the stress generated by the energy delivered in biological systems by mechanical vibration produced by different sources through studies involving human beings and experimental models. The evaluation of effects in molecular, cellular, and systemic level will contribute to increase the medical and biological knowledge about the interaction of mechanical vibration, as well as the understanding of the stress and mechanisms of the biological responses of the mechanical vibrations. The main topics will be related to neurophysiological responses to mechanical vibration generated in different sources, clinical approaches of the mechanical vibration generated in oscillating/vibratory platform, undesirable effect of the mechanical vibration generated in oscillating/vibratory platform, mechanical vibration in occupational activities, biological effects of ultrasound and infrasound, and quantification and physical approaches of the mechanical vibration. PMID- 30245602 TI - A mixed methods study of the social support networks of female sex workers and their primary noncommercial male partners in Tijuana, Mexico. AB - Female sex workers (FSWs) are at risk for multiple health harms, including HIV. This article describes a mixed methods study of the social support networks of 19 FSWs and their primary male sex partners in Tijuana, Mexico. We collected quantitative and qualitative social network data, including quantitative network measures, qualitative narratives, and network visualizations. Methodologically, we illustrate how a convergent mixed methods approach to studying personal social support networks of female sex workers can yield a more holistic understanding of network composition and role. From a health-related perspective, we show how migration/deportation and stigma shape social networks and might be leveraged to support HIV prevention interventions. We believe others can benefit from a mixed methods approach to studying social networks. PMID- 30245604 TI - Amelioration of the Protein Expression of Cox2, NFkappaB, and STAT-3 by Some Antioxidants in the Liver of Sodium Fluoride-Intoxicated Rats. AB - The present study aimed to explore the efficiency of N-acetyl cysteine (NACC) or thymoquinone (TMQ) alone or in combination in the downregulation of inflammatory molecule expression and decreasing hepatic injury in response to sodium fluoride (SF). Sodium fluoride upregulated serum alanine and aspartate transferases activities, tumor necrosis factor alpha and hepatic malondialdehyde and nitric oxide levels, and the expression of cyclooxygenase 2, nuclear factor kappaB cell, and signal transducer and activator of transcription 3. In contrast, hepatic glutathione level, superoxide dismutase activity, and nuclear factor erythroid 2 related factor 2 expression were decreased. However, the concurrent treatment with antioxidants, alone or in combination, modulated the levels of these parameters. Histopathological examination revealed that SF treatment resulted in focal areas of massive hepatic degeneration and many degenerated hepatocytes, whereas the treatment with TMQ or NACC exhibited moderate improvement in cellular degeneration of the liver with many abnormal cells. Rats receiving a combination of TMQ and NACC showed marked improvement in cellular degeneration of liver with apparently normal hepatic architecture with very few degenerated hepatocytes. The results also revealed that the combination of TMQ and NACC is the most effective regimen in ameliorating SF toxicity, suggesting their efficacy against the toxicity of fluoride compounds. Their activities might be mediated via multiple molecular pathways. PMID- 30245605 TI - Defining a Structure and Methodology for the Practice of Lifestyle Medicine. AB - Lifestyle medicine (LM) is a relatively new branch of clinical practice (like travel medicine, sports medicine, etc), but to date with little accepted structure or methodology. The current review extends a previous attempt to define the determinants of chronic disease by expanding this to include (1) the knowledge base (the science) or epidemiology of chronic disease, (2) the skills (the art) or practice of LM, (3) the tools (the materials) that can add to LM diagnoses and prescription, and (4) the procedures (the actions) that help update conventional medicine to include practices required for a new era of lifestyle and environmentally related chronic disease. PMID- 30245606 TI - The Lifestyle History: A Neglected But Essential Component of the Medical History. AB - There is increased recognition that lifestyle factors, including nutrition, physical activity, emotional well-being and stress management, tobacco use, alcohol consumption, and sleep habits, are major determinants of health. There is a need to teach practicing physicians, medical trainees, and other health care providers how to perform a "lifestyle history." This article proposes 13 screening questions physicians should consider exploring with patients. It provides the rationale and scientific evidence supporting each question and includes key lifestyle counseling points for clinicians to consider. PMID- 30245607 TI - Advancing Lifestyle Medicine Education in Undergraduate Medical School Curricula Through the Lifestyle Medicine Education Collaborative (LMEd). AB - Physicians are uniquely positioned to stem the tide of the world's top lifestyle related diseases; however, most are not trained to provide effective patient care. The Lifestyle Medicine Education Collaborative (LMEd) has a plan that is a comprehensive and sustainable approach to policies, programs, and initiatives to increase graduating US medical students' knowledge and application of lifestyle medicine. LMEd's strategic plan is to (1) provide high-quality curricular material; (2) solicit support of medical school deans, critical administration, and faculty; (3) influence federal and state policy; (4) develop and conduct assessment; and (5) support medical students as lifestyle medicine champions. Accomplishments to date include (1) collaboration with Association of American Medical Colleges' MedEdPORTAL for the curation of a LM Collection; (2) creation of a network of >350 members, 80 medical schools including 33 hospitals/clinics; 1:1 mentoring sessions >70 medical school faculty/administration; and (4) establishment of a relationship with the National Board of Medical Examiner's Customized Assessment Services to create a subject test in lifestyle medicine. National awareness is being increased through webinars and hosting the first annual LMEd Summit in October 2016. LMEd strives to alter the health care landscape by enhancing physician competency in lifestyle-related disease and value-based care and affecting the health of populations. PMID- 30245608 TI - "Dealing with the Hospital has Become too Difficult for Us to Do Alone" - Developing an Integrated Care Program for Children with Medical Complexity (CMC). AB - Introduction: Children with medical complexity (CMC) require highly specialised care, often from multiple providers and over many years. This paper describes the first 18 months of development of the Kids Guided Personalised Services (GPS) Integrated Care Program (the Program). This Program aims to improve health care experience; communication and to streamline provision of care. Discussion: Key enablers across the Program were put in place and 5 individual project streams were used to implement change. An extensive formative evaluation process was undertaken to truly understand all perspectives in developing the Program. Conclusion/Key Lessons: This Program supports families who are caring for CMC by developing shared care models that bring together local health services with the tertiary hospitals. The methodology used has resulted in comprehensive system change and transformation; reduced presentations to the Emergency Department (ED), avoidable admissions and travel time. A challenge remains in meaningfully engaging primary health care providers. PMID- 30245609 TI - Study of suspension grafting process of polypropylene. AB - Grafting efficiency is an important indicator of polypropylene grafting reaction. A series of studies have been accomplished, including the conditions of free radical presence on PP backbone during peroxide initiation, the effect of preheat treatment and reaction time on PP suspension grafting results, and the effect of peroxide residue on properties of modified PP. An optimized grafting process was proposed by mixing and preheating polypropylene (PP) and the initiator benzoyl peroxide (BPO) before adding the grafting monomer glycidyl methacrylate (GMA),resulting in an increase in grafting efficiency from 50.0% to 78.2%. With initiator residue removed by alternating temperature treatment, the suspension grafting reaction time could be substantially reduced. PMID- 30245610 TI - Quality of medicines in resource-limited settings: need for ethical guidance. AB - The quality of medicines is generally adequately assured by manufacturers and regulatory authorities for well-resourced settings, while the implementation of existing quality standards is challenged in many low- and middle-income countries. This situation of multiple pharmaceutical standards raises the question whether it could ever be ethically justified to compromise on the quality assurance of medicines depending on what individuals, communities, or societies can afford. In this paper, we contend that ethically, any unjustified exceptions to medicines' quality assurance represents a violation of the principles of beneficence and non-maleficence. Exceptions are only acceptable in exceptional and temporary circumstances, if based on a meaningful quality risk assessment, guided by a rigorous ethical framework built on the principles of independence, technical competence, transparency, and accountability. We also discuss how such exceptional and temporary circumstances should be defined/justified. Finally, we propose that empirical bioethics should acknowledge the existence of these dilemmas in public health, and help to build a normative approach to dealing with them. Ideally, an international group of experts in quality assurance/regulatory affairs and health ethicists should be set up to take up this topic and formulate a Guide to Ethical Principles of Quality Assurance of Medical Products. PMID- 30245611 TI - Rational Assembly of Optoplasmonic Hetero-nanoparticle Arrays with Tunable Photonic-Plasmonic Resonances. AB - Metallic and dielectric nanoparticles (NPs) have synergistic electromagnetic properties but their positioning into morphologically defined hybrid arrays with novel optical properties still poses significant challenges. A template-guided self-assembly strategy is introduced for the positioning of metallic and dielectric NPs at pre-defined lattice sites. The chemical assembly approach facilitates the fabrication of clusters of metallic NPs with interparticle separations of only a few nanometers in a landscape of dielectric NPs positioned hundreds of nanometers apart. This approach is used to generate two-dimensional interdigitated arrays of 250 nm diameter TiO2 NPs and clusters of electromagnetically strongly coupled 60 nm Au NPs. The morphologydependent near- and far-field responses of the resulting multiscale optoplasmonic arrays are analyzed in detail. Elastic and inelastic scattering spectroscopy in combination with electromagnetic simulations reveal that optoplasmonic arrays sustain delocalized photonic-plasmonic modes that achieve a cascaded E-field enhancement in the gap junctions of the Au NP clusters and simultaneously increase the E field intensity throughout the entire array. PMID- 30245612 TI - A Process Systems Framework for Rapid Generation of Life Cycle Inventories for Pollution Control and Sustainability Evaluation. AB - Life Cycle Assessment (LCA) is a tool that aids in sustainable decision-making among product and process alternatives. When implementing LCA, the efficient and accurate modeling of chemical processes for Life Cycle Inventory (LCI) generation is still challenging. Challenges include a lack of systematic design and simulation tools and approaches to develop chemical process models for obtaining and analyzing more realistic LCI results. In this contribution, a novel process systems framework is proposed for estimating LCI results when implementing pollution control technologies. This framework involves the development and incorporation of pollution control unit (PCU) modules into process simulation and generation of LCI data associated with the PCUs for use in a sustainability evaluation. Different pollution control modules are designed for rapid LCI estimation and applied to obtain emissions, utility consumption, material, and land footprint results related to waste streams of a process simulation. Then, the LCI results are analyzed with the objectives of minimizing the environmental impact and utility consumption. The proposed framework is illustrated via a biomass/coal gasification process for syngas production with the end goal of acetic acid manufacturing. Results associated with this case study show that the developed framework can provide guidelines for sustainable decision-making based on generated LCI results. PMID- 30245613 TI - Osteocyte Characterization on Polydimethylsiloxane Substrates for Microsystems Applications. AB - In the body, osteocytes reside in lacunae, lenticular shaped cavities within mineralized bone. These cells are linked to each other and surface-residing osteoblasts via physical channels known as gap junctions. It has been suggested that osteocytes sense mechanical load applied to bone and relay that signal to osteoclasts and osteoblasts. Current in vitro and in vivo models of mechanotransduction face temporal and spatial barriers. Recent advances in polydimethylsiloxane (PDMS) based microfabrication techniques may be able to overcome some of these hurdles. However, before the bone research field can effectively utilize microsystems techniques, fundamental groundwork must be completed. This study characterized the behaviour of osteocytes on PDMS coated with collagen type I (CTI) and provides the framework for bone cell mechanotransduction studies using microsystems. The goal was to determine whether osteocytes were adversely affected by the substrate material by comparing their behaviour to a standard glass substrate. In addition, optimal culture conditions and time points for growing osteocytes on PDMS substrates were determined. Results of this study suggested that use of PDMS does not adversely affect osteocyte behaviour. Furthermore, the results demonstrated that osteocytes should be cultured for no less than 72 hours prior to experimentation to allow the establishment and maintenance of phenotypic characteristics. These results completed essential groundwork necessary for further studies regarding osteocytes in microsystems modelling utilizing PDMS. PMID- 30245616 TI - Totally Implantable Bidirectional Neural Prostheses: A Flexible Platform for Innovation in Neuromodulation. AB - Implantable neural prostheses are in widespread use for treating a variety of brain disorders. Until recently, most implantable brain devices have been unidirectional, either delivering neurostimulation without brain sensing, or sensing brain activity to drive external effectors without a stimulation component. Further, many neural interfaces that incorporate a sensing function have relied on hardwired connections, such that subjects are tethered to external computers and cannot move freely. A new generation of neural prostheses has become available, that are both bidirectional (stimulate as well as record brain activity) and totally implantable (no externalized connections). These devices provide an opportunity for discovering the circuit basis for neuropsychiatric disorders, and to prototype personalized neuromodulation therapies that selectively interrupt neural activity underlying specific signs and symptoms. PMID- 30245615 TI - Decreased CX3CL1 Levels in the Cerebrospinal Fluid of Patients With Alzheimer's Disease. AB - Alzheimer's disease (AD) is a neurodegenerative disease characterized by the presence of neurofibrillary tangles, constituted by tau protein, and plaques formed by amyloid-beta protein. The disease courses with high neural damage, which leads to memory loss and death. Here we analyzed the presence of CX3CL1, a chemokine expressed by neurons, in cerebrospinal fluid (CSF) samples from control subjects and patients with mild cognitive impairment and AD dementia. CX3CL1 was decreased in the CSF of AD dementia patients compared to control subjects. However, there was not difference in plasma samples from the same subjects. PMID- 30245614 TI - Shared Biological Pathways Between Alzheimer's Disease and Ischemic Stroke. AB - Alzheimer's disease (AD) and ischemic stroke (IS) are an immense socioeconomic burden worldwide. There is a possibility that shared genetic factors lead to their links at epidemiological and pathophysiological levels. Although recent genome-wide association studies (GWAS) have provided profound insights into the genetics of AD and IS, no shared genetic variants have been identified to date. This prompted us to initiate this study, which sought to identify shared pathways linking AD and IS. We took advantage of large-scale GWAS summary data of AD (17,008 AD cases and 37,154 controls) and IS (10,307 cases and 19,326 controls) to conduct pathway analyses using genetic pathways from multiple well-studied databases, including GO, KEGG, PANTHER, Reactome, and Wikipathways. Collectively, we discovered that AD and IS shared 179 GO categories (56 biological processes, 95 cellular components, and 28 molecular functions); and the following pathways: six KEGG pathways; two PANTHER pathways; four Reactome pathways; and one in Wikipathways pathway. The more fine-grained GO terms were mainly summarized into different functional categories: transcriptional and post-transcriptional regulation, synapse, endocytic membrane traffic through the endosomal system, signaling transduction, immune process, multi-organism process, protein catabolic metabolism, and cell adhesion. The shared pathways were roughly classified into three categories: immune system; cancer (NSCLC and glioma); and signal transduction pathways involving the cadherin signaling pathway, Wnt signaling pathway, G-protein signaling and downstream signaling mediated by phosphoinositides (PIPs). The majority of these common pathways linked to both AD and IS were supported by convincing evidence from the literature. In conclusion, our findings contribute to a better understanding of common biological mechanisms underlying AD and IS and serve as a guide to direct future research. PMID- 30245617 TI - Sleep Promotes, and Sleep Loss Inhibits, Selective Changes in Firing Rate, Response Properties and Functional Connectivity of Primary Visual Cortex Neurons. AB - Recent studies suggest that sleep differentially alters the activity of cortical neurons based on firing rates during preceding wake-increasing the firing rates of sparsely firing neurons and decreasing those of faster firing neurons. Because sparsely firing cortical neurons may play a specialized role in sensory processing, sleep could facilitate sensory function via selective actions on sparsely firing neurons. To test this hypothesis, we analyzed longitudinal electrophysiological recordings of primary visual cortex (V1) neurons across a novel visual experience which induces V1 plasticity (or a control experience which does not), and a period of subsequent ad lib sleep or partial sleep deprivation. We find that across a day of ad lib sleep, spontaneous and visually evoked firing rates are selectively augmented in sparsely firing V1 neurons. These sparsely firing neurons are more highly visually responsive, and show greater orientation selectivity than their high firing rate neighbors. They also tend to be "soloists" instead of "choristers"-showing relatively weak coupling of firing to V1 population activity. These population-specific changes in firing rate are blocked by sleep disruption either early or late in the day, and appear to be brought about by increases in neuronal firing rates across bouts of rapid eye movement (REM) sleep. Following a patterned visual experience that induces orientation-selective response potentiation (OSRP) in V1, sparsely firing and weakly population-coupled neurons show the highest level of sleep-dependent response plasticity. Across a day of ad lib sleep, population coupling strength increases selectively for sparsely firing neurons-this effect is also disrupted by sleep deprivation. Together, these data suggest that sleep may optimize sensory function by augmenting the functional connectivity and firing rate of highly responsive and stimulus-selective cortical neurons, while simultaneously reducing noise in the network by decreasing the activity of less selective, faster-firing neurons. PMID- 30245618 TI - MouBeAT: A New and Open Toolbox for Guided Analysis of Behavioral Tests in Mice. AB - Animal behavioral tests are essential to understand the bases of neurologic and psychological disorders, which can be evaluated by different methodological and experimental models. However, the quantification of behavioral tests results is limited by the considerable amount of time needed for manual evaluation and the high costs of automated analysis software. To overcome these limitations, we describe here a new, open source toolbox for ImageJ, called Mouse Behavioral Analysis Toolbox (MouBeAT), designed to analyze different behavioral tests in rodents semi-automatically. These tests include Open Field (OF), Elevated Plus Maze (EPM), Y-maze (YM) test and Morris Water Maze (MWM). MouBeAT showed a high correlation with manual evaluation in all the parameters analyzed for all the behavioral tests, reinforcing its value as an accurate analysis tool. This new tool is freely available online. PMID- 30245620 TI - On the Relationship Between Sensory Eye Dominance and Stereopsis in the Normal Sighted Adult Population: Normative Data. AB - The extent of sensory eye dominance, a reflection of the interocular suppression in binocular visual processing, can be quantitatively measured using the binocular phase combination task. In this study, we aimed to provide a normative dataset for sensory eye dominance using this task. Based on that, we also assessed the relationship between perceptual eye dominance and stereopsis. One hundred and forty-two adults (average age: 24.00 +/- 1.74 years old) with normal or corrected to normal monocular visual acuity (logMAR < 0.00) participated. Observer's sensory eye dominance was quantified in two complementary ways: the interocular contrast ratio when the two eyes were balanced (i.e., the balance point) and the absolute value of the binocular perceived phase when each eye viewed maximum contrast stimuli in binocular phase combination task. Stereo acuities were measured with maximum contrast stimuli using an identical spatial frequency (0.30 cycles/degree) and stimulus arrangement to that used in the eye dominance assessment. The averaged balance point was 0.93 +/- 0.06 (Mean +/- SD), the averaged absolute value of the binocular perceived phase when both eyes viewed maximum contrast stimuli was 7.62 +/- 5.91 degrees , and the averaged stereo acuity was 2.19 +/- 0.34 log arc seconds. Neither of these two sensory eye dominance measures were significantly correlated with stereo acuity (Balance point: rho = 0.14, P = 0.10; Phase: rho = -0.13, P = 0.13). The sensory eye dominance, as reflected using a phase combination task, and stereopsis are not significantly correlated in the normal-sighted population at low spatial frequencies. PMID- 30245621 TI - Discrete Sequential Information Coding: Heteroclinic Cognitive Dynamics. AB - Discrete sequential information coding is a key mechanism that transforms complex cognitive brain activity into a low-dimensional dynamical process based on the sequential switching among finite numbers of patterns. The storage size of the corresponding process is large because of the permutation capacity as a function of control signals in ensembles of these patterns. Extracting low-dimensional functional dynamics from multiple large-scale neural populations is a central problem both in neuro- and cognitive- sciences. Experimental results in the last decade represent a solid base for the creation of low-dimensional models of different cognitive functions and allow moving toward a dynamical theory of consciousness. We discuss here a methodology to build simple kinetic equations that can be the mathematical skeleton of this theory. Models of the corresponding discrete information processing can be designed using the following dynamical principles: (i) clusterization of the neural activity in space and time and formation of information patterns; (ii) robustness of the sequential dynamics based on heteroclinic chains of metastable clusters; and (iii) sensitivity of such sequential dynamics to intrinsic and external informational signals. We analyze sequential discrete coding based on winnerless competition low-frequency dynamics. Under such dynamics, entrainment, and heteroclinic coordination leads to a large variety of coding regimes that are invariant in time. PMID- 30245619 TI - How Breath-Control Can Change Your Life: A Systematic Review on Psycho Physiological Correlates of Slow Breathing. AB - Background: The psycho-physiological changes in brain-body interaction observed in most of meditative and relaxing practices rely on voluntary slowing down of breath frequency. However, the identification of mechanisms linking breath control to its psychophysiological effects is still under debate. This systematic review is aimed at unveiling psychophysiological mechanisms underlying slow breathing techniques (<10 breaths/minute) and their effects on healthy subjects. Methods: A systematic search of MEDLINE and SCOPUS databases, using keywords related to both breathing techniques and to their psychophysiological outcomes, focusing on cardio-respiratory and central nervous system, has been conducted. From a pool of 2,461 abstracts only 15 articles met eligibility criteria and were included in the review. The present systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: The main effects of slow breathing techniques cover autonomic and central nervous systems activities as well as the psychological status. Slow breathing techniques promote autonomic changes increasing Heart Rate Variability and Respiratory Sinus Arrhythmia paralleled by Central Nervous System (CNS) activity modifications. EEG studies show an increase in alpha and a decrease in theta power. Anatomically, the only available fMRI study highlights increased activity in cortical (e.g., prefrontal, motor, and parietal cortices) and subcortical (e.g., pons, thalamus, sub-parabrachial nucleus, periaqueductal gray, and hypothalamus) structures. Psychological/behavioral outputs related to the abovementioned changes are increased comfort, relaxation, pleasantness, vigor and alertness, and reduced symptoms of arousal, anxiety, depression, anger, and confusion. Conclusions: Slow breathing techniques act enhancing autonomic, cerebral and psychological flexibility in a scenario of mutual interactions: we found evidence of links between parasympathetic activity (increased HRV and LF power), CNS activities (increased EEG alpha power and decreased EEG theta power) related to emotional control and psychological well-being in healthy subjects. Our hypothesis considers two different mechanisms for explaining psychophysiological changes induced by voluntary control of slow breathing: one is related to a voluntary regulation of internal bodily states (enteroception), the other is associated to the role of mechanoceptors within the nasal vault in translating slow breathing in a modulation of olfactory bulb activity, which in turn tunes the activity of the entire cortical mantle. PMID- 30245622 TI - Angular Upsampling in Infant Diffusion MRI Using Neighborhood Matching in x-q Space. AB - Diffusion MRI requires sufficient coverage of the diffusion wavevector space, also known as the q-space, to adequately capture the pattern of water diffusion in various directions and scales. As a result, the acquisition time can be prohibitive for individuals who are unable to stay still in the scanner for an extensive period of time, such as infants. To address this problem, in this paper we harness non-local self-similar information in the x-q space of diffusion MRI data for q-space upsampling. Specifically, we first perform neighborhood matching to establish the relationships of signals in x-q space. The signal relationships are then used to regularize an ill-posed inverse problem related to the estimation of high angular resolution diffusion MRI data from its low-resolution counterpart. Our framework allows information from curved white matter structures to be used for effective regularization of the otherwise ill-posed problem. Extensive evaluations using synthetic and infant diffusion MRI data demonstrate the effectiveness of our method. Compared with the widely adopted interpolation methods using spherical radial basis functions and spherical harmonics, our method is able to produce high angular resolution diffusion MRI data with greater quality, both qualitatively and quantitatively. PMID- 30245623 TI - Analysis of Alzheimer's Disease Based on the Random Neural Network Cluster in fMRI. AB - As Alzheimer's disease (AD) is featured with degeneration and irreversibility, the diagnosis of AD at early stage is important. In recent years, some researchers have tried to apply neural network (NN) to classify AD patients from healthy controls (HC) based on functional MRI (fMRI) data. But most study focus on a single NN and the classification accuracy was not high. Therefore, this paper used the random neural network cluster which was composed of multiple NNs to improve classification performance. Sixty one subjects (25 AD and 36 HC) were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. This method not only could be used in the classification, but also could be used for feature selection. Firstly, we chose Elman NN from five types of NNs as the optimal base classifier of random neural network cluster based on the results of feature selection, and the accuracies of the random Elman neural network cluster could reach to 92.31% which was the highest and stable. Then we used the random Elman neural network cluster to select significant features and these features could be used to find out the abnormal regions. Finally, we found out 23 abnormal regions such as the precentral gyrus, the frontal gyrus and supplementary motor area. These results fully show that the random neural network cluster is worthwhile and meaningful for the diagnosis of AD. PMID- 30245624 TI - Uncoupling DISC1 * D2R Protein-Protein Interactions Facilitates Latent Inhibition in Disc1-L100P Animal Model of Schizophrenia and Enhances Synaptic Plasticity via D2 Receptors. AB - Both Disrupted-In-Schizophrenia-1 (DISC1) and dopamine receptors D2R have significant contributions to the pathogenesis of schizophrenia. Our previous study demonstrated that DISC1 binds to D2R and such protein-protein interaction is enhanced in patients with schizophrenia and Disc1-L100P mouse model of schizophrenia (Su et al., 2014). By uncoupling DISC1 * D2R interaction (trans activator of transcription (TAT)-D2pep), the synthesized TAT-peptide elicited antipsychotic-like effects in pharmacological and genetic animal models, without motor side effects as tardive dyskinesia commonly seen with typical antipsychotic drugs (APDs), indicating that the potential of TAT-D2pep of becoming a new APD. Therefore, in the current study, we further explored the APD-associated capacities of TAT-D2pep. We found that TAT-D2pep corrected the disrupted latent inhibition (LI), as a hallmark of schizophrenia associated endophenotype, in Disc1-L100P mutant mice-a genetic model of schizophrenia, supporting further APD' capacity of TAT-D2pep. Moreover, we found that TAT-D2pep elicited nootropic effects in C57BL/6NCrl inbred mice, suggesting that TAT-D2pep acts as a cognitive enhancer, a desirable feature of APDs of the new generation. Namely, TAT-D2pep improved working memory in T-maze, and cognitive flexibility assessed by the LI paradigm, in C57BL/6N mice. Next, we assessed the impact of TAT-D2pep on hippocampal long-term plasticity (LTP) under basal conditions and upon stimulation of D2 receptors using quinpirole. We found comparable effects of TAT D2pep and its control TAT-D2pep-scrambled peptide (TAT-D2pep-sc) under basal conditions. However, under stimulation of D2R by quinpirole, LTP was enhanced in hippocampal slices incubated with TAT-D2pep, supporting the notion that TAT-D2pep acts in a dopamine-dependent manner and acts as synaptic enhancer. Overall, our experiments demonstrated implication of DISC1 * D2R protein-protein interactions into mechanisms of cognitive and synaptic plasticity, which help to further understand molecular-cellular mechanisms of APD of the next generation. PMID- 30245625 TI - p58IPK Is an Endogenous Neuroprotectant for Retinal Ganglion Cells. AB - p58IPK is an endoplasmic reticulum (ER)-resident chaperone playing a critical role in facilitating protein folding and protein homeostasis. Previously, we have demonstrated that p58IPK is expressed broadly in retinal neurons including retinal ganglion cells (RGCs) and loss of p58IPK results in age-related RGC degeneration. In the present study, we investigate the role of p58IPK in neuroprotection by in vitro and in vivo studies using primary RGC culture and two well-established disease-relevant RGC injury models: retinal ischemia/reperfusion (I/R) and microbead-induced ocular hypertension. Our results demonstrate that in both in vivo models, p58IPK -/- mice exhibit significantly increased RGC loss compared to wild type (WT) mice. In vitro, p58IPK-deficient RGCs show reduced viability and are more susceptible to cell death induced by the ER stress inducer tunicamycin (TM). Overexpression of p58IPK by adeno-associated virus (AAV) significantly diminishes TM-induced cell death in both WT and p58IPK -/- RGCs. Interestingly, we find that loss of p58IPK leads to reduced mRNA expression, but not the protein level, of mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor that resides in the ER. Treatment with recombinant MANF protein protects R28 retinal neural cells and mouse retinal explants from TM induced cell death. Taken together, our study suggests that p58IPK functions as an endogenous neuroprotectant for RGCs. The mechanisms underlying p58IPK's neuroprotective action and the potential interactions between p58IPK and MANF warrant future investigation. PMID- 30245626 TI - Visual Attention Performances and Related Cerebral Microstructural Integrity Among Subjects With Subjective Cognitive Decline and Mild Cognitive Impairment. AB - Objective: To compare visual attention performances and diffusion tensor imaging (DTI) between subjects with subjective cognitive decline (SCD) and mild cognitive impairment (MCI), and to discover neuronal substrates related to visual attention performances. Methods: Thirty-nine subjects with SCD and 15 with MCI, diagnosed following neuropsychological tests and conventional brain magnetic resonance imaging, were recruited. All subjects were further examined by the Conners Continuous Performance Test 3 (CPT3) and DTI including fractional anisotropy (FA) and mean diffusivity (MD), in which group comparisons and stepwise linear regression were made. Results: Subjects with MCI had a worse performance in all retrieval indices of verbal/nonverbal memory tests than those with SCD in the context of comparable general cognition and demographic status. In the CPT3, subjects with MCI had a significant longer hit reaction time (HRT) by univariate but not multivariate comparisons. Further analysis suggested that a longer HRT across all interstimuli intervals and at the point of fourth to sixth blocks were noted among MCI subjects. In DTI evaluations, FA value within the left forceps major was the only hotspot with significant between-group differences after the Bonferroni correction of FA and MD values. On the basis that HRT had significant inverse correlations with FA value within the genu of the corpus callosum and left forceps minor, regression analysis was conducted, showing HRT was best predicted by the FA value within the left forceps minor. Area under receiver operative characteristic curve was 0.70; the optimum cut-off for HRT was 515.8 ms, with a sensitivity of 85% but specificity of 47%. Conclusions: Our report suggested that impaired sustained attention and vigilance to be an early cognitive marker in differentiating MCI from SCD, where MCI subjects had a longer HRT across all interstimuli intervals and more profoundly in later blocks. FA measures appeared to be more sensitive DTI parameters than MD values in detecting microstructural changes between SCD and MCI. The role of the anterior interhemispheric fibers in sustained attention implementation during visual signal detection task was highlighted. PMID- 30245628 TI - CuO and CeO2 Nanostructures Green Synthesized Using Olive Leaf Extract Inhibits the Growth of Highly Virulent Multidrug Resistant Bacteria. AB - One of the major challenges of nano-biotechnology is to engineer potent antimicrobial nanostructures (NS) with high biocompatibility. Keeping this in view, we have performed aqueous olive leaf extract mediated one pot facile synthesis of CuO-NS and CeO2-NS. Prepared NS were homogenous, less than 26 nm in size, and small crystallite units as revealed by scanning electron microscopy (SEM) and X-ray diffraction (XRD) analyses. Fourier transform infrared spectroscopy (FTIR) of CuO-NS and CeO2-NS showed typical Cu-O prints around 592 660 cm-1 and Ce-O bond vibrations at 453 cm-1. The successful capping of CuO-NS and CeO2-NS by compounds present in the plant extract was further validated by high performance liquid chromatography (HPLC) and thermal gravimetric analysis (TGA). Active phyto-chemicals from the leaf extract simultaneously acted as strong reducing as well as capping agent in the NS synthesis. NS engineered in the present study showed antibacterial potential at extremely low concentration against highly virulent multidrug-resistant (MDR) gram-negative strains (Escherichia coli, Enterobacter cloacae, Acinetobacter baumannii and Pseudomonas aeruginosa), alarmed by World Health Organization (WHO). Furthermore, CuO-NS and CeO2-NS did not show any cytotoxicity on HEK-293 cell lines and Brine shrimp larvae indicating that the NS green synthesized in the present study are biocompatible. PMID- 30245629 TI - 3-Chloro-N'-(2-hydroxybenzylidene) benzohydrazide: An LSD1-Selective Inhibitor and Iron-Chelating Agent for Anticancer Therapy. AB - Despite the discovery and development of novel therapies, cancer is still a leading cause of death worldwide. In order to grow, tumor cells require large quantities of nutrients involved in metabolic processes, and an increase in iron levels is known to contribute to cancer proliferation. Iron plays an important role in the active site of a number of proteins involved in energy metabolism, DNA synthesis and repair, such as ribonucleotide reductase, which induce G0/S phase arrest and exert a marked antineoplastic effect, particularly in leukemia and neuroblastoma. Iron-depletion strategies using iron chelators have been shown to result in cell cycle arrest and apoptosis. Deferoxamine (DFO) was the first FDA-approved drug for the treatment of iron overload pathologies, and has also been recognized as having anticancer properties. The high cost, low permeability and short plasma half-life of DFO led to the development of other iron-chelating drugs. Pyridoxal isonicotinoyl hydrazone (PIH) and its analogs chelate cellular iron by tridentate binding, and inhibit DNA synthesis more robustly than DFO, demonstrating an effective antiproliferative activity. Here, we investigated the biological effects of a PIH derivative, 3-chloro-N'-(2 hydroxybenzylidene)benzohydrazide (CHBH), known to be a lysine-specific histone demethylase 1A inhibitor. We showed that CHBH is able to induce cell proliferation arrest in several human cancer cell lines, including lung, colon, pancreas and breast cancer, at micromolar levels. Our findings indicate that CHBH exerts a dual anticancer action by strongly impairing iron metabolism and modulating chromatin structure and function. PMID- 30245630 TI - In silico Prioritization of Transporter-Drug Relationships From Drug Sensitivity Screens. AB - The interplay between drugs and cell metabolism is a key factor in determining both compound potency and toxicity. In particular, how and to what extent transmembrane transporters affect drug uptake and disposition is currently only partially understood. Most transporter proteins belong to two protein families: the ATP-Binding Cassette (ABC) transporter family, whose members are often involved in xenobiotic efflux and drug resistance, and the large and heterogeneous family of solute carriers (SLCs). We recently argued that SLCs are collectively a rather neglected gene group, with most of its members still poorly characterized, and thus likely to include many yet-to-be-discovered associations with drugs. We searched publicly available resources and literature to define the currently known set of drugs transported by ABCs or SLCs, which involved ~500 drugs and more than 100 transporters. In order to extend this set, we then mined the largest publicly available pharmacogenomics dataset, which involves approximately 1,000 molecularly annotated cancer cell lines and their response to 265 anti-cancer compounds, and used regularized linear regression models (Elastic Net, LASSO) to predict drug responses based on SLC and ABC data (expression levels, SNVs, CNVs). The most predictive models included both known and previously unidentified associations between drugs and transporters. To our knowledge, this represents the first application of regularized linear regression to this set of genes, providing an extensive prioritization of potentially pharmacologically interesting interactions. PMID- 30245631 TI - Ulinastatin Inhibits Osteoclastogenesis and Suppresses Ovariectomy-Induced Bone Loss by Downregulating uPAR. AB - Recent studies indicate that uPAR acts a crucial part in cell migration and the modulation of bone homeostasis. As a natural serine protease inhibitor, ulinastatin owns the capacity to reduce proinflammatory factors, downregulate the activation of NF-kappaB and mitogen-activated protein kinases (MAPKs) signaling pathways. Osteoclastogenesis has been demonstrated to be related with low-grade inflammation which involves cell migration, thus we speculate that ulinastatin may have a certain kind of impact on uPAR so as to be a potential inhibiting agent of osteoclastogenesis. In this research, we investigated the role which ulinastatin plays in RANKL-induced osteoclastogenesis both in vivo and in vitro. Ulinastatin inhibited osteoclast formation and bone resorption in a dose dependent manner in primary bone marrow-derived macrophages (BMMs), and knockdown of uPAR could completely repress the formation of osteoclasts. At the molecular level, ulinastatin suppressed RANKL-induced activation of cathepsin K, TRAP, nuclear factor-kappaB (NF-kappaB) and MAPKs, and decreased the expression of uPAR. At the meantime, ulinastatin also decreased the expression of osteoclast marker genes, including cathepsin K, TRAP, RANK, and NFATc1. Besides, ulinastatin prevented bone loss in ovariectomized C57 mice by inhibiting the formation of osteoclasts. To sum up, this research confirmed that ulinastatin has the ability to inhibit osteoclastogenesis and prevent bone loss, and uPAR plays a crucial role in that process. Therefore, ulinastatin could be chosen as an effective alternative therapeutics for osteoclast-related diseases. PMID- 30245627 TI - Raging the War Against Inflammation With Natural Products. AB - Over the last few decade Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are the drugs of choice for treating numerous inflammatory diseases including rheumatoid arthritis. The NSAIDs produces anti-inflammatory activity via inhibiting cyclooxygenase enzyme, responsible for the conversation of arachidonic acid to prostaglandins. Likewise, cyclooxegenase-2 inhibitors (COX-2) selectively inhibit the COX-2 enzyme and produces significant anti-inflammatory, analgesic, and anti pyretic activity without producing COX-1 associated gastrointestinal and renal side effects. In last two decades numerous selective COX-2 inhibitors (COXIBs) have been developed and approved for various inflammatory conditions. However, data from clinical trials have suggested that the prolong use of COX-2 inhibitors are also associated with life threatening cardiovascular side effects including ischemic heart failure and myocardial infection. In these scenario secondary metabolites from natural product offers a great hope for the development of novel anti-inflammatory compounds. Although majority of the natural product based compounds exhibit more selectively toward COX-1. However, the data suggest that slight structural modification can be helpful in developing COX-2 selective secondary metabolites with comparative efficacy and limited side effects. This review is an effort to highlight the secondary metabolites from terrestrial and marine source with significant COX-2 and COX-2 mediated PGE2 inhibitory activity, since it is anticipated that isolates with ability to inhibit COX-2 mediated PGE2 production would be useful in suppressing the inflammation and its classical sign and symptoms. Moreover, this review has highlighted the potential lead compounds including berberine, kaurenoic acid, alpha-cyperone, curcumin, and zedoarondiol for further development with the help of structure-activity relationship (SAR) studies and their current status. PMID- 30245632 TI - Estimation of Diabetic Retinal Microaneurysm Perfusion Parameters Based on Computational Fluid Dynamics Modeling of Adaptive Optics Scanning Laser Ophthalmoscopy. AB - Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. Microaneurysms (MAs), which are abnormal outpouchings of the retinal vessels, are early and hallmark lesions of DR. The presence and severity of MAs are utilized to determine overall DR severity. In addition, MAs can directly contribute to retinal neural pathology by leaking fluid into the surrounding retina, causing abnormal central retinal thickening and thereby frequently leading to vision loss. Vascular perfusion parameters such as shear rate (SR) or wall shear stress (WSS) have been linked to blood clotting and endothelial cell dysfunction, respectively in non-retinal vasculature. However, despite the importance of MAs as a key aspect of diabetic retinal pathology, much remains unknown as to how structural characteristics of individual MAs are associated with these perfusion attributes. MA structural information obtained on high resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) was utilized to estimate perfusion parameters through Computational Fluid Dynamics (CFD) analysis of the AOSLO images. The HemeLB flow solver was used to simulate steady-state and time dependent fluid flow using both commodity hospital-based and high performance computing resources, depending on the degree of detail required in the simulations. Our results indicate that WSS is lowest in MA regions furthest away from the feeding vessels. Furthermore, areas of low SR are associated with clot location in saccular MAs. These findings suggest that morphology and CFD estimation of perfusion parameters may be useful tools for determining the likelihood of clot presence in individual diabetic MAs. PMID- 30245633 TI - Strength-Endurance Training Reduces the Hamstrings Strength Decline Following Simulated Football Competition in Female Players. AB - Hamstring strains are the most common injury in multiple sprint sports, with inadequate eccentric hamstring strength and fatigue identified as important risk factors. Resistance training interventions aimed at reducing injury risk typically focus on the development of maximum strength, while little is known about the impact of training on hamstring fatigue resistance. The present study compared the effects of strength endurance (SE) with a strength intervention (S) on the eccentric hamstring strength decline induced by a simulated soccer match. Twenty-one female soccer players were randomly assigned to a S group (n = 10) or a SE group (n = 11). Hamstrings and quadriceps isokinetic concentric and eccentric peak torque (PT) were assessed at 120 degrees .s-1 and hamstrings-to quadriceps ratio (HEcc:QCon) calculated, pre- and immediately post a 90-min simulated match (BEAST90). This was repeated following a 7-week intervention of either three to five sets of 6RM leg curl and stiff-leg deadlift with 3-min inter set rest (S), or the same exercises performed using three sets of 12-20 RM with 45-90 s inter-set rest (SE). At baseline, the simulated match led to significant declines in hamstrings eccentric peak torque (EccPT) in both groups in both dominant (D) and non-dominant (ND) legs [SE: (D: -15.5, ND: -15.6%), P = 0.001 to 0.016; S: (D: -12.3%, ND: -15.5%), P = 0.001 to 0.018]. After the 7-week intervention, we observed a group*intervention*match interaction such that there was no significant decline in EccPT in the SE group following the simulated match (D: 5.3%, ND: 2.0%), but there remained significant declines in the S group (D: 14.2%, ND: -15.5%, P = 0.018-0.001). Similarly, in the SE group, there was a significant decrease in the HEcc:QCon in D before (-14.2%, P = 0.007), but not after the training intervention, whereas declines were observed in the S group both at baseline, and following the intervention (D: -13.9%, ND: -15.6%, P = 0.045). These results demonstrate that SE training can reduce the magnitude of the EccPT decline observed during soccer competition. As inadequate eccentric strength and fatigue are both risk factors for hamstring injury, SE training should be considered along with the development of peak eccentric strength, as a component of programs aimed at reducing injury risk in multiple-sprint sports. PMID- 30245634 TI - Estimating Attractor Reachability in Asynchronous Logical Models. AB - Logical models are well-suited to capture salient dynamical properties of regulatory networks. For networks controlling cell fate decisions, cell fates are associated with model attractors (stable states or cyclic attractors) whose identification and reachability properties are particularly relevant. While synchronous updates assume unlikely instantaneous or identical rates associated with component changes, the consideration of asynchronous updates is more realistic but, for large models, may hinder the analysis of the resulting non deterministic concurrent dynamics. This complexity hampers the study of asymptotical behaviors, and most existing approaches suffer from efficiency bottlenecks, being generally unable to handle cyclical attractors and quantify attractor reachability. Here, we propose two algorithms providing probability estimates of attractor reachability in asynchronous dynamics. The first algorithm, named Firefront, exhaustively explores the state space from an initial state, and provides quasi-exact evaluations of the reachability probabilities of model attractors. The algorithm progresses in breadth, propagating the probabilities of each encountered state to its successors. Second, Avatar is an adapted Monte Carlo approach, better suited for models with large and intertwined transient and terminal cycles. Avatar iteratively explores the state space by randomly selecting trajectories and by using these random walks to estimate the likelihood of reaching an attractor. Unlike Monte Carlo simulations, Avatar is equipped to avoid getting trapped in transient cycles and to identify cyclic attractors. Firefront and Avatar are validated and compared to related methods, using as test cases logical models of synthetic and biological networks. Both algorithms are implemented as new functionalities of GINsim 3.0, a well established software tool for logical modeling, providing executable GUI, Java API, and scripting facilities. PMID- 30245635 TI - Description of the Human Atrial Action Potential Derived From a Single, Congruent Data Source: Novel Computational Models for Integrated Experimental-Numerical Study of Atrial Arrhythmia Mechanisms. AB - Introduction: The development of improved diagnosis, management, and treatment strategies for human atrial fibrillation (AF) is a significant and important challenge in order to improve quality of life for millions and reduce the substantial social-economic costs of the condition. As a complex condition demonstrating high variability and relation to other cardiac conditions, the study of AF requires approaches from multiple disciplines including single-cell experimental electrophysiology and computational modeling. Models of human atrial cells are less well parameterized than those of the human ventricle or other mammal species, largely due to the inherent challenges in patch clamping human atrial cells. Such challenges include, frequently, unphysiologically depolarized resting potentials and thus injection of a compensatory hyperpolarizing current, as well as detecting certain ion currents which may be disrupted by the cell isolation process. The aim of this study was to develop a laboratory specific model of human atrial electrophysiology which reproduces exactly the conditions of isolated-cell experiments, including testing of multiple experimental interventions. Methods: Formulations for the primary ion currents characterized by isolated-cell experiments in the Workman laboratory were fit directly to voltage-clamp data; the fast sodium-current was parameterized based on experiments relating resting membrane potential to maximal action potential upstroke velocity; compensatory hyperpolarizing current was included as a constant applied current. These formulations were integrated with three independent human atrial cell models to provide a family of novel models. Extrapolated intact-cell models were developed through removal of the hyperpolarizing current and introduction of terminal repolarization potassium currents. Results: The isolated-cell models quantitatively reproduced experimentally measured properties of excitation in both control and pharmacological and dynamic-clamp interventions. Comparison of isolated and intact-cell models highlighted the importance of reproducing this cellular environment when comparing experimental and simulation data. Conclusion: We have developed a laboratory specific model of the human atrial cell which directly reproduces the experimental isolated-cell conditions and captures human atrial excitation properties. The model may be particularly useful for directly relating model to experiment, and offers a complementary tool to the available set of human atrial cell models with specific advantages resulting from the congruent input data source. PMID- 30245636 TI - EEG Multiscale Complexity in Schizophrenia During Picture Naming. AB - : Introduction: Patients with schizophrenia show cognitive deficits that are evident both behaviourally and with EEG recordings. Recent studies have suggested that non-linear analyses of EEG might more adequately reflect the complex, irregular, non-stationary behavior of neural processes than more traditional ERP measures. Non-linear analyses have been mainly applied to EEGs from patients at rest, whereas differences in complexity might be more evident during task performance. Objective: We aimed to investigate changes in non-linear brain dynamics of patients with schizophrenia during cognitive processing. Method: 18 patients and 17 matched healthy controls were asked to name pictures. EEG data were collected at rest and while they were performing a naming task. EEGs were analyzed with the classical Lempel-Ziv Complexity (LZC) and with the Multiscale LZC. Electrodes were grouped in seven regions of interest (ROI). Results: As expected, controls had fewer naming errors than patients. Regarding EEG complexity, the interaction between Group, Task and ROI indicated that patients showed higher complexity values in right frontal regions only at rest, where no differences in complexity between patients and controls were found during the naming task. EEG complexity increased from rest to task in controls in left temporal-parietal regions, while no changes from rest to task were observed in patients. Finally, differences in complexity between patients and controls depended on the frequency bands: higher values of complexity in patients at rest were only observed in fast bands, indicating greater heterogeneity in patients in local dynamics of neuronal assemblies. Conclusion: Consistent with previous studies, schizophrenic patients showed higher complexity than controls in frontal regions at rest. Interestingly, we found different modulations of brain complexity during a simple cognitive task between patients and controls. These data can be interpreted as indicating schizophrenia-related failures to adapt brain functioning to the task, which is reflected in poorer behavioral performance. Highlights: - We measured classical and multiscale Lempel-Ziv Complexity (LZCN and MLZC) of the EEG signal of patients with schizophrenia and controls at rest and while performing a cognitive task. - We found that patients and controls showed a different pattern of brain complexity depending on their cognitive state (at rest or under cognitive challenge). - Our results illustrate the value of the MLZC in the characterization of the pattern of brain complexity in schizophrenia on function of frequency bands. - Nonlinear methodologies of EEG analysis can help to characterize brain dysfunction in schizophrenia. PMID- 30245637 TI - Expression of Na+/K+-ATPase Was Affected by Salinity Change in Pacific abalone Haliotis discus hannai. AB - Na+/K+-ATPase (NKA) belongs to the P-type ATPase family, whose members are located in the cell membrane and are distributed in diverse tissues and cells. The main function of the NKA is to regulate osmotic pressure. To better understand the role of NKA in osmoregulation, we first cloned and characterized the full-length cDNAs of NKA alpha subunit and beta subunit from Pacific abalone Haliotis discus hannai in the current study. The predicted protein sequence of the NKA alpha subunit, as the catalytic subunit, was well conserved. In contrast, the protein sequence of the beta subunit had low similarity with those of other species. Phylogenetic analysis revealed that both the alpha and beta subunits of the NKA protein of Pacific abalone were clustered with those of the Gastropoda. Then, the relationship between salinity changes and the NKA was investigated. Sudden salinity changes (with low-salinity seawater (LSW) or high-salinity seawater (HSW)) led to clear changes in ion concentration (Na+ and K+) in hemolymph; however, the relative stability of ion concentrations in tissue revealed that Pacific abalone has a strong osmotic pressure regulation ability when faced with these salinity changes. Meanwhile, the expression and activity of the NKA was significantly decreased (in LSW group) or increased (in HSW group) during the ion concentration re-establishing stages, which was consistent with the coordinated regulation of ion concentration in hemolymph. Moreover, a positive correlation between cyclic adenosine monophosphate (cAMP) concentrations and NKA mRNA expression (NKA activity) was observed in mantle and gill. Therefore, the sudden salinity changes may affect NKA transcription activation, translation and enzyme activity via a cAMP-mediated pathway. PMID- 30245639 TI - Electroconvulsive Therapy and Risk of Dementia-A Nationwide Cohort Study in Taiwan. AB - Background: Electroconvulsive therapy (ECT) is an effective treatment for schizophrenia, bipolar disorder, and major depressive disorder, and a temporary memory loss may occur after ECT. However, the association between ECT in patients with schizophrenia, bipolar disorder, and major depressive disorder, and the risk of dementia is yet to be examined. Objective: This study aimed to clarify as to whether ECT is associated with the risk of dementia after ECT in patients with schizophrenia, bipolar disorder, and major depressive disorder, using Taiwan's National Health Insurance Research Database (NHIRD). Methods: A total of 3,796 enrolled participants (schizophrenia, 46.68%; bipolar disorder, 11.77%; and major depressive disorder, 41.55%) with 994 patients who had received ECT and 2,982 controls matched for sex and age, between January 1, and December 31, 2000, were selected from the NHIRD. After adjusting for confounding factors, Fine and Gray's survival analysis was used to compare the risk of developing dementia during the 10 years of follow-up. Results: Of the study patients, 45 (4.53%) of them developed dementia when compared to 149 (5.0%) in the control group. Fine and Gray's survival analysis revealed that the study patients were not associated with an increased risk of dementia [hazard ratio (HR) = 0.612, 95% confidence interval (CI) = 0.438-1.854, P = 0.325]. After adjusting for sex, age, monthly income, urbanization level, geographic region, and comorbidities, the adjusted HR was 0.633 (95% CI = 0.448 - 1.895, P = 0.304). Conclusion: This study supports that ECT was not associated with the increased risk of dementia in patients with schizophrenia, bipolar disorder, and major depressive disorder, using the NHIRD. PMID- 30245638 TI - Nesprins and Lamins in Health and Diseases of Cardiac and Skeletal Muscles. AB - Since the discovery of the inner nuclear transmembrane protein emerin in the early 1990s, nuclear envelope (NE) components and related involvement in nuclei integrity and functionality have been highly investigated. The NE is composed of two distinct lipid bilayers described as the inner (INM) and outer (ONM) nuclear membrane. NE proteins can be specifically "integrated" in the INM (such as emerin and SUN proteins) or in the ONM such as nesprins. Additionally, flanked to the INM, the nuclear lamina, a proteinaceous meshwork mainly composed of lamins A and C completes NE composition. This network of proteins physically interplays to guarantee NE integrity and most importantly, shape the bridge between cytoplasmic cytoskeletons networks (such as microtubules and actin) and the genome, through the anchorage to the heterochromatin. The essential network driving the connection of nucleoskeleton with cytoskeleton takes place in the perinuclear space (the space between ONM and INM) with the contribution of the LINC complex (for Linker of Nucleoskeleton to Cytoskeleton), hosting KASH and SUN proteins interactions. This close interplay between compartments has been related to diverse functions from nuclear integrity, activity and positioning through mechanotransduction pathways. At the same time, mutations in NE components genes coding for proteins such as lamins or nesprins, had been associated with a wide range of congenital diseases including cardiac and muscular diseases. Although most of these NE associated proteins are ubiquitously expressed, a large number of tissue-specific disorders have been associated with diverse pathogenic mutations. Thus, diagnosis and molecular explanation of this group of diseases, commonly called "nuclear envelopathies," is currently challenging. This review aims, first, to give a better understanding of diverse functions of the LINC complex components, from the point of view of lamins and nesprins. Second, to summarize human congenital diseases with a special focus on muscle and heart abnormalities, caused by mutations in genes coding for these two types of NE associated proteins. PMID- 30245640 TI - Demographic and Clinical Characteristics of Completed Suicides in Mexico City 2014-2015. AB - Objective: To analyze sex differences in demographic and clinical characteristics of individuals who died by suicide in Mexico City. Method: Statistical analysis of residents of Mexico City whose cause of death was suicide, during two years period from January 2014 to December 2015, with a coroner's report. Suicide mortality rates were calculated by age, sex, and location within the city. The Chi-squared test was used to assess statistical differences. Results: From January 2014 to December 2015, 990 residents of Mexico City died by suicide (men: 78.28%, women: 21.72%). Among males, the highest mortality rates were among the groups of 20-24 and 75-79 years old, whereas in women, the group with the highest mortality rate was 15 to 19 years old. 74% of the sample used hanging as suicide method. However, men had higher rates of a positive result in the toxicology test (40%) (p < 0.05). There was no concordance between male and female suicide by city jurisdictions. Conclusion: Our results provide evidence that the characteristics of Mexico City's residents who committed suicide had significant sex-related differences, including where they used to live. Understanding the contributory factors associated with completed suicide is essential for the development of effective preventive strategies. PMID- 30245641 TI - Response and Remission Rates Following High-Frequency vs. Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Over Right DLPFC for Treating Major Depressive Disorder (MDD): A Meta-Analysis of Randomized, Double-Blind Trials. AB - Background: High-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (L-DLPFC) is the most widely applied treatment protocol for major depressive disorder (MDD), while low frequency (LF) rTMS over the right DLPFC (R-DLPFC) also exhibits similar, if not better, efficacy for MDD. Therefore, a meta-analysis is warranted to compare the efficacy of the two protocols for MDD. Method: We searched the literature from 1990 through to August 1, 2017 using MEDLINE, and the literature from 1995 through to August 1, 2017 using EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), SCOPUS, and ProQuest Dissertations and Theses (PQDT). We included randomized controlled trials (RCT) comparing the efficacy of HF rTMS over the L-DLPFC and LF rTMS over the R-DLPFC for MDD, which used response and/or remission rates as the primary endpoints, with and without sham controlled. Results: (1) The meta-analysis of the response rates was based on 12 studies, including 361 patients with MDD (175 for HF (> 5 Hz) over the L-DLPFC, and 186 for LF (<5 Hz) over the R-DLPFC; odds ratio = 1.08; 95%, confidence interval = 0.88-1.34). (2) The meta-analysis of the remission rate was based on 5 studies, including 131 MDD patients (64 for HF over the L-DLPFC and 67 for LF over the R-DLPFC; odds ratio = 1.29; 95% confidence interval = 0.54-3.10). Conclusion: Both HF rTMS over the L-DLPFC and LF over the R-DLPFC demonstrated similar therapeutic efficacy for the treatment of patients with MDD. The results suggested that further investigation on treatment efficacy indicators before/during treatment is necessary and helpful for optimizing a personalized protocol for patients. PMID- 30245642 TI - The Neural Correlates of Implicit Cognitive Bias Toward Internet-Related Cues in Internet Addiction: An ERP Study. AB - Internet addiction is a sort of non-psychoactive substance dependence. The Implicit Association Test (IAT) is used to measure implicit cognition. Event related potential (ERP) is one of the most widely used methods in cognitive neuroscience research to investigate the physiological correlates of cognitive activity associated with processing information. Further investigating the ERP characteristics of implicit cognitive bias in Internet addiction would be helpful in understanding the nature of Internet addiction. This study investigated the ERP characteristics of implicit cognitive bias in Internet addiction. The participants included 60 Internet-addicted individuals (IAG) and 60 normal controls (NCG). All participants were measured with ERPs using the IAT. The results showed that there was a significant difference in the Internet-related IAT effect for reaction times between IAG and NCG, and there were stronger positive implicit associations toward Internet related cues in IAG than NCG. Using P1, N2, P3, and N4 as dependent variables, a mixed repeated-measures analysis of variance (ANOVA) on the mean latencies and mean amplitudes revealed a significant interaction between the groups (IAG vs. NCG) and stimulus condition (compatible trials vs. incompatible trials) for the N2 and P3 amplitudes; the simple effects analysis showed that the N2 and P3 amplitudes were larger under the IAG-compatible trial conditions than under the IAG-incompatible trial conditions. In the IAG group, the positive implicit associations with Internet related cues elicited larger N2 and P3 amplitudes at the occipital lobe sites. These results indicated that Internet addictive individuals show stronger positive implicit associations toward Internet-related cues, and the positive implicit associations toward Internet-related cues elicited ERP changes at occipital lobe sites. PMID- 30245643 TI - Human Endogenous Retroviral Envelope Protein Syncytin-1 and Inflammatory Abnormalities in Neuropsychological Diseases. AB - Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome. Recent studies have considered HERVs as potential pathogenic factors. The majority of HERV genes are mutated and not capable of encoding functional proteins; regardless, some HERV genes, such as HERV-W envelope (env) glycoprotein, are known to have intact open reading frames. The HERV-W element on 7q21.2, which encodes a protein referred to as Syncytin-1, participates in human placental morphogenesis and can activate a pro-inflammatory and autoimmune cascade. Neuropsychological disorders are typically linked to inflammatory abnormalities. In this study, we review that Syncytin-1 has been increasingly involved in the development of neuropsychological disorders, such as schizophrenia and multiple sclerosis (MS). This study also presents inflammation imbalances in schizophrenia and MS. More importantly, we discuss the potential role and molecular mechanisms by which Syncytin-1 regulates inflammatory abnormalities in neuropsychological diseases. In summary, Syncytin-1 activity may represent a novel molecular pathogenic mechanism in neuropyschological diseases, such as schizophrenia and MS. PMID- 30245644 TI - Mechanisms of Perceived Treatment Assignment and Subsequent Expectancy Effects in a Double Blind Placebo Controlled RCT of Major Depression. AB - Objective: It has been suggested that patients' perception of treatment assignment might serve to bias results of double blind randomized controlled trials (RCT). Most previous evidence on the effects of patients' perceptions and the mechanisms influencing these perceptions relies on cross-sectional associations. This re-analysis of a double blind, placebo controlled RCT of pharmacological treatment of major depression set out to gather longitudinal evidence on the mechanism and effects of patients' perceived treatment assignment in the pharmacological treatment of major depression. Methods: One-hundred eighty nine outpatients with DSM-IV diagnosed major depression were randomized to SAMe 1,600-3,200 mg/d, escitalopram 10-20 mg/days, or placebo for 12 weeks. Data on depressive symptoms (17-item Hamilton Depression Scale; HDRS-17), adverse events and patients' perceived treatment assignment was collected at baseline, week 6, and week 12. The re-analysis focused on N = 166 (out of the originally included 189 participants) with available data on perceived treatment assignment. Results: As in the parent trial, depressive symptoms (HDRS-17) significantly decreased over the course of 12 weeks and there was no difference between placebo, SAMe or escitalopram. A significant number of patients changed their perceptions about treatment assignment throughout the trial, especially between baseline and week 6. Improvement in depressive symptoms, but not adverse events significantly predicted perceived treatment assignment at week 6. In turn, perceived treatment assignment at week 6, but not actual treatment, predicted further improvement in depressive symptoms at week 12. Conclusions: The current results provide longitudinal evidence that patients' perception of treatment assignment systematically change despite a double blind procedure and in turn might trigger expectancy effects with the potential to bias the validity of an RCT. Parent study grant number: R01 AT001638 Parent study ClinicalTrials. gov Identifier: NCT00101452. PMID- 30245646 TI - Sensory Memory Is Allocated Exclusively to the Current Event-Segment. AB - The Atkinson-Shiffrin modal model forms the foundation of our understanding of human memory. It consists of three stores (Sensory Memory (SM), also called iconic memory, Short-Term Memory (STM), and Long-Term Memory (LTM)), each tuned to a different time-scale. Since its inception, the STM and LTM components of the modal model have undergone significant modifications, while SM has remained largely unchanged, representing a large capacity system funneling information into STM. In the laboratory, visual memory is usually tested by presenting a brief static stimulus and, after a delay, asking observers to report some aspect of the stimulus. However, under ecological viewing conditions, our visual system receives a continuous stream of inputs, which is segmented into distinct spatio temporal segments, called events. Events are further segmented into event segments. Here we show that SM is not an unspecific general funnel to STM but is allocated exclusively to the current event-segment. We used a Multiple-Object Tracking (MOT) paradigm in which observers were presented with disks moving in different directions, along bi-linear trajectories, i.e., linear trajectories, with a single deviation in direction at the mid-point of each trajectory. The synchronized deviation of all of the trajectories produced an event stimulus consisting of two event-segments. Observers reported the pre-deviation or the post-deviation directions of the trajectories. By analyzing observers' responses in partial- and full-report conditions, we investigated the involvement of SM for the two event-segments. The hallmarks of SM hold only for the current event segment. As the large capacity SM stores only items involved in the current event segment, the need for event-tagging in SM is eliminated, speeding up processing in active vision. By characterizing how memory systems are interfaced with ecological events, this new model extends the Atkinson-Shiffrin model by specifying how events are stored in the first stage of multi-store memory systems. PMID- 30245647 TI - Gender Differences in Meaningful Leisure Among Older Adults: Joint Displays of Four Phenomena. AB - Vital events, such as widowhood and retirement, are broadly accepted as points of inflection in the lives of older adults that often differ according to gender. In this study, we analyzed the influence of gender on meaningful leisure among older adults through the integration of qualitative and quantitative findings. The use of joint displays revealed that in this sample of people from Northern Spain: (1) there were no significant differences in the influence of retirement and widowhood on the leisure of the two genders, (2) the ethic of care was a constraining factor in older women's leisure, (3) women were more innovative in their leisure in older age, and (4) volunteer activities were highly segregated by gender. The use of joint displays helped illuminate these four phenomena in light of quantitative and qualitative data. PMID- 30245645 TI - Direct Experience While Eating in a Sample With Eating Disorders and Obesity. AB - Background: Individuals with eating disorders might be characterized by lower levels of direct engagement with the eating experience. This study aims to explore similarities and differences in direct experience while eating in four different weight conditions and healthy controls (HCs): anorexia nervosa (AN), bulimia nervosa (BN), eating disorders not otherwise specified (EDNOS), and obesity (OB). Methods: A total sample of 143 women were recruited. Participants were asked to eat an orange slice and write down 10 things about the experience of eating, classifying the focus of these thoughts as either experiential ("direct experience") or analytical ("thinking about"). A direct experience index (DEI) was calculated by dividing the number of times a participant classified an experience as a "direct experience" (the numerator) by the total number of observations. Participants completed the Five Facet Mindfulness Questionnaire (FFMQ) and rated their level of anxiety after the task. Results: Between-groups significant differences were found on the DEI, with individuals in the OB group scoring higher than AN and BN, and similar to HC. After the task, the AN group reported significantly higher anxiety levels than HC, and EDNOS reported more anxiety than HC and OB. Between-group significant differences were also found for all the FFMQ facets. Conclusion: AN and BN presented lower access to direct experience while eating. Individuals with OB did not respond in the same way as the other clinical groups, showing a similar performance to HC. PMID- 30245649 TI - The Prosodic Characteristics of Non-referential Co-speech Gestures in a Sample of Academic-Lecture-Style Speech. AB - Many studies have documented a close timing relationship between speech prosody and co-speech gesture, but some studies have not, and it is unclear whether these differences in speech-gesture alignment are due to different speaking tasks, different target gesture types, different prosodic elements, different definitions of alignment, or even different languages/speakers. This study contributes to the ongoing effort to elucidate the precise nature of the gesture speech timing relationship by examining an understudied variety of American English, i.e., academic-lecture-style speech, with a focus on an understudied type of gesture: Non-Referential gestures, which make up the majority of this corpus. Results for the 1,334 Stroke-Defined Gestures in this 20-min sample suggest that the stroke phase of a Non-Referential gesture tends to align with a pitch-accented syllable, just as reported in studies of other gesture types (e.g., deictic gestures) and in other speaking styles (such as narration). Preliminary results are presented suggesting that trajectory shapes of these Non Referential gestures are consistent across a higher-level prosodic grouping, supporting earlier proposals for kinematic constancy across spoken prosodic constituents (Kendon, 1972, 1980, 2004). Analysis also raises the possibility that the category of Non-Referential gestures is not solely made up of 'beats,' defined as simple bi-phasic flick-like movements that beat out the rhythm of the speech, but includes gestures with multiple phases and various types of rhythmicity. Taken together, the results of this analysis suggest (1) a wide range of gesture configurations within the undifferentiated category of Non Referential gestures or 'beats,' which requires further investigation, and (2) a close coordination between co-speech gestures and the prosodic structure of spoken utterances across speaking styles and gesture referentiality, which has profound implications for modeling the process of planning an utterance. PMID- 30245650 TI - Modeling Nonlinear Conditional Dependence Between Response Time and Accuracy. AB - The most common process variable available for analysis due to tests presented in a computerized form is response time. Psychometric models have been developed for joint modeling of response accuracy and response time in which response time is an additional source of information about ability and about the underlying response processes. While traditional models assume conditional independence between response time and accuracy given ability and speed latent variables (van der Linden, 2007), recently multiple studies (De Boeck and Partchev, 2012; Meng et al., 2015; Bolsinova et al., 2017a,b) have shown that violations of conditional independence are not rare and that there is more to learn from the conditional dependence between response time and accuracy. When it comes to conditional dependence between time and accuracy, authors typically focus on positive conditional dependence (i.e., relatively slow responses are more often correct) and negative conditional dependence (i.e., relatively fast responses are more often correct), which implies monotone conditional dependence. Moreover, most existing models specify the relationship to be linear. However, this assumption of monotone and linear conditional dependence does not necessarily hold in practice, and assuming linearity might distort the conclusions about the relationship between time and accuracy. In this paper we develop methods for exploring nonlinear conditional dependence between response time and accuracy. Three different approaches are proposed: (1) A joint model for quadratic conditional dependence is developed as an extension of the response moderation models for time and accuracy (Bolsinova et al., 2017b); (2) A joint model for multiple-category conditional dependence is developed as an extension of the fast slow model of Partchev and De Boeck (2012); (3) An indicator-level nonparametric moderation method (Bolsinova and Molenaar, in press) is used with residual log response time as a predictor for the item intercept and item slope. Furthermore, we propose using nonparametric moderation to evaluate the viability of the assumption of linearity of conditional dependence by performing posterior predictive checks for the linear conditional dependence model. The developed methods are illustrated using data from an educational test in which, for the majority of the items, conditional dependence is shown to be nonlinear. PMID- 30245651 TI - The Power of EI Competencies Over Intelligence and Individual Performance: A Task Dependent Model. AB - Prior research on emotional intelligence (EI) has highlighted the use of incremental models that assume EI and general intelligence (or g) make independent contributions to performance. Questioning this assumption, we study EI's moderation power over the relationship between g and individual performance, by designing and testing a task-dependent interaction model. Reconciling divergent findings in previous studies, we propose that whenever social tasks are at stake, g has a greater effect on performance as EI increases. By contrast, in analytic tasks, a compensatory (or negative) interaction is expected, whereby at higher levels of EI, g contributes to performance at a lesser extent. Based on a behavioral approach to EI, using 360-degree assessments of EI competencies, our findings show that EI moderates the effect of g on the classroom performance of 864 MBA business executives. Whilst in analytic tasks g has a stronger effect on performance at lower levels of EI competencies, our data comes short to show a positive interaction of EI and g in affecting performance on social tasks. Contributions and implications to research and practice are discussed. PMID- 30245652 TI - Trauma, Temperament, Alexithymia, and Dissociation Among Persons Addicted to Alcohol: Mediation Model of Dependencies. AB - Objective: The attachment theory has been conceptualized as an affect regulation theory, proposing that attachment is associated with the expression and recognition of emotions as well as interpersonal functioning. The purpose of the study was to examine a model, in which a relation was analyzed between childhood trauma, temperament, alexithymia, and dissociation in a group of individuals addicted to alcohol. Method: The total number of 201 persons were examined, comprising 67 women (33.3% of participants) and 134 men (66.7% of participants). The participants aged from 18 to 68 (M = 32.81; SD = 12.12). In order to measure the analyzed variables, the following questionnaires were applied: MAST, SSSV, TAS20, TEC, and CES. Results: A comparative analysis between the group of alcohol addicts and non-addicts showed statistically significant differences related to: the intensity of trauma, temperament, alexithymia, and dissociation. The study of models related to the impact of traumatic experience intensity on the level of alcohol addiction with regard to a mediatory role of alexithymia, dissociation, and temperament showed the existence of several important indirect effects, and the model, which takes into account all three mediators, is statistically significant F(4,196) = 35.1964; p < 0.001. Conclusion: Childhood trauma, as well as alexithymia and dissociation block dealing with stress based on self reflection and self-control, and contribute to affective disorders and their regulation with alcohol. Limitations: The selection of participants to homogeneous groups with regard to age and gender constituted the most important difficulty and limitation. A perfect age criterion for investigating the interaction between the temperament and the consequences of traumatic development would be early adulthood. PMID- 30245653 TI - How to Analyze (Intentional) Consciousness in Terms of Meta-Belief and Temporal Awareness. AB - The paper presents and defends a metadoxastic view on (intentional) consciousness that is novel in four respects: (1) It is motivated both by Husserl's dynamic approach, which looks upon mental acts as momentary components of certain cognitive structures - "dynamic intentional structures" - in which one and the same object is intended throughout a period of time (during which the subject's cognitive perspective upon that object is constantly changing) and by his conception of consciousness in terms of internal time-consciousness (temporal awareness). (2) It combines a dispositionalist higher-order judgment theory about the structure of (intentional) consciousness with the claim that the contents of these judgments are such that they can be expressed by essentially indexical sentences containing the temporal indexical "now," thus accommodating the basic role of internal time-consciousness. (3) It is immune against the "objection from lack of mental concepts" raised, e.g., by Dretske against any higher-order representation theory, as it employs counterfactuals in the framework of a disjunctive account of (intentional) consciousness. (4) It explains the unity of consciousness at a time as well as across time. PMID- 30245648 TI - Psychedelics, Meditation, and Self-Consciousness. AB - In recent years, the scientific study of meditation and psychedelic drugs has seen remarkable developments. The increased focus on meditation in cognitive neuroscience has led to a cross-cultural classification of standard meditation styles validated by functional and structural neuroanatomical data. Meanwhile, the renaissance of psychedelic research has shed light on the neurophysiology of altered states of consciousness induced by classical psychedelics, such as psilocybin and LSD, whose effects are mainly mediated by agonism of serotonin receptors. Few attempts have been made at bridging these two domains of inquiry, despite intriguing evidence of overlap between the phenomenology and neurophysiology of meditation practice and psychedelic states. In particular, many contemplative traditions explicitly aim at dissolving the sense of self by eliciting altered states of consciousness through meditation, while classical psychedelics are known to produce significant disruptions of self-consciousness, a phenomenon known as drug-induced ego dissolution. In this article, we discuss available evidence regarding convergences and differences between phenomenological and neurophysiological data on meditation practice and psychedelic drug-induced states, with a particular emphasis on alterations of self-experience. While both meditation and psychedelics may disrupt self consciousness and underlying neural processes, we emphasize that neither meditation nor psychedelic states can be conceived as simple, uniform categories. Moreover, we suggest that there are important phenomenological differences even between conscious states described as experiences of self-loss. As a result, we propose that self-consciousness may be best construed as a multidimensional construct, and that "self-loss," far from being an unequivocal phenomenon, can take several forms. Indeed, various aspects of self-consciousness, including narrative aspects linked to autobiographical memory, self-related thoughts and mental time travel, and embodied aspects rooted in multisensory processes, may be differently affected by psychedelics and meditation practices. Finally, we consider long-term outcomes of experiences of self-loss induced by meditation and psychedelics on individual traits and prosocial behavior. We call for caution regarding the problematic conflation of temporary states of self-loss with "selflessness" as a behavioral or social trait, although there is preliminary evidence that correlations between short-term experiences of self-loss and long term trait alterations may exist. PMID- 30245655 TI - Do Infants Attribute Moral Traits? Fourteen-Month-Olds' Expectations of Fairness Are Affected by Agents' Antisocial Actions. AB - We investigated whether and how infants link the domains of harm, help and fairness. Fourteen-month-old infants were familiarized with a character that either helped or hindered another agent's attempts to reach the top of a hill. Then, in the test phase they saw the helper or the hinderer carrying out an equal or an unequal distribution toward two identical recipients. Infants who saw the helper performing an unequal distribution looked longer than those who saw the helper performing an equal distribution, whereas infants who saw the hinderer performing an unequal distribution looked equally long than those who saw the hinderer performing an equal distribution. These results suggest that infants linked the hindering actions to a diminished propensity for distributive fairness. This provides support for theories that posit an early emerging ability to attribute moral traits to agents and to generate socio-moral evaluations of their actions. RESEARCH HIGHLIGHTS - Infants expect agents that previously helped another agent to perform egalitarian distributions, but they do not generate such expectation about agents that previously hindered another agent. - This ability to link hindering and distributive actions is important because it may help the development of reasoning about agents' stable moral traits. - Results provide support for recent theories on early social evaluation skills and they constraint theories on the acquisition of moral competence. PMID- 30245654 TI - Evolving Concepts of Emotion and Motivation. AB - This review takes a historical perspective on concepts in the psychology of motivation and emotion, and surveys recent developments, debates and applications. Old debates over emotion have recently risen again. For example, are emotions necessarily subjective feelings? Do animals have emotions? I review evidence that emotions exist as core psychological processes, which have objectively detectable features, and which can occur either with subjective feelings or without them. Evidence is offered also that studies of emotion in animals can give new insights into human emotions. Beyond emotion, motivation concepts have changed over decades too, and debates still continue. Motivation was once thought in terms of aversive drives, and reward was thought of in terms of drive reduction. Motivation-as-drive concepts were largely replaced by motivation-as-incentive concepts, yet aversive drive concepts still occasionally surface in reward neuroscience today. Among incentive concepts, incentive salience is a core motivation process, mediated by brain mesocorticolimbic systems (dopamine-related systems) and sometimes called 'wanting' (in quotation marks), to distinguish it from cognitive forms of desire (wanting without quotation marks). Incentive salience as 'wanting' is separable also from pleasure 'liking' for the same reward, which has important implications for several human clinical disorders. Ordinarily, incentive salience adds motivational urgency to cognitive desires, but 'wanting' and cognitive desires can dissociate in some conditions. Excessive incentive salience can cause addictions, in which excessive 'wanting' can diverge from cognitive desires. Conversely, lack of incentive salience may cause motivational forms of anhedonia in depression or schizophrenia, whereas a negatively-valenced form of 'fearful salience' may contribute to paranoia. Finally, negative 'fear' and 'disgust' have both partial overlap but also important neural differences. PMID- 30245656 TI - Why the Cells Look Like That - The Influence of Learning With Emotional Design and Elaborative Interrogations. AB - We investigated emotional design features that may influence multimedia learning with a self-generated learning (SGL) activity, namely answering elaborative interrogations. We assumed that a positive emotional design would be associated with a higher motivation to accomplish the additional SGL activity. Moreover, an interaction was expected: Learners learning with a positive emotional design should profit from learning with elaborative interrogations whereas learners learning with a negative emotional design would not profit from this strategy to the same extent but would rather benefit through reading. Since no negative emotional design existed yet, we additionally took the challenge to construct one. In a preliminary study, the emotional design features were pre-tested for their influence on emotional state and according to evaluation results, emotional design features were modified for the final versions. For the main study, German students (N = 228) were randomly assigned to one of six conditions that resulted from a 3 * 2 Design with emotional design (intended-positive vs. intended-neutral vs. intended-negative) and SGL activity (elaborative interrogations vs. no elaborative interrogations). Contrary to expectations, the intended-negative design worked not out as intended, but was rather comparable with the positive emotional design with respect to learners' emotional states. Learner motivation was higher when learning with the intended-negative emotional than the neutral design. The quality of the elaborated answers and learner motivation correlated positively with the performance of all learning outcome scores. For transfer questions which addressed the elaborated concepts, an interaction can be reported: learners learning with the positive emotional design benefitted from learning by reading compared to answering the elaborative interrogations. Regarding transfer questions whose concepts were explicitly described in the instructional material, it was better to learn with the intended-negative emotional than the neutral design. According to results of mediation analyses, the influence of motivation on learning outcomes could mostly be explained by the influence of motivation on answering the elaborative interrogations. Implications for creating emotional design as well as its effect on learning are discussed. PMID- 30245658 TI - The Predictive Value of Dyadic Coping in the Explanation of PTSD Symptoms and Subjective Well-Being of Work Accident Victims. AB - Objective: Work accidents may be considered dyadic stressors in so far as they not only affect the worker, but also the couple's relationship. Dyadic coping, as the process by which couples manage the stress experienced by each partner, can strengthen individual health and well-being as well as couple relationship functioning. Accidents at work have progressively been studied from a perspective that focuses on their negative effects on PTSS, anxiety, and depression. However, to a large extent, the dyadic coping processes and results following a work accident are still to be identified and clarified. In this study, we examined the predictive value of dyadic coping in the explanation of PTSS and subjective well being of work accident victims. Method: This study comprised a sample of 62 individuals involved in work accidents within the last 24 months (61.3% males) and their partners (N = 124; M = 46.25 years, SD = 11.18). All participants responded to the Dyadic Coping Inventory and the work accident victims also answered the PTSD Checklist - Civilian (PCL-C) and the Mental Health Continuum - Short Form (MHC-SF). Two hierarchical multiple regression analyses were performed using two different variable set models: Model 1 comprised the control variables gender and age, and Model 2 included the workers' and the partners' dyadic coping variables. Results: Results showed that dyadic coping reported by both workers and their respective partners (Model 2) was a significant predictor of workers' PTSS (p < 0.01) and subjective well-being (p < 0.001), explaining 31.2% of the variance in PCL-C and 68.7% in MHC-SF results. More specifically, the partners' supportive dyadic coping (by the self) and delegated dyadic coping (by the partner) were significant predictors of the workers' lower PTSS and virtually all the dyadic copying strategies of both the workers' and their partners' were significant predictors of the workers' higher subjective well-being. Conclusion: Dyadic coping of both the workers and their partners predicts the workers' PTSS and subjective well-being. These findings point to the need to work with couples who have experienced a work accident, with a view to improving the workers' mental health outcomes. PMID- 30245657 TI - Beyond Self-Report: A Review of Physiological and Neuroscientific Methods to Investigate Consumer Behavior. AB - The current paper investigates the value and application of a range of physiological and neuroscientific techniques in applied marketing research and consumer science, highlighting new insights from research in social psychology and neuroscience. We review measures of sweat secretion, heart rate, facial muscle activity, eye movements, and electrical brain activity, using techniques including skin conductance, pupillometry, eyetracking, and magnetic brain imaging. For each measure, after a brief explanation of the underlying technique, we illustrate concepts and mechanisms that the measure allows researchers in marketing and consumer science to investigate, with a focus on consumer attitudes and behavior. By providing reviews on recent research that applied these methods in consumer science and relevant related fields, we also highlight methodological and theoretical strengths and limitations, with an emphasis on ecological validity. We argue that the inclusion of physiological and neuroscientific techniques can advance consumer research by providing insights into the often unconscious mechanisms underlying consumer behavior. Therefore, such technologies can help researchers and marketing practitioners understand the mechanisms of consumer behavior and improve predictions of consumer behavior. PMID- 30245660 TI - Exploiting Language Variation to Better Understand the Cognitive Consequences of Bilingualism. AB - Within the past decade, there has been an explosion of research investigating the cognitive consequences of bilingualism. However, a controversy has arisen specifically involving research claiming a "bilingual advantage" in executive function. In this brief review, we re-examine the nature of the "bilingual advantage" and suggest three themes for future research. First, there must be a theoretical account of how specific variation in language experience impacts aspects of executive function and domain general cognition. Second, efforts toward adequately characterizing the participants tested will be critical to interpreting results. Finally, designing studies that employ converging analytical approaches and sensitive methodologies will be important to advance our knowledge of the dynamics between bilingual language experience and cognition. PMID- 30245659 TI - Reminders of Mortality Alter Pain-Evoked Potentials in a Chinese Sample. AB - Pain is of evolutionary importance to human survival. However, the perception of pain could be changed when death-related thoughts are accessible. Although the influence of mortality salience (MS) on pain processing has been investigated in Westerners recently, it is unclear whether this effect is constrained by specific culture context since humans may employ cultural worldviews to defend the existence problem. The current study tested whether and how MS affected pain processing in a Chinese male sample. We primed participants with sentences indicating MS or negative affect (NA) on either of two days. Both before and after the priming, event-related potentials (ERPs) elicited by painful and non painful electrical stimulations were recorded. Results showed that pain-evoked potentials were identified as an early negative complex N60-P90-N130 and a late positivity P260. Pain-evoked N130 after MS priming was larger than that after NA priming. Meanwhile, pain-evoked P260 decreased after MS priming but not after NA priming. These findings indicate that reminders of mortality affect both early sensory and late cognitive neural responses related to physical pain. Although previous studies reporting an increased effect of MS on perceived pain intensity in Westerners, we found an unchanged or possibly reduced effect in Chinese. Thus, the current work provides insight into a culture-sensitive perspective on how pain processing would be modulated when existential problem occurs. PMID- 30245661 TI - The Integrative Effects of Leading by Example and Follower Traits in Public Goods Game: A Multilevel Study. AB - As an important way to understand leadership based on voluntary contribution mechanisms, the importance of leading by example to teamwork is becoming more and more evident in recent years. However, existing theories based on signaling and reciprocity perspectives, respectively, provide incomplete theoretical explaining. This study adds clarity by conducting a cross-level study that indicates a possible integrative framework of both signaling and reciprocity perspective on leading by example. Results were using data gathered from 130 Chinese college students, which were allocated into one baseline group and three experimental groups. A hierarchical model was used to examine the effects of leading by example on different levels. It is found that leading by example has positive effects on the cooperation of followers on both the group level and the individual level. Risk attitudes have positive effects on the cooperation of followers while trust attitudes have negative effects. Our findings suggest that both leading by example and personal traits significantly influence cooperation but on different levels. It also reminds us that a more systematic way to understand leadership is needed. PMID- 30245662 TI - Language Dominance and Cognitive Flexibility in French-English Bilingual Children. AB - Some studies have reported a cognitive advantage for bilingual children over monolinguals and other studies have not. One possible reason for these conflicting results is that the degree of cognitive flexibility is related to individual differences in language dominance and use. More balanced bilinguals who separate their languages by context might have to learn to reduce inter language interference and therefore show greater cognitive flexibility. The goal of the present study was to test if language dominance is related to French English bilingual children's cognitive flexibility, using three different measures of language dominance: (1) parental reports of dominance, (2) relative scores on vocabulary tests, and (3) knowledge of translation equivalents. We also included two measures of language use: (1) living in a bilingual community (Montreal) or a monolingual community (Edmonton) and (2) language separation. Sixty-two French-English bilingual between 46 and 85 months of age participated. Children's cognitive flexibility was assessed using the Advanced Dimensional Change Card Sort task. Children's language knowledge and use was assessed in both French and English using a battery of tests. The results showed that none of the measures of language dominance or language use predicted cognitive flexibility. These results are inconsistent with the claim that individual differences in language dominance and use predict bilinguals' executive function s. PMID- 30245663 TI - A Bayesian Network Model for Predicting Post-stroke Outcomes With Available Risk Factors. AB - Bayesian network is an increasingly popular method in modeling uncertain and complex problems, because its interpretability is often more useful than plain prediction. To satisfy the core requirement in medical research to obtain interpretable prediction with high accuracy, we constructed an inference engine for post-stroke outcomes based on Bayesian network classifiers. The prediction system that was trained on data of 3,605 patients with acute stroke forecasts the functional independence at 3 months and the mortality 1 year after stroke. Feature selection methods were applied to eliminate less relevant and redundant features from 76 risk variables. The Bayesian network classifiers were trained with a hill-climbing searching for the qualified network structure and parameters measured by maximum description length. We evaluated and optimized the proposed system to increase the area under the receiver operating characteristic curve (AUC) while ensuring acceptable sensitivity for the class-imbalanced data. The performance evaluation demonstrated that the Bayesian network with selected features by wrapper-type feature selection can predict 3-month functional independence with an AUC of 0.889 using only 19 risk variables and 1-year mortality with an AUC of 0.893 using 24 variables. The Bayesian network with 50 features filtered by information gain can predict 3-month functional independence with an AUC of 0.875 and 1-year mortality with an AUC of 0.895. We also built an online prediction service, Yonsei Stroke Outcome Inference System, to substantialize the proposed solution for patients with stroke. PMID- 30245664 TI - Excitability of Rat Superficial Dorsal Horn Neurons Following a Neonatal Immune Challenge. AB - Previous studies have shown that neonatal exposure to a mild inflammatory challenge, such as lipopolysaccharide (LPS, Salmonella enteriditis) results in altered pain behaviors later in life. To further characterize the impact of a neonatal immune challenge on pain processing, we examined the excitability of superficial dorsal horn (SDH) neurons following neonatal LPS exposure and subsequent responses to noxious stimulation at three time-points during early postnatal development. Wistar rats were injected with LPS (0.05 mg/kg i.p.) or saline on postnatal days (PNDs) 3 and 5, and later subjected to the formalin test at PNDs 7, 13, and 22. One hour after formalin injection into the plantar hindpaw, animals were euthanized (Ketamine, 100 mg/kg i.p.) and transverse slices from the lumbosacral spinal cord were prepared. Whole-cell patch-clamp recordings were made from SDH neurons (KCH3SO4-based internal, 22-24 degrees C) on the ipsi- and contralateral sides of the spinal cord. Depolarising current steps were injected into SDH neurons to categorize action potential (AP) discharge. In both saline- and LPS-treated rats we observed age-related increases the percentage of neurons exhibiting tonic-firing, with concurrent decreases in single-spiking, between PND 7 and 22. In contrast, neonatal exposure to LPS failed to alter the proportions of AP discharge patterns at any age examined. We also assessed the subthreshold currents that determine AP discharge in SDH neurons. The rapid outward potassium current, IAr decreased in prevalence with age, but was susceptible to neonatal LPS exposure. Peak IAr current amplitude was greater in ipsilateral vs. contralateral SDH neurons from LPS-treated rats. Spontaneous excitatory synaptic currents (sEPSCs) were recorded to assess network excitability. Age-related increases were observed in sEPSC frequency and time course, but not peak amplitude, in both saline- and LPS-treated rats. Furthermore, sEPSC frequency was higher in ipsilateral vs. contralateral SDH neurons in LPS-treated animals. Taken together, these data suggest a neonatal immune challenge does not markedly affect the intrinsic properties of SDH neurons, however, it can increase the excitability of local spinal cord networks via altering the properties of rapid A-type currents and excitatory synaptic connections. These changes, made in neurons within spinal cord pain circuits, have the capacity to alter nociceptive signaling in the ascending pain pathway. PMID- 30245665 TI - Headache Secondary to Isolated Sphenoid Sinus Fungus Ball: Retrospective Analysis of 6 Cases First Diagnosed in the Neurology Department. AB - Fungal sphenoid sinusitis is easily misdiagnosed in clinic, particularly for patients with normal immunological status. Due to the anatomic characteristics of sphenoid sinus, patients presented with various nonspecific symptoms and complications. Headache is the most common presentation, but location of headache is not fixed. We intended to analyze 6 cases of headache secondary to the isolated sphenoid sinus fungus ball (SSFB) which were first diagnosed in the Neurology Department. There was significant female predominance with mean ages of 55 years. They had repeatedly headache history from months to years. The headache was unilateral and usually on the side of lesions. Medication of pain relievers worked well in the beginning of SSFB, but not in the late stage of disease. Notably, all patients did not present positive nervous systemic signs. A preoperative computed tomography (CT) scan or magnetic resonance imaging (MRI) demonstrated the inflammation in sphenoid sinus. Some cases showed calcification in soft tissue or bone lesions of sinus wall. All of 6 patients undertook transnasal endoscopic sphenoidotomy without antifungal therapy after operation. Characteristic fungus ball (FB) was detected after histopathological examination. No headache recurrence was found after average 15.5 months follow-up. Our results suggested that transnasal endoscopic sphenoidotomy is the treatment of choice to remove the FB in sphenoid sinus with a low rate of morbidity and recurrence. PMID- 30245666 TI - Driving Ability in Alzheimer Disease Spectrum: Neural Basis, Assessment, and Potential Use of Optic Flow Event-Related Potentials. AB - Driving requires multiple cognitive functions including visuospatial perception and recruits widespread brain networks. Recently, traffic accidents in dementia, particularly in Alzheimer disease spectrum (ADS), have increased and become an urgent social problem. Therefore, it is necessary to develop the objective and reliable biomarkers for driving ability in patients with ADS. Interestingly, even in the early stage of the disease, patients with ADS are characterized by the impairment of visuospatial function such as radial optic flow (OF) perception related to self-motion perception. For the last decade, we have studied the feasibility of event-related potentials (ERPs) in response to radial OF in ADS and proposed that OF-ERPs provided an additional information on the alteration of visuospatial perception in ADS (1, 2). Hence, we hypothesized that OF-ERPs can be a possible predictive biomarker of driving ability in ADS. In this review, the recent concept of neural substrates of driving in healthy humans are firstly outlined. Second, we mention the alterations of driving performance and its brain network in ADS. Third, the current status of assessment tools for driving ability is stated. Fourth, we describe ERP studies related to driving ability in ADS. Further, the neural basis of OF processing and OF-ERPs in healthy humans are mentioned. Finally, the application of OF-ERPs to ADS is described. The aim of this review was to introduce the potential use of OF-ERPs for assessment of driving ability in ADS. PMID- 30245667 TI - 24S-Hydroxycholesterol Correlates With Tau and Is Increased in Cerebrospinal Fluid in Parkinson's Disease and Corticobasal Syndrome. AB - 24S-hydroxycholesterol (24OHC) and Tau are produced in neuronal cells and neurodegeneration leads to increased flux of both of them into cerebrospinal fluid (CSF). In the present study, CSF levels of 24OHC and 27S-hydroxycholesterol (27OHC) along with those of Tau, P-Thr181-Tau and Abeta42 were measured in patients with early Parkinson's disease (PD), Corticobasal syndrome (CBS), Corticobasal Degeneration (CBD), and controls. Using mouse models with increased or no formation of Tau protein and increased production of 24OHC, we have also tested the hypothesis that there is a direct association between neuronal turnover of 24OHC and Tau. The levels of 24OHC are increased, at a group level, in patients with PD or CBS. We found significant correlations between levels of 24OHC and Tau or P-Thr181-Tau in CSF from patients with PD, CBS or CBD. There were no similar correlations between 24OHC and Abeta42 in CSF from these patients. The neuronal levels of 24OHC were not altered in Tau knockout or Tau overexpressing mice. Vice versa, Tau species levels were not changed in Cyp46 overexpressing mice with increased neuronal levels of 24OHC. We conclude that the strongly correlative fluxes of 24OHC and Tau from neuronal cells to CSF are likely to be secondary to neurodegeneration and not due to direct interaction between the two factors. We suggest that this high correlation reflects a rapid neurodegeneration of specific neuronal subtypes with simultaneous release of 24OHC and Tau into the CSF. PMID- 30245668 TI - Multimodal Treatment of Bone Metastasis-A Surgical Perspective. AB - Over the past decades there has been an increase in the incidence of cancer worldwide. With the advancement in treatment, patient survival has improved in tandem with the increasing incidence. This, together with the availability of advanced modern diagnostic modalities, has resulted in more cases of metastatic bone disease being identified. Bone metastasis is an ongoing problem and has significant morbidity implications for patients affected. Multimodal treatment strategies are required in dealing with metastatic bone disease, which include both surgical and non-surgical treatment options. In the multidisciplinary team, orthopedic surgeons play an important role in improving the quality of life of cancer patients. Surgical intervention in this setting is aimed at pain relief, restoration of function and improvement in functional independence. In selected cases with resectable solitary metastasis, surgical treatment may be curative. With the advancement of surgical technique and improvement in implant design and manufacture, a vast array of surgical options are available in the modern orthopedic arena. In the majority of cases, limb salvage procedures have become the standard of care in the treatment of metastatic bone disease. Non-surgical adjuvant treatment also contributes significantly to the improvement of cancer patient care. A multidisciplinary approach in this setting is of paramount importance. PMID- 30245670 TI - Helicobacter pylori Outer Membrane Vesicles Protect the Pathogen From Reactive Oxygen Species of the Respiratory Burst. AB - Outer membrane vesicles (OMVs) play an important role in the persistence of Helicobacter pylori infection. Helicobacter OMVs carry a plethora of virulence factors, including catalase (KatA), an antioxidant enzyme that counteracts the host respiratory burst. We found KatA to be enriched and surface-associated in OMVs compared to bacterial cells. This conferred OMV-dependent KatA activity resulting in neutralization of H2O2 and NaClO, and rescue of surrounding bacteria from oxidative damage. The antioxidant activity of OMVs was abolished by deletion of KatA. In conclusion, enrichment of antioxidative KatA in OMVs is highly important for efficient immune evasion. PMID- 30245669 TI - Differences in the Gut Microbiota Establishment and Metabolome Characteristics Between Low- and Normal-Birth-Weight Piglets During Early-Life. AB - Low-birth-weight (LBW) piglets are at a high-risk for postnatal growth failure, mortality, and metabolic disorders later in life. Early-life microbial exposure is a potentially effective intervention strategy for modulating the health and metabolism of the host. Yet, it has not been well elucidated whether the gut microbiota development in LBW piglets is different from their normal littermates and its possible association with metabolite profiles. In the current study, 16S rRNA gene sequencing and metabolomics was used to investigate differences in the fecal microbiota and metabolites between LBW and normal piglets during early life, including day 3 (D3), 7 (D7), 14 (D14), 21 (D21, before weaning), and 35 (D35, after birth). Compared to their normal littermates, LBW piglets harbored low proportions of Faecalibacterium on D3, Flavonifractor on D7, Lactobacillus, Streptococcus, and Prevotella on D21, as well as Howardella on D21 and D35. However, the abundance of Campylobacter on D7 and D21, Prevotella on D14 and D35, Oscillibacter and Moryella on D14 and D21, and Bacteroides on D21 was significantly higher in LBW piglets when compared with normal piglets. The results of the metabolomics analysis suggested that LBW significantly affected fecal metabolites involved in fatty acid metabolism (e.g., linoleic acid, alpha linolenic acid, and arachidonic acid), amino acid metabolism (e.g., valine, phenylalanine, and glutamic acid), as well as bile acid biosynthesis (e.g., glycocholic acid, 25-hydroxycholesterol, and chenodeoxycholic acid). Spearman correlation analysis revealed a significant negative association between Campylobacter and N1-acetylspermine on D7, Moryella and linoleic acid on D14, Prevotella and chenodeoxycholic acid on D21, and Howardella and phenylalanine on D35, respectively. Collectively, LBW piglets have a different gut bacterial community structure when compared with normal-birth-weight (NBW) piglets during early-life, especially from 7 to 21 days of age. Also, a distinctive metabolic status in LBW piglets might be partly associated with the altered intestinal microbiota. These findings may further elucidate the factors potentially associated with the impaired growth and development of LBW piglets and facilitate the development of nutritional interventions. PMID- 30245671 TI - Polyphosphate in Lactobacillus and Its Link to Stress Tolerance and Probiotic Properties. AB - The synthesis of the inorganic polymer polyphosphate (poly-P) in bacteria has been linked to stress survival and to the capacity of some strains to sequester heavy metals. In addition, synthesis of poly-P by certain strains of probiotic lactobacilli has been evidenced as a probiotic mechanism due to the homeostatic properties of this compound at the intestinal epithelium. We analyzed the link between poly-P synthesis, stress response, and mercury toxicity/accumulation by comparing wild-type strains of Lactobacillus and their corresponding mutants devoid of poly-P synthesis capacity (defective in the poly-P kinase, ppk, gene). Results showed that resistance to salt (NaCl) and acidic (pH 4) stresses upon ppk mutation was affected in Lactobacillus casei, while no effect was observed in two different Lactobacillus plantarum strains. Inorganic [Hg(II)] and organic (CH3Hg) mercury toxicity was generally increased upon ppk mutation, but no influence was seen on the capacity to retain both mercurial forms by the bacteria. Notwithstanding, the culture supernatants of ppk-defective L. plantarum strains possessed a diminished capacity to induce HSP27 expression, a marker for cell protection, in cultured Caco-2 cells compared to wild-type strains. In summary, our results illustrate that the role of poly-P in stress tolerance can vary between strains and they reinforce the idea of probiotic-derived poly-P as a molecule that modulates host-signaling pathways. They also question the relevance of this polymer to the capacity to retain mercury of probiotics. PMID- 30245672 TI - Blood or Serum Exposure Induce Global Transcriptional Changes, Altered Antigenic Profile, and Increased Cytotoxicity by Classical Bordetellae. AB - The classical bordetellae sense and respond to a variety of environments outside and within their mammalian hosts. By causing inflammation and tissue damage, we reasoned that bordetellae are likely to encounter components of blood and/or serum during the course of a respiratory infection, and that detecting and responding to these would be advantageous. Therefore, we hypothesized that classical bordetellae have the ability to sense and respond to blood or serum. Blood or serum exposure resulted in substantial transcriptional changes in Bordetella bronchiseptica, including enhanced expression of many virulence associated genes. Exposure to blood or serum additionally elicited production of multiple antigens not otherwise detectable, and led to increased bacterial cytotoxicity against macrophages. Transcriptional responses to blood/serum were observed in a Bvg- phase-locked mutant, indicating that the response is not solely dependent on a functional BvgAS system. Similar transcriptional responses to blood/serum were observed for the other classical bordetellae, Bordetella pertussis and Bordetella parapertussis. These data suggest the classical bordetellae respond to signals present in blood and serum by changing their behavior in ways that likely contribute to their remarkable success, via effects on pathogenesis, persistence and/or transmission between hosts. PMID- 30245674 TI - Tedizolid Activity Against Clinical Mycobacterium abscessus Complex Isolates-An in vitro Characterization Study. AB - Mycobacterium abscessus complex consist of three rapidly growing subspecies: M. abscessus, M. massiliense, and M. bolletii. They are clinically important human pathogens responsible for opportunistic pulmonary and skin and soft tissue infections. Treatment of M. abscessus infections is difficult due to in vitro resistance to most antimicrobial agents. Tedizolid (TZD) is a next-generation oxazolidinone antimicrobial with a wide spectrum of activity even against multidrug resistant Gram-positive bacteria. In this study, the in vitro activity of TZD against the M. abscessus complex (n = 130) was investigated. Susceptibility testing by broth microdilution showed lower TZD minimum inhibitory concentrations (MICs) when compared to linezolid. The MIC50 and MIC90 was 1 mg/L and 4 mg/L, respectively across all M. abscessus complex members, reflecting no difference in subspecies response to TZD. Pre-exposure of M. abscessus complex to subinhibitory concentrations of TZD did not trigger any inducible drug resistance. Single-drug time kill assays and bactericidal activity assays demonstrated bacteriostatic activity of TZD in all three M. abscessus subspecies, even at high drug concentrations of 4 to 8x MIC. Combination testing of TZD with clarithromycin, doxycycline and amikacin using the checkerboard approach showed no antagonistic interactions. TZD may be an effective therapeutic antimicrobial agent for the treatment of M. abscessus infections. PMID- 30245675 TI - Comparative Genomic Analysis and Characterization of Two Salmonella enterica Serovar Enteritidis Isolates From Poultry With Notably Different Survival Abilities in Egg Whites. AB - Salmonellaenterica serovar Enteritidis (Salmonella Enteritidis) is a globally important foodborne pathogen, and the contaminated chicken eggs are the major source of salmonellosis in humans. Salmonella Enteritidis strains are differentially susceptible to the hostile environment of egg whites. Strains with superior survival ability in egg whites are more likely to contaminate eggs and consequently infect humans. However, the genetic basis for this phenotype is unclear. We characterized two Salmonella Enteritidis strains isolated from chicken meat that had similar genetic backgrounds but large differences in survival ability in egg whites. Although genome comparisons indicated that the gene content and genomic synteny were highly conserved, variations including six insertions or deletions (INDELs) and 70 single nucleotide polymorphisms (SNPs) were observed between the two genomes. Of these, 38 variations including four INDELs and 34 non-synonymous SNPs (nsSNP) were annotated to result in amino acid substitutions or INDELs in coding proteins. These variations were located in 38 genes involved in lysozyme inhibition, vitamin biosynthesis, cell division and DNA damage response, osmotic and oxidative protection, iron-related functions, cell envelope maintenance, amino acid and carbohydrate metabolism, antimicrobial resistance, and type III secretion system. We carried out allelic replacements for two nsSNPs in bioC (biotin synthesis) and pliC (lysozyme inhibition), and two INDELs in ftsK and yqiJ (DNA damage response) by homologous recombination, and these replacements did not alter the bacterial survival ability in egg whites. However, the bacterial survival ability in egg whites was reduced when deletion mutation of the genes bioC and pliC occurred. This study provides initial correlations between observed genotypes and phenotypes and serves as an important caveat for further functional studies. PMID- 30245673 TI - Investigating the Composition and Metabolic Potential of Microbial Communities in Chocolate Pots Hot Springs. AB - Iron (Fe) redox-based metabolisms likely supported life on early Earth and may support life on other Fe-rich rocky planets such as Mars. Modern systems that support active Fe redox cycling such as Chocolate Pots (CP) hot springs provide insight into how life could have functioned in such environments. Previous research demonstrated that Fe- and Si-rich and slightly acidic to circumneutral pH springs at CP host active dissimilatory Fe(III) reducing microorganisms. However, the abundance and distribution of Fe(III)-reducing communities at CP is not well-understood, especially as they exist in situ. In addition, the potential for direct Fe(II) oxidation by lithotrophs in CP springs is understudied, in particular when compared to indirect oxidation promoted by oxygen producing Cyanobacteria. Here, a culture-independent approach, including 16S rRNA gene amplicon and shotgun metagenomic sequencing, was used to determine the distribution of putative Fe cycling microorganisms in vent fluids and sediment cores collected along the outflow channel of CP. Metagenome-assembled genomes (MAGs) of organisms native to sediment and planktonic microbial communities were screened for extracellular electron transfer (EET) systems putatively involved in Fe redox cycling and for CO2 fixation pathways. Abundant MAGs containing putative EET systems were identified as part of the sediment community at locations where Fe(III) reduction activity has previously been documented. MAGs encoding both putative EET systems and CO2 fixation pathways, inferred to be FeOB, were also present, but were less abundant components of the communities. These results suggest that the majority of the Fe(III) oxides that support in situ Fe(III) reduction are derived from abiotic oxidation. This study provides new insights into the interplay between Fe redox cycling and CO2 fixation in sustaining chemotrophic communities in CP with attendant implications for other neutral-pH hot springs. PMID- 30245676 TI - Identification of Enantiomeric Byproducts During Microalgae-Mediated Transformation of Metoprolol by MS/MS Spectrum Based Networking. AB - Metoprolol (MPL) is a chiral beta-blocker ubiquitously detected in various environments due to its low to moderate removal in wastewater treatment plants. This study was conducted to test the potential of using microalgae to degrade emerging contaminant MPL and to characterize the enantiomeric enrichment during MPL degradation by microalgae. The results showed that PO43-- P, NO3-- N and MPL could be simultaneously removed in the synthetic effluent by the targeted microalgae species, indicating microalgae were promising in wastewater treatment. Stereoselectivity was observed during MPL degradation by microalgae, with R-form enrichment. A marginal linear relationship between MPL degradation and enantiomeric enrichment was observed, implying that the enantiomeric tool, used as a quantitative indicator of biodegradation, could possibly be applied in MPL degradation by microalgae. An efficient liquid chromatograph tandem high resolution mass spectrometry (LC-HRMS/MS) chiral analytical method was developed to identify transformation products (TPs). The results showed that MS/MS spectral similarity networking could be used as a powerful tool to quickly identify unknown TPs. A total of 6 pairs of chiral TPs were identified, among which two new TPs of MPL including hydroxy{4-[2-hydroxy-3 (isopropylamino)propoxy]phenyl}acetic acid (alpha-HMPLA) and 4-[2-Hydroxy-3 (isopropylamino)propoxy]benzaldehyde (DMPLD) were firstly reported, and proposed transformation pathways of MPL by microalgae were given. Considering the paired TPs detected and that the degradation of the two enantiomers followed first order kinetics, the two enantiomers likely had the same degradation mechanism. PMID- 30245677 TI - Antimicrobial Effect of Asiatic Acid Against Clostridium difficile Is Associated With Disruption of Membrane Permeability. AB - Antibiotic resistance is a major concern in Clostridium difficile, the causative agent of antibiotic-associated diarrhea. Reduced susceptibility to first- and second-line agents is widespread, therefore various attempts have been made to seek alternative preventive and therapeutic strategies against this pathogen. In this work, the antimicrobial properties of asiatic acid were evaluated against C. difficile. Asiatic acid displayed substantial inhibitory effects on 19 C. difficile isolates collected from different sources with minimal inhibitory concentrations ranging from 10 to 20 MUg/ml. Time kill analysis and minimal bactericidal concentration revealed potential bactericidal activity of this compound. Asiatic acid induced membrane damages and alterations in morphological ultrastructure in C. difficile, thereby causing the leakage of intracellular substances. Moreover, asiatic acid also displayed an inhibitory effect on cell motility, but did not interfere with biofilm formation and spore germination. Analysis of drug combination showed no synergistic effect between asiatic acid and vancomycin/metronidazole. Altogether, asiatic acid exhibited strong antimicrobial activity against vegetative cells and could serve as an alternative resource for tackling C. difficile. PMID- 30245678 TI - Biogeochemical Cycling by a Low-Diversity Microbial Community in Deep Groundwater. AB - Olkiluoto, an island on the south-west coast of Finland, will host a deep geological repository for the storage of spent nuclear fuel. Microbially induced corrosion from the generation of sulphide is therefore a concern as it could potentially compromise the longevity of the copper waste canisters. Groundwater at Olkiluoto is geochemically stratified with depth and elevated concentrations of sulphide are observed when sulphate-rich and methane-rich groundwaters mix. Particularly high sulphide is observed in methane-rich groundwater from a fracture at 530.6 mbsl, where mixing with sulphate-rich groundwater occurred as the result of an open drill hole connecting two different fractures at different depths. To determine the electron donors fuelling sulphidogenesis, we combined geochemical, isotopic, metagenomic and metaproteomic analyses. This revealed a low diversity microbial community fuelled by hydrogen and organic carbon. Sulphur and carbon isotopes of sulphate and dissolved inorganic carbon, respectively, confirmed that sulphate reduction was ongoing and that CO2 came from the degradation of organic matter. The results demonstrate the impact of introducing sulphate to a methane-rich groundwater with limited electron acceptors and provide insight into extant metabolisms in the terrestrial subsurface. PMID- 30245679 TI - Sialic Acid-Like Sugars in Archaea: Legionaminic Acid Biosynthesis in the Halophile Halorubrum sp. PV6. AB - N-glycosylation is a post-translational modification that occurs in all three domains. In Archaea, however, N-linked glycans present a degree of compositional diversity not observed in either Eukarya or Bacteria. As such, it is surprising that nonulosonic acids (NulOs), nine-carbon sugars that include sialic acids, pseudaminic acids, and legionaminic acids, are routinely detected as components of protein-linked glycans in Eukarya and Bacteria but not in Archaea. In the following, we report that the N-linked glycan attached to the S-layer glycoprotein of the haloarchaea Halorubrum sp. PV6 includes an N-formylated legionaminic acid. Analysis of the Halorubrum sp. PV6 genome led to the identification of sequences predicted to comprise the legionaminic acid biosynthesis pathway. The transcription of pathway genes was confirmed, as was the co-transcription of several of these genes. In addition, the activities of LegI, which catalyzes the condensation of 2,4-di-N-acetyl-6-deoxymannose and phosphoenolpyruvate to generate legionaminic acid, and LegF, which catalyzes the addition of cytidine monophosphate (CMP) to legionaminic acid, both heterologously expressed in Haloferax volcanii, were demonstrated. Further genome analysis predicts that the genes encoding enzymes of the legionaminic acid biosynthetic pathway are clustered together with sequences seemingly encoding components of the N-glycosylation pathway in this organism. In defining the first example of a legionaminic acid biosynthesis pathway in Archaea, the findings reported here expand our insight into archaeal N-glycosylation, an almost universal post-translational modification in this domain of life. PMID- 30245680 TI - A Novel Natural Antimicrobial Can Reduce the in vitro and in vivo Pathogenicity of T6SS Positive Campylobacter jejuni and Campylobacter coli Chicken Isolates. AB - Human campylobacteriosis is considered one of the most common foodborne diseases worldwide with poultry identified as the main source of infection accounting for 50-80% of human cases. Highly virulent Campylobacter spp., positive for the Type VI secretion system (T6SS), which have an increased ability to adhere to and invade the host gastrointestinal epithelium are highly prevalent in poultry. Multidrug resistant strains of bacteria are rapidly evolving and therefore, new antimicrobials to supplement animal feed that are able to control Campylobacter species, are in great need. The work presented herein indicates that a novel phenolic antimicrobial, Auranta 3001, is able to reduce the adhesion and invasion of human intestinal epithelial cells (HCT-8) by two T6SS positive chicken isolates, C. jejuni RC039 (p < 0.05) and C. coli RC013 (p < 0.001). Exposure of C. jejuni RC039 and C. coli RC013 to Auranta 3001 downregulated the expression of hcp and cetB genes, known to be important in the functionality of T6SS. Furthermore, the reduced adhesion and invasion is associated with a significant decrease in bacterial motility of both isolates (p < 0.05-p < 0.001) in vitro. Most importantly our in vivo results show that Auranta 3001 is able to reduce cecum colonization levels from log 8 CFU/ml to log 2 CFU/ml for C. jejuni RC039 and from log 7 CFU/ml to log 2 CFU/ml for C. coli RC013. In conclusion, this novel antimicrobial is able to reduce the pathogenic properties of T6SS campylobacters in vitro and also to decrease colonization in vivo. PMID- 30245681 TI - Investigation of Detection Limits and the Influence of DNA Extraction and Primer Choice on the Observed Microbial Communities in Drinking Water Samples Using 16S rRNA Gene Amplicon Sequencing. AB - In recent years, 16S rRNA gene amplicon sequencing has been widely adopted for analyzing the microbial communities in drinking water (DW). However, no comprehensive attempts have been made to illuminate the inherent method biases specifically relating to DW communities. In this study, we investigated the impact of DNA extraction and primer choice on the observed microbial community, and furthermore estimated the detection limit of the 16S rRNA gene amplicon sequencing in these experimental settings. Of the two DNA extraction kits investigated, the PowerWater DNA Isolation Kit resulted in higher yield, better reproducibility and more OTUs identified compared to the FastDNA SPIN Kit for Soil, which is also commonly used within DW microbiome research. The use of three separate primer-sets targeting the V1-3, V3-4, and V4 region of the 16S rRNA gene revealed large differences in OTU abundances, with some of the primers unable to detect entire phyla. Estimations of the detection limit were based on bacteria free water samples (1 L) spiked with Escherichia coli cells in different concentrations [101-106 cells/ml]. E.coli could be detected in all samples, however, samples with ~101 cells/ml had several contaminating OTUs constituting approximately 8% of the read abundances. Based on our findings, we recommend using the PowerWater DNA Isolation Kit for DNA extraction in combination with PCR amplification of the V3-4 or V4 region for DW samples if a broad overview of the microbial community is to be obtained. PMID- 30245682 TI - Bacteria Display Differential Growth and Adhesion Characteristics on Human Hair Shafts. AB - Apart from the skin surface, hair represents a significant tissue component with a capacity of bacterial interactions. New information can be obtained about hair function through the characterization of bacterial adherence, colonization, and responses to hair shafts per se. In this proof-of-principle study, we examine the growth kinetics of Gram-positive Staphylococcus aureus and Staphylococcus epidermidis, and Gram-negative Pseudomonas aeruginosa and Escherichia coli in the presence of human hair shafts. We explore the ability of these bacteria to adhere to and colonize hair shaft surfaces, as well as the resulting impact on the hair's surface morphology. We show that hair shafts inhibit the growth of Gram positive S. aureus and S. epidermidis, while the growth kinetics of P. aeruginosa and E. coli remain unaffected. Scanning electron microscope analysis and steeping studies show that P. aeruginosa and E. coli to adhere to and colonize on human hair shafts without significantly affecting the hair shaft's surface morphology. P. aeruginosa produced a substantial amount of biofilm on the hair shaft surfaces, while E. coli specifically inhabited the edges of the cuticle scales. Taken together, our results demonstrate differences in bacterial responses to human hair shafts, which may provide novel insights into hair and scalp health. PMID- 30245683 TI - A Comparative Analysis of Microbial DNA Preparation Methods for Use With Massive and Branching Coral Growth Forms. AB - In the last two decades, over 100 studies have investigated the structure of the coral microbiome. However, as yet there are no standardized methods applied to sample preservation and preparation, with different studies using distinct methods. There have also been several comparisons made of microbiome data generated across different studies, which have not addressed the influence of the methodology employed over each of the microbiome datasets. Here, we assess three different preservation methods; salt saturated dimethyl sulfoxide (DMSO) - EDTA, snap freezing with liquid nitrogen and 4% paraformaldehyde solution, and two different preparation methodologies; bead beating and crushing, that have been applied to study the coral microbiome. We compare the resultant bacterial assemblage data for two coral growth forms, the massive coral Goniastrea edwardsi and the branching coral Isopora palifera. We show that microbiome datasets generated from differing preservation and processing protocols are comparable in composition (presence/absence). Significant discrepancies between preservation and homogenization methods are observed in structure (relative abundance), and in the occurrence and dominance of taxa, with rare (low abundance and low occurrence) phylotypes being the most variable fraction of the microbial community. Finally, we provide evidence to support chemical preservation with DMSO as effective as snap freezing samples for generating reliable and robust microbiome datasets. In conclusion, we recommend where possible a standardized preservation and extraction method be taken up by the field to provide the best possible practices for detailed assessments of symbiotic and conserved bacterial associations. PMID- 30245684 TI - The Role of Outer Membrane Proteins and Lipopolysaccharides for the Sensitivity of Escherichia coli to Antimicrobial Peptides. AB - Bacterial resistance to classical antibiotics is emerging worldwide. The number of infections caused by multidrug resistant bacteria is increasing and becoming a serious threat for human health globally. In particular, Gram-negative pathogens including multidrug resistant Escherichia coli are of serious concern being resistant to the currently available antibiotics. All Gram-negative bacteria are enclosed by an outer membrane which acts as an additional protection barrier preventing the entry of toxic compounds including antibiotics and antimicrobial peptides (AMPs). In this study we report that the outer membrane component lipopolysaccharide (LPS) plays a crucial role for the antimicrobial susceptibility of E. coli BW25113 against the cationic AMPs Cap18, Cap11, Cap11-1 18m2, melittin, indolicidin, cecropin P1, cecropin B, and the polypeptide antibiotic colistin, whereas the outer membrane protease OmpT and the lipoprotein Lpp only play a minor role for the susceptibility against cationic AMPs. Increased susceptibility toward cationic AMPs was found for LPS deficient mutants of E. coli BW25113 harboring deletions in any of the genes required for the inner part of core-oligosaccharide of the LPS, waaC, waaE, waaF, waaG, and gmhA. In addition, our study demonstrates that the antimicrobial activity of Cap18, Cap11, Cap11-1-18m2, cecropin B, and cecropin P1 is not only dependent on the inner part of the core oligosaccharide, but also on the outer part and its sugar composition. Finally, we demonstrated that the antimicrobial activity of selected Cap18 derivatives harboring amino acid substitutions in the hydrophobic interface, are non-active against wild-type E. coli ATCC29522. By deleting waaC, waaE, waaF, or waaG the antimicrobial activity of the non-active derivatives can be partially or fully restored, suggesting a very close interplay between the LPS core oligosaccharide and the specific Cap18 derivative. Summarizing, this study implicates that the nature of the outer membrane component LPS has a big impact on the antimicrobial activity of cationic AMPs against E. coli. In particular, the inner as well as the outer part of the core oligosaccharide are important elements determining the antimicrobial susceptibility of E. coli against cationic AMPs. PMID- 30245685 TI - Thymopoiesis in Pre- and Post-Hematopoietic Stem Cell Transplantation. AB - Hematopoietic stem cell transplantation (HSCT) is an important therapeutic option for some hematological diseases. However, patients who undergo HSCT acquire a state of immunodeficiency that causes significant mortality. Reconstitution of thymic function is needed to support the immune system. One way to measure thymic function is through T-cell receptor excision circle (TREC) quantification. TRECs are generated by T-cell receptor gene rearrangements during T-cell maturation in the thymus and represent a reliable marker for thymic output. In this study, we aimed to assess aging and malignant hematological diseases as two important factors that may influence thymic output before HSCT. We observed that patients before HSCT presented signal joint TREC (sjTREC) numbers lower than 606.55 copies/MUg DNA (low values) compared with healthy individuals, with an odds ratio (OR) of 12.88 [95% confidence interval (CI): 5.26-31.53; p < 0.001]. Our results showed that a group of older individuals (>=50 years old), comprising both healthy individuals and patients, had an OR of 10.07 (95% CI: 2.80-36.20) for low sjTREC values compared with younger individuals (<=24 years old; p < 0.001). Multiple logistic regression analysis confirmed that both older age (>=50 years old) and malignant hematological diseases and their treatments were important and independent risk factors related to thymic function impairment (p < 0.001). The median sjTREC value for patients of all ages was significantly lower than the sjTREC median for the subgroup of older healthy individuals (>=50 years old; p < 0.001). These data suggested that patients before HSCT and healthy individuals exhibited age-dependent thymic impairment, and that prior treatment for hematological diseases may exacerbate aging-related deterioration of natural thymic function. Furthermore, we analyzed these patients 9 months post-HSCT and compared patients who underwent autologous HSCT with those who underwent allogeneic HSCT. Both groups of patients achieved sjTREC copy numbers similar to those of healthy individuals. We did not find a close relationship between impaired thymic function prior to HSCT and worse thymic recovery after HSCT. PMID- 30245687 TI - Local Clonal Diversification and Dissemination of B Lymphocytes in the Human Bronchial Mucosa. AB - The efficacy of the adaptive humoral immune response likely requires diverse, yet focused regional B cell antibody production throughout the body. Here we address, in the first study of its kind, the B cell repertoire in the bronchial mucosa, an important barrier to antigens inhaled from the atmosphere. To accomplish this, we have applied high-throughput Adaptive Immune Receptor Repertoire Sequencing (AIRR Seq) to 10 bronchial biopsies from altogether four different sites in the right lungs from an asthmatic patient and a healthy subject. While the majority of identified B cell clones were restricted to a single site, many were disseminated in multiple sites. Members of a clone were shared more between adjacent biopsies than between distal biopsies, suggesting local mucosal migration and/or a homing mechanism for B cells through the blood or lymph. A smaller fraction of clones spanned the bronchial mucosa and peripheral blood, suggesting ongoing trafficking between these compartments. The bronchial mucosal B cell repertoire in the asthmatic patient was geographically more variable but less diverse compared to that of the healthy subject, suggesting an ongoing, antigen-driven humoral immune response in atopic asthma. Whether this is a feature of atopy or disease status remains to be clarified in future studies. We observed a subset of highly mutated and antigen-selected IgD-only cells in the bronchial mucosa. These cells were found in relative high abundance in the asthmatic individual but also, albeit at lower abundance, in the healthy subject. This novel finding merits further exploration using a larger cohort of subjects. PMID- 30245688 TI - An Adaptive Chlamydia trachomatis-Specific IFN-gamma-Producing CD4+ T Cell Response Is Associated With Protection Against Chlamydia Reinfection in Women. AB - Background: Adaptive immune responses that mediate protection against Chlamydia trachomatis (CT) remain poorly defined in humans. Animal chlamydia models have demonstrated that CD4+ Th1 cytokine responses mediate protective immunity against reinfection. To better understand protective immunity to CT in humans, we investigated whether select CT-specific CD4+ Th1 and CD8+ T cell cytokine responses were associated with protection against CT reinfection in women. Methods: Peripheral blood mononuclear cells were collected from 135 CT-infected women at treatment and follow-up visits and stimulated with CT antigens. CD4+ and CD8+ T-cells expressing IFN-gamma, TNF-alpha, and/or IL-2 were assessed using intracellular cytokine staining and cytokine responses were compared between visits and between women with vs. without CT reinfection at follow-up. Results: A CD4+TNF-alpha response was detected in the majority (77%) of study participants at the treatment visit, but a lower proportion had this response at follow-up (62%). CD4+ IFN-gamma and CD4+ IL-2 responses occurred less frequently at the treatment visit (32 and 18%, respectively), but increased at follow-up (51 and 41%, respectively). CD8+ IFN-gamma and CD8+ TNF-alpha responses were detected more often at follow-up (59% for both responses) compared to the treatment visit (30% for both responses). At follow-up, a CD4+IFN-gamma response was detected more often in women without vs. with reinfection (60 vs. 33%, P = 0.005). Conclusions: Our findings suggest that a CT-specific CD4+ IFN-gamma response is associated with protective immunity against CT reinfection and is thus an important component of adaptive immunity to CT in women. PMID- 30245689 TI - Influenza Virus-Host Co-evolution. A Predator-Prey Relationship? AB - Influenza virus continues to cause yearly seasonal epidemics worldwide and periodically pandemics. Although influenza virus infection and its epidemiology have been extensively studied, a new pandemic is likely. One of the reasons influenza virus causes epidemics is its ability to constantly antigenically transform through genetic diversification. However, host immune defense mechanisms also have the potential to evolve during short or longer periods of evolutionary time. In this mini-review, we describe the evolutionary procedures related with influenza viruses and their hosts, under the prism of a predator prey relationship. PMID- 30245690 TI - Clinical Application of iNKT Cell-mediated Anti-tumor Activity Against Lung Cancer and Head and Neck Cancer. AB - Invariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to T-cell receptor (TCR) stimulation by recognizing antigens such as alpha-galactosylceramide (alpha-GalCer) presented on CD1d; thus, orchestrating other immune cells to fight against pathogen infection and tumors. Because of their ability to induce strong anti-tumor responses and the convenience of their invariant TCR activated by a synthetic ligand, alpha-GalCer, iNKT cells have been intensively studied for application in immunotherapeutic approaches to treat cancer patients in the clinic. Here, we summarize the clinical trials of iNKT cell based immunotherapy for non-small cell lung cancer, and head and neck cancer. Although solid tumors are thought to be refractory to immunotherapeutic approaches, our clinical trials showed that the intravenous injection of alpha GalCer-pulsed antigen presenting cells (APCs) activated endogenous iNKT cells and iNKT cell dependent responses. Moreover, an increase in the number of IFN-gamma producing cells in PBMCs was associated with prolonged survival. The marked infiltration of iNKT cells and the accumulation of conventional T cells in the tumor microenvironment were also observed after the administration of alpha GalCer-pulsed APCs and/or ex vivo activated iNKT cells. In cases of advanced head and neck squamous cell carcinoma, the increased accumulation of iNKT cells in the tumor microenvironment was correlated with objective clinical responses. We will also discuss potential combination therapies of iNKT cell based immunotherapy to achieve enhanced anti-tumor activity and provide better treatment options for these patients. PMID- 30245686 TI - Chemokine-Induced Macrophage Polarization in Inflammatory Conditions. AB - Macrophages represent a heterogeneous cell population and are known to display a remarkable plasticity. In response to distinct micro-environmental stimuli, e.g., tumor stroma vs. infected tissue, they polarize into different cell subtypes. Originally, two subpopulations were defined: classically activated macrophages or M1, and alternatively activated macrophages or M2. Nowadays, the M1/M2 classification is considered as an oversimplified approach that does not adequately cover the total spectrum of macrophage phenotypes observed in vivo. Especially in pathological circumstances, macrophages behave as plastic cells modifying their expression and transcription profile along a continuous spectrum with M1 and M2 phenotypes as extremes. Here, we focus on the effect of chemokines on macrophage differentiation and polarization in physiological and pathological conditions. In particular, we discuss chemokine-induced macrophage polarization in inflammatory diseases, including obesity, cancer, and atherosclerosis. PMID- 30245692 TI - Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS. AB - Introduction: Malignant pleural mesothelioma (MPM) is a malignancy with a very poor prognosis for which new treatment options are urgently needed. We have previously shown that dendritic cell (DC) immunotherapy provides a clinically feasible treatment option. In the current study, we set out to assess the immunological changes induced by DC immunotherapy in peripheral blood of MPM patients. Methods: Peripheral blood was collected from nine patients enrolled in a phase I dose escalation study, before and after treatment with DCs that were pulsed with an allogeneic tumor lysate preparation consisting of a mixture of five cultured mesothelioma cell lines. We used immune profiling by multiplex flow cytometry to characterize different populations of immune cells. In particular, we determined frequencies of T cell subsets that showed single and combinatorial expression of multiple markers that signify T cell activation, maturation and inhibition. Therapy-induced T cell reactivity was assessed in peptide/MHC multimer stainings using mesothelin as a prototypic target antigen with confirmed expression in the clinical tumor lysate preparation. T cell receptor (TCR) diversity was evaluated by TCRB gene PCR assays. Results: We observed an increase in the numbers of B cells, CD4 and CD8 T cells, but not NK cells at 6 weeks post treatment. The increases in B and T lymphocytes were not accompanied by major changes in T cell reactivity toward mesothelin nor in TCRB diversity. Notably, we did observe enhanced proportions of CD4 T cells expressing HLA-DR, PD-1 (at 2 weeks after onset of treatment) and ICOS (6 weeks) and a CD8 T cell population expressing LAG3 (2 weeks). Discussion: DC immunotherapy using allogeneic tumor lysate resulted in enhanced frequencies of B cells and T cells in blood. We did not detect a skewed antigen-reactivity of peripheral CD8 T cells. Interestingly, frequencies of CD4 T cells expressing activation markers and PD-1 were increased. These findings indicate a systemic activation of the adaptive immune response and may guide future immune monitoring studies of DC therapies. PMID- 30245691 TI - Radiation and Local Anti-CD40 Generate an Effective in situ Vaccine in Preclinical Models of Pancreatic Cancer. AB - Radiation therapy induces immunogenic cell death, which can theoretically stimulate T cell priming and induction of tumor-specific memory T cell responses, serving as an in situ vaccine. In practice, this abscopal effect is rarely observed. We use two mouse models of pancreatic cancer to show that a single dose of stereotactic body radiation therapy (SBRT) synergizes with intratumoral injection of agonistic anti-CD40, resulting in regression of non-treated contralateral tumors and formation of long-term immunologic memory. Long-term survival was not observed when mice received multiple fractions of SBRT, or when TGFbeta blockade was combined with SBRT. SBRT and anti-CD40 was so effective at augmenting T cell priming, that memory CD8 T cell responses to both tumor and self-antigens were induced, resulting in vitiligo in long-term survivors. PMID- 30245693 TI - Multi-Step Regulation of the TLR4 Pathway by the miR-125a~99b~let-7e Cluster. AB - An appropriate immune response requires a tight balance between pro- and anti inflammatory mechanisms. IL-10 is induced at late time-points during acute inflammatory conditions triggered by TLR-dependent recognition of infectious agents and is involved in setting this balance, operating as a negative regulator of the TLR-dependent signaling pathway. We identified miR-125a~99b~let-7e as an evolutionary conserved microRNA cluster late-induced in human monocytes exposed to the TLR4 agonist LPS as an effect of this IL-10-dependent regulatory loop. We demonstrated that microRNAs generated by this cluster perform a pervasive regulation of the TLR signaling pathway by direct targeting receptors (TLR4, CD14), signaling molecules (IRAK1), and effector cytokines (TNFalpha, IL-6, CCL3, CCL7, CXCL8). Modulation of miR-125a~99b~let-7e cluster influenced the production of proinflammatory cytokines in response to LPS and the IL-10-mediated tolerance to LPS, thus identifying this gene as a previously unrecognized major regulatory element of the inflammatory response and endotoxin tolerance. PMID- 30245694 TI - The Treatment of Activated PI3Kdelta Syndrome. AB - Activated phosphoinositide 3-kinase delta syndrome (APDS), also known as PASLI disease (p110d-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency) are combined immunodeficiencies resulting from gain-of function mutations in the genes (PIK3CD and PIK3R1) encoding the subunits of phosphoinositide 3-kinase delta (PI3Kdelta) and were first described in 2013. These mutations result in the hyperactivation of the PI3K/AKT/mTOR/S6K signally pathways. In this mini-review we have detailed the current treatment options for APDS. These treatments including conventional immunodeficiency therapies such as immunoglobulin replacement, antibiotic prophylaxis, and hematopoietic stem cell transplant. We also discuss the more targeted therapies of mTOR inhibition with sirolimus and selective PI3Kdelta inhibitors. PMID- 30245695 TI - Vascular Leaking, a Pivotal and Early Pathogenetic Event in Systemic Sclerosis: Should the Door Be Closed? AB - The early phase of systemic sclerosis (SSc) presents edema as one of the main features: this is clinically evident in the digital swelling (puffy fingers) as well as in the edematous skin infiltration of the early active diffuse subset. Other organs could be affected by this same disease process, such as the lung (with the appearance of ground glass opacities) and the heart (with edematous changes on cardiac magnetic resonance imaging). The genesis of tissue edema is tightly linked to pathological changes in the endothelium: various reports demonstrated the effect of transforming growth factor beta, vascular endothelial growth factor and hypoxia-reperfusion damage with reactive oxygen species generation in altering vascular permeability and extravasation, in particular in SSc. This condition has an alteration in the glycocalyx thickness, reducing the protection of the vessel wall and causing non-fibrotic interstitial edema, a marker of vascular leak. Moreover, changes in the junctional adhesion molecule family and other adhesion molecules, such as ICAM and VCAM, are associated with an increased myeloid cells' extravasation in the skin and increased myofibroblasts transformation with further vascular leak and cellular migration. This mini-review examines current knowledge on determinants of vascular leak in SSc, shedding light on the role of vascular protection. This could enhance further studies in the light of drug development for early treatment, suggesting that the control of vascular leakage should be considered in the same way that vasodilation and inflammation reduction, as potential therapeutic targets. PMID- 30245696 TI - Variation in the Untranslated Genome and Susceptibility to Infections. AB - The clinical outcomes of infections are highly variable among individuals and are determined by complex host-pathogen interactions. Genome-wide association studies (GWAS) are powerful tools to unravel common genetic variations that are associated with disease risk and clinical outcomes. However, GWAS has only rarely revealed information on the exact genetic elements and their effects underlying an association because the majority of the hits are within non-coding regions. Some of the variants or the linked polymorphisms are now being discovered to have functional significance, such as regulatory elements in the promoter and enhancer regions or the microRNA binding sites in the 3'untranslated region of the protein coding genes, which influence transcription, RNA stability, and translation of the protein-coding genes. However, only 3% of the entire transcriptome is protein coding, signifying that non-coding RNAs represent most of the transcripts. Thus, a large portion of previously identified intergenic GWAS single nucleotide polymorphisms (SNPs) is in the non-coding RNAs. The non-coding RNAs form a large scale regulatory network across the transcriptome, greatly expanding the complexity of gene regulation. Accumulating evidence also suggests that the "non coding" genome regions actively regulate the highly dynamic three dimensional (3D) chromatin structures, which are critical for genome function. Epigenetic modulation like DNA methylation and histone modifications further affect chromatin accessibility and gene expression adding another layer of complexity to the functional interpretation of genetic variation associated with disease outcomes. We provide an overview of the current information on the influence of variation in these "untranslated" regions of the human genome on infectious diseases. The focus of this review is infectious disease-associated polymorphisms and gene regulatory mechanisms of pathophysiological relevance. PMID- 30245697 TI - Molecular and Cellular Response to Experimental Anisakis pegreffii (Nematoda, Anisakidae) Third-Stage Larval Infection in Rats. AB - Background: Anisakiasis is a zoonotic disease caused by accidental ingestion of live Anisakis spp. third-stage larvae present in raw or undercooked seafood. Symptoms of this emerging infectious disease include mild-to-severe abdominal pain, nausea, and diarrhea. Some patients experience significant allergic reactions. Aims: In order to better understand the onset of anisakiasis, we aimed to: (i) histopathologically describe severe inflammatory/hemorrhagic infection site lesions in Sprague-Dawley rats experimentally infected with Anisakis pegreffii larvae; and (ii) qualitatively and quantitatively characterize the transcriptomes of affected tissues using RNA-Seq. Methodology: The experiment was performed on 35 male rats, sacrificed at 5 time points (6, 10, 18, 24, and 32 h post-infection). Gastric intubation was performed with 10 A. pegreffii larvae (N = 5 infected rats per time point) or 1.5 ml of saline (external control N = 2 rats). 16 pools, seven for muscle tissues and nine for stomach tissues, were created to obtain robust samples for estimation of gene expression changes depicting common signatures of affected versus unaffected tissues. Illumina NextSeq 500 was used for paired-end sequencing, while edgeR was used for count data and differential expression analyses. Results: In total, there were 1372 (855 up and 517 down) differentially expressed (DE) genes in the Anisakis infected rat stomach tissues, and 1633 (1230 up and 403 down) DE genes in the muscle tissues. Elicited strong local proinflammatory reaction seems to favor the activation of the interleukin 17 signaling pathway and the development of the T helper 17-type response. The number of DE ribosomal genes in the Anisakis infected stomach tissue suggests that A. pegreffii larvae might induce ribosomal stress in the early infection stage. However, the downstream pathways and post infection responses require further study. Histopathology revealed severe inflammatory/hemorrhagic lesions caused by Anisakis infection in the rat stomach and muscle tissues in the first 32 h. The lesion sites showed infiltration by polymorphonuclear leukocytes (predominantly neutrophils and occasional eosinophils), and to a lesser extent, macrophages. Conclusion: Understanding the cellular and molecular mechanisms underlying host responses to Anisakis infection is important to elucidate many aspects of the onset of anisakiasis, a disease of growing public health concern. PMID- 30245699 TI - The Role of Humans in a Protracted Transition From Hunting-Gathering to Plant Domestication in the Fertile Crescent. PMID- 30245698 TI - Generation of Transgene-Free Maize Male Sterile Lines Using the CRISPR/Cas9 System. AB - Male sterility (MS) provides a useful breeding tool to harness hybrid vigor for hybrid seed production. It is necessary to generate new male sterile mutant lines for the development of hybrid seed production technology. The CRISPR/Cas9 technology is well suited for targeting genomes to generate male sterile mutants. In this study, we artificially synthesized Streptococcus pyogenes Cas9 gene with biased codons of maize. A CRISPR/Cas9 vector targeting the MS8 gene of maize was constructed and transformed into maize using an Agrobacterium-mediated method, and eight T0 independent transgenic lines were generated. Sequencing results showed that MS8 genes in these T0 transgenic lines were not mutated. However, we detected mutations in the MS8 gene in F1 and F2 progenies of the transgenic line H17. A potential off-target site sequence which had a single nucleotide that was different from the target was also mutated in the F2 progeny of the transgenic line H17. Mutation in the MS8 gene and the male sterile phenotype could be stably inherited by the next generation in a Mendelian fashion. Transgene-free ms8 male sterile plants were obtained by screening the F2 generation of male sterile plants, and the MS phenotype could be introduced into other elite inbred lines for hybrid production. PMID- 30245700 TI - Genome-Wide Analysis of Glycine soja Response Regulator GsRR Genes Under Alkali and Salt Stresses. AB - Soil salt-alkalization is a dramatic challenging factor for plant growth. Wild soybean (Glycine soja) exhibits a favorable trait of superior tolerance to salt alkali stress, and recent discoveries show that response regulator family genes are involved in diverse abiotic stresses. Genomic and transcriptomic analyses of all response regulator genes in wild soybean will provide insight into their function in plant stress response. In this study, we identified and characterized a total of 56 Glycine soja response regulator (GsRR) genes. Phylogenetic analysis suggested that GsRR genes could be classified into five subclasses (A1, A2, B1, B2, and C). We further investigated the chromosome locations, gene duplications and conserved domains of the GsRRs. Furthermore, the clustering analysis of GsRR transcript profiles revealed five different expression patterns under alkali stress. The A1 and A2 subclasses display significantly higher transcriptional levels than the B subclass. In addition, quantitative real-time PCR results verified that the GsRR genes were also significantly influenced by salt stress. Notably, GsRR2a in the A1 subclass showed opposite expression patterns under salt stress comparing with alkali stress. Moreover, overexpression of GsRR2a in Arabidopsis significantly improved the tolerance to alkali stress, but not salt stress. These results suggest the important roles of GsRR genes in response to salt and alkaline stresses, and also provide valuable clues for further functional characterization of GsRR family genes. PMID- 30245701 TI - Does Late Maturity Alpha-Amylase Impact Wheat Baking Quality? AB - Late maturity alpha-amylase (LMA) and pre-harvest sprouting (PHS) are both recognized as environmentally induced grain quality defects resulting from abnormally high levels of alpha-amylase. LMA is a more recently identified quality issue that is now receiving increasing attention worldwide and whose prevalence is now seen as impeding the development of superior quality wheat varieties. LMA is a genetic defect present in specific wheat genotypes and is characterized by elevated levels of the high pI TaAMY1 alpha-amylase, triggered by environmental stress during wheat grain development. TaAMY1 remains present in the aleurone through the harvest, lowering Falling Number (FN) at receival, causing a down-grading of the grain, often to feed grade, thus reducing the farmers' income. This downgrading is based on the assumption within the grain industry that, as for PHS, a low FN represents poor quality grain. Consequently any wheat line possessing low FN or high alpha-amylase levels is automatically considered a poor bread wheat despite there being no published evidence to date, to show that LMA is detrimental to end product quality. To evaluate the validity of this assumption a comprehensive evaluation of baking properties was performed from LMA prone lines using a subset of tall non-Rht lines from a multi-parent advanced generation inter-cross (MAGIC) wheat population grown at three different sites. LMA levels were determined along with quality parameters including end product functionality such as oven spring, bread loaf volume and weight, slice area and brightness, gas cell number and crumb firmness. No consistent or significant phenotypic correlation was found between LMA related FN and any of the quality traits. This manuscript provides for the first time, compelling evidence that LMA has limited impact on bread baking end product functionality. PMID- 30245702 TI - Assessing the impact of anthropogenic pollution on isoprene-derived secondary organic aerosol formation in PM2.5 collected from the Birmingham, Alabama, ground site during the 2013 Southern Oxidant and Aerosol Study. AB - In the southeastern US, substantial emissions of isoprene from deciduous trees undergo atmospheric oxidation to form secondary organic aerosol (SOA) that contributes to fine particulate matter (PM2.5). Laboratory studies have revealed that anthropogenic pollutants, such as sulfur dioxide (SO2), oxides of nitrogen (NO x ), and aerosol acidity, can enhance SOA formation from the hydroxyl radical (OH)-initiated oxidation of isoprene; however, the mechanisms by which specific pollutants enhance isoprene SOA in ambient PM2.5 remain unclear. As one aspect of an investigation to examine how anthropogenic pollutants influence isoprene derived SOA formation, high-volume PM2.5 filter samples were collected at the Birmingham, Alabama (BHM), ground site during the 2013 Southern Oxidant and Aerosol Study (SOAS). Sample extracts were analyzed by gas chromatography electron ionization-mass spectrometry (GC/EI-MS) with prior trimethylsilylation and ultra performance liquid chromatography coupled to electrospray ionization high-resolution quadrupole time-of-flight mass spectrometry (UPLC/ESI-HR-QTOFMS) to identify known isoprene SOA tracers. Tracers quantified using both surrogate and authentic standards were compared with collocated gas- and particle-phase data as well as meteorological data provided by the Southeastern Aerosol Research and Characterization (SEARCH) network to assess the impact of anthropogenic pollution on isoprene-derived SOA formation. Results of this study reveal that isoprene-derived SOA tracers contribute a substantial mass fraction of organic matter (OM) (~ 7 to ~ 20 %). Isoprene-derived SOA tracers correlated with sulfate ( SO42- ) (r2 = 0.34, n = 117) but not with NO x . Moderate correlations between methacrylic acid epoxide and hydroxymethyl-methyl-alpha-lactone (together abbreviated MAE/HMML)-derived SOA tracers with nitrate radical production (P[NO3]) (r2 = 0.57, n = 40) were observed during nighttime, suggesting a potential role of the NO3 radical in forming this SOA type. However, the nighttime correlation of these tracers with nitrogen dioxide (NO2) (r2 = 0.26, n = 40) was weaker. Ozone (O3) correlated strongly with MAE/HMML-derived tracers (r2 = 0.72, n = 30) and moderately with 2-methyltetrols (r2 = 0.34, n = 15) during daytime only, suggesting that a fraction of SOA formation could occur from isoprene ozonolysis in urban areas. No correlation was observed between aerosol pH and isoprene-derived SOA. Lack of correlation between aerosol acidity and isoprene-derived SOA is consistent with the observation that acidity is not a limiting factor for isoprene SOA formation at the BHM site as aerosols were acidic enough to promote multiphase chemistry of isoprene-derived epoxides throughout the duration of the study. All in all, these results confirm previous studies suggesting that anthropogenic pollutants enhance isoprene-derived SOA formation. PMID- 30245703 TI - Co-benefits of global and regional greenhouse gas mitigation on U.S. air quality in 2050. AB - Policies to mitigate greenhouse gas (GHG) emissions will not only slow climate change, but can also have ancillary benefits of improved air quality. Here we examine the co-benefits of both global and regional GHG mitigation on U.S. air quality in 2050 at fine resolution, using dynamical downscaling methods, building on a previous global co-benefits study (West et al., 2013). The co-benefits for U.S. air quality are quantified via two mechanisms: through reductions in co emitted air pollutants from the same sources, and by slowing climate change and its influence on air quality, following West et al. (2013). Additionally, we separate the total co-benefits into contributions from domestic GHG mitigation versus mitigation in foreign countries. We use the WRF model to dynamically downscale future global climate to the regional scale, the SMOKE program to directly process global anthropogenic emissions into the regional domain, and we provide dynamical boundary conditions from global simulations to the regional CMAQ model. The total co-benefits of global GHG mitigation from the RCP4.5 scenario compared with its reference are estimated to be higher in the eastern U.S. (ranging from 0.6-1.0 MUg m-3) than the west (0-0.4 MUg m-3) for PM2.5, with an average of 0.47 MUg m-3 over U.S.; for O3, the total co-benefits are more uniform at 2-5 ppb with U.S. average of 3.55 ppb. Comparing the two mechanisms of co-benefits, we find that reductions of co-emitted air pollutants have a much greater influence on both PM2.5 (96% of the total co-benefits) and O3 (89% of the total) than the second co-benefits mechanism via slowing climate change, consistent with West et al. (2013). GHG mitigation from foreign countries contributes more to the U.S. O3 reduction (76% of the total) than that from domestic GHG mitigation only (24%), highlighting the importance of global methane reductions and the intercontinental transport of air pollutants. For PM2.5, the benefits of domestic GHG control are greater (74% of total). Since foreign contributions to co-benefits can be substantial, with foreign O3 benefits much larger than those from domestic reductions, previous studies that focus on local or regional co-benefits may greatly underestimate the total co-benefits of global GHG reductions. We conclude that the U.S. can gain significantly greater domestic air quality co-benefits by engaging with other nations to control GHGs. PMID- 30245706 TI - Super-Resolution of Magnetic Resonance Images via Convex Optimization with Local and Global Prior Regularization and Spectrum Fitting. AB - Given a low-resolution image, there are many challenges to obtain a super resolved, high-resolution image. Many of those approaches try to simultaneously upsample and deblur an image in signal domain. However, the nature of the super resolution is to restore high-frequency components in frequency domain rather than upsampling in signal domain. In that sense, there is a close relationship between super-resolution of an image and extrapolation of the spectrum. In this study, we propose a novel framework for super-resolution, where the high frequency components are theoretically restored with respect to the frequency fidelities. This framework helps to introduce multiple simultaneous regularizers in both signal and frequency domains. Furthermore, we propose a new super resolution model where frequency fidelity, low-rank (LR) prior, low total variation (TV) prior, and boundary prior are considered at once. The proposed method is formulated as a convex optimization problem which can be solved by the alternating direction method of multipliers. The proposed method is the generalized form of the multiple super-resolution methods such as TV super resolution, LR and TV super-resolution, and the Gerchberg method. Experimental results show the utility of the proposed method comparing with some existing methods using both simulational and practical images. PMID- 30245704 TI - Atmospheric mercury concentrations observed at ground-based monitoring sites globally distributed in the framework of the GMOS network. AB - Long-term monitoring of data of ambient mercury (Hg) on a global scale to assess its emission, transport, atmospheric chemistry, and deposition processes is vital to understanding the impact of Hg pollution on the environment. The Global Mercury Observation System (GMOS) project was funded by the European Commission (http://www.gmos.eu) and started in November 2010 with the overall goal to develop a coordinated global observing system to monitor Hg on a global scale, including a large network of ground-based monitoring stations, ad hoc periodic oceanographic cruises and measurement flights in the lower and upper troposphere as well as in the lower stratosphere. To date, more than 40 ground-based monitoring sites constitute the global network covering many regions where little to no observational data were available before GMOS. This work presents atmospheric Hg concentrations recorded worldwide in the framework of the GMOS project (2010-2015), analyzing Hg measurement results in terms of temporal trends, seasonality and comparability within the network. Major findings highlighted in this paper include a clear gradient of Hg concentrations between the Northern and Southern hemispheres, confirming that the gradient observed is mostly driven by local and regional sources, which can be anthropogenic, natural or a combination of both. PMID- 30245705 TI - Antibacterial Activity of Partially Oxidized Ag/Au Nanoparticles against the Oral Pathogen Porphyromonas gingivalis W83. AB - Advances in nanotechnology provide opportunities for the prevention and treatment of periodontal disease. While physicochemical properties of Ag containing nanoparticles (NPs) are known to influence the magnitude of their toxicity, it is thought that nanosilver can be made less toxic to eukaryotes by passivation of the NPs with a benign metal. Moreover, the addition of other noble metals to silver nanoparticles, in the alloy formulation, is known to alter the silver dissolution behavior. Thus, we synthesized glutathione capped Ag/Au alloy bimetallic nanoparticles (NPs) via the galvanic replacement reaction between maltose coated Ag NPs and chloroauric acid (HAuCl4) in 5% aqueous triblock F127 copolymer solution. We then compared the antibacterial activity of the Ag/Au NPs to pure Ag NPs on Porphyromonas gingivalis W83, a key pathogen in the development of periodontal disease. Only partially oxidized glutathione capped Ag and Ag/Au (Au:Ag~0.2) NPs inhibited the planktonic growth of P. gingivalis W83. This effect was enhanced in the presence of hydrogen peroxide, which simulates the oxidative stress environment in the periodontal pocket during chronic inflammation. PMID- 30245707 TI - Synthesis, Characterization, and Antimicrobial Activity of Novel Sulfonated Copper-Triazine Complexes. AB - Metallotriazine complexes possess interesting biological and medicinal properties, and the present study focuses on the synthesis, characterization, and antimicrobial activity of four novel copper-triazine derivatives in search of potent antibacterial and antifungal drug leads. In this study, 3-(2-pyridyl)-5,6 diphenyl-1,2,4-triazine-4,4'-disulfonic acid monosodium salt (L1, ferrozine) and 3-(2-pyridyl)-5,6-di(2-furyl)-1,2,4-triazine-5,5'-disulfonic acid disodium salt (L2, ferene) have been used as ligands to study the complexation towards copper(II). The synthesized complexes, [CuCl2(ferrozine)].7H2O.MeOH (1), [CuCl2(ferrozine)2].5H2O.MeOH (2), [CuCl2(ferene)].H2O.MeOH (3), and [CuCl2(ferene)2].H2O.MeOH (4), have been characterized spectroscopically, and preliminary bioassays have been carried out. FTIR spectroscopic data have shown that N=N and C=N stretching frequencies of complexes have been shifted towards lower frequencies in comparison with that of the ligands, confirming new bond formation between Cu and N, which in turn lowers the strength of N=N and C=N bonds. In addition, a bathochromic shift has been observed for UV-visible spectra of complexes (1), (2), (3), and (4). Furthermore, elemental analysis data have been useful to obtain empirical formulas of these complexes and to establish the purity of each complex. Complexes (1) and (2) have shown antibacterial activity for both S. aureus (ATCC(r) 25923) and E. coli (ATCC(r) 25922) at 1 mg/disc concentration, and ferrozine has shown a larger inhibition zone against the clinical sample of C. albicans at 1 mg/disc concentration in comparison with the positive control, fluconazole. PMID- 30245708 TI - Different Performances of Different Intelligent Algorithms for Solving FJSP: A Perspective of Structure. AB - There are several intelligent algorithms that are continually being improved for better performance when solving the flexible job-shop scheduling problem (FJSP); hence, there are many improvement strategies in the literature. To know how to properly choose an improvement strategy, how different improvement strategies affect different algorithms and how different algorithms respond to the same strategy are critical questions that have not yet been addressed. To address them, improvement strategies are first classified into five basic improvement strategies (five structures) used to improve invasive weed optimization (IWO) and genetic algorithm (GA) and then seven algorithms (S1-S7) used to solve five FJSP instances are proposed. For the purpose of comparing these algorithms fairly, we consider the total individual number (TIN) of an algorithm and propose several evaluation indexes based on TIN. In the process of decoding, a novel decoding algorithm is also proposed. The simulation results show that different structures significantly affect the performances of different algorithms and different algorithms respond to the same structure differently. The results of this paper may shed light on how to properly choose an improvement strategy to improve an algorithm for solving the FJSP. PMID- 30245709 TI - Risk Evaluation Model of Highway Tunnel Portal Construction Based on BP Fuzzy Neural Network. AB - Risk assessment for tunnel portals in the construction stage has been widely recognized as one of the most critical phases in tunnel construction as it easily causes accident than the overall length of a tunnel. However, the risk in tunnel portal construction is complicated and uncertain which has made such a neural network very attractive to the construction projects. This paper presents a risk evaluation model, which is obtained from historical data of 50 tunnels, by combining the fuzzy method and BP neural network. The proposed model is used for the risk assessment of the Tiefodian tunnel. The results show that the risk evaluation level is IV, slope instability is the greatest impact index among four risk events, and the major risk factors are confirmed. According to the evaluation results, corresponding risk control measures are suggested and implemented. Finally, numerical simulation is carried out before and after the implementation of risk measures, respectively. The rationality of the proposed risk evaluation model is proved by comparing the numerical simulation results. PMID- 30245710 TI - Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats. AB - Ciliary neurotrophic factor (CNTF) promotes survival and enhances long-distance regeneration of injured axons in parts of the adult CNS. Here we tested whether CNTF gene therapy targeting corticospinal neurons (CSN) in motor-related regions of the cerebral cortex promotes plasticity and regrowth of axons projecting into the female adult F344 rat spinal cord after moderate thoracic (T10) contusion injury (SCI). Cortical neurons were transduced with a bicistronic adeno associated viral vector (AAV1) expressing a secretory form of CNTF coupled to mCHERRY (AAV-CNTFmCherry) or with control AAV only (AAV-GFP) two weeks prior to SCI. In some animals, viable or nonviable F344 rat mesenchymal precursor cells (rMPCs) were injected into the lesion site two weeks after SCI to modulate the inhibitory environment. Treatment with AAV-CNTFmCherry, as well as with AAV CNTFmCherry combined with rMPCs, yielded functional improvements over AAV-GFP alone, as assessed by open-field and Ladderwalk analyses. Cyst size was significantly reduced in the AAV-CNTFmCherry plus viable rMPC treatment group. Cortical injections of biotinylated dextran amine (BDA) revealed more BDA-stained axons rostral and alongside cysts in the AAV-CNTFmCherry versus AAV-GFP groups. After AAV-CNTFmCherry treatments, many sprouting mCherry-immunopositive axons were seen rostral to the SCI, and axons were also occasionally found caudal to the injury site. These data suggest that CNTF has the potential to enhance corticospinal repair by transducing parent CNS populations. PMID- 30245711 TI - Machine Learning Creates a Simple Endoscopic Classification System that Improves Dysplasia Detection in Barrett's Oesophagus amongst Non-expert Endoscopists. AB - Introduction: Barrett's oesophagus (BE) is a precursor to oesophageal adenocarcinoma (OAC). Endoscopic surveillance is performed to detect dysplasia arising in BE as it is likely to be amenable to curative treatment. At present, there are no guidelines on who should perform surveillance endoscopy in BE. Machine learning (ML) is a branch of artificial intelligence (AI) that generates simple rules, known as decision trees (DTs). We hypothesised that a DT generated from recognised expert endoscopists could be used to improve dysplasia detection in non-expert endoscopists. To our knowledge, ML has never been applied in this manner. Methods: Video recordings were collected from patients with non dysplastic (ND-BE) and dysplastic Barrett's oesophagus (D-BE) undergoing high definition endoscopy with i-Scan enhancement (PENTAX(r)). A strict protocol was used to record areas of interest after which a corresponding biopsy was taken to confirm the histological diagnosis. In a blinded manner, videos were shown to 3 experts who were asked to interpret them based on their mucosal and microvasculature patterns and presence of nodularity and ulceration as well as overall suspected diagnosis. Data generated were entered into the WEKA package to construct a DT for dysplasia prediction. Non-expert endoscopists (gastroenterology specialist registrars in training with variable experience and undergraduate medical students with no experience) were asked to score these same videos both before and after web-based training using the DT constructed from the expert opinion. Accuracy, sensitivity, and specificity values were calculated before and after training where p < 0.05 was statistically significant. Results: Videos from 40 patients were collected including 12 both before and after acetic acid (ACA) application. Experts' average accuracy for dysplasia prediction was 88%. When experts' answers were entered into a DT, the resultant decision model had a 92% accuracy with a mean sensitivity and specificity of 97% and 88%, respectively. Addition of ACA did not improve dysplasia detection. Untrained medical students tended to have a high sensitivity but poor specificity as they "overcalled" normal areas. Gastroenterology trainees did the opposite with overall low sensitivity but high specificity. Detection improved significantly and accuracy rose in both groups after formal web-based training although it did it reach the accuracy generated by experts. For trainees, sensitivity rose significantly from 71% to 83% with minimal loss of specificity. Specificity rose sharply in students from 31% to 49% with no loss of sensitivity. Conclusion: ML is able to define rules learnt from expert opinion. These generate a simple algorithm to accurately predict dysplasia. Once taught to non-experts, the algorithm significantly improves their rate of dysplasia detection. This opens the door to standardised training and assessment of competence for those who perform endoscopy in BE. It may shorten the learning curve and might also be used to compare competence of trainees with recognised experts as part of their accreditation process. PMID- 30245712 TI - Different Anatomical Subsites of Colon Cancer and Mortality: A Population-Based Study. AB - Background: In terms of incidence and pathogenesis, right-sided colon cancer (RCC) and left-sided colon cancer (LCC) exhibit several differences. However, whether existing differences could reflect the different survival outcomes remains unclear. Therefore, we aimed to ascertain the role of location in the prognosis. Methods: We identified colon cancer cases from the Surveillance, Epidemiology, and End Results database between 1973 and 2012. Differences among subsites of colon cancer regarding clinical features and metastatic patterns were compared. The Kaplan-Meier curves were conducted to compare overall and disease specific survival in relation to cancer location. The effect of tumour location on overall and cancer-specific survival was analysed by Cox proportional hazards model. Results: A total of 377,849 patients from SEER database were included in the current study, with 180,889 (47.9%) RCC and 196,960 (52.1%) LCC. LCC was more likely to metastasize to the liver and lung. Kaplan-Meier curves demonstrated that LCC patients had better overall and cancer-specific survival outcomes. Among Cox multivariate analyses, LCC was associated with a slightly reduced risk of overall survival (HR, 0.92; 95% CI, 0.92-0.93) and cancer-specific survival (HR, 0.92; 95% CI, 0.91-0.93), even after adjusted for other variables. However, the relationship between location and prognosis was varied by subgroups defined by age, year at diagnosis, stage, and therapies. Conclusions: We demonstrated that LCC was associated with better prognosis, especially for patients with distant metastasis. Future trails should seek to identify the underlying mechanism. PMID- 30245713 TI - Monthly or Weekly Supplementation with Cholecalciferol 20,000 IU in People Living with HIV: Results from a Nested Cohort Study. AB - Background: There is still considerable uncertainty in handling vitamin D deficiency in people living with HIV (PLWH), due to a lack of comparative data and the wide range of recommended daily intake. Nondaily supplementation might be preferred in many PLWH, but recommendation on dosing has not been established. We aimed to compare the efficacy of weekly versus monthly supplementation with cholecalciferol 20,000 IU in a group of PLWH with vitamin D deficiency in Western Europe. Study Design: Longitudinal, retrospective nested cohort study of PLWH from two large clinical care centers in Munich, Germany. Results: Of 307 patients with vitamin D deficiency, 124 patients received vitamin D supplementation (weekly supplementation in 84 (67.7%)). 46.4% and 22.5% of patients achieved 25(OH)D levels >=30 ng/mL after 12 months of weekly and monthly supplementation with cholecalciferol 20,000 IU, respectively (p=0.011). Dosing interval as well as 25(OH)D baseline levels >15 ng/mL were associated with the normalization of 25(OH)D. Conclusion: A higher rate of 25(OH)D level normalization can be achieved via weekly supplementation. For several PLWH, even a weekly dose of cholecalciferol 20,000 IU might not be adequate to maintain 25(OH)D levels >30 ng/mL without an initial "loading" dose. The response to supplementation is poorly predictable at an individual level. PMID- 30245714 TI - An Appraisal of Pumpkin Seed Extract in 1, 2-Dimethylhydrazine Induced Colon Cancer in Wistar Rats. AB - Background: Cancer is one of the most important public health burdens in developed and developing countries. Colon cancer (CC) is the sixth most common cause of death in India and third most important cause in developed countries. For treating cancer, several synthetic agents are available but they cause side effects. Therefore, there is a need to investigate plant derived anticancer agents with lesser side effects. In this direction, we have made an attempt to unravel the potential of pumpkin seed extract for treating colon cancer. Objective: The objective of this study was to evaluate pumpkin seed extract as prophylactic and treatment for 1, 2-dimethylhydrazine (DMH) induced colon cancer in Wistar rats. Materials and Methods: Male Wistar rats were divided into seven groups, namely, control, DMH (disease control), 5-Flurouracil (standard), treatment groups (100mg/kg and 200 mg/kg), and pretreatment groups (100mg/kg and 200 mg/kg) with pumpkin seed extract. The animals were euthanised at the end of study and colons were examined. Results: A significant difference in the aberrant crypt foci (ACF) number in all treatment groups compared to control and DMH groups were noted. Pretreatment group at a dose of 200 mg/kg showed a significant decrease in the colon length/weight ratio. Pretreatment groups showed a significant change in the colonic glutathione (GSH) and superoxide dismutase (SOD) levels when compared to control and DMH control. The nitrite content was decreased in treatment group 200 mg/kg at 5.203+/-0.852 when compared to DMH control at 8.506+/-3.866. All treatment groups demonstrated decreased hyperplasia and ACF in histology. Conclusion: Pumpkin seed may prevent the risk of CC when consumed in dietary proportions. PMID- 30245715 TI - An Investigation into Tetrodotoxin (TTX) Levels Associated with the Red Dorsal Spots in Eastern Newt (Notophthalmus viridescens) Efts and Adults. AB - We investigated the concentration of tetrodotoxin (TTX) in sections of skin containing and lacking red dorsal spots in both Eastern newt (Notophthalmus viridescens) efts and adults. Several other species, such as Pleurodeles waltl and Echinotriton andersoni, have granular glands concentrated in brightly pigmented regions on the dorsum, and thus we hypothesized that the red dorsal spots of Eastern newts may also possess higher levels of TTX than the surrounding skin. We found no difference between the concentrations of TTX in the red spots as compared to neighboring skin lacking these spots in either efts or adults. However, efts with more red dorsal spots had elevated TTX levels relative to efts with fewer spots. PMID- 30245716 TI - Cardiometabolic Changes in Different Gonadal Female States Caused by Mild Hyperuricemia and Exposure to a High-Fructose Diet. AB - Background: The objective of this study is to observe if mild hyperuricemia and a high-fructose diet influence the cardiovascular and metabolic systems in hypogonadic female Wistar rats compared to normogonadic female rats. Methods: Fifty-six (56) adult female Wistar rats were used in the present work. Animals were divided into two groups: normogonadic (NGN) and hypogonadic (HGN). These groups were also divided into four subgroups in accordance with the treatment: control with only water (C), fructose (F), oxonic acid (OA), and fructose + oxonic acid (FOA). Lipid profile, glycemia, uric acid, and creatinine determinations were assessed. Cardiovascular changes were evaluated by measuring blood pressure, myocyte volume, fibrosis, and intima-media aortic thickness. Results: HGN rats had higher levels of total cholesterol (TC) (p < 0.01) and noHDLc (p < 0.01), in addition to higher levels of uric acid (p < 0.05). The OA group significantly increased myocyte volume (p < 0.0001) and the percentage of fibrosis as well as the group receiving FOA (p < 0.001) in both gonadal conditions, being greater in the HGN group. Hypogonadic animals presented a worse lipid profile. Conclusion: Mild hyperuricemia produces hypertension together with changes in the cardiac hypertrophy, fibrosis, and increased thickness of the intima media in hypogonadic rats fed high-fructose diet. PMID- 30245717 TI - Selected Metabolic Markers in Girls with Turner Syndrome: A Pilot Study. AB - Background: Turner syndrome (TS) predisposes an individual to obesity and related metabolic disorders. As the TS population is at a higher risk of cardiovascular diseases and malformations, research into laboratory markers of metabolic complications has been ongoing. Special significance has recently been attributed to matrix metalloproteinases (MMPs), their inhibitors (TIMPs), and neurotrophic factors, such as BDNF and GDNF. Objective: To establish whether cardiometabolic risk in patients with TS is reflected in the concentrations of metalloproteinases and neurotrophic factors. Method: The concentrations of circulating MMP-1, MMP-2, MMP-9, TIMP-1, BDNF, GDNF, and VEGF were measured in 17 patients with TS. The control group was composed of 11 girls with nonpathologic short stature and normal karyotype. Results: There were no differences in chronological or bone age. No significant differences were observed in mean weight, although the Z score BMI was higher in the study group. The mean baseline values of MMP-1 and BDNF were significantly lower in the control group than in the study group (p < 0.001, p = 0.001). Regression analysis revealed a positive correlation between MMP-1 concentrations and Z-score BMI (r = 0.36, p = 0.047) and between BDNF and Z score BMI (r = 0.48, p = 0.013). Conclusion: Our pilot study showed that MMP-1 may be a potential indicator of a higher risk of cardiometabolic complications in girls with TS. The elevated concentrations of BDNF in normal-weight girls with TS need to be studied further, taking into consideration the influence of estrogen androgen imbalance. PMID- 30245718 TI - Prevalence of Human Sapovirus in Low and Middle Income Countries. AB - Background: Sapovirus (SV) infection is a public health concern which plays an important role in the burden of diarrhoeal diseases, causing acute gastroenteritis in people of all ages in both outbreaks and sporadic cases worldwide. Objective/Study Design: The purpose of this report is to summarise the available data on the detection of human SV in low and middle income countries. A systematic search on PubMed and ScienceDirect database for SV studies published between 2004 and 2017 in low and middle income countries was done. Studies of SV in stool and water samples were part of the inclusion criteria. Results: From 19 low and middle income countries, 45 published studies were identified. The prevalence rate for SV was 6.5%. A significant difference (P=0) in SV prevalent rate was observed between low income and middle income countries. Thirty-three (78.6%) of the studies reported on children and 8 (19%) studies reported on all age groups with diarrhoea. The majority (66.7%) of studies reported on hospitalised patients with acute gastroenteritis. Sapovirus GI was shown as the dominant genogroup, followed by SV-GII. Conclusion: The detection of human SV in low and middle income countries is evident; however the reports on its prevalence are limited. There is therefore a need for systematic surveillance of the circulation of SV, and their role in diarrhoeal disease and outbreaks, especially in low and middle income countries. PMID- 30245719 TI - Development and Validation of 3D Finite Element Models for Prediction of Orthodontic Tooth Movement. AB - Objectives: The aim of this study was to develop and validate three-dimensional (3D) finite element modeling for prediction of orthodontic tooth movement. Materials and Methods: Two orthodontic patients were enrolled in this study. Computed tomography (CT) was captured 2 times. The first time was at T0 immediately before canine retraction. The second time was at T4 precisely at 4 months after canine retraction. Alginate impressions were taken at 1 month intervals (T0-T4) and scanned using a digital scanner. CT data and scanned models were used to construct 3D models. The two measured parameters were clinical tooth movement and calculated stress at three points on the canine root. The calculated stress was determined by the finite element method (FEM). The clinical tooth movement was measured from the differences in the measurement points on the superimposed model. Data from the first patient were used to analyze the tooth movement pattern and develop a mathematical formula for the second patient. Calculated orthodontic tooth movement of the second patient was compared to the clinical outcome. Results: Differences between the calculated tooth movement and clinical tooth movement ranged from 0.003 to 0.085 mm or 0.36 to 8.96%. The calculated tooth movement and clinical tooth movement at all reference points of all time periods appeared at a similar level. Differences between the calculated and clinical tooth movements were less than 0.1 mm. Conclusion: Three-dimensional FEM simulation of orthodontic tooth movement was achieved by combining data from the CT and digital model. The outcome of the tooth movement obtained from FEM was found to be similar to the actual clinical tooth movement. PMID- 30245720 TI - Rapid, Validated UPLC-MS/MS Method for Determination of Glibenclamide in Rat Plasma. AB - Quick and specific bioanalytical methods are required for analyzing drugs in biological samples. A simple, quick, sensitive, and specific UPLC-MS/MS method was developed and validated for glibenclamide determination in plasma samples. The plasma samples were processed by protein precipitation technique. Glimepiride was used as internal standard (IS). Glibenclamide and glimepiride were eluted on C18 column (Acquity UPLC(r)BEH). Mobile phase consisting of acetonitrile (0.1% formic acid) and water (0.1% formic acid) was pumped in binary gradient mode at flow rate of 150 MUL/min. Glibenclamide and IS elution time was about 1.0 min, and total run time was 2.0 min. The mass spectrometer (triple-quadrupole) was operated in positive electrospray ionization mode. Sodium adducts [M + Na]+ of glibenclamide and IS were monitored in MRM mode. A linear calibration curve was obtained in the range of 10-1280 ng/mL, with regression equation Y = 0.0076 X - 0.0165 and linear regression coefficient r2 = 0.999. Lower limit of quantitation was 10 ng/mL. Accuracy of the method at LQC, MQC, and HQC was 109.7% (+/- 6.7), 93.6% (+/- 0.4), and 99.3% (+/- 1.9), respectively. The coefficient of variation for precision at all QC concentrations was less than 6%. Recovery at LLQC, MQC, and HQC was 104.2% (+/- 4.9), 100.6% (+/- 0.9), and 102.9% (+/- 5.8), respectively. The method was successfully implemented for pharmacokinetic investigations (in-house data). PMID- 30245721 TI - Quantitative Detection of miRNA-21 Expression in Tumor Cells and Tissues Based on Molecular Beacon. AB - As a new tumor marker, the microRNA-21 (miRNA21) level can provide important information for early diagnosis, drug treatment, and prognosis of gastric cancer. With the tool of molecular beacons which can hybridize specifically with target miRNA-21 and generate fluorescence signal change, this paper develops a direct, simple, and rapid method for miRNA-21 detection with detection limit of 0.5 nM. Under the optimal conditions, the method was used to detect the expression of miRNA-21 in tumor cells and tissues. The results showed significant differences of miRNA-21 levels in tumor cells which have different origins and different degree of malignancy. In 8 cases of gastric cancer tissues and adjacent tissues, the level of miRNA-21 in 6 cases was higher than that in adjacent tissues, 1 case had lower expression level than that in adjacent tissues, and 1 case had no significant difference. Furthermore, qRT-PCR method was used to verify the detection results based on the fluorescent probe detection method. The consistent results show that the molecular beacon assay has a good prospect in direct and rapid detection of miRNA-21 expression and will be widely used in the functional research and clinical diagnosis of microRNA. PMID- 30245722 TI - Determination of Chlorpromazine, Haloperidol, Levomepromazine, Olanzapine, Risperidone, and Sulpiride in Human Plasma by Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS). AB - Background and Objective: In this study, turbo-ion spray as an interface of tandem mass spectrometry (MS/MS) was performed for sensitive and accurate quantification of chlorpromazine, haloperidol, levomepromazine, olanzapine, risperidone, and sulpiride in plasma samples. Methods: Separation was performed by gradient reversed phase high-performance liquid chromatography using a mobile phase containing ammonium formiate 2 mM, pH 2.7, and acetonitrile flowing through a Restek PFP Propyl C18 analytical column (50 mm*2.1 mm i.d.) with particle size of 5 um, at a flow rate of 800 uL/min. Positive ion fragments were detected in multiple reaction monitoring (MRM) mode. Sample preparation was achieved by solid phase extraction (SPE) (Oasis HLB). Results: Mean extraction recoveries ranged from 82.75% to 100.96%. The standard calibration curves showed an excellent linearity, covering subtherapeutic, therapeutic, and toxic ranges. Intraday and interday validation using quality control (QC) samples were performed. The inaccuracy and imprecision were below 12% at all concentration levels. The limits of detection (LOD) and quantification (LOQ) for all analytes were under therapeutic ranges for all tested analytes. Thus, the proposed method was sensitive enough for the detection and determination of subtherapeutic levels of these antipsychotics in plasma samples. No interference of endogenous or exogenous molecules was observed and no carryover effects were recorded. Conclusion: According to the results, the proposed method is simple, specific, linear, accurate, and precise and can be applied for antipsychotic analysis in clinical routine. This method was applied for the determination of the tested antipsychotics in plasma samples taken from 71 individuals. PMID- 30245723 TI - Comparative Glycopeptide Analysis for Protein Glycosylation by Liquid Chromatography and Tandem Mass Spectrometry: Variation in Glycosylation Patterns of Site-Directed Mutagenized Glycoprotein. AB - Glycosylation is one of the most important posttranslational modifications for proteins, including therapeutic antibodies, and greatly influences protein physiochemical properties. In this study, glycopeptide mapping of a reference and biosimilar recombinant antibodies (rAbs) was performed using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) and an automated Glycoproteome Analyzer (GPA) algorithm. The tandem mass analyses for the reference and biosimilar samples indicate that this approach proves to be highly efficient in reproducing consistent analytical results and discovering the implications of different rAb production methods on glycosylation patterns. Furthermore, the comparative analysis of a mutagenized rAb glycoprotein proved that a single amino acid mutation in the Fc portion of the antibody molecule caused increased variations in glycosylation patterns. These variations were also detected by the mass spectrometry method efficiently. This mapping method, focusing on precise glycopeptide identification and comparison for the identified glycoforms, can be useful in differentiating aberrant glycosylation in biosimilar rAb products. PMID- 30245724 TI - Prevalence and Factors Associated with Anemia among Pregnant Women Attending Antenatal Clinic at St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia. AB - Background: In pregnancy, anemia is an important factor associated with an increased risk of maternal, fetal, and neonatal mortality, poor pregnancy outcomes, and impaired cognitive development, particularly in developing countries like Ethiopia. This study aimed to assess prevalence and factors associated with anemia among pregnant women attending antenatal clinic at St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia. Method: A cross-sectional health facility based study was conducted on 284 pregnant women to assess prevalence and factors associated with anemia at St. Paul's Hospital Millennium Medical College from June to August 2014. Data on sociodemographic and clinical characteristics of the study participants were collected using a pretested structured questionnaire by interview and review of medical records. About 4 ml of venous blood was collected from each subject for peripheral blood film and complete blood counts (CBC). Binary Logistic regression analysis had been used to check for association between dependent and independent variables. In all cases, P value less than 0.05 was considered statistically significant. Result: The prevalence of anemia was found to be 11.6% (95 % CI; 7.8%-14.8%). Pregnant women in the second [AOR (95% CI), 6.72 (1.17-38.45), and P=0.03] and third trimester [AOR (95% CI), 8.31 (1.24-55.45), and P=0.029] were more likely to be anemic when compared to pregnant women in their first trimester. Pregnant women who did not receive iron/folic acid supplementation [AOR (95%CI), 4.03(1.49 10.92), and P=0.01] were more likely to be anemic when compared to pregnant women who did take supplementations. Conclusion: In this study the prevalence of anemia in pregnancy was low compared to the findings of others. Gestational age (trimester) and iron/folic acid supplementation were statistically associated with anemia. Therefore, iron supplementation and health education to create awareness about the importance of early booking for antenatal care are recommended to reduce anemia. PMID- 30245725 TI - An Improved Method for Temporary Suture Medialisation of the Middle Turbinates following Endoscopic Sinus Surgery. AB - Background: Middle turbinate (MT) lateralisation with adhesion formation (MiTLAF) is a common complication following endoscopic sinus surgery, frequently resulting in surgical failure, persistence of preoperative symptoms, and delayed secondary complications. Packing materials, splints, or spacers reduce the risk of MiTLAF but often result in postoperative nasal obstruction and discomfort, along with reduced access for irrigation. Temporary suture medialisation of the MTs reduces the risk of MiTLAF and prevents the problems encountered with packing, splints, or spacers. However, the techniques described in the literature are technically challenging and often ineffectual. Methods: We describe a method of suture placement that provides a secure temporary MT medialisation, without the technical challenges of traditional techniques, using a 4-0 Monocryl (Poliglecaprone 25, Ethicon, Somerville, NJ, USA) suture on a 19 mm precision point reverse cutting PS-2 curved needle. We review 25 consecutive patients undergoing sinonasal procedures with our new technique and assess for MiTLAF. Results: In our cohort, only one patient experienced MiTLAF which was not clinically significant. Conclusions: Our method is simple, easy to perform, and highly effective and prevents adhesion formation without the need for postoperative splints or packing. PMID- 30245727 TI - Retrospective Cohort Analysis of Central Line Associated Blood Stream Infection following Introduction of a Central Line Bundle in a Neonatal Intensive Care Unit. AB - Background: Central Line Associated Bloodstream Infections (CLABSI) constitute a leading cause of morbidity and mortality in neonatal populations. There has been an overwhelming increase in the use of evidence-based care practices, also known as bundles, in the reduction of these infections. In this report, rates of CLABSI and central line utilisation were examined following the introduction of a central line bundle in our Neonatal Intensive Care Unit (NICU) at the Canberra Hospital. Methods: The research undertaken was a retrospective cohort study in which newborn infants admitted to the Canberra Hospital NICU between January 2011 and December 2016 and had a central line inserted were included in the study. Data regarding central line days, bed days, infection rates, and patient demographics were collected before and after the introduction of an intervention bundle. CLABSI rates were calculated per 1,000 central line days for before (2011 2013) and after (2014-2016) the introduction of the bundle. The postintervention period was retrospectively analysed for compliance, with data regarding the completion of maintenance forms and insertion forms collected. Results: Overall, the results showed a significant decrease in CLABSI rates from 8.8 per 1,000 central line days to 4.9 per 1,000 central line days in the intervention period (p<0.001). Central line utilisation ratio (CLUR: ratio of central line days to bed days) was also reduced between pre- and postintervention periods, from 0.177 (4414/25013) to 0.13 (3633/27384; p<0.001). Compliance to insertion forms and maintenance forms was observed to increase within the intervention period. Conclusion: The implementation of a central line bundle was effective in reducing both CLABSI rates and dwell time (CLUR) for central venous catheters. PMID- 30245728 TI - High Occurrence of Staphylococcus aureus Isolated from Fitness Equipment from Selected Gymnasiums. AB - Introduction: Staphylococcus aureus is a leading cause of cutaneous bacterial infection involving community. Methods: In this study, a total of 42 swab samples were collected from the surface of various fitness equipment such as back machines, exercise mats, dip stations, dumbbells, and treadmills. Identification of the bacterial isolates was conducted using biochemical tests and further analysed molecularly using the PCR method targeting nuc gene (270 bp). The nuc gene encodes for the thermonuclease enzyme, a virulent factor of S. aureus. Results: The findings showed 31 out of 42 swab samples (73.81%) were positive with S. aureus. Conclusion: This study showed that gymnasium equipment is a potential reservoir for S. aureus and might play an important role in transmitting the pathogen to humans. Objective: This study was undertaken to assess the presence of S. aureus on the surface of fitness equipment from selected gymnasiums in Kuching and Kota Samarahan, Sarawak (Malaysia). PMID- 30245726 TI - Integration of Genome-Wide DNA Methylation and Transcription Uncovered Aberrant Methylation-Regulated Genes and Pathways in the Peripheral Blood Mononuclear Cells of Systemic Sclerosis. AB - Objective. Systemic sclerosis (SSc) is a systemic connective tissue disease of unknown etiology. Aberrant gene expression and epigenetic modifications in circulating immune cells have been implicated in the pathogenesis of SSc. This study is to delineate the interaction network between gene transcription and DNA methylation in PBMC of SSc patients and to identify methylation-regulated genes which are involved in the pathogenesis of SSc. Methods. Genome-wide mRNA transcription and global DNA methylation analysis were performed on PBMC from 18 SSc patients and 19 matched normal controls (NC) using Illumina BeadChips. Differentially expressed genes (DEGs) and differentially methylated positions (DMPs) were integrative analyzed to identify methylation-regulated genes and associated molecular pathways. Results. Transcriptome analysis distinguished 453 DEGs (269 up- and 184 downregulated) in SSc from NC. Global DNA methylation analysis identified 925 DMPs located on 618 genes. Integration of the two lists revealed only 20 DEGs which harbor inversely correlated DMPs, including 12 upregulated (ELANE, CTSG, LTBR, C3AR1, CSTA, SPI1, ODF3B, SAMD4A, PLAUR, NFE2, ZYX, and CTSZ) and eight downregulated genes (RUNX3, PRF1, PRKCH, PAG1, RASSF5, FYN, CXCR6, and F2R). These potential methylation-regulated DEGs (MeDEGs) are enriched in the pathways related to immune cell migration, proliferation, activation, and inflammation activities. Using a machine learning algorism, we identified six out of the 20 MeDEGs, including F2R, CXCR6, FYN, LTBR, CTSG, and ELANE, which distinguished SSc from NC with 100% accuracy. Four genes (F2R, FYN, PAG1, and PRKCH) differentially expressed in SSc with interstitial lung disease (ILD) compared to SSc without ILD. Conclusion. The identified MeDEGs may represent novel candidate factors which lead to the abnormal activation of immune regulatory pathways in the pathogenesis of SSc. They may also be used as diagnostic biomarkers for SSc and clinical complications. PMID- 30245729 TI - New Contributions to Asarum Powder on Immunology Related Toxicity Effects in Lung. AB - Objective. Asarum is widely used in clinical practice of Chinese medicine in the treatment of respiratory diseases. Many toxic ingredients (safrole, etc.) had been found in Asarum that show multiple visceral toxicities. In this study, we performed systematic investigation of expression profiles of genes to take a new insight into unclear mechanism of Asarum toxicities in lung. Methods. mRNAs were extracted from lungs of rats after intragastric administration with/without Asarum powders, and microarray assays were applied to investigate gene expression profiles. Differentially expressed genes with significance were selected to carry out GO analysis. Subsequently, quantitative PCRs were performed to verify the differential expression of Tmprss6, Prkag3, Nptx2, Antxr11, Klk11, Rag2, Olr77, Cd7, Il20, LOC69, C6, Ccl20, LOC68, and Cd163 in lung. Changes of Ampk, Bcl2, Caspase 3, Il1, Il20, Matriptase2, Nfkappab, Nptx2, and Rag2 in the lung on protein level were verified by western blotting and immunohistochemistry. Results. Compared with control group, the estimated organ coefficients were relatively increased in Asarum group. Results of GO analysis showed that a group of immune related genes in lung were expressed abnormally. The result of PCRs showed that Ccl20 was downregulated rather than other upregulated genes in the Asarum group. Western blotting and immunohistochemistry images showed that Asarum can upregulate the expression of Ampk, Caspase 3, Il1, Il20, Matriptase2, Nfkappab, and Rag2 and downregulate the expression of Bcl2 in lung. Conclusion. Our data suggest that expressions of immune related genes in lung were selectively altered by Asarum. Therefore, inflammatory response was active, by regulating Caspase 3, Il1, Il20, Matriptase2, Nfkappab, Rag2, Tmprss6, Prkag3, Nptx2, Antxr1, Klk11, Olr77, Cd7, LOC69, C6, LOC68, Cd163, Ampk, Bcl2, and Ccl20. Our study indicated that inflammatory factors take effect in lung toxicity caused by Asarum, which provides a new insight into molecular mechanism of Asarum toxicities in lung. PMID- 30245730 TI - Aqueous Extract of Semen Ziziphi Spinosae Exerts Anxiolytic Effects during Nicotine Withdrawal via Improvement of Amygdaloid CRF/CRF1R Signaling. AB - Anxiety during nicotine withdrawal (NicW) is a key risk factor for smoking relapse. Semen Ziziphi Spinosae (SZS), which is a prototypical hypnotic-sedative herb in Oriental medicine, has been clinically used to treat insomnia and general anxiety disorders for thousands of years. Thus, the present study evaluated the effects of the aqueous extract of SZS (AESZS) on NicW-induced anxiety in male rats that received subcutaneous administrations of nicotine (Nic) (0.4 mg/kg, twice a day) for 7 d followed by 4 d of withdrawal. During NicW, the rats received four intragastric treatments of AESZS (60 mg/kg/d or 180 mg/kg/d). AESZS dose-dependently attenuated NicW-induced anxiety-like behaviors in the elevated plus maze (EPM) tests and 180 mg/kg/d AESZS inhibited NicW-induced increases in plasma corticosterone. Additionally, the protein and mRNA expressions of corticotropin-releasing factor (CRF) and CRF type 1 receptor (CRF1R) increased in the central nucleus of the amygdala (CeA) during NicW, but these changes were suppressed by 180 mg/kg/d AESZS. A post-AESZS infusion of CRF into the CeA abolished the attenuation of anxiety by AESZS and 180 mg/kg/d AESZS suppressed NicW-induced increases in norepinephrine and 3-methoxy-4-hydroxy-phenylglycol levels in the CeA. The present results suggest that AESZS ameliorated NicW induced anxiety via improvements in CRF/CRF1R and noradrenergic signaling in the CeA. PMID- 30245731 TI - UPLC-QTOF/MS-Based Lipidomic Profiling of Liver Qi-Stagnation and Spleen Deficiency Syndrome in Patients with Hyperlipidemia. AB - Hyperlipidemia is a common disease caused by abnormal plasma lipid metabolism. Lipidomics is a powerful and efficient technology to study the integration of disease and syndrome of Chinese medicine. This study investigated specific changes in lipid metabolites from hyperlipidemia patients with syndrome of liver qi-stagnation and spleen-deficiency (SLQSD). Lipid profiles in plasma samples from 29 hyperlipidemia patients including 10 SLQSD and 19 non-SLQSD and 26 healthy volunteers (NC) were tested by UPLC-QTOF/MS. PLS-DA analysis and database searching were performed to discover differentiating metabolites. Differences in lipid metabolites between hyperlipidemia and healthy people mainly include phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, and ceramides. Hyperlipidemia patients with SLQSD and non-SLQSD could be differentiated by using identified lipid metabolites including phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, triglycerides, diacylglycerols, lysophosphatidylethanolamines, sphingomyelins, lysophosphatidylcholines, and lactosylceramides. There were significant differences of lipid metabolism between between different syndromes of the same disease such as hyperlipidemia which showed significant differences between SLQSD and non-SLQSD. PMID- 30245733 TI - Targeting HPV16 DNA using CRISPR/Cas inhibits anal cancer growth in vivo. AB - Aim: The goal of this study was to determine if a single AAV vector, encoding Cas9 and guide RNAs specific for the HPV16 E6 and E7 genes, could inhibit the growth of an HPV16-induced tumor in vivo. Materials & methods: We grew HPV16+, patient-derived anal cancer explants in immunodeficient mice and then challenged these by injection of AAV-based vectors encoding Cas9 and control or HPV16 specific guide RNAs. Results & conclusion: We observed a significant and selective reduction in tumor growth when the HPV16 E6 and E7 genes were targeted using Cas9. These studies provide proof of principle for the hypothesis that CRISPR/Cas has the potential to be used to selectively treat HPV-induced tumors in humans. PMID- 30245732 TI - Effects of Mantra Meditation versus Music Listening on Knee Pain, Function, and Related Outcomes in Older Adults with Knee Osteoarthritis: An Exploratory Randomized Clinical Trial (RCT). AB - Objective: Disease-modifying treatments for OA remain elusive, and commonly used medications can have serious side effects. Although meditation and music listening (ML) have been shown to improve outcomes in certain chronic pain populations, research in OA is sparse. In this pilot RCT, we explore the effects of two mind-body practices, mantra meditation (MM) and ML, on knee pain, function, and related outcomes in adults with knee OA. Methods: Twenty-two older ambulatory adults diagnosed with knee OA were randomized to a MM (N=11) or ML program (N=11) and asked to practice 15-20 minutes, twice daily for 8 weeks. Core outcomes included knee pain (Knee Injury and Osteoarthritis Outcome Score [KOOS] and Numeric Rating Scale), knee function (KOOS), and perceived OA severity (Patient Global Assessment). Additional outcomes included perceived stress (Perceived Stress Scale), mood (Profile of Mood States), sleep (Pittsburgh Sleep Quality Index), and health-related quality of life (QOL, SF-36). Participants were assessed at baseline and following completion of the program. Results: Twenty participants (91%) completed the study (9 MM, 11 ML). Compliance was excellent; participants completed an average of 12.1+/-0.83 sessions/week. Relative to baseline, participants in both groups demonstrated improvement post intervention in all core outcomes, including knee pain, function, and perceived OA severity, as well as improvement in mood, perceived stress, and QOL (Physical Health) (p's<=0.05). Relative to ML, the MM group showed greater improvements in overall mood and sleep (p's<=0.04), QOL-Mental Health (p<0.07), kinesiophobia (p=0.09), and two domains of the KOOS (p's<0.09). Conclusions: Findings of this exploratory RCT suggest that a simple MM and, possibly, ML program may be effective in reducing knee pain and dysfunction, decreasing stress, and improving mood, sleep, and QOL in adults with knee OA. PMID- 30245734 TI - Defective (interfering) viral genomes re-explored: impact on antiviral immunity and virus persistence. AB - Defective viral genomes (DVGs) are natural products of virus replication that occur in many positive and negative sense RNA viruses, including Ebola, dengue and respiratory syncytial virus. DVGs, which have severe genomic truncations and require a helper virus to replicate, have three well-described functions: interference with standard virus replication, immunostimulation, and establishment of virus persistence. These functions of DVGs were first described almost 50 years ago, yet only recent studies have shown the molecular intersection between their immunostimulatory and pro-persistence activities. Here, we review more than half a century of scientific literature on the immunostimulatory and pro-persistence functions of DVGs. We highlight recent advances in the field and the critical role DVGs have in both the acute and long term virus-host interactions. PMID- 30245736 TI - A quantitative performance study of two automatic methods for the diagnosis of ovarian cancer. AB - We present a quantitative study of the performance of two automatic methods for the early detection of ovarian cancer that can exploit longitudinal measurements of multiple biomarkers. The study is carried out for a subset of the data collected in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). We use statistical analysis techniques, such as the area under the Receiver Operating Characteristic (ROC) curve, for evaluating the performance of two techniques that aim at the classification of subjects as either healthy or suffering from the disease using time-series of multiple biomarkers as inputs. The first method relies on a Bayesian hierarchical model that establishes connections within a set of clinically interpretable parameters. The second technique is a purely discriminative method that employs a recurrent neural network (RNN) for the binary classification of the inputs. For the available dataset, the performance of the two detection schemes is similar (the area under ROC curve is 0.98 for the combination of three biomarkers) and the Bayesian approach has the advantage that its outputs (parameters estimates and their uncertainty) can be further analysed by a clinical expert. PMID- 30245735 TI - Antiviral therapeutic approaches for human rhinovirus infections. AB - Human rhinoviruses are the primary etiological agent of the common cold. This infection can be mild and self-limiting in immunocompetent hosts, but can be associated with bronchiolitis in infants, pneumonia in the immunosuppressed and exacerbations of pre-existing pulmonary conditions such as asthma or chronic obstructive pulmonary disease. Many of these conditions can place significant economic costs upon healthcare infrastructure. There is currently no licensed vaccine for rhinovirus, as the large variety of rhinovirus serotypes has posed significant challenges for research. In this review, we discuss current knowledge around antiviral drugs and small molecule inhibitors of rhinovirus infection, as well as antiviral host defense peptides as exciting prospects to approach the development of novel therapeutics which target human rhinovirus. PMID- 30245738 TI - Validity and Reliability of the Newly Developed Surface Electromyography Device for Measuring Muscle Activity during Voluntary Isometric Contraction. AB - Objective: The purpose of this study was to establish the validity and reliability of the newly developed surface electromyography (sEMG) device (PSL EMG-Tr1) compared with a conventional sEMG device (BTS-FREEEMG1000). Methods: In total, 20 healthy participants (10 males, age 30.3 +/- 2.9 years; 10 females, age 22.3 +/- 2.7 years) were recruited. EMG signals were recorded simultaneously on two devices during three different isometric contractions (maximal voluntary isometric contraction (MVIC, 40% MVIC, 80% MVIC)). Two trials were performed, and the same session was repeated after 1 week. EMG amplitude recorded from the dominant biceps brachii (BB) and rectus femoris (RF) muscles was analyzed for reliability using intrasession intraclass correlation coefficient (ICC). Concurrent validity of the two devices was determined using Pearson's correlation coefficient. Results: Nonnormalized sEMG data showed moderate to very high reliability for all three contraction levels (ICC = 0.832-0.937 (BB); ICC = 0.814 0.957 (RF)). Normalized sEMG values showed no to high reliability (ICC = 0.030 0.831 (BB); ICC = 0.547-0.828 (RF)). sEMG signals recorded by the PSL-EMG-Tr1 showed good to excellent validity compared with the BTS-FREEEMG1000, at 40% MVIC (r = 0.943 (BB), r = 0.940 (RF)) and 80% MVIC (r = 0.983 (BB); r = 0.763 (RF)). Conclusions: The PSL-EMG-Tr1 was performed with acceptable validity. Furthermore, the high accessibility and portability of the device are useful in adjusting the type and intensity of exercise. PMID- 30245737 TI - Mathematical Analysis of Influenza A Dynamics in the Emergence of Drug Resistance. AB - Every year, influenza causes high morbidity and mortality especially among the immunocompromised persons worldwide. The emergence of drug resistance has been a major challenge in curbing the spread of influenza. In this paper, a mathematical model is formulated and used to analyze the transmission dynamics of influenza A virus having incorporated the aspect of drug resistance. The qualitative analysis of the model is given in terms of the control reproduction number, Rc. The model equilibria are computed and stability analysis carried out. The model is found to exhibit backward bifurcation prompting the need to lower Rc to a critical value Rc* for effective disease control. Sensitivity analysis results reveal that vaccine efficacy is the parameter with the most control over the spread of influenza. Numerical simulations reveal that despite vaccination reducing the reproduction number below unity, influenza still persists in the population. Hence, it is essential, in addition to vaccination, to apply other strategies to curb the spread of influenza. PMID- 30245739 TI - Adapting Psychological Therapies for Autism - Therapist Experience, Skills and Confidence. AB - Background: Psychological interventions informed by cognitive behavioural theory have proven efficacy in treating mild-moderate anxiety and depression. They have been successfully adapted for autistic children and adults who experience disproportionately high rates of co-occurring emotional problems. There has been little research into the perspectives and experience of psychological therapists adapting cognitive behavioural therapy (CBT) as part of routine clinical practice. We surveyed therapist skills, experience and confidence in working psychologically with autistic people, in order to highlight gaps and needs, as well as strengths in terms of therapist skills when working with this group. Method: Fifty therapists attending a training event completed a survey about their experience of adapting CBT for autistic clients, alongside a measure of therapist confidence. Results: Almost all therapists reported making adaptations to CBT practice when working with autistic clients. Key challenges identified were rigidity in thinking and pacing sessions appropriately. Therapists were relatively confident about core engagement and assessment skills but reported less confidence in using their knowledge to help this group. Therapist confidence was not associated with years of practice or number of adaptations made, but was positively associated with level of therapy training received. Conclusions: This study highlights a need for training and ongoing supervision to increase therapist confidence in and ability to make appropriate adaptations to CBT treatment protocols for autistic people. PMID- 30245740 TI - An Investigation of Dynamic Responses and Head Injuries of Standing Subway Passengers during Collisions. AB - With the development of the subway and the pressing demand of environmentally friendly transportation, more and more people travel by subway. In recent decades, the issues about passenger passive safety on the train have received extensive attention. In this research, the head injury of a standing passenger in the subway is investigated. Three MADYMO models of the different standing passenger postures, defined as baseline scenarios, are numerically set up. HIC15 values of passengers with different postures are gained by systematic parametric studies. The injury numerical simulation results of various scenarios with different friction coefficients, collision acceleration, standing angle, horizontal handrail height, and ring handrail height are analyzed. Results show that the horizontal handrail provides better protection in the three different standing passenger postures. Different friction coefficients and the standing angle have great impact on the head injuries of passengers in three different scenarios. The handrail height also has some effects on head injury of passengers with different standing postures, so it is necessary to be considered when designing the interior layout of the subway. This study may provide guidance for the safety design of the subway and some advices for standing subway passengers. PMID- 30245741 TI - Transcriptome and gene expression analysis of docosahexaenoic acid producer Schizochytrium sp. under different oxygen supply conditions. AB - Background: Schizochytrium sp. is a promising strain for the production of docosahexaenoic acid (DHA)-rich oil and biodiesel, and has been widely used in the food additive and bioenergy industries. Oxygen is a particularly important environmental factor for cell growth and DHA synthesis. In general, higher oxygen supply favors lipid accumulation, but could lead to a reduction of the DHA percentage in total fatty acids in Schizochytrium sp. To tackle this problem, it is essential to understand the mechanisms regulating the response of Schizochytrium sp. to oxygen. In this study, we aimed to explore the acclimatization of this DHA producer to different oxygen supply conditions by examining the transcriptome changes. Results: Two different fermentation processes, namely normal oxygen supply condition (shift agitation speeds from 400 rpm to 300 rpm) and high oxygen supply condition (constant agitation speeds: 400 rpm), were designed to study how the fermentation characteristics of Schizochytrium sp. HX-308 were affected by different oxygen supply conditions. The results indicated that high oxygen supply condition resulted in 49% and 37.5% improvement in the maximum cell dry weight (CDW) and total lipid concentration, respectively. However, the DHA percentage in total fatty acids decreased to 35%, which was 31.4% lower than that produced by normal oxygen supply condition. Moreover, transcriptome analysis was performed to explore the effect of the oxygen supply condition on genetic expression and metabolism. The results showed that glycolysis and pentose phosphate pathway metabolism-associated genes (hexokinase, phosphofructokinase, fructose-bisphosphate aldolase, glucose-6 phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase) were substantially upregulated in response to high oxygen supply, resulting in more NADPH was available for Schizochytrium. Specially, high oxygen supply condition also led to genes (Delta6 desaturase, Delta12 desaturase, FAS, ORFA, ORFB, and ORFC) involved in fatty acid biosynthesis upregulation. In addition, a transcriptional upregulation of catalase (CAT) became apparent under high oxygen supply condition, while superoxide dismutase (SOD) and ascorbate peroxidase (APX) were found to be down-regulated. Conclusions: This study is the first to investigate the differences of gene expression at different levels of oxygen availability in the DHA producer Schizochytrium. The results of transcriptome analyses indicated that high oxygen supply condition resulting in more NADPH and acetyl-CoA production for cell growth and lipid synthesis in Schizochytrium. Delta12 desaturase and ORFC showed higher expression levels at high oxygen supply condition, which might be the key regulators for enhancing fatty acid biosynthesis in the future. These results enrich the current knowledge regarding genetic expression and provide important information to enhance DHA production in Schizochytrium sp. PMID- 30245742 TI - Improving enzymatic digestibility of wheat straw pretreated by a cellulase-free xylanase-secreting Pseudomonas boreopolis G22 with simultaneous production of bioflocculants. AB - Background: Xylan removal by bacterial pretreatments has been confirmed to increase the digestibility of biomass. Here, an effective xylan removal technique has been developed to enhance the digestibility of wheat straw and simultaneously produce bioflocculants by a cellulase-free xylanase-secreting strain, Pseudomonas boreopolis G22. Results: The results indicated that P. boreopolis G22 is an alkaliphilic strain which can secrete abundant amounts of xylanase. This xylanase had activity levels of 2.67-1.75 U mL-1 after an incubation period of 5-25 days. The xylanase showed peak activity levels at pH 8.6, and retained more than 85% relative activity in the pH range of 7.2-9.8. After 15 days of cultivation, the hemicellulose contents of the wheat straw were significantly decreased by 32.5%, while its cellulose contents were increased by 27.3%, compared to that of the control. The maximum reducing sugars released from the 15-day-pretreated wheat straw were 1.8-fold higher than that of the untreated wheat straw, under optimal enzymatic hydrolysis conditions. In addition, a maximum bioflocculant yield of 2.08 g L-1 was extracted from the fermentation broth after 15 days of incubation. The aforementioned bioflocculants could be used to efficiently decolorize a dye solution. Conclusions: The results indicate that the cellulase-free xylanase secreting P. boreopolis G22 may be a potential strain for wheat straw pretreatments. The strain G22 does not only enhance the enzymatic digestibility of wheat straw, but also simultaneously produces a number of bioflocculants that can be used for various industrial applications. PMID- 30245743 TI - Role of polymorphonuclear neutrophils in the reperfused ischemic brain: insights from cell-type-specific immunodepletion and fluorescence microscopy studies. AB - Polymorphonuclear neutrophil granulocytes (PMNs) are part of the early post ischemic immune response that orchestrates the removal of infarcted brain tissue. PMNs contribute to secondary brain injury in experimental stroke models. In human patients, high PMN-to-lymphocyte ratios in peripheral blood are predictive of poor stroke outcome. Following earlier studies indicating that the cerebral microvasculature forms an efficient barrier that impedes PMN brain entry even under conditions of ischemia, more recent studies combining intravital two-photon microscopy and ex vivo immunohistochemistry unequivocally demonstrated the accumulation of PMNs in the ischemic brain parenchyma. In the meantime, transgenic mouse lines, such as mice expressing Cre-recombinase and the red fluorescent reporter protein tdTomato under the highly granulocyte-specific locus for the gene Ly6G (so-called Catchup mice), have become available that allow study of dynamic interactions of PMNs with brain parenchymal cells. These mice will further help us understand how PMNs promote brain injury and disturb brain remodeling and plasticity. PMID- 30245744 TI - Neurological complications of immune checkpoint inhibitors: what happens when you 'take the brakes off' the immune system. AB - Patients with advanced malignancies treated with immune checkpoint inhibitors are at increased risk for developing immune-related neurological complications. It is a phenomenon of immunological twist when immunotherapy against co-stimulatory molecules activates previously normal T cells to kill tumor cells but, in so doing, the T cells become unrestrained, triggering other autoimmune diseases for which conventional immunotherapy is needed. The most common autoimmune neurological diseases, usually occurring within 2-12 weeks after immune checkpoint inhibitor initiation, include: inflammatory myopathies, myasthenia gravis, acute and chronic demyelinating polyradiculoneuropathies, vasculitic neuropathies, isolated cranial neuropathies, aseptic meningitis, autoimmune encephalitis, multiple sclerosis and hypophysitis. The neurological events can evolve rapidly, necessitating the need for vigilance at all stages of treatment, even after completion, because early immunotherapeutic interventions are effective. The review addresses these complications and the applied therapies, discusses immune pathomechanisms including triggering preexisting autoimmunity, highlights the distinction between paraneoplastic and autoimmune etiologies, and identifies uncertainties regarding risk factors, use of immune checkpoint inhibitors in patients with known immune diseases or restarting therapy after a neurological event. Although the autoimmune neurological complications are not very common, their incidence will likely increase as the use of immune checkpoint inhibitors in metastatic cancer is growing rapidly. PMID- 30245745 TI - FUTURE GLOBAL MORTALITY FROM CHANGES IN AIR POLLUTION ATTRIBUTABLE TO CLIMATE CHANGE. PMID- 30245746 TI - Epidemiology of in-hospital cardiac arrest in Abu Dhabi, United Arab Emirates, 2013-2015. AB - Objective: Estimate the incidence and outcomes of in-hospital cardiac arrest (IHCA) in a tertiary-care hospital in Abu Dhabi emirate, United Arab Emirates (UAE). Methods: Retrospective data from 685 inpatients who experienced an IHCA at a hospital in Abu Dhabi (UAE) between 1 January 2013 and 31 December 2015 were analysed. Sociodemographic variables were age and gender, and IHCA event variables were shift, day, event location, initial cardiac rhythm and the total number of IHCA events. Outcome variables were the return of spontaneous circulation (ROSC) and survival to discharge (StD). Results: The incidence of IHCA was 11.7 (95% CI 10.8 to 12.6) per 1000 hospital admissions. Non-shockable rhythms were 91.1% of the cardiac rhythms at presentation. The majority of IHCA cases occurred in the intensive care unit (46.1%) and on weekdays (74.6%). More than a third (38.3%) of patients who experienced an IHCA achieved ROSC and 7.7% StD. Both ROSC and StD were significantly higher in patients who were younger and presenting with a shockable rhythm (all p's<=0.05). Survival outcomes were not significantly different between dayshifts and nightshifts or weekdays and weekends. Conclusions: The incidence of IHCA was higher and its outcomes were lower compared with other high-income/developed countries. Survival outcomes were better for patients who were younger and had a shockable rhythm, and similar between time of day and days of the week. These findings may help to inform health managers about the magnitude and quality of IHCA care in the UAE. PMID- 30245747 TI - "I Have No Idea What's Going On Out There:" Parents' Perspectives on Promoting Sexual Health in Lesbian, Gay, Bisexual, and Transgender Adolescents. AB - Lesbian, gay, bisexual, transgender, and other sexual and gender minority (LGBTQ) adolescents experience higher rates of negative sexual health outcomes relative to their heterosexual and cisgender peers. Healthy parent-adolescent relationships and effective parenting are robust predictors of sexual health in heterosexual adolescents, but very little is known about barriers to and facilitators of effective parenting from the perspective of parents of LGBTQ adolescents. This study conducted online focus groups with 44 parents of LGBTQ adolescents in order to describe the factors influencing effective sexual health communication and parental monitoring in this population. Parents described generally positive relationships with teens, but many noted they went through a transition process in which they struggled with their child's identity and were less supportive of their LGBTQ teen. Lack of understanding about LGBTQ-specific sexuality was a commonly endorsed barrier to effective communication, and this was most commonly endorsed by parents of cisgender girls. Parents of cisgender boys and transgender/gender-nonconforming teens described fears about long-term sexual health (i.e., sexual predators, consent) as a barrier to parental monitoring. Parents of LGBTQ adolescents need information and skills to optimize their teen's sexual health. Parent-based programs for LGBTQ adolescents are long overdue for addressing these issues. PMID- 30245748 TI - Estimation of on-road NO2 concentrations, NO2/NOX ratios, and related roadway gradients from near-road monitoring data. AB - This paper describes a new regression modeling approach to estimate on-road nitrogen dioxide (NO2) and oxides of nitrogen (NOX) concentrations and near-road spatial gradients using data from a near-road monitoring network. Field data were collected in Las Vegas, NV at three monitors sited 20, 100, and 300 m from Interstate-15 between December, 2008 and January, 2010. Measurements of NO2 and NOX were integrated over 1-hour intervals and matched with meteorological data. Several mathematical transformations were tested for regressing pollutant concentrations against distance from the roadway. A logit-ln model was found to have the best fit (R2 = 94.7%) and also provided a physically realistic profile. The mathematical model used data from the near-road monitors to estimate on-road concentrations and the near-road gradient over which mobile source pollutants have concentrations elevated above background levels. Average and maximum on-road NO2 concentration estimates were 33 ppb and 105 ppb, respectively. Concentration gradients were steeper in the morning and late afternoon compared with overnight when stable conditions preclude mixing. Estimated on-road concentrations were also highest in the late afternoon. Median estimated on-road and gradient NO2 concentrations were lower during summer compared with winter, with a steeper gradient during the summer, when convective mixing occurs during a longer portion of the day On-road concentration estimates were higher for winds perpendicular to the road compared with parallel winds and for atmospheric stability with neutral to-unstable atmospheric conditions. The concentration gradient with increasing distance from the road was estimated to be sharper for neutral-to-unstable conditions when compared with stable conditions and for parallel wind conditions compared with perpendicular winds. A regression of the NO2/NOX ratios yielded on road ratios ranging from 0.25 to 0.35, substantially higher than the anticipated tail-pipe emissions ratios. The results from the ratios also showed that the diurnal cycle of the background NO2/NOX ratios were a driving factor in the on road and downwind NO2/NOX ratios. PMID- 30245749 TI - Indication of Disrupted Temporal Structure in the Case of Thought Blocks in Schizophrenia: The Role of the Metastable Balance. AB - This study is aimed at investigating probable disruption of the metastable balance relevant to a disruption of the mental processes observed in the neurophenomenal level. This disruption was found to occur under dense auditory verbal hallucinations (AVHs) which are accompanied by thought blocking (TB) phenomena. The entropy that quantifies the complexity of the spontaneous coupling has been used to describe the observed transitions. According to our findings, the high synchrony-derived entropy (SE) defines a metastable state, where formations of cortical areas are able to coordinate transiently under the demands of stimulus-oriented processes or other internal cognitive associations. It was also found that the disruption of the sensitive balance to the side of oversynergy (overconnectedness) rather than the side of independence (coincidental coupling) is relevant with functional fixations under the specific symptom of schizophrenia. An introduced measure relative to the persistence of coupling indicated that the overcoupled brain areas exhibit a kind of "stiffness" in processing incoherent phasic components. Our consideration enhances the understanding of the role the metastability plays in the interpretation of deeply subjective phenomena, such as AVHs and TBs that affect the normal information routing in the brain. PMID- 30245750 TI - Scoping Review of the Driving Behaviour of and Driver Training Programs for People on the Autism Spectrum. AB - Gaining a driver's licence represents increased independence and can lead to improved quality of life for individuals and their families. Learning to drive a motor vehicle and maintaining safe on-road skills are often more difficult for people on the autism spectrum. Many countries currently have no autism-specific licencing requirements for learner drivers, and there is a general lack of ASD specific support and training packages for individuals, their families, and driving instructors. This review synthesises the peer-reviewed literature about the driving characteristics of drivers on the spectrum and driver training available for the cohort. The evidence in this review showed that individuals on the autism spectrum drive differently from their neurotypical counterparts. There are shortcomings in tactical skills of drivers on the autism spectrum, but the extent to which this affects their own safety or the safety of other road users is unclear. Tactical skills can be improved through training programs. There are few autism spectrum-specific learner training programs available. Development of an effective training program will benefit individuals on the spectrum to learn to drive, be independent, and be safe on the road. PMID- 30245751 TI - Gamma-Glutamyltransferase and Risk of Acute Coronary Syndrome in Young Chinese Patients: A Case-Control Study. AB - Background: Serum gamma-glutamyltransferase (GGT) is a biomarker of hepatic disease. Recent studies have shown that GGT may also associate with the risk of coronary artery disease. However, the underlying mechanisms of this association are still unclear. Methods: This study included 216 young patients with acute coronary syndrome (aged <=55years) and 227 age-matched controls with normal findings by coronary angiography or coronary computed tomography angiography. We use standard colorimetric techniques and sandwich enzyme-linked immunosorbent assay to measure the levels of GGT and oxidized low-density lipoprotein (ox-LDL), respectively. Traditional risk factors of coronary artery disease, including smoking, diabetes mellitus, hypertension, dyslipidemia, and obesity/overweight, were evaluated according to the current guidelines. Results: The levels of GGT were significantly correlated with body mass index and levels of triglyceride, fasting plasma glucose, aspartate aminotransferase, and ox-LDL (all P < 0.05). Multivariate logistic regression analysis showed that GGT was significantly associated with the risk of acute coronary syndrome in young Chinese patients (OR = 1.53, 95% CI = 1.09-2.15) after adjusting for traditional risk factors, including sex, age, quantity of smoking, hypertension, diabetes, body mass index, dyslipidemia, and high-sensitivity C-reactive protein. However, this association was significantly attenuated (OR = 1.20, 95% CI = 0.91-1.58) after further adjusting for the levels of ox-LDL. Conclusions: GGT was associated with the risk of ACS in relatively young patients. The link between GGT and the risk of ACS may be dependent on ox-LDL levels, indicating that the prooxidant action is an important pathway for GGT in the development of cardiovascular disease. PMID- 30245753 TI - Circulating Heat Shock Protein 70 Is a Novel Biomarker for Early Diagnosis of Lung Cancer. AB - Heat shock protein 70 (HSP70) was a highly conserved protein which was significantly induced in response to cellular stresses. HSP70 played an important role in the pathogenesis of cancer which stabilized the production of large amount of oncogenic proteins and finally supported growth and survival of tumor. However, there was no report about the diagnosis of circulating HSP70 in lung cancer patients. In this study, a total of 297 participants (lung cancer: 197, healthy control: 100) were enrolled in the detection of circulating HSP70 level in plasma by ELISA assay. The results indicated that circulating HSP70 significantly decreased in lung cancer patients compared to healthy controls (P < 0.0001). Receiver operating characteristic (ROC) analysis showed that HSP70 (AUC: 82.2%, SN: 74.1%, SP: 80.0%) had higher diagnosis value than clinical existing biomarkers CEA (AUC: 80.1%, SN: 76.8%, SP: 67.3%) and CA 19-9 (AUC: 63.7%, SN: 64.2%, SP: 54.0%). In the analysis of early lung cancer patients, ROC results also revealed that HSP70 (AUC: 83.8%, SN: 71.2%, SP: 84.0%) have higher sensitivity, specificity, and AUC than CEA (AUC: 73.7%, SN: 73.2%, SP: 69.1%) and CA 19-9 (AUC: 61.5%, SN: 69.4%, SP: 53.4%). In analysis of specific histological classifications, HSP70 showed more valuable in the diagnosis of SCC (AUC: 85.9%, SN: 86.1.9%, SP: 81.0%) than ADC (AUC: 81.0%, SN: 69.1%, SP: 81.0%). Combined analysis of HSP70 and existing biomarker: CEA and CA 19-9 exhibited that HSP70 combined CEA and CA 19-9 showed the highest AUC (0.945, 95% CI, 0.855-1.000). The importance of our results was that we found decreased circulating HSP70, in combination with elevated CEA and CA 19-9, could be utilized in the diagnosis of early (stage I and II) lung cancer. PMID- 30245754 TI - High-Sensitivity Troponin T and Soluble Form of AXL as Long-Term Prognostic Biomarkers after Heart Transplantation. AB - Antecedents: Cardiac allograft vasculopathy (CAV) is a frequent complication limiting the long-term (>1 year) survival after heart transplantation (HTx). CAV is initiated by endothelial dysfunction and can lead to severe cardiovascular (CV) complications. Since CAV is often clinically silent, biomarkers could help identifying HTx patients at risk of CAV and their severe complications. Aim: Evaluate the clinical yield of high-sensitivity cardiac troponin T (hs-cTnT), marker of cardiomyocyte damage, and the soluble form of AXL (sAXL), biomarker of endothelial dysfunction, to assess the prognosis of long-term cardiovascular (CV) events occurring after HTx. Methods: 96 patients were evaluated at least > 1 year after HTx. CAV was evaluated by coronary angiography or multisliced tomography, and hs-cTnT and sAXL measured 6 months before or after CAV evaluation. Patients were followed during 42 +/- 15 months for a combined end point including cardiac death, angina or acute myocardial infarction, left ventricular ejection fraction < 50%, or heart failure not due to an acute rejection. Results: 51 patients (53%) presented CAV at evaluation; 21 of them had CV events. Hs-cTnT (56 +/- 45 versus 20 +/- 18 ng/L; p = 0.04) and sAXL concentrations (98 +/- 51 versus 26 +/- 26 ng/L; p = 0.01) were significantly higher in patients with CV events. Hs-cTnT (HR 1.03; 95% CI 1.015-1.042, p = 0.0001) and sAXL (HR 1.01; 95% CI 1.001-1.019, p = 0.02) were independent predictors of CV events. A hs-cTnT concentration < 21 ng/L, detected by AUC ROC, predicted the absence of CV events with a predictive value of 91%; sAXL did not add more predictive value to hs-cTnT. Survival free of CV events was 92% in patients with hs-cTnT < 21 ng/L and 57% in those with hs cTnT > 21 ng/L (p < 0.001). Conclusion: Hs-cTnT, but not sAXL, measured during the long-term follow-up of HTx patients appears as a helpful biomarker to identify patients at low risk of adverse CV outcomes. PMID- 30245752 TI - Association between MnSOD Val16Ala Polymorphism and Cancer Risk: Evidence from 33,098 Cases and 37,831 Controls. AB - Manganese superoxide dismutase (MnSOD) plays a critical role in the defense against reactive oxygen species. The association between MnSOD Val16Ala polymorphism and cancer risk has been widely studied, but the results are contradictory. To obtain more precision on the association, we performed the current meta-analysis with 33,098 cases and 37,831 controls from 88 studies retrieved from PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of association. We found that the polymorphism was associated with an increased overall cancer risk (homozygous: OR = 1.09, 95% CI = 1.00-1.19; heterozygous: OR = 1.07, 95% CI = 1.02-1.12; dominant: OR = 1.08, 95% CI = 1.02-1.14; and allele comparison: OR = 1.06, 95% CI = 1.02-1.11). Stratification analysis further showed an increased risk for prostate cancer, Asians, Caucasians, population-based studies, hospital-based studies, low quality and high quality studies. However, the increased risk for MnSOD Val16Ala polymorphism among Asians needs further validation based on the false-positive report probability (FPRP) test. To summarize, this meta-analysis suggests that the MnSOD Val16Ala polymorphism is associated with significantly increased cancer risk, which needs further validation in single large studies. PMID- 30245755 TI - Effects of Kudiezi Injection on Serum Inflammatory Biomarkers in Patients with Acute Cerebral Infarction. AB - Background: Kudiezi injection is a traditional Chinese medicine for acute cerebral infarction, but the exact mechanisms are poorly understood. Objective: To investigate the mechanisms of Kudiezi injection on the inflammatory response in the treatment of acute cerebral infarction. Methods: This was a prospective study of patients with acute cerebral infarction within 48 h of onset and treated between July 2012 and July 2016 at three hospitals in China. The patients were randomized to routine treatments (control group) versus routine treatments and Kudiezi injection (Kudiezi group). The National Institutes of Health Stroke Score was assessed on days 1, 3, 5, 7, and 14. The patients were tested for serum levels of pro- and anti-inflammatory cytokines (S100 calcium-binding protein B, neuron-specific enolase, interleukin-6, interleukin-10, interleukin-18, and matrix metaloproteinase-9; by enzyme-linked immunosorbent assay) immediately after admission and on days 3, 5, and 14. Results: Stroke scores were improved in both groups from days 1 to 14. On days 5 and 7, stroke scores in the Kudiezi group were lower than in the control group (P < 0.05). Compared with controls, the Kudiezi group had lower serum S100 calcium-binding protein B on day 14; higher interleukin-6 and interleukin-10 on day 3; lower interleukin-6 and interleukin-18 on day 5; and lower interleukin-18 and matrix metaloproteinase-9 on day 14. Conclusion: Kudiezi injection could lead to early reduction of interleukin-6, interleukin-18, matrix metaloproteinase-9, neuron-specific enolase, and S100 calcium-binding protein B levels and increases of interleukin 10 levels in patients with acute ischemic stroke. This trial is registered with ClinicalTrials.gov NCT01636154. PMID- 30245756 TI - Procalcitonin (PCT) Predicts Worse Outcome in Patients with Chronic Heart Failure with Reduced Ejection Fraction (HFrEF). AB - Introduction: Procalcitonin (PCT) is an excellent marker of sepsis but was not extensively studied in cardiology. The present study investigated PCT plasma concentration in patients with chronic heart failure with reduced ejection fraction (HFrEF) and its prognostic value during 24-month follow-up. Material and Methods: Study group consisted of 130 patients with HFrEF (LVEF <= 45%) and 32 controls. PCT level was assessed on admission in all patients. Telephone follow up was performed every three months over a period of 2 years. Endpoints were death of all causes and readmission for HFrEF exacerbation. Results: HFrEF patients had significantly higher PCT concentration than controls (166.95 versus 22.15 pg/ml; p < 0.001). Individuals with peripheral oedema had increased PCT comparing to those without oedema (217.07 versus 152.12 pg/ml; p < 0.02). In ROC analysis, PCT turned out to be a valuable diagnostic marker of HFrEF (AUC 0.91; p < 0.001). Kaplan-Meier survival curves revealed that patients with PCT in the 4th quartile had significantly lower probability of survival than those with PCT in the 1st and 2nd quartiles. In univariate, but not multivariate, analysis, procalcitonin turned out to be a significant predictor of death during 24-month follow-up. (HR 1.002; 95% CI 1.000-1.003; p < 0.03). Conclusions: Elevated PCT concentration may serve as another predictor of worse outcome in patients with HFrEF. PMID- 30245757 TI - Relation extraction with weakly supervised learning based on process-structure property-performance reciprocity. AB - In this study, we develop a computer-aided material design system to represent and extract knowledge related to material design from natural language texts. A machine learning model is trained on a text corpus weakly labeled by minimal annotated relationship data (~100 labeled relationships) to extract knowledge from scientific articles. The knowledge is represented by relationships between scientific concepts, such as {annealing, grain size, strength}. The extracted relationships are represented as a knowledge graph formatted according to design charts, inspired by the process-structure-property-performance (PSPP) reciprocity. The design chart provides an intuitive effect of processes on properties and prospective processes to achieve the certain desired properties. Our system semantically searches the scientific literature and provides knowledge in the form of a design chart, and we hope it contributes more efficient developments of new materials. PMID- 30245758 TI - Implementing an Information System Strategy: A Cost, Benefit, and Risk Analysis Framework for Evaluating Viable IT Alternatives in the US Federal Government. AB - In the US Federal government, an analysis of alternatives (AoA) is required for a significant investment of resources. The AoA yields the recommended alternative from a set of viable alternatives for the investment decision. This paper presents an integrated AoA and project management framework for analyzing new or emerging alternatives (e.g., Cloud computing), as may be driven by an information system strategy that incorporates a methodology for analyzing the costs, benefits, and risks of each viable alternative. The case study in this paper, about a business improvement project to provide public health and safety services to citizens in a US Federal agency, is a practical application of this integrated framework and reveals the benefits of this integrated approach for an investment decision. The decision making process in the framework-as an integrated, organized, and adaptable set of management and control practices-offers a defensible recommendation and provides accountability to stakeholders. PMID- 30245759 TI - Risk Factors Associated with Dengue Transmission and Spatial Distribution of High Seroprevalence in Schoolchildren from the Urban Area of Medellin, Colombia. AB - Dengue fever is an increasing health problem in tropical and subtropical regions. During 2010 in Medellin, the younger population presented a particularly high dengue incidence rate. This study estimated dengue virus (DENV) transmission in schoolchildren (aged 5-19 years) in Medellin from 2010 to 2012. A longitudinal serological survey (IgG) and spatial analysis were conducted to determine the distribution of DENV seroprevalence. A total of 4,385 schoolchildren participated for at least one year. Dengue seroprevalence significantly increased during the studied period (53.8% to 64.6%; p < 0.001). A significantly higher seroconversion rate was observed in 2010-2011 (16.8%) compared to 2011-2012 (7.8%). Multivariate regression analysis showed that the main factor associated with the seroprevalence was the aging. Furthermore, in 2010, patients with high socioeconomic status presented a lower risk. Predominant multitypic and DENV4 monotypic antibody responses were demonstrated. Geostatistical analysis evidenced a temporal clustering distribution of DENV seroprevalence in 2010. Population density and Ae. aegypti House Index were significantly correlated with the observed pattern. This study revealed high DENV transmission in schoolchildren determined as "sentinel population." High DENV risk was found in districts with combined poorly socioeconomic conditions and densest human and mosquito populations. These findings may allow to target population for effective prevention and vaccination campaigns. PMID- 30245761 TI - Dynamics of Formation of a Vapor Nanobubble Around a Heated Nanoparticle. AB - We study the formation of a nanobubble around a heated nanoparticle in a bulk liquid by using molecular dynamics simulations. The nanoparticle is kept at a temperature above the critical temperature of the surrounding liquid, leading to the formation of a vapor nanobubble attached to it. First, we study the role of both the temperature of the bulk liquid far away from the nanoparticle surface and the temperature of the nanoparticle itself on the formation of a stable vapor nanobubble. We determine the exact conditions under which it can be formed and compare this with the conditions that follow from a macroscopic heat balance argument. Next, we demonstrate the role of dissolved gas on the conditions required for nucleation of a nanobubble and on its growth dynamics. We find that beyond a certain threshold concentration, the dissolved gas dramatically facilitates vapor bubble nucleation due to the formation of gaseous weak spots in the surrounding liquid. PMID- 30245760 TI - Cuboidal Supraparticles Self-Assembled from Cubic CsPbBr3 Perovskite Nanocrystals. AB - Colloidal CsPbBr3 nanocrystals (NCs) have emerged as promising candidates for various opto-electronic applications, such as light-emitting diodes, photodetectors, and solar cells. Here, we report on the self-assembly of cubic NCs from an organic suspension into ordered cuboidal supraparticles (SPs) and their structural and optical properties. Upon increasing the NC concentration or by addition of a nonsolvent, the formation of the SPs occurs homogeneously in the suspension, as monitored by in situ X-ray scattering measurements. The three dimensional structure of the SPs was resolved through high-angle annular dark field scanning transmission electron microscopy and electron tomography. The NCs are atomically aligned but not connected. We characterize NC vacancies on superlattice positions both in the bulk and on the surface of the SPs. The occurrence of localized atomic-type NC vacancies-instead of delocalized ones indicates that NC-NC attractions are important in the assembly, as we verify with Monte Carlo simulations. Even when assembled in SPs, the NCs show bright emission, with a red shift of about 30 meV compared to NCs in suspension. PMID- 30245763 TI - Electrochemical Detection of NG-Hydroxy-L-arginine. AB - NG-hydroxy-L-arginine (NOHA) is a stable intermediate product in the consumption of L-arginine in the urea cycle by nitric oxide synthase (NOS) to produce nitric oxide (NO) and L-citrulline. Research has shown that the urea cycle is disrupted in various diseases. As one of the few electrochemically active species in the urea cycle, NOHA shows promise as a marker for detection of various diseases. Electrochemical detection is an established, cost-effective method that is able to successfully detect low levels of analyte concentrations. NOHA, to the best of our knowledge, has not been electrochemically detected previously. Using cyclic voltammetry with a glassy carbon electrode, we have found that NOHA has an oxidation peak at 355 mV with a sensitivity of 5.4 nA/MUM. We also investigated detecting NOHA with differential pulse voltammetry, which shows similar sensitivity and oxidation peaks. While there is significant work ahead to understand the kinetics of NOHA detection, the results here represent the first steps in making a NOHA biosensor. PMID- 30245762 TI - Tumor Digital Masking Allows Precise Patient Triaging: A Study Based on Ki-67 Scoring in Gastrointestinal Stromal Tumors. AB - Background: Technological advances constantly provide cutting-edge tools that enhance the progress of diagnostic capabilities. Gastrointestinal stromal tumors belong to a family of mesenchymal tumors where patient triaging is still based on traditional criteria such as mitotic count, tumor size, and tumor location. Limitations of the human eye and randomness in choice of area for mitotic figure counting compel us to seek more objective solutions such as digital image analysis. Presently, the labelling of proliferative activity is becoming a routine task amidst many cancers. The purpose of the present study was to compare the traditional method of prediction based on mitotic ratio with digital image analysis of cell cycle-dependent proteins. Methods: Fifty-seven eligible cases were enrolled. Furthermore, a digital analysis of previously performed whole tissue section immunohistochemical assays was executed. Digital labelling covered both hotspots and not-hotspots equally. Results: We noted a significant diversity of proliferative activities, and consequently, the results pointed to 6.5% of Ki 67, counted in hotspots, as the optimal cut-off for low-high-grade GIST. ROC analysis (AUC = 0.913; 95% CI: 0.828-0.997, p < 0.00001) and odds ratio (OR = 40.0, 95% CI: 6.7-237.3, p < 0.0001) pointed to Ki-67 16% as the cut-off for very high-grade (groups 5-6) cases. With help of a tumor digital map, we revealed possible errors resulting from a wrong choice of field for analysis. We confirmed that Ki-67 scores are in line with the level of intracellular metabolism that could be used as the additional biomarker. Conclusions: Tumor digital masking is very promising solution for repeatable and objective labelling. Software adjustments of nuclear shape, outlines, size, etc. are helpful to omit other Ki 67-positive cells especially small lymphocytes. Our results pointed to Ki-67 as a good biomarker in GIST, but concurrently, we noted significant differences in used digital approaches which could lead to unequivocal results. PMID- 30245764 TI - Thrombolysis May Dislodge Intracardiac Thrombus. PMID- 30245765 TI - Frequent Emergency Department Visits After Spontaneous Intracerebral Hemorrhage: Who Is at Risk? AB - Background: The long-term prognosis of spontaneous intracerebral hemorrhage (SICH) is poor. Frequent emergency department (ED) visits can signal increased risk of hospitalization and death. There are no studies describing the risk of frequent ED visits after SICH. Methods: Retrospective cohort study of a community representative consecutive SICH survivors (2009-2015) from southern Portugal. Logistic regression analysis was performed to identify sociodemographic and clinical factors associated with frequent ED visits (>=4 visits) within the first year after hospital discharge. Results: A total of 360 SICH survivors were identified, 358 (98.6%) of whom were followed. The median age was 72; 64% were males. The majority of survivors (n = 194, 54.2%) had at least 1 ED visit. Reasons for ED visits included infections, falls with trauma, and isolated neurological symptoms. Forty-four (12.3%) SICH survivors became frequent ED visitors. Frequent ED visitors were older and had more hospitalizations (P < .001) and ED visits (P < .001) prior to the SICH, unhealthy alcohol use (P = .049), longer period of index SICH hospitalization (P = .032), pneumonia during hospitalization (P = .001), and severe neurological impairment at discharge (P = .001). Pneumonia during index hospitalization (odds ratio [OR]: 3.08; confidence interval [CI]: 1.39-6.76; P = .005) and history of ED visits prior to SICH (OR: 1.64; CI: 1.19-2.26, P = .003) increased the likelihood of becoming a frequent ED visitor. Conclusions: Predictors of frequent ED visits are identifiable at hospital discharge and during any ED visit. Improvement of transitional care and identification of at-risk patients may help reduce multiple ED visits. PMID- 30245767 TI - Chronic and Subacute Meningitis: Differentiating Neoplastic From Non-Neoplastic Etiologies. AB - Background and Purpose: Although incidence rates vary, infectious, autoimmune, and neoplastic diseases can all cause chronic and subacute meningitis (CSM). We report a Latin-American, single center, CSM case series, analyzing the main clinical characteristics as well as ancillary diagnostic methods differentiating neoplastic from non-neoplastic etiologies. Methods: Retrospective review of CSM cases from a single center in Buenos Aires, Argentina. Results: Seventy patients with CSM diagnosis were identified, 49 with neoplastic and 21 with non-neoplastic meningitis. A history of previous cancer was significantly higher in neoplastic cases, whereas prevalence of autoimmune disease and fever was more common in non neoplastic meningitis. C-reactive protein values were higher in non-neoplastic CSM, as was pleocytosis in cerebrospinal fluid analysis. The most frequent etiologies were breast and lung cancer for neoplastic meningitis cases; and idiopathic, tuberculous, and fungal infection for non-neoplastic cases. Conclusions: Chronic and subacute meningitis diagnosis is challenging in daily neurological practice. The results we report contribute information from Latin America regarding etiologies of CSM, which can be identified after a comprehensive evaluation in a majority of cases. PMID- 30245766 TI - Trends in Tracheostomy After Stroke: Analysis of the 1994 to 2013 National Inpatient Sample. AB - Background: Real-world data on long-term trends in the use of tracheostomy after stroke are limited. Methods: Patients who underwent tracheostomy for acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH) were identified from the 1994 through 2013 releases of the National Inpatient Sample using previously validated International Classification of Diseases, Ninth Revision, Clinical Modification codes. Survey weights were used to report nationally representative estimates. Our primary outcome was the trend in tracheostomy use during the index stroke hospitalization over the last 20 years. Additionally, we evaluated trends in in-hospital mortality, timing of placement, and discharge disposition among patients who received a tracheostomy. Results: We identified 9.9 million patients with AIS, ICH, or SAH in the United States from 1994 to 2013, of which 170 255 (1.7%; 95% confidence interval [CI]: 1.6%-1.8%) underwent tracheostomy. Among all patients with stroke, tracheostomy use increased from 1.2% (95% CI: 1.1%-1.4%) in 1994 to 1.9% (95% CI: 1.8%-2.1%) in 2013, with similar trends across stroke types. From 1994 to 2013, the timing of tracheostomy decreased from 16.5 days (95% CI: 14.9-18.1 days) to 10.3 days (95% CI: 9.9-10.8 days) after mechanical ventilation. In-hospital mortality decreased from 32.6% (95% CI: 29.1%-36.1%) to 13.8% (95% CI: 12.3%-15.3%) among tracheostomy patients; however, discharge to a nonacute care facility increased from 42.9% (95% CI: 38.0%-47.8%) to 83.3% (95% CI: 81.6%-85.0%) and home discharge declined from 9.3% (95% CI: 7.3%-11.3%) to 2.9% (95% CI: 2.1%-3.7%). Conclusion: Over the past 2 decades, tracheostomy use has increased among patients with stroke. This increase was associated with earlier placement, reduced in-hospital mortality, and lower rates of home discharge. PMID- 30245768 TI - Activity Aprons for Inpatients Requiring Individual Nursing Assignment Care: A Prospective Randomized Controlled Pilot Study. AB - Background: Activity aprons are commercially available products used to occupy patients with dementia at home or in long-term care facilities. We hypothesized that inpatient use of activity aprons could potentially reduce or eliminate behaviors that result in self-harm, increased nursing supervision, and restraint use in an inpatient hospital setting. Methods: A single-center prospective randomized controlled pilot study was performed from July 2015 to November 2016 comparing activity apron plus standard care versus standard care alone. Consecutively enrolled patients were randomized by stratified randomization using age (cutoff: 80 years) and preexisting diagnosis of dementia or cognitive impairment. Primary outcomes were safety and feasibility of apron use. Secondary outcomes included duration of hospitalization postrandomization and individual nursing assignment (IA), time in restraints, nonphysical restraints use, falls, apron-related complications, dismissal destination, and 30-day hospital readmission. Results: Thirty patients were enrolled, with 13 randomized to apron and 17 randomized to the control group. There was no statistically significant reduction in mean length of hospital stay (15.8 vs 21.5 day; P = .40), duration of IA compared to non-apron control group (6.4 vs 9.1, respectively; P = .39), or antipsychotic medication use (61.5% vs 70.6% in control group; P = .60). No complications secondary to apron use were seen. Conclusions: Activity aprons are a safe addition to the standard of care when managing encephalopathic patients in the inpatient setting. These aprons may have a role as part of a comprehensive complement of interventions to address delirium and encephalopathy in hospitalized patients. PMID- 30245769 TI - Skull Base Metastasis Revealed by Bone Scintigraphy in a Patient With Hypoglossal Nerve Palsy. AB - Even though different imaging modalities are available in sole or in combination for the optimal detection of bone metastases, whole-body bone scintigraphy (BS) in a single session seems to be advantageous. We present an 80-year-old male with unilateral left hypoglossal nerve palsy (HNP) and no other focal deficits on neurological examination. Initial brain computed tomography (CT) scan revealed no pathological findings, while the subsequent cranial CT and magnetic resonance imaging (MRI) scans uncovered only mild nonspecific sclerotic lesions in left occipital condyle. All laboratory examinations were within normal limits, except for an elevated alkaline phosphatase (170 U/L) and a markedly increased prostate specific antigen (609 ng/mL). The patient underwent whole-body BS with technetium 99m that revealed increased radiotracer deposition compatible with metastases in multiple foci, including the left occipital condyle. Prostate biopsy confirmed the diagnosis of prostate adenocarcinoma. Our case suggests that a complete and thorough workup for hidden malignancies should be performed in all patients with HNP, even in the absence of a finding in brain neuroimaging. Bone scintigraphy is an essential investigation that should be considered in uncertain cases of HNP, and especially in those with negative CT and MRI scans. PMID- 30245771 TI - Clinical Problem-Solving: Fever and Rapidly Progressive Weakness in an Immunocompromised Patient. AB - Here we report the challenging case of a 41-year-old man with HIV complicated by AIDS and a history of prior neurologic injury from progressive multifocal leukoencephalopathy who presented with headache, fevers, lower extremity weakness, hyperreflexic upper extremities, and diminished lower extremity reflexes. We review the clinical decision-making and differential diagnosis for this presentation as the physical examination evolved and diagnostic testing changed over time. PMID- 30245770 TI - Miller Fisher Syndrome Associated With Immunotherapy for Metastatic Melanoma. AB - Immunotherapy is a treatment strategy that has demonstrated survival benefit for metastatic melanoma. Ipilimumab and nivolumab are examples of immunotherapy, in which monoclonal antibodies antagonize cytotoxic T-lymphocyte-associated protein 4 and programmed death-ligand 1 receptors, respectively, resulting in upregulation of the host immune response to cancer cells. There is increasing recognition of immune-mediated adverse events associated with immune therapies in patients with cancer. We present a case report of a patient who developed Miller Fisher syndrome associated with these therapies for metastatic melanoma along with a discussion of its management. PMID- 30245772 TI - Hypoglossal Nerve Palsy Due to Internal Carotid Artery Dissection. PMID- 30245773 TI - Dural Arteriovenous Fistula Causing Recurrent Transient Global Amnesia. PMID- 30245774 TI - Simvastatin Does Not Affect Nitric Oxide Generation Increased by Sesame Oil in Obese Zucker Rats. AB - Current treatments for cardiovascular and obesity-associated diseases, such as statin therapy, may be associated with several side effects. Products from food sources with polyphenolic compounds may represent promising agents in the treatment of cardiovascular and metabolic diseases with minimal side effects. Thus, we aimed to study the effect of sesame oil and simvastatin treatment on plasma lipid profile, nitric oxide generation, and oxidative load in obese Zucker rats. 12-week-old male Zucker rats were divided into the control and sesame oil- (1.25 ml/kg/day) treated Zucker lean groups, the control and sesame oil (1.25 ml/kg/day), or simvastatin (15 mg/kg/day) together with sesame oil-treated Zucker fa/fa groups, n = 6 in each group. The treatment lasted for 6 weeks. Sesame oil composition and plasma lipid profile were analyzed. Nitric oxide synthase (NOS) activity, endothelial NOS (eNOS), phosphorylated eNOS, and inducible NOS (iNOS) protein expressions were determined in the left ventricle and aorta. Oxidative load, measured as conjugated diene (CD) and thiobarbituric acid reactive substance (TBARS) concentrations, was detected in the liver. Neither sesame oil nor cotreatment with simvastatin affected plasma lipid profile in Zucker fa/fa rats. Sesame oil and similarly cotreatment with simvastatin markedly increased NOS activity and phosphorylated eNOS protein expressions in the left ventricle and aorta of Zucker fa/fa rats. There were no changes in eNOS and iNOS protein expressions within the groups and tissues investigated. Hepatic CD concentration was higher in Zucker fa/fa comparing Zucker lean rats, and sesame oil treatment decreased it significantly. Interestingly, this decrease was not seen after cotreatment with simvastatin. In conclusion, phosphorylation of eNOS and decreased oxidative load may significantly contribute to increase in total NOS activity with potential beneficial properties. Interestingly, simvastatin did not affect NO generation already increased by sesame oil in obese Zucker rats. PMID- 30245776 TI - Development and evaluation of a physics-based windblown dust emission scheme implemented in the CMAQ modeling system. AB - A new windblown dust emission treatment was incorporated in the Community Multiscale Air Quality (CMAQ) modeling system. This new model treatment has been built upon previously developed physics-based parameterization schemes from the literature. A distinct and novel feature of this scheme, however, is the incorporation of a newly developed dynamic relation for the surface roughness length relevant to small-scale dust generation processes. Through this implementation, the effect of nonerodible elements on the local flow acceleration, drag partitioning, and surface coverage protection is modeled in a physically based and consistent manner. Careful attention is paid in integrating the new windblown dust treatment in the CMAQ model to ensure that the required input parameters are correctly configured. To test the performance of the new dust module in CMAQ, the entire year 2011 is simulated for the continental United States, with particular emphasis on the southwestern United States (SWUS) where windblown dust concentrations are relatively large. Overall, the model shows good performance with the daily mean bias of soil concentrations fluctuating in the range of +/-1 MUg m-3 for the entire year. Springtime soil concentrations are in quite good agreement (normalized mean bias of 8.3%) with observations, while moderate to high underestimation of soil concentration is seen in the summertime. The latter is attributed to the issue of representing the convective dust storms in summertime. Evaluations against observations for seven elevated dust events in the SWUS indicate that the new windblown dust treatment is capable of capturing spatial and temporal characteristics of dust outbreaks. PMID- 30245777 TI - The evaluation of malignant mucosal melanoma of nasal cavity with a rare occasion. AB - Malignant mucosal melanoma is an uncommon disease with a low rate of survival. Malignancies of nasal mucosa which usually presents with nasal obstruction, epistaxis and back drip are difficult to treat and often have poor prognosis. The present case had presented to our clinic with classic symptoms and diagnostic findings of nasal polyposis. Consistently, the patient had previously been diagnosed with and treated for nasal polyposis in another ENT clinic. Physical examination, rhinoscopic examination, computed tomography (CT) scan of the head did not reveal any findings which might imply malignant formations. The operation had been planned for nasal polypectomy and taking deep biopsy specimens. The incised mass showed characteristic features of malignant tissues and the pathology report of the biopsy samples revealed that the specimen showed the histological signs of malignancy. Based on physical examination, CT findings and pathology reports the case was diagnosed as nasal mucosal melanoma. Following an oncosurgical operation, postoperative radio-therapy and chemotherapy were given to the patient and PET/CT examination of the patient did not indicate distant metastases. PMID- 30245778 TI - Nuestra Casa: An advocacy initiative to reduce inequalities and tuberculosis along the US-Mexico border. AB - The US-Mexico border provides a rich learning environment for professional social workers and at the same time poses some challenges. This article explores some of the unique demographics and social and cultural characteristics in the border region. These characteristics have implications for social work teaching, research, policy and practice. The study of borders includes exploring social disparities and inequalities. Health risks and diseases travel fluidly between borders and kill indiscriminately. The US-Mexico border is at high-risk of elevated tuberculosis (TB) and HIV incidence due to socio-economic stress, rapid and dynamic population growth, mobility and migration, and the hybridization of cultures. Every minute, four people die from TB, and 15 more become infected worldwide. The number of deaths due to tuberculosis is unacceptable given that most cases of TB are preventable. Cross-border cooperation and collaboration among social workers, health professionals and public officials between communities and countries can reduce social injustices to move towards a healthier borderland, as demonstrated in the collaborative prevention of TB. Rather than limiting our work to define social inequalities, we seek to further the conversation and suggest social action to address TB. This article contributes ideas and examples of experiences to encourage innovative, community academic engaged inter- and multidisciplinary interventions like the Nuestra Casa (Our House) initiative. Nuestra Casa is an advocacy, communication and social mobilization strategy to address TB and HIV health disparities and inequalities in underserved communities, which we argue provides a useful model for combating TB and other inequalities plaguing the US-Mexico borderland. PMID- 30245775 TI - Biological Activities, Health Benefits, and Therapeutic Properties of Avenanthramides: From Skin Protection to Prevention and Treatment of Cerebrovascular Diseases. AB - Oat (Avena sativa) is a cereal known since antiquity as a useful grain with abundant nutritional and health benefits. It contains distinct molecular components with high antioxidant activity, such as tocopherols, tocotrienols, and flavanoids. In addition, it is a unique source of avenanthramides, phenolic amides containing anthranilic acid and hydroxycinnamic acid moieties, and endowed with major beneficial health properties because of their antioxidant, anti inflammatory, and antiproliferative effects. In this review, we report on the biological activities of avenanthramides and their derivatives, including analogs produced in recombinant yeast, with a major focus on the therapeutic potential of these secondary metabolites in the treatment of aging-related human diseases. Moreover, we also present recent advances pointing to avenanthramides as interesting therapeutic candidates for the treatment of cerebral cavernous malformation (CCM) disease, a major cerebrovascular disorder affecting up to 0.5% of the human population. Finally, we highlight the potential of foodomics and redox proteomics approaches in outlining distinctive molecular pathways and redox protein modifications associated with avenanthramide bioactivities in promoting human health and contrasting the onset and progression of various pathologies. The paper is dedicated to the memory of Adelia Frison. PMID- 30245779 TI - ERCC5 rs751402 polymorphism is the risk factor for sporadic breast cancer in Thailand. AB - Breast cancer is a complex disease. Single Nucleotide Polymorphisms (SNPs) can modify the risk of cancer. They may be regarded as potential markers of carcinogenesis. Currently, the diversity or polymorphism of ERCC5 gene (excision repair cross-complementary group 5 gene or ERCC5) was reported to associate with an increased risk of breast cancer. This study aims to investigate the relationship between ERCC5 polymorphism and the breast cancer risk in the lower northeastern region women of Thailand. One hundred fifty five samples from breast cancer patients and 122 samples from healthy control group were analysed. Genomic DNA was extracted from white blood cell of all samples. The real-time polymerase chain reaction (qPCR) was used to demonstrate genetic polymorphism of ERCC5. The results showed that the ERCC5 rs751402 polymorphism variant AG was associated with an increased risk of breast cancer. The frequency of ERCC5 rs751402 in patients with breast cancer was higher than healthy control group. The ERCC5 rs751402 variant AG carrier was associated with increased breast cancer risk to 2.3 folds, with OR = 2.30, 95% CI = 1.22-4.35, P = 0.01, when age, menopause period, number of child, smoking and alcohol drinking were adjust. This study demonstrated that ERCC5 rs751402 genotype AG was associated with breast cancer risk in the lower northeastern region women of Thailand. PMID- 30245780 TI - Study of the genetic load and diversity of hereditary diseases in the Russian population of the Karachay-Cherkess Republic. AB - The genetic load and diversity of monogenic hereditary diseases (HD) in the Russian population of Karachay-Cherkess Republic (KCHR), living in 10 administrative and municipal divisions, were studied. The total size of the population surveyed was 410,367 people, including 134,756 Russians. In total, 385 patients from 281 families were registered among Russians of KCHR. Genetic load of AD, AR, and X-linked diseases (3.01 +/- 0.32, 1.98 +/- 0.26, and 1.23 +/- 0.29, respectively) are more than twice higher in cities and municipal centers than in corresponding rural regions (1.00 +/- 0.10, 0.89 +/- 0.09, and 0.42 +/- 0.09, respectively). The diversity of HD was 96 nosological forms: 56 diseases with AD type of inheritance (193 patients from 126 families), 28 clinical forms with AR (152 patients out of 124 families) and 12 diseases with the X-linked type of inheritance (40 affected from 31 families). A comparative analysis of the diversity of AD and AR HD with the previously studied populations and ethnic groups of the European part of Russia (Russians of 7 regions, 5 peoples of the Volga-Ural region, and 5 populations of the North Caucasus) was conducted, showing that Russians in the KCHR preserved genetic load with other Russian populations and its difference from the same mutation pool of Karachays and Circassians. PMID- 30245781 TI - INTRODUCTION TO THE EMF 32 STUDY ON U.S. CARBON TAX SCENARIOS. AB - This paper is an introduction to, "The EMF 32 Study on U.S. Carbon Tax Scenarios," part of the Stanford Energy Modeling Forum (EMF) Model Inter comparison Project (MIP) number 32. Eleven modeling teams participated in this study examining the economic and environmental impacts of various carbon tax trajectories and differing uses of carbon tax revenues. This special issue of Climate Change Economics documents the results of this study with four crosscutting papers that summarize results across models, and ten papers from individual modeling teams. PMID- 30245782 TI - An Evaluation of HTML5 and WebGL for Medical Imaging Applications. AB - Despite the fact that a large number of web applications are used in the medical community, there are still certain technological challenges that need to be addressed, for example, browser plug-ins and efficient 3D visualization. These problems make it necessary for a specific browser plug-in to be preinstalled on the client side when launching applications. Otherwise, the applications fail to run due to the lack of the required software. This paper presents the latest techniques in hypertext markup language 5 (HTML5) and web graphics library (WebGL) for solving these problems and an evaluation of the suitability of the combination of HTML5 and WebGL for the development of web-based medical imaging applications. In this study, a comprehensive medical imaging application was developed using HTML5 and WebGL. This application connects to the medical image server, runs on a standard personal computer (PC), and is easily accessible via a standard web browser. The several functions required for radiological interpretation were implemented, for example, navigation, magnification, windowing, and fly-through. The HTML5-based medical imaging application was tested on major browsers and different operating systems over a local area network (LAN) and a wide area network (WAN). The experimental results revealed that this application successfully performed two-dimensional (2D) and three dimensional (3D) functions on different PCs over the LAN and WAN. Moreover, it demonstrated an excellent performance for remote access users, especially over a short time period for 3D visualization and a real-time fly-through navigation. The results of the study demonstrate that HTML5 and WebGL combination is suitable for the development of medical imaging applications. Moreover, the advantages and limitations of these technologies are discussed in this paper. PMID- 30245783 TI - On the Development of Virtual Reality Scenarios for Computer-Assisted Biomedical Applications. AB - The modelling of virtual environments and scenarios is an important area of research for the development of new computer-assisted systems in the areas of engineering and medicine, particularly in the area of biomechanics and biomedical engineering. One of the main issues while designing a virtual environment is the level of realism, which depends on the computing capacity and the level of accuracy and usefulness of the generated data. Thus, the dilemma is between the aesthetic realism and the information utility. This paper proposes a methodology to develop low-cost and high-quality virtual environments and scenarios for computer-aided biomedical applications. The proposed methodology is based on the open-source software Blender and the Visualization Toolkit libraries (VTK). In order to demonstrate the usability of the proposed methodology, the design and development of a computer-assisted biomedical application is presented and analysed. PMID- 30245785 TI - Excellence is a habit, not an act. PMID- 30245784 TI - Implementing Medical Technological Equipment in the OR: Factors for Successful Implementations. AB - Operating rooms (ORs) more and more evolve into high-tech environments with increasing pressure on finances, logistics, and a not be neglected impact on patient safety. Safe and cost-effective implementation of technological equipment in ORs is notoriously difficult to manage, specifically as generic implementation activities omit as hospitals have implemented local policies for implementations of technological equipment. The purpose of this study is to identify success factors for effective implementations of new technologies and technological equipment in ORs, based on a systematic literature review. We accessed ten databases and reviewed included articles. The search resulted in 1592 titles for review, and finally 37 articles were included in this review. We distinguish influencing factors and resulting factors based on the outcomes of this research. Six main categories of influencing factors on successful implementations of medical equipment in ORs were identified: "processes and activities," "staff," "communication," "project management," "technology," and "training." We identified a seventh category "performance" referring to resulting factors during implementations. We argue that aligning the identified influencing factors during implementation impacts the success, adaptation, and safe use of new technological equipment in the OR and thus the outcome of an implementation. The identified categories in literature are considered to be a baseline, to identify factors as elements of a generic holistic implementation model or protocol for new technological equipment in ORs. PMID- 30245786 TI - Faecal microbiota transplantation as a treatment for inflammatory bowel disease: a national survey of adult and paediatric gastroenterologists in the UK. AB - Background: Interest in the use of faecal microbiota transplantation (FMT) in inflammatory bowel disease (IBD) has increased following outcomes in patients with Clostridioides difficile infection (CDI). While research exploring clinician awareness and attitude towards the use of FMT in CDI has been carried out, data for IBD are currently lacking. Objective: To assess the perceptions of gastroenterologists and current practice relating to FMT as a treatment for IBD in the UK. Design: A web-based survey (Snap Survey software) was distributed through the British Society of Gastroenterology (BSG) and British Society of Paediatric Gastroenterology, Hepatology and Nutrition e-newsletters, and at the BSG Conference in June 2017. Results: 61 respondents completed the survey including presubspecialty trainees, gastroenterology specialists, associate specialists and consultants. Most (95%; n=58) respondents stated that they had heard of FMT being used as a treatment for IBD prior to participating in the survey. Based on current evidence, 34% (n=21) of respondents would consider using FMT in patients with IBD, 26% (n=16) would not and 39% (n=24) were undecided. When asked to rank routes of delivery in terms of preference, nasogastric tube was the least preferred route (39%; n=24) and oral capsule was the most preferred route (34%; n=21). Conclusions: A clear majority of UK gastroenterologists recognise FMT as a potential treatment for IBD; however, uptake is limited. A proportion of clinicians would consider FMT in IBD and the majority would consider entering patients into clinical trials. Future work should explore the utility and efficacy of oral FMT capsules in IBD. PMID- 30245787 TI - Examining the relationship between sepsis and oropharyngeal dysphagia in hospitalised elderly patients: a retrospective cohort study. AB - Introduction: Elderly people are recognised to be at increased risk of oropharyngeal dysphagia (OPD), the causes of which are multifactorial. Our aim was to identify if sepsis is associated with OPD in the elderly during hospitalisation in the absence of known other risk factors for OPD. Methods: A hospital electronic database was searched for elderly patients (>=65 years) referred for assessment for suspected dysphagia between March 2013 and 2014. Exclusion criteria were age <65 years, pre-existing OPD or acute OPD secondary to acute intracranial event, space-occupying lesion or trauma. Data were collected on factors including age, sex, comorbidities, existing OPD, sepsis, microbiology, recovery of OPD and medication. Sepsis was defined as evidence of a systemic inflammatory response syndrome with a clinical suspicion of infection. Results: A total of 301 of 1761 screened patients referred for dysphagia assessment met the inclusion criteria. The prevalence of sepsis and subsequent OPD was 16% (51/301). The mean age was 83 years (median 81 years). The most common comorbidity was dementia (31%). The majority (84%) failed to recover swallowing during their hospital stay, 12% had complications of aspiration and 35% died. The most common source of sepsis was from the chest (55%). Other factors contributing to the risk for dysphagia included delirium (22%) and neuroactive medication (41%). However, 10% of patients had sepsis and subsequent OPD without other identified risk factors. Conclusion: The prevalence of sepsis and subsequent dysphagia is significant and should be taken into account in any elderly person in hospital with new-onset OPD without other predisposing risk factors. PMID- 30245788 TI - Oral direct-acting antivirals and the incidence or recurrence of hepatocellular carcinoma: a systematic review and meta-analysis. AB - Background: The influence of direct-acting antiviral (DAA) therapy for chronic hepatitis C virus on the risk of hepatocellular carcinoma (HCC) is conflicting. Methods: We conducted a systematic review and meta-analysis to determine the incidence or recurrence of HCC associated with oral DAA therapy. We searched PubMed, Scopus, Embase from inception to August 2017 to identify observational studies reporting on HCC among patients treated with DAAs. Two independent reviewers extracted data and assessed the risk of bias. Data were pooled by random-effects model. The primary outcome was the proportion of participants with incidence or recurrence of HCC (PROSPERO number CRD42017057040). Results: After reviewing 2080 citations, we included 8 controlled studies and 36 uncontrolled studies. The pooled proportion for incident HCC was 1.5 % (95% CI 1.0% to 2.1%; I2=90.1%; n= 542/39 145) from 18 uncontrolled studies and 3.3% (95% CI 1.2% to 9%; I2 =96%; n=109/6909) from 5 controlled studies, respectively. The pooled proportion for recurrent HCC was 16.7% (95% CI 10.2% to 26%; I2=84.8%; n=136/867) from 12 uncontrolled studies and 20.1% (95% CI 5.5% to 52.1%; I2=87.5%; n=36/225) from 3 controlled studies, respectively. There was no statistically significant effect on the risk of recurrent HCC (OR 0.50, 95%CI 0.16 to 1.59; I2 =73.4%) in a meta-analysis of three studies. Conclusions: Our findings show low proportion of incident HCC, but high proportion of recurrent HCC on treatment with DAAs. Continued active surveillance for HCC after treatment with DAAs remains prudent. PMID- 30245789 TI - Curriculum review: colorectal cancer surveillance and management of dysplasia in IBD. AB - The significantly increased risk of colorectal cancer (CRC) in longstanding colonic inflammatory bowel disease (IBD) justifies the need for endoscopic surveillance. Unlike sporadic CRC, IBD-related CRC does not always follow the predictable sequence of low-grade to high-grade dysplasia and finally to invasive carcinoma, probably because the genetic events shared by both diseases occur in different sequences and frequencies. Surveillance is recommended for patients who have had colonic disease for at least 8-10 years either annually, every 3 years or every 5 years with the interval dependant on the presence of additional risk factors. Currently, the recommended endoscopic strategy is high-definition chromoendoscopy with targeted biopsies, although the associated lengthier procedure time and need for experienced endoscopists has limited its uniform uptake in daily practice. There is no clear consensus on the management of dysplasia, which continues to be a challenging area particularly when endoscopically invisible. Management options include complete resection (and/or referral to a tertiary centre), close surveillance or proctocolectomy. Technical advances in endoscopic imaging such as confocal laser endomicroscopy, show exciting potential in increasing dysplasia detection rates but are still far from being routinely used in clinical practice. PMID- 30245790 TI - Systematic review and meta-analysis: does colonic mural thickening on CT correlate with endoscopic findings at colonoscopy? AB - Background: Colonic mural thickening (MT) is often reported on standard CT examinations of the abdomen and pelvis. It often presents a dilemma for the clinician on whether any further evaluation is needed, especially in the absence of any set guidelines. Objective: To evaluate the significance of colonic MT and to assess its correlation with colonoscopy. Methods: The search strategy was initially developed in Medline and adapted for use in Embase, Medline, NHS Evidence and TRIP. Studies were included if they had reported colonic MT and subsequent colonoscopy in adults. Results: A total of 9 cohort studies examining 1252 patients were selected having undergone both CT and colonoscopy. Of the 1252 patients with MT, 950 had an abnormal colonoscopy. In the presence of MT, the pooled positive predictive value (PPV) of having any abnormal findings at colonoscopy was 0.73 (95% CI 0.60 to 0.84). The pooled PPV for colorectal cancer, in the presence of MT reporting suspicion of cancer, was 0.63 (95% CI 0.49 to 0.75), and MT suggestive of inflammation confirmed at colonoscopy was 0.97. Conclusion: The probability of having an abnormal colonoscopy in the presence of MT identified on CT is high, especially for inflammation. Asymptomatic cancers may also be detected; hence, further endoscopic confirmation is reasonable when a finding of MT is demonstrated on CT examinations. Small sample sizes of the available studies and lack of data on the description of MT detected are the main limiting factors in this review. Trial registration number: CRD42016039378. PMID- 30245791 TI - Evaluation of the clinical and cost-effectiveness of the York Faecal Calprotectin Care Pathway. AB - Objective: To evaluate the sensitivity and specificity of the York Faecal Calprotectin Care Pathway (YFCCP) and undertake a health economics analysis. The YFCCP has been introduced in support of the National Institute for Health and Care Excellence (NICE) guidance DG11. It is designed to improve the sensitivity and specificity of faecal calprotectin (FC) in discriminating the irritable bowel syndrome from inflammatory bowel disease in primary care. Design: To prospectively evaluate the clinical outcomes at 6 months of the first 1005 patients entering the YFCCP. To develop a cost-consequence model using two comparators: one based on clinical assessment and the C reactive protein/erythrocyte sedimentation rate without using FC, and the second using single testing of the standard FC cut-off. Setting: North Yorkshire primary care practices. Patients: Primary care patients fulfilling NICE DG11. Interventions: The YFCCP. Main outcome measures: Clinical outcome measures from secondary care records. Results: The sensitivity and specificity of the YFCCP are 0.94 (0.85 to 0.98) and 0.92 (0.90 to 0.94), giving a negative and positive predictive value of 0.99 (0.98 to 1.0) and 0.51 (0.43 to 0.59), respectively. Conclusions: The YFCCP overcomes the challenges experienced with FC use in primary care, its efficacy matching initial NICE projections. It is readily incorporated into clinical practice. It should represent the framework on which to increase NICE DG11 implementation nationally. PMID- 30245792 TI - A prospective study of faecal immunochemical testing following polypectomy in a colorectal cancer screening population. AB - Introduction: 52% of faecal immunohistochemistry test (FIT)-positive clients in the Irish National Colorectal Cancer Screening Programme (BowelScreen) have adenomatous polyps identified at colonoscopy in round 1. Although it is known that advanced adenomas and cancers cause an elevated FIT, it is not known if small (<5 mm) adenomas cause a positive FIT. Aims: Determine if removal of small polyps in an FIT-based colorectal cancer (CRC) screening programme is associated with a negative FIT on follow-up. Methods: A single-centre prospective observational study of consecutive participants attending for first round screening colonoscopy who had a positive FIT (>45 ug Hb/g) as part of the Irish Colorectal Cancer Screening Programme. Subjects were consented at the time of colonoscopy and were sent a repeat FIT 4-6 weeks later. Precolonoscopy and postcolonoscopy FITs were compared and correlated with clinical findings and endoscopic intervention. Results: 112 consecutive first round participants were recruited. Eight (7%) had cancer, 75 (67%) adenomatous polyps, 17 (15%) a normal colonoscopy and 12 (11%) other pathology. There was a clear difference in median FIT levels between the four groups (P=0.006). Advanced pathology (tumour or adenomatous polyp >1 cm) was associated with higher FIT than non-advanced pathology (median FIT 346 vs 89 P=0.0003). 83% (86/104) of subjects completed a follow-up FIT. Follow-up FIT remained positive in 20% (17/86). Polypectomy was associated with a reduction in FIT from a median of 100 to 5 ug Hb/g (P<0.0001). Removal of polyps >5 mm was the only factor independently associated with a negative follow-up FIT on multivariate analysis (OR 3.9 (1.3-11.9, P=0.04)). Conclusion: FIT is a sensitive test and levels increase with advanced colonic pathology. Polypectomy of advanced adenomas is associated with a negative follow up FIT. However, alternative causes for a positive FIT should be considered in patients who have adenomas less than 5 mm detected or a normal colonoscopy. PMID- 30245794 TI - Standardising assessment and documentation of pouchoscopy. AB - Background/aims: Variation in quality of reporting on endoscopic procedures is a common clinical problem. Findings are not documented in a standardised manner and there is a tendency towards reporting abnormal findings only. This study aimed to review quality of flexible pouchoscopy reports and to develop a standardised reporting template. Methods: Ileo-anal-pouch experts (n=5) compiled a list of items that should be documented at flexible pouchoscopy. Reports were reviewed retrospectively for their completeness compared with the template. The template was then introduced and quality of reports was analysed prospectively. Results: One hundred and twenty-one reports produced between March 2015 and June 2015 were reviewed. Between August 2015 and November 2015, the template was introduced and reports were analysed. There was significant improvement in documentation of anus and perianal area (before template (B) 12% to after template (A) 51%, p<0.0001), rectal cuff (B: 55% to A: 75%, p=0.01), pouch-anal anastomosis (B: 37% to A: 67%, p=0.0002) and pouch inlet (B: 13% to A: 41%, p<0.0001). Pouch body was described in high percentage regardless of introduction of the template (B: 98% to A: 97%, p=0.61). Conclusions: Documentation of pouchoscopy findings was suboptimal and introduction of a template improved documentation of flexible pouchoscopy significantly. PMID- 30245793 TI - Optimising the performance and interpretation of small bowel capsule endoscopy. AB - Small bowel capsule endoscopy has become a commonly used tool in the investigation of gastrointestinal symptoms and is now widely available in clinical practice. In contrast to conventional endoscopy, there is a lack of clear consensus on when competency is achieved or the way in which capsule endoscopy should be performed in order to maintain quality and clinical accuracy. Here we explore the evidence on the key factors that influence the quality of small bowel capsule endoscopy services. PMID- 30245795 TI - Positioning cholangioscopy in bile duct stone management: mind the technology gap. PMID- 30245796 TI - Day case 'treat and transfer' ERCP service under general anaesthesia. AB - Objective: General anaesthesia (GA) has been increasingly used for advanced endoscopic procedures in particular endoscopic retrograde cholangiopancreatography (ERCP). Given the increasing pressure on many hospitals, the delivery of such service on a regular basis may not always be possible. We established a new day case 'GA ERCP' service. We describe our experience in evaluating the safety and overall feasibility of this new service. Design: Prospective database has been interrogated for the period from March 2015 to December 2016. We documented patients' demographics, ERCP indications, American Society of Anesthesiologists (ASA) status, Cotton grade and complications. Results: 67 patients were referred to endoscopy unit at King's College Hospital (KCH), for urgent day case GA ERCP from nine referring hospitals. The main indications were failed ERCP under sedation 47.8% (32/67), and unavailability of ERCP locally 41.8% (28/67). A total of 64 patients were actually transferred to KCH; 57.8% (37/64) women with a median age 55.8 years (range 23-90). 78.1% (50/64) of patients had a virgin papilla, with 39% (25/64) were ASA >=3. The Cotton grade was >= 3 in 50% (32/64) patients. ERCP was completed successfully in 87.5% (56/64). For patients with previous failed ERCP, repeat ERCP under GA was successful in 75% (24/32). All patients were safely discharged back to their referring hospitals after the short observation period post-ERCP. Conclusions: Urgent inpatient transfers between hospitals for performing ERCP under GA as a day case is safe and feasible. The new GA ERCP pathway can be replicated by other UK centres. PMID- 30245797 TI - Thoracic and abdominal pain in a 28-year-old woman with a failing kidney transplant. AB - This case report describes a young, immunocompromised patient who presented with thoracic pain. After an extensive workup, she was diagnosed with a varicella zoster virus infection with involvement of the gastric mucosa, pancreas and lungs for which she was treated with acyclovir. Although the viral load decreased significantly, the patient had persistent postherpetic neuralgia and nausea. PMID- 30245798 TI - Sheffield Clinical Research Fellowship programme: a transferable model for UK gastroenterology. AB - Out of programme (OOP) opportunities are to be encouraged. This article gives an insightful view of the Sheffield Clinical Research Fellowship Programme. Unique trainee feedback is provided. The take home message is clear - trainees should grab OOP experiences with both hands! For consultants the logistics described are potentially transferrable to their own regions. PMID- 30245799 TI - First UK data for CT angiography in persisting upper GI bleeding. PMID- 30245800 TI - Relationship of Depth Adaptation Between Disparity-Specified Plaids and Their Components. AB - In the luminance domain, studies show that perceived contrasts of plaids are a nonlinear summation of their components. In the disparity domain, perceived depth has been studied by using a depth adaptation paradigm with simple surfaces; however, the relationship between depth adaptation between plaids and their components has not been investigated. To clarify this, combinations of disparity defined horizontal corrugation (marked as horizontal) and disparity-defined plaids as adaptor-probe pairs were used. Three experiments were performed: The first two compared the aftereffects between horizontal-horizontal and plaid horizontal pairs (Comparison 1) and between horizontal-plaid and plaid-plaid pairs (Comparison 2). Experiments 1 and 2 controlled the plaids to have the same and doubled peak-to-trough amplitudes as the horizontal corrugation, respectively. In Comparison 1, the horizontal or horizontally oriented component of the plaids was adapted. In Comparison 2, the plaid adaptor or horizontally oriented component of the plaid test stimuli was adapted. Thus, depth adaptation may be linked to cyclopean-oriented depth-from-disparity bandpass filters. The depth adaptation degree was determined by the adaptation of amplitudes of the similar oriented channels between the adaptation and test stimuli. Experiment 3 compared the aftereffects between noise-horizontal and horizontal-horizontal pairs. Since the noise adaptor contained multispatial frequency channels, only the channels with similar spatial frequencies as the horizontal corrugation were adapted, thus causing smaller depth aftereffects. PMID- 30245801 TI - The effect of low-magnitude, high-frequency vibration on poly(ethylene glycol) microencapsulated mesenchymal stem cells. AB - Low-magnitude, high-frequency vibration has stimulated osteogenesis in mesenchymal stem cells when these cells were cultured in certain types of three dimensional environments. However, results of osteogenesis are conflicting with some reports showing no effect of vibration at all. A large number of vibration studies using three-dimensional scaffolds employ scaffolds derived from natural sources. Since these natural sources potentially have inherent biochemical and microarchitectural cues, we explored the effect of low-magnitude, high-frequency vibration at low, medium, and high accelerations when mesenchymal stem cells were encapsulated in poly(ethylene glycol) diacrylate microspheres. Low and medium accelerations enhanced osteogenesis in mesenchymal stem cells while high accelerations inhibited it. These studies demonstrate that the isolated effect of vibration alone induces osteogenesis. PMID- 30245802 TI - The Sources of Reactive Oxygen Species and Its Possible Role in the Pathogenesis of Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra. The precise mechanism underlying pathogenesis of PD is not fully understood, but it has been widely accepted that excessive reactive oxygen species (ROS) are the key mediator of PD pathogenesis. The causative factors of PD such as gene mutation, neuroinflammation, and iron accumulation all could induce ROS generation, and the later would mediate the dopaminergic neuron death by causing oxidation protein, lipids, and other macromolecules in the cells. Obviously, it is of mechanistic and therapeutic significance to understand where ROS are derived and how ROS induce dopaminergic neuron damage. In the present review, we try to summarize and discuss the main source of ROS in PD and the key pathways through which ROS mediate DA neuron death. PMID- 30245805 TI - Gendered violences and rule of/by law in Cambodia. AB - This intervention is based on research in Cambodia on domestic violence and forced eviction. It draws on the distinction between rule of/by law to examine women's experiences of rights claiming. While 'rule of law' is a value to be respected and a mechanism via which to guarantee justice and human rights to all citizens, 'rule by law' is a distortion that is more easily conceived of as an instrument of power and oppression. The intervention's emphasis on the blurring between these distinctions highlights the stark absence of feminist geography work in the growing field of legal geographies. PMID- 30245804 TI - A Transdiagnostic Temperament-Phenotype Profile Approach to Emotional Disorder Classification: An Update. AB - Although the emotional disorders (EDs) have achieved favorable reliability in the Diagnostic and Statistical Manual of Mental Disorders (DSM), accumulating evidence continues to underscore limitations in ED diagnostic validity. In particular, taxometric, comorbidity, and other descriptive psychopathology studies of transdiagnostic phenotypes studies suggest that the EDs may be best conceptualized as dimensional entities that are more similar than different. Despite optimism that the fifth edition of the DSM (DSM-5) would constitute a meaningful shift toward dimensional ED assessment and diagnosis, most changes contribute little movement in that direction. In the present report, we summarize past and anticipate persisting (i.e., in DSM-5) limitations of a purely categorical approach to ED diagnosis. We then review our alternative dimensional categorical profile approach to ED assessment and classification, including preliminary evidence in support of its validity and presentation of two ED profile case examples using our newly developed Multidimensional Emotional Disorder Inventory. We end by discussing the transdiagnostic treatment implications of our profile approach to ED classification and directions for future research. PMID- 30245803 TI - Potential Pitfalls of the Humanized Mice in Modeling Sepsis. AB - Humanized mice are a state-of-the-art tool used to study several diseases, helping to close the gap between mice and human immunology. This review focuses on the potential obstacles in the analysis of immune system performance between humans and humanized mice in the context of severe acute inflammation as seen in sepsis or other critical care illnesses. The extent to which the reconstituted human immune system in mice adequately compares to the performance of the human immune system in human hosts is still an evolving question. Although certain viral and protozoan infections can be replicated in humanized mice, whether a highly complex and dynamic systemic inflammation like sepsis can be accurately represented by current humanized mouse models in a clinically translatable manner is unclear. Humanized mice are xenotransplant animals in the most general terms. Several organs (e.g., bone marrow mesenchymal cells, endothelium) cannot interact with the grafted human leukocytes effectively due to species specificity. Also the interaction between mice gut flora and the human immune system may be paradoxical. Often, grafting is performed utilizing an identical batch of stem cells in highly inbred animals which fails to account for human heterogeneity. Limiting factors include the substantial cost and restricting supply of animals. Finally, humanized mice offer an opportunity to gain knowledge of human-like conditions, requiring careful data interpretation just as in nonhumanized animals. PMID- 30245806 TI - Gendering Islamophobia, racism and White supremacy: Gendered violence against those who look Muslim. AB - Defendants in both racist and religiously motivated hate crimes in the United Kingdom are usually White men, with these incidents tending to take place in public spaces, especially those close to religious and community buildings. Focusing on the experiences of Muslim men and women in the United Kingdom - including others who look Muslim - I explore common forms of religiously and racially motivated violence and argue that these constitute gendered violence. Policies targeted at key groups who are victims and perpetrators of religiously and racially motivated violence ignore the issue of violence and fail to acknowledge its gendered nature. PMID- 30245807 TI - Geography's contribution to the Sustainable Development Goals: Ambivalence and performance. AB - Building on Liverman's critique of the Sustainable Development Goals (SDGs), I argue SDGs must be conceptualized as situated by (i) unpacking the black box of social, political and intellectual consensus behind indicators and (ii) reimagining development goals as dynamic performances that are uneven over time and space for both populations and individuals. Poverty, justice and other targets of SDGs are not a state of being but rather a punctuated experience for the individuals and populations in question. For the SDGs to be effective, they need to go beyond simple statistics to account for how situated, performative aspects of lives evolve, rather than as they are. PMID- 30245808 TI - Evaluation of Routine Microscopy Performance for Malaria Diagnosis at Three Different Health Centers in Brazzaville, Republic of Congo. AB - Background: In Republic of Congo, malaria diagnosis still widely relies on microscopy. We aimed to evaluate the performance of routine microscopy for malaria diagnosis at three different health centers in Brazzaville. Methods: A total of 259, 416, and 131 patients with clinical signs of uncomplicated malaria were enrolled at the Hopital de Mfilou, Centre de Sante Integre "Maman Mbouale," and Laboratoire National de Sante Publique, respectively. Two thick blood smears were prepared for each patient, the first being examined by routine microscopists and the second by expert. Results: At the Hopital de Mfilou, sensitivity was 62.1% and specificity was 67.3%. Positive and negative predictive values were 55.6% and 72.9%, respectively. At the Centre de Sante Integre "Maman Mbouale," sensitivity was 94.2% and specificity was 33.6%. Positive and negative predictive values were 50% and 89.1%, respectively. At the Laboratoire National de Sante Publique, sensitivity and specificity were high with 91.7% and 94.9%, respectively. Positive and negative predictive values were 64.7% and 99.1%, respectively. Conclusion: The performance of routine malaria microscopy in Brazzaville remains inaccurate with large variations among different health centers. Therefore, repeated training including supervision and evaluation would improve routine malaria diagnosis for better management of malaria in Brazzaville, the Republic of Congo. PMID- 30245809 TI - On-chip excitation of single germanium vacancies in nanodiamonds embedded in plasmonic waveguides. AB - Monolithic integration of quantum emitters in nanoscale plasmonic circuitry requires low-loss plasmonic configurations capable of confining light well below the diffraction limit. We demonstrated on-chip remote excitation of nanodiamond embedded single quantum emitters by plasmonic modes of dielectric ridges atop colloidal silver crystals. The nanodiamonds were produced to incorporate single germanium-vacancy (GeV) centres, providing bright, spectrally narrow and stable single-photon sources suitable for highly integrated circuits. Using electron beam lithography with hydrogen silsesquioxane (HSQ) resist, dielectric-loaded surface plasmon polariton waveguides (DLSPPWs) were fabricated on single crystalline silver plates to contain those of deposited nanodiamonds that are found to feature appropriate single GeV centres. The low-loss plasmonic configuration enabled the 532-nm pump laser light to propagate on-chip in the DLSPPW and reach to an embedded nanodiamond where a single GeV centre was incorporated. The remote GeV emitter was thereby excited and coupled to spatially confined DLSPPW modes with an outstanding figure-of-merit of 180 due to a ~six fold Purcell enhancement, ~56% coupling efficiency and ~33 MUm transmission length, thereby opening new avenues for the implementation of nanoscale functional quantum devices. PMID- 30245810 TI - Full-space Cloud of Random Points with a Scrambling Metasurface. AB - With the rapid progress in computer science, including artificial intelligence, big data and cloud computing, full-space spot generation can be pivotal to many practical applications, such as facial recognition, motion detection, augmented reality, etc. These opportunities may be achieved by using diffractive optical elements (DOEs) or light detection and ranging (LIDAR). However, DOEs suffer from intrinsic limitations, such as demanding depth-controlled fabrication techniques, large thicknesses (more than the wavelength), Lambertian operation only in half space, etc. LIDAR nevertheless relies on complex and bulky scanning systems, which hinders the miniaturization of the spot generator. Here, inspired by a Lambertian scatterer, we report a Hermitian-conjugate metasurface scrambling the incident light to a cloud of random points in full space with compressed information density, functioning in both transmission and reflection spaces. Over 4044 random spots are experimentally observed in the entire space, covering angles at nearly 90 degrees . Our scrambling metasurface is made of amorphous silicon with a uniform subwavelength height, a nearly continuous phase coverage, a lightweight, flexible design, and low-heat dissipation. Thus, it may be mass produced by and integrated into existing semiconductor foundry designs. Our work opens important directions for emerging 3D recognition sensors, such as motion sensing, facial recognition, and other applications. PMID- 30245811 TI - Metasurface-based multi-harmonic free-electron light source. AB - Metasurfaces are subwavelength spatial variations in geometry and material where the structures are of negligible thickness compared to the wavelength of light and are optimized for far-field applications, such as controlling the wavefronts of electromagnetic waves. Here, we investigate the potential of the metasurface near-field profile, generated by an incident few-cycle pulse laser, to facilitate the generation of high-frequency light from free electrons. In particular, the metasurface near-field contains higher-order spatial harmonics that can be leveraged to generate multiple higher-harmonic X-ray frequency peaks. We show that the X-ray spectral profile can be arbitrarily shaped by controlling the metasurface geometry, the electron energy, and the incidence angle of the laser input. Using ab initio simulations, we predict bright and monoenergetic X-rays, achieving energies of 30 keV (with harmonics spaced by 3 keV) from 5-MeV electrons using 3.4-eV plasmon polaritons on a metasurface with a period of 85 nm. As an example, we present the design of a four-color X-ray source, a potential candidate for tabletop multicolor hard X-ray spectroscopy. Our developments could help pave the way for compact multi-harmonic sources of high energy photons, which have potential applications in industry, medicine, and the fundamental sciences. PMID- 30245812 TI - Quantifying single plasmonic nanostructure far-fields with interferometric and polarimetric k-space microscopy. AB - Optically resonant nanoantennae are key building blocks for metasurfaces, nanosensors, and nanophotonic light sources due to their ability to control the amplitude, phase, directivity, and polarization of scattered light. Here, we report an experimental technique for the full recovery of all degrees of freedom encoded in the far-field radiated by a single nanostructure using a high-NA Fourier microscope equipped with digital off-axis holography. This method enables full decomposition of antenna-physics in its multipole contributions and gives full access to the orbital and spin angular momentum properties of light scattered by single nano-objects. Our results demonstrate these capabilities through a quantitative assessment of the purity of the "selection rules" for orbital angular momentum transfer by plasmonic spiral nanostructures. PMID- 30245814 TI - Posterior dislocation of a constrained total knee arthroplasty: A case report. AB - Introduction: Dislocation of the knee after primary total knee arthroplasty is rare in a posterior stabilized knee and extremely rare in a constrained total knee arthroplasty. Constrained total knee prostheses are used for severe knee deformities and to provide stable and mobile knees. Presentation of case: In this case, we describe a dislocation of a primary constrained total knee arthroplasty using the Genesis II (Smith & Nephew, Memphis Tennessee, USA) prosthesis. Without any significant trauma, the constrained insert dislocated fifteen months after surgery and revision surgery with a bigger insert was needed. Surgical error may have been the cause of dislocation, but we were unable to establish a clear reason behind this dislocation. Discussion: Knee dislocation after TKA is rare but easily overlooked and can lead to serious complications and permanent disability. This system should provide stable and mobile knees to correct collateral ligament laxity. Conclusion: Here, we report the first case, to our knowledge, of dislocation with a constrained prosthesis without any history of trauma. PMID- 30245813 TI - A deep learning-enabled portable imaging flow cytometer for cost-effective, high throughput, and label-free analysis of natural water samples. AB - We report a deep learning-enabled field-portable and cost-effective imaging flow cytometer that automatically captures phase-contrast color images of the contents of a continuously flowing water sample at a throughput of 100 mL/h. The device is based on partially coherent lens-free holographic microscopy and acquires the diffraction patterns of flowing micro-objects inside a microfluidic channel. These holographic diffraction patterns are reconstructed in real time using a deep learning-based phase-recovery and image-reconstruction method to produce a color image of each micro-object without the use of external labeling. Motion blur is eliminated by simultaneously illuminating the sample with red, green, and blue light-emitting diodes that are pulsed. Operated by a laptop computer, this portable device measures 15.5 cm * 15 cm * 12.5 cm, weighs 1 kg, and compared to standard imaging flow cytometers, it provides extreme reductions of cost, size and weight while also providing a high volumetric throughput over a large object size range. We demonstrated the capabilities of this device by measuring ocean samples at the Los Angeles coastline and obtaining images of its micro- and nanoplankton composition. Furthermore, we measured the concentration of a potentially toxic alga (Pseudo-nitzschia) in six public beaches in Los Angeles and achieved good agreement with measurements conducted by the California Department of Public Health. The cost-effectiveness, compactness, and simplicity of this computational platform might lead to the creation of a network of imaging flow cytometers for large-scale and continuous monitoring of the ocean microbiome, including its plankton composition. PMID- 30245815 TI - Clinical instructors' perceptions of virtual reality in health professionals' cardiopulmonary resuscitation education. AB - Objectives: Cardiopulmonary resuscitation (CPR) is lifesaving. Yet, cardiac arrest survival remains low despite CPR intervention. Education has been highlighted as a strategy to overcome this issue. Virtual Reality technology has been gaining momentum in the field of clinical education. Published studies report benefits of virtual reality for CPR education; yet, perceptions of CPR instructors towards virtual reality remain unexplored. CPR instructors are key stakeholders in CPR education and their perceptions are valuable for the design and adoption of virtual reality-enhanced learning. The purpose of this study is therefore to understand the perceptions of CPR instructors towards using virtual reality for health professionals' CPR education. The aim was addressed via three research questions: (1) What are the perceptions of CPR instructors towards current health professionals' CPR education? (2) What are the perceptions of CPR instructors towards features of virtual reality ideal for health professionals' CPR education? (3) What are the perceptions of CPR instructors towards the potential role of virtual reality in health professionals' CPR education? Methods: A total of 30 CPR instructors were surveyed on their views towards current health professionals' CPR education and the use of virtual reality for health professionals' CPR education, before and after interacting with a CPR virtual reality simulation. Responses were analysed using interpretative thematic analysis. Results: CPR instructors perceived current health professionals' CPR education as limited due to unideal test preparation (resources, practice, motivation, and frame of mind) and performance. They perceived fidelity, engagement, resource conservation, and memory enhancement as features of virtual reality ideal for health professionals' CPR education. Virtual reality was viewed by CPR instructors as having potential as a blended learning tool, targeting both 'novice' and 'experienced' health professionals. Conclusion: The study highlighted the gaps in current health professionals' CPR education that can be addressed using virtual-reality-enabled learning. Future research could investigate virtual reality simulations with features desirable for CPR education of target populations. PMID- 30245817 TI - Knowledge mapping of medication literacy study: A visualized analysis using CiteSpace. AB - Objective: The objective of this study was to analyze knowledge mapping and demonstrate the status quo, intellectual base, and hotspots in the field of medication literacy. Methods: Using the data from Web of Science Core database, we constructed a knowledge map to visualize medication literacy using CiteSpace, which revealed the power of the studies, core authors and journals, intellectual base, and hotspots in this field. Results: According to an analysis of 2025 literature reports, the stronger studies were mainly conducted at research institutions of higher education in the United States. Core author groups with a higher influence were not identified. The core journals included Patient Educ Couns and Fam Med. The health literacy studies served as the foundation for the medication literacy studies. The keywords formed 13 clusters including 5 major clusters. Conclusion: The topics in medication literacy study focused on instruments assessing medication literacy, measurement and assessment of medication literacy, medication literacy for the prevention of chronic disease and medication treatment adherence, medication literacy education, and family practice. This study provides an insight into medication literacy and valuable information for medication literacy researchers to identify new perspectives on potential collaborators and cooperative institutions and hotspots. PMID- 30245816 TI - Opposite relations of epicardial adipose tissue to left atrial size in paroxysmal and permanent atrial fibrillation. AB - Objectives: Atrial fibrillation has been associated with obesity in epidemiological studies. Epicardial adipose tissue is an ectopic fat depot in the proximity of atria, with endocrine and inflammatory properties that is implicated in the pathophysiology of atrial fibrillation. Inflammation also has a role in atrial arrhythmogenesis. The aim of this study was to investigate the potential relations of epicardial adipose tissue to left atrial size and to adiponectin and the pro-inflammatory mediators, high-sensitivity C-reactive protein, and interleukin-6 in paroxysmal and permanent atrial fibrillation. Methods: This was a cross-sectional study of 103 atrial fibrillation patients, divided into two subgroups of paroxysmal and permanent atrial fibrillation, and 81 controls, in sinus rhythm. Echocardiography was used for estimation of epicardial adipose tissue and left atrial size and high-sensitivity C-reactive protein, interleukin 6 and adiponectin were measured in all subjects. Results: Atrial fibrillation patients had significantly larger epicardial adipose tissue compared with controls (0.43 +/- 0.17 vs 0.34 +/- 0.17 cm, p = 0.002). Atrial fibrillation presence was independently related to epicardial adipose tissue thickness (b = 0.09, p = 0.002). Opposite associations of epicardial adipose tissue with left atrial volume existed in atrial fibrillation subgroups; in the paroxysmal subgroup, epicardial adipose tissue was directly related to left atrial volume (R = 0.3, p = 0.03), but in the permanent one the relation was inverse (R = -0.7, p < 0.0001). Adiponectin, high-sensitivity C-reactive protein and interleukin-6 were elevated in both atrial fibrillation groups. Only interleukin-6 was related to epicardial adipose tissue size. Conclusion: Opposite associations of epicardial adipose tissue with left atrial size in paroxysmal and permanent Atrial fibrillation and elevated inflammatory markers, suggest a role of epicardial adipose tissue and inflammation in the fibrotic and remodeling process. PMID- 30245818 TI - A novel prostate cancer immunotherapy using prostate-specific antigen peptides and Candida skin test reagent as an adjuvant. AB - Objectives: Our group developed the use of the Candida skin test reagent as an adjuvant of cell-mediated immunity in designing a human papillomavirus therapeutic vaccine. Here, this technology is being applied for designing a prostate cancer immunotherapy. Methods: Peptides based on the prostate-specific antigen amino acid sequences were selected, synthesized, and evaluated in terms of their (1) solubility, (2) maturation effects on Langerhans cells by fluorescence-activated cell sorter analysis, and (3) recognition by peripheral immune cells from prostate cancer patients using interferon-gamma enzyme-linked immunospot assay. Results: The peptides were soluble in 10 mM succinate at pH of 5 with 5% glycine, and they demonstrated no maturation effects on Langerhans cells from healthy donors. On the other hand, peripheral immune cells from 4 of 10 prostate cancer patients examined had positive responses in enzyme-linked immunospot assay to one or more prostate-specific antigen peptides. Conclusion: In summary, a design and a formulation of a novel prostate cancer immunotherapy are described. The immunogenicity of prostate-specific antigen peptides in some prostate cancer patients supports further development of this immunotherapy. PMID- 30245819 TI - Population health challenges in primary care: What are the unfinished tasks and who should do them? AB - Background: There are numerous recommendations from expert sources that help guide primary care providers in cancer screening, infectious disease screening, metabolic screening, monitoring of drug levels, and chronic disease management. Little is known about the potential effort needed for a healthcare system to address these recommendations, or the patient effort needed to complete the recommendations. Methods: For 73 recommended population healthcare items, we examined each of 28,742 patients in a primary care internal medicine practice to determine whether they were up-to-date on recommended screening, immunizations, counseling, and chronic disease management goals. We used a rule-based software tool that queries the medical record for diagnoses, dates, laboratory values, pathology reports, and other information used in creating the individualized recommendations. We counted the number of uncompleted recommendations by age groups and examined the healthcare staff needed to address the recommendations and the potential patient effort needed to complete the recommendations. Results: For the 28,742 patients, there were 127,273 uncompleted recommendations identified for population health management (mean recommendations per patient 4.36, standard deviation of 2.65, range of 0-17 recommendations per patient). The age group with the most incomplete recommendations was age of 50-65 years with 5.5 recommendations per patient. The 18-35 years age group had the fewest incomplete recommendations with 2.6 per patient. Across all age groups, initiation of these recommendations required high-level input (physician, nurse practitioner, or physician's assistant) in 28%. To completely adhere to recommended services, a 1000-patient cross-section cohort would require a total of 464 procedures and 1956 lab tests. Conclusion: Providers and patients face a daunting number of tasks necessary to meet guideline-generated recommendations. We will need new approaches to address the burgeoning numbers of uncompleted recommendations. PMID- 30245820 TI - Audit of computed tomography brain findings in HIV-infected patients with space occupying infective lesions at a regional level hospital in KwaZulu-Natal. AB - Background: With the increased prevalence of HIV pandemic, more focus is placed on pathology involving the central nervous system secondary to HIV infection. Medical computerised tomography scans have become an integral investigation at a regional hospital level. Objective: To provide a description of central nervous system space occupying infective lesion found within this cohort of patients. Setting: Edendale Hospital, Pietermaritzburg, KwaZulu-Natal. Methods: This was a retrospective study in which the charts of all HIV-infected medical patients with findings of a space occupying infective lesion on computerised tomography brain seen for the time period 1 January 2015 up to and including 31 December 2015 were analysed. A total of 110 patient files were evaluated. Results: Most patients were in the third to fourth decade of life with mean cluster of differentiation 4 of 125 cells/mm3. A differential comprising toxoplasmosis or tuberculoma (80.9%) was the leading aetiology described. Most frequent clinical features in these patients included seizures (41.8%), confusion or altered mental state (38.2%), headaches (33.6%), hemiparesis (48.2%) and cranial nerve abnormality (22.7%). The most common central nervous system sites involved were, in order of decreasing prevalence was parietal, basal ganglia, frontal cortex (31.8% vs 31.8% vs 26.4%, respectively). Early initiation of co-trimoxazole and anti-tuberculosis treatment yielded better outcomes compared to the group who received delayed or no treatment with p-values (Pearson's chi2) of 0.0002 and <0.0001, respectively. Conclusion: Computerised tomography scans to detect space-occupying infective lesion of the brain are invaluable for rapid diagnosis and to reduce morbidity and mortality. PMID- 30245821 TI - Family physicians' knowledge, attitudes, and behaviors regarding the weight effects of added sugar. AB - Background and objectives: Added sugar consumption is a major risk factor for negative health outcomes and family physicians play an important role in educating patients regarding nutrition behaviors, such as consumption of added dietary sugar. The aim of this study was to describe the knowledge, attitudes, and behaviors of family physicians regarding added dietary sugar. Methods: An online questionnaire was administered to family physician members of the Council of Academic Family Medicine organizations, which support teaching physicians that train family physicians throughout the United States. Survey items underwent rigorous pilot and cognitive testing prior to administration. Descriptive statistics and Pearson's chi-square test were performed to evaluate physician's dietary counseling for patients with overweight and obesity. Results: Among practicing family physician members (n = 1196), 72% reported providing dietary counseling to the majority (?50%) of their patients with overweight and obesity. Most (90%) believed that their counseling was ineffective for the majority of patients. Frequency of counseling was significantly associated with beliefs about counseling effectiveness (p-value < 0.001). Nearly all physicians (97%) advised against consuming sugary beverages, while advising patients to limit foods with added sugar was less common (82%). Discussion: Dietary counseling is often, but not always, provided to patients with overweight and obesity by family physicians in our sample, though most physicians believed their counseling is ineffective. National attention to added sugar as a risk for poor health should serve as a catalyst for renewed efforts from primary care educators and clinicians to engage in innovative practices to empower at-risk patients to improve their nutrition. PMID- 30245822 TI - Cancer cell targeting, controlled drug release and intracellular fate of biomimetic membrane-encapsulated drug-loaded nano-graphene oxide nanohybrids. AB - Nano-graphene oxide (NGO) has been proposed as a novel drug carrier. However, the poor biocompatibility and physiological stability as well as lack of cancer targeting capability have limited its further applications in cancer therapy. To solve this problem, we developed a novel nanohybrid of NGO/DOX@SPC-FA by first allowing soy phosphatidylcholine membrane (SPC) to encapsulate DOX-loaded NGO (NGO/DOX) and then modifying the SPC membrane with PEGylated lipid-FA conjugate to achieve the display of cancer targeting FA on the nanohybrid surface. The SPC membrane (mimicking cell membrane) enabled the resultant nanohybrids (NGO/DOX@SPC FA) to exhibit good stability and biocompatibility, high drug loading capability, efficient cellular uptake, and controlled drug release. Moreover, compared with NGO/DOX and SPC-modified NGO/DOX (NGO/DOX@SPC), the FA-modified NGO/DOX@SPC nanohybrids (NGO/DOX@SPC-FA) could deliver NGO/DOX to cancer cells with improved delivery and killing efficacy due to the presence of FA targeting motifs on the surface. The NGO/DOX@SPC-FA nanohybrids were found to be internalized specifically by FA-positive cancer cells (Hela cells) through both macropinocytosis-directed engulfment and clathrin-dependent endocytosis, and then become localized into the lysosomes. In vivo biodistribution study showed that NGO/DOX@SPC-FA had a high tumor targeting ability because of the active targeting mechanism with folate modification. In vivo antitumor therapy study demonstrated NGO/DOX@SPC-FA could significantly inhibit tumour growth and prolong the survival time of mice. Our results suggest that NGO/DOX@SPC-FA, as a novel drug delivery system with high drug loading and targeted delivery efficiency, holds promise for future cancer therapy. PMID- 30245823 TI - Development and testing of a simple field-based intermittent-flow respirometry system for riverine fishes. AB - By understanding range-wide intraspecific variation in metabolic rate we can better understand how organisms have adapted to their environment. However, methods to quantify metabolic rate of fishes from remote areas or those that cannot be brought back to the laboratory because of imperilment status are lacking. Consequently, practical and reliable field-based methods are needed. To address this need, we developed a simple yet robust intermittent-flow respirometry system, adapted from a design commonly used in the laboratory that is readily suited for field use. Standard metabolic rate (SMR), maximum metabolic rate (MMR) and aerobic scope (AS) estimates were obtained from juvenile lake trout (Salvelinus namaycush) and brook trout (Salvelinus fontinalis) using both field- and laboratory-based systems. Whole-fish SMR, MMR and AS estimates from the field and laboratory methods did not differ from one another (ANCOVA and LMM: all P > 0.05) for either species and were comparable to estimates previously reported. Our field setup is a simpler system than the conventional laboratory based system that requires less power and equipment to operate, yet still offers users the ability to: (1) acclimate fish to the respirometry chamber; (2) measure oxygen consumption during a shorter period (1 h), which yield metabolic rate estimates comparable to systems that take measurements over longer periods; and (3) take repeated oxygen consumption measurements with manual user-defined flush and measurement phase routines. Developing practical and reliable field respirometry methods, as demonstrated here, is important if we wish to improve our ability to predict how imperiled species will respond to changes in their environment. Such knowledge is critical for informing conservation strategies. PMID- 30245824 TI - The clinical presentation, utilization, and outcome of individuals with sickle cell anaemia presenting to urban emergency department of a tertiary hospital in Tanzania. AB - Background: Sickle cell anaemia (SCA) is prevalent in sub-Saharan Africa, with high risk of complications requiring emergency care. There is limited information about presentation of patients with SCA to hospitals for emergency care. We describe the clinical presentation, resource utilization, and outcomes of SCA patients presenting to the emergency department (ED) at Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania. Methods: This was a prospective cohort study of consecutive patients with SCA presenting to ED between December 2014 and July 2015. Informed consent was obtained from all patients or patients' proxies prior to being enrolled in the study. A standardized case report form was used to record study information, including demographics, relevant clinical characteristics and overall patients outcomes. Categorical variables were compared with chi-square test or Fisher's exact test; continuous variables were compared with two-sample t-test or Mann-Whitney U-test. Results: We enrolled 752 (2.7%) people with SCA from 28,322 patients who presented to the MNH-ED. The median age was 14 years (Interquartile range [IQR]: 6-23 years), and 395 (52.8%) were female. Pain 614 (81.6%), fever 289 (38.4%) were the most frequent presenting complaint. Patients with fever, hypoxia, altered mental status and bradycardia had statistically significant relative risk of mortality of 10.4, 153, 50 and 12.1 (p < 0.0001) respectively, compared to patients with normal vitals. Overall, 656 (87.2%) patients received Complete Blood Cell counts test, of these 342 (52.1%) had severe anaemia (haemoglobin < 7 g/dl), and a 30.3 (p = 0.02) relative risk of relative risk of mortality compare to patients with higher haemoglobin. Patients who had malaria, elevated renal function test and hypoglycemia, had relative risk of mortality of 22.9, 10.4 and 45.2 (p < 0.0001) respectively, compared to patient with normal values. Most 534 (71.0%) patients were hospitalized for in patients care, and the overall morality rate was 16 (2.1%). Conclusions: We described the clinical presentation, management, and outcomes of patients with SCA presenting to the largest public ED in Tanzania, as well as information on resource utilization. This information can inform development of treatment guidelines, clinical staff education, and clinical research aimed at optimizing care for SCA patients. PMID- 30245825 TI - Testicular abscesses due to Brucella melitensis. AB - Brucella may cause testicular masses, which may be confused with a testicular tumour. We present the case of a man with fever and oedema in the scrotum. Ultrasound and colour Doppler ultrasound with a 6 to 15 MHz high-frequency linear array transducer was performed, revealing bilateral scrotal wall oedema, heterogeneous echo texture and slightly increased vascularization of the right testis, with hypoechoic lesions characterized by hypervascular margins and no flow within them. These findings were compatible with testicular abscesses. Three blood cultures grew Brucella melitensis, so the patient received treatment with doxycycline and rifampin for 8 weeks, which resulted in disappearance of the testicular abscesses. PMID- 30245826 TI - First isolation of Yersinia entomophaga in human urinary tract. AB - Yersinia entomophaga is an insect pathogen first isolated from larvae of Coleoptera in New Zealand in 2011. We report here the first isolation of Y. entomophaga from human urine. Using whole-genome sequencing, we confirmed the presence of specific chromosomal virulence genes and identified a plasmid harbouring a quinolone resistance gene. PMID- 30245827 TI - Coxiella burnetii infection with women's febrile spontaneous abortion reported in Algiers. AB - We investigated Q fever infection in Febrile Spontaneous Abortions in women by using a serologic method (Immuno-Fluorescence Assay, IFA) and a molecular method (real-time quantitative PCR, qPCR) in Obstetric-Gynaecology (OB-GYN) services in two hospitals in Algiers. We included in the case group 380 women who experienced Febrile Spontaneous Abortion; the control group comprised 345 women who gave birth without any other infections or complications. Among the 725 women included, antibodies against Coxiella burnetii were detected by IFA in three (03) cases patients; all control group samples were IFA negative. In other hand, only four (04) placental samples among the case group came back with q PCR positive for IS1111 and IS30a too. A relationship between C. burnetii infection and febrile spontaneous abortion exists in OB-GYN services in Algiers. PMID- 30245828 TI - Genotypic characterization of Staphylococcus aureus isolated from a burn centre by using agr, spa and SCCmec typing methods. AB - Infections caused by Staphylococcus aureus remain a major global healthcare problem. We aimed to find the common lineages of S. aureus strains circulating in a burn hospital in Tehran. A total of 167 isolates of S. aureus obtained from patients, healthcare workers (HCWs) and environment in Shahid Motahari burn hospital were genotyped by using spa, agr and staphylococcal cassette chromosome mec (SCCmec) typing methods. Antimicrobial susceptibility testing was performed by using the disc diffusion method. The frequency of methicillin-resistant S. aureus (MRSA) was 64.7% (n = 108), with distribution frequencies among patient, HCW and surface isolates of 64.2% (n = 79), 50% (n = 7) and 73.3% (n = 22), respectively. SCCmec type III (75%, n = 81) was found to be the most frequent SCCmec type among MRSA isolates, followed by SCCmec type I (20.4%, n = 22) and SCCmec type IV (1.8%, n = 2). The remaining MRSA isolates (2.8%, n = 3) were nontypeable by this method. About 78.4% (n = 131), 10.2% (n = 17) and 4.8% (n = 8) of all isolates were characterized as agr types I, II and III, respectively, and the other isolates (6.6%) were nontypeable. spa types t030 and t037 constituted the first and second most predominant spa types found in 56.4% (n = 57) and 25.6% (n = 26) of isolates, respectively. We also report here a novel spa type, t16471. The most prevalent genotypes of the isolates found among patient, surface and HCW samples were SCCmec type III/t030, t037/agr type I. Continuous tracking of epidemic isolates and better hospital infection control policies are recommended to efficiently prevent the spread of bacteria to inpatients. PMID- 30245829 TI - Lodderomyces elongisporus: a bloodstream pathogen of greater clinical significance. AB - The true clinical significance of Lodderomyces elongisporus remains underestimated as a result of problems associated with its identification by the VITEK 2 yeast identification system. Here we describe a case of L. elongisporus primary progressive fungaemia in a woman with no known risk factors for invasive fungal infections. The isolate was identified by PCR sequencing of the internally transcribed spacer region of ribosomal DNA. Despite treatment with caspofungin, the patient died within 3 days of onset of fungaemia. Our literature review highlights this organism's emerging role as a bloodstream pathogen. A need for application of molecular methods for its accurate identification is emphasized. PMID- 30245830 TI - Azole-resistant Candida blankii as a newly recognized cause of bloodstream infection. AB - Candida blankii is a newly recognized human pathogen. Here we describe a case of bloodstream infection in a preterm neonate. The yeast was repeatedly isolated from blood, and its identity was confirmed by PCR sequencing of rDNA. Additionally, C. blankii DNA was detected directly in a blood sample. The isolates initially developed pink colonies on CHROMagar Candida which later turned into dark metallic blue similar to Candida tropicalis. Inaccurate identification by the VITEK 2 yeast identification system as Stephanoascus ciferrii and intrinsic resistance to fluconazole (MIC 12-16 MUg/mL) underscore the need for its accurate identification for appropriate therapeutic management. PMID- 30245831 TI - Fatal case of ST8/SCCmecIVl community-associated methicillin-resistant Staphylococcus aureus infection in Japan. AB - Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) with ST8/SCCmecIV threatens human health. However, its pathogenesis remains unclear. ST8 CA-MRSA (CA-MRSA/J) with SCCmecIVl, which carries the large LPXTG-motif containing putative adhesin gene, spj, has emerged in Japan. We present the first reported case of death from CA-MRSA/J. The patient was a 64-year-old woman with iliopsoas abscesses complicated by septic pulmonary embolism and multiorgan abscesses. Vancomycin, arbekacin, daptomycin and rifampicin were ineffective. CA MRSA/J was resistant to erythromycin, clindamycin and antiseptics and was invasive in a HEp-2 cell assay, in contrast to skin-derived villous-adherent CA MRSA/J. This suggests the strongly invasive pathotype of CA-MRSA/J. PMID- 30245832 TI - Respiratory carriage of the novel Kingella negevensis species by young children. AB - Kingella negevensis, a novel Kingella species implicated in a pediatric joint infection, has been recently characterized but its epidemiology remains largely unknown. The pharyngeal carriage of K. negevensis was studied by re-examining the results of a previous longitudinal study conducted in a cohort of healthy Israeli children from whom upper respiratory tract specimens were sequentially cultured between the ages of 2 and 36 months. Isolates were identified as K. negevensis by a species-specific nucleic amplification assay and genotyped by pulsed-field gel electrophoresis. beta-lactamase production was determined by the nitrocephin test. Kingella negevensis was detected in 26 of 4,472 (0.58%) oropharyngeal cultures obtained from 24 of 716 children (3.35%) and was not isolated from any of 4,472 nasopharyngeal specimens. Following the first 6 months of life during which none of the children was colonized, the prevalence of carriage gradually increased reaching a peak of 1.09% at 24 months of age and decreased thereafter. Kingella negevensis strains showed genomic heterogeneity, and two clones represented 22 of 26 (84.62%) isolates. Twelve of the 26 (46.15%) isolates, belonging to two distinct clones, produced beta-lactamase. Kingella negevensis shows remarkable similarities with K. kingae in terms of colonization site, age related patterns of acquisition and carriage, and clonal distribution of beta lactamase production. Additional research is needed to investigate potential colonization sites of K. negevensis outside the respiratory tract, explore the mechanisms of pharyngeal colonization by the organism, and determine its role as an invasive human pathogen. PMID- 30245833 TI - Expert opinion on livestock antimicrobial usage indications and patterns in Denmark, Portugal and Switzerland. AB - We aimed at describing antimicrobial usage patterns throughout livestock production cycles, and comparing them across three countries from Northern, Central and Southern Europe. Given the difficulties to collect such detailed usage data, an expert opinion was deemed the most appropriate study design. This study provides new insights into the time periods and indications for which specific antimicrobial substances are used in different livestock sectors. Veterinary experts (n=67) from different livestock sectors (broilers, pigs, dairy cattle and veal/fattening calves) and countries (Denmark, Portugal and Switzerland) replied to a questionnaire focusing on the time periods in the production cycle when antimicrobial substances were administered, and the respective indications for treatment. Our results showed that for several antimicrobials, between-country and within-country variations exist regarding the temporal distributions of treatments and indications for use. These differences were also true for several critically important antimicrobials, which is a matter of concern. Furthermore, differences between countries were also evident regarding the antimicrobial substances licensed. Based on our results, it is recommended to establish and promote treatment guidelines, invest in the prevention of diseases during critical moments of the production cycle and target undifferentiated use of antimicrobials. Moreover, discrepancies between countries should be further investigated to better understand the factors underlying the identified patterns and to distinguish prudent from non-prudent use. The results can inform decision-making with the aim to foster antimicrobial prudent use in the veterinary setting and, therefore, protect public health from the threat of antimicrobial resistance. PMID- 30245835 TI - PGD: Pineapple Genomics Database. AB - Pineapple occupies an important phylogenetic position as its reference genome is a model for studying the evolution the Bromeliaceae family and the crassulacean acid metabolism (CAM) photosynthesis. Here, we developed a pineapple genomics database (PGD, http://pineapple.angiosperms.org/pineapple/html/index.html) as a central online platform for storing and integrating genomic, transcriptomic, function annotation and genetic marker data for pineapple (Ananas comosus (L.) Merr.). The PGD currently hosts significant search tools and available datasets for researchers to study comparative genomics, gene expression, gene co expression molecular marker, and gene annotation of A. comosus (L). PGD also performed a series of additional pages for a genomic browser that visualizes genomic data interactively, bulk data download, a detailed user manual, and data integration information. PGD was developed with the capacity to integrate future data resources, and will be used as a long-term and open access database to facilitate the study of the biology, distribution, and the evolution of pineapple and the relative plant species. An email-based helpdesk is also available to offer support with the website and requests of specific datasets from the research community. PMID- 30245834 TI - Small RNAs, emerging regulators critical for the development of horticultural traits. AB - Small RNAs (sRNAs) have been recently recognized as key genetic and epigenetic regulators in various organisms, ranging from the modification of DNA and histone methylations to the modulation of the abundance of coding or non-coding RNAs. In plants, major regulatory sRNAs are classified as respective microRNA (miRNA) and small interfering RNA (siRNA) species, with the former primarily engaging in posttranscriptional regulation while the latter in transcriptional one. Many of these characterized sRNAs are involved in regulation of diverse biological programs, processes, and pathways in response to developmental cues, environmental signals/stresses, pathogen infection, and pest attacks. Recently, sRNAs-mediated regulations have also been extensively investigated in horticultural plants, with many novel mechanisms unveiled, which display far more mechanistic complexity and unique regulatory features compared to those studied in model species. Here, we review the recent progress of sRNA research in horticultural plants, with emphasis on mechanistic aspects as well as their relevance to trait regulation. Given that major and pioneered sRNA research has been carried out in the model and other plants, we also discuss ongoing sRNA research on these plants. Because miRNAs and phased siRNAs (phasiRNAs) are the most studied sRNA regulators, this review focuses on their biogenesis, conservation, function, and targeted genes and traits as well as the mechanistic relation between them, aiming at providing readers comprehensive information instrumental for future sRNA research in horticulture crops. PMID- 30245836 TI - Decrease in exhaled hydrogen as marker of congestive heart failure. AB - Objective: Hydrogen excretion is thought to be related to systemic antioxidation activity. H2 selectively reduces the hydroxyl radical of free hydrogen (.OH), a highly cytotoxic form of reactive oxygen species, in cultured cells. Methods: We investigated whether exhaled H2 decreased during night sleep, reflected .OH production and was associated with heart failure severity. We enrolled 108 patients with chronic heart failure (CHF) and 15 control participants without CHF. H2 concentration was measured by gas chromatography in exhaled breath collected before sleep and in the morning after overnight fasting. Overnight change in H2 concentration (DeltaH2) was calculated. Mitochondrial morphology evaluated by transmission electron microscopy in endomyocardial biopsies collected from 18 patients with dilated cardiomyopathy. Results: DeltaH2 was significantly lower in patients with CHF compared with controls (-4.3+/-1.0 vs 2.0+/-2.1 ppm, p=0.030) and was positively correlated with cardiac index (CI; r = -0.285, p=0.003). Patients with a DeltaH2<0 ppm had a significantly lower CI compared with those who had a DeltaH2>0 ppm (2.85+/-0.61 vs 3.24+/-0.65 L/min/m2, p=0.005). DeltaH2 was negatively correlated with both the percentage of vacuole containing mitochondria and indices of cristae remodelling (r = -0.61, p=0.007). Conclusions: Decrease in exhaled H2 during night sleep was associated with CHF severity. DeltaH2 warrants investigation as marker of CHF severity. PMID- 30245837 TI - Association of peripartum troponin I levels with left ventricular relaxation in women with hypertensive disorders of pregnancy. AB - Objective: Women with hypertensive disorders of pregnancy (HDP) show elevated risk of heart failure despite decreased circulating plasma volume compared with those with normotensive control pregnancies (NCP). This study was performed to better characterise the heart in women with HDP and determine whether high sensitivity troponin I (hs-TnI) around childbirth predicts reduced left ventricular (LV) relaxation at 1 month postpartum. Methods: Echocardiography was performed longitudinally during the first, second and third trimesters and immediately postpartum within 1 week and 1 month postpartum in 24 women with HDP, with simultaneous determination of blood variables in comparison with 51 women with NCP. Results: Compared with NCP, HDP showed greater antepartum left atrial (LA) volume, LV mass and inferior vena cava (IVC) diameter, higher peripartum brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide and hs-TnI with the highest value immediately postpartum, and lower early diastolic mitral annular velocity (e') during pregnancy/postpartum. In analyses of data on HDP and NCP, hs-TnI at the third trimester as well as that immediately postpartum was negatively correlated with later e' at 1 month postpartum. The areas under the receiver operating characteristic curves were 0.82 and 0.81 for hs-TnI at the third trimester and immediately postpartum, respectively, in the prediction of reduced LV relaxation at 1 month postpartum. Conclusion: Reduced LV diastolic function and decreased splanchnic blood reservoir may contribute to the increased third trimester IVC diameter and LA volume in women with HDP. The rise in hs-TnI around childbirth was associated with poor LV relaxation ability at 1 month postpartum. PMID- 30245838 TI - Impact of residence altitude on readmission in patients with heart failure. AB - Objective: Mountain districts normally have tougher geographic conditions than plain districts, which might worsen heart failure (HF) conditions in patients. Also, those places frequently are associated with social problems of ageing, underpopulation and fewer medical services, which might cause delay in detection of disease progression and require more admissions. We investigated the association of residence altitude with readmission in patients with HF. Methods: We followed 452 patients with HF to determine all-cause readmissions over a median of 1.1 years. The altitude of patient residences, population, proportion of the elderly and number of hospitals or clinics in a minor administrative district (Cho-Aza district) located at the residences were examined using data from the 2010 census and Google Maps. Results: All-cause readmissions were observed in 269 (60%) patients. The altitude of >=200 m was significantly associated with readmissions (HR, 1.49; 95 % CI 1.12 to 1.96; p=0.006) after adjustment for physical and haemodynamic parameters, left ventricular ejection fraction, brain natriuretic peptide and components of the established score for predicting readmission for HF. Altitude was significantly associated with ageing, underpopulation, fewer hospitals or clinics and lower temperature (all p<0.01), with an increased tendency for readmission during the winter season; however, it was not associated with patient clinical parameters. Conclusions: High altitude residence may be an important predictor for readmission in patients with HF. This relationship may be confounded by unfavourable sociogeographic conditions at higher altitudes. PMID- 30245839 TI - Prognostic relevance of the right ventricular myo-mechanical index (RV-MMI) in patients with precapillary pulmonary hypertension. AB - Objective: The aim of the prospective New-RV study was to evaluate a parameter for non-invasive quantification of right ventricular (RV) dysfunction in patients with precapillary pulmonary hypertension (PH) that yields prognostic information and is applicable in daily clinical routine. Methods: Sixty-five consecutive patients with precapillary PH under guideline conform therapy (43 women, 22 men) underwent clinical assessment, serological testing, as well as a comprehensive transthoracic echocardiography including strain imaging and a detailed assessment of RV haemodynamics. Results: The mean follow-up time was 844 days. Sixteen patients died during clinical follow-up. Right ventricular myo-mechanical index (RV-MMI) was calculated by right atrial size, mean RV pressure gradient and strain imaging of the RV free wall, and was measurable in all examinations. RV MMI was tested for its diagnostic accuracy (sensitivity of 88% and specificity of 73% for an optimal cut-off value of <=0.31 mm Hg*%; area under the curve=0.85), as well as its predictive value (HR=3.3, 95% CI 1.6 to 7.0, p<0.001), and was compared in detail with established parameters. RV-MMI and N-terminal pro-brain natriuretic peptide (NTproBNP)were independent predictors of survival (HR=2.9, 95% CI 1.4 to 6.2, p=0.006; and HR=2.6, 95% CI 1.5 to 4.6, p=0.001, respectively). Conclusion: In a cohort of patients with precapillary PH, the RV MMI differentiates the outcome of patients better than other available non invasive parameters of RV function by preload and afterload adjusted quantification. Trial registration number: NCT01230294. PMID- 30245840 TI - Long-range haplotype analysis of the malaria parasite receptor gene ACKR1 in an East-African population. AB - The human ACKR1 gene encodes a glycoprotein expressing the Duffy blood group antigens (Fy). The Duffy protein acts as a receptor for distinct pro-inflammatory cytokines and malaria parasites. We determined the haplotypes of the ACKR1 gene in a population inhabiting a malaria-endemic area. We collected blood samples from 60 healthy volunteers in Ethiopia's southwestern low-altitude tropical region. An assay was devised to amplify the ACKR1 gene as a single amplicon and determine its genomic sequence. All haplotypes were resolved at 5178 nucleotides each, covering the coding sequence (CDS) of the ACKR1 gene and including the 5'- and 3'-untranslated regions (UTR), intron 1, and the 5'- and 3'-flanking regions. When necessary, allele-specific PCR with nucleotide sequencing or length polymorphism analysis was applied. Among the 120 chromosomes analyzed, 18 ACKR1 alleles were confirmed without ambiguity. We found 18 single-nucleotide polymorphisms (SNPs); only one SNP was novel. The non-coding sequences harbored 14 SNPs. No SNP, other than c.-67T>C, indicative of a non-functional allele, was detected. We described haplotypes of the ACKR1 gene in an autochthonous East African population and found 18 distinct ACKR1 alleles. These long-range alleles are useful as templates to phase and analyze next-generation sequencing data, thus enhancing the reliability of clinical diagnostics. PMID- 30245841 TI - A Retrospective Study of Chronic Kidney Disease Burden in Saskatchewan's First Nations People. AB - Background: Chronic kidney disease is more prevalent among First Nations people than in non-First Nations people. Emerging research suggests that First Nations people are subject to greater disease burden than non-First Nations people. Objective: We aimed to identify the severity of chronic kidney disease and quantify the geographical challenges of obtaining kidney care by Saskatchewan's First Nations people. Design: This study is a retrospective analysis of the provincial electronic medical record clinical database from January 2012 to December 2013. Setting: The setting involved patients followed by the Saskatchewan provincial chronic kidney care program, run out of two clinics, one in Regina, SK, and one in Saskatoon, SK. Patients: The patients included 2478 individuals (379 First Nations and 2099 non-First Nations) who were older than 18 years old, resident in Saskatchewan, and followed by the provincial chronic kidney care program. First Nations individuals were identified by their Indigenous and Northern Affairs Canada (INAC) Number. Measurements: The demographics, prevalence, cause of end-stage renal disease, severity of chronic kidney disease, use of home-based therapies, and distance traveled for care among patients are reported. Methods: Data were extracted from the clinical database used for direct patient care (the provincial electronic medical record database for the chronic kidney care program), which is prospectively managed by the health care staff. Actual distance traveled by road for each patient was estimated by a Geographic Information System Analyst in the First Nations and Inuit Health Branch of Health Canada. Results: Compared with non-First Nations, First Nations demonstrate a higher proportion of end-stage renal disease (First Nations = 33.0% vs non-First Nations = 21.4%, P < .001), earlier onset of chronic kidney disease (MFN = 56.4 years, SD = 15.1; MNFN = 70.6 years, SD = 14.7, P < .001), and higher rates of end-stage renal disease secondary to type 2 diabetes (First Nations = 66.1% vs non-First Nations = 39.0%, P < .001). First Nations people are also more likely to be on dialysis (First Nations = 69.7% vs non-First Nations = 40.2%, P < .001), use home-based therapies less frequently (First Nations = 16.2% vs non-First Nations = 25.7%; P = 003), and must travel farther for treatment (P < .001), with First Nations being more likely than non-First Nations to have to travel greater than 200 km. Limitations: Patients who are followed by their primary care provider or solely through their nephrologist's office for their chronic kidney disease would not be included in this study. Patients who self-identify as Aboriginal or Indigenous without an INAC number would not be captured in the First Nations cohort. Conclusions: In Saskatchewan, First Nations' burden of chronic kidney disease reveals higher severity, utilization of fewer home-based therapies, and longer travel distances than their non-First Nations counterparts. More research is required to identify innovative solutions within First Nations partnering communities. PMID- 30245842 TI - Illness perception of adolescents with well-controlled type 1 diabetes mellitus. AB - In this study, to explore the illness perceptions of adolescents with well controlled type 1 diabetes mellitus in South Africa, semi-structured interviews were conducted with nine, purposively selected adolescents (mean = 13.9 years; median = 12). Themes that emerged from the thematic analysis include the following: accepting diabetes and the diabetes care plan as part of their lives; viewing diabetes as manageable and as their responsibility; and the important role of gaining information on diabetes and diabetes management. These perceptions contributed to adherence to diabetes care plans and should be explored and developed among adolescents with type 1 diabetes mellitus to improve their diabetes management. PMID- 30245843 TI - Thoracic and paraspinal extramedullary hematopoiesis in a cat with chronic non regenerative anemia. AB - Case summary: A 6-year-old neutered male domestic shorthair cat presented with non-regenerative macrocytic anemia of 2 years' duration and minimally ambulatory paraparesis. Neurologic examination suggested an upper motor neuron paresis or T3 L3 myelopathy. The cat was positive for feline immunodeficiency virus (FIV), neutropenic, had polyclonal gammopathy and was euthanized following a hemolytic crisis. At autopsy, multifocal bilateral dark red masses were observed subpleurally around the costochondral junctions, extradurally and paraspinally in the spinal canal, and paravertebrally, on the lateral and ventral subpleural surfaces of the T4-11 vertebrae. Histologic examination of the masses revealed extramedullary hematopoietic tissue composed primarily of erythroid precursors and megakaryocytes, with occasional myeloid precursors and blood-filled sinuses. Bone marrow findings supported ineffective granulopoiesis, and decreased erythropoiesis and megakaryopoiesis, with probable myelodysplasia as the underlying cause of the hematologic abnormalities. Relevance and novel information: Thoracic, paraspinal and paravertebral extramedullary hematopoietis presenting as masses has not been described previously in cats with chronic anemia. This is a unique case of a thoracic-spinal-epidural extramedullary hematopoietic masses resulting in possible spinal cord compression and paraparesis in a cat. PMID- 30245844 TI - Annotation and functional clustering of circRNA expression in rhesus macaque brain during aging. AB - The abundance and function of circular RNAs (circRNAs) in mammalian brain have been reported, but their alterations in the biology of brain aging remain elusive. Here, using deep RNA profiling with linear RNA digestion by RNase R we explored a comprehensive map of changes in circRNA expression in rhesus macaque (macaca mulatta) brain in two age groups from adult (10 y) to aged (20 y) periods. Total 17,050 well expressed, stable circRNAs were identified. Cluster analysis reveals that dynamic changes in circRNA expression show the spatial-, sex- and age-biased specificities. On the basis of separate profiling of the RNAs, age-related circRNAs show differential correlation to host mRNA expression. Furthermore, two voltage-dependent L- and R-type calcium channel gene-derived circCACNA2D1 and circCACNA1E negatively regulate their host mRNA expression. Our results demonstrate the power of changes in circRNA expression to reveal insights into a potentially circRNA-mediated regulatory mechanism underlying the biology of brain aging. PMID- 30245845 TI - Human embryonic stem cell-derived retinal pigment epithelium transplants as a potential treatment for wet age-related macular degeneration. AB - Stem cell therapy may provide a safe and promising treatment for retinal diseases. Wet age-related macular degeneration (wet-AMD) is a leading cause of blindness in China. We developed a clinical-grade human embryonic stem cell (hESC) line, Q-CTS-hESC-2, under xeno-free conditions that differentiated into retinal pigment epithelial cells (Q-CTS-hESC-2-RPE). A clinical trial with three wet-AMD patients was initiated in order to study the safety and tolerance to Q CTS-hESC-2-RPE cell transplants. The choroidal neovascularization membrane was removed and then a suspension of 1 * 106 Q-CTS-hESC-2-RPE cells were injected into a subfoveal pocket. The patients were followed for 12 months during which no adverse effects resulting from the transplant were observed. Anatomical evidence suggested the existence of new RPE-like cell layer in the previously damaged area. Visual and physiological testing indicated limited functional improvement, albeit to different degrees between patients. This study provides some promising early results concerning the use of transplanted hESC-RPE cells to alleviate wet AMD. PMID- 30245846 TI - Electron microscopy of Chaetomium pom152 shows the assembly of ten-bead string. PMID- 30245847 TI - Context-dependent prediction of protein complexes by SiComPre. AB - Most cellular processes are regulated by groups of proteins interacting together to form protein complexes. Protein compositions vary between different tissues or disease conditions enabling or preventing certain protein-protein interactions and resulting in variations in the complexome. Quantitative and qualitative characterization of context-specific protein complexes will help to better understand context-dependent variations in the physiological behavior of cells. Here, we present SiComPre 1.0, a computational tool that predicts context specific protein complexes by integrating multi-omics sources. SiComPre outperforms other protein complex prediction tools in qualitative predictions and is unique in giving quantitative predictions on the complexome depending on the specific interactions and protein abundances defined by the user. We provide tutorials and examples on the complexome prediction of common model organisms, various human tissues and how the complexome is affected by drug treatment. PMID- 30245849 TI - Rehabilitative exercise and spatially patterned nanofibrillar scaffolds enhance vascularization and innervation following volumetric muscle loss. AB - Muscle regeneration can be permanently impaired by traumatic injuries, despite the high regenerative capacity of skeletal muscle. Implantation of engineered biomimetic scaffolds to the site of muscle ablation may serve as an attractive off-the-shelf therapeutic approach. The objective of the study was to histologically assess the therapeutic benefit of a three-dimensional spatially patterned collagen scaffold, in conjunction with rehabilitative exercise, for treatment of volumetric muscle loss. To mimic the physiologic organization of skeletal muscle, which is generally composed of myofibers aligned in parallel, three-dimensional parallel-aligned nanofibrillar collagen scaffolds were fabricated. When implanted into the ablated murine tibialis anterior muscle, the aligned nanofibrillar scaffolds, in conjunction with voluntary caged wheel exercise, significantly improved the density of perfused microvessels, in comparison to treatments of the randomly oriented nanofibrillar scaffold, decellularized scaffold, or in the untreated control group. The abundance of neuromuscular junctions was 19-fold higher when treated with aligned nanofibrillar scaffolds in conjunction with exercise, in comparison to treatment of aligned scaffold without exercise. Although, the density of de novo myofibers was not significantly improved by aligned scaffolds, regardless of exercise activity, the cross-sectional area of regenerating myofibers was increased by > 60% when treated with either aligned and randomly oriented scaffolds, in comparison to treatment of decellularized scaffold or untreated controls. These findings demonstrate that voluntary exercise improved the regenerative effect of aligned scaffolds by augmenting neurovascularization, and have important implications in the design of engineered biomimetic scaffolds for treatment of traumatic muscle injury. PMID- 30245848 TI - Effectiveness of mesenchymal stem cells for treating patients with knee osteoarthritis: a meta-analysis toward the establishment of effective regenerative rehabilitation. AB - This systematic review with a meta-analysis aimed to summarize the current evidence of the effectiveness of mesenchymal stem cell (MSC) treatment for knee osteoarthritis (OA) and to examine whether rehabilitation is an effect modifier of the effect estimate of MSC treatment. A literature search yielded 659 studies, of which 35 studies met the inclusion criteria (n = 2385 patients; mean age: 36.0 74.5 years). The meta-analysis results suggested that MSC treatment through intra articular injection or arthroscopic implantation significantly improved knee pain (standardized mean difference [SMD]: -1.45, 95% confidence interval [CI]: -1.94, 0.96), self-reported physical function (SMD: 1.50, 95% CI: 1.09, 1.92), and cartilage quality (SMD: -1.99; 95% CI: -3.51, -0.47). However, the MSC treatment efficacy on cartilage volume was limited (SMD: 0.49; 95% CI: -0.19, 1.16). Minor adverse events (knee pain or swelling) were reported with a wide-ranging prevalence of 2-60%; however, no severe adverse events occurred. The evidence for these outcomes was "very low" to "low" according to the Grades of Recommendation, Assessment, Development and Evaluation system because of the poor study design, high risk of bias, large heterogeneity, and wide 95% CI of the effects estimate. Performing rehabilitation was significantly associated with better SMD for self reported physical function (regression coefficient: 0.881, 95% CI: 0.049, 1.712; P = 0.039). We suggest that more high quality randomized controlled trials with consideration of the potential rehabilitation-driven clinical benefit would be needed to facilitate the foundation of effective MSC treatment and regenerative rehabilitation for patients with knee OA. PMID- 30245851 TI - Ancillary benefits of bladder chemodenervation for SCI neurogenic bladder. AB - Study design: Case series. Objective: Bladder chemodenervation is effective in treating neurogenic detrusor overactivity (NDO) in patients with neurogenic bladder due to spinal cord injury. Anecdotal reports also describe the improvement of non-bladder symptoms, specifically those related to autonomic dysreflexia (AD) and muscle spasticity. We conducted a study to further investigate this phenomenon. Setting: USA, Urban Tertiary Care Center. Methods: Twenty-one persons with SCI completed the study between March and December 2015. Mean age was 45 years (range 21-69). All were scheduled to undergo bladder chemodenervation with onabotulinumtoxinA 200 units to treat bothersome NDO refractory to oral medications. Each completed a questionnaire detailing symptoms unrelated to NDO immediately prior to the procedure, and again between 6 and 12 weeks after. Results: All patients reported improvement in NDO symptoms following chemodenervation. Ten patients with prior symptoms of AD reported improvement in AD symptoms after injection. Seventeen patients reported skeletal muscle spasticity in the 3-month period before chemodenervation. In the follow up period, only 14 patients reported having muscle spasticity. In aggregate, 12 of 21 patients reported improvement of non-bladder symptomatology following chemodenervation. Conclusions: Chemodenervation of the bladder in patients with SCI can provide ancillary benefits in addition to mitigation of lower urinary symptoms. The mechanism may be related to dampening the bladder's ability to initiate noxious reflex responses. PMID- 30245850 TI - Density and tailored breast cancer screening: practice and prediction - an overview. AB - Mammography, as the primary screening modality, has facilitated a substantial decrease in breast cancer-related mortality in the general population. However, the sensitivity of mammography for breast cancer detection is decreased in women with higher breast densities, which is an independent risk factor for breast cancer. With increasing public awareness of the implications of a high breast density, there is an increasing demand for supplemental screening in these patients. Yet, improvements in breast cancer detection with supplemental screening methods come at the expense of increased false-positives, recall rates, patient anxiety, and costs. Therefore, breast cancer screening practice must change from a general one-size-fits-all approach to a more personalized, risk based one that is tailored to the individual woman's risk, personal beliefs, and preferences, while accounting for cost, potential harm, and benefits. This overview will provide an overview of the available breast density assessment modalities, the current breast density screening recommendations for women at average risk of breast cancer, and supplemental methods for breast cancer screening. In addition, we will provide a look at the possibilities for a risk adapted breast cancer screening. PMID- 30245852 TI - Is Fitbit Charge 2 a feasible instrument to monitor daily physical activity and handbike training in persons with spinal cord injury? A pilot study. AB - Study design: It is a longitudinal pilot study. Objectives: To investigate the feasibility of a low-cost and widely used fitness tracker with step count and heart rate data to monitor daily physical activity in wheelchair users with spinal cord injury (SCI). Setting: Dutch community. Methods: Six participants with SCI who were in training for a handbike event were recruited. They were asked to wear a Fitbit Charge 2(r) 24 h a day for at least 2 weeks and were questioned about the utility and user-friendliness of this device. Results: Five out of six participants managed to wear the device nonstop for 2 weeks, and continued to wear the device after this initial period. Most participants were enthusiastic about the direct feedback provided by the tracker and reported the data to be accurate. Data collected during more than 2 months of three participants and during 8 months on one of them showed the possibility of detecting training days and observing interpersonal and intrapersonal variation in daily physical activity level. Conclusions: A commercially available, low cost, self-monitoring multi-sensor wrist device or a fitness tracker like the Fitbit Charge 2(r) can be a promising instrument to monitor daily activity levels among wheelchair users with SCI. The free commercial dashboard and log data clearly show trends of variations in physical activity and increases in heart rate, which are of value to both researchers and clinicians interested in identifying training schedules of wheelchair athletes. PMID- 30245853 TI - BTK modulates p73 activity to induce apoptosis independently of p53. AB - Bruton's tyrosine kinase (BTK) is a key component of B cell receptor signalling. Because of this, BTK plays an important role in cell proliferation and survival in various B cell malignancies. However, in certain contexts, BTK can also have tumour suppressor functions. We have previously shown that BTK activates the p53 transcriptional activity by binding to and phosphorylating p53, as well as acting on MDM2 to reduce its inhibitory effects. This results in increased p53 functions, including enhanced cell death. Here, we report that BTK can also induce cell death and increase responses to DNA damage independently of p53. This is concomitant to the induction of p21, PUMA and MDM2, which are classic target genes of the p53 family of proteins. Our results show that these p53-independent effects of BTK are mediated through p73. Similar to what we observed in the p53 pathway, BTK can upregulate p73 after DNA damage and induce expression of its target genes, suggesting that BTK is a modulator of p73 functions and in the absence of p53. This effect allows BTK to have pro-apoptotic functions independently of its effects on the p53 pathway and thus play an important role in the DNA damage-related induction of apoptosis in the absence of p53. This provides a novel role of BTK in tumour suppression and contributes to the understanding of its complex pleiotropic functions. PMID- 30245854 TI - KLLN-mediated DNA damage-induced apoptosis is associated with regulation of p53 phosphorylation and acetylation in breast cancer cells. AB - KLLN is a target of p53 involved in S-phase cell cycle regulation deemed necessary and sufficient for p53-mediated apoptosis. Germline promoter hypermethylation of KLLN is associated with a cancer-predisposition syndrome, Cowden syndrome. KLLN's DNA-binding ability is associated with transcription regulation and maintenance of genomic stability. Here, we report on KLLN's role in DNA damage response (DDR) mediated through apoptosis in breast cells with and without a cancer phenotype. KLLN expression was upregulated after doxorubicin induced DNA damage and this upregulation can be abrogated using RNAi-mediated gene silencing. Silencing KLLN after doxorubicin treatment effected DDR shown by decreased gamma-H2AX foci and expression, and apoptosis assessed by decreased frequency of apoptotic nuclei and decreased expression of definitive markers of apoptosis. Contrary to expectations, there was no change in cell cycle regulation after KLLN silencing. These results were observed in breast cells with wildtype and mutant p53. At early timepoints after doxorubicin treatment, knocking down KLLN resulted in decreased Ser15-phosphorylation of p53 but not Thr68 phosphorylation of CHK2 or the phosphorylation of upstream regulators such as ATM and ATR. Interestingly, a second pathway for p53 activation was also affected by knockdown of KLLN. After doxorubicin treatment, Thr454-phosphorylation of DBC1, required to inhibit deacetylation of p53 by SIRT1, was decreased and therefore acetylation of p53 was also decreased with KLLN knockdown. Therefore, our observations suggest that KLLN's role in DNA damage-induced apoptosis is likely independent of p53 and is associated with a two-pronged regulation of p53 activation. PMID- 30245856 TI - Autophagy regulates vinorelbine sensitivity due to continued Keap1-mediated ROS generation in lung adenocarcinoma cells. AB - Autophagy is one of the induced mechanisms in metastatic cancer to escape death due to starvation, hypoxia, metabolic stresses, chemotherapy, and radiation. Some publications have revealed that chemotherapy combined with autophagy inhibitor will overcome drug resistance. We modified AS2 cells with PTEN overexpression, mTOR knockdown, or Keap1 knockdown, and made modification of A549 cells with PTEN knockdown, Atg5 knockdown, and Keap1 overexpression. Our study was aimed toward an exploration of how autophagy modulates Keap1, ROS generation, and vinorelbine induced apoptosis in these cell lines. We found that lung cancer PC14PE6/AS2 (AS2) had higher mTOR and Akt and also lower PTEN expression than A549 cells. Descended autophagy was demonstrated with more decreased p62 accumulation and LC3 II conversion in AS2 cells as compared to A549 cells. The A549 cells had lower Keap1/Nrf2 and more active anti-oxidant response element (ARE) activity than the AS2 cells. We modified AS2 cells with PTEN overexpression, mTOR knockdown, Keap1 knockdown, and revealed amplified p62 and LC3 expression accompanied with decreased Akt, Keap1, ROS, and vinorelbine-induced apoptosis. Declined p62, LC3 expression were accompanied with increased Akt, Keap1, ROS, and vinorelbine induced apoptosis after modification of A549 cells with PTEN knockdown, Atg5 knockdown, and Keap1 overexpression. Keap1 overexpression lowered ARE levels in A549 cells, and ARE level exhibited up-growth in Keap1 knockdown AS2 cells. The autophagy inhibitor caused more ROS generation and vinorelbine-induced apoptosis in the A549 and CL1-5 cells. According to these findings, autophagy regulates vinorelbine sensitivity by continuing Keap1-mediated ROS generation in lung adenocarcinoma cells. PMID- 30245855 TI - NDRG2 suppression as a molecular hallmark of photoreceptor-specific cell death in the mouse retina. AB - Photoreceptor cell death is recognized as the key pathogenesis of retinal degeneration, but the molecular basis underlying photoreceptor-specific cell loss in retinal damaging conditions is virtually unknown. The N-myc downstream regulated gene (NDRG) family has recently been reported to regulate cell viability, in particular NDRG1 has been uncovered expression in photoreceptor cells. Accordingly, we herein examined the potential roles of NDRGs in mediating photoreceptor-specific cell loss in retinal damages. By using mouse models of retinal degeneration and the 661 W photoreceptor cell line, we showed that photoreceptor cells are indeed highly sensitive to light exposure and the related oxidative stress, and that photoreceptor cells are even selectively diminished by phototoxins of the alkylating agent N-Methyl-N-nitrosourea (MNU). Unexpectedly, we discovered that of all the NDRG family members, NDRG2, but not the originally hypothesized NDRG1 or other NDRG subtypes, was selectively expressed and specifically responded to retinal damaging conditions in photoreceptor cells. Furthermore, functional experiments proved that NDRG2 was essential for photoreceptor cell viability, which could be attributed to NDRG2 control of the photo-oxidative stress, and that it was the suppression of NDRG2 which led to photoreceptor cell loss in damaging conditions. More importantly, NDRG2 preservation contributed to photoreceptor-specific cell maintenance and retinal protection both in vitro and in vivo. Our findings revealed a previously unrecognized role of NDRG2 in mediating photoreceptor cell homeostasis and established for the first time the molecular hallmark of photoreceptor-specific cell death as NDRG2 suppression, shedding light on improved understanding and therapy of retinal degeneration. PMID- 30245858 TI - PIDD-dependent activation of caspase-2-mediated mitochondrial injury in E1A induced cellular sensitivity to macrophage nitric oxide-induced apoptosis. AB - Expression of the adenovirus E1A oncogene sensitizes tumor cells to innate immune rejection by apoptosis induced by macrophage-produced tumor necrosis factor (TNF) alpha and nitric oxide (NO). E1A sensitizes cells to TNF-alpha and NO through two distinct mechanisms, by repressing NF-kappaB-dependent antiapoptotic responses and enhancing caspase-2 activation and mitochondrial injury, respectively. The mechanisms through which E1A enhances caspase-2 activation in response to NO were unknown. Here, we report that E1A-induced sensitization to NO-induced apoptosis is dependent on expression of PIDD (p53-inducible protein with a death domain) and enhancement of primary immunodeficiency diseases (PIDD) processing for formation of the PIDDosome, the core component of the caspase-2 activation complex. NO-induced apoptosis in E1A-expressing cells did not require expression Bak or Bax, indicating that NO-induced caspase-2-mediated mitochondrial injury does not proceed through the activities of typical, proapoptotic Bcl-2 family members that induce mitochondrial cytochrome C release. These results define a PIDD-dependent pathway, through which E1A enhances casapse-2-mediated mitochondrial injury, resulting in increased sensitivity of mammalian cells to macrophage-induced, NO-mediated apoptosis. PMID- 30245857 TI - Kindlin-2 regulates hepatic stellate cells activation and liver fibrogenesis. AB - Liver fibrosis, the common response associated with chronic liver diseases, ultimately leads to cirrhosis, a major public health problem worldwide. Activation of hepatic stellate cells (HSCs) by transforming growth factor (TGF) beta1 is a key step in liver fibrosis. Here we report that Kindlin-2 expression is elevated in the livers of mice with experimental liver fibrosis and also in the livers of patients with liver fibrosis. TGF-beta1 increases Kindlin-2 expression in cultured HSCs in a p38 and ERK mitogen-activated protein kinase (MAPK)-dependent manner, partly. More importantly, Kindlin-2 deficiency significantly attenuated mouse liver fibrosis and HSC activation. Mechanistically, Kindlin-2 promotes TGF-beta signaling through upregulation of Smad2 and Smad3 phosphorylation. Our work demonstrates an important role for Kindlin-2 in liver fibrosis, and inhibiting Kindlin-2 in the livers may represent a novel strategy to treat liver fibrosis. PMID- 30245859 TI - An Ad/MVA vectored Theileria parva antigen induces schizont-specific CD8+ central memory T cells and confers partial protection against a lethal challenge. AB - The parasite Theileria parva is the causative agent of East Coast fever (ECF), one of the most serious cattle diseases in sub-Saharan Africa, and directly impacts smallholder farmers' livelihoods. There is an efficient live-parasite vaccine, but issues with transmission of vaccine strains, need of a cold chain, and antibiotics limit its utilization. This has fostered research towards subunit vaccination. Cytotoxic T lymphocytes (CTL) are crucial in combating the infection by lysing T. parva-infected cells. Tp1 is an immunodominant CTL antigen, which induces Tp1-specific responses in 70-80% of cattle of the A18 or A18v haplotype during vaccination with the live vaccine. In this study, human adenovirus serotype 5 (HAd5) and modified vaccinia Ankara (MVA) were assessed for their ability to induce Tp1-specific immunity. Both viral vectors expressing the Tp1 antigen were inoculated in cattle by a heterologous prime-boost vaccination regimen. All 15 animals responded to Tp1 as determined by ELISpot. Of these, 14 reacted to the known Tp1 epitope, assayed by ELISpot and tetramer analyses, with CTL peaking 1-week post-MVA boost. Eleven animals developed CTL with specific cytotoxic activity towards peripheral blood mononuclear cells (PBMC) pulsed with the Tp1 epitope. Moreover, 36% of the animals with a Tp1 epitope-specific response survived a lethal challenge with T. parva 5 weeks post-MVA boost. Reduction of the parasitemia correlated with increased percentages of central memory lymphocytes in the Tp1 epitope-specific CD8+ populations. These results indicate that Tp1 is a promising antigen to include in a subunit vaccine and central memory cells are crucial for clearing the parasite. PMID- 30245861 TI - Erratum: Publisher Correction: Augmented CD4+ T-cell and humoral responses after repeated annual influenza vaccination with the same vaccine component A/H1N1pdm09 over 5 years. AB - [This corrects the article DOI: 10.1038/s41541-018-0069-1.]. PMID- 30245860 TI - Using vaccine Immunostimulation/Immunodynamic modelling methods to inform vaccine dose decision-making. AB - Unlike drug dose optimisation, mathematical modelling has not been applied to vaccine dose finding. We applied a novel Immunostimulation/Immunodynamic mathematical modelling framework to translate multi-dose TB vaccine immune responses from mice, to predict most immunogenic dose in humans. Data were previously collected on IFN-gamma secreting CD4+ T cells over time for novel TB vaccines H56 and H1 adjuvanted with IC31 in mice (1 dose groups (0.1-1.5 and 15 MUg H56 + IC31), 45 mice) and humans (1 dose (50 MUg H56/H1 + IC31), 18 humans). A two-compartment mathematical model, describing the dynamics of the post vaccination IFN-gamma T cell response, was fitted to mouse and human data, separately, using nonlinear mixed effects methods. We used these fitted models and a vaccine dose allometric scaling assumption, to predict the most immunogenic human dose. Based on the changes in model parameters by mouse H56 + IC31 dose and by varying the H56 dose allometric scaling factor between mouse and humans, we established that, at a late time point (224 days) doses of 0.8-8 MUg H56 + IC31 in humans may be the most immunogenic. A 0.8-8 MUg of H-series TB vaccines in humans, may be as, or more, immunogenic, as larger doses. The Immunostimulation/Immunodynamic mathematical modelling framework is a novel, and potentially revolutionary tool, to predict most immunogenic vaccine doses, and accelerate vaccine development. PMID- 30245862 TI - New Insights into the Role of Phosphoinositide 3-Kinase Activity in the Physiology of Immature Oocytes: Lessons from Recent Mouse Model Studies. AB - The immature oocytes within primordial follicles are arrested at Prophase I of meiosis and remain dormant until awakened by an increase in intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Oocyte PIP3 level is determined by the balance between the activity of phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homologue (PTEN). When this balance favours PI3K, PIP3 levels elevate and trigger the cascade of PI3K/protein kinase B (AKT)/the mammalian target of rapamycin (mTOR) pathway, leading to activation of primordial follicles. This short review aims to provide new insights into the physiological functions of PI3K and PTEN in immature oocytes by summarising recent findings from murine model studies, including oocyte-specific transgenic mice with constitutively-active mutant PI3K. PMID- 30245863 TI - ALK IHC and FISH discordant results in patients with NSCLC and treatment response: for discussion of the question-to treat or not to treat? AB - Introduction: Lung cancer is the most common cancer worldwide. Latest guidelines from the College of American Pathologist and the European society of medical oncologists indicate anaplastic lymphoma kinase (ALK) rearrangement testing is standard practice. Historically, diagnostics for ALK used fluorescence in situ hybridisation (FISH); however, immunohistochemical (IHC) assays are becoming common practice. Unfortunately, recent assessment of current practice indicated that not all patients who should be tested for ALK translocation are undergoing ALK testing. Methods: From a series of European and Israeli labs, we collected patients with discordant IHC and FISH testing, which were subsequently treated with ALK-targeted therapy, for discussion of the question, to treat or not to treat? Results: Our study may support ALK IHC testing as a better predictor of response to targeted therapy provided that the labs implement controlled preanalytical procedures, use correct clone, run protocols on automated staining platforms and validate using external quality assessments. PMID- 30245864 TI - Preparing for the incoming wave of biosimilars in oncology. AB - With the imminent arrival of oncology biosimilars in the therapeutic paradigm, stakeholders including a clinician, specialist nurse, patient advocate, regulator and economist provide their perspective on optimising the uptake of these new agents in the treatment of cancer. A number of key messages emerge, based on the discussion that took place during a session of the European Society for Medical Oncology's Annual Congress, ESMO Madrid 2017. First, for successful integration of biosimilars into the global healthcare paradigm, informing and educating the full scope of stakeholders, including clinicians, nurses, pharmacists and patients, is primordial. Success is dependent on providing solid evidence and ensuring all voices are heard. Second, for oncology medicines, much can be learnt from the growing experience of approved biosimilars in other disease indications, with success stories for patients, their healthcare providers and healthcare budgets alike. Finally, effective sustainability of the impact on healthcare budgets and the redirection of these savings require education and transparency. PMID- 30245865 TI - Evidence of a distinct group of Black African patients with systemic lupus erythematosus. AB - Background: The autoimmune disease systemic lupus erythematosus (SLE) occurs more frequently in patients of African descent with high morbidity and mortality. Current SLE diagnostic criteria including antinuclear antibody (ANA) reactivity are derived largely from non-African populations. This study characterises ANA reactivity patterns and relates them to SLE clinical presentation in Black African patients. Methods: Sera from Black participants (61 patients with SLE and 100 controls) aged 1-81 years were analysed for reactivity against the antigens: uridine 1-ribonuclear protein, Smith uridine-1-5 ribonuclear protein antigen, soluble substance-A, recombinant Ro-52, soluble substance-B, Scl-70, cytoplasmic histidyl-tRNA synthetase antigen, proliferating cell nuclear antigen (PCNA), nucleosomes, ribonuclear P-protein, antimitochondrial antibody M2 (AMA-M2), histones, double-stranded DNA (dsDNA), centromere protein B and polymyositis sclerosis overlap antigen. Findings: A significantly higher proportion (97%) of the 61 patients with SLE had detectable autoantibody reactivity compared with 15% of the 100 controls (p<0.001). The highest frequencies of autoantibody reactivity in patients with SLE were against the dsDNA antigen (41%) and PCNA (54%). Anti PCNA and anti-dsDNA reactivity were mutually exclusive (p<0.001) giving rise to two distinct groups of Black African patients with SLE. The first group (n=25) had reactivity profiles consistent with international standard SLE definitions, including anti-dsDNA reactivity, and was 13 times more likely to present with joint symptoms. The larger, second group (n=34), characterised by anti-PCNA and anti-AMA-M2 reactivity, was nine times more likely to present with only cutaneous symptoms. Interpretation: Our study demonstrates a need to extend autoantibody panels to include anti-PCNA in the diagnostic process of Black African patients and further refine the predictive values of the reactivity to different antigens to differentiate SLE syndromes in African populations. PMID- 30245867 TI - Creating a specialist physician workforce in low-resource settings: reflections and lessons learnt from the East African Training Initiative. AB - Many African countries have extremely low ratios of physicians to population, and there are very, very few specialists. This leaves most patients without access to specialised care, and importantly also leaves many countries with insufficient expertise to properly evaluate the burden of illness and the needs of the population overall. The challenges to training a specialised physician workforce in resource-limited settings are many, and they go far beyond the (relatively simple) task of transmission of clinical skills. We initiated a capacity-building programme to train pulmonary physicians in Ethiopia, a country of 105 million persons with a high burden of lung disease that had no prior existing training programme in pulmonary medicine. Using volunteer faculty from the USA and Europe, we have provided high-quality training and established a cohort of pulmonary specialists there. We have identified several components of training that go beyond clinical skills development but which we feel are crucial to sustainability. These components include the delineation of viable career pathways that allow professional growth for subspecialist physicians and that support the permanent establishment of a local faculty; the development of important non-clinical skills, including leadership and pedagogical techniques; training in clinical research methodologies; and the development of mechanisms to amplify the impact of a still relatively small number of specialised physicians to address the needs of the population generally. Our programme, the East African Training Initiative, has successfully addressed many of these challenges and we hope that it can be replicated elsewhere. PMID- 30245866 TI - Integration of HIV and reproductive health services in public sector facilities: analysis of client flow data over time in Kenya. AB - Introduction: Integration of HIV/AIDS with reproductive health (RH) services can increase the uptake and efficiency of services, but gaps in knowledge remain about the practice of integration, particularly how provision can be expanded and performance enhanced. We assessed the extent and nature of service integration in public sector facilities in four districts in Kenya. Methods: Between 2009 and 2012, client flow assessments were conducted at six time points in 24 government facilities, purposively selected as intervention or comparison sites. A total of 25 539 visits were tracked: 15 270 in districts where 6 of 12 facilities received an intervention to strengthen HIV service integration with family planning (FP); and 10 266 visits in districts where half the facilities received an HIV postnatal care intervention in 2009-2010. We tracked the proportion of all visits in which: (1) an HIV service (testing, counselling or treatment) was received together with an RH service (FP counselling or provision, antenatal care, or postnatal care); (2) the client received HIV counselling. Results: Levels of integrated HIV-RH services and HIV counselling were generally low across facilities and time points. An initial boost in integration was observed in most intervention sites, driven by integration of HIV services with FP counselling and provision, and declined after the first follow-up. Integration at most sites was driven by temporary rises in HIV counselling. The most consistent combination of HIV services was with antenatal care; the least common was with postnatal care. Conclusions: These client flow data demonstrated a short-term boost in integration, after an initial intervention with FP services providing an opportunity to expand integration. Integration was not sustained over time highlighting the need for ongoing support. There are multiple opportunities for integrating service delivery, particularly within antenatal, FP and HIV counselling services, but a need for sustained systems and health worker support over time. Trial registration number: NCT01694862. PMID- 30245868 TI - Nanosphere Lithography of Chitin and Chitosan with Colloidal and Self-Masking Patterning. AB - Complex surface topographies control, define, and determine the properties of insect cuticles. In some cases, these nanostructured materials are a direct extension of chitin-based cuticles. The cellular mechanisms that generate these elaborate chitin-based structures are unknown, and involve complicated cellular and biochemical "bottom-up" processes. We demonstrated that a synthetic "top down" fabrication technique-nanosphere lithography-generates surfaces of chitin or chitosan that mimic the arrangement of nanostructures found on the surface of certain insect wings and eyes. Chitin and chitosan are flexible and biocompatible abundant natural polymers, and are a sustainable resource. The fabrication of nanostructured chitin and chitosan materials enables the development of new biopolymer materials. Finally, we demonstrated that another property of chitin and chitosan-the ability to self-assemble nanosilver particles-enables a novel and powerful new tool for the nanosphere lithographic method: the ability to generate a self-masking thin film. The scalability of the nanosphere lithographic technique is a major limitation; however, the silver nanoparticle self-masking enables a one-step thin-film cast or masking process, which can be used to generate nanostructured surfaces over a wide range of surfaces and areas. PMID- 30245869 TI - HLA-C Alleles and Cytomegalovirus Retinitis in Brazilian Patients with AIDS. AB - Purpose: Since cytomegalovirus retinitis (CR) is an important cause of visual impairment among AIDS patients and HLA-C alleles have been associated with AIDS disease outcome, we typed HLA-C locus in patients with AIDS exhibiting or not CR. Methods: Three groups of individuals were studied: (i) 49 patients with AIDS and CR (Group I), (ii) 161 patients with AIDS without CR (Group II), and (iii) 202 healthy HIV-negative individuals (Group III). HLA-C typing was performed using commercial kits. Results: The HLA-C*07 allele group was underrepresented in AIDS patients with CR (P=0.005) when compared to controls or when compared to AIDS patients without CR (P=0.006). The HLA-C*05 allele group was overrepresented in Group II in comparison to Group III (P=0.017). The frequency of the HLA-C*16 allele group was increased in Group III in comparison to Group II (P=0.004). Conclusion: The HLA-C*07 allele group conferred protection against the development of CR in Brazilian AIDS patients, whereas the HLA-C*05 and HLA-C*16 allele groups were associated with AIDS susceptibility or protection, respectively. PMID- 30245871 TI - Genetics in Ophthalmology. PMID- 30245870 TI - Development of Corneal Astigmatism (CA) according to Axial Length/Corneal Radius (AL/CR) Ratio in a One-Year Follow-Up of Children in Beijing, China. AB - Purpose: The correlations between the axial length-to-corneal radius (AL/CR) ratio and corneal astigmatism (CA) were studied by prospectively analyzing and comparing survey data from school children in the Beijing urban area from 2014 to 2015. Methods: In this longitudinal study, a total of 2,970 students were enrolled in 2014, and 2,179 students were enrolled in 2015. The students were in grades 1 and 4 of primary schools located in the Yangfangdian district of Beijing. The students were examined using the standard logarithmic visual acuity chart for uncorrected visual acuity (UCVA) and IOLMaster for ocular components. Results: From 2014 to 2015, the students from grades 1 and 4 had significantly worse UCVA results, longer axial lengths (AL), and greater AL/CRs (p < 0.001). The boys had a longer AL and corneal radius (CR) than the girls (p < 0.001). A significantly higher rate of increased CA was observed for the students with increased AL/CR than for those with decreased or unchanged ratios (AL/CR for grade 1, X2 = 12.304, p=0.001; for grade 4, X2 = 29.044, p < 0.001). In addition, with increased AL/CR over one year, the CA value of the students in grades 1 and 4 became significantly larger (grade 1, p=0.001; grade 4, p < 0.001); moreover, the UCVA became worse (p < 0.001). Conclusions: We found that UCVA and AL growth were affected by aging. An increase in the AL/CR ratio is a risk factor for the progression of corneal astigmatism for school children. PMID- 30245872 TI - Postexercise Recovery of Schlemm's Canal and Intraocular Pressure in Healthy Individuals: An Observational Study Using Swept-Source Optical Coherence Tomography. AB - Purpose: To observe the recovery process of postexercise Schlemm's canal (SC) and intraocular pressure (IOP) in healthy individuals. Methods: Twenty healthy individuals were recruited. SC and IOP were evaluated before exercise, immediately after exercise, and 15, 30, and 60 minutes after exercise. Superior, inferior, nasal, and temporal SC quadrants were evaluated using swept-source optical coherence tomography (SS-OCT). Results: Average SC area (3726.81 +/- 1167.06 vs. 4660.57 +/- 1284.82 um2) and perimeter (324.11 +/- 58.95 vs. 367.19 +/- 73.34 um) increased, and IOP (14.02 +/- 2.33 vs. 11.65 +/- 1.90 mmHg) decreased significantly during exercise (all p < 0.001). After exercise, both SC and IOP recovered to preexercise values, and the recovery time for postexercise SC dimensions (15 minutes) was shorter than that for postexercise IOP (60 minutes). After adjusting for age, gender, axial length, central corneal thickness, and spherical equivalent, postexercise changes in SC dimensions were not significantly associated with postexercise changes in IOP compared with preexercise values (all p > 0.05). There were no significant differences in the observable SC proportion before and after exercise (all p > 0.05). Conclusions: The exercise-induced SC expansion and IOP reduction could recover to preexercise values after exercise, and SC recovered to preexercise values ahead of IOP. Moreover, SC might be regulated by the sympathetic nerves and could be an important causative factor of changes in IOP during and after exercise. PMID- 30245873 TI - Characteristics, Outcomes, and Cost Patterns of High-Cost Patients in the Intensive Care Unit. AB - Background: ICU care is costly, and there is a large variation in cost among patients. Methods: This is an observational study conducted at two ICUs in an academic centre. We compared the demographics, clinical data, and outcomes of the highest decile of patients by total costs, to the rest of the population. Results: A total of 7,849 patients were included. The high-cost group had a longer median ICU length of stay (26 versus 4 days, P < 0.001) and amounted to 49% of total costs. In-hospital mortality was lower in the high-cost group (21.1% versus 28.4%, P < 0.001). Fewer high-cost patients were discharged home (23.9% versus 45.2%, P < 0.001), and a large proportion were transferred to long-term care (35.1% versus 12.1%, P < 0.001). Patients with younger age or a diagnosis of subarachnoid hemorrhage, acute respiratory failure, or complications of procedures were more likely to be high cost. Conclusions: High-cost users utilized half of the total costs. While cost is associated with LOS, other drivers include younger age or admission for respiratory failure, subarachnoid hemorrhage, or after a procedural complication. Cost-reduction interventions should incorporate strategies to optimize critical care use among these patients. PMID- 30245874 TI - Robotic-Assisted versus Conventional Laparoscopic Approach for Rectal Cancer Surgery, First Egyptian Academic Center Experience, RCT. AB - Background: Undoubtedly, robotic systems have largely penetrated the surgical field. For any new operative approach to become an accepted alternative to conventional methods, it must be proved safe and result in comparable outcomes. The purpose of this study is to compare the short-term operative as well as oncologic outcomes of robotic-assisted and laparoscopic rectal cancer resections. Methods: This is a prospective randomized clinical trial conducted on patients with rectal cancer undergoing either robotic-assisted or laparoscopic surgery from April 2015 till February 2017. Patients' demographics, operative parameters, and short-term clinical and oncological outcomes were analyzed. Results: Fifty seven patients underwent permuted block randomization. Of these patients, 28 were assigned to undergo robotic-assisted rectal surgery and 29 to laparoscopic rectal surgery. After exclusion of 12 patients following randomization, 45 patients were included in the analysis. No significant differences exist between both groups in terms of age, gender, BMI, ASA score, clinical stage, and rate of receiving upfront chemoradiation. Estimated blood loss was evidently lower in the robotic than in the laparoscopic group (median: 200 versus 325 ml, p= 0.050). A significantly more distal margin is achieved in the robotic than in the laparoscopic group (median: 2.8 versus 1.8, p< 0.001). Although the circumferential radial margin (CRM) was complete in 18 patients (85.7%) in the robotic group in contrast to 15 patients (62.5%) in the laparoscopic group, it did not differ statistically (p=0.079). The overall postoperative complication rates were similar between the two groups. Conclusion: To our knowledge, this is the first prospective randomized trial of robotic rectal surgery in the Middle East and Northern Africa region. Our early experience indicates that robotic rectal surgery is a feasible and safe procedure. It is not inferior to standard laparoscopy in terms of oncologic radicality and surgical complications. Organization number is IORG0003381. IRB number is IRB00004025. PMID- 30245875 TI - Fear Avoidance Beliefs and Risk of Long-Term Sickness Absence: Prospective Cohort Study among Workers with Musculoskeletal Pain. AB - Background and Objective: Musculoskeletal pain is common in the population. Negative beliefs about musculoskeletal pain and physical activity may lead to avoidance behavior resulting in absence from work. The present study investigates the influence of fear avoidance beliefs on long-term sickness absence. Methods: Workers of the general working population with musculoskeletal pain (low back, neck/shoulder, and/or arm/hand pain; n = 8319) from the Danish Work Environment Cohort Study were included. Long-term sickness absence data were obtained from the Danish Register for Evaluation and Marginalization (DREAM). Time-to-event analyses (cox regression) controlled for various confounders estimated the association between fear avoidance beliefs (very low, low, moderate [reference category], high, and very high) at baseline and long-term sickness absence (LTSA; >=6 consecutive weeks) during a 2-year follow-up. Results: During the 2-year follow-up, 10.2% of the workers experienced long-term sickness absence. In the fully adjusted model, very high-level fear avoidance increased the risk of LTSA with hazard ratio (HR) of 1.48 (95% CI 1.15-1.90). Similar results were seen analyses stratified for occupational physical activity, i.e., sedentary workers (HR 1.72 (95% CI 1.04-2.83)) and physically active workers (HR 1.48 (95% CI 1.10 2.01)). Conclusion: A very high level of fear avoidance is a risk factor for long term sickness absence among workers with musculoskeletal pain regardless of the level of occupational physical activity. Future interventions should target fear avoidance beliefs through information and campaigns about the benefits of staying active when having musculoskeletal pain. PMID- 30245876 TI - Retrospective Analysis of Ventriculitis in External Ventricular Drains. AB - Background: Nosocomial EVD-related ventriculitis is a major complication and a significant cause of morbidity and mortality in critically ill neurological patients. Questions remain about best management of EVDs. The purpose of this study is to compare our incidence of ventriculitis to studies using different catheters and/or antibiotic coverage schemes and determine whether c-EVD with prolonged antibiotics given for the duration of drain placement is inferior to ac EVD with pp-abx or ac-EVD with prolonged antibiotics for prevention of ventriculitis. Methods: A retrospective chart review of all patients who had EVDs placed from January 2010 through December 2015 at home institution was performed. Statistical analysis was performed using Fisher's exact test to compare incidence of ventriculitis identified in other studies with that of home institution. Results: The study included 107 patients, 66 (61.7%) males and 41 (38.3%) females. Average age was 56 years ranging from 18 to 95 years. Average length of drain placement was 7.8 days ranging from 2 to 23 days. Average length of drain placement in infected drains was 13.3 days ranging from 11 to 15 days. There were 3 cases with positive CSF cultures (Staphylococcus haemolyticus and Staphylococcus epidermidis x 2). There were 2 cases with a CSF having a positive gram stain but failed to yield any bacterial growth on culture and did not meet predefined criteria. Conclusions: The c-EVD with prolonged antibiotics given for the duration of drain placement is not inferior to ac-EVD with pp-abx or ac-EVD with prolonged antibiotics for prevention of ventriculitis. The c-EVD with prolonged antibiotics is superior to c-EVD with pp-abx and conventional EVD without antibiotics for prevention of ventriculitis. Selection should include considerations for antibiotic stewardship and cost effectiveness. Future studies should also utilize clinical and CSF profile criteria in addition to positive CSF cultures for identifying ventriculitis to prevent line colonization from classification as ventriculitis in analysis. PMID- 30245877 TI - Serotonin Reuptake Inhibitors in Obstructive Sleep Apnea: Associations in People with and without Epilepsy. AB - Purpose: Positive airway pressure remains the gold-standard treatment for OSA, but many are intolerant. The neurotransmitter serotonin is involved in respiratory control. Evidence exists for SRIs in reducing OSA severity in the general population and ictal hypoxemia and seizure-induced respiratory arrest in people with epilepsy (PWE). However, the association between SRIs and OSA severity has not been studied in populations consisting of both groups. This study aims to determine if SRIs are associated with OSA severity in both PWE and people without epilepsy (PWO) and whether differences exist between the two groups. Methods: A retrospective study of adults with OSA was conducted. Subjects were categorized as PWE or PWO and for the use (+SRI) or absence (-SRI) of an SRI. The primary outcome was OSA severity relative to SRI status. OSA severity as a function of SRI status was also compared between PWE and PWO and within the PWE and PWO cohorts. Oxygen saturation nadir was a secondary outcome measure. Statistical adjustment of pertinent characteristics was performed. Results: There were 125 subjects (57 PWE, 68 PWO, 80 -SRI, and 45 +SRI). +SRI was associated with reduced odds of severe compared to moderate OSA, in unadjusted and adjusted analysis. Compared to PWO, PWE demonstrated a more robust association between OSA severity and +SRI. When analyzed as separate cohorts, only PWE demonstrated reduced OSA severity, with adjustment for age (OR:0.140, CI:0.021-1.116, and p=0.042). Oxygen saturation nadir was not significant in any model. Conclusions: SRIs represent a potential treatment option for OSA and may demonstrate a more robust association with reduced OSA severity in PWE compared to PWO. PMID- 30245878 TI - Long-Acting Injectable Second-Generation Antipsychotics Improve Negative Symptoms and Suicidal Ideation in Recent Diagnosed Schizophrenia Patients: A 1-Year Follow up Pilot Study. AB - Long-acting injectable second-generation antipsychotics (LAI-SGA) are typically used to maintain treatment adherence in patients with chronic schizophrenia. Recent research suggests that they may also provide an effective treatment strategy for patients with early-phase disease. The aim of this study is to evaluate clinical and psychosocial outcomes among recent and long-term diagnosed schizophrenia outpatients treated with LAI-SGA during a follow-up period of 12 months. Stable schizophrenia patients receiving LAI-SGA with 5 or less years of illness duration (n = 10) were compared to those with more than 5 years of illness duration (n = 15). Clinical data was assessed through the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning (GAF), the Columbia Suicide Severity Rating Scale (C-SSRS), the Recovery Style Questionnaire (RSQ), and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) Managing Emotion branch. Recently diagnosed patients showed greater improvement versus patients diagnosed for more than 5 years in adjusted mean GAF score, in PANSS factor score for negative and depressive symptoms, and in severity and intensity of suicidal ideation. Our preliminary findings support the hypothesis that LAI SGA may influence the course of the illness if administered at the early phase of the illness. However, replicate studies are needed, possibly with larger samples. PMID- 30245879 TI - The Urinary Phosphate to Serum Fibroblast Growth Factor 23 Ratio, Deemed the Nephron Index, Is a Useful Clinical Index for Early Stage Chronic Kidney Disease in Patients with Type 2 Diabetes: An Observational Pilot Study. AB - Renal function decline is associated with progressive type 2 diabetes mellitus, which causes mineral and bone disorders. In the present study, we defined the ratio of urinary phosphate excretion (mg/day) to serum fibroblast growth factor 23 as the nephron index. We examined changes in the nephron index in type 2 diabetes patients with early stage chronic kidney disease (stages 1-3), enrolling 15 patients and retrospectively analysing the follow-up data. After follow-up at 5.4 years, we observed no significant changes in the estimated glomerular filtration rate; the nephron index, however, was significantly reduced between the baseline and the follow-up. We propose that the nephron index may be potentially useful as a biomarker for monitoring the decline of renal function in the early stages of diabetic chronic kidney disease patients. PMID- 30245880 TI - Phosphate, Calcification in Blood, and Mineral Stress: The Physiologic Blood Mineral Buffering System and Its Association with Cardiovascular Risk. AB - Phosphate is an important cardiovascular risk factor and lowering elevated blood phosphate concentrations is a main therapeutic target in kidney patients. Phosphate is subject to the blood mineral buffering system which controls the precipitation of calcium and phosphate. Calciprotein particles (CPP), self assembling complexes of calcium phosphate and serum proteins, are the nanomorphological correlates of this system. CPP1 are spherical, 50-100 nm in diameter, and contain amorphous mineral. CPP2 are oblongated, 100-200nm in the long axis, and they contain a crystalline mineral core. The relative abundance and biological activity of these particles are a matter of intense research, because they can cause oxidative stress, inflammation, and calcification in cellular assay. Therapeutically reducing this endogenous stressor by prolonging crystal formation time might improve patient outcome. This concise review article summarizes our current knowledge about the blood mineral buffering system and proposes Mineral Stress as a novel modifiable cardiovascular risk factor. It furthermore outlines possible implications this might have for improving patient care. PMID- 30245881 TI - Vitamin D Postpartum Concentrations: Relationship with Nutritional Condition and Morbidities during Pregnancy. AB - Objective: To evaluate postpartum vitamin D deficiency/insufficiency and to relate it to pregestational BMI, gestational weight gain, and sociodemographic variables. Methods: This is a cross-sectional study with 225 full-term pregnant women. Data collected are as follows: maternal health, socioeconomic status, pregestational body mass index (BMI), and gestational weight gain. Laboratory evaluation included vitamin D [25(OH)D], calcium, phosphorus, magnesium, and alkaline phosphatase. Results: The mean age of women was 25.6+/-6.6 years. Dark skin color, low education, and work in the urban region were predominant. Regular sun exposure, photoprotection, and vitamin D supplementation were reported by 144 (64.0%), 44 (19.6%), and 5 (2.2%) women, respectively. The mean plasma concentrations of 25(OH)D were 26.0+/-6.8 ng/mL. Levels compatible with deficiency (<20 ng/mL) and insufficiency (20-30 ng/mL) were observed in 43 (19.1%) and 124 (55.1%) women, respectively. The increase of 1 ng/mL in 25(OH)D concentrations was associated with an increase of 0.16 mg/dL (95%CI 0.19 to 2.02; p=0.018) for calcium. There were no associations with 25(OH)D concentrations with pregestational BMI and with gestational weight gain. Conclusions: The high frequency of postpartum vitamin D deficiency/insufficiency in women with a full term pregnancy in a region with a large and permanent sun exposure reminds us of the need for intervention policies aimed at preventing vitamin D deficiency during pregnancy. PMID- 30245882 TI - Can Obstetric Risk Factors Predict Fetal Acidaemia at Birth? A Retrospective Case Control Study. AB - Background: Despite major advances in perinatal medicine, intrapartum asphyxia remains a leading and potentially preventable cause of perinatal mortality and long-term morbidity. The umbilical cord pH is considered an essential criteria for the diagnosis of acute intrapartum hypoxic events. The purpose of this study was to evaluate whether obstetric risk factors are associated with fetal acidaemia at delivery. Methodology: In a case-control study, 294 women with term singleton pregnancies complicated by an umbilical artery cord pH < 7.20 at birth were individually matched by controls with umbilical artery cord pH > 7.20. Groups were compared for differences in maternal, obstetric, and fetal characteristics using logistic regression models presented as odds ratio (OR) with 95% confidence intervals (CI). Results: The study showed pregestational diabetes (PGDM) [OR: 5.31, 95% CI: 1.15- 24.58, P = 0.018], urinary tract infection (UTI) [OR: 3.21, 95% CI: 1.61- 6.43, P < 0.001], and low Apgar scores to be significantly associated with acidaemia, whereas low maternal BMI [OR: 0.19, 95% CI: 0.04-0.87, P = 0.032], pyrexia in labour [OR 0.23; 95% CI 0.12 0.53; P < 0.001], electronic fetal monitoring (EFM) [OR 0.65; 95% CI 0.43-0.99; P = 0.042), and emergency caesarean section [OR 0.42; 95% CI 0.26-0.66; P < 0.001] were found to be protective of acidaemia. Conclusion: Certain obstetric risk factors before and during labour can identify newborns at risk of developing acidaemia. Further research is needed to gain quantitative insight into the predictive capacity of these risks that can inform obstetric clinical management for improved outcomes. PMID- 30245883 TI - The Association between Earlobe Crease (Frank's Sign) and Abnormal Ankle-Brachial Index Determination Is Related to Age: A Population-Based Study. AB - Background: Information on the association between earlobe crease (ELC) and peripheral artery disease is limited. We assessed this association in community dwelling older adults. Study Design: A total of 294 Atahualpa residents aged >=60 years were enrolled. ELC were visually identified by two raters. The ankle brachial index (ABI), used as a surrogate of peripheral artery disease, was categorized using American Heart Association criteria. Using logistic regression and probability models, adjusted for demographics and cardiovascular risk factors, we assessed the relationship between ELC and abnormal ABI determinations, as well as the influence of age on this association. Results: ELC was identified in 141 (48%) individuals, and abnormal ABI determination was carried out in 56 (19%). The association between ELC and abnormal ABI was nonsignificant in logistic regression and probability models with individuals stratified according to their median age. Conclusions: The association between ELC and abnormal ABI determinations is probably attenuated by the high prevalence of both conditions in older persons. ELC might not be useful for identifying candidates for ABI determination. PMID- 30245884 TI - A Sustainable Ambulance Operation Model in a Low-Resource Country (the Democratic Republic of Congo). AB - Due to an increase in traffic collisions, the demand for prehospital medical services is on the rise, even in low-resource countries where emergency ambulance services have not been previously provided. To build a sustainable and continuous prehospital ambulance operation model, it is necessary to consider the medical system and economic conditions of the corresponding country. In an attempt to construct a prehospital ambulance operation model that ensures continuous operation, a pilot "emergency patient transporting service from field to hospital" operation was established for approximately three months in Kinshasa, the capital of the DR Congo. To construct a continuously operating model even after the pilot operation, willingness to pay (WTP) by type of emergency medical and transport service was investigated by implementing the contingent valuation method (CVM). Using CVM, the WTP for prehospital emergency services targeting ambulance services personnel, patients, policemen, and hospital staff participating in the pilot operation was calculated. The results of the pilot operation revealed that there were a total of 212 patients with a mean patient number of 2.4 per day. A total of 155 patients used the services for hospital transport, while 121 patients used the services for traffic collisions. Traffic collisions were the category in which ambulance services were most frequently needed (66.2%). Pay services were most frequently utilized in the home-visit services category (40.9%). Based on these results, eight independently operated ambulance operation models and sixteen models that utilize hospital medical personnel and policemen already belonging to existing institutions were proposed. In an effort to implement emergency medical ambulance services in the DR Congo, medical staff receiving pay for performance (incentive pay) should be deployed in the field and on call. Accordingly, with respect to sustainable development goals, various pay-for-service models should be used. PMID- 30245885 TI - Mitochondrial-Targeted Antioxidant MitoQ Prevents E. coli Lipopolysaccharide Induced Accumulation of Triacylglycerol and Lipid Droplets Biogenesis in Epithelial Cells. AB - The effect of bacterial lipopolysaccharide (LPS) on eukaryotic cell could be accompanied by a significant metabolic shift that includes accumulation of triacylglycerol (TAG) in lipid droplets (LD), ubiquitous organelles associated with fatty acid storage, energy regulation and demonstrated tight spatial and functional connections with mitochondria. The impairment of mitochondrial activity under pathological stimuli has been shown to provoke TAG storage and LD biogenesis. However the potential mechanisms that link mitochondrial disturbances and TAG accumulation are not completely understood. We hypothesize that mitochondrial ROS (mROS) may play a role of a trigger leading to subsequent accumulation of intracellular TAG and LD in response to a bacterial stimulus. Using isolated epithelial cells from the frog urinary bladder, we showed that LPS decreased fatty acids oxidation, enhanced TAG deposition, and promoted LD formation. LPS treatment did not affect the mitochondrial membrane potential but increased cellular ROS production and led to impairment of mitochondrial function as revealed by decreased ATP production and a reduced maximal oxygen consumption rate (OCR) and OCR directed at ATP turnover. The mitochondrial-targeted antioxidant MitoQ at a dose of 25 nM did not prevent LPS-induced alterations in cellular respiration, but, in contrast to nonmitochondrial antioxidant alpha tocopherol, reduced the effect of LPS on the generation of ROS, restored the LPS induced decline of fatty acids oxidation, and prevented accumulation of TAG and LD biogenesis. The data obtained indicate the key signaling role of mROS in the lipid metabolic shift that occurs under the impact of a bacterial pathogen in epithelial cells. PMID- 30245886 TI - Lipids and the Permeability and Antimicrobial Barriers of the Skin. AB - The primary purpose of the epidermis of terrestrial vertebrates is to produce the stratum corneum, which serves as the interface between the organism and the environment. As such, the stratum corneum provides a permeability barrier which both limits water loss through the skin and provides a relatively tough permeability barrier. This provides for a degree of resistance to mechanical trauma and prevents or limits penetration of potentially harmful substances from the environment. The stratum corneum consists of an array of keratinized cells embedded in a lipid matrix. It is this intercellular lipid that determines the permeability of the stratum corneum. The main lipids here are ceramides, cholesterol, and fatty acids. In addition, the skin surface of mammals, including humans, is coated by a lipid film produced by sebaceous glands in the dermis and secreted through the follicles. Human sebum consists mainly of squalene, wax monoesters, and triglycerides with small proportions of cholesterol and cholesterol esters. As sebum passes through the follicles, some of the triglycerides are hydrolyzed by bacteria to liberate free fatty acids. Likewise, near the skin surface, where water becomes available, some of the ceramides are acted upon by an epithelial ceramidase to liberate sphingosine, dihydrosphingosine, and 6-hydroxysphingosine. Some of the free fatty acids, specifically lauric acid and sapienic acid, have been shown to have antibacterial, antifungal, and antiviral activity. Also, the long-chain bases have broad spectrum antibacterial activity. PMID- 30245887 TI - Propagation and Molecular Characterization of Bioreactor Adapted Very Virulent Infectious Bursal Disease Virus Isolates of Malaysia. AB - Two Malaysian very virulent infectious bursal disease virus (vvIBDV) strains UPM0081 (also known as B00/81) and UPM190 (also known as UPM04/190) isolated from local IBD outbreaks in 2000 and 2004, respectively, were separately passaged for 12 consecutive times in 11-day-old specific pathogen free (SPF) chicken embryonated eggs (CEE) via the chorioallantoic membrane (CAM) route. The CEE passage 8 (EP8) isolates were passaged once in BGM-70 cell line yielding UPM0081EP8BGMP1 and UPM190EP8BGMP1, while the EP12 isolates were passaged 15 times in BGM-70 cell line yielding UPM0081EP12BGMP15 and UPM190EP12BGMP15 using T25 tissue culture flask. These isolates were all propagated once in bioreactor using cytodex 1 as microcarrier at 3 g per liter (3 g/L) yielding UPM0081EP8BGMP1BP1, UPM190EP8BGMP1BP1, UPM0081EP12BGMP15BP1, and UPM190EP12BGMP15BP1 isolates. The viruses were harvested at 3 days after inoculation, following the appearance of cytopathic effects (CPE) characterized by detachment from the microcarrier using standard protocol and filtered using 0.2 MUm syringe filter. The filtrates were positive for IBDV by RT-PCR and immunofluorescence. Sequence and phylogenetic tree analysis indicated that the isolates were of the vvIBDV strains and were not different from the flask propagated parental viruses. PMID- 30245888 TI - Prevalence of Panton-Valentine Leukocidin Gene among Community Acquired Staphylococcus aureus: A Real-Time PCR Study. AB - Panton-Valentine leukocidin (luk-pv) is a cytotoxin that causes leukocyte destruction and tissue necrosis. The aim of this study was to determine the prevalence of the pv1, mecA, and nuc genes in Staphylococcus aureus isolates obtained from anterior nares and superficial infection sites of skin in a slum population of West Bengal, India. Expression level of pv1 gene was also analysed. Twenty-two S. aureus strains were isolated, and phenotype and genotype specific examinations for S. aureus isolates were carried out. Molecular identification was done by PCR using species-specific 16S rRNA primer pairs and finally 22 isolates were found to be positive as S. aureus. The antibiotic responsiveness of all these isolates and the minimum inhibitory concentration (MIC) of MRSA isolates were determined using the broth dilution method with vancomycin. Antibiogram analysis of isolated S. aureus strains with respect to different antimicrobial agents revealed antibiotic resistance ranging from 27 to 91%. The results of MIC for vancomycin showed 95% of strains to be VSSA and 5% to be VISA. 68% isolates were resistant to methicillin. All the isolates were subjected to detection of pv1, mecA, and nuc genes, and 9%, 68%, and 27% were found to harbour pvl, mecA, and nuc genes, respectively. All the MRSA strains produced high to moderate levels of biofilm. pvl gene expression was carried out in vitro by Real Time PCR. The low ?Ct value (0.493) was indicative of high expression of pvl in one S. aureus strain. Thus, detection of pvl gene in community acquired S. aureus indicates the emergence of pathogenic S. aureus in community setup in the studied region. The existing exploration is extremely imperative and informative for the high level multi-drug resistant S. aureus infections inclusive of MRSA. PMID- 30245889 TI - Comparative Protective Effects of N-Acetylcysteine, N-Acetyl Methionine, and N Acetyl Glucosamine against Paracetamol and Phenacetin Therapeutic Doses-Induced Hepatotoxicity in Rats. AB - Background and Aims: Both paracetamol (PA) and phenacetin (PH) are analgesic and antipyretic agents. Part of phenacetin therapeutic activity is attributed to its metabolism into paracetamol. Paracetamol causes direct hepatic oxidative stress damage. The present study aimed to investigate the possible damaging effects of both PA and PH, when used in therapeutic doses, on rat liver and to compare the antioxidant and hepatoprotective effects of N-acetylcysteine (NAC), N-acetyl methionine (NAM), and N-acetylglucosamine (NAG) against PA- or PH-induced hepatic damage. Methods: 90 male Wistar albino rats (120-140 gm) were undertaken, categorized randomly into 9 groups of 10 rats each, and administered by gavage for 2 weeks with DMSO 1% (controls), PA, PA+NAC, PA+NAM, PA+NAG, PH, PH+NAC, PH+NAM, and PH+NAG. Biochemical assays of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), total thiols, and alpha-fetoprotein (AFP) in liver homogenates and serum assays of ALT, AST, 8-hydroxy guanine (8-OH-Gua), and AFP were done. Also histopathological examinations of liver tissues in various groups were done. Results: PA and PH cause significant increase in hepatic levels of MDA, NO, and AFP and serum ALT, AST, and 8-OH-Gua levels, with significant decrease in hepatic GSH and total thiols. NAG and NAC significantly improve the PA- and PH-induced hepatic and blood, biochemical, and histopathological disturbances, respectively. Conclusions: Both PA and PH induce oxidative stress in rat liver within their therapeutic doses. NAG and NAC in pharmacological doses can antagonize the oxidative damaging effect of both PA and PH. PMID- 30245890 TI - The Effect of Season and Weather on Orthopaedic Trauma: Consult Volume Is Significantly Correlated with Daily Weather. AB - Introduction: On-call orthopedic clinicians have long speculated that daily consult volume is closely correlated with weather. While prior studies have demonstrated a relationship between weather and certain fracture types, the effect of weather on total orthopaedic consult volume has not yet been examined. The aim of this study was to investigate this relationship. Methods: We retrospectively reviewed orthopaedic consult data from 405 consecutive days at an urban, level one trauma center. The number, mechanism of injury, and type of consult were collected, along with daily weather data (temperature, wind, and precipitation). Statistical analysis was then performed to determine the relationship between weather and orthopaedic trauma consults. Results: A total of 4543 consults were received during the study period. There was a significant difference in total number of consults between months of the year (p<0.001). A post hoc analysis revealed that this was due to increased volume in the summer months relative to the winter months (i.e., August 13.7 consults/day; January 9.3 consults/day). Average daily temperature and consult volume were also positively correlated (p<0.001, r= 0.30). While there was no significant association between precipitation and total consult volume, when there was over 0.25 inches of rain, there were less penetrating trauma (p=0.034) and motorcycle collision consults (p=0.013). Conclusion: Weather parameters, specifically average temperature and precipitation, were found to be associated with daily orthopedic consult type and volume. Additionally, consult volume varies significantly between months of the year. Because trauma centers are often resource scarce, this is an important relationship to understand for proper resource allocation. PMID- 30245891 TI - A Case of Lyme Carditis Presenting with Atrial Fibrillation. AB - We report a case of a 20-year-old man who presented to our institution with a new arrhythmia on a routine EKG. Serial EKG tracings revealed various abnormal rhythms such as episodes of atrial fibrillation, profound first degree AV block, and type I second degree AV block. He was found to have positive serologies for Borrelia burgdorferi. After initiation of antibiotic therapy, the atrial arrhythmias and AV block resolved. Here, we present a case of Lyme carditis presenting with atrial fibrillation, a highly unusual presentation of Lyme carditis. PMID- 30245892 TI - Coil Embolization of Coronary-Cameral Fistula Complicating Revascularization of Chronic Total Occlusion. AB - Traumatic vessel perforation is a potential complication of chronic total occlusion (CTO) percutaneous coronary artery intervention (PCI). A rare consequence of this complication is a coronary-cameral fistula. The management of this condition is not well elucidated. Herein, we present such a case of symptomatic left anterior descending to the right ventricle (LAD-RV) fistula which was treated with coil embolization. PMID- 30245893 TI - A Fatal Case of Influenza B Myocarditis with Cardiac Tamponade. AB - Background: Influenza B is generally regarded as a less severe counterpart to influenza A, typically causing mild upper respiratory symptoms. Myocardial involvement with influenza B is a rare complication, better described in children than adults. However, when it occurs, it can lead to profound myocarditis with progression to shock requiring aggressive supportive care. Case Presentation: We present a case of cardiac tamponade in the setting of influenza B infection in a previously healthy 57-year-old woman, with progression to refractory shock and death. Autopsy revealed myocardial necrosis with infiltration of CD3+ lymphocytes, and little evidence of viral pneumonia. Conclusions: Myocarditis is a rare complication of influenza B in adults, and subsequent pericardial effusion with tamponade physiology is a previously unreported event in an otherwise healthy adult without other medical comorbidities. While rare, this is a serious and potentially fatal complication that clinicians should be aware of when evaluating a patient with suspected viral illness who is exhibiting shock physiology. PMID- 30245894 TI - Prurigo Nodularis after Radiotherapy: An Isoradiotopic Response? AB - Prurigo nodularis is a rare and chronic skin disorder with multiple, pruritic, and firm nodules. The exact pathophysiology is still unknown. Skin disorders appearing at sites of radiation can be defined as isoradiotopic. A 35-year-old male had developed a skin lesion in the left submandibular area on a base of irradiated skin which was initially suspected as a skin malignancy. The patient had a history of undifferentiated nasopharyngeal cancer with lymph node involvement which was treated by radiochemotherapy thirteen years previously. Histological examination confirmed that it was a case of prurigo nodularis which subsequently evolved at distant sites. This presentation may suggest a case of an isoradiotopic response. PMID- 30245895 TI - Acute Pancreatitis Secondary to Hemobilia after Percutaneous Liver Biopsy: A Rare Complication of a Common Procedure, Presenting in an Atypical Fashion. AB - Percutaneous Liver Biopsy is an often-required procedure for the evaluation of multiple liver diseases. The complications are rare but well reported. Here we present a case of a 60-year-old overweight female who underwent liver biopsy for elevated alkaline phosphatase. She developed acute pancreatitis secondary to hemobilia, with atypical signs and symptoms, following the biopsy. She never had the classic triad of RUQ pain, jaundice, and upper GI hemorrhage. There were also multiple negative imaging studies, thus complicating the presentation. She was successfully treated with ERCP, sphincterotomy, balloon sweep, and stent placement. Angiography and transcatheter embolization were not required. PMID- 30245896 TI - A Case of Invasive Gastrointestinal Mycotypha Infection in a Patient with Neutropenia. AB - Gastrointestinal mucormycosis is a rare life-threatening infection to which neutropenic patients are especially vulnerable. Mycotypha microspora is a mucormycete that has not been described as a human pathogen. We discuss the successful eradication of gastrointestinal Mycotypha microspora in a neutropenic patient with simultaneous pulmonary Aspergillus fumigatus infection. PMID- 30245897 TI - Hysterectomy with Fetus In Situ for Uterine Rupture at 21-Week Gestation due to a Morbidly Adherent Placenta. AB - Background: Uterine rupture due to a morbidly adherent placenta is a rare obstetrical cause of acute abdominal pain in the pregnant patient. We present a case to add to the small body of published literature describing this diagnosis. Case: A 32-year-old G5T2P1A1L2 with multiple prior cesarean sections presented at 21+3 weeks' gestation with abdominal pain and presyncope. Ultrasound showed a large volume of complex intraabdominal free fluid and a heterogenous placenta with irregular lacunae and increased vascularity extending to the posterior bladder wall. Exploratory laparotomy identified a uterine defect and a hysterectomy was performed due to significant bleeding. Pathology confirmed a diagnosis of placenta percreta. Conclusion: Early recognition and management of uterine rupture due to a morbidly adherent placenta are essential to prevent catastrophic hemorrhage. PMID- 30245898 TI - Disseminated Granulomatous Disease from Intravesical Instillation of Bacillus Calmette-Guerin. AB - Intravesical instillation of Bacillus Calmette-Guerin is one of the standard treatment options for superficial bladder cancer. While Bacillus Calmette-Guerin therapy is usually well tolerated with most patients experiencing only cystitis, in rare cases, it can lead to disseminated granulomatous disease. We present a case of a 72-year-old man with disseminated granulomatous disease from intravesical BCG instillation whose treatment was complicated by antimycobacterial drug toxicity. PMID- 30245900 TI - Implication of Topical Steroids in the Onset of Osteoporosis. AB - The systemic bioavailability of steroids has long been implicated as a cause for osteoporosis (OP); however, much less is known about the effect of topical steroids on bone homeostasis. This is a case of an 11-year-old male who is a known case of generalised pustular psoriasis for 8-year duration with frequent exacerbations controlled with topical betamethasone dipropionate. He presented with generalised progressive bone pain and positive history of bone fracture. The diagnosis of OP was established on the results of DEXA, which were -2.7 SD and 2.4 SD for the lumbar spine and whole body, respectively. Although the cutoff value is the same (<-2 SD) in children, the definition of OP is more reliant on the densitometry Z score, as opposed to adults, who are approached using the T score. The element of psoriasis poses a risk for the development of OP due to the presence of a chronic inflammatory disease state that increases bone turnover. Furthermore, the compromised skin barrier and associated vasodilation seen in psoriasis enhance the absorption of topically applied agents and increase their bioavailability. Children are a targeted risk group as they are more vulnerable to the manifestation of systemic adverse affects of topically applied steroids as a result of their increased ratio of total surface area relative to their body weight and slower drug metabolism. We recommend that children undergoing long term topical steroid therapy be screened for OP with the consideration of instituting prophylactic treatment especially in those suffering from chronic inflammatory disease states. PMID- 30245899 TI - Type IV Laryngotracheoesophageal Cleft Associated with Type III Esophageal Atresia in 1p36 Deletions Containing the RERE Gene: Is There a Causal Role for the Genetic Alteration? AB - The causes of embryological developmental anomalies leading to laryngotracheoesophageal clefts (LTECs) are not known, but are proposed to be multifactorial, including genetic and environmental factors. Haploinsufficiency of the RERE gene might contribute to different phenotypes seen in individuals with 1p36 deletions. We describe a neonate of an obese mother, diagnosed with type IV LTEC and type III esophageal atresia (EA), in which a 1p36 deletion including the RERE gene was detected. On the second day of life, a right thoracotomy and extrapleural esophagus atresia repair were attempted. One week later, a right cervical approach was performed to separate the cervical esophagus from the trachea. Three months later, a thoracic termino-terminal anastomosis of the esophagus was performed. An anterior fundoplication was required at 8 months of age due to severe gastroesophageal reflux and failure to thrive. A causal role of 1p36 deletions including the RERE gene in the malformation is proposed. Moreover, additional parental factors must be considered. Future studies are mandatory to elucidate genomic and epigenomic susceptibility factors that underlie these congenital malformations. A multiteam approach is a crucial factor in the successful management of affected patients. PMID- 30245901 TI - Traumatic Epiglottitis following a Blind Insertion of the Hand during Convulsion. AB - Traditionally, it has been recommended that first-responders should place chopsticks or their hand in a child's mouth to prevent the child from biting their tongue during convulsion. The practice persists locally in parts of Japan and can cause adverse events. We report a traumatic epiglottitis following the thrusting of a guardians' hand into a 13-month-old girl's mouth to prevent her from biting her tongue. PMID- 30245902 TI - Hemosuccus Pancreaticus: A Rare Bleeding Pseudoaneurysm of the Inferior Pancreaticoduodenal Artery Treated with Embolization. AB - Hemosuccus pancreaticus is a very rare cause of gastrointestinal bleeding and can be life-threatening if not managed appropriately. Still thought to be a surgical problem, advances in medical therapy now afford these patients the opportunity to undergo less-invasive angiography techniques to manage this illness when it occurs. Here, we present a case of hemosuccus pancreaticus safely managed with liquid N-butyl-2-cyanoacrylate embolization. PMID- 30245904 TI - Towards an Understanding of Conservation-Based Costs, Benefits, and Attitudes of Local People Living Adjacent to Save Valley Conservancy, Zimbabwe. AB - Communities juxtaposed to protected areas (PAs) often disproportionally accrue the costs of conservation, but they can also receive benefits from the existence of a PA. The extent to which local communities benefit or incur costs as a result of residing next to PAs is of interest to conservationists and policy-makers. This study sought to understand the costs, benefits, and attitudes of local people living adjacent to Save Valley Conservancy (SVC), Zimbabwe. The purpose was to determine whether benefit and loss accrual has a bearing on the levels of illicit wildlife-based activities experienced in the SVC. Data were collected through a household questionnaire survey and key informant interviews from April to July 2014. A three-stage sampling was adopted: firstly, purposive sampling was employed to select wards adjacent to the SVC; secondly, random sampling was used to select villages within the selected wards; and thirdly, systematic sampling was used to select 71 household questionnaire respondents. Snowball sampling was used to select 9 key informants. The study results show that the majority of locals living close to SVC are not deriving discernable benefits and the costs of conservation are escalating influencing negative attitudes towards wildlife conservation, thus causing them to view wildlife as a nuisance. Overall, our results indicate that conservation losses and benefit accrual by local communities influence their attitudes toward SVC and conservation in general. We conclude that costs incurred outweighed the benefits accrued, a situation that triggers a more negative form of reciprocity towards SVC and wildlife conservation. It is recommended that a more socially and economically inclusive management approach based on a stakeholder-driven access and benefit sharing (ABS) framework be instituted to promote a more positive form of reciprocity towards SVC and nature conservation. PMID- 30245903 TI - Collaborative Penalized Least Squares for Background Correction of Multiple Raman Spectra. AB - Although Raman spectroscopy has been widely used as a noninvasive analytical tool in various applications, backgrounds in Raman spectra impair its performance in quantitative analysis. Many algorithms have been proposed to separately correct the background spectrum by spectrum. However, in real applications, there are commonly multiple spectra collected from the close locations of a sample or from the same analyte with different concentrations. These spectra are strongly correlated and provide valuable information for more robust background correction. Herein, we propose two new strategies to remove background for a set of related spectra collaboratively. Based on weighted penalized least squares, the new approaches will use the fused weights from multiple spectra or the weights from the average spectrum to estimate the background of each spectrum in the set. Background correction results from both simulated and real experimental data demonstrate that the proposed collaborative approaches outperform traditional algorithms which process spectra individually. PMID- 30245905 TI - Optimization of Fermentation Conditions and Media for Production of Glucose Isomerase from Bacillus megaterium Using Response Surface Methodology. AB - Glucose isomerase is an enzyme widely used in food industry for producing high fructose corn syrup. Many microbes, including Bacillus megaterium, have been found to be able to produce glucose isomerase. However, the number of studies of glucose isomerase production from Bacillus megaterium is limited. In this study, we establish the optimal medium components and culture conditions for Bacillus megaterium glucose isomerase production by evaluating the combined influence of multiple factors and different parameters via Plackett-Burman design and response surface methodology in Modde 5.0 software. The optimized conditions, which were experimentally confirmed as follows: D-xylose (1.116%), K2HPO4 (0.2%), MgSO4.7H2O (0.1%), yeast extract (1.161%), peptone (1%), pH 7.0, inoculum size 20% (w/v), shaking 120 rpm at 36.528 degrees C for 48 hours, give rise to production of highest activity of glucose isomerase (0.274 +/- 0.003 U/mg biomass). These results provide additional important information for future development of large scale glucose isomerase production by Bacillus megaterium. PMID- 30245906 TI - Retrospective Analysis of Geriatric Patients Undergoing Hip Fracture Surgery: Delaying Surgery Is Associated With Increased Morbidity, Mortality, and Length of Stay. AB - Introduction: Hip fractures are common in elderly patients. However, this population frequently presents with significant medical comorbidities requiring extensive medical optimization. Methods: This study sought to elucidate optimal time to surgery and evaluate its effect on postoperative morbidity, mortality, and length of stay (LOS). We performed a retrospective analysis of data collected from 2008 to 2010 on 841 patients who underwent hip fracture surgery. Patients were classified based on time to surgery and were also classified and analyzed according to the American Society of Anesthesiologists (ASA) physical classification system. Results: Patients with a delay of greater than 48 hours had a significant increase in overall LOS, postoperative days, and overall postoperative complications. Patients classified as ASA 4 had an odds ratio for postoperative morbidity of 3.32 compared to the ASA 1 and 2 group (P = .0002) and 2.26 compared to the ASA 3 group (P = .0005). Delaying surgery >48 hours was also associated with increased in-hospital mortality compared to 24 to 48 hours (P = .0197). Increasing ASA classification was also associated with significantly increased mortality. Patients classified as ASA 4 had 5.52 times the odds of ASA 1 and 2 (P = .0281) of in-hospital mortality. Those classified ASA 4 had 2.97 times the odds of ASA 3 (P = .0198) of an in-house mortality. Anesthetic technique (spinal vs general) and age were not confounding variables with respect to mortality or morbidity. Discussion: Surgical timing and ASA classification were evaluated with regard to LOS, number postoperative days, morbidity, and mortality. Conclusions: Delaying surgery >48 hours, especially in those with increased ASA classification, is associated with an increase in overall LOS, postoperative days, morbidity, and mortality. However, rushing patients to surgery may not be beneficial and 24 to 48 hours of preoperative optimization may be advantageous. PMID- 30245907 TI - Arthroscopic Fixation of Osteochondral Avulsion Fracture of the Femoral Attachment of the Posterior Cruciate Ligament in an 82-Year-Old Patient: A Case Report. AB - Femoral avulsion fracture of the posterior cruciate ligament (PCL) is less common compared to the tibial side. Especially, femoral avulsion in an elderly patient is an extremely rare condition. Until now, there is no report that describes its treatment and clinical outcome in elderly patients. We demonstrate an 82-year-old female who presented with osteochondral avulsion fracture of the femoral attachment of the PCL. The osteochondral fragment was fixed with an arthroscopic transfemoral suture technique. After treatment, the pain was improved and the patient achieved previous daily activity within 6 weeks. After 6 months, plain X ray and computed tomography scans demonstrated consolidation of osteochondral fragment. The Lysholm score was 78 points at final office visit. This simple and less invasive approach is useful for pain relief and earlier return to daily activity in an elderly patient with osteoporosis. PMID- 30245908 TI - Pain Deterioration Within 1 Year Predicts Future Decline of Walking Ability: A 7 Year Prospective Observational Study of Elderly Female Patients With Knee Osteoarthritis Living in a Rural District. AB - Introduction: Knee osteoarthritis (KOA) is commonly a main cause of locomotive syndrome. Consequently, appropriate timing of intervention is clinically important. Materials and Method: Fifty female patients of a primary care clinic in a rural district fulfilled the criteria for KOA and were recruited and underwent knee medical checkups. They initially underwent physical examination bilaterally of knees by an orthopedic surgeon, radiological evaluation, and they answered the outcome of Japanese Knee Osteoarthritis Measurement (JKOM). They were asked to answer JKOM 1 and 7 years after the initial checkup. Fourteen patients were lost to follow-up due to death or moving to a nursing home. Thirty six patients were finally included and divided into 2 age-matched groups according to walking ability at the 7-year follow-up: group A, walking ability did not decline (n = 24), and group B, walking ability did decline (n = 12). The walking ability was measured as per ordinal classification as: 5 (walking without any aid), 4 (walking with a crutch), 3 (walking using walker), 2 (walking only possible in parallel bars), and 1 (wheelchair). We completed between-group comparisons of each of the 3 subsections of the JKOM (pain, limitation in mobility related to daily activity, and restriction of participation in social life and health perception), during each period. Results: There were significant differences in JKOM pain score (12.9 vs 18.3, P = .0058) and total score (41.3 vs 55.8, P = .0093) between the groups at 1-year follow-up, even though base scores did not differ. Discussion: Clinicians should pay attention to changes in perceived knee pain and should not continue prolonged conservative therapy in patients exhibiting rapid deterioration. Conclusion: Female patients with KOA whose pain deteriorated within 1 year may require early intervention to prevent future decline in walking ability. PMID- 30245909 TI - "Above All Things, Be Glad and Young": Advancing Research on Violence in Adolescence. AB - Adolescence is a unique developmental period in which youth are at heightened risk for violence perpetration and victimization, both of which can adversely affect the course of normal psychosocial development and health across the life course. The possible range of violent experiences during adolescence is broad, including physical and relational peer violence, bullying, sexual violence, cyber aggression, child maltreatment, exposure to parental intimate partner violence, exposure to aggressive media, and more. The 8 articles in this special issue span this wide range of violence experiences. In helping to fill gaps in knowledge about the nature and processes by which violence develops, and how violence experiences affect adolescents, these articles as a group also offer direction for future research. They illustrate the need for research that cuts across the separate bodies of research on violence involving youth, that tackles thorny questions about the conceptualization of violence in its myriad forms, and that considers the ways in which the various forms and dimensions of violence operate together, across levels of the social ecology, to influence outcomes. The findings in this collection of studies also have implications for the development of prevention and intervention programs to address the problem of violence in adolescence. PMID- 30245910 TI - Effects of Exposure to New Car Interiors in Patients With Asthma and Allergic Rhinitis. AB - Rationale: Vehicle interiors are an important microenvironment for atopic subjects. This study evaluated the subjective and objective physiologic and clinical effects of exposing subjects with asthma and allergic rhinitis to new 2017 Mercedes vehicles during 90-minute rides. Methods: Ten adult asthmatics with allergic rhinitis were assessed before and 45 and 90 minutes into rides in a 2017 Mercedes-Benz S-Class sedan and GLE-Class SUV on 2 separate days. Assessments included spirometry, fractional exhaled nitric oxide, peak nasal inspiratory flow, asthma symptom scores, and physical examinations. Results: Of the 10 subjects, 6 were women, mean age was 32 years, and 6 and 4 were using chronic asthma controllers or intranasal corticosteroids, respectively. None of the subjects had worsening of asthma or rhinitis symptoms during the rides. There were no statistically significant changes from baseline in forced expiratory volume in 1 second, forced expiratory volume in 1 second:forced vital capacity ratio, forced expiratory flow at 25%-75% of vital capacity, fractional exhaled nitric oxide, or peak nasal inspiratory flow at 45 or 90 minutes into the rides with either Mercedes vehicle (all P values > .1 using generalized linear mixed model). Conclusion: The interior environment of the tested Mercedes vehicles did not cause changes in subjective or objective measures of asthma and allergic rhinitis. We suggest that this model system can be used to test other vehicles for putatively adverse effects on patients with allergic respiratory disorders. PMID- 30245911 TI - The 2015 Outbreak of Severe Influenza in Kashmir, North India: Emergence of a New Clade of A/H1n1 Influenza Virus. AB - INTRODUCTION: Following the initial outbreak of A/H1N1pdm09, periodic resurgences of the virus, with variable morbidity and mortality, have been reported from various parts of India including the temperate Kashmir region of northern India. An outbreak of A/H1N1 was reported in early 2015 across India with a high morbidity and mortality. We studied patients during the outbreak in Kashmir. METHODS: Patients (n=1780, age 1 month to 90 years, median 35 years) presenting with acute respiratory illness to a tertiary care hospital in Srinagar, Kashmir from October 2014 to April 2015 were recruited. After clinical data recording, combined throat and nasal swabs were collected in viral transport medium and tested by real-time RT-PCR for influenza viruses. All influenza A positive samples were further subtyped using primers and probes for A/H1N1pdm09 and A/H3 whereas influenza B samples were further subtyped into B/Yamagata and B/Victoria lineages. Virus isolation, hemagglutination inhibition testing, sequencing and phylogenetic analysis was carried out using standard procedures. Testing for H275Y mutation was done to determine sensitivity to oseltamivir. All patients received symptomatic therapy and influenza positive patients were administered oseltamivir. RESULTS: Of the 1780 patients, 540 (30%) required hospitalization and 533 tested positive for influenza [influenza A=517(A/H1N1pdm09=437, A/H3N2=78 with co-infection of both in 2 cases); influenza B=16 (B/Yamgata=15)]. About 14% (n=254) had been vaccinated against influenza, having received the NH 2014-15 vaccine, 27 (11.3%) of these testing positive for influenza. Sixteen patients, including 4 pregnant females, died due to multi-organ failure. HA sequencing depicted that 2015 isolates belonged to Clade 6B.1. No H275Y mutation was reported from A/H1N1 positives. CONCLUSION: Resurgent outbreak of A/H1N1pdm09, with emergence of clade 6B.1, in 2014-15 resulted in high rate of hospitalizations, morbidity and mortality. Periodic resurgences and appearance of mutants emphasize continued surveillance so as to identify newer mutations with potential for outbreaks and severe outcomes. PMID- 30245913 TI - Construction and analysis of alginate-based honey hydrogel as an ointment to heal of rat burn wound related infections. AB - Developing a strategy for making the alginate base hydrogel components against burned wound infections could be promising for healing the mentioned wounds followed by elimination of the biofilm forming bacteria colonization. Construction of an alginate based hydrogel and evaluating healing activities of the mentioned component as local ointment were the main objectives of the current study. Following the collection of the honey from three different provinces of Iran, the components and structures of the collected materials were analyzed taking advantage of INSO-92 procedure subsequently, antibacterial effect of diluted three different kinds of honey against wild-type bacterial species got evaluated via agar well diffusion method. An alginate base hydrogel was prepared by the use of calcium chloride as a linker between the alginate and honey functional groups. Then, component was structurally analyzed by Fourier Transform Infrared spectroscopy (FTIR). Afterward, under in vivo conditions, the healing activities of prepared ointment were studied in infected burned rat models. According to the antibacterial effect of the honeys, 75% diluted thymol based honeys collected from Damavand province were the most efficient ones. Furthermore, it was the healing activity of mentioned ointment was proven in vivo studies. The difference between 1600-1800 wave numbers in constructed alginate based hydrogel alginate and honey because of C = O bond variations structurally confirmed proper construction of hydrogel. The hydrogel was the better healing activity in rats burned wound too. In conclusion the promising efficiency of alginate-based hydrogel in an elimination of bacterial infections was confirmed as the main aim of the current survey. PMID- 30245914 TI - Bacteriology of the burn wound at the Bai Jerbai Wadia hospital for children, Mumbai, India-A 21 year study of predominant Pseudomonas species. AB - This study aims to assess the change in the antibiotic sensitivity pattern of Pseudomonas species with time. Microbiological data of 2399 patients admitted to the burns unit of the Bai Jerbai Wadia Hospital for Children, Mumbai over a period of 21 years (1994-2014) was reviewed. The age group of patients admitted to our facility ranged from one month to fifteen years. A total of 11,402 burn wound swabs were cultured and 17507 isolates were tested for their antibiotic sensitivity. Pseudomonas was found to be 31.8% of the total number of isolates found on the burn wound which is second in line to Klebsiella species at our unit. It was found that the sensitivity of Pseudomonas species to various antibiotics tested has been restricted to very few antibiotics. The organism out plays most of the antibiotics that it is subjected to in vitro. Our efforts should now be channelized towards limiting the use of antibiotics. We must focus on preparing proper antibiotic policy which exercises control of irrelevant and excessive use of antibiotics. It should also be noted that every treatment facility has microorganisms unique to it and these change with time. It is, therefore of paramount importance to have an in-depth knowledge of the resident organisms and their antibiotic sensitivity. This will not only help to control infection related morbidity and mortality but will also curb the growing resistance to antibiotics. PMID- 30245912 TI - New technologies in global burn care - a review of recent advances. AB - There have been truly incredible strides in the standard of burn care. The mortality from burn injuries has more than halved since the 1950s, making it hugely unique among major diseases of the developed world. There can be no doubt technology and technological advances have driven this process, dramatically improved every aspect of burn care, from the intensive care management, the surgical management, management of the healing wound to the post burn sequelae, specifically scar management. This review aims to identify key technological advances in burns, in both the developed and developing world, and evaluate their influence in the continued strategy to improve the standards of global burn care. PMID- 30245915 TI - Stem cell therapy in chronic obstructive pulmonary disease. How far is it to the clinic? AB - Chronic obstructive pulmonary disease (COPD) is a respiratory disease that has a major impact worldwide. The currently-available drugs mainly focus on relieving the symptoms of COPD patients. However, in the latter stages of the disease, the airways become largely obstructed and lung parenchyma becomes destructed due to underlying inflammation. The inappropriate repair of lung tissue after injury may contribute to the development of disease. Novel regenerative therapeutic approaches have been investigated with the aim of repairing or replacing the injured functional structures of the respiratory system. Endogenous and exogenous sources of stem cells are available for the treatment of many diseases. Stem cell therapy is newly introduced to the field of COPD. Currently the research is in its infancy; however, the field is profoundly growing. Previous studies suggest that cell-based therapies and novel bioengineering approaches may be potential therapeutic strategies for lung repair and remodelling. In this paper, we review the current evidence of stem cell therapy in COPD. PMID- 30245916 TI - Z-score maps from low-dose 18F-FDG PET of the brain in neurodegenerative dementia. AB - Neuroimaging is a central part of diagnostic work-up of patients with suspected neurodegenerative disease. FDG-PET can reveal pathological changes earlier and more reliably than morphological imaging. Diagnostic accuracy can be improved by constructing 3D SSP Z-score maps, showing patterns of significant deficits. During FDG-PET, the subject receives a moderate but not insignificant dose of ionizing radiation, and a dose reduction with retained image quality is desirable. With lower dose, repeated examinations can become a useful tool for monitoring disease progress and potential effects of disease-modifying interventions. The aim of this study was to evaluate Z-maps created from low-dose and normal-dose FDG-PET of the brain, with quantitative and qualitative methods. Nine patients with neurodegenerative disorders were prospectively enrolled and nine age-matched controls were recruited through advertising. All subjects (n=18) underwent two FDG-PET scans on separate occasions; a routine and a low-dose scan. The routine dosage of FDG was 3 MBq/kg, and low dosage was 0.75 MBq/kg. 3D-SSP images showing Z-scores of < -1.96 were created from 10-minute summations. The study was comprised of a quantitative part comparing the Z-scores, and a qualitative part where experienced nuclear medicine specialists visually assessed the images. Regarding the quantitative part, Bland-Altman analysis showed a slight constant bias (0.206). Regarding qualitative discrimination between patients and controls, the performance between normal- and low-dose were equal, both showing 72% sensitivity, 83% specificity and 78% accuracy. In this study, visual assessment of 3D-SSP Z-score maps from low-dose FDG-PET provided diagnostic information highly comparable to normal-dose, with minor quantitative discrepancies. PMID- 30245918 TI - 18F-labeled radiopharmaceuticals for the molecular neuroimaging of amyloid plaques in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with tremendous impact on the affected individuals and the society. Definitive diagnosis can be achieved only by post mortem examination. Clinical diagnosis criteria currently applied in clinical practice for AD often fail to accurately discriminate between AD and non-AD dementia with up to 40% of misdiagnosed patients. Several published papers demonstrated that the pre-clinical phase of AD is characterized by an early rise in beta-amyloid accumulation into inter neuronal space, followed by a severe synaptic dysfunction. Thus, beta-amyloid protein, detected in the cerebrospinal fluid, has been considered a specific AD biomarker. Molecular imaging of beta-amyloid deposits, with positron emission tomography (PET) and 18F-labeled radiopharmaceuticals such as 18F-florbetapir, 18F-florbetaben, and 18F-flutemetamol, has emerged as potential powerful tool for aiding AD diagnosis. The aim of the present paper is to review the existing literature on the clinical use of these new amyloid tracers in order to delineate their diagnostic value and limitations. PMID- 30245919 TI - Effects of allergic stimulation and glucocorticoids on miR-155 in CD4+ T-cells. AB - RATIONALE: MicroRNAs (miRNAs) are emerging as important regulators of allergic inflammation and potential therapeutic targets. We sought to identify which miRNAs are expressed in CD4+ T-cells and determine whether allergic stimuli or glucocorticoids alter their expression. METHODS: After IRB approval, blood was collected from dust mite (DM) allergic rhinitis subjects (n=20), non-allergic controls (n=8), and asthmatics (n=16). Peripheral blood mononuclear cells were incubated with dust mite extract (DME), diluent control, or DME + dexamethasone (0.1 uM). CD4+ T-cells were collected by magnetic bead column, and RNA was isolated by guanidinium/phenol-chloroform extraction. MicroRNA expression was measured using Nanostring microarray and quantitative real time PCR (qPCR). RESULTS: We identified 196 miRNAs that were stably expressed in circulating CD4+ T-cells. Allergen stimulation of CD4+ T-cells with DME differentially induced miR 155 expression in cells of DM-allergic subjects as compared to non-allergic subjects. Induction of miR-155 expression was also observed with anti-CD3/anti CD28 simulation and phorbol-12-Myristate-13-Acetate (PMA) treatment, and further augmented by calcium inophore and bromocyclic AMP in the latter treatment. The level of miR-155 expression was positively associated with expression of the TH2 cytokines IL-5 and IL-13. Inhibition of miR-155 in Jurkat T-cells inhibited the production of these cytokines. Glucocorticoids attenuated the effects of dust mite allergen, raising the possibility that inhibition of this miRNA could be a mechanism through which glucocorticoids exhibit their anti-inflammatory effects. The CD4+ T-cells had a higher level of miR-155 expression in asthma compared to in allergic rhinitis and non-asthmatics. The inhibitory effects of glucocorticoids on CD4+ T-cell miR-155 expression were lost in severe asthmatics. CONCLUSION: Mir-155 is differentially expressed in allergic T-cells exposed to DM extract compared to in non-allergic cells and it is inhibited by glucocorticoids. MiR-155 may play a role in mediating allergic inflammation in T-cells and could be an anti-inflammatory target of steroids. This pathway may be de-regulated in severe asthma. PMID- 30245917 TI - Targeted alpha-therapy of prostate cancer using radiolabeled PSMA inhibitors: a game changer in nuclear medicine. AB - Prostate cancer (PCa) is one of the most common malignancies in men and is a major contributor to cancer related deaths worldwide. Metastatic spread and disease progression under androgen deprivation therapy signify the onset of metastatic castration resistant prostate cancer (mCRPCa)-the lethal form of the disease, which severely deteriorates the quality of life of patients. Over the last decade, tremendous progress has been made toward identifying appropriate molecular targets that could enable efficient in vivo targeting for non-invasive imaging and therapy of mCPRCa. In this context, a promising enzymatic target is prostate specific membrane antigen (PSMA), which is overexpressed on PCa cells, in proportion to the stage and grade of the tumor progression. This is especially relevant for mCRPCa, which has significant overexpression of PSMA. For therapy of mCRPCa, several nuclear medicine clinics all over the world have confirmed that 177Lu-labeled-PSMA enzyme inhibitors (177Lu-PSMA-617 and 177Lu-PSMA I&T) have a favorable dosimetry and convincing therapeutic response. However, ~30% of patients were found to be short or non-responders and dose escalation was severely limited by chronic hematological toxicity. Such limitations could be better overcome by targeted alpha therapy (TAT) which has the potential to bring a paradigm shift in treatment of mCRPCa patients. This concise review presents an overview of the successes and challenges currently faced in TAT of mCRPCa using radiolabeled PSMA inhibitors. The preclinical and clinical data reported to date are quite promising, and it is expected that this therapeutic modality will play a pivotal role in advanced stage PCa management in the foreseeable future. PMID- 30245921 TI - Melanocortin-4 receptor in subthalamic nucleus is involved in the modulation of nociception. AB - Deep brain stimulation of the subthalamic nucleus (STN-DBS) stimulation produces significant improvement of overall pain related to Parkinson disease; however, the mechanisms underlying analgesic effects of STN-DBS are still unknown. This report describes direct neuroanatomical evidence for the central melanocortinergic-opioidergic circuits in the STN. We investigated melanocortin-4 receptor (MC4R) and mu-opioid receptor (MOR)-positive expression of the STN in MC4R-GFP transgenic mice using fluorescence immunohistochemical detection. Immunohistochemistry showed a large number of MC4R-GFP- and MOR-positive neurons within the STN region, and approximately 50% of MC4R-GFP-positive neurons coexpressed MOR. The results of this study showed direct neuroanatomical evidence for the central melanocortinergic-opioidergic signaling in the STN region. These findings contribute to the view of melanocortinergic-opioidergic circuits in the subthalamic nucleus as a reliable source of modulating of nociception with therapeutic potential for alleviating pain. PMID- 30245922 TI - "There Is Always a Teacher Among Them": Reflections From an American Medical Student on Time Spent With Medical Providers in the United States, China, and Vietnam. AB - There is a famous Chinese saying by Confucius that goes "With three men walking, there is always a teacher among them." In this narrative essay, I recount the story of how curiosity led me to find lessons about medicine from research on complementary and alternative medicine and medical service experiences in the "three men walking" of China, Vietnam, and the United States. As we visit the many teachers I had along the way, we will draw out various lessons from each experience and reflect on the value in experiencing cross-cultural medicine as a medical provider-in-training, with the hope that it will inspire other aspiring healers to cultivate their own curiosity. Travel with me from a bench outside a traditional Chinese medicine clinic in Beijing to orphanages in Vietnam and unearth what the "three men walking" of the United States, China, and Vietnam have to teach us. PMID- 30245920 TI - Induction therapy downregulates the expression of Th17/Tfh cytokines in patients with active lupus nephritis. AB - To determine the potential changes of IL-6, IL-17A and IL-21 levels during induction therapy, and to assess their relationship with disease activity and immunologic features on patients with active lupus nephritis, twenty-eight patients treated with corticosteroid and immunosuppressants were included in this study. Demographic, clinical, serological data and disease activity were assessed. Blood samples were collected at week 0, 12 and 24, and serum concentrations of IL-17A, IL-6 and IL-21 were measured by cytometric bead array. The serum concentrations of IL-6, IL-17A and IL-21 (P<0.001, P<0.01, P=0.001, respectively) decreased progressively during induction therapy. Concentration of IL-6, IL-17A and IL-21 was higher in non-remission group than that in remission group. A positive correlation was established between the concentration of these cytokines and the severity of proteinuria (P<0.001, P=0.020, P=0.045, respectively), ESR (P<0.001), SLEDAI scores (P<0.05), and ANA titers (P=0.018, P=0.048, P<0.05, respectively). Additionally, ROC curve analysis for IL-6, IL-17A and IL-21 was performed to predict the disease activity. The optimal cutoff level was 5.78 pg/ml, 1.98 pg/ml and 8.59 pg/ml, with AUC=0.809, 0.735 and 0.786. The concentration of IL-6 and IL-21 may be regarded as an indicator for the remission of active lupus nephritis, with cutoff value of 9.12 pg/ml and 11.30 pg/ml, while AUC=0.930 and 0.896. The production of serum IL-6, IL-17A and IL-21 in active LN was dramatically declined during induction therapy, which may improve disease activity while delay disease progression of LN. PMID- 30245923 TI - Functional significance of cuckoo Cuculus canorus calls: responses of conspecifics, hosts and non-hosts. AB - Male cuckoos Cuculus canorus produce calls that differ in number of syllables depending on environmental conditions and presence of male and female conspecifics. Why different males produce so repeatable calls that vary greatly in duration among males remains an open question. We used playback of cuckoo calls with few or many syllables (hereafter short and long calls), and woodpigeon calls (a control that also produces few or many syllables), predicting that playback of longer cuckoo calls should attract more male cuckoos (if males with such calls are dominant and successfully out-compete other males due to intraspecific competition), and attract more hosts mobbing male cuckoos (cuckoos with such calls and their females attract more hosts because of an increased risk of parasitism). Because cuckoos differentially parasitize hosts away from human habitation, we also tested whether the number of syllables in cuckoo calls differed with distance from buildings. Playback showed significant effects of number of syllables in cuckoo calls, but not woodpigeon Columba palumbus calls, with an additional effect of distance from human habitation decreasing the response to playback. These findings are consistent with the hypothesis that longer cuckoo calls, especially played back near human habitation, attract more conspecifics and hosts than shorter calls. To the best of knowledge this is the first study showing that cuckoo call response modified both other cuckoo individuals, as well as hosts response. PMID- 30245924 TI - Th2 cytokine bias induced by silver nanoparticles in peripheral blood mononuclear cells of common bottlenose dolphins (Tursiops truncatus). AB - Background: Silver nanoparticles (AgNPs) have been widely used in many commercial products due to their excellent antibacterial ability. The AgNPs are released into the environment, gradually accumulate in the ocean, and may affect animals at high trophic levels, such as cetaceans and humans, via the food chain. Hence, the negative health impacts caused by AgNPs in cetaceans are of concern. Cytokines play a major role in the modulation of immune system and can be classified into two types: Th1 and Th2. Th1/Th2 balance can be evaluated by the ratios of their polarizing cytokines (i.e., interferon [IFN]-gamma/Interleukin [IL]-4), and animals with imbalanced Th1/Th2 response may become more susceptible to certain kinds of infection. Therefore, the present study evaluated the in vitro cytokine responses of cetacean peripheral blood mononuclear cells (cPBMCs) to 20 nm citrate-AgNPs (C-AgNP20) by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Methods: Blood samples were collected from six captive common bottlenose dolphins (Tursiops truncatus). The cPBMCs were isolated and utilized for evaluating the in vitro cytokine responses. The cytokines evaluated included IL-2, IL-4, IL-10, IL-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha. The geometric means of two housekeeping genes (HKGs), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and beta2 microglobulin (B2M), of each sample were determined and used to normalize the mRNA expression levels of target genes. Results: The ratio of late apoptotic/necrotic cells of cPBMCs significantly increased with or without concanavalin A (ConA) stimulation after 24 h of 10 ug/ml C-AgNP20 treatment. At 4 h of culture, the mRNA expression level of IL-10 was significantly decreased with 1 ug/ml C-AgNP20 treatment. At 24 h of culture with 1 ug/ml C-AgNP20, the mRNA expression levels of all cytokines were significantly decreased, with the exceptions of IL-4 and IL-10. The IFN-gamma/IL-4 ratio was significantly decreased at 24 h of culture with 1 ug/ml C-AgNP20 treatment, and the IL-12/IL-4 ratio was significantly decreased at 4 or 24 h of culture with 0.1 or 1 ug/ml C AgNP20 treatment, respectively. Furthermore, the mRNA expression level of TNF alpha was significantly decreased by 1 ug/ml C-AgNP20 after 24 h of culture. Discussion: The present study demonstrated that the sublethal dose of C-AgNP20 (<=1 ug/ml) had an inhibitory effect on the cytokine mRNA expression levels of cPBMCs with the evidence of Th2 cytokine bias and significantly decreased the mRNA expression level of TNF-alpha. Th2 cytokine bias is associated with enhanced immunity against parasites but decreased immunity to intracellular microorganisms. TNF-alpha is a contributing factor for the inflammatory response against the infection of intracellular pathogens. In summary, our data indicate that C-AgNP20 suppresses the cellular immune response and thereby increases the susceptibility of cetaceans to infection by intracellular microorganisms. PMID- 30245925 TI - Phylogeography of Swertia perennis in Europe based on cpDNA markers. AB - Background: Swertia perennis (Gentianaceae) is a perennial diploid and clonal plant species that is discontinuously distributed in peat bogs in the mountains of Europe, Asia and North America as well as in the lowlands of Europe. The current geographical dispersion of S. perennis is probably the result of quaternary climatic changes that have played an important role in determining the distribution of Swertia and other plant and animal species. Methods: In this study we used molecular techniques and combined data from chloroplast DNA markers (trnLF region and trnH-psbA spacer) to elucidate the phylogeography of S. perennis in Europe. Plants were collected from 28 populations in different locations in the lowlands and mountainous areas of Europe (e.g., the Carpathians, Sudetes, Bohemian Forest and Alps). cDNA was analysed to detect the genetic relationship between specimens from different locations. Results: A total of 20 haplotypes were identified across the dataset. They were characterised by a high level of genetic variability but showed a lack of phylogeographical structure. This pattern may be the result of repeated recolonization and expansion from several areas. Such genetic differentiation may also be attributed to the relatively long-term isolation of S. perennis in Pleistocene refugia in Europe, which resulted in independent separation of different cpDNA phylogenetic lineages and variation in the nucleotide composition of cpDNA. Discussion: The lack of strong phylogeographical structure makes it impossible to indicate the centre of haplotype diversity; however, refugia located in the Carpathians, Sudetes or Alps are the most probable sites where S. perennis existed in Europe. This lack of structure may also indicate a high level of gene flow in times when the landscape and fen systems were not fragmented in numerous geographically-isolated populations. This makes it difficult to speculate about the relationships between Asiatic and European plant populations and the origin and distribution of this species in Europe. Today, it seems to be restricted due to the occurrence of plants which clearly reflects the genetic variability from the ancient period. PMID- 30245926 TI - Exome sequencing study of 20 patients with high myopia. AB - Background: High myopia is a common ocular disease worldwide. To expand our current understanding of the genetic basis of high myopia, we carried out a whole exome sequencing (WES) study to identify potential causal gene mutations. Methods: A total of 20 individuals with high myopia were exome sequenced. A novel filtering strategy combining phenotypes and functional impact of variants was applied to identify candidate genes by multi-step bioinformatics analyses. Network and enrichment analysis were employed to examine the biological pathways involved in the candidate genes. Results: In 16 out of 20 patients, we identified 20 potential pathogenic gene variants for high myopia. A total of 18 variants were located in myopia-associated chromosomal regions. In addition to the novel mutations found in five known myopia genes (ADAMTS18, CSMD1, P3H2, RPGR, and SLC39A5), we also identified pathogenic variants in seven ocular disease genes (ABCA4, CEP290, HSPG2, PCDH15, SAG, SEMA4A, and USH2A) as novel candidate genes. The biological processes associated with vision were significantly enriched in our candidate genes, including visual perception, photoreceptor cell maintenance, retinoid metabolic process, and cellular response to zinc ion starvation. Discussion: Systematic mutation analysis of candidate genes was performed using WES data, functional interaction (FI) network, Gene Ontology and pathway enrichment. FI network analysis revealed important network modules and regulator linker genes (EP300, CTNNB1) potentially related to high myopia development. Our study expanded the list of candidate genes associated with high myopia, which increased the genetic screening performance and provided implications for future studies on the molecular genetics of myopia. PMID- 30245927 TI - Natural history and molecular evolution of demersal Mediterranean sharks and skates inferred by comparative phylogeographic and demographic analyses. AB - Background: The unique and complex paleoclimatic and paleogeographic events which affected the Mediterranean Sea since late Miocene deeply influenced the distribution and evolution of marine organisms and shaped their genetic structure. Following the Messinian salinity crisis and the sea-level fluctuations during the Pleistocene, several Mediterranean marine species developed deep genetic differentiation, and some underwent rapid radiation. Here, we consider two of the most prioritized groups for conservation in the light of their evolutionary history: sharks and rays (elasmobranchs). This paper deals with a comparative multispecies analysis of phylogeographic structure and historical demography in two pairs of sympatric, phylogenetically- and ecologically-related elasmobranchs, two scyliorhinid catsharks (Galeus melastomus, Scyliorhinus canicula) and two rajid skates (Raja clavata, Raja miraletus). Sampling and experimental analyses were designed to primarily test if the Sicilian Channel can be considered as effective eco-physiological barrier for Mediterranean demersal sympatric elasmobranchs. Methods: The phylogeography and the historical demography of target species were inferred by analysing the nucleotide variation of three mitochondrial DNA markers (i.e., partial sequence of COI, NADH2 and CR) obtained from a total of 248 individuals sampled in the Western and Eastern Mediterranean Sea as well as in the adjacent northeastern Atlantic Ocean. Phylogeographic analysis was performed by haplotype networking and testing spatial genetic differentiation of samples (i.e., analysis of molecular variance and of principal components). Demographic history of Mediterranean populations was reconstructed using mismatch distribution and Bayesian Skyline Plot analyses. Results: No spatial genetic differentiation was identified in either catshark species, while phylogeographic structure of lineages was identified in both skates, with R. miraletus more structured than R. clavata. However, such structuring of skate lineages was not consistent with the separation between Western and Eastern Mediterranean. Sudden demographic expansions occurred synchronously during the upper Pleistocene (40,000-60,000 years ago) in both skates and G. melastomus, likely related to optimal environmental conditions. In contrast, S. canicula experienced a slow and constant increase in population size over the last 350,000 years. Discussion: The comparative analysis of phylogeographic and historical demographic patterns for the Mediterranean populations of these elasmobranchs reveals that historical phylogeographic breaks have not had a large impact on their microevolution. We hypothesize that interactions between environmental and ecological/physiological traits may have been the driving force in the microevolution of these demersal elasmobranch species in the Mediterranean rather than oceanographic barriers. PMID- 30245928 TI - Dramatic decline and limited recovery of a green crab (Carcinus maenas) population in the Minas Basin, Canada after the summer of 2013. AB - This paper reports the results of a ten-year monitoring program of an Atlantic Canadian population of green crabs, Carcinus maenas, in the Minas Basin of the Bay of Fundy. Intertidal densities, sex and reproductive ratios, juvenile recruitment, subtidal catch-per-unit-effort (CPUE), and sizes of crabs in this population were recorded from 2008 to 2017. In 2013 intertidal densities, mean crab sizes, subtidal CPUE, and proportions of crabs mature and reproducing all dramatically decreased to all-time lows, and large crabs virtually disappeared from the population. From 2014 to 2017 the population partially recovered but remained in an altered state. Potential causes of interannual changes to this population were investigated by correlating intertidal densities to 257 monthly environmental variables and performing stepwise multiple regression analyses. Crab densities in a given year were best explained by potential settlement during the summer and the maximum sea-surface temperature during March of the same year. However, potential roles of other factors (e.g., autumn winds, summer temperatures, North Atlantic Oscillation index) could not be ruled out. Changes in abundances of other species in the area, particularly predators and prey of green crabs, have also been observed and present possible alternative causative agents that should be investigated. Populations of other marine species in the Gulf of Maine-Bay of Fundy region within which the Minas Basin is situated have also been reported to have undergone dramatic changes in and after 2013, suggesting the occurrence of some oceanographic event or regime shift in the region. Declines to the monitored crab population in this study may have resulted from this same 2013 event. These observations have implications for recruitment to marine populations in this region. PMID- 30245929 TI - Nonspecific stress response to temperature increase in Gammarus lacustris Sars with respect to oxygen-limited thermal tolerance concept. AB - The previously undescribed dynamics of the heat shock protein HSP70 and subsequent lipid peroxidation products have been assessed alongside lactate dehydrogenase activity for Gammarus lacustris Sars, an amphipod species from the saltwater Lake Shira (Republic of Khakassia). Individuals were exposed to a gradual temperature increase of 1 degrees C/hour (total exposure duration of 26 hours) starting from the mean annual temperature of their habitat (7 degrees C) up to 33 degrees C. A complex of biochemical reactions occurred when saltwater G. lactustris was exposed to the gradual changes in temperature. This was characterized by a decrease in lactate dehydrogenase activity and the launching of lipid peroxidation. The HSP70 level did not change significantly during the entire experiment. In agreement with the concept of oxygen-limited thermal tolerance, an accumulation of the most toxic lipid peroxides (triene conjugates and Schiff bases) in phospholipids occurred at the same time and temperature as the accumulation of lactate. The main criterion overriding the temperature threshold was, therefore, the transition to anaerobiosis, confirmed by the elevated lactate levels as observed in our previous associated study, and by the development of cellular stress, which was expressed by an accumulation of lipid peroxidation products. An earlier hypothesis, based on freshwater individuals of the same species, has been confirmed whereby the increased thermotolerance of G. lacustris from the saltwater lake was caused by differences in energy metabolism and energy supply of nonspecific cellular stress-response mechanisms. With the development of global climate change, these reactions could be advantageous for saltwater G. lacustris. The studied biochemical reactions can be used as biomarkers for the stress status of aquatic organisms when their habitat temperature changes. PMID- 30245930 TI - The role of miRNAs 34a, 146a, 320a and 542 in the synergistic anticancer effects of methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC) with doxorubicin in breast cancer cells. AB - Combination Index (CI) analysis suggested that MBIC and doxorubicin synergistically inhibited up to 97% of cell proliferation in ER+/PR+MCF-7 and triple negative MDA-MB-231 breast cancer cell lines. Moreover, treatment of the breast cancer cells with the combined drugs resulted in lower IC50 values in contrast to the individual drug treatment. Small noncoding microRNAs (miRNA) may function as non-mutational gene regulators at post-transcriptional level of protein synthesis. In the present study, the effect of the combined treatment of MBIC and doxorubicin on the expression level of several miRNAs including miR-34a, miR-146a, miR-320a and miR-542 were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines. These miRNAs have the potential to alter the protein level of survivin, the anti-apoptotic protein and reduce the metastatic activity in human breast cancer cell lines by interfering with the nuclear accumulation of NF kappaB. Our results demonstrated the several fold changes in expression of miRNAs, which is drug and cell line dependent. This finding demonstrated a functional synergistic network between miR-34a, miR-320a and miR-542 that are negatively involved in post-transcriptional regulation of survivin in MCF-7 cells. While in MDA-MB-231 cells, changes in expression level of miR-146a was correlated with inhibition of the nuclear translocation of NF-kappaB. The overall result suggested that alteration in protein level and location of survivin and NF kappaB by miR-34a, miR-320a, miR-146a and miR-542, remarkably influenced the synergistic enhancement of combined MBIC and doxorubicin in treatment of aggressive and less aggressive human breast cancer cell lines. PMID- 30245931 TI - The influence of sample distribution on growth model output for a highly exploited marine fish, the Gulf Corvina (Cynoscion othonopterus). AB - Estimating the growth of fishes is critical to understanding their life history and conducting fisheries assessments. It is imperative to sufficiently sample each size and age class of fishes to construct models that accurately reflect biological growth patterns, but this may be a challenging endeavor for highly exploited species in which older fish are rare. Here, we use the Gulf Corvina (Cynoscion othonopterus), a vulnerable marine fish that has been persistently overfished for two decades, as a model species to compare the performance of several growth models. We fit the von Bertalanffy, Gompertz, logistic, Schnute, and Schnute-Richards growth models to length-at-age data by nonlinear least squares regression and used simple indicators to reveal biased data and ensure our results were biologically feasible. We then explored the consequences of selecting a biased growth model with a per-recruit model that estimated female spawning-stock-biomass-per-recruit and yield-per-recruit. Based on statistics alone, we found that the Schnute-Richards model described our data best. However, it was evident that our data were biased by a bimodal distribution of samples and underrepresentation of large, old individuals, and we found the Schnute-Richards model output to be biologically implausible. By simulating an equal distribution of samples across all age classes, we found that sample distribution distinctly influenced model output for all growth models tested. Consequently, we determined that the growth pattern of the Gulf Corvina was best described by the von Bertalanffy growth model, which was the most robust to biased data, comparable across studies, and statistically comparable to the Schnute-Richards model. Growth model selection had important consequences for assessment, as the per recruit model employing the Schnute-Richards model fit to raw data predicted the stock to be in a much healthier state than per-recruit models employing other growth models. Our results serve as a reminder of the importance of complete sampling of all size and age classes when possible and transparent identification of biased data when complete sampling is not possible. PMID- 30245932 TI - Effects of income and residential area on survival of patients with head and neck cancers following radiotherapy: working age individuals in Taiwan. AB - Objectives: The five-year survival rate of head and neck cancer (HNC) after radiotherapy (RT) varies widely from 35% to 89%. Many studies have addressed the effect of socioeconomic status and urban dwelling on the survival of HNC, but a limited number of studies have focused on the survival rate of HNC patients after RT. Materials and methods: During the period of 2000-2013, 40,985 working age individuals (20 < age < 65 years) with HNC patients treated with RT were included in this study from a registry of patients with catastrophic illnesses maintained by the Taiwan National Health Insurance Research Database (NHIRD). Results: The cumulative survival rate of HNC following RT in Taiwan was 53.2% (mean follow-up period, 3.75 +/- 3.31 years). The combined effects of income and geographic effect on cumulative survival rates were as follows: high income group > medium income group > low income group and northern > central > southern > eastern Taiwan. Patients with moderate income levels had a 36.9% higher risk of mortality as compared with patients with high income levels (hazard ratio (HR) = 1.369; p < 0.001). Patients with low income levels had a 51.4% greater risk of mortality than patients with high income levels (HR = 1.514, p < 0.001). Conclusion: In Taiwan, income and residential area significantly affected the survival rate of HNC patients receiving RT. The highest income level group had the best survival rate, regardless of the geographic area. The difference in survival between the low and high income groups was still pronounced in more deprived areas. PMID- 30245933 TI - Mitogenomics of Perumytilus purpuratus (Bivalvia: Mytilidae) and its implications for doubly uniparental inheritance of mitochondria. AB - Animal mitochondria are usually inherited through the maternal lineage. The exceptional system allowing fathers to transmit their mitochondria to the offspring exists in some bivalves. Its taxonomic spread is poorly understood and new mitogenomic data are needed to fill the gap. Here, we present for the first time the two divergent mitogenomes from Chilean mussel Perumytilus purpuratus. The existence of these sex-specific mitogenomes confirms that this species has the doubly uniparental inheritance (DUI) of mitochondria. The genetic distance between the two mitochondrial lineages in P. purpuratus is not only much bigger than in the Mytilus edulis species complex but also greater than the distance observed in Musculista senhousia, the only other DUI-positive member of the Mytilidae family for which both complete mitochondrial genomes were published to date. One additional, long ORF (open reading frame) is present exclusively in the maternal mitogenome of P. purpuratus. This ORF evolves under purifying selection, and will likely be a target for future DUI research. PMID- 30245934 TI - Local-scale determinants of arboreal spider beta diversity in a temperate forest: roles of tree architecture, spatial distance, and dispersal capacity. AB - Spiders are a functionally important taxon in forest ecosystems, but the determinants of arboreal spider beta diversity are poorly understood at the local scale. We examined spider assemblages in 324 European beech (Fagus sylvatica) trees of varying sizes across three forest stands in Wurzburg (Germany) to disentangle the roles of tree architecture, spatial distance, and dispersal capacity on spider turnover across individual trees. A large proportion of tree pairs (66%) showed higher compositional dissimilarity in spider assemblages than expected by chance, suggesting prominent roles of habitat specialization and/or dispersal limitation. Trees with higher dissimilarity in DBH and canopy volume, and to a lesser extent in foliage cover, supported more dissimilar spider assemblages, suggesting that tree architecture comprised a relevant environmental gradient of sorting spider species. Variation partitioning revealed that 28.4% of the variation in beta diversity was jointly explained by tree architecture, spatial distance (measured by principal coordinates of neighbor matrices) and dispersal capacity (quantified by ballooning propensity). Among these, dispersal capacity accounted for a comparable proportion as spatial distance did (6.8% vs. 5.9%). Beta diversity did not significantly differ between high- and low-vagility groups, but beta diversity in species with high vagility was more strongly determined by spatially structured environmental variation. Altogether, both niche specialization, along the environmental gradient defined by tree architecture, and dispersal limitation are responsible for structuring arboreal spider assemblages. High dispersal capacity of spiders appears to reinforce the role of niche-related processes. PMID- 30245935 TI - Neural processing of working memory in adults with ADHD in a visuospatial change detection task with distractors. AB - Individuals with Attention-Deficit Hyperactivity Disorder (ADHD) are often characterized by deficits in working memory (WM), which manifest in academic, professional, and mental health difficulties. To better understand the underlying mechanisms of these presumed WM deficits, we compared adults with ADHD to their peers on behavioral and neural indices of WM. We used a visuospatial change detection task with distractors which was designed to assess the brain's ability to effectively filter out distractors from WM, in addition to testing for effects of WM load. Twenty-seven unmedicated adults with ADHD were compared to 27 matched peers on event-related potential (ERP) measures of WM, i.e., the contralateral delay activity (CDA). Despite severe impairments in everyday life functioning, findings showed no difference in deficits in behavioral tests of working memory for adults with ADHD compared to their peers. Interestingly, there were differences in neural activity between individuals with ADHD and their peers showing that the CDA of individuals with ADHD did not distinguish between high, distractor, and low memory load conditions. These data suggest, in the face of comparable behavioral performance, a difference in neural processing efficiency, wherein the brains of individuals with ADHD may not be as selective in the allocation of neural resources to perform a WM task. PMID- 30245936 TI - Metabolic marker gene mining provides insight in global mcrA diversity and, coupled with targeted genome reconstruction, sheds further light on metabolic potential of the Methanomassiliicoccales. AB - Over the past years, metagenomics has revolutionized our view of microbial diversity. Moreover, extracting near-complete genomes from metagenomes has led to the discovery of known metabolic traits in unsuspected lineages. Genome-resolved metagenomics relies on assembly of the sequencing reads and subsequent binning of assembled contigs, which might be hampered by strain heterogeneity or low abundance of a target organism. Here we present a complementary approach, metagenome marker gene mining, and use it to assess the global diversity of archaeal methane metabolism through the mcrA gene. To this end, we have screened 18,465 metagenomes for the presence of reads matching a database representative of all known mcrA proteins and reconstructed gene sequences from the matching reads. We use our mcrA dataset to assess the environmental distribution of the Methanomassiliicoccales and reconstruct and analyze a draft genome belonging to the 'Lake Pavin cluster', an uncultivated environmental clade of the Methanomassiliicoccales. Analysis of the 'Lake Pavin cluster' draft genome suggests that this organism has a more restricted capacity for hydrogenotrophic methylotrophic methanogenesis than previously studied Methanomassiliicoccales, with only genes for growth on methanol present. However, the presence of the soluble subunits of methyltetrahydromethanopterin:CoM methyltransferase (mtrAH) provide hypothetical pathways for methanol fermentation, and aceticlastic methanogenesis that await experimental verification. Thus, we show that marker gene mining can enhance the discovery power of metagenomics, by identifying novel lineages and aiding selection of targets for in-depth analyses. Marker gene mining is less sensitive to strain heterogeneity and has a lower abundance threshold than genome-resolved metagenomics, as it only requires short contigs and there is no binning step. Additionally, it is computationally cheaper than genome resolved metagenomics, since only a small subset of reads needs to be assembled. It is therefore a suitable approach to extract knowledge from the many publicly available sequencing projects. PMID- 30245937 TI - Insomnia and intellect mask the positive link between schizotypal traits and creativity. AB - Background: Schizotypy is a set of personality traits that resemble the signs and symptoms of schizophrenia in the general population, and it is associated with various subclinical mental health problems, including sleep disturbances. Additionally, dimensions of schizotypy show specific but weak associations with creativity. Given that creativity demands cognitive control and mental health, and that sleep disturbances negatively impact cognitive control, we predicted that positive, impulsive and disorganised schizotypy will demonstrate stronger associations with indicators of creativity, if the effect of mental health, insomnia, and intellect are statistically controlled. Methods: University students (N = 182) took part in the study. Schizotypy was assessed with the shortened Oxford-Liverpool Inventory of Feelings and Experiences (sO-LIFE). Creative achievements were measured with the Creative Achievement Questionnaire (CAQ), divergent thinking was assessed with the 'Just suppose' task, and remote association problem solving was tested with Compound Remote Associate (CRA) problems. Mental health was assessed with the 12-item version of the General Health Questionnaire (GHQ-12), and insomnia was examined with the Athens Insomnia Scale (AIS). Verbal short term memory was measured with the forward digit span task, and intellect was assessed with the Rational-Experiential Inventory (REI). Multiple linear regressions were performed to examine the relationship between creativity and schizotypy. Indicators of creativity were the dependent variables. In the first block, dimensions of schizotypy, age, gender and smoking were entered, and in the second block, the models were extended with mental health, insomnia, verbal short term memory, and intellect. Results: Positive schizotypy positively predicted real-life creative achievements, independently from the positive effect of intellect. Follow-up analyses revealed that positive schizotypy predicted creative achievements in art, while higher disorganised schizotypy was associated with creative achievements in science (when intellect was controlled for). Furthermore, disorganised schizotypy positively predicted remote association problem solving performance, if insomnia and verbal short term memory were statistically controlled. No dimension of schizotypy was significantly associated with divergent thinking. Discussion: In line with previous findings, positive schizotypy predicted real-life creative achievements. The positive effects of disorganised schizotypy might be explained in terms of the simultaneous involvement of enhanced semantic priming and cognitive control in problem solving. We speculate that the lack of associations between divergent thinking and schizotypy might be related to instruction effects. Our study underscores the relevance of sleep impairment to the psychosis-spectrum, and refines our knowledge about the adaptive aspects of schizotypy in the general population. PMID- 30245939 TI - 60S dynamic state of bacterial ribosome is fixed by yeast mitochondrial initiation factor 3. AB - The processes of association and dissociation of ribosomal subunits are of great importance for the protein biosynthesis. The mechanistic details of these processes, however, are not well known. In bacteria, upon translation termination, the ribosome dissociates into subunits which is necessary for its further involvement into new initiation step. The dissociated state of the ribosome is maintained by initiation factor 3 (IF3) which binds to free small subunits and prevents their premature association with large subunits. In this work, we have exchanged IF3 in Escherichia coli cells by its ortholog from Saccharomyces cerevisiae mitochondria (Aim23p) and showed that yeast protein cannot functionally substitute the bacterial one and is even slightly toxic for bacterial cells. Our in vitro experiments have demonstrated that Aim23p does not split E. coli ribosomes into subunits. Instead, it fixes a state of ribosomes characterized by sedimentation coefficient about 60S which is not a stable structure but rather reflects a shift of dynamic equilibrium between associated and dissociated states of the ribosome. Mitochondria-specific terminal extensions of Aim23p are necessary for "60S state" formation, and molecular modeling results point out that these extensions might stabilize the position of the protein on the bacterial ribosome. PMID- 30245938 TI - Zooming into plant-flower visitor networks: an individual trait-based approach. AB - Understanding how ecological communities are structured is a major goal in ecology. Ecological networks representing interaction patterns among species have become a powerful tool to capture the mechanisms underlying plant-animal assemblages. However, these networks largely do not account for inter-individual variability and thus may be limiting our development of a clear mechanistic understanding of community structure. In this study, we develop a new individual trait based approach to examine the importance of individual plant and pollinator functional size traits (pollinator thorax width and plant nectar holder depth) in mutualistic networks. We performed hierarchical cluster analyses to group interacting individuals into classes, according to their similarity in functional size. We then compared the structure of bee-flower networks where nodes represented either species identity or trait sets. The individual trait-based network was almost twice as nested as its species-based equivalent and it had a more symmetric linkage pattern resulting from of a high degree of size-matching. In conclusion, we show that by constructing individual trait-based networks we can reveal important patterns otherwise difficult to observe in species-based networks and thus improve our understanding of community structure. We therefore recommend using both trait-based and species-based approaches together to develop a clearer understanding of the properties of ecological networks. PMID- 30245940 TI - Neuroblastomas in Eastern China: a retrospective series study of 275 cases in a regional center. AB - Purpose: Most studies on neuroblastoma (NB) have been conducted in Western countries or Japan. The objective of our study was to analyze clinical and pathological features, MYCN status, surgical methods, and prognosis in Chinese NB patients. Methods: A retrospective, single-center case series study of 275 NBs was implemented. Clinical manifestations, pathological features, MYCN status, and surgical treatment were analyzed. Log-rank test and Cox hazards models were used to assess overall survivals (OSs). Results: The cohort consisted of 105 females and 170 males, with an age range of five days to 15 years. MYCN amplification was detected in 21.5% of all cases. The median OS was 15.0 months for MYCN amplified group. The five-year OS rates were 70.8% and 18.3% for MYCN unamplified and amplified groups, respectively, and the comparison of Kaplan-Meier curves for these two groups showed statistical significance (P < .001 by log-rank test). Gross total resection (GTR, n = 111) and subtotal resection (STR, n = 58) were administered in 169 patients at stages 3 and 4 who received chemotherapy and the comparison of Kaplan-Meier curves for different groups in these patients had statistical significance (STR vs. GTR, P = .009; MYCN unamplified vs. amplified, P < .001 by log-rank test, respectively).The multivariate survival analyses showed statistical significance (STR vs. GTR, P = .047; MYCN unamplified vs. amplified, P = .001 by Cox regression model). Conclusions: MYCN amplification is an independently adverse prognostic factor in Chinese NB patients at stages 3 and 4 and GTR is associated with improved OS compared with STR in these patients. PMID- 30245941 TI - Hydroxylation of Benzene via C-H Activation Using Bimetallic CuAg@g-C3N4. AB - Bimetallic CuAg@g-C3N4 catalyst system has been designed and synthesized by impregnating copper and silver nanoparticles over the graphitic carbon nitride surface. Its application has been demonstrated in the hydroxylation of benzene under visible light. PMID- 30245942 TI - Coupling Computer-Aided Process Simulation and Estimations of Emissions and Land Use for Rapid Life Cycle Inventory Modeling. AB - A methodology is described for developing a gate-to-gate life cycle inventory (LCI) of a chemical manufacturing process to support the application of life cycle assessment in the design and regulation of sustainable chemicals. The inventories were derived by first applying process design and simulation to develop a process flow diagram describing the energy and basic material flows of the system. Additional techniques developed by the United States Environmental Protection Agency for estimating uncontrolled emissions from chemical processing equipment were then applied to obtain a detailed emission profile for the process. Finally, land use for the process was estimated using a simple sizing model. The methodology was applied to a case study of acetic acid production based on the Cativa process. The results reveal improvements in the qualitative LCI for acetic acid production compared to commonly used databases and top-down methodologies. The modeling techniques improve the quantitative LCI results for inputs and uncontrolled emissions. With provisions for applying appropriate emission controls, the proposed method can provide an estimate of the LCI that can be used for subsequent life cycle assessments. PMID- 30245943 TI - Chest Compression Quality in a Newborn Manikin: A Randomized Crossover Trial (August 2016). AB - The objective of this paper was to examine the changes in applied force and rate of chest compression (CC) during 5 min of CC with a target CC rate of 90/min (CC90) or 120/min (CC120) with and without metronome guidance during simulated neonatal cardiopulmonary resuscitation (CPR). We performed a randomized controlled manikin trial. Fourteen neonatal resuscitation program providers performed CC90 and CC120 with or without a metronome in a randomized order. Peak and residual leaning force and CC rate each minute of CPR were analyzed with Friedman's analysis of variance (ANOVA) (within interventions) and two-way repeated measures ANOVA (between interventions). There was a large variability in force application, with no difference between groups. Peak and residual leaning forces in CC90 and CC120 did not change with time with or without a metronome. The CC rate increased with time in all groups except CC90 without a metronome. In conclusion, neither the target CC rate nor using a metronome influenced the peak and residual leaning forces during simulated neonatal CPR. PMID- 30245945 TI - An Ultra-Low Power Smart Headband for Real-Time Epileptic Seizure Detection. AB - In this paper, the design of a smart headband for epileptic seizure detection is presented. The proposed headband consists of four key components: 1) an analog front-end circuitry; 2) an epileptic seizure detection tag (ESDT); 3) a Bluetooth low-power chip; and 4) customized electrodes. All the above components are integrated into a fabric headband with only 50.3 g. The smart headband system dissipates 55.89 mW. The epileptic seizure detection algorithm inside ESDT is validated by using Boston Children's Hospital's CHB-MIT scalp EEG clinical database with the detection rate of 92.68% and the false alarm of 0.527/h. We develop a service APP connected to the cloud so that the patients' health condition can be recorded and then referenced by doctors for further diagnosis or research. PMID- 30245946 TI - Accelerometer-Based Assessment of Intestinal Peristalsis: Toward Miniaturized Low Power Solutions for Intestinal Implants. AB - Intestinal electrical stimulation via implants is already used to treat several disorders like constipation or incontinence. Stimulation parameters are most often empiric and not based on systematic studies. One prerequisite to evaluate effects of intestinal electrical stimulation is a direct assessment of intestinal motility. Some common methods are strain gauge transducers or manometry. With both the methods, it is not possible to record the exact 3-D movement. Therefore, we established a new method to record gastrointestinal motility with ultraminiaturized accelerometers, directly glued to the outer surface of the stomach, small intestine, and colon. With this technique, we were able to record precise local motility changes after electrical stimulation. Due to the low energy demand and the small size of the system, it is potentially useful for chronic measurements at multiple sites of the intestinal tract. We will present our first results regarding stimulation-dependent motility changes using up to eight implanted accelerometers in an acute pig model. PMID- 30245944 TI - Radial Pulse Spectrum Analysis as Risk Markers to Improve the Risk Stratification of Silent Myocardial Ischemia in Type 2 Diabetic Patients. AB - Diabetic patients with silent myocardial ischemia (SMI) have elevated rates of morbidity and mortality and need intensive care and monitoring. An early predictor of SMI may lead to early diagnosis and medical treatment to prevent progression and adverse clinical events. Therefore, this paper was aimed to evaluate the radial pulse spectrum as risk markers to improve the risk stratification of SMI in type-2 diabetic patients; 195 diabetic patients at high risk of SMI were enrolled. All patients underwent myocardial perfusion imaging and radial pressure wave measurement. The spectrum analysis of the radial pressure wave was calculated and transformed into Fourier series coefficients Cns and Pns. The risk of SMI (odds ratio: 4.46, 95%, C.I. 1.61-12.4, [Formula: see text]) was raised in diabetic patients classified high-risk group by C2. Multivariable regression analysis showed that C2 ([Formula: see text]) and ankle brachial index [(ABI) [Formula: see text])] were related to SMI ([Formula: see text] and [Formula: see text]). The myocardial ischemic score (MIS), combining C2, C3, and P5, the albumin-to-creatinine ratio (ACR), and ABI, presented an excellent risk stratification performance in enrolled patients (odds ratio: 5.78, 95%, C.I. 2.29-14.6, [Formula: see text]). The area under receiver operating characteristic curves for C2, C3, P5, ABI, ACR, and MIS were 0.66, 0.60, 0.68, 0.51, 0.56, and 0.74, respectively, in identifying SMI. This paper demonstrated that C2 was independently associated with the extent of SMI in multivariable regression analysis. Odds ratio and chi-square tests reflected that C2 could be an important marker for the risk stratification of SMI. Furthermore, MIS, adding radial pulse spectrum analysis to ACR and ABI, could significantly improve the risk stratification of SMI in type-2 diabetic patients compared to any single risk factor. PMID- 30245947 TI - Magnitude and Associated Risk Factors of Superficial Skin Fungal Infection Among Primary School Children in Southern Tanzania. AB - INTRODUCTION: Superficial skin fungal infections are among the neglected communicable diseases in many developing countries. Schoolchildren are among the most affected groups in Southern Tanzania. The main objective of this study was to determine the magnitude and associated risk factors of superficial skin fungal infections among primary schoolchildren in Southern Tanzania. METHODS: A cross sectional descriptive community-based study was conducted in October 2017 in a public primary school in Songea Municipal, Southern Tanzania. A sample of 500 pupils was interviewed and a physical examination performed to assess for the presence of clinically suspected skin fungal infections. Data were analyzed by SPSS v21 (IBM Corp., Armonk, NY, US). RESULTS: A total of 500 pupils (52.40% males) with a mean age of 9.92+/-1.13 years were recruited. The point-prevalence of skin fungal infections was 35.20%. Tinea capitis was the leading suspected skin fungal disease found in 73 (80.22%) pupils. Age between 10 and 12 years and sharing of a bed with more than three people were significantly associated with the development of superficial skin fungal infections (p<0.05). CONCLUSION: Our findings indicate that the magnitude of superficial skin fungal infections among schoolgoing children in this study area is moderately high. We recommend the provision of health education programs for preventing and controlling diseases in schoolchildren, with the aim to reduce long-term morbidity and the socioeconomic impact. PMID- 30245948 TI - Cardiotoxicity: Myocardium or Endothelium. AB - Endothelial biomarkers are gaining interest in the stratification of cardiovascular risk and early diagnosis of cardiotoxicity secondary to antineoplastic drugs. Interestingly, some drugs, such as anthracyclines, have been recently associated with vascular damage, which reveals the pivotal role of research in identifying biomarkers that could potentially be included into more specific cardiotoxicity risk scores. An extensive report of the incidences of cardiovascular adverse effects of oncologic drugs is presented, with the main purpose of highlighting not only the risk of developing heart failure but also the importance of associated vascular adverse effects (i.e., hypertension, venous, and arterial thrombosis) experienced by patients in the post-chemotherapy phase. PMID- 30245949 TI - The Effect of Physical Activity in Parkinson's Disease: A Mini-Review. AB - This article will discuss the effects of physical activity in patients with Parkinson's disease. Presently, the motor and non-motor symptoms are difficult to treat with the current treatment of Parkinson's; therefore, as an adjuvant to the current treatment physical activity, has been recommended. Physical activity has been known to improve many symptoms in patients with Parkinson's disease. Some of these symptoms include the physical capacities, physical and cognitive functional capacities. Physical activity also slows the disease process, decreases the pain associated with Parkinson's disease, prolongs the independent mobility (gait, balance, strength) and improves sleep, mood, memory hence improving the overall quality of life. Furthermore, physical activity has the potential to improve the non-motor symptoms (depression, apathy, fatigue, constipation) and the secondary complications of immobility (cardiovascular, osteoporosis) in Parkinson's disease. PMID- 30245950 TI - Combined Albendazole and Praziquantel Therapy in an Adult Female with Neurocysticercosis and Generalized Tonic-clonic Seizures. AB - The use of albendazole monotherapy has been favored as the treatment option for neurocysticercosis. This case reports an incidence of neurocysticercosis in a 32 year-old woman who presented to the emergency department with a generalized tonic clonic seizure. Neurocysticercosis was confirmed by magnetic resonance imaging (MRI) of the brain and a positive Taenia solium serologic test. The patient was treated with the combined dual therapy of albendazole and praziquantel at standard doses for a minimum effective duration of 14 days in the setting of scarce patient resources. She tolerated therapy without any adverse reactions and remained seizure free. A repeat MRI scan post-treatment revealed the complete eradication of cysticerci. Clinicians should be aware of and consider the efficacy and safety of combined albendazole and praziquantel therapy for the treatment of neurocysticercosis. PMID- 30245951 TI - Updating the Surgical Preference List. AB - Surgical procedure 'preference lists' are used worldwide, but their practice varies widely. Despite being positioned at a critical point in a surgical care pathway, they are often underemphasized, poorly maintained, and substandard. The following editorial material is gleaned from our experience in the set-up of a tertiary hospital on a green field site in Qatar. We comment on the use of preference lists, and contend that focus on standardizing and maintaining preference lists within an electronic record affords substantial opportunities for cost containment, whilst adding efficiency, safety, and value. We believe this approach represents an 'easy win' which would be applicable elsewhere. PMID- 30245952 TI - Macrolunula: Case Reports of Patients with Trauma-associated Enlarged Lunula and a Concise Review of this Nail Finding. AB - The lunula refers to the visible portion of the distal nail matrix that extends beyond the proximal nail fold. Macrolunula, or enlarged lunula, is not only a physiologic variant but also has been associated with a variety of local and systemic disorders. Macrolunula has been described in congenital conditions including hereditary onycho-osteodysplasia, neoplasms such as superficial acral fibromyxoma, as well as iatrogenic causes as in the topical administration of hydrocortisone; it can also occur in systemic disorders including hyperthyroidism, ischemia, leprosy, and scleroderma. While macrolunula has been described in self-induced trauma secondary to habit-tic deformity, we observe in this case report that any mechanism of trauma to the nail unit may produce enlargement of the lunula. PMID- 30245953 TI - Evaluation of the Community Multiscale Air Quality Model for Simulating Winter Ozone Formation in the Uinta Basin. AB - The Weather Research and Forecasting (WRF) and Community Multiscale Air Quality (CMAQ) models were used to simulate a 10 day high-ozone episode observed during the 2013 Uinta Basin Winter Ozone Study (UBWOS). The baseline model had a large negative bias when compared to ozone (O3) and volatile organic compound (VOC) measurements across the basin. Contrary to other wintertime Uinta Basin studies, predicted nitrogen oxides (NO x ) were typically low compared to measurements. Increases to oil and gas VOC emissions resulted in O3 predictions closer to observations, and nighttime O3 improved when reducing the deposition velocity for all chemical species. Vertical structures of these pollutants were similar to observations on multiple days. However, the predicted surface layer VOC mixing ratios were generally found to be underestimated during the day and overestimated at night. While temperature profiles compared well to observations, WRF was found to have a warm temperature bias and too low nighttime mixing heights. Analyses of more realistic snow heat capacity in WRF to account for the warm bias and vertical mixing resulted in improved temperature profiles, although the improved temperature profiles seldom resulted in improved O3 profiles. While additional work is needed to investigate meteorological impacts, results suggest that the uncertainty in the oil and gas emissions contributes more to the underestimation of O3. Further, model adjustments based on a single site may not be suitable across all sites within the basin. PMID- 30245955 TI - Satellite observation of particulate organic carbon dynamics in two river dominated estuaries. AB - Particulate organic carbon (POC) plays an important role in coastal carbon cycling and the formation of hypoxia. Yet, coastal POC dynamics are often poorly understood due a lack of POC observations and the complexity of coastal hydrodynamic and biogeochemical processes that influence POC sources and sinks. Using a dataset of field observations and satellite ocean color products, we developed a new multiple regression algorithm to derive POC from satellite observations in two river-dominated estuaries in the northern Gulf of Mexico: the Louisiana Continental Shelf (LCS) and Mobile Bay. The algorithm had reliable performance with mean relative error (MRE) of ~40%, and root mean square error (RMSE) of ~50% for MODIS and SeaWiFS images in the two systems. Substantial spatio-temporal variability was observed from satellite on the LCS, with higher POC on the inner shelf (< 10 m depth) and lower POC on the middle (10-50 m depth) and outer shelves (50-200 m depth), and with higher POC in winter (January to March), and lower POC in summer to fall (August to October). Correlation analysis between long-term POC time series and several potential influencing factors indicated that river discharge dominants POC dynamics on the LCS. Wind and surface currents also affect POC spatial patterns on short time scales. This study demonstrates that algorithms that can determine coastal POC from satellites greatly increase the spatial and temporal extent of observations available for characterizing POC dynamics and their relations to various dominant physical forcings to the continental shelf and estuaries. PMID- 30245954 TI - Modeling NH4NO3 Over the San Joaquin Valley During the 2013 DISCOVER-AQ Campaign. AB - The San Joaquin Valley (SJV) of California experiences high concentrations of particulate matter NH4NO3 during episodes of meteorological stagnation in winter. A rich data set of observations related to NH4NO3 formation was acquired during multiple periods of elevated NH4NO3 during the Deriving Information on Surface Conditions from Column and Vertically Resolved Observations Relevant to Air Quality (DISCOVER-AQ) field campaign in SJV in January and February 2013. Here NH4NO3 is simulated during the SJV DISCOVER-AQ study period with the Community Multiscale Air Quality (CMAQ) model, diagnostic model evaluation is performed using the DISCOVER-AQ data set, and integrated reaction rate analysis is used to quantify HNO3 production rates. Simulated NO3- generally agrees well with routine monitoring of 24-hr average NO3-, but comparisons with hourly average NO3- measurements in Fresno revealed differences at higher time resolution. Predictions of gas-particle partitioning of total nitrate (HNO3 + NO3-) and NHx (NH3 + NH4+) generally agree well with measurements in Fresno, although partitioning of total nitrate to HNO3 is sometimes overestimated at low relative humidity in afternoon. Gas-particle partitioning results indicate that NH4NO3 formation is limited by HNO3 availability in both the model and ambient. NH3 mixing ratios are underestimated, particularly in areas with large agricultural activity, and additional work on the spatial allocation of NH3 emissions is warranted. During a period of elevated NH4NO3, the model predicted that the OH + NO2 pathway contributed 46% to total HNO3production in SJV and the N2O5 heterogeneous hydrolysis pathway contributed 54%. The relative importance of the OH + NO2 pathway for HNO3 production is predicted to increase as NOx emissions decrease. PMID- 30245956 TI - Estramustine Phosphate Inhibits TGF-beta-Induced Mouse Macrophage Migration and Urokinase-Type Plasminogen Activator Production. AB - Transforming growth factor-beta (TGF-beta) has been demonstrated as a key regulator of immune responses including monocyte/macrophage functions. TGF-beta regulates macrophage cell migration and polarization, as well as it is shown to modulate macrophage urokinase-type plasminogen activator (uPA) production, which also contributes to macrophage chemotaxis and migration toward damaged or inflamed tissues. Microtubule (MT) cytoskeleton dynamic plays a key role during the cell motility, and any interference on the MT network profoundly affects cell migration. In this study, by using estramustine phosphate (EP), which modifies MT stability, we analysed whether tubulin cytoskeleton contributes to TGF-beta induced macrophage cell migration and uPA expression. We found out that, in the murine macrophage cell line RAW 264.7, EP at noncytotoxic concentrations inhibited cell migration and uPA expression induced by TGF-beta. Moreover, EP greatly reduced the capacity of TGF-beta to trigger the phosphorylation and activation of its downstream Smad3 effector. Furthermore, Smad3 activation seems to be critical for the increased cell motility. Thus, our data suggest that EP, by interfering with MT dynamics, inhibits TGF-beta-induced RAW 264.7 cell migration paralleled with reduction of uPA induction, in part by disabling Smad3 activation by TGF-beta. PMID- 30245957 TI - PAK5 Induces EMT and Promotes Cell Migration and Invasion by Activating the PI3K/AKT Pathway in Ovarian Cancer. AB - Ovarian cancer is the most lethal gynecologic cancer and currently ranks fifth in causing cancer-related deaths among women. P21cdc42/rac1-activated kinase 5 (PAK5) is a newly identified protein that has been indicated to have oncogenic potential. The present study investigated the expression level of PAK5 in clinical ovarian cancer and the functional roles of PAK5 in ovarian cancer progression. It was initially found that PAK5 was highly expressed in ovarian cancer tissues, particularly in patients with distant metastasis. Higher expression of PAK5 predicted poor survival fates in patients with ovarian cancer (p = 0.008). Knockdown of PAK5 in SKOV3 cells caused epithelial cell phenotypes, whereas overexpression of PAK5 led to remarkable mesenchymal cell phenotypes in A2780 cells. When PAK5 was depleted from SKOV3 cells, cells exhibited impaired wound recovery abilities. Cell migration and invasion abilities were also significantly inhibited. On the contrary, when PAK5 was overexpressed in A2780 cells, the wound recovery ability was enhanced by 68%. Cell migration and invasion abilities were consistently increased to approximately 2-fold. After knockdown of PAK5, the phosphorylation levels of PI3K p85 at Tyr458 and its downstream AKT at Ser473 were both decreased. The total protein of PI3K and AKT as well as the phosphorylation level of AKT at Thr308 remained unaffected. These data suggested that PI3K induced epithelial-to-mesenchymal transition and promoted cell migration and invasion by activating the PI3K/AKT pathway in ovarian cancer. The oncogenic potential of PAK5 in ovarian cancer might suggest that any therapeutic strategies targeting PAK5 had the promising value for ovarian cancer treatment. PMID- 30245958 TI - Behavioral Treatments for Tourette Syndrome. AB - Tourette syndrome (TS) is a neuropsychiatric condition associated with substantial distress and functional impairment. Pharmacotherapy has traditionally been considered the first-line intervention for this condition, but there is strong evidence that behavior therapy is a comparably effective treatment option. Here we review empirically supported behavior therapy protocols for treating TS and the evidence associated with each. Potential mechanisms through which behavior therapy operates and concerns surrounding the utilization of behavioral interventions are also discussed. PMID- 30245959 TI - Human carboxylesterases: a comprehensive review. AB - Mammalian carboxylesterases (CEs) are key enzymes from the serine hydrolase superfamily. In the human body, two predominant carboxylesterases (CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications. PMID- 30245961 TI - Drug metabolism in drug discovery and development. AB - Drug metabolism as a discipline plays an important role in drug discovery and development and the effects of drug metabolism on pharmacokinetics (PK), pharmacodynamics (PD), and safety should be carefully considered. This communication provides an overview of common strategies in the area of drug metabolism for improving PK/PD and safety profiles of drug candidates; these include, but are not limited to, collaboration with medicinal chemists on structure-activity relationships (SAR) to overcome high clearance, using deuterium replacement to further optimize a lead, prodrug approaches to circumvent formulation and delivery difficulties, and addressing issues such as species differences in metabolism, drug-drug interactions (DDI) and formation of reactive metabolites. PMID- 30245960 TI - Ganglioside GD3 synthase (GD3S), a novel cancer drug target. AB - Gangliosides are a class of important glycosphingolipids containing sialic acid that are widely distributed on the outer surface of cells and are abundantly distributed in brain tissue. Disialoganglioside with three glycosyl groups (GD3) and disialoganglioside with two glycosyl groups (GD2) are markedly increased in pathological conditions such as cancers and neurodegenerative diseases. GD3 and GD2 were found to play important roles in cancers by mediating cell proliferation, migration, invasion, adhesion, angiogenesis and in preventing immunosuppression of tumors. GD3 synthase (GD3S) is the regulatory enzyme of GD3 and GD2 synthesis, and is important in tumorigenesis and the development of cancers. The study of GD3S as a drug target may be of great significance for the discovery of new drugs for cancer treatment. This review will describe the gangliosides and their roles in physiological and pathological conditions; the roles of GD3 and GD2 in cancers; the expression, functions and mechanisms of GD3S, and its potential as a drug target in cancers. PMID- 30245963 TI - Serum and glucocorticoid inducible protein kinases (SGKs): a potential target for cancer intervention. AB - The serum and glucocorticoid inducible protein kinase (SGK) family members share similar structure, substrate specificity and function with AKT and signal downstream of the phosphatidylinositol 3-kinase (PI3K) signalling pathway. They regulate a range of fundamental cellular processes such as cell proliferation and survival, thereby playing an important role in cancer development. This perspective intends to give an overview on the involvement of SGKs (particularly SGK3) in cancer progression, and compares the actions of SGK3 and AKT in cell cycle regulation, oncogenic signalling, and the potential as a therapeutic target for cancer. PMID- 30245962 TI - Parenteral nanosuspensions: a brief review from solubility enhancement to more novel and specific applications. AB - Advancements in in silico techniques of lead molecule selection have resulted in the failure of around 70% of new chemical entities (NCEs). Some of these molecules are getting rejected at final developmental stage resulting in wastage of money and resources. Unfavourable physicochemical properties affect ADME profile of any efficacious and potent molecule, which may ultimately lead to killing of NCE at final stage. Numerous techniques are being explored including nanocrystals for solubility enhancement purposes. Nanocrystals are the most successful and the ones which had a shorter gap between invention and subsequent commercialization of the first marketed product. Several nanocrystal-based products are commercially available and there is a paradigm shift in using approach from simply being solubility enhancement technique to more novel and specific applications. Some other aspects in relation to parenteral nanosuspensions are concentrations of surfactant to be used, scalability and in vivo fate. At present, there exists a wide gap due to poor understanding of these critical factors, which we have tried to address in this review. This review will focus on parenteral nanosuspensions, covering varied aspects especially stabilizers used, GRAS (Generally Recognized as Safe) status of stabilizers, scalability challenges, issues of physical and chemical stability, solidification techniques to combat stability problems and in vivo fate. PMID- 30245964 TI - Identification of anti-Gram-negative bacteria agents targeting the interaction between ribosomal proteins L12 and L10. AB - Gram-negative bacteria have become the main pathogens and cause serious clinical problems with increased morbidity and mortality. However, the slow discovery of new antimicrobial agents is unable to meet the need for the treatment of bacterial infections caused by drug-resistant strains. The interaction of L12 and L10 is essential for ribosomal function and protein synthesis. In this study, a yeast two-hybrid system was established to successfully detect the interaction between L12 and L10 proteins from gram-negative bacteria Escherichia coli, which allows us to screen compounds that specifically disrupt this interaction. With this system, we identified two compounds IMB-84 and IMB-87 that block L12-L10 interaction and show bactericidal activity against E. coli. We used glutathione-S transferase (GST) pull-down and surface plasmon resonance (SPR) assays to demonstrate that these compounds disrupt L12-L10 interaction in vitro and the target of compounds was further confirmed by the overexpression of target proteins. Moreover, protein synthesis and elongation factor G-dependent GTPase activities are inhibited by two compounds. Therefore, we have identified two antibacterial agents that disrupt L12-L10 interaction by using yeast two-hybrid system. PMID- 30245967 TI - Helioscopianoids A-Q, bioactive jatrophane diterpenoid esters from Euphorbia helioscopia. AB - The EtOH extracts of the whole plants of Euphorbia helioscopia afforded 17 new jatrophane diterpenoid esters, helioscopianoids A-Q (1-17), along with eight known compounds (18-25). Their structures were elucidated by extensive spectroscopic methods and Mo2(OAc)4-induced ECD analysis, and the structures of compounds 1, 2, and 7 were confirmed by X-ray crystallography. Compounds 1-17 were evaluated for inhibitory effects on P-glycoprotein (P-gp) in an adriamycin (ADM)-resistant human breast adenocarcinoma cell line (MCF-7/ADR) and neuroprotective effects against serum deprivation-induced and rotenone-induced PC12 cell damage. Compounds 8 and 16 increased the accumulation of ADM in MCF 7/ADR cells by approximately 3-fold at a concentration of 20 MUmol/L. Compound 8 could attenuate rotenone-induced PC12 cell damage, and compounds 2, 8, and 12 showed neuroprotective activities against serum deprivation-induced PC12 cell damage. PMID- 30245965 TI - Arenobufagin is a novel isoform-specific probe for sensing human sulfotransferase 2A1. AB - Human cytosolic sulfotransferase 2A1 (SULT2A1) is an important phase II metabolic enzyme. The detection of SULT2A1 is helpful for the functional characterization of SULT2A1 and diagnosis of its related diseases. However, due to the overlapping substrate specificity among members of the sulfotransferase family, it is difficult to develop a probe substrate for selective detection of SULT2A1. In the present study, through characterization of the sulfation of series of bufadienolides, arenobufagin (AB) was proved as a potential probe substrate for SULT2A1 with high sensitivity and specificity. Subsequently, the sulfation of AB was characterized by experimental and molecular docking studies. The sulfate conjugated metabolite was identified as AB-3-sulfate. The sulfation of AB displayed a high selectivity for SULT2A1 which was confirmed by in vitro reaction phenotyping assays. The sulfation of AB by human liver cytosols and recombinant SULT2A1 both obeyed Michaelis-Menten kinetics, with similar kinetic parameters. Molecular docking was performed to understand the interaction between AB and SULT2A1, in which the lack of interaction with Met-137 and Tyr-238 of SULT2A1 made it possible to eliminate substrate inhibition of AB sulfation. Finally, the probe was successfully used to determine the activity of SULT2A1 and its isoenzymes in tissue preparations of human and laboratory animals. PMID- 30245966 TI - Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of cardiac stem cells through HIF-1alpha/Jagged1/Notch1 signaling. AB - Hypoxia is beneficial for the differentiation of stem cells transplanted for myocardial injury, but mechanisms underlying this benefit remain unsolved. Here, we report the impact of hypoxia-induced Jagged1 expression in cardiomyocytes (CMs) for driving the differentiation of cardiac stem cells (CSCs). Forced hypoxia-inducible factor 1alpha (HIF-1alpha) expression and physical hypoxia (5% O2) treatment could induce Jagged1 expression in neonatal rat CMs. Pharmacological inhibition of HIF-1alpha by YC-1 attenuated hypoxia-promoted Jagged1 expression in CMs. An ERK inhibitor (PD98059), but not inhibitors of JNK (SP600125), Notch (DAPT), NF-kappaB (PTDC), JAK (AG490), or STAT3 (Stattic) suppressed hypoxia-induced Jagged1 protein expression in CMs. c-Kit+ CSCs isolated from neonatal rat hearts using a magnetic-activated cell sorting method expressed GATA4, SM22alpha or vWF, but not Nkx2.5 and cTnI. Moreover, 87.3% of freshly isolated CSCs displayed Notch1 receptor expression. Direct co-culture of CMs with BrdU-labeled CSCs enhanced CSCs differentiation, as evidenced by an increased number of BrdU+/Nkx2.5+ cells, while intermittent hypoxia for 21 days promoted co-culture-triggered differentiation of CSCs into CM-like cells. Notably, YC-1 and DAPT attenuated hypoxia-induced differentiation. Our results suggest that hypoxia induces Jagged1 expression in CMs primarily through ERK signaling, and facilitates early cardiac lineage differentiation of CSCs in CM/CSC co-cultures via HIF-1alpha/Jagged1/Notch signaling. PMID- 30245968 TI - Bioactive thionic compounds and aromatic glycosides from Ligusticum chuanxiong. AB - Three new thionic compounds, (S)-2-(2-carboxyl-2-hydroxyethylthio)-ferulic acid (1), (E)-2-methoxy-4-(3-(methylsulfonyl)prop-1-en-1-yl)phenol (2), and thiosenkyunolide C (3), together with two new aromatic glycosides (4 and 5) were isolated from the rhizome of Ligusticum chuanxiong Hort. Two known compounds (6 and 7) were also obtained. Their structures were elucidated based on extensive spectroscopic data (UV, IR, 1D and 2D NMR, and HR-ESI-MS). Furthermore the absolute configurations were established by comparison of their calculated and experimental circular dichroism spectra and by a dimolybdenum tetraacetate [Mo2(AcO)4]-induced circular dichroism procedure. All compounds were evaluated against lipopolysaccharide (LPS)-induced NO production in BV2 cells, and compounds 4 and 5 showed strong inhibitory activities with IC50 values of 2.03 and 3.09 umol/L, respectively (positive control curcumin, IC50 = 6.17 umol/L). In addition, compound 1 showed weak proteintyrosine phosphatase-1B (PTP1B) inhibitory activity. PMID- 30245969 TI - Efficacy of inverso isomer of CendR peptide on tumor tissue penetration. AB - The dense extracellular matrix and high interstitial fluid pressure of tumor tissues prevent the ability of anti-tumor agents to penetrate deep into the tumor parenchyma for treatment effects. C-end rule (CendR) peptides can enhance the permeability of tumor blood vessels and tumor tissues via binding to neuropilin-1 (NRP-1), thus aiding in drug delivery. In this study, we selected one of the CendR peptides (sequence RGERPPR) as the parent l-peptide and substituted d-amino acids for the l-amino acids to synthesize its inverso peptide D(RGERPPR). We investigated the NRP-1 binding activity and tumor-penetrating ability of D(RGERPPR). We found that the binding affinity of D(RGERPPR) with NRP-1 and the cellular uptake was significantly higher than that of RGERPPR. Evans Blue tests revealed that D(RGERPPR) exhibited improved tumor-penetrating ability in C6, U87 and A549 tumor-bearing nude mice. Using nude mice bearing A549 xenograft tumors as a model, we found that the rate of tumor growth in the group co-administered with D(RGERPPR) and gemcitabine (Gem) was significantly lower than the gemcitabine-treated group with a tumor suppression rate (TSR%) of 55.4%. Together, our results demonstrate that D(RGERPPR) is a potential tumor penetrating peptide. PMID- 30245971 TI - Partial neuromuscular blockage to promote weaning from mechanical ventilation in severe ARDS: A case report. AB - Spontaneous breathing efforts during mechanical ventilation can lead to patient self-inflicted lung injury (P-SILI). In order to prevent P-SILI, patients are generally heavily sedated and receive muscle relaxation, resulting in a slower weaning process. We present a case in which we applied partial neuromuscular blockage in order to prevent P-SILI while allowing spontaneous breathing but with limited efforts during assist mechanical ventilation. PMID- 30245972 TI - Successful prevention of perinatal HIV transmission utilizing direct observation therapy in the setting of Acquired Immunodeficiency Syndrome (AIDS) and progressive multifocal leukoencephalopathy. AB - We report a case of a 22-year-old G1P0010 African-American female with poorly controlled perinatally acquired HIV/AIDS and recent diagnosis of progressive multifocal leukoencephalopathy (PML) by magnetic resonance imaging (MRI). She presented to a tertiary care facility for prenatal care and direct observation therapy after poor medication adherence during pregnancy. After multiple attempts at outpatient ART management, the patient was admitted at 35 weeks' gestation for direct observation therapy for both antiretroviral therapy and anti-seizure medication. Viral load at that time was 22,487 copies/mL and she was admitted and started on a salvage regimen which included: dolutegravir, tenofovir disoproxil fumarate/emtricitabine, darunavir, ritonavir, and trimethoprim/sulfamethoxazole for Pneumocystis jirovecii prophylaxis. The patient remained on direct observation therapy throughout her two-week hospital stay with final viral load of 1211 copies/mL, CD4 284/uL at time of delivery at 37 weeks' gestation, with minimal seizure activity. The infant received postnatal antiretroviral therapy including three doses of zidovudine and nevirapine with negative HIV PCR at birth, 2, 4, and 6 months postpartum and is currently HIV negative. PMID- 30245973 TI - Modeling the combined effects of changing land cover, climate, and atmospheric deposition on nitrogen transport in the Neuse River Basin. AB - Study region: The SWAT model was used to estimate the combined effects of changing land cover, climate and Clean Air Act (CAAA)-related atmospheric nitrogen (N) deposition to watershed nitrogen fate and transport for two watersheds in North Carolina, USA. Study focus: Two different model simulation scenarios were applied: one included CAAA-related atmospheric N deposition, climate and land cover (CAAD+C+L) and the other only included CAAA-related N deposition (CAAD) in simulation. New hydrological insights for the region: Results show both scenarios generated overall decreasing trends for nearly all N outputs between 2010 and 2070 which resulted primarily from CAAA-related reductions in oxidized N deposition. In both watersheds, including climate and land cover change in simulation resulted in a relative 30% higher NO3 load, 30% higher denitrification, 10% higher organic N load and a 20% smaller level of plant N uptake in year 2070 compared to not including climate and landcover changes in simulation. The increases in N transport for both watersheds indicates the combined impacts from climate and land cover change may offset benefits provided by the CAAA regulations; however, future NO3 loads for the Little River watershed were small relative to current N loading rates. Conversely, the increasing NO3 and organic N loads for the nearby Nahunta watershed were significant compared to current rates demonstrating that watershed nutrient responses to climate and land cover changes may vary significantly over relatively small spatial scales. PMID- 30245970 TI - beta2ARs stimulation in osteoblasts promotes breast cancer cell adhesion to bone marrow endothelial cells in an IL-1beta and selectin-dependent manner. AB - Progression and recurrence of breast cancer, as well as reduced survival of patients with breast cancer, are associated with chronic stress, a condition known to impact the hypothalamic-pituitary axis and the autonomic nervous system. Preclinical and clinical evidence support the involvement of the sympathetic nervous system in the control of bone remodeling and in pathologies of the skeleton, including bone metastasis. In experimental mouse models of skeletal metastasis, administration of the betaAR agonist isoproterenol (ISO), used as a surrogate of norepinephrine, the main neurotransmitter of sympathetic neurons, was shown to favor bone colonization of metastatic breast cancer cells via an increase bone marrow vascularity. However, successful extravasation of cancer cells into a distant organ is known to be favored by an activated endothelium, itself stimulated by inflammatory signals. Based on the known association between high sympathetic outflow, the expression of inflammatory cytokines and bone metastasis, we thus asked whether betaAR stimulation in osteoblasts may alter the vascular endothelium to favor cancer cell engraftment within the skeleton. To address this question, we used conditioned medium (CM) from PBS or ISO-treated bone marrow stromal cells (BMSCs) in adhesion assays with bone marrow endothelial cells (BMECs) or the endothelial cell line C166. We found that ISO treatment in differentiated BMSCs led to a robust induction of the pro-inflammatory cytokines interleukin-1 beta (IL-1beta) and interleukin-6 (IL-6). The CM from ISO-treated BMSCs increased the expression of E- and P-selectin in BMECs and the adhesion of human MDA-MB-231 breast cancer cells to these cells in short-term static and dynamic adhesion assays, and a blocking antibody against IL-1beta, but not IL-6, reduced this effect. Direct IL-1beta treatment of BMECs had a similar effect, whereas the impact of IL-6 treatment on the expression of adhesion molecules by BMECs and on the adhesion of cancer cells to BMECs was negligible. Collectively, these in vitro results suggest that in the context of the multicellular and dynamic bone marrow environment, sympathetic activation and subsequent betaAR stimulation in osteoblasts may profoundly remodel the density but also the activation status of bone marrow vessels to favor the skeletal engraftment of circulating breast cancer cells. PMID- 30245974 TI - Vulvodynia: A disease commonly hidden in plain sight. AB - *Vulvodynia affects at least 6% of women, and can be found at any age and in all ethnic groups.*The diagnosis is one of exclusion but is very often missed.*Women with vulvodynia are frequently misdiagnosed as having vaginismus.*Failure to make the diagnosis often leads to irrelevant or deleterious examinations and treatments. PMID- 30245976 TI - Downregulation of Autophagy-Related Proteins 1, 5, and 16 in Testicular Germ Cell Tumors Parallels Lowered LC3B and Elevated p62 Levels, Suggesting Reduced Basal Autophagy. AB - Autophagy is a cellular "self-digestion" process known to be essential for various physiological and pathological pathways, including cancer, where its role appears to be context-dependent. In this work, we aimed to investigate the level of autophagy by evaluating the expression of key autophagy-related proteins (ATGs) in testicular germ cell tumors (TGCT) for which autophagy has been rarely investigated. We decided to use an immunohistochemical (IHC) staining approach employing a tissue microarray (TMA). Software-based evaluation of the integrated optical densities (IODs) of these proteins indicated a significant downregulation of ATG1, ATG5, and ATG16L1. Accordingly, reduced levels of microtubule-associated proteins 1A/1B light chain 3B (LC3B) were found to parallel increases in sequestosome-1 (SQSTM1 or p62), a protein normally degraded via autophagy, suggesting an in vivo reduction in autophagy with TGCT. Thus, our work provides evidence for a tumor suppressive function of autophagy in the development of TGCT and supports the concept of a context-dependent role of autophagy in tumorigenesis which is tumor type-dependent. PMID- 30245975 TI - Urinary Markers in Bladder Cancer: An Update. AB - Bladder cancer (BC) is ones of the most common cancer worldwide. It is classified in muscle invasive (MIBC) and muscle non-invasive (NMIBC) BC. NMIBCs frequently recur and progress to MIBCs with a reduced survival rate and frequent distant metastasis. BC detection require unpleasant and expensive cystoscopy and biopsy, which are often accompanied by several adverse effects. Thus, there is an urgent need to develop novel diagnostic methods for initial detection and surveillance in both MIBCs and NMIBCs. Multiple urine-based tests approved by FDA for BC detection and surveillance are commercially available. However, at present, sensitivity, specificity and diagnostic accuracy of these urine-based assays are still suboptimal and, in the attend to improve them, novel molecular markers as well as multiple-assays must to be translated in clinic. Now there are growing evidence toward the use of minimally invasive "liquid biopsy" to identify biomarkers in urologic malignancy. DNA- and RNA-based markers in body fluids such as blood and urine are promising potential markers in diagnostic, prognostic, predictive and monitoring urological malignancies. Thus, circulating cell-free DNA, DNA methylation and mutations, circulating tumor cells, miRNA, IncRNA and mRNAs, cell-free proteins and peptides, and exosomes have been assessed in urine specimens. However, proteomic and genomic data must to be validated in well designed multicenter clinical studies, before to be employed in clinic oncology. PMID- 30245978 TI - The Antiapoptotic Effect of Curcumin in the Fibroblast of the Cochlea in an Ototoxic Rat Model. AB - Introduction: This study aimed to show the potency of curcumin as an antiapoptotic agent that decreases the apoptotic index in the cochlea lateral wall in ototoxic rat models. Materials and Methods: A total of 24 Rattus norvegicus were divided into eight groups: Group 1 (control group), Group 2 (gentamicin (+)), Group 3 (gentamicin + curcumin 20 mg/day), Group 4 (gentamicin + curcumin 40 mg/day), Group 5 (gentamicin + curcumin 20 mg/day for 7 days), Group 6 (gentamicin + curcumin 40 mg/day for 7 days), Group 7 (curcumin 20 mg/day for 3 days + gentamicin), and Group 8 (curcumin 40 mg/day for 3 days + gentamicin). After the division, the rats were terminated in order to measure the apoptotic index using a terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay in the fibroblasts of the cochlea lateral walls. The data were analyzed using analysis of variance (ANOVA), and P<0.05 was used as the cut off for statistical significance. Results: Administration of gentamicin showed significant differences (P<0.05) in the apoptotic index. Groups undergoing curcumin treatment at a higher dose (200 mg/kg bw) and the prevention groups showed significant differences compared with groups not treated with curcumin. Conclusion: This study concluded that the apoptotic index can be decreased by curcumin and has a preventive benefit toward ototoxic rat models. The administration of curcumin depended on the dose and duration. PMID- 30245977 TI - Alterations in the Abundance and Co-occurrence of Akkermansia muciniphila and Faecalibacterium prausnitzii in the Colonic Mucosa of Inflammatory Bowel Disease Subjects. AB - Akkermansia muciniphila and Faecalibacterium prausnitzii, cohabitants in the intestinal mucosa, are considered members of a healthy microbiota and reduction of both species occurs in several intestinal disorders, including inflammatory bowel disease. Little is known however about a possible link between the reduction in quantity of these species, and in which circumstances this may occur. This study aims to determine the abundances and co-occurrence of the two species in order to elucidate conditions that may compromise their presence in the gut. Loads of A. muciniphila, total F. prausnitzii and its two phylogroup (16S rRNA gene copies) were determined by quantitative polymerase chain reaction in colonic biopsies from 17 healthy controls (H), 23 patients with ulcerative colitis (UC), 31 patients with Crohn's disease (CD), 3 with irritable bowel syndrome (IBS) and 3 with colorectal cancer (CRC). Data were normalized to total bacterial 16S rRNA gene copies in the same sample. Prevalence, relative abundances and correlation analyses were performed according to type of disease and considering relevant clinical characteristics of patients such as IBD location, age of disease onset, CD behavior, current medication and activity status. Co-occurrence of both species was found in 29% of H, 65% of UC and 29% of CD. Lower levels of total F. prausnitzii and phylogroups were found in subjects with CD, compared with H subjects (P <= 0.044). In contrast, no differences were found with the regard to A. muciniphila abundance across different disease states, but CD patients with disease onset below 16 years of age featured a marked depletion of this species. In CD patients, correlation between A. muciniphila and total F. prausnitzii (rho = 0.362, P = 0.045) was observed, and particularly in those with non-stricturing, non-penetrating disease behavior and under moderate immunosuppressants therapy. Altogether, this study revealed that co-occurrence of both species differs between disease status. In addition, IBD patients featured a reduction of F. prausnitzii but similar loads of A. muciniphila when compared to H subjects, with the exception of those with early onset CD. Depletion of A. muciniphila in this subgroup of subjects suggests that it could be a potential biomarker to assist in pediatric CD diagnosis. PMID- 30245979 TI - Comparing the Effect of Oral Clonidine and Tranexamic Acid on Bleeding and Surgical Field Quality during Functional Endoscopic Sinus Surgery. AB - Introduction: Bleeding during functional endoscopic sinus surgery (FESS) is an important issue for both anesthesiologists and surgeons as it can affect the safety and efficiency of the procedure. We compared the efficacy of tranexamic acid (TXA) and clonidine in reducing blood loss and improving surgical field visualization during FESS. Materials and Methods: In a double-blind, randomized, clinical trial, 52 patients, American Society of Anesthesiologists (ASA) physical status 1-2, aged 13-75 years, suffering from rhinosinusitis with or without polyposis, and who were candidates for FESS, were enrolled. The first group received intravenous TXA 15 mg/kg diluted in 100 ml normal saline, administered during 10-min infusion after induction. In the second group, 0.2 mg oral clonidine was given 1 to 1.5 hours before surgery. Duration of surgery, hemoglobin level, heart rate, blood pressure, and quality of surgical field based on Boezzart's scale and surgeon satisfaction based on Likert's scale were recorded in both groups. Results: In total, 52 patients, 27 (51.9%) males and 25 (48.07%) females were studied. Twenty-two (42.3%) and 30 (57.7%) were in the TXA and clonidine groups, respectively. The mean pre- and post-surgical hemoglobin level showed no meaningful difference between the two groups. The same result was obtained for blood pressure and heart rate at different time points (P>0.05). Mean anesthesia time (P=0.859), mean surgical time (P=0.880), surgeon's satisfaction of the surgical field (P=0.757) and surgical field quality at different time points revealed no significant difference between the two groups. Conclusion: Premedication with oral clonidine and intravenous TXA has the same effect on bleeding during FESS, surgical field visualization, and surgeon satisfaction. PMID- 30245980 TI - Overexpression of High-Mobility Motor Box 1 in the Blood and Tissues of Patients with Head and Neck Squamous Cell Carcinoma. AB - Introduction: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world. Extra- and intra-cellular high-mobility motor box 1 (HMGB1) proteins are invovled in the pathogenesis and prognosis of cancer. Regarding this, the present study was conducted with the aim of investigating the expression of HMGB1 protein and mRNA levels in the blood, tumor tissue, and marginal normal tissue of patients with head and neck squamous cell carcinoma (HNSCC) using the quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Materials and Methods: This study was performed on 88 patients with HNSCC, who referred to the otorhinolaryngology and oral pathology departments, affiliated to Mashhad University of Medical Sciences, Mashhad, Iran, and a group of healthy subjects (i.e., control group) matched in terms of age and gender. RNA was collected from fresh tumor tissues, marginal tissues, and blood, followed by the implementation of quantitative PCR on the specimens. Furthermore, the expression of HMGB1 in tumor and normal margins was evaluated by means of IHC. The data were analyzed in SPSS software. Results: According to the results the expression levels of HMGB1 protein and mRNA were significantly higher in the tumor tissue than in the normal margin tissues (P<0.01). In addition, there was a significant correlation between histologic grading and the expression of HMGB1 protein and mRNA in tissues (P<0.05). Furthermore, the receiver operating characteristic curve of the HMGB1 mRNA in tissue was located closer to the theoretical 100% sensitivity. Conclusion: The findings revealed a higher increase in the levels of mRNA and HMGB1 protein in HNSCC, compared to those in the normal margin tissues. In addition, HMGB1 mRNA showed a significant expression in the tissue and blood of the patients with lymph node involvement. PMID- 30245981 TI - Study of Correlation of Pre-Operative Findings with Intra-Operative Ossicular Status in Patients with Chronic Otitis Media. AB - Introduction: Chronic otitis media (COM) has been broadly classified into mucosal and squamous subtypes. COM types are associated with erosion of the ossicular chain. The aim of the present study was to correlate the type of COM, the site of perforation/retraction, and the type of disease pathology with the pattern and degree of ossicular chain necrosis. Materials and Methods: A prospective cross sectional study was performed in 76 cases of COM, who were subjected to tympanomastoidectomy. Pre-operative findings were compared with per-operative ossicular chain status and pathology. Results: Incus was found to be the most vulnerable ossicle for erosion, followed by malleus and suprastructure of stapes. The pattern of multiple ossicle involvement was more common. Ossicular chain erosion was more common in squamous COM than mucosal COM (X2=66.25; P=0.0001) and in the presence of cholesteatoma and granulations. Ossicular necrosis was most common in squamous disease with cholesteatoma, followed by squamous disease with granulations, mucosal disease with granulations, and inactive mucosal disease in that order. Conclusion: The degree of ossicular necrosis has a positive correlation with the type of disease pathology, being higher in squamous disease than in mucosal disease. The pattern of ossicular necrosis varies with the site of origin of the disease and the pattern of spread of cholesteatoma, being variable for pars tensa and pars flaccida squamous disease. PMID- 30245982 TI - Management of Laryngotracheal Trauma: A Five-Year Single Institution Experience. AB - Introduction: Laryngotracheal trauma is a rare life-threatening emergency that requires early identification and immediate intervention. Here, we present 26 patients with laryngotracheal trauma from a tertiary hospital in India. The aim was to describe the clinical presentation and management of laryngotracheal trauma patients. Materials and Methods: This was a retrospective study of laryngotracheal trauma patients treated between January 2011 and March 2016. Patients who presented with a breach in the laryngotracheal framework were included, while those who had penetrating neck injuries superficial to strap muscles/platysma, burn injuries, caustic ingestion, or endotracheal injuries were excluded from the study. Results: Of 253 patients with neck injury, 26 (23 adults, three children; 21 males, five females; age range, 5-60 years) presented with a breach in the laryngotracheal framework (15 blunt neck-trauma patients and 11 penetrating neck-trauma patients). The most common cause of neck injury was road traffic accidents, seen in 12 patients (46.2%). Computed tomography (CT) was performed in all blunt trauma cases and in four patients with penetrating trauma. All penetrating trauma patients underwent neck exploration. Twelve blunt trauma patients (46.1%) were managed conservatively, while three (11.5%) required surgical intervention. The most common neck exploration finding noted in patients with a penetrating injury was fracture of the thyroid cartilage, which was seen in eight patients (30.8%). Twenty patients (76.9%) had a normal voice, five patients (19.2%) had a hoarse voice, and one patient (3.8%) had a breathy voice post treatment. Conclusion: Early intervention of laryngotracheal trauma is crucial. The role of a CT scan is essential in decision making in blunt trauma cases. PMID- 30245984 TI - Mantle Cell Lymphoma of the Palatine Tonsil: A Rare Case Report. AB - Introduction: Primary mantle cell lymphoma (MCL) of the palatine tonsil without involvement of the regional lymph nodes is rarely reported. Case Report: A 52 year-old male presented with complaints of a change in his voice over 3 months, with neither sore throat nor fever. Physical examination revealed right-sided grade IV and left-sided grade III tonsillar enlargement with prominent vessels. The patient underwent bilateral tonsillectomy. An initial histopathological report revealed chronic tonsillitis on the left side and suspicion of atypical lymphoproliferative disorder on the right. Immunohistochemically, the neoplastic cells were positive for Bcl2, CD20, CD5 and Cyclin D1 and negative for CD10, Bcl6 and CD3; thus a diagnosis of MCL was confirmed. Conclusion: MCL of the tonsil is rare. The microscopic diagnosis is challenging as the picture is very similar compared with other types of small cell lymphomas. A detailed immunohistochemistry panel is required for an accurate diagnosis. PMID- 30245983 TI - New Metal Shield for the Endotracheal Tube during Laser Endolaryngeal Surgery. AB - Introduction: To present and assess a newly designed autoclavable, reusable tube shield for an endotracheal tube (ETT) during laser laryngeal surgery. Materials and Methods: This study included patients scheduled for endolaryngeal laser surgery. A carbonated stainless-steel hemisphere shield (~1.5*0.6 mm) connected to a silk thread passing through a hole in its middle near upper edge was used. Under general anesthesia, patients were intubated orally using a small cuffed polyvinyl ETT, filling the cuff with saline. When the laser was used, the shield was applied either to the side of the tube or anterior to it, depending on the site of the laser procedure. The shield could easily be repositioned when needed during surgery. Results: In 25 cases (six cordectomy for glottic carcinomas and 19 posterior cordotomy for bilateral vocal cord paralysis), application of the shield over the ETT was easy and the shield could be easily and simply fitted in all cases, with change in position achieved easily during the work as required. The shield over the ETT could not be penetrated by the laser, regardless of the gas composition or laser energy. No intraoperative complications were encountered in any of our cases. Recovery was event-free in all patients without the need for admission to an intensive care unit. Conclusion: The newly designed autoclavable reusable stainless-steel shield designed for an ETT could be safely, easily, and effectively used during laser laryngeal surgery with low cost and easy availability. However, comparative and multicenter studies are still needed. PMID- 30245985 TI - Intraorbital and Intracranial Complications of Acute Rhinosinusitis: A Rare Case Report. AB - Introduction: Complications of acute sinusitis affecting multiple sites are very uncommon in the antibiotic era. However, a significant proportion of patients (5 40%) suffering from acute sinusitis can have these complications mostly due to the delayed diagnosis of the disease. Patients can have variable presentations according to the site and extent of the infection. Case Report: A 21-year-old male student presented with subperiosteal abscess and a brain abscess with a history of acute sinusitis. The patient had short history of left-side hemiplegia with foot drop. Endoscopic orbital decompression was performed and the subperiosteal abscess was drained when it did not respond to medical treatment. Complete clinical and radiological recovery was achieved after 1 month of medical treatment. Conclusion: Complications affecting the multiple sites in acute sinusitis is very uncommon in the antibiotic era. A proper history and thorough clinical examination along with a radiological evaluation are key factors in the final diagnosis of the patients with suspected complications. A quick multidisciplinary approach among otorhinologsts, ophthalmologists and general physicians is always necessary to avoid unwanted life-threatening complications. PMID- 30245986 TI - Laryngocele after Subtotal Laryngectomy. AB - Introduction: Laryngocele is an air-filled dilatation of the laryngeal saccule that extends upward within the false vocal folds. Different etiologies lead to laryngocele congenital malformation, weakness of the laryngeal tissues and increased intralaryngeal pressure. Laryngocele may be a secondary iatrogenic complication following subtotal laryngectomy. Case Report: We report the case of a 61-year-old patient who presented an external laryngomucocele 8 years after a supracricoid partial laryngectomy with cricohyoidoepiglottopexy (SCPL-CHEP). We focus on the clinical aspects and therapeutic attitude, then discuss the physiopathological conditions that could generate this late complication. Conclusion: Laryngocele after subtotal laryngectomy should be considered a late iatrogenic complication. Histological examination is necessary after surgical management of laryngocele, as the association with cancer is frequent. PMID- 30245987 TI - Differentiation of Cocaine-Induced Midline Destructive Lesions from ANCA Associated Vasculitis. AB - Introduction: Cocaine-induced midline destructive lesions (CIMDL) are complications of regular nasal cocaine inhalation. CIMDL can mimic systemic diseases with positive anti-neutrophil cytoplasmic antibodies (ANCA), such as granulomatosis with polyangiitis (GPA). Case Report: In this article, we describe the case of a young woman who presented with nasal perforation induced by cocaine, along with positive perinuclear ANCA test (proteinase 3 antigen), misdiagnosed as limited GPA. The patient was treated with immunosuppressive therapy, which partially improved her symptoms. Admittance of cocaine use aided in the diagnosis of CIMDL. This patient was advised to stop cocaine use. Three month follow-up revealed no further complications. Conclusion: Considering the seropositivity of ANCA in both CIMDL and GPA, early diagnosis of CIMDL and its differentiation from GPA is crucial, and clinicians play an important role in this regard. Lack of distinct histologic characteristics of vasculitis or unresponsiveness to standard therapeutic regimens may favor the diagnosis of CIMDL syndrome. It is crucial to recognize that these conditions may have similar presentations, so that undesired and potentially toxic treatments can be prevented. PMID- 30245988 TI - Use of oral anticoagulants for the prevention of thromboembolic events in the post-operative period of hip arthroplasty: a systematic review. AB - Oral anticoagulants are being used in the postoperative period of hip arthroplasty to prevent of thromboembolic events, create doubts as to the effectiveness of thromboprophylaxis and reduce the risk of hemorrhage. This systematic revision is aimed at evaluating the use of oral anticoagulants in the prevention of thromboembolic events in the postoperative period of patients undergoing hip arthroplasty. Research with descriptors found on PubMed, BVS, and the CAPES portal for medical journal publications from September 2015 to June 2016, from the last ten years (2005-2015), complete, free, and written in Portuguese and in English were the methods used. The results of the studies showed some cases of pulmonary embolism, deep vein thrombosis, and bleeding; even then, the NOACs were effective in preventing thromboembolic events. There is no consensus regarding the prophylaxis method for these events, which is why the challenge is to obtain high levels of prevention while minimizing the adverse effects. The most studied oral anticoagulant was rivaroxaban (67%). The three drugs that were studied have shown to be effective in preventing thromboembolic events, but the best results were obtained with rivaroxaban 10 mg, one tablet daily; treatment duration ranged from 30 to 35 days with oral anticoagulants and from 28 to 42 days with anti-platelet drugs. PMID- 30245989 TI - Evaluation of the discal height gain and lumbar lordosis variation obtained by the techniques of transforaminal and posterior lumbar intersomatic fusion. AB - Objective: Evaluate the discal height and lumbar lordosis gains, comparatively, according to the two lumbar arthrodesis techniques, transforaminal lumbar interbody fusion (TLIF) and posterior lumbar interbody fusion (PLIF), used in the treatment of spinal degenerative diseases. Methods: The present study, retrospective, was done with 60 patients who underwent decompression and 1 level lumbar arthrodesis in the Hospital Santa Casa de Misericordia de Vitoria (HSCMV), between January 2010 and December 2015. The patients were divided in two groups of 30 each, according to the utilized intersomatic arthrodesis technique: TLIF or PLIF. All patients presented pathologies at the L4-L5 level. In this study, the discal height gain and lumbar lordosis variation were evaluated by analyzing spinal radiographies of the pre and post-operatory periods from patients of the two groups, measured by the software Surgimap(r). In addition, the pain intensity in the post-operatory period was estimated by the Visual Analog Scale for Pain (VAS Pain). Results: Both techniques presented a gain in the discal height in the post-operatory. There was no statistically significant difference between the discal height variation obtained with the PLIF technique when compared to the TLIF technique (p = 0.139). In the same way, there was no statistically significant difference in the lumbar lordosis variation between the two studied groups (p = 0.184). By the EVA Pain analysis, there was no significant difference in the pain intensity in the post-operatory period between both arthrodesis surgeries. Conclusion: There is no difference in the discal height gain and lumbar lordosis variation, as well as in the pain intensity in the post-operatory periods, in patients who underwent 1 level intersomatic arthrodesis when comparing the PLIF and TLIF techniques. PMID- 30245990 TI - Anterior fixation of odontoid fractures: results. AB - Objective: To evaluate the clinical and radiological outcomes of the surgical treatment in patients diagnosed with odontoid fracture who underwent open reduction and internal fixation (ORIF) with screws. Methods: This was a retrospective study with nine patients. Pain (visual analog scale [VAS]) and neurological status (Frankel scale) were assessed. The neck disability index (NDI) and the post-operative cervical range of motion were calculated. The cervical spine was radiologically evaluated (X-ray and CT) pre- and postoperatively. Results: The mean age of patients was 70 years. All patients presented type IIb (Grauer classification) fractures, with a mean deviation of 2.95 mm. Two patients had subaxial lesions. The mean follow-up was 30 months. The mean time from trauma to surgery was seven days. The pre-operative Frankel score was E in all except one patient (B), in whom a post-operative improvement from B to D was observed. Post-operative pain was 2/10 (VAS). A total of 77% of patients presented a mild or moderate disability (NDI). Six patients regained full range of cervical movement, and bone union required approximately 14 weeks. Pseudarthrosis complications were observed in two patients (77% union rate), one patient presented screw repositioning and one case, dysphonia. Conclusion: Delayed diagnosis is still an issue in the treatment of odontoid fractures, especially in elderly patients. Concomitant lesions, especially in younger patients, are not uncommon. The literature presents high fusion rates with ORIF (>=80%), which was also observed in the present study. However, surgical success depends on proper patient selection and strict knowledge of the technique. This pathology presents a reserved functional prognosis in the medium-term, especially in the elderly. PMID- 30245991 TI - What is the role of core decompression in the early stages of osteonecrosis of the femoral head? Evaluation of the surgical result by functional score and radiological follow-up. AB - Objectives: This study is aimed at evaluating whether core decompression of the femoral head in the early stages of femoral head osteonecrosis improves patients' subjective perception of pain and avoids the progression of the disease to a femoral head collapse and a final indication of total hip arthroplasty. Methods: Eighteen patients (30 hips) in the early stages of the disease (Ficat and Arlet 1 and 2A) were evaluated through clinical, radiological, risk factor maintenance, and by the functional Merle D'Aubigne, and Postel score before and after core decompression of the femoral head. Results: There was an improvement of symptoms up to the sixth month in 83.3% of the hips evaluated through the Merle D'Aubigne and Postel score. However, 73.3% of the cases evolved with femoral head collapse, and in 50%, total hip arthroplasty was indicated regardless of whether or not the risk factors were maintained. Conclusions: Core decompression of the femoral head improves patients' pain early in the initial stages of the pathology. However, it does not alter the prognosis and the ultimate indication of total hip arthroplasty in the final stages of the disease. PMID- 30245992 TI - Comorbidities, clinical intercurrences, and factors associated with mortality in elderly patients admitted for a hip fracture. AB - Objective: To analyze comorbidities and clinical complications, and to determine the factors associated with mortality rates of elderly patients admitted with a hip fracture in a tertiary public hospital. Methods: Sixty-seven medical records were reviewed in a retrospective cohort study, including patients equal to or older than 65 years admitted to this institution for hip fracture between January 2014 and December 2014. The evaluated items constituted were the following: interval of time between fracture and hospital admission, time between admission and surgical procedure, comorbidities, clinical complications, type of orthopedic procedure, surgical risk, cardiac risk, and patient outcome. Results: The average patients' age in the sample was 77.6 years, with a predominance of the female gender. Most patients (50.7%) had two or more comorbidities. The main clinical complications during hospitalization included cognitive behavioral disorders, respiratory infection and of the urinary tract. The times between fracture and admission and between admission and surgery were more than seven days in most of cases. The mortality rate during hospitalization was 11.9%, and was directly connected to the presence of infections during hospital stay (p = 0.006), to time between admission and surgery longer than seven days (p = 0.005), to the Goldman Cardiac Risk Index class III (p = 0.008), and to age equal to or greater than 85 years (p = 0.031). Conclusion: Patients with hip fractures generally present comorbidities, are susceptible to clinical complications, and have an 11.9% mortality rate. PMID- 30245993 TI - Allograft of the knee extensor in cases of patellar tendon rupture in total arthroplasty patients. AB - Objective: Retrospective study to evaluate the functional results of patients with total knee arthroplasty and rupture of the patellar tendon, submitted to transplantation of the extensor knee apparatus with fresh frozen allograft. Method: Nine patients, operated between 2003 and 2015, with a minimum of one year of follow-up. All patients were reviewed by performing a functional evaluation using the Knee Society score. Preoperative values were compared with those of the final evaluation. Results: Mean survival was 2.7 +/- 1.9 years (14-1). The knee score improved from 38 +/- 4.5 to 70 +/- 8.5, and functional score from 30 +/- 6.5 to 90 +/- 3.5. Mean extension deficit was 5 (1-15). Mean range of motion was 80 (60-100). Conclusion: The use of allograft is a solution for extreme cases of patellar rupture after total knee arthroplasty, providing reasonable functional results and representing an alternative to knee arthrodesis. PMID- 30245994 TI - Evaluation of different commercial hyaluronic acids as a vehicle for injection of human adipose-derived mesenchymal stem cells. AB - Objective: The main purpose of this study is to evaluate, in vitro, the cytotoxicity of different commercial brands of hyaluronic acids to be used as a vehicle for injection of human adipose-derived mesenchymal stem cells (AD-MSCs). Methods: AD-MSCs were divided into seven groups: one control group where AD-MSCs were cultivated with phosphate-buffered saline (PBS) and six other groups where AD-MSCs were cultivated with different commercial brands of hyaluronic acid. AD MSC viability analysis was performed after 4, 24, and 48 h in contact with each treatment, using the trypan staining method on a Countess automated cell counter (Thermo Fisher Scientific). Results: The results clearly demonstrated a significant difference in cell viability when AD-MSCs were exposed to different hyaluronic acids when compared with the control group. Conclusion: These data suggest that hyaluronic acid can be used as a vehicle for injection of human AD MSCs, but caution is needed to choose the best product, aiming at its future therapeutic application. PMID- 30245995 TI - Biomechanical analysis of a double fixation method for tendon graft in porcine tibia - using an interference screw plus staple. AB - Objective: The aim of the study was to compare the mechanical behavior of interference screw tibial fixation vs. screw-plus-staple tibial fixation in an animal model. Methods: Thirty-six pieces of swine knee specimens were selected and divided into two groups: Group 1, tibial fixation with interference screw (n = 17), and Group 2, fixation with interference screw and staple (n = 19). The models were submitted to a single cycle of tension testing. The following variables were measured: graft cross-sectional area, failure point on 10 mm (F10), yield load (Fy), and stiffness. Results: The mean values of graft cross sectional area, F10, Fy, and stiffness did not present significant differences between the groups. Conclusion: The addition of a second staple-type ligament fixation device, complementing the interference screw, did not increase the mechanical safety of the system. PMID- 30245996 TI - Outcomes of medial patellofemoral ligament reconstruction in patients with patella alta. AB - Objective: To compare the clinical outcomes and the results of knee functional scores in patients with normal patellar height and patella alta who underwent isolated medial patellofemoral ligament reconstruction. Methods: A total of 37 knees from 33 patients with recurrent patellar dislocation who underwent isolated medial patellofemoral ligament reconstruction were included. Retrospectively, the postoperative clinical results were compared using the Kujala and Lysholm scores in the group of patients with normal patellar height and in those with patella alta. Results: The sample consisted of 37 patients; 16 knees of 14 patients in the group with normal patellar height, 21 knees of 19 patients in the group with patella alta. In the first group, the mean Kujala score was 85.8 and the mean Lysholm score was 85.6. In the second, the mean Kujala score was 78.1 and the mean Lysholm score was 79.7. No significant differences were observed between the groups in relation to the Lysholm (p = 0.296) and Kujala scores (p = 0.181). Conclusion: Isolated medial patellofemoral ligament reconstruction presented similar results in patients with normal patellar height and patella alta. PMID- 30245997 TI - Anterior interosseous nerve: anatomical study and clinical implications. AB - Objective: The goal of this study was to describe anatomical variations and clinical implications of anterior interosseous nerve. In complete anterior interosseous nerve palsy, the patient is unable to flex the distal phalanx of the thumb and index finger; in incomplete anterior interosseous nerve palsy, there is less axonal damage, and either the thumb or the index finger are affected. Methods: This study was based on the dissection of 50 limbs of 25 cadavers, 22 were male and three, female. Age ranged from 28 to 77 years, 14 were white and 11 were non-white; 18 were prepared by intra-arterial injection of a solution of 10% glycerol and formaldehyde, and seven were freshly dissected cadavers. Results: The anterior interosseous nerve arose from the median nerve, an average of 5.2 cm distal to the intercondylar line. In 29 limbs, it originated from the nerve fascicles of the posterior region of the median nerve and in 21 limbs, of the posterolateral fascicles. In 41 limbs, the anterior interosseous nerve positioned between the humeral and ulnar head of the pronator teres muscle. In two limbs, anterior interosseous nerve duplication was observed. In all members, it was observed that the anterior interosseous nerve arose from the median nerve proximal to the arch of the flexor digitorum superficialis muscle. In 24 limbs, the branches of the anterior interosseous nerve occurred proximal to the arch and in 26, distal to it. Conclusion: The fibrous arches formed by the humeral and ulnar heads of the pronator teres muscle, the fibrous arch of the flexor digitorum superficialis muscle, and the Gantzer muscle (when hypertrophied and positioned anterior to the anterior interosseous nerve), can compress the nerve against deep structures, altering its normal course, by narrowing its space, causing alterations longus and flexor digitorum profundus muscles. PMID- 30245998 TI - APSI scaphoid hemiarthroplasty - long-term results. AB - Objective: This study is aimed at evaluating the long-term results of proximal scaphoid hemiarthroplasty for post-traumatic avascular necrosis at this institution. Methods: Twelve patients who underwent this procedure were identified, and the mean follow-up time was 6.5 years (range: 5-8 years). All patients were male, with a mean age of 39 years (range: 28-55 years). In eight patients, the non-dominant limb was affected. The procedure was carried out through a dorsal approach and all patients underwent the same rehabilitation protocol. Cases were evaluated regarding complications, pain, range of motion, functional status (Mayo Wrist Score), and disability (QuickDASH Score). Results: No immediate post-operative complications, such as infection or dislocation of the implant, were observed. All patients presented with peri-implant osteolysis at follow-up, on a radiograph study. None of the patients was forced to abandon their previous professional activity, although about 50% required some type of adaptation at their workplace. The mean functional capacity was, according to the Mayo Wrist Score, of 67.5 points (range: 50-80), corresponding to a satisfactory degree of function. The QuickDASH disability score presented a mean of 25 (range: 3-47.7). Conclusion: The results of this series are in line with previously published studies about this technique. Hemiarthroplasty with a pyrocarbon implant is a safe technique for the treatment of post-fracture avascular necrosis of the scaphoid proximal pole. This technique allowed for satisfactory functional results at a mean follow-up of 6.5 years. PMID- 30245999 TI - Biometric, histomorphometric, and biochemical profile in atorvastatin calcium treatment of female rats with dexamethasone-induced osteoporosis. AB - Objective: To assess the effects of atorvastatin calcium in the treatment of dexamethasone-induced osteoporosis. Methods: Osteoporosis induction consisted of the administration of an intramuscular dose of 7.5 mg/kg of body weight of dexamethasone, once a week for four weeks, except for the control animals (G1). The animals were divided into the following groups: G1 (control group without osteoporosis), G2 (control group with untreated osteoporosis), G3 (control group with osteoporosis treated with sodium alendronate 0.2 mg/kg) and G4 (group with osteoporosis treated with atorvastatin calcium 1.2 mg/kg). Serum alkaline phosphatase, bone alkaline phosphatase, and biometric and bone histomorphometric assessments were performed after 30 and 60 days of treatment onset. Results: In relation to the biometric and histomorphometric analyses, at 60 days of treatment, G4 presented bone density (Seedor index), bone trabecular density, and cortical thickness of 0.222 +/- 0.004 g/cm, 59.167 +/- 2.401%, and 387,501 +/- 8573 MUm, respectively, with a positive and statistically significant difference (p < 0.05), in relation to G2. At 30 and 60 days of treatment, G4 presented statistically significant serum levels of alkaline phosphatase alkaline phosphatase (p < 0.05) that were higher than all groups (7.451 +/- 0.173 MUg/L and 7.473 +/- 0.529 MUg/L, respectively). Conclusion: Treatment with atorvastatin calcium demonstrated the ability of this drug to increase osteoblastic activity and bone tissue repair activity, acting differently from alendronate sodium, which demonstrated predominantly antirebsorptive activity. PMID- 30246000 TI - Comparison of the effects of volemic reposition with 7.5% NaCl or blood in an experimental model of muscular compression and hemorrhagic shock. AB - Objective: Crush syndrome is characterized by traumatic muscular injuries with severe systemic clinical repercussions. The systemic inflammatory reaction characterized acutely by infiltration of neutrophils in the lungs has been studied as part of the spectrum of crush syndrome. Experimental research may demonstrate alternative treatments for crush syndrome. The authors studied the hypothesis that hypertonic saline solution (7.5% NaCl) could minimize the local and systemic effects in a model of muscular compression and hemorrhagic shock. Methods: Rabbits were submitted to a new model of muscle compression associated with hemorrhagic shock. Compression was applied through an Esmarch bandage, used for 1 h on the entire right lower limb. Hemorrhagic shock was induced for 1 h by dissection and catheterization of the carotid artery. Blood replacement or hypertonic saline solution was used to treat the shock. Biochemical analysis of plasma, quantification of muscular edema, and infiltration of inflammatory cells in the lungs were carried out. Results: Animals treated with hypertonic solution presented the same hemodynamic response as the blood treated patients, less water in the compressed muscles and less infiltration of inflammatory cells in the lungs. The blood group presented hypocalcemia, a facet of crush syndrome. Conclusions: The proposed model was effective for the study of crush syndrome associated with hemorrhagic shock. The treatment with hypertonic solution showed benefits when compared with blood volume replacement. PMID- 30246001 TI - NOVEL CELLULAR STAINING PROTOCOL AND ANTIPROLIFERATIVE EFFECT OF VERNONIA AMYGDALINA DELILE ON LUNG AND PROSTATE CANCER CELLS. AB - There is a critical need for more effective therapeutic approaches for cancer. Vernonia amygdalina Delile (VAD) has been used in African traditional medicine for the prevention and/or treatment of several diseases including diarrhea, intestinal illnesses, and cancer. However, the effects of VAD on human lung cancer and human prostate cancer cells remain largely unknown. The aim of this study was to explore a novel cellular staining protocol using acridine orange/propidium iodide (AO/PI) and to test the antiproferative activity of VAD against human lung cancer (A-549) cells and human prostate cancer (PC-3) cells. Our studies demonstrate that VAD inhibits the proliferation of both A-549 and PC 3 cells in a dose-dependent manner. This finding suggests that VAD may be useful in lung and prostate cancer prevention. However, further research is needed to elucidate the chemopreventive effects of VAD against cancer. PMID- 30246002 TI - A Systematic Review of the Efficacy and Safety of Fecal Microbiota Transplant for Clostridium difficile Infection in Immunocompromised Patients. AB - Background: Fecal microbiota transplantation (FMT) has been shown to be effective in recurrent Clostridium difficile (CD) infection, with resolution in 80% to 90% of patients. However, immunosuppressed patients were often excluded from FMT trials, so safety and efficacy in this population are unknown. Methods: We searched MEDLINE and EMBASE for English language articles published on FMT for treatment of CD infection in immunocompromised patients (including patients on immunosuppressant medications, patients with human immunodeficiency virus (HIV), inherited or primary immunodeficiency syndromes, cancer undergoing chemotherapy, or organ transplant, including-bone marrow transplant) of all ages. We excluded inflammatory bowel disease patients that were not on immunosuppressant medications. Resolution and adverse event rates (including secondary infection, rehospitalization, and death) were calculated. Results: Forty-four studies were included, none of which were randomized designs. A total of 303 immunocompromised patients were studied. Mean patient age was 57.3 years. Immunosuppressant medication use was the reason for the immunocompromised state in the majority (77.2%), and 19.2% had greater than one immunocompromising condition. Seventy-six percent were given FMT via colonoscopy. Of the 234 patients with reported follow up outcomes, 207/234 (87%) reported resolution after first treatment, with 93% noting success after multiple treatments. There were 2 reported deaths, 2 colectomies, 5 treatment-related infections, and 10 subsequent hospitalizations. Conclusion: We found evidence that supports the use of FMT for treatment of CD infection in immunocompromised patients, with similar rates of serious adverse events to immunocompetent patients. PMID- 30246003 TI - Anaphylactic Shock During Pediatric Anesthesia: An Unexpected Reaction to Sevoflurane. AB - During general anesthesia, while muscle relaxants, latex and antibiotics are normally considered as very common causes of anaphylactic reactions, there are no documented cases of anaphylaxis due to inhalational agents. We report the case of a 6-year-old child scheduled for adenotonsillectomy who had an anaphylactic shock reaction due to Sevoflurane. Several allergic tests were performed to detect the trigger. Drugs used during operation were tested on both patient and three matched controls. While controls were negative, the patient displayed a positive reaction to Sevoflurane. To our knowledge, this is the first published report describing an allergic reaction caused by a volatile anesthetic. PMID- 30246004 TI - Vitamin D and IL-10 Deficiency in Preterm Neonates With Bronchopulmonary Dysplasia. AB - Introduction: Vitamin D deficiency and inflammation are involved with bronchopulmonary dysplasia (BPD) in preterm neonates; however, the clinical evidence still remains scarce. We hypothesized that vitamin D and inflammatory cytokines may be risk factors for BPD in infants. Methods: Preterm infants born between 28 and 31 weeks' gestation were recruited between January 2016 and 2017. Blood samples were all collected at corresponding time points. Vitamin D was measured using an automatic biochemical analyzer, and inflammatory cytokines (TNF alpha, IL-1beta, IL-6, and IL-10) were measured using ELISA. Results: The baseline characteristics for preterm infants without BPD (non-BPD control, n = 20) or with BPD (n = 19) were similar. In the blood samples collected 24-h post birth, vitamin D was significantly reduced in the BPD neonates (non-BPD vs. BPD, 28.96 +/- 3.404 vs. 17.99 +/- 2.233 nmol/l, p = 0.0134). Inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 were comparable in both groups. The anti inflammatory cytokine IL-10, however, was significantly decreased in 24-h blood samples from BPD preterm infants (non-BPD vs. BPD, 44.61 +/- 10.48 vs. 11.64 +/- 2.351 pg/ml, p = 0.0054). In the BPD infants with mild or moderate disease, vitamin D deficiency was quite similar. IL-10 deficiency, however, was more aggravated in the BPD infants with moderate disease. No changes in Vitamin D or cytokines (TNF-alpha, IL-1beta, IL-6, and IL-10) were observed for blood samples collected 2 or 4 weeks after birth. Conclusion: In our pilot study, Vitamin D and IL-10 levels at 24-h of life were risk factors for the development of BPD in very preterm infants. PMID- 30246005 TI - Sino-Australian University Partnership in Health Management Education. AB - This paper outlines a successful partnership program between La Trobe University in Melbourne Australia, and Harbin Medical University in Harbin, China. These two universities have been collaborating for more than 15 years to provide a comprehensive Master of Health Administration program that adapts the Australian curriculum to meet the rapidly increasing need for qualified health services managers throughout China. This paper describes the mechanisms by which the joint programs were developed and how the two universities work together in partnership to continually improve the program components and outcomes, taking into account the significant differences in context and cultures. Since 2001, La Trobe University has enrolled about 1000 Chinese health services managers, with 721 completing a Master's degree, who are now having increasing influence on the reforms of the Chinese health care system. The partnership has enriched Australian knowledge of Chinese culture and values, as well as the Chinese health system and health policies, as evidenced by the large volume of joint publications. The profession of health management has been substantially strengthened in China, and working together, Chinese and Australian academics have had demonstrated impact on enhancing the reforms of the Chinese public health system. Further studies, with sufficient funds for data collection, are needed to evaluate the long-term impacts of transnational programs on academic and health system development in China. PMID- 30246006 TI - Inverting Thermal Degradation ( iTD) of Paper Using Chemi- and Physi-Sorbed Modifiers for Templated Material Synthesis. AB - Fibrous cellulosic materials have been used as templates for material synthesis or organization via thermal degradation of the cellulose. Most of these methods, however, fail to exploit fiber organization, in part due to loss of structure with processing. Herein, we demonstrate that chemi- and physi-sorbed modifiers of cellulose alters the thermal degradation mechanism allowing for controlled deposition of oxide and carbon (incomplete combustion) along the original paper fiber network. We demonstrate that the degradation of the cellulose fibers depends on the amount of physisorbed material due, in part, to effect on the propagation of the ignition event. From the distribution of the residual elements and shape of the deposits, we can infer that the thermal degradation process depends on the nature, and concentration, of filler(s) or occluded. PMID- 30246007 TI - Easily Tunable Membrane Thickness of Microcapsules by Using a Coordination Assembly on the Liquid-Liquid Interface. AB - A model solvent, 1,3,5-trimethylbenzene, was encapsulated using coordination assembly between metal ions and tannic acid to reveal the deposition of coordination complexes on the liquid-liquid interface. The deposition was confirmed by zeta potential, energy dispersive spectroscopy and X-ray photoelectron spectroscopy. Scanning electron microscopy and transmission electron microscopy were integrated to characterize the microcapsules (MCs). According to atomic force microscopy height analysis, membrane thickness of the MCs increased linearly with sequential deposition. For MCs prepared using the Fe3+-TA system, the average membrane thicknesses of MCs prepared with 2, 4, 6, and 8 deposition cycles were determined as 31.3 +/- 4.6, 92.4 +/- 15.0, 175.4 +/- 22.1, and 254.8 +/- 24.0 nm, respectively. Dissolution test showed that the release profiles of all the four tested MCs followed Higuchi kinetics. Membrane thicknesses of MCs prepared using the Ca2+-TA system were much smaller. We can easily tune the membrane thickness of the MCs by adjusting metal ions or deposition cycles according to the application requirements. The convenient tunability of the membrane thickness can enable an extensive use of this coordination assembly strategy in a broad range of applications. PMID- 30246008 TI - Urea-Doped ZnO Films as the Electron Transport Layer for High Efficiency Inverted Polymer Solar Cells. AB - In this paper, urea-doped ZnO (U-ZnO) is investigated as a modified electron transport layer (ETL) in inverted polymer solar cells (PSCs). Using a blend of Poly{4,8-bis[(2-ethylhexyl)oxy] benzo [1,2-b:4,5-b'] dithiophene-2,6-diyl-alt-3 fluoro-2-[(2-ethylhexyl)carbonyl] thieno [3,4-b] thiophene-4,6-diyl}(PTB7), and [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) as light absorber, a champion power conversion efficiency (PCE) of 9.15% for U-ZnO ETL based PSCs was obtained, which is 15% higher than that of the pure ZnO ETL based PSCs (7.76%). It was demonstrated that urea helps to passivate defects in ZnO ETL, resulting in enhanced exciton dissociation, suppressed charge recombination and efficient charge extraction efficiency. This work suggests that the utilization of the U ZnO ETL offer promising potential for achieving highly efficient PSCs. PMID- 30246010 TI - EUPATI and Patients in Medicines Research and Development: Guidance for Patient Involvement in Ethical Review of Clinical Trials. AB - Involvement of patients in the research and development process (R&D) of new medicines-in all areas of indications-today is a widely accepted strategy in pharmaceutical industry to ensure relevance and suitability of the treatment under development. This may consist in, but is not limited to, patient input to achieve more patient-friendly protocol design, endpoint, and comparator selection as well as disease-adapted study conditions in a pre- or post-marketing clinical trial. Ethical aspects and especially the balance of benefit and risk in a clinical trial are frequently judged differently by clinical researchers, regulators, ethics committees, and patients due to their different focus. The final assessment of the ethical aspects of a planned clinical trial is provided by an independent ethics committee consisting of physicians and other experts in healthcare and clinical trial methodology as well as of lay persons. The participation of patients in ethics committees is a much-discussed concept, its suitability disputed in many countries, and only limited experience on best practices is available. In order to be effective and yield the best results for all stakeholders, integration of patients into the medicines development process needs to be structured and governed by clear, mutually agreed rules and modes of operation. Communication and collaboration processes need to be systematically implemented to establish transparency, trust and respect between those developing new medicines and their users, respectively between those involved in design and approval of clinical trials and participants. In particular agreement on the ethical aspects of a clinical trial and/or its overall ethical acceptability is a prerequisite before the start of a clinical trial. Existing codes of practice for patient involvement with various stakeholders do not comprehensively cover the full scope of R&D, with the exception of more general statements on interaction. Overarching guidance on meaningful and ethical interaction is missing. One specific aim of the European Patients' Academy on Therapeutic Innovation (EUPATI) was to close this gap through the development of guidance documents for ethics committees, pharmaceutical industry-led medicines R&D, regulatory authorities, and health technology assessment (HTA). This EUPATI "Guidance for patient involvement in ethical review of clinical trials" gives practical recommendations for ground rules and lists options for conditions and practices for involving patients in the work of ethics committees to enable trustful and constructive collaboration whatever the national (legal) framework for patient involvement in ethics committees might be. The guidance sets the collaboration of patients in ethics committees in the broader context of relevance and opportunities for patient input on ethics in the overall medicines R&D and specifically the overall clinical trial process from concept development to trial result reporting in lay summaries. In addition to a presentation of the full text of the Guidance, this article aims at providing additional background information on the development process of the Guidance, as well as insight into the current debate on this topic. PMID- 30246011 TI - Changes in Plasma Metabolites Concentrations in Obese Dogs Supplemented With Anti oxidant Compound. AB - The aim of this study is to discuss the effect of anti-oxidant supplement (Rv PEM01-99, Kibun Foods, Inc., Tokyo, Japan) on changes in energy metabolism in obese dogs. 200 mg/kg/day of Rv-PEM01-99 (equivalent to 5 mg kg/day of quercetin derivative) were applied for 6 weeks to the Beagle dogs fed high fat diet (HFD) or control diet (CD). In the present study, body weight (BW) decreasing effect of Rv-PEM 01-99 in obese dogs was not clear. However, plasma alkaline phosphatase (ALP) activities at the end of experiment were significantly decreased compared to those at the start of experiment in obese dogs supplemented with Rv-PEM 01-99 (paired-t test, p < 0.05). In control dogs supplemented with Rv-PEM 01-99, Plasma malondialdehyde (MDA), and triglycerides (TG) levels and lactate dehydrogenase (LDH) activities were significantly decreased compared to those at the start of experiment (paired-t test, p < 0.05). From these findings, Rv-PEM 01-99 seems to be not harmful for dogs. Anti-lipid peroxide effect and liver function improvement are expected in the dogs supplemented with Rv-PEM 01-99. PMID- 30246012 TI - Difference in Frequency and Distribution of Nodal Metastases Between Intermediate and High Risk Prostate Cancer Patients: Results of a Superextended Pelvic Lymph Node Dissection. AB - Objectives: To evaluate the frequency and distribution of pelvic nodes metastases, in intermediate-high risk prostate cancer (PCa) patients (pts), who underwent open radical prostatectomy (ORP) and superextended pelvic lymph node dissection (sePLND). Patients and Methods: We retrospectively evaluated 630 consecutive pts with clinically localized, intermediate-high risk PCa, treated with ORP and sePLND from 2009 to 2016 at a single institution. The sePLND always removed all nodal/fibro-fatty tissue of the internal iliac, external iliac, obturator, common iliac, and presacral regions. Results: Positive lymph nodes (LN+) were found in 133 pts (21.1%). The median number of removed nodes and LN+ was 25 and 1, respectively. LN+ were found in 64 (48.1%), 58 (43.6%), 53 (39.8%), 16 (12%), and 20 (15%) pts and were present as a single site in 27 (20.3%), 22 (16.5%), 20 (15%), 0, and 6 (4.5%) cases in the internal iliac, external iliac, obturator, common iliac, and presacral chain, respectively. An ePLND would have correctly staged 127 (95%) pts but removed all LN+ in only 97 (73%) pts. Presacral nodes harbored LN+ in 20 patients. Among them, 18 were high-risk patients. Moreover, all but 1 pts with common iliac LN+ were in high risk group. Conclusions: These results suggest that removal of presacral and common iliac nodes could be omitted in intermediate risk pts. However, a PLND limited to external iliac, obturator, and internal iliac region may be adequate for nodal staging purpose, but not enough accurate if we aim to remove all possible site of LN+ in high risk pts. PMID- 30246009 TI - Periconceptional Maternal Mediterranean Diet Is Associated With Favorable Offspring Behaviors and Altered CpG Methylation of Imprinted Genes. AB - Background: Maternal diet during pregnancy has been shown to influence the child neuro-developmental outcomes. Studies examining effects of dietary patterns on offspring behavior are sparse. Objective: Determine if maternal adherence to a Mediterranean diet is associated with child behavioral outcomes assessed early in life, and to evaluate the role of differentially methylated regions (DMRs) regulating genomically imprinted genes in these associations. Methods: Among 325 mother/infant pairs, we used regression models to evaluate the association between tertiles of maternal periconceptional Mediterranean diet adherence (MDA) scores derived from a Food Frequency Questionnaire, and social and emotional scores derived from the Infant Toddler Social and Emotional Assessment (ITSEA) questionnaire in the second year of life. Methylation of nine genomically imprinted genes was measured to determine if MDA was associated with CpG methylation. Results: Child depression was inversely associated with maternal MDA (Bonferroni-corrected p = 0.041). While controlling for false-discovery, compared to offspring of women with the lowest MDA tertile, those with MDA scores in middle and high MDA tertiles had decreased odds for atypical behaviors [OR (95% CI) = 0.40 (0.20, 0.78) for middle and 0.40 (0.17, 0.92) for highest tertile], for maladaptive behaviors [0.37 (0.18, 0.72) for middle tertile and 0.42 (0.18, 0.95) for highest tertile] and for an index of autism spectrum disorder behaviors [0.46 (0.23, 0.90) for middle and 0.35 (0.15, 0.80) for highest tertile]. Offspring of women with the highest MDA tertile were less likely to exhibit depressive [OR = 0.28 (0.12, 0.64)] and anxiety [0.42 (0.18, 0.97)] behaviors and increased odds of social relatedness [2.31 (1.04, 5.19)] behaviors when compared to low MDA mothers. Some associations varied by sex. Perinatal MDA score was associated with methylation differences for imprinted control regions of PEG10/SGCE [females: Beta (95% CI) = 1.66 (0.52, 2.80) - Bonferroni-corrected p = 0.048; males: -0.56 (-1.13, -0.00)], as well as both MEG3 and IGF2 in males [0.97 (0.00, 1.94)] and -0.92 (-1.65, -0.19) respectively. Conclusion: In this ethnically diverse cohort, maternal adherence to a Mediterranean diet in early pregnancy was associated with favorable neurobehavioral outcomes in early childhood and with sex-dependent methylation differences of MEG3, IGF2, and SGCE/PEG10 DMRs. PMID- 30246014 TI - Relationship Between Historical Lameness, Medication Usage, Surgery, and Exercise With Catastrophic Musculoskeletal Injury in Racehorses. AB - Background: The rate of catastrophic musculoskeletal injuries (CMI) in racehorses is high in the United States compared to other countries. Few modifiable risk factors related to lameness, medication, and surgery history have been identified. Objective: To detect management factors that increase risk of CMI by comparing medical histories between horses that sustained, and horses that did not sustain, a CMI. Study design: Case-control. Methods: Racehorse necropsy data (May 2012-June 2013) were obtained through the California Horse Racing Board Postmortem Program. Attending veterinarians of Thoroughbreds (TB) and Quarter Horses (QH) that experienced CMI, and of three matched control horses, were invited to complete an online veterinary medical history survey. We investigated associations between CMI and lameness, medication, surgery, and exercise history using multivariable logistic regression. Results: There were 146 TB (45 cases, 101 controls) and 17 QH (11 cases, 6 controls) surveys completed. TB cases were more likely to show signs of lameness within the 3 months prior to death compared to controls. A high proportion of both cases (64.3%) and controls (76.8%) were administered medications, but unraced TB case horses were more likely to have been administered systemic medications compared to those that previously raced. TB cases were more likely to have raced with greater intensity during their career, but had eased off in the month preceding CMI. For QHs, there was insufficient power to detect significant differences between cases and controls that showed signs of lameness, or that were administered medications. Surgery history was not associated with CMI. Main limitation: Insufficient power to detect small effect sizes. Conclusions: The study provides information that can be used to aid in identification of horses at high risk for catastrophic injury, and management factors that can be modified to reduce the risk for all horses. PMID- 30246013 TI - The Cancer Spliceome: Reprograming of Alternative Splicing in Cancer. AB - Alternative splicing allows for the expression of multiple RNA and protein isoforms from one gene, making it a major contributor to transcriptome and proteome diversification in eukaryotes. Advances in next generation sequencing technologies and genome-wide analyses have recently underscored the fact that the vast majority of multi-exon genes under normal physiology engage in alternative splicing in tissue-specific and developmental-specific manner. On the other hand, cancer cells exhibit remarkable transcriptome alterations partly by adopting cancer-specific splicing isoforms. These isoforms and their encoded proteins are not insignificant byproducts of the abnormal physiology of cancer cells, but either drivers of cancer progression or small but significant contributors to specific cancer hallmarks. Thus, it is paramount that the pathways that regulate alternative splicing in cancer, including the splicing factors that bind to pre mRNAs and modulate spliceosome recruitment. In this review, we present a few distinct cases of alternative splicing in cancer, with an emphasis on their regulation as well as their contribution to cancer cell phenotype. Several categories of splicing aberrations are highlighted, including alterations in cancer-related genes that directly affect their pre-mRNA splicing, mutations in genes encoding splicing factors or core spliceosomal subunits, and the seemingly mutation-free disruptions in the balance of the expression of RNA-binding proteins, including components of both the major (U2-dependent) and minor (U12 dependent) spliceosomes. Given that the latter two classes cause global alterations in splicing that affect a wide range of genes, it remains a challenge to identify the ones that contribute to cancer progression. These challenges necessitate a systematic approach to decipher these aberrations and their impact on cancer. Ultimately, a sufficient understanding of splicing deregulation in cancer is predicted to pave the way for novel and innovative RNA-based therapies. PMID- 30246015 TI - Prevalence of Stress and Associated Factors among Regular Students at Debre Birhan Governmental and Nongovernmental Health Science Colleges North Showa Zone, Amhara Region, Ethiopia 2016. AB - Background: Stress is very common among medical students across the globe with the prevalence of 80%. In Ethiopia, the prevalence is 47.7% among college students. Unless it is managed early, it leads to deterioration of academic performance and overall dissatisfaction with life and different serious health problems including anxiety, depression, and suicide. The objective of this study is to assess the prevalence of academic related stress among Debre Birhan governmental and nongovernmental health science college regular students 2015/16. Method: A cross-sectional study was conducted on a sample of 422 health science students selected by stratified proportional random sampling at Debre Birhan governmental and nongovernmental health science colleges in North Shewa zone, Amhara region, Ethiopia in 2016. Data was collected using the Depression Anxiety Stress Scaling (DASS-21). The level of significance of association for multivariable was determined at P value <0.05. Result: Prevalence of stress among Debre Birhan governmental and nongovernmental health science college regular students is 4.1%. There is a significant association between stress and sex AOR = 8.525 (1.023, 71.077), fear of examination AOR = 5.096 (1.183, 21.96), living in uncomfortable environment AOR = 14.86 (3.84, 57.515), and perceived present illness AOR = .030 (0.003, 0.286). Depression and anxiety were also seen among 19.7% and 23.6%, respectively. Conclusion: According to this study, the prevalence of stress among governmental and nongovernmental health science college regular students is not high. However, depression and anxiety were found to be higher than stress and they need immediate management plan. Colleges had better prepared simple screening tool and support students to prevent stress before they cause severe mental health problems. PMID- 30246016 TI - A Randomized, Double-Blind, Controlled Clinical Study on the Curative Effect of Huaier on Mild-to-Moderate Psoriasis and an Experimental Study on the Proliferation of Hacat Cells. AB - The antitumor effects of Huaier have been recently revealed. However, no research has been conducted on the effects of Huaier on keratinocyte proliferation and for the treatment of psoriasis. Hacat cells were treated with different concentrations of Huaier for different periods of times. The effects on cell proliferation and vitality and on the cell cycle were detected. Patients with mild-to-moderate psoriasis were randomized and divided into two groups in a double-blind manner. The experimental group was given sugar-free Yinxie granules and Huaiqihuang (HQH) granules, and the control group was given sugar-free Yinxie granules and placebo. After 4 weeks, various therapeutic indexes were compared. Huaier significantly inhibited Hacat cell proliferation, suppressed vitality, and blocked the cell cycle in the G1 phase compared with the control group (P < 0.01, respectively). After treatment for 4 weeks, the number of patients between the two groups that experienced a 50% reduction in the Psoriasis Area and Severity Index (PASI 50), PASI 75 and PASI 90, was significantly different (P <0.01). The body surface area (BSA) affected by psoriasis and static physician's global assessment (sPGA) was significantly reduced (P < 0.01); additionally, a significant improvement in the Dermatology Life Quality Index (DLQI) (P < 0.01) was observed. Huaier has shown promising effects in both clinical and experimental setting in this preliminary study and it might provide some benefit in the treatment of psoriasis vulgaris in the future. PMID- 30246017 TI - Single Dose Based Ertapenem Prophylaxis Reduces Surgical Site Infection after Selective Hepatectomy of Hepatocellular Carcinoma: A Propensity Score Matching Study. AB - Objective: This study aimed to assess whether a single dose of ertapenem prophylaxis was more effective than other antibiotics to prevent surgical site infection (SSI) after selective hepatectomy for hepatocellular carcinoma (HCC). Methods: The data from HCC patients with open hepatectomy between January 2012 and June 2017 in Shengjing Hospital were retrospectively analyzed. These patients were divided into two groups: ertapenem (ER) group, where a single dose of ER was administered; non-ertapenem (NER) group, where NER antibiotics were administered. The SSI rates were compared between two groups before and after matching the propensity scores. Results: The enrolled patients consisted of 78 in the ER group and 197 in the NER group. After matching the propensity scores, each group was down-selected to 65 patients. The SSI rate among the matched 130 patients was 14.6%, 7.7% occurred in the ER group and 21.5% in the NER group (P<0.05). The SSI rates in organ/space of the ER and NER groups were 3.1% and 13.8%, respectively (P<0.05). Conclusions: A single dose of ER before surgery was more effective in mitigating SSI after selective hepatectomy compared with other antibiotics use. The results imply that the selection of both antibiotics and administration timing is important for the efficacy in preventing SSI. PMID- 30246018 TI - Hypoxia Imaging and Biological Evaluation of the Radiosensitizing Effect of Oleanolic Acid. AB - Background and Purpose: The aim of this study was to evaluate the radiosensitizing effect of oleanolic acid (OA) on C6 rat glioma and the changes in tumor biology during radiosensitization therapy on 18F-fluoromisonidazole (18F FMISO) positron emission tomography/computed tomography (PET/CT). Methods: The radiosensitizing effect of OA on C6 tumors was assessed in vivo by measuring the tumor inhibitory rate and rat survival time. Meanwhile, rats with C6 tumors were imaged with 18F-FMISO PET/CT during radiosensitization therapy. Tumor-to-muscle ratio (TMR) of 18F-FMISO maximum uptake was calculated by region of interest analysis. Changes in tumor biology after therapy were assessed with immunohistochemical staining. 18F-FMISO uptake was analyzed in relation to expression of tumor biomarkers including hypoxia-inducible factor (HIF)-1alpha, glucose transporter (Glut-1), the proliferation antigen Ki67, tumor suppressor P53, and microvessel density (MVD). Results: The results showed that OA combined with radiation inhibited the growth rates of tumors and prolonged the survival period of tumor-bearing rats effectively (chi2 = 12.5, p < 0.01). 18F-FMISO PET/CT indicated decreases in hypoxia after radiosensitization therapy. Statistical differences were observed in TMR of the irradiation group and OA combined with irradiation group (t = 3.32, p < 0.05). HIF-1alpha, Glut-1, Ki67, P53, and MVD expressions in tumors were downregulated by OA combined with radiation as well as with radiation alone. Additionally, there was a significant positive linear correlation between TMR and HIF-1alpha, Glut-1, Ki67, P53, and MVD. Conclusions: These results suggest that OA has a radiosensitizing effect on C6 tumors in terms of tumor volume inhibition, survival extension, and multiple poor prognosis biological markers downregulation. 18F-FMISO PET/CT can be of value for tumor biology noninvasive capture and radiosensitization response evaluation. PMID- 30246020 TI - Modulation of Diabetes Mellitus-Induced Male Rat Reproductive Dysfunction with Micro-Nanoencapsulated Echinacea purpurea Ethanol Extract. AB - Diabetes mellitus is a major health problem that affects a patient's life quality throughout the world due to its worst complications. It was recognized that chronic hyperglycemia with oxidative stress was the major cause of male infertility. Echinacea purpurea ethanol extract (EE) contains phenolic acid and isobutylamides had been proven to ameliorate diabetic complications. Chitosan/silica nanoparticles are well-known in the medicinal field because of its controlled release and drug delivery properties. This study was aimed at investigating whether the EE encapsulated chitosan/silica nanoparticle (nano-EE) can enhance the amelioration of male infertility. Our results indicated that the average size of nano-EE was 218 +/- 42 nm with an encapsulation efficiency of 66.9% and loading capacity of 39.9%. The reduction in oxidative stress and antioxidant activity of nano-EE was observed in LC-540 cells. In in vivo experiment, 33 mg/kg of streptozotocin (STZ) was used to induce diabetes in male Sprague-Dawley rats. Diabetic rats were treated with nano (465 mg/kg), nano-EE 1 (93mg/kg), nano-EE3 (279mg/kg), nano-EE5 (465 mg/kg), and metformin (Met) (200 mg/kg) for 7 weeks. The results show that the nano-EE5 can improve hyperglycemia, insulin resistance, and plasma fibroblast growth factor 21 (FGF 21) resistance. It was also confirmed that nano-EE5 significantly improved the testis tissue structure, increasing sperm quality and DNA integrity as well as reducing reactive oxygen species level. PMID- 30246019 TI - Probiotics and Their Potential Preventive and Therapeutic Role for Cancer, High Serum Cholesterol, and Allergic and HIV Diseases. AB - The potential health benefits of probiotics have long been elucidated since Metchnikoff and his coworkers postulated the association of probiotic consumption on human's health and longevity. Since then, many scientific findings and research have further established the correlation of probiotic and gut-associated diseases such as irritable bowel disease and chronic and antibiotic-associated diarrhea. However, the beneficial impact of probiotic is not limited to the gut associated diseases alone, but also in different acute and chronic infectious diseases. This is due to the fact that probiotics are able to modify the intestinal microbial ecosystem, enhance the gut barrier function, provide competitive adherence to the mucosa and epithelium, produce antimicrobial substances, and modulate the immune activity by enhancing the innate and adaptive immune response. Nevertheless, the current literature with respect to the association of probiotic and cancer, high serum cholesterol, and allergic and HIV diseases are still scarce and controversial. Therefore, in the present work, we reviewed the potential preventive and therapeutic role of probiotics for cancer, high serum cholesterol, and allergic and HIV diseases as well as providing its possible mechanism of actions. PMID- 30246021 TI - Efficacy of Ingenol Mebutate in the Treatment of Actinic Keratoses: A Pre- and Posttreatment Dermoscopic Comparative Analysis. AB - Actinic keratosis (AK) is a common skin lesion in adults which usually occurs on chronically photoexposed areas and considered as a precancerous lesion or a superficial squamous-cell carcinoma. Many classifications have been proposed and its diagnosis is generally clinical but, sometimes, its wide variety of presentations can make diagnosis difficult, even among expert observers. The malignant potential of AKs imposes an early diagnosis and treatment in order to reduce morbidity and mortality, and, for the characterization of photodamaged skin, noninvasive diagnostic techniques, such as dermoscopy, have proved to be useful, while multiple therapeutic strategies, lesion-directed versus field directed therapies, are available for the treatment of AKs. In this study, we evaluated the efficacy of ingenol mebutate for the treatment of AKs, with a particular focus on patients' compliance, correlating it to clinical and dermoscopic grading, pre- and posttreatment, of these lesions. Fifty-two enrolled patients with AKs received treatment with ingenol mebutate gel (0.015% for face and scalp; 0.05% for trunk and extremities) and multiple dermatological evaluations. End points of the study were complete and partial clearance of clinically visible AKs on day 90. All acquired data were recorded and statistical analyses were performed. Univariate and multivariate analyses were used to identify possible predictive factors. We retrospectively analyzed patient-related and lesion-related factors to identify which variables, among age, gender, lesion site, pain, LSR score, and pretreatment clinical and dermoscopic grading, could independently predict the response to ingenol mebutate treatment. Our findings showed that pretreatment dermoscopic grade II represents an independent predictive factor of the efficacy of ingenol mebutate therapy (OR=14.78, 95% CI: 1.83-119.59, P=0.012) and that response rates differ on the basis of the treated anatomical sites (OR=0.16, 95% CI: 0.03-0.85, P=0.031). Data from this study provide evidence that ingenol mebutate gel is an effective treatment for AK, with relative ease of use, short exposure, and rapid resolution of local reactions, benefits contributing to high adherence of this therapy. Moreover, dermoscopic analysis of skin lesions offers more information than clinical evaluation alone and can be helpful in identifying different groups of AKs, thus selecting the adequate therapeutic choice. PMID- 30246022 TI - Sentinel Amenable Mortality: A New Way to Assess the Quality of Healthcare by Examining Causes of Premature Death for Which Highly Efficacious Medical Interventions Are Available. AB - Background: Amenable mortality, or premature deaths that could be prevented with medical care, is a proven indicator for assessing healthcare quality when adapted to a country or region's specific healthcare context. This concept is currently used to evaluate the performance of national and international healthcare systems. However, the levels of efficacy and effectiveness determined using this indicator can vary greatly depending on the causes of death that are included. We introduce a new approach by identifying a subgroup of causes for which there are available treatments with a high level of efficacy. These causes should be considered sentinel events to help identify limitations in the effectiveness and quality of health provision. Methods: We conducted an extensive literature review using a list of amenable causes of death compiled by Spanish researchers. We complemented this approach by assessing the time trends of amenable mortality in two high-income countries that have a similar quality of healthcare but very different systems of provision, namely, Spain and the United States. This enabled us to identify different levels of efficacy of medical interventions (high, medium, and low). We consulted a group of medical experts and combined this information to help make the final classification of sentinel amenable causes of death. Results: Sentinel amenable mortality includes causes such as surgical conditions, thyroid diseases, and asthma. The remaining amenable causes of death either have a higher complexity in terms of the disease or need more effective medical interventions or preventative measures to guarantee early detection and adherence to treatment. These included cardiovascular diseases, diabetes, hypertension, all amenable cancers, and some infectious diseases such as pneumonia, influenza, and tuberculosis. Conclusions: Sentinel amenable mortality could act as a good sentinel indicator to identify major deficiencies in healthcare quality and provision and detect inequalities across populations. PMID- 30246023 TI - Molecular Analysis and Modeling of Hepatitis E Virus Helicase and Identification of Novel Inhibitors by Virtual Screening. AB - The hepatitis E virus- (HEV-) helicase as a novel drug-target was evaluated. While cell culture model was used for mutational characterization of helicase, in silico protein modeling and virtual screening were employed to identify helicase inhibitors. None of the saturation mutant replicons significantly affected RNA replication. Notably, mutants encompassing the Walker motifs replicated as wild type, showing indispensability of nucleotides conservation in viability compared to known criticality of amino acids. A 3D modeling of HEV-helicase and screening of a compound dataset identified ten most promising inhibitors with drug likeness, notably, JFD02650, RDR03130, and HTS11136 that interacted with Walker A residues Gly975, Gly978, Ser979, and Gly980. Our model building and virtual identification of novel helicase inhibitors warrant further studies towards developing anti-HEV drugs. PMID- 30246024 TI - Ubiquitin-Mimicking Peptides Transfer Differentiates by E1 and E2 Enzymes. AB - Ubiquitin and ubiquitin like proteins (UBLs) play key roles in eukaryotes. These proteins are attached to their target proteins through an E1-E2-E3 cascade and modify the functions of these proteins. Since the discovery of ubiquitin, several UBLs have been identified, including Nedd8, SUMO, ISG15, and Atg8. Ubiquitin and UBLs share a similar three-dimensional structure: beta-grasp fold and an X-X [R/A/E/K]-X-X-[G/X]-G motif at the C-terminus. We have previously reported that ubiquitin, Nedd8, and SUMO mimicking peptides which all contain the conserved motif X-X-[R/A/E/K]-X-X-[G/X]-G still retained their reactivity toward their corresponding E1, E2, and E3 enzymes. In our current study, we investigated whether such C-terminal peptides could still be transferred onto related pathway enzymes to probe the function of these enzymes when they are fused with a protein. By bioinformatic search of protein databases, we selected eight proteins carrying the X-X-[R/A/E/K]-X-X-[G/X]-G motif at the C-terminus of the beta-grasp fold. We synthesized the C-terminal sequences of these candidates as short peptides and found that three of them showed significant reactivity with the ubiquitin E1 enzyme Ube1. We next fused the three reactive short peptides to three different protein frames, including their respective native protein frames, a ubiquitin frame and a peptidyl carrier protein (PCP) frame, and measured the reactivities of these peptide-fused proteins with Ube1. Peptide-fused proteins on ubiquitin and PCP frames showed obvious reactivity with Ube1. However, when we measured E2 UbcH7 transfer, we found that the PCP-peptide fusions lost their reactivity with UbcH7. Taken together, these results suggested that the recognition of E2 enzymes with peptide-fused proteins depended not only on the C terminal sequences of the ubiquitin-mimicking peptides, but also on the overall structures of the protein frames. PMID- 30246025 TI - Serum Stem Cell Growth Factor Beta for the Prediction of Therapy Response in Hepatocellular Carcinoma. AB - Introduction: Chronic inflammatory response is one of major contributors in the development of hepatocellular carcinoma (HCC). Inflammatory molecules, such as cytokines and growth factors in the circulation, can be useful in the diagnosis and prognosis of the patients. The stem cell growth factor beta (SCGFbeta), a newly found protein, is a secreted sulfated glycoprotein and it functions as a growth factor for primitive hematopoietic progenitor cells. The level of SCGFbeta had been reported to be elevated in several cancer types. However, there is very few or even no information on this protein in the study of HCC, even more in clinical studies. Methods: A multiplex immunoassay panel of 48 cytokines and growth factors were utilized to screen 68 sera from 29 HCC patients at pretreatment (T0), 1 month (T1), and 6 months (T6) after treatment by either radiofrequency ablation (RF) or transarterial chemoembolization (TACE). Treatment response was evaluated according to mRECIST criteria. Results: Immunoassay screening showed that the levels of IL-17, CTACK, TNFalpha, IL-2Ralpha, IL-8, and SCGFbeta were different in Complete Responders (CR) and Nonresponders (NR) groups. At T0 and T1, the SCGFbeta level was significantly the highest in NR (23.8 and 40.7 ng/mL, respectively), followed by early recurrence (25.4 and 25.0 ng/mL), and CR (6.7 and 5.3 ng/mL), independently from HCV, stages, and treatment type. Low basal SCGFbeta level was associated with longer disease-free survival compared to high SCGFbeta. Conclusion: In this study, for the first time, we demonstrate that the high level of serum SCGFbeta at pre- and posttreatment is associated with HCC nonresponsiveness. PMID- 30246027 TI - Eradication of HCV in Renal Transplant Recipients and Its Effects on Quality of Life. AB - Background: The use of direct antiviral agents (DAA) has radically modified the course of HCV hepatitis in renal patients. Aim of this study was to assess the effects of HCV eradication on quality of life (QOL) in renal transplant recipients (RTR), measured by CLDQ and SF-36. Methods: Sixteen RTR with well preserved GFR (mean: 60.3+/-19.3 ml/min) and chronic HCV infection with moderate liver stiffness (9.3+/-1.7 kPa) were given a sofosbuvir-based regimen for 12 weeks and had a 1 year follow-up. Results: At end of treatment (EOT) a complete viral clearance was observed in all the patients, with normalization of most laboratory data and a consistent reduction in liver stiffness. All these parameters remained stable after 1 year, as well as renal function and proteinuria. Questionnaire data showed consistent amelioration in different "emotional" domains at EOT, which persisted after 1 year and were associated with a globally improved QOL, although there was no change in most of the "physical" domains in both questionnaires. One patient under ribavirin developed an acute anemia and withdrew from the study, but no further adverse episode was observed throughout the study. Conclusions: Our data, while confirming the efficacy of oral DAA, show that HCV infection represents a heavy psychological burden in renal transplant recipients, greatly alleviated by viral eradication, which determines a significant improvement in QOL that represents an important outcome in management of all transplant recipients. This trial is registered with ISRCTN97560076. PMID- 30246026 TI - Pharmacological Management of Diabetic Macular Edema in Real-Life Observational Studies. AB - Objectives of the Study: of observational studies concerning the pharmacological management of diabetic macular edema (DME). Methods: A literature review was conducted using the PubMed database on 1 February 2018 to identify studies evaluating the efficacy of anti-VEGF and dexamethasone (DEX) implants for DME. Studies with more than 10 patients and follow-up of more than 6 months were selected. Analyses were carried out on the overall population and on subgroups defined according to baseline visual acuity (BVA) and the patients' naive or non naive status. Results: Thirty-two studies evaluating the efficacy of anti-VEGF and 31 studies evaluating the efficacy of DEX-implants were retained, concerning 6,842 and 1,703 eyes, respectively. A mean gain of +4.7 letters for a mean of 5.8 injections (mean follow-up: 15.6 months) and +9.6 letters for a mean of 1.6 injections (10.3 months) was found in the anti-VEGF and DEX-implant studies, respectively. Final VA appears to be similar for both treatment (62 letters for anti-VEGF, 61.2 letters for DEX-implant), and BVA appears lower for DEX-implant, which may partially explain the greater visual gain. The DEX-implant studies show greater gains in VA compared to the anti-VEGF studies, especially for higher BVA. Indeed, mean gains for the subgroups of patients with BVA<50 letters, 5060 letters are +4.3, +5.8, and +3.1 letters, respectively, in the anti-VEGF studies and +10.5, +9.3, and +8.8 letters, respectively, in the DEX implant studies. Regarding the patient's initial status, only naive status appears to confer the best functional response in DEX-implant studies. Conclusion: Observational studies investigating DEX-implant report clinically similar final VA when compared to anti-VEGF, but superior visual gains in real life practice. This latter difference could be due to the better BVA, but also to the fact that less injections were administered in the anti-VEGF observational studies than in the interventional studies. PMID- 30246028 TI - Cross-Protective Efficacy of Monovalent Live Influenza B Vaccines against Genetically Different Lineages of B/Victoria and B/Yamagata in Ferrets. AB - Background: Currently, two genetic lineages of influenza B virus, B/Victoria and B/Yamagata, are cocirculating in humans in various countries. This situation has raised a question regarding the possibility of cross-protection between B components of live attenuated influenza vaccine (LAIV) belonging to different lineages. This study aimed to assess in naive ferrets the potential protective activity of monovalent B-LAIVs against challenge with homologous and heterologous wild-type (WT) influenza B viruses. Methods: Groups of seronegative female ferrets 5-6 months of age were given one dose of monovalent LAIV based on B/Victoria or B/Yamagata lineage virus. Ferrets were challenged 21 days later with B/Victoria or B/Yamagata WT virus. Ferrets were monitored closely for clinical signs and morbidity outcomes including febrile response, body weight loss, nasal symptoms, and level of activity one week prior to vaccination and for three days following vaccination/challenge. Nasal washes were collected three days after vaccination/challenge. Samples of lung tissue were taken three days after challenge. All samples were analyzed for the presence of challenge virus by culturing in embryonated chicken eggs and real-time polymerase chain reaction. Antibody response to vaccination was assessed by routine hemagglutination inhibition assay and microneutralization test. Results: Vaccination led to intensive production of specific neutralizing and antihemagglutinating antibodies to vaccine virus, protected ferrets from homologous challenge infection, and significantly reduced clinical signs and replication of homologous challenge virus. In contrast, cross-lineage serum antibodies were not detected. However, ferrets vaccinated with monovalent B-LAIV had a significantly lower level of heterologous challenge virus in the respiratory tract than those given challenge virus only. Conclusions: Monovalent B-LAIV has the potential to be cross protective against infection with genetically different influenza lineages. Further studies are required to confirm this effect. PMID- 30246029 TI - PTPN2 Downregulation Is Associated with Albuminuria and Vitamin D Receptor Deficiency in Type 2 Diabetes Mellitus. AB - Objective: Inflammation plays a major role in albuminuria in type 2 diabetes mellitus (T2DM). Our previous studies have shown that the expression of vitamin D receptor (VDR) is downregulated in T2DM which is closely associated with the severity of albuminuria. In this study, we investigated the expression of anti inflammatory cytokine protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in T2DM and explored its relationship to albuminuria and VDR. Methods: 101 T2DM patients were divided into three groups based on urinary albumin-to-creatinine ratio (uACR): normal albuminuria (uACR < 30 mg/g, n = 29), microalbuminuria (30 mg/g <= uACR < 300 mg/g, n = 34), and macroalbuminuria (uACR >= 300 mg/g, n = 38). Thirty healthy individuals were included as controls. Serum was analyzed for PTPN2 and IL-6 expression, and peripheral blood mononuclear cells (PBMCs) were analyzed for PTPN2 and VDR expression. THP-1 cells were incubated with high glucose and further treated with or without paricalcitol, a vitamin D analog. The levels of PTPN2, VDR, IL-6, TNFalpha, and MCP-1 were analyzed. In addition, anti inflammatory activities of PTPN2 were further explored in THP-1 cells stimulated with high glucose after PTPN2 silencing or overexpression. Results: PTPN2 expression was downregulated in T2DM with the lowest level observed in macroalbuminuria patients. PTPN2 level positively correlated with VDR but negatively correlated with uACR and IL-6. When stimulated with high glucose, there was an increase in inflammatory factors and a decrease in PTPN2 expression. Treatment with paricalcitol reversed these effects. However, paricalcitol failed to exert anti-inflammatory effects in the setting of PTPN2 knockdown. Thus, low levels of PTPN2 aggravated glucose-stimulated inflammation, while high levels of PTPN2 reduced it. Conclusion: PTPN2, an anti-inflammatory factor regulated by VDR, was reduced in T2DM CKD stages 1-2. Taken together, our results suggest that therapeutic strategies that enhance PTPN2 may be beneficial for controlling inflammation in T2DM. PMID- 30246031 TI - Sex Differences in Correlation with Gene Expression Levels between Ifi200 Family Genes and Four Sets of Immune Disease-Relevant Genes. AB - Background: The HIN-200 family genes in humans have been linked to several autoimmune diseases-particularly to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Recently, its human counterpart gene cluster, the Ifi200 family in mice, has been linked to spontaneous arthritis disease (SAD). However, many immune-mediated diseases (including RA and SLE) show gender difference. Understanding whether or not and how these genes play a role in sex difference in immune-mediated diseases is essential for diagnosis/treatment. Methods: This study takes advantage of the whole genome gene expression profiles of recombinant inbred (RI) strain populations from female and male mice to analyze potential sex differences in a variety of genes in disease pathways. Expression levels and regulatory QTL of Ifi200 family genes between female and male mice were first examined in a large mouse population, including RI strains derived from C57BL/6J, DBA/2J (BXD), and classic inbred strains. Sex similarities and differences were then analyzed for correlations with gene expression levels between genes in the Ifi200 family and four selected gene sets: known immune Ifi200 pathway-related genes, lupus-relevant genes, osteoarthritis- (OA-) and RA relevant genes, and sex hormone-related genes. Results: The expression level of Ifi202b showed the most sex difference in correlation with known immune-related genes (the P value for Ifi202b is 0.0004). Ifi202b also showed gender difference in correlation with selected sex hormone genes, with a P value of 0.0243. When comparing coexpression levels between Ifi200 genes and lupus-relevant genes, Ifi203 and Ifi205 showed significant sex difference (P values: 0.0303 and 0.002, resp.). Furthermore, several key genes (e.g., Csf1r, Ifnb1, IL-20, IL-22, IL-24, Jhdm1d, Csf1r, Ifnb1, IL-20, IL-22, IL-24, and Tgfb2 that regulate sex differences in immune diseases) were discovered. Conclusions: Different genes in the Ifi200 family play different roles in sex difference among dissimilar pathways of these four gene groups. PMID- 30246032 TI - Two-Parametric Immunological Score Development for Assessing Renal Involvement and Disease Activity in Systemic Lupus Erythematosus. AB - Objective: Anti-double-stranded (ds) DNA and anti-C1q autoantibodies are useful tools in the assessment of disease activity and nephritis in systemic lupus erythematosus (SLE) patients. This study aimed to explore the utility of these antibodies along with anti-Ku antibodies in an oligoparametric model approach for the assessment of disease activity and lupus nephritis. Methods: Samples from 261 well-characterized SLE patients were tested using chemiluminescent immunoassays (CIA) for anti-dsDNA and anti-Ku antibodies as well as by anti-C1q antibody ELISA (Inova Diagnostics, USA). Of these SLE patients, 26.4% had lupus nephritis (LN) at the time of blood draw or had a history of LN, and modified SLE disease activity index-2K (SLEDAI) scores were used to assess disease activity. Results: All three antibodies demonstrated higher prevalence and higher antibody levels in active versus inactive SLE patients and in LN versus non-LN patients. When oligoparametric analysis was performed, the likelihood of LN and patients with active disease increased with dual and triple positivity. Conclusions: Anti-dsDNA and anti-C1q antibodies are useful tools to identify disease activity and/or renal involvement in SLE patients. In addition, the combination of those antibodies in a two-parametric score might improve the clinical utility of those markers. PMID- 30246030 TI - The Pattern of mRNA Expression Is Changed in Sinoatrial Node from Goto-Kakizaki Type 2 Diabetic Rat Heart. AB - Background: In vivo experiments in Goto-Kakizaki (GK) type 2 diabetic rats have demonstrated reductions in heart rate from a young age. The expression of genes encoding more than 70 proteins that are associated with the generation and conduction of electrical activity in the GK sinoatrial node (SAN) have been evaluated to further clarify the molecular basis of the low heart rate. Materials and Methods: Heart rate and expression of genes were evaluated with an extracellular electrode and real-time RT-PCR, respectively. Rats aged 12-13 months were employed in these experiments. Results: Isolated spontaneous heart rate was reduced in GK heart (161 +/- 12 bpm) compared to controls (229 +/- 11 bpm). There were many differences in expression of mRNA, and some of these differences were of particular interest. Compared to control SAN, expression of some genes were downregulated in GK-SAN: gap junction, Gja1 (Cx43), Gja5 (Cx40), Gjc1 (Cx45), and Gjd3 (Cx31.9); cell membrane transport, Trpc1 (TRPC1) and Trpc6 (TRPC6); hyperpolarization-activated cyclic nucleotide-gated channels, Hcn1 (HCN1) and Hcn4 (HCN4); calcium channels, Cacna1d (Cav1.3), Cacna1g (Cav3.1), Cacna1h (Cav3.2), Cacna2d1 (Cavalpha2delta1), Cacna2d3 (Cavalpha2delta3), and Cacng4 (Cav gamma 4); and potassium channels, Kcna2 (Kv1.2), Kcna4 (Kv1.4), Kcna5 (Kv1.5), Kcnb1 (Kv2.1), Kcnd3 (Kv4.3), Kcnj2 (Kir2.1), Kcnk1 (TWIK1), Kcnk5 (K2P5.1), Kcnk6 (TWIK2), and Kcnn2 (SK2) whilst others were upregulated in GK SAN: Ryr2 (RYR2) and Nppb (BNP). Conclusions: This study provides new insight into the changing expression of genes in the sinoatrial node of diabetic heart. PMID- 30246034 TI - Luteolin Induces Apoptosis and Autophagy in Mouse Macrophage ANA-1 Cells via the Bcl-2 Pathway. AB - Plants rich in luteolin have been used as Chinese traditional medicines for inflammatory diseases, hypertension, and cancer. However, little is known about the effect of luteolin on the apoptosis or autophagy of the macrophages. In this study, mouse macrophage ANA-1 cells were incubated with different concentrations of luteolin. The viability of the cells was determined by an MTT assay, apoptosis was determined by flow cytometric analysis, the level of cell autophagy was observed by confocal microscopy, and the expression levels of apoptotic or autophagic and antiapoptotic or antiautophagic proteins were detected by Western blot analysis. The results showed that luteolin decreased the viability of ANA-1 cells and induced apoptosis and autophagy. Luteolin induced apoptosis accompanied by downregulation of the expression of Bcl-2 and upregulation of the expression of caspase 3 and caspase 8. And luteolin increased FITC-LC3 punctate fluorescence accompanied by the increased expression levels of LC3-I, ATG7, and ATG12, while it suppressed the expression level of Beclin-1. Luteolin treatment resulted in obvious activation of the p38, JNK, and Akt signaling pathways, which is important in modulating apoptosis and autophagy. Thus, we concluded that luteolin induced the apoptosis and autophagy of ANA-1 cells most likely by regulating the p38, JNK, and Akt pathways, inhibiting the activity of Bcl-2 and Beclin-1 and upregulating caspase 3 and caspase 8 expression. These results provide novel insights into a therapeutic strategy to prevent and possibly treat macrophage related diseases through luteolin-induced apoptosis and autophagy. PMID- 30246033 TI - Caveolin-1-Knockout Mouse as a Model of Inflammatory Diseases. AB - Caveolin-1 (CAV1) is the scaffold protein of caveolae, which are minute invaginations of the cell membrane that are involved in endocytosis, cell signaling, and endothelial-mediated inflammation. CAV1 has also been reported to have a dual role as either a tumor suppressor or tumor promoter, depending on the type of cancer. Inflammation is an important player in tumor progression, but the role of caveolin-1 in generating an inflammatory milieu remains poorly characterized. We used a caveolin-1-knockout (CAV1-/-) mouse model to assess the inflammatory status via the quantification of the pro- and anti-inflammatory cytokine levels, as well as the ability of circulating lymphocytes to respond to nonspecific stimuli by producing cytokines. Here, we report that the CAV1-/- mice were characterized by a low-grade systemic proinflammatory status, with a moderate increase in the IL-6, TNF-alpha, and IL-12p70 levels. CAV1-/- circulating lymphocytes were more prone to cytokine production upon nonspecific stimulation than the wild-type lymphocytes. These results show that CAV1 involvement in cell homeostasis is more complex than previously revealed, as it plays a role in the inflammatory process. These findings indicate that the CAV1-/ mouse model could prove to be a useful tool for inflammation-related studies. PMID- 30246035 TI - Immunomodulatory Effects of 17beta-Estradiol on Epithelial Cells during Bacterial Infections. AB - The innate immune system can function under hormonal control. 17beta-Estradiol (E2) is an important sexual hormone for the reproductive cycle of mammals, and it has immunomodulatory effects on epithelial cells, which are the first line of defense against incoming bacteria. E2 regulates various pathophysiological processes, including the response to infection in epithelial cells, and its effects involve the regulation of innate immune signaling pathways, which are mediated through estrogen receptors (ERs). E2 modulates the expression of inflammatory and antimicrobial elements such as cytokines and antimicrobial peptides. The E2 effects on epithelial cells during bacterial infections are characterized by an increase in the production of antimicrobial peptides and by the diminution of the inflammatory response to abrogate proinflammatory cytokine induction by bacteria. Here, we review several novel molecular mechanisms through which E2 regulates the innate immune response of epithelial cells against bacterial infections. PMID- 30246036 TI - TLR3 Modulates the Response of NK Cells against Schistosoma japonicum. AB - Natural killer (NK) cells are classic innate immune cells that play roles in many types of infectious diseases. NK cells possess many kinds of TLRs that allow them to sense and respond to invading pathogens. Our previous study found that NK cells could modulate the immune response induced by Schistosoma japonicum (S. japonicum) in C57BL/6 mice. In the present study, the role of TLRs in the progress of S. japonicum infection was investigated. Results showed that the expression of TLR3 on NK cells increased significantly after S. japonicum infection by using RT-PCR and FACS (P < 0.05). TLR3 agonist (Poly I:C) increased IFN-gamma and IL-4 levels in the supernatant of cultured splenocytes and induced a higher percentage of IFN-gamma- and IL-4-secreting NK cells from infected mouse splenocytes (P < 0.05). Not only the percentages of MHC II-, CD69-, and NKG2A/C/E expressing cells but also the percentages of IL-4-, IL-5-, and IL-17-producing cells in TLR3+ NK cells increased significantly after infection (P < 0.05). Moreover, the expression of NKG2A/C/E, NKG2D, MHC II, and CD69 on the surface of splenic NK cells was changed in S. japonicum-infected TLR3-/- (TLR3 KO mice, P < 0.05); the abilities of NK cells in IL-4, IL-5, and IL-17 secretion were decreased too (P < 0.05). These results indicate that TLR3 is the primary molecule which modulates the activation and function of NK cells during the course of S. japonicum infection in C57BL/6 mice. PMID- 30246037 TI - Smart implants in orthopedic surgery, improving patient outcomes: a review. AB - Smart implants are implantable devices that provide not only therapeutic benefits but also have diagnostic capabilities. The integration of smart implants into daily clinical practice has the potential for massive cost savings to the health care system. Applications for smart orthopedic implants have been identified for knee arthroplasty, hip arthroplasty, spine fusion, fracture fixation and others. To date, smart orthopedic implants have been used to measure physical parameters from inside the body, including pressure, force, strain, displacement, proximity and temperature. The measurement of physical stimuli is achieved through integration of application-specific technology with the implant. Data from smart implants have led to refinements in implant design, surgical technique and strategies for postoperative care and rehabilitation. In spite of decades of research, with very few exceptions, smart implants have not yet become a part of daily clinical practice. This is largely because integration of current sensor technology necessitates significant modification to the implants. While the technology underlying smart implants has matured significantly over the last several decades, there are still significant technical challenges that need to be overcome before smart implants become part of mainstream health care. Sensors for next-generation smart implants will be small, simple, robust and inexpensive and will necessitate little to no modification to existing implant designs. With rapidly advancing technology, the widespread implementation of smart implants is near. New sensor technology that minimizes modifications to existing implants is the key to enabling smart implants into daily clinical practice. PMID- 30246039 TI - Comparison of KD3-M and KD3-L Multiligamentous Knee Injuries and Analysis of Predictive Factors That Influence the Outcomes of Single-Stage Reconstruction in KD3 Injuries. AB - Background: The knee dislocation-3 (KD3) injury pattern is the most common form of multiligamentous injury. Medial KD3 (KD3-M) and lateral KD3 (KD3-L) are 2 anatomically different varieties of this injury. Purpose: To compare the surgical outcomes of KD3-M and KD3-L multiligamentous knee injury patterns and to determine the factors that could influence the outcomes after single-stage reconstruction. Study Design: Cohort study; Level of evidence, 3. Methods: A cohort of 45 patients with multiligamentous knee injuries (31 KD3-M, 14 KD3-L) who were operated on between 2011 and 2015 were compared. The cruciate ligaments were reconstructed, and the collateral ligaments were managed either conservatively or surgically depending on intraoperative laxity, tissue condition, injury site, and chronicity. The mean follow-up was 36 months (range, 24-72 months). The International Knee Documentation Committee (IKDC) score, Lysholm score, knee flexion range of motion (ROM), and laxity on stress radiographs were compared. Various factors likely to influence the outcomes were also analyzed. Results: The mean IKDC score, Lysholm score, and knee flexion ROM for the 45 patients were 74.74, 87.66, and 126.78 degrees , respectively. There was no significant difference between the KD3-M and KD3-L groups in terms of the postoperative IKDC score (P = .768), Lysholm score (P = .689), knee flexion ROM (P = .798), and laxity on stress radiographs (P = .011). Patients with a transient dislocation had better outcomes (76.51, 89.41, and 128.61 degrees , respectively) than those with a frank dislocation (67.62, 80.66, and 119.44 degrees ) (P = .037, .007, and .043). The acute group had better outcomes (77.00, 89.51, and 127.86 degrees ) when compared with the subacute (66.26, 86.00, and 121.00 degrees ) and chronic groups (67.40, 76.40, and 125.00 degrees ) (P = .045, .006, and .486). Regression analysis showed the influence of these factors on outcomes. The presence or absence of dislocations, time frame in which surgery was performed, and follow-up duration were found to influence the outcome. All other factors had no bearing on outcomes. Two patients had knee stiffness and underwent arthrolysis. Conclusion: Despite anatomic and biomechanical differences between KD3-M and KD3-L injuries, single-stage management did not produce any significant difference in results. The presence of a frank dislocation, delay in surgery, and duration of follow-up were found to influence outcomes. PMID- 30246040 TI - Patient Perceptions of Surgeon Reimbursement for Rotator Cuff Repair. AB - Background: Previous studies in the arthroplasty, spine, and shoulder and elbow literature have shown that patients perceive Medicare reimbursement to surgeons to be much higher than current reimbursement schedules. Purpose: To evaluate patient perceptions of surgeon reimbursement for various rotator cuff repair (RCR) procedures. Study Design: Cross-sectional study. Methods: We surveyed 153 patients who presented to a single surgeon's orthopaedic sports medicine clinic between October 2016 and March 2017. Patients with a new complaint of hip or knee pain, those with a new complaint of shoulder pain, or those who had undergone shoulder surgery 1 year or more prior to their current visit were included. Patients were asked how much they thought surgeons should be reimbursed for RCR procedures, including arthroscopic repair of a simple tear and a massive tear as well as open repair of an acute tear and a chronic tear. They were also asked to estimate how much they thought surgeons were reimbursed by Medicare for these procedures. They were then given actual Medicare reimbursement rates for these procedures and asked whether they believed surgeons should be reimbursed that amount. Results: For arthroscopic repair of a rotator cuff tear, patients believed that surgeons should receive a mean (+/-SEM) reimbursement of US$5645 +/ $442. This was significantly more than their estimate of what surgeons were actually reimbursed by Medicare ($3644 +/- $408; P = .001). Patients also believed that surgeons should be reimbursed more than their estimate of what surgeons were actually reimbursed for arthroscopic repair of a massive tear ($8066 +/- $708 vs $4694 +/- $476; P = .0001), open repair of an acute tear ($8428 +/- $768 vs $4549 +/- $396; P = .00001), and open repair of a chronic tear ($8902 +/- $844 vs $4639 +/- $438; P = .00001). Both types of patient perceptions were higher than the actual state Medicare reimbursement data for all procedures surveyed (P < .001). Conclusion: Consistent with previous literature, patients perceive Medicare reimbursement for RCR to be higher than what surgeons are actually reimbursed. As the United States health care system enters a bundled care environment, price transparency is increasingly important. This study indicates a need for patient education on how their health care costs are allocated. PMID- 30246038 TI - Acute Life-Threatening Hemorrhage in Neonates With Severe Hemophilia A: A Report of 3 Cases. AB - Hemorrhagic shock is a rare, emergent condition that is often fatal in newborns. In this article, we report cases of 3 neonates presenting with acute, life threatening hemorrhage who were subsequently diagnosed with severe hemophilia (<1% factor VIII). The first infant was tachycardic, pale, and had a precipitous drop in his hemoglobin secondary to a subgaleal hemorrhage. The second patient sustained a splenic rupture, a sequela that has been reported in only 4 other neonatal cases. The last infant presented with tonic-clonic seizures and respiratory distress. Head imaging demonstrated extracranial and intracranial hemorrhage, complications that can result in 20% mortality. All 3 patients were successfully treated with clotting factor concentrate and blood products. After normalization of factor VIII levels, the newborns did not develop any new hemorrhages and were discharged home within 3 weeks of birth. Pediatric providers should be aware that these signs and symptoms may be potentially lethal complications in neonates with severe factor VIII deficiency. PMID- 30246041 TI - Role of the Extracellular Matrix in Muscle Injuries: Histoarchitectural Considerations for Muscle Injuries. PMID- 30246042 TI - Factors Affecting the Preferred Surgical Technique in Pediatric Anterior Cruciate Ligament Reconstruction. AB - Background: Despite several well-described operative techniques, the optimal management of anterior cruciate ligament (ACL) injuries in pediatric patients remains unclear. Purpose: To identify surgeons' preferred ACL reconstruction techniques and postoperative protocols for pediatric patients of various ages. Study Design: Cross-sectional study. Methods: An electronic survey was administered to surgeons in the Pediatric Research in Sports Medicine (PRiSM) society, resulting in a cohort of experienced respondents who performed a relatively high volume of ACL reconstructions in skeletally immature patients. Surgeon and practice demographic information was recorded. The survey presented the scenario of a patient who had a physical examination and imaging consistent with an acute, isolated ACL tear. The respondents were asked to select their preferred reconstruction technique for female and male patients at consecutive skeletal ages from 8 to 15 years. Surgeons were also asked about postoperative protocol. Results: Of 103 surgeons, 88 (85%) responded to the survey, the majority of whom (68%) performed more than 25 pediatric ACL reconstructions annually. The greatest variation in technique was from ages 11 to 13 years in female patients and from 11 to 14 years in male patients. The modified MacIntosh was the most frequently used technique for patients aged 8 to 10 years. An all epiphyseal technique was preferred over a broader age range in male patients than female patients, with peak use at age 11 in both. A partial transphyseal (hybrid) technique was preferred in slightly older patients, with peak use at age 12 in female patients and 13 in male patients. The transphyseal technique was most widely used at age 13 and older in female patients and 14 and older in male patients. The impact of fellowship training (pediatrics, sports, or both) on technique preference was statistically significant for male patients aged 11 to 13 and female patients 11 and 12 (all P < .05). Surgeons with pediatric orthopaedic training tended to prefer an all-epiphyseal reconstruction, while those with both pediatric and sports medicine training preferred the modified MacIntosh. Conclusion: The preferred ACL reconstruction technique varied considerably, especially for patients aged 11 to 13 years. The modified MacIntosh reconstruction was favored in patients aged 10 years or younger, while the transphyseal technique was preferred in female patients aged 13 years and older and in male patients 14 years and older. The surgeon's fellowship training was significantly associated with his or her preferred surgical technique. PMID- 30246043 TI - Sports Hernia/Athletic Pubalgia Among Women. AB - Background: "Athletic pubalgia," a term that has gained acceptance over "sports hernia," is more common in men than women; however, it represents a significant source of morbidity for patients of both sexes. Inconsistent terminology surrounding this entity poses a diagnostic challenge and makes studying the populations at risk difficult. Purpose: To review a case series of women with athletic pubalgia by analyzing their presentations, concomitant pathologies, and surgical outcomes. Study Design: Case series; Level of evidence, 4. Methods: Between 2013 and 2016, 197 patients were seen and evaluated for the diagnosis of athletic pubalgia. Eighteen patients seen during this time were women. All patients received "pubalgia protocol" magnetic resonance imaging and subsequent surgical intervention for their pathologies. Outcomes among 17 women were assessed with a patient questionnaire >1 year after surgery. Results: Of the 17 women, 9 had rectus aponeurotic plate injury only, or pure athletic pubalgia; the remaining 8 had athletic pubalgia in combination with >=1 inguinal, obturator, and femoral hernias. Regarding female patients in both groups, 88.2% reported that the surgery was a success at follow-up. Conclusion: Surgical repair of athletic pubalgia among women is successful in dramatically reducing pain levels in this important subset of patients. PMID- 30246044 TI - Fresh Femoral Condyle Allograft Transplant for Knee Osteonecrosis in a Young, Active Patient. PMID- 30246045 TI - Is reading automatic? Are the ERP correlates of masked priming really lexical? AB - Humans have an almost unbounded ability to adapt their behaviour to perform different tasks. In the laboratory, this flexibility is sometimes viewed as a nuisance factor that prevents access to the underlying cognitive mechanisms of interest. For example, in order to study "automatic" lexical processing, psycholinguists have used masked priming or evoked potentials. However, the pattern of masked priming can be radically altered by changing the task. In lexical decision, priming is observed for words but not for nonwords, yet in a same-different matching task, priming is observed for same responses but not for different responses, regardless of whether the target is a word or a nonword [Norris & Kinoshita, 2008. Perception as evidence accumulation and Bayesian inference: Insights from masked priming. Journal of Experimental Psychology: General, 137(3), 434-55. doi:10.1037/a0012799]. Here we show that evoked potentials are equally sensitive to the nature of required decision, with the neural activity normally associated with lexical processing being seen for both words and nonwords on same trials, and for neither on different trials. PMID- 30246046 TI - Occurrence and Distribution of Two Hydroxylated Polychlorinated Biphenyl Congeners in Chicago Air. AB - We measured hydroxylated polychlorinated biphenyls (OH-PCBs) in both gas and particulate phases in 30 Chicago air samples, the first report of OH-PCBs in environmental air samples. Concentrations of 2OH-PCB2 and 6OH-PCB2 in both phases were similar to PCB2 measured in the same samples, from non-detect to 11 pgm-3 and 12 ngg-1 for the gas and particulate phases, respectively. We found that OH PCB2s sorbed more to particulates than did PCB2; seasonal variability was larger than spatial variability across Chicago; and partial pressure and temperature strongly correlated with the two OH-PCBs (p<0.0001). Similar 6OH-PCB2:2OH-PCB2 ratios were found in our air samples and Aroclors, suggesting that Aroclors are a legacy source of OH-PCB2s to the atmosphere and appear to be volatilizing proportionally to PCBs in Aroclors. Although degradation by the hydroxyl radical has been proposed as an efficient loss process for airborne PCBs, we found no evidence that this mechanism results in the formation of OH-PCB2s. PMID- 30246047 TI - Autism Spectrum Disorder and Neonatal Serum Magnesium Levels in Preterm Infants. AB - Premature birth is associated with increased risk of autism spectrum disorder. Antenatal maternal magnesium administration is known to reduce subsequent risk of cerebral palsy including among premature infants, suggesting a potentially broader neuroprotective role for magnesium. Our objective was to determine whether magnesium could be protective against autism spectrum disorders in premature infants. A cohort of 4855 preterm children was identified, magnesium levels from 24 to 48 hours of life recorded, and subsequent autism spectrum disorder status determined. Adjusted relative risk of autism spectrum disorder with each 1 mg/dL increase in neonatal magnesium level was 1.15 (95% confidence interval: 0.86-1.53). Analysis of variance indicated that magnesium levels varied by gestational age and maternal antenatal magnesium supplementation, but not autism spectrum disorder status (F1,4824 = 1.43, P = .23). We found that neonatal magnesium levels were not associated with decreased autism spectrum disorder risk. Future research into autism spectrum disorder risks and treatments in premature infants is needed. PMID- 30246048 TI - Dynamic multiple-scattering treatment of X-ray absorption: Parameterization of a new molecular dynamics force field for myoglobin. AB - We present a detailed analysis of the X-ray absorption near-edge structure (XANES) data on the Fe K-edge of CO Myoglobin based on a combined procedure of Molecular Dynamics (MD) calculations and MXAN (Minuit XANes) data analysis that we call D-MXAN. The ability of performing quantitative XANES data analysis allows us to refine classical force field MD parameters, thus obtaining a reliable tool for the atomic investigation of this important model system for biological macromolecules. The iterative procedure here applied corrects the greatest part of the structural discrepancy between classical MD sampling and experimental determinations. Our procedure, moreover, is able to discriminate between different heme conformational basins visited during the MD simulation, thus demonstrating the necessity of a sampling on the order of tens of nanoseconds, even for an application such X-ray absorption spectroscopy data analysis. PMID- 30246049 TI - Ultrafast extreme ultraviolet photoemission without space charge. AB - Time- and Angle-resolved photoelectron spectroscopy from surfaces can be used to record the dynamics of electrons and holes in condensed matter on ultrafast time scales. However, ultrafast photoemission experiments using extreme-ultraviolet (XUV) light have previously been limited by either space-charge effects, low photon flux, or limited tuning range. In this article, we describe XUV photoelectron spectroscopy experiments with up to 5 nA of average sample current using a tunable cavity-enhanced high-harmonic source operating at 88 MHz repetition rate. The source delivers >1011 photons/s in isolated harmonics to the sample over a broad photon energy range from 18 to 37 eV with a spot size of 58 * 100 MUm2. From photoelectron spectroscopy data, we place conservative upper limits on the XUV pulse duration and photon energy bandwidth of 93 fs and 65 meV, respectively. The high photocurrent, lack of strong space charge distortions of the photoelectron spectra, and excellent isolation of individual harmonic orders allow us to observe laser-induced modifications of the photoelectron spectra at the 10-4 level, enabling time-resolved XUV photoemission experiments in a qualitatively new regime. PMID- 30246051 TI - WNT2 is necessary for normal prostate gland cyto-differentiation and modulates prostate growth in an FGF10 dependent manner. AB - Wnt proteins are highly conserved secreted morphogens that function in organ development across species. This study investigates the role(s) of Wnt2 during prostate gland development. Wnt2 mRNA ontogeny in the rat ventral prostate rapidly declines in expression from peak value at post-natal day (pnd) 1 to nadir levels sustained through adulthood. Wnt2 mRNA is expressed in prostate mesenchymal cells and Wnt2 protein localizes to both mesenchymal and epithelial cells. Sustained expression of Wnt2 by adenoviral expression during rat postnatal prostate gland development resulted in significant reduction in gland size confirming its necessary decline to permit normal development. Wnt2 overexpression in a murine embryonic urogenital sinus mesenchyme cell line, UGSM2 revealed Wnt2 modulated several growth factors including significant down regulation of Fgf10, an essential stimulator of normal prostate gland branching morphogenesis. Growth inhibitory effects of Wnt2 were reversed by exogenous Fgf10 addition to developing rat ventral prostates. Renal grafts of Wnt2-/- male urogenital sinus revealed that Wnt2-/- grafts had a disruption in normal lateral polarity, disruption in cell to cell adhesion, and a reduction in the differentiated luminal cell marker, cytokeratin 8/18. Our results demonstrate that the growth inhibiting effects of sustained Wnt2 during prostate development are mediated, in part, by reduction in Fgf10 expression by mesenchymal cells and Wnt2 plays a role in normal prostate luminal cell differentiation and cell to cell integrity. These findings add to the body of work that highlights the unique roles of individual Wnts during prostate development and suggest that their deregulation may be implicated in prostate pathology. PMID- 30246050 TI - Hot phonon and carrier relaxation in Si(100) determined by transient extreme ultraviolet spectroscopy. AB - The thermalization of hot carriers and phonons gives direct insight into the scattering processes that mediate electrical and thermal transport. Obtaining the scattering rates for both hot carriers and phonons currently requires multiple measurements with incommensurate timescales. Here, transient extreme-ultraviolet (XUV) spectroscopy on the silicon 2p core level at 100 eV is used to measure hot carrier and phonon thermalization in Si(100) from tens of femtoseconds to 200 ps, following photoexcitation of the indirect transition to the Delta valley at 800 nm. The ground state XUV spectrum is first theoretically predicted using a combination of a single plasmon pole model and the Bethe-Salpeter equation with density functional theory. The excited state spectrum is predicted by incorporating the electronic effects of photo-induced state-filling, broadening, and band-gap renormalization into the ground state XUV spectrum. A time-dependent lattice deformation and expansion is also required to describe the excited state spectrum. The kinetics of these structural components match the kinetics of phonons excited from the electron-phonon and phonon-phonon scattering processes following photoexcitation. Separating the contributions of electronic and structural effects on the transient XUV spectra allows the carrier population, the population of phonons involved in inter- and intra-valley electron-phonon scattering, and the population of phonons involved in phonon-phonon scattering to be quantified as a function of delay time. PMID- 30246052 TI - Androgen represses opioid growth factor receptor (OGFR) in human prostate cancer LNCaP cells and OGFR expression in human prostate cancer tissue. AB - Opioid receptors are G protein-coupled receptors that bind opioid ligands including endorphins and enkephalins. The existence of a number of opioid receptors, including the mu-opioid receptor (OPRM1), delta-opioid receptor (OPRD1), kappa-opioid receptor (OPRK1) and zeta-opioid receptor (OGFR) have been reported. However, the potential expression and role of these receptors on human prostate carcinogenesis is unknown. In the present study, we examined opioid receptor expression in human prostate cancer cell lines and in prostate cancer tissue. We observed using quantitative real-time PCR analysis that OGFR and OGFRL1 mRNA is expressed in all examined prostate cancer cell lines as well as in an immortalized, non-tumorigenic prostate epithelial cell line (RWPE-1). Conversely, OPRK1 mRNA expression was detected in a more limited number of cell lines (LNCaP and VCaP), while OPRD1 and OPRM1 mRNA expression was undetectable in all examined prostate cell lines. Interestingly, androgen sensitive LNCaP cells expressed high amounts of OPRK1, OGFR and OGFRL1 compared to other cell lines. Therefore, we investigated the effect of androgen on the mRNA expression of OPRK1, OGFR, OGFRL1 in the LNCaP cell line. Our results demonstrated that the synthetic androgen (R1881) represses mRNA of OPRK1, OGFR and OGFRL1 in a time dependent manner. Furthermore, immunohistochemistry demonstrated OGFR is expressed at high levels in prostate cancer tissue compared to benign tissue, and that OGFR expression is high in undifferentiated and aggressive prostate cancer tissue. This is the first study showing OGFR and OGFRL1 are androgen repressed genes, and these results suggest a role for the opioid signaling axis in prostate cancer. PMID- 30246053 TI - Nonlinear Photoacoustic Imaging by in situ Multiphoton Upconversion and Energy Transfer. AB - In recent years, photoacoustic tomography (PAT) is increasingly used in biomedical research, as it allows for direct visualization of optical absorption in deep tissue. In addition to vascular and hemodynamic imaging using endogenous contrasts, PAT is also capable of imaging neural and molecular dynamics with extrinsic contrasts. While near-infrared (NIR)-absorbing contrasts are preferred for deep tissue imaging, compared to visible-light-absorbing contrasts, they are much harder to design and synthesize with good environmental stability. We introduce here a new PAT mode which utilizes nonlinear multiphoton upconversion of NIR light in situ to visible light, thus exciting locally a dye that can generate strong photoacoustic signal. This approach allows to take advantage of a large library of visible-light-absorbing dyes that can enable functional imaging, such as imaging of voltage, oxygen, pH, and ion channel activities. Two types of upconversion materials are utilized in this work: 1) a two-photon absorbing and emitting dye that is efficiently excited by NIR nanosecond laser pulses to enable pulsed laser-based PAT (pulsed-PAT); and 2) rare-earth containing inorganic nanocrystals that absorb continuous-wave (CW) NIR light by sequential multiphoton absorption through real intermediate states to enable intensity-modulated CW laser-based PAT (CW-PAT). Since both cases produce highly localized nonlinear photoacoustic signal, which has very weak scattering in tissue, we can achieve high contrast 3-D volume imaging of deep tissues. In this study, we validated the principle of our approach in different PAT modes and successfully detected enhanced photoacoustic signals from a visible-light-absorbing dye embedded deep in tissue. With vast variety of functionalized organic dyes operating in the visible range, our mode of nonlinear photoacoustic imaging will find great applications in preclinical and clinical researches. PMID- 30246054 TI - A multipollutant evaluation of APEX using microenvironmental ozone, carbon monoxide, and particulate matter (PM2.5) concentrations measured in Los Angeles by the exposure classification project. AB - This paper describes an operational evaluation of the US Environmental Protection Agency's (EPA) Air Pollution Exposure Model (APEX). APEX simulations for a multipollutant ambient air mixture, i.e. ozone (O3), carbon monoxide (CO), and particulate matter 2.5 microns in diameter or less (PM2.5), were performed for two seasons in three study areas in central Los Angeles. APEX predicted microenvironmental concentrations were compared with concentrations of these three pollutants monitored in the Exposure Classification Project (ECP) study during the same periods. The ECP was designed expressly for evaluating exposure models and measured concentrations inside and outside 40 microenvironments. This evaluation study identifies important uncertainties in APEX inputs and model predictions useful for guiding further exposure model input data and algorithm development efforts. This paper also presents summaries of the concentrations in the different microenvironments. PMID- 30246055 TI - Proton Radiotherapy for Recurrent or Metastatic Head and Neck Cancers with Palliative Quad Shot. AB - Purpose: Some patients with previously treated, unresectable, recurrent or metastatic head and neck malignancies are not amenable to curative-intent treatment. Here, we investigated the quad-shot (RTOG 8502) regimen of hypofractionated proton radiotherapy (RT) in that patient population. Materials and Methods: From 2013 to 2015, 26 patients with recurrent or metastatic cancers were treated with palliative proton RT to the head and neck with quad shot (3.7 Gy twice daily for 2 days). Patient characteristics and survival data were reviewed. Results: Seventeen (65%) patients received >= 3 quad-shot cycles and 23 (88%) had prior head and neck RT. Overall palliative response was 73% (n = 19). The most common presenting symptom was pain (50%; n = 13), which improved in 85% (n = 22) of all patients. The overall grade-1 acute-toxicity rate was 58% (n = 15), and no acute grade 3 to 5 toxicities were observed. Conclusions: The proton quad-shot regimen demonstrates favorable palliative response and toxicity profile, even in patients that received prior RT. PMID- 30246056 TI - Varied antibody reactivities and clinical relevance in anti-GQ1b antibody-related diseases. AB - Objective: To investigate the relationship between antibody reactivities against glycolipid complexes and clinical features in Miller Fisher syndrome (MFS), Bickerstaff brainstem encephalitis (BBE), and Guillain-Barre syndrome with ophthalmoplegia (GBS-OP). Methods: Using glycoarray, antibodies against 10 glycolipid antigens (GM1, GM2, GM4, GD1a, GD1b, GQ1b, galactocerebroside, lactosylceramide, GA1, and sulfatide) and 45 glycolipid complexes consisting 2 of the glycolipids were examined in the sera of 63 patients with GBS-OP, 37 patients with MFS, and 27 patients with BBE. Results: Antibodies to antigens containing GQ1b were identified in 73% of patients with GBS-OP (46/63), 86.5% of patients with MFS (32/37), and 74.1% of patients with BBE (20/27), and GD1b-related antibodies were identified in 49.2% of patients with GBS-OP (31/63), 29.7% of patients with MFS (11/37), and 11.1% of patients with BBE (3/27). Comparing clinical features between patients with GBS-OP with and without both antibodies, the proportion of patients requiring artificial ventilation and presenting moderate or severe muscle weakness was higher in the positive group than in the negative group (p = 0.017 and p = 0.046, respectively). Conclusions: Antibodies binding to antigens containing GD1b and to those containing GQ1b may be involved in the development of limb weakness and respiratory failure in anti-GQ1b antibody related diseases. PMID- 30246057 TI - MOG antibodies in combined central and peripheral demyelination syndromes. PMID- 30246058 TI - General Practitioners' Barriers Toward Medication Reviews in Polymedicated Multimorbid Patients: How can a Focus on the Pharmacotherapy in an Outpatient Clinic Support GPs? AB - Purpose: The aim of this study was to explore whether general practitioners (GPs) experienced barriers toward medication reviews in polymedicated, multimorbid patients, and how a clinical pharmacologist with a focus on pharmacotherapy can support the GPs in an outpatient clinic. Design: The study was descriptive and exploratory and had a qualitative design with a phenomenological/hermeneutic orientation for the interviews. Participants: The study comprised 14 interviews with 14 different GPs from the Capital Region of Denmark. Results: Three themes emerged from the interviews: (1) The care of patients With polypharmacy is challenged by the lack of professional dialogue and collaboration between GPs and hospital-based clinical pharmacologists, (2) the relationship between the patients with polypharmacy and the GP is characterized by care and individual considerations, and (3) the culture encourages adding medication and inhibits dialogue about medication withdrawal even for patients with polypharmacy. Conclusion and implications for practice: This study found that the primary barriers toward multimorbid patients with polypharmacy were the need for communication and teamwork with specialists (cardiologists, neurologists, endocrinologists, etc). Often, GPs felt that the specialists at the hospitals were more concerned about following standards and guidelines regarding specific diseases instead of a more holistic patient approach. To improve management of polypharmacy patients, the GPs suggest that a joint force is necessary, a partner like relationship with greater transparency regarding information transfer, feedback, and shared decision-making, but also more education in the pharmacological field is essential. PMID- 30246059 TI - Rates of Screening for Breast, Colorectal, and Cervical Cancers in Older People With Cognitive Impairment or Dementia: A Meta-Analysis. AB - Purpose: Cancer screening may not be appropriate for some older people. We compare the likelihood of screening for colorectal, breast, and cervical cancers in older people with versus without cognitive impairment or dementia. Method: Systematic search of MEDLINE, Embase, and PsycINFO (to March 9, 2018) for articles reporting screening for colon, breast, and cervical cancers in patients with and without cognitive impairment or dementia. Studies were summarized quantitatively (random effects meta-analysis), according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Studies reported data 1989-2008. The rate of screening for breast cancer by mammography was lower in women with cognitive impairment or dementia compared with those without (pooled odds ratio [OR] = 0.81, 95% confidence interval [CI] = [0.71, 0.91], p = .0007, six studies, N = 18,562). The rates of screening for cervical cancer by Pap smear (pooled OR = 0.88, 95% CI = [0.71, 1.08], p = 0.22, five studies, N = 409,131) and colorectal cancer by fecal occult blood test (pooled OR = 0.87, 95% CI = [0.55, 1.38], p = .55, two studies, N = 2,718) were not significantly lower in people with cognitive impairment or dementia. Conclusion: These historical rates provide a baseline for discussions around the need for more specific guidance to assist with decisions to discontinue screening. The study also identifies a gap in reported knowledge with respect to screening under current guidelines. PMID- 30246060 TI - Public Employment Policy for an Aging Workforce. AB - Americans are working longer. For many older workers, employment earnings are essential for self-sufficiency. When older workers are forced to change jobs, they suffer bigger earnings losses and take longer to find new jobs than prime age workers. Unfortunately, public workforce policy has not adapted to serve older workers. Our strategic survey of published research evidence and government statistics suggests a variety of ways that employment programs could be adapted to benefit older workers. In this article, we examine the changing age composition of the labor force, the employment patterns of older workers, and offer specific improvements in public employment policy for an aging workforce. PMID- 30246061 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/2333721418778169.]. PMID- 30246062 TI - Ptychographic X-ray CT characterization of the osteocyte lacuno-canalicular network in a male rat's glucocorticoid induced osteoporosis model. AB - Ptychographic X-ray computed tomography (PXCT) is a quantitative imaging modality that non-destructively maps the 3D electron density inside an object with tens of nanometers spatial resolution. This method provides unique access to the morphology and structure of the osteocyte lacuno-canalicular network (LCN) and nanoscale density of the tissue in the vicinity of an osteocyte lacuna. Herein, we applied PXCT to characterize the lacunae and LCN in a male Wistar rat model of glucocorticoid-induced osteoporosis (GIO). The ptychographic images revealed significant (p < 0.05) differences in the number of canaliculi originating from the lacuna per ellipsoidal surface unit, Ca.Nb (p = 0.0106), and the 3D morphology of the lacuna (p = 0.0064), between GIO and SHAM groups. Moreover, the mean canalicular diameter, Ca.Dm, was slightly statistically un-significantly smaller in GIO (152 +/- 6.5) nm than in SHAM group (165 +/- 8) nm (p = 0.053). Our findings indicate that PXCT can non-destructively provide detailed, nanoscale information on the 3D organization of the LCN in correlative studies of pathologies, such as osteoporosis, leading to improved diagnosis and therapy. PMID- 30246063 TI - A moderate form of osteogenesis imperfecta caused by compound heterozygous LEPRE1 mutations. AB - Osteogenesis imperfecta (OI) is a genetic disorder causing skeletal fragility, multiple fractures, and other extraskeletal manifestations. Most cases are caused by mutations in COL1A1 or COL1A2. Recent investigations have discovered several other autosomal recessive genes responsible for OI. Among these genes is LEPRE1, which is involved in post-translational modifications of collagen. To date, more than 40 LEPRE1 mutations have been described. One of these mutations is carried by 1.5% of West Africans and 0.4% of African Americans, and is associated with OI Type VIII. We describe the case of a five year old male with a moderate form of OI and compound heterozygous LEPRE1 mutations (c.1080 + 1G > T; c.1646 T > G, p.Met549Arg). He was diagnosed shortly after birth following a skeletal survey demonstrating multiple healing fractures as well as lower extremity deformity suggestive of remote fractures. He was then without a fracture until a calvarial fracture at 18 months of age, a femur fracture at 4 years and seven months and a second femur fracture at 5 years and 4 months. He walked at age 14 months and has been an active boy. Pamidronate infusions began at seven weeks of age and were discontinued at three years of age due to increased bone mineral density and absence of fractures. Type VIII OI typically causes a severe to lethal phenotype presenting at birth with severe osteopenia, congenital fractures and other clinical manifestations. Only a few individuals have survived to childhood. This case description serves to expand the clinical phenotyping of this recessive form of OI into the more moderate spectrum. PMID- 30246065 TI - Data on optimisation of a multiplex HRM-qPCR assay for native and invasive crayfish as well as the crayfish plague in four river catchments. AB - The data presented here corresponds to the research paper "Simultaneous detection of invasive signal crayfish, endangered white-clawed crayfish and the crayfish plague using environmental DNA". A crayfish-specific assay was designed and optimised using three real-time PCR supermixes (SYBRTM Green, SsoFastTM EvaGreen(r) and HOT FIREPol(r) EvaGreen(r)). Diagnostic high resolution melt (HRM) data from direct application of assay on both ex-situ eDNA water samples and field samples from four catchments (two in Wales, two in England) is presented in this article, displaying positive HRM profiles for invasive signal crayfish (Pacifastacus leniusculus), native white-clawed crayfish (Austropotamobius pallipes) and crayfish plague causal agent (Aphanomyces astaci). PMID- 30246064 TI - Dataset on statistical analysis of jet A-1 fuel laboratory properties for on-spec into-plane operations. AB - Safety is of utmost essence in the aviation sector, both on-ground and in the air. Aviation Turbine Kerosene (ATK) commonly referred to as jet fuel is one of the major resources of the aviation sector, contributing significantly to the operating cost of an airline. Flight safety is a top-notch requirement in air transportation management. Jet fuel quality affects flight safety, and this makes it mandatory to ensure that, at all points in the jet A-1 aviation fuel supply chain, the jet fuel is contamination free and on-spec. Jet fuel quality is determined via various mandatory Joint Inspection Group (JIG) based quality analysis test procedures; both baseline and extensive lab tests by third party labs. Acceptable parameter range has been established for each jet fuel property, the electrical conductivity of jet A-1 fuel must be between 50 and 600 pS/m and the density at 15 degrees C must be between 0.775 and 0.840 g/cm3. Beyond this range, the fuel is deemed off-spec and unsafe for into-plane fuelling operations. This data article presents daily jet fuel test records for jet-A1 fuel. The dataset contains the date of the test, the conductivity, the specific gravity at ambient temperature, the converted specific gravity at 15 degrees C, and the temperature of the jet fuel sample under study. All the tests were performed at standard laboratory conditions using approved and certified equipment. The dataset provides an opportunity for developing a predictive model that can be used for jet fuel properties prediction on a given day, based on previous data trends and analysis using data pattern recognition, as an indication of the variation of jet fuel properties with daily weather variation. PMID- 30246066 TI - Faculty commitment, effectiveness of job responsibilities and the moderating role of institutional support: A survey data set. AB - The main objective of this paper is to present the data set which depicts faculty commitment and effectiveness of job responsibilities in a changing world and the moderating role of the university's support system. The population of the study consisted all the 1912 Faculty members of six selected private universities in Southwest, Nigeria [5]. The sample size determination formula by [5] was adopted, resulting in the selection of 400 respondents to whom a structured questionnaire was administered accordingly. Only 343 copies of the questionnaire were valid and used for this data set. Structural equation modeling, which combines factor analysis and multiple regression, was used to present the structural relationship between dependent and independent variables. When the data is analysed, it will help to determine the degree of relationship and the strength of significance between the observed variables and the latent constructs. PMID- 30246068 TI - PhytoMolecularTasteDB: An integrative database on the "molecular taste" of Indian medicinal plants. AB - PhytoMolecularTaste database (PhytoMolecularTasteDB) described in the present work is related to the article "Main phytocompunds' tastes: a better predictor for the ethnopharmacological activities of medicinal plant than the phytochemical class?" (Dragos and Gilca, 2018) [1]. It includes a comprehensive list of plant derived tastants, as well as details on the "phyto-molecular taste" (PMT) (the combination of tastes resulted from the main tastants found in a medicinal plant). To collect the data, we searched publications in various databases and journals by using relevant keywords. Wherever necessary, manual search of lacking information was also performed in several books. We then extracted the reported phytoconstituents and PMT of all the ayurvedic medicinal plants included in DB. Data were compiled in Excel. In total, PhytoMolecularTasteDB includes 431 ayurvedic medicinal plants, 94 EPAs, 223 phytochemical classes, and 438 plant derived tastants. PMID- 30246067 TI - Data on leukocyte PDZK1 deficiency affecting macrophage apoptosis but not monocyte recruitment, cell proliferation, macrophage abundance or ER stress in atherosclerotic plaques of LDLR deficient mice. AB - PDZK1 (Post-synaptic density protein/Drosophila disc-large protein/Zonula occludens protein containing 1) is an adaptor protein that binds to the HDL receptor, Scavenger receptor class B type I. Leukocyte PDZK1 deficiency in high fat-diet fed LDL receptor knockout mice has been found to increase atherosclerotic necrotic core formation and apoptosis of cells within atherosclerotic plaques. To explore mechanisms that may be involved, we examined the effects of leukocyte PDZK1 deficiency in mice on a number of processes that may impact macrophage abundance within atherosclerotic plaques. We found that leukocyte PDZK1 deficiency in high fat diet fed LDL receptor knockout mice did not affect the abundance of circulating red blood cells, myeloid cells or B- or T lymphocytes. Leukocyte selective PDZK1 deficiency did not affect the levels of the ER chaperone proteins, detected with an antibody against the KDEL peptide, in macrophages or macrophage abundance, cellular proliferation or monocyte recruitment in atherosclerotic plaques. Leukocyte PDZK1 deficiency in otherwise wild type mice did result in increased sensitivity of macrophages to tunicamycin induced apoptosis in a peritonitis model. HDL protected wild type macrophages from apoptosis induced by a variety of agents, including the ER stressor tunicamycin, oxidized LDL and exposure to UV irradiation. However, this protection afforded by HDL was lost when macrophages were deficient in PDZK1. HDL did not affect the level of ER stress induction by tunicamycin. Finally, PDZK1 deficiency in macrophages did not affect lipopolysaccharide-mediated induction of markers of M1 polarization. These data, utilizing mouse and cellular models, help to demonstrate that leukocyte PDZK1 plays a role in atherosclerosis by affecting macrophage apoptosis within atherosclerotic plaques. PMID- 30246069 TI - Performances of full cross-validation partial least squares regression models developed using Raman spectral data for the prediction of bull beef sensory attributes. AB - The data presented in this article are related to the research article entitled "Application of Raman spectroscopy and chemometric techniques to assess sensory characteristics of young dairy bull beef" [1]. Partial least squares regression (PLSR) models were developed on Raman spectral data pre-treated using Savitzky Golay (S.G.) derivation (with 2nd or 5th order polynomial baseline correction) and results of sensory analysis on bull beef samples (n = 72). Models developed using selected Raman shift ranges (i.e. 250-3380 cm-1, 900-1800 cm-1 and 1300 2800 cm-1) were explored. The best model performance for each sensory attributes prediction was obtained using models developed on Raman spectral data of 1300 2800 cm-1. PMID- 30246070 TI - Data for crystallisation, dissolution and saturation temperatures of the ternary system: Hexadecane and octadecane representative in fuel solvents. AB - The data presented in this article relates to the crystallisation of hexadecane (C16H34) and octadecane (C18H38), being the predominant alkanes present in hydrotreated vegetable oil (HVO), from solvents representative of fuel (dodecane, toluene and kerosene). Data was collected for eleven C16H34/C18H38 compositions for each solvent used. Raw crystallisation and dissolution data is provided over a range of solution concentrations and cooling rates used under a poly-thermal crystallisation methodology. Equilibrium saturation temperature data is also presented for each composition, concentration and solvent system, indicating the trend in solubility for each solution. PMID- 30246071 TI - Epidemiological data of falciparum malaria in Ado-Odo/Ota, Southwest Ogun State, Nigeria. AB - In this data article, Blood and corresponding saliva samples from subjects presenting with fever and parasetaemia >=2000 were obtained from selected hospitals in Ado-Odo/Ota, Ogun State over a period of two years and analyzed using Polymerase chain reaction-Restriction fragment Length Polymorphism (PCR/Nested PCR-RFLP) to detect genetic mutations of Plasmodium falciparum chloroquine resistance transporter (Pfcrt), Plasmodium falciparum multidrugs resistance (Pfmdr1) and non-synonymous Pkelch (pk13) mutated genes. The study confirmed the presence of resistance genes in the blood and saliva samples collected from the study site. PMID- 30246072 TI - Data set on interactive service quality in higher education marketing. AB - This paper provides data on the interactive quality of the educational services rendered in south west, Nigeria. Data were gathered based on conclusive research design. Stratified and convenience sampling techniques were adopted. Responses were elicited from the alumni as regards to their perception towards the interactive quality; learning, group discussion, breadth, assignment, examination as well as social relationships. Interactive quality component of the Student Evaluation of Educational Quality (SEEQ) developed by previous scholars was adapted. The research instrument was confirmed to have all the necessary psychometric values considered appropriate for the study. Some descriptive statistical analyses were carried out to further clarify the data and provide the necessary platform for further analyses. PMID- 30246073 TI - Data on quality indices of groundwater resource for agricultural use in the Jolfa, East Azerbaijan, Iran. AB - The aim of this study was to evaluate the groundwater quality Indices of Groundwater resource for Agricultural Use in jolfa city (Iran) during one decade (2003-2013). Data showed in the first and end year of the study period, the Mean+/-SD of Sodium Adsorption Ratio (SAR) and Sodium Percentage (Na%) indices 5455.77+/-3878.02, 3638.69+/-3565.19 and 51.49+/-15.65, 41.58+/-17.69, respectively. The data indicate that the, in terms of sodium percentage and sodium adsorption ratio, the water quality in this area is not suitable for irrigation. PMID- 30246074 TI - Spectral data of nicotabaflavonoidglycoside. AB - The dataset addressed in this article relates to the research article entitled"Nicotabaflavonoidglycoside, the first example of cembranoid and flavonoid heterodimer from Nicotiana tabacum" (Yang et al., 2018) [1]. The dataset presents the MS4(879-571-421-335), MS n fragment pathways, (+) HR-ESI-MS, (-) HR-ESI-MS, UV, IR, 1H NMR, 13C NMR, HSQC, 1H-1H COSY, HMBC, ROESY, ORD and ECD data of Nicotabaflavonoidglycoside. The MS4(879-571-421-335), (+) HR-ESI-MS, (-) HR-ESI-MS, UV, IR, 1H NMR, 13C NMR, HSQC, 1H-1H COSY, HMBC, ROESY, ORD and ECD data were collected by experimental methods, and the MSn fragment pathways were acquired by analyses. PMID- 30246075 TI - Dataset of plasma and aqueous humor cytokine profiles in patients with exudative age related macular degeneration and polypoidal choroidal vasculopathy. AB - In this report the data was obtained from a prospective case-control study with a sample size of sixteen patients with exudative age related macular degeneration (AMD) due to choroidal neovascularization (CNV) and eighteen patients with polypoidal choroidal vasculopathy (PCV) and fifty controls (cataract patients without any other ocular diseases). Luminex bead based multiplex assay with a panel of 41 analytes was used to study the cytokine levels in plasma and aqueous humor. PMID- 30246076 TI - Data on perception of faculty members on the influence of faculty support initiatives on the efficacy of job responsibilities. AB - The main objective of this survey is to present data on the perception of the influence of faculty support initiatives on efficacy of job responsibilities using six private university in Nigeria as case study. The population of the study included all faculty members of selected private universities with a total of 1912 faculty members. A sample size of 500 were selected to participate in the survey based on the outcome of the sample size determination formula suggested by Falola et al. (2016) [5]. The validity and reliability of the research instrument were carried out. Regression analysis and structural equation modeling were used as statistical tool of analysis. It is believed that when the data is analysed, it will give insight into how faculty support initiatives of various universities can help in enhancing the effectiveness of job responsibilities. PMID- 30246077 TI - Data on biosurfactant assisted removal of TNT from contaminated soil. AB - Contamination of environment, especially soil, is in great concern and can cause health problems. Thus, remediation of these pollutants through environmentally friendly methods should be considered. The aim of this data was bioremediation of TNT from contaminated soil. Two plastic pans were used as bioreactor. In each pan, 3 kg of soil was used. Concentration of TNT in contaminated soil was 1000 mg/kg. Rhamnolipid in concentration of 60 mg/l was added to intended pan. Sampling was done in each two weeks. In order to assessment of TNT degradation, samples were analyzed with HPLC. The data showed that after 154 days of experiment, TNT removal in soil that amended with rhamnolipid was 73% and in experiment with no addition of rhamnolipid was 58%. Based on the obtained data rhamnolipid was effective in remediation of TNT contaminated soil. PMID- 30246078 TI - Learning analytics: Data sets on the academic record of accounting students in a Nigerian University. AB - This paper presents data on the academic performance of a particular set of accounting students from the year of inception into a Nigerian university to the year of graduation. Descriptive analysis was performed on the dataset and a regression model which is capable of making predictions was fitted to the dataset. From the dataset, 24 out of the students who started with a first class result (CGPA above 4.50) still maintained a first class result at graduation. 4 out of the students who started with a first class result dropped to second class upper division before graduation. 4 out of the students who started with a second class upper division result moved to first class result before graduation. 28 out of 35 students who started with a second class upper division maintained a second class upper division result at graduation. PMID- 30246079 TI - Data on the effect of incorporation of nanoparticles and process characteristics of Ni-SiO2 coating on oil and gas steel. AB - In this work, data on the effect of process parameter and particle concentration on the developed Ni-SiO2 produced via electrocodeposition were presented. The influence of current density from 0.6 to 1.0 A/dm2 and applied time difference from 10 to 25 min observed on the hardness characteristics and texture performance of the deposited alloy was checked. The weight gained and thickness of surface coverage was acquired and could be further used as a protoype for designing a ternary alloy coating system for oil and gas services. PMID- 30246080 TI - Rheology of Gum Arabic Polymer and Gum Arabic Coated Nanoparticle for enhanced recovery of Nigerian medium crude oil under varying temperatures. AB - The dataset in this article are related to the rheology of dispersions containing Gum Arabic coated Alumina Nanoparticles (GCNPs) and Gum Arabic (GA) polymer for Enhanced Oil Recovery (EOR) of Nigerian medium crude oil under varying temperatures. The data included the viscosity of the dispersion containing GCNPs compared to GA at different shear rates. In addition, data on the rheological properties (plastic viscosity, yield point, and apparent viscosity) of the dispersions under varying temperatures was also presented. PMID- 30246081 TI - Data on modeling of UV/Na2S2O8/FeS2 process in amoxicillin removal using Box Behnken methodology. AB - Among the pharmaceutical compounds, antibiotics have been paid specific consideration, due to their acute and chronic toxic effects on organisms. Amoxicillin (AMX) is used widely for treatment of bacterial infections. About 80% of amoxicillin excreted unchanged and enters the aquatic environment through different routes including disposal of municipal wastewaters, hospital wastewaters and farm wastewaters. In this study degradation of amoxicillin by UV/Na2S2O8/FeS2 process was evaluated. According to the results, the R-squared and adjusted R-squared were 0.9877 and 0.9828, respectively. The AMX removal efficiency was 93% at optimum conditions. Thus, UV/Na2S2O8/FeS2 process is a useful process for amoxicillin removal. PMID- 30246082 TI - Survey data on employees' development and employees' satisfaction in oil and gas firms in Nigeria. AB - Employees' development involves ensuring that employees are compensated fairly, are not exposed to dangerous or environmentally unhealthy working environment and are treated ethically in the workplace, especially in a technology intense industry as that of the oil and gas sector. Thus, this article presents data on the effect of employees' development on employees' satisfaction. The study employed a descriptive quantitative research design engaging survey method. The study population consists of 1748 employees from four top oil and gas firms quoted in the Nigerian stock exchange. A sample size of 350 employees was selected. Data was analysed using statistical Package for Social Sciences (SPSS). Regression analysis was employed as the statistical tool of analysis. The field data set is made widely accessible in this article. PMID- 30246083 TI - Data on prevalence of atrial fibrillation and its association with stroke in low , middle-, and high-income regions of China. AB - Data presented in this article are supplementary material to our research article entitled " Prevalence of Atrial Fibrillation in Different Socioeconomic Regions of China and Its Association with Stroke: Results from a National Stroke Screening Survey" (Wang et al., 2018) [1]. This data article summarizes previous studies of Atrial Fibrillation (AF) prevalence in China, and estimates the association between AF and stroke in different socioeconomic regions of China through a national survey. PMID- 30246084 TI - Datasets for board meeting frequency and financial performance of Nigerian deposit money banks. AB - This article provides data on the impact of board meeting frequency and financial performance of deposit money banks in Nigeria. We obtained the dataset from Nigeria stock exchange (NSE) database. The time frame used for this work is 2010 2016. TOBIN Q was used as a major determinant of financial performance. The raw data is easily accessible on Nigeria stock exchange website. We describe the value of this data as well as the method to analyze the data. PMID- 30246085 TI - Survey dataset on architect's awareness and adoption of building envelope technologies for energy efficient housing in Lagos State. AB - Low energy houses are forms of housing that use less energy from the design, technologies and building products from any source than a traditional or average contemporary house. The survey dataset examines architect's awareness and adoption of building envelope technologies (BET) for energy efficient housing in Lagos State, Nigeria. The dataset was based on seventy-four (74) returned questionnaires of both registered and non-registered Architects. A multistage sampling that involved cluster sampling and random sampling of architects in Lagos State was adopted. Descriptive statistical tools were used to present the dataset. The dataset contains the intent of promoting energy sustainability by architect while designing their building envelopes, the awareness of the building envelope strategies to adopt, factors influencing their adoption of these strategies, strategies that can be adopted to improve adoption of building envelope technologies for energy efficiency in housing units. The dataset can be used for evolving housing energy policy by decision makers. PMID- 30246086 TI - Survey data on work environments and productivity of academic staff of selected public universities in Nigeria. AB - The article presented a survey data on work environment predictors and productivity of selected academic staff of selected public universities in Southern, Nigeria. The study adopted a quantitative approach with a survey research design to establish the major determinants of work environments in the selected public universities. Data was analysed with the use of structural equation modelling and the field data set is made widely accessible to enable critical or a more comprehensive investigation. The findings identified meaningful work and growth opportunities as predictive factors for maximizing productivity in the sampled institutions. PMID- 30246087 TI - Dataset on cost comparative analysis of different walling materials in residential buildings in a developing economy. AB - The walls which form the envelope of a building are very important, therefore, the choice of materials used for it is very important. The dataset presents a comparative analysis of different walling materials used in residential buildings in a developing economy. The data was presented using descriptive tools of figures and tables. The dataset was obtained within several parts in Lagos State, Nigeria. The dataset showed the awareness and rate of use of selected walling materials by home owners in residential apartments. Furthermore, a comparative analysis of the cost implication of using eight (8) different walling materials in a typical two (2)- bedroom residential building was carried out. Using a market survey armed with current prices, a bill of quantities showed the varying cost of different walling materials for residential buildings. The dataset when analyzed can help in understanding the dynamics of providing affordable housing in developing economies. In addition, prospective home owners and building materials' investors can benefit from the dataset. PMID- 30246088 TI - Physico-chemical, biochemical and nutritional characterisation of 42 organic wastes and residues from France. AB - The data presented in this article regroup characterisation of organic matter and nutritional composition of 42 organic wastes and residues usually used as substrates for anaerobic digestion. Those wastes have different origins from agro industrial, agricultural and urban sectors in France including: algae, slaughterhouse waste, fat, food waste, fruits and vegetables residues, green waste, slurry, manure, wastewater treatment plant sludge and agricultural residues. The properties of organic matter are distinguished between global parameters (pH, total solids, volatile solids, COD and BMP), organic matter fractionation (biochemical and Van Soest) and the main nutrients content (N, P, K, Mg, Ca and S). PMID- 30246089 TI - Data on the influence of TiN on wear and corrosion behavior of Ti-6Al-4V alloy fabricated through spark plasma sintering. AB - Data about bulk properties of Ti-6Al-4V based composites specimen achieved by powder metallurgy route using spark plasma sintering (SPS) technique is presented, with focus on the effect of TiN particles on wear and corrosion behavior of the resultant composites. Two microsized kind of powders are combined; Ti-6Al-4V and TiN. The powder mixing and SPS processing has been enhanced and consolidated. PMID- 30246090 TI - Data set on concentrations, bioavailability, dose and lung deposition of labile metals bound to inhalable and respirable fractions of ambient particulate matters in Akure suburbs. AB - This article consists of data sets of concentrations, dose and deposition of some labile metals bound to inhale ambient particulate matter collected at human breathing height of 1.5-2 m in Akure, South Western Nigeria. Ten (10) data points, of different air quality, were selected for study using active sampling method; during the dry season months of November, 2016 to March, 2017. At each data point, the dust particles were collected four times, sorted into inhalable and respirable fractions. The metal concentrations in each fraction were determined using Perkin-Elmer 6000 Inductively Coupled Plasma - Atomic Emission Spectrometry (ICP-AES) analysis. The data set were processed and analyzed via descriptive statistics (averages and standard deviations), and numerical analyses. The data were explored further to estimate the exposure dose of metal particles and deposition in various regions of lung (alveolar, trachea-bronchial and extra thoracic) in adults (male and female) dwelling in the area. The data revealed that the highest dose and deposition of metals (Pb, Cd and Cr) occur in the alveolar region of the lung of adults. PMID- 30246091 TI - Data on the rheological behavior of cassava starch paste using different models. AB - Proper selection of rheological models is very important in flow characterization. These models are often used to evaluate parameters that help in the characterization of food samples. Rheological models also provide flow predictions for extreme conditions where the flow nature of the fluid cannot be determined, hence the need for appropriate selection of rheological models. The principal aim of this study is to suggest a rheological model that best characterize the rheological behavior of native cassava starch and to determine the effect of state variables like temperature and concentration on the accuracy of rheological models. Five rheological models (i.e. Herschel-Bulkley model, Robertson-Stiff model, Power-law model, Bingham plastic model and Prandtl-Eyring model) were selected for this study and these models were modified into statistical models by the inclusion of the error variance (epsilon). The least square method was used in evaluating the various model parameters for each model. From this study, it was seen that the Herschel-Bulkley model and the Robertson Stiff model most accurately described the rheological patterns in cassava starch production. The sensitivity analysis of the different rheological models also shows that the accuracy of the Herschel-Bulkley model, Robertson-Stiff model and Power-law model is not significantly affected by variations in temperature and concentration of the cassava starch. However, it was observed that the Bingham plastic model and Prandtl-Eyring model gave less accurate predictions at higher concentration and lower temperature respectively. A lot of the industrially accepted models such as the Bingham plastic model may not necessarily be the best model for characterization cassava starch production as shown in this study, hence rheological model optimization is recommended for further study. PMID- 30246092 TI - Inhibition of anaerobic digestion by phenol and ammonia: Effect on degradation performances and microbial dynamics. AB - Data in this article provide detailed information on the microbial dynamics during inhibition of anaerobic digestion by phenol and ammonia. Ten concentrations of both inhibitors were tested in triplicates. Data include the operational conditions and degradation performance measurements, as well as microbial community analysis, by 16S rRNA gene sequencing, at different time points for the different conditions (96 samples). Sequencing data were generated by using IonTorrent PGM sequencer. This data is associated with the research articles "Community shifts within anaerobic digestion microbiota facing phenol inhibition: Towards early warning microbial indicators?" (Poirier et al., 2016a) [1] and "Anaerobic digestion of biowaste under extreme ammonia concentration: Identification of key microbial phylotypes" (Poirier et al., 2016b) [2]. The sequencing data have been deposited in the bioproject PRJNA450311, with the dataset identifier (TaxID) 1263854. Samples accession numbers go from SAMN08934853 to SAMN08934947. PMID- 30246093 TI - Data on the treatment of used lubricating oil from two different sources using solvent extraction and adsorption. AB - The data in this article were obtained from a research designed to investigate the effects of choice of solvent, mixing speed, temperature and solvent to oil ratio on the treatment process of used lubricating oils using solvent extraction and adsorption method. Various data on the performance of the three solvents chosen were studied and compared based on certain parameters are presented and discussed. From the results obtained, it was observed that MEK (Methyl Ethyl Ketone) had the best performance because it gave the highest sludge removal and closest properties to the fresh lubricating base stock. Furthermore, it was also determined that increase in temperature improved the quality of oil obtained up till 50 degrees C above this temperature poorer quality of oil was observed. But above all the factors investigated, it was concluded that solvent to oil ratio has a greater effect on the quality of oil produced after treatment. PMID- 30246094 TI - Data on groundwater quality, scaling potential and corrosiveness of water samples in Torbat-e-Heydariyeh rural drinking water resources, Khorasan-e-Razavi province, Iran. AB - According to World Health Organization guidelines, corrosion control is an important aspect of safe drinking-water supplies. The data presented is physical and chemical parameters of drinking water in the rural areas of Torbat-e Heydariyeh city, also to determine corrosion indices. This cross-sectional study has carried out with 188 taken samples during 2014 with 13 parameters, which has been analyzed based on standard method. Also with regard to standard conditions, result of this paper is compared with Environmental Protection Agency and Iran national standards. Five indices, Langlier Saturation Index (LSI), Ryznar Stability Index (RSI), Puckorius Scaling Index (PSI), Larson-Skold Index (LS) and Aggressive Index (AI), programmed by using Microsoft Excel software. Owing to its simplicity, the program can easily be used by researchers and operators. Parameters included Sulfate, Sodium, Chloride, and Electrical Conductivity respectively was 13.5%, 28%, 10.5%, and 15% more than standard level. The amounts of Nitrate, in 98% of cases were in permissible limits and about 2% were more than standard level. Result of presented research indicate that water is corrosive at 10.6%, 89.4%, 87.2%, 59.6% and 14.9% of drinking water supply reservoirs, according to LSI, RSI, PSI, LS and AI, respectively. PMID- 30246095 TI - Dataset on experimental investigation of optimum carburizing temperature and holding time of bi- nano additives treatment of AISI 5130 steel. AB - Investigation of optimum carburizing temperature and holding time on bi- nano additives treatment of AISI 5130 steel was presented in this study. AISI 5130 steel of 100 kg mass of 0.35% carbon content was buried in pulverized additives consisting of palm kernel and coconut shell using eggshell as an energizer. Four sets of 150*150*150 mm3 steel boxes packed with additives mixed at varying weight ratio of 50: 30:20 and sixty-four pieces of 20*20*5 mm3 AISI 5130 steel were case hardened using muffle furnace (2500 degrees C max capacity) at respective temperatures and time of 950, 1000, 1050, 1100 degrees C and 60, 90, 120, 180 min. The core, interface and surface hardness of the treated samples with their respective weight loss, wear volume and rate were investigated. This dataset could be used in nano-composite match mixed ratio and optimization of carburizing medium and time for any industrial used case hardened steel. PMID- 30246096 TI - Integrating local knowledge and remote sensing for eco-type classification map in the Barotse Floodplain, Zambia. AB - This eco-type map presents land units with distinct vegetation and exposure to floods (or droughts) in three villages in the Barotseland, Zambia. The knowledge and eco-types descriptions were collected from participatory mapping and focus group discussions with 77 participants from Mapungu, Lealui, and Nalitoya. We used two Landsat 8 Enhanced Thematic Mapper (TM) images taken in March 24th and July 14th, 2014 (path 175, row 71) to calculate water level and vegetation type which are the two main criteria used by Lozi People for differentiating eco types. We calculated water levels by using the Water Index (WI) and vegetation type by using the Normalized Difference Vegetation Index (NDVI). We also calculated the Normalized Burn Ratio (NBR) index. We excluded burned areas in 2014 and built areas to reduce classification error. Control points include field data from 99 farmers' fields, 91 plots of 100 m2 and 65 waypoints randomly selected in a 6 km radius around each village. We also used Google Earth Pro to create control points in areas flooded year-round (e.g., deep waters and large canals), patches of forest and built areas. The eco-type map has a classification accuracy of 81% and a pixel resolution of 30 m. The eco-type map provides a useful resource for agriculture and conservation planning at the landscape level in the Barotse Floodplain. PMID- 30246097 TI - Supplementary data for the quantum chemical calculation of free radical substitution reaction mechanism of camptothecin. AB - This data article contains the truncated view of the transition states for methyl radical attacking camptothecin at the site of 9, 10, 11, 12 and 14 in acidic conditions obtained from quantum computation of Gaussian 09 with B3LYP/6 31+G(d,p) level, also the truncated view of transition states for H abstraction by singlet O2 from sites of 9, 10, 11 and 12 of the intermediates of methyl combination with camptothecin and that by triplet O2 from site 9 of the intermediate of methyl combination with camptothecin in acidic condition are included. The corresponding parameters of reaction rate constant calculation for the formation of methyl radical from acetaldehyde, the first and second step of radical substitution of camptothecin under acidic conditions are listed. The data of the basic parameters for the computation of the total energy of the spin projection of singlet oxygen, and the S2 values for the reactants, transition states and intermediates in the free radical substitution reaction of camptothecin are also included. PMID- 30246098 TI - The data on the relationship between polymorphism of HTR1B and DBH genes and attention-deficit hyperactivity disorder in adults with or without substance use disorders. AB - There is a positive relationship between attention-deficit hyperactivity disorder and tendency toward drug use in numerous studies. The present study was aimed to investigate the relationship between polymorphism of serotonin receptor 1B gene (HTR1B) and Dopamine beta-hydroxylase gene (DBH) with attention-deficit hyperactivity disorder in adults with or without substance use disorders. In the present case-control study, as many as 355 individuals entered the present study and was categorized in different groups: control healthy group, substance use disorders group, and attention-deficit hyperactivity disorder group. For confirming attention-deficit hyperactivity disorder in adults, demographic and Conners forms were used. Moreover, SCID-I questionnaire was used to confirm or reject the individual's suffering from substance use disorders and other psychiatric diseases. The polymorphism of abovementioned genes was conducted by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). In case of DBH gene-Rs2519152, the findings indicated that TT, TC, and CC genotypes and T and C alleles are not different in the attention-deficit hyperactivity disorder group, substance use disorder group, the group with patients suffering from both disorders, and control group. Moreover, the frequency of TT, TA, and AA genotypes as well as T and A alleles was same in the attention-deficit hyperactivity disorder group, substance use disorder group, the group with patients suffering from both disorders, and control group. PMID- 30246099 TI - Data for the level of women's self-esteem and couples' sexual satisfaction before and after mammoplasty. AB - Nowadays, one of the existing problems in the societies is the increase in the rate of plastic surgeries such as mammaplasty, especially among the women in Iran. The present study was conducted on the positive and negative effects of this surgery on Iranian women's self-esteem and couples' sexual satisfaction before and after mammaplasty. The analysis is based on data of a pretest posttest design with only one group conducted on 100 couples. Three questionnaires of demographic characteristics, Rosenberg's self-esteem, and women's and men's sexual satisfaction were adopted. The questionnaires were completed before surgery and two months after by the couples. Among 100 studied participants, mean self-esteem before and after mammaplasty were 18.77 and 17.96 respectively. Mean women's sexual satisfaction before and after surgery were 30.80 and 39.80 respectively. In conclusion, mammaplasty is effective on increase of women's sexual satisfaction, but it has no effect on increase of their self esteem and their husbands' sexual satisfaction. PMID- 30246100 TI - Chemical composition, antimicrobial and antioxidant activities data of three plants from Tunisia region: Erodium glaucophyllum, Erodium hirtum and Erodium guttatum. AB - In the present work, phytochemical contents (total phenolic content, total flavonoids, and condensed tannins), antioxidant potentials, and antimicrobial activities of three plants in the Mediterranean genus Erodium (Erodium glaucophyllum, Erodium hirtum, and Erodium guttatum) from the Tunisia region were analyzed. The results showed that E. glaucophyllum contained high levels of polyphenols, flavonoids, and tannins. Therefore, E. glaucophyllum possesses high antioxidant activities (2,2-diphenyl-1-picrylhydrazyl and ferric reducing antioxidant power scavenging activities), and high inhibition of linoleic acid oxidation. All three plants exhibited high antimicrobial activities. This study highlights tree plants' importance as dietary sources for natural antioxidants can be used in traditional medicine and the pharmaceutical industry. PMID- 30246101 TI - Biomass data for young, planted Norway spruce (Picea abies (L.) Karst.) trees in Eastern Carpathians of Romania. AB - Tree biomass data are essential for developing the biomass allometric models that are necessary for estimating carbon stock and for monitoring changes in forest biomass. In this 'data article' biomass records are presented for 240 Norway spruce trees (Picea abies (L.) Karst.). Trees were between 4 and 15 years of age and were sampled from 24 pure plantations located in Eastern Carpathians of Romania. Ten trees were sampled from each plantation using a cluster sampling method. For each tree, diameter at root collar height (D) and tree height (H) are provided as potential predictors for biomass. Oven-dried biomass is also recorded for the following partitions: stem (ST); branches (BR); needles (ND); roots (RT); as well as their combinations representing total aboveground biomass (AGB) and overall tree biomass (TB). Sampled trees were between 0.6 and 10.0 cm in diameter and between 53.0 and 552.0 cm in height. Total tree biomass ranged between 0.019 and 15.53 kg/tree. This dataset is related to the research article entitled "Site effects on biomass allometric models for early growth plantations of Norway spruce (Picea abies (L.) Karst.)" (Dutca et al., 2018) [1]. PMID- 30246102 TI - Electrical resistivity imaging (ERI) data for characterising crystalline basement structures in Abeokuta, southwestern Nigeria. AB - This article consists of data sets for five (5) traverses of 2D electrical resistivity imaging (ERI) collected in Abeokuta, southwestern Nigeria. ABEM Terrameter (SAS1000/4000) system and dipole-dipole array were used for the data collection. RES2DINV computer program was used to invert the observed apparent resistivity data to obtain 2D inverse model images of resistivity distribution of the subsurface. The 2D resistivity images were used to characterise the subsurface and delineate the crystalline basement features of hydrological importance in the area. PMID- 30246103 TI - Data on System Approach to Process of urban housing construction, renewal and upgrading. AB - Data about system that could be used in urban housing Construction process, renewal and upgrading is presented in this data article. Urban upgrading has been widely recognized as an essential issue in developing sustainable built environment. The aim is to identify the system approach that could be used for renewing and upgrading urban housing generally with view to expanding cities, redevelopment, redesigning and beautification of settlement layout, upgrading of facilities and public goods and services, repair, construction and silting of drainage system. Stratified survey method was used in generating the data, through identifying the current housing system in some selected locations in Ota, Ogun State, Nigeria, examining the factors that affects urban housing renewal and upgrading, identifying and examine the system approaches for urban housing renewal and upgrading and to develop a template for alternative material intervention for urban housing. The data was generated through questionnaire survey of 100 respondents; through Stratified sampling technique. Data collected were analyzed using Statistical Package for Social Sciences (SPSS) with Descriptive Statistics such as percentage distribution, charts and relative agreement index for the interpretation of findings. Data was presented on system that could be used in urban construction process, renewal and upgrading as includes: Redevelopment system, Revitalization system, Rehabilitation system, Regeneration system, Integration system, Conservation system and Afforestation system. PMID- 30246104 TI - Data of the first de novo transcriptome assembly of the inflorescence of Curcuma alismatifolia. AB - Curcuma alismatifolia, is an Asian crop from Zingiberaceae family, popularly used as ornamental plant in floriculture industry of Thailand and Cambodia. Different varieties with a wide range of colors can be found in species. Until now, few breeding programs have been done on this species and most commercially important cultivars are hybrids that are propagated vegetatively. In spite of other flowering plants, there is still lack of transcriptomic-based data on the functions of genes related to flower color in C. alismatifolia. The raw data presented in this article provides information on new original transcriptome data of two cultivars of C. alismatifolia by Illumina Hiseq. 4000 RNA-Seq technology which is the first ever report about this plant. The data is accessible via European Nucleotide Archive (ENA) under project number PRJEB18956. PMID- 30246105 TI - Data set on training assistance and the performance of small and medium enterprises in Lagos, Nigeria. AB - Human capital is considered a major asset of any business. This is even more vital in a knowledge-driven economy, where non-visible factors and services are of increasingly significant. The focus of this study was to determine the impact of training assistance on the performance of SMEs in Lagos, Nigeria. Only few studies have investigated how training support programmes by government facilitate the performance of SMEs under Small and Medium Enterprises Agency of Nigeria (SMEDAN) in Nigeria. Descriptive research method was adopted for this study. Statistical Package for Social Sciences (SPSS 22) was used to analyse 203 copies of questionnaire retrieved. The reliability and validity of research instruments was also established. This data set indicated that training and development can facilitate innovative processes among SMEs owners to create economic, social values and remain globally competitive. PMID- 30246106 TI - Corrigendum to "Data on insulin therapy refusal among type II diabetes mellitus patients in Mashhad, Iran" [Data in Brief 18 (2018) 2047-2050]. AB - [This corrects the article DOI: 10.1016/j.dib.2018.04.136.]. PMID- 30246107 TI - Data to support a simultaneous testosterone and estradiol assay in serum by LC MS/MS. AB - A very sensitive LC-MS/MS assay was developed implementing a liquid-liquid extraction step followed by mass spectrometry which was operated in both positive and negative ion modes. The assay was calibrated with readily available commercial calibrators and compared with international reference standards. This data is also presented in "Sensitive Simultaneous Quantitation of Testosterone and Estradiol in Serum by LC-MS/MS without Derivatization and Comparison with the CDC HoSt Program" (Schofield et al., 2017). This article includes the comparison of the LC-MS/MS assay with a commonly available chemiluminescencent immunoassay for the quantitation of both estradiol and testosterone. In addition we show baseline separation of estradiol and testosterone from other structurally related and/or isobaric compounds that could potentially interfere with the assay. In addition, various calibrator materials were tested and compared with internationally-recognized reference materials. PMID- 30246108 TI - Histological evaluation of experimental porcine bruises. AB - Age estimation is a crucial part of the forensic investigation of bruises in livestock pigs [1], [2], [3]. Currently, age estimations are based on histological evaluation of the lesions in the skin and underlying muscle tissue [2]. However, the intensity of inflammation and tissue damage depends not only on the age of bruises but also on sampling site, anatomical location and the speed, mass and force used to inflict the lesions [1], [4], [5]. Twelve experimental slaughter pigs were anesthetized and on each animal, four blunt traumas were inflicted on the back (area of impact Nos. 1-4). The pigs were euthanized at 2, 5 or 8 h after infliction. Skin and underlying muscle tissue were sampled from the center (B) and both ends of bruises (A, C) and evaluated histologically. Descriptive statistics were performed on the data obtained and presented in figures and tables. Differences (odds ratios) between sampling sites (A, B and C), object used to inflict bruises (plastic tube or iron bar), anatomical location (area of impact Nos. 1-4) and bruise age (2, 5 and 8 h) were evaluated using the GENMOD procedure in SAS Enterprise Guide 7.1 and presented in tables. In addition, the agreements (estimated as Cohen's kappa) between two observers evaluating the histological parameters were calculated and presented. Data have been further analyzed and discussed in a recent paper [1]. PMID- 30246109 TI - Group analysis data representing the effects of frontopolar transcranial direct current stimulation on the default mode network. AB - The current data provide information about altered activities of the default mode network (DMN) after applying transcranial direct current stimulation (tDCS) over the frontopolar prefrontal cortex. To explore whether frontopolar tDCS with a small current intensity and small electrodes can induce changes in the DMN, resting-state functional magnetic resonance imaging (fMRI) data were collected before and after the application of tDCS. The results of independent component analysis using the resting-state fMRI data are reported in this article. PMID- 30246110 TI - Synthesis and characterization of new dialkylacylphosphonylhydrazones. AB - The present work refers to the synthesis of novel dialkylacylphosphonylhydrazones that occurs in three reaction steps: the first one is the synthesis of different dialkyl acetate phosphonoacetates obtained by the reaction of ethyl bromoacetate with the trialkyl phosphite of interest. The second one is the synthesis of acetic diethoxyphosphonylhydrazines which is from the reaction between the synthesized dialkyl phosphonoacetates and hydrazine. The third and final steps is the condensation of acetic diethoxyphosphonylhydrazides with different heterocyclic aldehydes. In total, 17 unpublished compounds, namely 1 to 17 (Table 1) were obtained with a diastereoisomeric mixture of the preferential conformation E and all the compounds were characterized by 1-H and 13-C and 31-P NMR, infrared (IR) and mass spectroscopy (MS). This work presents the characterization data of these compounds. PMID- 30246111 TI - Herbicide tolerance-assisted multiplex targeted nucleotide substitution in rice. AB - Acetolactate synthase (ALS) catalyzes the initial step in the biosynthesis of branched-chain amino acids, and is highly conserved from bacteria to higher plants. ALS is encoded by a single copy gene in rice genome and is a target enzyme of several classes of herbicides. Although ALS mutations conferring herbicide-resistance property to plants are well documented, effect of Imazamox (IMZ) on rice and the mutations in ALS correlated with IMZ tolerance were unclear. In this article, the effect of IMZ on rice calli and seedlings in tissue culture conditions were evaluated. Also, the ALSA96V mutation was confirmed to improve IMZ tolerance of rice calli. Based on these results, ALS-assisted multiplex targeted base editing in rice was demonstrated in combination with Target-AID, a CRISPR/Cas9-cytidine deaminase fusion system [1], [2]. PMID- 30246112 TI - Data showing the shapes of cones and Muller cells within the fovea of monkeys reconstructed from serial sections and focused ion beam analysis. AB - The data presented in this article are related to the research paper entitled "The anatomy of the foveola reinvestigated" (Tschulakow et al., 2018) [1]. Here we show the original aligned serial sections through the foveal centre of monkeys at different planes of section and 3 D models of central foveal cells. PMID- 30246113 TI - Data to reproduce and modify "An approach for screening single phase high-entropy alloys using an in-house thermodynamic database". AB - XRD raw data of the milled and heat-treated Co,Fe,Mn,Ni,Zn-containing high entropy alloys (HEAs) is presented. Complete description of the quaternary, quinary and senary binary priority lists, including the names of the most relevant binary sets of elements for solid solution screening and the details of the parametric criterion used for making these lists are offered alongside a detailed thermodynamic description used to design Co,Fe,Mn,Ni,Zn-containing HEAs. In addition, a complete parametric study for quaternary, quinary and senary HEAs is shown. All the files and codes necessary to replicate and modify the previously mentioned results are available; commented by the authors in order to facilitate their usage. For further interpretation follow the research article: An approach for screening single phase high-entropy alloys using an in-house thermodynamic database (Tapia et al., 2018). PMID- 30246114 TI - Survey datasets on sick building syndrome: Causes and effects on selected public buildings in Lagos, Nigeria. AB - This dataset focuses on the causes and effects of sick building syndrome among users of selected facilities in Lagos. A mixed research approach of field measurement and cross-sectional survey was adopted. Descriptive statistics were implemented on the data acquired and are reported on tables and figures. The significance of this data leverages on providing insight and consciousness of sick building syndrome to users and occupants of constructed facilities. The survey dataset when analyzed can show direction on physical quantities levels that can be experienced in public buildings in tropical region. PMID- 30246115 TI - Data based investigation of the peer education methods on self-efficacy in patients with myocardial infarction using a randomized control trial design. AB - This database aims to show the effects of peer-education (PE) on self-efficacy in patients with MI referring to Zabol Emam Ali Hospital in 2016. The data provided in this paper are for a descriptive-analytical and experimental study which included 70 patients with MI that randomly assigned to PE group (n = 35) and control group (n = 35). We used two tools for data collection in this data article. Patient's demographic data questionnaire, consisting of two parts: the first section had questions about general details such as age, education, marital status, while the second section had questions about health status information. Cardiac self-efficacy questionnaire was the second questionnaire. Finally, the data of 30 intervention and 30 control individuals were then analyzed by SPSS software and P value < 0.05 was considered to be statistically significant. The data indicated that PE can be useful for providing a better care in MI patients, thus, it is recommended that it's better to use this training method besides the routine training of nurses for MI patients. PMID- 30246116 TI - Prioritization of the micro-watersheds through morphometric analysis in the Vasishta Sub Basin of the Vellar River, Tamil Nadu using ASTER Digital Elevation Model (DEM) data. AB - The dataset for this article includes morphological analysis of the level to which groundwater potential of the Vasishta River, Salem and Perambalur districts of Tamil Nadu. The method for the computation of morphometric parameters using data Digital Elevation Model (DEM) of the Vasishta River, is also prepared using SRTM (Shuttle Radar Topographic Mission) 90 m resolution data Morphometric parameter linear, aerial and relief limits, such as a bifurcation ratio (Rb), Drainage density (Dd) Stream Frequency (Fs) Elongation ratio (Re), Length of overland flow (Lg), Relief ratio, ruggedness number (Rn) and Slope (sb) of Vasishta Sub Basin (VSB). The relief ratio indicates that the discharge should be considered high priority given to the following micro-watersheds numbers 9,1,15,11 and 10. This data could be very useful to help with sustainable groundwater planning in any similar basins. PMID- 30246117 TI - Detection of common biogenic amines in fermented sausage produced in Turkey. AB - The application of HPLC method to detect the BA concentration in fermented sausage was successful and proved that HPLC system and method served its purposes. Biogenic amines are generated in foods as a result of free amino acid decarboxylation by bacterial enzymes. Biogenic amines accumulations are unwanted in all foods and beverages because if consumed at high concentrations, they may induce foodborne intoxications. Histamine, putrescine, cadaverine, tyramine, tryptamine, beta-phenylethylamine, spermine and spermidine are considered to be the most important biogenic amines occurring in foods. The determination of biogenic amines in foods is of great interest due to their potential toxicity and can be used as indicators for food quality markers. PMID- 30246118 TI - Data on thermal and hydrolytic stability of both domiphen bromide and para bromodomiphen bromide. AB - In this data article, HPLC analyses were applied to investigate the hydrolytic and thermal stability of domiphen bromide a FDA approved OTC ingredients endowed with antimicrobial activity. The data obtained by stressing domiphen bromide in acid, base and thermal conditions enlarge the research article published by Fumagalli et al. [2]. The chromatograms herein presented reveal that domiphen bromide is stable under acidic and thermal stress while the treatment with base yield to a by-product. The para-bromo derivative, p-bromodomiphen bromide shows the same behavior under the up mentioned stressed conditions. PMID- 30246119 TI - Granulomatous dermatitis as a postherpetic isotopic response in immunocompromised patients: A report of 5 cases. PMID- 30246120 TI - Nivolumab-induced alopecia areata: A reversible factor of good prognosis? PMID- 30246121 TI - Case series of psoriasis associated with tumor necrosis factor-alpha inhibitors in children with chronic recurrent multifocal osteomyelitis. PMID- 30246122 TI - The musician's mark. PMID- 30246123 TI - Successful treatment of type I pityriasis rubra pilaris with ixekizumab. PMID- 30246124 TI - Folliculotropic CD8+ mycosis fungoides associated with diffuse mucosal involvement. PMID- 30246125 TI - Neonatal lupus erythematosus or Sweet syndrome? PMID- 30246126 TI - Morphea associated with primary biliary cirrhosis and Waldenstrom macroglobulinemia: Response to rituximab. PMID- 30246127 TI - Correction. AB - [This corrects the article DOI: 10.1016/j.jdcr.2017.12.017.]. PMID- 30246128 TI - Systemic scleroderma and lupus panniculitis with atypical clinical features: A case report and comprehensive review. PMID- 30246129 TI - Worsening solid facial edema: An unusual case of angiosarcoma. PMID- 30246130 TI - Superficial granulomatous pyoderma of the leg improved after conservative management with Unna boot and intralesional steroid injections. PMID- 30246131 TI - Pityriasis rosea and pityriasis rosea-like eruptions: How to distinguish them? PMID- 30246132 TI - An atypical case of papular necrobiosis lipoidica masquerading as sarcoidosis. PMID- 30246133 TI - Acquired epidermodysplasia verruciformis in setting of tumor necrosis factor alpha inhibitor therapy. PMID- 30246134 TI - Palisaded neutrophilic and granulomatous dermatitis associated with ledipasvir/sofosbuvir. PMID- 30246135 TI - Medium-vessel vasculitis presenting as multiple leg ulcers after treatment with abatacept. PMID- 30246136 TI - Nodules developing after radiofrequency ablation of varicosities: A potential clinical and histopathologic mimic of polyarteritis nodosa. PMID- 30246137 TI - Recalcitrant annular pustular psoriasis associated with psoriatic arthritis successfully treated with secukinumab. PMID- 30246138 TI - Dramatic clinical response following dabrafenib and trametinib therapy in a heavily pretreated low grade serous ovarian carcinoma patient with a BRAF V600E mutation. AB - Low grade serous ovarian cancer (LGSOC) is a slowly growing, relatively chemoresistant neoplasm that is associated with a more favorable prognosis, especially compared to the disease's high-grade serous counterpart. We recount a case involving a 47-year-old, heavily pretreated LGSOC patient who presented with an elevated CA-125 of 1047 U/mL during her recent course of pemetrexed therapy. Thereafter, she underwent molecular profiling, which revealed a BRAF V600E mutation; accordingly, the patient was administered dabrafenib and trametinib combination therapy, a regimen that resulted in a precipitous decline of her CA 125 to 35 U/mL following the 6th cycle. The patient's favorable response to BRAF and MEK 1/2 inhibitor therapy underscores the significance of molecular profile testing and the use of targeted therapy regardless of tissue origin, especially in cases for whom standard management is limited or ineffective. PMID- 30246139 TI - Religious landscape in Brazil: Comparing different representative nationwide approaches to obtain sensitive information in healthcare research. AB - Although the basis of religious studies start with demographics, nation-wide data are often extracted from face-to-face interviews (leading to a social desirability bias) and in studies not originally designed to assess religion. This study aims to understand the religious landscape in Brazil and to investigate the feasibility of carrying out a representative nation-wide survey without interviewers, comparing it with other representative face-to-face surveys. We conducted a nationwide online survey representing all regions in Brazil. These results were compared with five other Brazilian representative surveys. A total of 1169 individuals completed the online questionnaires. The percentage of participants according to the gender and in relation to the Brazilian region was quite similar for all surveys. However, the online survey had the higher level of education among all surveys. In relation to the religious characteristics, the percentage of each variable varied from survey to survey. Those surveys originally designed to assess religion tended to yield more religious affiliations and less ceiling effects. The online survey was able to identify more diverse religious affiliations and more balanced responses in the religious attendance and importance of religion in life. The present study found that, even in nation-wide representative surveys, there are important differences in the results obtained while investigating religion. These differences could be associated with the type of data collection (face-to-face and online), the design of the study (originally designed to investigate religion or not) and options and the type of the questions used. PMID- 30246140 TI - Critical epidemiology in action: Research for and by indigenous peoples. AB - Global social justice movements, including transnational activism for indigenous rights, are working to promote health equity by transforming public health research and policy. Yet little social scientific research has examined how professional epidemiologists are figuring within such efforts. Discussions are unfolding, however, in critical sectors of epidemiology about how to improve the profession's input into advocacy. Findings from a multi-sited ethnographic study of epidemiological research for and by indigenous peoples in three settings (Aotearoa/New Zealand, the continental U.S., and Hawai'i) demonstrate how researchers/practitioners connect epidemiology and advocacy by: (1) linking the better-known legitimacy of quantitative methods to a lesser-known causal framework that positions colonialism as a sociopolitical determinant of health, (2) producing technical critiques that aim to improve the accuracy and accessibility of indigenous population health statistics, and (3) adopting a pragmatic flexibility in response to the shifting political conditions that shape when, whether and how epidemiological findings support advocacy for indigenous health equity. Attending closely to the credibility tactics at hand in this work, and to the skills and sensibilities of its practitioners, charts new directions for future research about epidemiology's contributions to advocacy for health equity. PMID- 30246142 TI - Educational Case: Infectious Diseases: Pathogenesis, Diagnosis, Treatment, and Prevention. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 30246141 TI - Sarcolab pilot study into skeletal muscle's adaptation to long-term spaceflight. AB - Spaceflight causes muscle wasting. The Sarcolab pilot study investigated two astronauts with regards to plantar flexor muscle size, architecture, and function, and to the underlying molecular adaptations in order to further the understanding of muscular responses to spaceflight and exercise countermeasures. Two crew members (A and B) spent 6 months in space. Crew member A trained less vigorously than B. Postflight, A showed substantial decrements in plantar flexor volume, muscle architecture, in strength and in fiber contractility, which was strongly mitigated in B. The difference between these crew members closely reflected FAK-Y397 abundance, a molecular marker of muscle's loading history. Moreover, crew member A showed downregulation of contractile proteins and enzymes of anaerobic metabolism, as well as of systemic markers of energy and protein metabolism. However, both crew members exhibited decrements in muscular aerobic metabolism and phosphate high energy transfer. We conclude that countermeasures can be effective, particularly when resistive forces are of sufficient magnitude. However, to fully prevent space-related muscular deterioration, intersubject variability must be understood, and intensive exercise countermeasures programs seem mandatory. Finally, proteomic and metabolomic analyses suggest that exercise benefits in space may go beyond mere maintenance of muscle mass, but rather extend to the level of organismic metabolism. PMID- 30246144 TI - Detection of Alkaline Phosphatase Enzyme Activity with a CatalyCEST MRI Biosensor. AB - Responsive CEST MRI biosensors offer good sensitivity and excellent specificity for detection of biomarkers with great potential for clinical translation. We report the application of fosfosal, a phosphorylated form of salicylic acid, for the detection of alkaline phosphatase (AP) enzyme. We detected conversion of fosfosal to salicylic acid in the presence of the enzyme by CEST MRI. Importantly the technique was able to detect AP enzyme expressed in cells in the presence of other cell components, which improves specificity. Various isoforms of the enzyme showed different Michaelis-Menten kinetics and yet these kinetics studies indicated very efficient catalytic rates. Our results with the fosfosal biosensor encourage further in vivo studies. PMID- 30246143 TI - A Universal Child Allowance: A Plan to Reduce Poverty and Income Instability Among Children in the United States. AB - To reduce child poverty and income instability, and eliminate extreme poverty among families with children in the United States, we propose converting the Child Tax Credit and child tax exemption into a universal, monthly child allowance. Our proposal is based on principles we argue should undergird the design of such policies: universality, accessibility, adequate payment levels, and more generous support for young children. Whether benefits should decline with additional children to reflect economies of scale is a question policymakers should consider. Analyzing 2015 Current Population Survey data, we estimate our proposed child allowance would reduce child poverty by about 40 percent, deep child poverty by nearly half, and would effectively eliminate extreme child poverty. Annual net cost estimates range from $66 billion to $105 billion. PMID- 30246145 TI - Transmission of Hepatitis B and D Viruses in an African Rural Community. AB - According to the World Health Organization (WHO), an estimated 257 million people worldwide are chronically infected with hepatitis B virus (HBV), with approximately 15 million of them being coinfected with hepatitis D virus (HDV). To investigate the prevalence and transmission of HBV and HDV within the general population of a rural village in Cameroon, we analyzed serum samples from most (401/448) of the villagers. HBV surface antigen (HBsAg) was detected in 54 (13.5%) of the 401 samples, with 15% of them also containing anti-HDV antibodies. Although Cameroon has integrated HBV vaccination into their Expanded Program on Immunization for newborns in 2005, an HBsAg carriage rate of 5% was found in children below the age of 5 years. Of the 54 HBsAg-positive samples, 49 HBV pre S/S sequences (7 genotype A and 42 genotype E sequences) could be amplified by PCR. In spite of the extreme geographical restriction in the recruitment of study participants, a remarkable genetic diversity within HBV genotypes was observed. Phylogenetic analysis of the sequences obtained from PCR products combined with demographic information revealed that the presence of some genetic variants was restricted to members of one household, indicative of intrafamilial transmission, which appears to take place at least in part perinatally from mother to child. Other genetic variants were more widely distributed, reflecting horizontal interhousehold transmission. Data for two households with more than one HBV-HDV coinfected individual indicate that the two viruses are not necessarily transmitted together, as family members with identical HBV sequences had different HDV statuses. IMPORTANCE This study revealed that the prevalence of HBV and HDV in a rural area of Cameroon is extremely high, underlining the pressing need for the improvement of control strategies. Systematic serological and phylogenetic analyses of HBV sequences turned out to be useful tools to identify networks of virus transmission within and between households. The high HBsAg carriage rate found among children demonstrates that implementation of the HBV birth dose vaccine and improvement of vaccine coverage will be key elements in preventing both HBV and HDV infections. In addition, the high HBsAg carriage rate in adolescents and adults emphasizes the need for identification of chronically infected individuals and linkage to WHO-recommended treatment to prevent progression to liver cirrhosis and hepatocellular carcinoma. PMID- 30246147 TI - Thermally Activated Second-Order Recombination Hints toward Indirect Recombination in Fully Inorganic CsPbI3 Perovskites. AB - The relationship between the dipole moment of the methylammonium cation and the optoelectronic properties of lead halide perovskites remains under debate. We show that both the temperature-dependent charge carrier mobility and recombination kinetics are identical for methylammonium and cesium lead iodide, indicating that the role of the monovalent cation is subordinate to the lead iodide framework. From the observation that for both perovskites the electron hole recombination is thermally activated, we speculate that the bandgap is slightly indirect. PMID- 30246148 TI - Photogrammetry of Human Specimens: An Innovation in Anatomy Education. AB - Cadaver-based anatomical education is supplemented by a wide range of pedagogical tools-from artistic diagrams, to photographs and videos, to 3-dimensional (3D) models. However, many of these supplements either simplify the true anatomy or are limited in their use and distribution. Photogrammetry, which overlaps 2 dimensional (2D) photographs to create digital 3D models, addresses such shortcomings by creating interactive, authentic digital models of cadaveric specimens. In this exploratory pilot study, we used a photogrammetric setup and rendering software developed by an outside group to produce digital 3D models of 8 dissected specimens of regional anatomy. The photogrammetrically produced anatomical models authentically and precisely represented their original specimens. These interactive models were deemed accurate and teachable by faculty at the Stanford University Division of Clinical Anatomy. Photogrammetry is, according to these results, another possible method for rendering cadaveric materials into interactive 3D models, which can be used for anatomical education. These models are more detailed than many computer-generated versions and provide more visuospatial information than 2D images. Future researchers and educators could use such technology to create institutional libraries of digital 3D anatomy for medical education. PMID- 30246146 TI - Characterization of Aspergillus niger Isolated from the International Space Station. AB - The initial characterization of the Aspergillus niger isolate JSC-093350089, collected from U.S. segment surfaces of the International Space Station (ISS), is reported, along with a comparison to the extensively studied strain ATCC 1015. Whole-genome sequencing of the ISS isolate enabled its phylogenetic placement within the A. niger/welwitschiae/lacticoffeatus clade and revealed that the genome of JSC-093350089 is within the observed genetic variance of other sequenced A. niger strains. The ISS isolate exhibited an increased rate of growth and pigment distribution compared to a terrestrial strain. Analysis of the isolate's proteome revealed significant differences in the molecular phenotype of JSC-093350089, including increased abundance of proteins involved in the A. niger starvation response, oxidative stress resistance, cell wall modulation, and nutrient acquisition. Together, these data reveal the existence of a distinct strain of A. niger on board the ISS and provide insight into the characteristics of melanized fungal species inhabiting spacecraft environments. IMPORTANCE A thorough understanding of how fungi respond and adapt to the various stimuli encountered during spaceflight presents many economic benefits and is imperative for the health of crew. As A. niger is a predominant ISS isolate frequently detected in built environments, studies of A. niger strains inhabiting closed systems may reveal information fundamental to the success of long-duration space missions. This investigation provides valuable insights into the adaptive mechanisms of fungi in extreme environments as well as countermeasures to eradicate unfavorable microbes. Further, it enhances understanding of host microbe interactions in closed systems, which can help NASA's Human Research Program maintain a habitat healthy for crew during long-term manned space missions. PMID- 30246149 TI - Xanthine oxidase inhibition for the improvement of long-term outcomes following ischaemic stroke and transient ischaemic attack (XILO-FIST) - Protocol for a randomised double blind placebo-controlled clinical trial. AB - Background: Allopurinol, a xanthine oxidase inhibitor, reduced progression of carotid-intima media thickness and lowered blood pressure in a small clinical trial in people with ischaemic stroke. Xanthine oxidase inhibition for improvement of long-term outcomes following ischaemic stroke and transient ischaemic attack (XILO-FIST) aims to assess the effect of allopurinol treatment on white matter hyperintensity progression and blood pressure after stroke. This paper describes the XILO-FIST protocol. Methods: XILO-FIST is a multicentre randomised double-blind, placebo-controlled, parallel group clinical trial funded by the British Heart Foundation and the Stroke Association. The trial has been adopted by the Scottish Stroke Research Network and the UK Clinical Research Network. The trial is registered in clinicaltrials.gov (registration number NCT02122718). XILO-FIST will randomise 464 participants, aged greater than 50 years, with ischaemic stroke within the past month, on a 1:1 basis, to two years treatment with allopurinol 300 mg twice daily or placebo. Participants will undergo brain magnetic resonance imaging, cognitive assessment, ambulatory blood pressure monitoring and blood sampling at baseline and after two years treatment. The primary outcome will be white matter hyperintensity progression, measured using the Rotterdam progression scale. Secondary outcomes will include change in white matter hyperintensity volume, mean day-time systolic blood pressure and measures of cognitive function. Up to 100 will undergo additional cardiac magnetic resonance imaging in a sub-study of left ventricular mass. Discussion: If white matter hyperintensity progression is reduced, allopurinol could be an effective preventative treatment for patients with ischaemic stroke and clinical endpoint studies would be needed. If allopurinol reduces blood pressure after stroke, then it could be used to help patients reach blood pressure targets. PMID- 30246151 TI - Sex, gender and blindness: a new framework for equity. AB - Four-fifths of all blind or vision impaired people live in middle-income and low income countries with the African region and parts of Asia and the Middle East bearing the heaviest burden. At the same time, we know that around two thirds of all blind people in the world are female. Hence, the poorest (and usually the oldest) women are most likely to have their lives limited by visual impairment. While recent strategies have focussed on international variations in eye health, very few have paid attention to the gender differences that are an inextricable element in these inequalities. This review will explore possible explanations for the advantage of men in the exercise of one of the most basic of human senses. It will show that this cannot be understood through the use of a biomedical approach alone. Broader social perspectives will also be needed in order to create an appropriate knowledge base for tackling global inequalities in blindness. PMID- 30246150 TI - PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke. Rationale and design of a randomised, open, phase III, clinical trial with blinded outcome assessment. AB - Background: Elderly patients are at high risk of complications after stroke, such as infections and fever. The occurrence of these complications has been associated with an increased risk of death or dependency.Hypothesis: Prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first four days after stroke onset will improve functional outcome at 90 days in elderly patients with acute stroke. Design: International, 3 * 2-factorial, randomised-controlled, open-label clinical trial with blinded outcome assessment (PROBE) in 3800 patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and an NIHSS score >= 6. Patients will be randomly allocated to any combination of oral, rectal, or intravenous metoclopramide (10 mg thrice daily); intravenous ceftriaxone (2000 mg once daily); oral, rectal, or intravenous paracetamol (1000 mg four times daily); or usual care, started within 24 h after symptom onset and continued for four days or until complete recovery or discharge from hospital, if earlier.Outcome: The primary outcome measure is the score on the modified Rankin Scale at 90 days (+/- 14 days), as analysed with multiple regression.Summary: This trial will provide evidence for a simple, safe and generally available treatment strategy that may reduce the burden of death or disability in patients with stroke at very low costs.Planning: First patient included in May 2016; final follow-up of the last patient by April 2020.Registration: ISRCTN, ISRCTN82217627, https://doi.org/10.1186/ISRCTN82217627. PMID- 30246153 TI - Blunt injury to the popliteal artery. PMID- 30246152 TI - A pilot study assessing the spiritual, emotional, physical/environmental, and physiological needs of mechanically ventilated surgical intensive care unit patients via eye tracking devices, head nodding, and communication boards. AB - Background: Mechanically ventilated patients in the intensive care unit (ICU) are unable to communicate verbally. We sought to evaluate their needs via a communication board (CB) and a novel eye tracking device (ETD) that verbalizes selections made by gazing. Methods: This was a pilot prospective study conducted in a tertiary care surgical ICU. Continuously mechanically ventilated adult surgical ICU patients with a Richmond Agitation-Sedation Scale score of -1 to +1, without cognitive impairment, were eligible. We asked patients four yes-or-no questions to assess basic needs regarding presence of pain, need for endotracheal suction, satisfactory room temperature, and position comfort. Patients were then asked if there was anything else that they wanted to communicate. All responses were confirmed by head nodding. Results: The median accuracy of the CB (100% (IQR 100%-100%)) for basic needs communication (yes/no questions) was comparable with that of the ETD (100% (IQR 68.8%-100%); p=0.14) in the 12 enrolled patients. Notably, 83% of patients desired to communicate additional information, ranging from spiritual (eg, desire for prayer/chaplain), emotional (eg, frustration, desire for comfort), physical/environmental (eg, television), to physiological (eg, thirst/hunger) needs. Discussion: The majority of patients desired to communicate something other than basic needs. Unless specifically assessed via an assistive communication device (eg, CB or ETD), some of these other needs would have been difficult to discern. Level of evidence: IV therapeutic care/management. PMID- 30246155 TI - Retrosplenial and postsubicular head direction cells compared during visual landmark discrimination. AB - Background: Visual landmarks are used by head direction (HD) cells to establish and help update the animal's representation of head direction, for use in orientation and navigation. Two cortical regions that are connected to primary visual areas, postsubiculum (PoS) and retrosplenial cortex (RSC), possess HD cells: we investigated whether they differ in how they process visual landmarks. Methods: We compared PoS and RSC HD cell activity from tetrode-implanted rats exploring an arena in which correct HD orientation required discrimination of two opposing landmarks having high, moderate or low discriminability. Results: RSC HD cells had higher firing rates than PoS HD cells and slightly lower modulation by angular head velocity, and anticipated actual head direction by ~48 ms, indicating that RSC spiking leads PoS spiking. Otherwise, we saw no differences in landmark processing, in that HD cells in both regions showed equal responsiveness to and discrimination of the cues, with cells in both regions having unipolar directional tuning curves and showing better discrimination of the highly discriminable cues. There was a small spatial component to the signal in some cells, consistent with their role in interacting with the place cell navigation system, and there was also slight modulation by running speed. Neither region showed theta modulation of HD cell spiking. Conclusions: That the cells can immediately respond to subtle differences in spatial landmarks is consistent with rapid processing of visual snapshots or scenes; similarities in PoS and RSC responding may be due either to similar computations being performed on the visual inputs, or to rapid sharing of information between these regions. More generally, this two-cue HD cell paradigm may be a useful method for testing rapid spontaneous visual discrimination capabilities in other experimental settings. PMID- 30246154 TI - Tumor evolution and chemoresistance in ovarian cancer. AB - Development of novel strategies to overcome chemoresistance is central goal in ovarian cancer research. Natural history of the cancer development and progression is being reconstructed by genomic datasets to understand the evolutionary pattern and direction. Recent studies suggest that intra-tumor heterogeneity (ITH) is the main cause of treatment failure by chemoresistance in many types of cancers including ovarian cancer. ITH increases the fitness of tumor to adapt to incompatible microenvironment. Understanding ITH in relation to the evolutionary pattern may result in the development of the innovative approach based on individual variability in the genetic, environment, and life style. Thus, we can reach the new big stage conquering the cancer. In this review, we will discuss the recent advances in understanding ovarian cancer biology through the use of next generation sequencing (NGS) and highlight areas of recent progress to improve precision medicine in ovarian cancer. PMID- 30246156 TI - Anterior cingulate cortex connectivity is associated with suppression of behaviour in a rat model of chronic pain. AB - A cardinal feature of persistent pain that follows injury is a general suppression of behaviour, in which motivation is inhibited in a way that promotes energy conservation and recuperation. Across species, the anterior cingulate cortex is associated with the motivational aspects of phasic pain, but whether it mediates motivational functions in persistent pain is less clear. Using burrowing behaviour as an marker of non-specific motivated behaviour in rodents, we studied the suppression of burrowing following painful confirmatory factor analysis or control injection into the right knee joint of 30 rats (14 with pain) and examined associated neural connectivity with ultra-high-field resting state functional magnetic resonance imaging. We found that connectivity between anterior cingulate cortex and subcortical structures including hypothalamic/preoptic nuclei and the bed nucleus of the stria terminalis correlated with the reduction in burrowing behaviour observed following the pain manipulation. In summary, the findings implicate anterior cingulate cortex connectivity as a correlate of the motivational aspect of persistent pain in rodents. PMID- 30246157 TI - Nursing attitudes towards continuous capnographic monitoring of floor patients. AB - Introduction: Nurses' perceptions of the utility of capnography monitoring are inconsistent in previous studies. We sought to outline the limitations of a uniform education effort in bringing about consistent views of capnography among nurses. Methods: A survey was administered to 22 nurses in three subacute care floors participating in a pragmatic clinical trial employing capnography monitoring in a large, urban tertiary care hospital. A 5-point Likert scale was used to assess the value and acceptance nurses ascribed to the practice. Means and SD were calculated for each response. Results: Survey results indicated inconsistency in the valuation of capnography, coupled with varying degrees of acceptance of its use. The mean for the level of perceived impact of capnography use on patient safety was 3.86, yet the perceived risk of removing capnography was represented by a mean of 2.57. The levels of urgency attached to apnoea alarms (mean 3.57, SD 1.57) were lower than those for alarms for oxygen saturation violations (mean 3.67, SD 1.32). The necessity for pulse oximetry monitoring was perceived as much higher than that for capnography monitoring (mean 1.76, SD 1.34), where '1' represented pulse oximetry as more necessary and '5' represented capnography as more necessary. Conclusions: Nursing acceptance of capnography monitoring is a difficult endpoint to achieve. There is a need for better accounting for the external and internal influences on nurse perceptions and values to have greater success with the implementation of similar monitoring. PMID- 30246158 TI - Effect of a pulmonary nodule fact sheet on patient anxiety and knowledge: a quality improvement initiative. AB - Introduction: The utilisation of chest CT for the evaluation of pulmonary disorders, including low-dose CT for lung cancer screening, is increasing in the USA. As a result, the discovery of both screening-detected and incidental pulmonary nodules has become more frequent. Despite an overall low risk of malignancy, pulmonary nodules are a common cause of emotional distress among adult patients. Methods: We conducted a multi-institutional quality improvement (QI) initiative involving 101 participants to determine the effect of a pulmonary nodule fact sheet on patient knowledge and anxiety. Males and females aged 35 years or older, who had a history of either screening-detected or incidental solid pulmonary nodule(s) sized 3-8 mm, were included. Prior to an internal medicine or pulmonary medicine clinic visit, participants were given a packet containing a pre-fact sheet survey, a pulmonary nodule fact sheet and a post-fact sheet survey. Results: Of 101 patients, 61 (60.4%) worried about their pulmonary nodule at least once per month with 18 (17.8%) worrying daily. The majority 67/101 (66.3%) selected chemotherapy, chemotherapy and radiation, or radiation as the best method to cure early-stage lung cancer. Despite ongoing radiographic surveillance, 16/101 (15.8%) stated they would not be interested in an intervention if lung cancer was diagnosed. Following review of the pulmonary nodule fact sheet, 84/101 (83.2%) reported improved anxiety and 96/101 (95.0%) reported an improved understanding of their health situation. Patient understanding significantly improved from 4.2/10.0 to 8.1/10.0 (p<0.01). Conclusion: The incorporation of a standardised fact sheet for subcentimeter solid pulmonary nodules improves patient understanding and alleviates anxiety. We plan to implement pulmonary nodule fact sheets into the care of our patients with low-risk subcentimeter pulmonary nodules. PMID- 30246160 TI - Axillary radiotherapy for nodal lymphoma: What CTV expansion is required to account for absence of pre-chemotherapy treatment position FDG PET-CT? AB - Involved site lymphoma radiotherapy clinical target volumes (CTV) require expansion in the absence of treatment-position pre-chemotherapy PET-CT. This prospective imaging study evaluates CTV contouring for axillary lymphoma using diagnostic imaging compared with co-registered treatment-position PET-CT. Generous expansion axially and cranio-caudally is required to encompass pre chemotherapy disease without treatment-position pre-chemotherapy PET-CT. PMID- 30246159 TI - Qualitative study investigating the perceptions of parents of children who failed vision screening at the age of 4-5 years. AB - Objective: To explore in depth parents' experiences and understanding of their children's eye care in order to better comprehend why there is relatively low uptake of services and variable adherence to treatment. Design: Semistructured interviews, informed by the Health Belief framework, were conducted with parents of children who had failed vision screening at age 4-5 years. Four were parents of children who never attended follow-up, 11 had children who attended but did not adhere to spectacle wear and 5 parents of children who had attended and adhered. Interviews were recorded and transcribed verbatim; thematic analysis based on the constant comparative method was undertaken. Results: Parents' beliefs led to uncertainty about the benefit of treatment, with parents testing their children to confirm the presence of a vision deficit and seeking advice from other family and community members. The stigma of spectacle wear explained the resistance of some to their child's treatment with the maintenance of 'normality' often more important than clinical advice. The combination of parents' own health beliefs, stigma and the practicalities of attending appointments together influenced parental decisions. Attendance following vision screening and the decision to adhere to spectacle wear were primarily based on the perceived severity of the visual reduction with the perceived benefit of spectacle wear outweighing any negative consequences. Conclusions: Healthcare professionals require a greater understanding of parents' decision-making processes in order to provide personalised information. Knowledge of the cues to attendance and adherence provides policy makers a framework with which to review the barriers, develop strategies and redesign children's eye care pathways. PMID- 30246161 TI - Synthesis, single crystal analysis, biological and docking evaluation of tetrazole derivatives. AB - Tetrazoles are conjugated nitrogen-rich heterocycles considered as bio-isosteres of carboxylic acids. Tetrazoles owing to their conjugated structures serve as biologically relevant potent scaffolds. The present research paper reports the successful synthesis and single crystal analysis of three different tetrazole derivatives (2, 4, 6). The synthesized tetrazole derivatives were evaluated for their possible cytotoxicity LD50 (52.89, 49.33, 17.28 MUg/ml) and antileishmanial activities IC50 (0.166, 10, 5.0 MUg/ml). Moreover, molecular docking studies were performed to determine the possible interaction sites of the tetrazole derivatives (2, 4, 6) with TryR, an enzyme involved in the redox metabolism of the Leishmania parasite. Docking computations demonstrates that the tetrazole derivatives (2, 4, 6) established prominent binding interactions with the key residues of the TryR and possess the potential to effectively inhibit the catalytic activities of the enzyme. The results suggested that the synthesized tetrazole derivative (2, 4, 6) can be possible hit candidates which can be tested further against amastigote stage of parasite and then in an animal model of leishmaniasis. PMID- 30246162 TI - Incidental extraspinal findings in the lumbar spine during magnetic resonance imaging of intervertebral discs. AB - Purpose: To calculate the frequencies of incidental extraspinal findings and incidentally detected congenital anomalies or anatomical differences in the lumbar spine on magnetic resonance imaging (MRI) scans of intervertebral discs. Materials and methods: A total of 379 lumbar spine MRI cases were prospectively investigated in the period spanning from August 2016 to January 2018. Both 1.5 and 0.35 Tesla MRI units (Toshiba and Siemens Medical Systems) were used to examine patients with clinically suspected intervertebral disc abnormalities at three MRI diagnostic centers in Khartoum State, Sudan. Results: Of the 379(100%) patients, 90(23.7%) patients were presented with incidental findings. Among the incidental findings, 39(10.3%) were renal cysts, 10(2.6%) were retroverted uteri, 5(1.3%) were Nabothian cysts, 4(1.1%) were ovarian cysts, 10(2.6%) were uterine fibroids, 3(0.8%) were endometrial thickening, 11(2.9%) were indicative of hydronephrosis, 4(1.1%) were uncovered prostatic enlargement, 2(0.5%) were atrophic kidney, and 1(0.3%) each was of an ectopic kidney and bladder wall thickening, respectively. Conclusions: A high percentage of extraspinal pathological findings were detected during MRI lumbar spine scans of intervertebral discs. Thus, it is important to be aware of the high percentage of patients who undergo further evaluation given the presence of unexpected findings, but for whom clinical confirmation of these abnormalities is not obtained. PMID- 30246163 TI - Molecular dynamics simulations of sodium alginate/sulfonated graphene oxide membranes properties. AB - The influence of methanol as a solvent on the properties of sodium alginate/sulfonated graphene oxide (SA/SGO) membranes was explored in water methanol mixed conditions with various methanol concentrations and temperatures through molecular dynamics simulations. The methanol uptake of the membrane showed an isolation phase determined from the simulation results. The distance between the sulfonic acid groups increased in higher methanol concentrations, as observed from S-S RDFs. Furthermore, the distance between the SA-chain RDFs and the solvent molecules was analysed to determine a) the affinity of water towards the sulfonic acid groups and b) the affinity of the aromatic backbone of the SA towards methanol molecules. A decrease in water molecule diffusion led to an increase in methanol diffusion and uptake. SA/SGO membranes exhibited a smaller diffusion coefficient than that for the Nafion membranes, as calculated from simulation results and compared to the experimental work. Additionally, the diffusion ability increased at higher temperatures for all permeants. The interaction information obtained is useful for DMFC applications. PMID- 30246164 TI - Descemet Membrane Endothelial Keratoplasty - Complication and management of a single case for tissue preparation and graft size linked to post-op descemetorhexis disparity. AB - Purpose: To report the management of an intraoperative complication during large (9.5 mm) ultra-thin Descemet Stripping Automated Endothelial Keratoplasty (UT DSAEK) surgery in a patient with a large area of dysfunctional endothelium. Observations: A single case study of an 89 y/o male with a history of Fuchs corneal endothelial dystrophy is presented. The patient was listed for a large UT DSAEK, but due to an intraoperative complication during graft preparation, an 8.00 mm Descemet membrane endothelial keratoplasty (DMEK) was prepared from the same graft using a standardized SCUBA technique and delivered. Early postoperative examination of the graft showed decentred, residual corneal oedema in the absence of DM detachment and a well-formed anterior chamber. The endothelial graft was found attached after 3 months and the corneal oedema was cleared. After 5 months, the patient's BSCVA was recorded at 6/6(20/20) in the left eye, but complained of mild discomfort. A circular ring of corneal oedema was observed around the graft and decentralization of the transplanted graft was observed. Endothelial cell density (ECD) of the central cornea at 5th month was 1506 cells/mm2 at a focal depth of 496 MUm with some polymegathism. Conclusions: and importance: It is possible to prepare DMEK starting from a failed DSAEK graft. Thickness map on corneal tomography could be a useful tool after DMEK for checking graft centration, function, and corneal recovery indirectly. It is recommended to only maintain a small distance between the descemetorhexis area and the size of the endothelial graft. PMID- 30246165 TI - Integration among databases and data sets to support productive nanotechnology: Challenges and recommendations. AB - Many groups within the broad field of nanoinformatics are already developing data repositories and analytical tools driven by their individual organizational goals. Integrating these data resources across disciplines and with non nanotechnology resources can support multiple objectives by enabling the reuse of the same information. Integration can also serve as the impetus for novel scientific discoveries by providing the framework to support deeper data analyses. This article discusses current data integration practices in nanoinformatics and in comparable mature fields, and nanotechnology-specific challenges impacting data integration. Based on results from a nanoinformatics community-wide survey, recommendations for achieving integration of existing operational nanotechnology resources are presented. Nanotechnology-specific data integration challenges, if effectively resolved, can foster the application and validation of nanotechnology within and across disciplines. This paper is one of a series of articles by the Nanomaterial Data Curation Initiative that address data issues such as data curation workflows, data completeness and quality, curator responsibilities, and metadata. PMID- 30246166 TI - A Workflow for Identifying Metabolically Active Chemicals to Complement in vitro Toxicity Screening. AB - The new paradigm of toxicity testing approaches involves rapid screening of thousands of chemicals across hundreds of biological targets through use of in vitro assays. Such assays may lead to false negatives when the complex metabolic processes that render a chemical bioactive in a living system are unable to be replicated in an in vitro environment. In the current study, a workflow is presented for complementing in vitro testing results with in silico and in vitro techniques to identify inactive parents that may produce active metabolites. A case study applying this workflow involved investigating the influence of metabolism for over 1,400 chemicals considered inactive across18 in vitro assays related to the estrogen receptor (ER) pathway. Over 7,500 first-generation and second-generation metabolites were generated for these in vitro inactive chemicals using an in silico software program. Next, a consensus model comprised of four individual quantitative structure activity relationship (QSAR) models was used to predict ER-binding activity for each of the metabolites. Binding activity was predicted for ~8-10% of metabolites in each generation, with these metabolites linked to 259 in vitro inactive parent chemicals. Metabolites were enriched in substructures consisting of alcohol, aromatic, and phenol bonds relative to their inactive parent chemicals, suggesting these features are potentially favorable for ER-binding. The workflow presented here can be used to identify parent chemicals that can be potentially bioactive, to aid confidence in high throughput risk screening. PMID- 30246167 TI - Maternal Cerebrospinal Fluid Glutamate in Response to Variable Foraging Demand: Relationship to Cerebrospinal Fluid Serotonin Metabolites in Grown Offspring. AB - Background: Maternal response to allostatic overload during infant rearing may alter neurobiological measures in grown offspring, potentially increasing susceptibility to mood and anxiety disorders. We examined maternal cerebrospinal fluid (CSF) glutamate response during exposure to variable foraging demand (VFD), a bonnet macaque model of allostatic overload, testing whether activation relative to baseline predicted concomitant CSF elevations of the stress neuropeptide, corticotropin-releasing factor. We investigated whether VFD-induced activation of maternal CSF glutamate affects maternal-infant attachment patterns and offspring CSF 5-hydroxyindoleacetic acid concentrations. Methods: Mother infant dyads were exposed to the "VFD stressor," a paradigm in which mothers experience 16 weeks of foraging uncertainty while rearing their infant offspring. Through staggering the infant age of VFD onset, both a cross-sectional design and a longitudinal design were used. Maternal CSF glutamate and glutamine concentrations post-VFD exposure were cross-sectionally compared to maternal VFD naive controls. Proportional change in concentrations of maternal glutamate (and glutamine), a longitudinal measure, was evaluated in relation to VFD-induced elevations of CSF corticotropin-releasing factor. The former measure was related to maternal-infant proximity scores obtained during the final phases of VFD exposure. Maternal glutamatergic response to VFD exposure was used as a predictor variable for young adolescent offspring CSF metabolites of serotonin, dopamine, and norepinephrine. Results: Following VFD exposure, maternal CSF glutamate concentrations correlated positively with maternal CSF CRF concentrations. Activation relative to baseline of maternal CSF glutamate concentrations following VFD exposure correlated directly with a) increased maternal-infant proximity during the final phases of VFD and b) offspring CSF concentrations of monoamine metabolites including 5-hydroxyindoleacetic acid, which was elevated relative to controls. Conclusions: Activation of maternal CSF glutamate in response to VFD-induced allostasis is directly associated with elevations of maternal CSF corticotropin-releasing factor. Maternal CSF glutamate alterations induced by VFD potentially compromise serotonin neurotransmission in grown offspring, conceivably modeling human vulnerability to treatment-resistant mood and anxiety disorders. PMID- 30246168 TI - Instrument flight to the inner ear. AB - Surgical robot systems can work beyond the limits of human perception, dexterity and scale making them inherently suitable for use in microsurgical procedures. However, despite extensive research, image-guided robotics applications for microsurgery have seen limited introduction into clinical care to date. Among others, challenges are geometric scale and haptic resolution at which the surgeon cannot sufficiently control a device outside the range of human faculties. Mechanisms are required to ascertain redundant control on process variables that ensure safety of the device, much like instrument-flight in avionics. Cochlear implantation surgery is a microsurgical procedure, in which specific tasks are at sub-millimetric scale and exceed reliable visuo-tactile feedback. Cochlear implantation is subject to intra- and inter-operative variations, leading to potentially inconsistent clinical and audiological outcomes for patients. The concept of robotic cochlear implantation aims to increase consistency of surgical outcomes such as preservation of residual hearing and reduce invasiveness of the procedure. We report successful image-guided, robotic CI in human. The robotic treatment model encompasses: computer-assisted surgery planning, precision stereotactic image-guidance, in-situ assessment of tissue properties and multipolar neuromonitoring (NM), all based on in vitro, in vivo and pilot data. The model is expandable to integrate additional robotic functionalities such as cochlear access and electrode insertion. Our results demonstrate the feasibility and possibilities of using robotic technology for microsurgery on the lateral skull base. It has the potential for benefit in other microsurgical domains for which there is no task-oriented, robotic technology available at present. PMID- 30246169 TI - Inference of Germline Mutational Status and Evaluation of Loss of Heterozygosity in High-Depth, Tumor-Only Sequencing Data. AB - PURPOSE: Inherited germline defects are implicated in up to 10% of human tumors, with particularly well-known roles in breast and ovarian cancers that harbor BRCA1/2-mutated genes. There is also increasing evidence for the role of germline alterations in other malignancies such as colon and pancreatic cancers. Mutations in familial cancer genes can be detected by high throughput sequencing (HTS), when applied to formalin-fixed paraffin-embedded (FFPE) tumor specimens. However, due to often lack of patient-matched control normal DNA and/or low tumor purity, there is limited ability to determine the genomic status of these alterations (germline versus somatic) and to assess the presence of loss of heterozygosity (LOH). These analyses, especially when applied to genes such as BRCA1/2, can have significant clinical implications for patient care. METHODS: LOHGIC (LOH-Germline Inference Calculator) is a statistical model selection method to determine somatic-versus-germline status and predict LOH for mutations identified via clinical grade, high-depth, hybrid-capture tumor-only sequencing. LOHGIC incorporates statistical uncertainties inherent to HTS as well as specimen biases in tumor purity estimates, which we use to assess BRCA1/2 mutations in 1,636 specimens sequenced at Rutgers Cancer Institute of New Jersey. RESULTS: Evaluation of LOHGIC with available germline sequencing from BRCA1/2 testing, demonstrates 93% accuracy, 100% precision, and 96% recall. This analysis highlights a differential tumor spectrum associated with BRCA1/2 mutations. CONCLUSION: LOHGIC can assess LOH status for both germline and somatic mutations. It also can be applied to any gene with candidate, inherited mutations. This approach demonstrates the clinical utility of targeted sequencing in both identifying patients with potential germline alterations in tumor suppressor genes as well as estimating LOH occurrence in cancer cells, which may confer therapeutic relevance. PMID- 30246170 TI - "Top-down" Does Not Mean "Voluntary". AB - Attention researchers have long debated the roles of top-down and bottom-up mechanisms in controlling attention. Theeuwes (2018) has argued that that top down control is much less common than typically assumed and that a third mechanism-selection history-plays an underappreciated role in guiding visual attention. Although Theeuwes has made a strong case for the importance of selection history, his arguments for a limited role of top-down mechanisms involve conflating the terms "top-down" and "voluntary." Cognitive psychologists typically use the term "top-down" processing to refer to any perceptual phenomenon that is influenced by context, learning, or expectation, which would include selection history. This highlights a broad problem in attention capture research: The terms used to describe attentional control are often poorly defined, and much current debate seems to be related to the meaning of words. To move forward in understanding the actual mechanisms of attentional control, we must agree on what terms such as "top-down" and "bottom-up" actually mean. PMID- 30246171 TI - "Nature versus Nurture" and the indigenous microbiome. PMID- 30246172 TI - Program & faculty evaluation. AB - Graduate medical education (GME) has shifted its curricula from process-oriented approach to outcomes-oriented models. Program and faculty evaluation are methods by which educational curricula may adjust the teaching and learning environment to meet the needs and fills the gaps in GME. The measurement of educational outcomes is an essential for assessing teaching effectiveness in a shifting health care environment. In addition to trainee, program, and faculty evaluations, annual program review (APR) and evaluation and navigational changes made by the program education committee are essential to maintain effectiveness of an educational curriculum in a contemporary graduate medical training program. PMID- 30246173 TI - The good doctor: more than medical knowledge & surgical skill. PMID- 30246175 TI - Development and Pilot Testing of an Internet-based Version of Parenting Wisely. PMID- 30246174 TI - Trends in Perioperative Venous Thromboembolism Associated with Major Noncardiac Surgery. AB - Background: Venous thromboembolism (VTE) is a common vascular complication of non cardiac surgery. Methods: We evaluated national trends in perioperative in hospital VTE incidence, management, and outcomes using a large database of hospital admissions from the United States. Patients aged >= 45 years undergoing major non-cardiac surgery from 2005 to 2013 were identified from the National Inpatient Sample. In-hospital perioperative VTE was defined as lower extremity deep vein thrombosis (DVT) or pulmonary embolism (PE), and the incidence was evaluated over time. Multivariable regression models with demographics and comorbidities as covariates were generated to estimate adjusted odds ratios (aOR). Results: Major non-cardiac surgery was performed in 9,431,442 hospitalizations that met inclusion criteria, and perioperative VTE occurred in 99,776 patients (1,057 per 100,000), corresponding to an annual incidence of ~53,000 after applying sample weights. Over time, perioperative VTE per 100,000 surgeries increased by 135 (95% CI 107 - 163), from 925 in 2005 to 1,060 in 2013 (p for trend <0.001; aOR [for 2013 versus 2005] 1.22, 95% CI 1.19 - 1.26), due to increases in non-fatal VTE rates (from 840 [per 100,000 surgeries] in 2005 to 987 in 2013; p for trend <0.001). Perioperative VTE occurred most frequently in patients undergoing thoracic (2.0%) and vascular surgery (1.8%). Mortality was higher in patients with VTE than those without VTE (aOR 3.12, 95% CI 3.05 - 3.20). Conclusions: Perioperative VTE occurs in approximately 1% of patients >=45 years undergoing major non-cardiac surgery, with increasing incidence of non fatal VTE over time. PMID- 30246176 TI - Estimation of evapotranspiration of temperate grassland based on high-resolution thermal and visible range imagery from unmanned aerial systems. AB - Spatially distributed high-resolution data of land surface temperature (LST) and evapotranspiration (ET) are important information for crop water management and other applications in the agricultural sector. While satellite data can provide LST high-resolution data of 100 m, the current development of unmanned aerial systems (UAS) and affordable low-weight thermal cameras allows LST and subsequent ET to be derived at resolutions down to centimetre scale. In this study, UAS based images in the thermal infrared (TIR) and visible spectral range were collected over a managed temperate grassland in July 2016 at the Terrestrial Environmental Observatories Networks TERENO preAlpine observatory site at Fendt, Germany. The UAS set-up included a lightweight thermal camera (Optris Pi Lightweight) and a regular digital camera (Sony alpha 6000) that allowed for the acquisition of thermal and optical images with a ground resolution of 5 cm and 1 cm, respectively. Three TIR-based ET models of different complexity were applied and the resulting ET estimates were compared to the Eddy covariance (EC) observations of turbulent energy fluxes and also to the evaporative fraction. While the Deriving Atmosphere Turbulent Transport Useful To Dummies Using Temperature (DATTUTDUT) model and the Triangle Method belong to the group of simpler contextual models, the Two-Source Energy Balance (TSEB) model incorporates a more physically based formulation of the surface energy balance. In addition to the comparison of UAS-based estimates of latent heat fluxes to EC observations, the effect of the spatial resolution of the model imagery input on the modelled results was analysed by running the models with imagery from the native resolution of the acquired images to resolutions that were aggregated up to 30 m. The results show that both contextual models are sensitive to the input image resolution and that the agreement with the EC observations improves with increasing image resolution. The TSEB model assumes that LST pixels represent a mixed signal of the soil and canopy components, thus an image resolution coarse enough to ensure this assumption should be chosen. However, with the exception of the native image resolution of 5 cm, we found no effect of image resolution on the spatially weighted mean TSEB estimates. For the studied grassland, the comparison of model estimates with EC observations indicates that all three models are able to reproduce observed energy fluxes with comparable accuracy with mean absolute errors of ET between 20 and 40 W m-2. The TSEB model showed larger deviations from the reference observations under cloudy conditions with rapid fluctuations of LST within the 30 min averaging period for EC. The two contextual models yielded similar results for most of the flights. The good performance of the DATTUTDUT model, which had the lowest input requirements of the three models, is especially promising in view of the application of UAS for routine near-real time ET monitoring. PMID- 30246177 TI - Estimating Learning Effects: A Short-Time Fourier Transform Regression Model for MEG Source Localization. AB - Magnetoencephalography (MEG) has a high temporal resolution well-suited for studying perceptual learning. However, to identify where learning happens in the brain, one needs to apply source localization techniques to project MEG sensor data into brain space. Previous source localization methods, such as the short time Fourier transform (STFT) method by Gramfort et al.([6]) produced intriguing results, but they were not designed to incorporate trial-by-trial learning effects. Here we modify the approach in [6] to produce an STFT-based source localization method (STFT-R) that includes an additional regression of the STFT components on covariates such as the behavioral learning curve. We also exploit a hierarchical L21 penalty to induce structured sparsity of STFT components and to emphasize signals from regions of interest (ROIs) that are selected according to prior knowledge. In reconstructing the ROI source signals from simulated data, STFT-R achieved smaller errors than a two-step method using the popular minimum norm estimate (MNE), and in a real-world human learning experiment, STFT-R yielded more interpretable results about what time-frequency components of the ROI signals were correlated with learning. PMID- 30246178 TI - Rotational 'cooling' and 'heating' of OH+(3Sigma-) by collisions with He: quantum dynamics revealing propensity rules under ion trap conditions. AB - Multichannel scattering calculations are presented for the low-energy collisions of the OH+ cation and He atoms, using an ab initio evaluation of the interaction potential, which had been obtained in earlier work, and a time-independent, multichannel treatment of the quantum dynamics carried out in this study using our in-house scattering code ASPIN. Given the presence of spin-rotation coupling effects, within an essentially electrostatic formulation of the interaction forces with He atoms in the trap, the ensuing propensity rules which control the relative size of the state-changing cross sections and of the corresponding inelastic rates, also computed at the most likely temperatures in an ion trap, are presented and analysed in detail. PMID- 30246179 TI - Automatic Segmentation of Hippocampus for Longitudinal Infant Brain MR Image Sequence by Spatial-Temporal Hypergraph Learning. AB - Accurate segmentation of infant hippocampus from Magnetic Resonance (MR) images is one of the key steps for the investigation of early brain development and neurological disorders. Since the manual delineation of anatomical structures is time-consuming and irreproducible, a number of automatic segmentation methods have been proposed, such as multi-atlas patch-based label fusion methods. However, the hippocampus during the first year of life undergoes dynamic appearance, tissue contrast and structural changes, which pose substantial challenges to the existing label fusion methods. In addition, most of the existing label fusion methods generally segment target images at each time-point independently, which is likely to result in inconsistent hippocampus segmentation results along different time-points. In this paper, we treat a longitudinal image sequence as a whole, and propose a spatial-temporal hypergraph based model to jointly segment infant hippocampi from all time-points. Specifically, in building the spatial-temporal hypergraph, (1) the atlas-to-target relationship and (2) the spatial/temporal neighborhood information within the target image sequence are encoded as two categories of hyperedges. Then, the infant hippocampus segmentation from the whole image sequence is formulated as a semi-supervised label propagation model using the proposed hypergraph. We evaluate our method in segmenting infant hippocampi from T1-weighted brain MR images acquired at the age of 2 weeks, 3 months, 6 months, 9 months, and 12 months. Experimental results demonstrate that, by leveraging spatial-temporal information, our method achieves better performance in both segmentation accuracy and consistency over the state of-the-art multi-atlas label fusion methods. PMID- 30246180 TI - Editorial: Overviews and umbrella reviews. PMID- 30246181 TI - Implant prosthetic rehabilitation in partially edentulous patients with bone atrophy. An umbrella review based on systematic reviews of randomised controlled trials. AB - PURPOSE: To summarise systematic reviews that assess the effects of different interventions for implant prosthetic rehabilitation in partially edentulous patients with the presence of bone atrophy. MATERIALS AND METHODS: Only systematic reviews of randomised controlled trials (RCTs) dealing with partially edentulous adult patients presenting bone defects were included. Treatments of interest were bone augmentation procedures, use of short, tilted or zygomatic implants, sinus lift and transposition of the inferior alveolar nerve. Outcome variables considered were: prosthetic and implant failure, complications, radiological and clinical peri-implant bone level variation, aesthetic and functional satisfaction, and vestibular peri-implant soft tissue recession. A search of systematic reviews of RCTs selected from MEDLINE, the Cochrane Database of Systematic Review, and the Prospero register published in the past 5 years (May 2012 - May 2017) was performed. Systematic reviews were also manually searched. Independent data extraction by two authors using predefined data fields, including ROBIS risk of bias, was executed. RESULTS: A total of 12 systematic reviews of RCTs were identified for inclusion in the overview. Eight reviews were considered at low risk of bias. Short implants (<= 8 mm) were associated with a notable decrease in complications compared to long implants with bone augmentation procedures. Many trials compared different sinus lift procedures and different bone augmentation techniques. None of these indicated that one procedure could reduce prosthetic or implant failures when compared to the other. The use of a membrane can contribute to the regeneration of the hard tissue in horizontal augmentation. Different membranes or bone substitutes did not give substantially different results. No data are available regarding comparisons involving zygomatic implants or tilted implants or transposition of the alveolar nerve. CONCLUSIONS: Overall, the evidence is not sufficiently robust to determine the best treatment for implant prosthetic rehabilitation in partially edentulous patients presenting bone atrophy. In terms of vertical defects, if the short implants can be used they should be used because the number of complications are reduced compared to longer implants with sinus lift or bone augmentation. Nevertheless, caution should be exercised because long-term follow up studies were not available. No conclusions can be drawn regarding the comparison between different vertical bone augmentation techniques in atrophic posterior mandible because quantitative meta-analyses were not performed. With regards to horizontal defects, the use of a membrane appears to increase the regeneration of the hard tissue but no differences were detected in prosthesis or implant failures or in complications. PMID- 30246182 TI - 6 mm vs 10 mm-long implants in the rehabilitation of posterior jaws: A 10-year follow-up of a randomised controlled trial. AB - PURPOSE: The aim of this study was to compare survival and success rates of 6 mm long and 10 mm-long implants in partially edentulous posterior areas. MATERIALS AND METHODS: Twenty-four patients with a partially edentulous area were included in the study. Patients were randomly allocated according to a parallel group design to receive 6 mm or 10 mm-long implants. A total of 54 implants were placed (26 * 6 mm implants). Patients were followed for 10 years after prosthetic loading. Outcome measures were prosthesis and implant survival, marginal bone level changes and complications. RESULTS: After 10 years, 17 patients (eight with 6 mm implants and nine with 10 mm implants) were available: three 6 mm and four 10 mm patients were lost to follow-up. One 6 mm implant failed during the healing period and its related prosthesis could not be placed. No implants were lost after loading. Nine patients in the 6 mm group registered a total of 15 complications: two mucositis, six decementations and seven chippings. Ten patients in the 10 mm group registered a total of 13 complications: five mucositis, two decementations and six chippings. Overall the difference for complications between the two groups was not statistically significant (P = 0.22; difference in proportion = -0.02; 95% CI: -0.31 to 0.27). Decementations in the 6 mm group were statistically significant higher than the 10 mm group (P = 0.04; difference in proportion = 0.39; 95% CI: 0.03 to 0.74). Marginal bone loss at 10 years was 0.84 and 0.37 mm with the 6 mm and 10 mm groups, respectively (difference between the two groups 0.49 mm; 95% CI -0.31; 1.29; not statistically significant: t test P = 0.22). CONCLUSIONS: Rehabilitations supported by 6 mm or 10 mm-long implants showed similar clinical outcomes in terms of survival and success rates, although 6 mm implants had more decementations. PMID- 30246183 TI - Immediate loading of fixed cross-arch prostheses supported by flapless-placed 5 mm or 11.5 mm long implants: 5-year results from a randomised controlled trial. AB - PURPOSE: To compare the outcome of cross-arch prostheses supported either by 5 mm long or 11.5 mm long implants placed flapless and immediately restored with a metal-resin screw-retained cross-arch prostheses. MATERIALS AND METHODS: Thirty patients with edentulous or to-be- rendered edentulous mandibles, and 30 with edentulous maxillas, having sufficient bone to allow the placement of four and six implants respectively, of at least 11.5 mm long, were randomised according to a parallel group design into two equal groups and received either 5 mm or 11.5 mm long implants at one centre. Implants had a diameter of 5 mm, were to be placed flapless, and with an insertion torque of at least 50 Ncm. Mandibles received four implants between the mental foramina. Implants were to be immediately loaded with metal-resin definitive prostheses the same day as implant placement. Patients were followed to 5 years post-loading and the outcome measures were: prosthesis and implant failures, complications, and peri-implant marginal bone level changes. RESULTS: Four patients per group dropped out. Two prostheses were remade, one on short maxillary implants and one on long mandibular implants (difference in proportions = 0; 95% CI: -0.15 to 0.15; P = 1.000). Three patients lost six short implants vs three patients who lost four long implants (difference in proportions = 0; 95% CI: -0.19 to 0.19; P = 1.000). Four short implant patients were affected by complications vs five patients with long implants (difference in proportions = 0.04; 95% CI: -0.17 to 0.25; P = 1.000). There were no statistically significant differences for prostheses failures, implant failures and complications. Patients with mandibular short implants lost on average 0.22 mm of peri-implant bone at 5 years while patients with long mandibular implants lost 0.83 mm. Patients with maxillary short implants lost on average 0.30 mm of peri-implant bone at 5 years and patients with long maxillary implants lost 0.89 mm. Short implants showed less bone loss when compared with long implants and the differences up to 5 years were statistically significant both in maxillae (mean difference = 0.59 mm, 95% CI: 0.33 to 0.86 mm, P < .0001) and in mandibles (mean difference = 0.61 mm, 95% CI: 0.36 to 0.86 mm, P < 0.0001). CONCLUSIONS: Flapless-placed 5 mm long implants achieved similar results as 11.5 mm long implants when supporting immediately loaded cross-arch prostheses both in maxillae and mandibles up to 5 years after loading. These results must be confirmed by other trials, and 10 years post-loading data is necessary before making reliable recommendations. PMID- 30246184 TI - Immediate loading of occluding definitive partial fixed prostheses vs non occluding provisional restorations - 3-year post-loading results from a pragmatic multicentre randomised controlled trial. AB - PURPOSE: To compare the clinical outcome of dental implants restored with definitive occluding partial fixed prostheses within 1 week after implant placement with immediate non-occluding provisional restorations to be replaced by definitive prostheses after 4 months. MATERIALS AND METHODS: Forty partially edentulous patients treated with one to three dental implants, at least 8.5 mm long and 4.0 mm wide, inserted with a torque of at least 35 Ncm, were randomised in two groups of 20 patients each, to be immediately loaded with partial fixed prostheses. Patients in one group received one definitive screw-retained, metal ceramic prosthesis in occlusion within 1 week after placement. Patients in the other group received one non-occluding provisional acrylic reinforced prosthesis within 24 h of implant placement. Provisional prostheses were replaced by definitive ones after 4 months. The follow-up for all patients was 3 years post loading. Outcome measures were prosthesis and implant failures, any complications, peri-implant marginal bone level changes, aesthetic evaluation by a dental practitioner, patient satisfaction, chair time and number of visits at the dental office from implant placement to delivery of definitive restorations. RESULTS: Three patients dropped out, one from the non-occlusal group and two from the occlusal group. Two immediately occlusally loaded implants with their related definitive prostheses failed early (difference in proportions = 0.10; 95% CI = 0.03 to 0.23; P = 0.488). Five patients from the occlusally loaded group were affected by six complications vs three patients (three complications) in the non occlusally loaded group. The difference in proportions was not statistically significant (difference in proportions = 0.08; 95% CI = -0.17 to 0.34; P = 0.697). Three years after loading, patients subjected to occlusal loading lost an average of 1.13 mm of peri-implant bone vs 1.03 mm of patients restored with non occluding definitive partial fixed prostheses. There were no statistically significant differences for marginal bone level changes between the two groups (mean difference = 0.10 mm; 95% CI -0.62 to 0.82; P = 0.779). No significant were the differences for pink aesthetic scores (7.09 vs 6.90; P = 0.873); for aesthetics evaluated by patients (Mann-Whitney U test P = 0.799) and function satisfaction (Mann-Whitney U test P = 0.578). Significantly less chair time (mean difference -38.00; 95% CI -58.96 to -17.04; P = 0.001) and number of visits (mean difference -2.15; 95% CI -2.77 to -1.53; P < 0.001) were required for the immediate definitive prosthesis group. CONCLUSIONS: This study did not provide a conclusive answer, but suggests that immediate occlusal loading by manufacturing immediate definitive partial fixed prostheses decreases chair time and number of visits. PMID- 30246185 TI - Immediate loading of three (fixed-on-3) vs four (fixed-on-4) implants supporting cross-arch fixed prostheses: 1-year results from a multicentre randomised controlled trial. AB - PURPOSE: To evaluate the outcome of three (fixed-on-3 = Fo3) vs four (fixed-on-4 = Fo4) implants immediately restored with metal-resin screw-retained cross-arch prostheses in fully edentulous jaws. MATERIALS AND METHODS: Forty-eight edentulous or to be rendered edentulous patients were randomised in six centres (eight patients per centre) to the Fo3 group (24 patients: 12 maxillae and 12 mandibles) and to the Fo4 group (24 patients: 12 maxillae and 12 mandibles) according to a parallel group design. To be immediately loaded, implants had to be inserted with a minimum torque of 40 Ncm. Outcome measures were prosthesis and implant failures, complications and peri-implant marginal bone level changes evaluated up to 1 year post-loading. RESULTS: One maxillary prosthesis per group was delayed loaded because implants could not be placed with a torque of at least 40 Ncm. Ten patients in the Fo3 group and four in the Fo4 group had implants placed flapless. One year after loading no drop out occurred. One patient of the Fo3 group lost three implants vs three patients of the Fo4 group who lost four implants, the difference being no statistically significant (risk difference = 0.08; 95% CI: -0.27 to 0.10; Fisher's exact test P = 0.609). One mandibular Fo3 and one maxillary Fo4 prosthesis failed. Six Fo3 patients were affected by complications vs three Fo4 patients (risk difference = 0.12; 95% CI: -0.10 to 0.34; Fisher's exact test; P = 0.461). Both groups lost marginal bone in a statistically significant way (0.22 +/- 0.20 mm for Fo3 patients and 0.40 +/- 0.21 mm for Fo4 patients), with Fo3 group showing less marginal peri-implant bone loss than Fo4 group (estimate of the difference = -0.18 (standard error: 0.06) mm; 95% CI: -0.30 to -0.06; P = 0.005). There were no differences in clinical outcomes between the six operators. CONCLUSIONS: These preliminary results suggest that immediately loaded cross-arch prostheses of both jaws can be supported by only three dental implants at least up to 1 year post-loading, though longer follow-ups are definitively needed. PMID- 30246186 TI - Immediate vs conventional loading of variable-thread tapered implants supporting three- to four-unit fixed partial dentures in the posterior maxilla: 1-year interim results of a split-mouth randomised controlled trial. AB - PURPOSE: To compare the outcome of immediately loaded and one-stage conventionally loaded variable-thread tapered implants in the posterior maxilla. MATERIALS AND METHODS: This study was designed as a split-mouth randomised controlled trial. Twenty-six patients missing teeth bilaterally in the posterior maxilla received three to four implants in each of the posterior sextants. Bone quality was recorded based on Misch criteria (D1-D4) and insertion torque values were measured using a manual wrench. The implants on one side were immediately loaded with a temporary resin fixed partial denture on definitive multi-unit abutments. The implants in the contralateral side received definitive multi-unit abutments according to the one-stage unloaded protocol. Three to 3.5 months following implant placement, the implants were restored with metal-ceramic fixed prostheses. Outcome measures were implant and prosthesis failure rates, complications, and peri-implant bone level changes at 1 year following delivery of the definitive prostheses. RESULTS: Two patients dropped out prior to the delivery of definitive prostheses. Four implants supporting a four-unit immediately loaded prosthesis failed in one patient, 3 months following delivery of the definitive prostheses. None of the conventionally loaded implants or prostheses failed. There were no significant differences in the proportions of implant and prosthesis failures (difference = 4.2%; 95% CI -4.2 to 12.6%; P = 0.999). In the immediately loaded group, four early prosthetic complications occurred during the provisionalization phase (three small resin chippings and one prosthetic screw loosening). No other complications were reported. The difference in the rate of complications between the two interventions was not statistically significant (difference = 16.7%; 95% CI -1.2% to 35.6%; P = 0.125). The 1-year peri-implant marginal bone level changes were evaluated in 23 patients (77 immediately loaded and 76 conventionally loaded implants). On average, patients lost 0.42 mm at the immediately loaded and 0.46 mm at the conventionally loaded implants, the difference being statistically not significant (difference = 0.044 mm; 95% CI -0.27 to 0.18 mm; P = 0.701). CONCLUSIONS: Immediate loading of 3- to 4-unit fixed partial prostheses supported by variable-thread implants in the posterior maxilla can yield good and similar 1-year results to one-stage conventionally loaded implants. PMID- 30246187 TI - 1-year results from a split-mouth randomised controlled pilot trial comparing implants with 0.75 mm of machined collar placed at bone level or supracrestally. AB - PURPOSE: The present study evaluated the hypothesis that implants inserted at bone level or supracrestally have different outcomes in single tooth replacements against the alternative hypothesis of no difference. MATERIALS AND METHODS: This study was designed as a randomised, split-mouth, controlled pilot trial. Ten patients, each missing two bicuspids or molars, were treated with 20 implants featuring 0.75 mm of machined collar. Each patient randomly received one implant inserted at bone level (BL) and one inserted 0.75 mm to 1 mm above the alveolar crest (SC), measured with a periodontal probe during surgery. All the implants were inserted into healed healthy bone with an insertion torque ranging between 35 Ncm and 45 Ncm. Both implants were loaded with screw-retained acrylic-resin temporary crowns 3 months after implant insertion and 3 months later with screw retained zirconia-ceramic definitive crowns. Outcome measures were implant/crown failures, biological and prosthetic complications, radiographic marginal bone level changes (MBL), probing pocket depth (PPD) and bleeding on probing (BOP). Clinical data were collected at baseline (implant insertion) and 1 year after implant placement (9 months after initial loading). RESULTS: After 1 year of follow-up, no patients dropped out, no implants failed, and no complications occurred. The mean MBL at the 1-year follow-up was 0.28 +/- 0.21 mm in the SC group and 0.93 +/- 0.37 mm in the BL group. While the difference in MBL was statistically significant between the two treatment groups (difference 0.65 +/- 0.34; 95% CI = 0.59 to 1.01; P = 0.0001), the soft-tissue parameters were not statistically different. The mean PPD was 2.63 +/- 2.4 in the SC group and 2.40 +/- 0.70 in the BL group (P = 0.419) and mean BOP was 0.50 +/- 0.71 in the SC group and 0.40 +/- 0.70 in the BL group (P = 0.754). CONCLUSIONS: The smooth collar implants inserted supracrestally showed 0.7 mm less radiographic marginal bone loss compared with implants inserted at the bone level 9 months after loading. PMID- 30246188 TI - A controlled study on the accuracy and precision of intraoral radiography in assessing interproximal bone defect morphology around teeth and implants. AB - PURPOSE: The primary objective of the present controlled study was to determine the accuracy and precision of intraoral radiography in assessing interproximal bone defect morphology in patients suffering from periodontal disease as well as in patients with peri-implantitis. A secondary objective was to evaluate the possible impact of clinical experience on accuracy and precision. MATERIALS AND METHODS: The study sample comprised a total of 99 interproximal bony defects (40 patients) needing surgical treatment. Forty-nine defects were periodontal (17 patients), while the remaining 50 were peri-implant defects (23 patients). Following reflection of a mucoperiosteal flap and removal of granulation tissue, the type of bone defect as classified by Goldman and Cohen (1958) was determined. This intrasurgical registration was considered the true bone defect morphology. An intraoral radiograph was taken for each interproximal site. Twenty clinicians determined the bone defect morphology on each intraoral radiograph twice, with a washout period of 3 months. RESULTS: Using the Goldman and Cohen (1958) classification, the overall accuracy of intraoral radiography in assessing interproximal bone defect morphology was slight for teeth/implants (kappa = 0.132; 95% CI: 0.091 to 0.173/kappa = 0.126; 95% CI: 0.091 to 0.162). Duplicate evaluation indicated fair precision (kappa = 0.369; 95% CI: 0.308 to 0.430/kappa = 0.355; 95% CI: 0.230 to 0.414). Pooling one-, two- and three-wall defects into one category had a positive impact on accuracy (kappa = 0.254; 95% CI: 0.201 to 0.307/kappa = 0.387; 95% CI: 0.340 to 0.435), as well as on precision (kappa = 0.504; 95% CI: 0.423 to 0.584/kappa = 0.560; 95% CI: 0.463 to 0.657). A significant difference between experienced clinicians and trainees was not found (P >= 0.285). CONCLUSIONS: Intraoral radiography lacks accuracy for assessing interproximal bone defect morphology around teeth and implants. Clinical experience does not seem to influence this. PMID- 30246189 TI - Research in focus. AB - This section presents a brief review of articles on dental implants considered of special interest for the reader, in order to encourage the developing of research, the interest for data analysis and the attention to scientific publications. Your comments are welcome. Please contact Dr Michele Nieri at michelenieri@gmail.com. PMID- 30246190 TI - Aggregation of lactic acid in cold rare-gas matrices and the link to solution: a matrix isolation-vibrational circular dichroism study. AB - The matrix isolation (MI) technique has been utilized with vibrational circular dichroism (VCD) spectroscopy to obtain MI-VCD spectra of lactic acid (LA) in cold argon matrices, in addition to their MI-IR spectra. The experiments have been done at three different deposition temperatures (10 K, 16 K and 24 K) under different Ar flow rates so that different degrees of LA self-aggregation occur. The structural and spectral investigations of the LA monomer and the larger (LA)2,3,4 aggregates have been undertaken at three levels of theory (B3LYP/6 311++G(2d,p), B3LYP-D3BJ/6-311++G(2d,p) and B3LYP-D3BJ/def2-TZVPD) to evaluate the effects of dispersion correction and basis sets on optimized structures, relative conformer energies, and IR/VCD spectral features. Interestingly, the relative conformer energies vary considerably with and without dispersion correction, especially when the molecule gets larger and when it is placed in solution. Such uncertainties in the relative energies and in the vibrational band positions and IR/VCD intensities highlight the challenges in interpreting experimental spectroscopic data, especially those obtained in solution. With the narrow MI-IR band width and highly characteristic MI-VCD spectral features and the trend observed at three temperatures, we have been able to correlate the spectral features confidently to those of the LA monomer and the larger (LA)2,3,4 aggregates, with the aid of theoretical modeling. Finally, by noting the similarity of MI-IR and especially MI-VCD features obtained at 24 K with those of the 0.2 M solution, and with the aid of spectral simulation at the B3LYP D3BJ/def2-TZVPD level, a composition of LA aggregates dominated by the LA tetramer and trimer has been identified. This conclusion differs from the previous reports where the LA dimer was identified as the main species at even higher concentration in CDCl3. The present work showcases the power of MI-VCD spectroscopy in aiding solution spectral assignment and in providing insight into the complex self-aggregation behavior of LA in solution. PMID- 30246191 TI - Excitonic phenomena in perovskite quantum-dot supercrystals. AB - Quantum confinement and collective excitations in perovskite quantum-dot (QD) supercrystals offer multiple benefits to the light emitting and solar energy harvesting devices of modern photovoltaics. Recent advances in the fabrication technology of low dimensional perovskites has made the production of such supercrystals a reality and created a high demand for the modelling of excitonic phenomena inside them. Here we present a rigorous theory of Frenkel excitons in lead halide perovskite QD supercrystals with a square Bravais lattice. The theory shows that such supercrystals support three bright exciton modes whose dispersion and polarization properties are controlled by the symmetry of the perovskite lattice and the orientations of QDs. The effective masses of excitons are found to scale with the ratio of the superlattice period and the number of QDs along the supercrystal edge, allowing one to fine-tune the electro-optical response of the supercrystals as desired for applications. We also calculate the conductivity of perovskite QD supercrystals and analyze how it is affected by the optical generation of the three types of excitons. This paper provides a solid theoretical basis for the modelling of two- and three-dimensional supercrystals made of perovskite QDs and the engineering of photovoltaic devices with superior optoelectronic properties. PMID- 30246192 TI - Highly sensitive and multiplexed miRNA analysis based on digitally encoded silica microparticles coupled with RCA-based cascade amplification. AB - Currently, miRNA analysis is significant for understanding miRNA regulation networks and clinical diagnostics and therapy. Analytical strategies feasible for multiplex miRNA-sensitive analysis are still in high demand. Herein, we propose a novel strategy for miRNA analysis by coupling cascade amplification with digitally encoded silica microparticles. The microparticles are precisely fabricated in a digital form through a one-step deposition strategy and are highly efficient for multiplex analysis. The cascade amplification composed of RCA and nicking-assisted strand-displacement amplification (SDA) exhibits high amplification efficiency and requires no complicated sequence design, thus improving the compatibility with base-stacking hybridization on our microparticles. Parallel and sensitive analyses for let-7a and miR-21 in one pot without mutual interference have been achieved with both high sensitivity (LOD, ~0.5 fM) and wide dynamic range (10 pM-1 fM). Moreover, our strategy exhibits high specificity for miRNAs of homologous sequence and good anti-interference ability in a complex sample matrix. Considering that there are up to 128 (27) kinds of microparticles available, our strategy can be applied for dozens of miRNA-sensitive analyses in one pot, and it has great potential for miRNA signature analysis as well as widespread clinical applications. PMID- 30246193 TI - Highly fluorescent, monolithic semiconductor nanorod clusters for ultrasensitive biodetection. AB - We have developed highly fluorescent, monolithic colloidal CdSe seeded CdS nanorod clusters comprising thousands of nanorods. Their use in the sandwich assay detection of a model protein yields a thousand-fold improvement in the detection limit compared to individual nanorods, making them suitable for the detection of low abundance molecular targets. PMID- 30246194 TI - Step-like band alignment and stacking-dependent band splitting in trilayer TMD heterostructures. AB - We propose for the first time a kind of van der Waals (vdW) heterostructure composed of three distinct transition-metal dichalcogenide (TMD) monolayers, where step-like band alignment could be realized. In this case, excitons can be spatially separated into constituent top and bottom layers segregated by the middle layer. In light of the reduced binding energy and long lifetime of the interlayer excitons, trilayer TMD heterostructures hold great promise in applications such as solar cells and light-harvesting. In addition, heterostructures with different constituents and stacking orders give rise to distinct band offsets between neighboring layers. Other factors, like strain and SOC, also have apparent effects on the band offset. Our results reveal that 2H stacking can enhance valence band splitting, while 3R stacking has a significant influence on conduction band splitting. On account of the proper step-like band alignment and stacking-dependent band splitting, these trilayer TMD heterostructures also have great potential for applications in spintronics. PMID- 30246195 TI - Molecular hydrides of divalent ytterbium supported by a macrocyclic ligand: synthesis, structure and olefin hydrofunctionalization catalysis. AB - Bis(triphenylsilyl) and dibenzyl ytterbium(ii) complexes supported by the macrocyclic polyamine ligand Me4TACD (1,4,7,10-tetramethyl-1,4,7,10 tetraazacyclododecane) reacted with H2 to give the cationic ytterbium hydrides [(Me4TACD)2Yb2(MU2-H)(2+n)](2-n)+ (n = 0, 1). The hydrides catalyzed the H2/D2 isotope exchange as well as hydrogenation and hydrosilylation of 1-hexene. PMID- 30246196 TI - "Chemistry-on-the-complex": functional RuII polypyridyl-type sensitizers as divergent building blocks. AB - Ruthenium polypyridyl type complexes are potent photoactive compounds, and have found - among others - a broad range of important applications in the fields of biomedical diagnosis and phototherapy, energy conversion schemes such as dye sensitized solar cells (DSSCs) and molecular assemblies for tailored photo initiated processes. In this regard, the linkage of RuII polypyridyl-type complexes with specific functional moieties is highly desirable to enhance their inherent photophysical properties, e.g., with a targeting function to achieve cell selectivity, or with a dye or redox-active subunits for energy- and electron transfer. However, the classical approach of performing ligand syntheses first and the formation of Ru complexes in the last steps imposes synthetic limitations with regard to tolerating functional groups or moieties as well as requiring lengthy convergent routes. Alternatively, the diversification of Ru complexes after coordination (termed "chemistry-on-the-complex") provides an elegant complementary approach. In addition to the Click chemistry concept, the rapidly developing synthesis and purification methodologies permit the preparation of Ru conjugates via amidation, alkylation and cross-coupling reactions. In this regard, recent developments in chromatography shifted the limits of purification, e.g., by using new commercialized surface-modified silica gels and automated instrumentation. This review provides detailed insights into applying the "chemistry-on-the-complex" concept, which is believed to stimulate the modular preparation of unpreceded molecular assemblies as well as functional materials based on Ru-based building blocks, including combinatorial approaches. PMID- 30246197 TI - High-symmetry tubular Ta@B183-, Ta2@B18, and Ta2@B27+ as embryos of alpha boronanotubes with a transition-metal wire coordinated inside. AB - Transition-metal doping leads to dramatic structural changes and results in novel bonding patterns in small boron clusters. Based on the experimentally derived mono-ring planar C9v Ta(c)B92- (1) and extensive first-principles theory calculations, we present herein the possibility of high-symmetry double-ring tubular D9d Ta@B183- (2) and C9v Ta2@B18 (3) and triple-ring tubular D9h Ta2@B27+ (4), which may serve as embryos of single-walled metalloboronanotube alpha Ta3@B48(3,0) (5) wrapped up from the recently observed most stable free-standing boron alpha-sheet on a Ag(111) substrate with a transition-metal wire (-Ta-Ta-) coordinated inside. Detailed bonding analyses indicate that, with an effective dz2-dz2 overlap on the Ta-Ta dimer along the C9 molecular axis, both Ta2@B18 (3) and Ta2@B27+ (4) follow the universal bonding pattern of sigma + pi double delocalization with each Ta center conforming to the 18-electron rule, providing tubular aromaticity to these Ta-doped boron complexes with magnetically induced ring currents. The IR, Raman, and UV-vis spectra of 3 and 4 are computationally simulated to facilitate their future experimental characterization. PMID- 30246198 TI - The electrochemical properties of Co3O4 as a lithium-ion battery electrode: a first-principles study. AB - Extensive first principles calculations were performed to study the structural and electrochemical features of Co3O4 during its lithiation process as an anode material for lithium-ion batteries (LIBs). We found that with up to 8 mol Li in Co3O4, the formed LinCo3O4 structures are stable for low Li concentrations of n <= 1, but obvious structure distortions and volume expansions occur for LinCo3O4 with n > 1. This may be the reason why Co3O4 has a high Li capability but low cycling life as a LIB anode. The ab initio molecular dynamics simulations for LinCo3O4 (n = 2, 4, 8) further suggest a two-step electrochemistry process of Co3O4 -> CoO -> Co upon the lithiation process. We detected a distorted surface structure as Li atoms react with the Co3O4(110) surface, which also reduces the rate capability of the Co3O4 anode. PMID- 30246199 TI - Structure-based discovery of a specific TLR1-TLR2 small molecule agonist from the ZINC drug library database. AB - We report herein the identification of urea structure-like small molecules by structure-based virtual screening of 10.5 million compounds. Based on a variety of HEK-Blue hTLRs reporter cell assay results, we validated a TLR1/2-specific small molecule agonist, ZINC666243 (SMU127), with EC50 of 0.55 +/- 0.01 MUM. SMU127 stimulates NF-kappaB activation and promotes TNFalpha secretion in human macrophages and mononuclear cells. Moreover, the in vivo assay indicated that SMU127 could inhibit the growth of breast cancer tumors in BABL/c mice. This work has shown for the first time that a small molecule TLR1/2 agonist can inhibit breast cancer in vivo. PMID- 30246200 TI - Carbon-coated FeP nanoparticles anchored on carbon nanotube networks as an anode for long-life sodium-ion storage. AB - A novel electrode design strategy of carbon-coated FeP particles anchored on a conducting carbon nanotube network (CNT@FeP-C) is designed to achieve superior sodium ion storage. Such a unique structure demonstrated excellent long-life cycling stability (a 95% capacity retention for more than 1200 cycles at 3 A g-1) and rate capability (delivered 272 mA h g-1 at 8 A g-1). PMID- 30246201 TI - ESIPT-based fluorescence probe for the rapid detection of peroxynitrite 'AND' biological thiols. AB - An ESIPT-based 'AND' logic fluorescence probe (GSH-ABAH) was developed for the simultaneous detection of ONOO- and biological thiols. GSH-ABAH was shown to have good cell permeability and with the addition of just SIN-1 (ONOO- donor) or GSH, no fluorescence response was observed in live cells. However, in the presence of both analytes GSH-ABAH could be used to image exogenous ONOO- 'AND' GSH added to RAW264.7 cells. PMID- 30246202 TI - Excited state intramolecular proton transfer in julolidine derivatives: an ab initio study. AB - We have studied, using ab initio tools, a series of recently prepared fluorescent julolidine derivatives, undergoing Excited State Intramolecular Proton Transfer (ESIPT). We show that the computed free energy change in the excited state (DeltaGES) can be used to predict the preference for enol, keto, or dual emission. Indeed, two julolidine molecules experimentally show dual emission, consistent with our finding of a small DeltaGES. In agreement with experimental outcomes the complexation between the ESIPT centre and BF2 increases the rigidity of the fluorophore and greatly facilitates emission at energies close to the original enol (E*) fluorescence band. The protonation of the imino group also suppresses ESIPT and sole E* emission is obtained. We disclose that chemical substitution can significantly tune the radiationless deactivation of the enol related to the C[double bond, length as m-dash]N bond rotation of the ESIPT centre. While there is a significant barrier for the experimentally studied compounds we have found a strong correlation between the barrier height and the electron donating strength of the phenyl substituent. Strong donors such as amines facilitate the barrierless non-radiative decay from E* back to the ground state, while weak electron donors make the barrier sufficiently high to allow ESIPT. Strong electron accepting groups such as -NO2 further increase this barrier. This work therefore illustrates the fine interplay necessary to design dual emitters. PMID- 30246203 TI - Quantum and classical IR spectra of (HCOOH)2, (DCOOH)2 and (DCOOD)2 using ab initio potential energy and dipole moment surfaces. AB - An accurate quantum mechanical description of the vibrational dynamics and IR spectra of molecules is illustrated here for the formic acid dimer, (HCOOH)2 and its isotopologues (DCOOH)2 and (DCOOD)2 in full dimensionality. The calculations make use of recent full-dimensional ab initio potential energy and dipole moment surfaces and are done with the code MULTIMODE. IR spectra are reported for the three dimers and also compared to available experimental spectra. In addition, standard classical and "semiclassically prepared" quasiclassical molecular dynamics calculations of the IR spectra of these complexes are reported and compared to the quantum spectra and also experiment. These comparisons indicate good accuracy of the MD spectra for sharp bands but not for the complex O-H stretch band, where the complex molecular dynamics band is upshifted from experiments by roughly 300 cm-1. For the fully deuterated dimer (DCOOD)2, the quantum spectral band for the O-D stretch sharpens relative to the O-H spectral bands in (HCOOH)2 and (DCOOH)2; however, the molecular dynamics OD stretch band does not exhibit this sharpening. PMID- 30246204 TI - Regio- and chemoselective rearrangement of terminal epoxides into methyl alkyl and aryl ketones. AB - The development of the highly active pincer-type rhodium catalyst 2 for the nucleophilic Meinwald rearrangement of functionalised terminal epoxides into methyl ketones under mild conditions is presented. An excellent regio- and chemoselectivity is obtained for the first time for aryl oxiranes. PMID- 30246205 TI - Facile synthesis of polylactide coarse microspheres as artificial antigen presenting cells. AB - Magnetic poly(l-lactide) coarse microspheres were synthesized via an emulsion method followed by chemical etching. Subsequently, anti-CD3 and anti-CD28 antibodies were attached to the microspheres via an avidin-biotin amplification system as artificial antigen-presenting cells. The activation of T cells was enhanced significantly due to the surface topographic structure and increased signal molecule amount. PMID- 30246206 TI - Unexpected stable phases of tungsten borides. AB - Tungsten borides are a unique class of compounds with excellent mechanical properties comparable to those of traditional superhard materials. However, the in-depth understanding of these compounds is hindered by the uncertainty of their phase relations and complex crystal structures. Here, we explored the W-B system systematically by ab initio variable-composition evolutionary simulations at pressures from 0 to 40 GPa. Our calculations successfully found all known stable compounds and discovered two novel stable phases, P4[combining macron]21m-WB and P21/m-W2B3, and three nearly stable phases, R3m-W2B5, Ama2-W6B5, and Pmmn-WB5, at ambient pressure and zero Kelvin. Interestingly, P4[combining macron]21m-WB is much harder than the known alpha and beta phases, while Pmmn-WB5 exhibits the highest hardness. Furthermore, it is revealed that the much debated WB4 becomes stable as the P63/mmc (2 f.u. per unit cell) phase at pressures above ~1 GPa, not at ambient pressure as reported previously. Our findings provide important insights for understanding the rich and complex crystal structures of tungsten borides, and indicate WB2, WB4, and WB5 as compounds with the most interesting mechanical properties. PMID- 30246207 TI - Defects on carbons for electrocatalytic oxygen reduction. AB - The exploration of highly active and durable cathodic oxygen reduction reaction (ORR) catalysts with economical production costs is still the bottleneck to realize the large-scale commercialization of fuel cells. In recent years, remarkable progress has been achieved in fabricating effective non-precious metal based ORR catalysts. In particular, modified carbon materials have aroused extensive research interest because of their excellent performance and low cost. In this review, we present an overview on recent advancements in developing defective carbon based materials for catalyzing the ORR. In particular, three general kinds of defective carbon electrocatalysts will be summarized. They are non-metal induced defective carbons (modified by heteroatoms), intrinsic defective carbons (defects created by a physical or chemical method), and atomic metal species induced/coordinated defective carbons (metal-macrocycle complexes with different coordination environments). The common configurations of various defective carbons will be discussed, with typical examples on recently developed both metal-free and precious/non-precious metal species coordinated carbons. Finally, the future research directions of the defective carbon materials are proposed. The newly established defect promoted catalysis mechanism will be beneficial for the design and fabrication of highly effective electrocatalysts for practical energy storage and conversion applications. PMID- 30246209 TI - Preferential intermolecular interactions lead to chiral recognition: enantioselective gel formation and collapse. AB - Interesting self-assembly of an amino acid based molecular material into a hydrogel in the presence of selective enantiomeric chiral amines leading to chiral recognition has been demonstrated. Moreover, collapse of a metallogel formed from the same material in the presence of selective enantiomers validated its enantioselective affinity. Importantly, in addition to relevant experimental techniques, DFT studies have been successfully explored to establish chiral recognition through enantioselective gelation. PMID- 30246208 TI - A synthetic model of the nonheme iron-superoxo intermediate of cysteine dioxygenase. AB - A nonheme Fe(ii) complex (1) that models substrate-bound cysteine dioxygenase (CDO) reacts with O2 at -80 degrees C to yield a purple intermediate (2). Analysis with spectroscopic and computational methods determined that 2 features a thiolate-ligated Fe(iii) center bound to a superoxide radical, mimicking the putative structure of a key CDO intermediate. PMID- 30246211 TI - Cognitive functions, emotions and personality in woman with fibromyalgia. AB - Background: Fibromyalgia (FM) is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue and cognitive difficulties. A person with FM suffers from pain diffused throughout the body, and accompanied by the feeling of exhaustion and concentration problems, which often impede even simple tasks. Many studies have shown that people with FM suffer from cognitive disorders, including memory disorders. The aim of the study was to evaluate the relationship between fibromyalgia and cognitive functioning (direct memory, arbitrary attention, learning processes), emotional functioning (anxiety and depression), personality traits, and interpersonal relationships. Material and methods: The sample in the study consisted of 60 women: 30 suffering from FM and 30 with other painful spinal disorders as a reference group. The following research tools were used: Wisconsin Card Sorting Test (WCST), 10 Words Test, NEO FFI, Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Benton Visual Memory Test, and Flexibility and Cohesion Evaluation Scales (FACES IV). Results: Results indicate a poorer memory function in FM patients. NEO-FFI analyses showed that women suffering from fibromyalgia are more agreeable and conscientious than population and reference group. Fibromyalgia patients were also more depressive and anxious than the reference group. Conclusions: In fibromyalgia patients, cognitive impairment in the field of direct memory was confirmed. There could be a specific type of personality in people who develop fibromyalgia; these people are more conscientious and agreeable than people in the reference group and the population. The presence and intensity of depressive symptoms correlate significantly with the symptoms of fibromyalgia. Anxiety is a relatively constant feature of the personality of people with fibromyalgia. People suffering from fibromyalgia assess their family relationships equally well as those suffering from other painful spine disorders. The study underlines the importance of involving psychotherapy in the therapy of patients with fibromyalgia. PMID- 30246210 TI - Interaction of Cu(i) with the Met-X3-Met motif of alpha-synuclein: binding ligands, affinity and structural features. AB - The identity of the Cu(i) binding ligands at Met-X3-Met site of AcalphaS and its role into the affinity and structural properties of the interaction were elucidated by NMR spectroscopy. We provide evidence that the source of ligands for Cu(i) binding to the Met-X3-Met site comes from the N-terminal acetyl group and the Met-1, Asp-2 and Met-5 residues. From the study of site-directed mutants and synthetic peptide models of alphaS we demonstrated the critical role played by Met-1 and Met-5 residues on the binding affinity of the Cu(i) complex, acting as the main metal anchoring residues. While having a more modest impact in the affinity features of Cu(i) binding, as compared to the Met residues, the N terminal acetyl group and Asp-2 are important in promoting local helical conformations, contributing to the stabilization of these structures by favoring Cu(i) binding. PMID- 30246212 TI - A national trauma database analysis of alcohol-associated injuries. AB - INTRODUCTION: Knowledge of the pattern of alcohol-associated injury (AAI) is lacking in Singapore. We aimed to determine the local demographic pattern, injury mechanism, injury severity and outcomes of AAI. METHODS: Data on trauma cases presenting to emergency departments in 2012-2013 was extracted from the National Trauma Registry. Cases with missing data fields and ages 1-15 years were excluded. Patients were classified as alcohol positive (A+) or negative (A-) based on clinical assessment. The two groups' demographics, injury mechanism, injury severity, mortality and disposition were compared. Logistic regression analysis was used to determine independent associations with mortality. RESULTS: 165,664 trauma cases met the inclusion criteria. 2.5% were A+ and their peak age range was 25-44 years. The A+ group had more Indian males (p < 0.001), and significantly more assaults, self-harm and falls (p < 0.001). Injuries in the A+ group were more common in public areas and less common in homes, recreational facilities and work places. Outcomes in the A+ group showed higher mean Injury Severity Score and mortality (p < 0.001). Significantly more A+ patients were admitted to hospital but had shorter mean length of stay (p < 0.001). Multivariate logistic regression revealed age > 44 years and male gender as independent predictors of mortality. CONCLUSION: AAI in Singapore is associated with more severe injuries and resource utilisation. Using data from the registry, 'at risk' demographic groups are identified for targeted injury prevention. However, alcohol use is not an independent predictor of mortality in trauma cases. PMID- 30246213 TI - Is cryosurgery a feasible local therapy for bone metastatic prostate cancer? AB - INTRODUCTION: This study aims to assess whether cryosurgery is a feasible local therapy for bone metastatic prostate cancer (bmPCa). METHODS: A total of 23 patients with bmPCa who received cryosurgery and adjuvant androgen deprivation therapy (ADT) were included in the cryosurgery group (Group 1). Another 23 matched patients who received only ADT served as the control (Group 2). Prostate specific antigen (PSA) nadir level, time to PSA nadir, time to castration resistant prostate cancer (CRPC), progression-free survival and therapy response of bone metastases were compared between the groups. RESULTS: The median follow up time in Group 1 and Group 2 patients was 37 (range 19-53) months and 42 (range 24-56) months, respectively. Patients in Group 1 had fewer local complications, lower PSA nadir level (0.23 ng/mL vs. 4.01 ng/mL; p = 0.024), shorter median time to PSA nadir (3 months vs. 7 months; p < 0.001), longer median time to CRPC (36 months vs. 27 months; p = 0.002) and longer progression-free survival (35 months vs. 26 months; p = 0.003) compared to those in Group 2. Therapy responses of bone metastases were similar in the two treatment groups (p = 0.689). CONCLUSION: Cryosurgery is a feasible local therapy for bmPCa patients with prostate volume less than 50 mL and without bulk tumours outside the prostate capsula. Cryosurgery may decrease PSA nadir level, local complications and time to PSA nadir, delay time to CRPC and improve progression-free survival. PMID- 30246214 TI - Cast immobilisation for the treatment of paediatric distal radius fracture: fibreglass versus polyolefin. AB - INTRODUCTION: Stable distal radius fractures in children are frequently treated by immobilisation with a cast and heal readily without complications. This randomised clinical trial aimed to assess patient satisfaction and casting related clinical outcomes when using polyolefin cast, a new cast material, against conventional fibreglass cast. METHODS: A total of 80 patients, age range 7-16 years, with radiograph-confirmed stable distal radius fractures were recruited. They were randomised to either the fibreglass group or polyolefin group, with short arm cast immobilisation for 20-30 days. After cast removal, the incidence of skin rash, growth of hair and cast breakage was recorded along with the administration of patient satisfaction questionnaires. Mann-Whitney U test or Fisher's exact test was applied to compare results. RESULTS: Overall, 34 patients from the fibreglass group and 31 patients from the polyolefin group were included in the final analysis. Significantly fewer patients from the polyolefin group reported itchiness during the casting period (p = 0.038). However, significantly more cast breakages were observed for the polyolefin group in the palmar bar region (p = 0.009). Patients from the polyolefin group were overall more satisfied (fibreglass group = 3.15/5 vs. polyolefin group = 3.74/5; p = 0.002). CONCLUSION: Polyolefin cast reduces itchiness during casting and provides higher overall patient satisfaction during the treatment of stable distal radius fractures in children in tropical climates. However, patients should be counselled regarding potential cast breakage, which is without safety compromise, and the higher costs involved. PMID- 30246215 TI - Effect of levodopa on frontal-subcortical and posterior cortical functioning in patients with Parkinson's disease. AB - INTRODUCTION: Parkinson's disease (PD) is associated with cognitive decline but little is known about frontal-subcortical and posterior cortical cognitive functioning in patients with PD. The present study was designed to: (a) compare frontal and posterior cognitive functioning between patients with PD and healthy controls; (b) determine the effect of levodopa (L-dopa) on frontal-subcortical and posterior cortical cognitive functions; and (c) identify predictors of cognitive functions in patients with PD. METHODS: 50 patients diagnosed with PD from April 2016 to May 2017 at Civil Hospital, Bahawal Victoria Hospital Bahawalpur and Nishter Hospital Multan, Pakistan, and 50 healthy individuals from the community participated in our study. Patients had two testing sessions - first, at the time of diagnosis before taking L-dopa medication to determine baseline scores; and second, at least after three months of L-dopa medication. Participants completed the Parkinson's Disease-Cognitive Rating Scale (PD-CRS). RESULTS: Patients with PD showed impaired performance on frontal-subcortical and posterior cortical functions in contrast with the control group. L-dopa medication had beneficial effects on frontal-subcortical and posterior cortical functioning in patients with PD. Disease duration was a significant predictor of cognitive performance in patients with PD. CONCLUSION: L-dopa medication improves frontal-subcortical and posterior cortical cognitive functioning in patients with PD. Disease duration is a marker of cognitive decline in PD. PMID- 30246216 TI - Behavioral and cognitive effects of docosahexaenoic acid in drug-naive children with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled clinical trial. AB - This study aimed to investigate the efficacy of docosahexaenoic acid (DHA) dietary supplementation on behavior and cognition in school-aged, drug-naive children with attention-deficit/hyperactivity disorder (ADHD). A total of 50 participants with ADHD aged 7 to 14 were enrolled in a 6-month randomized, placebo-controlled clinical trial and received either DHA or placebo. The primary outcome measure was the change in the ADHD rating scale IV Parent Version Investigator (ADHD-RS-IV) after 4 and 6 months. Secondary outcome measures included Conners Parent Rating Scale-revised, other behavioral rating scales including quality of life and global functioning, and computerized cognitive tasks. Baseline assessment also addressed the blood fatty acids profile. No superiority of DHA supplement to placebo was observed on ADHD-RS-IV, the a priori primary outcome. DHA supplementation showed a significant, nonetheless quite small, effect on children's psychosocial functioning, emotional problems, and focused attention. Neither major nor minor adverse events were reported throughout the trial. This study shows that 6-month DHA supplementation has no beneficial effect on the symptoms of ADHD in school-aged, drug-naive children with an established diagnosis of ADHD. Nevertheless, the 6 months treatment with supplemental DHA appears to have small positive effects on other behavioral and cognitive difficulties, which, in light of the absence of side-effects, could be reasonably followed up in future intervention studies. ( https://clinicaltrials.gov/ct2/show/NCT01796262 : The Effects of DHA on Attention Deficit and Hyperactivity Disorder (DADA)). PMID- 30246218 TI - Respiratory syncytial virus-associated hospitalization rates in high-risk populations: an observational comparative cohort analysis. PMID- 30246220 TI - A novel fluorescent immunochromatographic strip combined with pocket fluorescence observation instrument for rapid detection of PRV. AB - Pseudorabies virus (PRV) is an acute and thermal infectious disease in domestic animals. Pigs are a main source of PRV infection, which causes high mortality rates for newborn infected piglets and high miscarriage rates for infected adults. Therefore, early control of PRV is necessary to avoid significant economic loss. We have developed a novel fluorescent immunochromatographic strip (F-ICS) for rapid, sensitive, and specific detection of PRV with a limit of detection (LOD) of 0.13 ng mL-1 and a detection linear range (DLR) between 0.13 and 2.13 ng mL-1. The detection limit was about 10 times lower than the colloidal gold strip. In tests of clinical samples, the F-ICS was largely consistent with PCR results, indicating its practical clinical application. In addition, for easy observation of the F-ICS signal by eye, we present a matching 3D-printed pocket fluorescence observation instrument (PFOI) that allows for use of the F-ICS in the field as easily as conventional colloidal gold strips. Graphical Abstract ?. PMID- 30246219 TI - A fluorescence turn-on probe for rapid monitoring of hypochlorite based on coumarin Schiff base. AB - A simple Schiff base was prepared by mild condensation reaction between a coumarin fluorescent group and diaminomaleonitrile, and it could serve as an excellent fluorescent probe for fast detection of ClO- with high selectivity and sensitivity. Along with addition of ClO-, this probe fleetingly showed noteworthy "turn-on" phenomenon accompanied by an increase of fluorescence intensity and the change of emission color from yellow to blue. This change of fluorescence is so significant that it can be observed by the naked-eye under a handheld ultraviolet light of 365 nm. However, other common reactive oxygen species exhibited no or very little fluorescent response under the same conditions. The limit of detection of this probe toward ClO- had a sensitivity feature as low as 9.6 nM. On account of these excellent features of short response time, remarkable fluorescence and color signal changes, high sensitivity and selectivity, this probe was effectively used for the fluorescence detection of ClO- in water samples. The values of the relative standard deviation were between 1.41% and 2.91%. More importantly, this probe displays excellent imaging capability in cytoplasm as well as very low cell toxicity and was unambiguously applied to image ClO- in living cells. Graphical abstract A fluorescent probe based on coumarin for detection of ClO- was successfully developed, which can besuccessfully used for the detection of ClO- in living cells and in water sample because of the excellentfeatures including short response time, remarkable fluorescence and color signal changes, high sensitivityand selectivity. PMID- 30246217 TI - Role of anatomical sites and correlated risk factors on the survival of orthodontic miniscrew implants: a systematic review and meta-analysis. AB - OBJECTIVES: The aim of this review was to systematically evaluate the failure rates of miniscrews related to their specific insertion site and explore the insertion site dependent risk factors contributing to their failure. SEARCH METHODS: An electronic search was conducted in the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Knowledge, Scopus, MEDLINE and PubMed up to October 2017. A comprehensive manual search was also performed. ELIGIBILITY CRITERIA: Randomised clinical trials and prospective non-randomised studies, reporting a minimum of 20 inserted miniscrews in a specific insertion site and reporting the miniscrews' failure rate in that insertion site, were included. DATA COLLECTION AND ANALYSIS: Study selection, data extraction and quality assessment were performed independently by two reviewers. Studies were sub grouped according to the insertion site, and the failure rates for every individual insertion site were analysed using a random-effects model with corresponding 95% confidence interval. Sensitivity analyses were performed in order to test the robustness of the reported results. RESULTS: Overall, 61 studies were included in the quantitative synthesis. Palatal sites had failure rates of 1.3% (95% CI 0.3-6), 4.8% (95% CI 1.6-13.4) and 5.5% (95% CI 2.8-10.7) for the midpalatal, paramedian and parapalatal insertion sites, respectively. The failure rates for the maxillary buccal sites were 9.2% (95% CI 7.4-11.4), 9.7% (95% CI 5.1-17.6) and 16.4% (95% CI 4.9-42.5) for the interradicular miniscrews inserted between maxillary first molars and second premolars and between maxillary canines and lateral incisors, and those inserted in the zygomatic buttress respectively. The failure rates for the mandibular buccal insertion sites were 13.5% (95% CI 7.3-23.6) and 9.9% (95% CI 4.9-19.1) for the interradicular miniscrews inserted between mandibular first molars and second premolars and between mandibular canines and first premolars, respectively. The risk of failure increased when the miniscrews contacted the roots, with a risk ratio of 8.7 (95% CI 5.1-14.7). CONCLUSIONS: Orthodontic miniscrew implants provide acceptable success rates that vary among the explored insertion sites. Very low to low quality of evidence suggests that miniscrews inserted in midpalatal locations have a failure rate of 1.3% and those inserted in the zygomatic buttress have a failure rate of 16.4%. Moderate quality of evidence indicates that root contact significantly contributes to the failure of interradicular miniscrews placed between the first molars and second premolars. Results should be interpreted with caution due to methodological drawbacks in some of the included studies. PMID- 30246222 TI - The use of a virtual journal club to promote cross-cultural learning in the reproductive sciences. AB - PURPOSE: Scientific literacy and communication are critical skills in the biological sciences. Journal clubs, in which peer-reviewed academic literature is discussed, are traditionally used to teach students to evaluate the literature, review scientific findings, and learn about historical, controversial, or current topics. METHODS: We used a virtual journal club to facilitate the international interaction between two universities with master's degree programs in the reproductive sciences: the University of Murcia (Spain) and Northwestern University (USA). The virtual journal club occurred over a 2-hour period and was held using Blue Jeans Conferencing Service software and involved a total of 29 students. During this event, the students who were separated physically by thousands of miles discussed and exchanged ideas about a high-impact publication in real time. A survey assessment was administered to students at the University of Murcia following the event. RESULTS: Positive perceptions included the establishment of cross-institutional interactions and the ability to practice scientific communication in another language. Areas noted for improvement included preparation time and engagement opportunities. CONCLUSION: Overall, the virtual journal club is an innovative technology that can easily be broadened and has the potential to foster collaboration, ameliorate multilingual communication, improve cultural competencies, and expand professional global networks. PMID- 30246223 TI - Rates of live birth after mosaic embryo transfer compared with euploid embryo transfer. AB - PURPOSE: Mosaicism is a prevalent characteristic of human preimplantation embryos. This retrospective cohort study aimed to investigate pregnancy outcomes after transfer of mosaic or euploid embryos. METHODS: The embryos, which had been transferred as "euploidy," were processed using array-based comparative genomic hybridization (aCGH). The original aCGH charts of the transferred embryos were reanalyzed. Mosaic and control euploid embryos were defined according to log2 ratio calls. RESULTS: Overall, 102 embryos were determined to be mosaic, of which 101 were estimated to harbor no more than 50% aneuploid mosaicism. Additionally, 268 euploid embryos were matched as controls. The rates of live birth (46.6% vs. 59.1%, odds ratio (OR) 0.60, 95% confidence interval (CI) 0.38-0.95), and biochemical pregnancy (65.7% vs. 76.1%, OR 0.60, 95% CI 0.37-0.99) per transfer cycle were significantly lower after mosaic embryo transfer than after euploid embryo transfer. The rates of clinical pregnancy and pregnancy loss and the risks of obstetric outcomes did not differ significantly between the two groups. CONCLUSIONS: Compared with euploid embryo transfer, mosaic embryo transfer is associated with a lower rate of live birth, which is mainly attributed to a decreased rate of conception. However, as mosaic embryo transfer yielded a live birth rate of 46.6%, patients without euploid embryos could be counseled regarding this alternative option. PMID- 30246224 TI - A review of the Rapid Response Radiotherapy Program in patients with advanced cancer referred for palliative radiotherapy over two decades. AB - INTRODUCTION: The Rapid Response Radiotherapy Program (RRRP) is an outpatient radiotherapy clinic for palliative cancer patients where consultation, planning, and radiation treatment can take place in 1 day, allowing for rapid access to care. The objective of this study was to compare the patient population and overall survival of patients seen in the RRRP from 2014 to 2017 to that of patients seen in 1999. METHOD: Patient characteristics including sex, primary cancer site, sites of metastases, and Karnofsky Performance Status (KPS) were recorded at each clinic visit. Date of death (DOD) was retrieved from the Patient Care System (PCS) and Excelicare. To show overall survival from the first clinic visit, a Kaplan-Meier overall survival curve was generated in all patients from 2014 to 2017. RESULTS: Five hundred ninety-six patients were included in the final analysis. Most patients were male (n = 347) with a primary cancer site of the lung (n = 165) and metastases to the bone (n = 475). Actuarial median overall survival was 15.3 months. In 1999, 395 patients were analyzed, in which a primary of the lung (n = 143) and metastases to the bone (n = 277) were the most prevalent. An additional 72 patients in this population had brain metastases. The actuarial median survival of the 1999 population was 4.5 months. CONCLUSION: The changing patient population in the RRRP has resulted in visible changes in survival. This may reflect differences in the proportion of patients with specific primaries and sites of metastases, as well as improvements in the availability of palliative radiation over the last two decades. PMID- 30246221 TI - The Impact of Psychotropic Medications on Bone Health in Youth. AB - PURPOSE OF REVIEW: Psychotropics are prescribed to youth at rapidly growing rates and may negatively impact bone health. Little awareness exists of this association among prescribing providers. Childhood and adolescence are critical times for bone development. Understanding these effects and their management is important to informed psychotropic use. RECENT FINDINGS: Through a variety of mechanisms, antidepressants, benzodiazepines, mood stabilizers, neuroleptics, and stimulants may all negatively impact pediatric bone health. This confers added risk of osteoporosis in a population already at high risk for suboptimal bone health. Awareness of psychotropic-mediated effects on pediatric bone development is clinically relevant to the use and monitoring of these agents. Clinicians can manage these effects through informed consent, vitamin D supplementation, lifestyle modifications, and reducing polypharmacy. For mood stabilizers, vitamin D level monitoring and secondary prevention is indicated. Future longitudinal studies and development of monitoring guidelines regarding psychotropic impact on bone health are necessary. PMID- 30246225 TI - Aim and Design of pREGnant, the Dutch Pregnancy Drug Register. AB - Information on the safety of medication use during pregnancy and breastfeeding is scarce, yet use of medication among pregnant and breastfeeding women is widespread. The pREGnant, the Dutch Pregnancy Drug Register, was set up to obtain insight into medication use among pregnant and breastfeeding women and potential effects on maternal and fetal/infant health. The systematically documented, good quality data on medication use during pregnancy and lactation in pREGnant will be used in signal detection, epidemiologic studies and counseling of healthcare providers and patients. The register has a prospective cohort design. The population is derived from pregnant women throughout the Netherlands. Data collection started in April 2014 and enrollment of women is continuous and is characterized by a relative high proportion of women born in the Netherlands with a high education compared with the general Dutch pregnant population. Data on current pregnancy, obstetric history, maternal lifestyle, health and medication use, delivery, and infant health are collected through web-based questionnaires completed by the participating women (three times during pregnancy and three times during the infant's first year of life). If permission is given, the self reported data can be complemented with information retrieved from Perined, the perinatal registry of the Netherlands, and from obstetric and medical records, and/or pharmacy records. Here, we provide detailed information on the design of the pREGnant, the Dutch Pregnancy Drug Register, as well as descriptive information on characteristics of the participants so far. Currently, steps are being taken to implement the register on a large scale in the Netherlands. PMID- 30246227 TI - 4-year-old boy referring for diffuse joint stiffness and progressive bilateral visual impairment. PMID- 30246226 TI - Performance and Microbial Community Analysis of Bioaugmented Activated Sludge System for Indigo Production from Indole. AB - Indole is a typical nitrogen-containing aromatic pollutant in coking wastewater, and it can be used for the microbial production of indigo, one of the oldest dyestuffs. In this study, the activated sludge system bioaugmented with two indigo-producing bacterial strains, wild strain Comamonas sp. MQ and recombinant Escherichia coli (ND_IND), was constructed to investigate indigo bioproduction from indole. During the operation, the bioaugmentation could promote the production of indigo, especially in early stages, and the indigo yields gradually increased from 17.5 +/- 0.4 to 44.3 +/- 0.5 mg/L with the increase of influent indole (80 to 282 mg/L). Illumina MiSeq sequencing revealed that the microbial community could have a noticeable shift driven by the bioaugmentation and high indole pressure. The indigenous bacteria could be more responsible for indigo production, and the dominant genera Comamonas, Diaphorobacter, Paracoccus, Aquamicrobium, Pseudomonas, and Truepera could be the key functional taxa. Based on FAPROTAX (Functional Annotation of Prokaryotic Taxa) analysis, the nitrogen metabolism-related functional groups could play important roles in indole biotransformation and indigo biosynthesis. This study should provide insights into microbial production of indigo by microbial communities. PMID- 30246228 TI - Ibrutinib for Treating Relapsed or Refractory Mantle Cell Lymphoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - As part of its Single Technology Appraisal process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of ibrutinib (Janssen) to submit evidence on the clinical effectiveness and cost effectiveness of ibrutinib for the treatment of relapsed or refractory (R/R) mantle cell lymphoma (MCL). The School of Health and Related Research Technology Assessment Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence contained within the company's submission to NICE. The clinical effectiveness evidence for ibrutinib included one randomised controlled trial comparing ibrutinib and temsirolimus and two single-arm studies. The company's indirect comparison of ibrutinib versus rituximab plus chemotherapy (R-chemo) produced a hazard ratio (HR) for progression-free survival (PFS) of 0.28. The ERG's random effects network meta-analysis (NMA) indicated that the treatment effect on PFS was highly uncertain (HR 0.27; 95% credible interval (CrI) 0.06-1.26). The company's Markov model assessed the cost effectiveness of ibrutinib versus R-chemo for the treatment of R/R MCL from the perspective of the National Health Service (NHS) and Personal Social Services over a lifetime horizon. Based on a re-run of the company's model by the ERG, the incremental cost-effectiveness ratio (ICER) for ibrutinib versus R-chemo [including the company's original patient access scheme (PAS)] was expected to be L76,014 per quality-adjusted life-year (QALY) gained. The ERG had several concerns regarding the company's model structure and the evidence used to inform its parameters. The ERG's preferred analysis, which used the ERG's NMA and the observed Kaplan-Meier curve for time to ibrutinib discontinuation and excluded long-term disutilities for R-chemo, produced ICERs of L63,340 per QALY gained for the overall R/R MCL population and of L44,711 per QALY gained for patients with one prior treatment. Following an updated PAS and consideration of evidence from a later data-cut of the RAY trial, the appraisal committee concluded that the most plausible ICER for the one prior treatment subgroup was likely to be lower than the company's estimate of L49,848 per QALY gained. The company's ICER for the overall R/R MCL population was higher, at L62,650 per QALY gained. The committee recommended ibrutinib as an option for treating R/R MCL in adults only if they have received only one previous line of therapy and the company provides ibrutinib with the discount agreed in the commercial access agreement with NHS England. PMID- 30246229 TI - CRYAB protects cardiomyocytes against heat stress by preventing caspase-mediated apoptosis and reducing F-actin aggregation. AB - CRYAB is a small heat shock protein (sHSP) that has previously been shown to protect the heart against various cellular stresses; however, its precise function in myocardial cell injury caused by heat stress remains unclear. This study aimed to investigate the molecular mechanism by which CRYAB protects cardiomyocytes against heat stress. We constructed two H9C2 cell lines that stably express CRYAB protein to differing degrees: CRYAB-5 and CRYAB-7. Both CRYAB-5 and CRYAB-7 showed significantly reduced granular degeneration and vacuolar degeneration following heat stress compared to control cells. In addition, CRYAB overexpression in H9C2 cells relieved cell cycle proportion at the G0/G1 phase following heat stress compared to control cells. These protective effects were associated with the level of CRYAB protein expression. Our immunofluorescence analysis showed CRYAB could translocate from the cytoplasm to the nucleus under heat stress conditions, but that CRYAB co-localized with F actin (which accumulates under stress conditions). Indeed, overexpression of CRYAB significantly reduced the aggregation of F-actin in H9C2 cells caused by heat stress. Furthermore, overexpressing CRYAB protein significantly reduced the apoptosis of cardiomyocytes induced by heat stress, likely by reducing the expression of cleaved-caspase 3. Collectively, our results show overexpression of CRYAB significantly increases the heat resistance of H9C2 cardiomyocytes, likely by reducing F-actin aggregation (thus stabilizing the cytoskeleton), regulating the cell cycle, and preventing caspase-mediated apoptosis. PMID- 30246230 TI - Sad, Scared, or Rejected? A Short-Term Longitudinal Study of the Predictors of Social Avoidance in Chinese Children. AB - The goal of the present study was to empirically examine different conceptual mechanisms previously postulated to underlie the development of social avoidance in childhood. Participants were N = 601 children (321 boys, 280 girls) attending elementary schools (Mage = 10.21 years) and middle schools (Mage = 12.77 years) in Shanghai, P.R. China. Measures of motivations for social withdrawal (shyness, unsociability, social avoidance) and socio-emotional adjustment were collected using self-reports and peer nominations at two time-points separated by 9 months. Results from cross-lagged panel analyses indicated that: (1) social avoidance and symptoms of social anxiety were not reciprocally related over time; (2) Time 1 social avoidance predicted incremental change in Time 2 peer problems (whereas Time 1 peer problems did not predict incremental change in Time 2 social avoidance); and (3) Time 1 symptoms of depression significantly predicted incremental change in Time 2 social avoidance (whereas Time 1 social avoidance did not predict incremental change in Time 2 symptoms of depression). These results provide evidence in support of depressive symptoms (but not symptoms of social anxiety or peer problems) as a salient predictor of social avoidance. Results are discussed in terms of the development and implications of social avoidance in Chinese culture. PMID- 30246231 TI - A longitudinal study of work-related injuries: comparisons of health and work related consequences between injured and uninjured aging United States adults. AB - BACKGROUND: Age may affect one's susceptibility to the myriad physical hazards that may pose risks for work-related injuries. Aging workers are not only at risk for work-related injuries but, also, at even higher risk for more severe health and work-related consequences. However, limited longitudinal research efforts have focused on such injuries among the aging workforce. This study aimed to investigate the association between physical work-related factors and injuries among United States (U.S.) workers, and then compare the injured and uninjured workers with regard to consequences including, functional limitations, and reduced working hours post injury. A cohort of 7212 U.S. workers aged 50 years and above from the U.S. Health and Retirement Study were retrospectively followed from 2004 to 2014. Data on exposures were lagged by one survey wave prior to the outcome of work-related injuries and consequences, respectively. Crude and adjusted incident rate ratios, and hazard ratios were estimated using generalized estimating equations and Cox models. RESULTS: Risk of experiencing a work-related injury event was over two times greater among those whose job had work requirements for physical effort, lifting heavy loads, and stooping/kneeling/crouching, compared to those who did not. Over time, injured compared to uninjured workers had higher risks of functional limitations and working reduced hours. CONCLUSIONS: The aging workforce is at a high risk of experiencing injuries. Further, injured adults were not only more likely to incur a disability prohibiting daily life-related activities, over time, but, also, were more likely to work reduced hours. It will be important to consider accommodations to minimize functional limitations that may impair resulting productivity. PMID- 30246232 TI - Chemistry, activity, and impact of plant biocontrol products. PMID- 30246233 TI - Tumoral MGMT content predicts survival in patients with aggressive pituitary tumors and pituitary carcinomas given treatment with temozolomide. PMID- 30246234 TI - Comparison of temperature measurements in esophagus and urinary bladder in comatose patients after cardiac arrest undergoing mild therapeutic hypothermia. AB - BACKGROUND: Mild therapeutic hypothermia (MTH) is a recommended method of treatment for comatose out-of-hospital cardiac arrest (OHCA) survivors. However, the proper site of temperature measurement in MTH is still not defined. The aim of this study was to compare temperature measurements in the esophagus and urinary bladder in comatose post-OHCA patients treated with MTH. METHODS: This temperature comparison protocol was a part of a prospective, observational, multicenter cohort study. The study population included 36 unconscious patients after resuscitation for OHCA. The patient's core temperature was independently measured every hour during MTH in the urinary bladder and in the esophagus. RESULTS: The mean temperature was lower in the esophagus (differences during induction phase: 1.04 +/- 0.92oC, p < 0.0001; stabilization phase: 0.54 +/- 0.39oC, p < 0.0001; rewarming phase: 0.40 +/- 0.47oC, p < 0.0001). Nevertheless, a strong correlation between both sites was found (R2 = 0.83, p < 0.001). The decrease in temperature observed in the esophagus during the induction phase was faster when compared with the urinary bladder (1.09 +/- 0.71 degrees C/h vs. 0.83 +/- 0.41 degrees C/h; p = 0.002). As a consequence, time to reach temperature < 34.0 degrees C was longer when temperature was measured in the urinary bladder (the difference between medians of the time 1.0 [0-1.5] h, p < 0.001). CONCLUSIONS: Urinary bladder temperature measurements may lag behind temperature changes measured in the esophagus.Monitoring temperature simultaneously in the esophagus and in the urinary bladder is an accessible and reliable combination, although esophageal measurements seem to better reflect the dynamics of temperature changes, thus it seems to be more appropriate for MTH control. ClinicalTrials.gov Identifier: NCT02611934. PMID- 30246235 TI - Rate of acquired pulmonary vein stenosis after ablation of atrial fibrillation referred to electroanatomical mapping systems: Does it matter? AB - BACKGROUND: Thermal injury during radiofrequency ablation (RFA) of atrial fibrillation (AF) can lead to pulmonary vein stenosis (PVS). It is currently unclear if routine screening for PVS by imaging (ECHO, CT) is clinically meaningful and if there is a correlation between PVS and the electroanatomical mapping system (EAMS) used for the ablation procedure. It was therefore investigated in the current single center experience. METHODS: All patients from January 2004 to December 2016 with the diagnosis of PVS after interventional ablation of AF by radiofrequency were retrospectively analyzed. From 2004 to 2007, transesophageal echocardiography (TEE) was routinely performed as screening for RFA-acquired PVS (group A). Since 2008, diagnostics were only initiated in cases of clinical symptoms suggestive for PVS (group B). RESULTS: The overall PVS rate after interventional RFA for AF of the documented institution is 0.72% (70/9754). The incidence was not influenced by screening: group A had a 0.74% PVS rate and group B a 0.72% rate (NS). Referred to as the EAMS, there were significant differences: 20/4229 (0.5%) using CARTO(r), 48/4510 (1.1%) using EnSite(r), 1/853 (0.1%) using MediGuide(r), and 1/162 (0.6%) using Rhythmia(r). Since 2009, no significant difference between technologies was found. CONCLUSIONS: The present analysis of 9754 procedures revealed 70 cases of PVS. The incidence of PVS is not related to screening but to the application of different EAMS. Possible explanations are technological backgrounds (magnetic vs. electrical), learning curves, operator experience, and work-flow differences. Furthermore, incorporation of new technologies seems to be associated with higher incidences of PVS before workflows are optimized. PMID- 30246236 TI - Identification of biomarkers and mechanisms of diabetic cardiomyopathy using microarray data. AB - BACKGROUND: The study aimed to uncover the regulation mechanisms of diabetic cardiomyopathy (DCM) and provide novel prognostic biomarkers. METHODS: The dataset GSE62203 downloaded from the Gene Expression Omnibus database was utilized in the present study. After pretreatment using the Affy package, differentially expressed genes (DEGs) were identified by the limma package, followed by functional enrichment analysis and protein-protein interaction (PPI) network analysis. Furthermore, module analysis was conducted using MCODE plug-in of Cytoscape, and functional enrichment analysis was also performed for genes in the modules. RESULTS: A set of 560 DEGs were screened, mainly enriched in the metabolic process and cell cycle related process. Hub nodes in the PPI network were LDHA (lactate dehydrogenase A), ALDOC (aldolase C, fructose-bisphosphate) and ABCE1 (ATP Binding Cassette Subfamily E Member 1), which were also highlighted in Module 1 or Module 2 and predominantly enriched in the processes of glycolysis and ribosome biogenesis. Additionally, LDHA were linked with ALDOC in the PPI network. Besides, activating transcription factor 4 (ATF4) was prominent in Module 3; while myosin heavy chain 6 (MYH6) was highlighted in Module 4 and was mainly involved in muscle cells related biological processes. CONCLUSIONS: Five potential biomarkers including LDHA, ALDOC, ABCE1, ATF4 and MYH6 were identified for DCM prognosis. PMID- 30246237 TI - A formula to calculate the contrast volume required for optimal imaging quality in optical coherence tomography with non-occlusive technique. AB - BACKGROUND: Non-occlusive technique is universally accepted for acquisition of coronary optical coherence tomography (OCT), but the amount of contrast infused is still inconsistently calculated. Proposed herein, is an empirical formula for accurate contrast volume calculation. METHODS: In an observational prospective study, contrast volume of consecutive patients undergoing OCT was either calculated with formula, or eyeballed based on manufacturer recommendations. The quality of pullback, defined as % of high quality cross-sections (CS) in the segment of interest (SOI), was analyzed by two independent operators and compared between groups, together with the amount of contrast per pullback. RESULTS: Sixty patients (115 pullbacks, 4252 CS) were imaged using the formula, vs. 18 patients (22 pullbacks, 777 CS) eyeballing the contrast volume. The formula group used 18 mm/s as pullback speed more often (82.6% vs. 40.9%, p = 0.0001), but there were no significant differences between groups in SOI length or vessel imaged. The formula resulted in higher pullback quality than eyeballing (96.55% vs. 63.55%, p < 0.0001), interobserver agreement Kappa 0.903 (p < 0.0001), and tended to use less contrast per pullback than the eyeball group (13.03 mL vs. 14.55 mL, p = 0.057). After adjusting for pullback speed, SOI length and vessel in multivariate linear regression, the use of the formula significantly reduced the amount of contrast in 4.50 mL on average. CONCLUSIONS: Optical coherence tomography acquisition with the non-occlusive technique can be substantially eased with the use of a novel formula to calculate the contrast volume required. This method optimises the quality of the images whilst reducing the amount of contrast per pullback. PMID- 30246238 TI - Coronary plaque redistribution after stent implantation is determined by lipid composition: A NIRS-IVUS analysis. AB - BACKGROUND: The composition of plaque impacts the results of stenting. The following study evaluated plaque redistribution related to stent implantation using combined near-infrared spectroscopy and intravascular ultrasound (NIRS IVUS) imaging. METHODS: The present study included 49 patients (mean age 66 +/- 11 years, 75% males) presenting with non-ST elevation myocardial infarction (8%), unstable angina (49%) and stable coronary artery disease (43%). The following parameters were analyzed: mean plaque volume (MPV, mm3), plaque burden (PB, %), remodeling index (RI), and maximal lipid core burden index in a 4 mm segment (maxLCBI4mm). High-lipid burden lesions (HLB) were defined as by maxLCBI4mm > 265 with positive RI. Otherwise plaques were defined as low-lipid burden lesions (LLB). Measurements were done in the target lesion and in 4 mm edges of the stent before and after stent implantation. RESULTS: MPV and maxLCBI4mm decreased in both HLB (MPV 144.70 [80.47, 274.25] vs. 97.60 [56.82, 223.45]; maxLCBI4mm: 564.11 +/- 166.82 vs. 258.11 +/- 234.24, p = 0.004) and LLB (MPV: 124.50 [68.00, 186.20] vs. 101.10 [67.87, 165.95]; maxLCBI4mm: 339.07 +/- 268.22 vs. 124.60 +/- 160.96, p < 0.001), but MPV decrease was greater in HLB (28.00 [22.60, 57.10] vs. 13.50 [1.50, 28.84], p = 0.019). Only at the proximal stent edge of LLB, maxLCBI4mm decreased (34 [0, 207] vs. 0 [0, 45], p = 0.049) and plaque burden increased (45.48 [40.34, 51.55] vs. 51.75 [47.48, 55.76], p = 0.030). CONCLUSIONS: NIRS-IVUS defined HLB characterized more significant decreases in plaque volume by stenting. Plaque redistribution to the proximal edge of the implanted stent occurred only in LLB. PMID- 30246239 TI - Use of a lumbar puncture needle to reduce the number of needle insertions in infiltration local anaesthesia of large areas in dermatologic surgery. PMID- 30246240 TI - Tanning, selfies and social media. PMID- 30246241 TI - Gendered and racialized social expectations, barriers, and delayed breast cancer diagnosis. AB - BACKGROUND: Black women are more likely to be diagnosed at a later stage of breast cancer in part due to barriers to timely screening mammography, resulting in poorer mortality and survival outcomes. Patient navigation that helps to overcome barriers to the early detection of breast cancer is an effective intervention for reducing breast cancer disparity. However, the ability to recognize and seek help to overcome barriers may be affected by gendered and racialized social expectations of women. METHODS: Data from a randomized controlled trial, the Patient Navigation in Medically Underserved Areas study, were used. The likelihood of obtaining a follow-up screening mammogram was compared between women who identified >=1 barriers and those who did not. RESULTS: Of the 3754 women who received the Patient Navigation in Medically Underserved Areas navigation intervention, approximately 14% identified >= 1 barriers, which led to additional navigator contacts. Consequently, those women who reported barriers were more likely to obtain a subsequent screening mammogram. Black women, women living in poverty, and women with a higher level of distrust were less likely to report barriers. CONCLUSIONS: Minority women living in poverty have always been the source of social support for others. However, gendered and racialized social expectations may affect the ways in which women seek help for their own health needs. A way to improve the effectiveness of navigation would be to recognize how minority women's gender images and expectations could shape how they seek help and support. A report of no barriers does not always translate into no problems. Proactive approaches to identify potential barriers may be beneficial. PMID- 30246242 TI - Evaluation of structural damage and pH of nail plates of hands after applying different methods of decorating. AB - BACKGROUND: The purpose of this study was to evaluate the effect of nail polish, gel polish hybrid, gel nail, and acrylic nail powder and the removal of these formulas on the nail plates properties, particularly the influence of different coatings on morphology and pH. METHODS: The morphology and structure of nail plates were analyzed with use of scanning electron microscopy. The pH values of the nail plates of hands were measured using the system Courage & Khazaka. RESULTS: The analysis of morphology and structure of the surface of nail plates showed distinct changes caused by decorative coatings. The most common ones include fragility and splitting of the nails. The pH value measured in the whole group ranged from 5.21 to 7.00. CONCLUSIONS: The methods used to prepare nails for decoration and all methods of removing the applied preparations damage the healthy nail plates. The most common changes are brittleness and nail splitting. The nail polish remover causes less damage than acetone, and the use of a nail drill machine and nail file causes the greatest destruction of nail plates. The biggest effect on the pH change has the gel polish hybrid, gel nail, and acrylic nail powder, causing the pH value of nail plates to rise above 6.0, whereas after the application of the nail polish, the pH of the plates was on average 5.8 which is closest to the normal value, assumed as physiological. PMID- 30246243 TI - Obstructive sleep apnea in refractory epilepsy: A pilot study investigating frequency, clinical features, and association with risk of sudden unexpected death in epilepsy. AB - OBJECTIVE: We aimed to determine the frequency of probable obstructive sleep apnea (pOSA) in refractory epilepsy monitoring unit inpatients and clinical features associated with pOSA, including risk for sudden unexpected death in epilepsy (SUDEP). METHODS: We prospectively recruited 49 consecutive adult patients admitted to the Mayo Clinic Epilepsy Monitoring Unit with focal, generalized, or unclassified epilepsy syndromes. pOSA was identified using oximetric oxyhemoglobin desaturation index (ODI) and the Sleep Apnea-Sleep Disorders Questionnaire (SA-SDQ) and STOP-BAG screening tools. Revised SUDEP Risk Inventory (rSUDEP-7) scores were calculated, and epilepsy patients with and without pOSA were compared with Wilcoxon signed-rank tests. Correlation and regression analyses were utilized to determine relationships between pOSA and rSUDEP-7 scores. RESULTS: Thirty-five percent of patients had pOSA, with a mean ODI of 11.3 +/- 5.1/h (range = 5.1-22.8). Patients with pOSA were older and heavier, and more frequently had a focal epilepsy syndrome and longer epilepsy duration, with higher SA-SDQ and STOP-BAG scores (all P < 0.05). Median rSUDEP-7 score was 3 +/- 1.4 (range = 0-6). Higher rSUDEP-7 scores were positively correlated with higher ODI (P = 0.036). rSUDEP-7 score >= 5 was associated with pOSA by ODI, SA-SDQ, and STOP-BAG questionnaire criteria (P < 0.05). SIGNIFICANCE: Our pilot study identified a high frequency of pOSA in refractory epilepsy monitoring patients, finding that pOSA patients were older and heavier, with higher screening symptoms for sleep apnea and more frequent focal seizures with a longer epilepsy duration. We also found a possible association between OSA and SUDEP risk. Identification and treatment of OSA in patients with epilepsy could conceivably provide a novel approach toward preventing the risk of SUDEP. Future studies with polysomnography are needed to confirm predictive features for OSA in epilepsy populations, and to determine whether OSA is associated with SUDEP risk. PMID- 30246244 TI - Genomic data reject the hypothesis of sympatric ecological speciation in a clade of Desmognathus salamanders. AB - Closely related taxa with dissimilar morphologies are often considered to have diverged via natural selection favoring different phenotypes. However, some studies have found these scenarios to be paired with limited or no genetic differentiation. Desmognathus quadramaculatus and D. marmoratus are sympatric salamander species thought to represent a case of ecological speciation based on distinct morphologies, but the results of previous studies have not resolved corresponding patterns of lineage divergence. Here, we use genome-wide data to test this hypothesis of ecological speciation. Population structure analyses partitioned individuals geographically, but not morphologically, into two adjacent regions of western North Carolina: Pisgah and Nantahala. Phylogenetic analyses confirmed the nominal species are nonmonophyletic and resolved deep divergence between the two geographic clusters. Model-testing overwhelmingly supported the hypothesis that lineage divergence followed geography. Finally, ecological niche modeling showed that Pisgah and Nantahala individuals occupy different climatic niches, and geographic boundaries for the two lineages correspond to differences in precipitation regimes across southern Appalachia. Overall, we reject the previous hypothesis of ecological speciation based on microhabitat partitioning. Instead, our results suggest that there are two cryptic lineages, each containing the same pair of morphotypes. PMID- 30246246 TI - Comparison of components of the Good Behavior Game in a preschool classroom. AB - The Good Behavior Game (GBG) is an effective intervention package for decreasing disruptive behavior in various populations and environments. There is, however, limited research evaluating the GBG with preschoolers. Furthermore, few studies have evaluated the effects of components of the GBG, and of those that have, most have done so only after exposure to the GBG package. We evaluated the effects (a) of the GBG on disruptive behavior of preschoolers during group instruction and (b) the major components of the GBG before and after implementation of the GBG package (c) at both the group and individual level. Results suggest that the GBG package was necessary for decreasing disruptive behavior. However, after exposure to the GBG, a response-independent contingency was effective for maintaining low levels of disruptive behavior at both the group and individual level. PMID- 30246245 TI - A fly in a tube: Macroevolutionary expectations for integrated phenotypes. AB - Phenotypic integration and modularity are ubiquitous features of complex organisms, describing the magnitude and pattern of relationships among biological traits. A key prediction is that these relationships, reflecting genetic, developmental, and functional interactions, shape evolutionary processes by governing evolvability and constraint. Over the last 60 years, a rich literature of research has quantified patterns of integration and modularity across a variety of clades and systems. Only recently has it become possible to contextualize these findings in a phylogenetic framework to understand how trait integration interacts with evolutionary tempo and mode. Here, we review the state of macroevolutionary studies of integration and modularity, synthesizing empirical and theoretical work into a conceptual framework for predicting the effects of integration on evolutionary rate and disparity: a fly in a tube. While magnitude of integration is expected to influence the potential for phenotypic variation to be produced and maintained, thus defining the shape and size of a tube in morphospace, evolutionary rate, or the speed at which a fly moves around the tube, is not necessarily controlled by trait interactions. Finally, we demonstrate this reduced disparity relative to the Brownian expectation for a given rate of evolution with an empirical example: the avian cranium. PMID- 30246247 TI - Distinct Tie2 tyrosine phosphorylation sites dictate phenotypic switching in endothelial progenitor cells. AB - Angiogenesis is a regulated process involving the proliferation, migration, and remodeling of different cell types particularly mature endothelial and their progenitor cells, nominated as endothelial progenitor cells (EPCs). Tie2/Tek is a tyrosine kinase receptor expressed by endothelial cells that induces signal transduction pathways involved in endothelial biology. To address the potential importance of the various tyrosine residues of Tie2 in EPC development, we generated a series of Tie2 tyrosine mutated (Y1106F, Y1100F, and Y1111F) EPCs and then assess the biological features of these cells. Clonogenic, tubulogenic, proliferative, migratory, and functional properties of these cells were analyzed. Next, GFP-positive EPCs containing Tie2 tyrosine mutations were systemically transplanted into sublethaly irradiated mice to analyze the potency of these cells for marrow reconstitution. We found that mutation in the Tie2 tyrosine 1106 residue directed EPCs toward a mature endothelial phenotype, which was associated with augmented tubulogenic and migratory properties, and increased phosphorylation of the active site (tyrosine 992) as well as increased vascular perfusion in the in vivo Matrigel plug assay. Moreover, transplantation of 1106 Tie2 mutant EPCs failed to reconstitute the bone marrow after myeloablation, whereas transplantation of EPCs with the 1100 or 1111 Tie2 tyrosine mutation resulted in bone marrow engraftment, leading to improved survival of recipient mice. Our findings demonstrate that the tyrosine 1106 residue in Tie2 plays a key role to maintain the stemness features of EPCs. PMID- 30246248 TI - Use of vitamin K antagonists and risk of prostate cancer: Meta-analysis and nationwide case-control study. AB - Use of vitamin K antagonists (VKAs) has been suggested to reduce the risk of prostate cancer. We conducted a nested case-control study using Danish demographic and health data registries and summarized existing evidence in a meta analysis. The case-control study included all Danish men aged 40-85 years with incident histologically verified prostate adenocarcinoma between 2005 and 2015 (cases). For each case, we selected 10 age-matched controls. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CI) for prostate cancer associated with long-term VKA use adjusted for concomitant drug use, medical history and socioeconomic status. Among 38,832 prostate cancer cases, 1,089 (2.8%) had used VKAs for 3 or more years compared to 10,803 (2.8%) controls yielding a crude OR of 1.01 (95% CI, 0.95-1.08). Multivariable adjustment for covariates had limited influence on the association (OR, 1.03; 95% CI, 0.97-1.10). We observed no dose-response relationship (e.g. OR for 5-10 years of use, 1.06 95% CI, 0.97-1.16). We included 8 studies in the meta analysis reporting effect estimates from 0.51 (95% CI, 0.23-1.13) to 1.10 (95% CI, 0.94-1.40). Using random effect methods, a pooled effect estimate of 0.86 (95% CI, 0.70-1.05) was obtained; however, there was considerable across-study heterogeneity (I2 : 93.9%). In conclusion, we did not observe a reduced risk of prostate cancer associated with VKA use in this nationwide study and, taken together with previous study findings, a major protective effect of VKAs against prostate cancer seems unlikely. PMID- 30246249 TI - Curcumin induces concentration-dependent alterations in mitochondrial function through ROS in C2C12 mouse myoblasts. AB - Curcumin exhibits antioxidant properties in normal cells where the uptake is low, unlike in tumor cells where uptake is high and curcumin increases reactive oxygen species (ROS) production and cell death. Mitochondria are the main source and primary target of cellular ROS. We hypothesized that curcumin would regulate cellular redox status and mitochondrial function, depending on cell sensitivity and/or curcumin concentration in normal cells. We examined the differences between low and high concentrations of curcumin, with specific attention focused on ROS levels, mitochondrial function, and cell viability in mouse C2C12 myoblast under normal and simulated conditions of diabetes. Cells incubated with high concentrations of curcumin (10-50 MUM) resulted in decreased cell viability and sustained robust increases in ROS levels. Mechanistic studies showed that increased ROS levels in cells incubated with 20 MUM curcumin induced opening of mitochondrial permeability transition pores and subsequent release of cytochrome c, activation of caspases 9 and 3/7, and apoptotic cell death. Low concentrations of curcumin (1-5 MUM) did not affect cell viability, but induced a mild increase in ROS levels, which peaked at 2 hr after the treatment. Incubation with 5 MUM curcumin also induced ROS-dependent increases in mitochondrial mass and membrane potential. Finally, pretreatment with 5 MUM curcumin prevented high glucose induced oxidative cell injury. Our study suggests that mitochondria respond differentially depending on curcumin concentration-dependent induction of ROS. The end result is either cell protection or death. Curcumin may be an effective therapeutic target for diabetes and other mitochondrial diseases when used in low concentrations. PMID- 30246250 TI - 1,7-Bis(4-hydroxyphenyl)-1,4-heptadien-3-one induces lung cancer cell apoptosis via the PI3K/Akt and ERK1/2 pathways. AB - 1,7-Bis(4-hydroxyphenyl)-1,4-heptadien-3-one (EB30) is a diarylheptanoid-like compound isolated from Viscum coloratum. This curcumin analog exhibits significant cytotoxic activity against HeLa, SGC-7901, and MCF-7 cells. However, little is known about the anticancer effects and mechanisms of EB30 in human lung cancer. The current study reports that EB30 significantly reduced the cell viability of A549 and NCI-H292 human lung cancer cells. Further examination revealed that EB30 not only induced cell cycle arrest and promoted the generation of reactive oxygen species (ROS) but also induced cell apoptosis through the intrinsic and extrinsic signaling pathways. Furthermore, EB30 upregulated the expression levels of p-ERK1/2 and p-P90RSK, whereas downregulating the phosphorylation of Akt and P70RSK. Cell viability was further inhibited by the combination of EB30 with LY294002 (a specific PI3K inhibitor) or U0126 (a MEK inhibitor). The current study indicates that EB30 is a potential anticancer agent that induces cell apoptosis via suppression of the PI3K/Akt pathway and activation of the ERK1/2 pathway. PMID- 30246251 TI - Bone morphogenetic protein receptor signal transduction in human diseases. AB - Bone morphogenetic proteins (BMPs) are secreted cytokines that were initially discovered on the basis of their ability to induce bone. Several decades of research have now established that these proteins function in a large variety of physiopathological processes. There are about 15 BMP family members, which signal via three transmembrane type II receptors and four transmembrane type I receptors. Mechanistically, BMP binding leads to phosphorylation of the type I receptor by the type II receptor. This activated heteromeric complex triggers intracellular signaling that is initiated by phosphorylation of receptor regulated SMAD1, 5, and 8 (also termed R-SMADs). Activated R-SMADs form heteromeric complexes with SMAD4, which engage in specific transcriptional responses. There is convergence along the signaling pathway and besides the canonical SMAD pathway, BMP-receptor activation can also induce non-SMAD signaling. Each step in the pathway is fine-tuned by positive and negative regulation and crosstalk with other signaling pathways. For example, ligand bioavailability for the receptor can be regulated by ligand-binding proteins that sequester the ligand from interacting with receptors. Accessory co-receptors, also known as BMP type III receptors, lack intrinsic enzymatic activity but enhance BMP signaling by presenting ligands to receptors. In this review, we discuss the role of BMP receptor signaling and how corruption of this pathway contributes to cardiovascular and muscle-skeletal diseases and cancer. We describe pharmacological tools to interrogate the function of BMP receptor signaling in specific biological processes and focus on how these agents can be used as drugs to inhibit or activate the function of the receptor, thereby normalizing dysregulated BMP signaling. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 30246252 TI - Microbial acidification, alcoholization, and aroma production during spontaneous lambic beer production. AB - Acidic beers, such as Belgian lambic beers and American and other coolship ales, are becoming increasingly popular worldwide thanks to their refreshing acidity and fruity notes. The traditional fermentation used to produce them does not apply pure yeast cultures but relies on spontaneous, environmental inoculation. The fermentation and maturation process is carried out in wooden barrels and can take up to three years. It is characterized by different microbial species belonging to the enterobacteria, acetic acid bacteria, lactic acid bacteria, and yeasts. This review provides an introduction to the technology and four fermentation strategies of beer production, followed by the microbiology of acidic beer production, focusing on the main microorganisms present during the long process used for the production of Belgian lambic beers. (c) 2018 Society of Chemical Industry. PMID- 30246254 TI - The anger incentive delay task: A novel method for studying anger in neuroscience research. AB - Unlike other basic emotions, anger is relatively difficult to produce in the lab, with the most reliable methods involving elaborate and time-consuming manipulations. These factors preclude the possibility of using them for studying short-lived changes in neural activity associated with the subjective experience of anger. In this paper, we present a novel task that allows for the trial-by trial manipulation of anger and the examination of associated ERPs. Participants completed an incentive delay task, in which accurate responses were rewarded with monetary gains (or breaking even, in a neutral condition), and inaccurate responses were punished with monetary losses. After participants received accuracy feedback, they received information that indicated the amount of money they won or lost on that trial. On a majority of trials, this amount was consistent with the feedback stimuli, while on a minority of trials this amount was inconsistent. Results indicated that participants reported the most anger after trials where goal pursuit was frustrated by monetary losses despite accurate responses. P3b amplitudes were greater for inconsistent outcomes than consistent outcomes, regardless of whether these resulted in unexpected gains or frustrating losses. On frustrating trials, P3b amplitudes were positively correlated with self-reported anger. The same correlation was not observed for trials with stimuli that signaled surprise gains. Discussion focuses on the implications of these results. PMID- 30246253 TI - Hepatitis B virus large surface protein is priming for hepatocellular carcinoma development via induction of cytokinesis failure. AB - Chronic hepatitis B virus (HBV) infection is a main risk factor for development of liver cirrhosis and hepatocellular carcinoma (HCC). Although HBV vaccination and antiviral therapy lead to substantial risk reduction for HCC development, it is evident that both can reduce, but not completely eliminate the risk. High serum levels of HBV surface antigen (HBsAg) were shown to predict disease progression of chronic HBV infection in patients harboring low viral load, and in line with this, HBV surface proteins were shown to exert oncogenic functions. As HBsAg seroclearance is infrequently achieved in patients who have undergone antiviral therapy, it is necessary to gain further insights into molecular mechanisms of HBsAg seroclearance failure after antiviral therapy and HCC development mediated by HBV surface proteins. A recent study published in this journal has shown that the HBsAg large surface protein (LHBs) contributes to HCC development by inducing cytokinesis failure and consequent aneuploidy via induction of DNA damage and polo-like kinase 1 (PLK1)-mediated G2/M checkpoint failure in hepatocytes. Inhibition of PLK1 by a PLK1-specific small molecule inhibitor was shown to restore G2/M checkpoint in vitro and to reduce tumor burden in vivo. The initial LHBs-induced hepatocyte aneuploidy may give rise to further aneuploidy and thereby lead to self-propagating cycles of chromosomal instability driving intra-tumor heterogeneity and clonal cancer evolution. Thus, LHBs-induced cytokinesis failure may be a priming event for HCC development. In conclusion, the study not only provides further mechanistic insights into the oncogenic role of LHBs, but also identifies a potential target to interfere with the vicious circle of LHBs-induced aneuploidy, which may be especially useful in patients showing failure of HBsAg seroclearance after antiviral therapy. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 30246255 TI - Cascade and no-repetition rules are comparable controls for the auditory frequency mismatch negativity in oddball tasks. AB - The mismatch negativity (MMN) has been widely studied with oddball tasks to index processing of unexpected auditory change. The MMN is computed as the difference of deviant minus standard and is used to capture the pattern violation by the deviant. However, this oddball MMN is confounded because the deviant differs physically from the standard and is presented less often. To improve measurement, the same tone as the deviant is presented in a separate condition. This control tone is equiprobable with other tones and is used to compute a corrected MMN (deviant minus control). Typically, the tones are in random order except that consecutive tones are not identical (no-repetition rule). In contrast, a recent study on frequency MMN presented tones in a regular up-and-down sequence (cascade rule). If the cascade rule is detected more easily than the no-repetition rule, there should be a lower risk of a confounding MMN within the cascade condition. However, in previous research, the cascade and no-repetition conditions differed not only in the regularity of the tone sequence but also in number of tones, frequency range, and proportion of tones. We controlled for these differences to isolate effects of regularity in the tone sequence. Results of our preregistered analyses provided moderate evidence (BF01 >6) that the corrected MMN did not differ between cascade and no-repetition conditions. These findings imply that no repetition and cascade rules are processed similarly and that the no-repetition condition provides an adequate control in frequency MMN. PMID- 30246256 TI - Comparative use of the Ages and Stages Questionnaires in the USA and Scandinavia: a systematic review. AB - AIM: The aim of this systematic review was to investigate screening practices with the Ages and Stages Questionnaires (ASQ) and the Ages and Stages Questionnaires: Social-Emotional (ASQ:SE) in the USA and Scandinavia and to identify practical lessons and research opportunities. METHOD: The review was performed for ASQ- and ASQ:SE-related studies in children from birth to 5 years. From nine databases and 1689 references (published from 1988-2018), 127 articles were included and categorized using Covidence online software. The Critical Appraisal Skills Programme Checklists were used before data synthesis. RESULTS: US studies primarily use the ASQ/ASQ:SE to detect delays in general and at-risk populations in medical settings, which increases early detection, clinician referral, and intervention rates. Scandinavian studies commonly use the ASQ/ASQ:SE to monitor developmental-behavioural differences in intervention/exposure-based cohorts. Pre-visit screening yields completion/return rates of 83% to more than 90% and fosters same-day interpretation. When referrals are indicated, systemwide care coordination or colocation with a developmental behavioural specialist is beneficial. INTERPRETATION: Practical implementation lessons are reviewed. Research opportunities include investigating and measuring the ASQ/ASQ:SE's 'overall' sections. Danish, Norwegian, and Swedish translations are available but up-to-date norming and validation studies are needed throughout Scandinavia. Randomized controlled trials are needed to investigate outcomes in screened versus unscreened cohorts. WHAT THIS PAPER ADDS: General and at-risk populations broadly benefited from periodic Ages and Stages Questionnaires (ASQ) and/or Ages and Stages Questionnaires: Social-Emotional (ASQ:SE) screening. Pre visit ASQ and/or ASQ:SE screenining implementation systems work best. The ASQ and ASQ:SE 'overall' sections are not quantifiable and under-researched. PMID- 30246257 TI - Procedural safety and long-term follow-up after pacemaker implantation in nonagenarians. AB - BACKGROUND: The rate of pacemaker (PM) implantations is constantly growing. Since life expectancy of the population is projected to increase, a large number of nonagenarian patients will need PM implantation. We aimed at analyzing short- and long-term outcomes after PM implantation in nonagenarians. METHODS: Patients aged >=90 years referred for PM implantation from 2004 to 2017 were included. The primary clinical endpoint was total mortality. Secondary endpoints included procedure-related and in-hospital complications. RESULTS: A total of 172 patients were included (92.6 +/- 2.1 years, from 90.0 to 101.4 years). Procedure duration was 50.0 +/- 19.7 minutes. Most of the patients had VVI devices implanted (143 pts, 83.1%) and mean hospital stay was 3.5 +/- 1.5 days. Nine patients (5.2%) had short-term device-related complications and 29 patients (16.8%) had post procedural complications, non-related to the implantation, including four leading to patients' death. During a follow-up of 22.5 months (interquartile range: 7.3 38.0), 94 patients (54.7%) died. Survival rates were 82.9% (95% confidence interval [CI]: 76.0-88.0), 73.7% (95% CI: 65.7-80.1) and 37.5% (95% CI: 27.5 47.5) after 1, 2, and 5 years, respectively. The Charlson comorbidity index was a predictive factor of procedural complications (odds ratio = 1.33; 95% CI: 1.05 1.69, P = 0.02) while having a complication (hazard ratio [HR] = 4.04; 95% CI: 1.79-9.11, P = 0.001) and atrial fibrillation (HR = 1.63; 95% CI: [1.02-2.63], P = 0.043) were predictors of post-implantation death. CONCLUSION: PM implantation in nonagenarians is safe, with a low risk of procedural complications, but many comorbidities-related complications can occur. Caution should be taken in this old and frail population since complications significantly impact patients' survival. PMID- 30246258 TI - Genome-wide scan reveals divergent selection among taurine and zebu cattle populations from different regions. AB - In this study, to identify genomic signatures of divergent selection, we genotyped 10 cattle breeds/populations (n = 275), representing eight Ethiopian cattle populations (n = 229) and two zebu populations (n = 46) adapted to tropical and sub-tropical environments, using the high-density single-nucleotide polymorphisms (SNPs) derived mainly from Bos indicus breeds, and using five reference taurine breeds (n = 212). Population genetic differentiation (FST ) values across sliding windows were estimated between zebu and reference combined taurine breeds. The most differentiated regions (FST >= 0.53), representing the top 1% smoothed FST values, were considered to represent regions under diversifying selection. In total, 285 and 317 genes were identified in the comparisons of Ethiopian cattle with taurine and Asian zebu with taurine respectively. Some of these genes are involved in stress responses/thermo tolerance and DNA damage repair (HSPA4, HSF1, CMPK1 and EIF2AK4), pigmentation (ERBB3 and MYO1A), reproduction/fertility (UBE2D3, ID3 and PSPC1), immune response (PIK3CD and AKIRIN2) and body stature and size (MBP2, LYN and NPM1). Additionally, the candidate genes were associated with functional terms (e.g. cellular response to stress, DNA repair, inflammatory response) important for physiological adaptation to environmental stresses. The results of our study may shed light on the influence of artificial and natural selection in shaping the genomic diversity of modern cattle breeds and also may serve as a basis for further genetic investigation of traits of tropical adaptation in cattle. PMID- 30246260 TI - The prevalence of undetectable vaccine-induced immunity against hepatitis B virus in US adults at high risk for infection. AB - In 2015, the Centers for Disease Control and Prevention (CDC) reported a substantial increase in the number of acute hepatitis B virus (HBV) infections in the United States (US). Although national guidelines recommend vaccination of adults at high risk for HBV infection, the prevalence of undetectable immunity (i.e., susceptibility) in this population remains unknown. In this study, we analyzed a nationally representative sample using the National Health and Nutrition Examination Survey (NHANES) to evaluate the prevalence, trend, and predictors of undetectable vaccine-induced antibodies against HBV surface antigen (anti-HBs <10 mIU/mL) among high-risk adults from 2003-2014. Among adults at high risk for HBV infection, the prevalence of undetectable immunity decreased from 83.2% in 2003-2004 (95% confidence interval [CI]: 81.3-85.0) to 69.4% (about 64 million) in 2013-2014 (95% CI: 66.0-72.6). The prevalence decreased significantly in individuals with multiple sex partners or sexually transmitted disease and in pregnant women. However, there were no significant changes in men who have sex with men (MSMs), injection drug users (IDUs), hepatitis C virus (HCV)-infected and diabetes mellitus (DM)-patients, and those with elevated aspartate aminotransferase/ alanine aminotransferase (AST/ALT). Mexican Americans had the highest prevalence of undetectable immunity (77.6%, 95% CI: 72.6-81.9%), followed by non-Hispanic whites (70.1%, 95% CI: 66.9-73.1%). Older age, lower socioeconomic status, and having >=1 high-risk factor(s) were associated with a higher risk of undetectable immunity, whereas an increased risk among the foreign born disappeared after multivariable adjustment. In conclusion, around 64 million high-risk adults in the US remain susceptible to HBV infection, especially MSMs, IDUs, diabetics, HCV patients, and populations with elevated AST/ALT. To eliminate HBV, efforts should be made to increase screening and vaccination in high-risk adults. This article is protected by copyright. All rights reserved. PMID- 30246259 TI - Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small fiber and mixed neuropathy. AB - INTRODUCTION: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small fiber neuropathy (SFN) or mixed neuropathy in a clinical setting. METHODS: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed. RESULTS: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD. DISCUSSION: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve, 2018. PMID- 30246261 TI - Potentiating apoptosis and modulation of p53, Bcl2, and Bax by a novel chrysin ruthenium complex for effective chemotherapeutic efficacy against breast cancer. AB - Breast cancer is the most frequent cause of cancer in women. In the current study, transition metal ruthenium was complexed with flavonoid chrysin to evaluate the chemotherapeutic potential of this compound in Michigan Cancer Foundation-7 (MCF-7) human mammary cancer cell line and 7,12 dimethylbenz(alpha)anthracene-induced mammary cancer in female Sprague-Dawley rats. The characterizations of the complex were accomplished through UV-visible, NMR, IR, Mass spectra, and XRD techniques and antioxidant activity was assessed by DPPH, FRAP, and ABTS methods. In vitro studies included cell viability, cell cycle analysis, DNA fragmentation, and marker analysis by western blot analysis and found that complex treatment suppressed cell growth-induced cell cycle arrest and enhanced the induction of apoptosis in cancer cells. Moreover, complex treatment modulated signaling pathways including mTOR, VEGF, and p53 in the MCF-7 cells. Acute and subacute toxicity was performed in rats to determine the therapeutic doses. Breast cancer in rats was initiated by the administration of 7,12-dimethylbenz(alpha)anthracene (0.5 mg/100 g body weight) via single tail vein injection. The histopathological analysis after 24 weeks of carcinogenesis study depicted substantial repair of hyperplastic lesions. Immunohistochemical analysis revealed upregulation of Bax and p53 and downregulation of Bcl2 proteins and TUNEL assay showed an increase in apoptotic index in ruthenium-chrysin treated groups as compared to the carcinogen control. Our findings from the in vitro and in vivo study support the continued investigation of ruthenium-chrysin complex possesses a potential chemotherapeutic activity against breast cancer and was efficient in reducing hyperplastic lesions in the mammary tissues of rats by inducing apoptosis. PMID- 30246262 TI - Residual detection of naproxen, methyltestosterone and 17alpha hydroxyprogesterone caproate in aquatic products by simple liquid-liquid extraction method coupled with liquid chromatography-tandem mass spectrometry. AB - In the present study, we aimed to develop a reliable screening method based on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) for the detection and quantification of naproxen, methyltestosterone and 17alpha hydroxyprogesterone caproate residues. The target analytes were extracted from samples of eel, flatfish and shrimp using acetonitrile with 1% acetic acid, followed by liquid-liquid purification with n-hexane. Chromatographic separation was achieved on a reversed-phase analytical column using 0.1% formic acid containing 10 mm ammonium formate in distilled water (A) and methanol (B) as mobile phases. All the matrix-matched calibration curves were linear (R2 >= 0.99) over the concentration range of the tested analytes. Recovery at three spiking levels (0.005, 0.01 and 0.02 mg/kg) ranged from 68 to 117% with intra- and inter-day precisions <10%. Five market samples for each matrix (eel, flatfish and shrimp) were collected and tested for method application. In summary, the proposed method is feasible to screen and quantify the analytes with high selectivity in aquatic food products meant for human consumption. PMID- 30246263 TI - Evaluation on the effect of hydrogen sulfide on the NLRP3 signaling pathway and its involvement in the pathogenesis of atherosclerosis. AB - BACKGROUND: As a common disease, the incidence of atherosclerosis (AS) in the world is high. Therefore, we aimed to evaluate the involvement of hydrogen sulfide (H 2 S)/cystathionine gamma-lyase (CSE) in the pathogenesis of AS as well as their possible signaling pathways. METHODS: Enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blot analysis were used to detect the effect of CSE on the expression of inflammatory cytokines, ie, H 2 S, thioredoxin-interacting protein (TXNIP), NLRP3, apoptosis-associated speck-like protein (ASC), caspase-1, and interleukin (IL)-1beta. In addition, immunohistochemistry and Western blot analysis were performed to detect the levels of TXNIP, NLRP3, ASC, caspase-1, IL-1beta, and IL-18 among different groups. RESULT: Knockdown of CSE by the transfection of CSE small interfering RNA upregulated the levels of two inflammatory cytokines, ie, IL-1beta and IL-18. In addition, the downregulation of CSE promoted the expression of TXNIP, NLRP3, ASC, caspase-1, and IL-1beta in THP-1 cells. Meanwhile, treating the cells with sodium hydrosulfide (NaHS) inhibited the productions of IL-1beta and IL-18. Furthermore, upregulation of H 2 S synthesis by treating the cells with NaHS also reduced the protein levels of TXNIP, NLRP3, ASC, caspase-1, and IL-1beta. Finally, the protein levels of TXNIP and NLRP3 in the AS group were much higher than those in the AS + H 2 S group, which in turn was higher than the sham group. In addition, the AS group displayed the highest protein levels of TXNIP, NLRP3, ASC, caspase 1, IL-1beta, and IL-18, while the levels of these proteins in the AS + H 2 S group were higher than those in the sham group. CONCLUSION: In summary, the present finding suggested a possible linkage between H 2 S metabolism and AS through the H 2 S/CSE-TXNIP-NLRP3-IL-18/IL-1beta-nitric oxide (NO) signaling pathway. PMID- 30246264 TI - Some pyrazoles derivatives: Potent carbonic anhydrase, alpha-glycosidase, and cholinesterase enzymes inhibitors. AB - A series of substituteed pyrazol-4-yl-diazene derivatives were found to be effective inhibitors against alpha-glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) with Ki values in the range of 33.72 +/- 7.93 to 90.56 +/- 27.52 nM for alpha-glycosidase, 1.06 +/- 0.16 to 9.83 +/- 0.74 nM for hCA I, 0.68 +/- 0.12 to 7.16 +/- 1.14 nM for hCA II, 44.66 +/- 10.06 to 78.34 +/- 17.83 nM for AChE, and 50.36 +/- 13.88 to 88.36 +/- 20.03 nM for BChE, respectively. Recently, inhibition of these metabolic enzymes has been considered as a promising factor for pharmacologic intervention in a diversity of disturbances, such as diabetes, glaucoma, obesity, epilepsy, cancer, and neurodegenerative diseases. PMID- 30246267 TI - The association of hemocyte profile and obstructive sleep apnea. AB - BACKGROUND: The hemocyte profile is one of the most frequently requested clinical laboratory tests. However, the analysis of blood cell indexes of obstructive sleep apnea (OSA) patients in previous studies was not comprehensive. And, this study aimed to fully analyze the blood routine in OSA patients. METHODS: A retrospective study was conducted on 1087 male patients, who were admitted to the sleep center of Nanfang Hospital from May 2013 to February 2018. According to the apnea hypopnea index (AHI), patients were divided into four groups: control group (AHI < 5, n = 135), mild OSA (5 ? AHI < 15, n = 185), moderate OSA (15 ? AHI < 30, n = 171), and severe OSA (AHI ? 30, n = 596). Data collected included sleep parameters, complete blood routine, body mass index (BMI), age, and comorbidities. RESULTS: In our study, leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils, erythrocytes, hemoglobin, hematocrit, platelets, MPV, and PDW-SD were statistically significant among the four groups based on AHI (P < 0.05), but no significant differences were found in MCV, RDW SD, N/L, and P/L ratio (P > 0.05). Neutrophils, lymphocytes, monocytes, eosinophils, basophils, hemoglobin, hematocrit, platelets, and MPV were significantly correlated with AHI. Moreover, multiple linear regression analysis demonstrated that hematocrit (beta = 73.254, P = 0.001), neutrophils (beta = 1.414, P = 0.012), and lymphocytes (beta = 4.228, P < 0.001) were independently associated with AHI. CONCLUSION: Neutrophils, lymphocytes, and hematocrit were independently associated with OSA severity. And combining these three blood cell indicators could contribute to the diagnosis of OSA. PMID- 30246266 TI - Timely diagnosis of dementia? Family carers' experiences in 5 European countries. AB - OBJECTIVES: Timely diagnosis of dementia is recommended in national strategies. To what extent is it occurring across Europe, what factors are associated with it, and what is the impact on carers emotions of quality of diagnostic disclosure? METHODS/DESIGN: Survey of family carers recruited through 5 Alzheimer's associations (Czech Republic, Finland, Italy, the Netherlands, and Scotland). One thousand four hundred and nine carers participated, 84% completing online. Fifty-two percent were adult children, and 37% were spouses, with median age 57. Most (83%) were female. RESULTS: Nearly half (47%) of carers reported that an earlier diagnosis would have been preferable. Delaying factors included reluctance of the person with dementia, lack of awareness of dementia, the response of professionals, and delays within health systems. Recent diagnoses were no more likely to be considered timely, although professional responses appeared to be improving. Delayed diagnoses were more often reported by adult child carers and where the diagnosis was made in the later stages of dementia, or another condition had been previously diagnosed. In all countries except Italy, the diagnosis was shared with the person with dementia in the majority of cases. Timely diagnoses and higher quality diagnostic disclosure are associated with better adjustment and less negative emotional impact on carers in the short and medium term. CONCLUSIONS: Although the study sample were well educated and likely to be in touch with an Alzheimer organisation, many continued to experience the diagnosis of dementia as coming too late, and further work on public awareness, as well as on professional responses, is needed. PMID- 30246265 TI - Creatine and phosphocreatine mapping of mouse skeletal muscle by a polynomial and Lorentzian line-shape fitting CEST method. AB - PURPOSE: To obtain high-resolution Cr and PCr maps of mouse skeletal muscle using a polynomial and Lorentzian line-shape fitting (PLOF) CEST method. METHODS: Wild type mice and guanidinoacetate N-methyltransferase-deficient (GAMT-/-) mice that have low Cr and PCr concentrations in muscle were used to assign the Cr and PCr peaks in the Z-spectrum at 11.7 T. A PLOF method was proposed to simultaneously extract and quantify the Cr and PCr by assuming a polynomial function for the background and 2 Lorentzian functions for the CEST peaks at 1.95 ppm and 2.5 ppm. RESULTS: The Z-spectra of phantoms revealed that PCr has 2 CEST peaks (2 ppm and 2.5 ppm), whereas Cr only showed 1 peak at 2 ppm. Comparison of the Z-spectra of wild-type and GAMT-/- mice indicated that, contrary to brain, there was no visible protein guanidinium peak in the skeletal-muscle Z-spectrum, which allowed us to extract clean PCr and Cr CEST signals. High-resolution PCr and Cr concentration maps of mouse skeletal muscle were obtained by the PLOF CEST method after calibration with in vivo MRS. CONCLUSIONS: The PLOF method provides an efficient way to map Cr and PCr concentrations simultaneously in the skeletal muscle at high MRI field. PMID- 30246268 TI - Validation of a European Cross-Cultural Neuropsychological Test Battery (CNTB) for evaluation of dementia. AB - BACKGROUND: The aims of this study were to establish the diagnostic accuracy of the European Cross-Cultural Neuropsychological Test Battery (CNTB) for dementia in different ethnic populations in Western Europe, to examine its ability to differentiate cognitive impairment profiles for dementia subtypes, and to assess the impact of demographic variables on diagnostic properties. METHODS: The study was a Western European cross-sectional multi-center study. A total of 66 patients with dementia and 118 cognitively intact participants were included across six memory clinics; 93 had ethnic minority background and 91 had ethnic majority background. Tests in the CNTB cover global cognitive function, memory, language, executive functions, and visuospatial functions. RESULTS: Significant differences with moderate to large effect sizes were present between patients with dementia and control participants on all CNTB measures. Area under the curves (AUC) ranged from .62 to .99 with a mean AUC across all measures of .83. Comparison of ethnic minority and majority groups generally revealed higher sensitivity in the minority group but no significant difference in the mean AUC's across all measures (.84 vs78, P = .42). Comparison of impairment profiles for patients with Alzheimer's disease (AD) and non-AD dementia revealed that AD patients were significantly more impaired on the memory domain, whereas patients with non-AD dementia were more impaired on the executive functions domain. CONCLUSIONS: The CNTB was found to have promising cross-cultural diagnostic properties for evaluation of dementia in the targeted minority and majority populations and could represent a valid cross-cultural alternative to other well-established neuropsychological test batteries when assessing patients from these populations. PMID- 30246269 TI - Effects of forage source and particle size on feed sorting, milk production and nutrient digestibility in lactating dairy cows. AB - The objectives of this study were to determine the effects of forage source (quality) and particle size on feed sorting, milk production and nutrient digestibility in lactating dairy cows. Twelve multiparous lactating Holstein cows were used in a replicated 4 * 4 Latin square experiment with a 2 * 2 factorial arrangement of treatments. Treatments were as follows: (a) feeding long oaten hay (OL), (b) feeding short oaten hay (OS), (c) feeding long wild-rye hay (WL) and (d) feeding short wild-rye hay (WS). The sorting activity of cows fed wild-rye hay diets was greater than that of cows fed oaten hay diets. Sorting activity decreased with reduced forage particle size (FPS) for wild-rye hay diets but was not affected for oaten hay diets. Cows fed oaten hay diets had a similar dry matter intake (DMI), but higher total tract nutrient digestibility, and hence higher milk yield than cows fed wild-rye hay diets. The increase in DMI as a result of reduced FPS was significant in cows fed wild-rye hay diets. Feed efficiency (4% fat-corrected milk (FCM)/DMI) decreased from 1.18 to 1.11 when FPS decreased, but was not affected by the forage source. The digestibility of DM, crude protein (CP) and organic matter (OM) in the total tract was decreased by a reduction in FPS for wild-rye hay diets, but was not affected for oaten hay diets. In conclusion, cows fed high-quality forage (oaten hay) had a lower sorting activity and higher production performance than those fed poor-quality forage (wild-rye hay). The optimal dietary FPS in lactating dairy cows should take the effect of forage source into account. PMID- 30246270 TI - Pelvic organ prolapse in Caucasian and Asian women: a comparative study. AB - OBJECTIVES: Ethnic differences have been suggested as a significant factor for pelvic organ prolapse; yet, the pelvic organ descent in various ethnic groups was not well studied, especially in Asian population. We aimed to compare prolapse stages, pelvic organ descent and hiatal dimensions of East Asian and Caucasian women presenting with symptoms of pelvic organ prolapse. METHODS: A prospective observation study was conducted in women who presented to tertiary urogynecology clinics with symptoms of pelvic organ prolapse in Hong Kong and Sydney. Demographics, prolapse symptoms and POP-Q staging were assessed. Transperineal ultrasound volume acquisition was performed using Voluson systems. Offline analysis of 4-dimensional ultrasound volume data was performed at a later date, blinded against all clinical data to ascertain pelvic organ descent and hiatal dimensions on Valsalva maneuver. Levator muscle avulsion was assessed in volumes obtained on pelvic floor muscle contraction. RESULTS: A total of 225 Asian women and 206 Caucasian women were included from clinics in Hong Kong from July 2012 to February 2014 and in Sydney from January 2015 to July 2016 respectively. There was no significant difference in the overall staging of prolapse. However, Asians more commonly showed apical compartment prolapse (99.6% vs 71.8%, p<0.001) and less posterior compartment prolapse (16.9% vs 48.5%, p<0.001) compared to Caucasians on POP-Q examination. The position of the uterus was lower in Asian women (-11mm vs 1.35mm, p<0.001) while the rectal ampulla was lower in Caucasians (-10.6 mm vs -4.1mm, p<0.001). Ethnicity of Caucasian was a significant factor for lower risk of apical compartment prolapse on clinical assessment (OR: 0.01, p<0.001) and on ultrasound (OR: 0.13, p<0.001) as well as for a higher risk of posterior compartment prolapse on clinical assessment (OR: 4.36, p<0.001) and true rectocele on ultrasound (OR: 8.14, p<0.001) in Caucasians found on multiple regression. CONCLUSIONS: Asian women more commonly present with uterine prolapse while Caucasians show more posterior compartment prolapse. Ethnicity was a significant predictor on multivariate analysis. This article is protected by copyright. All rights reserved. PMID- 30246271 TI - Identification of candidate domestication-related genes with a systematic survey of loss-of-function mutations. AB - Domestication is an important key co-evolutionary process through which humans have extensively altered the genomic make-up and appearance of both plants and animals. The identification of domestication-related genes remains very arduous. In this study, we present a systematic analytical approach that harnesses two recent advances in genomics, whole-genome sequencing (WGS) and prediction of loss of-function (LOF) mutations, to greatly facilitate the assembly of an enriched catalogue of domestication-related candidate genes. Using WGS data for 296 cultivated (Glycine max) and 64 wild soybean accessions, we identified 8699 LOF variants, and 116 genes that are uniquely fixed for one or more LOF allele(s) in domesticated soybeans. Existing soybean transcriptomic data led us to overcome analytical challenges associated with whole-genome duplications and to identify neo- or subfunctionalized genes. This systematic approach allowed us to identify 110 candidate domestication-related genes in an efficient and rapid way. This catalogue contains previously well characterized domestication genes in soybean, as well as some orthologs from other domesticated crop species. In addition, it comprises many promising candidate domestication genes. Overall, this collection of candidate domestication-related genes in soybean is almost twice as large as the sum of all previously reported candidate genes in all other crops. We believe this systematic approach could readily be used in wide range of species. PMID- 30246272 TI - Putting our best foot forward: Clinical, treatment-based and ethical considerations of nusinersen therapy in Canada for spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality. SMA is a spectral disorder and is categorised based on symptom onset and severity. The median life expectancy for infants with SMA presenting before 6 months of age is less than 2 years without respiratory support. To date, there is no cure for SMA. In June 2017, nusinersen was approved in Canada as the first disease-modifying drug for SMA because of its demonstrated benefits on motor function and survival in clinical trials. However, with a price tag of almost 1 million dollars for the first year of therapy, careful clinical, treatment-based and ethical consideration of the principles of (i) best interests; (ii) universality; (iii) portability; (iv) public administration; (v) accessibility; and (vi) comprehensiveness are important guideposts to ensure transparent and equitable allocation of health-care resources for nusinersen and all other future orphan drugs. PMID- 30246273 TI - Blood transfusion for anaemia of prematurity: Current practice in Australia and New Zealand. AB - AIM: To characterise the current transfusion practice among clinicians in Australasian neonatal units and factors that influence their decision-making. METHODS: Members of the Australia and New Zealand Neonatal Network (ANZNN) and practitioners at their local institutions were invited to participate in a 15 question web-based survey between 1 June and 31 July 2016. The survey was designed to assess (i) haemoglobin-based transfusion thresholds; (ii) presence of local guidelines; (iii) preference for a restrictive or liberal transfusion policy; (iv) perceived benefits and risks of transfusion; and (v) use of clinical adjuncts to assist decision-making. RESULTS: Overall, 130 participants responded to at least one question. Haemoglobin transfusion thresholds for anaemia of prematurity (AOP) varied significantly from <60 to <120 g/L. Of 103 participants, 36 (35%) reported that they do not have access to local transfusion guidelines. The majority utilise multiple clinical and haematological parameters to guide their decision-making, and approximately half (45/84, 54%) believe that tissue hypoxia detected by near-infrared spectroscopy (NIRS) may better inform transfusion thresholds. Of 102 participants, 51 (50%) support a restrictive rather than liberal transfusion policy. The most commonly reported perceived risks of transfusion for AOP were suppression of endogenous erythropoiesis and increased rates of necrotising enterocolitis. CONCLUSIONS: There is a significant variation in transfusion practice in Australasian neonatal units. Quality and safety initiatives may assist with improved consistency of transfusion practice across the ANZNN. However, further research is required to better define optimal transfusion thresholds, quantify potential risks of transfusion and determine clinical utility of newer adjuncts such as NIRS. PMID- 30246274 TI - Recent advances in fertility preservation. AB - BACKGROUND: Most cancer treatments like chemotherapy, radiotherapy or a combination of both are highly toxic to the gonads, putting girls and young women at risk of premature ovarian insufficiency and subsequent infertility. Non oncological conditions may also require therapies that put women's reproductive potential at risk. Fertility preservation counseling should therefore be offered to all patients requiring gonadotoxic treatments, and to those who wish to postpone motherhood for social/personal reasons. Among the most effective fertility preservation options available today, oocyte and embryo cryopreservation, and ovarian tissue cryopreservation have emerged as the front runners. AIM: This review focuses on the currently available and most widely accepted fertility preservation and restoration strategies, with a special focus on recent advances in ovarian tissue cryopreservation and transplantation. CONCLUSIONS: To manage cancer patients satisfactorily and offer proper counsel on the most appropriate option available to them, different parameters need to be taken into account, including pubertal status, partner status and urgency of treatment for the underlying pathology. When fertility preservation is carried out for non-oncological indications or personal reasons, oocyte cryopreservation by vitrification is clearly the highest-yield clinical strategy. Ovarian tissue cryopreservation followed by transplantation is rapidly gaining ground as a fertility preservation and restoration strategy, and will hopefully soon have its 'experimental' label removed to allow practitioners to move on to open clinical application. Techniques to improve grafted ovarian tissue life span and quality as well as to avoid transmission of malignant cells have been developed, showing promise as a way to expand this procedure. PMID- 30246275 TI - People with low back pain show reduced movement complexity during their most active daily tasks. AB - BACKGROUND: Actigraphy is a quantitative method for the investigation of human physical activity and is normally based on accelerometric and/or kinematic data. METHODS: A multichannel actigraphy system, able to record both acceleration and spine angles, was employed in this study to measure the quality of movement in 17 individuals with chronic low back pain (LBP) and 18 healthy individuals during unrestricted daily activities. An indication of movement complexity was computed by means of non-negative matrix factorization throughout the 24 hr period and in the 60 min of highest activity. RESULTS: Movement complexity differed only when the 60 min of highest activity was taken into account, with the LBP group showing reduced complexity (e.g., for dimensionality = 8, over 90% of the comparisons showed a significant reduction in the LBP group). CONCLUSIONS: The results are compatible with the hypothesis that pain induces a reduction in the available kinematic trajectories and degrees of freedom during natural movements, which becomes more evident when more demanding tasks are performed. A reduced movement complexity suggests a persistent alteration of the descending neural pathways and/or a disrupted somatosensory information processing, which could be possibly contrasted by administering highly variable motor tasks. SIGNIFICANCE: People with chronic pain move differently. Movement quality is difficult to evaluate during daily activities, yet it may prove more informative than quantitative measurements. We proposed a new approach for computing movement complexity and found out that patients' movements get more stereotyped when higher spinal acceleration is required. PMID- 30246277 TI - Do the two transcription factors form a positive feedback amplifier circuit in their common fight against pathogens? PMID- 30246276 TI - The efficacy and safety of dydrogesterone for treatment of dysmenorrhea: An open label multicenter clinical study. AB - AIMS: Dydrogesterone is a retro-progesterone preparation widely used for over a half century. We sought to evaluate the efficacy and safety of dydrogesterone in Japanese women with dysmenorrhea. METHODS: This study was conducted as an open label, single-arm, multicenter study. One dydrogesterone 5-mg tablet (Duphaston) was administered orally twice daily for 21 days from the 5th to 25th day of each menstrual cycle. A total of 44 (safety analysis) and 31 patients (efficacy analysis) were enrolled. Total dysmenorrhea score, dysmenorrhea subscale scores, dysmenorrhea visual analog scale, severity of menstruation-related lower abdominal pain, low back pain, headache, and nausea/vomiting, basal body temperature, and serum estradiol and progesterone levels were evaluated. RESULTS: Baseline of the total dysmenorrhea score was 4.61, which went down over time following the administration of dydrogesterone, and the decrease was statistically significant at and after 2nd cycle of menstruation. Mean change from baseline at the final evaluation point was -1.84 (P < 0.001). Severity of menstruation-related lower abdominal pain, low back pain, headache, and nausea/vomiting, in the evaluated menstruation cycles tended to decrease over time. Basal body temperature showed a biphasic pattern in 70% at baseline, 50% in 2nd menstruation cycle, and 61% in 5th menstruation cycle, and at least half of the patients may have had ovulation during the treatment. Incidence of adverse drug reactions was 31.8%, and the most common adverse event was metrorrhagia. CONCLUSION: Dydrogesterone is efficacious, safe, and clinically beneficial in patients with dysmenorrhea, thereby indicating that dydrogesterone can be considered as a treatment option for patients with dysmenorrhea. PMID- 30246278 TI - Letter to the Editor regarding "Ertapenem - a potent treatment for clinical and quality of life improvement in patients with hidradenitis suppurativa". PMID- 30246279 TI - The large GTPase Mx1 binds Kif5B for cargo transport along microtubules. AB - A highly specific transport and sorting machinery directing secretory cargo to the apical or basolateral plasma membrane maintains the characteristic polarized architecture of epithelial cells. This machinery comprises a defined set of transport carriers, which are crucial for cargo delivery to the correct membrane domain. Each carrier is composed of a distinct set of proteins to verify precise routing and cargo selection. Among these components, the dynamin-related GTPase Mx1 was identified on post-Golgi vesicles destined for the apical membrane of MDCK cells. In addition to the presence on late secretory compartments, Mx1 was also detected on compartments of the early secretory pathway. Vesicular structures positive for this GTPase are highly dynamic, and we have studied the influence of the microtubule cytoskeleton on this motility. Live-cell microscopy indicated that microtubule disruption using nocodazole inhibits long-range trafficking of these structures. Mx1 directly or indirectly interacts with alpha tubulin and the kinesin motor Kif5B as assessed by coimmunoprecipitation. In agreement with these observations knock out of Mx1 or a mutation in the unstructured L4 loop of Mx1 decreases the efficiency of apical cargo delivery. Interestingly, the L4 loop mutant still interacts with Kif5B; however, it causes vesicle elongation. This suggests that Mx1 aids in vesicle fission and stabilizes the interaction between Kif5B, microtubules and apical transport carriers. PMID- 30246280 TI - Successful percutaneous transhepatic recanalization of a completely obstructed hepatico-jejunal anastomosis in a child with liver transplantation: Unusual employment of the transseptal puncture system. AB - Stenosis of the HJ is a common complication of pediatric split LT with high morbidity and possible evolution to secondary biliary cirrhosis and re transplantation if not treated. Because the endoscopy is generally infeasible in the Roux-en-Y, percutaneous interventional radiology management is usually the safest and most effective approach to avoid surgical revision of a stenotic bilio enteric anastomosis. We present the case of a child with acute onset of cholestasis 7 months after left lateral segment partial LT due to occlusion of the HJ. The biliary stricture was found to be non-crossable with conventional interventional radiological techniques. The obstruction was resolved creating a new bilio-digestive communication via percutaneous transhepatic approach using the TPS. This device is usually employed by the interventional cardiologist to perform some procedures requiring the direct access to the left atrium through interatrial septal puncture. In conclusion, percutaneous transhepatic recanalization of the hepato-jejuno anastomosis is a rare but feasible and valuable procedure alternative to the surgical resolution even in small infants. Although few cases have been reported in literature, it has to be considered an additional treatment option when the conventional approaches fail. PMID- 30246281 TI - A Complex Zeolite Containing Multiple Ring Sizes in a Single Channel: One Dimensional Zeolite UZM-55. AB - Zeolites are porous aluminosilicate materials utilized in a variety of sorption, separation, and catalytic applications. The oil refining industry in particular has seen a number of significant advances due to the introduction of new technologies enabled by new zeolites. Of particular importance are zeolites with 10- or 12-membered ring pores, resulting in pore shapes and sizes appropriate for the interaction with small hydrocarbon molecules. Here, the synthesis of a new zeolite UZM-55 is reported and the idealized structure thereof is presented. The most complex structure solved to date, UZM-55 possesses a large triclinic unit cell containing 52 T-sites. The material uniquely contains both 10- and 12 membered ring pores in a single, undulating one-dimensional channel, the first example in a zeolitic material of multiple delimiting rings in a single channel. This discovery opens new opportunities in shape-selective adsorption and catalysis. Demonstrated here is the unique adsorption behavior of UZM-55, shown both experimentally and computationally to adsorb one nonane molecule per unit cell in a linear conformation. PMID- 30246282 TI - Multiple factors behind early diversification of skull morphology in the continental radiation of New World monkeys. AB - Understanding the origin of diversity is a fundamental problem in evolutionary biology. The null expectation for the evolutionary diversification is that all changes in biological diversity are the result of random processes. Adaptive radiations depart from this expectation as ecological factors and natural selection are supposed to play a central role in driving exceptional diversification. However, it is not well understood how large-scale continental radiations, given their characteristics, fit to these opposing theoretical models. Here, we used phylogenetic comparative methods and geometric morphometrics to study the evolutionary process of cranial diversification in the continental radiation of New World monkeys. Particularly, we tested several alternative evolutionary scenarios for morphological evolution in the clade. Results indicated that despite the platyrrhine radiation being old and geographically widespread, the formative patterns arising from the initial stages of diversification probably associated with an adaptive radiation can still be recognized today. We also show that no single explored factor (e.g., ecological or allometric) can be invoked as a complete explanation for the observed phenotypic diversity patterns in the clade and, moreover, that different cranial regions exhibit particular macroevolutionary patterns. Together, our results highlight the evident complexity behind large-scale evolutionary radiations. PMID- 30246283 TI - Population genomics reveals evolution and variation of Saccharomyces cerevisiae in the human and insects gut. AB - The quest to discover the variety of ecological niches inhabited by Saccharomyces cerevisiae has led to research in areas as diverse as wineries, oak trees and insect guts. The discovery of fungal communities in the human gastrointestinal tract suggested the host's gut as a potential reservoir for yeast adaptation. Here, we report the existence of yeast populations associated with the human gut (HG) that differ from those isolated from other human body sites. Phylogenetic analysis on 12 microsatellite loci and 1715 combined CDSs from whole-genome sequencing revealed three subclusters of HG strains with further evidence of clonal colonization within the host's gut. The presence of such subclusters was supported by other genomic features, such as copy number variation, absence/introgressions of CDSs and relative polymorphism frequency. Functional analysis of CDSs specific of the different subclusters suggested possible alterations in cell wall composition and sporulation features. The phenotypic analysis combined with immunological profiling of these strains further showed that sporulation was related with strain-specific genomic characteristics in the immune recognition pattern. We conclude that both genetic and environmental factors involved in cell wall remodelling and sporulation are the main drivers of adaptation in S. cerevisiae populations in the human gut. PMID- 30246284 TI - MoPpe1 partners with MoSap1 to mediate TOR and cell wall integrity signalling in growth and pathogenicity of the rice blast fungus Magnaporthe oryzae. AB - In the rice blast fungus Magnaporthe oryzae, the cell wall integrity (CWI) signalling pathway governs cell wall changes in response to external cues and normal CWI signalling is critical for appressorium function and pathogenicity. We previously characterized the mitogen-activated protein kinase (MAPK) kinase MoMkk1 as an integral component of the CWI pathway. Using the affinity purification approach, we have identified MoMkk1-interacting MoPpe1 as a homologue of Saccharomyces cerevisiae serine/threonine protein phosphatase Sit4/Ppe1. We found that MoPpe1 is required for vegetative growth, conidiation and full virulence. In addition, we found that MoPpe1 interacts with MoSap1, a protein with functions similar to MoPpe1. Intriguingly, we found that MoPpe1 MoSap1 interaction is related to CWI and target of rapamycin (TOR) pathways. We presented evidence suggesting that MoPpe1 and MoSap1 function as an adaptor complex linking CWI and TOR signalling and that the activation of the TOR pathway leads to suppression of CWI signalling, resulting in defects in appressorium function and pathogenicity. Taken together, our studies not only reveal important functions of MoMkk1-MoPpe1-MoSap1 interactions in growth and pathogenicity of the blast fungus, but also highlight the complexity of regulatory networks involving conserved yet novel regulatory mechanisms of CWI and TOR signalling. PMID- 30246285 TI - Cryptic haplotype-specific gamete selection yields offspring with optimal MHC immune genes. AB - Females choose specific mates in order to produce fitter offspring. However, several factors interfere with females' control over fertilization of their eggs, including sneaker males and phenotypically unpredictable allele segregation during meiosis. Mate choice at the individual level thus provides only a poor approximation for obtaining the best genetic match. Consequently, postcopulatory sperm selection by female oocytes has been proposed as a mechanism to achieve complementary combinations of parental haplotypes. Here, using controlled in vitro fertilization of three-spined stickleback eggs, we find haplotype-specific fertilization bias toward gametes with complementary major histocompatibility complex (MHC) immunogenes. The resulting zygote (and thus offspring) genotypes exhibit an intermediate level of individual MHC diversity that was previously shown to confer highest pathogen resistance. Our finding of haplotype-specific gamete selection thus represents an intriguing mechanism for fine-tuned optimization of the offspring's immune gene composition and an evolutionary advantage in the Red Queen dynamics of host-parasite coevolution. PMID- 30246286 TI - Effect of canagliflozin on nocturnal home blood pressure in Japanese patients with type 2 diabetes mellitus: The SHIFT-J study. AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on several cardiometabolic biomarkers, but this is not sufficient to fully explain the significant reduction in cardiovascular risk and mortality reported with SGLT2 inhibitor treatment in patients with diabetes mellitus. The 8-week, randomized, open-label SHIFT-J study investigated the effects of adding canagliflozin vs intensified antihyperglycemic therapy on nocturnal home blood pressure (BP) in patients with poorly controlled type 2 diabetes and nocturnal BP on existing therapy. Patients were randomized to oral canagliflozin 100 mg/d or control (increased hypoglycemic dosage/addition of another hypoglycemic agent). The efficacy analysis included 78 patients (mean 69 years; 59% male). Nocturnal home systolic BP [HSBP] decreased by 5.23 mm Hg in the canagliflozin group and by 1.04 mm Hg in the control group (P = 0.078 for between-group difference in change from baseline to week 8 [primary endpoint]); corresponding decreases in HSBP from baseline to week 4 were 5.08 and 1.38 mm Hg, respectively (P = 0.054). Reductions in morning HSBP from baseline to week 4 (-6.82 mm Hg vs -1.26 mm Hg, P = 0.038) and evening HSBP from baseline to week 8 (-8.74 mm Hg vs -2.36 mm Hg, P = 0.012) were greater in the canagliflozin group than in the control group. Body mass index (P < 0.001) and N-terminal pro B-type natriuretic peptide level (NT-proBNP; P = 0.023) decreased more in the canagliflozin group than in the control group. Glycemic control improved comparably in both groups. Reduction of HSBP and NT proBNP level may be potential mechanism by which SGLT2 inhibitors reduce cardiovascular event risk. PMID- 30246288 TI - Assessment of practice efficacy by retrospective analysis of long-term patient outcomes: A proposed method. AB - BACKGROUND: Regardless of changes in clinical techniques and approaches, practices may find value in self-assessment. OBJECTIVE: To propose a retrospective method by which an aesthetic practice may use patient before and after photographs to assess practice efficacy among long standing patients. METHODS: Patients who had been with the practice and undergone various aesthetic procedures (n = 73, 59 women, age range 25-83 years) were selected, with associated photographs before treatment and after their last intervention, covering an average period of 10.71 +/- 1.32 years. Photographs were examined by 11 non-expert graders in random order (along with duplicate photographs of 50 untreated individuals) who guessed and recorded the perceived age of each patient. The difference between the actual and estimated age was compared with that of the after picture to derive numerical values, averaged from among the 11 graders for each patient photo set, followed by statistical testing for confidence interval (CI) to group patients as high, medium, or low responders. RESULTS: Of 73 patients, 26 were graded as responders, 23 as medium, and 24 as low, meaning that average perceived aging changed little as per the non-expert graders. CONCLUSION: Statistical analysis of before and after photographs over time may provide physicians with a window into their performance. PMID- 30246287 TI - Helicobacter pylori-associated peptic ulcer disease: A retrospective analysis of post-treatment testing practices. AB - BACKGROUND & AIMS: Guidelines recommend that patients with Helicobacter pylori (H. pylori)-associated peptic ulcer disease (PUD) receive H. pylori eradication therapy followed by post-treatment testing to prove eradication; however, post treatment testing rates are suboptimal and barriers to testing are poorly understood. Our aim was to identify factors that predicted receipt of post treatment testing. METHODS: We performed a retrospective cohort study of 152 patients with H. pylori-associated PUD diagnosed between 2007 and 2015 at a large tertiary medical center in the United States, who received standard eradication therapy and ambulatory follow-up within one year. The primary outcome of interest was receipt of post-treatment testing. Logistic regression models compared post treatment testing rates in those diagnosed while outpatient vs inpatient, patients with vs without repeat endoscopy, and patients with vs without gastroenterology (GI) clinic follow-up. Propensity scores controlled for age, sex, race, ulcer location, and symptom persistence. RESULTS: Among 152 patients, 67 (44%) patients received post-treatment testing. There were significant differences in post-treatment testing rates in those diagnosed as outpatients vs inpatients (57% vs 33%; OR 3.87, P = 0.001) and in patients with vs without GI follow-up (62% vs 11%; OR 9.85, P < 0.0001). CONCLUSIONS: The rate of testing for eradication after treatment in patients with H. pylori- associated PUD was low. However, this was significantly improved in patients who have GI follow-up and whose diagnosis was made in the outpatient setting. Our study demonstrates a clear opportunity for quality improvement initiatives. PMID- 30246289 TI - Tannic acid protects against experimental acute lung injury through downregulation of TLR4 and MAPK. AB - Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) remain a major cause of morbidity and mortality in critically ill patients, and no specific therapies are still available to control the mortality rate. Thus, we explored the preventive and therapeutic effects of tannic acid (TA), a natural polyphenol in the context of ALI. We used in vivo and in vitro models, respectively, using lipopolysaccharide (LPS) to induce ALI in mice and exposing J774 and BEAS-2B cells to LPS. In both preventive and therapeutic approaches, TA attenuated LPS-induced histopathological alterations, lipid peroxidation, lung permeability, infiltration of inflammatory cells, and the expression of proinflammatory mediators. In addition, in-vitro study showed that TA treatment could reduce the expression of proinflammatory mediators. Further studies revealed that TA-dampened inflammatory responses by downregulating the LPS-induced toll-like receptor 4 (TLR4) expression and inhibiting extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) activation. Furthermore, cells treated with the inhibitors of ERK1/2 (PD98059) and p38 (SB203580) mitigated the expression of cytokines induced by LPS, thus suggesting that ERK1/2 and p38 activity are required for the inflammatory response. In conclusion, TA could attenuate LPS-induced inflammation and may be a potential therapeutic agent for ALI-associated inflammation in clinical settings. PMID- 30246291 TI - 2-Methoxyestradiol attenuates chronic-intermittent-hypoxia-induced pulmonary hypertension through regulating microRNA-223. AB - Pulmonary hypertension (PH) is prevalent in patients with obstructive sleep apnea (OSA) syndrome, and coexistence of PH and OSA indicates a worse prognosis and higher mortality. Chronic intermittent hypoxia (CIH) is the key pathogenesis of OSA. Also, microRNA-223 (miR-223) plays a role in the regulation of CIH-induced PH process. However, the detailed mechanism of CIH inducing PH is still unclear. This study aimed to investigate the pathological process of CIH associated PH and explore the potential therapeutic methods. In this study, adult Sprague-Dawley rats were exposed to CIH or normoxic (N) conditions with 2-methoxyestradiol (2 Me) or vehicle treatment for 6 weeks. The results showed that 2-Me treatment reduced the progression of pulmonary angiogenesis in CIH rats, and alleviated proliferation, cellular migration, and reactive oxygen species formation was induced by CIH in pulmonary artery smooth muscle cells (PASMCs). CIH decreased the expression of miR-223, whereas 2-Me reversed the downregulation of miR-223 both in vivo and in vitro. Furthermore, the antiangiogenic effect of 2-Me observed in PASMCs was abrogated by miR-223 inhibitor, while enhanced by miR-223 mimic. These findings suggested that miR-223 played an important role in the process of CIH inducing PH, and 2-Me might reverse CIH-induced PH via upregulating miR-223. PMID- 30246290 TI - Combined brain-derived neurotrophic factor with extinction training alleviate impaired fear extinction in an animal model of post-traumatic stress disorder. AB - Impaired fear memory extinction (Ext) is one of the hallmark symptoms of post traumatic stress disorder (PTSD). However, since the precise mechanism of impaired Ext remains unknown, effective interventions have not yet been established. Recently, hippocampal-prefrontal brain-derived neurotrophic factor (BDNF) activity was shown to be crucial for Ext in naive rats. We therefore examined whether decreased hippocampal-prefrontal BDNF activity is also involved in the Ext of rats subjected to a single prolonged stress (SPS) as a model of PTSD. BDNF levels were measured by enzyme-linked immunosorbent assay (ELISA), and phosphorylation of TrkB was measured by immunohistochemistry in the hippocampus and medial prefrontal cortex (mPFC) of SPS rats. We also examined whether BDNF infusion into the ventral mPFC or hippocampus alleviated the impaired Ext of SPS rats in the contextual fear conditioning paradigm. SPS significantly decreased the levels of BDNF in both the hippocampus and mPFC and TrkB phosphorylation in the ventral mPFC. Infusion of BDNF 24 hours after conditioning in the infralimbic cortex (ILC), but not the prelimbic cortex (PLC) nor hippocampus, alleviated the impairment of Ext. Since amelioration of impaired Ext by BDNF infusion did not occur without extinction training, it seems the two interventions must occur consecutively to alleviate impaired Ext. Additionally, BDNF infusion markedly increased TrkB phosphorylation in the ILC of SPS rats. These findings suggest that decreased BDNF signal transduction might be involved in the impaired Ext of SPS rats, and that activation of the BDNF-TrkB signal might be a novel therapeutic strategy for the impaired Ext by stress. PMID- 30246293 TI - Practitioner experiences from the structured implementation of evidence-based practice in primary care physiotherapy: A qualitative study. AB - RATIONALE, AIMS, AND OBJECTIVES: To provide best available care, the practitioners in primary health care (PHC) must have adequate knowledge about effective interventions. The implementation of such interventions is challenging. A structured implementation strategy developed by researchers at Linkoping University, Sweden, was used for the implementation of an evidence-based assessment and treatment programme for patients with subacromial pain among physiotherapists in PHC. To further develop strategies for implementation of evidence-based practices, it was deemed important to study the implementation from the practitioners' perspective. The aim of this study was to explore the practitioners' experiences from the implementation. METHODS: A qualitative design with focus group discussions was applied. The implementation in terms of perceptions of process and outcome was evaluated by focus group discussions with, in total, 16 physiotherapists in the target group. Data were analysed using the method qualitative content analysis. RESULTS: The components of the strategy were viewed positively, and the applicability and evidence base behind the programme were appreciated. The programme was perceived to be adopted, and the practitioners described a changed behaviour and increased confidence in handling patients with subacromial pain. Both patient- and provider-related challenges to the implementation were mentioned. CONCLUSIONS: The practitioners' experiences from the implementation were mainly positive. A strategy with collaboration between academy and practice, and with education and implementation teams as facilitators, resulted in changes in practice. Critical voices concerned interprofessional collaboration and that the programme was focused explicitly on the shoulder, not including other components of physical function. PMID- 30246292 TI - Strain out a gnat and swallow a camel? - vision and driving in the Nordic countries. AB - PURPOSE: This study describes the present legislation for visual requirements for driving in the Nordic countries in relation to the European Driving License Directive. METHODS: Information about the formal legislation was gathered from each countries legal text. Further information about the implementation and common practices were achieved from national authorities in vision and driving. RESULTS: Even though the Nordic countries use the same framework of legislation, the implementation varies widely. Sweden and Norway have more specified visual field requirements than the others. On the other hand, no periodic testing of visual acuity (VA) is performed in Sweden as in all other Nordic countries. Physicians on Iceland are not obliged to report a person no longer fulfilling the visual requirements, as in other Nordic countries. In Denmark, Finland and Norway a person may apply for dispensation from the requirements by performing a practical driving test. In Sweden, a person applying for dispensation can undergo a traffic simulator test. CONCLUSION: Because of the national legislation in the Nordic countries, a person with a visual impairment may be given different permissions depending on which country they live in. As the inhabitants in the Nordic countries frequently cross the regional borders, a harmonization of the legislation would be of value. More research in this field could provide future standards, combining the greatest autonomy with the highest possible safety. PMID- 30246294 TI - Molecular investigation of "Candidatus Mycoplasma haemobos" in goats and sheep in central China. AB - Hemoplasma "Candidatus Mycoplasma haemobos" infections in cattle have been reported in East Asia, Europe, and South America, whereas same cases were documented in buffalo and cattle in Southern China. From April 2018 to May 2018, a mycoplasma epidemic was reported in the mountainous area of central China; Boophilus microplus has also been documented, causing severe haematuria in goats and sheep. The infected animals slowly recovered after diminazene aceturate and praziquantel treatment. To determine whether the hemoplasma caused this infection, 67 blood samples (42 from goats, 25 from sheep) and 132 B. microplus samples were collected for PCR and sequence analysis. The results showed that 19 out of the 42 goat blood samples, 10 out of the 25 sheep blood samples, and 70 out of the 132 B. microplus samples (53%) tested positive for "C. M. haemobos". This study provides molecular evidence of "C. M. haemobos" infections in goat and sheep, and that B. microplus harbours "C. M. haemobos". PMID- 30246295 TI - Visuospatial sequence learning on the serial reaction time task modulates the P1 event-related potential. AB - This study examined whether the P1, N1, and P3 ERP components would be sensitive to sequence learning effects on the serial reaction time task. On this task, participants implicitly learn a visuospatial sequence. Participants in this study were 35 healthy adults. Reaction time (RT) data revealed that, at the group level, participants learned the sequence. Specifically, RT became faster following repeated exposure to the visuospatial sequence and then slowed down in a control condition. Analyses of ERP data revealed no evidence for sequence learning effects for the N1 or P3 component. However, sequence learning effects were observed for the P1 component. Mean P1 amplitude mirrored the RT data. The analyses showed that P1 amplitude significantly decreased as participants were exposed to the sequence but then significantly increased in the control condition. This suggests that visuospatial sequence learning can modulate visual attention levels. Specifically, it seems that, as sequence knowledge is acquired, fewer demands are placed on visual attention resources. PMID- 30246296 TI - Protective Effect of Baicalin Against TLR4-mediated UVA-induced Skin Inflammation. AB - UVA irradiation is known to cause photoaging via production of reactive oxygen species (ROS) and activation of inflammatory processes. Previously, we have demonstrated that baicalin, a plant-derived flavonoid possessing both antioxidant and anti-inflammatory activity, protects mouse keratinocytes against damage from UVB irradiation. However, the role of baicalin in vivo has not been well studied, particularly in the setting of UVA irradiation. To explore the protective effects and mechanisms of baicalin treatment in mice after UVA irradiation, mice were exposed to acute and chronic doses of UVA irradiation with or without baicalin or vehicle. Skin samples were collected for histological staining, RNA isolation, flow cytometry and protein extraction. Our results demonstrate the protective effect of baicalin against UVA-induced oxidative damage and inflammation in mouse skin. These effects are likely mediated via the TLR4 pathway, which may serve as a target for photochemoprevention against skin inflammation. PMID- 30246297 TI - Effects of contrast cryolipolysis on flank region adiposity: Case study. AB - BACKGROUND: The Contrast Cryolipolysis is a non-invasive technique that aims to reduce localized adiposity with its heating-cooling-heating method, resulting in a 45% fat loss in the treated area, with no damage to the skin. OBJECTIVE: To investigate the effects of contrast cryolipolysis compared to conventional cryolipolysis on localized adiposity. MATERIALS AND METHODS: This is a case study was carried out with two volunteers. The cirtometry, ultrasonography, and the anthropometric characteristics' analyses of volunteers were performed before and after the intervention. The right flank region underwent conventional cryolipolysis, and the left flank underwent contrast cryolipolysis. RESULTS: The procedures performed in both volunteers had positive results. However, the use of Contrast Cryolipolysis promoted greater loss of adipose tissue, reducing perimetry and cirtometry measurements, as well as the adipose tissue thickness, acknowledged via ultrasonography. CONCLUSION: The contrast cryolipolysis promotes greater localized adiposity reduction than the conventional cryolipolysis. PMID- 30246298 TI - Trastuzumab-monomethyl auristatin E conjugate exhibits potent cytotoxic activity in vitro against HER2-positive human breast cancer. AB - Targeted therapy using specific monoclonal antibodies (mAbs) conjugated to chemotherapeutic agents or toxins has become one of the top priorities in cancer therapy. Antibody-drug conjugates (ADCs) are emerging as a promising strategy for cancer-targeted therapy. In this study, trastuzumab, a humanized monoclonal anti HER2 antibody, was reduced by dithiothreitol and conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE) through a valine-citrulline peptide linker (trastuzumab-MC-Val-Cit-PABC-MMAE [trastuzumab-vcMMAE]). After conjugation, ADCs were characterized by using UV-vis, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and flow cytometry. The antitumor activity of the ADC was evaluated in breast cancer cells in vitro. In addition, ADCs were further characterized using purification by the protein A chromatography, followed by assessment using apoptosis and MTT (3-(4,5 dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assays. Hydrophobic interaction chromatography was used to determine drug-to-antibody ratio species of ADCs produced. Our finding showed that approximately 5.12 drug molecules were conjugated to each mAb. H2L2, H2L, HL, H2, H, and L forms of ADCs were detected in nonreducing SDS-PAGE. The binding of trastuzumab-vcMMAE to HER2-positive cells was comparable with that of the parental mAb. The MTT assay showed that our ADCs induced significant cell death in HER2-positive cells, but not in HER2-negative cells. The ADCs produced was a mixture of species, unconjugated trastuzumab (14.147%), as well as trastuzumab conjugated with two (44.868%), four (16.886%), six (13.238%), and eight (10.861%) molecules of MMAE. These results indicated that MMAE-conjugated trastuzumab significantly increases the cytotoxic activity of trastuzumab, demonstrating high affinity, specificity, and antitumor activity in vitro. Trastuzumab-vcMMAE is an effective and selective agent for the treatment of HER2-positive breast tumors. PMID- 30246299 TI - Efficacy and Safety of Lesinurad in Patients with Hyperuricemia Associated with Gout: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: To evaluate the efficacy and safety of lesinurad for the treatment of hyperuricemia in patients with gout. DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). PATIENTS OR PARTICIPANTS: Five RCTs, which included 1959 patients, compared the efficacy and safety of lesinurad in patients with hyperuricemia associated with gout. MEASUREMENTS AND RESULTS: Relevant studies were identified from PubMed, EMBASE, Cochrane Library databases, and the ClinicalTrials.gov registry. Two reviewers independently assessed the studies. Individual effect sizes were standardized, and a meta-analysis was conducted to calculate the pooled effect size by using a random-effect model. The primary outcomes were the proportion of patients achieving target serum uric acid (sUA) levels by month 6 and the mean sUA levels at month 6 and month 12. Gout related outcomes were also assessed. The secondary outcome was the number of treatment-emergent adverse events (TEAEs). Compared with xanthine oxidase inhibitor (XOI) monotherapy, lesinurad 200 mg or 400 mg in combination with allopurinol or febuxostat exhibited a higher proportion of patients achieving target sUA levels of < 6.0 mg/dl or < 5.0 mg/dl, respectively, by month 6. Lesinurad-plus-XOI groups also significantly sustained lower mean sUA levels at month 6 and month 12 compared to XOI alone group. In gout-related outcomes, no significant treatment group differences favored lesinurad. The number of TEAEs was comparable between the lesinurad 200 mg-plus-XOI group and the XOI monotherapy group. Although lesinurad 400 mg monotherapy demonstrated superior efficacy compared with placebo, significantly more TEAEs occurred. CONCLUSIONS: Although the combination of lesinurad 200 mg and XOI is effective and well tolerated for treating patients with gout who have not achieved an adequate response to XOI monotherapy, clinical gout-related outcomes were not improved. Therefore, additional studies investigating the long-term clinical implication of lesinurad are warranted. PMID- 30246300 TI - Long noncoding RNA PAGBC contributes to nitric oxide (NO) production by sponging miR-511 in airway hyperresponsiveness upon intubation. AB - BACKGROUND AND OBJECTIVES: In this study, we aimed to study the molecular mechanisms underlying the symptoms of hyperresponsiveness during intubation. METHOD: The value of circulating long noncoding RNA (lncRNA)-prognosis-associated gallbladder cancer (PAGBC) in the prediction of hyperresponsiveness upon intubation during general anesthesia was evaluated via the receiver operating characteristic analyses of serum miR-511, serum PAGBC, and serum nitric oxide (NO). In addition, the possible association between lncRNA-PAGBC/NOS1 messenger RNA (mRNA) and miR-511 was further validated via real-time quantitative polymerase chain reaction, immunohistochemistry assay, computational analysis, and luciferase assay. Enzyme-linked immunosorbent assay and Western blot analysis were also conducted to establish the regulatory relationship among PAGBC, miR 511, and NO synthase 1 (NOS1). RESULTS: Compared with circulating miR-511 and serum NO, circulating PAGBC was associated with a higher predictive value. In addition, a negative correlation was found between serum miR-511 and serum PAGBC (multicorrelation coefficient: -0.5) as well as between serum miR-511 and serum NO (multicorrelation coefficient: -0.6). In addition, both lncRNA-PAGBC and NO were decreased in patients with hyperresponsiveness, whereas the levels of miR 511 and NOS1 in these patients were similar to those in normal patients. Furthermore, our computational analyses and luciferase assays validated the direct binding between miR-511 and lncRNA-PAGBC, whereas NOS1 mRNA was identified as a virtual target gene of miR-511. Moreover, in the presence of lncRNA-PAGBC, we also observed an evident increase in the levels of NOS1 and NO accompanied by an obvious decrease of miR-511 expression. CONCLUSION: LncRNA-PAGBC downregulated the expression of miR-511, which in turn upregulated the expression of NOS1 mRNA and led to the increase in NOS1 expression, thus leading to the inhibited responsiveness (normal-responsiveness rather than hyperresponsiveness) to intubation in patients. PMID- 30246301 TI - The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis. AB - Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock-out Irx3- /Irx5- mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was already activated in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3-/- cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/beta-catenin-signalling. In contrast, IRX5-/- cells displayed activation of Hippo and non-canonical WNT signalling and generated small tumours with abundant tubulogenesis. Our findings suggest that promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 30246302 TI - Filaggrin gene polymorphisms in Iranian ichthyosis vulgaris and atopic dermatitis patients. AB - BACKGROUND: Filaggrin is a key structural epidermal protein in terminal differentiation and formation of skin barrier. The important role of filaggrin and its effects in various cutaneous and noncutaneous disorders initiated a cascade of considerable research in recent years. Loss-of-function mutations in FLG, the human gene encoding profilaggrin/filaggrin, is the cause of the common skin condition ichthyosis vulgaris (IV) and major genetic predisposing factor for atopic dermatitis (AD). Several null mutations in the FLG gene that lead to a decrease or absence of filaggrin in skin and predispose these conditions have been described. OBJECTIVE: The aim of this study was to investigative genetic polymorphism of FLG in Iranian patients with IV and AD. METHODS: In the current study, we carried out full sequencing of the entire FLG coding region in 30 IV patients and 30 AD patients, and also 60 healthy controls. RESULTS: In our research, we identified 43 variants reported previously and two novel variants. CONCLUSION: In our study, in the AD and IV patients, loss-of-function FLG mutation was not found. This means that another mechanism other than FLG nonsense mutation is involved in the pathogenesis of these patients. PMID- 30246304 TI - Isothiocyanates for Human Health. PMID- 30246303 TI - Influence of 2 Veress needles and 4 insertion sites on Veress needle penetration depth: A comparative study in cadaveric dogs. AB - OBJECTIVE: To evaluate the penetration depth (VNPD) of 2 disposable Veress needles (VN) at 4 insertion sites in the abdomen. STUDY DESIGN: Descriptive study. SAMPLE POPULATION: Canine cadavers (n = 22, 6 for confirmation of the test methods and 16 for the comparative study). METHODS: Two disposable VN (VN A and VN B) were inserted at 4 sites (9th intercostal space [ICS] and preumbilical, paraumbilical, and subumbilical sites) in dorsally recumbent dogs by using a hand cranked jig. The VNPD was measured as the distance traveled by the VN between the subcutaneous tissue and the perforation of the peritoneum on the basis of audible clicks and visible feedback from the VN. The effects of the VN type and insertion site on the VNPD were analyzed by using a linear mixed-effects model. RESULTS: VNPD varied between insertion sites (P = .01) and VN (P < .01). The VNPD was less at the 9th ICS than at the preumbilical, paraumbilical, and subumbilical sites. The maximal magnitude of change was 7.4 mm. Veress needle B (with a low spring rate, lower forces, and a back-cut bevel design) penetrated farther than VN A (with a high spring rate, high forces, and a lancet-type bevel) at 3 of 4 insertion sites. The maximal magnitude of change was 6.8 mm. CONCLUSION: Veress needle penetration depth varied between VN designs but was the least at the 9th ICS in canine cadavers. CLINICAL SIGNIFICANCE: Insertion of a VN at the 9th ICS is recommended to minimize its penetration into the abdomen. Associations between VNPD and mechanical factors, such as the sharpness and spring rate of VN, warrant additional research. PMID- 30246306 TI - Editorial: STAT-4 polymorphism - a tool to personalise clinical practice in chronic HBV infection. Authors' reply. PMID- 30246305 TI - Editorial: surviving your genes-the role of PNPLA3 variation in end-stage liver disease. PMID- 30246307 TI - Editorial: surviving your genes-the role of PNPLA3 variation in end-stage liver disease. Authors' reply. PMID- 30246308 TI - Editorial: interferon-free DAAs are a great boon for patients with hepatitis C and cryoglobulinaemia-Authors' reply. PMID- 30246309 TI - Editorial: interferon-free DAAs are a great boon for patients with hepatitis C and cryoglobulinaemia. PMID- 30246310 TI - Editorial: STAT-4 polymorphism - a tool to personalise clinical practice in chronic HBV infection. PMID- 30246311 TI - Prognostic value of aberrantly expressed methylation gene profiles in lung squamous cell carcinoma: A study based on The Cancer Genome Atlas. AB - Currently, research on genome-scale epigenetic modifications for studying the pathogenesis of lung cancer is lacking. Aberrant DNA methylation, as the most common and important modification in epigenetics, is an important means of regulating genomic function and can be used as a biomarker for the diagnosis and prognosis of lung squamous cell carcinoma (LUSC). In this paper, methylation information and gene expression data from patients with LUSC were extracted from the TCGA database. Univariate and multivariate COX analyses were used to screen abnormally methylated genes related to the prognosis of LUSC. The relationship between key DNA methylation sites and the transcriptional expression of LUSC related genes was explored. A prognostic risk model constructed by four abnormally methylated genes (VAX1, CH25H, AdCyAP1, and Irx1) was used to predict the prognosis of LUSC patients. Also, the methylation levels of the key gene IRX1 are significantly correlated with the prognosis and correlated with the methylation of the site cg09232937 and cg10530883. This study is based on high throughput data mining and provides an effective bioinformatics basis for further understanding the pathogenesis and prognosis of LUSC, which has important theoretical significance for follow-up studies on LUSC. PMID- 30246312 TI - Partial likelihood ratio test for X-chromosome association models. PMID- 30246313 TI - New three-dimensional/four-dimensional volume rendering imaging software for detecting the abnormally invasive placenta. AB - OBJECTIVE: This study aimed to determine the role of three-dimensional (3D)/four dimensional (4D) volume rendering ultrasound (VRU) in the diagnosis of abnormally invasive placenta (AIP). MATERIALS AND METHODS: Twelve consecutive patients strongly suspected of having AIP on the basis of conventional ultrasound (US) and clinical history performed between September 2016 and December 2016 in the main tertiary referral hospital in Surabaya, East Java were included in this prospective observational study. A Samsung WS 80A Elite US scanner with a 3D/4D "crystal vue" and "realistic vue" volume rendering mode was used to establish the diagnosis of AIP and evaluate the site, and depth of placental invasion. The VRU images were compared with the intraoperative findings. RESULTS: Using this novel US technique, all cases of suspected AIP were subsequently confirmed during surgery. Importantly, the new US technique provided a correct diagnosis of the degree of invasion in 11 out of these 12 suspected AIP cases: 5/5 for placenta percreta, 3/3 for placenta increta, and 2/3 for placenta accreta; one patient was misdiagnosed in terms of the degree of placenta accreta, and one patient had normal implantation). CONCLUSION: This new software of 3D/4D VRU represents a promising technique for the preoperative diagnosis and staging of AIP. PMID- 30246314 TI - Dementia in older people admitted to hospital: An analysis of length of stay and associated costs. AB - OBJECTIVES: Patients with dementia in the acute setting are generally considered to impose higher costs on the health system compared to those without the disease largely due to longer length of stay (LOS). Many studies exploring the economic impact of the disease extrapolate estimates based on the costs of patients diagnosed using routinely collected hospital discharge data only. However, much dementia is undiagnosed, and therefore in limiting the analysis to this cohort, we believe that LOS and the associated costs of dementia may be overestimated. We examined LOS and associated costs in a cohort of patients specifically screened for dementia in the hospital setting. METHODS: Using primary data collected from a prospective observational study of patients aged >=70 years, we conducted a comparative analysis of LOS and associated hospital costs for patients with and without a diagnosis of dementia. RESULTS: There was no significant difference in overall length of stay and total costs between those with (MU = 9.9 days, MU = ? 8246) and without (MU = 8.25 days, MU = ? 6855) dementia. Categorical data analysis of LOS and costs between the two groups provided mixed results. CONCLUSIONS: The results challenge the basis for estimating the costs of dementia in the acute setting using LOS data from only those patients with a formal dementia diagnosis identified by routinely collected hospital discharge data. Accurate disease prevalence data, encompassing all stages of disease severity, are required to enable an estimation of the true costs of dementia in the acute setting based on LOS. PMID- 30246315 TI - Exosomes and their importance in metastasis, diagnosis, and therapy of colorectal cancer. AB - Extracellular vesicles are known as actual intermediaries of intercellular communications, such as biological signals and cargo transfer between different cells. A variety of cells release the exosomes as nanovesicular bodies. Exosomes contain different compounds such as several types of nucleic acids and proteins. In this study, we focused on exosomes in colorectal cancer as good tools that can be involved in various cancer-related processes. Furthermore, we summarize the advantages and disadvantages of exosome extraction methods and review related studies on the role of exosomes in colorectal cancer. Finally, we focus on reports available on relations between mesenchymal stem cell-derived exosomes and colorectal cancer. Several cancer-related processes such as cancer progression, metastasis, and drug resistance of colorectal cancer are related to the cargoes of exosomes. A variety of molecules, especially proteins, microRNAs, and long noncoding RNAs, play important roles in these processes. The microenvironment features, such as hypoxia, also have very important effects on the properties of the origin cell-derived exosomes. On the other hand, exosomes derived from colorectal cancer cells also interfere with cancer chemoresistance. Furthermore, today it is known that exosomes and their contents can likely be very effective in noninvasive colorectal cancer diagnosis and therapy. Thus, exosomes, and especially their cargoes, play different key roles in various aspects of basic and clinical research related to both progression and therapy of colorectal cancer. PMID- 30246316 TI - Relevant factors of depression in dementia modifiable by non-pharmacotherapy: a systematic review. AB - Depression in dementia patients is associated with complications such as decreased activities of daily living and decreased quality of life. Because pharmacotherapeutic treatments for depression in dementia patients may have a poor risk-benefit ratio, effective non-pharmacotherapeutic interventions are favourable. However, the development of effective treatments requires the identification of depression-associated factors that can be modified by non pharmacotherapeutic means in dementia patients. This systematic literature review aimed to identify modifiable factors related to depression and confirm that these factors can be improved by non-pharmacotherapeutic interventions. We searched PubMed, SpringerLink, the Web of Science, and the Cochrane Library for articles published between June 2007 and June 2017. We included studies that investigated causes of depression in dementia patients and excluded studies with unclear dementia diagnostic criteria or operational definitions. Of 9004 records screened, 6 studies were included. The participants included community-dwelling individuals and long-term care facility residents. The severity of dementia varied from mild to severe. After reviewing the studies, we identified five modifiable relevant factors in community-dwelling individuals: (i) pain; (ii) neuropsychiatric symptoms; (iii) cognitive decline; (iv) social isolation; and (v) quality of life. In long-term care facility residents, we identified neuropsychiatric symptoms and quality of life as relevant factors. Our results indicated that non-pharmacological interventions that improve these factors may improve symptoms of depression. A longitudinal study is recommended to clarify the mechanisms underlying depression symptoms and treatment in dementia patients. In addition, further investigation is needed to elucidate the ways in which differing dementia types and severity affect symptoms of depression. PMID- 30246317 TI - Thrombocytosis and portal vein thrombosis after splenectomy for paediatric haemolytic disorders: How should they be managed? AB - Splenectomy is indicated in selected children with haemolytic anaemia. Postoperatively, thrombocytosis occurs in at least 80% and is one of the factors implicated in the development of acute portal venous thrombosis after splenectomy in adults. A literature review shows that children are also at risk of this complication, but the incidence is low. The risk is greatest in those with particularly large spleens. Laparoscopic splenectomy does not reduce the risk of this complication. Early detection and anticoagulation usually leads to successful resolution of the thrombosis and can mitigate the risk of developing cavernous transformation of the portal vein and chronic portal hypertension. Any child with severe or unexplained postoperative abdominal pain, fever and/or vomiting after splenectomy demands urgent abdominal imaging to exclude this complication. In asymptomatic individuals, a routine Doppler ultrasound scan 1 week postoperatively is advisable if they had a particularly large spleen, longer than usual duration of surgery and/or have a marked postoperative thrombocytosis. There is no evidence for routine administration of antiplatelet drugs and/or subcutaneous heparin prophylaxis in children after splenectomy, including those who develop postoperative thrombocytosis, but children with particularly large spleens may be a subset that benefit. PMID- 30246318 TI - COL6A3-derived endotrophin links reciprocal interactions among hepatic cells in the pathology of chronic liver disease. AB - Extracellular matrix dysregulation is associated with chronic liver disease. CollagenVI-alpha3 chain (COL6A3) is a biomarker for hepatic fibrosis and poor prognosis of hepatocellular carcinoma (HCC), but its function in liver pathology remains unknown. High levels of COL6A3 and its cleaved product, endotrophin (ETP) in tumor-neighboring regions are strongly associated with poor prognosis in HCC patients. Here, we report that the high levels of ETP in injured hepatocytes induce JNK-dependent hepatocyte apoptosis and activate nonparenchymal cells to lead further activation of hepatic inflammation, fibrosis, and apoptosis. Nevertheless ETP per se showed limited phenotypic changes in normal liver tissues. Furthermore, inhibition of ETP activity by utilizing neutralizing antibodies efficiently suppressed the pathological consequences in chronic liver diseases. Our results implicate ETP mechanistically as a crucial mediator in reciprocal interactions among various hepatic cell populations in the pathogenesis of chronic liver disease, and it could be a promising therapeutic target particularly in individuals with high local levels of COL6A3. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 30246319 TI - Piezochromic Luminescence of Donor-Acceptor Cocrystals: Distinct Responses to Anisotropic Grinding and Isotropic Compression. AB - Piezochromic luminescent materials that exhibit distinct luminescence responses to different types of mechanical stresses have been emerging as new kinds of materials which are rarely investigated. Herein, we report a donor-acceptor (D-A) charge-transfer (CT) cocrystal, which shows distinct hypochromatic and bathochromatic shifts upon anisotropic grinding and isotropic compression, respectively. Detailed spectroscopic and structural analyses revealed that the hypochromatic shifted emission under grinding is attributable to a structural reorganization from a loosely segregated-stack to a mixed-stack, while the bathochromatic shifted emission originates from the formation of a tighter packing structure. We present rare evidence of a distinct luminescent response to anisotropic grinding and isotropic compression on the basis of structural rearrangement in a D-A cocrystal, and thus enriches our insight into piezochromic luminescence. PMID- 30246320 TI - Inhaled procaterol for the treatment of transient tachypnea of the newborn. AB - BACKGROUND: Transient tachypnea of the newborn (TTN) is a respiratory disorder that results from inadequate or delayed clearance of fetal lung fluid following delivery. At present, supportive care is generally practiced for the treatment of TTN. In this study, we focused on inhaled beta-agonists for the treatment of TTN, and the aim was to verify the efficacy and the safety of inhaled procaterol for the treatment of TTN. METHODS: Inhaled procaterol or normal saline solution was administered to infants. Respiratory rate and mixed venous carbon dioxide (PvCO2 ) were evaluated as the primary outcomes. The duration of hospitalization, duration of oxygen therapy, and changes in respiratory support were evaluated as secondary outcomes. RESULTS: Thirty-seven neonates diagnosed with TTN were randomly assigned to the procaterol group (n = 18) or the placebo group (n = 19). There were no differences in PvCO2 or respiratory rate between the two groups before and after intervention. Median duration of oxygen therapy (3 days; IQR, 3 6.5 days vs 2 days, IQR, 2-4.75 days; P = 0.13) and of hospitalization (15 days; IQR, 11.25-20 days vs 11 days, IQR, 8-15.5 days; P = 0.14) were not significantly different. CONCLUSIONS: Inhaled procaterol was not effective for the treatment of TTN. PMID- 30246321 TI - IgG/IgA pemphigus: Report of a rare subtype of pemphigus. PMID- 30246322 TI - Assessment of overall thoracic limb axial alignment in dogs with antebrachial deformity. AB - OBJECTIVE: To assess overall thoracic limb axial alignment in dogs with and without angular limb deformity (ALD). STUDY DESIGN: Ex vivo and retrospective observational clinical study. ANIMALS: Forty canine thoracic limbs from bilateral normal specimens (10 pairs) and unilateral antebrachial ALD (10 uniapical and 10 biapical deformities). METHODS: Computed tomography images of the entire thoracic limb were collected for multiplanar reconstruction. Baseline limb axis was defined by the humeral anatomic axis. Axial alignment of the distal humerus, proximal and distal radius, and metacarpal bones were obtained and compared among levels and groups. RESULTS: The mean overall thoracic limb rotation of normal dogs was 35.4 degrees (95% CI, 27.2 degrees , 43.6 degrees ). Mean overall limb rotation in uniapical and biapical deformity was 41.6 degrees (95% CI, 33.0 degrees , 50.1 degrees ) and 54.4 degrees (95% CI, 45.8 degrees , 62.9 degrees ), respectively, but was not statistically different (P = .096). Only overall limb rotation in limbs with biapical ALD was different from normal limbs (P = .008). Rotation at the level of the elbow was 77% and 85% of overall limb rotation in normal and deformity limbs, respectively, and was increased from normal in limbs with ALD (both P < .05). Radial torsion did not differ among groups but was moderately correlated with overall limb rotation. CONCLUSION: Rotation arising in the elbow of limbs with ALD was higher than in normal limbs and accounted for the greatest contribution of overall limb rotation. CLINICAL SIGNIFICANCE: Assessment of radial torsion alone is insufficient to understand overall limb axial alignment in dogs with antebrachial bone deformity. PMID- 30246323 TI - Distinguishing Tumor from Bland Portal Vein Thrombus in Liver Transplant Candidates with Hepatocellular Carcinoma: The "A-VENA" Criteria. AB - Differentiating tumor versus bland portal vein thrombosis (PVT) is essential in determining liver transplant (LT) candidacy for patients with hepatocellular carcinoma (HCC). We aimed to evaluate radiographic and clinical features that could noninvasively distinguish tumor PVT from bland PVT in HCC patients. Of 467 patients with HCC listed for LT from 2004-2011, 59 (12.6%) had PVT and 12 of 59 (20.3%) were deemed malignant. When comparing tumor versus bland PVT, thrombus enhancement was seen in 100% versus 8.5%, venous expansion in 91.7% versus 10.6%, neovascularity in 58.3% versus 2.1% and being adjacent to HCC or prior treatment site in 100% versus 21.2% (all p<0.001). Combining these four imaging characteristics with alpha-fetoprotein (AFP) >1000 ng/dL, the presence of >=3 criteria best characterized tumor PVT with 100% sensitivity, 93.6% specificity, 80% positive predictive value and 100% negative predictive value. No LT recipients with presumed bland PVT had macro-vascular invasion on explant. There were no differences in post-LT survival or HCC recurrence with bland PVT versus no PVT. In conclusion, we proposed noninvasive criteria (A-VENA) based on the presence of >=3 of the following - AFP >1000, Venous expansion, thrombus Enhancement, Neovascularity, and Adjacent to HCC that could accurately differentiate tumor PVT from bland PVT. Use of A-VENA criteria can assist in standardizing the evaluation of PVT in patients with HCC being considered for LT. This article is protected by copyright. All rights reserved. PMID- 30246324 TI - Isotope discrimination by form IC RubisCO from Ralstonia eutropha and Rhodobacter sphaeroides, metabolically versatile members of 'Proteobacteria' from aquatic and soil habitats. AB - RubisCO, the CO2 fixing enzyme of the Calvin-Benson-Bassham (CBB) cycle, is responsible for the majority of carbon fixation on Earth. RubisCO fixes 12 CO2 faster than 13 CO2 resulting in 13 C-depleted biomass, enabling the use of delta13 C values to trace CBB activity in contemporary and ancient environments. Enzymatic fractionation is expressed as an epsilon value, and is routinely used in modelling, for example, the global carbon cycle and climate change, and for interpreting trophic interactions. Although values for spinach RubisCO (epsilon = ~290/00) have routinely been used in such efforts, there are five different forms of RubisCO utilized by diverse photolithoautotrophs and chemolithoautotrophs and epsilon values, now known for four forms (IA, B, D and II), vary substantially with epsilon = 110/00 to 270/00. Given the importance of epsilon values in delta13 C evaluation, we measured enzymatic fractionation of the fifth form, form IC RubisCO, which is found widely in aquatic and terrestrial environments. Values were determined for two model organisms, the 'Proteobacteria' Ralstonia eutropha (epsilon = 19.00/00) and Rhodobacter sphaeroides (epsilon = 22.40/00). It is apparent from these measurements that all RubisCO forms measured to date discriminate less than commonly assumed based on spinach, and that enzyme epsilon values must be considered when interpreting and modelling variability of delta13 C values in nature. PMID- 30246325 TI - A different ultrastructural face of ribbon synapses in the rat retina. AB - Ribbon synapses located exclusively within retinal, cochlear and vestibular connections belong to the most interesting cellular structures but their molecular nature and functions had remained unclear. The study has provided a descriptive morphological analysis of rat eye ribbon synapses using high resolution transmission electron microscopy (TEM). An original collection of untypical, rarely present in the literature sagittal or tangential sections through the single RIBEYE domain of the particular ribbon have been delivered. PMID- 30246326 TI - Maternal hemodynamics in screen positive and negative women of the ASPRE trial. AB - OBJECTIVE: To compare maternal hemodynamics and perinatal outcomes in women identified at 11-13 weeks' gestation as being screen positive (N=170) or negative (N=926) for preterm preeclampsia (PE) by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index and serum placental growth factor and pregnancy associated plasma protein-A. METHODS: This was a prospective, longitudinal cohort study of maternal cardiovascular function, assessed by a bioreactance method, in women undergoing first trimester screening for PE. We investigated screen positive and screen negative women that did not have medical co-morbidities, did not develop PE or pregnancy induced hypertension (PIH) and delivered livebirths at term with birthweight between the 5th to 95th percentiles. A multilevel linear mixed-effects model was performed to compare the repeated measures of the cardiac variables controlling for maternal characteristics. RESULTS: The screen negative group had normal cardiac function changes across gestation, whereas, the screen positive group demonstrated static or reducing cardiac output and stroke volume and higher mean arterial pressure and peripheral vascular resistance with advancing gestation. In the screen positive, compared to screen-negative women, the birth-weight z-score was shifted to the left with about 70% higher prevalence of babies below the 35th, 30th or 25th percentile, and the rate of operative delivery for fetal distress in labour. CONCLUSIONS: Patients who screen positive for impaired placentation, even if they do not develop PE or deliver SGA neonates, have pathological cardiac adaptation in pregnancy and increased risk of adverse perinatal outcome. This article is protected by copyright. All rights reserved. PMID- 30246327 TI - Effectiveness of dorsal root ganglion stimulation and dorsal column spinal cord stimulation in a model of experimental painful diabetic polyneuropathy. AB - AIMS: Conventional dorsal root ganglion stimulation (DRGS) is known to achieve better pain-paresthesia overlap of difficult-to-reach areas like the feet compared to dorsal column spinal cord stimulation (SCS). As in painful diabetic polyneuropathy (PDPN) pain is mostly present in the feet, we hypothesized that DRGS is more effective in relieving pain in PDPN when compared to SCS. METHODS: Diabetes was induced in female Sprague-Dawley rats with an intraperitoneal injection of 65 mg/kg of streptozotocin (STZ; n = 48). Rats with a significant decrease in mechanical paw withdrawal response to von Frey filaments 4 weeks after injection were implanted with DRGS electrodes (n = 18). Rats were assigned to DRGS (n = 11) or sham-DRGS (n = 7). Mechanical paw withdrawal thresholds (WT, measured in grams) in response to DRGS (50 Hz, 0.18 +/- 0.05 mA) were assessed with von Frey testing. The results of the experiments on these animals were compared to the results of a previous study using exactly the same model on PDPN animals selected for SCS (n = 8) (40-50 Hz, 0.19 +/- 0.01 mA) and sham-SCS (n = 3). RESULTS: In the SCS group, the log10 (10 000 * 50% WT) increased from 4910 to 5211 at t = 15 minutes (P < 0.05) and 5264 at t = 30 minutes (P = 0.11). In the DRGS group, the log10 (10,000 * 50% WT) increased from 4376 to 4809 at t = 15 minutes (P < 0.01) and 5042 at t = 30 minutes (P < 0.01). Both DRGS and SCS induced a similar and complete reversal of mechanical hypersensitivity. After cessation of stimulation (t = 60), the return of the log10 (10 000 * 50% WT) response was significantly faster with DRGS than that of SCS (P < 0.05). CONCLUSIONS: We conclude that conventional DRGS is as effective as SCS in reduction of PDPN-associated mechanical hypersensitivity in STZ-induced diabetic rats. The wash-in effect of DRGS and SCS was similar, but DRGS showed a faster washout course. Long-term efficacy should be studied in future animal research. PMID- 30246328 TI - Specific nutritional infections early in life as risk factors for human colon and breast cancers several decades later. PMID- 30246329 TI - Contracture formation in the upper limb in cerebral palsy starts early. PMID- 30246330 TI - Does feeding frequency during lactation affect sows' body condition, reproduction and production performance? AB - The present study investigated whether a three-times compared to two-times feeding frequency during lactation affects sows' body condition, reproductive performance as well as growth performance of the piglets . In a commercial farm, eight groups (8-10 animals) with a total number of 68 sows were included in the study. During lactation, four groups received feed two times (treatment 2DF) and four groups three times daily (treatment 3DF). Within treatments, sows were classified into young (<2 parities) and old (>=3 parities). Body condition score (BCS), shoulder lesions, return to estrus rate and piglet's growth performance were recorded. The 3DF sows had a higher (p < 0.05) feed intake and less shoulder lesions (p < 0.05) than 2DF animals. Return to estrus rate in the 3DF treatment was 0% for young and 29% for old sows. In the 2DF treatment return to estrus rate was 20% for young and 5% for old sows. In conclusion, three-times versus two times daily feeding frequency during lactation increased feed intake and had a positive effect on sows' BCS and the frequency of shoulder lesions, while it also reduced incidents of return to estrus rate in young sows. PMID- 30246331 TI - Decadal-scale response of detritivorous surgeonfishes (family Acanthuridae) to no take marine reserve protection and changes in benthic habitat. AB - No-take marine reserves (NTMR) are increasingly being implemented to mitigate the effects of fishing on coral reefs, yet determining the efficacy of NTMRs depends largely on partitioning the effects of fishing from the effect of benthic habitat. Species of coral-reef fishes typically decline in density when subjected to fishing or benthic disturbances, but this is not always the case. This study documents the long-term (8-31 years) response of six species of detritivorous surgeonfishes (family Acanthuridae) to NTMR protection and benthic habitat change at four islands (Apo, Sumilon, Mantigue, Selinog) in the central Philippines, each island with a NTMR and a monitored fished site. Despite being subject to moderate fishing pressure, these species did not increase in density with NTMR protection. However, density of these surgeonfishes had a strong negative relationship with cover of live hard coral and a strong positive relationship with cover of dead substratum (sand, rubble, hard dead substratum). These surgeonfishes typically feed over dead substrata and thus probably increase in density following large environmental disturbances that substantially reduce live hard coral cover. Here, we describe effects of environmental disturbance events (e.g., use of explosives, typhoons) that reduced live hard-coral cover and subsequent large increases (up to 25 fold) in surgeonfish densities, which then slowly (over 5-15 years) decreased in density as live hard coral recovered. Density of these functionally important surgeonfish species was influenced more by changes to benthic cover than by NTMR protection. Thus, we highlight the greater importance of bottom-up controls (i.e., benthic changes to food availability) than top-down control (i.e., fishing) on a functionally important group of coral-reef fishes. PMID- 30246332 TI - The miR-15a/16 gene cluster in human cancer: A systematic review. AB - MicroRNAs (miRNAs) are an important class of endogenous small noncoding single stranded RNAs that suppress the expression of their target genes through messenger RNA (mRNA) degradation to inhibit transcription and translation. MiRNAs play a crucial regulatory role in many biological processes including proliferation, metabolism, and cellular malignancy. miR-15a/16 is an important tumor suppressor gene cluster with a variety of factors that regulate its transcriptional activity. It has been discovered that a relative reduction of miR 15a/16 expression in various cancers is closely related to the occurrence and progression of tumors. miR-15a/16 takes part in a wide array of biological processes including tumor cell proliferation, apoptosis, invasion, and chemoresistance by binding to the 3'-untranslated region of its target gene's mRNA. In this review, we will examine the complex regulatory network of miR 15a/16 gene expression and its biological functions in human cancers to further elucidate the molecular mechanisms of its antitumor effects. PMID- 30246333 TI - Using simple clinical measures to predict insulin resistance or hyperglycemia in girls with polycystic ovarian syndrome. AB - BACKGROUND: Polycystic ovarian syndrome (PCOS) includes insulin resistance (IR) and impaired glucose tolerance (IGT) in youth, and a greatly elevated risk of type 2 diabetes in adulthood. Identifying IR is challenging and documenting IGT requires an oral glucose tolerance test (OGTT). OBJECTIVE: Identify easily applied surrogate measures for IR and IGT in girls with PCOS. METHODS: We studied 28 girls with PCOS (body mass index [BMI] percentile 98 (83.99); 15.5 (14.5,16.6) years of age) and 20 with normal menses [BMI percentile (97 (88.99); 15.5 (13.3,16.1) years]. Hyperinsulinemic-euglycemic clamps (insulin dose of 80 MUU/ml/min) to determine glucose infusion rate (GIR) and a 75 g OGTT were performed. Surrogates for IR including fasting insulin, homeostatic model assessment-insulin resistant (HOMA-IR), Matsuda index, and estimate of insulin sensitivity (e-IS) were compared to IGT status and GIR. Spearman correlations were performed between surrogates and GIR or IGT, and receiver operator curve (ROC) analysis to predict GIR below the median or IGT status. RESULTS: GIR was lower in PCOS (12.9 +/- 4.6 vs 17.1 +/- 5.1 mg/kg fat-free mass.min; P = 0.01). Within PCOS, HOMA-IR (r = -0.78, P < 0.0001), e-IS (r = 0.70, P < 0.001), and Matsuda (r = 0.533, P < 0.001) correlated with GIR. e-IS provided a good sensitivity (100%) and specificity (71%) to identify IR (e-IS cutoff: <6.3, ROC area under curve = 0.898). Fasting insulin >22 IU/mL had the best sensitivity (88%), specificity (78%), and ROC (0.760) for IGT status. CONCLUSIONS: Girls with PCOS have significant IR, and IGT is common. Both e-IS and fasting insulin are obtainable without an OGTT or clamp and could be used clinically to guide treatment in PCOS. PMID- 30246335 TI - Ankle-brachial index in psoriasis: a population-based study. PMID- 30246334 TI - Response to treatment schedules after the first antiepileptic drug failed. AB - OBJECTIVE: After the failure of the first antiepileptic drug (AED) at doses > 50% defined daily dose (DDD), there are three options for patients with epilepsy: combination therapy, alternative therapy, and increased dosage of the first AED. However, present studies have not provided evidence for which option is best. Therefore, we conducted this retrospective observational cohort study to compare the effects of three treatment schedules. METHODS: Patients diagnosed with newly diagnosed epilepsy at the epilepsy clinic of West China Hospital between August 2006 and February 2016 were evaluated for eligibility for this study. Patients who failed to respond to the first AED at doses > 50% DDD were included, and divided into three cohorts: increased dosage, combination therapy, and alternative therapy. Cumulative incidence curves for time to seizure freedom were compared for different cohorts by Gray test. Competing risk regression was conducted to evaluate the association of clinical predictors with seizure freedom. RESULTS: Altogether, 502 patients (277 male, 55.2%) were included for further analysis, and the median duration of follow-up was 32 months (range = 8 127). The probability of seizure freedom was significantly higher in patients receiving combination therapy (n = 323) compared to the alternative therapy cohort (n = 76, P < 0.001) and increased dosage cohort (n = 103, P = 0.025). Competing risk regression analysis showed that combination therapy significantly increased the probability of seizure freedom (hazard ratio [HR] = 2.423, 95% confidence interval [CI] = 1.529-3.841, P < 0.001). In addition, male sex and generalized seizure were significantly associated with increased probability of seizure freedom (male sex: HR = 1.440, 95% CI = 1.106-1.880, P = 0.007; generalized seizure: HR = 1.543, 95% CI = 1.176-2.020, P = 0.002). SIGNIFICANCE: Combination therapy may increase the probability of seizure freedom for patients with first AED failure due to lack of efficacy. PMID- 30246336 TI - Gene expression of TWIST1 and ZBTB16 is regulated by methylation modifications during the osteoblastic differentiation of mesenchymal stem cells. AB - BACKGROUND: Osteoblastic differentiation of mesenchymal stem cells (MSCs) is the principal stage during the restoration and regeneration of bone tissue. Epigenetic modifications such as DNA methylation play a key role in the differentiation process of stem cells. In this study, the methylation status of the promoter region of ZBTB16 and Twist1 genes and their role in controlling osteoblastic differentiation in MSCs was investigated during the osteoblastic differentiation of MSCs. METHODS: The MSCs were cultured under standard conditions and differentiated into the osteoblasts. We had three treatment groups including 5-azacytidine (methylation inhibitor), metformin (Twist-inhibitor), and procaine (Wnt/beta-catenin inhibitor) and a non-treated group (control). Methylation level of DNA in the promoter regions was monitored by methylation specific-quantitative polymerase chain reaction (PCR). Also, the mRNA levels of key genes in osteoblastic differentiation were measured using real-time PCR. RESULTS: ZBTB16 gene expression was upregulated, and promoter methylation was decreased. For Twist1 messenger RNA (mRNA) level decreased and promoter methylation increased during osteoblastic differentiation of MSCs. 5-Azacytidine caused a significant reduction in methylation and increased the mRNA expression of ZBTB16 and Twist1. Metformin repressed the Twist1 expression, and therefore osteoblastic differentiation was increased. On the opposite side, procaine could block the WNT/beta-catenin signaling pathway, as a consequence the gene expression of key genes involved in osteoblastic differentiation was declined. CONCLUSION: We found that methylation of DNA in the promoter region of ZBTB16 and Twist1 genes might be one of the main mechanisms that controlling the gene expression during osteoblastic differentiation of MSCs. Also, we could find an association between regulation of Twist1 and ZBTB16 genes and osteoblastic differentiation in MSCs by showing the relation between their expression and some key genes involved in osteoblastic differentiation. In addition, we found a connection between the Twist1 expression level and osteoblastic differentiation by using a Twist-inhibitor (metformin). PMID- 30246337 TI - Effects of long-term care setting on spousal health outcomes. AB - OBJECTIVE: To provide empirical evidence on the effects of home and community based services (HCBS) (vs nursing home) use on spousal health. DATA SOURCES: Merged data from the 1996 to 2012 Health and Retirement Study (HRS) and the Area Health Resource File (AHRF). STUDY DESIGN: We assess the impact of HCBS use on spousal health. We use an instrumental variable (IV) approach to account for the potential endogeneity of the choice of care setting and reverse causality. Our instrument is the supply of skilled nursing home beds per 1000 people older than 65 years. DATA EXTRACTION METHODS: Our sample includes spouses of HCBS or nursing home users, resulting in 8608 observations. PRINCIPAL FINDINGS: We find that HCBS use leads to harmful effects on spousal physical health, which may be caused by increased informal care responsibilities. We also find improved spousal mental health, especially in depression symptoms, which may be caused by increased satisfaction. CONCLUSIONS: We find evidence of both beneficial (mental health) and harmful (physical health) consequences for spouses of individuals receiving LTC at home relative to in an institution. Our results are important in estimating the potential cost and effectiveness of HCBS expansion. PMID- 30246338 TI - Aqueous flare as a marker of retinal disease activity after anti-VEGF injections. PMID- 30246339 TI - Amelanotic melanoma arising in an area of SLURP-1 mutated Mal de Meleda. PMID- 30246340 TI - Allogeneic skin donors from a tissue bank in Southern Brazil: clinical and epidemiological profiles and microbial colonization of skin. AB - BACKGROUND: An allogeneic human skin graft is a temporary biologic dressing used in extensive burns that can be a providential treatment for affected patients. Skin quality depends directly on its microbial decontamination after processing in a tissue bank. Our objective was to describe the skin donor profiles in relation to the analysis of the microbial colonization of the donated skin. METHODS: This clinical study includes epidemiological and microbiological data on skin donors from 2012 to 2014. The donor information database was compiled from the medical records of skin donors filed in the tissue bank. The donors were assessed regarding the microbial colonization of the skin at the time of processing in the tissue bank. RESULTS: We found a statistically significant association (P = 0.020) between lower average age of the donor and the presence of microbial colonization. We observed that Gram-negative bacteria (GNB) are associated with male gender (P = 0.015), source hospital A (P = 0.034), and over 7 days stay in an intensive care unit (ICU) (P = 0.001). We also observed that Staphylococcus aureus is associated with skin-harvesting hospital C (P = 0.034) and that Gram-positive bacilli (GPB) are associated with up to 7 days stay in an ICU (P = 0.009). CONCLUSIONS: We found significant associations between the type of microorganism colonizing the skin and the epidemiological and clinical profiles of the donors. This information is extremely important when determining the potential use of skin source and so optimizing the donation of allogeneic skin for transplantation. PMID- 30246341 TI - Variation in DNA methylation is associated with migratory phenotypes of lake sturgeon Acipenser fulvescens in the St. Clair River, MI, USA. AB - Lake sturgeon Acipenser fulvescens populations show a variety of movement patterns that are poorly understood. To compare two migratory phenotypes of A. fulvescens in the St. Clair River, MI, USA, multiple data types were analysed. Individual fish were classified into migratory phenotypes based on acoustic telemetry data collected 2012-2015. Acipenser fulvescens consistently showed movement from the St. Clair River upriver into Lake Huron or downriver into Lake St. Clair. The two migratory phenotypes were then compared for differences in morphometrics, genetics and epigenetics. Morphological differences based on linear measurements were not detected between phenotypes. Microsatellite data from 11 loci suggested one population with no genetic differentiation between migratory phenotypes. Our epigenetic results indicated that the migratory phenotypes are differentially methylated (P < 0.05), thus epigenetics may be associated with migratory differences in A. fulvescens. Only one restriction site was identified to be driving the differential methylation (P < 0.05). While little evidence at neutral loci occurred for genetic differentiation of A. fulvescens, DNA methylation may play a role in the observed movement pattern variation. When combined with microsatellite and morphometric analyses, our results suggested that different migratory patterns may reflect phenotypic plasticity, allowing A. fulvescens to acclimate to short-term environmental variability. Without an integrated approach, the role of epigenetics in the migratory phenotype of A. fulvescens may have been overlooked. Further characterization of migratory phenotypes could be important for management to conserve behavioural variation across the distribution of A. fulvescens and for design of stocking guidelines. PMID- 30246343 TI - Lest we forget the microvascular complications of diabetes. PMID- 30246342 TI - Dictionary-based electric properties tomography. AB - PURPOSE: To develop and validate a new algorithm called "dictionary-based electric properties tomography" (dbEPT) for deriving tissue electric properties from measured B1 maps. METHODS: Inspired by Magnetic Resonance fingerprinting, dbEPT uses a dictionary of local patterns ("atoms") of B1 maps and corresponding electric properties distributions, derived from electromagnetic field simulations. For reconstruction, a pattern from a measured B1 map is compared with the B1 atoms of the dictionary. The B1 atom showing the best match with the measured B1 pattern yields the optimum electric properties pattern that is chosen for reconstruction. Matching was performed through machine learning algorithms. Two dictionaries, using transmit and transceive phases, were evaluated. The spatial distribution of local matching distance between optimal atom and measured pattern yielded a reconstruction reliability map. The method was applied to reconstruct conductivity of 4 volunteers' brains. A conventional, Helmholtz-based Electric properties tomography (EPT) reconstruction was performed for reference. Noise performance was studied through phantom simulations. RESULTS: Quantitative values of conductivity agree with literature values. Results of the 2 dictionaries exhibit only minor differences. Somewhat larger differences are visible between dbEPT and Helmholtz-based EPT. Quantified by the correlation between conductivity and anatomic images, dbEPT depicts brain details more clearly than Helmholtz-based EPT. Matching distance is minimal in homogeneous brain ventricles and increases with tissue heterogeneity. Central processing unit time was approximately 2 minutes per dictionary training and 3 minutes per brain conductivity reconstruction using standard hardware equipment. CONCLUSION: A new, dictionary-based approach for reconstructing electric properties is presented. Its conductivity reconstruction is able to overcome the EPT transceive-phase problem. PMID- 30246344 TI - Ruling out BGN variants as simple X-linked causative mutations for bilateral corneal stromal loss in Friesian horses. PMID- 30246345 TI - Hydrogeochemical Evolution Along Groundwater Flow Paths in the Manas River Basin, Northwest China. AB - The impacts of long-term pumping on groundwater chemistry remain unclear in the Manas River Basin, Northwest China. In this study, major ions within five surface water and 105 groundwater samples were analyzed to identify hydrogeochemical processes affecting groundwater composition and evolution along the regional scale groundwater flow paths using the multivariate techniques of hierarchical cluster analysis (HCA) and principal components analysis (PCA) and traditional graphical methods for analyzing groundwater geochemistry. HCA classified the groundwater samples into four clusters (C1 to C4). PCA reduced the dimensionality of geochemical data into three PCs, which explained 86% of the total variance. The results of HCA and PCA were used to identify three zones: "recharge," "transition," and "discharge." In the recharge zone the groundwater type is Ca HCO3 -SO4 and is primarily impacted by the dissolution of calcite and silicate weathering. In the transition zone the groundwater type is Ca-HCO3 -SO4 -Cl and is impacted by rock dissolution and reverse ion exchange. In the discharge zone the groundwater type is Na-Cl and is impacted by evaporation and reverse ion exchange. In addition, anthropogenic activities impact the groundwater chemistry in the study area. The groundwater type generally changes from Ca-HCO3 -SO4 in the recharge area to Na-Cl in the discharge area along the regional-scale groundwater flow paths. This study provides a process-based knowledge for understanding the interaction of groundwater flow patterns and geochemical evolution within the Manas River Basin. PMID- 30246346 TI - Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry. AB - BACKGROUND: The CARPE registry was set up in 2009 to prospectively investigate the management of patients with chronic hand eczema (CHE). OBJECTIVES: To report comprehensive follow-up data from the CARPE registry. PATIENTS AND METHODS: We investigated sociodemographic and clinical characteristics, provision of medical care, physician-assessed outcomes, and patient-reported outcomes (PROs). Data were collected between 2009 and 2016, with up to 5 years of follow-up, and are reported descriptively. RESULTS: Overall, 1281 patients were included in the registry (53.7% female). Mean age was 47.0 years. Of the patients, 793 and 231 completed the 2-year follow-up and 5-year follow-up, respectively. At baseline, 5.4% had changed or given up their job because of CHE, the average duration of CHE was 6.1 years, and, in 22.4%, the CHE was severe according to physician global assessment. Systemic treatment (alitretinoin, acitretin, and methotrexate) was prescribed at least once to 39.0% of the patients during the course of the follow-up. Disease severity, quality of life and treatment satisfaction improved over time, and the proportion of patients receiving systemic treatments decreased. CONCLUSIONS: Under continued dermatological care, substantial improvements in disease severity and PROs over time was achieved during the course of the CARPE registry, even in patients with long-standing and severe hand eczema. PMID- 30246347 TI - 2017 ICGP early career Investigators' awards. PMID- 30246348 TI - Long noncoding RNA NEAT1 modulates cell proliferation and apoptosis by regulating miR-23a-3p/SMC1A in acute myeloid leukemia. AB - The aim of this study was to determine the function of the NEAT1/miR-23a-3p/SMC1A axis in cell proliferation and apoptosis in acute myeloid leukemia (AML). Microarray analysis was used to screen differentially expressed lncRNAs/miRNAs/mRNAs in primary AML cells. The expression of nuclear paraspeckle assembly transcript 1 (NEAT1), miR-23a-3p, and structural maintenance of chromosome 1 alpha (SMC1A) in primary AML cells and THP-1 cells were measured by quantitative real-time polymerase chain reaction (qRT-PCR). A Cell Counting Kit-8 (CCK-8) assay was used to analyze proliferation. Cell cycle progression and apoptosis were examined by flow cytometry. RNA immunoprecipitation (RIP) and dual luciferase assays were performed to determine the correlation between miR-23a-3p and NEAT1 or SMC1A. The qRT-PCR illustrated that NEAT1 and SMC1A expression was decreased but that miR-23a-3p expression was increased in primary AML cells and THP-1 cells compared with that in normal cells. The RIP assay and dual-luciferase assay revealed the targeting relationship between miR-23a-3p and NEAT1 or SMC1A. The CCK-8 assay showed that the overexpression of NEAT1 and SMC1A or repression of miR-23a-3p inhibited cell proliferation. Flow cytometry showed that the upregulation of NEAT1 and SMC1A or repression of miR-23a-3p promoted apoptosis and affected the cell cycle. NEAT1 repressed the expression of miR-23a-3p, and therefore promoted SMC1A, which in turn suppressed myeloid leukemia cell proliferation and enhanced apoptosis. PMID- 30246349 TI - Topical dapsone gel is a new treatment option for acne agminata. PMID- 30246350 TI - Delayed timing of successful spawning of an estuarine dependent fish, black bream Acanthopagrus butcheri. AB - In this paper, we investigate the period of successful spawning for black bream Acanthopagrus butcheri, an obligate estuarine species in southern Australia that typically spawn in spring and early summer. However, back-calculated spawning dates of juveniles sampled in Gippsland Lakes, Victoria from February to May 2016 indicated that spawning was concentrated over a short period in the Austral mid summer (January), with a second spawning in late summer and early autumn (late February-early March). Ichthyoplankton sampling in the tributary estuaries from October to early December collected substantial numbers of fish larvae, dominated by gobiids, eleotrids and retropinnids of freshwater origin, but no A. butcheri. The lack of A. butcheri larvae was consistent with the delayed successful spawning indicated by juvenile otolith data. Freshwater flows declined from late winter to summer, with consistent salinity stratification of the water column. Dissolved oxygen (DO) concentrations were generally very low below the halocline. These conditions may have delayed the upstream spawning migration of adults or may have been unsuitable for survival of eggs and newly-hatched larvae. Longer term predictions for climate change in southern Victoria, including the Gippsland Lakes region, are for lower winter-spring freshwater flows, potentially benefiting the reproductive success of A. butcheri through high water-column stratification, but only if DO concentrations are not compromised by a lack of high winter flows needed to flush low DO water from the system. PMID- 30246351 TI - Clinical features and mid-term follow-up in infants younger than 3 months with Kawasaki disease in a Chinese population. AB - AIM: To explore the clinical features and mid-term follow-up of Kawasaki disease (KD) in infants younger than 3 months of age in a Chinese population. METHODS: We performed a retrospective analysis of clinical signs, laboratory data, echocardiography results and outcomes for patients with KD diagnosed at our hospital from January 2009 to December 2013. A total of 1150 children were diagnosed with KD, and 200 KD patients were enrolled in this study. Group 1 included 40 children younger than 3 months of age. We randomly selected a control group as Group 2 included 160 children older than 3 months of age who fulfilled diagnostic criteria for KD and maintained follow-up for more than 1 year. RESULTS: There was a significant difference in clinical manifestations between the two groups, except respiratory infection. Group 1 was more likely to have incomplete presentation (P < 0.001). There were no significant differences in laboratory data except for white blood cell counts between the two groups. Coronary artery abnormalities were significantly different between the two groups (P < 0.001). At a mean follow-up of 18 months (range 12-48 months), all patients with coronary artery abnormalities, except for giant coronary aneurysms, returned to normal in terms of diameter as assessed by echocardiography. CONCLUSIONS: Infants younger than 3 months of age with KD often present with incomplete criteria, and diagnosis may be delayed. In addition, there may be a higher risk of developing coronary artery abnormalities. All patients except those with giant coronary aneurysms recovered well without complications at mid-term follow-up. PMID- 30246352 TI - Circumcision in the paediatric patient: A review of indications, technique and complications. AB - Circumcision is one of the most commonly performed surgical procedures in the world. Despite this, the practice of paediatric circumcision remains highly controversial, and continues to generate ongoing debate. This debate has become more relevant recently with the provisional guidelines from the Centers for Disease Control and Prevention recommending a change of practice. In this review article, we provide an overview of the history and incidence of circumcision, normal preputial development, types of phimosis, the absolute and relative indications for circumcision as well as the evidence base for its use as a preventative measure. Our aim is to provide paediatricians with a greater understanding of this common surgical procedure and the conditions it treats, to guide their clinical practice and parent counselling. PMID- 30246353 TI - Individualized estimates of overall survival in radiation therapy plan optimization - A concept study. AB - PURPOSE: Current radiation therapy planning uses a set of defined dose-volume constraints to ensure a specified level of tumor coverage while constraining the dose distribution in the organs at risk. Such constraints are aggregated, population-based quantities that do not adequately consider patient-specific risk factors. Furthermore, these constraints are calculated for each organ independently and it is therefore not guaranteed that the optimal trade-off between organs is achieved. We introduce a novel radiotherapy planning approach where a patient-specific all-cause mortality risk is minimized using inverse plan optimization. As illustration of concept, our outcome risk model incorporates patient age, sex, cardiac risk factor (CRF), and smoking. METHODS AND MATERIALS: We retrospectively analyzed a left-sided breast cancer case and a Hodgkin's lymphoma case, both clinically treated with three-dimensional conformal radiotherapy (3D-CRT). Our objective function for inverse plan optimization was an equally weighted summation of risk models for cancer recurrence and mortality from radiation-induced coronary heart disease and secondary lung and breast cancers incorporating patient age, sex, CRF, and smoking. We allowed the optimization algorithm to choose from a large set of gantry angles. The optimization task was to choose beams and optimize monitor units (MUs) so that overall survival was maximized (and the total risk of cancer recurrence and mortality from radiation-induced causes were minimized). The sensitivity analysis was performed in the lymphoma case by changing the tumor control probability model from using mean dose (Model 1) to using generalized equivalent uniform dose (Model 2). RESULTS: For the breast case in this study, the 3D-CRT clinical plan used eight beams while the proposed 3D-CRT outcome-optimized plan used five beams, reducing the total risk - summation of the risks of recurrence and secondary disease mortality - from 3% to 2%. The mean doses to clinical target volume (CTV) and internal mammary nodes (IMN) were increased in the outcome optimized plan by 1.9 and 1.8 Gy, respectively. For the Hodgkin's lymphoma case, the clinical 3D-CRT plan used two beams, while the proposed 3D-CRT outcome optimized plan used three beams, reducing the total risk by 6% (from 16% to 10%). Using either of the two tumor control models for the lymphoma case resulted in outcome-optimized plans where tumor control was compensated at the cost of saving organs at risk. However, the impact of sensitivity to models was comparatively large. Using Model 1 resulted in a reduction in mean target dose by 15.2 vs 7.1 Gy for Model 2. In all cases, the chosen beams in outcome-optimized plans were different from clinically used beams. CONCLUSIONS: The proposed optimization strategy, supplanting dosimetric objectives with comprehensive individual risk estimates, has the potential to yield improved outcomes in terms of reduced mortality risk in cancer patients treated with radiotherapy. The approach is, however, currently limited by gaps in knowledge about the effect of compromising dose to part of the target, for example, in order to spare cardiac structures. PMID- 30246354 TI - Inequalities in living well with dementia-The impact of deprivation on well being, quality of life and life satisfaction: Results from the improving the experience of dementia and enhancing active life study. AB - OBJECTIVES: Area level factors, such as deprivation and urban/rural settings, have been associated with variation in local resources and services and health inequality in later life. The aim of this study is to investigate the potential impact of deprivation and urban/rural areas on capability to live well with dementia and to examine whether availability of informal carers modified the associations. METHODS: The analysis was based on a large cohort study of 1547 community-dwelling people with dementia across Great Britain. Quality of life, life satisfaction, and well-being were measured as indices of "living well." Multivariate modelling was used to investigate differences in living well measures across deprivation quintiles and urban/rural areas adjusting for sociodemographic factors and number of comorbidities and stratifying by three groups: those living with a carer, those with a noncoresident carer and those without a carer. RESULTS: Negative dose-response relationships between deprivation and measures of quality of life (-2.12; 95% CI: -3.52, -0.73), life satisfaction (-1.27; 95% CI: -2.70, 0.16), and well-being (-5.24; 95% CI: -10.11, -0.36) were found in participants living with a carer. The associations were less clear in those with a noncoresident carer and those without a carer but these two groups generally reported lower scores on living well indicators than participants living with a carer. There was no urban/rural difference. CONCLUSIONS: The findings suggest inequalities in living well with dementia according to levels of deprivation. Additional resources are needed to improve postdiagnostic care in highly deprived areas and support those who have no informal carer. PMID- 30246355 TI - MicroRNA-21 as a predictor and prognostic factor for trastuzumab therapy in human epidermal growth factor receptor 2-positive metastatic breast cancer. AB - Breast cancer is the second most common cancer diagnosed worldwide. Human epidermal growth factor receptor 2 (HER2)-positive breast cancer represents about 20% to 30% of all breast cancers. Trastuzumab is used in the treatment of HER2 positive breast cancer. MicroRNA-21 (miR-21) is an oncomiR that acts by inhibiting many tumor-suppressor genes. We analyzed the relative expression levels of serum miR-21 in 20 HER2-positive metastatic breast cancer patients before and after 3 months of treatment with trastuzumab. miR-21 levels decreased with a high significant difference after trastuzumab therapy (P = 0.001). Although miR-21 expression levels were lower in responders than in nonresponders, the difference was not statistically significant ( P = 0.6). Our results demonstrated a significant negative correlation between its basal expression, expression levels after treatment, and time to progression ( P = 0.03 and 0.01, respectively). These results make miR-21 a potential prognostic factor for HER2 positive metastatic breast cancer patients. Additionally, it can be an interesting potential target in therapy using antisense oligonucleotides for miR 21. PMID- 30246356 TI - Endodontic pathogens possess collagenolytic properties that degrade human dentine collagen matrix. AB - AIM: To measure collagenolytic protease activity from Enterococcus faecalis and Micrococcus luteus and their ability to degrade human dentinal collagen. METHODOLOGY: Proteases activity of E. faecalis ATCC 29212, ATCC 47077 and M. luteus towards generic and specific human matrix metalloproteinase (MMP) substrates was measured using a fluorimetric assay. The ability of the bacteria to degrade dentinal collagen was tested by quantifying the amount of hydroxyproline released into the media following incubation of the bacteria or heat-inactivated bacteria (HIN) with demineralized human dentine samples for 24 h and by scanning electron microscopy (SEM). Multifactorial anova and Tukey's post hoc test were used to analyse the data (P < 0.05). RESULTS: All strains had MMP like activities, but with different substrate affinity; E. faecalis ATCC 29212, ATCC 47077 and M. luteus had the greatest affinity towards MMP-8 (7.75 +/- 0.88 MUmol L-1 /3 * 106 CFU), MMP-9 (33.86 +/- 5.16 MUmol L-1 /3 * 106 CFU) and generic MMP (26.08 +/- 4.48 MUmol L-1 /3 * 106 CFU), respectively. The amount of hydroxyproline released from demineralized dentine was similar (P > 0.05) for the three strains (range 1.8 +/- 0.17 to 2.38 +/- 0.39 MUg 50 MUL-1 ) and was significantly higher (P < 0.001) compared to their HIN counterparts (0.61 +/- 0.22 MUg 50 MUL-1 ). SEM revealed increased collagen network degradation after incubation with bacteria versus HIN. CONCLUSIONS: Endodontic pathogens possess collagenolytic protease properties that enable them to degrade dentinal collagen, potentially compromising the restoration-tooth and sealer-tooth interfaces. These collagenolytic protease properties could facilitate the migration of pathogenic bacteria into the root canal system and explain in part their role in root canal infections. PMID- 30246357 TI - Intraoperative S-ketamine for the reduction of opioid consumption and pain one year after spine surgery: A randomized clinical trial of opioid-dependent patients. AB - BACKGROUND: We aimed to explore the effect of intraoperative S-ketamine on analgesic consumption and pain one year after spine surgery in chronic opioid dependent patients undergoing spinal fusion surgery. METHODS: Single-centre, randomized, blinded trial of 147 patients. INTERVENTION: Perioperative S-ketamine bolus 0.5 mg/kg followed by S-ketamine 0.25 mg kg-1 hr-1 infusion or placebo. MAIN OUTCOMES: Analgesic use, pain (visual analogue scale 0-100 mm [VAS]) and labour market attachment one year after surgery assessed by written questionnaires. RESULTS: Response rate was 67%. One year after surgery, the daily use of oral morphine equivalents was lower in the ketamine group versus the placebo group: 0 (0-20) mg versus 20 (0-62) mg, (p = 0.02), and fewer patients had a daily use of any analgesics in the ketamine group versus placebo group, 42% (95% CI 23-61) versus 74% (95% CI 58-87), (p = 0.04). Mobilization pain was lower in the ketamine group compared to the placebo group: Median difference 17 mm (95% CI -30 to -3), (p = 0.02). Pain at rest was lower in the ketamine group compared to the placebo group with median difference: 13 mm (95% CI -23 to -3), (p = 0.01). Further, labour market attachment was better in the ketamine group, (p = 0.02). CONCLUSION: Intraoperative ketamine may reduce analgesic use, pain, and improve labour market attachment one year after spine surgery in a chronic opioid dependent population. SIGNIFICANCE: This randomized clinical trial shows that intraoperative ketamine may reduce opioid use and pain and improve labour market attachment one year after spine surgery in an opioid-dependent population. PMID- 30246358 TI - Canopy structure and topography jointly constrain the microclimate of human modified tropical landscapes. AB - Local-scale microclimatic conditions in forest understoreys play a key role in shaping the composition, diversity and function of these ecosystems. Consequently, understanding what drives variation in forest microclimate is critical to forecasting ecosystem responses to global change, particularly in the tropics where many species already operate close to their thermal limits and rapid land-use transformation is profoundly altering local environments. Yet our ability to characterize forest microclimate at ecologically meaningful scales remains limited, as understorey conditions cannot be directly measured from outside the canopy. To address this challenge, we established a network of microclimate sensors across a land-use intensity gradient spanning from old growth forests to oil-palm plantations in Borneo. We then combined these observations with high-resolution airborne laser scanning data to characterize how topography and canopy structure shape variation in microclimate both locally and across the landscape. In the processes, we generated high-resolution microclimate surfaces spanning over 350 km2 , which we used to explore the potential impacts of habitat degradation on forest regeneration under both current and future climate scenarios. We found that topography and vegetation structure were strong predictors of local microclimate, with elevation and terrain curvature primarily constraining daily mean temperatures and vapour pressure deficit (VPD), whereas canopy height had a clear dampening effect on microclimate extremes. This buffering effect was particularly pronounced on wind exposed slopes but tended to saturate once canopy height exceeded 20 m-suggesting that despite intensive logging, secondary forests remain largely thermally buffered. Nonetheless, at a landscape-scale microclimate was highly heterogeneous, with maximum daily temperatures ranging between 24.2 and 37.2 degrees C and VPD spanning two orders of magnitude. Based on this, we estimate that by the end of the century forest regeneration could be hampered in degraded secondary forests that characterize much of Borneo's lowlands if temperatures continue to rise following projected trends. PMID- 30246359 TI - Radiographic and histologic observations of sequential healing processes following ridge augmentation after tooth extraction in buccal-bone-deficient extraction sockets in beagle dogs. AB - OBJECTIVES: To evaluate dimensional ridge alterations and sequential healing processes following ridge augmentation after tooth extraction in damaged extraction sockets with buccal-bone-deficiency. MATERIAL AND METHODS: Bilateral dental roots of three mandibular premolars were extracted with entire removal of the buccal-bone plate in eight beagle dogs. Unilateral sites were grafted with biomaterials (test group) and contralateral sites were healed without grafting (control group). Observations were made after 1, 2, 4, and 8 weeks, and all sites were distributed evenly (n = 6 for each group and period). Radiographic/histomorphometric analyses were performed. RESULTS: In spontaneous healing of damaged extraction sockets, the dimension of regenerated alveolar ridge gradually increased until 4 weeks and then remained stable, but radiographic/histomorphometric analyses revealed evident dimensional shrinkage compared to the pristine tissue at 8 weeks in the coronal and middle areas. Bone grafting retained the pristine dimension of alveolar ridge, and newly formed bone area within the augmented space continuously expanded during the observational period to the outermost border of the space. CONCLUSIONS: Spontaneous healing of damaged extraction sockets caused substantial dimensional shrinkage. However, ridge augmentation can provide space into which new bone may grow continuously, resulting in the final dimensions comparable to those of the pristine alveolar ridge. PMID- 30246360 TI - Measurement properties of three assessments of burden used in atopic dermatitis in adults. AB - BACKGROUND: Standardized quality-of-life (QoL) assessments can provide important and clinically relevant information. There is currently a lack of standardization in QoL assessments used in atopic dermatitis (AD). OBJECTIVES: To determine the content validity, construct validity, internal consistency, differential reporting, responsiveness, floor or ceiling effects and feasibility of the Dermatology Life Quality Index (DLQI), Itchy Quality of Life (ItchyQoL) and 5 dimensions (5-D) itch scales for assessing burden of AD in adults and to compare their performance. METHODS: Self-administered questionnaires and skin examination were performed in 340 adults with AD in a dermatology practice setting. RESULTS: DLQI, ItchyQoL and 5-D all had good content validity. DLQI, mean ItchyQoL and 5-D itch all had strong correlations with frequency of AD symptoms (Patient-Oriented Eczema Measure) and intensity of itch (numerical rating scale for itch), and moderate correlations with AD severity (Eczema Area and Severity Index and Scoring Atopic Dermatitis) (Spearman correlations, P < 0.001 for all). DLQI and 5 D itch showed good internal consistency (Cronbach's alpha = 0.89 and 0.84), although ItchyQoL appeared to have several redundant items (alpha = 0.96). Uniform and nonuniform differential item functioning by age, sex and/or race/ethnicity was found for multiple items in DLQI, ItchyQoL and 5-D itch. DLQI, ItchyQoL and 5-D itch scores all demonstrated responsiveness, although ItchyQoL demonstrated the greatest responsiveness. There were no floor or ceiling effects for total scores. The median times for completion of DLQI, ItchyQoL and 5-D itch were 2 min. CONCLUSIONS: The DLQI, ItchyQoL and 5-D itch scales all showed good content and construct validity, and responsiveness in the assessment of AD in adults, and were feasible for use in clinical trials and practice. PMID- 30246361 TI - An extremely rare association of multiple familial trichoepitheliomas and hereditary multiple osteochondromas. PMID- 30246362 TI - A novel methodological approach using superimposed Micro-CT and STL images to analyze hard and soft tissue volume in immediate and delayed implants with different cervical designs. AB - OBJECTIVES: To study the hard and soft tissue volume after placing immediate (IMI) or delayed implants (DLI) with a triangular coronal macro-design (Test/T) or a conventional cylindrical design (Control/C). MATERIAL AND METHODS: T/C implants were inserted in healed ridges or in fresh extraction sockets of eight beagle dogs. Biopsies were processed for Micro-CT analysis and dental stone casts were optically scanned to obtain STL files revealing the soft tissue contours at 12 weeks. Image analysis software was utilized to match common landmarks superimposing the two sets of data. Three distinct volumes were calculated; buccal bone volume (B-BV), soft tissue volume below the implant shoulder (EC STV), and the soft tissue volume above the implant shoulder (SC-STV). Using linear measurements, the soft tissue height (STH), the mucosal thickness (MT-IS), and the distance from the implant shoulder to the bone crest (I-BC) were assessed in the digital images and in conventional histology to assess the concordance, reproducibility, and reliability. RESULTS: There were no significant differences between test and control implants regarding the buccal bone volume, although test implants had greater B-BV in all locations except for PM2. The soft tissue volume was similar at T/C implants. The surgical approach influenced the distribution of the total tissue volume. In the IMI, a low position of the bone crest was correlated with low values of B-BV, SC-STV, MT-IS, and STH. Linear measurements showed a high correlation between the histology and digital measurements and high inter and intra examiner agreement. CONCLUSION: The superimposition of Micro CT/STL allowed the analysis of soft and hard tissue volumes. Reduction of the implant buccal aspect resulted in nonsignificant higher bone volume although similar soft tissue volume while the surgical approach influenced soft tissue response. PMID- 30246363 TI - Three-dimensional nail imaging by optical coherence tomography: a novel biomarker of response to therapy for nail disease in psoriasis and psoriatic arthritis. PMID- 30246364 TI - Subcutaneous nodules at progesterone injection sites after fertility treatment. PMID- 30246366 TI - Therapeutical effects of vaccine from Trypanosoma cruzi amastigote surface protein 2 by simultaneous inoculation with live parasites. AB - The aim of this study was to evaluate the efficacy of vaccine using replication deficient human recombinant Type 5 replication-defective adenoviruses (AdHu5) carrying sequences of the amastigote surface protein 2 (ASP2) (AdASP2) in mice infected with the Trypanosoma cruzi ( T cruzi) Y strain. A total of 16 A/Sn mice female were distributed into four groups, as follows (n = 4 per group): Group 1 - Control Group (CTRL); Group 2 - Infected Group (TC): animals were infected by subcutaneous route with 150 bloodstream trypomastigotes of T cruzi Y strain; Group 3 - Immunized Group (AdASP-2): animals were immunized by intramuscular injection (im) route with 50 uL of AdSP-2 (2 * 10 8 plaque forming units [pfu]/cam) at day 0; Group 4-Immunized and Infected Group (AdASP-2+TC): animals were immunized by im route with 50 uL of ASP-2 (2 * 10 8 pfu/cam) and infected by T cruzi at the same day (day 0). It was observed a significant decrease of nests in the group that was immunized with AdASP-2 and infected on the same day. Tumor necrosis factor alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) gene expressions showed a significant increase in the AdASP-2+TC group when compared to TC group, but it was noted that Cyclooxygenase-2 (Cox-2) was increased in TC group when compared to AdASP-2+TC group. Increase of matrix metalloproteinases-2 (MMP-2) and decrease of MMP-9 immunoexpression in the AdASP 2+TC group was noticed as well. Oxidative DNA damage was present in myocardium for AdASP-2+TC group as a result of 8-hydroxydeoxyguanosine immunoexpression. Taken together, our results highlighted an increased oxidative stress, MMP-2 activity and inflammatory host response promoted by AdASP-2 against T cruzi infection. PMID- 30246365 TI - Metagenomic analyses highlight the symbiotic association between the glacier stonefly Andiperla willinki and its bacterial gut community. AB - The glacier stonefly Andiperla willinki is the largest metazoan inhabiting the Patagonian glaciers. In this study, we analysed the gut microbiome of the aquatic nymphs by 16S rRNA gene amplicon and metagenomic sequencing. The bacterial gut community was consistently dominated by taxa typical of animal digestive tracts, such as Dysgonomonadaceae and Lachnospiraceae, as well as those generally indigenous to glacier environments, such as Polaromonas. Interestingly, the dominant Polaromonas phylotypes detected in the stonefly gut were almost never detected in the glacier surface habitat. Fluorescence in situ hybridization analysis revealed that the bacterial lineages typical of animal guts colonized the gut wall in a co-aggregated form, while Polaromonas cells were not included in the aggregates. Draft genomes of several dominant bacterial lineages were reconstructed from metagenomic datasets and indicated that the predominant Dysgonomonadaceae bacterium is capable of degrading various polysaccharides derived from host-ingested food, such as algae, and that other dominant bacterial lineages ferment saccharides liberated by the polysaccharide degradation. Our results suggest that the gut bacteria-host association in the glacier stonefly contributes to host nutrition as well as material cycles in the glacier environment. PMID- 30246367 TI - Measuring levels of muscle fatigue in spastic cerebral palsy. PMID- 30246369 TI - Appearance-based vs health-based sun protective messages: A randomized, double blind controlled study. AB - BACKGROUND: Appearance-based messages have shown promise in improving sun protection habits among Caucasians but have scarcely been investigated in Hispanic populations. OBJECTIVE: To compare the effectiveness of appearance-based vs health-based messages in an ethnic patient population, where hyperpigmentation disorders are prevalent and often cosmetically concerning. METHODS: One hundred thirty-seven patients were randomized to receive images of (a) skin cancer, (b) hyperpigmentation, or (c) wrinkles. Analysis of variance tests for repeated measures were used to estimate the effects of the different stimuli on participants' knowledge and intention to sun protect. RESULTS: Appearance-based interventions were more effective in improving intentions to sun protect among both Hispanics and non-Hispanic Whites (P < 0.05). They were furthermore more effective among younger patient populations (<=40 years old) and patients who thought that a tanned appearance is attractive (P < 0.05). CONCLUSIONS: Appearance-based photos of sun damage were more effective than health-based messages among Hispanics, younger patient populations, and those who find tanned appearances to be attractive. PMID- 30246368 TI - Costs Associated with Health Care Services Accessed through VA and in the Community through Medicare for Veterans Experiencing Homelessness. AB - OBJECTIVE: To estimate health care utilization and costs incurred by homeless Veterans relative to nonhomeless Veterans and to examine the impact of a VA homelessness program on these outcomes. DATA SOURCES/STUDY SETTING: Combined Department of Veterans Affairs (VA) administrative and Medicare claims data. STUDY DESIGN: Observational study using longitudinal data from Veterans engaged with the VA system and enrolled in Medicare. Veterans with administrative evidence of homelessness at any point during 2006-2010 were matched on period of military service to Veterans with no evidence of homelessness. PRINCIPAL FINDINGS: Experience of homelessness was associated with 1.37 (95 percent CI = 1.34-1.40) and 0.16 (95 percent CI = 0.14-0.17) more outpatient encounters per quarter in VA and non-VA settings, respectively, and 1.31 (95 percent CI = 1.30 1.32) and 0.49 (95 percent CI = 0.48-0.49) more inpatient days per quarter in VA and non-VA hospitals, respectively. These were associated with higher costs. Relative to stably housed Veterans less than 65 years of age, those enrolled in a VA homelessness program had 94.4 percent (95 percent CI = 90.7 percent-98.1 percent) more VA outpatient visits but 5.5 percent (95 percent CI = 3.0 percent 7.9 percent) fewer Medicare outpatient visits. CONCLUSIONS: Homelessness was associated with an increase in VA and Medicare utilization and cost. A VA homelessness program decreased use of Medicare outpatient services. PMID- 30246371 TI - Growing the phenotype of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in children. PMID- 30246370 TI - Brassinosteroids function in spikelet differentiation and degeneration in rice. AB - Brassinosteroids (BRs) play crucial roles in many aspects of plant development. However, their function in spikelet differentiation and degeneration in rice (Oryza sativa L.) remains unclear. Here, we investigated the roles of these phytohormones in spikelet development in field-grown rice subjected to five different nitrogen (N) fertilization treatments during panicle differentiation. BR levels and expression of genes involved in BR biosynthesis and signal transduction were measured in spikelets. Pollen fertility and the number of differentiated spikelets were closely associated with 24-epicastasterone (24 epiCS) and 28-homobrassinolide (28-homoBL) levels in spikelets. Enhanced BR biosynthesis and signal transduction, in response to N treatment, enhanced spikelet differentiation, reduced spikelet degeneration, and increased grain yield. Increases in proton-pumping ATPase activity, ATP concentration, energy charge, and antioxidant system (AOS) levels were consistent with 24-epiCS and 28 homoBL concentrations. Exogenous application of 24-epiCS or 28-homoBL on young panicles induced a marked increase in endogenous 24-epiCS or 28-homoBL levels, energy charge, AOS levels, spikelet differentiation, and panicle weight. The opposite effects were observed following treatment with a BR biosynthesis inhibitor. Our findings indicate that, in rice, BRs mediate the effects of N fertilization on spikelet development and play a role in promoting spikelet development through increasing AOS levels and energy charge during panicle development. PMID- 30246372 TI - Traumatic dental injury incidence of unseen children. AB - BACKGROUND/AIMS: There is a lack of information about the incidence of dental trauma in Turkish children with disabilities and those in detention centers. The aim of this study was to investigate the occurrence of dental trauma in two groups estimated to have high-potential risk, young prisoners and disabled children, compared with healthy peers. MATERIALS AND METHODS: A total of 530 children were included in the study. The participants were divided into three groups: Disability Group (n=238), Imprisoned Children Group (n=231) and school children (n=61) as the Control Group. The occurrence of dental trauma was evaluated according to age and gender. Statistical evaluations were done by using SPSS statistics-22 programme. RESULTS: The mean age of all participants was 14.85 +/- 3.43 years. Males predominated (75.8%). In the Imprisoned Children Group, not only maxillary and mandibular incisors but also canines had dental trauma. Time of imprisonment and education level did not have any significant effect on dental trauma occurrence among children in detention centers. In the Disability Group, the disability type did not have any significant effect. In the Control Group, maxillary central incisors were the most traumatized teeth. The incidence of dental trauma was 11.3% in the Imprisoned Children Group, 4.6% in the Disability Group, and 9.8% in the Control Group. There was a significant difference among the three groups (p:0.027; p<0.05). CONCLUSION: Dental trauma incidence may differ among disabled, imprisoned, and healthy children. Hence, children from different parts of the community should be included in epidemiological studies to provide a more accurate incidence of dental trauma. PMID- 30246373 TI - Characterization of eomesodermin and T-bet expression by allostimulated CD8+ T cells of healthy volunteers and kidney transplant patients in relation to graft outcome. AB - Memory T cell (Tmem) responses play a critical role in the outcome of allo transplantation. While the role of the T-box transcription factor Eomesodermin (Eomes) in the maintenance of antigen-specific Tmem is well studied, little is known about Eomes+ CD8+ T cell responses after transplantation. We evaluated the phenotype and function of allo-reactive Eomes+ CD8+ T cells in healthy volunteers and kidney transplant patients and their relation to transplant outcome. High Eomes expression by steady-state CD8+ T cells correlated with effector and memory phenotype. Following allo-stimulation, the expression of both the T-box proteins Eomes and T-bet by proliferating cells increased significantly, where high expression of Eomes and T-bet correlated with higher incidence of allo-stimulated IFNgamma+ TNFalpha+ CD8+ T cells. In patients with no subsequent rejection, Eomes but not T-bet expression by donor-stimulated CD8+ T cells, increased significantly after transplantation. This was characterized by increased Eomeshi T-bet-/lo and decreased Eomes-/lo T-bethi CD8+ T cell subsets, with no significant changes in the Eomeshi T-bethi CD8+ T cell subset. No upregulation of exhaustion markers programmed-death-1 (PD-1) and cytotoxic-T-lymphocyte associated-antigen-4 (CTLA4) by donor-stimulated Eomes+ CD8+ T cells was observed. Before transplantation, in patients without rejection, there were higher incidences of Eomeshi T-bet-/lo , and lower incidences of Eomeshi T-bethi and Eomes-/lo T-bethi donor-stimulated CD8+ T cell subsets, compared to those with subsequent rejection. Overall, our findings indicate that high Eomes expression by allo-stimulated T-bet+ CD8+ T cells is associated with enhanced effector function, and that an elevated incidence of donor-stimulated CD8+ T cells co-expressing high levels of Eomes and T-bet before transplantation, may correlate with an increased incidence of acute cellular rejection. PMID- 30246374 TI - HDAC8 regulates canonical Wnt pathway to promote differentiation in skeletal muscles. AB - Histone deacetylase 8 (HDAC8) is a class 1 histone deacetylase and a member of the cohesin complex. HDAC8 is expressed in smooth muscles, but its expression in skeletal muscle has not been described. We have shown for the first time that HDAC8 is expressed in human and zebrafish skeletal muscles. Using RD/12 and RD/18 rhabdomyosarcoma cells with low and high differentiation potency, respectively, we highlighted a specific correlation with HDAC8 expression and an advanced stage of muscle differentiation. We inhibited HDAC8 activity through a specific PCI 34051 inhibitor in murine C2C12 myoblasts and zebrafish embryos, and we observed skeletal muscles differentiation impairment. We also found a positive regulation of the canonical Wnt signaling by HDAC8 that might explain muscle differentiation defects. These findings suggest a novel mechanism through which HDAC8 expression, in a specific time window of skeletal muscle development, positively regulates canonical Wnt pathway that is necessary for muscle differentiation. PMID- 30246375 TI - Assessment of multiple stressors on the growth of larval green sturgeon Acipenser medirostris: implications for recruitment of early life-history stages. AB - Early developmental stages of fishes are particularly sensitive to changes in environmental variables that affect physiological processes such as metabolism and growth. Both temperature and food availability have significant effects on the growth and survival of larval and juvenile fishes. As climate change and anthropogenic disturbances influence sensitive rearing environments of fishes it is unlikely that they will experience changes in temperature or food availability in isolation. Therefore, it is critical that we determine the effects of each of these potential stressors on larval growth and development, as well as understand the additive, synergistic or antagonistic effects of both. We reared threatened green sturgeon Acipenser medirostris (initial age ca. 32 days post hatch) at four temperatures (11, 13, 16 and 19 degrees C) and two food availability rates (100% and 40% of optimal) to assess the effects of these stressors and their interactions on larval growth. We compared the overall size (fork length, total length and mass), growth rates (cm day-1 and g day-1 ) and relative condition factor of these larval and juvenile fish at 3 week intervals for up to 12 weeks. Our results indicated that temperature and food availability both had significant effects on growth and condition and that there was a significant interaction between the two. Fish reared with limited food availability exhibited similar patterns in growth rates to those reared with elevated food rates, but the effects of temperature were greatly attenuated when fish were food-limited. Also, the effects of temperature on condition were reversed when fish were reared with restricted food, such that fish reared at 19 degrees C exhibited the highest relative condition when fed optimally, but the lowest relative condition when food was limited. These data are critical for the development of relevant bioenergetics models, which are needed to link the survival of larval sturgeons with historic environmental regimes, pinpoint temperature ranges for optimal survival and help target future restoration sites that will be important for the recovery of sturgeon populations. PMID- 30246376 TI - Endoscopic closure method using a dental floss O-ring for mucosal defect after endoscopi resection. PMID- 30246378 TI - Angiotensin (1-7) inhibits arecoline-induced migration and collagen synthesis in human oral myofibroblasts via inhibiting NLRP3 inflammasome activation. AB - Arecoline induces oral submucous fibrosis (OSF) via promoting the reactive oxygen species (ROS). Angiotensin (1-7) (Ang-(1-7)) protects against fibrosis by counteracting angiotensin II (Ang-II) via the Mas receptor. However, the effects of Ang-(1-7) on OSF remain unknown. NOD-like receptors (NLRs) family pyrin domain containing 3 (NLRP3) inflammasome is identified as the novel mechanism of fibrosis. Whereas the effects of arecoline on NLRP3 inflammasome remain unclear. We aimed to explore the effect of Ang-(1-7) on NLRP3 inflammasome in human oral myofibroblasts. In vivo, activation of NLRP3 inflammasomes with an increase of Ang-II type 1 receptor (AT1R) protein level and ROS production in human oral fibrosis tissues. Ang-(1-7) improved arecoline-induced rats OSF, reduced protein levels of NADPH oxidase 4 (NOX4) and the NLRP3 inflammasome. In vitro, arecoline increased ROS along with upregulation of the angiotensin-converting enzyme (ACE)/Ang-II/AT1R axis and NLRP3 inflammasome/interleukin-1beta axis in human oral myofibroblasts, which were reduced by NOX4 inhibitor VAS2870, ROS scavenger N-acetylcysteine, and NOX4 small interfering RNA (siRNA). Furthermore, arecoline induced collagen synthesis or migration via the Smad or RhoA-ROCK pathway respectively, which could be inhibited by NLRP3 siRNA or caspase-1 blocker VX 765. Ang-(1-7) shifted the balance of RAS toward the ACE2/Ang-(1-7)/Mas axis, inhibited arecoline-induced ROS and NLRP3 inflammasome activation, leading to attenuation of migration or collagen synthesis. In summary, Ang-(1-7) attenuates arecoline-induced migration and collagen synthesis via inhibiting NLRP3 inflammasome in human oral myofibroblasts. PMID- 30246379 TI - KDM5 demethylases and their role in cancer cell chemoresistance. AB - Histone methylation is important in the regulation of genes expression, and thus its dysregulation has been observed in various cancers. KDM5 enzymes are capable of removing tri- and di- methyl marks from lysine 4 on histone H3 (H3K4) which makes them potential players in the downregulation of tumor suppressors, but could also suggest that their activity repress oncogenes. Depending on the methylation site, their effect on transcription can be either activating or repressing. There is emerging evidence for deregulation of KDM5A/B/C/D and important phenotypic consequences in various types of cancer. It has been suggested that the KDM5 family of demethylases plays a role in the appearance of drug tolerance. Drug resistance remains a challenge to successful cancer treatment. This review summarizes recent advances in understanding the functions of KDM5 histone demethylases in cancer chemoresistance and potential therapeutic targeting of these enzymes, which seems to prevent the emergence of a drug resistant population. PMID- 30246377 TI - UGT1A1 polymorphisms in rectal cancer associated with the efficacy and toxicity of preoperative chemoradiotherapy using irinotecan. AB - The purpose of the present study was to assess the efficacy and toxicity of preoperative chemoradiotherapy using irinotecan against locally advanced lower rectal cancer according to UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms. Between 2009 and 2016, 46 patients with resectable rectal cancer (T3-T4, N0-N2, M0) received preoperative chemoradiotherapy consisting of 80 mg/m2 per day tegafur/gimeracil/oteracil (S-1; days 1-5, 8-12, 22-26, and 29-33), 60 mg/m2 per day irinotecan (days 1, 8, 22, and 29), and 45 Gy radiation (1.8 Gy/day, 5 days per week for 5 weeks). Six to eight weeks after completing chemoradiotherapy, total mesorectal excision was carried out. Patients with UGT1A1 polymorphisms were divided into WT (n = 26), heterozygous (n = 15), and homozygous (n = 5) groups, the latter including double heterozygosities. We evaluated associations between clinical characteristics, including UGT1A1 polymorphisms, and chemoradiotherapy efficacy and toxicity. Incidence rates of grade 3+ neutropenia and diarrhea were 17.0% and 30.4%, respectively. Relative dose intensity was 89.3%. Pathological complete response rate (grade 3) was 26.1%, and the good response (grade 2/3) rate was 84.8%. UGT1A1 polymorphisms were significantly associated with neutropenia and pathological good responses, but not with diarrhea. UGT1A1 polymorphism was the only predictive factor for pathological good responses. Our results indicate that UGT1A1 polymorphism is a predictive factor to determine the clinical efficacy of preoperative chemoradiotherapy and hematological toxicity induced by chemoradiotherapy using irinotecan in locally advanced rectal cancer patients. PMID- 30246380 TI - Raman spectroscopy investigation of biochemical changes in tumour spheroids with ageing and after treatment with staurosporine. AB - There has been increasing use of in vitro cell culture models that more realistically replicate the three dimensional (3D) environment found in vivo. Multicellular tumour spheroids (MTS) using cell lines or patient-derived organoids have become an important in vitro drug development tool, where cells are grown in a 3D 'sphere' that exhibits many of the characteristics found in vivo. Significantly, MTS develop gradients in nutrients and oxygen, commonly found in tumours, that contribute to therapy resistance. While MTS show promise as a more realistic in vitro culture model, there is a massive need to improve imaging technologies for assessing biochemical characteristics and drug response in such models to maximize their translation into useful applications such as high throughput screening (HTS). In this study we investigate the potential for Raman spectroscopy to unveil biochemical information in MTS and have investigated how spheroid age influences drug response, shedding light on increased therapy resistance in developing tumours. The wealth of molecular level information delivered by Raman spectroscopy in a noninvasive manner, could aid translation of these 3D models into HTS applications. This article is protected by copyright. All rights reserved. PMID- 30246382 TI - Occupational allergic contact dermatitis caused by cobalt in machine oil. PMID- 30246381 TI - Coronary stent implantation and adverse cardiac events after surgery. AB - BACKGROUND: In the risk assessment of patients considered for non-cardiac surgery and with recent coronary stent implantation, coronary drug-eluting stent implantation procedure characteristics may be taken into account. We aimed to evaluate associations between coronary drug-eluting stent implantation procedure characteristics and the risk of myocardial infarction and all-cause death within 30 days after non-cardiac surgery. DESIGN: Patients with coronary drug-eluting stents were identified using the Western Denmark Heart Registry. Surgical procedures performed after stent implantation were detected using the Danish National Patient Registry. We used registry-based detection of myocardial infarction and all-cause death. RESULTS: Of 22 590 patients treated with drug eluting stents between 2005 and 2012, 4046 underwent non-cardiac surgery within 1 and 12 months after stent implantation. We found no significant association between the risk of myocardial infarction or all-cause death within 30 days after surgery and number of arteries treated (1 [reference] vs more), number of lesions treated (1 [reference] vs more), segments treated (left main and proximal left anterior descending artery vs other [reference]), total stent length (<20 mm [reference] vs >=20 mm), number of stents (1 [reference] vs >1) and largest balloon diameter (>=3 mm [reference] vs <3 mm). All-cause death, but not myocardial infarction, risk was lower among patients treated with first generation vs second-generation stents (odds ratio 0.58). CONCLUSIONS: We identified no significant associations between stent implantation procedure characteristics and risk of myocardial infarction or all-cause death among patients undergoing non-cardiac surgery. All-cause death was lower with first- vs second-generation drug-eluting stents. PMID- 30246383 TI - The pathogenesis of thyroid autoimmune diseases: New T lymphocytes - Cytokines circuits beyond the Th1-Th2 paradigm. AB - Autoimmune thyroid disease (AITD) is one of the most common organ-specific autoimmune disorders. It mainly manifests as Hashimoto's thyroiditis (HT) and Graves' disease (GD). HT is characteristic of hypothyroidism resulting from the destruction of the thyroid while GD is characteristic of hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. T lymphocytes and their secretory cytokines play indispensable roles in modulating immune responses, but their roles are often complex and full of interactions among distinct components of the immune system. Dysfunction of these T cells or aberrant expressions of these cytokines can cause the breakdown of immune tolerance and result in aberrant immune responses during the development of AITDs. This review summarizes recently identified T subsets and related cytokines and their roles in the pathogenesis of AITDs with the hope to provide a better understanding of the precise roles of notably identified T subsets in AITDs and facilitate the discovery of functional molecules or novel immune therapeutic targets for AITDs. PMID- 30246384 TI - Commentary on Grebely et al. (2018): Ending HCV epidemics among people who inject drugs. PMID- 30246385 TI - Gliosarcoma arising from oligodendroglioma (Oligosarcoma): A case report with genetic analyses. AB - Gliosarcomas are a type of bimorphic tumor composed of glial and sarcomatous elements, and are considered to be a variant of glioblastoma, WHO grade IV. To date, only rare cases of gliosarcoma with oligodendroglial components (oligosarcoma) have been reported. We report a case of oligosarcoma consisting of gliosarcoma arising from recurrent oligodendroglioma. A 53-year-old man, who had undergone a gross total resection of oligodendroglioma (WHO grade II) 11 years earlier, presented with a local tumor recurrence. The patient underwent a second gross total resection, whereupon a histopathological examination further revealed residual features of classical oligodendroglioma, and newly-developed sarcomatous characteristics. Both the primary and recurrent tumors showed 1p/19q co-deletion and mutation of the isocitrate dehydrogenase 1 (IDH1) gene, consistent with being oligodendroglial in nature. Loss of heterozygosity (LOH) of chromosome 1p/19q and IDH1 mutation have seldom been analyzed in previous reports of oligosarcomas. We report a rare case study supported by the results of genetic analyses. Our analyses have revealed that the sarcomatous component represents a metaplastic change occurring in the oligodendroglial element. PMID- 30246387 TI - Anatomy and homology of the accessory electric organs of the toothless knifefishes (Rhamphichthyoidea: Gymnotiformes). AB - We describe the anatomy and histology of the accessory electric organs of several knifefish taxa. Accessory electric organs are observed among Rhamphichthyoidea in the opercular, mental and humeral regions. Within this group, some species of Brachyhypopomus possess an accessory electric organ in the opercular region. Rhamphichthyinae and Steatogenys possess accessory electric organs in the mental region of the body that differs in many aspects, such as general electrocyte shape and its number of caudal ridges. Steatogenys, Hypopygus and Rhamphichthys possess an accessory electric organ in the humeral region that differs in position, electrocyte configuration and shape. Electrocytes of both humeral and mental accessory electric organs in Steatogenys share a number of common features (e.g., electrocyte shape and innervation pattern), which distinguishes them from the electric organs of related groups. Rhamphichthys has an accessory electric organ in the humeral (specifically subpectoral) region, which has not previously been reported in the literature and differs in arrangement and electrocyte shape from those previously described electric organs of other taxa. Homology of these accessory electric organs is discussed in the context of hypothesized relationships among rhamphichthyoid taxa, indicating that accessory electric organs originated multiple times with apparently no subsequent losses. This article is protected by copyright. All rights reserved. PMID- 30246386 TI - Unstimulated saliva: Background noise in taste molecules. AB - : Saliva is a highly complex bodily fluid composed of many proteins, peptides, small organic molecules, and ions. Saliva is produced and secreted by the major and minor salivary glands to protect the mouth and to participate in digestion. Generally, a distinction is made between unstimulated saliva that is a result of autonomic stimulation and stimulated saliva that is produced during chewing and taste stimulation. The link between saliva and sensory perception can thus be regarded in two ways: the role of unstimulated saliva as a background taste and the mechanistic role of stimulated saliva during eating. Indeed, unstimulated saliva (and its components) is continuously bathing our oral cavity and as such stimulates our taste receptors, thus playing a role in taste sensitivity. However, the role of unstimulated salivary components in mediating taste has been studied only in very few substances. To explore this question, this review attempts to compare data from the literature on unstimulated salivary composition with those on taste sensitivity. The main conclusion centres around the concept that the gustatory self-adaptation phenomenon may be relevant for only a few salivary compounds. Further studies at the level of the salivary Von Ebner glands and salivary pellicle are necessary before arriving at definitive conclusions on this subject. PRACTICAL APPLICATION: Unstimulated saliva contains taste substances that can influence sensory perception through taste adaptation. However, large inter-individual variability exists in unstimulated salivary composition both qualitatively and quantitatively. These differences may explain the variability in taste perception and thus the food choices and behaviors of an individual. Thus, in the context of providing personalized food and nutrition to the consumer, variability of unstimulated saliva should be considered for specific formulation of food products. PMID- 30246388 TI - Clinical and dermoscopic features of pleomorphic dermal sarcoma. PMID- 30246389 TI - TGF-beta1-PML SUMOylation-peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) form a positive feedback loop to regulate cardiac fibrosis. AB - Transforming growth factor-beta (TGF-beta) signaling pathway is involved in fibrosis in most, if not all forms of cardiac diseases. Here, we evaluate a positive feedback signaling the loop of TGF-beta1/promyelocytic leukemia (PML) SUMOylation/Pin1 promoting the cardiac fibrosis. To test this hypothesis, the mice underwent transverse aortic constriction (3 weeks) were developed and the morphological evidence showed obvious interstitial fibrosis with TGF-beta1, Pin1 upregulation, and increase in PML SUMOylation. In neonatal mouse cardiac fibroblasts (NMCFs), we found that exogenous TGF-beta1 induced the upregulation of TGF-beta1 itself in a time- and dose-dependent manner, and also triggered the PML SUMOylation and the formation of PML nuclear bodies (PML-NBs), and consequently recruited Pin1 into nuclear to colocalize with PML. Pharmacological inhibition of TGF-beta signal or Pin1 with LY364947 (3 MUM) or Juglone (3 MUM), the TGF-beta1-induced PML SUMOylation was reduced significantly with downregulation of the messenger RNA and protein for TGF-beta1 and Pin1. To verify the cellular function of PML by means of gain- or loss-of-function, the positive feedback signaling loop was enhanced or declined, meanwhile, TGF-beta-Smad signaling pathway was activated or weakened, respectively. In summary, we uncovered a novel reciprocal loop of TGF-beta1/PML SUMOylation/Pin1 leading to myocardial fibrosis. PMID- 30246391 TI - Somatic cell evolution: how to improve with age. AB - A recent article published in this journal illuminates a rare example of somatic evolution where cells improve rather than deteriorate with age. In mitotic intestinal crypts, stem cells with higher levels of a deleterious heteroplasmic germline mitochondrial mutation are purged through time, leading to crypts without the mutation. Similar somatic mitochondrial mutations are not purged from crypts, indicating that special conditions are needed to improve with age. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 30246390 TI - Role of serum 25-hydroxyvitamin D levels and vitamin D receptor gene polymorphisms in patients with rosacea: a case-control study. AB - BACKGROUND: Vitamin D has significant effects on the immune system and thereby on the pathogenesis of rosacea. However, there is a lack of information on the vitamin D status and vitamin D receptors (VDRs) of patients with rosacea. AIM: To evaluate the role of vitamin D in rosacea susceptibility. METHODS: A case-control study was conducted, enrolling patients with rosacea and healthy controls (HCs). Five VDR gene single nucleotide polymorphisms (SNPs) (Cdx2, FokI, ApaI, BsmI and TaqI) and serum 25-hydroxyvitamin D3 [25(OH)D3 ] levels were compared between patients and HCs. RESULTS: The study enrolled 60 patients (M/F: 14/46) and 60 age and sex-matched HCs (M/F: 14/46). Age (mean +/- SD) was 48 +/- 11 years for both groups. The serum 25(OH)D3 levels (median +/- interquartile range) were higher in patients with rosacea (12.9 +/- 6.8 ng/mL) than in HCs (10.5 +/- 3.7 ng/mL) (P < 0.001). Subjects with high serum 25(OH)D3 levels had a 1.36-fold increased risk of rosacea (95% CI 1.17-1.58). Heterozygous and mutant ApaI polymorphisms increased rosacea risk by 5.26-fold (95% CI 1.51-18.35) and 3.69-fold (95% CI 1.19-11.48), respectively, whereas mutant TaqI polymorphisms decreased the risk by 4.69 times (95% CI 1.37-16.67). Heterozygosity for Cdx2 alleles increased rosacea risk, whereas wildtype ApaI and mutant TaqI alleles decreased it. CONCLUSIONS: The present study suggests that an increase in vitamin D levels may contribute to the development of rosacea. ApaI and TaqI polymorphisms, and heterozygous Cdx2, wildtype ApaI and mutant TaqI alleles were significantly associated with rosacea. These results indicate a possible role of vitamin D and VDR pathways in the pathogenesis of rosacea, although causality could not be assessed. PMID- 30246393 TI - Review of safety and efficacy of approved systemic psoriasis therapies. AB - Psoriasis is a chronic inflammatory disease which affects nearly 3% of the adult US population. Due to the chronic nature of the disease and need for long-term treatment, psoriasis is associated with substantial disease burden and negative impact on patients' quality of life. In the past, systemic agents such as methotrexate, cyclosporine, and acitretin have been the mainstay treatment for moderate to severe psoriasis. Multiple new molecular targets have been recently identified, and novel biologic therapies directed at these targets have been approved leading to a paradigm shift in psoriasis management. However, despite the availability of several treatment options and continued introduction of highly efficacious biologics, undertreatment of psoriasis patients remains a huge problem. This can be largely attributed to several causes including high cost of biologics, lack of experience, and reluctance of practitioners to initiate or switch to systemic treatment regimens in moderate to severe psoriasis patients. In this article, we aim to provide a concise review of mechanism, safety, and efficacy of the approved systemic treatments for psoriasis. PMID- 30246392 TI - Ameliorating effects and mechanisms of chronic electroacupuncture at ST36 in a rodent model of dyspepsia induced by cisplatin. AB - BACKGROUND: Chemotherapy-associated dyspepsia syndrome (CADS) is among the most intensive side effects and critical concerns for patients with cancer. To investigate the effects and mechanisms of chronic electroacupuncture (EA) at ST36 on chemotherapy-associated dyspeptic symptoms (CADS) in rats. METHODS: Cisplatin (8 mg/kg, ip) was given once to establish CADS model. EA or sham-EA treatment was then performed one hour daily for 21 days. KEY RESULTS: (a) EA treatment decreased kaolin intake within 24 hours (1.67 +/- 0.23 g vs 2.36 +/- 0.37 g in sham-EA, P < 0.05); EA increased food intake (9.43 +/- 2.28 vs 4.32 +/- 1.26 in sham-EA, P < 0.05) and cisplatin-induced reduction of body weight (426.38 +/- 13.25 vs 407.92 +/- 13.26 in sham-EA, P = 0.05). (b) The incidence of normal behavioral satiety sequence (53%) in EA group was greater than that in sham-EA (32%) group (X2 = 17.68, P < 0.01). (c) EA increased the percentage of normal gastric slow waves (82.6 +/- 5.98 vs 22.8 +/- 1.90 in sham-EA, P < 0.05). (d) EA normalized cisplatin delayed gastric emptying (71.3% +/- 6.8% vs 44.6% +/- 11.2% in control, P < 0.05). (e) EA decreased ratio of heart rate variability (0.30 +/- 0.03 vs 0.56 +/- 0.05 in sham-EA, P < 0.05). (f) EA decreased fasting ghrelin, glucagon-like peptide-1 and peptide YY (P < 0.01 vs sham-EA for all). CONCLUSIONS AND INFERENCES: Chronic EA ameliorates dyspepsia symptom and improves gastric dysmotility induced by Cisplatin, mediated via the vagal and gastrointestinal hormonal mechanisms. PMID- 30246395 TI - Reconsidering the Meaning of Concepts in Biology: Why Distinctions Are So Important. AB - Concepts have a central and important place in science, therefore, it is important that their meanings are always made clear. However, such clarity does not always exist, even in the case of such fundamental biological concepts as "gene" and "adaptation." A quick look at textbooks reveals that different meanings may be attributed to the same concept, even within the same textbook, without explicitly discussing the differences of those meanings. This can be misleading, and mask important conceptual differences. Therefore, the differences between the various meanings of the same concept should be discussed and explained in order for conceptual understanding to be achieved. PMID- 30246394 TI - Evaluating the ecosystem services and benefits of wetland restoration by use of the rapid benefit indicators approach. AB - Wetlands in urban and urbanizing areas are often smaller, more degraded, and subject to more stressors than those in undeveloped locations. Their restored level of functioning may never equal that of a site in an undisturbed landscape. Yet, the social benefits from restoring these wetlands may be significant because of the relative scarcity of wetlands and natural areas in urban settings and also the large number of people who may benefit. In this study, we have outlined a systematic approach to compiling nonmonetary indicators of wetlands restoration benefits: The Rapid Benefit Indicators (RBI) Approach. The RBI approach is grounded in economic theory and compatible with methods used by environmental economists to value ecosystem services. We illustrate the RBI approach with a comparison of 2 sites within the Woonasquatucket River Watershed in Rhode Island. As an urbanizing watershed, the Woonasquatucket illustrates how decisions may differ when based primarily on evaluations of ecological functioning versus those that incorporate benefits to people. It demonstrates how small urban sites with relatively low ecological function can provide large social benefits. Integr Environ Assess Manag 2018;00:000-000. Published 2018. This article is a US Government work and is in the public domain in the USA. PMID- 30246396 TI - Transient symptomatic zinc deficiency in a breast-fed African infant: case report and literature review. PMID- 30246397 TI - Diagnostic values of KOH examination, histological examination, and culture for onychomycosis: a latent class analysis. AB - BACKGROUND: In the absence of a real gold standard, comparative studies are still done on diagnostic methods for onychomycosis. There are only a few attempts using latent class analysis to determine the value of polymerase chain reaction in comparison to conventional methods. We aimed to determine the value of histological examination in such a way for the diagnosis of onychomycosis. METHODS: Potassium hydroxide mount (KOH), culture and histological examination with periodic acid-Schiff (PAS), and Gomori's methenamine silver (GMS) stains were done in 106 patients having clinically suspected toenail onychomycosis. RESULTS: KOH was positive in 74% of the patients; culture in 14%; PAS in 30%; and GMS in 66%. According to the results of the latent class analysis, culture and PAS were highly specific but poorly sensitive; KOH, highly sensitive but poorly specific; and GMS, both highly sensitive and specific. CONCLUSIONS: Based on these results, we have proposed KOH as a screening test and GMS as a confirmatory test for the diagnosis of onychomycosis in our own practice. However, since positivity rates of different diagnostic methods vary widely in different centers, it is more suitable that every center should determine their own diagnostic strategy by evaluating their own results with latent class analysis. PMID- 30246398 TI - Fast Wide-Line Solid-State NMR on a Low-Cost Benchtop Spectrometer. AB - Solid-state NMR may provide access to a wealth of information on molecular structure and dynamics. However, for many applications, the acquisition is challenged by broad resonances implying large spectral linewidths and low sensitivity. Conventionally, this is tackled by using costly and laboratory-fixed spectrometers based on large high-field superconducting magnets. In this Communication, we demonstrate that a range of challenging wide-line solid-state NMR spectra can be acquired on a robust, maintenance-free, low-cost benchtop/mobile NMR spectrometer with a sensitivity comparable to common high field instruments. The performance and versatility for recording sensitive wide line spectra is demonstrated through acquisition of 31 P NMR of paramagnetic FePO4 and full quadupolar lineshapes of Al2 O3 (27 Al) and KNO3 (14 N). Also, we introduce interleaved acquisition of frequency-stepped slices providing a dramatic reduction of the required experiment time. PMID- 30246399 TI - Presence of Fatty-Acid Ethyl Esters in Krill Oil Dietary Supplements. AB - Krill oil dietary supplements are increasingly used for their high concentrations of phospholipids (PL), which offer reportedly greater bioavailability of n-3 polyunsaturated fatty acids (PUFA) than those of triacylglycerols or fatty-acid ethyl esters (FAEE) commonly found in fish oils and fish-oil concentrates. This work evaluated the lipid composition of 22 commercial krill oil (CKO) supplements available in the US market, and found ten products (i.e. 45%) contained significant amounts of FAEE, varying from 41% to 75%, by weight. These concentrations of FAEE differed from the minor abundances of FAEE (<3%, by weight) found in manufacturer-supplied krill oil. The potential clinical and regulatory implications for these findings warrant further investigation. PMID- 30246400 TI - MiR-218 regulated cardiomyocyte differentiation and migration in mouse embryonic stem cells by targeting PDGFRalpha. AB - MicroRNAs (miRNAs) have been identified as key players in cardiogenesis and heart pathophysiological processes. However, many miRNAs are still not recognized for their roles in cardiomyocytes differentiation. In this study, we evaluated the effects of microRNA-218 (miR-218) in cardiomyocyte differentiation of the mouse embryonic stem cells (ESCs) in vitro. The percentage of the beating embryoid bodies (EBs) in miR-218 mimic-treated cells was reduced to 32% compared with miR 218 mimic negative control (56%) on day 5 + 3. The amplitude of the intracellular Ca2+ transients in the cardiomyocytes derived from ESCs was reduced upon miR-218 overexpression, followed by the decreased calcium-related proteins and cell junction proteins expressions. Besides, miR-218 expression in ESCs was related to the directional spreading ability of EBs during differentiation. The increased expression of miR-218 could promote the migration of ESCs in vitro, while the decreased expression of miR-218 could inhibit the migration by the transwell experiment. Meanwhile, miR-218 could regulate cell migration-related proteins Cdc42 and Rac1. Platelet-derived growth factor receptor alpha (PDGFRalpha) was further confirmed to be a direct target of miR-218 both physically and functionally by dual-luciferase reporter assay. Our data further described that overexpression of PDGFRalpha rescued the miR-218-mediated inhibition of cardiomyocyte differentiation and restored the miR-218-mediated promotion of cell migration. In conclusion, miR-218 was demonstrated to exert an inhibitory function and promoted cell migration via targeting PDGFRalpha during cardiomyocyte differentiation from ESCs. The current study revealed the role of miR-218 and may provide an important hint for cardiomyocyte differentiation of ESCs and induced pluripotent stem cells. PMID- 30246401 TI - Anatomic site and etiology of hemorrhage in small versus large dogs with spontaneous hemoperitoneum. AB - OBJECTIVE: To compare anatomic sources and underlying etiology of hemorrhage in small vs large dogs with spontaneous hemoperitoneum (SH). STUDY DESIGN: Retrospective cross-sectional study. ANIMALS: Client-owned dogs with SH at 2 academic institutions. METHODS: Medical records were reviewed for age, breed, sex, weight, and results of imaging, surgery, necropsy, cytology, and histopathology. Dogs were divided according to body weight (<= 20 kg = small, > 20 kg = large). Confidence intervals were calculated to estimate rates of splenic and hepatic hemorrhage in small and large dog SH populations. Multivariable regression was used to compare prevalence of anatomic sources of hemorrhage and etiology in small vs large dogs. RESULTS: We identified 742 dogs with SH, including 637 in which the anatomic site of hemorrhage was investigated. Splenic hemorrhage was diagnosed in 43.2% (95% CI, 34.3-52.4) of small dogs and 61.3% (95% CI, 57.0-65.6) of large dogs. Small dogs had lower prevalence of splenic hemorrhage (prevalence ratio, 0.70; 95% CI, 0.58-0.87; P < .001) and higher prevalence of hemorrhage from liver (prevalence ratio, 1.72; 95% CI, 1.20-2.47; P = .003) or from another location such as retroperitoneal mass, kidney, or adrenal (prevalence ratio, 2.73; 95% CI, 1.66-4.47; P < .001) vs large dogs. Hemangiosarcoma was associated with splenic hemorrhage and occurred more frequently in large vs small dogs (P = .011). CONCLUSION: Small dogs had a lower rate of splenic hemorrhage and higher rates of hemorrhage from liver and other sites compared to large dogs. Etiologies other than splenic hemangiosarcoma were common, particularly among dogs weighing <= 20 kg. CLINICAL SIGNIFICANCE: Clinicians should perform diagnostics and consider body size before making presumptive diagnoses in dogs with SH. PMID- 30246402 TI - Dichomitus squalens partially tailors its molecular responses to the composition of solid wood. AB - White-rot fungi, such as Dichomitus squalens, degrade all wood components and inhabit mixed-wood forests containing both soft- and hardwood species. In this study, we evaluated how D. squalens responded to the compositional differences in softwood [guaiacyl (G) lignin and higher mannan content] and hardwood [syringyl/guaiacyl (S/G) lignin and higher xylan content] using semi-natural solid cultures. Spruce (softwood) and birch (hardwood) sticks were degraded by D. squalens as measured by oxidation of the lignins using 2D-NMR. The fungal response as measured by transcriptomics, proteomics and enzyme activities showed a partial tailoring to wood composition. Mannanolytic transcripts and proteins were more abundant in spruce cultures, while a proportionally higher xylanolytic activity was detected in birch cultures. Both wood types induced manganese peroxidases to a much higher level than laccases, but higher transcript and protein levels of the manganese peroxidases were observed on the G-lignin rich spruce. Overall, the molecular responses demonstrated a stronger adaptation to the spruce rather than birch composition, possibly because D. squalens is mainly found degrading softwoods in nature, which supports the ability of the solid wood cultures to reflect the natural environment. PMID- 30246403 TI - Analysis of microbial communities in natural halite springs reveals a domain dependent relationship of species diversity to osmotic stress. AB - Microbial species diversity may peak at certain optimal environmental conditions and decrease toward more extreme conditions. Indeed, bell-shaped relationships of species diversity against pH and temperature have been demonstrated, but diversity patterns across other environmental conditions are less well reported. In this study, we investigated the impact of salinity on the diversity of microorganisms from all three domains in a large set of natural springs with salinities ranging from freshwater to halite saturated. Habitat salinity was found to be linearly and inversely related to diversity of all three domains. The relationship was strongest in the bacteria, where salinity explained up to 44% of the variation in different diversity metrics (OTUs, Shannon index, and Phylogenetic Diversity). However, the relationship was weaker for Eukarya and Archaea. The known salt-in strategist Archaea of the Halobacteriaceae even showed the opposite trend, with increasing diversity at higher salinity. We propose that high energetic requirements constrain species diversity at high salinity but that the diversity of taxa with energetically less expensive osmotolerance strategies is less affected. Declining diversity with increasing osmotic stress may be a general rule for microbes as well as plants and animals, but the strength of this relationship varies greatly across microbial taxa. PMID- 30246404 TI - Attributable Cost of Dementia: Demonstrating Pitfalls of Ignoring Multiple Health Care System Utilization. AB - OBJECTIVES: To determine dementia prevalence and costs attributable to dementia using Veterans Health Administration (VHA) data with and without Medicare data. DATA SOURCES: VHA inpatient, outpatient, purchased care and other data and Medicare enrollment, claims, and assessments in fiscal year (FY) 2013. STUDY DESIGN: Analyses were conducted with VHA data alone and with combined VHA and Medicare data. Dementia was identified from a VHA sanctioned list of ICD-9 diagnoses. Attributable cost of dementia was estimated using recycled predictions. DATA COLLECTION: Veterans age 65 and older who used VHA and were enrolled in Traditional Medicare in FY 2013 (1.9 million). PRINCIPAL FINDINGS: VHA records indicated the prevalence of dementia in FY 2013 was 4.8 percent while combined VHA and Medicare data indicated the prevalence was 7.4 percent. Attributable cost of dementia to VHA was, on average, $10,950 per veteran per year (pvpy) using VHA alone and $6,662 pvpy using combined VHA and Medicare data. Combined VHA and Medicare attributable cost of dementia was $11,285 pvpy. Utilization attributed to dementia using VHA data alone was lower for long-term institutionalization and higher for supportive care services than indicated in combined VHA and Medicare data. CONCLUSIONS: Better planning for clinical and cost-efficient care requires VHA and Medicare to share data for veterans with dementia and likely more generally. PMID- 30246405 TI - Anti-tumour effect of lapatinib in canine transitional cell carcinoma cell lines. AB - Transitional cell carcinoma (TCC) accounts for >90% of canine malignant tumours occurring in urinary bladder, and the prognosis is poor. Our previous study, using RNA sequencing, showed that human epidermal growth factor 2 (HER2) was the most activated upstream regulator related to carcinogenesis in canine TCC. The aim of this study was to examine the anti-tumour effect of lapatinib, a tyrosine kinase inhibitor of HER2, on canine TCC cell lines in vitro and in vivo. Five canine TCC cell lines (TCCUB, Love, Sora, LCTCC, and MCTCC) were used. Western blotting showed that HER2 protein expression was observed in all of the canine TCC cell lines. Lapatinib inhibited phosphorylation of HER2 and cell growth in a dose-dependent manner. Cell cycle analyses using flow cytometry showed that lapatinib significantly increased the sub-G1 and G0 /G1 phase fractions and significantly decreased the S and G2 /M phase fractions in the cell lines (Sora and TCCUB). For the in vivo experiments, the canine TCC cells (Sora) were subcutaneously injected into nude mice. Six days after inoculation, lapatinib (100 mg/kg) or vehicle was administered daily via intraperitoneal administration for 14 days. Tumour volume was significantly smaller in the lapatinib group compared with the vehicle control group. Histologically, lapatinib significantly increased necrotic areas in the tumour tissues. These findings suggest that lapatinib exerts anti-tumour effects on canine TCC cells by inhibiting HER2 signalling and inducing cell cycle arrest. PMID- 30246406 TI - A frameshift variant in the COL5A1 gene in a cat with Ehlers-Danlos syndrome. AB - Ehlers-Danlos syndrome (EDS) is a group of heritable connective tissue disorders caused by defective collagen synthesis or incorrect assembly of the collagen triple helical structure. EDS is characterised by joint hypermobility, skin hyperextensibility, abnormal scarring, poor wound healing and tissue friability. Human EDS may be caused by variants in several different genes including COL5A1, which encodes the collagen type V alpha 1 chain. For the present study we investigated a 1.5-year-old, spayed female, domestic shorthair cat with EDS. The affected cat showed multiple recurrent skin tears, hyperextensibility of the skin and joint abnormalities. We obtained whole genome sequencing data from the affected cat and searched for variants in candidate genes known to cause EDS. We detected a heterozygous single base-pair deletion in exon 43 of the COL5A1 gene, namely c.3420delG. The deletion was predicted to result in a frameshift and premature stop codon: p.(Leu1141SerfsTer134). Sanger sequencing confirmed that the variant was present in the affected cat and absent from 103 unaffected cats from different breeds. The variant was also absent from a Burmese cat with EDS. Based on knowledge about the functional impact of COL5A1 variants in other species, COL5A1:c.3420delG represents a compelling candidate causative variant for the observed EDS in the affected cat. PMID- 30246407 TI - Management of venous thromboembolism in patients with cancer. AB - Current guidelines for anticoagulant therapy do not so far suggest any form of differentiated approach to cancer patients with venous thromboembolism (VTE). This review article provides an overview of the published literature in cancer patients with VTE, mostly using data from the RIETE registry. Our findings provide some insights into what factors may be used to guide physicians in adapting recommended anticoagulant regimens to the individual patient, as oncologists are increasingly doing with cancer treatments. For instance, patients presenting with deep vein thrombosis (DVT) alone might benefit from curtailing treatment intensity as anticoagulant therapy progresses. The site of cancer also needs to be considered. In patients with incidental PE or splanchnic vein thrombosis, we should be more cautious before prescribing anticoagulant therapy. The optimal duration of anticoagulant therapy is unknown. PMID- 30246408 TI - The effect of reminiscence therapy on cognitive functions, depression, and quality of life in Alzheimer patients: Randomized controlled trial. AB - BACKGROUND: Alzheimer is a disease leading to various neuropsychiatric behavioral disorders, and the most common symptom observed during the prognosis of Alzheimer's disease is dysmnesia. The aim of the present study is to investigate the effect of reminiscence therapy on cognitive functions, depression, and quality of life in Alzheimer's patients. METHODS: The present study was a randomized controlled single blind study with two groups, which was designed in the experimental pretest-posttest pattern in the city of Konya, Turkey. It was decided to include a total of 60 elderly individuals. Information form that evaluated socio-demographic characteristics and disease history of individuals in intervention and control groups and was developed by the researcher. Standardized Mini-Mental State Examination (SMMSE), Cornell Scale for Depression in Dementia, and the Quality of Life in Alzheimer's Disease (QOL-AD) Scale were used to collect the data. Reminiscence therapy was applied once a week and lasted for 8 weeks. Every session took 60 minutes. Groups consisted of six people. RESULTS: Mini-Mental Test, depression, and quality of life mean scores of the elderly in intervention group before reminiscence therapy program increased after the administration, and the difference was statistically significant (P < 0.05). In the intergroup comparison, a significant difference was found between elderly individuals' posttest Mini-Mental Test, depression, and quality of life mean scores (P < 0.05). CONCLUSIONS: Our results suggest that regular reminiscence therapy should be considered for inclusion as routine care for the improvement of cognitive functions, depressive symptoms, and quality of life in elderly people with Alzheimer. PMID- 30246409 TI - Histological and micro-CT analysis of peri-implant soft and hard tissue healing on implants with different healing abutments configurations. AB - OBJECTIVE: The aim of this study was to assess the effect of different abutment configurations on peri-implant soft and hard tissue healing. MATERIALS AND METHODS: Two-piece dental implants, 3.5 mm in diameter and 8 mm in length, were placed in four beagle dogs. Two different transmucosal healing abutment configurations were randomly selected: one with a wide emergence profile (WE) (45 degrees angulation with implant long axis) and the other with a narrow emergence profile (NE) (15 degrees angulation with implant long axis). After four months of healing, the animals were sacrificed. Micro-CT scans were taken for mesio distal analysis; subsequently, the biopsies were prepared for bucco-lingual histometric analyses. Several measurements were taken using the following reference points: marginal mucosal level (MML), apical barrier epithelium (aBE), implant shoulder (IS), marginal bone crest (BC), and first bone-to-implant contact (fBIC). RESULTS: In the micro-CT analysis, the distance from IS-fBIC was 1.11 +/- 0.66 mm for WE and 0.12 +/- 0.21 mm for NE (p = 0.004). The IS-BC of WE was -0.54 +/- 0.80 mm, whereas NE presented 0.76 +/- 0.48 mm (p = 0.002). The histometric analysis showed that both groups presented comparable dimensions of peri-implant biologic width (p > 0.05). However, in the distance from IS to BC, the WE showed a mean distance of -0.66 +/- 0.78 mm while NE was 0.06 +/- 0.42 mm (p = 0.039); the IS to fBIC was 0.89 +/- 0.68 mm for WE while NE was 0.30 +/- 0.30 mm (p = 0.041). CONCLUSION: The design of the transmucosal component can influence the establishment of the peri-implant biologic width. The flat and wide emergence profile induced an apical displacement of the peri-implant biologic width and more bone loss. PMID- 30246410 TI - Neurocutaneous disorders. PMID- 30246411 TI - Raloxifene attenuates oxidative stress and preserves mitochondrial function in astrocytic cells upon glucose deprivation. AB - Oxidative stress and mitochondrial dysfunction induced by metabolic insults are both hallmarks of various neurological disorders, whereby neuronal cells are severely affected by decreased glucose supply to the brain. Likely injured, astrocytes are important for neuronal homeostasis and therapeutic strategies should be directed towards improving astrocytic functions to improve brain's outcome. In the present study, we aimed to assess the actions of raloxifene, a selective estrogen receptor modulator in astrocytic cells under glucose deprivation. Our findings indicated that pretreatment with 1 uM raloxifene results in an increase in cell viability and attenuated nuclei fragmentation. Raloxifene's actions also rely on the reduction of oxidative stress and preservation of mitochondrial function in glucose-deprived astrocytic cells, suggesting the possible direct effects of this compound on mitochondria. In conclusion, our results demonstrate that raloxifene's protective actions might be mediated in part by astrocytes in the setting of a metabolic insult. PMID- 30246412 TI - Benthic habitat selection in juvenile European eel Anguilla anguilla: implications for coastal habitat management and restoration. AB - The critically endangered European eel Anguilla anguilla is dependent on suitable habitat qualities over a vast geographic area. Even though a significant proportion of the population never enters fresh water, the preferred benthic habitat is largely unknown in the marine environment. Examining substratum selection in A. anguilla reveals that elvers prefer coarse gravel, suggesting that conservation efforts may benefit from targeting this type of substratum in marine coastal areas. PMID- 30246414 TI - Prokaryotic niche partitioning between suspended and sinking marine particles. AB - Suspended particles are major organic carbon substrates for heterotrophic microorganisms in the mesopelagic ocean (100-1000 m). Nonetheless, communities associated with these particles have been overlooked compared with sinking particles, the latter generally considered as main carbon transporters to the deep ocean. This study is the first to differentiate prokaryotic communities associated with suspended and sinking particles, collected with a marine snow catcher at four environmentally distinct stations in the Scotia Sea. Amplicon sequencing of 16S rRNA gene revealed distinct prokaryotic communities associated with the two particle-types in the mixed-layer (0-100 m) and upper-mesopelagic zone (mean dissimilarity 42.5% +/- 15.2%). Although common remineralising taxa were present within both particle-types, gammaproteobacterial Pseudomonadales and Vibrionales, and alphaproteobacterial Rhodobacterales were found enriched in sinking particles up to 32-fold, while Flavobacteriales (Bacteroidetes) favoured suspended particles. We propose that this niche-partitioning may be driven by organic matter properties found within both particle-types: K-strategists, specialised in the degradation of complex organic compounds, thrived on semi labile suspended particles, while generalists r-strategists were adapted to the transient labile organic contents of sinking particles. Differences between the two particle-associated communities were more pronounced in the mesopelagic than in the surface ocean, likely resulting from exchanges between particle-pools enabled by the stronger turbulence. PMID- 30246413 TI - Inhibition of silkworm vacuolar-type ATPase activity by its inhibitor Bafilomycin A1 induces caspase-dependent apoptosis in an embryonic cell line of silkworm. AB - Vacuolar-type ATPase (V-ATPase) is a type of hydrogen ion transporter located in the vesicular membrane-like system, which mediates active transport and intracellular acidification in various compartments. In mammals, V-ATPase has been reported to play a key role in cell proliferation and apoptosis. The studies of V-ATPase in silkworm mainly focus on the acidification regulation of midgut and silk gland and immune resistance. However, there are few reports about the function of silkworm V-ATPase on cell proliferation, autophagy, and apoptosis. Thus, the function of V-ATPase in a cell line of Bombyx mori (BmE) was investigated by treating the cell line with bafilomycin A1, a specific inhibitor of V-ATPase. Cell counting kit 8 (CCK8) and flow cytometry analysis showed that bafilomycin A1 treatment decreased the cell proliferation activity, affected the cell cycle progression and induced cell apoptosis. LysoTracker Red staining showed that the target of bafilomycin A1 is lysosome. The expression of all autophagy-related genes ( BmATG5, BmATG6, and BmATG8) decreased, indicating that cell autophagy was inhibited. The analysis of the apoptosis pathway demonstrated that inhibiting the activity of V-ATPase of BmE cells could promote mitochondria to release cytochrome C, inhibit the expression of BmIAP, and activate the caspase cascade to induce apoptosis. All these findings systematically illustrate the effects of V-ATPase on the proliferation, autophagy, and apoptosis in BmE cells, and provide new ideas and a theoretical basis for further study on the function of V-ATPase in BmE. PMID- 30246415 TI - Catalytic Enantio- and Diastereoselective Mannich Addition of TosMIC to Ketimines. AB - Chiral amines bearing a stereocenter in the alpha position are ubiquitous compounds with many applications in the pharmaceutical and agrochemical sectors, as well as in catalysis. Catalytic asymmetric Mannich additions represent a valuable method to access such compounds in enantioenriched form. This work reports the first enantio- and diastereoselective addition of commercially available p-toluenesulfonylmethyl isocyanide (TosMIC) to ketimines, affording 2 imidazolines bearing two contiguous stereocenters, one of which is fully substituted, with high yields and excellent stereocontrol. The reaction, catalyzed by silver oxide and a dihydroquinine-derived N,P-ligand, is broad in scope, operationally simple, and scalable. Derivatization of the products provides enantioenriched vicinal diamines, precursors to NHC ligands and sp3 rich heterocyclic scaffolds. Computations are used to understand catalysis and rationalize stereoselectivity. PMID- 30246416 TI - How to organise teaching activities for the scoring of cardiorespiratory polygraphies? Experiences from three Swedish Sleep Society teaching courses. AB - Education in the scoring of sleep-disordered breathing is organised differently and data on the evaluation of teaching strategies based on student ratings are sparse. The aim of the study was to analyse the gain in theoretical and practical knowledge achieved during different course settings offered by a national sleep society. The course contained 1 hr of theoretical teaching (scoring rules and recording methodology) and 2.5 hr of practical scoring (physiological breathing, obstructive/central sleep apnea and hypoventilation). Three different settings were provided: a large scoring group including participants with mixed experiences (1), a small scoring group with inexperienced scorers (2), and guided scoring for experienced scorers (3). Evaluation was performed at the end of the course. Data from 67 out of 82 participants (79%) were analysed (42 nurses/technicians and 25 physicians/dentists). Previous scoring experience was limited, moderate and extended in 25, 26, and 15 students, respectively. Gain of practical knowledge and overall course rating were significantly higher in settings 2 and 3 compared with 1 (p = 0.005 and p = 0.018 respectively). Guided scoring was the preferred practical teaching setting in experienced scorers, whereas scoring in large groups together with an experienced student was preferred in newcomers. Profession did not influence gain of knowledge, course satisfaction or preferred course design. From the student's perspective, consensus scoring in groups or guided scoring for all students may have advantages compared with single/small-group scoring settings. Technical teaching knowledge of faculty members is of significant importance. PMID- 30246417 TI - Design, Synthesis, and SAR Studies of Heteroarylpyrimidines and Heteroaryltriazines as CB2 R Ligands. AB - Herein we describe the design and synthesis of a new series of heteroarylpyrimidine/heteroaryltriazine derivatives on the basis of quinazoline 2,4(1H,3H)-diones as CB2 R-selective ligands using a bioisosterism strategy. An acetamide group was explored to displace the enamine linker of the lead compound for the purpose of stereoisomerism elimination and hydrophilicity increase. As a result, some of the synthesized compounds showed high bioactivity and selectivity for CB2 R in calcium mobilization assays, and four displayed CB2 R agonist activity, with EC50 values below 30 nm. The compound exhibiting the highest agonist activity toward CB2 R (EC50 =7.53+/-3.15 nm) had a selectivity over CB1 R of more than 1328-fold. Moreover, structure-activity relationship (SAR) studies indicated that the substituents on the nucleus play key roles in the functionality of a ligand, with one such example demonstrating CB2 R antagonist activity. Additionally, molecular docking simulations were conducted with the aim of better understanding of these new derivatives in relation to the structural requirements for agonists/antagonists binding to CB2 R. PMID- 30246418 TI - Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia. AB - Congenital hyperinsulinism is a rare disease, but is the most frequent cause of persistent and severe hypoglycaemia in early childhood. Hypoglycaemia caused by excessive and dysregulated insulin secretion (hyperinsulinism) from disordered pancreatic beta cells can often lead to irreversible brain damage with lifelong neurodisability. Although congenital hyperinsulinism has a genetic cause in a significant proportion (40%) of children, often being the result of mutations in the genes encoding the KATP channel (ABCC8 and KCNJ11), not all children have severe and persistent forms of the disease. In approximately half of those without a genetic mutation, hyperinsulinism may resolve, although timescales are unpredictable. From a histopathology perspective, congenital hyperinsulinism is broadly grouped into diffuse and focal forms, with surgical lesionectomy being the preferred choice of treatment in the latter. In contrast, in diffuse congenital hyperinsulinism, medical treatment is the best option if conservative management is safe and effective. In such cases, children receiving treatment with drugs, such as diazoxide and octreotide, should be monitored for side effects and for signs of reduction in disease severity. If hypoglycaemia is not safely managed by medical therapy, subtotal pancreatectomy may be required; however, persistent hypoglycaemia may continue after surgery and diabetes is an inevitable consequence in later life. It is important to recognize the negative cognitive impact of early-life hypoglycaemia which affects half of all children with congenital hyperinsulinism. Treatment options should be individualized to the child/young person with congenital hyperinsulinism, with full discussion regarding efficacy, side effects, outcomes and later life impact. PMID- 30246420 TI - The polarizing effects of group discussion in a negative normative context: Integrating societal-, group-, and individual-level factors. AB - In this research, we investigate how a negative (or hostile) norm regarding minorities at the societal level can fuel polarization between majority subgroups at the local level. We hypothesize that rapid social change in the form of polarization results from the interplay between small group processes and perceptions of society at large. By employing a novel analytic approach that uses variances to capture non-linear societal change, we were able to study polarization processes. In three studies among high school and university students (N = 347), we manipulated the majority norm about a minority category (positive vs. negative). Subsequently, participants read about a minority member's ambiguous behaviour and evaluated this target. All studies used a similar paradigm, but they varied in whether or not participants discussed the ambiguous behaviour within local groups. Results showed that the majority norm at the societal level affected perceptions of the minority member's behaviour when people discussed this behaviour in a local majority group but not when they reflected on it individually. Specifically, group discussions led to polarization between local groups within a broader social category, but only in the context of a negative majority norm. This effect was predicted by the a priori perception of the local group norm. Results are discussed in terms of the integration of society- and group-level processes when studying the development of intergroup attitudes and practical implications for the coarsening climate of the societal debate about current societal issues. PMID- 30246419 TI - Media violence exposure and aggression in adolescents: A risk and resilience perspective. AB - Media violence exposure (MVE) is associated with aggressive outcomes in adolescents. However, based on the differential susceptibility hypothesis, this risk is expected to vary based on the individual's unique risk and protective factors. Using survey data from 1,990 adolescents (Mean age = 15.6 +/- 1.10 years; 48% female) and content analysis of U.S. top-grossing films and popular TV shows, we evaluated the effect of MVE in relation to both risk (i.e., family conflict, impulsivity, sensation seeking) and protective factors (i.e., parental monitoring, parental involvement, parental mediation). Relative weights analyses revealed that MVE was one of the strongest predictors of aggression, after impulsivity and family conflict. The cumulative risk score showed a linear and quadratic relation with the likelihood of aggression, with MVE and family conflict having an interactive relation in predicting aggression. Parental monitoring remained a significant protective factor even when all risk factors were accounted for. Targeted preventive interventions that reduce family conflict, promote parental monitoring, and reduce exposure to violent media may be effective in reducing aggressive tendencies and related negative outcomes. PMID- 30246421 TI - An Iron-Based Long-Lived Catalyst for Direct C-H Arylation of Arenes and Heteroarenes. AB - Direct C-H arylation of arenes and heteroarenes to biaryls at ambient temperature has been accomplished using a phenalenyl-supported iron(III) catalyst. The present catalyst requires a chemical reductant such as potassium and functions without any light stimulation. C-H arylation of various heteroarenes including pyridine as well as unactivated arene such as benzene delivered good to excellent yield (28 examples, up to 92 %) at room temperature. A combined effort based on experiments and theoretical calculations established that a phenalenyl-based radical species (generated by chemical reduction of the iron(III) coordinated phenalenyl complex) plays key role during the catalysis. Furthermore, this catalyst displayed remarkable stability during the catalysis, as evident from the fact that it was still usable over ten consecutive catalytic runs without losing its catalytic efficiency. PMID- 30246422 TI - Derivation and measurement consistency of a novel biofluid dynamics measure of deglutitive bolus-driving function-pharyngeal swallowing power. AB - BACKGROUND: The primary function of the pharyngeal swallowing mechanism is to drive ingested materials into the esophagus. Currently, a definitive measure of pharyngeal bolus-driving function that accounts for bolus movement remains lacking. The primary objectives of this study were to describe the derivation of a novel biofluid dynamics measure of deglutition-that is, pharyngeal swallowing power (PSP)-and to demonstrate the consistency of PSP in normal swallowing. METHODS: The pharyngeal swallowing mechanism was conceptualized as a hydraulic power system with the upper esophageal sphincter (UES) as a conduit. PSP was calculated as the product of bolus pressure and flow across the UES. Thirty-four young healthy subjects swallowed materials consisting of two bolus volumes (10, 20 mL) and four bolus viscosities (thin liquid, nectar-thick liquid, honey-thick liquid, pudding). High-resolution impedance manometry was used for data collection. The consistency of PSP across specific bolus conditions was evaluated using standardized Cronbach's coefficient alpha. KEY RESULTS: Standardized Cronbach's coefficient alphas in specific bolus conditions ranged between 0.85 and 0.93. Fisher weighted mean Cronbach's coefficient alphas for swallow trials across bolus volumes and across bolus viscosities ranged from 0.86 to 0.90. Fisher weighted mean Cronbach's coefficient alpha for overall consistency of PSP across all swallow trials was 0.88. CONCLUSIONS AND INFERENCES: PSP estimates the output power of the pharyngeal bolus-driving mechanism during deglutition. PSP's high consistency indicates that it can be a useful biofluid dynamics measure of pharyngeal bolus-driving function. Current results also demonstrate that consistency in pharyngeal bolus propulsion is an important physiological target for the pharyngeal swallowing mechanism. PMID- 30246423 TI - Role of Helicobacter pylori infection in cancer-associated fibroblast-induced epithelial-mesenchymal transition in vitro. AB - BACKGROUND: Major human gastrointestinal pathogen Helicobacter pylori (H. pylori) colonizes the gastric mucosa causing inflammation and severe complications including cancer, but the involvement of fibroblasts in the pathogenesis of these disorders in H. pylori-infected stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts. Their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue; however, the interaction between H. pylori and fibroblasts remains unknown. We determined the effect of coincubation of normal rat gastric fibroblasts with alive H. pylori (cagA+vacA+) and H. pylori (cagA-vacA-) strains on the differentiation of these fibroblasts into cells possessing characteristics of cancer-associated fibroblasts (CAFs) able to induce epithelial-mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM-1). MATERIALS AND METHODS: The panel of CAFs markers mRNA was analyzed in H. pylori (cagA+vacA+) infected fibroblasts by RT-PCR. After insert coculture of differentiated fibroblasts with RGM-1 cells from 24 up to 48, 72, and 96 hours, the mRNA expression for EMT-associated genes was analyzed by RT-PCR. RESULTS: The mRNA expression for CAFs markers was significantly increased after 72 hours of infection with H. pylori (cagA+vacA+) but not H. pylori (cagA-vacA-) strain. Following coculture with CAFs, RGM-1 cells showed significant decrease in E cadherin mRNA, and the parallel increase in the expression of Twist and Snail transcription factors mRNA was observed along with the overexpression of mRNAs for TGFbetaR, HGFR, FGFR, N-cadherin, vimentin, alpha-SMA, VEGF, and integrin beta1. CONCLUSION: Helicobacter pylori (cagA+vacA+) strain induces differentiation of normal fibroblasts into CAFs, likely to initiate the EMT process in RGM-1 epithelial cell line. PMID- 30246424 TI - Alpha- and beta-mannan utilization by marine Bacteroidetes. AB - Marine microscopic algae carry out about half of the global carbon dioxide fixation into organic matter. They provide organic substrates for marine microbes such as members of the Bacteroidetes that degrade algal polysaccharides using carbohydrate-active enzymes (CAZymes). In Bacteroidetes genomes CAZyme encoding genes are mostly grouped in distinct regions termed polysaccharide utilization loci (PULs). While some studies have shown involvement of PULs in the degradation of algal polysaccharides, the specific substrates are for the most part still unknown. We investigated four marine Bacteroidetes isolated from the southern North Sea that harbour putative mannan-specific PULs. These PULs are similarly organized as PULs in human gut Bacteroides that digest alpha- and beta-mannans from yeasts and plants respectively. Using proteomics and defined growth experiments with polysaccharides as sole carbon sources we could show that the investigated marine Bacteroidetes express the predicted functional proteins required for alpha- and beta-mannan degradation. Our data suggest that algal mannans play an as yet unknown important role in the marine carbon cycle, and that biochemical principles established for gut or terrestrial microbes also apply to marine bacteria, even though their PULs are evolutionarily distant. PMID- 30246425 TI - Parental care and sibling competition independently increase phenotypic variation among burying beetle siblings. AB - Several recent hypotheses suggest that parental care can influence the extent of phenotypic variation within populations; however, there have been few tests of these ideas. We exploited the facultative nature of posthatching parental care in the burying beetle, Nicrophorus vespilloides, to test whether parental care influences the expression of phenotypic variation in an important fitness trait (body size). We found that parental care and brood size (which influences sibling competition) had positive and independent effects on variation in body size. First, the mean coefficient of variation (CV) of body size was significantly greater in broods that received care than in those that did not. Second, CV body size increased with brood size in both parental care treatments. These results are not consistent with predictions from recent hypotheses that predict parental care will reduce phenotypic variation among siblings. The positive effects of parental care and brood size on phenotypic variation that we observed are likely due to sibling competition for access to provisioning parents and competition for limiting resources contained in the breeding carcass. Our results suggest that future theory linking parental care to the generation and maintenance of phenotypic variation must integrate the nature of interactions among family members. PMID- 30246426 TI - Differences in relationships of maternal and paternal age at childbirth with body fat distribution in offspring. AB - OBJECTIVES: Although delayed parenthood has been linked to various adverse health outcomes in offspring, little attention has been given to the relationship between an increased parental age at childbirth and fat distribution in offspring. We aimed to determine the relationship between parental age at childbirth and body fat partitioning in Chinese children. METHODS: A total of 463 children (mean age, 8 years; 43% female) were recruited. Dual-energy X-ray absorptiometry was used to determine the fat mass (FM) and percentage of fat mass (%FM) in various areas of the body. Weight and height were measured. The body mass index (BMI) and fat mass index (FMI) were calculated. A questionnaire was used to collect information about parental variables and other confounders. RESULTS: Multiple linear regression analyses suggested that for each additional year of maternal age at delivery, the BMI, FMI, and FM at whole-body, trunk, android, gynoid, and appendicular region increased by 0.115 kg/m2 , 0.076 kg/m2 ; 128.4 g, 57.71 g, 10.96 g, 25.07 g, and 67.88 g, respectively, after adjusting for covariates (P = .002-.017). In the analysis of covariance, children of mothers aged >=31 years exhibited higher BMI, FMI, total-body and segmental FM, compared to those of mothers aged <=25 years (P-trend = 0.002-0.017). Similar tendencies were also observed for the %FM (P-trend = 0.002-0.017). However, there was no significant relationship between paternal age at childbirth and any of the body fat measures in children. CONCLUSIONS: An increasing maternal age at childbirth was associated with increased body fat accumulation in offspring, whereas paternal age at childbirth appeared to have no such association. PMID- 30246428 TI - Dynamics changes in the transcription factors during early human embryonic development. AB - Development of an embryo from a single cell, zygote, to multicellular morulae requires activation of hundreds of genes that were mostly inactivated before fertilization. Inevitably, transcription factors (TFs) would be involved in modulating the drastic changes in gene expression pattern observed at all preimplantation stages. Despite many ongoing efforts to uncover the role of TFs at the early stages of embryogenesis, still many unanswered questions remained that need to be explored. This could be done by studying the expression pattern of multiple genes obtained by high-throughput techniques. In the current study, we have identified a set of TFs that are involved in the progression of the zygote to blastocyst. Global gene expression patterns of consecutive stages were compared and differences documented. Expectedly, at the early stages of development, only a few sets of TFs differentially expressed while at the later stages hundreds of TFs appear to be upregulated. Interestingly, the expression levels of many TFs show an oscillation pattern during development indicating a need for their precise expression. A significant shift in gene expression was observed during the transition from four- to eight-cell stages, an indication of zygote genome activation. Additionally, we have found 11 TFs that were common in all stages including ATF3, EN1, IFI16, IKZF3, KLF3, NPAS3, NR2F2, RUNX1, SOX2, ZBTB20, and ZSCAN4. However, their expression patterns did not follow similar trends in the steps studied. Besides, our findings showed that both upregulation and active downregulation of the TFs expression is required for successful embryogenesis. Furthermore, our detailed network analysis identified the hub TFs for each transition. We found that HNF4A, FOXA2, and EP300 are the three most important elements for the first division of zygote. PMID- 30246429 TI - Metastasis suppressor protein 1 regulated by PTEN suppresses invasion, migration, and EMT of gastric carcinoma by inactivating PI3K/AKT signaling. AB - Epithelial-mesenchymal transition (EMT) is a crucial event for cancer progression and metastasis. Metastasis suppressor protein 1 (MTSS1) is a metastasis suppressor in several cancers. In this study, we elucidated the potential physiological function of MTSS1 in the invasion and migration of gastric cancer (GC), and its distinct role in EMT and subsequently determined the potential molecular mechanism. We observed that MTSS1 expression was downregulated in GC tissues and several GC cell lines (SGC-7901, MGC-803, MKN-28, MKN-45, and BGC 823). Importantly, forced expression of MTSS1 drastically diminished the cell viability in both SGC-7901 and MKN-45 cells. Moreover, overexpression of MTSS1 attenuated the invasion ability of these two cell lines. In addition to the invasive capability, introduction of MTSS1 led to a loss of migratory potential. Furthermore, augmentation of MTSS1 exhibited the typical EMT phenotype switch, accompanied by enhanced the expression of vimentin and N-cadherin and reduced E cadherin expression. Interestingly, MTSS1 also repressed transforming growth factor beta 1 (TGF-beta1)-induced EMT. Our mechanistic investigations revealed that MTSS1 was positively regulated by the phosphatase and tensin homolog (PTEN), and it functioned as a tumor suppressor, possibly by inactivating the phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene (AKT) pathway in GC cells. Collectively, our data provide insight into an important role for MTSS1 in suppressing tumor cell invasion, migration and EMT, which indicates that MTSS1 may act as a prospective prognostic biological marker and a promising therapeutic target for GC. PMID- 30246430 TI - Resilience, health perceptions, (QOL), stressors, and hospital admissions Observations from the real world of clinical care of unstable health journeys in Monash Watch (MW), Victoria, Australia. AB - RATIONALE, AIMS, AND OBJECTIVES: Monash Watch (MW) aims to reduce potentially preventable hospitalisations in a cohort above a risk "threshold" identified by Health Links Chronic Care (HLCC) algorithms using personal, diagnostic, and service data. MW conducted regular patient monitoring through outbound phone calls using the Patient Journey Record System (PaJR). PaJR alerts are intended to act as a self-reported barometer of stressors, resilience, and health perceptions with more alerts per call indicating greater risk. AIMS: To describe predictors of PaJR alerts (self-reported from outbound phone calls) and predictors of acute admissions based upon a Theoretical Model for Static and Dynamic Indicators of Acute Admissions. METHODS: Participants: HLCC cohort with predicted 3+ admissions/year in MW service arm for >40 days; n = 244. Baseline measures Clinical Frailty Index (CFI); Connor Davis Resilience (CD-RISC): SF-12v2 Health Survey scores Mental (MSC) and Physical (PSC) and ICECAP-O. Dynamic measures: PaJR alerts/call in 10 869 MW records. Acute (non-surgical) admissions from Victorian Admitted Episode database. ANALYSIS: Logistic regression, correlations, and timeseries homogeneity metrics using XLSTAT. FINDINGS: Baseline indicators were significantly correlated except SF-12_MCS. SF12-MSC, SF12-PSC and ICECAP-O best predicted PaJR alerts/call (ROC: 0.84). CFI best predicted acute admissions (ROC: 0.66), adding CD-RISC, SF-12_MCS, SF-12_PCS and ICECAP-O with two-way interactions improved model (ROC: 0.70). PaJR alerts were higher <=10 days preceding acute admissions and significantly correlated with admissions. Patterns in PaJR alerts in four case studies demonstrated dynamic variations signifying risk. Overall, all baseline indicators were explanatory supporting the theoretical model. Timing of PaJR alerts and acute admissions reflecting changing stressors, resilience, and health perceptions were not predicted from baseline indicators but provided a trigger for service interventions. CONCLUSION: Both static and dynamic indicators representing stressors, resilience, and health perceptions have the potential to inform threshold models of admission risk in ways that could be clinically useful. PMID- 30246432 TI - The cutaneous manifestations of tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is a genetic multisystem disease with variable manifestations that can prominently involve the skin. The diagnosis of this disorder has evolved over the past two centuries. The 2012 TSC criteria emphasizes the importance of dermatological findings; orocutaneous manifestations account for 4 of 11 major criterion and 3 of 6 minor criterion. A detailed clinical dermatological evaluation is recommended for both pediatric and adult patients undergoing initial evaluation for TSC. Comprehensive dermatologic evaluation is extremely helpful when assessing these lesions and constructing a differential diagnosis. PMID- 30246431 TI - Facial trauma reconstruction with polymethyl methacrylate-A case report. AB - BACKGROUND: Polymethyl methacrylate (PMMA) is a dermatologic filler commonly used in esthetic procedures. However, it can also be used in more severe cases such as reconstruction of facial traumas. AIMS: The aim of this report was to describe the use of PMMA in a nasal reconstruction of a patient victim of an automobilist accident which presented previous rejection of autograft. PATIENT: A young female patient, 26 y, victim of automobilist accident, with no bone support due to trauma both in the mandibulum and maxilla, presented fracture of several facial bones. Presented rejection of a bone autograft from the skullcap implanted on the nose. In order to harmonize the facial aspect, a nasal fill with PMMA for the anatomic reconstruction of the nose was performed. RESULTS AND CONCLUSIONS: PMMA promoted the recovery of facial and nasal esthetic characteristics of the patient ensuring a satisfactory result. PMID- 30246433 TI - Resource use and its association to cognitive impairment, ADL functions, and behavior in residents of Swedish nursing homes: Results from the U-Age program (SWENIS study). AB - OBJECTIVES: We aimed to investigate resource use and its association to cognitive impairment, activities of daily living, and neuropsychiatric symptoms in residents of Swedish nursing homes. METHODS: Data were collected in 2014 from a Swedish national sample of nursing home residents (n = 4831) and were collected by staff in the facility. The sample consists of all nursing homes in 35 of 60 randomly selected Swedish municipalities. Demographic data and data on resource use, cognitive and physical function as well as neuropsychiatric symptoms were collected through proxies. Descriptive statistics and regression modeling were used to investigate this association. RESULTS: We found that cognitive impairment, activities of daily living, and neuropsychiatric symptoms were associated with 23 hours per week increase in total resource use versus cognitively intact persons. This was also the case for being dependent in activities of daily living. Being totally dependent increased the amount of resource use by 25 hours per week. The sex of a resident did not influence the resource use. Annual costs of resource use with no functional dependency were 359 685 SEK, and in severely cognitive impaired resident, the cost was 825 081 SEK. CONCLUSION: Being cognitively impaired as well as functionally dependent increases the resource use significantly in nursing homes. This has implications for differentiation of costs in institutional settings in health economic evaluations. PMID- 30246435 TI - Autophagy participates in cyst breakdown and primordial folliculogenesis by reducing reactive oxygen species levels in perinatal mouse ovaries. AB - The reserve of primordial follicles, which serves all oocytes for the female reproductive lifespan, is established a few days after birth in mice. During this process, more than half of the oocytes are primarily eliminated by apoptosis. Autophagy, the conserved intracellular process maintaining cellular homeostasis, serves as a protective mechanism for oocyte survival. In the current study, we speculate a new role for autophagy during primordial folliculogenesis. Active autophagy was observed in perinatal ovaries from 16.5 days post coitus to 3 days post parturition. The inhibition of autophagy by 3-methyladenine (3-MA) increased the number of cyst oocytes and delayed follicle formation in vivo and in organ cultures. Furthermore, the reactive oxygen species (ROS) level was elevated in ovaries treated with 3-MA, while N-acetylcysteine, an oxidant, alleviated the inhibitory effect of 3-MA on primordial folliculogenesis. Additionally, the expression of growth differentiation factor 9 and transforming growth factor beta1, which regulates follicle activation, was decreased after 3-MA treatment. These data suggest that the physiological level of autophagy in perinatal ovaries regulates germ cell cyst breakdown and primordial follicle assembly by ROS clearance and exerts extensive effects on further follicular development. PMID- 30246436 TI - False image of intracarotideal air after a suicide attempt. PMID- 30246434 TI - Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features. AB - Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo-rosettes, small to medium-sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot-like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1 MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1-11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow up, 4.84 years). In this to date, largest series of ependymomas with YAP1-MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings. PMID- 30246437 TI - Early childcare enrollment and childhood wheezing phenotypes. AB - The "hygiene hypothesis" proposes that microbial exposures in early life - such as a farming lifestyle, early childcare attendance, older siblings and pet ownership protect against atopy by maintaining a balanced Th1/Th2 immune cytokine milieu.1-3 The newly described "biodiversity hypothesis" or "old friends" hypothesis further suggests that co-evolved trans-generationally transmitted commensal microbiota played important immunoregulatory roles, which have now been diminished due to loss of biodiversity in modern urbanized environments. This article is protected by copyright. All rights reserved. PMID- 30246438 TI - The effect of hypoglycaemia on neurocognitive outcome in children and adolescents with transient or persistent congenital hyperinsulinism. AB - AIM: To examine the hypoglycaemic effect on neurodevelopmental outcome in patients with transient and persistent congenital hyperinsulinism (CHI) born in the 21st century. METHOD: A cohort of 117 patients (66 males, 51 females) with CHI aged 5 to 16 years (mean age 8y 11mo, SD 2y 7mo) were selected from a Finnish nationwide registry to examine all the patients with similar methods. Neurodevelopment was first evaluated retrospectively. The 83 patients with no risk factors for neurological impairment other than hypoglycaemia were recruited and 44 participated (24 males, 20 females; mean age 9y 7mo, SD 3y 1mo) in neuropsychological assessment with the Wechsler Intelligence Scale for Children, Fourth Edition and the Finnish version of the Developmental Neuropsychological Assessment, Second Edition domains of attention, language, memory, sensorimotor, and visual functioning. RESULTS: In retrospective analysis, transient and persistent CHI groups had similar prevalences of mild (22% and 18% respectively) or severe (5% and 7% respectively) neurodevelopmental difficulties. In clinical assessment, the neurocognitive profile was within the average range in both groups, but children with persistent CHI showed significant but restricted deficits in attention, memory, visual, and sensorimotor functions compared with the general population. The transient CHI group did not differ from the standardization samples. INTERPRETATION: Besides the more apparent broader neurological deficits, children with persistent CHI have an increased risk for milder specific neurocognitive problems, which should be considered in the follow up. WHAT THIS PAPER ADDS: Children with persistent congenital hyperinsulinism showed deficits in attention, memory, visual, and sensorimotor functions. The deficits were potentially of hypoglycaemic origin. Children with transient hyperinsulinism did not differ from the general population. PMID- 30246440 TI - Stress-strain analysis of duodenal contractility in response to flow and ramp distension in rabbits fed low-fiber diet. AB - BACKGROUND: Previously we demonstrated that low-fiber diet in rabbits affects the passive mechanomorphological properties in the small intestine, resulting in reduced intestinal wall thickness and collagen content, as well as intestinal wall softening. The aim of the present study was to evaluate the contractility in rabbits on long-term low-fiber diet and specifically to compare the contraction threshold, the frequency, and the amplitude of flow-induced and distension induced contractions in the duodenum between rabbits on normal diet and on long term low-fiber diet. METHODS: Ten rabbits were fed a low-fiber diet for 5 months (Intervention group), and five rabbits were fed normal diet (Control group). The duodenal segments were used for determination of mechanical parameters for analyses of contractility. The duodenal experiments were carried out in organ baths containing physiological Krebs solution. Pressure and diameter changes induced by contractions in response to flow and ramp distension were measured. The frequencies and amplitude of contractions were analyzed. Distension-induced contraction thresholds and maximum contraction amplitude of flow-induced contractions were calculated in terms of mechanical stress and strain. Multiple linear regression analyses were applied to study dependencies between contractility parameters and wall thickness, wall area, and muscle layer thickness. KEY RESULTS: During distension, the pressure, stress, and strain thresholds for induction of phasic contraction were biggest in the Intervention Group (P < 0.05). In addition, the contraction frequencies during flow-induced contraction were highest in the Intervention Group (P < 0.05), whereas the maximum contraction amplitudes in terms of pressure, diameter, stress, and strain were lowest in the Intervention Group (P < 0.05). The contraction thresholds and contraction frequencies were negatively associated with the wall thickness, wall area, and muscle layer thickness, whereas maximum contraction amplitudes were positively associated with the wall thickness, wall area, and muscle layer thickness. CONCLUSIONS AND INFERENCES: Duodenal contractility in rabbits fed with long-term low-fiber diet exhibited low contraction amplitudes and high contraction thresholds and frequencies. The changes were associated with the low fiber diet-induced histomorphological remodeling. Studies on detailed structural and functional diet-induced changes in smooth muscle and intestinal nerves are needed for better understanding the remodeling mechanisms. PMID- 30246439 TI - Recombinant Newcastle disease virus expressing human IFN-lambda1 (rL-hIFN lambda1)-induced apoptosis of A549 cells is connected to endoplasmic reticulum stress pathways. AB - BACKGROUND: IFN-lambdas are a kind of cytokine with anti-tumor, immunomodulatory, and anti-proliferative activity. Recent studies have shown that the recombinant Newcastle disease virus expresses human IFN-lambda1 (rL-hIFN-lambda1), which plays a role in gastric cancer cell apoptosis. Endoplasmic reticulum stress (ERS) induces autophagy and apoptosis in tumor cells. In this study, we explored the relationship between ERS and rL-hIFN-lambda1-induced apoptosis of lung adenocarcinoma A549 cells and its underlying mechanism. METHODS: First, we investigated the effect of rL-hIFN-lambda1 on cellular proliferation, migration, and proteins associated with ERS, autophagy, and apoptosis of A549. Second, after administration of the ERS inhibitor, the associated proteins induced by rL-hIFN lambda1 were detected. Finally, a subcutaneous mouse model was used to examine the effect of rL-hIFN-lambda1 on tumor growth and the ERS and apoptosis associated proteins in tumor tissues. RESULTS: The results showed that the proliferation and migration of A549 cells, and tumor tissue growth were significantly inhibited and the ERS, autophagy, and apoptosis associated proteins were upregulated in the experimental group. Additionally, both 4-PBA and knockdown of PERK or CHOP reduced the levels of rL-hIFN-lambda1-induced autophagy and apoptosis-associated proteins. BCL-2 knockdown caused autophagy and apoptosis associated protein upregulation. CONCLUSIONS: In summary, rL-hIFN-lambda1 inhibited cell proliferation and activated ERS, autophagy, and apoptosis in A549 cells and tissues, and when ERS pathways were blocked, the inhibiting effect was even more pronounced. Therefore, the recombinant Newcastle disease virus rL-hIFN lambda1-induced apoptosis of A549 cells is connected to ER stress and could be a promising therapeutic agent for lung adenocarcinoma. PMID- 30246442 TI - Contralateral delay activity tracks the storage of visually presented letters and words. AB - Electrophysiological studies have demonstrated that the maintenance of items in visual working memory (VWM) is indexed by the contralateral delay activity (CDA), which increases in amplitude as the number of objects to remember increases, plateauing at VWM capacity. Previous work has primarily utilized simple visual items, such as colored squares or picture stimuli. Despite the frequent use of verbal stimuli in seminal investigations of visual attention and memory, it is unknown whether temporary storage of letters and words also elicit a typical load sensitive CDA. Given their close associations with language and phonological codes, it is possible that participants store these stimuli phonologically, and not visually. Participants completed a standard visual change-detection task while their ERPs were recorded. Experiment 1 compared the CDA elicited by colored squares compared to uppercase consonants, and Experiment 2 compared the CDA elicited by words compared to colored bars. Behavioral accuracy of change detection decreased with increasing set size for colored squares, letters, and words. We found that a capacity-limited CDA was present for colored squares, letters, and word arrays, suggesting that the visual codes for letters and words were maintained in VWM, despite the potential for transfer to verbal working memory. These results suggest that, despite their verbal associations, letters and words elicit the electrophysiological marker of VWM encoding and storage. PMID- 30246441 TI - Oestradiol and leptin have separate but additive anorexigenic effects and differentially target fat mass in rats. AB - We recently showed that male rats exhibit lower hypophagia and body weight loss compared to female rats following central leptin delivery, suggesting a role for oestradiol in leptin responsiveness. Accordingly, we delivered Ob (leptin) or GFP (control) gene into the brain of male rats that were simultaneously treated with oestradiol or vehicle. In a reciprocal approach, we compared oestradiol-deficient (OVX) with intact females (sham) that received leptin or control vector. Changes in food intake), body weight and body composition were examined. In males, oestradiol and leptin resulted in lower cumulative food intake (15%) and endpoint body weight (5%), although rats receiving dual treatment (oestradiol-leptin) ate 28% less and weighed 22% less than vehicle-control. Changes in food intake were unique to each treatment, with a rapid decrease in vehicle-leptin followed by gradual renormalisation. By contrast, hypophagia in oestradiol-control was of lower amplitude and sporadic. Leptin selectively targeted fat mass and endpoint abdominal fat mass was 65%-80% lower compared to their respective control groups. In females, both leptin groups had lower body weight (endpoint values 20% lower than control groups) with the highest extent in sham animals (endpoint value was 28% less in sham-leptin than in sham-control). OVX rats rapidly started regaining their lost body weight reminiscent of the pattern in males. Leptin rapidly and robustly reduced fat mass with endpoint values 30%-35% less than control treated animals. It appears that leptin and oestradiol decreased food intake and body weight via different mechanisms, with the pattern of oestradiol-leptin being reminiscent of that observed in females and the pattern of OVX-leptin reminiscent of that observed in males. Oestrogen status did not influence initial fat mass loss by leptin. It can be concluded that oestradiol modulates the long-term response to central leptin overexpression, although its actions on energy homeostasis are additive and independent of those of leptin. PMID- 30246443 TI - Context dependency of animal resource subsidies. AB - The transport of resource subsidies by animals has been documented across a range of species and ecosystems. Although many of these studies have shown that animal resource subsidies can have significant effects on nutrient cycling, ecosystem productivity, and food-web structure, there is a great deal of variability in the occurrence and strength of these effects. Here we propose a conceptual framework for understanding the context dependency of animal resource subsidies, and for developing and testing predictions about the effects of animal subsidies over space and time. We propose a general framework, in which abiotic characteristics and animal vector characteristics from the donor ecosystem interact to determine the quantity, quality, timing, and duration (QQTD) of an animal input. The animal input is translated through the lens of recipient ecosystem characteristics, which include both abiotic and consumer characteristics, to yield the QQTD of the subsidy. The translated subsidy influences recipient ecosystem dynamics through effects on both trophic structure and ecosystem function, which may both influence the recipient ecosystem's response to further inputs and feed back to influence the donor ecosystem. We present a review of research on animal resource subsidies across ecosystem boundaries, placed within the context of this framework, and we discuss how the QQTD of resource subsidies can influence trophic structure and ecosystem function in recipient ecosystems. We explore the importance of understanding context dependency of animal resource subsidies in increasingly altered ecosystems, in which the characteristics of both animal vectors and donor and recipient ecosystems may be changing rapidly. Finally, we make recommendations for future research on animal resource subsidies, and resource subsidies in general, that will increase our understanding and predictive capacity about their ecosystem effects. PMID- 30246445 TI - Morphological and molecular responses in ovaries of Mytilus galloprovincialis collected in two different sites of the Naples Bay. AB - Mytilus galloprovincialis female specimens were collected from two mussel farms located in two sites next to Castel dell'Ovo, a historical complex located in the Naples Bay. Such sites were named, respectively, A-area and B-area for the different microbiological parameters so that mussels from A-area can be sold without purification, whereas mussels from B-area must be purified before sale. The mussels were collected during the nonreproductive (summer 2009) and reproductive periods (autumn 2009). Gonadosomatic index, structural organization of the ovary, presence of apoptosis, estrogen receptors expression, as well as the bisphenol A (BPA) content in the ovaries, were evaluated. Ovaries from specimens collected in area B showed a different and significant distribution of the investigated biomarkers as well as of BPA content in respect to those measured in the A-area specimens, confirming that mussels are valid sentinel organisms to biomonitor in the Naples bay too. PMID- 30246446 TI - PCSK9: A novel inflammation modulator in atherosclerosis? AB - Proprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the secretory serine protease family. It binds to low-density lipoprotein receptor (LDLR) for endocytosis and lysosome degradation in the liver, resulting in an increasing in circulating LDL-cholesterol (LDL-c) level. Since a PCSK9 induced increase in plasma LDL-c contributes to atherosclerosis, PCSK9 inhibition has become a new strategy in preventing and treating atherosclerosis. However, in addition to the effect of PCSK9 on elevating blood LDL-c levels, accumulating evidence shows that PCSK9 plays an important role in inflammation, likely representing another major mechanism for PCSK9 to promote atherosclerosis. In this review, we discuss the association of PCSK9 and inflammation, and highlight the specific effects of PCSK9 on different vascular cellular components involved in the atherosclerotic inflammation. We also discuss the clinical evidence for the association between PCSK9 and inflammation in atherosclerotic cardiovascular disease. A better understanding of the direct association of PCSK9 with atherosclerotic inflammation might help establish a new role for PCSK9 in vascular biology and identify a novel molecular mechanism for PCSK9 therapy. PMID- 30246444 TI - Differences of Mohs micrographic surgery in basal cell carcinoma versus squamous cell carcinoma. AB - BACKGROUND: The two main tumors treated with Mohs micrographic surgery (MMS) are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). There are no studies analyzing whether MMS is different when treating these two types of tumors. OBJECTIVE: We aim to compare the characteristics of the patients, the tumors, and MMS, and first-year follow-up of MMS in BCC and SCC. METHODS: REGESMOHS is a prospective cohort study of patients treated with MMS. The participating centers are 19 Spanish hospitals where at least one MMS is performed per week. Data on characteristics of the patients, tumors, and surgery were recorded. The follow-up was done with two visits: the first visit within 1 month after surgery and the second one within the first year. RESULTS: From July 2013 to April 2017, a total of 2,669 patients who underwent MMS were included in the registry. Of them, 2,448 (93%) were diagnosed with BCC, and 181 (7%) were diagnosed with SCC. Patients with SCC were older than those with BCC (median age 73 years vs. 68 years) and presented immunosuppression more frequently. The tumor size was significantly larger in the SCC group. Regarding surgery, deeper invasion was more frequent in SCC, resulting in larger defects. Despite this, SCC did not require more stages to get clear margins or more time in the operating room. Incomplete Mohs was more frequent in the SCC group (6%) than in the BCC group (2%). The incidence of perioperative complications was higher when treating SCC. There were more relapses in the first-year follow-up in the SCC group. CONCLUSION: There are significant differences when comparing MMS in BCC and SCC. Knowledge of these differences can help to prepare the patient and plan the surgery, optimizing results. PMID- 30246448 TI - Delirium detection by a novel bispectral electroencephalography device in general hospital. AB - AIM: Delirium is common and dangerous among elderly inpatients; yet, it is underdiagnosed and thus undertreated. This study aimed to test the diagnostic characteristics of a noninvasive point-of-care device with two-channel (bispectral) electroencephalography (EEG) for the screening of delirium in the hospital. METHODS: Patients admitted to the University of Iowa Hospitals and Clinics were assessed for the presence of delirium with a clinical assessment, the Confusion Assessment Method for Intensive Care Unit and Delirium Rating Scale. Subsequently, we obtained a 10-min bispectral EEG (BSEEG) recording from a hand-held electroencephalogram device during hospitalization. We performed power spectral density analysis to differentiate between those patients with and without delirium. RESULTS: Initially 45 subjects were used as a test dataset to establish a cut-off. The BSEEG index was determined to be a significant indicator of delirium, with sensitivity 80% and specificity 87.7%. An additional independent validation dataset with 24 patients confirmed the validity of the approach, with a sensitivity of 83.3% and specificity of 83.3%. CONCLUSION: In this pilot study, the BSEEG method was able to distinguish delirious patients from non-delirious patients. Our data showed the feasibility of this technology for mass screening of delirium in the hospital. PMID- 30246449 TI - Effects of zooplankton carcasses degradation on freshwater bacterial community composition and implications for carbon cycling. AB - Non-predatory mortality of zooplankton provides an abundant, yet, little studied source of high quality labile organic matter (LOM) in aquatic ecosystems. Using laboratory microcosms, we followed the decomposition of organic carbon of fresh 13 C-labelled Daphnia carcasses by natural bacterioplankton. The experimental setup comprised blank microcosms, that is, artificial lake water without any organic matter additions (B), and microcosms either amended with natural humic matter (H), fresh Daphnia carcasses (D) or both, that is, humic matter and Daphnia carcasses (HD). Most of the carcass carbon was consumed and respired by the bacterial community within 15 days of incubation. A shift in the bacterial community composition shaped by labile carcass carbon and by humic matter was observed. Nevertheless, we did not observe a quantitative change in humic matter degradation by heterotrophic bacteria in the presence of LOM derived from carcasses. However, carcasses were the main factor driving the bacterial community composition suggesting that the presence of large quantities of dead zooplankton might affect the carbon cycling in aquatic ecosystems. Our results imply that organic matter derived from zooplankton carcasses is efficiently remineralized by a highly specific bacterial community, but does not interfere with the bacterial turnover of more refractory humic matter. PMID- 30246447 TI - Cutaneous leishmaniasis in Sri Lanka: effect on quality of life. AB - BACKGROUND: The quality of life in many patients is affected by skin lesions. Cutaneous leishmaniasis (CL), the commonest form of leishmaniasis, is no exception. In Sri Lanka, CL is an emerging parasitological condition with over 3,000 cases within the last decade. Lesions are often seen on exposed parts of the body which may cause social stigma, and hence a study was done to assess the changes in quality of life of CL patients. METHOD: A total of 294 patients (200 civilians and 94 army personnel) answered a previously validated Sinhala self administered Dermatology Life Quality Index (DLQI) questionnaire and an interviewer-administered questionnaire. RESULTS: From the majority of the civilian population, 47% had no effect on their quality of life due to CL lesions, 33.5% were affected in a small way, 12.5% were affected moderately, 6.5% suffered in a large way, and 0.5% (one patient) were extremely affected due a large ulcerative lesion being on the face. The effect on quality of life was negligible in the majority of army patients as well (35.1% no effect, 31.9% small effect), with a few patients affected moderately and very largely (22.3 and 10.6%, respectively). The most affected domain in patients was symptoms and feeling 1.27 +/- 1.400 (mean +/- SD), and the least was the relationships domain 0.27 +/- 0.625. CONCLUSION: CL does not seem to affect the quality of life in the majority of Sri Lankan patients when compared to CL in other parts of the world or other skin diseases. PMID- 30246451 TI - An Accurate 2020 Census as a Public Health Imperative. PMID- 30246450 TI - Phospho-l-tyrosine-agarose chromatography: Adsorption of human IgG and its proteolytic fragments. AB - The behavior of human immunoglobulin G (IgG) and antigen-binding fragment (Fab fragment) adsorption onto phospho-l-tyrosine immobilized on agarose (P-Tyr agarose) was evaluated by pseudoaffinity chromatography. The effects of buffer systems MES, MOPS, Bis-Tris, Tris-HCl and sodium phosphate (NaP) and pH on IgG adsorption were studied and high purity values were obtained (96%, based on ELISA analysis of albumin, transferrin and immunoglobulins A, G and M) when IgG was purified from human plasma diluted in 10 mmol L-1 NaP buffer at pH 6.0. The capture of IgG by the P-Tyr-agarose was also promising, since 91% of the IgG was adsorbed when plasma was diluted in 25 mmol L-1 MES buffer at pH 5.5, recommending its use for IgG depletion from human plasma under this condition. The experimental data on IgG adsorption kinetics were in agreement with the pseudo-second-order model. The adsorption isotherm data were well described by the Langmuir-Freundlich model with the value of parameter n being <1 (0.72), indicating negative cooperativity. Selectivity was achieved on P-Tyr-agarose from digested human IgG in HEPES 25 mmol L-1 buffer at pH 7.0 where Fab fragments were obtained in eluted fractions without Fc fragments (but with uncleaved IgG) with 86.2% recovery. PMID- 30246452 TI - Recent advances in endotoxin tolerance. AB - Endotoxin tolerance is defined as a reduced capacity of a cell to respond endotoxin (lipopolysaccharide, LPS) challenge after an initial encounter with endotoxin in advance. The body becomes tolerant to subsequent challenge with a lethal dose of endotoxin and cytokines release and cell/tissue damage induced by inflammatory reaction are significantly reduced in the state of endotoxin tolerance. The main characteristics of endotoxin tolerance are downregulation of inflammatory mediators such as tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and C-X-C motif chemokine 10 (CXCL10) and upregulation of anti-inflammatory cytokines such as IL-10 and transforming growth factor beta (TGF-beta). Therefore, endotoxin tolerance is often regarded as the regulatory mechanism of the host against excessive inflammation. Endotoxin tolerance is a complex pathophysiological process and involved in multiple cellular signal pathways, receptor alterations, and biological molecules. However, the exact mechanism remains elusive up to date. To better understand the underlying cellular and molecular mechanisms of endotoxin tolerance, it is crucial to investigate the comprehensive cellular signal pathways, signaling proteins, cell surface molecules, proinflammatory and anti-inflammatory cytokines, and other mediators. Endotoxin tolerance plays an important role in reducing the mortality of sepsis, endotoxin shock, and other endotoxin-related diseases. Recent reports indicated that endotoxin tolerance is also related to other diseases such as cystic fibrosis, acute coronary syndrome, liver ischemia reperfusion injury, and cancer. The aim of this review is to discuss the recent advances in endotoxin tolerance mainly based on the cellular and molecular mechanisms by outline the current state of the knowledge of the involvement of the toll-like receptor 4 (TLR4) signaling pathways, negative regulate factor, microRNAs, apoptosis, chromatin modification, and gene reprogramming of immune cells in endotoxin tolerance. We hope to provide a new idea and scientific basis for the rational treatment of endotoxin-related diseases such as endotoxemia, sepsis, and endotoxin shock clinically. PMID- 30246453 TI - Evolutionary reversals in Bossiella (Corallinales, Rhodophyta): first report of a coralline genus with both geniculate and nongeniculate species. AB - This is the first report of a coralline genus with both geniculate (upright fronds with non-calcified joints) and nongeniculate species that has been verified by DNA sequence data. Two nongeniculate (crustose) species of Bossiella are recognized, B. mayae sp. nov. and B. exarticulata sp. nov. DNA sequencing of the lectotype specimen of Pseudolithophyllum whidbeyense revealed that this name had been misapplied and instead belongs to an undescribed coralline species in the Hapalidiales. Phylogenetic analyses of concatenated DNA sequences (psbA, rbcL, COI-5P) indicate that B. mayae and B. exarticulata represent phenotypic reversals from the geniculate character state back to the nongeniculate character state. Secondary loss of genicula has occurred three times in the subfamily Corallinoideae, once to generate the entirely nongeniculate genus Crusticorallina and twice in the now morphologically heterotypic Bossiella. Since phenotypic reversals have occurred several times during the evolution of coralline algae, we speculate about the putative mechanism and adaptive significance of this phenomenon. PMID- 30246455 TI - Inhibitory role of lentivirus-mediated aquaporin-4 gene silencing in the formation of glial scar in a rat model of traumatic brain injury. AB - Traumatic brain injury (TBI), an acute degenerative pathology of the central nervous system, is a leading cause of death and disability. As the glial scar is a mechanical barrier to nerve regeneration, inhibitory molecules in the forming scar and methods to overcome them have suggested molecular modification strategies to allow neuronal growth and functional regeneration. Herein, we aim to investigate the effects of aquaporin-4 (AQP4) gene silencing on the glial scar formation after TBI by establishing rat models. After modeling, TBI rats were transfected with AQP4 small hairpin RNA [shRNA] (AQP4 gene silencing by lentiviral vector-delivered shRNA) and empty vectors, respectively. Neurological functions of the rats were evaluated after TBI. The hematoxylin and eosin staining was conducted to observe histomorphological changes in rat brain tissues. The messenger RNA (mRNA) and protein expressions of glial fibrillary acidic protein (GFAP), vimentin, fibronectin, laminin, and AQP4 were measured by reverse transcription-quantitative polymerase chain reaction and Western blot analysis. The ratio of positive expression area was calculated, and the glial scar was observed by immunohistochemistry. At the 7th, 14th, and 28th days after TBI, TBI rats treated with AQP4 shRNA showed improved neurological function and lessened histomorphological changes. AQP4 gene silencing mediated by lentivirus decreased the mRNA and protein expressions of GFAP, vimentin, fibronectin, and laminin, the number of positive cells, the ratio of positive expression area, and the glial scar. Our study demonstrates that lentivirus-mediated AQP4 gene silencing could inhibit the formation of glial scar after TBI, which is beneficial to the recovery of neurological function. PMID- 30246454 TI - Does Effectiveness of Weight Management Programs Depend on the Food Environment? AB - OBJECTIVE: To estimate the causal effects of a population-scale behavioral weight management program and to determine whether the program's effectiveness depends on participants' geographic access to places to purchase healthy and less healthy foods. DATA SOURCES: Secondary data from U.S. Department of Veterans Affairs clinical and administrative records (2008-2014), retail food environment measures from commercial databases (2008-2014), and the American Community Survey (2009 2014). STUDY DESIGN: We estimated the effect of the VA's MOVE! weight management program on body mass index after 6 months using difference-in-difference regressions to compare participants with a propensity score-matched control group. We estimated treatment effects overall and in subgroups with different access to supermarkets, fast-food restaurants, and convenience stores. PRINCIPAL FINDINGS: MOVE! reduced BMI by about 0.71 units among men and 0.70 units among women. The program was slightly less effective for men living near fast-food restaurants or convenience stores. We found no evidence that treatment effects varied with the food environment among women. CONCLUSIONS: The residential food environment modestly alters MOVE! effectiveness among men. A greater understanding of environmental barriers to and facilitators of intentional weight loss is needed. This study highlights important potential intersections between health care and the community. PMID- 30246457 TI - USP49 inhibits ischemia-reperfusion-induced cell viability suppression and apoptosis in human AC16 cardiomyocytes through DUSP1-JNK1/2 signaling. AB - Dual-specificity protein phosphatases (DUSP) also known as mitogen-activated protein kinase (MAPK) phosphatases (MKPs) can dephosphorylate MAPKs, including extracellular signal-regulated kinase, c-Jun N-terminal kinase (JNK), and p38. DUSP1-mediated JNK dephosphorylation has been found to play an antiapoptotic role against cardiac ischemia-reperfusion (I/R) injury. However, the regulation of DUSP1-JNK pathway remains unclear. In the current study, ubiquitin-specific peptidase 49 (USP49) expression in human AC16 cardiomyocytes following I/R injury was measured by real-time polymerase chain reaction and western blot analysis. Cell viability, apoptosis, the Bax, Bcl-2, and DUSP1 expression, and the activity of MAPKs in AC16 cardiomyocytes following indicated treatment was measured by CCK 8, flow cytometry, and western blot analysis. The direct interaction between USP49 and DUSP1 was measured by coimmunoprecipitation and ubiquitination analysis. The effect of USP49 on apoptosis and JNK activity in rat cardiomyocytes following I/R injury was also measured by TUNEL and western blot analysis. Here, we found that USP49 expression was time-dependently increased in AC16 cardiomyocytes following I/R. I/R-induced cell apoptosis and JNK1/2 activation both in in vivo and in vitro reversed by USP49 overexpression in AC16 cardiomyocytes. Inhibiting JNK1/2 activation significantly inhibited USP49 knockdown-induced the cell viability inhibition, apoptosis and the JNK1/2 activation in AC16 cardiomyocytes. Moreover, USP49 positively regulated DUSP1 expression through deubiquitinating DUSP1. Overall, our findings establish USP49 as a novel regulator of DUSP1-JNK1/2 signaling pathway with a protective role in cardiac I/R injury. PMID- 30246456 TI - Galectin-3 promotes CXCR2 to augment the stem-like property of renal cell carcinoma. AB - Although targeted therapy is usually the first-line treatment for advanced renal cell carcinoma (RCC), some patients can experience drug resistance. Cancer stem cells are tumour-initiating cells that play a vital role in drug resistance, metastasis and cancer relapse, while galectins (Gal) participate in tumour progression and drug resistance. However, the exact role of galectins in RCC stemness is yet unknown. In this study, we grew a subpopulation of RCC cells as tumour spheres with higher levels of stemness-related genes, such as Oct4, Sox2 and Nanog. Among the Gal family, Gal-3 in particular was highly expressed in RCC tumour spheres. To further investigate Gal-3's role in the stemness of RCC, lentivirus-mediated knockdown and overexpression of Gal-3 in RCC cells were used to examine both in vitro and in vivo tumorigenicity. We further assessed Gal-3 expression in RCC tissue microarray using immunohistochemistry. Upon suppressing Gal-3 in parental RCC cells, invasion, colony formation, sphere-forming ability, drug resistance and stemness-related gene expression were all significantly decreased. Furthermore, CXCL6, CXCL7 and CXCR2 were down-regulated in Gal-3 knockdown tumour spheres, while CXCR2 overexpression in Gal-3-knockdown RCC restored the ability of sphere formation. Gal-3 overexpression in RCC promoted both in vitro and in vivo tumorigenicity, and its expression was correlated with CXCR2 expression and tumour progression in clinical tissues. RCC patients with higher co-expressions of Gal-3 and CXCR2 demonstrated a worse survival rate. These results indicate that highly expressed Gal-3 may up-regulate CXCR2 to augment RCC stemness. Gal-3 may be a prognostic and innovative target of combined therapy for treating RCC. PMID- 30246458 TI - HIV-1 Tat-induced bystander apoptosis in Jurkat cells involves unfolded protein responses. AB - The HIV transactivator protein (Tat) is a multifunctional protein that plays a critical role in viral replication and contributes to several pathological symptoms of HIV-1 infection, which has the loss of CD4+ T lymphocytes as one of its hallmark features. It has been shown that endoplasmic reticulum (ER) stress, including viral infections, is implicated in cellular dysfunction and cell death through activation of the unfolded protein response (UPR). Here, we demonstrate that the bystander stimulus of Tat on Jurkat cells resulted in time-dependent overexpression of major UPR markers including ER chaperone BiP, ER stress sensors ATF6, PERK, and IRE1, as well as an increase in levels of downstream mediators eIF2alpha, ATF4, XBP-1, and proapoptotic factors CHOP, GADD34, and BIM. This upregulation of UPR mediators was accompanied by decreased cell viability and increased apoptosis as evidenced by blue trypan dye exclusion and flow cytometry assays, respectively. Furthermore, we found that the Tat-associated apoptosis of Jurkat cells led to the loss of mitochondrial membrane potential and caspase-12 and -3 activation. Taken together, these results suggest that the exposure of HIV 1 Tat leads to ER stress/UPR triggering which in turn contributes to apoptotic death in Jurkat cells. SIGNIFICANCE OF THE STUDY: In the present work, we provide a substantial insight into the link between ER impairment and apoptotic death following a bystander HIV Tat stimulus, revealing an underlying ER-mediated apoptotic mechanism which could explain the continuous depletion of uninfected CD4+ T lymphocytes observed in HIV-related disease. Our findings reinforce the relevance of ER stress molecular responses in the course of HIV infection and may afford valuable information for the development of new therapeutic strategies to avoid CD4+ T lymphocyte loss and other disorders induced by circulant Tat. PMID- 30246459 TI - Long noncoding RNA SNHG12 promotes the progression of cervical cancer via modulating miR-125b/STAT3 axis. AB - Increasing evidence showed that long noncoding RNAs (lncRNAs) played an important role in the occurrence and development of tumors. To date, lncRNA small nucleolar RNA host gene 12 (SNHG12) has revealed an oncogenic role in various tumors. However, the role of SNHG12 in cervical cancer is still unclear. Therefore, we focused on the biological function and molecular mechanism of SNHG12 in the tumorigenesis of cervical cancer. In this study, the expression of miR-125b was observably downregulated in cervical cancer cells. Meanwhile, the expression of SNHG12 was obviously upregulated in cervical cancer cell lines (HeLa, SiHa, Caski, C4-1, and C33A) compared with the immortalized cervical epithelial cells. The further assay showed that miR-125b was a target of SNHG12 in cervical cancer. Moreover, a negative relationship between miR-125b and SNHG12 was found in cervical cancer. In addition, SNHG12 inhibition restrained the proliferation, migration, and invasion of cervical cancer cells. Meanwhile, miR-125b mimics repressed the expression of signal transducer and activator of transcription 3 (STAT3). The further assay showed that STAT3 was a target of miR-125b in cervical cancer. In addition, sh-STAT3 repressed the migration and invasion of cervical cancer cells. Furthermore, it showed that miR-125b inhibitors reversed STAT3 expression restrained by the reduction of SNHG12 expression. In general, SNHG12 modulated STAT3 by sponging miR-125b in cervical cancer and played an important role in the development of cervical cancer. PMID- 30246460 TI - Primary pulmonary histiocytic sarcoma in dogs: A retrospective analysis of 37 cases (2000-2015). AB - Primary pulmonary histiocytic sarcoma (PHS) has been reported, but is not well characterized. The aim of this retrospective study was to describe clinical characteristics, characterize prognostic factors and report the outcome of a larger group of dogs with primary PHS. Medical records of dogs diagnosed with primary PHS at 11 institutions were retrospectively reviewed. Thirty-seven dogs were included; 13 received CCNU-based chemotherapy alone, 18 received surgery and adjuvant CCNU-based chemotherapy, 3 received medical management alone and 3 dogs received surgery alone. The overall median progression free survival (PFS) and the median survival (overall survival [OS]) were 197 and 237 days, respectively. Measurable responses were noted in dogs receiving only chemotherapy; however, responses were not durable with PFS (91 days) and OS times (131 days) shorter than overall medians. Dogs that received surgery and chemotherapy had significantly prolonged PFS (276 days, P = 0.001) and OS (374 days, P = 0.001), compared with dogs not receiving surgery. As only three dogs undergoing surgery did not receive chemotherapy, it is not possible to determine the contribution of chemotherapy as an adjuvant to surgery. Dogs without evidence of intra-thoracic metastatic disease were much more likely to undergo surgery (odds ratio = 7.04; P = 0.018). While the presence of metastasis or clinical signs at diagnosis negatively impacted PFS, only the former negatively impacted OS. These data imply that dogs presenting with PHS amenable to surgery (ie, no clinical evidence of metastasis) benefit from surgical intervention; however, the lack of a comparable surgery alone group precludes assessment of the efficacy of post-surgical adjuvant chemotherapy. PMID- 30246462 TI - Preparation and Properties of a Polycyclic p-Quinodimethane with Two Oxygen Bridges and its Radical Cation in Comparison with the Isomeric o-Quinodimethane. AB - We prepared an electron-rich p-quinodimethane compound, 2,9-dibromo-7,14 dimesityl-5,12-dioxapentacene (1). The quinoidal character was clarified by bond length alternation in the central ring. Clear vibrational structures in both absorption and emission bands and small Stokes shift indicate the rigid dioxapentacene framework. The reversible redox waves of 1 were observed at +0.14 and +0.69 V vs. Fc+ /Fc, respectively. The radical cation salt 1?+ ?SbF6 - was successfully isolated and characterized by means of X-ray structural analysis and ESR and UV/Vis-near infrared absorption spectroscopies. The molecular structure and electronic properties of the neutral and radical cation species were compared to those of the isomeric o-quinodimethane. PMID- 30246461 TI - Noninvasive brain stimulation for behavioural and psychological symptoms of dementia: A systematic review and meta-analysis. AB - BACKGROUND: Pharmacological and conventional nonpharmacological treatments for behavioural and psychological symptoms of dementia (BPSD) have only modest efficacy. Furthermore, pharmacotherapy carries the risk of important side effects. Noninvasive brain stimulation (repetitive transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS)) are valuable and safe for cognitive function in Alzheimer disease (AD). However, there have been few studies, and there is no consensus, regarding the use of these techniques to treat BPSD. METHODS: We performed a systematic review of the literature and meta-analysis of studies reporting the effect of rTMS or tDCS on BPSD. RESULTS: Seven articles were included: five randomized, controlled clinical trials and two open-label clinical trials. Five studies investigated the effects of rTMS and two the effects of tDCS. Both studies using tDCS reported no evidence of efficacy on BPSD, while two of the three RCTs using rTMS found statistically significant benefits. In an exploratory meta-analysis with four of the RCT studies, we did not find evidence of efficacy of noninvasive brain stimulation techniques, with an overall effect of -0.02 (95% CI = -0.90, 0.94; I2 = 85%). However, when we used only the data from the studies that applied rTMS, we found a positive effect on BPSD, with an overall effect of -0.58 (95% CI = -1.02, 0.14; I2 = 0%). With regards to the adverse effects reported, these were mild and not clinically relevant. CONCLUSIONS: Our results establish a tendency for efficacy of rTMS protocols on BPSD, while corroborating their safety and tolerability, suggesting the need for further research. PMID- 30246463 TI - Investigating the management of potentially cancerous nonhealing mouth ulcers in Australian community pharmacies. AB - We sought to examine the management and referral of nonhealing mouth ulcer presentations in Australian community pharmacies in the Greater Brisbane region. Trained simulated patients visited 220 randomly selected community pharmacies within the Greater Brisbane region in 2016. Simulated patients enacted two nonhealing (>1 month) mouth ulcer scenarios: A direct product request (DPR) (n = 110) and a symptom-based request (SBR) (n = 110). Results were documented and evaluated against Australian national pharmacy practice standards. Referral rates for pharmacy staff (pharmacist, pharmacy assistant or mixed-pharmacist and assistant) were also assessed. Australian pharmacy practice standards recommend staff ask six key questions during SBR and DPR consultations to enable informed decision-making. Two questions relating to identifying the patient and their symptoms were asked in the majority of interactions (76% and 69% respectively); the remaining four questions relating to symptom duration, treatments tried, other medications, and medical conditions were enquired in only 32%, 53%, 31%, and 27% of interactions, respectively. Simulated patients were referred to the doctor/dentist in only 11.8% of all interactions (both scenarios requiring referral). Overall, staff handling of nonhealing mouth ulcer consultations was suboptimal compared to national professional standards. In particular, duration of the nonhealing mouth ulcer was enquired in less than one-third of consultations potentially resulting in low referral rates by staff. This study identifies the need for increased oral cancer awareness and education for community pharmacy staff and reinforcing the importance of practising according to professional standards to effectively screen for potentially cancerous nonhealing mouth lesions. PMID- 30246465 TI - A novel differential diagnosis to nonobstructive diffuse and dilated bowel loops with polyhydramnios: Bartter syndrome. PMID- 30246464 TI - Metabolic Syndrome and Preeclampsia. AB - OBJECTIVE: To identify former preeclamptic (PE)women with worse cardiovascular risk profile with necessity for tailored postpartum follow up, we studied the association between postpartum metabolic syndrome and different PE phenotypes. METHODS: In this cohort study, cardiovascular and cardiometabolic evaluation was performed in 1102 former preeclamptic women at least 6 months postpartum. Women were subdivided in 4 subgroups based on disease resulting in delivery at 34 weeks or earlier and after 34 weeks (early onset vs late onset PE, respectively), and whether or not small for gestational age infancy (SGA) co-occurred. Data were analyzed with ANOVA after Bonferroni correction. Odds ratios (OR) were calculated with logistic regression to determine the association between metabolic syndrome and the 4 subgroups. RESULTS: The prevalence of metabolic syndrome was higher in the early onset PE with SGA group (25.8%) compared to early onset PE without SGA (14.7%), (OR 2.01 [95%CI 1.34-3.03]) and fivefold higher compared to late onset PE with SGA (5.6%) (OR 5.85 [95%CI 2.61-13.10]). CONCLUSIONS: Metabolic syndrome was strongest associated with early onset PE with SGA. Both onset and fetal growth affect the risk on underlying metabolic syndrome in these young women. This article is protected by copyright. All rights reserved. PMID- 30246466 TI - Reversible cerebral vasoconstriction syndrome in paediatric patients with systemic lupus erythematosus: implications for management. AB - Microvascular brain injury is well recognized in neuropsychiatric systemic lupus erythematosus (SLE), but cerebral large artery involvement is being debated. Three females with SLE, aged 9 to 14 years, had immunosuppressive treatment intensification because of lupus nephritis. Within the following days or weeks, they presented with intense cephalalgia - isolated or associated with neurological symptoms - and no or mild hypertension. Magnetic resonance angiography showed multiple stenoses within the circle of Willis. One patient had subsequent small subcortical cerebral infarction. Two patients were treated for neuropsychiatric SLE; one patient was treated for reversible cerebral vasoconstriction syndrome (RCVS). Angiography normalized within a few weeks in all three patients. Retrospectively, clinical and radiological features suggest that RCVS was the most likely diagnosis in all patients. Multidisciplinary analysis of clinical and angiographic features is recommended, as RCVS is rare in children and its recognition may help to adjust treatment. WHAT THIS PAPER ADDS: Reversible vasoconstriction syndrome was observed in paediatric systemic lupus erythematosus. Thorough imaging analysis was necessary to address this diagnosis in paediatric patients. PMID- 30246467 TI - Low intensity intimate partner aggression in Ghana: Support for the revised gender symmetry theory in an African country. AB - Sex differences in the perpetration and victimization of low intensity intimate partner aggression (IPA) were investigated in Ghana. The sample consisted of 1,204 adults (mean age 44.1 yrs., SD 13.5), 602 males and 602 females. IPA was measured with the DIAS-Adult questionnaire, which measures perpetration and victimization of physical, indirect, nonverbal, cyber, and economic aggression in a relationship. Males scored higher than females on being victimized by their partner from physical, indirect, and nonverbal aggression, while females scored higher than males on being perpetrators of physical, indirect, nonverbal, and cyber aggression. A high educational level was positively associated with both perpetration and victimization of IPA. This is the second study to report men being more victimized by low intensity IPA than women in an African nation, thus finding support for Archer's (2018) revised gender symmetry theory of IPA not only in Western, but also in African countries. PMID- 30246468 TI - The severity and degree of hypomineralisation in teeth and its influence on oral hygiene and caries prevalence in children. AB - AIM: The purpose of this study was to investigate the relationship between the severity of hypomineralised teeth, plaque accumulation, hypersensitivity, associated caries risk, and oral health-related quality of life limitations of affected children. MATERIALS AND METHODS: A total of 250 children (mean age 9.0 years) presenting with at least one hypomineralised molar or incisor were included in the study. The hypersensitivity of the teeth was evaluated using the Schiff Cold Air Sensitivity Scale and the Wong-Baker Faces Scale. Furthermore, the Decayed, Missing, and Filled Teeth Index was documented, the Quigley Hein Index was obtained, and personal questioning was used to document the patients' limitations with intake of food. These data were analysed using general linear models that control influencing factors such as age and sex. RESULTS: The Quigley Hein Index increased with the severity of the hypomineralised teeth (1.64 in the unaffected, 2.77 in the moderately, and 3.63 in the severely affected teeth). Problems with intake of food were only observed in subjects with severe hypomineralisation. There was no immediate effect on dental caries. CONCLUSION: Increased severity of tooth hypomineralisation leads to increased hypersensitivity, which resulted in inadequate oral hygiene among children and limitations to their daily life. PMID- 30246469 TI - A prompt and practical on-site support programme for family caregivers of persons with dementia: a preliminary uncontrolled interventional study. PMID- 30246470 TI - The optimal order of stimulation modalities and reproducibility of the multimodal esophageal stimulation paradigm. AB - BACKGROUND: Esophageal hypersensitivity can be triggered by different stimuli. We use a multimodal stimulation model to study esophageal sensitivity to four sensory modalities: thermal, mechanical, electrical, and chemical stimulation. The optimal order of these stimulations needs further validation. METHODS: Esophageal sensitivity to thermal (heated saline solution), mechanical (balloon distention), electrical (block pulses with electrodes), and chemical stimulation (acid solution, 0.1 N HCl) was assessed in 10 subjects. In one session, thermal stimulation was performed first, followed by mechanical stimulation ("original protocol"). In a second session, mechanical stimulation was performed first, followed by temperature stimulation ("reversed protocol"). Besides, the impact of balloon distention speed (25 mL/min vs 50 mL/min) during mechanical stimulation was evaluated. Secondly, in order to establish reproducibility, independent control sessions of multimodal stimulations in 15 healthy volunteers were used retrospectively. KEY RESULTS: A significant difference in pain perception threshold for thermal stimulation was found between the original and reversed protocol (P = 0.046), indicating that mechanical stimulation can sensitize the esophagus to thermal stimulation. Balloon distention rate had no impact on sensitivity thresholds for mechanical stimulation. Concerning the reproducibility, there were no differences for thermal, mechanical, electrical, and chemical stimulation in any of the control sessions. CONCLUSIONS: The optimal order of the multimodal stimulation protocol was to start with the thermal stimulation, followed by mechanical, electrical, and chemical stimulation. The optimal balloon distention rate was 25 mL/min. Multimodal esophageal stimulation generates reproducible perception scores in health and therefore provides a reliable method to assess esophageal sensitivity changes after interventions that may alter esophageal sensitivity. PMID- 30246471 TI - Lectin-binding pattern of glycoconjugates during spontaneous testicular recrudescence in Syrian hamster (Mesocricetus auratus) after exposure to short photoperiod. AB - Lectin histochemistry was used to characterise glycoconjugates and cellular apoptosis in the seminiferous epithelium and interstitium of hamster testis during spontaneous recrudescence. An increase in the LTA lectin affinity was observed in spermatids in the Golgi phase. An increase in labelling of PNA and Con-A lectin in acrosome of spermatids (acrosome phase) as well as increased labelling with Con-A in spermatids (cap phase) was observed. Spermatocytes showed decreased affinity with PNA and AAA lectins and an increase in positivity for LTA and GNA lectins. Spermatogonia showed a slight decrease in positivity to WGA and an increase in labelling with Con-A and a decreased affinity for the AAA lectin. At the end of recrudescence, all these germinal cells showed a similar pattern to the control. The Sertoli cells showed a gradual decrease in labelling with the GNA lectin and the Leydig cells an increase in labelling with Con-A and GNA. Particularly unusual was the observation of apoptotic spermatocytes and spermatids positive for PNA, GNA, AAA and Con-A, together with spermatocytes positive to LTA. In conclusion, the normal lectin pattern is recovered during testis recrudescence and germ cell apoptotic activity is low, as is observed by specific lectins for germ cells in apoptosis. PMID- 30246472 TI - Basolateral presence of the proinflammatory cytokine tumor necrosis factor -alpha and secretions from adipocytes and macrophages reduce intestinal sugar transport. AB - We have previously demonstrated in Caco-2 cells that tumor necrosis factor-alpha (TNF-alpha) inhibits sugar uptake, acting from the apical membrane, by decreasing the expression of the Na+ -glucose cotransporter SGLT1 in the brush border membrane. The goal was to investigate the hypothesis that TNF-alpha from abdominal adipose tissue (adipocytes and macrophages) would decrease sugar and amino acid transport acting from the basolateral membrane of the enterocytes. TNF alpha placed in the basal compartment of Caco-2 cells decreased alpha-methyl- d glucose (alphaMG) and glutamine uptake. The apical medium derived from these Caco 2 cells apically placed in another set of cells, also reduced sugar and glutamine transport. Reverse-transcription polymerase chain reaction analysis demonstrated upregulation of TNF-alpha, IL-1beta, and MCP1 expression in Caco-2 cells exposed to basal TNF-alpha. Similarly, alphaMG uptake was inhibited after Caco-2 cells were incubated, in the basal compartment, with medium from visceral human mesenchymal stem cells-derived adipocytes of overweight individuals. The apical medium collected from those Caco-2 cells, and placed in the upper side of other set of cells, also decreased sugar uptake. Basal presence of medium derived from lipopolysaccharide-activated macrophages and nonactivated macrophages decreased alphaMG uptake as well. Diet-induced obese mice showed an increase in the visceral adipose tissue surrounding the intestine. In this physiological condition, there was a reduction on alphaMG uptake in jejunal everted rings. Altogether, these results suggest that basolateral TNF-alpha, which can be produced by adipocytes and macrophages during obesity, would be able to activate TNF-alpha and other proinflammatory proteins expression in the small intestine and diminish intestinal sugar and amino acids transport. PMID- 30246473 TI - Cardiovascular disease prevalence and risk factor prevalence in Type 2 diabetes: a contemporary analysis. AB - AIMS: To describe the prevalence of major cardiovascular disease (CVD) and risk factor control in a contemporary population with Type 2 diabetes. METHODS: We used data from the national registry in Scotland, Scottish Care Information Diabetes, linked to hospital admissions. Using descriptive statistics and logistic regression we described associations of risk factors with CVD. CVD was defined based on diagnostic codes in primary or secondary care data for ischaemic heart disease, cerebrovascular disease peripheral arterial disease, heart failure, cardiac arrhythmia, hypertensive heart disease and revascularization procedures. RESULTS: Among 248 400 people with Type 2 diabetes with a median age of 67.5 years (IQR 58.2, 76.1) and median diabetes duration of 7.8 years (3.8, 13.0), 32% had prior CVD (35% of men, 29% of women). Median HbA1c overall was 55 mmol/mol (7.2%), median SBP was 132 mmHg, median total cholesterol was 4.1 mmol/l and mean BMI was 32 kg/m2 . Overall two-thirds (65% of men, 68% of women) have two or more of the following CVD risk factor thresholds: HbA1c >= 53 mmol/mol (7%), SBP > 130 mmHg or DBP > 80 mmHg, total cholesterol >= 5 mmol/l or BMI >= 30 kg/m2 , or were currently smoking. Overall 84% were taking anti-hypertensives and 75% a statin. Use of metformin was common at 58%, but other diabetes drugs that reduce CVD were rarely used. CONCLUSIONS: There continues to be a high prevalence of CVD among people with Type 2 diabetes and a high level of unmet need for risk factor control. This implies substantial scope for reducing the excess risk of CVD in diabetes through improved management of known risk factors. PMID- 30246474 TI - Marine biofilms: diversity of communities and of chemical cues. AB - Surfaces immersed in seawater are rapidly colonized by various microorganisms, resulting in the formation of heterogenic marine biofilms. These communities are known to influence the settlement of algae spores and invertebrate larvae, triggering a succession of fouling events, with significant environmental and economic impacts. This review covers recent research regarding the differences in composition of biofilms isolated from different artificial surface types and the influence of environmental factors on their formation. One particular phenomenon bacterial quorum sensing (QS) - allows bacteria to coordinate swarming, biofilm formation among other phenomena. Some other marine biofilm chemical cues are believed to modulate the settlement and the succession of macrofouling organisms, and they are also reviewed here. Finally, since the formation of a marine biofilm is considered to be an initial, QS-dependent step in the development of marine fouling events, QS inhibition is discussed on its potential as a tool for antibiofouling control in marine settings. PMID- 30246475 TI - Primary cutaneous non-pigmented mycotic cyst contained in an epidermal inclusion cyst: Case report and review of the literature. AB - Primary cutaneous mycotic cysts are uncommon dermal or subcutaneous fungal lesions. The most commonly implicated organisms are species within a heterogeneous group of pigmented fungi called dematiaceous fungi. Mycotic cysts usually present as solitary lesions and can be caused by traumatic introduction of fungal elements by foreign bodies or present as a cutaneous manifestation of systemic fungal infections, especially in immunocompromised patients. We present a case of a 63-year-old immunocompetent male who developed a non-erythematous solitary nodule after doing yardwork. Histopathologically, a benign-appearing epidermal inclusion cyst was apparent containing a splinter with keratinous granular debris and no indication of inflammatory host reaction. However, abundant non-pigmented hyphae were visualized after a periodic acid-Schiff stain was performed. This case offers an interesting histopathological view of a non pigmented mycotic cyst contained within an epidermal inclusion cyst with a true epithelial lining. It also raises the question of whether mycotic cysts caused by non-pigmented fungi are rare or simply under-diagnosed because of their deceptively benign initial appearance. Even in the absence of an inflammatory or granulomatous host response, we recommend investigating for fungal elements in lesions where a splinter or other foreign body material is present in order to avoid misdiagnosis. PMID- 30246476 TI - Ectopic pregnancy following oral levonorgestrel emergency contraception use. AB - Levonorgestrel is used worldwide as an emergency oral contraceptive. There have been occasional reports of ectopic pregnancy after oral levonorgestrel use. We present a case of ectopic tubal pregnancy after the use of oral levonorgestrel as an emergency contraceptive in a 37-year-old woman with a history of treatment for Chlamydia trachomatis infection. She conceived after sexual intercourse on menstrual day 14 of the first menstrual cycle following a normal delivery. After salpingectomy for this right tubal pregnancy, her following pregnancy was an ectopic pregnancy in the contralateral tube, which was treated with laparoscopic salpingectomy. Histopathological examination revealed endometriosis. We should be aware of ectopic pregnancy even after emergency contraceptive use, especially in patients with risk factors, such as Chlamydia infection and endometriosis. Because the efficacy of levonorgestrel decreases after ovulation, we should check the stage of the cycle before prescription. PMID- 30246477 TI - Modelling dimethylsulfide diffusion in the algal external boundary layer: implications for mutualistic and signalling roles. AB - Dimethylsulfide (DMS), a dominant organic sulfur species in the surface ocean, may act as a signalling molecule and contribute to mutualistic interactions between bacteria and marine algae. These proposed functions depend on the DMS concentration in the vicinity of microorganisms. Here, we modelled the DMS enrichment at the surface of DMS-releasing marine algal cells as a function of DMS production rate, algal cell radius and turbulence. Our results show that the DMS concentration at the surface of unstressed phytoplankton with low DMS production rates can be enriched by <1 nM, whereas for mechanically stressed algae with high activities of the enzyme DMSP-lyase (a coccolithophore and a dinoflagellate) DMS cell surface enrichments can reach ~10 nM, and could potentially reach MUM levels in large cells. These DMS enrichments are much higher than the median DMS concentration in the surface ocean (1.9 nM), and thus may attract and support the growth of bacteria living in the phycosphere. The bacteria in turn may provide photoactive iron chelators (siderophores) that enhance algal iron uptake and provide algal growth factors such as auxins and vitamins. The present study highlights new insights on the extent and impact of microscale DMS enrichments at algal surfaces, thereby contributing to our understanding of the potential chemoattractant and mutualistic roles of DMS in marine microorganisms. PMID- 30246478 TI - Cavitands as Containers for alpha,omega-Dienes and Chaperones for Olefin Metathesis. AB - Described herein is the behavior of alpha,omega-dienes sequestered within cavitands in aqueous (D2 O) solution. Hydrophobic forces drive the dienes into the cavitands in conformations that best fill the available space. Shorter dienes (C9 and C10) bind in compressed conformations that tumble rapidly in the cavitands. Longer dienes induce capsule formation between cavitands with self complementary hydrogen bonding sites, where the dienes exist in extended conformations. In cavitands unable to form capsules, longer dienes adopt folded structures. The wider open ends allow the synthesis of medium-sized cycloalkenes by ring-closing metathesis reactions with the Hoveyda-Grubbs-II catalyst. Yields of cycloheptene and cyclooctene were enhanced by the chaperones in water when compared with reactions of the free dienes in either aqueous media or chloroform, and even cyclononene could be prepared within the cavitand. PMID- 30246479 TI - TIEG1 is upregulated in Lrp5/6-mediated valve osteogenesis. AB - We have previously demonstrated that Lrp5/6/beta-catenin plays an important role in valve calcification with a specific osteogenic phenotype defined by increased bone mineral content and overall valve thickening. Recent studies indicate that TIEG1 may be involved in mediating the Wnt signaling pathway in bone, which is known to play critical roles in osteoblast differentiation and bone mineralization. Therefore, we sought to test the role of TIEG1 in mediating Wnt signaling, in an established model of hypercholesterolemic valve disease. Our previous model treated null mice with cholesterol diets: Lrp5 -/- /ApoE -/- mice versus wild-type control (n = 180). Group I (n = 60) normal diet, Group II (n = 60) 0.25% chol diet (w/w), and Group III (n = 60) 0.25% (w/w) chol diet + atorv was tested for gene expression for TIEG1, Lrp6, and Runx2. Real-time polymerase chain reaction confirmed that there is upregulation of the gene expression for TIEG1 and Runx2 in the hypercholesterolemic double knockout and single knockout valves as compared with controls with a mild increase in Lrp6. To confirm the mechanism, coexpression of beta-catenin, TIEG1, and LEF1 in valve cells in vitro, led to the coactivation of the TOPFLASH reporter, which was further confirmed by the observation that TIEG1 and beta-catenin colocalize with one another in the nucleus of valvular interstitial cells (VICs) following stimulation with transforming growth factor-beta treatment, an established activator of TIEG1. Taken together, these data implicate an important role for TIEG1 in mediating valve osteogenesis. PMID- 30246480 TI - Individual differences in emotion regulation goals: Does personality predict the reasons why people regulate their emotions? AB - OBJECTIVE: We investigated how the Big Five traits predict individual differences in five theoretically important emotion regulation goals that are commonly pursued-pro-hedonic, contra-hedonic, performance, pro-social, and impression management. METHOD: We conducted two studies: (a) a large survey study consisting of undergraduates (N = 394; 18-25 years; 69% female; 56% European American) and community adults (N = 302; 19-74 years; 50% female; 75% European American) who completed a newly developed global measure of individual differences in emotion regulation goals and (b) a 9-day daily diary study with community adults (N = 272; 23-85 years; 50% female; 84% European American) who completed daily reports of emotion regulation goals. In both studies, participants completed a measure of the Big Five. RESULTS: Across global and daily measures, pro-hedonic goals and pro-social goals were positively associated with Agreeableness, performance goals were positively associated with Openness, and impression management goals were positively associated with Neuroticism. Globally, contra-hedonic goals were also negatively associated with Agreeableness and Conscientiousness. CONCLUSIONS: The Big Five systematically predict the emotion regulation goals people typically pursue. These findings have important implications for understanding why people engage in certain forms of regulatory behavior and why personality has consequences for well-being. PMID- 30246481 TI - Identification, characterization, and functional investigation of circular RNAs in subventricular zone of adult rat brain. AB - Adult neural stem cells (NSCs) are able to self-renew and generate new neural cells. Identifying regulators of NSCs is significant for the development of NSC based therapies for neurodegenerative diseases and brain injuries. Recently, circular RNAs (circRNAs) have been characterized in various cell lines and brain tissues, and found to participate in multiple biological processes. However, the expression pattern of circRNAs in adult NSCs is still unknown. Here, the subventricular zone (SVZ) of the lateral ventricle was isolated as the niche of NSCs in adult rat brain for RNA sequencing and the characteristics of circRNAs profiling in both SVZ and cerebral cortex were also investigated. As a result, 29 049 and 31 975 circRNAs were identified in SVZ and cortex, respectively. Among them, 41 were SVZ-specific and 48 were cortex-specific. 467 circRNAs were also found to express predominately in SVZ, while the cortex had other 423 circRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the SVZ-specific circRNAs have close relationship with the regulation of NSC expansion and NSC-niche interaction, while the other differentially expressed circRNAs might be involved in neural cellular construction and nerve system function. Furthermore, the interactions between circRNAs and microRNAs were also explored, and the result showed that one SVZ specific circRNA was capable to competitively bind miR-138-5p as a potential derepressive regulator in NSCs proliferation. Hence, our work has laid the foundations to decipher regulation mechanisms of circRNAs in adult NSCs and to develop circRNAs as novel biomarkers for adult NSCs. PMID- 30246482 TI - Effect of red propolis extract isolated or encapsulated in nanoparticles on the in vitro culture of sheep preantral follicle: Impacts on antrum formation, mitochondrial activity and glutathione levels. AB - This study aimed to characterize the hydroethanolic extract of red propolis (HERP) and nanoparticles containing HERP for using as an additive in the culture medium of isolated ovine preantral follicles. HERP was characterized by high performance liquid chromatography (HPLC) and determination of flavonoid content, and the nanoparticles by the mean particle diameter, polydispersity index (PI) and encapsulation efficiency (EE). The effect of HERP (10 and 20 etag/ml-HERP10 and HERP20 groups) and nanoparticles (NP10 and NP20 groups) on isolated secondary follicles cultured in vitro for 12 days was observed by morphological evaluation, oxidative stress markers (reactive oxygen species-ROS and glutathione-GSH) and active mitochondria. HPLC showed formononetin as the major compound in the HERP (63.92 +/- 0.21 MUg/mL). The content of flavonoids ranged from 2.14% to 11.00%. The nanoparticles showed mean diameter of 287.5 +/- 3.9 and 479 +/- 18.1 etam; PI of 0.117 +/- 0.018 and 0.316 +/- 0.039; and EE of 67.15% and 41%, respectively, for the NP10 and NP20 groups. After 12 days of culture, HERP20 and NP20 increased (p < 0.05) the percentage of normal follicles compared to NP10. HERP20 showed significantly higher percentages of antrum formation than control medium (MEM) and NP10 (p < 0.05). HERP20 also showed an increase (p < 0.05) in mitochondrial activity compared to the other treatments, except NP20 (p > 0.05), and increased GSH levels (p < 0.05) compared to MEM and HERP10. In conclusion, use of HERP (20 etag/ml) on in vitro culture of isolated ovine preantral follicles can increase antrum formation, mitochondrial activity and GSH levels. PMID- 30246483 TI - Necrotizing fasciitis caused by Mucor indicus in a pediatric bone marrow transplant recipient. AB - Necrotizing fasciitis is a life-threatening, rapidly progressing infection of fascia and subcutaneous cellular tissue typically caused by mixed aerobic and anaerobic bacteria. We present a case report of an immunocompromised 4-year-old female with necrotizing fasciitis from a rare fungal organism, Mucor indicus. The patient underwent multiple debridements and was treated for 10 months, first on liposomal amphotericin B (2 months) then posaconazole (8 months). Mucor indicus is a rarely described pathogen with only nine other cases described. Identification of this organism remains a challenge, and the need for further understanding of risk factors and organism susceptibility testing to help guide treatment is crucial. PMID- 30246485 TI - Development of a rapid methodology for biological efficacy assessment in banana plantations: application to reduced dosages of contact fungicide for Black Leaf Streak Disease (BLSD) control. AB - BACKGROUND: Black sigatoka is the main disease of banana crop production and it is usually controlled by using either systemic or contact fungicides through spray applications. Biological efficacy is typically assessed on a whole cropping cycle with a natural infestation and periodical spray applications. Developing a faster methodology for the biological efficacy assessment of a contact fungicide offers promising perspectives for the test of current and new fungicides or application techniques. RESULTS: The methodology is based on the time of occurrence of the first BLSD symptoms. The artificial infestation protocol was optimized by multiplying the infestation spots and by covering the infested plants. Biological efficacy tests were based on a single spray application after infestation combining three mancozeb dose reductions and two nozzle types. Results demonstrated that dosage reduction of 50% of mancozeb rated dosage gave a significant efficacy independently from the nozzle type with a reduction of the number of lesions up to 55 % compared to control plants. CONCLUSIONS: The infestation method provides a rapid and significant infestation level. The further comparison of spray settings and fungicide doses was made possible. This methodology will be tested at plantation scale on a longer time period covering the whole crop cycle. This article is protected by copyright. All rights reserved. PMID- 30246486 TI - Conversations for Connection: An Outcome Assessment of the Hold-Me-Tight Relationship-Education Program, and Recommendations for Improving Future Research Methodology in Relationship Education. AB - The Hold Me Tight (HMT) program is a new approach to relationship education based on Emotionally-Focused Therapy (Johnson, ), an evidence-based approach to couple therapy. In this exploratory longitudinal research, we examined individual growth in relationship satisfaction and trust for partners in 95 couples in 16 HMT groups across four occasions of measurement: Baseline, Pre-Program, Post-Program and at either 3- or 6-month Follow-Up. We found that relationship satisfaction and trust increased during program participation, and declined during follow-up. We believe our findings provide support for the short-term effectiveness of the HMT program, and suggest a longer period of program delivery may result in improved retention of gains. Finally, we present recommendations for improving the design of future longitudinal research in relationship education. PMID- 30246484 TI - Meridianin C inhibits the growth of YD-10B human tongue cancer cells through macropinocytosis and the down-regulation of Dickkopf-related protein-3. AB - Meridianin C is a marine natural product known for its anti-cancer activity. At present, the anti-tumour effects of meridianin C on oral squamous cell carcinoma are unknown. Here, we investigated the effect of meridianin C on the proliferation of four different human tongue cancer cells, YD-8, YD-10B, YD-38 and HSC-3. Among the cells tested, meridianin C most strongly reduced the growth of YD-10B cells; the most aggressive and tumorigenic of the cell lines tested. Strikingly, meridianin C induced a significant accumulation of macropinosomes in the YD-10B cells; confirmed by the microscopic and TEM analysis as well as the entry of FITC-dextran, which was sensitive to the macropinocytosis inhibitor amiloride. SEM data also revealed abundant long and thin membrane extensions that resemble lamellipodia on the surface of YD-10B cells treated with meridianin C, pointing out that meridianin C-induced macropinosomes was the result of macropinocytosis. In addition, meridianin C reduced cellular levels of Dickkopf related protein-3 (DKK-3), a known negative regulator of macropinocytosis. A role for DKK-3 in regulating macropinocytosis in the YD-10B cells was confirmed by siRNA knockdown of endogenous DKK-3, which led to a partial accumulation of vacuoles and a reduction in cell proliferation, and by exogenous DKK-3 overexpression, which resulted in a considerable inhibition of the meridianin C induced vacuole formation and decrease in cell survival. In summary, this is the first study reporting meridianin C has novel anti-proliferative effects via macropinocytosis in the highly tumorigenic YD-10B cell line and the effects are mediated in part through down-regulation of DKK-3. PMID- 30246487 TI - Patient Uncertainty as a Predictor of 30-day Return Emergency Department Visits: An Observational Study. AB - OBJECTIVE: The objective was to examine the relationship between patient uncertainty at the time of emergency department (ED) discharge as measured by the "Uncertainty Scale" (U-Scale) and 30-day return ED visits. We hypothesized that a higher score on the U-Scale predicts a higher likelihood of a 30-day return ED visit. METHODS: This was a cross-sectional single-site pilot study performed with adult patients discharged from an urban academic ED to assess the relationship of U-Scale total and subscale scores with 30-day return ED visits. We collected demographic and U-Scale scores at the time of ED discharge and subsequent 30-day ED utilization data by follow-up telephone call. RESULTS: No association was found between the total U-Scale score and subsequent ED utilization. Patients with higher uncertainty on the Treatment Quality subscale of the U-Scale had higher odds of a 30-day return ED visit (adjusted odds ratio [AOR] = 1.16), while patients with lower uncertainty on the Decision to Seek Care subscale had higher odds of a 30-day return ED visit (AOR = 0.68). CONCLUSION: Patient uncertainty as measured by the U-Scale total score was not predictive of subsequent ED utilization. However, uncertainty related to treatment quality and the decision to seek care as measured by the U-Scale subscales may be important in predicting repeat ED utilization. Unlike individual patient factors such as age and race that have been associated with frequent ED visits in prior studies, these domains of uncertainty are potentially modifiable. Providers and health systems may successfully prevent recurrent acute care encounters through implementation of interventions designed to address patient uncertainty. Further work is needed to refine the U-Scale and test its predictive utility among a larger patient cohort. PMID- 30246488 TI - Antibody Fragment and Affibody ImmunoPET Imaging Agents: Radiolabelling Strategies and Applications. AB - Antibodies have long been recognised as potent vectors for carrying diagnostic medical radionuclides, contrast agents and optical probes to diseased tissue for imaging. The area of ImmunoPET combines the use of positron emission tomography (PET) imaging with antibodies to improve the diagnosis, staging and monitoring of diseases. Recent developments in antibody engineering and PET radiochemistry have led to a new wave of experimental ImmunoPET imaging agents that are based on a range of antibody fragments and affibodies. In contrast to full antibodies, engineered affibody proteins and antibody fragments such as minibodies, diabodies, single-chain variable region fragments (scFvs), and nanobodies are much smaller but retain the essential specificities and affinities of full antibodies in addition to more desirable pharmacokinetics for imaging. Herein, recent key developments in the PET radiolabelling strategies of antibody fragments and related affibody molecules are highlighted, along with the main PET imaging applications of overexpressed antigen-associated tumours and immune cells. PMID- 30246489 TI - Isolated pigment epithelium detachment: evidence for relation to central serous chorioretinopathy and effect of photodynamic therapy. AB - PURPOSE: To describe clinical characteristics and response to verteporfin therapy (PDT) in eyes with retinal pigment epithelium detachment (PED) in the absence of primary disease other than characteristics compatible with central serous chorioretinopathy (CSC). METHODS: Retrospective review of 634 consecutive patients diagnosed with isolated PED or CSC in one or both eyes in the period from 2007 to 2014 at a single institution. RESULTS: Pigment epithelium detachment (PED) in the absence of primary pathology other than angiographic choroidal hyperpermeability in the incident or fellow eye or manifest CSC in the fellow eye was found in 22 eyes in 19 patients. Follow-up ranged from 4 to 61 months. Five of 19 patients (26%) had classic CSC in the fellow eye. Transition from isolated PED to manifest CSC in the eye with PED was observed in seven eyes (33%) over a median untreated period of observation of 11 months (range, 1-32 months). A single session of PDT followed up 1-6 months later showed full resolution of the PED in seven (78%) of nine eyes. Of the 13 untreated eyes, five eyes (38%) underwent spontaneous resolution of the PED. CONCLUSION: Fellow-eye findings, conversion to CSC, resolution of PED after PDT or, less commonly, spontaneously support that isolated PED is a manifestation of CSC that represents an intermediate stage between pachychoroid and classic CSC. The chance of experiencing resolution of the PED was roughly twice as high with PDT as with untreated observation. PMID- 30246490 TI - Combined effects of warming and nutrients on marine communities are moderated by predators and vary across functional groups. AB - Warming, nutrient enrichment and biodiversity modification are among the most pervasive components of human-induced global environmental change. We know little about their cumulative effects on ecosystems; however, even though this knowledge is fundamental to predicting and managing their consequences in a changing world. Here, we show that shifts in predator species composition can moderate both the individual and combined effects of warming and nutrient enrichment in marine systems. However, all three aspects of global change also acted independently to alter different functional groups in our flow-through marine rock-pool mesocosms. Specifically, warming reduced macroalgal biomass and assemblage productivity, whereas enrichment led to increased abundance of meso-invertebrate consumers, and loss of predator species led to increased gastropod grazer biomass. This disparity in responses, both across trophic levels (macroalgae and intermediate consumers), and between detecting additive effects on aggregate measures of ecosystem functioning, yet interactive effects on community composition, illustrates that our forecasting ability depends strongly on the level of ecological complexity incorporated within global change experiments. We conclude that biodiversity change-and loss of predator species in particular-plays a critical and overarching role in determining how ecological communities respond to stressors. PMID- 30246491 TI - Cortical disruption is the most reliable and accurate plain radiographic sign in the diagnosis of diabetic foot osteomyelitis. AB - The Infectious Diseases Society of America guidelines recommend that if film radiographies show classic changes suggestive of diabetic foot osteomyelitis, it is reasonable to initiate treatment for presumptive osteomyelitis. No accuracy and reliability studies have stratified different radiographic signs in the diagnosis of diabetic foot osteomyelitis to determine the most reliable and accurate plain radiographic sign. This study aims to analyse the reliability and accuracy of four parameters of plain radiography in the diagnosis of diabetic foot osteomyelitis. This article is protected by copyright. All rights reserved. PMID- 30246492 TI - Bioorthogonal Metalloporphyrin-Catalyzed Selective Methionine Alkylation in the Lanthipeptide Nisin. AB - Bioorthogonal catalytic modification of ribosomally synthesized and post translationally modified peptides (RiPPs) is a promising approach to obtaining novel antimicrobial peptides with improved properties and/or activities. Here, we present the serendipitous discovery of a selective and rapid method for the alkylation of methionines in the lanthipeptide nisin. Using carbenes, formed from water-soluble metalloporphyrins and diazoacetates, methionines are alkylated to obtain sulfonium ions. The formed sulfonium ions are stable, but can be further reacted to obtain functionalized methionine analogues, expanding the toolbox of chemical posttranslational modification even further. PMID- 30246493 TI - Impact of the carer on length of hospital stay for mental health: Results from two Australian surveys. AB - Informal carers play a vital role in supporting Australians living with a mental illness, including during the acute phases of illness; however, little is known about their impact on length of hospital stay. We aimed to investigate the impact of having a carer and of carer burden on length of hospital stay for mental health. Two Australian datasets were used. Data from the 2010 National Survey of High Impact Psychosis (n = 1825) were used to investigate the impact of having versus not having a carer on length of hospital stay for mental health. Data from the UQ Carer Survey 2016 (n = 105), a convenience sample of mental health carers, were used to investigate the impact of weekly hours of care (a measure of objective carer burden) on length of stay. Multiple logistic regression and correlation analyses were performed to investigate the association between carer status/burden and length of stay. Having a carer was associated with a significantly longer length of hospital stay; however, this relationship was no longer significant after adjusting for diagnosis, global functioning, depressive symptoms, deliberate self-harm, mental health outpatient contacts and type of admission. Weekly hours of care did not significantly impact on length of stay. Patients with carers had poorer functioning which may be related to longer stays. Our analysis was not able to look at subgroups of carers with different needs. Future work is required to determine other components of the admission and discharge process where having a carer is influential. PMID- 30246494 TI - Genetic regulation of plasma von Willebrand factor levels in health and disease. AB - Plasma levels of the multimeric glycoprotein von Willebrand factor (VWF) constitute a complex quantitative trait with a continuous distribution and wide range in the normal population (50-200%). Quantitative deficiencies of VWF (< 50%) are associated with an increased risk of bleeding, whereas high plasma levels of VWF (> 150%) influence the risk of arterial and venous thromboembolism. Although environmental factors can strongly influence plasma VWF levels, it is estimated that approximately 65% of this variability is heritable. Interestingly, although variability in VWF can account for ~ 5% of the genetic influence on plasma VWF levels, other genetic loci also strongly modify plasma VWF levels. The identification of the additional sources of VWF heritability has been the focus of recent observational trait-mapping studies, including genome-wide association studies or linkage analyses, as well as hypothesis-driven research studies. Quantitative trait loci influencing VWF glycosylation, secretion and clearance have been associated with plasma VWF antigen levels in normal individuals, and may contribute to quantitative VWF abnormalities in patients with a thrombotic tendency or type 1 von Willebrand disease (VWD). The identification of genetic modifiers of plasma VWF levels may allow for better molecular diagnosis of type 1 VWD, and enable the identification of individuals at increased risk for thrombosis. Validation of trait-mapping studies with in vitro and in vivo methodologies has led to novel insights into the life cycle of VWF and the pathogenesis of quantitative VWF abnormalities. PMID- 30246495 TI - Application of the Patient-Reported Outcomes Measurement Information System (PROMIS) item parameters for Anxiety and Depression in the Netherlands. PMID- 30246496 TI - A cost-effectiveness analysis of Erwinia asparaginase therapy in children with acute lymphoblastic leukemia. AB - OBJECTIVES: Erwinia asparaginase is used as a second-line formulation after a neutralizing hypersensitivity reaction to the first-line formulation of asparaginase. Here, we have performed a cost-effectiveness analysis of Erwinia asparaginase treatment. METHODS: Children with acute lymphoblastic leukemia treated according to the Dutch Childhood Oncology ALL-10 or ALL-11 protocol were included and initially treated with PEGasparaginase in the intensification phase. The total treatment costs of this treatment phase, quality of life (QoL), and life years saved (LYS) were studied for two scenarios: (a) patients were switched to Erwinia asparaginase treatment after a hypersensitivity reaction, or (b) asparaginase would have been permanently stopped. RESULTS: Sixty-eight patients were included. There was no difference in QoL between patients with and without a hypersensitivity reaction. The mean costs of the intensification phase per patient were $40,925 if PEGasparaginase could be continued, $175,632 if patients had to switch to Erwinia asparaginase, and $21,190 if asparaginase would have been permanently stopped. An extrapolation of the literature suggests that the 5 year event-free survival would be 10.3% lower without intensive asparaginase treatment if asparaginase is stopped after a reaction. Thus, the costs per LYS were $1892 for scenario 1 and $872 for scenario 2. CONCLUSIONS: Switching to Erwinia asparaginase increases the costs per LYS by $1020, which is modest in view of the total costs. Moreover, when asparaginase treatment can be completed by switching to Erwinia asparaginase, relapses-and consequential costs-will be avoided. Therefore, from a cost perspective, we recommend a switch to Erwinia asparaginase to complete asparaginase treatment. PMID- 30246497 TI - Receiver Operating Characteristic Analysis and Clinical Trial Simulation to Inform Dose Titration Decisions. AB - Optimal dose selection in clinical trials is problematic when efficacious and toxic concentrations are close. A novel quantitative approach follows for optimizing dose titration in clinical trials. A system of pharmacokinetics (PK), pharmacodynamics, efficacy, and toxicity was simulated for scenarios characterized by varying degrees of different types of variability. Receiver operating characteristic (ROC) and clinical trial simulation (CTS) were used to optimize drug titration by maximizing efficacy/safety. The scenarios included were a low-variability base scenario, and high residual (20%), interoccasion (20%), interindividual (40%), and residual plus interindividual variability scenarios, and finally a shallow toxicity slope scenario. The percentage of subjects having toxicity was reduced by 87.4% to 93.5%, and those having efficacy was increased by 52.7% to 243%. Interindividual PK variability may have less impact on optimal cutoff values than other sources of variability. ROC/CTS methods for optimizing dose titration offer an individualized approach that leverages exposure-response relationships. PMID- 30246498 TI - Vibrio responses to extracytoplasmic stress. AB - A critical factor for bacterial survival in any environment is the ability to sense and respond appropriately to any stresses encountered. This is especially important for bacteria that inhabit environments that are constantly changing, or for those that inhabit more than one biological niche. Vibrio species are unique in that they are aquatic organisms, and must adapt to ever-changing temperatures, salinity levels and nutrient concentrations. In addition, many species of Vibrio colonize other organisms, and must also deal with components of the host immune response. Vibrio infections of humans and other organisms have become more common in recent years, due to increasing water temperatures in many parts of the world. Therefore, understanding how these ubiquitous marine bacteria adapt to their changing environments is of importance. In this review, we discuss some of the ways that Vibrios sense and respond to the variety of stresses that negatively affect the bacterial cell envelope. Specifically, we will focus on what is currently known about the sigmaE response, the Cpx response and the contributions of OmpU to extracytoplasmic stress relief. PMID- 30246499 TI - Artificial intelligence in the lab: ask not what your computer can do for you. PMID- 30246500 TI - Breast cancer metastasis to gynaecological organs: a clinico-pathological and molecular profiling study. AB - Breast cancer metastasis to gynaecological organs is an understudied pattern of tumour spread. We explored clinico-pathological and molecular features of these metastases to better understand whether this pattern of dissemination is organotropic or a consequence of wider metastatic dissemination. Primary and metastatic tumours from 54 breast cancer patients with gynaecological metastases were analysed using immunohistochemistry, DNA copy-number profiling, and targeted sequencing of 386 cancer-related genes. The median age of primary tumour diagnosis amongst patients with gynaecological metastases was significantly younger compared to a general breast cancer population (46.5 versus 60 years; p < 0.0001). Median age at metastatic diagnosis was 54.4, time to progression was 4.8 years (range 0-20 years), and survival following a diagnosis of metastasis was 1.95 years (range 0-18 years). Patients had an average of five involved sites (most frequently ovary, fallopian tube, omentum/peritoneum), with fewer instances of spread to the lungs, liver, or brain. Invasive lobular histology and luminal A like phenotype were over-represented in this group (42.8 and 87.5%, respectively) and most patients had involved axillary lymph nodes (p < 0.001). Primary tumours frequently co-expressed oestrogen receptor cofactors (GATA3, FOXA1) and harboured amplifications at 8p12, 8q24, and 11q13. In terms of phenotype conversion, oestrogen receptor status was generally maintained in metastases, FOXA1 increased, and expression of progesterone receptor, androgen receptor, and GATA3 decreased. ESR1 and novel AR mutations were identified. Metastasis to gynaecological organs is a complication frequently affecting young women with invasive lobular carcinoma and luminal A-like breast cancer, and hence may be driven by sustained hormonal signalling. Molecular analyses reveal a spectrum of factors that could contribute to de novo or acquired resistance to therapy and disease progression. PMID- 30246501 TI - Optical coherence tomography and magnetic resonance imaging visual pathway evaluation in Wolfram syndrome. AB - AIM: The aim of this study was to assess parameters of retinal morphology by using high-definition optical coherence tomography (OCT) in patients with Wolfram syndrome (WFS) and their relation to optic tract atrophy in magnetic resonance imaging (MRI). METHOD: High-definition OCT and MRI parameters were evaluated in 12 patients with WFS (three males, nine females; median age at examination 12y 8mo, range 10y 2mo-15y 11mo) and referred to 30 individuals with type 1 diabetes (T1D) (12 males, 18 females; median age at examination 20y 5mo, range 16y 8mo-21y 4mo) and 33 typically developing comparison participants (10 males, 23 females; median age at examination 20y 7mo, range 13y-22y 4mo). RESULTS: Total thickness and quadrant thickness of the retinal nerve fibre layer (RNFL), macular full thickness parameters and macular ganglion cell layer/inner plexiform layer, intraorbital and intracranial thickness of the optical nerve, as well as the optic chiasm and visual tracts were significantly reduced in patients with WFS compared with those having T1D and the typically developing comparison participants. Optic chiasm thickness correlated negatively in patients with WFS with both age (r=-0.79; p=0.002) and duration of diabetes (r=-0.62; p=0.032). Thickness of the intraorbital parts of the optic nerves in patients with WFS correlated positively with thickness of the superior RNFL (r=0.73; p=0.006). INTERPRETATION: High-definition OCT in combination with MRI could become an important tool for evaluating the effectiveness of therapeutic trials in patients with WFS. WHAT THIS PAPER ADDS: Provides evidence of significant reduction of retinal parameters and optic nerves in patients with Wolfram syndrome (WFS). Shows correlations between magnetic resonance imaging parameters and retinal morphology parameters in patients with WFS. PMID- 30246502 TI - Deglycosylation of epithelial cell adhesion molecule affects epithelial to mesenchymal transition in breast cancer cells. AB - The transmembrane glycoprotein epithelial cell adhesion molecule (EpCAM) is overexpressed in most epithelial cancers including breast cancer, where it plays an important role in cancer progression. Previous study has demonstrated that knockdown of EpCAM inhibits breast cancer cell growth and metastasis via inhibition of the Ras/Raf/ERK signaling pathway and matrix metallopeptidase-9 (MMP-9). Although glycosylation is believed to be associated with the function of EpCAM, the contribution of N-glycosylation to this function remains unclear. We constructed the N-glycosylation mutation plasmid of EpCAM and used it to treat breast cancer cells. Loss of N-glycosylation at all three sites EpCAM had no effect on its level of expression or membrane localization. However, mutation at glycosylation sites significantly reduced the ability of EpCAM to promote epithelial to mesenchymal transition in breast cancer. N-glycosylation mutation of EpCAM led to decrease phosphorylation of Raf, ERK, and Akt, and inhibited the Ras/Raf/ERK and PI3K/Akt signaling pathways. Furthermore, we demonstrated that N glycosylation mutation of EpCAM-mediated invasion and metastasis of breast carcinoma cells required the downregulation of MMP-9 via inhibition of these two signaling pathways. Our results identified the characteristics and function of EpCAM glycosylation. These data could illuminate molecular regulation of EpCAM by glycosylation and promote our understanding of the application of glycosylated EpCAM as a target for breast cancer therapy. PMID- 30246504 TI - Calorie Restriction off the Menu for the Time Being?.... PMID- 30246503 TI - Hydrocolloid clustering based on their rheological properties. AB - In this study, we proposed an objective classification of seven commercial hydrocolloids and four novel hydrocolloids. Total of 74 rheological parameters was generated by steady (flow behavior, hysteresis loop, single shear decay, in shear structural recovery experiments), dynamic (strain sweep and frequency sweep tests), and transient (creep/recovery and stress relaxation) shear measurements. Subsequently, the parameters were classified into seven categories with more than 60% similarity indexes in each group using agglomerative hierarchical clustering based on those properties related to the number of linkage, strength of linkage, distance of linkage, rupture and flow, rate of destruction, the extent of destruction, and the state of destructured samples in the absence of flow field. Fuzzy c-means classifier used to extract patterns for each class. Our results correspond to four different classes; kappa-carrageenan and agar gum were categorized in the first class, high methoxyl pectin, xanthan, sage seed gum and basil seed gum in the second class, alginate gum and Balangu-Shirazi seed gum in the third class, and guar gum, cress seed gum and carboxymethyl cellulose in the fourth class. Using this classification technique, complete rheological patterns can be extracted for each class. This classification provides a map for other researchers to rationally design the best test type which could describe adequately different properties of materials and avoid experiments with a similar type of parameters. The main reason for the frequent use of hydrocolloids in various industries is their ability to modify the rheology. A lot of works have been done to study the rheological behavior of many hydrocolloids in model and food systems. As there is still demand for new sources of hydrocolloids with more specific functionality in foods, probing the similarities among commercial and emerging hydrocolloids could help us to rationally design structural features in different formulations, besides gives insight into the structure-function relationship between them. This object could be attained by clustering, a part of the pattern recognition theory. Contrary to the traditional clustering methods, in which the membership of a product is exclusive for only a class, in constraint clustering by fuzzy logic methods, a partial membership can be shared by two or more classes. In this way, using the fuzzy logic clustering method, we clustered a number of commercial and novel hydrocolloids based on the steady, transient, and dynamic shear rheological properties and found a specific pattern among them. PRACTICAL APPLICATIONS: The main reason for the frequent use of hydrocolloids in various industries is their ability to modify the rheology. A lot of works have been done to study the rheological behavior of many hydrocolloids in model and food systems. As there is still demand for new sources of hydrocolloids with more specific functionality in foods, probing the similarities among commercial and emerging hydrocolloids could help us to rationally design structural features in different formulations, besides gives insight into the structure-function relationship between them. This object could be attained by clustering, a part of the pattern recognition theory. Contrary to the traditional clustering methods, in which the membership of a product is exclusive for only a class, in constraint clustering by fuzzy logic methods, a partial membership can be shared by two or more classes. In this way, using the fuzzy logic clustering method, we clustered a number of commercial and novel hydrocolloids based on the steady, transient, and dynamic shear rheological properties and found a specific pattern among them. PMID- 30246505 TI - Oral sweet solution to prevent pain during neonatal hip examination: a randomised controlled trial. AB - AIM: To determine if oral glucose can have a pain-relieving effect during routine hip examinations in newborn infants. METHODS: In this randomised controlled study 100 newborn infants undergoing the routine physical examination including the potentially painful hip examination were included between March 2016 and April 2017. Fifty infants were randomised to water (control) and 50 to oral glucose (intervention) before their examination. Pain was assessed using crying time, Astrid Lindgren and Lund Children's Hospital Pain and Stress Assessment Scale (ALPS-Neo) and Visual analogue scale (VAS). RESULTS: Total crying time (p = 0.006), crying time during the hip examination (p = 0.026), ALPS-Neo (p = 0.004) and VAS (p = 0.006) (when assessed by the physician) were all significantly decreased in the group of infants receiving glucose. VAS assessment made by the parents did not reach statistical significance (p = 0.127). CONCLUSION: Oral glucose given before the examination has a pain-relieving effect during the hip examination in healthy newborn infants. PMID- 30246506 TI - Gene and protein expression in the reproductive tract of Brazilian Somalis rams. AB - Brazilian Somalis is a locally-adapted breed of rams raised in tropical climate and native pastures. The present study was conducted to evaluate gene expression and proteome of the reproductive tract of such rams. Samples were collected from testes, epididymides, seminal vesicles and bulbourethral glands of four rams. Expression of clusterin (CLU), osteopontin (OPN) and prostaglandin D2 synthase (PGDS) genes were evaluated in all samples by real-time PCR. Shotgun proteomic analysis was performed using samples from the head, corpus and cauda epididymides and from all other structures as well. Gene ontology terms and protein interactions were obtained from UniProtKB databases and MetaCore v.6.8 platform. CLU trasncripts were detected in the testes, epididymides, seminal vesicles and bulbourethral glands of the Somalis rams. The initial region and body of the epididymis had the greatest CLU expression. OPN mRNA was localized in all tissues of the ram reproductive tract. PGDS mRNA was detected in the testes and epididymides. Lable-free mass spectrometry allowed the identification of 137 proteins in all samples. Proteins of the epididymis head mainly participate in cellular processes and response to stimulus, participating in catalityc activity and binding. Proteins of epididymis body acted as regulatory proteins and in cellular processes, with binding and catalytic activity. Cauda epididymis molecules were associated with cellular processes and regulation, with binding function and catalytic activity as well. Testis proteins were mainly linked to cell processes and response to stimuli, and had catalytic function. Seminal vesicle proteins were involved in regulation and mainly with binding functions. Most bulbourethral gland proteins participated in cellular processes. The present study is the first to evaluate the proteome and gene expressions in the reproductive tract of Brazilian Somalis rams. Such pieces of information bring significant cointribution for the understanding of the reproductive physiology of locally-adapted livestock. This article is protected by copyright. All rights reserved. PMID- 30246507 TI - Helicobacter pylori and non-alcoholic fatty liver disease: A new enigma? AB - BACKGROUND AND AIM: The relationship between Helicobacter pylori (H. pylori) and nonalcoholic fatty liver disease (NAFLD) is a matter of debate. We achieved this prospective work to study whether H. pylori infection is a risk factor for NAFLD. METHODS: A cohort multicenter pilot study of 369 adults without NAFLD at baseline was followed up for 2 years. Serum leptin, insulin, tumor necrosis factor-alpha, adiponectin, and interleukin-6 were measured using an enzyme-linked immunosorbent assay (ELISA). Homeostasis model assessment of insulin resistance (HOMA-IR) and leptin/adiponectin ratio (LAR) were calculated. Fecal H. pylori antigen was measured by ELISA. A total of 127 participants with H. pylori positive were treated and then followed up for 3 months. RESULTS: Helicobacter pylori-positive patients (46.3%) were associated with an increase in IR, proinflammatory cytokines, C-reactive protein (CRP), LAR, NAFLD-liver fat score (NAFLD-LFS), and hepatic steatosis index (HSI) (all P < 0.01). Multivariate analysis of NAFLD according to HSI and NAFLD-LFS reported that presence of H. pylori, LAR, CRP, IL 6, smoking, and age (all P < 0.01) were independent risk factors for the presence of NAFLD. Multiple models adjusted for potential mediators or confounders such as metabolic, inflammatory, and biochemical factors were constructed. After therapy of H. pylori infection, there was a significant reduction in lipogenic profile, IR, leptin, LAR, CRP, proinflammatory cytokines, HSI, and NAFLD-LFS, as well as, increasing HDL. CONCLUSION: Helicobacter pylori infection was related to an increased risk of NAFLD development, through increased markers of IR, inflammatory mediators, and lipid metabolism. Moreover, its eradication can recover these NAFLD risk factors. PMID- 30246508 TI - Socio-economic and health status as a predictor of apical periodontitis in adult patients in Croatia. AB - OBJECTIVE: A few studies focused on determinants of apical periodontitis other than technical or biological factors. This research aimed to investigate to what extent socio-economic and health status can predict apical periodontitis in adult patients. SUBJECTS AND METHODS: The cross-sectional study included 599 adult patients. Medical history, health habits and socio-economic status of each participant were recorded using a self-administered structured questionnaire. For caries detection, the World Health Organization diagnostic thresholds were used, and oral hygiene level was estimated using plaque index. Periapical index system was used to analyse the periapical status of all teeth. Dental, socio-economic and health-related variables were tested against dependent variable (periapical disease ratio) in a multiple linear regression analysis. RESULTS: Dental independent variables explained 71.7% of the observed variation in periapical disease ratio (R2 = 0.717; p < 0.001). Periapical disease ratio increased with the increase in number of carious teeth, plaque index and number of root-filled teeth, but also with decrease in number of coronal fillings (all p < 0.001). Socio-economic and health-related variables accounted for lower portion of variability, 15.5% and 12.9%, respectively (both p < 0.001). CONCLUSIONS: Dental variables are more important predictors of periapical status than socio-economic and health-related variables. PMID- 30246509 TI - Mobile-phone-based Rheinberg microscope with a light-emitting diode array. AB - Mobile phone technology has led to implementation of portable and inexpensive microscopes. Light-emitting diode (LED) array microscopes support various multicontrast imaging by flexible illumination patterns of the LED array that can be achieved without changing the optical components of the microscope. Here, we demonstrate a mobile-phone-based LED array microscope to realize multimodal imaging with bright-field, dark-field, differential phase-contrast, and Rheinberg illuminations using as few as 37 LED bulbs. Using this microscope, we obtained high-contrast images of living cells. Furthermore, by changing the color combinations of Rheinberg illumination, we were able to obtain images of living chromatic structures with enhanced or diminished contrast. This technique is expected to be a foundation for high-contrast microscopy used in modern field studies. PMID- 30246510 TI - Raman and Visible-Near Infrared Spectra of Cu(InGa)Se2 Films. AB - Cu(InxGa1-x)Se2(CIGS) precursor films were prepared on ITO glass with potentiostatic electrodeposition. High quality CIGS films were obtained by selenization of the precursor films at high temperature in tubular furnace full of argon gas. X-ray diffraction (XRD), scanning electron microscopy (SEM) and UV Vis-NIR spectroscopy were used to characterize the structure, morphology, composition and Vis-NIR absorption of CIGS films, respectively. XRD results show the selenized CIGS films have a preferential orientation (112) with average crystallite of 24.7 nm. Raman spectroscopy reveals that the CIGS films are pure quaternaryphases with chalcopyrite structure, and without binary or ternary phases in the films. Vis-NIR measurements determine that the bandgap of CIGS increases with the increase of Ga concentration in the film. When the Ga concentration is 5.41%, its bandgap is about 1.11 eV, and the calculated ratio of Ga to (Ga+In) is 16.3%, which is less than the ratio of Ga to (Ga+In), 21.4%, measured by SEM. This indicates that crystallinity of CIGS filmsneeds to be further improved. All the measurements demonstratethat optimum ITO/CIGS has a promising application in bifacial solar cells. In this paper, we provide a newmethodtoelectrodeposit low cost CIGS precursor films and a new method forselenization ofthe precursor films at high temperature. As a result, theuniform and compact CIGS films with good adhesion on ITO are successfully fabricated by these methods. The above characterization show that we have obtained CIGS films with high crystallinity, near stoichiometry, few impurity phases and superior light absorption. Electrodeposition, like magnetron sputtering, is very suitable for large-scale industrial production. The research work in this paper is therefore important and considerable to massive production of electrodeposition of CIGS films. PMID- 30246511 TI - Identification Study of Edible Oil Species with Laser Induced Fluorescence Technology Based on Liquid Core Optical Fiber. AB - A laser- induced fluorescence detection set based on liquid core optical fiber was established in this study. Eight edible oils were discriminated by using this detection set combined with chemometrics method. The effect of length of liquid core optical fiber on laser induced fluorescence spectrum was explored, and the differences between the spectra of different edible oils were analyzed. The fluorescence spectra of 320 samples covering 8 types of edible oil were measured in 1 meter liquid core optical fiber. Principal component analysis was used in fluorescence data dimensionality reduction process. Partial least squares discriminant analysis (PLS-DA) method was used to develop the identification model to distinguish edible oil species. The results showed that the oil fluorescence intensity is greatly enhanced when liquid core optical fiber was used. With the increase of liquid core optical fiber length,the peaks of laser induced edible oil fluorescence spectra increased and the fluorescence spectra will produce red shift. The red shift tended to a constant value when the fiber length was more than 80 cm. The fluorescence spectra of different edible oils were quite different, its can be used to distinguish different types of edible oil. Principal component scores chart were get using PC1 and PC2 of edible oils fluorescence data which result in a trend of certain gather of same type of edible oil. The recognition rates of PLS-DA model for the calibration set and prediction set were both 100%. The study shows that the developed device in this study has high accuracy for identifying the edible oil species. PMID- 30246512 TI - Bet v 1 sensitization modulates allergenic molecular 1 immune response. AB - Summary: Background Allergy is characterized by allergen-specific IgE production. Molecular-based allergy diagnostic allows to define the precise sensitization profile. Bet v 1 is the major allergen of the PR-10 family. It has been reported that pan-allergens could affect the sensitization panel in adults. This study aimed to evaluate the impact of Bet v 1 sensitization on sensitization pattern in a large sample of children. Methods Serum IgE molecular components were assessed by ISAC method. Sera from 1,205 children, 708 males (58.76%) and 497 females (41.24%), median age 8.61 years (4.93 - 12.54 years) were analyzed. Results A total of 354 PR-10-positive subjects were detected out of 1,205 subjects. Bet v 1 positive children were significantly more frequently sensitized to other molecules belonging to PR-10 family and noteworthy also to other allergenic families than Bet v 1 negative children. Conclusions The present study demonstrates that Bet v 1 sensitization may significantly affect the sensitization pattern in children living in Genoa, a Mediterranean city located in a birch-free area. PMID- 30246513 TI - Difference of Nonlinear Degree between Healthy and Diabetic Rat Erythocyte Fluorescence Spectrum. AB - Diabetes mellitus is one kind of chronic diseases which seriously threaten human health. It is very important to diagnose in the early stage. With the development of diabetes, the structure and function of erythrocyte in the blood will change. So the peak position and peak height of erythrocyte fluorescence spectrum are different. These differences can be used to determine the status of diabetes. In the selection of the difference of spectral signal as the feature vector, the nonlinear degree of fluorescence spectrum can be used as the feature vector. In order to describe the nonlinearity of the fluorescence spectrum signal, the nonlinear degree of the signal is described with the delay vector variance (DVV) method. By using the method of iterative amplitude adjusted Fourier transformation (IAAFT) to generate surrogate data of raw data, the nonlinear characteristic of the raw data is determined by comparing the DVV of the original data and the surrogate data. The variance of the original data is the horizontal coordinates, and the variance of the surrogate data is the longitudinal coordinates, thus the DVV scatter plot is drawn. The DVV scatter plot of healthy rat erythrocyte fluorescence spectrum is almost coincident with its diagonal, which means the nonlinear degree of healthy rat erythrocyte fluorescence spectrum is lower. The DVV scatter plot of diabetic rat erythrocyte fluorescence spectrum deviates from its diagonal, which means the nonlinear degree of healthy rat erythrocyte fluorescence spectrum is higher, also the corresponding amino acid spectrum nonlinearity is deeper. Therefore, it is proposed that the nonlinear difference between the healthy and diabetic fluorescence spectrum can be used as a feature of early diabetes diagnosis. PMID- 30246514 TI - A Study on Synthesis of CaAl12O19?xMn4+ Red Phosphor with Combustion Method. AB - The CaAl12O19?xMn4+ phosphor was rapidly synthesized at low temperatures with combustion method with urea as combustion agent. The influence of calcination temperature and time, the doping amount of Mn4+ ions, the molar ratio of combustion agent to CaAl12O19, on luminous intensity of fluorescent powder were examined with orthogonal analytical method. The optimum conditions for preparing phosphors are: sintering temperature 1 200 C, the amount of Mn4+ 0.02, the molar ratio of combustion agent to CaAl12O19 50?1, and sintering time 5 hrs. The corresponding luminous intensity of this powder was 95.8, which is the largest. The phosphor shows a strong red luminescence at the 643 and 656 nm due to the 2E 4A2 transition of the Mn4+. The maximum excitation peak was at 470 nm due to the 4A2-4T2 transition of Mn4+ ligand field. The 470 nm excitation peak was matched with the 465 nm emission of the LED chips. PMID- 30246515 TI - Rapid and Noninvasive Detection of Skin Cholesterol with Diffuse Reflectance Spectroscopy Technology. AB - Due to the urgent need for noninvasive detection of skin cholesterol, a portable, intelligent and real-time skin diffuse reflectance spectroscopy measurement system was designed based on a micro-spectrometer. Digitonin-horseradish peroxidase copolymer solution was prepared. According to the properties digitonin binds to the hydroxy of cholesterol molecular specifically and the horseradish peroxidase reacts with TMB color solution (the main component is 3,3',5,5' tetramethylbenzidine ) a color change was produced, by which the skin cholesterol was identified and instructed with high sensitivity and high specificity, and the concentration of skin cholesterol was quantified by measuring the degree of color change. In order to validate the feasibility of this method, pig skin which is similar to human skin was taken as the experimental subject, and cholesterol samples of gradient concentration were achieved through the extraction. After that the spectroscopy measurement system was adopted to detect the cholesterol concentration. The experiment result showed that, relative diffuse reflectance can distinguish the cholesterol samples with different concentrations, and the diffuse reflectance intensity factor can quantity the concentrations of cholesterol at characteristic wavelengths (442, 450 and 463 nm) and characteristic wavelength band of 442~500 nm. Linear fitting curves were obtained with the determination coefficient R2 were 0.960, 0.959, 0.958 and 0.958, respectively. The study has shown that, using diffuse reflectance spectroscopy technology can realize noninvasive rapid detection of skin cholesterol, and applying it to the risk assessment of atherosclerotic diseases would contribute to the prevention and control of such diseases significantly. PMID- 30246516 TI - A Mechanism Study of Reflectance Spectroscopy for Predicting Soil Total Nitrogen. AB - Reflectance spectroscopy has been widely used for predicting soil properties due to its rapidity and convenience. In past decades, the application of soil spectroscopy on soil science studies has increased exponentially. The total nitrogen (TN) content in soil is an important index for soil fertility and the rapid prediction of TN content with spectroscopy serves an important function in precision agriculture. However, whether the TN content in soil is predicted through its relationship with soil organic carbon (SOC) or on its specific absorption is still debatable. The objective of this study was to explore the mechanism of reflectance spectroscopy for predicting TN in soils. Soils used for calibration were sampled from coastal soil in the north of Jiangsu province. Partial least squares regression (PLSR) analysis was used for the calibration datasets with different TN content when the sample number is the same in every dataset. In order to explore the mechanism of reflectance spectroscopy for predicting total nitrogen in soil, the changes of model accuracies and the correlation of TN and SOC were analyzed. The results indicated that the contents of TN and SOC in soil were relatively lower because the soil was derived from coastal sediments in the past 1 000 years and formed during cultivation. There was strong correlation between TN and SOC (R=0.98). The prediction accuracy of TN increased at first and then decreased slightly with the increase of mean, standard deviation of TN content. Meanwhile, the changes of prediction accuracy comply well with coefficients of variation. In conclusion, when the TN content is relatively low (mean TN<0.27 g.kg-1), the correlation coefficient between TN and SOC was moderately-high and TN was predicted on the basis of N absorbers. When the TN content is relatively high (mean TN>0.29 g.kg-1), strong correlation coefficients were obtained for TN and SOC and the model accuracy of SOC were better than TN. The effect of SOC to spectroscopy enhanced with the increase of SOC content, which masked the spectral features of N. Therefore, TN was predicted through the correlation with SOC when the TN content is high. This study revealed the mechanism of reflectance spectroscopy for predicting TN in soil and it could provide a theoretical basis for predicting soil TN content rapidly using reflectance spectroscopy. PMID- 30246517 TI - Simulation Analysis & Experimental Study of the Effects of Satellite Vibration Frequency and Amplitude on Hyperspectral Image. AB - In the imaging process of satellite-based pushbroom hyperspectral imager, attitude motions of satellite platform, represented by vibrations, will cause aliasing of the object information comes from different sub-areas of the detector, leading to degradation of hyperspectral image quality. In order to suppress and correct the imaging errors caused by satellite vibrations more effectively, spatial and spectral degradation mechanisms of typical dispersive pushbroom imaging spectrometer caused by satellite vibration are studied in this paper, including theoretical simulation and experimental study. With the analysis of spectral mixing process during exposure, the relationship between spectrum of ground object and satellite attitude is obtained, and a degradation model of pushbroom spectral imaging is presented. The effects of different attitudes of vibration are considered in the degradation model. Mean mixing ratios of each pixel are easy to calculate with a universal coefficient matrix, as long as the satellite attitude parameters of each moment are known. Then the simulation degraded spectral image data cube is achieved. The common expression of mean mixing ration is derived in detail. More important, the effects of vibration amplitude and frequency are quantitative analyzed separately. Degraded simulation and ground simulation experiments are carried out based on real hyperspectral data cubes, then the quality of the cubes before and after degradation are evaluated. Results show that simulation is in good agreement with reality. Mean mixing ratio can reflect the degradation extent of hyperspectral data directly. The satellite vibrations bring about spatial quality deteriorate of hyperspectral image, and lead to the aliasing of spectrum comes from different ground object. The degradation extent of hyperspectral data is determined mainly by vibration amplitude. The influence of frequency is limited. PMID- 30246518 TI - Absorption Characteristics and Environmental Significance of Dissolved Organic Matter in Lake Dongping. AB - As an important water source in Shandong Province, Lake Dongping is one of the most important inland lakes to South-to-North Water Diversion East Route Project. We tried to provide the basis for real-time monitoring of water quality mutation by using CDOM absorption characteristics. The average values of CDOM absorption coefficients [a(280),a(350),a(440)] were (12.90+/-1.17),(3.11+/-0.40) and (0.65+/ 0.09) m-1. a(440) had linear relationships with total nitrogen (p<0.01), total phosphorus (p<0.001), dissolved organic carbon (p<0.001), chemical oxygen demand (p<0.001), Chlorophyll a (p<0.001), which can be used to estimate the water quality parameters. The results showed that CDOM absorption coefficient reflects the nutritional status of Lake Dongping, which is close to eutrophication level. There was an obvious decrease of CDOM absorption coefficients from river mouth of Dawen River to lake center and then to the outlets of lake. This illustrated that terrestrial input is the main source of nutrients and pollutants in Lake Dongping. PMID- 30246519 TI - Synthesis, Surface Grafting, and Fabrication of Ultrathin Polymeric SAMFETs with High Field-Effect Mobility. AB - Densely surface-grafted monolayer (3-4 nm) poly(3-hexylthiophene) (P3HT) brushes are prepared by click chemistry. For this, P3HT chains with alkyne end groups were synthesized and chemically coupled to a surface-immobilized self-assembled monolayer (SAM) having azide functionality in an organic field-effect transistor channel. The grafted P3HT-alkyne with a molecular weight of Mn,MALDI = 11 400 g mol-1 ( Mn,SEC = 17 400 g mol-1) and a narrow distribution of D = 1.15, has the highest reported molecular weight for surface-immobilized P3HT brushes. We show the successful grafting of P3HT on the substrate surface with atomic force microscopy, contact angle, and absorption studies. From the film thickness, we can calculate the reduced tethered densities of ? = 10.3-12.1, which is indicative of the monolayers being in the true brush regime with high grafting density that is enough to form a compact self-assembled monolayer. The aggregation behavior of the films is characterized by UV-vis spectroscopy and compared to linear P3HT and a bottlebrush copolymer polystyrene- g-P3HT (PS- g P3HT) with similar P3HT lengths. For such an SAM-based organic field-effect transistor (SAMFET) nanodevice with an ultrathin P3HT layer of 3-4 nm, a very high field-effect mobility of up to 1.8 * 10-3 cm2 V-1 s-1 is achieved in channel lengths of 5-20 MUm, which is nearly 2 orders of magnitude higher than reported values for polymer-based SAMFETs. PMID- 30246520 TI - Specific and Highly Sensitive Detection of Ketone Compounds Based on p-Type MoTe2 under Ultraviolet Illumination. AB - The selective and sensitive detection of chemical agents is demanded by a wide range of practical applications. In particular, sensing of volatile organic compounds (VOCs) at parts-per-billion level is critical for environmental monitoring, process control, and early diagnosis of human diseases. In this report, we demonstrate a specific and highly sensitive detection of ketone compounds using two-dimensional (2D) molybdenum ditelluride (MoTe2). We investigated the effects of UV activation on the sensing performance to a variety of VOCs. It is found that the MoTe2 field-effect transistor (FET) exhibits an opposite sensing response to ketone compounds before and after UV light activation, whereas the responses to other types of VOCs remain in the same direction regardless of the illumination. This unique behavior enables the discriminative detection of ketone molecules including acetone and pentanone from other VOCs in a gas mixture. The activation of UV light also results in a very high sensitivity and low detection limit toward acetone (~0.2 ppm). Moreover, the MoTe2 FET shows a stable sensing performance in a high humidity environment. The results demonstrate the potential of MoTe2 as a promising candidate for high performance acetone sensors in important applications such as human breath analysis. The scheme of light-tunable sensing can be applied to a broad range of sensing platforms based on 2D materials. PMID- 30246521 TI - High-Performance Structural Flexible Strain Sensors Based on Graphene-Coated Glass Fabric/Silicone Composite. AB - Recently, various piezoresistive composites with good flexibility have been developed as sensing materials for flexible strain sensors (FSSs). External forces will be applied to strain sensors when they are used in some circumstances such as wrist bending, etc. However, conventional flexible composites may fail upon being subjected to external forces since they have low strength and are unable to protect the inner vulnerable structure of flexible sensors. In this work, the reduced graphene oxide-coated glass fabric (RGO@GF)/silicone composite is fabricated and used to make high-performance structural flexible strain sensors. The composite is not only flexible and sensitive to strain, but also exhibits the high tensile strength needed to maintain the structural integrity of the flexible strain sensor. Silicone resin and GF are employed to provide flexibility and high strength, respectively. By coating RGO on the surface of GF, the nonconductive GF becomes conductive, which renders the piezoresistive behavior and strain-sensing ability to the RGO@GF/silicone composite. The as prepared structural flexible sensor not only possesses a good strain sensitivity with a gauge factor of around 113, which is much higher than that of typical strain sensors based on metals, but can also maintain its structural integrity until the applied external force is over 800 N, while the conventional flexible strain sensor fails upon being subjected to an external force of only 5 N. Moreover, the as-prepared structural FSS is applied to monitor wrist movement and breathing to demonstrate its applicability. Overall, the RGO@GF/silicone composite exhibits great potential as a sensing material for structural FSSs for wrist movement, etc. PMID- 30246522 TI - Red Fluorescence Conjugated Polymer with Broad Spectrum Antimicrobial Activity for Treatment of Bacterial Infections In Vivo. AB - To address the problem of bacterial resistance, a practical strategy for broad spectrum antimicrobial based on conjugated polymers was proposed in the work. Three red fluorescence conjugated polymers (P1, P2, and P3) bearing quaternary ammonium groups with different length of side chains were designed and synthesized. By virtue of inserting capacity of the longer side chain, conjugated polymer (P3) displayed well broad spectrum antimicrobial activity toward Gram negative and Gram-positive bacteria and fungi under a white light density of 25 mW cm-2 and short time (15 min) by aid of dark toxicity and light toxicity, derived from the quaternary ammonium groups and reactive oxygen species produced by the backbone, respectively. Notably, for ampicillin-resistant Escherichia coli TOP10, P3 could kill the bacteria 100% at a very low concentration of 5 MUM upon light irradiation. Furthermore, wound healing tests indicated that the polymer could be expediently employed for wound disinfection in vivo without any tissue damaging. The contribution of the work not only provides an efficient and broad spectrum antimicrobial material but also offers a multimodal antimicrobial strategy to fight against bacterial infections in vivo. PMID- 30246523 TI - Bilayer Tubular Micromotors for Simultaneous Environmental Monitoring and Remediation. AB - There are two main aspects of environmental governance including monitoring and remediation, both of which are essential for environmental protection. Self propelled micro/nanomotors (MNM) have shown promising potential for achieving on demand tasks in environmental field, including environmental sensing and pollutant removal or degradation. However, most of the current MNM used in environmental protection can hardly accomplish the two major tasks of both monitoring and pollutant degradation. Hereby, we present a bubble-propelled mesoporous silica-coated titania (TiO2@mSiO2) bilayer tubular micromotor with platinum (Pt) and magnetic Fe3O4 nanoparticles modified on their inner walls. The outer mesoporous silica (mSiO2) layer can effectively adsorb and collect the pollutants, and the adsorption capacity of the TiO2@mSiO2 tube is about 3 times higher than that of the TiO2 tube due to the presence of mSiO2 shell. By magnetic manipulation, the micromotors can be recovered to release the collected pollutant for precise analysis of the composition of the pollutants, such us pollutant molecule identification by surface-enhanced Raman scattering. The active motion and photocatalytic TiO2 inner layer of the micromotors can greatly enhance the degradation rate of the model pollutant rhodamine 6G (R6G). Our results show that within 30 min, up to 98% of R6G can be degraded by the motors. The successful demonstration of the TiO2@mSiO2 bilayer tubular motors for simultaneous environmental monitoring and pollutant degradation paves the way for future development of active and intelligent micro/nanorobots for advanced environmental governance. PMID- 30246524 TI - Unusual Ferroelectricity of Trans-Unitcell Ion-Displacement and Multiferroic Soliton in Sodium and Potassium Hydroxides. AB - We show the first-principles evidence of a hitherto unreported type of ferroelectricity with ultralong ion-displacement in sodium and potassium hydroxides. Even a small number of proton vacancies can completely change the mode of proton-transfer from intra-unitcell to trans-unitcell, giving rise to multiferroic soliton with "mobile" magnetism and a tremendous polarization that can be orders of magnitude higher compared with most perovskite ferroelectrics. Their vertical polarizations of thin-film are robust against a depolarizing field, rendering various designs of two-dimensional ferroelectric field transistors with nondestructive readout and ultrahigh on/off ratio via sensing the switchable metallic/insulating state. PMID- 30246525 TI - Controlling the Wettability of Steel Surfaces Processed with Femtosecond Laser Pulses. AB - The wettability of a material surface is an essential property that can define the range of applications it can be used for. In the particular case of steel, industrial applications are countless but sometimes limited because of the lack of control over its surface properties. Although different strategies have been proposed to tune the wetting behavior of metal surfaces, most of them require the use of processes such as coatings with different materials or plasma/chemical etching. In this work, we present two different laser-based direct-write strategies that allow tuning the wetting properties of 1.7131 steel over a wide range of contact angles using a high repetition rate femtosecond laser. The strategy consists in the writing of parallel and crossed lines with variable spacing. A detailed morphological analysis confirmed the formation of microstructures superimposed with nanofeatures, forming a hierarchical surface topography that influences the wetting properties of the material surface. Contact angle measurements with water confirm that this behavior is mostly dependent on the line-to-line spacing and the polarization-dependent orientation of the structures. Moreover, we demonstrate that the structures can be easily replicated in a polymer using a laser-fabricated steel master, which enables low cost mass production. These findings provide a practical route for developing user-defined wetting control for new applications of steel and other materials functionalized by rapid laser structuring. PMID- 30246526 TI - Fe-N-C Artificial Enzyme: Activation of Oxygen for Dehydrogenation and Monoxygenation of Organic Substrates under Mild Condition and Cancer Therapeutic Application. AB - Developing highly efficient biomimetic catalysts that directly use O2 as the terminal oxidant to dehydrogenate and monoxygenate substrates with high selectivity under mild conditions has long been pursued but rarely achieved yet. Herein, we report that heterogeneous Fe-N-C, which is commonly used as an electrocatalyst for oxygen reduction reaction, had unusual biomimetic catalytic activity in both dehydrogenation and monoxygenation of a series of organic molecules (~100% selectivity) by directly using O2. The Fe-N x center was verified to be the active site that reductively activated O2 by spontaneously generating specific reactive oxygen species (ROS) (1O2, O2*-, and H2O2). Aided by these ROS, under physiological conditions, the Fe-N-C was further successfully exampled to kill proliferative lung cancer cells. Fe-N-C had several striking superior features with respect to natural enzymes, classical heterogeneous nanozymes, and homogeneous artificial enzymes incapable of working under harsh conditions (extreme pH and high temperature), ease of separation and recycling, and direct use of O2. It would open up a new vista of Fe-N-C as an artificial enzyme in biomimetic catalysis, ranging from fundamental simulation of oxidase/oxygenase metabolism to industrial oxidation processes and to disease treatment. PMID- 30246527 TI - Synthesis of a Base-Stabilized Silicon(I)-Iron(II) Complex for Hydroboration of Carbonyl Compounds. AB - The reaction of the amidinatosilicon(I) dimer [LSi:]2 (1; L = PhC(N tBu)2) with FeBr2 in tetrahydrofuran (THF) at ambient temperature afforded the silicon(I) iron(II) dimer [LSi(FeBr2.THF)]2 (2) after 40 h. Compound 2 can catalyze hydroboration of aliphatic and aromatic ketone compounds with HBpin in the absence of any strong reducing agent. Mechanistic studies show that complex 2 reacts with ketone compounds to form a zwitterionic intermediate in the first step of catalysis. Subsequent reaction with HBpin affords the corresponding boron esters and then regenerates complex 2. PMID- 30246528 TI - Understanding the Passivation Mechanisms and Opto-Electronic Spectral Response in Methylammonium Lead Halide Perovskite Single Crystals. AB - Attaining control over the surface traps in halide perovskites is critical for the tunability of ultimate device characteristics. Here, we present a study on the modulation of photophysical properties, surface traps, and recombination in MAPbI3 single crystals (MSCs) with methylamine (MA) vapor surface treatment. Transient photoluminescence spectroscopy in conjunction with density functional theory calculations reveals that nonradiative recombination related to Pb2+ becomes mitigated after MA vaporing while radiative recombination via bimolecular path tends to increase, which originates from the passivation of Pb ions with the Lewis base nitrogen in MA. In contrast to the broad photoresponse in the pristine MSC photodiodes, application of MA surface treatments leads to a spectral narrowing effect (SNE) in MSCs with the response peak width <40 nm. On the basis of the examined photon-cycling effect with MA treatment that indicates a reduction of exciton diffusion into the interior region of MSCs, we attempt to propose an operation mechanism for the SNE which can be related to the overall stronger surface recombination and resulting severe photocarrier losses, such that the charge collection and quantum efficiency from the above-band gap absorption decrease. This work provides a facile approach with chemical means to tune the surface properties and eventual spectral selectivity in MSCs that are promising for photon-detection device applications. PMID- 30246529 TI - Molecularly Imprinted Polymers. AB - Molecularly imprinted polymers are synthetic receptors for a targeted molecule. As such, they are analogues of the natural antibody-antigen systems. In this review, after a recounting of the early history of the general field, we specifically focus on the application of these polymers as sensors. In these applications, the polymers are paired with a reporting system, which may be electrical, electrochemical, optical, or gravimetric. The presence of the targeted molecule effects a change in the reporting agent, and a calibrated quantity of the target is recorded. In this review, we describe the imprinted polymer production processes, the techniques used for reporting, and the applications of the reported sensors. A brief survey of recent applications to gas-phase sensing is included, but the focus is primarily on the development of sensors for targets in solution. Included among the applications are those designed to detect toxic chemicals, toxins in foods, drugs, explosives, and pathogens. The application of computational chemistry to the development of new imprinted polymers is included as is a brief assessment of future developments. PMID- 30246530 TI - Correction to Importance of Dermal Absorption of Polycyclic Aromatic Hydrocarbons Derived from Barbecue Fumes. PMID- 30246531 TI - Visible-Light-Induced Organophotoredox-Catalyzed Phosphonylation of 2 H-Indazoles with Diphenylphosphine Oxide. AB - A metal-free visible-light-induced phosphonylation of 2 H-indazoles with diphenylphosphine oxide has been developed using rose bengal as an organophotoredox catalyst under ambient air at room temperature. A library of diphenyl(2-phenyl-2 H-indazol-3-yl)phosphine oxide with broad functionalities has been synthesized in high yields. The experimental result suggests the radical pathway of the reaction. PMID- 30246532 TI - High-Efficiency Air-Stable Colloidal Quantum Dot Solar Cells Based on a Potassium Doped ZnO Electron-Accepting Layer. AB - High-efficiency colloidal quantum dot (CQD) solar cells (CQDSCs) with improved air stability were developed by employing potassium-modified ZnO as an electron accepting layer (EAL). The effective potassium modification was achievable by a simple treatment with a KOH solution of pristine ZnO films prepared by a low temperature solution process. The resulting K-doped ZnO (ZnO-K) exhibited EAL properties superior to those of a pristine ZnO-EAL. The Fermi energy level of ZnO was upshifted, which increased the internal electric field and amplified the depletion region (i.e., charge drift) of the devices. The surface defects of ZnO were effectively passivated by K modification, which considerably suppressed interfacial charge recombination. The CQDSC based on ZnO-K achieved improved power conversion efficiency (PCE) of ~10.75% ( VOC of 0.67 V, JSC of 23.89 mA cm 2, and fill factor of 0.68), whereas the CQDSC based on pristine ZnO showed PCE of 9.97%. Moreover, the suppressed surface defects of ZnO-K substantially improved long-term stability under air. The device using ZnO-K exhibited superior long-term air storage stability (96% retention after 90 days) compared to that using pristine ZnO (88% retention after 90 days). The ZnO-K-based device also exhibited improved photostability under air. Under continuous light illumination for 600 min, the ZnO-K-based device retained 96% of its initial PCE, whereas the pristine ZnO-based device retained only 67%. PMID- 30246533 TI - Using Diamagnetic Yttrium and Lanthanum Complexes to Explore Ligand Reduction and C-H Bond Activation in a Tris(aryloxide)mesitylene Ligand System. AB - [Y(N(SiMe3)2)3] reacts with (Ad,MeArOH)3mes to form the Y3+ complex [((Ad,MeArO)3mes)Y], 1-Y. This complex reacts with potassium metal in the presence of 2.2.2-cryptand to give a cocrystallized mixture of [K(2.2.2 cryptand)][((Ad,MeArO)3mes)Y], 2-Y, and [K(2.2.2-cryptand)][((Ad,MeArO)3mes)YH], 3-Y. The electron paramagnetic resonance spectrum of this crystalline mixture exhibits an isotropic signal at 77 K ( giso = 2.000, Wiso = 1.8 mT), suggesting that 2-Y is best described as a Y3+ complex of the tris(aryloxide)mesitylene radical ((Ad,MeArO)3mes)4-. Evidence of the hydride ligand in 3-Y was obtained by 89Y-1H heteronuclear multiple quantum coherence NMR spectroscopy, and a coupling constant of JYH = 93 Hz was observed. A single crystal of 3-Y was also obtained in pure form and structurally characterized for comparison with the crystal data on the mixed component 2-Ln/3-Ln crystals. The origin of the hydride in 3-Ln is unknown, but further studies of the reduction of 1-La, previously found to form 2 La, revealed a possible source. Ligand-based C-H bond activation and loss of hydrogen can occur under reducing conditions to form a tetraanionic ligand derived from ((Ad,MeArO)3mes)3-, as observed in [K(2.2.2 cryptand)][((Ad,MeArO)3(C6Me3(CH2)2CH)La], 4-La. PMID- 30246535 TI - What Limits the Intrinsic Mobility of Electrons and Holes in Two Dimensional Metal Dichalcogenides? AB - Two-dimensional (2D) metal dichalcogenides (MX2) are the most common type of 2D semiconductors and have shown great potential for a wide range of chemical and physical applications. However, they are limited by a low electron/hole mobility, which has been recognized as one of the major challenges impeding their further developments, and urges efforts to understand the mobility-limiting factors and discovery of higher-mobility alternatives. Here using density functional perturbation theory and Wannier interpolation of the electron-phonon matrix to study a wide range of MX2, we find that the intrinsic carrier mobility, in contrast to common belief, neither correlates with the effective mass nor can be assessed by the widely used deformation potential theory; instead it is limited by the longitudinal optical (LO) phonon scattering for most MX2, while for MoS2 and WS2, the mobility is limited by the longitudinal acoustic (LA) phonon scattering. Furthermore, we find that the LO scattering strength is strongly correlated with the magnitude of the Born effective charge, suggesting that the carrier transport is greatly affected by the electric polarization change induced by the atomic vibration. This finding enables us to use the Born effective charge to rapidly screen the 2D MX2 database for high-mobility semiconductor candidates. Our work reveals the underlying factors governing the intrinsic carrier mobility of 2D MX2, offers a practical descriptor for discovering high-mobility candidates, and serves as a paradigm to accurately assess the carrier mobility in 2D semiconductors, thereby paving critical steps toward the development of 2D materials. PMID- 30246534 TI - Metabolic Engineering of Four GATA Factors to Reduce Urea and Ethyl Carbamate Formation in a Model Rice Wine System. AB - Urea is the most important precursor of ethyl carbamate (EC), a harmful carcinogenic product, in fermented wines. In this study, the effects of four GATA transcriptional factors (Gln3p, Gat1p, Dal80p ,and Gzf3p) on extracellular urea and EC formation and transcriptional changes in urea degradation related genes ( DUR1,2 and DUR3) were examined. Compared to the WT strain, the Delta gzf3 mutant showed 18.7% urea reduction and exhibited synergistic effects with overexpressed Gln3p1-653 and Gat1p1-375 on extracellular urea reduction. Moreover, Delta gzf3+Gln3p1-653 and Delta gzf3+Gat1p1-375 showed significant 38.7% and 43.7% decreases in urea concentration and 41.7% and 48.5% decreases in EC concentration, respectively, in a model rice wine system. These results provide a promising way to reduce urea and EC formation during wine fermentation and raise some cues for the regulations of the four GATA transcriptional factors on the expression of individual nitrogen catabolite repression sensitive genes and their related metabolism pathway. PMID- 30246537 TI - Primary, Secondary, and Tertiary gamma-C(sp3)-H Vinylation of Amides via Organic Photoredox-Catalyzed Hydrogen Atom Transfer. AB - An efficient strategy for primary, secondary and tertiary aliphatic gamma-C(sp3) H vinylation of amides with alkenylboronic acids is reported. These reactions are catalyzed by visible-light organic photoredox agents. Regioselective gamma-C(sp3) H vinylation of amides is controlled by a 1,5-hydrogen atom transfer of an amidyl radical generated in situ. PMID- 30246538 TI - Catalytic Enantioselective Synthesis of Guvacine Derivatives through [4 + 2] Annulations of Imines with alpha-Methylallenoates. AB - P-Chiral [2.2.1] bicyclic phosphines (HypPhos catalysts) have been applied to reactions between alpha-alkylallenoates and imines, producing guvacine derivatives. These HypPhos catalysts were assembled from trans-4-hydroxyproline, with the modular nature of the synthesis allowing variations of the exocyclic P and N substituents. Among them, exo-( p-anisyl)-HypPhos was most efficacious for [4 + 2] annulations between ethyl alpha-methylallenoate and imines. Through this method, ( R)-aplexone was identified as being responsible for the decrease in the cellular levels of cholesterol. PMID- 30246539 TI - Origins of Selectivities in the Stork Diels-Alder Cycloaddition for the Synthesis of (+/-)-4-Methylenegermine. AB - The remarkably high stereoselectivity of a Diels-Alder cycloaddition designed by Stork for the synthesis of germine has been examined with theory. We conceived a collaboration with Gilbert Stork, the great synthetic chemist and collaborator. We wished to complement Stork's insights with computations to explain the extraordinary selectivity he designed to introduce four new stereocenters in one step. Stork passed away on October 21, 2017, at age 95, sadly before we finished this work. PMID- 30246536 TI - PEGylated Multistimuli-Responsive Dendritic Prodrug-Based Nanoscale System for Enhanced Anticancer Activity. AB - A PEGylated multistimuli-responsive dendritic copolymer-doxorubicin (DOX) prodrug based nanoscale system was developed as a delivery model for hydrophobic drugs. In this system, PEGylation did not only prolong circulation of the nanoscale system in the body (average half-life of 14.6 h, four times longer than that of the free drug), but also allowed the system to aggregate into nanoparticles (NPs) because of interactions between hydrophilic (polyethylene glycol) and hydrophobic (dendritic prodrug) moieties for better uptake through endocytosis (around 150 nm of particle size with a neutrally charged surface for the PEGylated dendritic prodrug with 12.1 wt % of DOX). The dendritic structure was built by bridging poly[ N-(2-hydroxypropyl)methacrylamide] segments with enzyme-responsive GFLG (Gly-Phe-Leu-Gly tetrapeptide) linkers. DOX was released by hydrolyzing the hydrazone bond between DOX and the copolymer framework in the acidic endosomes/lysosomes. In vitro studies on DOX released from the NPs induced mitochondrial dysfunction during apoptosis. By imaging the main organs and tumor tissues from mice treated with the NPs, boosted accumulation of this nanoscale medicine was found in tumor tissues, leading to a decrease in toxicity and side effects to normal tissues and enhancement in drug tolerance. In the 4T1 breast cancer model, these NPs exhibited a superior antitumor efficacy confirmed by inhibiting angiogenesis, proliferation of tumor tissues, and inducing procedural apoptosis of tumor cells. The highest tumor growth inhibition value mediated by the NPs was up to 86.5%. Therefore, this PEGylated multistimuli-responsive dendritic copolymer-DOX prodrug-based nanoscale system may be further explored as an alternative to traditional chemotherapy for breast cancer treatment. PMID- 30246540 TI - Copper-Catalyzed Synthesis of beta-Azido Sulfonates or Fluorinated Alkanes: Divergent Reactivity of Sodium Sulfinates. AB - A new and general method for the synthesis of beta-azidosulfonates has been achieved through Cu(I)-mediated radical oxidative sulfonylation-azidation of alkenes with sodium sulfinates. Under identical conditions, azido fluoroalkyated products could be readily obtained instead using CF3SO2Na or CHF2SO2Na as reagents. The starting materials of sulfinate compounds, alkenes, and azidotrimethylsilane are stable and cheap. This method can be easily adapted for large-scale preparation. PMID- 30246541 TI - A Comparative Analysis of Academic and Nonacademic Hospitals on Outcome Measures and Patient Satisfaction. AB - Academic hospitals contribute to health care through patient care, research, and teaching; however, their outcomes may not be equivalent to nonacademic hospitals. Multivariate analysis of variance is used to compare publicly reported data on patient satisfaction, readmission rates, mortality rates, and hospital-acquired injury scores between 1906 academic and nonacademic hospitals, while controlling for hospital-level covariates. Results show that academic hospitals have higher levels of patient satisfaction on 7 of the 11 measures and are equivalent to nonacademic hospitals on the remaining 4 measures. Academic hospitals have lower pneumonia mortality rates than nonacademic hospitals, with no difference for other mortality or disease-specific readmissions. However, academic hospitals have a slightly higher overall readmission rate. Infection rates were equivalent between academic and nonacademic hospitals for central line-associated bloodstream infections, pressure ulcers, and wound dehiscence for abdominal and pelvic injuries, but academic hospitals have higher catheter-associated urinary tract infection rates. PMID- 30246542 TI - Reference values of pattern reversal visual evoked potentials in Bulgarian population. AB - AIMS: The aim of this study is to evaluate pattern visual evoked potentials as an objective electrophysiological method and to create reference values for Bulgarian population. METHODS AND MATERIALS: Standardized four-channel equipment 'Neuro-MEP 4' produced by 'Neurosoft' Company was used. A group of 47 healthy individuals (94 eyes) was studied. The stimulation was monocular, with a contrast reversing pattern from black to white and vice versa. The investigation was performed with a three-channel recording with equipment adjustments according to the latest published ISCEV standard for pattern visual evoked potentials (2016). Based on a comprehensive overview of the available literature, a protocol of stimulating, amplifying and recording the obtained potentials has been created. The values of pattern visual evoked potential wave components, P50, N75, P100, N145 and P200, were measured. RESULTS: Based on a created protocol, latency and amplitudes of the individual wave components of pattern visual evoked potentials were obtained. The results were statistically processed to create reference values of all pattern visual evoked potentials components, which are used as reference of the laboratory for the Bulgarian population. CONCLUSION: Pattern visual evoked potentials are objective electrophysiological method which is used to diagnose and monitor numerous ophthalmological and neurological diseases as well as for objective study of visual acuity and visual field in children and aggravation. The creation of pattern visual evoked potentials reference values for the Bulgarian population and its implementation in clinical practice are of particular importance for studying the visual analyser function. PMID- 30246543 TI - A Milestone in Point of Care Capillary Blood Glucose Monitoring of Critically Ill Hospitalized Patients. PMID- 30246544 TI - Low body mass index and efavirenz use are independently associated with self reported fatigue in HIV-infected patients. AB - This retrospective cohort study was conducted from January 2009 to July 2016 to explore the occurrence and risk factors of self-reported fatigue within the first 6 months after receiving antiretroviral treatment (ART) among patients living with HIV in Taizhou City of Zhejiang province, Eastern China. In total, 1163 HIV infected patients with a median follow-up duration of 27.8 months were included in the analysis. Among them, 261 (22.4%) reported fatigue within the first 6 months after ART. In the multivariable logistic regression analysis, self reported fatigue within the first 6 months after ART was negatively associated with junior middle-school education or above, baseline CD4 cell count of 200-349 and >350 cells/MUL (vs < 200 cells/MUL), overweight at baseline (vs normal weight) but positively associated with >=50 years old at initiation of ART (vs <30 years old), underweight at baseline, use of efavirenz (EFV) in the first-line regimen. Our data suggest that earlier initiation of ART and higher body mass index are preferred to restore the energy of HIV-infected patients with the EFV use in the era of ART in China. PMID- 30246546 TI - Impact of diabetes type on treatment and outcome of patients with peripheral artery disease. AB - BACKGROUND:: The prevalence of diabetes mellitus and its associated complications such as peripheral artery disease is increasing worldwide. We aimed to explore the distinct impact of type 1 diabetes mellitus and type 2 diabetes mellitus on treatment and on short- and long-term outcome in patients with peripheral artery disease. METHODS:: Retrospective analysis of anonymized data of hospitalized patients covered by a large German health insurance. Assessment of patient's characteristics (comorbidities, complications, etc.) and outcome using multivariable Cox regression and Kaplan-Meier curves. RESULTS:: Among 41,702 patients with peripheral artery disease, 339 (0.8%) had type 1 diabetes mellitus and 13,151 (31.5%) had type 2 diabetes mellitus. Patients with diabetes mellitus had more comorbidities and complications than patients without diabetes mellitus ( p < 0.001). Type 1 diabetes mellitus patients exhibited the highest risk for limb amputation at 4-year follow-up (44.6% vs 35.1%, p < 0.001), while type 2 diabetes mellitus patients had higher mortality than type 1 diabetes mellitus (43.6% vs 31.0%, p < 0.001). CONCLUSION:: Although the fraction of type 1 diabetes mellitus among patients with peripheral artery disease and diabetes mellitus is low, it represents a subset of patients being at particular high risk for limb amputation. Research focused on elaborating the determinants of limb amputation and mortality in peripheral artery disease patients with diabetes mellitus is warranted to improve the poor prognosis of these patients. PMID- 30246547 TI - A therapeutic group for young people with diverse gender identifications. AB - Young people are presenting to specialist gender services in higher numbers than before and many with significant psychosocial difficulties. Negative experiences of stigma, difficult peer relationships and discrimination exacerbate distress and psychological difficulties, negatively impacting wellbeing and resilience. Social support is advocated as a means of supporting young people with diverse gender identifications, such as through peer support groups. This article describes the establishment of a young persons' group in 2011 within the United Kingdom's Gender Identity Development Service (GIDS), for those attending the service as a means of enabling their coping with difficult experiences and facilitating their wellbeing and resilience through effective social support. The group was evaluated using qualitative and quantitative measures and has subsequently run each year. Now in its sixth year, the authors reflect on their learning and experiences. PMID- 30246545 TI - Intralesional Bevacizumab for the Treatment of Recurrent Sinonasal Hemangioma. AB - INTRODUCTION:: Sinonasal hemangioma is a rare benign tumor of vascular endothelial cells. The pathogenesis is closely linked to abnormalities in the vascular endothelial growth factor signaling pathway. Multiple treatment modalities are available, though wide local excision remains the preferred treatment. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, has known efficacy against hemangiomas, though there are no cases of sinonasal hemangiomas managed with bevacizumab. METHODS:: Case report. RESULTS:: The authors review the case of a 67-year-old man with a left-sided nasal hemangioma originating from the nasal septum. He presented with progressive left nasal obstruction and recurrent epistaxis. At the time of his presentation, the lesion had recurred after 1 excision/polypectomy at an outside institution. He then underwent revision surgery via wide local excision and septoplasty. After tumor recurrence following the revision surgery, the hemangioma was noted to recur on 1 year postoperative surveillance nasal endoscopy. In-office intralesional injection of 50 mg bevacizumab was then performed under endoscopic visualization. No improvement in the tumor size was noted at 2 months after injection, with the tumor measuring 1.5 cm. At the 10-month surveillance clinical visit following injection, the tumor had dramatically involuted to 3 mm in greatest dimension. The patient reported complete resolution of his primary symptoms of epistaxis and nasal obstruction. CONCLUSIONS:: This report demonstrates the first reported successful treatment of a sinonasal hemangioma with intralesional bevacizumab. Intralesional bevacizumab confers an additional option for adjuvant treatment of sinonasal hemangiomas. Further evaluation of intralesional bevacizumab in the treatment of these tumors is warranted. PMID- 30246548 TI - First detection of efrAB, an ABC multidrug efflux pump in Enterococcus faecalis in Tehran, Iran. AB - Enterococcus faecalis is one of the most significant pathogen in both nosocomial and community-acquired infections. Reduced susceptibility to antibiotics is in part due to efflux pumps. This study was conducted on 80 isolates of E. faecalis isolated from outpatients with urinary tract infection during a period of 1 year from April 2014 to April 2015. The antibiotic susceptibility patterns of isolates were determined by the disk diffusion method and presence of efrA and efrB genes was detected by PCR and sequencing. Minimum inhibitory concentrations (MICs) to ciprofloxacin (CIP) were measured with and without carbonyl cyanide 3 chlorophenylhydrazone (CCCP) by broth microdilution. The highest resistance rate was observed to erythromycin (83.3%) and the prevalence of efrA and efrB genes in all E. faecalis isolates was 100%. This study showed that 9 out of 13 (69.2%) ciprofloxacin-resistant isolates became less resistant at least fourfolds to CIP in the presence of efflux pump inhibitor. Our result showed that CCCP as an efflux inhibitor can increase effect of CIP as an efficient antibiotic and it is suggested that efrAB efflux pumps are involved in resistance to fluoroquinolone. PMID- 30246549 TI - Total Thumb Carpometacarpal Joint Arthroplasty: A Retrospective Functional Study of 28 MOOVIS Prostheses. AB - BACKGROUND: Trapeziometacarpal prostheses have been used for more than 50 years in the treatment of first carpometacarpal joint arthritis. Even though this technique is more expensive than trapeziectomy, it has many advantages such as faster convalescence with better patient comfort and improved strength and range of motion. The aim of this study was to report the early functional results of a patient cohort treated with a dual mobility thumb carpometacarpal joint prosthesis. METHODS: A retrospective study was performed to assess the functional results of 25 patients treated for trapeziometacarpal advanced osteoarthritis (Eaton and Littler stage III) with 28 MOOVIS prostheses. Preoperative and postoperative assessments included pain, range of motion, and pinch and grip strength. The average follow-up time was 27.5 months. RESULTS: The mean pain score measured by a visual analog scale was 8 preoperatively and 1 postoperatively. The mean preoperative Kapandji opposition score was 7 and counter-opposition score was 1; postoperative scores were 10 and 4, respectively. The grip strength improved after the surgery and the results were compared separately between dominant and nondominant sides. Final functional results were good: the mean Quick Disabilities of the Arm, Shoulder and Hand Questionnaire score was 12, and the mean Michigan Hand Outcomes score was 87%. CONCLUSIONS: Total joint arthroplasty with a dual mobility prosthesis appears to be a satisfactory solution in our series. The absence of prosthesis instability encourages us to recommend this technique for the treatment of advanced trapeziometacarpal osteoarthritis for people having an activity without too many manual constraints. PMID- 30246550 TI - Reconsidering the experience machine: Self-reported versus objective measures of physical activity to increase positive affect. AB - This article tests the utility of self-report and objective assessment of physical activity to predict increased positive affect. Participants wore Fitbit activity trackers and responded to single-item assessments of momentary affect and self-reported physical activity following an experience sampling method protocol. A test of the within-person mediation indicated that, on average, 63 percent of the relationship between objective physical activity and affect was accounted for by self-reported physical activity. This research adds to the body of literature demonstrating the benefits of physical activity and discusses the utility of perceived over actual assessments of physical activity in naturalistic settings. PMID- 30246551 TI - How do users adopt health information from social media? The narrative paradigm perspective. AB - INTRODUCTION: A recent trend in health information seeking and sharing is the use of social media. Although there are several benefits to the use of social media for health communication, the quality of health information exchanged on social media is troubling due to its informal, unregulated mechanisms for information collection, sharing and promotion. Therefore, it is important to understand how users adopt health information from social media. METHOD: Considering the user generated and storytelling nature of social media messages, this research employed the narrative paradigm perspective to explain the social media health information adoption phenomenon. Specifically, narrative coherence (NC) and narrative fidelity (NF) were hypothesised to have positive effects on the intention to adopt (IA). Additionally, socio-economic status (SES) was viewed as a proxy variable to cognitive capability and was hypothesised to moderate the effects of NC and NF. A scenario-based survey was conducted to test the proposed research model. RESULTS: We obtained a total of 257 valid questionnaires. The results indicated that NF ( p < 0.001) had a positive effect on the IA social media health information. The NC ( p < 0.01) had no impact on the low SES users but a positive impact on the high SES users. Further, the effect of NF ( p < 0.01) on the IA was higher for high SES users than low SES users. CONCLUSIONS: NC and NF are two major driving forces in social media health information adoption, and the effect of both narrative paradigm variables depends on the SES users. Implications Results of this study show how the narrative paradigm, with a focus on the storytelling method of communication rather than logical scientific argument, can not only explain the uptake of health messages from social media, but also provide guidance as to how to create health messages on social media that more effectively target end users. PMID- 30246552 TI - BPT for Early-Onset Behavior Disorders: Examining the Link Between Treatment Components and Trajectories of Child Internalizing Symptoms. AB - Behavioral Parent Training (BPT) is the standard of care for early-onset Behavior Disorders (BDs). Preliminary evidence suggests that BPT may also lead to improvement in comorbid symptomatology, particularly internalizing problems, in children with BDs, yet less is currently known about how BPT produces such cascading effects. To begin to address this gap in the literature, trajectory analyses were used to examine the link between treatment components of one mastery-based BPT program, Helping the Noncompliant Child ( HNC), and child internalizing symptoms over the course of treatment. Findings revealed that parental use of the Attends skill (i.e., parental description of child activity with warmth and enthusiasm) over time was significantly associated with decreases in trajectories of child internalizing symptoms across treatment. Further probing of these effects revealed that parent use of average or above-average levels of Attends across treatment sessions led to significant reductions in child internalizing symptoms by Sessions 7 to 10 of treatment. Consistent with the movement toward a modular approach to the treatment of children, findings highlight the importance of identifying particular BPT skills that can be used in treatment to target multiple comorbid child symptom clusters. Clinical implications and future directions are discussed. PMID- 30246553 TI - Spotlight on avian pathology: current growth-related breast meat abnormalities in broilers. AB - Selection for fast-growing and high-breast-yield hybrids has enormously increased the pressure on muscle development rate and mass, indirectly promoting the development of muscular abnormalities affecting the pectoral muscles such as White Striping, Wooden Breast and Spaghetti Meat. Macroscopically, the muscles affected by these defects exhibit distinctive traits, whereas the microscopic examinations evidenced similar histological alterations. Therefore, a common causative mechanism (involving genes related to several metabolic pathways and functional categories) underpinning the occurrence of these abnormalities may be hypothesized and directly associated with muscle hypertrophy induced by selection. Within this context, as the occurrence of growth-related abnormalities may negatively affect consumer attitude and certainly leads to considerable economic losses, resulting from meat downgrading, it clearly emphasizes the need to consider those issues related to muscle growth and meat quality when selecting meat-type genotypes. PMID- 30246554 TI - Intraosseous Sliding Plate Fixation Used in Double Osteotomy Bunionectomy. AB - BACKGROUND: Distal chevron metatarsal osteotomy bunionectomy is a commonly performed procedure for the treatment of mild to moderate hallux valgus. We continue to use the intraosseous sliding osteotomy plate system for fixation of the distal metatarsal osteotomy. With the addition of the Akin osteotomy, we are able to obtain reliable, reproducible correction with better cosmesis and increased patient satisfaction for more advanced deformities. METHODS: We prospectively evaluated 138 (145 feet) consecutive patients who underwent double osteotomy bunionectomy using the intramedullary plate system and 3.2-mm cannulated screw system. The senior author performed all operative procedures. Patients were evaluated preoperatively, postoperatively, and at the final follow up using the American Orthopaedic Foot & Ankle Society (AOFAS) forefoot scoring system. RESULTS: All osteotomy sites of operatively corrected feet healed. There were no hardware failures. A small number of patients complained of stiffness and pain related to the hardware. All patients dramatically improved their AOFAS scores compared with preoperative values. The hallux valgus angle was corrected by a mean of 17.3 degrees (range, 10 to 20 degrees), and the intermetatarsal angle was corrected by a mean of 6.8 degrees (range, 5 to 9 degrees). CONCLUSION: Chevron osteotomy paired with an Akin osteotomy (double osteotomy bunionectomy) resulted in excellent function and pain relief. We continue to recommend the use of the intramedullary plate system and 3.2-mm cannulated screw system because of its low profile, reliability of fixation, and relative ease of use. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 30246555 TI - Addition of blood flow restriction to passive mobilization reduces the rate of muscle wasting in elderly patients in the intensive care unit: a within-patient randomized trial. AB - OBJECTIVE: To evaluate the addition of blood flow restriction to passive mobilization in patients in the intensive care unit. DESIGN: The study was a within-patient randomized trial. SETTING: Two intensive care units in Belem, from September to October 2017. SUBJECTS: In total, 34 coma patients admitted to the intensive care unit sector, and 20 patients fulfilled the study requirements. INTERVENTIONS: All participants received the passive mobilization protocol for lower limbs, and blood flow restriction was added only for one side in a concurrent fashion. Intervention lasted the entire patient's hospitalization time. MAIN OUTCOME MEASUREMENT: Thigh muscle thickness and circumference. RESULTS: In total, 34 subjects were enrolled in the study: 11 were excluded for exclusion criteria, 3 for death, and 20 completed the intervention (17 men and 3 women; mean age: 66 +/- 4.3 years). Despite both groups presented atrophy, the atrophy rate was lower in blood flow restriction limb in relation to the control limb (-2.1 vs. -2.8 mm, respectively, in muscle thickness; P = 0.001). In addition, the blood flow restriction limb also had a smaller reduction in the thigh circumference than the control limb (-2.5 vs. -3.6 cm, respectively; P = 0.001). CONCLUSION: The use of blood flow restriction did not present adverse effects and seems to be a valid strategy to reduce the magnitude of the rate of muscle wasting that occurs in intensive care unit patients. PMID- 30246556 TI - Maternal Behavior, Posture Change, and Production Performance of Lactating Sows Housed in an Enriched Environment. AB - This study aimed to evaluate whether adding straw to a loose-farrowing house promotes maternal functions and production. Forty-eight sows (Landrace* Large White) were housed in either a farrowing pen without straw (C, n = 24) or with straw (S, n = 24). Behaviors were observed using video recordings and were statistically analyzed. Lateral recumbency was higher and standing was lower in S compared with C (p = .034 and p = .020, respectively), and lateral recumbency to other postures, ventral to lateral recumbency and standing to lying were markedly lower in S than C (p = .014, p = .025 and p = .023, respectively) on Day 1 postpartum. However, except piglet losses during the first three days postpartum (p = .032), piglet weight on Day 21 (p = .037), and piglet weaning weight (p = .020), other production performances were not significantly different between the two groups during the whole experimental period (p ?.05). The results suggest the enrichment of a farrowing pen with straw has important beneficial effects on sow and piglet welfare and improves piglet survival rates. PMID- 30246557 TI - Cost-effectiveness of the HiBalance training program for elderly with Parkinson's disease: analysis of data from a randomized controlled trial. AB - OBJECTIVE: To determine the cost-effectiveness of the HiBalance training program for managing Parkinson's disease (PD)-related balance and gait disorders. DESIGN: Cost comparison design following the randomized controlled trial comparing a novel balance training intervention with care as usual. SUBJECTS: A total of 100 participants with mild-moderate PD were randomized to either the intervention ( n = 51) or the control group ( n = 49). INTERVENTION: A 10-week (three times per week), group-based, progressive balance training program, led by two physical therapists. MAIN OUTCOMES: All program costs were collected for both groups. Cost utility was evaluated using quality-adjusted life years (QALYs) and cost effectiveness measures were the Mini Balance Evaluation Systems Test (Mini BESTest; assessing balance performance) and gait velocity. Incremental cost effectiveness ratios were calculated and a probabilistic sensitivity analysis was conducted. RESULTS: The between-group difference in QALYs was 0.043 (95% confidence interval (CI): 0.011-0.075), favoring the intervention group. Between group differences in balance performance and gait velocity were 2.16 points (95% CI: 1.19-3.13) and 8.2 cm/second (95% CI: 2.9-13.6), respectively, favoring the intervention group. The mean cost per participant in the intervention group was 16,222 SEK (?1649) compared to 2696 SEK (?274) for controls. The estimated incremental cost-effectiveness ratios were 314,558 SEK (?31,969) for an additional QALY, 6262 SEK (?631) for one point improvement in balance performance, and 1650 SEK (?166) for 1 cm/second increase in gait velocity. Sensitivity analyses indicated a high probability (85%) of program success. CONCLUSION: In terms of QALYs, the HiBalance program demonstrated a high probability of cost-effectiveness in the short-term perspective when considering the willingness-to-pay thresholds used in Europe. PMID- 30246558 TI - Analysis of Relation Between Electroclinical Features and Cerebrospinal Fluid Antibody Titers in Patients With anti-NMDAR Encephalitis. AB - PURPOSE: This study aimed to determine the relation between electroclinical features and cerebrospinal fluid (CSF) antibody titers in patients with anti- N methyl-d-aspartate receptor (anti-NMDAR) encephalitis. METHOD: Clinical symptoms and electroencephalography (EEG) at different stages were analyzed in 51 hospitalized patients with anti-NMDAR encephalitis. RESULTS: Behavioral changes were the initial symptoms in 90.9% (20/22) of female patients with high (1:10 or 1:32) CSF antibody titers. A greater number of clinical symptoms were observed in the patients with high CSF antibody titers than in those with low (1:1 or 1:3.2) CSF antibody titers (mean 3.11 +/- 1.06 vs 1.62 +/- 0.65, P = .000). The number of clinical symptoms was greater in the female patients than in the male patients (mean 3.52 +/- 0.98 vs 2.69 +/- 1.09, P = .000). At the peak stage, worse background activity (BA) in EEG recordings was observed in patients with high CSF antibody titers than in those with low CSF antibody titers (Mann-Whitney U test, P = .001). The peak-stage BA in EEG was worse in female patients than in male patients (Mann-Whitney U test, P = .000). Modified Rankin scale scores were higher in patients with high CSF antibody titers than in those with low CSF antibody titers (mean 2.62 +/- 1.42 vs 0.75 +/- 0.97, P = .000). Brush patterns and constant chewing were observed primarily in female patients with high CSF antibody titers. Epileptic discharges were located predominately in the frontal regions and were noted to vary. CONCLUSION: The electroclinical features of patients with anti-NMDAR encephalitis were associated with gender and CSF antibody titers. PMID- 30246560 TI - The role of self-compassion during difficult economic times. AB - BACKGROUND AND OBJECTIVES: The negative effects of the financial crisis of 2007/2008 are still being felt today as seen in the relatively high levels of youth unemployment in many countries. As a result, many young people experience high stress levels when facing an uncertain and precarious job market. METHODS: Participants were 178 undergraduate students (79% female; Mage = 20.00, SD = 4.29) who were randomly assigned to read a news article that documented an uncertain financial future with limited job opportunities (the economic stress group), or an article that documented a tour of the Royal Canadian Mint (the control group). The role of self-compassion was explored in its relation to distress. RESULTS: Correlational and hierarchical regression analyses indicated that, in the economic stress group, self-compassion negatively predicted anxiety above and beyond self-esteem and familial support. In the control group, however, self-compassion did not negatively predict anxiety above and beyond self-esteem and familial support. Additionally, structural equation modeling indicated that self-compassion was directly associated with lower anxiety and indirectly related to anxiety through perceptions of financial threat. CONCLUSIONS: These findings suggest that self-compassion may be an important resource that is associated with less distress during times of economic threat. PMID- 30246559 TI - Avian parvovirus: classification, phylogeny, pathogenesis and diagnosis. AB - Poultry parvoviruses identified during the early 1980s are found worldwide in intestines from young birds with enteric disease syndromes as well as healthy birds. The chicken parvovirus (ChPV) and turkey parvovirus (TuPV) belong to the Aveparvovirus genus within the subfamily Parvovirinae. Poultry parvoviruses are small, non-enveloped, single-stranded DNA viruses consisting of three open reading frames, the first two encoding the non-structural protein (NS) and nuclear phosphoprotein (NP) and the third encoding the viral capsid proteins 1 (VP1 and VP2). In contrast to other parvoviruses, the VP1-unique region does not contain the phospholipase A2 sequence motif. Recent experimental studies suggested the parvoviruses to be the candidate pathogens in cases of enteric disease syndrome. Current diagnostic methods for poultry parvovirus detection include PCR, real-time PCR, enzyme linked immunosorbent assay using recombinant VP2 or VP1 capsid proteins. Moreover, sequence-independent amplification techniques combined with next-generation sequencing platforms have allowed rapid and simultaneous detection of the parvovirus from affected and healthy birds. There is no commercial vaccine; hence, the development of an effective vaccine to control the spread of infection should be of primary importance. This review presents the current knowledge on poultry parvoviruses with emphasis on taxonomy, phylogenetic relationship, genomic analysis, epidemiology, pathogenesis and diagnostic methods. PMID- 30246561 TI - Managing dementia in rural Nigeria: feasibility of cognitive stimulation therapy and exploration of clinical improvements. AB - OBJECTIVES: We investigated the feasibility and clinical impact of a psychosocial intervention, Cognitive Stimulation Therapy (CST), to help manage dementia in a rural setting in Nigeria. METHOD: People with dementia were identified from a prevalence study in Lalupon in the south-west of Nigeria. Prior to this feasibility study CST was adapted for the setting and pilot by our team. Fourteen sessions of CST were provided over a 7-week period by a trained nurse specialist and occupational therapist. Change in quality of life was the main outcome. RESULTS: Nine people were enrolled in CST. Significant improvements in cognitive function, quality of life (physical, psychosocial and environmental domains), physical function, neuro-psychiatric symptoms and carer burden were seen. CONCLUSIONS: CST appears to be feasible in this setting, although adaptation for low literacy levels, uncorrected visual and hearing impairment and work and social practices is needed. The clinical improvements seen were encouraging. PMID- 30246562 TI - Validation of the Intelligibility in Context Scale for Korean-speaking pre-school children. AB - PURPOSE: The Intelligibility in Context Scale (ICS) is a parent-reported screening tool focussed on parents' perception of their child's speech intelligibility. The purposes of this study were to evaluate the psychometric properties of the Korean version of the ICS (ICS-K) and to investigate whether the ICS-K is a useful tool for distinguishing between Korean-speaking children with typical development (TD) and those with speech sound disorder (SSD). METHOD: A total of 178 Korean-speaking pre-school children (145 children with TD and 33 children with SSD) participated in this study. Speech skills were assessed using the Assessment of Phonology and Articulation for Children. The parents of the children completed the ICS-K. RESULT: The ICS-K showed high internal consistency and test-retest reliability. Criterion validity was established through a significant correlation between the ICS-K and the percentage of consonants correct. Construct validity was also established through significant correlations between the ICS-K mean scores and the item scores. A discriminant analysis revealed that the ICS-K had high sensitivity (90.9%) and adequate specificity (77.9%) in classifying children into either the TD or the SSD group. CONCLUSION: The psychometric properties of the ICS-K support its clinical value in measuring functional speech intelligibility in Korean-speaking children with SSD. PMID- 30246563 TI - Evaluation of cellular and transcriptional targeting of breast cancer stem cells via anti-HER2 nanobody conjugated PAMAM dendrimers. AB - According to the cancer stem cell (CSC) theory, a small subset of cells with stem cell-like characteristics is responsible for tumor initiation, progression, and recurrence. CD44+/CD24- phenotype is assumed to be one of the main characteristics of the breast CSCs. We developed an MDA-MB-231 cell line overexpressing cell surface HER2 antigen for the evaluation of targeting efficiency of anti-HER2 nanobody (Nb)-conjugated polyamidoamine (PAMAM) polyplexes. Apoptosis-inducing tBid gene under control of CXCR1 promoter was delivered by this nanoparticle. Cellular uptake study showed higher uptake of Nb targeted PAMAM carriers compared to non-targeted nanoparticles after 6 h of incubation. Gene expression analysis showed a significant rise in the expression of tBid in both MDA-MB-231/HER2+ and MDA-MB-231 compared to the two other cell lines. The same effect was observed after transfection with Nb-conjugated polyplexes within MDA-MB-231/HER2+ cell line compared to non-conjugated PAMAM polyplexes. We confirmed the killing efficiency of the gene construct in both MDA MB-231/HER2+ and MDA-MB-231 cell lines by caspase 3 activity assay. These findings suggest that imposing pre-entry and post-entry restrictions on tBid killer gene might be a promising approach to specifically target the breast CSCs. PMID- 30246564 TI - Comparative toxicity of selected PAHs in rainbow trout hepatocytes: genotoxicity, oxidative stress and cytotoxicity. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants in aquatic ecosystems, which may have potentially toxic effects on organisms. In this study occurrence of DNA strand breaks, oxidative stress, and cytotoxicity were investigated in rainbow trout hepatocytes following in vitro exposure for 24 h to four PAHs (0.01-10 uM): naphthalene, fluoranthene, pyrene, and benzo[a]pyrene (B[a]P). The exposed hepatocytes were analyzed for DNA strand breaks using the comet assay and for antioxidant status by measuring intracellular glutathione (GSH) content using the fluorescent probe mBCl. The cytotoxicity of PAHs was assessed using the fluorescent probe CFDA-AM. The results showed that fluoranthene, pyrene, and B[a]P were genotoxic at all exposure concentrations, whereas naphthalene was genotoxic at concentrations >=0.1 uM. All treatments reduced the intracellular concentrations of GSH for all four PAHs, except 10 uM of B[a]P, suggesting that some level of oxidative stress was present. The cytotoxic effect was observed for naphthalene at concentrations >=0.1 uM and pyrene at all exposure concentrations, whereas fluoranthene and B[a]P were not cytotoxic at the tested concentrations. The study shows that low-molecular-weight PAHs may cause DNA strand breaks as high-molecular-weight PAHs do in fish tissue. In addition, two- to five-ring PAHs can induce oxidative stress and cytotoxicity. PMID- 30246566 TI - Pars plana vitrectomy with silicone oil tamponade for primary and secondary macular hole closure: Is it still a useful procedure? AB - PURPOSE: To evaluate usefulness of posterior vitrectomy with silicone oil tamponade for primary and secondary macular hole closure. METHODS: We searched for publications on the surgical treatment of full-thickness idiopathic and recurrent macular hole. We divided reports into two groups: primary macular hole repair and recurrent macular hole repair with silicone oil tamponade. RESULTS: In primary macular hole treatment, different authors confirmed effectiveness of silicone oil tamponade. They suggest that the most important factor for successful outcome was completeness of vitreous cavity filling with oil. Complications after this method were comparable to those after gas tamponade. However, even if good anatomical results are achieved in secondary macular hole closure, visual acuity is sometimes less rewarding. CONCLUSION: There are reports on good efficacy of silicone oil tamponade for primary and recurrent macular hole closure. Anatomical closure and visual acuity rates in pars plana vitrectomy with silicone oil and with gas filling are comparable. Gas tamponade seems to be safer and needs no more surgery. Postoperative complications in both methods are similar, but all patients with silicone oil filling need to undergo a reoperation to have the silicone removed. There are also other surgical techniques for primary macular hole closure as well as for unsuccessful primary macular hole procedures. We think that primary macular hole closure should be performed with gas tamponade, supported with different adjuvants, as a method of choice. Silicone oil tamponade could be still an alternative in cases, when there are no more efficient techniques or possibilities to treat with success recurrent macular hole. PMID- 30246565 TI - Caffeic Acid Versus Caffeic Acid Phenethyl Ester in the Treatment of Breast Cancer MCF-7 Cells: Migration Rate Inhibition. AB - Epithelium mammary carcinoma is a cancer with a high death rate among women. One factor having a significant impact on metastasis is cell migration. The aim of this study was to compare migration rate inhibition of caffeic acid (CA) and its phenethyl ester (CAPE) on MCF-7 breast cancer cells. Microscopic evaluation was used to determine the morphology of carcinoma cells, before and after 24-hour treatment with CA and CAPE using a dose of 50 uM. The cytotoxic effect was measured by XTT-NR-SRB assay (tetrazolium hydroxide-neutral red-Sulforhodamine B) for 24-hour and 48-hour periods, using CA and CAPE, with doses of 50 and 100 uM. These doses were used to determine cell migration inhibition using a wound closure assay for 0-hour, 8-hour, 16-hour, and 24-hour periods. Both CA and CAPE treatments displayed cytotoxic activity in a dose- and time-dependent trend. CAPE displayed IC50 values more than twice as low as CA. IC50 values for the XTT assay were as follows: CA was 102.98 uM for 24 hours and 59.12 uM for 48 hours, while CAPE was 56.39 uM for 24 hours and 28.10 uM for 48 hours. For the NR assay: CA was 84.87 uM at 24 hours and 65.05 uM at 48 hours, while CAPE was 69.05 uM at 24 hours and 29.05 uM at 48 hours. For the SRB assay: At 24 hours, CA was 83.47 uM and 53.46 uM at 48 hours, while CAPE was 38.53 uM at 24 hours and 20.15 uM at 48 hours. Both polyphenols induced migration inhibition, resulting in practically halting the wound closure. CAPE produced better results than CA with the same doses and experiment times, though both CA and CAPE displayed cytotoxic activity against MCF-7 cells, as well as inhibited migration. PMID- 30246567 TI - Goldmann applanation tonometer versus ocular response analyzer for measuring intraocular pressure after congenital cataract surgery. AB - PURPOSE: To compare intraocular pressure measured using the Goldmann applanation tonometer with that measured using the ocular response analyzer after congenital cataract surgery. METHODS: This study included 113 eyes of 64 patients who underwent lensectomy and vitrectomy. In all, 36 eyes remained aphakic after surgery. Intraocular lens implantation was performed at the time of surgery in 47 eyes and secondarily in 30 eyes. Corneal hysteresis, corneal resistance factor, and cornea-compensated intraocular pressure were measured. The influences of independent factors on the difference between the cornea-compensated intraocular pressure and intraocular pressure measured with Goldmann applanation tonometer were investigated using linear regression analyses. Agreement between the two tonometers was investigated using the Bland and Altman and 95% limits of agreement analysis. RESULTS: Central corneal thickness, corneal hysteresis, and corneal resistance factor were 591.2 +/- 53.3 um, 10.83 +/- 2.27 mmHg, and 11.36 +/- 2.14 mmHg, respectively. Cornea-compensated intraocular pressure (16.75 +/- 4.82 mmHg) was significantly higher than intraocular pressure measured with Goldmann applanation tonometer (14.41 +/- 2.27 mmHg, p < 0.001). Central corneal thickness (p = 0.02) and corneal hysteresis (p < 0.001) were identified as the main predictors of difference between cornea-compensated intraocular pressure and intraocular pressure measured with Goldmann applanation tonometer readings. A 95% limits of agreement for cornea-compensated intraocular pressure and intraocular pressure measured with Goldmann applanation tonometer was between -4.86 and 9.53 mmHg in the entire group. Cornea-compensated intraocular pressure showed the best agreement with intraocular pressure measured with Goldmann applanation tonometer in the primary pseudophakic subgroup as compared to the other subgroups. CONCLUSION: The Goldmann applanation tonometer and ocular response analyzer cannot be used interchangeably for measuring intraocular pressure after congenital cataract surgery. The difference between the cornea-compensated intraocular pressure and intraocular pressure measured with Goldmann applanation tonometer was primarily affected by central corneal thickness and corneal hysteresis. Among the subgroups, the primary pseudophakic subgroup had the thinnest cornea and the highest corneal hysteresis values and demonstrated the best agreement between the two tonometers. PMID- 30246568 TI - Novel platinum agents and mesenchymal stromal cells for thoracic malignancies: state of the art and future perspectives. AB - INTRODUCTION: Non-small cell lung cancer and malignant pleural mesothelioma represent two of the most intriguing and scrutinized thoracic malignancies, presenting interesting perspectives of experimental development and clinical applications. Areas covered: In advanced non-small cell lung cancer, molecular targeted therapy is the standard first-line treatment for patients with identified driver mutations; on the other hand, chemotherapy is the standard treatment for patients without EGFR mutations or ALK rearrangement or those with unknown mutation status. Once considered an ineffective therapy in pulmonary neoplasms, immunotherapy has been now established as one of the most promising therapeutic options. Mesenchymal stromal cells are able to migrate specifically toward solid neoplasms and their metastatic localizations when injected intravenously. This peculiar cancer tropism has opened up an emerging field to use them as vectors to deliver antineoplastic drugs for targeted therapies. Expert opinion: Molecular targeted therapy and immunotherapy are the new alternatives to standard chemotherapy. Mesenchymal stromal cells are a new promising tool in oncology and-although not yet utilized in the clinical practice, we think they will represent another main tool for cancer therapy and will probably play a leading role in the field of nanovectors and molecular medicine. PMID- 30246569 TI - Interatrial shunts: technical approaches to percutaneous closure. AB - INTRODUCTION: Interatrial shunt closure is considered the first-line therapy for congenital simple communications such as patent forame ovale (PFO), atrial septal defect (ASD), and post surgical interatrial communications. Areas covered: Anatomical, functional, and technical details useful for planning a transcatheter based closure procedure are discussed as well as the available equipments and their use and the procedural routes and the specific closure techniques. Expert commentary: Anatomical and functional details, appreciated at both pre-procedural and intraprocedural steps, are of paramount importance for planning interatrial shunts transcatheter - based closure procedures. Rims of the defects, borders of the fossa ovalis, presence and relevance of atrial septal aneurysm, persistence of Eustachian valve or cor triatriatum dexter, and interatrial septum hypertrophy or lipomatosis are all factors to be investigated when planning the procedure and selecting the device. Routes for interventions should include femoral, and eventually the jugular and hepatic vein approaches. Intraprocedural transoesophageal echocardiography (TTE) or intracardiac echocardiography (ICE) should be used at least in most complex cases to have the exact definition of the anatomy of the defects. Future developments of device material and imaging tools are expected to improve safety and long-term efficacy even in the most complex cases. PMID- 30246570 TI - Comparison of the effect of narrative writing and art therapy on maternal stress in neonatal intensive care settings. AB - OBJECTIVE: This study was conducted to examine the effect of narrative writing and art therapy on maternal stress in the neonatal intensive care units (NICUs) during infants' hospitalization. MATERIAL AND METHODS: randomized controlled clinical trial with three parallel arms study was conducted among three groups of mothers with preterm infants in the NICUs of two teaching hospitals of Shahroud University of Medical Sciences. Pre- and post-tests were administered to a sample size of 105 during 9 months. The parental stressor scale (PSS) was used. The data were analyzed using descriptive and analytical statistical methods. RESULTS: The mean maternal stress score was 54.94, 47.08, and 47.57 in the art therapy, narrative writing, and control before the intervention respectively, indicating no significant difference between the groups (p = .28). There was also no significant difference in the mean score of stress between the groups after the intervention (p = .92). Also, we found no significant difference in the mean score of parental role and parents' relationship and sights and sounds between the three groups on the second day (p = .22 and p = .12, respectively) but there was a significant difference in the mean score of infant behavior and appearance between the three groups (p = .05). There was no significant difference in parental role and parents' relationship (p = .31), infant behavior and appearance (p = .58), and sights and sounds (p = .67) between the three groups on the sixth day of intervention. CONCLUSIONS: Narrative writing and art therapy are only effective on the subscale of infant behavior and appearance in the PSS: NICU. PMID- 30246571 TI - Acrodermatitis continua of Hallopeau successfully treated with secukinumab. AB - Acrodermatitis continua of Hallopeau is considered an uncommon variant of pustular psoriasis, characterised by a relapsing, sterile, pustular eruption of hands and feet. It is not easily treated by anti-psoriatic therapies, and may progress toward sclerosis and osteolysis. Numerous topical and systemic treatments have been used, with inconsistent results. The therapeutic response of pustular psoriasis to biologics supports the pivotal role of the tumour necrosis alpha (TNF-alpha)/interleukin (IL)-23/IL-17/IL-22 axis in the pathogenesis of the disorder. Based on these data, secukinumab was used in a patient with uncontrolled acrodermatitis continua of Hallopeau. PMID- 30246572 TI - The time-sequential changes of risk factors for adult T-cell leukemia development in human T-cell leukemia virus-positive patients with rheumatoid arthritis: a retrospective cohort study. AB - OBJECTIVE: This study aimed to investigate the time-sequential changes of risk factors for adult T-cell leukemia (ATL) development in human T-cell leukemia virus type 1 (HTLV-1)-positive rheumatoid arthritis (RA) patients. METHODS: HTLV 1 infection was screened using particle agglutination assay and confirmed via western blotting in 365 RA patients. Twenty-three HTLV-1-positive RA patients were included in the study cohort. Blood samples were obtained from these patients at each observation time point. The values of HTLV-1 proviral load (PVL) and serum soluble IL-2 receptor (sIL2-R), which are risk factors for ATL development, were measured using real-time PCR and enzyme immunoassay, respectively. RESULTS: The study cohort comprised 79 person-years. The median HTLV-1 PVL and sIL2-R values of the HTLV-1-positive RA patients were 0.44 copies per 100 white blood cells (WBCs) and 406 U/mL, respectively. Three HTLV-1 positive RA patients showed a high PVL value. No remarkable changes were observed in the PVL and sIL2-R values during the observation period. However, one elderly HTLV-1-positive RA patient who had a high PVL value developed ATL during treatment with methotrexate and infliximab. CONCLUSION: A thorough clinical assessment of the risk factors for ATL development may be necessary in daily clinical practice for RA patients in HTLV-1-endemic areas in Japan. PMID- 30246573 TI - Bovine serum albumin nanoparticles improve the antitumour activity of curcumin in a murine melanoma model. AB - Curcumin is a natural compound presenting important antitumour activity. However, due to its low aqueous solubility, instability at physiological pH, and low oral bioavailability, its clinical use is limited. Bovine serum albumin (BSA) nanoparticles have been used as drug carriers to improve the drug properties. In this work, curcumin-loaded BSA nanoparticles were developed and the in vitro cytotoxicity over murine melanoma cells and the in vivo antitumour activity in a murine melanoma model were assessed. Nanoparticles presented 150 nm, polydispersity index of 0.16, negative zeta potential, and 45% of curcumin encapsulation efficiency. Curcumin release from nanoparticles was slow and diffusion dependent. In the cytotoxicity assay, free curcumin was more efficient than curcumin-loaded nanoparticles, probably due to the prolonged curcumin release from nanoparticles. However, in a murine melanoma model, curcumin-loaded nanoparticles presented higher antitumour efficiency than free curcumin. BSA nanoparticles are efficient curcumin carriers that may have relevant applications in melanoma treatment. PMID- 30246574 TI - Cardiac arrest in the delivery room after spinal anesthesia for cesarean section: a case report and review of literature. AB - Cardiac arrest in pregnancy is a rare event due to different cause. When it occurs after spinal anesthesia a cause that can explain this event is the Bezold Jarish Reflex (BJR). A cardiac arrest occurs in a pregnant women after spinal anesthesia admistered for urgent caesarean section. During this event perimortem caesarean delivery (PMCD) is the rapid surgical way that can improve maternal and fetal outcomes. In this situation, it is very important to have a multidisciplinary team of midwives, obstetricians, anesthetists, neonatologists, intensivists that is able to perform perimortem caesarean delivery according to the guidelines. PMID- 30246575 TI - Abatacept for the treatment of psoriatic arthritis. AB - INTRODUCTION: Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by the presence of psoriasis, arthritis, and enthesitis, with the association of other musculoskeletal and extra-articular manifestations. Current treatment of PsA is based on the use of conventional, biological and targeted synthetic disease modifying anti-rheumatic drugs; however, patients may not respond or have a loss of response to these agents. Recently, a deeper understanding of the pathogenetic mechanisms has made possible the development of new drugs that actively interact with the activation of immune system, inhibiting the co-stimulation between antigen-presenting cells and lymphocytes. Areas covered: The aim of this paper is to review the role of the activation of the immune system in the pathogenesis and treatment of PsA, with a discussion on the emerging CTLA4Ig drugs (abatacept) for PsA. A search in PubMed and EMBASE was performed with the keywords: 'abatacept', 'CTLA4,' and 'Psoriatic Arthritis.' We considered preclinical studies, phase I, II and III clinical trials. Expert commentary: The inhibitors of co-stimulation may represent an effective treatment strategy by acting on the very early phase of the immunological process that brought about the development of inflammation and activation of the immune system, mainly for patients with peripheral joint involvement and mild psoriasis. PMID- 30246576 TI - Fermented barley extracts with Lactobacillus plantarum dy-1 changes serum metabolomic profiles in rats with high-fat diet-induced obesity. AB - We have previously reported an aqueous extract of fermented barley with Lactobacillus plantarum dy-1 (LFBE) has more efficient anti-obesity effect compared with that of Saccharomyces cerevisiae. To further explore associated effects of LFBE on body weight and body fat distribution, and lipid profiles related metabolic outcomes, serum metabolites were analysed using LC-MS-MS and partial least-squares-discriminant analysis (PLS-DA). Obese and lean groups were clearly discriminated from each other on PLS-DA score plot and major metabolites contributing to the discrimination were assigned as lipid metabolites (fatty acids), lipid metabolism intermediates (choline, betaine, carnitine and butyryl carnitine), amino acids and citric acid. A high-fat diet increased lipid metabolites and decreased lipid metabolism intermediates, indicating that abnormal lipid metabolism induced by a high-fat diet resulted in fat accumulation via decreased beta-oxidation. But LFBE can inhibit fat accumulation by reducing lipid metabolites and increasing lipid metabolism intermediates. Furthermore, the level changes of these metabolites can be used to assess the risk of obesity and the therapeutic effect of obesity management. PMID- 30246577 TI - Ovotestis at 18 years: an accidental discovery in an internally displaced persons' camp in North-Eastern Nigeria. PMID- 30246578 TI - Amnioinfusion for variable decelerations caused by umbilical cord compression without oligohydramnios but with the sandwich sign as an early marker of deterioration. AB - We report prophylactic amnioinfusion (AI) for variable decelerations in umbilical cord compression without oligohydramnios as an early sign of deterioration. We performed a transabdominal AI in cases without oligohydramnios using the ultrasonography findings of umbilical cord compression (i.e. sandwich sign [SWS]) and variable decelerations (VD) in a foetal heart rate. Thirteen cases and 21 AIs were analysed. Nine (69%) cases were of a foetal growth restriction and 4 (31%) had umbilical hyper-coiled cords. VD frequency (p < .0001), umbilical artery pulsatility index (PI) (p < .01) and ductus venous PI (0.66 vs. 0.48; p < .05) significantly decreased, and an umbilical venous (UV) flow volume (121 vs. 197 ml/min/kg; p < .05) significantly increased after AI. The umbilical artery diastolic blood flow abnormalities and UV pulsation improved. In conclusion, AI improves the umbilical cord compression even without oligohydramnios. The SWS is an important marker of deterioration to severe oligohydramnios and latent foetal damage. IMPACT STATEMENT What is already known on this subject? Antepartum variable decelerations due to umbilical cord compression are significantly associated with the deceleration in labour. In particular, foetal hypoxia leads to other adverse events such as foetal distress, hypoxic-ischemic encephalopathy, and pulmonary arterial hypertension after birth. Amnioinfusion has been shown to be effective in patients who also have oligohydramnios. What do the results of this study add? Amnioinfusion may be effective in the cases with ultrasonography findings of umbilical cord compression (i.e. sandwich sign) and in cases with variable decelerations in foetal heart rate, but without oligohydramnios. What are the implications of these findings for clinical practice and/or further research? Amnioinfusion may be helpful to prevent adverse events including oligohydramnios and anhydroamnios. PMID- 30246579 TI - Combining genetic and biophysical approaches to probe the structure and function relationships of the notch receptor. AB - Notch is a conserved cell signalling receptor regulating many aspects of development and tissue homeostasis. Notch is activated by ligand-induced proteolytic cleavages that release the Notch intracellular domain, which relocates to the nucleus to regulate gene transcription. Proteolytic activation first requires mechanical force to be applied to the Notch extracellular domain through an endocytic pulling mechanism transmitted through the ligand/receptor interface. This exposes the proteolytic cleavage site allowing the signal to be initiated following removal of the Notch extracellular domain. Ligands can also act, when expressed in the same cell, through non-productive cis-interactions to inhibit Notch activity. Furthermore, ligand selectivity and Notch activation are regulated by numerous post-translational modifications of the extracellular domain. Additional non-canonical trans and cis interactions with other regulatory proteins may modulate alternative mechanisms of Notch activation that depend on endocytic trafficking of the full-length receptor and proteolytic release of the intracellular domain from endo-lysosomal surface. Mutations of Notch, located in different regions of the protein, are associated with a spectrum of different loss and gain of function phenotypes and offer the possibility to dissect distinct regulatory interactions and mechanisms, particularly when combined with detailed structural analysis of Notch in complex with various regulatory partners. PMID- 30246580 TI - A fifty-year odyssey: prospects for a cytomegalovirus vaccine in transplant and congenital infection. AB - INTRODUCTION: It has been almost fifty years since the Towne strain was used by Plotkin and collaborators as the first vaccine candidate for cytomegalovirus (CMV). While that approach showed partial efficacy, there have been a multitude of challenges to improve on the promise of a CMV vaccine. Efforts have been dichotomized into a therapeutic vaccine for patients with CMV-infected allografts, either stem cells or solid organ, and a prophylactic vaccine for congenital infection. Areas covered: This review will evaluate research prospects for a therapeutic vaccine for transplant recipients that recognizes CMV utilizing primarily T cell responses. Similarly, we will provide an extensive discussion on attempts to develop a vaccine to prevent the manifestations of congenital infection, based on eliciting a humoral anti-CMV protective response. The review will also describe newer developments that have upended the efforts toward such a vaccine through the discovery of a second pathway of CMV infection that utilizes an alternative receptor for entry using a series of antigens that have been determined to be important for prevention of infection. Expert commentary: There is a concerted effort to unify separate therapeutic and prophylactic vaccine strategies into a single delivery agent that would be effective for both transplant-related and congenital infection. PMID- 30246582 TI - Erratum. PMID- 30246581 TI - A cohort study of isolated brainstem infarction based on head MR imaging and clinical findings. AB - Objective The prognosis of patients with isolated brainstem infarction (BSI) differs on an individual patient basis. This study was undertaken to analyze the influences of different imaging and clinical features with the prognosis of patients with BSI. Methods The study population was derived from a multicenter study of intracranial atherosclerosis in China. In the present study, 300 patients were selected who had experienced non-cardiogenic brain stem infarction within the prior 7 days. Evaluations included clinical characteristics, location and size of the brainstem infarction, and whether the infarction was located in multiple perforating branches of the brainstem. Poor prognosis was defined as the presence of disability within 1 year from the onset of disease. Results In total, 281 patients were followed up at 1 year post-infarction. Of these 281 patients, 84 (29.9%) exhibited disability at 1 year; these patients showed a median National Institutes of Health Stroke Scale score of 6 on admission. Multiple logistic regression analysis showed that patients with BSI located in the territory of multiple perforating arteries, who were discharged without administration of statins, showed a poor 1-year prognosis. Conclusion Isolated BSI involving multiple perforating arteries, without statin medication at discharge, indicated poor prognosis for patients with BSI. PMID- 30246583 TI - Influence of propofol on the electroencephalogram default mode network in patients of advanced age. AB - OBJECTIVE: This study was performed to evaluate the effects of propofol on the electroencephalogram (EEG) default mode network (DMN) in patients of advanced age. METHODS: Fifteen men aged >60 years (mean, 70 years) were selected. Propofol target-controlled infusion was performed under EEG bispectral index monitoring. The propofol target effect-site concentration, blood pressure, heart rate, and distributions and powers of the EEG spectrum were recorded in an awake state and under anesthesia. The EEG included seven bands: delta (0.5-3.5 Hz), theta (4.0 7.0 Hz), alpha-1 (7.5-9.5 Hz), alpha-2 (10-12 Hz), beta-1 (13-23 Hz), beta-2 (24 34 Hz), and gamma (35-45 Hz). RESULTS: From an awake state to anesthesia, the brain topographic map showed that the energies of delta, theta, alpha-1, alpha-2, and beta-1 were concentrated in the frontoparietal site, and the power increased significantly. The energy distribution of beta-2 was significantly decreased and the power significantly reduced. The energy distribution of gamma in the temporal lobe was also markedly decreased and the power significantly reduced. CONCLUSIONS: This study revealed the changes in the spatial distribution and regional energy of the EEG DMD in men of advanced age from the awake state to the anesthetized state. PMID- 30246584 TI - Mirizzi syndrome complicated by common hepatic duct fistula and left hepatic atrophy: a case report. AB - BACKGROUND: Mirizzi syndrome is a rare complication of chronic cholecystitis, usually caused by gallstones impacted in the cystic duct or the neck of the gallbladder. Mirizzi syndrome results in compression of the hepatic duct or fistula formation between the gallbladder and common bile duct (or hepatic duct, right hepatic duct, or even mutative right posterior hepatic duct). Clinical features include abdominal pain, fever, and obstructive jaundice. Severe inflammation and adhesion at Calot's triangle are potentially very dangerous for patients with Mirizzi syndrome undergoing cholecystectomy. Case presentation: We report the case of a 68-year-old Asian woman who presented with abdominal pain and jaundice. She had a medical history of gallstones, but no fever. Magnetic resonance cholangiopancreatography revealed cholecystitis, cholelithiasis, common hepatic duct stones, and ascites. Findings at surgery included a porcelainized, atrophic gallbladder that was full of gallstones, fistula formation between the gallbladder and common hepatic duct, and left hepatic atrophy. The prominent feature was the left hepatic atrophy, but stones were not visible pre-operatively in the left liver by radiologic examination. CONCLUSIONS: This patient exhibited what can be considered a special type II of Mirizzi syndrome with a fistula of the common hepatic duct as well as left hepatic atrophy. PMID- 30246585 TI - Intestinal dysbacteriosis activates tumor-associated macrophages to promote epithelial-mesenchymal transition of colorectal cancer. AB - In this study we investigated the association between intestinal dysbacteriosis with colorectal cancer progress and the underlying molecular mechanisms. Tumor progression was evaluated using xenograft mice model. The epithelial-mesenchymal transition (EMT) markers were quantified by both real-time PCR and immunoblotting. The serum content of IL-6 and TNF-alpha were measured with ELISA kits. Cell proliferation was determined by the Cell Counting Kit-8. Intestinal dysbacteriosis was successfully simulated by the administration of a large dose of antibiotics and was demonstrated to promote xenograft tumor growth and induce EMT. Accordingly, the serum concentrations of cytokines IL-6 and TNF-alpha were significantly increased. Furthermore, the production and secretion of IL-6 and TNF-alpha were remarkably elevated in macrophages isolated from intestinal dysbiotic mice in comparison with the normal counterparts, and conditioned medium from these was shown to significantly stimulate EMT process in HT29 cells in vitro. Macrophage depletion completely abrogated the pro-tumor effect of intestinal dysbacteriosis. Our results suggest that intestinal dysbacteriosis stimulates macrophage activation and subsequently induces EMT process via secreted pro-inflammatory cytokines IL-6 and TNF-alpha. PMID- 30246586 TI - Encephaloduroarteriosynangiosis for Pediatric Moyamoya Disease: A Single-Center Experience With 67 Cases in China. AB - The purpose of this study is to investigate the surgical results and long-term outcomes of encephaloduroarteriosynangiosis for moyamoya disease in pediatric patients. We performed a retrospective analysis of 67 pediatric patients with moyamoya disease who underwent encephaloduroarteriosynangiosis in Beijing Tiantan Hospital. The case series included 36 boys and 31 girls. All the patients underwent surgical revascularization, and a total of 93 encephaloduroarteriosynangiosis procedures were performed (41 unilateral, 26 bilateral). The mean follow-up period after surgery was 30 months. During follow up, ischemic stroke events were detected in 5 patients and the stroke rate for pediatric patients who underwent encephaloduroarteriosynangiosis procedure was 7.1% per patient-years. At the last follow-up, favorable outcomes (modified Rankin Scale score <= 2) were observed in 65 cases (97.0%). Our study suggests that long-term surgical outcome of encephaloduroarteriosynangiosis in pediatric moyamoya disease patients is satisfactory, and this technique has a positive impact on the prevention of stroke recurrence. PMID- 30246587 TI - A systematic review of injuries in gymnastics. AB - OBJECTIVES: To identify all studies of gymnastics injuries and assess injury rates, types, locations, and causes. METHODS: Seven electronic and two grey literature databases were searched. Two reviewers independently assessed titles/abstracts, abstracted data, and calculated average rates weighted by study size. RESULTS: One study (n = 963) of three Olympic games (2008,2012,2016) provided injury rates for females of 86.4/1000gymnasts and males 79.9. For 29 databases one study of males (n = 64) provided a rate of 8.8 injuries/1000hours/AE (AE = athletic-exposure) and three of females varied rates (8.5, 9.4, and 91). Three studies for males (n = 153) provided a weighted average rate of 1.4 injuries/1000hours/training, and for females six studies (n = 476) 1.5 injuries. Four studies of males (n = 286) provided a weighted average of 678 injuries/1000gymnasts per year and eight studies of females (n = 1,764) a rate of 306. Of 19 surveys, eight provided rates for females (n = 1,463) of 596 injuries/gymnast per year and two for males (n = 40) a rate of 1,036. In the Olympics injuries were preponderately lower limb (63%) then trunk (23%) and upper limb (14%); injury type was sprains (35%) followed by tendinopathy/arthritis/impingements (17%), contusions (10%), and fractures (7%). Five database studies provided injury location data for 274 males: averages weighted by study size were upper extremity 42.8%, lower extremity 33.6%, torso/spine 11.8%, and head/neck 4.9% and 12 studies with 843 females provided average rates for lower extremity 51%, upper extremity 30.8%, torso/spine 13% and head/neck 0.8%. Official gymnastics organizations' websites provide no readily available data about injury rates or methods of prevention. CONCLUSIONS: Studies need to collect comprehensive data for injury rates by training/competitions, gender, age, injury location/type/cause. Studies could assess whether trainers and physiotherapists monitoring gymnasts closely for injury risk would reduce injuries. Studies including randomized controlled trials (RCTs) of interventions in training, videotaping and performance feedback to reduce injury rates would be helpful. PMID- 30246588 TI - Utilization of Screening Mammograms in the Medicare Population Before and After the Affordable Care Act Implementation. AB - OBJECTIVE: This study examined screening mammograms in women aged 65 to 74 years and 75+ years before and after the Affordable Care Act (ACA) implementation. METHOD: This repeated cross-sectional study of community-dwelling women age 65+ years without a history of breast cancer or mastectomy utilized the Medicare Current Beneficiary Survey and Medicare fee-for-service claims data from 2001 to 2013. We used covariate-adjusted logistic regression with generalized estimating equations, stratified by age group. RESULTS: The adjusted odds of screening mammograms in women aged 65-74 ( n = 742) and 75+ years ( n = 681) were lower in 2013 (odds ratio [OR]: 0.75, 95% confidence interval [CI]: [0.67, 0.83]; OR: 0.67, 95% CI: [0.60, 0.75], respectively) than the odds of screening mammograms in 2001. DISCUSSION: Annual screening mammograms decreased in women aged 65 to 74 years and 75+ years, despite increased access from the ACA implementation. Future research as to why women are no longer receiving screening mammograms, such as changes in physician specialty guidelines, is warranted. PMID- 30246589 TI - Social Reactions to Sexual Assault Disclosure: The Role of Posttraumatic Cognitions. AB - Sexual assault can have a detrimental impact on women's mental, physical, sexual, and interpersonal health and well-being. After experiencing sexual assault, 74% to 88% of individuals disclose the assault to someone they trust. After such disclosures, individuals experience both perceived positive and negative reactions. While positive reactions may be protective and aid in recovery, negative reactions can contribute to feelings of self-blame and maladaptive beliefs about the cause of the assault. Previous studies have shown independent associations between social reactions, negative cognitions, and posttraumatic stress symptoms (PTSS) following sexual assault. However, prior research has not explored the joint role of social reactions and posttraumatic cognitions in relationship to PTSS and sexual assertiveness. Moreover, the mechanism regarding these associations is not well established. The present study tested a path model of the effects of social reactions (positive and negative) to disclosure of sexual assault on posttraumatic cognitions, PTSS, and sexual assertiveness in college women. It was hypothesized that posttraumatic cognitions would mediate the relationship between social reactions and both sexual assertiveness and PTSS. A total of 102 college women participated in the study and completed measures of Sexual Experiences, Social Reactions, Posttraumatic Cognitions, PTSS, and Sexual Assertiveness. Results indicated that negative social reactions were indirectly associated with sexual assertiveness through posttraumatic cognitions. Social reactions were indirectly associated with PTSS partially through posttraumatic cognitions. Furthermore, there was a direct relationship between negative social reactions and PTSS. Positive social reactions were not significantly associated with outcome variables. Results highlight the influential nature of negative social reactions and posttraumatic cognitions. The importance of educating bystanders on the influence of social reactions is further discussed. PMID- 30246590 TI - Do dietary amino acid ratios predict risk of incident hypertension among adults? AB - In the current study, we investigated the association between dietary amino acid ratios and the 3-year incidence of hypertension, conducted in the framework of the Tehran Lipid and Glucose Study with 4287 adults(41.9% men), aged 20-70 y. Dietary intakes of amino acids were assessed using a valid and reliable food frequency questionnaire and reported as percentage of protein. Then amino acid ratios including Leu.Ser/Thr.Trp, Leu/Trp, Leu/Thr, and Ser/Thr were calculated. We identified 429(10%) cases of hypertension during 3.1 y of follow up. The adjusted OR of the highest quartile of dietary Leu.Ser/Thr.Trp intake was 1.48 (95%CI:1.04-2.09, P for trend:0.02) compared with the lowest one. Furthermore, the OR of hypertension in the highest, compared with the lowest quartile of the leu/Thr ratio(2.19 vs 2.02) was 1.46(1.01-2.12), P for trend = 0.07. Our findings suggest that high dietary intakes of Leu.Ser/Thr.Trp ratio were associated with higher risk of incident hypertension and BP levels. PMID- 30246591 TI - "Crossover" in Depressive Symptoms Among Older Couples: Are Previous Findings Artifactual? AB - OBJECTIVE: This study examined effects of a partner's depressive symptoms on those of a focal respondent. METHOD: Data were from the 2008-through-2014 waves of the Health and Retirement Study. Linear growth modeling was used to distinguish within- from between-person variation, and genetic instrumental variables to take endogeneity into account. RESULTS: A partner's 2008 depressive symptoms had no associations with within-person change in those of a respondent between 2010 and 2014. Corresponding linkages with their between-person variation in 2010 were positive and significant for both genders. Among women, these last estimates remained intact in genetic instrumental variable models restricted to white couples. DISCUSSION: Results indicate that contrary to previous literature, late life relationships are not marked by "crossover" of depressive symptoms. Women's affect may, however, be influenced by such transmission in the relationship's history. Beyond depression, findings suggest current theories of dyadic health effects may partly rest on flawed evidence. PMID- 30246592 TI - Induction of the pneumococcal vncRS operon by lactoferrin is essential for pneumonia. AB - Streptococcus pneumoniae (pneumococcus), the major pathogen for pneumonia, commonly colonizes the lung, but the mechanism underlying the coordination of virulence factors during invasion via the host protein remains poorly understood. Bacterial lysis releases the components of the cell wall, and triggers innate immunity and the subsequent secretion of pro-inflammatory cytokines. Previously, the virulence of the pep27 mutant was shown to be attenuated as a feasible candidate for vaccine development. However, the role of pep27 gene, belonging to the vancomycin-resistance locus (vncRS operon), in virulence, is largely unknown. This study demonstrates that transferrin in the host serum reduces the survival of the host during S. pneumoniae infections in mice. The exposure of the pneumococcal D39 strain to lactoferrin induced the vncRS operon, lysis, and subsequent in vivo cytokine production, resulting in lung inflammation. However, these responses were significantly attenuated in pneumococci harboring a mutation in pep27. Mechanistically, the VncS ligand, identified as lactoferrin, induced the vncRS operon and increased the in vivo mortality rates. Thus, serum-induced activation of vncRS plays an essential role in inducing pneumonia. PMID- 30246594 TI - Preterm and term preeclampsia: differences in biochemical parameter and pregnancy outcomes. AB - OBJECTIVE: To analyze the similarities and differences in the clinical parameters, laboratory biomarkers, and pregnancy outcomes between preterm and term preeclampsia (PE). METHODS: Data on 185 women diagnosed with PE were collected from a Jiangsu Province Hospital from January 2017 to December 2017 and analyzed. 74 (40%) patients were diagnosed with preterm PE, of which 70 (94.6%) patients with PE with severe features (PEs) and the rest with PE. 111 (60%) patients were diagnosed with term PE, of which 54 (48.6%) patients with PEs and the rest with PE. RESULTS: Preterm PE group had significantly higher blood pressure than that of term PE, with mean delivery at gestational age of 34.3[Formula: see text]2.1 weeks for preterm PE and 39[Formula: see text]1.2 weeks for term PE. Preterm PE group was associated with previous cesarean section and PE history, fetal growth restriction (FGR), non-reassuring fetal status (NRFS), and fetal umbilical artery (UA) systolic velocity/diastolic velocity ratio (S/D R) abnormality, neonatal lower birth weight, lower APGAR score, and higher NICU transfer rate. 74.3% of pregnant women from preterm PE group had proteinuria of +2 to +4, whilst only 37.8% pregnant women from term PE group developed that condition. Liver and renal function, also serum Ca and K were significantly higher in preterm PE. CONCLUSION: Our study found that preterm PE significantly correlated with higher incidence of PEs, neonatal morbidities, also higher liver and kidney function compared to term PE. These results may be helpful for obstetricians to make accurate quantification of risk regarding every result of antenatal check-up, and perform close follow up if any abnormalities were found on blood pressure, ultrasound, or blood tests. PMID- 30246595 TI - Mortality during US FDA clinical trials in patients with diabetes, hypertension, depression and schizophrenia. AB - OBJECTIVES: To evaluate the relationship between the mortality rates associated with psychiatric conditions like depression and schizophrenia compared with chronic medical conditions like hypertension and diabetes. METHODS: Examined clinical trial safety data from New Drug Approval programmes reviewed by the US Food and Drug Administration and calculated all-cause and suicide/non-suicide mortality rates per 100,000 patient-exposure-years (PEY) for seven diabetes, 12 hypertension, 11 depression, and nine schizophrenia programmes (126,151 patients, 63,106.3 PEY). RESULTS: Depression (894.8 +/- 201.2) and schizophrenia (935.3 +/- 214.6) had significantly higher all-cause mortality rates than diabetes (462.8 +/ 70.8) and hypertension (448.4 +/- 123.1). Psychiatric conditions had 1.9-2.1* the medical conditions' mortality (p < 0.001). Non-suicide mortality rates for depression (506.2 +/- 151.3), schizophrenia (550.9 +/- 164.7), diabetes (457.2 +/ 70.4) and hypertension (430.8 +/- 120.6) were comparable. Only antidiabetics showed a signal for all-cause mortality (reduction of 37%, p = 0.008). CONCLUSIONS: Depression and schizophrenia trial patients had comparable (if not higher) all-cause mortality rates as older populations in diabetes and hypertension trials, even when excluding suicides. While generalizability of the rates themselves is limited, this study can adequately estimate the relational mortality among these conditions because of the high internal consistency of clinical trials. Potential signals for mortality reduction with active treatment should be considered for all investigational medications for chronic conditions with increased mortality, including psychotropics. PMID- 30246593 TI - Rare-Earth-Doped Nanoparticles for Short-Wave Infrared Fluorescence Bioimaging and Molecular Targeting of alphaVbeta3-Expressing Tumors. AB - The use of short-wave infrared (SWIR) light for fluorescence bioimaging offers the advantage of reduced photon scattering and improved tissue penetration compared to traditional shorter wavelength imaging approaches. While several nanomaterials have been shown capable of generating SWIR emissions, rare-earth doped nanoparticles (REs) have emerged as an exceptionally bright and biocompatible class of SWIR emitters. Here, we demonstrate SWIR imaging of REs for several applications, including lymphatic mapping, real-time monitoring of probe biodistribution, and molecular targeting of the alphavbeta3 integrin in a tumor model. We further quantified the resolution and depth penetration limits of SWIR light emitted by REs in a customized imaging unit engineered for SWIR imaging of live small animals. Our results indicate that SWIR light has broad utility for preclinical biomedical imaging and demonstrates the potential for molecular imaging using targeted REs. PMID- 30246597 TI - Melatonin Administration Methods for Research in Mammals and Birds. AB - Endocrine research in animals often entails exogenous hormone administration. Special issues arise when developing administration protocols for hormones with circadian and seasonal periodicity. This article reviews various methods for the exogenous administration of hormones with such periodicities by focusing on melatonin. We discuss that methodological variations across studies can affect experimental results. Melatonin administration techniques used in vertebrates includes infusion pumps, beeswax pellets, oral administration, injections, SILASTIC capsules, osmotic pumps, transdermal delivery, beads, and sponges. PMID- 30246596 TI - Experimental effects of exercise on memory function among mild cognitive impairment: systematic review and meta-analysis. AB - OBJECTIVE: The objective of this study was to evaluate the experimental effects of exercise on memory function among adults with mild cognitive impairment (MCI). METHODS: A systematic review and meta-analysis were employed. Studies were identified using electronic databases, including PubMed, PsychInfo, SPORTDiscus, and Google Scholar. To be eligible for inclusion, studies had to employ an experimental design, be conducted in humans (no animal models) with mild cognitive impairment, include an exercise intervention arm (either acute exercise or chronic training), and measure memory function (any type) as the outcome measure. Comprehensive Meta-Analysis software was used to compute the standardized mean difference effect size (Cohen's d) and 95% CI using a random effects model. RESULTS: In total, 11 studies met our criteria, contributing to 20 effect size estimates. Among the 20 effect size estimates, 13 contributed to a short-term memory recall, with 7 contributing to a delayed/long-term memory recall. The overall weighted mean effect size was d = 0.30 (95% CI: 0.16-0.44; P < 0.001), indicating a small to medium effect of exercise on improving memory function. For the moderation analysis, there was no evidence of a moderation effect for recall duration (Q = 0.004, df(1), P = 0.95), as exercise (vs. control) demonstrated both short-term (d = 0.31; 95% CI: 0.14-0.47; P < 0.001) and long-term memory (d = 0.29; 95% CI: 0.06-0.53; P = 0.013) benefits. CONCLUSION: Current evidence suggests that exercise may help to improve memory function among those with MCI. Safe and progressive forms of exercise should be promoted among MCI patients. PMID- 30246598 TI - A preliminary investigation of reaction time variability in relation to social functioning in children evaluated for ADHD. AB - Reaction time variability (RTV) is a ubiquitous phenomenon in Attention Deficit/Hyperactivity Disorder (ADHD). Few studies have examined RTV in relation to functional outcomes such as social impairment in children with ADHD. In this exploratory study, we investigated whether RTV is associated with social functioning in children at risk for ADHD. Specifically, we explored the association between RTV (tau derived from correct go trials of a Stop-Signal task) and social functioning in 198 children ages 7-12 years referred for an ADHD evaluation. Social functioning measures included child and/or parent ratings of social competence, aggression, social problems, and impairment in relationships. In regression analyses that also included Oppositional Defiant Disorder symptoms and sex, higher RTV was significantly associated with lower ratings of social competence, and higher proactive/reactive aggression ratings on the child self report measures. RTV was not significantly associated with parent report of social functioning or relationship impairment. This study provides preliminary evidence that RTV may be associated with social functioning in children at risk for ADHD. We propose that lapses of attention affecting cognitive control may also negatively impact social information processing thereby affecting social functioning. Replication is warranted and longitudinal studies are needed to investigate whether RTV predicts social dysfunction in ADHD. PMID- 30246599 TI - Adipose tissue and body composition in women six years after gestational diabetes: factors associated with development of type 2 diabetes. AB - Factors differentiating women at highest risk of progression to type 2 diabetes mellitus (T2DM) after gestational diabetes mellitus (GDM) are incompletely known. Our aim was to characterize adipose tissue and body composition in relation to glucose metabolism in women with a history of GDM and to identify factors associated with development of T2DM. We examined glucose tolerance (OGTT), insulin sensitivity (HOMA-IR), body composition (anthropometry, air displacement plethysmography), and blood chemistry in 39 women 6 years after GDM. An adipose tissue biopsy was obtained to assess the size, number, and lipolytic activity of adipocytes, and adipokine release and density of immune cells and blood vessels in adipose tissue. Normal glucose tolerance (NGT) was identified in 31 women and impaired glucose metabolism (IGM) in 8. Women with IGM had higher BMI/fat mass, and related expected adipose tissue features, than women with NGT. Ethnicity was similar in the groups, but numerically there was a higher proportion of European women in the NGT group and a higher proportion of non-European women in the IGM group. BMI was the best discriminator of NGT versus IGM (multivariable logistic regression: OR = 1.34, P < 0.01). Waist-to-height ratio and adipocyte volume were most strongly associated with HOMA-IR (multivariable linear regression: R2 = 0.656, P < 0.001). After adjustment for BMI/ethnicity, women with IGM had increased serum adipocyte fatty acid-binding protein, weight gain after index pregnancy, and a lower proportion of fat-free mass. These factors, together with high BMI, abdominal fat distribution, and enlarged adipocytes, may increase the risk of progression to T2DM after GDM. PMID- 30246600 TI - Indirect Effects From Childhood Sexual Abuse Severity to PTSD: The Role of Avoidance Coping. AB - Men who have sex with men (MSM) disproportionately experience childhood sexual abuse (CSA) compared with heterosexual men, often resulting in continued trauma related sequelae, including symptoms of posttraumatic stress disorder (PTSD) such as avoidance. The variability in trauma-related sequelae may be associated with chronicity or duration of CSA. The relationship between duration of CSA and later PTSD symptom severity is not well understood, including the extent coping strategies account for these relationships. We used linear regression to examine these relationships and to assess the indirect effects of avoidance (behavioral disengagement and denial) and adaptive coping strategies on the relationship between CSA duration and adult PTSD symptom severity on a diverse sample included 290 MSM with a history of CSA. In adjusted models, CSA duration was significantly associated with adult PTSD symptom severity (standardized beta = .23, p < .000) and with avoidance coping (standardized beta = .19, p = .002). Separating this out, behavioral disengagement was significantly associated with CSA duration (standardized beta = .20, p = .001) but denial was not. In adjusted analyses assessing indirect effects, avoidance coping partially accounted for the relationship between CSA duration and total trauma symptom severity (standardized beta reduced from .23 to .17; Sobel = 2.90, p = .004). Similarly, behavioral disengagement partially accounted for the association between CSA duration and total symptoms (standardized beta reduced from .23 to .18; Sobel = 2.68, p = .007). Avoidance coping, and behavioral disengagement specifically, may play a role in the severity of PTSD symptoms experienced by MSM with CSA histories. This work emphasizes the need for clinicians to consider behavioral disengagement in understanding PTSD symptom severity among MSM with histories of CSA. PMID- 30246602 TI - Clinical predictors of active LN development in children - evidence from the UK JSLE Cohort Study. AB - BACKGROUND: Juvenile-onset systemic lupus erythematosus (JSLE) patients may develop lupus nephritis (LN) during their initial presentation, or later in their disease. This study aimed to assess whether clinical/demographic factors characterize patients with LN within the United Kingdom JSLE Cohort Study, and whether such factors predict subsequent LN development. METHODS: Univariate logistic regression modelling compared clinical/demographic factors in patients with and without LN at baseline. For those who subsequently developed LN, Cox proportional-hazard modelling was used to test the association between such factors and time to LN development. Covariates with p < 0.2 univariately were included within a multiple-regression model. RESULTS: A total of 121/331 (37%) patients presented with active LN at baseline, with first American College of Rheumatology (ACR) score ( p < 2.0 * 10-16), severe hypertension ( p = 0.0006), proteinuria ( p < 2.0 * 10-16), creatinine ( p = 1.0 * 10-16), erythrocyte sedimentation rate ( p = 1.0 * 10-16), neutrophils ( p < 2.0 * 10-16), complement 3 (C3) ( p = 4.0 * 10-16) and ethnicity ( p = 3.0 * 10-13) differing between those with and without LN. Of the 210 individuals without active LN at baseline, 13 patients had a single visit and were excluded from further analysis. Thirty four of 197 (17%) developed LN after a median of 2.04 years (interquartile range, 0.8-3.7), with higher ACR scores ( p = 0.014 , hazard ratio (HR) = 1.45, 95% confidence interval (CI) = 1.08-1.95) and lower C3 levels ( p = 0.0082 , HR = 0.27, 95% CI = 0.10-0.68) demonstrated as predictors of subsequent LN. CONCLUSIONS: Clinical and demographic factors can help to characterize patients at increased risk of LN. PMID- 30246603 TI - Parental presence with encouragement alters feedback processing in preschoolers: An ERP study. AB - External feedback plays an important role in adapting to the environment; however, feedback processing in preschoolers has not been fully understood. The present event-related brain potential (ERP) study sought to understand the influence of parental presence with encouragement on feedback processing by focusing on reward positivity (RewP: mean amplitude between 200-350 ms). Five year-old children (N = 21) completed an animal search task both alone (the alone condition) and with a parent who offered words of encouragement (the with a parent condition). ERPs were recorded while they received negative and positive feedback. We found a larger RewP amplitude in response to positive feedback in the with a parent condition relative to in the alone condition. In addition, differences in RewP between positive and negative feedback were only observed in the with a parent condition. These findings suggest that everyday parental encouragement has the potential to promote differential positive and negative feedback processing possibly by enhancing the reward value of positive feedback. PMID- 30246604 TI - Attachment security in companion dogs: adaptation of Ainsworth's strange situation and classification procedures to dogs and their human caregivers. AB - This exploratory study describes the development of a classification system for dogs' attachment security to caregivers that adheres closely to Ainsworth's seminal methodology. Fifty-nine adult dogs and caregivers participated in a mildly threatening laboratory encounter with a stranger (TS) and the Strange Situation (SSP). Dog and attachment experts adapted Ainsworth's classification system for the behavioral repertoire of the dog. Four potentially comparable patterns of attachment were identified. The proportions of secure and insecure classifications (61% and 39%) were similar to those found in human toddlers. Caregivers' sensitivity to their dogs during the TS procedure significantly differentiated dogs with secure vs. insecure classifications Lower scores on the Active/excited personality scale on the Monash Canine Personality Questionnaire Revised (MCPQ-R) also were related to secure classification. This system now makes it possible to compare directly the effects of human and dog attachment patterns on the health and emotional well-being of humans and dogs. PMID- 30246605 TI - A contemporary view of platelet-rich plasma therapies: moving toward refined clinical protocols and precise indications. AB - The positive extensive clinical experience with platelet-rich plasma (PRP) in different medical areas has prompted researchers to explore clinical opportunities for optimized PRP therapies. PRP is safe but we have to make it more effective. The growing diversity of formulations and presentations enrich the field of PRP research and offer hope to refine clinical indications. Moving toward targeting the right disease phenotypes with the right PRP formulation or combination product (PRP + cell products) can offer opportunities to change treatment options in osteoarthritis and nonhealing wounds. Both are active areas of research that could offer opportunities, although cost efficacy is still an open question. Our position is to believe that these serious disease areas are likely to benefit from PRP therapies. PMID- 30246606 TI - Relative age effect: Characteristics of youth soccer players by birth quarter and subsequent playing status. AB - PURPOSE: To compare characteristics of club level male soccer players 11 and 13 years of age, and to evaluate playing status in soccer two and 10 years after baseline by birth quarter (BQ). METHODS: Youth players 11 (n = 62, born 1992, observed December 2003) and 13 (n = 50, born 1990, observed April 2004) years were grouped by BQ. Baseline data included stature, weight, maturity status, functional capacities, soccer skills, goal orientation, and coach evaluation of potential. Playing status in soccer in 2006 and 2014 was also available. Baseline characteristics and subsequent playing status were compared by BQ. RESULTS: Baseline characteristics did not differ by BQ except for age and percentage of predicted adult height. Though not significant, coaches tended to rate players in BQ1as higher in potential. For those competing in soccer as adults, BQ2 (4), BQ3 (5) and BQ4 (2) were represented among players11 years, and BQ1 (3), BQ2 (2), BQ3 (1) and BQ4 (4) among players 13 years. CONCLUSION: Although limited to small numbers, differences among players by BQ were inconsistent. The results indicate a need to extend potential explanations of the RAE to include behavioral variables, coaches, training environment, and perhaps the culture of the sport. PMID- 30246607 TI - Acid-related anal lesions in an Ivory Coast refugee. PMID- 30246609 TI - Unexpected cause of recurrent haemoptysis. PMID- 30246608 TI - Distribution-free models for latent mixed population responses in a longitudinal setting with missing data. AB - Many biomedical and psychosocial studies involve population mixtures, which consist of multiple latent subpopulations. Because group membership cannot be observed, standard methods do not apply when differential treatment effects need to be studied across subgroups. We consider a two-group mixture in which membership of latent subgroups is determined by structural zeroes of a zero inflated count variable and propose a new approach to model treatment differences between latent subgroups in a longitudinal setting. It has also been incorporated with the inverse probability weighted method to address data missingness. As the approach builds on the distribution-free functional response models, it requires no parametric distribution model and thereby provides a robust inference. We illustrate the approach with both real and simulated data. PMID- 30246610 TI - Framing Blame in Sexual Assault: An Analysis of Attribution in News Stories About Sexual Assault on College Campuses. AB - This article examines media coverage of sexual assault cases on college campuses using content analysis methodology. Utilizing Attribution Theory and Media Framing, this article analyzes the methods and frequency in which the language in sexual assault news stories assigns or minimizes attribution. Key variables include references to alcohol consumption, clothing, Greek systems, and case management by school administrators. Key discoveries were made, including the journalists' use of language showing support or doubt of victims. This study has implications for scholars, journalists, educational administrators, and society in general as we consider the ongoing framing of sexual assault. PMID- 30246611 TI - Why industrial production of red blood cells from stem cells is essential for tomorrow's blood transfusion. PMID- 30246612 TI - Exploring the Influence of Hookup Culture on Female and Male Rape Myths. AB - The present study systematically assesses the influence of hookup culture endorsement on the acceptance of female rape myths (i.e., false, stereotypical, or prejudicial beliefs regarding sexual assault involving female survivors) and male rape myths (i.e., false, stereotypical, or prejudicial beliefs about sexual assault involving male survivors). Multivariate regression analyses were conducted to assess the primary hypotheses that a particular form of hookup culture endorsement (i.e., the belief that hookups elevate an individual's social status) would act as the primary predictor of male and female rape myth acceptance among a sample of 376 U.S. college students. As with prior research, a complex relationship emerged for both male and female rape mythology in which acceptance increases or decreases based upon the form of hookup culture endorsement examined, as the endorsement of beliefs reflecting heterosexual power dynamics (e.g., harmlessness and status attainment) functioned as positive predictors of rape myth acceptance, while beliefs challenging such assumptions (e.g., sexual freedom) served to decrease rape myth acceptance. Results supported the primary hypotheses that beliefs concerning hookups and status attainment would be the largest predictor of male rape myth acceptance and female rape myth acceptance. Consistent with prior research, the predictive power of gender and religiosity was initially significant across both male and female rape myth acceptance yet diminished when controlling for levels of hookup culture endorsement. Furthermore, analyses indicated gender differences among the influences of hookup culture endorsement for female rape myth acceptance alone, as even though beliefs concerning status served as an aggravating factor for female rape myth acceptance, beliefs concerning sexual freedom served as a mitigating factor for women only. PMID- 30246613 TI - Improved quality of life following constraint-induced movement therapy is associated with gains in arm use, but not motor improvement. AB - BACKGROUND: Constraint-induced movement therapy (CI therapy) is one of few treatments for upper extremity (UE) hemiparesis that has been shown to result in motor recovery and improved quality of life in chronic stroke. However, the extent to which treatment-induced improvements in motor function versus daily use of the more affected arm independently contribute to improved quality of life remains largely unexplored. OBJECTIVE: The objective of this study is to identify whether motor function or daily use of a hemiparetic arm has a greater influence on quality of life after CI therapy. METHODS: Two cohorts of participants with chronic stroke received either in-person CI therapy (n = 29) or video-game home based CI therapy (n = 16). The two cohorts were combined and the motor-related outcomes (Wolf Motor Function Test, Action Research Arm Test, Motor Activity Log [MAL]) and quality of life (Stroke-Specific Quality of Life) were jointly modeled to assess the associations between outcomes. RESULTS: The only outcome associated with improved quality of life was the MAL. Improvements in quality of life were not restricted to motor domains, but generalized to psychosocial domains as well. CONCLUSIONS: Results suggest that improved arm use during everyday activities is integral to maximizing quality of life gains during motor rehabilitation for chronic post-stroke UE hemiparesis. In contrast, gains in motor function were not associated with increases in quality of life. These findings further support the need to implement techniques into clinical practice that promote arm use during daily life if improving quality of life is a main goal of treatment. ClinicalTrials.gov Registration Numbers: NCT01725919 and NCT03005457. PMID- 30246614 TI - Channels in a porous scaffold: a new player for vascularization. AB - Vascularization is essential for tissue regeneration. Despite extensive efforts in the past decades, sufficient and rapid vascularization remains a major challenge in tissue engineering. Many studies have shown that the addition of channels in a porous scaffold can provide the ability to promote cell growth and rapid vascularization, thus leading to better outcomes in new tissue formation. Large size scaffolds lack perfusable channel networks and negatively impair the survival of transplanted cells and tissue function development, leading to necrotic core formation and the failure of functional tissue formation. Presently, there are many methods to produce channels in porous scaffolds for vascularization. Here, we review the function of channels in porous scaffolds and the approaches to produce those channels. PMID- 30246615 TI - The experience and professional development of medical appraisers. AB - This article explores the experiences of General Practitioner (GP) appraisers working in a unfamiliar setting (Jersey) with appraisees new to the process. Findings were interpreted using the learning theory, 'situated cognition', to shed light on the experience of appraisers working with new appraisees more generally and contribute to new understandings of workplace learning. Rich qualitative data derived from transcripts of nine in-depth interviews with GP appraisers were analysed thematically in a rigorous and iterative manner process. GP appraisers working in an unfamiliar environment shared a common sense of culture shock and discomfort. Initially, they needed to work much harder than usual to establish rapport and credibility, but by the second round of appraisals, appraisers were reminded of the power of appraisal. The innovative application of 'situated cognition' helps to explain why appraisers felt like 'novices' in Jersey and how they were required to reconstruct their professional knowledge. This is the first time appraiser development has been considered in this way and appraisers can be helped to develop professionally if they are offered a mix of appraisal-related activities in new places and with new people. Such implications for educational support apply internationally where doctors are involved in a process of peer review as part of on-going professional development. PMID- 30246616 TI - 'How was it for you?' - GP trainees' experiences of a novel practice swap. AB - Newly-qualified General Practitioners (GPs) are underprepared for the challenges of working as independent GPs. This study describes a practice swap - an innovative experiential learning opportunity to increase confidence amongst final year GP trainees for the challenges of future work. The effectiveness of the practice swap was evaluated across two separate GP training areas using questionnaires for GP trainees, practice managers, educational supervisors and newly-qualified GPs. In addition, GP trainees were interviewed in focus groups. The results demonstrated the positive educational value of the practice swap. GP trainees reported increased confidence in the ability to work as independent GPs specifically as a locum doctor, improved Information Technology (IT) competence, clinical knowledge and time keeping. The practice swap helped to inform the trainees on future career choices. Practice swapping has become one of the building blocks of a wider programme to equip newly-qualified GPs for the numerous challenges of being a GP, with a series of workshops on self-employment, job applications, practice management and IT training. The arrangements and benefits of practice swapping are transferrable to other GP Training Schemes across the UK and possibly internationally. PMID- 30246617 TI - Examining Men's Perceptions of GBV Prevention Programming Content. AB - As global efforts to engage men in preventing gender-based violence (GBV) continue to grow, understanding male participants' perceptions of prevention events is needed. Data from a global sample of 319 men who had attended GBV prevention events were used to (a) assess men's perceptions of what topics were covered, (b) determine whether profiles of these perceptions could be identified, and (c) describe the degree to which content prerception profiles are associated with levels of men's motivation and confidence related to antiviolence action. Latent class analysis identified four perception profiles of prevention topics. Implications for GBV prevention programming are discussed. PMID- 30246618 TI - Toll-like receptor 2 and Toll-like receptor 4 predict favorable prognosis in local pancreatic cancer. AB - Toll-like receptors play an essential role in our innate immune system and are a focus of interest in contemporary cancer research. Thus far, Toll-like receptors have shown promising prognostic value in carcinomas of the oral cavity, colon, and ovaries, but the prognostic role of Toll-like receptors in pancreatic ductal adenocarcinoma has not been established. We set out to investigate whether Toll like receptor expression could serve in prognostic evaluation in pancreatic ductal adenocarcinoma, as well. Our study comprised 154 consecutive stage I-III pancreatic ductal adenocarcinoma patients surgically treated at Helsinki University Hospital between 2002 and 2011. Patients who received neoadjuvant therapy were excluded. Tissue microarrays and immunohistochemistry allowed assessment of the expression of Toll-like receptor 2 and Toll-like receptor 4 in pancreatic ductal adenocarcinoma tissue, and we matched staining results against clinicopathological parameters using Fisher's test. For survival analysis, we used the Kaplan-Meier method and the log-rank test, and the Cox regression proportional hazard model for univariate and multivariate analyses. The hazard ratios were calculated for disease-specific overall survival. Strong Toll-like receptor 2 expression was observable in 51 (34%) patients and strong Toll-like receptor 4 in 50 (33%) patients. Overall, neither marker showed any direct coeffect on survival. However, strong Toll-like receptor 2 expression predicted better survival when tumor size was less than 30 mm (hazard ratio = 0.30; 95% confidence interval = 0.13-0.69; p = 0.005), and strong Toll-like receptor 4 expression predicted better survival in patients with lymph-node-negative disease (hazard ratio = 0.21; 95% confidence interval = 0.07-0.65; p = 0.006). In conclusion, we found strong Toll-like receptor 2 and Toll-like receptor 4 expressions to be independent factors of better prognosis in pancreatic ductal adenocarcinoma patients with stage I-II disease. PMID- 30246619 TI - Osteopontin is indispensable for activation of astrocytes in injured mouse brain and primary culture. AB - OBJECTIVES: Osteopontin (OPN) is an inflammatory cytokine inducer involved in cell proliferation and migration in inflammatory diseases or tumors. To investigate the function of OPN in astrocyte activation during brain injury, we compared OPN-deficient (OPN/KO) with wild-type (WT) mouse brains after stab wound injury and primary culture of astrocytes. METHODS: Primary cultures of astrocytes were prepared from either WT or OPN/KO postnatal mouse brains. Activation efficiency of astrocytes in primary culture was accessed using Western blotting by examining the protein levels of glial fibrillary acidic protein (GFAP) and tenascin-C (TN-C), which are markers for reactive astrocytes, following lipopolysaccharide (LPS) stimulation. Furthermore, the stab wound injury on the cerebral cortex as a brain traumatic injury model was used, and activation of astrocytes and microglial cells was investigated using immunofluorescent analysis on fixed brain sections. RESULTS: Primary cultures of astrocytes prepared from WT or OPN/KO postnatal mouse brains showed that only 25% of normal shaped astrocytes in a flask were produced in OPN/KO mice. The expression levels of both GFAP and TN-C were downregulated in the primary culture of astrocytes from OPN/KO mice compared with that from WT mice. By the immunofluorescent analysis on the injured brain sections, glial activation was attenuated in OPN/KO mice compared with WT mice. DISCUSSION: Our data suggest that OPN is essential for proper astrocytic generation in vitro culture prepared from mouse cerebral cortex. OPN is indispensable for astrocyte activation in the mouse brain injury model and in LPS stimulated primary culture. ABBREVIATIONS: AQP4: aquaporin 4; BBB: blood brain barrier; BrdU: bromo-deoxy uridine; CNS: central nervous system; GFAP: glial fibllirary acidic protein; IgG: immunoglobulin G; LPS: lipopolysaccharide; OPN: osteopontin; OPN/KO: osteopontin-deficient; TN-C: tenascin-C. PMID- 30246620 TI - Prevalence and Risk Factors of Frailty in a Community-Dwelling Population: The HELIAD Study. AB - OBJECTIVE: To estimate the prevalence of frailty using five different instruments in a cohort of older adults and explore the association between frailty and various risk factors. METHOD: 1,867 participants aged 65 years and above were included in the current retrospective cross-sectional study. Frailty was operationalized according to the Fried definition, the FRAIL Scale, the Frailty Index (FI), the Tilburg Frailty Indicator (TFI), and the Groningen Frailty Index (GFI). We explored the role of various frailty risk factors using logistic regression analyses. RESULTS: The prevalence of frailty varied depending on the definition used (Fried definition = 4.1%, FRAIL Scale = 1.5%, FI = 19.7%, TFI = 24.5%, and GFI = 30.2%). The only risk factors consistently associated with frailty irrespectively of definition were education and age. CONCLUSION: The frailty prevalence reported in our study is similar or lower to that reported in other population studies. Qualitative differences between frailty definitions were observed. PMID- 30246622 TI - Factors predisposing to work-related lower back pain in automobile industry workers. AB - OBJECTIVE: This study aimed to assess the presence of lower back pain (LBP) in automobile industrial workers and correlate it with the factors known to be contributing to the development of work-related LBP. METHOD: Post ethical approval, an analytical cross-sectional assessment was conducted for a correlation study on 317 workers from different automobile industries, garages and service centres, who were then assessed by Nordic musculoskeletal questionnaire for the presence of LBP. Their pain intensity was assessed using a numerical rating scale, their core strength with a pressure biofeedback unit, their flexibility via the sitting and reach test and their work posture with the rapid entire body assessment tool. Pain intensity was correlated with core strength, flexibility and posture in all of the workers using Spearman's correlation coefficient r with alpha set at p <= 0.05 at a 95% confidence interval. RESULTS: There was no significant correlation of the pain intensity with the core strength (r = 0.052, p = 0.424), flexibility (r = 0.020, p = 0.755) or posture (r = 0.002, p = 0.974). CONCLUSION: The present study indicates that internal factors like core strength and flexibility, and work postures have no correlation with intensity and severity of LBP in automobile industry workers. PMID- 30246621 TI - The predictive and diagnostic accuracy of vascular endothelial growth factor and pentraxin-3 in severe dengue. AB - This study aimed to evaluate vascular endothelial growth factor (VEGF) and pentraxin 3 (PTX-3) as predictive and diagnostic markers in differentiating severe dengue from non-severe dengue. The study was conducted in Ampang Health Clinic, Ampang Hospital and Serdang Hospital. The plasma levels of VEGF and PTX-3 were compared between severe dengue and non-severe dengue by ELISA from the day of presentation until discharged. Multiple logistic regression was used to develop predictive and diagnostic models by incorporating other clinical parameters. The receiver operating characteristics (ROC) analysis was used to assess the accuracy of the biomarkers and the developed models. Eighty-two patients were recruited, 29 with severe dengue and four died. The Area Under the Curve (AUC) was statistically significant in VEGF as diagnostic marker at Day 2 and 3 of illness with sensitivity of 80.00%-100.00% and specificity of 76.47% 80.00%. The predictive model with AUC of 0.84 (p < 0.01) has a sensitivity of 100.00% and specificity of 79.25% for predicting severe dengue. The diagnostic model with AUC of 0.71 (p < 0.01) has a sensitivity of 76.19% and specificity of 73.58% for diagnosing severe dengue. The AUC for PTX-3 was not statistically significant. VEGF may be used in combination with other clinical parameters to predict the severity of the disease. As a single biomarker, it may be used as an adjunct investigation to support the diagnosis of severe dengue. PTX-3 was not able to differentiate severe dengue from non-severe dengue. PMID- 30246624 TI - Policies in Activity-based Flexible Offices -'I am sloppy with clean-desking. We don't really know the rules.' AB - Activity-based Flexible Offices (A-FOs) are offices with unassigned desks that provide a variety of workspaces. This paper presents desk-sharing and speech rules identified in A-FOs in four Swedish organisations, the emergence of and compliance with these rules, and their consequences for work conditions. Data collection involved 105 semi-structured interviews, document analyses, and observations. The identified rules were: (1) to remove belongings, (2) temporal restrictions on using the same workstations, (3) temporal restrictions on using scarce zones, (4) restrictions on verbal interactions, and (5) restrictions on phone conversations. The cases with extensive user involvement in their planning process had explicit unambiguous rules. A better compliance with rules occurred when (i) the employees were well-prepared and had a unified understanding regarding how and why to follow the rules, (ii) the rules were explicitly communicated and were regarded as easy to follow, and (iii) following the rules facilitated work and improved work conditions. PMID- 30246623 TI - Evaluation of dexamethasone treated mesenchymal stem cells for recovery in neurotmesis model of peripheral nerve injury. AB - OBJECTIVE: Peripheral nerve injuries comprise significant portion of the nervous system injuries. Although peripheral nerves show some capacity of regeneration after injury, the extent of regeneration is not remarkable. The present study aimes to evaluate the regeneration of transected sciatic nerve by a therapeutic value of dexamethasone (DEX) associated with cell therapy (Cell) and biodegradable membrane (Mem) in rat. METHODS: Male Wistar rats (n = 42, 180-200g) were randomly divided into control (Ctrl), Membrane+ Cell, Mem, DEX, DEX+ Cell, DEX+ Mem and DEX+ Cell+ Mem groups. Functional recovery was evaluated at 2, 4, 6, 8 and 12 weeks after surgery using sciatic functional index (SFI), withdrawal reflex latency (WRL) test, electrophysiological and histological analyses. RESULTS: The rats in the DEX+ Cell+ Mem-treated group showed a significant improvement in SFI, WRL and electrophysiological findings during the 2nd to 12th weeks after surgery. In addition, histomorphological findings showed a significant improvement in the DEX+ Cell+ Memtreated group, at 12 weeks after surgery. DISCUSSION: Taken together, use of DEX associated with cell and biodegradable membrane could improve functional and histomorphological properties of the sciatic nerve after injury. PMID- 30246625 TI - Resumes. PMID- 30246626 TI - Vencer a las enfermedades no transmisibles con equidad: seamos serios. PMID- 30246627 TI - Battre les maladies non transmissibles de maniere equitable - soyons serieux. PMID- 30246628 TI - Beating non-communicable diseases equitably - let's get serious. PMID- 30246629 TI - Health promotion and knowledge translation: two roads to the same destination? AB - Health Promotion (HP), a continuously evolving field, is riddled with complexities as experts and community members develop new approaches to researching social behaviours, addressing health concerns and advocating for the values of equity, empowerment and healthy public policy. Similarly complex is the field of knowledge translation (KT), putting research into action for the purpose of changing behaviours, policy and practice. Similar values, methods and techniques govern these two practices. This paper is based on a series of discussions between two young professionals who found themselves navigating the complexities of HP and KT and attempting to understand their chosen fields of practice. The discussions considered such issues as discipline-based silos, the use and purpose of new terminologies and languages in research, and whether or not existing practices are simply being renamed or branded in order to appear innovative and new. PMID- 30246631 TI - Resumenes. PMID- 30246630 TI - Developpement et implantation d'une intervention ciblee encourageant le depistage regulier du VIH chez les travailleuses du sexe au Benin : application du protocole d' intervention mapping. AB - Cet article presente le processus suivi pour developper et implanter une intervention ciblee encourageant les femmes travailleuses du sexe (TS) a se faire depister regulierement pour le virus de l'immunodeficience humaine (VIH) dans les services de sante adaptes au Benin. Le modele de planification d' intervention mapping (IM) de Bartholomew et al. (2006), structure en six etapes, a servi de reference pour guider le developpement et l'implantation de l'intervention. Une analyse des besoins a ete realisee a partir d'une revue de litterature et d'une etude basee sur la theorie du comportement planifie, d'Ajzen (1991). Cette analyse a permis d'identifier les determinants associes au comportement sur lesquels ont porte les actions de changement. Les methodes et strategies d'intervention ont ete basees sur des theories et adaptees aux besoins des femmes TS. Les resultats consistent en une intervention de neuf mois visant a couvrir plus de 1200 femmes TS, en impliquant divers acteurs (intervenants communautaires, agents de sante et pairs educatrices). La perception de controle comportemental, la norme descriptive, les connaissances, l'attitude et l'intention d'adopter le depistage regulier du VIH constituent les cibles d'action. L'intervention comporte des activites visant des changements individuels et environnementaux a travers diverses methodes comme le counseling motivationnel, l'education par les pairs, le modeling, la communication persuasive, le renforcement de capacites et la reorganisation des services cliniques. L'IM a permis de structurer et d'implanter avec transparence une intervention ciblee visant l'adoption d'un comportement favorable a la sante chez les femmes TS. Les enjeux rencontres et les lecons tirees de l'application de l'IM en contexte africain francophone peuvent inspirer les planificateurs et professionnels pour ameliorer leurs interventions en promotion de la sante. PMID- 30246632 TI - Delving deeper into dermal and transdermal drug delivery: Factors and mechanisms associated with nanocarrier-mediated strategies. AB - Advances in material science and particle engineering have led to the development of a rapidly growing number of nanoparticulate carriers for drug and gene delivery. These carriers are increasingly being investigated in dermal and transdermal routes of drug administration. In this paper, we examine the interaction of nanoparticles (NPs) with skin after topical application and their consequent fate, based on the material of construction or type of NPs (and surface chemistry), particle size, shape, surface charge, dispersion vehicle, duration of exposure of skin to NPs, combination of NPs with physical agents and other factors. PMID- 30246633 TI - Pilot study of eyesight characteristics and thickness of the retinal nerve fiber and ganglion cell-inner plexiform layers in adolescent patients with type one diabetes mellitus on an insulin pump. AB - AIM: Estimation of the ocular status in adolescents with diabetes mellitus type 1 (DM1) treated with continuous subcutaneous insulin infusion (CSII), assessment of the development of the diabetic retinopathy (DR) and nephropathy (DN) within 10 years. METHODS: 37 patients (74 eyes) aged 16-33 years, treated with CSII were enrolled to the study. Baseline, and a 10-year follow-up evaluation, included: best corrected visual acuity (BCVA), tonometry, slit lamp exam and fluorescein angiography (FLA). Additionally, spectral-domain optical coherence tomography (SD OCT) was done in the 7th year of observation to assess the thickness of the retinal nerve fiber (RNFL) and the ganglion cell-inner plexiform layers (GCL-IPL) complex thickness. Glycated haemoglobin (HbA1) and albuminuria were also analysed. RESULTS: During the 10-year observation period DR (non-proliferative - NPDR, proliferative - PDR, diabetic macular edema - DME) was diagnosed in 3 (8%) patients. In the DR group: BCVA was significantly lower, intraocular pressure (IOP) levels and albuminuria were higher. There were no differences in HbA1 in both groups. The thinning of RNFL was observed in both groups. Macular RNFL, GCL IPL complex thickness assessment showed a significantly higher number of borderline results in the group with DR. CONCLUSIONS: Diabetic patients treated with CSII are at a lower risk of developing vascular complications even with poor metabolic control. Increased albuminuria may be a predictive sign for early ocular complications, and requires intense observation. Diagnosis of RNFL and GCL IPL decreased values is crucial prior to diabetic retinopathy development. SD-OCT is a non-invasive, easy-to-perform, relatively inexpensive procedure, and can be a useful tool to monitor neuropathy progression. PMID- 30246634 TI - Protective role of endogenous PACAP in inflammation-induced retinal degeneration. AB - PURPOSE: Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuroprotective peptide that has been shown to exert protective effects in different models of neurodegenerative diseases, including retinal degenerations. Data obtained from PACAP-deficient (PACAP KO) mice provide evidence that endogenous PACAP has neuroprotective role in different pathologies. PACAP KO mice show enhanced sensitivity to different insults, such as oxidative stress, hypoxia and inflammation. The aim of the present study was to investigate the protective effects of endogenous PACAP in retinal inflammation. METHODS: Endotoxin-caused eye inflammation was induced by intraperitoneal injection of lipopolysaccharide (LPS) in PACAP KO and wild type (Wt) mice. After LPS treatment, retinas were processed for histological examination. To detect the alterations of different proteins and cytokines, immunohistochemical, western blot and cytokine array were used. We also performed dark-adapted electroretinography (ERG) to detect the functional differences. RESULTS: The thickness of nearly all layers was significantly less in LPS-injected PACAP KO mice compared to Wt animals. Increased expression of glial fibrillary acidic protein (GFAP) was induced in Muller glial cells after LPS treatment, which was more intense in PACAP KO mice. The levels of pAkt and pGSK were decreased in PACAP KO group during inflammation. LPS treatment significantly increased cytokines (sICAM-1, JE, TIMP-1) in both treated groups, but it was more expressed in PACAP KO animals. Furthermore, ERG responses were disturbed after LPS injection in PACAP KO mice. CONCLUSION: Our results showed that endogenous PACAP has a protective role in LPS-caused retinal inflammation. PMID- 30246635 TI - The circadian PER2 enhancer Nobiletin reverses the deleterious effects of midazolam in myocardial ischemia and reperfusion injury. AB - BACKGROUND: Recently, we identified the circadian rhythm protein Period 2 (PER2) in robust cardioprotection from myocardial ischemia (MI). Based on findings that perioperative MI is the most common major cardiovascular complication and that anesthetics can alter the expression of PER2, we hypothesized that an anesthesia mediated downregulation of PER2 could be detrimental if myocardial ischemia and reperfusion (IR) would occur. METHODS AND RESULTS: We exposed mice to pentobarbital, fentanyl, ketamine, propofol, midazolam or isoflurane and determined cardiac Per2 mRNA levels. Unexpectedly, only midazolam treatment resulted in an immediate and significant downregulation of Per2 transcript levels. Subsequent studies in mice pretreated with midazolam using an in-situ mouse model for myocardial (IR)-injury revealed a significant and dramatic increase in infarct sizes or Troponin-I serum levels in the midazolam treated group when compared to controls. Using the recently identified flavonoid, nobiletin, as a PER2 enhancer completely abolished the deleterious effects of midazolam during myocardial IR-injury. Moreover, nobiletin treatment alone significantly reduced infarct sizes or Troponin I levels in wildtype but not in Per2-/- mice. Pharmacological studies on nobiletin like flavonoids revealed that only nobiletin and tangeritin, both found to enhance PER2, were cardioprotective in our murine model for myocardial IR-injury. CONCLUSION: We identified midazolam mediated downregulation of cardiac PER2 as an underlying mechanism for a deleterious effect of midazolam pretreatment in myocardial IR-injury. These findings highlight PER2 as a cardioprotective mechanism and suggest the PER2 enhancers nobiletin or tangeritin as preventative therapy for myocardial IR injury in the perioperative setting where midazolam pretreatment occurs frequently. PMID- 30246637 TI - Towards Computational Models of Identifying Protein Ubiquitination Sites. AB - Ubiquitination is an important post-translational modification in regulating protein functions, which provides a key insight to discover the causes associated with cancer, cardiovascular and other diseases. Recent attempts have been made for capturing potential ubiquitination sites with the aid of chemo-proteomic approaches and computational methods. Experimental identification of ubiquitination sites is especially vulnerable to the temporality and reversibility of ubiquitination processes, which is also costly and time consuming. It has been demonstrated that computational methods are effective in extracting potential rules or inferences from biological sequences collection. Up to now, computational strategy has been one of the critical pursuits in identification ubiquitination sites, and we have been witnessed plenty of state of-the-art computational methods developed from machine learning and statistical analysis. In this study, we summarized the benchmark datasets construction, feature representation methods, feature selection approaches and classifiers involved in the several pervious literatures. In an attempt to explore the pertinent development trends of identifying ubiquitination sites, we constructed an independent dataset and reported the prediction results on four predicting tools with conclusive comments. PMID- 30246638 TI - Novel Sulfones with Antifungal Properties: Antifungal Activites and Interactions with Candida spp. Virulence Factors. AB - Since candidiasis is so difficult to eradicate with antifungal treatment and existing antimycotics display many limitations, hopefully new sulfone derivatives may overcome these deficiencies. It is pertinent to study new strategies such as sulfone derivatives targeting virulence attributes of C. albicans that diverge from pathogens and host. During infection, the pathogenic potential of C. albicans relies on the virulence factors as follows: hydrolytic enzymes, transcriptional factors, adhesion, and development of biofilms. Moreover, in the article we explored how the above-presented fitness and virulence attributes provided a robust response to the environmental stress exerted by sulfones upon C. albicans, inactivation of which attenuates virulence. Our understanding of how these mechanisms and factors are inhibited by sulfones has increased over the last years. As a prerequisite for medical approaches is lack of toxicity, sulfones (non-toxic as assessed in vitro and in vivo) may prove useful for reducing C. albicans pathogenesis in humans. The antifungal sulfones activity dealing with multiple virulence factors and fitness attributes are discussed. PMID- 30246636 TI - Safety and Efficacy of Rifaximin in Prophylaxis of Spontaneous Bacterial Peritonitis: Is this time to abandon fluoroquinolones for prevention of spontaneous bacterial peritonitis? : A Systematic Review. AB - AIM: The role of rifaximin in the prevention of spontaneous bacterial peritonitis(SBP) is not well studied. The aim of this meta-analysis was to evaluate the role of rifaximin in the prevention of SBP. METHODS: A computerized literature search for relevant clinical trials was conducted during August 2017. Data on Frequency of SBP, the success rate of prevention of SBP, mortality rate, hepatorenal syndrome, septic shock, hepatic encephalopathy, and GIT bleeding were extracted and pooled as risk ratio (RR) with their 95% confidence interval (CI) in a meta-analysis model. Heterogeneity was assessed by Chi-square test. RESULTS: Six studies involving 973 patients were included in the final analysis. The pooled effect estimate showed that the rifaximin plus norfloxacin group had less incidence of SBP (RR 0.58, 95% CI[0.37, 0.92], P=0.02) and hepatic encephalopathy (RR 0.38, 95% CI[0.17, 0.84], P=0.02) than the norfloxacin-based regimen group. No significant difference between rifaximin and norfloxacin in terms of frequency of SBP and success rate of primary prevention of SBP (RR 0.49, 95% CI [0.24, 1.01], P=0.05; RR1.21, 95% CI [0.95, 1.55], P=0.13, respectively). CONCLUSION: Based on our analysis, Rifaximin is a promising drug and appears to be a good alternative to norfloxacin in prevention of SBP. PMID- 30246639 TI - Phytochemical, Anti-Diabetic And Cardiovascular Properties Of Urtica Dioica L. (Urticaceae): A Review. AB - Type 2 diabetes mellitus (DM) and cardiovascular diseases (CVD) have become the main cause of morbidity and death worldwide. In addition, current anti-diabetic and cardiovascular therapy is based on conventional drugs that have limited effectiveness and adverse side effects. In this regard, the role of medicinal herbs as a complementary or an alternative medicine is of great interest. Urtica dioica L. (Urticaceae), which is the focus of this review, has been widely used in traditional medicine to treat a variety of ailments, including, diabetes, hypertension and prostate cancer. The aim of this article is to review current knowledge related to the anti-diabetic and cardiovascular properties of U. dioica, with particular emphasis on the bioactive compounds, the plant parts used, and the action mechanism behind lowering blood glucose level and reducing risk of CVD. We also discuss the chemical composition and toxicological properties of the plant. From this review, it was suggested that the anti diabetic and the cardiovascular effects of U. dioica are attributed to different classes of compounds, such as polyphenols, triterpens, sterols, flavonoids, and lectin which reduce the blood glucose level and the risk of CVD by their antihypertensive, antioxidant and anti-inflammatory properties and/or by interfering with different cellular signalization pathways, including increase of NO, inhibition of alpha-amylase and alpha-glycosidase, modulation of GLUT4 and protection of pancreatic beta-cells, among others. The identification of the plant constituents and the understanding of their exact action mechanisms are necessary to prove the efficacy of the plant and develop it as pharmacological drug. PMID- 30246640 TI - Improved In vivo Effect of Chrysin as an Absorption Enhancer Via the Preparation of Ternary Solid Dispersion with Brij(r)L4 and Aminoclay. AB - BACKGROUND: Chrysin is a strong inhibitor of breast cancer resistance protein (BCRP) but it is practically insoluble in water. Effective solubilization of chrysin is critical for its pharmaceutical application as an absorption enhancer via inhibition of BCRP-mediated drug efflux. OBJECTIVE: This study aimed to develop an effective oral formulation of chrysin to improve its in vivo effect as an absorption enhancer. METHOD: Solid dispersions (SDs) of chrysin were prepared with hydrophilic carriers having surface acting properties and a pH modulator. In vitro and in vivo characterizations were performed to select the optimal SDs of chrysin. RESULTS: SDs with Brij(r)L4 and aminoclay was most effective in increasing the solubility of chrysin by 13-53 fold at varying drug-carrier ratios. Furthermore, SDs significantly improved the dissolution rate and extent of drug release. SDs (chrysin: Brij(r)L4: aminoclay=1:3:5) achieved approximately 60% and 83% drug release within 1 h and 8 h, respectively, in aqueous medium, while the dissolution of the untreated chrysin was less than 13%. XRD patterns indicated the amorphous state of chrysin in SDs. The SD formulation was effective in improving the bioavailability of topotecan, a BCRP substrate in rats. Following oral administration of topotecan with the SDs of chrysin, the Cmax and AUC of topotecan was enhanced by approximately 2.6- and 2-fold, respectively, while the untreated chrysin had no effect. CONCLUSION: The SD formulation of chrysin with Brij(r)L4 and aminoclay appeared to be promising in improving the dissolution of chrysin and enhancing its in vivo effect as an absorption enhancer. PMID- 30246641 TI - Formulation and in-vivo Evaluation of Novel Topical Gel of Lopinavir for Targeting HIV. AB - BACKGROUND: Lopinavir is specific reversible inhibitors of the enzyme HIV protease with mean oral bioavailability of less than 20% due to extensive hepatic metabolism by cytochrome P450 3A4. The reported half-life of Lopinavir is 5-6 hours and the maximum recommended daily dose is 400 mg/day. All the marketed tablet and capsule formulations of lopinavir are generally combined with Ritonavir, a potent inhibitor of cytochrome P450 3A4, to minimize presystemic metabolism of lopinavir. Hence, to overcome limitations associated with oral administration of lopinavir and to promote single drug administration, utilization of vesicular nanocarriers through topical route could prove to be effective, as the approach combines the inherent advantages of topical route and the drug carrying potential of vesicular nanocarriers across the tough and otherwise impervious skin barrier layer, i.e., stratum corneum. OBJECTIVE: The objective was to develop solid lipid nanoparticles (SLN) of lopinavir and formulate a topical gel for improved systemic bioavailability of lopinavir. METHOD: SLNs were prepared using high pressure homogenization technique and the optimized. The nanoparticles were characterized by SEM to confirm their spherical shape. Differential Scanning Calorimetry (DSC) analysis was carried out to ensure the entrapment of drug inside the SLNs. Comparative evaluation was done between SLN based gel and plain gel of drug by performing ex-vivo skin permeation studies using Franz diffusion cell. To explore the potential of topical route, in-vivo bioavailability study was conducted in male Wistar rats. RESULTS: The optimized formulation composed of Compritol 888ATO (0.5%) as lipid, Poloxamer 407 (0.25%) as surfactant and Labrasol (0.25%) as co-surfactant gave the maximum entrapment of 69.78% with mean particle size of 48.86nm. Plain gel of the drug gave a release of 98.406 +/- 0.007% at the end of 4hours whereas SLN based gel gave a more sustained release of 71.197 +/-0.006% at the end of 12hours ex-vivo. As observed from the results of in-vivo studies, highest Cmax was found with SLN based gel (20.3127 +/- 0.6056) ug/ml as compared to plain gel (8.0655 +/- 1.6369) ug/ml and oral suspension (4.2550 +/- 16.380) ug/ml of the drug. Also, the AUC was higher in the case of SLN based gel indicating good bioavailability as compared to oral suspension and plain gel of drug. CONCLUSION: Lopinavir SLN based gel was found to have modified drug release pattern providing sustained release as compared to plain drug gel. This indicates that Lopinavir when given topically has a good potential to target the HIV as compared to when given orally. PMID- 30246642 TI - Association of High Levels of Spot Urine Protein with High Blood Pressure, Mean Arterial Pressure and Pulse Pressure with Development of Diabetic Chronic Kidney Dysfunction or Failure among Diabetic Patients. Statistical Regression Modeling to Predict Diabetic Proteinuria. AB - INTRODUCTION: In research elevated blood pressure (BP) has been demonstrated to be a risk for the development of nephropathy and chronic renal disease (CKD) or diabetic kidney disease(DKD) among diabetics. However, no study has find correlation for the spot urine protein (UPr) excretion with elevated BP, pulse pressure (PP) and mean arterial pressure MAP). This technique was invented in the current study. 10,270 were recruited for more than 12 years. Demographically, 43% , 38%, and 16% showed hypertension, nephropathy and chronic renal disease, respectively. UPr demonstrated significant correlations with systolic BP (SBP) and diastolic BP (DPB), MAP and PP (p < 0.0001 for all). SBP, DBP, PP and MAP, UPr were observed to be higher among the groups with nephroaphty and CKD/DKD with highly significant p-values (all p < 0.05). With logistic regression, odds ratio of hypertension (HTN) with nephropathy was observed to be 2.99 (95% CI 2.44 to 3.7; p < 0.0001); and odds ratio of HTN with CKD/DK was 7.1 (95% CI 4.3 to 11.84; p<0.0001), indicating that HTN significantly contributes to the development of nephropathy and CKD/DKD in diabetics. Invented regression models for the excretion of UPr from the kidney with elevated SBP, DBP, MAP and PP were highly significant (p < 0.0001 for all); UPr = -138.6 + [ 1.347 * SBP] ; UPr = -93.4 + [ 1.62 * DBP] ; UPr = -149.5 + [ 1.922 * MAP] ; UPr = -41.23 +[ 1.541 * PP ]. CONCLUSION: Current study is the first one to introduce this technique. These invented new equations can be used by physicians to estimate protein excretion in urine at bedside and outpatients departments for monitoring proteinuria and CKD/DKD. PMID- 30246643 TI - Glycation and HMG-CoA Reductase Inhibitors: Implication in Diabetes and Associated Complications. AB - INTRODUCTION: Diabetes mellitus (DM) acts as an absolute mediator of cardiovascular risk, prompting the prolonged occurrence, size and intricacy of atherosclerotic plaques via enhanced advanced glycation endproducts (AGEs) formation. Moreover, hyperglycemia is associated with enhanced glyco-oxidized and oxidized low-density lipoprotein (LDL) possessing greater atherogenicity and decreased ability to regulate HMG-CoA reductase (HMG-R). Although aminoguanidine (AG) prevents the AGE-induced protein cross-linking due to its anti-glycation potential, it exerts several unusual pharmaco-toxicological effects thus restraining its desirable therapeutic effects. HMG-R inhibitors/statins exhibit a variety of beneficial impacts in addition to the cholesterol-lowering effects. OBJECTIVE: Inhibition of AGEs interaction with receptor for AGEs (RAGE) and glyco oxidized-LDL by HMG-R inhibitors could decrease LDL uptake by LDL-receptor (LDL R), regulate cholesterol synthesis via HMG-R, decrease oxidative and inflammatory stress to improve the diabetes-associated complications. CONCLUSION: Current article appraises the pathological AGE-RAGE concerns in diabetes and its associated complications, mainly focusing on the phenomenon of both circulatory AGEs and those accumulating in tissues in diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy, discussing the potential protective role of HMG-R inhibitors against diabetic complications. PMID- 30246644 TI - Blunted Overnight Blood Pressure Dipping in second trimester; a strong predictor of Gestational hypertension and Preeclampsia. AB - BACKGROUND: Preeclampsia is a global burden with 10 million incidence annually and 210 daily deaths worldwide. Diagnosis is mainly based on the features following full presentation. OBJECTIVE: This study explored whether early pregnancy circadian changes of ambulatory blood pressure monitoring (ABPM) could predict preeclampsia and hypertension. METHODS: In a prospective study, 294 pregnant women who were referred to Sarem Women's Hospital, Iran were recruited. Systolic, diastolic and mean arterial pressures (MAP) were recorded (diurnally and nocturnally) in each trimester. Dipping was defined as a minimum 10% decrease in blood pressure. RESULTS: Of the 251 women who completed the study, 25 percent (n=63) experienced blunted MAP dipping during sleep phases in the second trimester. Eighty nine percent (n=56) experienced hypertensive disorder in the third trimester, one third of which experienced preeclampsia. Of the women with normal MAP dipping (n=188), 5 percent (n=10) had gestational hypertension and 1 percent (n=2) became preeclamptic. (P<0.0001) Conclusion: This study clearly demonstrated blunted blood pressure dipping overnight during the second trimester is a strong predictor of forthcoming pregnancy induced hypertension and preeclampsia. A scoring system was developed to predict hypertensive disorder and it was significantly correlated with preeclampsia occurrence. PMID- 30246645 TI - Biotechnological Applications of Serine proteases: A Patent Review. AB - BACKGROUND: Serine proteases have long been recognized to play key roles in various physiological processes. However, their disequilibrium can be linked to several diseases. Taking into account their wide diversity and specificity, they have been actively investigated by many industrial, academic and pharmaceutical industries. OBJECTIVE: This review aims to provide a concise analysis of the described serine proteases as well as their relevant biotechnological and therapeutic applications. METHOD: Here we give an overview of the recent knowledge on serine proteases with a particular focus on their biotechnological applications reported in European Patent Office (Espacenet), United States Patent and National Patent Collections (WIPO) patent databases. RESULTS: Serine proteases are probably the enzymes that have been most studied over the past few decades. However, despite their increasing interest, no significant patent so far has dealt with the identity of overactive serine proteases in disease settings. CONCLUSION: This review displays that serine proteases have several relevant industrial uses. New potential applications of such proteins require more functional analyses seeing the key role of serine proteases in many biomedical and biotechnological processes. PMID- 30246646 TI - Computational Fluid Dynamics (CFD) Simulation of Cross-flow mode operation of Membrane for downstream processing. AB - BACKGROUND: Membrane filtration process produced good quality of permeate flux due to which it is used in different industries like dairy, pharmaceutical, sugar, starch and sweetener industry, bio separation, purification of biomedical materials, and downstream polishing etc. The cross flow mode of operation has also been used to improve the quality of the Rubber Industrial effluent of Tripura, India. METHODS: The Computational Fluid Dynamics (CFD) simulation of the cross flow membrane is done by using ANSYS Fluent 6.3. The meshing of the geometry of the membrane is done by Gambit 2.4.6 and a grid size of 100674, the number of faces is 151651 and number of nodes are 50978 has been selected for the simulation purpose from the grid independence test. We have revised and included all patents in the manuscripts related to membrane filtration unit. RESULTS: Single phase Pressure-Velocity coupled Simple Algorithm and laminar model is used for the simulation of the developed model and Fluent 6.3 is used for the prediction of pressure, pressure drop, flow phenomena, wall shear stress and shear strain rate inside the module is studied for cross flow membrane. CONCLUSIONS: From the study it has been found that CFD simulated results hold good agreement with the experimental values. PMID- 30246647 TI - Updated indicators to evaluate harmful drug use, in particular polydrug use. AB - BACKGROUND: Drug use indicators that are capable of measuring the individual levels of harm following drug use, and in particular poly-drug use, have previously been proposed, based on individual drug and frequency of use data and expert rankings of harms related to various substances. These indicators allow the estimation of risk profiles for selected groups of individuals and comparisons, both over time and between populations. Recent advances regarding the ranking of drug use harms allow a refinement of these indicators, separating the effects on self and others. We define updated indicators and compare their performance to previous ones on datasets related to the Italian ESPAD longitudinal data set. A new harm-to-self drug use indicator is shown to correlate strongly with the previous poly-drug use indicator; and another new indicator, defined as harm-to-others, is introduced and commented upon. Using further ESPAD survey information related to personal behaviour, it is shown that high values of poly-drug use indicators are linked to specific behaviours related to interest in school, relationship with parents and use of leisure time. CONCLUSION: These results are consistent with previous analyses based on surveys among high school students in Italy. PMID- 30246648 TI - Evaluation of the superabsorbent effect on the yield and some growth factors of Pisum sativum L. under drought stress conditions. AB - BACKGROUND: Deficit irrigation is an optimum technique for producing products under drought stress conditions. The superabsorbent hydrogel is a hydrophilic polymer with cross-linked 3-D hydrophilic nets that is able to take up and keep noteworthy values of water and aquatic liquids. Recently published patents have shown significant information in the superabsorbent application in agriculture. OBJECTIVE: The aim of this study was to investigate the superabsorbent effect on the yield and some of the growth factors of Pisum sativum L. under the drought stress conditions. METHOD: The experimental factors included: irrigation treatments at two levels of 100% and 75% water requirement by the plant. The second factor included the levels of superabsorbent application which included three levels of control treatment, potting soil with a weight percentage of 0.5 and 1. The third factor was the location of superabsorbent application. RESULTS: According to the results, the largest root length value corresponded to I2S1U treatment plan, the largest root dry weight value corresponded to I1S2U treatment plan, the largest plant dry weight corresponded to I2S1U treatment plan, the largest grain dry weight corresponded to I2S1U treatment plan, the largest number of grains per pod corresponded to I2S2U treatment plan and the largest number of pods per plant corresponded to I2S1U treatment plan which were significant at 5% level. CONCLUSION: It was concluded that the presence of the superabsorbent at the lower end of the pot was effective in providing water and nutrients for the plant root. PMID- 30246649 TI - The associations of dietary acid load with insulin resistance and type 2 diabetes: a systematic review of existing human studies. AB - BACKGROUND: Type 2 diabetes is a multifactorial disorder influenced by both genetic and environmental factors and is rising dramatically throughout the world. Recently, consideration to dietary acid-base load has been raised as a nutritional indicator that could have metabolic effects. OBJECTIVE: The aim of this study was to systematically investigate the associations of dietary acid load indices with glucose/insulin homeostasis and type 2 diabetes in a patent based review. METHODS: Systematic literature review was conducted using of PubMed, Scopus and Google scholar, from inception up to 10 January 2018. All human studies publications investigated the association of dietary acid load indices (PRAL or NEAP or Pro:K) and incidence of diabetes or glucose/insulin metabolism were included. RESULTS: In all, 174 studies were included for title and abstract screening. A total of 164 articles were excluded because they did not meet the inclusion criteria. Finally 10 articles (five cross-sectional studies and five cohort studies) in accordance with our inclusion criteria were chosen for further evaluations that were published between 2008 and 2017. CONCLUSION: Although there are some evidence of association between dietary acid load and type 2 diabetes, definitive declarations in this regard will be needed to intervention human studies modifying acid-base dietary intake. PMID- 30246650 TI - The role of endobronchial and endoscopic ultrasound guided fine needle aspiration for mediastinal nodal staging of non-small-cell lung cancer. AB - Introduction: Mediastinal and hilar nodal staging is one of the key points for differentiating treatment modalities in patients with non-small-cell lung cancer (NSCLC). The aim of the present study was to determinate the diagnostic yields of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and combined EBUS TBNA and EUS-FNA modalities for nodal staging in potentially operable NSCLC patients. Materials and Methods: Twenty consecutive patients were prospectively enrolled in the study between March 2014 and November 2015. All patients had a potentially operable NSCLC diagnosis before endosonographic procedures. Result: Thirty lymph nodes were sampled by EBUS-TBNA and 17 lymph nodes were sampled by EUS-FNA in all 20 patients. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of F-18 fluorodeoxyglucose positron emission tomography with computed tomography (PET CT), EBUS-TBNA, EUS-FNA and combined EBUS-TBNA and EUS-FNA were 100%, 33.3%, 64.7%, 100% and 70.0%; 81.8%, 100%, 100%, 81.8% and 90%; 81.8%, 100%, 100%, 75% and 88.2%; 90.9%, 100%, 100%, 90.0% and 95.0%, respectively. Conclusions: The combined EBUS-TBNA and EUS-FNA technique is a successful procedure for nodal staging in potentially operable NSCLC patients. PMID- 30246651 TI - The utility of RDW in discrimination of sarcoidosis and tuberculous lymphadenitis diagnosed by ebus. AB - Introduction: Erythrocyte distribution width (RDW) is an important indicator of anisocytosis, which is used in the differential diagnosis of anemia and is easily accessible in the complete blood count results. Increased RDW values in coronary artery diseases, pulmonary hypertension and malignancies were detected in the studies. We aimed to demonstrate the usefulness of blood RDW level for the differential diagnosis of granulomatous lymphadenitis associated with tuberculosis and sarcoidosis in our study. Materials and Methods: A total of 331 patients, 229 with sarcoidosis (stage I and stage II) and 102 with TB-LA and 50 healthy control group were included in the study. The biopsies were obtained via EBUS-TBNA from 705 lymph nodes of 331 patients. Of tissue diagnosis was non erosive granulomatous inflammation patients with tuberculosis negative proved by microbiological tests were accepted as sarcoidosis after other causes of granulomatous disease were excluded. Result: Of the sarcoidosis patients, 169 (73.7%) were in stage I, and 60 (26.3%) were in stage II. The mean RDW was 14.31 (+/- 1.6) in the stage I group, 14.99 (+/- 2.3) in the stage II group, 14.11 (+/- 2.0) in the TB-LA group, and 13.89 (+/- 1.3) in the control group. There was a significant difference between the stage II group and the stage I, TB-LA, and control groups (p< 0.05 for all). There was a significant difference in the C reactive protein levels between the TB-LA and stage I groups (p< 0.01). The eritrocyte sedimentation rate values were higher in the TB-LA group than in both the stage I and stage II groups (p< 0.05). Conclusions: This is the first study to demonstrate the diagnostic value of RDW in patients with TB-LA and sarcoidosis (Stage I-II) patients diagnosed by EBUS-TBNA. Higher RDW in stage II sarcoidosis than in stage I, TB-LA and control group is related with parenchymal involvement and indicates active inflammation. PMID- 30246652 TI - The effects of smoking on body composition, pulmonary function, physical activity and health-related quality of life among healthy women. AB - Introduction: Smoking leads to more respiratory symptoms and negative effects on the health-related quality of life (HRQOL) in women than men for the same smoking burden. However, the relationship between smoking and body composition and its influencing factors remains unclear. In this study, we aim to investigate the effects of smoking on body composition, pulmonary function, physical activity and health-related quality of life (HRQOL) among healthy women. Materials and Methods: A total of 73 young healthy women, current cigarette smokers and who had never smoked were included. The level of physical activity was assessed using the International Physical Activity Questionnaire; body mass index, circumference measurements, waist-to-hip ratio, skinfold measurements and body fat percentage were used to determine the body composition; HRQOL was assessed through the World Health Organization Quality of Life Instrument; level of depression and anxiety were evaluated using the Hospital Anxiety and Depression Scale; pulmonary functions were evaluated with spirometry. Result: We found higher incidence of respiratory symptoms and lower physical activity levels in smokers than those of non-smokers (p< 0.05). There was no significant difference between smokers and non-smokers in respect of HRQOL, depression and anxiety (p> 0.05). In smokers whom cigarette consumption more than 150 p-years, we observed positive correlations between cigarette consumption and arm circumference, waist circumference, waist-to-hip ratio (p< 0.05). Conclusions: Our results show that the smoking causes an increase in the incidence of respiratory symptoms and reduces the level of physical activity in healthy women. Additionally it leads to abdominal obesity depending on cigarette consumption. PMID- 30246653 TI - Efficacy and safety of endobronchial ultrasound-guided transbronchial needle aspiration through the pulmonary arteries for the diagnosis of left hilar lesions. AB - Introduction: Endobronchial ultrasonography (EBUS) is an endoscopic method that aids needle aspiration to see the bronchial wall and adjacent tissues with an ultrasound probe. Pulmonary arteries are rarely present between the bronchus wall and the tissue. In this case, it was necessary to make a selection between invasive processes and transbronchial needle aspiration (TBNA) through the pulmonary artery. There are few case reports about the safety of TBNA through the pulmonary artery. We aimed to present the results of EBUS guided TBNA through the pulmonary arteries. Materials and Methods: The data on four cases (three men) in whom EBUS guided TBNA was performed through the pulmonary artery between August 2010 and December 2015 were reviewed retrospectively. Procedures were conducted under local anesthesia and conscious sedation. For TBNA, 22-gauge needles were used. Cases were monitored for 24 hour after the procedures. Antibiotic prophylaxis and onsite cytopathology were not used. Result: All lesions existed were on the left hilar localization. Two of the diagnosed cases were carcinoma and one was the granulomatous lymphadenitis. We were not able to diagnose the last case. No complication was observed in any cases during the procedure. Conclusions: EBUS guided TBNA through the pulmonary arteries at left hilar lesions is safe. The rate of diagnoses from the tissues obtained is high. No special preparation is needed for the cases have no the pulmonary hypertension. PMID- 30246654 TI - Diagnostic utility of endobronchial ultrasound-guided transbronchial needle aspiration in elderly patients. AB - Introduction: In the elderly population, diagnosis and initial treatment should be considered as soon as possible because of co-morbidities and complications. We aimed to evaluate the Pndings of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to determine the diagnostic utility of EBUS-TBNA in patients 65 years of age and older. Materials and Methods: We retrospectively evaluated records of patients who underwent EBUS-TBNA from February 2014 to August 2017 for diagnosis and/or staging. The demographic data, clinical and EBUS Pndings, diagnostic procedures during EBUS-TBNA and the incidence of accurate diagnosis with EBUS-TBNA in patients 65 years of age and older and in younger patients were determined. Result: A total of 496 patients [younger patients (< 65 years, n= 293, M/F: 198/95) and older patients (>= 65 years, n= 203, M/F: 155/48)] who underwent EBUS-TBNA at our clinic were included. The mean age of the older patients was 69.7 +/- 5.1 years, while the mean age of the younger patients was 51.4 +/- 10.4 years. Overall, the diagnostic accuracy of EBUS-TBNA was 96.5% in the older patients and 98% in the younger patients. The diagnostic utility of EBUS-TBNA in the two study groups was similar (p= 0.191). While 196 (96.6%) of the older patients had no complications during EBUS-TBNA, 285 (97.3%) of the younger patients had no complications. Complication rates were not statistically different between the two groups (p= 0.389). Conclusions: In general, EBUS-TBNA is a safe method. The results of this study demonstrated the high diagnostic value of EBUS-TBNA and its low complication rates in patients 65 years of age and older. PMID- 30246655 TI - Altered pulmonary functions due to biomass smoke in a rural population of Turkish women: a descriptive study. AB - Introduction: Wood or other organic sources of fuel are used as source of energy for heating or cooking particularly in developing countries. The aim of the current study was to evaluate the association between biomass exposure time and parameters of pulmonary function tests. Materials and Methods: Four hundred twenty-four consecutive women who lived and exposed to biomass smoke in a small province in Eastern Turkey were involved. This study was performed with women who had come to pulmonology out-patient clinic with symptom of dyspnea. Result: The independent variables assessed in the study patients were age, BMI, starting age of cooking, hours per day and weeks per month spent cooking, and cooking years; the dependent variables were PFT parameters. Ninety-two (21.6%) patients had an obstructive PFT pattern. Sixty-seven (73%) of these patients were classified as GOLD 2 and 25 (27%) patients were classified as GOLD 3. Seventy-five (17.6 %) of the patients had restrictive lung disease; 54 (72%) of these patients were found to have a mild and 21 (27%) had a moderate restrictive pattern. Increased number of years in cooking and to start cooking at younger ages were a risk factors for the development of obstructive and restrictive disease. There was a statistically significant and negative correlation between increased number of years and the value of FEV1 (r= -0.917; p=< 0.001), FEV1/FVC (r= -0.739; p< 0.001), and FVC (r= -0.906; p< 0.001). The median time of cooking required was 23 years for the development of obstruction, and 25 years for restriction, respectively. Conclusions: Cumulative biomass exposure time is associated with impairment in PFT parameters; results in both obstructive and restrictive lung disease. Biomass exposure is a public health problem and pre-cautions should be taken in order to prevent impaired pulmonary functions. PMID- 30246656 TI - The role of F-18 FDG PET/CT in differentiating benign from malignant pulmonary masses and accompanying lymph nodes. AB - Introduction: The aim of this study was to evaluate the usefulness of SUVmax and lesion size to differentiate benign and malignant lesions of the lung and accompanying mediastinal lymph node on F-18 FDG PET/CT imaging. Materials and Methods: A retrospective analysis was carried out on 100 patients with suspected lung cancer who were recommended for PET/CT scans for diagnosis and staging. The results of the SUVmax, lesion size and patient's age were compared with histopathology which was considered to be the 'gold standard' and sensitivity and specificity were calculated respectively. Lymph nodes greater than 1 cm in patients with benign pathology were evaluated and the SUVmax values were recorded. Result: Of the 100 patients, 38 were found to have benign, whereas 62 had malignant on histopathology. The SUVmax was significantly more elevated in malign masses (13.1 +/- 6.4) than in benign masses (8 +/- 5.7) (p< 0.05). The dimensions of malignant masses (4.5 +/- 2.5 cm) were larger than benign ones (3 +/- 1.6 cm) (p< 0.05). SUVmax of 7.6 was determined as the cut-off value, while the sensitivity and specificity were 82% and 55% respectively. The sensitivity was 87% and specificity was 45% for the lesion sizes in differentiation of the malignant and benign lesions. Conclusions: There are significant overlaps between benign and malignant lesions and specialists must be aware of the various pathological conditions that can give false positives and negatives. PMID- 30246657 TI - TST, QuantiFERON-TB Gold test and T-SPOT.TB test for detecting latent tuberculosis infection in patients with rheumatic disease prior to anti-TNF therapy. AB - Introduction: Before starting tumour necrosis factor (TNF)-alpha blocking agents, standard tests should be used for the diagnosis of tuberculosis infection. The specificity of traditional tuberculin skin test (TST) is low in immunosuppressed patients due to prior Bacille Calmette Guerin (BCG) vaccination, non-tuberculous mycobacteria infections, false positive and negative results. In this study, we aimed to compare TST and Interferon-Gamma Release Assay (IGRA) tests for detecting latent tuberculosis infection in patients with rheumatic disease planned to receive TNF-alpha blocking agents. Materials and Methods: One hundred and nine patients (45 male, 64 female) with the diagnosis of rheumatoid arthritis (RA) (n= 70) and ankylosing spondylitis (AS) (n= 39) were included in the study. Age, sex, number of BCG scar, results of TST (using the Mantoux method), QuantiFERON-TB Gold test and T-SPOT.TB test were recorded for all patients. Correlation between the tests was assessed by Pearson correlation coefficient. Result: The mean age of RA and AS patients were 50 +/- 13 (19-78 years). The prevalence of latent tuberculosis was 43.1% for TST, 39.4% for QuantiFERON-TB Gold test and 13.8% for T-SPOT.TB test, compared with the evaluation using the composite criteria such as close contact with active tuberculosis infection and/or suspicious fibrotic/calcific lesions on chest X-Ray without active tuberculosis infection. There was a moderate correlation between BCG scar number and TST (p< 0.001, r= 0.495), T-SPOT.TB test and QuantiFERON-TB Gold test (p= 0.007, r= 0.406), T-SPOT.TB test and composite criteria (p= 0.024, r= 0.343). The specificity of QuantiFERON-TB Gold test was 85.7%, and sensitivity was 73.9% for all patients with rheumatic disease. It was 73.5% and 66.7% for T-SPOT.TB test, respectively. The specificity of TST was 60.3% and sensitivity was 47.8% for TST. Conclusions: IGRA tests are not affected prior vaccination and useful for detecting latent tuberculosis infection in patients treated with corticosteroid due to lack of correlation between test negativity and corticosteroid therapy. Also, they are useful tests for diagnosis of latent tuberculosis infection as an alternative to TST due to their specificity and sensitivity. PMID- 30246658 TI - Clinical, radiological and prognostic features of influenza cases in the influenza epidemic during years 2016-2017. AB - Introduction: Influenza subtypes vary by clinical, radiological, and prognostic courses and may go along with viral pneumonia. We aimed to identify clinical, radiological, and prognostic aspects of influenza epidemic during years 2016 2017. Materials and Methods: Influenza cases reported to the Public Health Directorate in our city was assessed retrospectively. Clinical, radiological, and prognostic parameters were compared based on influenza subtypes. Result: We analyzed samples from 197 cases with suspected influenza. Mean age of the subjects was 51.17 +/- 26.74. We found influenza A/H1N1, influenza A/H3N2, and influenza B in 59 (30.0%), 29 (14.7%), and 3 (1.5%) cases, respectively. Comorbidity was present in 48 (24.4%) cases. Most common radiological finding was interstitial pattern. Seventy-one and 79 per cent of H1N1 and H3N2 cases were influenza pneumonia, respectively. The prevalence of overall mortality was 5.5% with a predominance in H1N1 over H3N2. Influenza vaccination had been performed in 6.8% and 3.4% of H1N1 and H3N2 cases, respectively. We detected no mortality in any vaccinated patient. We identified 6 pregnant women, 2 of which ended up with preterm birth, and another one with abortion. Conclusions: Often manifested as lower respiratory tract infection, influenza may cause epidemics with increased mortality rate. Influenza should be suspected when interstitial pattern was seen on radiological images. H1N1 cases course worse. Since the prognosis is better in vaccinated patients, seasonal influenza vaccination among the community needs to be elevated. In addition, protective measures like vaccination should be taken in pregnancy to avoid preterm delivery or abortion. PMID- 30246659 TI - [Evaluation of asthma awareness among teachers in Bursa]. AB - Introduction: The purpose of this study was to elucidate the asthma knowledge level of primary-secondary school teachers in Bursa, and factors associated with this subject. Materials and Methods: In our study 1812 teachers from 64 randomly selected primary schools in Bursa were included. Result: It was known by the vast majority of participants that asthma symptoms, asthma is not a contagious disease and may be familial, medications taken by inhalation. It was known by 64.1% of the teachers that asthmatic children do not mind doing sports. Approximately one of the two teachers knew that the medication were not addictive. Conclusions: The knowledge level of the teachers was related to female gender and age. We think that an asthma education program is needed for Turkish teachers to increase their understanding about what asthma is, its impact and how to meet the needs of a child with asthma to achieve improved wellbeing and school attendance. PMID- 30246660 TI - [Bronchial thermoplasty for asthma treatment]. AB - New asthma therapies such as omalizumab, mepolizumab and reslizumab are used according to the inflammatory phenotype, but there are many patients with asthma which are not suitable for these therapies or do not improve with these therapies. Bronchial thermoplasty (BT) was approved by FDA for the treatmet of adults with severe asthma and uncontrolled symptoms despite treatment with inhaler corticosteroids (ICS) and long-acting bronchodilators in 2010. BT is a minimally invasive bronhoscopic intervention based on radiofrequency energy delivery to the larger airways to reduce excessive airway smooth muscle mass. BT has been shown to be effective at reducing asthma exacerbations and improving asthma control for patients with severe asthma. BT is safe for 5 years after BT in patients with severe refractory asthma. BT may be primarily preferred for patients with nonallergic, non-eosinophilic (non-TH2) severe asthma not improving with standart treatments. Unfortunately, the mechanism of action of BT is incompletely understood. Uncertainty remains how to identify patients who will responde to this intervention. Several studies are underway that may show the place of BT in severe asthma and identify responders. There is also a need for studies comparing BT with other treatment options. This review will provide an overwiew of BT. We will discuss the latest evidence on the use of BT in asthma, patient selection criteria and performing the procedure will be reviewed. PMID- 30246661 TI - [Alarmins and anti-alarmin biologics in asthma]. AB - Alarmins are endogenous, constitutively expressed, chemotactic, and immune activating proteins/peptides that are released as a result of degranulation, cell injury or death, or in response to immune induction. Alarmins are involved in a variety of processes including antimicrobial gene expression regulation, cellular homeostasis, wound healing, inflammation, allergy, autoimmunity and oncogenesis. IL-25, IL-33, thymic stromal lymphopoietin (TSLP) are airway epithelial-derived alarmins and the characteristics of alarmins are that they are rapidly released after nonprogrammed cell death, they activate the immune cells. It is thought that the inhibition of the effects of alarmin on the immune system may be useful in the treatment of asthma. The effects of anti-IL-25 (Brodalumab) and anti-TSLP (Tezepelumab) treatments on asthmatic patients were investigated for that purpose. Brodalumab provided limited benefit only in the asthmatic group with high reversibility. Tezepelumab was found to be the first biological drug to have significant positive effect on two important indicators of asthmatic inflammation such as blood eosinophils and nitric oxide fraction in exhaled air. The effect of anti-IL-33 on airway inflammation was shown in animal experiments and anti-IL-33 was found to be protective by reducing eosinophilia, inflammatory cytokines, airway hypersensitivity. In this review, we aimed to summarize the role of alarmines in the pathogenesis of asthma and the results of studies with anti alarmin biologics. PMID- 30246662 TI - [MASK (Mobile Airways Sentinel networK) in Turkey-the ARIA integrated mobile solution for allergic rhinitis and asthma multimorbidity]. AB - mHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential to profoundly affect healthcare and health outcomes. Allergic Rhinitis and its impact on asthma (ARIA) has evolved from a guideline using the best evidence-based approach to care pathways suited to real life using mobile technology in allergic rhinitis (AR) and asthma multimorbidity MASK-rhinitis (Mobile Airways Sentinel networK), the Phase 3 ARIA initiative, is based on the freely available app. The Allergy Diary is used by people who were informed by physicians, searched the internet, Apple App Store, Google Play. Turkish Validation has been available and currently in use. PMID- 30246663 TI - [Pulmonary tuberculasis in sarcoidosis patients: two cases]. PMID- 30246664 TI - Prospects for the elimination of schistosomiasis and soil-transmitted helminthiasis: exploring disease trends through time at the Barombi crater lakes, South-West Cameroon. AB - In Cameroon, there is a national programme engaged in the control of schistosomiasis and soil-transmitted helminthiasis. In certain locations, the programme is transitioning from morbidity control towards local interruption of parasite transmission. The volcanic crater lake villages of Barombi Mbo and Barombi Kotto are well-known transmission foci and are excellent context-specific locations to assess appropriate disease control interventions. Most recently they have served as exemplars of expanded access to deworming medications and increased environmental surveillance. In this paper, we review infection dynamics through time, beginning with data from 1953, and comment on the short- and long term success of disease control. We show how intensification of local control is needed to push towards elimination and that further environmental surveillance, with targeted snail control, is needed to consolidate gains in preventive chemotherapy as well as empower local communities to take ownership of interventions. PMID- 30246665 TI - Zoonotic pathogens in fluctuating common vole (Microtus arvalis) populations: occurrence and dynamics. AB - Diseases and host dynamics are linked, but their associations may vary in strength, be time-lagged, and depend on environmental influences. Where a vector is involved in disease transmission, its dynamics are an additional influence, and we often lack a general understanding on how diseases, hosts and vectors interact. We report on the occurrence of six zoonotic arthropod-borne pathogens (Anaplasma, Bartonella, Borrelia, Coxiella, Francisella and Rickettsia) in common voles (Microtus arvalis) throughout a population fluctuation and how their prevalence varies according to host density, seasonality and vector prevalence. We detected Francisella tularensis and four species of Bartonella, but not Anaplasma, Borrelia, Coxiella or Rickettsia. Bartonella taylorii and B. grahamii prevalence increased and decreased with current host (vole and mice) density, respectively, and increased with flea prevalence. Bartonella doshiae prevalence decreased with mice density. These three Bartonella species were also more prevalent during winter. Bartonella rochalimae prevalence varied with current and previous vole density (delayed-density dependence), but not with season. Coinfection with F. tularensis and Bartonella occurred as expected from the respective prevalence of each disease in voles. Our results highlight that simultaneously considering pathogen, vector and host dynamics provide a better understanding of the epidemiological dynamics of zoonoses in farmland rodents. PMID- 30246666 TI - Timing of onset of lithium relapse prevention in bipolar disorder: evidence from randomised trials. AB - SummaryLithium is widely prescribed, but the timing of key effects remains uncertain. The timing of onset of its relapse prevention effects is clarified by placebo-controlled randomised trials (3 studies, n = 1120). Lithium reduced relapse into any mood episode over the first 2 weeks of treatment (hazard ratio 0.40, 95% CI 0.16-0.97). Fewer manic relapses were evident within the first 4 weeks, however, early effects on depressive relapse were not demonstrated. There is an early onset of lithium relapse prevention effects in bipolar disorder, particularly against manic relapse. Full effects against depressive relapse may develop over a longer period.Declaration of interestM.J.T. reports personal fees from Sunovion, Otsuka, Lundbeck, outside the submitted work. PMID- 30246668 TI - Numerous Fasciola plasminogen-binding proteins may underlie blood-brain barrier leakage and explain neurological disorder complexity and heterogeneity in the acute and chronic phases of human fascioliasis. AB - Human fascioliasis is a worldwide, pathogenic food-borne trematodiasis. Impressive clinical pictures comprising puzzling polymorphisms, manifestation multifocality, disease evolution changes, sequelae and mortality, have been reported in patients presenting with neurological, meningeal, neuropsychic and ocular disorders caused at distance by flukes infecting the liver. Proteomic and mass spectrometry analyses of the Fasciola hepatica excretome/secretome identified numerous, several new, plasminogen-binding proteins enhancing plasmin generation. This may underlie blood-brain barrier leakage whether by many simultaneously migrating, small-sized juvenile flukes in the acute phase, or by breakage of encapsulating formations triggered by single worm tracks in the chronic phase. Blood-brain barrier leakages may subsequently occur due to a fibrinolytic system-dependent mechanism involving plasmin-dependent generation of the proinflammatory peptide bradykinin and activation of bradykinin B2 receptors, after different plasminogen-binding protein agglomeration waves. Interactions between diverse parasitic situations and non-imbalancing fibrinolysis system alterations are for the first time proposed that explain the complexity, heterogeneity and timely variations of neurological disorders. Additionally, inflammation and dilation of blood vessels may be due to contact system-dependent generation bradykinin. This baseline allows for search of indicators to detect neurological risk in fascioliasis patients and experimental work on antifibrinolytic treatments or B2 receptor antagonists for preventing blood-brain barrier leakage. PMID- 30246667 TI - Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. AB - BACKGROUND: Ketamine has been demonstrated to improve depressive symptoms.AimsEvaluation of efficacy, safety and feasibility of repeated oral ketamine for out-patients with treatment-resistant depression (TRD). METHOD: In a randomised, double-blind, placebo-controlled, proof-of-concept trial, 41 participants received either 1 mg/kg oral ketamine or placebo thrice weekly for 21 days (ClinicalTrials.gov Identifier: NCT02037503). Evaluation was performed at baseline, 40 and 240 min post administration and on days 3, 7, 14 and 21. The main outcome measure was change in Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Twenty-two participants were randomised to the ketamine group, and 19 to the control, with 82.5% (n = 33) completing the study. In the ketamine group, a decrease in depressive symptoms was evident at all time points, whereas in the control group a decrease was evident only 40 min post administration. The reduction in MADRS score on day 21 was 12.75 in the ketamine group versus 2.49 points with placebo (P < 0.001). Six participants in the ketamine group (27.3%) achieved remission compared with none of the controls (P < 0.05). The number needed to treat for remission was 3.7. Side-effects were mild and transient. CONCLUSIONS: Repeated oral ketamine produced rapid and persistent amelioration of depressive symptoms in out-patients with TRD, and was well tolerated. These results suggest that add-on oral ketamine may hold significant promise in the care of patients suffering from TRD in the community.Declaration of interestNone. PMID- 30246669 TI - Decision-making ability in psychosis: a systematic review and meta-analysis of the magnitude, specificity and correlates of impaired performance on the Iowa and Cambridge Gambling Tasks. AB - To identify factors which may help or hinder decision-making ability in people with psychosis, we did a systematic review and meta-analysis of their performance on the Iowa and Cambridge Gambling Tasks. Analysis of 47 samples found they had moderately poorer performance than healthy individuals (N = 4264, g = -0.57, 95% confidence interval (CI) -0.66 to -0.48). Few studies (k = 8) used non-psychotic clinical comparator groups, although very low-quality evidence (k = 3) found people with bipolar disorder may perform better. Negative symptoms (k = 13, N = 648, r = -0.17, 95% CI -0.26 to -0.07) and lower IQ (k = 11, N = 525, r = 0.20, 95% CI 0.29-0.10), but not positive symptoms (k = 10, N = 512, r = -0.01, 95% CI 0.11 to 0.08), each had small-moderate associations with poorer decision-making. Lower quality evidence suggested general symptoms, working memory, social functioning, awareness of emotional responses to information, and attentional bias towards gain are associated with decision-making, but not education, executive functioning or overall symptoms. Meta-regression suggested an inverse association between decision-making and depression severity (k = 6, Q = 6.41, R2 100%, p = 0.01). Those taking first-generation (k = 6, N = 305, g = -0.17, 95% CI -0.40 to 0.06, p = 0.147) or low-dose antipsychotics (k = 5, N = 442, g = -0.19, 95% CI -0.44 to 0.06, p = 0.139) had unimpaired decision-making. Although meta regression found no linear association between dose and performance, non reporting of the dose was common and associated with larger impairments (k = 46, Q = 4.71, R2 14%, p = 0.03). Those supporting people with psychosis to make decisions, including treatment decisions, should consider the potential effect of these factors. Interventionist-causal trials are required to test whether reducing antipsychotic dose and treating anxiety and depression can improve decision-making in this group. PMID- 30246670 TI - Epilepsia Partialis Continua of the Abdominal Musculature Caused by Acute Ischemic Stroke. PMID- 30246671 TI - EARLY DIALOGUE IN EUROPE: PERSPECTIVES ON VALUE, CHALLENGES, AND CONTINUING EVOLUTION. AB - OBJECTIVES: This study aims to assess participants' views on previous experiences, the current situation and future perspectives for early dialogue between the pharmaceutical industry, a regulatory agency and health technology assessment bodies (HTABs) in Europe. METHODS: Eleven semi-structured interviews were arranged purposively with experienced people from the pharmaceutical industry, the European Medicines Agency, and an expert in Health Economics. The interview questions focused on the value of early dialogue, the challenges faced during the process of early dialogue, the best time to start an early dialogue, the kind of products most suitable for early dialogue, the current situation, and future perspectives for the early dialogue process. The interviews were recorded and then transcribed for open and axial coding to summarize the findings. RESULTS: All interviewees agreed that early dialogue is a valuable process that helps to inform the development program and accordingly provide patients with faster access to new medicines. However, at this stage, the pharmaceutical industry acknowledged certain challenges: (i) Finding resources within pharmaceutical companies and HTABs to support early dialogues (ii) Requirements between regulators and HTABs in different countries diverge. CONCLUSIONS: This study revealed that people from the pharmaceutical industry perceive early dialogue as a valuable tool that can bring medicines to patients faster by streamlining development. However, the challenges mentioned above need to be mitigated to build a sustainable mechanism for early dialogue. PMID- 30246673 TI - School Performance Paths: Personal and Contextual Factors Related to Top Performers and Low Achievers in Portugal and Spain. AB - School performance is a critical aspect of adolescents' lives. Several factors have an impact on school performance. The aim of this study is to analyze the relevant personal and contextual variables associated with top performance and low achievement in a sample of Portuguese and Spanish adolescent students. The sample included 1,564 adolescents, mean age 14 years old, and was collected from the HBSC (Health Behavior in School-aged Children) survey. The questions in this study covered sociodemographic, health and wellbeing, health-related behaviors, family, school and peers. Results show that students with low performance more frequently have worse social-contextual and personal/health-related indicators, while the opposite is the case for top performers. Student-teacher relationships appeared as the most influential variable on school performance paths, chi2(2) = 328.11, p < .001; but other variables within families, e.g. mother studies, chi2(2) = 50.54, p < .001, and schools, e.g. liking the school, chi2(1) = 16.27, p < .001 and chi2(1) = 22.54, p < .01 (in the low and high student-teacher relationship branches of the decision tree, respectively), as well as some health and wellbeing variables, e.g. health related-quality of life, chi2(2) = 53.58, p < .001, and chi2(2) = 63.86, < .001 (in the low and high student-teacher relationship branches, respectively), appeared significant in the paths. PMID- 30246672 TI - pH-mediated inhibition of a bumble bee parasite by an intestinal symbiont. AB - Gut symbionts can augment resistance to pathogens by stimulating host-immune responses, competing for space and nutrients, or producing antimicrobial metabolites. Gut microbiota of social bees, which pollinate many crops and wildflowers, protect hosts against diverse infections and might counteract pathogen-related bee declines. Bumble bee gut microbiota, and specifically abundance of Lactobacillus 'Firm-5' bacteria, can enhance resistance to the trypanosomatid parasite Crithidia bombi. However, the mechanism underlying this effect remains unknown. We hypothesized that the Firm-5 bacterium Lactobacillus bombicola, which produces lactic acid, inhibits C. bombi via pH-mediated effects. Consistent with our hypothesis, L. bombicola spent medium inhibited C. bombi growth via reduction in pH that was both necessary and sufficient for inhibition. Inhibition of all parasite strains occurred within the pH range documented in honey bees, though sensitivity to acidity varied among strains. Spent medium was slightly more potent than HCl, d- and l-lactic acids for a given pH, suggesting that other metabolites also contribute to inhibition. Results implicate symbiont mediated reduction in gut pH as a key determinant of trypanosomatid infection in bees. Future investigation into in vivo effects of gut microbiota on pH and infection intensity would test the relevance of these findings for bees threatened by trypanosomatids. PMID- 30246674 TI - Development of ADHD symptoms in preschool children: Genetic and environmental contributions. AB - We examined genetic and environmental contributions to the development of symptoms of attention-deficit/hyperactivity disorder (ADHD) in preschool children. ADHD symptoms in siblings at 1.5, 3, and 5 years of age were investigated in a population-based sample from the prospective Norwegian Mother and Child Cohort Study. The longitudinal contributions of additive genetic, shared, twin-specific, and unique environmental influences were estimated using biometric structural equation models. Heritability of ADHD symptoms ranged from 54% to 70%. There was evidence of partially new genetic influences at successive ages, with genetic correlations ranging from .58 to .89. Contributions from shared environmental factors and twin-specific factors were minor. The importance of unique environmental effects appeared to increase across ages, and was mostly specific to a given age. There was no evidence suggesting that this pattern differs across males and females. Symptoms of ADHD are highly heritability in young children from as early as 1.5 years of age. Longitudinal stability of ADHD symptoms is mainly attributable to genetic influences, but there is also some evidence for age-specific genetic influences. These findings contribute to our understanding of development of ADHD early in life, and can guide future molecular genetics studies. PMID- 30246675 TI - Challenges to Prehospital Care in Honduras. AB - Through a longitudinal field experience and interviews with rural and urban clinic workers in Honduras, the following data were collated regarding the challenges to prehospital Emergency Medical Services (EMS) in this country. In Honduras, both private and public organizations provide prehospital emergency care for citizens and face both financial and resource constraints. These constraints manifest in operational concerns such as challenges of integration of EMS systems with each other, differences in medical direction oversight, and barriers to public access. Despite the availability of public health care services, authorities and locals alike do not recommend using the public systems due to lack of needed resources and time of emergency response.Private volunteer EMS organizations are scattered throughout the country and each operates as their own separate system. There is no single dispatch center available, nor is there a guarantee that calling for EMS will result in the patient's desired response. In this report, the challenges are discussed with possible solutions presented.Bast HE, Jenkins JL. Challenges to prehospital care in Honduras. PMID- 30246676 TI - Co-morbid anaemia and stunting among children of pre-school age in low- and middle-income countries: a syndemic. AB - OBJECTIVE: To determine the prevalence of co-morbidity of two important global health challenges, anaemia and stunting, among children aged 6-59 months in low- and middle-income countries. DESIGN: Secondary analysis of data from Demographic and Health Surveys (DHS) conducted 2005-2015. Child stunting and anaemia were defined using current WHO classifications. Sociodemographic characteristics of children with anaemia, stunting and co-morbidity of these conditions were compared with those of 'healthy' children in the sample (children who were not stunted and not anaemic) using multiple logistic models. SETTING: Low- and middle income countries. SUBJECTS: Children aged 6-59 months. RESULTS: Data from 193 065 children from forty-three countries were included. The pooled proportion of co morbid anaemia and stunting was 21.5 (95 % CI 21.2, 21.9) %, ranging from the lowest in Albania (2.6 %; 95 % CI 1.8, 3.7 %) to the highest in Yemen (43.3; 95 % CI 40.6, 46.1 %). Compared with the healthy group, children with co-morbidity were more likely to be living in rural areas, have mothers or main carers with lower educational levels and to live in poorer households. Inequality in children who had both anaemia and stunting was apparent in all countries. CONCLUSIONS: Co morbid anaemia and stunting among young children is highly prevalent in low- and middle-income countries, especially among more disadvantaged children. It is suggested that they be considered under a syndemic framework, the Childhood Anaemia and Stunting (CHAS) Syndemic, which acknowledges the interacting nature of these diseases and the social and environmental factors that promote their negative interaction. PMID- 30246678 TI - TorsinA Is Functionally Associated with Spermatogenesis. AB - TorsinA is a member of the AAA+ superfamily of adenosine triphosphatases. These AAA+ proteins have numerous biological functions, including vesicle fusion, cytoskeleton dynamics, intracellular trafficking, protein folding, and degradation as well as organelle biogenesis. Of particular interest is torsinA, which is mainly located in the endoplasmic reticulum (ER) and nuclear envelope (NE). Interestingly, mutations in the TOR1A gene (the gene encoding torsinA) are associated with DYT1 dystonia and with the preferential localization of mutated torsinA at the NE, where it is associated with lamina-associated polypeptide 1. A bioinformatics study of the torsinA interactome revealed reproductive processes to be highly relevant, as proteins in this class were found to interact with the former. Interestingly, the torsin protein family had never been previously described to be associated with the mammalian spermatogenic process. Histological staining of torsinA in human testis tissue revealed a granular cytoplasmic localization in mid- and late spermatocytes. We further sought to understand this newly discovered expression of torsinA in the meiotic phase of human spermatogenesis by studying its specific subcellular distribution. TorsinA is not present in the ER as commonly described. The proposal that torsinA might relocate to the pro-acrosomal vesicles in the Golgi apparatus is discussed. PMID- 30246677 TI - Microstructural Characterization of Carbon Nanotubes (CNTs)-Reinforced Nickel Matrix Nanocomposites. AB - This research focuses on the microstructural characterization of nickel matrix composites reinforced by carbon nanotubes (CNTs). The nanocomposites were produced by a conventional powder metallurgy process and the dispersion of CNTs and mixture with nickel powders was performed in a single step by ultrasonication. Microstructural characterization of Ni-CNT nanocomposites was performed by scanning and transmission electron microscopy, electron backscattered diffraction, high-resolution transmission electron microscopy, selected area electron diffraction, and fast Fourier transform analyses. This characterization revealed CNTs embedded in the nickel grains and mainly presented as clusters at the grain boundaries. CNTs hinder recrystallization during sintering, and dislocation cells and subgrains form as a result of the recovery process. PMID- 30246679 TI - From Light Microscopy to Analytical Scanning Electron Microscopy (SEM) and Focused Ion Beam (FIB)/SEM in Biology: Fixed Coordinates, Flat Embedding, Absolute References. AB - Correlative light and electron microscopy (CLEM) has been in use for several years, however it has remained a costly method with difficult sample preparation. Here, we report a series of technical improvements developed for precise and cost effective correlative light and scanning electron microscopy (SEM) and focused ion beam (FIB)/SEM microscopy of single cells, as well as large tissue sections. Customized coordinate systems for both slides and coverslips were established for thin and ultra-thin embedding of a wide range of biological specimens. Immobilization of biological samples was examined with a variety of adhesives. For histological sections, a filter system for flat embedding was developed. We validated ultra-thin embedding on laser marked slides for efficient, high resolution CLEM. Target cells can be re-located within minutes in SEM without protracted searching and correlative investigations were reduced to a minimum of preparation steps, while still reaching highest resolution. The FIB/SEM milling procedure is facilitated and significantly accelerated as: (i) milling a ramp becomes needless, (ii) significant re-deposition of milled material does not occur; and (iii) charging effects are markedly reduced. By optimizing all technical parameters FIB/SEM stacks with 2 nm iso-voxels were achieved over thousands of sections, in a wide range of biological samples. PMID- 30246680 TI - Adult safeguarding under the Care Act 2014. AB - SummarySafeguarding adults is everybody's business, and it is now standard practice for clinicians to undertake safeguarding training as part of their mandatory training in the UK. Nevertheless, safeguarding work is complex and can involve significant dilemmas for professionals. The Care Act 2014 has introduced a number of differences in the way safeguarding is approached, emphasising the overall well-being and choice of the patient rather than merely focusing on their safety. This paper sets out to illustrate evolving safeguarding demand and practice, and aid clinicians in protecting people at risk by describing how they can approach challenging presentations.Declaration of interestNone. PMID- 30246681 TI - Bench to Bedside to Bystanders - Moving Antidotes and Management Guidelines Out of the Hospital and Into the Field. PMID- 30246682 TI - The effects of psychological meaning-centered therapies on quality of life and psychological stress: A metaanalysis. AB - : ABSTRACTObjective:Many psychotherapists speak with clients about meaning in life. Meaning is an neutral evidence-based term for a subjective sense of purpose, values, understanding, self-worth, action-directed goals, and self regulation. Since little is known about its effectiveness, our study aimed to determine the effects of meaning-centered therapies (MCTs) on improving quality of life and reducing psychological stress. METHOD: Independent researchers selected and scored articles in multiple languages in multiple search engines. Weighted pooled mean effects were calculated following a random-effects model. Sensitivity analyses included moderators, study and sample characteristics, risk of bias, randomization, types of MCT, control condition, and outcome instruments. RESULTS: Some 52,220 citations included 60 trials (total sample N = 3,713), of which 26 were randomized controlled trials (N = 1,975), 15 nonrandomized controlled trials (N = 709), and 19 nonrandomized noncontrolled trials with pre/post measurements (N = 1,029). Overall analyses showed large improvements from baseline to immediate posttreatment and follow-up on quality of life (Hedges' g = 1.13, SE = 0.12; g = 0.99, SE = 0.20) and psychological stress (g = 1.21, SE = 0.10; g = 0.67, SE = 0.20). As effects varied between studies, further analyses focused only on controlled trials: MCT had large effect sizes compared to control groups, both immediate and at follow-up, on quality of life (g = 1.02, SE = 0.06; g = 1.06, SE = 0.12) and psychological stress (g = 0.94, SE = 0.07, p < 0.01; g = 0.84, SE = 0.10). Immediate effects were larger for general quality of life (g = 1.37, SE = 0.12) than for meaning in life (g = 1.18, SE = 0.08), hope and optimism (g = 0.80, SE = 0.13), self-efficacy (g = 0.89, SE = 0.14), and social well-being (g = 0.81, SE = 13). The homogeneity of these results was validated by the lack of significance of moderators and alternative ways of selecting studies. Metaregression analyses showed that increases in meaning in life predicted decreases in psychological stress (beta = -0.56, p < 0.001). SIGNIFICANCE OF RESULTS: MCT strongly improves quality of life and reduces psychological stress. MCT should be made more widely available, particularly to individuals in transitional moments in life or with a chronic or life-threatening physical illness as they explicitly report meaning-centered concerns. PMID- 30246684 TI - From Genes to Behavior Through Sex Hormones and Socialization: The Example of Gender Development - Erratum. PMID- 30246683 TI - Association of riverine prawns and intermediate host snails and correlation with human schistosomiasis in two river systems in south-eastern Cote d'Ivoire. AB - The current emphasis of schistosomiasis control is placed on preventive chemotherapy using praziquantel. However, reinfection may occur rapidly in the absence of complementary interventions. Recent studies from Senegal suggest that predatory prawns might feed on intermediate host snails and thus impact on schistosomiasis transmission. We designed a study with four repeated cross sectional surveys pertaining to prawns and snails, coupled with a single cross sectional parasitological survey among humans. We assessed for potential associations between the presence/density of prawns and snails and correlation with Schistosoma infection in a composite sample of school-aged children and adults. The study was carried out between October 2015 and December 2016 in 24 villages located near the Agneby and Me coastal river systems in south-eastern Cote d'Ivoire. At each site, snails and prawns were collected, and in each village, 150 individuals were subjected to stool and urine examination for the diagnosis of Schistosoma mansoni and S. haematobium. We found peaks of relative abundance of intermediate host snails in the villages of the Agneby River system, while predatory prawns were predominantly recorded in the Me River system. A negative association was observed between intermediate host snail densities and riverine prawns; however, no pattern was found between this trend in the predator prey relationship and the prevalence of human schistosomiasis. PMID- 30246685 TI - Improving spine surgical access, appropriateness and efficiency in metropolitan, urban and rural settings. AB - BACKGROUND: The Inter-professional Spine Assessment and Education Clinics (ISAEC) were developed to improve primary care assessment, education and management of patients with persistent or recurrent low back pain-related symptoms. This study aims to determine the effect of ISAEC on access for surgical assessment, referral appropriateness and efficiency for patients meeting a priori referral criteria in rural, urban and metropolitan settings. METHODS: We conducted a retrospective review of prospective data from networked ISAEC clinics in Thunder Bay, Hamilton and Toronto, Ontario. For patients meeting surgical referral criteria, wait times for surgical assessment, surgical referral-related magnetic resonance imaging (MRI) scans and appropriateness of referral were recorded. RESULTS: Overall 422 patients, representing 10% of all ISAEC patients in the study period, were referred for surgical assessment. The average wait times for surgical assessment were 5.4, 4.3 and 2.2 weeks at the metropolitan, urban and rural centres, respectively. Referral MRI usage for the group decreased by 31%. Of the patients referred for formal surgical assessment, 80% had leg-dominant pain and 96% were deemed appropriate surgical referrals. CONCLUSION: Contrary to geographic concentration of health care resources in metropolitan settings, the greatest decrease in wait times was achieved in the rural setting. A networked, shared cared model of care for patients with low back pain-related symptoms significantly improved access for surgical assessment despite varying geographic practice settings and barriers. The greatest reductions were noted in the rural setting. In addition, significant improvements in referral appropriateness and efficiency were achieved compared with historical reports across all sites. PMID- 30246686 TI - Cerebral blood flow in striatal regions is associated with apathy in patients with schizophrenia. AB - BACKGROUND: Striatal dysfunction has been proposed as a pathomechanism for negative symptoms in schizophrenia. There is consensus that negative symptoms can be grouped into 2 dimensions: apathy and diminished expression. Recent studies suggest that different neural mechanisms underlie these dimensions, but the relationship between regional resting-state cerebral blood flow (rCBF) and negative symptom dimensions has not been investigated. METHODS: This study included 29 patients with schizophrenia and 20 healthy controls. We measured rCBF in the striatum using arterial spin labelling (ASL) MRI. We assessed negative symptoms using the Brief Negative Symptom Scale. RESULTS: In the ventral and dorsal striatum, rCBF was not different between patients with schizophrenia and controls. However, we did find a positive association between the severity of apathy and increased rCBF in the ventral and dorsal striatum in patients with schizophrenia. This effect was not present for diminished expression. LIMITATIONS: All patients were taking atypical antipsychotics, so an effect of antipsychotic medication on rCBF could not be excluded, although we did not find a significant association between rCBF and chlorpromazine equivalents. CONCLUSION: The main finding of this study was a specific association between increased striatal rCBF and the negative symptom dimension of apathy. Our results further support the separate assessment of apathy and diminished expression when investigating the neural basis of negative symptoms. The ASL technique can provide a direct and quantitative approach to investigating the role of rCBF changes in the pathophysiology of negative symptoms. PMID- 30246687 TI - Affect, interpersonal behaviour and interpersonal perception during open-label, uncontrolled paroxetine treatment of people with social anxiety disorder: a pilot study. AB - BACKGROUND: Laboratory-based research with community samples has suggested changes in affective, behavioural and cognitive processes as possible explanations for the effects of serotonergic medications. Examining the effects of serotonergic medications using an ecological momentary measure (such as event contingent recording) in the daily lives of people with social anxiety disorder would contribute to establishing the effects of these medications on affect, behaviour and one form of cognition: perception of others' behaviour. METHODS: The present study assessed changes in affect, interpersonal behaviour and perception of others' behaviour in adults with social anxiety disorder using ecological momentary assessment at baseline and over 4 months of a single-arm, uncontrolled, open-label trial of treatment with the selective serotonin reuptake inhibitor paroxetine. RESULTS: Anxiety and concurrent depressive symptoms decreased. Participants also reported increased positive and decreased negative affect; increased agreeable and decreased quarrelsome behaviour; increased dominant and decreased submissive behaviour; and increased perception that others behaved agreeably toward them. Moreover, participants demonstrated reduced intraindividual variability in affect, interpersonal behaviour and perception of others' behaviour. LIMITATIONS: Limitations included the lack of a placebo group, the inability to identify the temporal order of changes and the restricted assessment of extreme behaviour. CONCLUSION: The results of the present study demonstrate changes during pharmacotherapy in the manifestation of affect, interpersonal behaviour and interpersonal perception in the daily lives of people with social anxiety disorder. Given the importance of interpersonal processes to social anxiety disorder, these results may guide future research seeking to clarify mechanisms of action for serotonergic medications. PMID- 30246689 TI - Rapid detection of heavy elements in blood extracted from wounds using x-ray fluorescence analysis. AB - In radiation emergency situations involving persons having plutonium (Pu) contaminated wounds, rapid assessment of the degree of Pu contamination is required to determine the appropriate course of treatment. Currently, rapid on site detection of Pu is usually performed by analysis of alpha-particles emitted from the adhesive tape peeled off the wound. However, the detection of alpha particles is difficult, especially in traumatic skin lesions with oozing blood, because of the low permeability of alpha-particles in blood. Therefore, we focused on x-ray fluorescence (XRF) analysis because x-rays easily pass through several millimetres of blood. In this study, we developed a new methodology for the rapid detection of heavy elements in wounds based on XRF analysis of the contaminated blood collected by gauze patch and filter paper, using stable lead (Pb) as a model contaminant substitute for Pu. Mouse blood samples contaminated with Pb were dropped on gauze patches or absorbed by filter papers and were subjected to XRF measurement. Small pieces of filter paper served as more suitable extraction materials than gauze patches because the entire amount of blood absorbed could be measured. When we used filter paper, the signal intensity of the Pb Lalpha peak was proportional to the Pb concentration in the blood. With a measurement time of 30 s, the minimum detection limit of Pb in blood collected by filter paper was 2.4 ppm. PMID- 30246688 TI - Psychoradiologic abnormalities of white matter in patients with bipolar disorder: diffusion tensor imaging studies using tract-based spatial statistics. AB - BACKGROUND: An increasing number of psychoradiology studies that use tract-based spatial statistics (TBSS) of diffusion tensor imaging have reported abnormalities of white matter in patients with bipolar disorder; however, robust conclusions have proven elusive, especially considering some important clinical and demographic factors. In the present study, we performed a quantitative meta analysis of TBSS studies to elucidate the most consistent white-matter abnormalities in patients with bipolar disorder. METHODS: We conducted a systematic search up to May 2017 for all TBSS studies comparing fractional anisotropy (FA) between patients with bipolar disorder and healthy controls. We performed anisotropic effect size-signed differential mapping meta-analysis. RESULTS: We identified a total of 22 data sets including 556 patients with bipolar disorder and 623 healthy controls. We found significant FA reductions in the genu and body of the corpus callosum in patients with bipolar disorder relative to healthy controls. No regions of increased FA were reported. In subgroup analyses, the FA reduction in the genu of the corpus callosum retained significance in patients with bipolar disorder type I, and the FA reduction in the body of the corpus callosum retained significance in euthymic patients with bipolar disorder. Meta-regression analysis revealed that the percentage of female patients was negatively correlated with reduced FA in the body of the corpus callosum. LIMITATIONS: Data acquisition, patient characteristics and clinical variables in the included studies were heterogeneous. The small number of diffusion tensor imaging studies using TBSS in patients with bipolar disorder type II, as well as the lack of other clinical information, hindered the application of subgroup meta-analyses. CONCLUSION: Our study consistently identified decreased FA in the genu and body of the corpus callosum, suggesting that interhemispheric communication may be the connectivity most affected in patients with bipolar disorder. PMID- 30246690 TI - Long-term recording reliability of liquid crystal polymer uECoG arrays. AB - OBJECTIVE: The clinical use of microsignals recorded over broad cortical regions is largely limited by the chronic reliability of the implanted interfaces. APPROACH: We evaluated the chronic reliability of novel 61-channel micro electrocorticographic (uECoG) arrays in rats chronically implanted for over one year and using accelerated aging. Devices were encapsulated with polyimide (PI) or liquid crystal polymer (LCP), and fabricated using commercial manufacturing processes. In vitro failure modes and predicted lifetimes were determined from accelerated soak testing. Successful designs were implanted epidurally over the rodent auditory cortex. Trends in baseline signal level, evoked responses and decoding performance were reported for over one year of implantation. MAIN RESULTS: Devices fabricated with LCP consistently had longer in vitro lifetimes than PI encapsulation. Our accelerated aging results predicted device integrity beyond 3.4 years. Five implanted arrays showed stable performance over the entire implantation period (247-435 d). Our regression analysis showed that impedance predicted signal quality and information content only in the first 31 d of recordings and had little predictive value in the chronic phase (>31 d). In the chronic phase, site impedances slightly decreased yet decoding performance became statistically uncorrelated with impedance. We also employed an improved statistical model of spatial variation to measure sensitivity to locally varying fields, which is typically concealed in standard signal power calculations. SIGNIFICANCE: These findings show that uECoG arrays can reliably perform in chronic applications in vivo for over one year, which facilitates the development of a high-density, clinically viable interface. PMID- 30246691 TI - Mimicking synaptic functionality with an InAs nanowire phototransistor. AB - We demonstrate a nanowire (NW) phototransistor with synaptic behavior based on inherent persistent photoconductivity. The device is comprised of a single crystalline InAs NW, covered by a native indium oxide layer acting as the photogating layer (PGL). In the negative photoresponse range, the device mimics synaptic neuromorphic behaviors of short-term plasticity, long-term plasticity (LTP), and paired-pulse facilitation. Moreover, the transition from short-term to LTP is observed as the stimulus intensity increases, behaving in accord with the feature of cooperativity. The synaptic behaviors of the device are attributed to the photo-generated electrons trapped/detrapped in the PGL. This NW-based photonic synaptic device would find promising applications in neuromorphic systems and networks. PMID- 30246692 TI - Role of Interleukin-37 in Inflammatory and Autoimmune Diseases. AB - Interleukin-1 family 7 (IL-1F7) is a novel member of IL-1F cytokines. IL-1F7 is more commonly known as IL-37. IL-37 can join the alpha-subunit of the IL-18 receptor, or IL-18 binding protein (IL-18BP), and binding of these proteins can enhance the IL-18 suppression. IL-37 also translocates to the cell nucleus and affects gene transcription. IL-37 inhibits the phosphorylation of p38 mitogen activated protein kinases. Almost all reports showed that IL-37 has remarkable anti-inflammatory activity. IL-37 plays an important role in a variety of inflammatory and autoimmune diseases, as well. Recently, studies demonstrated that the expression of IL-37 is abnormal in many diseases such as inflammatory bowel diseases, inflammatory respiratory diseases, atherosclerosis, hepatitis, obesity, contact hypersensitivity, Graves' disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, and Behcet's disease. Here, we will review the biological characteristics of IL-37 and its key roles in various inflammatory and autoimmune diseases. PMID- 30246693 TI - T Helper Cells Profile and CD4+CD25+Foxp3+Regulatory T Cells in Polycystic Ovary Syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is considered as the most common cause of female infertility that affects 4-10% of women in the reproductive age. Previous studies have shown the role of a balanced immune response in a successful pregnancy and fertility. OBJECTIVE: To investigate the T helper cells type 1 (Th1) /Th2/Th17/Treg paradigms in peripheral blood of infertile PCOS compared with normal fertile women. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated at the late follicular phase from 10 PCOS and 10 fertile women. PBMCs were stimulated with PMA and ionomycin in the presence of Berefeldin A as Golgi stop agent to detect intracellular cytokine production (IFN-gamma, IL 17, and IL-4) from CD3+CD4+T cells population indicating T helper (Th) cells subsets by flowcytometry. Moreover, regulatory T cells were enumerated using CD25 and Foxp3 markers. RESULTS: In this study, we report that the frequency of Th1 cells was increased compared to Th2 cells in infertile PCOS when considering Th1/Th2 ratio (P=0.05). Analysis of Th17/Th2 ratio showed a significant difference with a bias toward Th17 dominancy in PCOS (P=0.02). The proportion of CD4+CD25+Foxp3+ regulatory T cells was significantly lower in PCOS patients than that of healthy fertile women (P=0.02). CONCLUSION: In summary, Th1 and Th17 bias and reduction of Treg and Th2 cells as regulators of immune responses might be involved in the pathogenesis of PCOS. These results are suggestive of an altered immune response to inflammatory status in PCOS patients, likely causing some complications such as infertility in these patients. PMID- 30246694 TI - Vitamin D3 Induced Decrease in IL-17 and Malondialdehyde, and Increase in IL-10 and Total Antioxidant Capacity Levels in Patients with Irritable Bowel Syndrome. AB - BACKGROUND: Given the variations in clinical presentation and physiopathological mechanisms in irritable bowel syndrome (IBS) subtypes, it is an acknowledged fact that the response to treatments can be disparate. OBJECTIVE: To assess the effect of vitamin D on inflammatory cytokines (IL-17, IL-10, TNF-alpha), and biomarkers of oxidative stress (total antioxidant capacity (TAC), and malondialdehyde (MDA)) among IBS patients. METHODS: A double-blind, randomized, placebo-controlled 6 month intervention study was carried out on 90 IBS patients (85 were analyzed), as defined by the Rome III criteria. Study participants were randomly assigned to receive either 50,000 IU vitamin D3 or a placebo fortnightly. RESULTS: Vitamin D supplementation significantly reduced the IL-17 and MDA serum levels (P<0.05) and observably increased the TAC and IL-10 serum levels (P<0.05), compared with the placebo group. Comparing different bowel habit subtypes, we observed that it was only in diarrhea predominant IBS (IBS-D) that vitamin D supplementation was able to significantly reduce the serum levels of TNF-alpha and IL-17 (P<0.05). However, in all subtypes, IL-10 and TAC increased, while MDA decreased (P<0.05) in vitamin D group, compared to the placebo group. CONCLUSION: Vitamin D3 supplementation reduces the serum IL-17 and MDA levels, and augments the serum IL 10 and TAC levels in IBS patients, particularly in IBS-D subtype. Thus, the present study demonstrates the beneficial effects of vitamin D on patients with IBS-D. PMID- 30246695 TI - Lower Frequency of HLA-DRB1*01 in Southwestern Iranian Patients with Atherosclerosis. AB - BACKGROUND: Human leukocyte antigen (HLA) complex is a gene family involved in antigen presentation associated with protection or susceptibility to inflammatory, infectious and autoimmune diseases. Atherosclerosis is a chronic inflammatory disease in which HLA molecules play a role in the initiation and development of the disease through presentation of self or foreign antigens to T cells. OBJECTIVE: To investigate the association of HLA-DRB1 alleles with atherosclerosis in a sample of southwestern Iranians. METHODS: We performed an analytical cross-sectional study involving 96 patients with atherosclerosis and 72 controls. HLA-DRB1 genotyping was performed by PCR-SSP method. RESULTS: We observed a significantly lower frequency of DRB1*01 in patients with coronary artery atherosclerosis than in controls (4.68% vs. 13.1, P=0.0052, OR=3.09, CI 95%: 1.35-7.05). However, this allele showed a positive association with high blood pressure (P=0.009) in patients. Furthermore, DRB1*16 allele was associated with hyperlipidemia (P=0.008) in patients. CONCLUSION: Our results demonstrated that DRB1*01 may be a protective allele against atherosclerosis in individuals who live in southwest of Iran. The mechanism of this protection needs further investigation. PMID- 30246696 TI - Designing and Expression of Recombinant Chimeric Protein Containing CtxB and OmpW from Vibrio Cholerae and Evaluation of Its Immunogenicity. AB - BACKGROUND: Cholera disease caused by Vibrio cholerae remains a major cause of morbidity and mortality throughout the world. Various strategies with different proteins as immunogens have been tried for vaccine development, none of which have been sufficiently effective to preclude cholera. Chimeric proteins, with their ability to present multiple antigens at the same time, can play important roles in immunization. OBJECTIVE: To evaluate the immunogenicity of a chimeric construct, comprised of OmpW and CtxB as immunogenic proteins of Vibrio cholera, in BALB/c mice. METHODS: The construct was designed after bioinformatics assessments and then expressed in E.coli. Chimeric protein, OmpW, and CtxB were purified with Ni-NTA chromatography and confirmed by Western blotting. Mice were immunized with purified recombinant proteins. The antibody titers and specificity of the immune sera were then analyzed by ELISA and challenged on the pups of immunized mice with 1, 5 and 10 LD50. Mice ileal loop assay was also performed. RESULTS: Significant differences were observed in antibody titers in immunized mice compared to the control groups. Infant mouse challenge was performed so as to compare the protective efficacies of the selected immunogen regimens. Of the Pups from dams immunized with chimeric protein which received 1 LD50, 75% survived. Pups belonging to PBS-immunized dams, experienced 100% mortality. The serum raised toward immunogenic construct, inhibited cholera toxin activity in ileal loop test up to 68%. CONCLUSION: Chimeric construct is able to induce the immune system and provide up to 75% inhibition of toxin activity against 1 LD50 of Vibrio cholerae. PMID- 30246697 TI - Circulating Levels of Interleukin-10 and -17 in Patients with Cerebral Sinovenous Thrombosis (CSVT) in Acute and Subacute Stages: A Prospective Case-Control Study. AB - BACKGROUND: Cerebral sinovenous thrombosis (CSVT) is a neurovascular disorder that occurs when a blood clot develops in a vein near the brain. Evaluating the subsequent changes in inflammatory cytokines can better reveal the underlying pathogeneses. OBJECTIVE: To assess the serum levels of interleukin-10 (an anti inflammatory cytokine) and IL-17 (a pro-inflammatory cytokine) in patients with aseptic non-vasculitic CSVT. METHODS: In this prospective case-control study, 31 patients with aseptic non-vasculitic CSVT (admitted in Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran) were enrolled. IL-10 and IL-17 serum levels were measured at diagnosis, before initiation of treatment (acute stage), 3 months later (subacute stage). These cytokines were also measured in samples obtained from 30 gender- and age-matched healthy subjects, which were considered as control values. RESULTS: Patients' IL-10 and IL-17 levels were higher in both acute and subacute stages as compared to controls. However, no significant differences existed between the acute stage and control groups for both cytokines. Moreover, subacute levels were significantly higher than their acute and control levels. CONCLUSION: This study demonstrated the alteration of IL-10 and IL-17 levels in aseptic non-vasculitic CSVT. The rise in subacute IL-10 can be explained by the assumption that IL-10 is released as an anti-inflammatory response to subside the effects of IL-17 mediated reactions. More importantly, the immediate sampling in the acute stage did not allow enough time for triggering the immune system to produce such mediators. However, a balance was established between IL-10 and IL-17 in the subacute stage to prevent further tissue damage. PMID- 30246698 TI - The Soluble and Particulate Form of Alginates Positively Regulate Immune Response. AB - BACKGROUND: Alginate materials have been widely employed for biomedical applications ranging from wound healing to cancer treatment. However, how alginate materials affect the immune system is largely unknown. OBJECTIVE: To explore the impact of alginate materials on immune system. METHODS: The effect of three types of alginate materials, low viscosity, high viscosity and particulate alginate, were examined by both in vivo and in vitro analyses. C57BL/6J (B6) mice were treated with alginate and peripheral blood was tested by ELISA for cytokine production. Dendritic cells, macrophages and splenocytes isolated from mice were analyzed for the response to alginate treatment. Administration of alginates by intra lymph node injection (I.L.N.) yielded more potent cytokines productions than other injection routes. RESULTS: Alginate materials did not affect the viability of lymphocytes. Particulate alginate induced the most potent inflammatory reaction as determined by the production of cytokines, such as, IL 1beta, IL-8, TNF-alpha and IFN-gamma. Low viscosity and particulate alginates are more effective than high viscosity alginates in activating dendritic cells as indicated by the expression of dendritic cells surface markers (CD80, CD86 and CD40). Similarly, the level of G-CSF was slightly higher in particulate alginate treated macrophages. CONCLUSION: Alginate materials could affect immune response through different ways, including promoting inflammatory cytokine production, and activating dendritic cells. Therefore, alginate materials, especially in particulate form, have the potential to be applied in inflammation related diseases. PMID- 30246699 TI - Soluble CD163 Levels and CD163+CD14+ Monocyte/Macrophage Counts in Patients with Asthma. AB - BACKGROUND: CD163-expressing macrophages are involved in the inflammatory response in asthma. OBJECTIVE: To assess sputum and serum soluble CD163 (sCD163) and cytokine levels in patients with asthma. Further discussed was the difference between sCD163 and other classic inflammatory mediators. METHODS: Sputum was successfully induced in asthma patients (n=85) and healthy controls (n=21). Interleukin (IL)-4, IL-5, IL-1beta, IL-8, IL-9, IL-6, and sCD163 levels in sputum were measured. CD163+ monocytes in blood were evaluated using flow cytometry. RESULTS: Sputum sCD163 level significantly increased in asthma (median: 22.4 pg/ml; IQR, 11.52-42.91), unlike healthy controls (10.54 pg/ml;9.85-23.5; P<0.001). Sputum sCD163 (P=0.020) and serum sCD163 (P=0.032) levels were significantly higher in patients with severe asthma compared to those with mild/moderate asthma. Percentage of CD163+ monocytes in patients with asthma was significantly lower than the controls (P<0.001). CONCLUSION: Increased sCD163 levels in sputum are associated with the impairment of lung function. PMID- 30246700 TI - A remnant suture can mimic malignancy after total thyroidectomy. AB - : Foreign body reactions may develop against exogenous or certain endogenous materials. Cases of suture granuloma that develop against nonabsorbable suture material are rare complications of thyroid surgery. Because of these postoperative complications, a history of cancer prior to the operation suggests recurrence of cancer. Appropriate clinical, radiological, and pathological evaluation is highly important in such cases. Postoperative foreign bodies may remain undetected for years, but they sometimes cause lethal complications. KEY WORDS: Cancer mimicking, Foreign body, Suture granuloma, Thyroid surgery. PMID- 30246701 TI - Intraoperative Endoscopic Retrograde Cholangiopancreatography in patients with complex benign biliary tract pathologies A case series. AB - INTRODUCTION: This study presents data about the intraoperative performance of Endoscopic Retrograde Cholangiopancreatography (ERCP) for different types of cases with acute, complex pathologies of the biliary tract. MATERIALS AND METHODS: We retrospectively enrolled cases with intraoperative ERCP performed for different acute complex bile duct pathologies (including injury and cystic stump leak). All patients were analyzed according to demographic findings, etiologies, management and results. RESULTS: Intraoperative ERCP was performed in 4 patients of whom 2 (50%) were female and 2 (50%) were male with different diagnoses. The median age of patients was 46.8 (range of 28-75) years. The diagnosis was bile duct injury in three patients and one had a complicated hydatid cyst with jaundice (T Bil: 18 mg dl-1). All patients were in septic condition. Patients underwent laparotomy and intraoperative ERCP was performed successfully by using the Rendezvous technique. For the last patient, intraoperative ERCP was used for diagnosis and management of bile leak in the cavity. CONCLUSION: Intraoperative endoscopic retrograde cholangiopancreatography is a safe and effective method for treatment of acute complex bile duct pathologies. KEY WORDS: Bile Duct Injury, Intraoperative ERCP, Rendezvous Technique. PMID- 30246702 TI - Dome-shaped solitary nodule. PMID- 30246703 TI - Differential expression of capecitabine-induced hand foot syndrome on paretic limb. PMID- 30246704 TI - Cutaneous inflammation as a marker of malignant transformation in a patient with linear unilateral basaloid follicular hamartoma. AB - Basaloid follicular hamartoma is a rare, benign and superficial malformation of hair follicles, characterized histologically by epithelial proliferation of basaloid cells with radial disposition. It can be mistaken for basal cell carcinoma. Even though these hamartomas are considered benign lesions, malignant transformation has rarely been reported. We report the case of a 45-year-old healthy woman, with linear, unilateral basaloid follicular hamartoma which developed inflamed papules histologically suggestive of basal cell carcinoma. We believe that identification of local inflammation could be a clinical clue to guide us towards a malignant transformation of basaloid follicular hamartoma. PMID- 30246705 TI - Docetaxel induced pellagroid dematitis. PMID- 30246706 TI - N-acetylcysteine in dermatology. AB - N-acetylcysteine is a mucolytic drug which is commonly used as an antidote for acetaminophen toxicity. It is a thiol compound, which acts as a donor of cysteine, leading to replenishment of glutathione and thus acts as an antioxidant. It also has anti-inflammatory effects, alters the levels of neurotransmitters, inhibits proliferation of fibroblasts and keratinocytes and causes vasodilatation. Due to these actions, n-acetylcysteine has found use in several dermatologic conditions in systemic and topical form. The drug has been used as an adjuvant in the management of conditions such as toxic epidermal necrolysis, drug hypersensitivity syndrome, trichotillomania, skin picking disorders and onychotillomania, ichthyoses, contact dermatitis, atopic dermatitis, melasma, pseudoporphyria, connective tissue diseases, wound healing and alopecia. It also has a role in protection from radiation-induced skin damage including photo-ageing, photocarcinogenesis and radiation dermatitis. Most indications in dermatology are supported by case reports, small case series and small trials. Higher quality of evidence is needed for its wider use. The drug is cheap and is generally safe with few adverse effects. Thus a greater role is possible for use of n-acetylcysteine in various skin conditions. This review explores the various uses of n-acetylcysteine in the field of dermatology, the evidence supporting the same, the possible mechanisms of action and the adverse effects of the drug. PMID- 30246708 TI - Feasibility and safety of EUS-guided selective portal vein embolization with a coil and cyanoacrylate in a live porcine model. AB - Background and Objectives: Preoperative portal vein (PV) embolization using the percutaneous transhepatic approach has been performed in patients with hepatobiliary malignancy before extensive liver resection. The aim of this study is to evaluate the technical feasibility and initial safety of EUS-guided selective PV embolization using a coil and cyanoacrylate in a live porcine model. Methods: EUS-guided selective intrahepatic PV embolization with a coil and cyanoacrylate was performed in 9 pigs. The selected PV was punctured with 19G fine-needle aspiration (FNA) needle, and the coil was inserted under EUS guidance. The cyanoacrylate was then immediately injected through the same FNA needle. The blood flow change in the embolized PV was evaluated using color Doppler EUS. A necropsy was performed following the 1-week observation period. Results: The success rates for the coil and cyanoacrylate delivery were 88.9% (8/9) and 87.5% (7/8), respectively. In 1 case, the coil migrated into the hepatic parenchyma. In another case, the cyanoacrylate injection failed due to early clogging in the FNA needle. There was a complete blockage of blood flow confirmed by color Doppler EUS in the embolized PV after coil and cyanoacrylate treatment. There was coil migration into the hepatic parenchyma in 1 case. There was no animal distress observed during the 1-week observation period before necropsy. The necropsy showed no evidence of damage to the intra-abdominal organs, and the selected PV was totally occluded with embolus. Conclusion: The study findings indicate EUS-guided selective PV embolization is both technically feasible and initially safe in an animal model. PMID- 30246707 TI - The survival and prognostic factors of primary testicular lymphoma: two-decade single-center experience. AB - This study aims to investigate the effect of different local testicular treatments and validate common prognostic factors on primary testicular lymphoma (PTL) patients. We retrospectively reviewed the clinical records of 32 patients from 1993 to 2017 diagnosed with PTL and included 22 patients for analysis. The Kaplan-Meier method, Log-rank test, and multivariate Cox proportional hazard regression analysis were applied to evaluate progression-free survival (PFS), overall survival (OS), and determine prognosis predictors. The median follow-up time was 30 months. Median OS and PFS were 96 months and 49 months, respectively. In univariate analysis, advanced Ann Arbor stage (III/IV) (P < 0.001), B symptoms (P < 0.001), and extranodal involvement other than testis (P = 0.001) were significantly associated with shorter OS and PFS. In multivariate analysis, Ann Arbor stage was significantly associated with OS (OR = 11.58, P = 0.049), whereas B symptom was significantly associated with PFS (OR = 11.79, P= 0.049). In the 10 patients with the systemic usage of rituximab, bilateral intervention could improve median OS from 16 to 96 months (P = 0.032). The study provides preliminary evidence on bilateral intervention in testes in the rituximab era and validates common prognostic factors for Chinese PTL patients. PMID- 30246709 TI - Discriminating chronic pancreatitis from pancreatic cancer: Contrast-enhanced EUS and multidetector computed tomography in direct comparison. AB - Background and Objectives: To compare the ability of multidetector computed tomography (MDCT) and contrast-enhanced EUS to discriminate chronic pancreatitis (CP) from pancreatic ductal adenocarcinoma (PDAC). Subjects and Methods: A total of 215 patients (age: 62 +/- 15 years, sex: f/m 80/135) were included in this retrospective study. All patients were examined by conventional endoscopic B-mode and contrast-enhanced high mechanical index EUS (CEHMI-EUS). CELMI-EUS was performed in 159 patients and endoscopic sonoelastography (ESE) in 210 patients. MDCT was carried out in 131 patients as part of their clinical work-up. Radiological reports were retrospectively analyzed. Final diagnosis was achieved by biopsy and evaluation of cytological specimens collected was performed by EUS FNA, surgery, or follow-up of 12 months or more in patients with benign findings. In a subgroup of 100 patients, all diagnostic five methods were performed, and head-to-head analysis was performed. Results: Sensitivity and specificity for MDCT were 89% and 70% and for CEHMI-EUS were 96% and 91%, respectively. Sensitivities and specificities for EUS were 92% and 63% for B-Mode EUS, 96% and 38% for ESE, and 82% and 76% for CELMI-EUS, respectively. In the head-to-head analysis, each modality had shown lower numbers for specificity than shown in the overall group analysis because of high drop-out rate. EUS-FNA for PDAC had a sensitivity of 96% and a specificity of 100%. Conclusions: Contrast-enhanced EUS is a reliable tool in discriminating PDAC from CP. PMID- 30246710 TI - Psychological impact of pancreatic cancer screening by EUS or magnetic resonance imaging in high-risk individuals: A systematic review. AB - Background and Objectives: There is an increasing global interest in screening programs aiming to detect pancreatic cancer (PC) in an early and potentially curable stage. Concerns still remain as to whether screening would confer any survival benefit. Another approach to evaluate the benefits of the pancreatic screening programs would be to consider its impact on the quality of life of the individuals who at risk of developing cancer. The aim of this systematic review was to investigate the current knowledge regarding the psychological impact of participation in routine screening for PC. Methods: A systematic literature search was carried out in January 2018 in three major databases which are as follows: PubMed, Scopus, and Web of Science. Cross-sectional and prospective studies evaluating the psychological aspects of screening in high-risk individuals were included in the study. For each study, the following data were recorded: name of first author, year of publication, study design, study population, aims, screening protocol, outcomes and instruments, main results, and summary of findings. Results: Six cohort studies and one cross-sectional study that addressed the psychological aspects of PC screening were included in the analysis. Overall, studies have shown that high-risk individuals have positive psychological outcomes from participating in PC screening programs. Conclusions: Although screening might not always be reassuring, it may improve individuals' quality of life, and this should be an important aspect when considering PC screening. PMID- 30246711 TI - Intrahepatic bile duct stone removal using peroral transluminal cholangioscopy (with videos). PMID- 30246712 TI - Association between Nonalcoholic Fatty Liver Disease and Carotid Artery Disease in a Community-Based Chinese Population: A Cross-Sectional Study. AB - Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases with a high prevalence in the general population. The association between NAFLD and cardiovascular disease has been well addressed in previous studies. However, whether NAFLD is associated with carotid artery disease in a community-based Chinese population remained unclear. The aim of this study was to investigate the association between NAFLD and carotid artery disease. Methods: A total of 2612 participants (1091 men and 1521 women) aged 40 years and older from Jidong of Tangshan city (China) were selected for this study. NAFLD was diagnosed by abdominal ultrasonography. The presence of carotid stenosis or plaque was evaluated by carotid artery ultrasonography. Logistic regression was used to analyze the association between NAFLD and carotid artery disease. Results: Participants with NAFLD have a higher prevalence of carotid stenosis (12.9% vs. 4.6%) and carotid plaque (21.9% vs. 15.0%) than those without NAFLD. After adjusting for age, gender, smoking status, income, physical activity, diabetes, hypertension, triglyceride, waist-hip ratio, and high-density lipoprotein, NAFLD is significantly associated with carotid stenosis (odds ratio [OR]: 2.06, 95% confidence interval [CI]: 1.45-2.91), but the association between NAFLD and carotid plaque is not statistically significant (OR: 1.10, 95% CI: 0.8 1.40). Conclusion: A significant association between NAFLD and carotid stenosis is found in a Chinese population. PMID- 30246713 TI - Feasibility Analysis of Oxygen-Glucose Deprivation-Nutrition Resumption on H9c2 Cells In vitro Models of Myocardial Ischemia-Reperfusion Injury. AB - Background: Oxygen-glucose deprivation-nutrition resumption (OGD-NR) models on H9c2 cells are commonly used in vitro models of simulated myocardial ischemia reperfusion injury (MIRI), but no study has assessed whether these methods for establishing in vitro models can effectively imitate the characteristics of MIRI in vivo. This experiment was designed to analyze the feasibility of six OGD-NR models of MIRI. Methods: By searching the PubMed database using the keywords "myocardial reperfusion injury H9c2 cells," we obtained six commonly used OGD-NR in vitro models of MIRI performed on H9c2 cells from more than 400 published papers before January 30, 2017. For each model, control (C), simulated ischemia (SI), and simulated ischemia-reperfusion (SIR) groups were assigned, and cell morphology, lactate dehydrogenase (LDH) release, adenosine triphosphate (ATP) levels, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and inflammatory cytokines were examined to evaluate the characteristics of cell injury. Subsequently, a coculture system of cardiomyocyte-endothelial-macrophage was constructed. The coculture system was dealt with SI and SIR treatments to test the effect on cardiomyocytes survival. Results: For models 1, 2, 3, 4, 5, and 6, SI treatment caused morphological damage to cells, and subsequent SIR treatment did not cause further morphological damage. In the models 1, 2, 3, 4, 5 and 6, LDH release was significantly higher in the SI groups than that in the C group (P < 0.05), and was significantly lower in the SIR groups than that in the SI groups (P < 0.05), except for no significant differences in the LDH release between C, SI and SIR groups in model 6 receiving a 3-h SI treatment. In models 1, 2, 3, 4, 5, and 6, compared with the C group, ATP levels of the SI groups significantly decreased (P < 0.05), ROS levels increased (P < 0.05), and MMP levels decreased (P < 0.05). Compared with the SI group, ATP level of the SIR groups was significantly increased (P < 0.05), and there was no significant ROS production, MMP collapse, and over inflammatory response in the SIR groups. In a coculture system of H9c2 cells-endothelial cells-macrophages, the proportion of viable H9c2 cells in the SIR groups was not reduced compared with the SI groups. Conclusion: All the six OGD-NR models on H9c2 cells in this experiment can not imitate the characteristics of MIRI in vivo and are not suitable for MIRI-related study. PMID- 30246714 TI - Effect of the Shensong Yangxin Capsule on Energy Metabolism in Angiotensin II Induced Cardiac Hypertrophy. AB - Background: Shensong Yangxin Capsule (SSYX), traditional Chinese medicine, has been used to treat arrhythmias, angina, cardiac remodeling, cardiac fibrosis, and so on, but its effect on cardiac energy metabolism is still not clear. The objective of this study was to investigate the effects of SSYX on myocardium energy metabolism in angiotensin (Ang) II-induced cardiac hypertrophy. Methods: We used 2 MUl (10-6 mol/L) AngII to treat neonatal rat cardiomyocytes (NRCMs) for 48 h. Myocardial alpha-actinin staining showed that the myocardial cell volume increased. Expression of the cardiac hypertrophic marker-brain natriuretic peptide (BNP) messenger RNA (mRNA) also increased by real-time polymerase chain reaction (PCR). Therefore, it can be assumed that the model of hypertrophic cardiomyocytes was successfully constructed. Then, NRCMs were treated with 1 MUl of different concentrations of SSYX (0.25, 0.5, and 1.0 MUg/ml) for another 24 h. To explore the time-depend effect of SSYX on energy metabolism, 0.5 MUg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h. Mitochondria was assessed by MitoTracker staining and confocal microscopy. mRNA and protein expression of mitochondrial biogenesis-related genes - Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), energy balance key factor - adenosine monophosphate-activated protein kinase (AMPK), fatty acids oxidation factor - carnitine palmitoyltransferase-1 (CPT-1), and glucose oxidation factor - glucose transporter- 4 (GLUT-4) were measured by PCR and Western blotting analysis. Results: With the increase in the concentration of SSYX (from 0.25 to 1.0 MUg/ml), an increased mitochondrial density in AngII-induced cardiomyocytes was found compared to that of those treated with AngII only (0.25 MUg/ml, 18.3300 +/- 0.8895 vs. 24.4900 +/- 0.9041, t = 10.240, P < 0.0001; 0.5 MUg/ml, 18.3300 +/ 0.8895 vs. 25.9800 +/- 0.8187, t = 12.710, P < 0.0001; and 1.0 MUg/ml, 18.3300 +/- 0.8895 vs. 24.2900 +/- 1.3120, t = 9.902, P < 0.0001; n = 5 per dosage group). SSYX also increased the mRNA and protein expression of PGC-1alpha (0.25 MUg/ml, 0.8892 +/- 0.0848 vs. 1.0970 +/- 0.0994, t = 4.319, P = 0.0013; 0.5 MUg/ml, 0.8892 +/- 0.0848 vs. 1.2330 +/- 0.0564, t = 7.150, P < 0.0001; and 1.0 MUg/ml, 0.8892 +/- 0.0848 vs. 1.1640 +/- 0.0755, t = 5.720, P < 0.0001; n = 5 per dosage group), AMPK (0.25 MUg/ml, 0.8872 +/- 0.0779 vs. 1.1500 +/- 0.0507, t = 7.239, P < 0.0001; 0.5 MUg/ml, 0.8872 +/- 0.0779 vs. 1.2280 +/- 0.0623, t = 9.379, P < 0.0001; and 1.0 MUg/ml, 0.8872 +/- 0.0779 vs. 1.3020 +/- 0.0450, t = 11.400, P < 0.0001; n = 5 per dosage group), CPT-1 (1.0 MUg/ml, 0.7348 +/- 0.0594 vs. 0.9880 +/- 0.0851, t = 4.994, P = 0.0007, n = 5), and GLUT-4 (0.5 MUg/ml, 1.5640 +/- 0.0599 vs. 1.7720 +/- 0.0660, t = 3.783, P = 0.0117; 1.0 MUg/ml, 1.5640 +/- 0.0599 vs. 2.0490 +/- 0.1280, t = 8.808, P < 0.0001; n = 5 per dosage group). The effect became more obvious with the increasing concentration of SSYX. When 0.5 MUg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h, the expression of AMPK (6 h, 14.6100 +/- 0.6205 vs. 16.5200 +/- 0.7450, t = 3.456, P = 0.0250; 12 h, 14.6100 +/- 0.6205 vs. 18.3200 +/- 0.9965, t = 6.720, P < 0.0001; 24 h, 14.6100 +/- 0.6205 vs. 21.8800 +/- 0.8208, t = 13.160, P < 0.0001; and 48 h, 14.6100 +/- 0.6205 vs. 23.7400 +/- 1.0970, t = 16.530, P < 0.0001; n = 5 per dosage group), PGC-1alpha (12 h, 11.4700 +/- 0.7252 vs. 16.9000 +/- 1.0150, t = 7.910, P < 0.0001; 24 h, 11.4700 +/- 0.7252 vs. 20.8800 +/- 1.2340, t = 13.710, P < 0.0001; and 48 h, 11.4700 +/- 0.7252 vs. 22.0300 +/- 1.4180, t = 15.390; n = 5 per dosage group), CPT-1 (24 h, 15.1600 +/- 1.0960 vs. 18.5800 +/- 0.9049, t = 6.048, P < 0.0001, n = 5), and GLUT-4 (6 h, 10.2100 +/- 0.9485 vs. 12.9700 +/- 0.8221, t = 4.763, P = 0.0012; 12 h, 10.2100 +/- 0.9485 vs. 16.9100 +/- 0.8481, t = 11.590, P < 0.0001; 24 h, 10.2100 +/- 0.9485 vs. 19.0900 +/- 0.9797, t = 15.360, P < 0.0001; and 48 h, 10.2100 +/- 0.9485 vs. 14.1900 +/- 0.9611, t = 6.877, P < 0.0001; n = 5 per dosage group) mRNA and protein increased gradually with the prolongation of drug action time. Conclusions: SSYX could increase myocardial energy metabolism in AngII-induced cardiac hypertrophy. Therefore, SSYX might be considered to be an alternative therapeutic remedy for myocardial hypertrophy. PMID- 30246715 TI - Effects of Risperidone and Paliperidone on Brain-Derived Neurotrophic Factor and N400 in First-Episode Schizophrenia. AB - Background: Risperidone and paliperidone have been the mainstay treatment for schizophrenia and their potential role in neuroprotection could be associated with brain-derived neurotrophic factor (BDNF) and N400 (an event-related brain potential component). So far, different effects on both BDNF and N400 were reported in relation to various antipsychotic treatments. However, few studies have been conducted on the mechanism of risperidone and paliperidone on BDNF and N400. This study aimed to compare the effects of risperidone and paliperidone on BDNF and the N400 component of the event-related brain potential in patients with first-episode schizophrenia. Methods: Ninety-eight patients with first-episode schizophrenia were randomly divided into the risperidone and paliperidone groups and treated with risperidone and paliperidone, respectively, for 12 weeks. Serum BDNF level, the latency, and amplitude of the N400 event-related potential before and after the treatment and Positive and Negative Syndrome Scale (PANSS) scores were compared between the two groups. Results: A total of 94 patients were included in the final analysis (47 patients in each group). After the treatment, the serum BDNF levels in both groups increased (all P < 0.01), while no significant difference in serum BDNF level was found between the groups before and after the treatment (all P > 0.05). After the treatment, N400 amplitudes were increased (from 4.73 +/- 2.86 MUv and 4.51 +/- 4.63 MUv to 5.35 +/- 4.18 MUv and 5.52 +/- 3.08 MUv, respectively) under congruent condition in both risperidone and paliperidone groups (all P < 0.01). Under incongruent conditions, the N400 latencies were shortened in the paliperidone group (from 424.13 +/- 110.42 ms to 4.7.41 +/- 154.59 ms, P < 0.05), and the N400 amplitudes were increased in the risperidone group (from 5.80 +/- 3.50 MUv to 7.17 +/- 5.51 MUv, P < 0.01). After treatment, the total PANSS score in both groups decreased significantly (all P < 0.01), but the difference between the groups was not significant (P > 0.05). A negative correlation between the reduction rate of the PANSS score and the increase in serum BDNF level after the treatment was found in the paliperidone group but not in the risperidone group. Conclusions: Both risperidone and paliperidone could increase the serum BDNF levels in patients with first-episode schizophrenia and improve their cognitive function (N400 latency and amplitude), but their antipsychotic mechanisms might differ. PMID- 30246716 TI - Cardiac Fibroblast-Specific Activating Transcription Factor 3 Promotes Myocardial Repair after Myocardial Infarction. AB - Background: Myocardial ischemia injury is one of the leading causes of death and disability worldwide. Cardiac fibroblasts (CFs) have central roles in modulating cardiac function under pathophysiological conditions. Activating transcription factor 3 (ATF3) plays a self-protective role in counteracting CF dysfunction. However, the precise function of CF-specific ATF3 during myocardial infarction (MI) injury/repair remains incompletely understood. The aim of this study was to determine whether CF-specific ATF3 affected cardiac repair after MI. Methods: Fifteen male C57BL/6 wild-type mice were performed with MI operation to observe the expression of ATF3 at 0, 0.5, 1.0, 3.0, and 7.0 days postoperation. Model for MI was constructed in ATF3TGfl/flCol1a2-Cre+ (CF-specific ATF3 overexpression group, n = 5) and ATF3TGfl/flCol1a2-Cre- male mice (without CF-specific ATF3 overexpression group, n = 5). In addition, five mice of ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2-Cre- were subjected to sham MI operation. Heart function was detected by ultrasound and left ventricular remodeling was observed by Masson staining (myocardial fibrosis area was detected by blue collagen deposition area) at the 28th day after MI surgery in ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2 Cre- mice received sham or MI operation. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect cell proliferation/cell cycle-related gene expression in cardiac tissue. BrdU staining was used to detect fibroblast proliferation. Results: After establishment of an MI model, we found that ATF3 proteins were increased in the heart of mice after MI surgery and dominantly expressed in CFs. Genetic overexpression of ATF3 in CFs (ATF3TGfl/flCol1a2-Cre+ group) resulted in an improvement in the heart function as indicated by increased cardiac ejection fraction (41.0% vs. 30.5%, t = 8.610, P = 0.001) and increased fractional shortening (26.8% vs. 18.1%, t = 7.173, P = 0.002), which was accompanied by a decrease in cardiac scar area (23.1% vs. 11.0%, t = 8.610, P = 0.001). qRT-PCR analysis of CFs isolated from ATF3TGfl/flCol1a2-Cre+ and ATF3TGfl/flCol1a2-Cre- ischemic hearts revealed a distinct transcriptional profile in ATF3-overexpressing CFs, displaying pro-proliferation properties. BrdU positive cells significantly increased in ATF3-overexpressing CFs than control CFs under angiotensin II stimuli (11.5% vs. 6.8%, t = 31.599, P = 0.001) or serum stimuli (31.6% vs. 20.1%, t = 31.599, P = 0.001). The 5(6)-carboxyfluorescein N hydroxysuccinimidyl ester assay showed that the cell numbers of the P2 and P3 generations were higher in the ATF3-overexpressing CFs at 24 h (P2: 91.6% vs. 71.8%, t = 8.465, P = 0.015) and 48 h (P3: 81.6% vs. 51.1%, t = 9.029, P = 0.012) after serum stimulation. Notably, ATF3 overexpression-induced CF proliferation was clearly increased in the heart after MI injury. Conclusions: We identify that CF-specific ATF3 might contribute to be MI repair through upregulating the expression of cell cycle/proliferation-related genes and enhancing cell proliferation. PMID- 30246717 TI - Role of X-Box Binding Protein-1 in Fructose-Induced De Novo Lipogenesis in HepG2 Cells. AB - Background: A high consumption of fructose leads to hepatic steatosis. About 20 30% of triglycerides are synthesized via de novo lipogenesis. Some studies showed that endoplasmic reticulum stress (ERS) is involved in this process, while others showed that a lipotoxic environment directly influences ER homeostasis. Here, our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 (XBP-1), one marker of ERS, on hepatic lipid accumulation stimulated by high fructose. Methods: HepG2 cells were incubated with different concentrations of fructose. Upstream regulators of de novo lipogenesis (i.e., carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1c [SREBP-1c]) were measured by polymerase chain reaction and key lipogenic enzymes (acetyl-CoA carboxylase [ACC], fatty acid synthase [FAS], and stearoyl-CoA desaturase-1 [SCD-1]) by Western blotting. The same lipogenesis-associated factors were then evaluated after exposure of HepG2 cells to high fructose followed by the ERS inhibitor tauroursodeoxycholic acid (TUDCA) or the ERS inducer thapsigargin. Finally, the same lipogenesis-associated factors were evaluated in HepG2 cells after XBP-1 upregulation or downregulation through cell transfection. Results: Exposure to high fructose increased triglyceride levels in a dose- and time-dependent manner and significantly increased mRNA levels of SREBP-1c and ChREBP and protein levels of FAS, ACC, and SCD-1, concomitant with XBP-1 conversion to an active spliced form. Lipogenesis-associated factors induced by high fructose were inhibited by TUDCA and induced by thapsigargin. Triglyceride level in XBP-1-deficient group decreased significantly compared with high-fructose group (4.41 +/- 0.54 MUmol/g vs. 6.52 +/- 0.38 MUmol/g, P < 0.001), as mRNA expressions of SREBP-1c (2.92 +/- 0.46 vs. 5.08 +/- 0.41, P < 0.01) and protein levels of FAS (0.53 +/- 0.06 vs. 0.85 +/- 0.05, P = 0.01), SCD-1 (0.65 +/- 0.06 vs. 0.90 +/- 0.04, P = 0.04), and ACC (0.38 +/- 0.03 vs. 0.95 +/- 0.06, P < 0.01) decreased. Conversely, levels of triglyceride (4.22 +/- 0.54 MUmol/g vs. 2.41 +/- 0.35 MUmol/g, P < 0.001), mRNA expression of SREBP-1c (2.70 +/- 0.33 vs. 1.00 +/- 0.00, P < 0.01), and protein expression of SCD-1 (0.93 +/- 0.06 vs. 0.26 +/- 0.05, P < 0.01), ACC (0.98 +/- 0.09 vs. 0.43 +/- 0.03, P < 0.01), and FAS (0.90 +/- 0.33 vs. 0.71 +/- 0.02, P = 0.04) in XBP-1s-upregulated group increased compared with the untransfected group. Conclusions: ERS is associated with de novo lipogenesis, and XBP-1 partially mediates high-fructose-induced lipid accumulation in HepG2 cells through augmentation of de novo lipogenesis. PMID- 30246718 TI - XB130 Knockdown Inhibits the Proliferation, Invasiveness, and Metastasis of Hepatocellular Carcinoma Cells and Sensitizes them to TRAIL-Induced Apoptosis. AB - Background: XB130 is a recently discovered adaptor protein that is highly expressed in many malignant tumors, but few studies have investigated its role in hepatocellular carcinoma (HCC). Therefore, this study explored the relationship between this protein and liver cancer and investigated its molecular mechanism of action. Methods: The expression of XB130 between HCC tissues and adjacent nontumor tissues was compared by real-time polymerase chain reaction, immunochemistry, and Western blotting. XB130 silencing was performed using small hairpin RNA. The effect of silencing XB130 was examined using Cell Counting Kit 8, colony assay, wound healing assay, and cell cycle analysis. Results: We found that XB130 was highly expressed in HCC tissues (cancer tissues vs. adjacent tissues: 0.23 +/- 0.02 vs. 0.17 +/- 0.02, P < 0.05) and liver cancer cell lines, particularly MHCC97H and HepG2 (MHCC97H and HepG2 vs. normal liver cell line LO 2: 2.35 +/- 0.26 and 2.04 +/- 0.04 vs. 1.00 +/- 0.04, respectively, all P < 0.05). The Cell Counting Kit-8 assay, colony formation assay, and xenograft model in nude mice showed that silencing XB130 inhibited cell proliferative ability both in vivo and in vitro, with flow cytometry demonstrating that the cells were arrested in the G0/G1 phase in HepG2 (HepG2 XB130-silenced group [shA] vs. HepG2 scramble group [NA]: 74.32 +/- 5.86% vs. 60.21 +/- 3.07%, P < 0.05) and that the number of G2/M phase cells was decreased (HepG2 shA vs. HepG2 NA: 8.06 +/- 2.41% vs. 18.36 +/- 4.42%, P < 0.05). Furthermore, the cell invasion and migration abilities were impaired, and the levels of the epithelial-mesenchymal transition related indicators vimentin and N-cadherin were decreased, although the level of E-cadherin was increased after silencing XB130. Western blotting showed that the levels of phosphorylated phosphoinositide 3-kinase (PI3K) and phospho-protein kinase B (p-Akt) also increased, although the level of phosphorylated phosphatase and tensin homolog increased, indicating that XB130 activated the PI3K/Akt pathway. Furthermore, we found that a reduction in XB130 increased liver cancer cell sensitivity to tumor necrosis factor-related apoptosis-inducing ligand induced apoptosis. Conclusions: Our findings suggest that XB130 might be used as a predictor of liver cancer as well as one of the targets for its treatment. PMID- 30246719 TI - Advances in the Surgical Treatment of Neuroblastoma. AB - Objective: This study was to review the efficacy of surgical resections in different clinical situations for a better understanding of the meaning of surgery in the treatment of neuroblastoma (NB). Data Sources: The online database ScienceDirect (201-2018) was utilized. The search was conducted using the keywords "neuroblastoma," "neuroblastoma resection," "neuroblastoma surgery," and "high-risk neuroblastoma." Study Selection: We retrospectively analyzed of patients who underwent surgical resections in different clinical situations. The article included findings from selected relevant randomized controlled trials, systematic reviews, and meta-analyses or good-quality observational studies. Abstracts only, letters, and editorial notes were excluded. Full-text articles and abstracts were extracted and reviewed to identify key articles discussing surgery management of NB, which were then selected for critical analysis. Results: A total of 7800 English language articles were found containing references to NB (201-2018). The 163 articles were searched which were related to the surgical treatment of NB (201-2018). Through the analysis of these important articles, we found that the treatments of NB at low- and intermediate-risk groups were basically the same. High-risk patients remained controversial. Conclusions: NB prognosis varies tremendously based on the stage and biologic features of the tumor. After reviewing the relevant literature, patients with low-risk disease are often managed with surgical resection or observation alone with tumors likely to spontaneously regress that are not causing symptoms. Intermediate patients are treated with chemotherapy with the number of cycles depending on their response as well as surgical resection of the primary tumor. High-risk patients remain controversial. Multidisciplinary intensive treatment is essential, especially for patients who received subtotal tumor resection. Minimally invasive surgery for the treatment of NBs without image-defined risk factors in low- to high-risk patients is safe and feasible and does not compromise the treatment outcome. We conclude that >=90% resection of the primary tumor is both feasible and safe in most patients with high-risk NB. New targeted therapies are crucial to improve survival. PMID- 30246721 TI - Emergent Endoscopic Retrograde Cholangiopancreatography with Placement of Biliary Double Stents to Salvage Endoscopic Retrograde Cholangiopancreatography-Induced Stapfer's Type II Perforation. PMID- 30246722 TI - Complete Closure of Gastric Defect with Improved Purse-String Suture Technique Using Single-Channel Endoscope. PMID- 30246720 TI - Common Injuries and Repair Mechanisms in the Endothelial Lining. AB - Objective: Endothelial cells (ECs) are important metabolic and endocrinal organs which play a significant role in regulating vascular function. Vascular ECs, located between the blood and vascular tissues, can not only complete the metabolism of blood and interstitial fluid but also synthesize and secrete a variety of biologically active substances to maintain vascular tension and keep a normal flow of blood and long-term patency. Therefore, this article presents a systematic review of common injuries and healing mechanisms for the vascular endothelium. Data Sources: An extensive search in the PubMed database was undertaken, focusing on research published after 2003 with keywords including endothelium, vascular, wounds and injuries, and wound healing. Study Selection: Several types of articles, including original studies and literature reviews, were identified and reviewed to summarize common injury and repair processes of the endothelial lining. Results: Endothelial injury is closely related to the development of multiple cardiovascular and cerebrovascular diseases. However, the mechanism of vascular endothelial injury is not fully understood. Numerous studies have shown that the mechanisms of EC injury mainly involve inflammatory reactions, physical stimulation, chemical poisons, concurrency of related diseases, and molecular changes. Endothelial progenitor cells play an important role during the process of endothelial repair after such injuries. What's more, a variety of restorative cells, changes in cytokines and molecules, chemical drugs, certain RNAs, regulation of blood pressure, and physical fitness training protect the endothelial lining by reducing the inducing factors, inhibiting inflammation and oxidative stress reactions, and delaying endothelial caducity. Conclusions: ECs are always in the process of being damaged. Several therapeutic targets and drugs were seeked to protect the endothelium and promote repair. PMID- 30246723 TI - Association between Age-Related Macular Degeneration and Lens Opacity in Senior Population in Hainan Province. PMID- 30246724 TI - Causes of Severe Visual Impairment and Blindness in Schools for the Blind. PMID- 30246726 TI - Effects of Nerve Growth Factor Expression on Perineural Invasion and Worse Prognosis in Early-Stage Cervical Cancer. PMID- 30246725 TI - Systemic-Related Factors of Nonarteritic Anterior Ischemic Optic Neuropathy. PMID- 30246727 TI - Successful Laparoscopic Management of Heterotopic Pregnancy at 12+2 Weeks of Gestation. PMID- 30246728 TI - Inversion of the Uterus Combined with Endometrial Carcinosarcoma. PMID- 30246729 TI - Severe Hyperhomocysteinemia with Two Novel Mutations of c.154T>C and c.457G>A in Cystathionine Beta-Synthase Gene. PMID- 30246730 TI - Giant Axonal Neuropathy with Unusual Neuroimagings Caused by Compound Heterozygous Mutations in GAN Gene. PMID- 30246731 TI - B/S Brace as an Alternative Treatment for Ingrown Toenails. PMID- 30246732 TI - Clinical and Genetic Features of Familial Cold Urticaria: A Report of Three Families. PMID- 30246733 TI - A Case Report on Acquired Tufted Angioma with Severe Pain after Healed Herpes Zoster. PMID- 30246734 TI - Genomic Disruption of FOXL2 in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Type 2: A Novel Deletion-Insertion Compound Mutation. PMID- 30246735 TI - A New Mutation Identified by Whole Exome Sequencing in a Cornelia de Lange Syndrome Newborn. PMID- 30246736 TI - Diffuse Pulmonary Alveolar Hemorrhage Secondary to All-Trans-Retinoic Acid in Acute Promyelocytic Leukemia. PMID- 30246737 TI - Access to Orphan Drugs is a Challenge for Sustainable Management of Cystinosis in China. PMID- 30246738 TI - Acute Myocardial Infarction Induced by Anaphylaxis in China: The Kounis Syndrome. PMID- 30246739 TI - Reply to "Acute Myocardial Infarction Induced by Anaphylaxis in China: The Kounis Syndrome". PMID- 30246740 TI - A vision for pediatric and preventive dentistry oral health policy in India. PMID- 30246741 TI - Comparison of effectiveness of quad helix appliance with other slow maxillary expanders in children with posterior crossbite: A systematic review. AB - Objective: The present review was conducted to compare the effectiveness of Quad Helix (QH) appliance with other slow maxillary expanders in children with posterior crossbite. Materials and Methods: Randomized controlled clinical trials and retrospective studies published between January 1, 1995, and December 31, 2016, were identified from MEDLINE, the Cochrane Central Register of Controlled Trials, the National Institutes of Health Trials, Clinical Trials Registry India, Google Scholar and major journals. After a comprehensive search, the articles were independently screened for eligibility by two reviewers. All cross-reference lists of the selected studies were screened for any additional papers. Results: The preliminary screening consisted of 608 articles, of which 33 articles were selected. A final total of only 9 articles were included as they met the inclusion and exclusion criteria. Of the nine papers, four articles clearly state that QH appliance was a more effective appliance, while the remaining five studies suggest that the maxillary expansion caused by QH is comparable to other slow maxillary expansion appliances. Of the nine included articles, four articles also describe the complications of QH in comparison to other slow maxillary expansion devices. Conclusion: The QH appliance is a viable alternative for the correction of posterior crossbite. The QH appliance is comparable to or even better than other slow maxillary expanders in terms of maxillary expansion while being cost-effective with very few complications. PMID- 30246742 TI - Maxillary labial frenum morphology and midline diastema among 3 to 12-year-old schoolgoing children in Sri Ganganagar city: A cross-sectional study. AB - Introduction: Dentofacial aesthetics plays an important role in social interaction and psychological well-being because it affects how people perceive themselves and how they are perceived by society. The maxillary labial frenum is a fold of tissue, usually triangular in shape, extending from the maxillary midline area of the gingiva into the vestibule and mid portion of the upper lip. Maxillary anterior spacing or diastema is a common aesthetic complaint of patients and is frequently seen in children especially in the mixed dentition stage. Aims and Objectives: 1. To estimate the prevalence of different morphologic types of maxillary labial frenum among children of age 3 - 12 years. 2. To find out the relationship between the level of insertion of the frenum and age of the child.3. To evaluate the correlation between frenum morphology, insertion and midline diastema in children. Materials and Methodology: The direct visual method under natural light was used and the upper lip was lifted with the index finger and thumb of both hands which allowed for the observation and classification of the labial frenum morphology according to Sewerin's typology and its attachment according to Placek et al. The midline diastema was determined by measuring the distance between the midpoints of the mesial surfaces of both central incisors with the help of divider and ruler. The values were recorded in the prepared schedule. Summary and Conclusions: The presence of an abnormal frenum can be a cause in persistent midline diastemas. Tooth movement usually is deferred until eruption of the permanent canines but can begin early in certain cases with very large diastemas. PMID- 30246743 TI - Knowledge, attitudes, and practices among gynecologists regarding oral health of expectant mothers and infants in Bhubaneswar City, Odisha. AB - Objective: Early intervention is aimed at preventing or mitigating common pediatric oral diseases and conditions while initiating a relationship between the mother, the child, and the dental caregiver. Every expectant mother should receive oral health education and risk assessment. There are a number of reports that showed the association between oral diseases and preterm, low birth weight, and gestational diabetes. The purpose of this study is to understand the attitude and knowledge regarding prenatal as well as infant oral health care among gynecologists in the medical colleges in Bhubaneswar, Odisha, India. Materials and Methods: The study involved a survey involving gynecologists in medical colleges in Bhubaneswar, Odisha. A pretested questionnaire was provided to all the gynecologists (21) working in the medical colleges in Bhubaneswar regarding prenatal and perinatal oral health care. Results: The study gave an idea that most gynecologists working in a medical college in Bhubaneswar, Odisha, India, had adequate knowledge regarding oral health of expectant mothers, but lack in knowledge when it comes to imparting knowledge on infants' health care. Conclusion: There is an adequate knowledge among the gynecologists about oral health of expectant mothers and infants, but still, there is a need of a multidisciplinary collaboration among gynecologists, pediatricians, and pediatric dentists to prevent the dental diseases rather than treating them. PMID- 30246745 TI - Factors associated with dental pain in toddlers detected using the dental discomfort questionnaire. AB - Background: Dental pain is one of the most common symptoms of untreated oral problems and exerts a strong impact on the well-being of children. Aims: The aim of this study was to evaluate the associated factors with dental pain in children aged 1-3 years using the Brazilian version of the Dental Discomfort Questionnaire (DDQ-B). Methods: A cross-sectional study was conducted in the city of Diamantina, Brazil. A total of 318 randomly selected children were submitted to an oral clinical examination for the evaluation of tooth injuries and dental caries (International Caries Detection and Assessment System, [ICDAS]). The caregivers of the children were asked to answer the DDQ-B as well as a questionnaire addressing demographic and socioeconomic aspects of the family. Statistical analysis was performed and involved the description of frequencies as well as Poisson hierarchical regression analysis. Results: Dental pain was associated with a household income less than the Brazilian minimum monthly wage (Prevalence ratios [PRs] = 1.33, 95% confidence interval [CI]: 1.07-1.66, P = 0.011) and dental caries in dentin - ICDAS codes 5 and 6 (PR = 1.48, 95% CI: 1.13 1.94, P = 0.004). Conclusions: Greater frequencies of dental pain were found in 1 3-year-old children from families with a low monthly income and dental caries with visible dentin with or without pulp involvement. PMID- 30246744 TI - Sociodemographic and behavioral factors associated with dental caries in preschool children: Analysis using a decision tree. AB - Background: Untreated dental caries can result a negative impact on oral health related quality of life. Aims: The aim of the present study was to determine the prevalence of dental caries and associated factors in children enrolled in public preschools in the city of Recife, Brazil. Settings and Design: A descriptive, analytical, cross-sectional study was conducted with a representative random sample of 556 children aged 3-5 years. Materials and Methods: Data were collected through clinical examinations using the International Caries Detection and Assessment System. The parents answered a questionnaire addressing sociodemographic and behavioral characteristics. Two examiners underwent training and calibration exercise for the calculation of interexaminer agreement (Kappa index of 0.83). Statistical Analysis Used: In addition to descriptive data, an inductive decision tree was constructed to analyze the results (Algorithm J48; alpha = 5%). Results: The prevalence of dental caries was 92.1%. The following factors were associated with dental caries: brushing performed by the child (prevalence ratio [PR] = 4.39, 95% confidence interval [CI]: 2.57-7.51 P < 0.001), household income less than the minimum wage (PR = 1.79; 95% CI: 1.18 2.72, P = 0.005), brushing frequency (PR = 1.50; CI 95%: 0.50-4.49; P = 0.001), and parent's/caregiver's school equal to an incomplete elementary school education (PR = 1.65, 95% CI: 1.56-1.74, P < 0.001). Conclusions: The occurrence of dental caries in children was high and was associated with brushing performed by the child, household income less than the monthly minimum wage, low brushing frequency, and low parent's/caregiver's schooling. PMID- 30246746 TI - Effect of fluoridated varnish and silver diamine fluoride on enamel demineralization resistance in primary dentition. AB - Background: International data on caries epidemiology confirm that dental caries remains a significant disease of childhood in both developing and developed countries. Based on preventive dentistry, topical fluoride may be a useful measure to arrest caries lesions. Fluoride used in various forms have been proven to be effective in dental caries prevention. Aim: This study aims to compare the effect of fluoridated varnish and silver diamine fluoride (SDF) solution on primary teeth enamel resistance to demineralization. Methods: Forty-five caries free deciduous canine teeth extracted due to orthodontic reasons, devoid of any defects were selected. Teeth were mounted on acrylic blocks as their buccal surface was exposed and baseline surface microhardness (SMH) determination was accomplished. Enamel samples were randomly distributed into three groups with 15 specimens each. One group was used as control (distilled and deionized water) (C); in the other groups, either a fluoridated varnish (V) or an SDF solution was applied to the enamel blocks. The blocks of each group were submitted to pH cycling solutions and treatment regimen. After pH-cycling process, SMH determination was done again for all samples. Results: According to the present findings, the percentage of decrease in SMH of control group is numerically greater than other groups and also SDF group shows the most resistance against mineral loss. However, based on one-way ANOVA test, this difference is not statistically significant (P = 0.217). Conclusion: SDF solution and fluoride varnish display similar effectiveness in preventing the demineralization of deciduous anterior teeth, and no significant difference was observed. PMID- 30246747 TI - Comparison of resorption rate of primary teeth treated with alternative lesion sterilization and tissue repair and conventional endodontic treatment: An in vivo randomized clinical trial. AB - Background: Complete pulpectomy and elimination of wide range of microorganisms from infected primary root canals is not possible through conventional endodontic procedures. Thus, lesion sterilization and tissue repair (LSTR) therapy employing 3Mix tri-antibiotic paste have been used as an alternative endodontic modality for infected primary teeth. Aim: This study aims to evaluate the root resorption rate of endodontically treated mandibular primary molars with conventional endodontic treatment or LSTR therapy and to compare it with their healthy contralateral teeth. Materials and Methods: Fifty carious first and second primary mandibular molars from 25 healthy children aged 7-10 years were treated with two different endodontic procedures using LSTR Therapy and conventional endodontic treatment. The resorption rate of these teeth with healthy contralateral teeth was compared clinically and radiographically at 3, 6, 12 and 36 months using Chi-square test. Results: At 12 months, clinically, there was no difference in the outcomes of both groups but radiographically, statistically significant difference (P < 0.001) in root resorption between treated teeth and their controls in both the groups was observed. At 36 months, interradicular bone resorption around the crown of succedaneous teeth and their delayed eruption was noted in LSTR group. Conclusions: LSTR therapy could be a viable treatment modality for infected/nonvital primary molars with poor prognosis and intended to be maintained for shorter duration in the oral cavity as natural space maintainers. PMID- 30246748 TI - Efficacy of various intracanal medicaments against aerobic and facultative anaerobic microorganism found in human primary teeth with necrotic pulp: A randomized clinical trial. AB - Aim: The aim of this in vivo study is to evaluate the antimicrobial efficacy of calcium hydroxide (Ca(OH)2), chlorhexidine (CHX), and metronidazole gel as intracanal medicaments against aerobic and facultative anaerobic microorganisms found in root canals of human primary teeth with necrotic pulp. Setting and Design: It is a double-blinded randomized clinical trial. Materials and Methods: Pulp canals of 45 single-rooted primary maxillary anterior teeth with pulp necrosis in 34 children were included in the study. They were divided into three groups of 15 samples each: Group I: Ca(OH)2; Group II: 1% CHX gel; and Group III: 1% metronidazole gel. Microbial count was obtained from each tooth at two different stages - (1) after instrumentation and (2) after placement of the medication. Statistical analysis using the SPSS 10.0 software program (SPSS Inc., Chicago, IL, USA) with Wilcoxon signed-rank test after grouping the samples was performed. Results: Ca(OH)2, 1% CHX gel, and 1% metronidazole gel were ineffective in completely eliminating aerobic and facultative anaerobic microorganism from root canal of human primary teeth with necrotic pulp. Conclusion: None of the commonly used intracanal medicaments, that is Ca(OH)2, 1% CHX gel, and 1% metronidazole gel, was effective in completely eliminating aerobic and facultative anaerobic microorganism from root canal of human primary teeth with necrotic pulp. Ineffectiveness of these medicaments against aerobic and facultative anaerobic microorganism has opened new door of research regarding the manner of bacterial growth in unfavorable environmental and nutritional conditions, the way root canal environment favors biofilm formation and the use of suitable intracanal medicaments against single and multispecies biofilms. PMID- 30246750 TI - Efficacy of probiotic and green tea mouthrinse on salivary pH. AB - Objectives: The aim of the study was to assess the efficacy of probiotic and green tea mouthrinse on salivary pH. Method: Study was conducted over a period of one month among 40 healthy school children aged between 6-8 years. The subjects who fulfilled inclusion criteria were selected and randomly divided into 2 groups namely probiotic and green tea groups. Salivary pH was recorded at baseline (0 day) and at the end of the specified time period using GC pH strips. Statistical analysis was done using paired 't' test P < 0.05 was considered statistically significant. Result: The comparison of mean pH scores for green tea showed that the pH of saliva was increased in the children after rinsing with green tea (6.15 to 7.65) and was statistically significant (p<0.001). Similarly when pre and post mean pH was compared in the probiotic group pH increased from (6.45 to 6.65) however, the results were not statistically significant. Conclusion: The study conducted shows the beneficial effects of green tea in providing a alkaline environment which is conducive to the oral health of children. PMID- 30246749 TI - Gingival, oral hygiene and periodontal status of the teeth restored with stainless steel crown: A prospective study. AB - Aim: To compare the gingival health and periodontal status in primary molars restored with stainless steel crowns with unrestored contralateral teeth. Materials and Methods: A split mouth design study was conducted on 60 children aged 5- 10 years who required stainless steel crown restoration on deciduous molars. The molar teeth restored with stainless steel crown were selected for study and healthy unrestored contralateral teeth were selected as controls. Bitewing radiograph of study and control tooth was taken at initial, three months and at six months. The gingival status, oral hygiene status was evaluated at three months and six month intervals using gingival index and oral hygiene index respectively. Result: On evaluating the oral hygiene status at three months study group showed the mean value of 0.7+/-0.700 whereas in control group it was 1+/ 0.368. At six months it was 1.183+/-0.390 in study group and 1.5+/-0.504 in control group. Chi square test shows that the crown marginal adaptation produced statistically significant difference at six months. Crown marginal extension did not produce any difference on gingival index and oral hygiene index. Conclusion: When compared to control teeth, the teeth restored with stainless steel crown showed lesser plaque and debris accumulation at three months and six months. Radiographic bone level the control teeth showed higher level of bone resorption compared to the teeth restored with stainless steel crown. PMID- 30246751 TI - A comparative evaluation of dental caries status and salivary properties of children aged 5-14 years undergoing treatment for acute lymphoblastic leukemia, type I diabetes mellitus, and asthma - In vivo. AB - Background: The subjective sensation of dry mouth, xerostomia, is a well recognized problem in adults, however, relatively little attention has been paid to this issue in children. Xerostomia commonly occurs as an adverse effect of drugs in asthma and leukemia, which alter the composition and flow of saliva and systemic diseases, including diabetes. It decreases the oral pH and significantly increases the development of plaque and dental caries. Aim: This study aims to evaluate and compare the dental caries status and salivary properties of children aged 5-14 years undergoing treatment for acute lymphoblastic leukemia, type 1 diabetes mellitus, and asthma - in vivo. Materials and Methods: The study was divided into two parts: Part I: Oral examination was performed and dental caries status Decayed, Missing, Filled Teeth/ decayed, extraction, filled teeth (DMFT/deft) was noted and Part II: Salivary analysis was performed by GC Saliva Check BUFFER kit to check for hydration, viscosity, pH of saliva, salivary flow, and buffering capacity. Statistical Analysis: All statistical analysis was performed using the SPSS 21 statistical software version. Inferential statistics were performed using Chi-square test and ANOVA. Post hoc pairwise comparison was done using Post hoc Tukey's test. Results: The prevalence of mean DMFT/deft with regard to salivary properties was highest in leukemic patients followed in descending order by diabetic and asthmatic patients. Conclusions: Leukemic patients had significantly higher caries and decreased salivary properties while asthmatic patients showed the least caries prevalence and best salivary properties. PMID- 30246752 TI - Isolation of Scardovia wiggsiae using real-time polymerase chain reaction from the saliva of children with early childhood caries. AB - Aim: This study aimed to quantitatively assess the levels of Scardovia wiggsiae in caries-free and early childhood caries (ECC)- and severe ECC (SECC)-affected children using real-time polymerase chain reaction (RT-PCR). Methods: Forty-five children aged <71 months were randomly recruited from the Outpatient Clinic at the Department of Pedodontics and Preventive Dentistry at Subharti Dental College and Hospital, Meerut, India. Fifteen children suffering from ECC, 15 with SECC, and 15 children without ECC were enrolled in the study. About 1-2 mL of unstimulated saliva was collected and subjected to microbial analysis using RT PCR. Results: The SECC group (n = 15) was found to have significantly higher mean relative 16s rRNA expression of S. wiggsiae (3.67) than both ECC (n = 15) and controls (n = 15) (1.69 and 0.85, respectively). S. wiggsiae was detected in 86.7% of the SECC and 60% ECC group and was detected negligibly in the control (caries free) group. The correlation of decayed, missing, or filled surface levels with 16s rRNA levels showed significant positive correlation with 16S rRNA in both ECC and SECC patients. Conclusion: Salivary levels of S. wiggsiae were significantly associated with ECC in children. S. wiggsiae represents a new frontier in the microbial etiology of ECC. This may lead to the development of new antimicrobial agents targeted to this organism and improve the treatment of ECC. PMID- 30246753 TI - Effectiveness of precooling the injection site using tetrafluorethane on pain perception in children. AB - Background: Injection of local anesthesia is one of the most important reasons for avoidance behavior in children. Applying a topical anesthetic before injection is the most popular way to control pain; however, topical anesthetics have some shortcomings such as longer duration of action, displeasing taste, and spread of the anesthetic agent to noninjection site areas. Cryoanesthesia using refrigerant as a topical anesthesia is being studied as an alternative to overcome the shortcomings of topical anesthetics and has shown promising results. Materials and Methods: In this split-mouth design study, 50 children of aged 8-10 years who required bilateral mandibular local anesthesia administration were selected. In the first visit, application of topical anesthetic spray (lidocaine) on one side and during the second appointment cryoanesthetic tetrafluorethane on the other side was used before local anesthetic administration. Patients were asked to report their discomfort and pain using visual analog scale (VAS) (subjective method). Patients' pain perception during injection is assessed by sound, eye, and motor (SEM) scale by the dentist (objective method). Results: The results were statistically analyzed using paired Wilcoxon signed-rank test and Mann-Whitney tests. In VAS scale (subjective method), pain scores were significantly lower in tetrafluorethane group when compared with lidocaine group. In SEM scale (objective method), pain scores were lower in tetrafluorethane group when compared with lidocaine group, but it was statistically insignificant. Conclusion: Precooling the injection site using refrigerant tetrafluorethane spray has shown to be effective in eliminating pain before local anesthesia administration in children when compared with topical anesthetic lidocaine spray. PMID- 30246754 TI - The effect of fiber-reinforced composite versus band and loop space maintainers on oral Lactobacillus acidophilus and Streptococcus mutans levels in saliva. AB - Background: Orthodontic bands have been shown to alter oral microbial flora that lead to convert caries-free patients to moderate or high caries risk individuals. Aim: This study aimed to evaluate the effect of conventional band and loop space maintainers versus fiber-reinforced composite (FRC) resin space maintainer on the salivary cariogenic microflora (Lactobacillus and Streptococcus mutans) in children over a period of 6 months. Materials and Methods: The study sample was divided equally into two groups: Group A: 25 patients received FRC (INFIBRA(r): Reinforcing ribbon, Bioloren, Italy) space maintainer and Group B: 25 patients received band and loop space maintainers. The saliva samples were collected from the patients before the insertion of the space maintainer and at 2 weeks, 3 months, and 6 months postinsertion. Results and Conclusion: The Lactobacillus acidophilus isolated was 1.7 colony-forming unit (CFU) (*106) and 1.8 CFU (*106) in Group A and Group B, respectively, prior to the insertion of space maintainers. There was no significant increase in L. acidophilus over the follow up of 6 months in both the groups (P > 0.05). However, the Streptococcus mutans isolated before insertion in both Group A and Group B was 2.6 CFU (*106), which over a period of 6 months showed significant increase to 3.13 CFU (*106) in Group B (P < 0.05) and no increase was seen in Group A. S. mutans level increased considerably in patients with band and loop space maintainer over the follow-up of 6 months. No significant increase in the L. acidophilus count was observed over the same period in both the groups. PMID- 30246755 TI - Postoperative assessment of diode laser zinc oxide eugenol and mineral trioxide aggregate pulpotomy procedures in children: A comparative clinical study. AB - Aim: The present study is an attempt to compare and evaluate postoperative assessment of diode laser zinc oxide eugenol (ZOE) pulpotomy and diode laser mineral trioxide aggregate (MTA) pulpotomy procedures in children. Materials and Methods: Forty carious primary molars indicated for pulpotomy within the age group of 4-9 years were selected and divided into two groups of 20 each using simple randomization, Group 1: Diode laser MTA and Group 2: Diode laser ZOE pulpotomy. The teeth were evaluated clinically for 1 year at 3, 6, and 12 months interval and radiologically for 6 and 12 months. Results: Clinically and radiographically, 100% teeth treated with diode laser MTA and 94% treated with diode laser ZOE were considered successful after 12-month follow-up interval. No significant difference was seen between two groups. Conclusion: Despite the success rate, the cost factor of diode laser and MTA could be the limiting factor in its judicious use in pulpotomy procedure. PMID- 30246756 TI - Blandin and Nuhn mucocele in a pediatric patient. AB - Oral mucoceles are benign lesions that may appear in any location on the mucosal surfaces of the oral cavity where underlying minor salivary glands are found. The lower lip is the most frequently affected and the most widely reported location. Mucoceles involving the glands of Blandin and Nuhn are infrequent and constitute only about 1.9%-10.3% of the reported cases. Superficial mucoceles are a rare subtype of the Blandin and Nuhn mucoceles and are found only in 4.3%-10% of the mucocele excisions. The purpose of this report is to present a case of a superficial mucocele in the ventral surface of the tongue in a 7-year-old child. The lesion was treated with excisional biopsy. PMID- 30246757 TI - Congenital granular cell tumor of the newborn - Spontaneous regression or early surgical intervention. AB - Congenital granular cell tumor of the newborn is a benign, relatively innocuous hamartomatous lesion arising from the alveolar ridge. Large lesions often warrant prompt surgical removal owing to the associated difficulty in breastfeeding and respiration of the infant. However, for medium-sized lesions, another approach could be observed for spontaneous regression. The present case report highlights the use of a combination approach for management of tumor in a 2-day-old female child presenting with a large protruding mass from the mouth associated with difficulty in breastfeeding. A combination of observation for regression in size followed by electrosurgical removal of the tumor was done. The infant was followed up regularly over a long period of 3 years to assess any adverse effects of surgical intervention on the maxillary primary anterior dentition of which none were recorded. PMID- 30246758 TI - A rare presentation of lobular panniculitis in the oral cavity of a 2-year-old patient. AB - Pannicultis is a rare disorder which usually affects the organ and tissue which are abundant in fat cells. It causes fatty degeneration of the fat cells and the diagnosis is usually made histologically. Here we present you a rare case of lobular pannicultis which occurred in a 2 year old patient in its oral cavity. PMID- 30246759 TI - Measuring the Moisture Content in Maize Kernel Based on Hyperspctral Image of Embryo Region. AB - Maize is among the most important economic corps in China while moisture content is a critical parameterin the process of storage and breeding. To measure the moisture content in maize kernel, a near-infrared hyperspectral imaging system has been built to acquire reflectance images from maize kernel samples in the spectral region between 1 000 and 2 500 nm. Near-infrared hyperspectral information of full surface and embryo of maize kernel were firstly extracted based on band ratio coupled with a simple thresholding method and the spectra analysis between moisture content in maize kernel and embryo was performed. The characteristic bands were then selected with the help of Competitive Adaptive Reweighted Sampling (CARS), Genetic Algorithm (GA) and Successive Projection Algorithm (SPA). Finally, these selected variables were used as the inputs to build Partial Least Square (PLS) models for determining the moisture content of maize kernel. In this study, a significant relation, which the spectral reflectance decreases as moisture content increase, between moisture content and spectral of embryo in maize kernel was observed. For the investigated independent test samples, all the proposed regression models, namely CARS-PLS, GA-PLS and SPA PLS, achieved a good performance by using the information of embryo region. The correlation coefficient (Rp) and Root Mean Squared Error of Prediction (RMSEP) and number of characteristic wavelength for the prediction set were 0.931 2, 0.315 3, 9 and 0.917 6, 0.336 9, 14 and 0.922 7, 0.336 6, 16 for CARS-PLS, GA-PLS and SPA-PLS models, respectively. And, compared with models obtained by full surface spectral information, less characteristic wavelengths is used for development of CARS-PLS, GA-PLS and SPA-PLS models, while similar results were obtained. Comprehensively analyzing to both model accuracy and model complexity, SPA-PLS model by using embryo region information achieved the best result. Wavelengths at 1 197,1 322 and 1 495 nm were applied to extracted the information of embryo region, and the bands at 1 322, 1 342, 1 367, 1 949, 2 070 and 2 496 nm were used to establish the SPA-PLS model. These results demonstrated that near infrared hyperspectral information from embryo region is more effective for determination of moisture nondestructive in maize kernel. PMID- 30246761 TI - Can a non-invasive urine-based test become the next-generation diagnostic tool for malaria? AB - This mini review summarises the non-invasive urine-based diagnostic approaches that have been used to diagnose malaria. Amongst all urine-based diagnosis methods, commercially available Rapid Diagnostic kit/strip is most likely to be suitable for malaria detection in a cost-effective, time-consuming and user friendly manner. With further improvement in sensitivity, specificity and accuracy, this technique may become a useful next-generation gold standard malaria diagnostic tool in resource-limited regions and in areas where invasive blood tests are restricted. PMID- 30246760 TI - What is new in infectious diseases: Nipah virus, MERS-CoV and the Blueprint List of the World Health Organization. AB - Not available. PMID- 30246762 TI - A three-year study entailing molecular characterization and epidemiology of Clostridium difficile in an Italian tertiary care hospital. AB - In Italy, there are limited studies on the molecular epidemiology of Clostridium difficile, possibly due to insufficient laboratory diagnostic capacity, low awareness and lack of high-quality surveillance systems. The aim of this study was to evaluate the diffusion of C. difficile in a tertiary care hospital and to genotype all the collected strains in order for hospital staff to take corrective action. All specimens were subjected to a CDI diagnostic algorithm. This included highly specific toxin PCRs and multilocus sequence typing (MLST) to obtain clear, unequivocal genotypization. During a three-year study period, as part of routine C. difficile testing, 711 stool samples were collected from 522 patients to detect the presence of toxigenic genes. After testing, 106 different samples were identified as toxigenic. The proportions of non-toxigenic and toxigenic isolates were respectively 8.7% (62/711) and 14.9% (106/711). The most infection findings in wards for toxigenic strains were in Internal Medicine (56), followed by Neurology (11) and Gastroenterology (11). Three novel sequence types (STs) were found. The two most prevalent STs in wards were clade 1 ST-378 (40) and clade 1 ST-379 (33). Other healthcare-acquired strains were clade 4 ST-37 (11) and clade 5 ST-11 (7). Two STs, namely clade 3 ST-5 (10) and clade 1 ST-380 (5), were isolated among external patients. To prevent an increase in outbreak probability, an active surveillance programme combined with proper hand hygiene, environmental cleaning and contact precautions should be implemented. PMID- 30246763 TI - A new strategy to control the proliferation of microorganisms in solid hospital waste and the diffusion of nosocomial infections. AB - A possible tool to reduce nosocomial infections is to identify unknown sources of contamination and then to provide a measure for controlling the related infections. In this study, solid hospital waste was considered a potential source of contamination, and a strategy to reduce the potential risk of pathogen contamination was tested. This paper describes a novel technique for waste management in healthcare settings with a view to facilitating infection prevention and control. We explored the innovative use of sodium dichloroisocyanurate (NaDCC) by investigating the microbicidal activity of chlorine, which derives from the hydrolysis of NaDCC mediated by humidity, and by testing its effect on the inhibition of microorganism growth. NaDCC was inserted in a solid hospital waste bin containing also Lauria-Bertani agar plates, with different dilutions of a known titre of three different microorganisms, namely Escherichia coli, Staphylococcus aureus and Aspergillus brasiliensis. The plates were incubated in the container with or without the antimicrobial agent (control, CNT) at room temperature for 5 days. The number of colony-forming units (CFUs) present on each plate was then counted. Microorganisms capable of proliferating in the CNT waste bin were not able to grow in the presence of NaDCC. Furthermore, the molecular chlorine which developed and was released in the waste bin under the experimental conditions (T=20 degrees C, t=5 days) was quantified using iodometric titration. NaDCC hydrolysis, mediated by humidity, has a strong and long-lasting microbicide effect. The proliferation of tested bacteria and fungi is totally inhibited. These results demonstrate the effectiveness of NaDCC in controlling and/or inhibiting microbial proliferation and support its possible use in the treatment of hospital waste to control the spread of nosocomial contamination. PMID- 30246764 TI - Metallo-beta-Lactamase-producing Pseudomonas aeruginosa in Iran: a systematic review and meta-analysis. AB - Metallo-beta-lactamase (MBL)-producing Pseudomonas aeruginosa is considered to be a serious threat to human health worldwide. Limited information is available concerning the prevalence of MBL-producing P. aeruginosa in Iran. The aim of the present study was to investigate the prevalence of MBL-producing P. aeruginosa in different parts of Iran. We searched major electronic databases including PubMed, ISI Web of Science, Scopus and Google Scholar as well as two Iranian search engines using appropriate keywords. After applying inclusion and exclusion criteria, related papers were recruited for the study. The prevalence of MBL producing P. aeruginosa in Iranian population was about 32.4 %. Our findings also revealed that the highest prevalence of MBL-producing P. aeruginosa was in Isfahan with 60% (95% CI: 0.27-0.86). In addition, in Iranian population the most reported MBL gene was blaVIM and blaIMP, with frequencies of 19% (95% CI: 0.15 0.23) and 11% (95% CI: 0.08-0.14), respectively. Based on our findings, in the majority of Iranian hospitals, the prevalence of MBL-producing P. aeruginosa is alarmingly high necessitating the need for designing appropriate infection control programs. PMID- 30246765 TI - Integron types, antimicrobial resistance genes, virulence gene profile, alginate production and biofilm formation in Iranian cystic fibrosis Pseudomonas aeruginosa isolates. AB - Cystic fibrosis (CF) patients commonly suffer from continuous and recurrent lung infections caused by Pseudomonas aeruginosa, the dominant pathogen in CF airways. This study aimed to determine the integron types, gene cassettes, virulence determinants, beta-lactam resistance genes, biofilm formation and alginate production in P. aeruginosa isolated from Iranian CF patients. A total of 143 P. aeruginosa isolates were obtained from CF patients. Susceptibility of isolates to different antimicrobials was evaluated by disc diffusion method. ESBL, MBL and KPC production was assessed. Congo red agar and tissue culture plates were used for evaluation of biofilm formation. Alginate production was determined using the Carbazole assay. Integrase genes, resistance determinants (ESBLs, MBLs and KPC) and genes encoding virulence factors were evaluated by PCR. All isolates were susceptible to colistin, piperacillin-tazobactam and ticarcillin; 8.4% of isolates were considered as MDR phenotype. Out of 6.3% IPM-resistant isolates, prevalence of virulence genes was as follows: lasB (100%) and plcB (100%), plcH (96.5%). Biofilm formation and alginate production ability were found in 54.5% of isolates. The prevalence of the alginate-encoding genes was 92.3%, 86.7% and 67.1% for algD, algU and algL genes, respectively. PpyR, pslA and pelA genes were detected in 98.6%, 89.5% and 57.3% of the isolates, respectively. The high prevalence of colonization in CF lungs may increase the pathogenicity of P. aeruginosa due to their adhesion and protective properties caused by biofilm- and alginate-production. LasB, plcB, plcH, exoS, toxA, algD, ppyR and pslA genes were predominant in CF P. aeruginosa strains. PMID- 30246766 TI - Prevalence of occult hepatitis C virus infection in patients who achieved sustained virologic response to direct-acting antiviral agents. AB - The reappearance of HCV infection months or years after sustained virologic response (SVR) may be due to the persistence of HCV in tissue cells in spite of being undetected in serum. This situation is known as occult hepatitis C infection (OCI). We aimed to assess the prevalence of OCI in Egyptian patients with chronic hepatitis C (CHC) who achieved SVR after treatment with direct acting antiviral agents (DAA). We carried out a cross-sectional study at the Advanced Center for Liver Diseases of Zagazig University Hospitals and Al-Ahrar Viral Hepatitis Treatment Center, Sharkia Governorate, Egypt. One hundred and fifty adult patients with CHC, who achieved SVR 12-24 weeks after end of treatment with sofosbuvir/daclatasvir +/- ribavirin (139 patients, 92.67%), sofosbuvir/ledipasvir +/- ribavirin (eight patients, 5.33%), sofosbuvir/simeprevir (two patients, 1.33%), and ombitasvir/ paritaprevir/ritonavir + ribavirin (one patient, 0.67%), according to the Egyptian National Committee for Control of Viral Hepatitis, were included in the study. We tested these patients for HCV RNA in peripheral blood mononuclear cells (PBMCs) immediately after confirmation of SVR12-24 weeks. Statistical analysis was performed by means of the Shapiro-Wilk test, Mann-Whitney U test, Chi-square test, and Fisher's exact test. Seventeen patients (11.33%) were positive for PBMNCs HCV RNA. The prevalence of OCI was highest in patients treated with simeprevir/sofosbuvir (2/2 patients). There is a substantially high prevalence of OCI after treatment with DAAs. We recommend dual testing for HCV RNA in both serum and PBMCs at the end of treatment of HCV infection with DAAs and during validation of the SVR following the initial response. PMID- 30246767 TI - No effect of MTP polymorphisms on PNPLA3 in HCV-correlated steatosis. AB - PNPLA3 and MTP genes have been associated with liver steatosis and chronic hepatitis C. We studied the influence of MTP and PNPLA3 polymorphisms in 114 Italian patients with chronic hepatitis C, evaluating the histological and clinical presentation of liver disease. The study confirmed the association of PNPLA3 polymorphisms with liver steatosis (p=0.041), but did not show any additive effect of MTP polymorphisms in the development of steatosis. MTP polymorphisms do not seem to influence PNPLA3 in the development of liver steatosis. Further studies with a larger number of patients are required. PMID- 30246768 TI - Redox alteration in patients infected by different HCV genotypes. AB - Chronic hepatitis C virus (HCV) infection plays a pivotal role in hepatocarcinogenesis and has been associated with oxidative DNA damage. Few data have been reported on the general redox state in patients infected with different HCV genotypes. Total antioxidant capacity (TAC) and hydrogen peroxide levels as well as oxidative stress index were measured in serum of hepatitis C chronic patients in relation to genotype, viral load, transaminases level and degree of fibrosis. Serum was obtained from two-hundred-fifty-two HCV infected patients and twenty-five healthy donors. TAC was measured by TAC Colorimetric Assay and hydrogen peroxide concentration by Hydrogen Peroxide Colorimetric Assay Kit. In HCV infected patients, mean serum TAC was 5.62 mM Trolox equivalents which was significantly lower (p < 0.0001) than control group (7.25 mM Trolox equivalents). TAC reduction was particularly evident in patients infected by genotype 2 compared to those infected by genotypes 1, 3 and 4. In parallel, high levels of hydrogen peroxide were found in the serum of infected patients, p=0.0015. Although no statistically significant correlation was found with the degree of fibrosis, transaminases level or viral load, oxidative stress index was higher in HCV infected patients compared to uninfected controls, p=0.003. The results indicate an imbalance of the redox state in HCV infected patients, with a strong reduction of the total antioxidant capacity and high oxidative stress index. Because oxidative burden may favour disease progression, a novel strategy aimed at counteracting it by using antioxidant molecules as adjunct therapy might represent a useful tool in the management of HCV chronic infection. PMID- 30246769 TI - Relationship between malaria epidemiology and the human development index in Colombia and Latin America. AB - Central nervous system (CNS) tuberculosis includes three clinical entities: tuberculous meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis. All three categories are encountered frequently in regions of the world where the incidence of TB is high. Meningeal tuberculosis is a medical emergency: it is the most severe, lethal and disabling form of tuberculosis. Early diagnosis and treatment can be lifesaving. Even, in developed countries the diagnosis of tuberculous meningitis is difficult, frequently delayed or missed, and is often not microbiologically confirmed. Here I report a case of miliary tuberculosis, in a patient with diabetes mellitus and chronic kidney disease, but without HIV infection. Although the patient had regular contact with healthcare staff (hemodialysis), miliary tuberculosis diagnosis was considerably delayed. This patient, subsequently evolved into tuberculous meningitis. In spite of quadruple anti-tuberculosis treatment, corticosteroids, and general supportive care, this case resulted in death. PMID- 30246770 TI - Brevibacterium casei bacteraemia in a port-a-cath carrier patient: a case report. AB - Brevibacteria are part of the normal flora of the skin and adjacent structures, but have been increasingly encountered in humans as opportunistic pathogens and have been isolated from various clinical specimens, generally causing infections in immuno-compromised patients. We present a case of a port-a-cath-related bacteraemia caused by Brevibacterium casei in a woman with a prior history of bilateral breast cancer. The clinical outcome was favourable. PMID- 30246771 TI - Liver abscess with Citrobacter koseri bacteremia. AB - Citrobacter koseri is a rare cause of liver abscess with two reported cases in diabetic patients. We report a rare case of C. koseri liver abscess with C. koseri bacteremia in an elderly male with chronic kidney disease. He presented vomiting and weakness without any other signs. He was diagnosed with liver abscess by ultrasound, and blood culture showed C. koseri growth. The patient was treated effectively with a course of antibiotics and drainage. When C. koseri is isolated in patients with comorbidity, such as chronic kidney disease, we should consider the possibility of abscess including liver abscess and utilize a combined treatment of drainage and course of antibiotics for mixed infection. PMID- 30246772 TI - Central nervous system tuberculosis following delayed and initially missed lung miliary tuberculosis: a case report. AB - Central nervous system (CNS) tuberculosis includes three clinical entities: tuberculous meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis. All three categories are encountered frequently in regions of the world where the incidence of TB is high. Meningeal tuberculosis is a medical emergency: it is the most severe, lethal and disabling form of tuberculosis. Early diagnosis and treatment can be lifesaving. Even, in developed countries the diagnosis of tuberculous meningitis is difficult, frequently delayed or missed, and is often not microbiologically confirmed. Here I report a case of miliary tuberculosis, in a patient with diabetes mellitus and chronic kidney disease, but without HIV infection. Although the patient had regular contact with healthcare staff (hemodialysis), miliary tuberculosis diagnosis was considerably delayed. This patient, subsequently evolved into tuberculous meningitis. In spite of quadruple anti-tuberculosis treatment, corticosteroids, and general supportive care, this case resulted in death. PMID- 30246773 TI - Multiple chronic parasitic infections in an immunocompetent immigrant: a challenge for healthcare management. AB - The case reports multiple helmintiasis and chronic hepatitis caused by hepatitis B virus (HBV)/hepatitis D virus (HDV) in an immunocompetent immigrant male. It highlights the importance of early diagnosis and treatment of neglected infectious diseases in low endemic areas, besides difficulties that Western countries encounter in responding to immigrants' health needs. PMID- 30246774 TI - Amedeo Modigliani and his "great secret": a brief history of medical and social aspects of tuberculosis in the nineteenth and early twentieth century. AB - The pathography of the famous painter and sculptor Amedeo Modigliani (1884-1920) shows that he had tuberculosis and died of tubercular meningitis aged 35. The nineteenth century was characterized by numerous milestones in the history of tuberculosis. In 1853, Hermann Brehmer, first used the term tuberculosis referred to at the time as "phthisis". In 1865, Jean Antoine Villemin demonstrated the infectious etiology of the disease. This was confirmed in 1882 by Robert Koch by identifying the tubercle bacillus. Koch also invented the diagnostic tuberculin test. Charles Mantoux and Florence Seibert improved this test. Identification of the infectious etiology of tuberculosis led to experiments of effective treatments for this disease. The most successful treatment for tuberculosis was by sanatorium regime. From the late nineteenth century, more invasive therapeutic approaches such as artificial pneumothorax were introduced. The advent of streptomycin in 1945 changed the social view of tuberculosis. This previously romanticized disease became a social stigma which was associated with poor social and moral standards; patients were kept in isolation. Fearing social ostracism, Modigliani refused treatment for tuberculosis and instead deliberately fostered his reputation as an alcoholic and addict in order to conceal the disease. PMID- 30246775 TI - The Knights Hospitaller of Rhodes and the Black Death of 1498: a poetic description of the plague. AB - The study is a presentation of the sole written testimony of the great plague epidemic that struck the island of Rhodes in 1498, at the time when the Order of the Knights of St. John was settled there. The Greek poem "The Thanatikon (i.e., plague) of Rhodes", which was written by Emmanuel Georgillas Limenitis in the late 15th century and recounts the terrible events of the epidemic, was used as a source of information. Among the 644 verses of the poem, elements like the place, time, duration and how the epidemic spread can be identified. Within the historical context of the era, evaluation and analysis of the data reveal the correlation between human activities and the physical history of the disease in the Mediterranean during the 15th century. The Plague of Rhodes confirms the value of non-medical sources in the medico-historical and historico epidemiological study of the evolution of the disease caused by Yersinia pestis while highlighting an enduring intrinsic weakness of surveillance systems. Despite modern means of epidemiological surveillance, the risk of relaxation of a health system after a long period of absence of an infectious disease constitutes a major factor for future resurgence of the specific disease. PMID- 30246776 TI - Mapping Zika by Geographic Information System. AB - Not available. PMID- 30246777 TI - Effects of Deferoxamine on Leukemia In Vitro and Its Related Mechanism. AB - BACKGROUND This study aimed to investigate the effect of deferoxamine (DFO) on leukemia in vitro, and to explore the underlying molecular mechanism. MATERIAL AND METHODS K562 leukemia cells were treated with various concentrations of DFO (10, 50, and 100 umol/l) with or without 10 umol/l ferric chloride for 12 h. Then, total cellular iron was detected. CCK-8 kit and flow cytometry were used for cell viability and apoptosis detection. In addition, expression of apoptosis related genes was determined by Western blotting and qRT-PCR, respectively. RESULTS The results suggested that DFO significantly inhibited K562 cell viability and induced cell apoptosis in a dose-dependent manner. We also found that the protein and mRNA levels of Bax, p53, and Fas dose-dependently increased in DFO-treated K562 cells, while the level of Bcl-2 markedly decreased in a dose dependent manner. Moreover, the findings showed that ferric chloride eliminated these effects on K562 cells caused by DFO treatment. CONCLUSIONS Our results indicate that DFO plays a protective role in leukemia via inhibiting leukemia cell viability and inducing cell apoptosis by the regulation of apoptosis-related genes expression. PMID- 30246778 TI - The Evaluation of Flow-Mediated Vasodilation in the Brachial Artery Correlates With Endothelial Dysfunction Evaluated by Nitric Oxide Synthase Metabolites in Marfan Syndrome Patients. AB - Marfan syndrome (MS) is of the most common connective tissue disorders. Although most patients have mutations in the fibrillin-1 gene (FBN1) and more than 1,700 mutations have been described, there are no mutations in less than 10% of patients. Aortic dilation is the most important complication; it involves chronic inflammatory processes and endothelial dysfunction. Prospective study from March 2015 to January 2017, in a cohort of 32 patients of MS confirmed by Ghent criteria and 35 controls of both genders, with a median age of 26 years (18-56). Patients had no comorbidities such as diabetes, hypertension, and/or neoplasms. They were not being treated with statin, NSAIDs, calcium antagonists, oral nitrates, and/or beta-blockers during 7 days prior to the study and patients with smoking history in the last 4 years. Controls were matched by age and gender. We analyzed endothelial dysfunction by flow-mediated vasodilation in the brachial artery, determining the maximum peak flow in the reactive hyperemia phase with a Philips Envisor device with Doppler capability. Its correlation with serum levels of biological markers that could participate in endothelial dysfunction pathways such as NO3-/NO2- ratio, NO2- , citrulline, TNFalpha, IL-1, IL-6, IL-10, IL-8, osteopontin, ICAM, VCAM, and NO3-/NO2- was determined. Endothelial dysfunction was found in 21 MS patients (65%). The aortic annulus (AAo) was of 27 mm (22-40) and 24 mm (22-30) (p = 0.04) in MS patients with and without dysfunction. The level of NO3-/NO2- ratio, was of 108.95 +/- 12.05 nM/ml in controls vs. 170.04 +/ 18.76 nM/ml in MS (p = 0.002), NO2- was of 33.78 +/- 3.41 vs. 43.95 +/- 2.59 nM/ml (p = 0.03), citrulline 62.65 +/- 3.46 vs. 72.81 +/- 4.35 MUMol/ml (p = 0.06). VCAM median was 39 pg/ml (0-86) vs. 32 pg/ml (11-66) (p = 0.03), respectively. The correlation of VCAM with triglycerides (TG) was of 0.62 (p = 0.005). There were no differences in TNFalpha, IL-1, IL-6, IL-8, IL-10, and osteopontin. MS endothelial dysfunction is related to aortic diameters, and increased levels of VCAM, L-citrulline and NO3-/NO2- ratio, NO2- . VCAM-1 has a significant correlation with TG and could play a significant role in endothelial dysfunction. PMID- 30246780 TI - Where to Step? Contributions of Stance Leg Muscle Spindle Afference to Planning of Mediolateral Foot Placement for Balance Control in Young and Old Adults. AB - Stable gait requires active control of the mediolateral (ML) kinematics of the body center of mass (CoM) and the base of support (BoS) in relation to each other. Stance leg hip abductor (HA) muscle spindle afference may be used to guide contralateral swing foot placement and adequately position the BoS in relation to the CoM. We studied the role of HA spindle afference in control of ML gait stability in young and older adults by means of muscle vibration. Healthy young (n = 12) and older (age > 65 years, n = 18) adults walked on a treadmill at their preferred speed. In unperturbed trials, individual linear models using each subject's body CoM position and velocity at mid-swing as inputs accurately predicted foot placement at the end of the swing phase in the young [mean R2 = 0.73 (SD 0.11)], but less so in the older adults [mean R2 = 0.60 (SD 0.14)]. In vibration trials, HA afference was perturbed either left or right by vibration (90 Hz) in a random selection of 40% of the stance phases. After vibrated stance phases, but not after unvibrated stance phases in the same trials, the foot was placed significantly more inward than predicted by individual models for unperturbed gait. The effect of vibration was stronger in young adults, suggesting that older adults rely less on HA spindle afference. These results show that HA spindle afference in the stance phase of gait contributes to the control of subsequent ML foot placement in relation to the kinematics of the CoM, to stabilize gait in the ML direction and that this pocess is impaired in older adults. PMID- 30246781 TI - FOXL2 and DMRT1L Are Yin and Yang Genes for Determining Timing of Sex Differentiation in the Bivalve Mollusk Patinopecten yessoensis. AB - Sex determination and differentiation have long been a research hotspot in metazoans. However, little is known about when and how sex differentiation occurs in most mollusks. In this study, we conducted a combined morphological and molecular study on sex differentiation in the Yesso scallop Patinopecten yessoensis. Histological examination on gonads from 5- to 13-month-old juveniles revealed that the morphological sex differentiation occurred at 10 months of age. To determine the onset of molecular sex differentiation, molecular markers were screened for early identification of sex. The gonadal expression profiles of eight candidate genes for sex determination or differentiation showed that only two genes displayed sexually dimorphic expression, with FOXL2 being abundant in ovaries and DMRT1L in testes. In situ hybridization revealed that both of them were detected in germ cells and follicle cells. We therefore developed LOG10(DMRT1L/FOXL2) for scallop sex identification and confirmed its feasibility in differentiated individuals. By tracing its changes in 5- to 13-month-old juveniles, molecular sex differentiation time was determined: some scallops differentiate early in September when they are 7 months old, and some do late in December when they are 10 months old. Two kinds of coexpression patterns were found between FOXL2 and DMRT1L: expected antagonism after differentiation and unexpected coordination before differentiation. Our results revealed that scallop sex differentiation co-occurs with the formation of follicles, and molecular sex differentiation is established prior to morphological sex differentiation. Our study will assist in a better understanding of the molecular mechanism underlying bivalve sex differentiation. PMID- 30246782 TI - Linear Decrease in Athletic Performance During the Human Life Span. AB - Master athletes maintain high physical activity levels and have better health than age-matched non-athletes. World records show accelerated declines after age 70 in swimming, long-distance running and sprint performance. However, less is known about age-related performance declines in the general master athlete population and whether decline rates differ between disciplines and genders. We interrogated a dataset including all track and field athletes of North Rhine from 2001 to 2014 to assess age-related changes in performance. 27,088 results of athletes between 11 and 89 years of age in 12 disciplines were analyzed by regression statistics. The analyses showed an accelerated decline beyond the age of 70 in sprint, middle- and long-distance running, while in throwing and jumping disciplines the performance continued a linear decline. Patterns of decline differed between men and women. The steepest declines were observed in javelin throw and 400 m (women), and in pole vault and 800 m (men). In conclusion, performance declines in aging depend more on the specific profile of requirements than previously assumed. PMID- 30246779 TI - Integrative Biomarker Assessment of the Influence of Saxitoxin on Marine Bivalves: A Comparative Study of the Two Bivalve Species Oysters, Crassostrea gigas, and Scallops, Chlamys farreri. AB - Harmful algae blooms have expanded greatly in recent decades, and their secreted toxins pose a severe threat to human health and marine ecosystems. Saxitoxin (STX) is a main paralytic shellfish poison naturally produced by marine microalgae of the genus Alexandrium. Despite numerous studies have assessed the impacts of STX on marine bivalves, comparative in vivo study on the toxicity of STX on bivalves with distinct accumulation ability (such as oysters and scallops) has been seldom investigated. The aim of this study was to identify whether distinct sensitivity exists between oysters, Crassostrea gigas, and scallops, Chlamys farreri under the same amount of STX exposure using multiple biomarker responses. The responses of different biochemical markers including oxidative stress markers (catalase, superoxide dismutase, glutathione S-transferase, and lipid peroxidation) and immunotoxicity biomarkers (hemocyte phagocytosis rate, reactive oxidative species production, and DNA damages) were evaluated in bivalves after 12, 48, and 96 h of exposure to STX. The integrated biomarker responses value combined with two-way ANOVA analysis suggested that STX posed slightly severer stress on scallops than oysters for the extended period of time. This study provided preliminary results on the usefulness of a multi-biomarker approach to assess the toxicity associated with STX exposure in marine bivalves. PMID- 30246783 TI - A Meta-Analysis to Determine Strength Training Related Dose-Response Relationships for Lower-Limb Muscle Power Development in Young Athletes. AB - It is well-documented that strength training (ST) improves measures of muscle strength in young athletes. Less is known on transfer effects of ST on proxies of muscle power and the underlying dose-response relationships. The objectives of this meta-analysis were to quantify the effects of ST on lower limb muscle power in young athletes and to provide dose-response relationships for ST modalities such as frequency, intensity, and volume. A systematic literature search of electronic databases identified 895 records. Studies were eligible for inclusion if (i) healthy trained children (girls aged 6-11 y, boys aged 6-13 y) or adolescents (girls aged 12-18 y, boys aged 14-18 y) were examined, (ii) ST was compared with an active control, and (iii) at least one proxy of muscle power [squat jump (SJ) and countermovement jump height (CMJ)] was reported. Weighted mean standardized mean differences (SMDwm) between subjects were calculated. Based on the findings from 15 statistically aggregated studies, ST produced significant but small effects on CMJ height (SMDwm = 0.65; 95% CI 0.34-0.96) and moderate effects on SJ height (SMDwm = 0.80; 95% CI 0.23-1.37). The sub-analyses revealed that the moderating variable expertise level (CMJ height: p = 0.06; SJ height: N/A) did not significantly influence ST-related effects on proxies of muscle power. "Age" and "sex" moderated ST effects on SJ (p = 0.005) and CMJ height (p = 0.03), respectively. With regard to the dose-response relationships, findings from the meta-regression showed that none of the included training modalities predicted ST effects on CMJ height. For SJ height, the meta-regression indicated that the training modality "training duration" significantly predicted the observed gains (p = 0.02), with longer training durations (>8 weeks) showing larger improvements. This meta-analysis clearly proved the general effectiveness of ST on lower-limb muscle power in young athletes, irrespective of the moderating variables. Dose-response analyses revealed that longer training durations (>8 weeks) are more effective to improve SJ height. No such training modalities were found for CMJ height. Thus, there appear to be other training modalities besides the ones that were included in our analyses that may have an effect on SJ and particularly CMJ height. ST monitoring through rating of perceived exertion, movement velocity or force-velocity profile could be promising monitoring tools for lower-limb muscle power development in young athletes. PMID- 30246784 TI - Impact of Modeling Assumptions on Stability Predictions in Reverse Total Shoulder Arthroplasty. AB - Reverse total shoulder arthroplasty (rTSA) is commonly used in the shoulder replacement surgeries for the relief of pain and to restore function, in patients with grossly deficient rotator cuff. Primary instability due to glenoid loosening is one of the critical complications of rTSA; the implants are designed and implanted such that the motion between the glenoid baseplate and underlying bone is minimized to facilitate adequate primary fixation. Finite element analysis (FEA) is commonly used to simulate the test setup per ASTM F2028-14 for comparing micromotion between designs or configurations to study the pre-clinical indications for stability. The FEA results can be influenced by the underlying modeling assumptions. It is a common practice to simplify the screw shafts by modeling them as cylinders and modeling the screw-bone interface using bonded contact, to evaluate micromotion in rTSA components. The goal of this study was to evaluate the effect of three different assumptions for modeling the screw-bone interface on micromotion predictions. The credibility of these modeling assumptions was examined by comparing the micromotion rank order predicted among three different modular configurations with similar information from the literature. Eight configurations were modeled using different number of screws, glenosphere offset, and baseplate sizes. An axial compression and shear load was applied through the glenosphere and micromotion at the baseplate-bone interface was measured. Three modeling assumptions pertaining to modeling of the screw-bone interface were used and micromotion results were compared to study the effect of number of peripheral screws, eccentricities, and baseplate diameter. The relative comparison of micromotion between configurations using two versus four peripheral screws remained unchanged irrespective of the three modeling assumptions. However, the relative comparison between two inferior offsets and baseplate sizes changed depending on the modeling assumptions used for the screw-bone interface. The finding from this study challenges the generally believed hypothesis that FEA models can be used to make relative comparison of micromotion in rTSA designs as long as the same modeling assumptions are used across all models. The comparisons with previously published work matched the finding from this study in some cases, whereas the comparison was contradicting in other cases. It is essential to validate the computer modeling approach with an experiment using similar designs and methods to increase the confidence in the predictions to make design decisions. PMID- 30246785 TI - The Cephalopod Large Brain Enigma: Are Conserved Mechanisms of Stem Cell Expansion the Key? AB - Within the clade of mollusks, cephalopods have developed an unusually large and complex nervous system. The increased complexity of the cephalopod centralized "brain" parallels an amazing amount of complex behaviors that culminate in one order, the octopods. The mechanisms that enable evolution of expanded brains in invertebrates remain enigmatic. While expression mapping of known molecular pathways demonstrated the conservation of major neurogenesis pathways and revealed neurogenic territories, it did not explain why cephalopods could massively increase their brain size compared to other mollusks. Such an increase is reminiscent of the expansion of the cerebral cortex in mammalians, which have enlarged their number and variety of neurogenic stem cells. We hypothesize that similar mechanisms might be at play in cephalopods and that focusing on the stem cell biology of cephalopod neurogenesis and genetic innovations might be smarter strategies to uncover the mechanism that has driven cephalopod brain expansion. PMID- 30246786 TI - STEAP1 Regulates Tumorigenesis and Chemoresistance During Peritoneal Metastasis of Gastric Cancer. AB - In China, majority of the mortality in gastric cancer are associated with peritoneal metastasis. Since most gastric tumors are metastatic at initial diagnosis, the treatment of gastric cancer is limited to radical resection. Therefore, it is imperative to identify diagnostic and prognostic biomarkers. From 2014 to 2015, 20 patients were enrolled in the study. To search translationally upregulated genes in the context of epithelial to mesenchymal transition (EMT), polysome profiling was performed. The MTT, migration, and invasion assay were conducted to determine cell proliferation, migration, and invasion ability respectively. Experiments of gain and loss of function were performed using the overexpression plasmid, siRNA, and shRNA. Xenograft assay was established using nude mice to explore the role of targets translationally upregulated gene in vivo. Polysome profiling defined the landscape of translationally regulated gene products with differential expression between non metastatic and metastatic cohorts. Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) was found to be the most translationally upregulated gene product in either experimental groups. STEAP1 was found to be required for cell proliferation, in vitro migration and invasion, and in vivo tumorigenesis. RNAi mediated silencing of STEAP1 potentiated chemosensitivity of the MKN45 cells to docetaxel treatment, highlighting the importance of STEAP1 as a novel biomarker in gastric cancer patients with peritoneal metastasis. STEAP1 is thus induced translationally and its expression promotes proliferation, migration, invasiveness, and tumorigenicity of gastric cancer. STEAP1 can be a potent candidate for designing of targeted therapy. PMID- 30246787 TI - Effects on Cognitive Functioning of Acute, Subacute and Repeated Exposures to High Altitude. AB - Objective: Neurocognitive functions are affected by high altitude, however the altitude effects of acclimatization and repeated exposures are unclear. We investigated the effects of acute, subacute and repeated exposure to 5,050 m on cognition among altitude-naive participants compared to control subjects tested at low altitude. Methods: Twenty-one altitude-naive individuals (25.3 +/- 3.8 years, 13 females) were exposed to 5,050 m for 1 week (Cycle 1) and re-exposed after a week of rest at sea-level (Cycle 2). Baseline (BL, 520 m), acute (Day 1, HA1) and acclimatization (Day 6, HA6, 5,050 m) measurements were taken in both cycles. Seventeen control subjects (24.9 +/- 2.6 years, 12 females) were tested over a similar period in Calgary, Canada (1,103 m). The Reaction Time (RTI), Attention Switching Task (AST), Rapid Visual Processing (RVP) and One Touch Stockings of Cambridge (OTS) tasks were administered and outcomes were expressed in milliseconds/frequencies. Lake Louise Score (LLS) and blood oxygen saturation (SpO2) were recorded. Results: In both cycles, no significant changes were found with acute exposure on the AST total score, mean latency and SD. Significant changes were found upon acclimatization solely in the altitude group, with improved AST Mean Latency [HA1 (588 +/- 92) vs. HA6 (526 +/- 91), p < 0.001] and Latency SD [HA1 (189 +/- 86) vs. HA6 (135 +/- 65), p < 0.001] compared to acute exposure, in Cycle 1. No significant differences were present in the control group. When entering Acute SpO2 (HA1-BL), Acclimatization SpO2 (HA6-BL) and LLS score as covariates for both cycles, the effects of acclimatization on AST outcomes disappeared indicating that the changes were partially explained by SpO2 and LLS. The changes in AST Mean Latency [DeltaBL (-61.2 +/- 70.2) vs. DeltaHA6 ( 28.0 +/- 58), p = 0.005] and the changes in Latency SD [DeltaBL (-28.4 +/- 41.2) vs. DeltaHA6 (-0.2235 +/- 34.8), p = 0.007] across the two cycles were smaller with acclimatization. However, the percent changes did not differ between cycles. These results indicate independent effects of altitude across repeated exposures. Conclusions: Selective and sustained attention are impaired at altitude and improves with acclimatization.The observed changes are associated, in part, with AMS score and SpO2. The gains in cognition with acclimatization during a first exposure are not carried over to repeated exposures. PMID- 30246789 TI - Higuchi Fractal Dimension of Heart Rate Variability During Percutaneous Auricular Vagus Nerve Stimulation in Healthy and Diabetic Subjects. AB - Analysis of heart rate variability (HRV) can be applied to assess the autonomic nervous system (ANS) sympathetic and parasympathetic activity. Since living systems are non-linear, evaluation of ANS activity is difficult by means of linear methods. We propose to apply the Higuchi fractal dimension (HFD) method for assessment of ANS activity. HFD measures complexity of the HRV signal. We analyzed 45 RR time series of 84 min duration each from nine healthy and five diabetic subjects with clinically confirmed long-term diabetes mellitus type II and with diabetic foot ulcer lasting more than 6 weeks. Based on HRV time series complexity analysis we have shown that HFD: (1) discriminates healthy subjects from patients with diabetes mellitus type II; (2) assesses the impact of percutaneous auricular vagus nerve stimulation (pVNS) on ANS activity in normal and diabetic conditions. Thus, HFD may be used during pVNS treatment, to provide stimulation feedback for on-line regulation of therapy in a fast and robust way. PMID- 30246788 TI - Regulation of the NRG1/ErbB4 Pathway in the Intrinsic Cardiac Nervous System Is a Potential Treatment for Atrial Fibrillation. AB - Background: The NRG1/ErbB4 signaling mechanism has been widely studied in the central nervous system for many years. However, the role of this pathway in modulating the intrinsic cardiac nervous system is largely unknown. Objective: The present study investigated whether the NRG1/ErbB4 signaling system affects the activity of major atrial ganglionated plexi (GP) in a paroxysmal atrial fibrillation (AF) model by 6-h rapid atrial pacing (RAP). Methods: Twenty-four dogs were randomly divided into (1) a control group (saline microinjections into GP), (2) RAP group (saline microinjections into GP plus 6 h-RAP), (3) NRG1 group (microinjections of neuregulin-1 into GP plus 6 h-RAP) and (4) NRG1 + ERA group (microinjections of neuregulin-1 and ErbB4 receptor antagonist-ERA into GP plus 6 h-RAP). The effective refractory period (ERP), window of vulnerability (WOV), anterior right GP (ARGP) function and neural activity were measured. ARGP tissues were excised for histological study and western blotting. Results: When compared to the control group, 6 h-RAP produced a significant (1) decrease in ERP, an increase in SigmaWOV, (2) an increase in ARGP neural activity and neural function, and (3) an increase in c-fos and nerve growth factor protein expression in the ARGP. However, microinjection of NRG1 into the ARGP prior to RAP prevented ERP shortening and AGRP activity enhancement and inhibited the expression of c Fos and NGF proteins. Furthermore, these changes were significantly attenuated by pretreatment with an ErbB4 receptor antagonist. Conclusion: The NRG1/ErbB4 signaling pathway may exist in the GP, and activation of this pathway suppressed RAP-induced GP activation, atrial electrical remodeling and AF. PMID- 30246790 TI - Elevated pCO2 Affects Feeding Behavior and Acute Physiological Response of the Brown Crab Cancer pagurus. AB - Anthropogenic climate change exposes marine organisms to CO2 induced ocean acidification (OA). Marine animals may make physiological and behavioral adaptations to cope with OA. Elevated pCO2 may affect metabolism, feeding, and energy partition of marine crabs, and thereby affect their predator-prey dynamics with mussels. Therefore, we examined the effects of simulated future elevated pCO2 on feeding behavior and energy metabolism of the brown crab Cancer pagurus. Following 54 days of pre-acclimation to control CO2 levels (360 MUatm) at 11 degrees C, crabs were exposed to consecutively increased oceanic CO2 levels (2 weeks for 1200 and 2300 MUatm, respectively) and subsequently returned to control CO2 level (390 MUatm) for 2 weeks in order to study their potential to acclimate elevated pCO2 and recovery performance. Standard metabolic rate (SMR), specific dynamic action (SDA) and feeding behavior of the crabs were investigated during each experimental period. Compared to the initial control CO2 conditions, the SMRs of CO2 exposed crabs were not significantly increased, but increased significantly when the crabs were returned to normal CO2 levels. Conversely, SDA was significantly reduced under high CO2 and did not return to control levels during recovery. Under high CO2, crabs fed on smaller sized mussels than under control CO2; food consumption rates were reduced; foraging parameters such as searching time, time to break the prey, eating time, and handling time were all significantly longer than under control CO2, and prey profitability was significantly lower than that under control conditions. Again, a two-week recovery period was not sufficient for feeding behavior to return to control values. PCA results revealed a positive relationship between feeding/SDA and pH, but negative relationships between the length of foraging periods and pH. In conclusion, elevated pCO2 caused crab metabolic rate to increase at the expense of SDA. Elevated pCO2 affected feeding performance negatively and prolonged foraging periods. These results are discussed in the context of how elevated pCO2 may impair the competitiveness of brown crabs in benthic communities. PMID- 30246792 TI - Differential Mechanism of Periodontitis Progression in Postmenopause. AB - Over the past four decades, it has become accepted that periodontal disease is caused by specific bacterial infections and that individuals are uniformly susceptible neither to these infections nor to the damage caused by them. The specific bacterial infections and the composition of the environment in which these bacteria easily settle cause an immune response. The immune cells involved in pathogenesis of periodontitis migrate into the periodontitis lesion and advance the disease. The purpose of the present study is to investigate the correlation between immune cell migration and progression of periodontal disease by inducing estrogen deficiency through ovariectomy (OVX) to mimic postmenopausal women and treatment with lipopolysaccharide (LPS). The LPS derived from Porphyromonas gingivalis induced periodontitis and absorption of the alveolar bone dose-dependently. However, the alveolar crest level reduction after LPS injection between OVX and Sham operated mice did not show a significant difference. Matrix metallopeptidase-9 (MMP-9), which is known to be able to detect the progression of periodontitis in general, was not significantly different between OVX and Sham groups. However, immune cells such as T lymphocytes and neutrophils migrated less overall in OVX groups than Sham operated groups. These findings can be a topic of debate on the old controversy regarding the relationship between periodontal disease and hormonal change. Currently, in clinical practice, menopause is not a major consideration in the treatment of periodontal disease. This study suggests that treatment methods and medication should be considered in the treatment of infectious periodontal disease in postmenopausal women. PMID- 30246793 TI - Inflammatory Cytokines and SIRT1 Levels in Subcutaneous Abdominal Fat: Relationship With Cardiac Performance in Overweight Pre-diabetics Patients. AB - Objectives: In obese patients the superficial adipose tissue expresses cytokines, and sirtuins, that may affect myocardial function. In this study, we investigated the effect of metformin therapy added to a hypocaloric diet on the inflammatory pattern and cardiac performance (MPI) in obese patients with pre-diabetic condition. Materials and Methods: Fifty-eight obese patients that were enrolled for abdominoplastic surgery were divided into patients with pre-diabetic condition (n 40) and normo-glycemic patients (n18). Patients with pre-diabetic condition were randomly assigned to metformin therapy added to a hypocaloric diet (group 1, n 20) or to a hypocaloric diet therapy alone (group 2, n20). Patients with normo-glycemic condition were assigned to a hypocaloric diet therapy. Results: During enrollment, obese patients with a pre-diabetic condition (group 1 and 2) presented higher glucose values, lower values of insulin, and higher values of the homeostasis model for the assessment of insulin resistance (HOMA IR) than obese patients with normo-glycemic condition(group 3). In addition, they had higher values of C Reactive protein (CRP), interleukin 6 (IL6), and lower values of sirtuin 1(SIRT1). In the 12th month of the follow-up, metformin therapy induced in patients with pre-diabetic condition (group 1) a significant reduction of glucose values, HOMA-IR, and inflammatory markers such as CRP (1.04 +/- 0.48 vs. 0.49 +/- 0.02 mmol/L, p < 0.05), IL6 (4.22 +/- 0.45 vs. 3.33 +/- 0.34 pg/ml, p < 0.05), TNFalpha (6.95 +/- 0.59 vs. 5.15 +/- 0.44 pg/ml, p < 0.05), and Nitrotyrosine (5,214 +/- 0,702 vs. 2,151 +/- 0,351 nmol/l, p < 0.05). This was associated with a significant reduction of Intima-media thickness (1.01 +/- 0.15 vs. 0.86 +/- 0.15 mm, p < 0.05), Septum (14 +/- 2.5 vs. 10.5 +/- 2 mm, p < 0.05), Posterior wall (11 +/- 1.5 vs. 8 +/- 1 mm, p < 0.05), LV mass (192.5 +/- 49.5 vs. 133.2 +/- 37.6 g, p < 0.05) and of MPI (0.58 +/- 0.03 vs. 0.38 +/- 0.02, p < 0.05). At 12 months of follow-up, group 2 experienced only a reduction of cholesterol (4.15 +/- 0.94 vs. 4.51 +/- 0.88 mmol/L, p < 0.05) and triglycerides (1.71 +/- 1.18 vs. 1.83 +/- 0.54 mmol/L, p < 0.05). At 12 months of follow-up, group 3 experienced a significant reduction of inflammatory markers, and also of echographic parameters, associated with amelioration of myocardial performance. To date, IL6 expression was related to higher values of left ventricle mass (R value 0.272, p-value 0.039), and to higher IMT (R-value 0.272, p-value 0.039), such as those observed for CRP (R-value 0.308, p-value 0.021), for glucose blood values (R-value 0.449, p-value 0.001), and for HOMA-IR (R-value 0.366, p-value 0.005). An inverse correlation was found between subcutaneous fat expression of SIRT1 and myocardial performance index (R-value-0.236, p-value 0.002). Conclusion: In obese patients with pre-diabetic condition a metformin therapy may reduce inflammation and oxidative stress, and this may be associated with the amelioration of the cardiac performance. Clinical research trial number: NCT03439592. PMID- 30246794 TI - Editorial: Neuromuscular Training and Adaptations in Youth Athletes. PMID- 30246795 TI - Low-Load Resistance Training With Blood Flow Restriction Improves Clinical Outcomes in Musculoskeletal Rehabilitation: A Single-Blind Randomized Controlled Trial. AB - Background: There is growing evidence to support the use of low-load blood flow restriction (LL-BFR) exercise in musculoskeletal rehabilitation. Purpose: The purpose of this study was to evaluate the efficacy and feasibility of low-load blood flow restricted (LL-BFR) training versus conventional high mechanical load resistance training (RT) on the clinical outcomes of patient's undergoing inpatient multidisciplinary team (MDT) rehabilitation. Study design: A single blind randomized controlled study. Methods: Twenty-eight lower-limb injured adults completed a 3-week intensive MDT rehabilitation program. Participants were randomly allocated into a conventional RT (3-days/week) or twice-daily LL-BFR training group. Outcome measurements were taken at baseline and 3-weeks and included quadriceps and total thigh muscle cross-sectional area (CSA) and volume, muscle strength [five repetition maximum (RM) leg press and knee extension test, isometric hip extension], pain and physical function measures (Y-balance test, multistage locomotion test-MSLT). Results: A two-way repeated measures analysis of variance revealed no significant differences between groups for any outcome measure post-intervention (p > 0.05). Both groups showed significant improvements in mean scores for muscle CSA/volume, 5-RM leg press, and 5-RM knee extension (p < 0.01) after treatment. LL-BFR group participants also demonstrated significant improvements in MSLT and Y-balance scores (p < 0.01). The Pain scores during training reduced significantly over time in the LL-BFR group (p = 0.024), with no adverse events reported during the study. Conclusion: Comparable improvements in muscle strength and hypertrophy were shown in LL-BFR and conventional training groups following in-patient rehabilitation. The LL-BFR group also achieved significant improvements in functional capacity. LL-BFR training is a rehabilitation tool that has the potential to induce positive adaptations in the absence of high mechanical loads and therefore could be considered a treatment option for patients suffering significant functional deficits for whom conventional loaded RT is contraindicated. Trial Registration: ISRCTN Reference: ISRCTN63585315, dated 25 April 2017. PMID- 30246796 TI - Wavelength and Fibrosis Affect Phase Singularity Locations During Atrial Fibrillation. AB - The mechanisms underlying atrial fibrillation (AF), the most common sustained cardiac rhythm disturbance, remain elusive. Atrial fibrosis plays an important role in the development of AF and rotor dynamics. Both electrical wavelength (WL) and the degree of atrial fibrosis change as AF progresses. However, their combined effect on rotor core location remains unknown. The aim of this study was to analyze the effects of WL change on rotor core location in both fibrotic and non-fibrotic atria. Three patient specific fibrosis distributions (total fibrosis content: 16.6, 22.8, and 19.2%) obtained from clinical imaging data of persistent AF patients were incorporated in a bilayer atrial computational model. Fibrotic effects were modeled as myocyte-fibroblast coupling + conductivity remodeling; structural remodeling; ionic current changes + conductivity remodeling; and combinations of these methods. To change WL, action potential duration (APD) was varied from 120 to 240ms, representing the range of clinically observed AF cycle length, by modifying the inward rectifier potassium current (IK1) conductance between 80 and 140% of the original value. Phase singularities (PSs) were computed to identify rotor core locations. Our results show that IK1 conductance variation resulted in a decrease of APD and WL across the atria. For large WL in the absence of fibrosis, PSs anchored to regions with high APD gradient at the center of the left atrium (LA) anterior wall and near the junctions of the inferior pulmonary veins (PVs) with the LA. Decreasing the WL induced more PSs, whose distribution became less clustered. With fibrosis, PS locations depended on the fibrosis distribution and the fibrosis implementation method. The proportion of PSs in fibrotic areas and along the borders varied with both WL and fibrosis modeling method: for patient one, this was 4.2-14.9% as IK1 varied for the structural remodeling representation, but 12.3-88.4% using the combination of structural remodeling with myocyte-fibroblast coupling. The degree and distribution of fibrosis and the choice of implementation technique had a larger effect on PS locations than the WL variation. Thus, distinguishing the fibrotic mechanisms present in a patient is important for interpreting clinical fibrosis maps to create personalized models. PMID- 30246791 TI - The Importance of Biophysical and Biochemical Stimuli in Dynamic Skeletal Muscle Models. AB - Classical approaches to engineer skeletal muscle tissue based on current regenerative and surgical procedures still do not meet the desired outcome for patient applications. Besides the evident need to create functional skeletal muscle tissue for the repair of volumetric muscle defects, there is also growing demand for platforms to study muscle-related diseases, such as muscular dystrophies or sarcopenia. Currently, numerous studies exist that have employed a variety of biomaterials, cell types and strategies for maturation of skeletal muscle tissue in 2D and 3D environments. However, researchers are just at the beginning of understanding the impact of different culture settings and their biochemical (growth factors and chemical changes) and biophysical cues (mechanical properties) on myogenesis. With this review we intend to emphasize the need for new in vitro skeletal muscle (disease) models to better recapitulate important structural and functional aspects of muscle development. We highlight the importance of choosing appropriate system components, e.g., cell and biomaterial type, structural and mechanical matrix properties or culture format, and how understanding their interplay will enable researchers to create optimized platforms to investigate myogenesis in healthy and diseased tissue. Thus, we aim to deliver guidelines for experimental designs to allow estimation of the potential influence of the selected skeletal muscle tissue engineering setup on the myogenic outcome prior to their implementation. Moreover, we offer a workflow to facilitate identifying and selecting different analytical tools to demonstrate the successful creation of functional skeletal muscle tissue. Ultimately, a refinement of existing strategies will lead to further progression in understanding important aspects of muscle diseases, muscle aging and muscle regeneration to improve quality of life of patients and enable the establishment of new treatment options. PMID- 30246798 TI - Gender Differences in Prognosis and Risk Stratification of Brugada Syndrome: A Pooled Analysis of 4,140 Patients From 24 Clinical Trials. AB - Background: Male gender has been consistently shown to be a risk factor for a greater number of arrhythmic events in patients with Brugada Syndrome (BrS). However, there have been no large-scale comprehensive pooled analyses to statistically and systematically verify this association. Therefore, we conducted a pooled analysis on gender differences in prognosis and risk stratification of BrS with a largest sample capacity at present. Methods: We searched PubMed, Embase, Medline, Cochrane Library databases, Chinese National Knowledge Infrastructure, and Wanfang Data for relevant studies published from 2002 to 2017. The prognosis and risk stratification of BrS and risk factors were then investigated and evaluated according to gender. Results: Twenty-four eligible studies involving 4,140 patients were included in the analysis. Male patients (78.1%) had a higher risk of arrhythmic events than female patients (95% confidence interval: 1.46-2.91, P < 0.0001). Among the male population, there were statistical differences between symptomatic patients and asymptomatic patients (95% CI: 2.63-7.86, P < 0.00001), but in the female population, no statistical differences were found. In the female subgroup, electrophysiological study (EPS) positive patients had a tendency toward a higher risk of arrhythmic events than EPS-negative patients (95% CI: 0.93-29.77, P = 0.06). Conclusions: Male patients are at a higher risk of arrhythmic events than female patients. Within the male population, symptomatic patients have a significantly higher risk profile compared to asymptomatic patients, but no such differences are evident within the female population. Consequently, in the female population, the risk of asymptomatic patterns cannot be underestimated. PMID- 30246799 TI - Caffeine and Placebo Improved Maximal Exercise Performance Despite Unchanged Motor Cortex Activation and Greater Prefrontal Cortex Deoxygenation. AB - Caffeine (CAF) is an ergogenic aid used to improve exercise performance. Independent studies have suggested that caffeine may have the ability to increase corticospinal excitability, thereby decreasing the motor cortex activation required to generate a similar motor output. However, CAF has also been suggested to induce a prefrontal cortex (PFC) deoxygenation. Others have suggested that placebo (PLA) may trigger comparable effects to CAF, as independent studies found PLA effects on motor performance, corticospinal excitability, and PFC oxygenation. Thus, we investigated if CAF and CAF-perceived PLA may improve motor performance, despite the likely unchanged MC activation and greater PFC deoxygenation. Nine participants (26.4 +/- 4.8 years old, VO2MAX of 42.2 +/- 4.6 mL kg-1 min-1) performed three maximal incremental tests (MITs) in control (no supplementation) and ~60 min after CAF and PLA ingestion. PFC oxygenation (near infrared spectroscopy at Fp1 position), MC activation (EEG at Cz position) and vastus lateralis and rectus femoris muscle activity (EMG) were measured throughout the tests. Compared to control, CAF and PLA increased rectus femoris muscle EMG (P = 0.030; F = 2.88; d = 0.84) at 100% of the MIT, and enhanced the peak power output (P = 0.006; F = 12.97; d = 1.8) and time to exhaustion (P = 0.007; F = 12.97; d = 1.8). In contrast, CAF and PLA did not change MC activation, but increased the PFC deoxygenation as indicated by the lower O2Hb (P = 0.001; F = 4.68; d = 1.08) and THb concentrations (P = 0.01; F = 1.96; d = 0.7) at 80 and 100% the MIT duration. These results showed that CAF and CAF-perceived PLA had the ability to improve motor performance, despite unchanged MC activation and greater PFC deoxygenation. The effectiveness of CAF as ergogenic aid to improve MIT performance was challenged. PMID- 30246797 TI - Integrative Transcriptomic and microRNAomic Profiling Reveals Immune Mechanism for the Resilience to Soybean Meal Stress in Fish Gut and Liver. AB - In aquafeeds, fish-meal has been commonly replaced with plant protein, which often causes enteritis. Currently, foodborne enteritis has few solutions in regards to prevention or cures. The recovery mechanism from enteritis in herbivorous fish may further help understand prevention or therapy. However, few reports could be found regarding the recovery or resilience to fish foodborne enteritis. In this study, grass carp was used as an animal model for soybean meal induced enteritis and it was found that the fish could adapt to the soybean meal at a moderate level of substitution. Resilience to soybean meal stress was found in the 40% soybean meal group for juvenile fish at growth performance, morphological and gene expression levels, after a 7-week feeding trial. Furthermore, the intestinal transcriptomic data, including transcriptome and miRNAome, was applied to demonstrate resilience mechanisms. The result of this study revealed that in juvenile grass carp after a 7-week feeding cycle with 40% soybean meal, the intestine recovered via enhancing both an immune tolerance and wound healing, the liver gradually adapted via re-balancing immune responses, such as phagosome and complement cascades. Also, many immune factors in the gut and liver were systemically revealed among stages of on-setting, remising, and recovering (or relief). In addition, miRNA regulation played a key role in switching immune states. Thus, the present data systemically demonstrated that the molecular adaptation mechanism of fish gut-liver immunity is involved in the resilience to soybean meal stress. PMID- 30246800 TI - Circulating Small Non-coding RNAs as Biomarkers for Recovery After Exhaustive or Repetitive Exercise. AB - Circulating microRNAs have proven to be reliable biomarkers, due to their high stability, both in vivo in the circulation, and ex vivo during sample preparation and storage. Small nucleolar RNAs (snoRNAs) are a different type of small non coding RNAs that can also be reliably measured in plasma, but have only been studied sporadically. In this study, we aimed to identify RNA-biomarkers that can distinguish between different exercise regimes and that entail clues about muscle repair and recovery after prolonged exhaustive endurance exercise. We compared plasma microRNA profiles between two cohorts of elite cyclists, subjected to two different types of exercise regimes, as well as a cohort of patients with peripheral artery disease (PAD) that were scheduled to undergo lower limb amputation, due to critical limb ischemia. In elite athletes, muscle tissue recovers quickly even after exhaustive exercise, whereas in PAD patients, recovery is completely impaired. Furthermore, we measured levels of a specific group of snoRNAs in the plasma of both elite cyclists and PAD patients. Using a multiplex qPCR screening, we detected a total of 179 microRNAs overall, of which, on average, 161 microRNAs were detected per sample. However, only 30 microRNAs were consistently expressed in all samples. Of these, two microRNAs, miR-29a-3p and miR193a-5p, that responded differently two different types of exercise, namely exhaustive exercise and non-exhaustive endurance exercise. Using individual rt/qPCR, we also identified a snoRNA, SNORD114.1, which was significantly upregulated in plasma in response to endurance exercise. Furthermore, two microRNAs, miR-29a-3p and miR-495-3p, were significantly differentially expressed in athletes compared to PAD patients, but only following exercise. We suggest that these two microRNAs could function as markers of impaired muscle repair and recovery. In conclusion, microRNAs miR-29a-3p and miR 193a-5p may help us distinguish between repeated exhaustive and non-exhaustive endurance exercise. MicroRNA miR-29a-3p, as well as miR-495-3p, may further mark impaired muscle recovery in patients with severe critical limb ischemia. Furthermore, we showed for the first time that a circulating snoRNA, SNORD114.1, is regulated in response to exercise and may be used as biomarker. PMID- 30246801 TI - Hemoglobin and Erythropoietin After Commercial Saturation Diving. AB - Saturation divers are exposed to elevated partial pressure of oxygen (ppO2) in their hyperbaric work environment. Experimental studies indicate that oxygen transport is altered, and we have previously reported a drop in hematocrit and extensive downregulation of genes involved in blood oxygen transport capacity after decompression from professional saturation diving. Here we investigate the initial period of hematological adjustment back to normobaric air after professional saturation diving. Erythropoietin (EPO) and hemoglobin (Hb) were measured in blood from 13 divers at two time-points after saturation assignments lasting up to 4 weeks; first immediately after decompression and again 24 h later. Pre-dive levels defined baselines. The ppO2 varied from 40 kPa in the saturation chambers during storage, 50 to 80 kPa during bell excursions, and gradually reduced to 21 kPa during decompression to surface pressure. EPO was similar to baseline immediately after saturation diving (P = 0.4), and markedly increased within the next 24 h (99%, P < 0.0002). Hb levels remained slightly reduced at both time-points (4% immediately after; P = 0.02, 8% 24 h after; P < 0.001). The results imply that the hematological acclimatization back to normobaric air was ongoing, but not completed, during the first 24 h after professional saturation diving. PMID- 30246802 TI - Microstructural Infarct Border Zone Remodeling in the Post-infarct Swine Heart Measured by Diffusion Tensor MRI. AB - Introduction: Computational models of the heart increasingly require detailed microstructural information to capture the impact of tissue remodeling on cardiac electromechanics in, for example, hearts with myocardial infarctions. Myocardial infarctions are surrounded by the infarct border zone (BZ), which is a site of electromechanical property transition. Magnetic resonance imaging (MRI) is an emerging method for characterizing microstructural remodeling and focal myocardial infarcts and the BZ can be identified with late gadolinium enhanced (LGE) MRI. Microstructural remodeling within the BZ, however, remains poorly characterized by MRI due, in part, to the fact that LGE and DT-MRI are not always available for the same heart. Diffusion tensor MRI (DT-MRI) can evaluate microstructural remodeling by quantifying the DT apparent diffusion coefficient (ADC, increased with decreased cellularity), fractional anisotropy (FA, decreased with increased fibrosis), and tissue mode (decreased with increased fiber disarray). The purpose of this work was to use LGE MRI in post-infarct porcine hearts (N = 7) to segment remote, BZ, and infarcted myocardium, thereby providing a basis to quantify microstructural remodeling in the BZ and infarcted regions using co-registered DT-MRI. Methods: Chronic porcine infarcts were created by balloon occlusion of the LCx. 6-8 weeks post-infarction, MRI contrast was administered, and the heart was potassium arrested, excised, and imaged with LGE MRI (0.33 * 0.33 * 0.33 mm) and co-registered DT-MRI (1 * 1 * 3 mm). Myocardium was segmented as remote, BZ, or infarct by LGE signal intensity thresholds. DT invariants were used to evaluate microstructural remodeling by quantifying ADC, FA, and tissue mode. Results: The BZ significantly remodeled compared to both infarct and remote myocardium. BZ demonstrated a significant decrease in cellularity (increased ADC), significant decrease in tissue organization (decreased FA), and a significant increase in fiber disarray (decreased tissue mode) relative to remote myocardium (all p < 0.05). Microstructural remodeling in the infarct was similar, but significantly larger in magnitude (all p < 0.05). Conclusion: DT-MRI can identify regions of significant microstructural remodeling in the BZ that are distinct from both remote and infarcted myocardium. PMID- 30246803 TI - Serum and Adipose Tissue mRNA Levels of ATF3 and FNDC5/Irisin in Colorectal Cancer Patients With or Without Obesity. AB - Objectives: To explore the activating transcription factor 3 (ATF3) and fibronectin type III domain-containing protein 5 (FNDC5)/irisin protein levels in serum and mRNA levels in subcutaneous and visceral white adipose tissue (sWAT and vWAT) in normal-weight (NW) and overweight/obese (OW/OB) patients with colorectal cancer (CRC). Methods: 76 CRC patients and 40 healthy controls were recruited. Serum ATF3 and irisin levels were detected by using ELISA kits, and the mRNA expression levels in sWAT and vWAT were measured by performing RT-qPCR. Results: The serum ATF3 levels were greater by 37.2%, whereas the irisin levels were lower by 23.3% in NW+CRC patients compared with those in healthy controls. CRC was independently associated with both ATF3 and irisin levels. The probability of CRC greater by 22.3-fold in individuals with high ATF3 levels compared with those with low ATF3 levels, whereas the risk of CRC in subjects with high irisin levels was lower by 78.0% compared to the risk in those with low irisin levels after adjustment for age, gender, BMI, and other biochemical parameters. Serum ATF3 and irisin could differentiate CRC patients from controls with receiver operating characteristic (ROC) curve areas of 0.745 (95% CI, 0.655-0.823) and 0.656 (95% CI, 0.561-0.743), respectively. The combination of ATF3 and irisin exhibited improved diagnosis value accuracy with ROC curve areas of 0.796 (95% CI, 0.710 0.866) as well as 72.6% sensitivity and 80.0% specificity. Conclusion: Increased ATF3 and reduced irisin levels were observed in sera from CRC patients. Individuals with high ATF3 and low irisin levels were more likely to have CRC. ATF3 and irisin represent potential diagnostic biomarkers for CRC patients. PMID- 30246804 TI - Muscle Free Fatty-Acid Uptake Associates to Mechanical Efficiency During Exercise in Humans. AB - Intrinsic factors related to muscle metabolism may explain the differences in mechanical efficiency (ME) during exercise. Therefore, this study aimed to investigate the relationship between muscle metabolism and ME. Totally 17 healthy recreationally active male participants were recruited and divided into efficient (EF; n = 8) and inefficient (IE; n = 9) groups, which were matched for age (mean +/- SD 24 +/- 2 vs. 23 +/- 2 years), BMI (23 +/- 1 vs. 23 +/- 2 kg m-2), physical activity levels (3.4 +/- 1.0 vs. 4.1 +/- 1.0 sessions/week), and V O2peak (53 +/- 3 vs. 52 +/- 3 mL kg-1 min-1), respectively, but differed for ME at 45% of V O2peak intensity during submaximal bicycle ergometer test (EF 20.5 +/- 3.5 vs. IE 15.4 +/- 0.8%, P < 0.001). Using positron emission tomography, muscle blood flow (BF) and uptakes of oxygen (m V O2), fatty acids (FAU) and glucose (GU) were measured during dynamic submaximal knee-extension exercise. Workload-normalized BF (EF 35 +/- 14 vs. IE 34 +/- 11 mL 100 g-1 min-1, P = 0.896), m V O2 (EF 4.1 +/ 1.2 vs. IE 3.9 +/- 1.2 mL 100 g-1 min-1, P = 0.808), and GU (EF 3.1 +/- 1.8 vs. IE 2.6 +/- 2.3 MUmol 100 g-1 min-1, P = 0.641) as well as the delivery of oxygen, glucose, and FAU, as well as respiratory quotient were not different between the groups. However, FAU was significantly higher in EF than IE (3.1 +/- 1.7 vs. 1.7 +/- 0.6 MUmol 100 g-1 min-1, P = 0.047) and it also correlated with ME (r = 0.56, P = 0.024) in the entire study group. EF group also demonstrated higher use of plasma FAU than IE, but no differences in use of plasma glucose and intramuscular energy sources were observed between the groups. These findings suggest that the effective use of plasma FAU is an important determinant of ME during exercise. PMID- 30246805 TI - Early Functional and Morphological Muscle Adaptations During Short-Term Inertial Squat Training. AB - Purpose: To assess early changes in muscle function and hypertrophy, measured as increases in muscle cross-sectional areas (CSAs) and total volume, over a 4 weeks inertial resistance training (RT) program. Methods: Ten young RT-naive volunteers (age 23.4 +/- 4.1 years) underwent 10 training sessions (2-3 per week) consisting of five sets of 10 flywheel squats (moment of inertia 900 kg?cm2). Magnetic resonance imaging (MRI) scans of both thighs were performed before (PRE), and after 2 (IN) and 4 (POST) weeks of training to compute individual muscle volumes and regional CSAs. Scans were performed after >=96 h of recovery after training sessions, to avoid any influence of acute muscle swelling. PRE and POST regional muscle activation was assessed using muscle functional MRI (mfMRI) scans. Concentric (CON) and eccentric (ECC) squat force and power, as well as maximal voluntary isometric contraction force (MVIC) of knee extensors and flexors, were measured in every training session. Results: Significant quadriceps hypertrophy was detected during (IN: 5.5% +/- 1.9%) and after (POST: 8.6% +/- 3.6%) the training program. Increases in squat force (CON: 32% +/- 15%, ECC: 31 +/- 15%) and power (CON: 51% +/- 30%, ECC: 48% +/- 27%) were observed over the training program. Knee extensor MVIC significantly increased 28% +/- 17% after training, but no changes were seen in knee flexor MVIC. No correlation was found between regional muscular activation in the first session and the % of increase in regional CSAs (r = -0.043, P = 0.164). Conclusion: This study reports the earliest onset of whole-muscle hypertrophy documented to date. The process initiates early and continues in response to RT, contributing to initial increases in force. The results call into question the reliability of mfMRI as a tool for predicting the potential hypertrophic effects of a given strengthening exercise. PMID- 30246806 TI - Paradigms of Lung Microbiota Functions in Health and Disease, Particularly, in Asthma. AB - Improvements in our knowledge of the gut microbiota have broadened our vision of the microbes associated with the intestine. These microbes are essential actors and protectors of digestive and extra-digestive health and, by extension, crucial for human physiology. Similar reconsiderations are currently underway concerning the endogenous microbes of the lungs, with a shift in focus away from their involvement in infections toward a role in physiology. The discovery of the lung microbiota was delayed by the long-held view that the lungs of healthy individuals were sterile and by sampling difficulties. The lung microbiota has a low density, and the maintenance of small numbers of bacteria seems to be a critical determinant of good health. This review aims to highlight how knowledge about the lung microbiota can change our conception of lung physiology and respiratory health. We provide support for this point of view with knowledge acquired about the gut microbiota and intestinal physiology. We describe the main characteristics of the lung microbiota and its functional impact on lung physiology, particularly in healthy individuals, after birth, but also in asthma. We describe some of the physiological features of the respiratory tract potentially favoring the installation of a dysbiotic microbiota. The gut microbiota feeds and matures the intestinal epithelium and is involved in immunity, when the principal role of the lung microbiota seems to be the orientation and balance of aspects of immune and epithelial responsiveness. This implies that the local and remote effects of bacterial communities are likely to be determinant in many respiratory diseases caused by viruses, allergens or genetic deficiency. Finally, we discuss the reciprocal connections between the gut and lungs that render these two compartments inseparable. PMID- 30246808 TI - Potts Shunt to Be Preferred Above Atrial Septostomy in Pediatric Pulmonary Arterial Hypertension Patients: A Modeling Study. AB - Aims: To quantitatively evaluate the basic pathophysiological process involved in the creation of Eisenmenger syndrome in pediatric pulmonary arterial hypertension (PAH) patients by either atrial septostomy (AS) or Potts shunt (PS) as well as to predict the effects of AS or PS in future PAH patients. Methods: The multi-scale lumped parameter CircAdapt model of the cardiovascular system was used to investigate the effects of AS and PS on cardiovascular hemodynamics and mechanics, as well as on oxygen saturation in moderate to severe PAH. The reference simulation, with cardiac output set to 2.1 l/min and mean systemic pressure to 61 mmHg, was used to create a compensated moderate PAH simulation with mPAP 50 mmHg. Thereupon we created a range of decompensated PAH simulations in which mPAP was stepwise increased from 50 to 80 mmHg. Then we simulated for each level of mPAP the acute effects of either PS or AS with connection diameters ranging between 0-16 mm. Results: For any mPAP level, the effect on shunt flow size is much larger for the PS than for AS. Whereas right ventricular pump work in PS is mainly dependent on mPAP, in AS it depends on both mPAP and the size of the defect. The effects on total cardiac pump work were similar for PS and AS. As expected, PS resulted in a drastic decrease of lower body oxygen saturation, whereas in AS both the upper and lower body oxygen saturation decreased, though not as drastically as in PS. Conclusion: Our simulations support the opinion that a PS can transfer suprasystemic PAH to an Eisenmenger physiology associated with a right-to-left shunt at the arterial level. Contrary to the current opinion that PS in PAH will decompress and unload the right ventricle, we show that while a PS does lead to a decrease in mPAP toward mean systemic arterial pressure, it does not unload the right ventricle because it mainly diverts flow from the pulmonary arterial system toward the lower body systemic arteries. PMID- 30246807 TI - The CCHamide1 Neuropeptide Expressed in the Anterior Dorsal Neuron 1 Conveys a Circadian Signal to the Ventral Lateral Neurons in Drosophila melanogaster. AB - The fruit fly Drosophila melanogaster possesses approximately 150 brain clock neurons that control circadian behavioral rhythms. Even though individual clock neurons have self-sustaining oscillators, they interact and synchronize with each other through a network. However, little is known regarding the factors responsible for these network interactions. In this study, we investigated the role of CCHamide1 (CCHa1), a neuropeptide expressed in the anterior dorsal neuron 1 (DN1a), in intercellular communication of the clock neurons. We observed that CCHa1 connects the DN1a clock neurons to the ventral lateral clock neurons (LNv) via the CCHa1 receptor, which is a homolog of the gastrin-releasing peptide receptor playing a role in circadian intercellular communications in mammals. CCHa1 knockout or knockdown flies have a generally low activity level with a special reduction of morning activity. In addition, they exhibit advanced morning activity under light-dark cycles and delayed activity under constant dark conditions, which correlates with an advance/delay of PAR domain Protein 1 (PDP1) oscillations in the small-LNv (s-LNv) neurons that control morning activity. The terminals of the s-LNv neurons show rather high levels of Pigment-dispersing factor (PDF) in the evening, when PDF is low in control flies, suggesting that the knockdown of CCHa1 leads to increased PDF release; PDF signals the other clock neurons and evidently increases the amplitude of their PDP1 cycling. A previous study showed that high-amplitude PDP1 cycling increases the siesta of the flies, and indeed, CCHa1 knockout or knockdown flies exhibit a longer siesta than control flies. The DN1a neurons are known to be receptive to PDF signaling from the s-LNv neurons; thus, our results suggest that the DN1a and s-LNv clock neurons are reciprocally coupled via the neuropeptides CCHa1 and PDF, and this interaction fine-tunes the timing of activity and sleep. PMID- 30246809 TI - Non-steroidal Anti-inflammatory Drug Consumption in a Multi-Stage and a 24-h Mountain Bike Competition. AB - Purpose: Excessive or inappropriate non-steroidal anti-inflammatory drug (NSAID) use during ultra-endurance events could cause potential risk to athletes' health. Reports on NSAID consumption in mountain bikers or ultra-mountain bikers are scarce. Therefore, the aim of this study was to investigate the prevalence of NSAID consumption immediately before, during and immediately after a mountain bike (MTB) race and to compare NSAID consumption in two different MTB competitions. Methods: This observational study took place at a three-stage MTB race (SMTB) (n = 63) and at a 24-h MTB race (24MTB) (n = 68), both held in the Czechia in 2017. NSAID consumption was evaluated via self-reported electronic questionnaires. Results: Of all finishers (n = 131), fourteen (10%) consumed NSAID at least once during the competition day (immediately before, during or immediately after the race). The number of NSAID consumers was the same in both competitions. Nevertheless, only three athletes (2%), all of them from the 24MTB, consumed NSAID during the race and 5% of all mountain bikers reported consumption after the race. In contrast to the SMTB, the intake reported by the 24MTB participants was quite homogeneous in terms of the timing of NSAID consumption. The NSAID users were older (p = 0.043) than the non-users. Ibuprofen was most commonly used by 79% of all consumers. Conclusion: The prevalence of NSAID use was higher in the older participants and seems to be lower in comparison with results from studies about runners, ultra-runners and triathletes suggesting that it is determined by the discipline (i.e., cycling). On the other hand, the timing of NSAID consumption was probably affected by the competition character (e.g., MTBS or 24MTB). Future studies should focus on a larger sample size of cyclists from various disciplines. PMID- 30246810 TI - Modulation of Ion Channels in the Superior Cervical Ganglion Neurons by Myocardial Ischemia and Fluvastatin Treatment. AB - Background: The superior cervical ganglion (SCG) of the autonomic nervous system plays an important role in different cardiovascular diseases. In this study, we investigated the effects of ischemia and fluvastatin treatment on the ion channel characteristics of SCG neurons in a rabbit myocardial ischemia (MI) model. Methods: MI was induced by abdominal subcutaneous injections of isoproterenol (ISO). The properties of the delayed rectifier potassium channel current (IK ), sodium channel current (INa ), and action potential (APs) on isolated SCG neurons in the control, MI-7d, MI-14d, fluvastatin-7d (fluvastatin pretreated 14 days and treated 7 days after ISO-induced MI), and fluvastatin-14d (fluvastatin pretreated 14 days and treated 14 days after ISO-induced MI) groups were studied. In addition, the RNA expressions of KCNQ3 and SCN9A in the SCG tissue were determined by performing real-time PCR. Intracellular calcium concentration was monitored using laser scanning confocal microscopy. Results: Compared with the control group, the current amplitude of IK and INa were increased in the MI-7d and MI-14d groups. KCNQ3 RNA (corresponding to channel proteins of IK ) expression and SCN9A RNA (corresponding to channel proteins of INa ) expression were also increased in MI groups. Activation and inactivation curves for INa in the two MI groups shifted negatively compared with the control group. These changes were reversed by fluvastatin treatment. Intracellular calcium concentration in SCG neurons was not altered significantly by MI or fluvastatin treatment. By contrast, increased AP amplitude and shortened APD90 were observed in the MI-7d and MI-14d groups. These changes were reversed in the fluvastatin treated MI group. Conclusion: Fluvastatin treatment partly reversed the characteristics of SCG neurons in MI. The ion channel of SCG neurons could be one of the potential targets of fluvastatin in treating coronary heart diseases. PMID- 30246811 TI - Green, fast, and large-scale synthesis of highly fluorescent Au nanoclusters for Cu2+ detection and temperature sensing. AB - Gold nanoclusters have attracted widespread attention because of their unique optical and physical properties. However, traditional synthesis methods are complicated and require additional reducing agents, while the yield is often very low. Such resource and time-consuming synthesis processes limit their further application. Herein, a rapid sonochemical route is used to synthesize fluorescent Au nanoclusters in large quantities using glutathione (GSH) both as a capping and reducing agent. These Au nanoclusters are synthesized quickly (~40 min) due to the presence of ultrasonic waves, and show orange red photoluminescence (Em = 598 nm), small size (~2 nm) and good dispersion in aqueous solution. Moreover, GSH, as a protecting agent on the surface of resultant Au nanoclusters, has many functional groups including carboxyl and amino groups because of which the nanoclusters show high photo-, storage-, metal- and pH-stability. A stable Au nanoclusters-based nano-sensor is designed for highly sensitive and selective label-free detection of Cu2+ with a low limit of detection of 7 ppb (based on S/N = 3). The fluorescent probe can be used in versatile nanothermometry devices, because their photoluminescence intensity correlates strongly with temperature and varies considerably over a wide temperature range (20-80 degrees C). Therefore, the novel fluorescent sensing probe has great application prospects in Cu2+ detection and temperature sensing. PMID- 30246812 TI - A ratiometric Raman probe for live-cell imaging of hydrogen sulfide in mitochondria by stimulated Raman scattering. AB - Stimulated Raman Scattering (SRS) coupled with alkyne tags has been an emerging imaging technique to visualize small-molecule species with high sensitivity and specificity. Here we describe the development of a ratiometric Raman probe for visualizing hydrogen sulfide (H2S) species in living cells as the first alkyne based sensor for SRS microscopy. This probe uses an azide unit as a selective reactive site, and it targets mitochondria with high specificity. The SRS ratiometric images show a strong response to H2S level changes in living cells. PMID- 30246819 TI - Activation-free fabrication of high-surface-area porous carbon nanosheets from conjugated copolymers. AB - High-surface-area porous carbon nanosheets have been successfully prepared by direct carbonization of graphene oxide sandwiched poly(aniline-co-pyrrole). Benefiting from the distinct structure features of the poly(aniline-co-pyrrole) and its homogeneous deposition on the graphene oxide surface, the surface area of the porous carbon nanosheets is as high as 1606 m2 g-1. PMID- 30246818 TI - Effective reduction of non-specific binding of blood cells in a microfluidic chip for isolation of rare cancer cells. AB - The high purity of target cells enriched from blood samples plays an important role in the clinical detection of diseases. However, non-specific binding of blood cells in the isolated cell samples can complicate downstream molecular and genetic analysis. In this work, we report a simple solution to non-specific binding of blood cells by modifying the surface of microchips with a multilayer nanofilm, with the outmost layer containing both PEG brushes for reducing blood cell adhesion and antibodies for enriching target cells. This layer-by-layer (LbL) polysaccharide nanofilm was modified with neutravindin and then conjugated with a mixture of biotinylated PEG molecules and biotinylated antibodies. Using EpCAM-expressing and HER2-expressing cancer cells in blood as model platforms, we were able to dramatically reduce the non-specific binding of blood cells to approximately 1 cell per mm2 without sacrificing the high capture efficiency of the microchip. To support the rational extension of this approach to other applications for cell isolation and blood cell resistance, we conducted extensive characterization on the nanofilm formation and degradation, antifouling with PEG brushes and introducing functional antibodies. This simple, yet effective, approach can be applied to a variety of microchip applications that require high purity of sample cells containing minimal contamination from blood cells. PMID- 30246821 TI - A novel luminescent hybrid material based on zinc complexes and graphene oxides for detection of Fe3+ in aqueous media. AB - Graphene oxide sheet-modified zinc complexes named Zn-PMA/GOSs have been synthesized based on the non-covalent interactions of Zn-PMA and graphene oxide sheets (GOSs) via an in situ reaction. Then, the as-synthesized products are characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA) and fluorescence spectroscopy. Zn PMA/GOSs not only show strong luminescence intensity and better thermal stability than pure zinc complexes but also have good dispersibility in aqueous solutions, and they are further used as fluorescence probes for detecting Fe3+. They show relative selectivity and high sensitivity to Fe3+ (Stern-Volmer constant KSV = 4 * 106 L mol-1), suggesting that Zn-PMA/GOSs can be a promising luminescent probe for selectively sensing Fe3+ ions. Moreover, the possible mechanisms of ion selective detection are also discussed. PMID- 30246822 TI - Theoretical and experimental investigations of 129Xe NMR chemical shift isotherms in metal-organic frameworks. AB - The pressure dependence of the 129Xe chemical shift in the metal-organic frameworks (MOFs) UiO-66 and UiO-67 (UiO - University of Oslo) has been investigated using both theory and experiment. The resulting chemical shift isotherms were analyzed with a theoretical approach based on model systems (as proposed by K. Trepte, J. Schaber, S. Schwalbe, F. Drache, I. Senkovska, S. Kaskel, J. Kortus, E. Brunner and G. Seifert, Phys. Chem. Chem. Phys., 2017, 19, 10020-10027) and experimental 129Xe NMR measurements at different pressures. All investigations were carried out at T = 237 K while the pressure range was chosen according to the maximum pressure at which Xe liquifies (p0 = 1.73 MPa or 17.3 bar), thus 0 < p <= p0. The theoretically predicted chemical shift isotherms agree well with the experimental ones. Additionally, a comparison of the chemical shift isotherms with volumetric adsorption isotherms was carried out to determine the similarities and differences of both isotherms. PMID- 30246823 TI - Roasting improves the hypoglycemic effects of a large-leaf yellow tea infusion by enhancing the levels of epimerized catechins that inhibit alpha-glucosidase. AB - Teas contain bioactive polyphenols, such as (-)-epigallocatechin gallate (EGCG), which is not stable during the processing of tea. EGCG can be epimerized into (-) gallocatechin gallate (GCG), which is present in very small amounts in fresh tea leaves. An infusion made from roasted large-leaf yellow tea inhibited alpha glucosidase more significantly than an infusion of unroasted yellow tea, with IC50 values of 76.08 +/- 8.96 and 170.17 +/- 33.00 MUg mL-1, respectively. After roasting, the content of GCG showed about a 5-fold increase, while EGCG showed a decrease of 56.6%. Of the two main alpha-glucosidase inhibitors, GCG exhibited a higher inhibitory effect on alpha-glucosidase than its corresponding epimer (EGCG), whose IC50 value was about 3-fold lower. Modeling of molecular docking suggested that GCG preferably binds to the target alpha-glucosidase protein; this was confirmed by in vitro protein-polyphenol binding, where GCG had a binding rate about 4 times higher than that of EGCG. Comparative in vivo studies using oral starch tolerance tests in mice verified that GCG exhibited lower postprandial blood glucose compared to EGCG. These results suggest that roasting is a simple and effective way to increase the capacity of large-leaf yellow tea to regulate postprandial blood glucose. PMID- 30246824 TI - In situ growth of copper rhodizonate complexes on reduced graphene oxide for high performance organic lithium-ion batteries. AB - Novel copper rhodizonate (CPR) complexes are in situ grown on reduced graphene oxide (rGO) through a one-pot hydrothermal method. As anode materials for LIBs, the CPR/rGO composites show outstanding electrochemical lithium-storage performances, benefitting from both the insolubility of CPR in electrolytes and the effective assembly between CPR and rGO. PMID- 30246825 TI - Charged impurity-tuning of midgap states in biased Bernal bilayer black phosphorus: an anisotropic electronic phase transition. AB - In this paper, we analytically investigate the electronic density of states (DOS) of bilayer Bernal black phosphorus (BBP) in order to study the anisotropic electronic phase transition. We employ the Green's function approach, the Born approximation, and the tight-binding Hamiltonian model including ten intra-layer and four inter-layer hopping energies. BBP consisting of two coupled layers of black phosphorus is a suitable candidate for studying the layer-dependent electronic properties of few-layer black phosphorus. We examine the electronic properties of BBP under conditions in which only one layer and both layers are subjected to a dilute charged impurity and a perpendicular electric field. Our findings show that there is no phase transition when the impurity is doped on only one layer, whereas in the case of both layers, BBP suffers a phase transition from semiconductor to semimetal at strong impurity scattering potentials. Also, applying the electric field on one layer of BBP leads to an increase in the band gap, whereas in the case of both layers, the band gap decreases with the electric field and eventually, a phase transition appears at a bias voltage of more than 1.8 eV. Consequently, the band gap of BBP can be tuned by applying an electric field and a charged impurity, and thereby these findings provide insights for future experimental research on black phosphorus. PMID- 30246826 TI - Metal-free direct C-arylation of 1,3-dicarbonyl compounds and ethyl cyanoacetate: a platform to access diverse arrays of meta-functionalized phenols. AB - A base mediated, highly convenient strategy for the direct C-arylation of 1,3 dicarbonyls and cyanoacetate with various phenol derivatives as aryl partners is presented. The present work excels in forming a C-C bond at the meta-position of the phenols, which is traditionally challenging to functionalize. This protocol further leads the way to have scalable, straightforward access to phenol assimilated heterocycles which have powerful applications both in synthetic chemistry and medicinal research. PMID- 30246829 TI - Ag nanosheets for efficient electrocatalytic N2 fixation to NH3 under ambient conditions. AB - The industrial-scale NH3 production still heavily depends on the Haber-Bosch process which demands not only high energy consumption but emits a large amount of CO2. Electrochemical fixation of N2 to NH3 under ambient conditions is regarded as an eco-friendly and sustainable approach, but stable and efficient electrocatalysts are demanded for the N2 reduction reaction (NRR). In this work, we report our recent finding that an Ag nanosheet acts as a high-performance NRR electrocatalyst at room temperature and pressure. Electrochemical tests in 0.1 M HCl reveal that such a catalyst achieves a high Faradaic efficiency of 4.8% and a NH3 yield rate of 4.62 * 10-11 mol s-1 cm-2 at -0.60 V vs. reversible hydrogen electrode (RHE), rivaling the performances of most of the reported aqueous-based NRR electrocatalysts. Additionally, the Ag nanosheet also shows excellent selectivity, strong long-term electrochemical stability and durability. PMID- 30246828 TI - Biosynthesis and isolation of selenoneine from genetically modified fission yeast. AB - Selenoneine, a naturally occurring form of selenium, is the selenium analogue of ergothioneine, a sulfur species with health relevance not only as a purported antioxidant but likely also beyond. Selenoneine has been speculated to exhibit similar effects. To study selenoneine's health properties as well as its metabolic transformation, the pure compound is required. Chemical synthesis of selenoneine, however, is challenging and biosynthetic approaches have been sought. We herein report the biosynthesis and isolation of selenoneine from genetically modified fission yeast Schizosaccharomyces pombe grown in a medium containing sodium selenate. After cell lysis and extraction with methanol, selenoneine was purified by three consecutive preparative reversed-phase HPLC steps. The product obtained at the mg level was characterised by high resolution mass spectrometry, NMR and HPLC/ICPMS. Biosynthesis was found to be a promising alternative to chemical synthesis, and should be suitable for upscaling to produce higher amounts of this important selenium species in the future. PMID- 30246830 TI - Reaction kinetics of OH + HNO3 under conditions relevant to the upper troposphere/lower stratosphere. AB - The OH initiated oxidation of HNO3 in the UT/LS plays an important role in controlling the O3 budget, removing HOx radicals whilst driving NOx/y partitioning chemistry by yielding NO3 radicals: OH + HNO3 -> H2O + NO3. In this paper, k1(T, P) was measured using OH (A <- X) Laser Induced Fluorescence (LIF) and the data was modelled over the 223-298 K temperature and 25-750 Torr pressure ranges, using the modified Lindemann-Hinshelwood expression , where k0 = 5.2 * 10 14 exp(200/T) cm3 s-1, k2 = 8.4 * 10-17 exp(1900/T) cm3 s-1 and k3 = 1.6 * 10-34 exp(1745/T) cm3 s-1. A significant source of experimental uncertainty derives from accurate determination of HNO3 concentration, which is impacted by heterogeneous uptake of the low volatility HNO3 onto cold surfaces of the reactors. Our results represent the determination of k1(T, P) using two different in situ [HNO3] measurements: VUV absorption and a new two photon Photolysis Induced Fluoresence (PIF). Experimental results are discussed along with a computational master equation calculation (MESMER), which highlight the need for further theoretical study into the OH + HNO3 mechanism and potential energy surface. The atmospheric impact of these new rate constants were modelled using the STOCHEM-CRI chemistry transport global model, which have shown a small reduction in global budgets of key atmospheric species, with more significant changes in the NOx/HNO3 ratio, peaking in the tropical upper troposphere regions. PMID- 30246831 TI - Molecular rectifiers based on five-coordinate iron(iii)-containing surfactants. AB - In this article we review the state-of-the-art of metallorganic-based molecular rectification with an emphasis on our research in five-coordinate FeIII containing surfactants. We place rectification in the broader context of molecular electronics, and include the description of methodology used in electrode|LB film|electrode assemblies, concluding with an outlook on future directions for metallosurfactants. PMID- 30246834 TI - Magnetron-sputtered copper nanoparticles: lost in gas aggregation and found by in situ X-ray scattering. AB - Magnetron discharge in a cold buffer gas represents a liquid-free approach to the synthesis of metal nanoparticles (NPs) with tailored structure, chemical composition and size. Despite a large number of metal NPs that were successfully produced by this method, the knowledge of the mechanisms of their nucleation and growth in the discharge is still limited, mainly because of the lack of in situ experimental data. In this work, we present the results of in situ Small Angle X ray Scattering measurements performed in the vicinity of a Cu magnetron target with Ar used as a buffer gas. Condensation of atomic metal vapours is found to occur mainly at several mm distance from the target plane. The NPs are found to be captured preferentially within a region circumscribed by the magnetron plasma ring. In this capture zone, the NPs grow to the size of 90 nm whereas smaller ones sized 10-20 nm may escape and constitute a NP beam. Time-resolved measurements of the discharge indicate that the electrostatic force acting on the charged NPs may be largely responsible for their capturing nearby the magnetron. PMID- 30246835 TI - Interpenetrating network gelatin methacryloyl (GelMA) and pectin-g-PCL hydrogels with tunable properties for tissue engineering. AB - The design of new hydrogel-based biomaterials with tunable physical and biological properties is essential for the advancement of applications related to tissue engineering and regenerative medicine. For instance, interpenetrating polymer network (IPN) and semi-IPN hydrogels have been widely explored to engineer functional tissues due to their characteristic microstructural and mechanical properties. Here, we engineered IPN and semi-IPN hydrogels comprised of a tough pectin grafted polycaprolactone (pectin-g-PCL) component to provide mechanical stability, and a highly cytocompatible gelatin methacryloyl (GelMA) component to support cellular growth and proliferation. IPN hydrogels were formed by calcium ion (Ca2+)-crosslinking of pectin-g-PCL chains, followed by photocrosslinking of the GelMA precursor. Conversely, semi-IPN networks were formed by photocrosslinking of the pectin-g-PCL and GelMA mixture, in the absence of Ca2+ crosslinking. IPN and semi-IPN hydrogels synthesized with varying ratios of pectin-g-PCL to GelMA, with and without Ca2+-crosslinking, exhibited a broad range of mechanical properties. For semi-IPN hydrogels, the aggregation of microcrystalline cores led to formation of hydrogels with compressive moduli ranging from 3.1 to 10.4 kPa. For IPN hydrogels, the mechanistic optimization of pectin-g-PCL, GelMA, and Ca2+ concentrations resulted in hydrogels with comparatively higher compressive modulus, in the range of 39 kPa-5029 kPa. Our results also showed that IPN hydrogels were cytocompatible in vitro and could support the growth of three-dimensionally (3D) encapsulated MC3T3-E1 preosteoblasts in vitro. The simplicity, technical feasibility, low cost, tunable mechanical properties, and cytocompatibility of the engineered semi-IPN and IPN hydrogels highlight their potential for different tissue engineering and biomedical applications. PMID- 30246836 TI - Palladium(0)-catalyzed C(sp3)-Si bond formation via formal carbene insertion into a Si-H bond. AB - Pd(0)-Catalyzed formal carbene insertion into Si-H bonds has been achieved as an efficient method for C(sp3)-Si bond formation. The reaction, which uses readily available N-tosylhydrazones as the diazo precursors, is highly efficient and shows a wide substrate scope. Rh(ii) and Cu(i) salts, which are the widely used catalysts for carbene insertion reactions, have been proved to be ineffective for the current reaction. A Pd(ii) carbene migratory insertion/reductive elimination mechanism is proposed. PMID- 30246837 TI - "Push-push and push-pull" polystannanes. AB - The synthesis and characterization of polystannanes with "push" or "pull" moieties attached to the tin backbone are described. Precursor tetra aryl- (1, 2) stannanes were converted to mono- (3) and dichloro- (4, 5) stannanes by either sequential chlorination or by redistribution reactions with SnCl4. Compounds 4 and 5 were transformed to polymerisable tin dihydride monomers 6 and 7 using a large excess (10*) of NaBH4. Homopolymer 8 with electron donating aryl substituents (p-MeOC6H4-) was synthesized by dehydrogenative polymerization using Wilkinson's catalyst. Attempts to prepare the homopolymer 9 with electron withdrawing aryl substituents (p-CF3C6H4-) from the dehydrocoupling of 7 using similar conditions led only to the formation of low molecular weight oligomeric species. Two alternating polymers, 10 and 11, were synthesized by condensation polymerization of (n-Bu)2Sn(NEt2)2 with monomers 6 or 7. The first was a "push push" alternating polymer, 10, comprised of a repeating unit consisting of two different electron donating groups (p-MeOC6H4-, n-Bu) at neighboring tin centres. The second was a "push-pull" alternating polymer, 11, bearing both an electron donating group (n-Bu) and a strongly electron withdrawing substituent (p-CF3C6H4 ) at neighboring tin atoms. All small molecule stannanes and tin-containing polymers were characterized by NMR (1H, 13C, 119Sn, and where required 19F) spectroscopy, MS or EA. The absolute molecular weights of tin polymers (8, 10, 11) were determined by triple detection GPC and in the range of 1.07 * 104 to 1.95 * 104 Da. Rapid photodegradation of polymers was observed by UV-Vis spectroscopy, with a slower degradation observed for the "push-pull" polymer, 11, compared to the "push-push" polymer, 10. PMID- 30246838 TI - Metal-organic frameworks induce autophagy in mouse embryonic fibroblast cells. AB - Autophagy is the lysosomal-dependent degradation process of intracellular substances in adaptation to environmental or developmental changes. It plays an essential role in maintaining cellular homeostasis while its dysfunction is involved in various human diseases. The regulation of autophagy has attracted more and more attention with the promise for improving treatment of diseases as a potential therapeutic target. Metal-organic frameworks (MOFs), as emerging biomaterials, have been investigated in the biological and biomedical fields in recent years. Therefore, it is interesting and significant to study the effects of MOFs on living cells from safety aspects as well as the therapeutic viewpoint, especially their effects on autophagy which have not been reported yet. In this study, the effects of Fe-MIL-101_NH2 on mouse embryonic fibroblasts (MEFs) were investigated and the potential applications of these nanoparticles in the regulation of autophagy were explored. Our results demonstrated that Fe-MIL 101_NH2 induced cytoprotective autophagy in MEFs instead of cytotoxicity. The activation of autophagy kept reactive oxygen species from accumulating, which protected MEFs from apoptosis. Further exploration of the possible mechanisms of MOF-induced autophagy revealed that the inhibition of mTOR pathway as well as the enhancement of Becline1 and Atg5 contributed to autophagy induction. Our study uncovered the autophagic effects and mechanistic insights of MOFs, which will be beneficial and meaningful to the safety evaluation and the reasonable and effective usage of MOFs. PMID- 30246840 TI - Graphene aerogels that withstand extreme compressive stress and strain. AB - Graphene aerogels combining elastic, lightweight, and robust mechanical properties have been explored for a wide variety of applications. However, graphene aerogels are generally subject to brittle mechanical properties and the irreversible damage of network structures during extreme compressions. Thus, the challenge of finding ways to enhance the strength and resilience of graphene aerogels remains. Herein, superelastic and ultralight aerogels are fabricated through a thermal-treatment of 3D ordered graphene aerogels. The treatments at 400-1000 degrees C eliminate most of the oxygen-containing functional groups and enhance the pi-pi stacking interactions between graphene sheets, forming a well ordered structure of graphene sheets in cell walls. The aerogels can withstand a loading of 100 000 N (109 times their own weight) for 60 min and retain their substantial elastic resilience. This loading corresponds to an ultimate compressive stress of approximately 1000 MPa and a strain of 99.8%, and this ultimate stress is 1-2 orders of magnitude higher than the values for other (carbon-based, polymer-based, inorganic-based, and metal-based) porous materials. The superelastic properties can be attributed to the graphite-like ordered structure of cell walls. The successful fabrication of such superelastic materials opens a new avenue to explore their potential applications in pressure sensors, mechanical shock absorbers, soft robots, and deformable electronic devices. PMID- 30246841 TI - Theoretical studies of atmospheric molecular complexes interacting with NIR to UV light. AB - The interaction of weakly bonded complexes of atmospheric constituents with the electromagnetic spectrum available in Earth's atmosphere can induce direct excitation to electronic excited states as well as the excitation of higher vibrational states (overtones) of the electronic ground state. A better understanding of these phenomena requires improved theoretical support by including the anharmonic and vibro-electronic effects on both the band positions and transition intensities. In this work, generalized second-order vibrational perturbation and time-independent Franck-Condon and Herzberg-Teller computations are exploited together with a density functional theory (DFT)/coupled cluster (CC) scheme and its extension to the excited electronic states. Structural and spectroscopic properties are calculated for isolated formaldehyde and its complexes with H2O, CO, SO2 and H2O2, focusing on how small molecules may affect the interactions with NIR to UV irradiation. PMID- 30246842 TI - Directed self-assembly of a high-chi block copolymer for the fabrication of optical nanoresonators. AB - In this paper, we report on the fabrication of optical nanoresonators using block copolymer lithography. The nanostructured gratings or nanofins were fabricated using a silicon-containing block copolymer on a chromium coated silicon-on insulator substrate. The etch resistance of the block copolymer template enables a unique patterning technique for high-aspect-ratio silicon nanofins. Integration of the directed self-assembly with nanoimprint lithography provides a well aligned array of nanofins with a depth of ~125 nm on a wafer scale. The developed nanopatterning method is an alternative to the previously reported nanopatterning techniques utilizing block copolymers. A dense array of sub-10 nm nanofins is used to realize a photonic guided-mode resonance filter. The nanostructured grating provides high sensitivity in refractive index sensing, as demonstrated by simulations and experiments in measuring varying contents of the tetrahydrofuran solvent. PMID- 30246843 TI - Effect of positional isomerism on the spectroelectrochemical response of 3,6 bis(2-pyridyl)-diketopyrrolopyrrolate bridged bis(carbonylhydridoruthenium) compounds. AB - Reaction of 3,6-bis(2-pyridyl)-diketopyrrolopyrrole (H2-BPDPP) with two equivalents of [Ru(H)(CO)(Cl)(PPh3)3] in EtOH produced two symmetrical dinuclear isomers, (MU-BPDPP)[Ru(CO)H(PPh3)2]2, green 1 and blue 2, which could be separated chromatographically and characterised spectroscopically (1H and 31P NMR, IR, and UV-VIS). Isomeric forms of 1 and 2 were authenticated using their single crystal X-ray structures. In addition to the essentially planar bis chelating bridge BPDPP2- and the mutually trans positioned axial PPh3 ligands in both complexes, compound 1 was established with the CO groups trans to the pyrrolate-N atoms, whereas 2 has the pi acceptors CO and pyridine-N situated trans to each other. While the reduction of 1 and 2 proceeds irreversibly at negative potentials, the reversible oxidations at rather low potentials could be monitored by EPR and UV-VIS-NIR absorption measurements. Together with TD-DFT calculations, these results reveal that the primary electron transfers are largely confined to the BPDPP ligand. Despite the bridge centred processes, small differences between the isomers 10/+ and 20/+ were found, affecting e.g. the near infrared absorption of the radical cation species. PMID- 30246844 TI - Challenges in the configuration assignment of natural products. A case-selective perspective. AB - Covering: up to 2018Even today, when planar structures of natural products can be determined with microgram samples, the configurational assignment continues to be a challenge. The relative and absolute configurations of natural products can be assigned by devising original approaches, relying on carefully acquired data on a case-by-case basis. In this review, the most widely available methods and techniques for the absolute configuration determination of novel natural products are concisely discussed. Selected illustrative examples (case studies) are presented, where original approaches integrating different chemical, spectroscopic, and/or computational methods have been devised to solve intriguing stereochemistry issues of natural small molecules. PMID- 30246845 TI - Velcro-mimicking surface based on polymer loop brushes. AB - We herein report the fabrication of a Velcro-mimicking surface based on polymer brushes. Using poly(epsilon-caprolactone) (PCL) as the model polymer, polymer loop brushes (PLBs) and singly tethered polymer brushes (STPBs) with nearly identical tethering point density and brush heights were synthesized using a polymer single crystal (PSC)-assisted grafting-to method. Atomic force microscopy based single molecular force spectroscopy (AFM-SMFS) and macroscale lap-shear experiments both demonstrated that the PLBs led to strong adhesion that is up to ~10 times greater than the STPBs, which is attributed to the enriched chain entanglement between the probing polymer and the brushes. We envisage that our results will pave the way towards a new materials design for strong adhesives and nanocomposites. PMID- 30246846 TI - Active tuning of directional scattering by combining magneto-optical effects and multipolar interferences. AB - An efficient route is proposed to actively manipulate directional scattering based on magneto-optical (MO) effects and multipolar interferences with a coated MO cylinder. We demonstrate that the presence of an external magnetic field B contributes to breaking the degeneracy of multipoles and making them rotate. The rotated modes further interfere with each other, thus reshaping scattering profiles and introducing novel directional optical switching (OS) phenomena. As a result, we show that forward scattering (FS) and backward scattering (BS) can be flexibly altered by turning on or off the B for both s-polarization and p polarization, and optical switching exhibits broadband performance as well. More specifically, the proposed nanostructure also operates robust and reliable functionalities when considering realistic MO materials with optical loss and dispersion; therefore, they are ideal candidates to develop reconfigurable, tunable and versatile optical devices. PMID- 30246847 TI - Phase coexistence in a monolayer of active particles induced by Marangoni flows. AB - Thermally or chemically active colloids generate thermodynamic gradients in the solution in which they are immersed and thereby induce hydrodynamic flows that affect their dynamical evolution. Here we study a mean-field model for the many body dynamics of a monolayer of spherically symmetric active particles located at a fluid-fluid interface. Due to the spherical symmetry, the particles do not self propel. Instead, the dynamics is driven by the long-ranged Marangoni flows, due to the response of the interface to the activity of the particles, which compete with the direct interaction between particles. We demonstrate analytically that, in spite of the intrinsic out-of-equilibrium character of the system, the monolayer evolves to a "pseudoequilibrium" state, in which the Marangoni flows force the coexistence of the thermodynamic phases associated to the direct interaction. In particular, we study the most interesting case of a r-3 soft repulsion that models electrostatic or magnetic interparticle forces. For a sufficiently large average density, two-dimensional phase transitions (freezing from liquid to hexatic, and melting from solid to hexatic) should be observable in a radially stratified, "onion-like" structure within the monolayer. Furthermore, the analysis allows us to conclude that, while the activity may be too weak to allow direct detection of such induced Marangoni flows, it is relevant as a collective effect in the emergence of the experimentally observable spatial structure of phase coexistences noted above. Finally, the relevance of these results for potential experimental realizations is critically discussed. PMID- 30246848 TI - Self-assembly of Gd3+-bound keplerate polyanions into nanoparticles as a route for the synthesis of positive MRI contrast agents. Impact of the structure on the magnetic relaxivity. AB - The present work introduces Gd3+ complexes with giant keplerate polyanions as a promising basis for MRI contrast agents. The impact of Gd3+ binding with different building blocks of keplerates on the magnetic relaxivity of the complexes is revealed by comparative study of the keplerates [{Mo6O21}12{Mo2O4(OAc)}30]42-, [{Mo6O21}12{Mo2O4(HPO4)}30]72-, and [{Mo6O21}12{Mo2O2S2(OAc)}30]42-. Unprecedentedly high longitudinal and transverse relaxivity values (up to 250 and 300 mM-1 s-1 correspondingly) are achieved for the keplerates possessing edl{Mo2O4(OAc)} and {Mo2O4(HPO42-)} moieties under their 1 : 1 complex formation with Gd3+. The transformation of the external pores from Mo9O9 to Mo9O6S3 in the {Mo2O2S2(OAc)}-keplerate and an increase in the Gd3+ to-keplerate ratio are the factors that decrease the relaxivity. The rapid degradation of the free keplerates in aqueous solutions restricts the use of the Gd3+-bound keplerates with 1 : 1 stoichiometry as MRI contrast agents. In this work, the optimized stoichiometry of the complexes, their self-assembly into ultra-small nanoparticles and their hydrophilic coating by a triblock copolymer are highlighted as tools for increasing both the colloid and chemical stability of the keplerate complexes. Optimal keplerate compositions have been identified to achieve a compromise of low cytotoxicity and high stability; these Gd3+-bound keplerates exhibit longitudinal and transverse relaxivity values (95 and 114 mM-1 s-1, respectively), well within the region of interest for MRI techniques. PMID- 30246849 TI - Disassembly-driven signal turn-on probes for bimodal detection of DNA with 19F NMR and fluorescence. AB - To image DNAs in vivo, molecular probes that can detect DNA with a highly transparent signal are required. In this study, we designed and synthesized amphiphilic molecular probes that can detect DNA with a highly transparent 19F NMR signal in a signal turn-on manner based on the self-assembly and target dependent-disassembly of the probe molecules in aqueous solution. Fluorescence and dynamic light scattering studies revealed that these amphiphilic probes consisting of bisbenzimide H 33258 and 3,5-bis(trifluoromethyl)benzene are assembled and form aggregates in aqueous solution, and that the aggregates are collapsed when the probes bind to double-stranded DNA via selective interaction between the bisbenzimide H 33258 moiety and AATT double-stranded region of DNA. Since the target-dependent-disassembly of the probes caused turn-on of 19F NMR and fluorescence signals, bimodal detection of double-stranded DNA was successfully achieved. PMID- 30246850 TI - Arrays of highly complex noble metal nanostructures using nanoimprint lithography in combination with liquid-phase epitaxy. AB - Current best-practice lithographic techniques are unable to meet the functional requirements needed to enable on-chip plasmonic devices capable of fully exploiting nanostructure properties reliant on a tailored nanostructure size, composition, architecture, crystallinity, and placement. As a consequence, numerous nanofabrication methods have emerged that address various weaknesses, but none have, as of yet, demonstrated a large-area processing route capable of defining organized surfaces of nanostructures with the architectural diversity and complexity that is routinely displayed in colloidal syntheses. Here, a hybrid fabrication strategy is demonstrated in which nanoimprint lithography is combined with templated dewetting and liquid-phase syntheses that is able to realize periodic arrays of complex noble metal nanostructures over square centimeter areas. The process is inexpensive, can be carried out on a benchtop, and requires modest levels of instrumentation. Demonstrated are three fabrication schemes yielding arrays of core-shell, core-void-shell, and core-void-nanoframe structures using liquid-phase syntheses involving heteroepitaxial deposition, galvanic replacement, and dealloying. With the field of nanotechnology being increasingly reliant on the engineering of desirable physicochemical responses through architectural control, the fabrication strategy provides a platform for advancing devices reliant on addressable arrays or the collective response from an ensemble of identical nanostructures. PMID- 30246851 TI - Effect of adhesion force on the height pesticide droplets bounce on impaction with cabbage leaf surfaces. AB - The relationship between adhesion force and the height drops containing difenoconazole-loaded mesoporous silica nanoparticles (DF-MSNs)/Tween 80 bounce on cabbage leaf surfaces was investigated as a function of Tween 80 concentration. The adhesion force of a pesticide droplet on cabbage leaf surfaces was assessed using a high-sensitivity microelectromechanical balance system and the impact behavior was recorded with a high-speed camera. The height droplets bounced decreased with increasing adhesion force, with a negative correlation between the height of the bouncing drops and adhesion force. Although droplets containing >=0.06% Tween 80 adhered to the cabbage leaves, the retraction height was still observed to decrease as the adhesion force increased. The experimental results indicate that for cabbage leaf surfaces, the adhesion force has a significant effect on the height drops bounce. The results provide new insights into how researchers can screen for formulations for hydrophobic target crops and how to increase spray adhesion to difficult-to-wet crop leaf surfaces. PMID- 30246852 TI - Mechanisms of the polyol reduction of copper(ii) salts depending on the anion type and diol chain length. AB - The mechanisms of the polyol reduction of copper(ii) compounds were investigated by various systematic experiments. The course of the reduction in ethylene glycol strongly depends on the anion present in solution. Elemental copper can only be obtained in high yields starting from Cu(NO3)2, Cu(OAc)2, or Cu(OH)2; but not from CuCl2 or CuSO4. Intermediate compounds were observed, namely Cu2O, and the alkoxide compounds Cu(C2H4O2) and Cu3(OAc)2(C2H4O2)2. Cu3(OAc)2(C2H4O2)2 was characterised by single-crystal X-ray diffraction. It is a 2D coordination polymer with bridging bidentate acetate and bidentate deprotonated EG ligands leading to vertex- and edge-linked CuO5 polyhedra. Alkoxide compounds were also detected for higher glycol ethers. With growing glycol ether chain length the stability of alkoxide intermediates decreases, enhancing the stability range of Cu2O. Because the majority of copper species is precipitated as copper(ii) alkoxide compounds or Cu2O before the reduction to elemental copper occurs, only few nuclei are formed in solution leading to microparticles instead of nanoparticles. Much smaller but strongly agglomerated particles were observed under alkaline reaction conditions. PMID- 30246853 TI - Visible light catalyzed reaction of alpha-bromochalcones with chalcones: direct access to the urundeuvine scaffold. AB - The alpha-keto vinyl radicals generated from alpha-bromochalcones under visible light photoredox catalyzed conditions were trapped by chalcones. The subsequent intramolecular cyclization of the resulting benzylic radicals led to the synthesis of dihydronaphthalenes, which were conveniently oxidized to the corresponding naphthalenes. The strategy was adopted successfully for synthesizing derivatives of urundeuvine chalcones, which are otherwise accessible only from natural sources. PMID- 30246854 TI - Suzuki-Miyaura coupling of unstrained ketones via chelation-assisted C-C bond cleavage. AB - Herein, we report that unstrained ketones can be efficiently employed as electrophiles in Suzuki-Miyaura reactions via catalytic activation of unstrained C-C bonds assist by an N-containing directing group. A wide range of aromatic ketones directly coupled with boronic ester with excellent functional group tolerance. This strategy provides an alternative and versatile approach to constructing biaryls from unstrained ketones. PMID- 30246855 TI - Activation of the hypervalent fluoroiodane reagent by hydrogen bonding to hexafluoroisopropanol. AB - Hexafluoroisopropan-2-ol (HFIP) is an excellent solvent for promoting fluorinations with the hypervalent fluoroiodane reagent 1 and crucially, it removes the need for transition metals or TREAT-HF activators. The fluoroiodane reagent 1 was used in HFIP to monofluorinate 1,3-ketoesters and to fluorocyclise unsaturated carboxylic acids in excellent yields under mild reaction conditions. PMID- 30246857 TI - Adsorption on alumina nanopores with conical shape. AB - Adsorption on porous solids depends on the morphology of the pores, the cylindrical one being the most studied in the literature. In this work, we present the first experimental investigation of adsorption and evaporation on conical nanopores produced by anodization of aluminium oxide. The pores are about 50 MUm long, with the wide ends having a diameter of ~79 nm and the narrow ones of ~30 nm. Three different pores configurations are considered: open at both ends, open only at the narrow end and open only at the wide end. Despite the very small value of the conical angle alpha, estimated to be ~0.06 degrees , just barely above alpha = 0 degrees corresponding to a cylindrical pore, the adsorption isotherms look strikingly different from those measured on cylindrical pores of similar size. First of all, the hysteresis loops of the conical pores with two open ends and with open wide ends practically coincide. Furthermore, they are narrower and the adsorption and evaporation branches are broader than those of the cylindrical pores with similar size. Finally, conical pores with open narrow ends exhibit a large hysteresis indicative of pore blocking. To unravel the mechanisms underlying adsorption and evaporation in such conical pores, we also report complementary results obtained using on-lattice grand canonical Monte Carlo simulations. PMID- 30246856 TI - Synthesis of near-infrared fluorescent rhodamines via an SNArH reaction and their biological applications. AB - Near-infrared (NIR) dyes are of great interest in biomedicine due to diminished interfering absorption and fluorescence from biological samples, reduced scattering, and enhanced tissue penetration depth. In this context, we report the synthesis of rectilinearly pi-extended rhodamine dyes using a unique intramolecular nucleophilic substitution of aromatic hydrogen (SNArH) strategy. The strategy makes use of an SNArH reaction between a preorganized aromatic amino nitrogen and an electron-deficient carbon in the xanthylium ion. The SNArH reaction presented herein can be performed under mild conditions without a transition metal catalyst and can be expected to enable the preparation of a wide variety of pi-extended near-infrared fluorescent rhodamine dyes. Using this strategy, seven rectilinearly pi-extended rhodamines (RE1-RE7) that had fluorescence emission wavelengths in the near-infrared region were synthesized. RE1, RE3, and RE4 were lysosome targetable and showed good photostabilities. In addition, using dye RE1 as a precursor, we constructed a novel NIR fluorescent turn-on probe (RE1-Cu), which can be used for detecting Cu2+ in living cells, demonstrating the value of our NIR functional fluorescent dyes. PMID- 30246858 TI - Clinical significance and EZH2, ERG and SPINK1 protein expression in pure and mixed ductal adenocarcinoma of the prostate. AB - BACKGROUND: Although ERG and SPINK1 molecular alterations have been studied in acinar and ductal adenocarcinoma of the prostate, EZH2 expression has not been previously evaluated in ductal adenocarcinoma. METHODS: We collected cases of pure and mixed ductal adenocarcinoma of the prostate and evaluated clinical significance and EZH2, ERG, and SPINK1 protein expression. RESULTS: We investigated 61 ductal adenocarcinomas, 22 pure and 39 mixed ductal/acinar. Except for tumor growth pattern, none of the clinical parameters studied significantly differed between pure and mixed tumors. Thirty-five percent of ductal adenocarcinomas were organ confined, 15% displayed seminal vesicle invasion. Lymph node and distal metastasis occurred in 13% and 24% of cases, respectively; 34% of patients experienced biochemical failure, 7% died of disease. Ninety-eight percent of tumors expressed EZH2; in 80% of cases >50% of tumor cells were positive. ERG and SPINK1 were expressed in 20% and 36% of cases, respectively. There was no difference in protein expression between pure and mixed ductal adenocarcinomas. ERG expression tended to be lower, and SPINK1 higher than reported for acinar tumors. Biochemical failure, metastasis and death did not differ between EZH2, ERG, and SPINK1 positive and negative patients, nor between <50% versus >50% expression of SPINK1 and EZH2, respectively. CONCLUSIONS: Pure and mixed ductal adenocarcinomas have similar clinical behavior and molecular alterations. Higher EZH2 and SPINK1 protein expression, compared to acinar prostatic adenocarcinoma, might account for the more aggressive clinical course of ductal adenocarcinoma. PMID- 30246859 TI - DYNC1H1 gene methylation correlates with severity of spinal muscular atrophy. AB - Methylation profiles of CpG islands within the SLC23A2, CDK2AP1, and DYNC1H1 genes and their association with spinal muscular atrophy (SMA) severity were studied. High clinical heterogeneity of SMA suggests the existence of different factors modifying SMA phenotype with gene methylation as a plausible one. The genes picked up in our earlier genome-wide methylation studies of SMA patients demonstrated obvious differences in their methylation patterns, thus suggesting the likely involvement of their protein products in SMA development. Significantly decreased methylation of CpG islands within exon 37 of the DYNC1H1 gene was observed in patients with a severe SMA manifestation (type I) compared to mildly affected SMA patients (types III-IV). This finding provides new information on peculiarities of methylation in clinically different types of SMA patients and gives a clue for identification of new SMA modifiers. PMID- 30246860 TI - Association between sense of coherence and untreated dental caries in preschoolers: a cross-sectional study. AB - OBJECTIVE: The aim of the present study was to evaluate factors associated with the clinical consequences of untreated dental caries in children attending public and private preschools. METHODS: A cross-sectional study was conducted with a complex, preschool-based sample of 769 children, 5 years of age, from public and private preschools in the city of Campina Grande, Brazil. Clinical examinations to diagnose the consequences of untreated caries were performed using the criteria of the pufa index (p - pulp exposure; u - ulceration caused by movement of tooth fragments; f - fistula; a - abscess). The psychological factor evaluated was parental/caregiver sense of coherence (SOC), which was determined using a validated assessment tool. Sociodemographic characteristics and the use of dental services were also considered. Two examiners were trained to examine the clinical consequences of untreated dental caries. The kappa statistic demonstrated a high level of agreement for the conditions evaluated. Descriptive analysis was performed, followed by the use of an inductive decision tree (J48 algorithm; alpha = 5%). RESULTS: The factors associated with the clinical consequences of untreated dental caries were toothache [prevalence ratio (PR) = 12.34; 95% confidence interval (95% CI): 7.87-19.35; P < 0.001], attending a public preschool (PR = 2.38; 95% CI: 1.83-3.09; P < 0.001), parents/caregivers younger than 30 years of age (PR = 1.45; 95% CI: 1.26-1.68; P < 0.001), parents/caregivers with more than two children (PR = 1.47; 95% CI: 1.28-1.69; P < 0.001) and parents/caregivers with a weak SOC (PR = 1.13; 95% CI: 1.01-1.28; P = 0.043). CONCLUSION: The prevalence of clinical consequences of untreated dental caries was low in the present sample and was associated with sociodemographic factors (type of preschool, caregiver's age and number of children in the family) as well as psychological factors (SOC). PMID- 30246861 TI - Risk of Serious Trauma with Glucose-Lowering Drugs in Older Persons: A Nested Case-Control Study. AB - OBJECTIVES: To assess the risk of hospitalization for trauma associated with use of hypoglycemic glucose-lowering drugs (GLDs) in individuals aged 65 and older. DESIGN: Observational, nested, case-control study. SETTING: The Echantillon Generaliste de Beneficiaires claims database, a 1/97th representative sample of the population covered by French healthcare insurance. PARTICIPANTS: All persons with a first hospitalization for trauma between 2009 and 2015 were considered as potential cases. They were selected if they had been followed for 365 days or longer at index date, were aged 65 and older, and had no diagnosed cancer. Cases (n=10,743) were matched with up to 10 randomly selected controls on age, sex, and length of follow-up (n=106,629). MEASUREMENTS: GLD exposure was considered globally and according to use of hypoglycemic GLDs alone, nonhypoglycemic GLDs alone, or both types of GLDs. Risk of hospitalization for trauma was estimated using hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Risk of hospitalization for trauma was significantly higher with use of GLDs (HR=1.15, 95% CI=1.08-1.22). Greater risk was found only in individuals treated with hypoglycemic GLDs alone (HR=1.26, 95% CI=1.15-1.38), particularly insulin (HR=1.49, 95% CI=1.32-1.68) and glinides (HR=1.34, 95% CI=1.12-1.61). CONCLUSION: This study highlights the excess risk of serious trauma with the use of insulin and glinides. J Am Geriatr Soc 66:2086-2091, 2018. PMID- 30246862 TI - Multimorbidity Burden and Adverse Outcomes in a Community-Based Cohort of Adults with Heart Failure. AB - OBJECTIVES: To assess multimorbidity burden and its association with clinical outcomes in adults with heart failure (HF) according to sex, age, and HF type. DESIGN: Retrospective cohort study. SETTING: Five healthcare delivery systems across the United States. PARTICIPANTS: Adults with HF (N=114,553). MEASUREMENTS: We characterized participants with respect to the presence of 26 chronic conditions categorized into quartiles based on overall burden of comorbidity (<5, 5-6, 7-8, >=9). Outcomes included all-cause death and hospitalization for HF or any cause. Multivariable Cox regression was used to evaluate the adjusted association between categorized burden of multimorbidity burden and outcomes. RESULTS: Individuals with more morbidities were more likely to die than those with fewer then 5 morbidities (5-6 morbidities: adjusted hazard ratio (aHR)=1.27 (95% confidence interval (CI)=1.24-1.31; 7-8 morbidities: aHR=1.52, 95% CI=1.48 1.57; >=9 morbidities: aHR=1.92, 95% CI=1.86-1.99). There was a graded, higher adjusted rate of any-cause hospitalization associated with 5 or 6 (aHR=1.28, 95% CI=1.25-1.30), 7 or 8 (aHR=1.47, 95% CI=1.44-1.50), or 9 or more (aHR=1.77, 95% CI=1.73-1.82) morbidities (vs <5). Similar findings were observed for HF-specific hospitalization in those with 5 or 6 (aHR=1.22, 95% CI=1.19-1.26), 7 or 8 (aHR=1.39, 95% CI=1.34-1.44), or 9 or more (aHR 1.68, 95% CI=1.61-1.74) morbidities (vs <5). Consistent findings were seen according to sex, age group, and HF type (preserved, reduced, borderline HF), in the association between categorical burden of multimorbidity and outcomes especially prominent in individuals younger than 65. CONCLUSION: After adjustment, higher levels of multimorbidity predicted worse HF outcomes and may be an important consideration in strategies to improve clinical and person-centered outcomes. PMID- 30246863 TI - Procedural Framework to Facilitate Hospital-Based Informed Consent for Dementia Research. AB - Improving quality and delivery of care for people with Alzheimer disease and related dementias (ADRD) requires a comprehensive research agenda that encompasses the entire care continuum. Logistical and ethical challenges of informed consent for research participation of persons with ADRD include determination of capacity to consent, surrogate consent when capacity to consent is compromised, timely identification of the legally authorized representative (LAR) providing surrogate consent, and balancing residual autonomy with surrogate consent. Short stays; limited access to patients, caregivers, and LARs; and fluctuating influences of acute illness on capacity determination compound these challenges in the acute care setting. To address these challenges, we worked with the University of Wisconsin Health Sciences Institutional Review Board to develop a procedural framework for obtaining informed consent from hospitalized individuals with ADRD and their caregivers to participate in a minimal risk care intervention. The framework is specially designed for minimal risk situations in which rapid enrollment is a necessity and uses rapid identification of surrogates to consent for patients who lack legal capacity to make medical decisions, indicated by an activated healthcare power of attorney, and individualized formal assent procedures for patients who lack capacity to consent. These methods were proven effective in facilitating hospital-based recruitment in an ongoing randomized controlled trial and provide a basis for increasing access to acute care clinical research for persons with ADRD. Bolstering research participation through more easily used consent procedures during acute illness is critical to fostering improvements in the delivery of high-quality care to persons with ADRD. PMID- 30246865 TI - Infectious skin disorders encountered in a pediatric emergency department of a tertiary care hospital in Argentina: a descriptive study. AB - BACKGROUND: Infectious skin disorders (ISDs) are commonly seen in pediatric emergency departments (PED), however the exact frequency is unknown. We provide an accurate evaluation of the incidence and characteristics of ISDs diagnosed in a PED from Buenos Aires, Argentina, over a 1-year period. METHODS: Prospectively, descriptive study of children evaluated in the PED with ISDs during 2016. ISDs were analyzed on the basis of their incidence, patient demographics, seasonal variations, and hospitalization rates. RESULTS: ISDs were diagnosed in 1680 (67.9%) of the skin consultations (M/F: 1.1; mean age: 4.4 +/- 3.7 years). Bacterial infections were observed in 932 (55.5%) cases. Viral infections were seen in 604 patients (35.9%). Fungal and parasite skin infections were diagnosed in 33 (2%) and 111 (6.6%) children, respectively. The most frequent ISDs according to the etiology group were impetigo 377 (22.4%), varicella 397 (23.6%), tinea capitis 10 (0.6%), and scabies 109 (6.5%). A higher frequency of ISDs were reported during the summer (38.4%) and spring (38.2%) months. Bacterial skin infections were more frequent during the summer months, while viral skin infections were more prevalent during spring. Parasitic skin infections were diagnosed more frequently during the winter months. No differences were seen for mycotic skin infections. Hospitalization rate was 1% (all for bacterial skin infections). CONCLUSION: Our data reveal the extremely high frequency of ISDs seen at the PED, underlying the need for closer cooperation between dermatologists and pediatricians. PMID- 30246864 TI - Risk of CIN3 or worse with persistence of 13 individual oncogenic HPV types. AB - Human papillomavirus (HPV) is essential in cervical carcinogenesis, however, less is known about the carcinogenic potential of individual HPV types. Our aim was to examine the risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) after persistence of 13 individual oncogenic HPV types. Liquid-based cervical samples (n=40399) collected in 2002-2005 were tested for HPV by hybrid capture 2 and genotyped with INNO-LiPAv2. Persistence was defined as having the same genotype twice 1-4.5 years apart. The absolute risk of CIN3+ was estimated by the Aalen-Johansen estimator and Cox proportional hazard regression was used to compare the rates of CIN3+ according to HPV type adjusting for age and time between HPV tests. Of 2875 oncogenic HPV-positive women, 874 had persistence of one or more types, and 761 persisted for one oncogenic HPV type only. Persistent HPV16 infection was associated with the highest risk of CIN3+, with an 8-year absolute risk of 55% (95% CI: 45%-66%), followed by HPV33 (33% (95% CI: 20% 50%)), HPV18 (32% (95% CI: 20%-48%)), and HPV31 (31% (95% CI: 21%-46%)). Other HPV types, including HPV52 and HPV45, were also associated with high risks. Persistent HPV56 had the lowest 8-year absolute risk of CIN3+ (3% (95% CI: 0.4% 20%)). In Cox analyses, a similar pattern remained after adjustment for age and time between tests. Our results add knowledge about the varying carcinogenic potential of individual persistent oncogenic HPV types, which may have implications for the clinical use of HPV testing. This article is protected by copyright. All rights reserved. PMID- 30246866 TI - Abeta and the dementia syndrome: Simple versus complex perspectives. AB - BACKGROUND: The amyloid cascade hypothesis (ACH) has dominated strategy in dementia research for decades despite evidence of its limitations including known heterogeneity of the dementia syndrome in the population and the narrow focus on a single molecule - the amyloid beta protein (Abeta) as causal for all Alzheimer type dementia. Other hypotheses relevant to Abeta are the presenilin (PS) hypothesis (PSH) relating to the involvement of PS in the generation of Abeta, and the amyloid precursor protein (APP) matrix approach (AMA), relating to the complex and dynamic breakdown of APP, from which Abeta derives. MATERIALS AND METHODS: In this article we explore perspectives relating to complex disorders occurring mainly in older populations through a detailed case study of the role of Abeta in AD. RESULTS: Scrutiny of the evidence generated so far reveals and a lack of understanding of the wider APP proteolytic system and how narrow research into the dementia syndrome has been to date. Confounding factors add significant limitations to the understanding of the current evidence base. CONCLUSIONS: A better characterisation of the entire APP proteolytic system in the human brain is urgently required to place Abeta in its complex physiological context. From a molecular perspective, a combination of the alternative hypotheses, the PSH and the AMA may better describe the complexity of the APP proteolytic system leading to new therapeutic approaches. The reductionist approach is widespread throughout biomedical research and this example highlights how neglect of complexity can undermine investigations of complex disorders, particularly those arising in the oldest in our populations. PMID- 30246868 TI - Blood immune cell biomarkers in lung cancer. AB - Characterization of host immune cell parameters prior to treatment is expected to identify biomarkers predictive of clinical outcome as well as to elucidate why some patients fail to respond to immunotherapy. We monitored blood immune cells from 58 patients with non-small- cell lung cancer (NSCLC) undergoing surgery of the primary tumor and from 50 age-matched healthy volunteers. Complete leukocyte blood count, the number of circulating dendritic cells (DC), HLA-DRlow monocytes and several lymphocytic subpopulations were determined by eight-color flow cytometry. Furthermore, the prognostic value of the immune cell parameters investigated was evaluated by patients' survival analysis. Compared to the control group, blood of NSCLC patients contained more neutrophils resulting in a higher neutrophil-to-lymphocyte ratio (NLR), but a lower number of blood DC, in particular of plasmacytoid DC (pDC), natural killer (NK) cells and naive CD4+ and CD8+ T cells. Furthermore, a higher frequency of CD4+ regulatory T cells (Treg) and HLA-DRlow monocytes was detected, and smoking had a significant impact on these values. HLA-DRlow monocytes were positively correlated to the number of neutrophils, monocytes and NLR, but negatively associated with the number of pDC and naive CD4+ T cells. The frequency of Treg, HLA-DRlow monocytes and naive CD4+ and CD8+ T cells as well as the ratios of CD4/HLA-DRlow monocytes and HLA-DRlow monocytes/pDC correlated with patient's overall survival. Next to Treg, HLA-DRlow monocytes and naive T cells represent prognostic markers for NSCLC patients and might be useful for monitoring of patients' responses to immunotherapies in future studies. PMID- 30246869 TI - Analysis of the cancer genome atlas data to determine the correlation between PROX1 and TERT in hepatocellular carcinoma. PMID- 30246870 TI - Short-term change and prediction of suicidal ideation among adolescents: a daily diary study following psychiatric hospitalization. AB - BACKGROUND: Our understanding of suicidal ideation (SI) and its risk precursors is largely informed by studies spanning over wide time intervals (weeks, months, years). Little is known about SI as it occurs in daily lives of individuals at risk for suicide, the extent to which suicidal thoughts are dynamic over short periods of time, and the degree to which theoretically informed risk factors predict near-term SI. METHODS: Thirty-four adolescents hospitalized due to last month suicide attempt and/or last-week SI (76% female; ages 13-17) responded to daily surveys sent to their cell phones for four consecutive weeks after discharge (n = 652 observations). RESULTS: There was notable variability in day to-day SI, with half of ideation ratings changing at least one within-person standard deviation from one day to the next. Results of mixed effects models revealed concurrent (same-day), but not short-term prospective (next-day), associations between SI (frequency, duration, urge) and well-established predictors (connectedness, burdensomeness, hopelessness). However, synergistic effects of low connectedness with either high burdensomeness or high hopelessness were reliably associated with more severe same- and next-day suicidal ideation. CONCLUSIONS: This study adds to emerging literature indicating that suicidal thoughts fluctuate considerably among individuals at risk for suicide, further extending it by focusing on adolescents in the critical posthospitalization period. Fostering high-risk adolescents' sense of connectedness to others may be an especially promising intervention target. Frequent assessment of SI and its predictors, independently and in combination, could help identify promising predictors of short-term risk and meaningful intervention targets in high-risk teens. PMID- 30246867 TI - Differential response of pineal microglia to surgical versus pharmacological stimuli. AB - Microglial cells are one of the interstitial elements of the pineal gland (PG). We recently reported the pattern of microglia colonization and activation, and microglia-Pax6+ cell interactions during normal pineal ontogeny. Here, we describe the dynamics of microglia-Pax6+ cell associations and interactions after surgical or pharmacological manipulation. In adult rats, the superior cervical ganglia (SCG) were exposed, and either bilaterally excised (SCGx) or decentralized (SCGd). In the SCGx PGs, the density of Iba1+ microglia increased after surgery and returned to sham baseline levels 13 days later. Pineal microglia also responded to SCGd, a more subtle denervation. The number of clustered Iba1+ /PCNA+ /ED1+ microglia was higher 4 days after both surgeries compared to the sham-operated group. However, the number of Pax6+ /PCNA- cells and the percentage of Pax6+ cells contacted by and/or phagocytosed by microglia increased significantly only after SCGx. Separate groups of rats were treated with either bacterial lipopolysaccharides (LPS) or doxycycline (DOX) to activate or inhibit pineal microglia, respectively. Peripheral LPS administration caused an increase in the number of clustered Iba1+ /PCNA+ /ED1+ microglial cells, and in the percentage of Pax6+ cells associated with and/or engulfed by microglia. In the LPS-treated PGs, we also noted an increase in the number of PCNA+ cells that were Iba1- within the microglial cell clusters. The density of Pax6+ cells did not change after LPS treatment. DOX administration did not influence the parameters analyzed. These data suggest that pineal microglia are highly receptive cells capable of rapidly responding in a differential manner to surgical and pharmacological stimuli. PMID- 30246871 TI - Tachycardia detected by an ICD with simultaneous activation of the atrium and ventricle-What is the mechanism? PMID- 30246872 TI - A case report of fixed drug eruption caused by several drugs because of cross reactivity and co-sensitization. PMID- 30246873 TI - A first case of hepatocellular carcinoma in the baboon (Papio spp.) placenta. AB - We present a case of hepatocellular carcinoma (HCC) in the placenta of healthy baboon (Papio spp.). Grossly, the fetal, maternal, and placental tissues were unremarkable. Histologically, the placenta contained an unencapsulated, poorly demarcated, infiltrative, solidly cellular neoplasm composed of cells that resembled hepatocytes. The neoplastic cells were diffusely positive for vimentin and focally positive for Ae1/Ae3, Arginase -1, glutamine synthetase, and CD10, and negative for ER, vascular markers (CD31 and D240), S100, glypican, C-reactive protein, FABP, desmin, and beta-catenin; INI1 positivity was similar to non neoplastic tissues. The case likely represents a unique subtype of HCC. PMID- 30246874 TI - Vitamin D for the management of multiple sclerosis. AB - BACKGROUND: This review is an update of a previously published review, "Vitamin D for the management of multiple sclerosis" (published in the Cochrane Library; 2010, Issue 12). Multiple sclerosis (MS) is characterised by inflammation, demyelination, axonal or neuronal loss, and astrocytic gliosis in the central nervous system (CNS), which can result in varying levels of disability. Some studies have provided evidence showing an association of MS with low levels of vitamin D and benefit derived from its supplementation. OBJECTIVES: To evaluate the benefit and safety of vitamin D supplementation for reducing disease activity in people with MS. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Specialized Register up to 2 October 2017 through contact with the Information Specialist with search terms relevant to this review. We included references identified from comprehensive electronic database searches and from handsearches of relevant journals and abstract books from conferences. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared vitamin D versus placebo, routine care, or low doses of vitamin D in patients with MS. Vitamin D was administered as monotherapy or in combination with calcium. Concomitant interventions were allowed if they were used equally in all trial intervention groups. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the methodological quality of studies, while another review author sorted any disagreements. We expressed treatment effects as mean differences (MDs) for continuous outcomes (Expanded Disability Status Scale and number of magnetic resonance imaging (MRI) gadolinium-enhancing T1 lesions), as standardised MDs for health-related quality of life, as rate differences for annualised relapse rates, and as risk differences (RDs) for serious adverse events and minor adverse events, together with 95% confidence intervals (CIs). MAIN RESULTS: We identified 12 RCTs enrolling 933 participants with MS; 464 were randomised to the vitamin D group, and 469 to the comparator group. Eleven trials tested vitamin D3, and one trial tested vitamin D2. Vitamin D3 had no effect on the annualised relapse rate at 52 weeks' follow-up (rate difference -0.05, 95% CI -0.17 to 0.07; I2 = 38%; five trials; 417 participants; very low-quality evidence according to the GRADE instrument); on the Expanded Disability Status Scale at 52 weeks' follow-up (MD 0.25, 95% CI -0.61 to 0.10; I2 = 35%; five trials; 221 participants; very low quality evidence according to GRADE); and on MRI gadolinium-enhancing T1 lesions at 52 weeks' follow-up (MD 0.02, 95% CI -0.45 to 0.48; I2 = 12%; two trials; 256 participants; very low-quality evidence according to GRADE). Vitamin D3 did not increase the risk of serious adverse effects within a range of 26 to 52 weeks' follow-up (RD 0.01, 95% CI -0.03 to 0.04; I2 = 35%; eight trials; 621 participants; low-quality evidence according to GRADE) or minor adverse effects within a range of 26 to 96 weeks' follow-up (RD 0.02, 95% CI -0.02 to 0.06; I2 = 20%; eight trials; 701 participants; low-quality evidence according to GRADE). Three studies reported health-related quality of life (HRQOL) using different HRQOL scales. One study reported that vitamin D improved ratings on the psychological and social components of the HRQOL scale but had no effects on the physical components. The other two studies found no effect of vitamin D on HRQOL. Two studies reported fatigue using different scales. One study (158 participants) reported that vitamin D3 reduced fatigue compared with placebo at 26 weeks' follow-up. The other study (71 participants) found no effect on fatigue at 96 weeks' follow-up. Seven studies reported on cytokine levels, four on T-lymphocyte proliferation, and one on matrix metalloproteinase levels, with no consistent pattern of change in these immunological outcomes. The randomised trials included in this review provided no data on time to first treated relapse, number of participants requiring hospitalisation owing to progression of the disease, proportion of participants who remained relapse-free, cognitive function, or psychological symptoms. AUTHORS' CONCLUSIONS: To date, very low-quality evidence suggests no benefit of vitamin D for patient-important outcomes among people with MS. Vitamin D appears to have no effect on recurrence of relapse, worsening of disability measured by the Expanded Disability Status Scale (EDSS), and MRI lesions. Effects on health-related quality of life and fatigue are unclear. Vitamin D3 at the doses and treatment durations used in the included trials appears to be safe, although available data are limited. Seven ongoing studies will likely provide further evidence that can be included in a future update of this review. PMID- 30246875 TI - Antibiotics for treating scrub typhus. AB - BACKGROUND: Scrub typhus, an important cause of acute fever in Asia, is caused by Orientia tsutsugamushi, an obligate intracellular bacterium. Antibiotics currently used to treat scrub typhus include tetracyclines, chloramphenicol, macrolides, and rifampicin. OBJECTIVES: To assess and compare the effects of different antibiotic regimens for treatment of scrub typhus. SEARCH METHODS: We searched the following databases up to 8 January 2018: the Cochrane Infectious Diseases Group specialized trials register; CENTRAL, in the Cochrane Library (2018, Issue 1); MEDLINE; Embase; LILACS; and the metaRegister of Controlled Trials (mRCT). We checked references and contacted study authors for additional data. We applied no language or date restrictions. SELECTION CRITERIA: Randomized controlled trials (RCTs) or quasi-RCTs comparing antibiotic regimens in people with the diagnosis of scrub typhus based on clinical symptoms and compatible laboratory tests (excluding the Weil-Felix test). DATA COLLECTION AND ANALYSIS: For this update, two review authors re-extracted all data and assessed the certainty of evidence. We meta-analysed data to calculate risk ratios (RRs) for dichotomous outcomes when appropriate, and elsewhere tabulated data to facilitate narrative analysis. MAIN RESULTS: We included six RCTs and one quasi-RCT with 548 participants; they took place in the Asia-Pacific region: Korea (three trials), Malaysia (one trial), and Thailand (three trials). Only one trial included children younger than 15 years (N = 57). We judged five trials to be at high risk of performance and detection bias owing to inadequate blinding. Trials were heterogenous in terms of dosing of interventions and outcome measures. Across trials, treatment failure rates were low.Two trials compared doxycycline to tetracycline. For treatment failure, the difference between doxycycline and tetracycline is uncertain (very low-certainty evidence). Doxycycline compared to tetracycline may make little or no difference in resolution of fever within 48 hours (risk ratio (RR) 1.14, 95% confidence interval (CI) 0.90 to 1.44, 55 participants; one trial; low-certainty evidence) and in time to defervescence (116 participants; one trial; low-certainty evidence). We were unable to extract data for other outcomes.Three trials compared doxycycline versus macrolides. For most outcomes, including treatment failure, resolution of fever within 48 hours, time to defervescence, and serious adverse events, we are uncertain whether study results show a difference between doxycycline and macrolides (very low-certainty evidence). Macrolides compared to doxycycline may make little or no difference in the proportion of patients with resolution of fever within five days (RR 1.05, 95% CI 0.99 to 1.10; 185 participants; two trials; low-certainty evidence). Another trial compared azithromycin versus doxycycline or chloramphenicol in children, but we were not able to disaggregate date for the doxycycline/chloramphenicol group.One trial compared doxycycline versus rifampicin. For all outcomes, we are uncertain whether study results show a difference between doxycycline and rifampicin (very low-certainty evidence). Of note, this trial deviated from the protocol after three out of eight patients who had received doxycycline and rifampicin combination therapy experienced treatment failure.Across trials, mild gastrointestinal side effects appeared to be more common with doxycycline than with comparator drugs. AUTHORS' CONCLUSIONS: Tetracycline, doxycycline, azithromycin, and rifampicin are effective treatment options for scrub typhus and have resulted in few treatment failures. Chloramphenicol also remains a treatment option, but we could not include this among direct comparisons in this review.Most available evidence is of low or very low certainty. For specific outcomes, some low-certainty evidence suggests there may be little or no difference between tetracycline, doxycycline, and azithromycin as treatment options. Given very low-certainty evidence for rifampicin and the risk of inducing resistance in undiagnosed tuberculosis, clinicians should not regard this as a first-line treatment option. Clinicians could consider rifampicin as a second-line treatment option after exclusion of active tuberculosis.Further research should consist of additional adequately powered trials of doxycycline versus azithromycin or other macrolides, trials of other candidate antibiotics including rifampicin, and trials of treatments for severe scrub typhus. Researchers should standardize diagnostic techniques and reporting of clinical outcomes to allow robust comparisons. PMID- 30246876 TI - Olanzapine for the prevention and treatment of cancer-related nausea and vomiting in adults. AB - BACKGROUND: Olanzapine as an antiemetic represents a new use of an antipsychotic drug. People with cancer may experience nausea and vomiting whilst receiving chemotherapy or radiotherapy, or whilst in the palliative phase of illness. OBJECTIVES: To assess the efficacy and safety of olanzapine when used as an antiemetic in the prevention and treatment of nausea and vomiting related to cancer in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase for published data on 20th September 2017, as well as ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform for unpublished trials. We checked reference lists, and contacted experts in the field and study authors. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of olanzapine versus any comparator with or without adjunct therapies for the prevention or treatment, or both, of nausea or vomiting in people with cancer aged 18 years or older, in any setting, of any duration, with at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. We used GRADE to assess quality of evidence for each main outcome. We extracted data for absence of nausea or vomiting and frequency of serious adverse events as primary outcomes. We extracted data for patient perception of treatment, other adverse events, somnolence and fatigue, attrition, nausea or vomiting severity, breakthrough nausea and vomiting, rescue antiemetic use, and nausea and vomiting as secondary outcomes at specified time points. MAIN RESULTS: We included 14 RCTs (1917 participants) from high-, middle- and low-income countries, representing over 24 different cancers. Thirteen studies were in chemotherapy-induced nausea and vomiting. Oral olanzapine was administered during highly emetogenic (HEC) or moderately emetogenic (MEC) chemotherapy (12 studies); chemoradiotherapy (one study); or palliation (one study). Eight studies await classification and 13 are ongoing.The main comparison was olanzapine versus placebo/no treatment. Other comparisons were olanzapine versus NK1 antagonist, prokinetic, 5-HT3 antagonist or dexamethasone.We assessed all but one study as having one or more domains that were at high risk of bias. Eight RCTs with fewer than 50 participants per treatment arm, and 10 RCTs with issues related to blinding, were at high risk of bias. We downgraded GRADE assessments due to imprecision, inconsistency and study limitations.Olanzapine versus placebo/no treatmentPrimary outcomesOlanzapine probably doubles the likelihood of no nausea or vomiting during chemotherapy from 25% to 50% (risk ratio (RR) 1.98, 95% confidence interval (CI) 1.59 to 2.47; 561 participants; 3 studies; solid tumours; HEC or MEC therapy; moderate-quality evidence) when added to standard therapy. Number needed to treat for additional beneficial outcome (NNTB) was 5 (95% CI 3.3 - 6.6).It is uncertain if olanzapine increases the risk of serious adverse events (absolute risk difference 0.7% more, 95% CI 0.2 to 5.2) (RR 2.46, 95% CI 0.48 to 12.55; 7 studies, 889 participants, low-quality evidence).Secondary outcomesFour studies reported patient perception of treatment. One study (48 participants) reported no difference in patient preference. Four reported quality of life but data were insufficient for meta analysis.Olanzapine may increase other adverse events (RR 1.71, 95% CI 0.99 to 2.96; 332 participants; 4 studies; low-quality evidence) and probably increases somnolence and fatigue compared to no treatment or placebo (RR 2.33, 95% CI 1.30 to 4.18; anticipated absolute risk 8.2% more, 95% CI 1.9 to 18.8; 464 participants; 5 studies; moderate-quality evidence). Olanzapine probably does not affect all-cause attrition (RR 0.99, 95% CI 0.57 to 1.73; 943 participants; 8 studies; I2 = 0%). We are uncertain if olanzapine increases attrition due to adverse events (RR 3.00, 95% CI 0.13 to 70.16; 422 participants; 6 studies). No participants withdrew due to lack of efficacy.We are uncertain if olanzapine reduces breakthrough nausea and vomiting (RR 0.38, 95% CI 0.10 to 1.47; 501 participants; 2 studies; I2 = 54%) compared to placebo or no treatment. No studies reported 50% reduction in severity of nausea or vomiting, use of rescue antiemetics, or attrition.We are uncertain of olanzapine's efficacy in reducing acute nausea or vomiting. Olanzapine probably reduces delayed nausea (RR 1.71, 95% CI 1.40 to 2.09; 585 participants; 3 studies) and vomiting (RR 1.28, 95% CI 1.14 to 1.42; 702 participants; 5 studies).Subgroup analysis: 5 mg versus 10 mgPlanned subgroup analyses found that it is unclear if 5 mg is as effective an antiemetic as 10 mg. There is insufficient evidence to exclude the possibility that 5 mg may confer a lower risk of somnolence and fatigue than 10 mg.Other comparisonsOne study (20 participants) compared olanzapine versus NK1 antagonists. We observed no difference in any reported outcomes.One study (112 participants) compared olanzapine versus a prokinetic (metoclopramide), reporting that olanzapine may increase freedom from overall nausea (RR 2.95, 95% CI 1.73 to 5.02) and overall vomiting (RR 3.03, 95% CI 1.78 to 5.14).One study (62 participants) examined olanzapine versus 5-HT3 antagonists, reporting olanzapine may increase the likelihood of 50% or greater reduction in nausea or vomiting at 48 hours (RR 1.82, 95% CI 1.11 to 2.97) and 24 hours (RR 1.36, 95% CI 0.80 to 2.34).One study (229 participants) compared olanzapine versus dexamethasone, reporting that olanzapine may reduce overall nausea (RR 1.73, 95% CI 1.37 to 2.18), overall vomiting (RR 1.27, 95% CI 1.10 to 1.48), delayed nausea (RR 1.66, 95% CI 1.33 to 2.08) and delayed vomiting (RR 1.25, 95% CI 1.07 to 1.45). AUTHORS' CONCLUSIONS: There is moderate-quality evidence that oral olanzapine probably increases the likelihood of not being nauseous or vomiting during chemotherapy from 25% to 50% in adults with solid tumours, in addition to standard therapy, compared to placebo or no treatment. There is uncertainty whether it increases serious adverse events. It may increase the likelihood of other adverse events, probably increasing somnolence and fatigue. There is uncertainty about relative benefits and harms of 5 mg versus 10 mg.We identified only RCTs describing oral administration. The findings of this review cannot be extrapolated to provide evidence about the efficacy and safety of any injectable form (intravenous, intramuscular or subcutaneous) of olanzapine. PMID- 30246877 TI - Intramuscular versus intravenous prophylactic oxytocin for the third stage of labour. AB - BACKGROUND: There is general agreement that oxytocin given either through the intramuscular or intravenous route is effective in reducing postpartum blood loss. However, it is unclear whether the subtle differences between the mode of action of these routes have any effect on maternal and infant outcomes. This is an update of a review first published in 2012. OBJECTIVES: To determine the comparative effectiveness and safety of oxytocin administered intramuscularly or intravenously for prophylactic management of the third stage of labour after vaginal birth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (7 September 2017) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials comparing intramuscular with intravenous oxytocin for prophylactic management of the third stage of labour after vaginal birth. We excluded quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Three studies with 1306 women are included in the review and compared intramuscular versus intravenous oxytocin administered just after the birth of the anterior shoulder or soon after the birth of the baby. Studies were carried out in hospital settings in Turkey and Thailand and recruited women with singleton, term pregnancies. Overall, the included studies were at moderate risk of bias: none of the studies provided clear information on allocation concealment or attempted to blind staff or women. For GRADE outcomes the quality of the evidence was very low, with downgrading due to study design limitations and imprecision of effect estimates.Only one study reported severe postpartum haemorrhage (blood loss 1000 mL or more) and showed no clear difference between the intramuscular and intravenous oxytocin groups (risk ratio (RR) 0.11, 95% confidence interval (CI) 0.01 to 2.04; 256 women; very low-quality evidence). No woman required hysterectomy in either group in one study (no estimable data, very low-quality evidence), and in another study one woman in each group received a blood transfusion (RR 1.00, 95% CI 0.06 to 15.82; 256 women; very low-quality evidence). Other important outcomes (maternal death, hypotension, maternal dissatisfaction with the intervention and neonatal jaundice) were not reported by any of the included studies. There were no clear differences between groups for other prespecified secondary outcomes reported (postpartum haemorrhage 500 mL or more, use of additional uterotonics, retained placenta or manual removal of the placenta). AUTHORS' CONCLUSIONS: Very low-quality evidence indicates no clear difference between the comparative benefits and risks of intramuscular and intravenous oxytocin when given to prevent excessive blood loss after vaginal birth. Appropriately designed randomised trials with adequate sample sizes are needed to assess whether the route of prophylactic oxytocin after vaginal birth affects maternal or infant outcomes. Such studies could be large enough to detect clinically important differences in major side effects that have been reported in observational studies and should also consider the acceptability of the intervention to mothers and providers as important outcomes. PMID- 30246879 TI - On-line electroextraction in capillary electrophoresis: Application on the determination of glutamic acid in soy sauces. AB - We present an on-line, single step coupling between liquid-liquid extraction and capillary electrophoresis with capacitively coupled contactless conductivity detection, which allows an efficient analysis of complex food matrices with high sodium content. The sodium depletion was demonstrated using an aqueous two-phase system. The aqueous two-phase system enables the electrically driven extraction of the target compounds. The sample was prepared in Dextran-rich phase (8% w/v 500 kDa Dextran, DEX). The background electrolyte (acetic acid 5.0 mol/L) contained 6% w/v of 6 kDa PEG. As proof of applicability, we employed the developed method for glutamic acid quantification on soy sauces. The peak area of glutamic acid presents no significant difference (alpha = 0.05), while the peak area of the sodium presented a reduction of 11.7 +/- 0.2 and 19 +/- 3% for premium and low-cost soy sauce samples analyzed. The glutamic acid concentration for premium soy sauce sample was 2.7 +/- 0.8 and 4.8 +/- 0.4 g/L, and for low cost soy sauce sample, the concentration was 9.9 +/- 0.9 g/L, which agreed with those obtained by other analytical techniques. PMID- 30246880 TI - Does Bowel Preparation Improve the Performance of Rectal Water Contrast Transvaginal Ultrasonography in Diagnosing Rectosigmoid Endometriosis? AB - OBJECTIVES: The primary objective of the study was to compare the performance of the rectal water transvaginal ultrasonography (RWC-TVS) with and without bowel preparation (BP) in diagnosing rectosigmoid endometriosis. The secondary objectives were to compare the performance of the 2 exams in estimating infiltration of the mucosa, length of the largest rectosigmoid nodules, distance of the nodules from the anal verge, and presence of multifocal disease. METHODS: This prospective study included patients with pain symptoms and intestinal complaints suggestive of endometriosis. Patients underwent RWC-TVS with and without BP within an interval of 1 week to 2 months. Two independent and blinded gynecologists performed the exams. The results of the 2 exams were compared with surgical and histologic findings. RESULTS: A total of 155 patients were included in the study; 92 patients had rectosigmoid endometriosis. There was no significant difference in the performance of RWC-TVS with or without BP in diagnosing rectosigmoid endometriosis (P = .727). There was no significant difference in the performance of RWC-TVS with or without BP in diagnosing infiltration of the mucosa (P = .424) and multifocal disease (P = .688), in estimating the main diameter of the largest nodule (P = .644) and the distance between the more distal rectosigmoid nodule and the anal verge (P = .090). The patients similarly tolerated the 2 exams (P = .799). CONCLUSIONS: Bowel preparation does not improve the performance of RWC-TVS in diagnosing rectosigmoid endometriosis and in assessing the characteristics of these nodules. PMID- 30246878 TI - Insulin and glucose-lowering agents for treating people with diabetes and chronic kidney disease. AB - BACKGROUND: Diabetes is the commonest cause of chronic kidney disease (CKD). Both conditions commonly co-exist. Glucometabolic changes and concurrent dialysis in diabetes and CKD make glucose-lowering challenging, increasing the risk of hypoglycaemia. Glucose-lowering agents have been mainly studied in people with near-normal kidney function. It is important to characterise existing knowledge of glucose-lowering agents in CKD to guide treatment. OBJECTIVES: To examine the efficacy and safety of insulin and other pharmacological interventions for lowering glucose levels in people with diabetes and CKD. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 February 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs looking at head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in people with diabetes and CKD (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) were eligible. DATA COLLECTION AND ANALYSIS: Four authors independently assessed study eligibility, risk of bias, and quality of data and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: Forty-four studies (128 records, 13,036 participants) were included. Nine studies compared sodium glucose co-transporter 2 (SGLT2) inhibitors to placebo; 13 studies compared dipeptidyl peptidase-4 (DPP 4) inhibitors to placebo; 2 studies compared glucagon-like peptide-1 (GLP-1) agonists to placebo; 8 studies compared glitazones to no glitazone treatment; 1 study compared glinide to no glinide treatment; and 4 studies compared different types, doses or modes of administration of insulin. In addition, 2 studies compared sitagliptin to glipizide; and 1 study compared each of sitagliptin to insulin, glitazars to pioglitazone, vildagliptin to sitagliptin, linagliptin to voglibose, and albiglutide to sitagliptin. Most studies had a high risk of bias due to funding and attrition bias, and an unclear risk of detection bias.Compared to placebo, SGLT2 inhibitors probably reduce HbA1c (7 studies, 1092 participants: MD -0.29%, -0.38 to -0.19 (-3.2 mmol/mol, -4.2 to -2.2); I2 = 0%), fasting blood glucose (FBG) (5 studies, 855 participants: MD -0.48 mmol/L, -0.78 to -0.19; I2 = 0%), systolic blood pressure (BP) (7 studies, 1198 participants: MD -4.68 mmHg, 6.69 to -2.68; I2 = 40%), diastolic BP (6 studies, 1142 participants: MD -1.72 mmHg, -2.77 to -0.66; I2 = 0%), heart failure (3 studies, 2519 participants: RR 0.59, 0.41 to 0.87; I2 = 0%), and hyperkalaemia (4 studies, 2788 participants: RR 0.58, 0.42 to 0.81; I2 = 0%); but probably increase genital infections (7 studies, 3086 participants: RR 2.50, 1.52 to 4.11; I2 = 0%), and creatinine (4 studies, 848 participants: MD 3.82 MUmol/L, 1.45 to 6.19; I2 = 16%) (all effects of moderate certainty evidence). SGLT2 inhibitors may reduce weight (5 studies, 1029 participants: MD -1.41 kg, -1.8 to -1.02; I2 = 28%) and albuminuria (MD 8.14 mg/mmol creatinine, -14.51 to -1.77; I2 = 11%; low certainty evidence). SGLT2 inhibitors may have little or no effect on the risk of cardiovascular death, hypoglycaemia, acute kidney injury (AKI), and urinary tract infection (low certainty evidence). It is uncertain whether SGLT2 inhibitors have any effect on death, end-stage kidney disease (ESKD), hypovolaemia, fractures, diabetic ketoacidosis, or discontinuation due to adverse effects (very low certainty evidence).Compared to placebo, DPP-4 inhibitors may reduce HbA1c (7 studies, 867 participants: MD -0.62%, -0.85 to -0.39 (-6.8 mmol/mol, -9.3 to -4.3); I2 = 59%) but may have little or no effect on FBG (low certainty evidence). DPP-4 inhibitors probably have little or no effect on cardiovascular death (2 studies, 5897 participants: RR 0.93, 0.77 to 1.11; I2 = 0%) and weight (2 studies, 210 participants: MD 0.16 kg, -0.58 to 0.90; I2 = 29%; moderate certainty evidence). Compared to placebo, DPP-4 inhibitors may have little or no effect on heart failure, upper respiratory tract infections, and liver impairment (low certainty evidence). Compared to placebo, it is uncertain whether DPP-4 inhibitors have any effect on eGFR, hypoglycaemia, pancreatitis, pancreatic cancer, or discontinuation due to adverse effects (very low certainty evidence).Compared to placebo, GLP-1 agonists probably reduce HbA1c (7 studies, 867 participants: MD 0.53%, -1.01 to -0.06 (-5.8 mmol/mol, -11.0 to -0.7); I2 = 41%; moderate certainty evidence) and may reduce weight (low certainty evidence). GLP-1 agonists may have little or no effect on eGFR, hypoglycaemia, or discontinuation due to adverse effects (low certainty evidence). It is uncertain whether GLP-1 agonists reduce FBG, increase gastrointestinal symptoms, or affect the risk of pancreatitis (very low certainty evidence).Compared to placebo, it is uncertain whether glitazones have any effect on HbA1c, FBG, death, weight, and risk of hypoglycaemia (very low certainty evidence).Compared to glipizide, sitagliptin probably reduces hypoglycaemia (2 studies, 551 participants: RR 0.40, 0.23 to 0.69; I2 = 0%; moderate certainty evidence). Compared to glipizide, sitagliptin may have had little or no effect on HbA1c, FBG, weight, and eGFR (low certainty evidence). Compared to glipizide, it is uncertain if sitagliptin has any effect on death or discontinuation due to adverse effects (very low certainty).For types, dosages or modes of administration of insulin and other head-to-head comparisons only individual studies were available so no conclusions could be made. AUTHORS' CONCLUSIONS: Evidence concerning the efficacy and safety of glucose-lowering agents in diabetes and CKD is limited. SGLT2 inhibitors and GLP 1 agonists are probably efficacious for glucose-lowering and DPP-4 inhibitors may be efficacious for glucose-lowering. Additionally, SGLT2 inhibitors probably reduce BP, heart failure, and hyperkalaemia but increase genital infections, and slightly increase creatinine. The safety profile for GLP-1 agonists is uncertain. No further conclusions could be made for the other classes of glucose-lowering agents including insulin. More high quality studies are required to help guide therapeutic choice for glucose-lowering in diabetes and CKD. PMID- 30246881 TI - A Data-Driven Approach to Assessing Supply Inadequacy Risks Due to Climate Induced Shifts in Electricity Demand. AB - The U.S. electric power system is increasingly vulnerable to the adverse impacts of extreme climate events. Supply inadequacy risk can result from climate-induced shifts in electricity demand and/or damaged physical assets due to hydro meteorological hazards and climate change. In this article, we focus on the risks associated with the unanticipated climate-induced demand shifts and propose a data-driven approach to identify risk factors that render the electricity sector vulnerable in the face of future climate variability and change. More specifically, we have leveraged advanced supervised learning theory to identify the key predictors of climate-sensitive demand in the residential, commercial, and industrial sectors. Our analysis indicates that variations in mean dew point temperature is the common major risk factor across all the three sectors. We have also conducted a statistical sensitivity analysis to assess the variability in the projected demand as a function of the key climate risk factor. We then propose the use of scenario-based heat maps as a tool to communicate the inadequacy risks to stakeholders and decisionmakers. While we use the state of Ohio as a case study, our proposed approach is equally applicable to all other states. PMID- 30246882 TI - Inferring disease risk genes from sequencing data in multiplex pedigrees through sharing of rare variants. AB - We previously demonstrated how sharing of rare variants (RVs) in distant affected relatives can be used to identify variants causing a complex and heterogeneous disease. This approach tested whether single RVs were shared by all sequenced affected family members. However, as with other study designs, joint analysis of several RVs (e.g., within genes) is sometimes required to obtain sufficient statistical power. Further, phenocopies can lead to false negatives for some causal RVs if complete sharing among affected is required. Here, we extend our methodology (Rare Variant Sharing, RVS) to address these issues. Specifically, we introduce gene-based analyses, a partial sharing test based on RV sharing probabilities for subsets of affected relatives and a haplotype-based RV definition. RVS also has the desirable feature of not requiring external estimates of variant frequency or control samples, provides functionality to assess and address violations of key assumptions, and is available as open source software for genome-wide analysis. Simulations including phenocopies, based on the families of an oral cleft study, revealed the partial and complete sharing versions of RVS achieved similar statistical power compared with alternative methods (RareIBD and the Gene-Based Segregation Test), and had superior power compared with the pedigree Variant Annotation, Analysis, and Search Tool (pVAAST) linkage statistic. In studies of multiplex cleft families, analysis of rare single nucleotide variants in the exome of 151 affected relatives from 54 families revealed no significant excess sharing in any one gene, but highlighted different patterns of sharing revealed by the complete and partial sharing tests. PMID- 30246883 TI - Effect of vitamin D supplementation along with weight loss diet on meta inflammation and fat mass in obese subjects with vitamin D deficiency: A double blind placebo-controlled randomized clinical trial. AB - BACKGROUND & AIMS: Low serum 25-hydroxyvitamin D (25OHD) is common in obese people. Obesity is associated with a state of low-grade inflammation (meta inflammation). There is an increasing evidence indicating that vitamin D has anti adipogenic activity and immunoregulatory effect. This study aimed to assess the effect of vitamin D supplementation on meta-inflammation and fat mass in obese subjects with vitamin D deficiency. MATERIALS AND METHODS: In this double-blind placebo-controlled randomized clinical trial, 44 obese subjects with vitamin D deficiency (25OHD < 50 nmol/L) were assigned into vitamin D (a weight reduction diet + bolus weekly dose of 50 000 IU vitamin D) or placebo group (weight reduction diet + edible paraffin weekly) for 12 weeks. Weight, fat mass and serum levels of 25OHD, calcium, parathyroid hormone (PTH), monocyte chemoattractant protein-1 (MCP-1), interleukin-1beta (IL-1beta) and Toll-like receptor 4 (TLR4) were assessed before and after the intervention. RESULTS: Vitamin D supplementation resulted in significant increase of serum 25OHD level (P < 0.001), and significant decrease in PTH (P < 0.001), MCP-1 (P < 0.05), IL-1beta (P < 0.05) and TLR-4 (P < 0.05); compared to the baseline values in vitamin D group. Weight, BMI and fat mass decreased in both groups (P < 0.05). Between the groups, there were significant decrease in weight, fat mass, serum MCP-1 and PTH concentrations and significant increase in serum 25OHD concentrations after intervention with vitamin D supplementation compared to placebo (P < 0.05). CONCLUSIONS: Improvement in vitamin D status in obese subjects with vitamin D deficiency in combination with weight loss diet resulted in weight, fat mass and MCP-1 decrease. Weight loss and vitamin D supplementation may act synergistically to reduce levels of meta-inflammation. PMID- 30246884 TI - Sulodexide inhibits angiogenesis via decreasing Dll4 and Notch1 expression in mouse proepicardial explant cultures. AB - Sulodexide (SDX) is a mixed drug containing low-molecular-weight heparin sulfate and dermatan sulfate. It exerts mild anticoagulant action but can also affect leukocytes, macrophages, and cell-cell adhesion and may interact with growth factors although its direct influence on endothelial cells is not well described. Clinically, SDX is used for the treatment of cardiovascular diseases, where it exerts anti-inflammatory and endothelial protective effects. The aim of this study was to determine the influence of SDX on tubule formation and angiogenesis related proteins' mRNA expression in endothelial cell line C166 and mouse proepicardial explants. C166 cells and explants were stimulated with a proangiogenic cocktail containing bFGF/VEGF-A120 /VEGF-A164 enriched with SDX. After stimulation, the number and morphology of tubules stained with anti-CD31 antibody were examined under confocal microscope and expression of mRNA for VEGF A, VEGF-B, VEGF-C, bFGF, IGF-1, Dll4, and Notch1 was measured with real-time PCR. In C166 cell line, there was no difference in tubule formation and mRNA expression, but in proepicardial explants, we observed reduction in tubule number and in mRNA level for DLL4 and Notch1 after SDX administration. In conclusion, SDX indirectly inhibits angiogenesis in mouse proepicardial explant cultures but has no direct effect on the C166 endothelial cell line. PMID- 30246885 TI - Human pegivirus-1 associated leukoencephalitis: Clinical and molecular features. AB - Etiologic diagnosis is uncertain in 35% to 50% of patients with encephalitis, despite its substantial global prevalence and disease burden. We report on 2 adult female patients with fatal leukoencephalitis associated with human pegivirus-1 (HPgV-1) brain infection. Neuroimaging showed inflammatory changes in cerebral white matter. Brain-derived HPgV-1 RNA sequences clustered phylogenetically with other pegiviruses despite an 87-nucleotide deletion in the viral nonstructural (NS)2 gene. Neuropathology disclosed lymphocyte infiltration and gliosis predominantly in brain white matter. HPgV-1 NS5A antigen was detected in lymphocytes as well as in astrocytes and oligodendrocytes. HPgV-1 neuroadaptation should be considered in the differential diagnosis of progressive leukoencephalitis in humans. Ann Neurol 2018;84:789-795. PMID- 30246886 TI - Day care vs home care: Effects on functional health outcomes among long-term care beneficiaries with dementia in Korea. AB - OBJECTIVES: First, to compare changes in cognitive function, behavioral symptoms, and physical function for Korean Long-Term Care Insurance (LTCI) beneficiaries with dementia in day care (DC) and home care (HC) settings over 1 year. Second, to examine the association between LTCI service type and the aforementioned health outcomes. METHODS: A retrospective matched cohort study was conducted using the national data set of the National Health Insurance Service in Korea. We identified 7822 beneficiaries with dementia who received either DC or HC services consistently for 1 year from 2008 to 2009. The propensity score matching method was used, yielding 416 participants in each group. Paired samples t-tests and logistic regression analyses were conducted. RESULTS: Baseline differences between the two groups are present. According to multiple regression models, DC, when compared with HC, was related to less deterioration in cognitive and physical function but was associated with less improved behavioral symptoms 1 year after the LTCI enrollment. In the comparison between matched cohorts, DC, when compared with HC, was associated with less cognitive decline, less disability progression, and similar decrease in behavioral symptoms. CONCLUSIONS: Cognitive function and disability declined less in the DC group, compared with the HC group. Conversely, behavioral symptoms showed a similar decrease between the two groups after 1-year follow-up. Further research is necessary to examine key features of DC services that have helped delay functional deterioration and alleviate behavioral symptoms. PMID- 30246888 TI - Three-Dimensional Printed Cardiac Models for Focused Cardiac Ultrasound Instruction. AB - BACKGROUND: Focused cardiac ultrasonography (FCU) is an increasingly integral component of routine medical training and practice. While various instructional methods have been described, few attempts have been made to incorporate a physical 3-dimensional (3D) instructional aid. OBJECTIVE: The aim of this study was to determine if a 3D printed heart model workshop for FCU instruction leads to equivalent structure recognition and scanning ability compared to traditional didactic FCU instruction. INTERVENTION: Twenty first-year medical students with no point-of-care ultrasonography experience were randomly assigned to a traditional lecture (n = 10) or a 3D printed heart model workshop (n = 10). Written examinations at 0 and 3 months as well as image acquisition at 3 months were compared. RESULTS: The median scores from the initial written structure identification in the traditional and 3D heart groups were 74% and 90%, respectively (P = 0.7). The second written exam at 3 months yielded median scores of 56% and 58% in the traditional and 3D heart groups, respectively (P = 0.8). The average scores on the image acquisition practical at 3 months were 3.3 of 5 and 2.7 of 5 (P = 0.1) in the traditional and 3D heart groups, respectively. CONCLUSIONS: Utilizing 3D heart models in an FCU workshop format results in similar skill acquisition and knowledge retention as traditional didactics. The 3D heart models are relatively inexpensive, portable, and reusable, enabling learners to practice repeatedly and at flexible intervals. The reduction in ongoing expenses and the ability to teach large groups may decrease training costs as well as the need for local faculty expertise. PMID- 30246887 TI - Relative neuron loss in hippocampal sclerosis of aging and Alzheimer's disease. AB - OBJECTIVE: To characterize the pattern of neuron loss in hippocampal sclerosis of aging (HS-Aging) and age-related diseases and to evaluate its contribution to cognitive impairment in the elderly. METHODS: Participants (n = 1,361) came from longitudinal observational studies of aging at the Knight Alzheimer Disease Research Center, Washington University (St. Louis, MO). Relative neuron loss in the hippocampus of HS-Aging was measured using unbiased stereological methods. Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy, a putative marker of HS-Aging, was assessed. Clinical and cognitive data were analyzed using parametric statistical methods. RESULTS: Ninety-three cases had HS Aging (6.8%), 8 cases had "pure" HS-Aging, and 37 cases had comorbid intermediate or high Alzheimer's disease neuropathological change (i/h ADNC). Relative neuron loss (ratio of neuron number in hippocampal subfield CA1 to the neuron number in parahippocampal gyrus) was 0.15 for HS-Aging; this was significantly lower than 0.64 for i/h ADNC and 0.66 for control cases (Kruskal-Wallis test, p < 0.0001; p = 0.0003, respectively). TDP-43 proteinopathy was present in 92.4% of HS-Aging cases, higher than that in i/h ADNC (52%) and control (25%) cases. Pure HS-Aging cases were more likely to have cognitive impairment in the memory domain. INTERPRETATION: Relative neuron loss in the hippocampus compared to the parahippocampus gyrus may be useful in distinguishing HS-Aging in the context of comorbid ADNC. HS-Aging contributes to cognitive impairment, which phenotypically resembles AD dementia. TDP proteinopathy is a frequent comorbidity in HS-Aging and may contribute to cognitive impairment to a modest degree. Ann Neurol 2018;84:749-761. PMID- 30246889 TI - Vibriosis in Fish: A Review on Disease Development and Prevention. AB - Current growth in aquaculture production is parallel with the increasing number of disease outbreaks, which negatively affect the production, profitability, and sustainability of global aquaculture industry. Vibriosis is among the most common diseases that leads to massive mortality of cultured shrimp, fish, and shellfish in Asia. High incidence of vibriosis can occur in hatchery and growing-out facilities, but juveniles are more susceptible to the disease. Various factors, particularly the source of fish, the environmental factors including water quality and farm management and the virulence factors of Vibrio influence the occurrence. Affected fish show weariness with necrosis of skin and appendages leading to body malformation, slow growth, internal organ liquefaction, blindness, muscle opacity, and mortality. Combination of control measures, particularly the disease-free source of fish, biosecurity of the farm, improved water quality and other preventive measures such as vaccination might be able to control the infection. While some control measures are expensive and less practical, vaccination is effective, relatively cheap and easily implemented. In this review, latest knowledge on the pathogenesis and control of vibriosis, including vaccination are discussed. This article is protected by copyright. All rights reserved. PMID- 30246890 TI - Effect of early probiotic supplementation on childhood cognition, behaviour and mood a randomised, placebo-controlled trial. AB - AIM: To determine whether probiotic supplementation in early life improves neurocognitive outcomes assessed at 11 years of age. METHODS: A total of 474 children who were born March 2004-Aug 2005 participated in a two-centre randomised placebo-controlled trial of infants at risk of developing allergic disease. Pregnant women were randomised to take Lactobacillus rhamnosus strain HN001, Bifidobacterium animalis subsp. lactis strain HN019 or placebo daily from 35 weeks gestation until six months if breastfeeding, and their infants the same treatment from birth to two years. Intelligence, executive function, attention, depression and anxiety were assessed when the children were 11 years of age. RESULTS: A total of 342 (72.2%) children were assessed (HN001 n = 109, HN019 n = 118 and placebo n = 115). Overall, there were no significant differences in the neurocognitive outcomes between the treatment groups. CONCLUSION: HN001 and HN019 given in early life were not associated with neurocognitive outcomes at 11 years of age in this study. However, we cannot exclude that other probiotics may have a beneficial effect. Further clinical trials are indicated. PMID- 30246891 TI - N-Heterocyclic Carbene-Modified Au-Pd Alloy Nanoparticles and Their Application as Biomimetic and Heterogeneous Catalysts. AB - The preparation of water-soluble, N-heterocyclic-carbene-stabilized Au-Pd alloy nanoparticles by a straightforward ligand exchange process is presented. Extensive analysis revealed excellent size retention and stability over years in water. The alloy nanoparticles were applied as biomimetic catalysts for aerobic oxidation of d-glucose, for which monometallic Au and Pd nanoparticles showed no or negligible activity. The alloy nanoparticles were further applied as titania supported heterogeneous catalysts for the mild hydrogenation of nitroarenes and the semihydrogenation of 1,2-diphenylacetylene with a solvent-dependent selectivity switch between E- and Z-stilbene. PMID- 30246892 TI - Quantitative susceptibility mapping (QSM) with an extended physical model for MRI frequency contrast in the brain: a proof-of-concept of quantitative susceptibility and residual (QUASAR) mapping. AB - Quantitative susceptibility mapping (QSM) aims to calculate the tissue's magnetic susceptibility distribution from its perturbing effect on the MRI static main magnetic field. The method is increasingly being applied to study iron and myelin in clinical and preclinical settings. However, recent experimental and theoretical findings have challenged the fundamental theoretical assumptions that form the basis of current numerical implementations of QSM algorithms. The present work introduces a new class of susceptibility mapping algorithms, termed quantitative susceptibility and residual mapping (QUASAR), which takes into account frequency contributions not related to the spatial variation of bulk magnetic susceptibility in the Lorentz sphere model. We present a simple proof-of concept QUASAR algorithm that, unlike most of the QSM algorithms currently used widely, results in an improved anatomical accuracy of the susceptibility distribution without any a priori assumptions about the susceptibility distribution during the field-to-source inversion. The algorithm was evaluated both in silico and in vivo in the preclinical setting. Our preliminary application of QUASAR in rodents provides the first in vivo evidence that the susceptibility-field model traditionally used in the QSM field cannot fully explain the frequency contrast in brain tissues. Only when an additional local frequency contribution is added to the physical model can the frequency contrast in the brain be related properly to the underlying anatomy. PMID- 30246893 TI - A Highly Enantio- and Diastereoselective Synthesis of Spirocyclic Dihydroquinolones via Domino Michael Addition-Lactamization of ortho-Quinone Methide Imines. AB - Spirocyclic dihydroquinolones have been obtained with good yields and excellent diastereoselectivity (>20:1 d.r.), and enantioselectivity (up to 99:1 e.r.) from in situ generated ortho-quinone methide imines and cyclic beta-oxo esters. This one-step domino Michael addition-lactamization process features mild reaction conditions, easily accessible starting materials, and products with two adjacent chiral centers one of which is quaternary. Mechanistic studies revealed the in situ generated chiral magnesium phosphate salt rather than the free phosphoric acid to be the more reactive catalyst for this reaction. PMID- 30246894 TI - The heritability of pampiniform plexus vessel size and varicocoele in boars. AB - Ultrasonography was used to capture a coronal-sagittal image of the veins of the pampiniform plexus (PP) and the testicular artery of 327 maternal-line boars at approximately 6 months of age at the University of Nebraska-Lincoln. Varicocoele was diagnosed by two methods. Method 1 diagnosed varicocoele when the average vessel area on one side of the scrotum was 1.5 times larger than the average vessel area on the other side of the scrotum. Method 2 diagnosed varicocoele when the average vessel area on one side of the scrotum of a boar was 1.5 times larger than the average vessel on the same side of the scrotum of the boar's cohorts (same population and year). Varicocoele was diagnosed in 23.17% and 15.1% of boars measured using method 1 and method 2, respectively. Ultrasonography showed to be an effective means to measure PP vessel size in boars and may even allow for earlier detection of varicocoele than by using palpation. Animal models were employed to estimate the heritability for: average area of right PP vessels (0.52), average area of the left PP vessels (0.46), varicocoele presence using method 1 (0.26) and varicocoele presence using method 2 (0.25). These heritability estimates suggest that vessel size and varicocoele could be selected against in breeding programmes to potentially improve boar semen quality. PMID- 30246895 TI - Noninvasive measurements of ovarian activity in Beira antelope (Dorcatragus megalotis). AB - As the natural habitat of more and more species becomes depleted, captive breeding programmes have become established to bring species back from the brink of extinction. Monitoring the reproductive status of an individual is essential in order to improve breeding success. Traditional methods have involved stressful blood sampling, and thus noninvasive methods have been proven to be reliable alternatives for monitoring reproductive function in both captive and free ranging animals. Subsequently, noninvasive methods have become an invaluable tool in longitudinal studies and conservation efforts, as animals can be observed without, or minimal human contact. The Beira antelope is a small antelope endemic to the northern part of the Horn of Africa. Population numbers of the Beira have been declining over the last few decades due to habitat fragmentation. We show here that the reproductive cycle of female Beira antelopes can be monitored noninvasively, by using faecal samples to analyse oestrogen (fEM) as well as progestagen (fPM) metabolites. The profiles of fPM and fEM of both females showed regular cyclic patterns in which the follicular and luteal phases could be distinguished. The overall mean cycle length is 22 days (range: 21-25 days), with a mean length of the follicular phase of 6 days (range: 4-7 days) and a mean length for the luteal phase being 15 days (range: 12-16 days). The suitability of these noninvasive techniques should assist in optimizing breeding efforts of this endemic small antelope in captivity. Being noninvasive, this method could also be a useful tool for monitoring reproductive function in the dwindling wild populations. PMID- 30246896 TI - Glycosylation and metastases. AB - The change of cellular glycosylation is one of the key events in malignant transformation and neoplastic progression, and tumor-related glycosylation alterations are promising targets in both tumor diagnosis and therapy. Both malignant transformation and neoplastic progression are the consequence of gene expression alterations and alterations in protein expression. Micro environmental factors such as extracellular matrix (ECM) also play an important role in their growth and metastasis. Tumor-associated glycans are important biomarker candidates for cancer diagnosis and prognosis, and analytical methods for their detection were developed recently. Glycoproteomics that use mass spectrometry for identification of cancer antigens and structural analysis of glycans play a key role in the investigation of changes of glycosylation during malignant transformation and tumor development and metastasis. Deep understanding of glycan remodeling in cancer and the role of glycosyltransferases that are involved in this process will require a detailed profiling of glycosylation patterns of tumor cells, and corresponding analytical methods for their detection were developed. PMID- 30246897 TI - Patients diagnosed with long QT syndrome after repair of congenital heart disease. AB - BACKGROUND: Patients with repaired congenital heart disease (CHD) can have both depolarization and repolarization abnormalities. A coexisting long QT syndrome (LQTS) may cause electrical instability in these patients; however, diagnosing LQTS is difficult owing to intraventricular conduction delay or paced rhythm after the operation. We report on six patients diagnosed with LQTS after CHD repair. METHODS: We investigated two male and four female patients. Clinical data, electrocardiographic findings, and genetic analysis results were reviewed. RESULTS: The range of patient age at LQTS diagnosis was 1.4-22 years. There were two patients with tetralogy of Fallot, four with septal defect, and one with tricuspid atresia. All patients underwent total correction or a staged operation, without events. The diagnosis of LQTS was made in four asymptomatic patients and two symptomatic patients with recurrent syncope and ventricular fibrillation. During the postoperative follow-up, their median QTc interval and QTc dispersion increased (from 474 and 41 ms preoperatively to 541 and 141 ms postoperatively, respectively; P = 0.043). T-wave notching over three leads was observed in three patients. Genetic analysis showed SCN5A mutation in one, KCNH2 mutation in three, KCNQ1 mutation in one, and no identified mutation in one patient. An implantable cardioverter defibrillator was placed in two patients. CONCLUSION: A coexisting LQTS may confer additional risk for arrhythmia and sudden cardiac death in patients with CHD. Suspicion of LQTS and careful monitoring of the QT interval and T-wave morphology are important during the follow-up of patients with repaired CHD. PMID- 30246898 TI - Changes in renal function with long-term exposure to antiretroviral therapy in HIV-infected adults in Asia. AB - PURPOSE: Renal disease is common among people living with human immunodeficiency virus (HIV). However, there is limited information on the incidence and risk factors associated with renal dysfunction among this population in Asia. METHODS: We used data from the TREAT Asia HIV Observational Database. Patients were included if they started antiretroviral therapy during or after 2003, had a serum creatinine measurement at antiretroviral therapy initiation (baseline), and had at least 2 follow-up creatinine measurements taken >=3 months apart. Patients with a baseline estimated glomerular filtration rate (eGFR) <=60 mL/min/1.73 m2 were excluded. Chronic kidney disease was defined as 2 consecutive eGFR values <=60 mL/min/1.73 m2 taken >=3 months apart. Generalized estimating equations were used to identify factors associated with eGFR change. Competing risk regression adjusted for study site, age and sex, and cumulative incidence plots were used to evaluate factors associated with chronic kidney disease (CKD). RESULTS: Of 2547 patients eligible for this analysis, tenofovir was being used by 703 (27.6%) at baseline. Tenofovir use, high baseline eGFR, advanced HIV disease stage, and low nadir CD4 were associated with a decrease in eGFR during follow-up. Chronic kidney disease occurred at a rate of 3.4 per 1000 patient/years. Factors associated with CKD were tenofovir use, old age, low baseline eGFR, low nadir CD4, and protease inhibitor use. CONCLUSIONS: There is an urgent need to enhance renal monitoring and management capacity among at-risk groups in Asia and improve access to less nephrotoxic antiretrovirals. PMID- 30246900 TI - Memory Image Completion: Establishing a task to behaviorally assess pattern completion in humans. AB - For memory retrieval, pattern completion is a crucial process that restores memories from partial or degraded cues. Neurocognitive aging models suggest that the aged memory system is biased toward pattern completion, resulting in a behavioral preference for retrieval over encoding of memories. Here, we built on our previously developed behavioral recognition memory paradigm-the Memory Image Completion (MIC) task-a task to specifically target pattern completion. First, we used the original design with concurrent eye-tracking in order to rule out perceptual confounds that could interact with recognition performance. Second, we developed parallel versions of the task to accommodate test settings in clinical environments or longitudinal studies. The results show that older adults have a deficit in pattern completion ability with a concurrent bias toward pattern completion. Importantly, eye-tracking data during encoding could not account for age-related performance differences. At retrieval, spatial viewing patterns for both age groups were more driven by stimulus identity than by response choice, but compared to young adults, older adults' fixation patterns overlapped more between stimuli that they (wrongly) thought had the same identity. This supports the observation that older adults choose responses perceived as similar to a learned stimulus, indicating a bias toward pattern completion. Additionally, two shorter versions of the task yielded comparable results, and no general learning effects were observed for repeated testing. Together, we present evidence that the MIC is a reliable behavioral task that targets pattern completion, that is easily and repeatedly applicable, and that is made freely available online. PMID- 30246899 TI - The Neuromodulation Appropriateness Consensus Committee on Best Practices for Dorsal Root Ganglion Stimulation. AB - INTRODUCTION: The Neuromodulation Appropriateness Consensus Committee (NACC) is dedicated to improving the safety and efficacy of neuromodulation and thus improving the lives of patients undergoing neuromodulation therapies. With continued innovations in neuromodulation comes the need for evolving reviews of best practices. Dorsal root ganglion (DRG) stimulation has significantly improved the treatment of complex regional pain syndrome (CRPS), among other conditions. Through funding and organizational leadership by the International Neuromodulation Society (INS), the NACC reconvened to develop the best practices consensus document for the selection, implantation and use of DRG stimulation for the treatment of chronic pain syndromes. METHODS: The NACC performed a comprehensive literature search of articles about DRG published from 1995 through June, 2017. A total of 2538 article abstracts were then reviewed, and selected articles graded for strength of evidence based on scoring criteria established by the US Preventive Services Task Force. Graded evidence was considered along with clinical experience to create the best practices consensus and recommendations. RESULTS: The NACC achieved consensus based on peer-reviewed literature and experience to create consensus points to improve patient selection, guide surgical methods, improve post-operative care, and make recommendations for management of patients treated with DRG stimulation. CONCLUSION: The NACC recommendations are intended to improve patient care in the use of this evolving therapy for chronic pain. Clinicians who choose to follow these recommendations may improve outcomes. PMID- 30246901 TI - Case series of oral minoxidil for androgenetic and traction alopecia: Tolerability & the five C's of oral therapy. PMID- 30246902 TI - Prognostic utility of novel biomarkers in acute-on-chronic liver failure (ACLF) associated with hepatitis B: A multicenter prospective study. AB - AIM: Flare-ups of chronic hepatitis B can sometimes be severe and even progress to acute-on-chronic liver failure (ACLF), with high short-term mortality. A timely estimation of the risk of death should be initiated early. The aim of the present study was to determine whether novel biomarkers add prognostic information beyond current clinical scoring systems. METHODS: Patients with hepatitis B-associated ACLF were prospectively enrolled from five hospitals in China between August 2017 and March 2018. Their plasma was screened for soluble CD163 (sCD163), neutrophil gelatinase-associated lipocalin (NGAL), and copeptin. The association between these biomarkers and mortality was analyzed. The performance of the Model for End-stage Liver Disease, Asian-Pacific Association for the Study of the Liver-ACLF Research Consortium score, and the Chronic Liver Failure Consortium ACLF score, with or without biomarkers, were compared. RESULTS: One hundred fifty one patients were enrolled. Advanced ACLF patients had significantly higher levels than early ACLF individuals of plasma biomarkers sCD163 (P = 0.001), NGAL (P = 0.006), and copeptin (P = 0.049). Thirty-four deaths occurred during the 28-day follow-up period (22.5%). Both sCD163 and NGAL showed a strong independent association with 28-day mortality, whereas copeptin did not. Scoring systems incorporating sCD163 and NGAL had better discrimination and calibration, as measured by area under the receiver operating characteristic curves, the Akaike information criteria, integrated discrimination improvement, and net reclassification improvement. CONCLUSIONS: Soluble CD163 and NGAL are independently associated with short-term mortality in hepatitis B-associated ACLF. Use of a combination of sCD163 and NGAL improves prognostication. PMID- 30246903 TI - Correction to Helman et al (2016) MRI spectrum of SDH deficiency-related infantile leukoencephalopathy. PMID- 30246905 TI - Objective Measures to Characterize the Physiological Effects of Spinal Cord Stimulation in Neuropathic Pain: A Literature Review. AB - OBJECTIVE: The physiological mechanisms behind the therapeutic effects of spinal cord stimulation (SCS) are only partially understood. Our aim was to perform a literature review of studies that used objective measures to characterize mechanisms of action of SCS in neuropathic pain patients. MATERIALS AND METHODS: We searched the PubMed data base to identify clinical studies that used objective measures to assess the effects of SCS in neuropathic pain. We extracted the study factors (e.g., type of measure, diagnoses, painful area[s], and SCS parameters) and outcomes from the included studies. RESULTS: We included 67 studies. Of these, 24 studies used neurophysiological measures, 14 studies used functional neuroimaging techniques, three studies used a combination of neurophysiological and functional neuroimaging techniques, 14 studies used quantitative sensory testing, and 12 studies used proteomic, vascular, and/or pedometric measures. Our findings suggest that SCS largely inhibits somatosensory processing and/or spinal nociceptive activity. Our findings also suggest that SCS modulates activity across specific regions of the central nervous system that play a prominent role in the sensory and emotional functions of pain. CONCLUSIONS: SCS appears to modulate pain via spinal and/or supraspinal mechanisms of action (e.g., pain gating, descending pain inhibition). However, to better understand the mechanisms of action of SCS, we believe that it is necessary to carry out systematic, controlled, and well-powered studies using objective patient measures. To optimize the clinical effectiveness of SCS for neuropathic pain, we also believe that it is necessary to develop and implement patient-specific approaches. PMID- 30246904 TI - Molecular and clinical relationship between live-attenuated Japanese encephalitis vaccination and childhood onset myasthenia gravis. AB - OBJECTIVE: The incidence of childhood onset myasthenia gravis (CMG) in China is higher than that in other countries; however, the reasons for this are unclear. METHODS: We investigated the clinical and immunological profiles of CMG, and assessed the potential precipitating factors. For the mouse studies, the possible implication of vaccination in the pathogenesis was explored. RESULTS: In our retrospective study, 51.22% of the 4,219 cases of myasthenia gravis (MG) were of the childhood onset type. The cohort study uncovered that the pathophysiology of CMG was mediated by immune deviation, rather than through gene mutations or virus infections. The administration of the live-attenuated Japanese encephalitis vaccine (LA-JEV), but not the inactivated vaccine or other vaccines, in mice induced serum acetylcholine receptor (AChR) antibody production, reduced the AChR density at the endplates, and decreased both muscle strength and response to repetitive nerve stimulation. We found a peptide (containing 7 amino acids) of LA JEV similar to the AChR-alpha subunit, and immunization with a synthesized protein containing this peptide reproduced the MG-like phenotype in mice. INTERPRETATION: Our results describe the immunological profile of CMG. Immunization with LA-JEV induced an autoimmune reaction against the AChR through molecular mimicry. These findings might explain the higher occurrence rate of CMG in China, where children are routinely vaccinated with LA-JEV, compared with that in countries, where this vaccination is not as common. Efforts should be made to optimize immunization strategies and reduce the risk for developing autoimmune disorders among children. Ann Neurol 2018;84:386-400. PMID- 30246906 TI - A case series of dupilumab-treated allergic contact dermatitis patients. AB - Atopic dermatitis is characterized by skin barrier abnormalities and immune dysregulation with increased TH 2 signaling playing a central role. Investigations of allergic contact dermatitis suggest that certain allergens may also activate particular T cell signatures such as TH 2-dominant responses to fragrance and rubber. We present a case series of patients with allergic contact dermatitis who were successfully treated with dupilumab, a biologic developed for atopic dermatitis that dampens TH 2 signaling. In our cohort of three patients, two had extensive allergic contact dermatitis on their torso and extremities primarily due to textile and rubber allergens. The third was a hairdresser with severe hand dermatitis due to occupational allergens. Two of the three patients had no history of atopic dermatitis during childhood. Each patient experienced at least 90% improvement in body surface area involvement and continues to maintain their clinical response on dupilumab (range 6-13 months). Our hypothesis that dupilumab suppressed contact allergic reactions is supported by the identification of clinically relevant contact allergens on patch testing, acute onset and/or worsening of dermatitis in adulthood, and absence of childhood atopic dermatitis in two cases. Further, larger investigations to understand which factors affect responses of allergic contact dermatitis to dupilumab are warranted. PMID- 30246907 TI - Anti-desmoglein-1 levels as predictor of prednisolone tapering in pemphigus vulgaris patients treated with rituximab. PMID- 30246909 TI - Designing Dimeric Lanthanide(III)-Containing Ionic liquids. AB - Herein, we report on the preparation of liquid dimeric lanthanide(III)-containing compounds. Starting from the design of dimeric solids, we demonstrate that by tuning of anion and cation structures we can lower the melting points below room temperature, whilst maintaining the dimeric structure. Magnetic measurements could establish the spin-spin interactions of the neighboring lanthanide(III) ions in the liquid state at low temperatures, and matched the interactions of the analogous crystalline solid compounds. PMID- 30246908 TI - Selective attention, filtering, and the development of working memory. AB - Selective attention is fundamental for learning across many situations, yet it exhibits protracted development, with young children often failing to filter out distractors. In this research, we examine links between selective attention and working memory (WM) capacity across development. One possibility is that WM is resource-limited, with development resulting in an increase in the amount of resources available for processing information. However, it is also possible that development results in greater efficiency of using available resources. In the current research, we explore the latter possibility by examining the developmental trajectory of selectivity and filtering in relation to WM capacity. We report that filtering efficiency of adults (N = 30), 7-year-olds (N = 29), and 4-year-olds (N = 28) was uniquely predictive of WM capacity. We also report that filtering efficiency continues to develop after 7 years of age, whereas WM capacity may reach an asymptote around 7 years of age. The latter finding suggests that selective attention plays a critical role in developmental and individual differences in visual working memory capacity. PMID- 30246910 TI - Short- and long-term effects of two emollients on itching and skin restoration in xerotic eczema. AB - Pruritus is associated with various skin diseases, dry skin, and with it an impaired skin barrier function. The study objective was to investigate short-term and long-term effects of two emollients on symptoms and skin barrier functions in xerotic eczema. Randomized, double-blind, study enrolling females/males, with bilateral itching. Two emollients, containing lactic acid and refined almond oil with/without polidocanol were administered on left versus right body sides. Itching severity, skin moisture, lipid content, and pH were assessed on Day 1, within 30-120 min after first administration, and on Days 7 and 14, and compared with baseline assessments. Severity of itching decreased 30 min after first administration of both emollients compared with baseline (p < .0001) and reached a maximum reduction of 63% (p < .0001) and 69% (p < .0001) on Day 14. Skin moisture and lipid content increased after first application, and further ameliorated within 14 days of treatment (p < .0001). Both emollients were tolerated well, and only a few adverse events were reported. This study confirmed the clinical efficacy of the two study emollients to substantially reduce itching already after first administration, and restore skin barrier integrity and thus should be considered as therapeutic approach for xerotic eczema. PMID- 30246911 TI - Methane Hydroxylation with Water as an Electron Donor under Light Irradiation in the Presence of Reconstituted Membranes Containing both Photosystem II and a Methane Monooxygenase. AB - Methane/methanol conversion is one of the most important chemical reactions. Methane monooxygenases from methanotrophs are enzymes that catalyze methane/methanol conversion under mild conditions. Here we report the reconstitution of purified photosystem II (PSII) from Thermosynechococcus elongatus BP-1 into the membrane fraction containing particulate methane monooxygenase (pMMO) from Methylosinus trichosporium OB3b. Photoinduced hydroxylation of methane to methanol was successfully achieved by using the PSII reconstituted membrane containing pMMO under light irradiation. This result indicates that the sequential redox chain from PSII through the quinone pool to pMMO can be constructed and that water can serve as the electron donor for methane hydroxylation under irradiation with light. pMMO in the membrane fraction produced hydrogen peroxide as a byproduct when an electron donor was added for methane hydroxylation, whereas under light irradiation conditions the PSII reconstituted membrane containing pMMO did not generate hydrogen peroxide. Optimization of the electron-transfer rate can easily be achieved with this system by tuning the light intensity. PMID- 30246912 TI - Polymerizing Like Mussels Do: Toward Synthetic Mussel Foot Proteins and Resistant Glues. AB - A novel strategy to generate adhesive protein analogues by enzyme-induced polymerization of peptides is reported. Peptide polymerization relies on tyrosinase oxidation of tyrosine residues to Dopaquinones, which rapidly form cysteinyldopa-moieties with free thiols from cysteine residues, thereby linking unimers and generating adhesive polymers. The resulting artificial protein analogues show strong adsorption to different surfaces, even resisting hypersaline conditions. Remarkable adhesion energies of up to 10.9 mJ m-2 are found in single adhesion events and average values are superior to those reported for mussel foot proteins that constitute the gluing interfaces. PMID- 30246913 TI - The therapeutic effect of tanshinone IIA on Propionibacterium acnes-induced inflammation in vitro. AB - Acne vulgaris, a chronic inflammatory skin disease, affects many adolescents. New therapeutic agents for acne allow for a higher therapeutic activity, but fewer side effects. Tanshinone IIA, a natural product, has been proved to exhibit antibacterial and anti-inflammatory abilities in many diseases. However, its antibacterial and anti-inflammatory activities against Propionibacterium acnes have not been described. In the present study, the broth microdilution method was used to evaluate the antibacterial activity of tanshinone IIA and it had an inhibitory effect on the growth of P. acnes. Enzyme-linked immunosorbent assay and quantitative real-time PCR were used to investigate the effect of tanshinone IIA on IL-1beta, IL-8, and TNF-alpha expression, and western blot was used to examine TLR2, NF-kappaB, and intercellular cell adhesion molecule-1 (ICAM-1) protein level induced by P. acnes in THP-1 cells. Results showed that the expression of inflammatory cytokines and TLR2, NF-kappaB, ICAM-1 protein levels were inhibited by Tanshinone IIA, suggesting that tanshinone IIA appeared to suppress P. acnes-induced inflammation by blockade of TLR2/NF-kappaB signaling pathway. In conclusion, the present study revealed the inhibitory effect of tanshinone IIA on P. acnes-induced inflammation, providing an evidence to support the mechanism of anti-acne properties of tanshinone IIA. PMID- 30246914 TI - Is skin microneedling a good alternative method of various skin defects removal. AB - Skin microneedling accelerates the process of skin regeneration through the creation of numerous microinjuries which emerge when skin is deeply punctured with very thin needles. The whole procedure evokes various reactions which can be divided into three major phases: inflammation, proliferation, and remodeling. It activates platelet growth factors which are responsible for the stimulation of fibroblasts to produce collagen and elastin. Moreover, skin breakdown enhances penetration of active ingredients. Treatment can be performed with the use of different devices, all equipped with needles of various lengths. Due to the fact that skin microneedling stimulates the synthesis of significant rebuilding and structural skin elements (collagen, elastin, proteoglycan), it is used in the treatment of many skin defects of different etiologies (e.g., photoaging, wrinkles, loss of elasticity, hypo- or hypertrophic scars, pigmentation changes, infraorbital dark circles, teleangiectasia, stretch marks, cellulite, alopecia, and vitiligo). In order to accelerate postsurgical regeneration and/or to enhance effects, microneedling is combined with the application of UV light (photodynamic therapy with ALA), LED light, platelet-rich plasma, chemical peels, stem cells, retinoids and other pharmaceuticals, and vitamins. High effectiveness, limited number of side effects, and short recovery time, make skin microneedling a popular cosmetic, and medical treatment. PMID- 30246915 TI - Successful treatment of dermatomyositis with low-dose naltrexone. PMID- 30246916 TI - Pain flare, complexity and analgesia in bone oligometastases treated with stereotactic body radiation therapy. AB - The aim of our study was to assess the incidence of pain flare and the effectiveness of stereotactic body radiotherapy (SBRT) in pain management of patients with bone oligometastases. We evaluated 48 patients accounting for 54 treatments. The Edmonton Classification System for Cancer Pain (ECS-CP) was applied to identify indicators of treatment-resistant pain, in patients with active pain (NRS >= 2) at baseline. Statistical analysis was performed to identify predictors of pain flare and pain control. Pain flare occurred in 38% of treated patients (n = 18/48): No correlation was found between pain flare and patient- or treatment-related variables. In the subset of patients with active pain at baseline (n = 23), pain control was obtained in 62% of patients at 1 year; median time to pain progression after SBRT was 29 months (CI95% 6-52 months). Presence of >=2ECS-CP features was correlated with earlier pain progression (4 vs. 30 months, p = 0.012). Pain flare occurred in 38% of cases irrespectively of steroid premedication and dose regimen. In patient with baseline active pain, durable pain control was obtained. Presence of >=2 complexity indicators at the ECS-CP assessment was correlated with impaired pain control and may deserve future investigation in prospective studies. PMID- 30246917 TI - Steric hindrance controls pyridine nucleotide specificity of a flavin-dependent NADH:quinone oxidoreductase. AB - The crystal structure of the NADH:quinone oxidoreductase PA1024 has been solved in complex with NAD+ to 2.2 A resolution. The nicotinamide C4 is 3.6 A from the FMN N5 atom, with a suitable orientation for facile hydride transfer. NAD+ binds in a folded conformation at the interface of the TIM-barrel domain and the extended domain of the enzyme. Comparison of the enzyme-NAD+ structure with that of the ligand-free enzyme revealed a different conformation of a short loop (75 86) that is part of the NAD+ -binding pocket. P78, P82, and P84 provide internal rigidity to the loop, whereas Q80 serves as an active site latch that secures the NAD+ within the binding pocket. An interrupted helix consisting of two alpha helices connected by a small three-residue loop binds the pyrophosphate moiety of NAD+ . The adenine moiety of NAD+ appears to pi-pi stack with Y261. Steric constraints between the adenosine ribose of NAD+ , P78, and Q80, control the strict specificity of the enzyme for NADH. Charged residues do not play a role in the specificity of PA1024 for the NADH substrate. PMID- 30246919 TI - Stressful Life Events in Young Adults With Type 1 Diabetes in the U.S. T1D Exchange Clinic Registry. AB - PURPOSE: The purpose was to test associations among stressful life events, frequency of missed insulin doses, and glycemic control in young adults with type 1 diabetes (T1D). DESIGN: The study was a cross-sectional descriptive secondary analysis. METHODS: Data from 2,921 participants (ages 18-26 years) in the U.S. T1D Exchange Clinic Registry were analyzed. Report of a stressful life event was defined as one or more positive responses on a 17-item stressful life events index and defined as a dichotomous variable (yes or no). Frequency of missed insulin doses was measured using a single self-report item and collapsed into two levels (fewer than three times a week, three or more times a week). The glycosylated hemoglobin (A1c) level recorded at the time of enrollment was used to assess glycemic control. FINDINGS: Nearly half (48.6%) of the participants reported having a stressful life event during the previous year. The most frequently reported stressful life events were problems at work or school (16.1%), serious arguments with family members or a close friend (15.2%), and financial problems in the family (13.8%). Compared to the participants not reporting stressful life events, those who reported stressful life events were more likely to be older, female, with a higher educational attainment level, and not working or unemployed. Those who reported a stressful life event were more likely than those who did not to say they typically missed insulin doses at least three times a week and less likely to say they typically missed insulin doses fewer than three times a week (p < .001 adjusted for age, sex, race or ethnicity, educational attainment level, duration of T1D diagnosis, and insulin delivery method). Mean A1c level was higher for the group who reported having a stressful life event in the past 12 months compared to the group who did not (8.7 +/- 1.8% vs. 8.2 +/- 1.6%; adjusted p < .001). The results of a mediation analysis suggest that the measure of frequency of missed insulin doses may be a mediator of the relationship between recent stressful life events and glycemic control (Sobel test: ab = .841, 95% confidence interval = 0.064-1.618). CONCLUSIONS: These findings suggest that, for young adults with T1D, the experience of stressful life events may increase their risk for poorer glycemic control, possibly by disrupting adherence with insulin doses. CLINICAL RELEVANCE: Further exploration of these relationships may allow for the potential for identifying those at risk and assisting them with more positive approaches to managing stressful events. PMID- 30246918 TI - Heterozygous WNT1 variant causing a variable bone phenotype. AB - Osteogenesis imperfecta (OI) is a family of heritable disorders of bone fragility. Most individuals with OI have mutations in the genes encoding type I collagen; at least 17 other genes have been associated with OI. Biallelic loss-of function mutations in WNT1 cause severe OI. Heterozygous missense variants in WNT1 are responsible for early-onset osteoporosis with variable bone phenotypes. Herein, we report a third-generation family with four affected individuals, some presenting with multiple low-impact fractures in childhood and others presenting with early-onset osteoporosis without a striking fracture history. A WNT1 variant (c. 1051 > C; p.Trp351Arg) was identified in the proband and segregated with a bone phenotype in three additional family members, consistent with autosomal dominant inheritance. In the proband, whole genome sequencing also revealed a de novo duplication (434 kb) of 22q11.2 that involves 25 genes, 4 of which are associated with human disease when haploinsufficient. Though smaller than the typical (1.5 Mb) 22q11.2 duplication, the duplication in the proband may be responsible for additional nonosseous aspects of his phenotype (hypotonia, developmental delay, small genitalia, strabismus, and depression in preadolescence). This case demonstrates the variability of bone phenotype conferred by a WNT1 variant and extends the spectrum of bone phenotypes associated with heterozygous WNT1 mutations. PMID- 30246920 TI - Circumcision is still the gold standard in management of plasma cell balanitis. PMID- 30246921 TI - Long non-coding RNA CRNDE promotes the proliferation, migration and invasion of hepatocellular carcinoma cells through miR-217/MAPK1 axis. AB - Hepatocellular carcinoma (HCC) is an invasive malignant tumour and the second major cause of cancer-related deaths over the world. CRNDE and miR-217 are non coding RNAs which play critical roles in cell growth, proliferation, migration. Mitogen-activated protein kinase 1 (MAPK1) also participates in cancer cell process. Hence, this study aimed at investigating the effect of CRNDE on migration and invasion of HCC and figuring out the role of miR-217 and MAPK1 in this process. The overexpression of CRNDE was demonstrated by a microarray-based lncRNA profiling study. CRNDE expression in HCC was verified by qRT-PCR. MTT assay and BrdU staining were applied to detect cell proliferation level. Transwell assay was utilized to examine cell migration and invasiveness abilities. Wound healing assay was performed for further exploration of cell migration capacity. MiR-217 was predicted by bioinformatics. The dual luciferase reporter assay was performed to corroborate the targeting relationship between CRNDE, miR-217 and MAPK1. MAPK1, the downstream target of miR-217, was predicted using bioinformatics and was further confirmed by qRT-PCR and Western blot. The interaction between CRNDE, miR-217 and MAPK1 was studied by qRT-PCR, Western blot, MTT, BrdU, transwell assay and wound healing assay. CRNDE was up-regulated in HCC tissues and HCC cell lines. The high expression of CRNDE facilitated cell proliferation, migration and invasion, while the inhibited one affected on the contrary. MiR-217, negatively correlated with CRNDE expression, was the target of CRNDE and was more lowly expressed in HCC. With the high expression of miR-217, HCC cell proliferation, migration and invasion were suppressed. MAPK1, the possible target of miR-217, was negatively correlated with miR-217 but positively correlated with CRNDE and had the same effect in HCC formation process as CRNDE. Long non-coding RNA CRNDE promotes the proliferation, migration and invasion of HCC cells through miR-217/MAPK1 axis. PMID- 30246922 TI - Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis. AB - OBJECTIVE: To investigate the association of single nucleotide variants in the candidate genes WNT10A, WNT10B and GREM2 with isolated tooth agenesis. SETTING AND SAMPLE POPULATION: A total of 435 Caucasian individuals (88 cases with isolated tooth agenesis and 347 unrelated controls) were ascertained at the University of Texas Health Science Center at Houston School of Dentistry. Clinical and radiographic examination by orthodontists confirmed the diagnosis of tooth agenesis. Genetic evaluation excluded syndromic forms of tooth agenesis. MATERIALS AND METHODS: Saliva samples were collected as source of genomic DNA. Fourteen variants in/nearby WNT10A, WNT10B and GREM2 were genotyped to test for association with tooth agenesis. Genotyping was performed using TaqMan chemistry in a real-time polymerase chain reaction assay. Allelic and haplotype frequencies were compared among cases and controls using chi-square tests as implemented in PLINK v.1.06. Bonferroni correction was used and P <= 0.004 indicates statistical differences between groups. RESULTS: Significant associations were found between individual SNPs and SNP combinations in WNT10A, WNT10B and GREM2 SNPs with isolated tooth agenesis (P < 0.004). CONCLUSION: Our findings further support a role for variants in WNT10A, WNT10B and GREM2 genes in the aetiology of isolated tooth agenesis. Functional studies are necessary to investigate the biological effects of these gene variants in tooth agenesis phenotypes. PMID- 30246923 TI - Feasibility and acceptability of a motivational interviewing breastfeeding peer support intervention. AB - An uncontrolled study with process evaluation was conducted in three U.K. community maternity sites to establish the feasibility and acceptability of delivering a novel breastfeeding peer-support intervention informed by motivational interviewing (MI; Mam-Kind). Peer-supporters were trained to deliver the Mam-Kind intervention that provided intensive one-to-one peer-support, including (a) antenatal contact, (b) face-to-face contact within 48 hr of birth, (c) proactive (peer-supporter led) alternate day contact for 2 weeks after birth, and (d) mother-led contact for a further 6 weeks. Peer-supporters completed structured diaries and audio-recorded face-to-face sessions with mothers. Semistructured interviews were conducted with a purposive sample of mothers, health professionals, and all peer-supporters. Interview data were analysed thematically to assess intervention acceptability. Audio-recorded peer-support sessions were assessed for intervention fidelity and the use of MI techniques, using the MITI 4.2 tool. Eight peer-supporters delivered the Mam-Kind intervention to 70 mothers in three National Health Service maternity services. Qualitative interviews with mothers (n = 28), peer-supporters (n = 8), and health professionals (n = 12) indicated that the intervention was acceptable, and health professionals felt it could be integrated with existing services. There was high fidelity to intervention content; 93% of intervention objectives were met during sessions. However, peer-supporters reported difficulties in adapting from an expert-by-experience role to a collaborative role. We have established the feasibility and acceptability of providing breastfeeding peer-support using a MI informed approach. Refinement of the intervention is needed to further develop peer-supporters' skills in providing mother-centred support. The refined intervention should be tested for effectiveness in a randomised controlled trial. PMID- 30246925 TI - State of the art, state of the science? PMID- 30246924 TI - CLEARED (Chemicals and Litmus testing with Effective Alkaline Range for Eye Damage): A Prospective, Interventional Study. AB - OBJECTIVES: While immediate diagnosis and irrigation is standard chemical eye burn practice, it is unknown to what extent specific pH measurements influence management, given the frequent clinical availability of narrow-spectrum nitrazine pH strips. We hypothesize that exclusive broad-spectrum pH strip implementation leads to more accurate measurement and expedited ophthalmologic consultation. METHODS: At a Level I trauma center over 25 months, all emergent adult ophthalmology consultations for chemical burns were included in a pre intervention (n = 22) and post-intervention (n = 20) study design. During this time, narrow-spectrum nitrazine pH strips available to non-obstetric emergency department (ED) staff were exclusively replaced by broad-spectrum strips. Causative chemical, time from triage to ophthalmology consultation, examination findings, ocular pH by ED and ophthalmology staff, and irrigation quantity were analyzed. RESULTS: Most burns were alkaline. Time from triage (p = 0.043) and irrigation quantity following consultation (p = 0.047) each decreased following exclusive ED implementation of broad-spectrum pH strips. There was greater pH congruence between consulting and primary physicians after intervention (p = 0.03). CONCLUSIONS: Exclusive non-obstetric implementation of broad-spectrum pH strips may allow greater accuracy and faster management of ocular chemical burns. Availability of narrow-spectrum pH strips may be dangerous clinically by falsely reassuring the examiner with inherent inaccuracy. PMID- 30246926 TI - A multicentre prospective randomised controlled comparative parallel study of dehydrated human umbilical cord (EpiCord) allograft for the treatment of diabetic foot ulcers. AB - The aim of this study was to determine the safety and effectiveness of dehydrated human umbilical cord allograft (EpiCord) compared with alginate wound dressings for the treatment of chronic, non-healing diabetic foot ulcers (DFU). A multicentre, randomised, controlled, clinical trial was conducted at 11 centres in the United States. Individuals with a confirmed diagnosis of Type 1 or Type 2 diabetes presenting with a 1 to 15 cm2 ulcer located below the ankle that had been persisting for at least 30 days were eligible for the 14-day study run-in phase. After 14 days of weekly debridement, moist wound therapy, and off-loading, those with <=30% wound area reduction post-debridement (n = 155) were randomised in a 2:1 ratio to receive a weekly application of EpiCord (n = 101) or standardised therapy with alginate wound dressing, non-adherent silicone dressing, absorbent non-adhesive hydropolymer secondary dressing, and gauze bandage roll (n = 54). All wounds continued to have appropriate off-loading during the treatment phase of the study. Study visits were conducted for 12 weeks. At each weekly visit, the DFU was cleaned and debrided as necessary, with the wound photographed pre- and post-debridement and measured before the application of treatment group-specific dressings. A follow-up visit was performed at week 16. The primary study end point was the percentage of complete closure of the study ulcer within 12 weeks, as assessed by Silhouette camera. Data for randomised subjects meeting study inclusion criteria were included in an intent-to-treat (ITT) analysis. Additional analysis was conducted on a group of subjects (n = 134) who completed the study per protocol (PP) (EpiCord, n = 86, alginate, n = 48) and for those subjects receiving adequate debridement (EpiCord, n = 67, alginate, n = 40). ITT analysis showed that DFUs treated with EpiCord were more likely to heal within 12 weeks than those receiving alginate dressings, 71 of 101 (70%) vs 26 of 54 (48%) for EpiCord and alginate dressings, respectively, P = 0.0089. Healing rates at 12 weeks for subjects treated PP were 70 of 86 (81%) for EpiCord-treated and 26 of 48 (54%) for alginate-treated DFUs, P = 0.0013. For those DFUs that received adequate debridement (n = 107, ITT population), 64 of 67 (96%) of the EpiCord-treated ulcers healed completely within 12 weeks, compared with 26 of 40 (65%) of adequately debrided alginate treated ulcers, P < 0.0001. Seventy-five subjects experienced at least one adverse event, with a total of 160 adverse events recorded. There were no adverse events related to either EpiCord or alginate dressings. These results demonstrate the safety and efficacy of EpiCord as a treatment for non-healing DFUs. PMID- 30246927 TI - How to Agree on a CTC: Evaluating the Consensus in Circulating Tumor Cell Scoring. AB - For using counts of circulating tumor cells (CTCs) in the clinic to aid a physician's decision, its reported values will need to be accurate and comparable between institutions. Many technologies have become available to enumerate and characterize CTCs, thereby showing a large range of reported values. Here we introduce an Open Source CTC scoring tool to enable comparison of different reviewers and facilitate the reach of a consensus on assigning objects as CTCs. One hundred images generated from two different platforms were used to assess concordance between 15 reviewers and an expert panel. Large differences were observed between reviewers in assigning objects as CTCs urging the need for computer recognition of CTCs. A demonstration of a deep learning approach on the 100 images showed the promise of this technique for future CTC enumeration. PMID- 30246928 TI - Regulation of Notch signaling in the developing Drosophila eye by a T-box containing transcription factor, Dorsocross. AB - Owing to a multitude of functions, there is barely a tissue or a cellular process that is not being regulated by Notch signaling. To allow the Notch signal to be deployed in numerous contexts, many different mechanisms have evolved to regulate the level, duration and spatial distribution of Notch activity. To identify novel effectors of Notch signaling in Drosophila melanogaster, we analyzed the whole transcriptome of the wing and eye imaginal discs in which an activated form of Notch was overexpressed. Selected candidate genes from the transcriptome analysis were subjected to genetic interaction experiments with Notch pathway components. Among the candidate genes, T-box encoding gene, Dorsocross (Doc) showed strong genetic interaction with Notch ligand, Delta. Genetic interaction between them resulted in reduction of eye size, loss of cone cells, and cell death, which represent prominent Notch loss of function phenotypes. Immunocytochemical analysis in Df(3L)DocA/Dl 5f trans-heterozygous eye discs showed accumulation of Notch at the membrane. This accumulation led to decreased Notch signaling activity as we found downregulation of Atonal, a Notch target and reduction in the rate of Notch-mediated cell proliferation. Doc mutant clones generated by FLP FRT system showed depletion in the expression of Delta and subsequent reduction in the Notch signaling activity. Similarly, Doc overexpression in the eye discs led to modification of Delta expression, loss of Atonal expression and absence of eye structure in pharate adults. Taken together, our results suggest that Doc regulates the expression of Delta and influence the outcome of Notch signaling in the eye discs. PMID- 30246930 TI - Cyclopentyl Methyl Ether: An Elective Ecofriendly Ethereal Solvent in Classical and Modern Organic Chemistry. AB - Solvents represent one of the major contributions to the environmental impact of fine-chemical synthesis. As a result, the use of environmentally friendly solvents in widely employed reactions is a challenge of vast real interest in contemporary organic chemistry. Within this Review, a great variety of examples showing how cyclopentyl methyl ether has been established as particularly useful for this purpose are reported. Indeed, its low toxicity, high boiling point, low melting point, hydrophobicity, chemical stability towards a wide range of conditions, exceptional stability towards the abstraction of hydrogen atoms, relatively low latent heat of vaporization, and the ease with which it can be recovered and recycled enable its successful employment as a solvent in a wide range of synthetic applications, including organometallic chemistry, catalysis, biphasic reactions, oxidations, and radical reactions. PMID- 30246931 TI - Diabetes and tuberculosis: A closer and closer relationship. PMID- 30246929 TI - Relapse after severe acute malnutrition: A systematic literature review and secondary data analysis. AB - The objectives of most treatment programs for severe acute malnutrition (SAM) in children focus on initial recovery only, leaving post-discharge outcomes, such as relapse, poorly understood and undefined. This study aimed to systematically review current literature and conduct secondary data analyses of studies that captured relapse rates, up to 18-month post-discharge, in children following recovery from SAM treatment. The literature search (including PubMed and Google Scholar) built upon two recent reviews to identify a variety of up-to-date published studies and grey literature. This search yielded 26 articles and programme reports that provided information on relapse. The proportion of children who relapsed after SAM treatment varied greatly from 0% to 37% across varying lengths of time following discharge. The lack of a standard definition of relapse limited comparability even among the few studies that have quantified post-discharge relapse. Inconsistent treatment protocols and poor adherence to protocols likely add to the wide range of relapse reported. Secondary analysis of a database from Malawi found no significant association between potential individual risk factors at admission and discharge, except being an orphan, which resulted in five times greater odds of relapse at 6 months post-discharge (95% CI [1.7, 12.4], P = 0.003). The development of a standard definition of relapse is needed for programme implementers and researchers. This will allow for assessment of programme quality regarding sustained recovery and better understanding of the contribution of relapse to local and global burden of SAM. PMID- 30246932 TI - Presenilin Regulates Retinotectal Synapse Formation through EphB2 Receptor Processing. AB - As the catalytic component of gamma-secretase, presenilin (PS) has long been studied in the context of Alzheimer's disease through cleaving the amyloid precursor protein. PS/gamma-secretase, however, also cleaves a multitude of single-pass transmembrane proteins that are important during development, including Notch, the netrin receptor DCC, cadherins, drebrin-A, and the EphB2 receptor. Because transgenic PS-KO mice do not survive to birth, studies of this molecule during later embryonic or early postnatal stages of development have been carried out using cell cultures or conditional knock-out mice, respectively. As a result, the function of PS in synapse formation had not been well-addressed. Here, we study the role of PS in the developing Xenopus tadpole retinotectal circuit, an in-vivo model that allows for protein expression to be manipulated specifically during the peak of synapse formation between retinal ganglion cells and tectal neurons. We found that inhibiting PS in the postsynaptic tectal neurons impaired tadpole visual avoidance behavior. Whole cell recordings indicated weaker retinotectal synaptic transmission which was characterized by significant reductions in both NMDA receptor (NMDAR)- and AMPA receptor (AMPAR) mediated currents. We also found that expression of the C-tail fragment of the EphB2 receptor, which is normally cleaved by PS/gamma-secretase and which has been shown to upregulate NMDARs at the synapse, rescued the reduced NMDAR mediated responses. Our data determine that normal PS function is important for proper formation and strengthening of retinotectal synapses through cleaving the EphB2 receptor. PMID- 30246933 TI - Understanding the Roles of NiOx in Enhancing the Photoelectrochemical Performance of BiVO4 Photoanodes for Solar Water Splitting. AB - Solar water oxidation is considered as a promising method for efficient utilization of solar energy and bismuth vanadate (BiVO4 ) is a potential photoanode. Catalyst loading on BiVO4 is often used to tackle the limitations of charge recombination and sluggish kinetics. In this study, amorphous nickel oxide (NiOx ) is loaded onto Mo-doped BiVO4 by photochemical metal-organic deposition method. The resulting NiOx /Mo:BiVO4 photoanodes demonstrate a two-fold improvement in photocurrent density (2.44 mA cm-2 ) at 1.23 V versus reversible hydrogen electrode (RHE) compared with the uncatalyzed samples. After NiOx modification the charge-separation and charge-transfer efficiencies improve significantly across the entire potential range. It is further elucidated by open circuit photovoltage (OCP), time-resolved-microwave conductivity (TRMC), and rapid-scan voltammetry (RSV) measurements that NiOx modification induces larger band bending and promotes efficient charge transfer on the surface of BiVO4 . This work provides insight into designing BiVO4 -catalyst assemblies by using a simple surface-modification route for efficient solar water oxidation. PMID- 30246934 TI - Molecular and Synaptic Bases of CDKL5 Disorder. AB - The X-linked gene cyclin-dependent kinase-like 5 (CDKL5) encodes a serine/threonine kinase abundantly expressed in the brain. Mutations in CDKL5 have been associated with neurodevelopmental disorders characterized by early onset epileptic encephalopathy and severe intellectual disability, suggesting that CDKL5 plays important roles in brain development and function. Recent studies using cultured neurons, knockout mice, and human iPSC-derived neurons have demonstrated that CDKL5 regulates axon outgrowth, dendritic morphogenesis, and synapse formation. The role of CDKL5 in maintaining synaptic function in the mature brain has also begun to emerge. Moreover, mouse models that are deficient for CDKL5 recapitulate some of the key clinical phenotypes in human patients. Here we review these findings related to the function of CDKL5 in the brain and discuss the underlying molecular and cellular mechanisms. PMID- 30246935 TI - Proteome Profiling by Label-Free Mass Spectrometry Reveals Differentiated Response of Campylobacter jejuni 81-176 to Sublethal Concentrations of Bile Acids. AB - PURPOSE: Bile acids are crucial components of the intestinal antimicrobial defense and represent a significant stress factor for enteric pathogens. Adaptation processes of Campylobacter jejuni to this hostile environment are analyzed in this study by a proteomic approach. EXPERIMENTAL DESIGN: Proteome profiling by label-free mass spectrometry (SWATH-MS) has been used to characterize the adaptation of C. jejuni to sublethal concentrations of seven bile acids. RESULTS: The bile acids with the lowest inhibitory concentration (IC50 ), deoxycholic and chenodeoxycholic acid, induce the most significant proteome changes. Overall a downregulation of all basic biosynthetic pathways and a general decrease in the transcription machinery are found. Concurrently, an induction of factors involved in detoxification of reactive oxygen species, protein folding, and bile acid exporting efflux pumps is detected. Exposure to deoxycholic and chenodeoxycholic acid results in an increased expression of components of the more energy-efficient aerobic respiration pathway, while the anaerobic branches of the electron transport chain are down-expressed. CONCLUSIONS AND CLINICAL RELEVANCE: The results show that C. jejuni has a differentiated system of adaptation to bile acid stresses. The findings enhance the understanding of the pathogenesis of campylobacteriosis, especially for survival of C. jejuni in the human intestine, and may provide clues to future medical treatment. PMID- 30246936 TI - Augmented-reality robot-assisted radical prostatectomy using hyper-accuracy three dimensional reconstruction (HA3DTM) technology: a radiological and pathological study. AB - OBJECTIVES: To assess the use of hyper-accuracy three-dimensional (HA3DTM; MEDICS, Moncalieri, Turin, Italy) reconstruction based on multiparametric magnetic resonance imaging (mpMRI) and superimposed imaging during augmented reality robot-assisted radical prostatectomy (AR-RARP). PATIENTS AND METHODS: Patients with prostate cancer (clinical stages cT1-3, cN0, cM0) undergoing RARP at our Centre, from June 2017 to April 2018, were enrolled. In all cases, cancer was diagnosed with targeted biopsy at the level of index lesion based on high resolution (1-mm slices) mpMRI. HA3D reconstruction was created by dedicated software to obtain the 3D virtual model of the prostate and surrounding structures. A specific system was used to overlay virtual data on the endoscopic video displayed by the remote da Vinci(r) surgical console (Intuitive Surgical Inc., Sunnyvale, CA, USA), and the virtual images were superimposed by the surgeon by the means of the TileProTM multi-input display technology (Intuitive Surgical Inc.). The AR technology was used in four standardised key steps during RARP. The procedures were modulated differently in cases of prostate cancer without extracapsular extension (ECE) at mpMRI (Group A) or in cases of prostate cancer with ECE (Group B) at mpMRI. In Group A, the virtual image of the prostate was overlaid on the endoscopic view and the intraprostatic lesion was marked on the prostate surface by a metallic clip at the level of the suspicious lesion as identified by the 3D virtual AR image. In Group B, the same step was performed; moreover, a metallic clip was placed at the level of the suspicious ECE on the neurovascular bundles (NVBs) according to the virtual images. Finally, selective biopsies were taken from the NVBs at this level, and then, the entire NVBs were removed for final pathological examination, according to standard clinical indications. For Group A, the pathologist performed a targeted needle biopsy at the level of the metallic clip on the surface of prostate before the sample reduction. For Group B, the presence of tumour was evaluated during the reduction phase, at the level of metallic clip on the prostate surface and at the level of NVBs, sent separately. Finally, an image 3D scanner (Kinect, Microsoft) was used to perform a dimensional comparison between the mpMRI-based 3D virtual reconstruction and the whole-mount specimen. RESULTS: In all, 30 patients were enrolled in the present study, 11 (36.6%) included in Group A and 19 (63.4%) in Group B. In all cases (30/30), final pathology confirmed the location of the index lesion, as cancer was found at the level of the metallic clip. The suspected ECE was confirmed on final pathology in 15/19 cases (79%). The AR guided selective biopsies at the level of the NVBs confirmed the ECE location, with 11/15 (73.3%) biopsies at the level of NVBs positive for cancer. The mismatch between the 3D virtual reconstruction and the prostate 3D scanning based on the whole-mount specimen was <3 mm in >85% of the gland. CONCLUSION: Our results suggest that a HA3D virtual reconstruction of the prostate based on mpMRI data and real-time superimposed imaging allow performance of an effective AR RARP. Potentially, this approach translates into better outcomes, as the surgeon can tailor the procedure for each patient. PMID- 30246937 TI - Characterising potential bone scan overuse amongst men treated with radical prostatectomy. AB - OBJECTIVES: To characterise bone scan use, and potential overuse, after radical prostatectomy (RP) using data from a large, national integrated delivery system. Overuse of imaging is well documented in the setting of newly diagnosed prostate cancer, but whether overuse persists after RP remains unknown. PATIENTS AND METHODS: We identified 12 269 patients with prostate cancer treated with RP between 2005 and 2008 using the Veterans Administration Central Cancer Registry. We used administrative and laboratory data to examine rates of bone scan use, including preceding prostate-specific antigen (PSA) levels, and receipt of adjuvant or salvage therapy. We then performed multivariable logistic regression to identify factors associated with post-RP bone scan use. RESULTS: At a median follow-up of 6.8 years, one in five men (22%) underwent a post-RP bone scan at a median PSA level of 0.2 ng/mL. Half of bone scans (48%) were obtained in men who did not receive further treatment with androgen-deprivation or radiation therapy. After adjustment, post-RP bone scan was associated with a prior bone scan (adjusted odds ratio [aOR] 1.55, 95% confidence interval [CI] 1.32-1.84), positive surgical margin (aOR 1.68, 95% CI 1.40-2.01), preoperative PSA level (aOR 1.02, 95% CI 1.01-1.03), as well as Hispanic ethnicity, Black race, and increasing D'Amico risk category, but not with age or comorbidity. CONCLUSION: We found a substantial rate of bone scan utilisation after RP. The majority were performed for PSA levels of <1 ng/mL where the likelihood of a positive test is low. More judicious use of imaging appears warranted in the post-RP setting. PMID- 30246938 TI - Engineering Artificial Fusion Proteins for Enhanced Methanol Bioconversion. AB - Methanol is a low-cost and abundantly available feedstock derived from natural gas and syngas. Although bioconversion holds promise for producing desired chemicals from methanol under economically viable operating conditions, the efficiency is limited by unfavorable kinetics of methanol oxidation and assimilation. Herein, artificial fusion proteins were engineered to enhance methanol bioconversion. Nicotinamide adenine dinucleotide (NAD)-dependent methanol dehydrogenase (Mdh), 3-hexulose-6-phosphate synthase (Hps) and 6-phospho 3-hexuloisomerase (Phi) from different sources were first screened for catalytic activity. Next, we designed six fusion proteins using the best enzyme candidates and flexible linkers. Fusing Mdh with Hps or Hps-Phi increased the Vmax of methanol oxidation up to 5.8-fold, and enhanced methanol conversion to fructose-6 phosphate up to 1.3-fold. Interestingly, fusion engineering changed the polymerization states of proteins and produced larger multimers, which may be responsible for the changed catalytic characteristics. This fusion engineering approach can be coupled with other metabolic engineering strategies for enhanced methanol bioconversion to valuable chemicals. PMID- 30246939 TI - Randomized double-blind clinical studies of ularitide and other vasoactive substances in acute decompensated heart failure: a systematic review and meta analysis. AB - AIMS: Acute decompensated heart failure (ADHF) has a poor prognosis and limited treatment options. No direct comparisons between ularitide-a synthetic natriuretic peptide being evaluated in ADHF-and other vasoactive substances are available. The aim of this meta-analysis was to determine haemodynamic effect sizes from randomized double-blind trials in ADHF. METHODS AND RESULTS: Eligible studies enrolled patients with ADHF requiring hospitalization and haemodynamic monitoring. Patients received 24-48 h of infusion with a vasoactive substance or comparator. Primary outcome measure was pulmonary artery wedge pressure (PAWP). Treatment effects were quantified as changes from baseline using mean differences between study drug and comparator. Results were analysed using random-effects (primary analysis) and fixed-effects meta-analyses. Twelve randomized, double blind studies were identified with data after 3, 6, and 24 h of treatment (n = 622, 644, and 644, respectively). At 6 h, significant PAWP benefits for ularitide over placebo were seen (Hedges' g effect size, -0.979; P < 0.0001). On meta analysis, treatment difference between ularitide and pooled other agents was statistically significant (-0.501; P = 0.0303). Effect sizes were numerically higher with ularitide than other treatments at 3 and 24 h. After 6 h, a significant difference in effect size between ularitide and all other treatments was observed for right atrial pressure (Hedges' g, -0.797 for ularitide and 0.304 for other treatments; P = 0.0274). CONCLUSIONS: After 6 h, ularitide demonstrated high effect sizes for PAWP and right atrial pressure. Improvements in these parameters were greater with ularitide vs. pooled data for other vasoactive drugs. PMID- 30246942 TI - Scientific Program. PMID- 30246941 TI - Abstracts of the 10th Congress of the European Academy of Andrology, 11 - 13 October 2018, Budapest, Hungary. PMID- 30246943 TI - Welcome. PMID- 30246944 TI - Monitoring Sphingolipid Trafficking in Cells using Fluorescence Microscopy. AB - Sphingolipids are structural components of organelle membranes that also participate in signal transduction pathways. Complex sphingolipids are trafficked from their site of synthesis in organelles of the early secretory pathway to the Golgi apparatus, the plasma membrane, and the endo-lysosomal system. We have developed fluorescence microscopy-based methods to monitor sphingolipid trafficking in coordination with secretory protein sorting. A sphingomyelin binding protein fused to a fluorescent protein, which we term "EQ-SM," is implemented to monitor sphingomyelin trafficking from the Golgi apparatus to the plasma membrane via secretory vesicles. A protocol is provided to determine if a query protein of interest is secreted from the cell via vesicles enriched in EQ SM, an indication that the vesicle membrane is enriched in sphingomyelin. A complementary protocol is described that implements a chemically modified form of sphingosine, a metabolic precursor to complex sphingolipids, to visualize ceramide and complex sphingolipids in fixed cells. (c) 2018 by John Wiley & Sons, Inc. PMID- 30246940 TI - High glucose-induced complement component 3 up-regulation via RAGE-p38MAPK-NF kappaB signalling in astrocytes: In vivo and in vitro studies. AB - Diabetes is considered as a risk for cognitive decline, which is characterized by neurodegenerative alteration and innate immunity activation. Recently, complement 3 (C3), the critical central component of complement system, has been reported to play a key role in neurodegenerative alterations under pathological condition. Receptor for advanced glycation end products (RAGE) activation is confirmed to mediate several inflammatory cytokines production. However, whether C3 activation participates in the diabetic neuropathology and whether this process is regulated by RAGE activation remains unknown. The present study aimed to investigate the role of C3 in streptozotocin-induced diabetic mice and high glucose-induced primary astrocytes and the underlying modulatory mechanisms. The decreased synaptophysin density and increased C3 deposition at synapses were observed in the diabetic brain compared to the control brain. Furthermore, the elevated C3 was co-localized with GFAP-positive astrocytes in the diabetic brain slice in vivo and high glucose-induced astrocytes culture in vitro. Diabetes/high glucose induced up-regulation of C3 expression at gene, protein and secretion levels, which were attenuated by pre-treatment with RAGE, p38MAPK and NF-kappaB inhibitors separately. These results demonstrate that high glucose induces C3 up regulation via RAGE- p38MAPK-NF-kappaB signalling in vivo and in vitro, which might be associated with synaptic protein loss. PMID- 30246945 TI - Decreased Neurogenesis Increases Spatial Reversal Errors in Chickadees (Poecile atricapillus). AB - Adult hippocampal neurogenesis has been proposed to both aid memory formation and disrupt memory. We examined the role of adult hippocampal neurogenesis in spatial working and reference memory in black-capped chickadees (Poecile atricapillus), a passerine bird that relies on spatial memory for cache retrieval and foraging. We tested spatial working and spatial reference memory in birds that had received methylazoxymethanol acetate (MAM), a neurotoxin that decreases hippocampal neurogenesis. MAM treatment significantly reduced neurogenesis in the hippocampus quantified by doublecortin (DCX) labeling of newly divided and migrating neurons. MAM treatment had little effect on the working or reference memory but caused an increase in errors on the reference memory task following reversal. Working memory for recently visited spatial locations and reference memory for familiar spatial locations were thus unaffected by a reduction in neurogenesis. An increase in errors following reference memory reversal may indicate that adult hippocampal neurogenesis aids in pattern separation, the differentiation of similar memories at the time of encoding. PMID- 30246946 TI - Preventing the development of heel pressure ulcers. AB - The heel is a common site for pressure ulcer development, particularly in people who are supine or semi-recumbent because of immobility. There is little protective subcutaneous tissue and no muscle or fascia within the heel, which means that it is vulnerable to pressure, friction and shear forces. Heel pressure ulceration remains a clinical challenge for nurses and the wider healthcare team, as well as a cause of pain and physical debilitation for the patient. This article examines the risk factors for heel pressure ulceration, and details patient assessment and specific measures that can be undertaken to prevent the development of heel pressure ulcers. PMID- 30246947 TI - Catalytic Liquefaction of Corn Stalk under Atomosphere Prssure and the Analysis of Liquefaction Products. AB - With concentrated phosphoric acid as catalyst and various organic solvents as liquefying agents, corn stalk powder was liquefied into bio-oil in an autoclave, under the condition of 170 C. Analysis was conducted to throw light on the liquefying effects of three different agents; they are glycerol triacetate with ethylene carbonate, glycerol with ethylene carbonate and polyethylene glycol with ethylene carbonate(6?1 omega/omega), and the properties of the biomass liquefaction oil products. FT-IR was applied to examine raw material and residues, whose chemical compositions were further analyzed with the use of GC MS. The results of experiments indicated that the liquefaction yield of polyethylene glycol was 97.84%, the yield of glycerol triacetate was 80.20%, the yield of glycerol were36.97%. FT-IR analysis showed that the functional groups of cellulose, hemicelluloses and lignin was disappeared and liquefaction is best when polyethylene glycol with ethylene carbonate was used as the liquefaction agent. GC-MS analysis showed that the oil composition produced in this way is complex, contains organic acids and ketones, alcohols and ethers, aromatic, sugars and esters compounds. PMID- 30246948 TI - Analysis of the Effect of Moisture on Soil Organic Matter Determination and Anti Moisture Interference Model Building Based on Vis-NIR Spectral Technology. AB - Soil moisture shows a strong absorption for spectroscopy while soil organic matter and moisture have identical absorption bands. Therefore, the soil moisture causes interference to soil organic matter detection. The study made the following works: firstly, different soil organic matter dynamic spectrums under different moisture content were acquired with visible near-infrared spectroscopy; secondly, different organic matter content features under the same moisture content were analyzed with two-dimensional synchronization correlation spectroscopy. When the soil moisture is 0%, around 600 and 1 660 nm which characterize soil organic matter band appear strong autocorrelation peaks. With moisture content increasing, around 600 and 1 660 nm band disappear and around 1 931, 2 200 and 1 480 nm band appear strong autocorrelation peaks in the near infrared region. Soil moisture covers information bands which characterize soil organic matter and affects soil organic matter detection; thirdly, the maximum moisture content samples approximately in the filed participated modeling to eliminate the effect of moisture on soil organic matter detection and improve the model prediction accuracy. The anti-moisture interference prediction model which used 550~650 and 1 610~1 710 nm wavelengths by PLS (Partial Least Squares) quantitative analysis method was established to predicate the soil organic matter content under different moisture content. The results are as follows: predicted correlation coefficient, SEP and RMSEP is 0.954, 0.744 and 0.844 respectively. Predicted effect improves significantly. It is that the method can reduce the effect of moisture on soil organic matter detection. PMID- 30246949 TI - Hyperspectral Study of Estimating Nitrification Microorganism in Wetland Soils. AB - Nitrogen cycle is an important process in the circle of soil ecosystem elements, and nitrification has significant effect on soil nitrogen cycling. The main completer of nitrification is nitrification microbial communities. Soil microorganisms are vital components of wetland ecosystem. They can indicate the variations of wetland ecological environment, and this helps us to have the correct understanding of nitrogen cycle and pollution purification function in wetland ecosystem. This paper tries to study nitrification microbial communities in wetland soils from the perspective of hyperspectral remote sensing technology, based on the monitoring mechanisms of soil nitrogen spectrum. The study explores hyperspectral estimation techniques for nitrification microbial communities in wetland soils, and it can provide a new technical approach to estimate the temporal and spatial distribution of nitrification microbial communities. The study adopted most probable number method (MPN) to count the numbers of ammonia oxidizing bacteria and nitrite oxidizing bacteria respectively, which were main completers of two independent stages in nitrification. And the total results of both count measurements were used as the values of soil nitrification microorganisms for each sampling area. The estimation models of nitrification microorganism and total nitrogen in wetland soils were developed respectively using spectral transformation techniques, such as log-transformed spectra (LR), first derivative (FD), second derivative (SD), continuum removal (CR) and band depth (BD), and modeling methods, such as stepwise multiple linear regression (SMLR) and partial least-squares regression (PLSR) based on the bootstrap technology. The results indicated that the selected estimation bands of nitrification microorganism and total nitrogen were close (especially for original spectral data (R) and SD spectra) when the modeling method of bootstrap SMLR was used. Compared to the bootstrap SMLR, the bootstrap PLSR achieved higher accuracies for estimating nitrification microorganism and total nitrogen in wetland soils. The spectral transformation technique of SD combined with the modeling method of bootstrap PLSR yielded the highest estimation accuracy to predict nitrification microorganism in wetland soils. The CR spectral data combined with bootstrap PLSR produced the highest estimation accuracy to predict total nitrogen content in wetland soils. PMID- 30246950 TI - The Comparison of Spectral Classification Based on DBN, BP Neural Network and SVM. AB - The stellar classification was an important research field for understanding the formation and evolution of stars and galaxies. With large sky surveys and its massive data, the speed and accuracy of the celestial automatic classification was very important. The depth confidence neural network (DBN), support vector machines (SVM) and BP neural networks used in the star classification were compared in this paper. And the applicability of star classification with these three methods was analyzed. First, K, F stars are classified according to the depth of confidence neural network and BP neural network and support vector machine.Then the K1, K3, K5 sub-type and F2, F5, F9 sub-type were separately identified. Finally, the data which did not belong to the k sub-type were excluded by a secondary classification model based on SVM support vector machine . The results shows that: the depth of belief networks is better for K, F-type star classification, but it is poor for K, F sub-type classification results; The recognition rate of SVM is high for the K, F-type stars and the classification effects of this method is better for K, F-type stars than the corresponding sub type stars by comparison; The recognition rate of BP neural network is ordinary general for K, F-type stars and their sub-types. The experiment showed that the accuracy of excluding non-k-sub-type data can be up to 100% which indicates that the unknown spectral data can be screened and classified with SVM. PMID- 30246951 TI - Skin and diabetes: an experts' opinion from the Italian diabetologists and dermatologists of the DiaDex group. AB - The metabolic changes associated with diabetes mellitus (DM) affect a variety of organs and systems, including the skin. Skin lesions are frequently observed in patients with DM, resulting from a complex interaction among biochemical, vascular, immune, and metabolic changes. Cutaneous manifestations may develop at any time in the course of DM. They can be the first sign of the disease, possibly helping in diagnosis, or represent a marker of poor glycemic control. Given the high prevalence of cutaneous manifestations in DM, their possible role in favoring DM early diagnosis, and their relationship with the patient's metabolic control, a group of Italian dermatologists and diabetologists, the DiaDex expert group, jointly formulated a few basic statements aimed at favoring a stricter interdisciplinary cooperation in order to improve patients' management. Deeper knowledge of the skin lesions most commonly associated with DM, their early identification, and prompt reciprocal referral, when appropriate, are the pivotal points of these statements and should represent the pillars of such desired cooperation. The dermatologists and diabetologists of the DiaDex group believe that their different diagnostic and therapeutic skills put together may significantly benefit the many DM patients with cutaneous complications and hope that this paper may provide some guidance on how to achieve this goal. PMID- 30246952 TI - A pigmented papule acting like a playful ghost: dermoscopy of three targetoid hemosiderotic hemangiomas. AB - Targetoid hemosiderotic hemangioma represents an uncommon, distinctive, benign lympho-vascular lesion, with a variable clinical appearance, typically occurs in the lower limbs and trunk. Most patients are in their 20's or 30's. We describe three dermoscopic cases followed by the review of the literature. Dermoscopic images have been collected and have been evaluated for the presence of dermoscopic features. Concerning the review, we researched on pubmed and records were reviewed noting patient age of onset, sex, location, overall size, dermoscopic appearance. The harmonic mean age of patients was 31 years; the female-to-male ratio was 1:1, and the most common locations were lower extremities (47%) and the trunk (29%). In the most recent years several pediatric cases were described, lowering the mean age of the patients in the literature. Most targetoid hemosiderotic hemangioma appear clinically as a small, solitary, reddish-violaceous vascular lesion with a targetoid appearance. The most typical dermoscopic findings are a homogeneous central area, red lacunae, dark lacunae, peripheric red-violaceous ring, whitish structures, peripheric vascular structures, yellowish intermediate areas, and a peripheral pigment network. Histologically, more superficially, in the papillary dermis there are dilated thin blood vessels lined by hobnail-appearing endothelial cells. In the deeper dermis there are typically slit-like capillaries that ramify in the dermis and dissect through collagen bundles. We wanted to evaluate the features of a large series of targetoid hemosiderotic hemangiomas for a better awareness of the entity, to improve its clinical and dermoscopic diagnostic accuracy, to focus attention on nontargetoid patterns, which often mimic other lesions, including melanoma. PMID- 30246953 TI - Cutaneous metastases of pancreatic neuroendocrine carcinoma. AB - Neuroendocrine carcinomas with distant metastases are rarely reported in the literature, with cutaneous metastases being among the most infrequently reported sites. The importance of distinguishing metastatic neuroendocrine carcinoma (NEC) from primary neuroendocrine carcinoma in the skin, or Merkel cell carcinoma (MCC), has been stressed in the literature, with CK20 positivity traditionally being reported as the key diagnostic feature of MCC. Our case not only serves as one of the few reported cases of cutaneous metastases of a visceral NEC, but also serves to caution providers as to the use of CK20 positivity as an absolute diagnostic feature. We present a case of a 67-year-old female with widespread cutaneous metastases of a pancreatic NEC. Immunohistochemical staining revealed CK20 positivity, despite visceral origin of the primary tumor. This case serves to highlight not only a rare presentation of cutaneous metastases of a pancreatic neuroendocrine carcinoma, which has yet to be reported in the literature, but also serves as the only report of a pancreatic NEC with CK20 positivity, providing evidence for cautionary use of CK20 staining for diagnostic purposes, particularly for visceral NECs which have been under-represented in the literature. PMID- 30246954 TI - Leukemia cutis in a Ph+ ALL patient treated with ponatinib. PMID- 30246956 TI - Shiny white streaks in juvenile xanthogranuloma: a worrisome feature in a benign disorder. PMID- 30246955 TI - Prognostic correlation between vitamin D serological levels, Body Mass Index and clinical-pathological features in melanoma patients. PMID- 30246958 TI - Introducing the Vortex quadrigeminal flap: the ultimate low-tension solution for reconstructive surgery of the temple. PMID- 30246957 TI - Spiny keratoderma of the palms in a patient with diabetes mellitus type 1: what came first, the chicken or the egg? PMID- 30246959 TI - Reinventing the wheel: a simple topical treatment for psoriasis. PMID- 30246960 TI - Giant plexiform neurofibroma in neurofibromatosis type 1. PMID- 30246961 TI - Thickness Calculation of Silicon Dioxide Nano-Film Based on GIXRR Reflectivity Curve. AB - To obtain nanometer thin film thickness fastly and accurately, a formula of linear fitting method based on the periodic Kiessig fringes for thickness determination is applied, and a series of SiO2 nanometer films on Si substrate with the film thickness ranging from 10 to 120 nm have been calculated with the formula. These samples are prepared with thermal atomic layer deposition (T-ALD) process and film thickness is measured with grazing incidence X-ray reflection (GIXRR) technique, in addition, the linear fitting procedure and several influencing factors among it are studied, all of the work is based on the reflectivity curve from GIXRR experiment. While at the same time, another fitting method based on a soft named Global Fit2.0 is brought into this study to compare the two obtained thicknesses from two kinds of analysis methods. In the end a novel method for film thickness determination-empirical curve is presented. The results show that: during the linear fitting process, the peak position series have a main effect on thickness determination, thickness will increase when the peak position adds up; Besides, any peak's corresponding reflection angle also has a significant effect on the thickness determination, it is expressed in the form of interference fringe period, thickness will decrease while the interference fringe period increases, however, the errors from either peak series or fringe period can be further weakened with trial and error method, calibration procedure of critical angle and interference fringe period individually. Choosing the same sample with random thickness, no matter using the linear fitting and soft fitting method, the two gained film thicknesses are consistent and the thickness deviation is less than 0.1 nm, which illustrates the accuracy of linear fitting method for thickness determination. An empirical relationship between film thickness and interference fringe period is then put forward on the foundation of the accurate thickness determination, according this curve, the target film thickness is directly got by putting an interference fringe period in the empirical curve. This novel method not only avoids the messy procedure of choosing peak position series or their corresponding angles during linear fitting process, but also avoids the complex task of building a correct structure for soft fitting process; it is of great significance in confirming thin film thickness with quick speed and high accuracy. PMID- 30246962 TI - Analyzing Spectral Characteristics of Water Involving In-Situ Multiangle Polarized Reflectance and Extraction of Water-Leaving Radiance. AB - Polarization is defined as an asymmetry in the direction of vibration with respect to the direction of light propagation. Polarization information is an important component to remote sensed data, which comprises spatial, spectral, and radiation information. In optical remote sensing, polarization information supplements spectral information. Polarization-based remote sensing has a significant application potential for analyzing the spectral characteristics of water bodies, wherein a very important technique is eliminating the mirror reflection caused by skylight on the water surface and extracting water-leaving radiance that carry the constituent information. The incident sunlight on the surface of water either reflects or scatters owing to the existence of particles in water, which results in water-leaving signals with strong polarization characteristics. The ongoing experiments on remote sensing involve water polarization cover either clean ocean waters under natural light or indoor simulations of water under artificial light; however, turbid inland waters under natural light have rarely been investigated. Through the combination of a field spectroradiometer and a Thompson polarizing prism, this study obtained in-situ measurements of the spectral polarization reflectance over inland waters under natural light conditions. Using the obtained multiangle polarized reflectance spectra, the polarization spectral characteristics of water under multiangle viewing conditions were quantitatively analyzed, and the water-leaving radiance was achieved by eliminating skylight reflection. When observing water bodies at an azimuth of 135 degrees and a zenith of 53 degrees , the measurement of polarization to eliminate skylight reflection had better elimination efficiency than at other viewing angles, and this observation angle was recommended for conducting spectral polarized above-water observations. Compared with the traditional methods including non-polarized above-water measurements, the proposed method is less prone to being affected by changes in weather conditions, and it can extract water-leaving radiance more accurately. PMID- 30246963 TI - The Spectral Prediction of Original Primary Pigment Based on Constrained Non Negative Matrix Factorization. AB - With direct prediction in the spectral reflectance space with principal component analysis, the numbers of eigenvectors will surpass the numbers of real primary pigments while the eigenvectors and the corresponding coefficients have negative value, which can not directly presented original primary pigment spectral characteristics and corresponding concentration. We proposed an innovative spectral prediction method in which a complete linear spectral space was created according to optical properties of originals pigment. A constrained non-negative matrix factorization algorithm to predict the numbers and spectral curve shapes of real primary pigments was used in the space. So, this paper designed an overall research plan and implementation process about spectral prediction method firstly, and studied how to select and establish a spectral linear space which was conformed to optical properties of originals; taking transparent pigments as example, and spectra constrained non-negative matrix factorization (SCNMF) algorithm was established to predict primary pigment spectra based on basic non negative matrix factorization algorithm (BNMF). Aiming at realizing multiple optimal solution of BNMF and improving the prediction accuracy as well as make the matrix decomposition results to be clearly physically meaningful; the proposed SCNMF needs to satisfy four constraints: non negative constraint, additive constraint, smoothness constraint and sparseness constraint. The objective function and iterative algorithm to meet four constraints were set up. The prediction results show that the proposed method can realize accurate prediction of original primary pigments' numbers and spectra effectively. PMID- 30246964 TI - Optimization of Maximum Light Use Efficiency in Inner Mongolian Steppe. AB - For the case that the value of the maximum light use efficiency (MLUE) is not optimized for different steppes, we simulated the MLUE for meadow steppe, typical steppe and desert steppe in Inner Mongolia based on the field observed NPP and CASA ecosystem model, and analyzed the spatial and temporal pattern of the LUE and net primary productivity (NPP) in Inner Mongolia. The result indicate that the MLUE is optimized to be 0.654,0.553 and 0.511 gC.MJ-1 for meadow steppe, typical steppe and desert steppe in Inner Mongolia, respectively, with an average of 0.573 gC.MJ-1. Compared to the result that used same value of 0.541 gC.MJ-1 for MLUE, the correlation coefficient and relative mean square error was improved 0.024 and 2.62 gC.(m2.month-1)-1, respectively after optimization. Affected by the hydrothermal condition and distribution of grassland types, the LUE and NPP in Inner Mongolia decreased from northeast to southwest, and showed one crest shape. However, the maximum value of LUE and NPP was appeared in August and July. This difference could be attributed to the difference in the maximum value between absorbed photosynthetically active radiation and LUE. The LUE and NPP decreased by meadow steppe, typical steppe and desert steppe. PMID- 30246965 TI - Study on Absorption Spectra of Lutein Aggregate with Experimental Analysis and Theoretical Calculation. AB - Compared with the monomer, aggregate exhibits unique features such as electron and energy transfer which can be understood with the study of absorption spectra. In the experimental the absorption spectra of lutein monomer in ethanol solution and aggregate in 1?1 aqueous ethanol solution are detected by utilizing UV-lVis spectrophotometer. The vibration structure of excited state of lutein monomer is obtained with Gauss decomposition of the absorption spectra. Theoretically, the molecular parameters of excitation energy, vibration frequency of characteristic mode, Huang-Phys factor are calculated by means of simulation of the monomer absorption spectra described by temporal correlation function and Frenkel exciton model. The spectral calculation of the lutein aggregate is conducted by using these parameters and then the factors of the spectral changes affected by the aggregate structure are analyzed. Some conclusions are drawn from the analysis: (1) The absorption peak position of the aggregate is determined mainly by intermolecular interaction. The calculation shows that the interaction is about 2 000 cm-1 according 77 nm blue shift of absorption spectra from experiment result. (2) With the increase of molecular number of the aggregate the half-width of the absorption spectra decreases and the peak position blue shift slightly due to enhanced cooperation effect. (3) Disorder degree from environment has great influence on half-width for the greater disorder degree the larger half-width. The results of this paper will provide a theoretical reference for the further study of lutein aggregate function in biological and materials systems. PMID- 30246966 TI - Effect of Acid Elution on the Surface Structure Characteristics and Spectral Characteristics of Biochars. AB - Biochar often refers to a carbon-rich product obtained by pyrolyzing biomass at relatively low temperatures (<700 C). The increasing interest in the applications of biochar in soil amendment and environmental contaminant reduction has spurred many studies in recent years. Due to the high content of ash in biochar, the adsorption capacity of bichar is limited. The ash of biochar formed during pyrolysis has great influence on the structure characteristics and spectral characteristics of biochar. The ash of biochar is expected to enchance their efficacy and minimize their influence. For this purpose, the corn straw biochar made at two different temperatures (400 and 600 C) was used to study the effect on the structure characteristics of biochars under the acid elution. The samples were characterized with element analysis, Brunaner-Emmett-Teller-N2 surface areas, pore size distributions and micro infrared for structure analysis in this study. The result indicate that: the elution solvent could remove the by-products and improve the adsorptive capacity of biochars. (1)After acid elution, the carbon content, hydrophobicity and the aromatic functional group content were increased; the polarity of biochar was decreased. (2) After acid treated, the specific surface area of the biochars was significantly increased, the increment of two biochars was 3.46 times and 6.75 times; the pore volume and the mesoporous quantity were also enhanced. (3) After acid elution, the infrared analysis is similar, but the content of key functional groups was different significantly. The result of infrared analysis showed that, several absorbance peaks were decrease at 3 398~3 447, 2 924~3 056, 1 378~1 439 cm-1, and the acid treated can make the content of aliphatic chain char and hydroxyl reduce. (4) Biochar with low polarity and high aromaticity displayed a superior 2,4- dichlorophenoxyacetic acid adsorption capacity. Acid elution made the surface of biochar exposed more organic surface and porosity and it is one of the most important factors for the adsorption of biochar. The date with elemental analyzer, BET,FTIR techniques and batch experiment allowed us to develop a better understanding of evolution of biochar properties during the acid elution and these results have significant implications for using biochar as a soil additive for soil pollution. PMID- 30246968 TI - Access to surgery is not an election priority PMID- 30246967 TI - Research on Heat Transfer Characteristics in Oil Pool Fire Based on Spectral Analysis. AB - The inner part of the oil pool flame could be divided into different combustion areas, and there have been a limited number of researches on the heat transfer characteristics within oil pool fire. Due to the lack of adequate researches on the characteristics of heat transfer in oil pool flame, this paper carries out an analytical study to pool flame spectrums of 92# gasoline,95# gasoline and lube by establishing flame infrared testing system. Spectral information about different combustion regions of oil pool fire is collected. The results show that three kinds of oil pool fire have similar spectral characteristics, with several characteristics emission bands of such combustion products as CO2, H2O and carbon black particles and that 3.4 MUm C-H stretching vibration peak is obvious; the main spectral characteristics of smoke zone is high temperature CO2 emission peak at the band range of 4~4.5MUm, the heat exchange of flame and air is violent; the temperature changes unstably, and flame pulse frequency is high; spectral characteristics in the intermittent area is high temperature CO2 emission peak at 4~4.5 MUm; and flame pulse frequency in intermittent zone is relatively lower compared with that in the smoke zone; compared with that in the flue gas zone and intermittent zone, the combustion in continuous zone is more stable, the spectral characteristics of the region is obvious, and carbon black particle emission intensity is high at 2.5~3 MUm, and C-H stretching vibration emission peak shows itself at 3.4 MUm, which showed that the characteristic peak oil pool flame spectrum at 3.4 MUm is caused by high temperature oil vapor steam. Spectral characteristics analysis of the oil pool flame in different combustion areas shows that the heat transfer is absorbed by the fuel rich layer on the surface of the oil pool flame, which leads to the change in the energy level of the oil vapor near 3.4 MUm. The calculation of the emission spectrum intensity of oil pool flame in different combustion areas shows that the intensity in flame continuous zone is the largest, followed by the intermittent zone, that the connection between the flame smoke zone and the air is strong, and that the emission spectrum intensity is the lowest. The results in this study provide a reference for the modification of flame oil heat transfer model. PMID- 30246970 TI - Adaptability of Different Nebulizer Systems to Different Silicon Chemical Forms for Gasoline in Inductively Coupled Plasma Optical Emission Spectrometry. AB - Silicon is not a natural component of gasoline but it can cause silica deposition in vehicle combustion system which may lead to severe engine failure. Silicon is present in gasoline in different chemical forms. The analysis of oil products by directly measuring under organic phase through inductively coupled plasma optical emission spectrometry (ICP-OES) is becoming a widely accepted approach as it is found to be simple and fast. The work focused on the influence of the sample nebulizer systems to different silicon chemical forms by ICP-OES. For a sample introduction system consisting of micronebulizer coupled to a cyclonic spray chamber, the results indicated that the ICP-OES signals depended strongly on the silicon chemical forms, and the higher emission intensities have been attributed to the compound volatility. The variability of the signals induced by the different silicon compounds was less significant for the same nebulizer system with a temperature control device. Nevertheless, the interferences were not effectively mitigated. Nevertheless, direct injection high efficiency nebulizer (DIHEN) introduced in the present work can effectively mitigate the interferences of different silicon chemical forms, is suitable for the determination of silicon in gasoline. The quantitative method with the potential DIHEN nebulizer system showed good linearity and the recoveries ranged from 92.8%~108.7%, the limit of detection was 0.05 mg.kg-1. The relative standard deviation (RSD) was between 1.05% and 4.63%. Compared with the microwavedigestion method, the proposed method was found to be highly simple, rapid, sensitive and accurate, which has foreseen a promising application for silicon determination in gasoline. PMID- 30246969 TI - [Modern methods of diagnosis and control of the effectiveness of treatment for newly diagnosed fibro-cavernous pulmonary tuberculosis caused by mycobacteria with multiple drug resistance]. AB - The clinical observation of the successful treatment of newly diagnosed fibro cavernous pulmonary tuberculosis caused by mycobacteria of multidrug-resistant tuberculosis and the results of control of the effectiveness of treatment with modern high-tech radiation methods are presented. The necessity of an individual approach to the treatment of tuberculosis in this category of patients is shown. PMID- 30246971 TI - Element Geochemistry of Lake Sediments from L07-10 in the "Great Ear" Area of Lop Nur and Its Significance for Climate Variation Change with ICP-OES. AB - Spectral analysis techniques were applied to geochemical element analysis to provide additional environmental data about evolution of salt lakes and climate change. The elements composition of lake sediments from L07-10 in the "Great Ear" Area of Lop Nur was analyzedby using Inductively Coupled Plasma Optical Emission Spectrometer (ICP-OES )and from 14 C carbon dating by using the EN accelerator mass spectrometry (AMS).This paper estimated the climate change in this region since 16.34 ka BP. Results demonstrate that the geochemical characteristics of major elements at all sediment levels can indicate environmental change sensitivity, and element composition is more sensitive to climate change. Overall, climate succession since 16.34 ka BP had been: warm-wet, warm-dry, cold wet and warm-dry. From 8.09~6.34 ka BP,the climate obviously heated up and was warmer and drier, which is consistent with global and regional climate change estimates from other studies. By about 2 ka BP, the climate becomes warmer and drier and the water carrying capacity of this lake was reduced. PMID- 30246972 TI - L'acces a la chirurgie n'est pas une priorite electorale PMID- 30246973 TI - [Unusual 99(m) Tc-pyrophosphate accumulation in aortic aneurysm detected by bone scintigraphy]. AB - A clinical observation of focal accumulation of 99(m)Tc-pyrophosphate in aortic aneurysm, simulating skeletal pathology of the lumbar vertebra in planar scintigraphy mode, is presented. Additional single-photon emission computed tomography combined with computed tomography-something view allowed to confirm that the radiotracer uptake focus was localized in the distal part of the aneurysm, in the zone of lumen subocclusion by a calcified thrombus. It is suggested that the local tracer accumulation is not only due to calcification but also due to inflammatory, a factor that plays a role in the genesis of aortic aneurysm. PMID- 30246974 TI - Oncoplastic and reconstructive breast surgery in Canada: breaking new ground in general surgical training AB - Summary: Oncoplastic breast surgery combines certain plastic surgery procedures with a breast cancer resection to minimize the cosmetic penalty. We compared current practices in breast surgery in Canada and the UK, looking at the classification of oncoplastic breast surgery, management of larger tumours that would otherwise mandate a mastectomy, and the breast surgeon's role in immediate breast reconstruction. Reconstructive breast surgery has always fallen within the domain of the plastic surgeon, but surgical subspecialization and more focused fellowship training have meant that breast surgeons with the appropriate skillset can offer these procedures. This evolution of the breast surgeon has led to the birth of a new field of breast surgery known as oncoplastic and reconstructive breast surgery. Those tasked with developing surgical training programs in Canada must now decide whether to train breast surgeons in these techniques to improve long-term quality of life among Canadian patients with breast cancer. PMID- 30246975 TI - Indigenous health disparities: a challenge and an opportunity AB - Summary: Clinical Indigenous health research is sparse and often not patient centred. Despite a broad acknowledgement that Indigenous patients have unique clinical considerations, specific interventional research in Indigenous health is lacking. PMID- 30246976 TI - Message in a bottle: the discovery of a young medical officer's map from the 1917 Battle of Hill 70 AB - Summary: We report the serendipitous discovery of a map drawn by an army surgeon during the First World War. The map, entitled "Loos 36 degrees NW3,'"was drawn by 24-year-old Captain Alexander Edward MacDonald in fall 1917 and was found in his old surgery textbook. MacDonald's map depicts the positions of Canadian frontlines and medical units after the Battle of Hill 70. During the battle, Dr. MacDonald tended to the wounded in an aid post that he constructed in a ruined coal mine near the Front. MacDonald would go on to serve with distinction in the Battle of Passchendaele and Canada's Hundred Days, and he received the Military Cross for gallantry. He maintained a passionate interest in cartography throughout his life and eventually became an authority among map collectors. Artifacts such as MacDonald's map remind us of the realities of war and the sacrifices of our surgeon predecessors. PMID- 30246977 TI - Application of LA-ICP-AES to Distinguish the Different Turquoise Mines. AB - Currently, the technological development of non-destructive analysis and micro damage analysis of turquoise is fast. LA-ICP-AES, an almost non-destructive analysis, has multiple advantages. This paper attempts to use this analysis method to examine sample turquoise from five places of origin on Mount East Qinling, including ancient turquoise ore in Laziya, in order to attain its major element and microelement data. Then the paper uses PCA to analyze and study its chemical elements in a comparative way. Three main elements are gained through analysis, and their cumulative variance contribution rate has reached 84.96%. The former two main elements' variance contribution rate is 72.289%. Therefore, the corresponding elements, including V2O5, NiO, B2O3, SrO, BaO, CaO, ZrO, MnO2, are the featured chemical elements of turquoise from different places of origin. Through comparative analysis and research on corresponding chemical elements, turquoise samples produced by different ores vary in terms of the content of some chemical element and chemical components. Two analysis methods combined together will basically realize the appreciation of turquoise in various places of origin. In addition, the research indicates that some chemical contents have positive or negative correlations. Such correlations can be regarded as features of producing area, and can also provide clues as to the cause of formation of turquoise ore. This study preliminarily indicates that LA-ICP-AES combined with PCA and comparative analysis of chemical composition and content has the function of distinguishing turquoise produced in different places of origin to a certain extent. PMID- 30246978 TI - Optimization of ICP-AES and ICP-MS Techniques for the Determination of Major, Minor and Micro Elements in Lichens. AB - Lichens are one of the best materials for air quality biomonitoring, and they have been widely used in atmospheric element deposition monitoring in many regions. Inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma atomic emission spectrometry (ICP-AES) are two efficient techniques widely used in quantifying and quantifying plant elements. However, elemental levels in lichens from some regions in China are much higher than in other plants, and their variation is highly dependent on space, time, species and elements. Although atmospheric pollution monitoring is urgently needed in China in recent decades, little studies have been performed on biomonitoring in the country. Therefore, the methodological studies on the determination of lichen elements in China are needed to accelerate future biomonitoring studies with lichens. Two techniques such as ICP-MS and ICP-AES were used to determine elements in four reference materials, as GBW10014 (cabbage), GBW10015 (spinach), GBW10052 (green tea) and IAEA-336 (lichen), with an attempt to reveal the effects of different digestions, sampling size, spectral lines, isotopes and internal standard elements on measured results. ICP-AES after dry ashing-alkali fusion digestion and ICP-MS after microwave digestion were optimized for lichen element determination. In the optimized techniques, good linear relationship (r>0.999 0), low detection limit, high analytic accuracy and precision were obtained. The optimized techniques were applied to lichen samples collected from Taihang Mountains of China and Ardley Island of Antarctica. The results show that all lichen samples from Taihang Mountains were much higher in elemental concentration with the contribution of atmospheric deposition higher than those from Antarctica. These results suggest the applicability of the techniques in determining lichen elements, and provide evidences and technique supports for air pollution biomonitoring in China. PMID- 30246979 TI - Determination of Trace Elements in the Melon of Indo-Pacific Humpback Dolphins (Sousa chinensis) with ICP-MS. AB - The Indo-Pacific humpback dolphins (Sousa chinensis) with long life-span are top predators in marine ecosystem -and they could accumulate heavy metals and persistent organic pollutants in their tissues, while the melon is a unique lipid rich structure within the cetacean forehead that functions in the transmission of echolocation signals. To explore the baseline levels and the main characteristics of the components, the concentrations of vanadium (V), nickel (Ni), chromium (Cr), manganese (Mn), copper (Cu), arsenic (As), zinc (Zn), mercury (Hg), selenium (Se), cadmium (Cd) and lead (Pb) were determined in the melon of the Indo-Pacific humpback dolphins with inductively coupled plasma mass spectrometry (ICP-MS). The results showed that this method was quite suitable for the determination of trace elements in the melon of Indo-Pacific humpback dolphins with highly accuracy and precision, and the trace elements in melon existed individual differences. The average contents were in the order of Zn>As>Cu>Mn>Se>Hg>Cr>Ni>V>Pb>Cd. It is worth noting that the within (1.158 MUg.g 1 ww), non-essential toxic trace element may cause toxic effect on the dolphins. Spearman correlation analysis showed positively significant correlations between As, Cd, Hg and body length, indicating that the concentrations of As, Cd, Hg may increase with age. Moreover, Cr and Ni were positively correlated (p<0.05), a significant negative correlation was observed between Mn and As (p<0.01), indicating that there are certain correlation among elements. In addition, the principal component analysis results showed that V, Mn, Ni, Se, Cu, Hg are the main characteristics of trace elements for melon. This study presents a reliable method for determination of the trace element analysis in cetacean melon, and this is the first study that reports the trance elements in the melon of the Indo Pacific humpback dolphins in PRE that could provide reasonable and effective information for its conservation work. PMID- 30246980 TI - Peripheral artery disease among Indigenous Canadians: What do we know? AB - Indigenous Canadians experience a disproportionate burden of chronic atherosclerotic diseases, including peripheral artery disease (PAD). Despite an estimated prevalence of 800 000 patients with PAD in Canada, the burden of the disease among Indigenous Canadians is unclear. Available evidence suggests that this population has a higher prevalence of several major risk factors associated with PAD (diabetes, smoking and kidney disease). Unique socioeconomic, geographic and systemic obstacles affecting Indigenous Canadians' health and health care access may worsen chronic disease outcomes. Little is known about the cardiovascular and limb outcomes of Indigenous peoples with PAD. A novel approach via multidisciplinary vascular health teams engaging Indigenous communities in a culturally competent manner may potentially provide optimal vascular care to this population. Further research into the prevalence and outcomes of PAD among Indigenous Canadians is necessary to define the problem and allow development of more ffective initiatives to alleviate the disease burden in this marginalized group. PMID- 30246981 TI - In Situ Investigating of the Interaction of Phenanthrene and Alkyl Phenanthrene with Humic Acid with Laser Induced Nanoseconds Time Resolved Fluorescence Quenching Method. AB - Investigations both on the binding properties and mechanisms of parent polycyclic aromatic hydrocarbons (PAHs) and alkyl PAHs with humic acid (HA) are crucial to understand the environment behavior and bioavailability of PAHs in aquatic ecosystems. Thus, a novel approach for in situ investigation of the interactions between parent PAHs and alkyl PAHs, exemplified by Phenanthrene (Phe), 9 Ethylphenanthrene (9-EP) and Retene (Ret), and HA was established by using fluorescence quenching method with laser-induced nanosecond time-resolved fluorescence (LITRF). By changing the delay time of 50 ns, the fluorescent interference of HA can be eliminated effectively and the concentrations of free Phe, 9-EP and Ret can be determined directly. The binding characteristics of the dissolved HA and Phe, 9-EP and Ret were described by Freundlich nonlinear isothermal model. The results of the model parameters and the single point binding coefficients KOC of Phe, 9-EP and Ret with HA by LITRF quenching method were consistent with those of the conventional fluorescence quenching method. Nonlinear bindings of Phe, 9-EP and Ret to HA were also observed because of the parameter n values below 1, and the degree of nonlinearity of Phe was lower than 9-EP and Ret duo to the n value of Phe larger than 9-EP and Ret. At a same given equilibrium concentration, the KOC of Phe was lower than 9-EP and Ret, and that of 9-EP was near to Ret. The binding affinity of the three PAHs increased with decreasing the equilibrium concentration. The binding characteristics of PAHs with HA largely depends on their hydrophobicity, substituent groups and its ability to fit into hydrophobic cavities in HA. The fluorescence lifetimes of Phe, 9-EP and Ret in presence of HA were 36.90, 35.34 and 35.13 ns, meanwhile the fluorescence lifetimes of Phe, 9-EP and Ret in absence of HA were 36.36, 35.34 and 35.84 ns. There was no significant difference of three PAHs fluorescence lifetime with or without HA, indicating the quenching mechanism for Phe, 9-EP and Ret with HA were primarily static quenching. The LITRF quenching method could be used to in situ explore the interactions between PAHs and HA, which could be contribute to realize the PAHs risk assessment in real time. PMID- 30246982 TI - [Professional standards and unsolved issues of vocational training of radiologists]. AB - This article describes the main statements of the Professional standards of radiologists, statements regarding vocational radiologists training, included in the Orders of the Ministry of Health of the Russian Federation and the educational standards in the specialty "Radiology', approved by the Ministry of Education and Science of the Russian Federation. PMID- 30246984 TI - Quantitative Analysis of Mg, Fe and Ca in Jade with Laser Induced Breakdown Spectroscopy. AB - Based on laser induced breakdown spectroscopy and X-ray fluorescence spectroscopy, The calibration curve of the main elements Mg, Cr and trace element Fe in the Jade samples is obtained based on experimental results. In the experiment, LIBS experiment conditions were 3 MUs delay, 110 accumulated laser pulse, 100 mJ.pulse-1, 10 Hz pulse repetition frequency, plasma in Nanyang jade was induced using nono-second Nd?YAG (wavelength: 1 064 nm) laser as the excitation source in the atmosphere envtronment of the laboratory. The spectral lines in the 300~1 000 nm wavelength range have been identified with the laser induced breakdown spectroscopy. Through comparing the characteristic spectrum with the National Institute of standards and Technology Research Institute (NIST) database, the element of Mg, Ca and Fe are found in the Jade samples. Using the X ray fluorescence spectra analyzed the metal elements Mg, Cr and Fe in Nanyang standard jade and obtained the content of elemental oxides, taking the content as standard data and selecting the high content element Al as internal standard element. According to LIBS calibration curve, we can calculate the content of 3 elements in the measured sample. The result shows that the concentration of elements locate in their corresponding standards range, for example, go(0.28%~1.73%), and Fe2O3 (0~0.8%), CaO ( 18%~20%).Because of its unique features, like the absence of sample preparation, the ability to perform real time, and in situ analysis as well as the quasi non-destruction and micro analysis character of the measurements, so as to verify the feasibility of LIBS application in jade. PMID- 30246983 TI - Can pain catastrophizing be changed in surgical patients? A scoping review AB - Background: Catastrophizing, a coping style characterized by an exaggerated negative affect when experiencing or anticipating pain, is an important factor that adversely affects surgical outcomes. Various interventions have been attempted with the goal of reducing catastrophizing and, by extension, improving treatment outcomes. We performed a systematic review to determine whether catastrophizing can be altered in surgical patients and to present evidence for interventions aimed atreducing catastrophizing in this population. Methods: Using a scoping design, we performed a systematic search of MEDLINE and Embase. Studies reporting original research measuring catastrophizing, before and after an intervention, on the Pain Catastrophizing Scale (PCS) or Coping Strategies Questionnaire (CSQ) were selected. Studies were assessed for quality, the nature of the intervention and the magnitude of the effect observed. Results: We identified 47 studies that measured the change in catastrophizing score following a broad range of interventions in surgical patients, including surgery, patient education, physiotherapy, cognitive behavioural therapy, psychologist-directed therapy, nursing-directed therapy and pharmacological treatments. The mean change in catastrophizing score as assessed with the PCS ranged from 0 to -19, and that with the CSQ, from +0.07 to -13. Clinically important changes in catastrophizing were observed in 7 studies (15%). Conclusion: Catastrophizing was observed to be modifiable with an intervention in a variety of surgical patient populations. Some interventions produced greater reductions than others, which will help direct future research in the improvement of surgical outcomes. PMID- 30246985 TI - Detection of Chromium Content in Soybean Oil by Laser Induced Breakdown Spectroscopy and UVE Method. AB - In order to monitor chromium (Cr) content in soybean oil, laser induced breakdown spectroscopy (LIBS) was used to detect Cr content in this research. Pine wood chips was used to enrich heavy metal of Cr, and the spectra of pine wood chips were acquired in the wavelength range of 206.28~481.77 nm by a two-channel high precision spectrometer. Then, uninformative variable elimination (UVE) method was used to select sensitive wavelength variables for heavy metal of Cr, and calibration model of Cr in soybean oil was developed with partial least squares (PLS) regression, the performance of the calibration model was compared to univariate and full PLS calibration models. The results indicate that the performance of UVE-PLS calibration model is better than that of univariate and full PLS calibration models, the correlation coefficient, root mean square error of calibration (RMSEC), root mean square error of cross validation (RMSECV), root mean square error of prediction (RMSEP) are 0.990, 0.045 mg.g-1, 0.050 mg.g-1 and 0.054 mg.g-1, respectively. After UVE variable selection, the number of wavelength variables in UVE-PLS calibration model is about 2% of wavelength variables in full PLS calibration model. This means UVE is an effective variable selection method which can select correlative variables for heavy metal of Cr. PMID- 30246986 TI - Study Physicochemical Characteristics of Spring Honeys from Yunnan with the Application of HPLC-RI and FAAS. AB - Many special honeys are produced in Yunnan province due to abundant nectar plants and minerals resources provided by the unique natural environment in this area. In this work, the physicochemical property of three honeys (Viciacracca honey, Hevea brasiliensis honey and Punica granatum honey) from Yunnan was studied. The results showed that in different honeys the moisture content, electrical conductivity and dynamic viscosity were different. The sugar contents of each honey were determined with HPLC-RI. The results showed that P. granatum honey had the most abundant glucose [35.62 g.(100 g)-1], and H. brasiliensis honey had the most abundant fructose [41.03 g.(100 g)-1]. Thirteen different mineral elements in three honey species were determined with FAAS. It was found that the mineral level was from 167.24 mg.kg-1 in P. granatum honey to 437.34 mg.kg-1 in H. brasiliensis. Based on the mineral content the three honey species were classified following the principal component analysis (PCA) method. The result showed that Cu, Zn and Na could act as the elemental markers for V. cracca honey, while Mg, K, Ca, As and Cd act as the elemental markers for H. brasiliensis honey, and Fe, Mn, Ni, and Cr act as the elemental markers for P. granatum honey. This study reported the physicochemical property of three special Yunnan honeys, which could help the further study and utilization of these honeys. PMID- 30246987 TI - Determination of Cadmium in Shrimp and Shell Fish Samples by Coprecipitation Enrichment with Mn(II)-5-Br-PADAP Flame Atomic Absorption Spectrometry. AB - A separation/preconcentration procedure with coprecipitation has been proposed for the flame atomic absorption spectrometric (FAAS) determination of cadmium at trace level in food and environmental samples. Manganese(II) was used as a carrier which chelated with 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol to detect the content of trace cadmium in shrimp and shell fish samples with flame atomic absorption spectrometry for the first time. The precipitate could be easily dissolved with concentrated nitric acid. The optimum coprecipitation of this new method including the amount of reagent, amount of manganese(II), the pH, and the standing time of the precipitate had been confirmed for the quantitative recoveries of the analytes. The effect of matrix ions and the interference of co existing ions were also evaluated. Under the experimental conditions established by the optimization step, the system of Mn(II)-5-Br-PADAP was able to overcome the matrix interference which showed the effect of separation and enrichment well. The linear range of cadmium content was determined to be 0.1~1.0 mg.L-1. The sensitivity and the relative standard deviation(RSD) were found 0.147(mg.L-1) 1, 0.73%, respectively. The optimum procedure allows the determination of cadmium with limit of detection of 4.27 MUg.L-1. The complexity of preprocessing was determined by the complexity of food samples. So the differences of cadmium content in the samples between the direct determination with atomic absorption spectrometry and the measurement after coprecipitation were examined, which providedevidences for the superiority of the system again. Cadmium in shell fish and shrimp samples were 1.85 mg.kg-1 and 1.74 mg.kg-1, which in line with international standards of the Codex Alimentarius Commission(CAC). The credibility of the method was evaluated by standard additional method and recovery experiments. The standard addition recoveries of sample and RSDs of the method were in the range of 99.9%~100.3% and 0.15%~0.83%. The results of recovery experiment showed that the presented coprecipitation procedure had good repetition, high accuracy. In addition, with the method, we could draw conclusions that the experiments were simple and rapid. The developed method described in the literature was successfully applied for the determination of trace cadmium in shrimp and shell fish samples with satisfactory results. PMID- 30246988 TI - Analysis of XRD Spectral Structure and Carbonization of the Biochar Preparation. AB - XRD spectroscopy is an important means of research material inside the crystalline structure of the material. In this study it was analyzed with X-ray sources in terms of manner of preparation of different materials carbon crystal structure of biological characteristics and charring mechanism. The results showed that: Biochar contain d101 and d002 crystal face diffraction peak of carbon graphite-like microcrystalline cellulose, but after charring precipitated salt with different materials, and have a big difference, such as ox dung, castor dregs and furfural dregs of CaCO3 carbon content than other organisms, but only ox dung and castor dregs containing CaMg (CO3)2. Corn stover charcoal preferentially decompose hemicelluloses and cellulose microcrystalline graphite with increasing temperature so with the degree of crystallinity which becomes more stable conversion of carbon compounds. Wherein the mineral salt as a pyrolysis carbonization temperature, gradually precipitated by metals oxides >Acetales->carbonate, and with increasing temperature the content of CaCO3 also increase. After different methods of carbonization, charring its mechanism is different from the first dry charring can promote the decomposition of hemicellulose, high temperature microwave treatment is highly volatile, mainly promoting substances multiple bond rupture decomposed substance carbonate precipitates relatively small. Comprehensive illustrated by X-ray diffraction study biochar may well feature the internal structure of the crystalline, can effectively reflect the cracking mechanism of carbonization process. PMID- 30246989 TI - [Radionuclide teranostic of malignancies]. AB - This review shows some basic information regarding the relatively new and one of the promising areas, called "theranostics' and also discusses its basic principles. Special attention is paid to the study of approaches in selecting the most appropriate in the application of radioisotopes for solutions appropriate diagnostic and therapeutic applications. Also presented the main directions in the work with monoclonal antibodies and their use in radionuclide theranostics. PMID- 30246990 TI - Discovering WDMS with Automatic Classification System Based on RBF Neural Network. AB - A model which is capable of capturing the spectral distribution features helps to improve the WDMS(White Dwarf + M Sequence Binaries) classification system running in SDSS-DR10 because the distribution feature of a spectra is one of the most important factors that determine its spectral type. Radial basis function (RBF) neural network is an efficient computational model that is widely used for numerical approximation and object classification. However, due to the reason that the network's hyper-parameters are usually determined empirically, the performance of the network is limited. In this paper, on the basis of analyzing the distribution features of WDMS in a high dimensional space, an automatic classification model for WDMS ia propose based on RBF neural network. And according to the features, we propose centroids criterion and width criterion to determine hyper-parameters for the network in a more theoretical way, which improves the accuracy of the model. After training and applying the model, a total number of 4 631 WDMS candidates are classified and 25 of them are newly identified, which proves the feasibility of the model and provides further researches on WDMS with more data. PMID- 30246991 TI - Retirement plans and perspectives among general surgeons: a qualitative assessment AB - Background: General surgeons' retirement plans have wide-ranging personal, professional and system-level effects. We explored the drivers of and barriers to surgeon retirement to identify opportunities to support career-long retirement planning. Methods: We conducted a qualitative study from May to October 2016 using semi-structured telephone interviews (mean duration 29 min) with general surgeons in Ontario. We used a purposive sampling strategy to recruit surgeons at 3 career stages(no plans to retire within next 5 yr, had slowed down practice or planned to slowdown within 5 yr, and no longer operating as primary surgeon). We analyzed the data using established techniques of thematic analysis. Results: We interviewed 22 general surgeons. Their retirement status ranged from fully retired to no plans to retire. Preservation of reputation and quality care, commitment and succession planning, and retirement planning were dominant themes. Mid-career and senior surgeons' plans were made later in their careers and were driven by desires to preserve reputations and surgical identity. Younger surgeons' (<= 50 yr) early retirement was driven by lifestyle choices and work environment. Logistical barriers and financial insecurity led to retirement delay. Conclusion: Surgeons begin to plan for retirement both early and late in their careers. Most surgeons wish to establish retirement plans that allow for the gradual reduction of surgical patient care and the creation of job opportunities for younger colleagues balanced by a continued contribution to the profession. Opportunities to support surgeons at all career stages in their retirement planning require further exploration. PMID- 30246992 TI - Outlier Data Mining and Analysis of LAMOST Stellar Spectra in Line Index Feature Space. AB - Large scale spectrum survey will produce mass spectral data and offer chances for searching rare and unknown types of spectra, which is contribute to revealing the evolution law of the universe and the origin of life. Data mining in outlier data in sky survey can serve the purpose of finding special spectra. Line index can be used in spectra data dimension reduction, keeping the spectral physical characteristics as much as possible, and at the same time, it can effectively solve the high dimensional spectral data clustering analysis in the high computation complexity. This paper proposed a method outlier data mining and analysis for massive stellar spectrum survey data based on line index characteristics, according to this, an outlier spectral data analysis method was proposed using line index characteristics space. Experimental results demonstrated that (1) using line index as the characteristic value of the spectrum can quickly perform the outlier data mining for high dimensional spectral data, and it can solve the problem of high computation complexity of the high dimensional spectral data. (2) this outlier data mining method was conducted based on the clustering results; it can effectively finding out emission stars, late type stars, late M type stars, extremely poor metal stars, and even finding spectra data missing certain data. (3) outlier data mining in line index feature space can help to analysis of rules of special stars found in the feature space. The mothed proposed in this paper based on the characteristics of line index outlier data mining and analysis method can be applied to the study of survey data. PMID- 30246993 TI - A Singular Value Decomposition Method for Tunable Diode Laser Absorption Spectroscopy System to Remove Systematic Noises. AB - Detection of gas concentration with tunable diode laser absorption spectroscopy (TDLAS) techniques is affected by baseline drift and high-frequency noise. Therefore, how to remove the systematic noises has been a hot spot. This paper analyzes the significance of singular value decomposition (SVD) in TDLAS detection system with two different methods of constructing a matrix, and it discusses the differences of processing results for different noises. The second harmonic signal is arranged in a matrix and decomposed. We select the appropriate threshold and putthose singular values smaller than the threshold into zero, then reconstruct the matrix. Experiments show that SVD method does not require additional system components or pass into the zero gas to subtract background. This method is able to remove noises of TDLAS system quickly and effectively. We found that the method of constructing a hankel matrix is suitable for removing high-frequency noise. However, the method of constructing a continuous-cutoff signal matrix is suitable for removing baseline drift. For example, we set up a TDLAS system to measure the concentration of NH3 while the noise removal rate of the second harmonic curve is up to 80% with this method. PMID- 30246994 TI - Development of a simple multidisciplinary arthroplasty wound-assessment instrument: the SMArt Wound Tool AB - Background: There are currently no validated instruments in the orthopedic literature for assessing the healing of acute surgical wounds. The creation of a simple wound-assessment tool would provide a standardized method of reporting wound outcomes. The objective of this study was to systematically develop a wound assessment tool that can be used to assess the early healing of arthroplasty incisions. Methods: The databases MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane reviews and CINAHL were searched. Articles that described objective assessment of acute incisional wounds were included. Items for the wound-assessment tool were then extracted from eligible studies based on the frequency of reporting. A multidisciplinary panel of wound experts compiled the items into an initial tool to assess key domains of wound healing. The items were reduced through several iterations of panel discussion. Results: Our search strategy yielded 3743 results, which were screened by title and abstract. Thirty four studies were included in the systematic review for the development of the wound-assessment tool, and 10 domains were extracted based on frequency of reporting. After item reduction, the final version of the wound-assessment tool, the SMArt Wound Tool, contained 3 major domains: blistering, peri-incisional skin colour and exudate type. Conclusion: There is currently a need for a standardized tool to assess the healing of orthopedic surgical incisions. The SMArt Wound Tool provides a simple, objective method of assessing arthroplasty incisions for the presence of early complications. PMID- 30246995 TI - Granary Temperature Measurement Network Based on Chirped FBG. AB - In conventional optical fiber grating temperature measuring system, it can be loaded into a small number of fibers grating probe. At the same time, the intensity of back waves is relatively weak, and its multiplexing capability is poor. In order to solve these problems, temperature measurement system was designed based on chirped Fiber Bragg Grating. Its purpose is to obtain large scale, multi-point temperature measurement data. The bandwidth of back waves was improved by chirp modulation techniques, so that available processing power of signal was increased, and the number of the chirped FBG probe in one fiber was greatly increased. Grating period expression was derived in chirp modulation, and modulation method and the wavelength range was provided. In the experiment, LPT 102 broadband light source and the FP optical fiber demodulator were used, and the modulation bandwidth of the system was from 1 535.0 to 1 555.0 nm. It used the WR-201 type temperature sensor as calibrated detector. Experimental results show that when the temperature changed by 1 C from 20~60 C, the test temperature error would be closed with traditional Fiber Bragg Grating probe and chirped Fiber Bragg Grating probe, and they both meet the design requirements. In contrast, the wavelength shift data of chirped FBG was more monotone linear than the characteristic FBG, so its data was more stable. Meanwhile, in one fiber, the number of probes in the chirped FBG system was greatly more than the Uniform FBG system. In the original FBG system, without increasing the number of optical fiber or reduced the temperature measurement accuracy, design requirements for increase with the number of probe points in the system was achieved. PMID- 30246996 TI - Effects of the DLA Light Source Quality on the Beam Quality of Combined Beam in Spectral Beam Combining Systems with Grating-External Cavity. AB - In Diode Laser Array (DLA) spectral beam combining (SBC) systems with grating external cavity, the beam quality of the combined beam tends to degrade due to comprehensive function of factors involving divergence angle of light, positional deviation and direction angle deviation caused by "smile" effect of emitters, etc.. Based on the consideration of the effects of the divergence angle and "smile" effect of DLA emitters on the beam propagation characteristics, the light propagation model of DLA SBC systems with grating-external cavity has been built up, and the effects of divergence angle and the positional deviation and direction angle deviation caused by "smile" effect of DLA emitters on the beam quality of the combined beam in SBC systems have been analyzed quantitatively. The results indicate that, the beam quality of the combined beam would be significantly affected by the DLA light source quality, i.e., the bigger the divergence angle and the direction angle deviation caused by "smile" effect are, the worse the beam quality of the combined beam is. The positional deviation of emitters in beam-combination direction caused by "smile" effect has little impact on the beam quality of the combined beam, whereas the positional deviation in non beam-combination direction would significantly degrade the beam quality of the combined beam. In practical applications, measures should be taken to improve the DLA light source quality in order to eliminate the effect on the beam quality of the combined beam PMID- 30246997 TI - Analysis of Glass Surface Modification with Ion Beam Based on Ellipsometry. AB - Etching treatment was performed on glass surface by dissociated nitrogen using anode layer linear ion source. The changes of glass surface after surface modification was analyzed and the effect of ionization voltage on surface roughness, refractive index and optical thickness was investigated. Accordingly, the relationship between Delta spectral characteristics of fixed wavelength changed angle of incidence and refractive index, Brewster angle, surface roughness and optical thickness was discussed through the comparison of Delta spectrum under different surface conditions based on spectroscopic ellipsometry. The results show that the shape of Delta spectrum near Brewster angle changes, the abrupt change of Delta spectrum shifts to larger angle, and the slope of Delta spectrum increase at the same time. Modeling and fitting analysis reveals that an optically denser layer was produced, the refraction index and Brewster angle increase and surface roughness decrease of glass caused by nitrogen ion beam etching treatment. However, the refraction remains consistence, and the depth of denser layer increase with increasing ionization voltage. The surface morphology analysis by AFM verified the leveling effect of glass surface by nitrogen ion beam. XPS measurement indicates the optional sputtering of glass surface by nitrogen ion beam, inferring the generation of denser layer arises from the compaction of ion beam. Furthermore, the general relationship between the characteristic of Delta spectrum and surface conditions of materials was theoretical derived and verified, and an evaluation of material surface variations was proposed. Such as the increase of abrupt change angle illustrates the increase of refractive index and Brewster angle, the increase of slope demonstrates the decrease of surface roughness, the increase of sharp corner of both sides evident the increase of optical thickness, vice-versa. PMID- 30246998 TI - Growth and Characteristics of ZnO Needles in the Surface of "Platanus Occidentalis" Made of Al2O3, Au and ZnO. AB - Complex ZnO compound material has great potential applications for optoelectronic devices. In this article, we give report to a simulation growth of a kind of special"fruiting ball"--natural "Platanus Occidentalis" made of Al2O3, Au and ZnO. The surface of "Platanus Occidentalis " has numerous tiny Au seeds on the surface of Al2O3 ball. ZnO needles synthesized by the electrodeposition technique grow well on the Au seed layer. The obtained mono dispersive needles (or hexagonal columns) have different distribution density. The prepared sample looks like the assembled "Platanus Occidentalis" in photographs of scanning electron microscopy (SEM). Photoluminescence (PL) of samples at 6 K temperature and other characteristics are investigated. The appearance of sharp bound exciton (BE) emission line and the longitudinal optical (LO)-phonon replicas imply that the ZnO nanocolumns are of high optical quality. PMID- 30246999 TI - Near Infrared Spectroscopy Study on Nitrogen in Shortcut Nitrification and Denitrification Using Principal Component Analysis Combined with BP Neural Networks. AB - To achieve efficient nitrogen removal and rapid detection of ammonia nitrogen and nitrite nitrogen, principal component analysis and neural networks were used to establish quantitative analysis model of ammonia nitrogen and nitrite nitrogen in shortcut nitrification and denitrification based on near infrared spectroscopy-BP neural networks model. The results showed that ammonia nitrogen concentration decreased from 45.3 to 2.7 mg.L-1 after aerobic, and nitrite nitrogen concentration increased from 0.01 to 19.6 mg.L-1, while nitrite nitrogen concentration decreased from 19.6 to 1.2 mg.L-1 after anoxic, which means that rapid nitrification and denitrification are successfully achieved. The principal component analysis of the original near infrared spectra for water samples showed the first 13 principal components represented the information of the original spectrum data, with cumulative contribution rate being 95.04%. In this way, redundant information can be eliminated to reduce the number of dimensions in the model. The spectral data matrix is accordingly reduced from 192*2203 to 192*13, which contributes greatly to easier calculations and improves the accuracy of the model. The correction results of BP neural networks model showed the coefficient of determination for ammonia nitrogen and nitrite nitrogen concentration was 0.950 4 and 0.976 2 respectively, with the root mean square error of calibration being 0.016 6 and 0.010 9. BP neural networks model yields predicted values fitting well with the expected values for ammonia nitrogen and nitrite nitrogen concentration, with R2 being 0.974 0 and 0.981 4 respectively, with the root mean square error of prediction being 0.033 7 and 0.028 7, suggesting that BP neural networks model had a good prediction results for ammonia nitrogen and nitrite nitrogen concentration. The study demonstrated that ammonia nitrogen and nitrite nitrogen concentration can be rapidly predicted with BP neural networks based analysis of the near infrared spectroscopy of the water sample in shortcut nitrification and denitrification, which may provide timely and flexible control to shortcut nitrification and denitrification operation according to the ammonia nitrogen and nitrite nitrogen concentration changes, and makes a quick and effective detection technique for denitrification. PMID- 30247000 TI - Raman Spectra of Bredigite at High Temperature and High Pressure. AB - Bredigite was synthesized by using the Piston-Cylinder in 1.2 GPa and 1 473 K. With external heating device and diamond anvil cell, high temperature and high pressure Raman spectra of bredigite were collected at temperatures 298, 353, 463, 543, 663, 773 and 873 K and with pressure from 1 atm up to 14.36 GPa (room temperature). The SEM image showed that the sample consisted of one crystalline phase with grain size ranging from 10~20 MUm. The EPMA data suggest a chemical formula of Ca7.03(2)Mg0.98(2)Si3.94(2)O16 which was identical to the theoretical component of bredigite. The Raman spectroscopic results indicate there were 29 vibration bands of bredigite at high temperature. Some bands were merging, weakening and disappearing increasingly with the temperature, which was obvious in the range of 800~1 200 cm-1. The vibration bands of 909, 927 and 950 cm-1 disappeared at 873, 773 and 873 K, respectively. The results primarily indicated that the structure of bredigite was stable under experimental condition. In addition, isobaric mode-Gruneisen parameters and isothermal mode-Gruneisen parameters were calculated, yielding 1.47(2) and 0.45(3) as their mean values, respectively. Anharmonic coefficients were estimated based on the high temperature and high pressure Raman experiments, showing that the contributions to anharmonic-effect induced with the Si-O vibration modes were smaller than other modes. PMID- 30247001 TI - The Effect of Chlorophyll Concentration of Paddy Rice on the Fluorescence Spectrum. AB - In order to enhance the monitoring of paddy growth, utilize the fertilizer more efficiently, increase crop yield and improve the quality of grain, thus the system of laser-induced fluorescence (LIF) was built. The system was designed to study the relationship between the rice leaf chlorophyll content and fluorescence ratio. In this paper, the samples came from the second upper leaves of paddy in shooting stage and the cultivated area was located in Jianghan plain of China. Firstly, the Kjeldahl method combined with the formula which was described by Zivcak et al. was utilized to calculate the chlorophyll content of paddy, then the fluorescence spectrum of paddy leaf with different chlorophyll content by the instrument of laser-induced fluorescence (the wavelength of excitation 355 nm). Fluorescence spectra of paddy leaf with different chlorophyll content were collected and then a fluorescence spectra database was established. It is discussed that the relationship between the ratio of fluorescence (F740/F685 is the ratio of fluorescence intensity of 740 nm dividing that by 685 nm) and the chlorophyll content of paddy. It is found that the effect of chlorophyll content on the fluorescence spectral characteristics is evident. The results demonstrated that it has the tightly positive correlation between the fluorescence ratio (F740/F685) and chlorophyll content of paddy leaf. The determination coefficient (R2) can reach up to 0.901 3 and 0.912 5 at tillering stage and shooting stage, respectively. The experimental analysis showed that the LIF technology has the advantages of convenient, quick and nondestructive, and it has the potential for quantitative monitoring of crop growth. PMID- 30247002 TI - Probing the Binding of Torasemide to Pepsin and Trypsin by Spectroscopic and Molecular Docking Methods. AB - Torasemide (TOR) belongs to the pyridine sulfonylurea class of loop diuretics and is widely and effectively used in the treatment of hypertension, heart failure, chronic renal failure and liver disease. One of the adverse reactions caused by TOR was a slight gastrointestinal discomfort in the course of treatment. However, the molecular interactions of TOR with digestive proteases (trypsin and pepsin) rarely reported. The attempt of this paper was to completely investigate the binding characteristics between TOR and trypsin or pepsin at different temperatures under imitated physiological conditions by fluorescence spectroscopy, UV-vis absorption, circular dichroism (CD) and molecular modeling technique. The inner filter effect of all fluorescence data in the paper was eliminated to get accurate binding parameters. It was found that the fluorescence quenching of trypsin and pepsin by TOR was a static quenching type. The Stern Volmer quenching constants (KSV) of TOR-pepisn and TOR-trypsin were inversely correlated with temperatures. The binding of TOR changed the conformational structures and internal micro-environment of pepsin and trypsin by UV-vis absorption, synchronous fluorescence, three dimensional (3D) fluorescence and circular dichroism (CD) spectroscopy. The results showed the polarity around Tyr residues of pepsin or trypsin was changed more obviously than that around Trp residues, the TOR alters the secondary structure of trypsin and pepsin and reduces the beta-sheet content of protein, which may affect its physiological function. The molecular docking results showed that TOR inserted into the active site of pepsin to interact with the catalytic residues Asp32 and Asp215, and caused a decrease in pepsin activity. TOR bound into the primary substrate binding pocket (S1 binding pocket) of trypsin by hydrophobic forces and affected the function of trypsin by increasing its catalytic activity. Our results offer insights for the binding and toxicity mechanism of TOR with pepsin and trypsin in vivo, which provides important information for using the TOR safely. PMID- 30247003 TI - Distribution of Mineral Elements and Influencing Factors in Scalp Hair of Childbearing Age Women in the County of Xinghe, Inner Mongolia of China. AB - The distribution and influencing factors on age, reproductive history and dietary habits in scalp hair of rural childbearing female in the county of XingHe, Inner Mongolia of China were studied. 21 mineral elements including essential and toxic elements (Al, B, Ba, Ca, Cd, Co, Cr, Cu, Fe, Mg, Mn, Mo, Ni, Pb, Se, Si, Sn, Sr, Ti, V and Zn ) in scalp hair samples from 180 females of childbearing age were measured with inductively coupled plasma-atomic emission spectrometry (ICP-AES) and atomic fluorescence spectrometry (AFS), respectively. The results demonstrated that the content of the most mineral elements (B, Cd, Co, Cr, Cu, Fe, Mg, Mn, Mo, Ni, Pb, Se, Si, Sn, Sr, Ti, V and Zn) existed in a descending order in the hair of young age group (18~29 years) to the elder age group (40~45 years), while elements of Ca, Mg, Mn and Pb were found to have the lowest content in the middle age group (30~39 years). Women having two children were more likely to have the lowest content of Ca, Mg, Mn, Mo, Ni, Pb, Sn, Sr and Zn due to the increased numbers of pregnancies, the statistically correlations had been proved among Ca, Pb and Sn. In addition, dietary habits also can affect the level of the mineral elements in hair, for example, consuming suancai food frequently can cause lower level of Zn, Fe, Cu, Mn, Sr, Mo and Pb, but higher Se, the frequent intake of meat resulted in increased content of Zn and Se. The individuals that declared intaking vegetables regularly had more Si in their hair. Also, daily intake of fruit leads to higher level of Mn, Ni and Ti. This study will provide basic and useful information when addressing reproductive and women health challenges in the rural areas where poor dietary habits are prevailing. PMID- 30247004 TI - Study on Heavy Metal Detection in Soil with Improved EDXRF. AB - Due to the low precision and accuracy of trace heavy metals detection wiith traditional energy dispersive X-ray fluorescence (EDXRF) system, an improved EDXRF system is proposed. In order to reduce the influence of reflected rays, the sample is irradiated with the incident X-rays vertically, and the detector is placed in parallel with the sample's section. The sample is connected with detector through collimator. With improved EDXRF measures certified reference materials, the results show that the detection limit of the improved EDXRF system for Mo,Zn,Cu,Pb,Zr,Nb is 0.4,6.68,1.97,6.84,1.60,7.59 mg.kg-1 respectively and the logarithm deviation of each element in the standard samples is between 0 and 0.05. The RSD%(GBW) is less than 7 as the element content is more than three times of the detection limit, and it is below 15 when the element content is less than three times of the detection limit. The soil samples collected from Da Xing'an Ling region are applied to verify the improved EDXRF system. The proposed EDXRF system can improve the measurement accuracy of trace heavy metal detection in soil, satisfying the requirements of geologic exploration. PMID- 30247005 TI - Study on Internal Information of the Two-Layered Tissue by Optimizing the Detection Position. AB - As to most methods of detecting the inner information of inhomogenous tissue, a significant issue is that the detection position is ambiguous because of the complexity of human tissue structure and discrepancies among individuals. This paper studies the best source-detector distance (SDSbest) to detect internal information of a fat-muscle tissue with spatially resolved diffuse reflectance spectra. In order to weaken the measurement error caused by the discrepancies among individuals and multiple backscattered photons, and according to the transmission model of light in complex biological tissue, then we added the constraint condition--two ideal "banana shape" paths--to define the effective photon ratio(SNR), which was used to select the best source-detector separations (SDSbest), and the results from Monte Carlo simulation modified by adding constraint condition were statistically analyzed, and we regard the SNR as a basis and analyze the relationship between the fat thickness (hf),the absorption coefficient of a fat layer (MUaf),the absorption coefficient of a muscle layer (MUam) and the source-detector distance (SDS), and hf is used as the independent variable to develop a linear regression model to predict SDSbest. The result showed that MUaf and MUam have no effect on SDSbest when 00.05 except p (group 1-4) = 0.020); SRS - 1.3+/-0.6, 1.9+/ 1.3, 1.6+/-1.4, 3.0+/-0.6 (all paired p (s)>0.05 except p (group 1-4)=0.013). Conclusion: Parameters osev and ohet are suitable for quantitative description of myocardial perfusion "inhomogeneity", they are better than Extent/SRS in delineating normal/equivocal (inhomogeneous)/abnormal perfusion patterns. PMID- 30247012 TI - Physical fitness of medical residents: Is the health of surgical residents at risk? AB - Background: Postgraduate medical residency programs are laborious and timeintensive, and can be physically, intellectually and emotionally demanding. These working conditions may lead to the neglect of personal health and well being. Theobjective of this study was to compare the anthropometric and fitness characteristics of surgical and nonsurgical medical residents. We hypothesized that there is a difference in physical health between these 2 groups. Methods: Medical residents completed a demographic information questionnaire and were assessed by trained staff for height, weight, body fat percentage, muscular strength and endurance, and peak oxygen consumption (V?2peak). The average number of working hours per week was also documented. Results: Forty-five residents (21 surgical and 24 nonsurgical; 31 men and 14 women) participated in the study. Surgical residents worked more hours per week on average than nonsurgical residents (p = 0.02) and had a higher body mass index (BMI) (p = 0.04) and lower V?2peak (p = 0.01). Conclusion: Surgical residents worked more hours than nonsurgical residents, which may have contributed to their higher BMI and lower aerobic fitness levels. Despite a heavy workload, it is important for all medical residents to find strategies to promote a healthy lifestyle for both themselves and their patients to ensure long-term well-being. PMID- 30247013 TI - [Descending perineum syndrome in children: Pathophysiology and diagnosis]. AB - Objective: To propose a safer, simpler, and more exact method for the diagnosis of descending perineum syndrome (DPS). Material and Methods: A total of 194 patients aged 5 days to 15 years were examined and divided into 2 groups: Group 1 consisted of 65 patients without anorectal anomalies (AA); Group 2 comprised 129 patients, including 66 children with functional constipation,55 with AA and visible fistulas, who were preoperatively examined, and 8 patients with anorectal angle (ARA), who were postoperatively examined. All the patients underwentirrigoscopy that was different from standard examination in the presence of X-ray CT contrast marker near the anus. Results and Conclusion: DPS is caused by puborectalis muscle dysfunction. A method was proposed to evaluate the status of the puborectalis muscle from the distance between the position of the ARA and the marker near the anus. This not only promotesan exacter estimate of DPS, but also allows refusal of defecography. The use of a barium enema with the minimum number of X-ray films decreases dose of ionizing radiation hazard and permits the use of this procedure not only in adults, but also in children with chronic constipation, fecal incontinence, and in AA for both pre- and postoperatively assessment of the causes of complications. PMID- 30247014 TI - Enabling Lithium-Metal Anode Encapsulated in a 3D Carbon Skeleton with a Superior Rate Performance and Capacity Retention in Full Cells. AB - Suppressing the formation of lithium (Li) dendrites is central to implementing Li metal anode, which has gained growing attention due to its ultrahigh specific capacity and low redox potential. Here, a novel approach is adopted to deposit Li metal within a rigid three-dimensional (3D) carbon paper (3DCP) network, which consists of a cross-link framework of carbon fibers and graphene nanosheets (GNs). This unique structure yields a uniform distribution of Li-nuclei during the preliminary stage of Li-plating and the formation of a stable solid electrolyte interface. The as-obtained anode can deliver a high areal capacity of 10 mAh cm-2 without the dendritic formation after 1000 cycles in a Li@3DCP/LiFePO4 full cell at 4 C. In addition, the Li@3DCP anode displays low voltage platform (<20 mV at 1 mA cm-2), high plating/stripping efficiency (99.0%), and long lifespan (>1000 h). When coupled with LiNi0.8Co0.15Al0.05O2 cathode, the Li@3DCP electrode exhibits a superior rate capability up to 10 C and high temperature performance (60 degrees C). The unprecedented performance is attributed to the desirable combination of micro/nanostructures in 3DCP, in which carbon fiber framework provides the mechanical stability for volume change, whereas numerous lithiophilicity sites on GNs enable the suppression of Li dendrite growth. PMID- 30247015 TI - Interface-Induced Anomalous Hall Conductivity in a Confined Metal. AB - The mature silicon technological platform is actively explored for spintronic applications. Metal silicides are an integral part of the Si technology used as interconnects, gate electrodes, and diffusion barriers; their epitaxial integration with Si results in premier contacts. Recent studies highlight the exceptional role of electronic discontinuities at interfaces in the spin dependent transport properties. Here, we report a new type of Hall conductivity driven by sharp interfaces of Eu silicide, an antiferromagnetic metal, sandwiched between two insulators - Si and SiO x. Quasi-ballistic transport probes spin orbit coupling at the interfaces, in particular, charge-spin interconversion. Transverse magnetic field results in anomalous Hall effect signals of an unusual line shape. The interplay between opposite-sign signals from the two interfaces allows efficient control over the magnitude and sign of the overall effect. Selective engineering of interfaces singles out a particular spin signal. The two channel nature of the effect and its high tunability offer new functional possibilities for future spintronic devices. PMID- 30247016 TI - Dispersion in Ferroelectric Switching Performance of Polycrystalline Hf0.5Zr0.5O2 Thin Films. AB - Interests in nanoscale integrated ferroelectric devices using doped HfO2-based thin films are actively reviving in academia and industry. The main driving force for the formation of the metastable non-centrosymmetric ferroelectric phase is considered to be the interface/grain boundary energy effect of the small grains in polycrystalline configuration. These small grains, however, can invoke unfavorable material properties, such as nonuniform switching performance. This study provides an in-depth understanding of such aspects of this material through careful measurement and modeling of the ferroelectric switching kinetics. Various previous switching models developed for conventional ferroelectric thin-film capacitors cannot fully account for the observed time- and voltage-dependent switching current evolution. The accurate fitting of the experimental results required careful consideration of the inhomogeneous field distribution across the electrode area, which could be acquired by an appropriate mathematical formulation of polarization as a function of electric field and time. Compared with the conventional polycrystalline Pb(Zr,Ti)O3 film, the statistical distribution of the local field was found to be three times wider. The activation field and characteristic time for domain switching were larger by more than 1 order of magnitude. It indicates that doped HfO2 is inhomogeneous and "hard" ferroelectric material compared with conventional perovskite-based ferroelectrics. PMID- 30247018 TI - Versatile and Robust Integrated Sensors To Locally Assess Humidity Changes in Fully Enclosed Paper-Based Devices. AB - The synergic combination of materials and interfaces to create novel functional devices is a crucial approach for various applications, including low-cost paper based point-of-care systems. In this work, we demonstrate the implementation of surface-modified polypyrrole (PPy) structures, monolithically integrated into a three-dimensional multilayered paper-based microfluidic device, to locally assess humidity changes. The fabrication and integration of the system include the deterministic incorporation of PPy into the paper-based structure by gas-phase polymerization and the modification of the polymer properties to allow local humidity monitoring. The functionalization of PPy changes both the wettability and the chemical composition of the interface, what is of fundamental importance for the sensor's operation. The PPy structure has excellent mechanical stability, enduring at least 600 bending cycles, what is of relevance on flexible electronics. The electrical resistance correlates with the local relative humidity (RH) inside of the sealed microfluidic system, and the sensor response is fully reversible. The integrated system capable of locally monitoring the RH allowed us to verify that inside the microfluidic channel, water molecules can diffuse across the wax barriers-a possibility disregarded so far. Our results attest that RH variations of 5-10% can affect the flow of extended channels (>5 cm) even when they are fully enclosed. PMID- 30247017 TI - Framework of Cytochrome/Vitamin B2 Linker/Graphene for Robust Microbial Electricity Generation. AB - A bioelectrochemical system (BES) allows direct electricity production from wastes, but its low-power density, which is mainly associated with its poor anodic performance, limits its practical applications. Here, the anodic performance of a BES can be significantly improved by electrodepositing vitamin B2 (VB2) onto a graphene [reduced graphene oxide (rGO)]-modified glassy carbon electrode (VB2/rGO/GC) with Geobacter sulfurreducens as the model microorganisms. The VB2/rGO/GC electrode results in 200% higher electrochemical activity than a bare GC anode. Additionally, in microbial electrolysis cells, the current density of this composite electrode peaks at ~210 MUA cm-2 after 118 h and is maintained for 113 h. An electrochemical analysis coupled with molecular simulations reveals that using VB2 as a linker between the electrochemically active protein of this model strain and the rGO surface accelerates the electron transfer, which further improves the bioelectricity generation and favors the long-term stability of the BES. The VB2 bound with a flexible ribityl group as the organic molecular bridge efficiently mediates energy conversion in microbial metabolism and artificial electronics. This work provides a straightforward and effective route to significantly enhance the bioenergy generation in a BES. PMID- 30247019 TI - Self-Healing Lamellar Structure Boosts Highly Stable Zinc-Storage Property of Bilayered Vanadium Oxides. AB - Rechargeable aqueous zinc-ion batteries have been considered one of the promising alternative energy-storage systems to lithium ion-batteries owing to their low cost and high safety. However, there is lack of long-life positive materials, which severely restricts the development of zinc-ion batteries. The strong interactions present between the intercalated multivalent cations and host materials inevitably cause structural distortions and create large migration barriers for the diffusion of cations, resulting in poor cycling stability and limited rate performance. Here, we report the application of bilayered ammonium vanadium oxide (NH4V4O10) as the cathode material for zinc-ion batteries. A self healing lamellar structure, which combines a macroscopically reversible morphological transformation and a microscopically adjustable interlayer spacing to accommodate the strong interactions, is observed upon insertion and release of cations. This stable architecture enables a specific capacity of 147 mA h g-1 at a current density of 200 mA g-1 (voltage window: 1.7-0.8 V vs Zn2+/Zn) and a capacity retention of more than 70.3% over 5000 cycles (5000 mA g-1). Our finding provides a new alternative for zinc-ion batteries and inspiration for how to further develop advanced positive electrodes by employing materials with flexible microarchitectures. PMID- 30247020 TI - Phase-Separation-Induced Crystal Growth for Large-Grained Cu2ZnSn(S,Se)4 Thin Film. AB - Large-grained Cu2ZnSn(S,Se)4 (CZTSSe) absorber layers are highly desirable for high-performance CZTSSe thin film solar cells. However, solution-deposited CZTSSe thin films usually consist of a large-grained top layer and a smaller-grained bottom layer. In this work, we adopt a phase-separation strategy to promote the crystal growth of the CZTSSe thin film. By choosing ZnCl2, SnCl2, CuCl (instead of CuCl2), and thiourea as the starting materials, a Cu2S/SnS/ZnS hybrid precursor thin film can be prepared, the composition of which has been testified by X-ray diffraction, X-ray photoelectron spectroscopy, Raman, and scanning electron microscopy-energy-dispersive spectrometry characterization. Owing to the volume expansion caused by Se incorporation and the high migration abilities of Cu(I) and Sn(II) ions during selenization, large-grained and compact CZTSSe films with a thickness up to 5 MUm can be obtained. The corresponding thin film solar cell devices have achieved active power conversion efficiencies above 10% (8.78% for total area), much higher than those of CuCl2-based CZTSSe devices in our lab. PMID- 30247021 TI - UV-Cross-linkable Donor-Acceptor Polymers Bearing a Photostable Conjugated Backbone for Efficient and Stable Organic Photovoltaics. AB - High-performance photovoltaic polymers bearing cross-linkable function together with a photorobust conjugated backbone are highly desirable for organic solar cells to achieve both high device efficiency and long-term stability. In this study, a family of such polymers is reported based on poly[(2,5-bis(2 hexyldecyloxy)phenylene)- alt-(5,6-difluoro-4,7-di(thiophen-2-yl)benzo[ c] [1,2,5]thiadiazole)] (PPDT2FBT), a high-performance photovoltaic donor-acceptor polymer, with different contents of terminal vinyl-appended side chains for cross linking. The polymers were named PPDT2FBT-V x and prepared by varying the feeding ratio ( x mol %, x = 0, 5, 10, and 15) of the vinyl-appended monomer in polymerization. It was found that the vinyl integration did not sacrifice the original high photovoltaic performance of the polymers, as evidenced by comparable average power conversion efficiencies (PCEs) (6.95, 7.02, and 7.63%) observed for optimized devices based on PPDT2FBT-V0, PPDT2FBT-V5, and PPDT2FBT V10, respectively, in blending with [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM). Unlike thermal cross-linking that greatly reduced device efficiency, UV cross-linking has proven to be an effective way to achieve both high device efficiency and thermostability for PPDT2FBT-V10 solar cells. UV-cross-linked PPDT2FBT-V10 solar cells displayed an initial average PCE of 5.28% and almost no decrease upon heat treatment at 120 degrees C for 40 h. Morphology studies revealed that UV-cross-linking did not only alter initial nanophase separation but also suppressed morphology evolution by aggregation in bulk heterojunction blend films. Photo-cross-linking requires material photostability. It is therefore worthwhile to note that these polymers and their blends with PC71BM were found to be extremely photostable, even upon continuous exposure to concentrated sunlight (up to 200 suns), and UV-cross-linking does not hamper this photostability. Further studies found that the devices fabricated with the UV cross-linked PPDT2FBT-V10/PC71BM active layer can endure continuous light exposure to a solar simulator without deteriorating their performance. PMID- 30247022 TI - Bioinorganic Chemistry of the Natural [Fe(NO)2] Motif: Evolution of a Functional Model for NO-Related Biomedical Application and Revolutionary Development of a Translational Model. AB - Identification of the distinctive electron paramagnetic resonance signal at g = 2.03 in the yeast cells and liver of mice treated with carcinogens opened the discovery and investigation of the natural [Fe(NO)2] motif in the form of dinitrosyliron complexes (DNICs). In this Viewpoint, a chronological collection of the benchmark for the study of DNIC demonstrates that the preceding study of its biological synthesis, storage, transport, transformation, and function related to NO physiology inspires the biomimetic study of structural and functional models supported by thiolate ligands to provide mechanistic insight at a molecular level. During the synthetic, spectroscopic, and theoretical investigations on the structure-to-reactivity relationship within DNICs, control of the Fe-NO bonding interaction and of the delivery of NO+/*NO/HNO/NO- by the supporting ligands and nuclearity evolves into the "redesign of the natural [Fe(NO)2] motif" as a strategy to develop DNICs for NO-related biomedical application and therapeutic approach. The revolutionary transformation of covalent a [Fe(NO)2] motif into a translational model for hydrogenase, triggered by the discovery of redox interconversion among [{Fe(NO)2}9-L*] <-> {Fe(NO)2}9 < > {Fe(NO)2}10 <-> [{Fe(NO)2}10-L*]-, echoes the preceding research journey on [Fe]/[NiFe]-hydrogenase and completes the development of an electrodeposited-film electrode for electrocatalytic water splitting. Through the 50-year journey, bioinorganic chemistry of DNIC containing the covalent [Fe(NO)2] motif and noninnocent/labile NO ligands highlights itself as a unique metallocofactor to join the longitudinal study between biology/chemistry/biomedical application and the lateral study toward multielectron (photo/electro)catalysis for industrial application. This Viewpoint discloses the potential [Fe(NO)2] motif awaiting continued contribution in order to emerge as a novel application in the next 50 years, whereas the parallel development of bioinorganic chemistry, guided by inspirational Nature, moves the science forward to the next stage in order to benefit the immediate needs for human activity. PMID- 30247023 TI - Field-Scale Heterogeneity and Geochemical Regulation of Arsenic, Iron, Lead, and Sulfur Bioavailability in Paddy Soil. AB - A method using miniaturized arrayed DGT-probes (PADDI) for high-frequency in situ sampling with LA-ICPMS and CID analysis was developed to measure the field-scale heterogeneity of trace-element bioavailability. Robust calibrations (R2 > 0.99) combined with high-sensitivity (LOD = 0.35 ng cm-2), multielemental detection, and short measurement times were achieved using a new LA-ICPMS microDGT analysis. In the studied paddy-site (size: ~2500 m2), total element concentrations across the field were approximately uniform (R.S.D. < 10%), but bioavailability was shown to vary significantly as determined from 864 microgel measurements housed within 72 PADDI arrays. Porewater As measurements were unable to differentiate the top/rhizosphere and bulk/deeper-soil layers. However, dynamic sampling with DGT revealed significant differences. Heterogeneity behaviors varied greatly between the different elements. Arsenic bioavailability was stable laterally across the field, but varied with depth, which was in contrast to the trends for Pb. Fe/S(-II) change was bidirectional, differing horizontally and vertically throughout the field. The heterogeneity in Pb bioavailability, due to the high frequency of hotspot maxima that were discretely dispersed across the paddy, proved the most difficult to simulate requiring the greatest number of probe deployments to determine a reliable field-average. The DGT-PADDI system provides a new characterization of infield trends for improved trace-inorganics' management in agricultural wetlands. PMID- 30247024 TI - Suppressed Phosphine Dissociation by Polarization Effects on the Donor-Acceptor Bonds in [Ni(PEt3)4- n(ECp*) n] (E = Al, Ga). AB - A series of heteroleptic complexes [Ni(PEt3)4- n(ECp*) n] (E = Al, Ga, Cp* = pentamethylcyclopentadienyl, n = 0-4) was prepared and characterized by experimental as well as computational means. The series of compounds was studied with respect to ligand dissociation processes which are fundamental for reactivity. In contrast to the homoleptic complexes [Ni(PR3) n] phosphine dissociation is remarkably suppressed in the heteroleptic title complexes. Single crystal X-ray structures as well as density functional theory calculations reveal a gradual decrease of the Ni-PEt3 distances with increasing number of coordinated group-13 ligands ECp*. Accordingly, variable-temperature UV-vis studies of [Ni(PEt3)4- n(AlCp*) n] in solution indicate no ligand dissociation equilibrium for n >= 2. Energy decomposition analysis with the natural orbital for chemical valence extension shows higher Ni-P interaction energies for [Ni(PEt3)4- n(AlCp*) n] than for [Ni(PEt3)4] which is mainly a result of an increase in columbic attraction forces induced by Ni-PEt3 bond polarization upon ECp* coordination. PMID- 30247025 TI - Plasmonic Biosensing. AB - Plasmonic biosensing has been used for fast, real-time, and label-free probing of biologically relevant analytes, where the main challenges are to detect small molecules at ultralow concentrations and produce compact devices for point-of care (PoC) analysis. This review discusses the most recent, or even emerging, trends in plasmonic biosensing, with novel platforms which exploit unique physicochemical properties and versatility of new materials. In addition to the well-established use of localized surface plasmon resonance (LSPR), three major areas have been identified in these new trends: chiral plasmonics, magnetoplasmonics, and quantum plasmonics. In describing the recent advances, emphasis is placed on the design and manufacture of portable devices working with low loss in different frequency ranges, from the infrared to the visible. PMID- 30247026 TI - Functional Nanomaterials and Nanostructures Enhancing Electrochemical Biosensors and Lab-on-a-Chip Performances: Recent Progress, Applications, and Future Perspective. AB - Electrochemical biosensors and associated lab-on-a-chip devices are the analytical system of choice when rapid and on-site results are needed in medical diagnostics and food safety, for environmental protection, process control, wastewater treatment, and life sciences discovery research among many others. A premier example is the glucose sensor used by diabetic patients. Current research focuses on developing sensors for specific analytes in these application fields and addresses challenges that need to be solved before viable commercial products can be designed. These challenges typically include the lowering of the limit of detection, the integration of sample preparation into the device and hence analysis directly within a sample matrix, finding strategies for long-term in vivo use, etc. Today, functional nanomaterials are synthesized, investigated, and applied in electrochemical biosensors and lab-on-a-chip devices to assist in this endeavor. This review answers many questions around the nanomaterials used, their inherent properties and the chemistries they offer that are of interest to the analytical systems, and their roles in analytical applications in the past 5 years (2013-2018), and it gives a quantitative assessment of their positive effects on the analyses. Furthermore, to facilitate an insightful understanding on how functional nanomaterials can be beneficial and effectively implemented into electrochemical biosensor-based lab-on-a-chip devices, seminal studies discussing important fundamental knowledge regarding device fabrication and nanomaterials are comprehensively included here. The review ultimately gives answers to the ultimate question: "Are they really needed or can bulk materials accomplish the same?" Finally, challenges and future directions are also discussed. PMID- 30247027 TI - Photoresist Contact Patterning of Quantum Dot Films. AB - Scalable and cost-effective protocols to pattern and integrate colloidal quantum dots (QDs) with high resolution have been challenging to establish. While their solubility can facilitate certain processes such as spin-casting into thin films, it also makes them incompatible with many conventional patterning techniques including photolithography that require solution processing. In this work, we present "photoresist (PR) contact patterning", a dry means to pattern QD films over large areas with high resolution while maintaining desired properties. Here, a PR layer on an elastomer substrate is patterned by conventional photolithography and used as a dry contact stamp to selectively peel off QDs in the contact regions, leaving behind a QD film with the negative of the PR pattern. Once patterned, QD films are readily transferred and integrated on foreign substrates by subsequent transfer printing processes. Patterned PR layers can also be transferred from elastomer substrates onto QD films and used as masking layers for subsequent deposition and patterning of additional materials, e. g., patterned metal electrodes or charge transport layers for QD-based devices. The study of the interfacial mechanics and energy of materials associated with PR contact patterning reveals why a lithographically patterned PR is superior for high-resolution QD film patterning. Applicability of PR contact patterning is demonstrated through the fabrication of red, green, and blue (RGB) QD light-emitting diode pixels. PR contact patterning presented in this work not only allows dry patterning of QD films but also enables high-resolution integration of functional multistack structures for future QD-based electronic and optoelectronic devices. PMID- 30247028 TI - 4-Vinylproline. AB - Enantiomerically pure 4-vinylproline (Vyp) was synthesized by a five-step approach from N-(Boc)iodo-alanine (2) featuring copper-catalyzed SN2' substitution of the corresponding zincate onto ( Z)-1,4-dichlorobut-2-ene to prepare methyl 2- N-(Boc)amino-4-(chloromethyl)hexenoate (3). Intra- and intermolecular displacement of the chloride provided respectively Vyp and methyl 2- N-(Boc)amino-4-(azidomethyl)hexenoate (7) suitable for the synthesis of constrained peptide analogs. PMID- 30247029 TI - Direct Sulfide-Catalyzed Diastereoselective [4+1] Annulations of ortho-Quinone Methides and Bromides. AB - Direct sulfide organocatalysis is an emerging topic in research on synthetic chemistry. Here, an unprecedented sulfide-catalyzed diastereoselective [4+1] annulation of (in situ generated) ortho-quinone methides and bromides is reported. Notably, the robustness of such sulfide organocatalysis was demonstrated by performing the catalytic reaction under oxidative conditions without significantly affecting the reaction outcome. Various dihydrobenzofurans with diverse substituents were obtained with high isolated yields of up to 98% and remarkable diastereoselectivity (>19:1 dr in general). PMID- 30247030 TI - Bifunctional Stabilization of All-Inorganic alpha-CsPbI3 Perovskite for 17% Efficiency Photovoltaics. AB - The all-inorganic alpha-CsPbI3 perovskite with the most suitable band gap faces serious challenges of low phase stability and high moisture sensitivity. We discover that a simple phenyltrimethylammonium bromide (PTABr) post-treatment could achieve a bifunctional stabilization including both gradient Br doping (or alloying) and surface passivation. The PTABr treatment on CsPbI3 only induces less than 5 nm blue shift in UV-vis absorbance but significantly stabilize the perovskite phase with much better stability. Finally, the highly stable PTABr treated CsPbI3 based perovskite solar cells exhibit a reproducible photovoltaic performance with a champion efficiency up to 17.06% and stable output of 16.3%. Therefore, this one-step bifunctional stabilization of perovskite through gradient halide doping and surface organic cation passivation presents a novel and promising strategy to design stable and high performance all-inorganic lead halide. PMID- 30247031 TI - Atomically Dispersed Pd on Nanodiamond/Graphene Hybrid for Selective Hydrogenation of Acetylene. AB - We reported here a strategy to use a defective nanodiamond-graphene (ND@G) to prepare an atomically dispersed metal catalyst, i.e., in the current case atomically dispersed palladium catalyst which is used for selective hydrogenation of acetylene in the presence of abundant ethylene. The catalyst exhibits remarkable performance for the selective conversion of acetylene to ethylene: high conversion (100%), ethylene selectivity (90%), and good stability. The unique structure of the catalyst (i.e., atomically dispersion of Pd atoms on graphene through Pd-C bond anchoring) blocks the formation of unselective subsurface hydrogen species and ensures the facile desorption of ethylene against the overhydrogenation to undesired ethane, which is the key for the outstanding selectivity of the catalyst. PMID- 30247032 TI - Calculating Kinetic Rates and Membrane Permeability from Biased Simulations. AB - We present a simple approach to calculate the kinetic properties of lipid membrane crossing processes from biased molecular dynamics simulations. We demonstrate that by using biased simulations, one can obtain highly accurate kinetic information with significantly reduced computational time with respect to unbiased simulations. We describe how to conveniently calculate the transition rates to enter, cross, and exit the membrane in terms of the mean first passage times. To obtain free energy barriers and relaxation times from biased simulations only, we constructed Markov models using the dynamic histogram analysis method (DHAM). The permeability coefficients that are calculated from the relaxation times are found to correlate highly with experimentally evaluated values. We show that more generally, certain calculated kinetic properties linked to the crossing of the membrane layer (e.g., barrier height and barrier crossing rates) are good indicators of ordering drugs by permeability. Extending the analysis to a 2D Markov model provides a physical description of the membrane crossing mechanism. PMID- 30247033 TI - Direct Synthesis of alpha-Iodoenones by IPy2BF4-Promoted Rearrangement of Propargylic Esters. AB - A direct access to alpha-iodoeones from iodonium ion and propargylic tosylates or acetates is described. Bis(pyridine) iodonium tetrafluoroborate (IPy2BF4, Barluenga's reagent) promotes the rearrangement of these propargylic alcohol derivatives in mild conditions. The transformation gives beta-unsubstituted, beta monosubstituted, and beta,beta-disubstituted alpha-iodoenones in high yields. beta-Substituted alpha-iodoenones are obtained with excellent ( Z)-selectivity. PMID- 30247034 TI - A Quantitative Model of Daptomycin Binding to Lipid Bilayers. AB - Daptomycin is a cyclic lipopeptide of clinical importance in the treatment of multidrug resistant infections, including those caused by methicillin-resistant S. aureus strains. Similar to many other antimicrobial peptides, daptomycin binds with preference to anionic membranes such as those typically found in prokaryotes. However, in contrast to most linear alpha-helical peptides, daptomycin binds to lipid bilayers only in the presence of calcium ions, and its activity in vivo is absolutely Ca2+-dependent. Here, we describe the early events that occur in the binding of daptomycin to lipid bilayers using a quantitative model to analyze both equilibrium and kinetic binding data. The goal of the analysis was to obtain a precise description of the early events that occur in the interaction of daptomycin with lipid and calcium ions at low daptomycin concentrations. In the course of the analysis, we also determined the rate and equilibrium constants for binding of daptomycin to lipid and Ca2+. The model used to describe the experimental data comprises a soluble daptomycin monomer that binds calcium ions in solution with low affinity, a soluble, Ca2+-bound dimer, and a 1:1 daptomycin-lipidCa complex. A strong interaction of daptomycin with Ca2+-complexed lipid, the amount of which depends on the availability of calcium ions in the bulk solution, appears central to its function. PMID- 30247035 TI - DBU-Mediated Construction of 1,3,5-Trisubstituted Benzenes via Annulation of alpha,beta-Unsaturated Carboxylic Acids and alpha-Cyano-beta-methylenones. AB - A DBU-mediated synthesis of 1,3,5-trisubstituted benzenes was developed via the [2 + 4] annulation of in situ activated alpha,beta-unsaturated carboxylic acids and alpha-cyano-beta-methylenones. The dual role of DBU as Bronsted base and nucleophilic Lewis base is the key for the success of the reaction. PMID- 30247036 TI - Improved Total Synthesis and Biological Evaluation of Coibamide A Analogues. AB - To enable the large-scale synthesis of coibamide A, we developed an improved synthetic strategy for this class of cyclodepsipeptide. The versatility of the synthetic procedure was demonstrated by the preparation of a series of designed coibamide A analogues, which enabled the preliminary structure-activity relationship (SAR) studies for this compound. Although most modifications of coibamide A resulted in decrease or loss of the antiproliferativity, we found that versatile substitution at position 3 was well tolerated. Remarkably, a simplified analogue, [MeAla3-MeAla6]-coibamide (1f), not only showed nearly the same inhibition as coibamide A against the tested cancer cells but also significantly inhibited tumor growth in vivo. The improved synthetic strategy and the relevant trends of SAR disclosed in this study will be valuable for further optimization of the overall profile of coibamide A. PMID- 30247038 TI - Prediction of Contact Angles and Density Profiles of Sessile Droplets Using Classical Density Functional Theory Based on the PCP-SAFT Equation of State. AB - This study demonstrates the capability of the density functional theory (DFT) formalism to predict contact angles and density profiles of model fluids and of real substances in good quantitative agreement with molecular simulations and experimental data. The DFT problem is written in cylindrical coordinates, and the solid-fluid interactions are defined as external potentials toward the fluid phase. Monte Carlo (MC) molecular simulations are conducted in order to assess the density profiles resulting from the Helmholtz energy functional used in the DFT formalism. Good quantitative agreement between DFT predictions and MC results for Lennard-Jones and ethane nanodroplets is observed, both for density profiles and for contact angles. That comparison suggests, first, that the Helmholtz energy functional proposed in a previous study [ Sauer , E. ; Gross , J. Ind. Eng. Chem. Res. 56 , 2017 , 4119 - 4135 ] is suitable for three-phase contact lines and, second, that Lagrange multipliers can be used to constrain the number of molecules, similar to a canonical ensemble. Experiments of sessile droplets on solid surfaces are performed to assess whether a real solid with its microscopic roughness can be described through a simple model potential. Comparison of DFT results to experimental data is done for a Teflon surface because Teflon can be regarded as a substrate exhibiting only attractive interactions of van der Waals type. It is shown that the real solid can be described as a perfectly planar solid with effective solvent-to-solid interactions, defined through a single adjustable parameter for the solid. Subsequent predictions for the contact angle of eight solvents, including polar components such as water, are found in very good agreement to experimental data using simple Berthelot-Lorentz combining rules. For the eight investigated solvents, we find mean absolute deviations of 3.77 degrees . PMID- 30247037 TI - An Electromechanical Approach to Understanding Binding Configurations in Single Molecule Devices. AB - The configuration of the molecule-electrode contact region plays an important role in determining the conductance of a single-molecule junction, and the variety of possible contact configurations have yielded multiple conductance values for a number of molecular families. In this report, we perform simultaneous conductance and electromechanical coupling parameter measurements on a series of oligophenylene-dithiol single-molecule junctions. These molecules show two distinct conductance values, and by examining the conductance changes, the electromechanical coupling, and the changes in the I- V characteristics coupled with a combination of analytical mechanical models and density functional theory (DFT) structure calculations, we are able to determine the most-probable binding configuration in each of the conductance states. We find that the lower conductance state is likely due to the thiols binding to each electrode at a gold top site, and in the higher-conductance state, the phenylene pi orbitals interact with electrodes, drastically modifying the transport behavior. This approach provides an expanded methodology for exploring the relationship between the molecule-electrode contact configuration and molecular conductance. PMID- 30247039 TI - Nanocrystallization of Rare Tolbutamide Form V in Mesoporous MCM-41 Silica. AB - Encapsulation of pharmaceuticals inside nanoporous materials is of increasing interest due to their possible applications as new generation therapeutics, theranostic platforms, or smart devices. Mesoporous silicas are leading materials to be used as nanohosts for pharmaceuticals. Further development of new generation of nanoscale therapeutics requires complete understanding of the complex host-guest interactions of organic molecules confined in nanosized chambers at different length scales. In this context, we present results showing control over formation and phase transition of nanosize crystals of model flexible pharmaceutical molecule tolbutamide confined inside 3.2 nm pores of the MCM-41 host. Using low loading levels (up to 30 wt %), we were able to stabilize the drug in highly dynamic amorphous/disordered state or direct the crystallization of the drug into highly metastable nanocrystalline form V of tolbutamide (at loading levels of 40 and 50 wt %), providing first experimental evidence for crystallization of pharmaceuticals inside the pores as narrow as 3.2 nm. PMID- 30247040 TI - Cobalt-Catalyzed Hydroarylations and Hydroaminations of Alkenes in Tunable Aryl Alkyl Ionic Liquids. AB - Tunable aryl alkyl ionic liquids (TAAILs) are a promising class of imidazolium- or triazolium-based ionic liquids. Contrary to "standard" all-alkyl ionic liquids, these carry an aryl ring together with a linear or branched alkyl chain. Their application in the cobalt-catalyzed hydroarylation/hydroamination of alkenes and anilines is presented. The catalytic system is tolerant toward air and is scalable and reusable. It has been successfully used for the synthesis of pharmacologically relevant primary to tertiary aryl amines. PMID- 30247041 TI - Quantitative 1H-1H Distances in Protonated Solids by Frequency-Selective Recoupling at Fast Magic Angle Spinning NMR. AB - Nuclear magnetic resonance (NMR) spectroscopy of protons in protonated solids is challenging. Fast magic angle spinning (MAS) and homonuclear decoupling schemes, in conjunction, with high magnetic fields have improved the proton resolution. However, experiments to quantitatively measure 1H-1H distances still remain elusive due to the dense proton-proton dipolar coupling network. A novel MAS solid-state NMR pulse sequence is proposed to selectively recouple and measure interproton distances in protonated samples. The phase-modulated sequence combined with a judicious choice of transmitter frequency is used to measure quantitative 1H-1H distances on the order of 3 A in l-histidine.HCl.H2O, despite the presence of other strongly coupled protons. This method provides a major boost to NMR crystallography approaches for structural determination of pharmaceutical molecules by directly measuring 1H-1H distances. The band selective nature of the sequence also enables observation of selective 1H-1H correlations (e.g., HN-HN/HN-Halpha/EtaNu-EtaMethyl) in peptides and proteins, which should serve as useful restraints in structure determination. PMID- 30247042 TI - Using Polymer Hydrogels for Glyphosate Sequestration from Aqueous Solutions: Molecular Theory Study of Adsorption to Polyallylamine Films. AB - A molecular theory has been applied to study the equilibrium conditions of glyphosate and aminomethylphosphonic acid (AMPA) adsorption from aqueous solutions to hydrogel films of cross-linked polyallylamine (PAH). This theoretical framework allows for describing the size, shape, state of charge/protonation, and configurational freedom of all chemical species in the system. Adsorption of glyphosate is a nonmonotonic function of the solution pH, which results from the protonation behavior of both the adsorbate and adsorbent material. Glyphosate and chloride ions compete for adsorption to neutralize the polymer charge; lowering the solution salt concentration enhances the partition of glyphosate inside the hydrogel film. AMPA adsorption is qualitatively similar to that of glyphosate but orders of magnitude smaller under the same conditions. AMPA is less charged than glyphosate, which unbalances the competition for adsorption with salt counter ions. In mixed solutions, glyphosate presence can significantly hinder AMPA adsorption. A higher pH establishes inside the film than in the bulk solution, which has important implications for the herbicide biodegradation because microbial activity is pH-dependent. Thus, PAH hydrogel films can be considered as functional materials that combine glyphosate sequestration and in situ degradation. In devising these materials, the polymer density is an important variable of design; polymer networks with high density of titratable units can enhance adsorption; this density can also be used to modify the pH inside the material. PMID- 30247043 TI - Macroscopic Model for Sessile Droplet Evaporation on a Flat Surface. AB - Evaporation of sessile droplets on a flat surface involves a complex interplay between phase change, diffusion, advection, and surface forces. In an attempt to significantly reduce the complexity of the problem and to make it manageable, we propose a simple model hinged on a surface free-energy-based relaxation dynamics of the droplet shape, a diffusive evaporation model, and a contact line pinning mechanism governed by a yield stress. Our model reproduces the known dynamics of droplet shape relaxation and of droplet evaporation, both in the absence and in the presence of contact line pinning. We show that shape relaxation during evaporation significantly affects the lifetime of a drop. We find that the dependence of the evaporation time on the initial contact angle is a function of the competition between the shape relaxation and evaporation and is strongly affected by any contact line pinning. PMID- 30247044 TI - Optimized Ag Nanovoid Structures for Probing Electrocatalytic Carbon Dioxide Reduction Using Operando Surface-Enhanced Raman Spectroscopy. AB - Surface-enhanced Raman spectroscopy is a powerful analytical tool and a strongly surface structure-dependent process. Importantly, it can be coupled with electrochemistry to simultaneously record vibrational spectroscopic information during electrocatalytic reactions. Highest Raman enhancements are obtained using precisely tuned nanostructures. The fabrication and evaluation of a high number of different nanostructures with slightly different properties is time-consuming. We present a strategy to systematically determine optimal nanostructure properties of electrochemically generated Ag void structures in order to find the void size providing highest signal enhancement for Raman spectroscopy. Ag-coated Si wafers were decorated with a monolayer of differently sized polymer nanospheres using a Langmuir-Blodgett approach. Subsequently, bipolar electrochemistry was used to electrodeposit a gradient of differently sized void structures. The gradient structures were locally evaluated using Raman spectroscopy of a surface-adsorbed Raman probe, and the surface regions exhibiting the highest Raman enhancement were characterized by means of scanning electron microscopy. High-throughput scanning droplet cell experiments were utilized to determine suitable conditions for the electrodeposition of the found highly active structure in a three-electrode electrochemical cell. This structure was subsequently employed as the working electrode in operando surface-enhanced Raman measurements to verify its viability as the signal amplifier and to spectroscopically rationalize the complex electrochemical reduction of carbon dioxide. PMID- 30247045 TI - Statistical learning for speech segmentation: Age-related changes and underlying mechanisms. AB - Statistical learning (SL) is a powerful learning mechanism that supports word segmentation and language acquisition in infants and young adults. However, little is known about how this ability changes over the life span and interacts with age-related cognitive decline. The aims of this study were to: (a) examine the effect of aging on speech segmentation by SL, and (b) explore core mechanisms underlying SL. Across four testing sessions, young, middle-aged, and older adults were exposed to continuous speech streams at two different speech rates, both with and without cognitive load. Learning was assessed using a two-alterative forced-choice task in which words from the stream were pitted against either part words, which occurred across word boundaries in the stream, or nonwords, which never appeared in the stream. Participants also completed a battery of cognitive tests assessing working memory and executive functions. The results showed that speech segmentation by SL was remarkably resilient to aging, although age effects were visible in the more challenging conditions, namely, when words had to be discriminated from part-words, which required the formation of detailed phonological representations, and when SL was performed under cognitive load. Moreover, an analysis of the cognitive test data indicated that performance against part-words was predicted mostly by memory updating, whereas performance against nonwords was predicted mostly by working memory storage capacity. Taken together, the data show that SL relies on a combination of implicit and explicit skills, and that age effects on SL are likely to be linked to an age-related selective decline in memory updating. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247046 TI - "1-in-X" bias: "1-in-X" format causes overestimation of health-related risks. AB - According to the "1-in-X" effect, "1-in-X" ratios (e.g., 1 in 12) trigger a higher subjective probability than do numerically equivalent "N-in-X*N" ratios (e.g., 3 in 36). Here we tested the following: (a) the effect on objective measures, (b) its consequences for decision-making, (c) whether this effect is a form of bias by measuring probability accuracy, and (d) its amplification in people with lower health literacy and numeracy. In parallel-designed experiments, 975 participants from the general adult population participated in 1 of 5 experiments following a 2(format: "1-in-X" or "N-in-X*N") * 4(scenarios) mixed design. Participants assessed the risk of contracting a disease on either a verbal probability scale (Experiment 1) or a numerical probability/frequency scale with immediate (Experiments 2-3) or delayed presentation (Experiments 4-5). Participants also made a health-related decision and completed a health literacy and numeracy scale. The "1-in-X" ratios yielded higher probability perceptions than did the "N-in-X*N" ratios and affected relevant decisions. Critically, the "1-in-X" ratios led to a larger objective overestimation of numerical probabilities than did the "N-in-X*N" ratios. People with lower levels of health literacy and numeracy were not more sensitive to the bias. Health professionals should use "1-in-X" ratios with great caution when communicating to patients, because they overestimate health risks. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247047 TI - Learning a skill with the expectation of teaching it impairs the skill's execution under psychological pressure. AB - When practicing a motor skill, learners who are expecting to teach it to another person exhibit superior gains in skill execution and declarative knowledge. Since skills acquired with large gains in declarative knowledge are highly susceptible to decrement under psychological pressure, it is possible the advantage of expecting to teach is lost when performing the learned skill under pressure. To test this hypothesis, we had 40 participants practice golf putting with the expectation of teaching (teach group) and 42 participants practice with the expectation of being tested (test group). The next day, all participants performed low- and high-pressure posttests. The teach group outperformed the test group under low pressure but not high pressure, where the teach group's performance declined to that of the test group. Further, the teach group reported using more declarative knowledge during the posttests than the test group, but declarative knowledge use did not mediate the performance decline from low- to high-pressure posttest. Taken together, results suggest expecting to teach benefits skill learning, but this advantage is lost when performing the skill under high pressure. However, whether skill breakdown under high pressure is caused by an increase in declarative knowledge use remains an open question. (PsycINFO Database Record PMID- 30247048 TI - The impact of organizational performance on the emergence of Asian American leaders. AB - Despite remarkably high levels of education and income, Asian Americans remain underrepresented at the top of the organizational hierarchy. Existing work suggests that a mismatch between the prototypical characteristics of business leaders (e.g., dominance) and stereotypes associated with Asian Americans (e.g., submissiveness) lowers the likelihood that Asian Americans will emerge as leaders. We predict that this reluctance to appoint Asian Americans will be attenuated when organizations experience performance decline because decision makers believe Asian Americans are inclined to sacrifice their self-interest to improve the welfare of others. We found support for these predictions using a multimethod approach. In an archival study of 4,951 CEOs across five decades, we find that Asian Americans were appointed almost two-and-a-half times more often during decline than nondecline (Study 1). Then, in three studies, we show that this pattern occurs because evaluators (a) prefer self-sacrificing leaders more when organizations are experiencing decline than success (Study 2); (b) expect Asian Americans leaders to behave in self-sacrificing ways in general (Study 3); and, consequently, (c) perceive that Asian Americans are better equipped to be leaders during decline than success (Study 4). We consider these findings in tandem with a set of exploratory analyses. This includes our finding that organizations experience decline only 12% of the time, suggesting that evaluators deem Asian Americans to be suitable leaders in circumstances that occur infrequently and are short-lived. (PsycINFO Database Record PMID- 30247049 TI - Opening the window: Size of the attentional window dominates perceptual load and familiarity in visual selection. AB - Perceptual load theory (Lavie, 1995) claims that visual selection is determined both by the perceptual demands a display imposes and by the perceptual resources an observer has available for processing. This theory is often tested by examining distractor interference in modified flanker tasks, which separate potential target locations from distractor locations and allow researchers to measure distractor processing. Although this task has provided significant insight into cognitive processing, it may also be an example of how a given task obscures potentially important experimental factors. Specifically, the structure of the target array could encourage observers to adopt a narrow attentional window, which could eliminate distractor interference as significant distractor processing has been shown to occur inside but not outside the attentional window (Belopolsky, Zwaan, Theeuwes, & Kramer, 2007). The present experiments included conditions that allowed the target to vary among the same locations as within a structured target array but varied possible nontarget locations that never overlapped with possible target locations. Whenever nontarget items remained in fixed locations, significant distractor processing occurred due to the observer adopting a wide attentional window even under high perceptual load conditions (Experiment 1). Further evidence showed that familiarity with these locations could not explain the interference (Experiment 2A). However, imposing a ring around the target array, similar to what a circular target array might impose, narrowed the attentional window and eliminated distractor interference (Experiment 2B). Thus, the size of the attentional window is capable of dominating both perceptual load and familiarity in visual selection. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247050 TI - Orthographic and root frequency effects in Arabic: Evidence from eye movements and lexical decision. AB - One of the more studied and robust effects in the reading literature is that of word frequency. Semitic words (e.g., in Arabic or Hebrew) contain roots that indicate the core meaning to which the word belongs. The effects of the frequency of these roots on reading as measured by eye movements is much less understood. In a series of experiments, we investigated and replicated traditional word frequency effects in Arabic: Eye movement measures showed the expected facilitation for high- over low-frequency target words embedded in sentences (Experiment 1). The same was found in response time and accuracy in a lexical decision task (Experiment 3a). Using target words that were matched on overall orthographic frequency and other important variables but that contained either high- or low-frequency roots, we found no significant influence of root frequency on eye movement measures during sentence reading (Experiment 2). Using the same target words in a lexical-decision task (Experiment 3b), we replicated the absence of root frequency effects on real Arabic word processing. At 1st glance, the results may not appear to be in line with theoretical accounts that postulate early morphological decomposition and root identification when processing Semitic words. However, these results are compatible with accounts where morphological decomposition does occur but is followed by recombination, and under certain conditions recombination costs can eliminate or even reverse root frequency effects. (PsycINFO Database Record PMID- 30247051 TI - Religious freedom restoration acts and sexual minority population health in the United States. AB - Religious freedom restoration acts (RFRAs) in the United States potentially facilitate discrimination against lesbian, gay, and bisexual individuals (i.e., sexual minorities). In the current investigation, we explored whether a population health metric among sexual minority adults changed over time based on the presence, absence, or introduction of a state RFRA. Data are from 21 of the United States that gathered sexual orientation data from population-based samples of noninstitutionalized adults in the 2015 Behavioral Risk Factor Surveillance System (CDC, 2015, 2016). The analytic sample included 4,911 sexual minority individuals. Time was measured in 4 3-month quarters (i.e., Q1, Q2, Q3, Q4). For each state, the prevalence of sexual minority adults reporting >=14 unhealthy days/30 days was calculated. Only Indiana (the only state in the sample that passed an RFRA in 2015) exhibited significant increasing proportions over time of sexual minority adults reporting >=14 unhealthy days (Q1 = 24.5%, Q2 = 34.8%, Q3 = 41.2%, Q4 = 59.5%; beta = 0.50, SE = 0.23, p = .037). Post hoc analyses revealed that unhealthy days did not increase for heterosexual adults in Indiana. Indiana's RFRA could have contributed to the increasing prevalence of unhealthy days among sexual minority adults in that state during 2015. Public health surveillance tools are needed to expedite analyses of the impact of laws on minority population health. (PsycINFO Database Record PMID- 30247052 TI - Functional independence after acquired brain injury: Prospective effects of health self-efficacy and cognitive impairment. AB - OBJECTIVE: To examine how health self-efficacy and cognitive impairment severity relate to functional independence after acquired brain injury (ABI). DESIGN: Observational. SETTING: Outpatient rehabilitation hospital. PARTICIPANTS: Seventy five adults with predominately stroke or traumatic brain injury who were beginning a course of occupational therapy. MAIN MEASURES: Health self-efficacy was assessed with the Self-Rated Abilities for Health Practices. Cognitive functioning was assessed via a composite z score of neuropsychological tests. Trait affectivity was assessed with the Positive and Negative Affect Schedule. Functional independence was assessed with the Barthel Index and Lawton Instrumental Activities of Daily Living Scale. RESULTS: Health self-efficacy correlated moderately with functional independence. A moderation threshold effect was detected that revealed for whom health self-efficacy predicted functional independence. Among participants with normal to mildly impaired cognition (>-2 z cognitive composite), health self-efficacy correlated positively with functional independence, which held after accounting for trait affectivity. In contrast, health self-efficacy was not correlated with functional independence among participants with greater impairment (<-2 z cognitive composite). CONCLUSIONS: Health self-efficacy predicts functional independence and may serve as a protective factor after ABI among individuals with relatively intact cognition. However, health self-efficacy does not predict functional independence among individuals with moderate or severe cognitive impairment, possibly due to limited self-awareness. This study extends the literature linking health self-efficacy with rehabilitation outcomes and reinforces the need for promoting self management in ABI. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247053 TI - Predictors of physical activity among rural adults following cardiac rehabilitation. AB - PURPOSE/OBJECTIVE: Cardiac rehabilitation aims to reduce the likelihood of recurrent cardiac events through physical activity (PA) and education. There is limited understanding about the predictors of physical activity behavior in rural adults beyond rehabilitation. This study explored predictors of regular physical activity in rural adults, 6-12 months post cardiac rehabilitation. Research Method/Design: A self-report questionnaire (quantitative cross-sectional design) was mailed to a simple random sample of rural South Australians who previously participated in cardiac rehabilitation (n = 315). Regression modeling was adjusted for physical activity history and gender to examine psychological, social, and environmental predictors of (a) current leisure-time physical activity, self-reported through the Godin Leisure Time Exercise Questionnaire expressed as the Leisure Score Index (LSI) and the weekly frequency of physical activity bouts that cause sweating ("sweat frequency"), and (b) stage of physical activity behavior change according to the Transtheoretical Model of Behavior Change ("Stage of PA change"). RESULTS: All measures of self-efficacy (barriers, task, and relapse), social assimilation, and self-regulation predicted LSI, whereas all measures of self-efficacy and self-regulation predicted both "Stage of PA change" and "sweat frequency." Self-regulation explained the highest percentage of explained variance in LSI (31.6%) and "sweat frequency" (12.5%). Home social support additionally predicted "Stage of PA change"; there were no environmental predictors of any of the outcome measures. CONCLUSION: Similar to urban populations, the predictors of post-cardiac-rehab physical activity among rural adults predominantly emanate from the psychological domain. Findings support the need to strengthen the focus of cardiac rehabilitation program design on self-management skills and behaviors. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247054 TI - Service needs and health outcomes among caregivers of service members and veterans following TBI. AB - PURPOSE/OBJECTIVE: The purpose of this study was to examine the (a) prevalence of unmet caregiver needs across eight health care and social service needs and the (b) impact of unmet needs on caregiver health and appraisal outcomes. Research Method/Design: Participants were 264 caregivers (95.8% female; 85.2% spouse/partner) providing help to service members and veterans who sustained a mild to severe or penetrating traumatic brain injury. Caregivers were recruited from Walter Reed National Military Medical Center (Maryland) and via community outreach to participate in the congressionally mandated 15-year Longitudinal Traumatic Brain Injury Study (Sec721 NDAA FY2007) supported by the Defense and Veterans Brain Injury Center. Caregivers completed the Caregiver Appraisal Scale, SF-36v2 Health Survey, and caregiver questionnaire. Participants were divided into 3 health care and social service needs groups: no unmet needs, 1-3 unmet needs, and 4-8 unmet needs. RESULTS: Six of the 8 needs were each endorsed by a majority of caregivers (59.1%-70.1%). Each need was reported as unmet by 29.5% to 52.7% of caregivers. A significant linear relation was found between number of needs and poorer outcomes (i.e., 4-8 needs < 1-3 needs < 0 needs). The cumulative number of unmet needs was significantly related to worse outcomes in most areas, while most individual needs were not significantly related to outcomes. One exception was the caregiver's unmet need for medical health, which was significantly related to increased bodily pain. CONCLUSIONS/IMPLICATIONS: Continued support from programs and expansion in the breadth and scope of health care and social services for caregivers is required, including identifying the issues that hinder caregivers accessing the services they need. (PsycINFO Database Record PMID- 30247055 TI - Emotional and cognitive difficulties, help-seeking, and barriers to treatment in neurological disorders. AB - PURPOSE/OBJECTIVE: To (a) explore the mental health and wellbeing of Australian adults with neurological disorders, (b) examine their history of help-seeking behavior and perceived barriers to treatment for emotional and cognitive difficulties, and (c) assess their interest in online self-management programs. METHOD/DESIGN: A sample of 2,254 (mean age = 46.3 year; SD = 14.1; 80% were female), Australians with a neurological disorder completed an online survey of standardized measures of mental health and wellbeing, and questions about help seeking and perceived barriers to treatment. RESULTS: There was consistent evidence of poor mental health and wellbeing across measures of psychological distress (Kessler 10, K10; M [24.6]; SD [8.6]), depression (Neurological Depressive Disorders Inventory-Epilepsy, NDDI-E; M [15.6]; SD [4.3]), disability (World Health Organization Disability Assessment Schedule 2.0, WHODAS 2.0; M [16.3]; SD [10.2]), Satisfaction With Life Scale (SWLS; M [20.0]; SD [8.0]), and perceived cognitive deficits (Perceived Cognitive Questionnaires, PDQ) in attention/concentration (M [2.1]; SD [1.2]); retrospective memory (M [2.0]; SD [1.0]); prospective memory (M [1.7]; SD [.9]); and planning/organization (M [2.0]; SD [1.0]). Participants reported using both formal (e.g., advice from GP and neurologist) and informal help-seeking (e.g., searching the Internet) for both emotional symptoms and cognitive difficulties, but most (>70%) reported unmet needs and experiencing barriers to seeking care, including the lack of available services and beliefs that symptoms could not change. CONCLUSIONS/IMPLICATIONS: We found high levels of comorbid psychological distress among people with neurological disorders, widespread barriers to receiving care, and a high level of interest in an online self-management program that might help overcome barriers to accessing psychological treatment for mood symptoms and impaired cognitive function. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247056 TI - Ensemble perception in depth: Correct size-distance rescaling of multiple objects before averaging. AB - Previous studies have shown that people are good at rapidly estimating ensemble summary statistics, such as the mean size of multiple objects. In the present study, we tested whether these average estimates are based on "raw" retinal representations (proximal sizes) or on how items should appear based on context, such as the viewing distance (distal sizes). In our experiments, observers adjusted the mean size of multiple objects presented at various apparent distances through a stereoscope. In Experiment 1, all items were shifted in depth by the same amount while the adjustable probe stayed at the fixed middle position. We found that presenting ensembles in an apparently remote plane made observers overestimate the mean size, which is consistent with angular sizes being rescaled to distance. In Experiment 2, we presented individual sizes in different planes. While angular sizes and apparent distances were kept controlled across conditions, we only manipulated correlations between them. These manipulations affected the precision of size averaging in line with changes in the range of apparent rather than angular sizes. This pattern is possible only if the visual system rescales each individual size to its distance prior to averaging. Our finding demonstrates that ensemble summaries of basic features, such as size, can be based on quite elaborated representations of multiple objects. We also discuss important implications for size constancy. (PsycINFO Database Record PMID- 30247057 TI - Prior exposure increases perceived accuracy of fake news. AB - The 2016 U.S. presidential election brought considerable attention to the phenomenon of "fake news": entirely fabricated and often partisan content that is presented as factual. Here we demonstrate one mechanism that contributes to the believability of fake news: fluency via prior exposure. Using actual fake-news headlines presented as they were seen on Facebook, we show that even a single exposure increases subsequent perceptions of accuracy, both within the same session and after a week. Moreover, this "illusory truth effect" for fake-news headlines occurs despite a low level of overall believability and even when the stories are labeled as contested by fact checkers or are inconsistent with the reader's political ideology. These results suggest that social media platforms help to incubate belief in blatantly false news stories and that tagging such stories as disputed is not an effective solution to this problem. It is interesting, however, that we also found that prior exposure does not impact entirely implausible statements (e.g., "The earth is a perfect square"). These observations indicate that although extreme implausibility is a boundary condition of the illusory truth effect, only a small degree of potential plausibility is sufficient for repetition to increase perceived accuracy. As a consequence, the scope and impact of repetition on beliefs is greater than has been previously assumed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247058 TI - The limits of learning: Exploration, generalization, and the development of learning traps. AB - Learning usually improves the accuracy of beliefs through the accumulation of experience. But are there limits to learning that prevent us from accurately understanding our world? In this article we investigate the concept of a "learning trap"-the formation of a stable false belief even with extensive experience. Our review highlights how these traps develop through the interaction of learning and decision making in unknown environments. We further document a particularly pernicious learning trap driven by selective attention, a mechanism often assumed to facilitate learning in complex environments. Using computer simulation, we demonstrate the key attributes of the agent and environment that lead to this new type of learning trap. Then, in a series of experiments we present evidence that people robustly fall into this trap, even in the presence of various interventions predicted to meliorate it. These results highlight a fundamental limit to learning and adaptive behavior that impacts individuals, organizations, animals, and machines. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247059 TI - Do the ends dictate the means in emotion regulation? AB - Although selecting emotion regulation strategies constitutes means to achieve emotion goals (i.e., desired emotional states), strategy selection and goals have been studied independently. We propose that the strategies people select are often dictated by what they want to feel. We tested the possibility that emotion regulation involves choosing strategies that match emotion goals. We expected people who are motivated to decrease emotional intensity to select strategies that are tailored for decreasing emotions (e.g., distraction), whereas those who are motivated to increase emotional intensity to select strategies that are tailored for increasing emotions (e.g., rumination). We expected this pattern to be evident both in the lab and in everyday life. We first verified that some strategies (i.e., distraction) are more effective in decreasing, and other strategies (i.e., rumination) more effective in increasing emotions (Study 1). Next, we tested whether emotion goals (decrease vs. increase emotion) direct the selection of strategies inside (Studies 2-3) and outside (Study 4) the laboratory. As predicted, participants were more likely to select strategies that decrease emotions (e.g., distraction, suppression) when motivated to decrease, and strategies that increase emotions (e.g., rumination) when motivated to increase negative (Studies 2-4) and positive (Study 3) emotions. Finally, in Study 5, we demonstrated that emotional dysfunction is linked to less flexibility in matching strategies to goals. Compared to healthy participants, depressed participants selected rumination less for increasing emotions and selected distraction less for decreasing emotions. Our findings show that what people want to feel can determine how they regulate emotions. (PsycINFO Database Record PMID- 30247060 TI - Child homicides by stepfathers: A replication and reassessment of the British evidence. AB - Daly and Wilson (1994, 2008) reported that rates of fatal assaults of young children by stepfathers are over 100 times those by genetic fathers, and they explain the difference in evolutionary terms. Their study was replicated by comparing updated homicide data and population data from 3 surveys. This indicated that the risk to young stepchildren was approximately 16 times that to genetic children, and stepfathers were twice as likely to kill by beating. However, when we controlled for father's age, the risk from cohabiting stepfathers was approximately 6 times greater. Above the age of 4 years, stepchildren were at no greater risk than genetic children. Children are at risk from fathers primarily when both are young and they do not live together; stepfathers' apparent overrepresentation results largely from their relative youth and from many nonresidential perpetrators being labeled stepfathers. Other factors are also influential, but if these include stepparenthood, its impact is considerably less than previous researchers have claimed. (PsycINFO Database Record PMID- 30247061 TI - Attention and choice across domains. AB - When people are faced with a decision, they tend to choose the option that draws their attention. In recent years, correlations between attention and choice have been documented in a variety of domains. This leads to the question of whether there is a general, stable relationship between attention and choice. Here, we examined choice behavior in tasks with and without risk and social considerations, using food or monetary rewards, within a single experiment. This allowed us to test the consistency of the decision-making process across domains. In the aggregate, we identified remarkable consistency in the attention-choice link. At the individual level, subjects with strong attentional effects in one task were likely to have strong attentional effects in the others. The strength of these effects also correlated with individuals' degree of tunnel vision. Thus, the attention-choice relationship appears to be a stable individual trait that is linked to more general attentional constraints. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247062 TI - New insights on real-world human face recognition. AB - Humans are supposedly expert in face recognition. Because of limitations in existing research paradigms, little is known about how faces become familiar in the real world, or the mechanisms that distinguish good from poor recognizers. Here, we capitalized on several unique features of the TV series Game of Thrones to develop a highly challenging test of face recognition that is ecologically grounded yet controls for important factors that affect familiarity. We show that familiarization with faces and reliable person identification require much more exposure than previously suggested. Recognition is impaired by the mere passage of time and simple changes in appearance, even for faces we have seen frequently. Good recognizers are distinguished not by the number of faces they recognize, but by their ability to reject novel faces as unfamiliar. Importantly, individuals with superior recognition abilities also forget faces and are not immune to identification errors. (PsycINFO Database Record PMID- 30247063 TI - Perceived peer support and diabetes management from adolescence into early emerging adulthood. AB - OBJECTIVES: The objective of the study was to examine longitudinal associations of perceived diabetes-specific peer support with adherence and glycemic control among late adolescents with type 1 diabetes as they transition out of high school and into early emerging adulthood. METHOD: As part of a larger study, 211 high school seniors with type 1 diabetes completed confidential online surveys and were reassessed 1 year later. Perceived diabetes-specific peer support and adherence were assessed in each survey. Glycemic control was measured with HbA1c assay kits. RESULTS: Perceived diabetes-specific peer support in high school predicted better adherence across the subsequent year while controlling for initial levels of adherence. Perceived peer support during early emerging adulthood was also associated with better adherence across time, after controlling for initial levels of both adherence and peer support. CONCLUSIONS: Perceived diabetes-specific peer support may be a protective factor as late adolescents with type 1 diabetes transition out of high school. Building strong peer support during the transition into early emerging adulthood may facilitate better diabetes management during this high-risk time of development. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247065 TI - Associations of daily partner responses with fatigue interference and relationship satisfaction in colorectal cancer patients. AB - OBJECTIVE: This study investigates the associations of daily partner responses toward patient's fatigue and well behavior with patient's fatigue interference and relationship satisfaction. The moderating effect of fatigue severity was also examined. METHOD: In an intensive longitudinal design, patients treated for colorectal cancer and their partners (n = 101 dyads) completed diaries for 14 days. Patients and partners reported on partner responses toward patient's fatigue behavior (e.g., resting), partner responses toward patient's well behavior (e.g., being active), and fatigue severity. Patients also indicated their fatigue interference and relationship satisfaction. Multilevel modeling was applied to assess within-person main and interaction effects. RESULTS: Patient reported solicitous responses toward fatigue behavior and negative responses toward well behavior were associated with increases in fatigue interference, while facilitative responses toward well behavior were associated with a decrease in fatigue interference. The latter two associations were intensified on days patients reported relatively high fatigue. Solicitous responses toward fatigue behavior and facilitative responses toward well behavior were also associated with increases in relationship satisfaction. Punishing responses toward fatigue behavior were associated with a decrease in relationship satisfaction, especially on days patients reported higher fatigue. Models using partner reports largely confirmed the main effects of partner responses on fatigue interference and relationship satisfaction but failed to reproduce the moderating effect of fatigue. CONCLUSIONS: Daily partner responses appear to impact patients' fatigue adjustment, especially on days patients experience high fatigue levels. Only facilitative responses toward well behavior seem to benefit both patients' fatigue interference and relationship satisfaction. Couple interventions should guide partners to encourage patients' well behavior and aid them to correctly estimate patients' current fatigue severity. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247064 TI - Relationship between antidepressant therapy and risk for cardiovascular events in patients with and without cardiovascular disease. AB - OBJECTIVE: The American Heart Association has endorsed depression as a cardiac risk factor and recommends screening as part of routine practice. This has been met with controversy due to inconsistencies in the data linking depression treatment to better cardiovascular outcomes. Our objective was to prospectively assess the association between depression treatment (defined as being prescribed antidepressant medication) and major adverse cardiovascular events (MACE) in patients referred for exercise stress tests. METHOD: Two thousand three hundred eighty-five consecutive patients presenting for myocardial perfusion exercise stress tests underwent a sociodemographic, medical, and psychiatric interview (Primary Care Evaluation of Mental Disorders [PRIME-MD]) and completed the Beck Depression Inventory (BDI). History of cardiovascular disease (CVD) and antidepressant use was self-reported and verified via chart review. Participants followed over an 8.8-year follow up, and information regarding MACE incidence (including cardiac mortality, nonfatal myocardial infarction, revascularization procedures, cerebrovascular events) was obtained from provincial administrative databases. RESULTS: 8% (n = 190) of the sample were taking antidepressants at baseline, 41% (n = 916) had a history of CVD, and 38.7% (n = 921) had depression according to the PRIME-MD or BDI. Antidepressant treatment was associated with a 30% reduced risk of MACE (Hazard ratio [HR] = 0.697; 95% confidence interval [CI] = [0.504, 0.964]; p = .029). A 46% reduction in risk was associated with antidepressant treatment among those without CVD (HR = 0.542; 95% CI [0.299, 0.981]; p = .043). In depressed patients, a 33% reduction in risk of MACE associated with antidepressant use was seen (adjusted HR = 0.674; 95% CI [0.440, 1.033]; p = .07). CONCLUSIONS: Antidepressants may be cardio-protective among patients presenting for stress testing independent of risk factors including CVD and depression. Results support treating depression with antidepressants in this population to reduce risk of MACE. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30247066 TI - Stress and verbal memory in patients with Alzheimer's disease: different role of cortisol and anxiety. AB - OBJECTIVES: Chronic stress has shown to have marked effects on learning and memory. A broader understanding of these effects has special interest in the context of Alzheimer's disease (AD). This study aims to analyze the moderating effect of cognitive impairment in the relationships between stress and verbal memory performance by considering biological and psychological measures of stress. METHOD: The sample consisted of 80 AD patients and 104 healthy controls. Salivary cortisol and state anxiety was measured as stress markers. Memory Alteration test (M@T) and Hopkins verbal learning test (HVLT-R) were used to measure verbal memory. RESULTS: In controls, cortisol level was negatively associated with HVLT-R total, learning and delayed recall scores as well as M@T free recall scores, while in patients, such associations were not significant. In this group, cortisol negative effects were limited to HVLT-R learning and M@T semantic memory scores. In both groups, anxiety was associated with better M@T encoding and free recall scores. Besides, inverted U-shaped relationships were observed between anxiety and HVLT-R total recall and learning scores as well as M@T orientation scores. CONCLUSION: Cortisol levels and anxiety are differentially associated with memory performance in older adults. In general, the negative relationship between cortisol levels and memory observed in healthy elderly weakens in AD. However, moderate state anxiety levels seem to be associated with a better memory performance in AD patients and in healthy elderly. PMID- 30247067 TI - Frailty as an instrument for evaluation of elderly patients with non-ST-segment elevation myocardial infarction: A follow-up after more than 5 years. AB - BACKGROUND: There is a growing body of evidence on the relevance of using frailty measures also in a cardiovascular context. The estimated time to death is crucial in clinical decision-making in cardiology. However, data on the importance of frailty in long-term mortality are very scarce. The aim of the study was to assess the prognostic value of frailty on mortality at long-term follow-up of more than 5 years in patients 75 years or older hospitalised for non-ST-segment elevation myocardial infarction. We hypothesised that frailty is independently associated with long-term mortality. DESIGN: This was a prospective, observational study conducted at three centres. METHODS AND RESULTS: Frailty was assessed according to the Canadian Study of Health and Aging clinical frailty scale (CFS). Of 307 patients, 149 (48.5%) were considered frail according to the study instrument (degree 5-7 on the scale). The long-term all-cause mortality of more than 5 years (median 6.7 years) was significantly higher among frail patients (128, 85.9%) than non-frail patients (85, 53.8%), ( P < 0.001). In Cox regression analysis, frailty was independently associated with mortality from the index hospital admission to the end of follow-up (hazard ratio 2.06, 95% confidence interval 1.51-2.81; P < 0.001) together with age ( P < 0.001), ejection fraction ( P = 0.012) and Charlson comorbidity index ( P = 0.018). CONCLUSIONS: In elderly non-ST-segment elevation myocardial infarction patients, frailty was independently associated with all-cause mortality at long-term follow up of more than 6 years. The combined use of frailty and comorbidity may be the ultimate risk prediction concept in the context of cardiovascular patients with complex needs. PMID- 30247068 TI - Obesity and hemoglobin content impact peak oxygen uptake in human heart failure. AB - BACKGROUND: Exercise intolerance, obesity, and low hemoglobin (hemoglobin<13 and <12 g/dl, men/women, respectively) are common features of heart failure. Despite serving as potent contributors to metabolic dysfunction, the impact of obesity and low hemoglobin on exercise intolerance is unknown. This study tested the hypotheses, compared with non-obese (NO) heart failure with normal hemoglobin, (a) counterparts with low hemoglobin and obesity or non-obesity will demonstrate reduced peak exercise oxygen uptake; (b) obese with normal hemoglobin will demonstrate decreased peak exercise oxygen uptake; (c) compared across stratifications, obese with low hemoglobin will demonstrate the sharpest decrement in peak exercise oxygen uptake. METHODS: Adults with heart failure ( n = 315; left ventricular ejection fraction<=40%; 77% men) (Group 1: normal hemoglobin and non-obese, n = 137; Group 2: low hemoglobin and non-obese, n = 51; Group 3: normal hemoglobin+obesity, n = 89; Group 4, n = 38: low hemoglobin+obesity; body mass index = 26 +/- 3, 26 +/- 2, 34 +/- 4, 34 +/- 4 kg/m2, respectively) completed treadmill cardiopulmonary exercise testing as part of routine clinical management. Peak exercise oxygen uptake was measured via standard metabolic system. RESULTS: There were no group-wise differences for heart failure class, gender, left ventricular ejection fraction, and resting cardiopulmonary function. Group 1 demonstrated increased peak exercise oxygen uptake versus Groups 2-4 (20 +/- 6 versus 17 +/- 6, 17 +/- 5, 13 +/- 4 ml/kg/min, respectively; all p < 0.001); whereas Group 4 peak exercise oxygen uptake was reduced versus all groups ( p < 0.001). Additionally, both body mass index (R2 = 0.10) and hemoglobin (R2 = 0.12) were significant predictors of peak exercise oxygen uptake in Group 1; which were relationships not mirrored for Groups 2-4. CONCLUSION: These data suggest obesity together with low hemoglobin are potent contributors to impaired peak exercise oxygen uptake and, hence, oxidative metabolic capacity. In diverse populations of heart failure where obesity and/or low hemoglobin are present, it is important to consider these features together when interpreting peak exercise oxygen uptake and underlying exercise limitations. PMID- 30247069 TI - Admission Glucose Number (AGN): A Point of Admission Score Associated With Inpatient Glucose Variability, Hypoglycemia, and Mortality. AB - AIMS: We investigated a point of admission metric of glycemia, the Admission Glucose Number (AGN), and its relationship with both high risk inpatient glucose patterns and mortality in hospital inpatients with type 2 diabetes (T2DM). METHODS: Inpatient capillary blood glucose (CBG) data for patients with T2DM in our health board were identified for a 5-year period and associated with most recent preadmission HbA1c. AGN was calculated as first CBG measured during admission (mmol/L), subtracted from most recent preadmission HbA1c (converted to estimated median glucose mmol/l) within 15 months preadmission. The association between AGN and CBG variability (interquartile range), hypoglycemia free survival (HR) and both inpatient and 100-day mortality (HR) were investigated. RESULTS: A total of 21 045 first admissions with available HbA1c data were identified. A positive correlation between AGN and glycemic variability was described (partial correlation coefficient 0.25, P < .001), which was stronger than the correlation of either of AGNs' individual components: adjusted CBG1 = 0.07 ( P < .001), eAG = 0.08 ( P < .001). The hazard ratio for time to first recorded CBG < 3 mmol/L for high AGN versus low AGN was 1.74 (95% CI 1.55-1.96), P < .001. A high AGN was associated with increased 100-day mortality (HR 1.26, P = .005), however not with in-hospital mortality (HR = 1.31, P = .08). CONCLUSION: AGN is a simple metric that combines 2 readily available measures associated with adverse outcome in T2DM. AGN may be a useful tool to stratify patients for risk of hypoglycemia and postdischarge death. PMID- 30247070 TI - Prevalence of exertional oscillatory ventilation in continuous-flow left ventricular assist device recipients. AB - BACKGROUND: Exercise oscillatory ventilation is an ominous outcome sign in heart failure due to reduced left ventricular ejection fraction; currently, the prevalence of exercise oscillatory ventilation is unknown in left ventricular assist device recipients. METHODS: We studied cardiopulmonary exercise testing in heart failure due to reduced left ventricular ejection fraction or left ventricular assist device patients and exercise oscillatory ventilation was defined according to Kremser's criteria. RESULTS: The occurrence of exercise oscillatory ventilation was similar in either heart failure due to reduced left ventricular ejection fraction (192 patients, 8%) or left ventricular assist device patients (85 recipients, 10%), even though the mean peak oxygen consumption and elevated ventilatory response to exercise slope was lower and higher in left ventricular assist device recipients, respectively, but the occurrence of exercise oscillatory ventilation was comparable among heart failure patients due to reduced left ventricular ejection fraction and left ventricular assist device, if those with impaired exercise capacity were considered. Of note, left ventricular assist device recipients with exercise oscillatory ventilation had a higher end-diastolic left ventricular volume and systolic pulmonary artery pressure at rest. CONCLUSIONS: Using the largest cohort of left ventricular assist device patients performing cardiopulmonary exercise testing, we demonstrated that the occurrence of exercise oscillatory ventilation is similar in heart failure due to reduced left ventricular ejection fraction and left ventricular assist device patients. Recipients with exercise oscillatory ventilation might have haemodynamic and ventilatory dysfunction during exercise, but other factors could play a role, i.e. the duration and severity of heart failure before left ventricular assist device implantation together with the coexistence of morbidity. PMID- 30247071 TI - Prevalence, incidence and mortality of inflammatory bowel disease in Catalonia. A population-based analysis. AB - INTRODUCTION: Few recent data on the epidemiology of inflammatory bowel disease (IBD) are available, especially in Southern Europe. AIM: To evaluate the prevalence, incidence and mortality of IBD in Catalonia during the period 2011 2016. MATERIAL AND METHODS: Data on the prevalence, incidence and mortality of IBD were obtained from the Catalan Health Surveillance System (CHSS). Crude incidence and prevalence rates were calculated for all the Catalan population. Trends in age-sex-adjusted rates were also estimated, and logistic regression was used to calculate the adjusted mortality odds ratio (OR). Data for Crohn's disease (CD) and ulcerative colitis (UC) were analyzed separately. RESULTS: The prevalence per 100,000 inhabitants in 2016 was 353.9 for UC and 191.4 for CD. The total number of IBD patients rose from 29543 in 2011 to 40614 in 2016. IBD was associated with significantly elevated adjusted mortality ratios: 1.28 (95% CI: 1.6-1.4) for UC and 1.85 (95% CI: 1.62-2.12) for CD. CONCLUSIONS: IBD prevalence is very high and is increasing rapidly in Catalonia. Both CD and UC are associated with significantly higher mortality rates. Key message Crohn disease and ulcerative colitis present a small but significant increase in mortality compared to non-inflammatory bowel disease. The prevalence of inflammatory bowel disease is increasing rapidly in Catalonia. Data on prevalence and incidence suggest that the number of patients may double in approximately 10 years. PMID- 30247072 TI - Showers: from a violent treatment to an agent of cleansing. AB - In the early nineteenth century, physicians designed the first manufactured showers for the purpose of curing the insane. Sustained falls of cold water were prescribed to cool hot, inflamed brains, and to instil fear to tame impetuous wills. By the middle of the century showers had appeared in both asylums and prisons, but shower-related deaths led to their decline. Rather than being abandoned, however, the shower was transformed by the use of warm water to economically wash the skins of prison and asylum populations. In stark contrast to an involuntary, deliberately unpleasant treatment, by the end of the century the shower was a desirable product for the improvement of personal hygiene and population health. PMID- 30247073 TI - Potentilla erecta (L.) rhizomes as a source of phenolic acids. AB - The aim of this study was to evaluate the content of major phenolic acids from Potentilla erecta rhiozomes. Water and ethanol-water mixture was used for extraction of these compounds. The extracts were also evaluated for the quantification of total phenolic content and the antioxidant capacity. The contents of phenolic acids and resulting antioxidant activities are dependent on the nature of extracting solvent due to the presence of different antioxidant compounds. Results showed that P. erecta rhiozomes contained high amount of gallic and p-HBA acids. The contents of chlorogenic and protocatechuic acids in the extracts of Potentilla species have not been reported yet. The results suggested that the extracts could be used as the active cosmetics ingredients and nutraceuticals. PMID- 30247074 TI - Oral micronised flavonoids versus tranexamic acid for treatment of heavy menstrual bleeding secondary to copper IUD use: a randomised double-blind clinical trial. AB - OBJECTIVE: The aim of the study was to compare the efficacy of micronised flavonoids versus tranexamic acid in reducing menstrual blood loss (MBL) associated with the use of the TCu 380A intrauterine contraceptive device (IUD) in women with heavy menstrual bleeding (HMB). METHODS: We conducted a randomised double-blind clinical trial between October 2016 and August 2017 in 100 women with HMB (defined as a pictorial blood assessment chart [PBAC] score >100) secondary to IUD use. After assessment of MBL using PBAC score in a baseline cycle, participants were randomised to receive either oral tranexamic acid 500 mg or oral micronised flavonoids 500 mg every 6 h for the first three days of menstruation. PBAC scores were collected in the three subsequent treatment cycles. The primary outcome was the difference in PBAC scores between the groups. Two-way repeated measures ANOVA was used to assess the primary outcome of the change in PBAC scores. RESULTS: Mean PBAC scores were significantly improved in the tranexamic acid group compared with the micronised flavonoids group (236 +/- 48, 105 +/- 26, 97 +/- 16 and 93 +/- 15 at the baseline, first, second and third study cycle, respectively, versus 227 +/- 52, 139 +/- 29, 128 +/- 25 and 125 +/- 24 in the micronised flavonoids group; p = .01). Moreover, the number of bleeding days and number of pads used were significantly reduced in the tranexamic acid group compared with the micronised flavonoids group (p = .009 and p = .03, respectively). Side effects were comparable between the two groups. CONCLUSION: Oral tranexamic acid compared with oral micronised flavonoids is more effective in reducing HMB associated with copper IUD use. Treating IUD-induced HMB using tranexamic acid was more effective compared with micronised flavonoids in decreasing MBL volume and the number of bleeding days. PMID- 30247075 TI - Exosomes at a glance - common nominators for cancer hallmarks and novel diagnosis tools. AB - Cancer represents a heterogeneous disease with multiple levels of regulation and a dynamic environment that sustains the evolution of the malignant mass. This dynamic is in part sustained by a class of extracellular vesicles termed exosomes that are able to imprint the pathological state by incorporating differential cargos in order to facilitate cell-to-cell communication. Exosomes are stable within the extracellular medium and function as shuttles secreted by healthy or pathological cells, being further taken by the accepting cell with direct effects on its phenotype. The exosomal trafficking is deeply involved in multiple levels of cancer development with roles in all cancer hallmarks. Nowadays, studies are constantly exploring the ability of exosomes to sustain the malignant progression in order to attack this pathological trafficking and impair the ability of the tumor mass to expand within the organisms. As important, the circulatory characteristics of exosomes represent a steady advantage regarding the possibility of using them as minimally invasive diagnosis tools, where cancer patients' present modified exosomal profiles compared to the healthy ones. This last characteristic, as novel diagnosis tools, has the advantage of a possible rapid transition within the clinic, compared to the studies that evaluate the therapeutic meaning. PMID- 30247076 TI - Managing large lead vegetations in transvenous lead extractions using a percutaneous aspiration technique. AB - BACKGROUND: Treatment of patients with systemic infections of cardiac implantable electronic devices and large lead vegetations are a clinical challenge. In such situations patients potentially had to undergo open surgical extraction in the past. The objective of this study was to evaluate the results of a concomitant percutaneous, minimal-invasive aspiration procedure with the use of an extracorporeal circulation in transvenous lead extraction procedures in patients with large lead vegetations. RESEARCH DESIGN AND METHODS: Prior and during transvenous lead extraction procedures lead vegetations were targeted for removal with a percutaneous aspiration technique based on a veno-venous extracorporeal circulation with an in-line filter. Clinical outcomes of the procedures were retrospectively analyzed. RESULTS: This innovative and minimal-invasive treatment concept was used in 35 patients with systemic CIED infections (mean echocardiographic lead vegetation size 22.6 (12-40) mm). Complete procedural success of the aspiration procedure was seen in 88.6% of the patients. No major complication related to the aspiration procedure occurred. Clinical success of the concomitant transvenous lead extraction procedures (35 patients, 83 leads) was 97.1%. CONCLUSION: The presented data show that the aspiration procedure is safe and efficient as an adjunct in transvenous lead extraction procedures avoiding the need for open surgical extraction in such cases. PMID- 30247077 TI - Sexuality education: the silent revolution in Europe. PMID- 30247078 TI - ?Que Sistema de Salud? Broken Health Care in Puerto Rico. AB - Puerto Rico's politically liminal status as a US territory has dire consequences for Puerto Rico's economy: the island does not receive the same funding as states for health insurance. In addition, Puerto Rico's unraveling health care system, coupled with the island's high poverty rate and the medical brain drain, interact. I weave my research on depression into this article as an example of the ways in which political and economic factors aggravate disease. PMID- 30247079 TI - Gene expression changes in human iPSC-derived cardiomyocytes after X-ray irradiation. AB - PURPOSE: Radiation-induced heart disease caused by cardiac exposure to ionizing radiation comprises a variety of cardiovascular effects. Research in this field has been hampered by limited availability of clinical samples and appropriate test models. In this study, we wanted to elucidate the molecular mechanisms underlying electrophysiological changes, which we have observed in a previous study. MATERIALS AND METHODS: We employed RNA deep-sequencing of human-induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) 48 h after 5 Gy X-ray irradiation. By comparison to public data from hiPSC-CMs and human myocardium, we verified the expression of cardiac-specific genes in hiPSC-CMs. Results were validated by qRT-PCR. RESULTS: Differentially gene expression analysis identified 39 and 481 significantly up- and down-regulated genes after irradiation, respectively. Besides, a large fraction of genes associated with cell cycle processes, we identified genes implicated in cardiac calcium homeostasis (PDE3B), oxidative stress response (FDXR and SPATA18) and the etiology of cardiomyopathy (SGCD, BBC3 and GDF15). CONCLUSIONS: Notably, observed gene expression characteristics specific to hiPSC-CMs might be relevant regarding further investigations of the response to external stressors like radiation. The genes and biological processes highlighted in our study present promising starting points for functional follow-up studies for which hiPSC-CMs could pose an appropriate cell model when cell type specific peculiarities are taken into account. PMID- 30247080 TI - A prospective evaluation of telemonitoring use by seniors with chronic heart failure: Adoption, self-care, and empowerment. AB - Telemonitoring leverages technology for the follow-up of patients with heart failure. Limited evidence exists on how telemonitoring influences senior patients' attitudes and self-care practices. This study examines telemonitoring impacts on patient empowerment and self-care, and explores adoption factors among senior patients. A longitudinal study design was used, involving three surveys of elderly with chronic heart failure (n = 23) 1 week, 3 months, and 6 months after beginning telemonitoring use. Self-care, patient empowerment, and adoption factors were assessed using existing scales. The patients involved in this study perceived value of using telemonitoring, did not expect it to be difficult to use, and did not encounter adoption barriers. There was a significant improvement in patients' confidence in their ability to evaluate their symptoms, address them, and evaluate the effectiveness of the measures taken to address these symptoms. Yet, patients performed less self-care maintenance activities, and the capability of involvement in the decision-making related to their condition decreased. Telemonitoring can improve seniors' confidence in evaluating and addressing their symptoms in relation to heart failure. This patient management approach should be coupled with targeted education geared toward self-maintenance and self-management practices. PMID- 30247081 TI - Fruits and vegetables embedded in classic video games: a health-promoting potential? AB - The proliferation of the video game era has increased sedentary behaviours among children and adolescents. Contemporary interventions involve the use of video games to introduce fruit and vegetable (F&V) consumption among children and adolescents. A comprehensive list of licenced video games (n = 671) released for the Nintendo Entertainment System (NES) console were reviewed for thematic content and qualitative characteristics of the game's activity relevant to F&V. Seventy-five video games were included in the study sample and categorised by release year, prevalence of F&V, and thematic content. Mild associations were found comparing release year to F&V totals (r = 0.21) and release year to theme (r = 0.19). F&V themes embedded within classic video games could serve as health promoting lessons for forthcoming video games. Future games produced by the video gaming industry should continue to focus on nutrition-embedded messages promoting F&V. Video game development and marketing could be an avenue that incorporates healthy nutrition themes. PMID- 30247082 TI - Occurrence of Salmonella in Ready-to-Eat Meat and Poultry Product Samples from U.S. Department of Agriculture-Regulated Producing Establishments. I. Results from the ALLRTE and RTE001 Random and Risk-Based Sampling Projects, from 2005 to 2012. AB - Ready-to-eat (RTE) meat and poultry product samples collected from RTE-producing establishments for the ALLRTE (random) and RTE001 (risk-based) sampling projects of the Food Safety and Inspection Service (FSIS) were tested for both Salmonella and Listeria monocytogenes. The FSIS analyzed Salmonella results for RTE meat and poultry product samples collected for the two sampling projects from 2005 to 2012. Data for 24,385 ALLRTE samples collected from 3,023 establishments and 66,653 RTE001 samples collected from 2,784 establishments were evaluated for the percentages of Salmonella-positive samples, product types of positive samples, and Salmonella serotypes. There also were descriptive summaries with respect to establishment hazard analysis and critical control point (HACCP) size, production volumes, L. monocytogenes control alternatives, geographic location, and season or month of sample collection. Results showed low occurrences of Salmonella positive samples from the ALLRTE and RTE001 sampling projects, with 14 positive samples (0.06%) for ALLRTE and 33 positive samples (0.05%) for RTE001. Percentages of establishments with at least one Salmonella-positive sample averaged 0.46% for ALLRTE and 1.11% for RTE001. Three product types-sausage products, pork barbecue, and head cheese-accounted for 62% of all positive samples. There were 27 distinct serotypes from 48 Salmonella isolates, with serotypes Infantis and Typhimurium being the most common (5 isolates each). All but one of the Salmonella-positive samples were obtained from establishments with HACCP sizes of small or very small. More than half of the positive samples were obtained from establishments using L. monocytogenes control alternative 3 (sanitation only, highest-risk category). Positive Salmonella samples were found in all geographic regions at all times of the year. Information obtained from these sampling projects is relevant to the prevention of foodborne Salmonella illnesses from RTE meat and poultry products. PMID- 30247083 TI - Occurrence of Salmonella in Ready-to-Eat Meat and Poultry Product Samples from U.S. Department of Agriculture-Regulated Producing Establishments. II. Salmonella in Ready-to-Eat Pork Barbecue Products, from 2005 to 2012. AB - Ready-to-eat (RTE) meat and poultry product samples from the random ALLRTE and risk-based RTE001 sampling projects of the Food Safety and Inspection Service (FSIS) were tested for both Listeria monocytogenes and Salmonella. In the course of analyzing Salmonella data for calendar years 2005 to 2012, it was observed that 8 (17.0%) of 47 positive samples were from pork barbecue. The eight Salmonella-positive samples, from seven establishments in a single state, were from 1,085 pork barbecue samples tested nationwide (0.74% positive) and from 296 samples tested from that one state (2.7% positive). The seven establishments represented 30.4% of 23 federal establishments in that state that had pork barbecue samples tested for Salmonella. A follow-up sample from intensified verification testing at one of the seven establishments also was positive for Salmonella. Upon further examination, contamination appeared to be influenced by regional differences in production methods. Notably, the style of pork barbecue that tested positive for Salmonella used a vinegar- and pepper-based sauce in which the ingredients were mixed without cooking. All the establishments with Salmonella-positive samples followed the practice of first cooking the pork and then adding the barbecue sauce ingredients (vinegar, pepper, other spices, etc.) after cooking (postlethality exposure). In addition to the sauce ingredients, other possible sources of contamination included employee hygiene and food handling practices and cross-contamination from other Salmonella-contaminated products and from commonly used equipment. Based on these findings, the FSIS issued guidelines recommending changes in production methods that would minimize or eliminate pork barbecue as a potential source of foodborne Salmonella infections. PMID- 30247084 TI - A strategic action framework for multipurpose prevention technologies combining contraceptive hormones and antiretroviral drugs to prevent pregnancy and HIV. AB - OBJECTIVE: Multipurpose prevention technologies (MPTs) are an innovative class of products that deliver varied combinations of human immunodeficiency virus (HIV) prevention, other sexually transmitted infection (STI) prevention, and contraception. Combining separate strategies for different indications into singular prevention products can reduce the stigma around HIV and STI prevention, improve acceptability of and adherence to more convenient products, and be more cost-effective by addressing overlapping risks. METHODS: This article outlines a strategic action framework developed as an outcome of a series of expert meetings held between 2014 and 2016. The meetings focused on identifying opportunities and challenges for MPTs that combine hormonal contraception (HC) with antiretroviral drugs into single products. The framework aims to present an actionable strategy, by addressing key research gaps and outlining the key areas for progress, to guide current and future HC MPT development. RESULTS: We identified eight primary action areas for the development of impactful HC MPTs, and includes aspects from epidemiology, pharmacology, clinical trial design, regulatory requirements, manufacturing and commercialisation, behavioural science, and investment needs for research and development. CONCLUSION: Overall, the challenges involved with reconciling the critical social-behavioural context that will drive MPT product use and uptake with the complexities of research and development and regulatory approval are of paramount importance. To realise the potential of MPTs given their complexity and finite resources, researchers in the MPT field must be strategic about the way forward; increased support among policy-makers, advocates, funders and the pharmaceutical industry is critical. PMID- 30247085 TI - Passive stiffness of the hamstrings and the rectus femoris in persons after an ACL reconstruction. AB - OBJECTIVES: The aim of the article is to investigate the passive stiffness (PS) of rectus femoris and hamstring muscles working for the knee joint in persons after anterior cruciate ligament (ACL) reconstruction surgery. METHODS: Thirty subjects (8 women and 22 men) aged 19-46 (x = 28.2 +/- 7) participated in the investigation; an experimental group comprised 15 persons (4 women and 11 men) who underwent ACL reconstruction surgery. The other persons had no knee injury and described themselves as healthy. All the subjects underwent an investigation of the PS of the hamstrings and the rectus femoris on the injured as well as on the healthy leg. RESULTS: The data shows vital difference in the PS of the hamstring muscles between the healthy and injured limb (p < 0.05), a significant difference in the PS of the rectus femoris (p < 0.001) was noted. Furthermore, the PS level of the hamstring muscles of the operated limb in the experimental group is significantly different to the both legs in control group (p < 0.001). CONCLUSIONS: Injury of the ACL results in a considerable increase in passive stiffness of the hamstring and rectus femoris muscles in both the injured leg and the healthy leg. PMID- 30247086 TI - Unravelling the genetic architecture of autosomal recessive epilepsy in the genomic era. AB - The technological advancement of next-generation sequencing has greatly accelerated the pace of variant discovery in epilepsy. Despite an initial focus on autosomal dominant epilepsy due to the tractable nature of variant discovery with trios under a de novo model, more and more variants are being reported in families with epilepsies consistent with autosomal recessive (AR) inheritance. In this review, we touch on the classical AR epilepsy variants such as the inborn errors of metabolism and malformations of cortical development. However, we also highlight recently reported genes that are being identified by next-generation sequencing approaches and online 'matchmaking' platforms. Syndromes mainly characterized by seizures and complex neurodevelopmental disorders comorbid with epilepsy are discussed as an example of the wide phenotypic spectrum associated with the AR epilepsies. We conclude with a foray into the future, from the application of whole-genome sequencing to identify elusive epilepsy variants, to the promise of precision medicine initiatives to provide novel targeted therapeutics specific to the individual based on their clinical genetic testing. PMID- 30247087 TI - Gene expression-based biodosimetry for radiological incidents: assessment of dose and time after radiation exposure. AB - PURPOSE: In order to ensure efficient use of medical resources following a radiological incident, there is an urgent need for high-throughput time-efficient biodosimetry tools. In the present study, we tested the applicability of a gene expression signature for the prediction of exposure dose as well as the time elapsed since irradiation. MATERIALS AND METHODS: We used whole blood samples from seven healthy volunteers as reference samples (X-ray doses: 0, 25, 50, 100, 500, 1000, and 2000 mGy; time points: 8, 12, 24, 36 and 48 h) and samples from seven other individuals as 'blind samples' (20 samples in total). RESULTS: Gene expression values normalized to the reference gene without normalization to the unexposed controls were sufficient to predict doses with a correlation coefficient between the true and the predicted doses of 0.86. Importantly, we could also classify the samples according to the time since exposure with a correlation coefficient between the true and the predicted time point of 0.96. Because of the dynamic nature of radiation-induced gene expression, this feature will be of critical importance for adequate gene expression-based dose prediction in a real emergency situation. In addition, in this study we also compared different methodologies for RNA extraction available on the market and suggested the one most suitable for emergency situation which does not require on-spot availability of any specific reagents or equipment. CONCLUSIONS: Our results represent an important advancement in the application of gene expression for biodosimetry purposes. PMID- 30247089 TI - The gaming healthcare practitioner: How practices of datafication and gamification reconfigure care. AB - This article explores how datafication, as an increasing use of quantified performance data (e.g. performance indicators, rating sites), and social media are enacted in everyday healthcare practice. Drawing on the literature about the quantified self, this article shows that datafication evokes practices of gamification: the application of frames of play and rewards to the healthcare setting. We discern three (intermingling) practices of gamification: adapting, ignoring and changing. 'Adapting' refers to the incorporation of quantifying features in healthcare, while 'ignoring' sheds light on how practitioners seek to circumvent quantifying mechanisms. Change refers to how practitioners actually embrace quantifying mechanisms in order to extend (and improve) their work and to highlight their quantified professional self. We elucidate how datafication of healthcare 'opens up' and reconfigures established practices of organizing care and caring - not only for the patient but also to (re)craft the professional clinical identity. PMID- 30247088 TI - A Three-Step Letter Advance Directive Procedure to Facilitate Patient-Proxy Alignment in Advance Care Planning. AB - BACKGROUND: Little is known about the extent of alignment between hematopoietic stem cell transplant (HSCT) patients and their healthcare proxies with respect to advance care planning (ACP). AIM: To determine if a structured three-step process using the letter advance directive (LAD) could (1) allow for the differences in opinion between patient-proxy dyads to surface and (2) help bridge preexisting discordance about specific treatment choices. DESIGN: Blinded to each other, the HSCT patient (LAD-1) and proxy (LAD-2) each completed the LAD (step 1). They unmasked, compared LAD-1 and LAD-2, and discussed their choices (step 2). They completed a final letter directive (LAD-3) by consensus (step 3). Settings/Participants: Convenience sample of eighty dyads (patient and proxy) at a regional HSCT referral center. RESULTS: The mean patient-proxy concordance was 72.9% for the 12 questions in the LAD. Wanting to be pain free at the end of life was the statement with the most amount of agreement (88.75% in LAD-1, 91.25% in LAD-2, and 90% in LAD-3). Patient-proxy dyads had notable discordance related to specific treatments. The highest discordance was related to ventilator support (46.3% of patients refused it, while 58.8% of proxies refused on behalf of the patient). Overall, proxies were more likely than patients to opt in for dialyses and hospice care but more likely to opt out for cardiac resuscitation and sedation to palliate refractory symptoms. On open discussion, patient-proxy discordance mostly resolved in favor of the patient. CONCLUSIONS: The ACP process should allow for patient-proxy differences to surface, facilitate a discussion about the granular details with the goal of reaching consensus. Our three-step approach using the LAD is an effective way to identify areas of patient-proxy concordance and discordance about specific treatment preferences. A structured patient-proxy discussion using the LAD helped reconcile discordance and most often in favor of a patient's original wishes. PMID- 30247090 TI - A liposome preparation based on beta-CD-LPC molecule and its application as drug delivery system. AB - AIM: The beta-CD-LPC molecule was synthesized based on the conjugation of LPC and beta-CD molecules and it could self-assemble into liposome which was used to encapsulate the Dox to form nanomedicine for the cancer therapy. MATERIALS & METHODS: The anticancer and antitumor effect of beta-CD-LPC-Dox nanomedicine was studied with the vitro and vivo experimental methods. RESULTS: The result showed that beta-CD-LPC liposome had high Dox drug-loading rate and a good sustained release effect. Cell experiment showed that the beta-CD-LPC-Dox nanomedicine could effectively induce cancer cell apoptosis and in vivo experiments showed that beta-CD-LPC-Dox liposome could effectively inhibit tumor growth and had an effective anticancer activity with lower biotoxicity. CONCLUSION: The beta-CD-LPC Dox nanomedicine could be applied as a candidate drug to therapy the cancer. PMID- 30247091 TI - Recovery of Over-Ground Walking after Chronic Motor Complete Spinal Cord Injury. AB - Persons with motor complete spinal cord injury, signifying no voluntary movement or sphincter function below the level of injury but including retention of some sensation, do not recover independent walking. We tested intense locomotor treadmill training with weight support and simultaneous spinal cord epidural stimulation in four patients 2.5 to 3.3 years after traumatic spinal injury and after failure to improve with locomotor training alone. Two patients, one with damage to the mid-cervical region and one with damage to the high-thoracic region, achieved over-ground walking (not on a treadmill) after 278 sessions of epidural stimulation and gait training over a period of 85 weeks and 81 sessions over a period of 15 weeks, respectively, and all four achieved independent standing and trunk stability. One patient had a hip fracture during training. (Funded by the Leona M. and Harry B. Helmsley Charitable Trust and others; ClinicalTrials.gov number, NCT02339233 .). PMID- 30247092 TI - Kluver & Bucy syndrome: an investigation of social and affective cognition. AB - Kluver-Bucy syndrome (KBS) leads to important behavioral symptoms and social maladaptation. Rarely described, no previous study has investigated its social and affective cognitive profile. We report the case of ASP, a patient who developed a complete KBS at 9 years that evolved into an incomplete KBS. Orbitofrontal and temporal damages were evidenced. While a classic neuropsychological assessment showed a preserved global functioning, an extensive evaluation of her social and affective cognition (reversal learning, decision making, emotion recognition, theory of mind, creative thinking) showed remarkable deficits. The relevancy of such findings for the characterization KBS and the field of neuropsychology are discussed. PMID- 30247093 TI - Chemistry and biology for the small molecules targeting characteristics of cancer cells. AB - : Despite the marked progress of cancer research, cancer is the predominant cause of death in Japan, and therefore development of effective therapeutic drugs is expected. Chemical biology is a research field utilizing small molecules to investigate biological phenomena. One of the most important aims of chemical biology is to find the small molecules, and natural products are ideal screening sources due to their structural diversity. Therefore, natural product screening based on the progress of chemical biology prompted us to find small molecules targeting cancer characteristics. Another contribution of chemical biology is to facilitate the target identification of small molecule. Therefore, among a variety of methods to uncover protein function, chemical biology is a remarkable approach in which small molecules are used as probes to elucidate protein functions related to cancer development. ABBREVIATIONS: EGF: Epidermal growth factor; PDGF: Platelet-derived growth factor; CRPC: Castration-resistant prostate cancer; AR: Androgen receptor; FTase: Farnesyl transferase; 5-LOX: 5 Lipoxygenase; LT: Leukotriene; CysLT1: Cysteinyl leukotriene receptor 1; GPA: Glucopiericidin A; PA: Piericidin A; XN: Xanthohumol; VCP: Valosin-containing protein; ACACA: Acetyl-CoA carboxylase-alpha. PMID- 30247094 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions 1 April-31 May 2018. PMID- 30247096 TI - 'Human' or 'objective' faces of science? Gender stereotypes and the representation of scientists in the media. AB - This article examines contemporary representations of female and male scientists in The New York Times with a particular emphasis on stereotypes related to gender and science as a profession. The selected series of profiles is approximately proportional in its representation of women in science and generally gives a rounded and diverse picture of their subjects. Traditionally 'masculine' characteristics (e.g. individual drive and brilliance) as well as 'feminine' communal skills (e.g. collaboration, communication and teamwork) are attributed to both male and female scientists. Nevertheless, textual and image analyses reveal that some differences remain in the treatment of male and female subjects, particularly in the unequal focus on combining family and career. This research identifies progress in media representations of scientists in comparison to previous studies. However, there is still room for improvement, especially in the representation of scientists from culturally and linguistically diverse backgrounds. PMID- 30247095 TI - Bio-monitoring of DNA damage in matchstick industry workers from Peshawar Khyber Pakhtunkhwa, Pakistan. AB - BACKGROUND: Safety protocols are usually neglected in most of the matchstick industries rendering the laborer prone to various occupational hazards. OBJECTIVE: The present study highlights DNA damage among matchstick factory workers (n = 92) against a control group (n = 48) of healthy individuals. METHODS: Genotoxicity was measured in peripheral blood lymphocytes of the test subjects using a Single Cell Gel Electrophoresis assay (SCGE/comet assay). RESULTS: Our results substantiate a high Total Comet Score (TCS) for factory workers (74.5 +/- 47.0) when compared to the control group (53.0 +/- 25.0) (P <= 0.001). Age and duration of occupational exposure had no significant effect (P > 0.05) on TCS value. As for job function, the TCS value was greatest in sweepers (91.0 +/- 56.1) and lowest in box-making operators (26.0 +/- 25.0) indicating that waste disposal poses the higher risk of DNA damage. CONCLUSIONS: Our study corroborates that matchstick chemicals can potentially damage the DNA of exposed subjects. PMID- 30247097 TI - Intravascular imaging in neuroendovascular surgery: a brief review. AB - Intravascular imaging has significantly contributed to the advancement of interventional cardiology. Intravascular ultrasound and optical coherence tomography have facilitated decision-making and interventional strategies in management of coronary artery lesions. Yet, applications of these modalities are limited in cerebrovascular practice. With the momentum in advancement of neuroendovascular interventions and techniques for treatment of strokes, cerebrovascular atherosclerotic diseases, aneurysms and vascular malformations, there is a need for the development of high-resolution platforms that can safely be used in cerebrovascular system, and to meet the imaging requirements in the field. In this brief review, we aim to discuss current and emerging intravascular imaging modalities and explore their potentials in field of neuroendovascular surgery. PMID- 30247098 TI - Learning from mental health research. PMID- 30247099 TI - Health Care Costs in a Cohort of HIV-Infected U.S. Veterans Receiving Regimens Containing Tenofovir Disoproxil Fumarate/Emtricitabine. AB - BACKGROUND: Tenofovir disoproxil fumarate (TDF), a key component in many human immunodeficiency virus (HIV) treatment regimens, is associated with increased renal and bone toxicities. The contributions of such toxicities to treatment costs, as well as the relative differences in treatment costs for various TDF/emtricitabine (FTC) regimens, remains unexplored. OBJECTIVE: To estimate and compare mean overall and renal- and bone-specific costs, including total, inpatient, outpatient, and pharmacy costs in patients treated with TDF/FTC+efavirenz (EFV) compared with several non-EFV-containing TDF/FTC regimens. METHODS: We conducted a national cohort study of treatment-naive HIV infected U.S. veterans who initiated treatment from 2003 to 2015 with TDF/FTC in combination with EFV, elvitegravir/cobicistat, rilpivirine, or ritonavir-boosted protease inhibitors (atazanavir, darunavir, or lopinavir). Outcomes of interest were quarterly total, inpatient, outpatient, and pharmacy costs using data from the Veterans Health Administration (VHA) electronic medical record and Managerial Cost Accounting System (an activity-based accounting system that allocates VHA expenditures to patient encounters). We controlled for measured confounders using inverse probability of treatment (IPT) weights and assessed differences using standardized mean differences (SMDs). For comparisons where SMDs exceeded 0.1 after IPT weighting, we used the more conservative matching weights in sensitivity analyses. For hypothesis testing, we compared IPT-adjusted differences in quarterly costs between treatment groups using Mann-Whitney U tests and generalized estimating equation (GEE) regression models. RESULTS: Of 33,048 HIV-positive veterans, 7,222 met eligibility criteria, including 4,172 TDF/FTC + EFV recipients; mean (SD) age of the cohort was 50.0 (10.0) years; 96.7% were male; 60.1% were black; and 30.1% were white. Quarterly periods of exposure to EFV-containing regimens were 22,499 and of exposure to non-EFV containing regimens were 11,633. After IPT weighting, absolute SMDs were < 0.1 except for a few covariates in the rilpivirine comparison. The per-patient adjusted mean total quarterly costs were $7,145 for EFV versus $8,726 for non-EFV (P < 0.001; Mann-Whitney U-test) and the per-patient adjusted mean difference in total quarterly costs was $1,419 lower for EFV versus all non-EFV combined (P < 0.001; GEE model). Corresponding values for outpatient costs ($2,656 vs. $2,942; P < 0.001; difference, -$254; P = 0.001), inpatient costs ($2,009 vs. $2,614; P < 0.001), radiology costs ($213 vs. $276; P < 0.001), and pharmacy costs ($2,480 vs. $3,170; P < 0.001; difference, -$600; P < 0.001) were all lower for EFV versus all non-EFV combined. Findings based on matching weights were qualitatively similar. Contributions of renal and bone costs to the total costs of treatment were very small, ranging between $52 and $94 per patient per quarter for renal outcomes and between $6 and $114 for bone outcomes. CONCLUSIONS: Among 7,222 HIV-treated veterans over an average follow-up of 1.2 years per patient, those patients receiving TDF/FTC + EFV had lower overall health care costs compared with those receiving non-EFV regimens. DISCLOSURES: This study was funded by Bristol-Myers Squibb. Nelson, Ma, Crook, Knippenberg, Nyman, and LaFleur are employees of the University of Utah, which received a grant from Bristol-Myers Squibb to conduct this study. Nyman also discloses honoraria for consulting from Otsuka and for writing a book chapter from Fresenius. La Fleur reports advisory board and consulting fees from Bristol-Myers Squibb outside of this study. Paul and Esker are employees of, and own stock in, Bristol-Myers Squibb. PMID- 30247100 TI - The Biosimilar Nocebo Effect? A Systematic Review of Double-Blinded Versus Open Label Studies. AB - BACKGROUND: Several authors have hypothesized that adverse drug events (ADEs) upon switching from reference biologics to biosimilar products are related to the nocebo effect. However, a thorough and current review of the existing literature has not been conducted. OBJECTIVE: To evaluate if patient and/or physician knowledge of a switch from a reference biologic product to a biosimilar product was associated with an increase in ADEs likely to be susceptible to the nocebo effect. METHODS: Studies reporting efficacy and safety outcomes of a switch from a reference product to a biosimilar product were reviewed. Biologics with FDA approved biosimilars in the United States were considered for review, including adalimumab, bevacizumab, etanercept, and infliximab. Studies were identified by searching controlled vocabulary (e.g., MeSH terms) and keywords within MEDLINE (via PubMed) and Embase. Descriptive statistics were used to quantify subjective and objective complications in double-blinded and single-blinded or open-label studies. RESULTS: Thirty-one trials including 3,271 patients were reviewed in the full analysis. Median discontinuation rates for any reason were 14.3% (range = 0.0-33.3) in open-label studies compared with 6.95% (range = 5.2-11.0) in double blinded studies. Discontinuation rates for ADEs were 5.6% (range = 0.0-24.2) in open-label studies versus 3.1% (range = 2.0-5.2) in double-blinded studies, suggesting the nocebo effect does affect biosimilar adoption. Subgroup analyses of antidrug antibody (ADA) development and infusion reactions were similar between infliximab open-label and double-blinded studies. Discontinuation rates for any reason, for ADEs, and for lack of efficacy were generally higher in infliximab open-label trials compared with double-blinded trials. Etanercept biosimilar discontinuation rates for any reason were similar between study designs; however, incidences of injection site reactions and discontinuation rates for ADEs were higher in double-blinded compared with open-label study designs. CONCLUSIONS: Current evidence is insufficient to confirm a biosimilar nocebo effect, although higher discontinuation rates in infliximab biosimilar open-label studies support this theory. Further studies are needed to evaluate the existence of a biosimilar nocebo effect. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to disclose. PMID- 30247101 TI - Costs Associated with Productivity Loss Among U.S. Patients Newly Diagnosed with Multiple Myeloma Receiving Oral Versus Injectable Chemotherapy. AB - BACKGROUND: The use of novel drug agents in the treatment of multiple myeloma (MM) has been associated with improved therapeutic outcomes and survival; however, MM continues to pose a significant economic burden on patients and health care systems. Evaluating economic implications of therapies can provide key points of distinctions between available treatment options. Patients with MM may experience productivity loss, including lost days from work or inability to work due to MM symptoms or to undergoing treatment. Although direct costs of illness have been well described in the literature, indirect costs associated with MM are understudied. OBJECTIVE: To compare the extent of disability benefit use and resultant workplace productivity loss among U.S. adult patients with newly diagnosed MM who received oral versus injectable MM therapy. METHODS: A retrospective cohort study was conducted using the Truven Health Analytics MarketScan Commercial Claims and Encounters, Medicare Supplemental Coordination of Benefits, and Health and Productivity Management databases (2008-2015). Workplace absenteeism, as measured by disability benefit use, was evaluated 1 year before and 1 year after first MM diagnosis. Patients receiving only oral chemotherapy were compared with those who received injectable therapy. Absenteeism days and associated costs were compared among study groups using multivariable zero-inflated Poisson regression. RESULTS: The final study cohort included 299 patients with newly diagnosed MM, of whom 73 received oral therapy only and 226 received injectable therapy. Treatment type was a significant predictor of disability benefit use. Patients who received injectable therapy missed an average of 110 work days in the 1 year after diagnosis, compared with 87 for patients receiving only oral therapy (difference of 23 days, 95% CI = 19 26, P < 0.001). Treatment type was also a significant predictor of costs associated with lost productivity. Patients who received injectable therapy experienced productivity loss valued at $18,315, compared with patients who only received oral drug therapy ($14,429). The difference between these estimates was statistically significant ($3,886, 95% CI = $3,540-$4,231, P < 0.001). CONCLUSIONS: Patients newly diagnosed with MM face significant losses in productivity. Patients receiving injectable MM therapy use significantly more disability benefits and incur higher productivity costs, compared with those receiving oral MM therapy. Further studies elucidating the nature of the differences between injectable and noninjectable chemotherapy users are needed. DISCLOSURES: This study was funded by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. Yong and Noga are employees of Millennium Pharmaceuticals. Merola reports personal fees from Millennium Pharmaceuticals during the time of this study. PMID- 30247102 TI - Cost-Effectiveness and Budget Impact of Lumacaftor/Ivacaftor in the Treatment of Cystic Fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is a chronic, progressive, genetic disease affecting more than 30,000 people in the United States and 70,000 people globally. The goals of treatment are to slow disease progression, reduce pulmonary exacerbations, relieve chronic symptoms, and improve the patient's quality of life. Lumacaftor/ivacaftor is a new therapy for CF that has demonstrated good clinical outcomes, including improved absolute percentage predicted forced expiratory volume in 1 second (FEV1%). However, given the high cost of therapy, there is a need to evaluate the overall value of lumacaftor/ivacaftor in CF management. OBJECTIVES: To (a) conduct a cost effectiveness analysis (CEA) of lumacaftor/ivacaftor to understand the overall effectiveness of the drug compared with its costs and (b) conduct a budget impact analysis (BIA) to understand the potential financial effect of introducing a new drug in a health plan. METHODS: Two static decision models were developed using Microsoft Excel to evaluate the cost-effectiveness and budget impact of lumacaftor/ivacaftor over a 1-year time frame from a payer perspective. Model inputs included drug costs (wholesale acquisition costs), drug monitoring schedules (package inserts), drug monitoring costs (Centers for Medicare & Medicaid physician fee schedule and published literature), FEV1% predicted and pulmonary exacerbation values (clinical trials), and cost to treat pulmonary exacerbations (published literature). The outcomes in the CEA included total cost of therapy; average cost-effectiveness ratio (ACER), defined as cost per FEV1% predicted; and incremental cost-effectiveness ratio (ICER), defined as the difference in the ratio of cost per FEV1% predicted of lumacaftor/ivacaftor and placebo. Outcomes in the BIA included total budget impact; cost per member per month (PMPM), defined as total budget impact per hypothetical plan population; and cost per treated member per month (PTMPM), defined as total budget impact per target CF population. All costs were adjusted to 2016 dollars, and one-way sensitivity analyses were conducted to test the model robustness given uncertainty in model inputs and study assumptions. RESULTS: The annual cost of therapy per patient for lumacaftor/ivacaftor was $379,780. The ACER for lumacaftor/ivacaftor was $151,912, while the ICER for lumacaftor/ivacaftor compared with placebo was $95,016 per FEV1% predicted. The annual total budget impact due to the inclusion of lumacaftor/ivacaftor on the health plan formulary was $266,046. The PMPM cost was $0.02 and the PTMPM cost was $6.21. CONCLUSIONS: In patients with CF, lumacaftor/ivacaftor has demonstrated better clinical effectiveness compared with placebo alongside an increased drug acquisition cost. However, the therapy may be a viable alternative to existing standard therapy over a short time horizon. Health care payers, both private and public, need to evaluate the cost-effectiveness and the financial effect when considering expansion of new drug coverage in CF management. DISCLOSURES: No outside funding supported this study. Covvey and Kamal have received research funding from Novartis Pharmaceuticals. Covvey, Giannetti, and Kamal have received research funding from the College of Psychiatric and Neurologic Pharmacists. Kamal serves as a consultant to the Lynx Group (Cranbury, NJ) and Manticore Consulting Group (Scottsdale, AZ). Mukherjee has nothing to disclose. A related poster abstract was presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting; March 27-30, 2017; Denver, CO. PMID- 30247103 TI - Effect of Standardized Infliximab Dose Rounding on an Outpatient Infusion Center. AB - BACKGROUND: Infliximab dose rounding is a commonly accepted practice at many institutions to contain costs. Currently, there is limited data on the clinical and financial implications of infliximab dose rounding standardization. OBJECTIVE: To determine whether standardized infliximab dose rounding is comparable with nonstandardized dosing in patients with Crohn's disease or ulcerative colitis in terms of cost and efficiency, using a cost comparison between the 2 dosing methods at an outpatient infusion center attached to a community teaching hospital. METHODS: A retrospective electronic chart review was conducted to identify patients who received infliximab for ulcerative colitis or Crohn's disease over a 6-month period. The primary endpoint was cost comparison between the 2 dosing methods. The secondary outcomes were estimated time taken for order verification, number of order clarifications, increase in dose or frequency of infliximab, number of patients who switched to alternative therapy, and use of medications for adverse drug effects. Descriptive statistics and Fisher's exact test were used for data analysis. RESULTS: 72 patients met the inclusion criteria. Because of patient overlap during the study period, 45 patients (62.5%) were in the standardized rounding arm, and 69 patients (95.8%) were in the nonstandardized rounding arm. One patient in each arm required an increased dose or frequency of infusion (2.2% vs. 1.5%, P = 1.000). Standardized infliximab dose rounding had a theoretical cost savings of at least $104,640 per year (based on our rough annual census of 480 patients) compared with the nonstandardized method that had been used previously. The cost savings can also be translated as $218 per patient per month on average. The mean times to order verification were 10 vs. 12 minutes in the nonstandardized and standardized groups, respectively. Two patients in the nonstandardized group switched to alternative therapy. There was no difference in usage of rescue medications for adverse drug effects. CONCLUSIONS: Standardization of infliximab dose rounding resulted in increased efficiency in the pharmacy workflow by reducing time for order verification. Furthermore, standardized dose rounding resulted in a significant reduction in expenditure for infliximab for the institution. DISCLOSURES: No outside funding supported this research. The authors have nothing to disclose. This research was presented as a poster at the ASHP Midyear Clinical Meeting & Exhibition 2017; December 3-7, 2017; Orlando, FL. PMID- 30247105 TI - Budget Impact Analysis of Eliglustat for the Treatment of Gaucher Disease Type 1 in the United States. AB - BACKGROUND: Gaucher disease type 1 (GD1) is a rare, genetic, lysosomal storage disease with no cure. Current treatment options include intravenous (IV) enzyme replacement therapy ([ERT]; imiglucerase, velaglucerase alfa, or taliglucerase alfa) or oral substrate reduction therapy ([SRT]; eliglustat or miglustat). The cost to U.S. payers of an IV-administered drug can vary depending on the site of care (i.e., home, outpatient clinic, or hospital setting). Treatment with oral eliglustat may present an opportunity for cost savings. OBJECTIVE: To evaluate the budget impact from a U.S. payer perspective associated with transitioning patients receiving ERTs to the oral SRT eliglustat for the treatment of adults with GD1. METHODS: A budget impact model estimated the change in pharmaceutical and administration costs resulting from increasing the market share of eliglustat from 12% (current) to 44% (new). The market share for eliglustat was drawn equally from existing shares of imiglucerase (40%) and velaglucerase alfa (40%) and assumed to be static over the analysis period. ERT costs were adjusted to account for site of care-based markup and the proportion of patients receiving infusions in each site of care (home, infusion center, or hospital outpatient). Annual ERT costs were calculated assuming a biweekly dose of 47.4 U per kg, a 72 kg patient weight, and 24 infusions per year. The effect of key variables was tested in the sensitivity analyses. All costs are expressed in 2017 U.S. dollars. RESULTS: In a new plan with 5 million members and 25 GD1 treated patients, increased use of eliglustat resulted in an annual savings of $1,526,710 and a total savings of $4,580,130 (13.6%) over 3 years. The corresponding annual per member per month savings was $0.025. This is further illustrated in the sensitivity and scenario analyses where the use of eliglustat was cost saving in all cases. Shifting more patients receiving ERT in the hospital outpatient setting to eliglustat resulted in increased savings. CONCLUSIONS: Based on these analyses, increased use of eliglustat resulted in meaningful cost savings to a payer's overall budget. Cost savings are highest among patients switching from ERT administered in a hospital outpatient setting. The results suggest that cost savings are also likely achievable from initiating patients on oral eliglustat instead of infusion-based therapy from the outset of treatment. DISCLOSURES: This study was sponsored by Sanofi Genzyme. Evidera received funding from Sanofi Genzyme to conduct this study and prepare the manuscript. The sponsor collaborated on the study design, analysis, interpretation of results, and writing of the manuscript. Nalysnyk is an employee of and shareholder in Sanofi Genzyme. Ward, Cele, and Uyei are employees of Evidera, which provides consulting and other research services to biopharmaceutical companies. Sugarman was also an Evidera employee when the study was being conducted and the manuscript written. This study was presented as a poster at the Academy of Managed Care Pharmacy Nexus 2016, October 3-6, 2016; National City, MD, and at the International Society for Pharmacoeconomics and Outcomes Research, 22nd Annual International Meeting; May 20-24, 2017; Boston, MA. PMID- 30247104 TI - Effect of a Pharmacist-Driven Monitoring Program and Electronic Health Record on Bleeding Log Completeness and Documentation. AB - BACKGROUND: Pharmacists have the ability to enhance comprehensive care for bleeding disorders patients by bridging the gap between hemophilia treatment centers (HTC) and specialty pharmacies, specifically by monitoring bleeding logs. In September 2015, a pharmacist-driven monitoring program was implemented through the specialty pharmacy associated with a medical center to improve bleeding log completeness and electronic documentation for HTC patients. OBJECTIVE: To measure the effect of a pharmacist-driven bleeding disorder monitoring program on bleeding log completeness, successful bleeding log documentation in the electronic health record (EHR), and pharmacist-driven clinical interventions using an EHR tool. METHODS: A single-group pre-post intervention study was conducted of a pharmacist-driven monitoring program. Pre-implementation (January 1, 2014-December 31, 2014), all patients who received and returned a bleeding log following an appointment at the HTC were included; post-implementation (September 1, 2015-December 30, 2015) included patients seen at the HTC who chose to participate in the program for at least 3 months. Before implementation, patient completed bleeding logs were scanned into the EHR by clinic staff. After implementation, bleeding logs were completed by a pharmacist and documented using a case management tool in the integrated EHR. Bleeding log records successfully documented in the EHR were collected. Completeness was calculated based on 10 clinical data elements for each bleeding log record. Pharmacist-driven interventions resulting from the program in the post-implementation period were recorded. RESULTS: In the pre-implementation period, 19 of 117 bleeding log records (16.2%) were documented in the EHR; all 15 (100%) records were documented post-implementation (P < 0.001). Among all clinical data elements across all records, 706 of 1,170 data elements were recorded pre-implementation (60.3%), and 120 of 150 (80.0%) were recorded post-implementation (P < 0.001). Pre implementation, no logs were 100% complete; post-implementation, only 6.7% of logs were fully complete (P = 0.114). For the 15 bleeding log records documented in the EHR during the post-implementation period, 14 documented pharmacist-driven clinical interventions occurred. The majority of interventions fell under coordination of care (8 [57.1%]). CONCLUSIONS: Improvement in bleeding log completeness and documentation in the EHR was associated with the use of an EHR tool and pharmacist-driven monitoring program. DISCLOSURES: Not outside funding supported this study. The authors have nothing to disclose. PMID- 30247109 TI - The Independent Inquiry into Child Sexual Abuse in the UK: reflecting on the mental health needs of victims and survivors. AB - SummaryThe nature and extent of the sexual abuse of children and young people and the pervasiveness of inappropriate institutional responses to its occurrence continues to raise serious concerns. The work of the Inquiry is a powerful reminder of the role of mental health services in addressing the needs of victims and survivors.Declaration of interestNone. PMID- 30247110 TI - Modelling out-of-area admissions. AB - SummaryOut-of-area (OOA) placements occur when patients cannot be admitted to local facilities, which can be extremely stressful for patients and families. Thus, the Department of Health aims to eliminate the need for OOA admissions. Using data from a UK mental health trust we developed a 'virtual mental health ward' to evaluate the potential impact of referral rates and length of stay (LOS) on OOA rates. The results indicated OOA rates were equally sensitive to LOS and referral rate. This suggests that investment in community services that reduce both LOS and referral rates are required to meaningfully reduce OOA admission rates.Declaration of interestP.A.T. holds an honorary consultant contract with the Tees, Esk and Wear Valleys NHS Foundation Trust. PMID- 30247116 TI - Violence, trauma, testimonials and truth. PMID- 30247115 TI - Kaleidoscope. PMID- 30247117 TI - Virtual reality compared with in vivo exposure in the treatment of social anxiety disorder. PMID- 30247118 TI - Microbispora triticiradicis sp. nov., a novel actinomycete isolated from the root of wheat (Triticum aestivum L.). AB - A novel actinomycete, designated strain NEAU-HRDPA2-9T, was isolated from the roots of wheat (Triticumaestivum L.) and characterized using a polyphasic approach. The morphological and chemotaxonomic characteristics of the strain coincided with those of members of the genus Microbispora. The 16S rRNA gene sequence analysis showed that the isolate was most closely related to Microbispora bryophytorum NEAU-TX2-2T (98.6 %), Microbispora hainanensis DSM 45428T (98.5 %), Microbispora camponoti 2C-HV3T (98.5 %), Microbispora amethystogenes JCM 3021T (98.2 %), Microbispora siamensis NBRC 104113T (98.1 %), Microbispora corallina JCM 10267T (98.0 %) and Microbispora roseasubsp.rosea JCM 3006T (97.9 %). However, two tree-making algorithms supported the position that strain NEAU-HRDPA2-9T formed a distinct clade with M. siamensis NBRC 104113T and M. hainanensis DSM 45428T. Furthermore, a combination of DNA-DNA hybridization results and some physiological and biochemical properties demonstrated that the strain could be distinguished from its closest relatives. Therefore, it is proposed that strain NEAU-HRDPA2-9T should be classified as representative of a novel species of the genus Microbispora, for which the name Microbisporatriticiradicis sp. nov. is proposed. The type strain is NEAU-HRDPA2 9T (=CGMCC 4.7399T=DSM 104649T). PMID- 30247120 TI - Disrupting folate metabolism reduces the capacity of bacteria in exponential growth to develop persisters to antibiotics. AB - Bacteria can survive high doses of antibiotics through stochastic phenotypic diversification. We present initial evidence that folate metabolism could be involved with the formation of persisters. The aberrant expression of the folate enzyme gene fau seems to reduce the incidence of persisters to antibiotics. Folate-impaired bacteria had a lower generation rate for persisters to the antibiotics ampicillin and ofloxacin. Persister bacteria were detectable from the outset of the exponential growth phase in the complex media. Gene expression analyses tentatively showed distinctive profiles in exponential growth at times when bacteria persisters were observed. Levels of persisters were assessed in bacteria with altered, genetically and pharmacologically, folate metabolism. This work shows that by disrupting folate biosynthesis and usage, bacterial tolerance to antibiotics seems to be diminished. Based on these findings there is a possibility that bacteriostatic antibiotics such as anti-folates could have a role to play in clinical settings where the incidence of antibiotic persisters seems to drive recalcitrant infections. PMID- 30247119 TI - Molecular analysis of Streptococcus pyogenes strains isolated from patients with recurrent pharyngitis after oral amoxicillin treatment. AB - PURPOSE: The most common illness caused by Streptococcus pyogenes (Group A streptococcus; GAS) is acute pharyngitis. It has been reported that a small percentage of patients experience recurrent GAS pharyngitis after 10 days of treatment with oral amoxicillin. The aim of this study was to clarify whether recurrent GAS pharyngitis is reactivation caused by the primary strain remaining at the infection site, or if the reinfection is caused by newly acquired strains. METHODOLOGY: A total of 135 GAS clinical strains were isolated from the tonsils of 116 pediatric patients with acute GAS pharyngitis between November, 2012 and April, 2014 in Saga, Japan. These strains were analysed by pulsed-field gel electrophoresis (PFGE)-typing methods. RESULTS: The isolates were grouped into 16 PFGE-types. The epidemic PFGE types that caused pharyngitis were found to change dynamically during 18 months. Eleven strains caused recurrent pharyngitis within 40 days after the last treatment, all of them showing the same PFGE-type as the primary strains. Eight of the strains caused recurrence more than 40 days after the treatment. Among them, six showed different PFGE-types from the primary strains. CONCLUSION: When recurrent pharyngitis emerges more than 40 days after the last treatment, penicillin can be prescribed again because reinfection is suspected. However, when recurrent pharyngitis takes place within 40 days after completing the treatment, alternative drugs should be considered for retreatment because the pharyngitis is likely to be due to reactivation. PMID- 30247121 TI - Bradyrhizobium ripae sp. nov., a nitrogen-fixing symbiont isolated from nodules of wild legumes in Namibia. AB - Root-nodule bacteria were isolated from wild legumes growing in the Kavango region, Namibia. Using a polyphasic approach, four strains belonging to the genus Bradyrhizobium (WR4T, WR87, T10 and T12) were further characterized to clarify the taxonomic status of this group. On the basis of 16S rRNA gene sequences, the four strains showed highest similarity to Bradyrhizobium elkanii USDA 76T (99.9 %), Bradyrhizobium pachyrhizi PAC48T (identical) and to Bradyrhizobiumbrasilense UFLA03-321T (identical). Multilocus sequence analysis of concatenated glnII-recA gyrB-dnaK-rpoB sequences and comparison of the intergenic transcribed spacer (ITS) sequences confirmed that the novel group belongs to a distinct lineage of the genus Bradyrhizobium, with <96.7 % (MLSA) and 97.25 % (ITS) nucleotide identity with B. elkanii USDA 76T. Results from the sequence-based analysis were validated by DNA-DNA hybridization experiments and suggested a novel species. Several phenotypic features including carbon compound utilization and growth characteristics supported the phylogenetic data, thus it is concluded that the strains represent a novel species, for which the name Bradyrhizobium ripae sp. nov. is proposed, with type strain WR4T [LMG 30283, DSM 105795, NTCCM 0019 (Windhoek)]. PMID- 30247124 TI - Plant-based metallic nanoparticles as potential theranostics agents: bioinspired tool for imaging and treatment. AB - Theranostic approach provides us a platform where diagnosis and treatment can be carried out simultaneously. Biosynthesis of theranostic-capable nanoparticles (NPs) can be carried out by phytoconstituents present inside the plants that can act as capping as well as stabilising agents by offering several advantages over chemical and physical methods. This article highlights the theranostic role of NPs with emphasis on potential of plants to produce these NPs through ecofriendly approach that is called 'Green synthesis'. Biosynthesis, advantages, and disadvantages of plant-based theronostics have been discussed for better understanding. Moreover, this article has highlighted the approaches required to optimise the plant-mediated synthesis of NPs and to avoid the toxicity of these agents. Anticipating all of the challenges, the authors expect biogenic NPs can appear as potential diagnostic and therapeutic agents in near future. PMID- 30247122 TI - Generation of a versatile BiFC ORFeome library for analyzing protein-protein interactions in live Drosophila. AB - Transcription factors achieve specificity by establishing intricate interaction networks that will change depending on the cell context. Capturing these interactions in live condition is however a challenging issue that requires sensitive and non-invasive methods. PMID- 30247125 TI - Biosynthesis of bimetallic and core-shell nanoparticles: their biomedical applications - a review. AB - Recently, researchers succeeded in designing and manufacturing a new class of nanoparticles (NPs) called hybrid NPs. Among hybrid NPs, bimetallic and core shell NPs were a revolutionary step in NPs science. A large number of green physiochemical and methods for nanostructures synthesis have been published. Eventually, physiochemical methods are either expensive or require the use of chemical compounds for the synthesis of bimetallic and core-shell nanostructures. The main challenges that scientists are facing are making the process cheaper, facile and eco-friendly efficient synthesis process. Green synthesis (biosynthesis) refers to the use of bio-resources (such as bacteria, fungi, plants or their derivatives) for the synthesis of nanostructures. The popularity of the green synthesis of nanostructures is due to their environmental friendliness and no usage of toxic materials, environmental friendliness for the synthesis or stability of nanostructure. Bimetallic and core-shell NPs have many biomedical applications such as removing heavy metals, parasitology, molecular and microbial sensor, gene carrier, single bacterial detection, oligonucleotide detection and so on. The purpose of this study is to discuss briefly the biosynthesised bimetallic and core-shell NPs, their biomedical applications. PMID- 30247123 TI - Human VMPFC encodes early signatures of confidence in perceptual decisions. AB - Choice confidence, an individual's internal estimate of judgment accuracy, plays a critical role in adaptive behaviour, yet its neural representations during decision formation remain underexplored. Here, we recorded simultaneous EEG-fMRI while participants performed a direction discrimination task and rated their confidence on each trial. Using multivariate single-trial discriminant analysis of the EEG, we identified a stimulus-independent component encoding confidence, which appeared prior to subjects' explicit choice and confidence report, and was consistent with a confidence measure predicted by an accumulation-to-bound model of decision-making. Importantly, trial-to-trial variability in this electrophysiologically-derived confidence signal was uniquely associated with fMRI responses in the ventromedial prefrontal cortex (VMPFC), a region not typically associated with confidence for perceptual decisions. Furthermore, activity in the VMPFC was functionally coupled with regions of the frontal cortex linked to perceptual decision-making and metacognition. Our results suggest that the VMPFC holds an early confidence representation arising from decision dynamics, preceding and potentially informing metacognitive evaluation. PMID- 30247127 TI - Synthesis and characterisation of nanostructured hardystonite coating on stainless steel for biomedical application. AB - Here, nanostructured hardystonite bioceramic (Ca2ZnSi2O7) was synthesised from tetraethyl orthosilicate, zinc nitrate hexahydrate, and calcium nitrate tetrahydrate via sol-gel method, dried at 60-120 degrees C, and finally calcinated at 1300 degrees C. X-ray diffraction (XRD) analysis confirmed the formation of hardystonite bioceramic. Afterwards, electrophoretic method was utilised to coat the hardystonite ceramic on 316L stainless steel (SS). Methanol solution was used as suspension solvent. The best deposition procedure was carried out by electrophoretic device in the voltage of 50 V for 5 min. XRD analysis was employed for phase characterisation and scanning electron microscopy was utilised for microstructural and morphological characterisations of the coatings. Chemical composition of the coating was evaluated by energy-dispersive X-ray spectroscopy. The hardystonite coating improved the corrosion resistance of the substrate, so the corrosion current density in the coated samples was less than the uncoated ones (nine times). In order to assess the bioactivity of the coating, simulated body fluid was used. The main results of the coated sample bioactivity demonstrated that the nanostructured hardystonite coating could amend the in vitro SS bioactivity. Therefore, SS coated with nanostructured hardystonite may be a promising candidate to be applied as bioactive hard tissue implants. PMID- 30247126 TI - Aqueous extract of broccoli mediated synthesis of CaO nanoparticles and its application in the photocatalytic degradation of bromocrescol green. AB - CaO nanoparticles have been prepared using CaCl2 and aqueous extract of broccoli as a precursor and reducing agent, respectively. Different volumes of the aqueous broccoli extract were utilised to obtain Ca(OH)2 and subsequent calcination gave CaO nanoparticles. The synthesised CaO was confirmed by powder X-ray diffraction (XRD). The morphology was studied using transmittance electron microscopy (TEM), and the surface composition of Ca(OH)2 was explored using Fourier transform infrared spectroscopy. The major functional groups present in the capping material responsible for the reduction of the metal salt and the surface passivation of Ca(OH)2 were identified. The XRD pattern revealed cubic phase for all the CaO nanoparticles, and the crystallite size was estimated using Scherrer's equation showed a variation which is dependent on the volume of the extract used. TEM analysis showed different shapes, while the selected area electron diffraction (SAED) results confirmed the crystallinity of the nanoparticles. Thermogravimetric analysis of Ca(OH)2 showed the decomposition product to be CaO. Sample C3, which has the smallest particle size, was used as a catalyst for the degradation of bromocresol green via photo irradiation with ultraviolet light and the result revealed a degradation efficiency of 60.1%. PMID- 30247128 TI - Microwave-mediated synthesis of zinc oxide nanoparticles: a therapeutic approach against Malassezia species. AB - A successful protocol was developed to aid in the reduction in dandruff-causing fungi, namely Malassezia globasa and Malassezia furfur. Both the species were isolated from volunteers aged between 20 and 22 suffering from dandruff, cultured ex vivo, and tested against the presence of synthesised zinc oxide nanoparticles (ZnNP). Direct microscopy, scanning electron microscopy (SEM), and biochemical assays specific to Malassezia species were conducted to identify dandruff-causing fungal species. Microwave-mediated synthesis of ZnNP was performed and characterised by UV-vis, X-ray diffraction, and SEM. The nanoparticles were tested against both Malassezia species and proved highly effective in inhibiting these fungi, although M. furfur was more susceptible than M. globosa. An optimum amount of 100 ppm was found to be sufficient to work as an antifungal agent. Synergistic effects of ZnNP with commercial shampoos were tested, and the result showed enhanced antifungal effects. To mimic the natural biofilm formed by these species on human skin, the formation of fungal biofilm was allowed on polystyrene coverslips. ZnNP was effective in eradication biofilm. Since zinc is an essential mineral for all living organism and is considered as biocompatible, the synthesised nanomaterials can be used in the formulation of antidandruff shampoos. PMID- 30247129 TI - Facile synthesis of gold nanoparticles using carbon dots for electrochemical detection of neurotransmitter, dopamine in human serum and as a chemocatalyst for nitroaromatic reduction. AB - Herein, the authors reported a carbon dots mediated synthesis of gold nanoparticles (AuNPs) at room temperature. Transmission electron microscopy revealed that the AuNPs are spherical in shape with a size of 10 nm. As-prepared AuNPs was immobilised on carbon paste electrode and subjected to electrochemical sensing of an important neurotransmitter dopamine. Differential pulse voltammetry studies revealed sensitive and selective determination of dopamine in the presence of commonly interfering ascorbic acid and uric acid. The linear detection range was 10-600 MUM and the limit of detection was 0.7 +/- 0.18 MUM. The practical application was demonstrated by measuring dopamine in human blood serum and urine samples. The catalytic activity of AuNPs was evaluated by sodium borohydride mediated reduction of nitroaromatic compounds. The reduction kinetics was found to be pseudo-first-order kinetics. All the tested nitroaromatics reduced to corresponding amines in <10 min. PMID- 30247130 TI - Cu-induced assembly of methanobactin-modified gold nanoparticles and its peroxidase mimic activity. AB - Methanobactin (Mb) is a small copper-chelating molecule that functions as an agent for copper acquisition, uptake and copper-containing methane monooxygenase catalysis in methane-oxidising bacteria. The UV-visible spectral and fluorescence spectral suggested that Mb/Cu coordination complex as a monomer (Mb-Cu), dimmer (Mb2-Cu) and tetramer (Mb4-Cu) could be obtained at different ratios of Mb to Cu (II). The kinetics of the oxidation of hydroquinone with hydrogen peroxide catalysed by the different Mb/Cu coordination complex were investigated. The results suggested that Mb2-Cu coordination form has highest catalytic capacity. Further, Mb-modified gold nanoparticles (AuNPs) were obtained by ligand exchange and assembled into two- and three-D nanocluster structure by metal-organic coordination as driving force. It has been found that AuNPs increased the catalytic activity of Mb2-Cu on AuNPs. The more significant catalytic activity was exhibited by the nanocluster assembly with multi-catalytic centres. This may be attributed to the multivalent collaborative characteristics of the catalytic active centres in the nanocluster network assembly. The assembly of Mb-modified AuNPs can act as excellent nanoenzyme models for imitating peroxidase. PMID- 30247131 TI - Role of AgNPs in the enhancement of seed germination and its effect on plumule and radicle length of Pennisetum glaucum. AB - The authors have investigated beneficial effects of 1 mM of silver nanoparticles (AgNPs) on agriculturally important plant Pennisetum glaucum (Bajara). The extracellular AgNPs were synthesised using Bacillus subtilis spizizenni and characterised using ultraviolet-visible absorption spectroscopy, Fourier transform infrared spectroscopy (FT-IR) and transmission electron microscopy (TEM). Optical absorption spectrum showed characteristic peak of AgNPs at 423 nm. FT-IR analysis of AgNPs showed peak at 3435 cm-1, which indicates the presence of N-H group (primary, secondary amines and amides) on the surface of AgNPs. TEM studies indicate that synthesised AgNPs have average size of ~2 nm. Energy dispersive X-ray spectroscopy showed strong signal of Ag at 3 keV. Treatment of 1 mM AgNPs to the bajara seeds was found to be sufficient for excellent germination of seeds within 3 days. There was also significant increase in radicle and plumule length as compared with control bajara seeds according to statistical analysis by one-way analysis of variance, followed by Tukey's test. The percentage of AgNPs detected in root samples was 0.003% (by inductively coupled plasma atomic emission spectroscopy), which is negligible. There is still need to study the bioavailability and the type of interaction of AgNPs with plants, necessary for application in agriculture. PMID- 30247132 TI - Effect of silver nanoparticles and silver nitrate on growth of rice under biotic stress. AB - This study was organised to check the effect of silver nanoparticles and silver nitrate on rice growth against biotic stress. Silver nanoparticles were synthesised by using plant extract as reducing agent, followed by characterisation through UV Vis spectroscopy, XRD, EDS and SEM. Aspergillus application significantly reduced rice plant fresh mass (0.9%), dry mass (0.21%), root length (2.3%), shoot length (5.2%) and root number (1%) in comparison to control. Similarly, leaf area, leaf fresh mass, dry mass and leaf number were also reduced by 23.1, 0.02, 0.11 and 0.9%, respectively. AgNPs and AgNO3 treatments increased the root length (16.2 & 12.8%), shoot length (21 & 20%), root number (8.1 & 6.8%), plant fresh weight (6.4 & 5%) and plant dry weight (4.6 & 3.5%) in 75mg/l treatment of AgNPs and AgNO3 respectively. Similarly, AgNPs and AgNO3 treatment (75 mg/l concentrations) reflected remarkable increase in leaf area (58.8 & 57.2 %), leaf number (4.3 & 3.7 %), leaf fresh weight (1.7 & 1.4 %) and leaf dry weight (0.9 & 0.8 %). Overall AgNPs showed more significant results as compared to AgNO3. The quantity of aflatoxins ranged from 3.1 to 7.7 MUg/kg against tolerable limit (4 ug/kg). Overall AgNPs and AgNO3 treatments showed significant results and it could be considered as a strategy for aflatoxin management in rice plants. PMID- 30247134 TI - Biosynthesis of waste pistachio shell supported silver nanoparticles for the catalytic reduction processes. AB - Silver nanoparticles (NPs) are immobilised on pistachio shell surface by Cichorium intybus L. leaves extract as an antioxidant media. The Fourier transform infrared spectra, X-ray diffraction, field-emission scanning electron microscopy equipped with energy-dispersive X-ray spectroscopy, and transmission electron microscope analyses confirmed the support of silver NPs on the pistachio shell (Ag NPs/pistachio shell). Ag NPs on the pistachio shell had a diameter basically in the 10-15 nm range. Reduction reactions of 4-nitrophenol (4-NP), and organic dyes at ambient condition were used in the investigation of the catalytic performance of the prepared catalyst. Through this research, the Ag NPs/pistachio shell shows a high activity and recyclability, and reusability without loss of its catalytic activity. PMID- 30247133 TI - Green biosynthesis, characterisation and antimicrobial activities of silver nanoparticles using fruit extract of Solanum viarum. AB - Green synthesis of nanoparticles is considered an efficient method when compared with chemical and physical methods because of its bulk production, eco friendliness and low cost norms. The present study reports, for the first time, green synthesis of silver nanoparticles (AgNPs) at room temperature using Solanum viarum fruit extract. The visual appearance of brownish colour with an absorption band at 450 nm, as detected by ultraviolet-visible spectrophotometer analysis, confirmed the formation of AgNPs. X-ray diffraction confirmed the AgNPs to be crystalline with a face-centred lattice. The transmission electron microscopy energy dispersive X-ray spectroscopy image showed the AgNPs are poly-dispersed and are mostly spherical and oval in shape with particle size ranging from 2 to 40 nm. Furthermore, Fourier transform-infrared spectra of the synthesised AgNPs confirmed the presence of phytoconstituents as a capping agent. The antimicrobial activity study showed that the AgNPs exhibited high microbial activity against Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus susp. aureus, Aspergillus niger, and Candida albicans. The highest antimicrobial activity of AgNPs synthesised by S. viarum fruit extract was observed in P. aeruginosa, S. aureus susp. aureus and C. albicans with zone of inhibition, 26.67 mm. PMID- 30247135 TI - Preparation of alginate oligosaccharide nanoliposomes and an analysis of their inhibitory effects on Caco-2 cells. AB - The conditions were optimised for preparing Alginate oligosaccharide (AOS) nanoliposomes, and Caco-2 cell experiments were carried out to examine their antitumour effects. The optimal formulation of AOS nanoliposomes was as follows: a phosphatidylcholine-to-cholesterol ratio of 5.12, AOS concentration of 8.44 mg/mL, Tween 80 concentration of 1.11%, and organic phase to aqueous phase ratio of 5.25. Under the above conditions, the experimental encapsulation efficiency was 65.84%, and the AOS nanoliposomes exhibited a small particle size of 323 nm. After Caco-2 cells were treated with AOS liposomes and AOS for 24 h, AOS nanoliposomes inhibited the growth of Caco-2 cells to a greater extent than AOS at concentrations of 0.0625, 0.125, 0.25, 0.5 and 1 mg/mL (P < 0.01). LDH leakage exhibited a concentration-dependent increase following treatment with 0.5-1 mg/mL AOS nanoliposomes, and the inhibitory effect of AOS nanoliposomes exhibited a more significant difference than AOS (P < 0.01). Cells treated with 0.5 mg/mL and 1 mg/mL AOS nanoliposomes displayed a substantial and significant increase in activity compared with AOS (P < 0.01). Based on these results, AOS nanoliposomes exerted a more significant effect on inhibiting Caco-2 cell proliferation than AOS. PMID- 30247136 TI - Comparative study on nanostructured order-disorder in the wing eyespots of the giant owl butterfly, Caligo memnon. AB - A characteristic feature of the giant owl butterfly, i.e. Caligo memnon, is its big wing eyespot. This feature could serve as deceiving functionality for the butterfly against predators. As evidenced by scanning electron microscope (SEM) image on black part of eyespot, the scales on wing eyespot contain nanostructured ridges and cross-ribs. Applying direct measurement, statistical method, and Fourier analysis, the authors evidence that these nanostructures display order disorder in their shape and position. The autocorrelation of SEM image provides average values of characteristic periods of the order-disorder nanostructures together with an estimation of corresponding correlation lengths. Linecuts obtained from the Fourier transform of SEM image were also analysed with the Hosemann function to extract similar information. These analyses indicate that the nanostructured order-disorder may contribute to blackness on wing eyespot. The authors thus conclude that the blackness on wing eyespot of C. memnon could be attributed to contributions from both the nanostructured order-disorder and melanin pigment. PMID- 30247137 TI - Surface characterisation and reaction kinetics of silver nanoparticles mediated by the leaf and flower extracts of French marigold (Tagetes patula). AB - In this study, French marigold's leaf and flower were used for the synthesis of silver nanoparticles (SNPs) in order to explore their potentials towards bioreduction of Ag+ to Ag?. The as-synthesised SNPs were characterised using UV Vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, powder X-ray diffraction, transmission electron microscopy, and zeta-potential analysis. The results obtained showed that the particles are polydispersed with sizes in the range 15.8-42.8 nm. The bioreduction was believed to be due to the amides, aldehyde functional groups, and essential oils present in the extracts as confirmed by the FTIR analysis. The growth mechanism involved in the reaction was studied which revealed oriented attachment (OA) onwards Ostwald ripening in the case of the flower-mediated synthesis and typical OA in the leaf-mediated synthesis. The studied kinetics of the particle formation showed that the reaction is possibly a pseudo-first-order reaction with some diffusion-controlled mechanism which is driven by high surface area to volume ratio in both the leaf- and flower-mediated synthesis. PMID- 30247138 TI - The use of slow releasing nanoparticle encapsulated Azadirachtin formulations for the management of Caryedon serratus O. (groundnut bruchid). AB - Nanobiotechnology is one of the emerging fields and its interventions in agriculture is been attracting the scientific community. Herein, the authors first to report on control of groundnut bruchid (Caryedon serratus O.) using nanoscale zinc oxide (ZnONPs) particles and nanoscale chitosan (CNPs) particles based Azadirachtin formulations. ZnONPs and CNPs were prepared using sol-gel and ion tropic gelation techniques, respectively. Neem seed kernel extract (NSKE) 5% and Neem oil (3000 and 1000 ppm) were encapsulated using the prepared nanoscale materials and characterised using the techniques such as dynamic light scattering, high-resolution transmission electron microscopy. Spherical-shaped nanoparticles were formed after encapsulation with the required bio-materials (ZnONPs 33.1 nm; CNPs 78.8 nm; neem oil encapsulated (3000 ppm) ZnONPs 182.9 nm; NSKE encapsulated ZnONPs 84.9 nm) and observed that the particles are stable (52.3 mV for ZnONPs, -36.2 mV for CNPs, -43.0 mV for neem oil encapsulated (3000 ppm) ZnONPs and -39.4 mV for NSKE encapsulated ZnONPs). NSKE encapsulated CNPs were able to contain groundnut bruchid up to 180 days with 54.61% weight loss compared to other formulations tested. Thus biomaterial encapsulated nanoscale material formulations are proved to be effective in controlling stored grain pests to reduce huge economic losses. PMID- 30247139 TI - Low-temperature synthesis of hierarchical structures of copper oxide and their superior biological activity. AB - In this work, the authors report a facile low-temperature wet-chemical route to prepare morphology-tailored hierarchical structures (HS) of copper oxide. The preparation of copper oxide collides was carried out using varying concentrations of copper acetate and a reducing agent at a constant temperature of 50 degrees C. The prepared HS of CuO were characterised by powdered X-rays diffraction that indicates phase pure having monoclinic structures. The morphology was further confirmed by field-emission scanning electron microscope. It reveals a difference in shape and size of copper oxide HS by changing the concentration of reactants. In order to evaluate the effect of H2O2 on CuO NPs, the prepared CuO are modified by treatment with H2O2. In general trend, CuOH2O2 collide showed enhanced protein kinase inhibition, antibacterial (maximum zone 16.34 mm against Staphylococcus aureus) and antifungal activities in comparison to unmodified CuO collides. These results reveal that CuO HS exhibit antimicrobial properties and can be used as a potential candidate in pharmaceutical industries. PMID- 30247140 TI - Efficacy of using oxygen microbubble device for facultative anaerobe removal. AB - Patients with serious gingivitis or periodontal diseases suffer from receding gums. Brushing teeth with a toothbrush may result in bleeding gums and new wounds, which increases the difficulty of removing facultative anaerobes from gum pockets, to decrease the damage inflicted on gums, this study proposed a cleaning device that can generate and emit oxygen microbubbles for eliminating facultative anaerobes in the mouth cavity. In this study, the authors conducted simulations with a denture to investigate the efficacy of using this method to remove facultative anaerobes. In this research for the optimal device design, several variables were manipulated including rotation speeds of the bubble generator, different nozzle diameters, and different numbers of nozzle holes. The results revealed that the device is effective in removing facultative anaerobes; moreover, of all design variables, the number of nozzle holes was the factor having the largest effect on anaerobe removal, as it influenced the flow volume and oxygen content of the discharge: the greater the number of nozzles, the greater the flow volume, oxygen content, and efficacy of anaerobe removal. PMID- 30247141 TI - Bio-fabrication of silver nanoparticles by Pseudomonas aeruginosa: optimisation and antibacterial activity against selected waterborne human pathogens. AB - Multiple drug resistance and treatment of contaminated water has become a serious issue in past years. Silver nanoparticles (AgNPs), being bactericidal, non-toxic, cheap and environment friendly behaviour, have drawn attention to overcome these problems. This study has been designed to synthesise AgNPs from Pseudomonas aeruginosa. AgNPs formation was confirmed by colour change and UV-vis spectroscopy. Furthermore, Fourier transform infrared spectroscopy peaks demonstrated the presence of capped proteins as reducing and stabilising agent. Transmission electron microscopy micrograph revealed spherical shape AgNPs with the size ranging between 10 and 20 nm. Antibacterial activity of AgNPs was evaluated against the most prevalent waterborne pathogens enterohaemorrhagic Escherichia coli and Salmonellae typhimurium. Moreover, the antibacterial activity of AgNPs was tested for the treatment of contaminated water which showed attenuation in bacterial load within 8 h as demonstrated by growth kinetics data. Furthermore, AgNPs did not exhibit haemolytic effects on human red blood cells (RBCs) even at 100 mg L-1 concentration of AgNPs. The results herein suggest that AgNPs synthesised by P. aeruginosa under optimised conditions exhibit microbicidal property against waterborne pathogens and having no toxic effect on human RBCs. These AgNPs could be employed for treatment of contaminated water after process optimisation. PMID- 30247142 TI - In vivo biosynthesis and spatial distribution of Ag nanoparticles in maize (Zea mays L.). AB - Nanoparticles (NPs), especially biosynthesised in living plants by absorbing soluble salts and reducing metal ions, are extensively used in various fields. This work aimed at investigating the in vivo biosynthesis of silver NPs (Ag-NPs) in maize and the spatial distribution of the NPs and some important nutrient elements in the plant. The content of silver in plant was examined by inductively coupled plasma-atomic emission spectrometer showing that Ag can be absorbed by plant as soluble salts. The NPs in different parts of maize plant were detected and analysed by transmission electron microscopy, demonstrating the synthesis of NPs and their transport from the root to the shoots. Two-dimensional proton induced X-ray emission of silver, chlorine and several nutrient elements elucidated the possible relationship between synthesis of NPs and several nutrient elements in plant tissues. To their knowledge, this is the first report of possibility of synthesis of Ag-NPs in living plants maize (Zea mays L.). This study presents direct evidence for synthesis of NPs and distribution of related nutrient elements in maize, which has great significance for studying synthetic application of NPs in crop plants. PMID- 30247143 TI - Silver nanoparticles biosynthesised using Centella asiatica leaf extract: apoptosis induction in MCF-7 breast cancer cell line. AB - The aim of this study was to green synthesised silver nanoparticles (AgNPs) using Centella asiatica leaf extract and investigate the cytotoxic and apoptosis inducing effects of these nanoparticles in MCF-7 breast cancer cell line. The characteristics and morphology of the green synthesised AgNPs were evaluated using transmission electron microscopy, scanning electron microscopy, UV-visible spectroscopy, X-ray diffraction, and Fourier-transform infrared spectroscopy. The MTT assay was used to investigate the anti-proliferative activity of biosynthesised nanoparticles in MCF-7 cells. Apoptosis test was performed using flow cytometry and expression of caspase 3 and 9 genes. The spherical AgNPs with an average size of 19.17 nm were synthesised. The results showed that biosynthesised AgNPs exhibited cytotoxicity, anti-cancer, apoptosis induction, and increased expression of genes encoding for caspases 3 and 9 in MCF-7 cancer cells in a concentration- and time-dependent manner. It seems that green synthesised AgNPs have potential uses for pharmaceutical industries. PMID- 30247144 TI - The effects of aerogen-bonding on the geometries and spectral properties of several small molecular clusters containing XeO3. AB - Aerogen bonding, as a specific noncovalent interaction, has attracted wide attention recently. A number of theoretical studies have proposed this effect based on the analysis of electronic structures of aerogen-containing systems though, the spectral characteristics have not been identified, which becomes the obstacle for the experimental confirmation of this interaction. In this paper, we employed the density functional theory to explore the energetic and geometric properties, infrared, Raman spectra of five small molecular clusters XeO3.H2O, XeO3.NH3, XeO3 dimer, XeO3 trimer, and XeO3.2H2O. Our results show the binding energies of the most favorable conformations for the dimers are larger than 10.00 kcal mol-1 and those for trimers are larger than -20.00 kcal mol-1, which indicates the strong aerogen bonding is favorable for the stabilities of these clusters. More importantly, some new IR and Raman vibrations at fingerprint region (<1000 cm-1) are identified, which corresponds to the formation of aerogen bonds. This study provides a viable way for the experimentalists to characterize the aerogen bonding in future. PMID- 30247145 TI - Unusual effects of Be doping in the iron-based superconductor FeSe. AB - Recent superconducting transition temperatures (T c) over 100 K for monolayer FeSe on SrTiO3 have renewed interest in the bulk parent compound. In KCl:AlCl3 flux-transport-grown crystals of FeSe0.94Be0.06, FeSe0.97Be0.03 and, for comparison, FeSe, this work reports doping of FeSe using Be-among the smallest of possible dopants, corresponding to an effective 'chemical pressure'. According to lattice parameter measurements, 6% Be doping shrank the tetragonal FeSe lattice equivalent to a physical pressure of 0.75 GPa. Using this flux-transport method of sample preparation, 6% of Be was the maximum amount of dopant achievable. At this maximal composition of FeSe0.94Be0.06, the lattice unit cell shrinks by 2.4%, T c-measured in the bulk via specific heat-increases by almost 10%, the T c versus pressure behavior shifts its peak [Formula: see text] downwards by ~1 GPa, the high temperature structural transition around T S = 89 K increases by 1.9 K (in contrast to other dopants in FeSe which uniformly depress T S), and the low temperature specific heat gamma increases by 10% compared to pure FeSe. Also, upon doping by 6% Be the residual resistivity ratio, rho(300 K)/rho(T -> 0), increases by almost a factor of four, while rho(300 K)/rho([Formula: see text]) increases by 50%. PMID- 30247146 TI - The effect of structural asymmetry on thermal rectification in nanostructures. AB - Three SWCNT-graphene nanostructure-based models are designed to probe the thermal rectification caused by the structural asymmetry in the boundary thermal contacts, the device, and the whole system, respectively. We find that both the asymmetry of entire system and the asymmetry of the device are not necessary condition for the existence of thermal rectification, and the asymmetry in boundary thermal contacts is more important than the asymmetry in device toward determining both the magnitude and the direction of thermal rectification. Interestingly, notable thermal rectification can exist in the systems with overall structural symmetry when the boundary thermal contacts are structurally asymmetric. Moreover, nanostructures with a structurally symmetric device and structurally asymmetric boundary thermal contacts can still display significant thermal rectification. These findings could offer insight into the future design and performance improvement of nanostructured thermal rectifiers. PMID- 30247147 TI - The photoelectric response of the graphene/GeSi QDs hybrid structure. AB - In this work, the photoelectric response properties of the graphene/GeSi QDs hybrid structure were demonstrated by measuring the I-V curve, and the incident photon-to-current conversion efficiency (IPCE). The maximal on-off ratio of the current value reaches 1500 at 10 K, due to the competition between the carrier freeze-out effect and the recombination center effect. The IPCE of the hybrid structure under different incident light indicated that the photoelectric response of hybrid structure is most sensitive to the ultraviolet light (325 nm), which is attributed to the enhanced ultraviolet absorption of graphene surface plasmon in the hybrid structure. Hence, our results represent that the graphene/GeSi QDs hybrid structure has potential application as a novel ultraviolet photoelectric device. PMID- 30247148 TI - 2D melting of confined colloids with a mixture of square and triangular order. AB - We implement Brownian dynamics to investigate the melting processes of colloidal particles confined isotropically and interacting via a potential which can be tailored in a repulsive-attractive-respulsive fashion as the interparticle distance increases. The stable configurations of such a system is composed of a large diversity of structures, which includes quasicrystalline, triangular, square, and mixed orderings, as well as the presence of fringes and holes, which are located, respectively, at the border and interior of the clusters. Our simulations demonstrate that during the melting process particles are able to swing between different micro phases. This intermediary stage, present in a finite range of temperature, precedes the melting in all cases investigated and is different from the hexatic phase of the KTNHY framework. We also test the fringes stability and find it to be higher than the one found in compact clusters. Finally, we show that, at the high temperature regime, the system loses its angular ordering while still preserves its radial interparticle confinement, which, ultimately, causes the proliferation of small subclusters. PMID- 30247149 TI - The tunable bandgap effect of SnS films. AB - Two-dimensional (2D) SnS has attracted much attention as a phosphorene analogue due to the promising applications in next-generation nanoelectronic and photovoltaic devices. It has a bandgap of 1.3 eV, which is matched very well with incident solar radiation. To improve the switching character of devices, it is significant to modulate the bandgap of 2D SnS. In this work, potassium ion (K+) or calcium ion (Ca2+) is absorbed on the top surface of SnS films to produce an electric field, by which the bandgap can be tuned effectively. By first principles method we studied the electronic properties and the modulation mechanism of bandgap in detail. The calculated ionization energy and formation energy are 0.41 eV and 0.26 eV for K (1.33 eV and 1.07 eV for Ca). Such little values indicate that it is feasible for ion absorbed on the surface to be used to modulate the bandgap of SnS films. Our calculations also show that the carrier mobility in plane of SnS films has a character of strong anisotropy and the electron mobility is very high in y direction (25.22 * 103 cm2 V-1 s-1 for SnS trilayer). Therefore 2D SnS has potential application in nanoelectronic and photovoltaic devices in the future. We hope our results will motivate experimental efforts of 2D SnS. PMID- 30247150 TI - Anisotropic conductivity in 2D massive Dirac Fermions: an effect of time reversal symmetry breaking in the surface states of a topological insulator. AB - We calculate the conductivity tensor for massive Dirac Fermions within the semiclassical Boltzmann approach. We consider the effect of two different types of scattering mechanism, namely scalar and magnetic, that act incoherently and use the symmetries of the transition rate to exactly solve the Boltzmann equation. We prove that the conductivity can be anisotropic depending on the strength of the magnetic scatterers in each direction. In the particular situation of magnetic impurities polarised in the x-direction, the conductivity is three times larger in y-direction as compared with the conductivity in the x direction, for white noise scattering correlation function. We compare the approach we apply with the most commonly used way of dealing with more than one source of scattering, namely with Matthiessen's rule, and show that the approach we applied is more general and suitable for anisotropic scattering. PMID- 30247151 TI - Universal scaling in first-order phase transitions mixed with nucleation and growth. AB - Matter exhibits phases and their transitions. These transitions are classified as first-order phase transitions (FOPTs) and continuous ones. While the latter has a well-established theory of the renormalization group, the former is only qualitatively accounted for by classical theories of nucleation, since their predictions often disagree with experiments by orders of magnitude. A theory to integrate FOPTs into the framework of the renormalization-group theory has been proposed but seems to contradict with extant wisdom and lacks numerical evidence. Here we show that universal hysteresis scaling as predicted by the renormalization-group theory emerges unambiguously when the theory is combined intimately with the theory of nucleation and growth in the FOPTs of the paradigmatic two-dimensional Ising model driven by a linearly varying externally applied field below its critical point. This not only provides a new method to rectify nucleation theories, but also unifies the theories for both classes of transitions and FOPTs can be studied using universality and scaling similar to their continuous counterpart when nucleation and growth are properly taken into account. PMID- 30247152 TI - Mechanical avalanches promoted by magnetoelastic coupling in magnetic metallic glasses. AB - The effect of magnetoelastic coupling on the mechanical behavior of magnetic metallic glasses is studied by superposing a magnetic field to the mechanical load during deformation experiments. The mechanical response is studied from the point of view of the global behavior, characterized by the Young's modulus, and from the perspective of the avalanches, estimated from the intermittency of the deformation signal. The influence of several intensities and orientations of magnetic field is analyzed in two amorphous alloys with different magnetostriction. For the highly magnetostrictive alloy, the decrease of the macroscopic Young's modulus under certain magnetic fields is accompanied by the promotion of mechanical avalanches, a fact that suggests that in this case the magnetoelastic coupling involves some extent of non-linear addition of the magnetic and mechanical energies. PMID- 30247153 TI - Meshfree simulations of ultrasound vector flow imaging using smoothed particle hydrodynamics. AB - Before embarking on a series of in vivo tests, design of ultrasound-flow-imaging modalities are generally more efficient through computational models as multiple configurations can be tested methodically. To that end, simulation models must generate realistic blood flow dynamics and Doppler signals. The current in silico ultrasound simulation techniques suffer mainly from uncertainty in providing accurate trajectories of moving ultrasound scatterers. In mesh-based Eulerian methods, numerical truncation errors from the interpolated velocities, both in the time and space dimensions, can accumulate significantly and make the pathlines unreliable. These errors can distort beam-to-beam inter-correlation present in ultrasound flow imaging. It is thus a technical issue to model a correct motion of the scatterers by considering their interaction with boundaries and neighboring scatterers. We hypothesized that in silico analysis of emerging ultrasonic imaging modalities can be implemented more accurately with meshfree approaches. We developed an original fluid-ultrasound simulation environment based on a meshfree Lagrangian CFD (computational fluid dynamics) formulation, which allows analysis of ultrasound flow imaging. This simulator combines smoothed particle hydrodynamics (SPH) and Fourier-domain linear acoustics (SIMUS = simulator for ultrasound imaging). With such a particle-based computation, the fluid particles also acted as individual ultrasound scatterers, resulting in a direct and physically sound fluid-ultrasonic coupling. We used the in-house algorithms for fluid and ultrasound simulations to simulate high-frame-rate vector flow imaging. The potential of the particle-based method was tested in 2D simulations of vector Doppler for the intracarotid flow. The Doppler-based velocity fields were compared with those issued from SPH. The numerical evaluations showed that the vector flow fields obtained by vector Doppler components were in good agreement with the original SPH velocities, with relative errors less than 10% and 2% in the cross-beam and axial directions, respectively. Our results showed that SPH-SIMUS coupling enables direct and realistic simulations of ultrasound flow imaging. The proposed coupled algorithm has also the advantage to be 3D compatible and parallelizable. PMID- 30247154 TI - 1D tungsten oxide nanostructures on a Cu(1 1 0) surface. AB - Thin epitaxial layers of tungsten oxide on metal substrates are suitable as model systems for investigation of chemical reactivity and catalytic properties. However, the ability to prepare epitaxial tungsten oxide model system in situ is quite rare. Here we present a method to prepare highly ordered tungsten oxide thin film on a Cu(1 1 0) single crystal substrate using physical vapor deposition in a reactive atmosphere of atomic oxygen. The oxygen induced reconstruction of the copper substrate gives rise to unique self-organized 1D structures of tungsten oxide parallel with the Cu[1 -1 0] crystallographic direction. Utilizing a combination of photoemission spectroscopy and density functional theory calculations we reveal emergent physicochemical properties related to the low-dimensionality of the system. Specifically, we observe a support mediated charge redistribution at the interface and a momentum dependent modulation of the valence-band electronic structure. The unusual character of the 1D oxide nanostructures on Cu(1 1 0) surface opens up a unique avenue for preparation of tungsten oxide-based functionalized nanostructures and provides options for further investigation of the fundamental properties of tungsten oxide. PMID- 30247155 TI - Consequences of the inherent density dependence in one dimensional Dirac materials. AB - Dirac materials are systems in which the dispersion is linear in the vicinity of the Dirac points. As a consequence of this linear dispersion, the Fermi velocity is independent of density and these systems exhibit unusual behavior and possess unique physical properties that are of considerable interest. In this work we study the ground state behavior of 1D Dirac materials in two ways. First, using the Virial theorem, we find agreement with a previous result in regards to the total average ground state energy. Namely, that the total average ground state energy, regardless of dimensionality, is found to be [Formula: see text] where r s is a dimensionless constant that's a measure of density and [Formula: see text] is a constant independent of r s . As a consequence, thermodynamic results as well as the characteristic exponents of 1D Fermi systems are density independent. Second, using conventional techniques, i.e. Tomanaga-Luttinger theory, we find several unique properties that are a direct consequence of the dispersion. Specifically, the collective modes of the system exhibit electron density independence predicted from the Virial theorem. Finally, possible experimental realization of our predictions of density independent exponents are briefly discussed. PMID- 30247156 TI - Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss. AB - The underlying molecular mechanisms of age-related hearing loss (ARHL) in humans and many strains of mice have not been fully characterized. This common age related disorder is assumed to be closely associated with oxidative stress. Here, we demonstrate that mTORC1 signaling is highly and specifically activated in the cochlear neurosensory epithelium (NSE) in aging mice, and rapamycin injection prevents ARHL. To further examine the specific role of mTORC1 signaling in ARHL, we generated murine models with NSE-specific deletions of Raptor or Tsc1, regulators of mTORC1 signaling. Raptor-cKO mice developed hearing loss considerably more slowly than WT littermates. Conversely, Tsc1 loss led to the early-onset death of cochlear hair cells and consequently accelerated hearing loss. Tsc1-cKO cochleae showed features of oxidative stress and impaired antioxidant defenses. Treatment with rapamycin and the antioxidant N acetylcysteine rescued Tsc1-cKO hair cells from injury in vivo. In addition, we identified the peroxisome as the initial signaling organelle involved in the regulation of mTORC1 signaling in cochlear hair cells. In summary, our findings identify overactive mTORC1 signaling as one of the critical causes of ARHL and suggest that reduction of mTORC1 activity in cochlear hair cells may be a potential strategy to prevent ARHL. PMID- 30247158 TI - Customized 3D-Printed Prosthetic Devices for Wounded Warriors. PMID- 30247159 TI - Motor Control Training Compared to Transcutaneous Electrical Nerve Stimulation in Patients with Disc Herniation with Associated Radiculopathy: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the effectiveness of motor control training(MCT)and transcutaneous electrical nerve stimulation (TENS) in relieving pain, reducing functional disability, and improving transversus abdominis (TrA) activation in patients with lumbar disc herniation(LDH) with associated radiculopathy. DESIGN: Randomized controlled trial. METHODS: Forty patients diagnosed with LDH were randomly divided into two groups: motor control training group (MCTG; n=20) and TENS group(TG; n=20). INTERVENTIONS: The MCTG and TG attended 60-minsessions twice a week for 8 weeks, totaling to 16 sessions. MAIN OUTCOME MEASURES: Pain, functional disability, and TrA activation capacity. RESULTS: Differences between both groups were observed after 8 weeks, favoring the MCTG. MCT was more effective than TENS in relieving pain (mean difference=3.3 points, 95% confidence interval [CI] 2.12-4.48), reducing functional disability (mean difference=8.4 points, 95% CI 5.44-11.36), improving the quality of pain (mean difference=17 points, 95% CI 7.93-26.07), sensory quality of pain (mean difference=10.3 points, 95% CI5.55-15.05), and TrA activation (mean difference=1.5 points, 95% CI0.90 2.10). CONCLUSIONS: The results suggest that MCT is more effective than TENS with respect to relieving pain, reducing functional disability, and improving TrA activation in patients with LDH. REGISTRATION NUMBER: NCT01640431 clinicaltrials.gov. PMID- 30247157 TI - Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection. AB - The E3 ubiquitin ligase Pellino 1 (Peli1) is a microglia-specific mediator of autoimmune encephalomyelitis. Its role in neurotropic flavivirus infection is largely unknown. Here, we report that mice deficient in Peli1 (Peli1-/-) were more resistant to lethal West Nile virus (WNV) infection and exhibited reduced viral loads in tissues and attenuated brain inflammation. Peli1 mediates chemokine and proinflammatory cytokine production in microglia and promotes T cell and macrophage infiltration into the CNS. Unexpectedly, Peli1 was required for WNV entry and replication in mouse macrophages and mouse and human neurons and microglia. It was also highly expressed on WNV-infected neurons and adjacent inflammatory cells from postmortem patients who died of acute WNV encephalitis. WNV passaged in Peli1-/- macrophages or neurons induced a lower viral load and impaired activation in WT microglia and thereby reduced lethality in mice. Smaducin-6, which blocks interactions between Peli1 and IRAK1, RIP1, and IKKepsilon, did not inhibit WNV-triggered microglia activation. Collectively, our findings suggest a nonimmune regulatory role for Peli1 in promoting microglia activation during WNV infection and identify a potentially novel host factor for flavivirus cell entry and replication. PMID- 30247161 TI - Gastric Carbon Dioxide Insufflation Can Lead to Misleading Capnography Trace During Esophageal Intubation. PMID- 30247162 TI - Never Say Never: The Use of Nitric Oxide in Patients With Obstructed Pulmonary Veins: A Case Report. AB - Pulmonary vein stenosis (PVS) is a progressive disease with pulmonary hypertension (PH) as a major cause of morbidity and mortality. Traditional management of PH with inhaled nitric oxide (iNO) is typically avoided in PVS patients because, while iNO may reduce pulmonary vascular resistance, PH persists as pulmonary blood flow increases in the presence of a downstream resistive lesion. We report 3 cases with primary PVS and PH in which iNO was used to successfully decrease mean pulmonary artery pressures with clinical improvement. Based on this experience, we suggest that iNO can be used to treat PH in select patients with PVS. PMID- 30247160 TI - Inflammation, Active Fibroplasia, and End-stage Fibrosis in 172 Biliary Atresia Remnants Correlate Poorly With Age at Kasai Portoenterostomy, Visceral Heterotaxy, and Outcome. AB - Published histologic studies of the hilar plate or entire biliary remnant at the time of Kasai portoenterostomy (KHPE) have not provided deep insight into the pathogenesis of biliary atresia, relation to age at surgery, prognosis or the basis for successful drainage. We report detailed histologic findings in 172 centrally reviewed biliary remnants with an average of 6 sections per subject. Active lesions were classified as either necroinflammatory (rare/clustered in a few subjects) or active concentric fibroplasia with or without inflammation (common). Inactive lesions showed bland replacement by collagen and fibrous cords with little or no inflammation. Heterogeneity was common within a given remnant; however, relatively homogenous histologic patterns, defined as 3 or more inactive or active levels in the hepatic ducts levels, characterized most remnants. Homogeneity did not correlate with age at KHPE, presence/absence of congenital anomalies at laparotomy indicative of heterotaxy and outcome. Remnants from youngest subjects were more likely than older subjects to be homogenously inactive suggesting significantly earlier onset in the youngest subset. Conversely remnants from the oldest subjects were often homogenously active suggesting later onset or slower progression. More data are needed in remnants from subjects <30 days old at KHPE and in those with visceral anomalies. Prevalence of partially preserved epithelium in active fibroplastic biliary atresia lesions at all ages suggests that epithelial regression or injury may not be a primary event or that reepithelialization is already underway at the time of KHPE. We hypothesize that outcome after KHPE results from competition between active fibroplasia and reepithelialization of retained, collapsed but not obliterated lumens. The driver of active fibroplasia is unknown. PMID- 30247163 TI - Ambulatory anesthesia: what's new in 2018. PMID- 30247164 TI - Anesthesiologists should bring in their expertise during the early postoperative period to improve surgical outcome. PMID- 30247165 TI - Family planning as a contributor to environmental sustainability: weighing the evidence. AB - PURPOSE OF REVIEW: To highlight recent evidence that family planning, readily accessible to all who seek it and exercised as a human right, can contribute to environmental sustainability. As global concern increases about the health of our planet, better understanding of the role family planning programs play in maintaining a sustainable environment could bolster public and policymaker support for access to family planning. RECENT FINDINGS: A recent Worldwatch Institute review of scientific literature (FPESA) exploring this relationship covered two potential cause-effect pathways: one demographic, one personal. Although nonconfirmatory, a decade of reviewed studies overwhelmingly supported the hypothesis that family planning benefits environmental sustainability. A complementary review by the Evidence Project of population, health and environment projects over a similar time period strongly suggests that transdisciplinary efforts including family planning can yield multiple benefits - health, empowerment, economic and environmental. SUMMARY: Cumulative research generally supports but cannot confirm the thesis that family planning contributes to efforts to achieve environmental sustainability. This does not equate to no relationship but rather a lack of adequate methodologies. For research on complex relationships like this, novel research designs may prove more effective. PMID- 30247166 TI - Evaluation and management of defecatory dysfunction in women. AB - PURPOSE OF REVIEW: To summarize the current recommendations for the evaluation and management of defecatory dysfunction in women and highlight key relationships between defecatory dysfunction and other pelvic floor disorders, including pelvic organ prolapse, fecal incontinence, and voiding dysfunction. RECENT FINDINGS: Conservative measures including lifestyle modifications, pharmacotherapy, and biofeedback continue to be the mainstay of treatment with newer therapies emerging. Physiologic testing and/or radiologic imaging should be considered for those who fail conservative therapy or are clinically complex. Surgical management is appropriate for carefully selected patients with anatomic causes of defecatory dysfunction. Further research is needed on surgical outcomes and patient expectations. SUMMARY: Pelvic floor disorders, including defecatory dysfunction, have a significant societal impact and are highly prevalent among women. Given its potential complexity, a broader focus is needed when evaluating women with defecatory symptoms and effective treatment may require multidisciplinary care. PMID- 30247167 TI - Postoperative Opioid Prescribing Following Gynecologic Surgery for Pelvic Organ Prolapse. AB - OBJECTIVES: The aim of this study was to evaluate postoperative pain scores, quantity of prescribed opioids at hospital discharge, and need for additional opioid prescriptions among women undergoing surgical treatment of pelvic organ prolapse. METHODS: Institutional billing data were used to identify all patients undergoing pelvic reconstructive surgery between January 1, 2012, and May 30, 2017. Inpatient records were utilized to obtain prescription data (reported in oral morphine equivalents for standardization) and pain scores. The cohort was organized by surgical approach (open, endoscopic, vaginal), number of concomitant procedures, and patient age stratified by decade. These factors were then matched to postoperative pain scores, amount of opioid prescribed at discharge, and number of subsequent opioid refills. Pain scores and opioid use were also compared for correlation. RESULTS: One thousand eight hundred thirty patients underwent surgical treatment of pelvic organ prolapse and met criteria for study participation. A significant decrease in pain scores, mean oral morphine equivalents prescribed, and opioid refill rates was seen with increasing patient age by decade regardless of surgical approach. Pain scores were significantly different only between patients undergoing vaginal surgery with 0 concomitant procedures versus 1 or more concomitant procedures. Finally, pain scores were directly correlated to the amount of opioid prescribed. CONCLUSIONS: Pain scores, opioid prescription amounts, and refills varied by patient age and surgical approach but were unaffected by concomitant procedures. Further work in correlating pain scores to opioid utilization is needed to ensure appropriate prescribing patterns and reduce risks of opioid dependence and diversion. PMID- 30247168 TI - Patient-Initiated Telephone Calls in the Postoperative Period After Female Pelvic Reconstructive Surgery. AB - OBJECTIVE: The aim of this study was to evaluate reasons and factors associated with patient calls in the postoperative period after female pelvic medicine and reconstructive surgery. METHODS: A retrospective review using electronic medical records was performed on consecutive patients who underwent surgery within our academic female pelvic medicine and reconstructive surgery practice during a 6 month period. Calls after postoperative discharge until first scheduled postoperative visit were included. Reasons and number of calls were tabulated. Clinical and surgical factors were extracted. Continuous data were evaluated with a Student t test or analysis of variance; categorical data were evaluated with a chi test. P < 0.05 was considered significant. RESULTS: During the designated period, 302 patients underwent surgery, and 173 (57.3%) patients made 345 calls (mean +/- SD, 2.0 +/- 1.5 calls). Reasons were categorized under 6 distinct domains: bowel, pain, activity, medication regimen, urinary, and bleeding. The most frequent concern within each domain was constipation (11.6%), abdominal pain (6.4%), physical activity (8.7%), pain regimen (14.5%), urinary catheter related (13.3%), and vaginal bleeding (12.1%), respectively. A greater number of phone calls were recorded among patients discharged home with catheters (P = 0.015), and patients who underwent posterior colporrhaphy (P = 0.005) and retropubic urethropexy (P = 0.014). Patients discharged with home nursing (11, 6.4%) demonstrated a significantly higher number of phone calls (3.8 +/- 2.5, P < 0.001). Evaluations were required for 37% of callers. Twelve patients were seen in the emergency department, of whom 3 (1.7%) were readmitted to the hospital. CONCLUSIONS: Postoperative patient-initiated telephone calls after pelvic reconstructive surgery are common. Bowel-, urinary-, and medication-based phone calls account for the highest frequency and volume. PMID- 30247169 TI - Recent progress in porcine islet isolation, culture and engraftment strategies for xenotransplantation. AB - PURPOSE OF REVIEW: Xenotransplantation of porcine islets is a realistic option to restore beta-cell function in type 1 diabetic patients. Among other factors, such as islet donor age (fetal, neonatal and adult) and genotype (wild type and genetically modified), choice of the transplantation site, and immune protection of the islets, efficient strategies for islet isolation, culture and engraftment are critical for the success of islet xenotransplantation. RECENT FINDINGS: Neonatal porcine islets (NPIs) are immature at isolation and need to be matured in vitro or in vivo before they become fully functional. Recent developments include a scalable protocol for isolation of clinically relevant batches of NPIs and a stepwise differentiation protocol for directed maturation of NPIs. In addition, different sources of mesenchymal stem cells were shown to support survival and functional maturation of NPIs in vitro and in various transplantation models in vivo. SUMMARY: A plethora of different culture media and supplements have been tested; however, a unique best culture system for NPIs is still missing. New insights, for example from single-cell analyses of islets or from stem cell differentiation toward beta cells may help to optimize culture of porcine islets for xenotransplantation in an evidence-based manner. PMID- 30247170 TI - What will it take before a bioengineered heart will be implanted in patients? AB - PURPOSE OF REVIEW: Heart transplantation is the only curative treatment option for end-stage heart failure. However, a shortage of donor organs is a major limitation of this approach. Regenerative medicine targets the goal of increasing the number of available hearts for transplantation. In this review, we highlight the state of the art of building a bioartificial heart. We summarize the components needed, the hurdles, and likely translational steps to make the dream of transplanting a totally functional bioartificial heart a possibility. RECENT FINDINGS: The therapies being developed in regenerative medicine aim not only to repair, but also to regenerate or replace failing tissues and organs. The engineering of bioartificial hearts utilizing patient-derived cells could theoretically solve the two main complications of heart transplantations: graft rejection and lifelong immunosuppression. Although many hurdles remain, scientists have reached a point in which some of these hurdles have been overcome. Decellularized heart scaffolds have emerged over the past decade as one of the most promising biofabrications. Two possible options for organ scaffolds exist: nontransplantable human hearts and porcine hearts. The use of these scaffolds could lead to the availability of an unlimited number of transplantable organs. The current challenge remains improving processes required for recellularization - including those for cells, bioreactors, and physiologic conditioning. Researchers should focus to solve these hurdles and pave the way toward the dream of in-vivo bioengineered heart maturation. SUMMARY: Regenerative medicine has emerged as one of the most promising fields of translational research and has the potential to both minimize the need for donor organs and increase their availability. Meeting the challenge of implanting a totally functional bioengineered heart lies in solving multiple issues simultaneously. Dwarfing the technical hurdles, cost is the largest barrier to success. The scientific hurdles mainly involve scaling up and scaling out of laboratory cell processes, building bioreactors, and delivering cells into every needed region of an organ scaffold. Maintaining sterility and quantifying readiness of the nascent organs are also critical for success. PMID- 30247171 TI - Wine consumption and colorectal cancer risk: a meta-analysis of observational studies. AB - There were inconsistent results with respect to the correlation between consumption of wine and the development of colorectal cancer (CRC). We carried out a meta-analysis to investigate this issue. We included observational studies on the aforementioned relationship according to a literature search of Embase and Pubmed from inception till 28 February 2017. The summary relative risk (SRR) and 95% confidence intervals (CI) were calculated using a random-effects model. A total of eight case-control and nine cohort studies were identified, involving 12 110 CRC cases. The study showed that wine drinking was not associated with any greater risk for CRC (SRR=0.99, 95% CI: 0.89-1.10; Pheterogeneity<0.001) compared with nondrinkers. The subgroup analyses indicated that null associations were observed in men and women for colon and rectal cancer. Neither light to moderate (<2 drinks/day; SRR=0.93, 95% CI: 0.80-1.08, I=69.2%) nor heavy (>=2 drinks/day; SRR=1.00, 95% CI: 0.86-1.16, I=39.9%) consumption of wine was associated statistically with CRC risk. This meta-analysis suggests that any wine consumption was not associated with the risk of CRC. Null associations were shown in men and women for colon and rectal cancer. PMID- 30247172 TI - Preoperative Evaluation of Pancreatic Fibrosis and Lipomatosis: Correlation of Magnetic Resonance Findings With Histology Using Magnetization Transfer Imaging and Multigradient Echo Magnetic Resonance Imaging. AB - OBJECTIVES: The purpose of this study was to evaluate the diagnostic performance of magnetization transfer (MT) imaging and multigradient echo magnetic resonance imaging (MRI) to quantify pancreatic fibrosis and lipomatosis in patients before pancreatoduodenectomy for postoperative risk stratification with histopathology as the reference standard. MATERIALS AND METHODS: Twenty-four patients (age, 68 +/- 8 years, 16 males) prospectively underwent quantitative MT imaging using a 2 dimensional gradient echo sequence with and without MT prepulse and multigradient echo imaging on a 3 T MRI 1 day before pancreatoduodenectomy due to adenocarcinoma of the pancreatic head region (n = 20), neuroendocrine tumor (n = 3), or intraductal papillary mucinous neoplasm (n = 1). Magnetization transfer ratio (MTR) and proton density fat fraction (PDFF) were measured in pancreatic tail (PT) and at the resection margin (RM). Histopathologically, pancreatic fibrosis was graded as mild, moderate, or severe (F1-F3), lipomatosis was graded as 0% to 10%, 11% to 30%, and greater than 30% fat deposition (L1-L3). In addition, MTR and histopathologic fibrosis was assessed in pancreatic adenocarcinoma. Mann-Whitney U test and Spearman correlation were used. RESULTS: Patients with advanced pancreatic fibrosis (F3) showed a significantly higher MTR compared with the F1 group at the RM and PT (38 +/- 4 vs 32.3 +/- 1.6, P = 0.018 and 39.7 +/- 5.5 vs 31.2 +/- 1.7, P = 0.001). Spearman correlation coefficient of MTR and fibrosis grade was r = 0.532 (P = 0.011) and 0.554 (P = 0.008), respectively. Pancreatic parenchyma with advanced fat deposition (L2-L3) showed significantly higher PDFF compared with lipomatosis grade L1 (RM: P = 0.002 and PT: P = 0.001). Proton density fat fraction of pancreatic parenchyma exhibited a moderate and significant correlation with histopathologic lipomatosis grade (RM: r = 0.668 and PT: r = 0.707, P < 0.001). Magnetization transfer ratio was significantly higher in pancreatic adenocarcinoma compared with pancreatic parenchyma (44 +/- 5.5 vs 36.0 +/- 4.4 and 37.4 +/- 5.4, P = 0.004). CONCLUSIONS: Multiparametric MRI of the pancreas including MTR and PDFF maps may provide quantitative and noninvasive information on pancreatic fibrosis and lipomatosis before surgery. PMID- 30247173 TI - The impact of integrated care for people with chronic conditions on hospital and emergency department utilization: a rapid review. AB - AIM: Integrated care commonly involves provision of comprehensive community-based care for people with chronic conditions. It is anticipated that implementation of integrated care, with a proactive approach to management of chronic conditions, will reduce reliance on hospital and emergency department (ED) services. The aim of this rapid review was to summarize the best available evidence on the impact of integrated care for patients with chronic conditions on hospital and ED utilization and investigate trends in outcomes over time. METHODS: Given the large body of literature available on this topic, this rapid review considered existing systematic reviews and meta-analyses that included adults with chronic conditions. Any model of integrated care that involved management of patients across the continuum of care, with the aim to provide more care in community settings, was considered for inclusion. A search of PubMed, CINAHL, Google Advanced, and websites of international healthcare provider organizations was conducted to locate relevant published and gray literature. RESULTS: A total of 13 systematic reviews were included. Overall, evidence suggests that integrated care may reduce the risk of hospitalization, with reviews including patients with diverse chronic conditions showing a 19% reduction. Integrated care appears effective in reducing readmissions for patients with heart failure, with an absolute risk reduction of 8% for first and 19% for subsequent rehospitalization. For ED presentations, evidence indicates that integrated care has no effect overall but may reduce ED visits for patients aged 65 years or more. For patients with chronic obstructive pulmonary disease, integrated care was associated with reductions in length of stay ranging from 2.5 to 4 days. Studies with shorter follow-up, from 3 to 12 months, in general appeared to show a greater impact of integrated care than studies with longer follow-up of 18 months or more. CONCLUSION: The evidence identified suggests integrated care generally reduces utilization of hospital services. In some instances, there were no differences observed between integrated care and usual care, but no included reviews reported increased utilization of these services. The impact of integrated care may be greater in the short-term, given the ultimate deterioration associated with advanced chronic disease which may negate any long-term benefits. PMID- 30247174 TI - Impact of new direct-acting antiviral drugs on hepatitis C virus-related decompensated liver cirrhosis. AB - BACKGROUND: The benefits of treatment of hepatitis C virus with direct-acting antiviral drugs in patients with decompensated liver cirrhosis (DLC) are still unclear. AIM: To evaluate the degree of improvement in hepatic decompensation events and quality of life (QOL) in treated patients with DLC. PATIENTS AND METHODS: One hundred and fifty patients with hepatitis C virus-related DLC were included; 75 of these patients received treatment (group I) [sofosbuvir (SOF) with either daclatasvir or ledipasvir for 24 weeks without ribavirin (RBV) or for 12 weeks with RBV] and 75 patients did not receive treatment as a comparable group (group II). Patients who achieved a sustained virological response at 12 weeks were assessed in terms of decompensation events, model for end-stage liver disease score, Child-Turcotte-Pugh score, biochemical changes, and QOL (applied on Mcguill QOL questionnaire) before starting treatment and 6 months after end of treatment, and were compared with untreated patients. RESULTS: Forty-two (56%) patients received SOF/daclatasvir for 24 weeks without RBV and 19 (25.3%) patients received SOF/ledipasvir for 24 weeks without RBV. The model for end stage liver disease score improved in treated patients (mean change -1.73), but worsened in untreated patients (mean change +11.8) before and after 6 months. Also, the Child-Turcotte-Pugh score improved significantly (P<0.001). Serum albumin, prothrombin time, bilirubin, alpha-fetoprotein, and alanine aminotransferase improved in treated patients (P<0.001). Health-related QOL improved in treated patients (mean change +17.65) and worsened in untreated ones (mean change -18.68; P<0.001). CONCLUSION: Treated patients with DLC showed an improvement in liver tests and health-related QOL. Longer durations of follow-up for decompensation events are needed. PMID- 30247175 TI - Evaluating the Managing Medicines for People With Dementia Website Version 2. AB - The Managing Medicines for People With Dementia version 2 website was developed in three languages, English, Italian, and Macedonian, to assist informal caregivers in the task of managing medications. Medication management is a complex task with potentially high stakes health outcomes, including hospitalization and death. A mixed-methods evaluation was carried out. A survey was available to site users and Web log data were collected over a 3-month period. Subsequently, the quality and suitability of the information and readability and usability of the Web site were evaluated. Focus groups and interviews were conducted with end users from all three language groups. Data collected from the evaluation surveys during the pilot test showed that users were generally satisfied with site usability (77%). The results of the readability testing indicate that future versions could be improved. Feedback from the focus groups and interviews was generally positive. The use of multiple methodologies provided comprehensive testing that is likely to have identified the majority of usability issues. Ways in which the site can be maintained with up-to-date information and be promoted to the target population, informal carers, need to be explored. PMID- 30247176 TI - Trends in Extracorporeal Membrane Oxygenation Growth in the United States, 2011 2014. AB - The use of extracorporeal membrane oxygenation (ECMO) has grown rapidly in recent years. We sought to describe the rate of ECMO use in the United States, regional variation in ECMO use, the hospitals performing ECMO, and the primary payers for ECMO patients. Detailed data were obtained using the Healthcare Cost and Utilization Project (HCUPnet) summaries of State Inpatient Databases from 34 participating states for the years 2011-2014. The ECMO rates over time were modeled, overall and within subcategories of age group, bed size, hospital ownership, teaching status, and payer type. During the study period, the overall rate of ECMO use increased from 1.06 (1.01, 1.12) to 1.77 (1.72, 1.82) cases per 100,000 persons per year (p = 0.005). The rate of ECMO use varied significantly by region. Most ECMO patients are cared for at large hospitals, and at private, not-for-profit hospitals with teaching designation. The most common payer was private insurance; a minority of patient were uninsured. The use of ECMO increased significantly during the study period, but regional variation in the rate of ECMO use suggests that this technology is not being uniformly applied. Further research is warranted to determine why differences in ECMO use persist and what impact they have on patient outcomes. PMID- 30247177 TI - QRS Shortens after Left Ventricular Assist Device Implantation. PMID- 30247178 TI - Pediatric Femoral Arterial Cannulations in Extracorporeal Membrane Oxygenation: A Review and Strategies for Optimization. AB - Venoarterial (VA) extracorporeal membrane oxygenation (ECMO) is a treatment strategy for pediatric patients with cardiopulmonary failure. Femoral cannulation is a commonly used technique for obtaining central access in children and adolescents despite high rates of vascular complications. Ischemic limb complications remain one of the most common problems facing survivors of femoral VA ECMO. Our aim is to review the literature on femoral cannulation in children and to present a review of techniques for femoral cannula placement, decannulation, and arterial repair to help minimize and ameliorate complications related to cannulation. We performed a literature review for pediatric ECMO cannulation, complications, and femoral artery repair in pediatric patients. We focused on the management of arterial and ischemia-related complications during and after ECMO support via femoral cannulation. Vascular complications are not infrequent for patients requiring ECMO support via femoral cannulation. As such, judicious distal perfusion monitoring as well as augmentation of distal flow are important strategies during mechanical support. The use of distal perfusion catheters can be used to minimize the risk of limb ischemia. As femoral cannulation grows more popular in pediatric patients, strategies for arterial repair are essential to ensure extremity perfusion upon decannulation. PMID- 30247179 TI - Electroencephalogram Modifications Associated With Atypical Strict Antipsychotic Monotherapies. AB - BACKGROUND: Antipsychotics produce electroencephalogram (EEG) modifications and increase the risk of epileptic seizure. These modifications remain sparsely studied specifically for atypical antipsychotics. In this context, our study focuses on EEG modifications associated with atypical strict antipsychotic monotherapies. METHODS: Electroencephalogram recordings of 84 psychiatric patients treated with atypical antipsychotics in strict monotherapy (clozapine, n = 22; aripiprazole, n = 22; olanzapine, n = 17; risperidone, n = 9; quetiapine, n = 8; risperidone long-acting injection, n = 4; and paliperidone long-acting injection, n = 2) were analyzed. The modifications were ranked according to both slowing and excitability scores. RESULTS: Electroencephalogram modifications (in 51 subjects, 60.71%) were graded according to 4 stages combining general slowing and sharp slow waves and/or epileptiform activities. The presence of sharp or epileptiform activities was significantly greater for clozapine (90.9%) compared with other second-generation antipsychotics (aripiprazole, 50%; olanzapine, 58.8%; quetiapine, 37.5%; risperidone, 44.4%). Age, duration of disease progression, and diagnosis were not associated as risk factors. Electroencephalogram modifications were associated with lower doses for treatment with quetiapine but not for specific antipsychotics. Electroencephalogram modifications and severe excitability were associated with higher chlorpromazine equivalent doses. CONCLUSIONS: Atypical antipsychotics (clozapine, aripiprazole, quetiapine, olanzapine, and risperidone) induce EEG modifications, and these are significantly greater for clozapine and appear dependent on chlorpromazine equivalent dose. No encephalopathy was observed in these antipsychotic monotherapies, whatever dose. PMID- 30247180 TI - A Waves in Diabetic Neuropathy: Pathophysiology and Neurographic Images. AB - INTRODUCTION: To evaluate the presence of A waves in diabetic neuropathy, we designed a retrospective observational study recruiting patients with type II diabetes and chronic diabetic distal sensorimotor polyneuropathy. METHODS: We recruited 238 patients of both sexes aged between 41 and 89 years. Neurography was undertaken on two bilateral upper (median and ulnar) and lower (peroneal and tibial) limb nerves. As controls, we considered that neurographs performed bilaterally on the same nerves of 40 healthy subjects. RESULTS: In addition to neurographic changes typical of chronic distal sensorimotor neuropathy, patients had a 32.77% incidence of A waves, mostly found in the tibial (16.38%) and peroneal (8.8%) nerves. Among controls, A waves were found only in the tibial nerve of a single subject (2.5%). Chi-square test with Yates correction to compare the two percentages (32.77% of patients and 2.5% of healthy subjects): 13.98, P = 0.0002, highly significant. CONCLUSIONS: We postulate that demyelination may be the site of backfiring or slowing of nerve conduction velocity, explaining the appearance of A waves in their different varieties. Implementing the search for A waves in routine neurographic examination can be a useful option for the diagnosis of neuropathy and the prediction of possible latent neuropathic processes. PMID- 30247181 TI - Understanding Respiratory Restrictions as a Function of the Scoliotic Spinal Curve in Thoracic Insufficiency Syndrome: A 4D Dynamic MR Imaging Study. AB - BACKGROUND: Over the past 100 years, many procedures have been developed for correcting restrictive thoracic deformities which cause thoracic insufficiency syndrome. However, none of them have been assessed by a robust metric incorporating thoracic dynamics. In this paper, we investigate the relationship between radiographic spinal curve and lung volumes derived from thoracic dynamic magnetic resonance imaging (dMRI). Our central hypothesis is that different anteroposterior major spinal curve types induce different restrictions on the left and right lungs and their dynamics. METHODS: Retrospectively, we included 25 consecutive patients with thoracic insufficiency syndrome (14 neuromuscular, 7 congenital, 4 other) who underwent vertical expandable prosthetic titanium rib surgery and received preimplantation and postimplantation thoracic dMRI for clinical care. We measured thoracic and lumbar major curves by the Cobb measurement method from anteroposterior radiographs and classified the curves as per Scoliosis Research Society (SRS)-defined curve types. From 4D dMRI images, we derived static volumes and tidal volumes of left and right lung, along with left and right chest wall and left and right diaphragm tidal volumes (excursions), and analyzed their association with curve type and major curve angles. RESULTS: Thoracic and lumbar major curve angles ranged from 0 to 136 and 0 to 116 degrees, respectively. A dramatic postoperative increase in chest wall and diaphragmatic excursion was seen qualitatively. All components of volume increased postoperatively by up to 533%, with a mean of 70%. As the major curve, main thoracic curve (MTC) was associated with higher tidal volumes (effect size range: 0.7 to 1.0) than thoracolumbar curve (TLC) in preoperative and postoperative situation. Neither MTC nor TLC showed any meaningful correlation between volumes and major curve angles preoperatively or postoperatively. Moderate correlations (0.65) were observed for specific conditions like volumes at end-inspiration or end-expiration. CONCLUSIONS: The relationships between component tidal volumes and the spinal curve type are complex and are beyond intuitive reasoning and guessing. TLC has a much greater influence on restricting chest wall and diaphragm tidal volumes than MTC. Major curve angles are not indicative of passive resting volumes or tidal volumes. LEVEL OF EVIDENCE: Level II-diagnostic. PMID- 30247182 TI - Parental emotion and pain control behaviour when faced with child's pain: the emotion regulatory role of parental pain-related attention-set shifting and heart rate variability. AB - This study investigated the moderating role of parental pain-related attention set shifting and heart rate variability (HRV) for parental distress and pain control behaviour when faced with their child's pain. Participants were 54 schoolchildren and one of their parents. Parental HRV was assessed at study commencement followed by a cued-switching task indexing parental ability to flexibly shift attention between pain-related and neutral attentional sets. In a subsequent phase, parents observed their child perform a cold-pressor task [CPT], allowing for assessment of parental pain control behavior (indexed by latency to stop their child's CPT performance) and parental distress-assessed through self report following observation of child CPT performance. Findings indicated that parental facilitated attentional shifting (ie, engage) towards a pain-related attentional set contributed to higher levels of pain control behaviour when faced with increasing levels of child facial display of pain. Pain control behaviour among parents who demonstrated impeded attentional shifting to a pain-related attentional set was equally pronounced regardless of low or high levels of child pain expression. Parental ability to shift attention away (ie, disengage) from a pain-related set to a neutral set did not impact findings. Results further indicated that although high levels of parental HRV buffer the impact of child facial pain display on parental emotional distress and pain control behaviour, low levels of HRV constitute a risk factor for higher levels of parental distress and pain control behaviour when faced with increased child facial pain display. Theoretical/clinical implications and further research directions are discussed. PMID- 30247183 TI - Outcome of High-risk Langerhans Cell Histiocytosis (LCH) in Egyptian Children, Does Intermediate-dose Methotrexate Improve the Outcome? AB - High-risk multisystem organ (RO+) Langerhans cell histiocytosis (LCH) has the least survival. We present the outcome of RO+ LCH in a pediatric single center. Fifty RO+ LCH patients, treated between 07/2007 and 07/2015, were retrospectively analyzed. Induction vinblastine (VBL) and prednisone (PRED) with intermediate dose methotrexate (idMTX) was adopted until 2012 (n=20) wherein idMTX was omitted (n=30). The 3-year overall survival (OS) of MTX and non-MTX groups was 75% and 63%, respectively, P=0.537, while the event-free survival (EFS) was 36.9% and 13.2%, respectively, P=0.005. At week 12 of induction, "better status" was obtained in 80% of those receiving MTX, and 55% of those who were not. The statistically significant factors associated with both poor OS and EFS were trihemopoietic cytopenias, hepatic dysfunction, tri RO+ combination, and single induction. The factors associated with disease progression (DP) on induction were trihemopoietic cytopenias, hepatic dysfunction, and lack of idMTX, while those for disease reactivations (REA), the season of autumn/winter, lung disease, male sex, and idMTX were the associated factors. The 1-year OS was remarkably affected with the occurrence of DP versus REA versus none, wherein it was 47%, 93%, and 95%, respectively, P=0.001. In conclusion, idMTX is associated with better EFS. DP on induction remains of dismal prognosis in relation to disease REA afterwards. Risk stratification should highlight the role of trihemopoietic cytopenias, hepatic dysfunction, tri RO+, central nervous system risk site, and lung association. PMID- 30247184 TI - Sagittal Imbalance Does Not Influence Cup Anteversion in Total Hip Arthroplasty Dislocations. AB - STUDY DESIGN: Retrospective Cohort. SUMMARY OF BACKGROUND DATA: Studies have shown that lumbar fusion procedures are associated with an increased risk of total hip arthroplasty (THA) dislocation. Some have speculated that the increased risk of dislocation is caused by mispositioning of the acetabular component because of spinal sagittal imbalance. Unfortunately, the exact relationship between spinal sagittal balance and cup orientation is unknown. OBJECTIVE: The objective of this study was to investigate the effect of spinal sagittal alignment on cup anteversion in THA dislocation. METHODS: Patients that suffered a THA dislocation were retrospectively identified. Cross-table lateral hip radiographs were used to measure cup anteversion with normal acetabular anteversion defined as 15+/-10 degrees. Lateral lumbar spine radiographs were used to measure lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt, and sacral slope. Normal sagittal balance was defined as a PI-LL difference of <10 degrees. The association between sagittal balance and THA characteristics was assessed using Pearson correlation coefficient, chi analysis, and independent t tests. RESULTS: A total of 29 patients had full radiographic imaging. Among these patients, 62.1% dislocated following a primary THA and 37.9% following a revision THA. Abnormal spinal sagittal balance was identified in 20 patients (69.0%). Eight (27.6%) patients had undergone spinal fusion prior to THA. Abnormal cup anteversion was demonstrated in 51.7% of all patients. Presence of a spinal fusion was not associated with cup anteversion, sagittal balance, or time to dislocation. Sagittal balance was not associated with direction of dislocation, time to dislocation, or cup anteversion. CONCLUSIONS: A majority of patients with a THA dislocation demonstrated abnormal sagittal balance. However, sagittal balance was not associated with acetabular cup anteversion. As such, the relationship between spinal deformity and dislocation rates after THA may not be because of inaccurate cup orientation. PMID- 30247185 TI - Spinopelvic Parameters and Sagittal Alignment of Symptomatic Degenerative Adult Spinal Disorder Patients With 6 Lumbar Vertebrae. AB - STUDY DESIGN: This was a cross-sectional, observational study. OBJECTIVE: The main objectives of this study were to observe the prevalence of a true L6 among patients with symptomatic adult spinal degeneration, and to evaluate similarities of their radiographic spinopelvic parameters to L5 patients. SUMMARY OF BACKGROUND DATA: Spinopelvic parameter values used for diagnosis and surgical planning are different between individuals with 5 or 6 lumbar vertebrae. The difference has not been studied in patients with symptomatic spinal degenerative conditions. MATERIALS AND METHODS: A total of 775 consecutive symptomatic patients with degenerative spinal disorders were classified as having 5 or 6 lumbar vertebrae in full spine radiographs. Pelvic incidence minus lumbar lordosis (PI-LL), sagittal vertical axis (SVA), pelvic tilt, and T1 pelvic angle were measured in 3 groups: sacral (L5 and L6s) and L6 upper endplate (L6e). Oswestry Disability Index (ODI) was obtained. RESULTS: In total, 715 (92.3%) patients had L5 and 60 (7.7%) had L6. LL values were comparable between the L5 and L6s (P=0.355) and SVA between all groups (P=0.869). Only SVA had excellent concordance correlation (rhoc=0.91) between the L6s and L6e groups. PI-LL had significantly different values (P<0.001 all groups) and distributions between L5 and L6s (P=0.038), and L6s and L6e (P<0.001) groups. In patients with severe disability (ODI>40%) the parameters that deteriorate with increasing degeneration (pelvic tilt, T1 pelvic angle, SVA, LL, PI-LL) were not significantly different between L5 and L6s groups unlike patients with ODI<40% while PI remained similarly different (P<0.001). PI and LL had a multivariate relationship in L6 patients computable as regression model equation: PI (sacrum)=-0.92*LL (L6e)+0.91*LL (sacrum) +1.11*PI (L6e)+10.81 (R=0.88). CONCULSIONS: L6 variant is fairly common. The radiographic L6 parameters were different from L5 except for SVA and values of patients with severe disability measured from sacrum. PI and LL have a mathematic relationship in L6 patients. The cutoff values for radiographic modifiers need further studies combining radiology and clinical outcome. LEVEL OF EVIDENCE: Level III. PMID- 30247186 TI - Electrophysiological Function of the Lumbar Multifidus and Erector Spinae Muscles in Elderly Patients With Chronic Low Back Pain. AB - STUDY DESIGN: This was a cross-sectional electrophysiological study. OBJECTIVE: The main objective of this study was to evaluate electrophysiological activation of lumbar multifidus (LM) and erector spinae (ES) in elderly patients with chronic low back pain (CLBP) classified by LBP developmental mechanisms. SUMMARY OF BACKGROUND DATA: Local and global muscles that function independently for stabilization and moment production, respectively, are crucial for stability and mobility of the lumbar spine. There is little research conducted on the electrophysiological functions of the LM as a local muscle and the ES as a global muscle in the lumbar spine, and their interrelation in patients with CLBP. MATERIALS AND METHODS: Elderly patients aged 65 years and above, with CLBP were assigned into motion-induced LBP (49 patients) or walking-induced LBP cohorts (57 patients), and compared with a control group (53 patients without LBP). Electrophysiological activation of the LM and ES was performed using surface electromyography (EMG) and mechanomyography (MMG) during lumbar extension and flexion. Electromechanical coupling efficiency (EMCE) was calculated using the ratio of MMG to EMG. RESULTS: EMG and MMG amplitudes in the LM tended to be lower in patients with LBP than in the control group. EMG and MMG amplitudes in the ES tended to be higher in patients with LBP than in the control group. EMCE was significantly higher in both the LM and ES during lumbar extension and flexion in the motion-induced LBP cohort than in the walking-induced LBP cohort; however, ES dominance was seen in the motion-induced LBP cohort, both in lumbar extension and flexion, according to the EMCE ratio. CONCLUSIONS: ES dominance was seen in the motion-induced LBP cohort, both in lumbar extension and flexion, according to the EMCE ratio. Subgrouping of patients according to the induction of LBP seems to be important for CLBP treatment, and the electrophysiological assessment for the deep and superficial back muscles may be beneficial to elderly patients. PMID- 30247187 TI - Pedicled Flaps Versus Free Flaps for Back Reconstruction. AB - BACKGROUND: Back reconstructions using a flap are relatively rare, and clinical reports on such reconstructions are few. We analyzed whether a pedicled flap or free flap was best for treating back defects and established a simplified algorithm for flap selection. METHODS: We retrospectively analyzed the cases of 22 patients who underwent flap reconstructions for the back between July 2000 and August 2016. We extracted data on the operative time, defect size, patients' height and body weight, and reoperation, and each defect size was calculated as a percentage in relation to the body surface area (BSA). We compared these values between both flap types using univariate analysis. In addition, reconstructions using pedicled flaps were classified as single pedicled flap and combination pedicled flap reconstructions. The reasons for reoperation were also reviewed. RESULT: Seventeen patients underwent reconstructions using pedicled flaps, and 5 patients underwent reconstructions using free flaps. The operative time and the percentage of defect size in relation to the BSA were significantly lower when using pedicled flaps than when using free flaps (P = 0.002, P = 0.046, respectively). There was no significant difference in terms of the rate of reoperation (P = 0.16) between the 2 types of reconstructions. The operative time was also significantly shorter when using combination pedicled flaps than when using free flaps. However, there was no significant difference in terms of the percentage of defect size in relation to the BSA between combination pedicled flaps and free flaps. Reoperation was necessary because of flap necrosis in pedicled flaps and skin graft necrosis in free flaps. CONCLUSIONS: Our results demonstrated that pedicled flaps should be the first choice for back reconstruction, independent of the defect size, reoperation rate, and reason for reoperation. This is because the operation time required is significantly lower, which benefits patients and surgeons. Free flaps can be used when pedicled flaps cannot be used efficiently. PMID- 30247188 TI - A New Surgical Method of Correcting Abnormal Cartilage in Mild or Moderate Cryptotia. AB - OBJECTIVE: This study aimed to introduce a new technique for the correction of mild or moderate types of cryptotia. METHODS: During January 2010 to March 2015, patients with cryptotia deformities came to our hospital and were enrolled in this study. A new surgical method of correction of abnormal cartilage by combining irregular incisions in auricle malformation and directional transplantation of auricular cartilage was designed. The irregular Z shaped flap was designed to correct the skin defects. In the ipsilateral cavum conchae, the auricular cartilage strut was harvested, followed with irregular cartilage incisions and cartilage transplantation. RESULTS: After correction, the corrected auricles in 3 cases showed natural contour with deep auriculotemporal sulcus and no conspicuous scars. The antihelix folding and backward rotation deformities of the auricular cartilage were corrected, and the morphology of superior and inferior crus of the antihelix was not destroyed. One case appeared necrotic. During 1 year of follow-up, there was no incidence of recurrence or revision. CONCLUSIONS: The combined techniques for correction of abnormal cartilage are simple and easy to operate, and the reconstructed auricles show natural contour without conspicuous scars. The new technique is suitable for correction of mild and moderate cryptotia. PMID- 30247189 TI - Nasal Reconstruction: Current Overview. AB - The nose, with its conspicuous location, intricate convexities, and delicate 3 dimensional structure, continues to challenge the reconstructive surgeon. Today, there are a myriad of options available for reconstruction. The practitioner must take into account the location of the defect as well as the components needed to be restored. This article addresses the current practices in nasal reconstruction, including the different strategies for skin coverage, nasal lining, and structural support. We discuss both the newest techniques as well as basic principles of this long-standing procedure. PMID- 30247190 TI - Body Wall Reconstruction for Conjoined Twins: Our Experience and Lessons Learned. AB - BACKGROUND: Conjoined twinning is a rare congenital malformation, and the resultant huge body wall defects after separation of conjoined twins represent a real challenge to surgeons. METHODS: From 2004 to 2009, authors performed body wall reconstruction for 2 pairs of thoraco-omphalopagus twins and 1 pair of ischiopagus tetrapus twins. Before separation, the techniques of tissue expansion and tractive training were adopted to acquire sufficient skin for final coverage. After separation, the defects of thoracic cage and abdominal myofascial system were repaired with synthetic materials. The closure of the wounds was performed with artificial skin temporarily or by the use of local flaps in 1 stage. RESULTS: The first pair of thoraco-omphalopagus twins died of circulatory and respiratory failure after emergency surgery, and the other 2 pairs of conjoined twins survived. The second pair of thoraco-omphalopagus twins had wound dehiscence and partial flap necrosis after surgery. The expanded polytetrafluoroethylene mesh in 1 sister of the ischiopagus twins was removed because of local infection 4 years after surgery. CONCLUSIONS: Compressive anatomical understandings and advanced skills in plastic surgery are required for body wall reconstruction in the separation of conjoined twins. In addition, the multidisciplinary team approach has an important role for obtaining satisfactory final surgical outcome. PMID- 30247191 TI - Skin-Reducing Mastectomy and Direct-to-Implant Breast Reconstruction With Submuscular-Dermal-Mesh Pocket. AB - BACKGROUND: Despite skin-sparing mastectomy techniques have significantly improved reconstructive options and aesthetic outcomes, patients with large and ptotic breasts remain a challenging group to treat satisfactorily. The Wise pattern skin-reducing mastectomy (SRM) has been designed for this kind of patients but is not without morbidity. To improve safety, the authors reviewed their experience with a modified SRM and immediate 1-stage implant-based breast reconstruction, using a synthetic absorbable mesh combined with a dermal flap. METHODS: A retrospective review was undertaken to identify women with medium to large ptotic breast and medium minimally ptotic breast who had undergone SRM and direct-to-implant breast reconstruction using definitive anatomical gel implant, de-epithelialized dermal flap, and absorbable synthetic mesh, between October 2014 and December 2016. Patient demographics were queried, and complication rates, aesthetic outcomes, and patients satisfaction were assessed. RESULTS: Sixty-two procedures of SRM were performed in 56 patients. Forty-five women received contralateral symmetrization. Twenty-one overall complications occurred in 16 patients. Statistical correlation between risk factors and complications onset was assessed. Body mass index resulted the most substantial risk factor (P = 0.0028) for developing complications, whereas preoperative chemotherapy (P = 0.0050) and comorbidities (P = 0.0117) played a decent role. Smoking attitude (P = 0.1122), age (P = 0.9990), and implant weight (P = 0.1583) did not result as significant risk factors. The reconstructive outcomes were good to excellent in 92.8%, with patient satisfaction ranking very to highly satisfied in 84%. CONCLUSIONS: The authors' series suggests that SRM with direct-to-implant breast reconstruction can be easily performed when an appropriate SRM pattern is designed, providing complete implant coverage with submuscular-dermal-mesh pocket. PMID- 30247192 TI - Reply to Letter to the Editor Following 'A Combination Flap for Nasal Defect Reconstruction'. PMID- 30247193 TI - Vascularized Fibula Epiphysis Transfer for Pediatric Extremity Reconstruction: A Systematic Review and Meta-analysis. AB - BACKGROUND: Vascularized fibula epiphysis transfer for pediatric extremity reconstruction intends to preserve growth potential. However, few cases are reported, and outcomes are poorly characterized. METHODS: Systematic review was performed through a MEDLINE search using keywords "pediatric" or "epiphyseal" and "vascularized fibula." Patients were divided into upper extremity or lower extremity groups. Functional and growth outcomes were assessed, and indications, pedicle, complications, and need for secondary surgery were recorded. RESULTS: Twenty publications with 62 patients were included. Mean age was 5.9 years, and mean follow-up was 5.8 years. Indications included sarcoma (60%), congenital deformity (21%), trauma (13%), and infection (6%). Anterior tibial pedicle was most common (63%) and was associated with significantly improved growth outcomes compared with the peroneal pedicle (23%; P < 0.001). Fifty-three patients underwent upper extremity reconstruction, with the most common complication being fracture (35%) and most common secondary surgery flap salvage (7%). Among upper extremity patients, full function was achieved in 25% and impaired function in 75%. Full growth was observed in 63% of patients, partial growth in 31%, and no growth in 4%. Nine patients underwent lower extremity reconstruction, with the most common complication being fracture (22%) and most common secondary surgery derotational osteotomy (22%). Among lower extremity patients, full function was achieved in 44% and impaired function in 56%. Full growth was observed in 56% of patients, partial growth in 22%, and no growth in 22%. CONCLUSIONS: Vascularized fibula epiphysis transfer can accomplish full long-term growth and function. However, complications, revision surgery, and chronic impairment are common. PMID- 30247194 TI - The Regenerative Capability of the Urodele Amphibians and Its Potential for Plastic Surgery. AB - Newts and salamanders, both urodele amphibians, are the only vertebrates with tremendous regenerative potency throughout their lifetime. In contrast to the limited regenerative potential of most mammals, including humans, they can regenerate an entire limb after amputation and many other structures of their bodies, whereas humans mainly respond to injury by the formation of a scar. The intention of plastic surgery is to restore function of injured body parts, with the highest principle to replace "like with like." Despite tremendous improvements in surgical techniques over the last century, the remaining drawbacks include the availability of autologous tissue for transfer to restore extensive tissue loss. Here, some regenerative features of the urodeles are reviewed, in particular wound healing, nerve and limb regeneration, and their potential impact for reconstructive surgery are discussed. With a detailed molecular and cellular understanding of the urodele regeneration processes in combination with recent advances in tissue engineering, new perspectives for plastic surgery and especially improvements in regards to tissue regeneration are opened. PMID- 30247196 TI - Acceptance of Vascularized Composite Allotransplantation (Face and Hand Transplant) in Singapore. AB - Recent advancements and innovations in the burgeoning field of vascularized composite allotransplantation has enabled face and hand transplant to become a reality in the Western world. Plastic surgeons from the United States, France, and Spain have since performed vascularized composite allotransplantation as a novel therapeutic option in patients suffering from severe facial disfigurement and limb loss. Results have demonstrated remarkable functional and esthetic outcomes with improvements in the immense psychological, social, and emotional burdens that can arise in these patients. Despite the success of existing national solid organ transplant programs, face and hand transplant has yet to be established in this region. The specific aims of this study were to assess the attitudes and amount of risk Singaporeans are willing to accept towards receiving or donating face and hand transplants; and hence ultimately evaluate the feasibility of establishing such a program in Singapore. PMID- 30247195 TI - Quality of Life of Patients After Immediate or Delayed Autologous Breast Reconstruction: A Multicenter Study. AB - INTRODUCTION: It is known that breast reconstruction improves quality of life (QoL) in women who underwent mastectomy. Previous studies showed that autologous immediate breast reconstruction is as safe as delayed breast reconstruction. However, there is not much known about the influence of the timing of the breast reconstruction on QoL. Therefore, this study aims to assess the effect of timing of the breast reconstruction on QoL, using the BREAST-Q questionnaire. METHODS: A total of 543 patients aged 18 years or older who underwent deep inferior epigastric perforator flap reconstruction after mastectomy (for prophylactic or oncological reasons) at least 12 months ago were selected in 3 hospitals in the Netherlands and invited to complete the BREAST-Q. Mean QoL outcomes were compared between patients who underwent immediate or delayed breast reconstruction. Furthermore, QoL outcomes were compared with recently published normative data of the BREAST-Q. RESULTS: Patients who underwent immediate reconstruction reported higher scores on satisfaction with psychosocial well-being, sexual well-being, physical well-being of the chest, and physical well-being of the abdomen. Patients who underwent delayed reconstruction reported higher scores on satisfaction with breasts, outcome, and nipples. However, after adjusting for potentially influencing factors, none of the differences were significant. Compared with the normative BREAST-Q data, both of our patient groups reported higher scores on satisfaction with breasts, psychological well-being, and sexual well-being, whereas they reported lower scores on satisfaction with physical well being of the chest and the abdomen. CONCLUSIONS: This study suggests that patients who underwent immediate or delayed deep inferior epigastric perforator flap breast reconstruction have comparable QoL more than 1 year after surgery, irrespective of the timing of the breast reconstruction. PMID- 30247197 TI - Pain-specific Reactions or Indicators of a General Stress Response? Investigating the Discriminant Validity of Five Well-established Neonatal Pain Assessment Tools. AB - OBJECTIVES: There are many neonatal pain assessment tools available nowadays. However, systematic psychometric comparisons between tools are still lacking, particularly those comparing tools regarding their ability to differentiate between pain and stressful procedures. The aim of the present study was to psychometrically compare five widely used neonatal pain assessment tools: Neonatal Facial Coding System-Revised (NFCS-R), Premature Infant Pain Profile Revised (PIPP-R), Neonatal Pain, Agitation and Sedation Scale (N-PASS) Neonatal Infant Pain Scale (NIPS) and Bernese Pain Scale Neonates (BPSN). METHODS: Two coders applied all pain assessment tools to videos of 42 neonates who were videotaped during a pain and a stressful procedure. RESULTS: Interrater reliability and relative convergent validity were high and internal consistency good to excellent for all five assessment tools. All tools could discriminate between painful and stressful events. Tools differed regarding their overall effect sizes as well as their items' effect sizes. Behavioral items tended to have larger effect sizes than physiological ones. Yet, even effect sizes of items from one behavioral category differed greatly, which may be due to different operationalization coding schemes. DISCUSSION: Given that the tools investigated in the present study appear to be fairly comparable psychometrically, aspects of their clinical utility are discussed and ways of improvement identified. PMID- 30247198 TI - The Magnitude of Offset Analgesia as a Measure of Endogenous Pain Modulation in Healthy Subjects and Patients with Chronic Pain - A Systematic Review and Meta analysis. AB - OBJECTIVE: Offset analgesia (OA) is a test paradigm increasingly used to estimate endogenous pain modulation characterized by a disproportionally profound analgesia after a small decrease of a heat stimulus. This systematic review and meta-analysis examined the magnitude and difference of OA in healthy subjects and chronic pain patients. METHODS: Controlled trials, case-control studies, cross sectional studies, case-series or other observational studies evaluating the effect of a +/-1 degrees C offset trial in healthy controls and patients with chronic pain were searched in PubMed, Web of Science, CINAHL, PEDro, PsycINFO and Cochrane CENTRAL. An additional hand search was conducted. Studies fulfilling the eligibility criteria were independently assessed for methodological quality with the Downs & Black scale by two reviewers. RESULTS: Twenty-six studies (healthy n=758; chronic pain n=134) were included in the qualitative synthesis and twelve in meta-analyses (healthy n=366; chronic pain n=73). A significant difference between offset and constant temperature trials was found for continuous pain intensity rating immediately after a 1 degrees C decrease in temperature (-0.46 [visual analogue scale, 0-10]; 95%CI -0.75, -0.17; P=0.002), but not after a fixed time period of 5 seconds. Furthermore, a significant difference of the magnitude of OA between chronic pain patients and healthy controls was calculated (-29.9%; 95%CI -40.3, -19.5]; P<0.00001). DISCUSSION: Results indicate that pain free subjects show a larger OA response when rating pain continuously compared to patients with chronic pain. PMID- 30247199 TI - Evaluation of Digital Face Recognition Technology for Pain Assessment in Young Children. AB - OBJECTIVES: Accurate assessment of pain in young children is challenging. An Emotion Application Programing Interface (API) can analyze and report 8 emotions from facial images. Each emotion ranges between 0 (no correlation) to 1 (greatest correlation). We evaluated correlation between the Emotion API with the FLACC scale (face, lets, activity, cry, and consolability) among children younger than 6 years old during blood sampling. METHODS: Prospective pilot exploratory study in children during blood sampling. Pictures with facial expressions were uploaded to Emotion API program. Primary outcome was the correlation coefficient between FLACC scale and emotions. Secondary outcomes included maximal correlation of each emotion for 3 pictures-before, during and after needle penetration; and the average of each emotion for 9 pictures-4 before, 1 during and 4 after needle penetration to the skin. RESULTS: A total of 77 children were included. During needle penetration, SADNESS was significantly correlated (0.887, P<0.05), and NEUTRAL was negative correlated with the FLACC scale (-0.841; P<0.05). The maximal correlation of each emotion showed increase in SADNESS and decrease in NEUTRAL emotions during, compared to before, needle penetration. Similar findings were observed when the average of each emotion was compared during to before needle penetration. DISCUSSION: During a blood test procedure, young children show higher SADNESS and lower NEUTRAL emotions as reported by the Emotion API. This software program may be useful in reporting emotions related to pain in young children, and more research is needed to compare its validity, reliability and real-time application compared to the FLACC scale. PMID- 30247200 TI - Contribution of Loss of Large Fiber Function to Pain in 2 Samples of Oncology Patients. AB - OBJECTIVES: Numbness associated with neuropathic pain suggests the loss of function in myelinated, large diameter sensory neurons. The purpose of this study was to examine the relationships between pain severity and subjective (ie, severity of numbness) and objective (ie, loss of light touch sensations, vibration thresholds) measures of loss of large fiber function in adult survivors with chemotherapy-induced peripheral neuropathy (CIPN, n=426) and breast cancer patients with persistent postsurgical pain (n=80). MATERIAL AND METHODS: For both samples, average pain and numbness were evaluated using a 0 to 10 numeric rating scale. Loss of light touch sensations in the hands and feet of patients with CIPN and in the upper arm of patients at 5 and 6 months following breast cancer surgery were assessed using Semmes Weinstein monofilaments. Loss of vibration in the hands and feet of patients with CIPN was assessed using a biothesiometer. Pearson Product Moment correlation coefficients were calculated between average pain and the number or percentage of sites with loss of light touch sensations, mean vibration thresholds, and the severity of numbness. RESULTS: For both pain conditions, average pain scores were significantly correlated with objective measures of large fiber function (r=0.12 to 0.34; all P<0.05) and numbness (r=0.22 to 0.52; all P<0.008). DISCUSSION: Our findings, in 2 independent samples of oncology patients, suggest that loss of function of myelinated, large diameter fibers contributes to the severity of neuropathic pain. PMID- 30247201 TI - Oropharyngeal Bacterial Colonization after Chlorhexidine Mouthwash in Mechanically Ventilated Critically Ill Patients. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Oropharyngeal care with chlorhexidine to prevent ventilator associated pneumonia is currently questioned, and exhaustive microbiologic data assessing its efficacy are lacking. The authors therefore aimed to study the effect of chlorhexidine mouthwash on oropharyngeal bacterial growth, to determine chlorhexidine susceptibility of these bacteria, and to measure chlorhexidine salivary concentration after an oropharyngeal care. METHODS: This observational, prospective, single-center study enrolled 30 critically ill patients under mechanical ventilation for over 48 h. Oropharyngeal contamination was assessed by swabbing the gingivobuccal sulcus immediately before applying 0.12% chlorhexidine with soaked swabs, and subsequently at 15, 60, 120, 240, and 360 min after. Bacterial growth and identification were performed, and chlorhexidine minimal inhibitory concentration of recovered pathogens was determined. Saliva was collected in 10 patients, at every timepoint, with an additional timepoint after 30 min, to measure chlorhexidine concentration. RESULTS: Two hundred fifty bacterial samples were analyzed and identified 48 pathogens including Streptococci (27.1%) and Enterobacteriaceae (20.8%). Oropharyngeal contamination before chlorhexidine mouthwash ranged from 10 to 10 colony-forming units (CFU)/ml in the 30 patients (median contamination level: 2.5.10 CFU/ml), and remained between 8.10 (lowest) and 3.10 CFU/ml (highest count) after chlorhexidine exposure. These bacterial counts did not decrease overtime after chlorhexidine mouthwash (each minute increase in time resulted in a multiplication of bacterial count by a coefficient of 1.001, P = 0.83). Viridans group streptococci isolates had the lowest chlorhexidine minimal inhibitory concentration (4 [4 to 8] mg/l); Enterobacteriaceae isolates had the highest ones (32 [16 to 32] mg/l). Chlorhexidine salivary concentration rapidly decreased, reaching 7.6 [1.8 to 31] mg/l as early as 60 min after mouthwash. CONCLUSIONS: Chlorhexidine oropharyngeal care does not seem to reduce bacterial oropharyngeal colonization in critically ill ventilated patients. Variable chlorhexidine minimal inhibitory concentrations along with low chlorhexidine salivary concentrations after mouthwash could explain this ineffectiveness, and thus question the use of chlorhexidine for ventilator-associated pneumonia prevention. PMID- 30247202 TI - Non-steady State Modeling of the Ventilatory Depressant Effect of Remifentanil in Awake Patients Experiencing Moderate-to-severe Obstructive Sleep Apnea. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Evidence suggests that obstructive sleep apnea promotes postoperative pulmonary complications by enhancing vulnerability to opioid induced ventilatory depression. We hypothesized that patients with moderate-to severe obstructive sleep apnea are more sensitive to remifentanil-induced ventilatory depression than controls. METHODS: After institutional approval and written informed consent, patients received a brief remifentanil infusion during continuous monitoring of ventilation. We compared minute ventilation in 30 patients with moderate-to-severe obstructive sleep apnea diagnosed by polysomnography and 20 controls with no to mild obstructive sleep apnea per polysomnography. Effect site concentrations were estimated by a published pharmacologic model. We modeled minute ventilation as a function of effect site concentration and the estimated carbon dioxide. Obstructive sleep apnea status, body mass index, sex, age, use of continuous positive airway pressure, apnea/hypopnea events per hour of sleep, and minimum nocturnal oxygen saturation measured by pulse oximetry in polysomnography were tested as covariates for remifentanil effect site concentration at half-maximal depression of minute ventilation (Ce50) and included in the model if a threshold of 6.63 (P < 0.01) in the reduction of objective function was reached and improved model fit. RESULTS: Our model described the observed minute ventilation with reasonable accuracy (22% median absolute error). We estimated a remifentanil Ce50 of 2.20 ng . ml (95% CI, 2.09 to 2.33). The estimated value for Ce50 was 2.1 ng . ml (95% CI, 1.9 to 2.3) in patients without obstructive sleep apnea and 2.3 ng . ml (95% CI, 2.2 to 2.5) in patients with obstructive sleep apnea, a statistically nonsignificant difference (P = 0.081). None of the tested covariates demonstrated a significant effect on Ce50. Likelihood profiling with the model including obstructive sleep apnea suggested that the effect of obstructive sleep apnea on remifentanil Ce50 was less than 5%. CONCLUSIONS: Obstructive sleep apnea status, apnea/hypopnea events per hour of sleep, or minimum nocturnal oxygen saturation measured by pulse oximetry did not influence the sensitivity to remifentanil-induced ventilatory depression in awake patients receiving a remifentanil infusion of 0.2 MUg . kg of ideal body weight per minute. PMID- 30247203 TI - Patterns of treatment and BRAF testing with immune checkpoint inhibitors and targeted therapy in patients with metastatic melanoma presumed to be BRAF positive. AB - Patients with BRAF V600 (BRAF) mutated metastatic melanoma are eligible for therapy with both immune checkpoint inhibitors and targeted therapies, making treatment choice a complex decision. The present study aimed to describe patterns of treatment with immunotherapy and targeted therapy and BRAF testing in patients with metastatic melanoma presumed to have BRAF mutations (BRAF+) in the years following the approval of the newer generation of immune checkpoint inhibitors and targeted therapies (2014-2016). Two large US commercial claims databases [Truven Health Analytics MarketScan and IQVIA Real-World Data Adjudicated Claims USA (IQVIA RWD Adjudicated Claims - USA)] were used. Patients were presumed BRAF+ if they received at least 2 lines of therapy of which at least 1 included targeted therapy. Sequence of lines of therapy and regimens used in first (1L), second (2L), and third (3L), as well as timing of BRAF testing by sequence of therapy were described. In the Truven sample (n=162), targeted therapy was used by 66% in 1L and by 54% in 2L, and 62% had a BRAF test; in the IQVIA RWD Adjudicated Claims - USA sample (n=247), targeted therapy was used by 62% in 1L and by 50% in 2L, and 68% had a BRAF test. Among those with a claim for a BRAF test prior to 1L, over two-thirds were initiated on targeted therapy. These findings suggest that the rate of BRAF testing remained low in the years following the approval of BRAF-targeted regimens for metastatic disease. Given the recently approved adjuvant treatment options for stage III melanoma, improving the rates of BRAF testing becomes increasingly important.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 30247204 TI - Deep and Durable Response With Combination CTLA-4 and PD-1 Blockade in Mismatch Repair (MMR)-proficient Endometrial Cancer. AB - Immune checkpoint inhibitors have shown promising efficacy in multiple cancer types. The recent food and drug administration approval of PD-1 inhibitors for mismatch repair (MMR)-deficient tumors has extended use of these treatments to all cancer types, and programmed death ligand 1 (PD-L1) positivity in tumor tissue has also been shown to predict susceptibility to immunotherapy. Despite these advances, the response to immunotherapy in endometrial cancer remains poorly understood. Here, we describe the case of a patient with MMR-proficient, PD-L1-negative stage IV endometrial cancer who exhibited a strong clinical response to combination PD-1 and CTLA-4 inhibition. She showed deep and durable ongoing partial response to nivolumab and ipilimumab that has persisted after 12 months. This case indicates the potential existence of an endometrial cancer subtype that is sensitive to immune checkpoint blockade based on mechanisms other than those driven by MMR deficiency or PD-L1 positivity. Improved understanding of immunotherapy in advanced endometrial cancer is clearly needed and offers the potential to significantly enhance patient outcomes. PMID- 30247206 TI - Testing Differential Associations Between Smoking and Chronic Disease Across Socioeconomic Groups: Pooled Data From 15 Prospective Studies. AB - BACKGROUND: For the same quantity of cigarettes smoked, relative to more affluent people, socioeconomically disadvantaged people have higher levels of smoking biomarkers. This may be ascribed to inhaling cigarette smoke more deeply and more frequently and/or choosing higher tar-containing brands. We investigated whether this increased tobacco load, as captured using cotinine measurements, is associated with a greater risk of mortality in lower social groups. METHODS: We used Cox proportional hazards models stratified by socioeconomic position to calculate hazard ratios in a pooled sample of 15 English and Scottish prospective cohort studies (N = 81,476). RESULTS: During a mean (SD) follow-up of 10.3 (4.4) years, 8234 deaths occurred. Risk of total mortality (hazard ratio; 95% confidence interval) for smokers relative to never-smokers in the high (2.5; 2.1, 3.1), intermediate (2.1; 1.8, 2.4), and low (2.0; 1.9, 2.2) educational groups did not differ markedly (P for interaction=0.61). Similar findings emerged when using cause-specific outcomes and occupational social class and housing tenure as socioeconomic indices. CONCLUSION: Contrary to our hypothesis, we found no indication that chronic disease mortality associated with smoking was higher in disadvantaged people. PMID- 30247205 TI - The Association Between Childhood Leukemia and Population Mixing: An Artifact of Focusing on Clusters? AB - BACKGROUND: Studies investigating the population-mixing hypothesis in childhood leukemia principally use two analytical approaches: (1) nonrandom selection of areas according to specific characteristics, followed by comparisons of their incidence of childhood leukemia with that expected based on the national average; and (2) regression analyses of region-wide data to identify characteristics associated with the incidence of childhood leukemia. These approaches have generated contradictory results. We compare these approaches using observed and simulated data. METHODS: We generated 10,000 simulated regions using the correlation structure and distributions from a United Kingdom dataset. We simulated cases using a Poisson distribution with the incidence rate set to the national average assuming the null hypothesis that only population size drives the number of cases. Selection of areas within each simulated region was based on characteristics considered responsible for elevated infection rates (population density and inward migration) and/or elevated leukemia rates. We calculated effect estimates for 10,000 simulations and compared results to corresponding observed data analyses. RESULTS: When the selection of areas for analysis is based on apparent clusters of childhood leukemia, biased assessments occur; the estimated 5-year incidence of childhood leukemia ranged between zero and eight per 10,000 children in contrast to the simulated two cases per 10,000 children, similar to the observed data. Performing analyses on region-wide data avoids these biases. CONCLUSIONS: Studies using nonrandom selection to investigate the association between childhood leukemia and population mixing are likely to have generated biased findings. Future studies can avoid such bias using a region-wide analytical strategy. See video abstract at, http://links.lww.com/EDE/B431. PMID- 30247207 TI - Decreasing the Time to Administration of First Dose of Antibiotics in Children With Severe Sepsis. AB - OBJECTIVES: To measure difference in median time to antibiotic administration in severe sepsis before and after making process changes and clinical outcomes such as duration of hospitalization and mortality. METHODS: The study was carried out in the emergency department in children <17 years of age with severe sepsis/septic shock. In phase 1, data were collected and reasons for delayed antibiotic administration were identified. Following this, process changes like creating a triage tool, re-enforcing the severe sepsis protocol and increasing the number of nurses were made to correct the delay. In phase 2, we measured outcomes to compare the effect of the process changes. RESULTS: A total of 28 and 13 children each were included during phase 1 and phase 2 of the study respectively. The median interquartile range time to administration of antibiotics from the time of admission decreased significantly from 50 minutes (18, 65) to 20 minutes (15, 20) (p = .02). Duration of hospital stay was longer in phase 1 as compared to phase 2 (12 days vs. 6 days). However, the difference was not statistically significant (p = .1). CONCLUSIONS: Use of a triage tool, severe sepsis protocol, and increasing the number of nurses resulted in earlier recognition and administration of first dose of antibiotics in children with severe sepsis. PMID- 30247209 TI - 68Ga PET Imaging in Patients With Neuroendocrine Tumors: A Systematic Review and Meta-analysis. AB - PURPOSE: The aim of this study was to systematically review the literature to assess the role of Ga PET imaging in neuroendocrine tumors (NETs). MATERIALS AND METHODS: The literature was searched using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews databases through OVID. Studies comparing PET or PET/CT with conventional imaging in the initial diagnosis, staging and restaging, assessment of treatment response, and routine surveillance of NETs were deemed eligible for inclusion. Risk of bias and applicability concerns were assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. RESULTS: Twenty two studies met the inclusion criteria. For the initial diagnosis of NETs, PET or PET/CT had a pooled sensitivity of 91% (95% confidence interval [CI], 85%-94%) and a pooled specificity of 94% (95% CI, 86%-98%). In the setting of staging and restaging, the sensitivity of PET or PET/CT for detecting primary and/or metastatic lesions ranged from 78.3% to 100%, whereas specificity ranged from 83% to 100%. Change in management occurred in 45% (95% CI, 36%-55%) of the cases, with majority of the changes involving surgical planning and patient selection for peptide receptor radionuclide therapy. CONCLUSIONS: Ga PET or PET/CT is recommended for initial diagnosis where conventional testing remained equivocal, for staging of patients with localized primary and/or limited metastasis where definitive surgery is planned, to determine somatostatin receptor status and suitability for peptide receptor radionuclide therapy, and for staging of patients where detection of occult disease will alter treatment options and decision making. PMID- 30247208 TI - 68Ga-Prostate-Specific Membrane Antigen PET/CT and 18F-FDG PET/CT of Primary Signet Ring Cell Breast Adenocarcinoma. AB - Primary signet ring cell adenocarcinoma of the breast is a rare neoplasm. Similar to other mucinous neoplasms, it has low FDG avidity and poor prognosis compared with the traditional ductal/lobular carcinomas. We present a case of a 40-year old woman with signet ring cell adenocarcinoma and skeletal fluorosis showing higher uptake of Ga-prostate-specific membrane antigen in the primary lesion and the metastatic sites compared with F-FDG on PET/CT imaging. Additionally, diffuse increased prostate-specific membrane antigen uptake was noticed in the entire skeleton, likely due to skeletal fluorosis. PMID- 30247211 TI - A Case of Radioactivity Concentrated in Orbital Implant in 99mTc-MDP Bone Scan and SPECT/CT. AB - A 27-year-old woman, who has received a hydroxyapatite orbital implant in the right eye due to a trauma 6 years ago, was newly diagnosis with left breast invasive ductal carcinoma. Tc-MDP bone scan showed an increased radiotracer accumulation in the right orbit and SPECT/CT confirmed the focal accumulation at the site of the implant, without any sign of local malignant lesions or orbital infection. Radionuclide imaging could provide certain useful information in diagnosing or differential diagnosing orbital disease. PMID- 30247210 TI - Uptake of Prostate-Specific Membrane Antigen-Targeted 18F-DCFPyL in Cerebral Radionecrosis: Implications for Diagnostic Imaging of High-Grade Gliomas. AB - Recent PET imaging of glioblastoma multiforme and other high-grade gliomas using prostate-specific membrane antigen (PSMA)-targeted small-molecule radiotracers suggests a role for these agents in diagnostic imaging of recurrent/residual tumor and that PSMA-targeted endoradiotherapies may provide a new approach to therapy for patients with these difficult-to-treat tumors. We present a case of cerebral radionecrosis demonstrating PSMA-targeted radiotracer uptake. Our findings may represent a potential pitfall and limitation to the diagnostic application of PSMA-targeted agents for high-grade gliomas. PMID- 30247212 TI - Thyroid Metastasis From Hepatocellular Carcinoma Visualized by 18F-FDG PET/CT Imaging. AB - Thyroid metastasis from hepatocellular carcinoma (HCC) is very rare. We present a case of a 41-year-old man with a markedly elevated serum alpha-fetoprotein (2,297 ng/mL) and a left neck mass 6 months after a hepatolobectomy for a primary HCC. F FDG PET/CT imaging showed a focal uptake in the left thyroid lobe corresponding to a mass. The patient underwent a left hemithyroidectomy. Subsequent pathology confirmed HCC metastasis to the thyroid. PMID- 30247213 TI - Renal replacement therapy in the ICU: intermittent hemodialysis, sustained low efficiency dialysis or continuous renal replacement therapy? AB - PURPOSE OF REVIEW: Severe acute kidney injury in the ICU setting often requires renal replacement therapy (RRT). Intermittent hemodialysis (IHD), hybrid forms of RRT such as sustained low-efficiency dialysis (SLED), as well as continuous renal replacement therapy (CRRT) are the three common modalities of extracorporeal RRT used in the adult ICU setting in developed countries. This review summarizes recently published data regarding comparisons of these three RRT modalities on clinical outcomes (e.g., mortality and recovery of renal function) in severe acute kidney injury (AKI) patients. RECENT FINDINGS: There is still controversy on the superiority of one RRT modality over another in terms of clinical outcomes in patients with AKI in ICU. Although there is increasing acceptance that CRRT should be used in hemodynamic unstable patients, its survival advantages over IHD remains unproven because of inadequate evidence from suitably powered randomized controlled trials (RCTs). Moreover, CRRT does not show superiority to intermittent renal replacement therapy (IRRT) in hemodynamic stable patients. Although patients receiving sustained low-efficiency dialysis appear to have lower mortality than CRRT, its survival benefit is largely derived from observational studies and is confounded by selection bias. Current literature supports no differences in mortality among the three RRT modalities. However, the effect of choice of RRT modality on short-term and long-term renal outcomes need further studies, especially larger RCTs and longer duration of follow-up. SUMMARY: There is lack of solid evidence showing superiority of any mode of RRT in patients with severe AKI in terms of patient survival. However, based on observational data, IHD treatment of AKI may delay renal recovery. Patients' hemodynamic status, coexisting medical conditions, local expertise, and availability of staff and resources as well as potential effect on long-term renal outcomes should be taken into consideration when selecting modalities of RRT for adult ICU patients. PMID- 30247214 TI - Regional citrate anticoagulation for continuous renal replacement therapy. AB - PURPOSE OF REVIEW: The delivery of an effective dialysis dose in continuous renal replacement therapy (CRRT) depends on adequate anticoagulation of the extracorporeal circuit. In most patients, either systemic heparin anticoagulation (SHA) or regional citrate anticoagulation (RCA) is used. This review will outline the basics and rationale of RCA and summarize data on safety and efficacy of both techniques. RECENT FINDINGS: The basic principle of RCA is to reduce the level of ionized calcium in the extracorporeal circuit via infusion of citrate. This way, effective anticoagulation restricted to the extracorporeal circuit is achieved. SHA and RCA were compared in a variety of studies. RCA significantly prolonged filter lifetime, reduced bleeding complications and provided excellent control of uremia and acid-base status. RCA was also safe in the majority of patients with impaired liver function, whereas caution must be exerted in those with severe multiorgan failure and persistent hyperlactatemia. SUMMARY: RCA per se is safe and effective for anticoagulation of CRRT. Compared to SHA, efficacy of anticoagulation is improved and adverse effects are reduced. RCA can be recommended as the anticoagulation mode of choice for CRRT in most ICU patients. PMID- 30247215 TI - An update on membranes and cartridges for extracorporeal blood purification in sepsis and septic shock. AB - PURPOSE OF REVIEW: This review aims to summarize the most recent advances on different membranes and cartridges used for extracorporeal blood purification in critically ill patients with sepsis or septic shock. RECENT FINDINGS: Despite positive signals from experimental, cases and small clinical studies, blood purification showed no distinct morbidity and mortality benefit in large clinical trials. SUMMARY: None of the discussed specific membranes or cartridges can currently be recommended as sole adjunctive treatment in sepsis and septic shock. Any available technique should be timely initiated and adapted to the patient's status. Sickest patients seem to benefit more from blood purification. Patient selection is thus of crucial importance and may be optimized by focusing on disease severity and degree of organ failure. Measurement of endotoxin activity and plasma procalcitonin levels can support the selection process but ideal cutoff values need to be defined. Well-designed prospective randomized clinical trials assessing or comparing the various available membranes and cartridges are eagerly awaited. PMID- 30247216 TI - Continuous renal replacement therapy: understanding circuit hemodynamics to improve therapy adequacy. AB - PURPOSE OF REVIEW: The utilization of continuous renal replacement therapy (CRRT) increases throughout the world. Technological improvements have made its administration easier and safer. However, CRRT remains associated with numerous pitfalls and issues. RECENT FINDINGS: Even if new-generation CRRT devices have built-in safety features, understanding basic concepts remains of primary importance. SUMMARY: CRRT circuits' maximum recommended lifespan (72 h) can often not be achieved. Such early artificial kidney failures are typically related to two processes: circuit clotting and membrane clogging. Although these processes are to some degree inevitable, they are facilitated by poor therapy management. Indeed, the majority of device-triggered alarms are associated with blood pump interruption, which through blood stasis, enhance clotting and clogging. If the underlying issue is not adequately managed, further alarms will rapidly lead to prolonged stasis and complete circuit clotting or clogging making its replacement mandatory. Hence, rapid recognition of issues triggering alarms is of paramount importance. Because most alarms are related to circuit's hemodynamics, a thorough understanding of these concepts is mandatory for the staff in charge of delivering the therapy.This review describes CRRT circuits, measured and calculated pressures and the way their knowledge might improve therapy adequacy. PMID- 30247217 TI - Oxygen therapy in acute resuscitation. AB - PURPOSE OF REVIEW: Avoidance and treatment of hypoxaemia is a cornerstone of acute resuscitation and yet the optimal approach to oxygen therapy in the acute care setting is uncertain. The aim of this review is to appraise recent evidence relating to the provision of supplemental oxygen to adult patients with acute illnesses with a focus on the resuscitation phase. RECENT FINDINGS: Recent findings generally support the notion that exposure to hyperoxaemia is associated with adverse outcomes in acutely ill adults with a range of diseases and raise the possibility that liberal provision of oxygen may cause harm. Several ongoing multicentre randomized trials aim to assess the effects of different oxygen therapy regimens on patient outcomes to provide a foundation for evidence-based recommendations regarding the use of supplemental oxygen in Intensive Care Unit patients. SUMMARY: At present, evidence is lacking to support routine liberal oxygen administration in acutely ill patients and, in most circumstances, a reasonable approach is to titrate supplemental oxygen to achieve an arterial oxygen saturation measured by pulse oximetry (SpO2) of 92-96% with the aim of avoiding both hypoxaemia and hyperoxaemia. PMID- 30247218 TI - Corticosteroids administration to improve outcome in high-risk surgical patients. AB - PURPOSE OF REVIEW: Postoperative complications are major healthcare problems and are associated with a reduced short-term and long-term survival. Major surgery is associated with a predictable and usually transient systemic inflammatory response (SIRS), depending on the magnitude of the surgical trauma. An excessive SIRS syndrome participates to the development of postoperative organ dysfunction, infection and mortality. Corticosteroids may decrease the postsurgical SIRS. This review aims to discuss recent findings on the use of corticosteroids in major surgery. RECENT FINDINGS: In acute medicine, several lines of evidence have shown that moderate doses of corticosteroids decrease the excessive inflammatory response, without inducing immunosuppression. Evidences from several meta analyses suggest that intraoperative administration of corticosteroids during major surgery decreases postoperative infectious complications, without significant risk of anastomotic leakage, or bleeding complications. SUMMARY: At present, no large randomized controlled trial has been performed in patients undergoing major noncardiac surgery. However, despite the widespread use of corticosteroids to improve analgesia and reduce postoperative nausea or vomiting, concerns continue to be raised about their safety. At present, the safety profile for using short course of moderate dose of corticosteroids is good, but glycaemic control and natremia should be carefully monitored during the postoperative period. PMID- 30247219 TI - Resuscitation fluids. AB - PURPOSE OF REVIEW: Intravenous fluid administration is a fundamental therapy in critical care, yet key questions remain unanswered regarding optimal fluid composition and dose. This review evaluates recent evidence regarding the effects of fluid resuscitation on pathophysiology, organ function, and clinical outcomes for critically ill patients. RECENT FINDINGS: Recent findings suggest that intravenous fluid composition affects risk of kidney injury and death for critically ill adults. Generally, the risk of kidney injury and death appears to be greater with semisynthetic colloids compared with crystalloids, and with 0.9% sodium chloride compared with balanced crystalloids. Whether a liberal, restrictive, or hemodynamic responsiveness-guided approach to fluid dosing improves outcomes during sepsis or major surgery remains uncertain. SUMMARY: As evidence on fluid resuscitation evolves, a reasonable approach would be to use primarily balanced crystalloids, consider 2-3 l for initial fluid resuscitation of hypovolemic or distributive shock, and use measures of anticipated hemodynamic response to guide further fluid administration. PMID- 30247220 TI - Identifying Incidence of and Risk Factors for Fluoroscopy-Guided Lumbar Puncture and Subsequent Persistent Low-Pressure Syndrome in Patients With Idiopathic Intracranial Hypertension. AB - BACKGROUND: To explore the incidence of and potential risk factors for developing persistent low-pressure syndrome after lumbar puncture (LP) in patients with idiopathic intracranial hypertension (IIH), as measured by use of blood patches. METHODS: A retrospective chart review was conducted of patients with definitively diagnosed IIH by clinical examination and LP, comparing them to patients with multiple sclerosis (MS) as controls who also received diagnostic LPs. Demographic, clinical, and radiological data were collected for each patient. The main outcome measure was the rate of post-LP blood patches in IIH patients compared with MS patients. Secondary outcome measures were the likelihood of undergoing an epidural blood patch related to age, body mass index, volume removed, opening pressure, the difference between opening and closing pressure, and the level of puncture within the IIH cohort. RESULTS: One hundred four IIH patients and 149 MS patients were included in the study. Among IIH patients, 12/104 (11.5%) underwent an epidural blood patch after LP as compared to 8/149 (5.4%) of the MS control patients (P = 0.086). Within the IIH population, none of the clinical or LP parameters were significantly correlated with increased risk of needing a blood patch. CONCLUSIONS: The incidence of low-pressure syndrome, as measured by blood patches, is similar in IIH patients and MS controls. This suggests that having elevated intracranial pressure before an LP is not protective against developing postpuncture low-pressure syndrome, contrary to common assumptions. PMID- 30247222 TI - Non-Exudative Conjunctival Injection With Limbal Sparing: A Pathognomonic Clinical Sign of Kawasaki Disease. PMID- 30247221 TI - Expression of Psoriasin in Human Papillomavirus-Induced Cervical High-Grade Squamous Intraepithelial Lesions. AB - OBJECTIVES: Persistent infection with human papillomavirus causes cervical high grade squamous intraepithelial lesions (HSILs). The role of antimicrobial peptides (AMPs) in premalignant and malignant transformation is not fully understood. In this study, we examined the expression of human beta-defensin 1 (HBD-1), HBD-2, HBD-3, LL37, psoriasin, and interleukin 8 (IL-8) in women with HSIL before and 6 months after surgery. MATERIALS AND METHODS: Biopsies and secretion samples from the cervical canal were collected from 19 patients with HSIL and 14 healthy controls. The mRNA expression of HBD-1, HBD-2, HBD-3, LL37, psoriasin, and IL-8 was analyzed before and 6 months after surgery excision using reverse transcriptase real time polymerase chain reaction. For protein analyses, ELISA and immunohistochemistry were used for psoriasin and ELISA for IL-8. RESULTS: The mRNA expression of psoriasin was lower in patients before treatment compared with healthy controls (p = .05). After surgery, when the infection was cleared, psoriasin increased on mRNA (p = .04) and protein (p = .03) levels compared with before treatment. Immunostaining for psoriasin after treatment was prominent and localized in the cytoplasm of the epithelial cells. After treatment, IL-8 mRNA was reduced compared with before treatment (p = .05), but not on the protein level. No changes in mRNA expression of the other AMPs analyzed were observed in pretreatment and posttreatment samples. CONCLUSIONS: In this study of AMP expression in human papillomavirus-induced HSIL, we observed lower psoriasin levels before surgery compared with after treatment, when both mRNA and protein levels were similar to healthy controls. Interleukin 8, on the other hand, was increased before treatment, indicating an inflammatory response. PMID- 30247223 TI - Novel Use of Rituximab in Treatment of Refractory Neurosarcoidosis in an 11-Year Old Girl. PMID- 30247224 TI - Visceral Leishmaniasis Versus Systemic Lupus Erythematosus Flare-Old Axioms Sometimes Stay True Other Times Not. PMID- 30247225 TI - Detection of Bacterial DNA in Septic Arthritis Samples Using the MYcrobiota Platform. PMID- 30247226 TI - Sweet Syndrome in a Patient With Systemic Lupus Erythematosus. PMID- 30247227 TI - Prevalence of Seizures in Pediatric Extracorporeal Membrane Oxygenation Patients as Measured by Continuous Electroencephalography. AB - OBJECTIVES: Standards for neuromonitoring during extracorporeal membrane oxygenation support do not currently exist, and there is wide variability in practice. We present our institutional experience at an academic children's hospital since establishment of a continuous electroencephalography monitoring protocol for extracorporeal membrane oxygenation patients. DESIGN: Retrospective, single-center study. SETTING: Neonatal ICU and PICU in an urban, quaternary care center. PATIENTS: All neonatal and pediatric patients requiring extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, 70 patients were cannulated for extracorporeal membrane oxygenation and had continuous electroencephalography monitoring for greater than 24 hours. Electroencephalographic seizures were observed in 16 of 70 patients (23%), including five patients (7%) who were in status epilepticus. Among patients with continuous electroencephalography seizures, nine (56%) had subclinical nonconvulsive status epilepticus and eight (50%) had seizures in the initial 24 hours of extracorporeal membrane oxygenation support. Survival to hospital discharge was significantly greater for extracorporeal membrane oxygenation patients without seizures (74% vs 44%; p = 0.02). CONCLUSIONS: Seizures occur in a significant proportion of pediatric and neonatal extracorporeal membrane oxygenation patients, frequently in the initial 24 hours after extracorporeal membrane oxygenation cannulation. Because seizures are associated with significantly decreased survival, neuromonitoring early in the extracorporeal membrane oxygenation course is important and useful. Further studies are needed to correlate electroencephalography findings with neurologic outcome. PMID- 30247228 TI - Does Surgery Reduce the Risk of Complications Among Patients with Multiple Rib Fractures? A Meta-analysis. AB - BACKGROUND: Multiple rib fractures are common in trauma patients, who are prone to trauma-associated complications. Surgical or nonsurgical interventions for the aforementioned conditions remain controversial. QUESTIONS/PURPOSES: The purpose of our study was to perform a meta-analysis to evaluate the clinical prognosis of surgical fixation of multiple rib fractures in terms of (1) hospital-related endpoints (including duration of mechanical ventilation, ICU length of stay [LOS] and hospital LOS), (2) complications, (3) pulmonary function, and (4) pain scores. METHODS: We screened PubMed, Embase, and Cochrane databases for randomized and prospective studies published before January 2018. Individual effect sizes were standardized; the pooled effect size was calculated using a random-effects model. Primary outcomes were duration of mechanical ventilation, intensive care unit length of stay (ICU LOS), and hospital LOS. Moreover, complications, pulmonary function, and pain were assessed. RESULTS: The surgical group had a reduced duration of mechanical ventilation (weighted mean difference [WMD], -4.95 days; 95% confidence interval [CI], -7.97 to -1.94; p = 0.001), ICU LOS (WMD, -4.81 days; 95% CI, -6.22 to -3.39; p < 0.001), and hospital LOS (WMD, 8.26 days; 95% CI, -11.73 to -4.79; p < 0.001) compared with the nonsurgical group. Complications likewise were less common in the surgical group, including pneumonia (odds ratio [OR], 0.41; 95% CI, 0.27-0.64; p < 0.001), mortality (OR, 0.24; 95% CI, 0.07-0.87; p = 0.030), chest wall deformity (OR, 0.02; 95% CI. 0.00 0.12; p < 0.001), dyspnea (OR, 0.23; 95% CI, 0.09-0.54; p < 0.001), chest wall tightness (OR, 0.11; 95% CI, 0.05-0.22; p < 0.001) and incidence of tracheostomy (OR, 0.34; 95% CI, 0.20-0.57; p < 0.001). There were no differences between the surgical and nonsurgical groups in terms of pulmonary function, such as forced vital capacity (WMD, 6.81%; 95% CI: -8.86 to 22.48; p = 0.390) and pain scores (WMD, -11.41; 95% CI: -42.09 to 19.26; p = 0.470). CONCLUSIONS: This meta analysis lends stronger support to surgical fixation, rather than conservative treatment, for multiple rib fractures. Nevertheless, additional trials should be conducted to investigate surgical indications, timing, and followup for quality of life. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 30247229 TI - Letter to the Editor: Art in Science: Jusepe de Ribera's Puzzle in The Clubfoot. PMID- 30247230 TI - CORR Insights(r): What Factors Are Associated With Disability After Upper Extremity Injuries? A Systematic Review. PMID- 30247231 TI - CORR Insights(r): Dual Interlocking Telescopic Rod Provides Effective Tibial Stabilization in Children With Osteogenesis Imperfecta. PMID- 30247232 TI - Cochrane in CORR(r): Topical NSAIDs for Chronic Musculoskeletal Pain in Adults. PMID- 30247233 TI - CORR Insights(r): A Possible New Radiographic Predictor of Progression of Osteoarthritis in Developmental Dysplasia of the Hip: The Center Gap. PMID- 30247234 TI - CORR Insights(r): Can Dynamic Ultrasonography of the Hip Reliably Assess Anterior Femoral Head Translation? PMID- 30247235 TI - CORR Insights(r): Does Robotic Milling For Stem Implantation in Cementless THA Result in Improved Outcomes Scores or Survivorship Compared with Hand Rasping? Results of a Randomized Trial at 10 Years. PMID- 30247236 TI - Virtue Ethics in a Value-driven World: Bias in Orthopaedics. PMID- 30247237 TI - The Relationship between Progression in Axial Length/Corneal Radius of Curvature Ratio and Spherical Equivalent Refractive Error in Myopia. AB - SIGNIFICANCE: This study demonstrates that mean axial length/corneal radius of curvature ratio (AL/CR) can be used to detect low and high myopia but cannot clinically monitor myopia progression because the relationship between AL/CR and progression in myopia is different between low and high myopia. PURPOSE: The purpose of this study was to investigate the relationship of AL/CR with magnitude and progression of myopia. METHODS: Retrospective analysis was conducted comparing the right eyes of those with high myopia (n = 308; age, 7 to 16 years; myopia sphere, -6.00 diopters or worse) with those with low myopia (n = 732; age, 7 to 16 years; myopia sphere, between -0.50 and -3.50 diopters; cylinder, <=1.00 diopters). Baseline axial length, corneal radii of curvature, and cycloplegic objective refraction were analyzed. Myopia progression in the low-myopia group at 6- and 12-month follow-up was measured, and the differences in slopes of AL/CR were compared for slow (<0.75 diopters) and fast progressing (>=0.75 diopters). RESULTS: Mean AL/CR values were significantly different (P < .001) between high myopia (3.46 +/- 0.10) and low myopia (3.16 +/- 0.07). In high and low myopia, slopes of axial length versus corneal curvature radius were not significantly different (P > .05), and slopes of AL/CR versus spherical equivalent were significantly different after adjusting for spherical equivalent and age (P < .05). Slopes of AL/CR progression and spherical equivalent progression were significantly different in low myopia between fast and slow progressing (P < .001), but the relationship between progression in AL/CR and progression in spherical equivalent was not strong. CONCLUSIONS: The AL/CR can be used to classify different grades of myopia, but it is not useful in determining the magnitude of myopia or monitoring progression because AL/CR is not linearly related to spherical equivalent and because progression in AL/CR is not strongly related to spherical equivalent progression. PMID- 30247239 TI - Minimal Impact of Implemented Early Warning Score and Best Practice Alert for Patient Deterioration. AB - OBJECTIVES: Previous studies have looked at National Early Warning Score performance in predicting in-hospital deterioration and death, but data are lacking with respect to patient outcomes following implementation of National Early Warning Score. We sought to determine the effectiveness of National Early Warning Score implementation on predicting and preventing patient deterioration in a clinical setting. DESIGN: Retrospective cohort study. SETTING: Tertiary care academic facility and a community hospital. PATIENTS: Patients 18 years old or older hospitalized from March 1, 2014, to February 28, 2015, during preimplementation of National Early Warning Score to August 1, 2015, to July 31, 2016, after National Early Warning Score was implemented. INTERVENTIONS: Implementation of National Early Warning Score within the electronic health record and associated best practice alert. MEASUREMENTS AND MAIN RESULTS: In this study of 85,322 patients (42,402 patients pre-National Early Warning Score and 42,920 patients post-National Early Warning Score implementation), the primary outcome of rate of ICU transfer or death did not change after National Early Warning Score implementation, with adjusted hazard ratio of 0.94 (0.84-1.05) and 0.90 (0.77-1.05) at our academic and community hospital, respectively. In total, 175,357 best practice advisories fired during the study period, with the best practice advisory performing better at the community hospital than the academic at predicting an event within 12 hours 7.4% versus 2.2% of the time, respectively. Retraining National Early Warning Score with newly generated hospital-specific coefficients improved model performance. CONCLUSIONS: At both our academic and community hospital, National Early Warning Score had poor performance characteristics and was generally ignored by frontline nursing staff. As a result, National Early Warning Score implementation had no appreciable impact on defined clinical outcomes. Refitting of the model using site-specific data improved performance and supports validating predictive models on local data. PMID- 30247238 TI - Neutralizing Peripheral Refraction Eliminates Refractive Scotomata in Tilted Disc Syndrome. AB - SIGNIFICANCE: We demonstrate that the visual field defects in patients with tilted disc syndrome can be reduced or eliminated by neutralizing the peripheral scotoma in the area of posterior retinal bowing, which may allow differentiation between a congenital anomaly and acquired pathology. PURPOSE: Tilted disc syndrome is a congenital and unchanging condition that may present with visual field defects mimicking loss seen in neurological diseases, such as transsynaptic retrograde degeneration. Our purpose was to systematically investigate the ability of a neutralized peripheral refraction to eliminate refractive visual field defects seen in tilted disc syndrome. This was compared with the same technique performed on patients with neurological deficits. METHODS: The Humphrey Field Analyzer was used to measure sensitivities across the 30-2 test grid in 14 patients with tilted disc syndrome using four refractive corrections: habitual near correction and with an additional -1.00, -2.00 or -3.00 D negative lens added as correction lenses. Peripheral refractive errors along the horizontal meridian were determined using peripheral retinoscopy and thus allowed calculation of residual peripheral refraction with different levels of refractive correction. Visual field defects were assessed qualitatively and quantitatively using sensitivities and probability scores in both patient groups. RESULTS: A smaller residual refractive error after the application of negative addition lenses correlated with improvement in visual field defects in terms of sensitivity and probability scores in patients with tilted disc syndrome. Patients with established neurological deficits (retrograde degeneration) showed improvement in sensitivities but not in probability scores. CONCLUSIONS: Neutralizing the refractive error at the region of posterior retinal bowing due to tilted disc syndrome reduces the apparent visual field defect. This may be a useful and rapid test to help differentiate between tilted disc syndrome and other pathological causes of visual field defects such as neurological deficits. PMID- 30247240 TI - Long-Term Functional Outcome Data Should Not in General Be Used to Guide End-of Life Decision-Making in the ICU. PMID- 30247241 TI - Peripherally Inserted Central Catheters in the ICU: A Retrospective Study of Adult Medical Patients in 52 Hospitals. AB - OBJECTIVES: To quantify variation in use and complications from peripherally inserted central catheters placed in the ICU versus peripherally inserted central catheters placed on the general ward. DESIGN: Retrospective cohort study. SETTING: Fifty-two hospital Michigan quality collaborative. PATIENTS: Twenty seven-thousand two-hundred eighty-nine patients with peripherally inserted central catheters placed during hospitalization. MEASUREMENTS AND MAIN RESULTS: Descriptive statistics were used to summarize patient, provider, and device characteristics. Bivariate tests were used to assess differences between peripherally inserted central catheters placed in the ICU versus peripherally inserted central catheters placed on the ward. Multilevel mixed-effects generalized linear models adjusting for patient and device factors with a logit link clustered by hospital were used to examine the association between peripherally inserted central catheter complications and location of peripherally inserted central catheter placement. Variation in ICU peripherally inserted central catheter use, rates of complications, and appropriateness of use across hospitals was also examined. Eight-thousand two-hundred eighty patients (30.3%) received peripherally inserted central catheters in the ICU versus 19,009 (69.7%) on the general ward. The commonest indication for peripherally inserted central catheter use in the ICU was difficult IV access (35.1%) versus antibiotic therapy (53.3%) on wards. Compared with peripherally inserted central catheters placed in wards, peripherally inserted central catheters placed in the ICU were more often multilumen (59.5% vs 39.3; p < 0.001) and more often associated with a complication (odds ratio, 1.30; 95% CI, 1.18-1.43; p < 0.001). Substantial variation in ICU peripherally inserted central catheter use and outcomes across hospitals was observed, with median peripherally inserted central catheter dwell time ranging from 3 to 38.5 days (p < 0.001) and complications from 0% to 40.2% (p < 0.001). Importantly, 87% (n = 45) of ICUs reported median peripherally inserted central catheter dwell times less than or equal to 14 days, a duration where traditional central venous catheters, not peripherally inserted central catheters, are considered appropriate by published criteria. CONCLUSIONS: Peripherally inserted central catheter use in the ICU is highly variable, associated with complications and often not appropriate. Further study of vascular access decision-making in the ICU appears necessary. PMID- 30247242 TI - Evaluation of a Measurement System to Assess ICU Team Performance. AB - OBJECTIVE: Measuring teamwork is essential in critical care, but limited observational measurement systems exist for this environment. The objective of this study was to evaluate the reliability and validity of a behavioral marker system for measuring teamwork in ICUs. DESIGN: Instances of teamwork were observed by two raters for three tasks: multidisciplinary rounds, nurse-to-nurse handoffs, and retrospective videos of medical students and instructors performing simulated codes. Intraclass correlation coefficients were calculated to assess interrater reliability. Generalizability theory was applied to estimate systematic sources of variance for the three observed team tasks that were associated with instances of teamwork, rater effects, competency effects, and task effects. SETTING: A 15-bed surgical ICU at a large academic hospital. SUBJECTS: One hundred thirty-eight instances of teamwork were observed. Specifically, we observed 88 multidisciplinary rounds, 25 nurse-to-nurse handoffs, and 25 simulated code exercises. INTERVENTIONS: No intervention was conducted for this study. MEASUREMENTS AND MAIN RESULTS: Rater reliability for each overall task ranged from good to excellent correlation (intraclass correlation coefficient, 0.64-0.81), although there were seven cases where reliability was fair and one case where it was poor for specific competencies. Findings from generalizability studies provided evidence that the marker system dependably distinguished among teamwork competencies, providing evidence of construct validity. CONCLUSIONS: Teamwork in critical care is complex, thereby complicating the judgment of behaviors. The marker system exhibited great potential for differentiating competencies, but findings also revealed that more context specific guidance may be needed to improve rater reliability. PMID- 30247243 TI - Estimating the False Positive Rate of Absent Somatosensory Evoked Potentials in Cardiac Arrest Prognostication. AB - OBJECTIVES: Absence of somatosensory evoked potentials is considered a nearly perfect predictor of poor outcome after cardiac arrest. However, reports of good outcomes despite absent somatosensory evoked potentials and high rates of withdrawal of life-sustaining therapies have raised concerns that estimates of the prognostic value of absent somatosensory evoked potentials may be biased by self-fulfilling prophecies. We aimed to develop an unbiased estimate of the false positive rate of absent somatosensory evoked potentials as a predictor of poor outcome after cardiac arrest. DATA SOURCES: PubMed. STUDY SELECTION: We selected 35 studies in cardiac arrest prognostication that reported somatosensory evoked potentials. DATA EXTRACTION: In each study, we identified rates of withdrawal of life-sustaining therapies and good outcomes despite absent somatosensory evoked potentials. We appraised studies for potential biases using the Quality in Prognosis Studies tool. Using these data, we developed a statistical model to estimate the false positive rate of absent somatosensory evoked potentials adjusted for withdrawal of life-sustaining therapies rate. DATA SYNTHESIS: Two thousand one-hundred thirty-three subjects underwent somatosensory evoked potential testing. Five-hundred ninety-four had absent somatosensory evoked potentials; of these, 14 had good functional outcomes. The rate of withdrawal of life-sustaining therapies for subjects with absent somatosensory evoked potential could be estimated in 14 of the 35 studies (mean 80%, median 100%). The false positive rate for absent somatosensory evoked potential in predicting poor neurologic outcome, adjusted for a withdrawal of life-sustaining therapies rate of 80%, is 7.7% (95% CI, 4-13%). CONCLUSIONS: Absent cortical somatosensory evoked potentials do not infallibly predict poor outcome in patients with coma following cardiac arrest. The chances of survival in subjects with absent somatosensory evoked potentials, though low, may be substantially higher than generally believed. PMID- 30247245 TI - Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome: EOLIA and Beyond. PMID- 30247244 TI - Combining National Early Warning Score With Soluble Urokinase Plasminogen Activator Receptor (suPAR) Improves Risk Prediction in Acute Medical Patients: A Registry-Based Cohort Study. AB - OBJECTIVES: Soluble urokinase plasminogen activator receptor is a prognostic biomarker associated with critical illness, disease progression, and risk of mortality. We aimed to evaluate whether soluble urokinase plasminogen activator receptor adds prognostic value to a vital sign-based score for clinical monitoring of patient risk (National Early Warning Score) in acute medical patients. DESIGN: Registry-based observational cohort study of consecutively admitted acute medical patients. SETTING: The Acute Medical Unit, Copenhagen University Hospital Amager and Hvidovre, Hvidovre, Denmark. PATIENTS: Acute medical patients admitted between November 18, 2013, and September 30, 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 17,312 included patients, admission National Early Warning Score was available for 16,244 (93.8%). During follow-up, 587 patients (3.4%) died in-hospital, 859 (5.0%) within 30 days, and 1,367 (7.9%) within 90 days. High soluble urokinase plasminogen activator receptor was significantly associated with in-hospital-, 30-day-, and 90-day mortality within all National Early Warning Score groups, in particular in patients with a low National Early Warning Score; for 30-day mortality, mortality rate ratios ranged from 3.45 (95% CI, 2.91-4.10) for patients with National Early Warning Score 0-1, to 1.86 (95% CI, 1.47-2.34) for patients with National Early Warning Score greater than or equal to 9 for every doubling in soluble urokinase plasminogen activator receptor (log2-transformed). Combining National Early Warning Score, age, and sex with soluble urokinase plasminogen activator receptor improved prediction of in-hospital-, 30-day-, and 90-day mortality, increasing the area under the curve (95% CI) for 30-day mortality from 0.86 (0.85-0.87) to 0.90 (0.89-0.91), p value of less than 0.0001, with a negative predictive value of 99.0%. CONCLUSIONS: The addition of soluble urokinase plasminogen activator receptor to National Early Warning Score significantly improved risk prediction of both low- and high-risk acute medical patients. Patients with low National Early Warning Score but elevated soluble urokinase plasminogen activator receptor had mortality risks comparable to that of patients with higher National Early Warning Score. PMID- 30247246 TI - Letter From Editor October 2018. PMID- 30247247 TI - Efficacy of Neoadjuvant Therapy With Cisplatin Plus Mitomycin C in BRCA1-Mutated Ovarian Cancer. AB - OBJECTIVES: Cisplatin and mitomycin C exert high activity towards BRCA1-deficient cells. This study aimed to evaluate the efficacy of a combination of these drugs in hereditary BRCA1-associated ovarian cancer (OC). METHODS: Twelve OC patients, who could not be treated by primary debulking surgery owing to extensive tumor spread, were given neoadjuvant cisplatin (100 mg/m) and mitomycin C (10 mg/m) every 4 weeks for 3 (n = 9), 2 (n = 2), or 4 (n = 1) cycles. RESULTS: The decrease of tumor burden and complete surgical cytoreduction were achieved in all patients. Pathologic complete response, defined as the absence of tumor cells in surgically removed tissues, was observed in 2 (17%) of 12 cases. Retrospective analysis of 62 OC in BRCA1 mutation carriers subjected to conventional neoadjuvant chemotherapy schemes revealed 36 objective tumor responses (58%) and 37 instances (60%) of complete cytoreductive surgery; however, none of these patients demonstrated pathologic complete response. CONCLUSIONS: The combination of cisplatin plus mitomycin C showed promising results in BRCA1-driven OC and therefore deserves further clinical evaluation. PMID- 30247248 TI - The Utility of Pretreatment and Posttreatment Lymphopenia in Cervical Squamous Cell Carcinoma Patients Treated With Definitive Chemoradiotherapy. AB - OBJECTIVE: The aim of this study was to investigate the prognostic significance of pretreatment and posttreatment lymphopenia in locally advanced squamous cell carcinoma (SCC) cervical cancer patients treated with definitive chemoradiotherapy (ChRT). METHODS: Data from 95 patients with SCC were retrospectively analyzed. Relationships between pretreatment or posttreatment lymphopenia and patient or tumor characteristics, and overall survival (OS) and disease-free survival (DFS) were evaluated. RESULTS: Median follow-ups for the entire cohort and survivors were 68 months (range, 3-133 months) and 88 months (range, 22-133 months), respectively. Ten patients (11%) exhibited pretreatment lymphopenia, whereas 58 patients (61%) exhibited posttreatment lymphopenia. Median pretreatment total lymphocyte counts decreased from 2029 cells/MUL to 506 cells/MUL 2 months after ChRT (P < 0.001). The 5-year OS and DFS rates were significantly higher in patients without pretreatment lymphopenia compared with patients with pre-retreatment lymphopenia (61% vs 20% [P < 0.001], 55% vs 20% [P < 0.001]). Patients without posttreatment lymphopenia had significantly higher 5 year OS and DFS rates than their counterparts (70% vs 46% [P = 0.02], 70% vs 39% [P = 0.004]). Complete response (CR) was observed in significantly fewer patients with pretreatment lymphopenia than in those without, after ChRT. Patients with posttreatment lymphopenia had higher rates of lymph node metastasis (P = 0.001) and lower posttreatment CR rates (P = 0.01) versus patients without posttreatment lymphopenia. In univariate analysis, International Federation of Gynecology and Obstetrics stage, tumor size, lymph node metastasis, and treatment response were prognostic for OS and DFS. In multivariate analysis, pretreatment lymphopenia, lymph node metastasis, and treatment response were independent predictors of OS and DFS. Age was predictive of OS. Tumor size was prognostic for DFS. CONCLUSIONS: Pretreatment lymphopenia and posttreatment lymphopenia are associated with worse treatment response in patients given ChRT for cervical SCC. Pretreatment lymphopenia is predictive for OS and DFS. Therapeutic strategies including pretreatment or posttreatment immune preservation or modulation may improve response rates and survival in women with cervical SCC. PMID- 30247249 TI - Rising Rates of Upfront Surgery in Early Locally Advanced Cervical Cancer: What Factors Predict for This Treatment Paradigm? AB - OBJECTIVE: In this study, we analyzed patterns of care for patients with locally advanced cervical cancer to identify predictors for upfront surgery compared with definitive chemoradiation (CRT). METHODS: The National Cancer Database was queried for patients aged 18 years or older with Federation of Gynecology and Obstetrics IB2-IIB cervical cancer. All patients underwent either upfront hysterectomy with or without postoperative radiation therapy versus definitive CRT. Logistic regression was used to assess variables associated with modality of treatment (surgery vs CRT). RESULTS: Of the 9494 patients included, 2151 (22.7%) underwent upfront surgery. Of those undergoing surgery, 380 (17.7%) had positive margins, 478 (22.2%) had positive nodes, and 458 (21.3%) had pathologic involvement of the parametrium. Under multiple logistic regression, rates of surgery significantly increased from 2004 (12.2%) to 2012 (31.2%) (odds ratio [OR] per year increase, 1.15; confidence interval [CI], 1.12-1.17; P < 0.001). Upfront surgery was more commonly performed in urban (OR, 1.21; 95% CI, 1.03 1.41; P = 0.018) and rural counties (OR, 1.79; 95% CI, 1.24-2.58; P = 0.002), for adenocarcinoma (OR, 2.14; 1.88-2.44; P < 0.001) and adenosquamous (OR, 2.69; 2.11 3.43; P < 0.001) histologies, and in patients from higher median income communities (ORs, 1.19-1.37). Upfront surgery was less common at academic centers (OR, 0.73; 95% CI, 0.58-0.93; P = 0.011). CONCLUSIONS: Rates of upfront surgery relative to definitive CRT have increased significantly over the past decade. In the setting of level 1 evidence supporting the use of definitive CRT alone for these women, the rising rates of upfront surgery raises concern for both unnecessary surgical procedures with higher rates of treatment-related morbidity and greater health care costs. PMID- 30247250 TI - Bevacizumab in Metastatic, Recurrent, or Persistent Cervical Cancer: The BC Cancer Experience. AB - OBJECTIVE: We conducted a population-based analysis of patient outcomes following treatment with bevacizumab and platinum-based chemotherapy for metastatic, recurrent, or persistent cervical carcinoma. METHODS: Eligible cases were identified using the BC Cancer provincial pharmacy database. Cases with small cell component or inadequate clinical follow-up were excluded. Overall response to therapy, progression-free survival (PFS), overall survival (OS), and toxicities were documented. RESULTS: Twenty-seven eligible cases were included with a median follow-up of 12.1 months. The median age at recurrence/metastatic diagnosis was 49 years (range, 27-83 years). Twenty-three of 27 women received carboplatin, paclitaxel, and bevacizumab as first-line treatment, and 4 of 27 as second-line treatment. The median number of cycles of bevacizumab delivered was 5.5 (range, 1-21). The overall response rate was 44% (12/27), with 11% (3/27) complete response and 33% (9/27) partial response. Median PFS and OS for the entire cohort were 5.3 and 12.1 months, respectively. In first-line therapy, the median PFS and OS were 6.3 and 17.5 months, respectively. Common toxicities included anemia (grade 1/2) 73% (19/27), and the following grade 2 or greater: neutropenia 38% (n = 10) with 1 occurrence of febrile neutropenia, hypertension 30% (n = 8), and thrombosis 22% (n = 6). The fistula rate was 3.7% (n = 1). CONCLUSIONS: In this population-based analysis, the combination of bevacizumab and platinum-based chemotherapy as first-line therapy for metastatic, recurrent, or persistent cervical carcinoma was safely delivered and had outcomes comparable to results from the GOG 240 phase III trial. PMID- 30247252 TI - In Recognition. PMID- 30247253 TI - Our Assistant Editors: Fostering Integrity in Dental Implant Literature. PMID- 30247251 TI - Treatment Results and Prognostic Factors of Brain Metastases From Ovarian Cancer: A Single Institutional Experience of 56 Patients. AB - OBJECTIVES: The most appropriate treatments for brain metastases from ovarian cancer have not been established mainly because of its rarity. The objective of this study was to describe clinical results of treatment and prognostic factors of patients with brain metastases from ovarian cancer treated at a single institution. MATERIALS AND METHODS: We retrieved information from the electronic medical records of 56 consecutive patients (2.8%) with brain metastases, from a total of 2008 patients with ovarian cancer. Endpoints were the pattern of treatment failure, progression-free survival, and overall survival (OS). RESULTS: Radiation was the most common initial treatment for brain metastases (59%), followed by surgery (23%). The median progression-free survival was 9.8 months. Radiological progression was confirmed in 20 patients: 7 had leptomeningeal carcinomatosis (37%), 8 had local recurrence, and 5 had distant recurrence. Median OS was 11.25 months, and the 1-year OS rate was 48.2%. Patients received surgery for single metastasis as initial treatment showed median OS of 24.1 months, which was significantly prolonged compared with the other patients (P = 0.0002). Of the 48 patients who died, 29 (60%) died of systemic disease and 7 (15%) died of central nervous system progression. Karnofsky Performance Status greater than or equal to 70, control of systemic cancer, serous histology, and surgery for brain metastases were associated with improved OS in multivariable analysis (P < 0.05). CONCLUSIONS: Surgical resection for single or symptomatic brain metastases from ovarian cancer prolonged OS significantly. Multimodality treatment, including control of systemic cancer, appeared to be an important factor in prolonging OS. PMID- 30247254 TI - Introduction From the Guest Editor: Hodgkin Lymphoma: Integrating New Therapies to Improve Outcomes. PMID- 30247256 TI - Improvements in Imaging of Hodgkin Lymphoma: Positron Emission Tomography. AB - 18-Fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG PET/CT) is currently the criterion standard of lymphoma imaging and recommended through all stages of Hodgkin lymphoma management. Accurate staging is important for risk stratification and initial choice of therapy and also for the planning of postchemoradiotherapy. 18-Fluoro-2-deoxy-D-glucose PET/CT frequently leads to upstaging and potentially a more intensive treatment. Visual-only assessment of staging and interim scans is being accompanied by quantitative and semiquantitative methods to measure metabolic tumor volume, total lesion glycolysis, and so on. It is still unclear if these methods significantly improve the value of FDG PET/CT by visual assessment only. Because of the good prognostic value of FDG PET/CT, a large number of studies have used interim FDG PET to tailor treatment to the individual patients, according to their early metabolic response rather than according to their pretreatment prognostic features. 18 Fluoro-2-deoxy-D-glucose PET/CT is standard of care for posttreatment response assessment but has no place in routine follow-up of Hodgkin lymphoma patients in remission. PMID- 30247255 TI - Novel Biomarker Approaches in Classic Hodgkin Lymphoma. AB - Classic Hodgkin lymphoma (cHL) is one of the most common lymphomas in the Western world. Advances in the management of cHL have led to high cure rates exceeding 80%. Nevertheless, relapse or refractory disease in a subset of patients and treatment-related toxicity still represents unsolved clinical problems. The introduction of targeted treatments such as PD-1 blockade and the CD30 antibody drug conjugate, brentuximab vedotin, has broadened treatment options in cHL, emphasizing the critical need to identify biomarkers with the goal to provide rationales for treatment selection, increase effective drug utilization, and minimize toxicity. The unique biology of cHL featuring low abundant tumor cells and numerous nonmalignant immune cells in the tumor microenvironment can provide various types of promising biomarkers related to the tumor cells directly, tumor microenvironment cross-talk, and host immune response. Here, we comprehensively review novel biomarkers including circulating tumor DNA and gene expression-based prognostic models that might guide the ideal management of cHL in the future. PMID- 30247257 TI - Limited-Stage Hodgkin Lymphoma: Minimizing Toxicity. AB - Early-stage classic Hodgkin lymphoma has been highly curable using extended-field radiation therapy (RT) alone, combined-modality therapy consisting of chemotherapy and RT, and more recently chemotherapy alone. Radiation therapy either to an extended field (extended-field RT) or to various iterations of an involved field (involved-field RT) is potentially associated with late morbidity and mortality, particularly second primary cancers and cardiovascular complications. Treatment with chemotherapy alone, when possible, can achieve a high cure rate while avoiding these risks. This review describes the evolution of treatment for early-stage classic Hodgkin lymphoma. PMID- 30247258 TI - Advanced-Stage Hodgkin Lymphoma: New Approaches Based on Novel Therapeutic Agents or Treatment Intensification. AB - Depending on a variety of prognostic factors including age, stage, laboratory abnormalities, and initial response to treatment, from 70% to 90% of patients with advanced-stage Hodgkin lymphoma can be cured with modern multiagent chemotherapy. Two effective strategies offer the promise to improve on those results. Early intensification of treatment, typically by increasing the doses and frequency of administration of standard chemotherapy agents, induces higher initial response rates but has the major drawback of causing unacceptably severe acute toxicity, increased numbers of secondary neoplasms, and infertility due to oligospermia in men and premature menopause in women. Alternatively, integration of novel therapeutic agents into primary treatment is attractive, especially when the introduction not only improves the frequency and durability of disease response but also does not unacceptably increase acute or long-term toxicity. Finally, widespread availability of functional imaging with positron emission tomography now enables response-adapted therapy, a separate innovation in the treatment of Hodgkin lymphoma that can be incorporated with either intensified chemotherapy or addition of novel agents. This article discusses these exciting new developments in the treatment of advanced-stage Hodgkin lymphoma. PMID- 30247259 TI - Radiotherapy for Hodgkin Lymphoma: Reducing Toxicity While Maintaining Efficacy. AB - Radiation therapy (RT) for Hodgkin lymphoma has changed dramatically over the past couple of decades, from the very large extended-field RT with prophylactic treatment of all the major lymph node regions to the very limited involved-site RT with treatment only of the initially macroscopically involved lymphoma volume in the combined modality setting. Technological developments in imaging, treatment planning, and treatment machines have enabled very significant reductions in radiation doses to normal organs without jeopardizing the coverage of the lymphoma. Hence, the risks of long-term adverse effects have become much smaller than those in the past. Radiation therapy for Hodgkin lymphoma is now a highly individualized treatment, tailored to each patient. The risks of this limited RT should be weighed against the risks of long-term toxicity of possible additional systemic treatment up-front and at relapse in order to select the optimal treatment combination for each individual patient. PMID- 30247261 TI - Immunotherapy of Hodgkin Lymphoma: Mobilizing the Patient's Immune Response. AB - Classic Hodgkin lymphoma has a unique tumor composition in that there is a paucity of malignant cells present, and most of the tumor consists of normal immune and stromal cells. Despite the presence of an immune infiltrate within the tumor microenvironment, the malignant cells effectively evade the immune system and appear to utilize the presence of immune cells to promote the growth and survival of Hodgkin-Reed-Sternberg cells. Hodgkin-Reed-Sternberg cells evade immune detection because of overexpression of programmed death 1 ligands, PD-L1 and PD-L2, which suppress T-cell activation, and loss of expression of major histocompatibility complex molecules that prevent effective immune recognition. Recognition of these immune defects has led to clinical use of immune checkpoint blockade in classic Hodgkin lymphoma. Clinical trials using antibodies that block programmed death 1/PD-L1 signaling have shown remarkable responses to therapy and have led to the approval of nivolumab and pembrolizumab for use in patients with relapsed and refractory disease. Trials are currently testing immune checkpoint blockade in earlier lines of therapy. PMID- 30247260 TI - Treatment-Resistant Hodgkin Lymphoma: Defining the Role of Autologous Transplantation. AB - Autologous hematopoietic stem cell transplant (AHCT) remains the current standard of care for patients with relapsed or refractory Hodgkin lymphoma (HL) after frontline chemotherapy. However, treatment paradigms for HL are rapidly changing with positron emission tomography-adapted therapy, as well as the incorporation of brentuximab vedotin and checkpoint inhibitors into frontline, salvage, and maintenance therapy for HL. Patients who relapse or are refractory to these novel agents are likely to have different responses and outcomes with AHCT than the 3 year event-free survivals of 50% historically reported with AHCT for patients failing conventional combination chemotherapy. This article reviews the current data on the efficacy of AHCT, pretransplant prognostic markers, pretransplant salvage regimens, peritransplant radiation therapy, and posttransplant maintenance therapy in classic HL. Future research should reexamine the efficacy, timing, risk factors, pretransplant salvage regimens, and maintenance approaches posttransplant in the era of brentuximab vedotin and checkpoint inhibitors for HL. PMID- 30247263 TI - PRISM: a brief screening tool to identify risk in parents of youth with chronic pain. AB - Having a child with chronic pain impacts a parent's life. Reciprocally, parent cognitive, affective, and behavioral responses to the child's chronic pain can influence the child's pain experience. The purpose of this study is to develop a brief self-report screening tool (Parent Risk and Impact Screening Measure [PRISM]) of parent psychosocial functioning and behavioral responses to child pain. This measure assesses parents' reports of their own stress, health, psychosocial functioning, and disruption in activities due to their child's pain and related disability. In an effort to preliminarily validate this screening tool, we examined the PRISM in relation to existing measures of parent distress, parent behavior, and child functioning. An initial 30-item PRISM was administered to 229 parents of children with persistent pain. Parents also reported on distress, protectiveness, pain catastrophizing and family impact, and youth completed measures of pain, pain-related disability, and quality of life. Item refinement resulted in a final 12-item PRISM tool. The PRISM demonstrates strong internal consistency, and initial support for construct validity was shown by associations with parent distress, protectiveness, and catastrophizing. Results also revealed higher PRISM scores are associated with higher child pain intensity, greater functional disability, and poorer quality of life. Cutoff scores were determined to identify parents at differing levels of risk. The PRISM is a brief and clinically important means of screening parent distress and behaviors associated with child pain-related dysfunction. Further validation will use PRISM in longitudinal studies, particularly testing PRISM scores as a predictor of parent and child outcomes over time. PMID- 30247262 TI - A novel nested real-time PCR for Treponema pallidum DNA in syphilis biospecimens. AB - BACKGROUND: Early diagnosis of Treponema pallidum infection is helpful for disease management, and conventional PCR is suitable for lesion swabs of patients with probable early syphilis. We thus tested nested and real-time PCR (NR-PCR) in various biosamples from syphilitic patients. METHODS: Samples were collected from syphilis patients before treatment. Specific primer sequences targeting the T. pallidum gene polA were designed for NR-PCR. RESULTS: Across syphilis types, most samples assayed with NR-PCR returned a positive result, including earlobe blood (92.0%), CSF (90.2%), lesion swabs (74.3%), serum (66.9%), and whole blood (64.2%). No significant differences were observed in positive samples for whole blood, serum, and lesion swabs between primary and secondary syphilis (p > 0.05 for all comparisons). However, more whole blood samples from patients with secondary syphilis were positive for NR-PCR than whole blood samples from patients with tertiary and latent syphilis. (p<0.05 for all comparisons).For neurosyphilis patients, significantly more earlobe blood samples tested positive than did whole blood samples (p<0.05), but there was no difference in positive results for earlobe blood and whole blood in latent syphilis. Significantly more serum samples tested positive in latent syphilis patients with rapid plasma regain (RPR) titers >=1:8, compared to those with RPR <=1:4. CONCLUSIONS: NR-PCR can use used to identify T. pallidum DNA in biosamples from syphilitic patients, especially earlobe blood.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30247264 TI - Exploring the transcriptome of resident spinal microglia after collagen antibody induced arthritis. AB - Recent studies have suggested a sexually dimorphic role of spinal glial cells in the maintenance of mechanical hypersensitivity in rodent models of chronic pain. We have used the collagen antibody-induced arthritis (CAIA) mouse model to examine differences between males and females in the context of spinal regulation of arthritis-induced pain. We have focused on the late phase of this model when joint inflammation has resolved but mechanical hypersensitivity persists. While the intensity of substance P, CGRP and galanin immunoreactivity in the spinal cord was not different from controls, the intensity of microglia (Iba-1) and astrocyte (GFAP) markers was elevated in both males and females. Intrathecal administration of the glial inhibitors minocycline and pentoxifylline reversed mechanical thresholds in male, but not female mice. We isolated resident microglia from the lumbar dorsal horns and observed a significantly lower number of microglial cells in females by flow cytometry analysis. However, while genome wide RNA sequencing results pointed to several transcriptional differences between male and female microglia, no convincing differences were identified between control and CAIA groups.Taken together, these findings suggest that there are subtle sex differences in microglial expression profiles independent of arthritis. Our experiments failed to identify the underlying mRNA correlates of microglial actions in the late phase of the CAIA model. It is likely that transcriptional changes are either subtle and highly localised and therefore difficult to identify with bulk isolation techniques or that other factors, such as changes in protein expression or epigenetic modifications are at play.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30247265 TI - Contribution of dorsal root ganglion octamer transcription factor 1 to neuropathic pain after peripheral nerve injury. AB - Neuropathic pain genesis is related to gene alterations in the dorsal root ganglion (DRG) after peripheral nerve injury. Transcription factors control gene expression. In this study, we investigated whether octamer transcription factor 1 (OCT1), a transcription factor, contributed to neuropathic pain caused by chronic constriction injury (CCI) of the sciatic nerve. Chronic constriction injury produced a time-dependent increase in the level of OCT1 protein in the ipsilateral L4/5 DRG, but not in the spinal cord. Blocking this increase through microinjection of OCT1 siRNA into the ipsilateral L4/5 DRG attenuated the initiation and maintenance of CCI-induced mechanical allodynia, heat hyperalgesia, and cold allodynia and improved morphine analgesia after CCI, without affecting basal responses to acute mechanical, heat, and cold stimuli as well as locomotor functions. Mimicking this increase through microinjection of recombinant adeno-associated virus 5 harboring full-length OCT1 into the unilateral L4/5 DRG led to marked mechanical allodynia, heat hyperalgesia, and cold allodynia in naive rats. Mechanistically, OCT1 participated in CCI-induced increases in Dnmt3a mRNA and its protein and DNMT3a-mediated decreases in Oprm1 and Kcna2 mRNAs and their proteins in the injured DRG. These findings indicate that OCT1 may participate in neuropathic pain at least in part by transcriptionally activating Dnmt3a and subsequently epigenetic silencing of Oprm1 and Kcan2 in the DRG. OCT1 may serve as a potential target for therapeutic treatments against neuropathic pain. PMID- 30247266 TI - Children and adolescents with sickle cell disease have worse cold and mechanical hypersensitivity during acute painful events. AB - Sickle cell disease (SCD) pain associates with cold temperature and touch. Patients and murine models with SCD have baseline thermal and mechanical pain. In SCD mice, the baseline hypersensitivity is exacerbated by experimental vaso occlusive crises. We hypothesized that patients with SCD will similarly experience increased hypersensitivity to thermal and mechanical stimuli during acute painful events compared with baseline health. We conducted a prospective study of 24 patients with SCD aged 7 to 19 years. Patients underwent quantitative sensory testing to thermal (cold/heat) and mechanical stimuli on the thenar eminence of the nondominant hand (glabrous skin) and the lateral dorsum of the foot (hairy skin) during baseline health and within 48 hours of hospitalization for acute pain. Primary outcomes were changes in: (1) cold pain threshold ( degrees C), (2) heat pain threshold ( degrees C), and (3) mechanical pain threshold (g). Median age was 10.5 (interquartile range [IQR] 9-14.8) years, 67% were females, and 92% were on hydroxyurea. Patients with SCD had increased cold pain sensitivity in the hand during hospitalization compared with baseline (25.2 degrees C [IQR 18.4-27.5 degrees C] vs 21.3 degrees C [IQR 4.9-26.2 degrees C]; P = 0.011) and increased mechanical pain sensitivity in the foot during hospitalization (0.32 g [IQR 0.09-1.1 g] vs 1.7 g [IQR 0.4-8.3 g]; P = 0.003). There were no differences in heat pain sensitivity. The increased cold (P = 0.02) and mechanical (P = 0.0016) pain sensitivity during hospitalization persisted after adjusting for age, sex, hydroxyurea use, opioid consumption, and numeric pain score. Thus, cold and mechanical pain is significantly worse during an acute SCD painful event as compared to baseline health in patients with SCD. PMID- 30247268 TI - Aorta Oughtta. PMID- 30247267 TI - Morphological and functional properties distinguish the substance P and gastrin releasing peptide subsets of excitatory interneuron in the spinal cord dorsal horn. AB - Excitatory interneurons account for the majority of neurons in the superficial dorsal horn, but despite their presumed contribution to pain and itch, there is still limited information about their organisation and function. We recently identified 2 populations of excitatory interneuron defined by expression of gastrin-releasing peptide (GRP) or substance P (SP). Here, we demonstrate that these cells show major differences in their morphological, electrophysiological, and pharmacological properties. Based on their somatodendritic morphology and firing patterns, we propose that the SP cells correspond to radial cells, which generally show delayed firing. By contrast, most GRP cells show transient or single-spike firing, and many are likely to correspond to the so-called transient central cells. Unlike the SP cells, few of the GRP cells had long propriospinal projections, suggesting that they are involved primarily in local processing. The 2 populations also differed in responses to neuromodulators, with most SP cells, but few GRP cells, responding to noradrenaline and 5-HT; the converse was true for responses to the MU-opioid agonist DAMGO. Although a recent study suggested that GRP cells are innervated by nociceptors and are strongly activated by noxious stimuli, we found that very few GRP cells receive direct synaptic input from TRPV1-expressing afferents, and that they seldom phosphorylate extracellular signal-regulated kinases in response to noxious stimuli. These findings indicate that the SP and GRP cells differentially process somatosensory information.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 30247269 TI - A Comparison of Mortality From Sepsis in Brazil and England: The Impact of Heterogeneity in General and Sepsis-Specific Patient Characteristics. AB - OBJECTIVES: To test whether differences in both general and sepsis-specific patient characteristics explain the observed differences in sepsis mortality between countries, using two national critical care (ICU) databases. DESIGN: Cohort study. SETTING: We analyzed 62 and 164 ICUs in Brazil and England, respectively. PATIENTS: Twenty-two-thousand four-hundred twenty-six adult ICU admissions from January 2013 to December 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After harmonizing relevant variables, we merged the first ICU episode of adult medical admissions from Brazil (ORganizational CHaractEeriSTics in cRitical cAre study) and England (Intensive Care National Audit & Research Centre Case Mix Programme). Sepsis-3 definition was used, and the primary outcome was hospital mortality. We used multilevel logistic regression models to evaluate the impact of country (Brazil vs England) on mortality, after adjustment for general (age, sex, comorbidities, functional status, admission source, time to admission) and sepsis-specific (site of infection, organ dysfunction type and number) patient characteristics. Of medical ICU admissions, 13.2% (4,505/34,150) in Brazil and 30.7% (17,921/58,316) in England met the sepsis definition. The Brazil cohort was older, had greater prevalence of severe comorbidities and dependency compared with England. Respiratory was the most common infection site in both countries. The most common organ dysfunction was cardiovascular in Brazil (41.2%) and respiratory in England (85.8%). Crude hospital mortality was similar (Brazil 41.4% vs England 39.3%; odds ratio, 1.12 [0.98-1.30]). After adjusting for general patient characteristics, there was an important change in the point estimate of the odds ratio (0.88 [0.75-1.02]). However, after adjusting for sepsis-specific patient characteristics, the direction of effect reversed again with Brazil having higher risk-adjusted mortality (odds ratio, 1.22 [1.05-1.43]). CONCLUSIONS: Patients with sepsis admitted to ICUs in Brazil and England have important differences in general and sepsis-specific characteristics, from source of admission to organ dysfunctions. We show that comparing crude mortality from sepsis patients admitted to the ICU between countries, as currently performed, is not reliable and that the adjustment for both general and sepsis-specific patient characteristics is essential for valid international comparisons of mortality amongst sepsis patients admitted to critical care units. PMID- 30247271 TI - Impact of Mean Arterial Pressure Fluctuation on Mortality in Critically Ill Patients. AB - OBJECTIVE: The purpose of this study was to investigate the association between mean arterial pressure fluctuations and mortality in critically ill patients admitted to the ICU. DESIGN: Retrospective cohort. SETTING: All adult ICUs at a tertiary care hospital. PATIENTS: All adult patients with complete mean arterial pressure records were selected for analysis in the Multiparameter Intelligent Monitoring in Intensive Care II database. Patients in the external cohort were newly recruited adult patients in the Medical Information Mart for Intensive Care III database. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The records of 8,242 patients were extracted. Mean arterial pressure fluctuation was calculated as follows: (mean nighttime mean arterial pressure - mean daytime mean arterial pressure)/mean arterial pressure. Patients were divided into two groups according to the degree of mean arterial pressure fluctuation: group A (between -5% and 5%) and group B (<-5% and >5%). The endpoints of this study were ICU and hospital mortality. Patients in group A (n = 4,793) had higher ICU and hospital mortality than those in group B (n = 3,449; 11.1% vs 8.1%, p < 0.001 and 13.8% vs 10.1%, p < 0.001, respectively). After adjusting for other covariates, the mean arterial pressure fluctuations between -5% and 5% were significantly correlated with ICU mortality (odds ratio, 1.296; 95% CI, 1.103-1.521; p = 0.002) and hospital mortality (odds ratio, 1.323; 95% CI, 1.142-1.531; p < 0.001). This relationship remained remarkable in patients with low or high Sequential Organ Failure Assessment scores in the sensitive analysis. Furthermore, external validation on a total of 4,502 individuals revealed that patients in group A still had significantly higher ICU (p < 0.001) and hospital mortality (p < 0.001) than those in group B. CONCLUSIONS: The reduced mean arterial pressure fluctuation (within -5% and 5%) may be associated with ICU and hospital mortality in critically ill patients. PMID- 30247270 TI - Adenosine Triphosphate Release is Required for Toll-Like Receptor-Induced Monocyte/Macrophage Activation, Inflammasome Signaling, Interleukin-1beta Production, and the Host Immune Response to Infection. AB - OBJECTIVES: Monocytes and macrophages produce interleukin-1beta by inflammasome activation which involves adenosine triphosphate release, pannexin-1 channels, and P2X7 receptors. However, interleukin-1beta can also be produced in an inflammasome-independent fashion. Here we studied if this mechanism also involves adenosine triphosphate signaling and how it contributes to inflammasome activation. DESIGN: In vitro studies with human cells and randomized animal experiments. SETTING: Preclinical academic research laboratory. SUBJECTS: Wild type C57BL/6 and pannexin-1 knockout mice, healthy human subjects for cell isolation. INTERVENTIONS: Human monocytes and U937 macrophages were treated with different inhibitors to study how purinergic signaling contributes to toll-like receptor-induced cell activation and interleukin-1beta production. Wild-type and pannexin-1 knockout mice were subjected to cecal ligation and puncture to study the role of purinergic signaling in interleukin-1beta production and host immune defense. MEASUREMENTS AND MAIN RESULTS: Toll-like receptor agonists triggered mitochondrial adenosine triphosphate production and adenosine triphosphate release within seconds. Inhibition of mitochondria, adenosine triphosphate release, or P2 receptors blocked p38 mitogen-activated protein kinase and caspase 1 activation and interleukin-1beta secretion. Mice lacking pannexin-1 failed to activate monocytes, to produce interleukin-1beta, and to effectively clear bacteria following cecal ligation and puncture. CONCLUSIONS: Purinergic signaling has two separate roles in monocyte/macrophage activation, namely to facilitate the initial detection of danger signals via toll-like receptors and subsequently to regulate nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 inflammasome activation. Further dissection of these mechanisms may reveal novel therapeutic targets for immunomodulation in critical care patients. PMID- 30247272 TI - Long-Term Mortality and Hospital Resource Use in ICU Patients With Alcohol Related Liver Disease. AB - OBJECTIVES: Data describing long-term outcomes following ICU for patients with alcohol-related liver disease are scarce. We aimed to report long-term mortality and emergency hospital resource use for patients with alcohol-related liver disease and compare this with two comparator cohorts. DESIGN: Retrospective cohort study linking population registry data. SETTING: All adult general Scottish ICUs (2005-2010) serving 5 million population. PATIENTS: ICU patients with alcohol-related liver disease were compared with an unmatched cohort with Acute Physiology and Chronic Health Evaluation defined diagnoses of severe cardiovascular, respiratory, or renal comorbidity and a matched general ICU cohort. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Outcomes were 5-year mortality, emergency hospital resource use, and emergency hospital readmission. Multivariable regression was used to identify risk factors and adjust for confounders. Of 47,779 ICU admissions, 2,463 patients with alcohol-related liver disease and 3,590 patients with severe comorbidities were identified; 2,391(97.1%) were matched to a general ICU cohort. The alcohol-related liver disease cohort had greater 5-year mortality than comorbid (79.2% vs 75.3%; p < 0.001) and matched general (79.8% vs 63.3%; p < 0.001) cohorts. High liver Sequential Organ Failure Assessment score and three-organ support were associated with 90% 5-year mortality in alcohol-related liver disease patients. After confounder adjustment, alcohol-related liver disease patients had 31% higher hazard of death (adjusted hazard ratio, 1.31; 95% CI, 1.17-1.47; p < 0.001) and used greater resource than the severe comorbid comparator group. Findings were similar compared with the matched cohort. CONCLUSIONS: ICU patients with alcohol related liver disease have higher 5-year mortality and emergency readmission rates than ICU patients with other severe comorbidities and matched general ICU patients. These data can contribute to shared decision-making for alcohol-related liver disease patients. PMID- 30247274 TI - Acute Physiological Responses to an Intensity-And Time-Under-Tension-Equated Single- vs. Multiple-Set Resistance Training Bout in Trained Men. AB - Cintineo, HP, Freidenreich, DJ, Blaine, CM, Cardaci, TD, Pellegrino, JK, and Arent, SM. Acute physiological responses to an intensity-and time under-under tension-equated single- vs. multiple-set resistance training bout in trained men. J Strength Cond Res 32(12): 3310-3318, 2018-Regardless of the setting, proper manipulation of resistance training program design variables is pivotal in eliciting the desired physiological adaptations. Furthermore, how these variables, especially volume and intensity, work together to affect training outcomes is a major topic of investigation. The purpose of this study was to compare the acute biochemical, physiological, and hormonal responses of a single set accentuated eccentric high-intensity training (HIT) protocol to a traditional 3-set protocol to better understand the acute effects of volume. Resistance trained male college students (N = 19; age = 21.11 +/- 2.5 years; height = 174.33 +/- 6.83 cm; body mass = 76.72 +/- 10.24 kg; %BF = 15.53 +/- 6.35%) participated in this study and were randomly assigned to either the 1-set HIT protocol (HIT) or the 3-set traditional (3ST) protocol. Heart rate (HR), blood lactate, salivary testosterone, and salivary cortisol levels were measured before, during, and at multiple time points after the exercise bout. Results showed no differences in average HR or testosterone at any time point between the 2 groups. However, the 3ST group exhibited higher values of peak HR, blood lactate during exercise, and cortisol during and 30 minutes after exercise than the HIT group. This indicated that the 3ST protocol induced greater metabolic stress and disrupted the homeostatic balance to a greater magnitude than the HIT protocol despite similar time under tension. These results show that even when training to momentary muscular failure, volume seems to be a key driver of the training stimulus. PMID- 30247275 TI - Maximal Strength Training Improves Strength Performance in Grapplers. AB - Ovretveit, K and Toien, T. Maximal strength training improves strength performance in grapplers. J Strength Cond Res 32(12): 3326-3332, 2018-The aim of this study was to assess the short-term effects of maximal strength training (MST) as an accessory to grappling training on strength performance in competitive Brazilian Jiu-Jitsu (BJJ) athletes. Fourteen male BJJ athletes underwent measurements of 1 repetition maximum (1RM) in the squat and bench press, rate of force development (RFD) and peak force (PF) in the squat jump, countermovement jump (CMJ) height, and muscular endurance in pull-ups, sit-ups, and push-ups. After baseline measurements, subjects were randomly allocated to either an MST group or control group (CON). The MST intervention consisted of 4 * 4 repetitions at >= 85% of 1RM in the squat and bench press, and 4 sets of pull ups to failure, performed 3* per week. Both groups were instructed to maintain their BJJ training and avoid additional strength training. Maximal strength training improved 1RM in the squat and bench press by 15 +/- 9% (p = 0.02) and 11 +/- 3% (p = 0.03), respectively, and CMJ height by 9 +/- 7% (p = 0.04). Muscular endurance performance increased by 33 +/- 33% in pull-ups (p = 0.03), 32 +/- 12% in push-ups (p = 0.03), and 13 +/- 13% in sit-ups (p = 0.03). Increases in RFD (35 +/- 55%, p = 0.13) and PF (8 +/- 9%, p = 0.09) did not reach significance. No improvements were apparent from BJJ training alone (p > 0.05). These findings suggest that MST is a potent approach to rapid improvements in maximal strength, power, and muscular endurance in active grapplers. PMID- 30247276 TI - Malnutrition and the Orthopaedic Trauma Patient: A Systematic Review of the Literature. AB - OBJECTIVES: To evaluate the available literature for associations between nutrition and outcomes after operative treatment of long bone and long bone periarticular fractures. DATA SOURCES: Systematic review of English-language articles in the MEDLINE, Embase, PubMed, and Cochrane computerized literature databases (through December 2015) using PRISMA guidelines. STUDY SELECTION: Randomized controlled trials, quasi-randomized controlled trials, case-control studies, and cohort studies (retrospective and prospective) involving long bone and long bone periarticular fractures that included the effect of nutritional status on fracture union, time to union, and any related soft-tissue complication were eligible for review. DATA EXTRACTION: Two authors independently extracted data from the selected studies using a standardized data collection form with predefined data fields for demographics, interventions, study methods, complications, and management outcomes. DATA SYNTHESIS: Although one of the original aims of the study was to conduct a meta-analysis, the available literature did not offer sufficient data for meta-analysis. CONCLUSIONS: Although our systematic review demonstrates a possible role for oral nutritional supplementation and vitamin supplementation in the orthopaedic trauma patient, there remains a need for well-designed trials to clarify this role. There is likely benefit to multidisciplinary approaches to nutritional optimization in the orthopaedic trauma patient, and this should be explored further in forthcoming work. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30247273 TI - Beyond Low Tidal Volume Ventilation: Treatment Adjuncts for Severe Respiratory Failure in Acute Respiratory Distress Syndrome. AB - OBJECTIVES: Despite decades of research, the acute respiratory distress syndrome remains associated with significant morbidity and mortality. This Concise Definitive Review provides a practical and evidence-based summary of treatments in addition to low tidal volume ventilation and their role in the management of severe respiratory failure in acute respiratory distress syndrome. DATA SOURCES: We searched the PubMed database for clinical trials, observational studies, and review articles describing treatment adjuncts in acute respiratory distress syndrome patients, including high positive end-expiratory pressure strategies, recruitment maneuvers, high-frequency oscillatory ventilation, neuromuscular blockade, prone positioning, inhaled pulmonary vasodilators, extracorporeal membrane oxygenation, glucocorticoids, and renal replacement therapy. STUDY SELECTION AND DATA EXTRACTION: Results were reviewed by the primary author in depth. Disputed findings and conclusions were then reviewed with the other authors until consensus was achieved. DATA SYNTHESIS: Severe respiratory failure in acute respiratory distress syndrome may present with refractory hypoxemia, severe respiratory acidosis, or elevated plateau airway pressures despite lung protective ventilation according to acute respiratory distress syndrome Network protocol. For severe hypoxemia, first-line treatment adjuncts include high positive end-expiratory pressure strategies, recruitment maneuvers, neuromuscular blockade, and prone positioning. For refractory acidosis, we recommend initial modest liberalization of tidal volumes, followed by neuromuscular blockade and prone positioning. For elevated plateau airway pressures, we suggest first decreasing tidal volumes, followed by neuromuscular blockade, modification of positive end-expiratory pressure, and prone positioning. Therapies such as inhaled pulmonary vasodilators, glucocorticoids, and renal replacement therapy have significantly less evidence in favor of their use and should be considered second line. Extracorporeal membrane oxygenation may be life-saving in selected patients with severe acute respiratory distress syndrome but should be used only when other alternatives have been applied. CONCLUSIONS: Severe respiratory failure in acute respiratory distress syndrome often necessitates the use of treatment adjuncts. Evidence-based application of these therapies in acute respiratory distress syndrome remains a significant challenge. However, a rational stepwise approach with frequent monitoring for improvement or harm can be achieved. PMID- 30247277 TI - Validation of Neck-Shaft Angle Correction After Cephalomedullary Nail Fixation. AB - OBJECTIVES: To validate a neck-shaft angle (NSA) correction formula using the known angle between the medullary nail and lag screw of an indwelling cephalomedullary nail (CMN). METHODS: Pertrochanteric femur fractures were created in 7 synthetic femurs and reconstructed with a CMN. Anteroposterior x rays were taken with the proximal femur in 0, 15, 30, and 45 degrees of internal/external rotation and 10 and 20 degrees of flexion with neutral rotation. The femoral NSA and the nail angle were measured on anteroposterior x rays. The corrected NSA was obtained by multiplying the known nail angle by the quotient of the measured NSA over the measured nail angle. RESULTS: With increasing degrees of internal or external rotation, the difference between the actual and the measured NSA increased. After correction using the known angle of the nail, the measured NSA was reduced to within 3 degrees of the actual NSA over all degrees of rotation. At neutral rotation, 15 degrees of external rotation, and 10 and 20 degrees of hip flexion, there was minimal difference between the actual NSA and the measured NSA, negating the effect of the correction formula. CONCLUSIONS: The measured NSA after CMN of intertrochanteric fractures is altered by hip rotation. This study validates the correction formula, which determines this difference by using the known angle between the lag screw and the nail. PMID- 30247278 TI - Biomechanical Evaluation of Osteoporotic Proximal Periprosthetic Femur Fractures With Proximal Bicortical Fixation and Allograft Struts. AB - OBJECTIVES: To evaluate the strength of proximal bicortical fixation using a novel osteoporotic synthetic bone model of Vancouver B1 periprosthetic proximal periprosthetic femur fractures (PFFs) and to assess the influence of strut allograft augmentation with regard to allowing early assisted weight bearing. The secondary aim was to evaluate whether the strut position, either medial or anterior, influenced the strength of the construct. METHODS: Thirty synthetic osteoporotic femurs were implanted with cemented stems. A segmental defect made distal to the stem simulated a fracture and was repaired with a stainless steel locking compression plate and 2 stainless steel proximal locking attachment plates. Specimens were then divided into 3 groups: no-strut, medial strut, and anterior strut. Cadaveric femoral struts were wired to the specimens. Cyclic axial compression simulated assisted weight bearing and was followed by loading to failure. RESULTS: Medial struts required higher failure load than no-strut (P = 0.008) and more energy to failure than anterior (P = 0.018) or no-strut (P < 0.001). The higher load to failure, however, would not be advantageous in clinical practice because estimates for assisted weight bearing after fractures in average-weight patients are well below these failure loads. Furthermore, all specimens tolerated cyclical loading. All failures occurred distal to the plate originating at the last screw hole. CONCLUSIONS: Failure loads for all groups were above what would be expected for low-demand activities of assisted weight bearing. Therefore, proximal bicortical fixation should allow for early, assisted weight bearing without allograft strut augmentation even with lower density bone. PMID- 30247279 TI - Radiographic and Clinical Outcomes of Periprosthetic Distal Femur Fractures Treated With Open Reduction Internal Fixation. AB - OBJECTIVES: To report outcomes and complications of periprosthetic distal femur fractures (PPDFF) treated with open reduction internal fixation (ORIF) using a plate construct, with or without endosteal augmentation. DESIGN: Retrospective Case Series. SETTING: One Level I trauma center and one tertiary care hospital. PATIENTS/PARTICIPANTS: Forty patients with PPDFFs, treated by 3 surgeons, were identified using an institutional trauma registry. Thirty-two patients with 12 months of clinical and radiographic follow-up were included, and 8 patients were lost to follow-up before 12 months. INTERVENTION: All patients underwent ORIF of the PPDFF with lateral locked plating, and 11 received additional endosteal augmentation using allograft fibula. RESULTS: Thirty-two patients were available for the final follow-up. Ninety-four percent of patients achieved union at an average of 6.5 months postoperatively. Twenty-one percent of patients underwent subsequent surgery, with more than half of those being for removal of implants. Anatomic limb alignment was achieved in all cases (no malunions). Almost half of the patients required assistive devices for ambulation in the long term. CONCLUSIONS: ORIF of PPDFF with direct visualization using periarticular locking plates +/- endosteal strut allograft resulted in a 94% union rate and no deep infections. There was no difference in outcomes between groups treated with or without additional endosteal fibular allograft. However, these are catastrophic injuries in frail patients, and 20% of patients either died or were lost to follow-up, and almost half required an assistive device for ambulation after surgery despite restoration of limb alignment. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30247280 TI - Importance of Mechanoreceptors and Other Neural Structures Within the Anterior Intermeniscal Ligament in the Etiology of Anterior Knee Pain After Tibial Nailing. AB - BACKGROUND: Anterior knee pain is the most common complication after intramedullary tibial nailing. The cause is often multifactorial and varies among individuals. Violation of the anterior intermeniscal ligament (AIL) during intramedullary tibial nailing might be a possible source of postsurgical anterior knee pain. Although there is a certain ambiguity regarding the importance and function of the AIL, neural structures in the AIL tissue might play a significant role with respect to functional purposes and pain perception. METHODS: We subjected 6 AIL specimens to histologic examination to identify the neural structures that are a mandatory requirement as a source of anterior knee pain. Specifically, we performed three-dimensional immunohistochemical investigation of subtyping, orientation, and detailed characterization of neural structures within the AIL tissue. RESULTS: Histologic and three-dimensional immunohistochemical examinations confirmed the presence of neural structures in all 6 AIL specimens. We identified myelinated and unmyelinated nerve fibers, as well as all types of mechanoreceptors. CONCLUSIONS: Free nerve endings are a mandatory requirement for pain perception as a result of AIL violation during tibial nailing. Our verification of all different types of mechanoreceptors in the AIL tissue makes a role of the ligament in knee joint function and proprioception highly probable. Further investigations are necessary to clarify possible correlations between neural supply and function of the AIL. Violation of the ligament during operative procedures should be avoided, although the significance of the AIL is still debated. PMID- 30247281 TI - Intrawound Vancomycin Powder Reduces Bacterial Load in Contaminated Open Fracture Model. AB - OBJECTIVES: To compare the effectiveness of both vancomycin powder and antibiotic bead placement to irrigation and debridement alone in prevention of infection in a contaminated open fracture model in rats. METHODS: In a previously described model of contaminated open fractures, 45 rats had simulated open fractures created, stabilized, and contaminated with Staphylococcus aureus. They were then treated 6 hours later with 3 interventions: irrigation and debridement alone (control group) or in combination with placement of polymethyl methacrylate beads containing vancomycin and tobramycin powders (antibiotic bead group) or placement of 10 mg of intrawound vancomycin powder (powder group). Rats were allowed to recover and then killed 14 days later for harvest of femurs and plates. Femurs and plates were both incubated overnight, and bacterial colonies were counted in each group for comparison. RESULTS: Quantitative counts of bacteria in bone showed significantly reduced growth in both bead and powder groups when compared with control group (P < 0.0001). Quantitative counts of bacteria in plates showed significantly reduced growth in both bead and powder groups when compared with control group (P < 0.0003; 0.029). No significant differences were seen in bacterial growth between bead and powder groups for either bones (P = 0.13) or plates (P = 0.065). CONCLUSIONS: When compared with irrigation and debridement alone, placement of intrawound vancomycin powder significantly decreased bacterial load in a contaminated open fracture model in rats similar to placing antibiotic beads. This may provide an additional adjuvant treatment that does not require a secondary surgery for bead removal. PMID- 30247282 TI - Osteonecrosis After Surgically Repaired Proximal Humerus Fractures Is a Predictor of Poor Outcomes. AB - OBJECTIVES: To determine the effect of osteonecrosis (ON) on the clinical and functional outcome after open reduction and internal fixation of proximal humerus fractures. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENTS: Over a 12-year period, patients were screened and identified on presentation to the emergency department or in the clinical office for inclusion in an institutional review board-approved registry. One hundred sixty-five patients with 166 proximal humerus fractures met inclusion criteria. Eight patients developed radiographic evidence of ON (4.8%). INTERVENTION: Surgical repair of proximal humerus fractures. MAIN OUTCOME MEASURE: Patients were divided into 2 cohorts; 1 cohort being those diagnosed with ON and the other cohort being those who were not. All patients were prospectively followed and assessed for clinical and functional outcomes at the latest follow-up visit (mean = 22.9 months) using the Disabilities of Arm, Shoulder and Hand survey along with ranges of motion of the injured extremity. RESULTS: Average postoperative forward elevation for patients with ON was worse than those without ON (P = 0.002). Additionally, there was a significant difference in Disabilities of Arm, Shoulder and Hand scores at the latest follow-up between the 2 groups (P = 0.026). There was no difference in external rotation or mean length of follow-up between the 2 groups (P > 0.05). CONCLUSIONS: This study demonstrates the negative effects of ON after open reduction and internal fixation of proximal humerus fractures. Those who develop ON have poorer functional and clinical outcomes as compared with patients without ON. Consequently, the development of ON can be used as a predictor of poor outcomes. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30247283 TI - Pedicled Vascularized Bone Graft of the Distal Radius for Recalcitrant Nonunion of the Distal Humerus. AB - OBJECTIVES: To analyze the clinical and radiological outcomes of a series of patients treated with a pedicled vascularized bone graft (VBG) of the distal radius for the treatment of recalcitrant atrophic nonunions of the distal humerus. DESIGN: Retrospective clinical study. SETTING: University-affiliated teaching hospital. PATIENTS: Fifteen patients with supracondylar humeral atrophic nonunions with at least 3 previous failed surgical interventions were included. INTERVENTION: Debridement of the distal humerus nonunion through a posterior elbow approach with provisional fixation was performed. Then, a pedicled VBG was harvested from the distal radius and tunneled back into the humeral bone defect. Iliac crest was used as needed, both for the nonunion and to stabilize the radius. Finally, definitive fixation with 2 locked plates was performed. MAIN OUTCOME MEASUREMENTS: Radiological results, complications, elbow range of motion, Mayo elbow performance score, and subjective pain were evaluated. RESULTS: There were 4 male and 11 female patients, with a mean age of 51 (range, 28-73) years. The mean follow-up period was 46 (range, 37-72) months with a minimum of 3 years. Radiological consolidation was achieved in all patients. Elbow range of motion was >100 degrees in 11 patients and between 50 and 100 degrees in 4 patients. Preoperative Mayo scores were poor in all patients. At final follow-up, Mayo scores were excellent in 3, good in 9, and fair in 3 patients. The mean postoperative visual analog scale score was 1.2 (range 0-3). CONCLUSIONS: Pedicled VBG of the distal radius was shown to be a reliable and effective alternative for the treatment of recalcitrant atrophic nonunions of the distal humerus, when other methods have failed. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30247284 TI - Rate of Open Reduction for Supracondylar Humerus Fractures Varies Across Pediatric Orthopaedic Surgeons: A Single-Institution Analysis. AB - OBJECTIVES: To (1) define a single institution's rate of open reduction for operative pediatric supracondylar humerus (SCH) fractures; (2) describe variability by surgeon in rates of irreducible fracture (IRF) and open reduction; and (3) determine whether variation in opening rate correlated with surgeon experience. DESIGN: Retrospective analytic study. SETTING: Urban tertiary care Level 1 trauma center. PATIENTS/PARTICIPANTS: Twelve fellowship-trained pediatric orthopaedists. MAIN OUTCOME MEASUREMENTS: Rate of open reduction for operatively treated SCH fractures (OTA/AO 13-M/3). RESULTS: One thousand two hundred twenty nine type II SCH fractures (none of which required open reduction) were excluded from the analysis. A total of 1365 other SCH fractures were included: 1302 type III fractures, 27 type IV fractures, and 36 fractures with unspecified type. 2.9% of type III and 22.2% of type IV fractures required open reduction. None of the injuries with unspecified type required open reduction. The rate of open reduction among 11 surgeons ranged from 0% to 15.0% in type III-IV fractures (P = 0.001). 86% (38/44) of open reductions were performed for IRF. In regression analysis, patient age was associated with open reduction for IRF (odds ratio 1.22, P = 0.001), but surgeon years-in-practice (0.321) and number of previous cases (0.327) were not associated with open reduction. Other indications for opening included suspected vascular or neurologic injury. CONCLUSIONS: Open reduction was rarely performed in this sample, but IRF was the dominant indication for opening. We found true variation in surgeons' rates of performing open reductions. More experience was not correlated with decreased likelihood of open reduction. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30247285 TI - Understanding the Opioid Epidemic: Factors Predictive of Inpatient and Postdischarge Prescription Opioid Use After Orthopaedic Trauma. AB - OBJECTIVE: The purpose of this study was to determine which factors influence inpatient and postdischarge opioid use after orthopaedic trauma. DESIGN: Retrospective cohort study. SETTING: Single Level 1 trauma center. PARTICIPANTS: The study included 235 adult trauma patients treated operatively for fracture with minimum 1 overnight hospital stay. INTERVENTION: Operative fracture management. MAIN OUTCOME MEASUREMENT: Total opioid pain medication use, in oral morphine equivalents, in inpatient and postdischarge settings. RESULTS: Controlling for length of stay, inpatient opioid use was negatively correlated with age and positively correlated with Injury Severity Score, intensive care unit (ICU) admission, and baseline tobacco use (P < 0.0001, adjusted R = 0.274). Discharge opioid prescription amount was negatively correlated with age, the presence of a complication, and ICU admission and positively correlated with inpatient opioid use (P < 0.0001, adjusted R = 0.201). Postdischarge opioid use was associated with larger amounts of opioids prescribed at discharge, a patient history of alcohol use at baseline, and ICU admission (P < 0.0001, R = 0.123). CONCLUSION: Nonmodifiable factors accounted for the level of inpatient opioid use in a trauma population. Higher inpatient use predicts larger opioid prescriptions at discharge, whereas larger discharge prescription predicts greater postdischarge opioid use. Strategies to reduce postdischarge opioid use should begin with reductions in inpatient opioid use. Multimodal pain strategies may be needed to achieve this goal. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30247286 TI - Clamshell Osteotomy for Acute Fractures in the Malunion Setting: A Technical Note. AB - Surgical management of lower extremity malunions and acute fractures in the setting of lower extremity deformities presents a unique challenge for orthopaedic surgeons. The objective of this study was to evaluate the outcomes of using the clamshell osteotomy in patients with acute fractures involving a malunion or deformity. A retrospective review of the cases performed by various orthopaedic traumatologists at 4 different trauma centers was performed to identify cases using the clamshell osteotomy from January 2012 to January 2016. Nine clamshell osteotomy cases were identified, 4 presenting fractures in the setting of previous malunions. All osteotomies healed within 15 months (average 6.8 +/- 4.4 SD). In this multicenter case series, we demonstrate that using clamshell osteotomies can result in excellent outcomes for permitting intramedullary nailing of acute fractures in patients with lower extremity deformity. PMID- 30247287 TI - In Response to "To the Editor: Presentation Coagulopathy and Persistent Acidosis Predict Complications in Orthopaedic Trauma Patients": Erratum. PMID- 30247288 TI - Practice Patterns of Stereotactic Radiotherapy in Pediatrics: Results From an International Pediatric Research Consortium. AB - PURPOSE/OBJECTIVES: There is little consensus regarding the application of stereotactic radiotherapy (SRT) in pediatrics. We evaluated patterns of pediatric SRT practice through an international research consortium. MATERIALS AND METHODS: Eight international institutions with pediatric expertise completed a 124-item survey evaluating patterns of SRT use for patients 21 years old and younger. Frequencies of SRT use and median margins applied with and without SRT were evaluated. RESULTS: Across institutions, 75% reported utilizing SRT in pediatrics. SRT was used in 22% of brain, 18% of spine, 16% of other bone, 16% of head and neck, and <1% of abdomen/pelvis, lung, and liver cases across sites. Of the hypofractionated SRT cases, 42% were delivered with definitive intent. Median gross tumor volume to planning target volume margins for SRT versus non-SRT plans were 0.2 versus 1.4 cm for brain, 0.3 versus 1.5 cm for spine/other bone, 0.3 versus 2.0 cm for abdomen/pelvis, 0.7 versus 1.5 cm for head and neck, 0.5 versus 1.7 cm for lung, and 0.5 versus 2.0 cm for liver sites. CONCLUSIONS: SRT is commonly utilized in pediatrics across a range of treatment sites. Margins used for SRT were substantially smaller than for non-SRT planning, highlighting the utility of this approach in reducing treatment volumes. PMID- 30247289 TI - An Uncommon Presentation of a Primary Bone Tumor: Anti-AMPA (Anti-alpha-Amino-3 Hydroxy-5-Methyl-4-Isoxazolepropionic acid) Receptor Limbic/Paraneoplastic Encephalitis as a Presenting Feature of Ewing Sarcoma. AB - Anti-AMPA (anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor limbic encephalitis is a rare autoimmune syndrome. It can be associated with an underlying malignancy, such as lung, breast, or thymus. We are reporting a case of a 19-year-old patient who presented with a 2-week history of confusion and short-term memory loss. A magnetic resonance imaging of brain showed increased T2 hyperintensity within the hippocampi bilaterally. Cerebrospinal fluid analysis was positive for anti-AMPA receptor antibodies. A computed tomography revealed multiple pulmonary metastases as well as an expansile lucent and sclerotic lesion in the ilium, which was subsequently biopsied. Histopathology confirmed a diagnosis of Ewing sarcoma (ES). Fluorescence in situ hybridization testing of the specimen identified EWSR1 (22q12.2) signal rearrangements in 80% of cells scored. To date, this is the first case report describing anti-AMPA receptor limbic/paraneoplastic encephalitis as a presenting feature of ES. Although it is rare, the possibility of ES may be considered in young patients presenting with anti-AMPA receptor limbic encephalitis. PMID- 30247290 TI - Cone Beam CT-Guided Bronchoscopy: Here to Stay? PMID- 30247291 TI - 19-G EBUS: Why, When, and How? PMID- 30247292 TI - Pneumothorax After a Bronchoalveolar Lavage. PMID- 30247293 TI - Reversed Halo Sign on Radial EBUS Imaging. PMID- 30247294 TI - The Utility of Linear Endobronchial Ultrasound for the Incidental Finding of Dieulafoy Disease of the Bronchus. PMID- 30247296 TI - Bronchial Thermoplasty in an Elderly Severely Asthmatic Patient With Obstructive Sleep Apnea. PMID- 30247295 TI - Endobronchial Foreign Body Removal Using a Coronary Artery Balloon Catheter. PMID- 30247297 TI - Successful Treatment of Recurrent Inflammatory Pseudotumor With High-dose Prednisone. PMID- 30247299 TI - Foreword. PMID- 30247298 TI - Pulmonary Sclerosing Pneumocytoma. PMID- 30247300 TI - Career Expectations of Obstetrics and Gynecology Residents and Future Residents. AB - OBJECTIVE: To understand contemporary fourth-year medical student and resident career expectations in obstetrics and gynecology. METHODS: Students invited for obstetrics and gynecology residency interviews and residents (postgraduate years 1-4) at the University of Colorado, University of Washington, University of California San Francisco, Loyola University, St. Joseph's Hospital, and Texas A&M in 2016-2017 received a voluntary, electronic survey regarding career expectations. Questions were compared between students and residents using a chi test for category responses and for age a two-sample t test. RESULTS: Response rates were similar between students (68% [277/409]) and residents (63% [97/153]). Residents compared with students were more frequently planning to enter private practice (43% vs 19%) and less frequently planning an academic career (19.4% vs 30.4%) or subspecialties (38% vs 51%) (P<.001). Although most respondents planned to work full-time (96% vs 94.9%), 83% (vs 94%) of residents planned to work greater than 40 hours per week (P<.001). Respondents reported greater than $150,000 in educational debt (65%) and anticipated starting salary greater than $200,000 (89%). More residents planned to retire by age 60 years (23% vs 7%) (P<.001). Thirty-eight percent of residents reported having changed career plans during residency, citing work-life balance as the most important factor (89%). DISCUSSION: Trainees' career expectations appear to evolve over time moving toward a higher likelihood to pursue private practice, work fewer hours, and retire earlier despite large educational debt. It is critical that the specialty understand these trends when planning to address national workforce needs. PMID- 30247301 TI - Trends in Fellow Education Research Among Obstetric and Gynecologic Subspecialties. AB - OBJECTIVE: To evaluate the frequency at which fellow education-related abstracts are presented at national meetings and compare presentation rates before and after the accreditation transition. METHODS: This cross-sectional study evaluated abstracts from the five most recent national meetings of the Society for Maternal Fetal Medicine (SMFM), the Society of Gynecologic Oncology, the American Society for Reproductive Medicine (ASRM), the American Urogynecologic Society (AUGS), and the Council on Resident Education in Obstetrics and Gynecology (CREOG) and Association of Professors of Gynecology and Obstetrics (APGO). Three independent reviewers assessed abstracts for education-specific content. Abstracts were included if two or greater reviewers identified them as related to fellow education. Descriptive statistics were used for data analysis. RESULTS: Fourteen thousand six hundred thirty abstracts were presented at obstetric and gynecologic subspecialty meetings between 2012 and 2017. Of these, 29 (0.20%) pertained to fellows' education. The percent of total abstracts that were fellow-related remained relatively constant over time. Of the four subspecialties, the AUGS presented fellow education research almost five times more frequently than ASRM (P<.01) or SMFM (P<.01). Over the study period, 1,283 abstracts were presented at the CREOG and APGO meeting, with four (0.31%) pertaining to fellows' education. At the CREOG and APGO meeting, fellow-related abstracts did not appear to increase over the period studied. CONCLUSION: Research regarding fellows' education is rarely presented at national meetings, representing less than 1% of all abstracts, and has not substantially increased since the transition to the Accreditation Council for Graduate Medical Education. PMID- 30247302 TI - Team-Based Learning Sessions Compared With Traditional Lecture in the Obstetrics and Gynecology Clerkship. AB - OBJECTIVE: To estimate the effects of team-based learning sessions as part of the curriculum for the obstetrics and gynecology clerkship. METHODS: This is a prospective cohort study of clinical clerkship curriculum undertaken in Kansas City and Wichita between 2013 and 2017. A team-based learning curriculum included the same topics as the traditional lecture-format lectures and was instituted in Kansas City. The primary outcome was the obstetrics and gynecology National Board of Medical Examiners examination given at the end of the clerkship, both before and after the implementation of the team-based learning curriculum in Kansas City. An online questionnaire issued by the University of Kansas School of Medicine assessed learner satisfaction. A voluntary multiple-choice examination taken by both Kansas City and Wichita students months after clerkship completion assessed knowledge retention. RESULTS: The post-team-based learning Kansas City cohort scored a mean of 78.6 (95% CI 77.8-79.4) on the National Board of Medical Examiners obstetrics and gynecology subject examination compared with the pre team-based learning Kansas City cohort scoring a mean of 74.6 (95% CI 73.6-75.6, P<.001). Student surveys did not show significant differences in satisfaction between pre-team- and post-team-based learning cohorts in Kansas City. There was no significant difference in knowledge retention scores between Kansas City and Wichita cohorts. DISCUSSION: We found significant improvement in National Board of Medical Examiners subject examination scores, which is likely the result of multiple curriculum changes, including the shift from didactic sessions to the active learning strategy of team-based learning. Team-based learning has provided a beneficial and stimulating learning experience for students. PMID- 30247303 TI - Development and Validation of a Simulation Model for Laparoscopic Colpotomy. AB - OBJECTIVE: To develop a realistic simulation model for performance of laparoscopic colpotomy and evaluate its construct and face validity. METHODS: A simulation model was developed and constructed using polyvinyl chloride piping, a uterine manipulator, and synthetic vaginal tissue paired with a commercially available laparoscopic trainer. An observational study was conducted to validate the simulation model for use as a teaching tool. Construct validity was measured through performance evaluation of novice and expert surgeons using a standard and modified Global Operative Assessment of Laparoscopic Skills scale with possible score ranges of 5-25 and 5-40, respectively. Expert surgeons included attending surgeons across various gynecologic subspecialties who teach total laparoscopic hysterectomy to trainees and perform more than 50 total laparoscopic hysterectomies annually. Novice surgeons included residents who perform total laparoscopic hysterectomy as part of their training. Standards were set using a modified contrasting groups approach. Interrater reliability was calculated using Kendall's tau correlation coefficient. Participants were surveyed regarding the realism of the model and its utility as a teaching tool to assess face validity. RESULTS: Five expert and 15 novice surgeons volunteered to participate. Expert surgeons scored higher than novice surgeons on the Global Operative Assessment of Laparoscopic Skills scale (22.8+/-1.52 vs 13.53+/-2.69, respectively) with a mean difference of 9.27 (95% CI 7.12-11.4, P<.01) and on a modified Global Operative Assessment of Laparoscopic Skills scale (36.9+/-2.19 vs 22.6+/-3.95, respectively) with a mean difference of 14.30 (95% CI 11.2-17.4, P<.01). Suggested passing range was set at 30.5-32.5 out of 40 total points. Kendall's tau interrater reliability was 0.86 (95% CI 0.798-0.923) and 0.87 (95% CI 0.818 0.922), respectively. All participants agreed that the training model was useful for teaching and learning laparoscopic colpotomy and for assessing the learner's ability to perform colpotomy before live surgery. CONCLUSION: This validated simulation system offers novice surgeons an opportunity to practice the skill set necessary to perform laparoscopic colpotomy efficiently and may be used as an educational tool. PMID- 30247304 TI - An Interactive Holographic Curriculum for Urogynecologic Surgery. AB - BACKGROUND: Urogynecologic surgery, transvaginal pelvic floor surgery in particular, requires learning by feel and high-volume pattern recognition. In the era of limited duty hours and case numbers, we sought to develop a curriculum, one that can be self-guided, to help trainees develop a spatial understanding of the relationships of pelvic floor musculature, ligamentous supports, and surrounding neurovasculature outside of the operating room. INSTRUMENT: We created and piloted an innovative interactive holographic using an augmented reality headset to teach surgical anatomy, procedural steps, recognition, and management of the uterosacral ligament suspension and sacrospinous ligament fixation, the two most common native tissue vaginal prolapse repairs. EXPERIENCE: Our curriculum was independently trialed by obstetrics and gynecology residents and subspecialty fellows and was widely accepted by trainees, postgraduate levels 1-6. As compared with usual self-study, 88% ranked the modules as "much" or "very much better" and 81% would be "likely" or "very likely" to use mixed reality smartglasses to prepare for surgery. CONCLUSION: This interactive holographic curriculum is a novel technique to teach complex pelvic floor anatomy, key steps, and management of complications of the uterosacral ligament suspension and sacrospinous ligament fixation. It is widely accepted by obstetrics and gynecology residents and gynecologic subspecialty fellows. PMID- 30247305 TI - Short Communication: Evaluation of infliximab and anti-infliximab LISA-TRACKER immunoassays for the therapeutic drug monitoring of SB2 infliximab biosimilar. AB - BACKGROUND: SB2, an infliximab (IFX) biosimilar to the reference infliximab (R.I.) product (Remicade), received approval in EU for all IFX indications. Many decision algorithms based on the measurement of IFX trough levels and antibodies to infliximab (ATI) are being increasingly used to optimize IFX treatment. The aim of our study was to evaluate if the biosimilar SB2 could be efficiently monitored using the LISA-TRACKER IFX and anti-IFX assays developed by Theradiag (Croissy Beaubourg, France). METHODS: Standard curves of R.I. and SB2 were compared and then accuracy of the LISA-TRACKER IFX assay in detecting the spiked concentration of SB2 was measured. Levels of IFX from SB2 spiked samples and R.I. clinical samples were calculated. Intra-run and inter-run imprecision were also measured with SB2 spiked samples. Ability of polyclonal antibodies directed against R.I. to block the detection of SB2 using the LISA-TRACKER IFX assay and the capacity of SB2 to block the detection of anti-R.I. antibodies using the LISA TRACKER anti-IFX assay were tested. RESULTS: Twelve patients treated with SB2 including 2 patients with SB2-specific antibodies were measured with the LISA TRACKER anti-IFX assay. We demonstrated that the LISA-TRACKER assay is suitable for the quantification of SB2 in human serum samples. The percentage of recovery was between 82% and 113%. High intra-run and inter-run imprecision were obtained with the LISA-TRACKER infliximab assay for the quantification of SB2 (SD ranged from 3.3 to 17.9%). The SB2-blocking capacity of R.I. polyclonal antibodies in spiked samples was demonstrated with inhibition between 80% and 97%. SB2 trough levels and anti-SB2 antibodies has also been confirmed in SB2-treated patients. CONCLUSIONS: LISA-TRACKER IFX and anti-IFX assays are suitable for the monitoring of patients treated with SB2. PMID- 30247307 TI - Day of Admission is Associated With Variation in Geriatric Hip Fracture Care. AB - INTRODUCTION: The transition to bundled payment reimbursement for geriatric hip fractures has incentivized the identification of avoidable inefficiencies in the cost and quality of care. Although a "weekend effect" has been described with regard to hip fracture mortality, measures of efficiency according to the day of hip fracture admission are currently unclear. METHODS: We identified 62,303 patients aged 65 years or older with a primary diagnosis of femoral neck or intertrochanteric hip fracture in the New York Statewide Planning and Research Cooperative System between 2009 and 2014. Outcome measures included preoperative delay, postoperative length of stay (LOS), and cost of admission. RESULTS: Preoperative delay was longer for weekend admissions, but shorter for admissions on Wednesday, Thursday, and Friday. Postoperative LOS was longer for admissions on Tuesday, Wednesday, and Thursday. Discharge rates varied considerably according to the day of admission, ranging from 12% to 43% by hospital day 4 and 53% to 72% by hospital day 6. No differences in cost according to day of admission were found once preoperative delay and postoperative LOS were accounted for. DISCUSSION: Notable variation exists in hospitalizations for geriatric hip fracture depending on the day of admission. Our data suggest the presence of a weekend effect, in which changes in staffing of surgical, medical, and ancillary services lead to increased waiting times for surgery for new admissions and delays in discharge of early- and mid-week admissions. LEVEL OF EVIDENCE: Level III, retrospective study. PMID- 30247306 TI - Optimal Management of Tethered Surgical Drains: A Cadaver Study. AB - BACKGROUND: Tethered drains are a complication of drain usage and may result in unintentional retained broken drains, as well as anxiety and uncertainty for the surgeon and the patient. To date, no study has examined the optimal approach for management and removal of tethered drains. METHODS: The study design sought to identify suture size, mechanism of drain fixation (through versus around), points of constriction (one versus multiple) and the efficacy of weighted traction as potential sources of tethered drains by means of four study arms. (1) Arm one compared drains sutured through the tubing versus a tight closure of the surrounding fascia, which were then subjected to weighted suspension. (2) Arm two compared drains sutured into the fascia using eight each of 4-0, 2-0 and 0 vicryl and then subject to manual traction. (3) Arm three compared drains sutured to the fascia through the tubing versus local tissue incarceration followed by manual traction. (4) Lastly, group four examined drains tethered at two distinct points after which they were subject to manual traction. RESULTS: Our results showed a 25% drain retention rate when manual traction was applied to 0 vicryl and 2-0 vicryl suture. In contrast, there were no instances of drain retention when suture was closed with 4-0 vicryl. When evaluating for multiple points of fixation, drains tethered in two locations were retained in 87.5% of trials versus drains with a single tether point (25%) representing a statistical significance (P = 0.041). There was no difference in rates of drain retention when pierced through the tubing versus incarcerated in local fascia. Only one of the 16 drains was successfully removed by weighted suspension (8.3%). Attempts at manual traction following weighted suspension resulted in a 50% drain retention rate which was higher than the rates of immediate manual traction (18.8%). CONCLUSION: Our results found that manual traction is a reasonable first line approach to address drains tethered by all methods and suture sizes. The use of weighted traction for the management of tethered drains is less effective than manual traction and may result in more retained drain fragments. LEVEL OF EVIDENCE: Level IV. PMID- 30247308 TI - Outpatient Total Hip Arthroplasty in the United States: A Population-based Comparative Analysis of Complication Rates. AB - INTRODUCTION: With healthcare expenditure in the national forefront, outpatient arthroplasty is an appealing option in select patient populations. The purpose of this study was to determine the complication rates associated with outpatient total hip arthroplasty (THA) in comparison to standard inpatient THA. METHODS: We performed a retrospective review of the Humana subset of the PearlDiver insurance records database to identify patients undergoing THA (Current Procedural Terminology-27130 and Current Procedural Terminology-27132) as either outpatients or inpatients from 2007 to 2016. Multivariate logistic regression adjusting for age, gender, and Charlson Comorbidity Index were used to calculate odds ratios of complications among outpatients undergoing THA relative to inpatients undergoing THA. RESULTS: The query identified 2,184 patients who underwent outpatient THA and 73,596 patients who underwent inpatient THA. The median age was in the 65 to 69 age group and in the 70 to 74 age group for the outpatient and inpatient cohorts, respectively (P < 0.001). Outpatients undergoing THA had a significantly lower incidence of comorbid hypertension (P < 0.001), cerebrovascular disease (P = 0.001), obesity (P = 0.017), chronic obstructive pulmonary disorder (P = 0.045), and chronic kidney disease (P = 0.049). The incidence of both outpatient THA (P = 0.001) and inpatient THA (P < 0.001) increased over the study period. After adjusting for age, gender, and Charlson Comorbidity Index, patients undergoing outpatient THA had comparable rates of all queried surgical complications, including component revision, irrigation and debridement, and hip dislocation at 1 year. Rates of postoperative medical complications were also comparable between the two cohorts. CONCLUSION: Outpatient THA is increasing in frequency nationwide and has comparable postoperative complication rates. With its potential to minimize arthroplasty care costs, outpatient THA is a safe and effective option among appropriately selected patients. PMID- 30247309 TI - Biomechanics and Clinical Outcomes of Partial Meniscectomy. AB - Partial meniscectomy for meniscus tears is one of the most common procedures performed by orthopaedic surgeons. Much research has been done to evaluate the biomechanical consequences and clinical outcomes from meniscus debridement. Biomechanically, as the portion of the meniscus that is removed increases, greater contact pressures are experienced by the cartilage, which leads to altered knee mechanics. The use of partial meniscectomy to manage degenerative meniscus tears in knees with mild preexisting arthritis and mechanical symptoms may be beneficial; however, its routine use in the degenerative knee over physical therapy alone is not supported. In younger populations, partial meniscectomy may provide equal long-term symptom relief, earlier return to play, and lower revision surgery rate compared with meniscal repair. Partial meniscectomy may result in earlier development of osteoarthritis. Treatment should be patient specific in a shared-decision making process with the patient after discussion about known outcomes. PMID- 30247310 TI - Validation of Patient-reported Outcomes Measurement Information System Computer Adaptive Tests in Lumbar Disk Herniation Surgery. AB - INTRODUCTION: Inadequate validation, floor/ceiling effects, and time constraints limit utilization of standardized patient-reported outcome measures. We aimed to validate Patient-reported Outcomes Measurement Information System (PROMIS) computer adaptive tests (CATs) for patients treated surgically for a lumbar disk herniation. METHODS: PROMIS, CATs, Oswestry Disability Index, and Short Form-12 measures were administered to 78 patients treated with lumbar microdiskectomy for symptomatic disk herniation with radiculopathy. RESULTS: PROMIS CATs demonstrated convergent validity with legacy measures; PROMIS scores were moderately to highly correlated with the Oswestry Disability Index and Short Form-12 physical component scores (r = 0.41 and 0.78, respectively). PROMIS CATs demonstrated similar responsiveness to change compared with legacy measures. On average, the PROMIS CATs were completed in 2.3 minutes compared with 5.7 minutes for legacy measures. DISCUSSION: The PROMIS CATs demonstrate convergent and known groups' validity and are comparable in responsiveness to legacy measures. These results suggest similar utility and improved efficiency of PROMIS CATs compared with legacy measures. LEVELS OF EVIDENCE: Level II. PMID- 30247311 TI - Hemolysis Is a Diagnostic Adjuvant for Propionibacterium acnes Orthopaedic Shoulder Infections. AB - INTRODUCTION: The purpose of this study was to further evaluate the pathogenicity of hemolytic and nonhemolytic phenotypes of Propionibacterium acnes (P acnes) isolates from shoulders of orthopaedic patients. METHODS: Thirty-one patient records were reviewed, which had a positive P acnes shoulder culture from joint aspiration fluid and/or intraoperative tissues for demographics, clinical course, culture, and laboratory data. Patients were categorized as definite infection, probable infection, or probable contaminant. Antibiotic resistance patterns and hemolysis characteristics were subsequently analyzed. RESULTS: Hemolysis demonstrated 100% specificity with a positive predictive value of 100% and 80% sensitivity with a negative predictive value of 73% for determining definite and probable infections. Hundred percent of the patients in the hemolytic group and only 27% of patients in the nonhemolytic group were classified as infected. Presenting inflammatory markers were markedly higher in the hemolytic group. Clindamycin resistance was found in 31% of the hemolytic strains, whereas no antibiotic resistance was observed in the nonhemolytic group. CONCLUSION: Hemolytic strains of P acnes exhibit enhanced pathogenicity to their host by eliciting a more prominent systemic inflammatory response, increased antibiotic resistance, and a more challenging clinical course. Hemolysis may serve as a specific marker for assisting in diagnosing true infection with P acnes. LEVEL OF EVIDENCE: Level III retrospective comparative study. PMID- 30247312 TI - Chronic Medial Epicondyle Avulsion: Technique of Fragment Excision and Ligament Reconstruction With Internal Brace Augmentation. AB - Medial epicondyle fracture nonunions of the elbow may lead to symptomatic instability in the high-demand or overhead athlete. These injuries are challenging to treat surgically because of the small residual bony fragment, the scarred and shortened chronically injured ulnar collateral ligament (UCL), which prevents it from being mobilized and reduced to its native position. To date, most described methods aim at reducing the displaced fragment and achieving union with the humerus. This usually can only be accomplished by releasing of the scarred UCL to mobilize the fragment. The scarred and attenuated residual ligament is then repaired to restore stability but is often inadequate to sustain high-level valgus loads. We describe a technique of excision of the bony fragment and UCL reconstruction with allograft, augmented with internal brace to provide medial stability to the elbow. The described method allows proper tensioning of the graft and provides immediate and secure fixation. PMID- 30247313 TI - Objective Predictors of Grit, Self-Control, and Conscientiousness in Orthopaedic Surgery Residency Applicants. AB - INTRODUCTION: The purpose of this study was to identify objective predictors of grit, self-control, and conscientiousness in orthopaedic surgery residency applicants. METHODS: The following attributes were assessed in 455 applicants: grit, self-control, conscientiousness, consistency of interest, perseverance of effort, and ambition. These measures were correlated with standard, objective demographics obtained during the application process. RESULTS: Alpha Omega Alpha status, additional degrees, and number of publications did not predict any of the studied attributes. Grit increased with age (P < 0.001) but decreased with increasing board scores (P = 0.004). Former collegiate athletes demonstrated greater grit (P < 0.001), consistency of interest (P = 0.007), perseverance (P = 0.006), and self-control (P = 0.019). Female applicants demonstrated more grit (P = 0.044), consistency of interest (P = 0.003), and conscientiousness (P = 0.029) than males. Applicants with military experience had increased ambition (P = 0.033) and conscientiousness (P = 0.001). CONCLUSION: Overall, orthopaedics applicants possess increased grit compared with the general public, and a number of objective variables reliably predicted the studied attributes. LEVEL OF EVIDENCE: Level III, Cross-sectional study. PMID- 30247315 TI - Equivalent Outcomes with Retransplantation and Primary Liver Transplantation in the Direct Acting Antiviral Era. AB - BACKGROUND: The present multicenter study investigated whether equivalent outcomes to primary LT could be achieved with reLT and whether improvements in outcomes have taken place over time, particularly in the Direct Acting Antiviral (DAA) Era. METHODS: All reLT performed at Mayo Clinic-Florida, Mayo Clinic Rochester and Mayo Clinic-Arizona were divided into Era 1 (2002-2007), Era 2 (2008-2012) and Era 3 (2013-2017) based on the date of reLT. RESULTS: Improvement in graft survival (GS) following reLT was seen over the 3 eras (p<0.001). In Era 1 GS following reLT was inferior to Primary LT (p<0.001), while no difference was seen between reLT and Primary LT in Era 2 (p=0.68) or in Era 3 (p=0.36). A significantly higher proportion of patients achieved sustained viral response(SVR) within the first year following reLT in each subsequent era (Era 1: 10.3%, Era 2: 22.5% and Era 3: 100%) (p<0.001). GS was superior in patients undergoing reLT for recurrent HCV who achieved SVR following reLT compared to those who did not (p=0.03). CONCLUSIONS: Results similar to primary LT were achieved in Era 3. These improvements coincide with the availability of DAAs, which resulted in a 100% SVR rate in Era 3 and a decrease in the number of patients undergoing reLT for recurrent HCV. The historic dogma that reLT results in inferior outcomes should be revisited. PMID- 30247314 TI - Building Kidney Exchange Programmes in Europe - An Overview of Exchange Practice and Activities. AB - BACKGROUND: Considerable differences exist among the living donor Kidney Exchange Programmes (KEPs) that are in use and being built in Europe, contributing to a variation in the number of living donor transplants [6]. Efforts of European KEPs to exchange (best) practices and share approaches to address challenges have, however, been limited. METHODS: Experts from 23 European countries, collaborating on the ENCKEP COST Action, developed a questionnaire to collect detailed information on the functioning of all existing KEPs in Europe, as well as their opportunities and challenges. Following a comparative analysis, results were synthesised and interpreted by the same experts. RESULTS: The practices, opportunities and challenges reported by 17 European countries reveal that some of the 10 operating programmes are mature, while others are in earlier stages of development. Over 1300 transplants were performed through existing KEPs up to the end of 2016, providing approximately 8% of their countries' living kidney donations in 2015. All countries report challenges to either initiating KEPs or increasing volumes. Some challenges are shared, whilst others differ because of differences in context (eg, country size, effectiveness of deceased donor programme) and ethical and legal considerations (eg, regarding living donation as such, nonrelated donors, and altruistic donation). Transnational initiatives have started in Central Europe, Scandinavia, and Southern Europe. CONCLUSIONS: Exchange of best practices and shared advancement of national programmes to address existing challenges, aided by transnational exchanges, may substantially improve access to the most (cost) effective treatment for the increasing number of patients suffering from kidney disease.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 30247316 TI - A Randomized Study of Quantiferon-CMV-Directed Versus Fixed Duration Valganciclovir Prophylaxis to Reduce Late CMV Following Lung Transplantation. AB - BACKGROUND: We provide the results of the first interventional study of CMV specific immune monitoring to direct the length of antiviral prophylaxis in lung transplantation (LTx). METHODS: Patients (n = 118) at risk of CMV infection were randomized 1:2 to either 5 months or variable length valganciclovir prophylaxis (5-11 months post-LTx), as determined by the QuantiFERON (QFN)-CMV assay. Patients with a negative QFN-CMV assay (<0.2 IU/ml) received prolonged valganciclovir prophylaxis. RESULTS: The primary end-point that was the incidence of CMV infection in the lung allograft within 18 months of LTx, was significantly reduced in the QFN-CMV directed arm (37% vs 58%, p = 0.03). Secondary end-points that included blood viremia, acute rejection and chronic lung allograft dysfunction (CLAD) did not differ between the 2 arms. Of the 80/118 patients who ceased antiviral prophylaxis at 5 months, the incidence of viremia (> 600 copies/ml) within the blood was significantly reduced in patients with a positive QFN-CMV assay compared to those without protective immunity (13% vs 67%, p = 0.0003), as was the incidence of severe viremia (>10,000 copies/ml) (3% vs 50%, p < 0.001). Ceasing antiviral prophylaxis at 11 months in patients with a negative assay was associated with a 25% incidence of late CMV viremia. CONCLUSIONS: CMV immune monitoring allows an individualised approach to CMV prophylaxis and reduces late CMV infection within the lung allograft. PMID- 30247317 TI - Waitlisted Patients and Serious Fall: May Have Implications After All! PMID- 30247319 TI - Recent History of Serious Fall Injuries and Posttransplant Outcomes among U.S. Kidney Transplant Recipients. AB - BACKGROUND: Serious fall injuries are associated with poor outcomes among dialysis patients, but whether these associations hold in patients with a history of serious fall injury before kidney transplantation is unknown. METHODS: In national administrative data, 22 474 U.S. adults receiving a first kidney transplant in 2011-2014 with at least 1 year of follow-up prior to transplant were identified. Serious fall injuries in the year prior to transplant were identified using diagnostic codes for falls and simultaneous fractures, dislocations, or head trauma in inpatient or outpatient claims. We used multivariable Cox proportional hazards models to estimate associations of incident posttransplant outcomes with serious fall injury in the year prior to transplant. RESULTS: A total of 620 recipients (2.8%) had serious fall injuries prior to transplant and were more likely to be white, female, and have more comorbid conditions than those without a fall injury. While posttransplant recipient survival did not differ by recent serious fall injuries (HR=1.03; 95% CI 0.78-1.36), these injuries were associated with 33% higher rates of graft failure (HR=1.33; 95% CI 1.03-1.72). Patients with serious fall injuries spent 12.1% of posttransplant follow-up hospitalized, a 3.3-fold higher rate than those without a fall, and had nearly 2-fold higher rates of skilled nursing facility utilization (HR=1.98; 95% CI 1.52-2.57). CONCLUSIONS: Serious fall injuries are independently associated with significantly greater resource requirements and lower graft survival. Further study is needed to delineate the relationship between falls and adverse outcomes in transplant and reduce the incidence and deleterious effects of these events. PMID- 30247318 TI - Effect of the Selective NLRP3 Inflammasome Inhibitor mcc950 on Transplantation Outcome in a Pig Liver Transplantation Model with Organs from Donors after Cardiac Death Preserved by Hypothermic Machine Perfusion. AB - BACKGROUND: We investigated whether the outcome of organs from donors after cardiac death (DCD) can be improved by the addition of mcc950 to the perfusate of the hypothermia machine perfusion (HMP) system and intravenous mcc950 injection after transplantation in a pig liver transplantation model. METHODS: Thirty-six healthy Bama mini pigs randomized into 3 groups. All the DCD livers were preserved in an HMP system after 2 h of simple cold storage (SCS).In HMP-Postop group, mcc950 was added to the perfusate; in the control group and Postop group, the perfusate was normal LPS. After transplantation, the pigs in the Postop group and HMP-Postop group were intravenously administered 3 mg/kg mcc950, at the time of reperfusion and on day 2 and day 3 after transplantation. During the 3-day follow-up period, general operative characteristics, and serological markers and histological features related to ischemia reperfusion injury were examined. RESULTS: The HMP-Postop group suffer the lightest ischemia reperfusion injury(IRI),and functioned best after transplantation. Model for the Early Allograft Function Score (MEAF, predictor of long-term survival), degree of injury in the hepatocytes and rate of apoptosis was lowest in the HMP-Postop group. Further, in the HMP-Postop group, the NLRP3 inflammasome pathway activation was lowest, and the level of IL-1beta was lowest. Postop group functioned better than control group, but not comparable with HMP-Postop group. CONCLUSIONS: The outcome of DCD organs can be improved by the addition of mcc950 to the perfusate of the HMP system and intravenous injection of mcc950 after transplantation. PMID- 30247320 TI - Novel Therapeutic Approaches to Allosensitization and Antibody-Medicated Rejection. AB - Modification of pathogenic antibodies for autoimmune diseases illuminated the biologic relevance of B cells, plasma cells and pathogenic antibodies in autoimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation and the production of immune stimulating and immune modulatory cytokines. Repurposing these drugs from autoimmunity and cancer immunotherapy has yielded important advancements in the care of ABMR patients and novel drug development aimed at HLA desensitization have recently emerged. We now stand on an important threshold that promises many advances in the care of our allosensitized patients. We hope these initial advances will encourage basic scientist, clinical investigators, industry, National Institutes of Health (NIH), our academic societies and the FDA to continue support of these important objectives. These advances clearly have implications for sensitized patients receiving solid organ transplants and ABMR treatment. Modification of alloimmunity and alloantibodies will also have relevance to xenotransplantation where the xenoantibodies present a formidable obstacle to advancement of this important therapy. Working together, we can advance transplant therapeutics where biologic agents are likely to play novel and important roles. Here we discuss novel drugs emerging in this area. PMID- 30247322 TI - ALPPS Versus Conventional Two-stage Hepatectomy in Patients With Advanced Colorectal Liver Metastases. PMID- 30247321 TI - Provider Characteristics Associated With Outpatient Opioid Prescribing After Surgery. AB - OBJECTIVE: To characterize differences in postoperative opioid prescribing across surgical, nonsurgical, and advanced practice providers. BACKGROUND: There is a critical need to identify best practices around perioperative opioid prescribing. To date, differences in postoperative prescribing among providers are poorly understood. METHODS: This is a retrospective multicenter analysis of commercial insurance claims from a statewide quality collaborative. We identified 15,657 opioid-naive patients who underwent a range of surgical procedures between January 2012 and October 2015 and filled an opioid prescription within 30 days postoperatively. Our primary outcome was total amount of opioid filled per prescription within 30 days postoperatively [in oral morphine equivalents (OME)]. Hierarchical linear regression was used to determine the association between provider characteristics [specialty, advanced practice providers (nurse practitioners and physician assistants) vs. physician, and gender] and outcome while adjusting for patient factors. RESULTS: Average postoperative opioid prescription amount was 326 +/- 285 OME (equivalent: 65 tablets of 5 mg hydrocodone). Advanced practice providers accounted for 19% of all prescriptions, and amount per prescription was 18% larger in this group compared with physicians (315 vs. 268, P < 0.001). Primary care providers accounted for 13% of all prescriptions and prescribed on average 279 OME per prescription. The amount of opioid prescribed varied by surgical specialty and ranged from 178 OME (urology) to 454 OME (neurosurgery). CONCLUSIONS: Advanced practice providers account for 1 in-5 postoperative opioid prescriptions and prescribe larger amounts per prescription relative to surgeons. Engaging all providers involved in postoperative care is necessary to understand prescribing practices, identify barriers to reducing prescribing, and tailor interventions accordingly. PMID- 30247324 TI - Workplace Bullying Among Surgeons-the Perfect Crime. PMID- 30247323 TI - Patient-specific 3D Printing: A Novel Technique for Complex Pediatric Renal Transplantation. AB - OBJECTIVE: The authors investigated a novel application of patient-specific three dimensional (3D) printing, to enhance preoperative, multidisciplinary planning in complex, living-donor pediatric renal transplantation. SUMMARY BACKGROUND DATA: For children with end-stage kidney disease, the transplantation of adult-sized, living-donor kidneys into small recipients (<20 kg) with increasingly complex structural anomalies can be difficult. Establishing the operative feasibility in such cases demands a surgical understanding of anatomy to be derived from medical imaging. However, this is hampered by the representation of complex structures in 2D, the inherent interpretive expertise this demands, and the challenge of conveying this appreciation to others. METHODS: We report the novel use of patient-specific 3D printed models to achieve personalized management for 3 children who underwent living-donor renal transplantation. Each presented a unique surgical challenge that would otherwise prevent preoperative determination of transplantation feasibility. Patient-specific geometries were segmented from imaging data and fabricated using polyjet, 3D printing technology. Models were verified by an expert radiologist and presented during multidisciplinary discussion and surgical simulation. RESULTS: 3D printed models enhanced preoperative deliberation and surgical simulation and allowed on-table exploration of a small child to be avoided. We have critically determined specific clinical indications, technical insights, limitations, and outcomes of this approach. At latest follow-up (>16 mo) all patients remain well with functioning renal allografts. CONCLUSIONS: We report the new and safe integration of patient-specific 3D printing into complex pediatric renal transplantation. This technique enhances surgical planning and can inform operative feasibility in those cases which would otherwise be uncertain. PMID- 30247326 TI - Reply to Letter: "Radiation is Not a Solution for Suboptimal Surgery. A Response to the Conclusions Drawn From the Impact of Surgical Approach on Long-term Survival in Esophageal Adenocarcinoma With or Without Neoadjuvant Chemoradiotherapy Study". PMID- 30247327 TI - Re: Laparoscopic Intragastric Resection: An Alternative Technique for Minimally Invasive Treatment of Gastric Submucosal Tumors. PMID- 30247325 TI - Response To "ALPPS Versus Conventional Two-stage Hepatectomy in Patients With Advanced Colorectal Liver Metastases". PMID- 30247328 TI - Radiation is Not a Solution for Suboptimal Surgery. A Response to the Conclusions Drawn From the Impact of Surgical Approach on Long-term Survival in Esophageal Adenocarcinoma With or Without Neoadjuvant Chemoradiotherapy Study. PMID- 30247329 TI - Long-term Outcome of Surgery Versus Conservative Management for Recurrent and Ongoing Complaints After an Episode of Diverticulitis: 5-year Follow-up Results of a Multicenter Randomized Controlled Trial (DIRECT-Trial). AB - OBJECTIVE: The aim of this study was to establish whether surgical or conservative treatment leads to a higher quality of life (QoL) in patients with recurring diverticulitis and/or ongoing complaints. SUMMARY OF BACKGROUND DATA: The 6 months' results of the DIRECT trial, a randomized trial comparing elective sigmoidectomy with conservative management in patients with recurring diverticulitis (>2 episodes within 2 years) and/or ongoing complaints (>3 months) after an episode of diverticulitis, demonstrated a significantly higher QoL after elective sigmoidectomy. The aim of the present study was to evaluate QoL at 5 year follow-up. METHODS: From January 2010 to June 2014, 109 patients were randomized to either elective sigmoidectomy (N = 53) or conservative management (N = 56). In the present study, the primary outcome was QoL measured by the Gastrointestinal Quality of Life Index (GIQLI) at 5-year follow-up. Secondary outcome measures were SF-36 score, Visual Analogue Score (VAS) pain score, EuroQol-5D-3L (EQ-5D-3L) score, morbidity, mortality, perioperative complications, and long-term operative outcome. RESULTS: At 5-year follow-up, mean GIQLI score was significantly higher in the operative group [118.2 (SD 21.0)] than the conservative group [108.5 (SD 20.0)] with a mean difference of 9.7 (95% confidence interval 1.7-17.7). All secondary QoL outcome measures showed significantly better results in the operative group, with a higher SF-36 physical (P = 0.030) and mental score (P = 0.010), higher EQ5D score (P = 0.016), and a lower VAS pain score (P = 0.011). Twenty-six (46%) patients in the conservative group ultimately required surgery due to severe ongoing complaints. Of the operatively treated patients, 8 (11%) patients had anastomotic leakage and reinterventions were required in 11 (15%) patients. CONCLUSION: Consistent with the short-term results of the DIRECT trial, elective sigmoidectomy resulted in a significantly increased QoL at 5-year follow-up compared with conservative management in patients with recurring diverticulitis and/or ongoing complaints. Surgeons should counsel these patients for elective sigmoidectomy weighing superior QoL, less pain, and lower risk of new recurrences against the complication risk of surgery. PMID- 30247330 TI - Workload, Recurrence, Quality of Life and Long-term Efficacy of Endoscopic Therapy for High-grade Dysplasia and Intramucosal Esophageal Adenocarcinoma. AB - OBJECTIVE: To review the workload, type and frequency of recurrence, long-term quality of life (QOL), and late oncologic outcomes with endoscopic therapy. BACKGROUND: The short-term oncologic efficacy of endoscopic resection (ER) and ablation for patients with high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) is well-established in the literature. METHODS: A retrospective chart review was performed of the initial 40 patients who had endoscopic therapy from 2001 to 2010 at 1 center by 1 physician. RESULTS: Initial pathology was HGD in 22 and IMC in 18 patients, but 9 patients (41%) with HGD progressed to invasive cancer during endotherapy. The median follow-up was 82 months. Four patients had an esophagectomy, and in the remaining 36 patients, 70 ERs and 111 ablations were performed. The median number of endoscopic sessions was 4 in patients with short segment compared with 7 in patients with long segment Barrett's. Complete resolution of intestinal metaplasia (CRIM) was achieved in 30 patients (83%) at a median of 21 months. In 18 patients (60%), CRIM was maintained, whereas 12 patients developed recurrence at a median of 14 months. Additional endotherapy (n = 11) led to CRIM again in 10 patients (83%). There were no cancer deaths when CRIM was achieved. Overall survival with endotherapy was 73% at 5 years and 67% at 10 years. Quality of life (QOL) was below population means in 4 of 8 areas, but alimentary satisfaction was good after endotherapy. CONCLUSIONS: Endotherapy is successful in most patients, but multiple sessions are usually required and disease progression can occur. Once CRIM is achieved, recurrence is common and mandates continued endoscopic follow up. QOL is impaired with endotherapy, but alimentary satisfaction and oncologic outcomes support esophageal preservation with endotherapy for patients with HGD or IMC. PMID- 30247331 TI - NASA-TLX Assessment of Surgeon Workload Variation Across Specialties. AB - OBJECTIVE: With advancements in surgical equipment and procedures, human-system interactions in operating rooms affect surgeon workload and performance. Workload was measured across surgical specialties using surveys to identify potential predictors of high workload for future performance improvement. SUMMARY BACKGROUND DATA: Surgical instrumentation and technique advancements have implications for surgeon workload and human-systems interactions. To understand and improve the interaction of components in the work system, NASA-Task Load Index can measure workload across various fields. Baseline workload measurements provide a broad overview of the field and identify areas most in need of improvement. METHODS: Surgeons were administered a modified NASA-Task Load Index survey (0 = low, 20 = high) following each procedure. Patient and procedural factors were retrieved retrospectively. RESULTS: Thirty-four surgeons (41% female) completed 662 surgery surveys (M = 14.85, SD = 7.94), of which 506 (76%) have associated patient and procedural data. Mental demand (M = 7.7, SD = 5.56), physical demand (M = 7.0, SD = 5.66), and effort (M = 7.8, SD = 5.77) were the highest rated workload subscales. Surgeons reported difficulty levels higher than expected for 22% of procedures, during which workload was significantly higher (P < 0.05) and procedural durations were significantly longer (P > 0.001). Surgeons reported poorer perceived performance during cases with unexpectedly high difficulty (P < 0.001). CONCLUSIONS: When procedural difficulty is greater than expected, there are negative implications for mental and physical demand that result in poorer perceived performance. Investigations are underway to identify patient and surgical variables associated with unexpected difficulty and high workload. Future efforts will focus on re-engineering the surgical planning process and procedural environment to optimize workload and performance for improved surgical care.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0. PMID- 30247332 TI - Disease-free Survival and Local Recurrence After Laparoscopic-assisted Resection or Open Resection for Rectal Cancer: The Australasian Laparoscopic Cancer of the Rectum Randomized Clinical Trial. AB - OBJECTIVE: The aim of the study was to determine the efficacy of laparoscopic rectal resection (Lap) versus open laparotomy and rectal resection (Open) for rectal cancer on locoregional recurrence (LRR) and disease-free survival (DFS) at 2 years. SUMMARY BACKGROUND DATA: Although a Lap approach to colon cancer surgery may offer similar oncological outcomes to Open with potentially less morbidity, this remains to be clearly established for the treatment of rectal cancer. METHODS: A randomized, multicenter noninferiority phase 3 trial of 475 patients with T1 to T3 rectal adenocarcinoma <15 cm from anal verge, given Lap or Open and followed for a minimum 2 years to assess LRR, DFS, and overall survival (OS). RESULTS: Secondary endpoint analyses included 450 patients (95%) without metastases at baseline (mean age 64; 34% women) who received Lap (n = 225) or Open (n = 225). Median follow-up was 3.2 years (range: 0.1-5.4 yrs). LRR cumulative incidence at 2 years: Lap 5.4%; Open 3.1% [difference, 2.3%; 95% confidence interval (CI), -1.5% to 6.1%; hazard ratio (HR) 1.7; 95% CI, 0.74 3.9]. DFS at 2 years: Lap 80%; Open 82% (difference, 2.0%; 95% CI, -9.3% to 5.4%; HR for recurrence or death, 1.17; 95% CI, 0.81-1.68; P = 0.41). After adjustment for baseline factors HR = 1.07 (95% CI, 0.7-1.6). OS at 2 years: Lap 94%; Open 93% (difference 0.9%; 95% CI, -3.6% to 5.4%). CONCLUSIONS: Laparoscopic surgery for rectal cancer did not differ significantly from open surgery in effects on 2 year recurrence or DFS and OS. Confidence intervals included potentially clinically important differences favoring open resection, so that the combination of primary and secondary study endpoints may not support laparoscopic resection of rectal cancer as a routine standard of care and further follow-up is required. PMID- 30247333 TI - Incidence and Efficacy of Stent Placement in Leak Management After Bariatric Surgery: An MBSAQIP Analysis. AB - OBJECTIVE: The aim of this study was to evaluate the rates of use and efficacy of stent placement for postoperative leak following bariatric surgery. SUMMARY OF BACKGROUND DATA: Endoscopically placed stents can successfully treat anastomotic and staple line leaks after bariatric surgery. However, the extent to which stents are used in the management of bariatric complications and rates of reoperation remain unknown. METHODS: Data from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program participant use files were analyzed for patients who experienced anastomotic or staple line leaks after bariatric surgery, and then evaluated for use of an endoscopically placed stent. Patient and procedure-level data were compared between those who underwent stent placement versus those who required reoperation. Multivariable logistic regression was used to compare outcomes between groups. RESULTS: A total of 354,865 bariatric cases were captured in 2015 to 2016. One thousand one hundred thirty patients (0.3%) required intervention for a leak, of whom 275 (24%) were treated with an endoscopically placed stent. One hundred seven (39%) of the patients who received stents required reoperation as part of their care pathway. Patient characteristics were statistically similar when comparing leaks managed with stents to those treated with reoperation alone. Those treated with stents, however, had a higher likelihood of readmission (odds ratio 2.59, 95% confidence interval -1.59 to 4.20). CONCLUSION: Placement of stents for management of leaks after bariatric surgery is common throughout the United States. The use of stents can be effective; however, it does not prevent reoperation and is associated with an increased likelihood of readmission. Both technique and resource utilization should be considered when choosing a management pathway for leaks. PMID- 30247335 TI - Association of CTRP13 with Liver Enzymes and Cognitive Symptoms in Nonalcoholic Fatty Liver Disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease in which patients present with metabolic dysregulation and obesity as well as fat accumulation in the liver. Those with NAFLD frequently have symptoms of fatigue, sleep disturbance, depression, and cognitive dysfunction. C1q/TNF-related protein 13 (CTRP13) regulates glucose metabolism and obesity in mice, yet the role of CTRP13 in human NAFLD has not been elucidated. AIMS: Our aims were to examine whether the plasma levels of CTRP13 are (a) increased in NAFLD patients; (b) associated with metabolic dysregulation, obesity, liver enzymes, and dyslipidemia; and (c) associated with putative symptoms of NAFLD. METHODS: An observational study was conducted with 23 adults with confirmed NAFLD. Plasma levels of CTRP13, insulin resistance, insulin sensitivity, HbA1C, lipid profile, and liver enzymes were collected. Anthropometric analysis (BMI, waist-hip circumference ratio) and bioelectrical impedance analysis of body composition were used to assess obesity. Symptom questionnaires were used to assess putative symptoms of NAFLD. Plasma levels of CTRP13 were measured in 21 age- and sex matched control samples from a biobank. Paired t-test was used for comparison of the CTRP13 between NAFLD and controls. Pearson's correlation coefficients were used to examine associations among variables. RESULTS: Plasma levels of CTRP13 were significantly higher in NAFLD patients than in normal controls (p < .001), were associated with higher levels of Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) (both p < .05), triglycerides (p < .001), and poorer cognitive function, particularly, visuospatial memory (p < .001). CONCLUSIONS: CTRP13 may be a surrogate biomarker of NAFLD symptoms and associated with hepatocellular damage, dyslipidemia, and cognitive dysfunction. PMID- 30247334 TI - Four Approaches for Determining Composite Scores for the Measurement of Transition in Cancer Scale. AB - BACKGROUND: We created the Measurement of Transitions in Cancer Scale to assess patients' perceptions of the extent of change they experience with cancer-related transitions, and how well they feel they are managing these transitions. For some transitions, we found that the more change that was reported, the worse management was reported; however, the benchmark by which patients assess how well they have managed may vary with the extent of change. OBJECTIVES: To identify approaches to combine reports of extent and management of change. METHODS: Among women with breast cancer, we explored relationships of composite measures (arithmetic and geometric means; subtractive and proportional need for improvement) with other indicators of well-being (symptoms, anxiety, depression, uncertainty, self-efficacy, knowledge of care options, medical communication competence). We examined statistical significance using False Rate Discovery for multiple tests on correlations with clinical outcomes. RESULTS: Greater extent and less management were significantly associated with higher total symptoms, anxiety, depression, uncertainty, and less self-efficacy in Personal Transitions but not in Care Transitions. The arithmetic and geometric means had weak correlations with clinical outcomes, while the subtractive and proportional need for improvement had significant correlations with most clinical outcomes both in Personal and Care Transitions. The combined proportional need for improvement in Personal Transitions was significantly associated with total symptoms, anxiety, depression, uncertainty, and self-efficacy. The Care Transitions score was also significantly associated with total symptoms, anxiety, uncertainty, and self efficacy. DISCUSSION: These approaches can be applied to other aspects of self management that require assessment of the extent and management of an experience. The four approaches yield different results. We recommend the need for improvement composites to capture correlations with the clinical outcomes. PMID- 30247336 TI - Measurement of the Background Gamma Dose Rates in Houston, Texas: A Descriptive Summary of an Undergraduate Research Mentored Project Performed by Students Underrepresented in the Health Physics Profession. AB - Natural background radiations include cosmic, terrestrial, and medical sources. Cosmic radiation is mostly shielded by the magnetic field of the Earth; however, those that penetrate can produce nuclear interactions within the Earth's atmosphere yielding cosmic ray showers. Terrestrial and medical sources of radioactivity are typically identified through radionuclide-specific decay signatures. Medical sources of radiation mainly result from diagnostic x rays, which attenuate into the environment. These x rays also contribute slightly to background radiation. The purpose of this study was to have students involved with the Texas Southern University (TSU) health physics program measure and report background gamma dose rates in Houston, Texas, using the Canberra InSpector 1000 Digital Hand-Held Multichannel Analyzer. The results were compared with the average gamma dose rate on Earth. Of note, TSU is one of the largest historically black colleges and universities (HBCUs) in the nation and currently boasts the only undergraduate health physics program in Houston. Targeted locations were selected within the I-610 loop of Houston covering an area of approximately 100 km. Measurements were performed at nine locations and verified by GPS latitude and longitude coordinates. The dose rate was measured over a 100 m area at each location, while spectral analysis was simultaneously performed for natural gamma-emitters. Our results suggest the dose rate averaged over all geographical locations in this study was 0.114 +/- 0.001 MUSv h and thus, consistent with most literature. The only radionuclide identified in the spectra in all measurements was K due to the limited energy resolution of the InSpector 1000. PMID- 30247337 TI - Neutron Rem Detector Response Changes due to Activation of Components. AB - The relative response of neutron rem detectors has previously been shown to increase after prolonged exposure to a neutron flux. This increase has been referred to as the "soak factor." The cause of the increased response has been previously unexplained. This note reports on a search for the underlying cause of the increased response. Testing involved gamma-ray spectroscopy of activated neutron rem detector components and testing of instrument response at various rates of neutron flux and accumulated fluence. The proposed primary cause of the increased response is activation of copper in the brass collar at the fill end of the gas-filled detector tube. This component allows for attachment of the extension housing on the tube containing BF3 or He gas. Under a neutron flux, some of this copper activates to Cu. In addition, Mn was detected in activated components but does not seem to be a significant contributor to the detector response. Cadmium isotopes did not appear to be significant. The activated component causes an increase in indicated neutron dose rate due to decay photons from activated components. Photons normally have little impact on neutron rem detector readings because the electrical pulses produced in the probes are below the lower-level discriminator. However, the photon pulses do impact the overall count rate when they occur simultaneously with normally uncounted, lower amplitude, wall-effect neutron pulses. PMID- 30247338 TI - Systematic Derivation of Safety Limits for Time-Varying 5G Radiofrequency Exposure Based on Analytical Models and Thermal Dose. AB - Extreme broadband wireless devices operating above 10 GHz may transmit data in bursts of a few milliseconds to seconds. Even though the time- and area-averaged power density values remain within the acceptable safety limits for continuous exposure, these bursts may lead to short temperature spikes in the skin of exposed people. In this paper, a novel analytical approach to pulsed heating is developed and applied to assess the peak-to-average temperature ratio as a function of the pulse fraction alpha (relative to the averaging time [INCREMENT]T; it corresponds to the inverse of the peak-to-average ratio). This has been analyzed for two different perfusion-related thermal time constants (tau1 = 100 s and 500 s) corresponding to plane-wave and localized exposures. To allow for peak temperatures that considerably exceed the 1 K increase, the CEM43 tissue damage model, with an experimental-data-based damage threshold for human skin of 600 min, is used to allow large temperature oscillations that remain below the level at which tissue damage occurs. To stay consistent with the current safety guidelines, safety factors of 10 for occupational exposure and 50 for the general public were applied. The model assumptions and limitations (e.g., employed thermal and tissue damage models, homogeneous skin, consideration of localized exposure by a modified time constant) are discussed in detail. The results demonstrate that the maximum averaging time, based on the assumption of a thermal time constant of 100 s, is 240 s if the maximum local temperature increase for continuous-wave exposure is limited to 1 K and alpha >= 0.1. For a very low peak-to-average ratio of 100 (alpha >= 0.01), it decreases to only 30 s. The results also show that the peak-to-average ratio of 1,000 tolerated by the International Council on Non-Ionizing Radiation Protection guidelines may lead to permanent tissue damage after even short exposures, highlighting the importance of revisiting existing exposure guidelines. PMID- 30247339 TI - Opioid Detoxification During Pregnancy: A Systematic Review. PMID- 30247340 TI - In Reply. PMID- 30247341 TI - Outpatient Foley Catheter for Induction of Labor in Parous Women: A Randomized Controlled Trial. PMID- 30247342 TI - In Reply. PMID- 30247343 TI - Accessing the Spectrum of High-Quality Women's Health Care. PMID- 30247344 TI - Decreased Surgical Site Infection Rate in Hysterectomy: Effect of a Gynecology Specific Bundle. PMID- 30247345 TI - In Reply. PMID- 30247346 TI - Gynecologic Care for Adolescents and Young Women With Eating Disorders. PMID- 30247347 TI - In Reply. PMID- 30247348 TI - Association of Patient Race With Surgical Practice and Perioperative Morbidity After Myomectomy. PMID- 30247350 TI - Research Gaps in Gestational Diabetes Mellitus: Executive Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop: Correction. PMID- 30247349 TI - Zika Virus Infection Among Pregnant Women and Their Neonates in New York City, January 2016-June 2017. PMID- 30247351 TI - The First National Summit on Women's Health: The Future of Obstetrics and Gynecology Training: Correction. PMID- 30247353 TI - ACOG Practice Bulletin No. 197: Inherited Thrombophilias in Pregnancy: Correction. PMID- 30247352 TI - ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy: Correction. PMID- 30247357 TI - ACOG publications: October 2018. PMID- 30247354 TI - The Adverse Outcome Index: Putting Quality Into an Outcome Measure: Correction. PMID- 30247358 TI - ACOG Committee Opinion No. 753 Summary: Assessment and Treatment of Pregnant Women With Suspected or Confirmed Influenza. AB - Pregnant and postpartum women are at high risk of serious complications of seasonal and pandemic influenza infection. Pregnancy itself is a high-risk condition, making the potential adverse effects of influenza particularly serious in pregnant women. If a pregnant woman has other underlying health conditions, the risk of adverse effects from influenza is even greater. Antiviral treatment is necessary for all pregnant women with suspected or confirmed influenza, regardless of vaccination status. Obstetrician-gynecologists and other obstetric care providers should promptly recognize the symptoms of influenza, adequately assess severity, and readily prescribe safe and effective antiviral therapy for pregnant women with suspected or confirmed influenza. Over-the-phone treatment for low-risk patients is preferred to help reduce the spread of disease among other pregnant patients in the office. Obstetrician-gynecologists and other obstetric care providers should treat pregnant women with suspected or confirmed influenza with antiviral medications presumptively based on clinical evaluation, regardless of vaccination status or laboratory test results. Pregnant women with suspected or confirmed influenza infection should receive antiviral treatment with oseltamivir or zanamivir based on the current resistance patterns. Treatment within 48 hours of the onset of symptoms is ideal but treatment should not be withheld if the ideal window is missed. Because of the high potential for morbidity and mortality for pregnant and postpartum patients, the Centers for Disease Control and Prevention advises that postexposure antiviral chemoprophylaxis can be considered for pregnant women and women who are up to 2 weeks postpartum (including after pregnancy loss) who have had close contact with infectious individuals. PMID- 30247359 TI - ACOG Committee Opinion No. 754 Summary: The Utility of and Indications for Routine Pelvic Examination. AB - The pelvic examination has long been considered a fundamental component of the well-woman visit, and many women and gynecologic care providers view this visit as an opportunity to discuss sexual and reproductive health issues. Traditionally, a pelvic examination is performed for asymptomatic women as a screening tool for gynecologic cancer, infection, and asymptomatic pelvic inflammatory disease; some obstetrician-gynecologists and patients consider it important in detecting subclinical disease, despite evidence to the contrary. Given changes in screening recommendations and the ability to screen for sexually transmitted infections using less-invasive methods, reevaluation of the role of the pelvic examination for asymptomatic, nonpregnant women is warranted. A limited number of studies have evaluated the benefits and harms of a screening pelvic examination for detection of ovarian cancer, bacterial vaginosis, trichomoniasis, and genital herpes. Data from these studies are inadequate to support a recommendation for or against performing a routine screening pelvic examination among asymptomatic, nonpregnant women who are not at increased risk of any specific gynecologic condition. It is recommended by the American College of Obstetricians and Gynecologists that pelvic examinations be performed when indicated by medical history or symptoms. Women with current or a history of cervical dysplasia, gynecologic malignancy, or in utero diethylstilbestrol exposure should be screened and managed according to guidelines specific to those gynecologic conditions. Based on the current limited data on potential benefits and harms and expert opinion, the decision to perform a pelvic examination should be a shared decision between the patient and her obstetrician-gynecologist or other gynecologic care provider. PMID- 30247360 TI - ACOG Committee Opinion No. 755 Summary: Well-Woman Visit. AB - A well-woman visit provides an excellent opportunity to counsel patients about maintaining a healthy lifestyle and minimizing health risks. Given the shifting and complex landscape of care, in which many women may not receive all the recommended preventive services, obstetrician-gynecologists have an opportunity to contribute to the overall health and well-being of women throughout the lifespan by providing recommended preventive services and counseling. Taking a comprehensive history (specifically obtaining detailed information on symptoms and past medical and gynecologic history) will inform if certain components of the physical examination, including breast or pelvic examination, are indicated at that visit and will inform shared decision making for these examinations. Family history should be used as a risk assessment tool and should be completed and updated regularly to ensure the most comprehensive assessment of a woman's personal risk factors. Another key component of a well-woman visit for a reproductive-aged woman is the development and discussion of her reproductive life plan to ensure that medical testing and treatments provided are aligned with her current and future plans. Obstetrician-gynecologists provide care for women across the lifespan, and periodic well-woman visits are appropriate and necessary for perimenopausal women and postmenopausal women as well. This Committee Opinion has been revised to reflect updated guidance on components of the physical examination and new sources for well-woman preventive services. PMID- 30247361 TI - ACOG Committee Opinion No. 756 Summary: Optimizing Support for Breastfeeding as Part of Obstetric Practice. AB - As reproductive health experts and advocates for women's health who work in conjunction with other obstetric and pediatric health care providers, obstetrician-gynecologists are uniquely positioned to enable women to achieve their infant feeding goals. Maternity care policies and practices that support breastfeeding are improving nationally; however, more work is needed to ensure all women receive optimal breastfeeding support during prenatal care, during their maternity stay, and after the birth occurs. Enabling women to breastfeed is a public health priority because, on a population level, interruption of lactation is associated with adverse health outcomes for the woman and her child, including higher maternal risks of breast cancer, ovarian cancer, diabetes, hypertension, and heart disease, and greater infant risks of infectious disease, sudden infant death syndrome, and metabolic disease. Contraindications to breastfeeding are few. Most medications and vaccinations are safe for use during breastfeeding, with few exceptions. Breastfeeding confers medical, economic, societal, and environmental advantages; however, each woman is uniquely qualified to make an informed decision surrounding infant feeding. Obstetrician gynecologists and other obstetric care providers should discuss the medical and nonmedical benefits of breastfeeding with women and families. Because lactation is an integral part of reproductive physiology, all obstetrician-gynecologists and other obstetric care providers should develop and maintain skills in anticipatory guidance, support for normal breastfeeding physiology, and management of common complications of lactation. Obstetrician-gynecologists and other obstetric care providers should support women and encourage policies that enable women to integrate breastfeeding into their daily lives and in the workplace. This Committee Opinion has been revised to include additional guidance for obstetrician-gynecologists and other obstetric care providers to better enable women in unique circumstances to achieve their breastfeeding goals. PMID- 30247362 TI - ACOG Committee Opinion No. 753: Assessment and Treatment of Pregnant Women With Suspected or Confirmed Influenza. AB - Pregnant and postpartum women are at high risk of serious complications of seasonal and pandemic influenza infection. Pregnancy itself is a high-risk condition, making the potential adverse effects of influenza particularly serious in pregnant women. If a pregnant woman has other underlying health conditions, the risk of adverse effects from influenza is even greater. Antiviral treatment is necessary for all pregnant women with suspected or confirmed influenza, regardless of vaccination status. Obstetrician-gynecologists and other obstetric care providers should promptly recognize the symptoms of influenza, adequately assess severity, and readily prescribe safe and effective antiviral therapy for pregnant women with suspected or confirmed influenza. Over-the-phone treatment for low-risk patients is preferred to help reduce the spread of disease among other pregnant patients in the office. Obstetrician-gynecologists and other obstetric care providers should treat pregnant women with suspected or confirmed influenza with antiviral medications presumptively based on clinical evaluation, regardless of vaccination status or laboratory test results. Pregnant women with suspected or confirmed influenza infection should receive antiviral treatment with oseltamivir or zanamivir based on the current resistance patterns. Treatment within 48 hours of the onset of symptoms is ideal but treatment should not be withheld if the ideal window is missed. Because of the high potential for morbidity and mortality for pregnant and postpartum patients, the Centers for Disease Control and Prevention advises that postexposure antiviral chemoprophylaxis can be considered for pregnant women and women who are up to 2 weeks postpartum (including after pregnancy loss) who have had close contact with infectious individuals. PMID- 30247363 TI - ACOG Committee Opinion No. 754: The Utility of and Indications for Routine Pelvic Examination. AB - The pelvic examination has long been considered a fundamental component of the well-woman visit, and many women and gynecologic care providers view this visit as an opportunity to discuss sexual and reproductive health issues. Traditionally, a pelvic examination is performed for asymptomatic women as a screening tool for gynecologic cancer, infection, and asymptomatic pelvic inflammatory disease; some obstetrician-gynecologists and patients consider it important in detecting subclinical disease, despite evidence to the contrary. Given changes in screening recommendations and the ability to screen for sexually transmitted infections using less-invasive methods, reevaluation of the role of the pelvic examination for asymptomatic, nonpregnant women is warranted. A limited number of studies have evaluated the benefits and harms of a screening pelvic examination for detection of ovarian cancer, bacterial vaginosis, trichomoniasis, and genital herpes. Data from these studies are inadequate to support a recommendation for or against performing a routine screening pelvic examination among asymptomatic, nonpregnant women who are not at increased risk of any specific gynecologic condition. It is recommended by the American College of Obstetricians and Gynecologists that pelvic examinations be performed when indicated by medical history or symptoms. Women with current or a history of cervical dysplasia, gynecologic malignancy, or in utero diethylstilbestrol exposure should be screened and managed according to guidelines specific to those gynecologic conditions. Based on the current limited data on potential benefits and harms and expert opinion, the decision to perform a pelvic examination should be a shared decision between the patient and her obstetrician-gynecologist or other gynecologic care provider. PMID- 30247364 TI - ACOG Committee Opinion No. 755: Well-Woman Visit. AB - A well-woman visit provides an excellent opportunity to counsel patients about maintaining a healthy lifestyle and minimizing health risks. Given the shifting and complex landscape of care, in which many women may not receive all the recommended preventive services, obstetrician-gynecologists have an opportunity to contribute to the overall health and well-being of women throughout the lifespan by providing recommended preventive services and counseling. Taking a comprehensive history (specifically obtaining detailed information on symptoms and past medical and gynecologic history) will inform if certain components of the physical examination, including breast or pelvic examination, are indicated at that visit and will inform shared decision making for these examinations. Family history should be used as a risk assessment tool and should be completed and updated regularly to ensure the most comprehensive assessment of a woman's personal risk factors. Another key component of a well-woman visit for a reproductive-aged woman is the development and discussion of her reproductive life plan to ensure that medical testing and treatments provided are aligned with her current and future plans. Obstetrician-gynecologists provide care for women across the lifespan, and periodic well-woman visits are appropriate and necessary for perimenopausal women and postmenopausal women as well. This Committee Opinion has been revised to reflect updated guidance on components of the physical examination and new sources for well-woman preventive services. PMID- 30247365 TI - ACOG Committee Opinion No. 756: Optimizing Support for Breastfeeding as Part of Obstetric Practice. AB - As reproductive health experts and advocates for women's health who work in conjunction with other obstetric and pediatric health care providers, obstetrician-gynecologists are uniquely positioned to enable women to achieve their infant feeding goals. Maternity care policies and practices that support breastfeeding are improving nationally; however, more work is needed to ensure all women receive optimal breastfeeding support during prenatal care, during their maternity stay, and after the birth occurs. Enabling women to breastfeed is a public health priority because, on a population level, interruption of lactation is associated with adverse health outcomes for the woman and her child, including higher maternal risks of breast cancer, ovarian cancer, diabetes, hypertension, and heart disease, and greater infant risks of infectious disease, sudden infant death syndrome, and metabolic disease. Contraindications to breastfeeding are few. Most medications and vaccinations are safe for use during breastfeeding, with few exceptions. Breastfeeding confers medical, economic, societal, and environmental advantages; however, each woman is uniquely qualified to make an informed decision surrounding infant feeding. Obstetrician gynecologists and other obstetric care providers should discuss the medical and nonmedical benefits of breastfeeding with women and families. Because lactation is an integral part of reproductive physiology, all obstetrician-gynecologists and other obstetric care providers should develop and maintain skills in anticipatory guidance, support for normal breastfeeding physiology, and management of common complications of lactation. Obstetrician-gynecologists and other obstetric care providers should support women and encourage policies that enable women to integrate breastfeeding into their daily lives and in the workplace. This Committee Opinion has been revised to include additional guidance for obstetrician-gynecologists and other obstetric care providers to better enable women in unique circumstances to achieve their breastfeeding goals. PMID- 30247366 TI - Evaluating Retinal Histology Using Multimodal Imaging: A Case Study of Coats Disease. PMID- 30247367 TI - Correspondence. PMID- 30247368 TI - Reply. PMID- 30247370 TI - Reply. PMID- 30247369 TI - Correspondence. PMID- 30247371 TI - Predictive Model for Medical and Surgical Readmissions Following Elective Lumbar Spine Surgery: A National Study of 33,674 Patients. AB - STUDY DESIGN: This study retrospectively analyzes prospectively collected data. OBJECTIVE: Here we aim to develop predictive models for 3-month medical and surgical readmission after elective lumbar surgery, based on a multi institutional, national spine registry. SUMMARY OF BACKGROUND DATA: Unplanned readmissions place considerable stress on payers, hospitals and patients. Medicare data reveals a 30-day readmission rate of 7.8% for lumbar-decompressions and 13.0% for lumbar-fusions, and hospitals are now being penalized for excessive 30-day readmission rates by virtue of the Hospital Readmissions Reduction Program. METHODS: The QOD (Quality and Outcomes Database) was queried for patients undergoing elective lumbar surgery for degenerative diseases. The QOD prospectively captures three-month readmissions through EMR review and self reported outcome questionnaires. Distinct multivariable logistic regression models were fitted for surgery-related and medical readmissions adjusting for patient and surgery-specific variables. RESULTS: Of the total 33,674 patients included in this study 2,079 (6.15%) reported at least one readmission during the 90-day post-operative period. The odds of medical readmission were significantly higher for older patients, males versus females, African Americans vs Caucasion, those with higher ASA grade, diabetes, coronary artery disease, higher numbers of involved levels, anterior only or anterior-posterior vs posterior approach; also, for patients who were unemployed compared to employed patients and those with high baseline ODI. The odds of surgery-related readmission were significantly greater for patients with a higher BMI, a higher ASA grade, female vs male, and African Americans versus Caucasians; also, for patients with severe depression, more involved spinal levels, anterior-only surgical approaches and higher baseline ODI scores. CONCLUSION: In this study we present internally validated predictive models for medical and surgical readmission after elective lumbar spine surgery. These findings set the stage for targeted interventions with a potential to reduce unnecessary readmissions, and also suggest that medical and surgical readmissions be treated as distinct clinical events. LEVEL OF EVIDENCE: 3. PMID- 30247372 TI - Safety of Outpatient Single-level Cervical Total Disc Replacement: A Propensity Matched Multi-Institutional Study. AB - STUDY DESIGN: Retrospective cohort comparison study. OBJECTIVE: To investigate the perioperative adverse event profile of cervical total disc replacement (CTDR) performed as an outpatient relative to inpatient procedure. SUMMARY OF BACKGROUND DATA: Recent reimbursement changes and a push for safe reductions in hospital stay have resulted in increased interest in performing CTDRs in the outpatient setting. However, there has been a paucity of studies investigating the safety of outpatient CTDR procedures, despite increasing frequency. METHODS: Patients who underwent single-level CTDR were identified in the 2005-2016 National Surgical Quality Improvement Program database. Outpatient versus inpatient procedure status was defined by length of stay, with outpatient being less than 1 day. Patient baseline characteristics and comorbidities were compared between the two groups. Propensity score matched comparisons were then performed for 30-day perioperative complications and readmissions between the two cohorts. Additionally, perioperative outcomes of outpatient single-level CTDR versus matched outpatient single-level anterior cervical discectomy and fusion (ACDF) cases were compared. RESULTS: In total, 373 outpatient and 1,612 inpatient single level CTDR procedures were identified. After propensity score matching was performed to control for potential confounders, statistical analysis revealed no significant difference in perioperative complications between outpatient versus matched inpatient CTDR. Notably, the rate of readmissions was not different between the two groups. Additionally, there was no difference in rates of perioperative adverse events between outpatient single-level CTDR versus matched outpatient single-level ACDF. CONCLUSIONS: The perioperative outcomes evaluated in the current study support the conclusion that, for appropriately selected patients, single-level CTDR can be safely performed in the outpatient setting without increased rates of 30-day perioperative complications or readmissions compared to inpatient CTDR or outpatient single-level ACDF. LEVEL OF EVIDENCE: 3. PMID- 30247373 TI - Predictors of a Non-Home Discharge Destination following Spinal Fusion for Adolescent Idiopathic Scoliosis (AIS). AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: Analyze risk factors associated with a non-home discharge following spinal fusions in adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Current evidence is limited with regard to which patient-level and provider/hospital-level factors predict a non-home discharge disposition following spinal fusions in AIS. Identifying these factors can allow providers to identify which patients would ultimately require facility care and can be discharged early to these facilities to reduce hospital costs. METHODS: The 2012-2016 American College of Surgeons - National Surgical Quality Improvement Program (ACS-NSQIP) Pediatric database was queried using Current Procedural Terminology codes for posterior spinal fusions (22800, 22802, and 22804) and anterior spinal fusions (22808, 22810 and 22812). Patients were categorized into those receiving a posterior-only fusion, anterior only fusion and combined anterior-posterior fusion. Only patients aged 10-18 undergoing corrective surgery for idiopathic scoliosis were included in the study. RESULTS: Out of a total of 8,452 patients - 90 (1.1%) were discharged to a destination other than home (skilled-care facility, separate acute care unit and/or rehabilitation unit). Following multi-variate analysis, children with a BMI of 20-30 (p = 0.002) or >30 (p = 0.003), structural pulmonary abnormality (p = 0.030), past history of childhood cancer (p = 0.018), an ASA grade >II (p<0.001), undergoing a revision surgery vs. a primary surgery (p = 0.039), a length of stay >4 days (p<0.001) and the occurrence of a pre-discharge complication (p = 0.003) were independent predictors associated with a non-home discharge disposition. CONCLUSIONS: In the current era of evolving health-care in which there is an increased focus toward decreasing costs, providers should consider utilizing these data to pre-operatively identify patients who can be discharged to facility, and tailor an appropriate post-operative course of care aimed at expediting discharge processes to curb the financial burden of a prolonged length of stay. LEVEL OF EVIDENCE: 3. PMID- 30247374 TI - Incidence, Risk Factors, and Clinical Implications of Postoperative Hematoma Requiring Reoperation Following Anterior Cervical Discectomy and Fusion. AB - STUDY DESIGN: Retrospective study of prospectively collected data. OBJECTIVE: To determine the incidence, timing, risk factors, and clinical implications of postoperative hematoma requiring reoperation following anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Postoperative hematomas requiring reoperation are rare but potentially catastrophic complications following ACDF. However, there has been a lack of large cohort studies investigating these complications in the ACDF population despite increasing outpatient procedure volume. METHODS: Patients who underwent ACDF in the 2012 2016 National Surgical Quality Improvement Program database were identified. The primary outcome was an occurrence of hematoma requiring reoperation within 30 days postoperatively. Risk factors for this outcome were identified using multivariate regression. Postoperative length of stay, subsequent complications, and mortality were compared between patients who did and did not develop a hematoma requiring reoperation. RESULTS: A total of 37,261 ACDF patients were identified, of which 148 (0.40%) developed a hematoma requiring reoperation (95% confidence interval [CI], 0.33%-0.46%). Of the cases that developed this complication, 37% occurred after discharge. Risk factors for the development of hematoma requiring reoperation were multi-level procedures (most notably >=3 levels, relative risk [RR] = 3.14, 95%CI = 1.86-5.32, p < 0.001), preoperative international normalized ratio >1.2 (RR = 2.85, 95%CI = 1.42-5.71, p = 0.006), lower body mass index (BMI) (notably BMI <=24, RR = 2.11, 95%CI = 1.21-3.67, p = 0.008), American Society of Anesthesiologists classification >=3 (RR = 2.07, 95%CI = 1.47-2.91, p < 0.001), preoperative anemia (RR = 1.71, 95%CI = 1.12-2.63, p = 0.027), and male gender (RR = 1.67, 95%CI = 1.18-2.37, p = 0.004). In addition, patients who developed a hematoma requiring reoperation before discharge had a longer length of stay. Further, those who developed a hematoma requiring reoperation were at higher risk for subsequent ventilator requirement, deep wound infection, pneumonia, and reintubation. CONCLUSIONS: Postoperative hematoma requiring reoperation occurred in approximately 1 in 250 patients following ACDF. High-risk patients should be closely monitored through the perioperative period. LEVEL OF EVIDENCE: 3. PMID- 30247375 TI - Time Taken to Return to Work Does Not Influence Outcomes of Minimally Invasive Transforaminal Lumbar Interbody Fusion - A Five-Year Follow-Up Study. AB - STUDY DESIGN: Retrospective cohort study using prospectively collected registry data. OBJECTIVES: The authors are to determine factors which influence return-to work (RTW) in patients undergoing minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and to determine if early RTW affects functional outcomes. SUMMARY OF BACKGROUND DATA: MIS-TLIF has been associated with accelerated return to work. RTW in non-WC working-age adults after MIS-TLIF is not well understood. METHODS: Prospectively collected registry data of 907 patients who underwent MIS-TLIF at a single institution from 2004-2013 were reviewed. 110 working adults who underwent single-level MIS-TLIF with complete preoperative and 5-year postoperative follow-up data were included. Patients were assigned into Early RTW (<=60 days, n = 40) and Late RTW (>60 days, n = 70). All patients were assessed pre- and post-operatively at two and five years. Length of operation, length of stay and comorbidities were also recorded. RESULTS: The Early RTW group had significantly lower ODI, NASS NS, NPRS back and leg pain scores than the Late RTW group (<0.01) There were no significant differences in age, body mass index (BMI) and prevalence of medical comorbidities (p > 0.05). In addition, there were no differences in terms of duration of surgery or length of hospitalization. There were no significant differences in ODI, NASS NS, SF-36 PCS/MCS, NPRS, satisfaction/expectation fulfilment between the Early and Late RTW groups at 2-year and 5-year follow-up. Both groups reported similar proportions that RTW without limitations and return-to-function (RTF) at 2-years and 5-years. CONCLUSIONS: Patients who RTW late have significantly poorer preoperative SF-36 physical component scores and higher ODI, NASS NS, NPRS back/leg pain scores. Surgeons should be cognizant that working adults with poorer preoperative function will tend to return to work later, but should reassure them that they will likely achieve similar clinical outcomes, satisfaction and expectation fulfilment when compared to patients who returned to work early. LEVEL OF EVIDENCE: 3. PMID- 30247376 TI - If You Don't Use It, You Lose It: The Age-Dependent Utility of Iliac Crest Cartilage for Intermediate Correction of Cleft Nasal Tip Asymmetry. PMID- 30247377 TI - Making Pharyngoplasty Simple and Safe: When Plastic Surgery Meets Sleep Surgery. PMID- 30247378 TI - Patient-Reported Outcome Measures Used in Gender Confirmation Surgery: A Systematic Review. PMID- 30247379 TI - Nasal Tip Reconstruction following Skin Cancer Resection: A Novel Approach Combining Reconstructive and Tip Rhinoplasty Principles. PMID- 30247380 TI - Hering's Law of the Frontal Facial Branch. PMID- 30247381 TI - Neurophysiological Evidence of Motor Network Reorganization in Myotonic Dystrophy Type 1: A Pilot Magnetoencephalographic Study. AB - PURPOSE: Myotonic dystrophy type 1 is the most common muscular dystrophy in adults. Although brain involvement is well recognized, the relationship between cortical motor control and voluntary movement has not been sufficiently explored. This study aims at assessing magnetoencephalographic (MEG) rhythms at oscillatory and connectivity levels to map central motor control. METHODS: Magnetoencephalographic data were acquired from healthy subjects and five myotonic dystrophy type 1 subjects during resting state and foot movement. Resting state EEG band power, event-related desynchronization/synchronization, functional connectivity, and network features (node strength and betweenness centrality) were estimated. A statistical comparison of these indexes between the two groups was run; a linear correlation between event-related desynchronization and motor performance was obtained. RESULTS: Myotonic dystrophy type 1 subjects showed higher theta power over central motor regions and lower beta power over frontal areas, with a decrease of beta node strength over the dominant hemisphere and an increase of betweenness centrality over the vertex. Foot movement in the most impaired myotonic dystrophy type 1 subjects was inefficient in evoking event related desynchronization. In less severely impaired participants, dominant foot movement was related to a bilateral sensorimotor event-related desynchronization. CONCLUSIONS: Results provide proof of a central dysfunction of movement. Identification of neurophysiological motor patterns in myotonic dystrophy type 1 could provide a guide for tailored therapy. PMID- 30247382 TI - Double-Shock Stimulation of the Superficial Radial Nerve Compared With Standard Medial Plantar Nerve Conduction in the Early Detection of Asymptomatic Diabetic Neuropathy: A Pilot Study. AB - PURPOSE: Diabetes mellitus is a major public health problem. Diabetic polyneuropathy (DP) is one of the most common complications of diabetes mellitus. The early detection of DP is very important for timely treatment of symptoms and preventative foot care. METHODS: Participants were sorted into 3 age- and sex matched groups: 20 "healthy" individuals; 21 diabetic patients without DP symptoms, "asymptomatic"; and 24 diabetic patients suffering from symptoms consistent with DP, "symptomatic." All study participants had normal results on conventional nerve conduction studies. All groups underwent both medial plantar mixed nerve conduction (as a single-shock stimulation technique) and superficial radial nerve conduction (double-shock stimulation) measurements. Interstimulus intervals of 2 to 8 ms were used to record sensory nerve action potentials (SNAP) 1 and SNAP 2 for both stimuli. RESULTS: We found statistically significant decreases in medial plantar NAPs' amplitude and conduction velocity, and SNAP1/SNAP2 ratios between the three groups, especially at smaller interstimulus intervals. CONCLUSIONS: Both medial plantar mixed nerve conduction and double shock superficial radial nerve stimulation are reliable methods for the early detection of asymptomatic DP. However, the medial plantar mixed nerve technique is easier and less time-consuming. PMID- 30247383 TI - Needle EMG of Thenar Muscles in Less Severe Carpal Tunnel Syndrome. AB - INTRODUCTION: The value of needle electromyography (EMG) in thenar muscles in patients with less severe carpal tunnel syndrome is controversial. METHODS: Patients referred for electrodiagnostic testing for carpal tunnel syndrome, in which nerve conduction study demonstrated median sensory nerve conduction study abnormalities and either normal median motor nerve conduction study or only prolonged median motor distal latencies (DLs) (with normal amplitudes) were prospectively studied. Patients with low-median compound muscle action potential amplitudes or any other EMG abnormality were excluded. Needle EMG of a thenar muscle was performed to assess for the presence and grade of fibrillation potentials and motor unit potential abnormalities. The frequency of abnormalities was recorded. Statistical comparison between patients with and without needle EMG abnormalities was performed. RESULTS: One-hundred two patients were included (50 with normal median motor DLs and 52 with abnormal DLs). Minimal or equivocal thenar needle EMG abnormalities were found in 12% of subjects with normal DLs. In patients with abnormal DLs, 32.6% had abnormalities, 15.4% with a mild degree of fibrillation potentials, and 25.0% with mild motor unit potential abnormalities. Patients with abnormal DLs and needle EMG abnormalities had significantly lower compound muscle action potential amplitudes compared to those without needle EMG changes. CONCLUSIONS: Patients with carpal tunnel syndrome with no involvement of the median motor nerve conduction study are unlikely to demonstrate prominent abnormalities on needle EMG of thenar muscles, and needle EMG of the thenar muscles is not necessary. However, in patients with carpal tunnel syndrome in which the median motor DL is prolonged but compound muscle action potential amplitudes are absolutely normal, needle EMG should be considered, as it may provide value in indicating some axonal loss despite a normal median compound muscle action potential amplitude. PMID- 30247384 TI - Predictive Value of Midline Spikes on Pediatric EEG for Seizure and Developmental Outcome. AB - PURPOSE: Midline spikes are epileptiform discharges localized to the midsagittal regions of the brain. Isolated midline spikes are rare, but more common in children. Our objective was to determine whether midline spikes are predictive of seizure characteristics and neurodevelopment. METHODS: EEGs and clinical information of 123 children with isolated midline spikes, and EEG follow-up within 12 to 24 months, were reviewed and compared with controls. RESULTS: Most children with midline spikes had seizures (91%), with an equal predisposition to focal or generalized seizure semiology. There was no difference between the midline spike and control groups in terms of neonatal complications, seizure characteristics (type, frequency, and etiology), and neurologic examination findings. In patients with abnormal neuro-maging, deep gray or white matter abnormalities were more frequent in the midline group (41% vs. 13%, P = 0.02). The midline group had a higher risk of development delay (DD) than controls (43% vs. 29%, odds ratio: 1.8, 95% CI [1.1-3.2], P = 0.03). A higher risk of DD was also noted in the midline group in those aged less than 4 years (52% vs. 26%, odds ratio: 3.1, 95% CI [1.0-9.2], P = 0.04) and in those without seizures (40% vs. 17%, odds ratio: 3.16, 95% CI [1.1-8.8], P = 0.03). CONCLUSIONS: This is the largest reported group of patients with midline spikes. Midline spikes have a strong association with seizures and DD. Our data suggest that midline spikes result from heterogeneous etiologies, are more common in young children, and are not benign. PMID- 30247385 TI - Intraoperative Neuromonitoring of Motor-Evoked Potentials in Infants Undergoing Surgery of the Spine and Spinal Cord. AB - PURPOSE: The aim of this single-center prospective cohort study is to record reliable transcranial motor-evoked potentials (TcMEPs) and to determine their thresholds under inhalational anesthesia in infants undergoing spine and spinal cord surgery. METHODS: A total of 15 infants (age <12 months) with mean (SD) months: 5.82 +/- 3.45 were included. The entry criteria were that the child should be no older than 1 year of age and undergoing a surgical procedure at the conus-cauda region. The patients were monitored with motor-evoked potentials (TcMEPs) and bulbocavernosus reflex. RESULTS: Transcranial motor-evoked potentials were recorded in all the patients in both upper and lower extremities in one muscle at least. All patients were monitored with a mean TcMEP threshold of 488.46 +/- 99.76 V (range 310-740 V). The lowest threshold of TcMEPs was used to record the musculus abductor pollicis brevis mean of 315.15 +/- 126.95 V (range 140-690 V) and the highest for musculus sphincter ani mean of 444.17 +/- 138.54 V (range 206-700 V). CONCLUSIONS: Intraoperative neuromonitoring for spine and spinal cord procedures of the infant population requires higher TcMEP thresholds and train count. Most patients aged older than 6 months require significantly lower TcMEPs. PMID- 30247386 TI - Modified fractal analysis of methionine positron emission tomography images for predicting prognosis in newly diagnosed patients with glioma. AB - OBJECTIVE: To assess intratumoural metabolic heterogeneity using modified fractal analysis and to determine its prognostic significance in patients with glioma. PATIENTS AND METHODS: A total of 57 patients with newly diagnosed glioma who underwent methionine PET-computed tomography between August 2012 and January 2017 were enrolled. The requirement for informed consent was waived for this retrospective study. Tumour-to-normal tissue ratio, metabolic tumour volume, total lesion methionine uptake and modified fractal dimension (m-FD) were calculated for each tumour using methionine PET-computed tomography. Associations between these indices and tumour grade and overall survival were analysed. RESULTS: Overall, eight patients had grade II, 20 had grade III and 29 had grade IV tumours. The tumour-to-normal tissue ratios of grade III and grade IV tumours were significantly greater than that of grade II tumours. The metabolic tumour volume and total lesion methionine uptake of grade III tumours were significantly greater than those of grade II and grade IV tumours. The m-FD of grade IV tumours was significantly greater than those of grade II and grade III tumours. A total of 47 patients were followed up, and their prognoses were evaluated. Only the m FD was significantly associated with a poor prognosis (P<0.05). Multivariate analyses identified age (>58 years) (hazard ratio: 5.73; 95.0% confidence interval: 1.4-29.9; P=0.015) and the m-FD (>0.87) (hazard ratio: 4.80; 95.0% confidence interval: 1.12-32.9; P=0.033) as independent prognostic factors for overall survival. CONCLUSION: Intratumoural metabolic heterogeneity is a useful imaging biomarker in patients with glioma. PMID- 30247388 TI - Young Children With Gender Nonconforming Behaviors and Preferences. AB - BACKGROUND: There is growing awareness and exposure in both the medical community and the lay media about the characteristics and complex needs of individuals who believe that their gender identity does not match their birth sex. Despite research and lay publications about teens with gender dysphoria and those who identify as transgender, little guidance is available regarding young (prepubertal) children with questions about their gender identity. Although many terms are used to describe these children, we have chosen to describe them as "gender nonconforming" (GNC). OBJECTIVE: Primary care and developmental behavioral pediatric providers are often the first professionals with whom young gender nonconforming children and their families discuss their concerns about their emerging gender identity. It is important, therefore, that pediatric providers be knowledgeable about the dilemmas, conflicts, and choices that are typical of these children and their families to guide them appropriately. OVERVIEW: In this special article, we present observations, informed by clinical experience, an emerging body of research, and a developmental-behavioral pediatric framework, of the complex needs of prepubertal gender nonconforming children and their families and an approach to their care. The article begins by outlining the cognitive and biological bases for gender identity development, as well as the natural history of gender nonconforming preferences and behaviors. It then sets the context for understanding the care of GNC children as an area in which developmentally sophisticated providers can play a crucial role in support of the complex developmental patterns and need for advocacy in multiple settings among these children. PMID- 30247387 TI - Influence of radioactive iodine therapy on liver function in patients with differentiated thyroid cancer. AB - AIM: This study aimed to investigate the influence of radioactive iodine (RAI) therapy on liver function in patients with differentiated thyroid cancer (DTC), with emphasis on sex and dose accumulation. PATIENTS AND METHODS: Liver function after the first RAI ablation with ~3700 MBq (100 mCi) dosage was compared with baseline liver function in 357 patients with DTC (male: 110 and female: 247). Further comparisons were conducted in patients after regular and successive RAI therapies with available data, 126 patients (male: 37 and female: 89) with two RAI therapies, 52 patients (male: 16 and female: 36) with three RAI therapies, and 19 patients (male: 5 and female: 14) with four RAI therapies. Analyses were performed to evaluate the potential effect of RAI on liver function, including total protein (TP), albumin (ALB), globulin (GLO), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT), lactic dehydrogenase, total bilirubin (TBIL), and direct bilirubin (DBIL) in both sexes. Continuous variables were analyzed by using nonparametric analysis. RESULTS: Compared with the original hepatic function, TP (P<0.01), ALB (P<0.05), GLO (P<0.01), ALT (P<0.05), ALP (P<0.01), and GGT (P<0.01) declined significantly after the first RAI ablation in both sexes. TP, GLO, and GGT declined significantly in both sex subgroups, whereas ALT (P<0.05), ALP (P<0.01), and lactate dehydrogenase (P<0.05) showed significant decline in male subgroup, and TBIL (P<0.05) in female subgroup. As to the level of liver function after the second RAI therapy, TP (P<0.01), GLO (P<0.01), ALP (P<0.01), GGT (P<0.01), and DBIL (P<0.05) showed a significant decreasing trend. In both sex subgroups, TP, GLO, and GGT reduced significantly. Moreover, only ALP (P<0.01) significantly decreased in the male subgroup. As to the level of liver function after the third RAI therapy session, TP (P<0.01) and GLO (P<0.01) reduced significantly, whereas DBIL (P<0.05) was higher than the original level. In sex subgroups, TP (P<0.05) decreased significantly in the male subgroup, and GLO (P<0.01) decreased significantly in the female subgroup, but DBIL (P<0.05) increased significantly in the female subgroup. As to the level of liver function after the fourth RAI therapy, TBIL (P<0.05) and DBIL (P<0.01) increased significantly. In sex subgroups, TBIL (P<0.05) and DBIL (2.09+/-0.92 vs. 2.91+/ 1.14 MUmol/l, P<0.05) showed an increasing trend in the female subgroup only. CONCLUSION: Liver function of patients with DTC after the first RAI ablation decreased significantly, including TP, ALB, GLO, ALT, ALP, and GGT. However, after multiple and regular RAI therapies, TBIL and DBIL showed an increasing trend. Particularly, TBIL and DBIL showed an increasing trend in the female subgroup only. PMID- 30247389 TI - From Mission Trips to Partnerships: The Evolution of International Outreach. PMID- 30247390 TI - Consortium of Orthopaedic Academic Traumatologists: A Model for Collaboration in Orthopaedic Surgery. AB - In March 2016, North American academic leaders with an interest in and commitment to the field of global orthopaedics met in Orlando, Florida, to gauge each institution's clinical, research, and educational programs in developing countries, establish the main limitations to participating in global health efforts, and assess areas of need for both the participating institutions and their international partners. After this inaugural meeting, a needs assessment survey was distributed to the group to better understand how to organize and unify the individual institutional global efforts. The results revealed that surgeons believed there was a vital need for improved communication, mentorship, and infrastructural support between North American universities. To this end, the Consortium of Orthopaedic Academic Traumatologists (COACT) was founded. The COACT seeks to promote a novel framework geared toward improving trauma care capacity by building collaborative partnerships among leading academic centers across the United States and Canada. The consortium represents a comprehensive partnership that promotes communication, collaboration, and advocacy through a central network to facilitate investigative, educational, and clinical services. Academic partners share best practices, resources, and opportunities in their international outreach projects in low- and middle-income countries in the field of orthopaedic trauma. Over the course of the past 2 years, the COACT has grown to more than 80 faculty, fellow, resident, and student members, representing over 20 orthopaedic institutions across North America. PMID- 30247392 TI - Partnership in Ethiopia: University of Utah's and UCLA's Departments of Orthopaedics Collaboration With Soddo Christian Hospital in Ethiopia. AB - Collaborations between orthopaedic training programs in developed countries and international sites in austere environments offer abundant benefits and mutual enrichment. It is often assumed that the exchange is one-sided and we hope to dispel that assumption. Despite the logistical challenges inherent in these partnerships, our experience has been unanimously reviewed as "greatly beneficial" to visiting residents/faculty and surgeons/trainees at the host location. We hope that this article will (1) encourage faculty at training programs to permit and enable residents to experience international orthopaedics while still in training; (2) encourage faculty to visit international hospitals while contributing expertise in subspecialty surgery, research, and teaching; and (3) encourage international hospitals to create opportunities for clinical and research collaboration with academic orthopaedics departments. PMID- 30247391 TI - Asociacion de Cirujanos Traumatologos de las Americas: Development of a Latin American Research Consortium. AB - Trauma continues to be a leading cause of mortality and morbidity in lower to middle-income countries. To meet the ever-growing need of musculoskeletal care in trauma patients, orthopaedic surgeons play an instrumental role in providing care, guided by relevant clinical research studies. Promoting research and publishing results are both crucial to influencing trauma-related skeletal injury treatment in lower to middle-income countries. Currently, few opportunities exist for trauma surgeons in Latin America to participate in clinical research or to contribute to academic publications, thereby limiting their ability to address potentially critical treatment questions faced by their specific patient populations. In response to these obstacles, in 2017, a group of 60 surgeon leaders representing 18 countries throughout Latin America developed the Asociacion de Cirujanos Traumatologos de las Americas (ACTUAR; www.actuarla.org). The ACTUAR supports investigative opportunities for Latin American orthopaedic trauma surgeons who want to contribute through collaborative research work. This pioneering initiative aims to improve trauma-related research, clinical care, and health care policies through the development of an international network across the Americas. PMID- 30247393 TI - Haitian Annual Conference on Orthopaedic Traumatology: Building Surgical Capacity Through Academic Collaboration. AB - The Assemblee Annuelle Haitienne de Traumatologie Orthopedique (Haitian Annual Conference on Orthopaedic Traumatology) is an international orthopaedic conference, conducted each Spring in Haiti in French and English. It brings together most of Haiti's practicing orthopaedic surgeons, trainees from Haiti's 3 residency training programs, and a visiting faculty from overseas. The Haitian Annual Conference on Orthopaedic Traumatology has become an unexpected cornerstone of 1 program to support and nurture the development of orthopaedic surgery in that country. PMID- 30247394 TI - Practical Guide to Delivering Surgical Skills Courses in a Low-Income Country: Knowledge Gained From a Surgical Education Partnership in Haiti. AB - Routine surgical skills training is known to advance a surgeon's technical proficiency. However, orthopaedic providers in low-income countries have limited access to skills training programs. International academic partnerships can augment locally available orthopaedic education, improving the quality of and capacity to deliver orthopaedic care in low-income countries. The objective of this study is to provide a practical guide to delivering an orthopaedic skills training course in a low-resource setting. The information provided is based on the experiences of the authors, along with specific feedback from previous course participants in Haiti. PMID- 30247395 TI - Role of North-South Partnership in Trauma Management: Uganda Sustainable Trauma Orthopaedic Program. AB - Uganda, as do many low-middle income countries, has an overwhelming volume of orthopaedic trauma injuries. The Uganda Sustainable Trauma Orthopaedic Program (USTOP) is a partnership between the University of British Columbia, McMaster University and Makerere University that was initiated in 2007. The goal of the project is to reduce the disabilities that occur secondary to musculoskeletal trauma in Uganda. USTOP works with local collaborators to build orthopaedic trauma capacity through teaching, innovation, and research. USTOP has maintained a multidisciplinary approach to training, involving colleagues in anesthesia, nursing, rehabilitation, and sterile reprocessing. The project was initiated at the invitation of the Department of Orthopaedics at Makerere University and Mulago Hospital in Kampala. The project is a collaboration between Canadian and Ugandan orthopaedic surgeons and is driven by the needs identified by the Ugandan surgeons. The program has also worked with collaborators to develop several technologies aimed at reducing the cost of providing orthopaedic care without compromising quality. As orthopaedic trauma capacity in Uganda advances, USTOP strives to continually evolve and provide relevant support to colleagues in Uganda to ensure that changes result in sustainable improvements in patient care. PMID- 30247396 TI - Developing Sustainable Orthopaedic Care in Northern Tanzania: An International Collaboration. AB - There is a devastating lack of access to surgical care, including orthopaedic surgery, in low- and middle-income countries. Similar to other low- and middle income countries, Tanzania has a severe shortage of trained orthopaedic surgeons. The surgeons available are inundated with acute trauma care and musculoskeletal infections; elective procedures are infrequently performed and the burden of neglected care continues to rise annually. Over the past several years, our interdisciplinary team of both American and Tanzanian members has worked to understand the current local cultural and economic barriers to increasing surgical capacity, ensuring surgical safety, delivering affordable care, providing adequate patient follow-up, and improving surgical education. We propose a new paradigm for the delivery of musculoskeletal care and creation of sustained surgical capacity in this setting by building an Orthopaedic Center of Excellence in Moshi, Tanzania, augmented by international partner institutions year-round. This initiative is a public-private partnership led by the University of Pennsylvania in conjunction with Kilimanjaro Christian Medical Center. A growing number of contributors, including the Tanzanian Health Ministry, several universities, and industry partners, including general electric (GE) Health Care Africa, are currently helping to advance this concept into reality. Through our model, we aim to increase surgical capacity and quality, as well as enhance local surgical education, with the ultimate objective of training the next generation of African surgeons in the latest surgical techniques and equipment. PMID- 30247397 TI - Perceptions of Orthopaedic Volunteers and Their Local Hosts in Low- and Middle Income Countries: Are We on the Same Page? AB - OBJECTIVE: Our goal was to compare the perceptions of overseas orthopaedic volunteers and their hosts in low- and middle-income countries (LMICs) regarding the role of international volunteerism. We also sought to determine if differences in perception exist between trainee and fully trained orthoapedic surgeon volunteers. METHODS: Surveys with similar multiple-choice and open-ended questions were administered to 163 Health Volunteers Overseas orthopaedic volunteers (response rate 45%) and 53 members of the host orthopaedic staff (response rate 40%). Fifty-four volunteers and 20 hosts also contributed open ended responses. Quantitative responses were analyzed for significance using Mantel-Haenzel chi tests. Open-ended responses were coded using thematic analysis. RESULTS: Both the international volunteers and their LMIC hosts agreed that volunteers learned new skills while volunteering. Both groups believed that international volunteerism had a positive overall impact on the local practice, but hosts viewed these benefits more favorably than volunteers did. LMIC staff believed that, besides altruistic reasons, volunteers were also motivated by professional gains, diverging from volunteer responses. In open-ended responses, hosts desired longer term commitments from volunteers and had some concerns regarding volunteers' qualifications. Between volunteer trainees and fully trained surgeons, trainees were more likely to be motivated by personal benefits. CONCLUSION: Efforts must be made to further align the expectations and goals of volunteers and their hosts in LMICs. Certain measures such as predeparture orientations for volunteers and developing a more longitudinal and bidirectional experience may enhance the impact of orthopaedic volunteerism in LMICs. Further studies are needed to explore the impact of international orthopaedic volunteerism on the host population. PMID- 30247398 TI - Clinical Research Course for International Orthopaedic Surgeons: 2-Year Outcomes. AB - BACKGROUND: Although orthopaedic trauma occurs at higher rates in low- and middle income countries (LMICs), most research on this topic is conducted in high resource settings. Few initiatives exist to promote local research in LMICs. Investigators created the Institute for Global Orthopaedics and Traumatology (IGOT) International Research Symposium to promote local research initiatives by surgeons practicing in low-resource environments. The purpose of this study is to determine the efficacy of this symposium in teaching orthopaedic surgeons practicing in LMICs how to conduct clinical research. METHODS: In this prospective observational study, orthopaedic surgeons from LMICs with no formal research training were recruited to attend the 1-day IGOT International Research Symposium in San Francisco. A survey was administered immediately before and after the symposium to inquire about the participants' confidence in different aspects related to research using a 1-5 Likert scale. A second survey, conducted 2 years later, recorded the attendees' research productivity after the workshop. RESULTS: Forty-three participants representing 10 different LMICs from Africa and Asia attended the 2013 course. At 2 year postcourse, participants reported starting 25 research projects, authored 7 "accepted or published manuscripts" (vs. 1 before the course; P < 0.01), and were selected for 12 podium or poster presentations (vs. 3 before the course; P < 0.01). Two research symposium attendees received "Top International Forum Paper" at the 2015 Orthopaedic Trauma Association Annual Meeting. DISCUSSION: A 1-day research course resulted in increased participant confidence in conducting research. This was associated with greater research productivity by participants 2 years later. These results suggest that the IGOT International Research Symposium can improve the number of initiated research projects by surgeons in LMICs. PMID- 30247399 TI - Can a 2-Day Course Teach Orthopaedic Surgeons Rotational Flap Procedures? An Evaluation of Data From the Nepal SMART Course Over 2 years. AB - INTRODUCTION: Traumatic lower extremity injuries requiring multidisciplinary treatment pose a challenge in low- and middle-income countries, where access to specialists may be limited. The surgical management and reconstructive training (SMART) course teaches orthopaedic surgeons muscle and fasciocutaneous flap procedures to address this scarcity. The purpose of this study is to assess the effectiveness of the SMART course in improving competency and comfort in performing common lower extremity flap procedures among participants. METHODS: Sixty-four orthopaedic surgeons from different regions of Nepal and Bhutan participated in the Nepal SMART course in 2016 and 2017. A competency test consisting of questions from US in-training plastic and orthopaedic surgery examinations-was administered to attendees before and after the course. Thirty two participants from 2016 were asked to rate their comfort level in performing flap procedures both pre- and postcourse. RESULTS: Overall competency test scores, as well as scores in the plastic surgery section, increased significantly after the course (P < 0.01). The precourse competency test scores were higher in 2016 compared with 2017 (P = 0.02). There was a higher increase in overall competency test scores after the course in 2016 compared with 2017 (P = 0.03). The procedure comfort levels reported by attendees increased for all flaps (P < 0.01). CONCLUSIONS: These results demonstrate the ability of the SMART course to improve the competency and comfort levels of orthopaedic surgeons in performing common lower extremity flap procedures. Despite the differences in years in practice and previous experience in performing flaps, the course yielded significantly better results in 2017 compared with 2016, showing that the implementation of the course has been improving. PMID- 30247400 TI - Orthopaedic Trauma in the Developing World: Where Are the Gaps in Research and What Can Be Done? AB - PURPOSE: There are an estimated 1.2 million deaths from road traffic injuries annually, disproportionately affecting patients in low-resource settings. The purpose of this scoping review is to identify knowledge gaps in global orthopaedic trauma in an effort to help prioritize future research. METHODS: Using the 6-stage Arksey and O'Malley framework for conducting a scoping review, orthopaedic trauma literature was reviewed over a ten-year period from 2004 to 2014. Studies from low-resource settings were included and categorized by geographic location, anatomic region, study type, and level of evidence. RESULTS: Of 548 included studies, 51.4% were from low- and middle-income countries in South Asia and 33.7% were from sub-Saharan Africa. Therapeutic (53.3%), epidemiologic (26.4%), and qualitative (8.9%) studies were most common. Only 10.2% of the studies were considered high level of evidence, whereas the vast majority (89.8%) was level 3 or below. Overall, lower extremity injuries were much more frequently represented in the literature compared with upper extremity injuries (233 vs. 78). Pelvic and acetabular fractures were the least studied anatomic region of the lower extremity (3.4%). CONCLUSIONS: Our study identified a lack of cost-effectiveness analyses pertaining to injury and intervention, paucity of high-quality research, and under-representation of pelvic, acetabular, and upper extremity injuries. Improved and prioritized research in low- and middle-income countries may help optimize care and inform policy makers of how to reduce the global burden of musculoskeletal trauma. PMID- 30247401 TI - Conducting a Randomized Controlled Trial in Tanzania: Institute for Global Orthopaedics and Traumatology and the Muhimbili Orthopaedic Institute. AB - INTRODUCTION: Low- and middle-income countries (LMICs) experience a large volume of orthopaedic trauma, but limited research exists to evaluate effective treatments using locally available means. Academic partners can help design and implement research studies through collaborative efforts with local investigators. We will describe the study design and lessons learned from a randomized controlled trial in Tanzania comparing outcomes of 2 operative treatments for open tibia fractures. STUDY DESIGN: The Institute for Global Orthopaedics and Traumatology at the University of California, San Francisco, and the Muhimbili Orthopaedic Institute in Dar es Salaam, Tanzania, partnered to design a prospective, randomized controlled trial. Adult patients with open tibia fractures were randomized to receive either intramedullary nailing or external fixation as definitive fixation. Our primary outcome was the rate of reoperation, and secondary outcomes included EQ-5D, pain, function, radiographic union, and return to work. RESULTS: We enrolled 40 patients in a pilot study that informed improvements in the study design and standard operating procedures. These modifications included development of a specific outline of the technical standards for each surgical intervention and held training workshops to disseminate this knowledge among operative surgeons. This resulted in the successful enrollment and standardized treatment of our target sample of 240 patients. DISCUSSION: There are several challenges in conducting high-quality, international research. Keys for success include maintaining a strong relationship between partners, having local research coordinators, simplifying data collection and storage, and incentivizing patients to attend follow-up visits. PMID- 30247402 TI - Developing Research to Change Policy: Design of a Multicenter Cost-Effectiveness Analysis Comparing Intramedullary Nailing to Skeletal Traction in Malawi. AB - INTRODUCTION: The purpose of our study is to prospectively evaluate the cost effectiveness of intramedullary nailing compared with skeletal traction in a resource-limited setting where traction remains the most common definitive treatment. METHODS: This multicenter, prospective multicenter investigation was conducted in Malawi at 2 central hospitals and 3 district hospitals. The project was divided into phases. In phase 1, the EuroQol-5D and SMFA were translated and validated in Chichewa. In phase 2, adult patents with OTA/AO 32 femur shaft fractures were prospectively enrolled, and a comparison of quality of life and functional status was made. In phase 3, a cost-effectiveness analysis was performed between those treated with intramedullary nail and those treated with skeletal traction. CONCLUSION: This study serves as an example of an economic study in orthopaedic surgery conducted in a resource-poor environment through academic collaboration. PMID- 30247403 TI - International Orthopaedic Multicenter Study in Fracture Care: Coordinating a Large-Scale Multicenter Global Prospective Cohort Study. AB - : Traditionally, the orthopaedic trauma literature has been dominated by small studies that were largely single-center initiatives. More recently, there has been a paradigm shift toward larger, multicenter studies because the orthopaedic community embraced the concepts of evidence-based medicine and the need for high quality research to guide clinical practice. The International Orthopaedic Multicenter Study in Fracture Care is a large multicenter international cohort study in musculoskeletal trauma in Africa, Asia, and Latin America. This is the first study of this magnitude within the global orthopaedic trauma community. The International Orthopaedic Multicenter Study in Fracture Care study has provided an opportunity to form new international collaborative relationships and to develop new research capacity and global collaborative relationships that will provide the foundation for future studies in injury prevention and management. LEVELS OF EVIDENCE: IV. PMID- 30247405 TI - A Visit to the Hill: Issues Affecting Orthopaedic Practice. PMID- 30247406 TI - NAON Foundation. PMID- 30247407 TI - NAON Award Winners 2018. PMID- 30247408 TI - NAON Foundation Scholarships 2018. PMID- 30247409 TI - Tobacco Use, Tobacco Cessation, and Musculoskeletal Health. AB - It is widely known that the physiological impacts of nicotine from cigarette smoking are harmful to almost every organ of the body, cause various diseases, and negatively impact the overall health of individuals. When it comes to musculoskeletal health and the specialty of orthopaedics, cigarette smoking has a significant influence on negative outcomes. This article discusses the impact of cigarette smoking and nicotine on the musculoskeletal system and the role of the orthopaedic nurse in educating patients on the importance of smoking cessation to improve musculoskeletal health and meet quality measures that serve to improve patient outcomes and lower healthcare costs. PMID- 30247404 TI - Current Status of Musculoskeletal Trauma Care Systems Worldwide. AB - BACKGROUND AND RATIONALE: Although general trauma care systems and their effects on mortality reduction have been studied, little is known of the current state of musculoskeletal trauma delivery globally, particularly in low-income (LI) and low middle-income (LMI) countries. The goal of this study is to assess and describe the development and availability of musculoskeletal trauma care delivery worldwide. MATERIALS & METHODS: A questionnaire was developed to evaluate different characteristics of general and musculoskeletal trauma care systems, including general aspects of systems, education, access to care and pre- and posthospital care. Surgical leaders involved with musculoskeletal trauma care were contacted to participate in the survey. RESULTS: Of the 170 surveys sent, 95 were returned for use for the study. Nearly 30 percent of surgeons reported a formalized and coordinated trauma system in their countries. Estimates for the number of surgeons providing musculoskeletal trauma per one million inhabitants varied from 2.6 in LI countries to 58.8 in high-income countries. Worldwide, 15% of those caring for musculoskeletal trauma are fellowship trained. The survey results indicate a lack of implemented musculoskeletal trauma care guidelines across countries, with even high-income countries reporting less than 50% availability in most categories. Seventy-nine percent of the populations from LI countries were estimated to have no form of health care insurance. Formalized emergency medical services were reportedly available in only 33% and 50% of LI and LMI countries, respectively. Surgeons from LI and LMI countries responded that improvements in the availability of equipment (100%), number and locations of trauma-designated hospitals (90%), and physician training programs (88%) were necessary in their countries. The survey also revealed a general lack of resources for postoperative and rehabilitation care, irrespective of the country's income level. CONCLUSION: This study addresses the current state of musculoskeletal trauma care delivery worldwide. These results indicate a greater need for trauma system development and support, from prehospital through posthospital care. Optimization of these systems can lead to better outcomes for patients after trauma. This study represents a critical first step toward better understanding the state of musculoskeletal trauma care in countries with different levels of resources, developing strategies to address deficiencies, and forming regional and international collaborations to develop musculoskeletal trauma care guidelines. PMID- 30247410 TI - Tobacco Use, Tobacco Cessation, and Musculoskeletal Health. PMID- 30247411 TI - The Relationship Between Life Purpose With Depression and Disability in Acute Low Back Pain Patients. AB - BACKGROUND: Life purpose in acute low back pain patients is not well described in published literature. METHODS/PURPOSE: We used linear regression models to describe the relationship of life purpose with perceived functional disability and depression in persons with acute low back pain (N = 42) participating in a randomized clinical trial to prevent transition to chronic low back pain. RESULTS: In our predominantly female sample (81.8%) with a mean age of 53 years (SD = 11.6 years), 52% worked full-time. Adjusting for age, gender, and working status, life purpose was a significant correlate of depression (p = .007). For every 10-unit increase in life purpose score, the estimated depression score decreased by almost 2.5 points. A significant relationship between life purpose and perceived functional disability was not identified. CONCLUSION: Life purpose likely is a modifiable risk factor for depression in acute low back pain patients. PMID- 30247413 TI - Literature Review on Brachymetatarsia. PMID- 30247412 TI - Literature Review on Brachymetatarsia. AB - Brachymetatarsia is a malformation characterized by an abnormal reduction in the length of 1 or more metatarsal bones. It occurs because of early closure of the growth plate of the affected metatarsal. Generally, it is caused by a congenital disorder and it usually occurs bilaterally. With a greater prevalence in females, it most often affects the fourth metatarsal, followed by the first metatarsal. Surgical treatments proposed include using external mini-fixators or bone grafts in a single step to lengthen the metatarsal. In this review, 62 scientific articles about brachymetatarsia were analyzed with key demographic and epidemiological aspects of this pathology. The prevalence of bilateral brachymetatarsia was 47%, and the female to male ratio was 10.53:1. Both these findings appear to contradict the usual data reported for brachymetatarsia. A better understanding of this disorder will enable an appropriate therapeutic approach according to the psychological and social profile of affected individuals. PMID- 30247414 TI - Causal Relationships Between Modifiable Risk Factors of Cognitive Impairment, Cognitive Function, Self-Management, and Quality of Life in Patients With Rheumatic Diseases. AB - BACKGROUND: Rheumatic diseases are one of the most common types of chronic conditions that affect cognitive functions. PURPOSE: To develop and verify a hypothetical model of causal relationships between modifiable risk factors for cognitive impairment, cognitive function, self-management, and quality of life in patients with rheumatic diseases. METHODS: A hypothetical model was developed on the basis of empirical evidence. The fitness of the model was verified on 210 patients with rheumatic diseases. RESULTS: The prevalence of cognitive impairment was 49.0%. Smoking, underlying diseases, pain, and fatigue had a significant direct effect on cognitive impairment. Only cognitive impairment had a significant direct effect on self-management. Fatigue, anxiety, depression, and cognitive function had a significant direct effect on quality of life. CONCLUSIONS: The importance of proper management of symptoms and health habits should be emphasized to prevent and delay the progression of cognitive impairment and improve adherence to self-management regimens and quality of life. PMID- 30247415 TI - Causal Relationships Between Modifiable Risk Factors of Cognitive Impairment, Cognitive Function, Self-Management, and Quality of Life in Patients With Rheumatic Diseases. PMID- 30247416 TI - Effectiveness of Posterior Decompression Techniques Compared With Conventional Laminectomy for Lumbar Stenosis. PMID- 30247419 TI - Metastatic Breast Cancer. PMID- 30247418 TI - Metastatic Breast Cancer. PMID- 30247420 TI - Postoperative Knee Bracing. PMID- 30247421 TI - Postoperative Knee Bracing. PMID- 30247422 TI - Alanyl-Glutamine protects against damage induced by enteroaggregative Escherichia coli strains in intestinal cells. AB - BACKGROUND: Enteroaggregative Escherichia coli (EAEC) is an important pathogen causing enteric infections worldwide. This pathotype is linked to malnutrition in children from developing countries. Alanyl-glutamine (Ala-Gln) is an immune modulator nutrient that acts during intestinal damage and/or inflammation. This study investigated the effect of EAEC infection and Ala-Gln on cell viability, cell death, and inflammation of intestinal epithelium cells (IEC-6). METHODS: Cells were infected with an EAEC prototype 042 strain, an EAEC wild-type strain isolated from a Brazilian malnourished child, and a commensal E. coli HS. Gene transcription and protein levels of caspases-3, -8, and -9 and cytokine-induced neutrophil chemoattractant 1 (CINC-1/CXCL1) were evaluated using RT-qPCR, western blot analysis, and ELISA. RESULTS: Infections with both EAEC strains decreased cell viability and induced apoptosis and necrosis after 24 hours. Ala-Gln supplementation increased cell proliferation and reduced cell death in infected cells. Likewise, EAEC strain 042 significantly increased the transcript levels of caspases-3, -8, and -9 when compared to the control group, and Ala-Gln treatment reversed this effect. Furthermore, EAEC induced CXCL1 protein levels, which were also reduced by Ala-Gln supplementation. CONCLUSION: These findings suggest that EAEC infection promotes apoptosis, necrosis, and intestinal inflammation with involvement of caspases. Supplementation of Ala-Gln inhibits cell death, increases cell proliferation, and attenuates mediators associated with cell death and inflammatory pathways in infected cells. PMID- 30247423 TI - Colonic Diverticulitis in an Infant with Hemophagocytic Histiocytosis and Prolonged Glucocorticoid Exposure. PMID- 30247424 TI - The Effect of Biologics on Post-Operative Complications in Children with Inflammatory Bowel Disease and Bowel Resection. AB - OBJECTIVES: There has been limited investigation of pediatric patients with inflammatory bowel disease (IBD) who have been treated with biologic agents and undergo operative management. Post-operative complications in the adult setting have been mixed and in the pediatric population the data has been limited. This study compares children with IBD treated with biologic agents to patients treated with non-biologic therapy prior to bowel resection. METHODS: This is a single center, retrospective chart review study of 62 children with IBD who underwent bowel resection between 2001 and 2017. Analysis included patient demographics, medications used prior to surgery, incidence of postoperative complications, indication for surgery, type of operation, and additional surgeries required. Post-operative complications were defined as superficial skin infection, leak at anastomotic site, intra-abdominal abscess, wound dehiscence, etc. Complications were compared based on medical therapy. RESULTS: Of the 62 children reviewed, 21 carried the diagnosis of ulcerative colitis (UC), 40 had Crohn's disease (CD), and 1 had IBD-unspecified. Thirty-seven of the patients were treated with infliximab, adalimumab, or vedolizumab prior to their bowel resection. There were four complications documented within 30 days of the operation, with an overall complication rate of 6.45 percent. There were two complications in each of the cohorts, including intra-abdominal abscess (2), abdominal wall abscess (1), and pouchitis (1). CONCLUSION: The number of complications was the same between those who did and did not receive a preoperative biologic agent. This study suggests that biologics may be safe to use in patients undergoing bowel resection. PMID- 30247425 TI - Red Spot Lesions in the Duodenal Bulb are a Highly Specific Endoscopic Sign of Celiac Disease: A Prospective Study. AB - We have recognized Red Spot Lesions (RSLs) in the duodenal bulb in children with celiac disease (CD) and believe they may represent an underappreciated and distinct endoscopic sign of CD. A total of 171 pediatric patients undergoing esophagogastroduodenoscopy with duodenal biopsy for symptoms consistent with CD were prospectively recruited. There were 75 patients who met criteria for CD and the remaining 96 patients served as symptomatic controls. As compared to endoscopic markers frequently mentioned in literature, RSLs had comparable sensitivity, specificity, positive predictive value, and negative predictive value of 31%, 94%, 80%, and 64%, respectively. If RSLs are noted during endoscopy in a patient with gastrointestinal symptoms that might be the result of CD, then sufficient duodenal biopsies to make the diagnosis of CD should be obtained. PMID- 30247428 TI - Making a case for volunteerism. PMID- 30247427 TI - Undisclosed Gluten in Pediatric Multivitamins May Impact Response to a Gluten free Diet. PMID- 30247426 TI - The Brussels Infant and Toddler Stool Scale: A Study On Inter-Observer Reliability. AB - OBJECTIVES: The Bristol Stool Form Scale (BSFS) is inadequate for non-toilet trained children. The Brussels Infant and Toddler Stool Scale (BITSS) was developed, consisting of 7 photographs of diapers containing stools of infants and toddlers. We aimed to evaluate inter-observer reliability of stool consistency assessment among parents, nurses and medical doctors (MDs) using the BITSS. METHODS: In this multicenter cross-sectional study (2016-2017), BITSS photographs were rated according to the BSFS. The reliability of the BITSS was evaluated using the overall proportion of perfect agreement and the linearly weighted kappa statistic. RESULTS: A total of 2,462 observers participated: 1,181 parents (48.0%), 624 nurses (25.3%) and 657 MDs (26.7%). The best-performing BITSS photographs corresponded with BSFS type 7 (87.5%) and type 4 (87.6%), followed by the BITSS photographs representing BSFS type 6 (75.0%), BSFS type 5 (68.0%), BSFS type 1 (64.8%), and BSFS type 3 (64.6%). The weakest performing BITSS photograph corresponded with BSFS type 2 (49.7%). The overall weighted kappa-value was 0.72 (95% CI 0.59-0.85; good agreement). Based on these results, photographs were categorized per stool group as hard (BSFS type 1-3), formed (BSFS type 4), loose (BSFS types 5&6) or watery (BSFS type 7) stools. According to this new categorization system, correct allocation for each photograph ranged from 83-96% (average: 90%).The overall proportion of correct allocations was 72.8%. CONCLUSIONS: BITSS showed good agreement with BSFS. Using the newly categorized BITSS photographs, the BITSS is reliable for the assessment of stools of non-toilet trained children in clinical practice and research. A multi language translated version of the BITSS can be downloaded at https://bitss stoolscale.com/. PMID- 30247429 TI - Speech Recognition in Noise for Adults With Normal Hearing: Age-Normative Performance for AzBio, BKB-SIN, and QuickSIN. AB - OBJECTIVE: Characterize performance for adults aged 20 to 79 years with normal hearing on tasks of AzBio, Bamford-Kowal-Bench speech-in-noise (BKB-SIN), quick speech-in-noise (QuickSIN), and acoustic Quick Spectral Modulation Detection (QSMD) in the sound field. SETTING: Cochlear implant (CI) program. PATIENTS: Eighty-one adults with normal hearing and cognitive function were recruited evenly across four age groups (20-49, 50-59, 60-69, and 70-79 yr). INTERVENTIONS: Subjects completed AzBio sentence recognition testing in quiet and in five signal to-noise ratios (SNRs: +10, +5, 0, -5, -10 dB), as well as the BKB-SIN, QuickSIN, and QSMD tasks. MAIN OUTCOME MEASURES: AzBio, BKB-SIN, QuickSIN, and acoustic QSMD scores were analyzed to characterize typical sound field performance in an older adult population with normal hearing. RESULTS: AzBio sentence recognition performance approached ceiling for sentences presented at >= 0 dB SNR with mean scores ranging from 3.5% at -10 dB SNR to 99% at +10 dB SNR. Mean QuickSIN SNR-50 was -0.02. Mean BKB-SIN SNR-50 was -1.31 dB. Mean acoustic QSMD score was 88%. Performance for all measures decreased with age. CONCLUSION: Adults with age normative hearing achieve ceiling-level performance for AzBio sentence recognition at SNRs used for clinical cochlear implant and/or hearing aid testing. Thus, these tasks are not inherently contraindicated for older listeners. Older adults with normal hearing, however, demonstrated greater deficits for speech in noise compared to younger listeners-an effect most pronounced at negative SNRs. Lastly, BKB-SIN data obtained in the sound field replicated previous normative data for only the youngest age group, suggesting that new norms should be considered for older populations. PMID- 30247430 TI - The Viability of Percutaneous Bone-Anchored Hearing Systems in the HIV Population. AB - OBJECTIVE: To determine the viability of percutaneous bone-anchored hearing systems (BAHS), in terms of local soft tissue complications, in the HIV population. STUDY DESIGN: Retrospective folder review. SETTING: Two tertiary level academic state hospitals in Cape Town, South Africa. PATIENTS: Twenty patients, of which six (30%) were HIV-positive. All HIV-positive patients had CD4 counts greater than 200, and were on highly-active antiretroviral therapy (HAART). INTERVENTION: Percutaneous BAHS implantation surgery was performed on all patients. MAIN OUTCOME MEASURE: Comparisons were made between HIV-positive and HIV-negative patients in terms of incidence of local soft tissue complications post-implantation. RESULTS: Soft tissue complications occurred in 50% of patients, and most were easily managed with topical treatment. No significant differences were found when comparing incidence of local soft tissue complications between HIV-positive and HIV-negative patients (p = 0.314). Similarly, surgical technique did not influence soft tissue complication incidence (p = 0.143). CONCLUSIONS: No significant differences in incidence of local soft tissue complications after percutaneous BAHS implantation were found between HIV-positive and HIV-negative patients. In a resource-constrained country like South Africa, where cost and time management are vital, these results indicate that the use of percutaneous BAHS implantation is a viable option, even in HIV-positive patients. PMID- 30247431 TI - Survival of the Fastest: The Multivariate Optimization of Performance Phenotypes. AB - INTRODUCTION: Tradeoffs are widespread in biological systems. Any investment in one trait must necessarily limit the investment in other traits. Still, many studies of physiological performance produce positive correlations between traits that are expected to tradeoff with one another. Here we investigate why predicted tradeoffs may often go unmeasured in studies of human athletes. METHODS: Triathletes compete in consecutive swimming, cycling, and running events as a single competition, events whose physical demands may be especially prone to generating performance tradeoffs. Performance variation in these three events interacts to explain overall variation in athletic performance. RESULTS: We show that individual variation in athletic performance can mask tradeoffs among disciplines, giving the impression that high performance triathletes are athletic generalists. Covariance in race performance across the three disciplines was positive in the most elite athletes, but became increasingly negative as race times increased. CONCLUSIONS: These performance trade-offs among the disciplines preclude the realization of a generalist athlete except in the most elite triathletes, a result similar to the 'big houses, big cars' phenomenon in life history evolution. This distinction between trait combinations that are favored for optimal performance, versus constrained by trade-offs was only apparent when accounting for individual level variation in athletic performance. Our results provide further evidence that meaningful tradeoffs may be missed if individual variation in quality is ignored. PMID- 30247432 TI - Preexercise Carbohydrate Ingestion and Transient Hypoglycemia: Fasting vs. Feeding. AB - PURPOSE: Carbohydrate (CHO) ingestion 30-45 min before exercise results in transient hypoglycemia after starting the exercise in some, but not all, subjects. However, whether transient hypoglycemia is more likely to occur under fed or fasted condition remains unknown. This study aimed to directly compare the effects of fasting vs. feeding on plasma glucose responses following pre-exercise CHO intake and to examine the relationship between insulin responses and onset of transient hypoglycemia. METHODS: Sixteen subjects performed 60-min cycle ergometer exercises at 75% maximal oxygen uptake (VO2max) under overnight fasted and fed (4 h after breakfast) conditions. In both conditions, they consumed 500 mL of beverage (150 g of glucose) 30 min before beginning exercise. RESULTS: The mean plasma glucose concentrations 15 min after starting the exercise did not fall below 4.0 mmol . l (criteria for hypoglycemia) in both states; however, individual differences in the occurrence of transient hypoglycemia were noted. In the fasted state, plasma glucose levels transiently dropped below 4.0 mmol . l in five subjects, who had substantially higher serum insulin levels at the start of exercise, compared with those who did not develop hypoglycemia. Although seven subjects developed transient hypoglycemia in the fed state, no relationship was observed between insulin responses and hypoglycemia. Three subjects developed hypoglycemia in both fasted and fed states. CONCLUSION: These results suggest that transient hypoglycemia following pre-exercise CHO ingestion occurs in some, but not all, subjects, under both conditions. Furthermore, subjects with enhanced insulin responses seem to be more prone to transient hypoglycemia in the fasted condition. PMID- 30247433 TI - Metabolic Costs of Standing and Walking in Healthy Military-Age Adults: A Metaregression. AB - INTRODUCTION: The Load Carriage Decision Aid (LCDA) is a US Army planning tool that predicts physiological responses of Soldiers during different dismounted troop scenarios. We aimed to develop an equation that calculates standing and walking metabolic rates in healthy military-age adults for the LCDA using a meta regression. METHODS: We searched for studies that measured the energetic cost of standing and treadmill walking in healthy men and women via indirect calorimetry. We used mixed effects meta-regression to determine an optimal equation to calculate standing and walking metabolic rates as a function of walking speed (S, m.s). The optimal equation was used to determine the economical speed at which the metabolic cost per distance walked is minimized. The estimation precision of the new LCDA walking equation was compared to that of seven reference predictive equations. RESULTS: The meta-regression included forty-eight studies. The optimal equation for calculating normal standing and walking metabolic rates (W.kg) was: 1.44 + 1.94.S + 0.24.S. The economical speed for level walking was 1.39 m.s (~ 3.1 mph). The LCDA walking equation was more precise across all walking speeds (Bias +/- SD, 0.01 +/- 0.33 W.kg) than the reference predictive equations. CONCLUSION: Practitioners can use the new LCDA walking equation to calculate energy expenditure during standing and walking at speeds < 2 m.s in healthy, military-age adults. The LCDA walking equation avoids the errors estimated by other equations at lower and higher walking speeds. PMID- 30247434 TI - Physical Activity Associates with Muscle Insulin Sensitivity Post Bariatric Surgery. AB - PURPOSE: Bariatric surgery is considered as an effective therapeutic strategy for weight loss in severe obesity. Remission of type 2 diabetes is often achieved following the surgery. We investigated whether increase in self-reported habitual physical activity associates with improved skeletal muscle insulin sensitivity and reduction of fat depots after bariatric surgery. METHODS: We assessed self reported habitual physical activity using Baecke questionnaire in 18 diabetic and 28 non-diabetic patients with morbid obesity (median age 46 years and BMI 42.0 kg.m-2) before and six months after bariatric surgery operation. Insulin stimulated femoral muscle glucose uptake was measured using FDG PET -method during hyperinsulinaemia. In addition, abdominal subcutaneous and visceral fat masses were quantified using magnetic resonance imaging and liver fat content using magnetic resonance spectroscopy. Also, serum pro-inflammatory cytokines were measured. RESULTS: Patients lost on average 22.9% of weight during the follow-up period of six months (p<0.001). Self-reported habitual physical activity level increased (p=0.017). Improvement in skeletal muscle insulin sensitivity was observed only in those patients who reported increase in their physical activity postoperatively (p=0.018). The increase in self-reported physical activity associated with the loss of visceral fat mass (p=0.029). Postoperative self-reported physical activity correlated also positively with postoperative hepatic insulin clearance (p=0.02) and tended to correlate negatively with liver fat content (p=0.076). Postoperative self-reported physical activity also correlated negatively with serum TNFalpha, MCP and interleukin 6 levels. CONCLUSION: Self-reported physical activity is associated with reversal of skeletal muscle insulin resistance following bariatric surgery as well as with the loss of visceral fat content and improved postoperative metabolism in bariatric surgery patients.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30247435 TI - Kidney Transplantation in Sudan. PMID- 30247437 TI - Telomerase Activity Links to Regenerative Capacity of Hepatocytes. PMID- 30247438 TI - Raimund Margreiter, MD, Emeritus Chair, Transplant Surgeon, Pioneer, and Adventurer: The Only Transplant Surgeon Who Has Done it All. PMID- 30247439 TI - Preliminary Findings From the First Pilot Phase of the Collaborative Innovation and Improvement Network. PMID- 30247440 TI - The Authors' Reply. PMID- 30247441 TI - Successful Treatment of Chronic Hepatitis C Virus Infection with Sofosbuvir and Ledipasvir in Renal Transplant Recipients: Erratum. PMID- 30247442 TI - Emergency Response Teams In and Outside of Medicine - Structurally Crafted To Be Worlds Apart. AB - : Medical Emergency Response Teams (MERTs) are widespread throughout inpatient hospital care facilities. Besides the rise of the ubiquitous rapid response team, current MERTs span trauma, stroke, myocardial infarction, and sepsis in many hospitals. Given the multiplicity of teams with widely varying membership, leadership, and functionality, the structure of MERTs is appropriate to review to determine opportunities for improvement. Since non-medical ERTs predate MERT genesis, and are similar across multiple disciplines, non-medical ERTs provides a standard against which to compare and review MERT design and function.Non-medical ERTs are crafted to leverage team members who are fully trained and dedicated to that domain, whose skills are regularly updated, with leadership tied to unique skill sets rather than based on hierarchical rank; activity is immediately reviewed at the conclusion of each deployment and teams continue to work together between team deployments. MERTs, in sharp contradistinction, often incorporate trainees into teams that do not train together, are not focused on the discipline required to be leveraged, are led based on arrival time or hierarchy, and are usually reviewed at a time remote from team action; teams rapidly disperse after each activity and generally do not continue to work together in between team activations. These differences between ERTs and MERTs may impede MERT success with regard to morbidity and mortality mitigation. Readily deployable approaches to bridge identified gaps include dedicated Advanced Practice Provider (APP) team leadership, reductions in trainee MERT leadership while preserving participation, discipline-dedicated rescue teams, and inter-team integration training.Emergency response teams in medical and non-medical domains share parallels yet lack congruency in structure, function, membership, roles, and performance evaluation. MERT structural redesign may be warranted to embrace the beneficial elements of non-medical ERTs to improve patient outcome and reduce variation in rescue practices and team functionality. STUDY TYPE: narrative review LEVEL OF EVIDENCE: N/A. PMID- 30247443 TI - Negative FAST Exam Predicts Successful Non-operative Management in Pediatric Solid Organ Injury: A Prospective ATOMAC+ Study. AB - INTRODUCTION: FAST exam has long been proven useful in the management of adult trauma patients, however, its utility in pediatric trauma patients is not as proven. Our goal was to evaluate the utility of a FAST exam in predicting the success or failure of non-operative management (NOM) of blunt liver and/or spleen (BLSI) in the pediatric trauma population. METHODS: A retrospective analysis of a prospective observational study of patients less than 18 years of age presenting with BLSI to one of ten level-1 pediatric trauma centers (PTC) between April 2013 and January 2016. 1008 patients were enrolled and 292 had a FAST exam recorded. We analyzed failure of NOM of BLSI in the pediatric trauma population. We then compared FAST exam alone or in combination with the pediatric age adjusted shock index (SIPA) as it relates to success of NOM of BLSI. RESULTS: FAST exam had a negative predictive value (NPV) of 97% and positive predictive value (PPV) of 13%. The odds ratio of failing with a positive FAST exam was 4.9 and with a negative FAST was 0.20. When combined with SIPA a positive FAST exam and SIPA had a PPV of 17%, and an odds ratio for failure of 4.9. The combination of negative FAST and SIPA had a NPV of 96% and the odds ratio for failure was 0.20. CONCLUSION: Negative FAST is predictive of successful NOM of BLSI. The addition of a positive or negative SIPA score did not affect the positive or negative predictive value significantly. FAST exam may be useful clinically in determining which patients are not at risk for failure of NOM of BLSI and do not require monitoring in an intensive care setting. LEVEL OF EVIDENCE: Level II, Prognostic Study. PMID- 30247445 TI - Local Delivery of Regulatory T Cells Promotes Corneal Allograft Survival. AB - BACKGROUND: Regulatory T cell (Treg)-based immunotherapies have been studied as potential cell-based modalities for promoting transplant survival. However, the efficacy of local delivery of Tregs in corneal transplantation has not been fully elucidated. Herein, we investigated the kinetics of migration of subconjunctivally injected Tregs and their role in promoting corneal allograft survival. METHODS: GFPCD4CD25Foxp3 Tregs were isolated from draining lymph nodes (DLNs) of GFP transgenic mice and were subconjunctivally injected to corneal allograft recipients. Next, Tregs, conventional T cells (Tconv) or a combination of both was locally injected to graft recipients, and graft survival was determined by evaluating opacity scores for 10 weeks. Transplanted mice without treatment served as controls. The frequencies of MHC-IICD11b antigen presenting cells (APCs), IFNgammaCD4 Th1 cells, and CD45 cells in the DLNs and cornea were evaluated at week 2 posttransplantation using flow cytometry. Expression of IFNgamma, IL-10 and TGF-beta in the grafts were assessed using RT-PCR and ELISA. RESULTS: GFP Tregs were detected in the ipsilateral cornea and DLNs of recipients 6 hours after injection. Subconjunctival injection of Tregs significantly decreased the frequencies of mature APCs in the graft and DLNs, suppressed Th1 frequencies in DLNs, and inhibited CD45 cell infiltration to the graft. Finally, locally delivered Tregs significantly reduced the expression of IFN-gamma, enhanced the levels of IL-10 and TGF-beta in the graft, and promoted long-term allograft survival. CONCLUSIONS: Our study elucidates the kinetics of migration of locally delivered Tregs and shows their role in suppressing host immune response against the allograft. PMID- 30247444 TI - Socioeconomic Status and Kidney Transplant Outcomes in a Universal Healthcare System: A Population-based Cohort Study. AB - BACKGROUND: Conflicting evidence exists regarding the relationship between socioeconomic status (SES) and outcomes following kidney transplantation. METHODS: We conducted a population-based cohort study in a publicly funded healthcare system using linked administrative healthcare databases from Ontario, Canada to assess the relationship between SES and total graft failure (ie, return to chronic dialysis, preemptive retransplantation, or death) in individuals who received their first kidney transplant between 2004 and 2014. Secondary outcomes included death-censored graft failure, death with a functioning graft, all-cause mortality and all-cause hospitalization (post hoc outcome). RESULTS: 4414 kidney transplant recipients were included (median age, 53 years; 36.5% female) and the median (25, 75 percentile) follow-up was 4.3 (2.1, 7.1) years. In an unadjusted Cox proportional hazards model, each $10 000 increase in neighborhood median income was associated with an 8% decline in the rate of total graft failure (hazard ratio 0.92 [95% confidence interval [CI]: 0.87, 0.97]). After adjusting for recipient, donor and transplant characteristics, SES was not significantly associated with total or death-censored graft failure. However, each $10 000 increase in neighborhood median income remained associated with a decline in the rate of death with a functioning graft (aHR 0.91, 95% CI: 0.83, 0.98), all-cause mortality (aHR 0.92, 95% CI: 0.86, 0.99) and all-cause hospitalization (aHR 0.95, 95% CI: 0.92, 0.98). CONCLUSIONS: In conclusion, in a universal healthcare system, SES may not adversely influence graft health but SES gradients may negatively impact other kidney transplant outcomes and could be used to identify patients at increased risk of death or hospitalization. PMID- 30247447 TI - The challenges associated with a calcineurin inhibitor free regimen after heart transplantation. PMID- 30247448 TI - Donor Hypothermia and Heart Transplantation. PMID- 30247446 TI - Perspectives on the Optimal Genetically Engineered Pig in 2018 for Initial Clinical Trials of Kidney or Heart Xenotransplantation. AB - For a clinical trial today, what might realistically be the optimal pig among those currently available? Deletion of expression of the 3 pig carbohydrate antigens, against which humans have natural (preformed) antibodies (triple knockout pigs), should form the basis of any clinical trial. However, because both complement and coagulation can be activated in the absence of antibody, the expression of human complement- and coagulation-regulatory proteins is likely to be important in protecting the graft further. Any genetic manipulation that might reduce inflammation of the graft, for example, expression of hemeoxygenase-1 or A20, may also be beneficial to the long-term survival of the graft. The transgene for human CD47 is likely to have a suppressive effect on monocyte/macrophage and T-cell activity. Furthermore, deletion of xenoantigen expression and expression of a human complement-regulatory protein are both associated with a reduced T cell response. Although there are several other genetic manipulations that may reduce the T-cell response further, it seems likely that exogenous immunosuppressive therapy, particularly if it includes costimulation blockade, will be sufficient. We would therefore suggest that, with our present knowledge and capabilities, the optimal pig might be a triple-knockout pig that expressed 1 or more human complement-regulatory proteins, 1 or more human coagulation regulatory proteins, a human anti-inflammatory transgene, and CD47. Absent or minimal antibody binding is important, but we suggest that the additional insertion of protective human transgenes will be beneficial, and may be essential. PMID- 30247449 TI - Early Hypertension and Diabetes after Living Kidney Donation: A National Cohort Study. AB - BACKGROUND: Living kidney donors have an increased risk of end-stage renal disease, with hypertension and diabetes as the predominant causes. In this study, we sought to better understand the timeline when these diseases occur, focusing on the early postdonation period. METHODS: We studied 41 260 living kidney donors in the US between 2008-2014 from the SRTR and modeled incidence rates and risk factors for hypertension and diabetes. RESULTS: At 6-months, 1-year, and 2-years postdonation, there were 74, 162, and 310 cases of hypertension per 10 000 donors. Donors who were older (per 10 years, aIRR 1.40, 95% CI 1.29-1.51), male (aIRR 1.31, 95% CI 1.14-1.50), had higher BMI (per 5 units, aIRR 1.29, 95% CI 1.17-1.43), and were related to their recipient (first degree relative, aIRR 1.28, 95% CI 1.08-1.52; spouse, aIRR 1.34, 95% CI 1.08-1.66) were more likely to develop hypertension, while donors who were Hispanic/Latino were less likely (aIRR 0.71, 95% CI 0.55-0.93). At 6-months, 1-year, and 2-years, there were 2, 6, and 15 cases of diabetes per 10 000 donors. Donors who were older (per 10 years, aIRR 1.42, 95% CI 1.11-1.82), had higher BMI (per 5 units, aIRR 1.52, 95% CI 1.04 2.21), and were Hispanic/Latino (aIRR 2.45, 95% CI 1.14-5.26) were more likely to develop diabetes. CONCLUSIONS: In this national study, new-onset diabetes was rare, but 3% of donors developed hypertension within 2 years of nephrectomy. These findings reaffirm that disease pathways for kidney failure differ by donor phenotype and estimate the population most at-risk for later kidney failure. PMID- 30247450 TI - Cardiotrophin-1 Improves Kidney Preservation, Graft Function, and Survival in Transplanted Rats. AB - BACKGROUND: Cold ischemia-reperfusion injury is unavoidable during organ transplantation, and prolonged preservation is associated with poorer function recovery. Cardiotrophin-1 (CT-1) is an IL-6 family cytokine with cytoprotective properties. This preclinical study in rats tested whether CT-1 mitigates cold renal ischemia-reperfusion injury in the context of the transplantation of long time preserved kidneys. METHODS: Kidneys were flushed with cold (4 degrees C) University of Wisconsin solution containing 0.2 MUg/mL CT-1 and stored for several periods of time at 4 degrees C in the same solution. In a second approach, kidneys were first cold-preserved for 6 hours and then were perfused with University of Wisconsin solution containing CT-1 (0, 16, 32, or 64 MUg/mL) and further cold-preserved. Organ damage markers were measured in the kidneys at the end of the storage period. For renal transplantation, recipient consanguineous Fischer rats underwent bilateral nephrectomy and received a previously cold-preserved (24 hours) kidney as described above. Survival and creatinine clearance were monitored over 30 days. RESULTS: Cardiotrophin-1 in perfusion and preservation fluids reduced oxidative stress markers (superoxide anion and inducible nitric oxide synthase), inflammation markers (NF-kappaB and tumor necrosis factor-alpha), and vascular damage (vascular cell adhesion molecule-1) and activated leukemia inhibitory factor receptor and STAT-3 survival signaling. Transplantation of kidneys cold-preserved with CT-1 increased rat survival and renal function (ie, lower plasma creatinine and higher creatinine clearance) and improved kidney damage markers after transplantation (ie, lower superoxide anion, tumor necrosis factor-alpha, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and higher NF-kappaB). CONCLUSIONS: Cardiotrophin-1 represents a novel therapeutic strategy to reduce ischemia reperfusion and cold preservation injury to rescue suboptimal kidneys and, consequently, to improve the clinical outcomes of renal transplantation. PMID- 30247452 TI - UW Versus HTK for Static Preservation in Liver Transplantation: Is There a "Solution Effect" on Outcomes? PMID- 30247451 TI - The Selective RNA Polymerase I Inhibitor CX-5461 Mitigates Neointimal Remodeling in a Modified Model of Rat Aortic Transplantation. AB - BACKGROUND: Transplant vasculopathy is a major cause of chronic rejection of transplanted organs. In the present study, we examined the effects of CX-5461, a novel selective inhibitor of RNA polymerase I, on development of transplant vasculopathy using a modified model of rat aortic transplantation. METHODS: The thoracic aortas from Fischer rats were transplanted into the abdominal cavity of Lewis rats. CX-5461 was mixed in pluronic gel and administered via perivascular release. RESULTS: Treatment with CX-5461 mitigated the development of neointimal hyperplasia and vascular inflammation. This effect was likely to be attributable in part to inhibition of macrophage-dependent innate immunity reactions. Specifically, CX-5461 exhibited potent inhibitory effects on macrophage migration and lipopolysaccharide-induced activation. Treatment with CX-5461 also prevented macrophage differentiation and maturation from primary bone marrow cells. In macrophages, CX-5461 did not alter the total amount of p53 protein, but significantly increased p53 phosphorylation, which was involved in regulating cytokine-stimulated macrophage proliferation. CONCLUSIONS: In conclusion, our results suggest that pharmacological inhibition of RNA polymerase I may be a novel strategy to treat transplantation-induced arterial remodeling. PMID- 30247453 TI - Comparison of Postdonation Kidney Function Between Caucasian Donors and Low-risk APOL1 Genotype Living Kidney Donors of African Ancestry. PMID- 30247454 TI - Estimating the Weight of Children During Simulated Emergency Situations Using the Broselow Tape: Are We Underestimating the Risks of Errors? AB - OBJECTIVE: The objective of this study was to evaluate whether residents can accurately estimate children's weight using the Broselow tape. METHOD: We conducted a preplanned secondary analysis from an experimental trial. Participants were residents in pediatrics, family medicine, and emergency medicine rotating in the ED. Residents were randomly assigned to 2 sets of paired scenarios during 2 sessions. They were asked to estimate the weight of a manikin using the Broselow tape at the beginning of each scenario. The first scenario from the initial session and the last scenario from the second session were used for the current study. The primary analysis was the proportion of participants who accurately estimated manikin weight within a 10% margin of error. RESULTS: Forty residents were recruited. Thirty-two (80%) reported knowledge of the Broselow tape and 13 (32.5%) reported previous use. Weight estimation was accurate in 60% (24/40; 95% confidence interval [CI], 45%-74%) during the first scenarios. Error in weight estimation differed by greater than 25% in 28% (11/40). Error in estimation was not associated with previous knowledge (odds ratio, 6.2; 95% CI, 0.68-56) or previous use (odds ratio, 0.9; 95% CI, 0.23-3.5) of the Broselow tape. In the last scenario, 88% accurately estimated manikin weight (35/40; 95% CI, 73%-95%). CONCLUSIONS: Although most residents reported knowledge of the Broselow tape, 40% made erroneous weight estimations by at least 10% with the first use in this simulation study. With repeated use, they improved significantly over time. Teaching appropriate use of the Broselow tape should be part of residency-training curricula and pediatric advanced life support course. PMID- 30247455 TI - Influenza A-Associated Epiglottitis and Compensatory Pursed Lip Breathing in an Infant. AB - The last 3 decades have seen a shift in the epidemiology of epiglottitis. Epiglottitis was once most commonly associated with Haemophilus influenzae type B. However, with the implementation of the H. influenzae type B vaccine in 1985, the incidence has drastically declined. There are now new emerging pathogens bacteria, viruses, and fungi-causing epiglottitis. Here, we report the first case of epiglottitis secondary to influenza A in a former full-term, vaccinated infant who presented with cough, fever, stridor, pursed lip breathing, and progressive respiratory distress and eventual respiratory failure. This case highlights the presentation and clinical course of epiglottitis and describes a rare clinical feature, pursed lip breathing, in an infant. PMID- 30247456 TI - Parental Attitudes and Knowledge About Lumbar Puncture in Children. AB - OBJECTIVES: Lumbar puncture (LP) is fundamental for diagnosis and treatment; however, some parents do not provide consent for their children to undergo the procedure, which can make diagnosis and determination of the optimal treatment difficult. The present study aimed to describe the level of knowledge and attitudes toward LP of parents whose children were scheduled to undergo the procedure. METHODS: A prospective cross-sectional descriptive study of a convenience sample of parents of 84 children aged 2 months to 17 years scheduled for LP at a single academic children's hospital between 2015 and 2017. Parents were administered a written survey and interviewed by a physician other than the person who did the LP. Data on parental level of knowledge and attitudes regarding LP, in addition to reasons for refusal, were collected.The parents of 84 patients scheduled for LP due to various indications were administered a face to-face survey interview. The survey was used to collect parental demographic data, as well as opinions and knowledge about LP and postinterventional complications. RESULTS: The mean age of the 84 patients (57% male and 43% female) was 6.4 +/- 5.17 years. Lumbar puncture was planned for the presumptive diagnosis of neurological disease in 45.25% of the patients, central nervous system infection in 45.25%, and acute encephalopathy in 9.5%. Among the parents, 65% (n = 55) had no knowledge or attitude about LP prior to the survey interview. The most common parental concern related to LP was paralysis (25%), followed by infertility (2%), mental retardation (1%), and disease progression (1%). Only 4.7% of the parents did not provide consent for their child to undergo LP. CONCLUSIONS: We found that most parents had little knowledge about LP, and the most common parental concern was paralysis. Despite this, in our study, only 5% of parents did not consent to LP. PMID- 30247457 TI - Acupuncture as a Nonpharmacologic Treatment for Pain in a Pediatric Emergency Department. AB - OBJECTIVES: With epidemic opioid deaths and abuse in the United States, government agencies recommend nonpharmacological treatments for pain. However nonopioid treatment options for moderate to severe pain in the pediatric emergency department (PED) are limited. Acupuncture has been shown to be effective for pain. The objective of this study was to evaluate the feasibility of using traditional acupuncture (TA) and battlefield acupuncture (BFA) in the treatment of pain in the PED. METHODS: A pediatric cohort treated with acupuncture for pain in an urban PED was assessed. All subjects received TA or BFA as treatment, and pre/postacupuncture pain scores, feedback, and adverse events were assessed. The primary outcome was a change in pain score. RESULTS: Twelve patients received BFA, and 13 received TA for these pain conditions: headaches, sciatica, paraphimosis, torticollis, joint pains (knee, shoulder, jaw), sprains (foot, wrist, thumb), dysmenorrhea, otitis externa, sickle cell, and muscle knot. The mean +/- SD pain score change, 5.8 +/- 2.5 (P < 0.05; 95% confidence interval, 4.9-7.0), was clinically and statistically significant. Over 90% of subjects reported significant improvement or resolution of pain; 96% were satisfied with pain relief and would receive acupuncture again. Two adverse events were noted: one patient reported dizziness, and another, a tinge of blood at 1 of 90 needled points. CONCLUSIONS: This study suggests that acupuncture is a potential nonpharmacologic therapeutic option for acute pain management in the PED. PMID- 30247458 TI - Multidisciplinary, In Situ Simulation Improves Experienced Caregiver Confidence With High-Risk Pediatric Emergencies. AB - OBJECTIVES: Emergency department (ED) caregivers have reported feeling uncomfortable performing emergency pediatric procedures, likely because of either a lack of training or infrequent exposure to these events. To address these gaps, ongoing education for experienced ED caregivers must aim to improve caregiver confidence with high-risk, low-volume pediatric emergency care. This study used multidisciplinary, in situ simulations to facilitate improved caregiver confidence when treating pediatric emergencies in an ED setting. METHODS: Two hour pediatric code blue simulations were held in 7 EDs throughout the Seattle, Washington, metropolitan area. Questionnaire data were collected from 353 simulation participants (60% nurses, 19.5% ED technicians, 14% ED physicians; median team size = 5) via pre simulation and post simulation surveys assessing confidence and understanding regarding interventions/treatments, standard protocols, culture of safety behavior, and team members' roles/responsibilities. Paired t tests were used to analyze changes in self-reported confidence. RESULTS: Confidence improved across all questions (37%-57% of participants reported good/complete confidence pre simulation, improving 94%-98% post simulation; P < 0.00001 for all). Participants cited learning equipment location/use (37%), hands on practice (32%), and discussion (22%) as the most helpful aspects of the simulations. Identified changes to practice made post simulation included more effective communication (18%) and utilization of a pediatric emergency drug sheet (13%). CONCLUSIONS: Multidisciplinary, in situ simulation improves experienced ED caregivers' confidence with pediatric emergencies in an ED setting. These findings suggest that investment in simulation-based education may improve clinical care and quality and safety improvement plans for the treatment of pediatric emergencies in general EDs. PMID- 30247459 TI - How Much Cardiopulmonary Resuscitation Does a Pediatric Emergency Provider Perform in 1 Year? A Video-Based Analysis. AB - OBJECTIVES: We aimed to quantify time performing chest compressions (CCs) per year of individual providers in a pediatric ED and to project a rate of opportunity for CC based on median clinical hours per provider category. METHODS: This was an observational study of video-recorded resuscitations in a pediatric ED over 1 year. Events where CCs were performed for more than 2 minutes were included. Identification of providers and duration of CCs per provider were determined by video review. Time of CCs was totaled per provider over the study period. Data were expressed as median and interquartile range (IQR). Rate of opportunity for providing CC to a child was calculated by dividing the median clinical hours per year per provider type by the number of CC events per year. RESULTS: Twenty-three CC events totaling 340 minutes of CCs were analyzed. Chest compressions were performed by 6 (13%) of 45 attending physicians, 3 (25%) of 12 fellows, 32 (22%) of 143 nurses, and 19 (59%) of 32 technicians. The median amount of time performing CC was 182 seconds (IQR, 91-396 seconds); by provider category, median amount of time was as follows: attending physicians, 83 seconds (IQR, 64-103 seconds); fellows, 45 seconds (IQR, 6-83 seconds); nurses, 128 seconds (IQR, 93-271 seconds); and technicians, 534 seconds (IQR, 217-793 seconds). The projected hours needed for an opportunity to perform CCs was 730 hours (91 shifts) for attending physicians, 243 hours (30 shifts) for fellows, and 1460 hours (121 shifts) for nurses and technicians. CONCLUSIONS: Performing CCs on children in the ED is a rare event, with a median of 3 minutes per provider per year. Future studies should determine training methods to optimize readiness for these rare occurrences. PMID- 30247460 TI - Detection of Antibodies That Neutralize the Cellular Uptake of Enzyme Replacement Therapies with a Cell-based Assay. AB - The administration of enzyme replacement therapies (ERTs) and other biologic therapies to patients may elicit an anti-drug immune response. The characterization of these anti-drug antibodies (ADA), especially those that may neutralize the biological activity of the drug, termed neutralizing antibodies (NAbs), is crucial in understanding the effects of these antibodies on the drug's pharmacological profile. This protocol describes a cell-based flow cytometry method to detect factors that neutralize the cellular uptake of a representative lysosomal ERT in human matrix. The protocol consists of three procedures: screening, a confirmatory step, and titer assays to detect, identify, and establish the relative level of neutralizing antibody titer in subject samples. In this method, samples are first mixed with the fluorophore-conjugated ERT product, then incubated with cells [e.g., human T lymphocytes (Jurkat cells)] that express a cell-surface cation-independent mannose 6-phosphate receptor (CI M6PR), and finally, analyzed with a flow cytometer. A sample without NAbs will result in the uptake of the fluorophore-conjugated ERT product via CI-M6PR, whereas, the presence of NAbs will bind to the drug and interfere with the CI M6PR binding and uptake. The amount of the fluorophore-conjugated ERT internalized by the Jurkat cells is measured by flow cytometry and evaluated as the percentage (%) signal inhibition compared to the response obtained in the presence of a representative drug-naive matrix. In the confirmatory step, the samples are pre-incubated with ERT-conjugated magnetic beads to deplete drug specific factors that bind to the drug (such as NAbs) prior to an incubation with cells. Samples that screen and confirm positive for drug-specific NAbs in the assay are then serially diluted to generate an antibody titer. Semi-quantitative antibody titers may be correlated with measurements of drug safety and efficacy. PMID- 30247462 TI - A Rabbit Model of Durable Transgene Expression in Jugular Vein to Common Carotid Artery Interposition Grafts. AB - Vein graft bypass surgery is a common treatment for occlusive arterial disease; however, long-term success is limited by graft failure due to thrombosis, intimal hyperplasia, and atherosclerosis. The goal of this article is to demonstrate a method for placing bilateral venous interposition grafts in a rabbit, then transducing the grafts with a gene transfer vector that achieves durable transgene expression. The method allows the investigation of the biological roles of genes and their protein products in normal vein graft homeostasis. It also allows the testing of transgenes for the activities that could prevent vein graft failure, e.g., whether the expression of a transgene prevents the neointimal growth, reduces the vascular inflammation, or reduces atherosclerosis in rabbits fed with a high-fat diet. During an initial survival surgery, the segments of right and left external jugular vein are excised and placed bilaterally as reversed end-to-side common carotid artery interposition grafts. During a second survival surgery, performed 28 days later, each of the grafts is isolated from the circulation with vascular clips and the lumens are filled (via an arteriotomy) with a solution containing a helper-dependent adenoviral (HDAd) vector. After a 20-min incubation, the vector solution is aspirated, the arteriotomy is repaired, and flow is restored. The veins are harvested at time points dictated by individual experimental protocols. The 28-day delay between the graft placement and the transduction is necessary to ensure the adaptation of the vein graft to the arterial circulation. This adaptation avoids rapid loss of transgene expression that occurs in vein grafts transduced before or immediately after grafting. The method is unique in its ability to achieve durable, stable transgene expression in grafted veins. Compared to other large animal vein graft models, rabbits have advantages of low cost and easy handling. Compared to rodent vein graft models, rabbits have larger and easier-to-manipulate blood vessels that provide abundant tissue for analysis. PMID- 30247463 TI - Generation of High-Throughput Three-Dimensional Tumor Spheroids for Drug Screening. AB - Cancer cells have routinely been cultured in two dimensions (2D) on a plastic surface. This technique, however, lacks the true environment a tumor mass is exposed to in vivo. Solid tumors grow not as a sheet attached to plastic, but instead as a collection of clonal cells in a three-dimensional (3D) space interacting with their neighbors, and with distinct spatial properties such as the disruption of normal cellular polarity. These interactions cause 3D-cultured cells to acquire morphological and cellular characteristics which are more relevant to in vivo tumors. Additionally, a tumor mass is in direct contact with other cell types such as stromal and immune cells, as well as the extracellular matrix from all other cell types. The matrix deposited is comprised of macromolecules such as collagen and fibronectin. In an attempt to increase the translation of research findings in oncology from bench to bedside, many groups have started to investigate the use of 3D model systems in their drug development strategies. These systems are thought to be more physiologically relevant because they attempt to recapitulate the complex and heterogeneous environment of a tumor. These systems, however, can be quite complex, and, although amenable to growth in 96-well formats, and some now even in 384, they offer few choices for large-scale growth and screening. This observed gap has led to the development of the methods described here in detail to culture tumor spheroids in a high throughput capacity in 1536-well plates. These methods represent a compromise to the highly complex matrix-based systems, which are difficult to screen, and conventional 2D assays. A variety of cancer cell lines harboring different genetic mutations are successfully screened, examining compound efficacy by using a curated library of compounds targeting the Mitogen-Activated Protein Kinase or MAPK pathway. The spheroid culture responses are then compared to the response of cells grown in 2D, and differential activities are reported. These methods provide a unique protocol for testing compound activity in a high-throughput 3D setting. PMID- 30247464 TI - A Tissue Culture Model of Estrogen-producing Primary Bovine Granulosa Cells. AB - Ovarian granulosa cells (GC) are the major source of estradiol synthesis. Induced by the preovulatory luteinizing hormone (LH) surge, cells of the theca and, in particular, of the granulosa cell layer profoundly change their morphological, physiological, and molecular characteristics and form the progesterone-producing corpus luteum that is responsible for maintaining pregnancy. Cell culture models are essential tools to study the underlying regulatory mechanisms involved in the folliculo-luteal transformation. The presented protocol focuses on the isolation procedure and cryopreservation of bovine GC from small- to medium-sized follicles (< 6 mm). With this technique, a nearly pure population of GC can be obtained. The cryopreservation procedure greatly facilitates time management of the cell culture work independent of a direct primary tissue (ovaries) supply. This protocol describes a serum-free cell culture model that mimics the estradiol active status of bovine GC. Important conditions that are essential for a successful steroid-active cell culture are discussed throughout the protocol. It is demonstrated that increasing the plating density of the cells induces a specific response as indicated by an altered gene expression profile and hormone production. Furthermore, this model provides a basis for further studies on GC differentiation and other applications. PMID- 30247461 TI - Fabrication of a Multiplexed Artificial Cellular MicroEnvironment Array. AB - Cellular microenvironments consist of a variety of cues, such as growth factors, extracellular matrices, and intercellular interactions. These cues are well orchestrated and are crucial in regulating cell functions in a living system. Although a number of researchers have attempted to investigate the correlation between environmental factors and desired cellular functions, much remains unknown. This is largely due to the lack of a proper methodology to mimic such environmental cues in vitro, and simultaneously test different environmental cues on cells. Here, we report an integrated platform of microfluidic channels and a nanofiber array, followed by high-content single-cell analysis, to examine stem cell phenotypes altered by distinct environmental factors. To demonstrate the application of this platform, this study focuses on the phenotypes of self renewing human pluripotent stem cells (hPSCs). Here, we present the preparation procedures for a nanofiber array and the microfluidic structure in the fabrication of a Multiplexed Artificial Cellular MicroEnvironment (MACME) array. Moreover, overall steps of the single-cell profiling, cell staining with multiple fluorescent markers, multiple fluorescence imaging, and statistical analyses, are described. PMID- 30247465 TI - Fabrication of Refractive-index-matched Devices for Biomedical Microfluidics. AB - The use of microfluidic devices has emerged as a defining tool for biomedical applications. When combined with modern microscopy techniques, these devices can be implemented as part of a robust platform capable of making simultaneous complementary measurements. The primary challenge created by the combination of these two techniques is the mismatch in refractive index between the materials traditionally used to make microfluidic devices and the aqueous solutions typically used in biomedicine. This mismatch can create optical artifacts near the channel or device edges. One solution is to reduce the refractive index of the material used to fabricate the device by using a fluorinated polymer such as MY133-V2000 whose refractive index is similar to that of water (n = 1.33). Here, the construction of a microfluidic device made out of MY133-V2000 using soft lithography techniques is demonstrated, using O2 plasma in conjunction with an acrylic holder to increase the adhesion between the MY133-V2000 fabricated device and the polydimethylsiloxane (PDMS) substrate. The device is then tested by incubating it filled with cell culture media for 24 h to demonstrate the ability of the device to maintain cell culture conditions during the course of a typical imaging experiment. Finally, quantitative phase microscopy (QPM) is used to measure the distribution of mass within the live adherent cells in the microchannel. This way, the increased precision, enabled by fabricating the device from a low index of refraction polymer such as MY133-V2000 in lieu of traditional soft lithography materials such as PDMS, is demonstrated. Overall, this approach for fabricating microfluidic devices can be readily integrated into existing soft lithography workflows in order to reduce optical artifacts and increase measurement precision. PMID- 30247466 TI - Surface Functionalization of Metal-Organic Frameworks for Improved Moisture Resistance. AB - Metal-organic frameworks (MOFs) are a class of porous inorganic materials with promising properties in gas storage and separation, catalysis and sensing. However, the main issue limiting their applicability is their poor stability in humid conditions. The common methods to overcome this problem involve the formation of strong metal-linker bonds by using highly charged metals, which is limited to a number of structures, the introduction of alkylic groups to the framework by post-synthetic modification (PSM) or chemical vapour deposition (CVD) to enhance overall hydrophobicity of the framework. These last two usually provoke a drastic reduction of the porosity of the material. These strategies do not permit to exploit the properties of the MOF already available and it is imperative to find new methods to enhance the stability of MOFs in water while keeping their properties intact. Herein, we report a novel method to enhance the water stability of MOF crystals featuring Cu2(O2C)4 paddle-wheel units, such as HKUST (where HKUST stands for Hong Kong University of Science & Technology), with the catechols functionalized with alkyl and fluoro-alkyl chains. By taking advantage of the unsaturated metal sites and the catalytic catecholase-like activity of CuII ions, we are able to create robust hydrophobic coatings through the oxidation and subsequent polymerization of the catechol units on the surface of the crystals under anaerobic and water-free conditions without disrupting the underlying structure of the framework. This approach not only affords the material with improved water stability but also provides control over the function of the protective coating, which enables the development of functional coatings for the adsorption and separations of volatile organic compounds. We are confident that this approach could also be extended to other unstable MOFs featuring open metal sites. PMID- 30247469 TI - Assessment of Methane and Nitrous Oxide Fluxes from Paddy Field by Means of Static Closed Chambers Maintaining Plants Within Headspace. AB - This protocol describes the measurement of greenhouse gas (GHG) emissions from paddy soils using the static closed chamber technique. This method is based on the diffusion theory. A known volume of air overlaying a defined soil area is enclosed within a parallelepiped cover (named "chamber"), for a defined period of time. During this enclosure period, gases (methane (CH4) and nitrous oxide (N2O)) move from soil pore air near their microbial source (i.e., methanogens, nitrifiers, denitrifiers) to the chamber headspace, following a natural concentration gradient. Fluxes are then estimated from chamber headspace concentration variations sampled at regular intervals throughout the enclosure and then analyzed with gas chromatography. Among the techniques available for GHG measurement, the static closed chamber method is suitable for plot experiments, as it does not require large homogenously treated soil areas. Furthermore, it is manageable with limited resources and can identify relationships among ecosystem properties, processes, and fluxes, especially when combined with GHG driving force measurements. Nevertheless, with respect to the micrometeorological method, it causes a minimal but still unavoidable soil disturbance, and allows a minor temporal resolution. Several phases are key to the method implementation: i) chamber design and deployment, ii) sample handling and analyses, and iii) flux estimation. Technique implementation success in paddy fields demands adjustments for field flooding during much of the cropping cycle, and for rice plant maintenance within the chamber headspace during measurements. Therefore, the additional elements to be considered with respect to the usual application of non flooded agricultural soils consist of devices for: i) avoiding any unintended water disturbance that could overestimate fluxes, and ii) including rice plants within the chamber headspace to fully consider gases emitted through aerenchyma transportation. PMID- 30247468 TI - Bioindication Testing of Stream Environment Suitability for Young Freshwater Pearl Mussels Using In Situ Exposure Methods. AB - Knowledge of habitat suitability for freshwater mussels is an important step in the conservation of this endangered species group. We describe a protocol for performing in situ juvenile exposure tests within oligotrophic river catchments over one-month and three-month periods. Two methods (in both modifications) are presented to evaluate the juvenile growth and survival rate. The methods and modifications differ in value for the locality bioindication and each has its benefits as well as limitations. The sandy cage method works with a large set of individuals, but only some of the individuals are measured and the results are evaluated in bulk. In the mesh cage method, the individuals are kept and measured separately, but a low individual number is evaluated. The open water exposure modification is relatively easy to apply; it shows the juvenile growth potential of sites and can also be effective for water toxicity testing. The within-bed exposure modification needs a high workload but is closer to the conditions of a natural juvenile environment and it is better for reporting the real suitability of localities. On the other hand, more replications are needed in this modification due to its high-hyporheic environment variability. PMID- 30247467 TI - High-throughput Measurement of Dictyostelium discoideum Macropinocytosis by Flow Cytometry. AB - Large-scale non-specific fluid uptake by macropinocytosis is important for the proliferation of certain cancer cells, antigen sampling, host cell invasion and the spread of neurodegenerative diseases. The commonly used laboratory strains of the amoeba Dictyostelium discoideum have extremely high fluid uptake rates when grown in nutrient medium, over 90% of which is due to macropinocytosis. In addition, many of the known core components of mammalian macropinocytosis are also present, making it an excellent model system for studying macropinocytosis. Here, the standard technique to measure internalized fluid using fluorescent dextran as a label is adapted to a 96-well plate format, with the samples analyzed by flow cytometry using a high-throughput sampling (HTS) attachment. Cells are fed non-quenchable fluorescent dextran for a pre-determined length of time, washed by immersion in ice-cold buffer and detached using 5 mM sodium azide, which also stops exocytosis. Cells in each well are then analyzed by flow cytometry. The method can also be adapted to measure membrane uptake and phagocytosis of fluorescent beads or bacteria. This method was designed to allow measurement of fluid uptake by Dictyostelium in a high-throughput, labor and resource efficient manner. It allows simultaneous comparison of multiple strains (e.g. knockout mutants of a gene) and conditions (e.g. cells in different media or treated with different concentrations of inhibitor) in parallel and simplifies time-courses. PMID- 30247470 TI - Ferric Chloride-induced Canine Carotid Artery Thrombosis: A Large Animal Model of Vascular Injury. AB - Occlusive arterial thrombosis leading to cerebral ischemic stroke and myocardial infarction contributes to ~13 million deaths every year globally. Here, we have translated a vascular injury model from a small animal into a large animal (canine), with slight modifications that can be used for pre-clinical screening of prophylactic and thrombolytic agents. In addition to the surgical methods, the modified protocol describes the step-by-step methods to assess carotid artery canalization by angiography, detailed instructions to process both the brain and carotid artery for histological analysis to verify carotid canalization and cerebral hemorrhage, and specific parameters to complete an assessment of downstream thromboembolic events by utilizing magnetic resonance imaging (MRI). In addition, specific procedural changes from the previously well-established small animal model necessary to translate into a large animal (canine) vascular injury are discussed. PMID- 30247471 TI - Large-scale Three-dimensional Imaging of Cellular Organization in the Mouse Neocortex. AB - The mammalian neocortex is composed of many types of excitatory and inhibitory neurons, each with specific electrophysiological and biochemical properties, synaptic connections, and in vivo functions, but their basic functional and anatomical organization from cellular to network scale is poorly understood. Here we describe a method for the three-dimensional imaging of fluorescently-labeled neurons across large areas of the brain for the investigation of the cortical cellular organization. Specific types of neurons are labeled by the injection of fluorescent retrograde neuronal tracers or expression of fluorescent proteins in transgenic mice. Block brain samples, e.g., a hemisphere, are prepared after fixation, made transparent with tissue clearing methods, and subjected to fluorescent immunolabeling of the specific cell types. Large areas are scanned using confocal or two-photon microscopes equipped with large working distance objectives and motorized stages. This method can resolve the periodic organization of the cell type-specific microcolumn functional modules in the mouse neocortex. The procedure can be useful for the study of three-dimensional cellular architecture in the diverse brain areas and other complex tissues. PMID- 30247472 TI - Phase Contrast Magnetic Resonance Imaging in the Rat Common Carotid Artery. AB - Phase contrast magnetic resonance imaging (PC-MRI) is a noninvasive approach that can quantify flow-related parameters such as blood flow. Previous studies have shown that abnormal blood flow may be associated with systemic vascular risk. Thus, PC-MRI can facilitate the translation of data obtained from animal models of cardiovascular diseases to pertinent clinical investigations. In this report, we describe the procedure for measuring blood flow in the common carotid artery (CCA) of rats using cine-gated PC-MRI and discuss relevant analysis methods. This procedure can be performed in a live, anesthetized animal and does not require euthanasia after the procedure. The proposed scanning parameters yield repeatable measurements for blood flow, indicating excellent reproducibility of the results. The PC-MRI procedure described in this article can be used for pharmacological testing, pathophysiological assessment, and cerebral hemodynamics evaluation. PMID- 30247473 TI - Generation and Control of Electrohydrodynamic Flows in Aqueous Electrolyte Solutions. AB - To drive electrohydrodynamic (EHD) flows in aqueous solutions, the separation of cation and anion transport pathways is essential because a directed electric body force has to be induced by ionic motions in liquid. On the other hand, positive and negative charges attract each other, and electroneutrality is maintained everywhere in equilibrium conditions. Furthermore, an increase in an applied voltage has to be suppressed to avoid water electrolysis, which causes the solutions to become unstable. Usually, EHD flows can be induced in non-aqueous solutions by applying extremely high voltages, such as tens of kV, to inject electrical charges. In this study, two methods are introduced to generate EHD flows induced by electrical charge separations in aqueous solutions, where two liquid phases are separated by an ion-exchange membrane. Due to a difference in the ionic mobility in the membrane, ion concentration polarization is induced between both sides of the membrane. In this study, we demonstrate two methods. (i) The relaxation of ion concentration gradients occurs via a flow channel that penetrates an ion-exchange membrane, where the transport of the slower species in the membrane selectively becomes dominant in the flow channel. This is a driving force to generate an EHD flow in the liquid. (ii) A long waiting time for the diffusion of ions passing through the ion-exchange membrane enables the generation of an ion-dragged flow by externally applying an electric field. Ions concentrated in a flow channel of a 1 x 1 mm2 cross-section determine the direction of the liquid flow, corresponding to the electrophoretic transport pathways. In both methods, the electric voltage difference required for an EHD flow generation is drastically reduced to near 2 V by rectifying the ion transport pathways. PMID- 30247474 TI - The Cutting and Floating Method for Paraffin-embedded Tissue for Sectioning. AB - Sectioning of the paraffin-embedded tissue is widely used in histology and pathology. However, it is tedious. To improve this method, several commercial companies have devised complex section transfer systems using fluid water. To simplify this technology, we created a simple method using homemade equipment that combines cutting and floating within a simple thermostatic chamber; therefore, the sections automatically enter the water bath on the water surface. The hippocampus from adult mouse brains, adult mouse kidneys, embryonic mouse brains, and adult zebrafish eyes were cut using both conventional paraffin sectioning and the presented method for comparison. Statistical analysis shows that our improved method saved time and produced higher quality sections. In addition, paraffin sectioning of a whole specimen in a short time is easy for junior operators. PMID- 30247475 TI - Engineering Transplantation-suitable Retinal Pigment Epithelium Tissue Derived from Human Embryonic Stem Cells. AB - Several pathological conditions of the eye affect the functionality and/or the survival of the retinal pigment epithelium (RPE). These include some forms of retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Cell therapy is one of the most promising therapeutic strategies proposed to cure these diseases, with already encouraging preliminary results in humans. However, the method of preparation of the graft has a significant impact on its functional outcomes in vivo. Indeed, RPE cells grafted as a cell suspension are less functional than the same cells transplanted as a retinal tissue. Herein, we describe a simple and reproducible method to engineer RPE tissue and its preparation for an in vivo implantation. RPE cells derived from human pluripotent stem cells are seeded on a biological support, the human amniotic membrane (hAM). Compared to artificial scaffolds, this support has the advantage of having a basement membrane that is close to the Bruch's membrane where endogenous RPE cells are attached. However, its manipulation is not easy, and we developed several strategies for its proper culturing and preparation for grafting in vivo. PMID- 30247476 TI - Evolution of Staircase Structures in Diffusive Convection. AB - Diffusive convection (DC) occurs when the vertical stratified density is controlled by two opposing scalar gradients that have distinctly different molecular diffusivities, and the larger- and smaller- diffusivity scalar gradients have negative and positive contributions for the density distribution, respectively. The DC occurs in many natural processes and engineering applications, for example, oceanography, astrophysics and metallurgy. In oceans, one of the most remarkable features of DC is that the vertical temperature and salinity profiles are staircase-like structure, composed of consecutive steps with thick homogeneous convecting layers and relatively thin and high-gradient interfaces. The DC staircases have been observed in many oceans, especially in the Arctic and Antarctic Oceans, and play an important role on the ocean circulation and climatic change. In the Arctic Ocean, there exist basin-wide and persistent DC staircases in the upper and deep oceans. The DC process has an important effect on diapycnal mixing in the upper ocean and may significantly influence the surface ice-melting. Compared to the limitations of field observations, laboratory experiment shows its unique advantage to effectively examine the dynamic and thermodynamic processes in DC, because the boundary conditions and the controlled parameters can be strictly adjusted. Here, a detailed protocol is described to simulate the evolution process of DC staircase structure, including its generation, development and disappearance, in a rectangular tank filled with stratified saline water. The experimental setup, evolution process, data analysis, and discussion of results are described in detail. PMID- 30247477 TI - Operant Protocols for Assessing the Cost-benefit Analysis During Reinforced Decision Making by Rodents. AB - Reinforcement-guided decision making is the ability to choose between competing courses of action based on the relative value of the benefits and their consequences. This process is integral to the normal human behavior and has been shown to be disrupted by neurological and psychiatric disorders such as addiction, schizophrenia, and depression. Rodents have long been used to uncover the neurobiology of human cognition. To this end, several behavioral tasks have been developed; however, most are non-automated and are labor-intensive. The recent development of the open-source microcontroller has enabled researchers to automate operant-based tasks for assessing a variety of cognitive tasks, standardizing the stimulus presentation, improving the data recording and consequently, improving the research output. Here, we describe an automated delay based reinforcement-guided decision-making task, using an operant T-maze controlled by custom-written software programs. Using these decision-making tasks, we show the changes in the local field potential activities in the anterior cingulate cortex of a rat whilst it performs a delay-based cost-and benefit decision-making task. PMID- 30247478 TI - Defined Xeno-free and Feeder-free Culture Conditions for the Generation of Human iPSC-derived Retinal Cell Models. AB - The production of specialized cells from pluripotent stem cells provides a powerful tool to develop new approaches for regenerative medicine. The use of human-induced pluripotent stem cells (iPSCs) is particularly attractive for neurodegenerative disease studies, including retinal dystrophies, where iPSC derived retinal cell models mark a major step forward to understand and fight blindness. In this paper, we describe a simple and scalable protocol to generate, mature, and cryopreserve retinal organoids. Based on medium changing, the main advantage of this method is to avoid multiple and time-consuming steps commonly required in a guided differentiation of iPSCs. Mimicking the early phases of retinal development by successive changes of defined media on adherent human iPSC cultures, this protocol allows the simultaneous generation of self-forming neuroretinal structures and retinal pigmented epithelial (RPE) cells in a reproducible and efficient manner in 4 weeks. These structures containing retinal progenitor cells (RPCs) can be easily isolated for further maturation in a floating culture condition enabling the differentiation of RPCs into the seven retinal cell types present in the adult human retina. Additionally, we describe quick methods for the cryopreservation of retinal organoids and RPE cells for long-term storage. Combined together, the methods described here will be useful to produce and bank human iPSC-derived retinal cells or tissues for both basic and clinical research. PMID- 30247479 TI - In Vitro Differentiation of Mouse Granulocyte-macrophage-colony-stimulating Factor (GM-CSF)-producing T Helper (THGM) Cells. AB - The granulocyte-macrophage-colony-stimulating factor (GM-CSF)-producing T helper (THGM) cell is a newly identified T helper cell subset that predominantly secretes GM-CSF without producing interferon (IFN)gamma or interleukin (IL)-17 and is found to play an essential role in the autoimmune neuroinflammation. A method of isolation of naive CD4+ T cells from a single-cell suspension of splenocytes and THGM cell generation from naive CD4+ T cells would be a useful technique in the study of T cell-mediated immunity and autoimmune diseases. Here we describe a method that differentiates mouse naive CD4+ T cells into THGM cells promoted by IL-7. The outcome of the differentiation was assessed by the analysis of the cytokines expression using different techniques, including intracellular cytokine staining combined with flow cytometry, a quantitative real-time polymerase chain reaction (PCR), and enzyme-linked immunosorbent assays (ELISA). Using the THGM differentiation protocol as described here, about 55% of the cells expressed GM-CSF with a minimal expression of IFNalpha or IL-17. The predominant expression of GM-CSF by THGM cells was further confirmed by the analysis of the expression of GM-CSF, IFNalpha, and IL-17 at both mRNA and protein levels. Thus, this method can be used to differentiate naive CD4+ T cells to THGM cells in vitro, which will be useful in the study of THGM cell biology. PMID- 30247480 TI - A Method for Investigating Change Blindness in Pigeons (Columba Livia). AB - Change blindness is a phenomenon of visual attention, whereby changes to a visual display go unnoticed under certain specific circumstances. While many laboratory procedures have been developed that produce change blindness in humans, the flicker paradigm has emerged as a particularly effective method. In the flicker paradigm, two visual displays are presented in alternation with one another. If successive displays are separated by a short inter-stimulus interval (ISI), change detection is impaired. The simplicity of the procedure and the clear, performance-based operational definition of change blindness make the flicker paradigm well-suited to comparative research using nonhuman animals. Indeed, a variant has been developed that can be implemented in operant chambers to study change blindness in pigeons. Results indicate that pigeons, like humans, are worse at detecting the location of a change if two consecutive displays are separated in time by a blank ISI. Furthermore, pigeons' change detection is consistent with an active, location-by-location search process that requires selective attention. The flicker task thus has the potential to contribute to investigations of the dynamics of pigeons' selective spatial attention in comparison to humans. It also illustrates that the phenomenon of change blindness is not exclusive to humans' visual perception, but may instead be a general consequence of selective attention. Finally, while the useful aspects of attention are widely appreciated and understood, it is also important to acknowledge that they may be accompanied by specific imperfections such as change blindness, and that these imperfections have consequences across a wide range of contexts. PMID- 30247481 TI - Correlative Light Electron Microscopy (CLEM) for Tracking and Imaging Viral Protein Associated Structures in Cryo-immobilized Cells. AB - Due to its high resolution, electron microscopy (EM) is an indispensable tool for virologists. However, one of the main difficulties when analyzing virus-infected or transfected cells via EM are the low efficiencies of infection or transfection, hindering the examination of these cells. In order to overcome this difficulty, light microscopy (LM) can be performed first to allocate the subpopulation of infected or transfected cells. Thus, taking advantage of the use of fluorescent proteins (FPs) fused to viral proteins, LM is used here to record the positions of the "positive-transfected" cells, expressing a FP and growing on a support with an alphanumeric pattern. Subsequently, cells are further processed for EM via high pressure freezing (HPF), freeze substitution (FS) and resin embedding. The ultra-rapid freezing step ensures excellent membrane preservation of the selected cells that can then be analyzed at the ultrastructural level by transmission electron microscopy (TEM). Here, a step-by-step correlative light electron microscopy (CLEM) workflow is provided, describing sample preparation, imaging and correlation in detail. The experimental design can be also applied to address many cell biology questions. PMID- 30247482 TI - Characterization of Thymus-dependent and Thymus-independent Immunoglobulin Isotype Responses in Mice Using Enzyme-linked Immunosorbent Assay. AB - Antibodies, also termed as immunoglobulins (Ig), secreted by differentiated B lymphocytes, plasmablasts/plasma cells, in humoral immunity provide a formidable defense against invading pathogens via diverse mechanisms. One major goal of vaccination is to induce protective antigen-specific antibodies to prevent life threatening infections. Both thymus-dependent (TD) and thymus-independent (TI) antigens can elicit robust antigen-specific IgM responses and can also induce the production of isotype-switched antibodies (IgG, IgA and IgE) as well as the generation of memory B cells with the help provided by antigen presenting cells (APCs). Here, we describe a protocol to characterize TD and TI Ig isotype responses in mice using enzyme-linked immunosorbent assay (ELISA). In this protocol, TD and TI Ig responses are elicited in mice by intraperitoneal (i.p.) immunization with hapten-conjugated model antigens TNP-KLH (in alum) and TNP polysaccharide (in PBS), respectively. To induce TD memory response, a booster immunization of TNP-KLH in alum is given at 3 weeks after the first immunization with the same antigen/adjuvant. Mouse sera are harvested at different time points before and after immunization. Total serum Ig levels and TNP-specific antibodies are subsequently quantified using Ig isotype-specific Sandwich and indirect ELISA, respectively. In order to correctly quantify the serum concentration of each Ig isotype, the samples need to be appropriately diluted to fit within the linear range of the standard curves. Using this protocol, we have consistently obtained reliable results with high specificity and sensitivity. When used in combination with other complementary methods such as flow cytometry, in vitro culture of splenic B cells and immunohistochemical staining (IHC), this protocol will allow researchers to gain a comprehensive understanding of antibody responses in a given experimental setting. PMID- 30247483 TI - Fat-Water Phantoms for Magnetic Resonance Imaging Validation: A Flexible and Scalable Protocol. AB - As new techniques are developed to image adipose tissue, methods to validate such protocols are becoming increasingly important. Phantoms, experimental replicas of a tissue or organ of interest, provide a low cost, flexible solution. However, without access to expensive and specialized equipment, constructing stable phantoms with high fat fractions (e.g., >50% fat fraction levels such as those seen in brown adipose tissue) can be difficult due to the hydrophobic nature of lipids. This work presents a detailed, low cost protocol for creating 5x 100 mL phantoms with fat fractions of 0%, 25%, 50%, 75%, and 100% using basic lab supplies (hotplate, beakers, etc.) and easily accessible components (distilled water, agar, water-soluble surfactant, sodium benzoate, gadolinium diethylenetriaminepentacetate (DTPA) contrast agent, peanut oil, and oil-soluble surfactant). The protocol was designed to be flexible; it can be used to create phantoms with different fat fractions and a wide range of volumes. Phantoms created with this technique were evaluated in the feasibility study that compared the fat fraction values from fat-water magnetic resonance imaging to the target values in the constructed phantoms. This study yielded a concordance correlation coefficient of 0.998 (95% confidence interval: 0.972-1.00). In summary, these studies demonstrate the utility of fat phantoms for validating adipose tissue imaging techniques across a range of clinically relevant tissues and organs. PMID- 30247485 TI - A Colorimetric Method for Measuring Iron Content in Plants. AB - Iron, one of the most important micronutrients in living organisms, is involved in basic processes, such as respiration and photosynthesis. Iron content is rather low in all organisms, amounting in plants to about 0.009% of dry weight. To date, one of the most accurate methods for measuring iron concentration in plant tissues is flame absorption atomic spectroscopy. However, this approach is time-consuming and expensive and requires specific equipment not commonly found in plant laboratories. Therefore, a simpler, yet accurate method that can be routinely used is needed. The colorimetric Prussian Blue method is regularly used for qualitative iron staining in animal and plant histological sections. In this study, we adapted the Prussian Blue method for quantitative measurements of iron in tobacco leaves. We validated the accuracy of this method using both atomic spectroscopy and Prussian Blue staining to measure iron content in the same samples and found a linear regression (R2 = 0.988) between the two procedures. We conclude that the Prussian Blue method for quantitative iron measurement in plant tissues is precise, simple, and inexpensive. However, the linear regression presented here may not be appropriate for other plant species, due to potential interactions between the sample and the reagent. Establishment of a regression curve is thus needed for different plant species. PMID- 30247484 TI - Comprehensive Evaluation of the Effectiveness and Safety of Placenta-Targeted Drug Delivery Using Three Complementary Methods. AB - No effective treatments currently exist for placenta-associated pregnancy complications, and developing strategies for the targeted delivery of drugs to the placenta while minimizing fetal and maternal side effects remains challenging. Targeted nanoparticle carriers provide new opportunities to treat placental disorders. We recently demonstrated that a synthetic placental chondroitin sulfate A binding peptide (plCSA-BP) could be used to guide nanoparticles to deliver drugs to the placenta. In this protocol, we describe in detail a system for assessing the efficiency of drug delivery to the placenta by plCSA-BP that employs three separate methods used in combination: in vivo imaging, high-frequency ultrasound (HFUS), and high-performance liquid chromatography (HPLC). Using in vivo imaging, plCSA-BP-guided nanoparticles were visualized in the placentas of live animals, while HFUS and HPLC demonstrated that plCSA-BP-conjugated nanoparticles efficiently and specifically delivered methotrexate to the placenta. Thus, a combination of these methods can be used as an effective tool for the targeted delivery of drugs to the placenta and development of new treatment strategies for several pregnancy complications. PMID- 30247486 TI - Design and Use of an Apparatus for Quantifying Bivalve Suspension Feeding at Sea. AB - As shellfish aquaculture moves from coastal embayments and estuaries to offshore locations, the need to quantify ecosystem interactions of farmed bivalves (i.e., mussels, oysters, and clams) presents new challenges. Quantitative data on the feeding behavior of suspension-feeding mollusks is necessary to determine important ecosystem interactions of offshore shellfish farms, including their carrying capacity, the competition with the zooplankton community, the availability of trophic resources at different depths, and the deposition to the benthos. The biodeposition method is used to quantify feeding variables in suspension-feeding bivalves in a natural setting and represents a more realistic proxy than laboratory experiments. This method, however, relies upon a stable platform to satisfy the requirements that water flow rates supplied to the shellfish remain constant and the bivalves are undisturbed. A flow-through device and process for using the biodeposition method to quantify the feeding of bivalve mollusks were modified from a land-based format for shipboard use by building a two-dimensional gimbal table around the device. Planimeter data reveal a minimal pitch and yaw of the chambers containing the test shellfish despite boat motion, the flow rates within the chambers remain constant, and operators are able to collect the biodeposits (feces and pseudofeces) with sufficient consistency to obtain accurate measurements of the bivalve clearance, filtration, selection, ingestion, rejection, and absorption at offshore shellfish aquaculture sites. PMID- 30247487 TI - Conversion of staphylococcal pathogenicity islands to CRISPR-carrying antibacterial agents that cure infections in mice. AB - Staphylococcus aureus and other staphylococci continue to cause life-threatening infections in both hospital and community settings. They have become increasingly resistant to antibiotics, especially beta-lactams and aminoglycosides, and their infections are now, in many cases, untreatable. Here we present a non-antibiotic, non-phage method of treating staphylococcal infections by engineering of the highly mobile staphylococcal pathogenicity islands (SaPIs). We replaced the SaPIs' toxin genes with antibacterial cargos to generate antibacterial drones (ABDs) that target the infecting bacteria in the animal host, express their cargo, kill or disarm the bacteria and thus abrogate the infection. Here we have constructed ABDs with either a CRISPR-Cas9 bactericidal or a CRISPR-dCas9 virulence-blocking module. We show that both ABDs block the development of a murine subcutaneous S. aureus abscess and that the bactericidal module rescues mice given a lethal dose of S. aureus intraperitoneally. PMID- 30247488 TI - A universal SNP and small-indel variant caller using deep neural networks. AB - Despite rapid advances in sequencing technologies, accurately calling genetic variants present in an individual genome from billions of short, errorful sequence reads remains challenging. Here we show that a deep convolutional neural network can call genetic variation in aligned next-generation sequencing read data by learning statistical relationships between images of read pileups around putative variant and true genotype calls. The approach, called DeepVariant, outperforms existing state-of-the-art tools. The learned model generalizes across genome builds and mammalian species, allowing nonhuman sequencing projects to benefit from the wealth of human ground-truth data. We further show that DeepVariant can learn to call variants in a variety of sequencing technologies and experimental designs, including deep whole genomes from 10X Genomics and Ion Ampliseq exomes, highlighting the benefits of using more automated and generalizable techniques for variant calling. PMID- 30247489 TI - Evaluation of 244,000 synthetic sequences reveals design principles to optimize translation in Escherichia coli. AB - Comparative analyses of natural and mutated sequences have been used to probe mechanisms of gene expression, but small sample sizes may produce biased outcomes. We applied an unbiased design-of-experiments approach to disentangle factors suspected to affect translation efficiency in E. coli. We precisely designed 244,000 DNA sequences implementing 56 replicates of a full factorial design to evaluate nucleotide, secondary structure, codon and amino acid properties in combination. For each sequence, we measured reporter transcript abundance and decay, polysome profiles, protein production and growth rates. Associations between designed sequences properties and these consequent phenotypes were dominated by secondary structures and their interactions within transcripts. We confirmed that transcript structure generally limits translation initiation and demonstrated its physiological cost using an epigenetic assay. Codon composition has a sizable impact on translatability, but only in comparatively rare elongation-limited transcripts. We propose a set of design principles to improve translation efficiency that would benefit from more accurate prediction of secondary structures in vivo. PMID- 30247491 TI - Understanding factors influencing the detection of mercury policies in modelled Laurentian Great Lakes wet deposition. AB - We used chemical transport modelling to better understand the extent to which policy-related anthropogenic mercury emissions changes (a policy signal) can be statistically detected in wet deposition measurements in the Great Lakes region on the subdecadal scale, given sources of noise. In our modelling experiment, we consider hypothetical regional (North American) and global (rest of the world) policy changes, consistent with existing policy efforts (Deltaglobal = -18%; Deltaregional = -30%) that divide an eight-year period. The magnitude of statistically significant (p < 0.1) pre- and post-policy period wet deposition differences, holding all else constant except for the policy change, ranges from 0.3 to -2.0% for the regional policy and -0.8 to -2.7% for the global policy. We then introduce sources of noise-trends and variability in factors that are exogenous to the policy action-and evaluate the extent to which the policy signals can still be detected. For instance, technology-related variability in emissions magnitude and speciation can shift the magnitude of differences between periods, in some cases dampening the policy effect. We have found that the interannual variability in meteorology has the largest effect of the sources of noise considered, driving deposition differences between periods to +/-20%, exceeding the magnitude of the policy signal. However, our simulations suggest that gaseous elemental mercury concentration may be more robust to this meteorological variability in this region, and a stronger indicator of local/regional emissions changes. These results highlight the potential challenges of detecting statistically significant policy-related changes in Great Lakes wet deposition within the subdecadal scale. PMID- 30247490 TI - A CRISPR-Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes. AB - In the human malaria vector Anopheles gambiae, the gene doublesex (Agdsx) encodes two alternatively spliced transcripts, dsx-female (AgdsxF) and dsx-male (AgdsxM), that control differentiation of the two sexes. The female transcript, unlike the male, contains an exon (exon 5) whose sequence is highly conserved in all Anopheles mosquitoes so far analyzed. We found that CRISPR-Cas9-targeted disruption of the intron 4-exon 5 boundary aimed at blocking the formation of functional AgdsxF did not affect male development or fertility, whereas females homozygous for the disrupted allele showed an intersex phenotype and complete sterility. A CRISPR-Cas9 gene drive construct targeting this same sequence spread rapidly in caged mosquitoes, reaching 100% prevalence within 7-11 generations while progressively reducing egg production to the point of total population collapse. Owing to functional constraint of the target sequence, no selection of alleles resistant to the gene drive occurred in these laboratory experiments. Cas9-resistant variants arose in each generation at the target site but did not block the spread of the drive. PMID- 30247492 TI - Systematic analysis of electron energy-loss near-edge structures in Li-ion battery materials. AB - Electrical conductivity, state of charge and chemical stability of Li-ion battery materials all depend on the electronic states of their component atoms, and tools for measuring these reliably are needed for advanced materials analysis and design. Here we report a systematic investigation of electron energy-loss near edge structures (ELNES) of Li-K and O-K edges for ten representative Li-ion battery electrodes and solid-state electrolytes obtained by performing transmission electron microscopy with a Wien-filter monochromator-equipped microscope. While the peaks of Li-K edges are positioned at about 62 eV for most of the materials examined, the peak positions of O-K edges vary within a range of about 530 to 540 eV, and the peaks can be categorised into three groups based on their characteristic edge shapes: (i) double peaks, (ii) single sharp peaks, and (iii) single broad peaks. The double peaks of group (i) are attributable to the d0 electronic configuration of their transition metal ions bonded to O atoms. The origin of the different peak shapes of groups (ii) and (iii) is more subtle but insights are gained using density functional theory methods to simulate O-K ELNES edges of group (ii) material LiCoO2 and group (iii) material LiFePO4. Comparison of their densities of states reveals that in LiCoO2 the Co-O hybrid orbitals are separated from Li-O hybrid orbitals, resulting in a sharp peak in the O-K edge, while Fe-O, Li-O and P-O hybrid orbitals in LiFePO4 partially overlap each other and produce a broad peak. PMID- 30247493 TI - The cationic dye basic orange 21 (BO21) as a potential fluorescent sensor. AB - The present study investigates the fluorescence properties of BO21 and their dependence on various intracellular conditions. The results obtained with cell free solutions indicate that the influences of pH and temperature on the fluorescence spectra are negligible, while viscosity, various proteins and heparin have significant influence. In the presence of heparin, a red shift of the emission spectrum (from 515 to 550 nm) is observed, suggesting that this shift cannot simply be attributed to electrostatic interaction between BO21 and the polyanionic heparin, but rather to aggregation of BO21 on the polyanion. In water, the quantum yield of BO21 was found to be 1000 times lower than that of fluorescein, yet surprisingly its fluorescence polarization (FP) was found to be about 40 times higher (FP = 0.470), even though both have similar structures and molecular weights. A thorough analytical and experimental investigation of these phenomena indicates that the very high FP of BO21 in water is a consequence of its very short lifetime. However, upon the addition of heparin to aqueous BO21, the fluorescence lifetime (FLT) of BO21 increases from tau = 10.35 to 56.5 ps, with a consequent dramatic drop in its fluorescence polarization from 0.470 to 0.230. From its behavior in aqueous glycerol solution, it is hypothesized, with support from theoretical calculations, that BO21 is a molecular rotor. Using these properties, BO21 may be a good candidate as a sensor, for example, of heparin levels in blood or of intracellular viscosity. PMID- 30247495 TI - Bridging solution properties to gas hydrate nucleation through guest dynamics. AB - By investigating the aqueous solution properties of several hydrate guests with molecular simulations, we find that with increasing guest concentration, the guest's hydration shell becomes more ordered and the system entropy decreases. A common critical value of the self-diffusion coefficient of different guest molecules is identified, below which hydrates will nucleate very readily. PMID- 30247494 TI - Integrative proteomics and metabolomics analysis reveals the toxicity of cationic liposomes to human normal hepatocyte cell line L02. AB - Cationic liposomes (CLs) are vital nonviral vectors with a wide range of applications. Although the toxicity of CLs is far lower than that of viral vectors, increasing evidence suggests that there are limited clinical applications of CLs because of their potential toxicity. In the present study, the toxicity of CLs toward L02 cells was investigated and comprehensively analyzed based on proteomics and metabolomics data. Using quantitative iTRAQ-LC MS/MS proteomics coupled with UHPLC-Q-TOF-MS based metabolomics, we determined that exposure to CLs generated 90 significantly altered proteins and 65 altered metabolites in cells. Metabolomic analysis also showed significant alterations in metabolic pathways, including small molecules involved in energy and lipid metabolism. Proteomics revealed that exposure to CLs significantly influenced multiple proteins, including those involved in the folding of proteins and metabolism. Furthermore, the proteins participated in oxidative stress, which also influenced lipid metabolism. Overall, our findings indicate that high throughput metabolomics and proteomics can provide insight into the toxicological mechanisms of CLs using high-resolution mass spectrometry. To our knowledge, this is the first study combining proteomics and metabolomics to investigate the potential effects of CLs on any cells. Specifically, we integrated quantitative iTRAQ-based proteomics with UHPLC-Q-TOF-MS-based metabolomics datasets to comprehensively assess the potential mechanisms of CL toxicity towards L02 cells. PMID- 30247497 TI - Inhibitory effect of IFITM5 on cementoblast differentiation is associated with Wnt signaling. PMID- 30247496 TI - Thymomas With a Prominent Alveolar Growth Pattern: A Clinicopathologic and Immunohistochemical Study of 12 Cases. AB - Objectives: Twelve cases of thymomas with prominent alveolar-like growth pattern are presented. Methods: The 12 cases were identified during a review of more than 350 cases of thymomas. Results: The patients were five women and seven men between the ages of 48 and 69 years (mean, 58.5 years). Clinically, all patients presented with nonspecific symptoms. Grossly the tumors varied in size from 3.5 to 5 cm in greatest diameter. Histologically, all tumors showed a predominant alveolar-like growth pattern without a significant lymphocytic component. Immunohistochemistry showed positive staining for pan-keratin, keratin 5/6, and p63. Clinical follow-up showed that nine patients have remained alive and well with no recurrence, while no follow-up was obtained in three patients. Conclusions: The cases herein described highlight the spectrum of growth patterns that thymomas may show and also highlight the importance to keep thymomas in the differential diagnosis of tumor with prominent alveolar-like growth pattern. PMID- 30247498 TI - 'Mrs Smith has no rehab potential': does rehabilitation have a role in the management of people with dementia? PMID- 30247500 TI - The Changing Face of the Face-Changing Game. PMID- 30247499 TI - Interactions between serum folate and human papillomavirus with cervical intraepithelial neoplasia risk in a Chinese population-based study. AB - Background: Although folate deficiency has long been implicated in cancer development, uncertainties remain concerning its role in cervical cancer prevention. In particular, the interaction between human papillomavirus (HPV) and folate in the risk of cervical intraepithelial neoplasia (CIN) has been little studied. Objective: The goal of this study was to evaluate the dose-response association of serum folate with the risk of CIN, and the potential for HPV to modify the risk of CIN. Design: We performed a cross-sectional analysis of screening data in 2304 women aged 19-65 y who participated in an ongoing cohort of 40,000 women in China. Both categoric and spline analyses were used to evaluate the dose-response relation between serum folate and CIN risk. Results: After adjusting for potential confounders, a statistically significant inverse association between serum folate concentration and at least grade 2 CIN (CIN2+) risk was observed (1st quartile compared with 4th quartile: OR = 1.40; 95% CI: 1.09, 1.79; P-trend < 0.01); however, serum folate concentration was not associated with CIN1 risk. The risk patterns are similar when limited to only CIN2 and CIN3. An inverse linear relation between increased serum folate concentration and the risk of higher-grade CIN (CIN2, CIN3, and CIN2+) was also observed (for CIN2+: P-overall < 0.01, P-nonlinearity = 0.96). The highest risk of CIN2+ was observed in women with high-risk HPV types, who also had the lowest serum folate concentrations (P-interaction < 0.01). Conclusions: Our study indicates that serum folate is inversely associated with the risk of higher-grade CIN in Chinese women either with or without high-risk HPV infection. Thus, maintenance of normal serum folate levels may prove important for reducing the risk of CIN in women. PMID- 30247501 TI - Computational models for lncRNA function prediction and functional similarity calculation. AB - From transcriptional noise to dark matter of biology, the rapidly changing view of long non-coding RNA (lncRNA) leads to deep understanding of human complex diseases induced by abnormal expression of lncRNAs. There is urgent need to discern potential functional roles of lncRNAs for further study of pathology, diagnosis, therapy, prognosis, prevention of human complex disease and disease biomarker detection at lncRNA level. Computational models are anticipated to be an effective way to combine current related databases for predicting most potential lncRNA functions and calculating lncRNA functional similarity on the large scale. In this review, we firstly illustrated the biological function of lncRNAs from five biological processes and briefly depicted the relationship between mutations or dysfunctions of lncRNAs and human complex diseases involving cancers, nervous system disorders and others. Then, 17 publicly available lncRNA function-related databases containing four types of functional information content were introduced. Based on these databases, dozens of developed computational models are emerging to help characterize the functional roles of lncRNAs. We therefore systematically described and classified both 16 lncRNA function prediction models and 9 lncRNA functional similarity calculation models into 8 types for highlighting their core algorithm and process. Finally, we concluded with discussions about the advantages and limitations of these computational models and future directions of lncRNA function prediction and functional similarity calculation. We believe that constructing systematic functional annotation systems is essential to strengthen the prediction accuracy of computational models, which will accelerate the identification process of novel lncRNA functions in the future. PMID- 30247502 TI - Protein-peptide docking using CABS-dock and contact information. AB - Short abstract: CABS-dock is a tool for flexible docking of peptides to proteins. In this article, we present a protocol for CABS-dock docking driven by information about protein-peptide contact(s). Using information on individual protein-peptide contacts allows to improve the accuracy of CABS-dock docking. PMID- 30247503 TI - East African diploid and triploid bananas: a genetic complex transported from South-East Asia. AB - Background and Aims: Besides bananas belonging to the AAA triploid Mutika subgroup, which predominates in the Great Lakes countries, other AAA triploids as well as edible AA diploids, locally of considerable cultural weight, are cultivated in East Africa and in the nearby Indian Ocean islands as far as Madagascar. All these varieties call for the genetic identification and characterization of their interrelations on account of their regional socio economic significance and their potential for banana breeding strategies. Methods: An extensive sampling of all traditional bananas in East Africa and near Indian Ocean islands was genotyped with simple sequence repeat (SSR) markers, with particular emphasis on the diploid forms and on the bananas of the Indian Ocean islands, which remain poorly characterized. Key Results: All the edible AA varieties studied here are genetically homogeneous, constituting a unique subgroup, here called 'Mchare', despite high phenotypic variation and adaptions to highly diverse ecological zones. At triploid level, and besides the well-known AAA Mutika subgroup, at least two other genetically related AAA subgroups specific to this region are identified. Neither of these East African AAA genotypes can be derived directly from the local AA Mchare diploids. However, it is demonstrated that the East African diploids and triploids together belong to the same genetic complex. The geographical distribution of their wild acuminata relatives allowed identification of the original area of this complex in a restricted part of island South-East Asia. The inferred origin leads to consideration of the history of banana introduction in Africa. Linked to biological features, documentation on the embedding of bananas in founding legends and myths and convincing linguistic elements were informative regarding the period and the peoples who introduced these Asian plants into Africa. The results point to the role of Austronesian-speaking peoples who colonized the Indian Ocean islands, particularly Madagascar, and reached the East African coasts. Conclusions: Understanding of the relations between the components of this complex and identifying their Asian wild relatives and related cultivars will be a valuable asset in breeding programmes and will boost the genetic improvement of East African bananas, but also of other globally important subgroups, in particular the AAA Cavendish. PMID- 30247504 TI - Consumption of sugars, saturated fat, and sodium among US children from infancy through preschool age, NHANES 2009-2014. AB - Background: Expert guidelines advise that intake of added sugars (ASs), free sugars, and saturated fats be limited to <10% total energy (TE), and that children's sodium not exceed 1500-1900 mg, yet intake among many older children and adolecents exceeds these limits. Although research suggests young children's diets influence future eating patterns, little is known about the intake of these nutrients throughout early childhood. Objective: The objective of this study was to describe intake and leading sources of sugars, saturated fats, and sodium among US children from infancy through preschool age. Design: Cross-sectional data from the NHANES 2009-2014 were used to estimate 1) mean intake of sugars [%TE from ASs, naturally occurring sugars (NOSs), and free sugars], saturated fats (%TE), and sodium (milligrams), 2) the proportion exceeding recommended limits, and 3) the leading sources of these nutrients in the diets of US (nonbreastfeeding) children <5 y old (n = 3345). Sampling weights and procedures to account for the complex sampling design were used to estimate intake by age and to compare across race/ethnicity, sex, and income subgroups. Results: Nonbreastfeeding children <5 y old consumed a mean +/- SE %TE of 10.1% +/- 0.2% from ASs, 13.9% +/- 0.2% from free sugars, 12.8% +/- 0.1% from saturated fats, and 1804 +/- 26 mg Na . Sugary beverages (sugar-sweetened beverages + 100% juices) contributed 6.7% +/- 0.2% TE, with consumption lowest among higher-income children. AS and sodium consumption rose rapidly from infancy to age 1-<2 y and gradually thereafter. Saturated fat intake was highest in infancy and decreased to a mean +/- SE of 11.3% +/- 0.3% TE among 4-<5-y-olds. Intake exceeded recommended limits for ASs, free sugars, saturated fats, and sodium for 45%, 63%, 72%, and 67% of all children, respectively. Conclusion: The consumption of sugars, fats, and sodium exceeds recommended guidelines before many US children reach school age. PMID- 30247505 TI - RNF34 modulates the mitochondrial biogenesis and exercise capacity in muscle and lipid metabolism through ubiquitination of PGC-1 in Drosophila. AB - The transcriptional co-activator PGC-1alpha is a key regulator of mitochondrial function and muscle fiber specification in the skeletal muscle. The E3 ubiquitin ligase RNF34 ubiquitinates PGC-1alpha and negatively regulates mammalian brown fat cell metabolism. However, the functional importance of RNF34 in the skeletal muscle and its impact on energy metabolism remain unknown. The Drosophila PGC-1 homolog dPGC-1 and its mammalian counterparts have conserved functions in mitochondria and insulin signaling. Here, we showed that the Drosophila RNF34 (dRNF34) ubiquitinates the Drosophila PGC-1alpha (dPGC-1) and promotes its degradation in HEK293T cells by immunoprecipitation and western blot analysis. This allows us to use Drosophila as a powerful model system to study the physiological role of RNF34 in mitochondrial function and metabolism. In the in vivo studies, by separately expressing two independent UAS-dRNF34 RNAi transgenes driven by the muscle-specific 24B-Gal4 driver, we found that knockdown of dRNF34 specifically in muscle promotes mitochondrial biogenesis, improves negative geotaxis, extends climbing time to exhaustion in moderate aged flies and counteracts high-fat-diet-induced high triglyceride content. Furthermore, we showed that knockdown of dPGC-1 reversed the effects of the dRNF34 knockdown phenotypes described above. Our results reveal that dRNF34 plays an important role in regulating mitochondrial biogenesis in muscle and lipid metabolism through dPGC-1. Thus, inhibition of RNF34 activity provides a potential novel therapeutic strategy for the treatment of age-related muscle dysfunction. PMID- 30247506 TI - Everyday Discrimination Prospectively Predicts Blood Pressure Across 10 Years in Racially/Ethnically Diverse Midlife Women: Study of Women's Health Across the Nation. AB - Background: Interpersonal discrimination is linked to greater risk for cardiovascular disease (CVD) and this association varies by race/ethnicity. Purpose: To examine whether exposure to everyday discrimination prospectively predicts elevated blood pressure (BP), whether this association differs by race/ethnicity, and is mediated by adiposity indices. Methods: Using data for 2,180 self-identified White, Black, Chinese, Japanese, and Hispanic participants from the Study of Women's Health Across the Nation, we examined associations among exposure to (higher vs. lower) everyday discrimination at baseline and BP and hypertension (HTN; systolic blood pressure [SBP] >= 140 mmHg; diastolic blood pressure [DBP] >= 90 mmHg; or self-reported HTN medication use) risk over a 10 year period. Additionally, we used the bootstrap method to assess repeated, time varying markers of central and overall adiposity (waist circumference and body mass index [BMI] (kg/m2), respectively) as potential mediators. Results: Exposure to everyday discrimination predicted increases in SBP and DBP over time, even after adjusting for known demographic, behavioral, or medical risk factors. However, greater waist circumference or BMI (examined separately) mediated these observations. Notably, there were no racial/ethnic differences in the observed association and HTN risk was not predicted. Conclusions: The current findings suggest that everyday discrimination may contribute to elevated BP over time in U.S. women, in part, through increased adiposity. These findings demonstrate the complexity of the linkage of discrimination to CVD risk and raise the need to closely examine biobehavioral pathways that may serve as potential mediators. PMID- 30247507 TI - Could vesicular transport of Na+ and Cl- be a feature of salt tolerance in halophytes? AB - Background: Halophytes tolerate external salt concentrations of 200 mm and more, accumulating salt concentrations of 500 mm and more in their shoots; some, recretohalophytes, excrete salt through glands on their leaves. Ions are accumulated in central vacuoles, but the pathway taken by these ions from the outside of the roots to the vacuoles inside the cells is poorly understood. Do the ions cross membranes through ion channels and transporters or move in vesicles, or both? Vesicular transport from the plasma membrane to the vacuole would explain how halophytes avoid the toxicity of high salt concentrations on metabolism. There is also a role for vesicles in the export of ions via salt glands. Scope and Methods: We have collected data on the fluxes of sodium and chloride ions in halophytes, based on the weight of the transporting organs and on the membrane area across which the flux occurs; the latter range from 17 nmol m-2 s-1 to 4.2 MUmol m-2 s-1 and values up to 1 MUmol m-2 s-1 need to be consistent with whatever transport system is in operation. We have summarized the sizes and rates of turnover of vesicles in plants, where clathrin-independent vesicles are 100 nm or more in diameter and can merge with the plasma membrane at rates of 100 s-1. We gathered evidence for vesicular transport of ions in halophytes and evaluated whether vesicular transport could account for the observable fluxes. Conclusions: There is strong evidence in favour of vesicular transport in plants and circumstantial evidence in favour of the movement of ions in vesicles. Estimated rates of vesicle turnover could account for ion transport at the lower reported fluxes (around 20 nmol m-2 s-1), but the higher fluxes may require vesicles of the order of 1 MUm or more in diameter. The very high fluxes reported in some salt glands might be an artefact of the way they were measured. PMID- 30247508 TI - Enzymes in the Seafood Industry: Time for Health Studies with High-Quality Exposure Assessment. PMID- 30247509 TI - Intentional endometrial injury increases embryo implantation potentials through enhanced endometrial angiogenesis. AB - Embryo implantation rates have been found to be enhanced by precedent endometrial injuries, but the underlying mechanism is not fully investigated. Endometrial inflammation occurs both at peri-implantation period and after endometrial injury, in which vascular reaction is a distinctive feature of inflammation. In this study, intentional endometrial injury was done with a 0.7-mm-diameter brush inserted into the left uterine horn of female ICR mice, then turned around 720 degrees (Group 2), and the right uterine horn served as the controls without endometrial injuries (Group 1). Intraperitoneal equine chorionic gonadotropin 2.5 IU was injected, followed by human chorionic gonadotropin 10 IU injection, and the uterus was dissected 5 days later, roughly at the peri-implantation period. The peri-implantation endometrium was obtained, and angiogenesis protein array revealed that matrix metalloproteinase-3 (MMP-3), plasminogen activator inhibitor 1 (PAI-1), insulin-like growth factor binding protein 1 (IGFBP-1), and IL-1alpha were more strongly expressed in injured endometrium (Group 2) than in the controls (Group 1). Immunohistochemical CD34 staining was more prominently expressed in Group 2 uterus, and the treatment with LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, significantly decreased CD34 immunopositive cells. The capabilities of permeability, proliferation, tube formation, and migration of mouse endometrial endothelial cells were significantly enhanced in Group 2 than in Group 1. Our results demonstrate that enhanced endometrial angiogenesis is a possible mechanism accounting for the increased endometrial receptivity after endometrial injury. PMID- 30247510 TI - Impaired sensorimotor processing during complex gait precedes behavioral changes in middle-aged adults. AB - Gait impairment during complex walking in older adults is thought to result from a progressive failure to compensate for deteriorating peripheral inputs by central neural processes. It is the primary hypothesis of this paper that failure of higher cerebral adaptations may already be present in middle-aged adults who do not present observable gait impairments. We therefore compared metabolic brain activity during steering of gait (i.e., complex locomotion) and straight walking (i.e., simple locomotion) in young and middle-aged individuals. Cerebral distribution of [18F]-fluorodeoxyglucose, a marker of brain synaptic activity, was assessed during over ground straight walking and steering of gait using positron emission tomography in seven young adults (aged 24+/-3) and seven middle aged adults (aged 59+/-3). Brain regions involved in steering of gait (posterior parietal cortex, superior frontal gyrus, and cerebellum) are retained in middle age. However, despite similar walking performance, there are age-related differences in the distribution of [ 18F]-FDG during steering: middle-aged adults have (i) increased activation of precentral and fusiform gyri, (ii) reduced deactivation of multisensory cortices (inferior frontal, postcentral, fusiform gyri), and (iii) reduced activation of the middle frontal gyrus and cuneus. Our results suggest that pre-clinical decline in central sensorimotor processing in middle-age is observable during complex walking. PMID- 30247511 TI - A road map for transforming stroke recovery. PMID- 30247512 TI - Infectious Diseases Specialty Intervention is Associated with Better Outcomes among Privately Insured Individuals Receiving Outpatient Parenteral Antimicrobial Therapy. AB - Background: Outpatient parenteral antimicrobial therapy (OPAT) can be managed by specialists in infectious disease (ID) or by other physicians. Better management of OPAT can reduce the likelihood of readmission or emergency department (ED) use. The relative success of ID specialists and other physicians in managing OPAT has received little study. Methods: We analyzed a national database of insurance claims for privately insured individuals under age 65, locating inpatient acute care stays in 2013 and 2014 that were followed by OPAT. Through propensity scoring, patients who received outpatient ID intervention (ID-led OPAT) were matched one-to-one with those who did not (Other OPAT). We estimated regression models of hospital and ED admission, and total healthcare payments, over the first 30 days after discharge. Results: The final analytic sample of 8,200 observations was well balanced on clinical and demographic characteristics. Soft tissue infection and osteomyelitis were the most common infections in the index event, each affecting more than 40% of individuals. Relative to those with Other OPAT, people with ID-led OPAT had lower odds of ED admission (OR 0.449, 95% confidence interval [CI] 0.311 - 0.645) or hospitalization (OR 0.661, 95% CI 0.557 - 0.791) over 30 days, and they accumulated $1,488 less in total healthcare payments (95% CI -2,2,688.56 - -266.58). Conclusions : Among privately insured individuals below age 65, ID consultation during OPAT is associated with large and significant reductions in the rate of ED admission and hospital admission in the 30 days after an index event, as well as lower total healthcare spending. PMID- 30247513 TI - Successful six-week antibiotic treatment for early surgical-site infections in spinal surgery. AB - Background: The incidence of spinal surgical site infections (SSI) remains stable at less than 10%. Surgical reinterventions may be hampered by decubitus, treatment-related adverse events, and cost. In the context of emergence of bacterial resistance, a short duration of antimicrobial treatment is of critical importance. If the duration of treatment for SSI is currently 12 weeks, the aim of our study was to assess the efficacy of an antimicrobial treatment shortened to six weeks. Method: This prospective study was carried out from November 2014 to July 2016 in an 827-bed teaching hospital. After surgical management of SSI, patients received broad-spectrum antibiotics, intravenously for 10 days and orally for the remainder, for a total of six weeks. Success was defined as absence of relapse, superinfection or surgical failure at the end of treatment and at one-year follow-up. Results: Eighty-five patients were included in this study. The median delay between initial surgery and diagnosis of SSI was 16 days. In 65 cases (76.4 %) SSIs were monomicrobial and among these, Staphylococcus aureus was found in 30 cases (46 %). Failure was observed in 7 cases (8.2%), with over half of them caused by anaerobic bacteria. Conclusions: Surgical management of SSI followed by a 6-week antibiotic treatment is associated with favourable outcome. Anaerobic bacteria seem to play a role in the occurrence of relapses. A 6-week reduction in antibiotic treatment leads to reduction in cost and, likely, also to reduction in the emergence and spread of resistant microorganisms. PMID- 30247514 TI - Protein Intake and Functional Integrity in Aging: The Framingham Heart Study Offspring. AB - Background: Higher protein intake is linked to maintenance of muscle mass and strength, but few studies have related protein to physical function and disability in aging. Methods: In participants of the Framingham Heart Study Offspring, we examined associations between protein intake (g/d), estimated from food frequency questionnaires, and maintenance of functional integrity, as a functional integrity score based on responses to 17 questions from Katz Activities of Daily Living, Nagi, and Rosow-Breslau questionnaires, repeated up to five times (1991/1995-2011/2014) over 23 years of follow-up. Cox proportional hazard models were used to estimate risk of incident loss of functional integrity (functional integrity score <= 15th percentile). Results: In 2,917 participants (age 54.5 [9.8] years), baseline protein intake was 77.2 (15.6) g/d. The functional integrity score (baseline, mean 98.9, range 82.4-100.0) was associated with objective performance (gait speed, grip strength) and lower odds of falls, fractures, and frailty. Across follow-up, there were 731 incident cases of loss of functional integrity. In fully adjusted models, participants in the highest category of protein intake (median 92.2 g/d) had 30% lower risk of loss of functional integrity (hazard ratio [95% confidence interval] 0.70 [0.52, 0.95], p trend = .03), versus those with the lowest intake (median 64.4 g/d). However, sex stratified analyses indicated the association was driven by the association in women alone (hazard ratio [95% confidence interval] 0.49 [0.32, 0.74], p trend = .002) and was nonsignificant in men (hazard ratio [95% confidence interval] 1.14 [0.70, 1.86], p trend = .59). Conclusions: Higher protein intake was beneficially associated with maintenance of physical function in middle-aged, high-functioning U.S. adults over the span of two decades. This association was particularly evident in women. PMID- 30247515 TI - Resistance to stress can be experimentally dissociated from longevity. AB - Based on multiple experiments demonstrating that high resistance to stress is associated with long lifespan, it has been proposed that stress resistance is a key determinant of longevity. However, the extent to which high resistance to stress is necessary or sufficient for long life is currently unclear. In this work, we use a genetic approach to disrupt different stress response pathways and examine the resulting effect on the longevity of the long-lived insulin-IGF1 receptor mutant daf-2. While mutation of the heat shock factor gene hsf-1, deletion of sod genes, deletion of the p38 MAPK kinase gene pmk-1 or deletion of the transcription factor gene egl-27 all resulted in decreased resistance to at least one form of stress and decreased lifespan, the magnitude of change in stress resistance did not correspond to the magnitude of change in lifespan. In addition, we found that deletion of the glycerol-3-phosphate dehydrogenase genes gpdh-1 and gpdh-2 or deletion of the DAF-16 co-factor gene nhl-1 also results in decreased resistance to at least one form of stress but increases lifespan. Overall, our results suggest that while increased stress resistance is associated with longevity, stress resistance and lifespan can be experimentally dissociated. PMID- 30247516 TI - Sources of All-Trans Retinal Oxidation Independent of the Aldehyde Dehydrogenase 1A Isozymes Exist in the Postnatal Testis. AB - Despite the essential role of the active metabolite of vitamin A, all trans retinoic acid (atRA) in spermatogenesis, the enzymes and cellular populations responsible for its synthesis in the postnatal testis remain largely unknown. The aldehyde dehydrogenase 1A (ALDH1A) family of enzymes residing within Sertoli cells are responsible for the synthesis of atRA, driving the first round of spermatogenesis. Those studies also revealed that the atRA required to drive subsequent rounds of spermatogenesis are possibly derived from the ALDH1A enzymes residing within the meiotic and post-meiotic germ cells. Three ALDH1A isozymes (ALDH1A1, ALDH1A2, and ALDH1A3) are present in the testis. Although, ALDH1A1 is expressed in adult Sertoli cells and is suggested to contribute to the atRA required for the pre-meiotic transitions, ALDH1A2 is proposed to be the essential isomer involved in testicular atRA biosynthesis. In this report, we first examine the requirement for ALDH1A2 via the generation and analysis of a conditional Aldh1a2 germ cell knockout and a tamoxifen-induced Aldh1a2 knockout model. We then utilized the pan-ALDH1A inhibitor (WIN 18,446) to test the collective contribution of the ALDH1A enzymes to atRA biosynthesis following the first round of spermatogenesis. Collectively, our data provide the first in vivo evidence demonstrating that animals severely deficient in ALDH1A2 postnatally proceed normally through spermatogenesis. Our studies with a pan-ALDH1A inhibitor (WIN 18,446) also suggest that an alternative source of atRA biosynthesis independent of the ALDH1A enzymes becomes available to maintain atRA levels for several spermatogenic cycles following an initial atRA injection. PMID- 30247517 TI - Learning and Imputation for Mass-spec Bias Reduction (LIMBR). AB - Motivation: Decreasing costs are making it feasible to perform time series proteomics and genomics experiments with more replicates and higher resolution than ever before. With more replicates and time points, proteome and genome-wide patterns of expression are more readily discernible. These larger experiments require more batches exacerbating batch effects and increasing the number of bias trends. In the case of proteomics, where methods frequently result in missing data this increasing scale is also decreasing the number of peptides observed in all samples. The sources of batch effects and missing data are incompletely understood necessitating novel techniques. Results: Here we show that by exploiting the structure of time series experiments, it is possible to accurately and reproducibly model and remove batch effects. We implement Learning and Imputation for Mass-spec Bias Reduction (LIMBR) software, which builds on previous block based models of batch effects and includes features specific to time series and circadian studies. To aid in the analysis of time series proteomics experiments, which are often plagued with missing data points, we also integrate an imputation system. By building LIMBR for imputation and time series tailored bias modeling into one straightforward software package, we expect that the quality and ease of large-scale proteomics and genomics time series experiments will be significantly increased. Availability: Python code and documentation is available for download at https://github.com/aleccrowell/LIMBR and LIMBR can be downloaded and installed with dependencies using 'pip install limbr'. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30247518 TI - Immune checkpoint inhibitors in non-small-cell lung cancer: current status and future directions. AB - Since 2015, immunotherapies, especially immune checkpoint inhibitors (ICIs), have made great breakthroughs in non-small-cell lung cancer (NSCLC). Among them, nivolumab, pembrolizumab and atezolizumab have been granted US Food and Drug Administration approval for NSCLC. It is imperative to combine ICIs with chemotherapy, radiotherapy, antivascular therapy and targeted therapy. But in the bright future, there are two problems. One is how to use biomarkers to select the beneficiaries. The other is how to achieve a balance between drug effectiveness and safety. There are now seven drugs targeting the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA 4) pathways that have been or are expected to enter clinical treatment. This review focuses on these drugs and summarizes clinical trials that have been reported or that ongoing ones have already entered the recruiting state. PMID- 30247519 TI - Insights of the tubulin code in gametes and embryos: from basic research to potential clinical applications in humans. AB - Microtubules are intracellular filaments that define in space and in time a large number of essential cellular functions such as cell division, morphology and motility, intracellular transport and flagella and cilia assembly. They are therefore essential for spermatozoon and oocyte maturation and function, and for embryo development. The dynamic and functional properties of the microtubules are in large part defined by various classes of interacting proteins including MAPs (Microtubule Associated Proteins), microtubule dependent motors, and severing and modifying enzymes. Multiple mechanisms regulate these interactions. One of them is defined by the high diversity of the microtubules themselves generated by the combination of different tubulin isotypes and by several tubulin post translational modifications (PTMs). This generates a so-called tubulin code that finely regulates the specific set of proteins that associates with a given microtubule thereby defining the properties and functions of the network. Here we provide an in depth review of the current knowledge on the tubulin isotypes and PTMs in spermatozoa, oocytes, and preimplantation embryos in various model systems and in the human species. We focus on functional implications of the tubulin code for cytoskeletal function, particularly in the field of human reproduction and development, with special emphasis on gamete quality and infertility. Finally, we discuss some of the knowledge gaps and propose future research directions. PMID- 30247520 TI - Minimal Incisions Vertical Endoscopic Lifting (MIVEL) for the Management of Lateral Canthal and Lower Eyelid Malposition. AB - The purpose of this article is to describe the necessary steps to correct both primary and postblepharoplasty lateral canthal and lower eyelid malpositions at the time of endoscopic face lifting. Endoscopic surgery is traditionally considered only for brow and forehead lifting. However, in our practice we have successfully expanded the indications of the minimal incision vertical endoscopic lifting technique from being primarily indicated for forehead/brow elevation to also treating both primary and secondary lower eyelid and lateral canthal malpositions. This has eliminated the need for direct lateral canthal manipulation in primary cases and any need for open canthoplasty and posterior spacers in secondary cases. In our series of 63 patients with a mean age of 54 years, overall subjective satisfaction was high in 92% of patients, and there were no long-term side effects or complications. PMID- 30247521 TI - Gaining power in multiple testing of interval hypotheses via conditionalization. AB - In this article, we introduce a novel procedure for improving power of multiple testing procedures (MTPs) of interval hypotheses. When testing interval hypotheses the null hypothesis $P$-values tend to be stochastically larger than standard uniform if the true parameter is in the interior of the null hypothesis. The new procedure starts with a set of $P$-values and discards those with values above a certain pre-selected threshold, while the rest are corrected (scaled-up) by the value of the threshold. Subsequently, a chosen family-wise error rate (FWER) or false discovery rate MTP is applied to the set of corrected $P$-values only. We prove the general validity of this procedure under independence of $P$ values, and for the special case of the Bonferroni method, we formulate several sufficient conditions for the control of the FWER. It is demonstrated that this "filtering" of $P$-values can yield considerable gains of power. PMID- 30247522 TI - III. Functions of short lifetime structures at large 9: case of nucleic acids. AB - The short lifetime structures of nucleic acids are not well studied because of the poor recognition of their importance and the methodological difficulty. In case of proteins, which are a type of single-stranded biopolymers, the essential roles of their transient structures are well established. Therefore, the role of transient structures of nucleic acids is, naturally, of great interest. There have been multiple reports on the function-related unstable (transient) structures of single-stranded nucleotides, though not as many as at present. Recent methodological advances are now enabling us to observe structures with ultra-short lifetime (less than a nanosecond). On the other hand, the biological importance of transient structures of ribonucleicacid (RNA) is increasingly recognized because of the findings of novel functional RNAs such as microRNA. Therefore, the time has come to tackle the structure and function dynamic of RNA/deoxyribonucleic acid in relation to their transient, unstable structures. The specific properties of rapidity and diversity are hypothesized to be involved in unexplored phenomena in neuroscience. PMID- 30247523 TI - Impact of Interventions to Change CBC and Differential Ordering Patterns in the Emergency Department. AB - Objectives: A CBC with leukocyte differential (CBC-DIFF) is a frequently ordered emergency department (ED) test. The DIFF component often does not add to clinical decision making. Our objective was to evaluate the impact of a performance improvement project on CBC ordering. Methods: ED orders for CBC-DIFF were identified through the laboratory information system. Two interventions were evaluated: an educational intervention regarding CBC-DIFF uses and a reprioritization of ED CBC-DIFF and CBC in the electronic medical record (EMR) orders. Pearson chi2 tests were used to assess for differences in the proportions. Results: There was no difference in the proportion of CBC tests performed after the education intervention (175/6,192, 2.8% [95% CI, 2.39%-3.21%] vs 219/6,270, 3.5% [95% CI, 3.05%-3.95%]). There was a significant increase in CBC samples ordered following the EMR intervention (604/6,044, 9.1% [95% CI, 8.37%-9.83%]; P < .01). Conclusions: Reprioritizing EMR laboratory orders can reduce overutilization of CBC-DIFF testing. PMID- 30247524 TI - The prognostic impact of Consensus Molecular Subtypes (CMS) and its predictive effects for bevacizumab benefit in metastatic colorectal cancer: molecular analysis of the AGITG MAX clinical trial. AB - Background: The Consensus Molecular Subtypes (CMS) is a transcriptome-based classification of colorectal cancer (CRC) initially described in early-stage cohorts, but the associations of CMS with treatment outcomes in the metastatic setting are yet to be established. This study aimed to evaluate the prognostic impact of CMS classification and its predictive effects for bevacizumab benefit in metastatic CRC by correlative analysis of the AGITG MAX trial. Patients and Methods: The MAX trial previously reported improved progression-free survival (PFS) for the addition of bevacizumab (B) to chemotherapy (capecitabine (C) +/- mitomycin (M)). Archival primary tumours from 237 patients (50% of trial population) underwent gene expression profiling and classification into CMS groups. CMS groups were correlated to PFS and overall survival (OS). The interaction of CMS with treatment was assessed by proportional hazards model. Results: The distribution of CMS in MAX were: CMS1 18%, CMS2 47%, CMS3 12%, CMS4 23%. CMS1 was the predominant subtype in right-sided primary tumours, while CMS2 was the predominant subtype in left-sided. CMS was prognostic of overall survival (OS) (P=0.008), with CMS2 associated with the best outcome and CMS1 the worst. CMS remained an independent prognostic factor in a multivariate analysis. There was a significant interaction between CMS and treatment (P-interaction=0.03), for PFS, with hazard ratios (95% CI) for CB+CBM versus C arms in CMS 1,2,3 and 4: 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25) respectively. Conclusions: This exploratory study found that CMS stratified OS outcomes in metastatic CRC regardless of first-line treatment, with prognostic effects of CMS groups distinct from those previously reported in early-stage cohorts. In CMS associations with treatment, CMS2 and possibly CMS3 tumours may preferentially benefit from the addition of bevacizumab to first-line capecitabine-based chemotherapy, compared to other CMS groups. Validation of these findings in additional cohorts is warranted. Clinical trial number: This is a molecular sub-study of MAX clinical trial (NCT00294359). PMID- 30247525 TI - Population structure of Miscanthus sacchariflorus reveals two major polyploidization events, tetraploid-mediated unidirectional introgression from diploid M. sinensis, and diversity centred around the Yellow Sea. AB - Background and Aims: Miscanthus, a C4 perennial grass native to East Asia, is a promising biomass crop. Miscanthus sacchariflorus has a broad geographic range, is used to produce paper in China and is one of the parents (along with Miscanthus sinensis) of the important biomass species Miscanthus * giganteus. The largest study of M. sacchariflorus population genetics to date is reported here. Methods: Collections included 764 individuals across East Asia. Samples were genotyped with 34 605 single nucleotide polymorphisms (SNPs) derived from restriction site-associated DNA sequencing (RAD-seq) and ten plastid microsatellites, and were subjected to ploidy analysis by flow cytometry. Key Results: Six major genetic groups within M. sacchariflorus were identified using SNP data: three diploid groups, comprising Yangtze (M. sacchariflorus ssp. lutarioriparius), N China and Korea/NE China/Russia; and three tetraploid groups, comprising N China/Korea/Russia, S Japan and N Japan. Miscanthus sacchariflorus ssp. lutarioriparius was derived from the N China group, with a substantial bottleneck. Japanese and mainland tetraploids originated from independent polyploidization events. Hybrids between diploid M. sacchariflorus and M. sinensis were identified in Korea, but without introgression into either parent species. In contrast, tetraploid M. sacchariflorus in southern Japan and Korea exhibited substantial hybridization and introgression with local diploid M. sinensis. Conclusions: Genetic data indicated that the land now under the Yellow Sea was a centre of diversity for M. sacchariflorus during the last glacial maximum, followed by a series of migrations as the climate became warmer and wetter. Overall, M. sacchariflorus has greater genetic diversity than M. sinensis, suggesting that breeding and selection within M. sacchariflorus will be important for the development of improved M. * giganteus. Ornamental M. sacchariflorus genotypes in Europe and North America represent a very narrow portion of the species' genetic diversity, and thus do not well represent the species as a whole. PMID- 30247526 TI - Anatomically and functionally relevant coronary stenoses in patients with normal single-photon emission computed tomography but persistent stable angina. AB - Aims: Single-photon emission computed tomography (SPECT) is widely used for the assessment of coronary artery disease and for decision making regarding revascularization. Concerns about possible false negative findings exist. Our aim was to assess the prevalence of stenoses which are both functionally and anatomically significant in patients referred for invasive fractional flow reserve (FFR) measurements following a normal SPECT, because of persistent complaints. Methods and results: One hundred and thirty-three consecutive patients with normal SPECT were included, with a total of 180 FFR measurements. Luminal narrowing of >=70% (>=50% for left main) together with a FFR <=0.80 denoted an anatomically and functionally significant coronary artery stenosis. Separate analyses were performed for FFR <0.75. Mean age of the patients was 65, 40% were women. Sixteen percent of the study population had both anatomically and functionally significant stenoses. Besides the use of nitrate, no differences in baseline characteristics, symptoms, coronary history, or pre-test likelihood could be identified for the prediction of functionally relevant obstructive coronary disease. If FFR <0.75 was used, only 7.5% of the patients had both anatomically and functionally significant stenoses. Conclusion: In patients with normal SPECT who undergo FFR measurements because of persistent complaints, the prevalence of stenoses which are both anatomically and functionally significant is low. This suggests that the prevalence of false-negative SPECT is (very) low. PMID- 30247527 TI - pH and a mixed carbon-substrate spectrum influence FocA- and FocB-dependent, formate-driven H2 production in Escherichia coli. AB - Escherichia coli encodes two formate channels, FocA and FocB, that either export formate or import it for further disproportionation by the formate hydrogenlyase (FHL) complex to H2 and CO2. We show that FocA/B appear to change their substrate translocation direction depending on pH and electron donor. When cells were grown on glucose and glycerol at pH 7.5, formate accumulated in focB or focA-focB mutants when glucose or formate was used as electron donor because H2 production increased ~2- and ~1.5-fold, respectively. Moreover, addition of external formate to the growth medium increased H2 production in a focA-focB mutant. This indicates that in the wild type, formate is preferentially exported at pH 7.5 and that another FocA/B-independent uptake system exists. At pH 6.5 and 5.5, the formate channel mutants showed reduced H2 production, suggesting that formate is usually imported by them to produce H2 at acidic pH. Addition of formate to the growth medium increased H2 production at these pHs. Notably, glycerol failed to act as an effective electron donor for formate production. Taken together, our results suggest that regulation of formate translocation direction by FocA/FocB channels is important for maintaining internal pH and proton motive force by modulating H2 production. PMID- 30247528 TI - Multimodality imaging in Fabry cardiomyopathy: from early diagnosis to therapeutic targets. AB - Fabry disease (FD) is a rare genetic X-linked disorder that can impact multiple organs. Cardiac involvement influences the prognosis of patients with FD, being one of the main causes of mortality. Cardiac imaging has proven essential in all aspects of Fabry cardiomyopathy evaluation, such as diagnosis (including detection of early organ changes), disease progression, and guideline for starting enzyme therapy. Imaging techniques used in cardiac evaluation of FD range from 2D and deformation studies in echocardiography to cardiac magnetic resonance (CMR), cardiac scintigraphy and positron emission tomography. The present review summarizes the imaging 'red flags' demonstrated to be able to differentiate early cardiac FD from normal controls and Fabry cardiomyopathy from other causes of hypertrophic cardiomyopathy. Also, it discusses the current evidence for the role of CMR in myocardial tissue characterization, as well as other imaging methods that have shown promise in FD. Current knowledge of the evaluation of the presence and extent of cardiac involvement at baseline and during follow-up of enzyme therapy efficiency are further presented. Multiple studies demonstrated that imaging parameters can be reliably used in establishing diagnosis and monitoring therapy in FD. Given the rarity of this disorder, we conclude that awareness should be raised about these imaging 'red flags' and likely patients sent for evaluation in expert centres. PMID- 30247529 TI - Unexpected prolapse of the anterior leaflet during saline testing in mitral valve repair. AB - OBJECTIVES: Saline testing is used in mitral valve (MV) surgery to evaluate the repair intra-operatively. Sometimes, saline testing shows a prolapse of the anterior leaflet, not seen on preoperative echocardiography. Our objective was to investigate the incidence, predisposing factors and consequences of this phenomenon. METHODS: We retrospectively reviewed all consecutive patients undergoing surgery for posterior leaflet prolapse between 2013 and 2017. All data, including intraoperative video recordings of the repair and saline testing, were collected prospectively. RESULTS: Isolated posterior leaflet repair was performed in 91 patients. In 17 patients (18.7%), saline testing showed an unexpected anterior leaflet prolapse. Patients with unexpected prolapse presented with higher body mass index (BMI) compared to the reference group (27.5 +/- 2.3 vs 25.0 +/- 4.2, P = 0.01). Binomial logistic regression analysis showed BMI, surgical approach, number of prolapsing segments, left ventricular ejection fraction, left ventricular end systolic diameter and left atrial diameter to be predictive for unexpected anterior leaflet prolapse. In patients with unexpected anterior leaflet prolapse, no adequate saline testing was possible and repair was accomplished based on correction of the prolapse as seen on a preoperative echocardiogram. In both groups, 100% repair rate was achieved. Predischarge mitral regurgitation grading showed mild or less mitral regurgitation in all the patients in the unexpected prolapse group in comparison with 98.6% of patients in the reference group. CONCLUSIONS: When saline testing shows an unexpected prolapse of the anterior leaflet, not present on preoperative echocardiography, no additional surgical techniques should be performed in order to achieve an excellent postoperative result. Further research is warranted to predict unexpected anterior leaflet prolapse preoperatively. PMID- 30247530 TI - Left ventricular global function index predicts incident heart failure and cardiovascular disease in young adults: the coronary artery risk development in young adults (CARDIA) study. AB - Aims: Left ventricular (LV) ejection fraction (LVEF) is an extensively utilized marker of LV function that is often interpreted without recourse to alterations in LV geometry and hypertrophy. LV global function index (LVGFI) is a novel marker that incorporates LV structure in the assessment of LV cardiac performance. We evaluated the prognostic utility of LVGFI from young adulthood into middle age for incident heart failure (HF) and cardiovascular disease (CVD) in comparison to LVEF. Methods and results: Included were 4107 CARDIA participants with echocardiograms in Year-5 (1990-1991). LVGFI was defined as LV stroke volume/LV global volume*100, where LV global volume was the sum of the LV mean cavity volume ((LV end-diastolic volume + LV end-systolic volume)/2) and myocardial volume (LV mass/density). Adjusted Cox proportional hazard models were utilized to predict incident HF and CVD outcomes. Mean age of participants was 29.8 +/- 3.7 years, 55% female, and 48.7% black. Higher body mass index [beta coefficient (B) = -0.11 standard error (SE) = 0.02, P < 0.001], higher blood pressure (B = -0.04, SE = 0.01, P < 0.01), smoking (B = -0.82, SE = 0.22, P < 0.001), male sex (P < 0.001), and black race (P < 0.001) were associated with worse LVGFI. A total of 207 incident CVD events were observed over the course of 98 035 person-years at risk. Higher LVGFI was associated with HF, hazard ratio (HR) = 0.70, 95% confidence interval (CI) (0.54-0.91), hard CVD HR = 0.83, 95% CI (0.71-0.96), and all CVD HR = 0.83, 95% CI (0.72-0.96). For HF outcomes, Harrell's C-statistic for LVGFI (0.80) was greater than LVEF (0.66). Conclusion: LVGFI is a strong, independent predictor of incident HF and CVD that provides incremental prognostic value compared with LVEF. Male sex, black race, obesity, hypertension, and smoking are associated with worse LVGFI in the early adult lifespan. PMID- 30247531 TI - Plant Water Stress and Vector Feeding Preference Mediate Transmission Efficiency of a Plant Pathogen. AB - Pathogen spread by arthropod vectors is the outcome of pathogen-vector-plant interactions, as well as how these interactions are impacted by abiotic and biotic factors. While plant water stress impacts each component of the Pierce's disease pathosystem (Xylella fastidiosa Wells et al., insect vectors, and grapevines), the outcome of interactions in relation to pathogen spread is unknown. The objectives of this study were 1) to determine the role of plant water stress on vector acquisition and inoculation of X. fastidiosa under choice and no-choice conditions for source or recipient vines, and 2) to provide insights into the effects of vineyard irrigation regimes on spread of X. fastidiosa by using a host-vector epidemic model. Under no-choice conditions, pathogen acquisition increased as water stress increased in source plants, while inoculation was not affected by water status of recipient vines. Thus, under no choice conditions, plant water stress increased transmission of X. fastidiosa. However, when vectors had a choice of an uninfected well-watered versus an infected water-stressed grapevine, transmission efficiency declined as water stress levels increased. While our experimental results produced wide uncertainty estimates, the epidemiological modeling suggested a non-linear relationship between water stress and pathogen spread: moderate water stress enhances pathogen spread but severe or no stress produce equivalent spread. In summary, both host plant condition and vector host preference interacted to determine transmission efficiency of X. fastidiosa. PMID- 30247532 TI - Simultaneous Determination of Ten Bioactive Components in Raw and Processed Radix Dipsaci by UPLC-Q-TOF-MS. AB - Radix Dipsaci is employed for treating bone fractures in traditional Chinese medicine. In the current, a quantitative approach was established for determination of ten bioactive components (loganic acid, loganin, 3,5-diCQA, 4 CQA, 3,4-diCQA, sweroside, dipsacussaponin B, dipsacoside A, asperosaponin V and asperosaponin VI) in raw and rice wine-sauteed Radix Dipsaci by using UPLC-Q-TOF MS based approach. The sample handling procedure was optimized. Chromatographic separation was operated on a Thermo Syncronis AQ-C18 UPLC column with mobile phase consisting of 0.01% aqueous formic acid and acetonitrile. The method was validated in terms of linearity, precision and recovery tests. All calibration curves displayed good linearity (R2 > 0.9991). The limit of detection and limit of quantification of these components were from 0.007 to 0.032 MUg/mL and from 0.020 to 0.095 MUg/mL, respectively. The average recoveries of these components were from 96.7 to 102.7% with relative standard deviation values from 0.13 to 3.81% for Radix Dipsaci. The developed approach can be employed for quality control of raw and wine-sauteed Radix Dipsaci. PMID- 30247533 TI - Classical mechanical dyssynchrony is rare in transcatheter aortic valve implantation-induced left bundle branch block. AB - Aims: Left bundle branch block (LBBB) is a frequent conduction abnormality after transcatheter aortic valve implantation (TAVI). We aimed to investigate how TAVI procedure related conduction abnormalities influence ventricular mechanics and prognosis, with particular focus on new-onset persistent LBBB. Methods and results: A total of 140 consecutive patients with severe aortic stenosis (83 +/- 8 years old, 49% women) undergoing TAVI in a single tertiary centre were included in a repeated measures study. Changes in myocardial function and contraction patterns were investigated in relation to changes in electrical conduction and afterload by speckle tracking echocardiography. Whether patients with new-onset LBBB acquired classical dyssynchronous contractions was assessed by longitudinal strain in apical four-chamber view. Global longitudinal strain improvement was seen in all patients (-15.1 +/- 4.3 vs. -16.1 +/- 3.9%, P < 0.01, n = 140), and all subgroups, regardless of pre-existing or procedure-acquired conduction abnormalities immediately after TAVI. New-onset LBBB fulfilling strict electrocardiogram (ECG) criteria was observed in 28 patients (20%). The vast majority of new-onset LBBB patients (n = 26, 93%) had homogenous contractions. Classical dyssynchronous LBBB contractions were only observed in 2 patients (7%) with new-onset LBBB. Patients with new-onset LBBB and patients without acquired conduction disorders had similar mortality rates during 19 +/- 9 months of follow up [11.1, 95% confidence interval (CI) 4.6-26.8 vs. 8.1, 95% CI 4.8-13.7 per 100 patients years, P = 0.53]. Conclusion: Classical dyssynchronous LBBB contractions were absent in most patients with new-onset post-TAVI LBBB, even when applying strict ECG criteria. Patients with and without new-onset LBBB experienced similar prognosis with regards to mortality. PMID- 30247534 TI - Commentary on: Current Trends in Breast Augmentation: Analysis of 2011-2015 Maintenance of Certification (MOC) Tracer Data. PMID- 30247535 TI - Predictive cluster level surrogacy in the presence of interference. AB - Surrogate evaluation is a difficult problem that is made more so by the presence of interference. Our proposed procedure can allow for relatively easy evaluation of surrogates for indirect or spill-over clinical effects at the cluster level. Our definition of surrogacy is based on the causal-association paradigm (Joffe and Greene, 2009. Related causal frameworks for surrogate outcomes. Biometrics65, 530-538), under which surrogates are evaluated by the strength of the association between a causal treatment effect on the clinical outcome and a causal treatment effect on the candidate surrogate. Hudgens and Halloran (2008, Toward causal inference with interference. Journal of the American Statistical Association103, 832-842) introduced estimators that can be used for many of the marginal causal estimands of interest in the presence of interference. We extend these to consider surrogates for not just direct effects, but indirect and total effects at the cluster level. We suggest existing estimators that can be used to evaluate biomarkers under our proposed definition of surrogacy. In our motivating setting of a transmission blocking malaria vaccine, there is expected to be no direct protection to those vaccinated and predictive surrogates are urgently needed. We use a set of simulated data examples based on the proposed Phase IIb/III trial design of transmission blocking malaria vaccine to demonstrate how our definition, proposed criteria and procedure can be used to identify biomarkers as predictive cluster level surrogates in the presence of interference on the clinical outcome. PMID- 30247536 TI - Treatment-risk paradox in acute coronary syndromes. PMID- 30247537 TI - Bayesian model averaging for the X-chromosome inactivation dilemma in genetic association study. AB - X-chromosome is often excluded from the so called "whole-genome" association studies due to the differences it exhibits between males and females. One particular analytical challenge is the unknown status of X-inactivation, where one of the two X-chromosome variants in females may be randomly selected to be silenced. In the absence of biological evidence in favor of one specific model, we consider a Bayesian model averaging framework that offers a principled way to account for the inherent model uncertainty, providing model averaging-based posterior density intervals and Bayes factors. We examine the inferential properties of the proposed methods via extensive simulation studies, and we apply the methods to a genetic association study of an intestinal disease occurring in about 20% of cystic fibrosis patients. Compared with the results previously reported assuming the presence of inactivation, we show that the proposed Bayesian methods provide more feature-rich quantities that are useful in practice. PMID- 30247538 TI - Biomarkers of maternal environmental enteric dysfunction are associated with shorter gestation and reduced length in newborn infants in Uganda. AB - Background: Adverse birth outcomes, including preterm birth and stunting at birth, have long-term health implications. The relation between adverse birth outcomes and chronic, asymptomatic gastrointestinal inflammation (environmental enteric dysfunction-EED) is poorly understood. Objective: We aimed to examine the relation between maternal EED and adverse birth outcomes in a sample of pregnant Ugandan women and their newborn infants. Design: We conducted a prospective cohort study in Mukono, Uganda. A total of 258 pregnant women were enrolled at their first prenatal visit (~18 weeks of gestation). EED was measured by urinary lactulose:mannitol (L:M) ratio and serum concentrations of antibodies to the bacterial components flagellin and LPS. Covariates were obtained from survey data collected at 2 time points. Associations were assessed through the use of unadjusted and adjusted simple linear regression models. Results: Complete birth outcome data were recorded for 220 infants within 48 h of delivery. Mean +/- SD gestational age was 39.7 +/- 2.1 wk, and 7% were born preterm. Mean +/- SD length and length-for-age z score (LAZ) at birth were 48.1 +/- 3.2 cm and -0.44 +/- 1.07, respectively. L:M ratio was not associated with any birth outcome. In adjusted models, higher concentrations of natural log-transformed anti-flagellin immunoglobin G (IgG) and anti-LPS IgG were significantly associated with shorter length of gestation (beta: -0.89 wk; 95% CI: -1.77, -0.01 wk, and beta: -1.01 wk; 95% CI: -1.87, -0.17 wk, respectively) and with reduced length (beta: -0.80 cm; 95% CI: -1.55, -0.05 cm, and beta: -0.79 cm; 95% CI: -1.54, -0.04 cm, respectively) and LAZ at birth (beta -0.44 z score; 95% CI: -0.83, -0.05, and beta: -0.40 z score; 95% CI: -0.79, -0.01, respectively). Conclusion: Maternal anti-flagellin and anti-LPS IgG concentrations in pregnancy, but not L:M ratio, were associated with shorter gestation and reduced infant length at birth. Further research on the relation between maternal EED and birth outcomes is warranted. PMID- 30247539 TI - Investigation of the Relationships Between Clinical and Environmental Isolates of Aspergillus fumigatus by Multiple-locus Variable Number Tandem Repeat Analysis During Major Demolition Work in a French Hospital. AB - Background: Genotyping is needed to explore the link between clinical cases from colonization of invasive aspergillosis (IA) and major building construction. Attempts to correlate Aspergillus fumigatus strains from clinical infection or colonization with those found in the environment remain controversial due to the lack of a large prospective study. Our aim in this study was to compare the genetic diversity of clinical and environmental A. fumigatus isolates during a demolition period. Methods: Fungal contamination was monitored daily for 11 months in 2015. Environmental surveillance was undertaken indoors and outdoors at 8 locations with automatic agar samplers. IA infection cases were investigated according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria. Isolates were identified by amplification and sequencing of the beta- tubulin gene. They were genotyped by multiple-locus variable number tandem repeat analysis (MLVA). The phylogenetic relationships between isolates were assessed by generating a minimum spanning tree. Results: Based on 3885 samples, 394 A. fumigatus isolates (383 environmental and 11 clinical) were identified and genotyped using MLVA. Clinical isolates were collected from patients diagnosed as having probable IA (n = 2), possible IA (n = 1), or bronchial colonization (n = 6). MLVA generated 234 genotypes. Seven clinical isolates shared genotypes identical to environmental isolates. Conclusions: Among the diversity of genotypes described, similar genotypes were found in clinical and environmental isolates, indicating that A. fumigatus infection and colonization may originate from hospital environments. PMID- 30247540 TI - Generalized integrative principal component analysis for multi-type data with block-wise missing structure. AB - High-dimensional multi-source data are encountered in many fields. Despite recent developments on the integrative dimension reduction of such data, most existing methods cannot easily accommodate data of multiple types (e.g. binary or count valued). Moreover, multi-source data often have block-wise missing structure, i.e. data in one or more sources may be completely unobserved for a sample. The heterogeneous data types and presence of block-wise missing data pose significant challenges to the integration of multi-source data and further statistical analyses. In this article, we develop a low-rank method, called generalized integrative principal component analysis (GIPCA), for the simultaneous dimension reduction and imputation of multi-source block-wise missing data, where different sources may have different data types. We also devise an adapted Bayesian information criterion (BIC) criterion for rank estimation. Comprehensive simulation studies demonstrate the efficacy of the proposed method in terms of rank estimation, signal recovery, and missing data imputation. We apply GIPCA to a mortality study. We achieve accurate block-wise missing data imputation and identify intriguing latent mortality rate patterns with sociological relevance. PMID- 30247541 TI - Corrigendum. PMID- 30247542 TI - Expression of Transcripts Selective for GABA Neuron Subpopulations across the Cortical Visuospatial Working Memory Network in the Healthy State and Schizophrenia. AB - Visuospatial working memory (WM), which is impaired in schizophrenia, depends on a distributed network including visual, posterior parietal, and dorsolateral prefrontal cortical regions. Within each region, information processing is differentially regulated by subsets of gamma-aminobutyric acid (GABA) neurons that express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). In schizophrenia, WM impairments have been associated with alterations of PV and SST neurons in the dorsolateral prefrontal cortex. Here, we quantified transcripts selectively expressed in GABA neuron subsets across four cortical regions in the WM network from comparison and schizophrenia subjects. In comparison subjects, PV mRNA levels declined and SST mRNA levels increased from posterior to anterior regions, whereas VIP mRNA levels were comparable across regions except for the primary visual cortex (V1). In schizophrenia subjects, each transcript in PV and SST neurons exhibited similar alterations across all regions, whereas transcripts in VIP neurons were unaltered in any region except for V1. These findings suggest that the contribution of each GABA neuron subset to inhibitory regulation of local circuitry normally differs across cortical regions of the visuospatial WM network and that in schizophrenia alterations of PV and SST neurons are a shared feature across these regions, whereas VIP neurons are affected only in V1. PMID- 30247543 TI - Five novel carbapenem-hydrolysing OXA-type beta-lactamase groups are intrinsic in Acinetobacter spp. AB - Objectives: Carbapenem resistance in Acinetobacter spp. is increasing and is primarily associated with the expression of OXA-type beta-lactamases. However, the role of intrinsic OXA-type beta-lactamases in the carbapenem resistance of Acinetobacter spp. has not been fully elucidated. The aim of this study was thus to understand this issue. Methods: We applied bioinformatic screening of putative blaOXA genes against available genome sequences. The putative blaOXA genes were cloned into pKFAb and expressed in Escherichia coli and Acinetobacter baumannii to determine their antibiotic susceptibility. blaOXA genes were knocked out in their native hosts using pEX18Gm. Results: Five novel groups of carbapenem hydrolysing OXA-type beta-lactamases were identified in Acinetobacter rudis, Acinetobacter bohemicus, Acinetobacter tandoii, Acinetobacter gyllenbergii, Acinetobacter proteolyticus, Acinetobacter dispersus, Acinetobacter colistiniresistens and Acinetobacter guillouiae. The five OXA groups clustered into five highly supported monophyletic clades and are distinct from known OXA type carbapenemases in the phylogenetic tree. Most of them conferred resistance to imipenem, meropenem, ertapenem, amoxicillin and ampicillin in E. coli and A. baumannii. The conserved location and prevalence of the blaOXA genes among the species suggest they are intrinsic. The blaOXA genes in A. rudis, A. guillouiae and A. gyllenbergii were knocked out separately and the blaOXA-665-deficient A. rudis and blaOXA-274-deficient A. guillouiae exhibited increased susceptibility to imipenem, meropenem, amoxicillin and ampicillin. Conclusions: Five novel intrinsic OXA groups were identified in the genus Acinetobacter and most of them can hydrolyse carbapenems. This study furthers our understanding of the wide distribution of carbapenem-hydrolysing OXA-type beta-lactamases in Acinetobacter spp. PMID- 30247545 TI - Kinase PIM1 promotes prostate cancer cell growth via c-Myc-RPS7-driven ribosomal stress. AB - Ribosomal stress is known to increase cancer risk, however, the molecular mechanism underlying its various effects on cancer remains unclear. To decipher this puzzle, we investigated the upstream signaling pathway that might be involved in promoting ribosomal stress that leads to tumor progression. Our results suggested that inhibition of kinase PIM1 attenuated PC3 cell growth and motility following the condensed cellular body and decreased protein translation in PIM1-inhibited cells. In addition, PIM1 was found to be a component of the small 40S ribosomal subunit, and could regulate the expression of RPS7. Our investigation also revealed that PIM1 enhanced the protein stability of c-Myc. Furthermore, a functional E-box motif was found upstream of the transcription start site in RPS7, and RPS7 has been proven to be a transcriptional target of c Myc. Additionally, knocking down RPS7 dramatically reduced cell growth in vitro and in vivo, while enhancing RPS7 expression reversed the condensed cellular body and decreased protein translation resulted from PIM1 inhibition. Finally, BCR free survival and overall survival analysis indicated that the concomitant upregulation of PIM1 and RPS7 correlated with the worst prognosis of prostate cancer (PCa). Overall, our results demonstrated that kinase PIM1 promotes cell growth through c-Myc-RPS7 induced ribosomal stress in PCa. These findings substantially expanded our understanding on the molecular mechanism of PIM1 promoted abnormal ribosomal biosynthesis in tumorigenesis and tumor progression in PCa, Therapies that target molecules involved in PIM1-RPS7 induced ribosomal stress could provide a promising approach to treating PCa. PMID- 30247544 TI - Conserved Genes Underlie Phenotypic Plasticity in an Incipiently Social Bee. AB - Despite a strong history of theoretical work on the mechanisms of social evolution, relatively little is known of the molecular genetic changes that accompany transitions from solitary to eusocial forms. Here, we provide the first genome of an incipiently social bee that shows both solitary and social colony organization in sympatry, the Australian carpenter bee Ceratina australensis. Through comparative analysis, we provide support for the role of conserved genes and cis-regulation of gene expression in the phenotypic plasticity observed in nest-sharing, a rudimentary form of sociality. Additionally, we find that these conserved genes are associated with caste differences in advanced eusocial species, suggesting these types of mechanisms could pave the molecular pathway from solitary to eusocial living. Genes associated with social nesting in this species show signatures of being deeply conserved, in contrast to previous studies in other bees showing novel and faster-evolving genes are associated with derived sociality. Our data provide support for the idea that the earliest social transitions are driven by changes in gene regulation of deeply conserved genes. PMID- 30247546 TI - Selection of mutants with resistance or diminished susceptibility to ceftazidime/avibactam from ESBL- and AmpC-producing Enterobacteriaceae. AB - Introduction: Difficult Gram-negative infections are increasingly treated with new beta-lactamase inhibitor combinations, e.g. ceftazidime/avibactam. Disturbingly, mutations in KPC carbapenemases can confer ceftazidime/avibactam resistance, which is sometimes selected during therapy. We explored whether this risk extended to AmpC and ESBL enzymes. Methods: Mutants were selected by plating AmpC-derepressed strains, ESBL producers and ceftazidime-susceptible controls on agar containing ceftazidime + avibactam (1 or 4 mg/L). MICs were determined by CLSI agar dilution; WGS was by Illumina methodology. Results: Using 2* MIC of ceftazidime + 1 mg/L avibactam, mutants were selected from all strain types at frequencies of 10-7-10-9. Rates diminished to <10-9 with 4 mg/L avibactam or higher MIC multiples, except with AmpC-derepressed Enterobacteriaceae. Characterized mutants (n = 10; MICs 4-64 mg/L) of AmpC-derepressed strains had modifications in ampC, variously giving Arg168Pro/His, Gly176Arg/Asp, Asn366Tyr or small deletions around positions 309-314. Mutants of ESBL producers (n = 19; MICs 0.5-16 mg/L) mostly had changes affecting permeability, efflux or beta lactamase quantity; only one had an altered beta-lactamase, with an Asp182Tyr substitution in CTX-M-15, raising the ceftazidime/avibactam MIC, but abrogating other cephalosporin resistance. Mutants of ceftazidime-susceptible strains were not sequenced, but phenotypes suggested altered drug accumulation or, for Enterobacter cloacae only, AmpC derepression. In further experiments, avibactam reduced, but did not abolish, selection of AmpC-derepressed Enterobacteriaceae by ceftazidime. Conclusions: Most mutants of AmpC-derepressed Enterobacteriaceae had structural mutations in ampC; those of ESBL producers mostly had genetic modifications outside beta-lactamase genes, commonly affecting uptake, efflux, or beta-lactamase quantity. The clinical significance of these observations remains to be determined. PMID- 30247548 TI - The impact of out-of-pocket costs on treatment commencement and adherence in chronic kidney disease: a systematic review. AB - Chronic kidney disease (CKD) is a significant and growing driver of the global non-communicable diseases (NCD) burden, responsible for 1.2 million deaths in 2016. While previous research has estimated the out-of-pocket costs of CKD treatment and resulting levels of catastrophic health expenditures, less is known about the impact of such costs on access to, and maintenance of, care. Our study seeks to fill this gap by synthesizing available evidence on cost as a determinant of CKD treatment discontinuation. We searched for studies which considered the financial burden of treatment and medication for CKD patients and the extent to which this burden was associated with patients forgoing or discontinuing treatment. We identified 14 relevant studies, 5 from high-income countries and 9 from low-middle income countries. All suggest that cost adversely influences adherence to CKD medication and dialysis treatment. In poorer countries, those entering treatment programs were typically diagnosed late, under dialysed and suffered very high levels of mortality. Identified studies present consistent findings regardless of study context: cost is barrier to treatment and a driver of non-adherence and discontinuation, with poorer households worst affected. This is in line with previous research. Major gaps in the literature remain, however, in relation to differential impact of the cost burden on men and women, the coping strategies of poor households and the effect of insurance coverage. PMID- 30247549 TI - Daily Routine: Associations With Health Status and Urgent Health Care Utilization Among Older Adults. AB - Background and Objectives: Chronically ill older adults must integrate self-care behaviors into their daily routine to promote health and reduce urgent health care utilization. Individuals of lower socioeconomic position (SEP) experience a disproportionate burden of stressors that challenge the formation of regular routines. We examined associations between the presence of a daily routine and older adults' health status and urgent health care utilization, to determine whether higher levels of daily routine mediates associations between SEP and health outcomes. Research Design and Methods: We used data from a cohort of older adult primary care patients in Chicago. Daily routine was measured using a brief, validated scale. A single factor score of SEP was created with measures of education, income, homeownership, and insurance status. Health status was assessed by Patient Reported Outcomes Measurement Information Service physical function, depression, and anxiety. Urgent health care utilization was patient reported. Multivariable models were used to assess the effect of routine and SEP on health status and urgent health care utilization. Results: Individuals reporting low levels of daily routine reported worse physical function (beta = 2.34; 95% CI -4.18, -0.50), more anxiety (beta = 2.73; 95% CI 0.68, 4.78) and depressive symptoms (beta = 2.83; 95% CI 0.94, 4.74) than those with greater daily routine. No differences in urgent health care utilization were observed by daily routine. Daily routine varied by SEP (p < .001); routine partially mediated the relationship between SEP and physical function and anxiety symptoms (ps < .05). Discussion and Implications: A daily routine may be an under recognized modifiable factor that could promote health outcomes among older adults. PMID- 30247550 TI - Biomonitoring an Albumin Adduct of the Cooked Meat Carcinogen 2-Amino-1-Methyl-6 Phenylimidazo[4,5-b]pyridine in Humans. AB - 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is formed in cooked meats and may be linked to dietary associated colorectal, prostate, and mammary cancers. Genotoxic N-oxidized metabolites of PhIP react with the Cys 34 of albumin (Alb) to form a sulfinamide adduct, a biomarker of the biologically effective dose. We examined the kinetics of PhIP-Alb adduct formation in plasma of volunteers on a 4-week semi-controlled diet of cooked meat containing known quantities of PhIP. The adduct was below the limit of detection (LOD) (10 femtograms PhIP/mg Alb) in most subjects before the meat feeding, but increased by up to 560-fold at week four in subjects who ate meat containing 8.0 to 11.7 MUg of PhIP per 150 - 200 g serving. In contrast, the adduct remained below the LOD in subjects who ingested 1.2 or 3.0 MUg PhIP per serving. Correlations were not seen between PhIP-Alb adduct levels and PhIP intake levels (P = 0.76), the amount of PhIP accrued in hair (P = 0.13), the amounts of N-oxidized urinary metabolites of PhIP (P = 0.66), or caffeine CYP1A2 activity (P = 0.55), a key enzyme involved in the bioactivation of PhIP. The half-life of the PhIP-Alb adduct was less than 2 weeks, signifying that the adduct was not stable. PhIP-Alb adduct formation is direct evidence of bioactivation of PhIP in vivo. However, the PhIP hair biomarker is a longer-lived and more sensitive biomarker to assess exposure to this potential human carcinogen. PMID- 30247551 TI - Index Severity Score and Early Readmission Predicts Increased Mortality in Ulcerative Colitis Patients. AB - Background: Readmissions are common after hospitalization related to ulcerative colitis (UC). A risk score to stratify the severity of UC hospitalizations and risk of colectomy has been previously reported. Our aim was to predict hospital related outcomes after hospitalizations for UC utilizing this severity score. Methods: We utilized the Nationwide Readmissions Database (2010-2014) for hospitalized patients with UC and differentiated patients by index severity (low, intermediate, high). Baseline characteristics, surgical rates, readmissions, mortality, and hospital outcomes were collected. The primary outcomes of interest included readmission and mortality rates. Results: There were 133,819 patients admitted with UC with 22,762 (17%) readmitted within 30 days. Those readmitted within 30 days had a 4.5% calendar year mortality rate, compared with 0.45% in those not readmitted within 30 days (P < 0.001). Index surgery rates (19.2% vs 12.3%), length of stay (6.9 vs 5.4 days), and hospital costs ($13,530 vs $10,366; P < 0.001 for all) were higher in those readmitted within 30 days. Patients with high-severity presentations had higher surgical rates (31.6%), higher 30-day and calendar year readmission rates (24.3% and 46.0%, respectively), increased index and calendar year mortality (2.5% and 2.0%, respectively), longer length of stay (15.1 days), and increased costs ($31,136) compared with those with low severity (P < 0.001 for all). Calendar-year survival rates in those with intermediate and high scores were significantly lower than in those with low scores. Conclusions: An index severity score of intermediate or high and early readmissions are predictors of calendar year mortality. Future efforts should emphasize more focused care in high-risk patients, as this may reduce readmissions and improve outcomes. 10.1093/ibd/izy297_video15837391984001izy297.video1. PMID- 30247552 TI - Dietary Patterns and Self-reported Incident Disability in Elderly. AB - Background: Disability in older adults is associated with low quality of life and higher mortality. Diet may be a potentially important public health strategy for disability prevention in aging. We examined the relations of the Mediterranean, DASH and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets to functional disability in the Rush Memory and Aging Project. Methods: A total of 809 participants (mean age= 80.7 +/- 7.2 years, 74% female) without functional disability at baseline were followed for an average of 5.3 years. Standardized measures for self-reported disability including, activities of daily living (ADL), instrumental activities of daily living (IADL) and mobility disability were assessed annually. The diet scores were computed based on a validated food frequency questionnaire administered at baseline. Results: In Cox proportional hazards models adjusted for age, sex, education, smoking, physical activity and total calories, the second (HR=0.75, 95%CI: 0.60-0.95) and third tertiles (HR=0.67, 95%CI: 0.53-0.86) of MIND diet scores had lower rates of ADL disability compared to the lowest tertile (p for trend=0.001), whereas only the third tertiles of the Mediterranean (HR=0.73, 95%CI: 0.57-0.94) and DASH (HR=0.75, 95%CI: 0.59-0.95)) diets were significantly associated with ADL disability. IADL disability was inversely and linearly associated with the MIND diet score only (p for trend=0.04). Mobility disability was associated with the MIND (p for trend=0.02), Mediterranean (p for trend=0.05) and DASH (p for trend=0.02) diet scores. Conclusion: These findings are encouraging that diet may be an effective strategy for the prevention of functional disability in older adults. PMID- 30247553 TI - Letter to the Editor: "Increased Circulating FGF23 Does Not Lead to Cardiac Hypertrophy in the Male Hyp Mouse Model of XLH". PMID- 30247554 TI - Highly cited papers in Microbiology: identification and conceptual analysis. AB - Microbiology is an area with a high research production, classified in different branches. Thus, it is difficult to identify research trends without many backgrounds. The present paper aims to apply bibliometric methods to identify the highly cited papers that contribute to the Microbiology development. Furthermore, a science mapping analysis allows discovering the main thematic areas covered by those detected papers. From the 572 153 papers (articles and reviews) indexed in the Web of Science Microbiology category (1900-2017), a total of 645 highly cited papers were detected. Concerning the main scientific producers in Microbiology, Applied and Environmental Microbiology as a journal, R. Knight from the University of Colorado (USA) as an author and the USA as a country are the most productive actors. Nevertheless, taking into account the gross domestic product per capita, China and Spain are remarkable countries. Furthermore, according to the relative priority index (RPI), Denmark, Belgium, Spain and The Netherlands are the countries that make a higher scientific effort in this field. About the co-word analysis, several important themes were detected, such as Next Generation Sequencing, Gene, Escherichia Coli or Gene Expression. Concerning these results, this work supposes a framework on which to base future research. PMID- 30247555 TI - Transcriptome Analyses of Female Somatotropes and Lactotropes Reveal Novel Regulators of Cell Identity in the Pituitary. AB - The differentiation of the hormone-producing cell lineages of the anterior pituitary represents an informative model of mammalian cell fate determination. The generation and maintenance of two of these lineages, the GH-producing somatotropes and prolactin (PRL)-producing lactotropes, are dependent on the pituitary-specific transcription factor POU1F1. Whereas POU1F1 is expressed in both cell types, and plays a direct role in the activation of both the Gh and Prl genes, GH expression is restricted to somatotropes and PRL expression is restricted to lactotropes. These observations imply the existence of additional, cell type-enriched factors that contribute to the somatotrope and lactotrope cell identities. In this study, we use transgenic mouse models to facilitate sorting of somatotrope and lactotrope populations based on the expression of fluorescent markers expressed under Gh and Prl gene transcriptional controls. The transcriptomic analyses reveal a concordance of gene expression profiles in the two populations. The limited number of divergent mRNAs between the two populations includes a set of transcription factors that may have roles in pituitary lineage divergence and/or in regulating expression of cell type specific genes after differentiation. Four of these factors were validated for lineage enrichment at the level of protein expression, two somatotrope enriched and two lactotrope enriched. Three of these four factors were shown to have corresponding activities in appropriate enhancement or repression of landmark genes in a cell culture model system. These studies identify novel regulators of the somatotropes and lactotropes, and they establish a useful database for further study of these lineages in the anterior pituitary. PMID- 30247556 TI - Corrigendum. PMID- 30247557 TI - Incorporating historical models with adaptive Bayesian updates. AB - This article considers Bayesian approaches for incorporating information from a historical model into a current analysis when the historical model includes only a subset of covariates currently of interest. The statistical challenge is 2 fold. First, the parameters in the nested historical model are not generally equal to their counterparts in the larger current model, neither in value nor interpretation. Second, because the historical information will not be equally informative for all parameters in the current analysis, additional regularization may be required beyond that provided by the historical information. We propose several novel extensions of the so-called power prior that adaptively combine a prior based upon the historical information with a variance-reducing prior that shrinks parameter values toward zero. The ideas are directly motivated by our work building mortality risk prediction models for pediatric patients receiving extracorporeal membrane oxygenation (ECMO). We have developed a model on a registry-based cohort of ECMO patients and now seek to expand this model with additional biometric measurements, not available in the registry, collected on a small auxiliary cohort. Our adaptive priors are able to use the information in the original model and identify novel mortality risk factors. We support this with a simulation study, which demonstrates the potential for efficiency gains in estimation under a variety of scenarios. PMID- 30247559 TI - Changing the Way We Think About Burn Size Estimation. AB - Background: Burn size estimation is a crucial component of acute burn management that guides referral to burn centers, fluid resuscitation parameters, hospital resource distribution, and mortality-based interventions. Referring providers often misestimate the total body surface area (TBSA) of burn injury, which contributes to unnecessary healthcare costs, misappropriation of limited resources, and delay in provision of appropriate patient care. Methods: A systematic literature review of articles available on PubMed, Scopus, Google Scholar, OvidSP Medline, and Web of Science was performed. All articles were evaluated in a standardized fashion by a panel of reviewers to assess applicability to the research question. Results: Twenty-six relevant articles identified pervasive TBSA miscalculations ranging from 5% to 339% regardless of provider level with < 20% TBSA burns being disproportionately overestimated. This resulted in up to 77% of burns being inappropriately transferred to burn centers from referring hospitals. Improper use of TBSA estimation tools (palm, hand, Rule of 9s) without considering patient body mass index, race, age, and sex standards contributes to TBSA misestimation. Few studies with limited sample sizes argue that TBSA misestimations significantly affect fluid resuscitation volume, although the findings suggest that small burns (<20% TBSA) are over-estimated and over-resuscitated - the opposite of larger burns. Conclusions: TBSA misestimation is associated with an increased incidence of inappropriate transfers to burn centers and the associated costs. The data remains lacking, however, and larger studies are required to further elucidate the clinical impact of such errors. A systematic approach with telemedicine-facilitated computer-based burn assessments is required. PMID- 30247560 TI - Histological and Anthropometric Changes in the Aging Nose. AB - Background: Rhinoplasty in the elderly requires different surgical approaches due to the morphological and structural changes affecting the nose by time. Objectives: In this study we aim to evaluate the age-related cellular and architectural changes of nasal cartilages and soft tissue attachments. Methods: This prospective study included 80 patients undergoing rhinoplasty. Patients were divided into 2 groups according to age. Group I included 40 patients with an age range of 19-39 years. Group II included 40 patients with an age range of >= 40 years. Samples from nasal cartilages (upper lateral, lower lateral and septum) and nasal attachments (interdomal, inter-cartilaginous, and septo-crural) were taken. All specimens were evaluated histologically to detect age-related changes. A modified version of the Mankin grading scale was used to score each nasal cartilage sample. All attachment samples were examined by image analysis for quantitative assessment. The results were correlated to preoperative anthropometric measurements: nasolabial angle and nasal projection. Results: Histologically in group II, the cartilage matrix showed fibrinoid degeneration with significant decrease in the number of chondrocytes and increased perichondrial fibrosis in comparison to group I. Attachments in group II showed a lower number of blood vessels and decreased percentage of collagen bundles. Modified Mankin scores were significantly higher in group II indicating weak cartilages in comparison to group I. There was negative correlation and significance between projection, nasolabial angle, cartilages and attachments in study groups. The linear regression model revealed that the lower lateral cartilage is the cartilage that is most affected by the aging process. Conclusions: These findings not only enhance our current understanding of the natural changes that occur in the nose with aging but may also affect surgical decision making when grafting or suturing are considered during rhinoplasty. PMID- 30247558 TI - Identification and Localization of Peroxisomal Biogenesis Proteins Indicates the Presence of Peroxisomes in the Cryptophyte Guillardia theta and Other "Chromalveolates". AB - Peroxisomes are single-membrane-bound organelles with a huge metabolic versatility, including the degradation of fatty acids (beta-oxidation) and the detoxification of reactive oxygen species as most conserved functions. Although peroxisomes seem to be present in the majority of investigated eukaryotes, where they are responsible for many eclectic and important spatially separated metabolic reactions, knowledge about their existence in the plethora of protists (eukaryotic microorganisms) is scarce. Here, we investigated genomic data of organisms containing complex plastids with red algal ancestry (so-called "chromalveolates") for the presence of genes encoding peroxins-factors specific for the biogenesis, maintenance, and division of peroxisomes in eukaryotic cells. Our focus was on the cryptophyte Guillardia theta, a marine microalga, which possesses two phylogenetically different nuclei of host and endosymbiont origin, respectively, thus being of enormous evolutionary significance. Besides the identification of a complete set of peroxins in G. theta, we heterologously localized selected factors as GFP fusion proteins via confocal and electron microscopy in the model diatom Phaeodactylum tricornutum. Furthermore, we show that peroxins, and thus most likely peroxisomes, are present in haptophytes as well as eustigmatophytes, brown algae, and alveolates including dinoflagellates, chromerids, and noncoccidian apicomplexans. Our results indicate that diatoms are not the only "chromalveolate" group devoid of the PTS2 receptor Pex7, and thus a PTS2-dependent peroxisomal import pathway, which seems to be absent in haptophytes (Emiliania huxleyi) as well. Moreover, important aspects of peroxisomal biosynthesis and protein import in "chromalveolates"are highlighted. PMID- 30247561 TI - Influence of non-polio enteroviruses and the bacterial gut microbiota on oral poliovirus vaccine response: a study from south India. AB - Background: Oral poliovirus vaccine (OPV) is less immunogenic in LMIC countries. We tested whether bacterial and viral components of the intestinal microbiota are associated with this phenomenon. Methods: We assessed prevalence of enteropathogens using TaqMan array cards 14 days before and at vaccination in 704 Indian infants (6-11 months) receiving monovalent type3 OPV (CTRI/2014/05/004588). Non-polio enterovirus (NPEV) serotypes were identified by VP1 sequencing. In 120 infants, pre-vaccination bacterial microbiota was characterised by 16S rRNA sequencing. Results: We detected 56 NPEV serotypes on the day of vaccination. Concurrent NPEVs were associated with a reduction in OPV seroconversion, consistent across species (odds ratios and 95% CIs of 0.57[0.36 0.90], 0.61[0.43-0.86], and 0.69[0.41-1.16] for species A, B, and C, respectively). Recently acquired enterovirus infections,detected at vaccination, but not 14 days earlier had greater interfering effect on mOPV3 sero-response compared to persistent infections,with enterovirus detected at both time points (44/127[35%] vs 63/129[49%] seroconversion,p=0.021). Abundance of specific bacterial taxa did not differ significantly according to OPV response, although microbiota diversity was higher in non-responders at the time of vaccination. Conclusion: Enteric viruses have greater impact on OPV response than the bacterial microbiota with recent enterovirus infections having greater inhibitory effect than persistent infections. PMID- 30247562 TI - Can We Link Thyroid Status, Energy Expenditure, and Body Composition to Management of Subclinical Thyroid Dysfunction? PMID- 30247563 TI - The Smallest Intestine (TSI)-a low volume in vitro model of the small intestine with increased throughput. AB - There is a growing interest in understanding the fate and behaviour of probiotic microorganisms and bioactive compounds during passage of the human gastrointestinal tract (GIT). Here, we report the development of a small volume in vitro model called The smallest Intestine (TSI) with increased throughput focusing on simulating passage through the stomach and small intestine (SI). The basic TSI module consists of five reactors, with a working volume of 12 ml each. During the simulated passage through the SI, bile is absorbed and pH is adjusted to physiologically relevant values for duodenum, jejunum and ileum. A consortium of seven representative bacterial members of the ileum microbiota is included in the ileal stage of the model. The behaviour of three putative probiotic Lactobacillus strains during in vitro simulated upper GIT passage was tested in the model and results were compared to previous studies describing probiotic survival. It was found, that probiotic persistence is strongly related to whether food was ingested, but also to presence of the ileal microbiota, which significantly impacted probiotic survival. In conclusion, TSI allows testing a substantial number of samples, at low cost and short time, and is thus suitable as an in vitro screening platform. PMID- 30247564 TI - Cardiovascular effect of varying interval training frequency in rehabilitation of severely burned children. AB - Structured exercise programs initiated after acute hospitalization can improve muscle strength and mass, cardiorespiratory capacity, and quality of life in severely burned children. In this retrospective study, we compared the cardiovascular effects of an exercise program incorporating a large number of interval training sessions with a traditional exercise program incorporating a small number of interval training sessions. Severely burned children who completed a large number of sessions (>=3 sessions per week, N=40) were matched to those completing a small number of sessions (<=2 sessions per week, N=40). Maximal oxygen consumption (VO2 max) was measured via the modified Bruce treadmill protocol at discharge, at completion of the exercise program, and at follow-up visits at 6, 12, and 24 months postburn. Both groups were comparable in age (large 13.5+/-3.0 years vs. small 13.1+/-3.3 years) and percent total body surface area burned (large 50.8+/-14.8% vs. small 49.2+/-13.3%). For both groups, VO2 max increased from discharge (large 22.6+/-3.8 mL/kg/min; small 22.6+/-5.0 mL/kg/min) to postexercise (large 29.5+/-6.0 mL/kg/min; small 28.0+/-5.8 mL/kg/min), 6 months (large 33.2+/-5.9 mL/kg/min; small 29.6+/-7.0 mL/kg/min), 12 months (large 35.0+/-7.5 mL/kg/min; small 31.7+/-7.1 mL/kg/min), and 24 months (large 37.0+/-7.2 mL/kg/min; small 32.4+/-9.2 mL/kg/min, p<0.001). VO2 increased to a greater extent with a large number of interval sessions than with a small number at 6 and 24 months (both p=0.021). These findings suggest that a large number of interval training sessions imparts a greater benefit on cardiorespiratory fitness than a small number of sessions. PMID- 30247565 TI - A salamander's top down effect on fungal communities in a detritivore ecosystem. AB - The soil decomposer community is a primary driver of carbon cycling in forest ecosystems. Understanding the processes that structure this community is critical to our understanding of the global carbon cycle. In North American forests, soil fungal communities are regulated by grazing soil invertebrates, which are in turn controlled by the predatory red-backed salamander (Plethodon cinereus). The presence of these soil invertebrate taxa is known to exert direct top-down control via selective grazing on saprotrophic fungi, with direct consequences for biogeochemical cycling in soil. We investigated whether the removal of P. cinereus would relieve top-down control on decomposer fungal communities in a tri trophic mesocosm study. Fungal communities were characterized using metabarcoding and high-throughput DNA sequencing. The beta-diversity of fungal communities differed between salamander presence and absence treatments with a strong effect on saprotrophic fungal communities. We concluded that P. cinereus, a mesopredator in the detritivore food chain, exerts a prominent control on the composition and functional diversity of fungal communities in soil through a multi-trophic top down process. Given their capacity to govern the compositions of soil invertebrates, the activity of these amphibians may be important for regulating ecosystem function and nutrient cycling in temperate forest systems. PMID- 30247566 TI - Sterilization impacts on marine sediment---Are we able to inactivate microorganisms in environmental samples? AB - To distinguish between biotic and abiotic processes in laboratory experiments with environmental samples, an effective sterilization method is required that prevents biological activity but does not change physico-geochemical properties of samples. We compared standard sterilization methods with respect to their impact on microbial abundance and activity. We exposed marine sediment to (i) autoclaving, (ii) gamma-radiation or (iii) sodium azide (NaN3) and determined how nucleic acids, microbial productivity, colony forming units (CFUs) and community composition of microorganisms, fungi, unicellular protists and protozoa were affected. In autoclaved and gamma-sterilized sediments, only few colonies formed within 16 days. After addition of NaN3 to the sediment, numerous CFUs (>50) but lower 3H-leucine incorporation rates, i.e. lower protein biosynthesis rates, were found compared to the other two sterilization techniques. Extractable RNA was detected immediately after all sterilization treatments (0.2-17.9 ng/g dry sediment) but decreased substantially by 84%-98% after 16 days of incubation. The total organic carbon content increased from 18 mg L-1 to 220 mg L-1 (autoclaving) and 150 mg L-1 (gamma-radiation) after sterilization. We compare advantages and disadvantages for each tested sterilization method and provide a helpful decision making resource for choosing the appropriate sterilization technique for environmental studies, particularly for marine sediments. PMID- 30247568 TI - The 2018 ESC Gold Medallists. PMID- 30247569 TI - Cardiovascular Anniversaries in 2018. PMID- 30247570 TI - Acute and chronic coronary syndromes: coronary dissection, intraplaque haemorrhage, and late lumen loss. PMID- 30247571 TI - Does supportive supervision enhance community health worker motivation? A mixed methods study in four African countries. AB - Supportive supervision is an important element of community health worker (CHW) programmes and is believed to improve CHW motivation and performance. A group supervision intervention, which included training and mentorship of supervisors, was implemented in Ethiopia, Kenya, Malawi and Mozambique. In three of the countries, this was combined with individual and/or peer supervision. A mixed methods implementation study was conducted to assess the effect of the supervision intervention on CHWs' perceptions of supervision and CHW motivation related outcomes. In total, 153 in-depth interviews were conducted with CHWs, their supervisors and managers. In addition, questionnaires assessing perceived supervision and motivation-related outcomes (organizational and community commitment, job satisfaction and conscientiousness) were administered to a total of 278 CHWs pre- and post-intervention, and again after 1 year. Interview transcripts were thematically analysed using a coding framework. Changes in perceived supervision and motivation-related outcomes were assessed using Friedman's ANOVA and post hoc Wilcoxon signed-rank tests. Interview participants reported that the supervision intervention improved CHW motivation. In contrast, the quantitative survey found no significant changes for measures of perceived supervision and inconsistent changes in motivation-related outcomes. With regard to the process of supervision, the problem-solving focus, the sense of joint responsibilities and team work, cross-learning and skill sharing, as well as the facilitating and coaching role of the supervisor, were valued. The empowerment and participation of supervisees in decision making also emerged in the analysis, albeit to a lesser extent. Although qualitative and quantitative findings differed, which could be related to the slightly different focus of methods used and a 'ceiling effect' limiting the detection of observable differences from the survey, the study suggests that there is potential for integrating supportive group supervision models in CHW programmes. A combination of group with individual or peer supervision, preferably accompanied with methods that assess CHW performance and corresponding feedback systems, could yield improved motivation and performance. PMID- 30247572 TI - Advertisement of electronic cigarettes in Italy: characteristics of online videos and the most popular promotional messages. AB - Given the increasing popularity of electronic cigarettes (ECs) and a lack of regulation of EC advertising, this study aimed to analyse online videos promoting ECs to assess the main marketing messages that could influence consumers' perceptions of associated risks and benefits. A web search of EC advertising videos was performed on YouTube by using keywords related to EC promotion. An evaluation grid was used to analyse promotional messages contained in each video. The most frequent promotional messages were related to health benefits (67.7%) and to the possibility of quitting smoking (57.4%). Messages that could also be appealing to adolescents and young adults, such as those promoting the multiple flavors available and the technological improvement of ECs, were present in 41.2% and 42.7% of the videos respectively. ECs similar to traditional cigarettes in appearance were included in 52.9% of the videos. EC promotional videos address messages not only to smokers who want to quit or decrease tobacco consumption but also to nonsmokers, especially young people. The use of ECs similar to traditional cigarettes may be a gateway to tobacco cigarette use. Since EC use may represent an important public health concern, regulatory policies on EC advertising should be established. PMID- 30247573 TI - Impact of social care supply on healthcare utilisation by older adults: a systematic review and meta-analysis. AB - Objective: to investigate the impact of the availability and supply of social care on healthcare utilisation (HCU) by older adults in high income countries. Design: systematic review and meta-analysis. Data sources: medline, EMBASE, Scopus, Health Management Information Consortium, Cochrane Database of Systematic Reviews, NIHR Health Technology Assessment, NHS Economic Evaluation Database, Database of Abstracts of Reviews of Effectiveness, SCIE Online and ASSIA. Searches were carried out October 2016 (updated April 2017 and May 2018). (PROSPERO CRD42016050772). Study selection: observational studies from high income countries, published after 2000 examining the relationship between the availability of social care (support at home or in care homes with or without nursing) and healthcare utilisation by adults >60 years. Studies were quality assessed. Results: twelve studies were included from 11,757 citations; ten were eligible for meta-analysis. Most studies (7/12) were from the UK. All reported analysis of administrative data. Seven studies were rated good in quality, one fair and four poor. Higher social care expenditure and greater availability of nursing and residential care were associated with fewer hospital readmissions, fewer delayed discharges, reduced length of stay and expenditure on secondary healthcare services. The overall direction of evidence was consistent, but effect sizes could not be confidently quantified. Little evidence examined the influence of home-based social care, and no data was found on primary care use. Conclusions: adequate availability of social care has the potential to reduce demand on secondary health services. At a time of financial stringencies, this is an important message for policy-makers. PMID- 30247574 TI - Baseline low-density lipoprotein cholesterol to predict the extent of cardiovascular benefit from lipid-lowering therapies: A Review. AB - Importance: Lipid-lowering therapies have been shown to improve cardiovascular outcome in a wide range of patients. The current guidelines recommend a graded approach to reduction in low-density lipoprotein cholesterol (LDL-C) proportional to the patient's risk, with the goal of achieving either a certain magnitude of reduction or a specific threshold of final LDL-C. Observations: Recent findings from a meta-analysis of numerous randomized trials suggest that more attention should be given to the baseline LDL-C of an individual patient. In this review we discuss how the baseline LDL-C level may provide a means to better understand the results of recent cardiovascular outcome trials and the expected benefits of lipid-lowering therapies. Conclusions and Relevance: The exact quantification of the clinical benefit associate with an intensified lipid-lowering therapy depends on the baseline LDL-C. Mortality is reduced in a log-linear fashion only when LDL C >100 mg/dl. PMID- 30247567 TI - Regional variation of Guillain-Barre syndrome. AB - Guillain-Barre syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barre syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barre Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barre syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barre syndrome was observed in patients from all countries participating in the International Guillain-Barre Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barre syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barre overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barre syndrome. PMID- 30247575 TI - Cardiovascular Safety During and After Use of Phentermine and Topiramate. AB - Context: Increases in heart rate were seen during the clinical program for fixed dose combination phentermine (PHEN) and topiramate (TPM), an oral medication indicated for weight management, but the effect on cardiovascular (CV) outcomes is uncertain. Objective: The aim of the study was to determine the extent to which rates of major adverse cardiovascular events (MACE) while patients were using PHEN and TPM (including fixed dose) differed from MACE rates during unexposed periods. Design: Retrospective cohort study. Setting: MarketScan, US insurance billing data. Patients or other participants: Patients over 18 years with at least 6 months continuous enrollment in database before taking PHEN and/or TPM or after stopping these medications. Intervention(s): PHEN and TPM, taken separately and together (including fixed dose). Main outcome measure(s): MACE, a composite of hospitalization for acute myocardial infarction and stroke, and in-hospital CV death. Results: Because the outcomes are rare and the duration of medication use was brief, there were few events. Rates of MACE among current users of PHEN/TPM, fixed-dose PHEN/TPM, and PHEN were lower than those among unexposed former users, whereas the rate of MACE among current users of TPM was higher than among unexposed former users (incidence rate ratio [95% confidence interval]: PHEN/TPM 0.57 [0.19-1.78]; fixed-PHEN/TPM 0.24 [0.03-1.70]; PHEN 0.56 [0.34-0.91]; TPM 1.58 [1.33-1.87]). Conclusions: Overall, the data indicate no increased risk of MACE for current PHEN/TPM users, but confidence intervals for the PHEN/TPM groups were broad, indicating that the data were compatible with a wide range of possible values. PMID- 30247576 TI - Cleaved PGAM5 is released from mitochondria depending on proteasome-mediated rupture of the outer mitochondrial membrane during mitophagy. AB - PGAM5 is a unique type of protein phosphatase that exists in mitochondria. It has been shown to exist in the inner mitochondrial membrane through its transmembrane domain and to be cleaved within the transmembrane domain upon mitochondrial dysfunction. However, its submitochondrial localization remains controversial; many researchers claim that PGAM5 localizes to the outer mitochondrial membrane based on the findings that PGAM5 associates with many cytoplasmic proteins. Here, we found that cleaved PGAM5 was released from mitochondria during mitophagy, a selective form of autophagy specific for mitochondria, and that the release was inhibited by proteasome inhibitors in HeLa cells stably expressing the E3 ubiquitin ligase Parkin. However, treatment of parental HeLa cells lacking Parkin with mitophagy-inducing agents caused PGAM5 cleavage but did not cause its release from mitochondria. Thus, cleaved PGAM5 appears to be released from mitochondria depending on proteasome-mediated rupture of the outer membrane during mitophagy, which has been previously shown to precede autophagy-mediated degradation of whole mitochondria. This study suggests that PGAM5 senses mitochondrial dysfunction in the inner mitochondrial membrane and serves as a signaling intermediate that regulates the cellular response to mitochondrial stress upon its cleavage and release from mitochondria. PMID- 30247577 TI - Diet Quality Scores Inversely Associated with Postmenopausal Breast Cancer Risk Are Not Associated with Premenopausal Breast Cancer Risk in the California Teachers Study. AB - Background: Evidence for the association between diet and breast cancer risk is inconsistent Thus, research that compares indexes of overall diet quality may provide new insight. Objective: We examined the association between diet quality indexes and pre- and postmenopausal breast cancer risk in a large prospective cohort. Methods: This was a prospective analysis of 96,959 women, aged 22-104 y, in the California Teachers Study cohort (1995-2011). Diet quality was characterized by 4 different indexes. Specifically, we examined Alternate Mediterranean Diet (aMED), Alternative Healthy Eating Index-2010 (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH), and Paleolithic index (PALEO) scores with the risk of developing breast cancer. We used multivariable Cox proportional hazards regression models to derive HRs and 95% CIs for breast cancer risk. Results: In the analysis of 42,517 women at risk of premenopausal breast cancer, there was no association between any of the indexes and incident breast cancer (346 cases). In the analysis of 54,442 women at risk of postmenopausal breast cancer at baseline, higher AHEI-2010, aMED, and DASH scores were inversely associated with incident breast cancer (3523 incident cases). Respectively, HRs (95% CIs) comparing quintile 5 to quintile 1 (reference) for AHEI-2010, aMED, and DASH indexes were 0.87 (0.78, 0.97; P-trend = 0.004), 0.91 (0.82, 1.02; P-trend = 0.03), and 0.89 (0.80, 1.00; P-trend = 0.03). The PALEO score was not associated with postmenopausal breast cancer (HR for quintile 5 compared with quintile 1: 1.05; 95% CI: 0.94, 1.17). Conclusions: Diet quality indexes that emphasize intake of whole grains, vegetables, fruits, legumes, and nuts and seeds and de-emphasize red and processed meats and sugar-sweetened beverages were modestly associated with a lower risk of incident postmenopausal breast cancer risk. However, they were not associated with premenopausal breast cancer, and the PALEO score was not associated with cancer risk regardless of menopausal status. PMID- 30247578 TI - Decrease in semen quality and Leydig cell function in infertile men: a longitudinal study. AB - STUDY QUESTION: Are infertile men with reduced semen quality at risk of a further decrease in testicular function? SUMMARY ANSWER: Infertile men with severely reduced semen quality risk further deterioration of semen quality 15 years after treatment for infertility, and a lower baseline sperm concentration was associated with a more pronounced increase in LH and decrease in testosterone/LH ratio at follow-up. WHAT IS KNOWN ALREADY: Male factors account for up to 50% of human infertility. The most common finding is spermatogenic failure (SgF) yet the life course of semen quality and testosterone production in such men has not been described. STUDY DESIGN, SIZE, DURATION: A follow-up study of men with SgF was performed 15 years after the initial infertility assessment between January 1995 and December 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Hospital records were used to identify potential participants in the study. A total of 137 men with primary male infertility due to SgF and 70 controls with good semen quality from couples with female factor infertility who attended a tertiary referral centre were included: the participation rate was 31% and 26%, respectively. The men provided semen samples and underwent a physical examination. Blood samples were taken to measure levels of reproductive hormones (FSH, LH, testosterone, sex hormone-binding globulin, estradiol and inhibin B). Current results were compared with results from the initial assessments. MAIN RESULTS AND THE ROLE OF CHANCE: At the time of follow up the SgF men had significantly lower Leydig cell capacity than the control group as well as much lower semen quality. For the SgF men, between baseline sampling and follow up, the median sperm concentration decreased from 1.9 to 0.6 mill/ml and total sperm count from 7.7 to 2.0 million (P = 0.019 and 0.012, respectively), and 10% developed azoospermia. Calculated free testosterone (cFT), but not total testosterone (tT) decreased in the SgF group by ~0.6% (95% CI 0.1-1.2%) per year. In the SgF group, LH increased by 1.6% (CI 0.9 2.3%) annually, and consequently tT/LH and cFT/LH ratios had decreased by 1.3% (CI 0.5-2.1) and 2.1% (CI 1.2-3.0%), respectively. The increase in LH and the decreases in tT/LH and cFT/LH ratios were more pronounced in men with lower baseline sperm concentrations. LIMITATIONS, REASONS FOR CAUTION: We consider the case group as representative of infertile men not in need of testosterone treatment at baseline investigation, but do not have information on those that chose not to participate in the follow-up study. There were alterations in some hormone analysis methods during the follow-up period that may introduce uncertainty in interpretation of long-term changes in hormone levels despite rigorous quality control. The validity of the control group suffers from a lack of hormone values at baseline. Also, at follow-up, for practical reasons only one semen sample could be obtained, which makes the effect estimate more uncertain and there is a risk of non-differential misclassification. WIDER IMPLICATIONS OF THE FINDINGS: Without being able to predict individual outcomes, it is prudent to consider sperm cryopreservation or advise not to postpone fertility treatment when men present with infertility due to impaired semen quality. Whether partly compensated Leydig cell insufficiency in men with SgF will eventually develop into overt testosterone deficiency cannot be determined from our study. STUDY FUNDING/COMPETING INTEREST(s): Aase and Einar Danielsen (Grant no. 10-001053), Nordic Research Committee (Grant no. 5109), The Kirsten and Freddie Johansen Fund, and Rigshospitalet's Research Fund (grant no. R24-A812). There are no competing interests. PMID- 30247580 TI - Analytical Performance of 10 High-Volume Clinical Chemistry Assays on the Alinity c System. AB - Background: Early access for routine testing with the Alinity c clinical chemistry system (Abbot Laboratories) presented the opportunity to characterize the analytical performance of multiple analytes across clinical laboratories in Europe. Methods: A total of 8 laboratories from 7 European countries evaluated 10 high-volume chemistry assays on the Alinity c system for imprecision, linearity, and accuracy by method comparison to the routine ARCHITECT (Abbott Laboratories) method. Results: Within-run precision was less than 4% coefficient of variation (CV), with total imprecision less than 5.6% CV for 5- and 20-day evaluations. Linearity met expectations, and method comparison showed strong correlation between the Alinity and ARCHITECT methods, with overall linear correlation coefficient between 0.980 to 1.000 and slopes of the regression line between 0.963 and 1.034. Mean percentage difference between the results of assays run on the ARCHITECT and the Alinity ranged between -1.7% and 2.15%. Conclusions: Our results demonstrated acceptable key analytical performance across all assays tested at each participating laboratory. PMID- 30247579 TI - Effect of fluconazole prophylaxis on Candida fluconazole susceptibility in premature infants. AB - Objectives: Extremely premature infants are at high risk of developing invasive candidiasis; fluconazole prophylaxis is safe and effective for reducing invasive candidiasis in this population but further study is needed. We sought to better understand the effect of prophylactic fluconazole on a selection of fluconazole resistant Candida species. Methods: We evaluated the susceptibility to fluconazole of Candida isolates from premature infants (<750 g birth weight) enrolled in a multicentre, randomized, placebo-controlled trial of fluconazole prophylaxis. Candida species were isolated through surveillance cultures at baseline (study day 0-7), period 1 (study day 8-28) and period 2 (study day 29 49). Fluconazole MICs were determined for all Candida isolates. Results: Three hundred and sixty-one infants received fluconazole (n = 188) or placebo (n = 173). After the baseline period, Candida colonization was significantly lower in the fluconazole group compared with placebo during periods 1 (5% versus 27%; P < 0.001) and 2 (3% versus 27%; P < 0.001). After the baseline period, two infants (1%) were colonized with at least one fluconazole-resistant Candida in each group. Median fluconazole MIC was similar in both treatment groups at baseline and period 1. However, in period 2, median MIC was higher in the fluconazole group compared with placebo (1.00 versus 0.50 mg/L, P = 0.01). There was no emergence of resistance observed and no patients developed invasive candidiasis with a resistant Candida isolate. Conclusions: Fluconazole prophylaxis decreased Candida albicans and 'non-albicans' Candida colonization and was associated with a slightly higher fluconazole MIC for colonizing Candida isolates. PMID- 30247581 TI - Feeding Infants and Toddlers Study (FITS) 2016: Findings and Thoughts on the Third Data Cycle. PMID- 30247582 TI - The Feeding Infants and Toddlers Study (FITS) 2016: Moving Forward. PMID- 30247585 TI - Safe Gluteal Fat Graft Avoiding a Vascular or Nervous Injury: An Anatomical Study in Cadavers. AB - Background: Fat grafting for gluteal augmentation (GA) is one of the most popular aesthetic surgery procedures. It has an associated mortality to fat embolism of 0.2%. Objectives: This study described which technique for synthetic graft application was least likely to cause a fat embolism. Methods: Ten fresh bodies were obtained and four groups arranged with five buttocks each randomly assigned. Group 1 was infiltrated through the upper medial intergluteal sulcus (upper medial intergluteal sulcus) with an angulation of -30o, -10o, and 0o. Group 2 was infiltrated through the middle lower gluteal sulcus (MLGS) with an angulation of 30o, 0o, and +15o. Group 3 was infiltrated through a peritrochanteric (PT) access at the level of the femur head at 0o, and +10o, and in the middle of the buttock (MB) at the level of the iliac crest at -30o directed to the trochanter (lateral direction). Group 4 was infiltrated in the same manner as Group 1 without -30o. A complication occurred when the graft was in contact with the vascular or nervous bundle, within the gluteus medius muscle, or both. Results: Group 1 had three buttocks with a complication (UMIGS -30o). Group 2 had complications in all of the injection techniques. Group 3 had five buttocks with a complication (PT at 0o). Group 4 had no complications. Conclusion: The injection of the fat graft through the UMIGS at 0o and -10o angles, and through the MB at a -30o angle, reaches the surface needed for GA. The Group 2 techniques should be avoided because of they have a high risk of a complication. PMID- 30247584 TI - WIC and non-WIC Infants and Children Differ in Usage of Some WIC-Provided Foods. AB - Background: USDA's Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) provides expert-chosen supplemental foods to improve the diets and health of low-income infants and children <5 y of age, but dietary behaviors of WIC participants are not well characterized. Objective: The purpose of this analysis was to examine differences in food consumption patterns between WIC participants and nonparticipants. Methods: FITS 2016 is a nationwide cross sectional study of children <4 y (n = 3235). Data were weighted to provide US population-representative results. Children were categorized as WIC participants or nonparticipants, with the latter divided into lower- and higher-income nonparticipants. Group differences were assessed via the Wald test (demographics) and Rao-Scott modified chi-square test (breastfeeding prevalence). Differences in percentage consuming WIC-provided and selected other foods between WIC participants and nonparticipants were evaluated with the use of ORs and 95% CIs. Results: WIC infants were less likely to breastfeed than were higher-income nonparticipants at 0-5.9 mo (45% compared with 74%) and less likely than both nonparticipant groups at 6-11.9 mo (30% compared with 49-60%). WIC 6- to 11.9-mo olds were more likely to consume infant cereals and vegetables than were lower income nonparticipants. WIC 12 to 23.9-mo-olds were more likely to drink whole milk (which WIC provides at this age) than were nonparticipants (72% compared with 59-64%), whereas WIC participants 24-47.9 mo were more likely to drink low- and nonfat milks (which WIC provides at this age) than were nonparticipants (45% compared with 13-22%). WIC participants 6-47.9 mo were more likely to drink juice than were nonparticipants. Conclusions: Continued improvements in early dietary patterns are warranted for WIC and non-WIC children. Breastfeeding among WIC participants is a continuing challenge. Findings suggest that baby-food cereals, vegetables, and fruits (all provided by WIC) contribute importantly to WIC infants' diets, whereas WIC children are more likely to use lower-fat milks after 2 y of age than are non-WIC participants. PMID- 30247583 TI - Food Consumption Patterns of Infants and Toddlers: Findings from the Feeding Infants and Toddlers Study (FITS) 2016. AB - Background: The prevalence of obesity and type 2 diabetes continues to increase. These conditions disproportionately affect minorities and are associated with poor nutrition early in life. Current food-consumption patterns can inform pending dietary guidelines for infants and toddlers. Objective: The aim of this study was to describe infant feeding, complementary feeding, and food and beverage consumption patterns of 0- to 23.9-mo-olds in the general population. Methods: The Feeding Infants and Toddlers Study 2016 is a cross-sectional survey of caregivers of children aged <4 y. Dietary data were collected from a national random sample by using a 24-h dietary recall (n = 3235). The percentage of children consuming foods from >400 food groups was calculated. Differences in the percentage consuming between Hispanic, non-Hispanic white, and non-Hispanic black children aged 0-23.9 mo were evaluated with the use of ORs and 95% CIs. Results: Eighty-three percent of 0- to 23.9-mo-olds (n = 2635) were ever breastfed, 34% of 0- to 3.9-mo-olds (n = 305) and 15% of 4- to 5.9-mo-olds (n = 295) were exclusively breastfed, and 24% of 12- to 14.9-mo-olds (n = 412) consumed breast milk on the day of the recall. Complementary foods were more likely to be introduced before 4 mo in formula-fed infants (27%) than in infants who did not consume formula (5%). Half of 4- to 5.9-mo-olds consumed iron-fortified infant cereal, but few consumed iron-rich meats. Among toddlers (12-23.9 mo; n = 1133), >20% consumed no servings of fruit or vegetables on the day of the recall, approximately half consumed 100% fruit juice, and one-quarter to one-third consumed a sugar-sweetened beverage (SSB). Conclusions: Breastfeeding initiation and duration have improved, but exclusivity remains low. Low consumption of iron rich foods, fruit, and vegetables and lack of variety in vegetable consumption are problems. Efforts to reduce the consumption of SSBs and 100% fruit juice are warranted in early childhood. PMID- 30247587 TI - Characterization of a clinical Clostridioides difficile isolate with markedly reduced fidaxomicin susceptibility and a V1143D mutation in rpoB. AB - Objectives: The identification and characterization of clinical Clostridioidesdifficile isolates with reduced fidaxomicin susceptibility. Methods: Agar dilution assays were used to determine fidaxomicin MICs. Genome sequence data were obtained by single-molecule real-time (SMRT) sequencing in addition to amplicon sequencing of rpoB and rpoC alleles. Allelic exchange was used to introduce the identified mutation into C. difficile 630Deltaerm. Replication rates, toxin A/B production and spore formation were determined from the strain with reduced fidaxomicin susceptibility. Results: Out of 50 clinical C. difficile isolates, isolate Goe-91 revealed markedly reduced fidaxomicin susceptibility (MIC >64 mg/L). A V1143D mutation was identified in rpoB of Goe 91. When introduced into C. difficile 630Deltaerm, this mutation decreased fidaxomicin susceptibility (MIC >64 mg/L), but was also associated with a reduced replication rate, low toxin A/B production and markedly reduced spore formation. In contrast, Goe-91, although also reduced in toxin production, showed normal growth rates and only moderately reduced spore formation capacities. This indicates that the rpoBV1143D allele-associated fitness defect is less pronounced in the clinical isolate. Conclusions: To the best of our knowledge, this is the first description of a pathogenic clinical C. difficile isolate with markedly reduced fidaxomicin susceptibility. The lower-than-expected fitness burden of the resistance-mediating rpoBV1143D allele might be an indication for compensatory mechanisms that take place during in vivo selection of mutants. PMID- 30247589 TI - Erratum. PMID- 30247588 TI - A disease burden analysis of garment factory workers in Bangladesh: proposal for annual health screening. AB - Background: To characterize the health status of selected garment and textile factory workers in Bangladesh using a workplace mobile health clinic. Methods: A retrospective review of de-identified worker health information was performed using 1906 medical records. Results: The mean age of the workers was 27.9+/-7.3 y, with 60.3% (1150/1906) female and 39.7% (756/1906) male workers. The most common medical conditions identified were anemia (19.0%; 362/1906), elevated BP (EBP) (11.9%; 226/1906) and elevated fasting blood glucose (FBG) (8.0%; 151/1906). Among the workers who had EBP, 86.3% (195/226) were previously undiagnosed, while out of the workers with elevated FBG, 72.8% (110/151) were newly diagnosed. Men were more likely than women to have EBP (OR 3.5, 95% CI [2.12-5.56], p<0.001), a family history of diabetes (OR 3.6, 95% CI [2.1-5.9], p<0.001) and no formal education (OR 4.9, 95% CI [3.6-6.7], p<0.001). Conclusions: Despite the relatively young mean age, significant percentages of workers were identified as having undiagnosed chronic health conditions, including EBP and elevated FBG, that require urgent medical attention and health education. The findings suggest that provision for annual health screening, either by mobile on-site clinics or by training the existing in-house paramedics, will help improve health of the factory workers. PMID- 30247586 TI - Impact of Above-Average Proanabolic Nutrients Is Overridden by High Protein and Energy Intake in the Muscle-Tendon Unit Characteristics of Middle- to Older-Aged Adults. AB - Background: The impact, within a single cohort, of independent modulators of skeletal muscle quality, including age, adiposity and obesity, habitual nutritional intake, and physical activity (PA), is unclear. Objective: We examined the bivariate associations between age, adiposity, habitual nutritional intake, and PA against 11 key intrinsic muscle-tendon unit (MTU) characteristics to identify the strongest predictors. We also compared overall profile differences between MTU categories with the use of z scores shown in radar graphs. Methods: Fifty untrained independently living men (n = 15) and women (n = 35) aged 43-80 y (mean +/- SD: 64 +/-9 y) were categorized by adiposity [men: normal adiposity (NA) <28%, high adiposity (HA) >=28%; women: NA <40%, HA >=40%] and body mass index [BMI (in kg/m2); normal: 18 to <25; overweight: >=25 to <30; and obese: >=30]. Group differences were examined by body composition assessed with the use of dual-energy X-ray absorptiometry, habitual nutritional intake through a 3-d food diary, PA (work, leisure, sport) using the Baecke questionnaire, 14 serum cytokine concentrations using multiplex luminometry, and 11 MTU characteristics of the gastrocnemius medialis using a combination of isokinetic dynamometry, electromyography, and ultrasonography. Results: Interestingly, classification by BMI highlighted differences between normal and obese individuals in 6 of 11 MTU characteristics (P < 0.001 to P = 0.043). No significant differences were reported in serum cytokine concentrations between adiposity and BMI classifications. BMI predicted 8 of 11 (r = 0.62-0.31, P < 0.001 to P = 0.032), daily energy intake predicted 7 of 11 (r = 0.45-0.34, P = 0.002-0.036), age predicted 5 of 11 (r = -0.49-0.32, P < 0.001 to P = 0.032), work-based PA predicted 5 of 11 (r = 0.43-0.32, P = 0.003-0.048), and adiposity predicted 4 of 11 (r = 0.51-0.33, P < 0.001 to P = 0.022) MTU characteristics. Mathematical z scores and radar graphs showed how endocrine and dietary profiles, but not PA, differed between the top and bottom ~20% of muscle unit size and specific force. Conclusions: Given the number of factors associated with MTU, education should be targeted to both adequate food quantity and quality (especially protein intake) and increasing habitual moderate to vigorous PA while decreasing sedentary behavior. Specific endocrine variables are also proposed as key pharmaceutical targets. PMID- 30247590 TI - Combining bottleneck analysis and quality improvement as a novel methodology to improve the quality of neonatal care in a northeastern state of India: a feasibility study. AB - Background: The State of Meghalaya, India, has some of the worst newborn health outcomes in the country. State health authorities commissioned an assessment of newborn service delivery to improve services. This study proposes bottleneck analysis (BNA) and quality improvement (QI) methods as a combined method to improve compliance with evidence-based neonatal interventions in newborn health facilities. Methods: An adapted Every Newborn BNA tool was applied to collect data on barriers to providing quality care in five district hospitals. Subsequently, health workers were coached to use QI methodology to overcome identified bottlenecks. Data from QI projects were analysed using run charts. Results: BNA revealed that interventions directed toward basic newborn care and special newborn care facilities needed attention. Facilities that undertook QI projects showed an improvement in neonates having early initiation of breastfeeding within the first hour of birth, from 64% to a peak of 94% in one facility and from 75% to 91% in another. Skin-to-skin contact increased from 49% to a peak of 78% and is sustained at 58%. Improved performance has been sustained in some facilities. Conclusions: The combination of BNA and QI is a successful method for identifying and overcoming bottlenecks in newborn care in resource limited settings. PMID- 30247591 TI - Molecular Genetic Insights Into Varicella Zoster Virus (VZV), the vOka Vaccine Strain, and the Pathogenesis of Latency and Reactivation. AB - Genetic tools for molecular typing of varicella zoster virus (VZV) have been used to understand the spread of virus, to differentiate wild-type and vaccine strains, and to understand the natural history of VZV infection in its cognate host. Molecular genetics has identified 7 clades of VZV (1-6 and 9), with 2 more mooted. Differences between the vOka vaccine strain and wild-type VZVs have been used to distinguish the cause of postimmunization events and to provide insight into the natural history of VZV infections. Importantly molecular genetics has shown that reinfection with establishment of latency by the reinfecting strain is common, that dual infections with different viruses can occur, and that reactivation of the superinfecting genotype can both occur. Whole-genome sequencing of the vOka vaccine has been used to show that vesicles form from a single virion, that latency is established within a few days of inoculation, and that all vaccine strains are capable of establishing latency and reactivating. Novel molecular tools have characterized the transcripts expressed during latent infection in vitro. PMID- 30247592 TI - Herpes Zoster Vaccines. AB - Background: Immunization for herpes zoster (HZ) aims to reverse the decline in cell-mediated immunity to varicella zoster virus that occurs with advancing age or immunocompromise. There are 2 vaccines available, one live attenuated (Zoster vaccine, live attenuated [ZVL]) and, recently, a recombinant subunit vaccine (HZ/su). Methods: The literature relevant to the two HZ vaccines was reviewed. Results: ZVL has overall efficacies of 51% and 65% against HZ and postherpetic neuralgia, respectively, with a prominent decline in efficacy with advancing age of the vaccinee. This compares to approximately 90% efficacy against HZ for HZ/su that is minimally affected with advancing age. The efficacy of ZVL against HZ declines over 4 and 8 years, compared with minimal decline so far over 4 years with HZ/su, and immunogenicity that is maintained for 9 years. Local and systemic reactogenicity to HZ/su is much greater than to ZVL. Conclusions: HZ/su establishes an important principle-that a single recombinant viral protein with an effective adjuvant combination can stimulate immunogenicity superior to that of a live attenuated vaccine, and that this can diminish immunosenescence. This provides hope for improvement of other vaccines for aging patients. However, key questions remain unanswered, including the durability of the efficacy of HZ/su, its efficacy as a booster for previous recipients of ZVL, and its efficacy in immunocompromised patients. PMID- 30247593 TI - Herpes Zoster: Epidemiological Links With Stroke and Myocardial Infarction. AB - Routine data from electronic health records (EHRs) provide insights into links between herpes zoster (HZ) and cardiovascular complications such as stroke or myocardial infarction (MI) in different populations worldwide. Evidence from large EHR studies using both self-controlled case series and traditional cohort designs suggests that there is a transient increase in the risk of stroke after HZ, which gradually resolves over 6-12 months. In these studies, herpes zoster ophthalmicus was associated with a higher risk of stroke than HZ at other sites. A larger effect size was seen in people aged under 40 years. Existing studies also suggest that HZ may have a triggering effect on MI, although fewer studies examined this outcome. Further evidence is needed on the effectiveness and cost effectiveness of vaccine and antiviral drugs to reduce cardiovascular complications after HZ from studies that are designed to minimize selection biases and confounding by indication. PMID- 30247594 TI - Advances and Controversies in Our Understanding of Herpes Zoster-Introduction. PMID- 30247595 TI - Use of Real-world Evidence to Evaluate the Effectiveness of Herpes Zoster Vaccine. AB - This article reviews the use of real-world evidence (RWE) from observational studies to evaluate herpes zoster vaccine effectiveness and complement clinical trial data that have known limitations. The use of RWE with appropriate study designs and cautious interpretation can be informative in decision-making. Understanding the advantages and limitations of studies yielding RWE can facilitate the critical evaluation of findings from different studies. This is a timely issue, as regulatory agencies are considering how RWE can contribute to the assessment of effectiveness in regulatory decision-making. PMID- 30247596 TI - Comparative Immune Responses to Licensed Herpes Zoster Vaccines. AB - Background: Live attenuated (ZV) and recombinant adjuvanted (HZ/su) zoster vaccines differ with respect to efficacy, effect of age, and persistence of protection. We compared cell-mediated immunity (CMI responses to ZV and HZ/su. Methods: This was a randomized, double-blind, placebo-controlled trial stratified by age (50-59 and 70-85 years) and by HZ vaccination status (received ZV >=5 years before entry or not). Varicella zoster virus (VZV)- and glycoprotein E (gE) specific CMI were analyzed by interleukin 2 (IL-2) and interferon gamma (IFN gamma) FluoroSpot and flow cytometry at study days 0, 30, 90, and 365. Results: Responses to ZV peaked on day 30 and to HZ/su (administered in 2 doses separated by 60 days) peaked on day 90. Age and vaccination status did not affect peak responses, but higher baseline CMI correlated with higher peak responses. HZ/su generated significantly higher VZV-specific IL-2+ and gE-specific IL-2+, IFN gamma+, and IL-2+/IFN-gamma+ peak and 1-year baseline-adjusted responses compared with ZV. VZV-specific IFN-gamma+ and IL-2+/IFN-gamma+ did not differ between vaccines. HZ/su generated higher memory and effector-memory CD4+ peak responses and ZV generated higher effector CD4+ responses . Conclusions: The higher IL-2 and other memory responses generated by HZ/su compared with ZV may contribute to its superior efficacy. Clinical Trials Registration: NCT02114333. PMID- 30247597 TI - Up-date on Clinical Management of Postherpetic Neuralgia and Mechanism-Based Treatment: New Options in Therapy. AB - Patients with postherpetic neuralgia may experience various sensory signs and symptoms of pain. Despite this, the recommendations for medicinal treatment do not differ accordingly. In order to find the appropriate treatment options for postherpetic neuralgia, several attempts have been made in the past. The crucial obstacle to these attempts was insufficient or no subgrouping of patients according to their sensory phenotype, mostly resulting in an unsatisfactory treatment response. Recently, a new concept of retrospective stratification according to the patients' sensory phenotype has been made in a large cohort of pain patients. This new stratification tool allows a predictive validity for treatment response in subgroups of patients and might be of potential value in determining the optimal treatment in postherpetic neuralgia patients. PMID- 30247598 TI - Immunobiology of Varicella-Zoster Virus Infection. AB - Varicella-zoster virus (VZV) causes clinically significant illness during acute and recurrent infection accompanied by robust innate and acquired immune responses. Innate immune cells in skin and ganglion secrete type I interferon (IFN-I) and proinflammatory cytokines to control VZV. Varicella-zoster virus subverts pattern recognition receptor sensing to modulate antigen presentation and IFN-I production. During primary infection, VZV hijacks T cells to disseminate to the skin and establishes latency in ganglia. Durable T- and B-cell memory formed within a few weeks of infection is boosted by reactivation or re exposure. Antigen-specific T cells are recruited and potentially retained in VZV infected skin to counteract reactivation. In latently VZV-infected ganglia, however, virus-specific T cells have not been recovered, suggesting that local innate immune responses control VZV latency. Antibodies prevent primary VZV infection, whereas T cells are fundamental to resolving disease, limiting severity, and preventing reactivation. In this study, we review current knowledge on the interactions between VZV and the human immune system. PMID- 30247599 TI - Varicella-Zoster Virus and the Enteric Nervous System. AB - Varicella zoster virus (VZV) infects and becomes latent in sensory, enteric, and other autonomic neurons during the viremia of varicella. Reactivation of VZV in neurons that project to the skin causes the rash of zoster; however, reactivation of VZV in enteric neurons can cause a painful gastrointestinal disorder ("enteric zoster") without cutaneous manifestations. Detection of VZV DNA in saliva of patients with gastrointestinal symptoms may suggest enteric zoster. This diagnosis is reinforced by observing a response to antiviral therapy and can be confirmed by detecting VZV gene products in intestinal mucosal biopsies. We developed an in vivo guinea pig model that may be useful in studies of VZV latency and reactivation. VZV-infected lymphocytes are used to induce latent infection in sensory and enteric neurons; evidence suggests that exosomes and stimulator of interferon genes (STING) may, by preventing proliferation play roles in the establishment of neuronal latency. PMID- 30247601 TI - Statistical Learning Methods to Determine Immune Correlates of Herpes Zoster in Vaccine Efficacy Trials. AB - Using Super Learner, a machine learning statistical method, we assessed varicella zoster virus-specific glycoprotein-based enzyme-linked immunosorbent assay (gpELISA) antibody titer as an individual-level signature of herpes zoster (HZ) risk in the Zostavax Efficacy and Safety Trial. Gender and pre- and postvaccination gpELISA titers had moderate ability to predict whether a 50-59 year old experienced HZ over 1-2 years of follow-up, with equal classification accuracy (cross-validated area under the receiver operator curve = 0.65) for vaccine and placebo recipients. Previous analyses suggested that fold-rise gpELISA titer is a statistical correlate of protection and supported the hypothesis that it is not a mechanistic correlate of protection. Our results also support this hypothesis. PMID- 30247600 TI - Varicella Zoster Virus Vasculopathy. AB - Varicella zoster virus (VZV) is a ubiquitous, exclusively human alphaherpesvirus that produces varicella then becomes latent in ganglionic neurons. In elderly and immunocompromised individuals, VZV reactivates and typically produces herpes zoster. Studies of patients with VZV vasculopathy have identified key clinical, imaging, and laboratory features to assist in diagnosis and treatment. Complementary studies have further expanded the spectrum of VZV vasculopathy to include the extracranial circulation and identified mechanisms contributing to its pathogenesis. Given our increasing aging population and recognition that VZV reactivation manifesting as zoster is a risk factor for stroke and myocardial infarction, recognition of VZV as a potential cause of vascular disease with or without associated zoster rash is essential to decrease associated morbidity and mortality because VZV vasculopathy can be treated with antiviral therapy. PMID- 30247602 TI - Point-Counterpoint: The Hope-Simpson Hypothesis and Its Implications Regarding an Effect of Routine Varicella Vaccination on Herpes Zoster Incidence. AB - Some 50 years ago, Edgar Hope-Simpson published his hypothesis regarding the interactions between varicella and herpes zoster. As part of this hypothesis, Hope-Simpson postulated that reactivation of varicella zoster virus (VZV) was under immunological control, and that this immunological control could be boosted "endogenously" due to reactivation of latent VZV, and "exogenously" due to exposure to varicella. This hypothesis has important policy implications and remains a source of debate today; namely, does reducing VZV circulation through effective pediatric varicella vaccination programs lead to unintended increases in herpes zoster (HZ) incidence? This article provides 2 very different perspectives on this issue. The first perspective (Rafael Harpaz: Evidence Against an Effect) highlights the empiric experience of the United States, with its population of >300 million, a highly effective national varicella vaccination program lasting >20 years, and with several credible sources of data regarding HZ incidence. The US data have shown an increase in HZ incidence that preceded the availability of varicella vaccination by decades; indeed, HZ rates appear to have plateaued among older adults since varicella vaccination was introduced. Furthermore, HZ rates are not different in states having higher vs lower preschool varicella vaccination rates. The second perspective (Albert J. van Hoek: Evidence for an Effect) cites data that persons with close exposure to children appear to be at lower risk of HZ before universal VZV vaccination, but not so thereafter. Due to historic demographic changes, exogenous boosting could play a role in explaining the observed increase in HZ before varicella vaccination. Thus, it might be difficult to separate declines in exogenous boosting due to demographic changes from those caused by the varicella vaccination program. Additional data will be needed to conclusively rule out an impact of varicella vaccination on HZ. PMID- 30247604 TI - Computed tomography-guided cyanoacrylate localization of small pulmonary nodules: feasibility and initial experience. AB - OBJECTIVES: We report our initial technical experience with computed tomography (CT)-guided cyanoacrylate localization for resection of small pulmonary nodules (SPNs) and evaluate the feasibility of this technique. METHODS: Between June 2016 and December 2017, the diagnostic results of 55 consecutive patients (69 SPNs) who underwent preoperative CT-guided cyanoacrylate localization and consequent video-assisted thoracoscopic surgery (VATS) resection were retrospectively evaluated. Localization-related outcomes and perioperative outcomes were assessed. RESULTS: Preoperative CT-guided cyanoacrylate localization was successfully performed in all the cases. Simultaneous localization was achieved in 8 (14.5%) patients with 2 nodules and 3 (5.5%) patients with 3 nodules. The mean size of the nodules was 8.5 +/- 3.2 mm (range 5-20 mm), and their mean depth from the nearest pleural surface was 10.9 +/- 7.7 mm (range 2-36 mm). The overall mean localization procedural time was 13.7 +/- 7.2 min (range 6-37 min). Two localization-related complications (intrapulmonary focal haemorrhage and pneumothorax) were observed in 7 (12.7%) and 12 (21.8%) patients, respectively. All patients with complications were asymptomatic and received conservative treatment only. All SPNs were resected under VATS without any conversion to minithoracotomy or thoracotomy. CONCLUSIONS: CT-guided cyanoacrylate localization is a feasible procedure to localize SPNs. The advantages of this technique include flexibility between insertion and excision, the ability to be applied to the whole lung field, a high success rate, patient comfort after insertion and a fast learning curve. Further studies are warranted to confirm the efficacy of this technique. PMID- 30247603 TI - Impact of Zostavax Vaccination on T-Cell Accumulation and Cutaneous Gene Expression in the Skin of Older Humans After Varicella Zoster Virus Antigen Specific Challenge. AB - Background: The live attenuated vaccine Zostavax was developed to prevent varicella zoster virus (VZV) reactivation that causes herpes zoster (shingles) in older humans. However, the impact of vaccination on the cutaneous response to VZV is not known. Methods: We investigated the response to intradermal VZV antigen challenge before and after Zostavax vaccination in participants >70 years of age by immunohistological and transcriptomic analyses of skin biopsy specimens collected from the challenge site. Results: Vaccination increased the proportion of VZV-specific CD4+ T cells in the blood and promoted the accumulation of both CD4+ and CD8+ T cells in the skin after VZV antigen challenge. However, Zostavax did not alter the proportion of resident memory T cells (CD4+ and CD8+) or CD4+Foxp3+ regulatory T cells in unchallenged skin. After vaccination, there was increased cutaneous T-cell proliferation at the challenge site and also increased recruitment of T cells from the blood, as indicated by an elevated T-cell migratory gene signature. CD8+ T-cell-associated functional genes were also highly induced in the skin after vaccination. Conclusion: Zostavax vaccination does not alter the abundance of cutaneous resident memory T cells but instead increases the recruitment of VZV-specific T cells from the blood and enhances T cell activation, particularly cells of the CD8+ subset, in the skin after VZV antigen challenge. PMID- 30247605 TI - The HMGA2-IMP2 Pathway Promotes Granulosa Cell Proliferation in Polycystic Ovary Syndrome. AB - Context: The high mobility group AT hook 2 (HMGA2) gene was previously identified in a genome-wide association study (GWAS) as a candidate risk gene that might be related to polycystic ovary syndrome (PCOS). Whether HMGA2 contributes to promoting granulosa cell (GC) proliferation in PCOS remains unknown. Objective: We sought to determine whether HMGA2 is involved in the ovarian dysfunction of PCOS and in the mechanism of increased GC proliferation. Patients and Cells: mRNA expression was analyzed in ovarian GCs from 96 women with PCOS and 58 healthy controls. Immortalized human GCs (KGN and SVOG cells) were used for the mechanism study. Main Outcome Measures: mRNA expression in ovarian GCs was measured using qRT-PCR, and KGN cells were cultured for proliferation assays after overexpression or knockdown of target genes. Protein expression analysis, luciferase assays, and RNA binding protein immunoprecipitation assays were used to confirm the mechanism study. Results: HMGA2 and IMP2 were highly expressed in the GCs of women with PCOS, and the HMGA2/IMP2 pathway promoted GC proliferation. CCND2 (Cyclin D2) and SERBP1 (SERPINE1 mRNA binding protein 1) were regulated by IMP2 and were highly expressed in women with PCOS. Conclusions: The HMGA2/IMP2 pathway was activated in women with PCOS and promoted the proliferation of GCs. This might provide new insights into the dysfunction of GCs in PCOS. PMID- 30247606 TI - Twenty years observation of health systems and policies: what has the European observatory meant for public health? PMID- 30247607 TI - Meeting the population health challenge: what should you know, and what should you be able to do? PMID- 30247608 TI - Regulation of H3K9me3 during preimplantation development. PMID- 30247609 TI - A genetic link between gender dysphoria and sex hormone signalling. AB - Context: There is a likely genetic component to gender dysphoria, but association study data have been equivocal. Objective: We explored the specific hypothesis that gender dysphoria in transwomen is associated with variants in sex hormone signalling genes responsible for undermasculinization and/or feminization. Design: Subject-control analysis included 380 transwomen and 344 control males. Associations and interactions were investigated between functional variants in 12 sex hormone signalling genes and gender dysphoria in transwomen. Setting: Patients were recruited from the Monash Gender Clinic, Monash Health, Melbourne, Australia and the University of California, Los Angeles. Patients: Caucasian transwomen, pre- and post-operative diagnosed with transsexualism (DSM-IV) or gender dysphoria (DSM-V) were recruited. Most were receiving hormone treatment at the time of recruitment. Main Outcome Measured: Genomic DNA was genotyped for repeat length polymorphisms or SNPs. Results: A significant association was identified between gender dysphoria and ERalpha, SRD5A2 and STS alleles, as well as ERalpha and SULT2A1 genotypes. Several allele combinations were also over represented in transwomen, most involving AR (AR-ERbeta, AR-PGR, AR-COMT, CYP17 SRD5A2). Over-represented alleles and genotypes are proposed to undermasculinize/feminise based on their reported effects in other disease contexts. Conclusions: Gender dysphoria may have an oligogenic component with several genes involved in sex hormone signalling contributing. PMID- 30247610 TI - Developing more participatory and accountable institutions for health: identifying health system research priorities for the Sustainable Development Goal-era. AB - Health policy and systems research (HPSR) is vital to guiding global institutions, funders, policymakers, activists and implementers in developing and enacting strategies to achieve the Sustainable Development Goals. We undertook a multi-stage participatory process to identify priority research questions relevant to improving accountability within health systems. We conducted interviews (n = 54) and focus group discussions (n = 2) with policymakers from international and national bodies (ministries of health, other government agencies and technical support institutions) across the WHO regions. Respondents were asked to reflect on challenges and current policy discussions related to health systems accountability, and to identify their pressing research needs. We also conducted an overview of reviews (n = 34) to determine the current status of knowledge on health systems accountability and to identify any gaps. We extracted research questions from the policymaker interviews and focus groups (70 questions) and from the overview of reviews (112 questions), and synthesized these into 36 overarching questions. Using the online platform Co-Digital, we invited researchers from around the world to refine and then rank the questions according to research importance. The questions that emerged amongst the top priorities focused on political factors that mediate the adoption or effectiveness of accountability initiatives, processes and incentives that facilitate the acceptability of accountability mechanisms among frontline healthcare providers, and the national governance reforms and contexts that enhance provider accountability. The process revealed different underlying conceptions of social accountability and how best to promote it, with some researchers and policymakers focusing on specific interventions and others embracing a more systems-oriented approach to understanding accountability, the multiple forms that it can take, how these interact with each other and the importance of power and underlying social relations. The findings from this exercise identify HPSR funding priorities and future areas for evidence production and policy engagement. PMID- 30247611 TI - Changes in Types of Dietary Fats Influence Long-term Weight Change in US Women and Men. AB - Background: The relation between dietary fat intake and body weight remains controversial. Few studies have examined long-term changes in types of dietary fat and weight change in longitudinal studies. Objective: The objective of this study was to examine associations between intake of different types of fat and long-term weight change in US women and men. Methods: The association between changes in consumption of varying types of fat and weight change was examined every 4 y through the use of multivariate models adjusted for age, baseline body mass index, and change in percentage energy from protein, intake of cereal fiber, fruits, and vegetables, alcohol use, and other lifestyle covariates in 3 prospective US cohorts, including 121,335 men and women free of diabetes, cardiovascular disease, cancer, or obesity over a 20- to 24-y follow-up. Dietary intakes and body weight were assessed via validated questionnaires. Cohort specific results were pooled with the use of a random-effect meta-analysis. Results: Compared with equivalent changes in carbohydrate intake, a 5% increase in energy from saturated fatty acid (SFA) and a 1% increase in energy from trans fat were associated with 0.61 kg (95% CI: 0.54, 0.68 kg) and 0.69 kg (95% CI: 0.56, 0.84 kg) greater weight gain per 4-y period, respectively. A 5% increase in energy from polyunsaturated fatty acid (PUFA) was associated with less weight gain (-0.55 kg; 95% CI: -0.81, -0.29 kg). Increased intake of monounsaturated fatty acid (MUFA) from animal sources by 1% was associated with weight gain of 0.29 kg (95% CI: 0.25, 0.33 kg), whereas MUFA from plant sources was not associated with weight gain. Conclusions: Different dietary fats have divergent associations with long-term weight change in US men and women. Replacing saturated and trans-fats with unsaturated fats, especially PUFAs, contributes to the prevention of age-related weight gain. These trials were registered at clinicaltrials.gov as NCT00005152 and NCT00005182. PMID- 30247612 TI - In cellulo phosphorylation of DNA double-strand break repair protein XRCC4 on Ser260 by DNA-PK. AB - XRCC4 is one of the core factors for DNA double-strand break (DSB) repair through non-homologous end joining (NHEJ). XRCC4 is phosphorylated by DNA-dependent protein kinase (DNA-PK), with Ser260 and Ser320 (Ser318 in the alternatively spliced form) being the major phosphorylation sites in vitro. It was recently reported that Ser320 is phosphorylated by DNA-PK in response to DNA damage; however, it is currently unclear whether Ser260 is phosphorylated in cellulo in response to DNA damage. Herein, we generated an antibody against XRCC4 phosphorylated on Ser260 and examined its phosphorylation status via Western blotting. XRCC4 Ser260 phosphorylation increased after irradiation with 30-300 Gy of gamma-rays and was suppressed by DNA-PK inhibitor but not by ATM inhibitor. Moreover, XRCC4 Ser260 phosphorylation decreased in DNA-PKcs-deficient cells. These observations indicate that XRCC4 Ser260 is phosphorylated by DNA-PK in cellulo. The XRCC4S260A mutant reversed the high radiosensitivity of XRCC4 deficient M10 cells to a similar level to that of wild-type XRCC4. However, the clonogenic survival of cells expressing the XRCC4S260A mutant was slightly but significantly lower than that of those expressing wild-type XRCC4. In addition, XRCC4S260A-expressing cells displayed a significantly greater number of gamma H2AX foci than XRCC4WT-expressing cells 4 h after 1 Gy irradiation and without irradiation. The present results suggest a potential role of XRCC4 Ser260 phosphorylation by DNA-PK in DSB repair. PMID- 30247613 TI - Exploring the genome and transcriptome of the cave nectar bat Eonycteris spelaea with PacBio long-read sequencing. AB - Background: In the past two decades, bats have emerged as an important model system to study host-pathogen interactions. More recently, it has been shown that bats may also serve as a new and excellent model to study aging, inflammation, and cancer, among other important biological processes. The cave nectar bat or lesser dawn bat (Eonycteris spelaea) is known to be a reservoir for several viruses and intracellular bacteria. It is widely distributed throughout the tropics and subtropics from India to Southeast Asia and pollinates several plant species, including the culturally and economically important durian in the region. Here, we report the whole-genome and transcriptome sequencing, followed by subsequent de novo assembly, of the E. spelaea genome solely using the Pacific Biosciences (PacBio) long-read sequencing platform. Findings: The newly assembled E. spelaea genome is 1.97 Gb in length and consists of 4,470 sequences with a contig N50 of 8.0 Mb. Identified repeat elements covered 34.65% of the genome, and 20,640 unique protein-coding genes with 39,526 transcripts were annotated. Conclusions: We demonstrated that the PacBio long-read sequencing platform alone is sufficient to generate a comprehensive de novo assembled genome and transcriptome of an important bat species. These results will provide useful insights and act as a resource to expand our understanding of bat evolution, ecology, physiology, immunology, viral infection, and transmission dynamics. PMID- 30247615 TI - Primary hyperparathyroidism in pregnancy: maternofetal outcomes at the Royal Brisbane and Women's Hospital 2000 to 2015. AB - Context: Primary hyperparathyroidism (PHPT) in pregnancy has historically been associated with significant maternofetal morbidity and mortality. The optimal treatment and timing of surgical intervention in pregnancy remains contested. Objective: To compare maternofetal outcomes of medically and surgically managed patients with PHPT in pregnancy. Design: Retrospective chart review. Setting: Quaternary referral hospital. Patients: Women with PHPT in pregnancy managed at the Royal Brisbane and Women's Hospital 1 January 2000 to 31 December 2015 inclusive. Interventions: Medical therapy or parathyroid surgery. Main Outcomes Measured: Timing of diagnosis; maternal corrected serum calcium concentrations; gestation, indication and mode of delivery; complications attributable to PHPT; birth weight and admission to the neonatal intensive care unit (NICU). Results: Twenty-two pregnancies were managed medically, whilst 6 patients underwent parathyroidectomy in pregnancy (5 in trimester 2, and 1 at 32 weeks gestation). Most patients managed medically either had a corrected serum calcium concentration less than 2.85 mmol/L in early pregnancy or were diagnosed in trimester 3. Of viable medically managed pregnancies, 30% were complicated by pre eclampsia, and pre-term delivery occurred in 50% of this group. All pre-term neonates required admission to NICU for complications related to prematurity. All surgically managed patients were delivered at term, and there were no complications of parathyroid surgery. Conclusions: Maternofetal outcomes have improved relative to that in early medical literature in medically and surgically managed patients, but the rate of pre-eclampsia and pre-term delivery was higher in medically managed patients. The study was limited by its retrospective design and small sample sizes. PMID- 30247614 TI - Engineering a responsive DNA triple helix into an octahedral DNA nanostructure for a reversible opening/closing switching mechanism: a computational and experimental integrated study. AB - We propose an experimental and simulative approach to study the effect of integrating a DNA functional device into a large-sized DNA nanostructure. We selected, as a test bed, a well-known and characterized pH-dependent clamp switch, based on a parallel DNA triple helix, to be integrated into a truncated octahedral scaffold. We designed, simulated and experimentally characterized two different functionalized DNA nanostructures, with and without the presence of a spacer between the scaffold and the functional elements. The experimental and simulative data agree in validating the need of a spacer for the occurrence of the pH dependent switching mechanism. The system is fully reversible and the switching can be monitored several times without any perturbation, maintaining the same properties of the isolated clamp switch in solution. PMID- 30247616 TI - A Mixed-Methods Investigation into the Acceptability, Usability and Perceived Effectiveness of Active and Passive Virtual Reality Scenarios in Managing Pain under Experimental Conditions. AB - Burns patients often suffer excruciating pain during clinical procedures, even with analgesia. Virtual Reality as an adjunct to pharmacological therapy has proved promising in the management of burn pain. More evidence is needed regarding specific forms of Virtual Reality. This mixed-method study examined the impact of active and passive Virtual Reality scenarios in experimental conditions, gathering data relating to user experience, acceptability and effectiveness in managing pain. Four scenarios were developed or selected following a consultative workshop with burns survivors and clinicians. Each was trialled using a cold pressor test with 15 University students. Data were gathered regarding pain threshold and tolerance at baseline and during each exposure. Short interviews were conducted afterwards. The two active scenarios were ranked highest and significantly extended participants pain threshold and tolerance times compared to passive and baseline conditions. Passive scenarios offered little distraction and relief from pain. Active scenarios were perceived to be engaging, challenging, distracting and immersive. They reduced subjective awareness of pain, though suggestions were made for further improvements. Results suggested that active Virtual Reality was acceptable and enjoyable as a means of helping to control experimental pain. Following suggested improvements, scenarios should now be tested in the clinical environment. PMID- 30247618 TI - New Developments in Psychological Wisdom Research: A Growing Field of Increasing Importance. PMID- 30247617 TI - Reply to Dale and Shulman. PMID- 30247619 TI - Cdk1 gates cell cycle-dependent tRNA synthesis by regulating RNA polymerase III activity. AB - tRNA genes are transcribed by RNA polymerase III (RNAPIII). During recent years it has become clear that RNAPIII activity is strictly regulated by the cell in response to environmental cues and the homeostatic status of the cell. However, the molecular mechanisms that control RNAPIII activity to regulate the amplitude of tDNA transcription in normally cycling cells are not well understood. Here, we show that tRNA levels fluctuate during the cell cycle and reveal an underlying molecular mechanism. The cyclin Clb5 recruits the cyclin dependent kinase Cdk1 to tRNA genes to boost tDNA transcription during late S phase. At tDNA genes, Cdk1 promotes the recruitment of TFIIIC, stimulates the interaction between TFIIIB and TFIIIC, and increases the dynamics of RNA polymerase III in vivo. Furthermore, we identified Bdp1 as a putative Cdk1 substrate in this process. Preventing Bdp1 phosphorylation prevented cell cycle-dependent recruitment of TFIIIC and abolished the cell cycle-dependent increase in tDNA transcription. Our findings demonstrate that under optimal growth conditions Cdk1 gates tRNA synthesis in S phase by regulating the RNAPIII machinery, revealing a direct link between the cell cycle and RNAPIII activity. PMID- 30247620 TI - The Comparative Toxicogenomics Database: update 2019. AB - The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is a premier public resource for literature-based, manually curated associations between chemicals, gene products, phenotypes, diseases, and environmental exposures. In this biennial update, we present our new chemical-phenotype module that codes chemical-induced effects on phenotypes, curated using controlled vocabularies for chemicals, phenotypes, taxa, and anatomical descriptors; this module provides unique opportunities to explore cellular and system-level phenotypes of the pre disease state and allows users to construct predictive adverse outcome pathways (linking chemical-gene molecular initiating events with phenotypic key events, diseases, and population-level health outcomes). We also report a 46% increase in CTD manually curated content, which when integrated with other datasets yields more than 38 million toxicogenomic relationships. We describe new querying and display features for our enhanced chemical-exposure science module, providing greater scope of content and utility. As well, we discuss an updated MEDIC disease vocabulary with over 1700 new terms and accession identifiers. To accommodate these increases in data content and functionality, CTD has upgraded its computational infrastructure. These updates continue to improve CTD and help inform new testable hypotheses about the etiology and mechanisms underlying environmentally influenced diseases. PMID- 30247621 TI - Misunderstood parameter of NCBI BLAST impacts the correctness of bioinformatics workflows. PMID- 30247622 TI - A new approach to assess myocardial work by non-invasive left ventricular pressure-strain relations in hypertension and dilated cardiomyopathy. AB - Aims: Non-invasive left ventricular (LV) pressure-strain loop (PSL) provides a novel method of quantifying myocardial work (MW) with potential advantages over conventional global longitudinal strain (GLS) by incorporating measurements of myocardial deformation and LV pressure. We investigated different patterns of LV PSL and global MW index (GWI) in patients with hypertension (HTN) and dilated cardiomyopathy (CMP). Methods and results: Seventy-four patients underwent transthoracic echocardiography and strain analysis before coronary angiography. Patients were divided into three groups: control, HTN, and CMP. GWI was calculated as the area of the LV PSL as a product of strain * systolic blood pressure. MW efficiency (GWE) is derived from the percentage ratio of constructive work (GCW) to sum of constructive work (GCW) and wasted work (GWW). Influences of HTN and LV function on its relationship with MW were evaluated. GLS and LV ejection fraction were preserved in the HTN group with no difference from controls. GWI was significantly higher in moderate to severe HTN patients (P = 0.004) as a compensatory mechanism to preserve LV contractility and function against an increase in afterload. GWE was preserved in HTN patients due to the proportional increase in GCW and GWW. GLS, GWI, and GWE were significantly reduced in CMP (P < 0.05), with a trend in rightward shift and reduction in the LV PSL. Conclusion: GWI is a potential new technique that allows better understanding of the relationship between LV remodelling and increased wall stress under different loading conditions. PMID- 30247623 TI - Seasonal Distribution and Movement of the Invasive Pest Delottococcus aberiae (Hemiptera: Pseudococcidae) Within Citrus Tree: Implications for Its Integrated Management. AB - Delottococcus aberiae (De Lotto) (Hemiptera: Pseudococcidae) is the most recent species of mealybug introduced to Spain that is affecting citrus. The feeding behavior of D. aberiae causes severe direct damage to citrus fruits, distorting their shape and/or causing reduction in size. There is no information available regarding its distribution within the citrus trees. The main objective of this study was to describe the seasonal distribution of D. aberiae within citrus trees and its migration patterns on the plants. Ten citrus orchards from eastern Spain were periodically sampled during 3 yr. In each orchard, the mealybug was sampled in different infested strata (canopy, trunk, and soil) and canopy structures (flower, fruit, leaf, and twig). Results showed that, within the sampled strata, D. aberiae was mostly in the canopy. Within the canopy, the feeding location of D. aberiae changed throughout the year. D. aberiae overwintered in the twigs and moved to the flowers and fruits in spring. Once there, its populations started to increase exponentially until August. From February to September, 5-30% of the mealybugs migrated to the trunk and soil. These results will facilitate an early detection of the pest in the areas where it is spreading and improve sampling protocols and pesticide applications. PMID- 30247624 TI - On the viability of unsupervised T-cell receptor sequence clustering for epitope preference. AB - Motivation: The T-cell receptor (TCR) is responsible for recognizing epitopes presented on cell surfaces. Linking TCR sequences to their ability to target specific epitopes is currently an unsolved problem, yet one of great interest. Indeed, it is currently unknown how dissimilar TCR sequences can be before they no longer bind the same epitope. This question is confounded by the fact that there are many ways to define the similarity between two TCR sequences. Here we investigate both issues in the context of TCR sequence unsupervised clustering. Results: We provide an overview of the performance of various distance metrics on two large independent data sets with 412 and 2835 TCR sequences respectively. Our results confirm the presence of structural distinct TCR groups that target identical epitopes. In addition, we put forward several recommendations to perform unsupervised T-cell receptor sequence clustering. Availability and Implementation: Source code implemented in Python 3 available at https://github.com/pmeysman/TCRclusteringPaper. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30247625 TI - iTerm-PseKNC: a sequence-based tool for predicting bacterial transcriptional terminators. AB - Motivation: Transcription termination is an important regulatory step of gene expression. If there is no terminator in gene, transcription couldn't stop, which will result in abnormal gene expression. Detecting such terminators can determine the operon structure in bacterial organisms and improve genome annotation. Thus, accurate identification of transcriptional terminators is essential and extremely important in the research of transcription regulations. Results: In this study, we developed a new predictor called "iTerm-PseKNC" based on Support Vector Machine (SVM) to identify transcription terminators. The binomial distribution approach was used to pick out the optimal feature subset derived from pseudo the K-tuple nucleotide composition (PseKNC). The five-fold cross-validation test results showed that our proposed method achieved an accuracy of 95%. To further evaluate the generalization ability of "iTerm-PseKNC", the model was examined on independent datasets which are experimentally confirmed Rho-independent terminators in Escherichia coli (E. coli) and in Bacillus subtilis (B. subtilis) genome. As a result, all the terminators in E. coli and 87.5% of the terminators in B. subtilis were correctly identified, suggesting that the proposed model could become a powerful tool for bacterial terminator recognition. Availability: For the convenience of most of wet-experimental researchers, the web-server for "iTerm-PseKNC" was established at http://lin-group.cn/server/iTerm-PseKNC/, by which users can easily obtain their desired result without the need to go through the detailed mathematical equations involved. PMID- 30247626 TI - The Influence of Selection on MHC DQA and DQB Haplotypes in the Endemic New Zealand Hector's and Maui Dolphins. AB - Strong balancing selection on the major histocompatibility complex (MHC) can lead to different patterns in gene frequencies and neutral genomic variation within species. We investigated diversity and geographic structure of MHC genes DQA and DQB, as well as their inferred functional haplotypes, from 2 regional populations (East and West Coast) of the endangered Hector's dolphin (Cephalorhynchus hectori hectori) and the critically endangered Maui dolphin (Cephalorhynchus hectori maui) (West Coast, North Island), and contrasted these results with patterns from neutral microsatellites. The Maui had the lowest number of alleles for DQA (2) and DQB (3), consistent with strong genetic drift acting on this remnant population. However, the 2 retained DQA alleles are among the most divergent combinations of all 4 alleles found across the Hector's metapopulation, potentially reflecting the retention of divergent alleles due to balancing selection. The high frequency of the divergent DQB*04 allele also gave this population the highest nucleotide diversity for DQB. Strong differentiation was evident for DQA, DQB, and DQA-DQB haplotypes between the regional populations of Hector's dolphins (FST > 0.213) and both subspecies (FST > 0.311). Differentiation was generally greater than observed at neutral microsatellite loci, suggesting the influence of selection between geographically proximate East and West Coast populations. This might be the result of spatial differences in directional selection on those opposite coastlines. In addition, measures of the ratio of nonsynonymous to synonymous substitutions (dN/dS) were consistent with balancing selection over evolutionary time. Together, these results suggest a complex interplay of balancing selection, directional selection, local fidelity, and genetic drift. PMID- 30247627 TI - Endogenous Amino Acid Losses from the Gastrointestinal Tract of the Adult Human-A Quantitative Model. AB - Background: The loss of endogenous (nondietary) amino acids (AAs) from the gastrointestinal tract (GIT) is an important component underlying the adult human dietary requirement for protein and essential AAs (EAAs). Although data with regard to endogenous AA losses to the end of the small intestine have been published, to our knowledge there are no direct measures of colonic endogenous AA losses. Objective: The objective was to derive quantitative estimates for daily endogenous protein and EAAs lost from the colon of the adult human. Methods: A factorial model was developed for the prediction of endogenous AA losses across the adult human GIT. Estimates of AAs entering the upper GIT lumen were combined with relative protein synthesis rates in the colon to predict colonic AA losses. The AA composition of human colonic endogenous protein was calculated by estimating the relative contributions of epithelial cell protein and mucin protein on the basis of published data for cell shedding in the pig small intestine, small intestinal protein synthesis rates in pigs and humans, and human upper and lower GIT surface areas. Colonic AA losses were summed with empirical estimates of ileal AA losses in humans to estimate total daily GIT endogenous AA losses. Results: Colonic AA loss was estimated to total 3.5 g/d in the adult male human, comprising 33% of total GIT endogenous AA loss (10.2 g/d). GIT essential AA losses accounted for 25-97% of the current recommended daily AA requirement for adult humans. For threonine, colonic losses were 54% of total GIT threonine losses, which were 97% of the current recommended daily threonine requirement. Conclusions: Colonic endogenous AA losses represent a significant fraction of total GIT endogenous AA losses. The requirement of the GIT for EAAs to replace AAs lost via the gut lumen comprises a substantial proportion of the Recommended Daily Intake of AAs. PMID- 30247628 TI - PySFD: Comprehensive Molecular Insights from Significant Feature Differences detected among many Simulated Ensembles. AB - Motivation: Many modeling analyses of molecular dynamics (MD) simulations are based on a definition of states that can be (groups of) clusters of simulation frames in a feature space composed of molecular coordinates. With increasing dimension of this feature space (due to the increasing size or complexity of a simulated molecule), it becomes very difficult to cluster the underlying MD data and estimate a statistically robust model. To mitigate this" curse of dimensionality", one can reduce the feature space, e.g., with principal component or time-lagged independent component analysis transformations, focusing the analysis on the most important modes of transitions. In practice, however, all these reduction strategies may neglect important molecular details that are susceptible to experimental verification. Results: To recover such molecular details, I have developed PySFD (Significant Feature Differences analyzer for Python), a multi-processing software package that efficiently selects significantly different features of any user-defined feature type among potentially many different simulated state ensembles, such as meta-stable states of a Markov State Model (MSM). Applying PySFD on MSMs of an aggregate of 300 microseconds MD simulations recently performed on the major histocompatibility complex class II (MHCII) protein, I demonstrate how this toolkit can extract and visualize valuable mechanistic information from big MD simulation data, e.g., in form of networks of dynamic interaction changes connecting functionally relevant sites of a protein complex. Availability: PySFD is freely available under the L GPL license at https://github.com/markovmodel/PySFD. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30247629 TI - Learning from experience in a National Healthcare System: organizational dynamics that enable or inhibit change processes. AB - Objective: To study the organizational dynamics that either enable or inhibit the changes needed by the system for the ongoing organizational development of the major acute general public hospital in Malta. Setting: The main public acute general hospital in Malta. Malta is the main island of a small archipelago in the Mediterranean with a total population reaching around 460 000. Design and participants: This qualitative study utilized two major research methods: action research and in-depth interviews. Data collection and analysis were guided by the grounded theory paradigm and operated within a constructivist and informed grounded theory approach. The action research was conducted through the documentation and interpretation of a practitioner-researcher experience working within a multi-disciplinary hospital team consisting of up to 15 members from different healthcare professional groups. The in-depth interviews involved 25 interviewees using theoretical sampling techniques. Results: The findings affirmed the high potential and capabilities of the hospital workforce. This potential is nonetheless susceptible to be affected and gradually transformed by identified organizational and external forces into a workforce that is highly territorial, cynical and showing lack of 'ownership' of the organizational vision and objectives. The organizational culture, structures, systems and leadership as well as external factors that were frequently rooted at the national level were identified as strong impacting and underlying factors. Conclusions: A theoretical framework was generated depicting a vicious circle that needs to be broken to enable the desired organizational development and learning. This additional knowledge can be used by and inspire other organizations operating within comparable conditions. PMID- 30247631 TI - Adjustment in Childhood Cancer Survivors, Healthy Peers, and Their Parents: The Mediating Role of the Parent-Child Relationship. AB - Objectives: Aims were to (1) determine whether the associations between parent psychological functioning and adjustment outcomes of childhood cancer survivors (CCS) were mediated by the parent-child relationship and (2) examine possible differences in pathways for CCS and healthy peers. Method: The study included CCS (n = 206), healthy peers (n = 132), and their primary caregivers. Youth (8-21 years) reported on the quality of the parent-child relationship and on their positive and negative adjustment outcomes. Parents reported on their own distress, posttraumatic growth, quality of the parent-child relationship, and their child's positive and negative adjustment outcomes. Two mediation models were tested, first examining youth-reported adjustment as the outcome and second examining parent-reported youth adjustment. Differences between model path coefficients of CCS and healthy peers were assessed by multigroup analyses. Results: In the youth-reported model, the parent-child relationship mediated the relation between parental distress and adjustment, with more care leading to better youth-reported adjustment outcomes and more overprotection leading to poorer adjustment outcomes. In the parent-reported model, relational frustration and attachment mediated the link between parental distress/growth and parent reported youth adjustment, with more relational frustration and less attachment relating to poorer youth adjustment outcomes. Multigroup analyses revealed no differences in model path coefficients between CCS and healthy peers. Conclusions: Parental distress and the parent-child relationship likely play an important role in both youth- and parent-reported adjustment, and associations among these constructs do not differ between CCS and healthy peers. Families with less optimal parental functioning may benefit from interventions improving the quality of parent-child interactions. PMID- 30247632 TI - Squiggle: a user-friendly two-dimensional DNA sequence visualization tool. AB - Summary: Squiggle is a software tool that automatically generates interactive web based two-dimensional graphical representations of raw DNA sequences. Built with ease of use in mind, Squiggle implements several prior sequence visualization algorithms and introduces novel visualization methods designed to maximize human usability. Availability and Implementation: Squiggle is written in Python 3 and freely available under the permissive MIT license. The open-source code can be downloaded from github.com/Lab41/squiggle as well as the Python Package Index. The installation instructions and user guide are available at squiggle.readthedocs.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30247630 TI - Enriched Physical Environment Attenuates Spatial and Social Memory Impairments of Aged Socially Isolated Mice. AB - Background: Social isolation in the elderly is one of the principal health risks in an aging society. Physical environmental enrichment is shown to improve sensory, cognitive, and motor functions, but it is unknown whether environmental enrichment can protect against brain impairments caused by social isolation. Methods: Eighteen-month-old mice were housed, either grouped or isolated, in a standard or enriched environment for 2 months, respectively. Behavioral tests were performed to evaluate cognitive functional and social interaction ability. Synaptic protein levels, myelination, neuroinflammation, brain derived neurotrophic factor, and NOD-like receptor protein 3 inflammasome signaling pathways were examined in the medial prefrontal cortex and hippocampus. Results: Isolated aged mice exhibited declines in spatial memory and social memory compared with age-matched littermates living within group housing. The aforementioned memory malfunctions were mitigated in isolated aged mice that were housed in a large cage with a running wheel and novel toys. Enriched housing prevented synaptic protein loss, myelination defects, and downregulation of brain derived neurotrophic factor, while also increasing interleukin 1 beta and tumor necrosis factor alpha in the medial prefrontal cortex and hippocampus of isolated mice. In addition, activation of glial cells and NOD-like receptor protein 3 inflammasomes was partially ameliorated in the hippocampus of isolated mice treated with physical environmental enrichment. Conclusions: These results suggest that an enriched physical environment program may serve as a nonpharmacological intervention candidate to help maintain healthy brain function of elderly people living alone. PMID- 30247633 TI - PRESM: Personalized Reference Editor for Somatic Mutation discovery in cancer genomics. AB - Motivation: Accurate detection of somatic mutations is a crucial step towards understanding cancer. Various tools have been developed to detect somatic mutations from cancer genome sequencing data by mapping reads to a universal reference genome and inferring likelihoods from complex statistical models. However, read mapping is frequently obstructed by mismatches between germline and somatic mutations on a read and the reference genome. Previous attempts to develop personalized genome tools are not compatible with downstream statistical models for somatic mutation detection. Results: We present PRESM, a tool that builds personalized reference genomes by integrating germline mutations into the reference genome. The aforementioned obstacle is circumvented by using a two-step germline substitution procedure, maintaining positional fidelity using an innovative workaround. Reads derived from tumor tissue can be positioned more accurately along a personalized reference than a universal reference due to the reduced genetic distance between the subject (tumor genome) and the target (the personalized genome). Application of PRESM's personalized genome reduced false positive somatic mutation calls by as much as 55.5%, and facilitated the discovery of a novel somatic point mutation on a germline insertion in PDE1A, a phosphodiesterase associated with melanoma. Moreover, all improvements in calling accuracy were achieved without parameter optimization, as PRESM itself is parameter-free. Hence, similar increases in read mapping and decreases in the false positive rate will persist when PRESM-built genomes are applied to any user provided dataset. Availability: The software is available at https://github.com/precisionomics/PRESM. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30247634 TI - Science Through Narrative: Engaging Broad Audiences - An Introduction to the Symposium. AB - SYNOPSIS: Due to the politicization of science and the proliferation of misinformation about science and its significance, it has never been more crucial for scientists to clearly articulate the importance of science to the public. Despite this, many scientists often (1) do not acknowledge the importance of broader scientific communication; (2) are not familiar with tools or resources that can improve their communication of science, both amongst colleagues and to the general public; and (3) do not receive such training through their degree or job training programs. In this symposium, scientists who work across multiple disciplines in entertainment, communication, and narrative are brought together with entertainment and communication industry professionals practiced in interpreting and presenting complex data in thoughtful and cogent ways. Together, they offer lessons learned and provide engagement strategies for integrative and comparative biology and for science in general. PMID- 30247635 TI - Impact of vertebral fractures and glucocorticoid exposure on height deficits in children during treatment for leukemia. AB - Objective: To assess the impact of vertebral fractures (VF) and glucocorticoid (GC) exposure on height deficits in children during treatment of acute lymphoblastic leukemia (ALL). Methods: Children with ALL treated without cranial radiation therapy (n = 160; median age 5.1 years; 58.1% male) were followed prospectively for six years. Spinal deformity index (SDI) was used to quantify VF status. Results: Baseline height Z-score was 0.3 +/- 1.2. It fell by 0.5 +/- 0.4 in the first six months for boys and by 0.4 +/- 0.4 in the first 12 months for girls (p < 0.01 for both), then subsequently recovered. The prevalence of VF peaked at one year (17.6%). Among those with VF, median SDI rose from 2 (interquartile range (IQR) 1, 7) at baseline to 8 (IQR 1, 8) at one year. A mixed model for repeated measures showed that height Z-score declined by 0.13 (95% CI, 0.02 to 0.24, p = 0.02) for each five-unit increase in SDI during the previous 12 months. Every 10 mg/m2 increase in average daily GC dose (prednisone equivalent) in the previous 12 months was associated with a height Z-score decrement of 0.26 (95% CI, 0.20 to 0.32, p < 0.01). Conclusions: GC likely play a major role in the observed height decline during therapy for ALL. Since only a minority of children had VF, fractures could not have contributed significantly to the height deficit in the entire cohort but may have been important among the sub-set with VF. PMID- 30247636 TI - Inherited thrombocytopenia associated with mutation of UDP-Galactose-4-Epimerase (GALE). AB - Severe thrombocytopenia, characterized by dysplastic megakaryocytes and intracranial bleeding, was diagnosed in six individuals from a consanguineous kindred. Three of the individuals were successfully treated by bone marrow transplant. Whole exome sequencing and homozygosity mapping of multiple family members, coupled with whole genome sequencing to reveal shared non-coding variants, revealed one potentially functional variant segregating with thrombocytopenia under a recessive model: GALE p.R51W (c.C151T, NM_001127621). The mutation is extremely rare (MAF=2.5 x 10-05), and the likelihood of the observed co-segregation occurring by chance is 1.2 x 10-06. GALE encodes UDP galactose-4-epimerase, an enzyme of galactose metabolism and glycosylation responsible for two reversible reactions: interconversion of UDP-galactose with UDP-glucose, and interconversion of UDP-N-acetylgalactosamine with UDP-N acetylglucosamine. The mutation alters an amino acid residue that is conserved from yeast to humans. The variant protein has both significantly lower enzymatic activity for both interconversion reactions and highly significant thermal instability. Proper glycosylation is critical to normal hematopoiesis, in particular to megakaryocyte and platelet development, as reflected in the presence of thrombocytopenia in the context of congenital disorders of glycosylation. Mutations in GALE have not previously been associated with thrombocytopenia. Our results suggest that GALE p.R51W is inadequate for normal glycosylation and thereby may impair megakaryocyte and platelet development. If other mutations in GALE are shown to have similar consequences, this gene may be proven to play a critical role in hematopoiesis. PMID- 30247637 TI - Janus kinase JAK1 maintains the ovarian reserve of primordial follicles in the mouse ovary. AB - STUDY QUESTION: Is the Janus kinase and signal transducer and activator of transcription (JAK-STAT) signalling pathway involved in ovarian follicle development and primordial follicle activation? SUMMARY ANSWER: JAK1 is a key factor involved in the regulation of primordial follicle activation and maintenance of the ovarian reserve. WHAT IS KNOWN ALREADY: A series of integrated, intrinsic signalling pathways (including PI3K/AKT, mTOR and KITL) are responsible for regulating the ovarian reserve of non-growing primordial follicles and ultimately female fertility. The JAK-STAT signal transduction pathway is highly conserved with established roles in cell division and differentiation. Key pathway members (specifically JAK1, STAT3 and SOCS4) have been previously implicated in early follicle development. STUDY DESIGN, SIZE, DURATION: A laboratory animal study was undertaken using the C57Bl/6 inbred mouse strain as a model for human ovarian follicle development. To determine which Jak genes were most abundantly expressed during primordial follicle activation, mRNA expression was analysed across a developmental time-course, with ovaries collected from female mice at post-natal days 1 (PND1), 4 (PND4), 8 (PND8), as well as at 6 weeks (6WK) and 7 months (7MTH) (n >= 4). Functional analysis of JAK1 was performed on PND2 mouse ovaries subjected to in vitro explant culture treated with 12.5 MUM Ruxolitinib (JAK inhibitor) or vehicle control (DMSO) for 48 h prior to histological assessment (n >= 4). PARTICIPANTS/MATERIALS, SETTING, METHODS: The expression and localization of the JAK family during ovarian follicle development in the C57Bl/6 inbred mouse strain were evaluated using quantitative PCR, immunoblotting and immunolocalisation. Functional studies were undertaken using the JAK inhibitor Ruxolitinib to investigate the underpinning cellular mechanisms via biochemical in vitro inhibition and histological assessment of intact neonate ovaries. All experiments were replicated at least three times using tissue from different mice unless otherwise stated. MAIN RESULTS AND THE ROLE OF CHANCE: Jak1 is the predominant Jak mRNA expressed in the C57Bl/6 mouse ovary across all developmental time-points assessed (P <= 0.05). Forty-eight hour inhibition of JAK1 with Ruxolitinib of PND2 ovaries in vitro demonstrated concomitant acceleration of primordial follicle activation and apoptosis (P <= 0.001) and upregulation of downstream JAK-STAT pathway members STAT3 and suppressors of cytokine signalling 4 (SOCS4). LARGE-SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Results are shown in one species, the C57Bl/6 mouse strain as an established model of human ovary development. Ruxolitinib also inhibits JAK2, with decreased efficacy. However, Jak2 mRNA had limited expression in the mouse ovary, particularly at the neonatal stages of follicle development, thus any effect of Ruxolitinib on primordial follicle activation was unlikely to be mediated via this isoform. WIDER IMPLICATIONS OF THE FINDINGS: This study supports a key role for JAK1 in the maintenance and activation of primordial follicles, with potential for targeting the JAK-STAT pathway as a method of regulating the ovarian reserve and female fertility. STUDY FUNDING AND COMPETING INTEREST(S): This project has been funded by the Australian National Health and Medical Research Council (G1600095) and The Hunter Medical Research Institute Bob and Terry Kennedy Children's Research Project Grant in Pregnancy & Reproduction (G1501433). All authors declare no conflict of interests. PMID- 30247638 TI - Comparative biogeography of forest-dependent mammals reveals paleo-forest corridors throughout Sundaland. AB - The evolutionary history of the colugo, a gliding arboreal mammal distributed throughout Sundaland, was influenced by the location of and connections between forest habitats. By comparing colugo phylogenetic patterns, species ecology, sample distributions, and times of divergence to those of other Sundaic taxa with different life history traits and dispersal capabilities, we inferred the probable distribution of paleo-forest corridors and their influence on observed biogeographic patterns. We identified a consistent pattern of early diversification between east and west Bornean lineages in colugos, lesser mouse deer, and Sunda pangolins. This phylogenetic pattern has not been commonly described in mammals, and we found no evidence for this pattern in the greater mouse deer. Colugos on West Borneo diverged from colugos in Peninsular Malaysia and Sumatra in the late Pliocene, however most other mammalian populations distributed across these same geographic regions diverged from a common ancestor more recently in the Pleistocene. Low genetic divergence between colugos on large landmasses and their neighboring satellite islands indicated that past forest distributions were recently much larger than present refugial distributions. Our analysis of colugo evolutionary history reveals dynamic forested connections throughout Sundaland, and reconstructs Borneo as the most likely ancestral area of origin for Sunda colugos. PMID- 30247639 TI - Robustness by intrinsically disordered C-termini and translational readthrough. AB - During protein synthesis genetic instructions are passed from DNA via mRNA to the ribosome to assemble a protein chain. Occasionally, stop codons in the mRNA are bypassed and translation continues into the untranslated region (3'-UTR). This process, called translational readthrough (TR), yields a protein chain that becomes longer than would be predicted from the DNA sequence alone. Protein sequences vary in propensity for translational errors, which may yield evolutionary constraints by limiting evolutionary paths. Here we investigated TR in Saccharomyces cerevisiae by analysing ribosome profiling data. We clustered proteins as either prone or non-prone to TR, and conducted comparative analyses. We find that a relatively high frequency (5%) of genes undergo TR, including ribosomal subunit proteins. Our main finding is that proteins undergoing TR are highly expressed and have intrinsically disordered C-termini. We suggest that highly expressed proteins may compensate for the deleterious effects of TR by having intrinsically disordered C-termini, which may provide conformational flexibility but without distorting native function. Moreover, we discuss whether minimizing deleterious effects of TR is also enabling exploration of the phenotypic landscape of protein isoforms. PMID- 30247640 TI - Adolescent Emotional Control Moderates Benefits of a Multicomponent Intervention to Improve Type 1 Diabetes Adherence: A Pilot Randomized Controlled Trial. AB - Objective: We previously tested via randomized controlled trial a novel intervention for adolescents with type 1 diabetes and above-target glycemic control that combined web-delivered incentives for self-monitoring of blood glucose (SMBG) and brief web counseling with working memory training and parental contingency contracting training. Results showed improved SMBG and decreased glycosylated hemoglobin (HbA1c) at 6- and 12-month follow-ups. However, it has not been elucidated if improvements in SMBG mediated the immediate benefits of this treatment on HbA1c nor if this intensive intervention uniquely benefited a subgroup of adolescents with higher problems in emotional control. Methods: Adolescents with type 1 diabetes and above-target glycemic control (n = 61) were randomized to receive the 6-month intervention (n = 30) or usual care (n = 31). Adolescents completed the Behavior Rating Inventory of Executive Function-Self Report, problems with emotional control subscale at baseline, and provided meter downloads to assess frequency of SMBG and completed an HbA1c blood draw at baseline and 6 months later. Results: At 6-month follow-up, improvements in SMBG mediated the effects of receiving the treatment on having lower average HbA1c. Further, problems in emotional control moderated the benefits of the intervention on improvements in SMBG and in turn HbA1c. Only adolescents with above average problems in emotional control evidenced improvements in SMBG in response to treatment, which then explained lower HbA1c levels at 6-month follow-up. Conclusions: This multicomponent, web-delivered intervention provided unique benefits for improving SMBG and lowering HbA1c in teens with higher problems in emotional control. PMID- 30247641 TI - Depressive Symptoms and the Buffering Effect of Resilience on Widowhood by Gender. AB - Background and Objectives: Spousal loss is a stressful life event that often results in significant depressive symptoms, with men often experiencing more significant depressive symptoms than women. Recent research suggests that psychological resilience may play a role in shaping how well people recover from the loss of a spouse. This study examined the moderating effect of resilience on widowhood in relation to changes in depressive symptoms for men and women. Research Design and Methods: This study used data from the Health and Retirement Study to examine a change in depressive symptoms for men and women who experience spousal loss compared to those who remain continuously married (N = 5,626). We used the Simplified Resilience Score, which is based on measures drawn from the psychosocial and lifestyle questionnaire. Ordinary least squares regression was used to assess depression following reported spousal loss for widows relative to their continuously married counterparts. Results: Results show resilience moderated depressive symptoms following spousal loss, but these effects varied by gender. Resilience was significantly and negatively associated with depressive symptoms for married but not for widowed women. However, for widowed men, resilience was significantly and negatively associated with depressive symptoms, and a high resilience score buffered the effect of widowhood. Discussion and Implications: Our study suggests that having high levels of resilience prior to spousal loss may help offset persistent depressive symptoms, especially for men. Implications for future research and clinical practice are discussed. PMID- 30247642 TI - Pathophysiology and Individualized Treatment for Hypothalamic Obesity Following Craniopharyngioma and Other Suprasellar Tumors: A Systematic Review. AB - The development of hypothalamic obesity (HO) following craniopharyngioma (CP) and other suprasellar tumors leads to reduced patient quality of life. No treatment algorithms are currently available for management of HO. Depending on which hypothalamic nuclei are destroyed, the pathophysiologic mechanisms and clinical symptoms that contribute to HO differ among patients. Here, we review the contribution of the hypothalamus to the pathophysiologic mechanisms and symptoms underlying CP-associated HO. In addition, we performed a systematic search of MEDLINE and Embase to identify all intervention studies for weight management in patients with CP or other suprasellar tumors published until September 2017. The search yielded 1866 publications, of which 40 were included. Of these 40 studies, we identified four modalities for intervention (i.e., lifestyle, dietary, pharmacotherapeutic, or surgical) within six clinical domains (i.e., psychosocial disorders, hyperphagia, sleep disturbances, decreased energy expenditure, hyperinsulinemia, and hypopituitarism). We used the findings from our systematic review, in addition to current knowledge on the pathophysiology of HO, to develop an evidence-based treatment algorithm for patients with HO caused by CP or other suprasellar tumors. Although the individual effects of the HO interventions were modest, beneficial individual effects may be achieved when the pathophysiologic background and correct clinical domain are considered. These two aspects can be combined in an individualized treatment algorithm with a stepwise approach for each clinical domain. Recently elucidated targets for HO intervention were also explored to improve future management of HO for patients with CP and other suprasellar tumors. PMID- 30247643 TI - A tribute to Lars Hennig (1970-2018). PMID- 30247644 TI - Metabolic profiling of human plasma reveals the activation of 5-lipoxygenase in the acute attack of gouty arthritis. AB - Objective: Monosodium urate-induced inflammation plays a vital role in acute gout (AG). Inflammation is a multi-stage process involved in the acute release of arachidonic acid and its metabolites. However, the function of the metabolism of arachidonic acid and other polyunsaturated fatty acids in AG is not well understood. This study aimed to investigate the modification of polyunsaturated fatty acid metabolism by AG. Methods: Plasma samples from patients with an AG attack (n = 26) and gender-matched healthy controls (n = 26) were analysed by metabolic profiling of polyunsaturated fatty acids. The findings were further validated with a second cohort (n = 20 each group). The associated mechanisms were investigated in whole blood cells from the second cohort and neutrophils in vitro. Results: Plasma metabolic profiling revealed a significant increase in leukotriene B4 (LTB4) for AG patients in both cohorts. The increase in plasma LTB4 was accounted for by the dynamic balance between the activation of 5 lipoxygenase and CYP4F3, the former mediating the biosynthesis of LTB4 and the latter mediating its metabolism. This was supported by significantly increased transcriptional levels of 5-lipoxygenase and CYP4F3 in whole blood cells from AG patients compared with those of controls, and the uric acid-caused dose-relevant and time-dependent activation of 5-lipoxygenase and CYP4F3 at the transcriptional and molecular levels in vitro. Conclusion: Increased LTB4 in AG patients is mainly due to activation of 5-lipoxygenase. 5-Lipoxygenase inhibition may be of therapeutic value clinically. PMID- 30247646 TI - Human Milk Oligosaccharide Concentrations Are Associated with Multiple Fixed and Modifiable Maternal Characteristics, Environmental Factors, and Feeding Practices. AB - Background: Human milk oligosaccharides (HMOs) shape the developing gut microbiome and influence immune function. Aside from genetic Secretor status, the factors influencing HMO synthesis and secretion are largely unknown. Objective: We aimed to identify modifiable and nonmodifiable factors associated with HMO concentrations. Methods: This prospective observational study included a representative subset of 427 mothers participating in the CHILD birth cohort (mean age: 33 y, 73% Caucasian). Breast milk was collected at 3-4 mo postpartum. Concentrations of 19 predominant HMOs were measured by rapid high-throughput HPLC. Secretor status was defined by the presence of 2'-fucosylactose. Associations with maternal, infant, and environmental factors were explored using multivariable regression. Breastfeeding duration was explored as a secondary outcome. Results: Overall, 72% of mothers were Secretors and the mean +/- SD duration of any breastfeeding was 12.8 +/- 5.7 mo. HMO profiles were highly variable; total HMO concentrations varied 3.7-fold and individual HMOs varied 20- to >100-fold. Secretor mothers had higher total HMO concentrations than did non Secretors (mean: 15.91 +/- 2.80 compared with 8.94 +/- 1.51 MUmol/mL, P < 0.001) and all individual HMOs differed by Secretor status, except for disialyllacto-N tetraose (DSLNT). Most HMO concentrations were lower in milk collected later in lactation, although some were higher including DSLNT and 3'-sialyllactose. Independent of Secretor status and lactation stage, seasonal and geographic variation was observed for several HMOs. Parity, ethnicity, and breastfeeding exclusivity also emerged as independent factors associated with some HMOs, whereas diet quality and mode of delivery did not. Together, these factors explained between 14% (for 6'-sialyllactose) and 92% (for 2'-fucosyllactose) of the observed variation in HMO concentrations. Lower concentrations of lacto-N hexaose or fucodisialyllacto-N-hexaose were associated with earlier breastfeeding cessation. Conclusions: HMO concentrations vary widely between mothers and are associated with multiple characteristics beyond genetic Secretor status, as well as feeding practices and environmental factors. Further research is warranted to determine how these associations affect infant health. This study was registered at clinicaltrials.gov as NCT03225534. PMID- 30247645 TI - Early identity recognition of familiar faces is not dependent on holistic processing. AB - It is widely accepted that holistic processing is critical for early face recognition, but recent work has suggested a larger role for feature-based processing. The earliest step in familiar face recognition is thought to be matching a perceptual representation of a familiar face to a stored representation of that face, which is thought to be indexed by the N250r event related potential (ERP). In the current face-priming studies, we investigated whether this perceptual representation can be effectively activated by feature based processing. In the first experiment, prime images were familiar whole faces, isolated eyes or isolated mouths. Whole faces and isolated eyes, but not isolated mouths, effectively modulated the N250r. In the second experiment, prime images were familiar whole faces presented either upright or inverted. Inverted face primes were no less effective than upright face primes in modulating the N250r. Together, the results of these studies indicate that activation of the earliest face recognition processes is not dependent on holistic processing of a typically configured face. Rather, feature-based processing can effectively activate the perceptual memory of a familiar face. However, not all features are effective primes as we found eyes, but not mouths, were effective in activating early face recognition. PMID- 30247647 TI - Convenience store visitors recall cigarette advertisements even if they do not purchase cigarettes. AB - Background: This study examined the extent to which visitors to convenience stores remember the cigarette advertisements they encounter in these stores and investigated the relationships between how advertisements are recalled and attitudes toward them. Methods: Exit surveys of 1007 visitors to three convenience stores located in Seoul, Korea, were conducted between 25 November 2015 and 7 December 2015. Results: Of the respondents, 23.4% (n = 236) freely recalled the cigarette advertisement in the store just visited. However, the percentage of participants who correctly recalled the advertisement increased to 55.2% (n = 556) after we presented them with a card showing options for the advertisement (i.e. a cued recall task). Regardless of sex or purchasing cigarettes, free recall performance was significantly associated with age, number of weekly visits to the convenience store and current smoking status. In addition, free recall increased with having a positive attitude toward cigarette advertisements. Conclusions: Repeated visits to convenience stores may continue to expose individuals to cigarettes and their advertisements; such exposure may subconsciously affect recall of the advertisements and maintenance of a positive attitude toward cigarette advertisements. Therefore, to denormalize smoking in society, cigarette advertising and displays at points of sale including convenience stores, should be banned. PMID- 30247648 TI - Cell-Enhanced Acellular Nerve Allografts for Peripheral Nerve Reconstruction: A Systematic Review and a Meta-Analysis of the Literature. AB - BACKGROUND: Peripheral nerve reconstruction is a difficult problem to solve. Acellular nerve allografts (ANAs) have been widely tested and are a promising alternative to the autologous gold standard. However, current reconstructive methods still yield unpredictable and unsuccessful results. Consequently, numerous studies have been carried out studying alternatives to plain ANAs, but it is not clear if nerve regeneration potential exists between current biological, chemical, and physical enrichment modes. OBJECTIVE: To systematically review the effects of cell-enhanced ANAs on regeneration of peripheral nerve injuries. METHODS: PubMed, ScienceDirect, Medline, and Scopus databases were searched for related articles published from 2007 to 2017. Inclusion criteria of selected articles consisted of (1) articles written in English; (2) the topic being cell-enhanced ANAs in peripheral nerve regeneration; (3) an in vivo study design; and (4) postgrafting neuroregenerative assessment of results. Exclusion criteria included all articles that (1) discussed central nervous system ANAs; (2) consisted of xenografts as the main topic; and (3) consisted of case series, case reports or reviews. RESULTS: Forty papers were selected, and categorization included the animal model; the enhancing cell types; the decellularization method; and the neuroregenerative test performed. The effects of using diverse cellular enhancements combined with ANAs are discussed and also compared with the other treatments such as autologous nerve graft, and plain ANAs. CONCLUSION: ANAs cellular enhancement demonstrated positive effects on recovery of nerve function. Future research should include clinical translation, in order to increase the level of evidence available on peripheral nerve reconstruction. PMID- 30247649 TI - Analysis of the genetic component of systemic sclerosis in Iranian and Turkish populations through a genome-wide association study. AB - Objectives: SSc is an autoimmune disease characterized by alteration of the immune response, vasculopathy and fibrosis. Most genetic studies on SSc have been performed in European-ancestry populations. The aim of this study was to analyse the genetic component of SSc in Middle Eastern patients from Iran and Turkey through a genome-wide association study. Methods: This study analysed data from a total of 834 patients diagnosed with SSc and 1455 healthy controls from Iran and Turkey. DNA was genotyped using high-throughput genotyping platforms. The data generated were imputed using the Michigan Imputation Server, and the Haplotype Reference Consortium as a reference panel. A meta-analysis combining both case control sets was conducted by the inverse variance method. Results: The highest peak of association belonged to the HLA region in both the Iranian and Turkish populations. Strong and independent associations between the classical alleles HLA-DRB1*11: 04 [P = 2.10 * 10-24, odds ratio (OR) = 3.14] and DPB1*13: 01 (P = 5.37 * 10-14, OR = 5.75) and SSc were observed in the Iranian population. HLA DRB1*11: 04 (P = 4.90 * 10-11, OR = 2.93) was the only independent signal associated in the Turkish cohort. An omnibus test yielded HLA-DRB1 58 and HLA DPB1 76 as relevant amino acid positions for this disease. Concerning the meta analysis, we also identified two associations close to the genome-wide significance level outside the HLA region, corresponding to IRF5-TNPO3 rs17424921 C (P = 1.34 * 10-7, OR = 1.68) and NFKB1 rs4648133-C (P = 3.11 * 10-7, OR = 1.47). Conclusion: We identified significant associations in the HLA region and suggestive associations in IRF5-TNPO3 and NFKB1 loci in Iranian and Turkish patients affected by SSc through a genome-wide association study and an extensive HLA analysis. PMID- 30247650 TI - Risk factors associated with Clostridium difficile infection in inflammatory bowel disease: a systematic review and meta-analysis. AB - Background: Clostridium difficile Infection (CDI) is a significant concern in Inflammatory Bowel Disease (IBD). Risk factors and consequences associated with CDI in Inflammatory Bowel Disease (IBD) patients are important to characterize. Aim: To perform a systematic review and meta-analysis to assess risk factors and outcomes associated with CDI in IBD patients. Methods: Multiple databases were searched for studies investigating risk factors, colectomy and mortality risk in IBD patients with and without CDI. This was stratified by short (<3 months) and long-term (>1 year) outcomes. Summary estimates were calculated using a random effects model. Quality assessment used the Newcastle-Ottawa scale. Results: Twenty-two studies met inclusion criteria. Antibiotics use within 30 days of diagnosis was associated with CDI infections (OR: 1.85, 95% CI:1.36, 2.52). Colonic involvement in Crohn's disease patients was associated with significantly higher CDI infection rates (OR: 2.76, 95% CI:1.75, 4.35). There was a significant association between biologic medication use and CDI (OR: 1.65 [1.18, 2.30]), with minimal heterogeneity (I 2= 4.0%). The long-term colectomy risk was significantly higher for IBD patients with CDI compared to without CDI (OR: 2.22, 95% CI: 1.17, 4.18). Significantly higher mortality was found in CDI in IBD patients both short term (OR:3.84, 95%CI: 2.62, 5.61) and long-term (OR: 3.65, 95% CI:1.58, 8.44). Substantial heterogeneity existed. Most studies were moderate quality. Conclusion: Colonic involvement, biologic and antibiotic use appear to be risk factors associated with CDI amongst IBD patients. CDI is associated with increased short and long-term mortality. PMID- 30247651 TI - Thirty-two years post-Chernobyl: risk perception about radiation and health effects among the young generation in Gomel, Republic of Belarus. PMID- 30247652 TI - Bacterial related events and the immunological response of onset and relapse adult Crohn's disease patients. AB - Background and Aims: Crohn's disease (CD) is a chronic, systemic inflammatory disease characterized by periods of remission and flare-ups. It has been associated with a disturbed gastrointestinal barrier function, an increase in the transport of luminal contents into the tissue and lower immune tolerance. Methods: Peripheral blood samples were collected from healthy controls and 33 adult active flare-up CD patients. We classified patients as onset or relapse flare-up subjects, according to the days of disease evolution. Plasma levels of lipopolysaccharide binding protein (LBP), Fatty acid-binding proteins (FABP), and antibodies against bacterial lysates, Interferons (IFN) and IL6 were measured by ELISA in each group of patients. Results: Onset CD patients had higher plasma levels of LBP (57.32+/-38.86 vs 30.22+/-9.80 ?g/ml) and IFNalpha (1.25+/-0.23 vs 0.95+/-0.36 log10pg/ml) and lower levels of IgG and IgA antibodies against bacterial lysates than relapse CD patients. We also observed a subgroup of onset patients with the highest levels of LBP. In this subgroup, LBP correlated negatively with CRP. Onset and relapse CD patients had similar levels of FABP6 and FABP2, though LBP and FABP6 correlated positively only in relapse patients. In relapse patients, anti-E coli IgG antibodies correlated positively with systemic IL6 and IFNalpha levels. Conclusions: Our findings suggest that onset and relapse flare-ups in adult CD patients are related to different systemic immune-related bacterial events. Characterizing these differences may provide insights into the etiology of Crohn's disease and would help in the selection of appropriate therapies. PMID- 30247653 TI - Detection of a broad range of low level MHC class II-restricted Hepatitis Delta Virus (HDV)-specific T cell responses regardless of the clinical status. AB - Background: This study aimed to comprehensively define the breadth and specificity of the HDV-specific T-cell response in patients at different stages of chronic co-infection with hepatitis B (HBV) and delta virus (HDV). Methods: Following in vitro stimulation with an overlapping set of 21 HDV-specific 20mer peptides and exogenous IL-2, HDV-specific CD4+ and CD8+ T-cell response of 32 HDV infected patients were analyzed by ELISpot and intracellular cytokine staining for interferon-gamma production on a single peptide level. Additionally, HLA binding studies both in silico and in vitro were performed. Results: We were able to detect one or more T-cell response in more than 50% our patients. Interestingly, there was no significant difference between the breadth of response in HDV PCR+ versus PCR- patients. HDV-specific T-cell responses focused on three distinct HDV-specific epitopes that were each detected by 12-21% of patients - two HLA class II restricted (aa11-30, aa41-60) as well as one MHC class I restricted epitope (aa191-210). In in vitro HLA binding assays, the two CD4 + T-cell specificities (aa11-30, aa41-60) showed promiscuous binding to multiple HLA-DR molecules. Conclusions: This comprehensive characterization of HDV T-cell epitopes provides important information that will facilitate further studies of HDV immunopathogenesis. PMID- 30247654 TI - HACER: an atlas of human active enhancers to interpret regulatory variants. AB - Recent studies have shown that disease-susceptibility variants frequently lie in cell-type-specific enhancer elements. To identify, interpret, and prioritize such risk variants, we must identify the enhancers active in disease-relevant cell types, their upstream transcription factor (TF) binding, and their downstream target genes. To address this need, we built HACER (http://bioinfo.vanderbilt.edu/AE/HACER/), an atlas of Human ACtive Enhancers to interpret Regulatory variants. The HACER atlas catalogues and annotates in-vivo transcribed cell-type-specific enhancers, as well as placing enhancers within transcriptional regulatory networks by integrating ENCODE TF ChIP-Seq and predicted/validated chromatin interaction data. We demonstrate the utility of HACER in (i) offering a mechanistic hypothesis to explain the association of SNP rs614367 with ER-positive breast cancer risk, (ii) exploring tumor-specific enhancers in selective MYC dysregulation and (iii) prioritizing/annotating non coding regulatory regions targeting CCND1. HACER provides a valuable resource for studies of GWAS, non-coding variants, and enhancer-mediated regulation. PMID- 30247655 TI - The UK guidelines for management and surveillance of Tuberous Sclerosis Complex. AB - Background: The severity of Tuberous Sclerosis Complex (TSC) can vary among affected individuals. Complications of TSC can be life threatening, with significant impact on patients' quality of life. Management may vary dependent on treating physician, local and national policies, and funding. There are no current UK guidelines. We conducted a Delphi consensus process to reach agreed guidance for the management of patients with TSC in the UK. Methods: We performed a literature search and reviewed the 2012/13 international guideline for TSC management. Based on these, a Delphi questionnaire was formed. We invited 86 clinicians and medical researchers to complete an online survey in two rounds. All the people surveyed were based in the UK. Clinicians were identified through the regional TSC clinics, and researchers were identified through publications. In round one, 55 questions were asked. In round two, 18 questions were asked in order to obtain consensus on the outstanding points that had been contentious in round one. The data was analysed by a core committee and subcommittees, which consisted of UK experts in different aspects of TSC. The Tuberous Sclerosis Association was consulted. Results: 51 TSC experts took part in this survey. Two rounds were required to achieve consensus. The responders were neurologists, nephrologists, psychiatrist, psychologists, oncologists, general paediatricians, dermatologist, urologists, radiologists, clinical geneticists, neurosurgeons, respiratory and neurodisability clinicians. Conclusions: These new UK guidelines for the management and surveillance of TSC patients provide consensus guidance for delivery of best clinical care to individuals with TSC in the UK. PMID- 30247657 TI - University of Derby research shows mindfulness improves sleep in fibromyalgia patients. PMID- 30247656 TI - Purified PEGylated human glucagon-like peptide-2 reduces the severity of irradiation-induced acute radiation enteritis in rats. AB - Radiation-induced acute intestinal injury after abdominal and pelvic irradiation is a common and serious problem in the clinical setting. Glucagon-like peptide-2 (GLP-2), a 33-amino acid peptide, exerts diverse effects related to the regulation of gastrointestinal growth and function. However, GLP-2 is relatively unstable in vivo. The aim of the present study was to improve GLP-2 stability in vivo and to evaluate its therapeutic effect on acute radiation enteritis. We generated long-lasting intestinal protection peptides by conjugating human GLP-2 (hGLP-2) peptides to polyethyleneglycol (PEG) to produce mPEGylation hGLP-2 (Mono PEG-hGLP-2) through an enzymatic site-specific transglutamination reaction. Mono PEG-hGLP-2 synthesized under optimal reaction conditions and separated by one step ion-exchange chromatography was found to be resistant to degradation in vitro. Pretreatment with Mono-PEG-hGLP-2 reduced the severity of radiation induced intestinal injury, oxidative stress, and the expression of NF-kappaB in rats with irradiation-induced acute radiation enteritis. The enhanced biological potency of Mono-PEG-hGLP-2 highlights its potential as a therapeutic agent for intestinal diseases. PMID- 30247658 TI - Don't Be Late on Latent TB: Inconsistent Tuberculosis Screening in IBD Patients on Biologics. PMID- 30247659 TI - Neoadjuvant chemotherapy with irinotecan and nedaplatin in a single cycle followed by esophagectomy on cT4 resectable esophageal squamous cell carcinoma: a prospective nonrandomized trial for short-term outcomes. AB - Neoadjuvant chemotherapy (NAC) significantly extends survival in advanced esophageal squamous cell carcinoma (ESCC), but the short-term outcomes for cT4 ESCC remain controversial. Many NAC regimens have been previously reported, although no study has reported a regimen of irinotecan and nedaplatin for cT4 potential resectable ESCC. We evaluated the short-term outcomes of NAC with irinotecan and nedaplatin in a single cycle followed by esophagectomy on cT4 resectable ESCC. A total of 51 patients with cT4 potentially resectable ESCC were eligible for this study. Twenty of these patients underwent NAC, and the other 31 patients underwent surgery alone. The toxicities and response of NAC were evaluated. The clinicopathologic characteristics, responses, toxicities, surgical outcomes, postoperative complications, and survival time between the two groups were analyzed. No significant differences were found in clinicopathologic characteristics between the groups (P > 0.05). The response rate of NAC was 75% (15/20). The differences in the long-axis diameter of the tumor and cT stage between pre- and post-NAC were significant (P < 0.05). Twenty-four toxic events occurred in 11 patients of the NAC group, and 20/24 of these were mild. The R0 resection rates in the NAC group and the surgery alone group were 85% and 64.5%, with no statistically significant difference (P > 0.05). Differences in the pathological T stage and pathological tumor-node-metastasis (TNM) stage were significant (P < 0.05). The overall survival (OS) time and mortality in the NAC group versus the surgery alone group were 31.57 +/- 3.06 months versus 15.24 +/- 1.46 months and 25% versus 61.3%, respectively. The differences in OS and mortality were significant (P < 0.05). The NAC group and R0 resection were significant and independent predictors of positive prognosis. NAC with irinotecan and nedaplatin in a single cycle followed by esophagectomy on cT4 resectable ESCC as a new NAC is safe and effective. PMID- 30247660 TI - Evolution of the surgical technique of minimally invasive Ivor-Lewis esophagectomy: description according to the IDEAL framework. AB - Totally minimally invasive Ivor-Lewis esophagectomy (Ivor Lewis TMIE) is a technically challenging procedure and is associated with a learning curve. Refinement of surgical technique is an important part of this learning curve. However, detailed descriptions of these refinements according to the idea, development, exploration, assessment, and long-term follow-up (IDEAL) framework are lacking and this study was undertaken to fill this knowledge gap. From 2010 until 2016, all consecutive patients (n = 164) were included from the first patient undergoing Ivor Lewis TMIE. Surgical reports were analyzed and surgeons were interviewed to determine surgical refinements. These data were used to describe the transition of the surgical technique from IDEAL stage IIB to stage III. The main findings were that four refinements were made to the surgical procedure in IDEAL stage IIB: (1) At case 9, the use of the 25 mm OrVil was abandoned, exchanged for a 28 mm EEA stapler and a large omental wrap around the anastomosis was introduced; (2) at case 27, the omental wrap was reduced in volume; (3) at case 60, the omental wrap was refined to cover the full 360 degrees of the anastomosis and (4) at case 77, the fixation of the anvil with the Endostitch was replaced by fixation with two Endoloops(r). During the transition from IDEAL stage IIB to stage III, the incidence of anastomotic leakage decreased from 26.0% to 4.6% (P < 0.001) and the incidence of textbook outcome increased from 31.2% to 47.1% (P = 0.039). In conclusion, this study describes the surgical refinements that were made during the progression of Ivor Lewis TMIE from IDEAL stage IIB to IDEAL stage III. During IDEAL stage IIB, postoperative outcome improved as surgical proficiency was gained and the technique was refined. PMID- 30247661 TI - Tracking the Origins of Fly Invasions; Using Mitochondrial Haplotype Diversity to Identify Potential Source Populations in Two Genetically Intertwined Fruit Fly Species (Bactrocera carambolae and Bactrocera dorsalis [Diptera: Tephritidae]). AB - Bactrocera carambolae Drew and Hancock and Bactrocera dorsalis (Hendel) (Diptera: Tephritidae) are important pests of many fruits. These flies have been spread across the world through global travel and trade, and new areas are at risk of invasion. Whenever new invasive populations are discovered, quick and accurate identification is needed to mitigate the damage they can cause. Determining invasive pathways can prevent further spread of pests as well as subsequent reinvasions through the same pathway. Molecular markers can be used for both species identification and pathway analysis. We analyzed 1,601 individuals from 19 populations using 765 base pairs of the mitochondrial cytochrome oxidase I (COI) gene to infer the haplotype diversity and population structure within these flies from across their native and invasive ranges. We analyzed these samples by either grouping by species or geographic populations due to the genetic similarity in the mitochondrial genome. We found no genetic structure between B. dorsalis and B. carambolae and our findings suggest recent and most likely ongoing, genetic exchange between these two species in the wild. Hyper-diverse mitochondrial genetic diversity in the native range suggests large population sizes and relatively high mutation rates. Only 52% of the haplotypes found in the trap captures from California are shared with haplotypes from flies found in our global survey, indicating significant genetic diversity in the native range that is missing from our samples. However, these results provide a foundation for the accurate determination of the provenance of invasive populations around the world. PMID- 30247662 TI - Radiomics with artificial intelligence for precision medicine in radiation therapy. AB - Recently, the concept of radiomics has emerged from radiation oncology. It is a novel approach for solving the issues of precision medicine and how it can be performed, based on multimodality medical images that are non-invasive, fast and low in cost. Radiomics is the comprehensive analysis of massive numbers of medical images in order to extract a large number of phenotypic features (radiomic biomarkers) reflecting cancer traits, and it explores the associations between the features and patients' prognoses in order to improve decision-making in precision medicine. Individual patients can be stratified into subtypes based on radiomic biomarkers that contain information about cancer traits that determine the patient's prognosis. Machine-learning algorithms of AI are boosting the powers of radiomics for prediction of prognoses or factors associated with treatment strategies, such as survival time, recurrence, adverse events, and subtypes. Therefore, radiomic approaches, in combination with AI, may potentially enable practical use of precision medicine in radiation therapy by predicting outcomes and toxicity for individual patients. PMID- 30247664 TI - Erratum. PMID- 30247663 TI - Protein kinase C beta deficiency increases glucose-mediated peritoneal damage via M1 macrophage polarization and up-regulation of mesothelial protein kinase C alpha. AB - Background: Peritoneal membrane (PM) damage during peritoneal dialysis (PD) is mediated largely by high glucose (HG)-induced pro-inflammatory and neo-angiogenic processes, resulting in PM fibrosis and ultrafiltration failure. We recently demonstrated a crucial role for protein kinase C (PKC) isoform alpha in mesothelial cells. Methods: In this study we investigate the role of PKCbeta in PM damage in vitro using primary mouse peritoneal macrophages (MPMPhi), human macrophages (HMPhi) and immortalized mouse peritoneal mesothelial cells (MPMCs), as well as in vivo using a chronic PD mouse model. Results: We demonstrate that PKCbeta is the predominant classical PKC isoform expressed in primary MPMPhi and its expression is up-regulated in vitro under HG conditions. After in vitro lipopolysaccharides stimulation PKCbeta-/- MPMPhi demonstrates increased levels of interleukin 6 (IL-6), tumour necrosis factor alpha, and monocyte chemoattractant protein-1 and drastically decrease IL-10 release compared with wild-type (WT) cells. In vivo, catheter-delivered treatment with HG PD fluid for 5 weeks induces PKCbeta up-regulation in omentum of WT mice and results in inflammatory response and PM damage characterized by fibrosis and neo angiogenesis. In comparison to WT mice, all pathological changes are strongly aggravated in PKCbeta-/- animals. Underlying molecular mechanisms involve a pro inflammatory M1 polarization shift of MPMPhi and up-regulation of PKCalpha in MPMCs of PKCbeta-/- mice. Finally, we demonstrate PKCbeta involvement in HG induced polarization processes in HMPhi. Conclusions: PKCbeta as the dominant PKC isoform in MPMPhi is up-regulated by HG PD fluid and exerts anti-inflammatory effects during PD through regulation of MPMPhi M1/M2 polarization and control of the dominant mesothelial PKC isoform alpha. PMID- 30247665 TI - Low Dose of Nanocapsules Containing Eucalyptus Oil Has Beneficial Repellent Effect Against Horn Fly (Diptera: Muscidae). AB - For the first time, the repellent and insecticidal effects of eucalypt essential oil (Eucalyptus globulus) in its free form and associated with different nanostructures (nanoemulsion and nanocapsules) were investigated against Musca domestica (Diptera: Muscidae) and Haemotobia irritans (Diptera: Muscidae) flies. Specimens of M. domestica were collected, separated into groups (n = 10), treated with aspersion of essential oil of eucalypt in its free (1, 5, and 10%) and nanostructured (nanoemulsion or nanoencapsulated at 1, 3, and 5%, respectively) forms. The determination of the insecticidal effect was performed by counting the number of dead flies at intervals of 30, 60, 120, 360 and 750 min after oil aspersion. E. globulus essential oil showed insecticidal effect against M. domestica at concentrations of 1 and 5%. Eucalypt essential oil (10%) caused 100% mortality of M. domestica after 750 min of the treatment. Nanocapsules (3 and 5%) showed efficacy by reducing the number of flies. On the other hand, nanoemulsion did not show insecticidal effect. The repellent action of E. globulus concentrations of 5% was tested against H. irritans on naturally infested cows. The repellent action against H. irritans was verified soon after pulverization. After 24 h, a significant reduction on horn flies' population (83.33 and 66.66%) was observed using free and nanoencapsulated forms tested, respectively. E. globulus essential oil demonstrated insecticidal and repellent effects against M. domestica and H. irritans flies. PMID- 30247667 TI - Commentary: Synopsis of the Location and Type of Training for Current Department Chairs and Program Directors of Academic Neurosurgical Departments in the United States. PMID- 30247666 TI - Prevalence of Adverse Events in Children With Congenital Hyperinsulinism Treated With Diazoxide. AB - Context: Diazoxide, the only U.S. Food and Drug Administration-approved drug to treat hyperinsulinemic hypoglycemia, has been associated with several adverse events, which has raised concerns about the safety of this drug. Existing reports are limited to small studies and case reports. Objective: To determine prevalence of and clinical factors associated with adverse events in infants and children treated with diazoxide. Design: Retrospective cohort study of children with hyperinsulinism (HI) treated with diazoxide between 2003 and 2014. Setting: The Congenital Hyperinsulinism Center at the Children's Hospital of Philadelphia. Patients: Children and infants with laboratory-confirmed diagnosis of HI. Main Outcome Measures: Prevalence of pulmonary hypertension (PH), edema, neutropenia, thrombocytopenia, and hyperuricemia was determined. Tests of association and logistic regression were used to identify potential risk factors. Results: A total of 295 patients (129 female) met inclusion criteria. The median age at diazoxide initiation was 29 days (interquartile range, 10 to 142 days; n = 226 available start dates); 2.4% of patients were diagnosed with PH after diazoxide initiation. Children with PH (P = 0.003) or edema (P = 0.002) were born at earlier gestational age and more frequently had potential PH risk factors, including respiratory failure and structural heart disease (P < 0.0001 and P = 0.005). Other adverse events included neutropenia (15.6%), thrombocytopenia (4.7%), and hyperuricemia (5.0%). Conclusion: In this large cohort, PH occurred in infants with underlying risk factors, but no identifiable risk profile emerged for other adverse events. The relatively high prevalence of neutropenia, thrombocytopenia, and hyperuricemia suggests the value in proactively screening for these side effects in children treated with diazoxide. PMID- 30247668 TI - Parent Distress Following Pediatric Burn Injuries. AB - Objective: Parents commonly report elevated distress following a child's burn injury, yet limited research has identified child or injury characteristics that may explain parent distress. The main goal of the current study is to examine prevalence and predictors of parent distress following children's burn injuries by evaluating distress symptoms in a clinic sample of parents whose children present for evaluation and treatment at a regional burn center. Methods: Participants included parents of 407 children who experienced a burn injury. Of this sample, follow-up data at a second time point was obtained for 130 children and their caregivers. Parents completed a measure of distress. Clinical and demographic variables were extracted retrospectively from the medical chart. Results: Clinical and at risk levels of distress were reported by nearly 19% of parents at Time 1. Parent distress at Time 1 was associated with child minority race, fewer days since burn injury, and greater burn size. A propensity score was used to account for potential differences between parents with data at Time 1 only versus those with data at Time 2. Parents with Time 2 data tended to have higher levels of distress at Time 1. Of parents with Time 2 data, 17% continued to report elevated distress, and Time 1 distress was the best predictor of later distress. Conclusions: A proportion of parents report elevated distress following their children's burn injuries. Our results suggest that best practices should include routine screening of parent distress following pediatric burn injuries to guide appropriate interventions. PMID- 30247669 TI - Commentary: Recanalization of Acute Common Carotid Artery Occlusion: 2 Dimensional Operative Video. PMID- 30247670 TI - Acute toxoplasmosis in an immunocompetent traveller to Senegal. PMID- 30247671 TI - C. P. Kurtzman's evolving concepts of species, genus and higher categories. AB - Cletus P. Kurtzman transformed the way yeast systematists practice their trade and how they perceive the yeast species. He redefined many genera of ascomycetous yeasts and provided a sound basis upon which to base higher taxonomic categories. Within his extraordinary corpus lies a trail of elements that can be used to reconstruct his evolving vision of the concepts that underlie the species and the genus, rarely set in a theoretical framework. While occasionally tipping his hat to the biological and phylogenetic species, Kurtzman espoused a concept founded primarily on genetic distance, even when claiming otherwise. In contrast, his notion of genus incorporated components of both genetic distance and phylogenetic structure, and possibly a size consideration. A phylogenetic approach predominated with higher taxa. PMID- 30247672 TI - MultiTwin: A Software Suite to Analyze Evolution at Multiple Levels of Organization Using Multipartite Graphs. AB - The inclusion of introgressive processes in evolutionary studies induces a less constrained view of evolution. Network-based methods (like large-scale similarity networks) allow to include in comparative genomics all extrachromosomic carriers (like viruses, the most abundant biological entities on the planet) with their cellular hosts. The integration of several levels of biological organization (genes, genomes, communities, environments) enables more comprehensive analyses of gene sharing and improved sequence-based classifications. However, the algorithmic tools for the analysis of such networks are usually restricted to people with high programming skills. We present an integrated suite of software tools named MultiTwin, aimed at the construction, structuring, and analysis of multipartite graphs for evolutionary biology. Typically, this kind of graph is useful for the comparative analysis of the gene content of genomes in microbial communities from the environment and for exploring patterns of gene sharing, for example between distantly related cellular genomes, pangenomes, or between cellular genomes and their mobile genetic elements. We illustrate the use of this tool with an application of the bipartite approach (using gene family-genome graphs) for the analysis of pathogenicity traits in prokaryotes. PMID- 30247673 TI - Recurrent Rathke's Cleft Cysts: Incidence and Surgical Management in a Tertiary Pituitary Center over 2 Decades. AB - Background: Limited data exist pertaining to outcomes following surgery for recurrent Rathke's cleft cysts (RCC). Objective: To determine treatment outcomes in patients undergoing reoperation for recurrent or residual RCCs. Methods: A retrospective analysis of 112 consecutive RCC operations in 109 patients between 1995 and 2017 was conducted. Results: Eighteen patients underwent 21 RCC reoperations with a mean follow-up of 58 mo. Patient symptoms prior to reoperation included headaches (14, 66.7%) and vision loss (12, 57.1%). Thirteen of 18 patients (72.2%) required hormone supplementation prior to reoperation including 5 with diabetes insipidus (DI). Mean RCC diameter was 16 mm and 76% had suprasellar extension. Compared to index RCC cases, intraoperative cerebrospinal fluid leak repair was more common in reoperation cases (15/21, 71% vs 43/91, 47%, P = .05). There was 1 carotid artery injury without neurological sequelae, and 2 postoperative cerebrospinal fluid (CSF) leaks (9.5%). Rates of transient hyponatremia (3/10, 30% vs 4/91, 4.4%, P = .04) and transient DI (5/10, 50% vs 17/91, 18.7%, P = .04) were higher in the reoperation vs index group. Improved headaches and vision were reported in 4/12 (33%) and 8/12 (61.5%) of RCC reoperation patients, respectively. Two patients developed new permanent DI. A higher proportion of reoperation patients had RCC squamous metaplasia (24% vs 5.4%, P = .02) or wall inflammation (42.9% vs 2.2%, P < .001) on pathological examination. CONCLUSION: Reoperation for RCCs is generally safe at tertiary pituitary centers and often results in improved vision. Hypopituitarism is less likely to improve following reoperation for recurrent RCCs. Several histopathological features may help characterize "atypical RCCs" with a higher likelihood of recurrence/progression. PMID- 30247674 TI - Effect of metal-containing topical agents on surface doses received during external irradiation. AB - The ability of topical metal-containing agents (MCAs) to enhance radiation dermatitis remains controversial. In the present study, we evaluated increases in surface doses associated with topical agents at different application thicknesses and with MCAs versus non-metal containing agents (NMCAs). We assessed two clinically available MCAs, zinc oxide ointment (ZOO) and silver sulfadiazine cream (SSDC), and eight NMCAs. Surface doses were measured using a Markus chamber placed on a polystyrene phantom. To evaluate the role of application thickness, each agent was applied to the chamber in oil-slick (<0.1-mm), 1-mm and 5-mm layers prior to irradiation of a 10 * 10 cm field with 4-, 6- and 10-MV X-ray beams. The surface dose enhancement ratio (SDER) was calculated as the ratio of the surface dose with an agent to the dose without an agent. The SDER values for the eight NMCAs, ZOO and SSDC at an oil-slick thickness were 101.6-104.6% (mean: 103.3%), 104.5% and 105.0%, respectively, using a 6-MV X-ray beam. The corresponding values at a 1-mm thickness were 196.8-237.8% (mean: 215.7%), 229.3% and 201.4%, respectively, and those at a 5-mm thickness were 342.2-382.4% (mean: 357.9%), 357.1% and 352.6%, respectively. A similar tendency was found using 4- and 10-MV X-ray beams. The lack of a significant difference in surface dose enhancement between MCAs and NMCAs, particularly when applied in oil-slick layers, suggests that MCAs do not need to be avoided or applied in a restricted manner during radiotherapy for dosimetric reasons. PMID- 30247675 TI - Possibilities of early life programming in broiler chickens via intestinal microbiota modulation. AB - The strong selection in search for a higher growth rate in broilers has resulted in adverse effects such as metabolic disorders, low responsiveness of the immune system, and decreased resistance to pathogens. On the other hand, newly hatched chicks rely mostly on innate immune responses until their gut gets colonized with microbiota. In consequence, early access to active substances or bacteria (pre- and post-hatch) is particularly relevant here because in broilers much of the immune system development occurs early in life. Therefore, early stimulation of beneficial microflora is critical, as it affects, to a great extent, the entire life-span of an individual, and also because the nutritional manipulations of the gastrointestinal tract (GIT) microbiome to enhance productivity and health are rather limited by the resilience of the ecosystem once established in the chicken's gut. Early life or developmental programming is based on the assumption that the development of diseases later in life can be modulated by perturbations or environmental exposures during critical pre- or early post-natal life. Substances such as plant derivatives, Na butyrate, pre- and probiotics, and beta glucans have been shown to induce beneficial microbiological and immunological changes within the GIT, and therefore are potential candidates to be used as tools to manipulate GIT functionality in the young chicken. Accordingly, substances as these might represent promising candidates to study intestinal microbiota/immune system modulation in broilers' early stages of breeding. In ovo delivered prebiotics and synbiotics have been shown to have no adverse effect on the development of the immune system in exposed chickens, while being able to affect lymphoid-organs' morphology in chickens. In ovo procedures have also been proposed as means of promoting a healthy microflora in embryonic guts and stimulating maturation of the cellular and humoral immune responses in central and peripheral immune organs, including those in the GIT. The purpose of this presentation is to discuss the potential usefulness of the instruments currently available to induce early life programming in broilers. PMID- 30247676 TI - Resting-state Functional Magnetic Resonance Imaging Identifies Cerebrovascular Reactivity Impairment in Patients With Arterial Occlusive Diseases: A Pilot Study. AB - BACKGROUND: The development of noninvasive approaches for identifying hypoperfused brain tissue at risk is of major interest. Recently, the temporal shift (TS) maps estimated from resting-state blood oxygenation level-dependent (BOLD) signals have been proposed for determining hemodynamic state. OBJECTIVE: To examine the equivalency of the TS map and the cerebrovascular reactivity (CVR) map derived from acetazolamide-challenged single-photon emission computed tomography (SPECT) in identifying hemodynamic impairment in patients with arterial occlusive diseases. METHODS: Twenty-three patients with arterial occlusive diseases who underwent SPECT were studied. With a recursive TS analysis of low-frequency fluctuation of the BOLD signal, a TS map relative to the global signal was created for each patient. The voxel-by-voxel correlation coefficient was calculated to examine the image similarity between TS and SPECT-based cerebral blood flow (CBF) or CVR maps in each patient. Furthermore, simple linear regression analyses were performed to examine the quantitative relationship between the TS of BOLD signals and CVR in each cerebrovascular territory. RESULTS: The within-patient, voxel-by-voxel comparison revealed that the TS map was more closely correlated with SPECT-CVR map ([Z(r)] = 0.42 +/- 0.18) than SPECT-CBF map ([Z(r)] = 0.058 +/- 0.11; P < .001, paired t-test). The regression analysis showed a significant linear association between the TS of BOLD signals and CVR in the anterior circulation where the reduction of CVR was evident in the patient group. CONCLUSION: BOLD TS analysis has potential as a noninvasive alternative to current methods based on CVR for identification of tissue at risk of ischemic stroke. PMID- 30247677 TI - AmtDB: a database of ancient human mitochondrial genomes. AB - Ancient mitochondrial DNA is used for tracing human past demographic events due to its population-level variability. The number of published ancient mitochondrial genomes has increased in recent years, alongside with the development of high-throughput sequencing and capture enrichment methods. Here, we present AmtDB, the first database of ancient human mitochondrial genomes. Release version contains 1107 hand-curated ancient samples, freely accessible for download, together with the individual descriptors, including geographic location, radiocarbon dating, and archaeological culture affiliation. The database also features an interactive map for sample location visualization. AmtDB is a key platform for ancient population genetic studies and is available at https://amtdb.org. PMID- 30247678 TI - RGG-box in hnRNPA1 specifically recognizes the telomere G-quadruplex DNA and enhances the G-quadruplex unfolding ability of UP1 domain. AB - hnRNPA1 is a member of heteronuclear ribonucleoproteins that has been shown to promote telomere elongation apart from its roles in RNA transport and alternative splicing. It is a modular protein with an N-terminal domain called UP1 that consists of two RNA Recognition Motifs (RRM1 and RRM2 domains) and a C-terminal region that harbors functional motifs such as RGG-box, a prion-like domain, and a nuclear shuttling sequence. UP1 has been reported to bind and destabilize telomeric DNA G-quadruplexes and thereby participate in DNA telomere remodeling. An RGG-box motif that consists of four RGG repeats (containing arginine and glycine residues) is located C-terminal to the UP1 domain and constitutes an additional nucleic acid and protein-binding domain. However, the precise role of the RGG-box of hnRNPA1 in telomere DNA recognition and G-quadruplex DNA unfolding remains unexplored. Here, we show that the isolated RGG-box interacts specifically with the structured telomere G-quadruplex DNA but not with the single-stranded DNA. Further the interaction of the RGG-box with the G-quadruplex DNA is dependent on the loop nucleotides of the G-quadruplex. Finally, we show that the RGG-box enhances the G-quadruplex unfolding activity of the adjacent UP1 domain. We propose that UP1 and RGG-box act synergistically to achieve complete telomere G-quadruplex DNA unfolding. PMID- 30247679 TI - The social buffering of pain by affective touch: a laser-evoked potential study in romantic couples. AB - Pain is modulated by social context. Recent neuroimaging studies have shown that romantic partners can provide a potent form of social support during pain. However, such studies have only focused on passive support, finding a relatively late-onset modulation of pain-related neural processing. In this study, we examined for the first time dynamic touch by one's romantic partner as an active form of social support. Specifically, 32 couples provided social, active, affective (vs active but neutral) touch according to the properties of a specific C-tactile afferent pathway to their romantic partners, who then received laser induced pain. We measured subjective pain ratings and early N1 and later N2-P2 laser-evoked potentials (LEPs) to noxious stimulation, as well as individual differences in adult attachment style. We found that affective touch from one's partner reduces subjective pain ratings and similarly attenuates LEPs both at earlier (N1) and later (N2-P2) stages of cortical processing. Adult attachment style did not affect LEPs, but attachment anxiety had a moderating role on pain ratings. This is the first study to show early neural modulation of pain by active, partner touch, and we discuss these findings in relation to the affective and social modulation of sensory salience. PMID- 30247681 TI - Corrigendum. PMID- 30247680 TI - In memoriam-Mark E. Shirtliff (1969-2018). PMID- 30247682 TI - A new "lnc" between non-coding RNA and cardiac regeneration. PMID- 30247683 TI - Engineering Candida phangngensis-an oleaginous yeast from the Yarrowia clade-for enhanced detoxification of lignocellulose-derived inhibitors and lipid overproduction. AB - Candida phangngensis is an ascomycetous yeast and a phylogenetic relative of the industrial workhorse Yarrowia lipolytica. Here, we report that genetic tools already established for use in the latter organism-including promoters, expression vectors, antibiotic resistance genes, a transformation protocol, and the Cre/lox system for marker recycle-can be transferred to the newer member of the Yarrowia clade with little or no need for modifications. Using these tools, we engineered C. phangngensis for improved cellulosic lipid production by introducing two heterologous yeast genes. First, overexpression of Saccharomyces cerevisiae ADH6 enhanced in situ detoxification of aldehyde fermentation inhibitors that are generated during biomass pretreatment (e.g. furfural). Subsequently, Y. lipolytica DGA1 expression boosted lipid accumulation in C. phangngensis by pulling additional carbon flux into the triacylglycerol synthesis pathway. In acid-pretreated switchgrass hydrolysate cultures, the final engineered strain JQCP04 showed a 58% decrease in lag time and a 32% increase in lipid titer as compared to wild-type PT1-17. Furthermore, we expect that this study will generate new interest in the highly oleaginous yeast C. phangngensis, which is closely related to a safe, industrial species, and is shown here to be quite amenable for genetic manipulation. PMID- 30247684 TI - Next-Generation Robotic Spine Surgery: First Report on Feasibility, Safety, and Learning Curve. AB - Background: Pedicle screw placement is a commonly performed procedure. Robot guided screw placement is a recent technological advance that has shown accuracy and reliability with first-generation platforms. Objective: To report our initial experience with the safety, feasibility, and learning curve associated with pedicle screw placement utilizing next-generation robotic guidance. Methods: A retrospective chart review was conducted to obtain data for 20 patients who underwent lumbar pedicle screw placement under robotic guidance after undergoing interbody fusion for lumbar spinal stabilization for degenerative disc disease with or without spondylolisthesis. The newest generation Mazor X (Mazor Robotics Ltd, Caesarea, Israel) was used. Accuracy of screw placement was determined to be grade I to IV. Grade I was in the pedicle (no breach/deviation), grade II was breach < 2 mm, grade III was breach 2 to 4 mm, and grade IV was breach >4 mm; breach direction (superior, lateral, inferior, or medial) was also recorded. Results: Twenty patients underwent robotically assisted pedicle screw placement of 75 screws at 24 levels. Seventy-four screw placements (98.7%) were grade I; 1 (1.3%) was grade II (medial). No complications occurred. Mean time for screw insertion was 3.6 min. Mean fluoroscopy time was 13.1 s and mean radiation dose was 29.9 mGy. CONCLUSION: We found that next-generation robotic spine surgery was safe and feasible with reliable and precise accuracy and a minimal learning curve. As this technology improves, further novel applications are expected to develop. Further research is needed to determine long-term efficacy. PMID- 30247685 TI - Effect of metallic tools on scattered radiation dose during the use of C-arm fluoroscopy in orthopaedic surgery. AB - This study investigated the effect of metallic tools on the scattered radiation dose delivered to surgeons' radiosensitive organs while simulating hip surgery using C-arm fluoroscopy. Two phantoms, a pelvis and a Rando phantom, were used to simulate a patient and a surgeon in this study. Photoluminescence dosimeters were inserted into the Rando phantom in the positions of the eye, thyroid and gonad. A drill was positioned above the hip of the pelvis phantom or beside the pelvis phantom of the same height. For each drill location, the scattered radiation dose was measured when the angle to the operator phantom was 45 degrees ; this was repeated when the angle was 90 degrees . The scattered radiation doses to the eye, thyroid and gonad when the drill was placed beside the pelvis phantom with 90 degrees angulation to the operator phantom were significantly lower than the reference values and those when the drill was placed beside the pelvis phantom at a 45 degrees angulation to the operator phantom. The scattered radiation doses to the eye and thyroid when the drill was placed above the hip were significantly lower than the references values. Of the four different scenarios, the scattered radiation doses to the eye, thyroid and gonad were lowest when the drill was placed beside the pelvis phantom with 90 degrees angulation. This study showed that the scattered radiation doses to radiosensitive organs were affected by the location and angle of the metallic tools in relation to the operator. Therefore, orthopedic surgeons should consider the effect of metallic tools on the scattered radiation dose during intraoperative use of C-arm fluoroscopy. PMID- 30247688 TI - Sex-related Differences in Drug-induced QT Prolongation and Torsades de Pointes: a New Model System with Human iPSC-CMs. AB - Numerous drugs have the potential to prolong the QT interval and may cause accidental cardiac arrest (torsade de pointes, TdP). Women are at a higher risk than men for experiencing drug-induced TdP. Due to the lack of appropriate tools, few studies have investigated whether genetic differences between men and women have any effects on drug-induced proarrhythmia. Sex hormones are believed to play a predominant role in the induction of TdP. Recently, progress in induced pluripotent stem cell (iPSC) technologies has made it possible to utilize human iPSC-derived cardiomyocytes (hiPSC-CMs) to investigate the influence of both genetics and sex hormones on cardiac ion channel gene expression and cardiomyocyte function. In this study, we investigated genetic and hormonal effects on sex differences of drug-induced QT prolongation and TdP with hiPSC-CMs from healthy male and female donors. We found that despite batch variations in beating rates and field potential durations (FPD), female-derived hiPSC-CMs showed steeper slopes of FPD to interspike interval ratios and were more sensitive to IKr blocker-induced FPD prolongation. 17beta-estradiol increased FPD and 5alpha-dihydrotestosterone shortened FPD, but the addition of sex hormones had limited effect on the responses of hiPSC-CMs to IKr blockades. The differential expression of KCNE1 gene and reduced repolarization reserve in female-derived hiPSC-CMs compared to male-derived hiPSC-CMs may partially explain why females are more susceptible to proarrhythmias. Human iPSC-CMs can be a useful new model to study mechanisms of sex differences in cardiomyocyte repolarization processes and aid in the prediction of drug-induced proarrhythmias in both men and women. PMID- 30247687 TI - Palatability of beef chuck, loin, and round muscles from three USDA quality grades. AB - The objective of this study was to determine the palatability of various beef cuts from 3 USDA quality grades. Five different beef subprimals from USDA Prime, Choice, and Select (n = 10/quality grade) carcasses were utilized for the study, including: strip loins, inside rounds, bottom rounds, shoulder clods, and chuck rolls. Subprimals were fabricated into 9 retail cuts, which contained the following beef muscles: longissimus lumborum (LL); longissimus thoracis, complexus, and spinalis dorsi (LCS); infraspinatus (IF); serratus ventralis (SV); triceps brachii (TB); teres major (TM); adductor (AD); semimembranosus (SM); and biceps femoris (BF). The pH and percentage of fat, moisture, protein, and collagen was determined for each muscle on a raw basis. Additionally, cooked steak measurements included Warner-Bratzler shear force (WBSF) and slice shear force (SSF). Consumer and trained sensory panelists evaluated palatability traits of each cut and quality grade combination. A quality grade * muscle interaction was determined for trained panelists assessment of overall tenderness (P = 0.03), SSF (P = 0.02), proximate composition (P < 0.01), and pH (P < 0.01). In all objective and subjective measurements of tenderness, the LCS was the most tender (P < 0.05), while cuts from the round (BF, AD, and SM) were among the toughest and least juicy (P < 0.05). Conversely, consumers and trained sensory panelists identified the LCS, IF, and SV to be juicier (P < 0.05) than all others. The TB, TM, and LL were perceived by consumers most often as being everyday quality. The LCS was found by consumers to be the most acceptable (P < 0.05) across all attributes, with the SM being the least (P < 0.05) acceptable muscle. For each muscle, fat percentage was the greatest (P < 0.05) in Prime cuts. Slice shear force determined Prime IF, LL, and SV to be more tender (P < 0.05) than Choice and Select. No SSF differences (P > 0.05) were found among quality grades for the AD, BF, and SM. The WBSF values decreased (P < 0.05) across all muscles, as quality grade increased (Prime < Choice < Select). The results of this study indicate that muscles from the chuck may be utilized to provide consumers with a positive eating experience. Meanwhile, muscles from the round are likely to provide consumers with a lower quality eating experience. PMID- 30247686 TI - Human Breast-Milk Feeding Enhances the Humoral and Cell-Mediated Immune Response in Neonatal Piglets. AB - Background: The benefits of breastfeeding infants are well characterized, including those on the immune system. However, determining the mechanism by which human breast milk (HBM) elicits effects on immune response requires investigation in an appropriate animal model. Objective: The primary aim of this study was to develop a novel porcine model and to determine the differential effects of feeding HBM and a commercial milk formula (MF) on immune response and gastrointestinal microbial colonization in a controlled environment. Methods: Male piglets were fed HBM (n = 26) or MF (n = 26) from day 2 through day 21. Piglets were vaccinated (n = 9/diet group) with cholera toxin and cholera toxin subunit B (CTB) and tetanus toxoid at 21 d or were fed placebo (n = 6/diet group) and then weaned to a standard solid diet at the age of 21 d. Humoral and cell mediated immune responses were assessed from blood on days 35 and 48. Immune response was further examined from tissues, including mesenteric lymph nodes (MLNs), Peyer's patches (PPs), and spleen. The colonization of gut microbiota was characterized from feces on days 16 and 49. Results: Serum antibody titers in piglets fed HBM were 4-fold higher (P < 0.05) to CTB and 3-fold higher (P < 0.05) to tetanus toxoid compared with piglets fed MF on day 48. Compared with MF, the numbers of immunoglobulin A antibody-producing cells to CTB were 13-fold higher (P < 0.05) in MLNs and 11-fold higher (P < 0.05) in PPs in the HBM diet group on day 51. In addition, significantly increased T cell proliferation was observed in the HBM group relative to the MF group. Furthermore, microbial diversity in the HBM group was lower (P < 0.05) than in the MF group. Conclusions: This porcine model appears to be valid for studying the effects of early postnatal diet on immune responses and the gastrointestinal microbiome. Our results lay the groundwork for future studies defining the role of infant diet on microbiota and immune function. PMID- 30247689 TI - Allyl sulfide counteracts 1-bromopropane-induced neurotoxicity by inhibiting neuroinflammation and oxidative stress. AB - Chronic exposure to 1-bromopropane (1-BP), an alternative to ozone-depleting solvents, produces potential neurotoxicity in occupational populations. However, no therapeutic strategy is available currently. Accumulating evidence suggests that cytochrome P4502E1 (CYP2E1) is critical for the active metabolism of 1-BP. The purpose of this study is aimed to test whether inhibition of CYP2E1 by allyl sulfide, a specific inhibitor of CYP2E1, could be able to protect against 1-BP induced neurotoxicity. Male Wistar rats were intoxicated with 1-BP for 9 continuous weeks with or without allyl sulfide pre-treatment. Results clearly demonstrated that 1-BP exposure induced decrease in NeuN+ cells and increase in cleaved caspase-3 expression and TUNEL+ cells in motor cortex of rats, which was significantly ameliorated by allyl sulfide. Allyl sulfide treatment also recovered the motor performance of rats treated with 1-BP. Mechanistically, allyl sulfide inhibited 1-BP-induced expression of CYP2E1 in microglia, which was associated with suppression of microglial activation and M1 polarization in motor cortex of rats. Reduced oxidative stress was also observed in rats treated with combined allyl sulfide and 1-BP compared with 1-BP alone group. Furthermore, we found that allyl sulfide abrogated 1-BP-induced activation of NF-kappaB and GSH/Thioredoxin/ASK1 pathways, the key factor for the maintenance of M1 microglial inflammatory response and oxidative stress-related neuronal apoptosis, respectively. Thus, our results showed that allyl sulfide exerted neuroprotective effects in combating 1-BP-induced neurotoxicity through inhibition of neuroinflammation and oxidative stress. Blocking CYP2E1 activity by allyl sulfide might be a promising avenue for the treatment of neurotoxicity elicited by 1-BP and other related neurotoxicants. PMID- 30247691 TI - Animal production and soil characteristics from integrated crop-livestock systems: toward sustainable intensification. PMID- 30247692 TI - On the Importance of Using the Right Metrics for Patient Outcomes and Payment: Pain, Pain Interference, and Physical Function. PMID- 30247690 TI - The effect of periodic energy restriction on growth performance, serum biochemical indices, and meat quality in sheep. AB - Energy is a key factor regulated by the neuroendocrine system. The objective of this study was to compare growth performance, serum biochemical indices, carcass traits, meat quality, and nutrient composition of lambs fed restricted metabolizable energy (ME) intakes to mimic the seasonal changes of the natural grasslands of northwest China. Nineteen male Dorper * Small Tailed Han lambs were assigned to treatments, control (CON) fed at 1.0 MJ/W0.75 * d-1 throughout the 180 d study, and restricted ME (RES) fed by sequentially restricting ME every 30 d (0.56, 0.84, 1.0, 0.84, 0.56, and 0.28 MJ/W0.75 * d-1). Lambs were harvested at the end of the study. Lambs fed the CON diet demonstrated higher (P < 0.05) average daily gain (ADG) compared with RES-fed lambs (158.79 and 57.01 g/d, for CON and RES, respectively), although ADG were lower in each period with the last period being a negative ADG for RES-fed lambs resulting in a loss of body weight. Both treatments demonstrated lower ADG in the last 3 study periods compared with the first 2 periods, which may be explained by cold stress (<-3 degrees C) increasing the lamb's energy requirement. Feeding lambs a restricted ME diet resulted in lower (P < 0.05) blood serum glucose, triglycerides, total protein, calcium, phosphorus, immunoglobulin G, immunoglobulin M, and immunoglobulin A concentrations compared with CON-fed lambs, but both treatments were similar (P > 0.05) for cholesterol and high-density lipoprotein-cholesterol. Feeding lambs a restricted ME diet increased (P < 0.05) meat pH, while reducing the cooked meat rate compared with CON-fed lambs. Thus, the carcass yield, rib eye muscle area, and shear force were lower (P < 0.05) for RES-fed lambs compared with CON-fed lambs. The meat water concentration was higher (P < 0.05), whereas the concentrations of dry matter, crude fat, crude protein, and carbohydrate were lower (P < 0.05) for lambs fed a RES ME diet compared to CON-fed lambs. These results demonstrate that sequentially restricting ME intake, as natural grasslands might experience during seasonal forage quality and quantity changes, resulted in a reduction of body weight because lambs were mobilizing body reserves as a source of ME. The reduction in concentrations of key serum nutrients, as well as carcass traits and meat composition, demonstrate the body is responding to the meet the lambs ME requirements, which has implications for both meat quality and the animal's physiological functions. PMID- 30247694 TI - The Sleep Research Society (SRS) is excited to be part of the evolution happening at SLEEP. PMID- 30247695 TI - Changes for SLEEP in 2017. PMID- 30247693 TI - Effects of reductive acetogenic bacteria and lauric acid on in vivo ruminal fermentation, microbial populations, and methane mitigation in Hanwoo steers in South Korea. PMID- 30247696 TI - Nailfold capillaroscopy-how many fingers should be examined to detect abnormality? AB - Objectives: Nailfold capillaroscopy is being increasingly used by rheumatologists in the diagnosis of SSc. However, assessment of all nailfolds can be time consuming in a busy outpatient clinic. Our aim was to answer the question as to how many (and which) fingers a clinician should routinely assess to capture accurately the true state. Methods: A total of 2994 assessments (by an international panel of expert observers) of 1600 images from 173 participants (101 with SSc, 22 with primary RP and 50 healthy controls) were included in this analysis. Seven single-finger or finger combinations (derived from the middle and ring fingers) were then tested for sensitivity for the presence of two markers of capillary abnormality [presence of giant capillaries and an SSc grade (early, active or late)] compared with assessment of all eight fingers. Results: For the eight-finger gold standard, sensitivity against the diagnostic criteria was 74.6% (53.0% for the presence of giants alone and 73.1% for image grade alone). Examining only one finger gave low sensitivity (ranging from right middle 31.7% to left ring 46.6%). Examining both ring fingers gave a sensitivity of 59.8%, whereas examining the four-finger combination of both ring and both middle fingers gave a sensitivity of 66.7%. Conclusion: During routine capillaroscopic examination, ideally all eight nailbeds (excluding thumbs) should be examined, otherwise some abnormalities will be missed. Examining only four fingers reduces capillaroscopy sensitivity. PMID- 30247697 TI - Microbiome profiling in extremely acidic soils affected by hydrothermal fluids: the case of the Solfatara Crater (Campi Flegrei, southern Italy). AB - An integrated geochemical and microbiological investigation of soils from the Solfatara Crater (Campi Flegrei, southern Italy) demonstrated that interstitial soil gases dominated by CO2 and other typical hydrothermal gaseous species (e.g. H2S, CH4, ethane, benzene, alkenes and S-bearing organic compounds) influenced the composition of microbial communities. The relatively high concentrations of hydrothermal fluids permeating the soil produced acidic conditions and whitish deposits that characterize the Solfatara Crater floor. Archaea and Bacteria showed almost equal cell abundance (up to 3.2 * 107 and 4.2 * 107 cell/g, respectively) with relatively low levels of biodiversity and equitability in sites characterized by elevated temperatures (up to 70 degrees C), very low pH values (up to 2.2) and reducing conditions. In these sites, high-throughput sequencing showed the marked selection of microorganisms, mainly affiliated with the genera Thermoplasma, Ferroplasma and Acidithiobacillus. A relatively high biodiversity and concomitant distinctive structure of the microbial community were observed in soils poorly affected by fumarolic emissions that were oxic and rich in organic matter. PMID- 30247698 TI - The Developmental Neurotoxicity of Tobacco Smoke Can Be Mimicked by a Combination of Nicotine and Benzo[a]pyrene: Effects on Cholinergic and Serotonergic Systems. AB - Tobacco smoke contains polycyclic aromatic hydrocarbons (PAHs) in addition to nicotine. We compared the developmental neurotoxicity of nicotine to that of the PAH archetype, benzo[a]pyrene (BaP), and also evaluated the effects of combined exposure to assess whether PAHs might exacerbate the adverse effects of nicotine. Pregnant rats were treated preconception through the first postnatal week, modeling nicotine concentrations in smokers and a low BaP dose devoid of systemic effects. We conducted evaluations of acetylcholine (ACh) and serotonin (5HT) systems in brain regions from adolescence through full adulthood. Nicotine or BaP alone impaired indices of ACh presynaptic activity, accompanied by upregulation of nicotinic ACh receptors and 5HT receptors. Combined treatment elicited a greater deficit in ACh presynaptic activity than that seen with either agent alone, and upregulation of nAChRs and 5HT receptors was impaired or absent. The individual effects of nicotine and BaP accounted for only 60% of the combination effects, which thus displayed unique properties. Importantly, the combined nicotine + BaP exposure recapitulated the effects of tobacco smoke, distinct from nicotine. Our results show that the effects of nicotine on development of ACh and 5HT systems are worsened by BaP coexposure, and that combination of the two agents contributes to the greater impact of tobacco smoke on the developing brain. These results have important implications for the relative safety in pregnancy of nicotine-containing products compared to combusted tobacco, both for active maternal smoking and secondhand exposure, and for the effects of such agents in "dirty" environments with high PAH coexposure. PMID- 30247699 TI - Should parents see their teen's medical record? Asking about the effect on adolescent-doctor communication changes attitudes. AB - Objective: Parents routinely access young children's medical records, but medical societies strongly recommend confidential care during adolescence, and most medical centers restrict parental records access during the teen years. We sought to assess public opinion about adolescent medical privacy. Materials and Methods: The Cornell National Social Survey (CNSS) is an annual nationwide public opinion survey. We added questions about a) whether parents should be able to see their 16-year-old child's medical record, and b) whether teens would avoid discussing sensitive issues (sex, alcohol) with doctors if parents could see the record. Hypothesizing that highlighting the rationale for adolescent privacy would change opinions, we conducted an experiment by randomizing question order. Results: Most respondents (83.0%) believed that an adolescent would be less likely to discuss sensitive issues with doctors with parental medical record access; responses did not differ by question order (P = .29). Most also believed that parents should have access to teens' records, but support for parental access fell from 77% to 69% among those asked the teen withholding question first (P = .01). Conclusions: Although medical societies recommend confidential care for adolescents, public opinion is largely in favor of parental access. A brief "nudge," asking whether parental access might harm adolescent-doctor communication, increased acceptance of adolescent confidentiality, and could be part of a strategy to prepare parents for electronic patient portal policies that medical centers impose at the beginning of adolescence. PMID- 30247700 TI - Stereoscopic Surgical Video of Combined Petrosectomy With Virtual Reality Headset: 3-Dimensional Operative Video. AB - The use of 3-dimensional (3D) videos allows students to visualize surgical procedures from the perspective of the surgeon without missing the essential parts.1 This 3D commented video demonstrates the operative technique and surgical nuances of the combined petrosectomy, visualize using virtual reality headsets. Historically, traditional intradural cisternal routes using suboccipital and pterional approaches have been proposed to remove petroclival tumors.2-5 It allows rapid identification of neurovascular structures and a short exposure time. However, access to the petroclival region is far, not direct, and requires intradural cerebral retraction.6 In order to improve the access for tumoral dissection, lateral transpetrosal approaches have been proposed.7-12 The extradural route shortened the distance to the petroclival region, allows to better preserve the veins, to decrease the cerebral retraction, to interrupt early the tumor vascular supply, and a larger extent of resection.6 Transpetrosal approaches includes middle fossa approach8,10 (removing the petrous apex), posterior petrosal approach9,13,14 (removing of presigmoid retrolabyrinthine bone), and translabyrinthine petrosectomy.12 A combined petrosectomy may be used to approach larger tumor extending across the clival midline, upward to the tentorium or downward to the lower cranial nerves.6,10,15,16 Alternatively, according to Nanda, a retrosigmoid approach may need to be performed to avoid critical draining veins injury.10,17 Good resection and outcomes are obtained when experienced surgeons use familiar approaches and microsurgical techniques.10. PMID- 30247701 TI - Smoking associated T-Cell imbalance in patients with chronic pain. AB - Introduction: Smoking is associated with several diseases and affects the immune system. Recently, published data demonstrate an involvement of Th17 and regulatory T cells (Tregs) in the pathogenesis of chronic pain and pain intensity. The role of these T cell subsets in smoking patients with chronic pain is nebulous so far. We therefore analyzed Th17 cells and Tregs in smokers and non smokers suffering from chronic pain. Methods: Analyses of T cell subsets, mRNA expression and T cell related cytokine profiles were done in 44 patients with chronic pain. 22 of these patients were smokers. Numbers of T cell subsets were quantified by flow cytometry. mRNA expression of the Th17 (RORgammaT) and Treg (FoxP3) specific transcription factors was determined by quantitative real-time PCR (qPCR), and levels of cytokines were measured by Human Cytokine Multiplex Immunoassay. Results: Compared to non-smokers, smokers showed significantly enhanced pain levels. On cellular basis, the number of pro-inflammatory Th17 cells (smokers: 2.+/-2.5 % vs. non-smokers: 0.5+/-0.4 %; p=0.04) was increased, whereas the amount of anti-inflammatory Tregs (smokers: 2.5+/-0.9 % vs. non smokers: 3.1+/-1.1 %; p=0.02) was significantly decreased, resulting in an altered Th17/Treg ratio (Th17/Treg ratio: 0.9+/-1.0 in smokers vs. 0.2+/-0.1 in non-smokers; p<0.01). These findings were confirmed by qPCR. Analyses of cytokines revealed only marginal changes. Conclusions: In chronic pain patients, smoking is associated with enhanced pain levels together with an imbalance of the Th17/Treg ratio. The shift of the Th17/Treg ratio towards inflammation may explain in part the increased pain intensity in these patients. German Clinical Trial Register (DRKS): Registration Trial DRKS00005954. PMID- 30247702 TI - SURVEY OF KEY RADIATION SAFETY PRACTICES IN INTERVENTIONAL RADIOLOGY: AN IRISH AND ENGLISH STUDY. AB - Interventional radiology is a rapidly evolving speciality with potential to deliver high patient radiation doses, as a result high standards of radiation safety practice are imperative. IR radiation safety practice must be considered before during and after procedures through appropriate patient consent, dose monitoring and patient follow-up. This questionnaire-based study surveyed fixed IR departments across Ireland and England to establish clinical practice in relation to radiation safety. Pre-procedure IR patient consent includes all radiation effects in 11% of cases. The patient skin dose surrogate parameter of Kerma to air at a reference point (Kar) is under-reported. Only 39% of respondents use a substantial radiation dose level and inform patients after these have been reached. Poor compliance with unambiguous, readily available best practice guidance was observed throughout highlighting patient communication, patient dose quantification and subsequent patient dose management concerns. PMID- 30247703 TI - Identification of Modulators that Activate the Constitutive Androstane Receptor from the Tox21 10K Compound Library. AB - The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor involved in all phases of drug metabolism and disposition. However, recently it's been implicated in energy metabolism, tumor progression, and cancer therapy as well. It is, therefore, important to identify compounds that induce hCAR activation to predict drug-drug interactions and potential therapeutic usage. In this study, we screen the Tox21 10,000 compound collection to characterize hCAR activators. A novel structural cluster of compounds was identified, which included nitazoxanide and tenonitrozole, while known structural clusters, such as flavones and prazoles, were also detected. Four compounds, neticonazole, diphenamid, phenothrin, and rimcazole, have been identified as novel hCAR activators, one of which, rimcazole, shows potential selectivity towards hCAR over its sister receptor, the pregnane X receptor (PXR). All four compounds translocated hCAR from the cytoplasm into the nucleus demonstrating the first step to CAR activation. Profiling these compounds as hCAR activators would enable an estimation of drug-drug interactions, as well as identify prospective therapeutically beneficial drugs. PMID- 30247705 TI - Life History Traits Impact the Nuclear Rate of Substitution but Not the Mitochondrial Rate in Isopods. AB - The rate of molecular evolution varies widely among species. Life history traits (LHTs) have been proposed as a major driver of these variations. However, the relative contribution of each trait is poorly understood. Here, we test the influence of metabolic rate (MR), longevity, and generation time (GT) on the nuclear and mitochondrial synonymous substitution rates using a group of isopod species that have made multiple independent transitions to subterranean environments. Subterranean species have repeatedly evolved a lower MR, a longer lifespan and a longer GT. We assembled the nuclear transcriptomes and the mitochondrial genomes of 13 pairs of closely related isopods, each pair composed of one surface and one subterranean species. We found that subterranean species have a lower rate of nuclear synonymous substitution than surface species whereas the mitochondrial rate remained unchanged. We propose that this decoupling between nuclear and mitochondrial rates comes from different DNA replication processes in these two compartments. In isopods, the nuclear rate is probably tightly controlled by GT alone. In contrast, mitochondrial genomes appear to replicate and mutate at a rate independent of LHTs. These results are incongruent with previous studies, which were mostly devoted to vertebrates. We suggest that this incongruence can be explained by developmental differences between animal clades, with a quiescent period during female gametogenesis in mammals and birds which imposes a nuclear and mitochondrial rate coupling, as opposed to the continuous gametogenesis observed in most arthropods. PMID- 30247704 TI - High Pregnancy, Cord Blood and Infant Vitamin D Concentrations May Predict Slower Infant Growth. AB - Context: The relationship of maternal and infant 25-hydroxyvitamin D concentration [25(OH)D] with infant growth is unclear. Objective: Our objective was to explore whether 25(OH)D in pregnancy, umbilical cord blood (UCB) or in infancy are associated with infant growth. Design: This study involved 798 healthy infants and their mothers in Finland. We assessed 25(OH)D during pregnancy, from UCB at birth and from the infant at the age of 12 months. Main Outcome Measures: Infant length, weight, length-adjusted weight, head circumference at 6 and 12 months and mid-upper-arm circumference at 12 months. Results: Of the mothers and infants 96% and 99% were vitamin D sufficient [25(OH)D >=50 nmol/L]. Mothers with pregnancy 25(OH)D >125 nmol/L had the shortest, lightest (in weight) and thinnest (in length-adjusted weight) infants at 6 months (P for all <0.05). For each 10 nmol/L higher UCB 25(OH)D, the infants were 0.03 standard deviation score (SDS) shorter at 6 months (95% confidence interval -0.05, -0.01), adjusted for birth size, infant 25(OH)D and parental height. Higher UCB 25(OH)D associated with smaller head circumference at 6 and 12 months (P for all <0.05) but attenuated after adjustments. Mothers with pregnancy 25(OH)D >125 nmol/L had the thinnest infants at 12 months (P=0.021). For each 10 nmol/L higher infant 25(OH)D, the infants were 0.03 SDS lighter (-0.05, -0.01) and 0.03 SDS thinner (-0.05, 0.00) at 12 months. Conclusions: Our results suggest that high pregnancy, cord blood and infant vitamin D concentration may have disadvantageous effects on infant growth. PMID- 30247706 TI - Umbilical Cord Hepcidin Concentrations Are Positively Associated with the Variance in Iron Status among Multiple Birth Neonates. AB - Background: Hepcidin is a systemic regulator of iron homeostasis. Little is known about the relative role of maternal compared with cord hepcidin on neonatal iron homeostasis. Objective: This study was undertaken to evaluate inter- and intrauterine variance in neonatal iron status, vitamin B-12, folate, and inflammatory markers in a cohort of twins (n = 50), triplets (n = 14), and quadruplets (n = 1) born to 65 women. Methods: Umbilical cord blood was obtained from 144 neonates born at 34.8 +/- 2.7 wk of gestation with a mean birth weight of 2236 +/- 551 g (means +/- SDs). Cord hemoglobin and cord serum measures of ferritin (SF), soluble transferrin receptor (sTfR), hepcidin, erythropoietin (EPO), iron, vitamin B-12, folate, interleukin 6, and C-reactive protein were evaluated. Results: Intraclass correlation coefficient (ICC) analyses were used to examine inter- and intrauterine variance in neonatal iron indicators. A greater variability in cord hepcidin (ICC = 0.39) was found between siblings. Cord hepcidin had the greatest association with cord iron indicators because cord hepcidin alone captured 63.8%, 48.4%, 44.4%, and 31.3% of the intrauterine variance in cord hemoglobin, SF, sTfR, and EPO, respectively, whereas maternal hepcidin had no effect on cord iron indicators. Significantly greater differences in cord SF (P = 0.03), sTfR (P = 0.03), hepcidin (P = 0.0003), and EPO (P = 0.03) were found between di- and trichorionic siblings than between monochorionic siblings. In contrast, cord folate (ICC = 0.79) and vitamin B-12 (ICC = 0.74) exhibited a greater variability between unrelated neonates. Conclusions: In summary, fetally derived hepcidin might have more control on intrauterine variance in iron indicators than maternal hepcidin and appears to be capable of regulating fetal iron status independently of maternal hepcidin. The use of a multiple-birth model provides a unique way to identify factors that may contribute to placental nutrient transport and iron stores at birth. PMID- 30247707 TI - Synanthropy and Community Structure of Ceratopogonidae From the Northeast of Buenos Aires Province, Argentina. AB - Synanthropy and community structure of Ceratopogonidae in temperate Argentina were compared across an urbanization gradient to assess the impact of urbanization on species diversity and abundance. Adult ceratopogonids were collected from one natural, one Peri-urban, and two urban sites monthly for 12 months using CDC light traps. Nine-hundred one individuals belonging to nine genera and 59 species were collected. Forcipomyia Meigen was the genus with the highest species richness (n = 20), followed by Atrichopogon Kieffer (14), Dasyhelea Kieffer (8), Stilobezzia Kieffer (7), Culicoides Latreille (5), Bezzia Kieffer (2), Alluaudomyia Kieffer, Monohelea Kieffer, and Palpomyia Meigen (1). Only 15 species were present at the three different areas. Indices of species abundance (ISA) values were statistically similar between urban and Peri-urban areas, but these were significantly lower than those from the natural area. Atrichopogon balseiroi Spinelli, Dasyhelea sp. C., Forcipomyia poulaineae Ingram, and Macfie and F. nana (Macfie) were positively associated with rain fall, while A. albinensis, A. delpontei, D. suarezi, Forcipomyia sp. B, F. sp. I, F. pinamarensis, and F. calchaqui were associated to relative humidity. Species diversity was reduced in urbanized areas and these areas favored ubiquitous species: Forcipomyia taragui Marino, Spinelli and Cazorla, F. poulaineae, and Culicoides venezuelensis Ortiz and Mirsa. PMID- 30247709 TI - New Geographical Records of Bat Flies (Diptera: Streblidae) Associated With Phyllostomid Bats (Chiroptera: Phyllostomidae) in the West Highlands of Mexico. AB - Streblidae are ectoparasites exclusive to bats and feed only on their blood. Studies on ectoparasite fauna have increased our ecological knowledge of the parasitic relationship between streblids and their bat hosts. We evaluate assemblages of phyllostomid bats and their ectoparasitic flies in three scenarios with different types of anthropogenic use: pine-oak forest, avocado orchards, and an urban park during an annual cycle in the highlands of Michoacan, Mexico. We recorded a total of 325 bats belonging to nine species in three subfamilies: Glossophaginae, Desmodontinae, and Stenodermatinae, and obtained 225 bat flies belonging to seven species. The nectivorous bat Anoura geoffroyi Gray, 1838, had the highest prevalence of infestation and the hematophagous bat Desmodus rotundus (E. Geoffroy, 1810) was the host with the highest mean parasite abundance and mean intensity. Aspidoptera delatorrei Wenzel, 1966, Megistopoda proxima (Seguy, 1926), Paratrichobius longicrus (Miranda Ribeiro, 1907), Trichobius brennani Wenzel, 1966, and T. parasiticus Gervais, 1844, are new records for the state of Michoacan reported in this study. PMID- 30247708 TI - Comprehensive analysis of the BC200 ribonucleoprotein reveals a reciprocal regulatory function with CSDE1/UNR. AB - BC200 is a long non-coding RNA primarily expressed in brain but aberrantly expressed in various cancers. To gain a further understanding of the function of BC200, we performed proteomic analyses of the BC200 ribonucleoprotein (RNP) by transfection of 3' DIG-labelled BC200. Protein binding partners of the functionally related murine RNA BC1 as well as a scrambled BC200 RNA were also assessed in both human and mouse cell lines. Stringent validation of proteins identified by mass spectrometry confirmed 14 of 84 protein binding partners and excluded eight proteins that did not appreciably bind BC200 in reverse experiments. Gene ontology analyses revealed general roles in RNA metabolic processes, RNA processing and splicing. Protein/RNA interaction sites were mapped with a series of RNA truncations revealing three distinct modes of interaction involving either the 5' Alu-domain, 3' A-rich or 3' C-rich regions. Due to their high enrichment values in reverse experiments, CSDE1 and STRAP were further analyzed demonstrating a direct interaction between CSDE1 and BC200 and indirect binding of STRAP to BC200 via heterodimerization with CSDE1. Knock-down studies identified a reciprocal regulatory relationship between CSDE1 and BC200 and immunofluorescence analysis of BC200 knock-down cells demonstrated a dramatic reorganization of CSDE1 into distinct nuclear foci. PMID- 30247710 TI - Mosquitoes of the Caatinga. III. Larval Habitats, Frequency, and Dynamics of Immature and Adult Stages in a Dry Brazilian Forest. AB - Even though the seasonally dry tropical Caatinga forest is an historically neglected biome, recent studies have enhanced our knowledge of its biodiversity. We investigated larval habitats as well as the frequency and dynamics of immature and adult Culicidae in a conservation unit within the Caatinga in the Brazilian state of Sergipe. We carried out monthly surveys between July 2011 and October 2012 to count both immature (tree holes, bromeliad tanks, ponds, and rock holes and depressions) and adult individuals (Shannon traps baited with light). In total 8,021 individuals representing 32 taxa, eight of which are currently undescribed, were collected. The majority of the specimens collected came from tree holes followed by bromeliads, ponds, and rock depressions. Ponds had the highest species richness in this survey while the bromeliad fauna exhibited high endemicity. We also reveal a correlation between precipitation during the month prior to collection and the abundance of immature individuals in tree holes. Peaks in Haemagogus sp. near spegazzinii and Aedes terrens abundance were observed soon after rain, whereas Culex conservator was abundant during the rainy season in tree holes evidencing a species rotation within this habitat. Although the results of this study contribute to our knowledge regarding the distribution of mosquitoes in Brazilian semiarid region, further taxonomic studies will be required to fully understand the richness and endemism of the Neotropical Culicidae fauna. PMID- 30247711 TI - Employing Dietary Comparators to Perform Risk Assessments for Anti-Androgens Without Using Animal Data. AB - This study investigated the use of androgen receptor (AR) reporter gene assay data in a non-animal exposure-led risk assessment in which in vitro anti androgenic activity and exposure data were put into context using a naturally occurring comparator substance with a history of dietary consumption. First, several dietary components were screened to identify which selectively interfered with AR signaling in vitro, using the AR CALUX(r) test. The IC50 values from these dose-response data together with measured or predicted human exposure levels were used to calculate exposure:activity ratios (EARs) for the dietary components and a number of other well-known anti-androgenic substances. Both diindolylmethane (DIM) and resveratrol are specifically-acting dietary anti androgens. The EARs for several anti-androgens were therefore expressed relative to the EAR of DIM, and how this 'dietary comparator ratio' (DCR) approach may be used to make safety decisions was assessed using an exposure-led case study for an anti-androgenic botanical ingredient. This highlights a pragmatic approach which allows novel chemical exposures to be put into context against dietary exposures to natural anti-androgenic substances. The DCR approach may have utility for other modes of action where appropriate comparators can be identified. PMID- 30247713 TI - Differential toxicity of alkylphenols in JEG-3 human placental cells: alteration of P450 aromatase and cell lipid composition. AB - Alkylphenols (APs) are a diverse class of chemicals that can cross the placental barrier and interfere with embryonic and foetal development. This work investigates the comparative toxicity, ability to inhibit aromatase activity and to alter the lipid composition of ten alkylphenols in the human placenta choriocarcinoma cell line JEG-3. Among the selected APs, 4-Dodecylphenol (DP), 4 heptylphenol (HP) and 4-cumylphenol (CP) showed the highest cytotoxicity (EC50: 18-65 uM). Aromatase inhibition was closely related to the hydrophobicity of APs. HP significantly induced the generation of reactive oxygen species (ROS) (43 fold), inhibited placental aromatase activity (IC50: 41 uM) and induced a general dose-dependent depletion of polyunsaturated lipids (10-20 uM), which were attributed to high levels of oxidative stress. In contrast, 2,4,6-tri-tert butylphenol (TTBP) significantly induced the intracellular accumulation of triacylglycerides (TGs), while DP increased the synthesis of phosphatidylcholines (PCs) and TGs at the expense of diacylglycerides (DGs). Overall, this study evidences the different modes of action of alkylphenols in human placental JEG-3 cells, describes differential lipidomic fingerprints, and highlights DP, HP, CP and TTBP as the ones that caused the most harmful effects. PMID- 30247712 TI - Monopoiesis in humans and mice. AB - Monocytes are a widely conserved cell population in vertebrates with important roles in both inflammation and homeostasis. Under both settings, monocytes continuously arise from hematopoietic progenitors in the bone marrow and, on demand, migrate into tissues through the bloodstream. Monocytes are classified into three subsets-classical, intermediate and non-classical-based on their cell surface expression of CD14 and CD16 in humans and Ly6C, CX3CR1 and CCR2 in mice. In tissues, monocytes differentiate further into monocyte-derived macrophages and dendritic cells to mediate innate and adaptive immune responses and maintain tissue homeostasis. Recently, the progenitors that strictly give rise to monocytes were identified in both humans and mice, thereby revealing the monocyte differentiation pathways. PMID- 30247714 TI - Protein Supplementation after Exercise and before Sleep Does Not Further Augment Muscle Mass and Strength Gains during Resistance Exercise Training in Active Older Men. AB - Background: The proposed benefits of protein supplementation on the skeletal muscle adaptive response to resistance exercise training in older adults remain unclear. Objective: The present study assessed whether protein supplementation after exercise and before sleep augments muscle mass and strength gains during resistance exercise training in older individuals. Methods: Forty-one older men [mean +/- SEM age: 70 +/- 1 y; body mass index (kg/m2): 25.3 +/- 0.4] completed 12 wk of whole-body resistance exercise training (3 sessions/wk) and were randomly assigned to ingest either protein (21 g protein, 3 g total leucine, 9 g carbohydrate, 3 g fat; n = 21) or an energy-matched placebo (0 g protein, 25 g carbohydrate, 6 g fat; n = 20) after exercise and each night before sleep. Maximal strength was assessed by 1-repetition-maximum (1RM) strength testing, and muscle hypertrophy was assessed at the whole-body (dual-energy X-ray absorptiometry), upper leg (computed tomography scan), and muscle fiber (biopsy) levels. Muscle protein synthesis rates were assessed during week 12 of training with the use of deuterated water (2H2O) administration. Results: Leg-extension 1RM increased in both groups (placebo: 88 +/- 3 to 104 +/- 4 kg; protein: 85 +/- 3 to 102 +/- 4 kg; P < 0.001), with no differences between groups. Quadriceps cross-sectional area (placebo: 67.8 +/- 1.7 to 73.5 +/- 2.0 cm2; protein: 68.4 +/ 1.4 to 72.3 +/- 1.4 cm2; P < 0.001) increased in both groups, with no differences between groups. Muscle fiber hypertrophy occurred in type II muscle fibers (placebo: 5486 +/- 418 to 6492 +/- 429 um2; protein: 5367 +/- 301 to 6259 +/- 391 um2; P < 0.001), with no differences between groups. Muscle protein synthesis rates were 1.62% +/- 0.06% and 1.57% +/- 0.05%/d in the placebo and protein groups, respectively, with no differences between groups. Conclusion: Protein supplementation after exercise and before sleep does not further augment skeletal muscle mass or strength gains during resistance exercise training in active older men. This study was registered at the Netherlands Trial Registry (www.trialregister.nl) as NTR5082. PMID- 30247715 TI - Video Game-Based Exercises for Older People With Chronic Low Back Pain: A Randomized Controlled Trial (GAMEBACK). AB - Background: Video game technology increases adherence to home exercise and could support self-management for older people with chronic low back pain (LBP). Objectives: The objective was to investigate the effects of home-based video game exercises on pain self-efficacy and care seeking in older people with chronic LBP. Design: The study was a randomized controlled trial. Setting: The setting was a community and waiting list. Patients: Sixty participants, aged 55 years or older, with chronic LBP were randomized (1:1) to Wii Fit U exercises or to continue their usual activities for 8 weeks. Intervention: Home-based Wii Fit U flexibility, strengthening, and aerobic exercises, for 60 minutes, 3 times per week, with fortnightly calls from a physical therapist was prescribed. Measurements: Measurements included pain self-efficacy and care seeking (primary outcomes), and physical activity, pain, function, disability, fear of movement/re injury, falls-efficacy, recruitment and response rates, adherence, experience with the intervention, and adverse events (secondary outcomes). Results: The mean age of participants was 67.8 (SD = 6.0) years. Adherence to the total recommended exercise time was 70.8%, and no adverse events were reported. Participants completing Wii Fit U exercises had significantly higher pain self-efficacy at 6 months, but not immediately post-intervention or at 3 months; there were no between-group differences in care-seeking. Compared with the control group, participants completing Wii Fit U exercises demonstrated significantly greater improvements in pain and function at 8 weeks and were more likely to engage in flexibility exercises at 6 months. There were no significant between-group differences for the remaining outcomes. Limitations: Participants and therapists were not blinded. Conclusion: Wii Fit U exercises improved pain self-efficacy at 6 months and pain and function immediately post-intervention in older people with chronic LBP, but the clinical importance of these changes are questionable. Wii Fit U exercises had no effect on care-seeking, physical activity, disability, fear of movement/re-injury, or falls-efficacy. PMID- 30247718 TI - A new, free, multidisciplinary e-book on Ehlers-Danlos syndrome has recently been published. PMID- 30247716 TI - Enterovirus 71 antagonizes the inhibition of the host intrinsic antiviral factor A3G. AB - Although the host restriction factor APOBEC3G (A3G) has broad spectrum antiviral activity, whether A3G inhibits enterovirus 71 (EV71) has been unclear until now. In this study, we demonstrated for the first time that A3G could inhibit EV71 virus replication. Silencing A3G in H9 cells enhanced EV71 replication, and EV71 replication was lower in H9 cells expressing A3G than in Jurkat cells without A3G expression, indicating that the EV71 inhibition was A3G-specific. Further investigation revealed that A3G inhibited the 5'UTR activity of EV71 by competitively binding to the 5'UTR through its nucleic acid binding activity. This binding impaired the interaction between the 5'UTR and the host protein poly(C)-binding protein 1 (PCBP1), which is required for the synthesis of EV71 viral proteins and RNA. On the other hand, we found that EV71 overcame A3G suppression through its non-structural protein 2C, which induced A3G degradation through the autophagy-lysosome pathway. Our research provides new insights into the interplay mechanisms of A3G and single-stranded positive RNA viruses. PMID- 30247717 TI - Pancreatic beta-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes. AB - Transfer RNAs (tRNAs) are non-coding RNA molecules essential for protein synthesis. Post-transcriptionally they are heavily modified to improve their function, folding and stability. Intronic polymorphisms in CDKAL1, a tRNA methylthiotransferase, are associated with increased type 2 diabetes risk. Loss of-function mutations in TRMT10A, a tRNA methyltransferase, are a monogenic cause of early onset diabetes and microcephaly. Here we confirm the role of TRMT10A as a guanosine 9 tRNA methyltransferase, and identify tRNAGln and tRNAiMeth as two of its targets. Using RNA interference and induced pluripotent stem cell-derived pancreatic beta-like cells from healthy controls and TRMT10A-deficient patients we demonstrate that TRMT10A deficiency induces oxidative stress and triggers the intrinsic pathway of apoptosis in beta-cells. We show that tRNA guanosine 9 hypomethylation leads to tRNAGln fragmentation and that 5'-tRNAGln fragments mediate TRMT10A deficiency-induced beta-cell death. This study unmasks tRNA hypomethylation and fragmentation as a hitherto unknown mechanism of pancreatic beta-cell demise relevant to monogenic and polygenic forms of diabetes. PMID- 30247719 TI - The APT complex is involved in non-coding RNA transcription and is distinct from CPF. AB - The 3'-ends of eukaryotic pre-mRNAs are processed in the nucleus by a large multiprotein complex, the cleavage and polyadenylation factor (CPF). CPF cleaves RNA, adds a poly(A) tail and signals transcription termination. CPF harbors four enzymatic activities essential for these processes, but how these are coordinated remains poorly understood. Several subunits of CPF, including two protein phosphatases, are also found in the related 'associated with Pta1' (APT) complex, but the relationship between CPF and APT is unclear. Here, we show that the APT complex is physically distinct from CPF. The 21 kDa Syc1 protein is associated only with APT, and not with CPF, and is therefore the defining subunit of APT. Using ChIP-seq, PAR-CLIP and RNA-seq, we show that Syc1/APT has distinct, but possibly overlapping, functions from those of CPF. Syc1/APT plays a more important role in sn/snoRNA production whereas CPF processes the 3'-ends of protein-coding pre-mRNAs. These results define distinct protein machineries for synthesis of mature eukaryotic protein-coding and non-coding RNAs. PMID- 30247720 TI - Phylogeography of African Locust Bean (Parkia biglobosa) Reveals Genetic Divergence and Spatially Structured Populations in West and Central Africa. AB - The evolutionary history of African savannah tree species is crucial for the management of their genetic resources. In this study, we investigated the phylogeography of Parkia biglobosa and its modeled distribution under past and present climate conditions. This tree species is very valued and widespread in West Africa, providing edible and medicinal products. A large sample of 1610 individuals from 84 populations, distributed across 12 countries in Western and Central Africa, were genotyped using 8 nuclear microsatellites. Individual-based assignments clearly distinguished 3 genetic clusters, extreme West Africa (EWA), center of West Africa (CWA), and Central Africa (CA). Overall, estimates of genetic diversity were moderate to high, with lower values for populations in EWA (allelic richness after rarefaction [AR] = 6.4, expected heterozygosity [HE] = 0.78, and observed heterozygosity [HO] = 0.7) and CA (AR = 5.9, HE = 0.67, and HO = 0.61) compared with populations in CWA (AR = 7.3, HE = 0.79, and HO = 0.75). The overall population differentiation was found to be moderate (FST = 0.09). A highly significant isolation by distance pattern was detected, with a marked phylogeographic signature suggesting possible effects of past climate and geographic barriers to migration. Modeling the potential distribution of the species showed a contraction during the last glaciations followed by expansion events. The exploratory approximate Bayesian computation conducted suggests a best-supported scenario in which the cluster CWA traced back to the ancestral populations and a first split between EWA and CWA took place about 160000 years before present (BP), then a second split divided CA and CWA, about 100000 years BP. However, our genetic data do not enable us to conclusively distinguish among a few alternative possible scenarios. PMID- 30247721 TI - Structural insights into DNA degradation by human mitochondrial nuclease MGME1. AB - Mitochondrial nucleases play important roles in accurate maintenance and correct metabolism of mtDNA, the own genetic materials of mitochondria that are passed exclusively from mother to child. MGME1 is a highly conserved DNase that was discovered recently. Mutations in MGME1-coding gene lead to severe mitochondrial syndromes characterized by external ophthalmoplegia, emaciation, and respiratory failure in humans. Unlike many other nucleases that are distributed in multiple cellular organelles, human MGME1 is a mitochondria-specific nuclease; therefore, it can serve as an ideal target for treating related syndromes. Here, we report one HsMGME1-Mn2+ complex and three different HsMGME1-DNA complex structures. In combination with in vitro cleavage assays, our structures reveal the detailed molecular basis for substrate DNA binding and/or unwinding by HsMGME1. Besides the conserved two-cation-assisted catalytic mechanism, structural analysis of HsMGME1 and comparison with homologous proteins also clarified substrate binding and cleavage directionalities of the DNA double-strand break repair complexes RecBCD and AddAB. PMID- 30247722 TI - A monovalent ion in the DNA binding interface of the eukaryotic junction resolving enzyme GEN1. AB - GEN1 is a member of the FEN/EXO family of structure-selective nucleases that cleave 1 nt 3' to a variety of branchpoints. For each, the H2TH motif binds a monovalent ion and plays an important role in binding one helical arm of the substrates. We investigate here the importance of this metal ion on substrate specificity and GEN1 structure. In the presence of K+ ions the substrate specificity is wider than in Na+, yet four-way junctions remain the preferred substrate. In a combination of K+ and Mg2+ second strand cleavage is accelerated 17-fold, ensuring bilateral cleavage of the junction. We have solved crystal structures of Chaetomium thermophilum GEN1 with Cs+, K+ and Na+ bound. With bound Cs+ the loop of the H2TH motif extends toward the active site so that D199 coordinates a Mg2+, buttressed by an interaction of the adjacent Y200. With the lighter ions bound the H2TH loop changes conformation and retracts away from the active site. We hypothesize this conformational change might play a role in second strand cleavage acceleration. PMID- 30247723 TI - Long-Term Hearing Outcomes Following Stereotactic Radiosurgery in Vestibular Schwannoma Patients-A Retrospective Cohort Study. AB - BACKGROUND: An understanding of the hearing outcomes is needed for treatment counseling for patients with vestibular schwannomas (VS). OBJECTIVE: To determine long-term hearing results following stereotactic radiosurgery (SRS) for VS and identify any influential variables. METHODS: Tertiary hospital retrospective cohort. RESULTS: There were 579 tumors (576 patients) treated with SRS. Eighty two percent (473) of tumors had >=1 yr and 59% (344 >=3 yr follow-up. In the 244 tumor ears, with measurable hearing before SRS who were followed >=1 yr, 14% (31) had improved hearing, 13% (29) unchanged hearing, and 74% (158) had worsened hearing. In 175 patients with >=3 yr follow-up and who had measurable hearing pretreatment, 6% (11 ears) improved hearing, 31% (54 ears) unchanged hearing, and 63% (110 ears) had worsened hearing. Patients with tumors with larger target volumes (P = 0.040) and with neurofibromatosis type 2 (NF2; P = 0.017) were associated with poorer hearing (P = 0.040). Patients with word recognition scores (WRS) of 50% or poorer had tumors with a larger volume (P = 0.0002), larger linear size (P = 0.032), and NF2 (P = 0.045). Traditionally reported hearing outcomes using the Gardner Robertson maintenance of PTA <=50 db or WRS >=50% were 48% at 3 yr, which overestimates hearing outcomes compared to the above reporting standards. CONCLUSION: Hearing declines over time in VS treated with SRS in a high proportion of cases. The frequency and magnitude of long-term hearing decline following SRS argues against prophylactic radiation for small tumors in hearing ears with undetermined growth behavior. PMID- 30247725 TI - Multiple Cerebral Ring Enhancing Lesions. AB - Multiple cerebral ring enhancing lesions is a common clinical scenario encountered in our daily clinical practice. There are various etiologies of it, can be classified into infection, neoplastic, inflammatory and etc. The diagnosis can be achieved by interpreting the radiological signs and correlation with clinical history. Here, we reported a case of multiple cerebral ring enhancing lesions due to central nervous system (CNS) tuberculoma. PMID- 30247726 TI - Trajectory of radiographic change over a decade: the effect of transition from conventional synthetic disease-modifying antirheumatic drugs to anti-tumour necrosis factor in patients with psoriatic arthritis. AB - Objectives: To describe the trajectory of radiographic progression among patients with PsA who transitioned from conventional synthetic DMARDs to anti-TNF-alpha inhibitors in routine care. Methods: A retrospective sample of patients with PsA (ClASsification criteria for Psoriatic ARthritis) was taken from the Bath longitudinal cohort. All patients had radiographs of the hands and feet taken: 5 years before (T0), at the time of (T1) and 5 years after (T2) commencing anti-TNF treatment. Radiographs were scored blinded using the PsA-modified Sharp-van der Heijde score (mSvdHS) and for osteoproliferation (Psoriatic Arthritis Ratingen Score) by A.Allard, A.Antony and W.T. This sample size was calculated to ensure 90% power to determine the smallest detectable difference of the mSvdHS to a 5% significance level. Cumulative probability plots were used to determine the probability of radiographic progression pre- (T0-T1) and post- (T1-T2) anti-TNF treatment. Results: Eighty-four radiographs from 28 patients were selected for inclusion. The median [interquartile range (IQR)] disease duration at baseline (T0) was 8.5 (0-19.5) years. The interval between T0-T1 and T1-T2 was 4.2 years (3.34-6.65) and 4.9 years (4.25-5.87), respectively. The median mSvdHS at baseline (T0) was 8.5 (IQR 1.75-27.5). The median (IQR) rate of change in mSvdHS per year reduced after commencing anti-TNF, from 2.1 (0.88-3.92) between T0-T1 to 1.0 (IQR 0.05-2.35) between T1-T2 (P = 0.012). Conclusion: The trajectory of damage accumulation over a 10-year period in this observational clinical cohort is low overall. The rate of radiographic damage as measured by the mSvdHS slows following commencement of anti-TNF. PMID- 30247727 TI - Differentiating knee pain phenotypes in older adults: a prospective cohort study. AB - Objective: To identify and validate knee pain phenotypes in an older population across different pain-related domains over 10.7 years. Methods: A total of 963 participants (mean age 63 years) from a population-based older adult cohort study were studied at baseline and followed up at 2.6 (n = 875), 5.1 (n = 768) and 10.7 years (n = 563). Baseline demographic, psychological, lifestyle and comorbidities data were obtained and MRI was performed to measure knee structural pathology. WOMAC pain and pain at multiple sites were assessed by questionnaires at each time-point. Latent class analysis was used to identify knee pain phenotypes, considering sex, BMI, emotional problems, education level, comorbidities, number of painful sites and knee structural pathology. Results: Three pain phenotypes were identified: Class 1: high prevalence of emotional problems and low prevalence of structural damage (25%); Class 2: high prevalence of structural damage and low prevalence of emotional problems (20%); Class 3: low prevalence of emotional problems and low prevalence of structural damage (55%). Participants within Class 1 and 2 had greater BMI, more comorbidities, a higher prevalence of radiographic knee OA and knee structural pathology compared with Class 3. Furthermore, compared with Class 2 and 3, WOMAC pain and number of painful sites were consistently greater at each time-point over 10.7 years in Class 1. Results were similar when the analyses were restricted to participants with radiographic knee OA. Conclusion: Psychological and structural factors interact with each other to exacerbate pain perception, suggesting that tailored treatment approaches for older people with knee pain in clinical practice are needed. PMID- 30247728 TI - Mees' Lines Associated with Heart Failure. PMID- 30247729 TI - DEVELOPMENT OF A MINIATURIZED VERSION OF DICENTRIC CHROMOSOME ASSAY TOOL FOR RADIOLOGICAL TRIAGE. AB - Use of ionizing radiation (IR) in various industrial, medical and other applications can potentially increase the risk of medical, occupational or accidental human exposure. Additionally, in the event of a radiological or nuclear (R/N) incident, several tens of hundreds and thousands of people are likely to be exposed to IR. IR causes serious health effects including mortality from acute radiation syndrome and therefore it is imperative to determine the absorbed radiation dose, which will enable physicians in making an appropriate clinical 'life-saving' decision. The 'Dicentric Chromosome Assay (DCA)' is the gold standard for estimating the absorbed radiation dose but its performance is time consuming and laborious. Further, timely evaluation of dicentric chromosomes (DCs) for dose estimation in a large number of samples provides a bottleneck because of a limited number of trained personnel and a prolonged time for manual analysis. To circumvent some of these technical issues, we developed and optimized a miniaturized high throughput version of DCA (mini-DCA) in a 96 microtube matrix with bar-coded 1.4 ml tubes to enable the processing of a large number of samples. To increase the speed of DC analysis for radiation dose estimation, a semi-automated scoring was optimized using the Metafer DCScore algorithm. The accuracy of mini-DCA in dose estimation was verified and validated though comparison with conventional DCA performed in 15 ml conical tubes. The mini-DCA considerably reduced the sample processing time by a factor of 4 when compared to the conventional DCA. Further, the radiation doses estimated by mini DCA using the triage mode of scoring (50 cells or 30 DCs) were similar to that of conventional DCA using 300-500 cells. The mini-DCA coupled with semi-automated DC scoring not only reduced the sample processing and analysis times by a factor of 4 but also enabled the processing of a large number of samples at once. Our mini DCA method, once automated for high throughput robotic platforms, will be an effective radiological triage tool for mass casualty incidents. PMID- 30247730 TI - Caution Indicated in Extrapolating Carditis in Rats to Rheumatic Heart Disease in Humans. PMID- 30247731 TI - Identifying and validating blood mRNA biomarkers for acute and chronic insufficient sleep in humans: a machine learning approach. AB - Acute and chronic insufficient sleep are associated with adverse health outcomes and risk of accidents. There is therefore a need for biomarkers to monitor sleep debt status. None are currently available. We applied Elastic-net and Ridge regression to entire and pre-filtered transcriptome samples collected in healthy young adults during acute total sleep deprivation and following 1 week of either chronic insufficient (< 6 h) or sufficient sleep (~8.6 h) to identify panels of mRNA biomarkers of sleep debt status. The size of identified panels ranged from 9 74 biomarkers. Panel performance, assessed by leave-one-subject-out cross validation and independent validation, varied between sleep debt conditions. Using between-subject assessments based on one blood sample, the accuracy of classifying 'Acute sleep loss' was 92%, but only 57% for classifying 'Chronic sleep insufficiency'. A reasonable accuracy for classifying 'chronic sleep insufficiency' could only be achieved by a within-subject comparison of blood samples. Biomarkers for sleep debt status showed little overlap with previously identified biomarkers for circadian phase. Biomarkers for acute and chronic sleep loss also showed little overlap but were associated with common functions related to the cellular stress response, such as heat shock protein activity, the unfolded protein response, protein ubiquitination and endoplasmic reticulum associated protein degradation, and apoptosis. This characteristic response of whole blood to sleep loss can further aid our understanding of how sleep insufficiencies negatively affect health. Further development of these novel biomarkers for research and clinical practice requires validation in other protocols and age groups. PMID- 30247732 TI - Long-branch attraction in species tree estimation: inconsistency of partitioned likelihood and topology-based summary methods. AB - With advances in sequencing technologies, there are now massive amounts of genomic data from across all life, leading to the possibility that a robust Tree of Life can be constructed. However, "gene tree heterogeneity", which is when different genomic regions can evolve differently, is a common phenomenon in multi locus datasets, and reduces the accuracy of standard methods for species tree estimation that do not take this heterogeneity into account. New methods have been developed for species tree estimation that specifically address gene tree heterogeneity, and that have been proven to converge to the true species tree when the number of loci and number of sites per locus both increase (i.e., the methods are said to be "statistically consistent"). Yet, little is known about the biologically realistic condition where the number of sites per locus is bounded. We show that when the sequence length of each locus is bounded (by any arbitrarily chosen value), the most common approaches to species tree estimation that take heterogeneity into account (i.e., traditional fully partitioned concatenated maximum likelihood and newer approaches, called summary methods, that estimate the species tree by combining estimated gene trees) are not statistically consistent, even when the heterogeneity is extremely constrained. The main challenge is the presence of conditions such as long branch attraction that create biased tree estimation when the number of sites is restricted. Hence, our study uncovers a fundamental challenge to species tree estimation using both traditional and new methods. PMID- 30247733 TI - Wolbachia and the near cessation of dengue outbreaks in Northern Australia despite continued dengue importations via travellers. PMID- 30247724 TI - Pre-ART HIV-1 DNA in CD4+ T cells correlates with baseline viro-immunological status and outcome in patients under first-line ART. AB - Objectives: We evaluated the association between pre-ART HIV DNA and HIV-infected participant characteristics at baseline as well as with their response to first line ART. Methods: Four hundred and thirty-three patients from the ICONA cohort, starting first-line ART after the year 2000, were analysed. Pre-ART HIV DNA was quantified with the modified COBAS TaqMan HIV-1 Test and normalized by CD4+ T cells. Linear correlation between pre-ART HIV DNA and other continuous markers (HIV RNA, CD4 count, markers of inflammation and coagulation) at baseline was evaluated by means of Pearson correlation coefficient and a linear regression model. Survival analyses and Cox regression models were used to study the association between pre-ART HIV DNA and time to viro-immunoclinical events. Results: Pre-ART HIV DNA [median (IQR): 10 702 (3397-36 632) copies/106 CD4+ T cells] was correlated with pre-ART HIV RNA [R2 = +0.44, (P < 0.0001)], CD4+ T cells [R2 = -0.58, (P < 0.0001)] and CD4/CD8 ratio [R2 = -0.48, (P < 0.0001)], while weaker correlations were observed with CD8+ T cells (R2 = -0.20, P = 0.01), IL-6 (R2 = +0.16, P = 0.002) and soluble CD14 (R2 = +0.09, P = 0.05). Patients with higher pre-ART HIV DNA showed lower rate and delayed virological response (defined as HIV RNA <=50 copies/mL), compared with those having lower HIV DNA (67.2% for >10 000, 81.1% for 1000-10 000 and 86.4% for 10-1000 copies/106 CD4+ T cells; P = 0.0004). Higher pre-ART HIV DNA was also correlated with increased risk of virological rebound (defined as HIV RNA >50 copies/mL) by 24 months (17.2% for >10 000, 7.4% for 1000-10 000 and 4.3% for 10-1000 copies/106 CD4+ T cells; P = 0.0048). Adjusted HRs of all virological rebound definitions confirmed these findings (P <= 0.02). Conclusions: Pre-ART HIV DNA, along with HIV RNA and CD4+ T cell count, should be considered as a new staging marker to better identify people at lower (or higher) risk of viral rebound following achievement of virological suppression (<=50 copies/mL). PMID- 30247734 TI - Bladder cancer incidence rates in the world from the Cancer Incidence in Five Continents XI. PMID- 30247735 TI - A novel FAM83H mutation in one Chinese family with autosomal-dominant hypocalcification amelogenesis imperfecta. AB - Autosomal-dominant hypocalcification amelogenesis imperfecta (ADHCAI) is characterized by soft enamel that easily disintegrates and exposed dark dentin. ADHCAI is caused by mutations in a gene called family with sequence similarity 83 member H (FAM83H). To investigate the molecular genetics of ADHCAI, a Chinese family in which three generations exhibited ADHCAI was recruited. The enamel ultrastructure was analysed by environmental scanning electron microscopy (ESEM), which showed altered enamel rod (prism) structures in ADHCAI patients compared to the structures in healthy controls. Mutational analysis of the FAM83H gene identified a novel nonsense mutation (c.1222A>T) in the affected family members that encodes a stop codon at amino acid position 408, causing premature protein truncation (p. K408X). Green fluorescent protein (GFP) and FAM83H fusion protein analyses in vitro showed that normal cytoplasmic accumulation of the FAM83H protein was prevented by the K408X mutation in both rat dental epithelial SF2 cells and human embryonic kidney 293T cells. The mutant fusion protein localized primarily to the nucleus, in contrast to the cytoplasmic subcellular localization of the wild-type FAM83H protein. Our results provide new genetic evidence that mutations in FAM83H contribute to ADHCAI. PMID- 30247736 TI - Hereditary spherocytosis presenting with branch retinal artery occlusion. PMID- 30247738 TI - Characterization of Neuropathic Pain in Primary Sjogren's Syndrome with Respect to Neurophysiological Evidence of Small-Fiber Neuropathy. AB - Objective: To determine whether clinical features of neuropathic pain differ with respect to the presence of small-fiber neuropathy (SFN) in patients with primary Sjogren's syndrome (pSS). Methods: We compared the clinical presentation of neuropathic pain between 15 patients with pSS and SFN detected by neurophysiological tests (laser-evoked potentials, cold and warm detection thresholds, sympathetic skin responses, and electrochemical skin conductance) and 15 patients with pSS but no neurophysiological evidence of SFN. Results: The patients with SFN had more intense squeezing and pressure sensations and more frequent dynamic mechanical allodynia (pain provoked by brushing) than the patients without SFN. Restless leg syndrome was also more frequently observed in patients with SFN, who had pain aggravated at rest that improved by moving. Conclusions: These findings are in favor of the sensitization of relatively spared large Abeta-fibers and second-order nociceptive neurons in patients with SFN. On the other hand, burning sensations, which rather reveal sensitization of small nociceptive fibers, were observed whether SFN was present or not. Thus, some discriminating clinical features may help to suggest the presence of SFN in patients with pSS and chronic neuropathic pain. PMID- 30247739 TI - Regional susceptibility to ER stress and protection by salubrinal following a single exposure to deltamethrin. AB - Endoplasmic reticulum (ER) stress is a significant contributor to neurodegeneration and cognitive dysfunction. Recently, we reported that repeated exposure to the pyrethroid insecticide deltamethrin caused ER stress in the hippocampus of adult mice, which was accompanied by deficits in learning (Hossain et al., 2015). Here, we investigated regional susceptibility to ER stress and the ability of salubrinal, an inhibitor of ER stress, to reduce apoptosis following a single oral administration of deltamethrin (6 mg/kg). Deltamethrin significantly increased the ER stress markers C/EBP-homologous protein (CHOP) in the hippocampus by 148% at 24 and 48 h compared to age-matched controls. In contrast, CHOP was increased by 146% in the frontal cortex only at 48 h after deltamethrin exposure. Similarly, the level of GRP-78 was increased by 314% and 262% in the hippocampus at 24 and 48 h, while the same factors were increased by 178% at 24 h and 139% at 48 h in the frontal cortex. These changes were accompanied by increased levels of activated caspase-12, caspase-3, and TUNEL positive cells in both brain regions, with the hippocampus showing a more robust response. Pre treatment of mice with the eIf2alpha inhibitor salubrinal prevented deltamethrin induced caspase-3 activation and attenuated the number of TUNEL positive cells. These data demonstrate that the hippocampus appears to be particularly vulnerable to deltamethrin exposure in adult animals, which may contribute to observed effects of deltamethrin on cognitive function. PMID- 30247737 TI - Adnectin-drug conjugates for Glypican-3-specific delivery of a cytotoxic payload to tumors. AB - Tumor-specific delivery of cytotoxic agents remains a challenge in cancer therapy. Antibody-drug conjugates (ADC) deliver their payloads to tumor cells that overexpress specific tumor-associated antigens-but the multi-day half-life of ADC leads to high exposure even of normal, antigen-free, tissues and thus contributes to dose-limiting toxicity. Here, we present Adnectin-drug conjugates, an alternative platform for tumor-specific delivery of cytotoxic payloads. Due to their small size (10 kDa), renal filtration eliminates Adnectins from the bloodstream within minutes to hours, ensuring low exposure to normal tissues. We used an engineered cysteine to conjugate an Adnectin that binds Glypican-3, a membrane protein overexpressed in hepatocellular carcinoma, to a cytotoxic derivative of tubulysin, with the drug-to-Adnectin ratio of 1. We demonstrate specific, nanomolar binding of this Adnectin-drug conjugate to human and murine Glypican-3; its high thermostability; its localization to target-expressing tumor cells in vitro and in vivo, its fast clearance from normal tissues and its efficacy against Glypican-3-positive mouse xenograft models. PMID- 30247740 TI - Trovafloxacin-induced liver injury: lack in regulation of inflammation by inhibition of nucleotide release and neutrophil movement. AB - The fluoroquinolone trovafloxacin (TVX) is associated with a high risk of drug induced liver injury (DILI). Although part of the liver damage by TVX+TNF relies on neutrophils, we have recently demonstrated that liver recruitment of monocytes and neutrophils is delayed by TVX.Here we show that the delayed leukocyte recruitment is caused by a combination of effects which are linked to the capacity of TVX to block the hemichannel pannexin 1. TVX inhibited find-me signal release in apoptotic HepG2 hepatocytes, decelerated freshly isolated human neutrophils toward IL-8 and f-MLF, and decreased the liver expression of ICAM-1. In blood of TVX+TNF-treated mice we observed an accumulation of activated neutrophils despite an increased MIP-2 release by the liver.Depletion of monocytes and neutrophils caused increased serum concentrations of TNF, IL-6 and MIP-2 in TVX-treated mice as well as in mice treated with the fluoroquinolone levofloxacin, known to have a lower DILI-inducing profile. This supports the idea that early leukocyte recruitment regulates inflammation.In conclusion, disrupted regulation by leukocytes appears to constitute a fundamental step in the onset of TVX-induced liver injury, acting in concert with the capability of TVX to induce hepatocyte cell death.Interference of leukocyte-mediated regulation of inflammation represents a novel mechanism to explain the onset of DILI. PMID- 30247741 TI - [A difficult case of the differential diagnosis of focal infiltrative lung changes in phthisiatric practice]. AB - Errors occur rather commonly in the differential diagnosis of respiratory diseases accompanied by X-ray lung tissue changes as foci and infiltration. Infiltrative and disseminated pulmonary tuberculosis, lung cancer, and pneumonia constitute a high proportion among the detected concurrent lung diseases. The rate of diagnostic discordance for these lung abnormalities accounts for more than 30%; and the diagnosis period for an infiltrative lung process lasts 2-3 weeks in 20% of cases and above 1-3 months in 80%. In particular, clinicians are faced with great difficulties in diagnosing aspiration pneumonia; this is due to that its X-ray manifestations are not purely specific and they are characterized by the parenchymal (alveolar) infiltration of lung tissue with a varying extent of lung inflammation. This paper describes a clinical case of a patient with salivary gland adenocarcinoma and focal infiltrative lung changes. Diagnostic difficulties have emerged in establishing the genesis of the changes in the lung. PMID- 30247743 TI - Abstracts of the 12th International Comet Assay Workshop held at the University of Navarra, Pamplona, Spain, 29-31 August 2017 (https://icaw.vito.be/). PMID- 30247744 TI - Inhibition of endothelial progenitor cells may explain the high cardiovascular event rate in patients with rheumatoid arthritis. PMID- 30247742 TI - Molecular Characterization of MbraOR16, a Candidate Sex Pheromone Receptor in Mamestra brassicae (Lepidoptera: Noctuidae). AB - Sex pheromone communication in Lepidoptera has long been a valuable model system for studying fundamental aspects of olfaction and its study has led to the establishment of environmental-friendly pest control strategies. The cabbage moth, Mamestra brassicae (Linnaeus) (Lepidoptera: Noctuidae), is a major pest of Cruciferous vegetables in Europe and Asia. Its sex pheromone has been characterized and is currently used as a lure to trap males; however, nothing is known about the molecular mechanisms of sex pheromone reception in male antennae. Using homology cloning and rapid amplification of cDNA ends-PCR strategies, we identified the first candidate pheromone receptor in this species. The transcript was specifically expressed in the antennae with a strong male bias. In situ hybridization experiments within the antennae revealed that the receptor expressing cells were closely associated with the olfactory structures, especially the long trichoid sensilla known to be pheromone-sensitive. The deduced protein is predicted to adopt a seven-transmembrane structure, a hallmark of insect odorant receptors, and phylogenetically clustered in a clade that grouped a majority of the Lepidoptera pheromone receptors characterized to date. Taken together, our data support identification of a candidate pheromone receptor and provides a basis for better understanding how this species detects a signal critical for reproduction. PMID- 30247745 TI - The Role of Maxillofacial Prosthetics for the Surgically Treated Patient at National Cancer Institute-Designated Comprehensive Cancer Centers. AB - OBJECTIVES/HYPOTHESIS: The current role of maxillofacial prosthetic care for head and neck cancer patients is not well understood. Additionally, perceived barriers for service provision are unknown. The purpose of this study was to evaluate the current role of maxillofacial prosthetic care at National Cancer Institute (NCI) designated comprehensive cancer centers and to identify perceived barriers to care. STUDY DESIGN: Multicenter, cross-sectional survey of head and neck division leaders at NCI-designated comprehensive cancer centers. METHODS: Each head and neck division leader from the 47 NCI-designated comprehensive cancer centers was invited to participate. The main outcomes of this study were: 1) to evaluate the current role of maxillofacial prosthetics for the surgically treated head and neck cancer patient within NCI-designated comprehensive cancer centers and 2) to identify perceived barriers to care. Measured outcomes were obtained from an anonymous online survey and reported. RESULTS: Twenty-eight of the 47 head and neck service chiefs responded (60% response rate). Respondents expressed preference for prosthetic rehabilitation for hard palate/upper gum, auricular, and nasal defects. Local flap or free tissue transfer was preferred for lower gum and soft palate defects. Cost-related factors were among the most reported perceived barriers to maxillofacial prosthetic care. CONCLUSIONS: Maxillofacial prosthetics have an important role in the rehabilitation of the head and neck cancer patient. Perceived barriers for services exist, particularly as it relates to cost. Providers should be aware that these issues are likely to be more severe in regional or community centers. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30247746 TI - Trends in Postinterview Communication Practices. AB - OBJECTIVES/HYPOTHESIS: Postinterview communication between residency programs and applicants is common during the US residency match process. To date, current communication practices between otolaryngology residency programs and applicants have not been studied. The objectives of this study were to characterize the frequency and type of postinterview communication and perceptions of how this communication influences ranking behavior of match participants. STUDY DESIGN: Survey. METHODS: A national survey of Accreditation Council for Graduate Medical Education-accredited otolaryngology programs was distributed via the Otolaryngology Program Directors Organization. RESULTS: Program directors were surveyed regarding methods and content of postinterview communication, perceived impact that communication has on final rank lists, and current interpretations of the National Resident Matching Program (NRMP) Code of Conduct. Thirty-three of 106 program directors (31.1%) responded. Thirty-eight percent of programs that responded initiate at least some form of postinterview communication. The program director most commonly initiated communication, typically in the form of an email. A minority of respondents (12.1%) indicated that specific information is revealed regarding rank status. Thirty-two percent of respondents indicated that communication initiated by applicants may influence final rank list. Twenty percent of respondents interpret the current NRMP Code of Conduct as allowing programs to reveal rank positions to applicants, and 63.6% of respondents as allowing applicants to reveal intended rank positions. CONCLUSIONS: The results of this study demonstrate that postinterview communication practices within otolaryngology vary widely. Program directors perceive that postinterview contact between applicants and programs has limited impact on ranking behavior. NRMP rules for postinterview communication between programs and candidates are interpreted variably by program directors. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30247747 TI - High Burden of Palliative Care Needs of Older Adults During Emergency Major Abdominal Surgery. AB - OBJECTIVES: To quantify preoperative illness burden in older adults undergoing emergency major abdominal surgery (EMAS), to examine the association between illness burden and postoperative outcomes, and to describe end-of-life care in the year after discharge. DESIGN: Retrospective study using data from Health and Retirement Study interviews linked to Medicare claims (2000-2012). SETTING: National population-based dataset. PARTICIPANTS: Medicare beneficiaries who underwent EMAS. MEASUREMENTS: High illness burden, defined as >=2 of the following vulnerabilities: functional dependence, dementia, use of helpers, multimorbidity, poor prognosis, high healthcare utilization. In-hospital outcomes were complications and mortality. Postdischarge outcomes included emergency department (ED) visits, hospitalization, intensive care unit (ICU) stay, and 365 day mortality. For individuals discharged alive who died within 365 days of surgery, outcomes included hospice use, hospitalization, ICU use, and ED use in the last 30 days of life. Multivariable regression was used to determine the association between illness burden and outcomes. RESULTS: Of 411 participants, 57% had high illness burden. More individuals with high illness burden had complications (45% vs 28% p=0.00) and in-hospital death (20% vs 9%, p=0.00) than those without. After discharge (n=349), individuals with high illness burden experienced more ED visits (57% vs 46%, P=.04) and were more likely to die (35% vs 13%, p=0.00). Of those who died after discharge (n=86), 75% had high illness burden, median survival was 67 days (range 21-141 days), 48% enrolled in hospice, 32% died in the hospital, 23% were in the ICU in the last 30 days of life and 37% had an ED visit in the last 30 days of life. CONCLUSION: Most older adults undergoing EMAS have preexisting high illness burden and experience high mortality and healthcare use in the year after surgery, particularly near the end of life. Concurrent surgical and palliative care may improve quality of life and end-of-life care in these people. J Am Geriatr Soc 66:2072-2078, 2018. PMID- 30247748 TI - An Evaluation of the Program-Specific Paragraph in the Otolaryngology Residency Application. AB - OBJECTIVES/HYPOTHESIS: The recent addition of mandatory program-specific paragraphs within the personal statement during the otolaryngology match process has been controversial. It is unclear whether applicants customize these paragraphs for programs, or if they are largely uniform across applications. The objective of our study was to assess the degree of variability among program specific paragraphs. STUDY DESIGN: Retrospective cohort analysis. METHODS: An analysis of deidentified program-specific paragraphs of 2016 otolaryngology residency applicants at two institutions was performed. Applicants who applied to both and had program-specific paragraphs were included. Paragraphs were assessed for 24 parameters, including quantitative content analysis. Subjective and objective similarity scores were assigned to each pair, using a five-point scale and Levenshtein distance function respectively. Differences between institutions were calculated using chi2 and two-sided t tests. RESULTS: Two hundred eight-five applications were reviewed, and 181 applied to both programs and had program specific paragraphs. The median subjective similarity score among all paragraphs was "mildly similar" (2/5). The mean objective similarity score was 0.59. There were statistical differences between institutions in 13 parameters. One institution garnered more applicants who mentioned interest in research or global surgery (71.3% vs. 57.5%, P = .006; 17.7% vs. 4.4%, P < .0001, respectively), whereas the other attracted mention of clinical aspects and geographical ties (80.0% vs. 45.3%, P < .0001; 72.4% vs. 45.3%, P < .0001, respectively). CONCLUSIONS: Our study suggests that applicants tailor program-specific paragraphs to the individual residency programs. These findings may aid programs and students in understanding the role of this new element of the application. LEVEL OF EVIDENCE: 4 Laryngoscope, 2508-2513, 2018. PMID- 30247749 TI - Gene Expression Subtype Predicts Nodal Metastasis and Survival in Human Papillomavirus-Negative Head and Neck Cancer. AB - OBJECTIVES/HYPOTHESIS: Gene expression analyses of head and neck cancer have revealed four molecular subtypes: basal (BA), mesenchymal (MS), atypical (AT), and classical (CL). We evaluate whether gene expression subtypes in oral cavity squamous cell carcinoma (OCSCC) and laryngeal squamous cell carcinoma (LSCC) can be used to predict nodal metastasis and prognosticate survival. STUDY DESIGN: Retrospective cohort study and genomic analysis. METHODS: OCSCC and LSCC cases were identified from the The Cancer Genome Atlas (TCGA) head and neck cancer cohort. RNA-seq by expected maximization (RSEM) was used to quantify gene expression levels from TCGA RNA-seq data and to assign each case to one of four subtypes. Descriptive statistics were used to describe patient, disease, and treatment characteristics in each subtype. Cox regression and Kaplan-Meier analyses were used to determine associations with survival. RESULTS: OCSCC cases were comprised primarily of the MS and BA subtypes, whereas LSCC was comprised primarily of CL and AT subtypes. In OCSCC, the MS subtype was significantly associated with higher risk of nodal metastasis. In a subset analysis of clinically T1-2N0M0 OCSCC, we demonstrate that the MS subtype was predictive of occult nodal metastasis (relative risk = 3.38, 95% confidence interval [CI]: 1.08 10.69). In LSCC, the CL subtype was associated with significantly worse overall survival (hazard ratio = 4.32, 95% CI: 1.77-10.54, P = .001). CONCLUSIONS: Gene expression analysis reveals potential novel markers of nodal metastasis and survival in human papillomavirus-negative head and neck cancer. Future studies will continue to refine and validate these markers, with the goal of providing molecular risk assessments that guide therapy and improve patient outcomes. LEVEL OF EVIDENCE: 2b Laryngoscope, 2018. PMID- 30247750 TI - Testing ecological theory with lianas. AB - Contents Summary 366 I. Introduction 366 II. Testing ecological theory: effects of the environment on lianas 369 III. A unified explanation for liana distribution and the maintenance of liana diversity 370 IV. Testing ecological theory: effects of lianas on the environment 373 V. Theoretical effects of lianas on forest diversity 375 VI. Lianas and trophic interactions in forests 375 VII. Unresolved challenges in liana ecology 376 VIII. Conclusions 377 Acknowledgements 377 References 377 SUMMARY: Lianas constitute a diverse polyphyletic plant group that is advancing our understanding of ecological theory. Specifically, lianas are providing new insights into the mechanisms that control plant distribution and diversity maintenance. For example, there is now evidence that a single, scalable mechanism may explain local, regional, and pan-tropical distribution of lianas, as well as the maintenance of liana species diversity. The ability to outcompete trees under dry, stressful conditions in seasonal forests provides lianas a growth advantage that, over time, results in relatively high abundance in seasonal forests and low abundance in aseasonal forests. Lianas may also gain a similar growth advantage following disturbance, thus explaining why liana density and diversity peak following disturbance at the local, forest scale. The study of ecology, however, is more than the effect of the environment on organisms; it also includes the effects of organisms on the environment. Considerable empirical evidence now indicates that lianas substantially alter their environment by consuming resources, suppressing tree performance, and influencing emergent properties of forests, such as ecosystem functioning, plant and animal diversity, and community composition. These recent studies using lianas are transcending classical tropical ecology research and are now providing novel insights into fundamental ecological theory. PMID- 30247751 TI - Using Placebo Beverages in Group Alcohol Studies. AB - BACKGROUND: Placebo beverage conditions remain a key element in the methodological toolkit for alcohol researchers interested in evaluating pharmacological and nonpharmacological factors influencing the effects of alcohol consumption. While interest in experimentally examining alcohol in social context is on the rise, there has been little research examining the effectiveness of placebo manipulations in group settings, when just 1 suspicious participant could potentially jeopardize the effect of the placebo on group members. Moreover, research has rarely considered the association between individual difference factors (e.g., gender) and placebo manipulation effectiveness. The present study, using an uncommonly large sample of placebo-consuming participants, was well suited to investigate fundamental questions regarding placebo efficacy that have not been assessed previously. Specifically, we aimed to examine placebo efficacy and general processes of placebo functioning in a group context. We also assessed potential associations between a variety of individual difference factors and placebo response. METHODS: A total of 240 participants (50% male) consumed placebo beverages during a triadic drinking period (across 80 three-person groups). Participants reported their subjective intoxication, stimulation, and sedation 8 minutes following drink consumption and estimated the alcohol content of their drink at the end of the study. RESULTS: Participants consuming placebo beverages in groups were nearly universal in reporting that they had consumed alcohol (>99%) and had experienced an increase in feelings of intoxication [t(239) = 22.03, p < 0.001] and stimulation [t(239) = 5.53, p < 0.001], levels that were similar to those observed in prior studies conducted with participants drinking placebos in isolation. Further, participants' placebo responses were independent of their 2 group members and were largely unaffected by a variety of individual difference factors. CONCLUSIONS: Placebo response generally operated independently of group-member influences, suggesting that researchers can successfully conduct placebo beverage studies utilizing group drinking designs. PMID- 30247752 TI - Nasal Reconstruction Using a Customized Three-Dimensional-Printed Stent for Congenital Arhinia: Three-Year Follow-up. AB - A male Mongolian child with a complete congenital absence of both nose and nasal passage had a poor survival prognosis due to respiratory distress. To enable his survival, a new nose capable of conferring respiratory function was constructed. Following reconstructive surgery, an absence of mucoepithelium in the nasal passage can lead to rhinostenosis. To avoid this complication, a custom-made nasal silicone stent was created using three-dimensional (3D) printing technology in conjunction with the patient's computed tomography data. The stent was implanted for 2 months to maintain the shape and size of the nasal passage. At 2 months after stent implantation, the mucoepithelium tissue in the passage had successfully regenerated with no immune reaction. Three years after stent removal, respiratory function, nasal passage structure, and external nose shape were maintained without additional medical care. These results indicate the successful nasal reconstruction in an arhinia patient using a customized, 3D printed nasal stent. Laryngoscope, 2018. PMID- 30247754 TI - Saliva Pepsin Detection and Proton Pump Inhibitor Response in Suspected Laryngopharyngeal Reflux. AB - OBJECTIVES/HYPOTHESIS: To evaluate the prediction value of saliva pepsin detection for an 8-week proton pump inhibitor (PPI) response in patients with a Reflux Symptoms Index (RSI) score >=13, which indicates possible laryngopharyngeal reflux. STUDY DESIGN: Prospective individual single-cohort study. METHODS: Patients were recruited who had experienced chronic laryngopharyngeal symptoms (RSI score >=13) for more than 3 months after excluding other etiologies. The patients received PPI (40 mg of esomeprazole once daily) treatment for 8 weeks. Prior to treatment, the patients submitted saliva/sputum samples that were collected during the time symptoms were observed. The samples were taken for pepsin detection, and performed using the commercially available Peptest lateral flow device. The association of the Peptest results and PPI response were statistically analyzed with the chi2 test. RESULTS: Seventy four patients completed the study, and upon completion of PPI treatment, the mean RSI score was significantly reduced from 19.22 +/- 5.18 to 8.99 +/- 5.69. Forty four (59.5%) patients exhibited a good response as defined by an RSI score reduction >=50%. The results of the Peptest were semiquantitatively graded as 0, 1, 2, 3 (negative, weak positive, moderate positive and strong positive, respectively) based upon the visual intensity of the test sample line as compared to the control line. Twenty-four patients (32.4%) exhibited grade 3 strong positive results. The Peptest strong positive results (P < .05) were significantly associated with a good PPI response, with the positive predictive value being 79.2%. CONCLUSIONS: Analysis of strong positive results for pepsin detection in saliva/sputum samples may be a useful, noninvasive method for predicting better PPI response in patients with suspected reflux induced chronic laryngopharyngeal symptoms. LEVEL OF EVIDENCE: 2 Laryngoscope, 2018. PMID- 30247753 TI - Predictors of Effective Working Memory Training in Individuals with Alcohol Use Disorders. AB - BACKGROUND: Low working memory (WM) capacity is associated with alcohol use disorders (AUDs). The importance of WM to adaptive functioning has led to a recent influx of studies attempting to improve individual WM capacity using various cognitive training methods. The present study aimed to examine the efficacy of complex WM training for improving WM capacity among individuals with AUD. METHODS: Individuals were randomized to complete either adaptive WM training or active control training. We applied a methodologically rigorous and structured approach, including a battery of near and moderate transfer measures in those with AUDs and a control group. Additionally, we examined cognitive factors (at baseline) and other predictors of adherence, training task improvement, and transfer. RESULTS: Results suggest improved WM in individuals with AUDs and controls, as evidenced by improved scores on several transfer measures, after adaptive WM training. However, individuals with AUDs showed poorer adherence and less improvement on the training tasks themselves. Neither IQ, WM, sex, nor condition predicted adherence. Level of training task performance, baseline WM, and IQ predicted transfer task improvement. CONCLUSIONS: This is the first study to rigorously examine both the efficacy of WM training in those with AUDs, and predictors of successful training program adherence and transfer in a large sample. Among study completers, results suggest that AUD status does not predict training improvement and transfer. However, AUD status did predict lower program adherence. WM training was more effective in those with higher cognitive ability at baseline. This study provides direct translation to the development of cognitive interventions for treating AUD. PMID- 30247755 TI - Sex Differences in Peer Selection and Socialization for Alcohol Use from Adolescence to Young Adulthood and the Influence of Marital and Parental Status. AB - BACKGROUND: Peer selection and socialization influences for alcohol and other substance use have been a prominent area of research especially, though not exclusively, across adolescence. This study used 4-wave prospective data from 1,004 young adults to evaluate selection and socialization influences for young adults' alcohol use and friends' alcohol use from late adolescence to later young adulthood, and incorporated the time-varying predictors of marital and parental status. In addition, sex differences in peer selection and socialization processes were tested. METHODS: Participants were recruited from high schools, and assessments were based on self-reports initially collected in adolescence (at age 17.0 years) via paper-and-pencil surveys and in young adulthood at ages 23.8, 28.9, and 33.5 years via computer-based individual interviews (computer-assisted personal interview and audio computer-assisted self-interviewing). Initial sampling included a 76% participation rate, and the retention rate was 83%. Cross lagged panel regression models were used to evaluate hypotheses about peer selection and socialization. RESULTS: Findings indicated that friend selection processes were stronger than socialization processes across adolescence to young adulthood. Adopting marital and (especially) parental roles was negatively associated with young adults' alcohol use and percentage of friends using alcohol, and the magnitude of these relationships was stronger and more consistent for females. CONCLUSIONS: These findings indicated that across the adolescence-to-young adulthood transition, peer selection processes were more influential than peer socialization. Marital and parental roles were associated with both lower young adult alcohol use and a lower percentage of friends using alcohol, with stronger role-related effects for females relative to males. PMID- 30247756 TI - Review of the effects of silver nanoparticle exposure on gut bacteria. AB - Gut bacteria are involved in regulating several important physiological functions in the host, and intestinal dysbacteriosis plays an important role in several human diseases, including intestinal, metabolic and autoimmune disorders. Although silver nanoparticles (AgNPs) are increasingly being incorporated into medical and consumer products due to their unique physicochemical properties, studies have indicated their potential to affect adversely the gut bacteria. In this review, we focus on the biotoxicological effects of AgNPs entering the gastrointestinal tract and the relationship of these effects with important nanoscale properties. We discuss in detail the mechanisms underlying the bactericidal toxicity effects of AgNPs and explore the relationships between AgNPs, gut bacteria and disease. Finally, we highlight the need to focus on the negative effects of AgNPs usage to facilitate appropriate development of these particles. PMID- 30247757 TI - Dosimetry of small static fields used in external photon beam radiotherapy: Summary of TRS-483, the IAEA-AAPM international Code of Practice for reference and relative dose determination. AB - PURPOSE: A joint IAEA/AAPM international working group has developed a Code of Practice (CoP) for the dosimetry of small static fields used in external megavoltage photon beam radiotherapy, published by the IAEA as TRS-483. This summary paper introduces and outlines the main aspects of the CoP. METHODS: IAEA TRS-483 is a condensation of the wide range of different approaches that have been described in the literature for the reference dosimetry of radiotherapy machines with nominal accelerating potential up to 10 MV that cannot establish the conventional 10 cm * 10 cm reference field, and for the determination of field output factors for relative dosimetry in small static photon fields. The formalism used is based on that developed by Alfonso et al. [Med Phys. 2008;35:5179-5186] for this modality. RESULTS: Three introductory sections describe the rationale and context of the CoP, the clinical use of small photon fields, and the physics of small-field dosimetry. In the fourth section, definitions of terms that are specific to the CoP (as compared to previous CoPs for broad-beam reference dosimetry, such as IAEA TRS-398 and AAPM TG-51) are given; this section includes a list of the symbols and equivalences between IAEA and AAPM nomenclature to facilitate the practical implementation of the CoP by end users of IAEA TRS-398 and AAPM TG-51. The fifth section summarizes the equations and procedures that are recommended in the CoP and the sixth section provides an overview of the methods used to derive the data provided in IAEA TRS 483. CONCLUSIONS: This is the first time an international Code of Practice for the dosimetry of small photon fields based on comprehensive data and correction factors has been published. This joint IAEA/AAPM CoP will ensure consistent reference dosimetry traceable to the international System of Units and enable common and internationally harmonized procedures to be followed by radiotherapy centers worldwide for the dosimetry of small static megavoltage photon fields. PMID- 30247758 TI - Comment on Women's Sexual Health and Aging. PMID- 30247759 TI - Upper-Airway Stimulation Before, After, or Without Uvulopalatopharyngoplasty: A Two-Year Perspective. AB - OBJECTIVE: Upper airway stimulation (UAS) is an effective second-line treatment for obstructive sleep apnea (OSA). In certain patients, there is a considerable need for advanced programming, notably with inadequate palatal response to therapy. The aim of the study was to investigate the impact of uvulopalatopharyngoplasty and tonsillectomy (UPPP-TE) on UAS therapy outcomes from a 2-year perspective after implantation. METHODS: This study included all consecutive patients implanted with UAS in which a full set of 1- and 2-year follow-up assessments (M12 and M24) were obtained. Cases were analyzed in three groups: patients with UPPP-TE after (group 1) and before (group 2) UAS, and those without UPPP-TE (group 3). RESULTS: Therapy success could be achieved in about 80% of the entire cohort. Groups 2 and 3 did not differ significantly with regard to obesity, Apnea-Hypopnea Index, or Oxygen Desaturation Index. With regard to initial sleep endoscopy, there were fewer patients without any obstruction at the palatal and oropharyngeal levels and higher prevalence of lateral obstruction patterns at oropharynx in group 1 in contrast to groups 2 and 3. Groups 2 and 3 showed similar results, although group 2 patients underwent UPPP-TE before UAS implantation. CONCLUSION: UPPP-TE should be considered in patients with persistent OSA after UAS implantation if the obstruction is identified at the level of velum and oropharynx. Although this approach has higher response rates and better outcomes can be achieved in patients with UAS, there is no indication for patients to routinely undergo UPPP-TE prior to UAS implantation. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30247760 TI - Prediction of Postoperative Vocal Fold Function After Intraoperative Recovery of Loss of Signal. AB - OBJECTIVES/HYPOTHESIS: This multicenter study aimed to 1) evaluate early postoperative vocal fold function in relation to intraoperative amplitude recovery, and 2) determine optimal absolute and relative thresholds of intraoperative amplitude recovery heralding normal early postoperative vocal fold function, both after segmental type 1 and after global type 2 loss of signal (LOS). STUDY DESIGN: Prospective outcome study. METHODS: This study, encompassing nine surgical centers from four countries, correlated intraoperative amplitude recovery with early postoperative vocal fold function using receiver operating characteristic analysis. RESULTS: Included in this study were 68 patients, 48 women and 20 men, who sustained transient recurrent laryngeal nerve injury during thyroid surgery under continuous intraoperative nerve monitoring. Early transient vocal fold palsy was seen in 18 (64%) of 28 patients with ipsilateral segmental LOS type 1, and in 10 (25%) of 40 patients with ipsilateral global LOS type 2. On receiver operating characteristic analysis, relative amplitude thresholds were superior to absolute amplitude thresholds in predicting vocal fold function after LOS type 2 (area under the curve [AUC]: 0.83 vs. 0.65; P = .01 vs. P = .15; Youden index 44% and 253 uV) and LOS type 1 (AUC: 0.96 vs. 0.97; P < .001 each; Youden index 49% and 455 uV). Amplitude recovery >=50% of baseline after LOS always indicated intact vocal fold function. CONCLUSIONS: When the nerve amplitude recovers >=50% of baseline after segmental LOS type 1 or global LOS type 2, it is appropriate to extend completion thyroidectomy to the other side during the same session. LEVEL OF EVIDENCE: 2b Laryngoscope, 2018. PMID- 30247761 TI - Higher diet-dependent acid load is associated with risk of breast cancer: Findings from the Sister Study. AB - Dietary factors that contribute to chronic low-grade metabolic acidosis have been linked to breast cancer risk, but to date no epidemiologic study has examined diet-dependent acid load and breast cancer. We used data from 43,570 Sister Study participants who completed a validated food frequency questionnaire at enrollment (2003-2009) and satisfied eligibility criteria. The Potential Renal Acid Load (PRAL) score was used to estimate diet-dependent acid load. Higher scores reflect greater consumption of protein and phosphorus, and lower consumption of potassium, calcium, and magnesium. The association between PRAL and breast cancer was evaluated using multivariable Cox proportional hazards regression. We identified 1,882 invasive breast cancers diagnosed at least 1 year after enrollment (mean follow-up, 7.6 years). The highest PRAL quartile, reflecting greater acid-forming potential, was associated with increased risk of breast cancer (HRhighest vs. lowest quartile : 1.21 [95% CI, 1.04-1.41], Ptrend =0.04). The association was more pronounced for estrogen receptor (ER)-negative (HRhighest vs. lowest quartile : 1.67 [95% CI, 1.07-2.61], Ptrend =0.03) and triple-negative breast cancer (HRhighest vs. lowest quartile : 2.18 [95% CI, 1.22 3.91], Ptrend =0.02). Negative PRAL scores, representing consumption of alkaline diets, were associated with decreased risk of ER-negative and triple-negative breast cancer, compared to a PRAL score of 0 representing neutral pH. Higher diet dependent acid load may be a risk factor for breast cancer while alkaline diets may be protective. Since PRAL scores are positively correlated with meat consumption and negatively correlated with fruit and vegetable intake, results also suggest that diets high in fruits and vegetables and low in meat may be protective against hormone receptor negative breast cancer. This article is protected by copyright. All rights reserved. PMID- 30247762 TI - Immediate Negative Pressure Wound Therapy After Free Flap Transfer for Head and Neck Cancer Surgery. AB - OBJECTIVE: This study aimed to assess the outcomes of administering negative pressure wound therapy (NPWT) in patients immediately following free flap reconstruction after head and neck cancer surgery and radical neck lymph node dissection. The outcomes were compared with those of patients who received conventional wound care (CWC). METHODS: A retrospective analysis was performed for 58 patients with head and neck cancer who underwent free flap reconstruction after tumor ablation and radical neck dissection between February 1, 2016, and October 31, 2016. All reconstructions were performed by the same plastic surgeon. Charts were reviewed for patient demographics, comorbidities, cancer type, operation time, flap type, postoperative drainage volume, complication rates, length of hospital stay, and wound outcomes. RESULTS: No significant difference was observed between patients receiving NPWT and CWC regarding operation time and drainage volume from the vacuum ball. After the application of NPWT, no patients experienced flap failure or developed a wound infection. Significantly fewer patients receiving NPWT developed complications (9.7% vs. 37.0%; P = 0.025) and developed infections (0.0% vs. 14.8%; P = 0.041) compared with those receiving CWC. CONCLUSION: On the basis of fewer associated complications and infections, this study supports the immediate use of NPWT after free flap reconstruction in patients who have undergone head and neck cancer ablation and radical neck lymph node dissection. LEVEL OF EVIDENCE: 4. Laryngoscope, 2478-2482, 2018. PMID- 30247763 TI - Higher Complication Rates in Self-Inflicted Gunshot Wounds After Microvascular Free Tissue Transfer. AB - OBJECTIVES/HYPOTHESIS: Microvascular free tissue transfer is often employed to reconstruct significant facial defects from ballistic injuries. Herein, we present our comparison of complications between self-inflicted and non-self inflicted gunshot wounds after microvascular free tissue transfer. STUDY DESIGN: Retrospective case review. METHODS: Approval was obtained from the JPS institutional review board. We performed a retrospective review of cases of ballistic facial injuries between October 1997 and September 2017 that underwent vascularized free tissue transfer for reconstruction. Comparisons were made between self-inflicted and non-self-inflicted gunshot wounds after microvascular free tissue transfer. The chi2 test was used for all comparisons. P value and 95% confidence interval (CI) were reported. RESULTS: There were 73 patients requiring free flap reconstruction after gunshot wounds to the face during the study period. There was a statistically significant difference in the rates of nonunion between self-inflicted and non-self-inflicted wounds (P = .02, 95% CI: 0.9 to 35.8) There were also no significant differences in flap failure (P = .10, 95% CI: -2.8 to 24.2), plate exposure (P = .28, 95% CI: -6.7 to 33.0), wound infection (P = .40, 95% CI: -8.9 to 31.2), scar contracture (P = .60, 95% CI: 8.1 to 25.1), and fistula formation (P = .13, 95% CI: -2.8 to 28.8) between patients with self-inflicted and those with non-self-inflicted wounds. Overall, complication rates were significantly higher in the self-inflicted group compared to the non-self-inflicted group (P < .0001, 95% CI: 32.6 to 68.6). CONCLUSIONS: Patients with self-inflicted injuries had more complications postoperatively than those with non-self-inflicted injuries. This is likely helpful in surgical planning and patient counseling. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30247764 TI - Transfusion in Head and Neck Cancer Patients Undergoing Pedicled Flap Reconstruction. AB - OBJECTIVE: Blood product utilization is monitored to prevent unnecessary transfusions. Head-and-neck pedicled flap reconstruction transfusion-related outcomes were assessed. METHODS: One hundred and thirty-six pedicled flap patients were reviewed: 64 supraclavicular artery island flaps (SCAIF), 57 pectoralis major (PM) flaps, and 15 submental (SM) flaps. Outcome parameters included flap-related complications, medical complications, length of stay (LOS), and flap survival. Multivariable logistic regression analyses were performed. Multivariable logistic regression analyses were performed to adjust for relevant pre- and perioperative factors. RESULTS: Of all head-and-neck pedicled flap patients included in our analyses (n = 136), 40 (29.4%) received blood transfusions. The average pretransfusion hematocrit (Hct) was 24.3% +/- 0.5%, with 2.65 +/- 0.33 units transfused and a posttransfusion Hct increase of 5.0% +/ 0.6%. Transfusion rates differed with PM (47.4%), SCAIF (17.2%), and SM (13.3%) flaps (P < 0.005). Patients undergoing PM reconstruction trended toward higher transfusion requirements (PM 2.89 +/- 0.47 units, SC 2.18 +/- 0.28 units, and SM 2.00 +/- 0.0 units), with transfusion occurring later in the postoperative course (4.9 +/- 1.3 days vs. 2.4 +/- 0.1 days for all other flaps; P = 0.08). Infection, dehiscence, fistula, or medical complications were not different. Transfusion thresholds of Hct < 21 versus Hct < 27 exhibited no difference in LOS, flap survival, or medical/flap-related complications. CONCLUSION: Transfusion is not associated with surgical or medical morbidity following head and neck pedicled flap reconstruction. There were no differences in outcomes between transfusion triggers of Hct < 21 versus Hct < 27, suggesting that a more conservative transfusion trigger may not precipitate adverse patient complications. Our data recapitulate findings in free flap patients and warrant further investigation of transfusion practices in head and neck flap reconstruction. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30247765 TI - Electromagnetic tracking in image-guided laparoscopic surgery: Comparison with optical tracking and feasibility study of a combined laparoscope and laparoscopic ultrasound system. AB - PURPOSE: In image-guided laparoscopy, optical tracking is commonly employed, but electromagnetic (EM) systems have been proposed in the literature. In this paper, we provide a thorough comparison of EM and optical tracking systems for use in image-guided laparoscopic surgery and a feasibility study of a combined, EM tracked laparoscope and laparoscopic ultrasound (LUS) image guidance system. METHODS: We first assess the tracking accuracy of a laparoscope with two optical trackers tracking retroreflective markers mounted on the shaft and an EM tracker with the sensor embedded at the proximal end, using a standard evaluation plate. We then use a stylus to test the precision of position measurement and accuracy of distance measurement of the trackers. Finally, we assess the accuracy of an image guidance system comprised of an EM-tracked laparoscope and an EM-tracked LUS probe. RESULTS: In the experiment using a standard evaluation plate, the two optical trackers show less jitter in position and orientation measurement than the EM tracker. Also, the optical trackers demonstrate better consistency of orientation measurement within the test volume. However, their accuracy of measuring relative positions decreases significantly with longer distances whereas the EM tracker's performance is stable; at 50 mm distance, the RMS errors for the two optical trackers are 0.210 and 0.233 mm, respectively, and it is 0.214 mm for the EM tracker; at 250 mm distance, the RMS errors for the two optical trackers become 1.031 and 1.178 mm, respectively, while it is 0.367 mm for the EM tracker. In the experiment using the stylus, the two optical trackers have RMS errors of 1.278 and 1.555 mm in localizing the stylus tip, and it is 1.117 mm for the EM tracker. Our prototype of a combined, EM-tracked laparoscope and LUS system using representative calibration methods showed a RMS point localization error of 3.0 mm for the laparoscope and 1.3 mm for the LUS probe, the lager error of the former being predominantly due to the triangulation error when using a narrow-baseline stereo laparoscope. CONCLUSIONS: The errors incurred by optical trackers, due to the lever-arm effect and variation in tracking accuracy in the depth direction, would make EM-tracked solutions preferable if the EM sensor is placed at the proximal end of the laparoscope. PMID- 30247766 TI - tsscds2018: A code for automated discovery of chemical reaction mechanisms and solving the kinetics. AB - A new software, called tsscds2018, has been developed to discover reaction mechanisms and solve the kinetics in a fully automated fashion. The program employs algorithms based on Graph Theory to find transition state (TS) geometries from accelerated semiempirical dynamics simulations carried out with MOPAC2016. Then, the TSs are connected to the corresponding minima and the reaction network is obtained. Kinetic data like populations vs time or the abundancies of each product can also be obtained with our program thanks to a Kinetic Monte Carlo routine. Highly accurate ab initio potential energy diagrams and kinetics can also be obtained using an interface with Gaussian09. The source code is available on the following site: http://forge.cesga.es/wiki/g/tsscds/HomePage (c) 2018 Wiley Periodicals, Inc. PMID- 30247767 TI - Automated Search of Minimum Free-Energy Path by Umbrella Integration. AB - The free-energy landscape is an important factor for understanding the conformational equilibria of chemical reactions, and many techniques have been developed to calculate the potential of the mean force. Unfortunately, these methods require a previous knowledge of the system for calculations because the results depend on the reaction coordinates. In this study, we combine the scaled hypersphere search method with the umbrella integration method to obtain the transition states on free-energy landscapes and minimum-free-energy paths (MFEPs). With this approach, the MFEP connections between known and unknown equilibrium points are constructed without the prior knowledge of the free-energy landscape. The problem of reaction coordinates can be solved by using a multidimensional, fully automated interrogation of MFEPs for acquiring the potential of mean force. The efficiency of the proposed method is demonstrated by applying it to alanine dipeptide and alanine tripeptide. (c) 2018 Wiley Periodicals, Inc. PMID- 30247768 TI - Direct inversion of the iterative subspace with contracted planewave basis functions. AB - Ways to reduce the computational cost of periodic electronic structure calculations by using basis functions corresponding to linear combinations of planewaves have been examined recently. These contracted planewave (CPW) basis functions correspond to Fourier series representations of atom-centered basis functions, and thus provide access to some beneficial properties of planewave (PW) and localized basis functions. This study reports the development and assessment of a direct inversion of the iterative subspace (DIIS) method that employs unique properties of CPW basis functions to efficiently converge electronic wavefunctions. This method relies on access to a PW-based representation of the electronic structure to provide a means of efficiently evaluating matrix-vector products involving the application of the Fock matrix to the occupied molecular orbitals. These matrix-vector products are transformed into a form permitting the use of direct diagonalization techniques and DIIS methods typically employed with atom-centered basis sets. The abilities of this method are assessed through periodic Hartree-Fock calculations of a range of molecules and solid-state systems. The results show that the method reported in this study is approximately five times faster than CPW-based calculations in which the entire Fock matrix is calculated. This method is also found to be weakly dependent upon the size of the basis set, thus permitting the use of larger CPW basis sets to increase variational flexibility with a minor impact on computational performance. (c) 2018 Wiley Periodicals, Inc. PMID- 30247769 TI - Halogen in materials design: Chloroammonium lead triiodide perovskite (ClNH3 PbI3 ) a dynamical bandgap semiconductor in 3D for photovoltaics. AB - Methylammonium lead trihalides and their derivatives are photovoltaic materials. CH3 NH3 PbI3 is the most efficient light harvester among all the known halide perovskites (PSCs). It is regarded as unsuitable for long-term stable solar cells, thus it is necessary to develop other types of PSC materials to achieve stable PSCs (Wang et al., Nat. Energy 2016, 2, 16195). Because of this, various research efforts are on-going to discover novel lead-based or lead-free single/double PSCs, which can be stable, synthesizable, transportable, abundant and efficient in solar energy conversion. Keeping these factors in mind, we report here the electronic structures, energetic stabilities and some materials properties (viz. band structures, density of states spectra and photo-carrier masses) of the PSC chloroammonium lead triiodide (ClNH3 PbI3 ). This emerges through compositional engineering that often focuses on B- and Y-site substitutions within the domain of the BMY3 PSC stoichiometry. ClNH3 PbI3 is found to be stable as orthorhombic and pseudocubic polymorphs, which are analogous with the low and high temperature polymorphs of CH3 NH3 PbI3 . The bandgap of ClNH3 PbI3 (values between 1.28 and 1.60 eV) is found to be comparable with that of CH3 NH3 PbI3 , (1.58 eV), both obtained with periodic DFT at the PBE level of theory. Spin orbit coupling is shown to have a pronounced effect on both the magnitude and character of the bandgap. The computed results show that ClNH3 PbI3 may act as a competitor for CH3 NH3 PbI3 for photovoltaics. (c) 2018 Wiley Periodicals, Inc. PMID- 30247770 TI - stk: A python toolkit for supramolecular assembly. AB - A tool for the automated assembly, molecular optimization and property calculation of supramolecular materials is presented. stk is a modular, extensible and open-source Python library that provides a simple Python API and integration with third party computational codes. stk currently supports the construction of linear polymers, small linear oligomers, organic cages in multiple topologies and covalent organic frameworks (COFs) in multiple framework topologies, but is designed to be easy to extend to new, unrelated, supramolecules or new topologies. Extension to metal-organic frameworks (MOFs), metallocycles or supramolecules, such as catenanes, would be straightforward. Through integration with third party codes, stk offers the user the opportunity to explore the potential energy landscape of the assembled supramolecule and then calculate the supramolecule's structural features and properties. stk provides support for high-throughput screening of large batches of supramolecules at a time. The source code of the program can be found at https://github.com/supramolecular-toolkit/stk. (c) 2018 Wiley Periodicals, Inc. PMID- 30247771 TI - Anemia Prevalence and Trends in Adults Aged 65 and Older: U.S. National Health and Nutrition Examination Survey: 2001-2004 to 2013-2016. PMID- 30247772 TI - The different roles of hcp1 and hcp2 of the type VI secretion system in Escherichia coli strain CE129. AB - Type VI secretion system (T6SS) is a secretory system found in Gram-negative bacteria. One of the main structures for T6SS is Hcp (hemolysin co-regulation protein) pipeline. To investigate the role of Hcp major sub-unit genes hcp1 and hcp2 , we deleted hcp1 and hcp2 genes for constructing the in-frame gene deletion mutants. The properties of biofilm formation and the adhesion to chicken embryo fibroblasts cells (DF1 cells) were reduced in the hcp2 mutant. The knockout of hcp1 and hcp2 genes reduced the ability of the avian pathogenic Escherichia coli (APEC) strain CE129 to infect developing chicken embryos. The expression of quorum sensing (QS)-associated genes luxS, lsrR, and pfs were down-regulated in the hcp1 mutant, and the expression of type 1 fimbriae gene fimA and the adhesion related genes fimC and papC were decreased in the hcp2 mutant, as well as the expression of anti-serum survival factor genes ompA and iss were inhibited in both hcp1 and hcp2 mutants. These results described above from this study help to further elaborate the role of HCP in APEC. PMID- 30247773 TI - Low-Dose Trazodone, Benzodiazepines, and Fall-Related Injuries in Nursing Homes: A Matched-Cohort Study. AB - OBJECTIVES: To evaluate whether risk of fall-related injuries differs between nursing home (NH) residents newly dispensed low-dose trazodone and those newly dispensed benzodiazepines. DESIGN: Retrospective, matched cohort study in linked, population-based administrative data. Matching was based on propensity score ( +/ 0.2 standard deviations of the score as a caliper), age ( +/- 1 year), sex, frailty status, and history of dementia. The derived propensity score included demographic characteristics, clinical comorbidities, cognitive and functional status, and risk factors for falls. SETTING: All NHs in Ontario, Canada. PARTICIPANTS: Propensity score-matched pairs of residents aged 66 and older who received a full clinical assessment between April 1, 2010, and March 31, 2015 (N=7,791). MEASUREMENTS: Hospitalization (emergency department visit or acute care admission) for a fall-related injury within 90 days of exposure. Subdistribution hazard functions accounted for competing risk of death. Sensitivity analyses were used to examine falls resulting in hip or wrist fracture only, as well as different lengths of follow-up at 30, 60, and 180 days. RESULTS: Cumulative incidence of a fall-related injury in the 90 days after index was 5.7% for low-dose trazodone users and 6.0% for benzodiazepine users (between group change=-0.29, 95% confidence interval (CI)=-1.02-0.44]; hazard ratio=0.94, 95% CI=0.83-1.08). Findings were consistent across sensitivity analyses. CONCLUSION: New use of low-dose trazodone was no safer with respect to a risk of a fall-related injury than new use of benzodiazepines. Additional studies to compare the effectiveness and risks of low-dose trazodone with those of a variety of psychotropic drug therapies are required in light of increasing trends in the use of trazodone in NHs. PMID- 30247774 TI - Selective serotonin reuptake inhibitor and selective serotonin and norepinephrine reuptake inhibitor use and risk of fractures in adults: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the association between selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) use and risk of fractures in older adults. METHODS: We systematically identified and analyzed observational studies comparing SSRI/SNRI use for depression with non-SSRI/SNRI use with a primary outcome of risk of fractures in older adults. We searched for studies in MEDLINE, PsycINFO, Embase, DARE (Database of Abstracts or Reviews of Effects), the Cochrane Library, and Web of Science clinical trial research registers from 2011 for SSRIs and 1990 for SNRIs to November 29, 2016. RESULTS: Thirty-three studies met our inclusion criteria; 23 studies were included in meta-analysis: 9 case-control studies and 14 cohort studies. A 1.67-fold increase in the risk of fracture for SSRI users compared with nonusers was observed (relative risk 1.67, 95% CI 1.56-1.79, P = .000). The risk of fracture increases with their long-term use: within 1 year, the risk is 2.9% or 1 additional fracture in every 85 users; within 5 years, the risk is 13.4% or 1 additional fracture in every 19 users. In meta-regression, we found that the increase in risk did not differ across age groups (odds ratio = 1.006; P = .173). A limited number of studies on SNRI use and the risk of fractures prevented us from conducting a meta-analysis. CONCLUSIONS: Our systematic review showed an association between risk of fracture and the use of SSRIs, especially with increasing use. Age does not increase this risk. No such conclusions can be drawn about the effect of SNRIs on the risk of fracture because of a lack of studies. PMID- 30247775 TI - Measuring the patient experience in community mental health services for older people: A study of the Net Promoter Score using the Friends and Family Test in England. AB - OBJECTIVES: The research aimed to explore the value of the Net Promoter Score as a service improvement tool and an outcome measure. The study objectives were to (1) explore associations between the Net Promoter Score with patient and service receipt characteristics; (2) evaluate the strength of association between the Net Promoter Score and a satisfaction score; and (3) evaluate its test-retest reliability. METHODS: A postal survey was sent to service users on caseloads of community mental health teams for older people in four localities of England. The survey collected the Net Promoter Score, a single satisfaction question, and data on socio-demographics, clinical profile, and service receipt. Analysis used non parametric tests of association and exploratory least squares regression. A second survey was administered for test-retest reliability analysis. Fieldwork concluded in April 2016. RESULTS: For 352 respondents, the Net Promoter Score was negatively related to age and was lowest for those still within 6 months of their initial referral. Receiving support from a psychiatrist and/or support worker was linked to higher scores. A strong but imperfect correlation coefficient with the satisfaction score indicates they evaluate related but distinct constructs. It had a reasonable test-retest reliability, with a weighted kappa of 0.706. CONCLUSIONS: Despite doubts over its validity in community mental health services, the Net Promoter Score may produce results of value to researchers, clinicians, service commissioners, and managers, if part of wider data collection. However, multi-item measures would provide greater breadth and improved reliability. PMID- 30247777 TI - Oxidative, Iodoarene-Catalyzed Intramolecular Alkene Arylation for the Synthesis of Polycyclic Aromatic Hydrocarbons. AB - A catalytic, metal-free and chemoselective oxidative intramolecular coupling of arene and alkene C-H bonds is reported. The active hypervalent iodine (HVI) reagent, generated catalytically in situ from iodotoluene and meta chloroperoxybenzoic acid (m-CPBA), reacts with o-vinylbiphenyls to generate polyaromatic hydrocarbons in up to 95 % yield. Experimental evidence suggests the reactions proceed though vinyliodonium and, possibly, vinylenephenonium intermediates. PMID- 30247778 TI - Concurrent cross-reactivity of microbiota-derived epitopes to both self and pathogens may underlie the "Hygiene hypothesis". AB - The current iteration of the "Hygiene hypothesis" proposes precipitous decline in exposure to conserved microbial products and metabolites in individuals in developed countries undermines innate self-nonself "training" of immune system leading to allergy and autoimmunity. However, lack of innate "training" alone fails to account for the antigen-driven nature of these immunopathologies. Here, we advance an alternative, antigen-specific interpretive framework, SPIRAL (Specific ImmunoRegulatory Algorithm) that predicts "loss" of commensal microbiota-derived epitopes cross-reactive to both self and pathogens, rather than conserved microbial moieties or metabolites, underlies the "Hygiene hypothesis." By mechanistically delineating how loss of selective microbiota in predisposed individuals could lead to corresponding "holes" in the epitope specific Foxp3+ regulatory T cell repertoire and subsequent selective immunopathologies, SPIRAL represents a novel interpretation of cross-reactivity that could enable targeted discovery of microbiota species and their associated Treg epitopes "missing" in the diseases "Hygiene hypothesis" implicates, and provides a roadmap for a novel unified interpretation of self-nonself discrimination and T helper phenotype selection. PMID- 30247779 TI - Atomic Modulation and Structure Design of Carbons for Bifunctional Electrocatalysis in Metal-Air Batteries. AB - With the extensive research and development of renewable energy technologies, there is an increasing interest in developing metal-free carbons as a new class of bifunctional electrocatalysts for boosting the performance of metal-air batteries. Along with significant understanding of the electrocatalytic nature and the rapid development of techniques, the activities of carbon electrocatalysts are well-tailored by introducing particular dopants/defects and structure regulation. Herein, the recent advances regarding the rational design of carbon-based electrocatalysts for the oxygen reduction reaction and oxygen evolution reaction are summarized, with a special focus on the bifunctional applications in Zn-air and Li-air batteries. Specifically, the atomic modulation strategies to regulate the electrocatalytic activities of carbons and structure modification are summarized to gain deep insights into bifunctional mechanisms and boost advanced Zn-air and Li-air batteries. The current challenges and future perspectives are also addressed to accelerate the exploration of promising bifunctional carbon catalysts for renewable energy technologies, particularly metal-air batteries. PMID- 30247780 TI - A Hierarchical Silver-Nanowire-Graphene Host Enabling Ultrahigh Rates and Superior Long-Term Cycling of Lithium-Metal Composite Anodes. AB - Metallic lithium (Li) is a promising anode for next-generation high-energy density batteries, but its applications are still hampered due to the limited charging/discharging rate and poor cycling performance. Here, a hierarchical 3D porous architecture is designed with a binary network of continuous silver nanowires assembled on an interconnected 3D graphene skeleton as the host for Li metal composite anodes, which offers a significant boost in both charging/discharging rates and long-term cycling performance for Li-metal batteries. This unique hierarchical binary network structure in conjunction with optimized material combination provides ultrafast, continuous, and smooth electron transportation channel and non-nucleation barrier sites to direct and confine Li deposition. It also offers outstanding mechanical strength and toughness to support massive Li deposition and buffer the internal stress fluctuations during long-term repeated Li stripping/plating thereby minimizing fundamental issues of dendrite formation and volume change even under ultrafast charging/discharging rates. As a result, the composite anode using this hierarchical host can work smoothly at an unprecedented high current density of 40 mA cm-2 over 1000 plating/stripping cycles with low overpotential (<120 mV) in symmetric cells. The as-constructed full cell, paired with LiNi0.5 Co0.2 Mn0.3 O2 cathode, also exhibits excellent rate capability and high-rate cycling stability. PMID- 30247781 TI - Do medical students who are multilingual have higher spatial and verbal intelligence and do they perform better in anatomy examinations? AB - We have already reported that medical students who have prior knowledge of classical Greek and Latin perform better in anatomy examinations. It has also been shown that fluency in more than one language can influence spatial and verbal intelligence and here we hypothesize that medical students who have linguistic skills develop higher spatial and verbal intelligence compared with monolingual students, that there are gender differences, and that there are positive effects on performance in anatomy examinations. One hundred and seventy three second year medical students at Cardiff University responded to spatial and verbal intelligence questions that were adapted from the British MENSA website. This is a 63% response rate for the student cohort. The students were then categorized into different groups depending upon their linguistic knowledge and skills. Across all groups, no gender differences were discerned for either spatial or verbal intelligence. Students who were categorized as monolingual (with only skills in English) had lower spatial and verbal intelligence than those who were multilingual. Medical students who had fluency in English and non European languages showed greater spatial and verbal intelligence than other groups. However, there was no significant improvement in their examination marks for anatomy, although the examination performance might be complicated by cultural considerations. A further finding from our study was that, where an anatomy test required spatial recognition using cadaveric specimens, students with low spatial intelligence had significantly poorer performances. Furthermore, where tests used multiple choice questions, the level of spatial and verbal intelligences had no influence. We would advocate that, when all newly-recruited medical students are tutored in medical terminologies to help them develop the extensive vocabulary required for their professional careers, they should also be made aware of any deficiencies in spatial and verbal skills that could affect their learning abilities. Given that we would expect students to benefit in their careers from developing spatial and verbal skills, we also recommend that examination tests in anatomy should avoid the exclusive use of multiple choice questions. Clin. Anat., 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30247782 TI - A Self-Healing Dielectric Supramolecular Elastomer Functionalized with Aniline Tetramer. AB - A new design strategy to produce a supramolecular elastomer with self-healing and dielectric properties by synthesizing an aniline tetramer (AT)-functionalized supramolecular elastomer (SE-AT) is demonstrated. The termination of AT in the supramolecular system not only shortens linear amide molecular chain to decrease glass transition temperature but also destroys the crystallization to achieve amorphous structure. The SE-AT provides two kinds of noncovalent bonding including pi-pi stacking and the hydrogen bond, which makes the material more easily healed. The SE-AT20% can heal mechanical properties within 24 h at room temperature without any external stimulus. The dielectric constant shows a continuous increase overall with increasing AT content. The material exhibits good electro-mechanical properties, which is attributed to a simultaneous increase in dielectric constant and decrease in modulus. The maximum actuated strain significantly increases with the increasing AT content and the SE-AT20% reaches 10% at 1 V um-1 . Moreover, SE-AT exhibits the ability to regain actuated strain on the location of the mechanical damage after self-healing. PMID- 30247783 TI - Cord Blood-Derived Stem Cells Suppress Fibrosis and May Prevent Malignant Progression in Recessive Dystrophic Epidermolysis Bullosa. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by mutations in the Col7a1 gene. Patients with RDEB suffer from recurrent erosions in skin and mucous membranes and have a high risk for developing cutaneous squamous cell carcinoma (cSCCs). TGFbeta signaling has been associated with fibrosis and malignancy in RDEB. In this study, the activation of TGFbeta signaling was demonstrated in col7a1-/- mice as early as a week after birth starting in the interdigital folds of the paws, accompanied by increased deposition of collagen fibrils and elevated dermal expression of matrix metalloproteinase (MMP)-9 and MMP-13. Furthermore, human cord blood-derived unrestricted somatic stem cells (USSCs) that we previously demonstrated to significantly improve wound healing and prolong the survival of col7a1-/- mice showed the ability to suppress TGFbeta signaling and MMP-9 and MMP-13 expression meanwhile upregulating anti-fibrotic TGFbeta3 and decorin. In parallel, we cocultured USSCs in a transwell with RDEB patient-derived fibroblasts, keratinocytes, and cSCC, respectively. The patient-derived cells were constitutively active for STAT, but not TGFbeta signaling. Moreover, the levels of MMP-9 and MMP-13 were significantly elevated in the patient derived keratinocytes and cSCCs. Although USSC coculture did not inhibit STAT signaling, it significantly suppressed the secretion of MMP-9 and MMP-13, and interferon (IFN)-gamma from RDEB patient-derived cells. Since epithelial expression of these MMPs is a biomarker of malignant transformation and correlates with the degree of tumor invasion, these results suggest a potential role for USSCs in mitigating epithelial malignancy, in addition to their anti-inflammatory and anti-fibrotic functions. Stem Cells 2018. PMID- 30247784 TI - Efficient and Stable Perovskite Solar Cells Using Low-Cost Aniline-Based Enamine Hole-Transporting Materials. AB - Metal-halide perovskites offer great potential to realize low-cost and flexible next-generation solar cells. Low-temperature-processed organic hole-transporting layers play an important role in advancing device efficiencies and stabilities. Inexpensive and stable hole-transporting materials (HTMs) are highly desirable toward the scaling up of perovskite solar cells (PSCs). Here, a new group of aniline-based enamine HTMs obtained via a one-step synthesis procedure is reported, without using a transition metal catalyst, from very common and inexpensive aniline precursors. This results in a material cost reduction to less than 1/5 of that for the archetypal spiro-OMeTAD. PSCs using an enamine V1091 HTM exhibit a champion power conversion efficiency of over 20%. Importantly, the unsealed devices with V1091 retain 96% of their original efficiency after storage in ambient air, with a relative humidity of 45% for over 800 h, while the devices fabricated using spiro-OMeTAD dropped down to 42% of their original efficiency after aging. Additionally, these materials can be processed via both solution and vacuum processes, which is believed to open up new possibilities for interlayers used in large-area all perovskite tandem cells, as well as many other optoelectronic device applications. PMID- 30247786 TI - Comparison of echocardiographic parameters in Fabry cardiomyopathy and light chain cardiac amyloidosis. AB - BACKGROUND: Fabry cardiomyopathy (FC) and light-chain amyloid cardiomyopathy (AL) present with concentric left ventricular (LV) hypertrophy/remodeling and diastolic rather than systolic dysfunction. Direct comparisons are difficult due to rarity and confounded by variability of LV thickness. AIMS: To compare LV diastolic and systolic properties between patients with FC and AL in a cohort matched for interventricular septal thickness (IVS). METHODS: A two-center echocardiographic analysis was performed, comprising 118 patients with IVS >=12 mm (FC and AL 59 patients each) matched by IVS. RESULTS: Fabry cardiomyopathy patients had larger LV end-diastolic diameter (47.7 [44.0-50.9] vs 45.0 [41.5 49.0] mm, P = 0.002), better LV ejection fraction (EF 68.7 [63.4-74.0] vs 63.0 [54.0-70.0]%, P = 0.001) and midwall fractional shortening (midFS 14.8 [13.0 16.1] vs 12.1 [8.9-15.0]%, P = 0.006). LV EF <40% was rare in both (2% vs 7%, P = 0.17). AL patients expressed higher LV diastolic dysfunction grade (III in 26% vs 4%, II in 21% vs 12% and I in 54% vs 84%, P = 0.004), with higher E/e' ratio (13.6 [10.2-18.8] vs 9.8 [7.5-12.3], P < 0.0001). Average E/e' ratio and midFS were significantly associated with NYHA severity in both groups (P < 0.05 for all). CONCLUSIONS: Matched AL patients had worse LV diastolic function than FC, driven by E/e'. Significant LV systolic dysfunction was rare overall. MidFS and E/e' were associated with heart failure severity in both groups. PMID- 30247785 TI - IFN-lambda4 inhibits HIV infection of macrophages through signalling of IFN lambdaR1/IL-10R2 receptor complex. AB - The recently discovered IFN-lambda4 has been found to have antiviral activity against several viruses. However, it's unknown whether IFN-lambda4 can inhibit HIV infection. Here, we show that IFN-lambda4 could suppress HIV infection of macrophages. This IFN-lambda4-mediated HIV inhibition was compromised by the antibodies against IFN-lambda receptor complex, IFN-lambdaR1/IL-10R2. IFN-lambda4 enhanced the phosphorylation of STAT1, and induced antiviral interferon stimulated genes. These findings indicated that IFN-lambda4 can inhibit HIV via JAK/STAT signalling pathway. PMID- 30247787 TI - Current approaches to dementia screening and case finding in low- and middle income countries: Research update and recommendations. AB - Approximately 47 million people have dementia worldwide, with this figure, it is expected to almost triple by 2050. Most people with dementia (approximately two thirds) live in low- and middle-income countries (LMICs). This presents a significant challenge for such countries that often have limited financial resources and less well-developed health and social care systems. In the absence of a cure, reducing the future costs of dementia care and burden of disease may be best achieved by a greater emphasis on (1) more timely diagnosis with earlier intervention to maintain functional independence and (2) undertaking "screening" in groups at high risk of developing dementia, case finding, and using brief cognitive assessment instruments. In clinical settings, a wide range of instruments for dementia screening and diagnosis are currently available; however, few cognitive assessment tools have been developed specifically for clinical use within LMIC settings. Screening for dementia and cognitive impairment in LMICs largely relies on tools adapted from high-income countries (HICs); these often lack validation in these settings leading to education, literacy, and cultural biases. Research is urgently needed to develop cognitive assessment tools and dementia diagnostic approaches that are appropriate and feasible for clinical use in LMIC settings. PMID- 30247788 TI - The association between orthostatic hypotension and dementia: A meta-analysis of prospective cohort studies. AB - OBJECTIVES: As for the association between orthostatic hypotension (OH) and dementia, results of published studies are inconsistent; therefore, current substantive conclusions have yet been obtained. This meta-analysis was conducted in hopes of producing progress in this topic. METHODS: A systematic database search was performed towards electronic databases including Chinese Biomedical Database, PubMed, Web of Science, Wiley Online Library, ScienceDirect, and the Cochrane Library. Five prospective cohort studies were included. Summary hazard ratio (HR) estimates with 95% confidence intervals (CIs) were calculated by random-effects model. Statistical heterogeneity was assessed with the Cochran Q test and I2 statistic. A sensitivity analysis was also conducted in this meta analysis. RESULTS: A 22.4% higher prevalence of dementia in subjects with OH was obtained (adjusted pooled HR was 1.224; 95% CI: 1.106-1.354; P < .001). This meta analysis also showed significant associations between OH and 2 dementia subtypes: Alzheimer disease (adjusted pooled HR was 1.175; 95% CI: 1.022-1.351; P = .023) and Vascular dementia (adjusted pooled HR was 1.403; 95% CI: 1.042-1.889; P = .026), respectively. CONCLUSIONS: Orthostatic hypotension is positively associated with the overall prevalence of dementia, and it may contribute to the prevalence of Alzheimer disease and Vascular dementia as well. PMID- 30247790 TI - Scope and Limitations of the Dehydrogenative Generation of Graphenic Nanoribbons from Methylene-Bridged, Aromatic Ladder Polymers. AB - A synthetic route to solubilized graphenic nanoribbons (GNRs) by oxidation of methylene-bridged, aromatic ladder polymers is presented. Hereby, the ladder polymer precursors are finally 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (or DDQ) oxidized into the desired GNRs. However, a detailed UV-vis analysis shows already partial oxidation/dehydrogenation during aqueous work-up under loss of ~50% of the bridgehead hydrogens as well as some indications for overoxidation with DDQ under formation of quinoid carbonyl defects, additionally driven by a reduction of the number of quinoid (quinodimethane) structural units. PMID- 30247789 TI - Metal-Organic Frameworks Encapsulating Active Nanoparticles as Emerging Composites for Catalysis: Recent Progress and Perspectives. AB - Beyond conventional porous materials, metal-organic frameworks (MOFs) have aroused great interest in the construction of nanocatalysts with the characteristics of catalytically active nanoparticles (NPs) confined into the cavities/channels of MOFs or surrounded by MOFs. The advantages of adopting MOFs as the encapsulating matrix are multifold: uniform and long-range ordered cavities can effectively promote the mass transfer and diffusion of substrates and products, while the diverse metal nodes and tunable organic linkers may enable outstanding synergy functions with the encapsulated active NPs. Herein, some key issues related to MOFs for catalysis are discussed. Then, state-of-the art progress in the encapsulation of catalytically active NPs by MOFs as well as their synergy functions for enhanced catalytic performance in the fields of thermo-, photo-, and electrocatalysis are summarized. Notably, encapsulation structured nanocatalysts exhibit distinct advantages over conventional supported catalysts, especially in terms of the catalytic selectivity and stability. Finally, challenges and future developments in MOF-based encapsulation-structured nanocatalysts are proposed. The aim is to deliver better insight into the design of well-defined nanocatalysts with atomically accurate structures and high performance in challenging reactions. PMID- 30247791 TI - Large and Ultrastable All-Inorganic CsPbBr3 Monocrystalline Films: Low Temperature Growth and Application for High-Performance Photodetectors. AB - Stability is a key problem that hinders the practical application of lead halide perovskite. Therefore, all-inorganic perovskite CsPbX3 monocrystalline films are urgently needed to fabricate photoelectric devices. Herein, a low-temperature and substrate-independent growth method is demonstrated to grow millimeter-level inorganic perovskite monocrystalline thin films. These films present good optical and electrical properties comparable to bulk ones. What is more, they exhibit excellent long-term stability toward humidity and thermal treatment. The as-grown CsPbBr3 monocrystalline films are then fabricated into photodetectors with high photodetection performance. These results demonstrate that the CsPbBr3 monocrystalline films have potential in fabricating high-performance optoelectronic devices. PMID- 30247792 TI - Diversity and environmental adaptation of phagocytic cell metabolism. AB - Phagocytes are cells of the immune system that play important roles in phagocytosis, respiratory burst and degranulation-key components of innate immunity and response to infection. This diverse group of cells includes monocytes, macrophages, dendritic cells, neutrophils, eosinophils, and basophils heterogeneous cell populations possessing cell and tissue-specific functions of which cellular metabolism comprises a critical underpinning. Core functions of phagocytic cells are diverse and sensitive to alterations in environmental- and tissue-specific nutrients and growth factors. As phagocytic cells adapt to these extracellular cues, cellular processes are altered and may contribute to pathogenesis. The considerable degree of functional heterogeneity among monocyte, neutrophil, and other phagocytic cell populations necessitates diverse metabolism. As we review our current understanding of metabolism in phagocytic cells, gaps are focused on to highlight the need for additional studies that hopefully enable improved cell-based strategies for counteracting cancer and other diseases. PMID- 30247793 TI - Changes in serum afamin and vitamin E levels after selective LDL apheresis. AB - BACKGROUND: Afamin is a plasma vitamin E-binding glycoprotein partially associated with ApoA1-containing high-density lipoprotein (HDL) subfractions. In a previous study, the serum vitamin E decreased after low-density lipoprotein (LDL) apheresis, while vitamin E/cholesterol ratio increased. We aimed to study the effect of LDL apheresis on serum afamin level. METHODS: The serum level of afamin and oxidized LDL were measured by enzyme-linked immunosorbent assay in six severe heterozygous FH patients before and after their first LDL apheresis treatments and in seven healthy controls. We also investigated the changes in total cholesterol, LDL-C, HDL-C, ApoB, ApoA1, HDL subfractions, and alpha- and gamma-tocopherol levels during the treatment. HDL subfractions were detected by an electrophoretic method on polyacrylamide gel (Lipoprint). Serum alpha- and gamma-tocopherol levels were detected by gas chromatography-mass spectrometry. RESULTS: The first treatment sessions decreased serum afamin levels by an average of 9.4%. Total cholesterol, LDL-C, HDL-C and ApoA1 levels decreased by 52.6; 61.8; 10.5; and 14.1%, respectively. We found that alpha- and gamma-tocopherol levels markedly decreased (by 34.1 and 32.9%, respectively), while alpha- tocopherol/cholesterol and gamma-tocopherol/cholesterol ratios significantly increased (by 41.4 and 40.3%, respectively). Oxidized LDL levels significantly decreased. There was a shift toward the larger HDL subfractions. CONCLUSION: LDL apheresis moderately decreases the circulating levels of afamin parallel to lowering HDL-C and ApoA1 levels. Tocopherol levels decreases markedly compared to afamin levels, however, beneficial changes in vitamin E/cholesterol ratios, oxidized LDL levels and HDL subfraction distribution were detected. These additional effects of LDL apheresis may result in further cardiovascular risk reduction in FH patients. PMID- 30247795 TI - Recent Progress in Fluorescence Imaging of the Near-Infrared II Window. AB - Near-infrared (NIR) fluorescent materials are considered to be the most promising labeling reagents for sensitive determination and biological imaging due to the advantages of lower background noise, deeper penetrating capacity, and less destructive effects on the biomatrix over those of UV and visible fluorophores. In the past decade, advances in biomedical fluorescence imaging in the NIR region have focused on the traditional NIR window (NIR-I; lambda=700-900 nm), and have recently been extended to the second NIR window (NIR-II; lambda=1000-1700 nm). In vivo NIR-II fluorescence imaging outperforms imaging in the NIR-I window as a result of further reduced absorption, tissue autofluorescence, and scattering. In this review, the applications of four types of NIR-II fluorescent materials, organic fluorophores, quantum dots, rare-earth compounds, and single-walled carbon nanotubes, are summarized and future trends are discussed. Some methods to enhance the NIR-II fluorescence quantum yield are also proposed. PMID- 30247794 TI - Transcutaneous Electrical Nerve Stimulation to Improve Female Sexual Dysfunction Symptoms: A Pilot Study. AB - OBJECTIVES: To perform a pilot study using transcutaneous electrical nerve stimulation (TENS) on the dorsal genital nerve and the posterior tibial nerve for improving symptoms of female sexual dysfunction (FSD) in women without bladder problems. We hypothesize that this therapy will be effective at improving genital arousal deficits. MATERIALS AND METHODS: Nine women with general FSD completed the study. Subjects received 12 sessions of transcutaneous dorsal genital nerve stimulation (DGNS; n = 6) or posterior tibial nerve stimulation (PTNS; n = 3). Stimulation was delivered for 30 min at 20 Hz. Sexual functioning was evaluated with the female sexual functioning index (FSFI), and surveys were also given on general health, urological functioning, and the Patients' Global Impression of Change (PGIC) after treatment. Surveys were given before treatment (baseline), after 6 and 12 weeks of treatment, and 6 weeks after the completion of stimulation sessions. RESULTS: The average total FSFI score across all subjects significantly increased from 15.3 +/- 4.8 at baseline to 20.3 +/- 7.8 after six sessions, 21.7 +/- 7.5 after 12 sessions, and 21.3 +/- 7.1 at study completion (p < 0.05 for all time points). Increases were observed in both DGNS and PTNS subjects. Significant FSFI increases were seen in the subdomains of lubrication, arousal, and orgasm, each of which is related to genital arousal. Bladder and general health surveys did not change across the study. PGIC had a significant increase. CONCLUSIONS: This study provides evidence that transcutaneous stimulation of peripheral nerves has the potential to be a valuable therapeutic tool for women with FSD. PMID- 30247796 TI - A Photoactivatable BODIPY Probe for Localization-Based Super-Resolution Cellular Imaging. AB - The synthesis and application of a photoactivatable boron-alkylated BODIPY probe for localization-based super-resolution microscopy is reported. Photoactivation and excitation of the probe is achieved by a previously unknown boron photodealkylation reaction with a single low-power visible laser and without requiring the addition of reducing agents or oxygen scavengers in the imaging buffer. These features lead to a versatile probe for localization-based microscopy of biological systems. The probe can be easily linked to nucleophile containing molecules to target specific cellular organelles. By attaching paclitaxel to the photoactivatable BODIPY, in vitro and in vivo super-resolution imaging of microtubules is demonstrated. This is the first example of single molecule localization-based super-resolution microscopy using a visible-light activated BODIPY compound as a fluorescent probe. PMID- 30247797 TI - Selenium-sensitive miRNA-181a-5p targeting SBP2 regulates selenoproteins expression in cartilage. AB - Selenium (Se) deficiency brings about defects in the biosynthesis of several selenoproteins and has been associated with aberrant chondrogenesis. Selenocysteine (Sec) Insertion Sequence (SECIS) and SECIS binding protein 2 (SBP2) interaction is a very critical node for the metabolic balance between Se and selenoproteins. The Gpx1, Gpx4 and SelS have different binding affinities with SBP2 in cells. According to our results, both miR-181a-5p and SBP2 appeared to be selenium-sensitive and regulated the expression of selenoproteins in C28/I2 cells under Se sufficient environment. However, they showed significantly opposite expression trend in Se deficiency rats cartilage and SeD C28/I2 cells. The SBP2 is a direct target gene of miR-181a-5p in C28/I2 cells as determined by reporter gene and off-target experiments. And the miR-181a-5p could regulate SBP2 and the selenoproteins in C28/I2 cells. Depending upon the Se supply levels, C28/I2 cells were divided into three groups, that is normal Se, SeD and SeS, which underwent through a 7-day Se deprivation process, then SBP2 was knocked down and overexpressed in all the groups. Moreover, the selected selenoproteins were down-regulated in second-generation low Se diet rat cartilage. The selenoproteins expression was decreased by Se deficiency which depended on the Selenium-sensitive miR-181a-5p to participate and regulate SBP2 at post transcriptional level. It involves a series of antioxidant and ECM (extracellular matrix) genes, to overcome the ROS-related stress for the protection of essential physiological functions and to maintain the balance between anabolism and catabolism of the cartilage. PMID- 30247798 TI - Construction of Heterostructured Fe2 O3 -TiO2 Microdumbbells for Photoelectrochemical Water Oxidation. AB - Designing advanced structures for heterojunction photocatalysts is an effective approach to enhance their performance toward solar-energy conversion. Herein we develop a facile synthetic strategy for the fabrication of Fe2 O3 -TiO2 microdumbbells. With the assistance of preferentially adsorbed hexadecylamine molecules, amorphous TiO2 nanospheres with tunable size are grown at the two ends of Fe-based metal-organic compound microrods. Subsequent annealing of the hybrid obtained leads to the formation of a novel heterostructured Fe2 O3 -TiO2 microdumbbell photocatalyst. Owing to the heterojunction formed and the unique structure, Fe2 O3 -TiO2 microdumbbells with optimized composition and morphology show enhanced performance for photoelectrochemical water oxidation, compared to monophasic Fe2 O3 and TiO2 materials as well as physical mixtures thereof. PMID- 30247799 TI - C5aR1 interacts with TLR2 in osteoblasts and stimulates the osteoclast-inducing chemokine CXCL10. AB - The anaphylatoxin C5a is generated upon activation of the complement system, a crucial arm of innate immunity. C5a mediates proinflammatory actions via the C5a receptor C5aR1 and thereby promotes host defence, but also modulates tissue homeostasis. There is evidence that the C5a/C5aR1 axis is critically involved both in physiological bone turnover and in inflammatory conditions affecting bone, including osteoarthritis, periodontitis, and bone fractures. C5a induces the migration and secretion of proinflammatory cytokines of osteoblasts. However, the underlying mechanisms remain elusive. Therefore, in this study we aimed to determine C5a-mediated downstream signalling in osteoblasts. Using a whole-genome microarray approach, we demonstrate that C5a activates mitogen-activated protein kinases (MAPKs) and regulates the expression of genes involved in pathways related to insulin, transforming growth factor-beta and the activator protein-1 transcription factor. Interestingly, using coimmunoprecipitation, we found an interaction between C5aR1 and Toll-like receptor 2 (TLR2) in osteoblasts. The C5aR1- and TLR2-signalling pathways converge on the activation of p38 MAPK and the generation of C-X-C motif chemokine 10, which functions, among others, as an osteoclastogenic factor. In conclusion, C5a-stimulated osteoblasts might modulate osteoclast activity and contribute to immunomodulation in inflammatory bone disorders. PMID- 30247800 TI - NEK4 kinase regulates EMT to promote lung cancer metastasis. AB - Epithelial-to-mesenchymal transition (EMT) is a dynamic transitional state from the epithelial to mesenchymal phenotypes. Numerous studies have suggested that EMT and its intermediate states play important roles in tumor invasion and metastasis. To identify novel regulatory molecules of EMT, we screened a siRNA library targeting human 720 kinases in A549 lung adenocarcinoma cells harboring E cadherin promoter-luciferase reporter vectors. NIMA-related kinase-4 (NEK4) was identified and characterized as a positive regulator of EMT in the screening. Suppression of NEK4 resulted in the inhibition of cell migration and invasion, accompanying with an increased expression of cell adhesion-related proteins such as E-cadherin and ZO1. Furthermore, NEK4 knockdown caused the decreased expression of the transcriptional factor Zeb1 and Smads proteins, which are known to play key roles in EMT regulation. Consistently, overexpression of NEK4 resulted in the decreased expression of E-cadherin and increased expression of Smad3. Using a mouse model with tail vein injection of NEK4 knockdown stable cell line, we found a lower rate of tumor formation and metastasis of the NEK4 knockdown cells in vivo. Thus, this study demonstrates NEK4 as a novel kinase involved in regulation of EMT and suggests that NEK4 may be further explored as a potential therapeutic target for lung cancer metastasis. PMID- 30247801 TI - Inhibition of autophagy enhances the antitumour activity of tigecycline in multiple myeloma. AB - Accumulating evidence shows that tigecycline, a first-in-class glycylcycline, has potential antitumour properties. Here, we found that tigecycline dramatically inhibited the proliferation of multiple myeloma (MM) cell lines RPMI-8226, NCI H929 and U266 in a dose and time-dependent manner. Meanwhile, tigecycline also potently impaired the colony formation of these three cell lines. Mechanism analysis found that tigecycline led to cell cycle arrest at G0/G1 with down regulation of p21, CDK2 and cyclin D1, rather than induced apoptosis, in MM cells. Importantly, we found that tigecycline induced autophagy and an autophagy inhibitor bafilomycin A1 further amplified the tigecycline-induced cytotoxicity, suggesting that autophagy plays a cytoprotective role in tigecycline-treated MM cells. Mechanisms modulating autophagy found that tigecycline enhanced the phosphorylation of AMPK, but did not decrease the phosphorylation of Akt, to inhibit the phosphorylation of mTOR and its two downstream effectors p70S6K1 and 4E-BP1. Tigecycline effectively inhibited tumour growth in the xenograft tumour model of RPMI-8226 cells. Autophagy also occurred in tigecycline-treated tumour xenograft, and autophagy inhibitor chloroquine and tigecycline had a synergistic effect against MM cells in vivo. Thus, our results suggest that tigecycline may be a promising candidate in the treatment of MM. PMID- 30247802 TI - Toxic adjuvants alter the function and phenotype of dendritic cells to initiate adaptive immune responses induced by oral Helicobacter pylori vaccines. AB - BACKGROUND: Toxic adjuvant is considered as an indispensable constituent for oral Helicobacter pylori (H. pylori) vaccines. However, the elaborate role of toxic adjuvant in the initiation of adaptive immune response is largely undescribed. MATERIALS AND METHODS: We employed an acid-resistant HP55/PLGA nanoparticles (NPs) delivery system encapsulating three antigens (Hsp, Nap, and Lpp20) from H. pylori and accompanied with three adjuvants (LPS, CpG, and chimeric flagellum (CF)) to explore the underlying mechanism of the adjuvant constituent. H. pylori specific antibody responses were detected by ELISA. Gastric inflammatory and Th1/Th17 responses were analyzed by flow cytometry. Expressions of inflammatory cytokines were measured by quantitative real-time PCR. RESULTS: In bone marrow derived dendritic cells' (BMDCs) model, the addition of toxic adjuvants is responsible for the proinflammatory function, but not the mature phenotype of BMDCs. In vivo, intestinal loop injection with NPs + LPS, rather than NPs alone, altered the dendritic cell (DC) phenotypes in mesenteric lymph nodes and drove a local proinflammatory microenvironment. In a prophylactic vaccination model, mice immunized with NPs + adjuvants significantly reduced the gastric colonization of H. pylori, induced antigen-specific antibody responses and Th1/Th17 cell responses. After H. pylori challenge, these mice showed potent recall responses involving both neutrophil and inflammatory monocyte infiltration. Additionally, TLR4 knockout mice were immunized with NPs + LPS and NPs + CF, respectively; only the recipients of NPs + CF orchestrated a protective response to control bacterial infection. CONCLUSIONS: Our study indicated that toxic adjuvants within oral H.pylori vaccines altered the function and phenotype of dendritic cells and facilitated the establishment of proinflammatory microenvironment to initiate adaptive immune responses. PMID- 30247803 TI - Characteristics of live parameters of the HS-5 human bone marrow stromal cell line cocultured with the leukemia cells in hypoxia, for the studies of leukemia stroma cross-talk. AB - The unique bone marrow microenvironment is created by stromal cells and such physical conditions as hypoxia. Both hypoxia and interactions with stromal cells have a significant impact on the biology of leukemia cells, changing their sensitivity to antileukemic therapies. Thus, it is crucial to introduce biological systems, which enable the investigation of leukemia-stroma cross-talk and verification of novel therapies effectiveness under such bone marrow niche mimicking conditions. Here, we have established an experimental setup based on the hypoxic co-culture of stromal cells with different cell lines derived from various leukemia patients. Flow cytometry enables simultaneous fluorescent tracking of viable cells and analysis of fundamental cellular processes, also to monitor the basal vital state of cells in the hypoxic co-culture. This is critically important, as the stromal cells deliver a big variability of signals to protect leukemia cells and provide drug resistance. Therefore, keeping stromal cells at the healthy state is crucial during experimental procedures. In the proposed studies, viability, apoptosis, proliferation, ROS production, and mitochondrial membrane potential were monitored in both cell types, which were separated on the basis of the fluorescence of a cell tracker. We have shown that the proposed hypoxic co-culture conditions do not affect basal live parameters of stromal cells, indicating the relevance of proposed model. Finally, we utilized this experimental setup to monitor the stroma-mediated protection of leukemia cells from the imatinib-induced cell death, which contributes to the leukemia progression and development of therapy resistance. Altogether, we recommend such flow cytometric strategy as an elementary screen of the vital state of stromal cells, which should be performed when using the co-culture hypoxic models. The proposed approach can also be broadly used for other studies of the leukemia stroma cross-talk and of the part played by the leukemic microenvironment in drug screening studies. PMID- 30247804 TI - Regulation of proliferation and invasion by the IGF signalling pathway in Epstein Barr virus-positive gastric cancer. AB - Several carcinomas including gastric cancer have been reported to contain Epstein Barr virus (EBV) infection. EBV-associated gastric cancer (EBVaGC) is classified as one of four molecular subtypes of gastric cancer by The Cancer Genome Atlas (TCGA) group with increased immune-related signatures. Identification of EBV dependent pathways with significant biological roles is needed for EBVaGC. To compare the biological changes between AGS gastric epithelial cells and EBV infected AGS (AGS-EBV) cells, proliferation assay, CCK-8 assay, invasion assay, cell cycle analysis, RT-PCR, Western blot and ELISA were performed. BI836845, a humanized insulin-like growth factor (IGF) ligand-neutralizing antibody, was used for IGF-related signalling pathway inhibition. AGS-EBV cells showed slower proliferating rate and higher sensitivity to BI836845 compared to AGS cells. Moreover, invasiveness of AGS-EBV was increased than that of AGS, and BI836845 treatment significantly decreased the invasiveness of AGS-EBV. Although no apoptosis was detected, entry into the S phase of the cell cycle was delayed in BI836845-treated AGS-EBV cells. In conclusion, AGS-EBV cells seem to modulate their proliferation and invasion through the IGF signalling pathway. Inhibition of the IGF signalling pathway therefore could be a potential therapeutic strategy for EBVaGC. PMID- 30247805 TI - An alternative renin isoform is cardioprotective by modulating mitochondrial metabolism. AB - The renin-angiotensin system promotes oxidative stress, apoptosis, necrosis, fibrosis, and thus heart failure. Secretory renin plays a central role in these processes, initiating the generation of angiotensins. Nevertheless, alternative renin transcripts exist, which code for a cytosolically localized renin isoform (cyto-renin) that is cardioprotective. We tested the hypothesis that the protective effects are associated with a beneficial switch of metabolic and mitochondrial functions. To assess H9c2 cell mitochondrial parameters, we used the Seahorse XF analyser. Cardiac H9c2 cells overexpressing cyto-renin exhibited enhanced nonmitochondrial oxygen consumption, lactate accumulation, and LDH activity, reflecting a switch to more aerobic glycolysis known as Warburg effect. Additionally, mitochondrial spare capacity and cell respiratory control ratio were enhanced, indicating an increased potential to tolerate stress conditions. Renin knockdown induced opposite effects on mitochondrial functions without influencing metabolic parameters. Thus, the protective effects of cyto-renin are associated with an altered bioenergetic profile and an enhanced stress tolerance, which are favourable under ischaemic conditions. Therefore, cyto-renin is a promising new target for the prevention of ischaemia-induced myocardial damage. PMID- 30247806 TI - Recent Advances in Targeted Tumor Chemotherapy Based on Smart Nanomedicines. AB - Efficacy and safety of chemotherapeutic drugs constitute two major criteria in tumor chemotherapy. Nanomedicines with tumor-targeted properties hold great promise for improving the efficacy and safety. To design targeted nanomedicines, the pathological characteristics of tumors are extensively and deeply excavated. Here, the rationale, principles, and advantages of exploiting these pathological characteristics to develop targeted nanoplatforms for tumor chemotherapy are discussed. Homotypic targeting with the ability of self-recognition to source tumors is reviewed individually. In the meanwhile, the limitations and perspective of these targeted nanomedicines are also discussed. PMID- 30247807 TI - A four-gene-based prognostic model predicts overall survival in patients with hepatocellular carcinoma. AB - With the development of new advances in hepatocellular carcinoma (HCC) management and noninvasive radiological techniques, high-risk patient groups such as those with hepatitis virus are closely monitored. HCC is increasingly diagnosed early, and treatment may be successful. In spite of this progress, most patients who undergo a hepatectomy will eventually relapse, and the outcomes of HCC patients remain unsatisfactory. In our study, we aimed to identify potential gene biomarkers based on RNA sequencing data to predict and improve HCC patient survival. The gene expression data and clinical information were acquired from The Cancer Genome Atlas (TCGA) database. A total of 339 differentially expressed genes (DEGs) were obtained between the HCC (n = 374) and normal tissues (n = 50). Four genes (CENPA, SPP1, MAGEB6 and HOXD9) were screened by univariate, Lasso and multivariate Cox regression analyses to develop the prognostic model. Further analysis revealed the independent prognostic capacity of the prognostic model in relation to other clinical characteristics. The receiver operating characteristic (ROC) curve analysis confirmed the good performance of the prognostic model. Then, the prognostic model and the expression levels of the four genes were validated using the Gene Expression Omnibus (GEO) dataset. A nomogram comprising the prognostic model to predict the overall survival was established, and internal validation in the TCGA cohort was performed. The predictive model and the nomogram will enable patients with HCC to be more accurately managed in trials testing new drugs and in clinical practice. PMID- 30247808 TI - Room-Temperature Phototransistor with Negative Photoresponsivity of 108 A W-1 Using Fullerene-Sensitized Aligned Carbon Nanotubes. AB - Detection of low intensity light down to a few photons requires photodetectors with high gain. A new photodetector is reported based on C60 -sensitized aligned carbon nanotube (CNT) transistors with an extremely high responsivity of 108 A W 1 (gain > 108 ) in the ultraviolet and visible range, and 720 A W-1 (gain = 940) in the infrared range. In contrast to most sensitized phototransistors that operate on the photogating effect, the new photodetector operates on the modulation of the electrons scattering in the CNTs, leading to negative photoconductivity. Comparison with similar photodetectors using random CNT networks shows the benefit of using aligned CNTs. At room temperature, the aligned CNT photodetectors are demonstrated to detect a few tens of photons per CNT. PMID- 30247809 TI - A Flexible Wearable Pressure Sensor with Bioinspired Microcrack and Interlocking for Full-Range Human-Machine Interfacing. AB - Flexible wearable pressure sensors have drawn tremendous interest for various applications in wearable healthcare monitoring, disease diagnostics, and human machine interaction. However, the limited sensing range (<10%), low sensing sensitivity at small strains, limited mechanical stability at high strains, and complicated fabrication process restrict the extensive applications of these sensors for ultrasensitive full-range healthcare monitoring. Herein, a flexible wearable pressure sensor is presented with a hierarchically microstructured framework combining microcrack and interlocking, bioinspired by the crack-shaped mechanosensory systems of spiders and the wing-locking sensing systems of beetles. The sensor exhibits wide full-range healthcare monitoring under strain deformations of 0.2-80%, fast response/recovery time (22 ms/20 ms), high sensitivity, the ultrasensitive loading sensing of a feather (25 mg), the potential to predict the health of patients with early-stage Parkinson's disease with the imitated static tremor, and excellent reproducibility over 10 000 cycles. Meanwhile, the sensor can be assembled as smart artificial electronic skins (E-skins) for simultaneously mapping the pressure distribution and shape of touching sensing. Furthermore, it can be attached onto the legs of a smart robot and coupled to a wireless transmitter for wirelessly monitoring human-motion interactivities. PMID- 30247810 TI - Tape Stripped Stratum Corneum Samples Prove to be Suitable for Comprehensive Proteomic Investigation of Actinic Keratosis. AB - PURPOSE: Actinic keratoses (AK) are premalignant tumors that can be clinically difficult to differentiate from skin cancer. An easy, quick, and reliable noninvasive alternative to biopsy is needed to definitively confirm the clinical diagnoses. This study evaluates Tape Stripping (TS) of stratum corneum (SC) for noninvasive biomarker analysis of AK. METHOD: Lesional and nonlesional human SC samples are obtained by application of stripping tapes on the skin of five AK patients. Following sample preparation, protein digests are analyzed by LC-MS/MS. Bioinformatics analyses are performed using Funrich, Ingenuity Pathway Analysis (IPA), and Oncomine bioinformatics and analytical tools. RESULTS: Of the total 613 unique proteins identified, 477 overlap with proteins identified in the proteomic analysis of formalin-fixed and paraffin-embedded (FFPE) AK samples. Additionally, 32 proteins are significantly increased and four proteins decreased in AK samples compared to the normal skin (p < 0.05). In line with proteomic analysis of FFPE samples, IPA and Funrich analysis show that differentially abundant proteins in the TS AK samples are implicated in PI3K/AKT and EGF signaling pathways. These findings are confirmed at the transcript level. CONCLUSION: Tape stripped AK sample is suitable for biomarker analysis. The application of this technique further could revolutionize management of keratinocytic skin tumors by reducing the need for traditional invasive biopsy. PMID- 30247811 TI - Data Curation can Improve the Prediction Accuracy of Metabolic Intrinsic Clearance. AB - A key consideration at the screening stages of drug discovery is in vitro metabolic stability, often measured in human liver microsomes. Computational prediction models can be built using a large quantity of experimental data available from public databases, but these databases typically contain data measured using various protocols in different laboratories, raising the issue of data quality. In this study, we retrieved the intrinsic clearance (CLint ) measurements from an open database and performed extensive manual curation. Then, chemical descriptors were calculated using freely available software, and prediction models were built using machine learning algorithms. The models trained on the curated data showed better performance than those trained on the non-curated data and achieved performance comparable to previously published models, showing the importance of manual curation in data preparation. The curated data were made available, to make our models fully reproducible. PMID- 30247812 TI - Photoacoustic and Magnetic Resonance Imaging Bimodal Contrast Agent Displaying Amplified Photoacoustic Signal. AB - Progress in photoacoustic (PA) and magnetic resonance imaging (MRI) bimodal contrast agents has been achieved mainly by utilizing the imaging capability of single or multiple components and consequently realizing the desired application for both imaging modalities. However, the mechanism of the mutual influence between components within a single nanoformulation, which is the key to developing high-performance multimodal contrast agents, has yet to be fully understood. Herein, by integrating conjugated polymers (CPs) with iron oxide (IO) nanoparticles using an amphiphilic polymer, a bimodal contrast agent named CP-IO is developed, displaying 45% amplified PA signal intensity as compared to bare CP nanoparticle, while the performance of MRI is not affected. Further experimental and theoretical simulation results reveal that the addition of IO nanoparticles in CP-IO nanocomposites contributes to this PA signal amplification through a synergistic effect of additional heat generation and faster heat dissipation. Besides, the feasibility of CP-IO nanocomposites acting as PA-MRI bimodal contrast agents is validated through in vivo tumor imaging using mice models. From this study, it is demonstrated that a delicately designed structural arrangement of various components in a contrast agent could potentially lead to a superior performance in the imaging capability. PMID- 30247814 TI - Organ procurement center allows for daytime liver transplantation with less resource utilization: May address burnout, pipeline, and safety for field of transplantation. AB - Abdominal organ transplantation faces several challenges: burnout, limited pipeline of future surgeons, changes in liver allocation potentially impacting organ procurement travel, and travel safety. The organ procurement center (OPC) model may be one way to mitigate these issues. Liver transplants from 2009 to 2016 were reviewed. There were 755 liver transplants performed with 525 OPC and 230 in-hospital procurements. The majority of transplants (87.4%) were started during daytime hours (5 am-7 pm). Transplants with any portion occurring after hours were more likely to have procurements in-hospital (P < .001). Daytime cases (n = 400) had more OPC procured livers and hepatitis C recipients and were less likely to have a donation after circulatory death donor (all P < .05). In adjusted analyses, daytime cases were independently associated with extubation in the operating room and less postoperative transfusion. There were no significant differences in short- or long-term postoperative outcomes. For exported livers, 54.3% were procured by a local team, saving 137 flights (151 559 miles). The OPC resulted in optimally timed liver transplants and decreased resource utilization with no negative impact on patient outcomes. It allows for ease in exporting organs procured by local surgeons, and potentially addresses provider burnout, the transplant surgery pipeline, and surgeon travel. PMID- 30247813 TI - Flow does not alter eNOS phosphoryation at Ser1179 or Thr495 in preconstricted mouse mesenteric arteries. AB - In arteries, endothelium-dependent vasodilatory agonists and flow-induced shear stress cause vasodilation largely by activation of the endothelial enzyme eNOS, which generates nitric oxide that relaxes vascular smooth muscle. Agonists activate eNOS in part through increased phosphorylation at Ser1179 and decreased phosphorylation at Thr495. We previously found that preconstriction of intact, isolated mouse mesenteric arteries with phenylephrine also caused increased Ser1179 and decreased Thr495 eNOS phosphorylation, and sequential treatment with the vasodilatory agonist acetylcholine did not cause any further change in phosphorylation at these sites, despite producing vasodilation. The present study tests the hypothesis that luminal flow in these arteries preconstricted with phenylephrine also produces vasodilation without phosphorylation changes at these sites. First-order mesenteric arteries, isolated from male C57/BL6 mice (7-20 weeks of age) anesthetized with pentobarbital (50 mg/kg, i.p.), were cannulated, pressurized, and treated with stepped increases in luminal flow (15-120 MUL/min). Flow resulted in dilation that plateaued at ~60 MUL/min (31.3 +/- 3.0% dilation) and was significantly (P < 0.001) NOS-dependent at all flow rates (determined by 10-4 mol/L L-NAME treatment). In separate arteries, preconstriction with phenylephrine (10-5 mol/L) resulted in increased eNOS phosphorylation at Ser1179 (P < 0.05) and decreased phosphorylation at Thr495, but subsequent flow at 60 MUL/min for 5 or 15 min did not cause further changes in phosphorylation, despite causing dilation. Thus, flow-induced dilation does not require changes in these eNOS phosphorylation sites beyond those induced by alpha1-adrenergic stimulation with phenylephrine, indicating that eNOS is activated by other mechanisms during acute flow-induced dilation of preconstricted arteries. PMID- 30247816 TI - Greater access to transplantation should be a priority: A view of the Dialysis PATIENTS Demonstration Act. AB - Fragmentation of care has been cited as a rationale toward moving to new care models with care coordination and a focus on value-based care delivery. This trend is gathering momentum in end-stage renal disease (ESRD) care given evident care gaps and the variety of healthcare entities that touch patients with ESRD in the course of their treatment. Although care models supported by chronic condition special needs plans and ESRD seamless care organizations (ESCOs) have advanced care and cost-effectiveness, their shortcomings limit their ability to support larger patient populations. New care models and potential organizational structures, such as those proposed in the Dialysis Patient Access To Integrated care, Empowerment, Nephrologists, Treatments, and Services (PATIENTS) Demonstration Act, provide another approach toward reducing fragmentation of care, increasing patient health, and helping define better approaches to care for patients with ESRD so that they have the opportunity to be better transplant candidates. We recognize that this type of innovation represents change without certainty. We also believe that multiple levels of accountability, ongoing support for transplantation, and continued freedom of access to transplant professionals who participate in Medicare would prioritize patient health, quality of life, and choice with regard to transplantation with this care model. PMID- 30247815 TI - Hybrid Synthetic-Biological Hydrogel System for Adipose Tissue Regeneration. AB - Hydrogels are promising scaffolds for adipose tissue regeneration. Currently, the incorporation of bioactive molecules in hydrogel system is used, which can increase the cell proliferation rate or improve adipogenic differentiation performance of stromal stem cells but often suffers from high expense or cytotoxicity because of light/thermal curing used for polymerization. In this study, decellularized adipose tissue is incorporated, at varying concentrations, with a thiol-acrylate fraction that is then polymerized to produce hydrogels via a Michael addition reaction. The results reveal that the major component of isolated adipose-derived extracellular matrix (ECM) is Collagen I. Mechanical properties of ECM polyethylene glycol (PEG) are not negatively affected by the incorporation of ECM. Additionally, human adipose-derived stem cells (hASCs) are encapsulated in ECM PEG hydrogel with ECM concentrations varying from 0% to 1%. The results indicate that hASCs maintained the highest viability and proliferation rate in 1% ECM PEG hydrogel with most lipids formation when cultured in adipogenic conditions. Furthermore, more adipose regeneration is observed in 1% ECM group with in vivo study by Day 14 compared to other ECM PEG hydrogels with lower ECM content. Taken together, these findings suggest the ECM PEG hydrogel is a promising substitute for adipose tissue regeneration applications. PMID- 30247817 TI - [Cancer of the tongue and floor of the mouth: Current aspects of diagnosis]. AB - The diagnosis and treatment of cancer of the tongue and floor of the mouth is a relevant problem, for 60-80% of patients first seek medical treatment only when they have late stages of the disease. The review analyzes the data available in the Russian and foreignliterature on mainstay techniques for radiodiagnosing cancer of the mouth and floor of the mouth. It highlights the capabilities of computed tomography in diagnosing this pathology, in assessing deepseated anatomic structures of the mouth and floor of the mouth, and in detecting metastatic neck lymph nodes. PMID- 30247818 TI - [The status of an X-ray mammography equipment park in the Russian Federation in 2011-2012]. AB - Breast cancer is the first most common cancer among women. Its increasingly threatening trends force to search for ways to accelerate the introduction of current technologies for the early diagnosis and prevention of breast malignancies. The paper gives data on the quantity and distribution of diagnostic and minimally invasive mammography equipment by the regions of the Russian Federation, which may lead to the conclusion about the regions' needs for equipment, trends, and possible prospects in the development of digital radiology in mammology. PMID- 30247819 TI - [New tasks of professional education in preparing the accreditation of radiologists]. AB - The paper sets forth the basic provisions of the accreditation of healthcare workers, the principles of a new approach to continuing postgraduate education, by introducing the storage system of credit units, and the tasks of educational establishments to form self-education motivation and to master novel competences. PMID- 30247854 TI - Prevalence of risky driving behaviours on popular television series AB - Summary: Motor vehicle crashes are a leading cause of death among young adults. Social media and television have been shown to affect the likelihood that young adults will engage in risk-taking behaviour. We watched 216 episodes of five populartelevision series on Netflix and identified 333 separate driving scenes, of which 271 (81.4%) portrayed at least one risky driving behaviour. Unsafe driving (not wearing a seat belt) was the most common risky driving behaviour noted,occurring in 245 (73.6%) of driving scenes. Distracted driving (36 [18.8%]) and driving while using a cellphone (28 [8.4%]) were also noted. Popular television series model unsafe driving behaviours. Seat belts are infrequently used. As well, drivers are often distracted, looking away from the road to talk or talking on their cellphones. Television producers should be sensitive to modelling unsafe driving behaviours, particularly if the audience consists largely of youngpeople. PMID- 30247820 TI - Outcomes of hip and knee total joint arthroplasty in a Canadian inmate population over a 10-yearperiod AB - Background: Little information exists regarding the risk of complications in inmates who receive total hip or knee arthroplasties in Canada. Inmates tend to be less healthy owing to socioeconomic factors and an increased number of medical and psychiatric comorbidities. We compared revision and complication rates of total joint replacements in a cohort of incarcerated Canadians versus a cohort of non-inmates. Methods: We obtained a list of all Canadian inmate inpatient hospital visits with diagnostic/procedure codes of primary hip or knee arthroplasty within the last 10 years from our institution's discharge abstract database. Demographic data andinformation related to the perioperative course, along with any data related to postoperative complications/readmissions, were obtained through manual chart review. Results: The inmate group consisted of 20 men (mean age 58 yr) with a total of 24 primary total joint arthroplasties; the comparison group included 171 men (mean age 62 yr). Postoperatively, the inmates had a 4-fold increased risk of major complication compared with non-inmates (33.3% v. 7.6%; odds ratio 4.21, p = 0.01). The inmates' revision rate was 20.8% compared with 5.8% in the comparison group (p = 0.03). The most common cause for revision in the inmate group was infection, with a rate of 16.7% compared with 3.5% in the comparison group (p = 0.03). Conclusion: Patients requiring total joint arthroplasty who are inmates in the Canadian penitentiary system are at increased risk of complication and revision surgeries followingtotal joint arthroplasty. PMID- 30247855 TI - [Diagnosis of Nonpalpable Breast Cancer in Premenopausal Women]. AB - Objective: To analyze the possibilities of standard and additional methods for X ray mammography (MG) in the comprehensive diagnosis of nonpalpable breast masses and preclinical cancers; to identify the important radiological signs of malignancy as predictors for the application of multislice spiral computed tomography/ magnetic resonance imaging (MSCT/MRI-MG), as well as invasive studies in premenopausal women. Material and Methods: The investigation enrolled 423 pre menopausal patients with nonpalpable breast masses; 129 women were found to have breast cancer. The diagnosis was verified by comprehensive clinical and instrumental examination using standard and additional methods for X-ray mammography, ultra-sonography, MRI, MSCT of the breast and biopsy. Significant radiological signs of malignancy of the lesions were detected and their diagnostic value was identified. Results: The use of additional diagnostic techniques for mammography contributes to the confident visualization of important radiological criteria for malignancy, enhances the informative value of by 5%, and promotes a decline in the number of unjustified biopsies by 11%. Conclusion: Problems in visualizing and categorizing nonpalpable breast masses necessitate additional diagnostic techniques for X-ray mammography. The identification and confident interpretation of important radiological criteria for benign or malignant lesions increase the diagnostic value of X-ray mammography: the sensitivity from 91% to 98%, specificity from 61% to 75%. MSCT MG and MRI-MG demonstrate even higher efficiency: contrast-enhanced (CE) MSCT-MG (100% sensitivity, 99% specificity) and CE MRI-MG (100% sensitivity, 98% specificity). Sequential radiological and morphological studies improve the quality and efficiency of diagnosis of nonpalpable breast cancer. PMID- 30247856 TI - Multidisciplinary in-situ simulation to evaluate a rare but high-risk process at a level 1 trauma centre: the "Mega-Sim" approach AB - Summary: Multidisciplinary simulation has been used to successfully teach crisis resource management in operating room and emergency department settings. This article describes a "Mega-Sim" approach using an in-situ simulation that movesamong multiple hospital departments to enhance multidisciplinary training and assess institutional response to a rare but high-risk event: trauma in a pregnant patient. It appears that a Mega-Sim can be used to identify systems issues,increase medical knowledge and improve perceptions of teamwork and communication within and among hospital departments. PMID- 30247857 TI - [Efficiency of Quantitative Analysis of Lung Computed Tomography Findings in Patients with Chronic Obstructive Pulmonary Disease]. AB - Objective: To evaluate the efficiency of detection of emphysema in the analysis of lung computed tomography (CT) images using the "Autoplan" program and to compare the data of quantitative analysis and clinical indicators. Material and methods. Sixty patients with chronic obstructive pulmonary disease (COPD) were examined; the diagnosis was confirmed by external respiratory function evaluation; all the patients underwent inspiratory-expiratory CT using a 32-row multidetector CT scanner, followed by postprocessing in the "Autoplan" system. The features of the system were a floating threshold value, constructing a histogram, and the possibility of preserving a report and polygonal models. Echocardiography was performed to evaluate the right heart and to estimate pulmonary arterial pressure. Material and Methods: Sixty patients with chronic obstructive pulmonary disease (COPD) were examined; the diagnosis was confirmed by external respiratory function evaluation; all the patients underwent inspiratory-expiratory CT using a 32-row multidetector CT scanner, followed by postprocessing in the "Autoplan" system. The features of the system were a floating threshold value, constructing a histogram, and the possibility of preserving a report and polygonal models. Echocardiography was performed to evaluate the right heart and to estimate pulmonary arterial pressure. Results: The obtained numerical values of lung density assessment (mean lung density and emphysema index) showed a high efficiency (a sensitivity of as high as 78%, a specificity of as high as 81%) in detecting emphysema. There was evidence for a relationship between the data of quantitative analysis and the values of external respiration function. Analysis of echocardiographic findings revealed that there was a relationship between emphysema index and systolic and diastolic right ventricle wall thickness (Spearman's rank correlation coefficient from -0.56 to 0.66). Conclusion. Thus, analysis of the lung density CT characteristics provides a physician with objective numerical values, which affect the progression of obstructive changes in patients and the development of signs of chronic cor pulmonale. Conclusion: Thus, analysis of the lung density CT characteristics provides a physician with objective numerical values, which affect the progression of obstructive changes in patients and the development of signs of chronic cor pulmonale. PMID- 30247858 TI - [Comparison of a Radiation Dose During Standard Digital Radiography, Tomosynthesis, and Multislice Spiral Computed Tomography in an Experimental Study of Pediatric Anthropomorphic Phantom]. AB - Objective: To compare a radiation dose obtained during standard digital radiography, tomosynthesis, and multislice spiral computed tomography (MSCT). Material and Methods: Life-size full body pediatric anthropomorphic mannequin phantom was examined with a Fujifilm FDR Ac Selerate 200 X-ray diagnostic apparatus and a Toshiba Aquilion Prime 64 computed scanner using the Piranha dosimetry equipment, as well as Gammex planar target, for comparison of the resolution of the apparatus. The effective radiation doses were calculated for different anatomical regions with the formulas specified in the methodical instructions, using the coefficients K and Kd. Results: The tables and graphs comparing the radiation dose when using different radiation diagnostic techniques were presented. The resolution of standard digital radiography versus that of tomosynthesis was analyzed. Fluctuations of the doses obtained were associated with the difference in the volume of irradiated tissue and in the presence of the doses in the irradiated volume of organs with high radiosensitivity. Optimal physical and technical parameters of photography were proposed, which could reduce a dose load on the patient, without significantly losing the quality of films. Conclusion: The effective doses of tomosynthesis were significantly higher than those of standard digital radiography (p < 0.05) while those of (MSCT) were above those of both X-ray and tomosynthesis, and the resolution of the latter was slightly lower. PMID- 30247859 TI - [Experience With Different Single-Stage Selective Arterial Catheterization Procedures During X-Ray Endovascular Interventions to Reduce a Radiation Dose for Patients]. AB - Objective: To evaluate the impact of single-stage selective arterial catheterizations during X-ray endovascular interventions to reduce obtained radiation doses in the treatment of patients. Material and Methods: X-ray endovascular interventions were carried out in the operating room equipped with a flat detector digital angiography system (Axiom Artis dTA, Siemens Medical System). The impact of single-stage selective arterial catheterization procedures was analyzed during endovascular interventions for coronary heart disease and uterine myomas on the time course of changes in the collective effective radiation doses for patients in the period 2013 to 2015. Results: Analysis of the findings showed that single-stage selective coronary angiography using a universal (multipurpose) radial coronary catheter and single-stage X-ray endovascular uterine artery embolization techniques could reduce collective effective doses for patients from 5.86 persons-Sv in 2013 to 1.6 persons-Sv in 2015. Conclusion: Different single-stage selective catheterization procedures used during endovascular interventions into the coronary and uterine arteries can reduce radiation doses for patients. PMID- 30247860 TI - [Recist 1.1 Criteria in the Assessment of Lung Tumors]. AB - The paper considers the main provisions of the 2009 RECIST guidelines (version 1.1.) criteria for a standard approach to measuring lung tumor lesions and assessing the dynamics of the tumor process during treatment. This paper contains a list of conditions for carrying out multislice spiral computed tomography, under which the latter becomes maximally reproducible for the same patient, as well as an assessment of the course of the disease does optimal. PMID- 30247861 TI - [Current Possibilities of Using Radiopharmaceuticals to Evaluate Cerebral Blood Flow]. AB - A comparison of the possibilities of using various neurotropic radiopharmaceuticals for scintigraphic evaluation of cerebral perfusion. In the whole range of radiopharmaceuticals used to diagnose cerebral blood flow disorders, there are Ceretec (99mTc-hexamethylpropyleneamine) and Neurolite (N,N 1,2-ethylenediylbis-L-cysteine-diethyl ether), which are the most optimal agents. Due to their high cost and related radiation exposure, the radiopharmaceuticals 123I-IMP (123I-isopropyl-iodoamphetamine) and 201Tl-DDC (diethyldithiocarbamate) labeled with thallium-201 virtually minimize the possibilities of being used in daily clinical practice. Fixation of 99mTc-DDC in the brain proves to be short term, which is insufficient for tomoscintigraphy studies. Literature has been sought in the Scopus, Web of Scince, Pubmed, EMBASE, and Russian Science Citation Index databases. PMID- 30247862 TI - [Inferior Vena Cava Suprarenal Filter Implantation]. AB - The paper analyzes indications for, frequency, safety, and efficiency of inferior vena cava (IVC) suprarenal filter implantation. The study based on the Medline database has indicated that an IVC suprarenal filter should be implanted following very strict indications, such as extensive caval thrombosis; renal vein thrombosis with a thrombus in the IVC; some vascular anomalies; a renal tumor process with a tumor thrombus in the IVC; prevention of pulmonary embolism in pregnant women with deep vein thrombosis; and prior to surgery. IVC suprarenal implantation done as clinically indicated is an effective and safe method to prevent pulmonary embolism. PMID- 30247863 TI - The Department of Radiation Diagnosis, Kazan State Medical Academy, Is 90 Years Old. PMID- 30247866 TI - Response to: Propofol administration by endoscopists versus anesthesiologists in gastrointestinal endoscopy: a systematic review and meta-analysis of patient safety outcomes PMID- 30247865 TI - Acute kidney injury following resection of hepatocellular carcinoma: prognostic value of the acute kidney injury network criteria AB - Background: Acute kidney injury (AKI) is associated with increased morbidity and mortality after liver resection. Patients with hepatocellular carcinoma (HCC) have a higher risk of AKI owing to the underlying association between hepatic and renal dysfunction. Use of the Acute Kidney Injury Network (AKIN) diagnostic criteria is recommended for patients with cirrhosis, but remains poorly studied following liver resection. We compared the prognostic value of the AKIN creatinine and urine output criteria in terms of postoperative outcomes following liver resection for HCC. Methods: All patients who underwent a liver resection for HCC from January 2010 to June 2016 were included. We used AKIN urine output and creatinine criteria to assess for AKI within 48 hours of surgery. Results: Eighty liver resections were performed during the study period. Cirrhosis was confirmed in 80%. Median hospital stay was 9 (interquartile range 7-12) days, and 30-day mortality was 2.5%. The incidence of AKI was higher based on the urineoutput than on the creatinine criterion (53.8% v. 20%), and was associated with prolonged hospitalization and 30-day postoperative mortality when defined by serum creatinine (hospital stay: 11.2 v. 20.1 d, p = 0.01; mortality: 12.5% v. 0%, p < 0.01), but not urine output (hospital stay: 15.6 v. 10 d, p = 0.05; mortality: 2.3% v. 2.7%, p > 0.99). Conclusion: The urine output criterion resulted in an overestimation of AKI and compromised the prognostic value of AKIN criteria. Revision may be required to account for the exacerbated physiologic postoperative reduction in urine output in patients with HCC. PMID- 30247867 TI - Author response: Response to: Propofol administration by endoscopists versus anesthesiologists in gastrointestinal endoscopy: a systematic review and meta analysis of patient safety outcomes PMID- 30247868 TI - Combining Chemical Genetics with Proximity-Dependent Labeling Reveals Cellular Targets of Poly(ADP-ribose) Polymerase 14 (PARP14). AB - Poly(ADP-ribose) polymerase 14 (PARP14) is a member of the PARP family of enzymes that transfer ADP-ribose from NAD+ to nucleophilic amino acids on target proteins, a process known as mono-ADP-ribosylation (MARylation). PARP14 is involved in normal immune function through the IL-4 signaling pathway and is a prosurvival factor in multiple myeloma and hepatocellular carcinoma. A mechanistic understanding of the physiological and pathophysiological roles of PARP14 has been limited by the dearth of PARP14-specific MARylation targets. Herein we engineered a PARP14 variant that uses an NAD+ analog that is orthogonal to wild-type PARPs for identifying PARP14-specific MARylation targets. Combining this chemical genetics approach with a BioID approach for proximity-dependent labeling of PARP14 interactors, we identified 114 PARP14-specific protein substrates, several of which are RNA regulatory proteins. One of these targets is PARP13, a protein known to play a role in regulating RNA stability. PARP14 MARylates PARP13 on several acidic amino acids. This study not only reveals crosstalk among PARP family members but also highlights the advantage of using disparate approaches for identifying the direct targets of individual PARP family members. PMID- 30247869 TI - Charge Carrier Lifetimes in Cr-Fe-Al-O Thin Films. AB - The effect of compositional variation on charge carrier lifetimes of Cr1Fe0.84Al0.16O3, a promising material for solar water splitting recently identified using combinatorial materials science, is explored using ultrafast time-resolved optical reflectance. The transient signal can be described by a biexponential decay, where the shorter time constant varies over 1 order of magnitude with changing Cr content while the longer one stays constant. Intrinsic performance limitations such as a low charge carrier mobility on the order of 10 3 cm2/(Vs) are identified. Charge carrier lifetime and mobility are discussed as screening criteria for solar water splitting materials. PMID- 30247870 TI - DARK Classics in Chemical Neuroscience: Opium, a Historical Perspective. AB - Opium is the latex from the opium poppy Papaver somniferum L., which humankind has utilized since ancient Mesopotamia all the way to modern times. Opium used to be surrounded in divine mystery or magic-like abilities and was given to cure a wide variety of diseases until its analgesic, antitussive, and antidiarrheal properties were understood, the resulting alkaloids were isolated, and their structure and properties unmasked. Opium went from being sold in any store front in the form of pills or tinctures with no prescription necessary for purchase or smoked in an opium den down the street, to then bringing about consumer advocacy and the right to know what is in a medication. Legislation was created to limit the prescribing and selling of medications to doctors and pharmacists as well as outlawing opium dens and smoking opium. This review focuses primarily on the uses of opium throughout history, the isolation of the principle alkaloids, and their structure elucidation. PMID- 30247871 TI - KA-11, a Novel Pyrrolidine-2,5-dione Derived Broad-Spectrum Anticonvulsant: Its Antiepileptogenic, Antinociceptive Properties and in Vitro Characterization. AB - Recently, compound KA-11 was identified as a promising candidate for a new broad spectrum anticonvulsant. This compound revealed wide protective activity across the most important animal models of seizures such as the maximal electroshock test (MES), the subcutaneous pentylenetetrazole test ( scPTZ), and the six-hertz test (6 Hz, 32 mA). Importantly, KA-11 was devoid of acute neurological activity, which was assessed by applying the chimney test (TD50 value higher than 1500 mg/kg). The preliminary in vivo results confirmed favorable anticonvulsant and safety properties of KA-11. With the aim of further biological characterization of KA-11, in the current studies we evaluated its antiepileptogenic activity in the kindling model of epilepsy induced by repeated injection of PTZ in mice. Furthermore, we assessed the antinociceptive activity of KA-11 in several animal pain models. As a result, KA-11 (at all doses applied: 25, 50, and 100 mg/kg) significantly delayed the progression of kindling induced by repeated injection of PTZ in mice. Additionally, KA-11 revealed potent antinociceptive activity in the formalin-induced tonic pain and, importantly, in the oxaliplatin-induced neuropathic pain model in mice. Moreover, KA-11 did not induce motor deficits in the rotarod test. Patch-clamp experiments revealed that one of the mechanisms of action of KA-11 is inhibition of voltage-gated sodium currents. Compound KA-11 appeared to be safe in relation to hepatotoxic properties as no phospholipidosis induction was determined in HepG2 cells at 50 MUM, and a small, statistically significant decrease of cell viability was observed only at the highest used dose of 100 MUM. Moreover, KA-11 did not affect the function of CYP2D6. The aforementioned hybrid substance proved to penetrate the biological membranes in the in vitro permeability assays. PMID- 30247872 TI - Acetate Mediates Alcohol Excitotoxicity in Dopaminergic-like PC12 Cells. AB - Neuronal excitotoxicity is the major cause of alcohol-related brain damage, yet the underlying mechanism remains poorly understood. Using dopaminergic-like PC12 cells, we evaluated the effect of N-methyl-d-aspartate receptors (NMDAR) on acetate-induced changes in PC12 cells: cell death, cytosolic calcium, and expression levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha). Treatment of PC12 cells with increasing concentrations of acetate for 4 h caused a dose-dependent increase in the percentage of cells staining positive for cell death using propidium iodide (PI) exclusion and cytosolic reactive oxygen species (ROS) using cell ROX detection analyzed via flow cytometry. The EC50 value for acetate was calculated and found to be 4.40 mM for PI and 1.81 mM for ROS. Ethanol up to 100 mM had no apparent changes in the percent of cells staining positive for PI or ROS. Acetate (6 mM) treatment caused an increase in cytosolic calcium measured in real-time with Fluo-4AM, which was abolished by coapplication with the NMDAR blocker memantine (10 MUM). Furthermore, cells treated with acetate (6 mM) for 4 h had increased expression levels of TNFalpha relative to control, which was abolished by coapplication of memantine (10 MUM). Co-application of acetate (6 mM) and memantine had no apparent reduction in acetate-induced cell death. These findings suggest that acetate is capable of increasing cytosolic calcium concentrations and expression levels of the pro inflammatory cytokine TNFalpha through an NMDAR-dependent mechanism. Cell death from acetate was not reduced through NMDAR blockade, suggesting alternative pathways independent of NMDAR activation for excitotoxicity. PMID- 30247873 TI - Sphingobacterium sp. T2 Manganese Superoxide Dismutase Catalyzes the Oxidative Demethylation of Polymeric Lignin via Generation of Hydroxyl Radical. AB - Sphingobacterium sp. T2 contains two extracellular manganese superoxide dismutase enzymes which exhibit unprecedented activity for lignin oxidation but via an unknown mechanism. Enzymatic treatment of lignin model compounds gave products whose structures were indicative of aryl-Calpha oxidative cleavage and demethylation, as well as alkene dihydroxylation and alcohol oxidation. 18O labeling studies on the SpMnSOD-catalyzed oxidation of lignin model compound guiaiacylglycerol-beta-guaiacyl ether indicated that the an oxygen atom inserted by the enzyme is derived from superoxide or peroxide. Analysis of an alkali lignin treated by SpMnSOD1 by quantitative 31P NMR spectroscopy demonstrated 20 40% increases in phenolic and aliphatic OH content, consistent with lignin demethylation and some internal oxidative cleavage reactions. Assay for hydroxyl radical generation using a fluorometric hydroxyphenylfluorescein assay revealed the release of 4.1 molar equivalents of hydroxyl radical by SpMnSOD1. Four amino acid replacements in SpMnSOD1 were investigated, and A31H or Y27H site-directed mutant enzymes were found to show no lignin demethylation activity according to 31P NMR analysis. Structure determination of the A31H and Y27H mutant enzymes reveals the repositioning of an N-terminal protein loop, leading to widening of a solvent channel at the dimer interface, which would provide increased solvent access to the Mn center for hydroxyl radical generation. PMID- 30247874 TI - Ultrasensitive, Mechanically Responsive Optical Metasurfaces via Strain Amplification. AB - Optical metasurfaces promise ultrathin, lightweight, miniaturized optical components with outstanding capabilities to manipulate the amplitude, phase, and polarization of light compared to conventional, bulk optics. The emergence of reconfigurable metasurfaces further integrates dynamic tunability with optical functionalities. Here, we report a structurally reconfigurable, optical metasurface constructed by integrating a plasmonic lattice array in the gap between a pair of symmetric microrods that serve to locally amplify the strain created on an elastomeric substrate by an external mechanical stimulus. The strain on the metasurface is amplified by a factor of 1.5-15.9 relative to the external strain by tailoring the microrod geometry. For the highest strain amplification geometry, the mechano-sensitivity of the optical responses of the plasmonic lattice array is a factor of 10 greater than that of state-of-the-art stretchable plasmonic resonator arrays. The spatial arrangement and therefore the optical response of the plasmonic lattice array are reversible, showing little hysteresis. PMID- 30247875 TI - Contact and Noncontact Measurement of Electronic Transport in Individual 2D SnS Colloidal Semiconductor Nanocrystals. AB - Colloidal-based solution syntheses offer a scalable and cost-efficient means of producing 2D nanomaterials in high yield. While much progress has been made toward the controlled and tailorable synthesis of semiconductor nanocrystals in solution, it remains a substantial challenge to fully characterize the products' inherent electronic transport properties. This is often due to their irregular morphology or small dimensions, which demand the formation of colloidal assemblies or films as a prerequisite to performing electrical measurements. Here, we report the synthesis of nearly monodisperse 2D colloidal nanocrystals of semiconductor SnS and a thorough investigation of the intrinsic electronic transport properties of single crystals. We utilize a combination of multipoint contact probe measurements and ultrafast terahertz spectroscopy to determine the carrier concentration, carrier mobility, conductivity/resistivity, and majority carrier type of individual colloidal semiconductor nanocrystals. Employing this metrological approach, we compare the electronic properties extracted for distinct morphologies of 2D SnS and relate them to literature values. Our results indicate that the electronic transport of colloidal semiconductors may be tuned through prudent selection of the synthetic conditions. We find that these properties compare favorably to SnS grown using vapor deposition techniques, illustrating that colloidal solution synthesis is a promising route to scalable production of nanoscale 2D materials. PMID- 30247876 TI - Naphthylthiazoles: Targeting Multidrug-Resistant and Intracellular Staphylococcus aureus with Biofilm Disruption Activity. AB - Thirty-two new naphthylthiazole derivatives were synthesized with the aim of exploring their antimicrobial effect on multidrug-resistant Gram-positive bacteria. Compounds 25 and 32, with ethylenediamine and methylguanidine side chains, represent the most promising derivatives, as their antibacterial spectrum includes activity against multidrug-resistant staphylococcal and enterococcal strains. Moreover, the new derivatives are highly advantageous over the existing frontline therapeutics for the treatment of multidrug-resistant Gram-positive bacteria. In this vein, compound 25 possesses three attributes: no bacterial resistance was developed against it even after 15 passages, it was very efficient in targeting intracellular pathogens, and it exhibited a concentration-dependent ability to disrupt the preformed bacterial biofilm. PMID- 30247877 TI - Alpha-7 Nicotinic Receptor-Targeted Cinobufagin Induces Antinociception and Inhibits NF-kappaB Signaling Pathway in DRG Neurons. AB - Cinobufagin (CBG) has been shown to have antinociceptive properties. Nevertheless, the antinociceptive effect and mechanism of CBG are still unclear. The present study was designed to investigate the antinociceptive effect of CBG in the thermal and chemical pain models and further to explore the molecular target and potential signal pathway. As shown in the hot-plate test, formalin test, and acetic acid writhing test in mice, administration of CBG produced significant antinociceptive activity in a dose-dependent manner, and the antinociceptive effect was blocked by intraperitoneal pretreatment of methyllycaconitine citrate (an alpha7 nicotinic receptor antagonist) and intrathecal delivery of an alpha7 nicotinic receptor antagonist siRNA (alpha7 siRNA). Immunofluorescence demonstrated that the alpha7 nicotinic receptor and IkappaB/NF-kappaB were coexpressed in primary cultured lumbar DRG neurons. In the chemical pain models and primary cultured DRG neurons, Western blot analysis showed that the formation of p-IkappaB and p-NF-kappaB was regulated by CBG, and the effect of CBG was inhibited by alpha7-siRNA, and ELISA analysis indicated that CBG also regulated the expression of inflammatory cytokines through the alpha7 nicotinic receptor in DRG. These results suggest that CBG may activate an alpha7 nicotinic receptor, thereby triggering the inhibition of the DRG NF-kappaB signaling pathway, resulting in an antinociceptive effect in mice. PMID- 30247878 TI - Good to the Last Drop: Interfacial Droplet Chemistry, from Crystals to Biological Membranes. AB - The study of the liquid-liquid interface has a long and storied history yet still holds important implications for science and technology. Although deep examination of this buried interface poses challenges, recent progress in experimental and theoretical methodology has allowed for advanced understanding of the molecular bases of such interfaces. This Account will focus on the behavior of surfaces of aqueous microdroplets immersed in an immiscible phase, exhibiting physicochemical behavior dependent on the presence of interfacial self assembled structures. Amphiphiles spontaneously form self-assembled nanostructures at the liquid interface, creating a soft liquid surface for the aqueous microdroplet that can modulate its behavior. A prominent characteristic of a micron-sized droplet is its elevated surface area/volume ratio, a feature that presents opportunities for investigating the role of the interface in aspects of droplet chemistry. In two notable examples, a surfactant self-assembly can act as a template for crystal nucleation of droplet solutes at the monolayer level, while at the level of a bilayer, formed when two monolayer-covered droplets are made to adhere, the apposition of monolayers bears remarkable similarities to cell membranes. Each type of system provides arbitrary control of important factors, both for studying crystallization nucleation and for modeling semipermeable lipid membranes at an interdroplet contact zone, the droplet interface bilayer (DIB). The droplet bilayer allows for direct observation of species transport across an unsupported bilayer and versatile parameter control to expore the effects of membrane lipid structure on bilayer transport. It is demonstrated that molecular shape for monoglycerides and phospholipids influences the surface characteristics of monolayers and bilayers. Additionally, subtle interfacial interactions between aqueous contents (ions, solutes) and the monolayer/bilayer are shown to have a marked influence on lipid packing and permeability. It is anticipated that this successful demonstration of surface engineering at the micron scale will deliver cogent insights into many biologically relevant phenomena, such as membrane transport and biomineralization. PMID- 30247879 TI - Confined Lithium-Sulfur Reactions in Narrow-Diameter Carbon Nanotubes Reveal Enhanced Electrochemical Reactivity. AB - We demonstrate an unusual electrochemical reaction of sulfur with lithium upon encapsulation in narrow-diameter (subnanometer) single-walled carbon nanotubes (SWNTs). Our study provides mechanistic insight on the synergistic effects of sulfur confinement and Li+ ion solvation properties that culminate in a new mechanism of these sub-nanoscale-enabled reactions (which cannot be solely attributed to the lithiation-delithiation of conventional sulfur). Two types of SWNTs with distinct diameters, produced by electric arc (EA-SWNTs, average diameter 1.55 nm) or high-pressure carbon monoxide (HiPco-SWNTs, average diameter 1.0 nm), are investigated with two comparable electrolyte systems based on tetraethylene glycol dimethyl ether (TEGDME) and 1,4,7,10,13 pentaoxacyclopentadecane (15-crown-5). Electrochemical analyses indicate that a conventional solution-phase Li-S reaction occurs in EA-SWNTs, which can be attributed to the smaller solvated [Li(TEGDME)]+ and [Li(15-crown-5)]+ ions within the EA-SWNT diameter. In stark contrast, the Li-S confined in narrower diameter HiPco-SWNTs exhibits unusual electrochemical behavior that can be attributed to a solid-state reaction enabled by the smaller HiPco-SWNT diameter compared to the size of solvated Li+ ions. Our results of the electrochemical analyses are corroborated and supported with various spectroscopic analyses including operando Raman, X-ray photoelectron spectroscopy, and first-principles calculations from density functional theory. Taken together, our findings demonstrate that the controlled solid-state lithiation-delithiation of sulfur and an enhanced electrochemical reactivity can be achieved by sub-nanoscale encapsulation and one-dimensional confinement in narrow-diameter SWNTs. PMID- 30247881 TI - Crystalline Dioxin-Linked Covalent Organic Frameworks from Irreversible Reactions. AB - Triangular 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP) and linear tetrafluorophthalonitrile (TFPN) or 2,3,5,6-tetrafluoro-4-pyridinecarbonitrile (TFPC) were linked by 1,4-dioxin linkages to form crystalline 2D covalent organic frameworks, termed COF-316 and -318. Unlike the condensation reactions commonly used to crystallize the great majority of COFs, the reactions used in this report are based on nucleophilic aromatic substitution reactions (SNAr) that are considered irreversible. Our studies show that the reactivity of TFPN and TFPC with HHTP is enhanced by the nitrile substituents leading to facile reactions of planar building units to yield the present 1,4-dioxin linked COFs. Because these reactions are irreversible, the resultant frameworks have high chemical stability in both acid and base. This has led to postsynthetic modifications of COF-316 by reactions necessitating extreme conditions to covalently install functionalities not otherwise accessible. We also report the permanent porosity of these COFs. PMID- 30247880 TI - Biporous Metal-Organic Framework with Tunable CO2/CH4 Separation Performance Facilitated by Intrinsic Flexibility. AB - In this work, we report the synthesis of SION-8, a novel metal-organic framework (MOF) based on Ca(II) and a tetracarboxylate ligand TBAPy4- endowed with two chemically distinct types of pores characterized by their hydrophobic and hydrophilic properties. By altering the activation conditions, we gained access to two bulk materials: the fully activated SION-8F and the partially activated SION-8P with exclusively the hydrophobic pores activated. SION-8P shows high affinity for both CO2 ( Qst = 28.4 kJ/mol) and CH4 ( Qst = 21.4 kJ/mol), while upon full activation, the difference in affinity for CO2 ( Qst = 23.4 kJ/mol) and CH4 ( Qst = 16.0 kJ/mol) is more pronounced. The intrinsic flexibility of both materials results in complex adsorption behavior and greater adsorption of gas molecules than if the materials were rigid. Their CO2/CH4 separation performance was tested in fixed-bed breakthrough experiments using binary gas mixtures of different compositions and rationalized in terms of molecular interactions. SION 8F showed a 40-160% increase (depending on the temperature and the gas mixture composition probed) of the CO2/CH4 dynamic breakthrough selectivity compared to SION-8P, demonstrating the possibility to rationally tune the separation performance of a single MOF by manipulating the stepwise activation made possible by the MOF's biporous nature. PMID- 30247882 TI - Managing Diffuse Phosphorus at the Source versus at the Sink. AB - Judicious phosphorus (P) management is a global grand challenge and critical to achieving and maintaining water quality objectives while maintaining food production. The management of point sources has been successful in lowering P inputs to aquatic environments, but more difficult is reducing P discharges associated with diffuse sources, such as nonpoint runoff from agriculture and urban landscapes, as well as P accumulated in soils and sediments. Strategies for effective diffuse-P management are imperative. Many options are currently available, and the most cost-effective and practical choice depends on the local situation. This critical review describes how the metrics of P quantity in kg ha 1 yr-1 and P form can influence decision-making and implementation of diffuse-P management strategies. Quantifying the total available pool of P, and its form, in a system is necessary to inform effective decision-making. The review draws upon a number of " current practice" case studies that span agriculture, cities, and aquatic sectors. These diverse examples from around the world highlight different diffuse-P management approaches, delivered at the source in the catchment watershed or at the aquatic sink. They underscore workable options for achieving water quality improvement and wider P sustainability. The diffuse-P management options discussed in this critical review are transferable to other jurisdictions at the global scale. We demonstrate that P quantity is typically highest and most concentrated at the source, particularly at farm scale. The most cost-effective and practically implementable diffuse-P management options are, therefore, to reduce P use, conserve P, and mitigate P loss at the source. Sequestering and removing P from aquatic sinks involves increasing cost, but is sometimes the most effective choice. Recovery of diffuse-P, while expensive, offers opportunity for the circular economy. PMID- 30247883 TI - Identification of Helicase Proteins as Clients for HSP90. AB - The 90-kDa heat shock protein (HSP90) is a molecular chaperone that maintains the proper folding of its client proteins including protein kinases and steroid hormone receptors. Helicases are a group of nucleic acid-binding ATPases that can unwind DNA and/or RNA and function in almost every aspect of nucleic acid metabolism. Not much, however, is known about the interactions between HSP90 and helicase proteins. Herein, we developed a parallel-reaction monitoring (PRM) based targeted proteomic method that allows for quantifying >80% of the human helicase proteome. By employing this method, we demonstrated that a large number of helicase proteins exhibited diminished expression in cultured human cells upon treatment with two small-molecule inhibitors of HSP90. We further introduced a tandem affinity tag to the C-terminus of endogenous HSP90beta protein by using the CRISPR-Cas9 genome editing method. Affinity purification followed by LC-PRM analysis revealed an enrichment of 40 out of the 66 quantified helicases from the lysate of cells expressing tagged HSP90beta. Together, we developed a high throughput targeted proteomic method for assessing quantitatively the human helicase proteome, and our results support that helicases may constitute an important group of client proteins for HSP90. PMID- 30247884 TI - Chemistry of Human Breast Milk-A Comprehensive Review of the Composition and Role of Milk Metabolites in Child Development. AB - Early nutrition has an enormous influence on a child's physiological function, immune system maturation, and cognitive development. Human breast milk (HBM) is recognized as the gold standard for human infant nutrition. According to a WHO report, breastfeeding is considered as an unequaled way of providing ideal food to the infant, which is required for his healthy growth and development. HBM contains various macronutrients (carbohydrates, proteins, lipids, and vitamins) as well as numerous bioactive compounds and interactive elements (growth factors, hormones, cytokines, chemokines, and antimicrobial compounds. The aim of this review is to summarize and discuss the current knowledge about metabolites, which are the least understood components of HBM, and their potential role in infant development. We focus on small metabolites (<1500 Da) and characterize the chemical structure and biological function of polar metabolites such as human milk oligosaccharides, nonprotein molecules containing nitrogen (creatine, amino acids, nucleotides, polyamines), and nonpolar lipids. We believe that this manuscript will provide a comprehensive insight into a HBM metabolite composition, chemical structure, and their role in a child's early life nutrition. PMID- 30247885 TI - Attenuation of Palm Stearin Emulsion Droplet in Vitro Lipolysis with Crystallinity and Gastric Aggregation. AB - Emulsions with partially crystalline solid (SE) and undercooled-liquid (LE) droplets with equivalent droplet sizes (centering ~416 nm), surface charges (~-56 mV), and spherical morphologies were prepared by hot microfluidization based on 10% palm stearin and 0.4% Span 60. Lipid crystallinity attenuated early gastroduodenal lipolysis in vitro ( p < 0.05), both with and without inclusion of a gastric phase ( p < 0.05). Gastric exposure, in particular acidic pH, led to partial coalescence of SE and flocculation and partial crystallization of LE, and it attenuated the rate and extent of lipolysis in both samples. In vitro shear conditions further impacted colloidal stability, particularly for SE, with implications for digestibility. Although lipid crystallinity consistently attenuated early lipolysis, gastric-phase SE partial coalescence had a relatively greater impact on digestibility than did droplet physical state. These findings show that a complex interplay exists among a droplet's physical state, colloidal properties, and digestion conditions, which combine to impact emulsion in vitro lipolysis. PMID- 30247886 TI - Aqueous Benzylic C-H Trifluoromethylation for Late-Stage Functionalization. AB - The installation of trifluoromethyl groups has become an essential step across a number of industries such as agrochemicals, drug discovery, and materials. Consequently, the rapid introduction of this critical functional group in a predictable fashion would benefit current practitioners in those fields. This communication describes a mild trifluoromethylation of benzylic C-H bonds with high selectivity for the least hindered hydrogen atom. The reaction provides monotrifluoromethylation and proceeds in an environmentally friendly acetone/water solvent system. The method can be used to install benzylic trifluoromethyl groups on highly functionalized drug molecules. PMID- 30247887 TI - Roadmaps and Detours: Active Chlorophyll- a Assessments of Primary Productivity Across Marine and Freshwater Systems. AB - Assessing phytoplankton productivity over space and time remains a core goal for oceanographers and limnologists. Fast Repetition Rate fluorometry (FRRf) provides a potential means to realize this goal with unprecedented resolution and scale yet has not become the "go-to" method despite high expectations. A major obstacle is difficulty converting electron transfer rates to equivalent rates of C fixation most relevant for studies of biogeochemical C-fluxes. Such difficulty stems from methodological inconsistencies and our limited understanding of how the electron requirement for C-fixation (Phie,C) is influenced by the environment and by differences in the composition and physiology of phytoplankton assemblages. We outline a "roadmap" for limiting methodological bias and to develop a more mechanistic understanding of the ecophysiology underlying Phie,C. We 1) re-evaluate core physiological processes governing how microalgae invest photosynthetic electron transport-derived energy and reductant into stored carbon versus alternative sinks. Then, we 2) outline steps to facilitate broader uptake and exploitation of FRRf, which could transform our knowledge of aquatic primary productivity. We argue it is time to 3) revise our historic methodological focus on carbon as the currency of choice, to 4) better appreciate that electron transport fundamentally drives ecosystem biogeochemistry, modulates cell-to-cell interactions, and ultimately modifies community biomass and structure. PMID- 30247888 TI - Zeolite-Encapsulated Pt Nanoparticles for Tandem Catalysis. AB - Encapsulation of metal nanoparticles in a zeolite matrix is a promising route to integrate multiple sequential reactions into a one-pot and one-step tandem catalytic reaction. We report a cationic polymer-assisted synthetic strategy to encapsulate Pt nanoparticles (NPs) into MFI zeolites. Degrees of encapsulation of Pt NPs in the synthesized catalysts exceeding 90% were demonstrated via kinetic studies of model reactions involving substrates with different molecular dimensions. HZSM-5 zeolite-encapsulated Pt NPs are able to selectively mediate the tandem aldol condensation and hydrogenation of furfural and acetone to form hydrogenated C8 products with a combined yield of 87%. In contrast, hydrogenation and decarbonylation of furfural dominate on Pt NPs supported on HZSM-5 at otherwise identical conditions. The high selectivity toward the tandem reaction on the encapsulated catalyst is attributed to the distribution of metal and acid sites, which limits the access of furfural to Pt sites and promotes the acid catalyzed aldol condensation. This is the first demonstration that the product distribution in a tandem reaction is manipulated by tailoring the architecture of catalytic materials via encapsulation. PMID- 30247889 TI - Structural Insight into Enantioselective Inversion of an Alcohol Dehydrogenase Reveals a "Polar Gate" in Stereorecognition of Diaryl Ketones. AB - Diaryl ketones are important building blocks for synthesizing pharmaceuticals and are generally regarded as "difficult-to-reduce" ketones due to the large steric hindrance of their two bulky aromatic side chains. Alcohol dehydrogenase from Kluyveromyces polyspora ( KpADH) has been identified as a robust biocatalyst due to its high conversion of diaryl ketone substrate (4-chlorophenyl)(pyridine-2 yl)ketone (CPMK) with a moderate R-selectivity of 82% ee. To modulate the stereoselectivity of KpADH, a "polarity scanning" strategy was proposed, in which six key residues inside and at the entrance of the substrate binding pocket were identified. After iterative combinatorial mutagenesis, variants Mu-R2 and Mu-S5 with enhanced (99.2% ee, R) and inverted (97.8% ee, S) stereoselectivity were obtained. The crystal structures of KpADH and two mutants in complex with NADPH were resolved to elucidate the evolution of enantioselective inversion. Based on MD simulation, Mu-R2-CPMKProR and Mu-S5-CPMKProS were more favorable in the formation of prereaction states. Interestingly, a quadrilateral plane formed by alpha-carbons of four residues (N136, V161, C237, and G214) was identified at the entrance of the substrate binding pocket of Mu-S5; this plane acts as a "polar gate" for substrates. Due to the discrepancy in charge characteristics between chlorophenyl and pyridine substituents, the pro- S orientation of CPMK is defined when it passes through the "polar gate" in Mu-S5, whereas the similar plane in wild-type is blocked by several aromatic residues. Our result paves the way for engineering stereocomplementary ADH toward bulky diaryl ketones and provides structural insight into the mechanism of stereoselective inversion. PMID- 30247890 TI - Far-Red Photoactivatable BODIPYs for the Super-Resolution Imaging of Live Cells. AB - The photoinduced disconnection of an oxazine heterocycle from a borondipyrromethene (BODIPY) chromophore activates bright far-red fluorescence. The high brightness of the product and the lack of autofluorescence in this spectral region allow its detection at the single-molecule level within the organelles of live cells. Indeed, these photoactivatable fluorophores localize in lysosomal compartments and remain covalently immobilized within these organelles. The suppression of diffusion allows the reiterative reconstruction of subdiffraction images and the visualization of the labeled organelles with excellent localization precision. Thus, the combination of photochemical, photophysical and structural properties designed into our fluorophores enable the visualization of live cells with a spatial resolution that is inaccessible to conventional fluorescence imaging. PMID- 30247891 TI - Proteomic Identification of Protein Tyrosine Phosphatase and Substrate Interactions in Living Mammalian Cells by Genetic Encoding of Irreversible Enzyme Inhibitors. AB - Protein tyrosine phosphatases (PTPs) play critical roles in cell signaling pathways, but identification of unknown PTPs for a given substrate in live cells remain technically challenging. Here, we synthesized a series of tyrosine-based irreversible PTP inhibitors and characterized by site-specific encoding on substrate proteins in cells with an expanded genetic code. By fine-tuning the chemical reactivity, we identified optimal active amino acid probes to covalently cross-link a PTP and its substrate both in vitro and in mammalian cells. Using HER2 as an example, we provide first direct evidence of HER2 Y1023 and SHP2 cross linking in situ in living human cells. Moreover, proteomic analysis using our approach identified PTP1B as a novel phosphatase for HER2 that specifically dephosphorylated pY1221 position, which may shed light on the puzzle of PTP1B's role in HER2 positive breast cancer. This novel method provides a useful tool for dissecting tyrosine phosphoregulation in living cells. PMID- 30247892 TI - Conductive Polymer Spray Ionization Mass Spectrometry for Biofluid Analysis. AB - We present a conductive polymer spray ionization (CPSI) method for the direct mass spectrometric analysis of hydrophilic drugs, saccharides, peptides, and proteins in biofluids. Carbon nanotubes (CNTs) were introduced into poly(methyl methacrylate) (PMMA) to fabricate a conductive composite substrate CNT/PMMA in the shape of a triangle (8 mm wide and 10 mm long) with its apex pointed toward the inlet of a mass spectrometer. In comparison with a traditional paper spray substrate, the conductive polymer absorbs less hydrophilic compounds owing to its hydrophobic nature. When aqueous biofluid samples are loaded, they also exhibit less diffusion on this nonporous surface. Only 1.0-2.0 MUL solvent suffices to extract the components in a dried biofluid spot and to form charged microdroplets (4.5 kV high voltage applied). Furthermore, the hydrophobic polymer surface only needs to overcome weak surface tension to emit charged microdroplets, so that the signal has a typical duration of 7.5 min. For sunitinib, acarbose, melamine, and angiotensin II, the ion intensity of the target compound from the conductive polymer support is significantly higher than paper spray, typically by a factor of 20 to 100. These results suggest that the CNT/PMMA conductive polymer spray has great potential in the analysis of hydrophilic drugs, saccharides, peptides, and proteins in biofluids. PMID- 30247893 TI - Enantioselective Oxidative Coupling of Carboxylic Acids to alpha-Branched Aldehydes. AB - A new reactivity in organocatalysis is proposed to account for the coupling of carboxylic acids to alpha-branched aldehydes by combining primary amine catalysis and an oxidant. The developed methodology is an enantioselective alpha-coupling of aromatic and aliphatic carboxylic acids to alpha-branched aldehydes and proceeds in high yields (up to 97%) and for most examples good enantioselectivities (up to 92% ee). On the basis of experimental and mechanistic observations, the role of the primary amine catalyst is discussed. PMID- 30247894 TI - Electron-Withdrawing Effects in the Photodissociation of CH2ICl To Form CH2Cl Radical, Simultaneously Viewed Through the Carbon K and Chlorine L2,3 X-ray Edges. AB - A fundamental chlorine-containing radical, CH2Cl, is generated by the ultrafast photodissociation of CH2ICl at 266 nm and studied at both the carbon K edge (~284 eV) and chlorine L2,3 edge (~200 eV) by femtosecond X-ray transient absorption spectroscopy. The electronic structure of CH2Cl radical is characterized by a prominent new carbon 1s X-ray absorption feature at lower energy, resulting from a transition to the half-filled frontier carbon 2p orbital (singly occupied molecular orbital of the radical; SOMO). Shifts of other core-to-valence absorption features upon photodissociation of CH2ICl to yield .CH2Cl indicate changes in the energies of core-level transitions of carbon and chlorine to the sigma*(C-Cl) valence orbital. When the C-I bond breaks, loss of the electron withdrawing iodine atom donates electron density back to carbon and shields the carbon 1s core level, resulting in a ~0.8 eV red shift of the carbon 1s to sigma*(C-Cl) transition. Meanwhile, the 2p inner shell of the chlorine atom in the radical is less impacted by the iodine atom removal, as demonstrated by the observation of a ~0.6 eV blue shift of the transitions at the chlorine L2,3 edges, mainly due to the stronger C-Cl bond and the increased energy of the sigma*(C-Cl) orbital. The results suggest that the shift in the carbon 1s orbital is greater than the shift in the sigma*(C-Cl) orbital upon going from the closed shell molecule to the radical. Ab initio calculations using the equation of motion coupled-cluster theory establish rigorous assignment and positions of the X-ray spectral features in the parent molecule and the location of the SOMO in the CH2Cl radical. PMID- 30247895 TI - Methionine Binding to Dirhodium(II) Tetraacetate. AB - The reaction between antitumor active dirhodium(II) tetraacetate and dl methionine (HMet) was followed in aqueous solution and showed initially mixtures of 1:1 and 1:2 adducts [Rh2(AcO)4(HMet)(H2O)] (AcO- = CH3COO-) and [Rh2(AcO)4(HMet)2] formed at room temperature (RT), as evidenced by UV-vis spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Rh K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy confirmed methionine thioether binding to the axial positions of the Rh2(AcO)4 cage structure. With excess HMet at RT, stepwise displacement of the acetate groups was observed after some time using ESI-MS. Heating the solution to 40 degrees for 24 h accelerated the substitution reaction leading to stable dirhodium(II) species with two acetate ligands displaced by two methionine groups. The crystal structure of the purple [RhII2(AcO)2(d-Met)(l-Met)].6H2O compound obtained from the solution revealed tridentate coordination of the methionine ligands to the Rh(II) ions, with the thioether S atoms in equatorial positions. A minor amount of a light orange monomeric [RhIII(Met)2](AcO) complex also formed in the solution was isolated by size exclusion chromatography and identified by ESI-MS. Crystals of [RhIII(d-Met)(l-Met)]Cl.3H2O were prepared by reacting RhCl3 and dl HMet. The crystal structure showed tridentate binding of the methionine ligands to the Rh(III) ion in a trans-S, N, O arrangement. PMID- 30247896 TI - Detection and Quantitation of Trace Fentanyl in Heroin by Surface-Enhanced Raman Spectroscopy. AB - The identification of fentanyl, a main culprit in opioid overdose deaths, has become critical. Whereas Raman spectroscopy is an effective tool for detecting illicit drugs, the weak intensity of Raman scattering can make it difficult to distinguish trace materials. This shortcoming is addressed by surface-enhanced Raman spectroscopy (SERS), which produces strong signal enhancements when target compounds are near metal nanoparticles. This work examines the use of a paper based substrate impregnated with silver nanoparticles for the detection of trace quantities of fentanyl alone and as an adulterant in heroin. In addition, intensity ratios of diagnostic peaks associated with each substance were fitted to a Langmuir isotherm calibration model and used for the quantitative analysis of fentanyl in heroin mixtures. Linearity was observed at <6% fentanyl, a significant finding that is consistent with concentrations found in drugs seized during law enforcement efforts. In addition, swabbing with these paper-based SERS substrates facilitated the recovery of fentanyl from surfaces, showing this to be applicable for crime scene investigations. However, assessment using the calibration model proved difficult for swabbed samples. Overall, this work demonstrates a potentially simple and sensitive technique for the forensic analysis and quantitation of fentanyl in trace amounts. PMID- 30247897 TI - The Rational Discovery of a Tau Aggregation Inhibitor. AB - Intrinsically disordered proteins play vital roles in biology, and their dysfunction contributes to many major disease states. These proteins remain challenging targets for rational ligand discovery or drug design because they are highly dynamic and fluctuate through a diverse set of conformations, frustrating structure-based approaches. To meet this challenge, we have developed protocols to efficiently identify active small molecule ligands of disordered proteins. Our approach utilizes enhanced sampling molecular dynamics and conformational analysis approaches optimized for disordered targets, coupled with computational docking and machine learning-based screens of compound libraries. By applying this protocol to an amyloid-forming segment of microtubule-associated protein tau, we successfully identified novel, chemically diverse tau ligands, including an inhibitor that delays the aggregation reaction in vitro without affecting the amount of aggregate formed at the steady state. Our results indicate that we have expanded the toolkit of protein aggregation inhibitors into new areas of chemical space and demonstrate the feasibility of our ligand discovery strategy. PMID- 30247898 TI - Structure, Assembly, and Disassembly of Tubulin Single Rings. AB - Single and double tubulin rings were studied under a range of conditions and during microtubule (MT) assembly and disassembly. Here, tubulin was purified from porcine brain and used without any further modifications or additives that promote ring assembly. The structure of single GDP-rich tubulin rings was determined by cryo-transmission electron microscopy and synchrotron solution X ray scattering. The scattering curves were fitted to atomic models, using our state-of-the-art analysis software, D+ . We found that there is a critical concentration for ring formation, which increased with GTP concentration with temperature. MT assembly or disassembly, induced by changes in temperature, was analyzed by time-resolved small-angle X-ray scattering. During MT assembly, the fraction of rings and unassembled dimers simultaneously decreased. During MT disassembly, the mass fraction of dimers increased. The increase in the concentration of rings was delayed until the fraction of dimers was sufficiently high. We verified that pure dimers, eluted via size-exclusion chromatography, could also form rings. Interestingly, X-ray radiation triggered tubulin ring disassembly. The concentration of disassembled rings versus exposure time followed a first-order kinetics. The disassembly rate constant and initial concentration were determined. X-ray radiation-triggered disassembly was used to determine the concentration of rings. We confirmed that following a temperature jump, the mass fraction of rings decreased and then stabilized at a constant value during the first stage of the MT assembly kinetics. This study sheds light on the most basic assembly and disassembly conditions for in vitro single GDP rich tubulin rings and their relation to MT kinetics. PMID- 30247899 TI - Imaging and Quantitative Detection of Lipid Droplets by Yellow Fluorescent Probes in Liver Sections of Plasmodium Infected Mice and Third Stage Human Cervical Cancer Tissues. AB - The diagnosis and prognosis of the disease associated with lipid irregularity are areas of extreme significance. In this direction, fluoranthene based yellow fluorescent probes (FLUN-550, FLUN-552, FLUN-547) were designed and synthesized by conjugating the ethanolamine headgroup of the phospholipid phosphatidyl ethanolamine present in biological membranes. Owing to unique photophysical properties and aqueous compatibility, these probes were successfully employed for staining lipid droplets (LDs) in preadipocytes and Leishmania donovani promastigotes. Furthermore, using the fluorescent probes FLUN-550 and FLUN-552 we successfully imaged and quantitatively detected the excess accumulation of lipids in a liver section of Plasmodium yoelii MDR infected mice (3- to 4-fold) and the tissue sections of third stage human cervical cancer patients (1.5- to 2-fold) compared to normal tissues. To the best of our knowledge, this is the first report of yellow fluorescent probes for imaging and quantitative detection of LDs in human cervical cancer tissues. These new yellow fluorescent lipid probes (FLUN 550 and FLUN-552) showed great potential for diagnosis of cervical cancer patients. PMID- 30247900 TI - Optimal Basis Set for Electron Dynamics in Strong Laser Fields: The case of Molecular Ion H2. AB - A clear understanding of the mechanisms that control the electron dynamics in a strong laser field is still a challenge that requires interpretation by advanced theory. Development of accurate theoretical and computational methods, able to provide a precise treatment of the fundamental processes generated in the strong field regime, is therefore crucial. A central aspect is the choice of the basis for the wave function expansion. Accuracy in describing multiphoton processes is strictly related to the intrinsic properties of the basis, such as numerical convergence, computational cost, and representation of the continuum. By explicitly solving the 1D and 3D time-dependent Schrodinger equation for H2+ in the presence of an intense electric field, we explore the numerical performance of using a real-space grid, a B-spline basis, and a Gaussian basis (improved by optimal Gaussian functions for the continuum). We analyze the performance of the three bases for high-harmonic generation and above-threshold ionization for H2+. In particular, for high-harmonic generation, the capability of the basis to reproduce the two-center interference and the hyper-Raman phenomena is investigated. PMID- 30247901 TI - The discovery, SAR and biological characterization of a novel series of 6-((1H pyrazolo[4,3-b]pyridin-3-yl)amino)-benzo[d]isothiazole-3-carboxamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4). AB - This work describes the discovery and characterization of novel 6-((1H pyrazolo[4,3-b]pyridin-3-yl)amino-benzo[d]isothiazolole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu4 PAMs. From this work, 27o was identified as a potent (EC50 = 28 nM, 49% Glu Max) and selective mGlu4 PAM with an excellent rat DMPK profile (in vivo rat CLp = 3.1 mL/min/kg, t1/2 = 445 min, CYP1A2 IC50 > 30 ?M). 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease. PMID- 30247902 TI - Heating-Aided pH Shifting Modifies Hemp Seed Protein Structure, Cross-Linking, and Emulsifying Properties. AB - Alkaline pH12 shift treatment performed at varying temperatures (20-80 degrees C for 1, 5, and 60 min) was applied to structurally modify hemp seed protein isolate (HPI). The solubility of HPI (~20%) was remarkably improved ( p < 0.05) with elevating the temperature and prolonging the holding time, reaching 97.5% at 80 degrees C for 60 min. The treated HPI exhibited a strong tendency of forming soluble large aggregates. To limit lysinoalanine (LAL) production, heating was methodically controlled to 60 degrees C and 5 min, where the LAL content never exceeded 100 mg/100 g of protein and the loss of cysteine and lysine was also minimal. The emulsifying activity of HPI was improved by this mild pH shift heating combination treatment as a result of the dissociation of protein subunits, unraveling of the tertiary structure, and exposure of hydrophobic groups. Moreover, the emulsion formed by the treated protein maintained a superior stability in particle size and distribution during storage. PMID- 30247903 TI - Development of Inhibitors of the Programmed Cell Death-1/Programmed Cell Death Ligand 1 Signaling Pathway. AB - The clinical success of inhibitors targeting the PD-1/PD-L1 pathway has made this an active field in cancer immunotherapy. Currently, most drugs targeting this pathway are monoclonal antibodies. Small-molecule inhibitors as the alternative to monoclonal antibodies are expected to overcome the disadvantages of mAbs which include production difficulties and their long half-life. Recently, progress has been reported on anti-PD-1/PD-L1 small-molecule inhibitors. In this paper, we review the development of inhibitors targeting the PD-1/PD-L1 pathway, focusing mainly on peptide-based and nonpeptidic small-molecule inhibitors. The structures and the preclinical and clinical studies of several peptide-based small-molecule candidate compounds in clinical trials are discussed. We also illustrate the design strategies underlying reported nonpeptidic small-molecule inhibitors and provide insight into possible future exploration. Development of small-molecule drugs for anti-PD-1/PD-L1 activity with specific cancer applications is a promising and challenging prospect. PMID- 30247904 TI - Synthesis of Expanded Porphyrinoids with Azulene and Indene Subunits and an opp Dioxadicarbaporphyrin from Fulvene Carbinols and a Dioxacarbatripyrrin. AB - In an attempt to prepare quatyrin derivatives, which are hydrocarbon analogues of the porphyrins, azulene-appended fulvene carbinols were self-condensed in the presence of BF3.Et2O. Although these investigations failed to give structures related to quatyrin, expanded porphyrin analogues were obtained instead. In dichloromethane, the major macrocyclic product consisted of three fulvene units, but when chloroform was used as the reaction solvent, a tetrafulvene macrocycle was isolated. Self-condensation of a furan-appended fulvene alcohol gave trace amounts of an opp-dioxadicarbaporphyrin. An alternative route to this novel system was developed where a dioxacarbatripyrrin was condensed with an indene dialdehyde in the presence of HBr. The heterodicarbaporphyrinoid proved to have strong globally aromatic properties as assessed by 1H NMR spectroscopy, anisotropy of induced current density, and NICS calculations. In the presence of excess trifluoroacetic acid, an unstable aromatic cation was formed by C protonation of an indene subunit. This species was also highly diatropic, and the 1H NMR spectrum gave an unusually high Deltadelta value of 17.46 ppm. PMID- 30247905 TI - Discovery and Optimization of Novel Hydrogen Peroxide Activated Aromatic Nitrogen Mustard Derivatives as Highly Potent Anticancer Agents. AB - We describe several new aromatic nitrogen mustards with various aromatic substituents and boronic esters that can be activated with H2O2 to efficiently cross-link DNA. In vitro studies demonstrated the anticancer potential of these compounds at lower concentrations than those of other clinically used chemotherapeutics, such as melphalan and chlorambucil. In particular, compound 10, bearing an amino acid ester chain, is selectively cytotoxic toward breast cancer and leukemia cells that have inherently high levels of reactive oxygen species. Importantly, 10 was 10-14-fold more efficacious than melphalan and chlorambucil for triple-negative breast-cancer (TNBC) cells. Similarly, 10 is more toxic toward primary chronic-lymphocytic-leukemia cells than either chlorambucil or the lead compound, 9. The introduction of an amino acid side chain improved the solubility and permeability of 10. Furthermore, 10 inhibited the growth of TNBC tumors in xenografted mice without obvious signs of general toxicity, making this compound an ideal drug candidate for clinical development. PMID- 30247906 TI - Hydrolysis and Transglycosylation Transition States of Glycoside Hydrolase Family 3 beta-Glucosidases Differ in Charge and Puckering Conformation. AB - beta-Glucosidases (betagls) from glycoside hydrolase family 3 play an important role in biomass degradation by catalyzing cellobiose hydrolysis. However, the hydrolysis rate decreases when the glucose product or another cellobiose competes with water to form oligosaccharides in a reaction called transglycosylation. Both reactions involve proton transfer to the acid/base residue and nucleophilic attack on the glycosyl-enzyme intermediate. To gain a deeper understanding of these competing reactions, quantum mechanics/molecular mechanics calculations were performed. Although both reactions are exothermic and have similar free energy barriers (~18 kcal/mol), the transition-state (TS) characteristics are different. The glycosyl-water bond is nearly formed in the hydrolysis TS, leading to reduced ionic character and a 4C1 chair conformation. The transglycosylation TS is more positively charged and adopts the 4H3 half-chair conformation because bond formation is less advanced. Water interacts solely with acid/base residue E441, though the long distance between them (2.1 A) suggests that E441 does not activate water for nucleophilic attack. In comparison, a glucose acceptor has a lower deprotonation enthalpy and hydrogen bonds to E441 (1.6 A) as well as to Y204, R169, and R67. Knowledge of these factors that are relevant to TS formation and stability is valuable for engineering betagls with enhanced hydrolytic activity for industrial applications. PMID- 30247907 TI - Graphene Oxide Quantum Dots Assisted Construction of Fluorescent Aptasensor for Rapid Detection of Pseudomonas aeruginosa in Food Samples. AB - We engineered an ingenious fluorescent aptasensor for detection of Pseudomonas aeruginosa ( P. aeruginosa) according to the DNA hybridization and fluorescence resonance energy transfer. In the absence of target bacteria, 5 carboxyfluorescein-labeled complementary DNA (FAM-cDNA) hybridizes with the partial sequences of aptamer and the fluorescence of FAM can be quenched by graphene oxide quantum dots (GOQDs). Upon the addition of target bacteria, the aptamer as a biorecognition element is bound with P. aeruginosa specifically. FAM cDNA prefers to hybridize with the aptamer, resulting in the desorption of FAM cDNA from GOQDs, thus recovering the fluorescence of FAM. The aptasensor shows a wide linear response to P. aeruginosa in the concentration range of 1.28 * 103 2.00 * 107 cfu/mL with acceptable selectivity. The detection limit is 100 cfu/mL. The whole process can be finished in 2 h. Moreover, the platform is successfully applied to detect P. aeruginosa in drinking water, orange juice, and popsicle samples. PMID- 30247908 TI - Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties. AB - Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clog P) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes. PMID- 30247909 TI - Distinguishing Intra- and Intermolecular Interactions in Liquid 1,2-Ethanediol by 1H NMR and Ab Initio Molecular Dynamics. AB - The central OCCO backbone of the 1,2-ethanediol molecule adopts the gauche conformer in the gaseous and crystalline states but exists in conformational equilibrium between gauche and trans in the liquid; an observation that has been attributed to the competition between intra- and intermolecular interactions. Here, we show that the nuclear Overhauser effect (NOE) has the ability to distinguish inter- from intramolecular interactions in liquid 1,2-ethanediol. We do so by exploiting the secondary isotope effect to distinguish the hydroxyl protons of HOCH2CH2OH and the deuterated HOCD2CD2OH in the 1H NMR spectra of mixtures of the two and, in conjunction with ab initio MD simulations, show how the interplay between inter- and intramolecular interactions gives rise to the conformational isomers in the liquid state of 1,2-ethanediol. PMID- 30247910 TI - Design of a Selective Ring-Closing Enyne Metathesis-Reduction for the Generation of Different Synthetic Scaffolds. AB - A tandem process of ring-closing enyne metathesis (RCEYM)-reduction using modern ruthenium catalysts and a hydrogen donor is described. This straightforward methodology is useful for C(sp3) generation under mild reaction conditions. Variables such as solvent, catalyst, hydride source, and temperature were adjusted toward the exclusive formation of different products. PMID- 30247911 TI - How Hydrophobic Hydration Destabilizes Surfactant Micelles at Low Temperature: A Coarse-Grained Simulation Study. AB - Micelles are self-assembled aggregates of amphiphilic surfactant molecules that are important in a variety of applications, including drug delivery, detergency, and catalysis. It is known that the micellization process is driven by the same physiochemical forces that drive protein folding, aggregation, and biological membrane self-assembly. Nevertheless, the molecular details of how micelle stability changes in water at low temperature are not fully clear. We develop and use a coarse-grained model to investigate how the interplay between nonionic surfactants and the surrounding water at the nanoscale affects the stability of micelles at high and low temperatures. Simulations of preformed C12E5 micelles in explicit water at a range of temperatures reveal the existence of two distinct surfactant conformations within the micelle, a bent structure and an extended structure, the latter being more prevalent at low temperature. Favorable interactions of the surfactant with more ordered solvation water stabilizes the extended configuration, allowing nanoscale wetting of the dry, hydrophobic core of the micelle, leading to the micelle breaking. Taken together, our coarse grained simulations unravel how energetic and structural changes of the surfactant and the surrounding water destabilize micelles at low temperature, which is a direct consequence of the weakened hydrophobicity. Our approach thus provides an effective mean for extracting the molecular-level changes during hydrophobicity-driven destabilization of molecular self-assembly, which is important in a wide range of fields, including biology, polymer science, and nanotechnology. PMID- 30247912 TI - Synthesis of Tetracyclic 2,3-Dihydro-1,3-diazepines from a Dinitrodibenzothiophene Derivative. AB - Triply fused 1,3-diazepine derivatives have been obtained by acidic reduction of rotationally locked and sterically hindered nitro groups in the presence of an aldehyde or ketone. The nitro groups are sited on adjacent rings of a dicyanodibenzothiophene-5,5-dioxide, which also displays fully reversible two electron-accepting behavior. The synthesis, crystallographically determined molecular structures, and aspects of the electronic properties of these new molecules are presented. PMID- 30247913 TI - Transition of Dielectrophoresis-Assembled 2D Crystals to Interlocking Structures under a Magnetic Field. AB - Aspherical cubic hematite colloids with cylindrical arms protruding from each face, referred to as "hexapods", were assembled via negative dielectrophoresis and then manipulated using an applied magnetic field. Upon application of an ac electric field, the hexapods aligned in close-packed linear chains parallel to the field direction. The chains then aggregated to the center of the device, with adjacent chains separated by distances approximately equal to twice the arm length. The resulting open packing structure exhibited cmm plane group symmetry due to the obstruction of arms, with a high density of incorporated defects. Subsequent application of a magnetic field to the dielectrophoresis (DEP) assembled structure was found to anneal the colloidal crystal by reorienting the hexapods to align their intrinsic magnetic dipoles with the magnetic field direction. During reorganization, the colloidal packing density was found to decrease by more than 10% at both the center and edges of the crystal, accompanied by a significant loss of ordering, prior to redensification of the 2D lattice with fewer defects. Reorganization at the edge was 1.5 times faster than at the center, consistent with the need for cooperative colloidal motion to remove defects at the centers of the crystals. PMID- 30247914 TI - One-Dimensional Assembly on Two-Dimensions: AuCN Nanowire Epitaxy on Graphene for Hybrid Phototransistors. AB - The van der Waals epitaxy of functional materials provides an interesting and efficient way to manipulate the electrical properties of various hybrid two dimensional (2D) systems. Here we show the controlled epitaxial assembly of semiconducting one-dimensional (1D) atomic chains, AuCN, on graphene and investigate the electrical properties of 1D/2D van der Waals heterostructures. AuCN nanowire assembly is tuned by different growth conditions, although the epitaxial alignment between AuCN chains and graphene remains unchanged. The switching of the preferred nanowire growth axis indicates that diffusion kinetics affects the nanowire formation process. Semiconducting AuCN chains endow the 1D/2D hybrid system with a strong responsivity to photons with an energy above 2.7 eV, which is consistent with the bandgap of AuCN. A large UV response (responsivity ~104 A/W) was observed under illumination using 3.1 eV (400 nm) photons. Our study clearly demonstrates that 1D chain-structured semiconductors can play a crucial role as a component in multifunctional van der Waals heterostructures. PMID- 30247915 TI - Peroxidase-Mimicking Nanoassembly Mitigates Lipopolysaccharide-Induced Endotoxemia and Cognitive Damage in the Brain by Impeding Inflammatory Signaling in Macrophages. AB - Oxidative stress during sepsis pathogenesis remains the most-important factor creating imbalance and dysregulation in immune-cell function, usually observed following initial infection. Hydrogen peroxide (H2O2), a potentially toxic reactive oxygen species (ROS), is excessively produced by pro-inflammatory immune cells during the initial phases of sepsis and plays a dominant role in regulating the pathways associated with systemic inflammatory immune activation. In the present study, we constructed a peroxide scavenger mannosylated polymeric albumin manganese dioxide (mSPAM) nanoassembly to catalyze the decomposition of H2O2 responsible for the hyper-activation of pro-inflammatory immune cells. In a detailed manner, we investigated the role of mSPAM nanoassembly in modulating the expression and secretion of pro-inflammatory markers elevated in bacterial lipopolysaccharide (LPS)-mediated endotoxemia during sepsis. Through a facile one step solution-phase approach, hydrophilic bovine serum albumin reduced manganese dioxide (BM) nanoparticles were synthesized and subsequently self-assembled with cationic mannosylated disulfide cross-linked polyethylenimine (mSP) to formulate mSPAM nanoassembly. In particular, we observed that the highly stable mSPAM nanoassembly suppressed HIF1alpha expression by scavenging H2O2 in LPS-induced macrophage cells. Initial investigation revealed that a significant reduction of free radicals by the treatment of mSPAM nanoassembly has reduced the infiltration of neutrophils and other leukocytes in a local endotoxemia animal model. Furthermore, therapeutic studies in a systemic endotoxemia model demonstrated that mSPAM treatment reduced TNF-alpha and IL-6 inflammatory cytokines in serum, in turn circumventing organ damage done by the inflammatory macrophages. Interestingly, we also observed that the reduction of these inflammatory cytokines by mSPAM nanoassembly further prevented IBA-1 immuno-positive microglial cell activation in the brain and consequently improved the cognitive function of the animals. Altogether, the administration of mSPAM nanoassembly scavenged H2O2 and suppressed HIF1alpha expression in LPS-stimulated macrophages and thereby inhibited the progression of local and systemic inflammation as well as neuroinflammation in an LPS-induced endotoxemia model. This mSPAM nanoassembly system could serve as a potent anti-inflammatory agent, and we further anticipate its successful application in treating various inflammation-related diseases. PMID- 30247916 TI - Grain Boundary Facilitates Photocatalytic Reaction in Rutile TiO2 Despite Fast Charge Recombination: A Time-Domain ab Initio Analysis. AB - TiO2 is an excellent photocatalytic and photovoltaic material but suffers low efficiency because of deep trap states giving rise to fast charge and energy losses. Using a combination of time-domain density functional theory and nonadiabatic molecular dynamics, we demonstrate that grain boundaries (GBs), which are common in polycrystalline TiO2, accelerate nonradiative electron-hole recombination by a factor of 3. Despite GBs increase the band gap without creating deep trap states, and accelerate coherence loss, they enhance nonadiabatic electron-phonon coupling, and facilitate the relaxation. Importantly, electrons accumulated at the boundaries together with the relatively long-lived excite state favor photocatalytic reaction. Our study rationalizes the experimental observations and provides valuable perspectives for improving the device performance by defect engineering. PMID- 30247917 TI - Exploring Local Disorder within CAU-1 Frameworks Using Hyperpolarized 129Xe NMR Spectroscopy. AB - The sorption properties of metal-organic frameworks (MOFs) can be influenced by introducing covalently attached functional side chains, which make this subclass of porous materials promising for applications as diverse as gas storage and separation, catalysis, and drug delivery. The incorporation of side groups usually comes along with disorder, as the synthesis procedures rarely allow for one specific position among a larger group of equivalent sites to be selected. For a series of isoreticular CAU-1 frameworks, chosen as model compounds, one out of four positions at every linker is modified with equal probability. Here, we investigate the influence of this disorder on Ar sorption and 129Xe nuclear magnetic resonance spectroscopy using hyperpolarized 129Xe gas. Models used for predicting the pore dimensions as well as their distributions were derived from the unfunctionalized framework by replacing one proton at every linker with either an amino, an acetamide, or a methyl urea functionality. The resulting structures were optimized using density functional theory (DFT) calculations. Results from void analyses and Monte Carlo force field simulations suggest that for available Ar nonlocal DFT (NLDFT) kernels, neither the pore dimensions nor the distributions induced by the side-chain disorder are well-reproduced. By contrast, we found the 129Xe chemical shift analysis for the shift observed at high temperature to be well-suited to develop a detailed fingerprint of the porosity and side-chain disorder within the isoreticular CAU-1 series. After calibrating the 129Xe limiting shift of the amino-functionalized framework with DFT calculations, the downfield shifts for the other two derivatives are an excellent measure for the reduction of the accessible pore space and reveal a strong preference for the side chains toward the octahedral voids for both cases. We expect that the strategy presented here can be commonly applied to disorder phenomena within MOFs in the future. PMID- 30247918 TI - Self-Supplied Tumor Oxygenation through Separated Liposomal Delivery of H2O2 and Catalase for Enhanced Radio-Immunotherapy of Cancer. AB - The recent years have witnessed the blooming of cancer immunotherapy, as well as their combinational use together with other existing cancer treatment techniques including radiotherapy. However, hypoxia is one of several causes of the immunosuppressive tumor microenvironment (TME). Herein, we develop an innovative strategy to relieve tumor hypoxia by delivering exogenous H2O2 into tumors and the subsequent catalase-triggered H2O2 decomposition. In our experiment, H2O2 and catalase are separately loaded within stealthy liposomes. After intravenous (iv) preinjection of CAT@liposome, another dose of H2O2@liposome is injected 4 h later. The sustainably released H2O2 could be decomposed by CAT@liposome, resulting in a long lasting effect in tumor oxygenation enhancement. As the result, the combination treatment by CAT@liposome plus H2O2@liposome offers remarkably enhanced therapeutic effects in cancer radiotherapy as observed in a mouse tumor model as well as a more clinically relevant patient-derived xenograft tumor model. Moreover, the relieved tumor hypoxia would reverse the immunosuppressive TME to favor antitumor immunities, further enhancing the combined radio-immunotherapy with cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade. This work presents a simple yet effective strategy to promote tumor oxygenation via sequential delivering catalase and exogenous H2O2 into tumors using well-established liposomal carriers, showing great potential for clinical translation in radio-immunotherapy of cancer. PMID- 30247920 TI - Attenuated Accumulation of Novel Fluorine (19F)-Labeled Bile Acid Analogues in Gallbladders of Fibroblast Growth Factor-15 (FGF15)-Deficient Mice. AB - Our work has focused on defining the utility of fluorine (19F)-labeled bile acid analogues and magnetic resonance imaging (MRI) to identify altered bile acid transport in vivo. In the current study, we explored the ability of this approach to differentiate fibroblast growth factor-15 (FGF15)-deficient from wild-type (WT) mice, a potential diagnostic test for bile acid diarrhea, a commonly misdiagnosed disorder. FGF15 is the murine homologue of human FGF19, an intestinal hormone whose deficiency is an underappreciated cause of bile acid diarrhea. In a pilot and three subsequent pharmacokinetic studies, we treated mice with two 19F-labeled bile acid analogues, CA-lys-TFA and CA-sar-TFMA. After oral dosing, we quantified 19F-labeled bile acid analogue levels in the gallbladder, liver, small and large intestine, and plasma using liquid chromatography mass spectrometry (LC-MS/MS). Both 19F bile acid analogues concentrated in the gallbladders of FGF15-deficient and WT mice, attaining peak concentrations at approximately 8.5 h after oral dosing. However, analogue levels in gallbladders of FGF15-deficient mice were several-fold less compared to those in WT mice. Live-animal 19F MRI provided agreement with our LC-MS/MS-based measures; we detected robust CA-lys-TFA 19F signals in gallbladders of WT mice but no signals in FGF15-deficient mice. Our finding that 19F MRI differentiates FGF15-deficient from WT mice provides additional proof-of-concept for the development of 19F bile acid analogues and 19F MRI as a clinical test to diagnose bile acid diarrhea due to FGF19 deficiency and other disorders. PMID- 30247919 TI - P-Glycoprotein (MDR1/ABCB1) Restricts Brain Penetration of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib, While Cytochrome P450-3A (CYP3A) Limits Its Oral Bioavailability. AB - Ibrutinib (Imbruvica), an oral tyrosine kinase inhibitor (TKI) approved for treatment of B-cell malignancies, irreversibly inhibits the Bruton's tyrosine kinase (BTK). Its abundant metabolite, dihydrodiol-ibrutinib (ibrutinib-DiOH), which is primarily formed by CYP3A, has a 10-fold reduced BTK inhibitory activity. Using in vitro transport assays and genetically modified mouse models, we investigated whether the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug-metabolizing CYP3A enzyme family can affect the oral bioavailability and tissue disposition of ibrutinib and ibrutinib-DiOH. In vitro, ibrutinib was transported moderately by human ABCB1 and mouse Abcg2 but not detectably by human ABCG2. In mice, Abcb1 markedly restricted the brain penetration of ibrutinib and ibrutinib-DiOH, either alone or in combination with Abcg2, resulting in 4.5- and 5.9-fold increases in ibrutinib brain-to-plasma ratios in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice relative to wild-type mice. Abcb1 and/or Abcg2 did not obviously restrict ibrutinib oral bioavailability, but Cyp3a deficiency increased the ibrutinib plasma AUC by 9.7-fold compared to wild-type mice. This increase was mostly reversed (5.1-fold reduction) by transgenic human CYP3A4 overexpression, with roughly equal contributions of intestinal and hepatic CYP3A4 metabolism. Our results suggest that pharmacological inhibition of ABCB1 during ibrutinib therapy might benefit patients with malignancies or (micro)metastases positioned behind an intact blood-brain barrier, or with substantial expression of this transporter in the malignant cells. Moreover, given the strong in vivo impact of CYP3A, inhibitors or inducers of this enzyme family will likely strongly affect ibrutinib oral bioavailability and, thus, its therapeutic efficacy, as well as its toxicity risks. PMID- 30247921 TI - Structure-Based Theory of Fluctuation-Induced Energy Transfer in a Molecular Dyad. AB - We present a microscopic theory for the description of fluctuation-induced excitation energy transfer in chromophore dimers to explain experimental data on a perylene biscarboximide dyad with orthogonal transition dipole moments. Our non Condon extension of Forster theory takes into account the fluctuations of excitonic couplings linear and quadratic in the normal coordinates, treated microscopically by quantum chemical/electrostatic calculations. The modulation of the optical transition energies of the chromophores is inferred from optical spectra of the isolated chromophores. The application of the theory to the considered dyad reveals a two to three order of magnitude increase in the rate constant by non-Condon effects. These effects are found to be dominated by fluctuations linear in the normal coordinates and provide a structure-based qualitative interpretation of the experimental time constant for energy transfer as well as its dependence on temperature. PMID- 30247923 TI - Origin of Prestress-Driven Optical Modulations of Flexible ZnO Thin Films Processed in Stretching Mode. AB - Experimental verification of optical modulation with external stress has not been easily available in flexible systems. Here, we intentionally induced extra stress in wide band gap ZnO thin films by a unique prestress-driven deposition processing that utilizes a stretching mode. The stretching mode provides homogeneous but biaxial stresses in the hexagonal wurtzite structure, leading to the extension of the c-axis and the contraction of the a-axis. As a result, the reduction of the optical band gap by ~150 meV was observed for the strain of ~4.87%. The band gap narrowing was found to occur from the respective downward and upward shifts of the conduction band minimum and valence band maximum under the applied stress. The experimental evidence of optical modulations was supported by the theoretical calculations using density functional theory. The reduced strong interactions between Zn d and O p orbitals were assumed to be responsible for the band gap narrowing. PMID- 30247924 TI - Ruthenium-Catalyzed Atropoenantioselective Synthesis of Axial Biaryls via Reductive Amination and Dynamic Kinetic Resolution. AB - The unprecedented ruthenium-catalyzed atropoenantioselective reductive amination of aldehydes with alkylamines via a cascade transfer hydrogenation and dynamic kinetic resolution strategy is described. This protocol features broad substrate scope and good functional group tolerance and allows the rapid assembly of axially chiral biaryls in good to high yields with high to excellent enantioselectivities. In addition, such structural motifs may have potential applications in enantioselective catalysis as chiral ligands or catalysts. PMID- 30247925 TI - Highly Stable New Organic-Inorganic Hybrid 3D Perovskite CH3NH3PdI3 and 2D Perovskite (CH3NH3)3Pd2I7: DFT Analysis, Synthesis, Structure, Transition Behavior, and Physical Properties. AB - The feasibility of Pd-based organic-inorganic hybrid perovskites is comprehensively explored with both theoretical and experimental methods for the first time. Experimentally, the new 3D perovskite CH3NH3PdI3 (tetragonal, I4 cm) can be transited to a new 2D perovskite (CH3NH3)3Pd2I7 (tetragonal, P4 mm) by modulating the ratio of the organic part to inorganic part. The structure, lattice parameters, and symmetry of these two perovskites are verified by a series of simulations, refinement, and characterizations. The basic optical and electronic properties of these two new perovskites are characterized and calculated with DFT for future applications. Interestingly, both types of perovskites exhibit long stability in air with 50% relative humidity. Two-day stability for the 3D perovskite and one-week stability for the 2D perovskite are observed, consistent with our DFT calculation that 2D perovskite (CH3NH3)3Pd2I7 is more energetically stable than 3D hybrid perovskite CH3NH3PdI3. PMID- 30247922 TI - Understanding Dissolution and Crystallization with Imaging: A Surface Point of View. AB - The tendency for crystallization during storage and administration is the most considerable hurdle for poorly water-soluble drugs formulated in the amorphous form. There is a need to better detect often subtle and complex surface crystallization phenomena and understand their influence on the critical quality attribute of dissolution. In this study, the interplay between surface crystallization of the amorphous form during storage and dissolution testing, and its influence on dissolution behavior, is analyzed for the first time with multimodal nonlinear optical imaging (coherent anti-Stokes Raman scattering (CARS) and sum frequency generation (SFG)). Complementary analyses are provided with scanning electron microscopy, X-ray diffraction and infrared and Raman spectroscopies. Amorphous indomethacin tablets were prepared and subjected to two different storage conditions (30 degrees C/23% RH and 30 degrees C/75% RH) for various durations and then dissolution testing using a channel flow-through device. Trace levels of surface crystallinity previously imaged with nonlinear optics after 1 or 2 days of storage did not significantly decrease dissolution and supersaturation compared to the freshly prepared amorphous tablets while more extensive crystallization after longer storage times did. Multimodal nonlinear optical imaging of the tablet surfaces after 15 min of dissolution revealed complex crystallization behavior that was affected by both storage condition and time, with up to four crystalline polymorphs simultaneously observed. In addition to the well-known alpha- and gamma-forms, the less reported metastable epsilon- and eta-forms were also observed, with the epsilon-form being widely observed in samples that had retained significant surface amorphousness during storage. This form was also prepared in the pure form and further characterized. Overall, this study demonstrates the potential value of nonlinear optical imaging, together with more established solid-state analysis methods, to understand complex surface crystallization behavior and its influence on drug dissolution during the development of amorphous drugs and dosage forms. PMID- 30247926 TI - Integrated Optomechanical Arrays of Two High Reflectivity SiN Membranes. AB - Multielement cavity optomechanics constitutes a direction to observe novel effects with mechanical resonators. Several exciting ideas include superradiance, increased optomechanical coupling, and quantum effects between distinct mechanical modes among others. Realizing these experiments has so far been difficult, because of the need for extremely precise positioning of the elements relative to one another due to the high-reflectivity required for each element. Here we overcome this challenge and present the fabrication of monolithic arrays of two highly reflective mechanical resonators in a single chip. We characterize the optical spectra and losses of these 200 MUm long Fabry-Perot interferometers, measuring finesse values of up to 220. In addition, we observe an enhancement of the coupling rate between the cavity field and the mechanical center-of-mass mode compared to the single membrane case. Further enhancements in coupling with these devices are predicted, potentially reaching the single-photon strong coupling regime, giving these integrated structures an exciting prospect for future multimode quantum experiments. PMID- 30247928 TI - An Organodiselenide with Dual Mimic Function of Sulfhydryl Oxidases and Glutathione Peroxidases: Aerial Oxidation of Organothiols to Organodisulfides. AB - A novel organodiselenide, which mimics sulfhydryl oxidases and glutathione peroxidase (GPx) enzymes for oxidation of thiols by oxygen and hydrogen peroxide, respectively, into disulfides has been presented. The developed catalyst oxidizes an array of organothiols into respective disulfides in practical yields by using aerial O2 to avoid any reagents/additives, base, and light source. The synthesized diselenide also catalyzes the reduction of hydrogen peroxide into water by following the GPx enzymatic catalytic cycle with a reduction rate of 49.65 +/- 3.7 MUM.min-1. PMID- 30247927 TI - Mechanical Vibrations of Atomically Defined Metal Clusters: From Nano- to Molecular-Size Oscillators. AB - Acoustic vibrations of small nanoparticles are still ruled by continuum mechanics laws down to diameters of a few nanometers. The elastic behavior at lower sizes (<1-2 nm), where nanoparticles become molecular clusters made by few tens to few atoms, is still little explored. The question remains to which extent the transition from small continuous-mass solids to discrete-atom molecular clusters affects their specific low-frequency vibrational modes, whose period is classically expected to linearly scale with diameter. Here, we investigate experimentally by ultrafast time-resolved optical spectroscopy the acoustic response of atomically defined ligand-protected metal clusters Au n(SR) m with a number n of atoms ranging from 10 to 102 (0.5-1.5 nm diameter range). Two periods, corresponding to fundamental breathing- and quadrupolar-like acoustic modes, are detected, with the latter scaling linearly with cluster diameters and the former taking a constant value. Theoretical calculations based on density functional theory (DFT) predict in the case of bare clusters vibrational periods scaling with size down to diatomic molecules. For ligand-protected clusters, they show a pronounced effect of the ligand molecules on the breathing-like mode vibrational period at the origin of its constant value. This deviation from classical elasticity predictions results from mechanical mass-loading effects due to the protecting layer. This study shows that clusters characteristic vibrational frequencies are compatible with extrapolation of continuum mechanics model down to few atoms, which is in agreement with DFT computations. PMID- 30247929 TI - Formal Bimolecular [2 + 2 + 2] Cycloaddition Strategy for the Synthesis of Pyridines: Intramolecular Propargylic Ene Reaction/Aza Diels-Alder Reaction Cascades. AB - Two methods for the synthesis of multisubstituted pyridines are described. In each strategy, a highly reactive vinylallene is generated via an intramolecular propargylic ene reaction in the presence of an azadienophile. Reactions employing ethyl N-(tosyl)iminoacetate furnish an intermediate that undergoes elimination and isomerization upon the addition of DBU. The reaction of the intermediate vinylallene with TsCN leads to the isolation of a 2-sulfonylpyridine that serves as a versatile intermediate undergoing substitution reactions with oxygen and carbon nucleophiles. PMID- 30247930 TI - Pegvaliase: a novel treatment option for adults with phenylketonuria. AB - OBJECTIVE: In May 2018, the US Food and Drug Administration approved pegvaliase pqpz (Palynziq*), the first enzyme substitution therapy for the treatment of phenylketonuria (PKU). This article provides an overview of the mechanism of action, pharmacokinetic properties, clinical efficacy, and the safety and tolerability profile of pegvaliase. METHODS: Relevant information was identified through a comprehensive literature search of several databases using the keywords pegvaliase, rAvPAL-PEG, and phenylketonuria. Additional information was gathered from the pegvaliase package insert, posters presented at scientific meetings, and materials provided from the manufacturer, BioMarin. RESULTS: Pegvaliase is effective in decreasing blood phenylalanine levels, and is associated with a manageable side-effect profile. Phase III clinical trial data demonstrated that 60.7% of patients were able to achieve blood phenylalanine levels less than the guideline recommended 360 umol/L at 24 months. Brief sub-studies also showed the improvement in inattention symptoms in patients treated with pegvaliase, compared to placebo. CONCLUSION: Pegvaliase is a promising new treatment option for adults living with PKU. Further studies are warranted to determine long-term safety and clinical efficacy in sub-populations. PMID- 30247931 TI - Omalizumab in Chronic Spontaneous Urticaria: steroid sparing effect. AB - Omalizumab has been recognized to be effective in the treatment of chronic spontaneous urticaria (CSU). The Italian Medicines Agency authorizes two omalizumab courses, only for patients with CSU unresponsive to antihistamines, and this schedule may limit omalizumab use. Unfortunately, in the majority of CSU the schedule is unsatisfactory because symptoms usually recur shortly after discontinuation of treatment. A case of a patient needing more than two treatment courses with omalizumab is reported, in order to discuss the rationale for its long-term use. Patient had needed systemic steroids almost continuously for 4 years. Two severe glucocorticoid-associated adverse events (GAEs) occurred during long-term treatment. Omalizumab 300 mg monthly was started with immediate disappearance of the urticarial lesions. Beneficial effects waned shortly after discontinuation of treatment, and further steroid use was needed. A second omalizumab course showed the same clinical pattern, with prompt response and recurrence of symptoms after suspension. Therefore, we decided to repeat the 6 months omalizumab treatment as soon as symptoms recurred, to avoid further emergency steroid treatments and GAEs. This experience suggests that long-term use of omalizumab could be useful. Evidences show that omalizumab is effective and safe for re-treatment and long-term use of responding patients after recurrence. PMID- 30247932 TI - Utilization and cost of electronic brachytherapy by dermatologists from 2012 to 2015. AB - Electronic brachytherapy (EBT) garnered interest among dermatologists as a noninvasive treatment for keratinocyte carcinomas. While the magnitude of use and cost burden had not yet been quantified, this interest prompted an official statement from the American Academy of Dermatology supporting its use as secondary option in special circumstances, and led to changes to billing and coding for the procedure. Using provider level Medicare claims, this study demonstrates increased use of EBT between 2012 and 2015. We also showed that very few dermatologists utilized EBT, with only 39 dermatologists billing for EBT in 2015. This study documents that large scale policy changes were implemented in response to the practice behaviors of a small number of dermatologists, and provides information regarding the cost of EBT for consideration on how to best optimize its use in clinical practice. PMID- 30247933 TI - Anabolic-androgenic steroids: procurement and administration practices of doping athletes. AB - Performance enhancing substances are becoming increasingly popular amongst bodybuilders and people who want to enhance their physiques. However, due to the rise of the Internet and laws prohibiting sales of these substances without prescription, the route of procurement and administration practices have become more and more dangerous. Prior to the mid-1970's, anabolic steroids were not regulated and easily available from physicians and pharmacies in several countries. In 1990, the United States enacted the Anabolic Steroid Control Act, leading to the proliferation of black markets and underground laboratories. The shift from pharmacy to underground online sites for the procurement of anabolic steroids led to an increase of fake products with low purity and the ability to potentially endanger the health of anabolic steroid users. Underground laboratories emerged both locally and in countries with lax legal regulations. 'Anabolic steroid tourism' and large networks of online resellers emerged, leading to the banalisation of the illegal procurement of anabolic steroids. Furthermore, the increase of anecdotal information spreading on the internet among anabolic steroid user forums nourishes the rampant misinformation and dangerous practices that currently exist. The dosages and ways of administration recommended on these forums can be false and misleading to those who lack a medical background and cannot go to their physician to seek advice because of the fear of repercussions. This review aims to elucidate and describe current practices of the anabolic-androgenic steroids black market and draw attention to potential dangers for users. PMID- 30247935 TI - EOV. PMID- 30247934 TI - Experiences from group basic body awareness therapy by patients suffering from fibromyalgia: A qualitative study. AB - The aim of this study was to obtain a deeper understanding of how patients with fibromyalgia experienced movement awareness through a basic body awareness therapy group treatment program. A total of 19 participants with fibromyalgia diagnosis were interviewed individually and in groups. Data collection was done from three sources: (1) interviews from the Basic Body Awareness Rating Scale (BARS) part 2 at baseline, at end of treatment, as well as at 12 and 24 weeks follow up; (2) focus group discussions that took place at the end of each session, and at the end of treatment; and (3) an in-depth focus group. Giorgi's method was followed for data construction and analysis. The researchers conducted 57 individual interviews, 10 focus groups, and one in-depth focus group. The findings revealed the following categories: "creating a new relation to self"; "change the pattern of body awareness"; "being in a group"; and "experiencing physical capacity", showing influences among them. Body awareness seems to have an impact in the therapeutic process in patients suffering from fibromyalgia. PMID- 30247936 TI - Treatment of psoriatic arthritis with secukinumab: a case series. AB - Psoriatic arthritis (PsA) is a chronic inflammatory disorder affecting up to 30% of psoriatic patients, worsening patients' quality of life. Secukinumab, a fully humanized monoclonal antibody that selectively inhibits interleukin (IL) 17A, has been recently approved for the treatment of PsA in adults, alone or in association with methotrexate (MTX). In the secukinumab registration studies, the primary endpoint was evaluated at 24 weeks; whether there is an early response in patients with psoriatic arthritis is not well characterized. Furthermore, the registration studies included a hierarchical analysis of end-points that led to a missing evaluation of many secondary endpoints. We report our real life experience with secukinumab in 13 patients with PsA who did not respond to previous therapies. Our patients underwent clinical evaluation for the assessment of PsA severity and inflammation markers at 4 and 16 weeks. Clinical scores and laboratory tests improved at week 4 and 16 with rapid remission of psoriatic lesions and improvements of arthritis. The speed of action of secukinumab and the improvement in the quality of life, underlined by our findings, can be useful in daily clinical practice. PMID- 30247937 TI - Detecting Bombs in X-Ray Images of Hold Baggage: 2D Versus 3D Imaging. AB - OBJECTIVE: This study compared the visual inspection performance of airport security officers (screeners) when screening hold baggage with state-of-the-art 3D versus older 2D imaging. BACKGROUND: 3D imaging based on computer tomography features better automated detection of explosives and higher baggage throughput than older 2D X-ray imaging technology. Nonetheless, some countries and airports hesitate to implement 3D systems due to their lower image quality and the concern that screeners will need extensive and specific training before they can be allowed to work with 3D imaging. METHOD: Screeners working with 2D imaging (2D screeners) and screeners working with 3D imaging (3D screeners) conducted a simulated hold baggage screening task with both types of imaging. Differences in image quality of the imaging systems were assessed with the standard procedure for 2D imaging. RESULTS: Despite lower image quality, screeners' detection performance with 3D imaging was similar to that with 2D imaging. 3D screeners revealed higher detection performance with both types of imaging than 2D screeners. CONCLUSION: Features of 3D imaging systems (3D image rotation and slicing) seem to compensate for lower image quality. Visual inspection competency acquired with one type of imaging seems to transfer to visual inspection with the other type of imaging. APPLICATION: Replacing older 2D with newer 3D imaging systems can be recommended. 2D screeners do not need extensive and specific training to achieve comparable detection performance with 3D imaging. Current image quality standards for 2D imaging need revision before they can be applied to 3D imaging. PMID- 30247938 TI - Secukinumab for plaque psoriasis with ocular comorbidity: a clinical experience. AB - Ocular comorbidity has been reported in 10-15% of patients with plaque psoriasis. This paper reports successful treatment with secukinumab of a patient with plaque psoriasis and dry eye syndrome. Both the skin condition and the ocular disease improved after treatment. PMID- 30247939 TI - "Sleep Well, Think Well" Group Program for Mild Cognitive Impairment: A Randomized Controlled Pilot Study. AB - OBJECTIVE/BACKGROUND: Sleep-wake disturbance is associated with poor cognitive functioning and several other adverse outcomes that increase dementia risk in older adults. Targeting sleep-wake disturbance in individuals at risk for dementia may be an important treatment. This study evaluated the efficacy of a four-session multicomponent group intervention for participants with mild cognitive impairment (MCI). PARTICIPANTS: Thirty-five older adults with MCI (mean age = 69.7 years, SD = 9.1), were recruited. MCI was determined via consensus from neuropsychological, medical, and neurological review. METHODS: Participants were randomized to the "Sleep Well, Think Well" (SWTW) group condition or a passive control group. The SWTW group received four fortnightly face-to-face sessions conducted by an experienced sleep psychologist and neuropsychologist. The control group received written material detailing strategies to improve sleep quality. Both groups received fortnightly coaching phone calls. The primary outcome was subjective sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI). Secondary outcomes included actigraphy sleep measures, daytime sleepiness, cognitive functioning, and depression severity. RESULTS: The SWTW intervention was associated with a large and statistically significant improvement in subjective sleep quality (Cohen's d = 0.83, p < 0.02). A moderate nonsignificant effect was evident in reducing daytime sleepiness (Cohen's d = 0.70, p = .08). No significant effects were found on actigraphy markers, depressive symptoms, or tests of cognitive functioning. CONCLUSIONS: The eight week SWTW group intervention for MCI significantly improved subjective sleep quality when compared with a passive control condition. The program also had a moderate (nonsignificant) effect on reducing daytime sleepiness. PMID- 30247941 TI - First and Second Trimester Biochemical Markers in Maternal Epilepsy: A Case Control Study. AB - BACKGROUND: Our aim is to investigate whether the maternal serum levels of first and second trimester serum analytes are altered in women with epilepsy in pregnancy. METHODS: Maternal serum biochemical markers (estriol, alpha fetoprotein [AFP], human chorionic gonadotrophin [hCG], free beta hCG, pregnancy associated plasma protein-A) were compared in a series of 122 pregnant women with epilepsy and in a cohort of 122 normal pregnant women. The serum samples were obtained between 11-13 6/7 weeks and 16-18 weeks gestation. RESULTS: Second trimester serum estriol levels, expressed as multiples of the median (MoM), in the epileptic group (1.55 +/- 0.77 MoM) were significantly higher than those in the control patients (1.13 +/- 0.40 MoM) (p < 0.001). Of the women with epilepsy, 66.3% (n = 81) were exposed to antiepileptic drugs. CONCLUSION: Our study revealed that otherwise uncomplicated pregnant epileptic women had higher second trimester (18-20 weeks of gestation) estriol levels compared to non-epileptic pregnant women. PMID- 30247940 TI - The intersection of professionalism and interprofessional care: development and initial testing of the interprofessional professionalism assessment (IPA). AB - Valid assessment of interprofessional education and collaborative practice (IPECP) is challenging. The number of instruments that measure various aspects of IPECP, or in various sites is growing, however. The Interprofessional Professionalism Assessment (IPA) measures observable behaviors of health care professionals-in-training that demonstrate professionalism and collaboration when working with other health care providers in the context of people-centered care. The IPA instrument was created by the Interprofessional Professionalism Collaborative (IPC), a national group representing 12 entry-level health professions and one medical education assessment organization. The instrument was created and evaluated over several years through a comprehensive, multi-phasic process: 1) development of construct and observable behaviors, 2) instrument design, expert review and cognitive interviews, and 3) psychometric testing. The IPA contains 26 items representing six domains of professionalism (altruism and caring, excellence, ethics, respect, communication, accountability), and was tested by 233 preceptors rating health profession learners in the final year of their practical training. These preceptors represented 30 different academic institutions across the U.S., worked in various types of practice sites, and evaluated learners representing 10 different entry-level health professions. Exploratory factor analysis suggested four factors (communication, respect, excellence, altruism and caring) using 21 items with the least amount of missing data, and confirmed, for the most part, a priori expectations. Internal consistency reliability coefficients for the entire instrument and its four subscales were high (all greater than 0.9). Psychometric results demonstrate aspects of the IPA's reliability and validity and its use across multiple health professions and in various practice sites. PMID- 30247942 TI - Should we instruct patients to rub topical agents into skin? The evidence. AB - BACKGROUND: At least 15 factors influence the ability of compounds to penetrate the skin. Massage (rubbing) may be another factor that has gone relatively unrecognized. METHOD: PubMed, Google Scholar, and EMBASE databases were accessed online in March 2018 in search of studies measuring absorption through skin with and without rubbing or massage. RESULTS: While some studies noted no difference in dermal absorption with regards to rubbing, others have demonstrated the opposite. In general, massage technique does indeed sometimes enhance dermal absorption. In addition to increase skin temperature and blood flow, rubbing likely modifies stratum corneum (SC) structure to enhance diffusion rates and increase retained penetrant amount within the skin. CONCLUSIONS: Understanding the mechanism of massage and its role in percutaneous penetration may help elucidate skin barrier function, dermal absorption, skin decontamination, and dermatotoxicology. To achieve such goals, an in vitro model that models in vivo behaviors must first be established. Subsequently, experiments with different penetrants, vehicles, massage time, and other variables may be considered. PMID- 30247943 TI - Sexual Victimization and Sex-Related Drinking Motives: How Protective is Emotion Regulation? AB - One in five college women experience sexual victimization (SV), and SV severity is associated with subsequent psychological distress, including sex-related distress. SV severity may also be associated with drinking motives to cope with sex-related distress and to enhance sex (sex-related drinking motives [SRDMs]), particularly if individuals suffer from emotion regulation (ER) difficulties. College women (N = 151) completed a survey assessment of ER, SV history, childhood sexual abuse (CSA), and SRDMs. Twelve regression models assessed six facets of ER as moderators between SV severity and SRDMs. Among women with no or low levels of prior SV severity, women with greater access to ER strategies were less likely to endorse drinking to cope SRDMs. At higher levels of SV severity, women at all levels of access to ER strategies were equally likely to endorse drinking to cope SRDMs, suggesting that access to ER strategies did not mitigate motivations to drink to cope with sex-related distress for these women. Women with severe SV histories may benefit from interventions that build on existing ER strengths or address other factors. However, greater access to ER strategies may serve as a protective factor against SRDMs when SV severity is low. PMID- 30247944 TI - Lack of Association Between TNF-alpha, IFN-gamma, IL-10 Gene Polymorphisms and Rheumatic Heart Disease in South Indian Population. AB - BACKGROUND: Proinflammatory and anti-inflammatory cytokines play a crucial role in the development and maintenance of immune mediated inflammatory diseases including rheumatic heart disease (RHD). Polymorphisms in tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-10 genes influence the differential cytokine expression as well as the pathogenesis of various inflammatory and autoimmune diseases. OBJECTIVE: The aim of the study is to investigate the association between TNF-alpha, IFN-gamma, and IL-10 gene polymorphisms and RHD in South Indian population. MATERIALS AND METHODS: TNF alpha (-308, -238), IFN-gamma (+874), and IL-10 (-1082, -819, -592) gene polymorphisms were determined in 100 patients with RHD and 127 healthy siblings by PCR. RESULTS: There was no significant difference in the genotype, allele, and haplotype frequencies of TNF-alpha, IFN-gamma, and IL-10 polymorphisms between RHD patients and healthy siblings. CONCLUSION: The present study suggests that TNF-alpha, IFN-gamma, and IL-10 gene variants may not be associated with the development of RHD in South Indian population. PMID- 30247947 TI - Proteomic analysis reveals geographic variation in venom composition of Russell's Viper in the Indian subcontinent: implications for clinical manifestations post envenomation and antivenom treatment. AB - INTRODUCTION: The Russell's Viper (RV) (Daboia russelii), a category I medically important snake, is responsible for a significant level of morbidity and mortality in the Indian sub-continent. Areas covered: The current review highlights the variation in RV venom (RVV) composition from different geographical locales on the Indian sub-continent, as revealed by biochemical and proteomic analyses. A comparison of these RVV proteomes revealed significant differences in the number of toxin isoforms and relative toxin abundances, highlighting the impact of geographic location on RVV composition. Antivenom efficacy studies have shown differential neutralization of toxicity and enzymatic activity of different RVV samples from the Indian sub-continent by commercial polyvalent antivenom (PAV). The proteome analysis has provided deeper insights into the variation of RVV composition leading to differences in antivenom efficacy and severity of clinical manifestations post RV-envenomation across the Indian sub-continent. Expert commentary: Variation in RVV antigenicity due to geographical differences and poor recognition of low molecular mass (<20 kDa) RVV toxins by PAV are serious concerns for effective antivenom treatment against RV envenomation. Improvements in immunization protocols that take into account the poorly immunogenic components and geographic variation in RVV composition, can lead to better hospital management of RV bite patients. PMID- 30247946 TI - The nature and benefits of team-based reflection on a patient death by healthcare professionals: a scoping review. AB - This scoping literature review was completed to understand the nature and benefits of team-based reflection on a patient death by healthcare professionals. The review was limited to publications in English between 2006 and 2016 that were identified in the Medline, CINAHL, PsycINFO, EMBASE and Web of Science databases. We identified 1450 articles and 19 studies were relevant for inclusion in this review. The published literature is mainly descriptive with no comparative studies. The process of team-based reflection on a patient death by healthcare professionals, using a variety of techniques, can lead to improved emotional well being and learning for quality improvement. However, there is little evidence for the impact on the care of the family and for future patient care. The need for a structured process for the reflection, with facilitation in a supportive healthcare context, appears to be essential for effective team-based reflection. Further research needs to be performed to ensure that team-based reflection on a patient death by healthcare professionals, meets the needs of practitioners and enhances their emotional well-being, supports learning from practice and leads to improved patient outcomes. PMID- 30247945 TI - Dacomitinib: an investigational drug for the treatment of glioblastoma. AB - INTRODUCTION: Standard treatment of newly diagnosed glioblastoma (GB) is surgery with radiotherapy and temozolomide, but tumors will recur with a median overall survival of only 15 months. It seems imperative to explore new possibilities of treatment based on targetable alterations known to be present in GB. Among others, Epidermal Growth Factor Receptor or EGFR (HER1) mutations or amplifications are the most prevalent alterations in GB. In fact, around 40% of GB cases show amplification of EGFR gene, and half of these patients carry the EGFRvIII mutation, a deletion that generates a continuous activation of the tyrosine kinase domain of the receptor. Areas covered: We review the current knowledge about Dacomitinib, an oral, irreversible, second-generation, pan-HER tyrosine kinase inhibitor, in the treatment of glioblastoma. Dacomitinib has noteworthy antiglioma activity in preclinical models and has been tested in one phase II trial in patients with recurrent GB with EGFR amplification. Expert opinion: Despite the poor global results of Dacomitinib in recurrent GB shown in a phase II trial, some patients had a significant benefit. Therefore, it is necessary to improve the knowledge about the mechanisms of failure or resistance to EGFR inhibitors in GB. PMID- 30247948 TI - Integrative Oncology: An Essential Feature of High-Quality Cancer Care. PMID- 30247949 TI - Exceptional Responders, Outliers, and Radical Remissions. PMID- 30247950 TI - Complementary Treatment with Mistletoe Extracts During Chemotherapy: Safety, Neutropenia, Fever, and Quality of Life Assessed in a Randomized Study. AB - OBJECTIVES: Evaluate the safety and clinical response of complementary treatment with European mistletoe extracts during chemotherapy. DESIGN: Monocentric controlled trial with 95 patients randomized into three groups. SETTINGS/LOCATION: National Cancer Research Center of Serbia. SUBJECTS: Breast cancer patients (stage T1-3N0-2M0) undergoing surgery and adjuvant chemotherapy with six cycles of cyclophosphamide, adriamycin, and 5-fluorouracil. INTERVENTIONS: Two different European mistletoe extracts (Helixor A, Iscador M Spez) were injected three times per week during 18 weeks of chemotherapy in the mistletoe group. Five-year follow-up of routine visits was documented in case report forms. OUTCOME MEASURES: Safety was assessed by measuring adverse events, body temperature during chemotherapy, and probability of relapse or metastasis in a 5-year follow-up. During chemotherapy, the neutrophil count and quality of life according to EORTC QLQ-C30 were assessed. RESULTS: The two patient groups receiving different complementary mistletoe treatments were integrated into one mistletoe group for this safety analysis. Patients in the mistletoe group did not develop more fever symptoms than patients in the control group (two short-term events in each group). No significant differences in probability of relapse or metastasis were measured between the groups (p = 0.7637). The mistletoe group showed a trend toward less neutropenia (p = 0.178) and improved pain and appetite loss scores (p < 0.0001 and p = 0.047, respectively) while having positive, but not significant, impact on other EORTC QLQ-C30 scores. CONCLUSIONS: Mistletoe extracts were safe in this clinical study. Neither did subcutaneous injections induce fever, nor did they influence the frequency of relapse and metastasis within 5 years. This result suggests that mistletoe extracts had no adverse interactions with the anticancer agents used in this study. Furthermore, certain side effects of chemotherapy decreased under this complementary treatment in breast cancer patients. PMID- 30247951 TI - Understanding the Use of Acupuncture for Insomnia Among Cancer Survivors: A Qualitative Study. AB - OBJECTIVE: To understand cancer survivors' perceptions regarding the use of acupuncture for the treatment of cancer-related insomnia. DESIGN: Semistructured interviews with cancer survivors participating in a randomized controlled trial comparing the effectiveness of Cognitive Behavioral Therapy for Insomnia (CBT-I) and acupuncture for the treatment of insomnia. Interviews were conducted before randomization into either treatment option, and structured to elicit participants' experiences with insomnia as well as their beliefs and understanding surrounding acupuncture for the treatment of insomnia. An integrated approach was used for data analysis. SUBJECTS: Sixty-three cancer survivors with DSM-V diagnosed insomnia. RESULTS: Participants shared a broad lack of understanding regarding acupuncture for the treatment of insomnia. Specifically, individuals in this study expressed confusion surrounding what symptoms or medical conditions acupuncture could be used to treat, how acupuncture works, and how long the effects of acupuncture last. CONCLUSIONS: This study identified three specific gaps in knowledge, including treatment target, mechanism, and durability, surrounding the use of acupuncture for insomnia in cancer survivors. Addressing these gaps by providing appropriate and timely education surrounding the use of acupuncture to treat insomnia is essential to increase the evidence-informed utilization of acupuncture and to better meet patients' needs among cancer survivors. PMID- 30247952 TI - Expanding the Circle for the Care of People with Cancer. PMID- 30247954 TI - The Problematic Economics of Integrative Oncology. PMID- 30247953 TI - Use of Supplements by Japanese Cancer Patients Receiving Outpatient Cancer Chemotherapy. PMID- 30247956 TI - Integrative Wellness for Patients Receiving Proton Therapy: A Patient-Centered Collaboration. PMID- 30247955 TI - Complementary and Integrative Medicine in Lung Cancer: Questions and Challenges. AB - Lung cancer represents 13% of all cancers, making it the second most common type of malignancy in the United States. Lung cancer is the leading cause of cancer death in men and women in the United States and accounts for nearly 18% of all deaths from cancer. Because of its high mortality rate, lung cancer is associated with an increased rate of distress. Patients use various strategies to cope with this distress during and after cancer treatments, and complementary and integrative medicine (CIM) has become a common coping strategy. This review covers major questions and challenges of incorporating CIM during and beyond treatment for lung cancer. The questions revolve around determining the value of nutrition and nutritional supplements, assessing the role of exercise, addressing the mind-body connection, enhancing the benefit of immunotherapy, and determining the benefit of incorporating complementary therapies such as acupuncture and homeopathy. This review may provide a basis for discussion that can enhance patient-doctor dialogue regarding the use of CIM during and after treatment for lung cancer. PMID- 30247957 TI - Advising Women Undergoing Treatment for Breast Cancer: A Narrative Review. AB - A majority of women undergoing conventional treatment for breast cancer also undertake complementary and integrative approaches. Practitioners knowledgeable about the evidence base behind common integrative approaches can help patients attain improved quality of life, and at times, improved survival. Evidence-based recommendations include the following: a plant-based diet for general health after diagnosis, and carbohydrate restriction for patients with estrogen receptor positive postmenopausal breast cancer may be prudent. Other dietary recommendations include a 13-h daily overnight fast. Carefully selected patients may choose to fast the day before and the day of chemotherapy to decrease side effects. Specific food recommendations include avoidance or limitation of alcohol, and liberal culinary use of cruciferous vegetables, coffee, green tea, soy, and flaxseed. Promising supplements include diindolylmethane and melatonin. Omega 3 fatty acids may help with bone density in patients on aromatase inhibitors, but may increase chemotherapy resistance. Findings regarding the usefulness of multivitamins, vitamin D, vitamin C, and vitamin E are weak and/or mixed different exercise modalities may have different effects and thus play different roles in breast cancer therapy. Aerobic and resistance training combined during breast cancer chemotherapy may confer a survival benefit, while yoga may improve outcome in lymphedema patients. Current evidence suggests that meditation, yoga, breathing, music therapy, guided imagery, and hypnosis may improve mood and quality of life during breast cancer treatment. Acupuncture is useful for treating side effects of breast cancer therapies, including hot flushes, aromatase inhibitor-induced joint pain, chemotherapy-induced peripheral neuropathy, and vulvodynia. Vaginal moisturizers and vaginal rings supplying low dose estrogen can be useful in the treatment of symptoms of estrogen-deprivation states caused by breast cancer treatments; such symptoms include vaginal dryness, dyspareunia, and sexual dysfunction. Carbon dioxide laser technology can rejuvenate atrophied vaginal mucosa and relieve dyspareunia, allowing avoidance of estrogen therapy. Tertiary sexual health centers are available for referral. PMID- 30247958 TI - Applying New Models of Care to Meet Patient Needs in Integrative Oncology. PMID- 30247959 TI - Impact of Penny Brohn UK's Living Well Course on Informal Caregivers of People with Cancer. AB - OBJECTIVES: This study evaluated the change in the concerns, wellbeing, and lifestyle behaviors of informal caregivers of people with cancer attending Penny Brohn UK's Living Well Course (LWC), a self-management education intervention. DESIGN: A pre-postcourse design collected self-reported quantitative and qualitative data from informal caregivers attending a LWC. SETTING/LOCATION: Penny Brohn UK is a United Kingdom-based charity (not-for-profit) providing specialist integrative, whole person support, free of charge, to people affected by cancer. SUBJECTS: Informal caregivers taking part in a Penny Brohn UK LWC between June 2014 and May 2016 attending alongside the person with cancer. INTERVENTION: The LWC is a structured 15 h, multimodal group self-management educational course, designed to help people affected by cancer learn tools and techniques to help build resilience. Trained facilitators deliver LWCs to around 12 people with various types and stages of cancer and their informal caregivers. OUTCOME MEASURES: Measure Yourself Concern and Wellbeing (MYCaW) completed precourse and at 6 weeks postcourse; and bespoke 6-week follow-up Patient Reported Experience Measure. RESULTS: Four hundred eighty informal caregivers attended a LWC June 2014 to May 2016. One hundred eighteen completed a 6-week follow-up MYCaW: MYCaW Concerns 1 and 2 showed statistically significant improvements (p < 0.0001), there was no significant improvement in wellbeing. Informal caregivers' most reported concerns relating to themselves were psychological and emotional issues (59%). The primary concern of the caregiver for the care recipient was related to the physical health of the person with cancer (40%). Eighty-seven percent of responding informal caregivers stated that the LWC enabled health self-management. CONCLUSIONS: The LWC was followed by an improvement in informal caregivers' concerns, and increased self-management of their own health needs. More studies, with larger sample size, are needed to explore if better self-management by informal caregivers may also lead to improvements in patients' health and wellbeing. PMID- 30247960 TI - Cancer Pain Relief After Healing Touch and Massage. AB - OBJECTIVES: To establish and compare the effectiveness of Healing Touch (HT) and Oncology Massage (OM) therapies on cancer patients' pain. DESIGN: pretest/post test, observational, retrospective study. SETTINGS/LOCATION: Outpatient oncology setting at an academic hybrid, multisite, community-based cancer institute. SUBJECTS: n = 572 cancer outpatients. INTERVENTIONS: Patients reported pain before and after receiving a single session of either HT or OM from a certified practitioner. OUTCOME MEASURES: Pain scores from 0 = no pain to 10 = worst possible pain. RESULTS: Two hundred ninety-one patients (50.9%) receiving HT and 281 (49.1%) receiving OM reported pretherapy and post-therapy pain. Pretherapy mean pain was higher in HT patients (M = 5.1, +/-2.2) than OM (M = 4.4, +/-2.2), p < 0.001; post-therapy mean pain remained higher in HT patients (M = 2.6, +/ 2.1) than OM (M = 2.0, +/-1.8), p < 0.001. Both HT (p < 0.01) and OM (p < 0.01) significantly reduced pain. Unadjusted rates of clinically significant pain improvement (defined as >=2-point reduction in pain score) were 0.68 HT and 0.71 OM. Adjusted for pretherapy pain, OM was associated with increased odds of pain improvement (odds ratio [OR] 1.49 95% confidence interval (1.02-2.19); p = 0.041). For patients with severe pretherapy pain, OM was not more effective in yielding clinically significant pain reduction (p = 0.236) when adjusting for pretherapy pain score. CONCLUSIONS: Both HT and OM provided immediate pain relief. Future research should explore the duration of pain relief, patient attitudes about HT compared with OM, and how this may differ among patients with varied pretherapy pain levels. PMID- 30247961 TI - A Randomized Study of Yoga for Fatigue and Quality of Life in Women with Breast Cancer Undergoing (Neo) Adjuvant Chemotherapy. AB - OBJECTIVES: To compare the effectiveness of yoga added to standard care (SC) versus SC only, in women with breast cancer during chemotherapy. DESIGN: A multicenter pragmatic, randomized controlled study. SETTINGS/LOCATION: Three hospitals in the Netherlands. SUBJECTS: Women with stage I-III breast cancer undergoing chemotherapy. INTERVENTIONS: Women were randomized either to a program based on Dru Yoga, once a week yoga sessions for 12 weeks (N = 47), or SC only (N = 36). OUTCOME MEASURES: Primary outcome fatigue (Multidimensional Fatigue Inventory [MFI]; general fatigue) and secondary outcomes fatigue (MFI, Fatigue Quality List [FQL]), quality of life (30-item Quality of Life Questionnaire-C of the European Organization for Research and Treatment of Cancer [EORTC-QLQ-C-30]) and psychological distress (Hospital Anxiety Depression Scale [HADS], Impact of Events Scale [IES]) were measured at baseline (T0), 3 months (T1), and 6 months (T2) and analyzed on observed cases. Other outcomes were adequate relief, reintegration to work, and adverse events. RESULTS: No significant differences were found in general fatigue at T1 (MFI: yoga; 14.6 +/- 4.5 vs. SC; 14.2 +/- 4.2, p = 0.987). Similar findings were observed for other fatigue (sub)scales of MFI and FQL and functional domains of EORTC. With respect to EORTCs symptom scales, women in the yoga group reported significantly less nausea and vomiting compared with SC at T2 (p = 0.004), but not at T1 (p = 0.807). Depressive symptoms were significantly lower with yoga at T1 (HADS: yoga; 4.7 +/- 4.1 vs. SC; 5.1 +/- 4.2, p = 0.031). More women in the yoga group experienced adequate relief compared with SC at T1 (yoga; 51% vs. SC; 19%) and had returned to work at T2 (yoga; 53% vs. SC; 23%). No adverse events were reported with yoga. CONCLUSIONS: A Dru-based yoga program failed to demonstrate a significant beneficial effect on fatigue. Possible favorable effects of the yoga program on nausea and vomiting and early return to work in breast cancer survivors warrant further research. PMID- 30247962 TI - Integrative Oncology Trials in the Real World: Assessing the Pragmatism of an Ongoing Integrative Oncology Trial of Mindfulness and T'ai Chi/Qigong. AB - OBJECTIVES: The aim of this study was to highlight features of pragmatic real world integrative oncology research by applying the PRagmatic Explanatory Continuum Indicator Summary (PRECIS-2) criteria to an ongoing integrative oncology clinical trial. The ongoing trial is a preference-based randomized comparative effectiveness trial of mindfulness-based cancer recovery (MBCR) versus t'ai chi/qigong (TCQ) for cancer survivors (the Mindfulness and T'ai Chi for Cancer Health [MATCH] study). The primary outcome of the MATCH study is distress, and secondary outcomes are quality of life, sleep disturbance, and physical functioning. The clinical trial is being undertaken at tertiary care cancer centers across two sites in Canada: Calgary (AB) and Toronto (ON), with a sample of 600 cancer survivors who have finished all cancer treatments and are distressed. METHODS AND RESULTS: The MATCH trial was scored on the explanatory pragmatic continuum for each of the nine domains of the PRECIS-2 criteria on a scale of 1-5, and was rated as more explanatory than pragmatic, despite initial design efforts being more pragmatic. Areas that were least pragmatic were methods of recruitment, follow-up, and intervention delivery. The more pragmatic areas were setting, outcomes, and data analysis. CONCLUSIONS: More efforts toward conducting pragmatic trials are needed in the field of integrative oncology, as cancer-care institutions and policy makers are looking for sustainable interventions within already established treatment models. The PRECIS-2 criteria can help researchers meet these goals in the planning stages of trial development. PMID- 30247963 TI - Integrative Medicine in Childhood Cancer. AB - The diagnosis of cancer in a child leaves parents and families devastated and vulnerable. In an effort to do everything possible, families often choose an integrative medicine approach to their child's care. Surveys have found that 31% 84% of children with cancer use complementary and alternative medicine and most often as supportive care agents. Several systematic reviews have demonstrated a clinical benefit for some select therapies; however, the safety and efficacy of the combination of biological therapies with conventional treatment remain largely unknown and garner concern due to the potential for interactions with conventional therapy. Given the sustained use and potential benefit of integrative medicine, additional research is warranted in pediatric oncology. Utilizing the available literature, clinical providers should aim to conduct open and nonjudgmental discussions with families about the use of integrative medicine so as to guide the safe integration of the two modalities. PMID- 30247964 TI - An Integrative Approach to Prostate Cancer. AB - OBJECTIVES: The mostly indolent natural history and long overall survival associated with a diagnosis of prostate cancer provides a unique opportunity for men to explore diet and lifestyle interventions to alter the trajectory of their disease. As many patients may be appropriate for postponing conventional therapy, the effects of various integrative interventions can be investigated. In addition, treatment of prostate cancer with surgery, radiation, or androgen deprivation therapy, all may produce physical or psychological side effects that could be amenable to complementary therapies. This article serves to review salient information in the published literature. DESIGN: A review of published research was conducted. RESULTS: A plant-based antioxidant-rich diet with an emphasis on cruciferous vegetables, tomatoes, soy, pomegranate, and marine omega 3 fatty acids while avoiding saturated fats, including dairy products is the best option. Supplementation with vitamin D3, omega 3, and some nutraceutical-based preparations may be advised. It is likely prudent to avoid vitamin E and selenium supplements. Physical activity has been shown to have multiple benefits in men diagnosed with all stages of prostate cancer from strengthening bones, improving body habitus, and enhancing overall wellbeing. Yoga, combining physical activity with a mind-body component, has been shown to have a salutogenic effect in both prostate cancer patients and their caregivers. Traditional Chinese Medicine may be particularly useful in managing side effects of conventional treatments, especially the hot flashes associated with androgen deprivation therapy. Although the long natural history, availability of a useful blood marker of disease progression and prolonged survival are overall positive features, they also combine to allow men to live for a long time with diagnosed cancer, fear of progression, or recurrence and fixation on changes in their prostate-specific antigen level. The resultant stress can be deleterious to general health as well as possibly the natural history of their disease. Mind-body interventions to reduce stress, including mindfulness-based stress reduction and support groups may be useful adjunctive therapies. CONCLUSION: Men with prostate cancer may benefit from lifestyle and complementary interventions integrated with their conventional care. PMID- 30247965 TI - Integrative Treatment for Colorectal Cancer: A Comprehensive Approach. AB - A comprehensive approach to integrative treatment of colorectal cancer (CRC) patients involves three spheres of intervention: lifestyle, biology, and conventional treatment. Individualization of treatment is emphasized. The lifestyle sphere includes nutritional therapies, biobehavioral strategies with circadian interventions, and physical care modalities. The biology sphere comprises six host factors in the patient's internal biochemical environment or "terrain": inflammation, glycemia, oxidative stress, immune dysregulation, coagulopathy, and stress chemistries. Laboratory testing of these factors guides integrative lifestyle and supplement recommendations. The conventional treatment sphere includes individualized lifestyle recommendations, and supplements or drugs used to enhance tolerability or effectiveness of conventional treatments. Innovative strategies are implemented, including chronomodulated chemotherapy, chemosensitivity testing, and using results of molecular genomic testing to guide nutritional infusions and supplement recommendations. In the lifestyle sphere, substantial evidence from cohort studies supports recommendations for a diet that emphasizes plant and fish proteins, healthful fats in amounts that are tailored to the clinical circumstance of the patient, and carbohydrates based on unrefined whole grains, vegetables and whole fruits. High glycemic diets and refined carbohydrates, especially sugar-sweetened beverages, should be avoided. Biobehavioral strategies include practice of the relaxation response and related approaches. In addition, specific strategies to promote robust circadian organization (CO) are used to combat quality of life concerns and worsened survival that accompany disrupted CO. Physical activity, including aerobic activity and muscle strengthening, is recommended at all disease stages. In the biology sphere, supplements and lifestyle recommendations for inflammation and glycemia are discussed. In the conventional treatment sphere, supplements and innovative and complementary therapies that may remedy treatment toxicities are reviewed. Approaching CRC treatment with a comprehensive, individualized intervention enables safe and beneficial outcomes in this patient population, which can vary widely in individual biology, treatment toxicities, and disease complications. Further research in integrative therapies for CRC patients is needed. PMID- 30247966 TI - Training Oncology Physicians to Advise Their Patients on Complementary and Integrative Medicine. AB - To address the needs of cancer patients, two things are important: (1) oncology physicians and other health professionals in cancer care should receive training so that they can guide their patients through the maze of available offers in complementary and integrative medicine (CIM), and (2) more CIM providers should possess competencies to provide evidence-informed CIM treatments to cancer patients. PMID- 30247971 TI - Ayurveda in Cancer Care in India: Scope, Challenges, and Suggested Approaches. PMID- 30247969 TI - Integrative Medicine for Female Patients with Gynecologic Cancer. AB - BACKGROUND: Integrative oncology provides a broad spectrum of complementary medicine therapies, many of which can augment the effects of supportive and palliative care for patients with gynecologic cancer. METHODS: The present review will focus on the findings of the research on the role of integrative medicine, within the challenges they face during treatment of gynecological cancer. RESULTS AND CONCLUSION: Integrative oncology focuses primarily on alleviating patients' suffering by reducing the adverse effects of chemotherapy and radiation, improving quality of life and function. At the same time, integrative oncology provides guidance on the safe and effective use of herbal and other dietary supplements during cancer treatment. This is a dynamic process requiring collaboration between conventional gynecologic oncologists and integrative physicians and practitioners, in an evolving process of care. PMID- 30247972 TI - Use of Dietary Supplements at a Comprehensive Cancer Center. AB - OBJECTIVES: The objectives of this study were to define dietary supplement (DS) use by cancer patients and to investigate factors associated with DS use during cancer treatment. METHODS: A cross-sectional survey of adults diagnosed with breast, colorectal, lung, or prostate cancer in 2010-2012 at the University of North Carolina Comprehensive Cancer Center was conducted. Questionnaires were sent to 1794 patients. Phone calls were made to nonrespondents. The authors described type of DS use before, during, and after initial cancer treatment, source of advice on DS use, and used logistic regression to investigate the association of DS use during or after cancer treatment with clinical/sociodemographic characteristics and source of advice. RESULTS: Six hundred and three (34%) patients completed the questionnaires. Nonvitamin nonmineral DS use during initial cancer treatments was common: any cancer treatment (49%), chemotherapy (52%), and radiation therapy (51%). Among patients seeking advice on DS use, 75% reported professional sources, 44% reported media sources, and 47% reported lay sources. DS use during cancer treatment was strongly predicted by prior DS use, followed by prior complementary therapies' use, receiving DS advice from a cancer care provider, being female, and higher education level. CONCLUSION: DS use is common and persists during cancer treatment. Among DS users during treatment, 18% used an herbal supplement, which are likely to carry greater risk of interaction with chemotherapy agents compared with vitamin, mineral, and other supplements. Although many respondents sought DS advice from professional sources, the use of nonprofessional sources remains high. PMID- 30247968 TI - Complementary and Integrative Medicine to Reduce Adverse Effects of Anticancer Therapy. AB - BACKGROUND: To address the side effects of anticancer treatments, the Clinic for Complementary Medicine and Diet in Oncology was opened, in collaboration with the oncology department, at the Hospital of Lucca (Italy) in 2013. AIM: To present the results of complementary medicine treatment targeted toward reducing the adverse effects of anticancer therapy and cancer symptoms, and improving patient quality of life. Dietary advice was aimed at the reduction of foods that promote inflammation in favor of those with antioxidant and anti-inflammatory properties. METHODS: This is a retrospective observational study on 357 patients consecutively visited from September 2013 to December 2017. The intensity of symptoms was evaluated according to a grading system from G0 (absent) to G1 (slight), G2 (moderate), and G3 (strong). The severity of radiodermatitis was evaluated with the Radiation Therapy Oncology Group (RTOG) scale. Almost all the patients (91.6%) were receiving or had just finished some form of conventional anticancer therapy. RESULTS: The main types of cancer were breast (57.1%), colon (7.3%), lung (5.0%), ovary (3.9%), stomach (2.5%), prostate (2.2%), and uterus (2.5%). Comparison of clinical conditions before and after treatment showed a significant amelioration of nausea, insomnia, depression, anxiety, fatigue, mucositis, hot flashes, joint pain, dysgeusia, neuropathy, and all symptoms. Moreover, in a subgroup of 17 patients in radiotherapy undergoing integrative treatment, the level of toxicities and the severity of radiodermatitis were much lower than in the 13 patients without integrative treatment. Twenty-one cancer patients (6.2%) either refused (18) or discontinued (3) conventional anticancer treatment against the recommendation of their oncologist; after the integrative oncology (IO) visit, 7 (41.2%) out of 17 patients with follow-up decided to accept standard oncologic treatments. CONCLUSIONS: An IO clinic may contribute to reducing the adverse effects of anticancer therapy and improving the quality of life of cancer patients. PMID- 30247970 TI - Absent and Discordant Electronic Health Record Documentation of Complementary and Alternative Medicine in Cancer Care. AB - OBJECTIVES: Many patients with cancer use complementary and alternative medicine (CAM), but the quality of CAM documentation in their electronic health records (EHRs) is unknown. The authors aimed to describe (i) the prevalence and types of CAM used after cancer diagnosis and the influence of oncologists on CAM use, as per patients' self-report, and (ii) the prevalence of CAM documentation in the EHR and its consistency with self-reported usage. DESIGN: Patient and provider surveys and chart review. SETTINGS/LOCATION: Medical oncology practices at one institution. SUBJECTS: Patients with cancer at oncologist visits. OUTCOME MEASURES: Patient self-reported rate of 3-month postvisit CAM use; provider EHR documentation of CAM use or discussion and its concordance with patient self report. RESULTS: Among 327 patients enrolled, 248 responded to the 3-month postvisit survey. Of these, 158 reported CAM use after diagnosis (63.7%). CAM users were younger (p < 0.001) and had a higher percentage of women (p = 0.03) than nonusers. Modalities most commonly used were supplements (62.6%), special diets (38.6%), chiropractor (28.4%), and massage (28.4%). CAM was used to improve well-being (68.7%), manage adverse effects (35.5%), and fight cancer (22.9%). Oncologists suggested CAM in 22.5% of instances of use. CAM use/discussion was documented for 58.2% of self-reported CAM users. Of the documented modalities, EHR and self-report were concordant for only 8.2%. CAM documentation was associated with physician provider (p = 0.03), older patients (p = 0.01), and treatment with radiation (p = 0.03) or surgery (p = 0.001). After adjusting for other factors, patients with breast cancer or "other" tumor category were four times more likely than patients with gastrointestinal cancer to have CAM use documentation (odds ratio [95% confidence interval]: 4.41 [1.48-13.10]; 3.76 [1.42-9.99], respectively). CONCLUSIONS: Most patients with cancer use CAM after diagnosis, yet EHR documentation is complete for very few. Oncologists should inquire about, document, and discuss CAM benefits and harm or refer patients to CAM specialists. PMID- 30247967 TI - Effectiveness of a Self-Care Toolkit for Surgical Breast Cancer Patients in a Military Treatment Facility. AB - OBJECTIVE: To assess whether a self-care toolkit (SCT) provided to breast cancer patients undergoing surgery could mitigate distress and lessen symptoms associated with surgery. DESIGN: One hundred women with breast cancer, planning to undergo initial surgery, were randomly assigned to either one of two groups: treatment as usual (TAU; n = 49) or TAU with the addition of an SCT (n = 51). The SCT contained an MP3 player with audio-files of guided mind-body techniques (breathing, progressive muscle relaxation, meditation, guided imagery, and self hypnosis) and acupressure antinausea wristbands. Anxiety, pain, nausea, sleep, fatigue, global health, and quality of life (QOL) were assessed using validated outcome measures. Two inflammatory blood markers (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) were measured serially. Data were collected at baseline (T1), immediately before surgery (T2), within 10 h postoperatively (T3), and ~2 weeks postsurgery (T4). SETTINGS: Numerous studies have shown that psychological distress associated with a cancer diagnosis can affect pain perception and QOL. RESULTS: Between T1 and T4, there were significant between group differences in Patient-Reported Outcomes Measurement Information System (PROMIS)-57 scores of Pain Interference, Fatigue, and Satisfaction with Social Roles, favoring the SCT group compared with TAU (p = 0.005, p = 0.023, and p = 0.021, respectively). There was a significant mean change in Defense and Veterans Pain Rating Scale (DVPRS) scores from T2 to T3, with the SCT group having significantly smaller increases in postoperative pain (p = 0.008) and in postoperative ESR (p = 0.0197) compared with the TAU group. Clinically significant reductions in anxiety occurred in the SCT group during the main intervention period. CONCLUSION: These results suggest that using the SCT in the perioperative period decreased pain perceptions, fatigue, and inflammatory cytokine secretion. PMID- 30247975 TI - Bioresponsive polyplexes - chemically programmed for nucleic acid delivery. AB - INTRODUCTION: The whole delivery process of nucleic acids is very challenging. Appropriate carrier systems are needed, which show extracellular stability and intracellular disassembly. Viruses have developed various strategies to meet these requirements, as they are optimized by biological evolution to transfer genetic information into host cells. Taking viruses as models, smart synthetic carriers can be designed, mimicking the efficient delivery process of viral infection. These 'synthetic viruses' are pre-programmed and respond to little differences in their microenvironment, caused by either exogenous or endogenous stimuli. Areas covered: This review deals with polymer-based, bioresponsive nanosystems (polyplexes) for the delivery of nucleic acids. Strategies utilizing pH-responsiveness, redox-responsiveness as well as sensitivity towards enzymes will be described more in detail. Systems, which respond to other endogenous triggers (i.e. reactive oxygen species, adenosine triphosphate, hypoxia), will be briefly illustrated. Moreover, some examples for combined bioresponsiveness will be presented. Expert opinion: Bioresponsive polyplexes are a smart way to facilitate programmed, timely delivery of nucleic acids to desired, specific sites. Nevertheless, further optimization is necessary to improve the still moderate transfection efficiency and specificity - also in regard to medical translation. For this purpose, precise carrier structures are desirable and stability issues of bioresponsive systems must be considered. PMID- 30247973 TI - Aquatic Exercise Training Outcomes on Functional Capacity, Quality of Life, and Lower Limb Lymphedema: Pilot Study. AB - OBJECTIVE: To investigate whether patients with lower limb lymphedema (LLL) can benefit from water immersion exercise training to improve functional capacity, quality of life (QOL), and help control/diminish limb volume. DESIGN: A before after trial. SETTING: A community University Sports Center. SUBJECTS: Eleven participants were recruited to participate and four declined to pursue the study for personal reasons. A convenient sample of seven female affected by either bilateral or unilateral LLL volunteered for this pilot study. Patients had primary or secondary lymphedema as complications of melanoma or gynecologic cancers. INTERVENTIONS: An aquatic training exercise intervention of moderate to vigorous intensity was conducted for a 6-week period (12 sessions of 45 min). This innovative circuit training program consisted of yoga exercises, aqua jogging, pedaling on a water bike, and muscular training on an aquastep and a trampoline. OUTCOME MEASURES: The physical characteristics of water could be used to overcome the physical and medical limitations encountered on dry land for patients with LLL to exercise and reach training benefits. Outcome measures were the 6-min walk test (6MWT), handgrip strength test, QOL for limb lymphedema questionnaire (LYMQOL), bioelectrical impedance spectroscopy, and limb circumference. RESULTS: The distance covered in the 6MWT and the handgrip strength were significantly improved. A trend toward an increase in the overall QOL score was noticeable, whereas a significantly improved emotions score was observed with the LYMQOL questionnaire. Limb circumferential volume was significantly lower and impedance was increased, denoting a decrease in lymphatic fluid. CONCLUSIONS: Innovative aquatic exercise training program allows moderate and vigorous intensity activities for patients with LLL, increases functional capacity and QOL. Thus, immersion exercise does not appear to exacerbate LLL and a randomized clinical trial with larger numbers is essential to consolidate the results of this study. PMID- 30247974 TI - Integrative Oncology Scholars Program: A Model for Integrative Oncology Education. AB - OBJECTIVES: Oncology providers are often confronted by patients who use complementary or alternative therapies, but have limited knowledge or confidence on how to advise patients on appropriate use. Despite this, there are few opportunities for oncology providers to learn about complementary or alternative therapies, while at the same time there is a high demand for integrative oncology (IO) training. To address a gap in IO educational opportunities, and particularly for nonphysicians, we created the Integrative Oncology Scholars (IOS) Program. The program's goal is to train 100 IO leaders and facilitate partnerships between them and complementary practitioners. DESIGN: Four iterations of a year-long National Cancer Institute-funded educational program that combines in-person team based learning and eLearning to teach the evidence, application, and philosophy supporting IO. SETTINGS: In-person sessions take place at the University of Michigan, and eLearning is implemented using a Canvas website (Instructure, Inc., Salt Lake City, UT). SUBJECTS: Nurses, social workers, physician assistants, psychologists, physicians, pharmacists, and physical/occupational therapists with active oncology practices. Educational intervention: Four cohorts of 25 oncology providers per year will learn the evidence base for complementary and alternative approaches to a wide number of oncology topics, including symptom control, dietary supplements commonly used by cancer patients, diet, and the utility of specific integrative approaches for common oncology side-effects such as fatigue. OUTCOME MEASURES: A mixed methods approach will be used to evaluate overall IOS Program progress and individual scholar's impact on IO research, education, and clinical endeavors. RESULTS: The first cohort of 25 IOS has been recruited and their education will begin in Summer 2018. Scholars come from 13 states and represent 23 different healthcare systems. CONCLUSIONS: The IOS Program has the potential to increase the number of trained IO providers, educators, and researchers in the United States. PMID- 30247976 TI - Optimizing Inpatient Body MRI Utilization: A Granular Look at Trends, Quality, Yield, and Timing. AB - OBJECTIVE: We sought to analyze body MRI utilization trends, quality, yield, and timing among inpatients in a tertiary care academic medical center. MATERIALS AND METHODS: By use of billing data from fiscal years (FYs) 2006-2015, the volume of admissions was compared with the total number of inpatient body MRI examinations. MRI examinations per admissions and discharge were adjusted using the Centers for Medicare & Medicaid Services case mix index by FY. Linear regression was used to assess trends. In addition, each inpatient body MRI examination performed in FY 2015 was evaluated and graded on its quality and yield and was judged as to whether it could have been performed on an outpatient basis. RESULTS: There was an increase in the number of inpatient body MRI examinations, from 637 examinations in FY 2006 to 871 examinations in FY 2015 (p = 0.005). By adjusting for case mix, the upward trend for body MRI use persisted (p = 0.012). Regarding quality, 2.3% of all inpatient body MRI examinations were nondiagnostic, 40.4% were limited quality, and 57.3% were of diagnostic quality. Concerning yield, 20.8% of all examinations had no yield, 5.1% of examinations had no yield but incidental findings, and 74.1% of examinations had a positive yield. Finally, regarding timing, 30.2% of examinations could have been performed as outpatient examinations. CONCLUSION: At our institution, the number of inpatient body MRI examinations has increased significantly over the past 10 years. Many of the examinations, however, are poor quality, often give redundant information, and could be performed in the outpatient setting. PMID- 30247978 TI - Postpartum Bone Marrow Edema at the Sacroiliac Joints May Mimic Sacroiliitis of Axial Spondyloarthritis on MRI. AB - OBJECTIVE: The objective of our study was to compare MRI findings in the sacroiliac joints of postpartum women (as a model of mechanical changes) and women with known axial spondyloarthritis (as an inflammatory model). SUBJECTS AND METHODS: For this prospective multicenter age-matched, case-control study, sacroiliac joint MRI examinations of 30 healthy women (mean age, 34.0 years) in the early postpartum period (mechanical group) and 30 age-matched women (mean age, 33.8 years) with known axial spondyloarthritis (retrospective inflammatory group) were compared. Blinded to clinical information, readers assessed MR images using the following scoring systems: Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index, Berlin method, Assessment of Spondyloarthritis International Society (ASAS) criteria, and SPARCC MRI structural score. Descriptive statistics as percentages of the different findings (i.e., bone marrow edema [BME], erosion, fatty bone marrow replacement, backfill, ankylosis) and scores between groups and between delivery modes were compared. RESULTS: In the postpartum group, 63.3% (19/30) of women showed BME around the sacroiliac joints compared with 86.7% (26/30) of women in the spondyloarthritis group (based on ASAS criteria). Erosions were uncommon in the postpartum group (10.0% [3/30] postpartum vs 56.7% [17/30] spondyloarthritis). Fatty bone marrow replacement, backfill, and ankylosis were not seen in the postpartum group. In subjects with positive MRI findings for sacroiliitis based on ASAS criteria, the SPARCC MRI index (mean +/- SD, 13.6 +/- 14.5 vs 13.0 +/- 10.7; p = 0.818) and Berlin method (4.5 +/- 3.0 and 5.5 +/- 3.5, p = 0.378) were not different between the postpartum and spondyloarthritis groups. Scores were not different between birth modalities. CONCLUSION: Pregnancy-induced BME at the sacroiliac joints, as a result of prolonged mechanical stress, was present in 63.3% of women who underwent MRI during the early postpartum period and may mimic sacroiliitis of axial spondyloarthritis. PMID- 30247979 TI - The Multidisciplinary Approach to the Diagnosis and Management of Nonobstetric Traumatic Brachial Plexus Injuries. AB - OBJECTIVE: Nonobstetric traumatic brachial plexus injuries can result in significant morbidity and chronic disability if not managed in a timely manner. Functional arm recovery is possible, but it requires a multidisciplinary approach toward the diagnosis and management of such injuries. CONCLUSION: This article provides an overview of the clinical, electrophysiology, and diagnostic imaging knowledge needed for accurate imaging interpretation and to participate in multidisciplinary discussions aimed at expediting optimal patient management. PMID- 30247977 TI - Multimodality Screening of Hepatic Nodules in Patients With Congenital Heart Disease After Fontan Procedure: Role of Ultrasound, ARFI Elastography, CT, and MRI. AB - OBJECTIVE: Currently, there is no consensus in the literature regarding the screening of hepatic nodules in patients who have undergone the Fontan procedure. The objectives of this study are to evaluate in this population the frequency of hepatic nodules at ultrasound (US), CT, and MRI; to measure liver stiffness using acoustic radiation force impulse (ARFI) elastography; and to investigate predictive factors for hepatic nodules. SUBJECTS AND METHODS: In this cross sectional study, 49 patients who underwent the Fontan procedure were prospectively recruited from August 2014 through June 2016. These patients underwent clinical evaluation for hepatic disorders, ARFI elastography, US, CT, and MRI. RESULTS: Most of the patients had no symptoms, and hepatic nodules were detected in three of 49 (6.1%) patients at US, 14 of 44 (31.8%) patients at CT, and 19 of 48 (39.6%) patients at MRI. Liver stiffness at ARFI elastography was significantly higher in patients with hepatic nodules than in patients without such nodules (2.64 +/- 0.81 m/s vs 1.94 +/- 0.49 m/s; p = 0.002) and was a significant predictor of hepatic nodule (AUC, 0.767; p = 0.002). No clinical or laboratory data had any significant correlation with the existence of hepatic nodules, including time since Fontan procedure. CONCLUSION: In our study, more than one-third of patients had hepatic nodules at CT or MRI, but US did not detect most hepatic nodules. Liver stiffness at ARFI elastography was significantly higher in patients with hepatic nodules, and it may help guiding which patient should be further imaged with CT or MRI. PMID- 30247980 TI - Introduction of Microwave Ablation Into a Renal Ablation Practice: Valuable Lessons Learned. AB - OBJECTIVE: The purpose of this study was to evaluate the early outcomes of percutaneous microwave ablation (MWA) for clinical stage T1 (cT1) renal masses when performed within a high-volume ablation practice with critical emphasis on procedural safety. MATERIALS AND METHODS: A retrospective review of a percutaneous renal ablation registry identified 26 patients with a total of 27 cT1 renal masses treated with MWA between 2011 and 2017. Mean patient age was 63.8 years and 16 (61.5%) patients were male. Mean renal mass size +/- SD was 2.3 +/- 0.8 cm (range, 1.1-4.7 cm). The main outcome parameters investigated were technical success, local tumor progression, survival rates, and complications. Complications were categorized using the Clavien-Dindo classification system. Rates of local progression-free and cancer-specific survival (PFS and CSS, respectively) were estimated using the Kaplan-Meier method. RESULTS: Technical success was 100% on contrast-enhanced CT or MRI performed immediately after renal MWA. Twenty-four patients (92%) with 25 tumors had follow-up imaging for 3 months or longer (mean, 20.6 +/- 11.6 months), with no local tumor recurrences identified. Estimated 3-year local PFS and CSS were 96% and 94%, respectively. The overall complication rate was 19.2%; two patients (7.7%) experienced minor complications (grade I or II) and three patients (11.5%) experienced major bleeding or urinary-related complications (grade III or higher), including one death. CONCLUSION: This study suggests that percutaneous MWA is a promising minimally invasive treatment option for cT1 renal masses. Nonetheless, major bleeding and urinary-related complications can occur, and further studies are needed to determine optimal patient and tumor selection for renal MWA. PMID- 30247981 TI - MRI-Guided Cryoablation of Epidural Malignancies in the Spinal Canal Resulting in Neural Decompression and Regrowth of Bone. AB - OBJECTIVE: The purpose of this article is to describe the use of MRI to safely monitor cryoablation for the treatment of spinal epidural malignancies. CONCLUSION: Use of MRI guidance to monitor percutaneous cryoablation allows ablation margins more distinct than those allowed by heat-based ablation modalities. MRI-guided cryoablation is a feasible option for treating epidural tumors involving the spinal canal, resulting in successful decompression of the tumor away from the spinal cord with regrowth of previously eroded bone around the spinal canal. PMID- 30247982 TI - JOURNAL CLUB: Hepatopancreaticobiliary Imaging Second-Opinion Consultations: Is There Value in the Second Reading? AB - OBJECTIVE: Tertiary care practices increasingly provide second-opinion consultations on reports from outside practices or institutions. This practice of providing a second opinion has been studied in a variety of subspecialties; however, its potential effect on the management of hepatopancreaticobiliary (HPB) disease is not known. The purpose of this study was to assess the rate of significant discrepancies between the initial report and the consultation report, the source of discrepancies, and the frequency of repeat imaging recommendations. MATERIALS AND METHODS: Retrospective chart review was performed for 480 consecutive CT and MRI consultation reports interpreted between January 2014 and December 2015 for patients with HPB diseases whose initial CT and MRI reports were generated at outside facilities. The initial report and the consultation report were independently reviewed and compared by two abdominal radiologists. Discrepancies between the initial report and the consultation report were divided into minor and major differences in the detection or interpretation of abnormalities. Clinical importance was defined as a change in a finding or interpretation that directly impacted management of the patient. RESULTS: A major discrepancy between the reports was identified in 27-28% of cases split evenly between detection and interpretation of abnormalities. Interreader agreement for categorization was moderate (weighted kappa value, 0.49). In consensus review, the rate of a major discrepancy occurring increased to 32%. Common sources of discrepancy were interpretation of findings as malignant versus benign (49% of cases) and accuracy of staging (15% of cases). Imaging limitations were described in 16% of cases, commonly as a result of an insufficient protocol or poor image quality. CONCLUSION: Discrepancies in interpretation resulting in direct implications for clinical management are seen in almost one-third of HPB consultation cases. Second-opinion imaging consultation in the tertiary care setting can frequently impact management. PMID- 30247983 TI - Highlights of ISPN on Its 20th Anniversary. PMID- 30247984 TI - Ferroportin disease mutations influence manganese accumulation and cytotoxicity. AB - Hemochromatosis is a frequent genetic disorder, characterized by the accumulation of excess iron across tissues. Mutations in the FPN1 gene, encoding a cell surface iron exporter [ferroportin (Fpn)], are responsible for hemochromatosis type 4, also known as ferroportin disease. Recently, Fpn has been implicated in the regulation of manganese (Mn), another essential nutrient required for numerous cellular enzymes. However, the roles of Fpn in Mn regulation remain ill defined, and the impact of disease mutations on cellular Mn levels is unknown. Here, we provide evidence that Fpn can export Mn from cells into extracellular space. Fpn seems to play protective roles in Mn-induced cellular toxicity and oxidative stress. Finally, disease mutations interfere with the role of Fpn in controlling Mn levels as well as the stability of Fpn. These results define the function of Fpn as an exporter of both iron and Mn and highlight the potential involvement of Mn dysregulation in ferroportin disease.-Choi, E.-K., Nguyen, T. T., Iwase, S., Seo, Y. A. Ferroportin disease mutations influence manganese accumulation and cytotoxicity. PMID- 30247988 TI - Women's recovery from anorexia nervosa: a systematic review and meta-synthesis of qualitative research. AB - Anorexia nervosa (AN) is a complex and challenging condition and recovery can be a slow and difficult process. Predicting factors remain largely unknown. This paper aims to systematically review qualitative studies which have investigated female service users' experiences of recovering from AN and carry out a meta synthesis of the themes they identified. Meta-ethnography was used to select and synthesize the studies. Articles published between 2002 and 2017 were searched in PsycInfo, EMBASE, CINAHL and Medline. Studies were included if they explored recovery from AN using a qualitative methodology. The methodological quality of the studies was systematically and critically appraised. Fourteen studies were selected for inclusion. Common themes reported by participants describe the process of recovery from AN as dealing with a fragmented sense of self, a turning point where insight and commitment to recovery is developed, and, in recovery, a reclamation of self through meaningful relationships, rebuilding identity and self-acceptance. Recovery from AN is experienced as a complex psychological process with many contributing factors. Findings highlight the need to reconsider clinical practice and treatment provision to incorporate the psychological components of self-identity into recovery programs. PMID- 30247987 TI - What psycho-social factors determine intimate partner violence of men against women? A social cognitive theory-based study. AB - Despite the multidimensionality of intimate partner violence (IPV) against women, there is a lack of research on the perspectives of men toward the phenomenon. Our aim in this cross-sectional study was to examine the predictability of social cognitive theory in explaining men's violent behaviors against women. We find among a sample of 576 Iranian married men showed a reciprocal determinism between outcome expectancy, attitude toward IPV, and observational learning in formation of men's IPV against women. Therefore, the interactive associations of cognitive and environmental factors, as a comprehensive approach, should be considered while studying the determinants of IPV against women among men. PMID- 30247989 TI - An Evaluation of the Counseling on Access to Lethal Means (CALM) Training with an Area Agency on Aging. AB - Firearms are a significant risk factor in suicide and older adults are disproportionately impacted in suicide by this means. This study investigated the impact of Counseling on Access to Lethal Means (CALM) training with geriatric case managers at an Area Agency on Aging. A concurrent mixed methods approach was used to explore 1) geriatric case managers' attitudes, beliefs, and behavioral intentions about counseling on access to lethal means following CALM training, and 2) perceived barriers to assessing for suicidality and counseling clients on access to firearms. The CALM evaluation data was collected immediately posttest at CALM training, at three-month follow up. Results indicated that 38% of respondents reported they had, since CALM training, discussed reducing access to lethal means with clients and/or families. At three-month follow up, data showed that most beliefs, attitudes, and behavioral intentions about counseling clients and families on this topic increased. Focus group findings indicated that training had a positive effect on participants' attitudes, beliefs, and behavioral intentions about counseling on access to lethal means.The findings of the present study offer additional evidence and implication for trainings of this type. PMID- 30247985 TI - Human fetal adrenal cells retain age-related stem- and endocrine-differentiation potential in culture. AB - The adrenal gland is a multiendocrine organ with a steroidogenic mesenchymal cortex and an inner catecholamine-producing medulla of neuroendocrine origin. After embryonic development, this plastic organ undergoes a functional postnatal remodeling. Elucidating these complex processes is pivotal for understanding the early bases of functional endocrine disorders and tumors affecting the mature gland. We developed an in vitro human adrenal cell model derived from fetal adrenal specimens at different gestational ages, consisting of neuroendocrine and cortical components and expressing the zona and functional markers of the original fetal organ. These cortical and neuroendocrine progenitor cells retain in vitro an intrinsic gestational-age-related differentiation and functional program. In vitro these cells spontaneously form 3-dimensional structure organoids with a structure similar to the fetal gland. The organoids show morphofunctional features and adrenal steroidogenic factor, steroid acute regulatory, cytochrome-P450-17A1, dosage-sensitive, sex-reversal, adrenal hypoplasia-critical region on chromosome X protein , NOTCH1, and nephroblastoma overexpressed/cysteine-rich protein 61/connective tissue growth factor/nephroblastoma overexpressed gene-3; stem (BMI1, nestin); and chromaffin (chromogranin A, tyrosine hydroxylase) markers similar to those of the populations of origin. This in vitro human adrenal system represents a unique but preliminar model for investigating the pathophysiological processes underlying physiologic adrenal remodeling and pathologic alterations involved in organ hypo- and hyperplasia and cancer.-Poli, G., Sarchielli, E., Guasti, D., Benvenuti, S., Ballerini, L., Mazzanti, B., Armignacco, R., Cantini, G., Lulli, M., Chortis, V., Arlt, W., Romagnoli, P., Vannelli, G. B., Mannelli, M., Luconi, M. Human fetal adrenal cells retain age-related stem- and endocrine-differentiation potential in culture. PMID- 30247986 TI - Precision toxicology shows that troxerutin alleviates ochratoxin A-induced renal lipotoxicity. AB - Lipotoxicity is the most common cause of severe kidney disease, with few treatment options available today. Precision toxicology can improve detection of subtle intracellular changes in response to exogenous substrates; thus, it facilitates in-depth research on bioactive molecules that may interfere with the onset of certain diseases. In the current study, troxerutin significantly relieved nephrotoxicity, increased endurance, and improved systemic energy metabolism and renal inflammation in OTA-induced nephrotic mice. Lipidomics showed that troxerutin effectively reduced the levels of triglycerides, phosphatidylcholines, and phosphatidylethanolamines in nephropathy. The mechanism was partly attributable to troxerutin in alleviating the aberrantly up-regulated expression of sphingomyelinase, the cystic fibrosis transmembrane conductance regulator, and chloride channel 2. Renal tubular epithelial cells, the main site of toxin-induced accumulation of lipids in the kidney, were subjected to transcriptomic profiling, which uncovered several metabolic factors relevant to aberrant lipid and lipoprotein metabolism. Our work provides new insights into the molecular features of toxin-induced lipotoxicity in renal tubular epithelial cells in vivo and demonstrates the function of troxerutin in alleviating OTA induced nephrosis and associated systemic energy metabolism disorders.-Yang, X., Xu, W., Huang, K., Zhang, B., Wang, H., Zhang, X., Gong, L., Luo, Y., He, X. Precision toxicology shows that troxerutin alleviates ochratoxin A-induced renal lipotoxicity. PMID- 30247990 TI - The World of Homosexuals. PMID- 30247991 TI - Disordered Eating Among a Diverse Sample of First-Year College Students. AB - OBJECTIVE: A cross-sectional study of first-year college students was conducted to identify the prevalence and predictors of disordered eating (DE). METHODS: College freshmen students, aged 18 years, (n = 106) completed the Eating Disorder Examination Questionnaire (EDE-Q) and a supplemental survey. A subset of the sample (n = 77) underwent measurements of height, weight, and body composition. DE was defined as an elevated (3) weight, shape, eating concern, or dietary restraint EDE-Q subscale score. RESULTS: The sample, consisting of 56.6%, 15.1%, 11.3%, and 11.3% Latino/a, Asian, African American, and Caucasian students, respectively (37% male), reported a 31.1% prevalence of DE. The current desire to lose weight was the strongest predictor of DE (odds ratio = 15.3; 95% confidence interval = 2.8, 82.5). Other variables linked to DE or elevated EDE-Q subscale scores included body mass index (BMI) 25.0 kg/m2, vegetarianism, weight loss in the past year, female gender, and eating breakfast < 5 d/wk. Participants with BMI 25.0 kg/m2 and the current desire to lose weight (n = 23) or following a vegetarian diet (n = 5) exhibited the highest prevalence of DE (78.3% and 80.0%, respectively). A higher proportion of Latinas reported binge episodes compared to female Caucasian, Asian, and African American students (36.4% vs. 0.0%, 6.7%, and 28.6%, respectively, p = 0.056, chi2 = 7.6). Males, versus females, were more likely to report excessive exercise (56.4% vs. 37.3%, p = 0.056, chi2 = 3.6). CONCLUSIONS: This study adds to the current body of literature on DE by providing a diverse sample and potentially novel predictors and risk factors for DE. PMID- 30247992 TI - Queer Youth in Educational Psychology Research. AB - Despite greater social acceptance of individuals with diverse sexual identities across the world, queer students still experience greater bullying, poorer academic motivation, and lower school attendance than heterosexual students. Educational psychology could provide additional insight toward these experiences for queer students in school, but the field of educational psychology is often absent from research on queer students. To partially address this concern, the current article examines why researching queer students is important, reviews extant research on queer youth in predominant educational psychology journals, and provides potential avenues of future research. Further, the article explores protective factors that help queer students succeed in school. PMID- 30247993 TI - Preschoolers' Anticipation of Sadness for Excluded Peers, Sympathy, and Prosocial Behavior. AB - We investigated the relations between anticipation of sadness for excluded peers, sympathy, and prosocial behavior in a sample of 127 Italian preschoolers (Mage = 4.84 years, SD = 0.85). Children attributed emotions to hypothetical excluded peers who exhibited withdrawn versus aggressive behavior, and these attributions were coded for the presence and intensity of sadness. Teachers rated children's sympathy and prosocial behavior via questionnaire. In general, children attributed more sadness to the withdrawn excluded peer than the aggressive excluded peer. A path analysis revealed that those who anticipated higher levels of sadness for the withdrawn excluded peer were rated higher in sympathy and, in turn, higher in prosocial behavior. Attributing high levels of sadness to withdrawn excluded peers-who portray relatively heightened need-may be an early social-emotional characteristic of children who are more sympathetic and more likely to channel other-oriented concerns into prosocial actions. PMID- 30247997 TI - Reminiscing with Nicholls: Our brilliant, eccentric colleagues. PMID- 30247994 TI - Distinguishing the meaning making processes of survivors of suicide loss: An expansion of the meaning of loss codebook. AB - Suicide loss represents particularly a difficult form of bereavement due to the challenges that volitional death poses to survivors. Understanding these challenges requires recognition of the idiosyncratic processes of meaning reconstruction for this specific group of grievers. The current study investigates such processes in survivors of suicide loss (SOSL) by utilizing the Meaning of Loss Codebook (MLC) to analyze the narratives of eight SOSL. The findings contribute to a broader understanding of meaning making following suicide, strengthen the validity of the MLC by demonstrating its appropriateness for SOSL, and illuminate unique challenges faced by SOSL, resulting in the proposal of supplemental MLC codes. Research and clinical implications are discussed. PMID- 30247995 TI - Do Foster Parents and Care Workers Recognize the Needs of Youth in Family Foster Care with a History of Sexual Abuse? AB - Children in family foster care have the right to participate in decisions regarding their life, however, adults often advocate on behalf of children. This Q methodological study explored whether shared perspectives among foster parents and care workers resemble shared perspectives of youth regarding the psychosocial needs experienced by youth with a history of sexual abuse. Participants sorted a set of statement cards according to what they thought was most important for youth. By-person factor analyses examined how the Q sorts of foster parents and care workers related to those of youth. The results showed that foster parents mostly recognized the group of youth who value an instrumental relationship with their carers, while care workers mostly recognized the group of youth who value support of both foster and birth parents with regard to their preparation for independent living. The two youth groups characterized by ambivalence and autonomy were barely recognized. Results are discussed in light of the expected roles of foster parents and care workers, and youth's contact with birth parents. Lastly, this study highlights the importance of youth participation, because youth offer unique and varying perspectives about their needs. PMID- 30247996 TI - Taxonomy and phylogeny of Macrolepiota: two new species from Brazil. AB - Macrolepiota is a poorly known genus in the Neotropics. In order to increase knowledge about this group, we collected specimens from the Atlantic Forest in southern and northeastern Brazil. Macrolepiota cyanolamellata and M. sabulosa from subtropical and tropical regions, respectively, are proposed as new species. We performed molecular phylogenetic analyses of the nuc rDNA internal transcribed spacer region ITS1-5.8S-ITS2 (ITS) and the combined data set ITS + nuclear large subunit rDNA (28S) + RNA polymerase II second largest (RPB2), as well as morphological analyses. Two lineages with unique morphotypes were found. The species proposed were strongly supported as the sister lineage closely related to M. clelandii and M. subcitrophylla. Detailed descriptions and illustrations of their macro- and microscopic characters are provided. PMID- 30247998 TI - Cow's Milk Consumption and Health: A Health Professional's Guide. AB - The most recent scientific evidence supports the consumption of cow's milk and dairy products as part of a balanced diet. However, these days, the public and practicing physicans are exposed to a stream of inconsistent (and often misleading) information regarding the relationship between cow's milk intake and health in the lay press and in the media. The purpose of this article, in this context, is to facilitate doctor-patient communication on this topic, providing physicians with a series of structured answers to frequently asked patient questions. The answers range from milk and milk-derived products' nutritional function across the life span, to their relationship with diseases such as osteoporosis and cancer, to lactose intolerance and milk allergy, and have been prepared by a panel of experts from the Italian medical and nutritional scientific community. When consumed according to appropriate national guidelines, milk and its derivatives contribute essential micro- and macronutrients to the diet, especially in infancy and childhood where bone mass growth is in a critical phase. Furthermore, preliminary evidence suggests potentially protective effects of milk against overweight, obesity, diabetes, and cardiovascular disease, while no clear data suggest a significant association between milk intake and cancer. Overall, current scientific literature suggests that an appropriate consumption of milk and its derivatives, according to available nutritional guidelines, may be beneficial across all age groups, with the exception of specific medical conditions such as lactose intolerance or milk protein allergy. Key teaching points: Milk and its derivatives contribute essential micro and macronutrients to the diet, when consumed according to appropriate national guidelines, especially in infancy and childhood where bone mass growth is in a critical phase. Preliminary evidence suggests potentially protective effects of milk against overweight, obesity, diabetes and cardiovascular disease No clear data are available about the association between milk intake and cancer. Current scientific literature suggests that an appropriate consumption of milk and its derivatives may be beneficial at all ages, with the exception of specific medical conditions such as lactose intolerance or milk protein allergy. PMID- 30247999 TI - Trends and Epidemiologic Factors Contributing to Soccer-Related Fractures That Presented to Emergency Departments in the United States. AB - BACKGROUND: Understanding the risks and trends of soccer-related injuries may prove beneficial in creating preventative strategies against season-ending injuries. HYPOTHESIS: Soccer-related fractures will have decreased over the past 7 years. STUDY DESIGN: Descriptive epidemiology study. LEVEL OF EVIDENCE: Level 3. METHODS: The National Electronic Injury Surveillance System (NEISS) database was queried to identify soccer-related injuries from 2010 through 2016. The sum of the weighted values provided in the NEISS database was used to determine injury frequency and allowed us to estimate the incidence and annual trends of soccer-related fractures. The estimated annual number of hospital admissions resulting from each fracture location was calculated. Statistical analyses were performed, and a linear regression was used to analyze the annual injury trends, reported as the correlation coefficient. RESULTS: Over the 6-year period, there were an estimated 1,590,365 soccer-related injuries. The estimated annual frequency of soccer-related injuries slightly increased from 225,910 in 2010 to 226,150 in 2016 ( P = 0.477). The most common injuries were sprains/strains (32.4%), followed by fractures (20.4%). Fractures at the wrist were the most common (18%), while upper leg fractures were the most common soccer-related fractures to be admitted to the hospital (51.6%). The annual trends of the most common soccer-related fractures demonstrated increases in shoulder ( r = 0.740; R2 = 0.547; P = 0.057) and wrist ( r = 0.308; R2 = 0.095; P = 0.502) fractures. There were no significant changes in the trends of soccer-related fractures of the lower arm ( r = 0.009; R2 = 7.3 * 10-5; P = 0.986), finger ( r = 0.679; R2 = 0.460; P = 0.094), lower leg ( r = 0.153; R2 = 0.024; P = 0.743), ankle ( r = 0.650; R2 = 0.422; P = 0.114), toe ( r = 0.417; R2 = 0.174; P = 0.353), or foot ( r = 0.485; R2 = 0.235; P = 0.270). CONCLUSION: Despite the reported growing number of soccer players in the United States, the overall number of soccer related injuries has remained relatively stable. Overall, 60% of reported fractures occurred in the upper extremity, with the wrist being the most common site, while lower extremity fractures were the most likely to lead to hospital admission. CLINICAL RELEVANCE: This study offers an overview of the most common types of fractures that affect soccer players and may prove beneficial in creating preventative strategies against season-ending injuries. PMID- 30248000 TI - Conflicts of interest policies for authors, peer reviewers, and editors of bioethics journals. AB - BACKGROUND: In biomedical research, there have been numerous scandals highlighting conflicts of interest (COIs) leading to significant bias in judgment and questionable practices. Academic institutions, journals, and funding agencies have developed and enforced policies to mitigate issues related to COI, especially surrounding financial interests. After a case of editorial COI in a prominent bioethics journal, there is concern that the same level of oversight regarding COIs in the biomedical sciences may not apply to the field of bioethics. In this study, we examined the availability and comprehensiveness of COI policies for authors, peer reviewers, and editors of bioethics journals. METHODS: After developing a codebook, we analyzed the content of online COI policies of 63 bioethics journals, along with policy information provided by journal editors that was not publicly available. RESULTS: Just over half of the bioethics journals had COI policies for authors (57%), and only 25% for peer reviewers and 19% for editors. There was significant variation among policies regarding definitions, the types of COIs described, the management mechanisms, and the consequences for noncompliance. Definitions and descriptions centered on financial COIs, followed by personal and professional relationships. Almost all COI policies required disclosure of interests for authors as the primary management mechanism. Very few journals outlined consequences for noncompliance with COI policies or provided additional resources. CONCLUSION: Compared to other studies of biomedical journals, a much lower percentage of bioethics journals have COI policies and these vary substantially in content. The bioethics publishing community needs to develop robust policies for authors, peer reviewers, and editors and these should be made publicly available to enhance academic and public trust in bioethics scholarship. PMID- 30248001 TI - Identification of novel adenovirus genotype 90 in children from Bangladesh. AB - Novel adenovirus genotypes are associated with outbreaks of disease, such as acute gastroenteritis, renal disease, upper respiratory tract infection and keratoconjunctivitis. Here, we identify novel and variant adenovirus genotypes in children coinfected with enterotoxigenic Escherichia coli, in Bangladesh. Metagenomic sequencing of stool was performed and whole adenovirus genomes were extracted. A novel species D virus, designated genotype 90 (P33H27F67) was identified, and the partial genome of a putative recombinant species B virus was recovered. Furthermore, the enteric types HAdV-A61 and HAdV-A40 were found in stool specimens. Knowledge of the diversity of adenovirus genomes circulating worldwide, especially in low-income countries where the burden of disease is high, will be required to ensure that future vaccination strategies cover the diversity of adenovirus strains associated with disease. PMID- 30248002 TI - Candida africana in recurrent vulvovaginal candidiasis (RVVC) patients: frequency and phenotypic and genotypic characteristics. AB - PURPOSE: Up to 75 % of all women develop vulvovaginal candidiasis (VVC), with symptoms such as vulvar erythema, pruritus and abnormal vaginal discharge. Despite the global distribution of Candida africana, its role in recurrent vulvovaginal candidiasis (RVVC) is still unclear and requires further investigation. Here, we report on the frequency of C. africana among clinical isolates from patients with RVVC in Bushehr in southern Iran. METHODOLOGY: Isolated Candida strains were identified by ITS-PCR-RFLP. Hyphal wall protein 1 (HWP1) was amplified to differentiate C. africana and the resulting sequences were subjected to phylogenetic analyses with a view to identifying similarities and differences in nucleotides. RESULTS: Ten out of 119 strains originally identified as C. albicans turned out to be C. africana. Pairwise nucleotide alignment of HWP1 DNA sequences showed 100 % similarity between C. africana strains. Inter-species variation between Iranian C. africana HWP1 sequences and the only three available C. africana type sequences in GenBank revealed 99.7-100 % nucleotide similarity. Phylogenetic analysis of the HWP1 DNA sequences of 10 Iranian C. africana isolates, the 3 C. africana sequences available in GenBank and 2 representative Iranian C. albicans sequences revealed that all 11 Iranian C. africana strains formed a well-supported cluster separated from the remaining C. africana. CONCLUSION: In our sample, C. africana was only isolated from 7.8 % of the patients with RVVC. While size polymorphisms in HPW1 genes allowed us to differentiate C. africana from C. albicans, no evidence of sequence variation within the Iranian C. africana isolates was observed. PMID- 30248006 TI - Beverage Consumption Among Youth in the United States, 2013-2016. AB - Beverages contribute to hydration and affect total calorie intake (1). For all individuals aged 2 years and over, the 2015-2020 Dietary Guidelines for Americans recommend that water, fat-free and low-fat milk, and 100% juice be the primary beverages consumed (2). The American Academy of Pediatrics also supports this advice for youth (3). This report describes the contribution of different beverage types to total beverage consumption, by grams, among U.S. youth. PMID- 30248004 TI - Prevalence of Total, Diagnosed, and Undiagnosed Diabetes Among Adults: United States, 2013-2016. AB - Diabetes is a major cause of morbidity and mortality in the United States (1-3). Diabetes can be present but undiagnosed, meaning that a person can have diabetes but not report having ever been told by a doctor or health professional that they have the condition. Type 2 diabetes can progress over an extended time period with gradual, often unnoticed, changes occurring before diagnosis. If left unmanaged, diabetes may contribute to serious health outcomes including neuropathy, nephropathy, retinopathy, coronary artery disease, stroke, and peripheral vascular disease (4). This report presents the prevalence of total, diagnosed, and undiagnosed diabetes in U.S. adults in 2013-2016. PMID- 30248005 TI - Patient Health Information Shared Electronically by Office-based Physicians: United States, 2015. AB - This report expands upon previous research that described the percentage of physicians who electronically sent, received, integrated, and searched for patient health information (PHI) by describing types of PHI that are electronically shared in physician offices. PMID- 30248007 TI - State Variation in Meeting the 2008 Federal Guidelines for Both Aerobic and Muscle-strengthening Activities Through Leisure-time Physical Activity Among Adults Aged 18-64: United States, 2010-2015. AB - This report presents national and state-level age-adjusted estimates of percentages of U.S. adults aged 18-64 who met the 2008 federal guidelines for both aerobic and muscle-strengthening activities during leisure-time physical activity (LTPA) in 2010-2015, by sex and work status (working compared with nonworking). State variation in work status, health status and difficulty in physical functioning, and occupational distributions for men and women were also considered. PMID- 30248003 TI - Gluconeogenic growth of Vibrio cholerae is important for competing with host gut microbiota. AB - PURPOSE: The gastrointestinal tract is home to thousands of commensal bacterial species. Therefore, competition for nutrients is paramount for successful bacterial pathogen invasion of intestinal ecosystems. The human pathogen Vibrio cholerae, the causative agent of the severe diarrhoeal disease, cholera, is able to colonize the small intestine, which is protected by mucus. However, it is unclear which metabolic pathways or nutrients V. cholerae utilizes during intestinal colonization and growth. METHODOLOGY: In this study, we investigated the effect of various metabolic key genes, including those involved in the gluconeogenesis pathway, on V. cholerae physiology and in vivo colonization. RESULTS: We found that gluconeogenesis is important for infant mouse colonization. Growth assays showed that mutations in the key components of gluconeogenesis pathway, PpsA and PckA, lead to a growth defect in a minimal medium supplemented with mucin as a carbon source. Furthermore, the ppsA/pckA mutants colonized poorly in the adult mouse intestine, particularly when more gut commensal flora are present. CONCLUSION: Gluconeogenesis biosynthesis is important for the successful colonization of V. cholerae in a niche that is full of competing microbiota. PMID- 30248008 TI - Identification of Substance-involved Emergency Department Visits Using Data From the National Hospital Care Survey. AB - This report describes the development of methods to identify emergency department (ED) visits involving substance use. Two different algorithms are compared using claims data from the 2013 National Hospital Care Survey (NHCS), a facility-based survey. While NHCS was designed to produce national estimates, this report is based on 2013 data, which are not nationally representative. PMID- 30248009 TI - Fertility of Men and Women Aged 15-44 in the United States: National Survey of Family Growth, 2011-2015. AB - This report presents national estimates of selected fertility measures for men and women aged 15-44 in the United States in 2011-2015 based on data from the National Survey of Family Growth (NSFG). Estimates for 2011-2015 are compared with those for 2006-2010. PMID- 30248010 TI - Health Conditions and Behaviors of Native Hawaiian and Pacific Islander Persons in the United States, 2014. AB - : The body of nationally representative health statistics for the Native Hawaiian and Pacific Islander (NHPI) population is limited, because even the largest health surveys generally do not have an adequate NHPI sample to calculate reliable NHPI statistics. Using data from the Native Hawaiian and Pacific Islander National Health Interview Survey (NHPI NHIS) from the National Center for Health Statistics (NCHS), this report fills this gap by presenting statistics on health conditions and behaviors for (a) the total NHPI population and the multiple- and singlerace NHPI populations, in comparison with other federal race groups and the total U.S. population; (b) single-race NHPI persons compared with multiple-race NHPI persons; and (c) detailed NHPI race groups in comparison with each other and the total U.S. POPULATION: PMID- 30248013 TI - Issues in Developing Multidimensional Indices of State-level Health Inequalities: National Health Interview Survey, 2013-2015. AB - To describe methodological issues that arise in the construction and design-based estimation of multidimensional indices that aggregate state-specific inequalities in core health measures, using data from the National Health Interview Survey (NHIS). PMID- 30248011 TI - Health Care Access and Utilization Among Native Hawaiian and Pacific Islander Persons in the United States, 2014. AB - : The body of nationally representative health statistics for the Native Hawaiian and Pacific Islander (NHPI) population is limited, because even the largest health surveys generally do not have an adequate NHPI sample to calculate reliable NHPI statistics. Using data from the Native Hawaiian and Pacific Islander National Health Interview Survey (NHPI NHIS) from the National Center for Health Statistics (NCHS), this report fills this gap by presenting statistics on health care access and utilization for (a) the total NHPI population and the multiple- and single-race NHPI populations in comparison with other federal race groups and the total U.S. population; (b) single-race NHPI persons compared with multiple-race NHPI persons; and (c) detailed NHPI race groups in comparison with each other and the total U.S. POPULATION: PMID- 30248014 TI - National Hospital Care Survey Demonstration Projects: Pneumonia Inpatient Hospitalizations and Emergency Department Visits. AB - This report demonstrates the use of the National Hospital Care Survey (NHCS) for the study of pneumonia inpatient hospitalizations and emergency department (ED) visits. The analysis is based on unweighted data of inpatient and ED encounters from the 2014 NHCS and is intended to illustrate the capabilities of the survey, including the ability to link inpatient hospitalizations or ED visits across settings and with other data sources, once hospital participation allows for nationally representative estimates. PMID- 30248012 TI - Data Quality Assessment of the 2014 Native Hawaiian and Pacific Islander National Health Interview Survey. AB - The 2014 Native Hawaiian and Pacific Islander National Health Interview Survey (NHPI NHIS) is the first federal survey designed exclusively to measure the health of the noninstitutionalized civilian NHPI population of the United States. PMID- 30248015 TI - Deaths: Final Data for 2016. AB - This report presents final 2016 data on U.S. deaths, death rates, life expectancy, infant mortality, and trends, by selected characteristics such as age, sex, Hispanic origin and race, state of residence, and cause of death. PMID- 30248016 TI - National Center for Health Statistics Data Presentation Standards for Proportions. AB - The National Center for Health Statistics (NCHS) disseminates information on a broad range of health topics through diverse publications. These publications must rely on clear and transparent presentation standards that can be broadly and efficiently applied. Standards are particularly important for large, cross cutting reports where estimates cannot be individually evaluated and indicators of precision cannot be included alongside the estimates. This report describes the NCHS Data Presentation Standards for Proportions. The multistep NCHS Data Presentation Standards for Proportions are based on a minimum denominator sample size and on the absolute and relative widths of a confidence interval calculated using the Clopper-Pearson method. Proportions (usually multiplied by 100 and expressed as percentages) are the most commonly reported estimates in NCHS reports. PMID- 30248018 TI - The U.S. National Vital Statistics System: Transitioning Into the 21st Century, 1990-2017. AB - This report describes the history of the National Vital Statistics System, with a focus on the period 1990-2017. The vital statistics system is the country's most enduring program of data collection on the health of the population. It is based on information reported on the certificates of births and deaths and reports of fetal deaths, collected in each of the states and independent registration areas. Over the last two decades, the vital statistics system has experienced far reaching changes, and has shifted in important ways to emphasize data quality, timeliness, and analysis. The changes underlying these areas are described. PMID- 30248017 TI - Deaths: Leading Causes for 2016. AB - This report presents final 2016 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements "Deaths: Final Data for 2016," the National Center for Health Statistics' annual report of final mortality statistics. PMID- 30248019 TI - Advance Directive Documentation Among Adult Day Services Centers and Use Among Participants, by Region and Center Characteristics: National Study of Long-Term Care Providers, 2016. AB - This report describes the percentage of adult day services centers (ADSCs) that typically maintain documentation of participants' advance directives by region and center characteristics. Further, among ADSCs that maintain documentation, this report describes the percentage of participants with advance directives by region and center characteristics. PMID- 30248021 TI - Final results from the REPRISE I study: five-year clinical outcomes with the repositionable and fully retrievable LOTUS valve system. PMID- 30248022 TI - Graphene/transition metal dichalcogenides hybrid supercapacitor electrode: status, challenges, and perspectives. AB - Supercapacitors, based on fast ion transportation, are among the most promising energy storage solutions that can deliver fast charging-discharging within seconds and exhibit excellent cycling stability. The development of a good electrode material is one of the key factors in enhancing supercapacitor performance. Graphene (G), an allotrope of carbon that consists of a single layer of carbon atoms arranged in a hexagonal lattice, elicits research attention among scientists in the field of energy storage due to its remarkable properties, such as outstanding electrical conductivity, good chemical stability, and excellent mechanical behavior. Furthermore, numerous studies focus on 2D materials that are analogous to graphene as electrode supercapacitors, including transition metal dichalcogenides (TMDs). Recently, scientists and researchers are exploring TMDs because of the distinct features that make 2D TMDs highly attractive for capacitive energy storage. This study provides an overview of the structure, properties, synthesis methods, and electrochemical performance of G/TMD supercapacitors. Furthermore, the combination of G and TMDs to develop a hybrid structure may increase their energy density by introducing an asymmetric supercapacitor system. We will also discuss the future prospect of this system in the energy field. PMID- 30248024 TI - Modified Finke-Watzky mechanisms for the two-step nucleation and growth of silver nanoparticles. AB - In this work, a new modification was made on the Finke-Watzky mechanism for investigating the nucleation and growth steps in the synthesis of silver nanoparticles (AgNPs). UV-vis spectrophotometry and transmission electron microscopy evaluations proved that the former linear form of Finke-Watzky mechanism is not efficient for describing the nucleation and growth steps of AgNPs synthesis. In this manner, the Finke-Watzky mechanism was modified by considering a reversible pseudo first-order reaction for nucleation step. In addition, no assumptions were made in mathematical calculations related to the rate law which were previously adapted by the researchers in this field; i.e. [A]0 > [A] and k 2[A] ? k 1. These considerations led to the development of a kinetic model that is more closely related to what really occurs within the synthesis system. Kinetics data were obtained in a well-known synthesis process of AgNPs namely as sodium borohydride reduction. Furthermore, it was elucidated that polyvinylpyrrolidone (PVP) retards both the nucleation and growth steps resulting in the isotropic growth of seeds; this effect subtly provides a tunable synthesis process for achieving desired size of AgNPs. Moreover, Fourier transform infrared spectroscopy revealed that the nitrogen atoms present in the PVP molecules are responsible for the interaction of PVP with AgNPs. PMID- 30248020 TI - Medium-Term Results of Percutaneous Pulmonary Valve Implantation using The Venus P-valveTM: international experience. AB - AIMS: To assess international procedural and short to medium-term experience with the new percutaneous Venus P-ValveTM. METHODS AND RESULTS: Retrospective data collection of patient characteristics, clinical and imaging follow-up of Venus P valveTM implantation outside China. Thirty-eight patients had attempted Venus P valve implantation between October 2013 and April 2017. Thirty-seven valves were successfully implanted during 38 procedures. There was one unsuccessful attempt and 2 valve migrations, one of which required surgical repositioning. The mean follow up was 25 months with no short or mid-term valve failure or deterioration in performance. ?Frame fractures occurred in 27% patients. The cohort demonstrated a statistically significant reduction in pulmonary regurgitation fraction and indexed right ventricular diastolic volumes at 6 and 12 months. CONCLUSIONS: Implantation of the Venus P-ValveTM has provided satisfactory short to mid-term results with high success and low complication rates in an inherently challenging patient substrate. PMID- 30248023 TI - MgCl2 passivated ZnO electron transporting layer to improve PbS quantum dot solar cells. AB - The unique tunable bandgaps and straightforward synthesis of colloidal quantum dots make them promising low-cost materials for photovoltaics. High-performance colloidal quantum dot solar cells rely on good-quality electron transporting layers to make carrier selective contacts. Despite extensive use of n-type oxides as electron transporting layers, a detailed understanding of their surface and interface states as well as mechanisms to improve their optical properties are still under development. Here, we report a simple procedure to produce MgCl2 passivated ZnO nanoparticles electron transporting layers that show improved device performance. The MgCl2 treated ZnO electron transporting layers boost the PbS colloidal quantum dot cell efficiency from 6.3% to 8.2%. The cell exhibits reduced defects leading to significant improvements of both FF and Jsc. This low-temperature MgCl2 treated ZnO electron transporting layer may be applied in solution processed tandem cells as a promising strategy to further increase cell efficiencies. PMID- 30248026 TI - Epicardial adipose tissue thickness as a new risk factor for atherosclerosis in patients with ankylosing spondylitis. AB - PURPOSE: The aim of this study was to compare epicardial adipose tissue thickness (EATT), which is a novel cardiometabolic risk factor in patients with ankylosing spondylitis (AS), and carotid intima media thickness (CIMT) with healthy controls to assess the relationship between these markers and disease activity. MATERIALS AND METHODS: This study involved 38 patients with AS and 38 controls with no history of cardiovascular disease. CIMT was measured by Doppler ultrasound, and EATT by echocardiography, in all participants. Total cholesterol (TC), low density lipoprotein (LDL) cholesterol, high density lipoprotein cholesterol, triglycerides, thyroid stimulating hormone, erythrocyte sedimentation rate, C reactive protein, and hemogram measurements were performed in all subjects after 8 hours of fasting. In addition, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI) scores of the patients with AS were recorded. RESULTS: EATT was significantly higher in patients with AS (0.45 +/- 0.17 mm) compared with healthy (0.37 +/- 0.10 mm) controls (p= 0.01). Significant positive correlations were detected between EAT thickness and BASFI, CIMT, and disease duration in patients with AS (p= 0.008, p= 0.024, and p= 0.012, respectively). Significant negative correlations were observed between EATT and TC and LDL cholesterol concentrations (p= 0.016 and p= 0.009, respectively). No significant difference was detected in CIMT between the patients (0.515 +/- 0.08 mm) and the controls (0.517 +/- 0.094 mm, p= 0.98). No significant correlation was observed between CIMT of the patients with AS and the BASDAI, BASFI, TC, HDL cholesterol, systolic blood pressure, or diastolic blood pressure values. Significant positive correlations were observed between CIMT and waist circumference, weight, body mass index, and LDL cholesterol in patients with AS and the controls. CONCLUSIONS: This study demonstrated increased EATT in patients with AS compared with a healthy population, which was positively correlated with disease duration and BASFI. PMID- 30248025 TI - Fast turnaround fabrication of silicon point-contact quantum-dot transistors using combined thermal scanning probe lithography and laser writing. AB - The fabrication of high-performance solid-state silicon quantum-devices requires high resolution patterning with minimal substrate damage. We have fabricated room temperature (RT) single-electron transistors (SETs) based on point-contact tunnel junctions using a hybrid lithography tool capable of both high resolution thermal scanning probe lithography and high throughput direct laser writing. The best focal z-position and the offset of the tip- and the laser-writing positions were determined in situ with the scanning probe. We demonstrate <100 nm precision in the registration between the high resolution and high throughput lithographies. The SET devices were fabricated on degenerately doped n-type >1020/cm3 silicon on insulator chips using a CMOS compatible geometric oxidation process. The characteristics of the three devices investigated were dominated by the presence of Si nanocrystals or phosphorous atoms embedded within the SiO2, forming quantum dots (QDs). The small size and strong localisation of electrons on the QDs facilitated SET operation even at RT. Temperature measurements showed that in the range 300 K > T > ~100 K, the current flow was thermally activated but at <100 K, it was dominated by tunnelling. PMID- 30248027 TI - Balance and fall risk in peritoneal dialysis patients. AB - BACKGROUND: Vestibular, neurological and musculoskeletal functions are affected in patients with renal failure. These problems can in turn affect the balance system in peritoneal dialysis (PD) patients. Previously, postural balance changes were shown in hemodialysis patients. This is the first study that evaluates whether there are similar changes in patients with PD. OBJECTIVE: This study aimed to compare balance and fall risk between patients undergoing PD treatment and healthy subjects, and aimed to determine the correlation between biochemical parameters and fall risk and balance assessments in PD patients. METHODS: This controlled study included 58 patients receiving PD treatment (PD Group) and 75 healthy subjects (Control Group). The Berg Balance Scale (BBS) and Tetrax(r) Interactive Balance System were used for the comparison of balance between groups. For patients in the PD Group, duration of PD, blood pressure, Kt/Vurea (actual mass of urea removed via peritoneal dialysis), and serum biochemical parameters were recorded and correlation analysis was performed between these parameters and balance measurements. RESULTS: There were no statistically significant differences between groups in terms of demographics or BBS scores (p> 0.05). The fall risk of patients in the PD Group was significantly higher than those in the Control Group (p< 0.0001) according to Tetrax measurements. Female gender, older age, higher BMI, and higher blood glucose levels were negatively correlated with balance parameters of PD patients (r> 0.3). There was no statistically significant correlation between duration of PD, blood pressure, and Kt/Vurea with balance parameters or fall risk. CONCLUSIONS: Balance was impaired in patients undergoing PD in comparison to healthy subjects. Fall risk may be evaluated using the Tetrax(r) instead of BBS for this population. Serum glucose level, BMI and age appear to affect balance and fall risk. Therefore, optimization of body weight and normalization of serum glucose levels are important factors for improving balance. The duration of PD, blood pressure, and Kt/Vurea do not affect balance system. PMID- 30248028 TI - Effect of core training on dynamic balance and agility among Indian junior tennis players. AB - BACKGROUND: The effect of core training on dynamic balance and agility has yet to be established in literature, especially among junior athletes. OBJECTIVE: To investigate the effect of core training on dynamic balance and agility among Indian junior tennis players. METHOD: Thirty junior tennis players from various parts of Delhi and the national capital region participated in the study. The study featured a pre-test/post-test experimental design. The subjects were divided into the experimental group (mean age = 15.20 +/- 0.41, mean BMI = 20.23 +/- 1.54) and the control group (mean age = 15.53 +/- 1.06, mean BMI = 20.71 +/- 1.53). The control group performed regular training, and the experimental group followed a five-week core training program along with regular training. The subjects were evaluated with t-test for agility and the Star Excursion Balance Test (SEBT) for dynamic stability. RESULTS: A significant difference was found in the post-test values of agility (t-test p= 0.000) and dynamic balance using SEBT ((anterolateral; p= 0.00), (lateral; p= 0.02), (posterolateral; p= 0.00), (posterior; p= 0.00), (posteromedial; p= 0.01), (medial; p= 0.03), and (anteromedial; p= 0.03)] except in the anterior direction (p= 0.23)) between the experimental and the control group. The experimental group showed a significant difference in the pre- and post-test values of the t-test and SEBT except in the anterior direction. CONCLUSION: Core training programs can be incorporated safely with players' regular training to improve their dynamic balance and agility, which can eventually lead to better performance. PMID- 30248030 TI - Short-term effects of the suboccipital muscle inhibition technique and cranio cervical flexion exercise on hamstring flexibility, cranio-vertebral angle, and range of motion of the cervical spine in subjects with neck pain: A randomized controlled trial. AB - BACKGROUND: Cervical spinal instability often leads to neck pain and forward head posture (FHP). To improve neck pain and FHP, both the suboccipital muscle inhibition (SMI) technique and cranio-cervical flexion exercise (CCFE) have been used. However, little is known regarding the validity of hamstring flexibility in neck pain subjects after CCFE as a treatment index, and comparison between the SMI technique and CCFE for neck pain treatment. OBJECTIVE: This study aimed to determine the short-term effects of SMI technique and CCFE, which represent passive and active exercise programs, respectively, and whether these improve the straight leg raise (SLR) test results, popliteal angle (PA), cranio-vertebral angle (CVA), and cervical range of motion (CROM) and are equally effective in immediate enhancement of such measures in neck pain subjects. METHODS: Twenty subjects with neck pain were randomly allocated to the SMI and CCFE groups (n= 10 each). The outcomes were evaluated via clinical evaluation and SLR, PA, CVA, and CROM measurement before and after intervention. RESULTS: SLR test results, PA, CVA (sitting and standing), and CROM (flexion, extension, lateral flexion, and right and left rotations) after both interventions were significantly higher than those before the interventions (P< 0.05). The SLR test results (left), PA, and CVA (standing) after the SMI technique improved to levels similar to those observed after CCFE. CONCLUSIONS: Both the SMI technique and CCFE improve SLR test results, PA, CVA, and CROM and are equally effective in immediate enhancement of the hamstring flexibility, CVA, and CROM in subjects with neck pain. PMID- 30248029 TI - The approach of physiatrists to low back pain across Europe. AB - BACKGROUND: Low back pain (LBP) is the most common type of musculoskeletal pain, thus it is one of the most commonly encountered conditions in Physical and Rehabilitation Medicine. The physicians who are primarily responsible for the nonsurgical management of LBP are physiatrists. OBJECTIVE: The present study aimed to investigate the approaches of physiatrists to low back pain across Europe. Preferences, tendencies, and priorities in the diagnosis, management, and treatment of LBP, as well as the epidemiological data pertaining to LBP in PRM practice were evaluated in this Europe-wide study. METHODS: The study was conducted under the control of the European Society of Physical and Rehabilitation Medicine (ESPRM) Musculoskeletal Disorders Research Committee. A total of 576 physiatrists from most European countries participated in the survey. RESULTS: The results show that physiatrists frequently deal with patients with LBP in their daily practice. Most patients are not referred to other departments and are treated with various conservative methods. Less than one fifth of patients are primarily referred for surgery. The physiatrists believe that a clear diagnosis to account for cases of low back pain is rarely established. The most common diagnosis is discopathy. History and physical examination remain the most valuable clinical evaluation tools for low back pain according to physiatrists. Less than half the patients require a magnetic resonance imaging. Non-steroidal anti-inflammatory drugs are the most commonly prescribed drugs for low back pain. Exercise, back care information, and physical therapy are the preferred conservative treatments. More than half of the physiatrists offer interventional treatments to patients with low back pain. CONCLUSION: The present study is a preliminary report that presents the attitudes of European physiatrists in the management of low back pain. Further researches are warranted to standardize the conservative management of LBP. PMID- 30248031 TI - Comparison of vascular arterial stiffness parameters of adolescent wrestlers with healthy subjects: Is heavy training harmful for wrestlers? AB - BACKROUND: The effect of different exercise modalities on the vascular structure has been the subject of clinical trials but there is not enough data about wrestlers. OBJECTIVE: This study aimed to compare the arterial stiffness parameters in adolescent wrestlers with those of age-matched sedentary controls to show the effects of long and heavy training. METHODS: This study was carried out as a case-control study. Thirty three elite male adolescent wrestlers (12-18 years) and 35 age and sex-matched control subjects (P= 0.438) with a sedentary lifestyle were included the study. The data was obtained by using sonography and a sphygmomanometer. Systolic and diastolic diameters and intima media thickness (IMT) measurements were performed from the carotid arteries of the subjects. The arterial tension was measured in the same session, and arterial stiffness parameters were calculated using specific formulas. RESULTS: The age range was 15.9 +/- 0.9 years and 16.0 +/- 0.8 years for the wrestlers and control subjects, respectively. Statistically, the Body Mass Index (BMI) was significantly higher in wrestlers (BMI mean = 23.7 +/- 4.0 kg/m2; P= 0.00). The groups had no difference in height (P= 0.80) and weight (P= 0.05). The systolic blood pressure (SBP) was significantly higher in wrestlers (SBP = 120 +/- 13.4 mmHg; P= 0.00); the pulse was significantly lower in wrestlers (pulse = 69.61 +/- 17.2 beats/min; P= 0.00); the IMT was significantly lower in wrestlers (IMT mean = 0.288 +/- 0.1 mm; P= 0.01); the diastolic wall stress (DWS) was significantly higher in wrestlers (DWS mean = 933.64 +/- 298.0 mmHg; P= 0.03) than controls. No significant differences were found in the elastic modulus (P= 0.11), compliance (P= 0.86), and distensibility (P= 0.86) values between the groups. CONCLUSION: Bradycardia is an expected condition for sportsmen. SBP and DWS were found to be high in wrestlers, suggesting that arterial tissue is more susceptible to stress. The low IMT indicates the protective effect of regular exercise against atherosclerosis. It is known that regular exercise is a good thing for the vascular structure of individuals who have a sedentary lifestyle, while heavy exercise puts a load on the vascular structure. The fact that the elastic modulus, compliance, and distensibility do not differ between the groups suggests that structural changes in the adolescents have no effect on the vascular wall. PMID- 30248033 TI - Tragus-to-wall: A systematic review of procedures, measurements obtained, and clinimetric properties. AB - OBJECTIVE: Our purpose was to summarize the literature on the applicability, procedures for performing, and clinimetric findings related to the measurement of tragus-to-wall (TTW) distance. METHOD: Pubmed, Scopus, and CINAHL databases were systematically searched using the key words "tragus" AND "wall". Articles were examined for information on the participants whose TTW distance was measured, the procedures used for measuring TTW, and findings regarding TTW distances measured and the clinimetric properties of the measurements. RESULTS: Thirty-nine articles were identified that described use of the TTW test. Most used the test with patients with ankylosing spondylitis. We found evidence for the convergent and known groups validity and reliability of the TTW measurements. Limited support for the responsiveness of TTW measurements was found. Two studies provided normative reference values. CONCLUSIONS: The TTW test is a simple objective indicator of forward flexed posture supported by research on its validity and reliability. More specific information on responsiveness and age-specific norms would increase the value of this nonspecific postural indicator. PMID- 30248032 TI - Prevalence of musculoskeletal disorders in patients with diabetes mellitus: A systematic review and meta-analysis. AB - BACKGROUND: Diabetes mellitus (DM) is associated with musculoskeletal disorders (MSDs) and is often not clinically diagnosed and managed. There are also no systematic reviews of literature relating to the prevalence of MSDs among people with diabetes. OBJECTIVE: To determine the prevalence and areas of the body affected by MSDs in diabetic patients. METHODS: A literature search of the electronic databases of CINAH, PubMed, Web of Science and Google Scholar using the keywords of "MSDs and DM" as the search term was conducted. Pooled estimates were calculated using a meta-analysis of proportion. RESULTS: Five thousand and eighty-eight studies were identified from the databases; 21 studies fulfilled the inclusion criteria and were included in the review. Five studies were of high quality, 13 were of moderate quality and three were of low quality. The prevalence of all types of MSDs among patients with diabetes was 58.15% (95% CI 41.4%-73.9%). The hand was the most common area of the body affected being 33.05% (95% CI 21.1-46.13) followed by the shoulder. CONCLUSIONS: A high prevalence of MSDs was found among diabetic patients with the hand and shoulder being the most frequently reported areas affected. However, future studies with a larger sample and the relevant type of diabetes are required. PMID- 30248034 TI - The effect of burn severity on functional capacity in patients with burn injury. AB - BACKGROUND: Burns are traumatic injuries that result in severe tissue damage. A reduction in exercise capacity is the most common functional impairment, although it is not clear to what extent the severity of the burn injury affects the exercise capacity. OBJECTIVE: The aim of this study was to examine the physiological responses to exercise and to evaluate exercise capacity according to burn severity. METHODS: The study included a total of 64 burn patients, comprising 33 with moderate injuries (Total body surface area: 9.93 +/- 4.73%; mean age: 37 +/- 11.93 years) and 31 with major injuries (Total body surface area: 39.03 +/- 10.36%; mean age: 41.09 +/- 14.96 years). Heart rate, systolic blood pressure, diastolic blood pressure, double product, dyspnea level, oxygen saturation and leg fatigue before and after the shuttle walk test were recorded. Walking distances were measured after the shuttle walk test. RESULTS: A significant difference was determined between patients with major and moderate burn injuries in respect of the cardiovascular responses to the shuttle walk test. Major burn injury patients had a significantly shorter walking distance than the moderate burn injury patients (p< 0.05). CONCLUSIONS: Burn injury severity was seen to affect the functional capacity and cardiovascular responses to the shuttle walk test. Shuttle walk test can be preferred to evaluate moderate and major burn injury patients' functional capacity in the acute period of injury. PMID- 30248035 TI - Treatment of disability associated with chronic non-specific low back pain using core stabilization exercises in pakistani population. AB - BACKGROUND: Chronic non-specific low back is the most common musculoskeletal complaint that significantly affects the general population. Exercises are advocated as the main part of treatment for chronic low back pain. OBJECTIVE: The purpose of this study was to compare the effects of workouts of the core musculature and routine physical therapy exercise training for the treatment of disability caused by chronic low back pain. METHODS: In this single-blinded, randomized, controlled trial, 120 patients with non-specific low back pain were examined in Lahore, Pakistan. They were randomly allocated into treatment groups A and B. Group A performed core stabilization workouts and Group B had routine physical therapy. The Oswestry Disability Index (ODI) was used to evaluate the outcome of each treatment. Statistical analysis was performed using SPSS v16.0 and a p-value < 0.05 was considered significant. RESULTS: Significant reduction in disability was observed in both groups at the end of the second, fourth, and sixth week of treatment (p-value < 0.05). The mean reduction in disability as measured by ODI score was 39.44 +/- 14.64 for Group A and 31.91 +/- 12.31 for Group B. CONCLUSION: A larger reduction in disability was observed for subjects treated with core stabilization exercises in comparison to those treated with routine physical therapy. PMID- 30248036 TI - Does rigid spinal orthosis carry more psychosocial implications than the flexible brace in AIS patients? A cross-sectional study. AB - BACKGROUND: A small body of data exists concerning psychosocial issues in adolescent idiopathic scoliosis (AIS) subjected to soft braces. No study was yet performed on the detailed psychosocial implications in AIS patients. OBJECTIVE: To compare the psychosocial implications of the flexible SpineCor with the Cheneau orthosis in AIS females. METHODS: Patients (aged 10-18 years) deliberately assigned to undergo SpineCor (SC group, 30 patients) or Cheneau brace (Ch group, 41 patients) intervention completed the Scoliosis Research Society-22 (SRS-22), the Spinal Appearance Questionnaire (SAQ), the Brace Questionnaire (BrQ) and the Pediatric Outcomes Data Collection Instrument (PODCI). RESULTS: Concerning the BrQ, study groups differ in regards to emotional functioning (p= 0.014), vitality (p= 0.022) and social functioning (p= 0.048), indicating better functioning in the Ch group. Considering the SAQ, the Ch group assesses body curve (p= 0.024) less critically. Regarding the PODCI, the Ch group scored higher in the Global Functioning Scale (p= 0.023), the Upper Extremity and Physical Function Scale (p= 0.000), the Transfer and Basic Mobility Scale (p= 0.088), the Pain/Comfort Scale (p= 0.009) and the Happiness Scale (p= 0.022). CONCLUSIONS: This study shows that patients treated with the rigid brace assess their vitality, physical function, emotional and social functioning better and are less critical towards body curve, in comparison to patients treated with the SpineCor. PMID- 30248037 TI - Evaluation of balance after surgery for cerebellopontine angle tumor. AB - BACKGROUND: The origin of about 10% of tumors located in the intracranial region is the cerebellopontine angle. Therefore Cerebellopontine Angle (CPA) tumors affect patients' balance. OBJECTIVE: The aim of this study was to compare the balance in individuals who underwent surgery for CPA tumors with healthy individuals. METHODS: Thirty patients who were being followed-up by the Department of Neurosurgery and had been operated on CPA tumor and 31 healthy individuals were included in the study as group 1 and group 2, respectively. The participants were evaluated using Romberg Test, Sharpened Romberg Test, One-leg Stance (OLS), Tandem Walking, Walk Across, Berg Balance Scale (BBS), Dizziness Handicap Inventory (DHI) and Short Form 36 (SF-36). RESULTS: In comparison of the groups, OLS tests (p< 0.001), BBS (p< 0.05) and DHI (p< 0.05) were significantly different in favor of healthy group. SF-36 results revealed a significant difference between the groups, except for Bodily Pain and Vitality (p< 0.05). CONCLUSIONS: The results of this study demonstrated a decrease in balance parameters and quality of life in individuals who underwent CPA tumor surgery in comparison to healthy individuals. Evaluation of balance in the preoperative and postoperative period should not be ignored in these patients and they are suggested to start rehabilitation in the early postoperative period. PMID- 30248040 TI - Comparison of effectiveness of the home exercise program and the home exercise program taught by physiotherapist in knee osteoarthritis. AB - BACKGROUND: Home-based exercise therapy is effective in reducing pain and improving function in adults with osteoarthritis of the knee. OBJECTIVE: To investigate and compare the effectiveness of the home exercise program and the home exercise program taught by a physiotherapist in knee osteoarthritis. METHODS: The study was conducted with 80 patients with knee osteoarthritis. The patients were randomized into two groups. The first group was given the home exercise brochure by the orthopedist, while the second group did home exercises under the guidance of the physiotherapist. The goniometer for the range of motion (ROM) of the knee, Myometer for evaluation of the quadriceps and hamstring muscles strength, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Short Form Health Survey (SF-36) were used for evaluation. RESULTS: Statistically significant improvements were found in the post-treatment ROM, VAS, quadriceps and hamstring muscles strength, WOMAC and SF-36 values in both groups (p< 0.05). When the change values were compared, the evaluation results of group II were better than group I statistically (p< 0.05). CONCLUSIONS: This study proved that home exercises taught by a physiotherapist were more useful for patients with knee osteoarthritis. When the home exercise program is implemented, a new role is created for a physiotherapist. PMID- 30248043 TI - Turkish validity and reliability of the patient satisfaction scale in physiotherapy for patients with musculoskeletal pain. AB - BACKGROUND: Patient satisfaction is a key point in evaluating the quality of physiotherapy services. OBJECIVE: The aim of this study was to determine the Turkish language validity and reliability of the Patient Satisfaction Scale in Physiotherapy (PSSP). METHODS: The study included 168 participants, aged 18-74 years, with musculoskeletal pain. The PSSP, which comprises 14 items in the four sub-dimensions of treatment, admission, logistics and general satisfaction, was applied to all participants. Structural validity was assessed using the principal components method with varimax rotation. Internal consistency and the intraclass correlation coefficient (ICC) were used for the reliability analysis. The Patient Satisfaction Scale for Physical Therapy Outpatient Clinics (PCCPTO) was used to assess concurrent validity. RESULTS: The participants comprised of 71% females and 29% males with a mean age of 41.9 +/- 14.9 years. The sampling competency index was 0.874. The Turkish version of the scale was found to be perfectly reliable (Cronbach's alpha reliability coefficient = 0.922). Internal consistency ranged from 0.762 to 0.904 in the subscales. Factor analysis revealed that the 14 item scale had four factors explaining 75.59% of the total variance. Floor and ceiling effects were not determined. Concurrent validity analysis showed a strong correlation between the PSSP and PCCPTO (r= 0.78; p< 0.0005). CONCLUSION: The Turkish version of the PSSP is a valid, reliable and easily applicable measure. PMID- 30248041 TI - Evaluation of rational drug use knowledge level in patients with musculoskeletal disorders. AB - BACKGROUND: For treatment of chronic musculoskeletal disorders pains to be successful, drug interventions are required. OBJECTIVE: In this study, we aimed to evaluate the Rational Drug Use Knowledge Level (RDUKL) in patients with musculoskeletal disorders and some relevant factors. METHOD: The study was carried out in October 2017 on patients treated in the Physical Therapy Rehabilitation Hospital in Turkey. The prepared questionnaire and RDUKL scale were administered to 239 patients by face-to-face interviews. The ANOVA test, chi squared test and logistic regression model were used for the statistical evaluation. RESULTS: Forty-three percent of the study group was found to have Rational Drug Use Knowledge (RDUK). The patients who used medicines under family supervision had twice as much RDUK as those who did not use medicines under family supervision, and those who were university graduates had six times as much RDUK as those who had primary education or below. Scale score was found to be low in patients with fibromyalgia and high in patients with rheumatoid arthritis (p< 0.05). CONCLUSION: RDUKL was found to be low in the group with chronic diseases and high average age. Besides training, it is important to provide patients with family support about their illness and its treatment. Thus, positive contributions can be made to the increase of the RDUKL. PMID- 30248042 TI - Comparison of responsiveness of Michigan Hand Outcomes Questionnaire, Disabilities of the Arm, Shoulder and Hand Questionnaire, and Duruoz Hand Index in patients with traumatic hand injury. AB - OBJECTIVE: Patient-reported outcome measures assessing self-reported disability, pain, and function are primary endpoints for determination of optimal treatment strategies in hand-related conditions. In this study, we aimed to compare responsiveness of Michigan Hand Outcomes Questionnaire (MHQ), Disabilities of the Arm, Shoulder and Hand Questionnaire (DASH), and Duruoz Hand Index (DHI) in patients with traumatic hand injury. METHODS: Consecutive patients with traumatic hand injury who were referred to our polyclinic for rehabilitation were included in the study. Depending on clinical status, patients underwent at least 14 sessions of physical therapy consisting of infrared heating, water submersion ultrasound, electrical stimulation, and exercise. MHQ, DASH, and DHI questionnaires were filled in by all patients both before and 3 months after physical therapy. RESULTS: A total of 60 patients were enrolled in the study. MHQ (ES =-1.89; SRM =-1.84), DASH (ES = 1.66; SRM = 1.40), and DHI (ES = 1.68; SRM = 1.48) were all highly responsive in traumatic hand injuries. CONCLUSION: Our study demonstrated that MHQ, DASH, and DHI are very responsive questionnaires for detection of treatment-induced changes in patients with traumatic hand injury. We suggest that when it is only intended to assess hand disability or when a quick assessment is desirable, DASH or DHI are more suitable, whereas MHQ will be more useful when a more detailed assessment including pain and aesthetical concerns is required. PMID- 30248044 TI - Upregulated FFAR4 correlates with the epithelial-mesenchymal transition and an unfavorable prognosis in human cholangiocarcinoma. AB - BACKGROUND: Free fatty acid receptor 4 (FFAR4) is associated with the epithelial mesenchymal transition (EMT) and is involved in the progression of several types of cancer. However, the role of FFAR4 in cholangiocarcinoma (CCA) remains unclear. OBJECTIVE: The present study evaluated the diagnosis and prognosis of CCA using FFAR4 as a biomarker. METHODS: Immunohistochemistry was employed to detect expression of FFAR4 in 98 samples of CCA tissues and adjacent tissues. In addition, expression of E-cadherin, vimentin, Snail-1, CK7 and CK19 in the 98 samples of CCA tissues was detected, and relationships with FFAR4 were analyzed. Correlation between FFAR4 and clinical pathological factors and prognosis was also analyzed. RESULTS: FFAR4 was highly expressed in 72.4% (71/98) of CCA tissues and 29.6% (29/98) of adjacent tissues, with a statistically significant difference between the two tissue types (P< 0.05). A negative correlation between high expression FFAR4 and E-cadherin expression in CCA tissues was also observed (r=-0.445, P< 0.001), and high expression of FFAR4 was positively correlated with vimentin (r= 0.354, P< 0.001), Snail-1(r= 0.496, P< 0.001), CK7(r= 0.494, P< 0.001) and CK19 (r= 0.532, P< 0.001). Moreover, the degree of FFAR4 expression was associated with aggressive clinicopathological characteristics, such as histological grade, perineural invasion (PNI), lymph node metastasis (LNM), advanced TNM stage and preoperative serum CA19-9 level (P< 0.05). In terms of prognosis, CCA patients with high FFAR4 expression showed shorter disease-free survival (DFS) (P< 0.05) and overall survival (OS) (P< 0.05) than did patients with low FFAR4 expression. CONCLUSIONS: FFAR4 overexpression may mediate the process of CCA EMT. In addition, FFAR4 is promising as a new diagnostic molecule and therapeutic target for CCA. PMID- 30248038 TI - Trunk and pelvic alignment in relation to postural control in children with cerebral palsy. AB - BACKGROUND: Trunk pelvic mal-alignment and postural control deficit are common problems facing children with cerebral palsy. OBJECTIVE: The aim of this study was to investigate the relation of trunk and pelvic alignment with postural control in children with diplegic cerebral palsy. METHODS: Seventy seven children with spastic diplegic cerebral palsy (CP), aged 6 to 8 years with level II on Gross Motor Function Classification System, participated in this study. Trunk imbalance, lateral deviation of the spine and pelvic tilt were evaluated by using Formetric instrumentation system while postural control was assessed by using Pediatric Balance Scale. RESULTS: The results showed that there is a moderate negative correlation of trunk imbalance, lateral deviation of the spine and pelvic tilt with postural control (-0.44, -0.59 and -0.57, respectively). CONCLUSIONS: Increased trunk imbalance, lateral deviation of the spine and pelvic tilt may be associated with decreased postural control ability in children with diplegic CP. PMID- 30248039 TI - The effect of mulligan mobilization on pain and life quality of patients with Rotator cuff syndrome: A randomized controlled trial. AB - BACKGROUND: Mulligan mobilization techniques cause pain and affect the function in patients with Rotator cuff syndrome. OBJECTIVE: The aim of the study was to investigate the effect of Mulligan mobilization on pain and quality of life in individuals with Rotator cuff syndrome. METHODS: This study was conducted on 30 patients with Rotator cuff syndrome. The patients were randomized into Mulligan and control group. All the patients participating in this study were treated with conventional physiotherapy. Additionally, the Mobilization with movement (MWM) technique was used in the Mulligan group. Visual Analog Scale (VAS), Disabilities of the Arm, Shoulder, and Hand (DASH), goniometer for the normal range of motion (ROM) and Short Form-36 (SF-36) questionnaires were used for assessment. RESULTS: Statistically significant improvement was found in the post-treatment VAS, DASH, SF-36, and ROM values significantly improved in both groups (p< 0.05). However, the Mulligan group showed much better results when compared to the control group in ROM, VAS, DASH (p< 0.05). In the SF-36 questionnaire, significant results were obtained for both groups, except the social function parameter. For the SF-36 parameters, both groups performed equally. CONCLUSIONS: Mulligan mobilization was more effective than general treatment methods for pain as well as normal joint motion, DASH scoring and some parameters of SF-36 compared with general treatment methods. PMID- 30248045 TI - Attenuated total reflectance spectroscopy to diagnose skin cancer and to distinguish different metastatic potential of melanoma cell. AB - Early diagnosing of skin cancer and investigation of metastatic potential of cancer cells are very important to treat it appropriately. Infrared spectroscopy of biological tissues is an emerging technique which gives the spectral differences between healthy and diseased cells. In this work, we have demonstrated that attenuated total reflectance Fourier transform (ATR-FTIR) spectroscopy can be used in diagnostic of skin cancer and in differentiating metastatic potential of cancer cells. Using IR spectroscopy, we can identify various types of cancer such as basal cell carcinoma, malignant melanoma, nevus and metastatic potential by alternations in hydration level and molecular changes. We examined biopsy of different types of cancer cells to diagnose skin cancer at early stages by using FTIR spectroscopy. To differentiate metastases we examined two human melanoma cells of same patient but at different metastatic potential and two murine melanoma cells with common genetic background but different metastatic potential. Our findings revealed that melanoma changes the permeability of cell membrane and higher metastatic potential is related to the hydration level of cell membrane. Thus, ATR-FTIR spectroscopy is a potential technique to help in early diagnosing of skin cancer and to differentiate different metastatic potentials. PMID- 30248046 TI - The clinicopathological significance of CD133 and Sox2 in Astrocytic glioma. AB - BACKGROUND: The treatment strategies of astrocytoma have not changed considerably due to the restricted appreciation of its biology. OBJECTIVES: This study aimed to evaluate the expression of the stem cell-related proteins (CD133 and Sox2) and their prognostic value in astrocytic glioma. METHODS: The immunohistochemical expression of CD133 and Sox2 in 40 patients with an astrocytic glioma of different grades was studied. The recorded data on the overall survival (OS), progression-free survival (PFS) and the response to the therapeutic protocol were collected and lastly analyzed. RESULTS: CD133 expression was observed in 87.5% of the cases, while positive Sox2 expression was found in all the studied cases. There was a significant association of CD133 expression with the histological grade and the tumor size (p< 0.001). A significant association of Sox2 with the histological grade and the tumor size was noted (p= 0.004, p= 0.006 respectively). Up-regulation of both CD133 and Sox2 had a significant association with poor clinical response to the therapy (p< 0.001 for each). Shorter OS and PFS were related to CD133 and Sox2 overexpression. CONCLUSIONS: Astrocytoma with CD133 and Sox2 overexpression had an unfavorable prognosis and poor clinical response to the current therapeutic protocol. PMID- 30248049 TI - Intraoperative US and contrast-enhanced intraoperative US during hepatic resection for patients with hepatocellular carcinoma in liver cirrhosis1. AB - PURPOSE: To retrospectively evaluate the role of intraoperative ultrasonography (IOUS) and contrast-enhanced IOUS (CE-IOUS) for the patients with hepatocellular carcinoma (HCC) undergoing hepatic resection (HR). METHODS: Twenty-one consecutive patients who had undergone HR for HCC were included in this study. The patients were subject to preoperative imaging modalities including preoperative ultrasonography (Pre-US) and preoperative contrast-enhanced ultrasonography (Pre-CEUS). All the patients then underwent intraoperative ultrasonography (IOUS) and contrast-enhanced intraoperative ultrasonography (CE IOUS) during surgery. The visualization of primary HCC and additional lesions of all patients were analysed. RESULTS: Twenty-one HCCs were detected during Pre-US and the remaining six lesions (28.6% ) were detected during IOUS and CE-IOUS. Thus the treatment plan was changed in 28.6% patients. Twenty-one HCCs (diameter, 0.6-3.0 cm; mean+SD, 1.98+0.85 cm) were measured on Pre-US and remeasured on IOUS (diameter, 0.9-3.3 cm; mean+SD, 2.19+0.84 mm) (p < 0.001). The 6 additional lesions consisted of three moderately differentiated HCCs, one cholangiocarcinoma, and two high-grade dysplastic nodules (DNs). The mean maximal diameter of the 6 additional lesions was 8.3 mm (range: 6-11 mm). The malignancy associated features such as capsule interruption, echo heterogeneity, hypo-echoic rim, and nodule in nodule pattern were more often depicted on IOUS than on Pre-US (all p < 0.01). CONCLUSIONS: IOUS detects more lesions and the treatment plan is changed in 28.6% patients. HCCs are larger on IOUS than on Pre-US. The typical imaging features of HCCs are better depicted on IOUS in comparison with Pre-US. PMID- 30248047 TI - miR-126: An indicator of poor prognosis and recurrence in histologically lymph node-negative gastric cancer. AB - BACKGROUND: Few biomarkers are available for the prediction of prognosis and recurrence in lymph node (LN)-negative gastric cancer (GC) currently. miR-126 functions as a tumor suppressor in GC, however, its clinical significance in LN negative GC remains unknown. AIM: To investigate the associations of tissue miR 126 level with the clinicopathological characteristics and clinical outcome of LN negative GC patients. METHODS: Quantitative real-time polymerase chain reaction was performed to examine the tissue miR-126 level in 315 LN-negative GC patients who underwent curative gastrectomy with D2 lymphadenectomy. The associations of tissue miR-126 level with clinicopathological characteristics and clinical outcome were evaluated. RESULTS: Compared with matched adjacent non-tumor tissues, miR-126 expression was significantly down-regulated in tumor tissues. A reduced tissue miR-126 level statistically correlated with aggressive clinicopathological characteristics, including larger tumor size, deeper local invasion, and poorer prognosis. Notably, multivariate analysis identified advanced T stage and low miR-126 level as independent predictors of the unfavorable prognosis and recurrence of LN-negative GC. CONCLUSIONS: These results indicate for the first time that advanced T stage and low miR-126 level are predictors of unfavorable prognosis and recurrence in LN-negative GC patients. These parameters should be taken into account to stratify patients for adjuvant therapy and close follow-up. PMID- 30248048 TI - Long-term radiation exposure in patients undergoing EVAR: Reflecting clinical day to-day practice to assess realistic radiation burden. AB - Endovascular repair of aortic aneurysms (EVAR) has become an established treatment option currently applied in an increasing numbers of patients with aortic aneurysms. Advantages include reduced surgical trauma, procedural time, intensive care unit and hospital lengths of stay, blood loss as well as morbidity and mortality.The optimal imaging modalities in EVAR follow-up as well as the appropriate intervals between these follow-ups remain subject of controversial discussion. Objective of this study was the evaluation of the realistic radiation exposure and risk estimate postop EVAR treatment.Of the follow-ups required according to the surveillance schedule during the first year post-EVAR, only 68.3% were actually implemented. Of those required from the second year onwards, an average of 70% was actually performed. During the observation period, each patient underwent a mean of 4.3 CTAs. The median ED calculated from all CTAs was 24. 5 mSv. The minimum and maximum cumulative EDs for the entire observation period were 55 mSv and 310 mSv, respectively. PMID- 30248051 TI - The In-Hospital Length of Stay after Hip Fracture in Octogenarians: Do Delirium and Dementia Shape a New Care Process? AB - BACKGROUND: Hip fracture is a major health problem and a patient's biological age, comorbidity, and cognitive vulnerability have an impact on its related outcomes. Length of stay (LOS) for these highly vulnerable patients is rather long and the possible causes have not been clearly identified yet. OBJECTIVE: We aimed to assess the main clinical factors associated with protracted LOS, focusing on delirium with or without dementia in older age hip fractured patients. METHODS: 218 subjects (mean age 86.70+/-6.18 years), admitted to the Orthogeriatric Unit of the Ospedale Policlinico San Martino (Italy), were recruited. All patients received physical and comprehensive geriatric assessment. Days to surgery, days from surgery to rehabilitation, and LOS were recorded. In hospital and three months' mortality were reported. RESULTS: Prevalent delirium at hospital admission was of 3.1%. 35% of patients developed incident delirium. 56.4% were affected by dementia of Alzheimer-type. In addition, 52% of patients developed delirium superimposed to dementia. Mean LOS was 13.5+/-4.99 days. Namely, delirium, time to surgery, and complication rate disproportionally affected LOS. The analysis with 3 months mortality, based on cognitive vulnerability profiles, showed how delirium mainly affect short-term mortality in patients with dementia. CONCLUSION: Our exploratory study originally pointed out the high incidence of delirium superimposed to dementia in orthogeriatric wards and how delirium turns to be a moderator of LOS. The results meet the need for additional research by virtue of a deeper understanding of the impact of delirium and dementia on orthogeriatric clinical management and outcomes. PMID- 30248050 TI - High-Density Lipoprotein Subclasses and Mild Cognitive Impairment: Study of Outcome and aPolipoproteins in Dementia (STOP-Dementia)1. AB - BACKGROUND: High-density lipoprotein (HDL) containing apolipoprotein A-I is associated with the pathogenesis of Alzheimer's disease (AD). HDL particle size is modified in the presence of pathological conditions, while the significance of the HDL particle size remains controversial. OBJECTIVE: The aim of this study was to investigate the HDL lipoprotein subclasses in mild cognitive impairment (MCI) and AD. METHODS: This cross-sectional study included 20 AD patients, 17 MCI patients, and 17 age-matched controls without cognitive impairment, selected from the database of the Study of Outcome and aPolipoproteins in Dementia (STOP Dementia) registry. The diagnoses of AD and MCI were performed by expert neurologists according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria. Serum HDL subclasses were measured by electrophoretic separation of lipoproteins using the Lipoprint System. The neutrophil-lymphocyte ratio (NLR), a marker of inflammation, was calculated by dividing the neutrophil count by the lymphocyte count. RESULTS: Small-sized HDL particle levels in the MCI group were significantly higher than in the control group, although there was no difference in serum HDL-cholesterol levels between MCI and control groups. NLR in the MCI group was higher than in the control group, but this difference was non-significant (p = 0.09). There was no difference in HDL subclasses or NLR between the AD and control groups. CONCLUSION: These findings suggest that HDL subclasses might be associated with the development of MCI. PMID- 30248052 TI - Association between Neuropsychiatric Improvement and Neurocognitive Change in Alzheimer's Disease: Analysis of the CATIE-AD Study. AB - BACKGROUND/OBJECTIVE: To assess associations between improvements in neuropsychiatric symptoms (NPS) and neurocognitive change in patients with Alzheimer's disease (AD) during treatment using the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer Disease (CATIE-AD) dataset. METHODS: AD outpatients with NPS who needed pharmacological treatment (n = 421) were followed up with antipsychotics, citalopram, or placebo for up to 36 weeks (mean+/-SD = 252+/-52 days). The study aim was to investigate associations between improvement in each NPS evaluating scale (by Clinical Global Impression of Change [CGI-C], Neuropsychiatric Inventory [NPI], or Brief Psychiatric Scale [BPRS]) at endpoint (week 36 or early termination [ET], n = 340) and neurocognitive change (change score in the Mini-Mental State Examination [MMSE] between endpoint and baseline during the treatment). Multiple logistic regression analyses were performed on the associations between each NPS improvement and neurocognitive change as well as socio-clinico-demographic variables of interest. RESULTS: At endpoint, NPS improvement rates were 76.1%, 70.8%, and 58.1% in CGI-C, NPI, and BPRS, respectively, while MMSE score change was -2.3+/-3.8. NPS improvement was significantly related to more severe psychotic symptoms at baseline and preserved levels of neurocognition (smaller MMSE score change) among several variables. CONCLUSIONS: Our findings suggested that neurocognitive preservation may be associated with attaining optimal benefits from any treatment against NPSs in a longitudinal treatment course of patients with AD. PMID- 30248053 TI - Internal Consistency Over Time of Subjective Cognitive Decline: Drawing Preclinical Alzheimer's Disease Trajectories. AB - BACKGROUND: Early intervention to prevent, or delay, the transition from healthy cognition to cognitive impairment in older adults is an important goal. In this way, it is critical to find sensitive, reproducible, and early markers to use low cost methods for the detection of that transition. One of those early markers for symptomatic manifestation of AD is subjective cognitive decline (SCD). OBJECTIVE: To examine the internal consistency of the concept of SCD and to evaluate its clinical significance on the progression through the continuum of AD. METHODS: 1,091 cognitively healthy individuals from the Vallecas Project cohort were followed for three years. Cognitive complaints were systematically collected and analyzed along with clinical data. All participants were classified in three groups at every visit based on specific features of their complaints. RESULTS: Concordance analyses showed a good agreement in longitudinal classification of SCD. The Multi-state Markov Model highlighted a unidirectional transition from the status of no cognitive complaints to SCD. Interestingly, a more severe condition of SCD, namely SCD Plus, showed the highest risk of progression to mild cognitive impairment. CONCLUSIONS: The concept of SCD is stable over time when it is operationally defined and consistently assessed. It provides not only a fast identification of individuals at higher risk of future mild cognitive impairment, but also it allows us to track longitudinal trajectories. PMID- 30248055 TI - Role of Noradrenergic Brain Nuclei in the Regulation of Carotid Artery Blood Flow: Pharmacological Evidence from Anesthetized Pigs with Alpha-2 Adrenergic Receptor Modulator Drugs. AB - BACKGROUND: Cerebral hypoperfusion and degeneration of the noradrenergic locus coeruleus (LC) occur early in Alzheimer's disease (AD). Cerebral blood vessels are densely innervated by noradrenergic projections from the LC suggesting a functional role for the regulation of cerebral blood flow (CBF). Experimental LC stimulation, however, has provided no clarity as decreases or increases in CBF were reported from different experimental settings and investigators. OBJECTIVE: To find out with pharmacological methods whether endogenously released norepinephrine (NE) increases or decreases carotid artery blood flow (CABF) in anesthetized pigs by investigating the effect of centrally acting alpha-2 adrenergic drugs, which increase (atipamezole) or decrease (xylazine) NE in the brain. METHODS: CABF was measured by a Doppler-flow probe placed around the left carotid artery in pentobarbital anesthetized young pigs. RESULTS: Neither current antihypertensive drugs nor pharmacological stimulation of dopamine, histamine, serotonin or acetylcholine receptors changed CABF. The alpha-2 adrenergic receptor agonist xylazine decreased, while the antagonist atipamezole raised CABF. This rise was abolished by a combined treatment with endothelial NO synthase inhibitor Nomega-Nitro-L-arginine methyl ester (L-NAME) and the non selective beta-receptor antagonist propranolol. Propranolol alone did not decrease CABF in contrast to L-NAME but decreased CABF after L-NAME, surprisingly. CONCLUSION: Pharmacological evidence suggests that NE released in the brain of anesthetized pigs raises CABF involving beta-adrenergic mechanisms and nitric oxide. If in awake humans NE released from the LC had vasodilator effects early LC degeneration could be involved in early cerebral hypoperfusion of AD. Moreover, a cerebral adrenergic vascular innervation deficit, possibly resulting from LC degeneration, and systemic endothelial dysfunction together may act synergistically to reduce CBF. PMID- 30248054 TI - Age-Dependent Decrease of Mitochondrial Complex II Activity in a Familial Mouse Model for Alzheimer's Disease. AB - Alzheimer's disease (AD) is a severe neurodegenerative disorder for which the exact etiology is largely unknown. An increasingly recognized and investigated notion is the pathogenic role of mitochondrial dysfunction in AD. We assessed mitochondrial oxidative-phosphorylation (OXPHOS) enzyme activities in the APPswe/PS1DeltaE9 mouse model from 4.5 to 14 months of age. We show an age dependent decrease in mitochondrial complex-II activity starting at 9 months in APP/PS1 mice. Other enzymes of the OXPHOS do not show any alterations. Since amyloid-beta (Abeta) plaques are already present from 4 months of age, mitochondrial dysfunction likely occurs downstream of Abeta pathology in this mouse model. PMID- 30248057 TI - The Effectiveness of Psychosocial and Behavioral Interventions for Informal Dementia Caregivers: Meta-Analyses and Meta-Regressions. AB - BACKGROUND: Many psychosocial and behavioral interventions have been developed for informal dementia caregivers. Because existing meta-analyses only focused on a limited number of interventions and outcomes, how effective these interventions are overall and which interventions components are associated with larger effects has yet to be explored. OBJECTIVE: To provide a comprehensive meta-analysis of the effectiveness of psychosocial and behavioral interventions on burden, depression, anxiety, quality of life, stress, and sense of competence in informal dementia caregivers. In addition, we examined if interventions which utilized more sessions and/or were delivered personally (face-to-face) had larger effect sizes. In exploratory meta-regressions, we examined seven additional moderators. METHODS: The protocol was registered with PROSPERO, number CRD42017062555. We systematically searched the literature to identify controlled trials assessing the effect of psychosocial and behavioral interventions on the six outcome measures, for informal dementia caregivers. We performed six random effects meta analyses, to assess the pooled effect sizes of the interventions. In addition, we performed separate meta-regressions, for each outcome, for each moderator. RESULTS: The sample consisted of 60 studies. For all outcomes except anxiety, the pooled effects were small and in favor of the intervention group. No moderator was found to systematically predict these effects. There were no indications for publication bias or selection bias based on significance. CONCLUSION: Overall, the interventions yield significant (small) effects, independent of intervention characteristics. Future research should explore options to enhance the effectiveness of interventions aimed at assisting informal caregivers. PMID- 30248056 TI - Effectiveness of a Personalized Brain-Computer Interface System for Cognitive Training in Healthy Elderly: A Randomized Controlled Trial. AB - BACKGROUND: Cognitive training has been demonstrated to improve cognitive performance in older adults. To date, no study has explored personalized training that targets the brain activity of each individual. OBJECTIVE: This is the first large-scale trial that examines the usefulness of personalized neurofeedback cognitive training. METHODS: We conducted a randomized-controlled trial with participants who were 60-80 years old, with Clinical Dementia Rating (CDR) score of 0-0.5, Mini-Mental State Examination (MMSE) score of 24 and above, and with no neuropsychiatric diagnosis. Participants were randomly assigned to the Intervention or Waitlist-Control group. The training system, BRAINMEM, has attention, working memory, and delayed recall game components. The intervention schedule comprised 24 sessions over eight weeks and three monthly booster sessions. The primary outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score after the 24-session training. RESULTS: There were no significant between-subjects differences in overall cognitive performance post-intervention. However, a sex moderation effect (p = 0.014) was present. Men in the intervention group performed better than those in the waitlist group (mean difference, +4.03 (95% CI 0.1 to 8.0), p = 0.046. Among females, however, both waitlist-control and intervention participants improved from baseline, although the between-group difference in improvement did not reach significance. BRAINMEM also received positive appraisal and intervention adherence from the participants. CONCLUSION: A personalized neurofeedback intervention is potentially feasible for use in cognitive training for older males. The sex moderation effect warrants further investigation and highlights the importance of taking sex into account during cognitive training. PMID- 30248059 TI - Acute Stroke Care in Dementia: A Cohort Study from the Swedish Dementia and Stroke Registries. AB - BACKGROUND: Previous studies have shown that patients with dementia receive less testing and treatment for stroke. OBJECTIVES: Our aim was to investigate hospital management of acute ischemic stroke in patients with and without dementia. METHODS: Retrospective analysis of prospectively collected data 2010-2014 from the Swedish national dementia registry (SveDem) and the Swedish national stroke registry (Riksstroke). Patients with dementia who suffered an acute ischemic stroke (AIS) (n = 1,356) were compared with matched non-dementia AIS patients (n = 6,755). Outcomes included length of stay in a stroke unit, total length of hospitalization, and utilization of diagnostic tests and assessments. RESULTS: The median age at stroke onset was 83 years. While patients with dementia were equally likely to be directly admitted to a stroke unit as their non-dementia counterparts, their stroke unit and total hospitalization length were shorter (10.5 versus 11.2 days and 11.6 versus 13.5, respectively, p < 0.001). Dementia patients were less likely to receive carotid ultrasound (OR 0.36, 95% CI [0.30 0.42]) or undergo assessments by the interdisciplinary team members (physiotherapists, speech therapists, occupational therapists; p < 0.05 for all adjusted models). However, a similar proportion of patients received CT imaging (97.4% versus 98.6%, p = 0.001) and a swallowing assessment (90.7% versus 91.8%, p = 0.218). CONCLUSIONS: Patients with dementia who suffer an ischemic stroke have equal access to direct stroke unit care compared to non-dementia patients; however, on average, their stay in a stroke unit and total hospitalization are shorter. Dementia patients are also less likely to receive specific diagnostic tests and assessments by the interdisciplinary stroke team. PMID- 30248058 TI - Preoperative Phosphorylated Tau Concentration in the Cerebrospinal Fluid Can Predict Cognitive Function Three Years after Shunt Surgery in Patients with Idiopathic Normal Pressure Hydrocephalus. AB - BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer's disease (AD) pathology is debated. OBJECTIVE: To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH. METHODS: Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (>=30 pg/mL) p-Tau groups and followed up for three years after lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low (n = 24; mean age 75.7 years [SD 5.3]) and high (n = 11; mean age 76.0 years [SD 5.6]) p-Tau groups. RESULTS: Cognitive function improved early in the low p-Tau group and was maintained thereafter (p = 0.005). In contrast, the high p-Tau group showed a gradual decline to baseline levels by the third postoperative year (p = 0.040). Although the p-Tau concentration did not correlate with the preoperative MMSE score, a negative correlation appeared and strengthened during follow-up (R2 = 0.352, p < 0.001). Furthermore, the low p-Tau group showed rapid and sustained mRS grade improvement, whereas mRS performance gradually declined in the high p Tau group. CONCLUSIONS: Preoperative CSF p-Tau concentration predicted some aspects of cognitive function after shunt intervention in patients with iNPH. The therapeutic effects of shunt treatment were shorter-lasting in patients with coexisting AD pathology. PMID- 30248061 TI - Report of the third outcome measures in myotonic dystrophy type 1 (OMMYD-3) international workshop Paris, France, June 8, 2015. PMID- 30248060 TI - Myotonic Dystrophy Type 2 - Data from the Serbian Registry. AB - BACKGROUND: Myotonic dystrophy type 2 (DM2) is a multisystem disorder, mostly presented with mild but heterogeneous spectrum of symptoms. OBJECTIVE: The aim of this research was to provide detailed sociodemographic, clinical and laboratory data of a large DM2 cohort from the Serbian registry. METHODS: In 2008, we started to prospectively enter data of all DM patients. We also retrospectively collected data of patients hospitalized from 1990 until 2008. RESULTS: At the end of 2017, registry comprised 87 (68%) of 128 genetically confirmed DM2 patients in Serbia, i.e. 1.2 registered cases per 100,000 inhabitants. Female subjects were more prevalent (63%). The diagnostic delay was 11.8+/-11.3 years. The most common first symptoms in our patients were lower limb weakness, handgrip myotonia and limb pain, although some percentage of patients presented with cataracts or extrapyramidal symptoms and signs. Lens opacities were present in 75% of patients. Severe ECG abnormalities were noted in 8% and pacemaker was implanted in 5% of DM2 subjects. Pulmonary restriction was observed in 10% of DM2 patients. Insulin resistance and diabetes mellitus were frequent in our cohort (21% and 17%, respectively). Male subjects more frequently had snoring, baldness, sterility, polyneuropathy, lower HDL and higher glycaemia, while waddling gait and increased muscle reflexes were more common in females. CONCLUSIONS: This registry offers a spectrum of different features presented in Serbian DM2 population, which could be at service of earlier diagnosis and better treatment. PMID- 30248062 TI - Investigating Voice as a Biomarker for Leucine-Rich Repeat Kinase 2-Associated Parkinson's Disease. AB - We investigate the potential association between leucine-rich repeat kinase 2 (LRRK2) mutations and voice. Sustained phonations ('aaah' sounds) were recorded from 7 individuals with LRRK2-associated Parkinson's disease (PD), 17 participants with idiopathic PD (iPD), 20 non-manifesting LRRK2-mutation carriers, 25 related non-carriers, and 26 controls. In distinguishing LRRK2 associated PD and iPD, the mean sensitivity was 95.4% (SD 17.8%) and mean specificity was 89.6% (SD 26.5%). Voice features for non-manifesting carriers, related non-carriers, and controls were much less discriminatory. Vocal deficits in LRRK2-associated PD may be different than those in iPD. These preliminary results warrant longitudinal analyses and replication in larger cohorts. PMID- 30248064 TI - Multimorbidity Predicts Quality of Life but not Motor Severity in Early Parkinson's Disease. AB - Recent guidance by the National Institute for Health and Care Excellence (NICE) focuses on the management of people with multimorbidity, including Parkinson's disease (PD). To date there has been little exploration of this in neurodegenerative diseases. This study aimed to explore the associations between multimorbidity, motor severity and quality of life (QoL) in early PD. Regression analyses determined whether multimorbidity was significantly associated with disease severity and QoL. Multimorbidity was a small but significant predictor of QoL in people with incident PD, but not motor severity, suggesting that they may benefit from a tailored multidisciplinary approach to care. PMID- 30248063 TI - PTPRC Expression in Blood is Downregulated in Parkinson's and Progressive Supranuclear Palsy Disorders. AB - BACKGROUND: Parkinson's disease (PD) shares pathological and clinical features with progressive supranuclear palsy (PSP) patients making the diagnosis challenging. Distinguishing PD from PSP is crucial given differences in disease course, treatment and clinical management. OBJECTIVE: Although some progress has been made in the discovery of biomarkers for PD and PSP, there is an urgent need to identify additional biomarkers capable of distinguishing between these diseases. METHODS: In this study, we tested the phosphatases DUSP8 and PTPRC for their diagnostic potential using quantitative PCR assays, in blood of 138 samples from participants nested in the Parkinson's Disease Biomarkers Program. RESULTS: Relative abundance of PTPRC mRNA was downregulated in PSP patients compared to PD and healthy controls, whereas there was no significant difference in the expression of DUSP8. Interestingly, PTPRC mRNA correlated with the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score and MDS-UPDRS- part III, thus indicating it might be useful as part of a biosignature to stratify patients according to disease severity and progression. CONCLUSIONS: Collectively, these results suggest that PTPRC expression may be useful for distinguishing PD from PSP patients as part of a biosignature. Evaluation of PTPRC along with additional biomarkers in a larger and well characterized longitudinal study is warranted. PMID- 30248071 TI - In Reply to Khoo and Teo. PMID- 30248069 TI - Accessing Electronic Health Records: A Misperception Corrected. PMID- 30248074 TI - Addressing Uncertainty in Burnout Assessment. PMID- 30248066 TI - Types and factors affecting injury rates of mechanical contractors. AB - BACKGROUND: In the United States, about 38,000 cases of nonfatal workplace injuries were reported in 2015, in the category of 'mechanical work' (plumbing, heating, and air conditioning); this is nearly identical to the number of cases reported under 'building construction'. OBJECTIVE: This paper analyzes the types and rates of injuries and illnesses of mechanical contractors of southern Nevada, including the nature of the injuries and illnesses, body parts affected by injuries, causes of injuries, and factors affecting the injury rates. METHODS: To obtain data, a survey consisting of questions regarding the number of injuries and types of injuries was conducted with 31 mechanical contractors of southern Nevada involved in plumbing, piping, heating, refrigeration, and air conditioning. RESULTS: The injury rate for larger mechanical contractors (n = 16), in terms of number of employees and annual revenue, was significantly lower than for smaller mechanical contractors (n = 15). Mechanical contractors who worked on residential buildings (n = 13) had significantly higher rates of injuries than those involved with industrial (n = 7) or commercial buildings (n = 10). Results showed that sprains and strains (31%) were dominant injuries, and the major causes were from parts and materials (39%), hand tools (16%), contact with objects (14%), and falls (7%). CONCLUSIONS: The study concluded that the injury rate for these mechanical contractors was found to be higher than that reported by the Occupational Safety and Health Administration for specialty trade contractors. PMID- 30248065 TI - Feasibility and Safety of Multicenter Tissue and Biofluid Sampling for alpha Synuclein in Parkinson's Disease: The Systemic Synuclein Sampling Study (S4). AB - BACKGROUND: alpha-synuclein is a lead Parkinson's disease (PD) biomarker. There are conflicting reports regarding accuracy of alpha-synuclein in different tissues and biofluids as a PD biomarker, and the within-subject anatomical distribution of alpha-synuclein is not well described. The Systemic Synuclein Sampling Study (S4) aims to address these gaps in knowledge. The S4 is a multicenter, cross-sectional, observational study evaluating alpha-synuclein in multiple tissues and biofluids in PD and healthy controls (HC). OBJECTIVE: To describe the baseline characteristics of the S4 cohort and safety and feasibility of this study. METHODS: Participants underwent motor and non-motor clinical assessments, dopamine transporter SPECT, biofluid collection (cerebrospinal fluid, saliva, and blood), and tissue biopsies (skin, sigmoid colon, and submandibular gland). Biopsy adequacy was determined based on presence of adequate target tissue. Tissue sections were stained with the 5C12 monoclonal antibody against unmodified alpha-synuclein. All specimens were acquired and processed in a standardized manner. Adverse events were systematically recorded. RESULTS: The final cohort consists of 82 participants (61 PD, 21 HC). In 68 subjects (83%), all types of specimens were obtained but only 50 (61%) of subjects had all specimens both collected and evaluable for alpha-synuclein. Mild adverse events were common, especially for submandibular gland biopsy, but only 1 severe adverse event occurred. CONCLUSION: Multicenter tissue and biofluid sampling for alpha-synuclein is feasible and generally safe. S4 will inform understanding of the concurrent distribution of alpha-synuclein pathology and biomarkers in biofluids and peripheral nervous system in PD. PMID- 30248070 TI - A Transformative Learning Approach to Teaching Management Skills in Medical Education. PMID- 30248068 TI - Moving From Professionalism to Empowerment: Taking a Hard Look at Resident Hours. PMID- 30248075 TI - A Neglected Problem in Burnout Research. PMID- 30248072 TI - The Daunting Career of the Physician-Investigator: Don't Blame It on the EMR. PMID- 30248067 TI - Experimental study to optimize configurations of PCD Spectral CT. AB - BACKGROUND: High dose efficiency of photon counting detector based spectral CT (PCD-SCT) and its value in some clinical diagnosis have been well acknowledged. However, it has not been widely adopted in practical use for medical diagnosis and security inspection. OBJECTIVE: To evaluate the influence on PCD-SCT from multiple aspects including the number of energy channels, k-edge materials, energy thresholding, basis functions in spectral information decomposition, and the combined optimal setting for these parameters and configurations. METHODS: Basis material decomposition after spatial reconstruction is applied for PCD-SCT. A "one-step" synthesis method, merging decomposition with synthesis, is proposed to obtain virtual monochromatic images. An I-RMSE is computed using the bias part of I-RMSE to describe the difference of a synthesized signal from ground truth and the standard deviation part of I-RMSE to express the noise level. In addition, virtual monochromatic images commonly used in the medical area are also synthesized. Both numerical simulations and practical experiments are conducted for validation. RESULTS: Results indicated that the I-RMSE for matters significantly reduced with an increased number of energy channels compared with dual-energy channel. The maximum reduction is 6% for triple-, 18% for quadruple and 24% for quintuple-energy, respectively. However, the improvement is not linear, and also slows down after the number of energy channels reaches a certain number. Contrast agents of high concentration can introduce up to 50% error to surrounding matters. Moreover, different energy partitions influence the total error, which demonstrates the necessity of energy threshold optimization. Last, the optimal basis-material combination varies according to targeted imaging matters and the interested monochromatic energies. CONCLUSIONS: Gain from more energy channels could be significant with the increase of energy channel number. Introduction of contrast agents in scanned objects will increase overall error in spectral CT imaging. Energy thresholding optimization is beneficial for information recovery. Moreover, the choice of basis materials could also be important to obtain low noise results. With these studies of the effect from various configurations for PCD-SCT, one may optimize the configuration of PCD-SCT accordingly. PMID- 30248073 TI - In Reply to Fochtmann. PMID- 30248076 TI - In Reply to Palamara and colleagues and to Bianchi and colleagues. PMID- 30248079 TI - Artist's Statement: To Zanzibar by Motor Car, Please! PMID- 30248077 TI - A Different View on Political Activism. PMID- 30248078 TI - In Reply to Lenchus. PMID- 30248080 TI - Take-Home Lessons From Abroad. PMID- 30248082 TI - Mansfield Park: [Excerpt]. PMID- 30248085 TI - Why Does This Learner Perform Poorly on Tests? Using Self-Regulated Learning Theory to Diagnose the Problem and Implement Solutions. AB - PROBLEM: Learners who underperform on standardized tests are common throughout all levels of medical education and require considerable faculty time and effort to remediate. Current methods for remediating test-taking difficulties are typically not grounded in educational theory or supported by high-quality evidence. APPROACH: A test-taking assessment was developed based on self regulated learning (SRL) microanalytic assessment and training and used during academic year 2012-2013. This method assesses the SRL subprocesses of strategic planning, self-monitoring, causal attributions, and adaptive inferences during the educational task of answering test questions. The method was designed for one on-one use by teacher and learner, and for learner self-assessment and practice. OUTCOMES: At one academic institution, this method was used to categorize learners into struggling test-taker subtypes which correspond to deficiencies in the SRL subprocesses outlined above. A learning plan based on the SRL deficiency was developed for each struggling test-taker subtype. In a small number of internal medicine residents with low in-training examination scores, use of this method yielded improvements in 2013 in-training examination score that doubled the expected improvement based on historical averages. NEXT STEPS: This method is a novel application of SRL theory to a commonly encountered problem in medical education: the learner who performs poorly on tests. Large-scale, multicenter studies of medical learners at a variety of training levels and program types are needed to determine the effectiveness and generalizability of this intervention. PMID- 30248084 TI - The Lessons We Learned From Each Other. PMID- 30248081 TI - Removing Barriers and Facilitating Access: Increasing the Number of Physicians With Disabilities. AB - : Nearly one-fifth of the U.S. population has a disability, and many of these Americans experience disparities in the health care they receive. In part, these health care disparities result from a lack of understanding about disability by health care providers. The education of physicians is grounded in a biomedical model that emphasizes pathology, impairment, or dysfunction, rather than a social model of disability that focuses on removing barriers for individuals with disabilities and improving their capabilities. According to a recent report, only 2.7% of medical students disclosed having disabilities-far fewer than the proportion of people with disabilities in the U.S. POPULATION: Including students and other trainees with disabilities-those with lived experiences of disability who can empathize with patients and serve as an example for their peers-in medical education is one mechanism to address the health care disparities faced by individuals with disabilities. At present, medical students and residents with disabilities face structural barriers related to policies and procedures, clinical accommodations, disability and wellness support services, and the physical environment. Additionally, many face cultural barriers related to the overarching attitudes, beliefs, and values prevalent at their medical school. In this Commentary, the authors review the state of disability in medical education and training, summarize key findings from an Association of American Medical Colleges special report on disability, and discuss considerations for medical educators to improve inclusion, including emerging technologies that can enhance access for students with disabilities. PMID- 30248083 TI - Commentary on an Excerpt From Mansfield Park. PMID- 30248090 TI - The slings and arrows of comparative linguistics. AB - In this Formal Comment the authors respond to objections to their previous Essay, reiterating that comparative linguistics is not an easy undertaking. PMID- 30248086 TI - Cantharidin Inhibits Anti-Apoptotic Bcl-2 Family Proteins and Induces Apoptosis in Human Osteosarcoma Cell Lines MG-63 and MNNG/HOS via Mitochondria-Dependent Pathway. AB - BACKGROUND Cantharidin (CTD) is one of the major active ingredients of blister beetles and has significant antitumor activity in many cancer cell lines. The aim of our study was to evaluate the effect of CTD on the apoptosis of human osteosarcoma cells MG-63 and MNNG/HOS, and to explore the possible molecular mechanism. MATERIAL AND METHODS Osteosarcoma cells MG-63 and MNNG/HOS were treated with varying concentrations of CTD. The proliferation inhibition of cells was detected by MTS. Flow cytometry and Hoechst 33258 staining were used to determine cell cycle arrest and apoptosis, and apoptosis-related protein levels were analyzed by Western blotting. RESULTS Our current findings suggest that CTD could inhibit the proliferation of these 2 osteosarcoma cells. The cells treated with CTD showed an obvious apoptotic morphology, and CTD promoted cells apoptosis in a dose-dependent manner. In addition, cantharidin-induced apoptosis was accompanied by increased expression of Bax and PARP and decreased expression of Bcl-2, p-Akt, and p-Cdc2. CONCLUSIONS CTD accelerates the apoptosis of MG-63 and MNNG/HOS cells in a concentration-dependent manner through the mitochondria dependent pathway, suggesting that use of CTD is a novel approach for the treatment of osteosarcoma. PMID- 30248092 TI - Phylogeography and demographic history of the Chagas disease vector Rhodnius nasutus (Hemiptera: Reduviidae) in the Brazilian Caatinga biome. AB - BACKGROUND: Rhodnius nasutus, a vector of the etiological agent Trypanosoma cruzi, is one of the epidemiologically most relevant triatomine species of the Brazilian Caatinga, where it often colonizes rural peridomestic structures such as chicken coops and occasionally invades houses. Historical colonization and determination of its genetic diversity and population structure may provide new information towards the improvement of vector control in the region. In this paper we present thoughtful analyses considering the phylogeography and demographic history of R. nasutus in the Caatinga. METHODOLOGY/PRINCIPAL FINDINGS: A total of 157 R. nasutus specimens were collected from Copernicia prunifera palm trees in eight geographic localities within the Brazilian Caatinga biome, sequenced for 595-bp fragment of the mitochondrial cytochrome b gene (cyt b) and genotyped for eight microsatellite loci. Sixteen haplotypes were detected in the cyt b sequences, two of which were shared among different localities. Molecular diversity indices exhibited low diversity levels and a haplotype network revealed low divergence among R. nasutus sequences, with two central haplotypes shared by five of the eight populations analyzed. The demographic model that better represented R. nasutus population dynamics was the exponential growth model. Results of the microsatellite data analyses indicated that the entire population is comprised of four highly differentiated groups, with no obvious contemporary geographic barriers that could explain the population substructure detected. A complex pattern of migration was observed, in which a western Caatinga population seems to be the source of emigrants to the eastern populations. CONCLUSIONS/SIGNIFICANCE: R. nasutus that inhabit C. prunifera palms do not comprise a species complex. The species went through a population expansion at 12-10 ka, during the Holocene, which coincides with end of the largest dry season in South America. It colonized the Caatinga in a process that occurred from west to east in the region. R. nasutus is presently facing an important ecological impact caused by the continuous deforestation of C. prunifera palms in northeast Brazil. We hypothesize that this ecological disturbance might contribute to an increase in the events of invasion and colonization of human habitations. PMID- 30248089 TI - Evolutionary emergence of infectious diseases in heterogeneous host populations. AB - The emergence and re-emergence of pathogens remains a major public health concern. Unfortunately, when and where pathogens will (re-)emerge is notoriously difficult to predict, as the erratic nature of those events is reinforced by the stochastic nature of pathogen evolution during the early phase of an epidemic. For instance, mutations allowing pathogens to escape host resistance may boost pathogen spread and promote emergence. Yet, the ecological factors that govern such evolutionary emergence remain elusive because of the lack of ecological realism of current theoretical frameworks and the difficulty of experimentally testing their predictions. Here, we develop a theoretical model to explore the effects of the heterogeneity of the host population on the probability of pathogen emergence, with or without pathogen evolution. We show that evolutionary emergence and the spread of escape mutations in the pathogen population is more likely to occur when the host population contains an intermediate proportion of resistant hosts. We also show that the probability of pathogen emergence rapidly declines with the diversity of resistance in the host population. Experimental tests using lytic bacteriophages infecting their bacterial hosts containing Clustered Regularly Interspaced Short Palindromic Repeat and CRISPR-associated (CRISPR-Cas) immune defenses confirm these theoretical predictions. These results suggest effective strategies for cross-species spillover and for the management of emerging infectious diseases. PMID- 30248088 TI - Proteome-scale relationships between local amino acid composition and protein fates and functions. AB - Proteins with low-complexity domains continue to emerge as key players in both normal and pathological cellular processes. Although low-complexity domains are often grouped into a single class, individual low-complexity domains can differ substantially with respect to amino acid composition. These differences may strongly influence the physical properties, cellular regulation, and molecular functions of low-complexity domains. Therefore, we developed a bioinformatic approach to explore relationships between amino acid composition, protein metabolism, and protein function. We find that local compositional enrichment within protein sequences is associated with differences in translation efficiency, abundance, half-life, protein-protein interaction promiscuity, subcellular localization, and molecular functions of proteins on a proteome-wide scale. However, local enrichment of related amino acids is sometimes associated with opposite effects on protein regulation and function, highlighting the importance of distinguishing between different types of low-complexity domains. Furthermore, many of these effects are discernible at amino acid compositions below those required for classification as low-complexity or statistically-biased by traditional methods and in the absence of homopolymeric amino acid repeats, indicating that thresholds employed by classical methods may not reflect biologically relevant criteria. Application of our analyses to composition-driven processes, such as the formation of membraneless organelles, reveals distinct composition profiles even for closely related organelles. Collectively, these results provide a unique perspective and detailed insights into relationships between amino acid composition, protein metabolism, and protein functions. PMID- 30248091 TI - Inferring decoding strategies for multiple correlated neural populations. AB - Studies of neuron-behaviour correlation and causal manipulation have long been used separately to understand the neural basis of perception. Yet these approaches sometimes lead to drastically conflicting conclusions about the functional role of brain areas. Theories that focus only on choice-related neuronal activity cannot reconcile those findings without additional experiments involving large-scale recordings to measure interneuronal correlations. By expanding current theories of neural coding and incorporating results from inactivation experiments, we demonstrate here that it is possible to infer decoding weights of different brain areas at a coarse scale without precise knowledge of the correlation structure. We apply this technique to neural data collected from two different cortical areas in macaque monkeys trained to perform a heading discrimination task. We identify two opposing decoding schemes, each consistent with data depending on the nature of correlated noise. Our theory makes specific testable predictions to distinguish these scenarios experimentally without requiring measurement of the underlying noise correlations. PMID- 30248094 TI - Hrg1 promotes heme-iron recycling during hemolysis in the zebrafish kidney. AB - Heme-iron recycling from senescent red blood cells (erythrophagocytosis) accounts for the majority of total body iron in humans. Studies in cultured cells have ascribed a role for HRG1/SLC48A1 in heme-iron transport but the in vivo function of this heme transporter is unclear. Here we present genetic evidence in a zebrafish model that Hrg1 is essential for macrophage-mediated heme-iron recycling during erythrophagocytosis in the kidney. Furthermore, we show that zebrafish Hrg1a and its paralog Hrg1b are functional heme transporters, and genetic ablation of both transporters in double knockout (DKO) animals shows lower iron accumulation concomitant with higher amounts of heme sequestered in kidney macrophages. RNA-seq analyses of DKO kidney revealed large-scale perturbation in genes related to heme, iron metabolism and immune functions. Taken together, our results establish the kidney as the major organ for erythrophagocytosis and identify Hrg1 as an important regulator of heme-iron recycling by macrophages in the adult zebrafish. PMID- 30248087 TI - Midgut-derived neuropeptide F controls germline stem cell proliferation in a mating-dependent manner. AB - Stem cell maintenance is established by neighboring niche cells that promote stem cell self-renewal. However, it is poorly understood how stem cell activity is regulated by systemic, tissue-extrinsic signals in response to environmental cues and changes in physiological status. Here, we show that neuropeptide F (NPF) signaling plays an important role in the pathway regulating mating-induced germline stem cell (GSC) proliferation in the fruit fly Drosophila melanogaster. NPF expressed in enteroendocrine cells (EECs) of the midgut is released in response to the seminal-fluid protein sex peptide (SP) upon mating. This midgut derived NPF controls mating-induced GSC proliferation via ovarian NPF receptor (NPFR) activity, which modulates bone morphogenetic protein (BMP) signaling levels in GSCs. Our study provides a molecular mechanism that describes how a gut derived systemic factor couples stem cell behavior to physiological status, such as mating, through interorgan communication. PMID- 30248093 TI - A metabolic checkpoint protein GlmR is important for diverting carbon into peptidoglycan biosynthesis in Bacillus subtilis. AB - The Bacillus subtilis GlmR (formerly YvcK) protein is essential for growth on gluconeogenic carbon sources. Mutants lacking GlmR display a variety of phenotypes suggestive of impaired cell wall synthesis including antibiotic sensitivity, aberrant cell morphology and lysis. To define the role of GlmR, we selected suppressor mutations that ameliorate the sensitivity of a glmR null mutant to the beta-lactam antibiotic cefuroxime or restore growth on gluconeogenic carbon sources. Several of the resulting suppressors increase the expression of the GlmS and GlmM proteins that catalyze the first two committed steps in the diversion of carbon from central carbon metabolism into peptidoglycan biosynthesis. Chemical complementation studies indicate that the absence of GlmR can be overcome by provision of cells with N-acetylglucosamine (GlcNAc), even under conditions where GlcNAc cannot re-enter central metabolism and serve as a carbon source for growth. Our results indicate that GlmR facilitates the diversion of carbon from the central metabolite fructose-6 phosphate, which is limiting in cells growing on gluconeogenic carbon sources, into peptidoglycan biosynthesis. Our data suggest that GlmR stimulates GlmS activity, and we propose that this activation is antagonized by the known GlmR ligand and peptidoglycan intermediate UDP-GlcNAc. Thus, GlmR presides over a new mechanism for the regulation of carbon partitioning between central metabolism and peptidoglycan biosynthesis. PMID- 30248096 TI - OptMDFpathway: Identification of metabolic pathways with maximal thermodynamic driving force and its application for analyzing the endogenous CO2 fixation potential of Escherichia coli. AB - Constraint-based modeling techniques have become a standard tool for the in silico analysis of metabolic networks. To further improve their accuracy, recent methodological developments focused on integration of thermodynamic information in metabolic models to assess the feasibility of flux distributions by thermodynamic driving forces. Here we present OptMDFpathway, a method that extends the recently proposed framework of Max-min Driving Force (MDF) for thermodynamic pathway analysis. Given a metabolic network model, OptMDFpathway identifies both the optimal MDF for a desired phenotypic behavior as well as the respective pathway itself that supports the optimal driving force. OptMDFpathway is formulated as a mixed-integer linear program and is applicable to genome-scale metabolic networks. As an important theoretical result, we also show that there exists always at least one elementary mode in the network that reaches the maximal MDF. We employed our new approach to systematically identify all substrate-product combinations in Escherichia coli where product synthesis allows for concomitant net CO2 assimilation via thermodynamically feasible pathways. Although biomass synthesis cannot be coupled to net CO2 fixation in E. coli we found that as many as 145 of the 949 cytosolic carbon metabolites contained in the genome-scale model iJO1366 enable net CO2 incorporation along thermodynamically feasible pathways with glycerol as substrate and 34 with glucose. The most promising products in terms of carbon assimilation yield and thermodynamic driving forces are orotate, aspartate and the C4-metabolites of the tricarboxylic acid cycle. We also identified thermodynamic bottlenecks frequently limiting the maximal driving force of the CO2-fixing pathways. Our results indicate that heterotrophic organisms like E. coli hold a possibly underestimated potential for CO2 assimilation which may complement existing biotechnological approaches for capturing CO2. Furthermore, we envision that the developed OptMDFpathway approach can be used for many other applications within the framework of constrained-based modeling and for rational design of metabolic networks. PMID- 30248097 TI - Nanoparticle delivery of a tetravalent E protein subunit vaccine induces balanced, type-specific neutralizing antibodies to each dengue virus serotype. AB - Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic shock syndrome. Dengue vaccine development is challenging because of the need to induce protection against four antigenically distinct DENV serotypes. Recent studies indicate that tetravalent DENV vaccines must induce balanced, serotype specific neutralizing antibodies to achieve durable protective immunity against all 4 serotypes. With the leading live attenuated tetravalent DENV vaccines, it has been difficult to achieve balanced and type-specific responses to each serotype, most likely because of unbalanced replication of vaccine viral strains. Here we evaluate a tetravalent DENV protein subunit vaccine, based on recombinant envelope protein (rE) adsorbed to the surface of poly (lactic-co-glycolic acid) (PLGA) nanoparticles for immunogenicity in mice. In monovalent and tetravalent formulations, we show that particulate rE induced higher neutralizing antibody titers compared to the soluble rE antigen alone. Importantly, we show the trend that tetravalent rE adsorbed to nanoparticles stimulated a more balanced serotype specific antibody response to each DENV serotype compared to soluble antigens. Our results demonstrate that tetravalent DENV subunit vaccines displayed on nanoparticles have the potential to overcome unbalanced immunity observed for leading live-attenuated vaccine candidates. PMID- 30248098 TI - Evaluation of antigen-specific immune responses for leprosy diagnosis in a hyperendemic area in China. AB - OBJECTIVE: To evaluate antigen-specific immune responses for leprosy diagnosis in a hyperendemic area in China. METHODS: Eighty-three leprosy patients and 161 non leprosy controls were enrolled from Hani-yi Autonomous Prefecture of Honghe, Yunnan Province, China. Leprosy patients were divided into multibacillary (MB, n = 38), paucibacillary (PB, n = 23), and post-multi-drug therapy (MDT, n = 22) groups. Controls were divided into the following groups: healthy household contacts (HHC, n = 119), tuberculosis (TB, n = 11), and endemic controls (EC, n = 31). The NDO-LID Rapid Test, M. leprae antigen-specific ELISA and antigen specific IFN-gamma secretion in a whole blood assay (WBA) were used to evaluate these subjects. RESULTS: The NDO-LID Rapid Test achieved higher positive response rates in MB than in PB patients[94.7%(36/38) vs 65.2%(15/23)], and these rates were higher than those observed by ELISA using anti-LID-1[92.1%(35/38) vs 52.2%(12/23)], anti-NDO-LID[92.1%(35/38) vs 47.8% (11/23)], and anti-ND-O BSA[89.5%(34/38) vs 60.9%(14/23)]. However, the NDO-LID Rapid Test also showed a higher positive response rate in the EC group (33.3%,10/31), which was higher than the rates observed for anti-NDO-LID (12.9%,4/31) and anti-ND-O-BSA (16.1%,5/31). M. leprae antigen-specific ELISA demonstrated relatively high specificity (86.84-97.37%) but low sensitivity (15.97-72.73%) in discriminating between leprosy patients and non-leprosy controls by ROC curve analysis. In contrast, M. leprae antigen-specific IFN-gamma secretion detection achieved higher positive response rates in PB than in MB patients (positive ratio of MB vs PB: 40% vs 56% for LID-1, 28.6% vs 47.8% for ML89, 31.4% vs 60.7% for ML2044, and 31.4 vs 47.8% for ML2028) and could distinguish MB from EC when stimulated with ML89(AUC = 0.6664) and PB fromTB when stimulated with ML2044 and ML2028(AUC = 0.7549 and 0.7372, respectively). CONCLUSION: The NDO-LID Rapid Test and M. leprae antigen-specific ELISA are useful tools to assist in the diagnosis of leprosy patients, especially MB patients, although the former had higher sensitivity but lower specificity than the latter. M. leprae antigen-specific IFN gamma release assessed by WBA has diagnostic value for distinguishing PB from TB but not for distinguishing PB from HHC or EC. Screening novel M. leprae-specific antigens, combining different M. leprae antigens and a multi-cytokine analyte model may be needed for more effective diagnosis of leprosy. PMID- 30248095 TI - The genomic basis of environmental adaptation in house mice. AB - House mice (Mus musculus) arrived in the Americas only recently in association with European colonization (~400-600 generations), but have spread rapidly and show evidence of local adaptation. Here, we take advantage of this genetic model system to investigate the genomic basis of environmental adaptation in house mice. First, we documented clinal patterns of phenotypic variation in 50 wild caught mice from a latitudinal transect in Eastern North America. Next, we found that progeny of mice from different latitudes, raised in a common laboratory environment, displayed differences in a number of complex traits related to fitness. Consistent with Bergmann's rule, mice from higher latitudes were larger and fatter than mice from lower latitudes. They also built bigger nests and differed in aspects of blood chemistry related to metabolism. Then, combining exomic, genomic, and transcriptomic data, we identified specific candidate genes underlying adaptive variation. In particular, we defined a short list of genes with cis-eQTL that were identified as candidates in exomic and genomic analyses, all of which have known ties to phenotypes that vary among the studied populations. Thus, wild mice and the newly developed strains represent a valuable resource for future study of the links between genetic variation, phenotypic variation, and climate. PMID- 30248099 TI - An Anopheles aquasalis GATA factor Serpent is required for immunity against Plasmodium and bacteria. AB - Innate immunity is an ancient and conserved defense system that provides an early effective response against invaders. Many immune genes of Anopheles mosquitoes have been implicated in defense against a variety of pathogens, including plasmodia. Nevertheless, only recent work identified some immune genes of Anopheles aquasalis mosquitoes upon P. vivax infection. Among these was a GATA transcription factor gene, which is described here. This is an ortholog of GATA factor Serpent genes described in Drosophila melanogaster and Anopheles gambiae. Gene expression analyses showed an increase of GATA-Serpent mRNA in P. vivax infected A. aquasalis and functional RNAi experiments identified this transcription factor as an important immune gene of A. aquasalis against both bacteria and P. vivax. Besides, we were able to identify an effect of GATA Serpent knockdown on A. aquasalis hemocyte proliferation and differentiation. These findings expand our understanding of the poorly studied A. aquasalis-P. vivax interactions and uncover GATA-Serpent as a key player of the mosquito innate immune response. PMID- 30248100 TI - Formative evaluation of a training intervention for community health workers in South Africa: A before and after study. AB - BACKGROUND: Community Health Workers (CHWs) have a crucial role in improving health in their communities and their role is being expanded in many parts of the world. However, the effectiveness of CHWs is limited by poor training and the education of CHWs has received little scientific attention. METHODS: Our study was carried out in two districts of KwaZulu-Natal, South Africa. We developed and piloted an inexpensive (two day) training intervention covering national government priorities: HIV/AIDS, sexually transmitted disease and Tuberculosis; and Women's Sexual and Reproductive Health and Rights. Sixty-four CHWs consented to participate in the main study which measured knowledge gains using a modified Solomon design of four different testing schedules to distinguish between the effects of the intervention, testing and any interaction between intervention and testing. We also measured confidence, satisfaction and costs. RESULTS: Following the training intervention, improvements in knowledge scores were seen across topics and across districts. These changes in knowledge were statistically significant (p<0.001) and of large magnitude (over 45 percentage points or four standard deviations). However, the CHWs assigned to the test-test-train schedule in one district showed high gains in knowledge prior to receiving the training. All CHWs reported high levels of satisfaction with the training and marked improvements in their confidence in advising clients. The training cost around US$48 per CHW per day and has the potential to be cost-effective if the large gains in knowledge are translated into improved field-based performance and thus health outcomes. CONCLUSION: Training CHWs can result in large improvements in knowledge with a short intervention. However, improvements seen in other studies could be due to test 'reactivity'. Further work is needed to measure the generalisability of our results, retention of knowledge and the extent to which improved knowledge is translated into improved practice. PMID- 30248101 TI - Impact of MMP-2 and MMP-9 enzyme activity on wound healing, tumor growth and RACPP cleavage. AB - Matrix metalloproteinases-2 and -9 (MMP-2/-9) are key tissue remodeling enzymes that have multiple overlapping activities critical for wound healing and tumor progression in vivo. To overcome issues of redundancy in studying their functions in vivo, we created MMP-2/-9 double knockout (DKO) mice in the C57BL/6 background to examine wound healing. We then bred the DKO mice into the polyomavirus middle T (PyVmT) model of breast cancer to analyze the role of these enzymes in tumorigenesis. Breeding analyses indicated that significantly fewer DKO mice were born than predicted by Mendelian genetics and weaned DKO mice were growth compromised compared with wild type (WT) cohorts. Epithelial wound healing was dramatically delayed in adult DKO mice and when the DKO was combined with the PyVmT oncogene, we found that the biologically related process of mammary tumorigenesis was inhibited in a site-specific manner. To further examine the role of MMP-2/-9 in tumor progression, tumor cells derived from WT or DKO PyVmT transgenic tumors were grown in WT or DKO mice. Ratiometric activatable cell penetrating peptides (RACPPs) previously used to image cancer based on MMP-2/-9 activity were used to understand differences in MMP activity in WT or knockout syngeneic tumors in WT and KO animals. Analysis of an MMP-2 selective RACPP in WT or DKO mice bearing WT and DKO PyVmT tumor cells indicated that the genotype of the tumor cells was more important than the host stromal genotype in promoting MMP-2/-9 activity in the tumors in this model system. Additional complexities were revealed as the recruitment of host macrophages by the tumor cells was found to be the source of the tumor MMP-2/-9 activity and it is evident that MMP-2/-9 from both host and tumor is required for maximum signal using RACPP imaging for detection. We conclude that in the PyVmT model, the majority of MMP-2/-9 activity in mammary tumors is associated with host macrophages recruited into the tumor rather than that produced by the tumor cells themselves. Thus therapies that target tumor-associated macrophage functions have the potential to slow tumor progression. PMID- 30248103 TI - Resistance gained, resistance lost: An explanation for host-parasite coexistence. AB - Host populations are under continual selection by parasites due to reduced fitness of infected individuals relative to uninfected individuals. This should select for host resistance against parasites, and ample evidence from the laboratory and natural populations demonstrates that hosts can respond rapidly to parasitism by evolving resistance. Why then do parasites still exist? In part, this is due to ongoing arms races as parasites evolve counteradaptations to overcome resistance and to the presence of spatial structure and refuges. However, host-parasite coexistence can also be explained through loss of resistance over time due either to selection against costly resistance mechanisms or constant loss of resistance via reversion mutations. PMID- 30248104 TI - Occupancy and detectability modelling of vertebrates in northern Australia using multiple sampling methods. AB - Understanding where species occur and how difficult they are to detect during surveys is crucial for designing and evaluating monitoring programs, and has broader applications for conservation planning and management. In this study, we modelled occupancy and the effectiveness of six sampling methods at detecting vertebrates across the Top End of northern Australia. We fitted occupancy detection models to 136 species (83 birds, 33 reptiles, 20 mammals) of 242 recorded during surveys of 333 sites in eight conservation reserves between 2011 and 2016. For modelled species, mean occupancy was highly variable: birds and reptiles ranged from 0.01-0.81 and 0.01-0.49, respectively, whereas mammal occupancy was lower, ranging from 0.02-0.30. Of the 11 environmental covariates considered as potential predictors of occupancy, topographic ruggedness, elevation, maximum temperature, and fire frequency were retained more readily in the top models. Using these models, we predicted species occupancy across the Top End of northern Australia (293,017 km2) and generated species richness maps for each species group. For mammals and reptiles, high richness was associated with rugged terrain, while bird richness was highest in coastal lowland woodlands. On average, detectability of diurnal birds was higher per day of surveys (0.33 +/- 0.09) compared with nocturnal birds per night of spotlighting (0.13 +/- 0.06). Detectability of reptiles was similar per day/night of pit trapping (0.30 +/- 0.09) as per night of spotlighting (0.29 +/- 0.11). On average, mammals were highly detectable using motion-sensor cameras for a week (0.36 +/- 0.06), with exception of smaller-bodied species. One night of Elliott trapping (0.20 +/- 0.06) and spotlighting (0.19 +/- 0.06) was more effective at detecting mammals than cage (0.08 +/- 0.03) and pit trapping (0.05 +/- 0.04). Our estimates of species occupancy and detectability will help inform decisions about how best to redesign a long-running vertebrate monitoring program in the Top End of northern Australia. PMID- 30248102 TI - Health care costs of case management for frequent users of the emergency department: Hospital and insurance perspectives. AB - BACKGROUND: In most emergency departments (EDs), few patients account for a relatively high number of ED visits. To improve the management of these patients, the university hospital of Lausanne, Switzerland, implemented an interdisciplinary case management (CM) intervention. This study examined whether the CM intervention-compared with standard care (SC) in the ED-reduced costs generated by frequent ED users, not only from the hospital perspective, but also from the third-party payer perspective, that is, from a broader perspective that takes into account the costs of health care services used outside the hospital offering the intervention. METHODS: In this randomized controlled trial, 250 frequent ED users (>5 visits during the previous 12 months) were allocated to either the CM or the SC group and followed up for 12 months. Cost data were obtained from the hospital's analytical accounting system for the entire sample and from health insurance companies for a subgroup (n = 140). Descriptive statistics and multivariate regressions were used to make comparisons between groups and assess the contribution of patient characteristics to the main cost components. RESULTS: At the end of the 12-month follow-up, 115 patients were in the CM group and 115 in the SC group (20 had died). Despite differences in economic costs between patients in the CM intervention and the SC groups, our results do not show any statistically significant reduction in costs associated with the intervention, either for the hospital that housed the intervention or for the third-party payer. Frequent ED users were big users of health services provided by both the hospital and community-based services, with 40% of costs generated outside the hospital that housed the intervention. Higher age, Swiss citizenship, and having social difficulty increased costs significantly. CONCLUSIONS: As the role of the CM team is to guide patients through the entire care process, the intervention location is not limited to the hospital but often extends into the community. PMID- 30248106 TI - An SEIR model of influenza A virus infection and reinfection within a farrow-to finish swine farm. AB - Influenza A virus (IAV) in swine is a pathogen that causes a threat to the health as well as to the production of swine. Moreover, swine can spread this virus to other species including humans. The virus persists in different types of swine farms as evident in a number of studies. The core objectives of this study are (i) to analyze the dynamics of influenza infection of a farrow-to-finish swine farm, (ii) to explore the reinfection at the farm level, and finally (iii) to examine the effectiveness of two control strategies: vaccination and reduction of indirect contact. The analyses are conducted using a deterministic Susceptible Exposed-Infectious-Recovered (SEIR) model. Simulation results show that the disease is maintained in gilts and piglets because of new susceptible pigs entering the population on a weekly basis. A sensitivity analysis shows that the results are not sensitive to variation in the parameters. The results of the reinfection simulation indicate that the virus persists in the entire farm. The control strategies studied in this work are not successful in eliminating the virus within the farm. PMID- 30248105 TI - Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. AB - BACKGROUND: This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS: NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of >=12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02 1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. CONCLUSIONS: The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27. PMID- 30248108 TI - Differential binding of chemokines CXCL1, CXCL2 and CCL2 to mouse glomerular endothelial cells reveals specificity for distinct heparan sulfate domains. AB - INTRODUCTION: Proliferative glomerulonephritis manifests in a range of renal diseases and is characterized by the influx of inflammatory cells into the glomerulus. Heparan sulfate (HS) is an important (co-)receptor for binding of chemokines, cytokines and leukocytes to the endothelial glycocalyx, a thick glycan layer that covers the inside of blood vessels. During glomerulonephritis, HS in the glomerular endothelial glycocalyx plays a central role in chemokine presentation and oligomerization, and in binding of selectins and integrins expressed by leukocytes. We hypothesize that distinct endothelial HS domains determine the binding of different chemokines. In this study we evaluated the interaction of three pro-inflammatory chemokines (CXCL1, CXCL2 and CCL2) with mouse glomerular endothelial cells (mGEnC-1) in ELISA in competition with different HS preparations and anti-HS single chain variable fragment (scFv) antibodies specific for distinct HS domains. RESULTS: HS appeared to be the primary ligand mediating chemokine binding to the glomerular endothelial glycocalyx in vitro. We found differential affinities of CXCL1, CXCL2 and CCL2 for HS in isolated mGEnC-1 glycocalyx, heparan sulfate from bovine kidney or low molecular weight heparin in competition ELISAs using mGEnC-1 as a substrate, indicating that chemokine binding is affected by the domain structure of the different HS preparations. Blocking of specific HS domains with anti-HS scFv antibodies revealed a domain-specific interaction of the tested chemokines to HS on mGEnC-1. Furthermore, chemokines did not compete for the same binding sites on mGEnC-1. CONCLUSION: CXCL1, CXCL2 and CCL2 binding to the glomerular endothelial glycocalyx appears differentially mediated by specific HS domains. Our findings may therefore contribute to the development of HS-based treatments for renal and possibly other inflammatory diseases specifically targeting chemokine-endothelial cell interactions. PMID- 30248109 TI - Rubella immunity and serum perfluoroalkyl substances: Sex and analytic strategy. AB - BACKGROUND: Perfluoroalkyl substances (PFASs) have been associated with decreased immunity to childhood tetanus and diphtheria immunizations. If these vaccinations are vulnerable to influence from PFASs, questions arise about associations with other common inoculations. OBJECTIVE: To examine whether serum PFASs were associated with reduced immunity to rubella immunization, and whether interactions with sex or ethnicity warranted analytic stratification. Usually, toxicology analyses are calculated controlling for race and sex. However, sex differences in immune function have been reported and a reduction of immunity to rubella in women could pose risks such miscarriage. METHODS: We analyzed a nationally representative sample of individuals >= 12 years from the National Health and Nutrition Examination Survey (NHANES) for years 1999-2000 and 2003 2004 for whom PFAS measures were available. Our analytic strategy was to start with separate analyses for youth and adults controlling for several covariates including ethnicity and sex, as well as the interaction of these terms with PFASs. If there was a main effect of PFASs and an interaction term, we would stratify analyses of effect size. The outcome variable was Rubella IgG titers by quartile of perfluoroalkyl substances. RESULTS: After exclusion for missing data, the analyzed sample contained 581 adult women, 621 adult men, and 1012 youth. There was no significant effect of PFASs on immunity in youths but a significant effect of both PFOA and PFOS in adults, as well as a significant interaction of PFOA x sex and a borderline significant interaction of PFOS x sex. When effect size analyses were stratified by sex, a significant association between rubella titres and PFOA was found in men but not women and PFOS was not significant in either sex. CONCLUSIONS: These results support our earlier studies showing sex specific responses to PFASs and indicate the importance of thinking carefully about analytic strategies in population based toxicology research. PMID- 30248110 TI - Vertical foraging shifts in Hawaiian forest birds in response to invasive rat removal. AB - Worldwide, native species increasingly contend with the interacting stressors of habitat fragmentation and invasive species, yet their combined effects have rarely been examined. Direct negative effects of invasive omnivores are well documented, but the indirect effects of resource competition or those caused by predator avoidance are unknown. Here we isolated and examined the independent and interactive effects of invasive omnivorous Black rats (Rattus rattus) and forest fragment size on the interactions between avian predators and their arthropod prey. Our study examines whether invasive omnivores and ecosystem fragment size impact: 1) the vertical distribution of arthropod species composition and abundance, and 2) the vertical profile of foraging behaviors of five native and two non-native bird species found in our study system. We predicted that the reduced edge effects and greater structural complexity and canopy height of larger fragments would limit the total and proportional habitat space frequented by rats and thus limit their impact on both arthropod biomass and birds' foraging behavior. We experimentally removed invasive omnivorous Black rats across a 100 fold (0.1 to 12 ha) size gradient of forest fragments on Hawai'i Island, and paired foraging observations of forest passerines with arthropod sampling in the 16 rat-removed and 18 control fragments. Rat removal was associated with shifts in the vertical distribution of arthropod biomass, irrespective of fragment size. Bird foraging behavior mirrored this shift, and the impact of rat removal was greater for birds that primarily eat fruit and insects compared with those that consume nectar. Evidence from this model study system indicates that invasive rats indirectly alter the feeding behavior of native birds, and consequently impact multiple trophic levels. This study suggests that native species can modify their foraging behavior in response to invasive species removal and presumably arrival through behavioral plasticity. PMID- 30248112 TI - An improved collaborative filtering method based on similarity. AB - The recommender system is widely used in the field of e-commerce and plays an important role in guiding customers to make smart decisions. Although many algorithms are available in the recommender system, collaborative filtering is still one of the most used and successful recommendation technologies. In collaborative filtering, similarity calculation is the main issue. In order to improve the accuracy and quality of recommendations, we proposed an improved similarity model, which takes three impact factors of similarity into account to minimize the deviation of similarity calculation. Compared with the traditional similarity measure, the advantages of our proposed model are that it makes full use of rating data and solves the problem of co-rated items. To validate the efficiency of the proposed algorithm, experiments were performed on four datasets. Results show that the proposed method can effectively improve the preferences of the recommender system and it is suitable for the sparsity data. PMID- 30248107 TI - Genome-wide association studies and CRISPR/Cas9-mediated gene editing identify regulatory variants influencing eyebrow thickness in humans. AB - Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51*10-10) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73*10-8). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81*10-11) near EDAR. We performed fine mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure. PMID- 30248111 TI - LDH-A regulates the tumor microenvironment via HIF-signaling and modulates the immune response. AB - Previous studies show that LDH-A knockdown reduces orthotopic 4T1 breast tumor lactate and delays tumor growth and the development of metastases in nude mice. Here, we report significant changes in the tumor microenvironment (TME) and a more robust anti-tumor response in immune competent BALB/c mice. 4T1 murine breast cancer cells were transfected with shRNA plasmids directed against LDH-A (KD) or a scrambled control plasmid (NC). Cells were also transduced with dual luciferase-based reporter systems to monitor HIF-1 activity and the development of metastases by bioluminescence imaging, using HRE-sensitive and constitutive promoters, respectively. The growth and metastatic profile of orthotopic 4T1 tumors developed from these cell lines were compared and a primary tumor resection model was studied to simulate the clinical management of breast cancer. Primary tumor growth, metastasis formation and TME phenotype were significantly different in LDH-A KD tumors compared with controls. In LDH-A KD cells, HIF-1 activity, hexokinase 1 and 2 expression and VEGF secretion were reduced. Differences in the TME included lower HIF-1alpha expression that correlated with lower vascularity and pimonidazole staining, higher infiltration of CD3+ and CD4+ T cells and less infiltration of TAMs. These changes resulted in a greater delay in metastases formation and 40% long-term survivors (>20 weeks) in the LDH-A KD cohort following surgical resection of the primary tumor. We show for the first time that LDH-depletion inhibits the formation of metastases and prolongs survival of mice through changes in tumor microenvironment that modulate the immune response. We attribute these effects to diminished HIF-1 activity, vascularization, necrosis formation and immune suppression in immune competent animals. Gene-expression analyses from four human breast cancer datasets are consistent with these results, and further demonstrate the link between glycolysis and immune suppression in breast cancer. PMID- 30248113 TI - Attraction of phlebotomine sandflies to volatiles from skin odors of individuals residing in an endemic area of tegumentary leishmaniasis. AB - BACKGROUND: Many studies have investigated what could attract insects of medical importance and a crucial role has lately been attributed to human skin odors. Most of these researches have been concerned with mosquitoes, e.g., vectors of dengue and malaria. Little is known about volatile organic compounds (VOCs) from human skin odors and their effects on leishmania vectors. OBJECTIVE: The present study aimed to identify the VOCs from human skin that can be attractive to female anthropophilic phlebotomine sandflies. RESULTS: Forty-two VOCs were identified from skin odors of 33 male volunteers, seven of which were tested in wind tunnel assays employing field-captured phlebotomine sandflies (75.4% identified as Lutzomyia intermedia). Hexane and (E)-oct-3-en-1-ol (octenol) were used as negative and positive controls, respectively. 2-Phenylacetaldehyde (hereafter called phenylacetaldehyde), 6-methylhept-5-en-2-one (also known as sulcatone), nonadecane and icosane were found to activate female phlebotomine sandflies, but only phenylacetaldehyde, 6-methylhepten-5-en-2-one and icosane elicited attraction responses. CONCLUSIONS: These results suggest that phenylacetaldehyde, 6-methylhepten-5-en-2-one and icosane may be suitable candidates for attractiveness experimentation in the field which can be an important tool to develop strategies concerning human beings protection against phlebotomine sandflies bites and consequently against leishmaniasis. PMID- 30248115 TI - Biodiversity of cyanobacteria and other aquatic microorganisms across a freshwater to brackish water gradient determined by shotgun metagenomic sequencing analysis in the San Francisco Estuary, USA. AB - Blooms of Microcystis and other harmful cyanobacteria can degrade water quality by producing cyanotoxins or other toxic compounds. The goals of this study were (1) to facilitate understanding of community structure for various aquatic microorganisms in brackish water and freshwater regions with emphasis on cyanobacteria, and (2) to test a hypothesis that Microcystis genotypes that tolerate higher salinity were blooming in brackish water environments during the severe drought, 2014. Shotgun metagenomic analysis revealed that cyanobacteria dominated the brackish water region while bacteria dominated the freshwater region. A group of cyanobacteria (e.g., Aphanizomenon, Microcystis, Planktothrix, Pseudanabaena), bacteria (e.g., Bacillus, Porphyrobacter), and diatoms (Phaeodactylum and Thalassiosira) were abundant in the brackish water region. In contrast, Hassallia (cyanobacteria) and green algae (Nannochloropsis, Chlamydomonas, and Volvox) were abundant in the landward freshwater region. Station variation was also apparent. One landward sampling station located downstream of an urbanized area differed substantially from the other stations in terms of both water chemistry and community structure, with a higher percentage of arthropods, green algae, and eukaryotes. Screening of the Microcystis internal transcribed spacer region revealed six representative genotypes, and two of which were successfully quantified using qPCR (Genotypes I and VI). Both genotypes occurred predominantly in the freshwater region, so the data from this study did not support the hypothesis that salinity tolerant Microcystis genotypes bloomed in the brackish water region in 2014. PMID- 30248114 TI - Seasonal association between ambient ozone and hospital admission for respiratory diseases in Hanoi, Vietnam. AB - BACKGROUND: Many studies have indicated the detrimental effect of ambient ozone to respiratory health in different countries. The levels of ozone in Hanoi, Vietnam are frequently above the WHO guideline but very few studies on the effects of ambient ozone on human health have been conducted in this location. This study aimed to examine the effects of ozone on hospital admission for respiratory diseases in Hanoi, by diseases, ages and seasons. METHODS: Hospital admissions, air pollutants and meteorological data were collected from January 2010 to June 2014. We used generalized linear models and distributed lag linear model to assess the association. In addition to full year analysis, we conducted restricted analysis of the data for two summer (from June-August) and winter (from December-February) seasons and grouped hospital admissions by diseases and ages (all ages, children 0 to 5 years and elderly >65 years). The delayed effect of ozone was assessed using lags of up to 5 days. RESULTS: Ozone has a stronger effect on the risk of hospital admission for respiratory diseases and wheeze associated disorders in the winter. For respiratory diseases, children were affected by ozone more than other age groups in both winter and summer. Each increase of 10 MUg/m3 of ozone is associated with an increase of 6.2% risk of admission for respiratory disease among children in the winter and 1.2% in the summer. For wheeze-associated disorders, the elderly group seemed to be more affected by ozone in full year and winter but no significant association was found between ozone and admission for wheeze-associated diseases in any age group. CONCLUSIONS: Ozone is a risk factor for respiratory admission, especially amongst children under 5 years old in Hanoi, and ozone has a stronger effect in the winter than in the summer in this city. PMID- 30248116 TI - Improvement of out-of-hospital cardiac arrest survival rate after implementation of the 2010 resuscitation guidelines. AB - OBJECTIVE: The implementation of cardiopulmonary resuscitation guidelines, updated every five years, appears to improve patient survival rates after Out-Of Hospital Cardiac Arrest (OHCA). The aim of this study is: 1) to measure the level of improvement in the prognosis of OHCA patient survival rates for the years 2009 and 2010 and the following two years 2011 and 2012; and 2) correlate the improvement in prognosis with the updated 2010 Advanced Cardiovascular Life Support (ACLS) Guidelines. METHOD: We performed a retrospective observational study based on Geneva's OHCA register that includes data from January 1, 2009 to December 31, 2012. We compared the evolution of prognostic factors that influenced survival at hospital discharge between the periods before and after the implementation of the 2010 guidelines. We then compared the survival rates between each period. Finally, we adjusted the effects on survival in the second period to prognostic factors not linked with the care provided by Emergency Medical Services (EMS) teams, using a multivariable logistic regression model. Changes in advanced resuscitation treatment provided by EMS personnel were also examined. RESULTS: 795 OHCA were resuscitated between 1st January, 2009 and 31st December, 2012. The prognosis of patient survival at the time of hospital discharge rose from 10.33% in 2009-2010 to 17.01% in 2011-2012 (p = 0.007). After making adjustments for the effect of improved survival rates on the second period with factors not related to care provided by EMS teams, the odds ratio (OR) remains comparable (OR = 1.87, 95% CI [1.08-3.22]). Measured changes in treatment provided by EMS personnel were minor. CONCLUSIONS: Survival rate for OHCA patients improved significantly in 2011-2012. This study suggests that it was probably the improvement in the quality of care provided during CPR and post cardiac arrest care that have contributed to the increase in survival rates at the time of hospital discharge. PMID- 30248117 TI - Patterns and controls of temperature sensitivity of soil respiration in a meadow steppe of the Songnen Plain, Northeast China. AB - Quantifying the temporal and spatial patterns of temperature sensitivity (Q10) of soil respiration (Rs) as well as its controlling factors is critical to reveal the response the soil ecological processes to global warming and improve carbon budget estimations at a regional scale. The seasonal and annual variations in the temperature response of Rs were assessed during the two growing seasons in 2011 and 2012 in four different vegetation sites in a meadow steppe of the Songnen Plain, China. The Q10 values across all sites exhibited significant seasonal variations with a minimum value (1.81-2.34) occurring during summer and a peak value (3.82-4.54) occurring in either spring or autumn. The mean seasonal Q10 values showed no significant differences among the four different vegetation types. On the annual scale, however, the Chloris virgata site had significantly higher annual Q10 values (3.67-4.22) than the other three community sites in 2011 and 2012 and over the two years (2.01-3.67), indicating that the response of the Rs to climate warming may vary with vegetation type. The soil temperature and moisture had interactive effects on the variations of Q10 values. Soil temperature was the dominant factor influencing Q10 values, while soil moisture was an additional contributor to the variations of Q10. Due to the significant temporal and spatial variations in soil respiration response to temperature, acclimation of Rs to temperature variation should be taken into account in forecasting future terrestrial carbon cycle and its feedback to global warming. PMID- 30248118 TI - The stability of memristive multidirectional associative memory neural networks with time-varying delays in the leakage terms via sampled-data control. AB - In this paper, we propose a new model of memristive multidirectional associative memory neural networks, which concludes the time-varying delays in leakage terms via sampled-data control. We use the input delay method to turn the sampling system into a continuous time-delaying system. Then we analyze the exponential stability and asymptotic stability of the equilibrium points for this model. By constructing a suitable Lyapunov function, using the Lyapunov stability theorem and some inequality techniques, some sufficient criteria for ensuring the stability of equilibrium points are obtained. Finally, numerical examples are given to demonstrate the effectiveness of our results. PMID- 30248119 TI - Elucidation and analyses of the regulatory networks of upland and lowland ecotypes of switchgrass in response to drought and salt stresses. AB - Switchgrass is an important bioenergy crop typically grown in marginal lands, where the plants must often deal with abiotic stresses such as drought and salt. Alamo is known to be more tolerant to both stress types than Dacotah, two ecotypes of switchgrass. Understanding of their stress response and adaptation programs can have important implications to engineering more stress tolerant plants. We present here a computational study by analyzing time-course transcriptomic data of the two ecotypes to elucidate and compare their regulatory systems in response to drought and salt stresses. A total of 1,693 genes (target genes or TGs) are found to be differentially expressed and possibly regulated by 143 transcription factors (TFs) in response to drought stress together in the two ecotypes. Similarly, 1,535 TGs regulated by 110 TFs are identified to be involved in response to salt stress. Two regulatory networks are constructed to predict their regulatory relationships. In addition, a time-dependent hidden Markov model is derived for each ecotype responding to each stress type, to provide a dynamic view of how each regulatory network changes its behavior over time. A few new insights about the response mechanisms are predicted from the regulatory networks and the time-dependent models. Comparative analyses between the network models of the two ecotypes reveal key commonalities and main differences between the two regulatory systems. Overall, our results provide new information about the complex regulatory mechanisms of switchgrass responding to drought and salt stresses. PMID- 30248120 TI - Estimating human-to-human transmissibility of hepatitis A virus in an outbreak at an elementary school in China, 2011. AB - Hepatitis A is caused by hepatitis A virus and occurs worldwide. Estimating the transmissibility, which is usually characterized by the basic reproductive number R0, the mean number of secondary infectious cases generated by a single primary infectious case introduced into a totally susceptible population, provides crucial information for the effort required to stop infection spreading. Hepatitis A virus is usually transmitted indirectly through contaminated food and environment. An outbreak from March to June 2011 was reported to have occurred at an elementary school of 698 pupils in China and it was found that the outbreak was due to direct transmission between school children. Based on the symptom onset date and the social contact network of the children, in this study we estimate the serial interval (i.e. the gap in symptom onset between an infectee and its infector) and use different statistical methods to estimate R0. Combining with the positivity of IgG antibodies tests, we develop a compartmental transmission dynamics model which includes both asymptomatic and symptomatic infections to estimate the overall R0. Our analysis suggests a serial interval of mean = 23.9 days and standard deviation = 20.9 days. The different statistical methods suggest estimates for R0 in the outbreak varying from 2.1 to 2.8, and the estimates from the transmission dynamics model are consistent with this range. Our estimates are in agreement with that from one study in England but are higher than that from one study in the United States. Our transmission dynamics model suggests that the proportion of symptomatic infections is about 9%, implying that there were about 344 asymptomatic infections along with the 32 observed symptomatic cases. Furthermore, it is shown that the inclusion of asymptomatic infection in the epidemic process increases the estimate of R0 but does not do so greatly provided that the proportion of symptomatic infections is constant over the outbreak and there is no difference in transmissibility between symptomatic and asymptomatic infections. PMID- 30248121 TI - Social cognition in myotonic dystrophy type 1: Specific or secondary impairment? AB - AIMS: The cognitive profile of Myotonic Dystrophy type 1 (DM1) has been described in recent decades. Moreover, DM1 patients show lowered social engagement and difficulties in social-cognitive functions. The aim of the present study is to explore whether social cognition impairment is present in DM1 taking into account the overall cognitive condition. METHOD: 38 patients and a control group paired in age and gender participated in the study. All the participants had an IQ within the normal range. Subjects were administered an abbreviated neuropsychological battery which comprised a facial emotion recognition test (POFA) and Faux Pas Test, as well as a self-report questionnaire on cognitive and affective empathy (TECA). RESULTS: Statistically significant differences were found only for facial emotion recognition (U = 464.0, p = .006) with a moderate effect size (.31), with the controls obtaining a higher score than the patients. Analyzing each emotion separately, DM1 patients scored significantly lower than controls on the recognition of anger and disgust items. Emotion recognition did not correlate with genetic load, but did correlate negatively with age. No differences were found between patients and controls in any of the other variables related to Theory of Mind (ToM) and empathy. CONCLUSION: DM1 does not manifest specific impairments in ToM since difficulties in this area predominantly rely on the cognitive demand of the tasks employed. However, a more basic process such as emotion recognition appears as a core deficit. The role of this deficit as a marker of aging related decline is discussed. PMID- 30248122 TI - An amine oxidase gene from mud crab, Scylla paramamosain, regulates the neurotransmitters serotonin and dopamine in vitro. AB - Amine oxidase, which participates in the metabolic processing of biogenic amines, is widely found in organisms, including higher organisms and various microorganisms. In this study, the full-length cDNA of a novel amine oxidase gene was cloned from the mud crab, Scylla paramamosain, and termed SpAMO. The cDNA sequence was 2,599 bp in length, including an open reading frame of 1,521 bp encoding 506 amino acids. Two amino acid sequence motifs, a flavin adenine dinucleotide-binding domain and a flavin-containing amine oxidoreductase, were highly conserved in SpAMO. A quantitative real-time polymerase chain reaction analysis showed that the expression level of SpAMO after quercetin treatment was time- and concentration-dependent. The expression of SpAMO tended to decrease and then increase in the brain and haemolymph after treatment with 5 mg/kg/d quercetin; after treatment with 50 mg/kg/d quercetin, the expression of SpAMO declined rapidly and remained low in the brain and haemolymph. These results indicated that quercetin could inhibit the transcription of SpAMO, and the high dose (50 mg/kg/d) had a relatively significant inhibitory effect. SpAMO showed the highest catalytic activity on serotonin, followed by dopamine, beta phenylethylamine, and spermine, suggesting that the specific substrates of SpAMO are serotonin and dopamine. A bioinformatics analysis of SpAMO showed that it has molecular characteristics of spermine oxidase, but a quercetin test and enzyme activity study indicated that it also functions like monoamine oxidase. It is speculated that SpAMO might be a novel amine oxidase in S. paramamosain that has the functions of both spermine oxidase and monoamine oxidase. PMID- 30248123 TI - Association between white matter lesions and cerebral Abeta burden. AB - INTRODUCTION: White matter lesions (WMLs), detected as hyperintensities on T2 weighted MRI, represent small vessel disease in the brain and are considered a potential risk factor for memory and cognitive impairment in older adults. The purpose of this study was to evaluate the association between WMLs and cerebral amyloid-beta (Abeta) burden in patients with cognitive impairment. METHODS: A total of 83 patients with cognitive impairment, who underwent brain MRI and F-18 florbetaben PET, were included prospectively: 19 patients were cognitively unimpaired, 30 exhibited mild cognitive impairment (MCI), and 34 exhibited dementia. The Fazekas scale was used to quantify WMLs on T2-weighted brain MR images. Cerebral Abeta burden was quantitatively estimated using volume-of interest analysis. Differences in cerebral Abeta burden were evaluated between low-WML (Fazekas scale <=1) and high-WML (Fazekas scale >=2) groups. The relationship between the Fazekas rating and cerebral Abeta burden was evaluated using linear regression analysis after adjusting for age and sex. RESULTS: In the overall cohort, the high-WML group exhibited significantly higher Abeta burden compared with the low-WML group (P = 0.011) and cerebral Abeta burden was positively correlated with Fazekas rating (beta = 0.299, P = 0.006). In patients with MCI, the high-WML group exhibited significantly higher Abeta burden compared with the low-WML group (P = 0.019) and cerebral Abeta burden was positively correlated with Fazekas rating (beta = 0.517, P = 0.003). CONCLUSION: The presence of WMLs was associated with cerebral Abeta burden in patients with MCI. Our findings suggest that small vessel disease in the brain is related to Alzheimer's disease pathology. PMID- 30248124 TI - A systematic meta-analysis of oxygen-to-glucose and oxygen-to-carbohydrate ratios in the resting human brain. AB - Glucose is the predominant fuel supporting brain function. If the brain's entire glucose supply is consumed by oxidative phosphorylation, the molar ratio of oxygen to glucose consumption (OGI) is equal to 6. An OGI of less than 6 is evidence of non-oxidative glucose metabolism. Several studies have reported that the OGI in the resting human brain is less than 6.0, but the exact value remains uncertain. Additionally, it is not clear if lactate efflux accounts for the difference between OGI and its theoretical value of 6.0. To address these issues, we conducted a meta-analysis of OGI and oxygen-to-carbohydrate (glucose + 0.5*lactate; OCI) ratios in healthy young and middle-aged adults. We identified 47 studies that measured at least one of these ratios using arterio-venous differences of glucose, lactate, and oxygen. Using a Bayesian random effects model, the population median OGI was 5.46 95% credible interval (5.25-5.66), indicating that approximately 9% of the brain's glucose metabolism is non oxidative. The population median OCI was 5.60 (5.36-5.84), suggesting that lactate efflux does not account for all non-oxidative glucose consumption. Significant heterogeneity across studies was observed, which implies that further work is needed to characterize how demographic and methodological factors influence measured cerebral metabolic ratios. PMID- 30248125 TI - Endoplasmic reticulum retention motif fused to recombinant anti-cancer monoclonal antibody (mAb) CO17-1A affects mAb expression and plant stress response. AB - The endoplasmic reticulum (ER) is the main site of protein synthesis, folding, and secretion to other organelles. The capacity of the ER to process proteins is limited, and excessive accumulation of unfolded and misfolded proteins can induce ER stress, which is associated with plant diseases. Here, a transgenic Arabidopsis system was established to express anti-cancer monoclonal antibodies (mAbs) that recognize the tumor-associated antigen GA733-2. Monoclonal antibody (mAb) CO17-1A recognize a tumor-associated epitope expressed on the colorectal cancer cell surface. The ER retention Lys-Asp-Glu-Leu (KDEL) motif sequence was added to the C-terminus of the heavy chain to retain anti-colorectal cancer mAbs in the ER, consequently boosting mAb production. Agrobacterium-mediated floral dip transformation was used to generate T1 transformants, and homozygous T4 seeds obtained from transgenic Arabidopsis plants expressing anti-colorectal cancer mAbs were used to confirm the physiological effects of KDEL tagging. Germination rates were not significantly different between both plants expressing mAb CO without KDEL mAb CO (CO plant) and mAb CO with KDEL mAb COK (COK plant). However, COK plants primary root lengths were shorter than those of CO plants and non transgenic Arabidopsis plants in in vitro media. Most ER stress-related genes, with the exception of bZIP28 and IRE1a, were upregulated in COK plants compared to CO plants. Western blot and SDS-PAGE analyses showed that COK plants exhibited up to five times higher expression and mAb amounts than plants. Enhanced expression in mAb COK plants was confirmed by immunohistochemical analyses. mAb COK was distributed across most of the area of leaf tissues, whereas mAb CO was mainly distributed in extracellular areas. Surface plasmon resonance analyses revealed that mAb CO and mAb COK possessed equivalent or slightly better binding activities to antigen EpCAM compared to a commercially available parental antibody. N-glycosylation analysis showed that mAb CO had plant specific residues whereas mAb COK mainly showed an oligo-mannose N-glycan structure without the plant specific glycan residues. In this study, the reduction of plant growth and biomass induced by ER retention signal peptide might be only in in vitro conditions, and thus should be carefully considered for the initial screening for transgenic lines on culture media. Taken together, nevertheless the fusion of ER retention signal peptide is an effective approach for enhancing the yields of recombinant proteins in vivo. PMID- 30248127 TI - Psychometric validation of the Serbian version of the Fear Avoidance Component Scale (FACS). AB - OBJECTIVE: The Fear Avoidance Components Scale (FACS) is a new patient-reported outcome (PRO) questionnaire designed to comprehensively evaluate fear avoidance (FA) beliefs and attitudes in persons with painful medical conditions. The original English version has demonstrated acceptable psychometric properties, including concurrent and predictive validity. Two factors have been identified: 1. general fear avoidance; and 2. types of activities that are avoided. METHODS: The FACS was first translated into Serbian, and then psychometrically validated. A cohort of 322 chronic musculoskeletal pain subjects completed the FACS-Serb and additional FA-related patient-reported outcome (PRO) measures. Their FACS-Serb scores were then compared to a cohort of 68 acute pain subjects. RESULTS: Test retest reliability (ICC2,1 = 0.928) and internal consistency for both Factors (Cronbach alpha 0.904 and 0,880 respectively) were very good. An acceptable fit was found with a confirmatory factor analysis of the 2-factor model found with the original English version of the FACS. Strong associations were found among FACS-Serb scores and other PRO measures of pain catastrophizing, depressive/anxiety symptoms, perceived disability, and pain intensity (p<0.001 for all analyses). FACS-Serb total scores, separate Factor scores, and subjective pain ratings were significantly higher in the chronic vs. acute pain cohorts (p<0.001 for all analyses). CONCLUSIONS: The FACS-Serb demonstrated strong psychometric properties, including strong reliability and internal consistency, criterion validity (through associations with other FA-related PRO measures), and discriminant validity (through comparisons with a separate acute pain cohort). The FACS-Serb appears to be a potentially useful pain-related assessment tool. PMID- 30248126 TI - Dietary diversity determinants and contribution of fish to maternal and under five nutritional status in Zambia. AB - BACKGROUND: This study examines socio-economic determinants of food consumption patterns amongst women of reproductive age and children aged 6-59 months from urban poor settlements of Lusaka and their implications for nutritional status. Particular emphasis was placed on the role of fish in their diets and nutritional status. METHODS: A cross-sectional survey design was applied, in which 714 mother child dyads, with children aged 6-59 months were enrolled. A three-stage randomized cluster sampling approach was applied. RESULTS: The mean dietary diversity score among children aged 6-23 and 24-59 months was 2.98 (+/-1.27) and 3.478 (+/-1.07), respectively. In children aged 6-23 months, there was a significant difference in their nutritional status, based on fish consumption (chi2 = 10.979, df = 2, p = 0.004). Children from poorer households consumed mostly small fish (Kapenta). The quantity of fish consumed by children was significantly associated with stunting in both age groups, odds ratio = 0.947 (95% CI: 0.896, 1.000) for children aged 6-23 months and odds ratio = 1.038 (95% CI: 1.006, 1.072) for children aged 24-59 months old. Other significant risk factors for stunting in children aged 6-23 months were the child's age, mother's body mass index, access to treated water and child morbidity. Child's age, mother's educational level and wealth status were determinants of dietary diversity in children aged 6-59 months as shown by the Poisson regression. CONCLUSION: Nutritional status of children aged 6-23 months is associated with fish consumption, with children consuming fish less likely to be stunted. Small fish (Kapenta) is an animal-source food that is particularly important in the diet of children in urban poor households in Zambia and contributes to better nutritional outcomes. As all small fish stem from capture fisheries, sustainable one health environmental integration, monitoring and management strategies are desirable. PMID- 30248128 TI - Burden of exposure to infectious bursal disease virus, infectious bronchitis virus, Newcastle disease virus, Mycoplasma gallisepticum, and intestinal parasites in introduced broiler chickens on the Galapagos. AB - Diseases in introduced broilers can possibly spill over to wild birds on the Galapagos. Knowledge about the current burden of exposure to pathogens in broilers on the Galapagos is very limited. The objective of the study reported here was to measure the burden of exposure to infectious bursal disease virus (IBDV), infectious bronchitis virus (IBV), Newcastle disease virus (NDV), Mycoplasma gallisepticum (MG), and intestinal parasites in a sample of broiler chickens on 13 farms on Santa Cruz Island and San Cristobal Island in July 2017. Blood serum samples were tested for detection of antibodies to IBDV, IBV, NDV, and MG by using an IDEXX Enzyme-linked Immunosorbent Assay. In addition, fecal samples and pen bedding environmental samples were processed and analyzed for diagnosis of intestinal parasite eggs under a compound light microscope. The frequency of seropositive broilers to IBDV was 74/130 or 56% (95% CI = 48, 65%), to IBV was 27/130 or 20% (14, 28%), and to NDV was 1/130 or 0.7% (0.1, 4%). All broilers tested negative to MG antibodies. Eimeria spp. infection was common in study broilers. Finally, we observed interaction between broiler chickens and wild birds (finches) inside broiler pens, as well as the presence of backyard chickens inside property limits of study farms. This study produced evidence that exposure to IBDV, IBV, and intestinal parasites in broilers on Santa Cruz Island and San Cristobal Island is important. Study results are relevant because (i) they provide new baseline data on the burden of exposure to avian pathogens in broiler farms, (ii) justify the need to verify standard operating procedures in hatcheries that supply (non-vaccinated) day-old chicks to the Galapagos and (iii) to implement enhanced biosecurity standards on broiler chicken farms to mitigate risk of disease transmission between broilers, backyard poultry, and wild birds on the Galapagos. PMID- 30248129 TI - Use of sedative-hypnotics and the risk of Alzheimer's dementia: A retrospective cohort study. AB - There has been a growing interest in the relationship between sedative-hypnotics use and the risk of Alzheimer's dementia (AD) risk. This study aimed to evaluate the risk of AD associated with the use of sedative-hypnotics. A retrospective cohort study was conducted with randomly selected 5% samples from >=50 years old beneficiaries of National Health Insurance Service (NHIS) of Korea from January 2002 to December 2015. The exposure to sedative-hypnotics was defined when prescribed over 30 defined daily dose (DDD) after January 2004 and it was categorized by prescribed dosage, types and half-lives of benzodiazepines. Time dependent Cox regression model with a lag period of 5-years was used to evaluate the association between use of sedative-hypnotics and the risk of subsequent AD. Sensitivity analysis was performed for restricting sedative-hypnotics only when prescribed with insomnia. A total of 268,170 subjects were identified and subjects exposed to sedative-hypnotics showed a higher risk of AD (HR: 1.79; 95% CI: 1.72-1.86) than those who were not. There was an increased risk of AD among subjects exposed to benzodiazepines or zolpidem (HR: 1.75; 95% CI: 1.67-1.82) and antidepressants or low-dose antipsychotics (HR: 1.63; 95% CI: 1.42-1.87). The risk of AD was increased regardless of dose of sedative-hypnotics and half-life among benzodiazepines, especially in exposure to more than 360 DDD of sedative hypnotics (HR: 1.78; 95% CI: 1.60-1.99) and the long-acting benzodiazepine (HR:1.77; 95% CI: 1.65-1.89). PMID- 30248130 TI - Variability of UK seagrass sediment carbon: Implications for blue carbon estimates and marine conservation management. AB - Seagrass meadows provide a multitude of ecosystem services, including a capacity to sequester carbon dioxide (CO2) within their sediments. Seagrass research in the UK is lacking and there is no published data on sediment carbon (C) within UK seagrass meadows. We sampled 13 Zostera marina meadows along the southwest coast of the UK to assess the variability in their sedimentary organic carbon (OC) stocks. The study sites were considered representative of sub-tidal Z. marina meadows in the UK, spanning a gradient of sheltered to exposed sites, varying in formation, size and density, but found along the same latitudinal gradient. OC stocks (Cstocks) integrated across 100cm depth profiles were similar among all sites (98.01 +/- 2.15 to 140.24 +/- 10.27 Mg C ha-1), apart from at Drakes Island, which recorded an unusually high Cstock (380.07 +/- 17.51 Mg C ha-1) compared to the rest of the region. The total standing stock of C in the top 100cm of the surveyed seagrass meadows was 66,337 t C, or the equivalent of 10,512 individual UK people's CO2 emissions per year. This figure is particularly significant relative to the seagrass area, which totalled 549.79 ha. Using estimates of seagrass cover throughout the UK and recent UK C trading values we approximate that the monetary value of the UK's seagrass standing C stock is between L2.6 million and L5.3 million. The C stock of the UK's seagrass meadows represent one of the largest documented C stocks within Europe and are, therefore, of important ecosystem service value. The research raises questions concerning the reliability of using global or regional data as a proxy for local seagrass C stock estimates and adds to a growing body of literature that is looking to understand the mechanisms of seagrass C storage. When taken with the fact that seagrass meadows are an important habitat for commercially important and endangered species in the UK, along with their declining health and cover, this research supports the need for more robust conservation strategies for UK seagrass habitats. PMID- 30248131 TI - Cortical reorganization after cochlear implantation for adults with single-sided deafness. AB - BACKGROUND: Adults with single sided deafness (SSD) have lost binaural function, which limits sound source localization, speech understanding in noise, and quality of life. For SSD patients, restoration of bilateral auditory input is possible only with a cochlear implant (CI). In this study, cortical auditory evoked potentials (CAEPs) and behavioral performance were measured in left implanted (SSD-CI-L) and right-implanted (SSD-CI-R) patients before and after cochlear implantation. We hypothesized that improvements in behavioral performance would be accompanied by changes in CAEPs after cochlear implantation. DESIGN: Prospective longitudinal study. SETTING: Tertiary referral center. METHOD: Nine right-handed adult SSD CI patients participated in the study. CAEPs were recorded before cochlear implantation and at 6 and 12 months post implantation. CAEPs were elicited using speech stimuli (/ba/) delivered in sound field at 70 dBA. Global field power (GFP) latency and amplitude were calculated for P1, N1 and P2 peaks at each test session. CAEP were analyzed at frontocentral (Cz) and temporal (P7, P8, T7 and T8) and mastoid electrodes (M1 and M2) contralateral to the CI ear. Behavioral measures (sentence recognition in noise, with and without spatial cues) were collected at the same test sessions as for CAEPs. Speech performance and CAEPs were also measured in a control group of normal-hearing (NH) subjects. RESULTS: While increased N1 amplitude was observed in the scalp potential maps for GFP and Cz for SSD-CI-L patients after implantation, the changes were not statistically significant. Peak CAEP amplitude at electrodes to contralateral to the CI ear increased after cochlear implantation for all SSD-CI patients, but significant increases were observed only for mastoid sites. Peak latencies for some components at temporal and mastoid sites remained significantly longer than for the NH control group, even after cochlear implantation. For SSD-CI-R patients, P2 peak amplitude for baseline GFP and Cz was significantly lower than for the NH control group. A significant improvement for speech understanding in noise was observed at 12 months post-implantation when speech was presented to the CI ear and noise to the non-implanted ear. CONCLUSION: After cochlear implantation, speech understanding significantly improved when speech and noise were spatially separated. The increased N1 amplitude for SSD-CI-L patients and the increased bilateral activation for all SSD-CI patients may reflect cortical reorganization and restoration of binaural function after one year of experience with the CI. However, because of the limited number of SSD patients, significant changes in cortical activity after cochlear implantation were often difficult to observe. PMID- 30248132 TI - ATP/P2X7 receptor signaling as a potential anti-inflammatory target of natural polyphenols. AB - Innate immune cells, such as macrophages, respond to pathogen-associated molecular patterns, such as a lipopolysaccharide (LPS), to secrete various inflammatory mediators. Recent studies have suggested that damage-associated molecular patterns (DAMPs), released extracellularly from damaged or immune cells, also play a role in the activation of inflammatory responses. In this study, to prevent excess inflammation, we focused on DAMPs-mediated signaling that promotes LPS-stimulated inflammatory responses, especially adenosine 5' triphosphate (ATP)-triggered signaling through the ionotropic purinergic receptor 7 (P2X7R), as a potential new anti-inflammatory target of natural polyphenols. We focused on the phenomenon that ATP accelerates the production of inflammatory mediators, such as nitric oxide, in LPS-stimulated J774.1 mouse macrophages. Using an siRNA-mediated knockdown and specific antagonist, it was found that the ATP-induced enhanced inflammatory responses were mediated through P2X7R. We then screened 42 polyphenols for inhibiting the ATP/P2X7R-induced calcium influx, and found that several polyphenols exhibited significant inhibitory effects. Especially, a flavonoid baicalein significantly inhibited ATP-induced inflammation, including interleukin-1beta secretion, through inhibition of the ATP/P2X7R signaling. These findings suggest that ATP/P2X7R signaling plays an important role in excess inflammatory responses and could be a potential anti inflammatory target of natural polyphenolic compounds. PMID- 30248133 TI - 4C-seq characterization of Drosophila BEAF binding regions provides evidence for highly variable long-distance interactions between active chromatin. AB - Chromatin organization is crucial for nuclear functions such as gene regulation, DNA replication and DNA repair. Insulator binding proteins, such as the Drosophila Boundary Element-Associated Factor (BEAF), are involved in chromatin organization. To further understand the role of BEAF, we detected cis- and trans interaction partners of four BEAF binding regions (viewpoints) using 4C (circular chromosome conformation capture) and analyzed their association with different genomic features. Previous genome-wide mapping found that BEAF usually binds near transcription start sites, often of housekeeping genes, so our viewpoints were selected to reflect this. Our 4C data show the interaction partners of our viewpoints are highly variable and generally enriched for active chromatin marks. The most consistent association was with housekeeping genes, a feature in common with our viewpoints. Fluorescence in situ hybridization indicated that the long distance interactions occur even in the absence of BEAF. These data are most consistent with a model in which BEAF is redundant with other factors found at active promoters. Our results point to principles of long-distance interactions made by active chromatin, supporting a previously proposed model in which condensed chromatin is sticky and associates into topologically associating domains (TADs) separated by active chromatin. We propose that the highly variable long-distance interactions we detect are driven by redundant factors that open chromatin to promote transcription, combined with active chromatin filling spaces between TADs while packing of TADs relative to each other varies from cell to cell. PMID- 30248134 TI - Soil productivity and structure of bacterial and fungal communities in unfertilized arable soil. AB - Soil productivity is strongly influenced by the activities of microbial communities. However, it is not well understood how community structure, including its richness, mass, and composition, influences soil functions. We investigated the relationships between soil productivity and microbial communities in unfertilized arable soils extending over 1000 km in eastern Japan. Soil properties, including C turnover rate, N mineralization rate, microbial C, and various soil chemical properties, were measured. Soil bacterial and fungal communities were analyzed by Illumina's MiSeq using 16S rRNA and ITS regions. In addition, root microbial communities from maize grown in each soil were also investigated. Soil bacterial communities shared many operational taxonomic units (OTUs) among farms. An ordination plot based on correspondence analysis revealed convergent distribution of soil bacterial communities across the farms, which seemed to be a result of similar agricultural management practices. Although fungal communities showed lower richness and a lower proportion of shared OTUs than bacterial communities, community structure between the farms tended to be convergent. On the other hand, root communities had lower richness and a higher abundance of specific taxa than the soil communities. Two soil functions, decomposition activity and soil productivity, were extracted by principal component analysis (PCA) based on eight soil properties. Soil productivity correlated with N mineralization rate, P2O5, and maize growth, but not with decomposition activity, which is characterized by C turnover rate, soil organic C, and microbial mass. Soil productivity showed a significant association with community composition, but not with richness and mass of soil microbial communities. Soil productivity also correlated with the abundance of several specific taxa, both in bacteria and fungi. Root communities did not show any clear correlations with soil productivity. These results demonstrate that community composition and abundance of soil microbial communities play important roles in determining soil productivity. PMID- 30248135 TI - Long-term development of refractive error in refractive, nonrefractive and partially accommodative esotropia. AB - Accommodative esotropia (AE) is a convergent deviation due to an excess of the convergence linked to the innervational stimulus for accommodation and it is usually associated to the presence of hyperopia. The development of hyperopia over time has been widely described but the lack of comparative analysis among accommodative esotropia subtypes, does not allow to verify the existence of different developmental patterns. In this study we aimed to describe the long term changes of refractive error in patients affected by accommodative esotropia as a function of the strabismus type: refractive (RAE), non-refractive (NRAE) and partially accommodative esotropia (PAE). The medical records of 66 patients (24 RAE, 22 PAE, 20 NRAE), who wore the full correction of their cycloplegic refraction error during the entire follow up period, were retrospectively reviewed. Mean outcome was the analysis of the variations, among groups, of refractive error over time; differences between mild (<=3.00D) and high (>=5.00D) hyperopia, effects of amblyopia and relationship with AC/A ratio were also investigated. All patients were followed up from approximately 4 years of age to 20, with mean follow up of 16.06+/-0.29 years. Our results described similar non linear trend of refractive error development among groups. The initial increase of hyperopia (up to 7-8 years) was followed by a decreasing trend persisting up to adulthood (approximately 20 years of age). During this period, spherical equivalent decreased at a lower mean annual rate in patients affected by RAE ( 0.07D) compared to other groups (NRAE -0.11D, p = 0.003 and PAE 0.13D, p = 0.002). In all groups, however, significant amount of hyperopia was found at last examination; indeed the observed difference in SE values from baseline to the end of follow up, was not significant (RAE: +0.27D, 95% C.I. -0.49 to +1.04D, p = 0.472; PAE: -0.69D, 95% C.I. -1.67 to +0.28D, p = 0.154; NRAE: -0.39D, 95% C.I. 1.11 to +0.34D, p = 0.278). AC/A ratio, amblyopia and amount of initial hyperopia appeared to have no significant role in longitudinal change of the refractive error. In conclusion, this study provides a complete overview, from childhood to adulthood, of refractive error development in different form of accommodative esotropia. PMID- 30248136 TI - Short-term effectiveness of HIV care coordination among persons with recent HIV diagnosis or history of poor HIV outcomes. AB - The New York City HIV Care Coordination Program (CCP) combines multiple evidence based strategies to support persons living with HIV (PLWH) at risk for, or with a recent history of, poor HIV outcomes. We assessed the comparative effectiveness of the CCP by merging programmatic data on CCP clients with population-based surveillance data on all New York City PLWH. A non-CCP comparison group of similar PLWH who met CCP eligibility criteria was identified using surveillance data. The CCP and non-CCP groups were matched on propensity for CCP enrollment within four baseline treatment status groups (newly diagnosed or previously diagnosed and either consistently unsuppressed, inconsistently suppressed or consistently suppressed). We compared CCP to non-CCP proportions with viral load suppression at 12-month follow-up. Among the 13,624 persons included, 15?3% were newly diagnosed; among the 84?7% previously diagnosed, 14?2% were consistently suppressed, 28?9% were inconsistently suppressed, and 41?6% were consistently unsuppressed in the year prior to baseline. At 12-month follow-up, 59?9% of CCP and 53?9% of non-CCP participants had viral load suppression (Relative Risk = 1.11, 95%CI:1.08-1.14). Among those newly diagnosed and those consistently unsuppressed at baseline, the relative risk of viral load suppression in the CCP versus non-CCP participants was 1.15 (95%CI:1.09-1.23) and 1.32 (95%CI:1.23 1.42), respectively. CCP exposure shows benefits over no CCP exposure for persons newly diagnosed or consistently unsuppressed, but not for persons suppressed in the year prior to baseline. We recommend more targeted case finding for CCP enrollment and increased attention to viral load suppression maintenance. PMID- 30248137 TI - Genome-wide identification and characterization of CONSTANS-like gene family in radish (Raphanus sativus). AB - Floral induction that initiates bolting and flowering is crucial for reproductive fitness in radishes. CONSTANS-like (CO-like, COL) genes play an important role in the circadian clock, which ensures regular development through complicated time keeping mechanisms. However, the specific biological and functional roles of each COL transcription factor gene in the radish remain unknown. In this study, we performed a genome-wide identification of COL genes in the radish genome of three cultivars including 'Aokubi', 'kazusa' and 'WK10039', and we analyzed their exon intron structure, gene phylogeny and synteny, and expression levels in different tissues. The bioinformatics analysis identified 20 COL transcription factors in the radish genome, which were divided into three subgroups (Group I to Group III). RsaCOL-09 and RsaCOL-12 might be tandem duplicated genes, whereas the others may have resulted from segmental duplication. The Ka/Ks ratio indicated that all the COL genes in radish, Arabidopsis, Brassica rapa, Brassica oleracea, Capsella rubella and rice were under purifying selection. We identified 6 orthologous and 19 co-orthologous COL gene pairs between the radish and Arabidopsis, and we constructed an interaction network among these gene pairs. The expression values for each COL gene during vegetable and flower development showed that the majority of Group I members had similar expression patterns. In general, the expression of radish COL genes in Groups I and III decreased during development, whereas the expression of radish COL genes in Group II first increased and then decreased. Substantial numbers of radish COL genes were differentially expressed after vernalization treatment. The expression levels of RsaCOL-02 and RsaCOL-04 were significantly increased during vernalization treatment, while the expression of RsaCOL-10 was significantly decreased. These outcomes provide insights for improving the genetic control of bolting and flowering in radish and other root vegetable crops, and they facilitate genetic improvements to radish yields and quality. PMID- 30248138 TI - How stem cell composition in bone marrow aspirate relates to clinical outcomes when used for cervical spine fusion. AB - Anterior cervical discectomy and fusion (ACDF) is performed to relieve pain caused by degenerative disk disease and nerve obstruction. As an alternative to bone graft, autologous concentrated bone marrow aspirate (CBMA) is used to achieve vertebral fusion with a satisfactory success rate. This has been attributed in part to bone marrow-resident mesenchymal stromal cells (MSCs) with the capacity to differentiate into osteoblasts and generate bone tissue. To date, there has been no study comparing cellular yields, MSC frequencies and their osteogenic potential with ACDF outcome. Patients (n = 24) received ACDF with CBMA and allograft bone matrix. Colony forming unit fibroblast (CFU-F) and CFU osteoblasts (CFU-O) assays were performed on CBMA samples to enumerate MSCs (CFU F) and osteogenic MSCs (CFU-O). CFUs were normalized to CBMA volume to define yield and also to mononuclear cells (MNC) to define frequency. After 1-year, fusion rates were good (86.7%) with pain and disability improved. There was a negative relationship between MNC and CFU-F measurements with age of patient and CFU-Os negatively correlated with age in females but not males. Tobacco use did not affect CBMA but was associated with poorer clinical outcome. Surprisingly, we found that while high-grade fusion was not associated with CFU-O, it correlated strongly (p<0.0067) with CBMA containing the lowest frequencies of CFU-F (3.0x10 6-5.83x10-5 CFU-F/MNC). MNC levels alone were not responsible for the results. These observations suggest that osteogenesis by human bone marrow is controlled by homeostatic ratio of MSCs to other cellular bone marrow components rather than absolute level of osteogenic MSCs, and that a lower ratio of MSCs to other cellular components in marrow tends to predict effective osteogenesis during ACDF. The results presented herein challenge the current dogma surrounding the proposed mechanism of MSCs in bone healing. PMID- 30248139 TI - Peptidomimetic inhibitors of L-plastin reduce the resorptive activity of osteoclast but not the bone forming activity of osteoblasts in vitro. AB - Sealing ring formation is a requirement for osteoclast function. We have recently identified the role of an actin-bundling protein L-plastin in the assembly of nascent sealing zones (NSZs) at the early phase of sealing ring formation in osteoclasts. TNF-alpha signaling regulates this actin assembly by the phosphorylation of L-plastin on serine -5 and -7 residues at the amino-terminal end. These NSZs function as a core for integrin localization and coordinating integrin signaling required for maturation into fully functional sealing rings. Our goal is to elucidate the essential function of L-plastin phosphorylation in actin bundling, a process required for NSZs formation. The present study was undertaken to determine whether targeting serine phosphorylation of cellular L plastin would be the appropriate approach to attenuate the formation of NSZs. Our approach is to use TAT-fused small molecular weight amino-terminal L-plastin peptides (10 amino acids) containing phospho- Ser-5 and Ser-7. We used peptides unsubstituted (P1) and substituted (P2- P4) at serine-to-alanine residues. Immunoblotting, actin staining, and dentine resorption analyses were done to determine cellular L-plastin phosphorylation, NSZ or sealing ring formation, and osteoclast function, respectively. Immunoblotting for bone formation markers, Alizarin red staining and alkaline phosphatase activity assay have been done to determine the effect of peptides on the mineralization process mediated by osteoblasts. Transduction of unsubstituted (P1) and substituted peptides at either Serine 5 or Serine 7 with Alanine (P3 and P4) demonstrated variable inhibitory effects on the phosphorylation of cellular L-plastin protein. Peptide P1 reduces the following processes substantially: 1) cellular L-plastin phosphorylation; 2) formation of nascent sealing zones and sealing rings; 3) bone resorption. Substitution of both Serine-5 and -7 with Alanine (P2) had no effects on the inhibitory activities described above. Furthermore, either the L-plastin (P1-P5) or (P6) control peptides had a little or no impact on the a) assembly/disassembly of podosomes and migration of osteoclasts; b) mineralization process mediated by osteoblasts in vitro. Small molecular weight peptidomimetics of L-plastin inhibits bone resorption by osteoclasts via attenuation of NSZ and sealing ring formation but not bone formation by osteoblasts in vitro. The L plastin may be a valuable therapeutic target to treat and prevent diseases associated with bone loss without affecting bone formation. PMID- 30248140 TI - Partial agonist activity of alpha1-adrenergic receptor antagonists for chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3. AB - We observed in PRESTO-Tango beta-arrestin recruitment assays that the alpha1 adrenergic receptor (AR) antagonist prazosin activates chemokine (C-X-C motif) receptor (CXCR)4. This prompted us to further examine this unexpected pharmacological behavior. We screened a panel of 14 alpha1/2- and beta1/2/3-AR antagonists for CXCR4 and atypical chemokine receptor (ACKR)3 agonist activity in PRESTO-Tango assays against the cognate agonist CXCL12. We observed that multiple alpha1-AR antagonists activate CXCR4 (CXCL12 = prazosin = cyclazosin > doxazosin) and ACKR3 (CXCL12 = prazosin = cyclazosin > alfuzosin = doxazosin = phentolamine > terazosin = silodosin = tamsulosin). The two strongest CXCR4/ACKR3 activators, prazosin and cyclazosin, were selected for a more detailed evaluation. We found that the drugs dose-dependently activate both receptors in beta-arrestin recruitment assays, stimulate ERK1/2 phosphorylation in HEK293 cells overexpressing each receptor, and that their effects on CXCR4 could be inhibited with AMD3100. Both alpha1-AR antagonists induced significant chemical shift changes in the 1H-13C-heteronuclear single quantum correlation spectrum of CXCR4 and ACKR3 in membranes, suggesting receptor binding. Furthermore, prazosin and cyclazosin induced internalization of endogenous CXCR4/ACKR3 in human vascular smooth muscle cells (hVSMC). While these drugs did not in induce chemotaxis in hVSMC, they inhibited CXCL12-induced chemotaxis with high efficacy and potency (IC50: prazosin-4.5 nM, cyclazosin 11.6 pM). Our findings reveal unexpected pharmacological properties of prazosin, cyclazosin, and likely other alpha1-AR antagonists. The results of the present study imply that prazosin and cyclazosin are biased or partial CXCR4/ACKR3 agonists, which function as potent CXCL12 antagonists. Our findings could provide a mechanistic basis for previously observed anti-cancer properties of alpha1-AR antagonists and support the concept that prazosin could be re-purposed for the treatment of disease processes in which CXCR4 and ACKR3 are thought to play significant pathophysiological roles, such as cancer metastases or various autoimmune pathologies. PMID- 30248141 TI - Characterization and comparative analysis of microRNAs in the rice pest Sogatella furcifera. AB - MicroRNAs (miRNAs) are a class of endogenous regulatory RNA molecules 21-24 nucleotides in length that act as functional regulators of post-transcriptional repression of messenger RNA. We report the identification and characterization of a conserved miRNA and 171 novel miRNAs in the migratory rice pest Sogatella furcifera by deep sequencing, which were observed to be biased towards female adults of the insect, modulating the functionality and targets of the miRNAs in sex differentiation. A switch in arm usage was also observed in 9 miRNA when compared to the insect ancestor during insect evolution. The miRNA loci showed high 5' fidelity in both miRNA and star species and about 93.4% of WBPH miRNAs conserved within non-planthopper species were homologous with planthopper species. The novel miRNAs identified in this study provide a better understanding of the sRNA and the regulatory role of miRNA in sexual dimorphism and alteration in the expression or function of miRNAs in the rice pest. PMID- 30248142 TI - Vaccination with whole-cell killed or recombinant leishmanial protein and toll like receptor agonists against Leishmania tropica in BALB/c mice. AB - One strategy to control leishmaniasis is vaccination with potent antigens alongside suitable adjuvants. The use of toll-like receptor (TLR) agonists as adjuvants is a promising approach in Leishmania vaccine research. Leishmania (L.) tropica is among the less-investigated Leishmania species and a causative agent of cutaneous and sometimes visceral leishmaniasis with no approved vaccine against it. In the present study, we assessed the adjuvant effects of a TLR4 agonist, monophosphoryl lipid A (MPL) and a TLR7/8 agonist, R848 beside two different types of Leishmania vaccine candidates; namely, whole-cell soluble L. tropica antigen (SLA) and recombinant L. tropica stress-inducible protein-1 (LtSTI1). BALB/c mice were vaccinated three times by the antigens (SLA or LtSTI1) with MPL or R848 and then were challenged by L. tropica. Delayed-type hypersensitivity (DTH), parasite load, disease progression and cytokines (IL-10 and IFN-gamma) responses were assessed. In general compared to SLA, application of LtSTI1 resulted in higher DTH, higher IFN-gamma response and lower lymph node parasite load. Also compared to R848, MPL as an adjuvant resulted in higher DTH and lower lymph node parasite load. Although, no outstanding ability for SLA and R848 in evoking immune responses of BALB/c mice against L. tropica infection could be observed, our data suggest that LtSTI1 and MPL have a better potential to control L. tropica infection and could be pursued for the development of effective vaccination strategies. PMID- 30248144 TI - Synergy between tuberculin skin test and proliferative T cell responses to PPD or cell-membrane antigens of Mycobacterium tuberculosis for detection of latent TB infection in a high disease-burden setting. AB - Tuberculin skin test (TST) is used most widely for the detection of latent tuberculosis infection (LTBI), even though evidences suggest that it could be underreporting the prevalence of LTBI particularly in high disease-burden settings. We have explored whether in vivo (TST) and in vitro (cell proliferative) T cell responses to PPD can serve as complementary measures. In addition, we also probed whether in vitro T cell response to cell-membrane antigens (Mem) of Mycobacterium tuberculosis (MTB) can serve as a biomarker for LTBI. Study subjects comprised 43 healthcare workers (HCWs), and 9 smear-positive TB patients served as 'disease control'. To measure proliferative T cell responses, 0.1 ml blood (diluted 1:10) was incubated (5 days) with test or control antigen. Cells were stained with fluorescent antibodies to T cell (CD3+/CD4+/CD8+) surface markers and, after fixation and permeabilization, to nuclear proliferation marker Ki67. Data was acquired on a flow cytometer. HCWs who had an intimate exposure to MTB showed significantly higher TST positivity (85%) than the rest (43%), notwithstanding their BCG vaccination status. The proliferative responses of CD4+ and CD8+ subsets of T cells were comparable. Sixty seven and 100% TST-negative HCWs, respectively, were positive for proliferative T cell response to PPD and MTBMem. Cumulative positivity (TST or in vitro) was 86% with PPD and 100% with MTBMem indicating complementarity of the two responses. As standalone in vitro assay, MTBMem provided a significantly higher positivity (95%) than PPD (67%). T cell responses of TB patients were 'generally' depressed, having implications for the development of immunological assays for 'progressive' LTBI. Altogether, these results demonstrate that in vivo and in vitro T cell responses to PPD are complementary and in vitro response to MTBMem can be developed as a highly sensitive biomarker for LTBI. PMID- 30248145 TI - Ranking stressor impacts on periphyton structure and function with mesocosm experiments and environmental-change forecasts. AB - Streams are being subjected to physical, chemical, and biological stresses stemming from both natural and anthropogenic changes to the planet. In the face of limited time and resources, scientists, resource managers, and policy makers need ways to rank stressors and their impacts so that we can prioritize them from the most to least important (i.e., perform 'ecological triage'). We report results from an experiment in which we established a periphyton community from the Huron River (Michigan, USA) in 84 experimental 'flumes' (stream mesocosms). We then dosed the flumes with gradients of six common stressors (increased temperature, taxa extinctions, sedimentation, nitrogen, phosphorus, and road salt) and monitored periphyton structure and function. A set of a priori deterministic functions were fit to each stressor-endpoint response and model averaging based on AICc weights was used to develop concentration-response best fit predictions. Model predictions from different stressors were then compared to forecasts of future environmental change to rank stressors according to the potential magnitude of impacts. All of the stressors studied altered at least one characteristic of the periphyton; however, the extent (i.e., structural and functional changes) and magnitude of effects expected under future forecasts differed significantly among stressors. Elevated nitrogen concentrations are projected to have the greatest combined effect on stream periphyton structure and function. Extinction, sediment, and phosphorus all had similar but less substantial impact on the periphyton (e.g., affected only structure not function, smaller magnitude change). Elevated temperature and salt both had measurable effects on periphyton, but their overall impacts were much lower than any of the other stressors. For periphyton in the Huron River, our results suggest that, among the stressors examined, increased N pollution may have the greatest potential to alter the structure and function of the periphyton community, and managers should prioritize reducing anthropogenic sources of nitrogen. Our study demonstrates an experimental approach to ecological triage that can be used as an additional line of evidence to prioritize management decisions for specific ecosystems in the face of ecological change. PMID- 30248143 TI - The papain-like protease determines a virulence trait that varies among members of the SARS-coronavirus species. AB - SARS-coronavirus (CoV) is a zoonotic agent derived from rhinolophid bats, in which a plethora of SARS-related, conspecific viral lineages exist. Whereas the variability of virulence among reservoir-borne viruses is unknown, it is generally assumed that the emergence of epidemic viruses from animal reservoirs requires human adaptation. To understand the influence of a viral factor in relation to interspecies spillover, we studied the papain-like protease (PLP) of SARS-CoV. This key enzyme drives the early stages of infection as it cleaves the viral polyprotein, deubiquitinates viral and cellular proteins, and antagonizes the interferon (IFN) response. We identified a bat SARS-CoV PLP, which shared 86% amino acid identity with SARS-CoV PLP, and used reverse genetics to insert it into the SARS-CoV genome. The resulting virus replicated like SARS-CoV in Vero cells but was suppressed in IFN competent MA-104 (3.7-fold), Calu-3 (2.6-fold) and human airway epithelial cells (10.3-fold). Using ectopically-expressed PLP variants as well as full SARS-CoV infectious clones chimerized for PLP, we found that a protease-independent, anti-IFN function exists in SARS-CoV, but not in a SARS-related, bat-borne virus. This PLP-mediated anti-IFN difference was seen in primate, human as well as bat cells, thus independent of the host context. The results of this study revealed that coronavirus PLP confers a variable virulence trait among members of the species SARS-CoV, and that a SARS-CoV lineage with virulent PLPs may have pre-existed in the reservoir before onset of the epidemic. PMID- 30248147 TI - Correction: Advancing the integration of spatial data to map human and natural drivers on coral reefs. AB - [This corrects the article DOI: 10.1371/journal.pone.0189792.]. PMID- 30248146 TI - Pharmacokinetics of intramuscular alfaxalone and its echocardiographic, cardiopulmonary and sedative effects in healthy dogs. AB - The pharmacokinetics and the effects of a single intramuscular (IM) dose of alfaxalone on sedation and cardiopulmonary and echocardiographic variables was studied in dogs. Twelve healthy adult Beagles (3 females, 9 males) were used in this prospective controlled cross-over trial. Echocardiography was performed with and without 4 mg kg-1 alfaxalone IM with a week wash-out interval. Sedation (19 point scale; 0 = no sedation), cardiopulmonary parameters, blood gas analysis and plasma concentration of alfaxalone were assessed every 5 minutes following the injection (T0). The influence of the alfaxalone plasma concentration and time on physiological variables was tested using a linear model whereas echocardiographic measurements were compared between conscious and alfaxalone-administered dogs using paired t-tests. Compared to baseline, alfaxalone administration was followed by an increase in heart rate (HR) from T5 to T30 and a decrease in mean arterial pressure (MAP) at T10, T25 and T30, in stroke volume (SV; 15 +/- 5 to 11 +/- 3 ml; P<0.0001), and end-diastolic volume (EDV; 24.7 +/- 5.7 to 19.4 +/- 4.9 ml). Cardiac output (CO) and blood gas analysis did not change significantly throughout. Mean plasma half-life was 29 +/- 8 minutes, volume of distribution was 1.94 +/- 0.63 L kg-1, and plasma clearance was 47.7 +/- 14.1 ml kg-1 minute 1. Moderate to deep sedation was observed from T5 to T35. Ten dogs showed paddling, trembling, nystagmus and strong reaction to sound during the procedure. Although there were no significant changes in CO and oxygenation, the impact of HR, MAP, SV, EDV alterations requires further investigations in dogs with cardiac disease. PMID- 30248148 TI - Urinary proteomic signatures associated with beta-blockade and heart rate in heart transplant recipients. AB - OBJECTIVES: Heart transplant (HTx) recipients have a high heart rate (HR), because of graft denervation and are frequently started on beta-blockade (BB). We assessed whether BB and HR post HTx are associated with a specific urinary proteomic signature. METHODS: In 336 HTx patients (mean age, 56.8 years; 22.3% women), we analyzed cross-sectional data obtained 7.3 years (median) after HTx. We recorded medication use, measured HR during right heart catheterization, and applied capillary electrophoresis coupled with mass spectrometry to determine the multidimensional urinary classifiers HF1 and HF2 (known to be associated with left ventricular dysfunction), ACSP75 (acute coronary syndrome) and CKD273 (renal dysfunction) and 48 sequenced urinary peptides revealing the parental proteins. RESULTS: In adjusted analyses, HF1, HF2 and CKD273 (p <= 0.024) were higher in BB users than non-users with a similar trend for ACSP75 (p = 0.06). Patients started on BB within 1 year after HTx and non-users had similar HF1 and HF2 levels (p >= 0.098), whereas starting BB later was associated with higher HF1 and HF2 compared with non-users (p <= 0.014). There were no differences in the urinary biomarkers (p >= 0.27) according to HR. BB use was associated with higher urinary levels of collagen II and III fragments and non-use with higher levels of collagen I fragments. CONCLUSIONS: BB use, but not HR, is associated with a urinary proteomic signature that is usually associated with worse outcome, because unhealthier conditions probably lead to initiation of BB. Starting BB early after HTx surgery might be beneficial. PMID- 30248149 TI - NLRP6 negatively regulates pulmonary host defense in Gram-positive bacterial infection through modulating neutrophil recruitment and function. AB - Gram-positive bacteria, including Staphylococcus aureus are endemic in the U.S., which cause life-threatening necrotizing pneumonia. Neutrophils are known to be critical for clearance of S. aureus infection from the lungs and extrapulmonary organs. Therefore, we investigated whether the NLRP6 inflammasome regulates neutrophil-dependent host immunity during pulmonary S. aureus infection. Unlike their wild-type (WT) counterparts, NLRP6 knockout (KO) mice were protected against pulmonary S. aureus infection as evidenced by their higher survival rate and lower bacterial burden in the lungs and extrapulmonary organs. In addition, NLRP6 KO mice displayed increased neutrophil recruitment following infection, and when neutrophils were depleted the protective effect was lost. Furthermore, neutrophils from the KO mice demonstrated enhanced intracellular bacterial killing and increased NADPH oxidase-dependent ROS production. Intriguingly, we found higher NK cell-mediated IFN-gamma production in KO mouse lungs, and treatment with IFN-gamma was found to enhance the bactericidal ability of WT and KO neutrophils. The NLRP6 KO mice also displayed decreased pyroptosis and necroptosis in the lungs following infection. Blocking of pyroptosis and necroptosis in WT mice resulted in increased survival, reduced bacterial burden in the lungs, and attenuated cytokine production. Taken together, these novel findings show that NLRP6 serves as a negative regulator of neutrophil-mediated host defense during Gram-positive bacterial infection in the lungs through regulating both neutrophil influx and function. These results also suggest that blocking NLRP6 to augment neutrophil-associated bacterial clearance should be considered as a potential therapeutic intervention strategy for treatment of S. aureus pneumonia. PMID- 30248151 TI - Tele-expertise for diagnosis of skin lesions is cost-effective in a prison setting: A retrospective cohort study of 450 patients. AB - CONTEXT: The prevalence of skin diseases among prisoners is higher than in the general population. Diagnosing and treating these lesions require a dermatologic advice. A tele-expertise network in dermatology for prisoners including 8 health facilities in prison and 2 hospital dermatological departments was developed to improve access to dermatologists' expertise in correctional facilities. Our objective was to evaluate the effectiveness and costs of tele-expertise in dermatology for prisoners. METHODS: We carried out a retrospective cohort study on data collected by the information system of the tele-expertise network. We used the MAST (Model for ASsessment of Telemedicine) model to perform a multidimensional assessment including the proportion of patients with a completed treatment plan for the skin lesions, the proportion of technical problems, the quality of the pictures, the investment and operating costs and the satisfaction of the professionals. RESULTS: Mean patient age was 34.2 years with 90% men. 511 requests for 450 patients were initiated. The delay from the connection to the tele-expertise software to the validation of the request was inferior to 7 min for 50% of the requests and inferior to 30 min for 85% of the requests. Overall, with tele-expertise, 82% of the patients had a completed treatment plan for the skin lesions, with 2.9% of all patients requiring a later face-to-face appointment or hospitalization, to be compared to a proportion of 35% of patients with a completed treatment plan when tele-expertise was not available. The most frequent lesions were acnea (22%) and atopic dermatitis (18%). The mean cost for one completed treatment plan was ?184 by tele-expertise and ?315 without tele expertise. Tele-expertise was well accepted among physicians with all responders (n = 9) willing to continue using it. CONCLUSION: Tele-expertise is a dominant intervention in comparison to a face-to face consultation taking into account the cost of transportation and the proportion of canceled appointments and is acceptable for physicians. TRIAL REGISTRATION: NCT02309905. PMID- 30248150 TI - Pre-eclampsia is associated with altered expression of the renal sodium transporters NKCC2, NCC and ENaC in urinary extracellular vesicles. AB - Pre-eclampsia is a hypertensive disorder of pregnancy characterised by hypertension and sodium retention by the kidneys. To identify changes in sodium uptake proteins in the tubules of the distal nephron, we studied their expression in urinary extracellular vesicles or exosomes (uEVs). Urine was collected from women with pre-eclampsia or during normal pregnancy, and from healthy non pregnant controls. uEVs were isolated by centrifugation and analyzed by Western blot. Expression, proteolytic cleavage and phosphorylation was determined by densitometric analysis normalized to the exosome marker CD9. Results showed a significant increase in phosphorylation of the activating S130 site in NKCC2, the drug target for frusemide, in women with pre-eclampsia compared with normal pregnant women. Phosphorylation of the activating sites T101/105 in NKCC2 was similar but the activating T60 site in NCC, the drug target for thiazide diuretics, showed significantly less phosphorylation in pre-eclampsia compared with normal pregnancy. Expression of the larger forms of the alpha subunit of ENaC, the drug target for amiloride, was significantly greater in pre-eclampsia, with more fragmentation of thegamma subunit. The differences observed are predicted to increase the activity of NKCC2 and ENaC while reducing that of NCC. This will increase sodium reabsorption, and so contribute to hypertension in pre eclampsia. PMID- 30248152 TI - C-Tb skin test to diagnose Mycobacterium tuberculosis infection in children and HIV-infected adults: A phase 3 trial. AB - BACKGROUND: C-Tb, an ESAT-6/CFP-10-based skin test, has similar sensitivity for active TB compared to tuberculin skin test (TST) and QuantiFERON-TB-Gold-In-Tube (QFT). However, data are limited in children and HIV-infected persons. METHODS: Asymptomatic South African contacts <5 years (n = 87; HIV-uninfected), or symptomatic individuals of all ages presenting to clinics with suspected TB (n = 1003; 30% HIV-infected) were recruited from eight South African centres. C-Tb and TST were allocated to either forearm double blinded. Samples for QFT were collected in parallel, and test-positivity rates were compared. RESULTS: In participants with microbiologically confirmed TB (n = 75; 45% HIV-infected) sensitivity of C-Tb, TST and QFT were similar (72% versus 75% versus 73%; p>0.5). All 3 tests had similar positivity rates in HIV-infected participants with active TB, however, positivity rates were reduced when CD4 counts were <100 cells/MUL. In participants where active TB was excluded (n = 920), C-Tb (41%), TST (43%), and QFT (44%) also had similar test-positivity rates. Among asymptomatic contacts aged below five, 32% (28/87) tested positive with C-Tb and 32% (28/87) with TST (concordance 89%). Overall, C-Tb and TST showed a similar safety profile. CONCLUSION: C-Tb was safe and showed similar test-positivity rates, compared to TST and QFT, in children and HIV-infected persons with active or latent M. tuberculosis infection. These data inform the utility of C-Tb in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT01642888. EudraCT 2011-005078 40. PMID- 30248153 TI - Alpha-amylase reactivity and recovery patterns in anhedonic young adults performing a tandem skydive. AB - BACKGROUND: Anhedonia (loss of pleasure) is characterized by low responsiveness to rewards and, by virtue of being one of the two core symptoms of depression, by altered responses to stress. We investigated the effect of an acute stress experience (i.e., a tandem skydive) that was expected to elicit both intense fear and intense euphoria in a sample of anhedonic young adults. OBJECTIVE: (1) To examine individual differences in alpha-amylase reactivity to and recovery from a tandem skydive in anhedonic young adults; (2) to investigate whether trait depressive and anxiety problems, trait positive affect (PA), i.e., level of pleasure and reward responsiveness, and state anxiety, PA and self-esteem prior to the skydive were associated with alpha-amylase reactivity and recovery patterns; (3) to investigate whether alpha-amylase reactivity and recovery patterns were associated with pre- to post-jump changes in state anxiety, PA, and self-esteem. METHOD: Participants were 61 individuals with persistent anhedonia (Mage = 21.38, 78.7% female), who filled out a baseline questionnaire at the start of the study, and momentary questionnaires (3 times per day) before and after the tandem skydive. Alpha-amylase was measured at four time points by means of salivettes (2 before and 2 after the skydive). RESULTS: Alpha-amylase reactivity and recovery patterns were highly similar across individuals, although mean levels varied greatly. No associations were found between any of the trait and state measures and reactivity and recovery. Only state self-esteem was affected by the reactivity and recovery patterns, in that individuals who showed high reactivity and low recovery experienced decreases in self-esteem after the skydive. CONCLUSIONS: Alpha-amylase patterns following a tandem skydive in anhedonic individuals are highly similar to patterns previously found in healthy individuals. Although replication is warranted, our findings tentatively suggest that a strong stress response that cannot be downregulated well predicts a decrease in self-esteem. PMID- 30248154 TI - Adolescents show collective intelligence which can be driven by a geometric mean rule of thumb. AB - How effective groups are in making decisions is a long-standing question in studying human and animal behaviour. Despite the limited social and cognitive abilities of younger people, skills which are often required for collective intelligence, studies of group performance have been limited to adults. Using a simple task of estimating the number of sweets in jars, we show in two experiments that adolescents at least as young as 11 years old improve their estimation accuracy after a period of group discussion, demonstrating collective intelligence. Although this effect was robust to the overall distribution of initial estimates, when the task generated positively skewed estimates, the geometric mean of initial estimates gave the best fit to the data compared to other tested aggregation rules. A geometric mean heuristic in consensus decision making is also likely to apply to adults, as it provides a robust and well performing rule for aggregating different opinions. The geometric mean rule is likely to be based on an intuitive logarithmic-like number representation, and our study suggests that this mental number scaling may be beneficial in collective decisions. PMID- 30248157 TI - Correction: Iron deficiency associates with deterioration in several symptoms independently from hemoglobin level among chronic hemodialysis patients. AB - [This corrects the article DOI: 10.1371/journal.pone.0201662.]. PMID- 30248156 TI - Expression of a recombinant, 4'-Phosphopantetheinylated, active M. tuberculosis fatty acid synthase I in E. coli. AB - BACKGROUND: Fatty acid synthase 1 (FAS I) from Mycobacterium tuberculosis (Mtb) is an essential protein and a promising drug target. FAS I is a multi-functional, multi-domain protein that is organized as a large (1.9 MDa) homohexameric complex. Acyl intermediates produced during fatty acid elongation are attached covalently to an acyl carrier protein (ACP) domain. This domain is activated by the transfer of a 4'-Phosphopantetheine (4'-PP, also termed P-pant) group from CoA to ACP catalyzed by a 4'-PP transferase, termed acyl carrier protein synthase (AcpS). METHODS: In order to obtain an activated FAS I in E. coli, we transformed E. coli with tagged Mtb fas1 and acpS genes encoded by a separate plasmid. We induced the expression of Mtb FAS I following induction of AcpS expression. FAS I was purified by Strep-Tactin affinity chromatography. RESULTS: Activation of Mtb FAS I was confirmed by the identification of a bound P-pant group on serine at position 1808 by mass spectrometry. The purified FAS I displayed biochemical activity shown by spectrophotometric analysis of NADPH oxidation and by CoA production, using the Ellman reaction. The purified Mtb FAS I forms a hexameric complex shown by negative staining and cryo-EM. CONCLUSION: Purified hexameric and active Mtb FAS I is required for binding and drug inhibition studies and for structure-function analysis of this enzyme. This relatively simple and short procedure for Mtb FAS I production should facilitate studies of this enzyme. PMID- 30248155 TI - Distinct epidemiological profiles associated with inflammatory breast cancer (IBC): A comprehensive analysis of the IBC registry at The University of Texas MD Anderson Cancer Center. AB - BACKGROUND: To date, studies on inflammatory breast cancer (IBC) lack comprehensive epidemiological data. We analyzed detailed prospectively collected clinical and epidemiological data from the IBC Registry at The University of Texas MD Anderson Cancer Center. METHODS: Patients with IBC (n = 248) were consecutively diagnosed and prospectively enrolled between November 2006 and April 2013. All patients were newly diagnosed and at least 18 years old. Secondary IBC was excluded. Overall 160 variables were collected and evaluated including sociodemographics, anthropometrics, tobacco and alcohol consumption, reproductive variables, and family history data. RESULTS: Mean age at diagnosis was 51.6 (+/-11.5 SD) years, and the majority of patients were White (77.8%). A mean BMI >= 25 kg/m2, irrespective of menopausal status, was observed in 80.2% of all patients, with 82.6% of African Americans being obese. Approximately 42.2% of patients were ever smokers, and 91% reported ever being pregnant. A history of breastfeeding was reported in 54% of patients, with significant differences between ethnic groups in favor of White women (P<0.0001). Other reproductive factors such as use of birth control pills & hormone replacement therapy were also more frequently associated with White women compare to other ethnic groups (P < 0.05). In the multivariate Cox proportional hazard analysis, African American or Hispanic ethnicity, not having breastfed, higher clinical stage, and TNBC subtype were associated with shorter survival. CONCLUSION: Our data suggest that IBC is associated with distinct epidemiological profiles. This information could assist in targeting patients with specific preventive strategies based on their modifiable behavioral patterns. PMID- 30248158 TI - Incidence rates of dysvascular lower extremity amputation changes in Northern Netherlands: A comparison of three cohorts of 1991-1992, 2003-2004 and 2012-2013. AB - OBJECTIVE: To analyze the incidence rates of dysvascular major lower extremity amputations (LEA) in Northern Netherlands in 2012-2013 compared to previous cohorts in 1991-1992 and 2003-2004. DESIGN: Retrospective cohort study. PARTICIPANTS: Adults (N = 343) with first ever dysvascular LEA at ankle disarticulation or more proximal levels. The median age (interquartile range) was 74.2 years (64.5-81.9), 64% were male and 55% had been diagnosed with diabetes mellitus (DM). MAIN OUTCOME MEASURES: Crude and age-standardized incidence rates of major LEA per 100.000 person-years. RESULTS: Crude incidence rate (IR) of first ever major LEA in 2012-2013 was 9.9 per 100.000 person-years, while the age standardized IR was 7.7 per 100.000 person-years. A Poisson regression analysis showed that amputation rates among men were 2.3 times higher compared to women (95%CI 1.9-2.6), while in 2012-2013 the population aged >63 years had decreased amputation rates compared to 1991-1992. In the DM population the crude IR decreased from 142.6 per 100.000 person-years in 2003-2004 to 89.2 per 100.000 person-years in 2012-2013 (p<0.001). CONCLUSIONS: In 2012-2013 a decrease in age standardized IR for the general population and a decrease in crude IR for the DM population were observed compared to cohorts from the previous two decades, despite considerable shifts in the age distribution of the Dutch population towards more elderly people and increased prevalence of DM. These findings might suggest that improved treatment of patients at risk of dysvascular amputations is associated with reduced incidence rates of major LEA at the population level. PMID- 30248159 TI - Bronchopulmonary dysplasia in neonates born to mothers with preeclampsia: Impact of small for gestational age. AB - BACKGROUND AND OBJECTIVES: Small for gestational age and preeclampsia have both been described as risk factors for bronchopulmonary dysplasia in preterm neonates, but their respective role in the occurrence of bronchopulmonary dysplasia is debated. We evaluated the relation between small for gestational age and bronchopulmonary dysplasia in neonates born to mothers with preeclampsia. We hypothesized that low birth weight is still associated with bronchopulmonary dysplasia in this homogeneous population. METHODS: Retrospective single-center cohort study including 141 neonates born between 24 and 30 weeks' gestation to mothers with preeclampsia. The main outcome measure was moderate to severe bronchopulmonary dysplasia at 36 weeks' postmenstrual age. Neonates born small for gestational age (birthweight < 10th percentile on the AUDIPOG curves) were compared to those with appropriate birthweight for gestational age by bivariable analyses and logistic regression models, estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Bronchopulmonary dysplasia rates were 61.5% (32/52) and 27.4% (20/73) for small for gestational age and appropriate birthweight for gestational age neonates (p < .001). On adjustment for gestational age and other confounding factors, the risk of moderate to severe bronchopulmonary dysplasia was greater for small for gestational age than appropriate birthweight for gestational age neonates (adjusted OR = 5.9, 95% CI [2.2-15.4]), as was the composite outcome death or moderate to severe bronchopulmonary dysplasia (adjusted OR = 4.7, 95% CI [1.9-11.3]). CONCLUSIONS: Small for gestational age was associated with bronchopulmonary dysplasia in very preterm neonates born to mothers with preeclampsia. REGISTRATION NUMBER: CNIL no. 1747084. PMID- 30248161 TI - Non-Invasive Gene Expression Testing to Rule Out Melanoma. AB - The Pigmented Lesion Assay (PLA) is a gene expression test that helps rule out melanoma and has the potential to reduce the need for surgical biopsies of atypical pigmented skin lesions. Utilizing a new technological platform for the non-invasive profiling of skin, the assay analyzes samples collected from adhesive patches for expression of two key genes (PRAME and LINC00518) known to be overexpressed in melanoma. The test result is binary (positive/negative) based on the detection of one or both genes. PLA positive cases are generally biopsied to establish the histopathologic diagosis, while PLA negative cases are considered for ongoing monitoring. The combination of visual inspection with histopathology, the current gold standard for melanoma diagnosis, has a relatively low negative predictive value (NPV) of approximately 83%, meaning that 17% of melanomas will be interpreted as benign lesions. In contrast, the PLA has a very high NPV (>99%). Further, with its high specificity (69-91%), use of the PLA can reduce the number of false positive samples subjected to histopathology review. By adding the PLA to the current care pathway, the number of surgical biopsies needed to find a melanoma (number needed to biopsy) is markedly reduced from 20-25 biopsies for dermatologists and 39 biopsies for physician assistants, to an average of 2.7. To date, unnecessary surgical procedures of benign lesions have been reduced by 88% based on a sample of more than 20,000 analyzed cases. This has resulted in fewer missed melanomas and significant cost savings to health care systems. PMID- 30248160 TI - Proteome-wide analysis of CD8+ T cell responses to EBV reveals differences between primary and persistent infection. AB - Human herpesviruses are antigenically rich agents that induce strong CD8+T cell responses in primary infection yet persist for life, continually challenging T cell memory through recurrent lytic replication and potentially influencing the spectrum of antigen-specific responses. Here we describe the first lytic proteome wide analysis of CD8+ T cell responses to a gamma1-herpesvirus, Epstein-Barr virus (EBV), and the first such proteome-wide analysis of primary versus memory CD8+ T cell responses to any human herpesvirus. Primary effector preparations were generated directly from activated CD8+ T cells in the blood of infectious mononucleosis (IM) patients by in vitro mitogenic expansion. For memory preparations, EBV-specific cells in the blood of long-term virus carriers were first re-stimulated in vitro by autologous dendritic cells loaded with a lysate of lytically-infected cells, then expanded as for IM cells. Preparations from 7 donors of each type were screened against each of 70 EBV lytic cycle proteins in combination with the donor's individual HLA class I alleles. Multiple reactivities against immediate early (IE), early (E) and late (L) lytic cycle proteins, including many hitherto unrecognised targets, were detected in both contexts. Interestingly however, the two donor cohorts showed a different balance between IE, E and L reactivities. Primary responses targeted IE and a small group of E proteins preferentially, seemingly in line with their better presentation on the infected cell surface before later-expressed viral evasins take full hold. By contrast, target choice equilibrates in virus carriage with responses to key IE and E antigens still present but with responses to a select subset of L proteins now often prominent. We infer that, for EBV at least, long-term virus carriage with its low level virus replication and lytic antigen release is associated with a re-shaping of the virus-specific response. PMID- 30248162 TI - Chronic Pruritus: A Review of Neurophysiology and Associated Immune Neuromodulatory Treatments. AB - Chronic pruritus remains a difficult condition to treat with many non-specific therapeutic options. Recent scientific discoveries have elucidated the physiology associated with pruritus. Combined with clinical and experimental trials with immune-modulatory agents, chronic pruritus now has novel treatment options with known mechanisms of action. This review goes over recent scientific progress in understanding the molecular mechanisms governing pruritus, the cross-talk between the immune and nervous systems that regulate itch, and central nervous pathways and projections affected by itch. In light of these recent discoveries, we briefly discuss a growing body of data from relevant clinical trials investigating immunomodulatory drugs targeting specific interleukin receptors (IL 4/13/31) and intracellular signaling (e.g, Janus kinase) pathways. We focus on the physiological processes that control this complex physical and emotional experience, as well as the role of newer drugs used to treat chronic itch. PMID- 30248163 TI - The Adjuvant Treatment of Stage III Colon Cancer: Might Less Be More? AB - Oxaliplatin-based chemotherapy (FOLFOX [folinic acid, fluorouracil, oxaliplatin] or XELOX [oxaliplatin, capecitabine; also called CAPOX]) for 6 months is the current standard for adjuvant therapy of stage III colon cancer patients with good performance status. However, these regimens are associated with significant toxicities, including myelosuppression, diarrhea, and oxaliplatin-induced, cumulative, dose-dependent neurotoxicity. A reduced duration of adjuvant therapy, which would reduce overall toxicity while maintaining overall clinical efficacy, would be optimal. The goal of the International Duration Evaluation of Adjuvant (IDEA) study was to evaluate the noninferiority of 3-month compared with 6-month adjuvant oxaliplatin-based treatment in stage III colon cancer using a prospectively designed pooled analysis of 6 concurrently conducted phase III randomized trials. Herein, we review the findings of the IDEA study and discuss the optimal duration of oxaliplatin-based adjuvant chemotherapy using patient based risk factors. PMID- 30248164 TI - DLBCL Cell of Origin: What Role Should It Play in Care Today? AB - Diffuse large B-cell lymphoma (DLBCL) is curable in about two-thirds of patients. Research has focused on determining which patients have less favorable prognoses so that they can be considered for novel targeted-treatment strategies. In 2000, gene expression profiling was used to define two principal DLBCL molecular subtypes, germinal center B-cell-like (GCB) and activated B-cell-like (ABC). Patients with GCB DLBCL have more favorable outcomes than those with ABC DLBCL when treated with standard immunochemotherapy. Alternate strategies to characterize molecular subtype include approximation with immunohistochemistry algorithms, and more recently the NanoString gene expression platform. Numerous studies have investigated novel agents in DLBCL with respect to GCB and ABC (or non-GCB) subtypes, but R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard of care for most patients. Here we review the methods of determining cell of origin (COO); use of COO in clinical practice; clinical trials in DLBCL according to COO; and future directions of tailoring treatment, including alternate categorization of genetic subtypes or clusters in DLBCL. PMID- 30248165 TI - Point: Should Radiation Therapy Be Routinely Used in the Adjuvant Treatment of Stage III Endometrial Cancer? Yes--Radiation Therapy Improves Local Control and Possibly Survival for Some Patients. PMID- 30248166 TI - Counterpoint: Should Radiation Therapy Be Routinely Used in the Adjuvant Treatment of Stage III Endometrial Cancer? No--The Literature Does Not Support Routine Use of Radiation Therapy. PMID- 30248167 TI - Eric Ko on Combining Radiation Therapy With Immunotherapy to Treat Non-Small-Cell Lung Cancer. PMID- 30248169 TI - Complications of Androgen Deprivation Therapy in Men With Prostate Cancer. AB - The standard treatment for men with metastatic prostate cancer is androgen deprivation therapy (ADT). This therapy is associated with a multitude of side effects that can impact quality of life. These include vasomotor complications (in particular, hot flushes), sexual dysfunction and gynecomastia, osteoporosis, metabolic syndrome, and depression. Additionally, ADT has been associated with neurocognitive deficits, thromboembolic disease, and cardiovascular disease, although the data regarding the latter associations are mixed. This article summarizes the key side effects associated with ADT and discusses strategies to optimize management. PMID- 30248168 TI - The Diagnosis and Management of Retroperitoneal Sarcoma. AB - Retroperitoneal sarcoma (RPS) is a rare tumor whose diagnosis and management can be challenging and for which management requires a multidisciplinary team in a specialized center. An important part of the diagnosis-identification of the histologic subtype-depends on pathology; identifying the histologic subtype is important because this can affect prognosis and treatment options. Complete surgical resection with negative margins remains the cornerstone of treatment of nonmetastatic RPS and is the only chance for cure. In order to achieve negative margins, multivisceral en bloc resection is often necessary. Neoadjuvant therapies (chemotherapy, external beam radiation, or combination radiation and chemotherapy) are safe in well-selected patients and may be considered after careful review by a multidisciplinary sarcoma tumor board when the recurrence risk is high. PMID- 30248170 TI - Prognostic Value of Low Tumor Burden in Patients With Melanoma. AB - The therapeutic landscape for cutaneous melanoma has dramatically advanced in the last several years with the development, validation, and approval by the US Food and Drug Administration of several new therapies that have proven effective in treating metastatic disease. Considerable effort has been put into identifying prognostic and predictive markers of therapeutic response to better delineate the patient populations most likely to benefit from treatment. Baseline tumor burden has been described as a common clinical factor associated with treatment response: lower tumor burden at the time of therapeutic intervention is associated with improved responses and survival outcomes on several therapies. Some therapies have shown efficacy as adjuvant interventions in patients with subclinical disease following definitive treatment, further supporting their role in patients with minimal tumor burden. The increasing evidence that patients with lower tumor burden may be the ones who derive maximal benefit from several melanoma-directed therapies points toward the critical need for risk-tailored surveillance to permit early identification of melanoma metastasis in patients at high risk for recurrence. PMID- 30248171 TI - Extending the clinical phenotype associated with biallelic NTHL1 germline mutations. PMID- 30248172 TI - Dabrafenib plus trametinib in BRAF K601E-mutant melanoma. AB - About 40 - 50% of cutaneous melanomas have activating BRAF mutations that are reachable with targeted therapy and combined BRAF-MEK inhibition improves clinical outcomes in advanced BRAF V600E/K-mutant melanoma. Three combinations are FDA-approved for this indication: dabrafenib-trametinib, vemurafenib cobimetinib and encorafenib-binimetinib. The K601E mutation comprises approximately 3% of BRAF mutations in patients with melanoma. This article is protected by copyright. All rights reserved. PMID- 30248173 TI - American Geriatrics Society and National Institute on Aging Bench-to-Bedside Conference: Sensory Impairment and Cognitive Decline in Older Adults. AB - This article summarizes the presentations and recommendations of the tenth annual American Geriatrics Society and National Institute on Aging Bench-to-Bedside research conference, "Sensory Impairment and Cognitive Decline," on October 2-3, 2017, in Bethesda, Maryland. The risk of impairment in hearing, vision, and other senses increases with age, and almost 15% of individuals aged 70 and older have dementia. As the number of older adults increases, sensory and cognitive impairments will affect a growing proportion of the population. To limit its scope, this conference focused on sensory impairments affecting vision and hearing. Comorbid vision, hearing, and cognitive impairments in older adults are more common than would be expected by chance alone, suggesting that some common mechanisms might affect these neurological systems. This workshop explored the mechanisms and consequences of comorbid vision, hearing, and cognitive impairment in older adults; effects of sensory loss on the aging brain; and bench-to-bedside innovations and research opportunities. Presenters and participants identified many research gaps and questions; the top priorities fell into 3 themes: mechanisms, measurement, and interventions. The workshop delineated specific research questions that provide opportunities to improve outcomes in this growing population. J Am Geriatr Soc 66:2052-2058, 2018. PMID- 30248174 TI - Whole-genome duplication decreases clonal stolon production and genet size in the wild strawberry Fragaria vesca. AB - PREMISE OF THE STUDY: Clonal reproduction is often associated with polyploidy and is expected to influence polyploid establishment success, but the immediate effects of whole-genome duplication (WGD) on clonal reproduction in autopolyploids are unknown. METHODS: We used synthesized neopolyploids to assess the direct effects of WGD on stolon and plantlet production in the wild strawberry Fragaria vesca by (1) comparing absolute clonal investment between diploids and neotetraploids under high and low resource conditions in the greenhouse and (2) determining realized clonal plantlet establishment and genet spatial structure using artificial field populations comprising both cytotypes. KEY RESULTS: Neotetraploids produced fewer stolons and plantlets than diploids at slower weekly rates in the greenhouse when resources were high, resulting in lower total investment in clonal reproduction. Low resources led to smaller reductions in clonal biomass for neotetraploids and less pronounced differences between cytotypes. Comparisons between neotetraploids representing 13 independent WGD events and close diploid relatives revealed considerable variation in the response to polyploidization for some clonal traits. Field populations corroborated greenhouse results; neotetraploid genets were smaller than diploid genets, containing 28% fewer stolons and 46% fewer rooted plantlets. CONCLUSIONS: WGD significantly decreases the clonal output of neotetraploid F. vesca, which is likely attributable to slower whole-plant growth of the neotetraploids than the diploids. In natural populations, smaller neotetraploid genets could decrease the probability of polyploid establishment in this species. However, variation between separate neopolyploid lines emphasizes that the response of clonal investment to WGD may not be uniform across polyploid origins. PMID- 30248175 TI - A Forensic Entomological Analysis Can Yield an Estimate of Postmortem Interval, and Not Just a Minimum Postmortem Interval: An Explanation and Illustration Using a Case. AB - Several authors claimed that a forensic entomological analysis can never be interpreted as the postmortem interval (PMI), but that it can be interpreted as a minimum postmortem interval (PMImin ), or dead for not less than X amount of time. Because in most instances, a PMI estimate should be a range, that is, the set of values from maximum postmortem interval (PMImax ) to PMImin , objections to PMI estimation are objections to PMImax estimation. The arguments for this position did not address the substantial body of literature describing estimation of both PMImax and PMImin using insect succession analysis. This report reviews the scientific issues and presents a recent homicide investigation in which several forensic entomology experts used the absence of carrion insects on the corpse, a kind of succession analysis, to estimate PMI or PMImax . PMID- 30248176 TI - Study of Color Laser Printer and Photocopier Class Using a Pattern Location Measurement Method. AB - A trace code pattern location measurement approach is proposed. It includes a method that can precisely extract the trace code pattern to identify the color laser printer or photocopier class. In this study, we collected 379 samples from 15 brands, including 129 models and 196 printers or photocopiers. The trace code pattern class is identified. Four class characteristics are used to identify the print source: (i) the relation between the pattern and print output direction; (ii) observation of the shape features from among the trace code pattern units; (iii) the feature arrangement from among the trace code pattern units; and (iv) the arrangement relation of the trace code pattern. Blind testing shows that the accuracy of the proposed method is approximately 96.9% for the Questioned Document Examiners, and 84.3% in the non-Questioned Document Examiners. It is thus an effective technique for determining a print's color laser printer or photocopier source class. PMID- 30248177 TI - Density-dependent positive feedbacks buffer aquatic plants from interactive effects of eutrophication and predator loss. AB - Self-facilitation allows populations to persist under disturbance by ameliorating experienced stress. In coastal ecosystems, eutrophication and declines of large predatory fish are two common disturbances that can synergistically impact habitat-forming plants by benefitting ephemeral algae. In theory, density dependent intraspecific plant facilitation could weaken such effects by ameliorating the amount of experienced stress. Here, we tested whether and how shoot density of a common aquatic plant (Myriophyllum spicatum) alters the response of individual plants to eutrophication and exclusion of large predatory fish, using a 12-week cage experiment in the field. Results showed that high plant density benefitted individual plant performance, but only when the two stressors were combined. Epiphytic algal biomass per plant more than doubled in cages that excluded large predatory fish, indicative of a trophic cascade. Moreover, in this treatment, individual shoot biomass, as well as number of branches, increased with density when nutrients were added, but decreased with density at ambient nutrient levels. In contrast, in open cages that large predatory fish could access, epiphytic algal biomass was low and individual plant biomass and number of branches were unaffected by plant density and eutrophication. Plant performance generally decreased under fertilization, suggesting stressful conditions. Together, these results suggest that intraspecific plant facilitation occurred only when large fish exclusion (causing high epiphyte load) was accompanied by fertilization, and that intraspecific competition instead prevailed when no nutrients were added. As coastal ecosystems are increasingly exposed to multiple and often interacting stressors such as eutrophication and declines of large predatory fish, maintaining high plant density is important for ecosystem-based management. PMID- 30248179 TI - Corpse Dismemberment and a Necrofetishist. AB - A case of postmortem dismemberment and evisceration is presented. Over a 5-year period, a serial killer murdered twelve men, with a necrophilic intent, so he could mimic relationship behaviors with the corpses of those he killed. Analysis of the methods he chose to dispose of his victims reveals a stark contrast to the motive for perpetrating the homicides, methods which are suggestive of anger toward the victim when they could no longer fulfill their role in the necrophile's fantasy. PMID- 30248178 TI - The impact of CYP2D6 mediated drug-drug interaction: a systematic review on a combination of metoprolol and paroxetine/fluoxetine. AB - AIM: Metoprolol (a CYP2D6 substrate) is often co-prescribed with paroxetine/fluoxetine (a CYP2D6 inhibitor) because the clinical relevance of this drug-drug interaction (DDI) is still unclear. This review aimed to systematically evaluate the available evidence and quantify the clinical impact of the DDI. METHOD: Pubmed, Web of Science, Cochrane Library and Embase were searched for studies reporting on the effect of the DDI among adults published until April 2018. Data on pharmacokinetics, pharmacodynamics and clinical outcomes from experimental, observational and case report studies were retrieved. The protocol of this study was registered in PROSPERO (CRD42018093087). RESULTS: We found nine eligible articles that consisted of four experimental and two observational studies as well as three case reports. Experimental studies reported that paroxetine increased the AUC of metoprolol three to five times, and significantly decreased systolic blood pressure and heart rate of patients. Case reports concerned bradycardia and atrioventricular block due to the DDI. Results from observational studies were conflicting. A cohort study indicated that the DDI was significantly associated with the incidence of early discontinuation of metoprolol as an indicator of the emergence of metoprolol-related side effects. In a case-control study, the DDI was not significantly associated with bradycardia. CONCLUSION: Despite the contradictory conclusions from the current literature, the majority of studies suggest that the DDI can lead to adverse clinical consequences. Since alternative antidepressants and beta-blockers with comparable efficacy are available, such DDIs can be avoided. Nonetheless, if prescribing the combination is unavoidable, a dose adjustment or close monitoring of the metoprolol-related side effects is necessary. PMID- 30248180 TI - Mechanical failure rates of artificial urinary sphincter components: Is the 3.5 cm urethral cuff at higher risk? AB - AIM: We report the rates of artificial urinary sphincter (AUS) mechanical failure in a contemporary cohort of patients stratified by component type and size to determine if the 3.5-cm cuff is at higher risk of failure. METHODS: From 2005 2016, a total of 486 male patients with stress incontinence underwent implantation or revision of an AUS. 993 individual cases were retrospectively reviewed (465 primary placements and 528 revisions). Components were separately tallied and cases of mechanical failure were identified. Multiple variables including duration until failure and follow-up interval were collected and analyzed for each malfunction. RESULTS: After median follow-up of 31.5 months, there were 48 distinct cases of mechanical failure. The urethral cuff was the most common component to fail (n = 27, 56.3%), followed by the pressure regulating balloon (PRB) (n = 6, 12.5%), tubing (n = 6, 12.5%), and the control pump, (n = 5, 10.4%). Four (8.3%) cases did not have the source of malfunction identifiable in available records though fluid loss was evident at the time of device interrogation. Sub-analyses of cuff failure events showed that the 3.5-cm cuff had a statistically significant higher risk of failure (HR: 7.313, (P < .0001) compared to larger cuff sizes. CONCLUSIONS: While each component is prone to malfunction, our study suggests that the 3.5-cm urethral cuff is more susceptible to failure and failure events occur earlier after placement than larger cuff sizes. PMID- 30248182 TI - Two distinct RHCE alleles in cis to weak D type 31 alleles in individuals from different ethnicities. PMID- 30248181 TI - Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma. AB - Like in many tumor types, immunotherapy is currently under investigation to assess its potential efficacy in glioblastoma patients. Trials are under way to assess the efficacy of new immune checkpoint inhibitors including anti-PD-1 or CTLA4. We here investigate the expression and efficacy of a novel immune checkpoint inhibitor, called LAG-3. We show that LAG-3 is expressed in human glioblastoma samples and in a mouse glioblastoma model we show that knock out or LAG-3 inhibition with a blocking antibody is efficacious against glioblastoma and can be used in combination with other immune checkpoint inhibitors toward complete eradication of the model glioblastoma tumors. From a mechanistic standpoint we show that LAG-3 expression is an early marker of T cell exhaustion and therefore early treatment with LAG-3 blocking antibody is more efficacious than later treatment. These data provide insight and support the design of trials that incorporate LAG-3 in the treatment of glioblastoma. PMID- 30248183 TI - Bladder changes after catheterizable channel creation in adults with cerebral palsy who are in chronic urinary retention. AB - AIMS: Cerebral palsy (CP) is characterized by motor impairments as a result of brain injury during development. Patients can have neurogenic bladder dysfunction and are often unable to catheterize through their native urethra. Catheterizable channel (CC) creation can facilitate clean intermittent catheterization (CIC). We have observed that patients with large capacity, low-pressure bladders can develop de novo neurogenic detrusor overactivity (NDO) postoperatively. We sought to better characterize this finding. METHODS: We reviewed the charts of patients 17 years or older with CP seen between 2006 and 2017. Patients undergoing creation of any type of CC without augmentation cystoplasty, due to adequate storage on pre-operative urodynamics (UDS), were included. Pre- and post operative UDS were reviewed. Frequency of incontinence and use of anticholinergics or intravesical injections of onabotulinum toxin A (Btx) were reviewed. RESULTS: Eight patients with CP underwent CC creation without augmentation. Preoperatively, six of eight patients were in chronic retention with two others performing CIC. Following CC creation, patients in retention required additional NDO management with anticholinergics, mirabegron, or onabotulinumtoxin A. Among those with complete UDS data, 67% demonstrated lower maximum cystometric capacity postoperatively. Median follow-up was 25 months. CONCLUSIONS: CC creation facilitates CIC in adults with CP who are in chronic retention due to pseudodyssynergia. Despite preoperative UDS suggesting an adequate capacity, low-pressure bladder, such patients often manifest de novo NDO and worsening incontinence upon initiation of CIC after surgery. These findings should be considered when determining whether to perform augmentation at the time of CC in adults with CP. PMID- 30248184 TI - Opportunities and challenges to utilization of quantitative imaging: Report of the AAPM practical big data workshop. AB - BACKGROUND: This article is a summary of the quantitative imaging subgroup of the 2017 AAPM Practical Big Data Workshop (PBDW-2017) on progress and challenges in big data applied to cancer treatment and research supplemented by a draft white paper following an American Association of Physicists in Medicine FOREM meeting on Imaging Genomics in 2014. AIMS: The goal of PBDW-2017 was to close the gap between theoretical vision and practical experience with encountering and solving challenges in curating and analyzing data. CONCLUSIONS: Recommendations based on the meetings are summarized. PMID- 30248185 TI - The Effect of Household Oxidizing Cleaners on Chemiluminescence of Blood Using Bluestar(r). AB - This study tests the effect of three common oxidizing cleaners on the ability of the Bluestar Forensic(r) presumptive test for blood to identify the presence of blood on ceramic tile after cleaning. The cleaners tested were Lysol(r), OxiClean(r), and Arm & Hammer(r). This study also tested which cleaner was the most effective at removing blood, measured by the intensity of chemiluminescence, which was quantified using RGB values in ImageJ. A "hasty" 1-min cleaning of a blood droplet was simulated using the three cleaners. The chemiluminescence of the Bluestar(r) reactions after cleaning the blood-treated region was compared to an untreated region of the same tile for each cleaner, as well as to the treated regions of tiles between the three cleaners. Results indicate that none of the three cleaners removed all of the blood (all p < 0.001) and that Lysol(r) removed more blood compared to the OxiClean(r) and Arm & Hammer(r). PMID- 30248188 TI - Cultural Values, Trust, and Benefit-Risk Perceptions of Hydraulic Fracturing: A Comparative Analysis of Policy Elites and the General Public. AB - Hydraulic fracturing ("fracking") has recently become a very intensely debated process for extracting oil and gas. Supporters argue that fracking provides positive economic benefits and energy security and offers a decreased reliance on coal-based electricity generation. Detractors claim that the fracking process may harm the environment as well as place a strain on local communities that experience new fracking operations. This study utilizes a recently conducted survey distributed to a sample of policy elites and the general public in Arkansas and Oregon to examine the role of cultural value predispositions and trust in shaping the perceptions of risks and benefits associated with fracking. Findings indicate that cultural values influence both trust and benefit-risk perceptions of fracking for both policy elites and the general public. More specifically, we found that trust in information from various sources is derived from the intrinsic values held by an individual, which in turn impacts perceptions of related benefits and risks. We also found that while the overall pattern of relationships is similar, trust plays a larger role in the formulation of attitudes for policy elites than for the general public. We discuss the implications of the mediating role of trust in understanding value-driven benefit risk perceptions, as well as the disparate role of trust between policy elites and the general public in the context of the policy-making process for both theory and practice. PMID- 30248186 TI - Alcohol binge disrupts the rat intestinal barrier: the partial protective role of oleoylethanolamide. AB - BACKGROUND AND PURPOSE: Chronic alcohol consumption alters the gut-brain axis, but little is known about alcohol binge episodes on the functioning of the intestinal barrier. We investigated the influence of ethanol binges on bacterial translocation, gut inflammation and immunity, and tight junction (TJ) structure and the ability of the biolipid oleoylethanolamide (OEA) to prevent ethanol binge induced intestinal barrier dysfunction. EXPERIMENTAL APPROACH: OEA was injected i.p. before repeated ethanol administration by oral gavage. Plasma, spleen, liver and mesenteric lymph nodes (MLN) were collected in sterile conditions for determination of bacterial load. Immune/inflammatory parameters, TJ proteins and apoptotic markers were determined in colonic tissue by RT-PCR and Western blotting. TJ ultrastructure was examined by transmission electron microscopy. KEY RESULTS: Ethanol binges induced bacterial translocation to the MLN (mainly) and spleen. Colonic tissues showed signs of inflammation, and activation of innate (Toll-like receptor-4) and adaptive (IgA) immune systems and TJ proteins (occludin and claudin-3) were decreased after ethanol binges. Pretreatment with OEA reduced intestinal inflammation and immune activation and partially preserved the TJ structure affected by alcohol binges but had no effect on alcohol-induced apoptosis. Ultrastructural analyses of colonic TJs revealed dilated TJs in all ethanol groups, with less electron-dense material in non-pretreated rats. The protective effects of i.p. OEA did not reduce bacterial translocation to the MLN. However, intragastric OEA administration significantly reduced plasma LPS levels and bacterial translocation to the MLN. CONCLUSION AND IMPLICATIONS: OEA-based pharmacotherapies could potentially be useful to treat disorders characterized by intestinal barrier dysfunction, including alcohol abuse. PMID- 30248187 TI - Feature characterization of scarring and non-scarring types of alopecia by multiphoton microscopy. AB - OBJECTIVES: Non-invasive visualization of hair follicles is important for proper diagnosis and management of alopecia; however, histological assessment remains the gold standard. Laser imaging technologies have made possible noninvasive in vivo evaluation of skin and hair follicle. The aim of this study was to evaluate the ability of multiphoton microscopy (MPM) to non-invasively identify morphological features that can distinguish scarring from non-scarring alopecia. METHODS: MPM images were obtained from areas on the scalp affected by alopecia. Investigators blinded to the diagnosis analyzed hair follicle and shaft sizes. Patients were recruited and imaged at the UC Irvine Health Medical Center and the University of California, Irvine Beckman Laser Institute. Patients with androgenetic alopecia (AGA) and alopecia areata (AA), and scarring alopecia, in particular frontal fibrosing alopecia (FFA) were recruited and imaged from July 2016 to July 2017. RESULTS: We imaged 5 normal scalp subjects and 12 patients affected by non-scarring (7 subjects) and scarring (5 subjects) alopecia. In normal and non-scarring alopecia patients, MPM identified presence of sebaceous glands associated with hair follicles. MPM images of scarring alopecia were characterized by the presence of inflammatory cells surrounding hair follicles. Measurements of hair follicle diameter sizes were found to be significantly smaller in scarring alopecia patients compared to normal (P < 0.001) and compared to non-scarring alopecia patients (P = 0.046); non-scarring hair follicles were also significantly smaller than normal hair follicles (P = 0.043). CONCLUSIONS: This study shows that MPM imaging can non-invasively identify morphological features that distinguish scarring from non-scarring alopecia. Further studies are needed to validate this technique and evaluate its potential to be used as an aid for guiding treatment. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 30248189 TI - Use of a simple in vitro fatigue test to assess materials used in the surgical treatment of stress urinary incontinence and pelvic organ prolapse. AB - AIMS: Stress urinary incontinence and pelvic organ prolapse are very common conditions with a proportion of patients requiring implantation of synthetic materials for a durable repair. However increasing numbers of post-surgical complications have been reported related to the use of polypropylene meshes. One hypothesis for the adverse response is poor mechanical matching of the relatively stiff polypropylene mesh particularly as materials in the pelvic floor will need to cope with decades of distension as occurs with increase of intraabdominal pressure on coughing, laughing, or sneezing. METHODS: In this study we have undertaken a very simple fatigue testing regime to compare the mechanical abilities of six materials. Four commercial meshes in clinical use and two novel electrospun materials not yet evaluated in the clinic were assessed using a uniaxial tensile test. This was performed on six samples of each dry material and on another six samples of each material after just 3 days of fatigue conditions using a dynamic bioreactor. RESULTS: The four commercial materials showed permanent mechanical deformation after just 3 days of stretching these materials by 25% elongation on a regular dynamic cycle, whereas the two new materials presented more elastic properties without deformation. CONCLUSIONS: We suggest that a test as simple as this 3-day fatigue testing is sufficient to distinguish between materials which have already been found to cause complications clinically and newer materials yet to be tested clinically which will hopefully prove more mechanically appropriate for implantation in the pelvic floor. PMID- 30248190 TI - Developmental Changes in Pharmacokinetics and Pharmacodynamics. AB - Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In pediatrics, age is a continuum that can and does add variability in drug disposition and effect. This article addresses the many important factors that influence drug disposition and effect relative to age. What is known about the influence of maturation on the processes of drug absorption, distribution, metabolism, excretion, and drug receptor dynamics are outlined. Our state of understanding of many of these factors remains in flux, however, and only with additional study will we be able to better anticipate and model drug-response relationships across the age continuum. Being able to continuously improve our care of the ill pediatric patient while simultaneously being able to accurately determine the utility of new drugs and chemical entities in this population requires our enhanced understanding of these disposition characteristics. PMID- 30248191 TI - Identifying the "Blip on the Radar Screen": Leveraging Big Data in Defining Drug Safety and Efficacy in Pediatric Practice. AB - The immense amount of electronic health data (pharmacy and administrative claims, electronic health records, and clinical registries) that is being generated every day in the care of patients has the potential to be leveraged for improving clinical decisions at the point of care, uncovering or validating drug efficacy and drug safety. The potential use of big data for improving safe and effective use of medications is especially important in children because of their low drug exposure relative to adults. Electronic health data is collected primarily for clinical or billing purposes and not for research purposes. The major steps involved in data acquisition, extraction, aggregation, analysis, modeling, and interpretation are discussed. It is important to understand the limitation of big data and utilize appropriate study design and statistical methods. Possible applications are presented along with specific examples of how big data has been used in drug research to find that blip on the radar screen that may give an efficacy or safety signal that can lead to further investigation. PMID- 30248192 TI - Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children. AB - Almost half of recent pediatric trials failed to achieve labeling indications, in large part because of inadequate study design. Therefore, innovative study methods are crucial to optimizing trial design while also reducing the potential harms inherent with drug investigation. Several methods exist to optimize the amount of pharmacokinetic data collected from the smallest possible volume and with the fewest number of procedures, including the use of opportunistic and sparse sampling, alternative and noninvasive matrices, and microvolume assays. In addition, large research networks using master protocols promote collaboration, reduce regulatory burden, and increase trial efficiency for both early- and late phase trials. Large pragmatic trials that leverage electronic health records can capitalize on central management strategies to reduce costs, enroll patients with rare diseases on a large scale, and augment study generalizability. Further, trial efficiency and safety can be optimized through Bayesian adaptive techniques that permit planned protocol changes based on analyses of prior and accumulated data. In addition to these trial design features, advances in modeling and simulation have paved the way for systems-based and physiologically based models that individualize pediatric dosing recommendations and support drug approval. Last, given the low prevalence of many pediatric diseases, collecting deidentified genetic and clinical data on a large scale is a potentially transformative way to augment clinical pharmacology research in children. PMID- 30248193 TI - Drug Formulations: Standards and Novel Strategies for Drug Administration in Pediatrics. AB - Child-appropriate drug formulations are a prerequisite of successful drug therapy in children. Efficacy and safety must be given for the active pharmaceutical ingredient, but safety also for the used excipients, components of primary packaging materials, and devices. We are presently experiencing exciting times for pediatric drug development, stimulated by previous governmental incentives in both the European Union and the United States. The most important advances in pediatric drug formulation development are reviewed and evaluated in this article. Scientific publications and recent industry strategies indicate a clear shift from liquid dosage forms to novel solid dosage forms. Solid formulations are usually composed from excipients generally regarded as safe, whereas many liquid formulations contain excipients such as preservatives, antioxidants, or taste-masking agents that raise concerns. Further, some recent clinical studies on swallowability, acceptability, and preference indicate superiority for small sized tablets, so-called mini-tablets, over conventional liquids. In general, multiparticulate solid dosage forms could partly replace the liquids and provide more stable and cheaper alternatives to existing drug products or new developments. Dispersible solid drug dosage forms like orodispersible tablets, mini-tablets and films are even better opportunities for efficient and safe use in pediatrics. Novel measuring and administration devices may facilitate the handling and drug administration of these modern drug dosage forms. Combination products (drug-device combinations) can easily be linked with new e-health technologies in near future to further improve pediatric drug therapy. PMID- 30248194 TI - Developmental Pharmacotherapy: The Interface Between Ontogeny and Drug Effect. PMID- 30248195 TI - Vaccine Update: Recent Progress With Novel Vaccines, and New Approaches to Safety Monitoring and Vaccine Shortage. AB - Vaccines are increasingly based on new constructs, new technologies, and new compounds. Novel immunization programs are rapidly implemented globally. In this article, we highlight selected hot topics of this highly dynamic and broad field of scientific and public health development. The first section focuses on novel vaccines including malaria, dengue, serogroup B meningococcal, and respiratory syncytial virus vaccines and antibodies. The second section is addressing emerging strategies and programmatic challenges including maternal immunization, integrated mother-child safety monitoring, and finally coping strategies with vaccine shortages. PMID- 30248196 TI - Adverse Drug Reactions Across the Age Continuum: Epidemiology, Diagnostic Challenges, Prevention, and Treatments. AB - Adverse drug reactions (ADRs) are common and important complications of drug therapy for children. The risk for ADRs changes over childhood, as do the nature and types of ADRs. Importantly, the risk and nature of ADRs in children are markedly different from those of adults, and adult data cannot be relied on to guide safe drug therapy in children. There are groups of children, notably those with complex and chronic diseases, who are at substantial risk for ADRs. The evaluation of an undesired effect during therapy is ideally accomplished by an organized approach that is a skill that clinicians who care for children especially those children at high risk for ADRs must have. Additionally, clinicians as well as drug regulatory agencies and industry need to be both vigilant and astute as well as aware that ADRs in children are often different in nature and frequency from those in adults. The increasing use of pharmacogenomics to guide drug dosing and the increasing number of biological agents will provide new sets of challenges to clinicians over the next decade. PMID- 30248197 TI - The Path to Perfect Pediatric Posology - Drug Development in Pediatrics. AB - Reluctance to enroll pediatric subjects in clinical trials has left gaps in information about dosing, safety, and efficacy of medications. Pharmacotherapeutic information for pediatric patients may be available for only a small range of ages and may be deficient, as children respond differently as they grow and mature from prematurity to adolescence. Current regulations, however, require early planning for the participation of children in drug development, as pediatric plans must be submitted at the end of phase 1 (European Union) or the end of phase 2 (United States). These plans are extensive, outlining planned studies, subjects to be enrolled, dose and dosage form justification, planned observations, and statistical analysis as well as planned modeling, simulation, and extrapolation analyses. The extent to which efficacy information in adults can be extrapolated to children depends on how similar the disease is in adults and each of the 5 pediatric age groups. Extrapolation may not be possible for conditions that do not occur in adults, requiring a complete development plan in adults, or extrapolation may be complete because of similar pathology and response to treatment. Pharmacokinetic and safety information cannot be extrapolated and must be collected in children of all ages, unless a waiver is granted. Physiologically based pharmacokinetic modeling, optimal design, population pharmacokinetics, and scavenged samples are all examples of new methodologies being used to study pediatric therapeutics. Clinicaltrials.gov and EU Clinical Trials registry are good sources of results of pediatric trials, although sponsors are also working toward prompt publication of study results in peer-reviewed journals. PMID- 30248198 TI - Pediatric Obesity: Influence on Drug Dosing and Therapeutics. AB - Obesity is an ongoing global health concern and has only recently been recognized as a chronic disease of energy homeostasis and fuel partitioning. Obesity afflicts 17% of U.S. children and adolescents. Severe obesity (>=120% of the 95th percentile of body mass index (BMI) for age, or a BMI >= 35 kg/m2 ) is the fastest-growing subgroup and now approaches 6% of all U.S. youth. Health consequences (eg, type 2 diabetes, coronary heart disease) are related in a dose dependent manner to severity of obesity. Because therapeutic interventions are less effective in severe obesity, prevention is a high priority. Treatment plans involving combinations of behavioral therapy, nutrition, and exercise achieve limited success. Only one drug, orlistat, is U.S. Food and Drug Administration approved for long-term obesity management in adolescents 12 years and older. As part of comprehensive medication management, clinicians should consider the propensity for a given drug to aggravate weight gain and to consider alternatives that minimize weight impact. Medication management must take into account developmental changes as well as the pathophysiology of obesity and comorbidities. Despite expanding insight into obesity pathophysiology, there are gaps in its translation to therapeutic application. The historical construct of obesity as simply a fat-storage disorder is fundamentally inaccurate. The approach to adjusting doses based solely on body size and extrapolating from therapeutic knowledge of adult obesity may be based on assumptions that are not fully substantiated. Classes of drugs commonly prescribed for comorbidities associated with obesity should be prioritized for clinical research evaluations aimed at optimizing dosing regimens in pediatric obesity. PMID- 30248199 TI - Pharmacometric Modeling and Simulation Is Essential to Pediatric Clinical Pharmacology. AB - Pediatric clinical pharmacology now encompasses a wide range of activities, including drug pharmacokinetic and pharmacodynamic modeling and simulation, also known as pharmacometrics. Pediatric clinical pharmacologists may be physicians but are more likely to be pharmacists or PhD scientists, and pediatric clinical pharmacology today is largely a research specialty rather than a subspecialty for direct patient care. Pharmacometrics, including "top-down" population modeling and "bottom-up" physiologically based pharmacokinetic modeling, has become an indispensable tool for pharmaceutical industry scientists, government regulators, academic researchers, and even a handful of patient-oriented practitioners. This review summarizes the application of pharmacometrics within each of these domains and predicts future trends of further applications across the spectrum of pediatric clinical pharmacology from drug development to patient care. PMID- 30248200 TI - Probiotics in Disease Prevention and Treatment. AB - Few treatments for human diseases have received as much investigation in the past 20 years as probiotics. In 2017, English-language meta-analyses totaling 52 studies determined the effect of probiotics on conditions ranging from necrotizing enterocolitis and colic in infants to constipation, irritable bowel syndrome, and hepatic encephalopathy in adults. The strongest evidence in favor of probiotics lies in the prevention or treatment of 5 disorders: necrotizing enterocolitis, acute infectious diarrhea, acute respiratory tract infections, antibiotic-associated diarrhea, and infant colic. Probiotic mechanisms of action include the inhibition of bacterial adhesion; enhanced mucosal barrier function; modulation of the innate and adaptive immune systems (including induction of tolerogenic dendritic cells and regulatory T cells); secretion of bioactive metabolites; and regulation of the enteric and central nervous systems. Future research is needed to identify the optimal probiotic and dose for specific diseases, to address whether the addition of prebiotics (to form synbiotics) would enhance activity, and to determine if defined microbial communities would provide benefit exceeding that of single-species probiotics. PMID- 30248201 TI - Opioids in Breast Milk: Pharmacokinetic Principles and Clinical Implications. AB - Safety of maternal drug therapy during breastfeeding may be assessed from estimated levels of drug exposure of the infant through milk. Pharmacokinetic (PK) principles predict that the lower the clearance is, the higher the infant dose via milk will be. Drugs with low clearance (<1 mL/[kg.min]) are likely to cause an infant exposure level greater than 10% of the weight-adjusted maternal dose even if the milk-to-plasma concentration ratio is 1. Most drugs cause relatively low-level exposure below 10% of the weight-adjusted maternal dose, but opioids require caution because of their potential for severe adverse effects. Furthermore, substantial individual variations of drug clearance exist in both mother and infant, potentially causing drug accumulation over time in some infants even if an estimated dose of the drug through milk is small. Such PK differences among individuals are known not only for codeine and tramadol through pharmacogenetic variants of CYP2D6 but also for non-CYP2D6 substrate opioids including oxycodone, indicating difficulties of eliminating PK uncertainty by simply replacing an opioid with another. Overall, opioid use for pain management during labor and delivery and subsequent short-term use for 2-3 days are compatible with breastfeeding. In contrast, newly initiated and prolonged maternal opioid therapy must follow a close monitoring program of the opioid naive infants. Until more safety data become available, treatment duration of newly initiated opioids in the postpartum period should be limited to 2-3 days in unsupervised outpatient settings. Opioid addiction treatment with methadone and buprenorphine during pregnancy may continue into breastfeeding, but infant conditions must be monitored. PMID- 30248202 TI - Optimizing Antibiotic Drug Therapy in Pediatrics: Current State and Future Needs. AB - The selection of the right antibiotic and right dose necessitates clinicians understand the contribution of pharmacokinetic variability stemming from age related physiologic maturation and the pharmacodynamics to optimize drug exposure for clinical response. The complexity of selecting the right dose arises from the multiplicity of pediatric age groups, from premature neonates to adolescents. Body size and age (which relate to organ function) must be incorporated to optimize antibiotic dosing in this vulnerable population. In the effort to optimize and individualize drug dosing regimens, clinical pharmacometrics that incorporate population-based pharmacokinetic modeling, Bayesian estimation, and Monte Carlo simulations are utilized as a quantitative approach to understanding and predicting the pharmacology and clinical and microbiologic efficacy of antibiotics. In addition, opportunistic study designs and alternative blood sampling strategies can serve as practical approaches to ensure successful conduct of pediatric studies. This review article examines relevant literature on optimization of antibiotic pharmacotherapy in pediatric populations published within the last decade. Specific pediatric antibiotic data, including beta-lactam antibiotics, aminoglycosides, and vancomycin, are critically evaluated. PMID- 30248203 TI - Analgesics and Sedatives in Critically Ill Newborns and Infants: The Impact on Long-Term Neurodevelopment. AB - Inadequate pain and/or stress management in preterm- and term-born infants has been associated with increased morbidity and even mortality. However, exposure to analgosedatives during early infancy may also be one of the risk factors for subsequent neurodevelopmental impairment, at least in animal studies. Because infants admitted to neonatal or pediatric intensive care units may receive high amounts of these drugs for prolonged periods of time and the majority of these infants nowadays survive to discharge, this is of major concern. A balanced approach that incorporates the assessment and quantification of both wanted effects as well as unwanted side effects is therefore needed. In this article, the optimal dose determination of commonly used analgosedative drugs as well as their potential long-term effects on the developing human brain and neuropsychological functioning are reviewed. PMID- 30248205 TI - A Gold Carbene Manifold to Prepare Fused gamma-Lactams by Oxidative Cyclisation of Ynamides. AB - Gold-catalysed oxidative cyclisation reactions of ynamides offer great promise in gamma-lactam synthesis but are limited by preferential over-oxidation to form alpha-keto imides. Evaluating the factors that might limit N-cyclisation pathways led to effective gold-catalysed conditions that allow access to different fused gamma-lactams on changing the ynamide N-substituent and accommodate previously incompatible substitution patterns. New and efficient methods for the synthesis of functionalised 3-aryl indoles and cyclohepta[c]pyrrol-1-one derivatives are presented. These conditions illustrate the complementarity of gold catalysis to other metals. PMID- 30248204 TI - Clonal architecture in patients with myelodysplastic syndromes and double or minor complex abnormalities: Detailed analysis of clonal composition, involved abnormalities, and prognostic significance. AB - The study analyzes the clonal architecture and the abnormalities involved in a series of 191 patients with myelodysplastic syndromes (MDS) and 2-3 clonal abnormalities. All patients were extracted from an international database. The patients were classified into six clonal subtypes (2A-3C) based on the number of abnormalities and the presentation of unrelated clones (UC) and/or a clonal evolution. UC were detected in 23/191 patients (12%). The composition of UC showed great variability. The only recurrent combination of abnormalities was del(5q) and + 8 in 8 of 23 patients (35%). In patients with clonal evolution, the clone size of the primary and secondary clone varied: Patients with -7 and + 8 in the primary clone showed a larger primary and a smaller secondary clone (-7: median 74% vs 10%; +8 73% vs 18%) while patients with del(5q) in the primary clone showed a smaller primary and a larger secondary clone (33% vs 61%). Univariate and multivariate analyses showed no significant differences regarding overall or AML-free survival between the clonal subtypes. Only the subtype 3C (3 abnormalities and clonal evolution) was an independent risk factor for developing AML (Hazard Ratio 5.5 as compared to subtype 2A, P < .05). Finally, our study confirms that the number of abnormalities clearly defines a significant risk factor for overall- as well as AML-free survival. Importantly, in patients with more than one clone, the calculation of the number of abnormalities in the entire sample instead of the number of abnormalities per clone allows a higher prognostic accuracy. PMID- 30248206 TI - Prevalence of lower urinary tract symptoms and overactive bladder in men and women over 18 years old: The Colombian overactive bladder and lower urinary tract symptoms (COBaLT) study. AB - AIMS: To estimate the prevalence of LUTS and overactive bladder (OAB) in the Colombian population. METHODS: A cross-sectional, population-based study was conducted in men and women >=18 years using directed interviews and self administered questionnaires in five main cities in Colombia. A sample size of 1054 subjects was estimated (prevalence of LUTS/OAB 15%, CI 95%, statistical power 80%, precision 3%). We used a multi-stage probabilistic sampling technique to randomly select individuals in the community, stratified by socioeconomic status, gender, and age. We used the 2002 ICS and 2010 IUGA/ICS definitions as well as validated questionnaires in Spanish. Descriptive statistics were employed. RESULTS: A total of 1060 participants were included. Mean age was 42 (range 18-89) years. The prevalence of at least one LUTS was 84%, while overactive bladder was reported by 31.8% participants. Among individuals with at least one LUTS, 13.2% would feel "mostly unsatisfied," "unhappy," or "terrible" to spend the rest of their lives with their current urinary condition. Nocturia was the most prevalent LUTS (55.3%), followed by urgency (46.4%) and frequency (45.8%). Urge, stress, and mixed urinary incontinence were reported by 15.3%, 8.6%, and 7% of participants, respectively. CONCLUSIONS: LUTS are highly prevalent in the Colombian population and severely affect quality of life. This is the first study conducted in Colombia and Latin America focused on evaluating LUTS in men and women of all age groups of interest using a multi-stage probabilistic sampling technique. These results may have a significant influence on health decision-making and assessment of future therapies. PMID- 30248207 TI - Does using a nasal barrier dressing prevent nasal injury in premature infants receiving nasal continuous positive airway pressure? PMID- 30248208 TI - The place for dementia-friendly communities in England and its relationship with epidemiological need. AB - OBJECTIVES: The dementia-friendly community (DFC) initiative was set up to enable people living with dementia to remain active, engaged, and valued members of society. Dementia prevalence varies nationally and is strongly associated with the age and sex distribution of the population and level of social deprivation. As part of a wider project to evaluate DFCs, we examined whether there is a relationship between provision of DFCs and epidemiological need. METHODS: Dementia-friendly communities were identified through the formal recognition process of DFC status by the Alzheimer's Society and mapped against areas defined by English Clinical Commissioning Groups. We tested whether provision of a DFC was associated with: (1) dementia prevalence, (2) number of known cases, and (3) known plus estimated number of unknown cases. RESULTS: Of the 209 English Clinical Commissioning Group areas, 115 had at least one DFC. The presence of a DFC was significantly associated with number of known dementia cases (mean difference = 577; 95% CI, 249 to 905; P = 0.001) and unknown dementia cases (mean difference = 881; 95% CI, 349 to 1413; P = 0.001) but not prevalence (mean difference = 0.03; 95% CI, -0.09 to 0.16; P = 0.61). This remains true when controlling for potential confounding variables. CONCLUSIONS: Our findings suggest that DFC provision is consistent with epidemiological-based need. Dementia-friendly communities are located in areas where they can have the greatest impact. A retrospective understanding of how DFCs have developed in England can inform how equivalent international initiatives might be designed and implemented. PMID- 30248209 TI - Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene specific DNA methylation patterns. AB - Aberrant alterations of DNA methylation are common events in oncogenesis. The origin of cancer-associated epigenetic defects is of interest for mechanistic understanding of malignant transformation and-in the long run-therapeutic modulation of DNA methylation in a locus-specific manner. Given the ability of certain long noncoding RNAs to operate as an interface between DNA and the epigenetic modification machinery which can interact with DNA methyltransferases, we hypothesized-considering HOTAIR as an example-that this transcript may contribute to gene specificity of DNA methylation. Using gastrointestinal stromal tumors (GISTs, n = 67) as a model, we confirmed upregulation of HOTAIR in tumors with high risk of recurrence and showed high abundance of the transcript in GIST cell lines. HOTAIR knockdown in GIST-T1 cells triggered transcriptional response of genes involved in the organization and disassembly of the extracellular matrix and, notably, induced global locus-specific alterations of DNA methylation patterns. Hypomethylation was induced at a total of 507 CpG sites, whereas 382 CpG dinucleotides underwent gain of methylation upon HOTAIR depletion. Importantly, orchestrated gain or loss of methylation at multiple individual CpG sites was shown for cancer-related DPP4, RASSF1, ALDH1A3, and other targets. Collectively, our data indicate that HOTAIR enables target specificity of DNA methylation in GIST and is capable of dual (hypo- and hypermethylation) regulation by a yet to be defined mechanism. The results further suggest the feasibility of manipulating DNA methylation in a targeted manner and are of interest in the context of epigenetic cancer therapy. PMID- 30248210 TI - Prompt initiation of high-dose i.v. corticosteroids seems to prevent progression to liver failure in patients with original acute severe autoimmune hepatitis. PMID- 30248211 TI - Prognosis of heart failure treated with digoxin or with ivabradine: A cohort study in the community. AB - BACKGROUND: Resting heart rate (HR) reduction with ivabradine (IVA) improves outcomes of patients with heart failure and reduced ejection fraction (HFrEF). Nevertheless, the best option to slow HR in patients with HFrEF treated with beta blockers and a HR >70 bpm is unsettled. AIMS: To evaluate whether, in patients with HFrEF, commencing therapy with digoxin (CT-DIG) is associated to a worse prognosis than commencing treatment with ivabradine (CT-IVA). METHODS: Observational study over 10 years on 2364 patients with HFrEF in sinus rhythm and a HR >70 bpm. Main outcomes were mortality, hospitalisations and visits. We analyse the independent relationship of CT-DIG or CT-IVA with the prognosis, stratifying patients for cardiovascular comorbidity, and for other potential confounders (378 patients who CT-DIG vs another 355 patients who CT-IVA vs another 1631 patients non-exposed to IVA or DIG). RESULTS: During a median follow up of 57.5 months, 1751 patients (74.1%) died, and 2151 (91.0%) were hospitalised for HF. CT-DIG or CT-IVA was associated with a lower all-cause mortality (DIG: HR = 0.86 [95% CI, 0.82-0.90], and IVA: HR = 0.88 [0.83-0.93]), cardiovascular mortality (DIG: HR = 0.84 [0.80-0.89] and IVA: HR = 0.83 [0.78-0.89]), hospitalisation (DIG: HR = 0.86 [0.83-0.89] and IVA: HR = 0.87 [0.83-0.91]) and 30-day readmission (DIG: HR = 0.84 [0.79-0.90] and IVA: HR = 0.88 [0.79-0.95]), after adjustment for cardiovascular comorbidity, and other potential confounders. These associations with the prognosis of HFrEF did not differ between patients who CT-DIG and those who CT-IVA. CONCLUSION: Commencing therapy with digoxin or with ivabradine is associated with an improved prognosis of patients with HFrEF. PMID- 30248213 TI - Dysbalanced sex hormone status is an independent predictor of decompensation and mortality in patients with liver cirrhosis. AB - AIMS: Endocrinological abnormalities, including low testosterone levels, are prevalent in cirrhosis. We assessed sexual hormone status in regard to hemodynamic abnormalities and its impact on hepatic decompensation and survival. METHODS: Males with cirrhosis were prospectively included in this study since 2010. Sexual hormones including bioavailable testosterone, total testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin, and sex hormone binding globulin as well as Child-Pugh score, Model for End-stage Liver Disease (MELD) score, and hepatic venous pressure gradient were recorded. Sarcopenia was also assessed in patients with available computed tomography scans. Clinical follow-up for hepatic decompensation, liver transplantation, and death was recorded until May 2017. RESULTS: One hundred fourteen male cirrhotic patients were included: age 55 +/- 9.4 years, MELD 13.5 (range, 7-20.7). Etiologies were alcoholic liver disease in 61(53.5%) patients, viral in 30 (26.3%) patients, and other in 23 (20.2%). Child-Pugh scores were A in 32 (28.1%) patients, B in 48 (42.1%), and C in 34 (29.8%). Levels of bioavailable testosterone and total testosterone decreased with advanced Child-Pugh score (P < 0.001 and P < 0.001) whereas prolactin increased (P = 0.002). Median bioavailable testosterone (0.8 ng/mL [0.1-2] vs. 1.68 ng/mL [0.07-2.65]; P = 0.004) and total testosterone (2.7 ng/mL [0.23-12.34] vs. 7 ng/mL [0.25-10]; P = 0.041) levels were lower in patients with severe portal hypertension (hepatic venous pressure gradient >12 mmHg). Median bioavailable testosterone (0.25 ng/mL [0.07-1.7] vs. 0.97 ng/mL [0.15-2.74)]; P = 0.017) and total testosterone levels (1.28 ng/mL [0.25-7.32] vs. 4.32 ng/mL [0.43-13.47]; P = 0.031) were significantly lower in sarcopenic patients. Median follow-up was 13 months (0.2-75 months) and liver-related events were recorded in 46 patients (40.4%; death, 31 [27.2%]). Low total testosterone was associated with an increased risk for hepatic decompensation and/or death, even after adjusting for Child-Pugh score, MELD, and other relevant factors (Child-Pugh score model: hazard ratio 2.503, 95% confidence interval, 1.214 5.157, P = 0.013; MELD model: hazard ratio 3.065, 95% confidence interval, 1.523 6.169, P = 0.002). CONCLUSION: In parallel to increasing severity of cirrhosis, levels of testosterone decline whereas prolactin levels increase. However, low testosterone levels are independently associated with a higher risk for hepatic decompensation and mortality. PMID- 30248212 TI - 19 F MRI of the Lungs Using Inert Fluorinated Gases: Challenges and New Developments. AB - : Fluorine-19 (19 F) MRI using inhaled inert fluorinated gases is an emerging technique that can provide functional images of the lungs. Inert fluorinated gases are nontoxic, abundant, relatively inexpensive, and the technique can be performed on any MRI scanner with broadband multinuclear imaging capabilities. Pulmonary 19 F MRI has been performed in animals, healthy human volunteers, and in patients with lung disease. In this review, the technical requirements of 19 F MRI are discussed, along with various imaging approaches used to optimize the image quality. Lung imaging is typically performed in humans using a gas mixture containing 79% perfluoropropane (PFP) or sulphur hexafluoride (SF6 ) and 21% oxygen. In lung diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), ventilation defects are apparent in regions that the inhaled gas cannot access. 19 F lung images are typically acquired in a single breath-hold, or in a time-resolved, multiple breath fashion. The former provides measurements of the ventilation defect percent (VDP), while the latter provides measurements of gas replacement (ie, fractional ventilation). Finally, preliminary comparisons with other functional lung imaging techniques are discussed, such as Fourier decomposition MRI and hyperpolarized gas MRI. Overall, functional 19 F lung MRI is expected to complement existing proton-based structural imaging techniques, and the combination of structural and functional lung MRI will provide useful outcome measures in the future management of pulmonary diseases in the clinic. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018. PMID- 30248214 TI - Interpretation of lymphocyte subset counts by the general pediatrician. AB - Immune system consists one of the greatest challenges for the scientific community. The general pediatrician should be able to screen and detect an immunodeficient patient based on certain clinical indications. Further investigation is crucial for the distinction between primary or secondary immunodeficiency as well as between cellular and humoral immunity defect. Full blood count is the best initial laboratory test when suspecting a PID, focusing on the absolute lymphocyte count (ALC), while lymphocyte subset count (LSC) offers the advantage of detecting the cell type that causes the immune defect. The aim of the present review is to guide the general pediatrician to investigate and diagnose an immunodeficient patient. Even though an immunodeficiency may seem a very difficult disease to diagnose, a balanced and rational way of thinking along with the help of modern technological advances can easily guide us towards the right direction. This article is protected by copyright. All rights reserved. PMID- 30248215 TI - Impact of intermediate-dose prophylaxis on progression of haemarthropathy in patients with severe haemophilia A: A 10-year, single-centre experience in Korea. AB - AIM: To determine the impact of 10-year intermediate-dose prophylaxis on haemarthropathy progression in patients with severe haemophilia A (SHA). METHODS: Prophylactic treatment with intermediate dose was given maximally for 10 years to 42 patients with SHA in a haemophilia treatment centre in Korea. Patients were divided into three groups based on prophylactic treatment started age: 1-10 (group A'), 11-20 (group B'), and >=21 (group C'). Average annual increase of Pettersson score (P-score) was compared between the treatment groups. RESULTS: Average ages and P-scores at initiation of prophylaxis were 4.65+/-3.43 years and 2.09+/-3.25, 16.13+/-1.73 years and 7.37+/-4.38, and 28.33+/-7.25 years and 12.33+/-6.50 for groups A', B', and C'. Average annual increase of P-score in groups A', B', and C' was 0.039+/-0.11, 0.063+/-0.123, and 0.078+/-0.124. Assuming that intermediate-dose prophylaxis started at the average age, P-score and annual increase of P-score would be the average values of each group; it would thus take 210 and 46.5 years to reach -2SD of the average critical level of haemarthropathy (The level of haemarthropathy (P-score 13.0 +/- 2.7) above which there is a significant impact on quality of life in Korean) in groups A' and B'. However, it would take 55 and 15.75 years if the annual P-score increase were +2SD of the average value in groups A' and B'. CONCLUSION: Intermediate-dose prophylaxis for patients with SHA in Korea would maintain arthropathy below the critical level for most of the patients' lifetime when started before adolescence. However, this would not be achieved in some adolescent patients with rapid progression of arthropathy and in most adult patients. PMID- 30248216 TI - The vocabulary spurt predicts the emergence of backward semantic inhibition in 18 month-old toddlers. AB - The current study examines the relationship between 18-month-old toddlers' vocabulary size and their ability to inhibit attention to no-longer relevant information using the backward semantic inhibition paradigm. When adults switch attention from one semantic category to another, the former and no-longer relevant semantic category becomes inhibited, and subsequent attention to an item that belongs to the inhibited semantic category is impaired. Here we demonstrate that 18-month-olds can inhibit attention to no-longer relevant semantic categories, but only if they have a relatively large vocabulary. These findings suggest that an increased number of items (word knowledge) in the toddler lexical semantic system during the "vocabulary spurt" at 18-months may be an important driving force behind the emergence of a semantic inhibitory mechanism. Possessing more words in the mental lexicon likely results in the formation of inhibitory links between words, which allow toddlers to select and deselect words and concepts more efficiently. Our findings highlight the role of vocabulary growth in the development of inhibitory processes in the emerging lexical-semantic system. PMID- 30248217 TI - Once-weekly prophylaxis with 40 IU/kg nonacog beta pegol (N9-GP) achieves trough levels of >15% in patients with haemophilia B: Pooled data from the paradigmTM trials. AB - INTRODUCTION: Prophylaxis with replacement factor IX (FIX) reduces bleeding frequency and improves quality of life in haemophilia B patients. With prophylaxis, the likelihood of bleeding is lowered with increasing trough levels. New products with extended half-life (EHL) can maintain high factor activity levels over prolonged periods, compared with standard FIX products. AIM: To evaluate the safety, efficacy and pharmacokinetics of the new recombinant FIX EHL product, nonacog beta pegol (N9-GP), using pooled data, with a focus on-but not limited to-prophylaxis at 40 IU/kg. METHODS: N9-GP has been investigated in males with congenital haemophilia B and FIX activity <=2% in the paradigmTM clinical trial programme. This analysis includes pooled data from five completed paradigmTM trials conducted in previously treated adults, adolescents and children, focusing on results of prophylaxis with 40 IU/kg once-weekly intravenous dosing. RESULTS: In total, 115 previously treated patients were exposed to N9-GP. Of 54 patients (47%) treated with N9-GP 40 IU/kg once-weekly prophylaxis, 72% experienced no spontaneous bleeds over 1 year. In all patients receiving 40 IU/kg once-weekly, median overall annualized bleeding rate (ABR) was 1.03 (interquartile range 0.00; 2.89); median spontaneous ABR was 0.00 (0.00; 0.80). No patients developed inhibitors. Estimated mean steady-state trough levels with N9-GP 40 IU/kg once-weekly were >=15% overall; 27.3% in adolescents and adults. CONCLUSION: N9-GP 40 IU/kg once-weekly was well tolerated and effective in preventing bleeding, maintaining mean FIX activity levels >=15% across all age groups. N9-GP may provide a new treatment option for preventing bleeding in haemophilia B patients. PMID- 30248218 TI - Metabolic Studies of Tumor Cells Using [1-13 C] Pyruvate Hyperpolarized by Means of PHIP-Side Arm Hydrogenation. AB - The kinetics of metabolic processes can be assessed, in real time by means of MR hyperpolarized (HP) metabolites. [1-13 C]pyruvate, hyperpolarized by means of d DNP, is, by far, the substrate most widely applied to the investigation of several pathologies characterized by deregulated glycolytic metabolic networks, including cancer. Hyperpolarization of [1-13 C]pyruvate by means of the cost effective, fast and easy to handle PHIP-SAH (para-hydrogen induced polarization side arm hydrogenation) method opens-up a pathway for the application of HP metabolites to a wide range of cancer-related studies. Herein, we report the first application of PHIP-SAH hyperpolarized [1-13 C]pyruvate in the investigation of upregulated glycolysis in two murine breast cancer cell lines (168FARN and 4T1). The results obtained using HP pyruvate have been validated with a conventional biochemical assay and are coherent with previously-reported lactate dehydrogenase activity measured in those cells. PMID- 30248219 TI - Structurally Ordered Intermetallic Cobalt Stannide Nanocrystals for High Performance Electrocatalytic Overall Water-Splitting. AB - The synthesis of structurally ordered non-noble intermetallic cobalt stannide (CoSn2 ) nanocrystals and their utilization for high-performance electrocatalytic overall water-splitting is presented. The structurally and electronically beneficial properties of the tetragonal CoSn2 exhibit a considerably low overpotential for the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) on fluorine-doped tin oxide (FTO) and Ni foam (NF). Loss of Sn from the crystal lattices and oxidation of Co under strongly alkaline conditions furnishes highly disordered amorphous active CoOx (H), the catalytically active structure for OER. The Co0 atoms in the CoSn2 act as active sites for HER and the presence of Sn provides efficient electrical conductivity. This intermetallic phase is a novel type of cost-effective and competitive bifunctional electrocatalysts and predestinated for overall water-splitting devices: A two electrode electrolyzer with CoSn2 on NF delivers a cell voltage of merely 1.55 V at 10 mA cm-2 maintaining long-term stability. PMID- 30248221 TI - Pervasive Delocalisation Error Causes Spurious Proton Transfer in Organic Acid Base Co-Crystals. AB - Dispersion-corrected density-functional theory (DFT-D) methods have become the workhorse of many computational protocols for molecular crystal structure prediction due to their efficiency and convenience. However, certain limitations of DFT, such as delocalisation error, are often overlooked or are too expensive to remedy in solid-state applications. This error can lead to artificial stabilisation of charge transfer and, in this work, it is found to affect the correct identification of the protonation site in multicomponent acid-base crystals. As such, commonly used DFT-D methods cannot be applied with any reliability to the study of acid-base co-crystals or salts, while hybrid functionals remain too restrictive for routine use. This presents an impetus for the development of new functionals with reduced delocalisation error for solid state applications; the structures studied herein constitute an excellent benchmark for this purpose. PMID- 30248220 TI - High-Flux High-Selectivity Metal-Organic Framework MIL-160 Membrane for Xylene Isomer Separation by Pervaporation. AB - Separation of p-xylene (kinetic diameter ca. 0.58 nm) from its bulkier isomers (o xylene and m-xylene, ca. 0.68 nm) is challenging, but important in the petrochemical industry. Herein, we developed a highly selective and stable metal organic framework (MOF) MIL-160 membrane for selective separation of p-xylene from its isomers by pervaporation. The suitable pore size (0.5~0.6 nm) of the MIL 160 membrane selectively allows p-xylene to pass through, while excluding the bulkier o-xylene and m-xylene. For the separation of equimolar binary p-/o-xylene mixtures at 75 degrees C, high p-xylene flux of 467 g m-2 h-1 and p-/o-xylene selectivity of 38.5 could be achieved. The stability of MIL-160, ensured the separation performance of the MIL-160 membrane was unchanged over a 24 h measurement. The high separation performance combined with its high thermal and chemical stability makes the MIL-160 membrane a promising candidate for the separation of xylene isomers. PMID- 30248222 TI - Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease. AB - PINK1 is a ubiquitously expressed mitochondrial serine/threonine protein kinase that has emerged as a key player in mitochondrial quality control. This protein kinase came to prominence in the mid-2000s, when PINK1 mutations were found to cause early onset Parkinson's disease (PD). As most of the PD-related mutations occurred in the kinase domain and impaired PINK1's catalytic activity, it was suggested that small molecules that activated PINK1 would maintain mitochondrial quality control and, as a result, have neuroprotective effects. Working on this hypothesis, a few small-molecule PINK1 activators that offer critical insights and distinct approaches for activating PINK1 have been discovered. Herein, we briefly highlight the discovery of these small molecules and offer insight into the future development of small-molecule PINK1 activators as potential treatments for PD. PMID- 30248223 TI - Adipose may actively delay progression of NAFLD by releasing tumor-suppressing, anti-fibrotic miR-122 into circulation. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology. Here we propose tissue-cooperative, homeostatic model of NAFLD. During early stages of NAFLD the intrahepatic production of miR-122 falls, while the secretion of miRNA containing exosomes by adipose increases. Bloodstream carries exosome to the liver, where their miRNA cargo is released to regulate their intrahepatic targets. When the deterioration of adipose catches up with the failing hepatic parenchyma, the external supply of liver-supporting miRNAs gradually tapers off, leading to the fibrotic decompensation of the liver and an increase in hepatic carcinogenesis. This model may explain paradoxical observations of the disease associated decrease in intrahepatic production of certain miRNAs with an increase in their levels in serum. Infusions of miR-122 and, possibly, some other miRNAs may be efficient for preventing NAFLD-associated hepatocellular carcinoma. The best candidates for exosome-wrapped miRNA producer are adipose tissue-derived mesenchymal stem cells (MSCs), known for their capacity to shed large amounts of exosomes into the media. Notably, MSC-derived exosomes with no specific loading are already tested in patients with liver fibrosis. Carrier exosomes may be co manufactured along with their cargo. Exosome-delivered miRNA cocktails may augment functioning of human organs suffering from a variety of chronic diseases. PMID- 30248225 TI - Pathological upgrading at radical prostatectomy for patients with Grade Group 1 prostate cancer: implications of confirmatory testing for patients considering active surveillance. AB - OBJECTIVE: To examine the association between National Comprehensive Cancer Network (NCCN) risk, number of positive biopsy cores, age, and early confirmatory test results on pathological upgrading at radical prostatectomy (RP), in order to better understand whether early confirmatory testing and better risk stratification are necessary for all men with Grade Group (GG) 1 cancers who are considering active surveillance (AS). PATIENTS AND METHODS: We identified men in Michigan initially diagnosed with GG1 prostate cancer, from January 2012 to November 2017, who had a RP within 1 year of diagnosis. Our endpoints were: (i) >=GG2 cancer at RP and (ii) adverse pathology (>=GG3 and/or >=pT3a). We compared upgrading according to NCCN risk, number of positive biopsy cores, and age. Last, we examined if confirmatory test results were associated with upgrading or adverse pathology at RP. RESULTS: Amongst 1966 patients with GG1 cancer at diagnosis, the rates of upgrading to >=GG2 and adverse pathology were 40% and 59% (P < 0.001), and 10% and 17% (P = 0.003) for patients with very-low- and low-risk cancers, respectively. Upgrading by volume ranged from 49% to 67% for >=GG2, and 16% to 23% for adverse pathology. Generally, more patients aged >=70 vs <70 years had adverse pathology. Unreassuring confirmatory test results had a higher likelihood of adverse pathology than reassuring tests (35% vs 18%, P = 0.017). CONCLUSIONS: Upgrading and adverse pathology are common amongst patients initially diagnosed with GG1 prostate cancer. Early use of confirmatory testing may facilitate the identification of patients with more aggressive disease ensuring improved risk classification and safer selection of patients for AS. PMID- 30248224 TI - Outcomes after placement of a SX-ELLA oesophageal stent for refractory variceal bleeding-A national multicentre study. AB - BACKGROUND: Current guidelines favour the use of bleeding stents over balloon tamponade (BT) for refractory variceal bleeding (VB) from oesophageal varices. However, data on the efficacy and safety of self-expandable metal SX-ELLA Danis stents (SEMS) are limited. METHODS: Cirrhotic patients receiving SEMS for VB at four tertiary care centres were included in this retrospective multicentre study. Rates of failure-to-control bleeding (within 5 days) and bleeding-related mortality (6 weeks) were assessed. RESULTS: SEMS controlled VB in 79.4% (27/34) of patients. In the rest of patients, other rescue treatments including endoscopic band ligation (EBL, n = 3), SEMS renewed (n = 2) or Linton (n = 2) were applied; however, VB was only controlled in one patient. Early rebleeding within six weeks occurred in 17.6% (6/34) patients. Median SEMS dwell time was three (IQR:6) days. Overall n = 13/34 (38.2%) patients died with SEMS in situ. After SEMS removal, rebleeding and bleeding-related death occurred in n = 7 (35%) and n = 5 (14.7%) patients respectively. Only 32.4% (10/34) patients did not experience any rebleeding within six weeks after SEMS removal. Bleeding-related mortality was 47.1% (n = 16/34) and the median survival after SEMS placement was 2.1 months. Notably, no patient received an early transjugular intrahepatic portosystemic shunt (TIPS). The most common adverse events were stent dislocations (n = 13; 38.2%), while ulcers/necrosis of the oesophageal mucosa was seen in only four (11.8%) patients. CONCLUSION: SEMS controlled refractory VB in most patients. However, bleeding-related mortality remained high. While SEMS dislocations were frequent, ulcers/necrosis of the oesophagus was rare. Further studies should investigate whether the wider use of early TIPS reduces bleeding related mortality after SEMS placement. PMID- 30248227 TI - Multiple livid-erythematous macules and plaques with slight scaling in a young man. PMID- 30248226 TI - A stable and productive marine microbial community was sustained through the end Devonian Hangenberg Crisis within the Cleveland Shale of the Appalachian Basin, United States. AB - The end-Devonian Hangenberg Crisis constituted one of the greatest ecological and environmental perturbations of the Paleozoic Era. To date, however, it has been difficult to precisely constrain the occurrence of the Hangenberg Crisis in the Appalachian Basin of the United States and thus to directly assess the effects of this crisis on marine microbial communities and paleoenvironmental conditions. Here, we integrate organic and inorganic chemostratigraphic records compiled from two discrete outcrop locations to characterize the onset and paleoenvironmental transitions associated with the Hangenberg Crisis within the Cleveland Shale member of the Ohio Shale. The upper Cleveland Shale records both positive carbon (delta13 Corg ) and nitrogen (delta15 Ntotal ) isotopic excursions, and replenished trace metal inventories with links to eustatic rise. These dual but apparently temporally offset isotope excursions may be useful for stratigraphic correlation with other productive end-Devonian epeiric marine locations. Deposition of the black shale succession occurred locally beneath a redox stratified water column with euxinic zones, with signs of strengthening denitrification during the Hangenberg Crisis interval, but with an otherwise stable and algal-rich marine microbial community structure sustained in the surface mixed layer as ascertained by lipid biomarker assemblages. Discernible trace fossil signals in some horizons suggest, however, that bioturbation and seafloor oxygenation occurred episodically throughout this succession and highlight that geochemical proxies often fail to capture these rapid and sporadic redox fluctuations in ancient black shales. The paleoenvironmental conditions, source biota, and accumulations of black shale are consistent with expressions of the Hangenberg Crisis globally, suggesting this event is likely captured within the uppermost strata of the Cleveland Shale in North America. PMID- 30248228 TI - Risk stratification of symptomatic patients suspected of colorectal cancer using faecal and urinary markers. AB - AIM: Faecal markers, such as the faecal immunochemical test for haemoglobin (FIT) and faecal calprotectin (FCP), have been increasingly used to exclude colorectal cancer (CRC) and colonic inflammation. However, in those with lower gastrointestinal symptoms there are considerable numbers who have cancer but have a negative FIT test (i.e. false negative), which has impeded its use in clinical practice. We undertook a study of diagnostic accuracy CRC using FIT, FCP and urinary volatile organic compounds (VOCs) in patients with lower gastrointestinal symptoms. METHOD: One thousand and sixteen symptomatic patients with suspected CRC referred by family physicians were recruited prospectively in accordance with national referring protocol. A total of 562 patients who completed colonic investigations, in addition to providing stool for FIT and FCP as well as urine samples for urinary VOC measurements, were included in the final outcome measures. RESULTS: The sensitivity and specificity for CRC using FIT was 0.80 [95% confidence interval (CI) 0.66-0.93] and 0.93 (CI 0.91-0.95), respectively. For urinary VOCs, the sensitivity and specificity for CRC was 0.63 (CI 0.46-0.79) and 0.63 (CI 0.59-0.67), respectively. However, for those who were FIT-negative CRC (i.e. false negatives), the addition of urinary VOCs resulted in a sensitivity of 0.97 (CI 0.90-1.0) and specificity of 0.72 (CI 0.68-0.76). CONCLUSIONS: When applied to the FIT-negative group, urinary VOCs improve CRC detection (sensitivity rises from 0.80 to 0.97), thus showing promise as a second stage test to complement FIT in the detection of CRC. PMID- 30248229 TI - AIDS-associated disseminated talaromycosis (penicilliosis) marneffei. PMID- 30248230 TI - Tension-free vaginal tape-obturator for the treatment of stress urinary incontinence: a 12-year prospective follow-up. AB - OBJECTIVE: To evaluate the long-term safety and effectiveness of inside-out transobturator tape (tension-free vaginal tape-obturator, TVT-O) for the treatment of stress urinary incontinence (SUI). PATIENTS AND METHODS: Between August 2004 and August 2006, 87 consecutive patients with SUI who underwent TVT-O were enrolled in this prospective cohort study. Patients with mixed UI, or pelvic organ prolapse requiring surgery, were excluded. Data relating to long-term postoperative complications, subjective satisfaction rate (Patient Global Impression of Improvement), objective cure rate (stress test), quality of life (QoL), and sexual function, were collected during follow-up. The Incontinence Impact Questionnaire (IIQ-7) and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) were used to assess QoL and sexual function, respectively. Statistical analyses were performed using paired-sample t-tests. RESULTS: At the 12-year follow-up, 73 patients (84%) were available for evaluation. Overall, the long-term complication rate was 45.2%. De novo overactive bladder was observed in 12.3% of patients. None of the patients reported severe voiding dysfunction that required treatment by tape removal or catheterisation. However, 16 patients (16/73, 21.9%) had voiding changes compared with their preoperative status. Persistent groin pain was reported in 1.4% of the patients, and tape exposure occurred in 5.5%. The subjective satisfaction rate and objective cure rate were 80.8% and 82.2%, respectively. Compared with preoperative scores, the IIQ-7 score decreased significantly (P < 0.05), whilst there was no significant difference in the PISQ-12 score (P = 0.893). CONCLUSIONS: This 12-year follow-up study showed that TVT-O is a highly effective procedure for the treatment of SUI. The long-term complication rate appears to be slightly high, which should raise concern. PMID- 30248231 TI - Transradial prostheses: Trends in development of hardware and control systems. AB - BACKGROUND: Prosthesis is a wearable device that intends to provide the functionality and/or appearance of a missing body part. In the case of trans radial prostheses, the wearer or the trans-radial amputee is fitted with an artificial wrist and a hand that is either mechanically or electro-mechanically operated. Main aim is to enable the wearer to perform activities of daily living with minimal external assistance. METHODS: In this review paper, hardware systems of state-of-the-art trans-radial prostheses have been briefly discussed. Focus is to provide an insight on the latest technologies employed in development of its mechanical systems: terminal devices, artificial wrist joints, and body attachments. In that context, latest hardware designs on terminal devices for grasping motion are presented as it is the primary function of trans-radial prostheses. Hardware designs of prosthetic wrists and body attachments are also reviewed. Finally, latest trends and future directions on design of trans-radial prostheses are explored and presented. CONCLUSIONS: Size, shape, weight, durability, appearance, and functionality are the key factors that need to be considered when developing a trans-radial prosthesis. Moreover, the current developments are moving closer to a human upper limb. However, the availability of these devices is minimum due to high-tech involved and the high cost, which necessitates further development trans-radial prostheses. PMID- 30248232 TI - The efficacy of ablation-based combination therapy for vitiligo: A systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVES: This study aimed to compare the efficacy of vitiligo treatments with and without ablation therapy. PATIENTS AND METHODS: We conducted a systematic review and meta-analysis of literature published before September 15, 2017. Comparative studies of vitiligo patients treated with and without ablation therapy were included. The primary outcome was >= 50 % repigmentation. Secondary outcomes were >= 75 % repigmentation and patient scores on a subjective visual analogue scale. RESULTS: Fifteen studies with a total of 401 participants were included. The ablation-based combination therapy group had significantly superior results to the control group (odds ratio [OR] for >= 50 % repigmentation: 10.490, 95 % confidence interval [CI]: 4.632-23.757; OR for >= 75 % repigmentation: 5.812, 95 % CI: 2.194-15.393). Patients receiving ablation based combination therapy were significantly more satisfied with the efficacy than the control group (standardized mean difference: 1.073, 95 % CI: 0.528 1.619). Subgroup analysis showed that the erbium laser group, CO2 laser group and fractional CO2 laser group achieved significantly better repigmentation than the control groups. CONCLUSIONS: According to objective and subjective evaluations, treatments for vitiligo are more effective when combined with ablation therapy than when used alone. PMID- 30248233 TI - Reducing NAFLD-screening time: A comparative study of eight diagnostic methods offering an alternative to ultrasound scans. AB - BACKGROUND & AIMS: The use of ultrasound scan (US) in non-alcoholic fatty liver disease (NAFLD) screening overloads US waiting lists. We hypothesized and tested a hybrid two-step method, consisting of applying a formula, to exclude subjects at low risk, before US. METHODS: The sample included 2970 males and females (937 with NAFLD) diagnosed by US. We selected eight formulas: Fatty Liver Index (FLI), Hepatic Steatosis Index (HIS), body mass index (BMI), waist circumference (WC), Abdominal Volume Index (AVI), waist-to-height ratio (WHtR), waist/height0.5 (WHT.5R) and Body Roundness Index (BRI), and calculated their performance in the two-step method evaluating percentage reduction of the number of liver US (US reduction percentage), percentage of false negative and percentage of NAFLD identified. RESULTS: The US reductions percentage were 52.2% (WHtR), 52.1% (HIS), 51.8% (FLI), 50.8% (BRI), 50.7% (BMI and WHt_5R), 46.5% (WC) and 45.2% (AVI). The false negative percentage were 8.5% (WHtR), 7.9% (BRI), 7.3% (WHt_5R), 7.2% (BMI), 6.7% (HIS), 6.6% (FLI), 5.6% (WC) and 5.2% (AVI). The best percentage of NALFD identified was obtained using AVI (83.6%) before US, then WC (82.2%), FLI (79%), HIS (78.9%), BMI (77.3%), WHt_5R (76.9%), BRI (74.8%) and WHtR (73%). CONCLUSION: The best formula to use in two-step diagnostic NAFLD screening was AVI, which showed a low false negative rate and a higher percentage of identified NAFLD. Other studies evaluating the economic advantages of this screening method are warranted. PMID- 30248234 TI - Hepatic fat as clinical outcome and therapeutic target for nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the leading cause of advanced liver disease in Western countries. NAFLD is defined in the presence of increased hepatic fat content, which is mainly stored under the form of neutral lipids within intracellular droplets and is not explained by at risk alcohol intake. In order to understand the pathogenesis, monitor the progression and find novel treatments for this condition, previous research efforts mainly addressed the role of inflammation. However, very recent data seem to suggest that hepatic lipid accumulation may be involved in NAFLD pathogenesis by driving secondary inflammation and fibrosis progression. Here, we will briefly review the novel results derived from natural history, genetics, imaging studies and therapeutic trials that support the notion that hepatic fat accumulation may represent a major clinical outcome and therapeutic target for NAFLD. Indeed, prospective and genetic data are consistent with hepatic fat being a driver of NAFLD progression. Furthermore, new technologies will render possible to monitor hepatic fat content without the need of invasive assessment, thereby allowing to identify patients at higher risk, and to monitor the response to drugs that act by decreasing hepatic lipid accumulation. PMID- 30248235 TI - Surgical checklist impact on recurrence-free survival of patients with non-muscle invasive bladder cancer undergoing transurethral resection of bladder tumour. AB - OBJECTIVES: To evaluate the impact of an eight-item surgical checklist (SC) on the recurrence-free survival (RFS) of patients with non-muscle-invasive bladder cancer (NMIBC) undergoing transurethral resection of bladder tumour (TURBT). PATIENTS AND METHODS: A group of urologists at two tertiary referral centres, with expertise in bladder cancer, identified eight critical items that should be performed in every high-quality TURBT. An eight-item SC was prospectively implemented into clinical practice and the operative reports of TURBTs performed before and after implementation were reviewed. Results from both institutions were combined to estimate the impact of introducing the SC on oncological outcomes. Multivariable logistic and Cox hazards regression analyses were performed to evaluate the impact of the SC on the presence of detrusor muscle in the TURBT specimen and on RFS, respectively. RESULTS: The operative reports of 266 TURBTs performed after the SC implementation were reviewed and compared to those of 281 TURBTs performed prior to the SC introduction. The SC was independently associated with a significant improvement in RFS (P = 0.02). However, the introduction of the SC was not significantly associated with the presence of detrusor muscle in the surgical specimen (P = 0.4). CONCLUSION: The use of an eight-item SC during TURBT in clinical practice increases the quality of operative reports thereby potentially improving individualised risk stratification and care resulting in lower disease recurrence rates. Therefore, the introduction of a SC can be recommended to enhance oncological outcomes by improving surgical standardisation and operative reporting. PMID- 30248236 TI - Histological intralesional heterogeneity of actinic keratoses relates to field cancerization. AB - BACKGROUND/OBJECTIVES: Histological heterogeneity within distinct actinic keratosis (AK) lesions has been described and might serve as an additional feature of AKs. We aimed to investigate and quantify the histological heterogeneity of AKs regarding different grading systems. METHODS AND MATERIAL: We assessed the histology of 3 mm biopsies of AK lesions located on the scalp or face. We documented basal proliferation (PRO I-III), histological grade (AK I III) and determined the overall classification of each lesion. RESULTS: Of the 305 lesions included, 48 (15.7 %) lesions were classified as AK I, 152 (49.8 %) as AK II and 105 (34.4 %) as AK III. 33 AKs (10.8 %) showed no basal proliferation, 94 (30.8 %) were graded as PRO I, 99 (32.5 %) as PRO II and 79 (25.9 %) as PRO III. One histological grade and basal growth pattern per lesion was observed in 94 (30.8 %) and 104 (34.1 %) cases respectively, two grades in 170 (55.7 %) and 168 (55.1 %) cases, and three grades in 41 (13.4 %) and 33 (10.8 %) cases (Chi-squared test, p < 0.0001). CONCLUSIONS: By analogy with the clinical heterogeneity of field cancerization, AKs show a high histological grade heterogeneity even within small lesions. Variations in AK grading reflect the heterogeneity of the cancerization field and might serve as additional feature. PMID- 30248237 TI - Late biochemical recurrence after radical prostatectomy is associated with a slower rate of progression. AB - OBJECTIVE: To characterise the pattern of late biochemical recurrence (BCR) in the largest contemporary cohort of patients with localised prostate cancer treated with radical prostatectomy (RP) in the active surveillance era. PATIENTS AND METHODS: Consecutive patients who underwent RP for localised prostate cancer between 2003 and 2017 were identified from a prospectively recorded, dedicated prostate cancer database. Patients who received neoadjuvant androgen-deprivation therapy were excluded. These patients were categorised into the following groups: no BCR, BCR at <12 months (early), BCR at 12-60 months (intermediate), and BCR at >60 months (late), after RP. Clinicopathological characteristics were analysed using the Student's t-test, Mann-Whitney U-test, or chi-squared test where appropriate. Multivariable binomial logistic regression models were used to assess predictors of BCR at various time-points. RESULTS: In all, 2312 patients were included in the final analysis with up to 12 years of follow-up data. The average patient had clinically localised prostate cancer, an elevated PSA level, and International Society of Urological Pathology (ISUP) Grade Group 2 on biopsy. In all, 88.7% of patients had ISUP Grade Group >=2 at RP. A subgroup of 446 patients had undetectable PSA levels at 5 years after RP; 11.7% of them progressed to experience BCR. In this subgroup, late recurrers had significantly higher-grade tumours on ISUP and Gleason sum (P <0.001 and P = 0.001, respectively), higher rates of extraprostatic extension (P = 0.022), and larger tumour volumes (P = 0.032). Logistic regression showed that RP ISUP Grade Group was a significant predictor of BCR (odds ratio 2.14, 95% confidence interval 1.43 3.20; P <0.001). CONCLUSION: This study characterises the pattern of late BCR in the largest contemporary active surveillance era cohort. We have identified that RP ISUP Grade Group is a strong predictive indicator for late BCR. We also propose that timing of BCR resides on a continuum of risk and that the potential concept of dormant micrometastatic involvement requires further research and evaluation. PMID- 30248238 TI - Validation and usability of a mobile phone application for epidemiological surveillance of traumatic dental injuries. AB - BACKGROUND/AIM: Traumatic dental injuries (TDI) are a public health problem, given their prevalence and consequences. However, their epidemiology is uncertain due to a general lack of quality data capture. The aim of this study was to evaluate the validity and usability of a mobile phone-based application for community-based surveillance of traumatic dental injuries. MATERIALS AND METHODS: A mobile phone-based application, Dental Trauma Tracker (DTT), was developed. This system involves a mobile application for general users to report TDIs and a Web application for researchers to generate epidemiological data. The DTT evaluation used mixed methods and was conducted in three phases: (a) validation of a trauma identification system using preselected TDI images; (b) design evaluation by experts; and (c) usability evaluation measured by the reporting of three fictitious TDI cases and using the System Usability Scale (SUS). RESULTS: In the first phase, 182 participants participated. Most images showed over 95% accuracy, indicating that they adequately represented the type of dentoalveolar trauma being evaluated (kappa = 0.75). The design evaluation identified nine usability problems-four of them with a "High priority" to be fixed, four with "Low priority," and one "No fix necessary." A total of 29 volunteers participated in the usability evaluation. The mean time for users to complete all of the reports was 7.8 +/- 3.0 minutes. Mean SUS score was 67.4 +/- 21.9 (Range: 0-100; worst to best). The global agreement between cases registered with the gold standard was also "Substantial" (kappa = 0.71). CONCLUSIONS: This preliminary evaluation confirmed the App's usability, using a sample of potential users, as well as reporting on the results of an expert panel review of the DTT. These are the minimum requirements necessary before further expansion and widespread implementation occurs to confirm these results. PMID- 30248239 TI - The emergence of the infection of subgroup J avian leucosis virus escalated the tumour incidence in commercial Yellow chickens in Southern China in recent years. AB - A total of 81 clinical cases of suspected tumours were submitted to our laboratory from Yellow chicken farms in southern China during the years 2010 through 2017. The tumour-like tissue samples were closely examined for common oncogenic avian viruses in cell culture and further analysed using polymerase chain reaction (PCR). During 2010-2012, Marek's disease virus (MDV) mono infection was found to be the dominant cause of the tumour incidences (52.4%, 11/21) followed by co-infection of MDV+ALVs (19.1%, 4/21). Starting from the year 2013 the mono-infection of avian leucosis virus subgroup J (ALV-J) became the dominant agent of the tumour cases (83.3%, 5/6). During the most recent four years (2014-2017), co-infections involving ALV-J and MDV or between ALV subgroups have increased (23.4% and 18.5%, respectively), but each of the co-infections was still slightly lower than the ALV-J mono-infection incidence (33.3%). In contrast to the dominant MDV mono-infection cases before 2013, more recently, the emerging ALV-J mono-infection and ALV-J co-infections were largely responsible for the occurrence of avian virus-induced tumour incidences in the commercial local Yellow breeds of chickens in southern China. These results indicate that eradication measures against ALV on all chicken farms, especially on farms with the Yellow chickens, ought to be enhanced to reverse this trend. PMID- 30248240 TI - Measuring Pain Avoidance-Like Behavior in Drug-Dependent Rats. AB - In contrast to their analgesic properties, excessive use of either opioids or alcohol produces a paradoxical emergence of heightened pain sensitivity to noxious stimuli, termed hyperalgesia, which may promote increased use of opioids or alcohol drinking to manage worsening pain symptoms. Hyperalgesia has traditionally been measured in rodents via reflex-based assays, including the von Frey method. To better model the motivational and affective dimensions of pain in a state of opioid/alcohol dependence and withdrawal, this unit describes the use of a non-reflex-based method for measuring pain avoidance-like behavior in dependent rats. In the mechanical conflict-avoidance task, rats run across probes of varying heights to avoid a bright aversive light and to reach a dark goal chamber. A longer latency to exit onto the nociceptive probes reflects increased pain avoidance-like behavior during withdrawal. Mechanical conflict-avoidance testing can be repeated to provide both baseline assessment of pain avoidance behavior and pain avoidance measures after the induction of dependence.(c) 2018 by John Wiley & Sons, Inc. PMID- 30248241 TI - Emotional competence: A core competence in gerontological nursing in Iran. AB - AIM AND OBJECTIVES: Defining the components of emotional competence in caring for older people in Iranian hospitals. BACKGROUND: People of older age are the largest recipients of healthcare services in hospitals. Thus, it is essential to establish what characteristics of emotional competence are required for nursing older people. DESIGN: This qualitative descriptive-exploratory study was conducted in Iran from September 2015 to April 2016. METHODS: Semi-structured interviews were conducted with 25 participants (nine nurses, 12 nurse managers, four clinical instructors), chosen by purposive and snowball sampling based on saturation. Data were analysed by content analysis method. RESULTS: Qualitative content analysis identified two core categories and seven subcategories from the data: (a) Individual emotional competence with five subcategories of positive attitude, spiritual maturity, emotional self-control, adherence to professional ethics and creativity and innovation, and (b) social emotional competence with two subcategories of relationship management and compassionate care. CONCLUSION: Emotional competence was identified as one of the main components of nursing skills when caring for older people. Gerontological nurses should demonstrate emotional competence in caring for older people and include a positive attitude, spiritual maturity, emotional self-control, adherence to professional ethics, creativity in care, successful relationship management and compassionate care in their practice. IMPLICATIONS FOR PRACTICE: These findings can be used to guide development of emotional competencies for nursing older people. PMID- 30248242 TI - Female type of adult acne: Physiological and psychological considerations and management. AB - Today we see more cases of acne after adolescence, with a greater prevalence in females than males. Adult female acne has a distinct clinical presentation and is associated with a number of specific pathophysiological features and gender specific triggers. The psychological impact of acne is generally significant and largely underestimated; stress during professional and private life, anxiety and sleep quality, in particular, have a reciprocal relationship with disease susceptibility and severity. It is essential to compare with males. Acne in females often causes greater distress in adults than in adolescents. The impact of disease may therefore be greater for female patients, triggering higher levels of psychosocial anguish and increasing the likelihood of sequelae such as skin picking and the risks of cutaneous superinfection, scarring and PIH and acne recurrence. The management of adult female acne should encompass not just medical treatment of the symptoms, but also a comprehensive, holistic approach to the patient as a whole, her individual lifestyle factors and the impact of acne on her quality of life. Future management of this disease should aim to improve patient adherence to therapy and to develop validated outcomes of treatment regarding overall skin appearance and quality of life. PMID- 30248243 TI - Paired APTTs of low and high lupus anticoagulant sensitivity permit distinction from other abnormalities and achieve good lupus anticoagulant detection rates in conjunction with dRVVT. AB - INTRODUCTION: A prolonged activated partial thromboplastin time (APTT) may be indicative of a specific or multiple factor deficiency, therapeutic anticoagulation, presence of a nonspecific factor inhibitor, or lupus anticoagulant (LA). Recently, pairing of the LA-sensitive APTT and standard APTT reagents, Cephen LS and Cephen, respectively, has been shown to be effective in LA detection. The present study aimed to evaluate the usefulness of this reagent pair for discriminating between causes of APTT elevation and the detection of LA in conjunction with dilute Russell's viper venom time (dRVVT). METHODS: Plasma samples from 50 normal and 105 non-anticoagulated LA-positive patients in routine dRVVT and/or dilute APTT (dAPTT) via the percent correction formula were employed. Cephen LS/Cephen and dRVVT reagents LA1/LA2 were used to screen/confirm, respectively. Thirty-four symptomatic LA-negative, 25 warfarinised non-antiphospholipid syndrome, 6 coagulation inhibitors, 17 samples with hereditary elevated APTT, and 24 FVIII/IX/XI/XII and 17 FII/V/X artificial single deficiency plasmas were used. RESULTS: Thirty-three samples out of 105 (31%) were LA-positive in Cephen LS/Cephen. The total percent positivity in Cephen LS/Cephen and LA1/LA2 pairs was 89.1% against samples with the routine dRVVT/dAPTT double positive. The percent corrections of Cephen LS/Cephen in the routine dAPTT/dRVVT positive group were significantly higher than those in all other groups. CONCLUSIONS: The percent correction of the APTT reagent pair showed higher values in LA-positive samples. The combination will be useful with respect to differentiating LA from other abnormal samples and is effective in LA detection when paired with dRVVT. PMID- 30248244 TI - Extracorporeal treatments in poisonings from four non-traditionally dialysed toxins (acetaminophen, digoxin, opioids and tricyclic antidepressants): A combined single-centre and national study. AB - The use of extracorporeal treatments (ECTRs) for poisonings with four non traditionally dialysed toxins (NTDTs) is increasing in the United States. This study evaluated whether ECTRs are prescribed for toxin removal or the treatment of other medical illnesses or complications. We performed a 2-Phase retrospective analysis evaluating the main indication for ECTRs in patients with poisoning from a NTDT (defined for this study as acetaminophen, opioids, tricyclic antidepressants (TCAs) or digoxin) and ECTR. The first phase assessed all cases from a single site (New York City Poison Control Center) between the years 2000 and 2016, and the second phase surveyed all United States Poison Control Centers (PCCs). In Phase 1, demographics, toxin ingested and main indication for ECTR were extracted. In Phase 2, a query to the National Poison Data System using the a pragmatic subset of inclusion criteria from Phase 1 restricted to single toxin ingestions over a narrower time frame (2014-2016) provided the cases for study. A structured online questionnaire was sent to all United States PCCs to request their database review regarding the indication for ECTR for their cases. In Phase 1, 92 cases met inclusion criteria. In Phase 2, 519 cases were screened and 425 met inclusion criteria. In Phase 1 91/92 (98.9%) and Phase 2 411/425 (96.7%), of extracorporeal treatments were used to treat underlying medical conditions or poisoning-related complications rather than accelerate toxin removal. The increasing number of ECTRs reported in patients who ingested one of the four NTDTs thus appears to be for medical indications rather than attempts at toxin removal, a distinction that is important. PMID- 30248245 TI - Survival of the fewest: Microbial dormancy and maintenance in marine sediments through deep time. AB - Microorganisms buried in marine sediments are known to endure starvation over geologic timescales. However, the mechanisms of how these microorganisms cope with prolonged energy limitation is unknown and therefore yet to be captured in a quantitative framework. Here, we present a novel mathematical model that considers (a) the physiological transitions between the active and dormant states of microorganisms, (b) the varying requirement for maintenance power between these phases, and (c) flexibility in the provenance (i.e., source) of energy from exogenous and endogenous catabolism. The model is applied to sediments underlying the oligotrophic South Pacific Gyre where microorganisms endure ultra-low fluxes of energy for tens of millions of years. Good fits between model simulations and measurements of cellular carbon and organic carbon concentrations are obtained and are interpreted as follows: (a) the unfavourable microbial habitat in South Pacific Gyre sediments triggers rapid mortality and a transition to dormancy; (b) there is minimal biomass growth, and organic carbon consumption is dominated by catabolism to support maintenance activities rather than new biomass synthesis; (c) the amount of organic carbon that microorganisms consume for maintenance activities is equivalent to approximately 2% of their carbon biomass per year; and (d) microorganisms must rely solely on exogenous rather than endogenous catabolism to persist in South Pacific Gyre sediments over long timescales. This leads us to the conclusion that under oligotrophic conditions, the fitness of an organism is determined by its ability to simply stay alive, rather than to grow. This modelling framework is designed to be flexible for application to other sites and habitats, and thus serves as a new quantitative tool for determining the habitability of and an ultimate limit for life in any environment. PMID- 30248246 TI - Long-term retention in an employer-based, commercial weight-loss programme. AB - The aim of this study is to examine factors associated with long-term retention in a commercial weight-loss programme. We conducted a retrospective analysis of an employer-based, commercial programme from 2013 to 2016. Our dependent variable was 'long-term retention', defined as continuously enrolled participants who actively engaged through coach calls at 6 and 12 months. Independent variables included baseline demographics, programme engagement and weight change. We conducted multivariate logistic regression analyses assessing for differences in long-term retention by several factors, adjusted for employer clustering. Overall, 68.3% were retained at 6% and 45.9% at 12 months. Greater number of coach calls and website logins during the first 3 months significantly increased the odds of long-term retention, while having chronic conditions significantly decreased the odds. Weight-loss success (>=5% loss at 6 months) was significantly associated with increased odds of retention (12-month: odds ratio [OR] 2.80, P < 0.001), while early weight-loss failure (>=0% weight change at 1 month) significantly decreased odds of retention (12-month: OR 0.66, P = 0.008). In an employer-based, commercial weight loss programme, greater early programme engagement was associated with long-term retention. Given these programmes' popularity and potential reach, our results could be used to develop and test strategies designed to improve retention in commercial weight-loss programmes. PMID- 30248247 TI - Gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide signaling in adipose tissue. AB - GIPR signaling in adipose tissue plays an important role in HFD-induced insulin resistance and hepatic steatosis in vivo, with no direct effect on fat accumulation, through IL-6 signaling. PMID- 30248249 TI - Fetal and Infancy Growth Pattern, Cord and Early Childhood Plasma Leptin, and Development of Autism Spectrum Disorder in the Boston Birth Cohort. AB - Leptin is a proinflammatory cytokine that plays an important role in energy homeostasis. Emerging evidence suggests that leptin levels are altered in children with autism spectrum disorder (ASD); however, this has not been studied prospectively. Rapid growth during infancy and early childhood has been implicated in ASD, but the evidence is inconsistent. As leptin is involved in growth and is a potential risk factor for ASD, we explored the associations between (a) cord, early childhood leptin and ASD; and (b) birth weight for gestational age, early childhood weight gain, and ASD. We also assessed the mediating role of leptin in the relationship between weight gain during infancy and ASD. This study was conducted in a sample of 822 subjects from the Boston Birth Cohort. ASD was defined from diagnostic codes in electronic medical records. Extremely rapid weight gain during infancy was associated with a greater ASD risk and this persisted after adjusting for potential confounders (aOR: 3.11; 95% CI: 1.37, 7.07). Similarly, children that had higher plasma leptin levels, prior to ASD diagnosis, had an increased ASD risk in both unadjusted and adjusted models (aOR: 7.87; 95% CI: 2.06, 30.04). Further, early childhood leptin indirectly mediated the relationship between rapid weight gain and ASD. No associations were found between birth weight for gestational age, cord leptin and risk of ASD. Our findings provide a basis to further explore whether the combination of early life growth pattern and a biomarker such as leptin can predict ASD earlier. Autism Res 2018, 11: 1416-1431. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Is early life growth and a biomarker leptin related to ASD risk? To answer this question, we followed 822 children from birth and found that those who gained weight very quickly in infancy, had higher leptin levels in early childhood, had a greater chance of later ASD diagnosis. More research is needed to see if infant's weight gain pattern along with a biomarker (such as leptin) can be used to identify children with ASD sooner. PMID- 30248250 TI - Prediction of recombinant protein production by Escherichia coli derived online from indicators of metabolic burden. AB - BACKGROUND: The oxygen transfer rate (OTR) and the biomass concentration are two important parameters describing a microbial fermentation. It has been shown before that from the course of these parameters over time information on metabolic burden during heterologous protein production can be obtained. While online monitoring in large fermenters is ubiquitously established, it is still not a common practice in small-scale cultures. Nevertheless, several techniques like the Respiration Activity MOnitoring System (RAMOS) device for online monitoring of the OTR in shake flasks and the BioLector device for measuring scattered light (ScL) representing biomass in microtiter plates have been developed. RESULTS: A new microtiter plate-based method is presented that reveals how online derived ScL signals can be transformed into signals that are proportional to the courses of OTR over time for Escherichia coli. The transformed signal is obtained by simply taking the first derivative of ScL (dScL/dt). The proportionality of both parameters is successfully validated for the strains E. coli BL21(DE3) and Tuner(DE3) expressing cellulases and the fluorescent protein FbFP, respectively. Relative amounts of produced heterologous proteins are predicted exclusively based on the course of the transformed ScL signal. A variety of induction conditions with varying inducer concentration and induction time were investigated with this method. CONCLUSION: The presented method based on ScL measurement allows for high-throughput online determination of signals proportional to OTR courses. They enable the interpretation of physiological states and offer the possibility to predict the recombinant protein production in E. coli. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30248251 TI - Subcutaneous adipose tissue therapy reduces fat by dual X-ray absorptiometry scan and improves tissue structure by ultrasound in women with lipoedema and Dercum disease. AB - Lipoedema is painful nodular subcutaneous adipose tissue (SAT) on legs and arms of women sparing the trunk. People with Dercum disease (DD) have painful SAT masses. Lipoedema and DD fat resists loss by diet and exercise. Treatments other than surgery are needed. Six women with lipoedema and one with DD underwent twelve 90-min sessions over 4 weeks. Body composition by dual X-ray absorptiometry scan, leg volume, weight, pain, bioimpedance, tissue size by caliper and ultrasound were analysed before and after SAT therapy by paired t tests. There was a significant decrease from baseline to end of treatment in weight, 87.6 +/- 21 to 86.1 +/- 20.5 kg (P = 0.03), leg fat mass 17.8 +/- 7.7 to 17.4 +/- 7.6 kg (P = 0.008), total leg volume 12.9 +/- 4 to 12 +/- 3.5 L (P = 0.007), six of 20 calliper sites and tissue oedema. Pain scores did not change significantly. By ultrasound, six women had 22 hyperechoic masses in leg fat that resolved after treatment; five women developed seven new masses. Fascia improved by ultrasound after treatment. SAT therapy reduced amount and structure of fat in women with lipoedema and Dercum disease; studies are needed to compare SAT therapy to other therapies. PMID- 30248252 TI - We Honor the Nurses. PMID- 30248254 TI - Clara Barton and the Missing Soldiers Office. PMID- 30248253 TI - When Place Matters: The 1918 Flu Pandemic in Small Towns and Villages in the United States. PMID- 30248255 TI - Tunable Multimodal Drop Bouncing Dynamics and Anti-Icing Performance of a Magnetically Responsive Hair Array. AB - Anti-icing materials that can efficiently limit ice formation have a strong potential to replace existing anti-icing techniques, such as Joule heating, chemical release, or mechanical removal, which are usually inefficient, expensive, and environmentally harmful. In this study, an anti-icing material based on a magnetically responsive hierarchical hair array that can actively modulate drop bouncing dynamics is presented. The magnetically responsive hair array exhibits an immediate and reversible structural bending motion in response to an external magnetic field. The array also exhibits superhydrophobicity, regardless of its tilt angle, due to the tapered geometry of the hairs and the multiscale surface roughness of the array. Due to its dynamic structure and water repellent characteristics, the array can induce distinct multiple modes of drop bouncing behavior by adjusting its structural bending state in a reversible fashion. Three different types of bouncing behavior, namely, quasi-pancake bouncing, directional bouncing, and macrotexture-induced droplet fragmentation, can be obtained with the vertical, tilted, and fully bent hair arrays, respectively. We demonstrate that the dynamically controllable drop bouncing behavior of the magnetically responsive hierarchical array enables the efficient and robust prevention of ice formation and accumulation. PMID- 30248256 TI - Three-Component Synthesis of a Library of m-Terphenyl Derivatives with Embedded beta-Aminoester Moieties. AB - The three-component reaction between alkyl- or arylamines, beta-ketoesters and chalcones in refluxing ethanol containing a catalytic amount of Ce(IV) ammonium nitrate allowed the construction of a large library of highly substituted dihydro m-terphenyl derivatives containing beta-alkylamino- or beta-arylamino ester moieties. This process generates three new bonds and one ring and proceeds in high atom economy, having two molecules of water as the only side product. Another domino process, in which the original MCR was telescoped with a subsequent aza Michael/retro-aza Michael sequence, allowed the one-pot preparation of a library of compounds with a N-unsubstituted beta-aminoester fragment. Finally, to extend the structural diversity of these libraries, we also examined the aromatization of the central ring of our compounds in the presence of dichlorodicyanoquinone. This reaction sequence did not affect the integrity of a stereogenic center belonging to the amino component. PMID- 30248257 TI - Conductive Shape Memory Microfiber Membranes with Core-Shell Structures and Electroactive Performance. AB - Conductive shape memory polymers as a class of functional materials play a significant role in sensors and actuators. A high conductivity and a high response speed are needed in practical applications. In this work, a conductive shape memory polylactic acid (PLA) microfiber membrane was synthesized by combining electrospinning with chemical vapor polymerization. The shape memory PLA was electrospun into microfibers with different diameters, and a conductive polypyrrole (PPy) coating was applied to the PLA microfiber membranes using vapor polymerization. The conductivity of the microfiber membrane was investigated as a function of different experimental parameters: FeCl3 concentration, PPy evaporation time, and PPy temperature. The maximum conductivity of the membrane prepared in a sub-zero environment is 0.5 S/cm, which can sustain a heat generating electric current sufficient to trigger the electro-actuated behaviors of the membrane within 2 s at 30 V. Thermographic imaging was used to assess the uniformity of the temperature distribution during the shape recovery process. The low surface temperature is compatible with potential applications in many fields. PMID- 30248258 TI - Quantum Dots-Doped Tapered Hydrogel Waveguide for Ratiometric Sensing of Metal Ions. AB - Advances in fluorescent nanomaterials and photonics have led to a new generation of photonic devices for applications in biosensing, diagnostics, and therapy. However, for clinical utility, biocompatibility and limited light guiding in tissues pose significant challenges. Here, we report a new type of soft, biocompatible, and tapered optical waveguide with capability of delivering light in deep tissues and demonstrate it as a ratiometric probe for rapid point-of-care detection of metal ions. The waveguide was made from quantum dots (QDs) incorporated biocompatible hydrogels and coated with a thin sensing film to ensure fast exchanges with the surrounding analytes. The tapered design of the waveguide allows more light extraction for efficient excitation of the coating film. To achieve ratiometric measurements, two types of QDs with well-resolved emission bands are synthesized and immobilized in the waveguide and the coating film, respectively. We show that the ratiometric readout of the waveguide sensor is free of environmental disturbances and exhibits negligible drifts when applied in various environments such as being immersed in water or embedded in tissues. The waveguide device provides a new photonic-sensing platform that may allow being engineered to sense a wide range of metal ions and analytes. PMID- 30248259 TI - Fouling-Release Properties of Dendritic Polyglycerols against Marine Diatoms. AB - Dendritic polyglycerols (PGs) were grafted onto surfaces using a ring-opening polymerization reaction, and the fouling-release properties against marine organisms were determined. The coatings were characterized by spectroscopic ellipsometry, contact angle goniometry, ATR-FTIR, and stability tests in different aqueous media. A high resistance toward the attachment of different proteins was found. The PG coatings with three different thicknesses were tested in a laboratory assay against the diatom Navicula incerta and in a field assay using a rotating disk. Under static conditions, the PG coatings did not inhibit the initial attachment of diatoms, but up to 94% of attached diatoms could be removed from the coatings after exposure to a shear stress of 19 Pa. Fouling release was found to be enhanced if the coatings were sufficiently thick. The excellent fouling-release properties were supported in dynamic field-immersion experiments in which the samples were continually exposed to a shear stress of 0.18 Pa. PMID- 30248260 TI - One-Pot Enol Silane Formation-Alkylation of Ketones with Propargyl Carboxylates Promoted by Trimethylsilyl Trifluoromethanesulfonate. AB - Ketones readily undergo conversion to enol silanes in the presence of a trialkylamine base and trimethylsilyl trifluoromethanesulfonate (TMSOTf) and add to propargyl cations to yield beta-alkynyl ketones. The propargyl cations are generated in the same reaction flask through the TMSOTf-promoted ionization of propargyl acetates or propargyl propionates. A range of enol silane precursors and propargyl carboxylates reacts efficiently (20 examples, up to 99% yield). Cyclization of a representative product in the presence of TMSOTf provided 61% yield of the trisubstituted furan. PMID- 30248261 TI - Preliminary Evaluation of Local Structure and Speciation of Lanthanoids in Aqueous Solution, Iron Hydroxide, Manganese Dioxide, and Calcite Using the L3 Edge X-ray Absorption Near Edge Structure Spectra. AB - We elucidate the application of L3-edge X-ray absorption near edge structure (XANES) spectra to the local structural analysis of lanthanoids in aqueous solution, iron hydroxide, manganese dioxide, and calcium carbonate. The L3-edge XANES spectra of lanthanoid compounds showed sharp white lines. The full width at half-maximum (FWHM) values of lanthanoid aqua ions exhibited a convex tetrad curve in the series variation across the lanthanoid series. The variation is attributable to 4f electron orbitals and can be explained by the refined spin pairing energy theory. For each lanthanoid, the FWHM values of lanthanoid compounds roughly decreased with increasing local coordination numbers. However, they did not faithfully reflect the local coordination sphere of the lanthanoid complex having a high and distorted coordination sphere and were rather sensitive to their chemical forms. The relationship between the magnitude of the FWHM values was determined by the crystal field splitting or degeneracy of 5d orbitals. The systematic variation of FWHM can be explained by the ligand strength of the ligand molecules (-H2O0, -O-, -OH-, -CO32-, -Cl-, and -O2-) that cause the crystal field splitting. Therefore, the FWHM values of L3-edge XANES of lanthanoid compounds may be more useful in speciation analysis rather than structural analysis. PMID- 30248262 TI - Spatial and Temporal Correlations of XY Macro Spins. AB - We use nano disk arrays with square and honeycomb symmetry to investigate magnetic phases and spin correlations of XY dipolar systems at the micro scale. Utilizing magnetization sensitive X-ray photoemission electron microscopy, we probe magnetic ground states and the "order-by-disorder" phenomenon predicted 30 years ago. We observe the antiferromagnetic striped ground state in square lattices, and 6-fold symmetric structures, including trigonal vortex lattices and disordered floating vortices, in the honeycomb lattice. The spin frustration in the honeycomb lattice causes a phase transition from a long-range ordered locked phase over a floating phase with quasi long-range order and indications of a Berezinskii-Thouless-Kosterlitz-like character, to the thermally excited paramagnetic state. Absent spatial correlation and quasi periodic switching of isolated vortices in the quasi long-range ordered phase suggest a degeneracy of the vortex circulation. PMID- 30248263 TI - Targeted Delivery of Cyclotides via Conjugation to a Nanobody. AB - Many naturally occurring peptides have poor proteolytic stability, which limits their therapeutic applications. Cyclotides are plant-derived cyclic peptides that resist proteolysis due to their highly constrained structure, comprising a head to-tail cyclic backbone and three disulfide bonds that form a cystine-knotted core. This structure makes them useful as scaffolds onto which peptide sequences (epitopes) can be grafted. In this study, VHH7, an alpaca-derived nanobody that targets murine class II MHC molecules, was used for the targeted delivery of cyclotides to antigen-presenting cells (APCs). The cyclotides MCoTI-I, and MCoTI I with a HA-tag (YPYDVPDYA) grafted into loop 6 (MCoTI-HA), were tested for immunogenic properties. To produce the requisite VHH7-peptide conjugates, a site specific sortase A-catalyzed reaction in combination with a copper-free strain promoted cycloaddition reaction was used. MCoTI-I alone did not display any obvious antibody response, thus showing the capacity of cyclotides as immunologically silent scaffolds. By contrast, MCoTI-I conjugated to VHH7 elicited antibodies against cyclic or linear MCoTI-I, thus suggesting a simple and robust approach for targeting cyclotides to APCs, and potentially to other cell types. A similar antibody response was observed when MCoTI-HA was conjugated to VHH7, but there was no reactivity toward a linear HA-tag itself, suggesting differences in conformational constraint between cyclotide-presented and linear epitopes. Studies of commercially available HA antibodies applied to MCoTI-HA confirmed that the conformation of peptide immunogens affects their reactivity. Thus, the production of antibodies that recognize constrained epitopes may benefit from engraftment onto scaffolds such as cyclotides. More broadly, this study validates that a prototypic cyclotide, a member of a peptide family that has proven to be useful as drug design scaffolds in many other studies, can efficiently reach a specific target in vivo. PMID- 30248264 TI - Intracity Variability of Particulate Matter Exposure Is Driven by Carbonaceous Sources and Correlated with Land-Use Variables. AB - Localized primary emissions of carbonaceous aerosol are the major drivers of intracity variability of submicron particulate matter (PM1) concentrations. We investigated spatial variations in PM1 composition with mobile sampling in Pittsburgh, Pennsylvania, United States and performed source-apportionment analysis to attribute primary organic aerosol (OA) to traffic (HOA) and cooking OA (COA). In high-source-impact locations, the PM1 concentration is, on average, 2 MUg m-3 (40%) higher than urban background locations. Traffic emissions are the largest source contributing to population-weighted exposures to primary PM. Vehicle-miles traveled (VMT) can be used to reliably predict the concentration of HOA and localized black carbon (BC) in air pollutant spatial models. Restaurant count is a useful but imperfect predictor for COA concentration, likely due to highly variable emissions from individual restaurants. Near-road cooking emissions can be falsely attributed to traffic sources in the absence of PM source apportionment. In Pittsburgh, 28% and 9% of the total population are exposed to >1 MUg m-3 of traffic- and cooking-related primary emissions, with some populations impacted by both sources. The source mix in many U.S. cities is similar; thus, we expect similar PM spatial patterns and increased exposure in high-source areas in other cities. PMID- 30248265 TI - Impact of a Mechanical Bond on the Activation of a Mechanophore. AB - Mechanical bonds are known to efficiently absorb mechanical energy at low forces, but their behavior at high forces is unknown. Here we investigate the impact of a mechanical bond on the rate of activation of a Diels-Alder mechanophore. Using a combination of experimental and computational techniques, we found that the rate of a retro-Diels-Alder reaction under tension is decreased when the mechanophore is embedded in the axle of a rotaxane due to the presence of a competing high stress region at the junction between the macrocycle and the axle. PMID- 30248266 TI - Toward the Absolute Spin-Valve Effect in Superconducting Tunnel Junctions. AB - A superconductor with a spin-split excitation spectrum behaves as an ideal ferromagnetic spin-injector in a tunneling junction. It was theoretically predicted that the combination of two such spin-split superconductors with independently tunable magnetizations may be used as an ideal absolute spin-valve. Here, we report on the first switchable superconducting spin-valve based on two EuS/Al bilayers coupled through an aluminum oxide tunnel barrier. The spin-valve shows a relative resistance change between the parallel and antiparallel configuration of the EuS layers up to 900% that demonstrates a highly spin polarized current through the junction. Our device may be pivotal for realization of thermoelectric radiation detectors, a logical element for a memory cell in cryogenics, superconductor-based computers, and superconducting spintronics in general. PMID- 30248267 TI - Imatinib-Loaded Micelles of Hyaluronic Acid Derivatives for Potential Treatment of Neovascular Ocular Diseases. AB - In this work, new micellar systems able to cross corneal barrier and to improve the permeation of imatinib free base were prepared and characterized. HA-EDA-C16, HA-EDA-C16-PEG, and HA-EDA-C16-CRN micelles were synthesized starting from hyaluronic acid (HA), ethylenediamine (EDA), hexadecyl chains (C16), polyethylene glycol (PEG), or l-carnitine (CRN). These nanocarriers showed optimal particle size and mucoadhesive properties. Imatinib-loaded micelles were able to interact with corneal barrier and to promote imatinib transcorneal permeation and penetration. In addition, a study was conducted to understand the in vitro imatinib inhibitory effect on a choroidal neovascularization process. Imatinib released from polymeric micelles was able to inhibit endothelial cell sprouting and to promote cell tube disruption. PMID- 30248268 TI - Bioinspired Surface Functionalization of Nanodiamonds for Enhanced Lubrication. AB - The addition of nanoparticles to water-based lubricants is a commonly used method to improve lubrication, but to the best of our knowledge few studies have been reported to investigate the lubrication property of surface-modified nanodiamonds (ND) with polyzwitterionic brushes. In this study, a bioinspired copolymer containing dopamine and 2-methacryloyloxyethyl phosphorylcholine (MPC) was synthesized (DMA-MPC) and then spontaneously grafted onto the ND surface (ND-MPC) through simple stirring in order to enhance lubrication. The characterization of transmission electron microscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis indicated that the DMA-MPC was successfully modified on the ND surface. Furthermore, a series of tribological experiment were performed on a universal materials tester using glycerol, glycerol + ND, and glycerol + ND-MPC as the lubricants. It was found that the addition of ND to the lubricant (i.e., glycerol + ND and glycerol + ND-MPC) significantly reduced wear with a smaller wear scar and wear track on the tribopairs, and the coefficient of friction further decreased by about 40% when using glycerol + ND-MPC as the lubricant, which could be attributed to the hydration lubrication of the polyzwitterionic brushes modified on the ND surface and the rolling effect of nanoparticles. In conclusion, in this study a universal and versatile surface modification method was proposed on the basis of the synthesis of bioinspired copolymer DMA-MPC, which remarkably enhanced the lubrication property of ND nanoparticles when added to water-based lubricants. PMID- 30248269 TI - Effects of order of resistance training exercises on muscle hypertrophy in young adult men. AB - The purpose of the present study was to analyze the effects of the order of resistance training (RT) exercises on hypertrophy in young adult men. Thirty-six young adult men (21.9 +/- 2.5 years, 72.6 +/- 12.1 kg, 176.9 +/- 7.4 cm, 23.1 +/- 3.3 kg/m2) were randomly assigned to one of two training groups that performed a 6-week RT program in either a traditional approach starting with multi-joint exercises (MJ) following to single-joint exercises (SJ) order (MJ-SJ, n = 19) or an inverse order (SJ-MJ, n = 17). Muscle thickness of the biceps brachii and mid thigh were assessed by ultrasound. Lean soft tissue (LST) was assessed by dual energy X-ray absorptiometry. Both groups similarly increased (P < 0.05) biceps brachii thickness (MJ-SJ = +14.2%, SJ-MJ = +13.8%). Alternatively, only the MJ-SJ group presented an increase in mid-thigh thickness from pre- to post-training (MJ SJ = +7.2%, SJ-MJ = +3.9%). Upper limbs LST (MJ-SJ = +5.2%, SJ-MJ = +7.5%) was statistically similar between conditions, and a trend for significance (P = 0.07) was found for trunk LST (MJ-SJ = +7.2%, SJ-MJ = +1.7%). Non-significant pre- to post-training changes were observed for lower limb LST (MJ-SJ = +0.7%, SJ-MJ = +1.8%). Our data suggest that both sequences are effective for increasing muscle hypertrophy over a short-term RT period; there may be a potentially beneficial hypertrophic effect for the mid-thigh to performing exercises in a manner that progresses from MJ to SJ exercises. PMID- 30248270 TI - Adequate vitamin B12 and riboflavin status from menus alone in residential care facilities in the Lower Mainland, British Columbia. AB - Older adults have potential increased risk of nutrient deficiencies due to age related decreased dietary intake and malabsorption; it is important to ensure nutrient needs are met to avoid adverse health outcomes. B vitamins are of particular interest: vitamin B12 deficiency can cause irreversible neurodegeneration; there is mandatory folic acid fortification in Canada; and suboptimal riboflavin status has been reported among older adults in the United Kingdom. In this exploratory secondary analysis study we assessed vitamin B12 and riboflavin biochemical status (via microparticle enzyme immunoassay and erythrocyte glutathione reductase activity coefficient (EGRac), respectively), and the vitamin B12, riboflavin, and folate content of menus served to a convenience sample of older adults (>=65 years) from five residential care facilities within the Lower Mainland of British Columbia, Canada. Diet was assessed from customized 28-day cycle meal plans. Participants (n=207, 53 men and 154 women) were 86 +/- 7 years, largely of European descent (92%), and non smokers (95%). The menus served had a low prevalence of inadequacy for vitamin B12 and riboflavin (only 4% and 1% of menus contained less than the estimated average requirement [EAR], respectively), but 93% contained less than the EAR for folate. Mean +/- SD serum total vitamin B12 concentration was 422 +/- 209 pmol/L, and EGRac was 1.30 +/- 0.19. The majority of older adults in residential care were provided with adequate vitamin B12 and riboflavin menu amounts, and only 5% were vitamin B12 deficient (<148 pmol/L). However, 26% were riboflavin deficient (EGRac >=1.4), which may warrant further investigation. PMID- 30248271 TI - Horizontal transfer of antibiotic resistance genes in clinical environments. AB - A global medical crisis is unfolding as antibiotics lose effectiveness against a growing number of bacterial pathogens. Horizontal gene transfer (HGT) contributes significantly to the rapid spread of resistance, yet the transmission dynamics of genes that confer antibiotic resistance are poorly understood. Multiple mechanisms of HGT liberate genes from normal vertical inheritance. Conjugation by plasmids, transduction by bacteriophages, and natural transformation by extracellular DNA each allow genetic material to jump between strains and species. Thus, HGT adds an important dimension to infectious disease whereby an antibiotic resistance gene (ARG) can be the agent of an outbreak by transferring resistance to multiple unrelated pathogens. Here, we review the small number of cases where HGT has been detected in clinical environments. We discuss differences and synergies between the spread of plasmid-borne and chromosomal ARGs, with a special consideration of the difficulties of detecting transduction and transformation by routine genetic diagnostics. We highlight how 11 of the top 12 priority antibiotic-resistant pathogens are known or predicted to be naturally transformable, raising the possibility that this mechanism of HGT makes significant contributions to the spread of ARGs. HGT drives the evolution of untreatable "superbugs" by concentrating ARGs together in the same cell, thus HGT must be included in strategies to prevent the emergence of resistant organisms in hospitals and other clinical settings. PMID- 30248272 TI - Native Language Promotes Access to Visual Consciousness. AB - Can our native language influence what we consciously perceive? Although evidence that language modulates visual discrimination has been accumulating, little is known about the relation between language structure and consciousness. We employed electroencephalography and the attentional-blink paradigm, in which targets are often unnoticed. Native Greek speakers ( N = 28), who distinguish categorically between light and dark shades of blue, showed boosted perception for this contrast compared with a verbally unmarked green contrast. Electrophysiological signatures of early visual processing predicted this behavioral advantage. German speakers ( N = 29), who have only one category for light and dark shades of blue, showed no differences in perception between blue and green targets. The behavioral consequence of categorical perception was replicated with Russian speakers ( N = 46), reproducing this novel finding. We conclude that linguistic enhancement of color contrasts provides targets with a head start in accessing visual consciousness. Our native language is thus one of the forces that determine what we consciously perceive. PMID- 30248273 TI - Risk factors for subclinical hypocalcaemia, and associations between subclinical hypocalcaemia and reproductive performance, in pasture-based dairy herds in New Zealand. AB - AIMS To estimate the herd-level prevalence of subclinical hypocalcaemia within 3 days of calving, to determine cow and herd-level risk factors for this condition, and associations with reproductive performance, in pasture-based cows in New Zealand. METHODS Between 10 and 15 clinically healthy cows >=3-years-old (n=1,051) were enrolled from 76 spring-calving dairy herds. Blood samples were collected from all cows on 1 or 2 days within 3 days of calving, and assayed for total concentrations of Ca in serum. Subclinical hypocalcaemia was defined as concentrations of Ca in serum <=2.14 mmol/L, and herd-level prevalence was the percentage of sampled cows with subclinical hypocalcaemia. Breeding and pregnancy diagnosis data were obtained for each cow to calculate reproductive outcomes. Herd-level data about management practices were collected from farmers at enrolment. Associations between cow-level variables, and reproductive outcomes, and subclinical hypocalcaemia were examined using multivariable logistic regression mixed models. Associations between herd-level variables and prevalence of subclinical hypocalcaemia were examined using a multivariable linear regression model. RESULTS Mean herd-level prevalence of subclinical hypocalcaemia was 52 (95% CI=49-55)%. Risk of subclinical hypocalcaemia at the cow-level was associated with an interaction between age of cow and interval from calving to sampling (p=0.03). Increasing age of cow was associated with increased risk of subclinical hypocalcaemia, and cows sampled on the day of calving had an increased risk compared with cows sampled 1 or 2 days after calving. Increased herd-level prevalence of subclinical hypocalcaemia was associated with feeding grass silage (p=0.06) or maize silage (p=0.004), and feeding increasing amounts of elemental Mg in the form of magnesium oxide (p=0.02). The mean farmer-reported herd-level prevalence of clinical hypocalcaemia was 2.9 (95% CI=2.1-3.8)%. Subclinical hypocalcaemia was not associated with any of the reproductive outcomes measured. CONCLUSIONS AND CLINICAL RELEVANCE There was a high prevalence of subclinical hypocalcaemia in the pasture-fed, spring-calving dairy herds sampled and a large between-herd variation in prevalence. Subclinical hypocalcaemia increased with increasing age, and declined with time postpartum. Herd-level prevalence was associated with feeding grass silage and maize silage to pre-calving cows and with increasing amounts of supplemented magnesium oxide. Subclinical hypocalcaemia was not associated with reproductive outcomes. PMID- 30248274 TI - Oxidative stress, inflammatory, psychological markers and severity of respiratory infections are negatively affected during the pre-contest period in amateur bodybuilders. AB - We examined whether off-season (OffS) and pre-contest (PreC) periods affect blood oxidative stress, inflammation, immunological and psychological markers in twenty bodybuilders. The athletes completed food intake (3-d record), physical activities, mood states (POMS), recovery-stress (RESTQ-sport), Wisconsin Upper Respiratory Symptom Survey (WURSS-21), and blood were obtained for biochemistry analyses. Almost all athletes were in a positive energy balance during the OffS, while bodybuilders presented markedly restricted energy intake (~45%) leading to a loss of weight (-9%) and fat mass (-45%), with a corresponding preservation of fat free mass in PreC. Protein intake was high during both periods, while lipid and carbohydrate intake were reduced ~50% in PreC. Almost all athletes consumed 100% of the RDA for micronutrients in OffS and 45% and 75% of the athletes had intakes bellow the RDA for vitamin A and E in PreC. Oxidative damage to lipids (TBARS), protein carbonyl, TBARS/ total antioxidant capacity ratio increased in PreC (32%, 27%, 60%), accompanied by an increase in plasma TNF-alpha (4x), and WURSS-21 scores (25%). There were no significant changes in serum antioxidant catalase, glutathione reductase and superoxide dismutase, nor in IL-1beta and immunoglobulin's. In PreC, POMS showed positive changes in vigor (-20%), and negative effects on fatigue (23%), as well as total mood disturbance (35%) and alterations in RESTQ-sport for general and sport stress (34 and 50%, respectively) and sport recovery (-23%). Thus, PreC negatively affects nutrient intake, which may exacerbate oxidative stress, inflammation and psychological status, as well as the severity of respiratory infections in bodybuilders. PMID- 30248275 TI - Toward Alignment in the Reporting of Economic Evaluations of Diagnostic Tests and Biomarkers: The AGREEDT Checklist. AB - OBJECTIVES: General frameworks for conducting and reporting health economic evaluations are available but not specific enough to cover the intricacies of the evaluation of diagnostic tests and biomarkers. Such evaluations are typically complex and model-based because tests primarily affect health outcomes indirectly and real-world data on health outcomes are often lacking. Moreover, not all aspects relevant to the evaluation of a diagnostic test may be known and explicitly considered for inclusion in the evaluation, leading to a loss of transparency and replicability. To address this challenge, this study aims to develop a comprehensive reporting checklist. METHODS: This study consisted of 3 main steps: 1) the development of an initial checklist based on a scoping review, 2) review and critical appraisal of the initial checklist by 4 independent experts, and 3) development of a final checklist. Each item from the checklist is illustrated using an example from previous research. RESULTS: The scoping review followed by critical review by the 4 experts resulted in a checklist containing 44 items, which ideally should be considered for inclusion in a model-based health economic evaluation. The extent to which these items were included or discussed in the studies identified in the scoping review varied substantially, with 14 items not being mentioned in >=47 (75%) of the included studies. CONCLUSIONS: The reporting checklist developed in this study may contribute to improved transparency and completeness of model-based health economic evaluations of diagnostic tests and biomarkers. Use of this checklist is therefore encouraged to enhance the interpretation, comparability, and-indirectly-the validity of the results of such evaluations. PMID- 30248276 TI - Nonidentifiability in Model Calibration and Implications for Medical Decision Making. AB - BACKGROUND: Calibration is the process of estimating parameters of a mathematical model by matching model outputs to calibration targets. In the presence of nonidentifiability, multiple parameter sets solve the calibration problem, which may have important implications for decision making. We evaluate the implications of nonidentifiability on the optimal strategy and provide methods to check for nonidentifiability. METHODS: We illustrate nonidentifiability by calibrating a 3 state Markov model of cancer relative survival (RS). We performed 2 different calibration exercises: 1) only including RS as a calibration target and 2) adding the ratio between the 2 nondeath states over time as an additional target. We used the Nelder-Mead (NM) algorithm to identify parameter sets that best matched the calibration targets. We used collinearity and likelihood profile analyses to check for nonidentifiability. We then estimated the benefit of a hypothetical treatment in terms of life expectancy gains using different, but equally good fitting, parameter sets. We also applied collinearity analysis to a realistic model of the natural history of colorectal cancer. RESULTS: When only RS is used as the calibration target, 2 different parameter sets yield similar maximum likelihood values. The high collinearity index and the bimodal likelihood profile on both parameters demonstrated the presence of nonidentifiability. These different, equally good-fitting parameter sets produce different estimates of the treatment effectiveness (0.67 v. 0.31 years), which could influence the optimal decision. By incorporating the additional target, the model becomes identifiable with a collinearity index of 3.5 and a unimodal likelihood profile. CONCLUSIONS: In the presence of nonidentifiability, equally likely parameter estimates might yield different conclusions. Checking for the existence of nonidentifiability and its implications should be incorporated into standard model calibration procedures. PMID- 30248277 TI - Future Directions for Cost-effectiveness Analyses in Health and Medicine. AB - OBJECTIVES: In 2016, the Second Panel on Cost-effectiveness in Health and Medicine updated the seminal work of the original panel from 2 decades earlier. The Second Panel had an opportunity to reflect on the evolution of cost effectiveness analysis (CEA) and to provide guidance for the next generation of practitioners and consumers. In this article, we present key topics for future research and policy. METHODS: During the course of its deliberations, the Second Panel discussed numerous topics for advancing methods and for improving the use of CEA in decision making. We identify and consider 7 areas for which the panel believes that future research would be particularly fruitful. In each of these areas, we highlight outstanding research needs. The list is not intended as an exhaustive inventory but rather a set of key items that surfaced repeatedly in the panel's discussions. In the online Appendix , we also list and expound briefly on 8 other important topics. RESULTS: We highlight 7 key areas: CEA and perspectives (determining, valuing, and summarizing elements for the analysis), modeling (comparative modeling and model transparency), health outcomes (valuing temporary health and path states, as well as health effects on caregivers), costing (a cost catalogue, valuing household production, and productivity effects), evidence synthesis (developing theory on learning across studies and combining data from clinical trials and observational studies), estimating and using cost-effectiveness thresholds (empirically representing 2 broad concepts: opportunity costs and public willingness to pay), and reporting and communicating CEAs (written protocols and a quality scoring system). CONCLUSIONS: Cost effectiveness analysis remains a flourishing and evolving field with many opportunities for research. More work is needed on many fronts to understand how best to incorporate CEA into policy and practice. PMID- 30248278 TI - Do Moderate to Vigorous Intensity Accelerometer Count Thresholds Correspond to Relative Moderate to Vigorous Intensity Physical Activity? AB - OBJECTIVES? We aim to predict %VO2max at absolute accelerometer thresholds, and estimate and compare durations of objective physical activity (PA) among body mass index (BMI) categories using thresholds that account for cardiorespiratory fitness. METHODS? 828 adults (53.5% male, age= 33.9+/-0.3 years) from NHANES 2003 2004 were analyzed. MET values at absolute thresholds were converted to %VO2max, and accelerometer counts corresponding to 40 or 60% VO2max were determined using 4 energy expenditure prediction equations. RESULTS? Absolute thresholds under estimated PA intensity for all adults; however, individuals with overweight and obesity work at significantly higher %VO2max at the absolute thresholds, and require significantly lower accelerometer counts to reach relative moderate and vigorous PA intensities compared to normal weight due to lower fitness (P<0.05). However, Moderate-to-Vigorous PA (MVPA) durations were shorter using relative thresholds compared to absolute thresholds (within all BMI groups, P<0.05), and remained shorter among individuals with obesity compared to normal weight when using relative thresholds (P<0.05). Regardless of the thresholds used, a greater proportion of individuals with normal weight met PA guidelines of 150 min/week of MVPA compared to individuals with obesity (absolute: 21.3 vs 6.7%, Yngve: 4.0 vs 0.2, Swartz: 10.7 vs 3.9, Hendelman: 4.7 vs 0.2, Freedson: 6.4 vs 0.5, P<0.05). CONCLUSIONS? Current absolute thresholds of accelerometry-derived PA may over estimate MVPA for all BMI categories compared with relative thresholds that account for cardiorespiratory fitness. Given the large variability in our results, more work may be needed to better understand how to use accelerometers for evaluating PA at the population level. PMID- 30248279 TI - Improving health information to address low health literacy for patients with multimorbidity. AB - A letter to the editor in response to the recently published article by Hill and Sofra (AHR, vol. 42, no. 2, pp. 134-9) on improving health information. PMID- 30248280 TI - Socioeconomic differences in access to care in Australia for women fearful of birth. AB - Objective Fear of childbirth is known to increase a woman's likelihood of having a Caesarean section. Continuity of midwifery care is known to reduce this risk, but less than 8% of women have access to this relationship-based, primary care model. The aims of this study were to determine whether healthcare use and access to continuity models are equal across different indicators of socioeconomic status for women who are fearful of birth.Methods A secondary analysis was conducted of data obtained during a randomised controlled trial of a psychoeducation intervention by trained midwives to minimise childbirth fear (the Birth Emotions and Looking to Improve Expectant Fear (BELIEF) study). In all, 1410 women were screened, with 339 women reporting high levels of fear (Wijma Delivery Expectancy/Experience Questionnaire >=66). Demographic, obstetric information, birth preference and psychosocial measures were collected at recruitment and at 36 weeks gestation for the 339 fearful women, with the birth method and health service use returned by 183 women at 6 weeks after the birth.Results Univariate analysis revealed no significant difference in the number of general practitioner and midwife visits between women of high and low income and high and low education. However, women with higher levels of education had 2.51-fold greater odds of seeing the same midwife throughout their pregnancy than women with lower education (95% confidence interval 1.25-5.04), after adjusting for age, parity and hospital site.Conclusions Given the known positive outcomes of continuity of midwifery care for women fearful of birth, health policy makers need to provide equity in access to evidence-based models of midwifery care.What is known about this topic? Caseload midwifery care is considered the gold standard care due to the known positive outcomes it has for the mother and baby during the perinatal period. Pregnant women who receive caseload midwifery care are more likely to experience a normal vaginal birth.What does this paper add? There is unequal access to midwifery caseload care for women fearful of birth across socioeconomic boundaries. Midwifery caseload care is not used for all fearful mothers during the perinatal period.What are the implications for practitioners? Health policy makers seeking to provide equity in access to maternity care should be aware of these inequalities in use to target delivery of care at this specific cohort of mothers. PMID- 30248281 TI - Adult morgagni hernia: A single-center experience of five cases and a review of literature. AB - Morgagni hernia is a rare congenital anomaly arising from the fusion defect between the septum transversum and sternum. The diagnosis is usually difficult since the presentation may be asymptomatic or with respiratory symptoms, abdominal and/or retrosternal pain, abdominal fullness, or gastrointestinal obstruction. In this report, we discuss the clinical presentation and management of this rare condition in five consecutive cases. Between 2009 and 2015, five cases underwent surgery for Morgagni hernia (three laparoscopic and two open repair surgeries); one patient developed recurrent hernia 7 months after the laparoscopic surgery. This case is the first reported recurrence in literature following laparoscopic repair in adults. Surgery is the only treatment option for Morgagni hernias, which can be performed through transthoracic, transabdominal, laparoscopic, or thoracoscopic approach. The issues of using mesh and reducing the hernial sac remain controversial. PMID- 30248282 TI - A rare adult morgagni hernia mimicking lobar pneumonia. AB - Morgagni hernia is the rarest form of congenital diaphragmatic hernia and is commonly found either in the first few hours of life or in the antenatal period. It is less common in adults and is mostly diagnosed accidentally in asymptomatic patients. Symptomatic adult cases are even rarer with a wide variety of symptoms. We report a patient with a 1-year history of chronic recurrent cough and dyspnea who had been misdiagnosed with recurrent pneumonia before being recognized and treated for Morgagni hernia. PMID- 30248283 TI - Laparoscopic resection of retroperitoneal bronchogenic cyst clinically presenting as adrenal cyst. AB - Bronchogenic cyst localized in the retroperitoneum is a rare clinical entity. It is a congenital malformation generally occurring in the posterior mediastinum due to the abnormal development of the foregut. We report the case of a retroperitoneal cyst presenting as left adrenal cyst. A 38-year-old female presented with left upper abdominal pain. Endocrinological evaluation was done, and no adrenal hormonal secretion was detected. The cyst was removed laparoscopically. Pathologic examination confirmed it as a bronchogenic cyst. Therefore, bronchogenic cysts should be considered in the differential diagnosis of retroperitoneal cysts. Laparoscopic resection of retroperitoneal cysts results in favorable outcome. PMID- 30248284 TI - Effects of different intraabdominal pressure levels on oxidative stress markers in laparoscopic cholecystectomy. AB - OBJECTIVE: To evaluate the effect of laparoscopic cholecystectomy performed under different intraabdominal pressure on oxidative stress markers. MATERIAL AND METHODS: This prospective, randomized, controlled study examined 90 consecutive healthy patients who underwent elective laparoscopic cholecystectomy with the diagnosis of symptomatic cholelithiasis. The patients were divided into three groups, 30 patients in each. Group 1 included patients who underwent laparoscopic cholecystectomy at a CO2 pneumoperitoneum pressure of 7 mmHg, Group 2 patients who underwent laparoscopic cholecystectomy at a CO2 pneumoperitoneum pressure of 10 mmHg, and Group 3 patients who underwent laparoscopic cholecystectomy at a CO2 pneumoperitoneum pressure of 13 mmHg. Blood samples were collected preoperatively, perioperatively, and postoperatively for measurement of the serum levels of ischemia modified albumin and an analysis of total antioxidant status and total oxidant status. Intra-group comparisons were made. RESULTS: Group 1 experienced a significant increase in the postoperative ischemia modified albumin values compared to preoperative ischemia modified albumin values (p=0.013). Group 2 experienced a significant decrease in the perioperative total antioxidant status values compared to preoperative and postoperative total antioxidant status values (p=0.009). Group 3 experienced a significant increase in the perioperative total oxidant status and oxidative stress index values compared to preoperative values (p<0.001). Group 3 experienced a significant increase in the perioperative and postoperative ischemia modified albumin values compared to preoperative values (p<0.001). CONCLUSION: Increased levels of oxidative stress markers were detected in patients who underwent laparoscopic cholecystectomy at a high intraabdominal pressure level. PMID- 30248285 TI - Does hyperthermic preconditioning affect the rate of surgical site infection rate and inflammatory reaction in colorectal cancer patients? A prospective randomized clinical trial. AB - OBJECTIVES: Hyperthermic preconditioning has been shown to protect against different insults in experimental studies. However, clinical studies assessing its effects remain limited. The aim of this study was to investigate the effects of hyperthermic preconditioning on the rate of surgical site infection and inflammatory reaction in patients undergoing elective colorectal cancer surgery. MATERIAL AND METHODS: Patients with colorectal cancer, scheduled to undergo elective surgery were enrolled in this prospective randomized study. Patients were randomly assigned to either the hyperthermic preconditioning group or control group. Postoperative superficial and deep surgical site infection were recorded. Blood samples were collected from all the patients in the hyperthermic preconditioning group prior to the application of hyperthermia 12 h before surgery, immediately prior to surgery, and 4 h and 24 h postoperatively. For the control group, blood samples were obtained within the same periods without the application of hyperthermia. Levels of interleukin-1, IL-6, and tumor necrosis factor-alpha were measured from blood samples. RESULTS: Twenty patients were randomized to the hyperthermic preconditioning group and 21 to the control group. No significant difference was found in deep or superficial surgical site infection between the groups. No significant difference in the tumor necrosis factor-alpha, interleukin-1, and IL-6 levels was found in serum samples collected before hyperthermia, during the operation, and postoperatively. CONCLUSION: This study showed that hyperthermic preconditioning has no effect on the surgical site infection and cytokine response in patients undergoing elective surgical intervention for colorectal cancer. PMID- 30248286 TI - A rare cause of acute abdomen: Isolated necrosis of the cecum. AB - We would like to present the case of a 76-year-old female patient with cecal necrosis, which is a rare cause of acute abdomen in elderly women and a variant of ischemic colitis. The patient was admitted to our hospital with abdominal pain, anorexia, and nausea. Physical examination, laboratory parameters, and abdominal computed tomography revealed acute abdomen. We operated the patient with an infra-umbilical midline incision. Considering the pain localized to the right lower quadrant, our initial diagnosis was acute appendicitis; however, we kept in mind other differential diagnoses as well. After laparotomy Non-occlusive cecal necrosis was detected. Arterial pulse was palpated; however, no signs of trombus were detected. Patient also have a Meckel's diverticulum. Terminal ileum plus cecum resection and Meckel's diverticulum excision were performed. Isolated necrosis of the cecum may be caused due to multiple reasons. Especially in elderly female patients with predisposing factors like hypotension, sepsis, shock, drug use, vasculitis, and hypercoagulability, cecal necrosis should be kept in mind. PMID- 30248287 TI - Treatment conundrums in osteosarcoma of the breast: Two clinical cases from a tertiary care cancer center in India. AB - Extraosseous sarcoma of the breast occurs infrequently and is a harbinger of poor prognosis. The histogenesis of this tumor is ambiguous, and it can arise both in de novo and metastatic settings. Morphologically, it is indistinguishable from its skeletal counterpart, and clinically, it presents similarly to any other subtype of breast cancer. Tumor recurrence with a propensity for hematogenous rather than lymphatic spread plagues this malicious disease. The treatment guidelines are mainly derived from the those of other extraskeletal sarcomas as the literature is limited in this context. We hereby present 2 clinical cases with similar clinical profiles and different treatment outcomes. The intent of this case report is to contribute to the limited database available for the management of this rare disease. PMID- 30248288 TI - Median arcuate ligament syndrome during pancreaticoduodenectomy. AB - Median arcuate ligament syndrome is caused by the compression of the celiac artery by a fibrous band called the median ligament, which originates from the crus of diaphragm. The prevalence of Median arcuate ligament syndrome has been reported as 10%-24% among patients; however, the etiology is unclear. The components of the clinical triad include a chronic post-prandial pain, epigastric murmur, and weight loss. Diagnosis is based on clinical and radiological findings. Median arcuate ligament syndrome has been reported in a small portion of patients undergoing pancreaticoduodenectomy. Most patients have been diagnosed prior to surgery. PMID- 30248289 TI - Gastrointestinal stromal tumors: A clinical and histopathological presentation of 27 cases. AB - OBJECTIVES: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that express type 3 tyrosine kinase receptors and are thought to develop from the neoplastic transformation of the interstitial Cajal cells. The present study was performed to morphologically and immunohistologically evaluate GISTs, to compare their qualities using a GIST risk categorization system, and to identify the diagnostic and prognostic parameters of GISTs. MATERIAL AND METHODS: A total of 27 patients with GISTs underwent treatment and were followed up at the Gaziosmanpasa Taksim Training and Research Hospital. Descriptive statistics was used to calculate the mean and median values. Survival analysis was performed by the Kaplan-Meier method. The analyses were performed using the SPSS version 22.0 software. RESULTS: The mean follow-up time was 3.5 (5 months to 13 years) years. The mean age was 60.4 (29-82) years. The tumors were localized in the stomach (62.9%), extraintestinal areas (14.8%), intestine (7.4%), esophagus (7.4%), and rectum (7.4%). Twenty-four patients were classified according to the Fletcher system. Of these patients, 7 (25.9%) were classified as very low risk, 8 (29.6%) as low risk, 7 (25.9%) as intermediate risk, and 2 (7.4%) as high risk. Twenty four patients underwent surgery. Of the 3 patients who did not undergo surgery, 1 had metastatic disease at the time of diagnosis, and 2 had mini- or micro-GISTs in the stomach. On endoscopic surveillance, all tumors remained stable. Three out of the 27 patients were lost to follow-up. Two patients developed recurrence, and 1 patient died of GIST. CONCLUSION: We analyzed the clinical and pathological characteristics of GIST. The most common site of tumor origin was the stomach. The size, mitotic index, and Ki-67 values were to be found high in intermediate- and high-risk groups and metastatic diseases. PMID- 30248290 TI - Heterotopic ossification of the anterior abdominal wall. AB - Heterotopic ossification is the formation of bone tissues in areas other than the skeletal system. It is more often seen as a complication of orthopedic surgery; however, it is a pathological condition that might be observed during the healing of abdominal incisions in the midline. The aim of this study is to present a case of a 63-year-old male patient with complaints of induration and pain on the region of his previous incision through which he had been operated for achalasia. Heterotopic ossification has also been discussed in the light of the current literature. PMID- 30248291 TI - Rhabdomyolysis as a rare but fatal complication of bariatric surgery: A case report. AB - Rhabdomyolysis after bariatric surgery is a quite rare occurrence with low recognition. Due to the breakdown of the striated muscle fibers, creatine kinase and myoglobin are released into the systemic circulation with variable effects on the renal filtration functions. Herein we present the case of a patient who developed rhabdomyolysis following revision bariatric surgery. A 34-year-old male patient was admitted for bariatric surgery. He had undergone a gastric band surgery approximately 6 years ago, with weight regain starting 1 year postoperatively gradually reaching the previous weight level. Consequently, the gastric band was removed with open surgery 3 years ago. The patient had a body mass index of 69 kg/m2 and an incisional hernia due to the previous surgery. Although initially, laparoscopic sleeve gastrectomy was planned, a switch to open surgery was made due to the presence of diffuse intra-abdominal adhesions and a giant incisional hernia precluding a laparoscopic intervention. The total duration of surgery was 420 min. Postoperative laboratory work-up showed elevated blood creatine kinase levels (25837 U/L). Upon the failure of fluid replacement and diuretics, hemodialysis was initiated on postoperative day 1. Despite daily sessions of hemodialysis, the patient's acidosis did not improve; his general status worsened, and he died on postoperative day 14. Rhabdomyolysis is a severe and potentially life-threatening complication of bariatric surgery. Its severity may vary from asymptomatic elevation in creatine kinase levels to death. Postoperative creatine kinase levels should be routinely monitored in high-risk patients as a practical and inexpensive laboratory modality for early diagnosis. PMID- 30248292 TI - Protective effects of laparoscopic sleeve gastrectomy on atherosclerotic and hemocytic parameters in obese patients. AB - OBJECTIVES: The aim of this study was to evaluate the effects of the change in the body mass index following laparoscopic sleeve gastrectomy on the vascular morphology structure and biochemical and hemocytic parameters. MATERIAL AND METHODS: A prospective evaluation of 60 patients who underwent sleeve gastrectomy was conducted. The relationship was evaluated between the vascular morphological parameters and biochemical and hemocytic inflammatory variables of the patients preoperatively and at 6, 12, and 18 months postoperatively. RESULTS: Compared to the baseline values, a significant decrease was determined in the carotid intima media thickness at 6, 12, and 18 months (p<0.001, p<0.001, p<0.001, respectively). The compliance and distensibility values were observed to increase over time (p<0.05, p<0.001, p<0.001, respectively). A statistically significant difference was determined in the carotid intima media thickness values according to gender, with males (n:7) measuring 0.618+/-0.123 mm and females (n:53) measuring 0.506+/-0.113 mm (p<0.01). When patients were grouped as neutrophil-to lymphocyte ratio <=2.54 (n:41) and neutrophil-to-lymphocyte ratio>2.55 (n:19), the increasing neutrophil-to-lymphocyte ratio values were observed to be in proportion to the carotid intima media thickness, and the difference was statistically significant (p<0.001). When factors affecting the vascular morphology parameters measured at baseline and throughout the study were evaluated with the correlation analysis, there was observed to be a positive correlation between the baseline carotid intima media thickness thickness and neutrophil percentage (r=0.736, p<0.001) and neutrophil-to-lymphocyte ratio (r=0.676, p<0.001), and between the negative correlation and lymphocyte percentage (r=-0.628, p<0.001). CONCLUSION: Laparoscopic sleeve gastrectomy is not only a cosmetic procedure reducing the body mass index values, but it also has a beneficiary effect on vascular morphology, biochemical, and hemocytic parameters. PMID- 30248293 TI - Routine histopathological examination of gallbladder specimens after cholecystectomy: Is it time to change the current practice? AB - OBJECTIVES: Routine histopathological examination of all gallbladder specimens, regardless of the clinical characteristics of the patient or macroscopic aspect of the gallbladder, is the current approach to detect the presence of gallbladder carcinoma. The aim of the present study was to assess whether or not it would be safe to adopt a policy of processing only gallbladder specimens with preoperative or intraoperative suspicion for malignancy without compromising patient safety. MATERIAL AND METHODS: From January 2009 to June 2017, all histopathology reports of 3423 consecutive gallbladder specimens after elective and emergency cholecystectomies were retrospectively analyzed in two university hospitals. RESULTS: A total of 3423 gallbladder specimens submitted for histopathological examination during the study period were included in the study. The results of histopathological examination of these gallbladder specimens showed that chronic cholecystitis was found in 2792 (81.6%), acute cholecystitis in 237 (6.9%), and cholesterolosis in 223 (6.5%) patients. Dysplasia was found in 5 (0.14%) patients, and gallbladder carcinoma was detected in 4 (0.11%) patients. All patients with gallbladder carcinoma were diagnosed either preoperatively or intraoperatively, and none of the patients with gallbladder carcinoma were diagnosed from the histopathological examination. CONCLUSION: A strategy of selective approach for histopathological examination of gallbladder specimens may be safe in areas with very low incidence of gallbladder carcinoma. Such selective strategy is more cost-effective, reduces the workload of pathologists, and does not appear to compromise patient outcome. PMID- 30248294 TI - Effects of subjective sleep quality on the quality of life in patients with chronic anorectal disorder. AB - OBJECTIVES: The aim of the present study was to evaluate the subjective sleep quality in patients with anorectal disorder, to determine the factors associated with subjective sleep quality, and to explore the relationship between subjective sleep quality and quality of life. MATERIAL AND METHODS: This descriptive study was conducted between April 8, 2015 and April 12, 2016. The research population consisted of 284 patients who attended the general surgery outpatient clinics of Konya Military Hospital and were subsequently diagnosed with one of the four most common anorectal disorders (hemorrhoidal disease, anal fissure, anorectal abscess/fistula, and sacrococcygeal pilonidal disease). Data were collected from 114 patients who volunteered to participate in the study. After establishment of the diagnosis based on proctological anamnesis and physical examination, the Pittsburgh Sleep Quality Index, Short-Form Health Survey, Beck Anxiety Inventory, and Beck Depression Inventory were administered to the patients, along with a questionnaire on sociodemographic data, via a face-to-face interview technique. RESULTS: Ninety-six (84.2%) patients had poor sleep quality, whereas 18 (15.8%) patients had good sleep quality. Among the patients with poor sleep quality, 16 were diagnosed with anorectal abscess and fistula (100.0%), 40 with hemorrhoidal disease (90.9%), 16 with sacrococcygeal pilonidal disease (80.0%), and 24 with anal fissure (70.6%). Overall, all patients with poor sleep quality (n=96) had low scores in all subcomponents of the quality of life scale. CONCLUSIONS: The sleep quality in patients with chronic anorectal disorder is significantly impaired, thus negatively affecting quality of life. Therefore, improvement in quality of life by improving sleep quality should be one of the main objectives in treating chronic anorectal disorders. PMID- 30248295 TI - Effect of postoperative ischemia on steroid hormone receptors and c-erbB-2 levels in breast cancer tissue. AB - OBJECTIVES: Postoperative ischemia could affect the evaluation of breast cancer tissue for steroid hormone receptors and c-erbB2 levels until fixation using formalin. The misevaluation of steroid hormone receptors and c-erbB2 levels, which are important prognostic factors in the treatment of breast cancer, could change treatment options. The aim of this study was to investigate the effects of postoperative ischemia on a breast cancer tissue sample, particularly on steroid hormone receptors and c-erbB2 expression level. MATERIAL AND METHODS: Twenty patients who underwent modified radical mastectomy were included in this study. Two histopathological methods, namely frozen and regular follow-up methods, were performed postoperatively on all specimens. Steroid hormone receptors, estrogen receptors, progesterone receptors, and c-erbB2 expression of breast cancer tissue samples were evaluated using both techniques. Two groups were created based on the results of steroid hormone receptors and c-erbB2 expression levels using the two histopathological techniques. RESULTS: We determined that ischemia has an adverse effect on the evaluation of steroid hormone receptors and c-erbB2, especially its effect on c-erbB2 expression level was significant (p<0.002). CONCLUSION: A mastectomy specimen should be examined at once to ensure accurate detection of steroid hormone receptors and c-erbB2 levels for the proper treatment of breast cancer patients. PMID- 30248296 TI - Long-term results of patients who were applied laparoscopic adjustable gastric banding. AB - OBJECTIVES: The most effective treatment step in morbid obesity is surgical treatment. The purpose of the present study was to investigate the long-term follow-up results and success rates in patients who were applied laparoscopic adjustable gastric band. MATERIAL AND METHODS: The change in body mass index, percentage of excess weight loss, comorbidities, and resulting complications were investigated in 220 patients who were morbidly obese who were applied laparoscopic adjustable gastric band between April 2006 and February 2012 throughout the 6-year follow-up period. Forty-six patients who did not show up for their routine follow-ups were excluded from the study. RESULTS: In the present study, the band removal percentage was 35.63%. The percentage of excess weight loss in patients who were followed up without removal of the band was 46.03%. Complications were observed in 46.5% of the patients. The most frequently observed complication among the major complications was band intolerance, which is also the most common cause of band removal. Band removal was considered as a failure in laparoscopic adjustable gastric band operations, and patients were referred to other surgical methods. CONCLUSION: When improved patient compliance and careful and close patient follow-up are provided in the early stages of laparoscopic adjustable gastric band application, it may be possible to reach percentage of excess weight loss results that would be the nearest to those achieved by gastric bypass or sleeve gastrectomy methods. However, high complication rates and necessity to perform other bariatric surgical procedures in the majority of the patients in the long-term follow-up suggest that the laparoscopic adjustable gastric band operation is not the first choice in bariatric surgery. PMID- 30248297 TI - Colon resection for endometriosis. AB - Endometriosis affects women during the reproductive period and can cause functional disorders. Sometimes general surgical intervention is necessary owing to disease boundary. The sigmoid colon and rectum are particularly affected because of their close relationship. In this case, treatment must be individualized according to the patient and symptoms. If the lesion penetrated the entire bowel wall, bowel resection may be inevitable. Laparoscopic resection of the sigmoid colon or rectum can be performed safely in this situation. When laparoscopic resection is not possible because of technical difficulties, open resection may be performed as a mode of treatment. PMID- 30248298 TI - Colorectal cancer surgery in octogenarians. AB - OBJECTIVES: The incidence of colorectal cancer becomes higher among octogenarians as the life expectancy increases. Whether advanced age is a risk factor for colorectal surgery is a matter of debate. In the present study, the clinical results of octogenarians who underwent colorectal cancer surgery are discussed to find an answer to this question. MATERIAL AND METHODS: Data of 63 octogenarians who were operated in a tertiary colorectal surgery department between January 1, 2010 and December 31, 2013 were reviewed retrospectively. Demographic data and preoperative, peroperative, and postoperative parameters were evaluated. RESULTS: Overall, 57.2% of the patients were men. The median age was 81 (80-89) years. Cancer was located at the right colon in 17.5%, left colon in 50.8%, and rectum in 31.7%. Eleven patients underwent emergency surgery (17.5%). The most common surgical procedure was low anterior resection in elective (22.2%) and Hartmann's procedure in the emergency setting (9.5%). Stoma creation was more frequent among patients undergoing emergency procedures (42% vs. 6.8%; p=0.0018). Histopathological diagnosis was adenocarcinoma in 90.5% of the patients, and 34.9% of the patients had stage IIIB disease. Surgical morbidity was significantly higher among patients who underwent rectal resection (66% vs. 10.2%; p=0.0124). Medical morbidity was observed in 10 (15.9%) patients. Preoperative blood transfusion was a risk factor for morbidity (83.4% vs. 29.8%; p=0.0170). Length of total hospital stay was 14 (3-39) days. Surgical (p=0.0004) and medical (p=0.0288) morbidity prolonged the length of total hospital stay. The overall mortality rate was 1.6%. CONCLUSION: Colorectal surgery may be safely performed in octogenarians with acceptable morbidity and mortality in specialized centers. PMID- 30248299 TI - Could local antibiotics be included in the treatment of acute anal fissure? AB - OBJECTIVE: Acute anal fissure is a very common disorder of the anorectal region. Its most widely used treatment method is the medications given in addition to conservative therapies. The objective of the present study was to investigate the effects of local metronidazole use in the treatment of acute anal fissure on the symptoms and remission processes of the patients. MATERIAL AND METHODS: This was a prospective, randomized, controlled clinical study conducted on 100 consecutive patients who presented to our clinic between March 2016 and March 2017 and who were diagnosed with acute anal fissure. Patients were randomly divided into two groups of 50 persons. Patients in Group 1 were given only 5% lidocaine pomade as a local anesthesia, and those in Group 2 were given 5% lidocaine pomade and metronidazole cream. Patients applied the medications topically to the anal margin 3 times per day for 4 weeks. Patients' demographic characteristics, such as age and gender, were recorded. All patients were invited for check-up at the end of weeks 1, 2, and 4 of treatment. The Visual Analogue Scale scores for pain and the healing status of their fissure by visual inspection, as well as any adverse effects of the drugs, were recorded. The results were compared statistically. A p-value <0.05 was considered significant. RESULTS: The mean ages of the patients were 34.2+/-4.1 years in Group 1 and 36.6+/-3.8 years in Group 2. As a result of the statistical comparison of the Visual Analogue Scale scores, there was a statistically significant difference between the two groups at the end of weeks 2 and 4 (p=0.004 and p<0.001, respectively). In Group 1, 28 (56%) patients recovered, but no recovery was observed in 22 (44%) patients. In Group 2, 43 (86%) patients recovered, whereas 7 (14%) patients had no recovery (p=0.004). CONCLUSION: The topical antimicrobial treatment with metronidazole as an addition to the classical medical treatments in acute anal fissure is an effective and safe practice resulting in further reduction in pain and increased healing rate. PMID- 30248300 TI - Circulating microRNAs are upregulated following acute aerobic exercise in obese individuals. AB - INTRODUCTION/PURPOSE: MicroRNAs (miRNAs), a class of non-coding RNAs, are involved in the regulation of gene expression and numerous biological processes, including inflammation and metabolism in obese populations. Emerging research indicates that physical activity provides health-related benefits in obesity associated inflammatory diseases. This study examined how acute aerobic exercise would mediate the changes in plasma level of inflammation-related circulating miRNA (ci-miRNA) expression (miR-21, miR-126, miR-130b, miR-221, and miR-222) in obese and normal-weight subjects. METHODS: Twenty-four subjects (12 obese and 12 normal-weight) were recruited to participate in a 30-min aerobic exercise (75% VO2max). Blood samples were taken prior to exercise, immediately following exercise, 1 h, and 2 h into recovery for analysis of target ci-miRNAs in plasma. RESULTS: A higher baseline levels of ci-miRNAs (miR-126, miR-130b, miR-221, and miR-222) were found in obese subjects than normal-weight subjects. In response to acute aerobic exercise, obese subjects exhibited a higher increase in plasma level of all ci-miRNAs: miR-21, miR-126, miR-130b, miR-221 and miR-222, even after controlling for VO2max and insulin resistance (HOMA-IR). Furthermore, all miRNA area-under-the curves "with respect to increase" (AUCi) were higher in obese subjects and also positively correlated with each other, even after controlling for VO2max and HOMA-IR. CONCLUSION: These findings indicate that acute aerobic exercise elicits a higher elevation in plasma level of inflammatory ci-miRNAs in obese than normal-weight individuals, irrespective of cardiorespiratory fitness and indicator of metabolic syndrome (HOMA-IR). PMID- 30248301 TI - Acute effect of three different exercise training modalities on executive function in overweight inactive men: A secondary analysis of the BrainFit study. AB - There is currently a consensus about the positive effects of physical exercise on cognition. However, the exercise intensity-dependent effect on executive function remains unclear. Thus, the aim of this study was to compare the acute effects of high-intensity aerobic interval training (HIIT), progressive resistance training (PRT), or combined training (PRT + HIIT) on executive function indicators in overweight inactive adult men (aged 18-30 years old). The participants were screened and excluded for medical conditions known to impact cognitive functioning, which was measured with the Montreal Cognitive Assessment (MoCA) screening cognitive test. A randomised, parallel-group clinical trial was conducted among 36 adults who were randomly assigned to a HIIT (n = 12), PRT (n = 7), PRT + HIIT (n = 7), or control group (n = 10) until the energy expenditure of 400-500 kcal. Cognitive inhibition and attention capacity were examined using the Stroop test and d2 test of attention, respectively, and were obtained pre exercise for baseline measurement and 1 min post-exercise for each exercise training modality. Cognitive inhibition measured by the Stroop test was improved after the HIIT protocol for the domains of reading by +5.89 (eta2 = 0.33), colour naming +9.0 (eta2 = 0.60), interference +10.1 (eta2 = 0.39), and index interference +6.0 (eta2 = 0.20). Additionally, the PRT + HIIT group had an increase for the reading condition of +7.1 (eta2 = 0.40), colour naming +7.5 (eta2 = 0.80), and interference +5.8 (eta2 = 0.39). In regard to attentional capacity, the HIIT group elicited small to medium improvements in the concentration level domain of +21.7 (eta2 = 0.44), total performance domain +56.6 (eta2 = 0.50), and consistency domain -3.0 (eta2 = 0.27). These results were similar in the PRT and PRT + HIIT groups in the concentration level and items processed domains (P < 0.05). In conclusion, acute HIIT and PRT + HIIT sessions reported important effect sizes than PRT alone for cognitive inhibition and attention capacity. Taken together, the results suggest that even short-term exercise interventions can enhance overweight adults' executive functions. PMID- 30248304 TI - Neurotensin and dynorphin Bi-Directionally modulate CeA inhibition of oval BNST neurons in male mice. AB - Neuropeptides are often co-expressed in neurons, and may therefore be working together to coordinate proper neural circuit function. However, neurophysiological effects of neuropeptides are commonly studied individually possibly underestimating their modulatory roles. Here, we triggered the release of endogenous neuropeptides in brain slices from male mice to better understand their modulation of central amygdala (CeA) inhibitory inputs onto oval (ov) BNST neurons. We found that locally-released neurotensin (NT) and dynorphin (Dyn) antagonistically regulated CeA inhibitory inputs onto ovBNST neurons. NT and Dyn respectively increased and decreased CeA-toovBNST inhibitory inputs through NT receptor 1 (NTR1) and kappa opioid receptor (KOR). Additionally, NT and Dyn mRNAs were highly co-localized in ovBNST neurons suggesting that they may be released from the same cells. Together, we showed that NT and Dyn are key modulators of CeA inputs to ovBNST, paving the way to determine whether different conditions or states can alter the neuropeptidergic regulation of this particular brain circuit. PMID- 30248302 TI - Sexual activity modulates neuroinflammatory responses in male rats. AB - Immune activity influences reproduction, however, the extent to which mating experience may inversely alter immune pathways is poorly understood. A few studies in humans suggest that mating triggers a circulating immune and hypothalamic-pituitary-adrenal axis response. In male rats, mating experience enhances neuroplasticity and improves cognitive function and affective-like behavior, independent of the physical activity component. Yet, the extent to which mating experience may influence immune responses in the brain remain unexplored. Here, we hypothesized that recent mating experience in male rats increases neuroinflammatory signaling (via lipopolysaccharide [LPS] stimulation, i.p.) and associated sickness behaviors (i.e., food intake, weight loss) relative to sexually-naive controls. Virgin male rats were exposed to a sexually non receptive (control) or sexually-receptive female for 30 min for six consecutive days. Immediately following the last mating experience, rats were administered a saline or LPS injection and euthanized four hours later. Mating increased Tnfalpha responses to LPS in the brain, which positively correlated with LPS induced weight loss. Mating also increased peripheral corticosterone among saline treated rats, but this corticosterone response was attenuated in the most proficient copulators (e.g., shortest latencies). Thus, recent mating experience may be a unique modulator of select stimulated inflammatory signals that are relevant to adaptive neuroimmune responses and behavior. PMID- 30248303 TI - Bumepamine, a brain-permeant benzylamine derivative of bumetanide, does not inhibit NKCC1 but is more potent to enhance phenobarbital's anti-seizure efficacy. AB - Based on the potential role of Na-K-Cl cotransporters (NKCCs) in epileptic seizures, the loop diuretic bumetanide, which blocks the NKCC1 isoforms NKCC1 and NKCC2, has been tested as an adjunct with phenobarbital to suppress seizures. However, because of its physicochemical properties, bumetanide only poorly penetrates through the blood-brain barrier. Thus, concentrations needed to inhibit NKCC1 in hippocampal and neocortical neurons are not reached when using doses (0.1-0.5 mg/kg) in the range of those approved for use as a diuretic in humans. This prompted us to search for a bumetanide derivative that more easily penetrates into the brain. Here we show that bumepamine, a lipophilic benzylamine derivative of bumetanide, exhibits much higher brain penetration than bumetanide and is more potent than the parent drug to potentiate phenobarbital's anticonvulsant effect in two rodent models of chronic difficult-to-treat epilepsy, amygdala kindling in rats and the pilocarpine model in mice. However, bumepamine suppressed NKCC1-dependent giant depolarizing potentials (GDPs) in neonatal rat hippocampal slices much less effectively than bumetanide and did not inhibit GABA-induced Ca2+ transients in the slices, indicating that bumepamine does not inhibit NKCC1. This was substantiated by an oocyte assay, in which bumepamine did not block NKCC1a and NKCC1b after either extra- or intracellular application, whereas bumetanide potently blocked both variants of NKCC1. Experiments with equilibrium dialysis showed high unspecific tissue binding of bumetanide in the brain, which, in addition to its poor brain penetration, further reduces functionally relevant brain concentrations of this drug. These data show that CNS effects of bumetanide previously thought to be mediated by NKCC1 inhibition can also be achieved by a close derivative that does not share this mechanism. Bumepamine has several advantages over bumetanide for CNS targeting, including lower diuretic potency, much higher brain permeability, and higher efficacy to potentiate the anti-seizure effect of phenobarbital. PMID- 30248305 TI - Muscarinic receptor antagonists activate ERK-CREB signaling to augment neurite outgrowth of adult sensory neurons. AB - A major cellular effector activated by G protein coupled receptors is extracellular signal-regulated kinase (ERK). The ERK signaling cascade regulates a variety of cellular processes including growth and proliferation. Both G protein and beta-arrestin-mediated signaling lead to ERK activation by phosphorylation through different kinases. Recently, we have shown muscarinic acetylcholine type 1 receptor (M1R) antagonists, muscarinic toxin 7 (MT7) and pirenzepine, elevated neurite outgrowth and protected from small and large fiber neuropathy in adult sensory neurons in various animal models. Thus, we tested the novel hypothesis that muscarinic antagonists could drive neurite outgrowth through altered M1R-ERK signaling. We have used two dimensional isoelectric focusing/SDS-PAGE combined with analysis using multiple phospho-epitope specific antibodies to study ERK1/2 phosphorylation and activation of its downstream nuclear effector cyclic response element binding protein (CREB). Activated CREB is known to exhibit neuroprotective and growth promoting effects. One hour of treatment with MT7 and pirenzepine activated ERK through M1R and induced a significant increase in levels of pCREB(S133) in cultured sensory neurons. Further, pharmacological blockade or siRNA based knockdown of ERK abolished the MT7 and pirenzepine mediated neuritogenic effect. In addition, we have shown drug induced alterations of charged protein fractions that may possess additional post translationally modified forms of ERK and CREB. For the first time we show that long-term treatment, e.g. 1 h, with muscarinic antagonists selective or specific for M1R can activate a biased beta-arrestin dependent ERK-CREB signal cascade. Our study gives novel insight into muscarinic antagonist-mediated modulation of M1R-ERK-CREB signaling which could be exploited for therapy in neuropathic diseases. PMID- 30248306 TI - KV1.2 channel-specific blocker from Mesobuthus eupeus scorpion venom: Structural basis of selectivity. AB - Scorpion venom is an unmatched source of selective high-affinity ligands of potassium channels. There is a high demand for such compounds to identify and manipulate the activity of particular channel isoforms. The objective of this study was to obtain and characterize a specific ligand of voltage-gated potassium channel KV1.2. As a result, we report the remarkable selectivity of the peptide MeKTx11-1 (alpha-KTx 1.16) from Mesobuthus eupeus scorpion venom to this channel isoform. MeKTx11-1 is a high-affinity blocker of KV1.2 (IC50 ~0.2 nM), while its activity against KV1.1, KV1.3, and KV1.6 is 10 000, 330 and 45 000 fold lower, respectively, as measured using the voltage-clamp technique on mammalian channels expressed in Xenopus oocytes. Two substitutions, G9V and P37S, convert MeKTx11-1 to its natural analog MeKTx11-3 (alpha-KTx 1.17) having 15 times lower activity and reduced selectivity to KV1.2. We produced MeKTx11-1 and MeKTx11-3 as well as their mutants MeKTx11-1(G9V) and MeKTx11-1(P37S) recombinantly and demonstrated that point mutations provide an intermediate effect on selectivity. Key structural elements that explain MeKTx11-1 specificity were identified by molecular modeling of the toxin-channel complexes. Confirming our molecular modeling predictions, site-directed transfer of these elements from the pore region of KV1.2 to KV1.3 resulted in the enhanced sensitivity of mutant KV1.3 channels to MeKTx11-1. We conclude that MeKTx11-1 may be used as a selective tool in neurobiology. PMID- 30248307 TI - The current state of artificial intelligence in ophthalmology. AB - Artificial intelligence (AI) is a branch of computer science that deals with the development of algorithms that seek to simulate human intelligence. We provide an overview of the basic principles in AI that are essential to the understanding of AI and its application in health care. We also present a descriptive analysis of the current state of AI in various fields of medicine, especially ophthalmology. Finally, we review the potential limitations and challenges that come along with the development and implementation of this new technology that will likely play a major role in clinical medicine in the near future. PMID- 30248308 TI - Targeting Nrf2-mediated heme oxygenase-1 enhances non-thermal plasma-induced cell death in non-small-cell lung cancer A549 cells. AB - Non-thermal plasma (NTP) treatment has been proposed as a potential approach for cancer therapy for killing cancer cells via generation of reactive oxygen species (ROS). As an antioxidant protein, Heme oxygenase-1 (HO-1) has been known to protect cells against oxidative stress. In this paper, we investigated the role of HO-1 activation in NTP-induced apoptosis in A549 cells. Distinctly increased ROS production and apoptosis were observed after NTP exposure. NTP exposure induced HO-1 expression in a dose- and time-dependent manner via activating the translocation of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) from cytoplasm to nucleus. Furthermore, inhibiting HO-1 activation with its specific inhibitor, ZnPP, increased "killing" effect of NTP. Knocking down HO-1 or Nrf2 with the special siRNA also led to elevated ROS level and enhanced NTP-induced cell death. In addition, the c-JUN N-terminal kinase (JNK) signaling pathway was shown to be involved in NTP-induced HO-1 expression. Interestingly, a higher resistance to NTP exposure of A549 cell compared to H1299 and H322 cells was found to be linked to its higher basal level of HO-1 expression. These findings revealed that HO-1 could be considered as a potential target to improve the effect of NTP in cancer therapy. PMID- 30248309 TI - Reply. PMID- 30248310 TI - A Population-Based, Case-Control Evaluation of the Association between Hormonal Contraceptives and Idiopathic Intracranial Hypertension. AB - PURPOSE: To determine if the use of oral contraceptive pills (OCP) and other hormonal contraceptives are associated with a higher incidence of idiopathic intracranial hypertension (IIH). DESIGN: Retrospective, population-based, case control study METHODS: Setting: Female IIH patients evaluated between January 1, 1990 and December 31, 2016 were identified using the Rochester Epidemiology Project (REP), a record-linkage system of medical records for all patient physician encounters among Olmsted County, Minnesota, residents. STUDY POPULATION: Fifty-three female residents of Olmsted County diagnosed with IIH between 15 and 45 years of age. The use of OCPs and other hormonal contraceptives was compared to controls matched for age, sex and body-mass index. INTERVENTIONS/EXPOSURES: Hormonal contraceptives MAIN OUTCOME MEASURE: Odds of developing IIH RESULTS: Of the 53 women diagnosed with IIH between 15 and 45 years of age, 11 (20.8%) had used hormonal contraceptives within <30 days of the date of IIH diagnosis, in contrast to 30 (31.3%) among the control patients. The odds ratio of hormonal contraceptive use and IIH was 0.55 (95% CI: 0.24-1.23, p=0.146). The odds ratio of OCP use was 0.52 (95% CI: 0.20-1.34, p=0.174). CONCLUSIONS: OCP and other hormonal contraceptives were not significantly associated with a higher incidence of IIH, arguing against the need for women with IIH to discontinue their use. PMID- 30248311 TI - Trends in and Predictors of Depression among Participants in the Collaborative Initial Glaucoma Treatment Study (CIGTS). AB - PURPOSE: To characterize longitudinal trends and factors predictive of depressive symptoms following glaucoma diagnosis in Collaborative Initial Glaucoma Treatment Study (CIGTS) participants. DESIGN: Cohort study using follow up data from a clinical trial. METHODS: 607 participants with newly-diagnosed open-angle glaucoma were enrolled at 14 clinical centers in the United States from October 1993 through April 1997, randomized to treatment with medication or surgery, and followed every 6 months through 2004.The 8-item Center for Epidemiologic Studies Depression Scale (CES-D) was administered at baseline and follow-up visits. Three outcome measures were investigated: overall CES-D depression score, presence of mild or worse depression (CES-D score>=7), and number of depressive symptoms endorsed. RESULTS: The average baseline CES-D score was 2.4 (SD=3.8), 12.5% of subjects reported symptomatology associated with mild or worse depression, and 55.3% reported at least one depressive symptom. By one-year post-treatment, depression measures decreased (1.5, 6.7%, and 38.4%, respectively), with modest decreases thereafter. Baseline factors predictive of mild or worse depression included worse vision-related quality of life (VRQOL) (odds ratio, OR=2.41), female sex (OR=1.42), younger age (OR per 10 years younger=1.24), and =1 RACHS-1 case (19,064 operations). 101 hospitals (66%) were located within 25 miles of another hospital. Median annual RACHS-1 case volume was 90 (range 1-797), with 55 hospitals performing <=50 cases. 111 hospitals (73%) performed >=1 high-risk case. Of these, 39 (35%) performed <=10 high-risk cases/year. Overall mortality rate was 3.5% (n=666), with risk-adjusted mortality being lowest at hospitals in highest volume quartile (>=150 cases/year). 25% of patients (n=4012) traveled >100 miles with most traveling to hospitals within the highest volume quartile. 53% of patients (n=8376) bypassed the nearest CHS hospital. Mortality was not associated with travel distance. CONCLUSIONS: We identified more US hospitals performing CHS than has been previously described. Many are small-volume and are in close proximity to one another. Patients are already traveling long distances to hospitals within the highest volume quartile. These data help define the current landscape of CHS and associated considerations regarding regionalization. PMID- 30248323 TI - Cardiopulmonary Bypass Ultrafiltrate Discoloration Following Hydroxocobalamin Administration. PMID- 30248325 TI - Giant Thrombus Formation Originating From the Aortic Annulus. PMID- 30248324 TI - A Giant Blood Cyst of Mitral Valve Resulting in Severe Left Ventricular Outflow Tract Obstruction. PMID- 30248326 TI - Functional Recovery After Lung Resection: A Before and After Prospective Cohort Study of Activity. AB - BACKGROUND: Postoperative recovery is an important measure in thoracic operations. Personal activity monitors can be used to track progress in the preoperative and postoperative settings. This study investigates associations of preoperative activity, lung resection extent, and operative approach with inpatient and outpatient functional recovery as measured by activity monitors. METHODS: In this prospective observational cohort study, patients undergoing lung resection at a single institution wore activity monitors 30 days before through 30 days after operation (between July 2015 and May 2017). Activity was recorded as steps per day, and each patient served as his or her own baseline. Patients were clustered into three activity level groups. Associations among preoperative and postoperative activity, length of stay (LOS), and operative approach were assessed by using generalized regression models with adjustment for patient demographic and clinical characteristics and operative details. RESULTS: Sixty six patients comprised the study cohort and were grouped by average preoperative activity: low, 21 patients (31.8%); moderate, 27 patients (40.9%); and high, 18 patients (27.3%). The mean age was 66.1 +/- 11.6 years; 32 patients (48.5%) were women. Sex, comorbidity, resection extent, and operative approach did not differ among groups. After adjustment for age, comorbidities, resection extent, operative approach, and complications, higher levels of preoperative activity were independently associated with higher postoperative activity in both inpatient and outpatient settings (beta = 1.11, 95% confidence interval [CI]: 1.00 to 1.22, p = 0.04; beta = 1.18, 95% CI: 1.07 to 1.30, p = 0.001) but not LOS. CONCLUSIONS: LOS is not associated with measures of preoperative or postoperative physical activity after adjustment for several factors. However, the association between preoperative activity and postoperative activity, irrespective of age, operative approach, resection extent, and other factors, offers a potential framework for designing recovery trajectory pathways and intervention development in both postoperative inpatient and outpatient settings. PMID- 30248327 TI - Evidence of selective activation of aryl hydrocarbon receptor nongenomic calcium signaling by pyrene. AB - In its classical genomic mode of action, the aryl hydrocarbon receptor (AhR) acts as a ligand activated transcription factor regulating expression of target genes such as CYP1A1 and CYP1B1. Some ligands may also trigger more rapid nongenomic responses through AhR, including calcium signaling (Ca2+). In the present study we observed that pyrene induced a relatively rapid increase in intracellular Ca2+ concentrations ([Ca2+]i) in human microvascular endothelial cells (HMEC-1) and human embryonic kidney cells (HEK293) that was attenuated by AhR-inhibitor treatment and/or transient AhR knockdown by RNAi. In silico molecular docking based on homology models, suggested that pyrene is not able to bind to the human AhR in the agonist conformation. Instead, pyrene docked in the antagonist conformation of the AhR PAS-B binding pocket, although the interaction differed from antagonists such as GNF-351 and CH223191. Accordingly, pyrene did not induce CYP1A1 or CYP1B1, but suppressed CYP1-expression by benzo[a]pyrene (B[a]P) in HMEC-1 cells, confirming that pyrene act as an antagonist of AhR-induced gene expression. Use of pharmacological inhibitors and Ca2+-free medium indicated that the pyrene-induced AhR nongenomic [Ca2+]i increase was initiated by Ca2+-release from intracellular stores followed by a later phase of extracellular Ca2+-influx, consistent with store operated calcium entry (SOCE). These effects was accompanied by an AhR-dependent reduction in ordered membrane lipid domains, as determined by di-4-ANEPPDHQ staining. Addition of cholesterol inhibited both the pyrene-induced [Ca2+]i-increase and alterations in membrane lipid order. In conclusion, we propose that pyrene binds to AhR, act as an antagonist of the canonical genomic AhR/Arnt/CYP1-pathway, reduces ordered membrane lipid domains, and activates AhR nongenomic Ca2+-signaling from intracellular stores. PMID- 30248328 TI - Protease-resistant cell meshworks: An indication of membrane nanotube-based syncytia formation. AB - Cell biology considers most animal tissues as assemblies of "individual" cells that rely on different contact-dependent communication mechanisms, including synapses, gap junctions or - a recent awareness - membrane nano- and microtubes. However, by protease-mediated singularization of dense 2D/ 3D cell cultures and tissue explants, we show here that cell collectives stay connected via a continuous meshwork of F-actin-based membrane tubes, resembling tunneling nanotube (TNT)-based networks observed between dispersed cell cultures. Fusion of respective tubes was accompanied by the ingrowth of microtubules and the invasion of mitochondria and lysosomes. Remarkably, in homology to the plasmodesmata-based plant symplast, we found evidence for expanded, membrane-based syncytia in animal tissues by observing dye transfer among the highly interlinked cells. This approach allows for the first time to visualize and quantify membrane continuity based connections among densely packed cells and to assess their potential physiological and pathological impact closer to the in vivo situation. PMID- 30248329 TI - Analysis of heterogeneous cardiac pacemaker tissue models and traveling wave dynamics. AB - The sinoatrial-node (SAN) is a complex heterogeneous tissue that generates a stable rhythm in healthy hearts, yet a general mechanistic explanation for when and how this tissue remains stable is lacking. Although computational and theoretical analyses could elucidate these phenomena, such methods have rarely been used in realistic (large-dimensional) gap-junction coupled heterogeneous pacemaker tissue models. In this study, we adapt a recent model of pacemaker cells (Severi et al., 2012), incorporating biophysical representations of ion channel and intracellular calcium dynamics, to capture physiological features of a heterogeneous population of pacemaker cells, in particular "center" and "peripheral" cells with distinct intrinsic frequencies and action potential morphology. Large-scale simulations of the SAN tissue, represented by a heterogeneous tissue structure of pacemaker cells, exhibit a rich repertoire of behaviors, including complete synchrony, traveling waves of activity originating from periphery to center, and transient traveling waves originating from the center. We use phase reduction methods that do not require fully simulating the large-scale model to capture these observations. Moreover, the phase reduced models accurately predict key properties of the tissue electrical dynamics, including wave frequencies when synchronization occurs, and wave propagation direction in a variety of tissue models. With the reduced phase models, we analyze the relationship between cell distributions and coupling strengths and the resulting transient dynamics. Further, the reduced phase model predicts parameter regimes of irregular electrical dynamics. Thus, we demonstrate that phase reduced oscillator models applied to realistic pacemaker tissue is a useful tool for investigating the spatial-temporal dynamics of cardiac pacemaker activity. PMID- 30248331 TI - Effects of water soluble perfluorinated pollutants on phospholipids in model soil decomposer membranes. AB - Water soluble perfluorinated compounds (PFCs) as perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA) and their shorter chain homologues are persistent organic pollutants widely distributed in the environment. PFCs accumulate in soils and sediments and because of their toxicity endanger the decomposer organisms. PFCs are toxic to a wide spectrum of soil bacteria and their biocide activity was related with their membrane activity; however, the exact mechanism of PFCs - bacterial membrane interactions is unknown. Therefore, to shed light on these questions we applied phospholipid Langmuir monolayers as simplified models of bacterial membranes and studied their interactions with selected environmentally relevant PFCs. The mechanical properties of the monolayers were characterized by surface pressure-mean molecular area isotherms and the analysis of compression modulus. The effects of PFC on the texture of the model membranes were studied with Brewster angle microscopy, whereas their influence on molecular packing in the 2D crystal lattice was searched by the Grazing Incidence X-ray diffraction technique. The effects of PFCs on the phospholipid polar heargroup conformation were studied by PM-IRRAS spectroscopy, whereas the effectivenes of the incorporation of PFCs into the model membrane was monitored in penetration tests. It turned out that the membranes rich in phosphatidylethanolamine typical to Gram negative bacteria are much PFCs susceptible than the cardiolipin rich membranes imitating Gram positive species. Moreover, the studies indicated that the switch from eight-carbon atom perfluorinated chains to shorter chain homologues is not necessarily environmentally benign as perfluorobutane sulfonate caused also significant structural changes in the model membranes. PMID- 30248330 TI - Characterization of an antigenic serine protease in the Trichinella spiralis adult. AB - Serine proteases have been identified as important molecules that are involved in many parasitic infections, and these molecules have also been suggested to play important roles in Trichinella spiralis infections. In the present study, the antigenic serine protease gene Ts-ADSp-7, which was screened from a cDNA library of Trichinella spiralis Adults at 3 days post-infection (p.i.), was cloned and expressed in Escherichia coli. The encoded protein, Ts-ADSp-7, revealed a potential trypsin-like serine protease domain but lacked substrate banding site at position 227 and protease activity. Transcription could be detected in the Adult and muscle larval stage but not in the newborn larval stage, where no fluorescent signal was detected. Western blot analysis revealed that the 3 days p.i. Adults and muscle larvae could secrete Ts-ADSp-7. Interestingly, strong fluorescent signal of Ts-ADSp-7 could be detected in the nucleoli of the enlarged muscle cell nuclei from 12 to 16 days p.i. and in the beta-stichosomes of the muscle larvae from 16 to 35 days p.i.. The coagulation assay indicated that Ts ADSp-7 could inhibit intrinsic coagulation pathway. Regarding the putatively important function of the serine protease in the helminth infection to hosts, a total of 81 serine proteases were found in the parasite and mainly comprised eight subfamilies. These subfamilies exhibited high similarity to transmembrane serine protease, coagulation factor XI, lipocalin, guanylin, ceropin, kallikrein, and plasminogen. Moreover, stage specificity was detected in several subfamilies. In summary, the putatively inactive serine protease-like protein Ts-ADSp-7 could inhibit blood coagulation, and the protein is located in the enlarged nuclei of nurse cells during capsule formation. Furthermore, members of the serine protease family in the parasite might be important molecules in the parasite-host interaction. PMID- 30248332 TI - Time dependent neuroprotection of dexamethasone in experimental focal cerebral ischemia: The involvement of NF-kappaB pathways. AB - We propose that the neuroprotective effect of glucocorticoid in ischemic damage may be time dependent. The present study was designed to test the proposal and its possible mechanismin cerebral ischemia/reperfusion (I/R) injury model. Reperfusion injury was induced after 120 min of middle cerebral artery occlusion (MCAO) in male Sprague-Dawley rats. Atdifferenttimepoints after MCAO, rats were treated with high dose dexamethasone (10 mg/kg), and neurological deficit and infarct sizes were measured 2 h, 24 h after MCAO. The expression of NF-kappaB target genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL 1beta), were determined by western blot analysis and ELISA. Dexamethasone delivered 30 min (but not 60 min, 120 min) after MCAO markedly decreased the infarct size, improved neurological deficits in I/R injury model. Dexamethasone delivered 30 min (but not 60 min) after MCAO significantly inhibited NF-kappaB p65 expression and phosphorylation, compared with I/R group. The expression of iNOS, COX-2, TNF-alpha and IL-1beta, were also suppressed by dexamethasone delivered 30 min (but not 60 min) after MCAO. The results imply that neuroprotective action of dexamethasone in focal ischemic stroke model may be time dependent and attributed to inhibiting inflammation-related NF-kappaB p65 pathways. PMID- 30248333 TI - Kindlin-1 Regulates Epidermal Growth Factor Receptor Signaling. AB - Kindler syndrome is an autosomal recessive genodermatosis that results from mutations in the FERMT1 gene encoding t kindlin-1. Kindlin-1 localizes to focal adhesion and is known to contribute to the activation of integrin receptors. Most cases of Kindler syndrome show a reduction or complete absence of kindlin-1 in keratinocytes, resulting in defective integrin activation, cell adhesion, and migration. However, roles for kindlin-1 beyond integrin activation remain poorly defined. In this study we show that skin and keratinocytes from Kindler syndrome patients have significantly reduced expression levels of the EGFR, resulting in defective EGF-dependent signaling and cell migration. Mechanistically, we show that kindlin-1 can associate directly with EGFR in vitro and in keratinocytes in an EGF-dependent, integrin-independent manner and that formation of this complex is required for EGF-dependent migration. We further show that kindlin-1 acts to protect EGFR from lysosomal-mediated degradation. This shows a new role for kindlin-1 that has implications for understanding Kindler syndrome disease pathology. PMID- 30248334 TI - A Proposed Complete Methodology to Predict Gravity Flow Obstruction of Pharmaceutical Powders in Drug Product Manufacturing. AB - We present herein a comprehensive methodology to evaluate the risks involved in gravity-driven flow of pharmaceutical powders, including mass flow/funnel flow pattern, arch formation under active stress state (initial discharging) and passive stress state (following initial discharging), and rathole formation. Built on original theories underpinning the hopper design procedure, the methodology was modified to accommodate practices of pharmaceutical powder handling. All data required are generated from conventional ring shear tester. We applied the methodology to evaluate the powder flow risks during drug product manufacturing campaigns, where two powder blends with distinct flow behavior were discharged from a 200-L bin. The predicted results are in agreement with experiments where visual observations were possible, including the flow pattern, arch formation under active stress state, and rathole formation. One notable discovery is that pharmaceutical powders exhibit high risk of arch formation under active stress state, because of the exceeding major principal stress than the passive state. This phenomenon has been so far overlooked and the existing flow function-based classification cannot capture this risk. We propose, through this methodology, that reliable powder flow assessment should consider factors preventing flow (i.e., flow function), as well as factors facilitating flow (i.e., external stress). PMID- 30248335 TI - Compression-Induced Polymorphic Transformation in Tablets: Role of Shear Stress and Development of Mitigation Strategies. AB - Our goals were to evaluate the effects of (i) hydrostatic pressure alone and (ii) its combined effect with shear stress during compaction, on the polymorphic transformation (form C -> A) of a model drug, chlorpropamide. The powder was either subjected to hydrostatic pressure in a pressure vessel or compressed in a tablet press, at pressures ranging from 25 to 150 MPa. The overall extent of phase transformation was determined by powder X-ray diffractometry, whereas 2D-X ray diffractometry enabled quantification of the spatial distribution of phase composition in tablets. Irrespective of the pressure, the extent of transformation following compaction was higher than that because of hydrostatic pressure alone, the difference attributed to the contribution of shear stress experienced during compaction. At a compression pressure of 25 MPa, there was a pronounced gradient in the extent of phase transformation when monitored from radial tablet surface to core. This gradient decreased with increase in compression pressure. Four approaches were attempted to minimize the effect of compression-induced phase transformation: (a) site-specific lubrication, (b) use of a viscoelastic excipient, (c) ceramic-lined die, and (d) use of cavity tablet. The ceramic-lined die coupled with site-specific lubrication was most effective in minimizing the extent of compression-induced phase transformation. PMID- 30248336 TI - Endoglin Mediates Vascular Endothelial Growth Factor-A-Induced Endothelial Cell Activation by Regulating Akt Signaling. AB - In diabetic nephropathy, differential expression of growth factors leads to vascular changes, including endothelial cell activation, monocyte infiltration, and inflammation. Endoglin plays an important role in endothelial function and is also associated with inflammation. In the kidney, vascular endoglin expression is increased in animal models of renal injury, where it contributes to disease severity, possibly by promoting endothelial cell activation and inflammation. Herein, we investigated whether endoglin expression is associated with diabetic nephropathy. In addition, we examined whether reducing endothelial endoglin expression in vitro affects endothelial cell activation and monocyte adhesion and, if so, which intracellular pathways are involved. Finally, we analyzed whether glomerular endoglin expression is correlated with endothelial cell activation in patients with diabetic nephropathy. Endoglin levels were significantly increased in mice with type 1 diabetes compared with control mice. Reducing endoglin expression in cultured endothelial cells significantly impaired the vascular endothelial growth factor-A-induced up-regulation of activation markers and monocyte adhesion. This was mediated by increased phosphorylation of Akt, thereby inhibiting activating transcription factor 2 phosphorylation, which regulates vascular cell adhesion molecule-1 (VCAM1) gene transcription in these cells. Last, endoglin colocalized with VCAM-1 in the glomeruli of diabetic patients, glomerular VCAM-1 expression was significantly increased in these patients, and this increase in VCAM-1 expression was correlated with increased glomerular endoglin expression. Thus, targeting endoglin function may have therapeutic value in patients at risk for diabetic nephropathy. PMID- 30248337 TI - Placental Adaptation to Early-Onset Hypoxic Pregnancy and Mitochondria-Targeted Antioxidant Therapy in a Rodent Model. AB - The placenta responds to adverse environmental conditions by adapting its capacity for substrate transfer to maintain fetal growth and development. Early onset hypoxia effects on placental morphology and activation of the unfolded protein response (UPR) were determined using an established rat model in which fetal growth restriction is minimized. We further established whether maternal treatment with a mitochondria-targeted antioxidant (MitoQ) confers protection during hypoxic pregnancy. Wistar dams were exposed to normoxia (21% O2) or hypoxia (13% to 14% O2) from days 6 to 20 of pregnancy with and without MitoQ treatment (500 MUmol/L in drinking water). On day 20, animals were euthanized and weighed, and the placentas from male fetuses were processed for stereology to assess morphology. UPR activation in additional cohorts of frozen placentas was determined with Western blot analysis. Neither hypoxic pregnancy nor MitoQ treatment affected fetal growth. Hypoxia increased placental volume and the fetal capillary surface area and induced mitochondrial stress as well as the UPR, as evidenced by glucose-regulated protein 78 and activating transcription factor (ATF) 4 protein up-regulation. MitoQ treatment in hypoxic pregnancy increased placental maternal blood space surface area and volume and prevented the activation of mitochondrial stress and the ATF4 pathway. The data suggest that mitochondria-targeted antioxidants may be beneficial in complicated pregnancy via mechanisms protecting against placental stress and enhancing placental perfusion. PMID- 30248339 TI - Hypertension Enhances Advanced Atherosclerosis and Induces Cardiac Death in Watanabe Heritable Hyperlipidemic Rabbits. AB - Hypertension is a major risk factor for the development of atherosclerosis. Cardiovascular risk has been reported to be significantly increased in hyperlipidemic patients with hypertension. However, it is not clear whether hypertension can directly destabilize plaques, thereby enhancing cardiovascular events. To examine whether hypertension enhances the development of atherosclerosis and increases plaque vulnerability, we generated hypertensive Watanabe heritable hyperlipidemic (WHHL) rabbits by surgical removal of one kidney and partial ligation of the other renal artery and compared the nature of aortic and coronary atherosclerosis in hypertensive WHHL rabbits with normotensive WHHL rabbits. All hypertensive WHHL rabbits died from 34 to 56 weeks after surgery, whereas no normotensive WHHL rabbits died. Pathologic examinations revealed that hypertensive WHHL rabbits showed different degrees of myocardial infarction caused by severe coronary stenosis along with myocardial hypertrophy. Furthermore, aortic lesions in hypertensive WHHL rabbits exhibited a higher frequency of intraplaque hemorrhage and vulnerable plaques than those in normotensive WHHL rabbits. These results indicate that hypertension induced by the surgical removal of one kidney and partial ligation of the other renal artery method in WHHL rabbits may not only enhance the development of atherosclerosis but also destabilize the plaques, increasing cardiac death. PMID- 30248338 TI - Angiopoietin-Like Protein 8 Is a Novel Vitamin D Receptor Target Gene Involved in Nonalcoholic Fatty Liver Pathogenesis. AB - Hepatic vitamin D receptor (VDR) expression is increased in patients with nonalcoholic fatty liver (NAFL) and is required for liver steatosis in an NAFL mouse model. However, how hepatocyte VDR is involved in setting up steatosis remains unclear. The authors transduced human hepatocyte-derived cells with an adenoviral vector encoding human VDR and found that angiopoietin-like protein 8 (ANGPTL8) expression was increased upon VDR activation by vitamin D or lithocholic acid. The mRNA levels of hepatic VDR- and vitamin D-related genes [cytochrome P450 (CYP) 2R1, CYP27A1, and CYP3A4] were higher in NAFL patients compared with normal liver subjects. Noteworthy, hepatic ANGPTL8 mRNA and protein levels were elevated in NAFL patients, and its mRNA correlated with VDR mRNA and with the steatosis grade. Moreover, increases in serum conjugated bile acids, including the VDR agonist glycine-lithocholic acid, were observed in NAFL patients. Additionally, free fatty acids and insulin were able to up-regulate both VDR and ANGPTL8 mRNA in human hepatocytes, whereas ANGPTL8 gene knockdown attenuated free fatty acids-induced triglyceride accumulation in these cells. In conclusion, activated VDR up-regulates ANGPTL8 expression, contributing to triglyceride accumulation in human hepatocytes. Moreover, hepatic ANGPTL8 mRNA positively correlates with VDR mRNA content and the grade of steatosis in NAFL patients, suggesting that this novel pathway may play a key role in the pathogenesis of hepatosteatosis. PMID- 30248340 TI - Loss of Prolyl-Hydroxylase 1 Protects against Biliary Fibrosis via Attenuated Activation of Hepatic Stellate Cells. AB - Liver fibrosis, eventually progressing to cirrhosis necessitating liver transplantation, poses a significant clinical problem. Oxygen shortage (hypoxia) and hypoxia-inducible transcription factors (HIFs) have been acknowledged as important drivers of liver fibrosis. The significance of oxygen-sensing HIF prolyl-hydroxylase (PHD) enzymes in this context has, however, remained elusive. In this study, we demonstrate that loss of PHD1 (PHD1-/-) attenuates the development of liver fibrosis in mice subjected to chronic bile duct injury, induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine. This effect was accompanied with reduced recruitment of inflammatory leukocytes and attenuated occurrence of profibrotic myofibroblasts in PHD1-/- livers. Further analyses focused on the significance of PHD1 in the activation of hepatic stellate cells (HSCs), which represent the driving force in liver fibrosis. Primary HSCs isolated from PHD1-/- mice displayed significantly attenuated myofibroblast differentiation and profibrogenic properties compared with HSCs isolated from wild-type mice. Consistently, the expression of various profibrogenic and promitogenic factors was reduced in PHD1-/- HSCs, without alterations in HIF-1alpha protein levels. Of importance, PHD1 protein was expressed in HSCs within human livers, and PHD1 transcript expression was significantly increased with disease severity in hepatic tissue from patients with liver fibrosis. Collectively, these findings indicate that PHD1 deficiency protects against liver fibrosis and that these effects are partly due to attenuated activation of HSCs. PHD1 may represent a therapeutic target to alleviate liver fibrosis. PMID- 30248341 TI - Expression of LRIG1, a Negative Regulator of EGFR, Is Dynamically Altered during Different Stages of Gastric Carcinogenesis. AB - Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a transmembrane protein that antagonizes epidermal growth factor receptor signaling in epithelial tissues. LRIG1 is down-regulated in various epithelial cancers, including bladder, breast, and colorectal cancer, suggesting that it functions as a tumor suppressor. However, its role in gastric carcinogenesis is not well understood. Here, we investigated the changes in LRIG1 expression during the stages of gastric cancer. We used a DMP-777-induced spasmolytic polypeptide-expressing metaplasia mouse model and a tissue array of human gastric cancer lesions. The effects of LRIG1 knockdown were also assessed using the human gastric cancer cell line SNU638 in a xenograft model. LRIG1 expression varied over the course of gastric carcinogenesis, increasing in spasmolytic polypeptide-expressing metaplasia lesions but disappearing in intestinal metaplasia and cancer lesions, and the increase was concurrent with the up-regulation of epidermal growth factor receptor. In addition, LRIG1 knockdown promoted the tumorigenic potential in vitro, which was manifested as increased proliferation, invasiveness, and migration as well as increased tumor size in vivo in the xenograft model. Furthermore, LRIG1 expression was determined to be a positive prognostic biomarker for the survival of gastric cancer patients. Collectively, our findings indicate that LRIG1 expression is closely related wto gastric carcinogenesis and may play a vital role as a tumor suppressor through the modulation of epidermal growth factor receptor activity. PMID- 30248342 TI - Characterization of a Clival Chordoma Xenograft Model Reveals Tumor Genomic Instability. AB - Patient-derived xenografts retain the genotype of the parent tumors more readily than tumor cells maintained in culture. The two previously reported clival chordoma xenografts were derived from recurrent tumors after radiation. To study the genetics of clival chordoma in the absence of prior radiation exposure we established a patient-derived xenograft at primary resection of a clival chordoma. Epicranial grafting of clival chordoma collected during surgery was performed. Tumor growth was established in a nonobese diabetic/severe combined immunodeficiency mouse and tumors have been passaged serially for seven generations. Physaliferous cell architecture was shown in the regenerated tumors, which stained positive for Brachyury, cytokeratin, and S100 protein. The tumors showed bone invasion. Single-nucleotide polymorphism analysis of the tumor xenograft was compared with the parental tumor. Copy number gain of the T gene (brachyury) and heterozygous loss of cyclin dependent kinase inhibitor 2A (CDKN2A) was observed. Heterozygous loss of the tumor-suppressor fragile histidine triad (FHIT) gene also was observed, although protein expression was preserved. Accumulation of copy number losses and gains as well as increased growth rate was observed over three generations. The patient-derived xenograft reproduces the phenotype of clival chordoma. This model can be used in the future to study chordoma biology and to assess novel treatments. PMID- 30248343 TI - Radical prostatectomy after vascular-targeted photodynamic therapy (VTP) with TOOKAD(r) : feasibility, early and intermediate results. AB - INTRODUCTION: and objectives: vascular-targeted photodynamic therapy with TOOKAD(r) (VTP) is a new therapeutic option for localized prostate cancer (PCa) management. The objectives are to assess the feasibility of radical prostatectomy (RP) after VTP and describe functional and oncological outcomes. MATERIAL AND METHODS: we retrospectively included 45 patients who underwent salvage RP after VTP for recurrent PCa in 14 surgical centres in Europe between October 2008 and March 2017.Forty-two RP were performed: 16 robot-assisted, 6 by laparoscopy, and 20 by open surgery. Primary endpoints were morbidity and technical difficulties. Secondary endpoints were early and intermediate post-operative functional and oncologic outcomes. RESULTS: Median operative time was 180 (150-223) minutes. Median blood loss was 200 (155-363) millilitres. According to the surgeons, the surgery was "easy" for 29 patients (69%), "difficult" for 13 patients (31%). Nerve sparing was feasible for 14 patients (33%). Five (12%) post-operative complications were found: 2 Claviens I, 2 Clavien II and 1 Clavien IIIB. There was 13 pT3 (31%), 21 (50%) pT2c. Surgical margins were positive for 13 patients (31%). PSA was undetectable at 6-12 months for 37 patients (88%). Nine patients had complementary radiotherapy. Four patients had a last PSA > 0.2 ng/mL with a median follow-up of 23 (12-36) months. At one year, 27 patients (64%) were completely continent (no pads), 10 (24%) had low incontinence (1 pads). Four patients (11 %) recovered potency without treatment, and 23 (64%) with appropriate treatment. CONCLUSION: Salvage RP after VTP treatment was feasible and safe without difficulties for most of the surgeons. PMID- 30248344 TI - Non-neuropathic Neuropathic Bladder: Is it Really Non-neuropathic? AB - PURPOSE: Hinman Syndrome is a rare disease with urodynamic findings and clinical course that resemble neuropathic bladder and no neuropathic etiology. Diffusion Tensor Imaging (DTI) is a special magnetic resonance imaging (MRI) technique that has recently been used for peripheral nerves but shown to be applicable for evaluation of lumbosacral plexus. Our aim was to evaluate the lumbosacral plexus using DTI, which was not previously performed in Hinman Syndrome. PATIENTS METHODS: Twelve patients who fulfill the criteria of Hinman syndrome with severe bladder dysfunction in urodynamics, renal scars in scintigraphies and no pathology in MRI were included in the study were included. Control group consisted of 12 subjects who required pelvic or spinal MRI for reasons other than spinal abnormalities. MRI was performed with 3.0 Tesla MRI system and 16 channel body coil. Tractography was done to evaluate lumbosacral plexus. Fractional anisotropy (FA) and mean diffusivity (MD) were computed and compared between groups for the right and left plexuses. RESULTS: For patient and control groups, mean FA was 0.24 and 0.35 for right and 0.24 and 0.36 for left plexuses, mean MD was 1.39 and 1.28 both for right and left plexuses respectively (p<0.001 for all). CONCLUSIONS: Our study focusing on the lumbosacral plexus as a possible origin of neuropathy revealed abnormal findings in patients with Hinman syndrome resembling nerve injury studies. It is the first study providing data to show that Hinman syndrome may have a neuropathic etiology. PMID- 30248345 TI - Serum levels of trace elements in children born after assisted reproductive technology. AB - INTRODUCTION: The health and development of newborn children born via assisted reproductive technology (ART), as well as their health in adulthood, have raised great concern. This study was designed to investigate whether ART children have differences in the levels of trace elements compared with naturally conceived children. METHODS: This study included those ART children and controls aged 1 to 12 years assessed with a follow-up protocol. Serum levels of the trace elements zinc, copper, iron, calcium, magnesium and lead were determined and analyzed. RESULTS: There were no significant differences in age, gender or body weight between the ART and control groups. There were no significant differences in the rates of deficiency or excess of trace elements between the two groups. Serum lead levels in children born via ART were significantly higher than those in the controls, whereas the levels of zinc and iron were significantly decreased in the ART group, although these levels were still within the normal ranges. DISCUSSION: These results indicate the need to monitor the blood levels of zinc, iron and lead in ART children aged 1-6 years old. These findings contribute to our understanding on the long-term safety of ART and may facilitate screening for potential diseases related to trace elements. PMID- 30248346 TI - Detection of WNT2B, WIF1 and beta-catenin expression in preeclampsia by placenta tissue microarray. PMID- 30248347 TI - Synergistic activity of imatinib and AR-42 against chronic myeloid leukemia cells mainly through HDAC1 inhibition. AB - AIMS: The aim of this study was to investigate the combinatorial effects of IM and a novel HDAC inhibitor AR-42 on the proliferation, apoptosis, cell cycle arrest, migration and invasion of CML cells, and to explore the underlying mechanisms. MAIN METHODS: We assessed the ability of the pan-HDAC inhibitor AR-42 and IM, to synergistically kill CML cells by survival, apoptosis, cell cycle, migration and invasion assays in vitro. We also assessed the HDAC1 expression by Western blot and real-time PCR. Synergy was calculated using combinatorial indices as determined by CalcuSyn. KEY FINDINGS: We found that Combining AR-42 with IM synergistically inhibited CML cell proliferation, enhanced cell apoptosis, induced cell cycle arrest, and decreased migration and invasion. The expression of HDAC1 in K562R cells was higher than that in K562 cells. AR-42 enhanced IM-induced HDAC1 expression inhibition in K562 and K562R cells. Importantly, HDAC1 overexpression partly reversed the apoptosis, G2/M phase arrest, migration and invasion of K562 cells induced by the combination of IM with AR-42. Moreover, HDAC1 knockdown partly promoted K562R cell apoptosis and G2/M phase arrest, migration and invasion induced by IM in combination with AR 42. SIGNIFICANCE: In conclusion, AR-42 may increase the sensitivity of CML cells to IM and reverse IM resistance by regulating HDAC1 expression. This study provides new insights into the effects of combined therapy using IM and pan-HDAC inhibitor AR-42, paving the way for overcoming IM resistance in clinical practice. PMID- 30248348 TI - HTLV-1 infection-induced motor dysfunction, memory impairment, depression, and brain tissues oxidative damage in female BALB/c mice. AB - AIMS: The HTLV-1 infection is associated with a neuro-inflammatory disease. In the present study, the behavioral consequences and brain oxidative damages were evaluated in HTLV-1-infected BALB/c mice. MATERIAL AND METHODS: 20 female BALB/c mice were divided into two groups comprising control and HTLV-1-infected. The HTLV-1-infected group was inoculated with a 106 MT-2 HTLV-1-infected cell line. Two months later, the behavioral tests were conducted. Finally, oxidative stress was assessed in the cortex and hippocampus tissues. KEY FINDINGS: In the HTLV-1 infected group, running time and latency to fall, travel distance and time spent in the peripheral zone, total crossing number and total traveled distance in open field test, the latency of entrance into the dark compartment in the passive avoidance test, the new object exploration percentage, and discrimination ratio were significantly lower than in the control group. The immobility time, time spent in the dark compartment in passive avoidance test, and total exploration time significantly increased in the HTLV-1-infected group compared to the control group. In the cortical tissue of the HTLV-1 group, the malondialdehyde levels were elevated while the total thiol levels decreased in comparison to the control group. The activity of superoxide dismutase in the cortical and hippocampal tissues, and catalase activity in cortical tissue significantly decreased in the HTLV-1 group in comparison to the control group. SIGNIFICANCE: The HTLV-1 infection seems to induce depression-like behavior, motor dysfunction, disruption in working and fear memory and also oxidative stress in the cortex and hippocampus. PMID- 30248349 TI - p-Coumaric acid as a prophylactic measure against normobaric hypoxia induced pulmonary edema in mice. AB - AIMS: Previous studies indicate that the anti-hypoxia effects of Tibetan Turnip (Brassica rapa ssp. rapa) were closely related to its characteristic components being p-coumaric acid (CA) and p-coumaric acid-beta-d-glucopyranoside (CAG). Since CAG would be converted to CA in vivo, this study aims to further examine the efficacy and mechanism of CA against pulmonary edema induced by normobaric hypoxia. MAIN METHODS: Male ICR mice were assigned to the normoxia group and several hypoxia groups, given sterile water, CA or dexamethasone orally, once daily for four consecutive days. One hour after the final gavage, mice in the above hypoxia groups were put into the normobaric hypoxia chamber (9.5% O2) for 24 h while mice in normoxia group remained outside the chamber. After hypoxia exposure, lung water content (LWC), pulmonary vascular permeability, the protein content of bronchoalveolar lavage fluid (BALF), plasma total nitrate/nitrite (NOx) and endothelin-1 (ET-1) content, histological and ultra-microstructure analyses were performed. Expression of occludin was assayed by immunohistochemistry. KEY FINDINGS: In a hypoxic environment of 9.5% O2, mice treated with 100 mg/kg body wt CA had significantly lower LWC and BALF protein content than mice in the hypoxia vehicle group. Meanwhile, mice in CA group showed intact lung blood-gas-barrier, increased levels of plasma total NO, decreased levels of plasma ET-1 and upregulation of occludin expression. SIGNIFICANCE: CA exerts preventive effects against normobaric hypoxic pulmonary edema in mice, its mechanisms involved improving the integrity of the lung barrier, inhibiting oxidative stress and inflammation. PMID- 30248350 TI - Celosia argentea L. (Amaranthaceae) a vasodilator species from the Brazilian Cerrado - An ethnopharmacological report. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Celosia argentea L. (Amaranthaceae), popularly known as "crista de galo", is used in folk medicine due to its diuretic and hypotensive effects. However, there are no reports in the literature regarding its pharmacological effects on the cardiovascular system as well as no data proving the safety of this species. AIM: To perform a detailed ethnopharmacological investigation of the ethanol soluble fraction from C. argentea (ESCA) using male and female Wistar rats. MATERIAL AND METHODS: Firstly, a morpho-anatomical characterization was performed to determine the quality control parameters for the identification of the species under investigation. Then, the ethanol extract was obtained and chemically characterized by LC-DAD-MS. Furthermore, an oral acute toxicity study was performed in female Wistar rats. Finally, the possible diuretic and hypotensive effects of three different doses of ESCA (30, 100 and 300 mg/kg) were evaluated in male Wistar rats. Besides, the vasodilatory response of ESCA in mesenteric vascular beds (MVBs) and its involvement with nitric oxide/cGMP and prostaglandin/cAMP pathways as well as potassium channels were evaluated. RESULTS: The main secondary metabolites present in ESCA were phenolic compounds, megastigmanes and triterpenoid saponins. ESCA caused no toxic effects in female rats nor increased urinary excretion in male rats after acute administration. However, ESCA significantly increased the renal elimination of potassium and chloride, especially at the end of 24 h after administration. Intermediary dose (100 mg/kg) of ESCA was able to promote significant acute hypotension and bradycardia. Moreover, its cardiovascular effects appear to be involved with the voltage-dependent K+ channels activation in MVBs. CONCLUSION: This study has brought new scientific evidence of preclinical efficacy of C. argentea as a hypotensive agent in normotensive rats. Apparently, these effects are involved with the activation of the voltage sensitive K+ channels contributing to the reduction of peripheral vascular resistance and cardiac output. PMID- 30248351 TI - Surgical Outcomes of Three vs Four Arm Robotic Partial Nephrectomy: Is the Fourth Arm Necessary? AB - OBJECTIVE: To compare the cost, efficacy, and safety of 3-arm versus 4-arm technique in robotic partial nephrectomy (RPN). Surgeons may either elect to utilize three vs four robotic instruments depending on preference. The purpose of this study is to compare the outcomes between the two techniques. METHODS: RPNs from June 2016 to August 2017 were retrospectively reviewed. Tumor features, surgical parameters, and operative outcomes were evaluated. The number of arms used was determined. Statistical analysis was performed with the Student's t test, chi-squared, and Mann-Whitney test. RESULTS: A total of 61 consecutive 3 arm RPNs and 59 consecutive 4-arm RPNs were evaluated. Mean tumor diameter and median nephrometry score were 3.4 cm (+/- 1.1 SD) and 7 (6-8 IQR) for the 3-arm group and 3.3 cm (+/-1.2 SD) and 6 (5-8 IQR) for the 4-arm group, respectively (size: p = 0.7, nephrometry: p = 0.07). Hospital length of stay, operative time, estimated blood loss, complication rate, blood transfusion rate, and readmission rate all demonstrated no statistically significant difference between 3-arm and 4 arm groups (p >0.05). Mean ischemia time was shorter by 5.1 minutes in the 4-arm group (p = 0.02). Rate of margin positivity was higher in the 4-arm group (0% vs 10%, p = 0.03). CONCLUSION: RPN can be safely and effectively completed with 3 robotic arms. While there was increased ischemia time, the difference was small and likely not of clinical significance. The routine addition of the fourth robotic arm in RPN is not necessary. PMID- 30248352 TI - The History of Urology at the Minneapolis Veterans Affairs Health Care System. AB - OBJECTIVE: The Section of Urology at the Minneapolis Veteran's Affairs (VA) Medical Center has a long history of contributions to Urology including the Gleason Score, Fuhrman Grading system, testicular tumor marker development and the birth of Endourology. The objective of this manuscript is to compile and present the Urologic history of the Minneapolis VA. METHODS: The Urologic literature and institutional records originating from the Minneapolis VA Medical Center from 1946-2017 were reviewed and presented herein. RESULTS: The Minneapolis VA Health Care System originated in 1921 and currently employs 5 Urologist who serve over 16,000 veterans per year. Historic achievements from the Minneapolis VA Section of Urology include the development of the Veteran's Affairs Cooperative Research Group (VACURG) which was instrumental to development of the Gleason grading system for prostate cancer in 1965. Additional urologic oncology achievements originating from the Minneapolis VA Section of Urology included the development of the diagnostic utility of tumor markers in testis cancer in 1976 and The Fuhrman Grading System in 1982. Perhaps the greatest contribution to the field of Urology was the birth of Endourology at the Minneapolis VA in the late 1970s under the direction of Dr. Paul Lange. Currently the Minneapolis VA is a premier center for Evidence Based Urology by housing Cochrane Urology and the U.S. Grading of Recommendations Assessment, Development and Evaluation network (US GRADE). CONCLUSION: Since 1946, the section of Urology at the Minneapolis VA has contributed basic science, clinical technique and evidence based medicine to the field of Urology while providing care to the nation's veterans. PMID- 30248353 TI - Malaria systems immunology: Plasmodium vivax induces tolerance during primary infection through dysregulation of neutrophils and dendritic cells. AB - OBJECTIVES: To dissect the transcriptional networks underpinning immune cells responses during primary Plasmodium vivax infection of healthy human adults. METHODS: We conducted network co-expression analysis of next-generation RNA sequencing data from whole blood from P. vivax and P. falciparum controlled human malaria infection (CHMI) of healthy naive and malaria-exposed volunteers. Single cell transcription signatures were used to deconvolute the bulk RNA-Seq data into cell-specific signals. RESULTS: Initial exposure to P. vivax induced activation of innate immunity, including efficient antigen presentation and complement activation. However, this effect was accompanied by strong immunosuppression mediated by dendritic cells via the induction of Indoleamine 2,3-Dioxygenase 1(IDO1) and Lymphocyte Activation Gene 3 (LAG3). Additionally, P. vivax induced depletion of neutrophil populations associated with down regulation of 3G-protein coupled receptors, CRXCR1, CXCR2 and CSF3R. Accordingly, in malaria-exposed volunteers the inflammatory response was attenuated, with a decreased class II antigen presentation in dendritic cells. While the immunosuppressive signalling was maintained between plasmodium species, response to P. falciparum was significantly more immunogenic. CONCLUSIONS: In silico analyses suggest that primary infection with P. vivax induces potent immunosuppression mediated by dendritic cells, conditioning subsequent anti-malarial immune responses. Targeting immune evasion mechanisms could be an effective alternative for improving vaccine efficacy. PMID- 30248354 TI - Expression and function of lncRNA MALAT-1 in the embryonic development of zebrafish. AB - Long non-coding RNAs (lncRNAs) are RNA molecules with a transcript length of >200 nt which do not encode proteins, however, they have important functions in the form of RNA at transcriptional level, post-transcriptional level, and epigenetics. MALAT-1 is the first discovered lncRNA in non-small cell lung cancer and its orthologs have been found in zebrafish in the recent years. The present study aimed to determine the expression and possible function of MALAT-1 in the embryonic development of zebrafish. The results of qPCR or in situ hybridization showed that MALAT-1 was dynamically expressed in zebrafish embryonic development and it was widely expressed in brain, eye, heart, and muscle of adult fish. By morpholino knockdown of MALAT-1, zebrafish embryos were found to have smaller body curvature, smaller eyes, enlarged pericardium, and reduced pigmentation. In particular, after morpholino knockdown of MALAT-1, the morphologically defective otic capsule was found to be smaller than the control fish. These results suggest that MALAT-1 may play a key role in the embryonic nervous system development of zebrafish. In addition, we also determined the expressions of seven development related genes (Scyl1, egr1, oc90, vsx1, nkx2.5, vmhc, and gata4) after MALAT-1 knockdown and found that four genes egr1, nkx2.5, gata4, and vmhc were up regulated, suggesting a potential regulatory role of MALAT-1 on these development related genes. PMID- 30248355 TI - Proline-rich protein 11 silencing inhibits hepatocellular carcinoma growth and epithelial-mesenchymal transition through beta-catenin signaling. AB - Proline-rich protein 11 (PRR11) has been shown to play an critical roles in the development of cancer. However, the clinical significance and the biological role of PRR11 in hepatocellular carcinoma (HCC) remains unknown. The present study aimed to investigate the expression pattern, prognostic value and the biological role of PRR11 in HCC. PRR11 expression in 80 HCC surgical specimens was examined, and its clinical significance was analyzed. The role of PRR11 in cell proliferation, colony formation, migration and invasion were also determined. The results showed that PRR11 mRNA was significantly up-regulated in 56.25% (45/80) HCC from that in matched adjacent non-tumor tissues. High PRR11 was correlated with tumor size (P = 0.01) and TNM stage (P = 0.006). Patients with higher PRR11 expression had poor overall survival time (P < 0.001). Furthermore, PRR11 silencing obviously inhibited cell proliferation, colony formation, as well as cell migration and invasion of HCC cell lines in vitro. Mechanistically, knockdown of PRR11 significantly decreased the expression of beta-catenin, cyclinD1, c-myc and N-cadherin in HCC cell lines. Additionally, the inhibitory effects of PRR11 silencing on cell migration was significantly enhanced by beta catenin inhibition. PRRl1 mRNA expression was found positively correlated with beta-catenin (R = 0.5472, P ? 0.0001), c-myc (R = 0.5527, P ? 0.0001) and cyclinD1 (R = 0.3948, P = 0.0003) in HCC tissues. Collectively, our data demonstrate that PRR11 plays an oncogenic role in HCC progression, through activating the Wnt/beta-catenin signaling pathway, and may represent a valuable prognostic marker and therapeutic target for HCC. PMID- 30248356 TI - Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease that is known to be, at least in part, genetically determined. Mutations in caspase recruitment domain-containing protein 14 (CARD14) have been shown to result in various forms of psoriasis and related disorders. OBJECTIVE: We aimed to identify rare DNA variants conferring a significant risk for AD through genetic and functional studies in a cohort of patients affected with severe AD. METHODS: Whole-exome and direct gene sequencing, immunohistochemistry, real-time PCR, ELISA, and functional assays in human keratinocytes were used. RESULTS: In a cohort of patients referred with severe AD, DNA sequencing revealed in 4 patients 2 rare heterozygous missense mutations in the gene encoding CARD14, a major regulator of nuclear factor kappaB (NF-kappaB). A dual luciferase reporter assay demonstrated that both mutations exert a dominant loss-of-function effect and result in decreased NF-kappaB signaling. Accordingly, immunohistochemistry staining showed decreased expression of CARD14 in patients' skin, as well as decreased levels of activated p65, a surrogate marker for NF kappaB activity. CARD14-deficient or mutant-expressing keratinocytes displayed abnormal secretion of key mediators of innate immunity. CONCLUSIONS: Although dominant gain-of-function mutations in CARD14 are associated with psoriasis and related diseases, loss-of-function mutations in the same gene are associated with a severe variant of AD. PMID- 30248357 TI - Modulation of age related protein expression changes by gelam honey in cardiac mitochondrial rats. AB - Aging is characterized by progressive decline in biochemical and physiological functions. According to the free radical theory of aging, aging results from oxidative damage due to the accumulation of excess reactive oxygen species (ROS). Mitochondria are the main source of ROS production and are also the main target for ROS. Therefore, a diet high in antioxidant such as honey is potentially able to protect the body from ROS and oxidative damage. Gelam honey is higher in flavonoid content and phenolic compounds compared to other local honey. This study was conducted to determine the effects of gelam honey on age related protein expression changes in cardiac mitochondrial rat. A total of 24 Sprague Dawley male rats were divided into two groups: the young group (2 months old), and aged group (19 months old). Each group were then subdivided into two groups: control group (force-fed with distilled water), and treatment group (force-fed with gelam honey, 2.5 g/kg), and were treated for 8 months. Comparative proteomic analysis of mitochondria from cardiac tissue was then performed by high performance mass spectrometry (Q-TOF LCMS/MS) followed by validation of selected proteins by Western blotting. Proteins were identified using Spectrum Mill software and were subjected to stringent statistical analysis. A total of 286 proteins were identified in the young control group (YC) and 241 proteins were identified in the young gelam group (YG). In the aged group, a total of 243 proteins were identified in control group (OC), and 271 proteins in gelam group (OG). Comparative proteome profiling identified 69 proteins with different abundance (p < 0.05) in OC when compared to YC, and also in YG when compared to YC. On the other hand, 55 proteins were found to be different in abundance when comparing OG with OC. In the aged group, gelam honey supplementation affected the relative abundance of 52 proteins with most of these proteins showing a decrease in the control group. Bioinformatics analysis showed that the majority of the affected proteins were involved in the respiratory chain (OXPHOS) which play an important role in maintaining mitochondrial function. PMID- 30248358 TI - Grape skin extract improves muscle function and extends lifespan of a Drosophila model of Parkinson's disease through activation of mitophagy. AB - Recent studies suggest that moderate red wine consumption may confer several health benefits, including protection against heart disease, certain cancers and multiple age-related neurological diseases such as Alzheimer's disease. These health benefits are assumed to come from a compound from grape skin called resveratrol, which has been proposed to be a pro-longevity agent. Whether resveratrol accounts for all the health benefits of grape-derived nutrients and the molecular and cellular mechanisms underlying the beneficial effects of such nutrients are not well understood. Here we investigated the effect of supplementing grape skin extract (GSE) left from red wine-production process to the daily food intake of a Drosophila melanogaster model of Parkinson's disease (PD) associated with PTEN-induced kinase 1 (PINK1) loss-of-function. Consumption of GSE resulted in rescue of mitochondrial morphological defects, improvement of indirect flight muscle function and health-span, and prolonged lifespan of the PINK1 mutant flies. Further biochemical and genetic studies revealed a link between activation of mitophagy and the beneficial effects of GSE. Our results indicate that GSE can promote autophagy activation, preserve mitochondria function, and protect against PD pathogenesis, and that the beneficial effect of GSE in mitophagy activation is not accounted for by resveratrol alone. PMID- 30248359 TI - Exploring the immune response, tolerance and resistance in proliferative kidney disease of salmonids. AB - Proliferative kidney disease (PKD) of salmonids is a disease of economic and environmental concern caused by the myxozoan parasite Tetracapsuloides bryosalmonae. Finer details of the immune repertoire during T. bryosalmonae infection have been elucidated in rainbow trout (Oncorhynchus mykiss). In contrast, there remain many unanswered questions regarding the immune response of the wild fish host in Europe, the brown trout (Salmo trutta) to this parasite. The first aim of this study is to examine the brown trout immune response to T. bryosalmonae and compare it with the published information on rainbow trout as two species that have undergone a different coevolution with the parasite. According to ecoimmunology terminology, infected organisms may manage infection by reducing the damage caused by parasites (tolerance) or by limiting parasite burden (resistance). The second aim of this study is to investigate tolerance/resistance patterns of these species during PKD infection. Our results suggest subtle differences in sequential aspects of the immune response and of immune genes that correlate with parasite intensity for the brown trout, in contrast to rainbow trout, in terms of the B cell response and Th-like interplay that may be linked to PKD pathogenesis. These differences in the immune response also correlate with species-specific differences in tolerance/resistance patterns, in that brown trout had increased tolerance but rainbow trout had greater resistance to infection. The variance in tolerance/resistance investment resulted in a different evolutionary outcome for each host-parasite interaction. A greater exploration of these concepts and an association of immune mechanisms could open an additional gateway for interpreting fish host-parasite interactions. PMID- 30248360 TI - Molecular identification and expression analysis of TAB1 from orange-spotted grouper (Epinephelus coioides). AB - Transforming growth factor-beta activated kinase 1 (TAK1) is a crucial signal transducer in multiple signaling pathways. TAK1 binds TAB1, TAB2, and TAB3, which act as activators and adaptors that specifically regulate the activation of TAK1. To date, the role of TABs is largely unknown in fish. In the present study, a TAB1 cDNA sequence was identified in grouper (Epinephelus coioides), and designated EcTAB1. The full-length open reading frame of EcTAB1 is 1, 521 bp; it encodes 506 amino acids that contains an N-terminal PP2C domain. Many important functional sites in mammalian TAB1 were conserved in TAB1 from grouper and from other fish. Multiple sequence alignment showed that EcTAB1 protein shared high sequence identity with TAB1 of other fish, especially with Stegastes partitus (95% identity). TAB1 was clustered into the same subgroup with other fish TAB1 in the phylogenetic tree. Tissue expression analysis indicated that TAB1 was widely distributed in different tissues. After infection with Cryptocaryon irritans, EcTAB1 expression was up-regulated in the infection site (gills). Besides, EcTAB1 was expressed throughout the grouper spleen (GS) cells and significantly enhanced the activation of NF-kappaB. PMID- 30248361 TI - Novel targets for delaying aging: The importance of the liver and advances in drug delivery. AB - Age-related changes in liver function have a significant impact on systemic aging and susceptibility to age-related diseases. Nutrient sensing pathways have emerged as important targets for the development of drugs that delay aging and the onset age-related diseases. This supports a central role for the hepatic regulation of metabolism in the association between nutrition and aging. Recently, a role for liver sinusoidal endothelial cells (LSECs) in the relationship between aging and metabolism has also been proposed. Age-related loss of fenestrations within LSECs impairs the transfer of substrates (such as lipoproteins and insulin) between sinusoidal blood and hepatocytes, resulting in post-prandial hyperlipidemia and insulin resistance. Targeted drug delivery methods such as nanoparticles and quantum dots will facilitate the direct delivery of drugs that regulate fenestrations in LSECs, providing an innovative approach to ameliorating age-related diseases and increasing healthspan. PMID- 30248362 TI - Efficient transgene insertion in a pseudorabies virus vector by CRISPR/Cas9 and marker rescue-enforced recombination. AB - For development of vectored vaccines against porcine pathogens the genome of the pseudorabies virus vaccine strain Bartha (PrV-Ba) was previously cloned as an infectious bacterial artificial chromosome (BAC), containing the bacterial replicon and a reporter gene cassette encoding enhanced green fluorescent protein (EGFP) at the nonessential glycoprotein G locus. To facilitate substitution of this insertion, this BAC was now modified by deletion of the adjacent promoter and initiation codon of the essential glycoprotein D (gD) gene of PrV-Ba. Furthermore, rabbit kidney (RK13) cells stably expressing Cas9 nuclease and an EGFP gene-specific guide RNA were prepared to induce site specific cleavage of the BAC DNA. After co-transfection of these cells with the modified BAC and recombination plasmids containing expression cassettes for new transgenes flanked by PrV DNA sequences including the intact 5'-end of the gD gene, >95% of the recombinants exhibited the desired gene substitutions, while no EGFP-expressing progeny virus was detectable. This approach was used for insertion and expression of the open reading frames E199L, CP204L (p30) and KP177R (p22) of African swine fever virus. The studies revealed that codon adaptation significantly enhanced expression of E199L, and that the chimeric CAG promoter increased transgene expression compared to cytomegalovirus immediate-early promoters. PMID- 30248363 TI - An IncX1 plasmid isolated from Salmonella enterica subsp. enterica serovar Pullorum carrying blaTEM-1B, sul2, arsenic resistant operons. AB - We have identified an IncX1 plasmid named pQJDSal1 from Salmonella enterica subsp. enterica serovar Pullorum (S. Pullorum). The plasmid is 67,685 bp in size and has 72 putative genes. pQJDSal1 harbors a conserved IncX1-type backbone with predicted regions for conjugation, replication and partitioning, as well as a toxin/antitoxin plasmid addiction system. Two regions (A and B) that have not been previously reported in IncX1 plasmids are inserted into the backbone. Region A (10.7 kb), inserted between parA and taxD, consists of a new Tn6168-like transposon containing an arsenic resistant operon arsB2CHR and sulfonamide resistance gene sul2. Region B contains another arsenic resistant operon arsADHR, resistance gene blaTEM-1B and three transposable elements. Conjugation experiments showed that pQJDSal1 could transfer from S. Pullorum to Escherichia coli (E. coli) J53. Statistical analysis of 70 sequenced IncX1 plasmids revealed that IncX1 plasmids harbored various antibiotic resistance genes. The results highlight the importance of IncX1 plasmids in disseminating antibiotic resistance genes. PMID- 30248364 TI - The impact of motor impairment on the processing of sensory information. AB - Sensorimotor adaptation is driven by mismatch errors between desired movements and actual movement outcomes. A mismatch error can be minimized by adjusting movements or by altering the interpretation of sensory information. While the effect of mismatch errors on the motor system has received much attention, the contribution of somatosensory feedback, particularly the sensory-motor interplay in the process of adaptation, remains poorly understood. Our study analyzes the impact of peripheral deefferentation on the plasticity of the brain networks responsible for sensory-motor adaptation, focusing particularly on changes in the processing of somatosensory information. For this aim, task-based and resting state functional MRI was performed on 24 patients in the acute state of a left sided idiopathic peripheral facial nerve palsy. The functional connectivity of cortical and subcortical networks was analyzed and compared to a healthy control group. We found a strong involvement of the somatosensory system and the thalamus in the adaptation process following an acute peripheral deefferentation. The investigated network shows the principal pattern of a reduced connectivity between cortical areas, while the connectivity to subcortical areas (the basal ganglia and the thalamus) is increased. We suggest that the increased connectivity between the subcortical and cortical structures indicates an active sensory-motor adaptation process. We further hypothesize that the decreased functional connectivity at the cortical level reflects an unsuccessful sensorimotor adaptation process due to the inability to solve the somatosensory motor mismatch. These results extend our understanding of the somatosensory-motor interaction in response to a mismatch signal and highlight the importance of the thalamus in this process. PMID- 30248365 TI - Effects of taurine acute intake on cortical excitability and post-exercise facilitation: A TMS study. AB - Taurine (TAU) is one of the most abundant amino acids in the brain. It has many important physiological functions. The effects of TAU supplementation on brain function need to be further characterized in humans. The purpose of this study was to investigate whether a single dose of Taurine (TAU) intake would modulate corticospinal excitability and post-exercise facilitation (PEF) of the motor evoked potentials (MEP). PMID- 30248366 TI - Chitotriosidase enhances TGFbeta-Smad signaling and uptake of beta-amyloid in N9 microglia. AB - TGFbeta-Smad signaling is involved in the modulation of beta-amyloid (Abeta) clearance in microglia. This signaling is impaired in the brain of Alzheimer's disease (AD). Chitotriosidase (CHIT1) is elevated in the cerebrospinal fluid and peripheral blood of AD patients, and has been reported to augment TGFbeta signaling in fibroblast and T cells. In this study, we investigated the role of CHIT1 in TGFbeta-Smad signaling and Abeta phagocytosis in N9 microglia. We found that CHIT1 significantly enhanced TGFbeta1-induced expression of TbetaRI (TGFbeta receptor I) and activation of Smad signaling. CHIT1 did not affect Abeta uptake in microglia by itself, but did enhance TGFbeta1-induced phagocytosis of Abeta, which was blocked by pretreatment with SB431542 (TbetaRI inhibitor). These results indicate that CHIT1 may play a protective role in Abeta clearance by enhancing TGFbeta signaling in microglia. PMID- 30248367 TI - The effects of array structure and secondary cognitive task demand on processes of visual search. AB - Many aspects of our everyday behaviour require that we search for objects. However, in real situations search is often conducted while internal and external factors compete for our attention resources. Cognitive distraction interferes with our ability to search for targets, increasing search times. Here we consider whether effects of cognitive distraction interfere differentially with three distinct phases of search: initiating search, overtly scanning through items in the display, and verifying that the object is indeed the target of search once it has been fixated. Furthermore, we consider whether strategic components of visual search that emerge when searching items organized into structured arrays are susceptible to cognitive distraction or not. We used Gilchrist & Harvey's (2006) structured and unstructured visual search paradigm with the addition of Savage, Potter, and Tatler's (2013) secondary puzzle task. Cognitive load influenced two phases of search: 1) scanning times and 2) verification times. Under high load, fixation durations were longer and re-fixations of distracters were more common. In terms of scanning strategy, we replicated Gilchrist and Harvey's (2006) findings of more systematic search for structured arrays than unstructured ones. We also found an effect of cognitive load on this aspect of search but only in structured arrays. Our findings suggest that our eyes, by default, produce an autonomous scanning pattern that is modulated but not completely eliminated by secondary cognitive load. PMID- 30248368 TI - A preference for minimal deformation constrains the perceived depth of a stereokinetic stimulus. AB - The current study examined whether the 'slow and smooth' hypothesis (Hildreth, 1984; Yuille & Grzywacz, 1989; Weiss, Simoncelli, & Adelson, 2002) could be extended to explaining a three-dimensional (3D) stereokinetic percept by specifying the smoothness term as a preference for minimal deformation. Stereokinetic stimuli are two-dimensional (2D) configurations that lead to 3D percepts when rotated in the image plane. In particular, a rotating ellipse with an eccentric dot gives rise to the percept of a cone with a defined height. In the current study, the spatial relationship between the ellipse and dot varied across trials in terms of the dot's relative location and the aspect ratio of the ellipse. During each trial, participants (n = 8) adjusted the length of a 2D bar centered along the minor axis of the ellipse to indicate their perceived height of the cone. Upon rotation, the 2D bar was perceived to be perpendicular to the circular base of the cone. Our results were qualitatively and quantitatively consistent with the traditional hypothesis of minimum object change (Jansson & Johansson, 1973), which is also similar to the maximal rigidity assumption (Ullman, 1979). As the dot shifted from the major axis towards the minor axis of the ellipse, observers consistently reported an increasingly taller cone. The results illustrate the tendency of observers to perceive the apex of the cone at a height that minimized its 3D distance to the surface normal at the center of the circular base of the cone to reduce the relative motion between the dot and the base of the cone. The current study provides empirical evidence suggesting that, when presented with an ambiguous stereokinetic stimulus, the visual system prefers the interpretation that corresponds to a 3D percept that is slowest and maximally rigid. PMID- 30248369 TI - Epithelial folding in the morphogenesis of the colonial marine hydrozoan, Dynamena pumila. AB - Epithelial folding (EF) is a fundamental morphogenetic process that can be observed in the development of many organisms ranging from metazoans to green algae. Being early branching metazoans, cnidarians represent the best models to study evolutionarily conserved morphogenetic processes, including EF. Hydrozoa is the most evolutionary advanced group of the phylum Cnidaria. All colonial hydrozoans grow continuously, changing the shape of their colonies and spreading over the substrate with the help of elongating stolons. Owing to high diversity of colony architecture, they are ideal objects for comparative and evolutionary morphology. In the hydrozoan Dynamena pumila, the growth of the colony proceeds via a variety of morphogenetic processes. Our work is focused on the formation of the anchoring disc of the stolon, which is accompanied by inward-folding morphogenesis of the ectodermal layer. Successive stages of anchoring disc development were described with light, confocal transmission electron microscopy. We have shown that EF in Dynamena is associated with accumulation of F-actin in the constricting apical domains of forming bottle cells located at the bottom of the emerging fold. In addition, the nuclei of these cells are displaced to the basal domains. Taken together, these features may indicate that EF in Dynamena proceeds as an active invagination, although this process has never been described in the development of hydrozoans. Apparently, development of the anchoring disc can be viewed as a reliable and versatile model system for studying the cell-shape-change-driven epithelial sheet morphogenesis, which can be easily observed and analysed. PMID- 30248370 TI - TbUTP10, a protein involved in early stages of pre-18S rRNA processing in Trypanosoma brucei. AB - Ribosome biosynthesis, best studied in opisthokonts, is a highly complex process involving numerous protein and RNA factors. Yet, very little is known about the early stages of pre-18S rRNA processing even in these model organisms, let alone the conservation of this mechanism in other eukaryotes. Here we extend our knowledge of this process by identifying and characterizing the essential protein TbUTP10, a homolog of yeast U3 small nucleolar RNA-associated protein 10 - UTP10 (HEATR1 in human), in the excavate parasitic protist Trypanosoma brucei. We show that TbUTP10 localizes to the nucleolus and that its ablation by RNAi knock-down in two different T. brucei life cycle stages results in similar phenotypes: a disruption of pre-18S rRNA processing, exemplified by the accumulation of rRNA precursors, a reduction of mature 18S rRNA, and also a decrease in the level of U3 snoRNA. Moreover, polysome profiles of the RNAi-induced knock-down cells show a complete disappearance of the 40S ribosomal subunit, and a prominent accumulation of the 60S large ribosomal subunit, reflecting impaired ribosome assembly. Thus, TbUTP10 is an important protein in the processing of 18S rRNA. PMID- 30248371 TI - Vagino-rectal colonization and maternal-neonatal transmission of Enterobacteriaceae producing extended-spectrum beta-lactamases or carbapenemases: a cross-sectional study. AB - This study sought to determine the prevalence and risk factors for colonization with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) and carbapenemase-producing Enterobacteriaceae (CPE) in 815 mothers and 800 newborns using a cross-sectional design; 59 women and 13 neonates were colonized by ESBL-E (prevalence (95% confidence interval): 6.7% (5.2-8.7) and 1.6 (0.7-2.5), respectively). No CPE were found. The most frequent ESBL-E were CTX-M-14 and SHV 12. Vertical transmission occurred in 14% of colonized mothers. The risk factors for colonization were, in mothers: complications in previous pregnancies, more than one urinary tract infection, non-Caucasian ethnicity, and frequently having the main meal outside home; in newborns: colonized mother and vaginal delivery. PMID- 30248372 TI - Targeting the androgen receptor (AR) with AR degradation enhancer ASC-J9 led to increase docetaxel sensitivity via suppressing the p21 expression. AB - Chemotherapy with docetaxel remains as the effective therapy to suppress castration resistant prostate cancer (CRPC) in some patients. However, most chemotherapy with docetaxel eventually fails with the development of docetaxel resistance after 18-weeks of treatment. Here we found docetaxel treatment might have adverse effect of increasing the androgen receptor (AR) protein level in the CRPC cells, and combined docetaxel with anti-AR therapy using AR-shRNA or the AR degradation enhancer ASC-J9 may increase docetaxel sensitivity to better suppress the CRPC cell growth. Mechanism dissection found docetaxel might have adverse effect of increasing the AR protein stability via suppressing the AR ubiquitination due to the increased AR phosphorylation. The consequence of such increased AR protein may then lead to increase p21 expression via transcriptional regulation. Preclinical studies with in vitro cell line also demonstrated that targeting AR with ASC-J9 led to suppressing the AR-increased p21 expression to improve the docetaxel sensitivity in the CRPC cells that already developed docetaxel resistance. Together, these results suggest that a combined therapy of docetaxel and anti-AR with small molecule of ASC-J9 is a novel therapy to better suppress CRPC in patients that already developed docetaxel resistance. PMID- 30248373 TI - Lethal influenza A virus preferentially activates TLR3 and triggers a severe inflammatory response. AB - The "cytokine storm" and excessive inflammation triggered by lethal avian influenza virus (IAV) are responsible for its high virulence and mortality. However, the molecular mechanism behind these effects is unclear. In this study, we used LA795 cells and a mouse model to assess the crucial role of TLR3 during infection with lethal avian influenza A virus and subsequent inflammation. The results showed that IAVs could replicate and proliferate well in LA795 cells and that the replication of H5N1 was more efficient than human H1N1 and lowly pathogenic avian H7N2 viruses. The TLR3 signaling pathways were activated preferentially in vitro and in vivo and a range of pro-inflammatory cytokines were released following H5N1 infection. RNAi and TLR3 knockout mice were used to validate the results. These results are the first to provide insight into the preferential involvement of TLR3 in lethal avian influenza A virus infection and inflammation compared with others such as human or lowly pathogenic avian influenza A viruses. The data will increase understanding of the pathogenesis of lethal avian influenza A virus infection and may help facilitate the development of novel therapeutic aids targeting TLR3 signaling pathways. PMID- 30248374 TI - Influenza virus replication raises the temperature of cells. AB - Influenza virus invades the cell by binding sialic acid on the cell membrane through haemagglutinin (HA), and then genome replication and transcription are carried out in the nucleus to produce progeny virus. Multiplication of influenza virus requires metabolites, such as nucleotides and amino acids, as well as cellular machinery to synthesize its genome and proteins, thereby producing viral particles. Influenza virus infection forces the start of several metabolic systems in the cell, which consume or generate large amounts of energy. Thus, the viral multiplication processes involved in both genome replication and transcription are considered to require large numbers of nucleotides. The high level consumption of nucleotides generates large amounts of energy, some of which is converted into heat, and this heat may increase the temperature of cells. To address this question, we prepared a tool based on rhodamine B fluorescence, which we used to measure the temperatures of influenza virus-infected and uninfected cells. The results indicated that influenza virus multiplication increased the temperature of cells by approximately 4 degrees C - 5 degrees C, ATP levels in the cells decreased at 3 h after infection, and mitochondrial membrane potential decreased with multiplication level. Thus, the increase in cellular temperature during influenza virus infection appears to be due to the massive consumption of ATP over a short period. PMID- 30248375 TI - Value of assessment of multivoxel proton chemical shift imaging to predict long term outcome in patients after out-of-hospital cardiac arrest: A preliminary prospective observational study. AB - BACKGROUND: Existing methods to predict recovery after out-of-hospital cardiac arrest (OHCA) lack of accuracy. The aim of this study was to determine whether quantitative proton chemical shift imaging (1H-CSI) during the subacute stage of OHCA can predict neurological outcome of such patients. METHODS: This monocentric prospective observational study was conducted in a Intensive Care Unit of a teaching hospital. Forty consecutive patients with OHCA were enrolled between January 1st 2011-December 31st 2013. Multivoxel 1H-CSI values were compared to structural magnetic resonance imaging (MRI) sequences (fluid-attenuated inversion recovery and diffusion-weighted imaging). Ratios of N-acetyl-aspartate (NAA) to creatine (Cr) and choline compounds were analyzed using region of interest in bilateral lenticular cores and thalami. The outcome evaluated was the Cerebral Performance Category (CPC) at 6 months, dichotomized as favorable (CPC 1-2) and unfavorable outcome (CPC 3-5). The performance was compared by area under the receiver operating characteristic (ROCAUC) curves analysis. RESULTS: Twenty nine OHCA had an interpretable MRI. Eight patients (28%) had favorable outcome at 6 months. The worst NAA/Cr in lenticular cores was the best 1H-CSI marker, with 80% sensitivity (95% confidence interval (CI), 57-94) and a 100% specificity (95% CI, 63-100) with a positive predictive value of 100%. Prognostic accuracy, as quantified by the ROCAUC, was higher with the worst NAA/Cr in lenticular cores (ROCAUC 0.88; 95% CI, 0.70-0.97) than with the structural MRI sequences. CONCLUSION: In this preliminary study we found that multivoxel 1H-CSI in lenticular cores was highly predictive of unfavorable outcome at 6 months. PMID- 30248376 TI - Identification of amino acid residues critical for the B cell growth-promoting activity of HIV-1 matrix protein p17 variants. AB - BACKGROUND: HIV-1 matrix protein p17 variants (vp17s) detected in HIV-1-infected patients with non-Hodgkin's lymphoma (HIV-NHL) display, differently from the wild type protein (refp17), B cell growth-promoting activity. Biophysical analysis revealed that vp17s are destabilized as compared to refp17, motivating us to explore structure-function relationships. METHODS: We used: biophysical techniques (circular dichroism (CD), nuclear magnetic resonance (NMR) and thermal/GuHCL denaturation) to study protein conformation and stability; Surface plasmon resonance (SPR) to study interactions; Western blot to investigate signaling pathways; and Colony Formation and Soft Agar assays to study B cell proliferation and clonogenicity. RESULTS: By forcing the formation of a disulfide bridge between Cys residues at positions 57 and 87 we obtained a destabilized p17 capable of promoting B cell proliferation. This finding prompted us to dissect refp17 to identify the functional epitope. A synthetic peptide (F1) spanning from amino acid (aa) 2 to 21 was found to activate Akt and promote B cell proliferation and clonogenicity. Three positively charged aa (Arg15, Lys18 and Arg20) proved critical for sustaining the proliferative activity of both F1 and HIV-NHL-derived vp17s. Lack of any interaction of F1 with the known refp17 receptors suggests an alternate one involved in cell proliferation. CONCLUSIONS: The molecular reasons for the proliferative activity of vp17s, compared to refp17, relies on the exposure of a functional epitope capable of activating Akt. GENERAL SIGNIFICANCE: Our findings pave the way for identifying the receptor(s) responsible for B cell proliferation and offer new opportunities to identify novel treatment strategies in combating HIV-related NHL. PMID- 30248377 TI - A noncanonical binding site of chloramphenicol revealed via molecular dynamics simulations. AB - Chloramphenicol, an antibiotic belonging to the family of amphenicols, is an inhibitor of translation. On the basis of X-ray structural analysis of the binding of chloramphenicol to free bacterial ribosomes, the chloramphenicol action mechanism that consists in preventing the binding of aminoacyl-tRNA to the A-site of the large subunit of the ribosome was adopted. However, the known structures of chloramphenicol complexes with bacterial ribosomes poorly explain the results of the experiments on the chemical modification of 23S rRNA, the resistance to chloramphenicol caused by mutations in 23S rRNA and, which is particularly important, the selectivity of chloramphenicol in suppression of translation, depending on the amino acid sequence of the nascent peptide. In the present study the putative structure of the chloramphenicol complex with a bacterial ribosome in the A,A/P,P-state has been obtained by molecular dynamics simulations methods. The proposed structure of the complex allows us to explain the results of biochemical studies of the interaction of chloramphenicol with the bacterial ribosome. PMID- 30248378 TI - The contribution of [1H] magnetic resonance spectroscopy to the study of excitation-inhibition in autism. AB - Autism spectrum disorder (ASD) affects over 1:100 of the population and costs the UK more than L32bn and the USA more than $175bn (L104bn) annually. Its core symptoms are social and communication difficulties, repetitive behaviours and sensory hyper- or hypo-sensitivities. A highly diverse phenotypic presentation likely reflects its etiological heterogeneity and makes finding treatment targets for ASD challenging. In addition, there are no means to identify biologically responsive individuals who may benefit from specific interventions. There is hope however, and in this review we consolidate how findings from magnetic resonance spectroscopy (MRS) add to the evidence that differences in the brain's excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) balance may be both a key biomarker and a tractable treatment target in ASD. PMID- 30248379 TI - Insular changes induced by electroconvulsive therapy response to symptom improvements in schizophrenia. AB - Although modified electroconvulsive therapy (MECT) has been employed as a treatment strategy and to resolve medication resistant symptoms in schizophrenia (SZ), its action mechanisms remain unclear. The insula has been demonstrated to associate with clinical symptoms and neuropathology in SZ. This study examined whether insular changes response to MECT outcomes in SZ. Forty-two SZ were divided into two groups according to their treatment strategies. One group (MSZ, n = 21) received 4-weeks MECT together with antipsychotics; another group (DSZ, n = 21) was treated only with antipsychotics. Twenty-three healthy controls (HC) were also included. Structural and functional MRI were scanned twice (baseline and after 4-week treatment) for SZ and once for HC. Firstly, the insula was divided into three subregions based on resting-state functional connectivity (FC). Subsequently, gray matter volume (GMV) and voxel-wise FC were assessed in each subregion. Finally, the relationship between insular changes and symptom improvements was also investigated. Compared with baseline, the DSZ group showed reduced GMV in insular subregions. In contrast, the MSZ group exhibited increased GMV in bilateral posterior insula (PIns); furthermore, the increase in the PIns was correlated with symptom improvements. Second, the decreased FC between right PIns and left orbitofrontal cortex, and left PIns and middle occipital gyrus was observed only in the MSZ group; moreover, these FC changes were associated with symptom improvements. The present study demonstrated that MECT induced insular changes, which may contribute to the mechanisms of MECT. PMID- 30248380 TI - Ex vivo microangioCT: Advances in microvascular imaging. AB - Therapeutic modulation of angiogenesis is believed to be a prospective powerful treatment strategy to modulate the microcirculation and therefore help millions of patients with cardiovascular and cancer diseases. The often-frustrating results from late-stage clinical studies indicate an urgent need for improved assessment of the pro- and anti-angiogenic compounds in preclinical stage of investigation. For such a proper assessment, detailed vascular visualization and adequate quantification are essential. Nowadays, there are few imaging modalities available, but none of them provides non-destructive 3D-visualization of the vasculature down to the capillary level. In many instances, the approaches cannot be combined with the subsequent histological or ultrastructural analysis. In this review, we address the latest developments in the microvascular imaging, namely, the microangioCT approach with a polymer-based contrast agent (MUAngiofil). This approach allows time-efficient non-destructive 3D-imaging of the organ and its vasculature including the finest capillaries. Besides the superior visualization, the obtained detailed 3D information on the organ vasculature enables its 3D skeletonization and further quantitative analysis. Probably the only significant limitation of the described approach is that it can be used only ex vivo, i.e., no longitudinal studies. In spite of this drawback, microangioCT with MUAngiofil is a relatively simple and straightforward tool with a broad application range for studying physiological and pathological alterations in the microvasculature of any organ. It provides microvascular imaging at unprecedented level and enables correlative microscopy. PMID- 30248381 TI - Protein-repellent and antibacterial effects of a novel polymethyl methacrylate resin. AB - OBJECTIVES: Heat-cured resins are commonly used in orthodontics; however, there is a high incidence of caries, periodontal diseases and denture-induced stomatitis. The objectives of this study were to: (1) develop a new bioactive polymethyl methacrylate (PMMA) resin containing 2-methacryloyloxyethyl phosphorylcholine (MPC) and quaternary ammonium dimethylaminohexadecyl methacrylate (DMAHDM), and (2) investigate the effects on mechanical properties, protein-repellency and antibacterial properties. METHODS: MPC and DMAHDM were mixed into a commercial acrylic resin (Nature CrylTM MC). Mechanical properties were measured in three-point flexure. Surface roughness was assessed using atomic force microscopy (AFM). Protein adsorption onto the PMMA resin was measured using a micro bicinchoninic acid (BCA) method. A human saliva microcosm model was used to investigate the live/dead staining and metabolic activity of the biofilms. RESULTS: Incorporation of 3% MPC and 1.5% DMAHDM into PMMA resin achieved protein repellent and antibacterial capabilities, without compromising the mechanical properties. PMMA resin with 3% MPC + 1.5% DMAHDM had protein adsorption that was 1/6 that of a commercial control (p < 0.05). The PMMA resin with 3% MPC + 1.5% DMAHDM had much greater reduction in biofilm growth than using MPC or DMAHDM alone (p < 0.05). CONCLUSIONS: A bioactive PMMA resin with a combination of strong protein-repellent and antibacterial capabilities was developed for the first time. The new resin greatly reduced the biofilm growth and metabolic activity, without compromising its mechanical properties. SIGNIFICANCE: Novel PMMA resin is promising for applications in orthodontic retainers and orthodontic appliances to reduce biofilm activity and protein adsorption around the resin. PMID- 30248382 TI - Piperonyl methacrylate: Copolymerizable coinitiator for adhesive compositions. AB - OBJECTIVES: This study describes the synthesis of piperonyl methacrylate (PipM) and evaluates its effect when used as coinitiator in the photoinitiated radical polymerization of experimental adhesive resins. METHODS: PipM was synthetized through an esterification reaction and characterized by FTIR and 1H NMR spectroscopy. Adhesive resins containing camphorquinone as photoinitiator and PipM or ethyl-4-dimethyl amine benzoate (EDAB) as coinitiators were formulated. Scotchbond Multipurpose (SBMP) adhesive was used as commercial reference. All materials were analyzed for polymerization kinetics, flexural strength, elastic modulus, water sorption/solubility, shear bond strength to bovine enamel and dentin, characterization of hybrid layer by scanning electron microscopy (SEM), microbiological direct contact test, and cytotoxicity. RESULTS: The adhesive with PipM presented higher degree of conversion and lower sorption/solubility when compared with other groups. Shear bond strength to enamel and dentin were similar for PipM and EDAB materials. The percentage of cellular viability was close to 100% and similar in the experimental groups and the commercial reference. CONCLUSIONS: PipM presented similar or superior performance to the tertiary amine used as control, representing a potential alternative coinitiator for photopolymerizable dental materials. CLINICAL SIGNIFICANCE: PipM could be potentially useful in the formulations of adhesive systems with enhanced chemical properties, which could mean improvement in the longevity of composite resin restorations. PMID- 30248384 TI - Molding Idle Musings Into Art: What Reflective Writing Does for Me? PMID- 30248383 TI - Response to Hyoscine Butylbromide for the Management of Death Rattle: Sooner Rather Than Later. PMID- 30248385 TI - When We Document End-of-Life Care, Words Still Matter. PMID- 30248386 TI - Hrd1 induces cardiomyocyte apoptosis via regulating the degradation of IGF-1R by sema3a. AB - OBJECTIVE: To explore the underlying mechanisms of Hrd1/sema3a/IGF-1R on cardiomyocyte apoptosis. METHODS: AMI model was established by the left-anterior descending coronary artery (LAD) ligation. The expressions of Hrd1, sema3a and IGF-1R were examined by western blot. The activity of caspase-3 and caspase-8 was measured using the corresponding activity detection kit. Cardiomyocyte apoptosis was detected by flow cytometry assay. Co-immunoprecipitation and ubiquitination assay were used to test the relationship among Hrd1, sema3a and IGF-1R. RESULTS: Hrd1 expression and the activity of caspase-3 and caspase-8 were increased in cardiac tissues of AMI rats and hypoxia-induced cardiomyocytes, while IGF-1R expression was decreased. Hrd1 overexpression promoted IGF-1R degradation, whereas knockdown of sema3a suppressed this degradation. Moreover, knockdown of Hrd1 or sema3a could inhibit the decrease of IGF-1R expression induced by hypoxia, and reverse the enhanced activity of caspase-3 and caspase-8 and the increase of cardiomyocytes apoptosis induced by hypoxia, while si-IGF-1R countered these effects. In AMI rat experiments, interfering Hrd1 or sema3a reduced the infarct size and increased IGF-1R expression, but these could be abolished by si-IGF-1R. CONCLUSION: Hrd1 might mediate the ubiquitination of IGF 1R through sema3a and then participate in the regulation of cardiomyocyte apoptosis. PMID- 30248387 TI - Characterization of neuroinflammation and periphery-to-CNS inflammatory cross talk in patients with disc herniation and degenerative disc disease. AB - : The aim of the study was to identify inflammatory cytokines/chemokines associated with neuroinflammation and periphery-to-CNS inflammatory cross-talk in degenerative disc disease (DDD) and lumbar disc herniation (LDH), common causes of low back pain (LBP). A secondary aim was to investigate the associations between cytokines and symptom severity. METHODS: In total, 40 DDD and 40 LDH patients were recruited from a surgical waiting list, as well as 39 healthy controls (HC) and 40 cerebrospinal fluid (CSF) controls. The subjects completed questionnaires and pressure algometry was performed at the lumbar spine and forearm. The CSF, serum and disc tissues were collected during surgery. Inflammatory mediators TNF, INFg, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13 and MCP1 were analysed by immunoassay (Meso Scale Discovery) and quantitative real-time polymerase chain reaction (qPCR) was used for analysis of IL-6, IL-8, MCP1 and TSPO expression in intervertebral discs (IVDs). RESULTS: In the LDH group, we found elevated IL-8 concentrations in CSF indicating neuroinflammation, while IL-8 and MCP1 concentrations in serum were lower compared to HC. The IVD expression of IL-6, IL-8 and TSPO was lower in LDH patients compared to DDD. LDH patients had a positive correlation between IL-8 concentrations in CSF and serum and IL-8 in CSF was associated with higher pain intensity and increased spinal pressure pain sensitivity. The MCP1 concentration in serum was associated with higher global pain ratings and increased spinal pressure pain sensitivity, while IL-6 serum concentration correlated with the intensity of the neuropathic pain component (leg pain) in LDH patients. IVD expression of TSPO in LDH patients was associated with increased intensity of back pain. No differences were found in cytokine CSF concentrations between DDD patients and CSF controls, but DDD patients had lower IL-8 and MCP1 serum concentrations than HC. In female DDD patients, IL-8 and MCP1 concentrations in serum were associated with increased intensity of back pain. CONCLUSION: Our results suggest that neuroinflammation mediated by elevated IL-8 concentrations in CSF and IL-8 mediated periphery-to-CNS inflammatory cross-talk contributes to pain in LDH patients and suggest a link between TSPO expression in discs and low back pain. PMID- 30248388 TI - Targeting oxidative stress using tri-needle electrospray engineered Ganoderma lucidum polysaccharide-loaded porous yolk-shell particles. AB - Chronic lung diseases (e.g. chronic obstructive pulmonary disease and asthma) are associated with oxidative stress and common treatments include various types of inhalation therapies. In this work Ganoderma lucidum polysaccharide (GLP), a naturally occurring antioxidant is loaded into porous Poly (epsilon-caprolactone) (PCL) particles using a single step tri-needle coaxial electrospray process (Tri needle CES); with a view to develop therapies to combat oxidative stress. Based on the core-shell structure of porous yolk shell particles (YSPs), GLP-loaded YSPs displayed a bi-phasic release pattern. In vitro cell studies indicate GLP loaded porous YSPs display good biocompatibility and positive attributes towards H2O2-induced oxidative stress in MRC-5 cells and dramatically attenuate intracellular reactive oxygen species (ROS) levels as well as significantly increase cell viability. In vivo inhalation studies indicate that GLP-loaded porous YSPs can be delivered to deep lung tissue and remain deposited for over 48 h and are subsequently removed by natural clearance mechanisms. Based on current findings GLP-loaded porous YSPs are suitable for pulmonary delivery and display good inhalation therapy potential to treat chronic lung diseases. PMID- 30248389 TI - Minimal physiologically-based pharmacokinetic model to investigate the effect of pH dependent FcRn affinity and the endothelial endocytosis on the pharmacokinetics of anti-VEGF humanized IgG1 antibody in cynomolgus monkey. AB - In this study, we developed a first minimal physiologically-based pharmacokinetic (mPBPK) model to investigate the complex interaction effects of endocytosis rate/FcRn binding affinity at both acidic/physiological pH on the pharmacokinetics (PK) of the anti-VEGF IgG1 antibodies. The data used in this study were the PK of the native IgG and humanized anti-VEGF IgG1 antibodies with a wide range FcRn-binding at both acidic and physiological pH in the cynomolgus monkey. The basic structure of the developed mPBPK models consisted of plasma, tissue and lymph compartments. The tissue compartment was subdivided into vascular, endothelial and interstitial spaces. Non-equilibrium binding mechanism was used to describe the FcRn-IgG interaction in the endosome. The fittings in the final model with three pH systems in the endosome compartment showed a good fit based on the visualization of the fitted graphs and the coefficient of variations of the estimated parameters (CV < 50%). The quantitative endocytosis/FcRn binding affinity PK relationships was constructed using the final model to provide better understanding of complex interaction effects of endocytosis rate and FcRn binding on PK of anti-VEGF IgG1 antibodies. This result may serve as an important model-based drug discovery platform to guide the design and development of the future generation of anti-VEGF IgG1 or other therapeutic IgG1 antibodies. In addition, the mPBPK model developed in cynomolgus monkey was successfully used to predict the PK of the anti-VEGF IgG1 antibody (bevacizumab) in human subjects. PMID- 30248390 TI - Smoking alters hydroxyprostaglandin dehydrogenase expression in fetal membranes. AB - INTRODUCTION: The way in which tobacco smoking increases the risk of preterm labor remains uncertain. Altered prostaglandin metabolism is one potential mechanism. METHODS: Proteins in fetal membrane samples (amniochoriodecidua) from 20 women were relatively quantified using Tandem Mass Tagging nano-liquid chromatography mass spectrometry. RESULTS: Prostaglandin synthases and two enzymes involved in prostaglandin degradation, hydroxyprostaglandin dehydrogenase (HPGD) and CBR1, were detected by the mass spectrometer. The expression of HPGD was significantly lower in smokers relative to non-smokers (0.43 fold, p = 0.016). There was no effect of labor, inflammatory status or gestational age on the HPGD levels. DISCUSSION: We describe for the first time an association between maternal smoking and HPGD expression. We propose that reduced expression of HPGD is one mechanism through which smoking may contribute to preterm labor. Lower levels of this enzyme, key to metabolising prostaglandins, may result in higher levels of prostaglandins and therefore precipitate labor prematurely. PMID- 30248391 TI - Reconsidering the minimally important difference: evidence of instability over time and across groups. AB - BACKGROUND CONTEXT: Underlying cognitive factors have been found to influence patients' symptom experience. Current evidence suggests that concomitant changes in appraisal must be taken into account to accurately interpret change as measured by standard spine patient-reported outcomes (PROs). PURPOSE: To investigate changes in patients' minimally important differences (MID) over recovery from spinal surgery; whether and how cognitive appraisal processes are implicated in the change trajectories. STUDY DESIGN/SETTING: Longitudinal cohort study with up to 12 months follow-up. PATIENT SAMPLE: Surgical patients (n = 167) with a diagnosis of disc herniation or spinal stenosis. OUTCOME MEASURES: Standard spine patient-reported PROs were used (Rand-36, Oswestry Disability Index, Numerical Rating Scale for pain, PROMIS Pain Impact). METHODS: This study was funded by the Feldberg Chair in Spinal Research, Sunnybrook Health Sciences Centre and the authors have no conflicts of interest. MID used an anchor technique and was computed by global assessment of change (GAC) grouping. Participants were binned into groups based on their GAC response patterns at all time points: Consistently better post-surgery, consistently worse post-surgery, and bouncers, whose GAC ratings fluctuate (ie, better-then-worse-then-better; or vice versa). Individuals' longitudinal quality of life (QOL) and appraisal slope scores were computed. QOL-appraisal slopes' correlations were computed by GAC group. Fisher's Z transformation tested the hypothesis that GAC groups differed in the QOL-appraisal relationship over time. RESULTS: Moderate to large changes are recognized as clinically important in the early stages of recovery (ie, 6 weeks post-surgery), and over time smaller and smaller changes become important. The three pattern groups emphasized and deemphasized different standards of comparison over time, with the Better group emphasizing personal goals and the Worse and Bouncers deemphasizing doctors' input. These group differences translated to differential relationships between PRO change and appraisal changes over time. CONCLUSIONS: The MID reflects increasingly subtle change over time in PROs. Appraisal may influence how patients experience the same (MID) change over time, with better outcomes associated with emphasizing long-term goals. PRO change seems to be driven by different standards of comparison. Potential avenues for clinical intervention are discussed. PMID- 30248392 TI - A 3D human placenta-on-a-chip model to probe nanoparticle exposure at the placental barrier. AB - With the commercialization of nanomaterials, environmental exposure to nanoparticles (NPs) has raised great concerns due to the long-term effects to human body, particularly to pregnant women. Previous studies found that NPs had an adverse impact on placenta in mice, but care must be taken when extrapolating the results to human pregnancy in consideration of the great difference between species. Here, we proposed a microengineered 3D placental barrier-on-a-chip microdevice and further explored complicated placental responses to NPs exposure in vitro. The microdevice recreated near-physiological 3D microenvironment and dynamic conditions in fetal maternal circulation combined with the extracellular matrix and flow. With the exposure to titanium dioxide nanoparticles (TiO2-NPs), a common nanomaterial, a series of placental responses were investigated, including oxidative stress, cell apoptosis, barrier permeability, and maternal immune cell behavior. By contrast to oxidative stress and cell apoptosis, placental barrier integrity and maternal immune cells were greatly influenced even with low concentrated NPs, suggesting the potential damages triggered by NPs in our daily life. Collectively, this in vitro experimental model of human placenta provides a simple platform to study environmental exposure to NPs, and might be potential for a wide range of applications in biological study, disease treatment and drug assessment. PMID- 30248393 TI - Sub-toxic exposure to lindane activates redox sensitive kinases and impairs insulin signaling in muscle cell culture: The possible mechanism of lindane induced insulin resistance. AB - Lindane exposure is claimed to be involved in pathogenesis of type 2 diabetes mellitus (T2DM) and insulin resistance state by an as yet unknown mechanism. The redox sensitive kinases (RSKs) and heat shock proteins (HSPs) interfere with insulin signaling and induce insulin resistance. The present study was designed to explore the mechanism of insulin resistance induced by sub-toxic lindane exposure. In an in vitro study, exposure to 60 mg/L and 120 mg/L of lindane for 18 h on rat L6 myoblasts derived myotubes significantly increased malondialdehyde level & superoxide dismutase activity, decreased total antioxidant level and insulin-induced glucose uptake in a dose dependent manner. The extent of activation of RSKs and HSP25 as measured by western blot from the extent of phosphorylation of IkappaBalpha, p38 MAPK, JNK & HSP25 in lindane-exposed myotubes was higher. HSP70 was induced and insulin signaling as measured from tyrosine phosphorylation of insulin receptor (IR) & insulin receptor substrate-1 (IRS-1) and serine phosphorylation of Akt was attenuated in comparison to those in untreated myotubes. We conclude that sub-toxic lindane exposure induces oxidative stress, activates RSKs & HSP25 and induces HSP25. These in turn, impair insulin signaling to impart insulin resistance in myotubes induced by sub-toxic lindane exposure. PMID- 30248394 TI - Preparation and characterization of multi-component tablets containing co amorphous salts: Combining multimodal non-linear optical imaging with established analytical methods. AB - Co-amorphous mixtures have rarely been formulated as oral dosage forms, even though they have been shown to stabilize amorphous drugs in the solid state and enhance the dissolution properties of poorly soluble drugs. In the present study we formulated tablets consisting of either spray dried co-amorphous ibuprofen arginine or indomethacin-arginine, mannitol or xylitol and polyvinylpyrrolidone K30 (PVP). Experimental design was used for the selection of tablet compositions, and the effect of tablet composition on tablet characteristics was modelled. Multimodal non-linear imaging, including coherent anti-Stokes Raman scattering (CARS) and sum frequency/second harmonic generation (SFG/SHG) microscopies, as well as scanning electron microscopy, X-ray diffractometry and Fourier-transform infrared spectroscopy were utilized to characterize the tablets. The tablets possessed sufficient strength, but modelling produced no clear evidence about the compaction characteristics of co-amorphous salts. However, co-amorphous drug arginine mixtures resulted in enhanced dissolution behaviour, and the PVP in the tableting mixture stabilized the supersaturation. The co-amorphous mixtures were physically stable during compaction, but the excipient selection affected the long term stability of the ibuprofen-arginine mixture. CARS and SFG/SHG proved feasible techniques in imaging the component distribution on the tablet surfaces, but possibly due to the limited imaging area, recrystallization detected with x ray diffraction was not detected. PMID- 30248395 TI - A Disposition Kinetic Study of Tramadol in Intoxicated Rats Induced by Ethanol and Acetaminophen in Perfused Rat Liver Model. AB - Damage to the liver can lead to changes in the metabolism of tramadol. In this study, the rate of tramadol metabolites in rats with damaged liver induced by ethanol and acetaminophen were assessed in a recirculation perfusion system. Tramadol hydrochloride (TrHC) is a central nervous system (CNS) acting synthetic analgesic drug having both opioid and non-opioid properties. Acetaminophen is a mild analgesic and antipyretic agent which can cause centrilobular hepatic necrosis in toxic doses. On the other hand, alcohol causes death from the hepatic disease. Alcoholic liver disease (ALD) such as alcoholic fatty liver, alcoholic hepatitis, and alcoholic fibrosis is the most common liver disease. Male rats were randomly assigned into three groups. The control group received normal saline, the group 2 receiving acetaminophen at the dose of 250 mg/kg/day and group 3 received ethanol at the beginning dose of 3 g/kg/day and slowly increased to 6 g/kg/day. Tramadol added to perfusion solution with the concentration of 500 ng/ml. Samples were collected during 180 minutes and analyte concentrations were determined by HPLC method. The concentration of tramadol and its three main metabolites O-desmethyltramadol (M1) and N-desmethyltramadol (M2) and N,O didesmethyltramadol (M5) were determined in perfusate samples. An increase in the elimination half-life and reduced clearance rate of tramadol was seen in acetaminophen and ethanol groups in comparison to control group. Also, significant reductions in the AUC of metabolites of tramadol in acetaminophen and ethanol groups were seen as compared to control group. PMID- 30248396 TI - Right Ventricular Free Wall Strain Is Associated With Long-Term Renal Function in Heart Failure With Preserved Ejection Fraction. PMID- 30248398 TI - Tolerogenic dendritic cells induced the enrichment of CD4+Foxp3+ regulatory T cells via TGF-beta in mesenteric lymph nodes of murine LPS-induced tolerance model. AB - Endotoxin tolerance is an important state for the prevention of lethal infection and inflammatory response, which is closely associated with the participation of innate immune cells. Moreover, mesenteric lymph nodes (MLNs)-resident immune cells, such as CD4+Foxp3+ regulatory T (Treg) cells and dendritic cells, play important roles in the maintenance of peripheral immune tolerance. However, the potential roles of these cells in MLNs in the development of endotoxin tolerance remain largely unknown. Recent research work showed that CD4+Foxp3+ Treg cells contributed to the development of endotoxin tolerance. Here, we further analyzed the possible change on CD4+Foxp3+Tregs population in MLNs in murine LPS-induced endotoxin tolerance model. Our data showed that the proportion and absolute number of CD4+Foxp3+Tregs, expressing altered levels of CTLA4 and GITR, significantly increased in MLNs of murine LPS-induced tolerance model. Moreover, the expression level of TGF-beta in MLNs also increased obviously. Furthermore, TGF-beta blockade could obviously reduce the proportion and absolute number of CD4+Foxp3+Tregs in MLNs and subsequently impair the protection effect against LPS rechallenge. Of note, we found that tolerogenic dendritic cell (Tol-DC), expressing lower levels of MHC-II and CD86 molecules, dominantly secreted TGF beta in MLNs in murine LPS-induced tolerance model. In all, our data provided an unknown phenomenon that the total cell number of CD4+Foxp3+Tregs significantly increased in MLNs in endotoxin tolerance, which was related to MLN-resident TGF beta secreting CD11c+DCs, providing a new fundamental basis for the understanding on the potential roles of MLN-resident immune cells in the development of endotoxin tolerance. PMID- 30248397 TI - Acute Hemodynamic Effects of Biventricular Pacing After Left Ventricular Assist Device. AB - BACKGROUND: Despite cardiac resynchronization therapy (CRT), some patients with heart failure progress and undergo left ventricular assist device (LVAD) implantation. Management of CRT after LVAD implantation has not been well studied. The purpose of this study was to determine whether RV pacing or biventricular pacing measurably affects acute hemodynamics in patients with an LVAD and a CRT device. METHODS AND RESULTS: Seven patients with CRT and LVAD underwent right heart catheterization. Pressures and oximetry were measured and LVAD parameters were recorded during 3 different conditions: RV pacing alone, biventricular pacing, and intrinsic atrioventricular conduction. Paired t tests were used to evaluate changes within subjects. There were no significant changes in right atrial pressure, pulmonary arterial pressures, pulmonary capillary wedge pressure, cardiac index, or any LVAD parameter (P > .05). CONCLUSIONS: Our data suggest that CRT probably has no acute hemodynamic effect in patients with LVADs, but further study is needed. PMID- 30248399 TI - Evaluation of circulating invariant T cells before and after IL-17 inhibitor treatment in a patient with psoriatic arthritis. PMID- 30248400 TI - AIM2 senses Brucella abortus DNA in dendritic cells to induce IL-1beta secretion, pyroptosis and resistance to bacterial infection in mice. AB - Absent in melanoma 2 (AIM2) is a sensor of cytosolic dsDNA and is responsible for the activation of inflammatory and host immune responses to DNA viruses and intracellular bacteria. AIM2 is a member of the hematopoietic interferon inducible nuclear proteins with a 200 amino-acid repeat (HIN200) family, containing a pyrin domain (PYD) at the N-terminus. Several studies have demonstrated that AIM2 is responsible for host defense against intracellular bacteria such as Francisella tularensis, Listeria monocytogenes and Mycobacerium tuberculosis. However, the role of AIM2 in host defenses against Brucella is poorly understood. In this study, we have shown that AIM2 senses Brucella DNA in dendritic cells to induce pyroptosis and regulates type I IFN. Confocal microscopy of infected cells revealed co-localization between Brucella DNA and endogenous AIM2. Dendritic cells from AIM2 KO mice infected with B. abortus showed impaired secretion of IL-1beta as well as compromised caspase-1 cleavage. AIM2 KO mice displayed increased susceptibility to B. abortus infection in comparison to wild-type mice, and this susceptibility was associated with defective IL-1beta production together with reduced IFN-gamma responses. In summary, the increased bacterial burden observed in vivo in AIM2 KO animals confirmed that AIM2 is essential for an effective innate immune response against Brucella infection. PMID- 30248401 TI - Variable morphology of the suprascapular notch: A proposal for classification in Chinese population. AB - BACKGROUND: The variable of the suprascapular notch (SSN) is a common cause in suprascapular nerve (SN) entrapment. Hence, knowledge of SSN variations may be predictive valuable for the predisposition to compression of SN. The aim of this study was to propose the classification of SSN in Chinese population and took this complex morphology into account. MATERIAL AND METHODS: 308 human dry scapulae were analyzed thoroughly and systematically in this study. Morphological variations of the SSN were observed by visual inspection and the classification of SSN was determined by geometrical measurements. Then measurement results were averaged and recorded. RESULTS: Chinese dry scapulae were measured, we found seven types of SSN. Type I (?, 44.8%) was the most common, followed by type II (U, 41.9%) to VII (double O, 0.6%). Right scapulae were larger in depth of SSN and thickness of A and C. Type VII (double O) had the deepest SSN and type I (?) was widest among five types. For BC, type I (?) was shorter than type III (V). For thickness of A, type VII (double O) was greater than type I (?). For thickness of C, type I (?) and type II (U) were shorter than type III (V). There were no significant differences in other measurements between types and sides of body. Seven types of SSN in Chinese population were defined in our study. CONCLUSION: These anatomical variations of the SSN may improve the diagnostic rate and success rate of the surgical for the suprascapular nerve entrapment. PMID- 30248402 TI - Small molecules for fat combustion: targeting thermosensory and satiety signals in the central nervous system. AB - Brown adipose tissue (BAT) dissipates fatty acids as heat to maintain body temperature in cold environments. The existence of BAT and beige cells in human adults supplies a promising weight-reduction therapy. The central thermogenic regulation descends through an excitatory neural pathway from the hypothalamus, medullar and spine towards BAT. This sympathoexcitatory thermogenic circuit is controlled by GABAergic (gamma-aminobutyric acid) signaling from the thermoregulatory center in the preoptic area and the satiety center in the ventromedial nucleus of the hypothalamus. This review summarizes recent research progresses in thermogenic regulators targeting thermosensory and satiety signals in the central nervous system, and speculates on their potential as antiobesity agents. PMID- 30248403 TI - Influence of bacteriophages cocktail on European eel (Anguilla anguilla) immunity and survival after experimental challenge. AB - Inland fishery belongs to those branches of animal production that use very large amounts of chemotherapeutics, in particular antibiotics. The accumulation of chemotherapeutic agents in bottom sediments is a direct threat to the aquatic environment and directly affects the condition and health of the fish. Finding a preparation that could be used both prophylactically to increase the resistance of fish and therapeutically in case of infection with pathogenic bacteria, without side effects for fish and aquatic environment could be a great solution to this problem. Our aim was to determine influence of BAFADOR(r) the new bacteriophage-based preparation on European eel immunity and survival after experimental challenge. Application of BAFADOR(r) increased total protein level, immunoglobulin level, lysozyme activity and ceruloplasmin level in European eel serum. Potential killing activity and metabolic activity of spleen phagocytes as well as pronephros lymphocyte proliferation of was higher compared to control. The preparation also reduced mortality after experimental infections with the pathogenic bacteria Aeromonas hydrophila and Pseudomonas fluorescens. Our results showed that preparation BAFADOR(r) is well tolerated by the fish organism causing stimulation of cellular and humoral immunity parameters and reduces the mortality of the European eel after experimental challenge. PMID- 30248405 TI - Targeting cysteinyl-leukotrienes in abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) is an asymptomatic dilatation of the vessel wall exceeding the normal vessel diameter by 50%, accompanied by intramural thrombus formation. Since the aneurysm can rupture, AAA is a life-threatening vascular disease, which may be amenable to surgical repair. At present, no pharmacological therapy for AAA is available. The 5-lipoxygenase (5-LOX) pathway of arachidonic acid metabolism leads to biosynthesis of leukotrienes (LTs), potent lipid mediators with pro-inflammatory biological actions. Among the LTs, cysteinyl leukotrienes (cys-LT) are well-recognized signaling molecules in human asthma and allergic rhinitis. However, the effects of these molecules in cardiovascular diseases have only recently been explored. Drugs antagonizing the CysLT1 receptor, termed lukasts and typified by montelukast, are established therapeutics for clinical management of asthma. Lukasts are safe, well-tolerated drugs that can be administered during long time periods. Here we describe recent data indicating that montelukast may be used for prevention and treatment of AAA, thus representing a promising pharmacological tool for a deadly vascular disease with significant socio-economic impact. PMID- 30248404 TI - Liver transcriptome analysis of the Sparus macrocephlus in response to Vibrio parahaemolyticus infection. AB - The black seabream (Sparus macrocephlus) is an economically pivotal aquaculture species cultured in China and Southeast Asian countries. To understand the molecular immune mechanisms underlying the response to Vibrio parahaemolyticus, a comparative gene transcription analysis were performed with utilized fresh livers of V. parahaemolyticus-immunized Sparus macrocephlus with a control group through RNA-Seq technology. A total of 256663 contigs were obtained after excluded the low-quality sequences and assembly. The average length of contigs collected from this research is 1066.93 bp. Furthermore, blast analysis indicates 30747 contigs were annotated based on homology with matches in the NT, NR, gene, and string databases. A gene ontology analysis was employed to classify 21598 genes according to three major functional categories: molecular function, cellular component, and biological process. A total of 14470 genes were discovered in 303 KEGG pathways. RSEM and EdgeR were introduced to estimate 3841 genes significantly different expressed (False Discovery Rate<0.001) which includes 4072 up-regulated genes and 3771 down-regulated genes. A significant enrichment analysis of these differentially expressed genes and isogenes were conducted to reveal the major immune-related pathways which refer to the toll-like receptor, complement, coagulation cascades, and chemokine signaling pathways. In addition, 92175 potential simple sequence repeats (SSRs) and 121912 candidate single nucleotide polymorphisms (SNPs) were detected and identified sequencely in the Sparus macrocephlus liver transcriptome. This research characterized a gene expression pattern for normal and the V. parahaemolyticus -immunized Sparus macrocephlus for the first time and not only sheds new light on the molecular mechanisms underlying the host-V. parahaemolyticus interaction but contribute to facilitate future studies on Sparus macrocephlus gene expression and functional genomics. PMID- 30248406 TI - Role of dyslipidemia in preeclampsia-A review of lipidomic analysis of blood, placenta, syncytiotrophoblast microvesicles and umbilical cord artery from women with preeclampsia. AB - Preeclampsia is a complex disorder and the pathogenesis of it is still not fully understood. The most commonly accepted theory of pathogenesis assumes that there occurs impaired trophoblastic invasion and failure in spiral artery remodeling. Nowadays, obesity becomes one of the most important, modifiable risk factors for the development of preeclampsia. Despite research into the condition, predicting which women with risk factors will develop preeclampsia remains problematic. Emerging evidence suggests that dysregulation of maternal and placental lipid metabolism are involved in the pathogenesis of the condition. Hence, researchers are focused on finding a lipid fingerprint, which contains information about the lipid composition and abundance of individual lipids by using new methods in the field of lipidomics. In this review we aimed to discuss the role of dyslipidemia in the pathogenesis of preeclampsia. In addition, on the basis of current research, we attempted to find a specific lipid profile of different tissues in women with preeclampsia. PMID- 30248407 TI - Penicillin minor determinants: History and relevance for current diagnosis. AB - OBJECTIVE: To review the history of the penicillin minor determinants and evaluate their relevance for current diagnosis. DATA SOURCES: Skin testing to detect immunoglobulin E (IgE) sensitivity to penicillins in patients with a history of penicillin allergy has been the subject of more than 55 years of published research involving tens of thousands of patients. STUDY SELECTIONS: Selection of data was based on its relevance to the objective of this article. RESULTS: It was established early on that testing with the major penicilloyl determinant using the polyvalent penicilloyl-polylysine (PPL) is negative in a substantial portion (10% to 64%, including recent increases) of those at risk for immediate hypersensitivity reactions. A variety of minor penicillin determinants are clinically significant in that their use in skin testing is essential to detect all those at risk. In particular, a minor determinant mixture of benzylpenicillin, benzylpenicilloate, and benzylpenilloate, used in conjunction with PPL, has been shown in numerous studies to achieve an average negative predictive value (NPV) of 97.9% in history-positive patients. Benzylpenicillin alone, as the sole minor determinant, leaves many skin test-positive patients undiscovered. Use of amoxicillin as an additional minor determinant reagent appears to identify another 2% to 8% of skin test-positive patients in some populations. CONCLUSION: IgE skin testing, using both the major and appropriate minor determinants of penicillin, can identify, with a high degree of reliability (NPV ~97%), penicillin allergy history-positive patients who can receive beta lactam antibiotics without concern for serious acute allergy, including anaphylaxis. The few false-negative skin tests reported globally are largely confined to minor, self-limited cutaneous reactions. PMID- 30248408 TI - The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process. AB - A chronic low-grade inflammation is one of the hallmarks of the aging process. This gradually augmenting inflammatory state has been termed inflammaging. Inflammaging is associated with increased myelopoiesis in the bone marrow. This myelopoiesis-biased process increases the generation not only of mature myeloid cells, e.g. monocytes, macrophages, and neutrophils, but also immature myeloid progenitors and myeloid-derived suppressor cells (MDSCs). It is known that the aging process is associated with a significant increase in the presence of MDSCs in the bone marrow, blood, spleen, and peripheral lymph nodes. Consequently, MDSCs will become recruited into inflamed tissues where they suppress acute inflammatory responses and trigger the resolution of inflammation. However, if the perpetrator cannot be eliminated, the long-term presence of MDSCs suppresses the host's immune defence and increases the susceptibility to infections and tumorigenesis. Chronic immunosuppression also impairs the clearance of waste products and dead cells, impairs energy metabolism, and disturbs tissue proteostasis. This immunosuppressive state is reminiscent of the immunosenescence observed in inflammaging. It seems that proinflammatory changes in tissues with aging stimulate the myelopoietic production of MDSCs which subsequently induces immunosenescence and maintains the chronic inflammaging process. We will briefly describe the functions of MDSCs and then examine in detail how inflammaging enhances the generation MDSCs and how MDSCs are involved in the control of immunosenescence occurring in inflammaging. PMID- 30248409 TI - Probing the role of Arg97 in Heat shock protein 90 N-terminal domain from the parasite Leishmania braziliensis through site-directed mutagenesis on the human counterpart. AB - In Brazil, the mucocutaneous form of leishmaniasis, caused by the parasite Leishmania braziliensis, is a widespread and very challenging disease responsible for disfiguration and, in the most severe cases, death. Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone playing a pivotal role in the folding process of client proteins, and therefore its activity is fundamental for cell survival and proliferation. Since the chaperone activity requires ATP hydrolysis, molecules able to occupy the ATP binding pocket in the protein N-terminal domain (NTD) act as Hsp90 inhibitors. The development of selective molecules targeting the ATPase site of protozoan Hsp90 is tricky for the high homology with the human Hsp90 NTD (hNTD). Notably, only the human Lys112 is replaced by Arg97 in the L. braziliensis enzyme. Recently, this difference has been probed to design selective inhibitors targeting parasite Hsp90s. Here, a reliable protocol for expression and purification of LbHsp90-NTD (LbNTD) was developed but its structural characterization was unsuccessful. The role of Arg97 in LbNTD was hence probed by means of the "leishmanized" K112R variant of hNTDalpha. To deeply investigate the role of this residue, also the hNTDalpha K112A variant was generated. Structural studies performed on hNTDalpha and its variants using various ADP and ATP analogues and cAMP revealed that this residue is not crucial for nucleotide binding. This finding strongly suggests that Arg97 in LbNTD and more generally the conserved arginine residue in parasite Hsp90s are not exploitable for the development of selective inhibitors. PMID- 30248410 TI - A survey of undetected, clinically relevant chromosome abnormalities when replacing postnatal karyotyping by Whole Genome Sequencing. AB - Whole genome sequencing (WGS) holds the potential to identify pathogenic gene mutations, copy number variation, uniparental disomy and structural rearrangements in a single genetic test. With its high diagnostic yield and decreasing costs, the question arises whether WGS can serve as a single test for all referrals to diagnostic genome laboratories ("one test fits all"). Here, we provide an estimate for the proportion of clinically relevant aberrations identified by light microscopy in postnatal referrals that would go undetected by WGS. To this end, we compiled the clinically relevant abnormal findings for each of the different referral categories in our laboratory during the period 2006 2015. We assumed that WGS would be performed on 300-500 bp DNA fragments with 150 bp paired sequence reads, and that the mean genome coverage is 30x, corresponding to current practice. For the detection of chromosomal mosaicism we set minimum thresholds of 10% for monosomy and 20% for trisomy. Based on the literature we assumed that balanced Robertsonian translocations and ~9% of other, balanced chromosome rearrangements would not be detectable because of breakpoints in sequences of repetitive DNA. Based on our analysis of all 14,957 referrals, including 1455 abnormal cases, we show that at least 8.1% of these abnormalities would escape detection (corresponding to 0.79% of all referrals). The highest rate occurs in referrals of premature ovarian failure, as 73.3% of abnormalities would not be identified because of the frequent occurrence of low-level sex chromosome mosaicism. Among referrals of recurrent miscarriage, 25.6% of abnormalities would go undetected, mainly because of a high proportion of balanced Robertsonian translocations. In referrals of mental retardation (with or without multiple congenital anomalies) the abnormality would be missed in only 0.35% of referrals. These include cases without imbalances of unique DNA sequences but of clinical relevance, as for example, r(20) epilepsy syndrome. The expected shift to large-scale implementation of WGS ("one test fits most") as initial genetic test will be beneficial to patients and their families, since a cause for the clinical phenotype can be identified in more cases by a single genetic test at an early phase in the diagnostic process. However, a niche for genome analysis by light microscopy will remain. For example, in referrals of newborns with a suspicion of Down syndrome, karyotyping is not only a cost effective method for providing a quick diagnosis, but also discriminates between trisomy 21 and a Robertsonian translocation involving chromosome 21. Thus, when replacing karyotyping by WGS, one must be aware of the rates and spectra of undetected abnormalities. In addition, it is equally important that requirements for cytogenetic follow-up studies are recognized. PMID- 30248411 TI - A comparison of short-term outcomes of neck dissection for head and neck cancers using ThunderbeatTM, LigaSureTM or treatment without an energy-based device: A case controlled study. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of the new energy based device Thunderbeat in neck dissection (ND) for head and neck cancer. MATERIALS AND METHODS: We retrospectively examined 95 consecutive patients who underwent ND for head and neck squamous cell carcinoma between April 2013 and March 2018. The patients were divided into three groups: ND without the energy based device (control group), ND using the LigaSure Small Jaw (LS group), and ND using the Thunderbeat Open Fine Jaw (TB group). The outcomes were compared among the three groups, as measured by the duration of ND (dissection time), blood loss during ND, and postoperative complications. We also analyzed the factors that may influence dissection time using multivariate analysis. RESULTS: Compared to the control group, dissection time was found to be significantly shorter in both energy-based device groups (LS group and TB group) (96.4, 71.1, and 66.0 min, respectively, p = 0.0015) by univariate analysis. Blood loss during ND did not differ significantly among the three groups. Multivariate analysis showed that ND using the Thunderbeat as well as elderly patients (70 years and over), less extensive surgery (3 or fewer neck levels), and absence of extracapsular invasion were independently and significantly associated with shorter dissection time (p = 0.0069, 0.0337, <0.0001, and 0.0015, respectively). The incidence of postoperative complications in the LS group (20%) tended to be higher than those in the other groups (5.6% in the control group and 3.4% in the TB group), although the differences were not significant. CONCLUSION: ND for head and neck cancers using the Thunderbeat is a safe and reliable method in terms of duration of dissection without increasing postoperative complications. PMID- 30248412 TI - Draft Genome Sequence of Pseudoalteromonas piscicida Strain 36Y RITHPW, an Hypersaline Seawater Isolate from the South Coast of Sonora, Mexico. AB - OBJECTIVES: The aim of this study was to report the first draft genome sequence of Pseudoalteromonas piscicida strain 36Y RITHPW, a marine gamma-proteobacteria that synthesize bioactive compounds with antagonistic activity against Vibrio parahaemolyticus, a multidrug resistant strain, causative agent of Acute Hepatopancreatic Necrosis Disease (AHPND), reported in shrimp farm outbreaks from Asia to Mexico with mortalities of 80-100%. METHODS: The genome was sequenced with an Ion Torrent platform (PGM). A total of 606,805 reads were obtained for a 308.48 Mbp and 33.5X coverage. A high-quality draft assembly and ordering of contigs were obtained with Mauve. The annotation was obtained with RAST and antiSMASH. RESULTS: The genome size consists of 5.15 Mbp, 4,548 genes, 4,217 protein coding sequences and a GC content of 43.3%, several resistance genes and others involved in production of bacteriocins and ribosomally synthesized antibacterial peptides. CONCLUSIONS: The mining of this draft genome provides valuable information to explain the antagonistic capacity of P. piscicida 36Y RITHPW, an useful strain as potential probiotic in shrimp aquaculture, against the pathogenic V. parahaemolyticus. PMID- 30248413 TI - First report of Pseudomonas aeruginosa co-harbouring blaVIM-2 and blaPER-1 in Latin America. PMID- 30248414 TI - Whole-genome sequencing reveals genetic signature of bedaquiline resistance in a clinical isolate of Mycobacterium tuberculosis. AB - OBJECTIVES: The emergence of multidrug-resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis strains has opened up new challenges for tuberculosis (TB) control in India. This study examined molecular markers of resistance to bedaquiline, a new antituberculous drug with the potential to dramatically improve MDR-TB treatment outcomes and to reduce mortality. METHODS: A clinical M. tuberculosis isolate with a MDR-TB profile was subjected to whole genome sequencing using an Illumina NextSeq500 platform, followed by genome-wide sequence analysis. RESULTS: A mutation in the Rv0678 coding region associated with in vitro bedaquiline resistance was identified. The strain represented the Delhi/CAS lineage. CONCLUSIONS: This first report of a potentially bedaquiline resistant M. tuberculosis strain in India highlights the role of genome-wide sequence analysis of isolates from TB cases with a history of treatment in countries with a high burden of MDR-TB and XDR-TB. PMID- 30248415 TI - Effect of N-(2-aminoethyl) ethanolamine on hypertrophic scarring changes in vitro: Finding novel anti-fibrotic therapies. AB - Hypertrophic scars (HS) limit movement, decrease quality of life, and remain a major impediment to rehabilitation from burns. However, no effective pharmacologic therapies for HS exist. Here we tested the in vitro anti-fibrotic effects of the novel chemical N-(2-aminoethyl) ethanolamine (AEEA) at non-toxic concentrations. Scanning electron microscopy showed that AEEA markedly altered the structure of the extracellular matrix (ECM) produced by primary dermal fibroblasts isolated from a HS of a burn patient (HTS). Compression atomic force microscopy revealed that AEEA stiffened the 3D nanostructure of ECM formed by HTS fibroblasts. Western blot analysis in three separate types of primary human dermal fibroblasts (including HTS) showed that AEEA exposure increased the extractability of type I collagen in a dose- and time-dependent fashion, while not increasing collagen synthesis. A comparison of the electrophoretic behavior of the same set of samples under native and denaturing conditions suggested that AEEA alters the 3D structure of type I collagen. The antagonization effect of AEEA to TGF-beta1 on ECM formation was also observed. Furthermore, analyses of the anti-fibrotic effects of analogs of AEEA (with modified pharmacophores) suggest the existence of a chemical structure-activity relationship. Thus, AEEA and its analogs may inhibit HS development; further study and optimization of analogs may be a promising strategy for the discovery for effective HS therapies. PMID- 30248416 TI - Emodin-induced hepatotoxicity was exacerbated by probenecid through inhibiting UGTs and MRP2. AB - Aggravating effect of probenecid (a traditional anti-gout agent) on emodin induced hepatotoxicity was evaluated in this study. 33.3% rats died in combination group, while no death was observed in rats treated with emodin alone or probenecid alone, indicating that emodin-induced (150 mg/kg) hepatotoxicity was exacerbated by probenecid (100 mg/kg). In toxicokinetics-toxicodynamics (TK TD) study, aspartate aminotransferase (AST) and systemic exposure (area under the serum concentration-time curve, AUC) of emodin and its glucuronide were significantly increased in rats after co-administrated with emodin and probenecid for 28 consecutive days. Results showed that the increased AUC (increased by 85.9%) of emodin was mainly caused by the decreased enzyme activity of UDP glucuronosyltransferases (UGTs, decreased by 11.8%-58.1%). In addition, AUC of emodin glucuronide was increased 5-fold, which was attributed to the decrease of multidrug-resistant-protein 2 (MRP2) protein levels (decreased by 54.4%). Similarly, in vitro experiments proved that probenecid reduced the cell viability of emodin-treated HepG2 cells through inhibiting UGT1A9, UGT2B7 and MRP2. Our findings demonstrated that emodin-induced hepatoxicity was exacerbated by probenecid through inhibition of UGTs and MRP2 in vivo and in vitro, indicating that gout patients should avoid taking emodin-containing preparations in combination with probenecid for a long time. PMID- 30248417 TI - 14-Deoxy-11,12-didehydroandrographolide suppresses adipogenesis of 3 T3-L1 preadipocytes by inhibiting CCAAT/enhancer-binding protein beta activation and AMPK-mediated mitotic clonal expansion. AB - Obesity is highly correlated with several metabolic disorders. Adipocyte differentiation is a key process in determining obesogenesis. 14-Deoxy-11,12 didehydroandrographolide (deAND) is a diterpenoid rich in Andrographis paniculata (Burm.f.) Nees., a herbal medicine commonly used to treat colds, infections, and liver diseases. We investigated whether deAND inhibits the adipogenesis of 3T3-L1 cells and the underlying mechanisms. We found that deAND (0-15 MUM) dose dependently inhibits the mRNA and protein expression of peroxisome proliferator activated receptor gamma, sterol regulatory element-binding protein 1c, fatty acid synthase, and stearoyl-CoA desaturase-1. Cellular lipid accumulation was decreased by deAND, and the early phase of adipocyte differentiation was critical for this inhibition. Immunoblotting revealed that deAND attenuated differentiation medium-induced protein kinase A (PKA) and cAMP response element binding protein (CREB) activation, which leads to down-regulating C/EBPbeta transcription. Moreover, deAND inhibited ERK- and GSK3beta-mediated C/EBPbeta transcriptional activity. Flow cytometry analysis showed that deAND impaired the progression of mitotic clonal expansion (MCE) by arresting the cell cycle at the G0/G1 phase, while the expression of cyclin D1, cyclin E, CDK6, and CDK2 was attenuated. deAND increased the phosphorylation of AMPK and raptor, an mTOR interacting partner, which inhibited the mTOR-driven phosphorylation of P70S6K and eukaryotic translation initiation factor 4E binding protein. In the presence of compound C, deAND modulation of AMPK-mTOR signaling and inhibition of cell cycle regulator expression were reversed. Our results reveal that the anti adipogenic effect of deAND is likely through inhibition of the PKA-CREB-C/EBPbeta and AMPK/mTOR pathways, which leads to down-regulating C/EBPbeta-driven lipogenic protein expression and halting MCE progression. PMID- 30248418 TI - Nrf2 activator for the treatment of kidney diseases. AB - Kidney diseases are highly prevalent worldwide, and significantly reduce the quality of life of patients, creating an urgent need for effective therapeutic modalities. Despite this significant unmet medical need, none of the drugs launched to date have demonstrated promising potential to cure kidney diseases. This is likely due to the structural complexity of the kidney as well as difficulties in setting appropriate endpoints for clinical trials and identifying appropriate therapeutic targets. Recently, an alternative endpoint for clinical trials (i.e., a 30% or 40% reduction in estimated glomerular filtration rate [eGFR] from baseline following 2-3 years of observation) has been considered in the United States, European Union, and Japan, and is expected to contribute to the progress of drug development for kidney diseases. Further, oxidative stress and inflammation are currently thought to be key factors in the progression of kidney diseases, prompting more research on drugs targeting the mechanisms related to these factors for treatment. The Kelch-like ECH-associated protein 1 nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) system has drawn much attention in recent years for its anti-oxidative and anti-inflammatory properties, and its pharmacological potential for treatment of kidney diseases is being widely investigated in both clinical and non-clinical studies. This review summarizes the current issues in the treatment of kidney diseases, including clinical endpoints, Nrf2 activators as treatment options, and perspectives on pharmaceutical applications of Nrf2 activators. PMID- 30248419 TI - ERK1/2-mediated autophagy is essential for cell survival under Ochratoxin A exposure in IPEC-J2 cells. AB - The intestinal epithelium represents the first physical barrier against food contaminations. Ochratoxin A (OTA), one of the most deleterious mycotoxins, is commonly detected in food and feed stuff. The purpose of this study is to explore the adaptive cyto-protection of intestinal epithelium against OTA exposure and relevant regulation mechanisms. The intestinal porcine epithelial cell line (IPEC J2) was applied as in vitro models for intestinal epithelium. Western blot and immunofluorescence analysis confirmed that OTA induced extracellular signal regulated protein kinases 1 and 2 (ERK1/2) activation in IPEC-J2 cells. Hoechst 33258 staining and Annexin V/PI analysis exhibited that U0126, the ERK1/2 inhibitor, aggravated OTA-induced apoptosis. Then, we observed that OTA could induce autophagy by western blot. Furthermore, OTA-induced autophagy could be inhibited by U0126. Chloroquine (CQ), the autophagy inhibitor, enhanced OTA induced apoptosis in IPEC-J2 cells. In addition, CQ aggravated the production of mitochondrial reactive oxygen species, the release of cytochrome c release, and the activation of caspase-3. Taken together, these results suggest that ERK1/2 mediated autophagy is required for porcine intestinal epithelial cell survival against OTA toxicity. PMID- 30248420 TI - Protective effects of lentinan on lipopolysaccharide induced inflammatory response in intestine of juvenile taimen (Hucho taimen, Pallas). AB - Antioxidant effects of lentinan on LPS induced inflammatory response in intestine of juvenile taimen were evaluated, and its prebiotic-like efficacy on intestinal microbiota was also investigated. The results showed that LPS decreased the activities of antioxidant enzymes and increased the expression levels of inflammatory cytokines in intestine of juvenile taimen. Dietary lentinan significantly enhanced intestinal antioxidant ability by increasing the activities of SOD, GSH-Px and CAT, and inhibiting the lipid peroxidation in juvenile taimen. Appropriate lentinan prevented the increases in the expression levels of TGF-beta, TNF-alpha, IL1beta, IL6 and IL8 and ensured the relatively high expression levels of claudin d, SOD, CAT and IkappaBalpha after LPS challenge. Furthermore, dietary lentinan effectively modified intestinal microbiota, represented by increasing the relative abundance of beneficial bacteria such as Lactobacillaceae, Lachnospiraceae and Ruminococcaceae, and decreasing those of detrimental bacteria such as Enterobacteriaceae, Fusobacteriaceae and Flavobacteriaceae. Taken together, dietary lentinan availably decreased LPS induced inflammatory response, indicating that lentinan has the potential anti-inflammatory effects for preventing inflammation diseases in cold-water fish. PMID- 30248421 TI - Development and characterization of edible films based on eggplant flour and corn starch. AB - In this study, biodegradable and edible films based on eggplant flour (EF) and corn starch (CS) were prepared using casting method at proportion of 0-100, 25 75, 50-50, 75-25 and 100-0%, w/w. The mechanical, barrier, physical, and biodegradability properties were evaluated. Tensile strength, elongation at break, Young's modulus, thickness, density and L* parameter of pure starch films were higher than those of other films. Solubility, water vapor permeability (WVP), moisture content and swelling index of films were augmented with the substitution of CS by EF. Color measurement of the edible films indicated that increasing the proportion of EF increased a*, b* and opacity values. The highest amount of water sorption was obtained for pure EF films. Moreover, the incorporation of EF accelerated films biodegradability compared to ones with only starch. In general, EF is a promising material for the formulation of edible and biodegradable films with adequate physical properties for food applications by direct contact. PMID- 30248422 TI - Scar free healing mediated by the release of aloe vera and manuka honey from dextran bionanocomposite wound dressings. AB - Scar preventive dextran based bionanocomposite dressings containing aloe vera (AV) and manuka honey (MH) were developed as wound care devices. This work was a challenge to fabricate herbal dressing that promotes healing, which at the same time is biocompatible, non-toxic, biodegradable, and cost effective in terms of the simplicity of application in complex chronic wound situations. With this aim, we synthesized in-situ crosslinked dextran/nanosoy/glycerol/chitosan (DNG/Ch) nanocomposite membranes via solvent casting technique followed by subsequent addition of AV and MH to obtain DNG/Ch/AV and DNG/Ch/MH herbal dressings. The drug release kinetics of the bionanocomposite dressings indicated an initial burst release of AV and MH, followed by controlled release when examined in-vitro using non-fickian and quasi-fickian model. Antibacterial studies confirmed >99% antibacterial activity against both Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) and bacterial adherence test demonstrated its efficacy for arresting microbial invasion. Wound healing analysis conducted in-vivo showed enhanced epithelialization in the terms scar prevention and aesthetics with absolute wound contraction for the mice treated with AV loaded dressings after 14th post wounding day. Histological features displayed ordered deposition of collagen with a thin epidermis layer. Hence, the present herbal dressing could function without many cytotoxicity and biocompatibility issues. PMID- 30248423 TI - Cytotoxicity of two water-soluble polysaccharides from Codonopsis pilosula Nannf. var. modesta (Nannf.) L.T.Shen against human hepatocellular carcinoma HepG2 cells and its mechanism. AB - Two water-soluble polysaccharides named CPP1a and CPP1c were isolated from C. pilosula Nannf. var. modesta L.T.Shen by hot-water extraction and purified by graded alcohol precipitation and DEAE-52 cellulose column. The structure of CPP1c with higher yield has been characterized while its antitumor activities has not been elucidated. In this study, we firstly analyzed the chemical structure of CPP1a. The results of instrumental analysis combined with chemical analysis showed that CPP1a was composed of ->1)- beta-l-Rhap-(4->, ->1)- beta-Arap-(5->, >1)- beta-d-GalpA-(4->, ->1)- beta-d-Galp-(6->, terminal-beta-d-Glcp in a molar ratio of 1:12:1:10:3 and its relative and absolute molecular weight were 1.01 * 105 Da and 1.03 * 105 Da respectively. Further, the cytotoxicity assay indicated that CPP1a and CPP1c were more sensitive to HepG2 cells than cervical carcinoma Hela cells and gastric carcinoma MKN45 cells. Both of CPP1a and CPP1c could influence cell morphology, inhibit the migration and induce apoptosis by affecting the G2/M phase of HepG2 cells. Preliminary mechanism studies confirmed that CPP1a and CPP1c could induce apoptosis through up-regulating the ratio of Bax/Bcl-2 and activating caspase-3. According to previous research, we might speculate that the reason for the stronger cytotoxicity and pro-apoptotic effect of CPP1c than that of CPP1a can be attributed to its high uronic acid content. PMID- 30248424 TI - Co-delivery of 5-fluorouracil and oxaliplatin in novel poly(3-hydroxybutyrate-co 3-hydroxyvalerate acid)/poly(lactic-co-glycolic acid) nanoparticles for colon cancer therapy. AB - In the present study, a novel 5FU and OXA co-loaded PHBV/PLGA NPs was developed which induced apoptosis in cancer cells. NPs were prepared by the double emulsion method and their preparation was optimized using D-optimal design of response surface methodology (RSM). 5FU-OXA loaded NPs were evaluated by SEM, DSC and DLS. NPs were spherical as shown by SEM and the results of DSC indicated that both drugs successfully entrapped into NPs. 5FU-OXA loaded NPs exhibited higher cytotoxicity effect than free drugs on cancer cells. For the first time to our knowledge, these results showed that more ROS generation and stronger activation of the ROS-dependent apoptotic pathway were induced by 5FU and OXA delivered by NPs. Furthermore, it was observed that NPs were hemocompatible. Co-loaded NPs exhibited significantly higher antitumor efficiency compared to free drugs combination, indicating this co-delivery system provides great potential in cancer therapy. The results of present study also confirmed that PHBV/PLGA NPs can be served as a promising platform for the co-delivery of antitumor drugs and present a new view for treatment of cancer with reducing side effect of drugs. PMID- 30248425 TI - Flow, dynamic viscoelastic and creep properties of a biological polymer produced by Sphingomonas sp. as affected by concentration. AB - In this work, the influence of the concentration on the flow behaviour, dynamic viscoelastic and creep properties of diutan gum in aqueous solution was investigated. Diutan gum is a biopolymer which belongs to the sphingans group. To know its rheological properties and its microstructure as a function of the concentration is directly related to the current and future applications of this biological polymer. Mechanical spectra showed a crossover point between G' and G" which changed as a function of diutan gum concentration. A master curve for the frequency dependence on the eta* was obtained. The creep compliance results made it possible to deduce the yield stress value and they were fitted to Burgers model. A shear-thinning behaviour was exhibited by diutan gum aqueous solutions, which was fitted to the Carreau-Yasuda model. Higher G', G", tau0 and eta0 values and lower omegac, Je0, gammac and n values were obtained by increasing the gum concentration, it is being possible to modulate the viscoelasticity, viscosity and shear resistance as a function of concentration. A more complex structure with stronger entanglements between macromolecules of diutan was obtained when the concentration of diutan increases. PMID- 30248426 TI - Structural and functional analysis of Glutaminyl-tRNA synthetase (TtGlnRS) from Thermus thermophilus HB8 and its complexes. AB - Aminoacyl-tRNA synthetases (AaRSs) are vital enzymes for translation of proteins in cells. AaRSs catalyse the esterification of a specific amino acid to corresponding tRNAs to form an aminoacyl-tRNA that is used in ribosome-based protein synthesis. We focused on Glutaminyl tRNA synthetase (GlnRS) enzyme from the extreme thermophile Thermus thermophilus for structural studies. Our thermal shift assays show binding of enzyme substrates L-Gln and ATP as well as of various metals including cesium. We resolved crystal structures of apo-GlnRS as well as those in complex with AMP and ATP at 2.8 A, 2.4 A and 2.6 A respectively. The bound cesium was found at the site of magnesium that typically binds to GlnRS. High structural conservation was evident in the Thermus thermophilus GlnRS when compared to those from Escherichia coli GlnRS. PMID- 30248427 TI - Silica nanoparticles induce conformational changes of tau protein and oxidative stress and apoptosis in neuroblastoma cell line. AB - The adverse effects of SiO2 NPs on the biological systems like nervous system have not been well explored. This study aimed to evaluate the toxicity of SiO2 NPs on the nervous system in vitro. Therefore, human tau protein and neuroblastoma cell line (SH-SY5Y) were used as targets. In this study we examined the side effects of SiO2 NPs on tau protein structure using several techniques including CD, ANS fluorescence, UV-vis (360 nm), Congo red absorbance, TEM, and molecular dynamic. Also, the cytotoxicity effects of SiO2 NPs against SH-SY5Y cell line were evaluated using MTT, ROS and apoptotic assays. Spectroscopic and molecular dynamic investigations indicated that natively unfolded structure of tau in the presence of SiO2 NPs experienced a partially folded and amorphous aggregated structure. Cellular assay demonstrated that SiO2 NPs exerted cytotoxic effect on SH-SY5Y cells through ROS accumulation and induction of apoptosis. Overall, these findings proved that SiO2 NPs could induce adverse effects on tau structure and SH-SY5Y cell integrity. Moreover, further studies are required to elucidate the molecular mechanism of SiO2 NPs-induced side effects in vivo. PMID- 30248428 TI - Preparation of biocompatible wound dressings with long-term antimicrobial activity through covalent bonding of antibiotic agents to natural polymers. AB - Wound dressings with long-term antimicrobial activity are highly desired for treatment of chronic wound infections. Herein, the sustained antimicrobial wound dressings were developed by using antibiotic agents, ciprofloxacin HCL (CIP) and gentamicin sulfate (GS), covalent bonding to natural polymer matrix composites, carboxymethyl chitosan (CMC) and collagen (COL). By amide bond formation between antibiotic agents and polymer chains, two antimicrobial wound dressings CMC-COL CIP and CMC-COL-GS were prepared. The presented wound dressings exhibited high water absorption capacity, excellent water vapor transmission rate (WVTR), appropriate mechanical properties, and impressive stability. Cytocompatibility of the dressings was demonstrated by in vitro human skin fibroblast (HSF) cells culture study. The results of in vitro and in vivo studies indicated that the two antimicrobial wound dressings have effective antimicrobial activity and prolonged antimicrobial period. Furthermore, the antimicrobial dressings could promote the wound healing, reepithelialization, collagen deposition, and angiogenesis. It also displays superiority wound healing effects compared to commercially available silver-based dressings (Aguacel Ag). This work indicates that the prepared antimicrobial wound dressings have great potential application in chronic wound healing, such as severe wound cure and diabetic foot ulcers. PMID- 30248429 TI - Enhancement of bio-desulfurization capability of a newly isolated thermophilic bacterium using starch/iron nanoparticles in a controlled system. AB - Due to the increasing application of oil and petroleum products, increased environmental contamination has become a matter of concern. Bio-desulfurization process may be used to eliminate sulfur from fossil fuels in the moderate condition. In this study, a thermophilic bacterium was isolated that was able to desulfurize dibenzothiophene. 16S rRNA sequencing indicated that this strain is related closely to Bacillus thermoamylovorans (97%). This strain grew in Basal salt medium containing DBT (100 mgl-1) as the only sulfur source, at 55 degrees C and showed maximum growth (OD660 = 0.850) following 72 h incubation time. 2 hydroxybiphenyl was produced at the maximal concentration (26.13 +/- 0.12 mgl-1) at 72 h. Bio-desulfurization and growth rate factors were optimized using response surface methodology. Starch/Fe3O4 and starch/Fe nanoparticles were used for enhancement of BDS efficiency. The size of starch/Fe3O4 and starch/Fe nanoparticles were 20 and 30-40 nm, respectively, as described by using scanning electron microscope and transmission electron microscope. The results showed that the immobilized cells by starch/Fe3O4 and starch/Fe nanoparticles had higher desulfurization capacity, about 10% and 22% more, respectively. Also, BDS in a bioreactor in the presence of nanoparticles was increased 25% with respect of the process occurred in the flask. PMID- 30248431 TI - Comprehensive analysis of damage associated SNPs of MMP9 gene: A computational approach. AB - Extracellular matrix is a dynamic meshwork of macromolecules that plays an important role in biological processes such as tissue remodeling and various developmental processes. Collagen is the chief component of ECM. Upon hydrolysis, it forms an irreversible left-handed helical structure which is further hydrolyzed by a specialized group of MMP family i.e. Gelatinases (MMP2 and MMP9). Present study was carried to figure out deleterious SNPs associated with MMP9 gene. Our results showed that two nsSNP (rs8125581 and rs41529445) that are present in catalytic domain are highly conserved and affect the protein structure and function.7 SNPs located in UTRs were found to alter miRNA seed region 13 SNPs of splice site were predicted to affect splice signals thereby affecting the post translational expression of MMP9. Most of the SNPs are still uncharacterized thereby present study provides a direction that can help to validate the relation between the altered expressions and functions of MMP9 protein in terms of disease susceptibility. PMID- 30248430 TI - Extraction, characterization and in vitro antioxidant activity of polysaccharides from Carex meyeriana Kunth using different methods. AB - Response surface methodology (RSM) combined with a Box-Behnken design (BBD) was used to optimize the hot-water extraction (HWE) conditions which were determined to be: liquid-solid ratio 29.25:1 mL/g, extraction time 1.66 h, extraction temperature 95 degrees C, the optimized yield of polysaccharides 0.47 +/- 0.01% (n = 3). Hot-water extraction polysaccharides (HWEP) and Microwave-assisted extraction polysaccharides (MAEP) both consist of Rha:Xyl:Ara:Fru:Glu with the molar ratio of 1.05:1.21:3.86:1:3.61:4.5 and 1:1.95:1.72:1.78:4.36:6.18, respectively. Ultrasound-assisted extraction polysaccharides (UAEP) consists of Rha:Xyl:Ara:Fru:Man:Glu with the molar ratio of 1:2.31:5.23:1.05:3.17:4.17:7.89. The molecular weight distribution of HWEP, MAEP and UAEP ranged from 16 kDa to 1698 kDa, 15 kDa to 913 kDa, and 17 kDa to 1118 kDa, respectively. The absorption peaks in FT-IR confirmed the skeletal modes of the pyranose ring in polysaccharides. The second derivative of FT-IR proved difference of polysaccharides obtained from different extraction methods. The antioxidant activity investigations shown all three polysaccharides extracts possess high scavenging activity of DPPH radicals, hydroxyl radical and ABTS+ radical. Polysaccharides from Carex meyeriana Kunth (CMKP) might be potentially used for various practical applications such as medical and food industries, and this paper provides a theoretical basis and reference for further study of CMK. PMID- 30248432 TI - "Polytox" synthetic cathinone abuse: A potential role for organic cation transporter 3 in combined cathinone-induced efflux. AB - Synthetic cathinone derivatives are a new class of psychoactive substances (NPS), also known as "bath salts", designed to exert psychostimulant effects resembling those of well-known psychostimulants, such as cocaine and 3,4 methylenedioxymethamphetamine (MDMA, "ecstasy"). As major constituents of bath salts, the cathinone derivatives 3,4-methylenedioxypyrovalerone (MDPV) and 4 methylmethcathinone (mephedrone), have received considerable media attention. MDPV and mephedrone interfere with the function of the high affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT), resulting in increased extracellular levels of these monoamines, though their mechanism of action differs. MDPV acts as a non-transported inhibitor of DAT, NET and SERT, whereas mephedrone promotes transporter-mediated release in an amphetamine-like fashion. MDPV and mephedrone are often taken together, creating a conundrum in as much as non-transported inhibitors, like MDPV, prevent mephedrone-induced reverse transport via DAT, NET and SERT. Here we provide evidence supporting a role for organic cation transporter 3 (OCT3) in the actions of mephedrone, which may account for its ability to enhance effects of MDPV. We show that mephedrone can induce substrate efflux via OCT3 in the presence of MDPV. Real-time recordings of the fluorescent OCT3 substrate (4-(4-dimethylamino)styryl)-N-methylpyridinium (ASP+) and radiotracer-flux studies using [3H]1-methyl-4-phenyl-pyridinium (MPP+), demonstrated that OCT3 is MDPV-insensitive when expressed in human embryonic kidney (HEK293) cells. Ex vivo experiments performed in cultured superior cervical ganglia (SCG) cells, rich in NET and OCT3, revealed that mephedrone induces [3H]MPP+ release in an OCT3-dependent manner when NET is fully occupied with MDPV. These results extend our recent findings that OCT3 is key in the mechanism of action of amphetamine-induced substrate release. OCT3 likewise appears to be a mechanism through which mephedrone can induce release of monoamines, thereby accounting for the paradoxically more potent psychostimulant effects of MDPV taken together with mephedrone, and greater risk for deleterious side effects. PMID- 30248433 TI - 1,8-cineole decreases neuropathic pain probably via a mechanism mediating P2X3 receptor in the dorsal root ganglion. AB - 1,8-cineole is a natural monoterpene cyclic ether present in eucalyptus and has been reported to exhibit anti-inflammatory and antioxidant effects. The therapeutic effects of 1,8-cineole on neuropathic pain and the molecular mechanisms of its pharmacological actions remain largely unknown. In the present study, we investigated the analgesic mechanisms of orally administered 1,8 cineole in a rat model of chronic constriction injury (CCI) and examined the drug induced modulation of P2X3 receptor expression in dorsal root ganglia. The mechanical withdrawal threshold and thermal withdrawal latency were measured in rats to assess behavioural changes 7 and 14 days after CCI surgery. Changes in P2X3 receptor mRNA expression of L4-5 dorsal root ganglia were analysed using quantitative real-time polymerase chain reaction at the 7th and 14th postoperative day. Additionally, we examined the expression of P2X3 receptor protein in L4-5 dorsal root ganglia 7 and 14 days after surgery using immunohistochemistry and western blots. We found that 1,8-cineole can alleviate pathological pain caused by P2X3 receptor stimulation and explored new methods for the prevention and treatment of neuropathic pain. PMID- 30248434 TI - The P2X7 Receptor, Cathepsin S and Fractalkine in the Trigeminal Subnucleus Caudalis Signal Persistent Hypernociception in Temporomandibular Rat Joints. AB - Temporomandibular joint (TMJ) is frequently involved with rheumatoid arthritis with a high prevalence that could result in a chronic pain state. Once the disease is established in the joint, the antigen-specific immune reaction initiates a neuro-immune cascade of events that causes sensitization of the central nervous system. This study establishes animal experimental models that evaluate the chronicity of albumin-induced arthritis hypernociception in the TMJ. Antigen-induced arthritis was generated in rats with methylated bovine serum albumin (mBSA) diluted in complete Freund's. Intra-articular injection of mBSA (10 ug/TMJ/week) during 3 weeks resulted in a persistent inflammatory hypernociception which was characterized by an inflammatory episode characterized by the increased of lymphocytes, macrophages and pro-inflammatory interleukins IL 12 and IL-18. The persistent model of inflammatory hypernociception induced by arthritis in the TMJ elicited protein levels of P2X7 receptors, cathepsin S and fractalkine in the trigeminal subnucleus caudalis. Overall, the results of the present work suggest that a persistent inflammatory hypernociception of albumin induced arthritis in the TMJ leads to the activation of the central nervous system signaling by P2X7/cathepsin S/fractalkine pathway. PMID- 30248435 TI - Sex-Dependent Effects of Mild Blast-induced Traumatic Brain Injury on Corticotropin-releasing Factor Receptor Gene Expression: Potential Link to Anxiety-like Behaviors. AB - Traumatic brain injury (TBI) affects 1.7 million people in the United States every year, resulting in increased risk of death and disabilities. A significant portion of TBIs experienced by military personnel are induced by explosive blast devices. Active duty military personnel are especially vulnerable to mild blast induced (mb)TBI and the associated long-term effects, such as anxiety disorders. Additionally, females are at an increased risk of being diagnosed with anxiety related disorders. The mechanism by which mbTBI results in anxiety disorders in males and females is unknown. The sexually dimorphic corticotropin-releasing factor (CRF) is a brain signaling system linked to anxiety. CRF and its family of related peptides modulate anxiety-related behaviors by binding to CRF receptor subtypes 1 and 2 (CRFR1, CRFR2, respectively). These receptors are distributed throughout limbic structures that control behaviors related to emotion, memory, and arousal. Therefore, the aim of this study was to understand the link between mbTBI and anxiety by examining the impact of mbTBI on the CRFR system in male and female mice. mbTBI increased anxiety-like behaviors in both males and females (p < 0.05). In the present study, mbTBI did not alter CRFR1 gene expression in males or females. However, mbTBI disrupted CRFR2 gene expression in different limbic structures in males and females. In males, mbTBI increased baseline CRFR2 gene expression in the ventral hippocampus (p < 0.05) and decreased restraint-induced expression in the anterior bed nucleus of the stria terminalis (aBNST) and amygdala (p < 0.05). In females, mbTBI decreased restraint-induced CRFR2 gene expression in the dorsal hippocampus (p < 0.05). The inherent sex differences and the mbTBI-induced decrease in restraint-induced CRFR2 gene expression may contribute to anxiety-like behaviors. The results of the present study show that the response to mbTBI within the limbic structures modulates anxiety in a sex dependent manner. The studies further suggest that CRFR2 may serve as a potential target to mitigate mbTBI effects. PMID- 30248436 TI - Frequency-Dependent Stimulus-Specific Adaptation and Regularity Sensitivity in the Rat Auditory Thalamus. AB - Recent electrophysiological studies in animals using oddball stimuli have demonstrated that neurons along the auditory pathway from the inferior colliculus to the auditory cortex (AC) have a strong response to rarely presented stimuli. This phenomenon is termed stimulus-specific adaptation (SSA), which is regarded as novelty detection. However, in the medial geniculate body (MGB), it is not clear whether SSA is frequency dependent or if neurons in the MGB are sensitive to the regularity of the stimuli. In this present study, we analyzed the relationship between stimulus frequency and SSA, as well as explored regularity sensitivity using extracellular recordings in the MGBs of rats with regular and irregular oddball stimuli. It was found MGB neurons exhibited strong SSA when the pure-tone stimulus of the oddball stimulus deviated far from the characteristic frequency, even in the ventral region of the MGB, suggesting that the MGB may contribute to SSA in the primary AC. Moreover, we found the neuronal population in the MGB was sensitive to high-order sound structure, where deviant responses were smaller and standard responses were stronger for irregular oddball stimuli. We conclude that regularity detection occurs in the MGB, but in a manner distinct from the AC. PMID- 30248437 TI - Dependence of the frequency distribution around a vessel on the voxel orientation. AB - In this work the frequency distribution around a vessel inside a cubic voxel is investigated. Therefore, the frequency distribution is calculated in dependence on the orientation of the voxel according to the external magnetic field. The frequency distribution exhibits an interesting peak structure that cannot be explained by the established Krogh's vessel model. The results were validated with phantom measurements and in vivo measurements that agree very well with the developed theory. PMID- 30248438 TI - Stigma control model of dysregulated eating: A momentary maintenance model of dysregulated eating among marginalized/stigmatized individuals. AB - Stigma is a factor commonly experienced by marginalized groups that may serve as a maintenance factor for dysregulated eating. In the current paper, we propose a momentary maintenance model, grounded in previous theoretical and empirical research, termed the stigma control model of dysregulated eating. Our model proposes that momentary experiences of stigma lead to emotional distress, which in turn is associated with engagement in numerous maladaptive stigma management strategies intended to curb future stigma. These stigma management strategies, however, serve to increase emotional distress, which in turn promotes dysregulated eating. This model has applications for understanding the maintenance of dysregulated eating among marginalized groups, as well as implications for developing novel treatments and refining existing treatments for dysregulated eating. Future studies should use methods that capture momentary experiences to evaluate the proposed stigma control model of dysregulated eating. PMID- 30248439 TI - Increasing consumers' attention capture and food choice through bottom-up effects. AB - To guide consumers in their decision process, especially food products often carry labels indicating production method or nutritional content. However, past research shows that many labels are rarely attended to in the consumer's decision process. In order to enhance the effectiveness of such labels and to increase choice likelihood of labeled products, the label must capture attention. We address the question of how a single label on the product packaging can capture attention through bottom-up effects and increase choice through increased attention capture. To this end, we conducted a combined eye tracking and choice experiment manipulating the surface size and visual saliency - the two most important bottom-up effects on attention - of the Danish organic label across three food product categories. Results show a strong and significant increase in attention capture towards a larger and more visually salient label. Most importantly, the effect of attention capture carried over into increased choice likelihood. Both marketers and policy makers might benefit from this approach, which provides directions for designing product labels that can influence attention capture and product choice. PMID- 30248440 TI - Life course influences on food provisioning among low-income, Mexican-born mothers with young children at risk of food insecurity. AB - BACKGROUND: World migration shifts emphasize the necessity of framing health behavior in the context of life course. Mexican-born households in the U.S. disproportionally experience food insecurity, a condition associated with poor health. Food assistance programs may not be accessible to immigrants, suggesting food provisioning strategies may play a critical protective role. OBJECTIVE: To explore life course and ecological system influences on food provisioning among low-income, Mexican-born mothers in the U.S. to identify target influences and behaviors for interventions. METHODS: Life Course Perspective and Ecological Systems Theory guided this qualitative study. INCLUSION CRITERIA: 1) woman born in Mexico, 2) <=10 years in U.S., 3) residing in one of two New York State counties, 4) at least one child <=5 years old, and 5) <200% of the federal poverty line. Participants completed two semi-structured interviews, including a participant-driven photo elicitation interview, in English or Spanish, and a food insecurity assessment. Thematic content analysis identified emergent themes. RESULTS: Five themes emerged that were related to three key life course concepts: social context in Mexico (food insecurity experiences, agrarian experiences, and traditional foods and flavors), transitions (motherhood), and turning points (health events). All themes related to mothers' overall priority of providing home-cooked meals, and demonstrated life course influences shaping food provisioning values and strategies. CONCLUSION: Considering life course experiences is important to creating effective, multi-level approaches to reduce food insecurity among Mexican-born families in the northeastern U.S. Programs should have a particular emphasis on new or soon-to-be mothers and should include improved access to affordable in-season produce or gardening opportunities, peer led food provisioning programs, and food and nutrition assistance programs. PMID- 30248441 TI - Development and evaluation of two multi-antigen serological assays for the diagnosis of bovine tuberculosis in cattle. AB - There is currently an increased interest in the use of serological approaches in combination with traditional cell-mediated immunity-based techniques to improve the detection of tuberculosis (TB)-infected animals. In the present study, we developed and validated two different serological TB-detection assays using four antigens, MPB70, MPB83, ESAT6 and CFP10, and the tuberculin PPDb. A conventional multi-antigen TB-ELISA method and a novel TB multiplex test, based on Luminex technology, were developed to detect antibodies to multiple antigen targets. The performance levels of the two tests were evaluated and compared using selected panels of samples having known TB states. The TB-ELISA test (containing five antigens, including PPDb) had a sensitivity (Se) of 74.2% and a specificity (Sp) of 94.9%, while the TB-Luminex test had higher Se (79.0%) and Sp (99.1%) rates even when only one reactive antigen was used to classify the test as positive. If a more restrictive criterion, requiring two positive antigens to classify the test as positive, was used, then the TB-ELISA's Sp rate increased to 99.8% but the Se decreased to 61.3%, while the TB-Luminex test's Sp rate increased to 100% but the Se decreased to 51.2%. TB-ELISA and TB-Luminex were applied to a panel of 257 sera collected from bTB-positive herds, as determined by a post-mortem inspection. They showed good performance levels, identifying 49 (80.3%) and 48 (78.7%), respectively, of 61 samples that had tested positive by the intradermal tuberculin (IDT) test and/or interferon-gamma assay. In addition, TB-ELISA and TB Luminex were able to identify 60 and 42 samples as positive, respectively, out of the 196 samples that tested negative to IDT and interferon-gamma at the time of serum collection. Subsequent IDT tests performed after 1-2 months, confirmed the positivity of 18 samples, indicating the strategic value of having two serological assays to detect TB-infected herds that were not reactive to initial IDT testing, thereby allowing for the rapid control of outbreaks and eradication of the disease. PMID- 30248442 TI - Bio oil production from microalgae via hydrothermal liquefaction technology under subcritical water conditions. AB - The upsurge in the concerning issues like global warming, environmental pollution and depletion of fossil fuel resources led to the thrust on third generation biofuels. Algal research has gained a lot of importance in the recent years. Effective utilization of algal biomass in a single step is necessary as it can produce Bio-oil (BO), gases and in addition to a variety of valuable products, along with nutrient recovery. Hydrothermal liquefaction technology does not require the energy intensive drying steps and is an attractive approach for the conversion of algae to liquid fuels. This study investigates direct hydrothermal liquefaction (HTL) of microalgae (Algal biomass) to produce bio-oil using a high pressure batch reactor under subcritical water conditions. Three different micro algae samples namely, Chlorella vulgaris, Botryococcus braunii and Scenedesmus quadricauda have been examined under hydrothermal liquefaction with different water concentrations (1:6, 1:7, 1:8, 1:9 & 1:10 ratio) at certain temperature range (200-320 degrees C), pressure (60 bars) and reaction time (30 min). Through liquefaction, the highest BO yield achieved with S. quadricauda was 18 wt% at 1:9 ratio. The chemical components of the obtained bio-oil were analyzed via gas chromatography and the results indicated that the algal BO was composed of furan, phenol, acid, and ester derivatives. Moreover, it was found that by increasing the temperatures, the BO yields increased. This was due to the polymerization reactions that converted the small biomass components into heavier molecules. FTIR spectra showed high percentage of Aliphatic, Phenolic, alcoholic, Carboxylic and Hydroxyl groups for solid residues. PMID- 30248443 TI - Impact of Trypanosoma cruzi infection on nitric oxide synthase and arginase expression and activity in young and elderly mice. AB - Elderly organisms are more susceptible to infectious diseases. However, the impact of aging on antiparasitic mechanisms, especially the nitric oxide pathway, is poorly understood. Using an integrated in vivo and in vitro model, we compared the severity of Trypanosoma cruzi infection in young and elderly (8 or 72 weeks old) mice. Forty C57BL/6 mice were randomized into four groups: Y-inf, young infected; Yn-inf, young uninfected; A-inf, aged infected; An-inf, aged uninfected. Parasitemia was measured daily, and animals were euthanized after 15 days of infection. Trypanosoma cruzi-induced inflammatory processes were analyzed in blood and heart samples, as well as in bone marrow-derived macrophages (BMDMs) co-cultured with splenocytes isolated from young or elderly mice. Our results indicated upregulated IgG2b and IL-17 production in elderly animals, which was not sufficient to reduce parasitemia, parasitic load and myocarditis to levels observed in young animals. The higher susceptibility of elderly mice to T. cruzi infection was accompanied by reduced cardiac inducible nitric oxide synthase (iNOS) gene expression, nitric oxide (NO) and IFN-gamma levels, as well as an antagonistic upregulation of arginase-1 expression and arginase activity. The same responses were observed when BMDMs co-cultured with splenocytes from elderly mice were stimulated with T. cruzi antigens. Our findings indicate that elderly mice were more susceptible to T. cruzi infection, which was potentially related to an attenuated response to antigenic stimulation, inhibition of iNOS gene expression and NO production, and antagonistic upregulation of arginase gene expression and activity, which created favorable conditions for heart parasitism and myocarditis development. PMID- 30248444 TI - Disruption of the superoxide anions-mitophagy regulation axis mediates copper oxide nanoparticles-induced vascular endothelial cell death. AB - Copper oxide nanoparticles (CuONPs) have been widely used in the industrial and pharmaceutical fields; however, their toxicity profile is deeply concerning. Currently, nanomaterials-induced toxicity in the cardiovascular system is receiving increased attention. Our previous toxicological study found that lysosomal deposition of CuONPs triggered vascular endothelial cell death, indicating that the involvement of autophagic dysfunction was crucial for CuONPs induced toxicity in human umbilical vein endothelial cells (HUVECs). In the current study, we investigated the detailed mechanism underlying the autophagic dysfunction induced by CuONPs. We demonstrated that CuONPs exposure caused accumulation of superoxide anions, which likely resulted from mitochondrial dysfunctions. MnTBAP, a superoxide anions scavenger, alleviated CuONPs-induced HUVECs death, indicating that excessive superoxide anions were directly related to the CuONPs cytotoxicity in HUVECs. Interestingly, we found that mitophagy (a protective mechanism for clearance of damaged mitochondria and excessive superoxide anions) was initiated but failed to be cleared in CuONPs-treated cells, resulting in the accumulation of damaged mitochondria. Inhibition of mitophagy through Atg5 knockout or blocking of mitochondria fission with Mdivi-1 significantly aggravated CuONPs-induced superoxide anions accumulation and cell death, suggesting that mitophagy is a protective mechanism against CuONPs cytotoxicity in HUVECs. In summary, we demonstrate that superoxide anions (originating from damaged mitochondria) are involved in CuONPs-associated toxicity and that impaired mitophagic flux aggravates the accumulation of excessive superoxide anions, which leads to HUVECs death. Our findings indicate that there are crucial roles for superoxide anions and mitophagy in CuONPs induced toxicity in vascular endothelial cells. PMID- 30248445 TI - Maternal Perinatal Calorie Restriction Temporally Regulates the Hepatic Autophagy and Redox Status in Male Rat. AB - Intrauterine growth restriction leads to adult obesity, cardiovascular disease, and non-alcoholic fatty liver disease/steatohepatitis. Animal models have shown that combined intrauterine and early postnatal calorie restriction (IPCR) ameliorates these sequelae in adult life. The mechanism by which IPCR protects against adult onset disease is not understood. Autophagy, a lysosomal degradative process, recycles cellular constituents and eliminates damaged organelles, proteins, and oxidants. In this study, we hypothesized that IPCR could regulate autophagy in the liver of male rat offspring. At birth (d1) and on day 21 (p21) of life, IPCR male rat offspring had a profound decrease in hepatic autophagy in all three stages of development: initiation, elongation, and maturation. However, upon receiving a normal diet ad-lib throughout adulthood, aged IPCR rats (day 450 of life (p450)), had increased hepatic autophagy, in direct contrast to what was seen in early life. The decreased autophagy at d21 led to the accumulation of ubiquitinated proteins and lipid oxidative products, whereas the increased autophagy in late life had the opposite effect. Oxidized lipids were unchanged at d1 by IPCR treatment indicating that decreased autophagy precedes oxidative stress in early life. When cellular signaling pathways regulating autophagy were examined, the 5' adenosine monophosphate-activated protein kinase pathway (AMPK), and not endoplasmic stress pathways, was found to be altered, suggesting that autophagy is regulated through AMPK signaling pathway in IPCR rats. Taken together, this study reveals that the perinatal nutritional status establishes a nutritionally sensitive memory that enhances hepatic autophagy in late life, a process that perhaps acts as a protective mechanism to limited nutrition. PMID- 30248446 TI - Development and evaluation of isothermal amplification assay for the rapid and sensitive detection of Clostridium perfringens from chevon. AB - Loop-mediated isothermal amplification (LAMP) is a promising, simple, rapid and sensitive molecular detection method. In the present study, LAMP assay was developed for detecting Clostridium perfringens in chevon. Primers were designed to detect the cpa gene of C. perfringens. A panel of 19 bacterial strains, including 3 C. perfringens and 16 other strains, were included in this study to standardize and evaluate the LAMP assay. No false positive amplification was observed indicating 100% specificity of the assay. The detection limit of LAMP and conventional PCR in the DNA extracted from pure C. perfringens was 0.34 pg and 3.4 pg, respectively. This revealed that LAMP assay is 10 times more sensitive than conventional PCR. The sensitivity of the LAMP assay for the detection of C. perfringens in raw chevon was found to be 1.2 * 102 CFU/g after 6 h enrichment and 1.2 * 105 CFU/g without enrichment in artificial spiking studies. Improved C. perfringens detection of 12 CFU/g within 12 h was obtained proving that LAMP assay is significantly faster than traditional methods that take >2 d. The developed LAMP assay also detected the targeted organism in clinical and environmental samples with the sensitivity and specificity of 97% and 84%, respectively with Kappa agreement of 0.824 respects to PCR assay. This method shows immense potential for routine diagnosis and monitoring of C. perfringens in food, environment and clinical samples. This is the first report in which the LAMP assay was optimized for the detection of C. perfringens in chevon. PMID- 30248447 TI - Effective doxorubicin-based nano-therapeutics for simultaneous malignant lymphoma treatment and lymphoma growth imaging. AB - In this study, we report the in vivo anti-lymphoma efficacy and diagnostic potential of newly designed near-infrared fluorescent dye containing polymer doxorubicin conjugates using murine models of malignant lymphomas including one cell line-derived xenograft (RAJI) and two patient-derived lymphoma xenografts (VFN-D1 and VFN-M2). Two types of passively targeted conjugates differing in architecture of the polymer backbone were synthesized. One of the conjugates was designed using a single linear polymer chain, and the second was more sophisticated with a star-shaped high-molecular-weight (HMW) polymer employing a dendrimer core. The linear HPMA copolymers were linked to the dendrimer core via a one-point attachment, thus forming a hydrophilic polymer shell. Both polymer doxorubicin conjugates were long-circulating with reduced side effects. Both polymer prodrugs were designed as stimuli-sensitive systems in which the anti cancer drug doxorubicin was attached to the hydrophilic copolymers via a pH labile hydrazone linkage. Such polymer prodrugs were fairly stable in aqueous solutions at pH 7.4, and the drug was readily released in mildly acid environments at pH 5-6.5 by hydrolysis of the hydrazone bonds. In addition, polymers were labelled with near-infrared fluorescent dye enabling long term in vivo visualization. Malignant lymphomas represent the most common type of haematological malignancies. Therapy for the majority of malignant lymphomas consists of multi-agent chemotherapy based on an anthracycline doxorubicin, the most prominent side effect of which is cardiotoxicity. We have demonstrated significant anti-lymphoma efficacy of the polymer-doxorubicin conjugates when compared to equally toxic doses of conventional (unbound) doxorubicin in all tested models. Favourable pharmacokinetics for carried drug and labelled polymer carrier was observed, showing predominant uptake of the drug and polymer itself in the tumour mass. In addition, we have observed a promising diagnostic potential of fluorescently labelled polymer prodrugs. Dynamically analyzed fluorescence intensity over subcutaneously xenografted lymphomas closely corresponded to changes in the lymphoma tumour volumes, thereby enabling a non invasive assessment of treatment efficacy. PMID- 30248448 TI - The Blind Leading the Not-So-Blind: A Meta-Analysis of Blinding in Pharmacological Trials for Chronic Pain. AB - Patient blinding is a critical feature of double-blind placebo-controlled randomized controlled trials (RCTs). Yet, very little is known about practices for assessing and reporting blinding in chronic pain trials. We examined the rates and predictors of assessing blinding and its success in pharmacological RCTs for chronic pain. Four-hundred eight trials (n = 103,983 participant) were identified via a systematic search between 2006 and 2016. Only 23 RCTs (5.6%) reported assessing patient blinding. Larger sample size, reference to a CONSORT statement, and pharmaceutical sponsorship were associated with lower rates of assessing blinding. A meta-analysis of the available data using Bang's Blinding Index indicated that blinding was not successful when combined across studies (g = 1.12, 95% confidence interval .92-2.01). Moderator analysis revealed that higher rates of adverse events and larger treatment effect sizes were associated with worse blinding outcomes, whereas including "don't know" responses seemed to improve blinding. Overall then, blinding is rarely reported and often fails in RCTs of pharmacological interventions for chronic pain. To address this finding, we recommend that all researchers conducting RCTs for chronic pain assess and report on the status of patient blinding when reporting the trial outcome. PERSPECTIVE: This meta-analysis examined patient blinding in pharmacological RCTs of chronic pain. The results indicated that blinding is rarely assessed and often fails. Some study characteristics were associated with lower rates of assessing blinding and its success, for example, pharmaceutical sponsorship and side effects. Implications and recommendations for chronic pain RCTs are discussed. PMID- 30248449 TI - Optimising the transient expression of GABA(A) receptors in adherent HEK293 cells. AB - Owing to their therapeutic relevance, considerable efforts are devoted to the structural characterisation of membrane proteins. Such studies are limited by the availability of high quality protein due to the difficulty of overexpression in recombinant mammalian systems. We sought to systematically optimise multiple aspects in the process of transiently transfecting HEK293 cells, to allow the rapid expression of membrane proteins, without the lengthy process of stable clone formation. We assessed the impact of medium formulation, cell line, and harvest time on the expression of GABAA receptors, as determined by [3H]muscimol binding in cell membranes. Furthermore, transfection with the use of calcium phosphate/polyethyleneimine multishell nanoparticles was optimised, and a dual vector system utilising viral enhancing elements was designed and implemented. These efforts resulted in a 40-fold improvement in GABAA alpha1beta3 receptor expression, providing final yields of 22 fmol/cm2. The findings from this work provide a guide to the optimisation of transient expression of proteins in mammalian cells and should assist in the structural characterisation of membrane proteins. PMID- 30248450 TI - Improvement of extracellular secretion efficiency of Bacillus naganoensis pullulanase from recombinant Escherichia coli: Peptide fusion and cell wall modification. AB - Pullulanases are well-known starch-debranching enzymes that are widely used for hydrolysis of a-1,6-glycosidic linkages in starch, pullulan, amylopectin, and other oligosaccharides. Escherichia coli is a popular heterologous expression host for generating target enzymes. However, cells have to be disrupted to obtain the target enzyme due to the weak extracellular secretion of E. coli. In order to facilitate subsequent characterization and application of pullulanase, improving its secretion efficiency from E. coli is a major challenge that must first be solved. Considering the transport mechanism involving signal peptide as well as permeability of the cell wall, we adopted two strategies to improve the extracellular secretion of pullulanase from E. coli: (1) fusion of a negatively charged peptide at the N-terminal of the target enzyme to guide it out of the membrane of E. coli and (2) modification of the composition of the cell wall to increase its permeability. In this study, both strategies showed positive influence on the extracellular secretion of pullulanase. After fusing a negatively charged peptide at the N-terminal, the extracellular enzymatic activity increased by more than 4 times compared to the pullulanase without peptide fusion. By modifying the permeability of the cell wall, the extracellular enzymatic activity increased by 12 times. In addition, the two strategies were also used to improve the secretion efficiency of the truncated pullulanase DeltaN106, which has higher enzymatic activity than the full-length protein. The strategies employed have valuable implications for increasing the extracellular secretion efficiency of target proteins from recombinant E. coli. PMID- 30248451 TI - Expression of a thermo- and alkali-philic fungal laccase in Pichia pastoris and its application. AB - The fungal laccase Lcc9 from Coprinopsis cinerea is a promising candidate for biotechnological applications due to its distinct biochemical properties. In the present work, Lcc9 cDNA was cloned from C. cinerea using reverse transcription polymerase chain reaction and heterologously expressed in Pichia pastoris GS115. The recombinant laccase was found to be a heavily hyperglycoprotein, with the molecular weight of 60.2 kDa as determined by MALDI-TOF. Laccase activity in the culture supernatant was 1750 +/- 83 U/L and reached 3138 +/- 62 U/L after expression condition optimization using orthogonal experiment. The biochemical property of the purified recombinant Lcc9 (rLcc9) was compared to that of wild type Lcc9. rLcc9 shows a higher specific activity (315.3 U/mg) than Lcc9 (92.9 U/mg) when using ABTS (2,2'-azino-bis(3-ethylbenzothazoline-6-sulfonate)) as the substrate. Although rLcc9 and Lcc9 showed comparable optimal pH (6.5) and temperature (70 degrees C) toward syringaldazine, rLcc9 displayed higher activity and stability in the pH range of 6.5-8.5. rLcc9 showed improved ability to oxidize indigo carmine and 5 azo dyes when methyl syringate was used as the mediator, with the decolorization rate range from 71.9 +/- 3.2% to 99.1 +/- 1.6% for different dyes in a wide pH (4.5-9.0) and temperature (4-70 degrees C) ranges. In comparison, Lcc9 decolorized 50.3 +/- 2.1% to 98.2 +/- 2.0% of the dyes used. The improved activity and stability in alkaline pH of rLcc9 relative to Lcc9, and improved dye decolorization ability towards 6 dyes suggested greater application potential of rLcc9 in biotechnologies such as wastewater treatment. PMID- 30248452 TI - Expression, purification of Zika virus membrane protein-NS2B in detergent micelles for NMR studies. AB - The Zika virus (ZIKV) genome encodes a polyprotein that can be post translationally processed into functional viral proteins. The viral protease is indispensable in the maturation of viral proteins. The Zika protease comprises of two components crucial for catalysis. The N-terminal region of NS3 contains the catalytic triad and approximately 40 amino acids of NS2B are essential for folding and protease activity. NS2B is a membrane protein with transmembrane domains that are critical for the localization of NS3 to the membrane. In this study, we expressed and purified full-length NS2B from ZIKV in E. coli. Purified NS2B was then reconstituted into lyso-myristoyl phosphatidylglycerol (LMPG) micelles. It was found that compared to wild type NS2B, NS2B C11S mutation in LMPG exhibited dispersed cross peaks in the 1H15N-HSQC spectrum, thereby suggesting the feasibility for structural characterization using solution NMR spectroscopy. PMID- 30248453 TI - Cloning, expression and characterization of an endo-acting bifunctional alginate lyase of marine bacterium Wenyingzhuangia fucanilytica. AB - Alginate is the major constituent of brown algae and a commercially important polysaccharide with wide applications. Alginate lyases are desired tools for degrading alginate. Based on the genome mining of marine bacterium Wenyingzhuangia funcanilytica, an alginate lyase Aly7B_Wf was discovered, cloned and expressed in Escherichia coli. Aly7B_Wf belonged to subfamily 6 of PL7 family. Its biochemical properties, kinetic constants, substrate specificity and degradation pattern were clarified. The enzyme is an endo-acting bifunctional alginate lyase, and preferably cleaved polymannuronate (polyM). The Km (0.0237 +/ 0.0004 MUM, 0.0105 +/- 0.0002 mg/mL) and kcat/Km (1180.65 +/- 19.81 MUM-1 s-1, 2654.34 +/- 44.54 mg-1 ml s-1) indicated relatively high substrate-binding affinity and catalysis efficiency of Aly7B_Wf. By using mass spectrometry, final products of alginate degraded by Aly7B_Wf were identified as alginate hexasaccharide to disaccharide, and final products of polyguluronate (polyG) and polyM were confirmed as tetrasaccharide to disaccharide. The most predominant oligosaccharide in the final products of polyG and polyM was trisaccharide and disaccharide respectively. The broad substrate specificity, endo-acting degradation pattern and high catalysis efficiency suggested that Aly7B_Wf could be utilizied as a potential tool for tailoring the size of alginate and preparing alginate oligosaccharides. PMID- 30248455 TI - P3b amplitude as a signature of cognitive decline in the older population: An EEG study enhanced by Functional Source Separation. AB - With the greying population, it is increasingly necessary to establish robust and individualized markers of cognitive decline. This requires the combination of well-established neural mechanisms, and the development of increasingly sensitive methodologies. The P300 event-related potential (ERP) has been one of the most heavily investigated neural markers of attention and cognition, and studies have reliably shown that changes in the amplitude and latency of the P300 ERP index the process of aging. However, it is still not clear whether either the P3a or P3b sub-components additionally index levels of cognitive impairment. Here, we used a traditional visual three-stimulus oddball paradigm to investigate both the P3a and P3b ERP components in sixteen young and thirty-four healthy elderly individuals with varying degrees of cognitive ability. EEG data extraction was enhanced through the use of a novel signal processing method called Functional Source Separation (FSS) that increases signal-to-noise ratio by using a weighted sum of all electrodes rather than relying on a single, or a small sub-set, of EEG channels. Whilst clear differences in both the P3a and P3b ERPs were seen between young and elderly groups, only P3b amplitude differentiated older people with low memory performance relative to IQ from those with consistent memory and IQ. A machine learning analysis showed that P3b amplitude (derived from FSS analysis) could accurately categorise high and low performing elderly individuals (78% accuracy). A comparison of Bayes Factors found that differences in cognitive decline within the elderly group were 87 times more likely to be detected using FSS compared to the best performing single electrode (Cz). In conclusion, we propose that P3b amplitude could be a sensitive marker of early, age-independent, episodic memory dysfunction within a healthy older population. In addition, we advocate for the use of more advanced signal processing methods, such as FSS, for detecting subtle neural changes in clinical populations. PMID- 30248456 TI - Modeling regional dynamics in low-frequency fluctuation and its application to Autism spectrum disorder diagnosis. AB - With the advent of neuroimaging techniques, many studies in the literature have validated the use of resting-state fMRI (rs-fMRI) for understanding functional mechanisms of the brain, as well as for identifying brain disorders or diseases. One of the main streams in recent studies of modeling and analyzing rs-fMRI data is to account for the dynamic characteristics of a brain. In this study, we propose a novel method that directly models the regional temporal BOLD fluctuations in a stochastic manner and estimates the dynamic characteristics in the form of likelihoods. Specifically, we modeled temporal BOLD fluctuation of individual Regions Of Interest (ROIs) by means of Hidden Markov Models (HMMs), and then estimated the 'goodness-of-fit' of each ROI's BOLD signals to the corresponding trained HMM in terms of a likelihood. Using estimated likelihoods of the ROIs over the whole brain as features, we built a classifier that can discriminate subjects with Autism Spectrum Disorder (ASD) from Typically Developing (TD) controls at an individual level. In order to interpret the trained HMMs and a classifier from a neuroscience perspective, we also conducted model analysis. First, we investigated the learned weight coefficients of a classifier by transforming them into activation patterns, from which we could identify the ROIs that are highly associated with ASD and TD groups. Second, we explored the characteristics of temporal BOLD signals in terms of functional networks by clustering them based on sequences of the hidden states decoded with the trained HMMs. We validated the effectiveness of the proposed method by achieving the state-of-the-art performance on the ABIDE dataset and observed insightful patterns related to ASD. PMID- 30248454 TI - The LURN Research Network Neuroimaging and Sensory Testing (NIST) Study: Design, protocols, and operations. AB - The Neuroimaging and Sensory Testing (NIST) Study of the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) is a cross-sectional, case control study designed to investigate whether disrupted brain connectivity and sensory processing are associated with abnormal lower urinary tract symptoms (LUTS) in patients with overactive bladder syndrome (OAB). The NIST Study tests the hypotheses that patients with urinary urgency will demonstrate: (1) abnormal functional and structural connectivity of brain regions involved in urinary sensation on magnetic resonance imaging (MRI), and (2) hypersensitivity to painful (pressure) and non-painful (auditory) sensory stimuli on quantitative sensory testing (QST), compared to controls. Male and female adults (18 years or older) who present at one of the six participating LURN clinical centers for clinical care of their LUTS, with symptoms of urinary urgency with or without urgency urinary incontinence, are eligible to participate. The NIST Study is the largest MRI and QST study of its kind, yielding a neuroimaging and sensory testing dataset unprecedented in OAB research. Advanced multi-modal techniques are used to understand brain functional and structural connectivity, including gray matter volume, and sensory function. Unlike previous MRI studies which involved invasive catheterization and repeated cycles of non-physiologic bladder filling and emptying via a catheter, we use a water ingestion protocol to mimic more physiological bladder filling through natural diuresis. Furthermore, these data will be used in concert with other phenotyping data to improve our understanding of clinically meaningful subtypes of patients with LUTS in order to improve patient care and management outcomes. PMID- 30248458 TI - Catheter ablation of right-sided para-Hisian ventricular arrhythmias using a simple pacing strategy. AB - BACKGROUND: Ablation of para-Hisian ventricular arrhythmias (PH-VAs) is challenging because of the close relationship of the origin site and His bundle. Using pacing techniques to differentiate the near-field from far-field His activations, thereby avoiding atrioventricular block, has been reported in patients with para-Hisian accessory pathways. OBJECTIVES: We applied the same pacing technique and 3-dimensional mapping to guide radiofrequency (RF) ablation in patients with right-sided PH-VAs and investigated the clinical outcome of such cases. METHODS: Fourteen patients with right-sided PH-VAs were included in this study. The earliest activation sites were confirmed in the right ventricle on the 3-dimensional map. Pacing with different outputs was performed at the largest His potential site (P1) and the earliest activation site (P2). If the minimum His bundle-right bundle branch-captured output at P2 was higher than that at P1, RF ablation was performed at the site. RESULTS: All the patients in this study had monomorphic premature ventricular contractions (PVCs) with a mean QRS duration of 118.3 +/- 8.1 ms. A His-right bundle branch potential with an amplitude of 0.05 +/- 0.02 mV was recorded at P2, with a mean distance of 5.97 +/- 1.84 mm away from P1. PVCs were successfully eliminated in 13 of 14 patients (92.9%). One patient exhibited persistent right bundle branch block after ablation, and 1 recurrence of ablated PVCs occurred during a median follow-up period of 15 months. CONCLUSION: Using a simple pacing technique to evaluate the safety of RF energy application led to a high success rate of RF catheter ablation of right sided PH-VAs without atrioventricular block. PMID- 30248457 TI - Mu rhythm desynchronization is specific to action execution and observation: Evidence from time-frequency and connectivity analysis. AB - Mu desynchronization is the attenuation of EEG power in the alpha frequency range recorded over central scalp locations thought to reflect motor cortex activation. Mu desynchronization during observation of an action is believed to reflect mirroring system activation in humans. However, this notion has recently been questioned because, among other reasons, the potential contamination of mu rhythm and occipital alpha activity induced by attention processes following presentation of visual stimuli in observation conditions. This study examined the validity of mu desynchronization as a measure of mirroring system activation in infants and further investigated the pattern of functional connectivity between the central and occipital regions during execution and observation of movement. EEG was recorded while 46 9-month-old infants executed grasping actions and observed an experimenter grasping. Current source density (CSD) was applied to EEG data and, time-frequency and connectivity analyses were performed in CSD transformed data. Mu desynchronization was evident over central regions during both execution and observation of movements. Independent alpha desynchronization over occipital region was also present in both conditions. The connectivity analyses revealed that central-occipital areas were functionally more connected compared to other areas of the brain during observation of movements. Collectively, the results demonstrate the validity of mu desynchronization as an index of infant mirroring system activity and support the proposal of a functional connection between distinct mirroring and attention processes during observation of action. PMID- 30248459 TI - Reverse left ventricular structural remodeling after catheter ablation of atrial fibrillation in patients with preserved left ventricular function: Insights from cardiovascular magnetic resonance native T1 mapping. AB - BACKGROUND: Catheter ablation of atrial fibrillation (AF) improves left ventricular (LV) function in patients with LV systolic dysfunction, suggestive of underlying arrhythmia-induced adverse remodeling. OBJECTIVES: The objectives of this study were to evaluate whether arrhythmia-induced LV remodeling occurs in patients with AF and preserved LV systolic function and to assess whether this remodeling is reversible after restoration of sinus rhythm by catheter ablation. METHODS: Forty-three patients with AF and preserved LV systolic function (LV ejection fraction 62% +/- 7%) underwent cardiovascular magnetic resonance (CMR) imaging before catheter ablation including native T1 mapping using a modified Look-Locker inversion recovery sequence. Twenty-five patients underwent follow-up CMR 3 months after catheter ablation. Twenty-two matched controls without AF underwent the same CMR protocol. RESULTS: Patients with AF had higher baseline LV native T1 values than did controls (1296 +/- 55 ms vs 1243 +/- 55 ms; P < .01). During a median follow-up of 9 months (interquartile range 4-14 months), 17 patients (40%) experienced AF recurrence. No differences in baseline T1 values were observed between patients with and without AF recurrence. There was a significant decrease in native T1 values in patients with successful restoration of sinus rhythm after catheter ablation at 3 months of follow-up CMR (1300 +/- 45 ms vs 1270 +/- 55 ms; P < .01), while they remain unchanged in patients with AF recurrence (1303 +/- 51 ms vs 1309 +/- 31 ms; P = .64). CONCLUSION: These preliminary results suggest that subclinical arrhythmia-induced LV structural remodeling occurs in patients with AF and preserved LV systolic function. This remodeling might be reversible after catheter ablation with successful restoration of sinus rhythm as quantified noninvasively and gadolinium-free by CMR native T1 mapping. PMID- 30248460 TI - Curcumin and allopurinol ameliorate fructose-induced hepatic inflammation in rats via miR-200a-mediated TXNIP/NLRP3 inflammasome inhibition. AB - Excess fructose consumption causes high prevalence of metabolic syndrome and inflammatory liver diseases. The aim of the current study was to investigate the therapeutic effects and underlying molecular mechanisms of curcumin and allopurinol in high fructose-induced hepatic inflammation. Male Sprague-Dawley rats were supplied with standard rat chow and drinking water containing 10% (w/v) fructose for consecutive 12 weeks. Curcumin (15, 30 and 60 mg/kg) and allopurinol (5 mg/kg) were administered to rats via oral gavage daily from Week 7 to 12. For in vitro experiments, curcumin (2.5 MUM) and allopurinol (100 MUM) were treated to 5 mM fructose-exposed Buffalo rat liver cell line (BRL-3 A) and human hepatoblastoma cell line (HepG2), respectively. The data from these animal and hepatocyte models showed that curcumin and allopurinol ameliorated fructose induced metabolic symptom, especially hepatic inflammation in rats. Interestingly, down-regulation of microRNA-200a (miR-200a) was screened out in livers of fructose-fed rats and then validated in fructose-exposed BRL-3 A and HepG2 cells. Fructose-induced miR-200a low-expression was identified as a negative mediator of thioredoxin interacting protein (TXNIP) by direct targeting of 3'UTR-rTXNIP, subsequently activating the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome in BRL-3 A cells. Curcumin, as well as allopurinol, notably up-regulated miR-200a expression, accordingly, down regulated TXNIP and inhibited NLRP3 inflammasome activation in fructose-fed rat livers and fructose-exposed BRL-3 A and HepG2 cells. Taken together, this study firstly identified miR-200a as a biomarker of fructose-induced hepatic inflammation, and revealed the hepatoprotection of curcumin and allopurinol via up-regulating miR-200a-mediated TXNIP/NLRP3 inflammasome pathway. PMID- 30248461 TI - 2'-Hydroxyflavanone induced changes in the proteomic profile of breast cancer cells. AB - In spite of rapid advances in understanding of signaling networks associated with the incidence and therapeutic-sensitivity, breast cancer (BC) still remains the most commonly diagnosed and prevalent cancer in women. Emergence of resistance to hormonal interventions in estrogen-receptor (ER) positive BC coupled to loss of ER expression and activation of ER-independent growth factor, heat-shock, MYC and WNT pathways along with distinct mechanisms of therapeutic-resistance in HER2 over-expressing and triple-negative subtypes of BC collectively necessitates deeper profiling of the mechanistic networks regulated by potential lead anticancer compounds intended for further development to target BC. A significant part of the search for novel lead anticancer compounds for BC has focused on phytochemicals including flavonoids found in citrus fruits, which have shown promising anticancer activity. Based on the initial studies which revealed the anticancer effect of 2HF in BC, we employed an advanced TMT 10plex labeled proteomic approach to characterize the changes in non-phosphorylated and phosphorylated proteomic profile of ER+ MCF7, triple-negative MDA-MB231 and HER2+ SKBR3 BC cells, and MCF10A normal breast epithelial cells. 2HF induced significant changes in the proteins responsible for BC incidence, metastases and therapeutic sensitivity in BC cells. PMID- 30248462 TI - Direct evidence supporting the existence of a helical dislocation in protofilament packing in the intermediate filaments of oxidized trichocyte keratin. AB - The X-ray diffraction patterns of quill and hair, as well as other trichocyte keratin appendages, contain meridional reflections that can be indexed on an axial repeat of 470 A. Unusually, however, many of the expected orders are not observed. A possible explanation, proposed by Fraser and MacRae (1983), was that the intermediate filaments (IF) that constitute the fibrillar component of the filament/matrix texture consist of 4-chain protofilaments arranged on a surface lattice subject to a helical dislocation. The radial projection of the resulting 8-protofilament ribbon was defined in terms of a two-dimensional unit cell characterized by vectors (a, b) with axial projections za ~ 74 A and zb ~ 198 A. This situation resembles that found in microtubules, where helical dislocations in subunit packing are also encountered, leading to a so-called "seam" along their length (Metoz and Wade, 1997). In keratin, however, the protofilaments are helical so the seam is inclined to the axis of the IF. Here we report details of the Patterson function that provides independent evidence for both the helical dislocation and the dimensions of the surface lattice. In addition, the observed meridional X-ray amplitudes have been compared with those predicted by various models of the axial distribution of electron density. A new model, adapted from one previously proposed, fits the data significantly better than has heretofore proved possible. An interpretation of the model in terms of either specific keratin-associated-protein (KAP) binding or the retention of IF symmetry by a portion of the head and/or tail domains is suggested. PMID- 30248463 TI - Prolonged coma in a scrub typhus patient. AB - Central nervous system symptoms occur in more than 80% of patients with scrub typhus infection; however, the entity of central nervous system involvement is still not fully understood. We present the case of a patient with fulminant scrub typhus with multiple organ failure, including prolonged deep coma, and detail the sequential neurological symptoms, signs, laboratory data, and neuroradiological findings. PMID- 30248464 TI - Diagnostic performance of the E6/E7 mRNA-based Optimygene HR-HPV RT-qDx assay for cervical cancer screening. AB - OBJECTIVES: Pap smear and high-risk human papillomavirus (HR-HPV) DNA testing are the most widely applied methods for cervical cancer screening, but both methods are limited by their low specificity and lack of association with patient prognoses. The aim of this study was to compare the clinical and prognostic significance of HPV E6/E7 mRNA as an early biomarker with cytology and HPV DNA detection in cervical cancer screening. METHODS: This study evaluated the performance of the Optimygene HR-HPV RT-qDx assay, which is an HPV E6/E7 mRNA based assay, to detect 16 HR-HPV subtypes: HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, and 69. The clinical evaluation was conducted using 563 ThinPrep liquid-based cytology samples and the results were compared to those of cytological and histological diagnoses and HPV DNA testing. RESULTS: The clinical sensitivity and specificity of the Optimygene HR-HPV RT-qDx assay for the detection of high-grade lesions, according to cervical cytology, were 92.4% (95% confidence interval (CI) 0.9167-0.9972, p<0.0001) and 96.9% (95% CI 0.8632 0.9524, p<0.0001), respectively; they were 85.9% (95% CI 0.7631-0.9211, p<0.0001) and 82.5% (95% CI 0.7491-0.8825, p<0.0001), respectively, for CIN2+. This assay showed a higher specificity and positive predictive value for cytological and histological diagnosis than HPV DNA testing. Overall, the agreement between the Optimygene HR-HPV RT-qDx assay and HPV DNA testing in cytological and histological diagnosis was 87.9% (kappa=0.76, 95% CI 0.7054-0.8128, p<0.0001) and 90.5% (k=0.81, 95% CI 0.7338-0.8878, p<0.0001), respectively. In this study, the most frequently detected HPV genotypes among HR-HPV-positive women were HPV 16 (37.9%), HPV 33-58 (21.5%), and HPV 18 (11.4%). CONCLUSIONS: These findings suggest that the higher specificity and positive predictive value of the Optimygene HR-HPV RT-qDx assay are valuable for predicting insignificant HPV DNA infections among patients with a borderline cytological diagnosis. This assay could be used to prevent unnecessary biopsy procedures and the over-referral of patients with transient HPV infections, as well as reduce patient anxiety during the follow-up period. PMID- 30248465 TI - Outcomes in patients with fungal endocarditis: A multicenter observational cohort study. AB - OBJECTIVE: To compare the clinical and epidemiological features, treatments, and outcomes of patients with isolated right-sided and left-sided fungal endocarditis and to determine the risk factors for in-hospital mortality in patients with Candida sp endocarditis. METHODS: A retrospective review of all consecutive cases of fungal endocarditis from five hospitals was performed. Clinical features were compared between patients with isolated right-sided and left-sided endocarditis. In the subgroup of fungal endocarditis due to Candida species, binary logistic regression analysis was performed to determine variables related to in-hospital mortality. RESULTS: Seventy-eight patients with fungal endocarditis were studied. Their median age was 50 years; 55% were male and 19 patients (24%) had isolated right-sided endocarditis. Overall, cardiac surgery was performed in 46 patients (59%), and in-hospital mortality was 54%. Compared to patients with left-side fungal endocarditis, patients with isolated right-sided endocarditis had lower mortality (32% vs. 61%; p=0.025) and were less often submitted to cardiac surgery (37% vs. 66%; p=0.024). The most frequent etiology was Candida spp (85%). In this subgroup, acute heart failure (odds ratio 5.0; p=0.027) and exclusive medical treatment (odds ratio 11.1; p=0.004) were independent predictors of in-hospital death, whereas isolated right-sided endocarditis was related to a lower risk of mortality (odds ratio 0.13; p=0.023). CONCLUSIONS: Patients with isolated right sided fungal endocarditis have particular clinical and epidemiological features. They were submitted to cardiac surgery less often and had better survival than patients with left-sided fungal endocarditis. Isolated right-sided endocarditis was also a marker of a less harmful illness in the subgroup of Candida sp endocarditis. PMID- 30248466 TI - Skull Base Venous Anatomy Associated with Endoscopic Skull Base Neurosurgery: A Literature Review. AB - An understanding of the anatomy and function of the skull base venous channels is fundamentally important for safe performance of endoscopic surgery for skull base lesions. This review focuses on 4 skull base venous channels-namely, the intercavernous sinuses, basilar plexus, osseous veins, and inferior petroclival vein-because these have been less recognized by neurosurgeons than other major venous channels such as the inferior petrosal sinus. We reviewed the literature concerning these 4 venous channels and discussed their anatomy and function. The literature review was mainly based on an electronic search in PubMed using the following terms: "intercavernous sinus," "basilar plexus," "emissary veins," "diploic vein," "basilar plexus," "intraosseous vein," "inferior petroclival/petro-occipital vein," and "transclival." A total of 50 articles were included in this review. Detailed anatomic features of the 4 structures have been elucidated in the literature. All of these venous channels run along the skull base and have multiple connections with surrounding venous structures. Because of their location, they occasionally obstruct the surgical view and are sometimes implicated in intraoperative hemorrhage, air embolism during endoscopic skull base surgery, and postoperative hematoma. They usually function as a venous reservoir of cranial venous drainage; however, they are less often directly involved in normal brain perfusion. Knowledge about the functional and morphologic anatomy of the skull base venous channels is important for neurosurgeons to avoid unexpected complications during endoscopic skull base surgery. PMID- 30248467 TI - A Worst-Case Scenario-Undiagnosed Ruptured Arteriovenous Malformation Managed with Limited Resources. AB - BACKGROUND: Treatment of arteriovenous malformations (AVMs) is currently performed at specialized neurosurgical centers well equipped with microscopes with green filters, neurosurgical catheterization laboratories, and experienced neurosurgical teams. Patients in whom AVMs are diagnosed at smaller hospitals should be referred to such specialized centers. This case report describes the unavoidable worst-case scenario of an emergency unplanned surgical excision of an undiagnosed ruptured AVM with large hematoma. CASE DESCRIPTION: A 26-year-old man was brought to the emergency department with episodes of seizures and sudden loss of consciousness. His Glasgow Coma Scale score was 5. He had anisocoria. Computed tomography of the head showed right occipital hematoma with mass effect and herniation. Suspected diagnosis was spontaneous tumor or hypertensive bleed. Emergency surgery was performed. Intraoperatively, ruptured AVM was found. After explaining to family members about nonavailability of conventional instruments (i.e., microscope, clips, indocyanine green), we planned for excision of AVM with available resources. CONCLUSIONS: Postoperatively the patient recovered satisfactorily with right-side vision loss. He underwent cranioplasty after 6 weeks. In such a worst-case scenario, remaining calm, following basic surgical steps, using blood transfusion, and employing lateral thinking regarding using available resources can result in satisfactory management of the patient. PMID- 30248468 TI - Endovascular Treatment for Venous Sinus Stenosis in Idiopathic Intracranial Hypertension: An Observational Study of Clinical Indications, Surgical Technique, and Long-Term Outcomes. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure. IIH causes significant morbidity marked by incapacitating headaches and visual disturbances. This study investigated the long-term outcomes of venous sinus stenting in a large group of patients with IIH. METHODS: We retrospectively reviewed all patients at our institution who underwent venous sinus stenting for IIH over 6 years (July 1, 2012-June 30, 2018). A particular focus was dedicated to collecting demographic, clinical, radiologic, and outcomes data. All patients had failed medical management. RESULTS: Of the 110 patients evaluated for IIH, 42 underwent venous sinus stenting, with a mean follow-up of 25.6 months (range, 8.7-60.7 months). The mean age was 32 years (range, 15-52 years), 38 (90%) were women, and the mean body mass index was 35.6 kg/m2 (range, 18.6-47.5 kg/m2). Prior to the stenting procedure, all patients had headaches, visual disturbances, and papilledema. Of the 39 patients who had an ophthalmologic evaluation poststenting, 29 (74%) had resolution of their papilledema. Eighteen patients (43%) had complete resolution of their headaches after the stenting procedure, whereas 22 patients (52%) remained under a neurologist's care for chronic migraine and other types of headaches. Two patients underwent a restenting procedure for disease progression, and 1 patient experienced an in-stent thrombosis. CONCLUSIONS: A multidisciplinary approach involving neurosurgeons, ophthalmologists, radiologists, and neurologists is integral in the management of patients with IIH to prevent the complications of papilledema. Venous sinus stenting offers a safe and effective means of treating IIH. PMID- 30248470 TI - Parental Optimism About Children's Risk of Future Tobacco Use and Excessive Weight Gain. AB - BACKGROUND: Adults tend to underestimate their personal risk of disease, but little is known about parents' perceptions of children's risk. METHODS: In total, 648 parents of children 0 to 18 years old attending 2 pediatric practices were surveyed about their children's exposure to smoking; 344 parents with children >=2 years old also were asked about their children's sugar-sweetened beverage (SSB) consumption and physical activity. Children were categorized as "at risk" or "not at risk" for each factor. Parents estimated the risk of their child becoming a smoker or gaining excessive weight and were categorized as "optimistic" if they believed their children were less likely than others to use tobacco or gain weight. RESULTS: Overall, 92% of parents thought their children were at lower risk than average for tobacco use, and 86% believed their children were at lower risk for excessive weight gain. A high frequency of optimistic bias occurred even among parents with "at-risk" children, including parents with children exposed to tobacco use (70.4%), SSB consumption (77.6%), >2 hours of screen time (82.1%), and low physical activity (84.1%). In multivariable analyses, parents with children exposed to tobacco smoke (odds ratio = 0.21, 95% confidence interval, 0.09-0.51); or who consumed SSBs daily (odds ratio = 0.44, 95% confidence interval 0.20-0.97) were less likely to be optimistic about their child's future tobacco use and excessive weight gain, respectively. CONCLUSIONS: Most parents believed their children were at lower risk than average for tobacco use or excessive weight gain. Eliciting parents' optimistic biases might facilitate behavior change counseling in pediatric settings. PMID- 30248469 TI - Hypophyseal Involvement of Acute Lymphoblastic Leukemia. AB - We present an unusual case of hypophyseal involvement in a boy with acute lymphoblastic leukemia via magnetic resonance imaging findings. In our case, the acute lymphoblastic leukemia of the pituitary gland was accurately distinguished from a pituitary adenoma by contrast-enhanced dynamic hypophysis magnetic resonance imaging studies. PMID- 30248471 TI - Parental Feeding Beliefs and Practices and Household Food Insecurity in Infancy. AB - OBJECTIVE: Food insecurity is associated with childhood obesity possibly mediated through caregiver feeding practices and beliefs. We examined if caregiver feeding practices differed by household food security status in a diverse sample of infants. We hypothesized that feeding practices differ based on food security status. PATIENTS AND METHODS: Included in the baseline cross-sectional analysis of data from a randomized controlled trial to prevent obesity were 842 caregivers of 2-month-old infants presenting for well-child care at 4 academic institutions. Food insecurity exposure was based on an affirmative answer to 1 of 2 items in a 2-item validated questionnaire. Chi-square tests examined the association between parent feeding practices and food security status. Logistic regression adjusted for covariates. Differences in caregiver feeding practices by food security status and race/ethnicity were explored with an interaction term (food security status x race/ethnicity). RESULTS: Forty-three percent of families screened as food insecure. In adjusted logistic regression, parents from food-insecure households were more likely to endorse that "the best way to make an infant stop crying is to feed him or her" (adjusted odds ratio [aOR], 1.72; 95% confidence interval [CI], 1.28-2.29) and "when my baby cries, I immediately feed him or her" (aOR, 1.40; 95% CI, 1.06-1.83). Food-insecure caregivers less frequently endorsed paying attention to their baby when he or she is full or hungry (OR, 0.57; 95% CI, 0.34-0.96). Racial/ethnic differences in beliefs and behaviors were observed by food security status. CONCLUSIONS: During early infancy, feeding practices differed among caregivers by household food security status. Further research is needed to examine whether these practices are associated with increased risk of obesity and obesity-related morbidity. PMID- 30248472 TI - The association between sex and most childhood cancers is not mediated by birthweight. AB - BACKGROUND: Male sex is associated with an increased risk of childhood cancer as is high birthweight. Given that sex determination precedes birthweight we conducted a mediation analysis to estimate the direct effect of sex in association with childhood cancer tumor type with birthweight as the mediator. METHODS: Cases (n = 12,632) and controls (n = 64,439) (ages 0-14 years) were identified from population-based cancer and birth registries in Minnesota, New York, and Washington states (1970-2014). An inverse odds weighting (IOW) mediation analysis was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) as the measure of association between sex and cancer. RESULTS: A significant indirect effect was observed for sex and lymphoid leukemia, mediated by birthweight (indirectOR: 1.03; 95% CI: 1.02-1.04). We observed significant direct effects for male sex and lymphoid leukemia (directOR: 1.16; 95% CI: 1.08-1.25), Hodgkin lymphoma (directOR: 1.48; 95% CI: 1.22-1.81), Burkitt lymphoma (directOR: 5.02; 95% CI: 3.40-7.42), other non-Hodgkin lymphoma (directOR: 1.42; 95% CI: 1.18-1.70), intracranial embryonal tumors (directOR: 1.49; 95% CI: 1.26-1.76), hepatoblastoma (directOR: 1.90; 95% CI: 1.40-2.59), and rhabdomyosarcoma (directOR: 1.47; 95% CI: 1.19-1.81). There were also inverse associations for extracranial GCTs (directOR: 0.41; 95% CI: 0.26-0.63) and thyroid carcinoma (directOR: 0.35; 95% CI: 0.25-0.50). CONCLUSION: Significant direct effects for sex and numerous childhood cancer types suggests sex-specific factors such as differences in gene expression from the autosomes or the X chromosome, rather than birthweight, may underlie sex differences in tumor risk. PMID- 30248473 TI - Temporal expectancies and rhythmic cueing in touch: The influence of spatial attention. AB - Attention resources can be allocated in both space and time. Exogenous temporal attention can be driven by rhythmic events in our environment which automatically entrain periods of attention. Temporal expectancies can also be generated by the elapse of time, leading to foreperiod effects (the longer between a cue and imperative target, the faster the response). This study investigates temporal attention in touch and the influence of spatial orienting. In experiment 1, participants used bilateral tactile cues to orient endogenous spatial attention to the left or right hand where a unilateral tactile target was presented. This facilitated response times for attended over unattended targets. In experiment 2, the cue was unilateral and non-predictive of the target location resulting in inhibition of return. Importantly, the cue was rhythmic and targets were presented early, in synchrony or late in relation to the rhythmic cue. A foreperiod effect was observed in experiment 1 that was independent from any spatial attention effects. In experiment 2, in synchrony were slower compared to out of synchrony targets but only for cued and not uncued targets, suggesting the rhythm generates periods of exogenous inhibition. Taken together, temporal and spatial attention interact in touch, but only when both types of attention are exogenous. If the task requires endogenous spatial orienting, space and time are independent. PMID- 30248474 TI - A family cluster of two fatal cases infected with influenza A (H7N9) virus in Kunming China, 2017. AB - Two imported family cases (mother and daughter) of fatal H7N9 infection in Kunming, China were reported in 2017. Epidemiological investigation showed that the two family members had both been exposed to sick chickens in a poultry market. The onset of illness and death of the mother was 7 days later than her daughter, raising concerns about human-to-human transmission of H7N9 in the locality. Sequence alignment and phylogenetic analysis of the virus strains isolated from the two patients revealed high sequence similarity (>= 99%) and homology to each other. The two virus strains shared a PEIPKGR/G cleavage motif and the same key amino acid mutations across 8 viral genes except for a R292K mutation in the neuraminidase (NA) gene isolated from the mother who had been treated with oseltamivir in the clinic. Moreover, the isolated H7N9 virus possesses avian and human dual-receptor specificity and is able to efficiently proliferate in human cell lines in vitro. Further epidemiological study demonstrated that five family members who had close contacted with the patients were free of illness and negative for the H7N9 genomic test. Collectively, the H7N9 virus described here is still limited to transmit efficiently from human-to human. PMID- 30248475 TI - Robust demarcation of fourteen different species groups within the genus Streptococcus based on genome-based phylogenies and molecular signatures. AB - The genus Streptococcus comprises many important pathogens that impact human and animal health. Despite their widespread relevance, accurate classification and methods to reliably distinguish its members remain inadequate. Hence, we conducted comprehensive phylogenomics and comparative genomic analyses on 70 genome-sequenced members of this genus to delineate their interrelationships. Comprehensive phylogenetic trees were constructed based on multiple datasets of proteins, including 737 core proteins for the genus Streptococcus, 87 proteins conserved within the phylum Firmicutes, GyrA-GyrB, and RpoB-RpoC sequences. Based on the core proteins for Streptococcus species, genetic relatedness based on average amino acid identity was also determined. In parallel, comparative genomic analyses on protein sequences from this genus have identified 134 highly specific molecular markers in the form of conserved signature indels (CSIs) that are specifically shared by either the entire genus or its distinct clades/subclades. Based on the results from these multiple lines of investigations, a reliable picture of the overall evolutionary relationships within the genus Streptococcus has emerged. At the highest level, members of this genus form 2 main clades termed the "Mitis-Suis" and "Pyogenes-Equinus-Mutans" clades. Among these 2 major clades, 14 distinct subclades have been identified which include 4 previously identified species groups (viz. Pyogenes, Mutans, Salivarius and Equinus (or Bovis)); the Mitis clade, which is comprised of the Anginosus subclade and three novel subclades (viz. Pneumoniae, Gordonii and Parasanguinis), and six novel subclades termed the Suis, Sobrinus, Halotolerans, Porci, Entericus and Orisratti subclades. Members of the aforementioned subclades are reliably distinguished on the basis of their distinct branching in phylogenetic trees and multiple identified CSIs that are specifically shared by them. The molecular markers described here serve to dermarcate and clarify the interrelationships among different species groups of streptococci, and provide important means for developing novel diagnostic tests and functional studies on these bacteria which should enhance our understanding of them. PMID- 30248476 TI - Epidemiological and genetic analysis of Avian avulavirus-1 in Israel reveals parallel circulating strains and a new sub-genotype within genotype VI. PMID- 30248478 TI - Toxicological effects of fumonisin B1 in combination with other Fusarium toxins. AB - Fusarium is a fungal genus spread worldwide commonly associated to the production of several mycotoxins, where fumonisins (FBs) are of major importance due to its prevalence. Since mycotoxins have been reported to cause deleterious effects on mammalians, including carcinogenic, neurotoxic, estrogenic, and immune suppressive, many countries had established regulations on the tolerated concentrations of such substances in foods and animal feed. Even though many mycotoxins - especially fusariotoxins - are concomitantly found in a single matrix, there is no regulation on co-occurrence levels. This is possibly a result of the lack of data in the literature on the toxicological interactions between different mycotoxins. Considering this, it is of utmost importance to gather what is currently known about the combination of FBs, considered to be the most ubiquitous mycotoxins, with other frequently reported fusariotoxins, such as zearalenone (ZEA), deoxynivalenol (DON), nivalenol (NIV), T-2 toxin (T-2), and other emerging mycotoxins. This paper gives an overview about the toxic effects of fusariotoxins individually and combined to FB1, also gathering the mechanisms and probable interactions between them. This important information may help to develop regulations covering multi-mycotoxins contamination, a growing concern of current days. PMID- 30248477 TI - Curcumin prevents potassium dichromate (K2Cr2O7)-induced renal hypoxia. AB - Curcumin exhibits several therapeutic properties. Potassium dichromate (K2Cr2O7) induced nephropathy is associated with oxidative stress. Reactive oxygen species production affects renal oxygenation that may participate in the progression of renal damage. The aim of the present work was to elucidate whether K2Cr2O7 induced nephropathy is associated to partial O2 pressure (pO2) impairment and if curcumin is able to prevent it. Four groups of rats were studied: control group; K2Cr2O7 group (12.5 mg/kg, s.c.); curcumin + K2Cr2O7 group, in which animals were treated with curcumin (400 mg/kg/day, p.o.) for 10 days before K2Cr2O7 injection; and curcumin group. All animals were sacrificed 48 h after the end of the treatments. K2Cr2O7 administration increased renal function markers and decreased glomerular filtration rate, pO2 and renal perfusion. Concerning hemodynamic parameters, K2Cr2O7 increased mean arterial pressure and renal vascular resistance and reduced renal blood flow. The hemodynamic changes were attributed to decreased availability of nitric oxide and increased 3-nitrotyrosine levels. Moreover, increased superoxide anion production and vascular endothelial growth factor levels were observed after K2Cr2O7 administration. Curcumin attenuated all the above-described alterations. Our results suggest that the protective effects of curcumin in K2Cr2O7-induced nephropathy are associated with its ability to prevent O2 supply reduction. PMID- 30248479 TI - Soy-deficient diet induces renal lesions in juvenile rats. AB - Certified LabDiet(r) 5K96 Advanced ProtocolTM Verified Casein Diet 10 IF (5K96) is a commercial diet low in soy isoflavones developed for use in developmental and reproductive toxicity (DART) studies, especially those designed to detect endocrine disruptors. The objective of this study was to determine the incidences and severities of 5K96-associated renal lesions in control F0 and F1 cohorts of rats fed the 5K96 diet. Kidneys from control animals of four DART studies involving Sprague-Dawley rats fed the 5K96 diet, were evaluated microscopically. Mineralization and basophilic tubules were present in high incidence/severity in males and females compared to historical controls fed conventional diets. F1 cohorts were affected to a far greater degree than F0 cohorts, and females were affected more than males. Consideration of target tissue and mode of action should be given before automatically incorporating the 5K96 diet into DART study designs, and caution should be exercised when identifying and interpreting renal toxicity in the F1 cohorts of such studies. PMID- 30248480 TI - Comparative in vitro studies of the biological potential and chemical composition of stems, leaves and berries Aronia melanocarpa's extracts obtained by subcritical water extraction. AB - Preparation of functional products as well as natural-based products requires non toxic but effective extraction techniques. In this study, subcritical water extraction was used for the extraction of different aronia parts in order to explore their potential. Stems, leaves and berries of Aronia melanocarpa were extracted under the following conditions: temperature 130 degrees C; pressure 35 bar; time 20 min. The total phenols and flavonoid contents of the produced extracts were evaluated by conventional spectrophotometric methods. Additionally, the main phenolic compounds were also identified and quantified by high performance liquid chromatography with diode array detection (HPLC-DAD). The biological potential of the extracts was evaluated by determining their antioxidant (DPPH, ABTS and lipid peroxidation assays), antimicrobial, enzyme inhibitory (cholinesterase and elastase) and cytotoxic effects (HeLa, A-549, LS 174T, MRC-5 cell lines). The results indicate that leaves and berries extracts exhibited stronger antioxidant action when compared with stems. The strongest cholinesterase and elastase inhibitory activity was also found in berries extract. Similarly, the extracts obtained from leaves and berries showed considerable cytotoxic effects against tested cell lines. A moderate antimicrobial effects was observed too. Demonstrated biological potential of all three aronia parts can trace a new road map for developing newly designed functional products. PMID- 30248481 TI - The role of mycotoxins in the human exposome: Application of mycotoxin biomarkers in exposome-health studies. AB - Mycotoxins are secondary metabolites produced by fungi that may contaminate different foods intended for human consumption, resulting in a widespread exposure worldwide. The novel exposome paradigm has the ambition to decipher the different environmental insults threating human health throughout the entire lifespan. Given the large potential impact of mycotoxins in terms of human exposure and related health effects, the ambition of this review is to present this group of chemical compounds and the high interest to be included in exposome projects. Furthermore, we also attempt to approach the novel exposome paradigm to more traditional disciplines such as mycotoxin exposure assessment and mycotoxicology, introducing the new methodological challenges and translational needs. Hence, we provide an overview of major biomarkers currently developed, biological matrices where these may be found, an overview of internal exposure levels and potential co-occurrence with environmental chemicals and finally an overview of major health effects with the illustrative example of the potent xenoestrogen zearalenol. Conversely, these new approaches may be an excellent opportunity to fill many research gaps on mycotoxins research as the identification of associations with human health, elucidation of join effect with other environmental exposures or the decipher of underlying molecular mechanisms by using advanced OMICs technologies. PMID- 30248482 TI - NRF2 mitigates acute alcohol-induced hepatic and pancreatic injury in mice. AB - Binge alcohol drinking is an important health concern and well-known risk factor for the development of numerous disorders. Oxidative stress plays a critical role in the pathogenesis of acute alcoholism. Nuclear factor erythroid 2 like 2 (NRF2) is a master regulator of cellular adaptive response to oxidative insults. However, the role of NRF2 in acute alcoholism and associated pathologies remains unclear. We found that Nrf2-knockout (Nrf2-KO) mice had exaggerated hypoglycemia and hypothermia and increased mortality compared to wildtype mice after binge ethanol exposure. This phenotype was partially rescued by providing warm environment and/or glucose administration. Acute high dose of alcohol exposure resulted in substantially worsened liver and pancreatic injuries in Nrf2-KO mice. Importantly, deficiency of Nrf2 allowed severe pancreatitis and pancreatic beta cell injury with increased insulin secretion and/or leaking during binge ethanol exposure, which contributed to hypoglycemia. In contrast, a clinically used NRF2 activator dimethyl fumarate (DMF) protected against hypoglycemia and lethality induced by acute ethanol exposure. Furthermore, Nrf2-KO mice likely had defective hepatic acetaldehyde metabolism. Taken together, NRF2 plays an important protective role against acute binge alcohol-induced hepatic and pancreatic damage, which may be partially attributable to its primary regulating role in antioxidant response and impact on ethanol metabolism. PMID- 30248483 TI - Cytogenetic and genotoxic effects of Rosmaniric Acid on Allium cepa L. root meristem cells. AB - Rosmarinic acid (RA) is a natural polyphenol carboxylic acid, an ester of caffeic acid with 3,4-dihydroxyphenyllactic acid, found in many species. Current study was aimed to investigate the mitotic division, chromosomal and genotoxic effects of RA on Allium cepa root meristematic cells. In Allium root growth inhibition test, EC50 value was found as 100 ppm. Three concentrations (50, 100, and 200 ppm) of RA under different exposure periods (24, 48, 72 and 96 h) were employed to onion tuber roots. Distilled water and methyl methane sulfonate (MMS, 10 ppm) were used as a negative and positive control, respectively. 100 (except 24 h) and 200 ppm of RA significantly decreased mitotic index (MI). There was an increase of total chromosomal aberrations (CAs) at 50 ppm and simultaneous decrease of CAs at 200 ppm concentrations (p < 0.05). A significant increase in DNA damage was also observed at 200 ppm by Comet assay. Quantitative analysis of RA in A. cepa root meristem cells was also done by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Further investigations are required to explore the molecular mechanism involved in the cytotoxicity and genotoxicity of RA on plants. PMID- 30248484 TI - Healthy aging does not impair lower extremity motor flexibility while walking across an uneven surface. AB - It is crucial to understand age-related degenerative processes that affect dynamic postural control and ultimately increase the risk of falling for older adults. Mediolateral stability during gait, which requires active control of foot placement, may be particularly diminished with age. Using the uncontrolled manifold-analysis (UCM), we aimed to quantify the effect of age and uneven surfaces on the ability to rely on motor equivalent control to stabilize the mediolateral trajectory of the swing limb during gait. The UCM analysis tests the extent to which all available degrees of freedom (DoF) that contribute to a task relevant performance variable co-vary so as to stabilize, i.e., reduce the variance of, that performance variable. Within the UCM analysis, variability is partitioned into two components: "good" variance that has no effect on the performance variable, and "bad" variance, that results in a variable performance. A synergy index quantifies the relative amount of "good" variance compared to "bad" variance. Thirteen healthy younger (mean age 23 years) and 11 healthy older adults (mean age 73 years) walked across an even lab floor and a more challenging uneven surface. The UCM analysis was performed using lower extremity segment angles as the DoF that contribute to the mediolateral trajectory of the swing limb. We found that both, young and older adults were able to exploit motor flexibility to stabilize the foot trajectory regardless of walking condition, resulting in similar synergy indices. However, to counteract the age-related increase in performance destabilizing variability on the uneven surface, older adults increased "good" variability to similar degree. We conclude that increasing variability is not a sign of decreased motor control but rather an intentional strategy of the neuromuscular system to compensate for possible age related declines in strength and balance. There is great potential to improve fall prevention programs by introducing tasks that promote, rather than limit, exploration of motor solutions to strengthen appropriate synergies. PMID- 30248485 TI - Theory of mind disturbances in borderline personality disorder: A meta-analysis. AB - Impairments of theory of mind (ToM) are widely accepted underlying factors of disturbed relatedness in borderline personality disorder (BPD). The aim of this meta-analysis a was to assess the weighted mean effect sizes of ToM performances in BPD compared to healthy controls (HC), and to investigate the effect of demographic variables and comorbidities on the variability of effect sizes across the studies. Seventeen studies involving 585 BPD patients and 501 HC were selected after literature search. Effect sizes for overall ToM, mental state decoding and reasoning, cognitive and affective ToM, and for task types were calculated. BPD patients significantly underperformed HC in overall ToM, mental state reasoning, and cognitive ToM, but had no deficits in mental state decoding. Affective ToM performance was largely task dependent in BPD. Comorbid anxiety disorders had a positive moderating effect on overall and affective ToM in BPD. Our results support the notion that BPD patients' have specific ToM impairments. Further research is necessary to evaluate the role of confounding factors, especially those of clinical comorbidities, neurocognitive functions, and adverse childhood life events. Complex ToM tasks with high contextual demands seem to be the most appropriate tests to assess ToM in patients with BPD. PMID- 30248486 TI - Facial emotion recognition deficits and alexithymia in borderline, narcissistic, and histrionic personality disorders. AB - Previous studies that aimed to support emotion recognition deficits and alexithymia in B cluster personality disorders have mainly focused on borderline personality disorder (BPD), and resulted in mixed findings. In our study we examine emotion recognition and alexithymia in patients with histrionic (HPD), narcissistic (NPD) and borderline (BPD) personality disorders compared to each other and healthy controls. Furthermore, the possibility is investigated that it is not the type of PD but the severity of psychopathology which predicts the severity of emotion recognition deficits and alexithymia. Patients with HPD, NPD, BPD and healthy controls (N = 20 for each group) were examined by using the Ekman 60 Faces Test (FEEST) and the Toronto Alexithymia Scale (TAS-20). To measure the extent and severity of psychopathology, the Symptom-Checklist-90 Revised (SCL-90 R) was used. Patient groups performed significantly worse compared to healthy controls on the Ekman test and TAS-20, while we found no significant differences among patient groups in emotion recognition and alexithymia. Furthermore, higher scores on the SCL-90-R predicted poorer emotion recognition performance and higher alexithymic features. The empirical data supports the conclusion that the severity of psychopathology plays an important role in predicting emotion recognition deficits and alexithymia in borderline, narcissistic, and histrionic personality disorders. PMID- 30248487 TI - The role of mitochondria in NLRP3 inflammasome activation. AB - The NLRP3 inflammasome is a multiprotein platform which is activated upon cellular infection or stress. Its activation leads to caspase-1-dependent secretion of proinflammatory cytokines like interleukin-1beta (IL-1beta) and IL 18, and an inflammatory form of cell death termed as pyroptosis. Recent studies have unveiled the pivotal roles of mitochondria in initiation and regulation of the NLRP3 (nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3) inflammasome. NLRP3 activators induce mitochondrial destabilization, NLRP3 deubiquitination, linear ubiquitination of ASC, and externalization or release of mitochondria-derived molecules such as cardiolipin and mitochondrial DNA. These molecules bind to NLRP3 that is translocated on mitochondria and activate the NLRP3 inflammasome. Here we review recently described mechanisms by which mitochondria regulate NLRP3 inflammasome activation. PMID- 30248489 TI - Identification of genes involved in steroid alkaloid biosynthesis in Fritillaria imperialis via de novo transcriptomics. AB - Crown imperial (CI) has been used in traditional medicine. Today it is known that such beneficial effects are due to its richness in steroidal alkaloids (SA). Using de novo transcriptomics, orthologues/paralogues finder, phylogenetic analysis and tissue- and developmental stage-specific expression analysis, we identified ten genes and several TFs involved in the biosynthesis of SA in CI. The comparative analysis of ten genes expression profiles revealed the possibility of their co-regulation, which may imply the possibility of their organization in metabolic gene clusters. Having in mind convergent evolution of steroidal biosynthetic pathways in flowering plants and records of convergent evolution of specific proteins, observed expression patterns open a reasonable interest to investigate the possibility of the existence of genes cluster organization in SA pathway in the family Liliaceae or at least in some species of genus Fritillaria. Obtained results support transcriptomics as useful approach in elucidating genes underlying complex biochemical pathways. PMID- 30248488 TI - Molecular pathology of adverse local tissue reaction caused by metal-on-metal implants defined by RNA-seq. AB - Total hip arthroplasty (THA) alleviates hip pain and improves joint function. Current implant design permits long-term survivorship of THAs, but certain metal on-metal (MoM) articulations can portend catastrophic failure due to adverse local tissue reactions (ALTR). Here, we identified biological and molecular differences between periacetabular synovial tissues of patients with MoM THA failure undergoing revision THA compared to patients undergoing primary THA for routine osteoarthritis (OA). Analysis of tissue biopsies by RNA-sequencing (RNA seq) revealed that MoM patient samples exhibit significantly increased expression of immune response genes but decreased expression of genes related to extracellular matrix (ECM) remodeling. Thus, interplay between local tissue inflammation and ECM degradation may account for the pathology and compromised clinical outcomes in select patients with MoM implants. We conclude that adverse responses of host tissues to implant materials result in transcriptomic modifications in patients with MoM implants that permit consideration of strategies that could mitigate ECM damage. PMID- 30248490 TI - Whole-genome methylation profiling from PBMCs in acute-exacerbation COPD patients with good and poor responses to corticosteroid treatment. AB - Identifying heterogeneity in chronic obstructive pulmonary disease (COPD) phenotypes is important for the development of personalized medicine. Genome-wide analysis was used to compare the methylation levels of peripheral blood mononuclear cell (PBMC) samples from 24 acute-exacerbation (AE) COPD patients with good/poor response to corticosteroid therapy and 12 non-COPD controls. Pyrosequencing was employed to validate the genome-wide analysis. In the dataset specific to COPD patients with a good response, enrichment was identified for the following: genes in the Ubl conjugation pathway, nicotinamide nucleotide metabolism, the alkaloid metabolic process, and regulation of the glucose metabolic process. Validation results confirmed CpG sites in PRKAG2 with different methylation levels in COPD patients and normal subjects. The CpG sites of ALOX5AP were specifically associated with a good response. The results suggested that a good response to corticosteroid treatment for AE-COPD should be considered a distinct subtype according to the putative epigenetic mechanism. PMID- 30248491 TI - Time course of neuromechanical and morphological adaptations to triceps surae isokinetic eccentric training. AB - OBJECTIVES: To document the magnitude and the time course of neuromechanical and morphological adaptations in response to a triceps surae eccentric training program. METHODS: Twenty healthy male subjects completed a control period followed by a 12-week isokinetic eccentric training program. Triceps surae neuromechanical and morphological evaluations were performed every 4 weeks. RESULTS: The training program led to increases in: eccentric (32%), isometric (13%) and concentric (20%) torques; eccentric (32%) and isometric (24%) electromyographic activity; and, muscle thickness (14%). Torque and muscle thickness increased until the 8th training week. Eccentric and isometric activation increased until the 4th training week. No change was found in concentric activation. The angles of peak torque in eccentric and concentric tests shifted towards longer muscle lengths. While eccentric and isometric strength gains are explained by increased neural activation and muscle mass, changes in concentric torque are not related to neural effects. CONCLUSIONS: Eccentric training led to increases in maximum eccentric and isometric force production due to adaptations in muscle activation and muscle mass. Among the advantages of the shift in the optimal length for force production towards longer lengths, are the increased total joint range of motion and a lower predisposition for muscle strain injuries. PMID- 30248492 TI - Parental harsh discipline and adolescent problem behavior in China: Perceived normativeness as a moderator. AB - This study examined the relations between parental harsh discipline (psychological aggression and corporal punishment) and adolescents' externalizing and internalizing problem behaviors and the moderating effects of adolescents' perceived normativeness of harsh discipline in Chinese society. Using a sample of 1158 Chinese middle-school students, our findings revealed that parental harsh discipline was associated with high levels of adolescent externalizing and internalizing behaviors. Adolescents' perceived normativeness of psychological aggression buffered the association between parental psychological aggression and adolescents' internalizing problem behaviors, whereas their perceived normativeness of corporal punishment buffered the association between parental corporal punishment and adolescents' externalizing problem behaviors. The findings from the current study highlight the importance of considering how adolescents' perceptions may influence the effects of parental harsh discipline on adolescent adjustment. PMID- 30248493 TI - The relation between dimensions of maltreatment, placement instability, and mental health among youth in foster care. AB - Youth in foster care with maltreatment experiences often demonstrate higher rates of mental and behavioral health problems compared to youth in the general population as well as maltreated youth who remain at home. Previous research has demonstrated that dimensions of maltreatment (type, frequency, and severity) and placement instability are two prominent factors that account for high rates of psychopathology (e.g., depression, anxiety, and disruptive behavior disorders). The present study sought to clarify the relation between maltreatment and mental health among youth in foster care by studying both the isolated dimensions of maltreatment and cumulative maltreatment, and to determine whether the effects of maltreatment on mental health operated indirectly through placement instability. Information on youth in foster care's (N = 496, Mage = 13.14) mental and behavioral health, maltreatment history, and placement changes were obtained from state records and primary caregivers. Using a SEM framework, the results suggest that maltreatment and placement instability each independently relate to mental and behavioral health problems. Further, none of the maltreatment types predicted greater placement instability in the current models. These findings suggest that placement stability is critical for mental health for youth in foster care, regardless of the type, severity, or frequency of their maltreatment experiences. Results also indicated that, although cumulative maltreatment predicted both internalizing and externalizing symptoms, maltreatment frequency and severity had direct relations to externalizing symptoms only. These findings underscore the utility of comprehensive maltreatment assessment, encouraging researchers and clinicians to assess and carefully consider the relation between maltreatment dimensions and outcomes. PMID- 30248494 TI - Hair cortisol in newly diagnosed bipolar disorder and unaffected first-degree relatives. AB - OBJECTIVE: Hair cortisol is a promising new biomarker of retrospective systemic cortisol concentration. In this study, we compared hair cortisol concentrations in patients with newly diagnosed bipolar disorder (BD), their unaffected first degree relatives and healthy individuals and identified potential predictors of hair cortisol concentrations in patients with BD. METHOD: In a cross-sectional design, we compared hair cortisol concentrations in 181 patients with newly diagnosed/first episode BD, 42 of their unaffected first-degree relatives and 101 healthy age- and sex-matched individuals with no personal or first-degree family history of affective disorder. In patients with BD, we further investigated whether medication- and illness related variables, as well as measures of stressful life events in the preceding 12 months and childhood trauma, were associated with hair cortisol concentrations. RESULTS: Hair cortisol concentrations were 35.1% (95%CI: 13.0-61.5) higher in patients with BD (P = 0.001) compared with healthy individuals in models adjusted for age and sex. Hair cortisol concentrations in unaffected first-degree relatives did not differ from healthy individuals (P = 0.8). In patients, neither medication, illness duration nor stress related variables were associated with hair cortisol concentrations. CONCLUSION: We found elevated hair cortisol concentrations in patients newly diagnosed with BD indicating the presence of physiological stress in early stages of BD. PMID- 30248495 TI - Clinical value of 99mTc-HYNIC-TOC SPECT/CT for the diagnosis primary small cell neuroendocrine carcinomas of the nasal cavity and paranasal sinuses. AB - PURPOSE: To evaluate the diagnostic value of 99mTc-HYNIC-TOC SPECT/CT in the detection of primary small cell neuroendocrine carcinomas of the nasal cavity and paranasal sinuses. METHODS: From September 2005 to November 2015, 19 patients (mean age 53.9 years, range 37-77; male 6, female 13) with sinonasal small cell neuroendocrine carcinoma (SNEC) underwent whole-body 99mTc-HYNIC-TOC SPECT/CT scan. RESULTS: All 19 primary lesions were detected by 99mTc-HYNIC-TOC SPECT/CT. A total of 212 metastatic lesions were identified by organ-based analysis, and the sensitivity and specificity of 99mTc-HYNIC-TOC SPECT/CT were 90.5% and 92.3%, respectively. The application of 99mTc-HYNIC-TOC SPECT/CT resulted in the detection of a higher number of lesions in 11 patients (57.9%) and in the successful alteration of the treatment in 7 patients (36.8%) compared with the morphological imaging methods. CONCLUSION: 99mTc-HYNIC-TOC scintigraphy is an effective method for the detection of the sinonasal SNEC. PMID- 30248496 TI - Identification of a mutagenic chlorination by-product produced from (E)-1, 3 dichloropropene (a component of nematocide DD) by using high resolution LC/MS and multivariate analysis. AB - The estimated domestic usage of DD (a typical nematocide) has been the greatest among all the agricultural chemicals in Japan. DD is involved in a document which is used to establish tap water quality standard in Japan. The document indicates that DD is potentially detectable in raw water for tap waters. DD in raw water will be treated with chlorine at waterworks, which raises concerns about formation of mutagenic chlorination by-products through the treatment. The objective of this work was to identify a mutagenic chlorination by-product by using high resolution mass spectrometers and multivariate analyses. Mutagenicity of the chlorination by-product was evaluated with the Ames Salmonella mutagenicity assay. (E)-1,3-Dichloropropene (DCP) was used as a model compound of DD. The mutagenicity of chlorine treated model aqueous solutions of DD increased with increasing chlorine dosages up to 3.00 mol-Cl2/mol-DCP. From the chlorine treated aqueous solutions of DD, 1,3-dichloroacetone (DCA) was identified as a major mutagen by a cochromatography with an authentic standard, precursor ion analyses and first-generation product ion analyses with the high resolution mass spectrometers. The mutagenicity of DCA against TA100 strain without microsomal activation was 160,000 net revertant colony/MUmol (the toxicity equivalent factor was 0.14). Based on the mutagenicity of the chlorine treated DCP sample, the specific mutagenicity of DCA, and the DCA concentration in the sample, the mutagenic contribution of DCA to the chlorine treated DCP sample was calculated. High contribution (98%) clearly shows that DCA is a major mutagen in the chlorine treated DCP sample. Because the exploration of DCA was performed by using the unrealistic high concentration samples of DCP and chlorine, formation of DCA in the practical concentration samples (0-200 MUg-DCP/L, 0.10 or 1.27 mg-Cl2/L) was examined. It was proven that DCA formation reaction takes place in the practical concentrations of DCA and chlorine. PMID- 30248497 TI - Occurrence of polybrominated diphenyl ethers, perfluorinated compounds, and nonsteroidal anti-inflammatory drugs in freshwater mussels from Latvia. AB - The occurrence of polybrominated diphenyl ethers (PBDE), perfluorinated compounds (PFC), and nonsteroidal anti-inflammatory drugs (NSAID) in Latvian freshwater ecosystems was evaluated by using filter-feeding mussels as bioindicators. Twenty four samples of mussels were collected from freshwater bodies throughout the territory of Latvia during the summer of 2017. PBDE contamination was ubiquitous, reaching the highest total concentration of 193.2 pg g-1 w.w. BDE-209 was the most abundant compound, followed by penta-BDE components BDE-49, -100, -99, -153, -154, and -47 in decreasing order. The levels of PFCs in Latvian mussels were generally lower than those reported from other regions. Perfluorooctanoic acid (PFOA) was more common in mussels than perfluorooctane sulfonate (PFOS). Ibuprofen was the only NSAID detected in mussels during this study (detection frequency 50%). The observed concentrations of this compound varied between 0.52 and 109 ng g-1 w.w., being noticeably higher than reported by other authors. Overall, the results indicate that among the three analysed groups of contaminants, ibuprofen is present in Latvian freshwater environment at relatively high levels and further monitoring should be carried out. PMID- 30248498 TI - Occurrence of benzophenones, parabens and triclosan in the Yangtze River of China, and the implications for human exposure. AB - Humans could be exposed to ingredients in personal care products (PCPs) via ingestion of water originated from contaminated water source, yet little attention has been focused on the distribution of benzophenones, parabens and triclosan in the Yangtze River water from China so far. Benzophenones, parabens and triclosan were analyzed in the water samples from 20 various sites in the middle reach of the Yangtze River, China from March to July, and September during 2015. Among the targeted compounds, p-hydroxybenzoic acid (PHBA, a paraben metabolite) was found with the highest concentration (median: 510 ng/L), followed by benzophenone-1 (2.79 ng/L), methylparaben (MeP, median 2.72 ng/L) and triclosan (median: 1.85 ng/L). Significant differences were observed in seasonal variations for most observed compounds. Parabens and benzophenones showed higher concentrations in spring while triclosan and PHBA showed higher concentration in summer. Spatial variations of benzophenone-1 were observed among 20 sampling sites, whereas other benzophenones, parabens and triclosan distributed evenly comparatively. Human exposure assessment showed higher estimated daily intake of the detected compounds for infants and toddlers from water than adults, implicating that infants may experience a higher exposed risk than adults. This study provides evidence that parabens, benzophenones and triclosan commonly occurred in the Yangtze River. PMID- 30248499 TI - Estimate of gas transfer velocity in the presence of emergent vegetation using argon as a tracer: Implications for whole-system denitrification measurements. AB - Denitrification associated with emergent macrophytes is a pivotal process underlying the treatment performance of wetlands and slow-flow waterways. Laboratory scale experiments targeting N losses via denitrification in sediments colonized by emergent macrophytes require the use of mesocosms that are necessarily open to the atmosphere. Thus, the proper quantification of N2 effluxes relies on the accurate characterization of the air-water gas exchanges. In this study, we present a simple approach for direct measurements of the gas transfer velocity, in open-top mesocosms with Phragmites australis, by using argon as a tracer. Different conditions of water velocity (0, 1.5, 3, and 6 cm s 1) and temperature (8.5, 16, and 28 degrees C), were tested, along with, for the first time, the presence of emergent vegetation. The outcomes demonstrated that water velocity and temperature are not the only factors regulating aeration at the mesocosm scale. Indeed, the gas transfer velocity was systematically higher, in the range of 42-53%, in vegetated compared to unvegetated sediments. The increase of small-local turbulence patterns created within water parcels moving around plant stems translated into significant modifications of the reaeration process. The adopted approach may be used to improve the accuracy of denitrification measurements by N2 efflux-based methods in wetland and slow-flow waterway sediments colonized by emergent macrophytes. Moreover, the present outcomes may have multiple implications for whole-system metabolism estimations from which largely depend our understanding of biogeochemical dynamics in inland waters that have strong connections to worldwide issues, such as nitrate contamination and greenhouse gas emissions. PMID- 30248500 TI - Poor replicability of recommended exercise interventions for knee osteoarthritis: a descriptive analysis of evidence informing current guidelines and recommendations. AB - OBJECTIVE: To examine the reporting completeness of exercise-based interventions for knee osteoarthritis (OA) in studies that form the basis of current clinical guidelines, and examine if the clinical benefit (pain and disability) from exercise is associated with the intervention reporting completeness. DESIGN: Review of clinical OA guidelines METHODS: We searched MEDLINE and EMBASE for guidelines published between 2006 and 2016 including recommendations about exercise for knee OA. The studies used to inform a recommendation were reviewed for exercise reporting completeness. Reporting completeness was evaluated using a 12-item checklist; a combination of the Template for Intervention Description and Replication (TIDieR) and Consensus on Exercise Reporting Template (CERT). Each item was scored 'YES' or 'NO' and summarized as a proportion of interventions with complete descriptions and each intervention's completeness was summarized as the percentage of completely described items. The association between intervention description completeness score and clinical benefits was analyzed with a multilevel meta-regression. RESULTS: From 10 clinical guidelines, we identified 103 original studies of which 100 were retrievable (including 133 interventions with 6,926 patients). No interventions were completely described on all 12 items (median 33% of items complete; range 17-75%). The meta-regression analysis indicated that poorer reporting was associated with greater effects on pain and no association with effects on disability. CONCLUSION: The inadequate description of recommended interventions for knee OA is a serious problem that precludes replication of effective interventions in clinical practice. By consequence, the relevance and usability of clinical guideline documents and original study reports are diminished. PROSPERO: CRD42016039742. PMID- 30248501 TI - Why past research successes do not translate to clinical reality: gaps in evidence on exercise program efficacy. PMID- 30248502 TI - OCD: an unsolved puzzle in articular cartilage problems. PMID- 30248503 TI - Juvenile osteochondritis dissecans of the knee is a result of failure of the blood supply to growth cartilage and osteochondrosis. AB - OBJECTIVE: Juvenile osteochondritis dissecans (JOCD) is similar to osteochondrosis dissecans (OCD) in animals, which is the result of failure of the cartilage canal blood supply, ischemic chondronecrosis and delayed ossification, or osteochondrosis. The aim of the current study was to determine if osteochondrosis lesions occur at predilection sites for JOCD in children. METHOD: Computed tomographic (CT) scans of 23 knees (13 right, 10 left) from 13 children (9 male, 4 female; 1 month to 11 years old) were evaluated for lesions consisting of focal, sharply demarcated, uniformly hypodense defects in the ossification front. Histological validation was performed in 11 lesions from eight femurs. RESULTS: Thirty-two lesions consisting of focal, uniformly hypodense defects in the ossification front were identified in the CT scans of 14 human femurs (7 left, 7 right; male, 7-11 years old). Defects corresponded to areas of ischemic chondronecrosis in sections from all 11 histologically validated lesions. Intra cartilaginous secondary responses comprising proliferation of adjacent chondrocytes and vessels were detected in six and two lesions, whereas intra osseous responses including accumulation of chondroclasts and formation of granulation tissue occurred in 10 and six lesions, respectively. One CT cyst-like lesion contained both a pseudocyst and a true cyst in histological sections. CONCLUSION: Changes identical to osteochondrosis in animals were detected at predilection sites for JOCD in children, and confirmed to represent failure of the cartilage canal blood supply and ischemic chondronecrosis in histological sections. PMID- 30248504 TI - T2-relaxation time of cartilage repair tissue is associated with bone remodeling after spongiosa-augmented matrix-associated autologous chondrocyte implantation. AB - OBJECTIVE: To investigate whether T2 relaxation time measurements of cartilage repair tissue and structural changes of the knee joint are associated with subchondral bone architecture after spongiosa-augmented matrix-associated autologous chondrocyte implantation (MACI). DESIGN: Both knees of 25 patients (25.5 +/- 7.8y; 10 women) were examined preoperatively and 2.7 years after unilateral spongiosa-augmented MACI with 3T magnetic resonance (MR) imaging. Cartilage composition was assessed using T2 relaxation time measurements, subchondral trabecular bone microstructure was quantified using a 3D phase-cycled balanced steady state free-precision sequence. Structural knee joint changes were assessed using the modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). The Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score was used for the postoperative description of the area that underwent MACI. Correlations were assessed using Spearman's rank correlation coefficients. RESULTS: Hypertrophy of the cartilage repair tissue was found in 2 of 25 patients, both after a MACI procedure at the patella, 21 patients showed congruent filling. In subchondral bone of the cartilage repair compartment, apparent trabecular thickness was significantly higher in compartments with elevated cartilage T2 (n = 17; 0.37 +/- 0.05 mm) compared to those showing no difference in cartilage T2 compared to the same compartment in the contralateral knee (n = 8; 0.27 +/- 0.05 mm; P = 0.042). Significant correlations were found between the overall progression of WORMS and the ipsilateral vs contralateral ratio of average trabecular thickness (r = 0.48, P = 0.031) and bone fraction (r = 0.57, P = 0.007). CONCLUSIONS: After spongiosa-augmented MACI, T2 values of cartilage repair tissue and structural knee joint changes correlated with the quality of the underlying trabecular bone. PMID- 30248505 TI - Human C-reactive protein aggravates osteoarthritis development in mice on a high fat diet. AB - OBJECTIVE: C-reactive protein (CRP) levels can be elevated in osteoarthritis (OA) patients. In addition to indicating systemic inflammation, it is suggested that CRP itself can play a role in OA development. Obesity and metabolic syndrome are important risk factors for OA and also induce elevated CRP levels. Here we evaluated in a human CRP (hCRP)-transgenic mouse model whether CRP itself contributes to the development of 'metabolic' OA. DESIGN: Metabolic OA was induced by feeding 12-week-old hCRP-transgenic males (hCRP-tg, n = 30) and wild type littermates (n = 15) a 45 kcal% high-fat diet (HFD) for 38 weeks. Cartilage degradation, osteophytes and synovitis were graded on Safranin O-stained histological knee joint sections. Inflammatory status was assessed by plasma lipid profiling, flow cytometric analyses of blood immune cell populations and immunohistochemical staining of synovial macrophage subsets. RESULTS: Male hCRP tg mice showed aggravated OA severity and increased osteophytosis compared with their wild-type littermates. Both classical and non-classical monocytes showed increased expression of CCR2 and CD86 in hCRP-tg males. HFD-induced effects were evident for nearly all lipids measured and indicated a similar low-grade systemic inflammation for both genotypes. Synovitis scores and synovial macrophage subsets were similar in the two groups. CONCLUSIONS: Human CRP expression in a background of HFD-induced metabolic dysfunction resulted in the aggravation of OA through increased cartilage degeneration and osteophytosis. Increased recruitment of classical and non-classical monocytes might be a mechanism of action through which CRP is involved in aggravating this process. These findings suggest interventions selectively directed against CRP activity could ameliorate metabolic OA development. PMID- 30248506 TI - Ovotesticular Disorders of Sex Development: Improvement in Spermatogonia after Removal of Ovary and Mullerian Structures. AB - BACKGROUND: Ovotesticular disorders of sex development is a condition defined as the presence of ovarian tissue containing ovarian follicles and testicular tissue containing seminiferous tubules in the same individual. CASE: We report on a 19 year-old who is phenotypically male, with a 46,XX/46,XY mosaicism karyotype, who presented later in life with cyclical abdominal pain that resembled menstrual cramps and unilateral undescended testes. SUMMARY AND CONCLUSION: He underwent laparoscopic hysterectomy and right salpingo-oophorectomy, resulting in cessation of his symptoms and improved sperm count. PMID- 30248507 TI - Synthesis, antiproliferative activity and molecular docking of thiocolchicine urethanes. AB - A number of naturally occurring compounds such as paclitaxel, vinblastine, combretastatin, and colchicine exert their therapeutic effect by changing the dynamics of tubulin and its polymer form, microtubules. The identification of tubulin as a potential target for anticancer drugs has led to extensive research followed by clinical development of numerous compounds from several families. In this paper we report on the design, synthesis and in vitro evaluation of a group of thiocolchicine derivatives, modified at ring-B, labelled here compounds 4-14. These compounds have been obtained in a simple reaction of 7-deacetyl-10 thiocolchicine 3 with eleven different alcohols in the presence of triphosgene. These novel agents have been checked for anti-proliferative activity against four human cancer cell lines and their mode of action has been confirmed as colchicine binding site inhibition (CBSI) using molecular docking. Molecular simulations provided rational tubulin binding models for the tested compounds. On the basis of in vitro tests, derivatives 4-8 and 14 demonstrated the highest potency against MCF-7, LoVo and A549 tumor cell lines (IC50 values = 0.009-0.014 MUM). They were more potent and characterized by a higher selectivity index than several standard chemotherapeutics including cisplatin and doxorubicin as well as unmodified colchicine. Further, studies revealed that colchicine and its several derivatives arrested MCF-7 cells in mitosis, while its selected derivatives caused microtubule depolymerization. PMID- 30248508 TI - Ugi multicomponent-reaction: Syntheses of cytotoxic dehydroabietylamine derivatives. AB - Isocyanide-based multicomponent reactions - especially the standard four component Ugi reaction - provide an easy and powerful access to compounds with an auspicious pharmacological potential. Therefore, a set of 16 novel derivatives of the diterpene dehydroabietylamine was synthesized by the Ugi-4CR. The subsequent screening of the synthesized alpha-acylamino carboxamides in colorimetric sulforhodamine B assays revealed an in vitro cytotoxicity towards several human tumor cell lines. Particularly, the rhodamine B conjugates 14-16 showed a remarkable cytotoxic activity, characterized by EC50 values in a low three-digit nanomolar range. The screening of rhodamine B amide 17 that was obtained for comparison by a Schotten-Baumann reaction showed that the linkage of the rhodamine B moiety and the diterpene influences significantly its cytotoxic potency. While 14 was highly cytotoxic and acted as a mitocan, compound 17 was not cytotoxic at all. This observation underlines the importance of the type of coupling between the diterpene and the rhodamine part. The presence of a rhodamine B moiety in the molecules doesn't necessarily guarantee that the compound is cytotoxic. PMID- 30248509 TI - Inhibitory properties of aromatic thiosemicarbazones on mushroom tyrosinase: Synthesis, kinetic studies, molecular docking and effectiveness in melanogenesis inhibition. AB - The group of 19 thiosemicarbazones (TSCs) were synthesized and its inhibitory activity toward mushroom tyrosinase and ability to inhibition of melanogenesis in B16 cells were investigated. Moreover, molecular docking of these compounds to the active site of the enzyme was performed. The obtained results allowed to make the structure-activity relationship (SAR) analysis. Kinetic studies revealed that TSCs 1, 2, 11 and 18 have better inhibitory properties than kojic acid, a reference compound, with the best inhibitory constant (Ki) value of 0.38 uM for TSC 2. According to SAR analysis, the smaller and less branched molecules exhibit higher affinity to the enzyme. Melanin production in B16 cells was inhibited by all investigated compounds at micromolar level. Most of compounds studied in this work can be considered as potent inhibitors of tyrosinase and melanogenesis. They may have broad application in food preservatives and cosmetics. Combined results of molecular docking and SAR analysis can be helpful in designing novel tyrosinase inhibitors of desired properties. PMID- 30248510 TI - Synthesis and in vitro antitumor evaluation of some new thiophenes and thieno[2,3 d]pyrimidine derivatives. AB - New thiophene (2-13) and thienopyrimidine (15-27) derivatives have been synthesized. Twenty three compounds were screened against five cell lines namely; hepatocellular carcinoma (liver) HepG-2, epidermoid carcinoma (larynx) Hep-2, mammary gland (breast) MCF-7, human prostate cancer PC-3 and epithelioid cervix carcinoma HeLa. The results revealed that compounds 15,16,17,24 and 25 showed the highest antitumor activity against all tested cell lines compared to Doxorubicin. In order to explain the expected mode of action of the observed anticancer activity, compounds 15,16,17,24 and 25 were selected to screen their DNA binding affinity and enzyme inhibitory activity against DNA polymerase, thymidylate synthase and tyrosine kinase. The results revealed that the tested compounds showed good DNA binding affinity as well as good inhibitory activity against the three enzymes which might explain the observed anticancer activity of the target compounds. PMID- 30248511 TI - Synthesis, antimicrobial activity and molecular modeling study of 3-(5-amino-(2H) 1,2,4-triazol-3-yl]-naphthyridinones as potential DNA-gyrase inhibitors. AB - Four series of triazolylnaphthyridinone derivatives were synthesized as structural surrogates of nalidixic acid. The targeted derivatives involve: 3-(5 acylamino-2H-1,2,4-triazol-3-yl)-naphtyridin-4-ones 6(a-e); 3-(5-benzylidineamino 2H-1,2,4-triazol-3-yl)-naphthyridin-4-ones 8(a-g) and their 6-bromonaphthyridin-4 one analogs 7(a-e); 9(a-g). The synthesized compounds were evaluated In vitro for their antimicrobial activity against selected resistant strains of G+ve, G-ve, and Mycobacterium phlei. The results revealed remarkable selectivity, of the tested compounds, against Bacillus subtilis and Aggregatibacter actinomycetemcomitans, which are resistant to nalidixic acid. The growth inhibition zones were ranging from 20 to 40 mm at 10 mg/ml and the respective MIC values ~3.68-6.3 uM. The results illustrate that the 6-bromo derivatives 7(a-e) and 9(a-g) were more potent than the non-brominated counterparts 6(a-e) and 8(a e) respectively. Inhibition of E. coli DNA-gyrase supercoiling activity is also evaluated. The 5-(4-methoxybanzamido)-triazolyl-6-bromonaphthyridinone (7e) exhibits IC50 = 1.94 MUg/ml, which is comparable to that of nalidixic acid (IC50: 1.74 MUg/ml). In addition, the most prominent IC50-values are displayed by: (7a;IC50: 2.77 MUg/ml); (8g; IC50: 3.78 MUg/ml); and (9d;IC50: 3.21 MUg/ml). Molecular docking to the active site of DNA-gyrase cleavage complex of Acinetobacter baumannii (PDB code: 2xkk) co-crystallized with moxifloxacin revealed similar binding modes in addition to new interactions. Assessment of drug-likeness characteristics illustrate that the synthesized compounds showed agreement to Lipinski's and Veper's parameters. The study could offer an exceptional framework that may lead to the discovery of new potent antimicrobial agents. PMID- 30248512 TI - Identification of new pyrrolo[2,3-d]pyrimidines as potent VEGFR-2 tyrosine kinase inhibitors: Design, synthesis, biological evaluation and molecular modeling. AB - Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In the current study, a series of novel pyrrolo[2,3 d]pyrimidine based-compounds was designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The newly synthesized compounds were evaluated for their ability to inhibit VEGFR-2 kinase enzyme in vitro. All the tested compounds demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range. Among these compounds, pyrrolo[2,3-d]pyrimidine derivatives carrying biaryl urea moieties (12d and 15c) exhibited IC50 values of 11.9 and 13.6 nM respectively. Additionally, most of the newly synthesized final compounds were tested on 60 human cancer cell lines. Docking of these compounds into the inactive conformation of VEGFR-2 was performed which showed comparable binding modes to that of the FDA approved VEGFR-2 kinase inhibitors. These newly discovered potent kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agent. PMID- 30248513 TI - Generalized polynomial chaos-based uncertainty quantification and propagation in multi-scale modeling of cardiac electrophysiology. AB - Uncertainty and physiological variability are ubiquitous in cardiac electrical signaling. It is important to address the uncertainty and variability in cardiac modeling to provide reliable and realistic predictions of heart function, thus ensuring trustworthy computer-aided medical decision-making and treatment planning. Statistical techniques such as Monte Carlo (MC) simulations have been applied to uncertainty quantification and propagation in cardiac modeling. However, MC simulation-based methods are computationally prohibitive for complex cardiac models with a great number of parameters and governing equations. In this paper, we propose to use the Generalized Polynomial Chaos (gPC) expansion in combination with Galerkin projection to analytically quantify parametric uncertainty in ion channel models of mouse ventricular cell, and further propagate the uncertainty across different organizational levels of cell and tissue. To identify the most significant parametric uncertainty in cardiac ion channel and cell models, variance decomposition-based sensitivity analysis was first performed. Following this, gPC was integrated with deterministic cardiac models to propagate uncertainty through ion current, ventricular cell, 1D cable, and 2D tissue to account for the stochasticity and cell-to-cell variability. As compared to MC, the gPC in this work shows the superior performance in terms of computational efficiency. In addition, the gPC models can provide a measure of confidence in model predictions, which can improve the reliability of computer simulations of cardiac electrophysiology for clinical applications. PMID- 30248514 TI - SCTICA: Sub-packet constrained temporal ICA method for fMRI data analysis. AB - Independent component analysis (ICA) has become a widely used method for functional magnetic resonance imaging (fMRI) data analysis. However, spatial ICA usually performs better than temporal ICA with regard to the stability and accuracy of functional connectivity detection, and temporal ICA is often not feasible when it is applied to the analysis of real fMRI data of the whole brain because of the excessive spatial dimensions. In this paper, to overcome these problems, we propose a sub-packet constrained temporal ICA (SCTICA) method to take advantage of the a priori information using a multi-objective optimization framework with the Newton iterative algorithm. Moreover, a splitting strategy is presented to improve the feasibility of the temporal ICA for whole brain fMRI data analysis. The experimental results of real data show that the splitting strategy improved the ability of the temporal ICA to analyze whole brain fMRI data. Furthermore, the experimental results also demonstrated that the proposed SCTICA method can not only improve the stability of the temporal ICA, but can also improve the functional connectivity detection ability compared with the classical ICA and ICA with a priori information methods. In brief, the proposed SCTICA method overcomes the problem that prevents temporal ICA from being applied to fMRI data of the whole brain, and the functional connectivity detection performance is greatly improved compared with that of traditional methods. PMID- 30248515 TI - Current state of fabrication technologies and materials for bone tissue engineering. AB - A range of traditional and free-form fabrication technologies have been investigated and, in numerous occasions, commercialized for use in the field of regenerative tissue engineering (TE). The demand for technologies capable of treating bone defects inherently difficult to repair has been on the rise. This quest, accompanied by the advent of functionally tailored, biocompatible, and biodegradable materials, has garnered an enormous research interest in bone TE. As a result, different materials and fabrication methods have been investigated towards this end, leading to a deeper understanding of the geometrical, mechanical and biological requirements associated with bone scaffolds. As our understanding of the scaffold requirements expands, so do the capability requirements of the fabrication processes. The goal of this review is to provide a broad examination of existing scaffold fabrication processes and highlight future trends in their development. To appreciate the clinical requirements of bone scaffolds, a brief review of the biological process by which bone regenerates itself is presented first. This is followed by a summary and comparisons of commonly used implant techniques to highlight the advantages of TE based approaches over traditional grafting methods. A detailed discussion on the clinical and mechanical requirements of bone scaffolds then follows. The remainder of the manuscript is dedicated to current scaffold fabrication methods, their unique capabilities and perceived shortcomings. The range of biomaterials employed in each fabrication method is summarized. Selected traditional and non traditional fabrication methods are discussed with a highlight on their future potential from the authors' perspective. This study is motivated by the rapidly growing demand for effective scaffold fabrication processes capable of economically producing constructs with intricate and precisely controlled internal and external architectures. STATEMENT OF SIGNIFICANCE: The manuscript summarizes the current state of fabrication technologies and materials used for creating scaffolds in bone tissue engineering applications. A comprehensive analysis of different fabrication methods (traditional and free-form) were summarized in this review paper, with emphasis on recent developments in the field. The fabrication techniques suitable for creating scaffolds for tissue engineering was particularly targeted and their use in bone tissue engineering were articulated. Along with the fabrication techniques, we emphasized the choice of materials in these processes. Considering the limitations of each process, we highlighted the materials and the material properties critical in that particular process and provided a brief rational for the choice of the materials. The functional performance for bone tissue engineering are summarized for different fabrication processes and the choice of biomaterials. Finally, we provide a perspective on the future of the field, highlighting the knowledge gaps and promising avenues in pursuit of effective scaffolds for bone tissue engineering. This extensive review of the field will provide research community with a reference source for current approaches to scaffold preparation. We hope to encourage the researchers to generate next generation biomaterials to be used in these fabrication processes. By providing both advantages and disadvantage of each fabrication method in detail, new fabrication techniques might be devised that will overcome the limitations of the current approaches. These studies should facilitate the efforts of researchers interested in generating ideal scaffolds, and should have applications beyond the repair of bone tissue. PMID- 30248516 TI - No evidence of seasonal variation in mild forms of depression. AB - BACKGROUND AND OBJECTIVES: Seasonal Affective Disorder (SAD) is ubiquitous in popular culture and has influenced psychiatric diagnosis with the inclusion of the seasonal pattern modifier for the Major Depressive Episode in DSM. However, recent research has not supported the association of Major Depressive Episode with seasonal changes. The present study was conducted to determine if a seasonally-related pattern of occurrence of mild variants of depression could be demonstrated in a population-based study. METHODS: This is a cross-sectional U.S. survey of adults who completed the PHQ-8 Depression Scale with mild depression defined using a PHQ-8 cut score and a second model based on the DSM-5 diagnosis, Depression with insufficient symptoms. Regression models were used to determine if either variant of mild depression was related to season, latitude, or measures of daylight hours. RESULTS: Neither measure of mild depression was related to daylight hours or its proxy measures. LIMITATIONS: Screening instruments for depression, even if consistent with DSM-5 diagnostic criteria, do not allow a formal diagnosis of depression or the exclusion of similar-appearing disorders. Current depression symptoms but not duration of depressive episode is measured. CONCLUSIONS: Mild depression is not related to seasonal changes or proxy measures of light exposure. The findings cast doubt on light deficiency as a causal factor of depressive disorders, which underpins the inclusion of the seasonal pattern modifier in DSM-5 and light supplementation as a treatment modality. PMID- 30248517 TI - Biochemical responses of common bean to white mold potentiated by phosphites. AB - Considering that the mechanisms for phosphite-afforded disease control remain elusive, this study investigated whether zinc (Zn) and copper (Cu) phosphites could possible potentiate common bean resistance to white mold, caused by Sclerotinia sclerotiorum, through the stimulation of biochemical defence responses. Lesion area and disease severity were decreased by phosphites spray, but Zn phosphite outcompeted Cu phosphite. Histopathological observations revealed fewer fungal hyphae and less collapse of the mesophyll cells in the Zn and Cu phosphite-sprayed plants compared to water-sprayed ones. The S. sclerotiorum-triggered accumulation of reactive oxygen species, oxalic acid (a fungal secreted toxin) and malondialdehyde (an indicator of cellular damage) were constrained as a result of Zn and Cu phosphites spray. Activities of antioxidant enzymes (superoxide dismutase, peroxidase, ascorbate peroxidase and glutathione-S transferase at 12 h after inoculation (hai) and catalase at 60 and 84 hai) were higher for Zn and Cu phosphites-sprayed plants than for water-sprayed ones. Activities of defence-related enzymes chitinase (CHI) at 12 hai, beta-1,3 glucanase (GLU) and polyphenoloxidase (PPO) were higher at 12-84 hai for Zn, and Cu phosphites sprayed plants, phenylalanine ammonia-lyase at 36-84 hai for the Zn phosphite sprayed ones, CHI at 12-36 hai, GLU at 12-60 hai, PPO at 36 hai and PAL and lipoxygenase at 12 hai for the Cu phosphite sprayed ones upon inoculation with S. sclerotiorum relative to their water-sprayed counterparts. Concentrations of total soluble phenols and lignin-thioglycolic acid derivatives were not affected by Cu phosphite spray on infected plants but were higher and lower, respectively, for Zn phosphite sprayed plants at 60 hai compared to water-sprayed ones. Taken together, the findings from the present study shed light on the biochemical defence mechanisms involved in the Zn and Cu phosphites-mediated suppression of white mold in common bean. PMID- 30248519 TI - Multi-parameter characterization of water stress tolerance in Vitis hybrids for new rootstock selection. AB - Drought in grapevine could be faced using tolerant rootstocks. The present work aims at the evaluation of 25 new genotypes potentially tolerant to drought by using recent methods of phenotypical screening (thermography and on-solid reaction spectroscopy). Plants were grown in well-watered and stressed field conditions. Proxi for transpiration, wood hydrophobicity and starch content were used to characterize and classify the genotypes. The predominant role of the environment was highlighted, nevertheless genotype and genotype * environment interaction showed significant variations as well. Hybrids were classified based on their steady, susceptible or adaptable behavior. The 14 most promising genotypes were identified, 5 of them showing two tolerance mechanisms. In the future, results from this experiment will support viticulture in water limited areas releasing new drought-tolerant interspecific hybrids to be tested after grafting with different scions. PMID- 30248520 TI - Subcellular distribution and chemical forms of lithium in Li-accumulator Apocynum venetum. AB - Apocynum venetum is a promising species to remediate an emerging environmental contaminant lithium (Li). However, no research has been conducted so far relating Li tolerance mechanism. In order to improve the understanding of Li transportation and detoxification, subcellular accumulation and distribution of different chemical forms of Li was studied in Apocynum venetum. Subcellular Li compartmentalization analysis showed that majority of Li was located in vacuole (45.52-72.65%) and cell wall (14.84-29.02%) under Li treatment. Furthermore, water soluble and ethonal extracted Li (inorganic Li) are the main chemical forms of Li taken up by A. venetum. With the increase of Li concentration in the medium, Li content in all subcellular fractions and proportion of F-ethanol form with high mobility increased. The greatest amount of Li was found in soluble fraction in leaves at 25 mg L-1 Li treatment, followed by soluble fraction in leaves at 2.5 mg L-1. These results suggest that Li compartmentation in leaf vacuoles is important in Li detoxification and Li accumulation of A. venetum. PMID- 30248518 TI - Genome-wide identification and characterization of apple long-chain Acyl-CoA synthetases and expression analysis under different stresses. AB - Long-chain acyl-CoA synthetases (LACSs) are members of the acyl-activating enzyme superfamily that have important roles in lipid synthesis and storage, fatty acid catabolism, vectorial acylation, and synthesis of cutin and wax. Here, 11 apple MdLACS genes were identified based on the Malus * domestica reference genome, clustered into six groups and mapped to ten chromosomes. Multiple sequence alignment and conserved motifs analyses showed that the sequences of the AtLACS and MdLACS proteins were highly conserved. A cis-element analysis in the promoter regions of the MdLACS genes revealed various elements related to stress responsiveness and plant hormones. Subsequently, expression analysis demonstrated that the MdLACS genes had different expression profiles in different tissues in response to various abiotic stresses. To further study the function of MdLACS genes in apple, MdLACS1 was isolated to identify its basic function, which the function of MdLACS1 in response to apple abiotic stress resistance was determined by the transgenic method. The results showed the MdLACS1 enhanced tolerance to polyethylene glycol, salt, and abscisic acid in the apple callus, suggesting that MdLACS1 is an important regulator in response to abiotic stresses. Finally, the functional interoperability network among the MdLACS proteins was predicted and analyzed, which could the understanding of the possible interactions among proteins and genes regulatory networks concerned with wax biosynthesis and regulatory mechanisms in response to abiotic stresses in apple. PMID- 30248521 TI - Microbiota - an amplifier of autoimmunity. AB - Many studies describe dysbiosis as a change in the microbiota that accompanies autoimmune illnesses, but little is known about whether these changes are a cause or consequence of an altered immune state. The immune system actively shapes the composition of the microbiota, with divergent outcomes in healthy or autoimmune prone individuals. The gut microbiota in turn acts as an acquired endocrine organ, influencing the physiology of the host via release of nutrients and chemical messengers. Dysbiosis arising from abnormal immune function can initiate or amplify autoimmunity through multiple mechanisms. We examine how the bidirectional relationship between resident microbes and the immune system contributes to autoimmune diseases. PMID- 30248522 TI - Extracellular matrix and the maintenance and loss of peripheral immune tolerance in autoimmune insulitis. AB - There is a growing appreciation that the extracellular matrix (ECM) contributes to both the maintenance of immune tolerance in healthy tissues and to its loss at sites of autoimmunity. Here, we review recent literature on the role of ECM and particularly the glycosaminoglycans hyaluronan and heparan sulfate in the development of autoimmune, type 1 diabetes (T1D). Data from transplant models suggest that healthy islets are embedded within an intact ECM that supports beta cell homeostasis and provides physical and immunoregulatory barriers against immune infiltration. However, studies of human insulitis as well as the non-obese diabetic (NOD) and DORmO mouse models of T1D indicate that autoimmune insulitis is associated with the degradation of basement membrane structures, the catabolism of the islet interstitium, and the accumulation of a hyaluronan-rich, pro-inflammatory ECM. Moreover, in these models of autoimmune diabetes, either the pharmacologic inhibition of heparan sulfate catabolism, the reduction of hyaluronan synthesis, or the targeting of the pathways that sense these ECM changes can all prevent beta-cell destruction. Together these data support an emerging paradigm that in healthy islets the local ECM contributes to both immune tolerance and beta-cell homeostasis while in chronic inflammation the islet ECM is permissive to immune infiltration and beta-cell destruction. Therapies that support ECM-mediated 'barrier tolerance' may have potential as adjunctive agents in combination regimens designed to prevent or treat autoimmunity. PMID- 30248523 TI - IL-6: a cytokine at the crossroads of autoimmunity. AB - IL-6 is implicated in the development and progression of autoimmune diseases in part by influencing CD4 T cell lineage and regulation. Elevated IL-6 levels drive inflammation in a wide range of autoimmune diseases, some of which are also characterized by enhanced T cell responses to IL-6. Notably, the impact of IL-6 on inflammation is contextual in nature and dependent on the cell type, cytokine milieu and tissue. Targeting the IL-6/IL-6R axis in humans has been shown to successfully ameliorate a subset of autoimmune conditions. In this review, we discuss recent studies investigating how IL-6 regulates the CD4 T cell response in the context of autoimmune disease and highlight how blocking different aspects of the IL-6 pathway is advantageous in the treatment of disease. PMID- 30248524 TI - Combined use of live-attenuated and inactivated influenza vaccines to enhance heterosubtypic protection. AB - The limited protection of current commerical vaccines necessitates the investigation of novel vaccine strategies for unpredictable outbreaks. To investigate the feasibility of using vaccines derived from Group 1 influenza A virus to induce broadly cross-reactive immune responses against multiple influenza subtypes, we tested a panel of sequential 4-dose immunization regimens in mice. Mice were treated with inactivated (seasonal H1N1, pandemic H1N1 and H5N1) and vaccinia virus-based H5N1 live-attenuated vaccines in different combinations. Mice were then challenged by viruses of either Group 1 (H1N1) or Group 2 (H3N2, H7N7) influenza virus. All studied sequential 4-dose vaccinations could induce some degrees of heterosubtypic protection in mice. Amongst all these regimens, the combined use of inactivated and live-attenuated vaccines could achieve the best heterologous protection. These results highlight the synergistic effect of combining different vaccine platforms to enhance heterosubtypic protection against influenza viruses. PMID- 30248525 TI - HSV-2 glycoprotein J promotes viral protein expression and virus spread. AB - HSV-2 spread is predominantly dependent on cell-to-cell contact. However, the underlying mechanisms remain to be determined. Here we demonstrate that HSV-2 gJ, which was previously assigned no specific function, promotes HSV-2 cell-to-cell spread and syncytia formation. In the context of viral infection, knockout or knockdown of gJ impairs HSV-2 cell-to-cell spread among epithelial cells or from epithelial cells to neuronal cells, which leads to decreased virus production, whereas ectopic expression of gJ enhances virus production. Mechanistically, gJ increases the expression levels of HSV-2 proteins, and also enhances viral protein expression and replication of heterologous viruses like HIV-1 and JEV, suggesting that HSV-2 gJ likely functions as a regulator of viral protein expression and virus production. Findings in this study provide a basis for further understanding the role of gJ in HSV-2 replication. PMID- 30248526 TI - Abnormal brain processing of gentle touch in anorexia nervosa. AB - Body image disturbance is a core symptom in anorexia nervosa (AN). Recent research suggests that abnormalities in touch perception may contribute to the disease mechanisms in AN. Here, we used functional magnetic resonance imaging (fMRI) to study possible abnormalities in cortical processing of affective touch in AN. Gentle skin strokes were applied to the right forearm during fMRI scanning in women diagnosed with AN (n = 25) and in matched healthy controls (HC; n = 25). Blocks of skin stroking were alternated with blocks of static skin indentation. Participants provided ratings of the pleasantness of skin stroking stimulation. AN participants perceived skin stroking as significantly less pleasant than HC. We observed no group differences for the contrast between skin stroking and skin indentation in primary tactile regions. We did find, however, significantly less activity in the AN group in areas including left caudate nucleus. Also, we found less activity in the AN group in bilateral lateral occipital cortex for the main effect of skin stroking. Our results suggest that abnormal functioning of the dorsal striatum could affect evaluation of pleasant tactile stimuli, and that abnormal functioning of the lateral occipital cortex might be related to disturbed body image perception. PMID- 30248527 TI - Prevalence of anti-aquaporin 4 antibody in a diagnostic cohort of patients being investigated for possible neuromyelitis optica spectrum disorder in Western Australia. AB - OBJECTIVE: To evaluate the prevalence of anti-AQP4 antibody in serum and CSF samples from patients being investigated for possible neuromyelitis optica spectrum disorder (NMOSD) referred to the PathWest State reference laboratory using a sensitive cell-based assay (CBA). BACKGROUND: NMOSD is an inflammatory CNS disease distinct from MS, which is relatively rare in Western countries. A proportion of patients with NMOSD have detectable serum IgG antibodies that target the water channel aquaporin-4 (AQP4-IgG), but the frequency varies in different populations studied and according to the assay method employed. METHODS: Sera or CSF from a diagnostic cohort of 196 consecutive patients with possible NMOSD which had previously been screened by indirect immunofluorescence (IIF) on primate cerebellum were re-tested for AQP4-IgG reactivity to the M1 and M23 isoforms of AQP4 using a commercial CBA. A control group of 205 patients with definite MS was also included in the study. RESULTS: Of the 196 patients, only 5 sera were AQP4-IgG positive, representing 2.6% of patients in the diagnostic cohort. All 5 AQP4-IgG positive patients fulfilled the 2015 revised diagnostic criteria for NMOSD and were females of varied ethnic origins, 4 of whom had longitudinally extensive transverse myelitis. The CBA confirmed AQP4-IgG positivity in the four patients previously reported as positive by IIF, and an additional patient with NMOSD who had previously been diagnosed as MS was also identified. None of the 205 MS sera were AQP4-IgG positive. CONCLUSIONS: Our study confirms the utility and greater reliability of the M1/M23 CBA for detecting AQP4-IgG in patients with possible NMOSD, and indicates a prevalence of seropositive NMOSD in the Western Australian population similar to that in other Western populations. PMID- 30248528 TI - Reduced expression of the IL7Ra signaling pathway in Neuromyelitis optica. AB - Neuromyelitis optica (NMO) is a chronic inflammatory demyelinating autoimmune disease of the central nervous system that most commonly affects the optic nerves and spinal cord. To characterize the immunological pathways involved in NMO, whole blood RNA expression array was performed using Nanostring nCounter technology. Two major clusters of genes were found associated with NMO: T cell associated genes and the TNF/NF-kB signaling pathway. Analysis of the genes within the first cluster confirmed significantly reduced expression of IL7Ra (CD127) in the peripheral blood of NMO patients vs that in healthy controls. IL7Ra upstream transcription factors and its downstream survival signaling pathway were also markedly reduced. In line with the essential role of IL7Ra in T cell maturation and survival, a significantly lower number of naive T cells, and reduced T cell survival signaling mediated by increased BID (BH3-interacting domain death agonist) expression and increased apoptosis was observed. Cumulatively, these findings indicate that the IL7Ra signaling pathway may play a role in the autoimmune process in NMO. PMID- 30248529 TI - Improving the quality of general practice services in the UK: Surveying the activities of GPs and practice managers (abstract & commentary). PMID- 30248530 TI - Influence of cyber-attacks on longitudinal safety of connected and automated vehicles. AB - Connected and automated vehicle (CAV) has been a remarkable focal point in recent years, since it is recognized as a potential method to reduce traffic congestion, emission and accident. However, the connectivity function makes CAVs vulnerable to cyber-attacks. An intuitive method to defend cyber-attacks on CAVs is that if the error between expected and measured behaviors exceeds a predetermined threshold, a security scheme should be activated. This study investigates another type of cyber-attack, denoted as slight attacks, in which the communicated data of CAVs are randomly deviated from the actual ones and deviations do not exceed the threshold. The primary objective is to evaluate the influence of slight cyber attacks on longitudinal safety of CAVs. An empirical CAV model is first utilized to describe vehicle dynamics and generate trajectory data. A rear-end collision risk index (RCRI) derived from safe stopping distance is used to establish relation between longitudinal safety and trajectory data. Two attacked factors, communicated positions and speeds from preceding vehicles are tested. Extensive simulations are conducted and parameters are also tested via sensitivity analysis. Results indicate that (1) when one CAV is under slight cyber-attacks, it is more dangerous if communicated positions are attacked than speeds; (2) when multi CAVs are under attacked, it is possible that a situation with more vehicles under attack at a low severity may be more dangerous than that with fewer vehicles but under attack at a high severity; (3) the impact of slight cyber attacks on deceleration period is more serious compared to acceleration period. The findings of this study provide useful suggestion for defending cyber-attacks on CAVs and improving longitudinal safety in the future. PMID- 30248531 TI - A discrete mixture regression for modeling the duration of non-hospitalization medical leave of motor accident victims. AB - Studies analyzing the temporary repercussions of motor vehicle accidents are scarcer than those analyzing permanent injuries or mortality. A regression model to evaluate the risk factors affecting the duration of temporary disability after injury in such an accident is constructed using a motor insurance dataset. The length of non-hospitalization medical leave, measured in days, following a motor accident is used here as a measure of the severity of temporary disability. The probability function of the number of days of sick leave presents spikes in multiples of five (working week), seven (calendar week) and thirty (month), etc. To account for this, a regression model based on finite mixtures of multiple discrete distributions is proposed to fit the data properly. The model provides a very good fit when the multiples for the working week, week, fortnight and month are taken into account. Victim characteristics of gender and age and accident characteristics of the road user type, vehicle class and the severity of permanent injuries were found to be significant when accounting for the duration of temporary disability. PMID- 30248532 TI - The effects of roadway and built environment characteristics on pedestrian fatality risk: A national assessment at the neighborhood scale. AB - Characteristics of the transportation system and built environment contribute to pedestrian fatality risks, including vehicular traffic and land-use characteristics associated with higher pedestrian activity. We combined data from FHWA, NHTSA, EPA, and the Census Bureau and performed regression modeling to explore associations between transportation system and built environment characteristics and pedestrian fatalities between 2012 and 2016 at the Census tract scale across the United States. In urban tracts, we found especially strong associations between traffic on non-access-controlled principal arterial and minor arterial roadways and pedestrian fatalities (0.91 and 0.68 additional annual pedestrian fatalities per 100,000 persons per 10,000 VMT/mi2 increase in traffic density, respectively). In both urban and rural tracts, we also found strong associations between employment density in the retail sector and pedestrian fatalities. Finally, we compared our model to the High Injury Network in Los Angeles, CA. Nearly half (43%) of observed fatalities were identified by both methods, while some fatalities were identified by only one (19% by our model and 23% by the High Injury Network). This work shows that traffic on certain roadway facility types and employment in certain sectors have especially strong associations with pedestrian fatality risk. More broadly, we illustrate how leveraging cross-disciplinary data in novel ways can support prospective, risk based assessments of pedestrian fatality risks and support integrated and systemic approaches to transportation safety. PMID- 30248533 TI - Here is a hint! How children integrate reliable recommendations in their memory decisions. AB - Children's own memory is not the only reliable source of information about past events. Others may possess relevant knowledge, and children must learn to appropriately consider it in combination with their own memories. In the current study, we investigated 5-, 7-, and 9-year-olds' (N = 72) ability to incorporate probabilistically reliable (70% accurate) hints into their memory decisions. Results revealed that children across ages were appropriately sensitive to these cues without following them blindly and indiscriminately. Furthermore, individual differences in metamemory monitoring predicted overall accuracy improvements after receiving cues in 9-year-olds but not in 5- and 7-year-olds, revealing a developmental role of metamemory for discerning when cues are most informative or needed. Although 5-year-olds increased overall confidence in their memory after receiving invalid cues, they still preserved the capacity to monitor their memory in the face of inaccurate information. Overall, children were sensitive to reliable recommendations, but developing metacognitive mechanisms predicted judicious benefits from cues. PMID- 30248534 TI - A cognitive processing therapy-based treatment program for veterans diagnosed with co-occurring posttraumatic stress disorder and substance use disorder: The relationship between trauma-related cognitions and outcomes of a 6-week treatment program. AB - Dysfunctional trauma-related cognitions are important in the emergence and maintenance of posttraumatic stress disorder (PTSD) and the modification of such cognitions is a proposed mechanism of trauma treatment. However, the authors are not aware of any research examining trauma-related cognitions as a treatment mechanism in a sample of individuals with comorbid PTSD and substance use disorder (SUD). Accordingly, the present study sought to address this gap in the literature and examined the relationship between trauma-related cognitions and treatment outcomes within a sample of seventy-two veterans diagnosed with PTSD and SUD. Veterans completed a 6-week day CPT-based treatment program that included cognitive processing therapy as a central component. Measures of trauma related cognitions, PTSD symptoms, depressive symptoms, and trauma-cued substance craving were completed at pre- and post-treatment. As expected, trauma-related cognitions were associated with several PTSD-related variables prior to treatment. Furthermore, results of a within-subjects mediational analysis indicated that maladaptive trauma-related cognitions decreased during the treatment program and accounted for a significant portion of the variance in the reduction of PTSD and depressive symptoms at post-treatment. This study provides support for the position that attempts to modify dysfunctional trauma-related cognitions among veterans with co-occurring PTSD and SUD can lead to desirable treatment outcomes. PMID- 30248535 TI - Human papillomavirus knowledge, beliefs, and behaviors: A questionnaire adaptation. AB - OBJECTIVE: This study aims to adapt a questionnaire about the knowledge, beliefs and behaviors regarding HPV and related subjects into Brazilian Portuguese. STUDY DESIGN: National Survey. METHODS: The instrument was translated into Portuguese and retranslated into English separately. Experts assessed the validity of the content and cross-cultural adaptation of the instrument. The instrument was administered to 8580 male and female Brazilian adolescents and young adults (aged between 16 and 25 years) who participated in the National Survey of Human Papillomavirus Prevalence (POP-Brazil). This large-scale survey enrolled participants from 26 Brazilian capitals and the Federal District. RESULTS: The full questionnaire is composed of 30 questions, with a good absolute agreement between its two halves (61.16 +/- 9.97). The preventive behavior section showed the lowest agreement. Men and women showed a difference concerning their knowledge about HPV (score for men 0.48 (+/- 8.93) vs. women 0.55 (+/- 4.51), p < 0.001). CONCLUSION: The proposed questionnaire is the first instrument able to describe the knowledge, beliefs and behaviors regarding HPV and related subjects in Brazilian women and men. This questionnaire appears to be adequate for use in future studies that may produce evidence and knowledge on these specific topics. PMID- 30248536 TI - Knowledge of age-related fertility decline in women: A systematic review. AB - Age-related fertility decline (ARFD) knowledge has been evaluated in the past decade, showing that there is a general knowledge of the reduction of fertility with age. Here we review the studies published up to date which quantitatively measure this ARFD knowledge, to answer the question: how aware about ARFD is our society? We searched the terms "age", "fertility knowledge", "fertility awareness", "reproduction knowledge", "reproductive knowledge" and "reproductive health knowledge" in PubMed, Web of Science, PsychINFO and Scopus, within January 2000 and December 2016. We found 41 studies that quantitatively measured ARFD knowledge by asking for the most fertile age for a woman and/or when there are a slight and a marked decrease in female fertility. We obtained this searching for the questions: What is the most fertile age for a woman? (Q1). When there is a slight decrease in female fertility? (Q2) and, When there is a marked decrease in female fertility? (Q3). We further evaluated the knowledge increase in the 6 studies assessing an educational intervention, 4 of them randomized controlled trials (RCT). Participants reporting the most fertile age for women to be at 20 24 y.o. ranged 16%-89.4% (Q1); participants reporting a slight decrease in female fertility at 25-29 y.o. ranged 5.1%-83% (Q2), and those reporting that a marked decrease occurs between 35-39 y.o. ranged 5.6%-60% (Q3). On the whole, the studies included in this review conclude that ARFD knowledge is insufficient, particularly in determining when female fertility markedly decreases. ARFD knowledge can be increased through targeted campaigns, but few interventional studies have been performed up to date. In view of these results, ARFD campaigns targeted to reproductive age people and healthcare providers are necessary; this would help the society to make informed reproductive decisions throughout life. PMID- 30248537 TI - Oxidative stress-elicited YY1 potentiates antioxidative response via enhancement of NRF2-driven transcriptional activity: A potential neuronal defensive mechanism against ischemia/reperfusion cerebral injury. AB - Cerebral ischemia challenge evokes an adaptive defensive system through the induction of antioxidant enzymes. Many of such antioxidant enzymes are regulated essentially by the nuclear factor erythroid 2-related factor-2 (NRF2). Compelling evidence supports that targeting NRF2 signaling is a promising therapeutic strategy to alleviate post-I/R brain injury, but the molecular mechanisms underlying this strategy have yet to be elucidated. Herein, we show that the expression of transcription factor Yin Yang 1 (YY1) is significantly upregulated during the recovery following middle cerebral artery occlusion (MCAO). Ablation of endogenous YY1 using cerebral ventricle injection of siRNA exacerbated I/R induced neuronal damage and attenuated the antioxidant defensive system. Mechanistically, low levels of reactive oxygen species (ROS) production stimulated neuronal YY1 expression, whereas high levels of ROS exhibited a noticeable inhibitory effect. The evoked YY1, in concert with other coregulators, recruited to the antioxidant responsive elements (AREs) binding site and then amplified the NRF2-mediated ARE transcription, thereby protecting cells against damage by potentiating antioxidant response. In this regard, compromise of YY1 expression by ROS overactivity is an important etiology that sabotages the antioxidant defensive system and consequently deteriorate s neuronal damage following I/R injury. Taken together, our findings provide novel evidence on a delicate and synergistical collaboration between YY1 and the master transcription factor NRF2 that functions to mobilize the cell's antioxidant machinery. PMID- 30248538 TI - Suppression of lncRNA-ATB prevents amyloid-beta-induced neurotoxicity in PC12 cells via regulating miR-200/ZNF217 axis. AB - OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline with loss of memory. The objective of this study was to investigate the role and regulatory mechanism of lncRNA-ATB in regulating amyloid-beta-induced neurotoxicity in neuronal PC12 cells. MATERIAL AND METHODS: The expression levels of lncRNA-ATB in cerebrospinal fluid (CSF) and serum of patients with Alzheimer's disease (AD) were determined. In addition, PC12 cells were incubated with 20 MUM Abeta25-35 to induce cell injury. The lncRNA-ATB expression in Abeta25-35-treated PC12 cells was also determined. Moreover, the effects of lncRNA-ATB suppression on Abeta25-35-induced PC12 cell injury were investigated by assessing cell viability, apoptosis, cytotoxicity, and oxidative stress (intracellular Ca2+ and ROS concentrations and JC-1 mitochondrial membrane potential). Moreover, the regulatory relationships between lncRNA-ATB and miR-200 were explored, as well as the targets of miR-200 were identified. RESULTS: The results showed that lncRNA-ATB was increased expressed in the CSF and serum of patients with AD. Abeta25-35-induced injury in PC12 cells and increased the expression of lncRNA-ATB. Suppression of lncRNA-ATB alleviated Abeta25-35-induced PC12 cell injury. Further studies showed that miR-200 was negatively regulated by lncRNA-ATB. Suppression of lncRNA-ATB alleviated Abeta25-35 injury by regulation of miR-200. Moreover, miR-200 negatively regulated ZNF217 expression and ZNF217 was a target of miR-200. CONCLUSIONS: Our findings indicate that lncRNA-ATB is highly expressed in AD patients. Suppression of lncRNA-ATB may protect PC12 cells against Abeta25-35-induced neurotoxicity via regulating miR-200/ZNF217 axis. LncRNA-ATB/miR-200/ZNF217 axis may provide a new insight for preventing AD. PMID- 30248539 TI - Effect of silibinin on CFLAR-JNK pathway in oleic acid-treated HepG2 cells. AB - AIMS: Silibinin is a flavonolignan from milk thistle with many pharmacological activities including lipid-lowering and antioxidant. Caspase 8 and Fas-associated protein with death domain-like apoptosis regulator (CFLAR) is an important target gene in regulating non-alcoholic steatohepatitis (NASH). At present, the effect of silibinin on CFLAR-JNK pathway related to NASH was unknown. Here the effect of silibinin on CFLAR-JNK pathway and its downstream target genes involved in lipid metabolism, glucose uptake, oxidative stress and inflammatory response were studied in oleic acid (OA)-treated HepG2 cells. MAIN METHODS: OA-treated HepG2 cells were employed as a in vitro model of steatosis, insulin resistance and oxidative stress. The model cells were then treated by silibinin (5, 20, 50, and 100 MUM) for 24 h and detected for the related indicators as follows: (1) cellular triglycerides (TG), nitric oxide (NO) and glucose uptake; (2) the mRNA levels of the sterol regulatory element binding protein-1C (SREBP-1C), patatin like phospholipase domain containing 3 (PNPLA3) and peroxisome proliferator activated receptor-alpha (PPARalpha); (3) the protein levels of PPARalpha, SREBP 1C, PNPLA3, CFLAR, phosphorylated c-Jun N-terminal kinase (pJNK), phosphatidylinositol 3-kinase (PI3K), phosphorylated serine-threonine protein kinase (pAKT), nuclear factor E2-related factor 2 (NRF2), cytochrome P450 2E1 (CYP2E1) and 4A (CYP4A). KEY FINDINGS: Compared to the control, OA-treatment led to a result as follows: (1) increased the intracellular levels of TG and NO; (2) up-regulated the protein expression of SREBP-1C, PNPLA3, pJNK, CYP 2E1 and CYP 4A; (3) decreased the uptake of 2-NBDG; (4) down-regulated the protein expression of CFLAR, PPARalpha, PI3K, pAKT and NRF2. Compared to OA-treated HepG2 cells, silibinin treatment could improve the indicators as follows: (1) decreased the intracellular levels of TG and NO; (2) down-regulated the protein expression of SREBP-1C, PNPLA3, pJNK, CYP 2E1 and CYP 4A; (3) increased the uptake of 2-NBDG; (4) up-regulated the protein expression of CFLAR, PPARalpha, PI3K, pAKT and NRF2. SIGNIFICANCE: Silibinin can ameliorate some metabolic alterations and induce some molecular changes by activating the CFLAR-JNK pathway and thereby regulating its downstream target genes involved in lipid metabolism (PPARalpha, SREBP-1C and PNPLA3), glucose uptake (PI3K-AKT), oxidative stress (NRF2, CYP2E1, CYP4A) and inflammatory response(NO) in OA-treated HepG2 cells demonstrating its possible use in ameliorating various symptoms of NASH. PMID- 30248540 TI - Saikosaponin D from Radix Bupleuri suppresses triple-negative breast cancer cell growth by targeting beta-catenin signaling. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most aggressive and poor prognosis breast cancers. Currently, chemotherapy with conventional cytotoxic agents is the only available option to treat TNBC. Hence, we identified new therapeutic agents against TNBC from traditional Chinese medicine Radix Bupleuri and unveiled the molecule mechanism of anti-TNBC effects. METHODS: Multi component bioactivity and structure-guided methods were used to identify the most effective anti-TNBC compound Saikosaponin D (SSD) from Radix Bupleuri. Cell viability and apoptosis assays were employed to demonstrate the effect of SSD on the proliferation and apoptosis of TNBC cells. Dynamic mass redistribution assay, TopFlash assay, western blotting, and special agonist were applied to dissect the potential molecular mechanisms of SSD. RESULTS: We screened twenty fractions in Radix Bupleuri and identified SSD as the most effective component to inhibit the proliferation of TNBC cells. Investigating the interaction of SSD with the frequently overexpressed targets in TNBC led to the identification that it markedly suppressed Wnt/beta-catenin signaling, but did not act on epidermal growth factor receptor and neurotensin receptor-1. Moreover, we demonstrated that SSD significantly repressed beta-catenin and its downstream target genes, resulting in TNBC cell apoptosis. Specifically, docking of SSD to the crystal structure of beta-catenin suggested that SSD interacted with beta-catenin via hydrogen bonds and hydrophobic interaction. CONCLUSION: We identified the most effective component SSD from Radix Bupleuri in inhibiting the proliferation of TNBC cells by targeting beta-catenin signaling. Given the important role of Wnt/beta-catenin signaling in breast cancer, SSD may present an opportunity to discover new therapeutics for the treatment of TNBC. PMID- 30248541 TI - Chemo-resistance of A172 glioblastoma cells is controlled by miR-1271-regulated Bcl-2. AB - MicroRNAs (miRNAs) have been reported to exert important effects on the initiation, progression and metastasis of glioblastoma multiforme (GBM). In this study, we aimed to explore the regulation role of miR-1271 on the development of GBM. We found that miR-1271 was a Bcl-2-targeting miRNA, and the levels of miR 1271was decreased in samples from patients with GBM, compared with those from corresponding normal tissue samples. On the other hand, the levels of miR-1271 were inversely related to the levels of Bcl-2, which have been significantly increased in GBM samples. The overall survival was poorer in patients with low levels of miR-1271, compared to those with high levels of miR-1271. In vitro, the chemo-resistant cell survival mediated with Bcl-2 was inhibited by overexpression of miR-1271 and was enhanced by depletion of miR-1271. Thus, the chemo-resistance of GBM cells may be promoted after suppressing miR-1271 through cell survival mediated with Bcl-2. The prognosis of patients with GBM receiving chemotherapy may be improved by overexpressing miR-1271 in cancerous cells. PMID- 30248542 TI - Downregulation of EB virus miR-BART4 inhibits proliferation and aggressiveness while promoting radiosensitivity of nasopharyngeal carcinoma. AB - OBJECTIVE: This study aims to explore the role of Epstein-Barr virus (EBV) miR BART4 in occurrence and progression of nasopharyngeal carcinoma (NPC) and its effect on radiosensitivity. METHOD: The expressions of EBV and miR-BART4 in 108 cases of NPC tissues and 97 cases of chronic nasopharyngeal inflammation tissues were determined by real time quantitative polymerase chain reaction (PCR), and the relationship between the expression of miR-BART4 and the clinicopathological features of NPC was analyzed. Cell lines, HONEl, CNEl, CNE2, C666-1, 6-10B, and NP-69 were used to compare the expression of miR-BART4, in which the CNE2 cells were selected for further experiments. CNE2 cells were grouped into blank group, negative control (NC) group, miR-BART4 inhibitors group and miR-BART4 mimics group. Cells in above groups were under radiation of 6 Gy X ray for 12 h before grouped into control group, 6 Gy group, NC + 6 Gy group, miR-BART4 inhibitors + 6 Gy group and miR-BART4 mimics + 6 Gy group. Cell proliferation, clone formation ability, cell apoptosis, invasion and migration ability were measured by MTT assay, clone formation assay, flow cytometry (FCM), Transwell assay and scratch test, respectively. Western blot analysis was used to detect the expression of apoptosis-related proteins (cleaved caspase-3, Bax and Bcl-2) and epithelial mesenchymal transition (EMT) marker protein E-cadherin and Vimentin. mRNA and protein expression of PTEN were detected by qRT-PCR and western blot. Bioinformatics software and luciferase activity experiments were used to verify the targeting relationship between miR-BART4 and PTEN. RESULTS: Positive rate of EBV in NPC tissues (93.5%) was remarkably higher than that in chronic nasopharyngeal inflammation tissues (21.6%). miR-BART4 was highly expressed and mRNA and protein expression of PTEN was lowly expressed in EBV positive NPC tissues compared with EBV negative NPC tissues and chronic nasopharyngeal inflammation tissues. The expression of miR-BART4 was related to the clinical stage, lymph node metastasis and differentiation degree of NPC. Expression of miR BART4 in CNE2, CNEl, HONEl, C666-1, 6-10B, 5-8F cells was higher than that in NP 69 cells. In CNE2 and C666-1 cell experiments, compared with blank group and NC group, miR-BART4 inhibitors group had decreased miR-BART4 expression, increased mRNA and protein expression of PTEN, cell survival rate, invasion and migration ability and increased cell apoptosis rate, which is totally contrary to the observation in miR-BART4 mimics group. The radiosensitive NPC tissues had higher miR-BART4 expression than that in radio-resistance NPC tissues. In comparison to 6 Gy group and NC + 6 Gy group, cell survival rate and clone number was inhibited, but the cell apoptosis rate was increased in miR-BART4 inhibitors +6 G group, in contrary to the observation in miR-BART4 inhibitors + 6 Gy group. Bioinformatics software and luciferase activity experiments confirmed that miR BART4 could inhibit the expression of PTEN. CONCLUSION: EBV may promote development and progression of NPC by up-regulating miR-BART4 expressions, consequently inhibiting its radiosensitivity, whose effect may be related to the targeting inhibition of PTEN expression. PMID- 30248543 TI - Ursolic acid a promising candidate in the therapeutics of breast cancer: Current status and future implications. AB - Breast cancer [BC] is the deadliest neoplasm in women globally and the second leading cause of cancer associated deaths. Current treatment methods include chemotherapy, hormonal therapy, radiation therapy and surgery. However, BC has shown resistance to these therapies and are often associated with side effects, multidrug resistance, recurrence are the major issues in BC treatment. Currently, dietary phytocompounds have emerged as beneficial agents for the prevention and treatment of cancer because of their safe and cost effective nature. Ursolic acid [UA] is widely spread in fruits and vegetables having the ability to inhibit BC proliferation, angiogenesis and metastasis, arrest cell cycle, induced apoptosis, scavenge free radicals and regulate several anti-apoptotic and pro-apoptotic proteins. UA has also shown potential anticancer, anti-inflammatory and antioxidant activities in several human BC cells. This review paper encompasses the role of UA against BC and their mechanism of action in vitro and in vivo studies. PMID- 30248545 TI - KIF26B promotes cell proliferation and migration through the FGF2/ERK signaling pathway in breast cancer. AB - BACKGROUND: Many studies have suggested that high KIF26B expression is directly linked to poor prognostic outcomes in breast cancer. However, the exact role of KIF26B in breast cancer progression is not fully understood. In this study, we aimed to explore the function and mechanism of KIF26B in breast cancer progression. METHODS: Quantitative real-time PCR and immunohistochemistry analysis were used to detect KIF26B expression in breast cancer cell lines and patient samples. Cell proliferation was assessed by CCK-8 assay, and cell migration and invasion were evaluated by wound healing assay and transwell assay. Western blot analysis was carried out to assess the underlying molecular mechanisms. Tumor formation and metastasis were determined by in vivo mouse experiments. RESULTS: KIF26B levels were significantly increased in breast cancer cells and patient samples. KIF26B level correlated with tumor size, TNM grade, and differentiation in patients with breast cancer. Overexpressing KIF26B in vitro promoted breast cancer cell proliferation and migration by activating FGF2/ERK signaling, while silencing KIF26B had the opposite effects. Similarly, KIF26B knockdown repressed tumor formation and metastasis in nude mice. CONCLUSION: KIF26B promoted the development and progression of breast cancer and might act as a potential therapeutic target for treating breast cancer. PMID- 30248544 TI - Attenuation of diethylnitrosamine (DEN) - Induced hepatic cancer in experimental model of Wistar rats by Carissa carandas embedded silver nanoparticles. AB - OBJECTIVE: Hepatic cancer is well known, and leading cancer around the world and remain asymptomatic diseases. Carissa carandas possess anti-proliferative, antioxidant, hepatoprotective property and used in hepatic cancer. The current study deals to evaluate the chemoprotective and therapeutic property of Carissa carandas embedded silver nanoparticles (CCAgNPs) against diethylnitrosamine (DEN) -induced hepatic cancer. MATERIAL AND METHOD: Wistar rats were divided into six groups and hepatic cancer was induced with diethylnitrosamine at the dose of 200 mg/kg BW. The animals were gastrogavaged with standard drug and CCAgNPs for 16 weeks. Serum biomarkers, haematological profile, antioxidants enzymes, inflammatory markers and membrane bound enzymes were assessed to find the anti proliferative potential of silver nanoparticles. Histological evaluation and microscopic characterizations were also performed to authenticate the outcomes of the present work. RESULTS: Biosynthesized CCAgNPs significantly down-regulated the serum marker enzymes of hepatic and non-hepatic parameter, elevated the levels of enzymatic and non-enzymatic antioxidant profile, elevation in membrane bound enzymes and diminish the levels of inflammatory markers (IL-6, TNF-alpha, and IL-1beta) via NF-kappaB pathway. Histopathological features also showed recovery of a hepatic architecture in cancer-induced rats in a dose-dependent manner. CONCLUSION: Our consequences established that such plant mediated silver nanoparticles shown a defensive impact against DEN-induced hepatocarcinogenesis, and serves as a better option to ameliorate the clinical results against hepatocellular carcinoma. PMID- 30248546 TI - Nur77 is a promoting factor in traumatic brain injury-induced nerve cell apoptosis. AB - Traumatic brain injury (TBI) poses a serious threat to human health. TBI has a high mortality rate, resulting in a great burden on the affected individual's family as well as society as a whole. The incidence of craniocerebral fractures continues to rise as both the economy and transportation options grow, making it imperative that the mortality and disability rate of craniocerebral trauma be reduced. Nur77 is a transcription factor of the nuclear receptor superfamily. Following stimulation of extracellular apoptosis, Nur77 is involved in a variety of diseases as a powerful pro-apoptotic molecule. Here, we determined the effect and mechanism of Nur77 in TBI-induced nerve cell apoptosis in vitro and in vivo. We found that Nur77 and Bcl-2 protein expression increased as nerve cell apoptosis increased in TBI tissues. Furthermore, inhibition of Nur77 improved nerve cell injury by regulation of Bcl-2 and downstream pathways in vitro and in vivo. PMID- 30248548 TI - Trends and patterns in UK treatment seeking gamblers: 2000-2015. AB - BACKGROUND AND AIMS: Gambling is an activity that for some can become disordered, with severe negative consequences. Existing literature does little to inform us regarding changing gambling habits of treatment seeking gamblers; the current study sought to measure trends and patterns in UK treatment seeking gambler behaviour and demographics over a 15-year period. METHODS: Case files for 768 gamblers seeking residential treatment with the Gordon Moody Association (GMA) were analysed, collected between 2000 and 2015. Case files comprised initial assessment questionnaires, demographic data, current gambling behaviour, mental and physical health status, and a risk assessment. Chi-squared analyses were used to measure change in categorical distribution. RESULTS: Prevalence of different forms of gambling identified as problematic have changed over time: Fixed Odds Betting Terminals (FOBTs), sports betting, and poker have become more common; horse and dog racing, and the National Lottery have become less common. Online gambling has also increased over time. In more recent years, gamblers are also more likely to have attempted suicide, to report a co-occurring mental health disorder, and to start treatment having already been prescribed medication. DISCUSSION AND CONCLUSIONS: This is the first study to demonstrate that UK treatment seeking gambler behaviour has changed over time; major changes relate to the forms of gambling engaged in problematically, and the mental health of disordered gamblers. Whilst much media focus is directed towards one form of gambling, this should not detract focus from other forms and associated disorders, and the impact of the legislative environment. PMID- 30248547 TI - Motivations for alcohol use to intoxication among young adult gay, bisexual, and other MSM in New York City: The P18 Cohort Study. AB - INTRODUCTION: Motivations for alcohol use to intoxication vary among young adults depending on social setting and other contextual factors. However, there is limited research exploring the role of different drinking motivations among young men who have sex with men (YMSM). METHODS: Data from a racially/ethnically and socioeconomically diverse sample of YMSM (n = 426) were used to examine associations between recent (last 30 days) alcohol use to intoxication and scores on three distinct drinking motivation subscales: convivial, intimate, and negative coping drinking. Multinomial logistic regression models were constructed to examine associations between drinking motivations and days of alcohol use to intoxication, controlling for sociodemographic characteristics. RESULTS: YMSM who scored higher on all three drinking motivation subscales were more likely to engage in recent alcohol use to intoxication compared to those who reported no alcohol use to intoxication. In multivariable models, Black and Hispanic YMSM had lower odds of intoxication compared to White YMSM, and those reporting lower perceived familial SES had lower odds compared to higher SES. In a final model including all three motivations, only convivial drinking was significantly associated with days of intoxication (1-2 days: AOR = 1.22; 3+ days: AOR = 1.45). CONCLUSIONS: This study identifies distinct associations between different motivations for drinking and alcohol use to intoxication in a sample of YMSM. These findings highlight a need to incorporate an understanding of motivations for alcohol use to intoxication into research and clinical practice with YMSM, as different reasons for drinking carry respective potential health risks. PMID- 30248549 TI - Axon formation, extension, and navigation: only a neuroscience phenomenon? AB - Understanding how neurons form, extend, and navigate their finger-like axonal and dendritic processes is crucial for developing therapeutics for the diseased and damaged brain. Although less well appreciated, many other types of cells also send out similar finger-like projections. Indeed, unlike neuronal specific phenomena such as synapse formation or synaptic transmission, an important issue for thought is that this critical long-standing question of how a cellular process like an axon or dendrite forms and extends is not primarily a neuroscience problem but a cell biological problem. In that case, the use of simple cellular processes - such as the bristle cell process of Drosophila - can aid in the fight to answer these critical questions. Specifically, determining how a model cellular process is generated can provide a framework for manipulations of all types of membranous process-containing cells, including different types of neurons. PMID- 30248550 TI - Incretin drugs as modulators of atherosclerosis. AB - Atherosclerosis is a major underlying cause of ischemic heart diseases, ischemic stroke, and peripheral artery disease. Atherosclerotic plaque progression is characterized by chronic progressive inflammation of the arterial wall, endothelial cell dysfunction, and subendothelial lipoprotein retention. Incretin drugs, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dipeptidyl peptidase-IV (DPP-IV) inhibitors, are promising anti-hyperglycemic agents used for the treatment of type 2 diabetes mellitus (T2DM). In addition to glucose lowering effects, emerging data suggest that incretin drugs have anti-atherogenic effects with the potential to stabilize atherosclerotic plaques and treat arterial inflammation. Clinical and preclinical studies have reported a plethora of therapeutic benefits of incretin drugs, including modulation of inflammatory response, reduction of intima-media thickening, improvement in lipid profiles, endothelial and smooth muscle cell modulation. Despite extensive research and widespread clinical use of incretin-based therapies, the research on the incretin hormones continues to expand. This review outlines clinical studies, molecular aspects, and potential therapeutic implications of incretin drugs in attenuation of atherosclerosis. PMID- 30248551 TI - Kruppel-like factor 14, a coronary artery disease associated transcription factor, inhibits endothelial inflammation via NF-kappaB signaling pathway. AB - BACKGROUND AND AIMS: Human genetic studies indicated that variations near the transcription factor Kruppel-like factor 14 (KLF14) gene locus are highly associated with coronary artery disease. Activation of endothelial cells (ECs) by pro-inflammatory molecules and pathways is a primary step in atherosclerosis development. We aimed to investigate the effects and mechanism of KLF14 on inflammatory responses in ECs. METHODS: Adenovirus-mediated overexpression of human KLF14 and EC specific Klf14 knockout mice were applied to study the role of KLF14 in EC inflammation. Intravital microscopy was used to examine leukocyte endothelial cell interactions in vivo. RESULTS: The expression of Klf14 was markedly decreased in mouse aortic ECs in both acute and chronic inflammatory conditions. Overexpression of KLF14 inhibited inflammatory activation of human ECs stimulated by interleukin 1beta and tumor necrosis factor alpha. Primary pulmonary ECs from Klf14 knockout mice showed increased expression of adhesion molecules under IL-1beta stimuli. Mechanistically, KLF14 inhibited NF-kappaB signaling pathway by transcriptionally suppressing the expression of p65, resulting in significantly decreased leukocyte adhesion to activated ECs. Using intravital microscopy, an increased leukocyte-endothelial cell interaction was observed in endothelial specific Klf14 knockout mice compared to wild type control mice. Additionally, perhexiline, a KLF14 activator, induces KLF14 expression in ECs and reduced leukocyte-endothelial cell interactions in vitro and in vivo. CONCLUSIONS: The data revealed that KLF14 inhibited the inflammatory response in ECs and the protective effects were mediated by transcriptional inhibition of NF-kappaB signaling pathway. Endothelial KLF14 could be a potential therapeutic target for cardiovascular diseases. PMID- 30248552 TI - Outpatient cervical ripening: discomfort/pain during speculum and Foley catheter insertion. AB - OBJECTIVE: To examine discomfort/pain associated with the Foley catheter insertion process and explore factors affecting discomfort/pain. DESIGN: This cohort study conducted in the context of larger randomised clinical trial comparing silicone and latex Foley catheters. SETTING: A tertiary hospital in Western Sydney. PARTICIPANTS: Outpatient pregnant women (eligible participants in the main study). INTERVENTIONS: We asked about the discomfort/pain expectations and experience during the digital vaginal examination and insertion of the speculum, insertion of the Foley catheter and while the catheter was in situ. MEASUREMENTS: We used visual analog scale and a purposefully designed questionnaire to measure outcomes. FINDINGS: We found digital vaginal examination and speculum insertion (mean pain score = 4.6-4.7/10) to be significantly more uncomfortable than Foley catheter insertion (mean pain score = 3/10), while having the catheter in situ for a median of 14 h was mid-way in discomfort (mean pain score = 3.7/10). Only 12-13% of women experienced no discomfort during digital vaginal examination and speculum insertion, while about 40% experienced no discomfort during Foley catheter insertion. We identified no factors that influenced the experience of discomfort during speculum insertion. However, being overseas-born (odds ratio = 1.91, 95% = 1.10, 3.33) and experiencing discomfort during the speculum insertion (odds ratio = 8.15, 95% = 3.19, 20.79) increased the chance of discomfort on catheter insertion. Women's discomfort was not influenced by inserter designation or experience. KEY CONCLUSIONS: Digital vaginal examination and speculum insertion were moderately uncomfortable while insertion of a Foley catheter and having the catheter in situ for several hours were less uncomfortable procedures. IMPLICATIONS FOR PRACTICE: Only 8% of insertions were rated as difficult by staff while 70% were rated easy. This, together with the fact that the inserter's level of experience had no influence on women's discomfort, are reassuring for midwives who wish to teach and learn this common procedure. PMID- 30248553 TI - Radical oxidation of methyl vinyl ketone and methacrolein in aqueous droplets: Characterization of organosulfates and atmospheric implications. AB - In-cloud processing of volatile organic compounds is one of the significant routes leading to secondary organic aerosol (SOA) in the lower troposphere. In this study, we demonstrate that two atmospherically relevant alpha,beta unsaturated carbonyls, i.e., but-3-en-2-on (methyl vinyl ketone, MVK) and 2 methylopropenal (methacrolein, MACR), undergo sulfate radical-induced transformations in dilute aqueous systems under photochemical conditions to form organosulfates previously identified in ambient aerosols and SOA generated in smog chambers. The photooxidation was performed under sun irradiation in unbuffered aqueous solutions containing carbonyl precursors at a concentration of 0.2 mmol and peroxydisulfate as a source of sulfate radicals (SO4-) at a concentration of 0.95 mmol. UV-vis analysis of solutions showed the fast decay of unsaturated carbonyl precursors in the presence of sulfate radicals. The observation confirms the capacity of sulfate radicals to transform the organic compounds into SOA components in atmospheric waters. Detailed interpretation of high-resolution negative ion electrospray ionization tandem mass spectra allowed to assign molecular structures to multiple aqueous organosulfate products, including an abundant isoprene-derived organosulfate C4H8SO7 detected at m/z 199. The results highlight the solar aqueous-phase reactions as a potentially significant route for biogenic SOA production in clouds at locations where isoprene oxidation occurs. A recent modelling study suggests that such processes could likely contribute to 20-30 Tg year-1 production of SOA, referred to as aqSOA, which is a non-negligible addition to the still underestimated budget of atmospheric aerosol. PMID- 30248554 TI - Phytoremediation of barium-affected flooded soils using single and intercropping cultivation of aquatic macrophytes. AB - Aquatic macrophytes are potentially useful for phytoremediation on flooded areas. A field study in Brazil was conducted to evaluate Eleocharis acutangula (E), Cyperus papyrus (C) and Typha domingensis (T) in monocropping and intercropping, aiming to phytoremediate barium-polluted flooded soils. The treatments were: monocroppings (E, C and T); double intercroppings (EC, ET and CT); and triple intercropping (ECT). The 180-d field trial was performed in a flooded area with high barium content, with a randomized complete block design and three replicates. Plant stand size, biomass yield, and Ba concentration aboveground/Ba concentration in roots (translocation factor - TF) as well as Ba mass aboveground/Ba mass in roots (mass translocation factor - mTF) were determined. Most of the treatments did not differ on dry biomass, except for EC, which showed the lowest yield. Consistently with its biology, E. acutangula in monocropping showed the largest plant stand. Otherwise, intercroppings with T. domingensis achieved the highest amounts of barium absorbed from the soil and transferred most of the barium content from belowground to aboveground (mTF > 1.0), especially ET, which showed the highest mTF among the intercroppings (2.03). Remarkably, TF values did not reflect such phytoextraction ability for CT and ECT. Thus, mTF was more appropriate than TF to assess phytoextraction capacity. Furthermore, it was demonstrated that intercropping can increase barium uptake from flooded soils. Particularly, the intercropping ET constituted the most cost effective treatment, with the cyperaceous species providing high plant coverage while T. domingensis facilitated barium removal by translocating it to the aboveground biomass. PMID- 30248555 TI - Preparation and properties of Cu-Ni bimetallic oxide catalyst supported on activated carbon for microwave assisted catalytic wet hydrogen peroxide oxidation for biologically pretreated coal chemical industry wastewater treatment. AB - A microwave (MW)-assisted catalytic wet hydrogen peroxide oxidation (CWHPO) process was investigated to treat biologically pretreated coal chemical industry wastewater (CCIW) in this study. The activated carbon (AC) supported Cu-Ni bimetallic oxide catalyst was prepared by impregnation and precipitation method for MWCWHPO. The catalytic performance of the catalyst was investigated, and the main influencing factors were discussed. The results showed that the removal efficiencies of quinoline and total organic carbon (TOC) with catalyst prepared by impregnation method were 85% and 70%, respectively, and the removal efficiencies of quinoline and TOC with catalyst prepared by precipitation method were up to 95% and 76%, respectively. The utilization rate of hydrogen peroxide (H2O2) and the generation quantity of hydroxyl radicals were higher in the reaction process with the catalyst prepared by precipitation method than those with the catalyst prepared by impregnation method. The characterization of the catalyst showed that the smaller active component grains size, larger surface area and higher proportion of chemical adsorption oxygen were the main reason for the high catalytic efficiency. Furthermore, the optimized reaction conditions were: reaction temperature of 60 degrees C, microwave power of 500 W, and H2O2 initial concentration of 0.066 M. Moreover, the Cu-Ni bimetallic oxide catalyst is an efficient and stable catalyst in the degradation and mineralization of pollutants in the MWCWHPO process. The synthesized catalyst was verified to be attractive for use in the heterogeneous wet peroxide oxidation system under microwave irradiation. PMID- 30248556 TI - Hormonal control of parthenocarpic fruit set in 'Rojo Brillante' persimmon (Diospyros kaki Thunb.). AB - In persimmon (Diospyros kaki Thunb.), one to three waves of fruit abscission can occur. The parthenocarpic cv. Rojo Brillante may abscise close to 50% of flowers, which implies a major economic losses. In order to study this process, 700 flowers were labelled, 600 had the lobes of the calyx removed at three stages to promote abscission. Half of them were also treated with gibberellic acid (GA3; 10 mg l-1) to counteract the effect, and 100 were used as control. In the second year, GA3 (25 mg l-1) was applied to whole trees. Calyx lobe removal (CLR) reduced fruit growth rates and advanced and increased fruitlet abscission, whereas GA3 counteracted this effect. Furthermore, when GA3 was applied to the whole tree, fruit set was increased. The time-course of fruit abscission paralleled a decreased in hormonal and carbohydrate contents. Control fruit showed a peak of gibberellin (GA1 and GA4) and IAA concentration at anthesis. Hexose concentrations remained almost constant from flower bud to fruit set, whereas that of sucrose diminished with time. A peak in ethylene production occurred at anthesis, which increased when CLR was performed prior to or at anthesis, but not when performed at fruit set, when ethylene was markedly smaller. GA3 also counteracted it. Accordingly, we suggest that fruit set depends on the induction of gibberellin (GA) and IAA responses in the persimmon, and since there is no shortage of hormones or carbohydrates at anthesis, ethylene production at anthesis seems the most plausible cause of the physiological fruitlet abscission. PMID- 30248557 TI - Dissecting plant hormone signaling with synthetic molecules: perspective from the chemists. AB - Synthetic molecules can be powerful tools to overcome the limitations of the biological approaches. Especially redundancy, lethality, and intractability of the target genes, which often hamper the progress of plant science, could be bypassed by elaborately designed small molecules. In this review, we discuss how synthetic chemistry can contribute to increasing our understanding of plant hormone signaling. Specific focus will be on the visualization and hijacking of hormone signaling with novel synthetic chemicals, with emphasis on perception of ABA, strigolactones, and auxins. PMID- 30248558 TI - Over the influence: The HIV care continuum among methamphetamine-using men who have sex with men. AB - BACKGROUND: HIV-positive persons who use stimulants such as methamphetamine experience greater difficulties in navigating the HIV care continuum. In the era of HIV treatment as prevention (TasP), little is known about the prevalence and correlates of success along the HIV care continuum among people who use stimulants. SETTING: San Francisco, California USA METHODS: Cross-sectional study that enrolled 129 HIV-positive men who have sex with men (MSM) from 2013 through 2017 who had biologically confirmed, recent methamphetamine use. Multivariable logistic regressions were built to identify correlates of success across the HIV care continuum. RESULTS: Although two-thirds (87/129) of participants had undetectable HIV viral load (<40 copies/mL), only one-in-four (32/129) reported taking at least 90% of their antiretroviral therapy (ART). Those who were homeless in the past year (adjusted odds ratio [aOR] = 0.20; 95% CI = 0.06-0.65) had 80% lower odds of being undetectable and adherent to ART. Substance use disorder treatment was associated with 77% lower odds of being engaged in HIV care (aOR = 0.23; 95% CI = 0.06-0.84) but also close to 3-fold greater odds of being adherent to ART (aOR = 2.91; 95% CI = 1.12-7.60). CONCLUSION: Despite the fact that many HIV-positive, methamphetamine-using MSM are able to achieve undetectable viral load in this sample, difficulties with ART adherence threaten to undermine the clinical and public health benefits of TasP. Expanded efforts to boost the effectiveness of TasP in this population should focus on meeting the unique needs of homeless individuals, optimizing ART adherence, and facilitating the integration of HIV care with substance use disorder treatment. PMID- 30248559 TI - Differentially classified methamphetamine-using men who have sex with men: A latent class analysis. AB - CONTEXT: Substance use interventions for methamphetamine-using men who have sex with men (MSM) are limited by the assumption that they are a uniform group. We hypothesized that an LCA would identify distinct patterns of substance use and demographic and psychosocial variables associated with different substance-using groups would aid in understanding distinctions. Using cross-sectional data from 343 methamphetamine-using MSM, we conducted an LCA to model the patterns of polysubstance use then examined how the classes varied on psychosocial variables defined by the Information-Motivation-Behavioral Skills (IMB) model. FINDINGS: Because we were interested in identifying patterns of polysubstance use (PSU) among our sample, we identified four classes: minimal PSU, marijuana PSU, cocaine/hallucinogens PSU, and designer drugs/heroin PSU. Men in the marijuana PSU class were less likely to have positive attitudes towards methamphetamine than participants in the other three classes. Men in the Cocaine and Hallucinogens PSU class were more likely to have higher PANAS scores (OR = 13.00 [3.25, 52.07]) compared to the other classes, and they were more likely to have higher self-efficacy to enact safer substance use strategies (OR = 10.72 [3.23, 35.47]). MSM in the Designer Drug and Heroin PSU class were more likely to have a diagnosis of Hepatitis B (OR = 4.07 [0.86, 19.36] despite having higher knowledge of sexual health practices (OR = 0.55 [0.36, 0.84]. CONCLUSIONS: Differential classification for methamphetamine-using MSM suggests an opportunity for tailored interventions and secondary prevention programs. By understanding how men vary on illicit substance use, interventionists can routinely screen and link men before they potentially progress to another classification. PMID- 30248561 TI - Comprehensive, robust, and sensitive UPLC-MS/MS analysis of free biogenic monoamines and their metabolites in urine. AB - Biogenic monoamines, including catecholamines and serotonin are important hormones and neurotransmitters. Abnormal urinary levels of biogenic monoamines and their metabolites are associated with smoking, neuroendocrine tumors, as well as neurological and cardiovascular diseases. Measurements of free biogenic monoamines and their metabolites have been challenging because of low concentrations in complex biological matrices. Current methods require extensive enrichment and removal of interfering substances and can analyze only basic or acidic compounds in a single run. We developed a simple and robust dilute-and shoot method capable of measuring 10 analytes, including free biogenic monoamines and their metabolites in human urine. The assay enables sensitive measurements of analytes within expected sample concentration ranges. To assess the assay's efficacy, we measured urinary levels of free biogenic monoamines and their metabolites in 255 non-smokers and 191 smokers. Our data show that while smokers had significantly higher urinary levels of free catecholamines and metanephrines, there was a decrease in levels of biogenic amine metabolites synthesized through the monoamine oxidase pathway - homovanillic acid and vanillylmandelic acid. The method could be used for high throughput measurement of the range of free biogenic amines and their metabolites in urine under a variety of different conditions. PMID- 30248562 TI - Effects of lomefloxacin on survival, growth and reproduction of Daphnia magna under simulated sunlight radiation. AB - Lomefloxacin, an antibacterial agent with known photo-induced toxicity in clinical studies, is frequently detected in aquatic environments. Investigating the photo-induced toxicity of lomefloxacin in aquatic organisms is therefore of importance for assessing its ecological risks. In this study, the effects of lomefloxacin on survival, growth and reproduction of Daphnia magna under simulated sunlight radiation (SSR) were investigated, and the mechanism of action was revealed. Results indicated that SSR containing UV radiation increased the acute toxicity of lomefloxacin to Daphnia magna relative to white fluorescent light irradiation. Under SSR, 100 MUM lomefloxacin significantly enhanced reactive oxygen species (ROS) generation and lipid peroxidation, and decreased activities of superoxide dismutase and catalase. The biochemical observations and apparent effects on the organism indicate that oxidative stress plays a central role in the acute photo-induced toxicity. Chronic toxicity results showed that SSR significantly affected growth and reproduction of Daphnia magna, whereas lomefloxacin reduced the damage of UV radiation in SSR through light shielding. This study provides insight into the mechanism of photo-induced toxicity and can support the risk assessment of chemicals in the aquatic environment by including the impacts of sunlight irradiation on toxicity. PMID- 30248560 TI - Response inhibition and fronto-striatal-thalamic circuit dysfunction in cocaine addiction. AB - BACKGROUND: Many studies have investigated how cognitive control may be compromised in cocaine addiction. Here, we extend this literature by employing spatial Independent Component Analysis (ICA) to describe circuit dysfunction in relation to impairment in response inhibition in cocaine addiction. METHODS: Fifty-five cocaine-dependent (CD) and 55 age- and sex-matched non-drug-using healthy control individuals (HC) participated in the study. Task-relatedness of 40 independent components (ICs) was assessed using multiple regression analyses of component time courses with the modeled time courses of hemodynamic activity convolved with go success (GS), stop success (SS) and stop error (SE). This procedure produced beta-weights that represented the degree to which each IC was temporally associated with, or 'engaged', by each task event. RESULTS: Behaviorally, CD participants showed prolonged stop signal reaction times (SSRTs) as compared to HC participants (p < 0.01). ICA identified two networks that showed differences in engagement related to SS between CD and HC (p < 0.05, FDR corrected). The activity of the fronto-striatal-thalamic network was negatively correlated with SSRTs in HC but not in CD, suggesting a specific role of this network in mediating deficits of response inhibition in CD individuals. In contrast, the engagement of the fronto-parietal-temporal network did not relate to SSRTs, was similarly less engaged for both SS and SE trials, and may reflect attentional dysfunction in cocaine addiction. CONCLUSIONS: This study highlights the utility of ICA in identifying neural circuitry engagement related to SST performance and suggests that specific networks may represent important targets in remedying executive-control impairment in cocaine addiction. PMID- 30248564 TI - Impact of foliar fungicides on target and non-target soil microbial communities in cucumber crops. AB - The application of foliar fungicides to horticultural crops has raised public concerns worldwide. In fact, it has been demonstrated that such fungicides have an impact on non-target microorganisms in the rhizosphere. Fluopyram, triadimenol and penthiopyrad are three broad-spectrum fungicides recommended to control foliar diseases. In our experiment, these fungicides were applied to a cucumber crop to mainly control downy mildew caused by Pseudoperonospora cubensis and grey mold caused by Botrytis cinerea. At the same time, we found that these treatments also controlled other fungal pathogens affecting cucumber crops, particularly penthiopyrad, which was more effective. Once the fungicide application period was over, the effect decreased, although fungicide traces remained in the soil. Furthermore, microbial soil community analysis indicated that both fungicide treatments affect fungal communities to a greater extent than bacterial communities. PMID- 30248563 TI - Autophagic effects and mechanisms of silver nanoparticles in renal cells under low dose exposure. AB - With the advancement of nanotechnology and unique properties, silver nanoparticles (AgNPs) have been generally used in our work and life. However, the concerns on nanosafety have not been thoroughly understood. Although mounting studies have documented AgNPs-mediated autophagy under toxic dose, very few studies have been made to reveal the mechanisms of AgNPs-induced autophagy at non toxic concentrations. Here, we investigated AgNPs-mediated biological effects on autophagy in renal cells under sublethal exposure. Sublethal AgNPs resulted in increase of LC3II level and accumulation of autophagy related genes in HEK293T and A498 cells, which demonstrated AgNPs could activate autophagy at lower concentrations. Mechanistic investigation manifested that AMPK-mTOR signaling was enrolled in AgNPs-induced autophagy process rather than PI3K/AKT/mTOR signaling. In addition, P62 was elevated in AgNPs-treated cells in an mTOR-independent manner. We further uncovered that sublethal AgNPs exposure impaired the integrity and protease activities of lysosome. Together, our results revealed the mechanism by which AgNPs induced autophagy in renal cells under sublethal concentration. PMID- 30248565 TI - Comparative susceptibility of thirteen selected pesticides to three different insect egg parasitoid Trichogramma species. AB - The parasitoid Trichogramma species are indispensable natural enemies of many lepidopterans and it plays an important role in integrated pest management (IPM) programs throughout the world. Laboratory studies were conducted to compare the susceptibility of three Trichogramma egg parasitoid species to ten common insecticides and three herbicides. The adults of Trichogramma dendrolimi, T. chilonis, and T. ostriniae were exposed to the above-mentioned pesticides by a glass-vial residue method. Among the four neonicotinoids, dinotefuran and thiamethoxam exhibited extremely toxic effects on the Trichogramma dendrolimi and T. chilonis, with Risk Quotient (RQ) values ranging from 1471.2 to 5492.5. However, these two neonicotinoids have a relatively low toxicity to T. ostriniae, with RQ values 433.6 and 915.4, respectively. In addition, Imidacloprid and acetamiprid were slightly to moderately toxic to all the tested parasitic wasps and their RQ values are less than 500. For pyrethroids, all the selected compounds were slightly to moderately toxic to three Trichogramma species except that cyhalothrin was dangerously toxic to T. dendrolimi and T. chilonis, with RQ values 2567.6 and 3950.4. Among the three herbicides tested, pendimethalin, butralin and napropamid were slightly to moderately toxic to egg parasitoids, with all RQ values below 1000. For two avermectins, abamectin were slightly to moderately toxic to all three wasps with RQ values 635.6, 148.3 and 254.2, respectively. However, emamectin benzoate was found to be safe for the parasitoids. Furthermore, T. dendrolimi showed higher sensitivity than T. chilonis and T. ostriniae to the pesticides based on the comparison of LR50 (application rate causing 50% mortality) values. The present results provide informative data for implementing biological and chemical control strategies in integrated pest management. PMID- 30248567 TI - Examining the unique contribution of body appreciation to heterosexual women's sexual agency. AB - Although numerous studies demonstrate links between negative body image and sexual well-being, recent research has emphasized studying the positive aspects of these constructs. The current study built upon this prior research by examining the association between body appreciation and sexual agency among a US community sample of 355 heterosexual women aged 18-40. This study also examined whether body appreciation is uniquely associated with sexual agency above and beyond levels of self-objectification. Regression analyses demonstrated that women who reported greater body appreciation also reported greater condom use self-efficacy, sexual satisfaction, sexual assertiveness, and feelings of entitlement to sexual pleasure, and lower levels of body self-consciousness during intimacy. These findings remained consistent even when self objectification was entered into the model as a covariate. Results highlight the importance of studying how body appreciation may promote women's sexual agency. PMID- 30248566 TI - Effect of oxidized lipids stored under different temperatures on muscle protein oxidation in Sichuan-style sausages during ripening. AB - This study was conceived to research muscle protein oxidation under the influence of four different degrees of oxidized lipids during the ripening of Sichuan-style sausages. Lipids were stored at different temperatures to obtain different oxidation degrees. To elucidate the relationship between lipid oxidation and protein oxidation, the indicators of lipid oxidation, protein oxidation and protein degradation were analysed. During ripening, the carbonyl, SH, SS and free amino acid contents changed significantly. The carbonyl and SS contents increased first in all samples, then decreased, whereas the SH content showed the opposite results. These results showed a positive correlation between protein oxidation and lipid oxidation. Lipids with a higher oxidation degree induced a stronger oxidation reaction to protein. Meanwhile, the results of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed that the influence of lipid oxidation on myofibrillar proteins was much more intense than on sarcoplasmic proteins. PMID- 30248569 TI - Prognosis of Juvenile myoclonic epilepsy with eye-closure sensitivity. AB - PURPOSE: Eye closure sensitivity (ECS) has been described as a reflex trait in juvenile myoclonic epilepsy (JME). However, there is no consensus regarding its significance on prognosis. The aim of this study is to clarify the long-term impact of ECS documented by a clinical interview and a video-EEG neuropsychological protocol (VNPP) in a series of 133 JME patients. METHODS: Data from 22 JME patients with ECS confirmed by a VNPP (Group 1) were compared with those of 20 JME patients without any reflex traits (Group 2). They were followed for a mean of 8.21 years (SD=+/-5.044). The frequency of seizures was assessed using a diary. Except for photosensitivity (PS), any other reflex traits occurrence, drugs/alcohol abuse intake, noncompliance, and Jeavons syndrome, were considered exclusion criteria. RESULTS: Group 1 had a lower age at epilepsy onset (p = 0.028), higher incidence of febrile seizures (13.6%), and familial history of epilepsy (p = 0.023). Only 18.2% had self-perception of eyelid myoclonia (EM) (kappa coefficient = 0.193), which persisted in 77.3% of patients. Limb myoclonia, tonic-clonic seizures (TCS) and/or myoclonic-tonic-clonic seizures (MTCS), as well as absences were more frequent (p = 0.015; p = 0.013; p = 0.011, respectively) in Group 1. PS did not influenced frequency of EM (p = 1.0), absences (p = 0.648), or TCS/MTCS (p = 0.934). Psychiatric comorbidities were not different between groups. CONCLUSIONS: ECS is related to a worse outcome regarding control of all seizure types, persistence of EM, and higher frequency of limb myoclonia, as well as the total number of TCS and/or MTCS. PMID- 30248568 TI - Synthesis and evaluation of an N-[18F]fluorodeoxyglycosyl amino acid for PET imaging of tumor metabolism. AB - INTRODUCTION: The limitations of [18F]fluorodeoxyglucose ([18F]FDG), including producing false-positive or -negative results, low image contrast in brain tumor diagnosis and poor differentiation of tumor and inflammatory, necessitate the development of new radiopharmaceuticals. In the present study, a novel [18F]fluoroglycoconjugate tracer, [18F]FDGly-NH-Phe, for tumor metabolism imaging was prepared and evaluated. METHODS: [18F]FDGly-NH-Phe was prepared by condensing [18F]FDG with L-4-aminophenylalanine in an acidic condition, and purified with semi-preparative-high performance liquid chromatography (HPLC). The in vitro stability study was conducted in phosphate-buffered saline (PBS, pH 4.0-9.18) at room temperature (RT) and in fetal bovine serum (FBS) at 37 degrees C. The preliminary cellular uptake studies were performed using Hep-2 cell. The bio distribution studies, PET/CT imaging and metabolism studies were performed and compared with [18F]FDG on ICR or BALB/c nude model mice. RESULTS: [18F]FDGly-NH Phe was derived from a direct condensation of [18F]FDG with L-4 aminophenylalanine with high stability in FBS and PBS (pH of 6.5-9.18). In vitro cell experiments showed that [18F]FDGly-NH-Phe uptake in Hep-2 cells was primarily transported through amino acid transporters including Na+-dependent A system, ASC system, and system B0,+ system. The bio-distribution of [18F]FDGly-NH Phe in normal ICR mice showed faster blood radioactivity clearance, and lower uptake in brain and heart than [18F]FDG. The performance of PET/CT imaging for [18F]FDGly-NH-Phe in the mice model manifested excellent tumor visualization, high tumor-to-background ratios, and low accumulation in inflammatory lesions. Metabolism studies for [18F]FDGly-NH-Phe indicated high in vivo stability in plasma and urine and decomposition into [18F]FDG in the tumor microenvironment. CONCLUSION: The results demonstrated that [18F]FDGly-NH-Phe as a novel amino acid PET tracer showed the capability to differentiate tumor from inflammation, and the potentials for future clinical applications. PMID- 30248570 TI - Predictors of long-term survival after spontaneous intracerebral hemorrhage in southern Portugal: A retrospective study of a community representative population. PMID- 30248571 TI - Long-term follow-up for multiple sclerosis patients initially treated with interferon-beta and glatiramer acetate. AB - OBJECTIVE: Our goal was to compare subjects treated with glatiramer acetate (GA) and interferon-beta (IFN-beta) in terms of long-term clinical outcomes. METHODS: Subjects enrolled in the CLIMB who initiated either GA or IFN-beta within five years of disease onset and prior to 2008 were identified (n = 150 for GA and n = 144 for IFN-beta). The two treatment groups were compared in terms of long-term clinical outcomes: time to EDSS 4, time to EDSS 6 and EDSS score seven years after treatment initiation. Baseline confounders included in our analysis were age, gender, disease duration, attacks in the previous year, EDSS prior to treatment initiation, and year of treatment initiation. The groups were compared using three approaches to handle confounders: multiple regression adjusting for confounders, adjustment for the propensity score, and inverse probability of treatment weighting. In addition, we assessed potential predictors of differential treatment response using multiple regression models including appropriate interaction terms. RESULTS: Subjects initially treated with GA had a slightly higher hazard of reaching EDSS 4 and EDSS 6, but the difference between the groups was not statistically significant (adjusted HR for EDSS 4 = 1.48; 95% CI: 0.77,2.84; p = .24; adjusted HR for EDSS 6 = 1.46; 95% CI: 0.70,3.05; p = .316). For the EDSS score at year 7, there was also only a small difference between the groups. Subjects treated with GA had a longer time until treatment cessation (adjusted HR = 0.70; 95% CI: 0.53,0.93; p = .012). The interaction models did not show strong evidence for the baseline predictors being associated with treatment response. CONCLUSIONS: Subjects treated with glatiramer acetate and interferon-beta had similar long-term clinical course. PMID- 30248572 TI - Cystic neutrophilic granulomatous mastitis: A clinicopathologic study of a distinct entity with supporting evidence of a role for Corynebacterium-targeted therapy. AB - Cystic neutrophilic granulomatous mastitis (CNGM) is a distinct histopathologic entity characterized by neutrophilic and granulomatous inflammation surrounding clear cystic spaces. Rare gram-positive bacilli are sometimes identified within these cystic spaces. Studies in the literature have identified these gram positive bacilli to be Corynebacterium species. We describe the clinicopathologic features of 7 cases of CNGM, including a case with evidence of Corynebacterium amycolatum. Patients were young to middle aged parous women ranging in age from 28 to 53 years (median age: 41 years). Gram-positive bacilli were identified in 4 cases, all within cystic spaces. Microbial culture from a 41-year old Hispanic woman grew Corynebacterium species on multiple occasions and Corynebacterium amycolatum was identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) on two separate occasions. Antibiotic susceptibility testing performed both times showed resistance to multiple antibiotics and susceptibility to vancomycin. Follow-up of all patients (range 3 12 months, median 6 months) showed a widely variable clinical course and varying response to a variety of treatment modalities. Five of the seven CNGM patients were parous, reproductive-aged Hispanic women who were born outside of the United States. Our findings further support the association of CNGM with corynebacteria and gram-positive bacilli. Furthermore, this study shows that Corynebacterium amycolatum, a nonlipophilic and multidrug-resistant corynebacterium can be associated with CNGM, hence the need for targeted antibiotic therapy. We propose identifying corynebacteria to the species level and performing antibiotic susceptibility testing in patients with CNGM because of the varied susceptibility testing profile that has been reported among different species of corynebacteria. PMID- 30248573 TI - Combining task shifting and community-based care to improve maternal health: Practical approaches and patient perceptions. AB - Globally, community-based care and task shifting strategies are used to address maternal healthcare shortages in low-income countries. Limited research exists on models that combine these strategies. Using a qualitative approach, we explored Haitian women's perceptions of the Midwives for Haiti model, which unites task shifting and community-based care by training nurses as skilled birth attendants and offering healthcare via rotating, mobile clinics. Eight focus groups (N = 52) were conducted in rural Haiti in March 2017. Thematic analysis of data indicated that perceptions of care were universally positive. Participants cited accessible patient-centred care, affordable services, and health education as primary motivators to attend. Results illustrated the importance of women's perceptions on the future use of mobile clinic sites or other formal care. Future efforts to address maternal healthcare shortages should consider the Midwives for Haiti model, combining task shifting and community-based care to address common social, topographical, or financial barriers to maternal healthcare. PMID- 30248574 TI - Key residues controlling bidirectional ion movements in Na+/Ca2+ exchanger. AB - Prokaryotic and eukaryotic Na+/Ca2+ exchangers (NCX) control Ca2+ homeostasis. NCX orthologs exhibit up to 104-fold differences in their turnover rates (kcat), whereas the ratios between the cytosolic (cyt) and extracellular (ext) Km values (Kint = KmCyt/KmExt) are highly asymmetric and alike (Kint <= 0.1) among NCXs. The structural determinants controlling a huge divergence in kcat at comparable Kint remain unclear, although 11 (out of 12) ion-coordinating residues are highly conserved among NCXs. The crystal structure of the archaeal NCX (NCX_Mj) was explored for testing the mutational effects of pore-allied and loop residues on kcat and Kint. Among 55 tested residues, 26 mutations affect either kcat or Kint, where two major groups can be distinguished. The first group of mutations (14 residues) affect kcat rather than Kint. The majority of these residues (10 out of 14) are located within the extracellular vestibule near the pore center. The second group of mutations (12 residues) affect Kint rather than kcat, whereas the majority of residues (9 out 12) are randomly dispersed within the extracellular vestibule. In conjunction with computational modeling-simulations and hydrogen deuterium exchange mass-spectrometry (HDX-MS), the present mutational analysis highlights structural elements that differentially govern the intrinsic asymmetry and transport rates. The key residues, located at specific segments, can affect the characteristic features of local backbone dynamics and thus, the conformational flexibility of ion-transporting helices contributing to critical conformational transitions. The underlying mechanisms might have a physiological relevance for matching the response modes of NCX variants to cell-specific Ca2+ and Na+ signaling. PMID- 30248575 TI - Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease. AB - Intracellular accumulation of oligomeric forms of beta amyloid (Abeta) are now believed to play a key role in the earliest phase of Alzheimer's disease (AD) as their rise correlates well with the early symptoms of the disease. Extensive evidence points to impaired neuronal Ca2+ homeostasis as a direct consequence of the intracellular Abeta oligomers. However, little is known about the downstream effects of the resulting Ca2+ rise on the many intracellular Ca2+-dependent pathways. Here we use multiscale modeling in conjunction with patch-clamp electrophysiology of single inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) and fluorescence imaging of whole-cell Ca2+ response, induced by exogenously applied intracellular Abeta42 oligomers to show that Abeta42 inflicts cytotoxicity by impairing mitochondrial function. Driven by patch-clamp experiments, we first model the kinetics of IP3R, which is then extended to build a model for the whole-cell Ca2+ signals. The whole-cell model is then fitted to fluorescence signals to quantify the overall Ca2+ release from the endoplasmic reticulum by intracellular Abeta42 oligomers through G-protein-mediated stimulation of IP3 production. The estimated IP3 concentration as a function of intracellular Abeta42 content together with the whole-cell model allows us to show that Abeta42 oligomers impair mitochondrial function through pathological Ca2+ uptake and the resulting reduced mitochondrial inner membrane potential, leading to an overall lower ATP and increased production of reactive oxygen species and H2O2. We further show that mitochondrial function can be restored by the addition of Ca2+ buffer EGTA, in accordance with the observed abrogation of Abeta42 cytotoxicity by EGTA in our live cells experiments. PMID- 30248576 TI - Spontaneously hypertensive rats exhibit higher sensitivity to ethanol-induced hypotensive effects: Role of NMDA receptors and nitric oxide in rostral ventrolateral medulla. AB - Intake of ethanol (alcohol) affects cardiovascular function. Acute ethanol intake has been shown to lower blood pressure (BP) in hypertensive patients. The present study was undertaken to examine the effects and mechanisms of acute administration of ethanol on BP in hypertensive and normotensive rats. Ethanol was given by intraperitoneal (i.p.) injection in male spontaneously hypertensive rats (SHRs) and the normotensive Wistar-Kyoto rats (WKYs). BP responses were measured in free-moving conscious rats or in urethane-anesthetized rats. Inhibitors were applied by bilateral microinjection into the rostral ventrolateral medulla (RVLM). Nitric oxide (NO*) levels and glutamate levels were determined by nitrate and nitrite (NOx) analyzer and HPLC-ECD, respectively. Intraperitoneal (i.p.) injection of ethanol (1.6 g/kg) caused a significant decrease in BP in free-moving or in anesthetized SHRs but not in WKYs. A higher dose (3.2 g/kg) of ethanol decreased BP in both SHRs and WKYs, although the depressor responses in SHRs occurred significantly earlier than those in WKYs. The blood ethanol concentrations 60 min after injection were similar in SHRs and WKYs. Bilateral microinjection of nitric oxide synthase (NOS) inhibitors or glutamatergic NMDA receptor antagonists into the RVLM 5 min after administration of ethanol significantly inhibited the ethanol-induced depressor effects in SHRs. The levels of NOx and glutamate release in the RVLM following ethanol administration and the NOx content in the RVLM areas 30 min after administration were significantly increased in SHRs, but not in WKYs. Our results showed that SHRs were more sensitive to ethanol-induced hypotensive effects than WKYs because of augmentation of ethanol-induced expression of the glutamatergic NMDA receptor/NO* signal in the RVLM of SHRs. PMID- 30248577 TI - Assessing nursing assistants' competency in palliative care: An evaluation tool. AB - Nursing assistants are the largest aged care workforce providing direct care to older people in residential aged care facilities (RACF) in Australia and internationally. A palliative approach is a large component of this direct care that necessitates nursing assistants possess requisite knowledge, skills and attitudes. While training needs have been identified to enhance their practices, preservice education is variable, educational interventions have been adhoc and professional development found to be inadequate to the demands of the workplace. In addition, evaluation of nursing assistants' knowledge, skills and attitudes has lacked an instrument specifically tailored to nursing assistants' level of education and role responsibilities when providing a palliative approach. This paper reports on Phase 3 of a research study to develop such an instrument capable of assessing nursing assistants' knowledge of, skills in, and attitudes within a palliative approach. This phase assesses the usability and performance capabilities of the new instrument on a purposive sample of nursing assistants in two RACFs using the survey method. Results showed that the instrument was able to discriminate between groups of nursing assistants based on experience in role. Usability results indicated that the instrument is user friendly and time efficient. PMID- 30248578 TI - Recent advances in computational phylodynamics. AB - Time-stamped, trait-annotated phylogenetic trees built from virus genome data are increasingly used for outbreak investigation and monitoring ongoing epidemics. This routinely involves reconstructing the spatial and demographic processes from large data sets to help unveil the patterns and drivers of virus spread. Such phylodynamic inferences can however become quite time-consuming as the dimensions of the data increase, which has led to a myriad of approaches that aim to tackle this complexity. To elucidate the current state of the art in the field of phylodynamics, we discuss recent developments in Bayesian inference and accompanying software, highlight methods for improving computational efficiency and relevant visualisation tools. As an alternative to fully Bayesian approaches, we touch upon conditional software pipelines that compromise between statistical coherence and turn-around-time, and we highlight the available software packages. Finally, we outline future directions that may facilitate the large-scale tracking of epidemics in near real time. PMID- 30248579 TI - Strategies for designing non-natural enzymes and binders. AB - The design of tailor-made enzymes is a major goal in biochemical research that can result in wide-range applications and will lead to a better understanding of how proteins fold and function. In this review we highlight recent advances in enzyme and small molecule binder design. A focus is placed on novel strategies for the design of scaffolds, developments in computational methods, and recent applications of these techniques on receptors, sensors, and enzymes. Further, the integration of computational and experimental methodologies is discussed. The outlined examples of designed enzymes and binders for various purposes highlight the importance of this topic and underline the need for tailor-made proteins. PMID- 30248580 TI - Genomic aberrations involving 12p/ETV6 are highly prevalent in blastic plasmacytoid dendritic cell neoplasms and might represent early clonal events. AB - BACKGROUND: Chromosomal aberrations at the ETV6 gene locus on 12p13.2 are common in bone marrow samples involved by blastic plasmacytoid dendritic cell neoplasm (BPDCN). However, their pathogenic role, incidence in cutaneous BPDCN lesions, and clinical significance have not been assessed systematically. RESULTS: The study group included 30 BPDCN patients, 25 men and 5 women, with a median age of 64 years. Conventional cytogenetic analysis demonstrated karyotypic aberrancies in 15 cases, of which 8 had chromosomal lesions involving 12p. In addition, 2 cases with normal diploid karyotype had cryptic 12p/ETV6 deletion by ETV6 FISH test. Notably, 2 bone marrow samples with ETV6 rearrangement had no detectable BPDCN involvement, but otherwise dynamic changes in the detection of 12p/ETV6 aberrations correlated with the presence of morphologically and/or immunophenotypically detectable disease. Tissue specimens from 6 patients with cutaneous BPDCN all tested positive for homozygous or heterozygous ETV6 deletions. CONCLUSION: We demonstrate that monoallelic and biallelic 12p/ETV6 deletions are highly prevalent in BPDCN, and their detection is enhanced by the use of FISH and aCGH. In addition, 12p/ETV6 may be present in the bone marrow of BPDCN patients in the absence of detectable disease suggesting that such alterations might represent an early pathogenic event. PMID- 30248581 TI - Response to Allen (2018): Points of agreement and disagreement on reactive attachment disorder. AB - Reactive attachment disorder (RAD) is a very rare, understudied, and controversial disorder. Research in Developmental Disabilities (RIDD) recently published our research study, "Reactive attachment/disinhibited social engagement disorders: Callous-unemotional traits and comorbidity" (Mayes, Waschbusch, Calhoun, Breaux, & Baweja, 2017) investigating comorbidity in children with RAD and demonstrating a high prevalence of conduct disorder and callous-unemotional traits, consistent with previous research. Allen (2018) responded with a paper published in RIDD criticizing our study and offering his points of view. In our response to Allen, which follows, we discuss areas where we agree with Allen, as well as areas of disagreement, all presented within the context of scientific research. A point we assume we all agree on is the importance of continued empirical research to advance our knowledge and understanding of RAD. PMID- 30248582 TI - How do maternal interaction style and joint attention relate to language development in infants with Down syndrome and typically developing infants? AB - Down syndrome (DS) is more detrimental to language acquisition compared to other forms of learning disability. It has been shown that early social communication skills are important for language acquisition in the typical population; however few studies have examined the relationship between early social communication and language in DS. The aim of the current study is to compare the relationship between joint attention and concurrent language skills, and maternal interactive style and concurrent language skills in infants with DS and in typically developing (TD) infants matched for mental age. We also investigated if these relationships differ between children with DS and TD children. Twenty-five infants with DS (17-23 months) and 30 TD infants (9-11 months) were assessed on measures of joint attention, maternal interactive style and language. The results indicated a significant positive relationship between responding to joint attention (RJA) and concurrent language for the DS group, and a significant positive relationship between maternal positive expressed emotion (PEEM) and concurrent language for the TD group. We hypothesise that different social communication factors are associated with language skills in DS, at least between 17 and 23 months of age compared to TD infants of similar non-verbal and general language abilities. PMID- 30248583 TI - Siblings' experiences of growing up with children with autism in Taiwan and the United Kingdom. AB - BACKGROUND: A child's diagnosis of autism impacts their whole family, in both positive and negative ways, that may be influenced by cultural beliefs. AIMS: We aimed to describe the experiences of mothers and typically-developing siblings of children with autism in two cultural contexts. METHODS: Fourteen mother-sibling dyads from Taiwan and the UK participated in semi-structured interviews. RESULTS: Whilst there were similarities in sibling experiences, a negative tone regarding the influence of autism was more evident in Taiwan, where families also cited societal judgement and cultural-specific expectations. In the UK, a more balanced tone was apparent: mothers emphasised educating and involving the siblings. It is speculated that UK siblings had a greater understanding of their parents' stress, leading to more adaptive family dynamics. Various types of support service were mentioned in the UK, whereas the availability of social services and support appeared to be relatively limited in Taiwan. IMPLICATIONS: Our data suggest that cultural context may have a significant impact on the responses of the family members. This is mediated by both differences in attitudes and traditions, and availability of resources. Support for family members needs to be sensitive to such cultural differences, as well as recognising positive experiences. PMID- 30248584 TI - Theoretical study on crystal morphologies of 1,1-diamino-2,2-dinitroethene in solvents: Modified attachment energy model and occupancy model. AB - In this study, the growth morphologies of 1,1-diamino-2,2-dinitroethene (FOX-7) in vacuum and solvent conditions were investigated by molecular dynamics simulation. The modified attachment energy (MAE) model and occupancy model were used separately to predict the crystal morphology by calculating relative growth rate of different crystal faces in H2O/NMP and DMSO/AC solvent system. The calculated results show that the (0 1 1) face and (1 0 1) face are the most important crystal face in both two solvents towards the MAE model and the occupancy model, respectively. Compared with that from the MAE model, the predicted morphologies from the occupancy model are in better agreement with the experimental results. Radial distribution function (RDF) analyses were employed to demonstrate that the hydrogen bonds and vdW interactions play the dominant role between solvent molecules and FOX-7 surfaces. The above results allow us to understand the role played by solvents and solute molecules on growth morphologies of FOX-7 crystals. PMID- 30248585 TI - Pubertal timing and callous-unemotional traits in girls: Associations across two samples from the UK and Cyprus. AB - INTRODUCTION: Girls remain an understudied group when examining delinquency. Callous-unemotional traits are chief among personality traits that relate to delinquency. Some suggest, however, that girls who evince callous-unemotional traits delay their delinquent behavior until adolescence. This transitional period encompasses physical factors that relate to engagement in risky decision making, but we don't know how these factors relate to callous-unemotional traits. Early pubertal timing shows positive associations with delinquency; we tested if this was also the case for callous-unemotional traits. METHODS: We tested associations among pubertal timing (i.e., maturity and menarche age), delinquency, and callous-unemotional traits within girls (ages 11-18 years) sampled from two European countries (UK and Cyprus). We also tested the interaction between callous-unemotional traits and pubertal timing in statistically predicting delinquency to test if associations between early puberty and delinquency were moderated by callous-unemotional traits. RESULTS: Greater callous-unemotional traits were surprisingly negatively related to early pubertal timing. Those girls in the delayed menarche group had the highest level of callous-unemotional traits, higher than the typical and early menarche groups. Only callous-unemotional traits statistically predicted variance in delinquency and no moderation was evident. CONCLUSIONS: The implications are that callous unemotional traits and the transition to puberty may be particularly important for girls' adjustment in adolescence, particularly if menarche is delayed allowing girls to avoid punishment by capitalizing on their immaturity. PMID- 30248586 TI - OSL dosimeters for dental panoramic radiography. AB - The aim of the present work is to determine dosimetric characteristics of commercial optically stimulated luminescence dosimeter (OSLD) to estimate equivalent dose in the patient undergoing panoramic radiography procedure. Digital panoramic unit "Instrumentarium OP200D" was used. OSL dosimeters were optically bleached before any exposure procedure. InLightTM OSL nanodosimeters were placed on the thyroid surface between the head and neck. The exposure parameters for all measurements was standard value consisted in 66 kV, 5 mA, and 14.1 s. Standard size field of view (FOV) scanning mode was used. Dosimeters were calibrated for the air kerma. Reported male adult equivalent doses from 21 to 45 uSv for each scanning for standard size field of view (FOV). Meanwhile reported female adult equivalent doses from 28 to 75 uSv for standard size field of view (FOV) considering all heights. The lowest equivalent dose (21 MUSv) was observed in the male thyroid gland surface (S) position for medium height. The highest equivalent dose (75 MUSv) was for female small height in the right parotid surface (R) position. In conclusion, the results demonstrate that OSL dosimeters are appropriate in vivo dosimetry system for dental panoramic dose measurements. PMID- 30248587 TI - CYSP-HS: A new version of the CYSP directional neutron spectrometer with increased sensitivity. AB - CSYP (CYlindrical SPectrometer) is a directional neutron spectrometer based on a single moderator embedding multiple thermal neutron detectors. Similarly to Bonner Spheres, CYSP responds from thermal up to GeV neutrons and the spectrum is obtained via few-channel unfolding methods. CYSP has the shape of a polyethylene cylinder with diameter 50 cm and height 65 cm. Owing on a thick collimator and on a specifically designed shielding structure, the internal detectors only respond to neutrons coming from a known direction. Internal thermal neutron detectors are one-cm2 6LiF-covered silicon diodes. Un upgraded version of CYPS was developed to work in low intensity applications, such as cosmic field measurements. It is called CYSP-HS (High-Sensitivity) and is equipped with large area 6LiF-covered silicon diodes (LATND, Large Area Thermal Neutron Detectors). Compared with the former CYSP, the sensitivity increased approximately by an order of magnitude. This paper presents CYSP-HS focusing on the new internal detectors, the response matrix and its verification in a reference field of Am-Be available at the Politecnico di Milano. PMID- 30248588 TI - Mathematical derivation of density log from total gamma ray and neutron logs in clastic rocks, a case study, Egypt. AB - An empirical equation was adequately prepared to calculate the density log values without running the density tool from total gamma ray and neutron log values, on clastic reservoir rocks. This equation was applied to calculate the density log values in three important regions in Egypt (Gulf of Suez, Nile Delta and Western Desert) for hydrocarbon exploration. The derived density log was calculated depending on the neutron and total gamma ray logs, which were used to calculate porosity and volume of shale percentages, and finally sand percentage. Applying the derived equation to calculate the density log values from total gamma ray and neutron logs, and comparing the results with the really measured log in the three wells, located with three different regions; the calculated values were mostly comparable with the measured log values. The computed correlation coefficients of the three linear regression equations attained 0.92, 0.96 and 0.97 for the Gulf of Suez, Western Desert and Nile Delta regions, Egypt, respectively. In spite of the fact that, the three empirical regression equations revealed different slopes and various intercept values, yet these equations were found to be nearly identical, when applied to the same values and compared to each other. The differences between the slopes and intercepts in the three equations refer to the various depositional environments in the three studied regions as well as their different depths and consequently their diverse pressures. PMID- 30248589 TI - Preparation and photoluminescence properties of aluminate phosphors produced by combustion synthesis. AB - In this work, Eu, Nd co-doped MAl2O4:Eu, Nd (M = Ca, Sr, Ba) phosphors were synthesized at low temperatures (550 degrees C) by the combustion method. The crystallinity of the phosphors was monitored by X-ray diffraction (XRD) and the morphology was examined by scanning electron microscope (SEM). Synthesis of phosphors, the effect of lanthanide concentrations on light emission intensity and duration investigated by using photoluminescence (PL) measurements. Narrow orange-red emissions from 500 to 750 nm in the PL spectra are assigned to 5D0 -> 7Fj (j = 0,1,2,3,...) transitions of Eu3+ ion. In contrast, the broad luminescence band of the samples in the range of 400-500 nm are attributed to the 5d-4 f transitions of Eu3+ ion in the same host materials. Investigated the effects of radiation on the severity of the trap depths of these structures. The decay curves of these phosphors show how long the phosphors are attenuated. Thermoluminescence (TL) glow curves have been recorded from room temperature to 300 degrees C at a constant heating rate of 1 degrees C/s after preheat process at 130 degrees C for 10 s using lexsyg smart TL/OSL reader. Nd3+ trap levels can be thought of as the lanthanide element that causes long composition in the phosphorescence structure at room temperature. PMID- 30248590 TI - An improved OSEM iterative reconstruction algorithm for transmission tomographic gamma scanning. AB - As one of the most advanced non-destructive analytical techniques for nuclear wastes, tomographic Gamma Scanning (TGS) is able to give accurate quantitative and qualitative measurements of nuclear waste barrels. OSEM (Ordered Subsets Expectation Maximization) has been used in transmission TGS image reconstruction on account of its good reconstruction quality and ideal convergence rate. In this paper, an improved method-NMO-OSEM (Non-minimization optimization OSEM) was proposed, it's an iterative algorithm with corrected initial values optimized by non-minimization optimization method. To evaluate its performance, a TGS system is used to perform transmission measurements on barreled nuclear wastes. The results show: 1Compared with the reconstructed images by traditional OSEM under 6 transmission energies (122 keV, 344 keV, 779 keV, 964 keV, 1112 keV, 1408 keV), the improved NMO-OSEM has a great advantage in reducing the artifacts and effectively improving the quality of the reconstructed images. 2the attenuation coefficients values of 72 voxels under 3 emission energies (662 keV, 1173 keV and 1332 keV) reconstructed by the proposed algorithm are more accurate (range of error: 0.22%-13.83%) than reconstructed by traditional OSEM (range of error: 1.31%-32.21%), which proves this method has more stable reconstruction precision and could be regarded as an ideal option for real applications. PMID- 30248591 TI - Evaluation of different LSC methods for 222Rn determination in waters. AB - Monitoring of 222Rn in drinking or surface waters, as well as in groundwater has been performed regularly in connection with geological, hydrogeological and hydrological surveys and health hazard studies. Liquid scintillation counting (LSC) is often preferred analytical method for 222Rn measurements in waters as it allows multiple-sample automatic analysis. LSC method implies mixing of water samples with organic scintillation cocktail, which triggers radon diffusion from the aqueous into an organic phase for which it has a much greater affinity, eliminating the possibility of radon emanation in that manner. The main aim of this paper is calibration of the liquid scintillation counter Qunatulus 1220TM for measuring of radon in water and evaluation of two different methods (one phase and two-phase) in order to obtain the most suitable LSC technique for radon in water measurement. In this study four different scintillation cocktails were tested: one miscible (Ultima Gold AB) and three immiscible (High Efficiency Mineral Oil Scintillator, Opti-Fluor O and Ultima Gold F). Evaluation of presented methods was based on obtained detection efficiency and achieved Minimal Detectable Activity (MDA) values. Comparison of presented methods, accuracy and precision, as well as different scintillation cocktail's performance, was considered from results of measurements of 226Ra spiked water samples with known activity and environmental samples. LSC results were compared with the results of radon in water measurement obtained by alpha spectrometer RAD7. Calibration was done as a dependence of calibration factor (CF) from Pulse Shape Analysis (PSA). According to the obtained results, with proper adjustment of calibration parameters, both methods could be used for radon in water measurements. The obtained MDA values for all four scintillation cocktails are very low, less than 0.1 Bq l-1 for measuring time of 300 min. PMID- 30248592 TI - Cerebrospinal fluid protein markers in PD patients after DBS-STN surgery-A retrospective analysis of patients that underwent surgery between 1993 and 2001. AB - OBJECTIVE: Cerebrospinal fluid (CSF) markers of neurodegeneration [neurofilament light chain (NFL), total Tau (T-Tau)], tau pathology [phosphorylated tau (p Tau)], glial cell damage or activation [glial fibrillary acidic protein (GFAP)], and brain amyloidosis [beta-amyloid 1-42 (Abeta42)] are useful for diagnosis and prognosis in several neurodegenerative disorders. In this paper we investigate these markers and their relationship to key clinical milestones in patients with advanced Parkinson's disease (PD) operated at our center with subthalamic nucleus deep brain stimulation (STN-DBS) for at least 15 years ago. PATIENTS AND METHODS: Retrospective analysis of available cerebrospinal fluid and clinical data in PD patients, 15 years or more after they underwent STN-DBS surgery. All PD-patients implanted with STN-DBS at Sahlgrenska University Hospital before January 1, 2001, were regularly assessed until January 10, 2018, or until death, or until lost to follow-up. RESULTS: Twenty three PD patients were operated with STN-DBS. Sixteen of these (six females and ten males) underwent at least one lumbar puncture (LP) immediately prior to or after STN-DBS. Their age at the latest available LP was 64 (55-75) years [median (range)], PD duration 20 (11-33) years, and Hoehn & Yahr (H&Y) stage 3 (2-4). Time between DBS operation and the last LP was 4.5 (0.3 10.8) years. Time from the last LP to the last follow up was 6 (0.1-18) years, and for the entire cohort 115 person-years. On January 10, 2018, four PD-patients (25%) were still alive. All preoperative CSF marker levels were normal. Between two days and six months after DBS, NFL and GFAP levels increased sharply but they normalized thereafter in most patients, and were normal up to almost 11 years after neurosurgery. Over time, all patients deteriorated slowly. At the last follow up, H&Y was 5 (3-5) and 12/16 were demented. There was no significant correlation between postoperative (> 6 months) CSF NFL, GFAP, T-Tau, p-Tau, beta amyloid levels and the presence of dementia, psychosis, inability to walk or need for nursing home at the time for LP, nor for presence of dementia at the last follow up or for death as of January 10, 2018. CONCLUSION: CSF protein biomarkers remain normal despite long PD duration, severe disability, and chronic STN-DBS. They cannot be used for PD staging or prognostication but may indicate brain damage caused by other pathological factors. PMID- 30248593 TI - Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A systematic review. AB - BACKGROUND: Psychiatric comorbidity is prevalent in persons with multiple sclerosis (MS). Few studies have assessed whether second-generation disease modifying therapies (DMT) are associated with adverse psychiatric effects. OBJECTIVE: We aimed to systematically review the literature regarding the APEs associated with natalizumab, fingolimod, dimethyl fumarate, teriflunomide and alemtuzumab in MS. As a secondary objective, we evaluated changes in anxiety or depression scores following treatment with the aforementioned DMTs. METHODS: We searched MEDLINE, EMBASE, International Pharmaceutical Abstracts, PsychINFO, Central Register of Controlled Trials & Cochrane database of systematic reviews for published studies, and clinicaltrials.gov and regulatory documents from the US and Canada for unpublished studies. Data sources were searched from inception to September 2017. Studies reporting adverse psychiatric effects involving any DMT of interest were included. We report the incidence proportions of the adverse psychiatric effects and, where applicable, risk differences between DMT-exposed and unexposed individuals along with the corresponding 95% confidence intervals. We calculated the standardized mean differences (SMD) of changes in anxiety and depression scores if reported as study outcomes, and pooled the data using random effects meta-analysis. RESULTS: Of 4389 abstracts screened, 78 met the inclusion criteria, including 48 clinical trials, 28 observational studies and 2 case reports. Depression was the most commonly reported adverse psychiatric effect. Incidence proportions for all adverse psychiatric effects ranged from 0 to 24.7%. None of the DMT studied were associated with a statistically significant increased risk of any adverse psychiatric effect (range of risk difference: 7.69% [95%CI: -16.06%, 5.56%] to 6.67 [-8.56, 15.59]). Eighteen studies examined changes in depression or anxiety following fingolimod, natalizumab or dimethyl fumarate treatment; depression symptoms improved in fingolimod-treated groups (SMD [95%CI]: 1.18 [0.17, 2.19]). We did not identify studies examining changes in these outcomes following treatment with any of the other DMTs. CONCLUSION: The DMTs reviewed were not associated with an increased risk of adverse psychiatric effect in MS, and some may reduce the incidence of depressive symptoms. This may reflect either a positive direct effect (e.g. immune modulation) or an indirect effect arising due to a positive impact on disease activity or course. PMID- 30248594 TI - "If walls could talk": A photo-elicitation-based observation of service users' perceptions of the care setting and of its influence on the therapeutic alliance in addiction treatment. AB - A good quality therapeutic alliance is central to the support and treatment of people who use psychoactive substances. Although previous research has suggested that place has an important role in sustaining the therapeutic alliance, this issue has been insufficiently explored in the field of addiction treatment. We conducted a qualitative study using photo-elicitation and interviewing service users in an outpatient addiction treatment centre. They reported both strongly positive and negative perceptions of the place, alongside an unstable therapeutic alliance. Apprehending the place in which care is delivered as a dynamic relational network helps to understand the role of place in shaping the therapeutic alliance in addiction treatment. There is a need for careful design and layout, and thoughtful organisation of these places. PMID- 30248595 TI - Populations, megapopulations, and the areal unit problem. AB - Models of epidemic disease and programs for their management require accurate population data as a critical component of most studies. But the traditional definitions of urban places assumed discrete borders and localized populations. The vast increase in urban travel at all scales has raised the problem of how we define those urban populations. This paper reviews the issues as an areal unit problem within the context of the evolving idea of "megaregions" and their defintion. PMID- 30248596 TI - Factors associated with voluntary testing for HBV in the Upper West Region of Ghana. AB - This study examined the role of health facilities on testing for Hepatitis B virus in a policy context where screening is only available at a cost. We fitted multivariate multinomial logistic regression models to cross-sectional data (n = 1374) collected from Upper West Region of Ghana. The analysis showed that approximately 28% of respondents reported ever testing for HBV. Although source of healthcare influenced HBV testing, traders (RRR = 0.29, p <= 0.001) and farmers (RRR = 0.34, p <= 0.01) were significantly less likely to test voluntarily. Wealth generally predicted voluntary testing, although less so for mandatory testing. The findings highlight the need for free HBV services targeting the very poor, especially those who use community-level health facilities as their primary source of care. PMID- 30248597 TI - It's not easy assessing greenness: A comparison of NDVI datasets and neighborhood types and their associations with self-rated health in New York City. AB - Growing evidence suggests that exposure to greenness benefits health, but studies assess greenness differently. We hypothesize greenness-health associations vary by exposure assessment method. To test this, we considered four vegetation datasets (three Normalized Difference Vegetation Index datasets with different spatial resolutions and a finely-resolved land cover dataset), and six aggregation units (five radial buffer sizes and self-described neighborhoods) of each dataset. We compared associations of self-rated health and these metrics of greenness among a sample of New York City residents. Associations with self-rated health varied more by aggregation unit than by vegetation dataset; larger buffers and self-described neighborhoods showed more positive associations. Researchers should consider spatial exposure misclassification in future greenness and health research. PMID- 30248598 TI - Measuring effects of SNAP on obesity at the intensive margin. AB - The effects of the Supplemental Nutrition Assistance Program (SNAP) on obesity have been the focus of much debate. However, causal interpretation of estimates from previous studies, comparing participants to non-participants, is complicated by endogeneity and possible misreporting of participation in SNAP. In this paper, we take a novel approach to examine quasi-experimental variation in SNAP benefit amount on adult obesity. Children of SNAP households qualify for free in-school meals, thus freeing some additional benefits for the household. A greater proportion of school-age children eligible for free in-school meals proxies for an exogenous increase in the amount of SNAP benefits available per adult. Using data from the National Longitudinal Survey of Youth-1979 we show that school meals represent a non-trivial part of the food budget for SNAP households. We find that increases in SNAP benefits have no effect on obesity levels for the full sample of those who report SNAP participation. To better isolate the effects of additional benefits from other potential changes we restrict our analysis to adults living in households with at least one child under 5 years of age. In this setting, we find that additional SNAP benefits reduce BMI and the probability of being obese for SNAP adults. Specifically, when one child in a household of four becomes school-aged, adult BMI is expected to decrease by 0.23 units and the probability of being obese decreases by 2.58 percentage points or by about 10%. PMID- 30248599 TI - A novel bioelectrochemical method for real-time nitrate monitoring. AB - Nitrate is one of the most common pollutants in the water environment. A key factor for the effective control and removal of nitrate is the ability to accurately determine the nitrate concentration in groundwater and the secondary effluent of wastewater treatment plants. Here, a bioelectrochemical method for real-time detection of the nitrate was developed. In this work, a kinetic model was developed to describe the correlation between the nitrate concentration and the current. Standard addition experiments showed the relative error between indicator predictions and ion chromatographic values ranged from 3.14% to 9.74%. The monitoring results of secondary effluent showed that the system could give a good response at different nitrate concentrations. The average error of not >10.85% between the indicator predictions and ion chromatographic values was demonstrated. This study offers a new method for the development of sustainable bioelectrochemical system (BES)-based technology for the real-time detection of nitrate in groundwater and the secondary effluent. PMID- 30248600 TI - Biomass burning and carbon monoxide patterns in Brazil during the extreme drought years of 2005, 2010, and 2015. AB - In the 21st century, severe droughts associated with climate change will increase biomass burning (BB) in Brazil caused by the human activities. Recent droughts, especially in 2005, 2010, and 2015, caused strong socioeconomic and environmental impacts. The 2015 drought considered the most severe since 1901, surpassed the 2005 and 2010 events in respect to area and duration. Herein, based on satellite data, the 2005, 2010 and 2015 drought impacts on wildfire episodes and carbon monoxide (CO) variability during the dry and the dry-to-wet transition seasons were examined. The BB occurrences in the dry season were fewer during 2015 than during 2005 (-44%) and 2010 (-47%). Contrasting, the BB events in the dry-to-wet transition season, were higher during 2015 than during 2005 (+192%) and 2010 (+332%). The BB outbreaks were concentrated in the southern and southwestern Amazon during 2005, in the Cerrado region during 2010, and mainly in the central and northern Amazon during 2015, an area normally with few fires. The CO concentration showed positive variations (up to +30%) occurred in the southern Amazon and central Brazil during the 2005 and 2010 dry seasons, and north of 20 degrees S during the 2015-2016 dry-to-wet transition season. The BB outbreaks and the CO emissions showed a considerable spatiotemporal variability among the droughts of 2005, 2010, and 2016, first of them driven by local conditions in the tropical North Atlantic (TNA), characterized by warm than normal sea surface waters and the other two by the El Nino occurrences. PMID- 30248601 TI - Nitrate reduced arsenic redox transformation and transfer in flooded paddy soil rice system. AB - Inhibition of reductive transformation of arsenic (As) in flooded paddy soils is of fundamental importance for mitigating As transfer into food chain. Anaerobic arsenite (As(III)) oxidizers maintain As in less mobile fraction under nitrate reducing conditions. In this study, we explored the dynamic profile of As speciation in porewater and As distribution among the pools of differential bioavailability in soil solid phase with and without nitrate treatment. In parallel, the abundance and diversity of As(III) oxidase gene (aioA) in flooded paddy soil with nitrate amendment was examined by quantitative PCR and aioA gene clone library. Furthermore, the impact of nitrate on As accumulation and speciation in rice seedlings was unraveled. With nitrate addition (25 mmol NO3- kg-1 soil), porewater As(III) was maintained at a consistently negligible concentration in the flooded paddy soil and the reductive dissolution of As bearing Fe oxides/hydroxides was significantly restrained. Specifically, nitrate amendment kept 81% of total soil As in the nonlabile fraction with arsenate (As(V)) dominating after 30 days of flooding, compared to only 61% in the unamended control. Nitrate treatment induced 4-fold higher abundance of aioA gene, which belonged to domains of bacteria and archaea under the classes alpha Proteobacteria (6%), beta-Proteobacteria (90%), gamma-Proteobacteria (2%), and Thermoprotei (2%). By nitrate addition, As accumulation in rice seedlings was decreased by 85% with simultaneously elevated As(V) ratio in rice plant relative to control after 22 days of growth under flooded conditions. These results highlight that nitrate application can serve an efficient method to inhibit reductive dissolution of As in flooded paddy soils, and hence diminish As uptake by rice under anaerobic growing conditions. PMID- 30248602 TI - Soil carbon inventory to quantify the impact of land use change to mitigate greenhouse gas emissions and ecosystem services. AB - Currently the land use and land use change (LULUC) emits 1.3 +/- 0.5 Pg carbon (C) year-1, equivalent to 8% of the global annual emissions. The objectives of this study were to quantify (1) the impact of LULUC on greenhouse gas (GHG) emissions in a subtropical region and (2) the role of conservation agriculture to mitigate GHG emissions promoting ecosystem services. We developed a detailed IPCC Tier 2 GHG inventory for the Campos Gerais region of southern Brazil that has large cropland area under long-term conservation agriculture with high crop yields. The inventory accounted for historical and current emissions from fossil fuel combustion, LULUC and other minor sources. We used Century model to simulate the adoption of conservation best management practices, to all croplands in the region from 2017 to 2117. Our results showed historical (1930-2017) GHG emissions of 412 Tg C, in which LULUC contributes 91% (376 +/- 130 Tg C), the uncertainties ranged between 13 and 36%. Between 1930 and 1985 LULUC was a major source of GHG emission, however from 1985 to 2015 fossil fuel combustion became the primary source of GHG emission. Forestry sequestered 52 +/- 24 Tg C in 0.6 Mha in a period of 47 years (1.8 Tg C Mha-1 year-1) and no-till sequestered 30.4 +/- 24 Tg C in 2 Mha in a period of 32 years (0.5 Tg C Mha-1 year-1) being the principal GHG mitigating activities in the study area. The model predictions showed that best management practices have the potential to mitigate 13 years of regional emissions (330 Tg C in 100 years) or 105 years of agriculture, forestry and livestock emissions (40 Tg C in 100 years) making the agriculture sector a net carbon (C) sink and promoting ecosystem services. PMID- 30248603 TI - Multi-element isotopic signature (C, N, Pb, Hg) in epiphytic lichens to discriminate atmospheric contamination as a function of land-use characteristics (Pyrenees-Atlantiques, SW France). AB - Multi-elemental isotopic approach associated with a land-use characteristic sampling strategy may be relevant for conducting biomonitoring studies to determine the spatial extent of atmospheric contamination sources. In this work, we investigated how the combined isotopic signatures in epiphytic lichens of two major metallic pollutants, lead (206Pb/207Pb) and mercury (delta202Hg, Delta199Hg), together with the isotopic composition of nitrogen and carbon (delta15N, delta13C), can be used to better constrain atmospheric contamination inputs. To this end, an intensive and integrated sampling strategy based on land use characteristics (Geographic information system, GIS) over a meso-scale area (Pyrenees-Atlantiques, SW France) was applied to more than 90 sampling stations. To depict potential relationships between such multi-elemental isotopic fingerprint and land-use characteristics, multivariate analysis was carried out. Combined Pb and Hg isotopic signatures resolved spatially the contribution of background atmospheric inputs from long range transport, from local legacy contamination (i.e. Pb) or actual industrial inputs (i.e. Pb and Hg from steel industry). Application of clustering multivariate analysis to all studied isotopes provided a new assessment of the region in accordance with the land-use characteristics and anthropogenic pressures. PMID- 30248604 TI - Mediation effect of AhR expression between polycyclic aromatic hydrocarbons exposure and oxidative DNA damage among Chinese occupational workers. AB - Polycyclic aromatic hydrocarbons (PAH) are well-known to be carcinogenic and the mechanisms that it contributes to oxidative DNA damage and aryl hydrocarbon receptor (AhR)-dependent induction are also well understood. However, little is known about the associations between PAH exposure, AhR expression, and oxidative DNA damage. We investigated their associations of AhR expression and oxidative DNA damage related to PAH exposure among 310 workers from a coke-oven plant in China. Urine biomarkers of PAH exposure (2-hydroxynaphthalene, 2-NAP; 2 hydroxyfluorene, 2-FLU; 9-hydroxyphenanthren, 9-PHE; and 1-hydroxypyrene, 1-OHP) and a marker of oxidative damage (8-hydroxy- 2'- deoxyguanosine, 8-OHdG) were measured by high performance liquid chromatography. AhR expression in venous blood was measured by reverse transcription -polymerase chain reaction. The results showed that increasing levels of urinary 1-OHP was positively associated with high 8-OHdG (OR (95% CI) was 4.01 (1.41-11.45) for 4th quartile, compared with 1st quartile, P for trend = 0.013). The similar associations were also found between urinary 1-OHP and high-AhR expressions (4th vs. 1st quartile = 3.50, 95% CI: 1.24-9.87, P for trend = 0.029). A significant association between AhR expression and high 8-OHdG was also found (4th vs. 1st quartile = 2.44, 95% CI: 1.05-5.70, P for trend = 0.027). In addition, mediation analysis showed the AhR expression could explain 35.9% of the association of oxidative DNA damage related to PAH exposure. Our findings implicated that the association between PAH exposure and oxidative DNA damage may be mediated by AhR expression among Chinese occupational workers. PMID- 30248605 TI - Road proximity influences indoor exposures to ambient fine particle mass and components. AB - Exposure to traffic-related PM2.5 mass and its components can affect human health. Meanwhile, indoor concentrations are better exposure predictors as compared to outdoor concentrations because individuals spend the majority of their time indoors. We estimated the impact of traffic emissions on indoor PM2.5 mass and its species as a function of road proximity in Massachusetts. A linear regression model was built using 662 indoor samples and 580 ambient samples. Analysis shows that indoor exposures to traffic-related particles increased dramatically with road proximity. We defined relative concentration decrease, R(alpha), as the ratio of the indoor concentration at perpendicular distance alpha in meters from the closest major road to the indoor concentration at 1800 m from the major road. R(13) values for PM2.5 mass and Black Carbon (BC) were 1.3 (95%CI: 1.4, 1.6) and 2.1 (95%CI: 1.3, 2.8) for A12 roads, and 1.3 (95%CI: 1.2, 1.4) and 1.2 (95%CI: 1.1, 1.3) for A3 roads. R(alpha) values were also estimated for Fe, Mn, Mo, Sr and Ti for A12 roads, and Ca, Cu, Fe, Mn, Mo, Ni, Si, Sr, V and Zn for A3 roads. R(alpha) values for species associated mainly with brakes, tires or road dust (e.g., Mn, Mo and Sr) were higher than others. For A12 roads, R(13) values for Mn and Mo were 10.9 (95%CI: 0.9, 20.9) and 6.5 (95%CI: 1.4, 11.5), and ranged from 1.3 to 2.1 for other species; for A3 roads, R(13) values for Mn, Mo and Sr were 1.9 (95%CI: 1.1, 2.9), 1.8 (95%CI: 1.1, 2.4), and 8.5 (95%CI: 5.9, 10.9), and ranged from 1.2 to 1.6 for others. Our results indicate a significant impact of local traffic emissions on indoor air, which depends on road proximity. Thus road proximity which has been used in many epidemiological studies is a reasonable exposure metric. PMID- 30248606 TI - Dose-dependent transcriptomic responses of zebrafish eleutheroembryos to Bisphenol A. AB - Despite the abundant literature on the adverse effects of Bisphenol A (BPA) as endocrine disruptor, its toxicity mechanisms are still poorly understood. We present here a study of its effects on the zebrafish eleutheroembryo transcriptome at concentrations ranging from 0.1 to 4 mg L-1, this latter representing the lowest observed effect concentration (LOEC) found in our study at three different macroscopical endpoints (survival, hatching and swim bladder inflation). Multivariate data analysis methods identified both monotonic and bi phasic patterns of dose-dependent responses. Functional analyses of genes affected by BPA exposure suggest an interaction of BPA with different signaling pathways, being the estrogenic and retinoid receptors two likely targets. In addition, we identified an apparently unrelated inhibitory effect on, among others, visual function genes. We interpret our data as the result of a sum of underlying, independent molecular mechanisms occurring simultaneously at the exposed animals, well below the macroscopic LOEC, but related to at least some of the observed morphological alterations, particularly in eye size and yolk sac resorption. Our data supports the idea that the physiological effects of BPA cannot be only explained by its rather weak interaction with the estrogen receptor, and that multivariate analyses are required to analyze the effects of toxicants like BPA, which interact with different cellular targets producing complex phenotypes. PMID- 30248607 TI - A nonparametric approach to filling gaps in satellite-retrieved aerosol optical depth for estimating ambient PM2.5 levels. AB - Satellite-retrieved aerosol optical depth (AOD) is commonly used to estimate ambient levels of fine particulate matter (PM2.5), though it is important to mitigate the estimation bias of PM2.5 due to gaps in satellite-retrieved AOD. A nonparametric approach with two random-forest submodels is proposed to estimate PM2.5 levels by filling gaps in satellite-retrieved AOD. This novel approach was employed to estimate the spatiotemporal distribution of daily PM2.5 levels during 2013-2015 in the Sichuan Basin of Southwest China, where the coverage rate of composite AOD retrieved by the Terra and Aqua satellites was only 11.7%. Based on the retrieved AOD and various covariates (including meteorological conditions and land use types), the first random-forest submodel (named AOD-submodel) was trained to fill the gaps in the AOD dataset, giving a cross-validation R2 of 0.95. Subsequently, the second random-forest submodel (named PM2.5-submodel) was trained to estimate the PM2.5 levels for unmonitored areas/days based on the gap filled AOD, ground-monitored PM2.5 levels, and the covariates, and achieved a cross-validation R2 of 0.86. By comparing the complete and incomplete (i.e., without the days when AOD data were missing) estimates, we found that the monthly PM2.5 levels could be overestimated by 34.6% if the PM2.5 values coincident with AOD gaps were not considered. The newly developed approach is valuable for deriving the complete spatiotemporal distribution of daily PM2.5 from incomplete remote-sensing data, which is essential for air quality management and human exposure assessment. PMID- 30248608 TI - New insights into the altered binding capacity of pharmaceutical-grade human serum albumin: site-specific binding studies by induced circular dichroism spectroscopy. AB - The ADMET profile of drugs is strongly affected by human serum albumin (HSA), due to its leading role as carrier of poorly soluble compounds in plasma; a critical assessment of the binding capacity of HSA and the evaluation of binding competition between drugs are therefore pivotal for a reliable pharmacokinetic and pharmacodynamic characterization. In clinical practice, a potential source of impairment in the binding properties of HSA is the use of octanoate and N acetyltryptophan as stabilizers during the production of pharmaceutical-grade HSA for infusion (i-HSA), which is currently administered in the treatment of a growing range of pathological conditions. The peculiar sensitivity of circular dichroism (CD) spectroscopy towards the stereochemical features of high-affinity binding events is herein exploited to achieve a site-specific assessment of the effect of stabilizers on the binding properties of i-HSA. The binding affinity and capacity of fatty-acid-free HSA towards site-selective induced circular dichroism (ICD) markers for the three high-affinity binding sites of HSA was compared to that of i-HSA submitted to ultrafiltration and dialysis to remove both stabilizers. Results showed a considerable impairment of the binding capacity of i-HSA at site II and a relatively lower influence on the binding properties of site I. Ultrafiltration proved to be ineffective in depleting octanoate, while the proposed dialysis protocol, which involves a pH-induced reversible unfolding of the protein, resulted in a total clearance of both stabilizers, confirmed by the full restoration of the binding properties of HSA at all binding sites. The outcomes of this study proved that CD spectroscopy is a suitable technique to evaluate the binding properties of i-HSA, ensuring an assessment of the availability of the binding sites and the possibility of monitoring the clearance of stabilizers. Eventually, the proposed method for their depletion might constitute a connection bridge between albumin in vitro studies and its clinical applications. PMID- 30248610 TI - Assessment of DNA degradation of buccal cells under humid conditions and DNA repair by DOP-PCR using locked nucleic acids. AB - We analyzed the degradation level of DNA from buccal cells under humid conditions using quantitative PCR analysis. Gauze samples with buccal cells were incubated for up to 12 months under three different conditions (25 degrees C/dry, 25 degrees C/humid, or 40 degrees C/humid). The degradation was evaluated based on two degradation ratios (129:41 and 305:41 bp). DNA degraded slowly under the 25 degrees C/humid condition, and significant differences in the two degradation ratios were detected between 25 degrees C/dry and 25 degrees C/humid conditions after 12 months. Moreover, the degradation rapidly progressed under the 40 degrees C/humid condition, and the two degradation ratios in this condition were much lower than those from 25 degrees C/dry and 25 degrees C/humid conditions after a short incubation period (3 months). To evaluate the effect of DNA repair on low-copy degraded DNA, degenerate oligonucleotide-primed PCR (DOP-PCR) was performed before short tandem repeats (STR) genotyping. As a standard DOP-PCR, we used a 22-base primer with 10 degenerate sequences (5'-CTCGAGNNNNNNNNNNATGTGG 3'), and additionally designed DOP-PCR primers with 2, 4, 6, or 8 locked nucleic acids (LNAs). When slightly degraded DNA (305:41-bp ratio = 0.60) was used, DOP PCR significantly increased the fluorescent intensity and success rate of genotyping using Identifiler and Globalfiler kits. In particular, the reaction with four LNAs produced the highest value. However, such benefits were not observed in the analysis of moderately degraded DNA (305:41-bp ratio = 0.13). Although the recovery rates of STR profiles by DOP-PCR were dependent on the degradation level of low-copy DNA, the effectiveness of DOP-PCR highlights the potential of LNA for degenerate sequences. PMID- 30248609 TI - Brain network connectivity associated with anticipatory postural control in children and adults. AB - Internal models provide a coherent framework for understanding motor behavior. Examples for the use of internal models include anticipatory postural adjustments (APAs), where the individual anticipates and cancels out the destabilizing effect of movement on body posture. Yet little is known about the functional changes in the brain supporting the development of APAs. Here, we addressed this issue by relating individual differences in APAs as assessed during bimanual load lifting to interindividual variation in brain network interactions at rest. We showed that the strength of the connectivity between three main canonical brain networks, namely the cingulo-opercular, the fronto-parietal and the somatosensory motor networks, is an index of the ability to implement APAs from late childhood (9- to 11-year-old children). We also found an effect of age on the relationship between APAs and coupling strength between these networks, consistent with the notion that APAs are near but not yet fully mature in children. We discuss the implications of these findings for our understanding of learning disorders with impairment in predictive motor control. PMID- 30248611 TI - Pre-harvest screening on-vine of spinach quality and safety using NIRS technology. AB - The study sought to perform a non-destructive and in-situ quality evaluation of spinach plants using near infrared (NIR) spectroscopy in order to establish its suitability for different uses once harvested. Modified partial least square (MPLS) regression models using NIR spectra of intact spinach leaves were developed for nitrate, ascorbic acid and soluble solid contents. The residual predictive deviation (RPD) values were 1.29, 1.21 and 2.54 for nitrate, ascorbic acid and soluble solid contents, respectively. Later, this predictive capacity increased for nitrate content (RPDcv = 1.63) when new models were developed, taking into account the influence on the robustness of the model exercised by the simultaneity between the NIR and laboratory analyses. Subsequently, using partial least squares discriminant analysis (PLS-DA), the ability of NIRS technology to classify spinach as a function of nitrate content was tested. PLS-DA yielded percentages of correctly classified samples ranging from 73.08-76.92% for the class 'spinach able to be used fresh' to 85.71-73.08% for the class 'preserved, deep-frozen or frozen spinach, both for unbalanced and balanced models respectively, based on NH signal associated with proteins. Overall, the data supports the capability of NIR spectroscopy to establish the final destination of the production of spinach analysed on the plant, as a screening tool for important safety and quality parameters. PMID- 30248612 TI - Micelle and inclusion complex enhanced spectrofluorimetric methods for determination of Retigabine: Application in pharmaceutical and biological analysis. AB - Two new, simple, selective, and highly sensitive spectrofluorimetric methods were developed and validated for the determination of the antiepileptic drug; retigabine (RTG). The first method (Method-I) depends on enhancement of the weak native fluorescence of RTG via the use of an organized medium; sodium dodecyl sulphate (SDS) in acetate buffer (pH 3.74). The second method (Method-II) depends on the enhancement of RTG weak native fluorescence through complexation with a macromolecule; beta cyclodextrin (beta-CD) in phosphate buffer (pH 3.20). A full study of different experimental parameters influencing the fluorescence intensity was carried out. In addition, a thorough investigation of the fluorescence quantum yield, fluorophore brightness and mechanism of fluorescence enhancement was performed. A seven-fold improvement in the fluorescence intensity was brought by the first method, whereas a six and half-fold enhancement of the fluorescence intensity was obtained by the second one. Linearity was achieved over wide ranges (0.05-12.5 MUg mL-1) and (0.05-15 MUg mL-1) with low limits of detection (LOD) of 10.6 and 14.3 ng mL-1, and limits of quantification (LOQ) of 32.0 and 43.2 ng mL 1 for (Method-I) and (Method-II), respectively. The proposed methods were validated according to ICH and US-FDA guidelines. The applicability of the proposed methods was tested for determination of RTG in its pharmaceutical dosage forms, and to study the stability of RTG under different stress conditions according to ICH guidelines including alkaline, acidic, oxidative, thermal, and photolytic stress conditions. Moreover, the high sensitivity achieved by the proposed methods permitted the determination and detection of RTG in both spiked and real rabbit plasma samples utilizing a simple protein precipitation step followed by liquid-liquid extraction method. Percentage recoveries from rabbit plasma samples were within the acceptable limits; (93.47-104.74%) and (91.33 105.70%) for (Method-I) and (Method-II), respectively. PMID- 30248613 TI - Effect of anti-apoptotic drug Z-VAD-FMK on in vitro viability of dog follicles. AB - It is recognized that ovarian follicular atresia is associated with apoptosis, and the most important effector of cell death is caspase-3. The aim of this study was to investigate the influence of anti-apoptotic drug Z-VAD-FMK on in vitro follicle growth in the domestic dog. Ovaries were obtained from peri-pubertal and adult domestic dogs, and cortical fragments recovered and incubated on 1.5% (w/v) agarose gel blocks within a 24-well culture plate containing Minimum Essential Medium Eagle-Alpha Modification (alphaMEM) supplemented with 4.2 MUg/mL insulin, 3.8 MUg/mL transferrin, 5 ng/mL selenium, 2 mM L-glutamine, 100 MUg/mL of penicillin G sodium, 100 MUg/mL of streptomycin sulfate, 0.05 mM ascorbic acid, 10 ng/mL of FSH and 0.1% (w/v) polyvinyl alcohol in humidified atmosphere of 5% CO2 and 5% O2. The cortices were randomly allocated in six treatments: 1) 10 ng/mL EGF (EGF V0); 2) 10 ng/mL of EGF plus 1 mM Z-VAD-FMK (EGF V1); 3) 10 ng/mL of EGF and 10 mM Z-VAD-FMK (EGF V10); 4) 1 mM Z-VAD-FMK; 5) 10 mM Z-VAD-FMK and (6) no EGF and Z-VAD-FMK supplementation (Control). The cortices were processed for histology and assessed for viability (based on morphology), density of structurally normal follicles, and diameter immediately after collection (non culture Control) or after 3 or 7 days of in vitro incubation. Evaluation of mRNA expression of Cas3 in fresh cortices and those incubated for 3 days was performed using real-time PCR. Histological analysis revealed that in vitro incubation decreased (P < 0.05) follicle viability and density compared to the fresh, non culture control. Addition of 10 MUM of Z-VAD-FMK alone to the culture medium sustained follicle viability at Day 3, but did not impact follicle diameter when compared to the other treatment groups (p < 0.001); however, the beneficial benefit of this anti-apoptotic drug diminished after 7 days of incubation. Furthermore, Z-VAD-FMK supplementation did not impact Cas3 expression. The findings demonstrated that dog ovarian tissues are highly susceptible to in vitro incubation and Z-VAD-FMK supported short-term survival of dog follicles enclosed within the ovarian cortex. PMID- 30248614 TI - Sacrificial template-based synthetic approach of polypyrrole hollow fibers for photothermal therapy. AB - In the present work, polypyrrole hollow fibers (PPy-HFs) were fabricated by sacrificial removal of soft templates of electrospun polycaprolactone (PCL) fibers with polypyrrole (PPy) coating through chemical polymerization of pyrrole monomer. Different physicochemical properties of as-fabricated PPy-HFs were then studied by Field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), Fourier transform infra-red (FT-IR) spectroscopy, Differential scanning calorimetry/Thermogravimetric analysis (DSC/TGA), and X-ray photoelectron spectroscopy (XPS). The photothermal activity of PPy-HF was studied by irradiating 808-nm near infra-red (NIR) light under different power values with various concentrations of PPy-HFs dispersed in phosphate buffer solution (PBS, pH 7.4). These PPy-HFs exhibited enhanced photothermal performance compared with polypyrrole nanoparticles (PPy-NPs). Furthermore, these PPy-HFs showed photothermal effect that was laser-power- and concentration-dependent. The photothermal toxicity of the resulting nanofiber was evaluated using cell counting kit-8 (CCK-8) and live and dead cell assays. Results showed that these PPy-HFs were more effective in killing cancer cells under NIR irradiation. In contrast, hollow-fiber showed no cytotoxicity without NIR exposure. Among different nanofiber formulations, PPy-160 exhibited the highest photothermal toxicity. It could be explained by its enhanced photothermal performance compared to other specimens. The resulting PPy-HFs showed superior drug-loading capacity to PPy-NPs. This might be attributed to adequate binding of the drug into both luminal and abluminal hollow-fiber surfaces. Fabrication of this substrate type opens a promising new avenue for architectural design of biocompatible organic polymer for biomedical field. PMID- 30248615 TI - Constructing efficient mixed-ion perovskite solar cells based on TiO2 nanorod array. AB - Oriented TiO2 nanorod array (TiO2 NA) is very attractive in the fields of halide perovskite solar cells (PSCs) due to its fewer grain boundaries and high crystallinity for effective charge collection. The optimization of TiO2 nanostructures has been proved to be an effective approach for efficient PSCs. On the other hand, tuning the crystallization of perovskite films on top of the TiO2 NA is very important for efficient TiO2-NA based PSCs. Herein, scanning electron microscopy (SEM) and X-ray powder diffraction (XRD) were used to study the crystallization of different mixed-ion Cs0.1(FA0.83MA0.17)0.9Pb(I0.83Br0.17)3 perovskite (in which MA = CH3NH3+, and FA = CH(NH2)2+) films, from different perovskite precursor concentrations, on the TiO2 nanorod arrays. A mechanism was proposed to reveal the inherent connection between the precursor concentration and the crystallite growth of the perovskite film prepared with anti-solvent quenching process. Meanwhile, both faster charge separation at perovskite/TiO2 NA interface and longer charge transport were observed on thicker perovskite film with larger grains, revealed by the time-resolved method. However, atomic force microscopy (AFM) results indicated that too thick perovskite film impaired the charge collection owing to the increased recombination. By balancing the charge collection and film thickness, highly efficient PSCs were prepared with a champion power conversion efficiency (PCE) of 19.33% with little hysteresis. The study highlights a great potential of incorporating oriented one-dimensional electron extraction materials in high-performance PSCs and other applications. PMID- 30248616 TI - Synthesis and optimization of polyurethane microcapsules containing [BMIm]PF6 ionic liquid lubricant. AB - Polyurethane (PU) microcapsules containing [BMIm]PF6 as a lubricant have been fabricated by interfacial polymerization. The stabilizing effect of 10 kinds of emulsifiers towards [BMIm]PF6 ionic liquid have been delineated. A Pickering emulsion stabilized by lignin showed the best emulsification effect on highly viscous [BMIm]PF6. The types and reactivities of monomers have an important influence on the formation of microcapsules. Three kinds of isocyanate (IPDI, MDI, TDI) were reacted with diamines or diols to prepare the PU microcapsules in this work. The optiaml [BMIm]PF6@PU microcapsules were obtained when using IPDI and TETA as monomers, under conditions of 5,000 rpm emulsifying rate, 0.5 wt% concentration of lignin Pickering emulsion, and a 3:1 mass ratio of [BMIm]PF6/IPDI. The synthesized microcapsules have a regular and compact spherical structure, smooth outer, and inner surfaces with a mean diameter of 43 +/- 15 um, and a thickness of 3.8 um. The core content of [BMIm]PF6@PU microcapsules was determined as >70%, and the initial decomposition temperature was 300 degrees C. The [BMIm]PF6 ionic liquid shown excellent lubricating property, ultralow friction coefficient (decreased by 72.7%) and wear rate (decreased by 160 times) were obtained by embedding 30 wt% microcapsules into epoxy compared with pure epoxy. PMID- 30248617 TI - Yolk-porous shell nanospheres from siliver-decorated titanium dioxide and silicon dioxide as an enhanced visible-light photocatalyst with guaranteed shielding for organic carrier. AB - A nagging problem for the decompostion of photocatalyst organic carrier can be expected to be resolved by shielding effect from our yolk-porous shell nanospheres. The nanospheres were synthesized by a facile strategy: polyporrole (PPy) and silver were deposited together on TiO2 by chemical oxidative polymerization; then PPy/Ag-coated TiO2 nanoparticles were encapsulated in silicon dioxide (SiO2) shell with polyethylene glycol (PEG) as a pore-forming agent via sol-gel method based on hydrolysis of tetraethyl orthosilicate (TEOS). After removing intermediary PPy between yolk and shell by calcination and washing off PEG in shell, yolk-porous shell (SiO2@void@Ag/TiO2) nanospheres were formed. The voids in SiO2@void@Ag/TiO2 can serve as photocatalytic reactors. The channels in porous shell at outer layer provide passages for light transmission, dye molecule accessing and degradants out. More importantly, the euphotic and porous shell exhibited an impressive protection to organic carrier, lest unfavorable decomposition occurred. Yolk-porous shell nanospheres showed commendable performance with >99.5% of dye removal efficiency under 3 h visible light irradiation, higher than pristine TiO2 and Ag/TiO2 nanoparticles, due to the synergy effect of robust adsorption capacity and photocatalysis. Our work could provide a good strategy for developing novel carrier-based photocatalysts for environmental remediation application, which can be readily extended to the combination of other nanophotocatalysts and organic carriers for enhancing sustainable photocatalytic performance. PMID- 30248618 TI - Sludge based micro-electrolysis filler for removing tetracycline from solution. AB - In this study, a novel catalytic micro-electrolysis filler (CMEF) was prepared using waste sludge as the main raw materials. The preparation process was optimized in terms of the mass ratio of raw materials and sintering temperature based on the tetracyclines (TCs) removal efficiency. The physicochemical characteristics (e.g., surface area, morphology features, function groups, and valence state of Fe) of the prepared CMEF were determined. Finally, the removing performance and mechanism of CMEF were discussed by removing TCs from solution. The results showed that the optimum conditions for CMEF preparation were a sintering temperature of 1050 degrees C, and the mass ration for sludge:clay:Fe powder of 3:2:2. The CMEF exhibited a high degradation capacity for TCs with a removal rate up to 99.9% in 2.5 h, and the removal kinetics fit well with a pseudo-second-order model. Introducing Fe into the CMEF significantly promoted TCs removal, comparing to the removal of TCs by sludge based ceramic (without addition of iron). This study provides a novel cost-effective CMEF based on sludge, and is also of significance for co-friend recycling of waste sludge. PMID- 30248619 TI - Evaluation of a new extraction platform in combination with molecular assays useful for monitoring immunosuppressed patients. AB - BACKGROUND: In the immunosuppressed, detection of viral reactivation at the earliest convenience and molecular monitoring are of paramount importance. Nucleic acid extraction has a major impact on the reliability of results obtained from molecular assays. OBJECTIVES: The aim of this study was to investigate the accuracy of the new EMAG(r) nucleic acid extraction platform and to compare the performance of the new platform to that of the standard NucliSENS(r) easyMAG(r) instrument in the routine clinical laboratory. STUDY DESIGN: For accuracy testing, reference material and for comparison studies, clinical specimens were used. In addition, a lab-flow analysis including estimation of hands-on time and that for automated extraction was performed. RESULTS: When accuracy was tested, all 89 results obtained were found to be concordant with the results expected. When 648 clinical results were compared, 85.7% were found to be within +/-0.5 log10 unit, 9.5% between +/-0.5 and +/-1.0 log10 unit, and 4.8% more than +/-1.0 log10 unit. The overall time required for nucleic acid extraction of 8 samples in parallel was 94 min for the fully automated extraction mode and 82 min for the partly automated mode with the new platform, and 73 min with the standard instrument. Hands-on time was found to be shorter with the new platform. CONCLUSIONS: The extraction performance of both platforms was found to be similar for EDTA whole blood, BAL, and urine specimens. The total turn-around time for nucleic acid extraction was found to be longer with the EMAG(r) platform, whereas hands-on time was reduced. PMID- 30248620 TI - A visual management tool for program planning, project management and evaluation in paediatric health care. AB - This article describes the development and implementation of a custom-designed Excel-based visual management tool. The tool's purpose was to support program planning and evaluation by our resource support team within a paediatric health care setting. Our aims in developing it were to 1) establish a streamlined process and supporting tools to efficiently plan and prioritize program directions and activities; 2) track progress; and 3) evaluate and report on our performance, outputs and outcomes. A collaborative approach based on the ADKAR (Awareness, Desire, Knowledge, Ability, Reinforcement) change management model and the LEADS (Lead self, Engage others, Achieve results, Develop coalitions, Systems transformation) leadership framework was used to guide the design and implementation processes. Team members reported high perceived effectiveness and efficiency with respect to the tool's utility in supporting its proposed aims. A graded approach to building knowledge and skills in using the tool, to individual responsibility for data entry, and to accountability by team members facilitated its successful implementation. Administrative support is important for sustainability and continual improvement of the tool to address changing team needs over time. PMID- 30248621 TI - Implementation fidelity and adolescent smoking: The X:IT study-A school randomized smoking prevention trial. AB - BACKGROUND: Assessing the actual implementation of multi-component interventions can provide important knowledge for future interventions. Intervention components may be implemented differently, knowledge about this can provide an understanding of which components are essential and therefore must be included. The aim of this study was to examine the implementation of one, two, or all three main intervention components at the individual level and to assess the association to current smoking among 13 year-olds in the X:IT study. METHODS: Data stems from a cluster-randomized controlled trial in 94 Danish elementary schools (51 intervention; 43 control schools). Implementation was measured by aspects of adherence, dose, quality of delivery, and participant responsiveness based on questionnaire data from 4161 pupils at baseline (mean-age: 12.5 years) and 3764 pupils at first follow-up eight months later. Coordinator responses from 49 intervention schools were also included. Associations between individual level implementation of the three main components and pupil smoking were examined through a 3-level logistic regression model. RESULTS: Although implementation fidelity for the three main intervention components was good, only one third (38.8%) of pupils in intervention schools were exposed to full implementation of the intervention. Among these pupils odds ratio for smoking was 0.25 (95% CI: 0.15 - 0.42). CONCLUSIONS: School-based programs can be very effective if carefully implemented. Future school-based smoking preventive initiatives should include multiple components, and seek to enhance implementation quality of all components. PMID- 30248622 TI - An EEG nicotinic acetylcholine index to assess the efficacy of pro-cognitive compounds. AB - OBJECTIVES: Cognitive impairment models are used in clinical studies aimed at proving pharmacology of drugs being developed for Alzheimer's disease and other cognitive disorders. Due to rising interest in nicotinic agonists, we aimed to establish a method to monitor neurophysiological effects of modulating the nicotinic cholinergic system. METHODS: In a four-way cross-over study, eyes closed rest EEG was recorded in 28 healthy subjects receiving mecamylamine-a nicotinic acetylcholine receptor (nAChR) antagonist, which induces temporary cognitive dysfunction in healthy subjects-with co-administration of placebo, nicotine or galantamine. RESULTS: Using machine learning to optimally contrast the effects of 30 mg of mecamylamine and placebo on the brain, we developed a nAChR index that consists of 10 EEG biomarkers and shows high classification accuracy (~95% non-cross-validated, ~70% cross-validated). Importantly, using the nAChR index, we demonstrate reversal of mecamylamine-induced neurophysiological effects due to 16 mg of galantamine as well as administering 21 mg of nicotine transdermally. CONCLUSIONS: Our findings indicate that the mecamylamine challenge model jointly with the nAChR index-a measure of the nicotinic EEG profile-could aid future proof-of-pharmacology studies to demonstrate effects of nicotinic cholinergic compounds. SIGNIFICANCE: This novel measure for quantifying nicotinic cholinergic effects on the EEG could serve as a useful tool in drug development of pro-cognitive compounds. PMID- 30248623 TI - The motor unit number index (MUNIX) profile of patients with adult spinal muscular atrophy. AB - OBJECTIVE: Objective of this study is the comprehensive characterisation of motor unit (MU) loss in type III and IV Spinal Muscular Atrophy (SMA) using motor unit number index (MUNIX), and evaluation of compensatory mechanisms based on MU size indices (MUSIX). METHODS: Nineteen type III and IV SMA patients and 16 gender- and age-matched healthy controls were recruited. Neuromuscular performance was evaluated by muscle strength testing and functional scales. Compound motor action potential (CMAP), MUNIX and MUSIX were studied in the abductor pollicis brevis (APB), abductor digiti minimi (ADM), deltoid, tibialis anterior and trapezius muscles. A composite MUNIX score was also calculated. RESULTS: SMA patients exhibited significantly reduced MUNIX values (p < 0.05) in all muscles, while MUSIX was increased, suggesting active re-innervation. Significant correlations were identified between MUNIX/MUSIX and muscle strength. Similarly, composite MUNIX scores correlated with disability scores. Interestingly, in SMA patients MUNIX was much lower in the ADM than in the ABP, a pattern which is distinctly different from that observed in Amyotrophic Lateral Sclerosis. CONCLUSIONS: MUNIX is a sensitive measure of MU loss in adult forms of SMA and correlates with disability. SIGNIFICANCE: MUNIX evaluation is a promising candidate biomarker for longitudinal studies and pharmacological trials in adult SMA patients. PMID- 30248624 TI - CAN anterior cervical fusion procedures prevent the progression of the natural course of Hirayama disease? An ambispective cohort analysis. AB - OBJECTIVE: To clarify the effectiveness of anterior cervical fusion (ACF) in the treatment of Hirayama disease (HD). METHODS: Sixty-nine HD patients who accepted ACF procedures underwent dynamic F-waves before and soon after operation, and 36 of the 69 patients underwent pre- and postoperative magnetic resonance imaging (MRI). Motor unit number estimation, handgrip strength (HGS) and disabilities of arm, shoulder and hand (DASH) were performed in these 36 HD patients and in the other 24 patients who accepted neither neck-collar support nor operation, and these tests were reassessed about one year after initial test. RESULTS: Postoperatively, dynamic F-wave abnormalities were observed in fewer HD cases (2/69 vs. 25/69), and neck-flexion MRI abnormalities decreased significantly (P < 0.05). Compared with motor unit loss in patients who were untreated, follow-up analysis demonstrated no differences in motor unit, HGS or DASH in HD patients who underwent operation (P > 0.05), and mild recovery of motor units was observed in patients with preoperative abnormal dynamic F-waves (P < 0.05). CONCLUSIONS: ACF procedures can immediately remove neck-flexion abnormalities and prevent or delay the progression of HD. SIGNIFICANCE: ACF procedures may provide effective, reliable and alternative methods for the treatment of HD, especially in HD patients with functional evidence of neck-flexion abnormalities. PMID- 30248625 TI - Ocular torsion responses to electrical vestibular stimulation in vestibular schwannoma. AB - OBJECTIVES: We determined if eye movements evoked by Electrical Vestibular Stimulation (EVS) can be used to detect vestibular dysfunction in patients with unilateral vestibular schwannoma (VS). METHODS: Ocular torsion responses to monaural sinusoidal EVS currents (+/-2 mA, 2 Hz) were measured in 25 patients with tumours ranging in size from Koos grade 1-3. For comparative purposes we also measured postural sway response to EVS, and additionally assessed vestibular function with the lateral Head Impulse Test (HIT). Patient responses were compared to age-matched healthy control subjects. RESULTS: Patients exhibited smaller ocular responses to ipsilesional versus contralesional EVS, and showed a larger asymmetry ratio (AR) than control subjects (19.4 vs. 3.3%, p < 0.05). EVS evoked sway responses were also smaller in ipsilesional ear, but exhibited slightly more variability than the eye movement response, along with marginally lower discriminatory power (patients vs. controls: AR = 16.6 vs 2.6%, p < 0.05). The HIT test exhibited no significant difference between groups. CONCLUSIONS: These results demonstrate significant deficits in the ocular torsion response to EVS in VS patients. SIGNIFICANCE: The fast, convenient and non-invasive nature of the test are well suited to clinical use. PMID- 30248626 TI - Ulnar head arthroplasty with posterior interosseous nerve neurectomy: A case report. AB - BACKGROUND: Distal Radioulnar joint (DRUJ) arthropathy can occur as a consequence of multiple mechanisms, including trauma, inflammatory or degenerative arthritis or even congenital anomalies. Ulnar head arthroplasty has been proposed as a viable therapeutic option, potentially restoring wrist function and improving pain control. This can also be achieved by complete wrist neurectomy but it has several risks associated with the procedure. A selective neurectomy may be more effective. CASE PRESENTATION: We report the case of a 51-year-old man, Tool Colector, who suffered from constant diffuse left wrist pain aggravated with activities and had a swollen and tender wrist at physical examination with limited range of motion on prono-supination. Radiographic and magnetic resonance imaging showed degenerative changes in the radiocarpal joint and distal radioulnar joint. In order to preserve the remaining mobility and reduce the wrist pain we proceeded with an ulnar head arthroplasty and a posterior interosseous nerve neurectomy, through a single skin incision in the dorso-ulnar side of the wrist. Afterwards, the patient followed a strict rehabilitation program with a hand therapist. Six months later he returned to his previous job with no limitations. CONCLUSIONS: Ulnar head arthroplasty seems to be a very good option in the treatment of severe DRUJ arthrosis. It significantly improves pain control while maintains or even improves range of motion. Posterior interosseous nerve neurectomy is a simple technique and highly effective. PMID- 30248627 TI - A case report of successful endovascular repair of a giant 15 cm diameter asymptomatic thoracic aortic aneurysm. AB - INTRODUCTION: Giant thoracic aortic aneurysms (TAA) are extremely uncommon, and there are only a few cases reported in the literature. Most patients presented with symptoms before the size of the aneurysm reached a magnitude >10 cm, and most of the reported cases were treated with open repair. PRESENTATION OF CASE: Here we report a 15 cm asymptomatic thoracic aortic aneurysm of a 72-year-old male patient, treated successfully with thoracic endovascular aortic repair (TEVAR). The patient was discharged asymptomatic on postoperative day 2. DISCUSSION: Only 20 case reports of giant TAAs were found in the literature, and this is the biggest TAA reported treated with TEVAR. This procedure is a promising treatment as morbidity and mortality is lower when compared with open aortic repair (OAR). CONCLUSION: Even though there is limited documented experience, use of TEVAR seems a safe and promising option in the treatment of giant thoracic aneurysms as presented in this case. PMID- 30248629 TI - Use of indocyanine green fluorescence imaging to determine the area of bowel resection in non-occlusive mesenteric ischemia: A case report. AB - INTRODUCTION: Non-occlusive mesenteric ischemia (NOMI) is a type of acute intestinal ischemia, and its associated mortality is very high. In laparotomy of NOMI, we often have difficulty determining the area of bowel resection. We herein describe a case in which we detected the area of bowel resection using indocyanine green (ICG) fluorescence imaging. PRESENTATION OF THE CASE: An 89 year-old man diagnosed as having advanced gastric cancer underwent distal gastrectomy. On the night of postoperative day 4, he strongly complained of distention of the abdomen. The laboratory data indicated severe metabolic acidosis and dehydration. The abdominal computed tomography scan showed a dilated small bowel, but there were no specific signs suggestive of bowel necrosis. We suspected NOMI and decided to perform emergency laparotomy because we could not exclude the possibility of bowel necrosis. During the operation, we could not detect the necrotic bowel macroscopically. After injecting 2.5 mg of ICG, the ischemic area of the bowel became visible as a region with poor fluorescence emission using the Photodynamic EyeTM (Hamamatsu Photonics K.K.). We resected the ischemic bowel and performed anastomosis. We confirmed that he was alive at 4 months after the operation of NOMI. CONCLUSION: Intraoperative ICG fluorescence imaging makes it possible to detect necrotic intestine that cannot be found with the naked eye. By using this method, planned reoperation to find any newly developed necrotic intestine might be unnecessary. Intraoperative ICG fluorescence imaging is useful for defining the area of ischemic bowel in a patient with NOMI. PMID- 30248628 TI - Hysterectomy and salpingo-oophorectomy by transvaginal natural orifice transluminal endoscopic surgery (V-NOTES) assisted by an umbilical camera: Case report and new hybrid technique in gynecology. AB - INTRODUCTION: Natural orifice transluminal endoscopic surgery (NOTES) is a new development in the field of minimally invasive surgery. The aim of this study was to demonstrate a new hybrid NOTES technique in gynecology which can be used for hysterectomy and salpingo-oophorectomy in patients with adnexal pathology and multiple operation histories. PRESENTATION OF CASE: A 50-year-old woman with gravida 2 para 2 was referred to our clinic with left-sided abdominal pain. She had a history of two previous abdominal surgeries and a persistent ovarian cyst for 2 years. An ultrasound examination revealed a left complex hypoechoic ovarian cyst of 10 cm. Tumor markers were normal and the patient had no suspicion for malignancy. The hybrid NOTES technique assisted by an umbilical camera was planned due to the possibility of pelvic adhesions and her concerns about cosmesis. DISCUSSION: The major difference between NOTES and umbilical camera assisted NOTES is seeing all of the major structures, such as the ureters, uterine vessels, bowels, and pelvic adhesions, which can lead to complications during the surgery. In fact, hybrid NOTES can make surgeries more feasible. CONCLUSION: This new hybrid NOTES offers effective and safer surgical management in patients who have had previous surgery and adnexal masses. PMID- 30248630 TI - The impact of epilepsy duration in a series of patients with mesial temporal lobe epilepsy due to unilateral hippocampal sclerosis. AB - PURPOSE: To evaluate if the duration of epilepsy influences MRI volumes of the hippocampus, amygdala, parahippocampal gyrus, entorhinal cortex and temporal pole of both hemispheres and epileptogenic hippocampus neuronal cell density and dentate gyrus granular cells distribution in patients with refractory mesial temporal lobe epilepsy due to hippocampal sclerosis (MTLE/HS). METHODS: Seventy seven patients with refractory MTLE/HS submitted to surgery were included. Histopathological analysis included: (1) quantitative: hippocampal subfields and total estimated hippocampal cell density (HCD), thickness of the dentate gyrus - normal, thinning or dispersion; (2) qualitative: type of HS and granule cells pathology in the dentate gyrus (normal, neuronal cell loss, dispersion and bilamination). Automated MRI-derived measurements from bilateral temporal structures (hippocampus, amygdala, parahippocampal gyrus, temporal pole, entorhinal cortex) were obtained for 58 subjects. Histopathological and imaging findings were compared with data from specimens obtained in autopsies of age matched individuals and living controls, respectively, and the data were adjusted for the age at epilepsy onset and the frequency of focal impaired awareness seizures/month. RESULTS: Forty-two (54.5%) patients presented right HS. The greater the duration of epilepsy, the smaller the total estimated HCD (p = 0.025; r = -0.259). Patients with a normal distribution of the granular cells had a shorter epilepsy duration than those with dispersion (p = 0.018) or thinning (p = 0.031). A reduced ipsilateral hippocampal volume (r = -0.551, p = 0.017) and a smaller hippocampal asymmetry index (r = -0.414, p = 0.002) were correlated to a longer epilepsy duration. The estimated HCD was correlated to the volume of the ipsilateral hippocampus (r = 0.420, p = 0.001). CONCLUSION: Our study showed an increasing atrophy of the ipsilateral hippocampus in patients with a longer epilepsy duration. Our data suggest that this reduction in hippocampal volume is related to neuronal loss. Besides that, we also showed an increased probability of exhibiting an abnormal distribution of the granular cells in the dentate gyrus in patients with longer epilepsy duration. PMID- 30248632 TI - Bipolar disorder and psychotropic medication: Impact on pregnancy and neonatal outcomes. AB - OBJECTIVE: The hypotheses were: (1) pregnant women with bipolar disorder (BD) have less favorable pregnancy outcomes than unaffected women, and (2) psychotropic treated women with BD have better outcomes than un-medicated women. METHOD: This prospective study included 174 mother-infant dyads. Women had BD without psychotropic exposure (BD-NP, n = 38), BD with psychotropic treatment (BD P, n = 49), or neither psychotropic exposure nor major mood disorder (Comp, n = 87). Maternal characteristics were completed at 20 weeks gestation and evaluated for associations with delivery and birth outcomes. We performed multiple regressions on infant outcomes with adjustment for maternal age, race, employment status, use of illicit drugs and pre-pregnancy BMI. RESULTS: The BP-P, BP-NP and Comp groups varied significantly on sociodemographic characteristics. Women with BD were more likely to be less educated, unemployed, single, and use tobacco and illicit drugs than women in the Comp group. Compared to women with BD-NP, women with BD-P were more likely to be older and educated. Approximately 10% of all infants were delivered preterm. No significant differences in outcome occurred for APGAR scores < 8, NICU admissions, sex or infant length. Infants of mothers with BD-NP had significantly smaller head circumferences (HC) than the other groups, adjustment for confounding variables mitigated this association. CONCLUSIONS: The overall pregnancy outcomes for women with BD were similar to those in the Comp group. The reduced HC in women with untreated BD appears due to factors related to disadvantaged sociodemographic status, a higher proportion of female births, and/or a protective effect of medication in the BD-P group. PMID- 30248631 TI - Shame as a mediator between posttraumatic stress disorder symptoms and suicidal ideation among veterans. AB - BACKGROUND: Suicidal ideation is a problem that disproportionately affects veterans. Moreover, veterans with posttraumatic stress disorder (PTSD) appear to be at particularly high risk for suicide. OBJECTIVE: The purpose of the present research was to examine whether shame mediates the association between PTSD and suicidal ideation. METHODS: Secondary analyses were conducted in a sample of 201 veterans with PTSD seeking care through an outpatient Veterans Affairs specialty PTSD clinic. RESULTS: Path analysis revealed that shame fully accounted for the effects of PTSD on suicidal ideation, suggesting that shame may represent a key link between PTSD and suicidal ideation among veterans. LIMITATIONS: Although the reverse mediation effect was also examined, the present sample was cross sectional and predominantly male. CONCLUSIONS: The present findings suggest that shame may be an effective point of treatment intervention to reduce suicidal ideation among veterans with PTSD; however, additional prospective research is still needed to delineate the precise nature of these associations over time. PMID- 30248633 TI - Suicide deaths by gas inhalation in Toronto: An observational study of emerging methods of suicide. AB - BACKGROUND: Suicide death by gas inhalation has been the subject of global scientific interest due to a rapid increase in the use of helium and charcoal gas for suicide. These may be particularly amenable to means restriction strategies. There has been little scientific attention of this phenomenon in Canada. METHODS: A review of coroner records was conducted for all suicide deaths in Toronto (1998 2015). Deaths were categorized as due to inhalational asphyxia by compressed gas (i.e. helium or nitrogen), charcoal burning or motor vehicle exhaust, with suicide deaths by other methods as a comparator. Demographic, clinical and suicide specific differences between decedents in these four categories were compared using chi-squared or ANOVA global test of significance with additional pairwise comparisons where appropriate. Secular trends were also examined. RESULTS: Gas inhalational deaths accounted for 190 (4.7%) of all suicides in Toronto (n = 4062) over the study period and a higher proportion of males used compressed gas or motor vehicle exhaust gases than those who died by other methods (83.3% and 84.0% vs.69.7%, both p = 0.01). Comparing 1998-2003 to 2010 2015 there was a 1075% increase in deaths by helium (4 vs. 43 deaths) and a 533% increase in deaths by charcoal burning (3 vs. 16 deaths) although helium and charcoal burning deaths still accounted for only 4.2% of total suicides 2010 2015. Deaths by helium were more likely to be accompanied by the book "Final Exit" than those by non-inhalational methods (15% vs. 0.7%, p < 0.0001) while 13 of 14 people who died by charcoal burning whose ethnicity could be determined were Asian. LIMITATIONS: Ethnicity and specific details of procurement of suicide methods were not systematically available in coroner records. DISCUSSION: Suicide by inhalational asphyxia, particularly by compressed gases, has increased substantially over time in Toronto consistent with observations in other countries. Increased surveillance of these deaths, efforts to restrict access to these methods, and timely interventions including minimizing media reporting are all warranted. PMID- 30248634 TI - Neuroticism and extraversion mediate the relationship between having a sibling with developmental disabilities and anxiety and depression symptoms. AB - Background Children growing up with a sibling with disabilities report higher levels of depression and anxiety symptoms as adults. Here, we examined whether personality characteristics also play a part in mediating this relationship. Method We tested for differences in personality traits between 132 individuals who have a sibling with developmental disabilities and 132 closely matched comparisons. Results Differences in Big Five factors of personality were demonstrated across the disability groups and between the disability groups and the comparisons, especially in Extraversion, Neuroticism and Openness. Individuals growing up alongside a sibling with developmental disabilities have a higher tendency to experience anxiety and depression symptoms, and this research is the first demonstration that personality traits mediate this relationship. Specifically, Neuroticism is a strong mediator of anxiety while both Neuroticism and Extraversion contribute mediating effects toward the development of depression. Limitations Our study made use of self-report methodology which, although having recognized limitations, is more reliable than parental reports. Given the cross-sectional nature of our design, we were not able to examine pre existing developmental factors that may have influenced the participant's propensity to particular personality traits and affective disorders. However, we obtained a large sample and closely matched participants to examine differences between those with a sibling with disabilities and those without. Conclusions As such, differences in personality traits have important implications for the understanding and treatment of siblings presenting with anxiety and depression symptoms. We recommend that intervention should target those high in Neuroticism among individuals who have a sibling with disabilities, and that more social support is put in place for siblings to mitigate their tendency towards introversion and buffer them against psychological maladjustment. PMID- 30248635 TI - Affective models of depression and anxiety: Extension to within-person processes in daily life. AB - BACKGROUND: Affective models (e.g., tripartite model) delineate shared and unique components of depression and anxiety. Specifically, negative affect is broadly associated with these symptoms, whereas low positive affect is relatively specific to depression and social anxiety. However, it is unknown how affect relates to symptoms as they occur naturalistically in daily life or as a within person dynamic process. METHOD: 135 treatment-seeking adults completed a baseline assessment of trait affect and then rated current affect and symptoms (depression, social anxiety, panic, worry) three times per day for 10 days. Multilevel structural equation modeling was used, and prospective analyses held constant current symptoms. RESULTS: Baseline trait negative affect and individual differences in momentary negative affect predicted all four symptoms in daily life, whereas low positive affect predicted greater depression only. Similar results were found for within-person concurrent analyses. Prospectively, momentary negative affect predicted increased depression up to 24 h later, and increased panic or worry up to 8-16 h later. Low momentary positive affect predicted greater depression only (8 h later). LIMITATIONS: All data were self reported, and some relevant anxiety and mood symptoms were excluded. The timing of reports was random and may have missed notable symptoms. Given the novelty of the study, replication is important. CONCLUSIONS: Affective models of depression and anxiety derived from retrospective assessments demonstrated strong ecological validity. With the exception of PA and social anxiety, associations found at the between-person level generally applied to within-person processes, which may be amenable to tracking and targeting in therapy. PMID- 30248637 TI - Persistent depressive disorder has long-term negative impacts on depression, anxiety, and somatic symptoms at 10-year follow-up among patients with major depressive disorder. AB - OBJECTIVE: The study aimed to investigate the impacts of persistent depressive disorder (PDD) and pharmacotherapy on depression, anxiety, and somatic symptoms among patients with major depressive disorder (MDD) over a ten-year period. METHODS: 290 outpatients with MDD were enrolled, including 117 with PDD, at baseline. Subjects were followed-up at six-month, two-year, and 10-year points. MDD and dysthymic disorder were diagnosed using the Structured Clinical Interview for DSM-IV-TR. The Hamilton Depression Rating Scale, the Hospital Anxiety and Depression Scale, and the Depression and Somatic Symptoms Scale were used. Generalized Estimating Equation models were used to investigate the impacts. RESULTS: MDD patients with PDD had greater severities of depression, anxiety, and somatic symptoms at the three follow-up points as compared with those without; however, these results were of statistical significance only in patients without pharmacotherapy. MDD patients with PDD had a longer duration of pharmacotherapy and a lower remission rate as compared with those without. After controlling for depression and anxiety at baseline, PDD was independently associated with more severe depression, anxiety, and somatic symptoms. LIMITATION: At the ten-year follow-up, approximately half of the subjects were lost to follow-up; this, in addition to the unequal follow-up intervals, might have caused bias. CONCLUSIONS: Among the patients, PDD continued to have negative impacts on depression, anxiety, and somatic symptoms over the subsequent ten years. Differences in symptomatology between the patients with and without PDD were statistically insignificant when pharmacotherapy was utilized; however, pharmacotherapy did not fully compensate for the negative impacts of PDD. PMID- 30248636 TI - Severity-dependent and -independent brain regions of major depressive disorder: A long-term longitudinal near-infrared spectroscopy study. AB - BACKGROUND: Long-term longitudinal studies are necessary to establish neuroimaging indicators which contribute to the detection of severity changes over time in patients with major depressive disorder (MDD). METHODS: One hundred sixty-five patients with MDD underwent clinical assessments and near-infrared spectroscopy (NIRS) examination at the initial evaluation (T0). After 1.5 years, 45 patients who visited for the follow-up evaluation (T1.5) were included in the analysis. The authors conducted analyses using the 17-item Hamilton Rating Scale for Depression (HAMD) scores and mean oxy-hemoglobin concentration ([oxy-Hb]) changes during a cognitive task in NIRS at T0 (T0_HAMD, T0_[oxy-Hb]) and at T1.5 (T1.5_HAMD, T1.5_[oxy-Hb]), and their intra-individual longitudinal changes (DeltaHAMD = T1.5_HAMD - T0_HAMD, Delta[oxy-Hb] = T1.5_[oxy-Hb] - T0_[oxy-Hb]). RESULTS: For severity-dependent regions, the Delta[oxy-Hb] in the right inferior frontal gyrus (IFG) was negatively correlated with the DeltaHAMD. For severity independent regions, the intra-class correlation coefficients between T0_ and T1.5_[oxy-Hb] were moderate in the bilateral middle frontal gyri (MFG). LIMITATIONS: The percentage of patients included in the follow-up examination was relatively small. CONCLUSIONS: Brain activation in the right IFG and the bilateral MFG as measured by NIRS may differentially indicate clinical severity and trait-related abnormalities in MDD. PMID- 30248638 TI - Transcranial and systemic photobiomodulation for major depressive disorder: A systematic review of efficacy, tolerability and biological mechanisms. AB - BACKGROUND: Photobiomodulation (PBM) with red and near-infrared light (NIR) -also known as Low-Level Light Therapy-is a low risk, inexpensive treatment-based on non-retinal exposure-under study for several neuropsychiatric conditions. The aim of this paper is to discuss the proposed mechanism of action and to perform a systematic review of pre-clinical and clinical studies on PBM for major depressive disorder (MDD). METHODS: A search on MEDLINE and EMBASE databases was performed in July 2017. No time or language restrictions were used. Studies with a primary focus on MDD and presenting original data were included (n = 17). References on the mechanisms of action of PBM also included review articles and studies not focused on MDD. RESULTS: Red and NIR light penetrate the skull and modulate brain cortex; an indirect effect of red and NIR light, when delivered non-transcranially, is also postulated. The main proposed mechanism for PBM is the enhancement of mitochondrial metabolism after absorption of NIR energy by the cytochrome C oxidase; however, actions on other pathways relevant to MDD are also reported. Studies on animal models indicate a benefit from PBM that is comparable to antidepressant medications. Clinical studies also indicate a significant antidepressant effect and good tolerability. LIMITATIONS: Clinical studies are heterogeneous for population and treatment parameters, and most lack an appropriate control. CONCLUSIONS: Preliminary evidence supports the potential of non-retinal PBM as a novel treatment for MDD. Future studies should clarify the ideal stimulation parameters as well as the overall efficacy, effectiveness and safety profile of this treatment. PMID- 30248639 TI - Nonlinear dynamics of mood regulation in unaffected first-degree relatives of bipolar disorder patients. AB - BACKGROUND: Mood regulation is a complex and poorly understood process. In this study, we aimed to analyze the underlying dynamics of mood regulation in unaffected first degree relatives of patients diagnosed with bipolar disorder using time-series analysis. METHODS: We recruited 30 unaffected first-degree relatives of bipolar disorder patients. Participants rated their mood, anxiety and energy levels using a paper-based visual analog scale; they recorded their sleep and life events as well. Participants provided information on these variables over a three month period, twice per day. We compared their data using Box-Jenkins time series analysis with data from 30 healthy controls (HC) and 30 euthymic bipolar patients (BD) to obtain information on the autocorrelation and cross-correlation of the series, and calculated entropy for mood, anxiety and energy series. RESULTS: We analyzed 14,980 data points: 5200 in the healthy control group; 4970 in the bipolar group and 4810 in the unaffected relatives group. There were no significant differences between groups in terms of age, sex or education levels. Using Kolmogorov-Smirnov test, we found that individual measures were normally distributed in the whole sample (D = 0.23, p > 0.1). Autocorrelation functions for mood in all groups are governed by the ARIMA (1,1,0) model, which means that current values in the series are related to one previous point only. In terms of entropy for the mood series, unaffected relatives and bipolar patients showed lower values [mean (SD) : 1.028 +/- 0.679; 1.042 +/- 0.680], respectively, compared to healthy controls [(1.476 +/- 0.33); F (2,74) = 4.39, p < 0.01]. The same case was seen in the energy series, with lower values in the unaffected relatives and bipolar patient groups [mean (SD) : 1.644 +/- 0.566; 1.511 +/- 0.879], respectively, compared to healthy controls [2.230 +/ 0.531; F(2, 75) = 7.89, p < 0.001]. LIMITATIONS: Low resolution for the visual analog scale. CONCLUSIONS: Using nonlinear analyses, we found that the underlying structure of mood regulation in unaffected relatives is undistinguishable from the one found in bipolar patients. Compared to healthy controls, both bipolar patients and their unaffected relatives showed lower entropy levels, which is in keeping with a more rigid system, not as flexible to cope with the demands of a changing environment. PMID- 30248640 TI - Novel biotechnological approaches to produce biological compounds: challenges and opportunities for science communication. AB - Novel biotechnological approaches such as Metabolic Engineering (ME) and New Plant Breeding Techniques (NPBTs) are currently being developed to produce biological compounds for food and non-food products. NPBTs span a range of methods for in vivo production in crops, some of which are classified as GMOs while others aren't. Deploying such techniques will not only provide new opportunities for industry, but also challenges with respect to the regulatory environment. Similarly, the process of communicating these new techniques and their products to stakeholders and consumers will not be without its own challenges. We argue that scientists should engage more with non-scientists, either directly or through collaborators. These engagements should not only be about the science, we suggest, but also explicitly deal with real world ramifications, such as economic, environmental and social issues. PMID- 30248641 TI - Construction and application of amperometric sarcosine biosensor based on SOxNPs/AuE for determination of prostate cancer. AB - An improved amperometric sarcosine biosensor was constructed based on covalent immobilization of sarcosine oxidase nanoparticles (SOxNPs) onto gold electrode (AuE). The SOxNPs/AuE was characterized by scanning electron microscopy (SEM), fourier transform infrared (FTIR) spectroscopy and electrochemical impedance spectroscopy (EIS) at different stages of its construction. The biosensor worked optimally within 2 s at a potential of 1.0 V, against Ag/AgCl, pH 6.5 and 35 degrees C. A linear relationship was observed between sarcosine concentration range, 0.1-100 MUM and the biosensor response i.e. current in mA under optimum conditions. The biosensor offered a low detection limit of 0.01 MUM and gratifying storage stability. The SOxNPs/AuE was unaffected by a number of serum substances at their physiological concentrations. The biosensor measured sarcosine level in sera collected from persons suffering from prostate cancer (mean13.5 MUM, n = 8), which was significantly higher (p < 0.01) than those in apparently healthy persons (mean 2.2 MUM, n = 8). The SOxNPs/Au electrode was reused 300- times during the span of 180 days, with only 10% loss in its initial activity while being stored dry at 4 degrees C. PMID- 30248642 TI - Atomic layer deposition for biosensing applications. AB - Atomic layer deposition (ALD) is a thin film deposition technique currently used in various nanofabrication processes for microelectronic applications. The ability to coat high aspect ratio structures with a wide range of materials, the excellent conformality, and the exquisite thickness control have made ALD an essential tool for the fabrication of many devices, including biosensors. This mini-review aims to provide a summary of the different ways ALD has been used to prepare biosensor devices. The materials that have been deposited by ALD, the use of the ALD layers prepared and the different types of biosensors fabricated are presented. A selected list of studies will be used to illustrate how the ALD route can be implemented to improve the operational performance of biosensors. This work comprehensively shows the benefits of ALD and its application in various facets of biosensing and will help in exploiting the numerous prospects of this emerging and growing field. PMID- 30248643 TI - Identifying design guidelines to meet the circular economy principles: A case study on electric and electronic equipment. AB - This study presents a methodology that allows the analysis of how an existing product design meets the design guidelines required from the circular economy perspective, and which are the design guidelines that would need to be incorporated into its design to become a better circular design product. For that, as a starting point, the design guidelines required for the circular product design have been identified from an extensive literature review. Then, criteria have been defined to measure the margin of improvement of a product design based on the level of compliance of each circular design guideline, and the relevance of each circular design guideline for the specific product category to which it belongs. Finally, the methodology has been applied to a representative sample of 127 appliances belonging to different categories of small household electrical and electronic equipment. The circular design guidelines related to extending life span and to product/components reuse have been identified as those that more urgently need to be incorporated, while the urgency of those related to connectors or product structure is moderate. PMID- 30248644 TI - Inorganic apatite nanomaterial: Modified surface phenomena and its role in developing collagen based polymeric bio-composite (Coll-PLGA/HAp) for biological applications. AB - Nano sized bio-composites containing inorganic particles conjugated with polymer and protein are considered as potential material for tissue engineering systems like bone repair and advanced drug delivery. More specifically, hydroxyapatite (HAp), a well known as the strong bioactive material has limitations on reactivity towards biological systems. Thus, this work explains the interaction betweena natural biomaterial Collagen and poly (lactide co-glycolide) Hydroxyapatite (HAp) composite. PLGA/HAp composite was fabricated by in-situ polymerization of DL-lactide, glycolide and HAp nanoparticles. The prepared PLGA/HAp composite was examined for physico-chemical properties by FTIR, DSC, SEM, and DLS. The microscopic image confirms the positioning of a highly ordered structure containing Coll-PLGA/HAp that leads to enhancement in thermal stability of collagen. The nature of bonding and structural orientation of bio-composite was thoroughly investigated by FTIR and SEM. Toxicity of bio-composites on A549 human lung cancer cell line and L929 mouse normal cell line were analysed, and results showed a decreasing trend in the cell viability, on increasing the concentration of bio-composite. As an effective option for tissue engineering, the scaffold was prepared by vacuum drying method. Porosity and tensile strength measurements of scaffold reveal that non-toxic characteristics of bio-composite, excellent pore distribution of scaffold and thermal resistivity make it a versatile material for tissue engineering. PMID- 30248645 TI - Interaction of a cationic amphiphile with monomeric and polymeric electrolytes: From morphological transition to associative phase separation. AB - The discrete effects of a series of structurally divergent monomeric viz. Sodium Chloride (NaCl), Tetra-butyl Ammonium Chloride (TBAC) and Sodium Benzoate (NaBz) and polymeric viz. Sodium Polystyrene Sulfonate (NaPSS) electrolytes towards the morphological and/or aggregation properties of Octadecyl-trimethyl Ammonium Bromide (OTAB) micelles have been quantified spectroscopically by means of the modulations of the absorption and emission spectral properties of an extrinsic anthracene-based probe 9-methyl anthroate (9-MA) within the concerned media. Further corroboration of the spectroscopic results was acquired from the non invasive dynamic light scattering technique. The qualitatively similar mode of action of all the monomeric salts has been explained on the basis of the archetypal Israelachvili model whereas the corresponding extent of the morphological transition of the micelles, which is found to follow the order NaBz > NaCl > TBAC, has been explained invoking the co-sphere overlap model. Conversely, to explain the aggregation behaviour of the micelles in the presence of the polymeric electrolyte, a two-step model has been formulated. According to this model, at the low concentration regime, the polymeric salt is found to only neutralize the surface charge of the micelles inducing micellar growth; whereas further increment in the concentration of the polymer assists the hydrophobic association between the micelles leading to the formation of larger aggregates, eventually causing a phase separation. PMID- 30248647 TI - Development of long in vivo tissue-engineered "Biotube" vascular grafts. AB - In-body tissue architecture (iBTA), a cell-free, in vivo tissue engineering technology that can produce autologous implantable tissues of the desired shape by subcutaneously embedding specially designed molds, was used to develop long tubular collagenous tissues called Biotubes. Spiral molds for long Biotubes were assembled with an outer pipe-shaped spiral shell and an inner spiral mandrel, and embedded into subcutaneous pouches of beagle dogs or goats for 1 or 2 months. Tubular collagenous tissues were formed at the space between the shell and the mandrel of the mold. Depending on the spiral turn number in the mold, Biotubes of 25 cm or 50 cm (internal diameter 4 mm or 5 mm) were prepared with nearly homogeneous mechanical and histological properties over their entire length. Biotubes stored in 70% ethanol were allogenically implanted into beagle dogs or goats to evaluate their in vivo performance. The 25-cm Biotubes functioned as arterial grafts with no need for luminal modification or mechanical support, and demonstrated vascular reconstruction within 3 months after implantation into dogs. The 50-cm Biotubes functioned as arteriovenous shunt grafts in the neck region of goats without thrombus formation and vascular deformation for 1 month. Thus, the world's longest tissue-engineered vascular grafts with small diameter could be developed using iBTA. PMID- 30248646 TI - 3D printed biofunctionalized scaffolds for microfracture repair of cartilage defects. AB - While articular cartilage defects affect millions of people worldwide from adolescents to adults, the repair of articular cartilage defects still remains challenging due to the limited endogenous regeneration of the tissue and poor integration with implants. In this study, we developed a 3D-printed scaffold functionalized with aggrecan that supports the cellular fraction of bone marrow released from microfracture, a widely used clinical procedure, and demonstrated tremendous improvement of regenerated cartilage tissue quality and joint function in a lapine model. Optical coherence tomography (OCT) revealed doubled thickness of the regenerated cartilage tissue in the group treated with our aggrecan functionalized scaffold compared to standard microfracture treatment. H&E staining showed 366 +/- 95 chondrocytes present in the unit area of cartilage layer with the support of bioactive scaffold, while conventional microfracture group showed only 112 +/- 26 chondrocytes. The expression of type II collagen appeared almost 10 times higher with our approach compared to normal microfracture, indicating the potential to overcome the fibro-cartilage formation associated with the current microfracture approach. The therapeutic effect was also evaluated at joint function level. The mobility was evaluated using a modified Basso, Beattie and Bresnahan (BBB) scale. While the defect control group showed no movement improvement over the course of study, all experimental groups showed a trend of increasing scores over time. The present work developed an effective method to regenerate critical articular defects by combining a 3D printed therapeutic scaffold with the microfracture surgical procedure. This biofunctionalized acellular scaffold has great potential to be applied as a supplement for traditional microfracture to improve the quality of cartilage regeneration in a cost and labor effective way. PMID- 30248648 TI - Long-term recovery profile of patients with severe disability or in vegetative states following severe primary intracerebral hemorrhage. AB - PURPOSE: We conducted a single-center retrospective review to investigate the long-term recovery of patients who were severely disabled or vegetative secondary to primary intracerebral hemorrhage upon discharge from hospital from January 2009 to November 2013. METHODS: Patients were categorized into two groups based on their Glasgow outcome scale (GOS) scores at discharge, namely vegetative state (GOS 2; n = 91) and severely disabled (GOS 3; n = 278). Long-term outcomes at three years post discharge were defined as death, stable, deterioration and improvement from discharge to follow-up. RESULTS: Lower mortality (29% versus 69%) and higher neurological improvement rates at three years (33% versus 10%) were observed in the SD compared to VS group (both p = .0001). Age was a significant predictor of survival in the VS group (p = .03) and the SD group (p = .012). Age was also the only predictor of neurological improvement in the SD group (p = .01). CONCLUSIONS: Neurological status at discharge from hospital was not truly indicative of long-term prognosis for patients who were severely disabled or vegetative. Patients in both groups can potentially improve in the long term and may benefit from prolonged rehabilitation programmes to maximize their recovery potential. PMID- 30248649 TI - Hospital case volume and clinical outcomes in critically ill patients with acute kidney injury treated with dialysis. AB - PURPOSE: To determine whether patients with severe acute kidney injury who receive dialysis (AKI-D) experience better outcomes at centres that care for more patients with AKI-D. MATERIALS AND METHODS: Linked administrative datasets where used to perform a retrospective cohort study of all critically ill patients in Ontario, Canada, who had a first episode of AKI-D between 2002 and 2011. Centre volume for a given year, was designated by calculating the mean number of patients treated with acute dialysis at that centre during that year and the one preceding it. Patients treated at that centre were then assigned to a centre volume quartile for that year. RESULTS: We identified 19,658 critically ill patients with AKI-D treated at 54 Ontario hospitals. Mortality and dialysis dependence at 90-days were 46% and 31%, respectively. Centre volume was not associated with mortality at 90 days (with quartile 1 as the reference, adjusted odds ratio (aOR) 1.16 (95% CI, 0.87 - 1.54) in quartile 2, aOR 1.17 (95% CI, 0.91 - 1.50) in quartile 3, and aOR 1.06 (95% CI, 0.81 - 1.41) in quartile 4). CONCLUSIONS: There are no Centre volume survival associations in the management of AKI-D despite high mortality and dependence rate. PMID- 30248650 TI - System performance and microbial community succession in a partial nitrification biofilm reactor in response to salinity stress. AB - The system performance and microbial community succession in a partial nitrification biofilm reactor in response to salinity stress was conducted. It was found that the NH4+-N removal efficiency decreased from 98.4% to 42.0% after salinity stress increased to 20 g/L. Specific oxygen uptake rates suggested that AOB activity was more sensitive to the stress of salinity than that of NOB. Protein and polysaccharides contents showed an increasing tendency in both LB-EPS and TB-EPS after the salinity exposure. Moreover, EEM results indicated that protein-like substances were the main component in LB-EPS and TB-EPS as self protection in response to salinity stress. Additionally, humic acid-like substances were identified as the main component in the effluent organic matter (EfOM) of partial nitrification biofilm, whereas fulvic acid-like substances were detected at 20 g/L salinity stress. Microbial community analysis found that Nitrosomonas as representative species of AOB were significantly inhibited under high salinity condition. PMID- 30248651 TI - Selective production of phenols from lignin via microwave pyrolysis using different carbonaceous susceptors. AB - With an objective to improve the yield and selectivity of phenols in pyrolysis bio-oil from lignin, this study investigates the effects of mass ratio of lignin to-susceptor and different types of susceptors (activated carbons of different particle sizes, charcoal and graphite) in microwave pyrolysis. Pyrolysis was carried out in a batch microwave reactor, and the temperature profiles at different operating conditions were captured. Increasing the mass of susceptor with respect to lignin enhanced the bio-oil yield, and maximum yield of 66 wt% with >90% selectivity to phenols was obtained with 10 g lignin:90 g activated carbon. Moisture present in the susceptor is shown to control the pyrolysis severity and lead to better phenol yields. This was verified by the high yield of hydrogen gas formed due to the steam-assisted cracking of lignin. With highly porous activated carbon, 80% selectivity of phenol was obtained, albeit with a low yield of bio-oil. PMID- 30248652 TI - Solvent and catalyst effect in the formic acid aided lignin-to-liquids. AB - The effect of the type of solvent, ethanol or water, and a Ru/C catalyst were studied in the formic acid aided lignin conversion. The best results were obtained in the presence of the Ru/C catalyst and using ethanol as solvent at 300 degrees C and 10 h (i.e. 75.8 wt% of oil and 23.9 wt% of solids). In comparison to the water system, the ethanol system yields a significantly larger amount of oil and, at 300 degrees C and 10 h, a smaller amount of solids. The main reasons for this positive effect of the ethanol solvent are i) the formation of ethanol derived esters, ii) C-alkylations of lignin fragments and iii) the generation of more stable lignin derivatives. The Ru/C exhibits significantly higher lignin conversion activity compared to other Ni-based catalysts, especially at 300 degrees C, which is related to the enhanced activity of the Ru0 sites towards hydrogenolysis, hydrodeoxygenation and alkylation reactions. PMID- 30248653 TI - Fast dissolution pretreatment of the corn stover in gamma-valerolactone promoted by ionic liquids: Selective delignification and enhanced enzymatic saccharification. AB - The dissolution of corn stover was investigated in gamma-valerolactone (GVL) assisted by ionic liquids. An enhanced subsequent enzymatic saccharification was reached with a total reducing sugar yield of 0.69 g.g-1 and a glucose of 0.38 g.g 1 within 24 h. The treatment effects on the physical-chemical features of corn stover in terms of the natural recalcitrance to the subsequent biological digest were systematically investigated using composition analysis, X-ray diffraction (XRD), scanning electron microscopy (SEM) and atomic force microscopy (AFM). The structures of the associated enzymatic hydrolysis lignin (EHL) and ionic liquid extracted lignin (IEL) were characterized by gel permeation chromatography (GPC), fourier transform infra-red spectroscopy (FTIR), phosphorous nuclear magnet resonance spectrometry (31P NMR), and heteronuclear single quantum coherence spectroscopy (HSQC) for an in-depth understanding of the delignification process and the basic structural information for further lignin valorization. PMID- 30248654 TI - Exploration of novel pyrrolo[2,1-f][1,2,4]triazine derivatives with improved anticancer efficacy as dual inhibitors of c-Met/VEGFR-2. AB - c-Met and VEGFR-2 have attracted interest as novel targets for treatment of various cancers. Aiming to develop potent dual c-Met and VEGFR-2 inhibitors, a series of pyrrolo[1,2-f][1,2,4]triazine derivatives were designed and synthesized. The majority of target compounds exhibited potent antiproliferative effect against c-Met addictive cancer cell lines with IC50 values ranged from 1.2 to 24.6 nM, especially 27a. In-depth studies demonstrated 27a has great selectivity to c-Met and VEGFR-2, and potent inhibitory activity against them (IC50 of 2.3 +/- 0.1 nM and 5.0 +/- 0.5 nM). Furthermore, it also showed the highest anticancer activity with IC50 of 0.71 +/- 0.16 nM (better than the positive compound) against BaF3-TPR-Met and 37.4 +/- 0.311 nM (comparable to the positive compound) against HUVEC-VEGFR2, consistent with that in c-Met sensitive tumor cell lines. Subsequently, physicochemical and pharmacokinetic characterization indicated 27a has favorable druggability and pharmacokinetic properties. Further docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, also indicating that 27a was a potential candidate for cancer therapy deserving further study. PMID- 30248656 TI - Piperidylthiosemicarbazones Cu(II) complexes with a high anticancer activity by catalyzing hydrogen peroxide to degrade DNA and promote apoptosis. AB - Copper(II) complexes efficiently catalyze hydrogen peroxide to generate reactive oxygen species (ROS), which is the major reason for its significant anti-tumor activity. We synthesized three Cu(II) piperidylthiosemicarbazone complexes and examined their structures by X-ray single crystal diffraction. These Cu(II) complexes have significant apoptosis-promoting activity at nanomolar concentrations. The antitumor activity of these Cu(II) complexes is increased by more than 40-fold relative to that of the ligand. The binding experiment results demonstrated that the Cu(II) complexes interact with DNA with moderate binding affinity by in situ intercalation. Gel electrophoresis analysis indicated that DNA is degraded when the copper complex catalyzes hydrogen peroxide to produce reactive oxygen species (ROS). Apoptosis mechanism results showed that excessive ROS leads to mitochondrial membrane potential dissipation and promote the release of apoptotic factors from mitochondria. PMID- 30248655 TI - Discovery of potent liver-selective stearoyl-CoA desaturase-1 (SCD1) inhibitors, thiazole-4-acetic acid derivatives, for the treatment of diabetes, hepatic steatosis, and obesity. AB - SCD1 is a rate-limiting enzyme in the conversion of saturated fatty acids to monounsaturated fatty acids. SCD1 inhibitors have potential effects on obesity, diabetes, acne, and cancer, but the adverse effects associated with SCD1 inhibition in the skin and eyelids are impediments to clinical development. To avoid mechanism-based adverse effects, we explored the compounds that selectively inhibit SCD1 in the liver in an ex vivo assay. Starting from a systemically active lead compound, we focused on the physicochemical properties tPSA and cLogP to minimize exposure in the off-target tissues. This effort led to the discovery of thiazole-4-acetic acid analog 48 as a potent and liver-selective SCD1 inhibitor. Compound 48 exhibited significant effects in rodent models of diabetes, hepatic steatosis, and obesity, with sufficient safety margins in a rat toxicology study with repeated dosing. PMID- 30248657 TI - Synthesis and antiproliferative activity of podocarpane and totarane derivatives. AB - The synthesis of podocarpanes, including 12,19-dihydroxy-13-acetyl-8,11,13 podocarpatriene (23), isolated from Gaultheria yunnanensis and not previously synthesized, and totarane-type terpenoids, starting from the natural labdane trans-communic acid (15), is described. Their antiproliferative activities against MCF-7, T-84 and A-549 human tumoural cell lines are studied. An antiproliferative effect was induced by compounds 23, 27 and 28, with IC50 < 10 MUM in two (27) or three cell lines (23 and 28). No correlation with log P values was observed. The totarane o-quinone 27, and especially the catechol 28, which is readily oxidisable to compound 27, were the most active compounds, highlighting the functional groups present in C11 and C12. Compound 28 showed limited toxicity in normal peripheral blood mononuclear cells (78.5% cell viability versus non treated control cultures at 10 MUM), and appeared to exert an antiproliferative effect in A-549 cells (IC50 0.6 MUM) through a mechanism that involves the induction of apoptosis mediated by an increased Bax/Bcl-2 ratio. The results of the present study indicate that compound 28, at least, might be useful as an antitumoral agent. Further studies are required to elucidate the cellular and molecular elements involved in its effect, and the activity/toxicity in preclinical models. PMID- 30248658 TI - DNA damages and offspring quality in sea urchin Paracentrotus lividus sperms exposed to ZnO nanoparticles. AB - The recent advances in nanotechnology lead to a potential increase of the release of nanoparticles (NPs) into marine environment through different routes, with possible toxic effects upon the living part of this ecosystem. One of the ways of NPs marine contamination gaining today increasing concern stems from the widespread use cosmetics containing ZnO NPs as UV-filter. Although the possible adverse effects on marine organisms have been already ascertained, the information about the possible genotoxicity of ZnO NPs is still scant. In this work the spermiotoxicity of ZnO particles of different sizes (ZnO Bulk > 200 nm, ZnO NPs 100 nm and ZnO NPs 14 nm) was assessed, using Paracentrotus lividus spermatozoa, by evaluating the DNA damage of the exposed sperm, fertilization capability and DNA damage transmission to progeny. Our results showed that ZnO NPs induced DNA damages in spermatozoa after 30 min of exposure. While the sperm fertilization capability was not affected, morphological alterations (skeletal alterations) in offspring were observed and a positive correlation between sperm DNA damage and offspring quality was reported. This study underlines that a possible spermiotoxic action of ZnO NPs at concentration close to those reported in marine coastal water could occur. PMID- 30248659 TI - Pretreatment with ticagrelor may offset additional inhibition of platelet and coagulation activation with bivalirudin compared to heparin during primary percutaneous coronary intervention. AB - BACKGROUND: It remains unknown if bivalirudin compared to heparin confers any additional inhibition of platelet and coagulation activation during primary percutaneous coronary intervention (PPCI) after pretreatment with ticagrelor. METHODS: In this substudy of VALIDATE-SWEDEHEART trial, 103 patients pretreated with ticagrelor were randomized before PPCI to heparin or bivalirudin. Blood samples were collected before and 1 and 12 h after PPCI. We measured platelet reactivity (PR) using Multiplate, soluble P-selectin, thrombin-antithrombin complexes (TAT) and prothrombin fragments 1 + 2 (F1 + 2) as markers of platelet and coagulation activation. RESULTS: The median (IQR) time from ticagrelor administration to randomization was 63 (29) vs 60 (24) minutes, p = 0.28. ADP induced PR did not significantly differ between groups over time (heparin vs bivalirudin, AUC 73 (62) vs 74 (68), p = 0.74, 32 (42) vs 43 (51), p = 0.38, 15 (15) vs 19 (15), p = 0.29, before, 1 and 12 h after PPCI). Soluble P-selectin did not significantly differ between groups. At 1 h TAT significantly increased with bivalirudin (3.0 (1.3) to 4.3 (4.2) ug/L; p < 0.01), but not with UFH (3.1 (2.1) to 3.5 (1.6) ug/L, p = 0.24). F1 + 2 increased in both groups but the rise was numerically higher with bivalirudin (170 (85) to 213 (126) pmol/L vs 168 (118) to 191 (103) pmol/L). At 12 h, a comparable significant increase in thrombin generation was observed in both groups. CONCLUSION: In patients treated with ticagrelor, we found no major differences between bivalirudin and heparin in platelet aggregation or coagulation markers, which is in agreement with the neutral clinical results of the VALIDATE-SWEDEHEART study. PMID- 30248660 TI - Hypermucoviscous Klebsiella pneumoniae infections induce platelet aggregation and apoptosis and inhibit maturation of megakaryocytes. AB - INTRODUCTION: Different Klebsiella pneumoniae strains carry different virulence factors and antibiotic resistance and may cause thrombocytopenia. This study aimed to investigate the effects of different infections caused by K. pneumoniae on platelets. METHODS: Two hypermucoviscous K. pneumoniae strains and two classic strains were collected from clinical blood culture, and in both groups, there was a carbapenem-resistant strain and a carbapenem-sensitive strain. Mouse infection models were constructed by intraperitoneally injecting different strains, and mice injected with phosphate-buffered saline served as a control. Count, aggregation rate and apoptosis proportion of platelets within 12 h were examined. CD41 expression was measured in bone marrow cells to determine the maturation of megakaryocytes. The concentrations of lipopolysaccharides and related signaling molecules were also measured. RESULTS: The platelet aggregation rate was much significantly higher in the two hypermucoviscous groups, while it showed no difference in the classic groups compared to the control group. All infections induced apoptosis of platelets, among which the highest apoptosis proportions were observed in infections caused by the hypermucoviscous carbapenem-sensitive strain. In both hypermucoviscous groups the CD41 mean fluorescence intensity was much lower than that in the control group, indicating that the maturation of megakaryocytes in the hypermucoviscous groups was significantly inhibited. Lipopolysaccharides were significantly higher and TLR4/Myd88 and JNK/MAPK pathways were strongly activated in hypermucoviscous groups. CONCLUSIONS: The results indicate that hypermucoviscous K. pneumoniae can reduce platelet count by several pathways. Although antibiotic resistance is rapidly emerging worldwide, it has little influence on the decrease in platelets. PMID- 30248661 TI - Mechanisms for metal removal established via electron microscopy and spectroscopy: a case study on metal tolerant fungi Penicillium simplicissimum. AB - Penicillium simplicissimum (isolate 10), a metal tolerant fungus, tolerated 1000 mg/L Cu and 500 mg/L Zn, but were inhibited by Cd (100 mg/L), evident by the Tolerance Index (TI) of 0.88, 0.83, and 0.08, respectively. Live cells of P. simplicissimum were more effective in removing Cr (88.6%), Pb (73.7%), Cu (63.8%), Cd (33.1%), and Zn (28.3%) than dead cells (5.3-61.7%). Microscopy approach via SEM-EDX and TEM-EDX suggested that metal removal involved biosorption and bioaccumulation, with metal precipitates detected on the cell wall, and in the cytoplasm and vacuoles. FTIR analysis revealed metals interacted with amino, carbonyl, hydroxyl, phosphoryl (except Cd) and nitro groups in the cell wall. Biosorption and bioaccumulation of metals by live cells reduced Cu and Pb toxicity, observed from good root and (4.00-4.28 cm) and shoot (8.07-8.36 cm) growth of Vigna radiata in the phytotoxicity assay. PMID- 30248662 TI - A novel gas-solids separator scheme of coupling cyclone with circulating granular bed filter (C-CGBF). AB - A novel gas-solids separator scheme of coupling cyclone with circulating granular bed filter (C-CGBF) was proposed. The influences of the operating regimes, the inlet dust concentrations and the inlet gas flow rates on the scheme were investigated in a pilot-scale cold-model experimental apparatus. The pressure drop and the collection efficiency were measured and analyzed. It was shown that, differing from that under the fixed bed (FB) operating regime, the pressure drop tended to assume a steady state after an increasing period under the moving bed (MB). Experiments under the MB revealed that stable/high collection efficiency, typically exceeding 95%, was achieved with considerably low pressure drop. The dust hold-up in the built-in granular bed and the filter cake formed on the outer screen wall contributed to high collection efficiency, as well as increased the pressure drop. Furthermore, the individual contribution of the cyclone shell and the built-in granular bed to the total collection efficiency under the MB were investigated. The size distributions of the captured particles were also analyzed. The contribution ratios of the cyclone shell were around 80%, while the majority of the particles captured by it were larger than 10 MUm. PMID- 30248663 TI - The measurement of tibial acceleration in runners-A review of the factors that can affect tibial acceleration during running and evidence-based guidelines for its use. AB - BACKGROUND: Impact loading in runners, assessed by the measurement of tibial acceleration, has attracted substantial research attention. Due to potential injury links, particularly tibial fatigue fractures, tibial acceleration is also used as a clinical monitoring metric. There are contributing factors and potential limitations that must be considered before widespread implementation. AIM: The objective of this review is to update current knowledge of the measurement of tibial acceleration in runners and to provide recommendations for those intending on using this measurement device in research or clinical practice. METHODS: Literature relating to the measurement of tibial acceleration in steady-state running was searched. A narrative approach synthesised the information from papers written in English. A range of literature was identified documenting the selection and placement of accelerometers, the analysis of data, and the effects of intrinsic and extrinsic factors. RESULTS AND DISCUSSION: Tibial acceleration is a proxy measurement for the impact forces experienced at the tibia commonly used by clinicians and researchers. There is an assumption that this measure is related to bone stress and strain, however this is yet to be proven. Multi-axis devices should be secured firmly to the tibia to limit movement relative to the underlying bone and enable quantification of all components of acceleration. Additional frequency analyses could be useful to provide a more thorough characterisation of the signal. CONCLUSIONS: Tibial accelerations are clearly affected by running technique, running velocity, lower extremity stiffness, as well as surface and footwear compliance. The interrelationships between muscle pre-activation and fatigue, stiffness, effective mass and tibial acceleration still require further investigation, as well as how changes in these variables impact on injury risk. PMID- 30248665 TI - Labor Induction in Late-Onset Fetal Growth Restriction: Foley Balloon versus Vaginal Dinoprostone. AB - OBJECTIVE: To compare vaginal delivery rate and perinatal outcomes of fetuses with late-onset fetal growth restriction (FGR) undergoing labor induction, depending on the method for cervical ripening (dinoprostone vs. Foley balloon). MATERIAL AND METHODS: We conducted a retrospective cohort study of 148 consecutive singleton gestations diagnosed with stage I late-onset FGR and Bishop score < 7, in which labor induction was indicated at >=37 + 0 weeks. Before January 2016, cervical ripening was achieved with 10 mg of vaginal dinoprostone (n = 77) and afterwards with Fo-ley balloon (n = 71). Logistic regression analysis was used to estimate the association between mode of delivery and induction method. RESULTS: Foley balloon had lower percentages of uterine tachysystole with fetal repercussion (4.2 vs. 16.9%, p = 0.01) and cesarean sections for suspected fetal distress (7.0 vs. 26.0%, p < 0.01) when compared to dino-prostone. Lower percentages of cesarean sections were found in the Foley balloon group (15.5 vs. 37.7%, p < 0.01). The odds ratio and adjusted odds ratio of cesarean section with dinoprostone were of 3.3 and 4.4, respectively. Perinatal mortality and severe morbidity were null in both groups. CONCLUSION: The use of Foley balloon resulted in a higher percentage of vaginal delivery compared to dinoprostone, with a favorable safety profile in both groups. PMID- 30248664 TI - miRNA Expression Profile of Saliva in Subjects of Yang Deficiency Constitution and Yin Deficiency Constitution. AB - BACKGROUND/AIMS: Based on the theory of constitution in Traditional Chinese Medicine (TCM), the Chinese Han population has been classified into nine constitutions. Of these, Yang deficiency constitution mainly exhibit cold intolerance while Yin deficiency constitution mainly exhibit heat intolerance. Some studies have been carried out to explore the modern genetic and biological basis of such constitution classification, but more remains to be done. MicroRNA (miRNA) serves as post-transcriptional regulators of gene expression and may play a role in the classification process. Here, we examined miRNA expression profile of saliva to further improve the comprehensiveness of constitution classification. METHODS: Saliva was collected from Chinese Han individuals with Yang deficiency, Yin deficiency and Balanced constitutions (n=5 each), and miRNA expression profile was determined using the Human miRNA OneArray(r)v7. Based on 1.5 Fold change, means log2|Ratio|>=0.585 and P-value< 0.05, differentially expressed miRNA was screened. Target genes were predicted using DIANA-TarBasev7.0 and analysis of KEGG pathway was carried out using DIANA-mirPathv.3. RESULTS: We found that 81 and 98 differentially expressed miRNAs were screened in Yang deficiency and Yin deficiency constitution, respectively. Among them, 16 miRNAs were identical and the others were unique. In addition, the target genes that are regulated by the unique miRNAs were significantly enriched in 27 and 20 signaling pathways in Yang deficiency and Yin deficiency constitution, respectively. Thyroid hormone signaling pathway is present in both constitutions. These unique miRNAs that regulated target genes of thyroid hormone signaling pathway may be associated with cold intolerance or heat intolerance. CONCLUSION: The results of our study show that Yang deficiency and Yin deficiency constitutions exhibit systematic differences in miRNA expression profile. Moreover, the distinct characteristics of TCM constitution may be explained, in part, by differentially expressed miRNAs. PMID- 30248666 TI - Cardiac Shock Wave Therapy Attenuates Cardiomyocyte Apoptosis after Acute Myocardial Infarction in Rats. AB - BACKGROUND/AIMS: Researches have showed that cardiac shock wave therapy (CSWT) could improve left ventricular function and attenuate LV remodeling of the ischemic heart. Apoptosis plays an important role in myocardial infarction and determines heart function and prognosis. However, it is still not clear whether CSWT is sufficient to attenuate acute myocardial infarction (AMI) induced cardiomyocyte apoptosis in vivo. In this study, we used a rat model to examine whether CSWT could attenuate cardiomyocyte apoptosis after AMI and to explore potential mechanisms. METHODS: We generated an AMI rat model to investigate the function and possible regulatory mechanisms of CSWT. All rats were randomly divided into four groups: the sham-operated only group, sham-operated with SW treatment group, AMI only group, and AMI treated with SW treatment group.The rats were treated with a left anterior descending coronary artery ligation for 12h and then treated with or without CSWT (800 shots at 0.1 mJ/ mm2). Cytochrome c release was measured to analyze mitochondrial function and integrity. The apoptotic cell rate was determined by TUNEL assay. Western blot was used to analyze the cell apoptosis-, inflammation-, and survival-related signaling pathways. RESULTS: First, the methodology of CSWT in the rat model of AMI was established. Second, CSWT attenuated the cardiomyocyte apoptosis rate in the infarct border zone. Third, CSWT suppressed the expression of apoptosis and inflammation molecules after AMI. Fourth, CSWT inhibited activation of the JNK pathway, which indicated inhibition of the cell inflammatory pathways and promotion of cardiomyocyte survival after AMI. CONCLUSION: These results indicate that CSWT exerts a protective effect against AMI-induced cardiomyocyte apoptosis, potentially by attenuating cytochrome c release from the mitochondria and inhibiting of the mitochondrial-dependent intrinsic apoptotic pathway. We also demonstrate that CSWT suppresses the JNK pathway and cardiomyocyte inflammation, which may also decrease cardiomyocyte apoptosis in vivo. PMID- 30248667 TI - Hyperactivation of the Frontal Control Network Revealed by Symptom Provocation in Obsessive-Compulsive Disorder Using EEG Microstate and sLORETA Analyses. AB - The aim of this study was to investigate the changes of brain electric field induced by symptom provocation in patients with obsessive-compulsive disorder (OCD) in comparison to healthy controls in the resting state. For this purpose, EEG recordings in conditions of initial rest, clean control, symptom provocation by imaginal exposure, and final rest were used for computing spatiotemporal activity characteristics based on microstate segmentation. Within-group comparisons were significant for the symptom provocation condition: OCD showed high global field power (GFP) and transition rates into a medial frontal microstate, whereas healthy controls showed high frequency of occurrence and high percent of dwelling time for a medial occipitoparietal microstate. Between-group comparisons demonstrated significantly lower GFP and dwelling time for the medial occipitoparietal microstate in OCD in several conditions including initial rest and symptom provocation. In addition, OCD compared to healthy controls showed significant instability of the medial occipitoparietal microstate, with high preference for transitions into the medial frontal microstate. In conclusion, during rest and symptom provocation, OCD patients make preferential use of a medial frontal brain network, with concomitant reduction of use of a medial occipitoparietal network, as shown by dwelling times, explained variance, and dynamic transition rates. These findings support the idea of a possible biological marker for OCD, which might correspond to pathological hyperactivation of the frontal control network. PMID- 30248668 TI - The Relationship between Cytokines and Verbal Memory in Individuals with Schizophrenia and Their Unaffected Siblings. AB - BACKGROUND: Verbal memory impairment may be considered an endophenotype in schizophrenia (SZ), also affecting the siblings of SZ subjects. Furthermore, the immune-inflammatory system response has an important modulatory effect on brain processes, especially on memory circuits. OBJECTIVE: Investigating the relationship between TNF-alpha and IL-6 and memory performance in patients with SZ, their unaffected siblings (SB) and healthy controls (HC). METHODS: 35 subjects with SZ, 36 SB, and 47 HC underwent a neurocognitive assessment for verbal memory by means of the revised Hopkins Verbal Learning Test (HVLT-R) in addition to serum cytokines analyses. RESULTS: SZ patients performed worse in HVLT-R than SB and HC, but SB and HC were not different. Regarding the biomarker levels, we found significant results of TNF-alpha for both groups. However, we did not find differences between groups after multiple-comparisons analysis. There were no significant correlations between episodic verbal memory, TNF-alpha, and IL-6. CONCLUSION: The results are compatible with the hypothesis that deficits in verbal memory of individuals with SZ could be secondary to inadequate functioning of cognitive processing areas, such as proactive cognitive control. PMID- 30248669 TI - Genome-Wide Network-Based Analysis of Colorectal Cancer Identifies Novel Prognostic Factors and an Integrative Prognostic Index. AB - BACKGROUND/AIMS: Colorectal cancer (CRC) is one of leading cancers in both incidence and mortality rate. The 5-year survival rate varies considerably depending on the pathological stage of the tumor. Although prominent progress has been made through screening for survival-associated factors from a certain type of genetic or epigenetic modifications, few attempts have been made to apply a network-based approach in prognostic factor identification, which could prove valuable for a complex, multi-faceted disease such as CRC. METHODS: In this study, a TCGA dataset of 379 CRC patients was subjected to a network-based analysis strategy consisting of multivariate regression, co-expression network and gene regulatory network analyses, and survival analyses. Both genetic and epigenetic aberrations, including those in gene expression and DNA methylation at specific sites, were screened for significant association with patient survival. A prognostic index (PI) integrating all potential prognostic factors was subsequently validated for its prognostic value. RESULTS: A collection of six miRNAs, eleven mRNAs, and nine DNA methylation sites were identified as potential prognostic factors. The low- and high-risk patient groups assigned based on PI level showed significant difference in overall survival (hazard ratio = 1.32, 95% confidence interval 1.29-1.36, p < 0.0001). Patients in the low- and high-risk groups can be further divided into a total of four subgroups, based on pathological staging. In the two high-risk subgroups (PI > 0), there was significant different (Cox p < 0.0001) in OS between the earlier (stages I/II) and later stages (stages III/IV). However, in the two low-risk subgroups (PI < 0), earlier (stages I/II) and later stages (stages III/IV) showed no significant difference in OS (Cox p = 0.185). On the other hand, there were significant differences in OS between the low- and high-risk subgroups when both subgroups were of earlier stages (Cox p < 0.001) or of later stages (Cox p < 0.0001). CONCLUSION: The novel network-based, integrative analysis adopted in this study was efficient in screening for prognostic predictors. Along with PI, the set of 6 miRNAs, 11 mRNAs, and 9 DNA methylation sites could serve as the basis for improved prognosis estimation for CRC patients in future clinical practice. PMID- 30248671 TI - Stromal Cellular Fragments in Breast Fine Needle Aspirates: Think Outside of the Box. AB - BACKGROUND: The presence of highly cellular stromal fragments in breast fine needle aspirates (FNA) suggests some classical differential diagnoses such as cellular fibroadenoma, phyllodes tumour (PT), metaplastic carcinomas, and some mesenchymal/myoepithelial proliferations. The other components of the smears can help in the differential diagnosis, but the presence of a low-grade epithelial proliferation does not always represent a fibro-epithelial lesion as we demonstrate in these two cases. CASES: We discuss two cases of breast FNA, previously presented in a slide seminar at the 29th European Congress of Pathology in Amsterdam, where the common cytological finding was the presence of stromal cellular fragments together with an epithelial component. One case is a typical PT and the other is a case of a mammary carcinoma with osteoclast-like giant cells. CONCLUSION: Mammary carcinoma with osteoclast-like giant cells is an unusual type of breast carcinoma that should be included in the differential diagnosis of breast lesions containing cellular stroma. Since the associated carcinoma is usually low grade, careful evaluation for malignant cells on cytological smears is necessary for an accurate differential diagnosis with PT where the epithelial component is benign. PMID- 30248670 TI - Effect of Ascorbic Acid on Mineral and Bone Disorders in Hemodialysis Patients: a Systematic Review and Meta-Analysis. AB - BACKGROUND/AIMS: Hemodialysis (HD) patients often have inadequate nutrition, especially with respect to ascorbic acid (AA). It is reported that every HD session may cause a 50%- 75% decrease in plasma AA levels. Some studies have shown that supplementation of AA can change the outcome of chronic kidney disease mineral bone disorders (CKD-MBD), but the effect of AA on HD patients with CKD MBD remains controversial. Consequently, we decided to perform a meta-analysis to evaluate the efficacy of AA supplementation in CKD-MBD patients requiring dialysis. METHODS: A search was conducted using Pubmed, EMBASE, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure (CNKI), Wanfang database and VIP information database up to April 2018 for all English and Chinese language publications. The main indicators of our study were changes in serum phosphate (P), calcium (Ca) and parathyroid hormone (PTH) levels after AA treatment. The efficacy of AA was evaluated by weighted mean difference (WMD) and confidence intervals (CI). Cardiovascular events, mortality and adverse events reported during the experiment were also noted. RESULTS: In total, 371 patients in six studies were involved in this meta-analysis. Compared to placebo, AA treatment had no positive effect on serum P (353 patients; WMD = -0.05; 95% CI, -0.3 to 0.2; I2 = 28%) or PTH levels (275 patients; WMD = -17.04; 95%CI, 63.79 to 29.72; I2 = 75%). The pooled mean difference of the change of Ca levels from baseline was higher in the AA therapy group versus placebo (353 patients; WMD = 0.15; 95% CI, 0.01 to 0.3; I2 = 0%). No side effects were observed. CONCLUSION: Our systematic review and meta-analysis does not support prescription of AA to HD patients with CKD-MBD. AA had no positive effect on CKD-MBD patients as it couldn't influence the serum P or PTH levels but did raise serum Ca levels in the short-term. PMID- 30248672 TI - Gender Difference in the Relationship of Albuminuria and Arterial Stiffness in Chinese Adults - a 6.6-Year Follow-Up Longitudinal Study. AB - BACKGROUND/AIMS: Brachial-ankle pulse wave velocity (baPWV) reflects the stiffness of muscular arteries. Albuminuria is recognized as a marker of vascular dysfunction. We assessed the association between arterial stiffness and albuminuria in a population-based longitudinal study. METHODS: 1116 adults aged >= 40 years in the Taichung Community Health Study (TCHS) in 2004 attended a follow-up visit in 2011. Albuminuria was defined as an urinary albumin-to creatinine ratio (UACR) >= 30 mg/g. Arterial stiffness was defined as BaPWV >= 1540 cm/sec in males and BaPWV >= 1480 cm/sec in females, respectively. ?baPWV was calculated as baPWV at follow-up minus baPWV at baseline, while ?UACR was calculated as UACR at follow-up minus UACR at baseline. Multiple linear and logistic regression analyses were used to explore the relationship between albuminuria and arterial stiffness. RESULTS: Among 652 subjects without arterial stiffness at baseline, 209 (32%) subjects developed incident arterial stiffness after an average of 6.6 years. In male subjects, baseline albuminuria was associated with development of arterial stiffness (odds ratio: 4.47, 95% confidence interval [CI]: 1.04-19.31) and ?baPWV was modestly positively associated with ?UACR. CONCLUSION: Our results indicated that male adults with albuminuria had an increased risk for developing arterial stiffness. PMID- 30248673 TI - Unmet medical needs in pulmonary neuroendocrine (carcinoid) neoplasms. AB - Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e. typical (TC) and atypical carcinoid (AC), respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic (GEP) NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication and treatment in the setting of PC with focus on unmet medical needs and directions for the future. PMID- 30248674 TI - Reply to Dr. Vassallo et al. (ms No. 201807012): Regional Citrate Anticoagulation During Coupled Plasma Filtration and Adsorption May Increase Survival in Septic Shock. PMID- 30248675 TI - 12th Congress of the International Society of Nutrigenetics/Nutrigenomics (ISNN). PMID- 30248676 TI - Critical Review of Complementary and Alternative Medicine Use in Amyotrophic Lateral Sclerosis: Prevalence and Users' Profile, Decision-Making, Information Seeking, and Disclosure in the Face of a Lack of Efficacy. AB - BACKGROUND: Despite a lack of evidence of clinical efficacy for complementary and alternative medicine (CAM) use in amyotrophic lateral sclerosis (ALS), these medicines remain popular around the world. OBJECTIVE: To examine the prevalence and cost of CAM use in ALS and CAM users' profile, decision-making, information seeking, and disclosure among ALS patients. METHODS: A comprehensive literature search was conducted of MEDLINE, CINAHL/SCOPUS, and AMED databases from their inception to April 2018. This review followed PRISMA guidelines and employed a quality scoring system to assess the included papers. RESULTS: Seven papers met the inclusion criteria and were thematically analysed. ALS patients utilized a range of CAM therapies and/or products, with acupuncture and vitamins being the most frequently reported. CAM modalities were often employed concurrently with conventional medications throughout the disease process. Although some ALS patients reported positive experience regarding CAM use, many were reluctant to disclose their CAM use to their clinicians. Research focusing on CAM use in ALS remains ad hoc and restricted to only a few countries. The rigour and quality of this research field to date has been varied, predominantly drawing upon regional/localized data and failing to report CAM users' characteristics. CONCLUSION: A proportion of ALS patients report utilizing CAM concurrently with conventional treatments. Such use, set amidst a dearth of evidence for the efficacy of CAM in ALS, poses potential direct and indirect risks to patient care, and medical providers should be mindful of and enquire about CAM use when treating ALS patients. PMID- 30248677 TI - Great Expectations: Principal Investigator and Trainee Perspectives on Hiring, Supervision, and Mentoring. AB - A functioning mentor-trainee relationship is of high importance in academia. Discrepancies in expectations between principal investigators (PIs) and trainees are a source of misunderstandings and conflicts, endangering scientific progress and career advancement. In this pilot study, we sought to explore the expectations of PIs and trainees, providing consensus data from physician scientists and junior researchers who attended an educational workshop, entitled "The EASL/AASLD Masterclass," in December 2017. Twenty-three Masterclass attendees, comprising nine trainees (four Ph.D. candidates, five postdoctoral researchers) and 14 PIs, responded to an online survey. Both parties were asked to score 29 predefined statements of important expectations, enabling a comparative analysis for each statement between the groups. For the trainees, the success of the PI, either mirrored by successful mentoring or scientific work, as well as a clear road for academic development are of utmost importance. PIs did not prioritize these aspects, highlighting discrepancies of expectations. PIs prioritized trainee competence, reliability, and strong daily initiative/work ethic, qualities that were also recognized to be important by the trainee group but not to same degree as PIs. Conclusion:Discrepancies in expectations pose a preventable threat to the mentor-trainee relationship if considered and discussed beforehand. The discrepancy in the most common expectations between the two groups could have resulted from the fact that trainees prioritize outcomes of success while PIs focus on the necessary qualities leading to those outcomes. PMID- 30248685 TI - [Update diagnostic algorithm for myopathies]. PMID- 30248686 TI - [Molecular therapies in muscular dystrophies]. AB - Muscular dystrophies (MD) are a clinically and genetically heterogeneous group of skeletal muscle-wasting diseases with progressive muscle weakness and atrophy, while disease severity depends on the subtype of the disease. Tremendous progress in basic research and an improved understanding of the pathophyisology of the disease have led to various molecular pipeline therapies for MD. Within the last years, promising new molecular therapies have been developed facilitating causative therapy in the near future. New developments of personalized gene therapy aim at genetically defined disease subgroups of MD, based on the underlying molecular mechanism and the resulting phenotype, and set an example for other hereditary diseases. We have learned tremendously within the last decade; however, there is still a long way to go until these therapeutic strategies will be able to finally cure MD, and not just modify the phenotype and pathology of DMD patients. PMID- 30248687 TI - [Spinal muscular atrophy - clinical spectrum and therapy]. AB - Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease with an incidence of 1:10,000 live births, caused by loss of the survival motor neuron 1 gene (SMN1), and represents the most frequent neurodegenerative disorder in children. With greater understanding of the molecular basis of SMA in the past two decades, a major focus of therapeutic developments has been on increasing the fulllength SMN protein by increasing the inclusion of exon 7 in SMN2 transcripts, enhancing SMN2 gene expression, stabilizing the SMN protein or replacing the SMN1 gene. Although the SMA research field is rapidly expanding with new therapeutic opportunities, there are still several issues that remain unsolved. The timing of an optimal intervention is not clear, in particular the point at which there is irreversible pathology precluding any meaningful therapeutic response. Early diagnosis will be crucial for therapeutic success; presumably, the clinical outcome will be much better if treatment already starts presymptomatically. Therefore, presymptomatic diagnosis of SMA via a nationwide genetic newborn screening will be key for an efficient therapy prior to motor neuron death. PMID- 30248688 TI - [Myasthenia gravis: current status of antibody diagnostics and aspects on refractory myasthenia gravis]. AB - Acquired myasthenia gravis (MG) is an autoimmune disease that leads to fluctuating muscle weakness and fatigue, caused by circulating antibodies against different structures of the neuromuscular junction. In most patients, antibodies against acetylcholine receptor (AChR) can be detected. In a smaller proportion of patients with and without AChR antibodies, antibodies to muscle-specific kinase (MuSK), or related proteins such as agrin, cortactin and low-density lipoprotein receptor-related protein 4 (LRP4), are present. With current therapy, most patients achieve a stable condition with good quality of life and normal life expectancy. Nevertheless, 10 to 15 % of patients fail to respond ad equately to current therapies and are defined as refractory myasthenia gravis. Their clinical course is characterized by recurrent episodes of severe, acute deterioration, which sometimes appear life threatening. This article gives an overview of the current state of myasthenic antibody diagnostics and recommended treatment of refractory myasthenia gravis. PMID- 30248689 TI - [Immune-mediated / inflammatory and hereditary neuropathies - overview and diagnostic algorithm]. AB - This paper is a practical survey of immune-mediated, inflammatory and hereditary neuropathies along with recommendations for diagnostic procedures. The large group of immune-mediated, inflammatory neuropathies includes the Guillain-Barre syndrome and chronic-inflammatory demyelinating polyradiculoneuropathy and their subtypes, vasculitic, paraneoplastic and paraproteinemic neuropathies as well as neuropathies resulting from connective tissue disorders. Besides clinical features such as time-dependent progression and distribution of sensorimotor deficits, characteristic electroneurographic findings and antibody profiles are considered. Recent studies in hereditary neuropathies reveal a prevalence of 10 28 out of 100 000 persons in Europe. Research into the genetic causes has made significant progress in the last 20 years; up to now more than 80 genes mutated in hereditary neuropathies have been identified. Besides classification into axonal, demyelinating or intermediate neuropathies based on electroneurography, distinguishing between sensorimotor, pure motor and (autonomous) sensory neuropathies as well as consideration of particular clinical features and ethnic origin can be helpful in orientating molecular genetic analysis. PMID- 30248690 TI - [Dystrophic and non-dystrophic myotonias]. AB - Myotonic syndromes are rare neuromuscular diseases characterized by the clinical or neurophysiological detection of myotonia. The genetic defects involve primarily or secondarily the muscular isoforms of the ion channels. The channel dysfunction consecutively leads to a hyper-excitability of the muscle membrane and the clinical symptom myotonia. Two forms of dystrophic myotonic diseases are currently known: the myotonic dystrophy type 1 (DM1) and the myotonic dystrophy type 2 (DM2). They are multisystemic diseases clinically characterized by a combination of myotonia and other muscular symptoms (muscle weakness, wasting and myalgia) together with the involvement of other organs and systems (cataract, diabetes, heart diseases, hormone dysfunctions). The non-dystrophic myotonic diseases are caused by mutations affecting either the chloride ion channels or the sodium ion channels. The clinical picture is dominated by the presence of myotonia and other minor muscular complaints as mild episodic weakness and muscle hypertrophy. The differential diagnosis among the myotonic syndromes is extremely challenging leading to a significant diagnostic delay. This review will update on the main clinical, diagnostic and therapeutic aspects of myotonic syndromes to guide general neurologists through an earlier diagnosis and better management. PMID- 30248692 TI - ? AB - One reason for the increasing use of new antidepressant drugs is due to a decreased toxicity compared to older agents. Nevertheless, there are still potentially dangerous side effects important to be considered. To improve treatment outcome it is therefore advantageous to obtain a detailed medical history, as well as to give specific information about the mechanisms of action of antidepressants before choosing the appropriate drug. Communicating known side effects to patients comprehensively can improve treatment and medication adherence. PMID- 30248691 TI - [Diagnostic and Therapeutic Approaches for Mitochondrial Diseases]. AB - Mitochondrial diseases (MD) represent a heterogenous group of disorders and syndromes caused either by mutations of the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). They belong to the most frequent neurogenetic diseases. The spectrum of clinical manifestations is very broad ranging from mild subclinical presentations to rapidly progressive debilitating conditions with reduced life expectancy. Mitochondrial dysfunction can affect any organ of the body; the clinical presentation is often most severe in tissues with high energy demands. The most common MD are Leber's Hereditary Optic Neuropathy (LHON), Chronic Progressive External Ophthalmoplegia (CPEO), Kearns-Sayre Syndrome (KSS), Mitochondrial Myopathy (MM) and Mitochondrial Encephalomyopathy, Lactic Acidosis and Strokelike episodes (MELAS). In the last couple of years, genetics have become more and more important for the diagnosis of MD. The majority of syndromes presents with a characteristic combination of clinical and laboratory findings which should guide the selection of tissues (blood cells, fibroblasts, urothelial cells or muscle) and methods for targeted genetic testing. Therapeutic approaches to MD include pharmacological stimulation of mitochondrial metabolism, supplementation, symptomatic treatment, assistive devices and physiotherapy. Moreover, strict anti-epileptic therapy and treatment or prevention of stroke like episodes are very important to prevent complications. In contrast, some medication should be avoided for its direct or indirect depressing effect on mitochondrial function. This article provides an introduction to mitochondrial diseases, an overview of the most common syndromes and an update on established and new therapeutic approaches. PMID- 30248696 TI - Updated S3 Guidelines - Diagnosis and Treatment of Colorectal Carcinoma: Relevance for Radiological Diagnosis and Intervention. AB - : The updated German S3 guidelines "Colorectal Carcinoma" were created as part of the oncology program of the Association of the Scientific Medical Societies (AWMF), German Cancer Society and the German Cancer Aid under the auspices of the German Society for Digestive and Metabolic Disorders (DGVS) and they replace the previous guidelines from 2013. The main changes in the updated guidelines include the latest recommendations regarding endoscopy and adjuvant/neoadjuvant therapies as well as a complete restructuring of the section regarding therapeutic approach in metastases and in the palliative situation. The present manuscript discusses the importance of the current recommendations for radiological diagnosis and treatment and is intended to enhance the quality of patient information and patient care by widespread distribution. KEY POINTS: . Radiological recommendations for treating patients with colorectal carcinoma are presented.. . The different possibilities of radiological imaging for diagnosis are documented in detail.. . Radiologists should be acquainted with the different possibilities of oncological intervention in patients with colorectal carcinoma.. CITATION FORMAT: . Vogl TJ, Pereira PL, Schreyer AG et al. Updated S3 Guidelines - Diagnosis and Treatment of Colorectal Carcinoma: Relevance for Radiological Diagnosis and Intervention. Fortschr Rontgenstr 2018; DOI: 10.1055/a-0721-1947. PMID- 30248701 TI - First Case of Laparoscopic Mini-Gastric Bypass for the Treatment of Morbid Obesity in Severe Haemophilia A. PMID- 30248704 TI - Serine Protease Mauritanicain from Euphorbia mauritanica and Phorbol-12-myristate 13-acetate Modulate the IL-8 Release in Fibroblasts and HaCaT Keratinocytes. AB - In recent years, skin reactions such as phytophotodermatitis, contact dermatitis, and other inflammatory responses after contact with chemicals from various plants, e.g., Heracleum mantegazzianum or Hippomane mancinella, are one of the hot topics in phytobiology. Occupational skin inflammation after contact with latices of plants from Euphorbiaceae are common among people who work with plants of this family. Activation of protein kinase C by G protein-coupled receptors such as protease-activated receptors is associated with skin inflammation. In this study, we focused on the inflammatory modulation potential of proteases combined with diterpenes on human skin. Because of its role as a proinflammatory cytokine, we concentrated on the release of IL-8 by fibroblasts and keratinocytes. Therefore, primary human dermal fibroblasts and the HaCaT keratinocytes cell line were used as a model. The results indicated that the combination of the protease mauritanicain from Euphorbia mauritanica and phorbol 12-myristate-13-acetate induced a significantly increased IL-8 release in HaCaT keratinocytes compared to single treatments. The obtained results also suggest that mauritanicain has an anti-inflammatory effect on primary human dermal fibroblasts. PMID- 30248705 TI - Isoflavones from Camphorosma lessingii Inhibit the Organic Anion Transporters OAT1 and OAT3. AB - Phytochemical investigation of Camphorosma lessingii has resulted in the isolation of four previously unreported isoflavones (1: -4: ) and eight known compounds (5: -12: ). Nine of these compounds (1: -6, 8: -10: ) are reported for the first time from members of the family Amaranthaceae. The structures of all isolated compounds were determined by spectroscopic methods, primarily one dimensional and two-dimensional nuclear magnetic resonance and mass spectrometry. The absolute configuration of 6: was confirmed by circular dichroism. Inhibition of the organic anion transporters, OAT1 and OAT3, by the isolated compounds was evaluated. Among them, 7, 2'-dihydroxy- 6,8-dimethoxyisoflavone (1: ), 2'-hydroxy 6,7,8-trimethoxyisoflavone (2: ), 6,2'-dihydroxy-7,8-dimethoxyisoflavone (3: ), and 7-methoxyflavone (5: ) showed a significant inhibitory effect on 6 carboxyfluorescein uptake mediated by OAT1 and OAT3. PMID- 30248706 TI - Development of an Open Metadata Schema for Clinical Pathway (openCP) in China. AB - BACKGROUND: By the end of the first quarter of 2017, 1212 standard Clinical Pathways (CPs) had been developed and implemented in China since 2009, however, Chinese standard CPs are still paper-based CPs. OBJECTIVES: To optimize the data structure and content of Chinese standard CPs based on Chinese health standards by two-level modeling approach and archetype method, and develop an Open Metadata Schema for Clinical Pathway (openCP) in China. METHODS: We chose 43 diseases covering 7 departments of internal medicine as samples and source materials including Respiratory, Gastroenterology, Neurology, Cardiology, Nephrology, Endocrinology, and Hematology, and we followed 4 steps to develop openCP: identify reference model of openCP; develop archetype models; standardize archetype terms and metadata; and evaluate its functionality. RESULTS: We have built hierarchical reference model and archetypes of openCP, created and standardized archetype terms and metadata, and evaluate the functionality of openCP. The qualitative comments from 5 doctors were inspiring. DISCUSSION AND CONCLUSIONS: Medical staff may easily build localized CPs in openCP which can be integrated into EHR systems and shared among different hospitals and clinics. PMID- 30248707 TI - Quality of the ICD-11 Beta Draft from the German Perspective: Evaluation Based on the Alphabet of ICD-10-GM 2017. AB - OBJECTIVES: The German Association for Medical Informatics, Biometry and Epidemiology implemented a field test for the ICD-11 Beta Draft. Aim was to analyze completeness and appropriateness of the ICD-11 Beta Draft in its entire breadth. METHODS: Starting point was the synonym thesaurus ("Alphabet") of the German modification of ICD-10. The Alphabet included a list of diagnoses terms that supports the coding of diagnoses with ICD-10. A sample of 60,328 diagnosis terms was drawn to be mapped to the ICD-11 Beta Draft. A subsample of 13,975 diagnosis terms was prepared for assessing reliability. First, the coders had to assign a diagnosis term from the sample to an appropriate English one. This included the automatic selection of the respective code from the ICD-11 Beta Draft. Secondly, the coders had to answer questions regarding completeness, appropriateness, and other issues. RESULTS: Finally, 49,184 results from 36 coders were available for the analysis. Problems with completeness were indicated in 4.7% of the results, problems with appropriateness in 5.3%. On the level of chapters, Cohen's kappa reached grade "fair" at a maximum. The coders agreed in 31.4% of the terms. CONCLUSIONS: Problems with the ICD-11 Beta Draft appeared to be moderate. Completeness was high, reliability was low as it is known for ICD 10. Concerns with the structure of the ICD-11 Beta Draft were noted, e. g. for neoplasms. A post processing of the ICD-11 Beta Draft seems to be sufficient with regard to the content. Methodologically, a thorough review of the structure might be advisable. PMID- 30248708 TI - Prediction of Sepsis and In-Hospital Mortality Using Electronic Health Records. AB - OBJECTIVES: Our goal was to develop predictive models for sepsis and in-hospital mortality using electronic health records (EHRs). We showcased the efficiency of these algorithms in patients diagnosed with pneumonia, a group that is highly susceptible to sepsis. METHODS: We retrospectively analyzed the Health Facts(r) (HF) dataset to develop models to predict mortality and sepsis using the data from the first few hours after admission. In addition, we developed models to predict sepsis using the data collected in the last few hours leading to sepsis onset. We used the random forest classifier to develop the models. RESULTS: The data collected in the EHR system is generally sporadic, making feature extraction and selection difficult, affecting the accuracies of the models. Despite this fact, the developed models can predict sepsis and in-hospital mortality with accuracies of up to 65.26+/-0.33% and 68.64+/-0.48%, and sensitivities of up to 67.24+/-0.36% and 74.00+/-1.22%, respectively, using only the data from the first 12 hours after admission. The accuracies generally remain consistent for similar models developed using the data from the first 24 and 48 hours after admission. Lastly, the developed models can accurately predict sepsis patients (with up to 98.63+/-0.17% accuracy and 99.74%+/-0.13% sensitivity) using the data collected within the last 12 hours before sepsis onset. The results suggest that if such algorithms continuously monitor patients, they can identify sepsis patients in a manner comparable to current screening tools, such as the rulebased Systemic Inflammatory Response Syndrome (SIRS) criteria, while often allowing for early detection of sepsis shortly after admission. CONCLUSIONS: The developed models showed promise in early prediction of sepsis, providing an opportunity for directing early intervention efforts to prevent/treat sepsis. PMID- 30248710 TI - Considering Relationship of Proteins for Radiotherapy Prognosis of Bladder Cancer Cells in Small Data Set. AB - BACKGROUND: Radiotherapy has serious side effects and thus requires prudent and cautious evaluation. However, obtaining protein expression profiles is expensive and timeconsuming, making it necessary to develop a theoretical and rational procedure for predicting the radiotherapy outcome for bladder cancer when working with limited data. OBJECTIVE: A procedure for estimating the performance of radiotherapy is proposed in this research. The population domain (range of the population) of proteins and the relationships among proteins are considered to increase prediction accuracy. METHODS: This research uses modified extreme value theory (MEVT), which is used to estimate the population domain of proteins, and correlation coefficients and prediction intervals to overcome the lack of knowledge regarding relationships among proteins. RESULTS: When the size of the training data set was 5 samples, the mean absolute percentage error rate (MAPE) was 31.6200%; MAPE fell to 13.5505% when the number of samples was increased to 30. The standard deviation (SD) of forecasting error fell from 3.0609% for 5 samples to 1.2415% for 30 samples. These results show that the proposed procedure yields accurate and stable results, and is suitable for use with small data sets. CONCLUSIONS: The results show that considering the relationships among proteins is necessary when predicting the outcome of radiotherapy. PMID- 30248709 TI - Learning to Detect Cognitive Impairment through Digital Games and Machine Learning Techniques. AB - OBJECTIVE: Alzheimer's disease (AD) is one of the most prevalent diseases among the adult population. The early detection of Mild Cognitive Impairment (MCI), which may trigger AD, is essential to slow down the cognitive decline process. METHODS: This paper presents a suit of serious games that aims at detecting AD and MCI overcoming the limitations of traditional tests, as they are time consuming, affected by confounding factors that distort the result and usually administered when symptoms are evident and it is too late for preventive measures. The battery, named Panoramix, assesses the main early cognitive markers (i.e., memory, executive functions, attention and gnosias). Regarding its validation, it has been tested with a cohort study of 16 seniors, including AD, MCI and healthy individuals. RESULTS: This first pilot study offered initial evidence about psychometric validity, and more specifically about construct, criterion and external validity. After an analysis using machine learning techniques, findings show a promising 100% rate of success in classification abilities using a subset of three games in the battery. Thus, results are encouraging as all healthy subjects were correctly discriminated from those already suffering AD or MCI. CONCLUSIONS: The solid potential of digital serious games and machine learning for the early detection of dementia processes is demonstrated. Such a promising performance encourages further research to eventually introduce this technique for the clinical diagnosis of cognitive impairment. PMID- 30248715 TI - Page for the General Public. PMID- 30248716 TI - E-cigarette product preferences among Australian young adult e-cigarette users. AB - OBJECTIVE: To assess preferences for e-cigarettes containing nicotine and flavourings among Australian young adult e-cigarette users. METHODS: An online survey was administered to 1,116 young adults (18-25 years), 104 of whom had used an e-cigarette in the last 30 days and were the focus of this study. Among users, 53% also smoked tobacco cigarettes, 27% were non-smokers and 20% had never smoked. RESULTS: Nearly two-thirds (64%) of e-cigarette users preferred nicotine containing e-cigarettes (71% of smokers, 56% of non-smokers, 55% of never smokers). The vast majority (89%) preferred flavoured e-cigarettes (92% of smokers, 82% of non-smokers, 95% of never smokers), with fruit flavours the most popular. CONCLUSIONS: E-cigarettes containing nicotine and flavourings were popular among users of these devices in this sample of young adults. Implications for public health: Previous research has documented potential harms associated with e-liquid additives, flavourings, and nicotine. The present results showing strong preferences for nicotine and flavourings among the sampled e-cigarette users suggest that: i) flavourings in e-liquids should be regulated; and ii) existing prohibitions on the unauthorised supply of liquid nicotine should be better enforced. Population-wide monitoring of the use of e-cigarettes with different product characteristics is also warranted. PMID- 30248717 TI - Analysis of the dissipation kinetics of thiophanate-methyl and its metabolite carbendazim in apple leaves using a modified QuEChERS-UPLC-MS/MS method. AB - As one of the main fungicides for the apple leaf disease control, thiophanate methyl (TM) mainly exerts its fungicidal activity in the form of its metabolite carbendazim (MBC), whose dissipation kinetics is very distinct from that of its parent but has been paid little attention. The aim of this work was to investigate the dissipation kinetics of TM and its active metabolite MBC in apple leaves using a modified QuEChERS-UPLC-MS/MS method. The results showed that TM and MBC could be quickly extracted by this modified QuEChERS procedure with recoveries of 81.7-96.5%. The method linearity was in the range of 0.01-50.0 mg kg-1 with the quantification limit of 0.01 mg kg-1 . Then this method was applied to the analysis of fungicide dissipation kinetics in apple leaves. The results showed that the dissipation kinetics of TM for the test in 3 months can be described by a first-order kinetics model with a DT50 (dissipation half-life) range of 5.23-6.03 days and the kinetics for MBC can be described by a first order absorption-dissipation model with the Tmax (time needed to reach peak concentration) range of 4.78-7.09 days. These models can scientifically describe the behavior of TM and MBC in apple leaves, which provides necessary data for scientific application. PMID- 30248719 TI - Optimization and validation of an SBSE-HPLC-FD method using laboratory-made stir bars for fluoxetine determination in human plasma. AB - Depression is the largest cause of disability worldwide, affecting 350 million people. Notwithstanding that clinical trials demonstrate antidepressants efficacy, the efficient response can vary individually concerning therapeutic dosage. Although important, plasma levels monitoring remains an analytical challenge whereas clean-up and pre-concentration represent critical steps. Therefore, this study aims to develop, optimize and validate a method for fluoxetine determination in human plasma, employing a laboratory-made device consisting of a PDMS stir bar sorptive for extraction, coupled with high performance liquid chromatography-fluorescence detection (SBSE-HPLC-FD). Optimization involved sorption-desorption steps. For sorption, temperature and time were assessed by factorial and central composite design approaches, taking into account the desirability and the response surface results, with stirring speed also examined. For desorption kinetics and ultrasonic and magnetic stirring mode were evaluated. The proposed method after validation was robust, linear (25.00-1000.00 ng mL-1 , R2 > 0.98) and presented good intra- (RSD 4.18%) and inter-day-assay (RSD 11.60%) precision and accuracy (recovery 109.60%), allowing reliable quantitation without interference. The method was successfully applied to real samples. SBSE-HPLC-FD could represent a feasible alternative with good cost-benefit for low-volume samples and therapeutic drug monitoring, as well as contributing to correlation studies between plasma fluoxetine levels and clinical response, which is still little studied. PMID- 30248718 TI - The social location of harm from others' drinking in 10 societies. AB - AIMS: Survey data from 10 diverse countries were used to analyse the social location of harms from others' drinking: which segments of the population are more likely to be adversely affected by such harm, and how does this differ between societies? METHODS: General-population surveys in Australia, Chile, India, Laos, New Zealand, Nigeria, Sri Lanka, Thailand, United States and Vietnam, with a primary focus on the social location of the harmed person by gender, age groups, rural/urban residence and drinking status. Harms from known drinkers were analysed separately from harms from strangers. RESULTS: In all sites, risky or moderate drinkers were more likely than abstainers to report harm from the drinking of known drinkers, with risky drinkers the most likely to report harm. This was also generally true for harm from strangers' drinking, although the patterns were more mixed in Vietnam and Thailand. Harm from strangers' drinking was more often reported by males, while gender disparity in harm from known drinkers varied between sites. Younger adults were more likely to experience harm both from known drinkers and from strangers in some, but not all, societies. Only a few sites showed significant urban/rural differences, with disparities varying in direction. In multivariate analyses, most relationships remained, although some were no longer significant. CONCLUSION: The social location of harms from others' drinking, whether known or a stranger, varies considerably between societies. One near-commonality among the societies is that those who are themselves risky drinkers are more likely to suffer harm from others' drinking. PMID- 30248720 TI - Higher-energy Collision Dissociation for the quantification by liquid chromatography-tandem ion trap mass spectrometry of nitric oxide metabolites coming from S-nitrosoglutathione in an in vitro model of intestinal barrier. AB - RATIONALE: The potency of S-nitrosoglutathione (GSNO) as a nitric oxide (NO) donor to treat cardiovascular diseases (CVDs) has been highlighted in numerous studies. In order to study its bioavailability after oral administration, which represents the most convenient route for the chronic treatment of CVDs, it is essential to develop an analytical method permitting (i) the simultaneous measurement of GSNO metabolites, i.e. nitrite, S-nitrosothiols (RSNOs) and nitrate and (ii) them to be distinguished from other sources (endogenous synthesis and diet). METHODS: Exogenous GSNO was labeled with 15 N, and the GS15 NO metabolites after conversion to nitrite ion were derivatized with 2,3 diaminonaphthalene. The resulting 2,3-naphthotriazole was quantified by liquid chromatography-tandem ion trap mass spectrometry (LC/ITMS/MS) in multiple reaction monitoring mode after Higher-energy Collision Dissociation (HCD). Finally, the validated method was applied to an in vitro model of intestinal barrier (monolayer of Caco-2 cells) to study GS15 NO intestinal permeability. RESULTS: A LC/ITMS/MS method based on an original transition (m/z 171 to 156) for sodium 15 N-nitrite, GS15 NO and sodium 15 N-nitrate measurements was validated, with recovery of 100.8 +/- 3.8, 98.0 +/- 2.7 and 104.1 +/- 3.3 %, respectively. Intra- and inter-day variabilities were below 13.4 and 12.6 %, and the limit of quantification reached 5 nM (signal over blank = 4). The permeability of labeled GS15 NO (10-100 MUM) was evaluated by calculating its apparent permeability coefficient (Papp ). CONCLUSIONS: A quantitative LC-ITMS/MS method using HCD was developed for the first time to selectively monitor GS15 NO metabolites. The assay allowed evaluating GS15 NO intestinal permeability and situated this drug candidate within the middle permeability class according to FDA guidelines. In addition, the present method has opened the perspective of a more fundamental work aiming at studying the fragmentation mechanism leading to the ion at m/z 156 in HCD tandem mass spectrometry in the presence of acetonitrile. PMID- 30248721 TI - An overview of lymphatic filariasis lymphedema. AB - Filariasis is caused by thread-like nematode worms and is classified according to their presence in the vertebrate host. The lymphatic group includes Wuchereria bancrofti, Brugia malayi, and Brugia timori. Lymphatic filariasis, a mosquito borne disease, has been one of the most prevalent diseases in tropical and subtropical countries and is accompanied by a number of pathological conditions. It is estimated that currently (after 13 years of the MDA programme) there are an estimated 67.88 million LF cases that include 36.45 million microfilaria carriers, 19.43 million hydrocele cases, and 16.68 million lymphedema cases. Adult filarial worms reside in the lymphatics and lymph nodes and induce changes that result in dilatation of lymphatics and thickening of the lymphatic vessel walls. Progressive lymphatic damage and pathology results from the summation of the effect of tissue alterations induced by both living and nonliving adult parasites. In recent years, there has been rapid progress in filariasis research, which has provided new insights into the pathogenesis of filarial disease, diagnosis, chemotherapy, the host-parasite relationship, and the genomics of the parasite. We examined the clinical manifestations of the disease, diagnosis, treatment, immune responses, and management including review of pharmaceutical agents against filariasis. Details on infection, safety profile, and status in clinical practices are also reported. PMID- 30248722 TI - Successful factor XIII treatment of refractory chylothorax in tuberous sclerosis complex-associated lymphangioleiomyomatosis, multifocal multinodular pneumocyte hyperplasia and mediastinal lymphadenopathy. AB - Tuberous sclerosis complex (TSC) or Bourneville disease is a rare autosomal dominant neurocutaneous disorder that affects various organs. Pulmonary involvement in TSC may consist of lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH), occurring together or alone. In patients with TSC-LAM, chylous pleural effusion (CPE) is a rare, though well recognized, complication with an unpredictable clinical course. In refractory or persistent CPE, optimal management remains a clinical challenge. We report the unique case of a 29-year-old Caucasian female, neversmoker, with definite TSC since infancy, characterized by seizures, facial angiofibromas ("adenoma sebaceum"), bilateral renal angiomyolipomas, hepatic angiomyolipomas, subcortical/cortical tubers, and subependymal nodules. At 27 years old, due to bleeding from the renal angiomyolipomas, she underwent nephrectomy, first of the right, and then a year and 9 months later, of the left kidney. She was hemodialysis dependent for the next five years until cadaveric kidney transplantation. The medical history was also remarkable for recurrent exudative lymphocytic PE despite repeated therapeutic thoracenteses, with first presentation at 23.5 years of age. Chylothorax was initially diagnosed at 24 years and 8 months old (PE triglycerides 4.53 mmol/L), and reconfirmed at age 29 (PE triglycerides 12.46-15.30 mmol/L). Computerized tomography scan of the thorax showed a large encapsulated PE in the left lung field, multiple thin walled cysts (<= 5 mm in diameter) in the lung parenchyma bilaterally, and mediastinal lymphadenopathy - all prominent features of LAM - as well as nodular pulmonary lesions (<= 3 mm in diameter) consistent with MMPH. Given the persistent nature of the CPE, a five-day course of recombinant human factor XIII (FXIII) was administered intravenously. The chylothorax completely resolved within three months. There has been no recurrence of CPE on follow-up chest X-rays (i.e., total follow-up period of 53 months). This report suggests that the transglutaminase FXIII, a blood coagulation factor, may have an important clinical benefit in treating recurrent or thoracentesis-refractory CPE in TSC LAM. To our knowledge, this is the first known case in the literature describing the successful treatment of CPE with FXIII in TSC-LAM. Because CPE is rare and there is currently no gold standard for its management, regardless of etiology, further research is warranted to investigate the potential clinical use of FXIII as an effective and safe treatment strategy in selected patients. PMID- 30248723 TI - Congenital pulmonary lymphangiectasia and chylothorax - a case series. AB - Congenital pulmonary lymphangiectasia (CPL) and chylothorax (CC) are rare lymphatic developmental disorders. We report six clinical cases of CPL and CC that were admitted to our level III neonatal intensive care unit over the last 20 years. One case of unilateral CC was successfully treated with pleuro-amniotic shunt; three cases of bilateral CC were associated to lung hypoplasia, hydrops fetalis, and generalized lymphangiectasias; one case of CPL was associated with obstructive congenital heart defect; one case of unilateral CC was successfully treated with thoracocentesis and medium-chain triglyceride diet. Mortality was high (66.6%). PMID- 30248724 TI - Lower limb dominance and volume in healthy individuals. AB - Upper limb dominance is associated with increased limb volume, however there is a paucity of evidence if this is true for the lower limbs. This study investigated if there is a normative volume difference between the dominant and nondominant leg. Healthy volunteers between the ages of 18-40 years were recruited. Exclusion criteria included previous lower limb surgery, BMI >30, or pregnancy. An experienced lymphedema nurse specialist measured the circumference of each limb at 4 cm intervals from the malleolus to the groin. Measurements were used to calculate volume of each limb in milliliters. 100 (52 male, 48 female) participants met our inclusion criteria. 86% were right leg dominant and 14% left leg dominant. 93% demonstrated an average increased volume of 349 ml (4.5%) in the dominant leg which is statistically significant (p<0.001). Age, sports, and gender did not affect lower limb volumes. This is the first study to show a normative variance in leg volume in healthy individuals, with a greater volume in the dominant leg. This should be taken into consideration when managing and measuring outcomes for patients with conditions resulting in enlarged lower limbs. PMID- 30248725 TI - Measurement of capillary fragility: a useful tool to differentiate lipedema from obesity? AB - Lipedema is a disproportional obesity featuring spontaneous or light pressure induce pain and frequent hematoma formation due to even minor traumatic injuries. It is generally distinguished from general obesity primarily based on clinical hallmarks; however, this becomes difficult when appearing in a concomitant form (combination of obesity and lipedema). Our study group has recently demonstrated that lipedema-associated bruising is correlated with increased capillary fragility (CF) and also that CF could be significantly improved by complex decongestive physiotherapy (CDP). In this study, we measured CF in female subjects with lipedema (15) or non-complicated obesity (15) who were body mass index (BMI) and waist-to-hip ratio (WHR) matched. CF was evaluated with the vacuum suction method (VSM) using Parrot's angiosterrometer in both groups. Application of VSM resulted in a significantly higher number of petechiae in subjects with lipedema. Capillary fragility measurement appears to be a useful differential diagnostic tool between lipedema and obesity under these trial parameters. PMID- 30248726 TI - Physiotherapeutic rehabilitation of lymphedema: state-of-the-art. AB - Lymphatic diseases, especially lymphedema, represent a serious problem in the health community. We investigated strategies and methods for physiotherapeutic rehabilitation of lymphedema by carrying out a comprehensive search of the Medline and Embase databases from 1990 to 2016 to identify relevant published studies, articles, and reviews. Approaches for conservative management of lymphedema include the following: manual lymphatic drainage, lymphedema rehabilitation exercises, compression therapy, skin care, pneumatic compression, elevation of the extremities, thermal therapy, complete decongestive physiotherapy (CDT), taping, and aqua lymphatic therapy. Treatment of lymphedema with CDT, which is a combination of four methods (manual lymphatic drainage, lymphedema rehabilitation exercises, compression therapy, skin care), can achieve a 45-70% reduction in lymphedema volume. Prerequisites for successful physiotherapy are the availability of physicians, nurses and therapists who are specifically trained, educated, and experienced in each method. CDT is the most effective treatment as it reduces the symptoms of lymphedema and improves patients' functionality, mobility, and quality of life. Although other therapeutic techniques have demonstrated positive results, these surveys are limited and more studies are needed to confirm findings. PMID- 30248727 TI - Are pre-operative lymphoscintigrams needed for localization prior to sentinel node biopsy?: An audit to ensure safe practice and to provide another view. AB - Traditionally lymphoscintigrams are taken after injection of peri-areolar Technetium-99m (Tc-99m) to quantify sentinel nodes before biopsy (SNB). However, recent research suggests that scintigraphy is not an essential adjunct. For service improvement, we stopped using lymphoscintigraphy so as to minimize delay to operating theater and reduce demand on the Nuclear Medicine Department. We audited early outcomes to ensure quality was maintained. 100 consecutive patients undergoing SNB with lymphoscintigrams were investigated. Lymphoscintigrams were reported by Consultant Radiologists. Reported node count (RNC) was compared to biopsied node count (BNC) using Cohen's kappa statistic. Lymphoscintigrams were then discontinued, and the results on the next 69 consecutive patients undergoing SNB were analyzed. The BNC was then compared to BNC in patients having lymphoscintigrams. Of the first 100 patients, RNC ranged from 0-5 (mean=1.84, mode=1) and BNC from 1-4 (mean=1.89, mode=1). 90% of lymphoscintigrams were performed on the day of surgery. Cohen's Kappa statistic was 0.34 (95%CI =0.195 to 0.482, i.e., Fair agreement). RNC was zero in two cases, but SNB was successful. Of 69 patients in the second group with no scan, BNC ranged from 0-4 (mean=1.80, mode=2). There were two cases of failed localization and no significant difference between BNC with or without scans (p=0.16). Sentinel node positivity rate was 36% for those with scans and 25.3% for those without scans, which was not significant (chi-squared, p=0.11). These results correlate to previously published studies. Correlation between RNC and BNC was only in fair agreement, and negative lymphoscintigrams did not result in failed SNB localization. Our study suggests that BNC without scans is safe and effective. Removing the lymphoscintigram will result in measurable cost savings, saving of clinical time (no delay to operating room while waiting for scan or multiple journeys to hospital), freeing the scanner for other scans, and allowing additional time for radiology physicians and staff. PMID- 30248728 TI - Primary versus trauma-induced Gorham-Stout disease. AB - Gorham-Stout disease - also known as "disappearing bone disease" is currently considered a single entity with varying clinical manifestations. We reviewed the existent literature from the earliest historic description(Jackson in 1838) and Gorham and Stout's original series of patients, multiple case reports and series since. After analyzing 212 reported cases, we identified 76 cases with details that recorded either a history of multifocal disease or an identifiable history of preceding trauma. From this review, we have defined two distinct Gorham-Stout entities - those characteristically associated with lymphangiomatosis [a form of GLA (generalized lymphangiomatosis) questionably distinguishable by bone biopsy and radiologic appearance] with multifocal distributed bone lesions, and those others, usually self-limited, first appearing after a traumatic event and always confined to a single bone or closely adjacent one. Multifocal disease is more likely to have chylothorax as a complication. These two Gorham-Stout entities differ in their demographic distribution, clinical history and manifestations, and they follow divergent clinical courses. The prognosis differs, and so should approaches to monitoring as well as acute and long-term treatment. Further research should seek to identify and define the differences in pathology and molecular mechanisms. PMID- 30248729 TI - The effect of different compression pressure in therapy of secondary upper extremity lymphedema in women after breast cancer surgery. AB - This study evaluated how different levels of pressure under inelastic multi-layer bandages affect the reduction of secondary arm lymphedema and patient comfort throughout therapy. Ninety-six women with lymphedema after breast cancer treatment were randomized into three groups of 32 patients depending on level of applied pressure in compression therapy: group I (control) at 21-30 mmHg; study groups II A at 31-40 mmHg and group II B at 41-60 mmHg. All patients were treated with complex decongestive therapy (CDT) and intermittent pneumatic compression (IPC) before compression. Fixed points of bilateral arms were measured at the start (first visit), after 24 h, 7 days, and 14 days of therapy. Edema severity was measured by summary calculation. Results were presented as a relative metric coefficient of arm lymphedema (RMCAL) which is the difference between sums of circumferences of the edematous arm and the contralateral side expressed in percents. In order to evaluate the patient comfort after finishing a two-week therapy all patients assessed the level of accompanying pain using the numeric pain rating scale (NRS). At the start of therapy median arm circumference difference (RMCAL) was 18.60%, 18.51%, and 19.05% in groups I-II B, respectively. After 24 h the median RMCAL was reduced to 14.49%, 12.13%, and 12.64%. This was further reduced to 10.77%, 6.98%, and 8.48% at one week and 10.28%, 5.75%, and 7.20% in each group, respectively. There was no statistically significant difference between RMCAL values in group II A and II B throughout the therapy. In group II A (NRS = 2), applied bandages were better tolerated than in both II B (NRS = 5) and control groups (NRS = 8). These results demonstrate that inelastic multi-layer bandages applied in groups II A and II B (41-60 mmHg) led to the same reduction of swollen arm circumference with group II being better tolerated. The lowest compression (control at 21-30 mmHg) produced the smallest reduction. In addition, since the greatest reduction was seen in the first week of therapy while the second week served to maintain the reduction, compression garments may be able to be ordered after one week of therapy for more efficient patient care. PMID- 30248730 TI - Surgical treatment of scrotal lymphedema: modified surgical technique. AB - Lymphedema is a chronic disease in which lymph accumulates under the subcutaneous tissue. The condition may be due to either congenital or acquired lymphatic system abnormalities. Genital lymphedema (scrotal lymphedema) has a high psychological and functional impact, and many surgical techniques have been tried in an attempt to improve function and cosmetic appearance. The aim of this study is to present our experience in treatment of a series of patients with scrotal lymphedema. Twenty patients suffering from moderate to severe scrotal lymphedema underwent treatment by using three flaps technique (2 inguinoscrotal flap and one perineoscrotal flap). The technique showed improvement in cosmetic, sexual, and voiding function with low incidence of recurrence up to 23 months of followup. PMID- 30248731 TI - [Effects of Blood-brain Barrier and Simulated metabolic system on Apoptosis of SH SY5Y Induced by Acrylamide in Vitro]. AB - Objective: To evaluate the effect of acrylamide on the apoptosis of nerve cells by integral cell modelling in vitro which simulates the barrier effect and metabolic micro-environment. Methods: A non-contact and co-cultured in vitro blood brain barrier (BBB) model was established by using human umbilical vein endothelial cells (HUVEC) and rat glioma cells (C6) . The trans-endotheilal electrical resistance (TEER) and horseradish peroxidase (HRP) tracer effects were measured to verify the tight connectivity and permeability of the established BBB model. An integrate discrete multiple organ cell co-culture (idMOC) model was established by inoculating the human renal cortical proximal tubular epithelial cells (HK-2) , human normal hepatocytes (L-02) and human neuroblastoma cells (SH SY5Y) into the self-made multi-organ plate for co-culturing. Then the model was verified by observing the growth curve of various tissue cells under co-culturing or culturing individually. SH-SY5Y cells were exposed to different concentrations of acrylamide directly and indirectly (through BBB model and idMOC model) . The changes of cell apoptosis rate were analyzed by flow cytometry to explore the impact of model on Acrylamide (ACR) injury of typical neurotoxic agents. Results: HUVEC cells can form a wide range of close-connected complex and then inhibit the external electric field under the cross-endothelial movement, and the mean was lower than that of endothelial cell culture group at 4, 5 and 6 days (P<0.05) ; After 20 min, the penetration rate of HRP in the co-culture group was less than that in the individual culture group, and the difference was statistically significant (P<0.05) , indicating that the barrier function of the co-culture group was higher than that of the individual culture group. All cells can exchange substances through the exchange hole of the culture plate, the cells grow well and there was no obvious death. The growth curve in individual culture group and co-culture group were basically the same, the difference was not statistically significant (P>0.05) . Under the condition of different concentrations of ACR (140, 270 g/ml) , compared with the direct exposure group, the apoptosis rate of the BBB model and the idMOC model were significantly decreased, and the difference was statistically significant (P<0.05) . Conclusion: Based on HUVEC cells and C6 cells co-culture system, a blood-brain barrier model in vitro was established and based on co-culture of HK-2, L-02 and SH-SY5Y, the idMOC model was established. The toxicity and toxic action characteristics of ACR on SH-SY5Y cells were evaluated by validation tests. PMID- 30248732 TI - [Study on the Specific Complexation of GMDTC and Metal Ion]. AB - Objective: Study the response of GMDTC to cadmium ions and metal ions in vivo to determine whether GMDTC are specifically complexed with cadmium ions to provide a reference for the safety and dfficacy of GMDTC. Methods: Complexometric titration, HPLC and HPLC-MS were applied to research the complexation reaction of GMDTC and various metal ions. The molecular ion peak of GMDTC, GMDTC-Cd complex and GMDTC-Pb complex also detected by LC-MS. Additionally, the initial structure was determined by DFT simulation method. Results: Results of complexometric titration and HPLC detection showed that GMDTC characteristic absorption peak area was proportional to the concentration of itself and there was no color change and peak time change when the GMDTC mixed with Ca(2+), Fe(2+), Mg(2+), Zn(2+). However, the color changed to black transition when the GMDTC mixed with Cu(2+) and the color changed from yellow precipitate to light yellow transparent transition when GMDTC mix with Hg(2+). Moreover, the peak area as well as the retention time has changed a lot which indicated that a chemical reaction has already happened. When the GMDTC mixed with Cd(2+) and Pb(2+), the color has changed from pale yellow to colorless transparent and the peak area of GMDTC has increased a lot. Finally, the GMDTC-Cd complex ratio both of which are 2:1 were calculated based on the results of LC-MS instrument and atomic calculations. Conclusion: The specific cadmium chelating agent GMDTC can not react with the Ca(2+), Fe(2+), Mg(2+), Zn(2+), but it can react chemically with Cu(2+) and Hg(2+), even specific complex with Pb(2+) and Cd(2+). PMID- 30248733 TI - [Comparison of knowledge and behavior toward hearing protection among workers in different workplaces and its influence factors]. AB - Objective: To compare the knowledge and behavior toward hearing protection among workers in different workplaces and investigate its influence factors. Methods: 2 manufacturing companies with obvious noise hazard in workplace were selected into the study. Health management level was distinguished through field investigation and verification. Questionnaire focus on basic knowledge of hearing health, acceptance level of noise hazard, comfort of wearing hearing protectors and atmosphere in workplace was designed and was used to investigate the knowledge and behavior toward hearing protection. Results: Hearing protectors that meet the level of protection are distributed throughout the workplaces. Although company A has a lower noise hazards level, the health management system was poorly executed. The proportion of workers persisting in wearing hearing protectors throughout the work shift in company A was lower than B (P<0.01) . Workers in company A intended to underestimate the noise level (P<0.01) and the health effect of hearing loss (P<0.01) . All the workers were worry about suffering from hearing loss (P>0.05) , but those in company B had more positive attitude toward the protection of hearing protector (P<0.01) and relied on the protector (P<0.01) . The awareness of protection, in turn, help workers adapt attitude and get used to wearing hearing protectors consciously in workplace (P<0.01) . Conclusion: Health management performance play a key role in help workers form good knowledge and behavior. To protect workplace health, employers need to creative a healthy supportive environment for workers. PMID- 30248734 TI - [Effects of Workload on Reproductive Health Status of Female Workers in Mechanical Manufacturing Industry]. AB - Objective: To investigate the reproductive health status of female workers in the machinery industry and to analysis the effect of workload on their reproductive health. Methods: 5 732 female mechanical workers were selected and investigated by the Female Workers' Reproductive Health Questionnaire, which was printed by the occupational health and poisoning control institute of China CDC to collect the information about the reproductive health status of from March to December in 2016. Results: The rate of abnormal menstruation was 27.15%, and the rate of gynecological diseases of female workers was 34.39%. The menstruation abnormality and gynecological diseases rate of female workers with high workload was higher than that female workers with low workload (both P<0.01) . High workload was the independent the risk factor associated with the menstruation abnormality (OR=1.88, 95%CI: 1.54~2.31, P<0.01) and gynecological diseases (OR=1.97, 95% CI: 1.61~2.40, P<0.01) . Conclusion: The workload has a large impact on the reproductive health status of female workers. PMID- 30248735 TI - [Current status of reproductive health and its occupational influencing factors among female medical staff in a provincial maternal and child health hospital]. AB - Objective: To investigate the current status of reproductive health among the female medical staff in a provincial maternal and child health hospital and analyze the occupational influencing factors for reproductive health, particularly the effects of high-intensity work, work shift, chemical poisons, and physical and biological factors on reproductive health, and to provide a scientific basis for developing related intervention measures and promoting the reproductive health of professional females. Methods: A reproductive health questionnaire was designed in terms of age, type of work, professional title, education level, working hours, working strength, and the reproductive health of female staff to analyze the current status of reproductive health, working strength, and occupational hazardous factors. The female medical staff in the provincial maternal and child health hospital completed the questionnaire on the internal network of the hospital voluntarily. Results: Of all respondents, 19.46% had a history of miscarriage, 5.90% visited the hospital due to infertility, 21.31% had irregular menstruation within the last 3 months, and 30.57% had reproductive system disease; 72.28% of the investigated medical staff often worked at night, 47.25% often worked overtime (more than 3 days a week) , and 22.27% worked over 8 hours daily. The respondents who often worked overtime had a significantly higher prevalence of reproductive system disease than those who did not often work overtime (chi(2)= 58.65, P<0.01) . The respondents who often worked at night had a significantly higher rate of miscarriage than those who did not work at night (chi(2)=41.57, P<0.01) . In all respondents, 87.08% were often exposed to chemical injuries such as disinfectants, and 78.15% had contact with noise, radiation, and other physical injuries; the medical staff exposed to chemical and physical injuries had a significantly higher proportion of individuals with a history of miscarriage than the unexposed staff (chi(2)=10.04, P<0.01; chi(2)=13.30, P<0.01) . Conclusion: Much attention should be paid to the reproductive health of female medical staff in the provincial maternal and child health hospital, who have high working strength. The occupational hazard factors can be avoided by reasonably arranging the work schedule and creating a supportive environment to improve the reproductive health of female medical staff. PMID- 30248737 TI - [The prevalence and influencing factors of work-related musculoskeletal disorders of oilfield workover workers]. AB - Objective: To investigate work-related musculoskeletal disorders (WMSDs) of workover workers in an oilfield and explore the influencing factors. Methods: In June 2016, 685 workover workers were selected as working group, and 191 other workers exposed to toxic and harmful operations were selected as control group. Cross sectional investigation was conducted by self-made questionnaire, and the influencing factors of musculoskeletal disorders were analyzed by unconditional multivariate Logistic regression. Results: The total annual prevalence of WMSDs for workover workers was 90.5%, with the highest prevalence of low back pain of 71.5%. The prevalence of WMSDs increased with the increase of service age, and the difference between the drinkers was higher than that of the non drinkers (P<0.05) . Multivariate Logistic regression analysis showed that working age, drinking and the posture of lifting heavy objects were risk factors for WMSDs in workover workers. Conclusion: The WMSDs appears to be a serious problem in oilfield workover workers. Corresponding measures should be taken to prevent the risk factors and control the occurrence of diseases effectively. PMID- 30248736 TI - [Comparison of Occupational Stress and Its Factors of Workers in An Oil Refinery]. AB - Objective: To explore the differences of occupational stress and its factors between petroleum refining workers and support staffs, and to propose more targeted measures to promote the health of petroleum refining and petrochemical workers. Methods: A questionnaire survey was conducted among 353 petroleum refining workers and 189 employees in the logistics department using the occupational stress inventory revised edition (OSI-R) scale between June 13, 2017 and July 27, 2017. Results: Among the occupational factors, there were significant differences in the job requirements, work risk, job monotony, participation in the decision-making scores among the male workers between labor group and logistics group (P<0.01) . And for female workers in the chemical group and logistics group there were also differences in the value of work control, job requirements, work monotonous, work prospects, improvement of opportunity (P<0.05) . In the aspect of personality traits, the score of work psychological control in chemical group was higher than that of the logistics group, while the organization loyalty score was lower than that of the logistics group. Be-sides, there were significant differences between chemical group and logistics group in the score of A behavior, self-esteem and anxiety traits among female group (P<0.05) . In terms of mitigating factors, there was a significant difference in social support score between chemical group and logistics group among female workers (P<0.01) . Comparison of the two groups of psychological stress showed that the mental health and anxiety status of the chemical group and the logistics group showed a difference (P<0.05) , and female workers in the chemical group job satisfaction score lower than the logistics group, but the body Complaints score higher than the logistics group. Conclusion: The psychological stress response of petroleum refining workers is obviously more serious than the staff of logistics department, and there were significant differences between the two groups on occupational stress factors. PMID- 30248738 TI - [An investigation and analysis of abnormal menstruation in female nurses in a hospital in Beijing, China]. AB - Objective: To investigate the status of abnormal menstruation in female nurses in a comprehensive hospital in Beijing, China and related influencing factors. Methods: In July 2016, a cross-sectional survey was performed, and a self administered questionnaire was used to investigate the status of menstruation and occupation in female nurses in a comprehensive hospital in Beijing. The chi square test and a multivariate logistic regression analysis were used for statistical analysis. Results: A total of 892 female nurses were investigated, and among them, 485 experienced abnormal menstruation within the past three months, resulting in an abnormal menstruation rate of 54.37%. The female nurses who were exposed to harmful factors during work, negative life events, or high workload had a significantly higher abnormal menstruation rate than those who were not exposed to such factors (chi(2)=5.199, 16.186, and 10.227, P<0.05 or P<0.01) . Negative life events (odds ratio [OR]=1.813, 95% confidence interval[CI]: 1.317-2.496) and high workload (OR=1.461, 95%CI: 1.112-1.918) were risk factors for abnormal menstruation. Conclusion: Nurses have an abnormal menstruation rate as high as 54.37%, and high workload and negative life events were risk factors for abnormal menstruation in nurses. PMID- 30248739 TI - [Analysis of the prevalence and related risk factors of prostate diseases in traffic policemen]. AB - Objective: To investigate the prevalence and related risk factors of prostate diseases in traffic policemen. Methods: A total of 848 traffic policemen who took part in the physical examination among August and September in 2016 were selected as research subjects, and a questionnaire survey was conducted to collect their information including smoking, alcohol drinking, biological and physiological indicators, as well as prostate disease etc. The relationship between the prevalence of prostate diseases and related risk factors was analyzed by Non conditional Logistic Regression. Results: The total prostate disease prevalence rate was 40.2% in the study subjects, and there is statistical significance (P<0.05) of differences between prostate disease group and non disease group in age, work age, smoking, drinking and field work. Single factor analysis showed that age, work age, smoking, and field work are independent risk factors of prostate disease (P<0.05) . Multivariate Logistic regression analysis showed that increasing age (OR 1.03) , smoking (OR 1.92) and field work time (OR 1.47) significantly increased the risk of prostate disease in male police after age, smoking, drinking, BMI, systolic blood pressure, diastolic blood pressure, fasting blood glucose, blood lipids and other indicators were adjusted. Conclusion: age, smoking and field work time are risk factors of prostate diseases in the traffic police. There is great significance in publicizing the harmful effects of smoking and reducing the duration of field work. PMID- 30248741 TI - [Comparison of Venous Blood for Radiation Workers using different standards]. PMID- 30248740 TI - [Study on the health effects of occupational exposure to low concentrations of benzene]. AB - Objective: The main purpose of this study was to ascertain whether (or not) exposure to benzene, toluene, xylene and ethylbenzene (BTXE) , under normal working conditions, was associated with any health effects. Methods: From January to December 2014, the workplaces concentrations of BTXE were measured of 71 enterprises in Suzhou Industrial Park. Occupational health examination were investigated on 764 employees who exposed to BTXE, as well as 4409 employees of the corresponding enterprises who unexposed to BTXE, and analyzed the data of the two groups. Results: A total of 6 monitoring sites in 3 enterprises BTXE concentrations excess of the standards, the unexposed group was under the limit of detection. The means of red blood cell count, hemoglobin, hematocrit, intermediate cell count and percentage of intermediate cells were significantly higher in exposed group than in unexposed group (P<0.05) . Conversely, platelet count was significantly lower in exposed group than in unexposed group (P<0.05) . The proportion of red blood cell volume, lymphocyte count and percentage of intermediate cells were significantly lower in exposed group than in unexposed group (P<0.05) . Both means and proportion of glutamic pyruvic transaminase and urea nitrogen were significantly higher in exposed group than in unexposed group (P<0.05) . The positive rate of protein, urine, urine red blood cell were significantly higher in exposed group than in unexposed group (P<0.05) . The abnormal rate of electrocardiogram, liver and kidney B scan were significantly higher in exposed group than in unexposed group (P<0.05) . Multivariate logistic regression analysis revealed that percentage of intermediate cells increased, urea nitrogen increased, urine protein positived, urine red blood cells positived in exposed group the OR values were 1.689, 3.291, 3.163 and 1.743 (P<0.05) . Conclusion: Occupational exposure to low concentrations of BTXE had a certain impact on the blood system and liver and kidney function of the employees, occupational health surveillance for such people should be strengthened. PMID- 30248742 TI - [Effects of Occupational stress and related factors on depression symtoms of workers in electronic manufacturing industry]. AB - Objective: To investigate the influence of depression symtoms and related occupational stress on workers in chip manufacturing industry. Methods: By using cluster sampling method, 2 251workers in electronic manufacturing industry were selected as study subjects in July-December 2016. The simple Occupational Stress Questionnnaire and The Chinese version of Effort-reword imbalance questionnaire (ERI) Questionnnaire were used to investigate and evaluate their job demand control-support questionnaire (JDC) and ERI Occupational stress stiuation respctively. Depression symptoms were measured by the depression module of the patient health questionnaire (PHQ-9) . Results: Among the 2 251 workers, 77.03% workers were found high level of depression symptom.486 workers were the highest level depression.1 248 workers were the higher level depression. The scores of depression symptoms in the related influceing factors JDC and ERI occupational stress were different (P<0.05) . The multivariate logistic analysis results indicated the main positve factors of depression were above college degree, more than 1 years of working age and high input (P<0.05) . The main protective factors of depression were non migrant workers and high return (P<0.05) . Conclusion: The rate of depression of workers is relatively higher in chip manufacturing factory. Enterprises should pay special attention to workers who were above college degree, more than 1 years of working age and high input, ERI occupational stress. PMID- 30248743 TI - [Analysis on characteristics of hearing loss in occupational noise-exposed workers in automotive manufacturing industry]. AB - Objective: To investigate the characteristics of hearing loss in occupational noise-exposed workers in automotive manufacturing industry. Methods: According to Technical Specifications for Occupational Health Surveillance (GBZ188-2014) , 530 noise-exposed workers were examined for health and pure tone audiometry during January to June, 2017, and the data were collected for analysis. Poisson regression analysis was used to analysis the relationship between work age and hearing loss. Results: After correction of age and gender, pure-tone threshold of 500, 1 000, 2 000, 3 000, 4 000, 6 000 of the noise-exposed workers in the <3 year-exposure group were 20.15+/-3.60, 18.80+/-3.43, 18.54+/-3.38, 19.10+/-4.03, 20.32+/-6.79, 23.48+/-8.92 dB (A) ; the values in the 3-10 year-exposure group were 20.96+/-5.38, 19.25+/-4.76, 19.22+/-5.29, 20.17+/-7.50, 21.36+/-8.88, 25.39+/-11.60 dB (A) ; the values in the >10 year-exposure group were 20.18+/ 3.67, 18.34+/-3.60, 18.36+/-4.25, 18.49+/-4.41, 20.32+/-9.24, 22.50+/-9.57 dB (A) . Poisson regression analysis showed that the relative risk (RR) of hearing loss of the noise-exposed workers compared with the noise-free workers was 4.38 (P<0.05) . Conclusion: The noise-exposed workers in automotive manufacturing industry revealed hearing loss, which was associated with their actual working age of noise exposure. PMID- 30248744 TI - [The application of failure mode and effect analysis to improve the hand hygiene compliance of medical staff in eye hospital]. AB - Objective: To discuss the application of failure mode and effect analysis to improve the hand hygiene compliance of medical staff in eye hospital. Methods: To form failure mode and effect analysis (FMEA) quality control team. By using FMEA method of risk management, to analyze the risk factors of hand hygiene compliance of medical staff in eye hospital. By performing analysis, to determine the high risk factors, develop and implement the improvement measures to reduce the risk of these factors. Results: the awareness rate of hand hygiene knowledge was increased significantly after the implementation of failure mode and effect analysis (P<0.01) , the correct rate of hand-washing method, and the implementing rate of 5 hand hygiene were increased significantly (P<0.05) . After the implementation of FMEA, the usage amount of hand washing liquid and quick hand disinfectant was increased from 13 292 ml to 28 390 ml, and difference of the hand hygiene qualification rate was statistically significant (P<0.05) . Conclusion: The application of FMEA contributes to analyze the causes of hand hygiene failure, and guide the development of improvement measures, which can effectively improve the hand hygiene compliance of medical staff, thereby reducing nosocomial infection. PMID- 30248745 TI - [Occupational health investigate of 1-bromopropane used in a factory]. AB - Objective: To investigate the occupational health survey of 1-brominepropane (1 BP) enterprises and understand the impact of 1-BP on the health of occupational exposure population. Methods: The occupational health data of 15 1-BP workers were collected from 3 time nodes in 0 months, June and December, and the effects of occupational exposure to 1-BP on health were analyzed. Results: In the workplace with pure 1-BP, the mean air concentration in the workplace was 26.8 mg/m(3), and the personal contact level was 29.7 to 63.4 mg/m(3). The occupational health monitoring data showed that white blood cell count (WBC) , red blood cell count (RBC) , aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were compared in 0 months, June, and 12 months, the difference was statistically significant (P<0.05) . Conclusion: During the 12 months observation period, the occupational exposure to 1-BP caused the number of peripheral blood erythrocyte and leukocyte count and the level of alanine transaminase in the workers, but it did not exceed the normal reference range. PMID- 30248746 TI - [The value of MRI in early diagnosis of dysbaric osteonecrosis]. AB - Objective: To investigate the value of MRI in the early diagnosis of diagnosis of dysbaric osteonecrosis. Methods: Labor hygiene investigation and occupation health were examined on 52 high pressure operating personnel, were selected for the examination of both shoulders, hips and knees with X-ray and CT scan. Results: The cystic sign in dysbaric osteonecrosis as an important imaging feature, which perform in the MRI examination for T1W I sequence showed low or slightly low signal and T2W I sequence showed high signal, and X-ray and CT have a lower detection rate than MRI. The Kappa consistency test showed a high consistency with the two methods. At the same time MRI examination also can discover the bone marrow cavity necrosis early pathological change. Conclusion: MRI is an effective method for the diagnosis of early dysbaric osteonecrosis, which can improve the early diagnosis rate of dysbaric osteonecrosis. PMID- 30248747 TI - [Application of simple clinical score combined with triage criteria in pre critical triage of critically ill patients in emergency department]. PMID- 30248748 TI - [Acute liver failure caused by occupoational dimothylfor mamide poisoning]. PMID- 30248750 TI - [The diagnosis of occupational disease in one non-freezing frosbite case]. PMID- 30248749 TI - [Analysis of pre-hospital and in-hospital linkage in the treatment of phenol burn patients]. AB - Objective: To analyze the pre-hospital and in-hospital linkage effect on reducing the degree and reduce the complications of phenol burn. Methods: From January 2015 to July 2016, 51 patients with phenol burns in Shanghai Chemical Industry Park Medical Center were treated by in-hospital and in-hospital treatment. Gathering the general data, clinical situation, treatment methods and treatment results were compared with the previous literature on phenol burn treatment. Results: Among the 51 cases, 50 patients with burn area <5%, 1 patient with burn area 5%~0%, 51 patients were cured, and the cure rate was 100%, during the period under observation and all treated patients out of follow-up after under observation, there were no obvious abnormalities in blood and urine routine, did not appear damage of liver and renal function. Conclusion: Phenol can damage many important organs and tissues of the whole body, and it can affect the body and develop corresponding symptoms within a few minutes and hours. Therefore, it is very important to quickly and correctly respond to the injury caused by phenol. The treatment of pre-hospital and in-hospital linkage treatment method has obvious effect on reducing phenol injury and reducing the incidence of complications. PMID- 30248751 TI - [Applications of the Fe(3)O(4) nanocomposite modified by Humic Acid in determination of S-phenylmercapturic acid in urine by dispersive solid-phase extraction and HPLC]. AB - Objective: To establish a method for determination the S-phenylmercapturic acid in urine by dispersive solid-phase extraction using Humic Acid/Fe(3)O(4) magnetic nanocomposite as adsorbent. Methods: The 5 ml of urine samples were adjusted to pH 1.0 and extracted by Fe3O4@HA. Then the analytes were separated on EC-C(18) capillary column and detected by HPLC-VWD. The S-phenylmercapturic acid was characterized by the retention time and quantified by peak area and external standard method. Results: The standard curves of SPMA showed significant linearity between 0.04~1.00 mg/L (r=0.999 7) . The average recovery was 94.2%~102.4%. The intra-day and inter-day precisions (RSD) were 2.9~6.7% (n=6) and 3.1~7.5% (n=6) respectively. The detect limit of SPMA was 0.012 g/L (S/N=3) . Conclusion: This method is simple, rapid, sensitive and accurate. It is applicable for determination of SPMA in the urine of works who were exposed to benzene. PMID- 30248752 TI - [Optimization of ion selective electrode method in detection of urinary fluorine]. AB - Objective: To optimize the ion selective electrode method of measuring urinary fluorine in WS/T 30-1996. Methods: The volume of 5 mol/L NaOH solution was fixed to confect the TISAB buffer solution. The samples were prepared by mixing 5 ml urine and equal volume of TISAB solution. Fluorine electrode and calomel electrode was used to test. When the potential value changed less than +/-0.5 mV in one minute, it could be recorded. The standard curve method was selected as a quantitive method. Results: The linear range of this method was 0.07~50.0 mg/L, E=238.96-57.50lgC, r=0.999 8. The LOD and LOQ were 0.02 mg/L and 0.07 mg/L (with 5 ml urine) , respectively. The RSD of intra -and inter-batch precision were 0.80%~2.82% and 2.17%~2.86%, respectively. The recovery rate was 102%~107%. The urine sample could be preserved stably for 14 days at room temperature, and for 30 days at 4 C and -20 C. Conclusion: In this method, the preparation process of TISAB buffer solution was simplified, and the linear range was expanded. It could meet the needs of occupational population detection. PMID- 30248753 TI - [Determination of p-Anisidine in workplace air by HPLC]. AB - Objective: To establish an HPLC method for determining p-Anisidine in workplace air. Methods: An C(18) capillary column was used with the detection wavelength of 240 nm, the methanol solution (v/v=62:38) as mobile phase, the flow rate was 0.9 ml/min, and the injection volume was 20 MUl. Results: The linear range (MUg/ml) for p-Anisidine was 0~100; correlation coefficient was 0.999 7; the detection limit was 0.15 MUg/ml; the average precision of RSD was 4.4%. The sampling efficiency was more than 95% using silicone tube as sampling filter. Sample can be stored at room temperature for more than 7 d. Conclusion: the method appered to be accurate, simple, sensitive and reliable, also have a high sampling efficiency, and can be usd to determine p-anisidine in workplace air simultaneously. PMID- 30248754 TI - [Study on determination of ethylal in workplace air by gas chromatography]. AB - Objective: A solvent desorption-gas chromatography method for determination of ethylal in workplace air has been established. Methods: Ethylal in workplace air was collected by activated carbon tube and desorbed with carbon disulfide, and the desorption solutions were analysed by capillary column GC with FID detector. Results: The method presented a good linearity in the range of 0.87~34 800.00 mg/L of ethylal in the standard solution, with the correlation coefficient being r=0.999 7. The limit of detection and the limit of quantification of this method were respectively 0.20 mg/L and 0.80 mg/L, and the minimum detectable concentration and the minimum quantification concentration of this method were respectively 0.17 mg/m(3) and 0.60 mg/m(3) per 1.50 L of air.The within-run precision of the method was 2.93%-6.20%, and the between-run precision 3.67% 6.44%. The desorption efficiency between 94.22%-97.27%. Ethylal in activated carbon tube could be kept at least 7 days at room temperature without significant loss. Conclusion: The method could be used for determination of ethylal in workplace air. PMID- 30248756 TI - [An overview on the fit test of hearing protection devices]. PMID- 30248755 TI - [Effects of occupational cadmium exposure on workers' cardiovascular system]. AB - Objective: To investigate the effects of cadmium exposure on cardiovascular system of occupational workers. Methods: Cross-sectional study was applied to 992 workers in a nickel-cadmium battery plant in November, 2011, of which 749 were cadmium exposed workers and 243 were controls without cadmium and other expose. Urinary cadmium,electrocardiogram (ECG) and blood pressure were examined simultaneously among 992 workers. The risk factors of ECG abnormality rate and hypertension rate were analyzed by Logistic regression. Results: The level of urinary cadmium in cadmium exposed workers was significantly higher than controls (8.89+/-4.00 vs 1.34+/-1.18 MUg/g creatinine, P<0.01) . Urinary cadmium level in women was significantly higher than men in both exposure and control group (P<0.05) . According to the group of working years, Urinary cadmium level raised with the increase of working years (F=28.272, P<0.001) . The ECG abnormality rate and hypertension rate of cadmium exposed workers were higher than that of control group, the differences were all statistically significant (P<0.01) . The abnormal rate of ECG and the hypertension rate increased with the prolonging of working years and demonstrated dose-response relationship. With the increase of urinary cadmium level, the abnormal rate of ECG and hypertension rate raised (OR=1.11, P<0.01) and (OR=1.15, P<0.01) respectively. Conclusion: Occupational cadmium exposure increased the abnormal rate of ECG and blood pressure and therefore damaged cardiovascular system of workers. This study provided base data for protecting health of cadmium exposed workers. PMID- 30248757 TI - [Studies on the DNA damage in the transformed bronchial epithelial cells induced by hexavalent chromium]. AB - Objective: To investigate DNA damage in the transformed human bronchial epithelial cells (16HBE) induced by hexavalent chromium (Cr(6+)) and further elucidate the potential carcinogenesis mechanism of Cr(6+). Methods: 16HBE were treated with different concentration of Cr(6+ ()0, 0.625, 1.25, 2.5 MUmol/L) for 15 weeks. The malignant degrees of transformed cells were identified by the assays for anchorage-independent growth and tumorigenicity. According to the single cell gel electrophoresis (SCGE) assay, the DNA damage rate was calculated. The expression level of 53BP1 was determined by Western blot. Results: Chromium treated cells could form colonies in soft agar and tumors in nude mice. Compared with the control group, colony formation efficiency of 1.25MUmol/L and 2.5 MUmol/L Cr(6+)-treated cells in soft agar showed significant increases (p<0.05) . The 2.5 MUmol/L Cr(6+)-treated cells also formed tumors subcutaneously in nude mice. Cr(6+) could cause different degree of DNA damage to 16HBE cells in a dose dependent manner. In addition, Western blot analyses showed that 53BP1 was aberrantly down-regulated at 2.5 MUmol/L dose and has no significant changes at 0.625 MUmol/L and 1.25 MUmol/L dose under the treatment of Cr(6+). Conclusion: The declined expression of 53BP1 may mediate Cr(6+)-induced DNA damage and further involved in the cell malignant transformation. PMID- 30248758 TI - [Study on the effect of oxidative stress on the cardiac injury induced by MEHP in rats]. AB - Objective: This study was to investigate the effects of MEHP on isolated rat heart and explore its mechanism. Methods: The experiments were performed with Langendorff-perfused rat heart with a Langendorff apparatus. 35 SD rats were used in the experiment and there were 5 rats per group. MEHP at doses of 3.125, 6.250, 12.500 and 25.000 MUmol/L were given to the hearts for 25 minutes. Effects of NAC at concentration of 5 mmol/L were evaluated by co-treatment with 12.500 or 25.000 MUmol/L MEHP. Data was collected per 5 minutes for 25 minutes. The heart rate, LVDP, LVEDP, dp/dtmax, and dp/dtmin were measured and analyzed using a PL3508 Data Acquisition and Analysis System. 200 waves at least were required each time. LDH contents in heart lavage fluid were determined by photometric assays using the automated biochemical analyzer. A section of the heart tissue was used for histopathological examination. DCFH-DA method was used to detect the levels of reactive oxygen species in different groups of heart tissues. Results: There was a concentration dependent decrease of heart rate (P<0.05) . At concentrations of 6.250, 12.500 and 25.000 MUmol/L, MEHP significantly decreased the LVDP, dp/dtmax and dp/dtmin (P<0.05) , and this decrease is more pronounced with perfusion time. As the MEHP was given up to 6.250, 12.500 and 25.000 MUmol/L, a statistical significance was found in the increase of LVEDP (P<0.05) . For dp/dtmin, a significant increase was observed at the concentration of 3.125 MUmol/L when perfused with 10 and 15 min (P<0.05) , but this increase disappeared over time. LDH in cardiac perfusate increased as the MEHP given a higher concentration (P<0.05) . Compared with the control group, Histopathological analysis showed edema of myocardial tissue and cells, and inflammatory cells infiltration and myocardial cells necrosis were obvious in the MEHP perfusion groups. Myocardial ROS levels of the four MEHP treatment groups were all significantly higher than that of control group (P<0.05) . These heart damage induced by MEHP could be attenuated by NAC in different degrees. Conclusion: MEHP can induce damage to myocardial tissue of isolated rat heart and one possible mechanism is the oxidative stress. PMID- 30248759 TI - [Correlation between FOXO3 gene polymorphisms and susceptibility to occupational noise-induced deafness]. AB - Objective: To investigate the association between the single nucleotide polymorphisms of rs12212067 in FOXO3 gene and the susceptibility to occupational noise-induced deafness in a Chinese Han population. Methods: A total of 1 066 cases of noise exposure workers from a large chemical fiber factory in Jiangsu Province were selected as the study subjects. All subjects' basic data and field exposure data were collected through questionnaires and occupational health surveys. The subjects were divided into case group (531 persons, double ear high frequency average hearing threshold>25 dB) and control group (535 persons, double ear high frequency average hearing threshold<=25 dB) according to their results of pure tone hearing test .2ml fasting venous blood was collected for DNA extraction and genotyping was performed by TaqMan-PCR technique. Results: Genotyping results suggested that the GT+GG genotype is a risk factor for occupational noise-induced deafness, with an adjusted OR 95% confidence interval of 2.044 (1.51-2.78) . After the noise exposure intensity was stratified, the adjusted OR values and the 95% confidence intervals of noise intensity <=85, 85 92 and>92 dB respectively 2.43 (1.52-3.90) , 2.17 (1.03-4.59) and 1.74 (1.07 2.83) . Conclusion: GT-GG genotype in rs12212067 of FOXO3 gene may be a risk factor for occupational noise-induced deafness. PMID- 30248760 TI - [Comparison of whole blood indium and the serum indium of the population exposed to the indium]. AB - Objective: The method was established for the detection of whole blood indium and serum indium. By comparing the results of two samples, it is possible to explore the significance of whole blood indium and serum indium in the population exposed to indium compounds. Methods: According to GBZ/T 295-2017 and GBZ 294-2017, the whole blood and serum samples were diluted 20 times by 0.5% nitric acid solution (including 0.05% Triton X-100) . Under the standard mode of inductively coupled plasma mass spectrometry (ICP-MS) , whole blood indium and serum indium of indirect exposure group, low exposure group and high exposure group in an indium mine were detected with 20 MUg/L rhodium standard solution as internal standard. Results: This method has a working range of 0.00~5.00 MUg/L and a correlation coefficien t>0.999. The detection limit and quantitative lower limit of whole blood indium were 0.076 MUg/L and 0.26 MUg/L respectively. Those of serum indium were 0.06 MUg/L and 0.20 MUg/L accordingly. The recovery rates of serum and whole blood samples were 88.5%~95.6% and 93.0%~101%. Intra batch precisions were 1.3%~4.4% and 1.9%~3.5% and inter batch precision were 2.4%~6.1% and 2.1%~4.6% in two samples. There were no significant differences between whole blood indium and serum indium in indirect exposure group. The serum indium level was lower than the detection limit in 3 cases, while their whole blood indium was only below the quantitative lower limit. However, in other groups whole blood indium level was significantly higher than serum indium level (P<0.05) and even was two-fold in the high exposure group. Conclusion: The detection of whole blood indium is more sensitive than that of serum indium, which can reflect the internal exposure level more accurately in exposure population. Therefore, the whole blood indium is of more important referential value to health examination and poisoning diagnosis in the population exposed to indium and its compounds. PMID- 30248761 TI - [Research on reproductive health of female nurses in a district and analysis of influencing factors]. PMID- 30248762 TI - [Sampling Survey of the Relationship Between Acute Mountain Sickness and Mental Health of Officers and soldiers]. AB - Objective: To sample survey the relationship between acute mountain sickness and mental health of officers and soldiers, so as to provide theoretical direction for the psychological prevent and counsel of them. Methods: In May 2017, 61 officers and soldiers were selectedas subject investigated, and divided to AMS group included 35 persons and non-AMS group included 26 persons according to the finding of theAMS symptom division point table, then used symptom self-testing tableto test and evaluate the mental health of them. Results: The AMS group showed significantly higher scores on the psychological parameters such as omatization, interpersonal sensitivity, depression, anxiety, phobicanxiety, parnoid ideation and so on (105.20+/-13.82, 1.37+/-0.26, 1.14+/-0.21, 1.16+/ 0.19, 1.16+/-0.18, 1.06+/-0.11, 1.10+/-0.17, 1.22+/-0.19, P<0.05) . Conclusion: The mental factors of omatization, interpersonal sensitivity, depression, anxiety, phobic anxiety, parnoid ideation and so on had great influence on AMS, we should pay attention to these factors and carry on mental intervention, and enhance anti-stress ability of individual, to ensure the successful completion of plateau military mission. PMID- 30248763 TI - [Analysis of The Quality of Pneumoconiosis Network Direct Report in Sichuan during 2006-2016]. AB - Objective: To evaluate the quality of Pneumoconiosis Network Direct Report in Sichuan Province in 2006-2016. Methods: download all the pneumoconiosis report cards from the Network Direct Report system. Screen out cards based on the diagnosis time that is between January 1st 2006 and December 31st 2016. Using R 3.4.0 software to analysis the number of missing or repeated cards, time-logical error rates, timeliness, reporting year, reporting intervals to evaluate the quality of Pneumoconiosis Network Direct Report and location distribution. Results: there are 38 855 pieces of Pneumoconiosis report card in total in 2006 2016. 352 pieces of cards were reported twice. 224 cards were missing. 229 cards have time-logical error. The rate of timely reporting for 2006-2016 years was 66.41% (2 5453/38 326) , 67.14% (24 658/36 726) for new cases, 58.87% (783/1 330) for promoting cases and 4.44% (12/270) for deaths. 87.38% (33 490/38 326) patients was reported in the same year. 10 days was needed to finish one report, confirming-filling cost much more time than filling-report (9.865/49.019) . Conclusion: the records of pneumoconiosis report cards are much more complete, logical errors are less, and the timeliness was a little bit higher than the average level in China. But it also should be improved. The death cases are difficult to report. It takes longer to diagnose and fill in cards. Improving the timeliness rate can significantly improve the quality of network direct reporting. PMID- 30248764 TI - [The analyze the epidemic trend and predict the incidence trend of occupational diseases in Guangdong province]. AB - Objective: This study was aimed to analyze the epidemic trend and predict the incidence trend of occupational diseases during 2006-2015 in Guangdong province, which may provide the theoretical foundation for occupational disease risk assessment and precise control and prevention. Methods: We analyzed the number of reported occupational disease cases, the constituent ratio, the average age and working-age of patients. We also performed the linear-by-linear association test of new incidence, median age and median working-age by curve-fitting method, of which the diagnostic year was set as the independent variable. Meanwhile, we designed an ARIMA model to predict the variation tendency of occupational diseases in 2017-2020. Results: (1) During 2006-2015, the total reported cases of occupational disease is 5289, including 2101 cases of occupational pneumoconiosis (39.7%) , 1363 cases of occupational poisoning (25.8%) , and 864 cases of occupational otolaryngological and stomatological disease (16.3%) . (2) The number of occupational diseases and pneumoconiosis have a straight upward trend (R(2)=0.851, R(2)=0.856) , while the number of occupational otolaryngological and stomatological disease and occupational tumor have a exponential trend (R(2)=0.914, R(2)=0.696) . The constituent ratio of occupational poisoning is decreasing, and the constituent ratio of occupational otolaryngological and stomatological disease is increasing. (3) The average onset age is 40 (33, 46) years old, and the average onset working-age is 6 (3, 11) years. Both of them have a straight upward trend (R(2)=0.954,R(2)=0.792) . The onset age of pneumoconiosis, occupational poisoning and occupational otolaryngological and stomatological disease have a upward trend. In addition, the onset working-age of occupational poisoning and pneumoconiosis have a upward trend. (4) The number of occupational diseases in 2017-2020 is predicted to be between 902-1231. Conclusion: Occupational diseases in Guangdong province showed a trend of high incidence. The age and working-age of occupational diseases showed an extended trend. Therefore, our work of occupational epidemic trend may provide some bases for the occupational disease risk assessment and precise control and prevention. PMID- 30248765 TI - [The application of ARIMA in forecasting the cases of rabies in China different human groups]. AB - Objective: To understand the situation of rabies in China different human groups. Seasonal ARIMA model is established to make forecasts and to provide suggestions for human rabies controlling in China. Methods: Build a model with data during 2004-2013, and validate the model by data of 2014. Then predict the cases of rabies from 2015-2017. Results: The long term trend is decreasing year by year, while seasonal effect is found that number of the third and fourth quarter are higher than others. The seasonal ARIMA model was built, whose residual are white noise. The RMAE in forecasting of peasants, students and scattered children are 19.10%,49.93% and 68.01%. Conclusion: The decreasing of rabies cases in China with time shows that the measures for control are effective. October for peasants, September for students, August for scattered children are critical period in future for rabies' control. Seasonal ARIMA model is a feasible model in forecasting the cases of rabies in China different groups in some way, error will be reduced by modeling separately for different wave sequence and combining with other models like ARIMA-GARCH. PMID- 30248767 TI - [Effects of Personality and Psychological Acceptance on Medical Workers' Occupational Stress]. AB - Objective: To assess psychological acceptance and occupational stress of medical staff, analyze the relationship among personality, psychological acceptance and occupational stress and discuss the direct or indirect effects of personality to occupational stress. Methods: Eysenck Personality Questionnaire (EPQ-RSC) , Acceptance and Action Questionnaire-II (AAQ-II) and Revised Occupational Stress Inventory (OSI-R) were administered to 749 medical staff. Results: The level of occupational stress of medical staff was high, the score of PSY was 26.8+/-7.13 and the score of PHS was 24.3+/-6.50. Personality and psychological acceptance can predict occupational stress. Psychological acceptance was a protective factor of occupational stress. Medical staff with personality of introversion, neuroticism and psychoticism suffered higher occupational stress. Personality have both direct and indirect effects on occupational stress. Neuroticism have the strongest effect on occupational stress with effect size of 0.496 (psychological stress) and 0.431 (physical strain) . Conclusion: Medical staff have heavier occupational stress. There is a significant correlation between personality and occupational stress. Measures depending on personality should be taken to deal with this situation. PMID- 30248766 TI - [The correlation of Occupational musculoskeletal disorders and occupational safety behaviors in assembly line workers]. AB - Objective: To study the correlation of occupation musculoskeletal disease (OMD) and safety behavior in assembly line workers. Methods: Selected assembly line workers of 3 manufacturing factory in Pacity as the objects of this study by judgement sampling. Questionnaires were used for messages collection including the general sociodemographic characteristic, OMD condition, occupational safety behaviors. Results: This study shows that, 826 OMD workers were found that the annual prevalence was 38.03%. The scores of work posture, handling habits, health habit in OMD group was lower than non-OMD group (P<0.01) but personal protection behavior was higher than non-OMD group (P<0.01) . Test of binary logistic regression revealed that age, workage, work posture, handling habits were the factors of OMD (P<0.01) . Conclusion: Safety behaviors were the potent factors of OMD that work posture and handling habits should be broadcast. PMID- 30248768 TI - [Establishment of a nomogram for predicting the high frequency hearing loss of workers exposed to noise]. AB - Objective: To explore the related influencing factors of high frequency hearing loss (HFHL) in workers exposed to noise and establish a prediction nomogram for HFHL. Methods: A total of 822 workers exposed to noise from 46 enterprises were included. A questionnaire survey and a pure-tone hearing test were conducted for the workers. The data of noise level of the workers exposed was also collected. After single factor analysis of related influencing factors, the multivariate Logistic regression analysis was performed to identify the final independent influencing factors of HFHL. Finally, a nomogram model was established by R software to achieve individual prediction of HFHL. Results: Among the 822 workers exposed to noise, 166 (20.2%) workers had HFHL. In multivariate Logistic regression analysis, increasing age, men, increasing wearing earphone time, less wearing earplugs, and high noise level were the independent risk factors for HFHL. The C-index of the nomogram model for predicting HFHL was 0.834 (95%CI: 0.748~0.903) . The area under the predictive power curve of nomogram model was 0.834 (95%CI: 0.799~0.869, P<0.001) . Conclusion: Age, sex, wearing earphone time, wearing earplugs, and noise level are independent influence factors for HFHL. The nomogram model is successfully established as a accurate and visible tool for individually predicting the HFHL risk in workers exposed to noise. PMID- 30248770 TI - [Clinical analysis of 10 cases of occupational acute vanadiumpoisoning]. PMID- 30248769 TI - [Detection and Analysis of the peripheral lymphocytes micronucleus rate of radiation workers in a city]. AB - Objective: To perform lymphocyte micronucleus analysis on radiation workers with long-term exposure to low doses ionizing radiation, Evaluate the health condition of radiation workers, and provide the evidence for strengthening surveillance of radiation workers. Methods: From January 1, 2013 to December 21, 2016, a statistical analysis and evaluation was conducted of the peripheral lymphocytes micronucleus rate in 5 901 radiation workers who had undergone medical examinations of employees at Chinese Academy of Medical Sciences Institute of Radiation Medicine. Results: The micronucleus rates in radiation workers of the on-job group were higher than the pre-job group (P<0.01) . Significant difference was found among the different sex (t=5.97) , different types (chi(2)=378.69) , different levels of work units (chi(2)=115.48) . Significant difference was found among the micronucleus rates of 672 radiation workers of the on-job group from 2013 to 2016 (chi(2)=92.57, P<0.01) . Conclusion: The peripheral lymphocytes micronucleus rate of radiation workers were significantly higher than non-contact workers. Significant increasing trend of micronucleus rates was noted among the radiation worker with increasing exposure time. The peripheral lymphocytes micronucleus rates of interventional therapy workers were highest. The peripheral lymphocytes micronucleus rates of Private hospitals workers were highest. This phenomenon deserves attention. Protection needs to be strengthened to ensure the health of radiation workers. PMID- 30248771 TI - [The application of stopping anesthesia step by step to reduce the stress response during extubation in Whole-Lung Lavage]. PMID- 30248772 TI - [Direct determination of manganese in urine by Graphite Furnace Atomic Absorption Spectrometry]. AB - Objective: To establish a method for the determination of manganese in urine by graphite furnace atomic absorption spectrometry (AAS) without the use of matrix modifier. Methods: The urine samples were 5 times diluted with 1% nitric acid then directly determined by AAS. Zeeman was used for background correction. Results: The linear range for determination of manganese in urine was 5~60 MUg/L (urine) . The correlation coefficient was greater than 0.995 with the detection limit of 1.5 MUg/L and with the lower limit of quantification of 5.0 MUg/L. The relative standard deviations (RSDs) of within-run precision was between 1.1%~4.3%, the RSDs of between-run precision was between 3.3%~7.0%. The average recovery was 102.6%. The samples can be stored for 14 days at room temperature, 4C, -8 C and -35 C. Conclusion: The method is feasible for determination of manganese in urine. PMID- 30248773 TI - [Simultaneous determination of 12 rodenticides in whole blood and urine samples by high performance liquid chromatography-tandemmass spectrometry]. AB - Objective: To develop a method for Simultaneous and rapid determination of 12 rodenticides including pindone, vacor, coumatetralyl, warfarin, diphacinone, coumachlor, chlorphacinon, difenacoum, brodifacoum, bromadiolone, difethialone and flocoumafen in whole blood and urine samples by high performance liquid chromatography-tandem mass (LC-MS-MS) . Methods: The whole blood samples were precipitated with acetonitrile, purified by OstroTM 96-well plate, The urine samples were extracted by acetonitrile, and then separated on a ODS column, analyzed with high-performance liquid chromatography-tandem mass spectrometry (LC MS/MS) . The external standard calibration were tested. Results: A good linearity was observed in their respective concentration ranges of 12 rodenticides. The related coefficients were 0.993 0~0.999 8. The limit of detections were 0.05 MUg/L~1.4 MUg/L. The rates of recovery were 92.5%~118.0%. The relative standard deviations were between 0.8%~17.3%. Conclusion: The method was simple, rapid, sensitive, accurate and suitable for simultaneous detection of the 12 rodenticides in whole blood and urine samples of intoxicated patients. PMID- 30248774 TI - [Discussion on calculation method of detection limit and quantitative limit of occupational health biological monitoring method]. AB - Objective: To discuss calculation method of detection limit and quantitative limit of occupational health biological monitoring. Methods: The detection limit and the quantitative limit of phenyl glyoxylic acid and Mandelic acid were calculated by using three different methods of IUPAC, NIOSH and OSHA respectively. Results: The IUPAC, NIOSH and OSHA methods were used to calculate the detection limit and the quantitative limit of the phenyl glyoxylic acid and Mandelic acid, and the results are different. Conclusion: To calculate the detection limit and quantitative limit of occupational health biological monitoring methods, the standard curve method is adopted to ensure that the rate of detection in the vicinity of detection limit and more than 75% of the quantitative limits are used. PMID- 30248776 TI - [Gas chromatographic determination of nicosulfuron in human plasma]. PMID- 30248775 TI - [Detecting the concentrations of diphenylamine in air of workplace with HPLC]. AB - Objective: To establish the method of detecting the concentrations of diphenylamine in air of workplace with high performance liquid chromatographic (HPLC) . Methods: According to standards of methods for determining the chemical substances in workplace air, diphenylamine in the air was collected by glass fiber filter treated with sulfuric acid, then dissolved by methanol and determined by high performance liquid chromatography with UV-detector. Results: There was a linear relationship within the range of 0-30.0 MUg/ml, and regression equation was y=8425.6x-150.7, correlation coefficient was 0.999 9, the detection limit was 0.045 MUg/ml. The lowest detected concentration was 0.030 mg/m(3) (sampling volume 15 L) . The within-run precision was 2.41 c/o-3.02%, the between run precision was 3.11%-4.45%. The desorption efficiencies was 97.8c/o and the sampling efficiencies were 100%. The samples in glass fiber filter could be stored for 7 d at room temperature. Conclusion: The present method could meet with the requirements of Guide for establishing occupational health standards Part 4 Determination methods of air chemicals in workplace and be feasible for determination of diphenylamine in workplace air. PMID- 30248778 TI - [Status and Prospect of Teleradiology for Diagnosing Pneumoconiosis]. PMID- 30248779 TI - [Treatment stragegy of immunosuprression for sepsis]. PMID- 30248780 TI - [Shock resuscitation: macrocirculation-microcirculation couple]. PMID- 30248777 TI - [The effects of Xuebijing injection on apoptosis and expression of regulatory factors TNF-alpha,NF-kappaB and Caspase-3 expression in the lung tissues of acute paraquat-induced rats]. AB - Objective: To explore the mechanism of Xuebijing injection in the treatment of acute paraquat poisoning by means of studying the expression of TNF-alpha, NF kappa B, Caspase-3 and the changes of cell apoptosis rate detected by TUNEL in the lung tissue of acute paraquat-induced rats. Methods: On the base of random number table, 126 Wister rats weighing 220 g to 270 g were divided into 3 groups: (1) Control group: 42 rats, (2) Poisoned group: 42 rats, (3) Treatment group: 42 rats. On 1(st),3(rd),7(th),14(th),21(st),28(th),and 35(th) day, six rats from each group were anaesthetized by intraperitoneal injection of chloral hydrate. To cut the chest and take the lung tissue samples. The expression levels of Tumor Necrosis Factor-alpha, Nuclear Factor-kappa B and Caspase-3 protein in lung tissue were detected by immunohistochemical staining, as well as apoptotic cell rate was detected by TUNEL staining. Results: The expression levels of Tumor Necrosis Factor-alpha, Nuclear Factor-kappa B, Caspase-3 protein and TUNEL staining in the lung tissue of the poisoned group was significantly higher than that of the control group (P<0.05) . Compared with the poisoned group, the expression of TNF-alpha, NF-kappa B, Caspase-3 and TUNEL in treatment group decreased significantly (P<0.05) , but they were still higher than those of the control group, and the difference was statistically significant compared with the control group (P<0.05) . Conclusion: Apoptosis and TNF-alpha, NF-kappa B and Caspase-3 play an important role in lung injury of paraquat-induced rats. Xuebijing injection can inhibit the expression of TNF-alpha, NF-kappa B, Caspase 3 in lung tissue, reduce the apoptosis rate and alleviate the damage of lung tissue in paraquat-poisoning rats. PMID- 30248781 TI - [Progress of diagnosis and treatment strategies in acute respiratory distress syndrome]. PMID- 30248782 TI - [Primary aim of the analgesia and sedation: protection of organs]. PMID- 30248783 TI - [Continuous blood purification and precision volume management]. PMID- 30248784 TI - [Topics and strateges for clinical managements of coagulation in critically ill patients]. PMID- 30248785 TI - [The favorable effects of KIR3DS1 and Bw4(80Ile) on viral set point and CD4 count decline in HIV-1 patients with acutely infected with HIV-1 infection]. AB - Objective: To investigate whether killer cell immunoglobulin-like receptor 3DS1(KIR3DS1)and Bw4(80Ile) could play a protective role during HIV-1 infection. Methods: KIR3DL1/3DS1 and Bw4, Bw6 were genotyped by SSP-PCR and Bw4 allotypes (Bw4(80Ile) and Bw4(80Thr))were classified via sequencing among 109 individuals acutely infected with HIV-1 in Beijing You'an Hospital between 2006 and 2012. Results: (1)Of the 109 patients, 65, 7, and 37 subjects respectively harbored KIR3DL1/KIR3DL1, KIR3DS1/KIR3DS1, and KIR3DL1/KIR3DS1 genotypes. Their viral set points were determined as 4.35+/-0.79, 4.24+/-0.49 and 3.99+/-0.85 respectively. The viral set point of patients carrying KIR3DL1/KIR3DS1 was significantly lower than the KIR3DL1/KIR3DL1 genotype patients (P=0.032). (2)26, 41, 42 subjects harbored Bw4(80Ile,) Bw4(80Thr,) Bw6/6, respectively. Viral set points of these subjects were respectively 3.89+/-0.49, 4.20+/-1.03 and 4.44+/-0.59.One-way ANOVA indicated that Bw4(80Ile)influenced the levels of viral set point(P=0.027). Moreover, the level of viral set point of the Bw4(80Ile) genotype was significantly lower than the Bw6/6 genotype (P=0.020). These outcomes indicated Bw4(80Ile) was associated with lower levels of viral set point.(3)Viral set point of patients harboring KIR3DS1 and Bw4(80Ile)was 3.26+/-0.81 and significantly lower than individuals possessing other genotypes (all P<0.05). KIR3DS1 and Bw4(80Ile) conferred an advantage over other genotypes, especially over KIR3DS1 and Bw6/6 (P=0.006), KIR3DL1 and Bw6/6 (P=0.015) and even KIR3DL1 and Bw4(80Ile) (P=0.019 6) in delaying CD4 count decline within 3 years after HIV-1 infection. Conclusions: KIR3DS1 and Bw4(80Ile) are synergistically related to lower viral set point and slowing down the CD4 count decline as Bw4(80Ile) in the presence of KIR3DS1. PMID- 30248786 TI - [Cryptococcus bloodstream infection: a retrospectively analysis of 16 cases in one tertiary hospital]. AB - Objective: To explore the clinical characteristics of cryptococcus bloodstream infection. Methods: A retrospectively analysis was performed by collecting data of clinical manifestations, underlying diseases, susceptible factors, therapy and prognosis of cryptococcus bloodstream infection in the First Affiliated Hospital of Soochow University from December 2006 to December 2017. Results: The most common symptom of the 16 patients was fever (12/16). When combined with cryptococcus infection of central nervous system, the manifestations may include dizziness, headache, nausea and vomiting.Among the 16 patients, 11 cases had underlying diseases, which listed as leukemia, lymphoma, diabetes mellitus, hepatitis B, cirrhosis, chronic kidney disease and carcinoma of the liver; 12 cases had invasive procedures, 6 cases had hypoproteinemia, 4 cases had long-term usage of glucocorticoids, and 5 cases received broad spectrum antibiotics longer than 1 week.8 cases died, 6 cases improved and 2 cases were transferred to the specialized hospital for their newly diagnosed AIDS. Conclusions: Bloodstream infection of cryptococcus is a relatively rare disease.Fever is one of the most common symptoms of cryptococcus bloodstream infection.Underlying diseases, invasive procedures, hypoproteinemia, long-term application of glucocorticoids and antibiotics are the risk factors for cryptococcus bloodstream infection. PMID- 30248787 TI - [Effect of progesterone on expression of ER, PR, PCNA, bcl-2, c-myc, c-fos, and EGFR in normal breast tissue implanted into nude mice]. AB - Objective: To investigate the effect of progesterone on estrogen receptor(ER), progesterone receptor(PR), proliferating cell nuclear antigen (PCNA) , bcl-2 , c myc, c-fos, and epidermal growth factor receptor(EGFR) expression in normal human breast tissues implanted into nude mice. Methods: A xenograft-model, pieces of normal human breast tissue implanted subcutaneously into 9-10-week-old athymic nude mice, was established.The tissue of each case was divided into 4 parts, and were transplanted into 4 nude mice.These mice were randomly divided into 4 groups, namely control group: normal saline 0.1 ml; estrogen group: estradiol benzoate 20 MUg (0.1 ml, 1 mg/kg); progesterone group: 60 MUg (0.1 ml, 3 mg/kg); estrogen plus progestin group: estradiol benzoate 20 MUg (0.1 ml, 1 mg/kg) and progesterone (0.1 ml, 3 mg/kg) 60 MUg.Treatment was given every other day, and human breast tissues were removed for experiments after treatment for 4 weeks.The implanted breast tissue were fixed and sliced.The expression of ER, PR PCNA and bcl-2 were assayed by immunohistochemical, c-myc, c-fos, and EGFR mRNAs were determined by in situ hybridization. Results: In estrogen group, and estrogen plus progestin group, the positive expression of ER was lower and PR was higher than those of the control group (P<0.05); the expression of ER and PR in progesterone group had no differences compared with the control group (P>0.05); the expression of PCNA and bcl-2 in estrogen group were higher than that of the control group (P<0.01, P<0.05), while they showed no significant difference in the other two drug groups compared with the control group (P>0.05). The expression of c-myc, c-fos and EGFR in estrogen group and estrogen plus progestin group were higher than those in control group (P<0.01). The expression of c-myc in the progesterone group was higher than that in the control group (P<0.01), and the expression of c-fos and EGFR in the estrogen and progesterone groups were not significantly different compared with those in the control group (P>0.05). Conclusions: Progesterone did not affect the proliferation and apoptosis of human normal breast tissue, but may have anti-proliferative and pro-apoptosis effects when coupled with estrogen.And it can up-regulate the expression of c-myc. PMID- 30248788 TI - [A meta-analysis of prognosis after bipolar umbilical cord coagulation or radiofrequency ablation to reduce complicated monochorionic multiple pregnancies]. AB - Objective: To evaluate the prognosis and complications after reduction of monochorionic multifetal pregnancies using bipolar umbilical cord coagulation (BCC) or radiofrequency ablation (RFA). Methods: A literature search were performed by using online databases including PubMed, Embase, and COCHRANE.The publications that described prognosis and complications after selective reduction of monochorionic twin pregnancies using either BCC or RFA for studies with clear outcome data were identified. Results: We identified five retrospective cohort studies for the meta-analysis and 231 cases of BCC and 174 cases of RFA.There was no statistical difference in overall survival after reduction between BCC group (79.2%) and RFA groups (76.4%) (RR=0.96; 95%CI: 0.86~1.08; P=0.48). Neonatal mortality was similar in both groups (8.2% vs 11.1%, respectively; RR=1.34; 95%CI: 0.60~2.99; P=0.48). However, intrauterine fetal death (IUFD) in the RFA group was 13.6%, and it significantly higher than that in the BCC group 7.7% (RR=2.15; 95%CI: 1.10~4.21; P=0.03). In contrast, after reduction, those in the RFA group had less preterm premature rupture of membranes (PPROM) compared with the BCC group (17.1% vs 27.5%, RR=0.58; 95%CI: 0.39~0.86; P=0.007). Conclusions: RFA and BCC groups have similar overall survival for complicated monochromic multiple pregnancies, but RFA was more prone to IUFD, and BCC tended to have more PPROM.Thus, procedures should be chosen according to specific clinical situations and pregnancy conditions. PMID- 30248789 TI - Conventional redo biological valve replacement over 20 years: Surgical benchmarks should guide patient selection for transcatheter valve-in-valve therapy. AB - OBJECTIVES: Although primary transcatheter valve interventions have demonstrated acceptable early- and intermediate-term outcomes, data are lacking to guide patient selection for transcatheter valve-in-valve therapy. Furthermore, very few surgical benchmarks have been established for repeat conventional biological valve replacement to refine momentum for broad application of transcatheter intervention for a degenerated bioprosthesis. METHODS: From January 1993 to July 2014, 694 patients underwent repeat biological valve replacement at our clinic. Median age at repeat operation was 71 years (range, 26-95 years) and there were 437 men (63%). Hypertension was present in 453 patients (65%), diabetes in 128 patients (18%), prior myocardial infarction in 85 patients (12%), and prior stroke in 81 patients (12%). Prior coronary bypass grafting was performed in 212 patients (31%). Median left ventricular ejection fraction was 41% (range, 20-61) and New York Heart Association functional class III or IV was present in 529 patients (76%). RESULTS: Biological valve re-replacement included most commonly aortic valve in 464 patients (67%) and mitral valve in 170 (24%). Concomitant coronary bypass grafting was performed in 134 patients (19%). Mortality at 30 days occurred in 56 patients (8%). Multivariable analysis with backward stepwise regression identified New York Heart Association functional class (per 1 increment) (hazard ratio, 2.1; 95% confidence interval, 1.06-4.3; P = .03) and prior coronary bypass grafting (hazard ratio, 3.5; 95% confidence interval, 1.2 10.9; P = .03) as independent predictors of early death. Patients with the combination of prior coronary bypass grafting and New York Heart Association functional class III or IV accounted for 26 out of 56 early deaths (46%) and in the absence of this combination, early death in the cohort was 30 out of 694 (4%). Follow-up was available in 602 out of 638 early survivors (94%) for a median of 45 months (range, 1 month-23.4 years). Survival at 5 and 10 years was 63% and 34%, respectively. For patients who died during follow-up, 2-dimensional scatter plots demonstrate durable length of postoperative survival (median, 5.5 years; maximum, 22 years). CONCLUSIONS: In a large population of patients undergoing repeat biological valve replacement, prior coronary bypass grafting and advanced New York Heart Association functional class were associated with increased 30-day mortality, with the remaining population having a low 30-day mortality of 4%. This study could serve as a surgical benchmark to guide patient selection for transcatheter valve-in-valve technology rather than employing a broader application of these techniques to those who may otherwise have low early risk of mortality and durable long-term survival after conventional valve surgery. PMID- 30248790 TI - Benchmark to avoid judgment under uncertainty in the choice. PMID- 30248791 TI - The pressure is on. PMID- 30248792 TI - Valve repair for mitral despair. PMID- 30248793 TI - De novo atrial fibrillation after mitral valve surgery. AB - OBJECTIVES: We sought to determine the incidence and risk factors for de novo atrial fibrillation (>90 days after surgery) in patients without preoperative atrial fibrillation. METHODS: From 2004 to 2014, 2261 patients underwent mitral valve surgery; 1288 patients (57%) did not have a history of atrial fibrillation, and 930 patients had rhythm information more than 90 days after surgery. De novo atrial fibrillation and death probabilities were estimated using a semi-competing risks, multi-state model. Univariable and multivariable risk factors for developing atrial fibrillation were identified using the Fine-Gray model. RESULTS: The 5- and 10-year incidences of de novo atrial fibrillation were 14% and 23%, respectively. Univariable risk factors were older age, more complex operations, more tricuspid regurgitation, and congestive heart failure (all P < .05). Patients with degenerative mitral regurgitation were less likely to develop atrial fibrillation (hazard ratio [HR], 0.4; 95% confidence interval [CI], 0.24 0.65; P < .001). Multivariable risk factors for de novo atrial fibrillation were tricuspid valve surgery (HR, 1.80; 95% CI, 1.22, 2.65; P = .003), aortic valve surgery (HR, 1.49; 95% CI, 1.03-2.17; P = .035), and older age (HR, 1.03; 95% CI, 1.02-1.05; P < .001). De novo atrial fibrillation did not affect overall survival (P = .41). Among patients who developed de novo atrial fibrillation, we observed increased use of warfarin (P < .001) and a strong trend toward an increased risk of stroke (P = .055). CONCLUSIONS: De novo atrial fibrillation develops progressively after mitral surgery and is associated with a strong trend toward stroke. Patients at high risk could be studied in a trial to reduce atrial fibrillation. PMID- 30248794 TI - Reinventing the atrial fibrillation wheel. PMID- 30248795 TI - Risk of conventional cardiac surgery among patients with severe left ventricular dysfunction in the era of mechanical circulatory support. AB - BACKGROUND: Despite suggestions that severe left ventricle dysfunction may warrant selection of durable mechanical circulatory support over conventional surgery, comparative studies are lacking due to incomplete characterization of patients at highest risk after conventional surgery. We sought to define subsets of patients with severe left ventricle dysfunction who are at greatest mortality risk following conventional cardiac surgery. METHODS: We studied 892 patients aged >= 18 years who underwent conventional coronary or valve surgery from 1993 to 2014, with preoperative ejection fraction <= 25%. Exclusions were transcatheter interventions, major concomitant procedures, active endocarditis, and prior/concurrent durable mechanical circulatory support use. Logistic and Cox regression identified determinants of early and late mortality. RESULTS: Median age was 70 years (interquartile range, 62-76 years), 46% (n = 411) had New York Heart Association (NYHA) functional class IV symptoms, and 16% (n = 142) had undergone prior surgery. Operative mortality was 7.5%. NYHA functional class IV (odds ratio [OR], 1.88; P = .033), prior cardiac surgery (OR, 2.13; P = .017), peripheral vascular disease (OR, 2.55; P = .001), emergency status (OR, 2.68; P = .024), and intra-aortic balloon pump use (OR, 4.95; P < .001) independently predicted operative death. Risk imparted by presence of both NYHA functional class IV symptoms and prior surgery was additive, with a 4-fold increase in early mortality risk (OR, 3.95; P = .003). Prior surgery increased the hazard of late death by 60% (P < .001). In patients without prior surgery, late mortality was greatest in those aged >= 70 years (hazard ratio, 1.86; P < .001), especially if NYHA functional class IV symptoms were concurrently present (hazard ratio, 2.25; P < .001). Surgery type (coronary artery bypass graft surgery, aortic valve surgery, or mitral valve surgery) did not predict long-term outcome. CONCLUSIONS: In patients referred for conventional surgery with an ejection fraction <= 25%, prior cardiac surgery, and/or NYHA functional class IV symptoms-particularly in those aged >= 70 years-confer significant and sustained survival disadvantages. Such high-risk subsets may benefit from durable mechanical circulatory support consideration. PMID- 30248796 TI - Eating well at your first job. PMID- 30248797 TI - Polymer cable tie closure of the sternum: Is it an acceptable fix? PMID- 30248798 TI - Cable ties for chest closure: ZipFix or ZipFail? PMID- 30248799 TI - To zip or wire: An ongoing debate. PMID- 30248800 TI - Amplifying art of valve design by science. PMID- 30248801 TI - Innovation and science: The future of valve design. PMID- 30248802 TI - Molecular (pathologic) markers of tumor invasiveness = more or less (clinical) malignant adenocarcinomas? Wait a second, we are not there yet! PMID- 30248803 TI - Effect of virtual-assisted lung mapping in acquisition of surgical margins in sublobar lung resection. AB - OBJECTIVE: Virtual-assisted lung mapping is a preoperative bronchoscopic multi spot dye-marking technique. This study aimed to examine the efficacy of virtual assisted lung mapping for obtaining sufficient surgical margins in sublobar lung resection. METHODS: The multicenter, prospective, single-arm study was conducted from September 2016 to July 2017 in 19 registered centers. Patients who required sublobar lung resection and careful determination of resection margins underwent virtual-assisted lung mapping followed by thoracoscopic surgery. Successful resection was defined as resection of the lesion with margins greater than the lesion diameter or 2 cm using the preoperatively planned resection without additional resection. We defined the primary goal of the study as achieving successful resection in 95% of lesions. RESULTS: The resection of 203 lesions (average diameter, 9.6 +/- 5.3 mm) was intended in 153 patients. The lesions included pure and mixed ground-glass nodules (75 [35.9%] and 36 [17.2%], respectively), solid nodules (91 [43.5%]), and others (7 [3.3%]). Surgical procedures included wedge resection (131, 71.2%), segmentectomy (51, 27.7%), and others (2, 1.1%). Successful resection was achieved in 178 lesions (87.8% [95% confidence interval, 82.4-91.9%]), and virtual-assisted lung mapping markings successfully aided in the identification of 190 lesions (93.6% [95% confidence interval, 89.3-96.5%]). Multivariable analysis showed that the most significant factor affecting resection success was the depth of the necessary resection margin (P = .0072). CONCLUSIONS: This study showed that virtual-assisted lung mapping has reasonable efficacy, although the successful resection rate did not reach the primary goal. The depth of the required margin was the most significant factor leading to resection failure. PMID- 30248804 TI - Time for the science of pneumonectomyology. PMID- 30248805 TI - From standardization to personalized medicine: Moving beyond cookie-cutter treatment of esophageal cancer. PMID- 30248806 TI - No sweat: Favorable outcomes of hyperhidrosis surgery with age. PMID- 30248807 TI - Notice of Correction. PMID- 30248808 TI - Letter to the Editor Regarding "Endovascular Patch Embolization for Blood Blister Like Aneurysms in Dorsal Segment of Internal Carotid Artery". PMID- 30248809 TI - Management of Broken Pedicle Screws. PMID- 30248810 TI - Letter to the Editor Regarding "Perineural Spread Along Spinal and Obturator Nerves in Primary Vaginal Carcinoma: A Case Report". PMID- 30248811 TI - Reliability and Agreement of Different Spine Fracture Classification Systems: Methodologic Issue. PMID- 30248812 TI - In Reply to "Reliability and Agreement of Different Spine Fracture Classification Systems: Methodologic Issue". PMID- 30248813 TI - Letter to the Editor Regarding "Percutaneous Full-Endoscopic Anterior Transcorporeal Procedure for Cervical Disc Herniation: A Novel Procedure and Early Follow-Up Study". PMID- 30248815 TI - Joy of Learning: Mammilotegmental Tract Connecting 2 Circuits of Memory and Pleasure in Brain. PMID- 30248814 TI - In Reply to the Letter to the Editor Regarding "Percutaneous Full-Endoscopic Anterior Transcorporeal Procedure for Cervical Disc Herniation: A Novel Procedure and Early Follow-Up Study". PMID- 30248816 TI - In Reply to "Joy of Learning: Mammilotegmental Tract Connecting 2 Circuits of Memory and Pleasure in Brain". PMID- 30248817 TI - Overestimated Role of Extracranial-to-Intracranial Bypass in Management of Blood Blister Aneurysm. PMID- 30248818 TI - In Reply to "Overestimated Role of Extracranial-to-Intracranial Bypass in Management of Blood-Blister Aneurysm". PMID- 30248819 TI - Statin Use in Patients Undergoing Carotid Artery Endarterectomy May Significantly Reduce the Occurrence of 30-Day Stroke and Myocardial Infarction. PMID- 30248820 TI - In Reply to "Statin Use in Patients Undergoing Carotid Artery Endarterectomy May Significantly Reduce the Occurrence of 30-day Stroke and Myocardial Infarction". PMID- 30248821 TI - Letter to the Editor Regarding "Unusual Magnetic Resonance Imaging Findings of a Glioblastoma Arising During Treatment with Lenvatinib for Thyroid Cancer". PMID- 30248823 TI - Sully, Simulation, and Neurosurgery. PMID- 30248822 TI - Dynamic Intraoperative Assessment of Draining Veins in Parasagittal Meningiomas: Changing the Paradigm? PMID- 30248824 TI - Doctor, don't Abandon Your Patient. PMID- 30248826 TI - Short-term effects of ambient air pollution exposure on lung function: A longitudinal study among healthy primary school children in China. AB - BACKGROUND: Short-term exposure to ambient air pollution has been associated with reduced lung function among asthmatic children. However, there is little information about the effects among healthy children, especially in areas with relatively high exposure background. OBJECTIVE: To examine the association between short-term effects of ambient air pollutants and lung function among healthy primary school-aged children in China. METHODS: A total of 334 healthy children (7-11 years) from four cities (Chengdu (Southwest China), Guangzhou (Southern China), Wuhan (Central China), and Xi'an (Northwest China)) in China with repeated lung function measurement in 2014-2016 were included. Daily ambient concentrations of PM2.5, PM10, NO2, SO2, mean temperature, and relative humidity data were obtained. Linear mixed model was used to estimate the percent change in lung function associated with per inter-quartile range (IQR) exposure (up to 3 days) increase after adjusting for confounders. RESULTS: Ambient PM2.5 and PM10 exposure were associated with decrements in lung function measurements. The moving average exposures generally showed stronger effect estimates than the single lag day exposures. An IQR increase in two-day average (lag01 day) PM10 exposure (IQR, 144 MUg/m3) was significantly associated with 2.56% decrease in FVC, 5.46% in FEV1, 4.23% in PEF, and 7.35% in FEF25%, respectively. The effect estimates were stronger after adjusting for gaseous pollutants in particulate matter (PM) models. The strengths of these associations were stronger in girls than those in boys. CONCLUSION: Short-term exposure to PM was associated with reduced lung function in healthy children. The estimated adverse effects were greater in girls than in boys. PMID- 30248827 TI - Coffea canephora silverskin from different geographical origins: A comparative study. AB - Coffee silverskin is the major by-product of coffee roasting. Among all the coffee by-products, it is a relatively stable product due to its low moisture content. Currently, silverskin is used as direct fuel (e.g. firelighters), for composting and soil fertilization. As it is a natural source of several bioactive compounds that can be extracted and further used for food or dermocosmetic purposes, the valorization of this by-product is of utmost importance, having in view the sustainability and circular economy principles. The aim of this work was to evaluate, for the first time, the influence of different geographical origins (Brazil, Uganda, Vietnam, Cameroon, Indonesia, and India) on the chemical composition of silverskin obtained from Coffea canephora beans. Different parameters were analysed, including ashes, protein, soluble and insoluble fiber, and total lipid amounts; vitamin E, fatty acid and phenolics profiles (by HPLC DAD-FLD, GC-FID, and HPLC-DAD, respectively); caffeine, 5-caffeoylquinic acid and hydroxymethyfurfural contents (by HPLC-DAD); and antioxidant profile (total phenolics and flavonoids contents, DPPH inhibition, and Ferric Reducing Antioxidant Power). Significant differences (p < 0.05) were found between the samples, especially regarding the fatty acid profile and the antioxidant composition. For instance, the Brazilian silverskin was the richest in total lipids and vitamin E, while the Indian silverskin was the poorest in phenolics and antioxidant activity, and presented a higher relative percentage of saturated fatty acids. A Principal Component Analysis allowed to group the studied samples according to their geographical proximity. PMID- 30248825 TI - Identifying aerosolized cyanobacteria in the human respiratory tract: A proposed mechanism for cyanotoxin-associated diseases. AB - Cyanobacteria produce harmful toxins that have been associated with several acute conditions and chronic human diseases, like gastroenteritis, non-alcoholic liver disease, and amyotrophic lateral sclerosis. Aerosol from waterbodies appears to be a likely mechanism for exposure. We conducted a study of human biospecimens focused on the cyanobacterial aerosilization process by evaluating the extent to which cyanobacteria can invade the human respiratory tract. Our study suggests that humans routinely inhale aerosolized cyanobacteria, which can be harbored in the nostrils and the lungs. Using PCR, cyanobacteria were found at high frequencies in the upper respiratory tract (92.20%) and central airway (79.31%) of our study subjects. Nasal swabs were not predictive of bronchoalveolar lavage (BAL) when detecting inhaled cyanobacteria. Interestingly, we found no evidence that time of year was a significant factor for cyanobacteria positivity (BAL cytology p = 1.0 and PCR p = 1.0); (nasal swab cytology p = 0.051 and PCR p = 0.65). Additionally, we found that proximity to a waterbody was not a significant factor for cyanobacteria positivity in BAL and nasal swabs collected during cyanobacteria bloom season [May-October] (p = 0.46 and p = 0.38). These data suggest that cyanobacteria exposure may be a prevalent and chronic phenomenon not necessarily restricted to waterbodies alone. Sources of indoor exposure warrant future investigation. Given the widespread prevalence of cyanobacterial exposure in the airway, investigation of the aerosol spread of cyanotoxins, more specifically, is warranted. Our findings are consistent with the hypothesis that aerosol is a significant route for cyanobacteria exposure, and thus a likely route of transmission for cyanotoxin-associated human diseases. PMID- 30248828 TI - Studies of the effects of microplastics on aquatic organisms: What do we know and where should we focus our efforts in the future? AB - The effects of microplastics (MP) on aquatic organisms are currently the subject of intense research. Here, we provide a critical perspective on published studies of MP ingestion by aquatic biota. We summarize the available research on MP presence, behaviour and effects on aquatic organisms monitored in the field and on laboratory studies of the ecotoxicological consequences of MP ingestion. We consider MP polymer type, shape, size as well as group of organisms studied and type of effect reported. Specifically, we evaluate whether or not the available laboratory studies of MP are representative of the types of MPs found in the environment and whether or not they have reported on relevant groups or organisms. Analysis of the available data revealed that 1) despite their widespread detection in field-based studies, polypropylene, polyester and polyamide particles were under-represented in laboratory studies; 2) fibres and fragments (800-1600 MUm) are the most common form of MPs reported in animals collected from the field; 3) to date, most studies have been conducted on fish; knowledge is needed about the effects of MPs on other groups of organisms, especially invertebrates. Furthermore, there are significant mismatches between the types of MP most commonly found in the environment or reported in field studies and those used in laboratory experiments. Finally, there is an overarching need to understand the mechanism of action and ecotoxicological effects of environmentally relevant concentrations of MPs on aquatic organism health. PMID- 30248829 TI - Where will threatened migratory birds go under climate change? Implications for China's national nature reserves. AB - Climate change, regarded as one of the major threats to biodiversity and ecosystems, can impact on the distribution and survival of migratory birds. To investigate the threats of climate change to threatened migratory bird distributions, we used species distribution model (SDM) and climatic data under current and future climate scenarios to predict future changes in species distributions and how the geographic distribution of these threatened birds may respond to climate change by 2050. Our results show the hotspots for all species may remain in the lower and middle reaches of the Yangtze River, while more species may dwell in the coastal regions of the Bohai Gulf and the Yellow Sea in the future. Our findings show that the percentage of all species distributions or hotspots for all threatened species covered by national nature reserves (NNRs) in China remain low by 2050. Thus, we propose that China should increase and expand reserves in eastern China. Significantly, we emphasize the creation of protected areas to make it the Ramsar sites in the world and recommend that China should (1) strengthen the cooperation with neighboring countries to share maximum species occurrence data (especially the threatened species), (2) overlay maps of individual species for each taxon to assess the efficiency of coastal nature reserves and predict the hotspots shift under climate change, (3) trade off urban development and ecosystem stability to create new and dynamic protected areas to make it the Ramsar sites, (4) appeal for long-term protection of ecosystem stability to achieve sustainable development in the world. PMID- 30248830 TI - Macro- and micro- plastics in soil-plant system: Effects of plastic mulch film residues on wheat (Triticum aestivum) growth. AB - Plastic residues have become a serious environmental problem in the regions with intensive use of plastic mulching. Even though plastic mulch is widely used, the effects of macro- and micro- plastic residues on the soil-plant system and the agroecosystem are largely unknown. In this study, low density polyethylene and one type of starch-based biodegradable plastic mulch film were selected and used as examples of macro- and micro- sized plastic residues. A pot experiment was performed in a climate chamber to determine what effect mixing 1% concentration of residues of these plastics with sandy soil would have on wheat growth in the presence and absence of earthworms. The results showed that macro- and micro- plastic residues affected both above-ground and below-ground parts of the wheat plant during both vegetative and reproductive growth. The type of plastic mulch films used had a strong effect on wheat growth with the biodegradable plastic mulch showing stronger negative effects as compared to polyethylene. The presence of earthworms had an overall positive effect on the wheat growth and chiefly alleviated the impairments made by plastic residues. PMID- 30248832 TI - Analysis of future climate change impacts on snow distribution over mountainous watersheds in Northern California by means of a physically-based snow distribution model. AB - The impacts of climate change on snow distribution through the 21st century were investigated over three mountainous watersheds in Northern California by means of a physically-based snow distribution model. The future climate conditions during a 90-year future period from water year 2010 to 2100 were obtained from 13 future climate projection realizations from two GCMs (ECHAM5 and CCSM3) based on four SRES scenarios (A1B, A1FI, A2, and B1). The 13 future climate projection realizations were dynamically downscaled at 9 km resolution by a regional climate model. Using the downscaled variables based on the 13 future climate projection realizations, snow distribution over the Feather, Yuba, and American River watersheds (FRW, YRW, and ARW) was projected by means of the physically-based snow model. FRW and YRW watersheds cover the main source areas of the California State Water Project (SWP), and ARW is one of the key watersheds in the California Central Valley Project (CVP). SWP and CVP are of great importance as they provide and regulate much of the California's water for drinking, irrigation, flood control, environmental, and hydro-power generation purposes. Ensemble average snow distribution over the study watersheds was calculated over the 13 realizations and for each scenario, revealing differences among the scenarios. While the snow reduction through the 21st century was similar between A1B and A2, the snow reduction was milder for B1, and more severe for A1FI. A significant downward trend was detected in the snowpack over nearly the entire watershed areas for all the ensemble average results. PMID- 30248831 TI - Air pollution, land use, and complications of pregnancy. AB - BACKGROUND: Mounting evidence suggests that the natural and built environment can affect human health, but relatively few studies have considered links between features of the residential natural and built environment other than air pollution and complications of pregnancy. OBJECTIVES: To quantify the impact of features of the maternal residential natural and built environments on risk of gestational diabetes mellitus (GDM), gestational hypertension and preeclampsia among 61,640 women who delivered at a single hospital in Rhode Island between 2002 and 2012. METHODS: We estimated residential levels of ambient fine particulate matter (PM2.5) and black carbon (BC) using spatiotemporal models, neighborhood green space using remote sensing and proximity to recreational facilities, and neighborhood blue space using distance to coastal and fresh water. We used logistic regression to separately estimate the association between each feature and GDM, gestational hypertension, and preeclampsia, adjusting for individual and neighborhood markers of socioeconomic status. RESULTS: GDM, gestational hypertension, and preeclampsia were diagnosed in 8.0%, 5.0%, and 3.6% of women, respectively. We found 2nd trimester PM2.5 (OR = 1.08, 95% CI: 1.00, 1.15 per interquartile range increase in PM2.5) and living close to a major roadway (1.09, 95% CI: 1.00, 1.19) were associated with higher odds of GDM, while living <1 km from the coast was associated with lower odds of GDM (0.87, 95% CI: 0.78, 0.96). Living <500 m from a recreational facility was associated with lower odds of gestational hypertension (0.89, 95% CI: 0.80, 0.99). None of these features were associated with odds of preeclampsia. Results were qualitatively similar in mutually-adjusted models and sensitivity analyses. CONCLUSIONS: In this small coastal US state, risk of GDM was positively associated with PM2.5 and proximity to busy roadways, and negatively associated with proximity to blue space, highlighting the importance of the natural and built environment to maternal health. PMID- 30248833 TI - Hydrological response of a large-scale mountainous watershed to rainstorm spatial patterns and reforestation in subtropical China. AB - This paper aims to investigate the hydrological response of a large-scale (8973 km2) mountainous watershed to different rainstorm spatial patterns and reforestation. Based on 32 years of observations, measurements of 184 rainstorm events and 125 sediment-producing events with complete hydrographs were analyzed. The K-means clustering method was used to classify the spatial patterns of rainstorm events in accordance with their event-based spatial rainfall characteristics. The 184 rainstorm events were classified into four spatial patterns, among which the spatial features differ significantly: (I) Spatial Pattern I (SPI) includes rainstorms with a low amount of cumulative areal rainfall (27.4 mm), the highest spatial variability (0.986), and the highest frequency; (II) Spatial Pattern II (SPII) includes rainstorms of high spatial variability (0.759) and the largest amount of local maximum daily rainfall (106.8 mm); (III) Spatial Pattern III (SPIII) includes rainstorms with a medium amount of cumulative areal rainfall (58.7 mm) and low spatial variability (0.362); and (IV) Spatial Pattern IV (SPIV) includes rainstorms with the largest amount of cumulative areal rainfall (117.2 mm) and the lowest spatial variability (0.313). Vegetation cover in the upper Du watershed was significantly improved after the implementation of the Grain-for-Green project. The average area-specific sediment yields (SSY) for the four SPs were 15.4, 65.5, 55.8, and 286.2 t km-2 before reforestation and decreased to 6.0, 59.3, 43.7 and 89.9 t km-2, respectively, after reforestation. ANOVA (analysis of variance) indicated that reforestation resulted in a significant reduction in runoff coefficient under SPIII and SPIV and a significant reduction in SSY under SPI and SPIV. A hysteresis analysis suggested that the proportion of events with a clockwise loop increased from 64.9% before reforestation to 82.1% after reforestation and that complex loops became less common during 2000-2010 under SPIV, thereby implying a reduced sediment supply. PMID- 30248834 TI - Bacteria from nodules of wild legume species: Phylogenetic diversity, plant growth promotion abilities and osmotolerance. AB - The demand for food with high nutritional value that can sustain the growth of human population while safeguarding sustainability deserves urgent attention. A possible strategy is the inoculation of crops with plant growth promoting (PGP) bacteria. Plants are naturally colonized by bacteria that can exert beneficial effects on growth and stress tolerance. N2 fixation by rhizobia in the root nodules of legumes is a well-known PGP effect. These bacteria can be used as inoculants to boost legumes productivity and can be especially interesting if they are able to survive to abiotic stresses, such as drought. Herein we report the phylogenetic diversity of bacteria colonizing the root nodules of several wild legume species, from four geographic locations in Portugal with different bioclimates. Interestingly, the vast majority of strains belonged to Flavobacterium, Pseudomonas and other genera apart from rhizobia. PGP abilities other than N2 fixation (production of indol acetic acid, siderophores and volatile organic compounds) and osmotolerance were screened. Location and host plant species did not influence PGP abilities and osmotolerance. Taken together, results evidenced that bacterial strains from wild legumes displaying PGP abilities and osmotolerance can be regarded as good candidates for inoculants of a broad range of hosts, including non-legumes. PMID- 30248835 TI - Toxicity of copper oxide nanoparticles on spring barley (Hordeum sativum distichum). AB - The rapid growth of copper oxide nanoparticles (CuO NPs) production and its abundant uses in many industries, and increasing release into an environment from both intentional and unintentional sources, create risks to spring barley (Hordeum sativum distichum), one of the most important staple food crop. Thereby, the aim of this study was to investigate the phytotoxicity of CuO NPs on H. sativum growth in hydroponic system. The CuO NPs inhibited H. sativum growth by affecting the germination rate, root and shoot lengths, maximal quantum yield of photosystem II, and transpiration rate. Structural and ultrastructural examination of H. sativum tissues using light, transmission and scanning electron microscopy showed effects on stomatal aperture and root morphology, metaxylem size and changes in cellular organelles (plastids, mitochondria), as well as in plastoglobules, starch granules, protoplasm, and membranes. The formation of electron-dense materials was noted in the intercellular space of cells of CuO NPs treated plants. In addition, relative root length was one-third (35%) that of the control, and relative shoot length (10%) was also reduced. Further, the Cu content of roots and leaves of CuO NPs-treated plants was 5.7 and 6.4-folds higher than the control (without CuO NPs), respectively. Presented data were significant at p <= 0.05 compared to control. Conclusively, the results provide insights into our understanding of CuO NPs toxicity on H. sativum, and findings could be used for developing strategies for safe disposal of NPs. PMID- 30248836 TI - Indicators of marine ecosystem integrity for Canada's Pacific: An expert-based hierarchical approach. AB - There is great interest and rapid progress around the world in developing sets of indicators of marine ecosystem integrity for assessment and management. However, the complexity of coastal marine ecosystems can challenge such efforts. To address this challenge, an expert-based, hierarchical, and adaptive approach was developed with the objectives of healthy marine ecosystems and community partnerships in monitoring and management. Small sets of the top-ranked indicators of ecosystem integrity and associated human pressures were derived from expert-rankings of lists of identified candidate indicators of the status of, and pressures on, each of 17 ecosystem features, organized within 8 elements in turn within 3 overlapping aspects of ecosystem health. Over 200 experts played a role in rating the relative value of 1035 candidate indicators. A panel of topic experts was assigned to each of the 17 ecosystem features to apply 21 weighted indicator selection criteria. Selection criteria and candidate indicators were identified through literature reviews, expert panels, and surveys, and they were evaluated in terms of the experts' judgements of importance to the health of Canada's Pacific marine ecosystems. This produced a flexible, robust, and adaptable approach to identifying representative sets of indicators for any scale and for any management unit within Canada's Pacific. At the broadest scale, it produced a top 20 list of ecosystem state and pressure indicators. These top indicators, or other sets selected for smaller regions, can then guide the development of both regional and nested local monitoring programs in a way that maximizes continuity while including locally unique values. This hierarchical expert-based approach was designed to address challenges of complexity and scale and to enable efficient selection of useful and representative sets of indicators of ecosystem integrity while also enabling the participation of broad government and stakeholder communities. PMID- 30248837 TI - Priority and emerging pollutants in the Moscow rain. AB - Air quality is a worldwide problem. Nowadays, thousands of chemicals may be found in the atmosphere from biogenic and anthropogenic sources due to numerous atmospheric reactions. Unfortunately, throughout the world only a small group of organic compounds is monitored on a regular basis. Therefore, an important environmental task involves discovering the most important pollutants for particular cities and regions for regular monitoring in the future. Direct measurements of contaminants in the atmosphere are not always efficient as air represents an extremely dynamic medium. Thus indirect analysis by using precipitations becomes a more popular method of environmental analysis. Over 700 organic compounds belonging to the various classes of chemicals were identified in the Moscow rainwater samples collected in the spring of 2017 using GC/MS instruments including the most analytically powerful modern technique - GC * GC HRMS. Here we report the nature and levels of 160 priority pollutants and emerging contaminants belonging to the most relevant classes from the environmental point of view: polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organophosphates, dialkylphthalates, phenols, and alkylpyridines. This is the first work dealing with GC-MS analysis of the rainwater in Moscow (Russia). PMID- 30248838 TI - Organophosphate pesticide exposure and differential genome-wide DNA methylation. AB - BACKGROUND: Organophosphates (OP) are widely used insecticides that acutely inhibit acetylcholinesterase enzyme activity. There is great interest in improving the understanding of molecular mechanisms related to chronic OP exposure induced toxicity. We aim to elucidate epigenetic changes associated with OP exposure, using untargeted analysis of genome-wide DNA methylation data. METHODS: In a population-based case control study of Parkinson's disease (PD), we assessed ambient OP exposure via residential and workplace proximity to commercial applications. We investigated associations between OP exposure and genome-wide DNA methylation (Illumina 450 k) in 580 blood samples (342 PD patients, 238 controls) and 259 saliva samples (128 patients, 131 controls). To identify differential methylation related to OP exposure, we controlled for age, sex, European ancestry, and PD status; in addition, we stratified by disease status. RESULTS: We identified 70 genome-wide significant CpGs, including cg01600516 in ALOX12 (cor = 0.27, p = 1.73E-11) and two CpGs in HLA genes, cg01655658 (cor = -0.24, p = 2.80E-09) in HLA-L (pseudogene) and cg15680603 (cor = 0.20, p = 7.94E-07) in HLA-DPA1. Among the 70 CpGs located in 41 genes, 14 were also differentially methylated in saliva samples. The most overrepresented pathway was the nicotinic acetylcholine receptor signaling pathway (fold enrichment = 15.63, p = 1.01E-03, FDR = 1.64E-01). Expanding to a larger number of genes (CpG p < 5E-04, FDR < 2.25E-01; 1077 CpGs, 662 genes), the most enriched pathway shifted to the muscarinic acetylcholine receptor 1 and 3 signaling pathway (p-value = 5.36E-04, FDR = 4.73E-02). When we stratified by PD status, results were similar. Of the 70 significant CpGs, 63 were detected among both patients and controls and 7 were only associated with OP exposure among patients. CONCLUSIONS: This study finds chronic low-level OP exposure is associated with differential DNA methylation in blood and saliva, both in elderly population controls and PD patients. Our study results suggest that long-term sub-acute OP exposure influences methylation in genes enriched for muscarinic and nicotinic acetylcholine receptor pathways. PMID- 30248839 TI - Electronics, interior decoration and cleaning patterns affect flame retardant levels in the dust from Dutch residences. AB - Consumer products such as furniture foam and electronic device casings are treated with flame retardant chemicals (FRs) to prevent the spread of fire. Many FRs are able to leach out of a product and end up in house dust. FRs in house dust can be taken up by humans through inhalation, ingestion or dermal adsorption. This study aims to identify factors in the home environment that are associated with FR levels in house dust. House dust and a wide range of data on characteristics of electronics, including age and use, interior decoration, domestic house and cleaning patterns, were collected from 50 households in the Netherlands. Decabromodiphenyl ether (BDE209) and several organophosphate flame retardants were measured in dust at detection percentages ranging from 58 to 94%, with median concentrations ranging from 32 ng/g (resorcinol bis(diphenyl)phosphate (PBDPP)) to 825 ng/g (tris(chloropropyl)phosphate (TCIPP)). For the first time, age, hours of operation and use of the standby function of electronic devices were found to affect FR levels in dust. We found that if the total number of electronic devices purchased before 2008 increased by 1 device, BDE209 levels in house dust significantly increased by 66%. In addition, house dust from homes with carpeted floors was significantly associated with a 70-80% lower concentration of several FRs compared to homes with smooth floors (e.g., laminate). Less frequent vacuum cleaning and dusting were significantly associated with 41 to 88% higher concentrations of several FRs in dust. These associations suggest that actions such as frequent vacuum cleaning and dusting as well as different FR regulations for electronic devices affect indoor exposure levels. PMID- 30248840 TI - Colloidal stabilization of CeO2 nanomaterials with polyacrylic acid, polyvinyl alcohol or natural organic matter. AB - Engineered nanomaterials (ENM) such as nano-sized cerium dioxide (CeO2) are increasingly applied. Meanwhile, concerns on their environmental fate are rising. Understanding the fate of ENM within and between environmental compartments such as surface water and groundwater is crucial for the protection of drinking water resources. Therefore, the colloidal stability of CeO2 ENM (2 mg L-1) was assessed with various surface coatings featuring different physico-chemical properties such as weakly anionic polyvinyl alcohol (PVA), strongly anionic polyacrylic acid (PAA) or complex natural organic matter (NOM) at various water compositions in batch experiments (pH 2-12, ionic strength 0-5 mM KCl or CaCl2). While uncoated CeO2 ENM aggregate in the range of pH 4-8 in 1 mM KCl solution, the results show that PAA, PVA and NOM surface coatings stabilize CeO2-ENM at neutral and alkaline pH in 1 mM KCl solution. Stabilization by PAA and NOM is associated with strongly negative zeta potentials below -20 mV, suggesting electrostatic repulsion as stabilization mechanism. No aggregation was detected up to 5 mM KCl for PAA- and NOM-coated CeO2 ENM. In contrast, CaCl2 induced aggregation at >2.2 mM CaCl2 for PAA and NOM-coated CeO2 ENM respectively. PVA-coated ENM showed zeta potentials of -15 mV to -5 mV in the presence of 0-5 mM ionic strength, suggesting steric effects as stabilization mechanism. The hydrodynamic diameter of PVA-coated ENM was larger compared to PAA and NOM at low ionic strength, but the size did not increase with ionic strength of the suspensions. The effect of ionic strength and counter ion valency (pH 7) on the colloidal stability of ENM depends on the prevailing stabilization mechanism of the organic coating. NOM can be similarly effective in colloidal stabilization of CeO2-ENM as PAA. Our results suggest natural Ca-rich waters will lead to ENM agglomeration even of coated CeO2-ENM. PMID- 30248841 TI - Hydrogeochemical evidences for targeting sources of safe groundwater supply in arsenic-affected multi-level aquifer systems. AB - Delineation of safe aquifers becomes highly imperative and challenging to ensure sustainable drinking water supply in rural areas of multi-level aquifer systems with complex water circulation under the impact of both geogenic and anthropogenic contamination. This work characterized hydrogeological and hydrogeochemical features of a multi-level Quaternary aquifer system of the central Yangtze River Basin to search for evidences of locating aquifers least contaminated. The results indicate modern hydrologic cycling is active in shallow phreatic aquifer (SPA) and in upper part of middle confined aquifer (MCA-1). The lower part of middle confined aquifer (MCA-2) and deep confined aquifer (DCA) have ages ranging from 200 to 2000 years and 4000 to >20,000 years, respectively. Vertical variations of hydrochemical compositions and Cl/Br ratios suggest the gradually decreasing and increasing contribution with depth from anthropogenic activities and natural water-mineral interactions, respectively. The SPA is characterized by high levels of anthropogenic components (Cl-, SO42-, NO3-, organic pesticides and antibiotics). The MCA-1 is the main aquifer where most private tube wells were installed, typically contains geogenic As, Fe, Mn and NH4+ at concentration levels several hundred times higher than the national drinking water standard values. Organic-abundant geochemical and stagnant hydrogeological conditions favor their enrichment. Both MCA-2 and DCA are slightly influenced by geogenic contamination and groundwater pumping from public wells screened in MCA-2 does not or slightly perturbs the groundwater flow condition in MCA-2 and DCA. The cost-effective water supply strategy is either to maintain safe yield of groundwater from public wells screened in MCA-2, or to use the groundwater after simple filtration and aeration treatment in case that groundwater pumping in MCA-2 were over a "safe yield" or induced leakage of groundwater containing As, Fe, Mn and NH4+ from the overlying MCA-1. And DCA could serve as a source for water supply under emergency circumstances. PMID- 30248842 TI - Spatiotemporal variability of hydrocarbons in surface sediments from an intensively human-impacted Xiaoqing River-Laizhou Bay system in the eastern China: Occurrence, compositional profile and source apportionment. AB - : Hydrocarbons in coastal sediments record organic matter sources, and thus are widely used to elucidate both natural and anthropogenic inputs and for the estimation of pollution levels. Surface sediments were taken from Xiaoqing River and Laizhou Bay of eastern China in spring and summer of 2014, and were analyzed to determine the characteristics of aliphatic and aromatic hydrocarbons. Various hydrocarbons were identified, including n-alkanes, monomethylated alkanes (MMAs), isoprenoid alkanes, linear alkylbenzenes (LABs), hopanes, steranes and polycyclic aromatic hydrocarbons (PAHs). They were used to track both biogenic (terrestrial plant and microbial inputs) and anthropogenic inputs (petroleum and fossil fuel or biomass burning) in this ecosystem. The major part of hydrocarbons identified came from anthropogenic inputs including petroleum residues and synthetic detergents related hydrocarbons (16.2-90.3%), followed by higher plant (4.5 80.5%) and microbial inputs (0.8-57.5%). Interestingly, significant differences in hydrocarbon concentrations and distributions were observed between spring and summer. In particular, significant higher percentages of microbially derived hydrocarbons, but lower percentages of anthropogenic and vascular plant derived hydrocarbons were observed in summer than spring. Further principal component analyses suggested that the overall distribution of aliphatic hydrocarbons was mainly controlled by seasonality instead of spatiality. In contrast, the distribution of PAHs showed insignificant spatial and seasonal differences. Physical processes such as atmospheric transportation and further deposition, may be factors influencing the distribution of PAHs in the study area with widely biomass and fossil fuel burning. The decoupled distributions of aliphatic and aromatic hydrocarbons warrant further study for a comprehensive understanding of long term sedimentary hydrocarbon sources and input dynamics with increasing human activities. MAJOR FINDING: Seasonal difference in aliphatic hydrocarbon composition was observed in surface sediments of Laizhou Bay, which is mainly caused by stronger phytoplankton and microbial inputs in summer under the overall high pollution background. PMID- 30248843 TI - Effects of irrigation on water and energy balances in the Heihe River basin using VIC model under different irrigation scenarios. AB - Investigations of the water and energy balance in large river basins is one of the most important and contemporary issues, which is helpful to guide agricultural production and regional water resource management. Traditionally, water and energy balance have been assessed by field-scale experiments. However, it is not easy to find the effective ways for a whole region using limited observed data from on-farm experiments. In our study, the effects of irrigation water on surface water and energy balance fluxes are examined by employing the Variable Infiltration Capacity (VIC) model and irrigation scheme, for the upper and middle reaches of the Heihe River Basin in Northwest China. The model simulations are calibrated and validated using both streamflow records at a gauge station and eddy covariance observations at two stations. Besides, three irrigation scenarios are set as full irrigation, 90% and 75% of irrigation water requirement (IWR). The results showed the infiltration curve parameter (b) and the thickness of lower soil moisture layer (d2) are the most sensitive model parameters. Long-term irrigation activities lead to a greater evapotranspiration (or latent heat). With considering local irrigation water-using coefficient for the period 2001-2010 of 0.527, the total IWR is about 2.81 * 109 m3/year (the net IWR is about 1.48 * 109 m3/year). Compared with the no-irrigation baseline, the increase in latent heat flux (about 4.45 W/m2) or the significant decrease in Bowen Ratio (about 1.05) due to full irrigation activities is accompanied by a decrease in annual average surface temperature (about 0.076 degrees C) for the middle reaches of the Heihe River basin during the 10-year period. PMID- 30248844 TI - A novel concept for syngas biomethanation by two-stage process: Focusing on the selective conversion of syngas to acetate. AB - Thermal gasification of nonrenewable and renewable sources produces syngas, containing CO, H2, CO2 and N2. Anaerobic conversion of syngas to CH4 is a promising way to replace natural gas. However, the high N2 content (>50%) in syngas would result in the low CH4 content in the biogas and CO in syngas also had serious inhibition on methanogens. The present study proposed a two-stage anaerobic process for syngas biomethanation, and syngas was first anaerobically converted to acetate by mixed culture, which could be further converted to methane easily without the negative effects of N2 and CO. The results showed that mesophilic condition was more suitable for the conversion of syngas to acetate compared to thermophilic and ambient conditions at pH 5.5 considering the higher acetate yield and syngas conversion rate. Although CO was efficiently converted at thermophilic condition, it was mostly converted to H2, which was then converted to acetate. CO was much easier to be converted compared to H2. Further study showed that pH 6.5 and 7.5 were optimal for selective conversion of syngas to acetate. The other products including butyrate and ethanol were also detected in relatively higher amounts at pH 4.5 and 9.5. Although pH 5.5 and 8.5 had relatively lower syngas conversion rates compared to pH 6.5 and 7.5, they might inhibit methanogens naturally without adding methane inhibitors. Finally, batch experiments showed that the acetate concentration had obvious inhibition on syngas conversion when the acetate concentration was higher than 2 g/L. PMID- 30248845 TI - Environmental controls on the abundance of methanotrophs and methanogens in peat bog lakes. AB - The aim of the present study was to identify the factors that influence the composition of methanogens and methanotrophs in the background prokaryotic community in peat bog lakes. We hypothesized that the microbial composition is a function of the physicochemical conditions of the water and a function of depth dependent oxygen (DO) concentrations. To address this aim, we collected water samples from subsurface and near-bottom layers, representing oxic and anoxic conditions in 4 peat bog lakes in NE Poland. The structure of methanogenic Archaea and methane-oxidizing bacteria (MOB) was determined with double labeled fluorescence in situ hybridization (DOPE-FISH). The results showed significant differences in Procaryota communities between the oxic (subsurface) and suboxic/anoxic (near-bottom) layers in peat bog lakes (t-test, p < 0.05). The methanogens from the Archaea domain were observed in anoxic periods, while methanotrophs were present regardless of water depth and season. The abundance of methanogens was inversely correlated with DO and CO2. Methanotrophs adapted better to the changing habitat conditions. The nonmetrical multidimensional scaling (NMS) and partial least square regression (PLS-R) models showed that the methanotrophs in subsurface layers are positively associated with temperature, DOC, and TON while negatively associated with pH. The DO availability is not a prerequisite condition for the presence of methanothrophs. The most important factors for MOB at the bottom were CO2 and TON. Due to a significant role of methanotrophs in the control of the methane emission flux rates, there is a need for further research on factors responsible for methanotroph development in peat bog lakes. PMID- 30248846 TI - Effects of anthropogenic activities on long-term changes of nitrogen budget in a plain river network region: A case study in the Taihu Basin. AB - Over recent decades, Taihu Lake, the third largest freshwater lake in China, has borne the brunt of intensive human activities. Non-point source pollutants and discharges of domestic wastewater are now the main cause of eutrophication. To control non-point source pollution, it is useful to have a good understanding of the spatial and temporal distribution of N (nitrogen). In this study, we applied Export Coefficient Model (ECM) and the Net Anthropogenic Nitrogen Inputs (NANI) method to estimate the N loads in the Taihu Basin at county scale since 1980. We found that N inputs and exports had increased from 6432 and 3170 kg N km-2 yr-1 in 1980 to 9722 and 4582 kg N km-2 yr-1 in 2010, respectively. The 151% increase of N inputs, but 144% increase of riverine N outputs suggested the more N was retained within the Taihu Basin. Both the population density and the urban areas were strongly correlated with N inputs and exports. Approximately 38% of the N inputs were exported in 2010, but only 19% were exported in 1980. This ratio illustrated that human activities, especially urbanization and population growth, have upset N budget in the Taihu Basin. This study supported by empirical models provides a case to demonstrate the N cascade in the Taihu Basin and can also be used to support decision making and to facilitate the development of measures to control N in the future. PMID- 30248848 TI - Long-term organic fertilization increased antibiotic resistome in phyllosphere of maize. AB - Phyllosphere contains various microorganisms that may harbor diverse antibiotic resistance genes (ARGs). However, we know little about the composition of antibiotic resistome and the factors influencing the diversity and abundance of ARGs in the phyllosphere. In this study, 16S rRNA gene amplicon sequencing and high-throughput quantitative PCR approaches were employed to investigate the effects of long-term (over 10 years) organic fertilization on the phyllosphere bacterial communities and antibiotic resistome. Proteobacteria, Bacteroidetes, Actinobacteria and Firmicutes dominated in the phyllosphere bacterial communities. Long-term application of sewage sludge and chicken manure altered the phyllosphere bacterial community composition, with a remarkable decrease in bacterial alpha-diversity. A total of 124 unique ARGs were detected in the phyllosphere. The application of sewage sludge and chicken manure significantly increased the abundance of ARGs, with a maximum 2638-fold enrichment. Variation partitioning analysis (VPA) together with network analysis indicated that the profile of ARGs is strongly correlated with bacterial community compositions. These results improve the knowledge about the diversity of plant-associated antibiotic resistome and factors influencing the profile of ARGs in the phyllosphere. PMID- 30248847 TI - Effect of hydrolyzed protein-based mulching coatings on the soil properties and productivity in a tunnel greenhouse crop system. AB - Polymeric protein-based biocomposites were used in this work as water dispersions to generate, in situ, biobased mulching coatings by spray technique, as alternative to low density polyethylene films for soil mulching. At the end of their lifetime, these biodegradable coatings degrade in soil thank to the microbial community that mineralizes them. Protein hydrolysates (PH) were derived from waste products of the leather industry, while poly(ethylene glycol) diglycidyl ether (PEG) and epoxidized soybean oil (ESO) were used to make the biodegradable spray coatings. A study under greenhouse condition was carried out using seedling test plots in order to investigate the performance of the spray coatings and their possible influence on some aspects of leaf growth, functionality and nutritional quality of lettuce (Lactuca sativa L., Mortarella selection Romanella variety Duende) and on soil properties. The biodegradable coatings showed the same good agronomic performances comparable with the ones of a commercial low density polyethylene mulching film, maintaining the mulching effect for the requested cultivation period and ensuring at the same time a similar rate of plant growth and dry matter accumulation. The research showed that 2 months after the tillage carried out at the end of the cultivation the amount of coating residues present in the soil was <5% of the initial weight of the biodegradable coatings. At the end of the field test, the soil mulched with the polyethylene film recorded an electrical conductivity value lower with respect to the soil mulched with the sprayed coatings, which release nutrients in the soil during their decomposition. PMID- 30248849 TI - Air stagnation in Europe: Spatiotemporal variability and impact on air quality. AB - This paper characterizes the spatiotemporal variability of air stagnation over the Euro-Mediterranean area for the 1979-2016 period by using a simplified air stagnation index (ASI) based on daily precipitation as well as near-surface and upper wind speed data. We have also undertaken the first comparison of stagnation as derived from meteorological reanalysis and observations, finding a reasonably good agreement between both datasets. The main differences arise from the surface wind speed, as this field depends on the local setting of the observational sites and imperfect parameterizations within the reanalysis model. Since air stagnation has considerable spatial heterogeneity over the region, we have regionalized the monthly frequency of stagnant days, resulting five regions with consistent temporal patterns: Scandinavia (SCAN), Northern-Europe (NEU), Central-Europe (CEU), South-West (SW) and South-East (SE). The northern regions (SCAN and NEU), which are affected by moderately strong near-surface winds and ample precipitation, present low frequency and temporal variability in stagnation compared to the southern regions (SW and SE). The winters and summers with the highest stagnation frequency often concur with positive 500 hPa geopotential height anomalies over the regions, with the exception of negative anomalies and a displacement of the extratropical jet to the south in the case of SCAN and NEU during winter. Air stagnation exerts a clear influence on air quality (AQ), with anomalies above 10% for summer ozone (O3) and 30% for winter PM10 (particulate matter <=10 MUm in diameter) on stagnant vs. non-stagnant days over most of the regions. These values exceed 20% and 50%, respectively, in the case of CEU, where air stagnation also drives significant changes in the frequency distributions of these pollutants and increases the likelihood of AQ exceedances. Moreover, persistent and widespread stagnation events favour the build-up of both O3 and PM10 over most of the continent. PMID- 30248850 TI - Lumbriculus variegatus (Annelida) biological responses and sediment sequential extractions indicate ecotoxicity of lake sediments contaminated by biomining. AB - We assessed potential ecotoxicity of lake sediments affected by biomining effluents in northeastern Finland. Growth, reproduction and behavior of the sediment-dwelling oligochaete Lumbriculus variegatus (Muller 1774) were used as ecotoxicity endpoints. Standardized chronic bioassays were used for growth and reproduction, and acute and chronic tests with Multispecies Freshwater Biomonitor (MFB) for behavior assessments. Sequential extractions were used to characterize metal bioavailability and exposure conditions in the sediments, which indicated mining-induced contamination gradients of S, Cu, Ni and U and also bioavailability gradients of S and Ni. Among the ecotoxicity endpoints, growth and reproduction responses of the standard bioassays appeared more sensitive than the behavioral responses at 21 d. In the two most mining-affected test sediments, mean number of worms and dry biomass decreased 35-42% and 46-51% in comparison to the reference sediment, respectively. The behavioral changes of worms, i.e. peristaltic and overall locomotory activity, decreased on average 20-70% and 2 61% at 21 d in the same sediments. However, these behavioral changes were observed at the onset of exposure indicating MFB technique is a suitable and rapid screening level ecotoxicity assessment tool. PMID- 30248851 TI - Development of an analytical methodology for the analysis of priority cytostatics in water. AB - The consumption of cytostatics has remarkably increased over the last years due to the high cancer incidence worldwide. In previous studies, seven cytostatics were already recognized to potentially induce chronic effects in aquatic organisms, taking into account their estimated concentrations in surface waters: cyclophosphamide (CYC), capecitabine (CAP), mycophenolic acid (MPA), imatinib (IMA), bicalutamide (BICA), prednisone (PRED) and 5-fluorouracil (5FU). The objective of the present study was to simultaneously analyse these 7 prioritized compounds, which have the highest chances to be found in surface and wastewaters. The analytical challenge relies in the determination of these very polar compounds, which have different chemical and structural properties. Solid-phase extraction with an Ultra Performance Liquid Chromatograph-Mass Spectrometer in electrospray ionization mixed mode (5-fluorouracil and bicalutamide in negative mode and the others in positive one) was developed to determine seven cytostatics in wastewater and surface water. Among eight tested cartridges with different sorbents and conditions, the best extraction performance was attained with Oasis WAX at pH 10, with recoveries ranging from 31 +/- 4 (5FU) and 103 +/- 17% (MPA). Regarding the chromatographic analysis, the best results were achieved with an XBridge amide column. The final analytical methodology was successfully applied for the analysis of real water samples, confirming the presence of risky cytostatics in surface and wastewaters. PMID- 30248852 TI - Assessment of growth, survival, and organ tissues of caged mussels (Bivalvia: Unionidae) in a river-scape influenced by coal mining in the southeastern USA. AB - The Clinch River contains one of the most diverse freshwater mussel assemblages in the United States, with 46 extant species, 20 of which are listed as federally endangered. In a 91 km section of the Clinch River, mussel densities have severely declined at key sites from 1979 to 2014 (zone of decline), compared to other river sections that support high density and stable mussel populations (zone of stability). Coal mining has occurred in tributary watersheds that drain to the zone of decline since the late nineteenth century. To determine differences in survival, growth, and organ (gills, digestive glands, kidneys, and gonads) tissue health between the river zones, laboratory-propagated mussels were deployed to cages for one year at four sites each within the zones of mussel stability and decline. Means of growth and survival of mussels in the zone of stability were significantly greater than in the zone of decline, and mean fractions of kidney lipofuscin in mussels in the zone of decline was significantly greater than in the zone of stability. Water concentrations of K+, Na+, Al, and Mn were significantly greater in the zone of decline than in the zone of stability. Statistical correlation results indicated that mussel survival was positively associated with concentrations of Mn in water, and kidney lipofuscin was negatively associated with concentrations of dissolved K+, SO42-, and Mg2+. Most concentrations of contaminants were below published benchmark criteria, yet our results suggest that conditions continue to exist in the zone of decline that promote impacts to mussels that are at least partially associated with low concentration coal-related contaminants. More research is needed to determine the additive, synergistic, or antagonistic effects of these complex ionic mixtures on freshwater mussels from river environments, such as in the Clinch River, where constituent concentrations are relatively low. PMID- 30248853 TI - Combating Staphylococcus aureus and its methicillin resistance gene (mecA) with cold plasma. AB - The increase in antibiotic resistance has become a global challenge to public health. In this study, an atmospheric cold plasma (ACP) system was applied for combating methicillin-resistant Staphylococcus aureus (MRSA) and its methicillin resistance gene (mecA) during food wastewater treatment. The plate count and flow cytometry methods were employed to estimate the damage in MRSA induced by plasma treatment. A quantitative real-time PCR (qPCR) method was used to assess the plasma-induced degradation of the mecA genes. The inactivation of MRSA and degradation of extracellular (e-) and intracellular (i-)mecA genes were investigated in phosphate buffered solution as a function of plasma exposure. A relatively low plasma influence of 0.12 kJ/cm2 accounted for 5-log MRSA and 1.4 log e-mecA genes reduction, while only around 0.19-log degradation for i-mecA genes. As the plasma intensity was accumulated to 0.35 kJ/cm2, the reduction of e and i-mecA genes was increased to 2.6 and 0.8 logs, respectively. The degradation of i-mecA genes was much slower than that of e-mecA genes due to the protective effects of the outer envelopes or intracellular components against plasma. The matrix effect of wastewater effluents shielded both antibiotic resistance bacteria (ARB) and antibiotic resistance genes (ARGs) from plasma disinfection, which led to a lower degradation efficacy. Our results could support the development and optimization of plasma-based wastewater treatment. PMID- 30248854 TI - Carbon footprint of main crop production in China: Magnitude, spatial-temporal pattern and attribution. AB - Agricultural management practices that increase carbon (C) sequestration and reduce greenhouse gas (GHG) emissions have been identified as attractive mitigation strategies. In this study, we evaluated the spatial-temporal dynamics of carbon footprints (CFs) in China and their driving factors aimed to analyze potential mitigation strategies. Our CF data comprised the GHG emissions and C sequestration of main crop production. The results indicated that from 2000 to 2015, the GHG emissions of main crop production reached 133.3 Tg CO2-C equivalents (Ce) year-1 and the soil C sequestration was 25.3 Tg Ce year-1, resulting in a CF of 108.0 Tg Ce year-1. In addition, the CF increased by only 1.9%, and 90.9% of the increase in GHG emissions was offset by C sequestration from straw return and fertilization. Moreover, the farm CF (FCF) and product CF (PCF) decreased by 9.7% and 30.4%, respectively, because the proportion of cropland practicing straw return increased by 26.4% and the improved efficiency of fertilization resulting from decrease in fertilizer use of 8 kg nitrogen (N) ha-1 year-1. At the regional scale, GHG emissions increased by 9.1-65.0%, and the primary drivers underlying this change were fertilization, machinery operation and rice paddy CH4 flux in the northeast-northwest, north and south, respectively. However, the PCF decreased by 15.0-47.0% as soil C sequestration increased because of the decreased use of fertilizer and the implementation of straw return. The expansion of straw return and promotion of fertilization efficiency significantly mitigated 25.3 Tg Ce year-1 emissions, indicating that these measures are important mitigation strategies and should be implemented specifically in different regions combined with other management practices. Our study provided a comprehensive method of calculating the CF of croplands and its driving factors in China and indicated potential mitigation strategies that would benefit policy selection for reduced emissions without influencing crop yields. PMID- 30248855 TI - The legitimacy principle within French risk public policy: A reflective contribution to policy analytics. AB - When dealing with public policy in the field of safety, security, and environmental health, legitimacy or illegitimacy is often evoked as a challenge that determines whether a policy will be embraced over time. Scholarly literature points to key variables of public support as well as the use of subject matter experts to build legitimacy in the policy process, yet few articles unpack the meaning and application of legitimacy in a manner that accounts for unique political, institutional, and cultural considerations. This article offers a holistic understanding of the various drivers and challenges behind the legitimacy principle. Specifically, this article reviews how policy successes and failures in France were driven at least in part by a perception of policy legitimacy by policymakers, stakeholders, and the general public. PMID- 30248856 TI - Insight into the sorption mechanism of metformin and its transformation product guanylurea in pastoral soils and model sorbents. AB - Single solute sorption mechanisms of metformin (MET) and guanylurea (GUA) were investigated in six soils and three model sorbents (kaolinite, bentonite and humic acid) at varying initial pH and background electrolyte (Ca2+) concentrations. Electrostatic interaction and cation exchange were proposed as mechanisms of MET sorption. At initial solution pH between pKa1 and pKa2, electrostatic interaction is the dominating mechanism of MET sorption. However, as pH approaches pKa1, cation exchange becomes a significant mechanism of sorption as evidenced by the increased distribution coefficient (Kd) values in Matawhero (130-fold) and Nelson (2000-fold) soils with high cation exchange capacities (CEC) and permanently negative charged sites and when equilibrium pH < pKa1 where the divalent cationic form dominates in the solution. Furthermore, results showed higher sorption of MET on bentonite with effective distribution coefficient (Kdeff) value of 14.92 L/kg with high permanent negative charges than on kaolinite (Kdeff = 6.70 L/kg), a variable charge clay. Increased MET sorption at low equilibrium pH on kaolinite (Kdeff = 2.3 * 107 L/kg) and humic acid (Kdeff = 20.86 L/kg) further suggest cation exchange is also possible at pH < pKa1. On the other hand, two lines of evidence suggest cation exchange as an important mechanism of GUA sorption: (a) the positive correlation between cation exchange capacity and Kdeff values and (b) decreased Kdeff values as the Ca2+ concentration in solution was increased in all soils. Biosolids amendment of three soils resulted in contrasting effects on sorption affinities with a decrease for MET and increase for GUA, further confirming sorption mechanisms and significance of solution pH and CEC on the sorption of MET and GUA, respectively. PMID- 30248857 TI - Quito's virome: Metagenomic analysis of viral diversity in urban streams of Ecuador's capital city. AB - In Quito, the microbiological contamination of surface water represents a public health problem, mainly due to the lack of sewage treatment from urban wastewater. Contaminated water contributes to the transmission of many enteric pathogens through direct consumption, agricultural and recreational use. Among the different pathogens present in urban discharges, viruses play an important role on disease, being causes of gastroenteritis, hepatitis, meningitis, respiratory infections, among others. This study analyzes the presence of viruses in highly impacted surface waters of urban rivers using next-generation sequencing techniques. Three representative locations of urban rivers, receiving the main discharges from Quito sewerage system, were selected. Water samples of 500 mL were concentrated by skimmed-milk flocculation method and the viral nucleic acid was extracted and processed for high throughput sequencing using Illumina MiSeq. The results yielded very relevant data of circulating viruses in the capital of Ecuador. A total of 29 viral families were obtained, of which 26 species were associated with infections in humans. Among the 26 species identified, several were related to gastroenteritis: Human Mastadenovirus F, Bufavirus, Sapporovirus, Norwalk virus and Mamastrovirus 1. Also detected were: Gammapapillomavirus associated with skin infections, Polyomavirus 1 related to cases of kidney damage, Parechovirus A described as cause of neonatal sepsis with neurological affectations and Hepatovirus A, the etiologic agent of Hepatitis A. Other emergent viruses identified, of which its pathogenicity remains to be fully clarified, were: Bocavirus, Circovirus, Aichi Virus and Cosavirus. The wide diversity of species detected through metagenomics gives us key information about the public health risks present in the urban rivers of Quito. In addition, this study describes for the first time the presence of important infectious agents not previously reported in Ecuador and with very little reports in Latin America. PMID- 30248858 TI - Jasmonic acid induced changes in physio-biochemical attributes and ascorbate glutathione pathway in Lycopersicon esculentum under lead stress at different growth stages. AB - Lead (Pb) is one of most toxic heavy metals that adversely affect growth and developmental in plants. It becomes necessary to explore environment safe strategies to ameliorate its toxic effects. Phytohormones play an imperative role in regulating stress protection in plants. Jasmonic acid (JA) is recognized as a potential phytohormone which mediates immune and growth responses to enhance plant survival under stressful environment. The present study was undertaken to evaluate the effect of JA on the growth, metal uptake, gaseous exchange parameters, and on the contents of pigments, osmolytes, and metal chelating compounds in tomato plants under Pb stress during different stages of growth (in 30-, 45-, and 60-day-old plants). We observed a decrease in shoot and root lengths under Pb stress. Treatment of JA improved the shoot and root lengths in the Pb-treated plants. The Pb uptake was increased with the increasing concentrations of Pb, however, seeds pretreated with JA reduced the Pb uptake by the plants. The chlorophyll and carotenoid contents increased by JA treatment in plants under Pb stress. Pre-soaking of seeds in JA, improved gaseous exchange parameters, such as internal CO2 concentration, net photosynthetic rate, stomatal conductance, and transpiration rate under Pb stress. JA enhanced the enzyme activity of ascorbate-glutathione cycle and reduced H2O2 concentration in Pb treated plants. The contents of osmolyte and metal chelating compounds (total thiols, and non-protein and protein-bound thiols) were increased with the increase in Pb stress. In seeds primed with JA, the contents of osmolytes and metal chelating compounds were further increased in the Pb-treated plants. Our results suggested that treatment of JA ameliorated the toxic effects of Pb stress by reducing the Pb uptake and improving the growth, photosynthetic attributes, activity of ascorbate-glutathione cycle and increasing the contents of osmolytes and metal chelating compounds in the tomato plants. PMID- 30248859 TI - Climatically-modulated decline in wind speed may strongly affect eutrophication in shallow lakes. AB - Surface wind speed has declined significantly globally. However, the response of aquatic systems to decreasing wind speeds has received little attention. We examined the effects of a long-term decrease in wind speed on shallow, eutrophic Lake Taihu, China's third largest lake, by combining high-frequency monitoring, long-term meteorological and water quality data with short-term laboratory sediment nutrient release experiments. The annual mean wind speed showed a significant decreasing trend and the maximum continuous days with wind speed <3 m/s increased significantly from 1996 to 2017. The high-frequency monitoring data showed that bottom water hypoxia occurred occasionally in summer and autumn. The water quality data combined with the experimental results suggest that lower wind speed and longer low wind duration can enhance the release of phosphorus (P) from the sediments and increase nitrogen (N) losses, likely via denitrification, because a longer stability period leads to lower dissolved oxygen concentrations near the lake bottom. The results of Bayesian functional Linear regression with Sparse Step functions (Bliss) indicated that wind speed during spring and summer strongly affected chlorophyll a (Chla) concentrations in the summer by enhancing the release of nutrients from the sediments. The results of the structural equation models indicated that declined wind speed might increase phytoplankton biomass (as Chla) by altering nutrient availability. Increasing water temperatures and decreasing wind speeds synergistically enhance water column stability, which may offset some of the immediate benefits of reductions in external nutrient loading by enhancing internal loading. Given predicted global change, it will become increasingly important to reduce the external nutrient loading for overall improvement of water quality in this and other shallow eutrophic lakes. PMID- 30248860 TI - Controls on high and low groundwater arsenic on the opposite banks of the lower reaches of River Ganges, Bengal basin, India. AB - Understanding the controls on spatial variability of groundwater arsenic (As) is critical for mitigating As contamination. The objective of this study is to determine controls on previously unexplained differences in groundwater As concentrations, which are high along the east bank and low along the west bank of the River Bhagirathi-Hoogly (B-H), the primary Indian distributary of the River Ganges, on the western margin of the Bengal basin. A total of 54 wells were sampled after the monsoon season at four sites (two each east and west of the B H) in Murshidabad district, West Bengal, for field parameters, major and minor solutes, and stable isotopes of water. An additional four boreholes were drilled for analyses of sediment texture, mineralogy, total organic and inorganic carbon, and total As and other metal(loid)s. Results show that higher As in east-bank groundwater (median 0.031 mg/L) is associated with generally more anoxic conditions (higher median total Fe and lower median EH and NO3-) relative to west bank groundwater (median As < 0.001 mg/L), consistent with previous studies. In contrast, concentrations of Mn in the study area are highest in west-bank wells near the B-H. Carbonate and silicate weathering appear to be more important in east- and west-bank groundwater, respectively, which may reflect differences in sediment sources. Ranges of total As are similar in east- and west-bank sediments. Relatively depleted values of delta18O and delta2H in the east-bank aquifer and streams appear to reflect focused recharge through paleochannels, while relatively enriched west-bank values suggest diffuse recharge to upland aquifers. We speculate that water infiltrating through erosional, stratigraphic "windows" carries organic matter capable of mobilizing As in east-bank groundwater. This comprehensive evaluation of groundwater chemistry provides a more detailed understanding of controls on As variability within the basin. PMID- 30248861 TI - Microplastics along the beaches of southeast coast of India. AB - Occurrence of microplastics (plastic debris <5 mm) along the coast is a growing concern worldwide, due to increased input of discarded wastes from various sources. In order to evaluate the extent of microplastic pollution on the sandy beaches (25 locations) along Tamil Nadu coast (1076 km), India, microplastic debris were quantified and categorized into four different size classes. The beaches were classified according to potential sources of pollution i.e. riverine, tourism and fisheries. Beach samples collected from the high tide line contained significantly higher abundance of microplastic than at the low tide line. Beaches adjacent to rivers exhibited relatively higher microplastic abundance compared to those influenced by tourism and fishing activities. Out of the total detected debris, plastic fragments were the maximum (47-50%), followed by line/fibres (24-27%) and foam (10-19%) materials. Fourier Transform Infrared Spectroscopy (FTIR) analysis revealed that polyethylene, polypropylene, and polystyrene were the main types of microplastics present in these beaches. Gut content analysis of commercially important fishes, collected from the coastal waters, revealed microplastics ingestion in 10.1% of fishes. The results indicate that microplastics accumulation in the coastal environment, especially close to the river mouths, may be a serious concern, due to its ability to enter into the marine food web and highlights the necessity of microplastics screening from estuarine, coastal waters and other potential sources. PMID- 30248862 TI - An overview of phthalate acid ester pollution in China over the last decade: Environmental occurrence and human exposure. AB - The toxicity and bioaccumulation potential of phthalate acid esters (PAEs) make their impact on the environment a matter of considerable concern. Due to China's recent economic development and population growth, it has become one of the largest manufacturers and consumers of PAEs, with an associated contamination threat to several environmental compartments. The aim of this overview is to present a systematic account of PAE occurrence in various environmental media in China in the last decade, including the air, surface water, sediments, soil, sewage, and sludge; human exposure to PAEs is also evaluated. This reveals a location-dependence that can be attributed to regional differences in economic and industrial development as well as specific geographic location. A need for further study into the transportation and transformation behavior of PAEs in different environmental media and into PAE control technologies is identified, as a means of effectively assessing potential ecological and health risks. PMID- 30248863 TI - Hydroclimatic influences and physiographic controls on phosphorus dynamics in prairie pothole wetlands. AB - While wetlands are known as long-term storages or sinks for contaminants, not all are equally effective at trapping phosphorus (P). The prevalence of P-sink behavior in prairie pothole wetlands remains unclear, especially across gradients of human disturbance. The objectives of the current study were three-fold: (1) characterize the spatiotemporal variability of wetland hydrology and wetland water P concentration across a range of prairie potholes; (2) establish the propensity of different pothole wetlands to act as sources or sinks of P; and (3) assess the potential controls of climatic conditions, landscape characteristics, wetland soil physiochemical properties and local hydrology on source versus sink dynamics. Ten intact and three consolidated (i.e., drained) wetlands located in southwestern Manitoba, Canada, were monitored for water level fluctuations and water soluble reactive P (SRP) concentration over two years with contrasting antecedent wetness conditions. Soil cores were also collected to measure soil physiochemical properties such as the equilibrium phosphorus concentration (EPC). Water column SRP concentrations were compared to EPC values to infer the time variable source versus sink behavior of each of wetland. Statistical analyses were then performed to assess whether the source versus sink behavior of individual wetlands could be linked to their physiographic or hydrologic characteristics. Results show that some wetlands persistently acted as P sinks while others switched between source and sink behavior. Persistent P-sink behavior was more common with intact wetlands, as opposed to consolidated wetlands. Wetland soil texture, storage volume and short-term water level fluctuations appeared to control the source versus sink behavior of individual wetlands. The dominant controls on P-sink behavior identified under dry conditions were, however, different from those identified under wetter conditions. This study therefore highlights the importance of considering the non stationary nature of P-sorption dynamics and their controls, even at sub-annual timescales, in the prairie pothole region. PMID- 30248864 TI - Groundwater nitrate contamination and agricultural land use: A grey water footprint perspective in Southern Apulia Region (Italy). AB - In this paper, we present a new approach based on the Grey Water Footprint (GWF) concept for the determination of groundwater nitrate contamination, with a focus on the agricultural impact in the Southern Apulia Region (Italy). The GWF assessment allows us to highlight wells where nitrate contamination is higher and for which a verification of the nature of contamination is necessary, potentially identifying certain contexts associated with risk factors present in the area. Data show higher nitrate GWF values for vineyards than for olive groves, particularly in areas used for the production of table grapes. Indeed, it is possible to observe that the Western Ionian-Tarantino arch is characterized by a high average level of the GWF indicator, area characterized by an agricultural land use (vineyards, orchards, simple arable land). Another important area is the Brindisi plain, predominantly characterized by an agricultural vocation and a related fertilizer use. The situation in the whole Salento peninsula is more heterogeneous. The results of the GWF show high values in equally distributed points with a clear frequency in the coastal areas of the Ionic arch (Eastern Tarantino and Salento). The Water Footprint methodology and in particular the GWF approach used in this study conceives a useful indicator for the agricultural policy planning processes, a criterion to establish land use management according to the status of hydrological basin and a tool for assessing the pollution monitoring programs. PMID- 30248865 TI - Odour impact from farms with animal husbandry and biogas facilities. AB - Agricultural biogas facilities are usually combined with animal husbandry. Their siting near residential areas can lead to odour complaints by residents. The aim of this study was to identify relevant odour sources, to record odour impact, and to determine the main variables influencing odour impact. Therefore, a combined approach was designed to account for individual odour sources as well as the farms as a whole. On eight farms with cattle husbandry and biogas facilities, two of which kept pigs and poultry, the odour-relevant area sources ranged between 475 and 1810 m2. Solid manure from poultry, cattle and horses as well as grass cuttings, vegetable peelings, liquid-silage effluent and fermentation residues figured among the odour-intensive sources, in addition to biogas. Odour-plume inspections were performed at various distances from the farm, and assessors determined their odour perception and -intensities. The odour intensity in the downwind plume axis was explainable in a linear mixed-effects model by distance (p < 0.001), emitting surface area (p = 0.002) and wind speed (p = 0.018). As distance increased, odour intensity decreased by a factor of two per 50 m. Higher odour intensities resulted from larger surface areas in the animal enclosure, substrate storage, or especially odour-relevant sources. A mixture of odours was frequently perceived in the odour plume. If biogas escaped, an increase in odour impact was recognisable (p = 0.021). Biogas leakage should be avoided with a sufficiently large storage capacity, process optimisation, and regular servicing. In summary, animal husbandry and biogas facilities are to be viewed as an entire plant in terms of downwind odour perception. In planning processes for biogas facilities with animal husbandry, great care in the choice of site is called for, as are structural-technical and organisational measures for abatement. PMID- 30248867 TI - A hybrid kriging/land-use regression model to assess PM2.5 spatial-temporal variability. AB - Proximate pollutant data can provide information for land-use predictors in LUR models, when coupled with spatial interpolation of ambient pollutant measurements, may provide better pollutant predictions. This study applies a hybrid kriging/LUR model to assess the spatial-temporal variability of PM2.5 for Taiwan. Using PM2.5 concentrations at 71 EPA monitoring stations from 2006 to 2011, pollutant gradient surfaces were spatially interpolated using a leave-one out ordinary kriging method based on "n-1" observations. The predicted concentration level of the targeted site was then extracted from the generated kriging map and adopted as a variable in LUR modelling. Annual and monthly resolutions of LUR models were developed to assess the effects by incorporating kriging-based estimates into pollutant predictions. The R2 obtained from conventional LUR procedures was 0.66 and 0.70 for annual and monthly models, respectively, whereas models using the hybrid approach showed better explanatory power (R2 of annual model: 0.85; R2 of monthly model: 0.88). Moreover, kriging based PM2.5 estimates were the most important factor in the resultant models according to the dominant partial R2 of 0.82 and 0.7 in monthly and yearly models. Cross-validation and external data verification showed similar results, demonstrating robustness of the proposed approach. Using governmental pollutant observations is usually publicly available for most areas, this method provides an efficient mean to better assess PM2.5 spatial-temporal variations and predicts levels for nonmonitored areas. PMID- 30248866 TI - Arsenic removal by natural and chemically modified water melon rind in aqueous solutions and groundwater. AB - Contamination of groundwater with toxic arsenic (As) has become an emerging health and environmental problem around the world, which has seen significant attention amongst the scientists for development of new sorbents to remediate As contaminated water. Here, we explored the arsenate (As(V)) and arsenite (As(III)) sorption to natural water melon rind (WMR), xanthated WMR and citric acid modified WMR in aqueous solutions, and determined potential of the most potent sorbent for As removal in groundwater. Xanthated WMR (X-WMR) showed relatively higher As(V) and As(III) removal than the citric acid modified WMR (CA-WMR) and natural WMR. The maximum As(III) (99%) and As(V) (98%) removal was obtained at pH 8.2 and 4.6, respectively, by X-WMR at 4 mg L-1 initial As(V) and As(III) concentrations and sorbent dose of 1 g L-1. Langmuir isotherm model best fitted (R2 of up to 0.96) the data both for As(III) and As(V) sorption to X-WMR. Sorption kinetics of As(V) and As(III) was well described (R2 of up to 0.99) by the pseudo second-order model on surface of the X-WMR. Thermodynamic investigations revealed that As(V) and As(III) sorption was endothermic and spontaneous. The FTIR spectroscopy depicted the presence of different surface function groups (OH, COOH, S-bearing (C=S, S=O and S-S)) which were involved in As(V) and As(III) sequestration on the sorbents examined here. Significantly, X WMR showed (up to 49%) greater As(III) and As(V) sorption than that of natural WMR. Our results demonstrated that X-WMR efficiently removed 94%-100% (n = 16) of As from As-contaminated drinking well water which possessed detectable concentrations of some anions (e.g., SO4, CO3, HCO3). This study highlights that the X-WMR has potential to remove As, notably As(III), from solutions and drinking water, and might be utilized as a reactive medium for the treatment of As-contaminated water. PMID- 30248868 TI - Modelled phototransformation kinetics of the antibiotic sulfadiazine in organic matter-rich lakes. AB - Xenobiotic compounds are commonly detected in inland waters. Sunlight-induced photochemical reactions contribute to xenobiotic degradation, but the role of different photoreactions on large geographic scales remains poorly understood. Here, we used a combination of photochemical modelling and large-scale field data from 1020 lakes across Sweden to elucidate the photodegradation kinetics of the commonly used antibiotic sulfadiazine (SDZ) in organic matter-rich lakes. SDZ occurs in two forms, namely acidic HSDZ (pKa = 6.5) and basic/deprotonated SDZ-. Both species are oxidised fast by the photogenerated triplet states of natural organic matter (3NOM*). However, they also undergo efficient back reactions because the partially oxidised HSDZ (and SDZ- to a larger extent) can be reduced back to the initial compounds by the phenolic moieties contained in NOM. Typical lakes in Sweden are rich in NOM and have low pH, with the consequence that SDZ photochemistry would be dominated by HSDZ. Our simulation results showed that SDZ photodegradation kinetics in Swedish lakes would become significantly slower with increasing water depth and pH, while it depended little on latitude, which affects irradiance, or on organic matter content. As a consequence, SDZ would be particularly persistent in lakewater in some densely populated areas with relatively deep and high-pH lakes such as, most notably, the Stockholm region. Here the surface waters could be more heavily contaminated by pharmaceuticals compared to the scarcely populated regions in the centre-north of the country, where lakewater could otherwise promote an efficient photodegradation of SDZ. PMID- 30248869 TI - Sorbents can tailor nitrogen release from organic wastes to match the uptake capacity of crops. AB - Delivering nutrients from mineral or organic fertilizers out of synchrony with crop uptake causes inefficiencies and pollution. We explore methodologies for evaluating sorbents as additives to organic agricultural wastes to retain nitrogen in an exchangeable form and deliver at rates that approximate the uptake capacity of roots. Focussing on ammonium (NH4+) as the main inorganic nitrogen form in the studied wastes (sugarcane mill mud, poultry litter), we tested geo sorbents and biochar for their ability to retain NH4+. Sorption capacity was ranked palagonite < bentonite, biochar, vermiculite < chabazite, clinoptilolite (5.7 to 24.3 mg NH4+ g-1 sorbent). Sorbent-waste formulations were analysed for sorption capacity, leaching and fluxes of NH4+. Ammonium-sorption capacity broadly translated to sorbent-waste formulations with clinoptilolite conferring the strongest NH4+ attenuation (80%), and palagonite the lowest (7%). A 1:1 ratio of sorbent:waste achieved stronger sorption than a 0.5:1 ratio, and similar sorption as a 1:1.5 ratio. In line with these results, clinoptilolite-amended wastes had the lowest in situ NH4+ fluxes, which exceeded the NH4+ uptake capacity (Imax) of sugarcane and sorghum roots 9 to 84-fold, respectively. Less efficient sorbent-waste formulations and un-amended wastes exceeded Imax of crop roots up to 274-fold. Roots preferentially colonized stronger sorbent-waste formulations and avoided weaker ones, suggesting that lower NH4+ fluxes generate a more favourable growth environment. This study contributes methodologies to identify suitable sorbents to formulate organic wastes as next-generation fertilizers with view of a crop's nutrient physiology. Efficient re-purposing of wastes can improve nutrient use efficiency in agriculture and support the circular nutrient economy. PMID- 30248870 TI - High stoichiometric food quality increases moulting organism vulnerability to pollutant impacts: An experimental test with Gammarus fossarum (Crustacea: Amphipoda). AB - Headwater organisms are most often simultaneously faced with multiple stressors such as low resource quality and pollutants. Higher food quality has been hypothesized to enhance the tolerance of organisms to pollutants, but the interactive effects of food quality and pollutants on species and ecosystems remain poorly studied. To better understand these interactive effects, we experimentally manipulated the phosphorus (P) content of two leaf litters with contrasted carbon quality (alder and maple). During four weeks, individuals of the detritivorous crustacean Gammarus fossarum were exposed to low levels of cadmium ([Cd] = 0, 0.35 or 0.70 MUg L-1) while being fed with one of the leaf P treatments. When organisms were not exposed to Cd, their high survival rate was more driven by the carbon quality of the resource (litter species) than by its stoichiometric quality. In contrast, their number of moults and growth rates were primarily increased by the P content of resources. When exposed to Cd, G. fossarum survival rate was reduced, but this effect was largely magnified by a higher P level in resources. Our results showed that despite positive effects of resource stoichiometric quality on organism life history traits (growth, survival), a resource of high stoichiometric quality might be detrimental for organisms exposed to low and environmentally realistic levels of pollutants. Two non-exclusive hypotheses are proposed to explain these results. First, organisms fed on the highest quality resource exhibited the highest moulting frequencies (moults being the most critical life cycle step of arthropods), which could have rendered them more sensitive to pollutants. Secondly, the metabolism of organisms fed on higher quality resources was potentially enhanced, increasing the uptake of dissolved Cd by gammarids. This study suggests that species sensitivity to pollutants might be underestimated in ecosystems facing both nutrient constraint and pollutants. PMID- 30248871 TI - Projections of actual evapotranspiration under the 1.5 degrees C and 2.0 degrees C global warming scenarios in sandy areas in northern China. AB - Actual evapotranspiration (ETa) is an essential component of Earth's global energy balance and water cycle. The Paris Agreement aspires to limit global mean surface warming to <2 degrees C and no >1.5 degrees C relative to preindustrial levels. However, it is uncertain how this global level will impact the shifts in the extents of sandy areas caused by global desertification. Using Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) datasets and advection-aridity models, we investigated the spatiotemporal features of ETa in sandy areas in northern China under global warming scenarios of 1.5 degrees C and 2.0 degrees C. The four climate models indicated significant increases in ETa in arid areas across northwestern China. Over time, the ETa value under only the representative concentration pathway 2.6 (RCP2.6) emission scenario increased towards a plateau and significantly increased in the other three emission scenarios (P < 0.01) under global warming of 1.5 degrees C and 2.0 degrees C. In terms of the spatial variations, ETa showed an increasing trend in all seasons except winter. The maximum ETa was 84.61 mm, and high values were mainly located in the southeast of the study area. Precipitation and the normalized difference vegetation index (NDVI) showed good correlations with ETa in the sandy areas in northern China. The sandy areas in northern China showed decreasing trends (0.45 km2/a) from 1980 to 2015. Under global warming of 2.0 degrees C (2040-2059) relative to that of 1.5 degrees C (2020-2039), the area of sandy land will increase at a rate of 27.04 km2 per decade (P < 0.01); after this period, the sandy land area in northern China may gradually stabilize, with a trend of 0.02 km2/a (2047-2100). Early efforts to achieve the 1.5 degrees C temperature goal could therefore markedly reduce the likelihood that large regions will face substantial global desertification and the related impacts. PMID- 30248872 TI - Understanding the association between climate variability and the Nile's water level fluctuations and water storage changes during 1992-2016. AB - With the construction of the largest dam in Africa, the Grand Ethiopian Renaissance Dam (GERD) along the Blue Nile, the Nile is back in the news. This, combined with Bujagali Dam on the White Nile are expected to bring ramification to the downstream countries. A comprehensive analysis of the Nile's waters (surface, soil moisture and groundwater) is, therefore, essential to inform its management. Owing to its shear size, however, obtaining in-situ data from "boots on the ground" is practically impossible, paving way to the use of satellite remotely sensed and models' products. The present study employs multi-mission satellites and surface models' products to provide, for the first time, a comprehensive analysis of the changes in Nile's stored waters' compartments; surface, soil moisture and groundwater, and their association to climate variability (El Nino Southern Oscillation (ENSO) and Indian Ocean Dipole (IOD)) over the period 1992-2016. In this regard, remotely sensed altimetry data from TOPEX/Poseidon (T/P), Jason-1, and Jason-2 satellites along with the Gravity Recovery And Climate Experiment (GRACE) mission, and the Tropical Rainfall Measuring Mission Project (TRMM) rainfall products are applied to analyze the compartmental changes over the Nile River Basin (NRB). This is achieved through the creation of 62 virtual gauge stations distributed throughout the Nile River that generate water levels, which are used to compute surface water storage changes. Using GRACE total water storage (TWS), soil moisture data from multi models based on the Triple Collocation Analysis (TCA) method, and altimetry derived surface water storage, Nile basin's groundwater variations are estimated. The impacts of climate variability on the compartmental changes are examined using TRMM precipitation and large-scale ocean-atmosphere ENSO and IOD indices. The results indicate a strong correlation between the river level variations and precipitation changes in the central part of the basin (0.77 on average) in comparison to the northern (0.64 on average) and southern parts (0.72 on average). Larger water storages and rainfall variations are observed in the Upper Nile in contrast to the Lower Nile. A negative groundwater trend is also found over the Lower Nile, which could be attributed to a significantly lower amount of rainfall in the last decade and extensive irrigation over the region. PMID- 30248873 TI - Arsenic, selenium, boron, lead, cadmium, copper, and zinc in naturally contaminated rocks: A review of their sources, modes of enrichment, mechanisms of release, and mitigation strategies. AB - Massive and ambitious underground space development projects are being undertaken by many countries around the world to decongest megacities, improve the urban landscapes, upgrade outdated transportation networks, and expand modern railway and road systems. A number of these projects, however, reported that substantial portions of the excavated debris are oftentimes naturally contaminated with hazardous elements, which are readily released in substantial amounts once exposed to the environment. These contaminated excavation debris/spoils/mucks, loosely referred to as "naturally contaminated rocks", contain various hazardous and toxic inorganic elements like arsenic (As), selenium (Se), boron (B), and heavy metals like lead (Pb), cadmium (Cd), copper (Cu), and zinc (Zn). If left untreated, these naturally contaminated rocks could pose very serious problems not only to the surrounding ecosystem but also to people living around the construction and disposal sites. Several incidents of soil and ground/surface water contamination, for example, have been documented due to the false assumption that excavated materials are non-hazardous because they only contain background levels of environmentally regulated elements. Naturally contaminated rocks are hazardous wastes, but they still remain largely unregulated. In fact, standard leaching tests for their evaluation and classification are not yet established. In this review, we summarized all available studies in the literature about the factors and processes crucial in the enrichment, release, and migration of the most commonly encountered hazardous and toxic elements in naturally contaminated geological materials. Although our focus is on naturally contaminated rocks, analogue systems like contaminated soils, sediments, and other hazardous wastes that have been more widely studied will also be discussed. Classification schemes and leaching tests to properly identify and regulate excavated rocks that may potentially pose environmental problems will be examined. Finally, management and mitigation strategies to limit the negative effects of these hazardous wastes are introduced. PMID- 30248874 TI - Quantitative analysis of the spatio-temporal evolution of the anthropogenic transfer of lead in China. AB - The redistribution of lead to meet human needs reflects the relationship between humans and land, and the redistribution process will influence the future evolution of the land surface. An analysis of the spatial transfer of lead was undertaken to determine the regional distribution of lead in each phase of its life cycle during 1990-2014 using the administrative unit of each province in Mainland China as the spatial unit. A quantitative analysis of the spatio temporal evolution of the anthropogenic transfer of lead in China was conducted through a comparison of the differences in the spatio-temporal distribution of lead at different stages of its life cycle. The results showed that during 1990 to 2014, the mining of lead ore was gradually transferred from southern China to the northwest inland area and northern China, and lead within products was finally transferred to the eastern coastal area of China to complete its life cycle. The distribution of natural and social resources, supply and demand of markets, and foreign trade affect the lead anthropogenic transfer. PMID- 30248875 TI - Long-chain n-alkane and n-fatty acid characteristics in plants and soil - potential to separate plant growth forms, primary and secondary grasslands? AB - Plant-derived lipid molecular proxies can provide insight into present-day soil carbon input and to what extent organic carbon is degraded within soil. To explore whether soil characteristics of 'primary' (i.e., native grasslands above the historic treeline) and 'secondary' (i.e., human-modified grasslands below the historic treeline) grasslands reflect recent and/or past vegetation input we compared lipid characteristics in modern vegetation and soil from 30 locations around the historic treeline (1150 m) in Central Otago, New Zealand. At each location the dominant plant species and the mineral topsoil (0-10 cm) were analyzed for a range of n-alkane and n-fatty acid proxies. Grass/herbs and trees differed in their total n-alkane concentration (88.9 vs 232.6 MUg/g plant dry weight), even-over-odd predominance (EOP, 10.2 vs 18.3) and n-C20/n-C24 ratio (2.2 vs 6.4). Soil samples under all plant growth forms had considerably lower n alkane and n-fatty concentrations than the corresponding plant samples. Soil under grass/herbs had lower (4.1) odd-over-even predominance (OEP) values compared to soil under trees (10.1) indicating that lipid degradation under grass/herbs cover was higher. Principle component analysis demonstrated that soil lipid characteristics reflected the current vegetation cover. Principal component analysis also revealed a separation between 'primary' and 'secondary' grasslands. However, further evaluations are required to confirm the validity of lipid proxies in reconstructing the vegetation history of secondary grasslands. PMID- 30248876 TI - Measurement-based investigation of ozone deposition to vegetation under the effects of coastal and photochemical air pollution in the Eastern Mediterranean. AB - Dry deposition of ozone (O3) to vegetation is an important pathway for its removal from the troposphere, and it can lead to adverse effects in plants and changes in climate. However, our mechanistic understanding of O3 dry deposition is insufficient to adequately account for it in global and regional models, primarily because this process is highly complicated by feedback mechanisms and sensitivity to specific characteristics of vegetative environment and atmospheric dynamics and composition. We hypothesized that measuring dry deposition of O3 to vegetation near the Eastern Mediterranean (EM) coast, where large variations in meteorological conditions and photochemical air pollution frequently occur, would enable identifying the mechanisms controlling O3 deposition to vegetation. Moreover, we have only limited knowledge of O3 deposition to vegetation occurring near a coastline, under air pollution, or in the EM. This study investigated O3 deposition to mixed Mediterranean vegetation between the summers of 2015 and 2017, 3.6 km away from the EM coast, using the eddy covariance technique to quantify vertical flux of O3 and its partitioning to stomatal and non-stomatal flux, concurrent with nitrogen oxide (NOx), sulfur dioxide and carbon monoxide. Surprisingly, nighttime O3-deposition velocity (Vd) was smaller than daytime Vd by only ~20-37% on average for all measurement periods, primarily related to moderate nighttime atmospheric stability due to proximity to the seashore. We provide evidence for the role of sea-salt aerosols in enhancing O3 deposition via surface-wetness buildup at low relative humidity near the coast, and for daytime enhancement of O3 deposition by the combined effects of biogenic volatile organic compound emission and surface-wetness buildup. We further show that NOx emitted from elevated emission sources can reduce O3 deposition, and even lead to a positive O3 flux, demonstrating the importance of adequately taking into account the impact of air pollution on O3 deposition to vegetation. PMID- 30248878 TI - The IADN data visualization tool. AB - Data on atmospheric levels of toxic pollutants in samples collected near the Great Lakes are now readily available online to scientists, researchers, and the public on a website called IADN Data Viz (https://iadnviz.iu.edu/). These data come from the Integrated Atmospheric Deposition Network (IADN), a long term monitoring program run by the U.S. Environmental Protection Agency (US EPA). PMID- 30248879 TI - Flow cytometry-based evaluation of the bacterial removal efficiency of a blackwater reuse treatment plant and the microbiological changes in the associated non-potable distribution network. AB - The study evaluated the changes in bacterial numbers across a full-scale membrane bioreactor (MBR) blackwater reuse system. Flow cytometry was used to quantify total and intact bacterial concentrations across the treatment train and during distribution of the recycled water. Membrane passage reduced bacterial numbers by up to 5-log units resulting in coliform-free permeate. A 2-log increase in bacterial cell concentration was subsequently observed after the granular activated carbon unit followed by a reduction in intact cells after chlorination, which corresponds to an overall intact bacteria removal of 3.4-log units. In the distribution network, the proportion of intact cells greatly depended on the free chlorine residual, with decreasing residual enabling regrowth. An initial target of 0.5 mg L-1 free chlorine ensured sufficient suppression of intact cells for up to 14 days (setting the time intervals for system flushes at times of low water usage). Bacterial regrowth was only observed when the free chlorine concentration was below 0.34 mg L-1. Such loss of residual chlorine mainly applied to distant points in the distribution network from the blackwater reuse treatment plant (BRTP). Flushing these network points for 5 min did not substantially reduce cell numbers. At points closer to the BRTP, on the other hand, flushing reduced cell numbers by up to 1.5-log units concomitant with a decreasing proportion of intact cells. Intact cell concentrations did not correlate with DOC, total nitrogen, or soluble reactive phosphate, but it was shown that dead biomass could be efficiently converted into new biomass within seven days. PMID- 30248877 TI - Small Water Bodies in Great Britain and Ireland: Ecosystem function, human generated degradation, and options for restorative action. AB - Small, 1st and 2nd-order, headwater streams and ponds play essential roles in providing natural flood control, trapping sediments and contaminants, retaining nutrients, and maintaining biological diversity, which extend into downstream reaches, lakes and estuaries. However, the large geographic extent and high connectivity of these small water bodies with the surrounding terrestrial ecosystem makes them particularly vulnerable to growing land-use pressures and environmental change. The greatest pressure on the physical processes in these waters has been their extension and modification for agricultural and forestry drainage, resulting in highly modified discharge and temperature regimes that have implications for flood and drought control further downstream. The extensive length of the small stream network exposes rivers to a wide range of inputs, including nutrients, pesticides, heavy metals, sediment and emerging contaminants. Small water bodies have also been affected by invasions of non native species, which along with the physical and chemical pressures, have affected most groups of organisms with consequent implications for the wider biodiversity within the catchment. Reducing the impacts and restoring the natural ecosystem function of these water bodies requires a three-tiered approach based on: restoration of channel hydromorphological dynamics; restoration and management of the riparian zone; and management of activities in the wider catchment that have both point-source and diffuse impacts. Such activities are expensive and so emphasis must be placed on integrated programmes that provide multiple benefits. Practical options need to be promoted through legislative regulation, financial incentives, markets for resource services and voluntary codes and actions. PMID- 30248880 TI - Study of carbon metabolic processes and their spatial distribution in the Beijing Tianjin-Hebei urban agglomeration. AB - It is necessary to reduce carbon emission, and land-use adjustment is one of the potential strategies. In this paper, we calculated the carbon emission and absorption rates in China's Beijing-Tianjin-Hebei agglomeration. We used ArcGIS to simulate their spatial patterns based on land-transfer matrices (land-use transitions) at 5-year intervals. From 2000 to 2015, carbon emission first increased and then decreased, but carbon absorption increased steadily. Transportation and industrial land accounted for 73.0% of carbon emission, whereas forest accounted for 55.0% of carbon absorption. The spatial distributions of emission and absorption evolved, developing obvious spatial gradients. Land transfers leading to increased emission or decreased absorption (negative transfers) increased by 115.1% from 2000 to 2015; the corresponding area of land transferred first decreased and then increased. The area of land transferred increased more slowly than negative carbon transfers, mainly due to transfers to transportation and industrial land, which accounted for 90.0% of the total; the land transfers leading to reduced emissions or increased absorption (positive carbon transfers) and the amount of carbon transferred decreased or increased simultaneously. The area of land transferred increased more than positive carbon transfers. The positive carbon transfers increased slightly at the start of the study, but showed no significant overall change, mainly due to transfers from transportation and industrial land to urban land. However, positive carbon transfers from 2010 to 2015 increased to 21 times the starting value, mainly due to transfers from transportation and industrial land (92% of the total). Our analysis revealed unfavorable transfer directions and sizes and their spatial distribution, thereby providing a scientific basis for regional planning to reduce carbon emission through adjustment of the land use pattern. PMID- 30248881 TI - Geochemical stability of acid-generating pyrrhotite tailings 4 to 5 years after addition of oxygen-consuming organic covers. AB - Oxygen-consuming organic covers can serve as a reactive barrier to minimize sulfide oxidation in acid-generating tailings but may lead to metal mobilization in surface oxidized layers. We evaluated changes in the bio-geochemical stability of acid-generating, Cu-Ni pyrrhotite tailings 4 to 5 years after addition of a 50 cm-thick or a 1 m-thick biosolid cover planted with energy crops. The original tailings (pH 2.5) were oxidized in the first 10 to 40 cm, and goethite was the dominant sink for Cu and Ni, the main metal contaminants in these tailings. Both covers increased pH, nutrient availability, microbial activity and diversity in the oxidized tailings, and led to a reduction of water-soluble Cu, Ni, Fe and Al after 4 to 5 years of application. Changes in pH, humidity, organic C content, and redox conditions resulted in partial dissolution of jarosite and gypsum below the cover but goethite apparently remained stable. Under both covers, total Ni decreased in the oxidized layer, indicating remobilization, but Cu was retained. Significant accumulation of Cu as Cu sulfide at the oxidized/unoxidized tailings interface was detected only under the 1 m-thick cover, suggesting that the thinner cover may not sufficiently decrease the oxidizing conditions to mitigate acid mine drainage. Migration of nitrate and P down to the unoxidized tailings was observed under both covers and raises the concern of continued sulfide oxidation in unoxidized tailings. Although the implementation of thinner covers is economically more sustainable than thick covers, our results indicate that further research is required to establish their long-term suitability and performance to prevent acid mine drainage. PMID- 30248882 TI - Zr, Hf and REE distribution in river water under different ionic strength conditions. AB - The Platani River flowing in south-central Sicily, interacting with evaporite rocks, generates a wide range of ionic strength in the water catchment from 0.1 to 5.0molkg-1. We sampled 38 river sites and analysed the composition for the dissolved fraction filtered through 0.45MUm, the truly dissolved fraction obtained through ultrafiltration (10kDa) and the relative included colloidal fraction. This study was focused on the recognition of Zr, Hf and REE behaviour under changing ionic strength conditions, since this is one of parameters responsible for colloid stability in natural waters. In turn, this phenomenon leads to REE release from the colloidal fraction and their scavenging onto surfaces of suspended particles or sediment, or their complexation with dissolved ligands. Our results indicated that in both dissolved and ultra-filtrated fractions REE increases either in the middle (Sm - Dy) or in the heavier (Ho - Lu) part of the PAAS-normalised distribution, while the Zr/Hf ratio value ranges from sub-chondritic to super-chondritic. Scanning Electron Microscopic and Energy Dispersive X-ray Spectrometric (SEM-EDS) analyses and dissolved Mg, Al and Fe concentrations suggested that the studied colloids consist of aggregations of Al oxyhydroxides, carbonate nanoparticles and clays where organic traces were not found. The studied colloids showed greater affinity with dissolved Zr than Hf determining Zr/Hf values larger than the chondritic values. The largest Zr/Hf values were found in colloidal fractions from waters with ionic strength larger than 0.6molkg-1. These Zr/Hf values up to 280 (w/w) are provided by the faster removal of Hf relative to Zr from coagulating colloids and its preferential scavenging onto authigenic Fe-oxyhydroxides in bottom sediment. Further studies are needed to clarify is this suggested process can represent a suitable starting point for the Zr-Hf decoupling observed in seawater. PMID- 30248883 TI - Time trends over 2003-2014 in the concentrations of selected perfluoroalkyl substances among US adults aged >=20 years: Interpretational issues. AB - Data (N = 9650) for US adults aged >=20 years downloaded from National Health and Nutrition Examination Survey for 2003-2014 were analyzed to study trends in adjusted and unadjusted concentrations of selected perfluoroalkyl substances (PFAS), namely, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA). Over 2003-2014, unadjusted concentrations of PFOA decreased by 50%, by 75% for PFOS, by 32% for PFDA, by 27% for PFHxS, and by 30% for PFNA. Females not only had substantially lower concentrations of every PFAS than males but rate of decrease was also higher for females than males, for example, 36.7% for females and 30.6% for males every two years for PFOS. For each survey period of two years, percent decrease in adjusted concentrations was 17% for PFOA, 33.5% for PFOS, 11.5% for PFDA, 6.3% for PFHxS, and 7.6% for PFNA. However, these trend data must be examined within the context of design changes in NHANES over 2003-2014 resulting in oversampling of Hispanics other than Mexican Americans starting 2007-2008 survey cycle and oversampling of non Hispanic Asians starting 2011-2012 survey cycle. In order to examine how design changes may have affected computations of adjusted and unadjusted concentrations, the data were analyzed using the racial/ethnic categories prior to and after oversampling of Hispanics other than Mexican Americans and non-Hispanic Asians was put into place. PMID- 30248884 TI - Characterization of BTEX group of VOCs and inhalation risks in indoor microenvironments at small enterprises. AB - Concentrations of BTEX group (benzene, toluene, ethylbenzene and xylene) were measured in indoor and outdoor environments at four printing shops and two photocopy centers in Sakaka city, KSA. Fifty four BTEX samples were collected using passive diffusion monitors (SKC VOC 575) and analyzed by GC-MS. The results showed that toluene was the most prevailing compound within the BTEX group and its indoor levels were much higher than outdoor. The average indoor concentrations (MUg/m3) ranged from 2.45 to 14.66, 81.59 to 955.65, 11.19 to 97.35, 35.66 to 291.88 and 3.90 to 28.39 for benzene, toluene, ethylbenzene, m/p xylene and o-xylene, respectively. The indoor/outdoor ratios of concentrations of BTEX species were more than one in most cases, indicating the effect of indoor emission sources. Based on (Toluene/Benzene) ratios, all sites were affected by the traffic emissions. Ventilation efficiency, ink type and outdoor pollutant concentration are responsible for results disparity. Cancer and non-cancer risks were assessed in the indoor environments by calculating the lifetime cancer risk (LCR) and hazard ratio (HR), respectively. For benzene and ethylbenzene measured concentrations, LCR values were more than the acceptable USEPA risk level of 1 * 10-6. HR values for BTEX species were in general lower than the threshold limit of one. PMID- 30248885 TI - Disentangling settlement responses to nutrient-rich contaminants: Elevated nutrients impact marine invertebrate recruitment via water-borne and substrate bound cues. AB - Anthropogenic contaminants, including nutrient enrichment, frequently alter environmental conditions in marine systems and affect the development of communities on hard-substrata. Biofilms can influence the settlement of marine invertebrates and hence impact on the structure of fouling communities. Few studies have examined bacteria, invertebrates and nutrient-rich contaminants in concert, with none yet to examine the effects of nutrient-rich contaminants on both biofilms and the recruitment of sessile invertebrate communities in-situ to ascertain the mechanistic basis behind observed impacts. Biofilm treatments were allowed to develop under manipulated environmental conditions of either ambient or enriched nutrient levels. Enrichment conditions were elevated via slow-release fertiliser and invertebrate recruitment was prevented during initial biofilm development. Biofilm treatments (including a no film control) were then subject to either ambient or enriched water-borne nutrients (in a fully-factorial design) during a period of invertebrate colonisation in the field. Effects of nutrient rich contaminants on invertebrate recruitment were observed as changes to community composition and the abundances of taxonomic groups. Communities on no biofilm control treatments differed from those with pre-developed biofilms. Naturally developed biofilms promoted recruitment by all organisms, except barnacles, which preferred nutrient-enriched biofilms. Water-borne nutrients increased the recruitment of ascidians and barnacles, but suppressed bryozoan, serpulid polychaete and sponge recruitment. The direct and indirect impacts observed on biofilm and invertebrate communities suggest that increasing nutrient levels via nutrient-rich contaminants will result in structural community shifts that may ultimately impact ecosystem functioning within estuaries. PMID- 30248886 TI - Quantitative microbial risk assessment and its applications in small water systems: A review. AB - Quantitative microbial risk assessment (QMRA) has been mainstreamed in many large municipal water systems as part of a paradigm shift in the drinking water industry towards water safety planning and risk-based system assessment. Small water systems (SWSs) are generally more vulnerable to typical water system hazards, and consequently have a higher risk of waterborne disease outbreak. In this paper, a review of experiences in implementing QMRA in SWSs helps elaborate the sources of risks and highlights some of the challenges facing SWSs in developed countries. A critical review of the important elements for practical implementation of QMRA was conducted. The investigation focuses on aspects related to challenges in identifying relevant hazards to SWSs to create failure scenarios, acquiring monitoring data for pathogens' concentrations in source water, estimating treatment efficiencies of typical small system technologies, and access to software tools to support successful implementation. The review helped outline ways through which SWSs can overcome the identified challenges in implementing QMRA. An adjusted framework for implementing QMRA for small water systems was formulated and discussed. PMID- 30248887 TI - Targeted Versus Nontargeted Communication About Electronic Nicotine Delivery Systems in Three Smoker Groups. AB - Background: This study used an audience segmentation and message targeting approach to identify three distinct smoker groups-Older Freedom Smokers (OFS), Reluctant Smokers (RS), and Young Enthusiasts (YE)-and examined whether an electronic nicotine delivery systems (ENDS) message targeting each smoker group (targeted message) was associated with more health-enhancing outcomes than messages targeting other groups (nontargeted messages). Methods: An online experiment was conducted among 580 adult smokers with 180 OFS, 200 RS, and 200 YE. Each smoker group viewed a targeted message and two nontargeted messages in a random order. Following the presentation of each message, participants reported their perceived message effectiveness, message reactions, ENDS- and cigarette related beliefs, and behavioral intentions. Results: The targeted vs. nontargeted messages mostly did not produce more health-enhancing outcomes on perceptions of absolute and comparative risks of ENDS and cigarettes, response efficacy of ENDS, and self-efficacy as well as intentions to quit smoking. Conclusions: Our targeted messages did not appear to be a better choice over nontargeted messages to communicate about ENDS to smokers. Given the increasing call to accurately inform the public of the risk differences among various tobacco products, future studies should continue to explore whether targeted messages could be employed to communicate about the comparative risks of ENDS. PMID- 30248889 TI - The Impact of Adding Sugars to Milk and Fruit on Adiposity and Diet Quality in Children: A Cross-Sectional and Longitudinal Analysis of the Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants (IDEFICS) Study. AB - Sugar, particularly as free sugars or sugar-sweetened beverages, significantly contributes to total energy intake, and, possibly, to increased body weight. Excessive consumption may be considered as a proxy of poor diet quality. However, no previous studies evaluated the association between the habit of adding sugars to "healthy" foods, such as plain milk and fresh fruit, and indicators of adiposity and/or dietary quality in children. To answer to these research questions, we Panalysed the European cohort of children participating in the IDEFICS study. Anthropometric variables, frequency of consumption of sugars added to milk and fruit (SAMF), and scores of adherence to healthy dietary pattern (HDAS) were assessed at baseline in 9829 children stratified according to age and sex. From this cohort, 6929 children were investigated again after two years follow-up. At baseline, a direct association between SAMF categories and adiposity indexes was observed only in children aged 6-<10 years, while the lower frequency of SAMF consumption was significantly associated with a higher HDAS. At the two year follow-up, children with higher baseline SAMF consumption showed significantly higher increases in all the anthropometric variables measured, with the exception of girls 6-<10 years old. The inverse association between SAMF categories and HDAS was still present at the two years follow-up in all age and sex groups. Our results suggest that the habit to adding sugars to foods that are commonly perceived as healthy may impact the adherence to healthy dietary guidelines and increase in adiposity risk as well. PMID- 30248890 TI - An In Vitro Model for Assessing Corneal Keratocyte Spreading and Migration on Aligned Fibrillar Collagen. AB - BACKGROUND: Corneal stromal cells (keratocytes) are responsible for developing and maintaining normal corneal structure and transparency, and for repairing the tissue after injury. Corneal keratocytes reside between highly aligned collagen lamellae in vivo. In addition to growth factors and other soluble biochemical factors, feedback from the extracellular matrix (ECM) itself has been shown to modulate corneal keratocyte behavior. METHODS: In this study, we fabricate aligned collagen substrates using a microfluidics approach and assess their impact on corneal keratocyte morphology, cytoskeletal organization, and patterning after stimulation with platelet derived growth factor (PDGF) or transforming growth factor beta 1 (TGFbeta). We also use time-lapse imaging to visualize the dynamic interactions between cells and fibrillar collagen during wound repopulation following an in vitro freeze injury. RESULTS: Significant co alignment between keratocytes and aligned collagen fibrils was detected, and the degree of cell/ECM co-alignment further increased in the presence of PDGF or TGFbeta. Freeze injury produced an area of cell death without disrupting the collagen. High magnification, time-lapse differential interference contrast (DIC) imaging allowed cell movement and subcellular interactions with the underlying collagen fibrils to be directly visualized. CONCLUSIONS: With continued development, this experimental model could be an important tool for accessing how the integration of multiple biophysical and biochemical signals regulate corneal keratocyte differentiation. PMID- 30248888 TI - Revisiting Current Photoactive Materials for Antimicrobial Photodynamic Therapy. AB - Microbial infection is a severe concern, requiring the use of significant amounts of antimicrobials/biocides, not only in the hospital setting, but also in other environments. The increasing use of antimicrobial drugs and the rapid adaptability of microorganisms to these agents, have contributed to a sharp increase of antimicrobial resistance. It is obvious that the development of new strategies to combat planktonic and biofilm-embedded microorganisms is required. Photodynamic inactivation (PDI) is being recognized as an effective method to inactivate a broad spectrum of microorganisms, including those resistant to conventional antimicrobials. In the last few years, the development and biological assessment of new photosensitizers for PDI were accompanied by their immobilization in different supports having in mind the extension of the photodynamic principle to new applications, such as the disinfection of blood, water, and surfaces. In this review, we intended to cover a significant amount of recent work considering a diversity of photosensitizers and supports to achieve an effective photoinactivation. Special attention is devoted to the chemistry behind the preparation of the photomaterials by recurring to extensive examples, illustrating the design strategies. Additionally, we highlighted the biological challenges of each formulation expecting that the compiled information could motivate the development of other effective photoactive materials. PMID- 30248892 TI - Co-Activation, Estimated Anterior and Posterior Cruciate Ligament Forces, and Motor Unit Activation Strategies during the Time Course of Fatigue. AB - This study aimed to combine co-activation as well as anterior and posterior cruciate ligament force estimations with the motor unit activation strategies employed by the primary muscles that are involved in the movement at the knee joint. Fourteen male subject performed 25 maximal concentric isokinetic leg extension muscle actions at 120 s-1. Electromyographic and mechanomyographic signals from the vastus lateralis and bicep femoris, as well as force, were used to measure co-activation, and estimated anterior and posterior ligament forces during the time course of fatigue. There were decreases in quadriceps force and increases in hamstring force during the 25 leg extensions. The posterior cruciate ligament force was greater than the anterior cruciate ligament force during each leg extension. Both the posterior and anterior cruciate ligament forces decreased during the 25 leg extensions. Each muscle indicated unique neuromuscular responses, which may explain the decreases in quadriceps force and increases in the hamstring force. The combination of anterior and posterior cruciate ligament force estimation and motor unit activation strategies helped to provide a better understanding of the fatigue-related mechanism that was utilized to avoid injury and increase or maintain joint stability during the time course of fatigue. PMID- 30248893 TI - Fruit Decay to Diseases: Can Induced Resistance and Priming Help? AB - Humanity faces the challenge of having to increase food production to feed an exponentially growing world population, while crop diseases reduce yields to levels that we can no longer afford. Besides, a significant amount of waste is produced after fruit harvest. Fruit decay due to diseases at a post-harvest level can claim up to 50% of the total production worldwide. Currently, the most effective means of disease control is the use of pesticides. However, their use post-harvest is extremely limited due to toxicity. The last few decades have witnessed the development of safer methods of disease control post-harvest. They have all been included in programs with the aim of achieving integrated pest (and disease) management (IPM) to reduce pesticide use to a minimum. Unfortunately, these approaches have failed to provide robust solutions. Therefore, it is necessary to develop alternative strategies that would result in effective control. Exploiting the immune capacity of plants has been described as a plausible route to prevent diseases post-harvest. Post-harvest-induced resistance (IR) through the use of safer chemicals from biological origin, biocontrol, and physical means has also been reported. In this review, we summarize the successful activity of these different strategies and explore the mechanisms behind. We further explore the concept of priming, and how its long-lasting and broad-spectrum nature could contribute to fruit resistance. PMID- 30248891 TI - Meeting Patients' Right to the Correct Diagnosis: Ongoing International Initiatives on Undiagnosed Rare Diseases and Ethical and Social Issues. AB - The time required to reach a correct diagnosis is a key concern for rare disease (RD) patients. Diagnostic delay can be intolerably long, often described as an "odyssey" and, for some, a diagnosis may remain frustratingly elusive. The International Rare Disease Research Consortium proposed, as ultimate goal for 2017-2027, to enable all people with a suspected RD to be diagnosed within one year of presentation, if the disorder is known. Subsequently, unsolved cases would enter a globally coordinated diagnostic and research pipeline. In-depth analysis of the genotype through next generation sequencing, together with a standardized in-depth phenotype description and sophisticated high-throughput approaches, have been applied as diagnostic tools to increase the chance of a timely and accurate diagnosis. The success of this approach is evident in the Orphanet database. From 2010 to March 2017 over 600 new RDs and roughly 3600 linked genes have been described and identified. However, combination of -omics and phenotype data, as well as international sharing of this information, has raised ethical concerns. Values to be assessed include not only patient autonomy but also family implications, beneficence, non-maleficence, justice, solidarity and reciprocity, which must be respected and promoted and, at the same time, balanced among each other. In this work we suggest that, to maximize patients' involvement in the search for a diagnosis and identification of new causative genes, undiagnosed patients should have the possibility to: (1) actively participate in the description of their phenotype; (2) choose the level of visibility of their profile in matchmaking databases; (3) express their preferences regarding return of new findings, in particular which level of Variant of Unknown Significance (VUS) significance should be considered relevant to them. The quality of the relationship between individual patients and physicians, and between the patient community and the scientific community, is critically important for optimizing the use of available data and enabling international collaboration in order to provide a diagnosis, and the attached support, to unsolved cases. The contribution of patients to collecting and coding data comprehensively is critical for efficient use of data downstream of data collection. PMID- 30248894 TI - Distribution of Canthon rutilans rutilans and Canthon rutilans cyanescens Along Spatio-Temporal and Temperature Gradients. AB - Subspecies is a debated taxonomic rank that, in some cases, could indicate that a speciation process is taking place. Studying the degree of co-occurrence among subspecies along environmental gradients may help to determine its taxonomic status. In this study, we explore the distribution of two subspecies of Canthon rutilans along spatio-temporal and temperature gradients in the Atlantic Forest of southern Brazil in order to reinforce their current subspecies status or to support their consideration as two different species. A yearly survey conducted along an elevational transect (from 250 m to 1630 m) shows that there is no spatio-temporal overlap between the two taxa. We collected 899 individuals of Canthon rutilans cyanescens and 29 individuals of Canthon rutilans rutilans. C. rutilans cyanescens can be found at 250 m (all year except in June), 430 m (August to April), and 840 m (September to April) in elevation, and when the air temperature oscillates from 15.3 degrees C to 24.0 degrees C. C. rutilans rutilans can be found at 1360 m (October to February), 1630 m (January) in elevation, and when the air temperature oscillates from 14.4 degrees C to 18.6 degrees C. Furthermore, local temperature data taken during the survey indicates that both subspecies also have a limited overlap in their thermal response curves. All these results suggest that these two taxa could be considered as two different species with dissimilar physiological and ecological requirements probably as a consequence of temperature-mediated divergent adaptation. Further molecular data can confirm or reject this supposition in the near future. PMID- 30248897 TI - Suicide on the Railways in Belgium: A Typology of Locations and Potential for Prevention. AB - Suicide on railway networks comprises a serious public health problem. However, the geographical distribution and the environmental risk factors remain unclear. This study analyzed the geographic distribution of railway suicides in Belgium from 2008-2013 at the level of a railway section (average length of 3.5 km). Principal component analysis (PCA) identified three groups of correlations that helped explain the variance of railway suicide. The three groups are related to characteristics of urban spaces, psychiatric facilities, and railway traffic density. Based on the PCA results, the study found four types of railway sections. The density of railway suicide was average and low in the urban and rural/industrial sections, respectively. However, it was high in the suburban sections and the sections close to psychiatric facilities. As the geographical proximity of a psychiatric facility comprises a specific risk factor for suicide on railways, preventative measures should target these sections and establish collaborations with psychiatric facilities. The typology of locations found in this study constitutes crucial information for national and local suicide prevention on the Belgian railway network. PMID- 30248896 TI - Factors Associated with the Risk of Developing Coronary Artery Disease in Medicated Patients with Major Depressive Disorder. AB - Background: The aim of this study was to identify factors associated with high Framingham Risk Score (FRS) in medicated patients with major depressive disorder (MDD). Methods: We examined 61 medicated patients with MDD (mean age 37.77 +/- 7.67, 90.2% women) and 43 non-depressed controls (mean age 38.26 +/- 9.20, 90.7% women). We administered the Hamilton Depression Rating Scale (HAM-D) and measured systolic blood pressure (SBP), diastolic BP (DBP), mean arterial BP (MAP), pulse wave velocity (PWV), intima-media thickness (IMT), interleukin-6 (IL-6) and triglycerides. Results: We found that medicated patients with MDD had significantly higher levels of HAM-D score (p < 0.01), SBP (p = 0.015), MAP (p = 0.037), IL-6 level (p = 0.007), as compared with controls. Medicated patients who remained moderately to severely depressed showed significantly higher SBP (p = 0.049), DBP (p = 0.009), MAP (p = 0.024), IL-6 level (p = 0.019), left PWV (p = 0.004) and average PWV (p = 0.026) than those with mild depression. Multivariate regression showed that the interaction effect between HAM-D score and triglyceride level (p = 0.018) was significantly associated with FRS in medicated patients with MDD. Conclusions: This study highlights that the interaction effect of the severity of depression and the triglyceride level, was a modifiable factor positively associated with high FRS. PMID- 30248898 TI - Secure Authentication Protocol for Wireless Sensor Networks in Vehicular Communications. AB - With wireless sensor networks (WSNs), a driver can access various useful information for convenient driving, such as traffic congestion, emergence, vehicle accidents, and speed. However, a driver and traffic manager can be vulnerable to various attacks because such information is transmitted through a public channel. Therefore, secure mutual authentication has become an important security issue, and many authentication schemes have been proposed. In 2017, Mohit et al. proposed an authentication protocol for WSNs in vehicular communications to ensure secure mutual authentication. However, their scheme cannot resist various attacks such as impersonation and trace attacks, and their scheme cannot provide secure mutual authentication, session key security, and anonymity. In this paper, we propose a secure authentication protocol for WSNs in vehicular communications to resolve the security weaknesses of Mohit et al.'s scheme. Our authentication protocol prevents various attacks and achieves secure mutual authentication and anonymity by using dynamic parameters that are changed every session. We prove that our protocol provides secure mutual authentication by using the Burrows-Abadi-Needham logic, which is a widely accepted formal security analysis. We perform a formal security verification by using the well known Automated Validation of Internet Security Protocols and Applications tool, which shows that the proposed protocol is safe against replay and man-in-the middle attacks. We compare the performance and security properties of our protocol with other related schemes. Overall, the proposed protocol provides better security features and a comparable computation cost. Therefore, the proposed protocol can be applied to practical WSNs-based vehicular communications. PMID- 30248899 TI - Characterisation of InGaN by Photoconductive Atomic Force Microscopy. AB - Nanoscale structure has a large effect on the optoelectronic properties of InGaN, a material vital for energy saving technologies such as light emitting diodes. Photoconductive atomic force microscopy (PC-AFM) provides a new way to investigate this effect. In this study, PC-AFM was used to characterise four thick (~130 nm) In x Ga 1 - x N films with x = 5%, 9%, 12%, and 15%. Lower photocurrent was observed on elevated ridges around defects (such as V-pits) in the films with x <= 12 %. Current-voltage curve analysis using the PC-AFM setup showed that this was due to a higher turn-on voltage on these ridges compared to surrounding material. To further understand this phenomenon, V-pit cross sections from the 9% and 15% films were characterised using transmission electron microscopy in combination with energy dispersive X-ray spectroscopy. This identified a subsurface indium-deficient region surrounding the V-pit in the lower indium content film, which was not present in the 15% sample. Although this cannot directly explain the impact of ridges on turn-on voltage, it is likely to be related. Overall, the data presented here demonstrate the potential of PC-AFM in the field of III-nitride semiconductors. PMID- 30248901 TI - Metabolomics Approach for Validation of Self-Reported Ibuprofen and Acetaminophen Use. AB - Over-the-counter analgesic use is common and is typically assessed through self report; therefore, it is subject to misclassification. Detection of drug metabolites in biofluids offers a viable tool for validating self-reported analgesic use. Thus, the aim of this study was to determine the utility of a metabolomics approach for the validation of acetaminophen and ibuprofen use in blood samples. Untargeted mass spectrometry-based metabolomics analysis was conducted in serum samples from 1547 women and plasma samples from 556 men. The presence of two metabolites each for acetaminophen and ibuprofen at levels at or above a defined cutoff value was used to determine concordance with self-reported use. For acetaminophen use based on the presence of both acetaminophen and acetamidophenylglucuronide, concordance was 98.5-100% among individuals reporting use today, and 79.8-91.4% for those reporting never or rare use. Ibuprofen use based on the presence of both carboxyibuprofen and hydroxyibuprofen resulted in concordance of 51.3-52.5% for individuals reporting use today and 99.4-100% for those reporting never or rare use. Our findings suggest that an untargeted metabolomics approach in blood samples may be useful for validating self-reported acetaminophen use. However, this approach appears unlikely to be suitable for validating ibuprofen use. PMID- 30248900 TI - Phenomic Impact of Genetically-Determined Euthyroid Function and Molecular Differences between Thyroid Disorders. AB - BACKGROUND: The thyroid plays a key role in development and homeostasis, but it has been difficult to establish causality with diseases and phenotypic traits because of several potential confounders. METHODS: To determine the causal effect of euthyroid function, we conducted a two-sample Mendelian randomization study of euthyroid thyrotropin (TSH) and free thyroxine (FT4) levels with respect to 2419 traits assessed in 337,199 individuals from UK Biobank. Additionally, we investigated the molecular differences between hypothyroidism and hyperthyroidism using genome-wide data. RESULTS: After multiple testing correction, sixteen traits appear to be affected by genetically-determined euthyroid TSH, including multiple thyroid-related traits, e.g., hypothyroidism (p = 2.39 * 10-17), height (p = 2.76 * 10-10), body fat distribution (impedance of whole body, p = 4.43 * 10 8), pulse rate (p = 2.84 * 10-8), female infertility (p = 4.91 * 10-6), and hearing aid use (p = 7.10 * 10-5). Moreover, we found a consistent genetic correlation between hypothyroidism and hyperthyroidism (rg = 0.45, p = 5.45 * 10 6) with several immune pathways shared between these diseases. Two molecular pathways survived multiple testing correction for specificity to hyperthyroidism, JAK/STAT signaling (p = 1.02 * 10-6) and Rac guanyl-nucleotide exchange factor activity (p = 4.39 * 10-6). CONCLUSION: Our data shed new light on the inter individual variability of euthyroid function and the molecular mechanisms of the two thyroid disorders investigated. PMID- 30248902 TI - Effects of Al3+ Substitution on Structural and Magnetic Behavior of CoFe2O4 Ferrite Nanomaterials. AB - A sol-gel autocombustion method was used to synthesize Al3+ ion-substituted cobalt ferrite CoAlxFe2-xO4 (x = 0-1.5). According to X-ray diffraction analysis (XRD), cobalt ferrite was in a single cubic phase after being calcined at 1000 degrees C for 3 h. Moreover, the lattice constant decreased with increase in aluminum substituents. When the sample was analyzed by Scanning Electron Microscopy (SEM), we found that uniformly sized, well-crystallized grains were distributed in the sample. Furthermore, we confirmed that Al3+ ion-substituted cobalt ferrite underwent a transition from ferrimagnetic to superparamagnetic behavior; the superparamagnetic behavior was completely correlated with the increase in Al3+ ion concentration at room temperature. All these findings were observed in Mossbauer spectra. For the cobalt ferrite CoAlxFe2-xO4, the coercivity and saturation magnetization decrease with an increase in aluminum content. When the annealing temperature of CoAl0.1Fe1.9O4 was steadily increased, the coercivity and saturation magnetization initially increased and then decreased. PMID- 30248895 TI - Vimentin Diversity in Health and Disease. AB - Vimentin is a protein that has been linked to a large variety of pathophysiological conditions, including cataracts, Crohn's disease, rheumatoid arthritis, HIV and cancer. Vimentin has also been shown to regulate a wide spectrum of basic cellular functions. In cells, vimentin assembles into a network of filaments that spans the cytoplasm. It can also be found in smaller, non filamentous forms that can localise both within cells and within the extracellular microenvironment. The vimentin structure can be altered by subunit exchange, cleavage into different sizes, re-annealing, post-translational modifications and interacting proteins. Together with the observation that different domains of vimentin might have evolved under different selection pressures that defined distinct biological functions for different parts of the protein, the many diverse variants of vimentin might be the cause of its functional diversity. A number of review articles have focussed on the biology and medical aspects of intermediate filament proteins without particular commitment to vimentin, and other reviews have focussed on intermediate filaments in an in vitro context. In contrast, the present review focusses almost exclusively on vimentin, and covers both ex vivo and in vivo data from tissue culture and from living organisms, including a summary of the many phenotypes of vimentin knockout animals. Our aim is to provide a comprehensive overview of the current understanding of the many diverse aspects of vimentin, from biochemical, mechanical, cellular, systems biology and medical perspectives. PMID- 30248903 TI - Heterocycles 48. Synthesis, Characterization and Biological Evaluation of Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives as Anti-Inflammatory Agents. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are an important pharmacological class of drugs used for the treatment of inflammatory diseases. They are also characterized by severe side effects, such as gastrointestinal damage, increased cardiovascular risk and renal function abnormalities. In order to synthesize new anti-inflammatory and analgesic compounds with a safer profile of side effects, a series of 2,6-diaryl-imidazo[2,1-b][1,3,4]thiadiazole derivatives 5a-l were synthesized and evaluated in vivo for their anti-inflammatory and analgesic activities in carrageenan-induced rat paw edema. Among all compounds, 5c showed better anti-inflammatory activity compared to diclofenac, the standard drug, and compounds 5g, 5i, 5j presented a comparable antinociceptive activity to diclofenac. None of the compounds showed ulcerogenic activity. Molecular docking studies were carried out to investigate the theoretical bond interactions between the compounds and target, the cyclooxygenases (COX-1/COX-2). The compound 5c exhibited a higher inhibition of COX-2 compared to diclofenac. PMID- 30248904 TI - Antibacterial Activity of Fructose-Stabilized Silver Nanoparticles Produced by Direct Current Atmospheric Pressure Glow Discharge towards Quarantine Pests. AB - Development of efficient plant protection methods against bacterial phytopathogens subjected to compulsory control procedures under international legislation is of the highest concern having in mind expensiveness of enforced quarantine measures and threat of the infection spread in disease-free regions. In this study, fructose-stabilized silver nanoparticles (FRU-AgNPs) were produced using direct current atmospheric pressure glow discharge (dc-APGD) generated between the surface of a flowing liquid anode (FLA) solution and a pin-type tungsten cathode in a continuous flow reaction-discharge system. Resultant spherical and stable in time FRU-AgNPs exhibited average sizes of 14.9 +/- 7.9 nm and 15.7 +/- 2.0 nm, as assessed by transmission electron microscopy (TEM) and dynamic light scattering (DLS), respectively. Energy dispersive X-ray spectroscopy (EDX) analysis revealed that the obtained nanomaterial was composed of Ag while selected area electron diffraction (SAED) indicated that FRU-AgNPs had the face-centered cubic crystalline structure. The fabricated FRU-AgNPs show antibacterial properties against Erwinia amylovora, Clavibacter michiganensis, Ralstonia solanacearum, Xanthomonas campestris pv. campestris and Dickeya solani strains with minimal inhibitory concentrations (MICs) of 1.64 to 13.1 mg L-1 and minimal bactericidal concentrations (MBCs) from 3.29 to 26.3 mg L-1. Application of FRU-AgNPs might increase the repertoire of available control procedures against most devastating phytopathogens and as a result successfully limit their agricultural impact. PMID- 30248905 TI - Associations Between the Dopamine D4 Receptor and DAT1 Dopamine Transporter Genes Polymorphisms and Personality Traits in Addicted Patients. AB - Many factors are involved in addiction. The dopaminergic system is thought to be the key element in this process. The mesolimbic dopamine system is a crucial element in the reward system. Changes in this system are thought to be leading to substance use disorders and dependence. Therefore, for our study we chose an analysis of two polymorphisms in genes (Variable Number of Tandem Repeats in DRD4 and DAT1) responsible for dopaminergic transmission, which might be implicated in the scores of personality traits measured by the NEO-FFI test. The study group consisted of 600 male volunteers-299 addicted subjects and 301 controls. Both groups were recruited by psychiatrists; in the case group addiction was diagnosed; in the controls a mental illness was excluded. In both groups the same psychometric test and genotyping by the PCR VNTR method were performed. The results were investigated by a multivariate analysis of the main effects ANOVA. In the presented study no DRD4 main effects were found for any of the analyzed traits but the DRD4 main effects approximated to the statistical significance for the extraversion scale. However, no DAT1 main effects were found for any of the analyzed traits but the DAT1 main effects approximated to the statistical significance for the agreeability scale.These associations open new possibilities for addiction research. PMID- 30248906 TI - The Multifaceted Zoonotic Risk of H9N2 Avian Influenza. AB - Poultry-adapted H9N2 avian influenza viruses (AIVs) are commonly found in many countries in Asia, the Middle East, Africa, and Europe, and although classified as low pathogenic viruses, they are an economically important disease. Besides the importance of the disease in the poultry industry, some H9N2 AIVs are also known to be zoonotic. The disease in humans appears to cause primarily a mild upper respiratory disease, and doesn't cause or only rarely causes the severe pneumonia often seen with other zoonotic AIVs like H5N1 or H7N9. Serologic studies in humans, particularly in occupationally exposed workers, show a large number of people with antibodies to H9N2, suggesting infection is commonly occurring. Of the four defined H9N2 poultry lineages, only two lineages, the G1 and the Y280 lineages, are associated with human infections. Almost all of the viruses from humans have a leucine at position 226 (H3 numbering) of the hemagglutinin associated with a higher affinity of binding with alpha2,6 sialic acid, the host cell receptor most commonly found on glycoproteins in the human upper respiratory tract. For unknown reasons there has also been a shift in recent years of poultry viruses in the G1 and Y280 lineages to also having leucine instead of glutamine, the amino acid found in most avian viruses, at position 226. The G1 and Y280 poultry lineages because of their known ability to infect humans, the high prevalence of the virus in poultry in endemic countries, the lack of antibody in most humans, and the shift of poultry viruses to more human-like receptor binding makes these viruses a human pandemic threat. Increased efforts for control of the virus, including through effective vaccine use in poultry, is warranted for both poultry and public health goals. PMID- 30248907 TI - Endogenous Omega (n)-3 Fatty Acids in Fat-1 Mice Attenuated Depression-Like Behavior, Imbalance between Microglial M1 and M2 Phenotypes, and Dysfunction of Neurotrophins Induced by Lipopolysaccharide Administration. AB - n-3 polyunsaturated fatty acids (PUFAs) have been reported to improve depression. However, PUFA purities, caloric content, and ratios in different diets may affect the results. By using Fat-1 mice which convert n-6 to n-3 PUFAs in the brain, this study further evaluated anti-depressant mechanisms of n-3 PUFAs in a lipopolysaccharide (LPS)-induced model. Adult male Fat-1 and wild-type (WT) mice were fed soybean oil diet for 8 weeks. Depression-like behaviors were measured 24 h after saline or LPS central administration. In WT littermates, LPS reduced sucrose intake, but increased immobility in forced-swimming and tail suspension tests. Microglial M1 phenotype CD11b expression and concentrations of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-17 were elevated, while M2 phenotype-related IL-4, IL-10, and transforming growth factor (TGF)-beta1 were decreased. LPS also reduced the expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (Trk B), while increasing glial fibrillary acidic protein expression and pro-BDNF, p75, NO, and iNOS levels. In Fat-1 mice, LPS-induced behavioral changes were attenuated, which were associated with decreased pro-inflammatory cytokines and reversed changes in p75, NO, iNOS, and BDNF. Gas chromatography assay confirmed increased n-3 PUFA levels and n-3/n-6 ratios in the brains of Fat-1 mice. In conclusion, endogenous n-3 PUFAs may improve LPS-induced depression-like behavior through balancing M1 and M2 phenotypes and normalizing BDNF function. PMID- 30248908 TI - Cognitive Load Changes during Music Listening and its Implication in Earcon Design in Public Environments: An fNIRS Study. AB - A key for earcon design in public environments is to incorporate an individual's perceived level of cognitive load for better communication. This study aimed to examine the cognitive load changes required to perform a melodic contour identification task (CIT). While healthy college students (N = 16) were presented with five CITs, behavioral (reaction time and accuracy) and cerebral hemodynamic responses were measured using functional near-infrared spectroscopy. Our behavioral findings showed a gradual increase in cognitive load from CIT1 to CIT3 followed by an abrupt increase between CIT4 (i.e., listening to two concurrent melodic contours in an alternating manner and identifying the direction of the target contour, p < 0.001) and CIT5 (i.e., listening to two concurrent melodic contours in a divided manner and identifying the directions of both contours, p < 0.001). Cerebral hemodynamic responses showed a congruent trend with behavioral findings. Specific to the frontopolar area (Brodmann's area 10), oxygenated hemoglobin increased significantly between CIT4 and CIT5 (p < 0.05) while the level of deoxygenated hemoglobin decreased. Altogether, the findings indicate that the cognitive threshold for young adults (CIT5) and appropriate tuning of the relationship between timbre and pitch contour can lower the perceived cognitive load and, thus, can be an effective design strategy for earcon in a public environment. PMID- 30248909 TI - Correlation of Materials Property and Performance with Internal Structures Evolvement Revealed by Laboratory X-ray Tomography. AB - Although X-rays generated from a laboratory-based tube cannot be compared with synchrotron radiation in brilliance and monochromaticity, they are still viable and accessible in-house for ex situ or interrupted in situ X-ray tomography. This review mainly demonstrates recent works using laboratory X-ray tomography coupled with the measurements of properties or performance testing under various conditions, such as thermal, stress, or electric fields. Evolvements of correlated internal structures for some typical materials were uncovered. The damage features in a graded metallic 3D mesh and a metallic glass under mechanical loading were revealed and investigated. Micro-voids with thermal treatment and void healing phenomenon with electropulsing were clearly demonstrated and quantitatively analyzed. The substance transfer around an electrode of a Li-S battery and the protective performance of a Fe-based metallic glass coating on stainless steel were monitored through electrochemical processes. It was shown that in situ studies of the laboratory X-ray tomography were suitable for the investigation of structure change under controlled conditions and environments. An extension of the research for in situ laboratory X-ray tomography can be expected with supplementary novel techniques for internal strain, global 3D grain orientation, and a fast tomography strategy. PMID- 30248911 TI - Genome-Wide Association Analysis of Mucilage and Hull Content in Flax (Linum usitatissimum L.) Seeds. AB - New flaxseed cultivars differing in seed mucilage content (MC) with low hull content (HC) represent an attractive option to simultaneously target the food and feed markets. Here, a genome-wide association study (GWAS) was conducted for MC and HC in 200 diverse flaxseed accessions genotyped with 1.7 million single nucleotide polymorphism (SNP) markers. The data obtained for MC and HC indicated a broad phenotypic variation and high (~70%) and a moderate (~49%) narrow sense heritability, respectively. MC and HC did not differ statistically between fiber and oil morphotypes, but yellow-seeded accessions had 2.7% less HC than brown seeded ones. The genome-wide linkage disequilibrium (LD) decayed to r2 = 0.1 at a physical distance of ~100 kb. Seven and four quantitative trait loci (QTL) were identified for MC and HC, respectively. Promising candidate genes identified include Linum usitatissimum orthologs of the Arabidopsis thaliana genes TRANSPARENT TESTA 8, SUBTILISIN-LIKE SERINE PROTEASE, GALACTUROSYL TRANSFERASE LIKE 5, MUCILAGE-MODIFIED 4, AGAMOUS-LIKE MADS-BOX PROTEIN AGL62, GLYCOSYL HYDROLASE FAMILY 17, and UDP-GLUCOSE FLAVONOL 3-O-GLUCOSYLTRANSFERASE. These genes have been shown to play a role in mucilage synthesis and release, seed coat development and anthocyanin biosynthesis in A. thaliana. The favorable alleles will be useful in flaxseed breeding towards the goal of achieving the ideal MC and HC composition for food and feed by genomic-based breeding. PMID- 30248912 TI - Algal Bloom Prediction Using Extreme Learning Machine Models at Artificial Weirs in the Nakdong River, Korea. AB - In this study, we design an intelligent model to predict chlorophyll-a concentration, which is the primary indicator of algal blooms, using extreme learning machine (ELM) models. Modeling algal blooms is important for environmental management and ecological risk assessment. For this purpose, the performance of the designed models was evaluated for four artificial weirs in the Nakdong River, Korea. The Nakdong River has harmful annual algal blooms that can affect health due to exposure to toxins. In contrast to conventional neural network (NN) that use backpropagation (BP) learning methods, ELMs are fast learning, feedforward neural networks that use least square estimates (LSE) for regression. The weights connecting the input layer to the hidden nodes are randomly assigned and are never updated. The dataset used in this study includes air temperature, rainfall, solar radiation, total nitrogen, total phosphorus, N/P ratio, and chlorophyll-a concentration, which were collected on a weekly basis from January 2013 to December 2016. Here, upstream chlorophyll-a concentration data was used in our ELM2 model to improve algal bloom prediction performance. In contrast, the ELM1 model only uses downstream chlorophyll-a concentration data. The experimental results revealed that the ELM2 model showed better performance in comparison to the ELM1 model. Furthermore, the ELM2 model showed good prediction and generalization performance compared to multiple linear regression (LR), conventional neural network with backpropagation (NN-BP), and adaptive neuro-fuzzy inference system (ANFIS). PMID- 30248910 TI - Metabolic Effects of Metformin in the Failing Heart. AB - Accumulating evidence shows that metformin is an insulin-sensitizing antidiabetic drug widely used in the treatment of type 2 diabetes mellitus (T2DM), which can exert favorable effects on cardiovascular risk and may be safely used in patients with heart failure (HF), and even able to reduce the incidence of HF and to reduce HF mortality. In failing hearts, metformin improves myocardial energy metabolic status through the activation of AMP (adenosine monophosphate) activated protein kinase (AMPK) and the regulation of lipid and glucose metabolism. By increasing nitric oxide (NO) bioavailability, limiting interstitial fibrosis, reducing the deposition of advanced glycation end-products (AGEs), and inhibiting myocardial cell apoptosis metformin reduces cardiac remodeling and hypertrophy, and thereby preserves left ventricular systolic and diastolic functions. While a lot of preclinical and clinical studies showed the cardiovascular safety of metformin therapy in diabetic patients and HF, to confirm observed benefits, the specific large-scale trials configured for HF development in diabetic patients as a primary endpoints are necessary. PMID- 30248913 TI - Monitoring Injuries Associated with Mandated Children's Products in Australia: What Can the Data Tell Us? AB - Mandatory standard regulation is used within Australia to ensure the safety of consumer products, preventing product-related injury. Standard regulation is particularly important for products designed for use by children, who are highly vulnerable to sustaining product-related injuries due to their small size and inability to identify product hazards. This project aims to investigate how effectively information regarding product-related injuries is able to be captured within Australian health and coronial data. Further, it aims to investigate the extent to which child injury occurs for products for which mandatory safety standards exist through the review of available data. This study highlights significant limitations in injury surveillance data for identification and monitoring of child product-related injuries. This in turn limits the evidence base to assess the efficacy of existing regulations. Available data show baby walkers, cots, prams, nightwear, and bunk beds to be associated with a considerable number of child hospital presentations, admissions, and deaths. A significant scope for improvement in current product injury recording practices in the health sector exists. PMID- 30248914 TI - Real-Time Traffic Sign Detection and Recognition Method Based on Simplified Gabor Wavelets and CNNs. AB - Traffic sign detection and recognition plays an important role in expert systems, such as traffic assistance driving systems and automatic driving systems. It instantly assists drivers or automatic driving systems in detecting and recognizing traffic signs effectively. In this paper, a novel approach for real time traffic sign detection and recognition in a real traffic situation was proposed. First, the images of the road scene were converted to grayscale images, and then we filtered the grayscale images with simplified Gabor wavelets (SGW), where the parameters were optimized. The edges of the traffic signs were strengthened, which was helpful for the next stage of the process. Second, we extracted the region of interest using the maximally stable extremal regions algorithm and classified the superclass of traffic signs using the support vector machine (SVM). Finally, we used convolution neural networks with input by simplified Gabor feature maps, where the parameters were the same as the detection stage, to classify the traffic signs into their subclasses. The experimental results based on Chinese and German traffic sign databases showed that the proposed method obtained a comparable performance with the state-of-the art method, and furthermore, the processing efficiency of the whole process of detection and classification was improved and met the real-time processing demands. PMID- 30248916 TI - Multitarget Tracking Algorithm Using Multiple GMPHD Filter Data Fusion for Sonar Networks. AB - Multitarget tracking algorithms based on sonar usually run into detection uncertainty, complex channel and more clutters, which cause lower detection probability, single sonar sensors failing to measure when the target is in an acoustic shadow zone, and computational bottlenecks. This paper proposes a novel tracking algorithm based on multisensor data fusion to solve the above problems. Firstly, under more clutters and lower detection probability condition, a Gaussian Mixture Probability Hypothesis Density (GMPHD) filter with computational advantages was used to get local estimations. Secondly, this paper provided a maximum-detection capability multitarget track fusion algorithm to deal with the problems caused by low detection probability and the target being in acoustic shadow zones. Lastly, a novel feedback algorithm was proposed to improve the GMPHD filter tracking performance, which fed the global estimations as a random finite set (RFS). In the end, the statistical characteristics of OSPA were used as evaluation criteria in Monte Carlo simulations, which showed this algorithm's performance against those sonar tracking problems. When the detection probability is 0.7, compared with the GMPHD filter, the OSPA mean of two sensor and three sensor fusion was decrease almost by 40% and 55%, respectively. Moreover, this algorithm successfully tracks targets in acoustic shadow zones. PMID- 30248917 TI - Progress toward Understanding the Molecular Basis of Fruit Response to Hypoxia. AB - Oxygen has shaped life on Earth as we know it today. Molecular oxygen is essential for normal cellular function, i.e., plants need oxygen to maintain cellular respiration and for a wide variety of biochemical reactions. When oxygen levels in the cell are lower than levels needed for respiration, then the cell experiences hypoxia. Plants are known to experience root hypoxia during natural environmental conditions like flooding. Fruit, on the other hand, is known to be hypoxic under normal oxygen conditions. This observation could be explained (at least partially) as a consequence of diffusional barriers, low tissue diffusivity, and high oxygen consumption by respiration. From the physiological point of view, hypoxia is known to have a profound impact on fruit development, since it is well documented that a low oxygen environment can significantly delay ripening and senescence of some fruit. This effect of a low-oxygen environment is readily used for optimizing storage conditions and transport, and for prolonging the shelf life of several fruit commodities. Therefore, further understanding of the complex relationship between oxygen availability within the cell and fruit development could assist postharvest management. PMID- 30248915 TI - The Role of Genetics in Moderating the Inter-Individual Differences in the Ergogenicity of Caffeine. AB - Caffeine use is widespread among athletes following its removal from the World Anti-Doping Agency banned list, with approximately 75% of competitive athletes using caffeine. While literature supports that caffeine has a small positive ergogenic effect for most forms of sports and exercise, there exists a significant amount of inter-individual difference in the response to caffeine ingestion and the subsequent effect on exercise performance. In this narrative review, we discuss some of the potential mechanisms and focus on the role that genetics has in these differences. CYP1A2 and ADORA2A are two of the genes which are thought to have the largest impact on the ergogenicity of caffeine. CYP1A2 is responsible for the majority of the metabolism of caffeine, and ADORA2A has been linked to caffeine-induced anxiety. The effects of CYP1A2 and ADORA2A genes on responses to caffeine will be discussed in detail and an overview of the current literature will be presented. The role of these two genes may explain a large portion of the inter-individual variance reported by studies following caffeine ingestion. Elucidating the extent to which these genes moderate responses to caffeine during exercise will ensure caffeine supplementation programs can be tailored to individual athletes in order to maximize the potential ergogenic effect. PMID- 30248918 TI - Effects of the Hormone Replacement Therapy and of Soy Isoflavones on Bone Resorption in Postmenopause. AB - Postmenopausal osteoporosis is the most common form of osteoporosis and one of the major public health problems in developed countries. The prevalence of this condition, associated with the physiological stage of menopause, is continuously increasing. This study evaluated the effectiveness of soy isoflavones as compared to hormone replacement therapy (HRT) in low doses, on the prevention of postmenopausal osteoporosis, by determining bone mineral density (BMD) and urinary deoxypyridinoline (D-pyr) in physiological postmenopausal women. The study was conducted over a period of 12 months, on three parallel groups, which included a total of 325 postmenopausal women (HRT group: n = 95; phytoestrogens group: n = 124; control group: n = 106). At the one-year evaluation, we observed T-score normalization in a small number of cases (5.26%, 2.42% and 0.00%, respectively). The average values of D-Pyr decreased by 11.38% in the group treated with phytoestrogens (p < 0.05) and by 15.32% in the group that followed HRT (p < 0.05); it increased by 4.38% in the control group (p > 0.05). Both therapies have beneficial effects on bone metabolism, leading to a significant decrease in the evolution of bone resorption and there are no major differences between the efficacy of HRT and phytoestrogens in terms of the effects on BMD and bone resorption. PMID- 30248919 TI - Non-Inherited Maternal Antigens Identify Acceptable HLA Mismatches: A New Policy for the Hellenic Cord Blood Bank. AB - BACKGROUND: During pregnancy, the maternal-fetal contact may lead to the development of tolerance against the maternal human leukocyte antigen (HLA) that is not inherited by the fetus. These non-inherited maternal antigens (NIMAs) define acceptable HLA mismatches; therefore, the number of HLA phenotypes that are suitable matches for patients who need a hematopoietic stem cell transplant could be increased. Cord blood unit (CBU) transplantations to patients mismatched for a HLA loci, but similar to the NuIotaMUAs of the CBU, have a prognosis similar to 6/6-matched ones. METHODS: The Hellenic Cord Blood Bank (HCBB) identified the maternal HLA of 380 cord blood donors, specifying the NIMA haplotypes of the related cryostored CBUs. RESULTS: The HCBB extended the pool of HLA phenotypes through the generation of unique virtual phenotypes (VPs). A "VP database" was set up, using Microsoft Office-AccessTM, in order to provide NIMA matched CBUs for potential recipients. The effectiveness of VPs' matching was tested in 80 Greek patients. CONCLUSION: This methodology may contribute to the increase of the number of available CBUs for patients, in the case where there is no available CBU, or in case an additional one is needed. Through this method, the CBUs could be used faster and more effectively, rather than being cryostored for long periods of time. PMID- 30248921 TI - Does the Number of Fingers on the Bag Influence Volume Delivery? A Randomized Model Study of Bag-Valve-Mask Ventilation in Infants. AB - We sought to compare the effectiveness of two versus five fingers used for bag valve-mask (BVM) ventilation on effective tidal volume (VTeff) delivery in an infant resuscitation model. In a randomised cross-over study, 40 healthcare professionals ventilated a modified leak-free infant resuscitation manikin with both two and five fingers, using a self-inflating bag. The delivered and effective tidal volumes, ventilation rate, and mask leak were measured and recorded using a respiratory function monitor. We found no significant differences in the VTeff (five-finger 61.7 +/- 23.9 vs. two-finger 58.8 +/- 16.6 mL; p = 0.35) or ventilatory minute volume (2.71 +/- 1.59 vs. 2.76 +/- 1.24 L/min; p = 0.40) of both BVM ventilation techniques. However, there was an increase in the delivered tidal volume (VTdel) and mask leak when using the five finger technique compared with the two-finger technique (VTdel 96.1 +/- 19.4 vs. 87.7 +/- 15.5 mL; p < 0.01; and mask leak 34.6 +/- 23.0 vs. 30.0 +/- 21.0%; p = 0.02). Although the five-finger technique was associated with an increased mask leak, the number of fingers used during the BVM ventilation had no effect on VTeff in an infant resuscitation model. PMID- 30248923 TI - Review of Recent Phased Arrays for Millimeter-Wave Wireless Communication. AB - Owing to the rapid growth in wireless data traffic, millimeter-wave (mm-wave) communications have shown tremendous promise and are considered an attractive technique in fifth-generation (5G) wireless communication systems. However, to design robust communication systems, it is important to understand the channel dynamics with respect to space and time at these frequencies. Millimeter-wave signals are highly susceptible to blocking, and they have communication limitations owing to their poor signal attenuation compared with microwave signals. Therefore, by employing highly directional antennas, co-channel interference to or from other systems can be alleviated using line-of-sight (LOS) propagation. Because of the ability to shape, switch, or scan the propagating beam, phased arrays play an important role in advanced wireless communication systems. Beam-switching, beam-scanning, and multibeam arrays can be realized at mm-wave frequencies using analog or digital system architectures. This review article presents state-of-the-art phased arrays for mm-wave mobile terminals (MSs) and base stations (BSs), with an emphasis on beamforming arrays. We also discuss challenges and strategies used to address unfavorable path loss and blockage issues related to mm-wave applications, which sets future directions. PMID- 30248922 TI - An Evaluation of the Potential of NMR Spectroscopy and Computational Modelling Methods to Inform Biopharmaceutical Formulations. AB - Protein-based therapeutics are considered to be one of the most important classes of pharmaceuticals on the market. The growing need to prolong stability of high protein concentrations in liquid form has proven to be challenging. Therefore, significant effort is being made to design formulations which can enable the storage of these highly concentrated protein therapies for up to 2 years. Currently, the excipient selection approach involves empirical high-throughput screening, but does not reveal details on aggregation mechanisms or the molecular level effects of the formulations under storage conditions. Computational modelling approaches have the potential to elucidate such mechanisms, and rapidly screen in silico prior to experimental testing. Nuclear Magnetic Resonance (NMR) spectroscopy can also provide complementary insights into excipient-protein interactions. This review will highlight the underpinning principles of molecular modelling and NMR spectroscopy. It will also discuss the advancements in the applications of computational and NMR approaches in investigating excipient protein interactions. PMID- 30248920 TI - The Unfolded Protein Response in Breast Cancer. AB - In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are urgently required. A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of novel breast cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis but has diverse physiological and disease-specific functions. In breast cancer, UPR signalling promotes a malignant phenotype and can confer tumours with resistance to widely used therapies. Here, we review several roles for UPR signalling in breast cancer, highlighting UPR-mediated therapy resistance and the potential for targeting the UPR alone or in combination with existing therapies. PMID- 30248924 TI - Laboratory-Assessed Markers of Cardiometabolic Health and Associations with GIS Based Measures of Active-Living Environments. AB - Active-living-friendly environments have been linked to physical activity, but their relationships with specific markers of cardiometabolic health remain unclear. We estimated the associations between active-living environments and markers of cardiometabolic health, and explored the potential mediating role of physical activity in these associations. We used data collected on 2809 middle aged adults who participated in the Canadian Health Measures Survey (2007-2009; 41.5 years, SD = 15.1). Environments were assessed using an index that combined GIS-derived measures of street connectivity, land use mix, and population density. Body mass index (BMI), systolic blood pressure (SBP), hemoglobin A1c, and cholesterol were assessed in a laboratory setting. Daily step counts and moderate-to-vigorous intensity physical activity (MVPA) were assessed for seven days using accelerometers. Associations were estimated using robust multivariable linear regressions adjusted for sociodemographic factors that were assessed via questionnaire. BMI was 0.79 kg/m2 lower (95% confidence interval (CI) -1.31, 0.27) and SBP was 1.65 mmHg lower (95% CI -3.10, -0.20) in participants living in the most active-living-friendly environments compared to the least, independent of daily step counts or MVPA. A 35.4 min/week difference in MPVA (95% CI 24.2, 46.6) was observed between residents of neighborhoods in the highest compared to the lowest active-living-environment quartiles. Cycling to work rates were also the highest in participants living in the highest living-environment quartiles (e.g., Q4 vs. Q1: 10.4% vs. 4.9%). Although active-living environments are associated with lower BMI and SBP, and higher MVPA and cycling rates, neither daily step counts nor MVPA appear to account for environment-BMI/SBP relationships. This suggests that other factors not assessed in this study (e.g., food environment or unmeasured features of the social environment) may explain this relationship. PMID- 30248925 TI - Preparation and Optimization of Optical pH Sensor Based on Sol-Gel. AB - Making use of the sol-gel technique, an optical pH sensor was prepared, which was made from an organic carrier with four indictors including congo red, bromophenol blue, cresol red, and chlorophenol red, cross-linked by tetraethyl orthosilicate (TEOS) and cellulose acetate. The actual detection range of the optical pH sensor is 2.5-11.0. The optimal ratio of ethyl orthosilicate, absolute ethanol, deionized water, and hydrochloric acid in glue precursor of the sensor-sensitive membrane was explored. The orthogonal experiment was designed to optimize the dosage of cellulose acetate, N,N-dimethylformamide (DMF), indicator, hydrochloric acid, and precursor glue in preparing the sensor-sensitive membrane. The linearity, measurement accuracy, repeatability, stability, and response time of the prepared pH sensor were tested. The measurement results were analyzed using a support vector machine and linear regression. The experimental results show that the optical pH sensor has a measurement accuracy of up to 0.2 pH and better stability and repeatability than the traditional pH glass electrode. PMID- 30248926 TI - Development and Application of a QuEChERS-Based Liquid Chromatography Tandem Mass Spectrometry Method to Quantitate Multi-Component Alternaria Toxins in Jujube. AB - A simple, rapid and efficient methodology was developed and validated for the analysis of four Alternaria toxins in jujube: Tenuazonic acid, alternariol, alternariol monomethyl ether, and tentoxin. Under the optimized extraction procedure, chromatographic conditions, and instrumental parameters, the four toxins were effectively extracted via a quick, easy, cheap, effective, rugged, and safe (QuEChERS) method, and quantified by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Matrix-matched calibrations ranging from 0.01 to 0.5 MUg mL-1 were conducted for the quantification due to the matrix effect. A blank jujube sample was spiked at 40, 80 and 160 MUg kg-1, obtaining recoveries in the range of 83.5-109.6%. Limits of detection and limits of quantification were in the range of 0.14-0.26 and 0.47 0.87 MUg kg-1, respectively. Finally, the developed method was applied for the quantification of the four toxins in 14 jujube samples, including black spot infected and uninfected samples. Results showed that the predominant toxin detected in all the samples was tenuazonic acid, the content of which was associated with the infection level; alternariol, alternariol monomethyl ether, and tentoxin were detected in all the infected samples and some of the uninfected samples with rather low contents. PMID- 30248927 TI - Hormesis: Path and Progression to Significance. AB - This paper tells the story of how hormesis became recognized as a fundamental concept in biology, affecting toxicology, microbiology, medicine, public health, agriculture, and all areas related to enhancing biological performance. This paper assesses how hormesis enhances resilience to normal aging and protects against a broad spectrum of neurodegenerative, cardiovascular, and other diseases, as well as trauma and other threats to health and well-being. This paper also explains the application of hormesis to several neurodegenerative diseases such as Parkinson's and Huntington's disease, macrophage polarization and its systematic adaptive protections, and the role of hormesis in enhancing stem cell functioning and medical applications. PMID- 30248929 TI - Evaluation of Antibiotic-Releasing Triphasic Bone Void Filler In-Vitro. AB - Bone void fillers (BVFs) containing calcium sulfate, tricalcium phosphate (TCP), and hydroxyapatite can be loaded with antibiotics for infection treatment or prevention under surgeon-directed use. The aim of this study was to characterize the handling and elution properties of a triphasic BVF loaded with common antibiotics. BVF was mixed with vancomycin and/or tobramycin to form pellets, and the set time was recorded. A partial refreshment elution study was conducted with time points at 4, 8, and 24 h, as well as 2, 7, 14, 28, and 42 days. Effects on dissolution were evaluated in a 14-day dissolution study. Set time increased to over 1 h for groups containing tobramycin, although vancomycin had a minimal effect. Pellets continued to elute antibiotics throughout the 42-day elution study, suggesting efficacy for the treatment or prevention of orthopedic infections. BVF containing vancomycin or tobramycin showed similar dissolution at 14 days compared to BVF without antibiotics; however, BVF containing both antibiotics showed significantly more dissolution. PMID- 30248928 TI - Characterization of Chicken-Derived Single Chain Antibody Fragments against Venom of Naja Naja Atra. AB - Traditional, horse-derived antivenin is currently the most efficient treatment against snake bites. However, it is costly and has unpredictable side effects. Thus, alternative, cost-effective strategies for producing antivenin are needed. In this study, we immunized hens with inactivated NNA venom proteins from the cobra Naja naja atra (NNA). Purified yolk IgY antibodies showed specific anti-NNA binding activity comparable to that of the equine-derived antivenin. We used phage display technology to generate two antibody libraries containing 9.0 * 108 and 8.4 * 108 clones with a short or long linker, respectively. The phage ELISA indicated that anti-NNA clones displaying single-chain variable fragments (scFv) were significantly enriched after biopanning. The nucleotide sequences of the light and heavy chain genes of 30 monoclonal scFv antibodies were determined and classified into six groups with the short linker and nine groups with the long linker. These scFv clones specifically bound to NNA proteins but not to venom proteins from other snakes. Their binding affinities were further determined by competitive ELISA. Animal model studies showed that anti-NNA IgY antibodies exhibited complete protective effects, while a combination of scFv antibodies raised the survival rates and times of mice challenged with lethal doses of NNA venom proteins. PMID- 30248931 TI - Dogs (Canis familiaris) as Sentinels for Human Infectious Disease and Application to Canadian Populations: A Systematic Review. AB - In a world where climate change, vector expansion, human activity, and pathogen dispersal do not respect boundaries, the human-animal-pathogen interface has become less defined. Consequently, a One Health approach to disease surveillance and control has generated much interest across several disciplines. This systematic review evaluates current global research on the use of domestic dogs as sentinels for human infectious disease, and critically appraises how this may be applied within Canada. Results highlighted a bias in research from high- and middle-income-economy countries, with 35% of the studies describing data from the Latin America/Caribbean region, 25% from North America, and 11% from the European/Central Asia region. Bacteria were the most studied type of infectious agent, followed by protozoa, viruses, helminths, and fungi. Only six out of 142 studies described disease in Canada: four researched a variety of pathogens within Indigenous communities, one researched Borrelia burgdorferi in British Columbia, and one researched arboviruses in Quebec. Results from this review suggest that dogs could provide excellent sentinels for certain infectious disease pathogens in Canada, yet are currently overlooked. Further research into the use of dog-sentinel surveillance is specifically recommended for California serogroup viruses, Chikungunya virus, West Nile virus, Lyme borreliosis, Rickettsia spp., Ehrlichia spp., and Dirofilaria immitis. PMID- 30248930 TI - Complete Chloroplast Genome Sequence and Phylogenetic Analysis of Aster tataricus. AB - We sequenced and analyzed the complete chloroplast genome of Aster tataricus (family Asteraceae), a Chinese herb used medicinally to relieve coughs and reduce sputum. The A. tataricus chloroplast genome was 152,992 bp in size, and harbored a pair of inverted repeat regions (IRa and IRb, each 24,850 bp) divided into a large single-copy (LSC, 84,698 bp) and a small single-copy (SSC, 18,250 bp) region. Our annotation revealed that the A. tataricus chloroplast genome contained 115 genes, including 81 protein-coding genes, 4 ribosomal RNA genes, and 30 transfer RNA genes. In addition, 70 simple sequence repeats (SSRs) were detected in the A. tataricus chloroplast genome, including mononucleotides (36), dinucleotides (1), trinucleotides (23), tetranucleotides (1), pentanucleotides (8), and hexanucleotides (1). Comparative chloroplast genome analysis of three Aster species indicated that a higher similarity was preserved in the IR regions than in the LSC and SSC regions, and that the differences in the degree of preservation were slighter between A. tataricus and A. altaicus than between A. tataricus and A. spathulifolius. Phylogenetic analysis revealed that A. tataricus was more closely related to A. altaicus than to A. spathulifolius. Our findings offer valuable information for future research on Aster species identification and selective breeding. PMID- 30248932 TI - Thin Film Composite Membrane for Oily Waste Water Treatment: Recent Advances and Challenges. AB - Oily wastewater discharge from various industry processes and activities have caused dramatic impacts on the human and environment. Treatment of oily wastewater using membrane technology has gained worldwide attention due to its efficiency in removing the amount and concentration of oil and grease as well as other specific pollutants in order to be reused or to fulfill stringent discharge standard. The application of thin film composite (TFC) membrane in reverse osmosis (RO) and forward osmosis (FO) for oily wastewater treatment is an emerging and exciting alternative in this field. This review presents the recent and distinctive development of TFC membranes to address the issues related to oily wastewater treatment. The recent advances in terms of TFC membrane design and separation performance evaluation are reviewed. This article aims to provide useful information and strategies, in both scientific knowledge advancement and practical implementation point of view, for the application TFC membrane for oily wastewater treatment. PMID- 30248933 TI - Differential Pharmacological Activities of Oxygen Numbers on the Sulfoxide Moiety of Wasabi Compound 6-(Methylsulfinyl) Hexyl Isothiocyanate in Human Oral Cancer Cells. AB - 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC) is a naturally occurring compound isolated from Wasabia japonica (wasabi). The synthetic derivatives, 6 (methylsulfenyl) hexyl isothiocyanate (I7447) and 6-(methylsulfonyl) hexyl isothiocyanate (I7557), were derived from 6-MITC with the deletion and addition of oxygen, respectively. We aimed to evaluate the effect of these synthetic compounds on human oral cancer cells, SAS and OECM-1. All three compounds (I7447, 6-MITC, and I7557) inhibited the viability of SAS and OECM-1 cells using MTT assay. Morphological observations showed various proportions of mitotic arrest and apoptosis in cells treated with these compounds. Cell cycle analysis revealed relatively abundant G2/M arrest in 6-MITC and I7557-treated cells, whereas sub-G1 accumulation was found in I7447-treated cells. In using phosphorylated histone H3 as a marker for mitosis, the addition of 6-MITC and I7557 (excluding I7447) could be shown to arrest cells during mitosis. In contrast, I7447 induced more prominent apoptosis than the 6-MITC or I7557 compounds. The down-regulated expression of the phosphorylated form of CHK1 and Cdc25c was noted in 6-MITC and I7557-treated cells. I7557 could sensitize SAS cells to death by radiation. The wasabi compound, 6-MITC, and its chemical derivatives with different numbers of oxygen may have differential pharmacological effects on human oral cancer cells. PMID- 30248935 TI - Oxidation Behavior of Multilayer Hard Coatings (TiCN/Al2O3/TiN) in Process of Recycling Coated Multicomponent Hardmetal Scrap. AB - The coating is one of the biggest problems in the recycling of coated multicomponent hardmetal scraps. The isothermal oxidation behavior of WC-Co multicomponent cemented carbide inserts with a TiCN/Al2O3/TiN hard coating in the recycling process was investigated. The oxidation rate slowed down as the protective coating blocked element diffusion. A rapid oxidation rate was obtained when they were milled into powders and isothermally oxidized at 900 degrees C. A rapid path for element diffusion was provided by the defects, which were promoted by stress, expansion, and gas volatilization. Both the TiN and TiCN layers were oxidized to a porous TiO2 scale, while the Al2O3 phase remained and the dense Al2O3 layer acted as a barrier for its good oxidation resistance. Pieces of the Al2O3 layer were obviously seen in the final oxides. This provides critical information to reduce the negative effect of coatings and improve the performance of recycled WC powders and hard alloys. PMID- 30248934 TI - Castration-Resistant Prostate Cancer Refractory to Second-Generation Androgen Receptor Axis-Targeted Agents: Opportunities and Challenges. AB - Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone and enzalutamide, enable stronger blockade of the androgen receptor (AR) axis and longer survival of men with castration-resistant prostate cancer (CRPC). However, the extent of the improved survival remains insufficient and the majority of patients eventually develop resistance to these novel agents. Some patients develop resistance against ARAT treatment through mechanisms termed "complete AR independence" or "AR indifference", and no longer require activation of the AR axis. However, a considerable proportion of CRPC patients remain persistently dependent on AR or its downstream signaling pathways. Ligand independent activation of the AR, an AR axis-dependent mechanism, is mediated by truncated forms of ARs that lack the ligand-binding domain (LBD), arising as products of AR splicing variants or nonsense mutations of AR. Post-translational modifications of ARs can also contribute to ligand-independent transactivation of the AR. Other mechanisms for AR axis activation are mediated by pathways that bypass the AR. Recent studies revealed that the glucocorticoid receptor can upregulate a similar transcription program to that of the AR, thus bypassing the AR. ARAT agents are essentially ineffective for CRPC driven by these AR independent mechanisms. This review article describes recent efforts to overcome these refractory machineries for the development of next-generation AR axis blockade in CRPC. PMID- 30248936 TI - Disubstituted 4-Chloro-3-nitrophenylthiourea Derivatives: Antimicrobial and Cytotoxic Studies. AB - 4-Chloro-3-nitrophenylthioureas 1-30 were synthesized and tested for their antimicrobial and cytotoxic activities. Compounds exhibited high to moderate antistaphylococcal activity against both standard and clinical strains (MIC values 2-64 MUg/mL). Among them derivatives with electron-donating alkyl substituents at the phenyl ring were the most promising. Moreover, compounds 1-6 and 8-19 were cytotoxic against MT-4 cells and various other cell lines derived from human hematological tumors (CC50 <= 10 MUM). The influence of derivatives 11, 13 and 25 on viability, mortality and the growth rate of immortalized human keratinocytes (HaCaT) was observed. PMID- 30248938 TI - Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization. AB - Naltrexone and naloxone are classical opioid antagonists. In substantially lower than standard doses, they exert different pharmacodynamics. Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid receptor blockade. Clinical reports of LDN have demonstrated possible benefits in diseases such as fibromyalgia, Crohn's disease, multiple sclerosis, complex regional pain syndrome, Hailey-Hailey disease, and cancer. In a dosing range at less than 1 MUg per day, oral naltrexone or intravenous naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in MU opioid receptor signaling. This dose is termed ultra low-dose naltrexone/naloxone (ULDN). It has been of use in postoperative control of analgesia by reducing the need for the total amount of opioids following surgery, as well as ameliorating certain side-effects of opioid-related treatment. A dosing range between 1 MUg and 1 mg comprises very low-dose naltrexone (VLDN), which has primarily been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper. In general, all of the low-dose features regarding naltrexone and naloxone have been only recently and still scarcely scientifically evaluated. This review aims to present an overview of the current knowledge on these topics and summarize the key findings published in peer-review sources. The existing potential of LDN, VLDN, and ULDN for various areas of biomedicine has still not been thoroughly and comprehensively addressed. PMID- 30248939 TI - Developmental Support for Sick Children through Play in Japan's ECEC System: A Comparison with Hospital Play Specialists. AB - Early childhood education and care (ECEC) workers and hospital play specialists (HPSs) share a role in supporting the development of sick children through play while respecting their autonomy. On the other hand, in supporting children's play, managing their anxiety, and making environmental arrangements for them, ECEC workers and HPSs play different roles. When supporting the development of sick children, the former should respect their autonomy and make the most of the characteristics of ECEC as a measure to comprehensively support their participation in play, including it in their daily lives. ECEC workers are also expected to contribute to the further development of comprehensive support by promoting collaboration and cooperation with various professionals, including HPSs. PMID- 30248937 TI - Hanks-Type Serine/Threonine Protein Kinases and Phosphatases in Bacteria: Roles in Signaling and Adaptation to Various Environments. AB - Reversible phosphorylation is a key mechanism that regulates many cellular processes in prokaryotes and eukaryotes. In prokaryotes, signal transduction includes two-component signaling systems, which involve a membrane sensor histidine kinase and a cognate DNA-binding response regulator. Several recent studies indicate that alternative regulatory pathways controlled by Hanks-type serine/threonine kinases (STKs) and serine/threonine phosphatases (STPs) also play an essential role in regulation of many different processes in bacteria, such as growth and cell division, cell wall biosynthesis, sporulation, biofilm formation, stress response, metabolic and developmental processes, as well as interactions (either pathogenic or symbiotic) with higher host organisms. Since these enzymes are not DNA-binding proteins, they exert the regulatory role via post-translational modifications of their protein targets. In this review, we summarize the current knowledge of STKs and STPs, and discuss how these enzymes mediate gene expression in prokaryotes. Many studies indicate that regulatory systems based on Hanks-type STKs and STPs play an essential role in the regulation of various cellular processes, by reversibly phosphorylating many protein targets, among them several regulatory proteins of other signaling cascades. These data show high complexity of bacterial regulatory network, in which the crosstalk between STK/STP signaling enzymes, components of TCSs, and the translational machinery occurs. In this regulation, the STK/STP systems have been proved to play important roles. PMID- 30248940 TI - Melatonin Can Strengthen the Effect of Retinoic Acid in HL-60 Cells. AB - Melatonin is produced by the pineal gland. It can be regarded as an anticancer agent and used for combined therapy, owing to its oncostatic, antioxidant, and immunoregulatory activities. Retinoic acid is widely used for the treatment of acute promyelocytic leukemia; however, it has adverse effects on the human organism. We investigated the effect of melatonin and reduced concentrations of retinoic acid on the activation of proliferation in acute promyelocytic leukemiaon a cell model HL-60. The combined effect of these compounds leads to a reduction in the number of cells by 70% and the index of mitotic activity by 64%. Combined treatment with melatonin and retinoic acid decreased the expression of the Bcl-2. The mitochondrial isoform VDAC1 can be a target in the treatment of different tumors. The combined effect of and retinoic acid at a low concentration (10 nM) decreased VDAC1 expression. Melatonin in combination with retinoic acid produced a similar effect on the expression of the translocator protein. The coprecipitation of VDAC with 2',3'-cyclonucleotide-3'-phosphodiesterase implies a possible role of its in cancer development. The combined effect of retinoic acid and melatonin decreased the activity of the electron transport chain complexes. The changes in the activation of proliferation in HL-60 cells, the mitotic index, and Bcl-2 expression under combined effect of retinoic acid (10 nM) with melatonin (1 mM) are similar to changes that are induced by 1 MUM retinoic acid. Our results suggest that MEL is able to improve the action the other chemotherapeutic agent. PMID- 30248942 TI - Major Stressors among Korean Adolescents According to Gender, Educational Level, Residential Area, and Socioeconomic Status. AB - Adolescents are exposed to many stressors which have been associated with poor mental health. Using data from the 2015 Korea Youth Risk Behavior Web-based Survey, we identified the major stressors among Korean adolescents based on gender, current educational level, residential area, and socioeconomic status (SES). The major stressors among girls were relationship- and appraisal-related factors, whereas boys more often reported health- and conflict-related factors. High school students more often reported academic performance and family circumstances as major stressors, whereas middle school students tended to report conflict-related factors. Urban adolescents reported academic performance and conflicts with parents as major stressors while rural adolescents reported conflicts with teachers and peer relationship problems. Finally, adolescents of lower SES reported multiple factors, including relational and family problems, as major stressors; contrarily, among those of higher SES, the primary stressor was uniquely related to academic performance. This result is significant in that adolescents' stress levels, as well as the types of major stressors, vary depending on individual factors. It could also be beneficial for developing and implementing individualized and thus more efficient stress-management strategies. PMID- 30248944 TI - Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells. AB - Thioredoxin (Trx) overexpression is known to be a cause of chemotherapy resistance in various tumor entities. However, Trx effects on resistance are complex and depend strictly on tissue type. In the present study, we analyzed the impact of the Trx system on intrinsic chemoresistance of human glioblastoma multiforme (GBM) cells to cytostatic drugs. Resistance of GBM cell lines and primary cells to drugs and signaling inhibitors was assessed by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Impact of Trx inhibition on apoptosis was investigated by proteome profiling of a subset of proteins and annexin V apoptosis assays. Trx-interacting protein (TXNIP) was overexpressed by transfection and protein expression was determined by immunoblotting. Pharmacological inhibition of Trx by 1-methyl-2-imidazolyl disulfide (PX-12) reduced viability of three GBM cell lines, induced expression of active caspase-3, and reduced phosphorylation of AKT-kinase and expression of beta-catenin. Sensitivity to cisplatin could be restored by both PX-12 and recombinant expression of the upstream Trx inhibitor TXNIP, respectively. In addition, PX-12 also sensitized primary human GBM cells to temozolomide. Combined inhibition of Trx and the phosphatidylinositide 3-kinase (PI3K) pathway resulted in massive cell death. We conclude that the Trx system and the PI3K pathway act as a sequential cascade and could potentially present a new drug target. PMID- 30248945 TI - Effect of Electrode Shape and Flow Conditions on the Electrochemical Detection with Band Microelectrodes. AB - In this work, we report the analysis of the electrochemical detection of electroactive species with band microelectrodes that operate under controlled convection. The study focuses on the determination of the collection efficiency of the analyte as a function of inlet flow velocity and microband geometry (inlaid, bumped and recessed), also providing a straightforward method for the theoretical determination of the lower detection limit. The analysis has been carried out by simulating the dimensionless mass transport with the finite element method, delivering the stationary limiting current density. Simulations have been performed on systems consisting of single and double band electrodes to investigate the trail effect on the electrochemical detection. We show that the obtained dimensionless results can be easily turned into dimensional data, providing a tool for the design of devices. The proposed method is general and can easily be extended to systems with different geometry. PMID- 30248943 TI - Effect of a 12-Week Online Walking Intervention on Health and Quality of Life in Cancer Survivors: A Quasi-Randomized Controlled Trial. AB - Cancer survivors are at an increased risk of experiencing physical and psychological ill-effects following cancer treatment. Rural cancer survivors are at a greater risk of future health problems following a cancer diagnosis compared to their urban counterparts. Physical activity has been targeted as a health promotion priority in cancer survivors. Research indicates that a large portion of cancer survivors do not meet physical activity recommendations. The purpose of this quasi-randomized controlled trial was to test the effectiveness of an online 12-week walking intervention designed for cancer survivors, and to explore its impact on physical health indicators and quality of life outcomes. Steps Toward Improving Diet and Exercise among cancer survivors (STRIDE) is an online resource designed according to Social Cognitive Theory and Self Determination Theory, based on individualized step goal setting. Measures of physiology, physical fitness, and quality of life were taken at the baseline, post-intervention, and three-month follow-up in an Intervention group (n = 46) and active Control group (n = 45). The Control group was provided with a pedometer but did not have access to the online program. Three-factor repeated measures ANOVAs indicated that there were improvements in physical fitness (p < 0.01), systolic blood pressure (p < 0.01), diastolic blood pressure (p < 0.01), waist girth (p < 0.01), mental health (p < 0.05), social functioning (p < 0.01), and general health (p < 0.01), but an increase in bodily pain (p < 0.01), from the baseline to week 12 and the three month follow-up, irrespective of group allocation. Pedometer interventions, delivered with or without online support and step goal setting, show promise for improving the overall health of cancer survivors, at least in the short term. PMID- 30248946 TI - Selected Socio-Demographic and Occupational Factors of Burnout Syndrome in Nurses Employed in Medical Facilities in Malopolska-Preliminary Results. AB - The study examined the relationship between socio-demographic and occupational factors and the level of occupational burnout using the dimensions of emotional exhaustion (EE), depersonalization (DEP), and personal accomplishment (PA). It examined 560 nurses working in hospitals and primary healthcare units. We used: Maslach Burnout Inventory and a questionnaire including socio-demographic (sex, age, marital status, education, parental status) and occupational (period of employment, workplace, managerial functions, additional employment) factors. An average respondent was 38.13 (SD = 10.16) and had a BA degree (56.0%). The respondents reported average values of the EE (22.8), a low level of DEP (Me = 6), and a low PA (27.63). Nurses working on the intensive care unit had a chance of a high level of DEP that was 75% lower (OR = 0.25, 95% CI = 0.13-0.50) than nurses working in conservative treatment units. Additional employment increased the risk of a high level of DEP (OR = 2.86, 95% CI = 1.70-4.84). The chance of low PA was 64% lower in the case of nurse managers (OR = 0.36, 95% CI = 0.13 0.998) than other nurses. Education, period of employment, additional employment, and managerial position had a significant influence on the level of occupational burnout. An analysis of nurses' work overload and additional employment can be an interesting research area. PMID- 30248948 TI - Spoofing Detection Algorithm Based on Pseudorange Differences. AB - Intentional spoofing interference can cause damage to the navigation terminal and threaten the security of a global navigation satellite system (GNSS). For spoofing interference, an anti-spoofing algorithm based on pseudorange differences for a single receiver is proposed, which can be used to detect simplistic and intermediate spoofing attacks, as well as meaconing attacks. Double-difference models using the pseudorange of two adjacent epochs are established followed by the application of Taylor expansion to the position relationship between the satellite and the receiver (or the spoofer). The authenticity of the signal can be verified by comparing the results of the proposed spoofing detection algorithm with the traditional least squares method. The results will differ when spoofing is present. The parameter setting of the proposed algorithm is introduced. The algorithm has the advantage of both simplicity and efficiency and needs only a single receiver and pseudorange data. A NovAtel receiver is adopted for the actual experiments. The Texas spoofing test battery (TEXBAT), as well as two other simulation experiments are used to verify the performance of the algorithm. The simulation results validate the feasibility and effectiveness of the algorithm. PMID- 30248947 TI - Syncope and Collapse Are Associated with an Increased Risk of Cardiovascular Disease and Mortality in Patients Undergoing Dialysis. AB - Objective: This study explored the impact of syncope and collapse (SC) on cardiovascular events and mortality in patients undergoing dialysis. Methods: Patients undergoing dialysis with SC (n = 3876) were selected as the study cohort and those without SC who were propensity score-matched at a 1:1 ratio were included as controls. Major adverse cardiovascular events (MACEs), including acute coronary syndrome (ACS), arrhythmia or cardiac arrest, stroke, and overall mortality, were evaluated and compared in both cohorts. Results: The mean follow up periods until the occurrence of ACS, arrhythmia or cardiac arrest, stroke, and overall mortality in the SC cohort were 3.51 +/- 2.90, 3.43 +/- 2.93, 3.74 +/- 2.97, and 3.76 +/- 2.98 years, respectively. Compared with the patients without SC, those with SC had higher incidence rates of ACS (30.1 vs. 24.7 events/1000 people/year), arrhythmia or cardiac arrest (6.75 vs. 3.51 events/1000 people/year), and stroke (51.6 vs. 35.7 events/1000 people/year), with higher overall mortality (127.7 vs. 77.9 deaths/1000 people/year). The SC cohort also had higher risks for ACS, arrhythmia or cardiac arrest, stroke, and overall mortality (adjusted hazard ratios: 1.28 (95% confidence interval (CI) = 1.11 1.46), 2.05 (95% CI = 1.50-2.82), 1.48 (95% CI = 1.33-1.66), and 1.79 (95% CI = 1.67-1.92), respectively) than did the non-SC cohort. Conclusion: SC was significantly associated with cardiovascular events and overall mortality in the patients on dialysis. SC may serve as a prodrome for cardiovascular comorbidities, thereby assisting clinicians in identifying high-risk patients. PMID- 30248941 TI - The "Yin and Yang" of Natural Compounds in Anticancer Therapy of Triple-Negative Breast Cancers. AB - Among the different types of breast cancers, triple-negative breast cancers (TNBCs) are highly aggressive, do not respond to conventional hormonal/human epidermal growth factor receptor 2 (HER2)-targeted interventions due to the lack of the respective receptor targets, have chances of early recurrence, metastasize, tend to be more invasive in nature, and develop drug resistance. The global burden of TNBCs is increasing regardless of the number of cytotoxic drugs being introduced into the market each year as they have only moderate efficacy and/or unforeseen side effects. Therefore, the demand for more efficient therapeutic interventions, with reduced side effects, for the treatment of TNBCs is rising. While some plant metabolites/derivatives actually induce the risk of cancers, many plant-derived active principles have gained attention as efficient anticancer agents against TNBCs, with fewer adverse side effects. Here we discuss the possible oncogenic molecular pathways in TNBCs and how the purified plant derived natural compounds specifically target and modulate the genes and/or proteins involved in these aberrant pathways to exhibit their anticancer potential. We have linked the anticancer potential of plant-derived natural compounds (luteolin, chalcones, piperine, deguelin, quercetin, rutin, fisetin, curcumin, resveratrol, and others) to their ability to target multiple dysregulated signaling pathways (such as the Wnt/beta-catenin, Notch, NF-kappaB, PI3K/Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Hedgehog) leading to suppression of cell growth, proliferation, migration, inflammation, angiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, and activation of apoptosis in TNBCs. Plant-derived compounds in combination with classical chemotherapeutic agents were more efficient in the treatment of TNBCs, possibly with lesser side effects. PMID- 30248949 TI - Grain-Boundary Interaction between Inconel 625 and WC during Laser Metal Deposition. AB - In this study, the laser metal deposition (LMD) of the Inconel 625-tungsten carbide (WC) metal matrix composite was investigated. The composite coating was deposited on Inconel 625 substrate by powder method. A powder mixture containing 10 wt% of WC (5 um) was prepared by wet mixing with dextrin binder. Coating samples obtained by low-power LMD were pore- and crack-free. Ceramic reinforcement was distributed homogenously in the whole volume of the material. Topologically close-packed (TCP) phases were formed at grain boundaries between WC and Inconel 625 matrix as a result of partial dissolution of WC in a nickel based alloy. Line analysis of the elements revealed very small interference of the coating in the substrate material when compared to conventional coating methods. The average Vickers hardness of the coating was about 25% higher than the hardness of pure Inconel 625 reference samples. PMID- 30248952 TI - Comparison of Inspecting Non-Ferromagnetic and Ferromagnetic Metals Using Velocity Induced Eddy Current Probe. AB - A velocity induced eddy current probe has been used to detect cracks in both non ferromagnetic and ferromagnetic metals. The simulation and experimental results show that this probe can successfully detect cracks in both cases, but further investigation shows that the underlying principles for inspecting non ferromagnetic and ferromagnetic metals are actually different. For an aluminum plate, the induced eddy current density and the signal amplitude both increase with probe speed, which means the signal is caused by velocity induced eddy currents. For a steel plate, probe speed changes the baselines of the testing signals; however, it has little influence on signal amplitudes. Simulation results show that the signal for cracks in a steel plate is mainly caused by direct magnetic field perturbation rather than velocity induced eddy currents. PMID- 30248951 TI - Polydopamine-Assisted Silver Nanoparticle Self-Assembly on Sericin/Agar Film for Potential Wound Dressing Application. AB - Silver nanoparticles (AgNPs) are extensively applied for their broad-spectrum and excellent antibacterial ability in recent years. Polydopamine (PDA) has great advantages for synthesizing large amounts of AgNPs, as it has multiple sites for silver ion binding and phenolic hydroxyl structure to reduce silver ions to AgNPs. Here, we mixed sericin and agar solution and dried at 65 degrees C to prepare a sericin (SS)/Agar composite film, and then coated polydopamine (PDA) on the surface of SS/Agar film by soaking SS/Agar film into polydopamine solution, subsequently synthesizing high-density AgNPs with the assistance of PDA to yield antibacterial AgNPs-PDA- SS/Agar film. Scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) spectra indicated the successful synthesis of high-density AgNPs on the surface of PDA-SS/Agar film. PDA coating and AgNPs modification did not affect the structure of sericin and agar. Furthermore, water contact angle, water absorption and mechanical property analysis showed that AgNPs-PDA-SS/Agar film had excellent hydrophilicity and proper mechanical properties. Inhibition zone and growth curve assays suggested the prepared film had excellent and long-lasting antibacterial ability. In addition, it had excellent cytocompatibility on the fibroblast NIH/3T3 cells. The film shows great potential as a novel kind of wound dressing. PMID- 30248950 TI - Anti-Candidal Activity and In Vitro Cytotoxicity Assessment of Graphene Nanoplatelets Decorated with Zinc Oxide Nanorods. AB - Candida albicans is the most common pathogenic fungus that is isolated in nosocomial infections in medically and immune-compromised patients. The ability of C. albicans to convert its form from yeast to hyphal morphology contributes to biofilm development that effectively shelters Candida against the action of antifungals molecules. In the last years, nanocomposites are the most promising solutions against drug-resistant microorganisms. The aim of this study was to investigate the antifungal activity of graphene nanoplateles decorated with zinc oxide nanorods (ZNGs) against the human pathogen Candida albicans. We observed that ZNGs were able to induce a significant mortality in fungal cells, as well as to affect the main virulence factors of this fungus or rather the hyphal development and biofilm formation. Reactive Oxygen Species (ROS) formation in yeast cells resulted one of the mechanisms of ZNGs to induce mortality. Finally, the toxicity of this nanomaterial was tested also on human keratinocyte cell line HaCaT. Our data indicated that ZNGs resulted not toxic when their aggregation state decreased by adding glycerol as emulsifier to ZNGs suspensions or when HaCaT cells were grown on ZNGs-coated glasses. Overall, the results that were obtained indicated that ZNGs could be exploited as an antifungal nanomaterial with a high degree of biocompatibility on human cells. PMID- 30248954 TI - Difficulties and Challenges of Anomaly Detection in Smart Cities: A Laboratory Analysis. AB - Smart cities work with large volumes of data from sensor networks and other sources. To prevent data from being compromised by attacks or errors, smart city IT administrators need to apply attack detection techniques to evaluate possible incidents as quickly as possible. Machine learning has proven to be effective in many fields and, in the context of wireless sensor networks (WSNs), it has proven adequate to detect attacks. However, a smart city poses a much more complex scenario than a WSN, and it has to be evaluated whether these techniques are equally valid and effective. In this work, we evaluate two machine learning algorithms (support vector machines (SVM) and isolation forests) to detect anomalies in a laboratory that reproduces a real smart city use case with heterogeneous devices, algorithms, protocols, and network configurations. The experience has allowed us to show that, although these techniques are of great value for smart cities, additional considerations must be taken into account to effectively detect attacks. Thus, through this empiric analysis, we point out broader challenges and difficulties of using machine learning in this context, both for the technical complexity of the systems, and for the technical difficulty of configuring and implementing them in such environments. PMID- 30248955 TI - 3D Printing of Resin Material for Denture Artificial Teeth: Chipping and Indirect Tensile Fracture Resistance. AB - 3D printing of denture artificial teeth with resin materials is worthy of study in a novel way. This study evaluated chipping and indirect tensile fracture resistance of 3D printing resin material (Dentca 3D printing denture teeth resin) compared with conventionally prefabricated resin denture teeth (Premium-8, Surpass, SR-Orthosit-PE, and Preference). One hundred tooth specimens were prepared for testing. The 3D printed tooth specimens were printed at a 50 um layer thickness with methacrylate-based photopolymerized resin by stereolithography 3D printing. Chipping and indirect tensile fracture tests were conducted at a speed of 1 mm/min until fracture. The indirect tensile fracture loads of the 3D printed resin teeth were higher than those of Premium-8, Surpass, and SR-Orthosit-PE, and lower than those of Preference teeth. Regarding chipping resistance, the 3D printed resin teeth were not different from Surpass and SR Orthosit-PE, and were lower than Premium-8 and Preference teeth. The 3D printed resin teeth exhibited vertical fracture of the loaded cusp without deformation in chipping. The 3D printed resin teeth showed simultaneous fracture of two cusps in indirect tensile fracture, unlike other teeth. The results of this study suggest that 3D printing technology using resin materials provides adequate fracture resistance for denture artificial tooth use. PMID- 30248953 TI - Blood Fatty Acid Status and Clinical Outcomes in Dialysis Patients: A Systematic Review. AB - Blood fatty acids (FAs) are derived from endogenous and dietary routes. Metabolic abnormalities from kidney dysfunction, as well as cross-cultural dietary habits, may alter the FA profile of dialysis patients (DP), leading to detrimental clinical outcomes. Therefore, we aimed to (i) summarize FA status of DP from different countries, (ii) compare blood FA composition between healthy controls and DP, and (iii) evaluate FA profile and clinical endpoints in DP. Fifty-three articles from 1980 onwards, reporting FA profile in hemodialysis and peritoneal DP, were identified from PubMed, Embase, and the Cochrane library. Studies on pediatric, predialysis chronic kidney disease, acute kidney injury, and transplant patients were excluded. Moderate to high levels of n-3 polyunsaturated fatty acids (PUFA) were reported in Japan, Korea, Denmark, and Sweden. Compared to healthy adults, DP had lower proportions of n-3 and n-6 PUFA, but higher proportion of monounsaturated fatty acids. Two studies reported inverse associations between n-3 PUFAs and risks of sudden cardiac death, while one reported eicosapentaenoic acid + docosahexaenoic acid)/arachidonic acid ratio was inversely associated with cardiovascular events. The relationship between all cause mortality and blood FA composition in DP remained inconclusive. The current evidence highlights a critical role for essential FA in nutritional management of DP. PMID- 30248956 TI - Distance-Resolving Raman Radar Based on a Time-Correlated CMOS Single-Photon Avalanche Diode Line Sensor. AB - Remote Raman spectroscopy is widely used to detect minerals, explosives and air pollution, for example. One of its main problems, however, is background radiation that is caused by ambient light and sample fluorescence. We present here, to the best of our knowledge, the first time a distance-resolving Raman radar device that is based on an adjustable, time-correlated complementary metal oxide-semiconductor (CMOS) single-photon avalanche diode line sensor which can measure the location of the target sample simultaneously with the normal stand off spectrometer operation and suppress the background radiation dramatically by means of sub-nanosecond time gating. A distance resolution of 3.75 cm could be verified simultaneously during normal spectrometer operation and Raman spectra of titanium dioxide were distinguished by this system at distances of 250 cm and 100 cm with illumination intensities of the background of 250 lux and 7600 lux, respectively. In addition, the major Raman peaks of olive oil, which has a fluorescence-to-Raman signal ratio of 33 and a fluorescence lifetime of 2.5 ns, were distinguished at a distance of 30 cm with a 250 lux background illumination intensity. We believe that this kind of time-correlated CMOS single-photon avalanche diode sensor could pave the way for new compact distance-resolving Raman radars for application where distance information within a range of several metres is needed at the same time as a Raman spectrum. PMID- 30248957 TI - Daphnauranins C-E, Three New Antifeedants from Daphne aurantiaca Roots. AB - Daphnauranins C-E (compounds 1-3), two sesquiterpenoids and one monoterpenoid were isolated from the roots of Daphne aurantiaca Diels. Daphnauranin C is a 9-O 13 etherified and hydroperoxy-substituted guaiane sesquiterpenoid, daphnauranin D is a guaiane sesquiterpenoid ketal, and daphnauranin E is a monoterpenoid lactone. Their structures were elucidated by comprehensive analyses of MS, 1D NMR, and 2D NMR spectroscopic data. In an anti-feeding activities test, daphnauranins C-E showed activity against male fruit fly with anti-feeding indexes (AI) up to 39.1, 39.2, and 27.8% respectively, at 1 mM. PMID- 30248958 TI - Erratum: Assari, S.; Mistry, R. Educational Attainment and Smoking Status in a National Sample of American Adults; Evidence for the Blacks' Diminished Return. Int. J. Environ. Res. Public Health 2018, 15, 763. AB - Due to an error during production, a citation of the published paper [1] was incorrect [...]. PMID- 30248960 TI - Dissecting the Repertoire of DNA-Binding Transcription Factors of the Archaeon Pyrococcus furiosus DSM 3638. AB - In recent years, there has been a large increase in the amount of experimental evidence for diverse archaeal organisms, and these findings allow for a comprehensive analysis of archaeal genetic organization. However, studies about regulatory mechanisms in this cellular domain are still limited. In this context, we identified a repertoire of 86 DNA-binding transcription factors (TFs) in the archaeon Pyrococcus furiosus DSM 3638, that are clustered into 32 evolutionary families. In structural terms, 45% of these proteins are composed of one structural domain, 41% have two domains, and 14% have three structural domains. The most abundant DNA-binding domain corresponds to the winged helix-turn-helix domain; with few alternative DNA-binding domains. We also identified seven regulons, which represent 13.5% (279 genes) of the total genes in this archaeon. These analyses increase our knowledge about gene regulation in P. furiosus DSM 3638 and provide additional clues for comprehensive modeling of transcriptional regulatory networks in the Archaea cellular domain. PMID- 30248959 TI - NACC1, as a Target of MicroRNA-331-3p, Regulates Cell Proliferation in Urothelial Carcinoma Cells. AB - The nucleus accumbens-associated protein 1 (NACC1) is a transcription factor constitutively expressed in the urothelium, where it regulates cell growth, senescence, autophagy, and epithelial-mesenchymal transition. microRNA (miRNA) constitutes a class of small non-coding RNAs which are involved in cell proliferation, differentiation, and progression of tumors. miRNAs and their target molecules are utilized for molecular diagnosis of urothelial carcinoma. NACC1 is one of several putative target molecules of miR-331-3p, and is associated with cell proliferation in cancers such as prostate and cervical cancer. Functional experiments involving miR-331-3p and its target molecule NACC1 were conducted using the urothelial carcinoma (UC) cell lines, T24, UMUC6, and KU7. Furthermore, quantitative reverse transcription polymerase chain reaction and immunostaining were performed to evaluate the expression of NACC1 in UC derived from transurethral resection of bladder tumor (TUR-Bt) specimens. The methane thiosulfonate (MTS) assay revealed that cell proliferation was significantly reduced after transient transfection of miR-331-3p precursor and/or NACC1 siRNA in UC cells. Cell senescence via cell cycle arrest at the G1 phase was induced by NACC1 inhibition. On the other hand, suppression of NACC1 induced cell migration and invasion abilities. Immunohistochemical analysis of TUR-Bt specimens revealed that over 70% of UC cells presented strongly positive results for NACC1. In contrast, normal urothelial cells were weakly positive for NACC1. It was also found that NACC1 expression was lower in invasive UC cells than in non-invasive UC cells. Loss of NACC1 induced vessel invasion in invasive UC tissues. The present results indicate that NACC1 regulated by miR-331-3p contributes to cell proliferation, and is involved in cell migration and invasion. This suggests that NACC1 can serve as a potential target molecule for the prediction and prognosis of UC, and can contribute to effective treatment strategies. PMID- 30248962 TI - Antifibrotic Activity and In Ovo Toxicity Study of Liver-Targeted Curcumin-Gold Nanoparticle. AB - Conjugation of curcumin and gold with green chemistry is an approach to improve the effectiveness of curcumin as anti-fibrosis. In this work, curcumin and gold were conjugated to deliver curcumin to the liver. Curcumin-gold nanoparticles (cAuNPs) were prepared by varying curcumin pH and concentration. The successful of cAuNPs formation were identified by using UV-visible and FTIR spectrophotometers. The particle size and morphology were analyzed using particle size analyzer and cryo-TEM respectively. In vitro antioxidant assay was performed to determine the curcumin activity after conjugation. Physical and chemical stabilities of cAuNPs were studied for one month at 5 degrees C, 25 degrees C, and 40 degrees C. Furthermore, the cAuNPs activity to modulate early marker of fibrosis was tested on NIH/3T3 cells. The optimum condition for cAuNPs synthesis was by using 1.5 mM curcumin at pH 9.3. As compared to free curcumin, cAuNPs showed higher antioxidant activity and maintained the nanosize after stored for one month. In line with the antioxidant activity, cAuNPs 0.25-1 MUg/mL reduced the collagen production by NIH/3T3 cells. More importantly, cAuNPs did not demonstrate any effect on the development of chicken embryo. Taken together, the attachment of gold to curcumin in the form of cAuNPs is promising for curcumin targeting to treat hepatic fibrosis. PMID- 30248961 TI - Isolation, Characterization and Antitumor Effect on DU145 Cells of a Main Polysaccharide in Pollen of Chinese Wolfberry. AB - Modern studies have shown that pollen has a certain role in the treatment of prostate-related diseases. In the present study, pollen polysaccharides from Chinese wolfberry (WPPs) were extracted by hot-water extraction and ethanol precipitation, further purified by chromatography on a DEAE-cellulose column and Sephadex G-100 column. Homogeneous polysaccharide CF1 of WPPS was obtained, the molecular weight of which was estimated to be 1540.10 +/- 48.78 kDa by HPGPC ELSD. HPLC with PMP derivatization analysis indicated that the monosaccharide compositions of CF1 were mannose, glucuronic acid, galacturonic acid, xylose, galactose, arabinose, and trehalose, in a molar ratio of 0.68:0.59:0.27:0.24:0.22:0.67:0.08. The antitumor effects of CF1 upon MTT, Tunel assay and flow cytometry assay were investigated in vitro. The results showed that CF1 exhibited a dose-dependent antiproliferative effect, with an IC50 value of 374.11 MUg/mL against DU145 prostate cancer cells. Tunel assay and flow cytometry assay showed that the antitumor activity of CF1 was related to apoptosis in vitro. The present study suggested that the CF1 of WPPs might be a potential source of antitumor functional food or agent. PMID- 30248964 TI - Personalised Medicine: The Odyssey from Hope to Practice. AB - In this endeavour, inspired by the Odyssey, we aim to embark with the reader on a journey on a ship from Troy to Ithaca, coursing through the history of the momentous events and achievements that paved the way for personalised medicine. We will set sail amidst important genetic discoveries, beginning with the discovery of the first human genome, and voyage through the projects that contributed to the progress of pharmacogenomic studies. Concurrently, we will propose methods to overcome the obstacles that are slowing the potential full implementation of accumulated knowledge into everyday practice. This journey aims to reflect on the frontiers of current genetic knowledge and the practical use of this knowledge in preventive, diagnostic and pharmacogenomic approaches to directly impact the socio-economic aspects of public health. PMID- 30248963 TI - Development of Policy Relevant Human Biomonitoring Indicators for Chemical Exposure in the European Population. AB - The European Union's 7th Environmental Action Programme (EAP) aims to assess and minimize environmental health risks from the use of hazardous chemicals by 2020. From this angle, policy questions like whether an implemented policy to reduce chemical exposure has had an effect over time, whether the health of people in specific regions or subpopulations is at risk, or whether the body burden of chemical substances (the internal exposure) varies with, for example, time, country, sex, age, or socio-economic status, need to be answered. Indicators can help to synthesize complex scientific information into a few key descriptors with the purpose of providing an answer to a non-expert audience. Human biomonitoring (HBM) indicators at the European Union (EU) level are unfortunately lacking. Within the Horizon2020 European Human Biomonitoring project HBM4EU, an approach to develop European HBM indicators was worked out. To learn from and ensure interoperability with other European indicators, 15 experts from the HBM4EU project (German Umweltbundesamt (UBA), Flemish research institute VITO, University of Antwerp, European Environment Agency (EEA)), and the World Health Organization (WHO), European Core Health Indicator initiative (ECHI), Eurostat, Swiss ETH Zurich and the Czech environmental institute CENIA, and contributed to a workshop, held in June 2017 at the EEA in Copenhagen. First, selection criteria were defined to evaluate when and if results of internal chemical exposure measured by HBM, need to be translated into a European HBM-based indicator. Two main aspects are the HBM indicator's relevance for policy, society, health, and the quality of the biomarker data (availability, comparability, ease of interpretation). Secondly, an approach for the calculation of the indicators was designed. Two types of indicators were proposed: 'sum indicators of internal exposure' derived directly from HBM biomarker concentrations and 'indicators for health risk', comparing HBM concentrations to HBM health-based guidance values (HBM HBGVs). In the latter case, both the percentage of the studied population exceeding the HBM HBGVs (PE) and the extent of exceedance (EE), calculated as the population's exposure level divided by the HBM HBGV, can be calculated. These indicators were applied to two examples of hazardous chemicals: bisphenol A (BPA) and per- and polyfluoroalkyl substances (PFASs), which both have high policy and societal relevance and for which high quality published data were available (DEMOCOPHES, Swedish monitoring campaign). European HBM indicators help to summarize internal exposure to chemical substances among the European population and communicate to what degree environmental policies are successful in keeping internal exposures sufficiently low. The main aim of HBM indicators is to allow follow-up of chemical safety in Europe. PMID- 30248966 TI - Sensoring a Generative System to Create User-Controlled Melodies. AB - The automatic generation of music is an emergent field of research that has attracted the attention of countless researchers. As a result, there is a broad spectrum of state of the art research in this field. Many systems have been designed to facilitate collaboration between humans and machines in the generation of valuable music. This research proposes an intelligent system that generates melodies under the supervision of a user, who guides the process through a mechanical device. The mechanical device is able to capture the movements of the user and translate them into a melody. The system is based on a Case-Based Reasoning (CBR) architecture, enabling it to learn from previous compositions and to improve its performance over time. The user uses a device that allows them to adapt the composition to their preferences by adjusting the pace of a melody to a specific context or generating more serious or acute notes. Additionally, the device can automatically resist some of the user's movements, this way the user learns how they can create a good melody. Several experiments were conducted to analyze the quality of the system and the melodies it generates. According to the users' validation, the proposed system can generate music that follows a concrete style. Most of them also believed that the partial control of the device was essential for the quality of the generated music. PMID- 30248967 TI - Magnesium Intake and Sleep Disorder Symptoms: Findings from the Jiangsu Nutrition Study of Chinese Adults at Five-Year Follow-Up. AB - (1) Background: In clinical trials, dietary magnesium use can improve insomnia symptoms. However, little is known about the association between dietary magnesium consumption and sleep disorder symptoms including daytime falling asleep, sleepiness and snoring at the population level. (2) Methods: We used data from 1487 adults aged 20 and above attending the Jiangsu Nutrition Study. At baseline in 2002, dietary magnesium was assessed by 3-day weighed food records. At follow-up in 2007, sleep disorder symptoms, including daytime falling asleep, sleepiness and snoring at night, were gathered using a sleep questionnaire. (3) Results: The mean intake of magnesium was 332.5 mg/day. In total, 5.3%, 13.2% and 35.7% of the subjects reported daytime falling asleep, daytime sleepiness, and snoring during sleep, respectively. Compared with the lowest quartile of magnesium intake, the highest quartile was associated with decreased likelihood of falling asleep (odds ratio (OR) 0.12 (0.02, 0.57)) in women but not in men after adjusting for demographic, anthropometric, lifestyle factors, hypertension, and overall dietary patterns. No associations were found between dietary magnesium intake and daytime sleepiness nor night snoring in either gender. (4) Conclusions: Dietary magnesium intake may have long-term benefits in reducing the likelihood of daytime falling asleep in women. PMID- 30248965 TI - Membrane-Bound Class III Peroxidases: Unexpected Enzymes with Exciting Functions. AB - Class III peroxidases are heme-containing proteins of the secretory pathway with a high redundance and versatile functions. Many soluble peroxidases have been characterized in great detail, whereas only a few studies exist on membrane-bound isoenzymes. Membrane localization of class III peroxidases has been demonstrated for tonoplast, plasma membrane and detergent resistant membrane fractions of different plant species. In silico analysis revealed transmembrane domains for about half of the class III peroxidases that are encoded by the maize (Zea mays) genome. Similar results have been found for other species like thale-cress (Arabidopsis thaliana), barrel medic (Medicago truncatula) and rice (Oryza sativa). Besides this, soluble peroxidases interact with tonoplast and plasma membranes by protein-protein interaction. The topology, spatiotemporal organization, molecular and biological functions of membrane-bound class III peroxidases are discussed. Besides a function in membrane protection and/or membrane repair, additional functions have been supported by experimental data and phylogenetics. PMID- 30248968 TI - Detection of Infantile Movement Disorders in Video Data Using Deformable Part Based Model. AB - Movement analysis of infants' body parts is momentous for the early detection of various movement disorders such as cerebral palsy. Most existing techniques are either marker-based or use wearable sensors to analyze the movement disorders. Such techniques work well for adults, however they are not effective for infants as wearing such sensors or markers may cause discomfort to them, affecting their natural movements. This paper presents a method to help the clinicians for the early detection of movement disorders in infants. The proposed method is marker less and does not use any wearable sensors which makes it ideal for the analysis of body parts movement in infants. The algorithm is based on the deformable part based model to detect the body parts and track them in the subsequent frames of the video to encode the motion information. The proposed algorithm learns a model using a set of part filters and spatial relations between the body parts. In particular, it forms a mixture of part-filters for each body part to determine its orientation which is used to detect the parts and analyze their movements by tracking them in the temporal direction. The model is represented using a tree structured graph and the learning process is carried out using the structured support vector machine. The proposed framework will assist the clinicians and the general practitioners in the early detection of infantile movement disorders. The performance evaluation of the proposed method is carried out on a large dataset and the results compared with the existing techniques demonstrate its effectiveness. PMID- 30248971 TI - Fucoidan Sulfatases from Marine Bacterium Wenyingzhuangia fucanilytica CZ1127T. AB - Fucoidans belong to a structurally heterogeneous class of sulfated polysaccharides isolated from brown algae. They have a wide spectrum of biological activities. The complex structures of these polysaccharides hinder structure-activity relationships determination. Fucoidan sulfatases can make useful tools for the determination of the fine chemical structure of fucoidans. In this study, identification and preparation of two recombinant sulfatases able to catalyze the cleavage of sulfate groups from fragments of fucoidan molecules is described for the first time. Two genes of sulfatases swf1 and swf4 of the marine bacterium Wenyingzhuangia fucanilytica CZ1127T were cloned and the proteins were produced in Escherichia coli cells. Sulfatases SWF1 and SWF4 are assigned to S1_17 and S1_25 subfamilies of formylglycine-dependent enzymes of S1 family (SulfAtlas). Some molecular and biochemical characteristics of recombinant fucoidan sulfatases have been studied. Detailed specificity and catalytic features of sulfatases were determined using various sulfated fucooligosaccharides. Structures of products produced by SWF1 and SWF4 were established by nuclear magnetic resonance (NMR) spectroscopy. Based on the obtained data, the enzymes are classified as fucoidan exo-2O-sulfatase (SWF1) and fucoidan exo-3O-sulfatase (SWF4). In addition, we demonstrated the sequential action of sulfatases on 2,3-di-O-sulfated fucooligosacchrides, which indicates an exolitic degradation pathway of fucoidan by a marine bacterium W. fucanilytica CZ1127T. PMID- 30248970 TI - Comprehensive Transcriptome Profiling and Identification of Potential Genes Responsible for Salt Tolerance in Tall Fescue Leaves under Salinity Stress. AB - Soil salinity is a serious threat to plant growth and crop productivity. Tall fescue utilization in saline areas is limited by its inferior salt tolerance. Thus, a transcriptome study is a prerequisite for future research aimed at providing deeper insights into the molecular mechanisms of tall fescue salt tolerance as well as molecular breeding. Recent advances in sequencing technology offer a platform to achieve this. Here, Illumina RNA sequencing of tall fescue leaves generated a total of 144,339 raw reads. After de novo assembly, unigenes with a total length of 129,749,938 base pairs were obtained. For functional annotations, the unigenes were aligned to various databases. Further structural analyses revealed 79,352 coding DNA sequences and 13,003 microsatellites distributed across 11,277 unigenes as well as single nucleotide polymorphisms. In total, 1862 unigenes were predicted to encode for 2120 transcription factors among which most were key salt-responsive. We determined differential gene expression and distribution per sample and most genes related to salt tolerance and photosynthesis were upregulated in 48 h vs. 24 h salt treatment. Protein interaction analysis revealed a high interaction of chaperonins and Rubisco proteins in 48 h vs. 24 h salt treatment. The gene expressions were finally validated using quantitative polymerase chain reaction (qPCR), which was coherent with sequencing results. PMID- 30248969 TI - Electromagnetic-Acoustic Sensing for Biomedical Applications. AB - This paper reviews the theories and applications of electromagnetic-acoustic (EMA) techniques (covering light-induced photoacoustic, microwave-induced thermoacoustic, magnetic-modulated thermoacoustic, and X-ray-induced thermoacoustic) belonging to the more general area of electromagnetic (EM) hybrid techniques. The theories cover excitation of high-power EM field (laser, microwave, magnetic field, and X-ray) and subsequent acoustic wave generation. The applications of EMA methods include structural imaging, blood flowmetry, thermometry, dosimetry for radiation therapy, hemoglobin oxygen saturation (SO2) sensing, fingerprint imaging and sensing, glucose sensing, pH sensing, etc. Several other EM-related acoustic methods, including magnetoacoustic, magnetomotive ultrasound, and magnetomotive photoacoustic are also described. It is believed that EMA has great potential in both pre-clinical research and medical practice. PMID- 30248973 TI - Genotype-Environment Interaction Shapes the Microbial Assemblage in Grapevine's Phyllosphere and Carposphere: An NGS Approach. AB - Plant surface or phyllosphere is the habitat of hyperdiverse microbial communities and it is always exposed to the fluctuating environmental factors, which is thought to be one of the potential drivers of microbial community structuring. Impact of grapevine genotypes in variable environmental factors (i.e., at different geographic locations) on the phyllosphere has never been studied and is the main objective of this report. Using high throughput short amplicon sequencing of 16S rRNA genes and internal transcribed spacer (ITS), we analyzed the impacts of genotypes of Vitis Vinifera (coming from three genetic pool), on the microbial (bacterial and fungal) assemblage in the phyllosphere. First, we performed the analysis of the phyllosphere microbiome while using fifteen genotypes that were chosen to maximize intra-specific diversity and grown in two Mediterranean vineyards. Then, the same analysis was performed on five commercially important varieties of Vitis vinifera that were sampled from three different French agro-climatic zones (or terroir: a combination of climate, soils, and human practices). Our study revealed that, at a particular geographic location, genotypes have an impact on microbial assemblage in the phyllosphere and carposphere of leaf and fruit (or berries), respectively, which is more prominent on the carposphere but the effect of terroir was much stronger than the genotype when the leaf phyllosphere of five grapevine varieties grown in different agro-climatic zones was compared. Impacts of the season and exterior plant organs (leaf and berries) on microbial taxa structuring in the phyllosphere was also assessed and presented in this report. PMID- 30248972 TI - Human Breast Milk NMR Metabolomic Profile across Specific Geographical Locations and Its Association with the Milk Microbiota. AB - The composition of human breast milk is highly variable, and it can be influenced by genetics, diet, lifestyle, and other environmental factors. This study aimed to investigate the impact of geographical location and mode of delivery on the nuclear magnetic resonance spectroscopy (NMR) metabolic profile of breast milk and its relationship with the milk microbiome. Human milk metabolic and microbiota profiles were determined using NMR and 16S rRNA gene sequencing, respectively, in 79 healthy women from Finland, Spain, South Africa, and China. Up to 68 metabolites, including amino acids, oligosaccharides, and fatty acid associated metabolites, were identified in the milk NMR spectra. The metabolite profiles showed significant differences between geographical locations, with significant differences (p < 0.05) in the levels of galactose, lacto-N fucopentaose III, lacto-N-fucopentaose I and 2-fucosyllactose, 3-fucosyllactose, lacto-N-difucohexaose II, lacto-N-fucopentaose III, 2-hydroxybutyrate, 3 hydroxybutyrate, proline, N-acetyl lysine, methyl-histidine, dimethylamine, kynurenine, urea, creatine and creatine phosphate, formate, lactate, acetate, phosphocholine, acetylcholine, LDL, VLDL, ethanolamine, riboflavin, hippurate, spermidine, spermine and uridine. Additionally, the effect of caesarean section on milk metabolome was dependent on the geographical region. Specific interrelations between human milk metabolites and microbiota were also identified. Proteobacteria, Actinobacteria, and Bacilli were most significantly associated with the milk metabolites, being either positively or negatively correlated depending on the metabolite. Our results reveal specific milk metabolomic profiles across geographical locations and also highlight the potential interactions between human milk's metabolites and microbes. PMID- 30248974 TI - Magnetic and Mossbauer Spectroscopy Studies of Zinc-Substituted Cobalt Ferrites Prepared by the Sol-Gel Method. AB - Zinc ion-substituted cobalt ferrite powders Co1-xZnxFe2O4 (x = 0-0.7) were prepared by the sol-gel auto-combustion process. The structural properties and magnetic of the samples were investigated with X-ray diffraction (XRD), superconducting quantum interference device, and a Mossbauer spectrometer. The results of XRD showed that the powder of a single cubic phase of ferrites calcined when kept at 800 degrees C for 3 h. The lattice constant increases with increase in Zn concentration, but average crystallite size does not decrease constantly by increasing the zinc content, which is related to pH value. It was confirmed that the transition from ferrimagnetic to superparamagnetic behaviour depends on increasing zinc concentration by Mossbauer spectra at room temperature. Magnetization at room temperature increases for x <= 0.3, but decreases for increasing Zn2+ ions. The magnetization of Co0.7Zn0.3Fe2O4 reached maximum value (83.51 emu/g). The coercivity decreased with Zn2+ ions, which were doped on account of the decrease of the anisotropy constant. PMID- 30248976 TI - Role of Chemosensory TRP Channels in Lung Cancer. AB - Transient receptor potential (TRP) channels represent a large family of cation channels and many members of the TRP family have been shown to act as polymodal receptor molecules for irritative or potentially harmful substances. These chemosensory TRP channels have been extensively characterized in primary sensory and neuronal cells. However, in recent years the functional expression of these proteins in non-neuronal cells, e.g., in the epithelial lining of the respiratory tract has been confirmed. Notably, these proteins have also been described in a number of cancer types. As sensor molecules for noxious compounds, chemosensory TRP channels are involved in cell defense mechanisms and influence cell survival following exposure to toxic substances via the modulation of apoptotic signaling. Of note, a number of cytostatic drugs or drug metabolites can activate these TRP channels, which could affect the therapeutic efficacy of these cytostatics. Moreover, toxic inhalational substances with potential involvement in lung carcinogenesis are well established TRP activators. In this review, we present a synopsis of data on the expression of chemosensory TRP channels in lung cancer cells and describe TRP agonists and TRP-dependent signaling pathways with potential relevance to tumor biology. Furthermore, we discuss a possible role of TRP channels in the non-genomic, tumor-promoting effects of inhalational carcinogens such as cigarette smoke. PMID- 30248975 TI - Blood-Based Cancer Biomarkers in Liquid Biopsy: A Promising Non-Invasive Alternative to Tissue Biopsy. AB - Cancer is one of the greatest threats facing our society, being the second leading cause of death globally. Currents strategies for cancer diagnosis consist of the extraction of a solid tissue from the affected area. This sample enables the study of specific biomarkers and the genetic nature of the tumor. However, the tissue extraction is risky and painful for the patient and in some cases is unavailable in inaccessible tumors. Moreover, a solid biopsy is expensive and time consuming and cannot be applied repeatedly. New alternatives that overcome these drawbacks are rising up nowadays, such as liquid biopsy. A liquid biopsy is the analysis of biomarkers in a non-solid biological tissue, mainly blood, which has remarkable advantages over the traditional method; it has no risk, it is non invasive and painless, it does not require surgery and reduces cost and diagnosis time. The most studied cancer non-invasive biomarkers are circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes. These circulating biomarkers play a key role in the understanding of metastasis and tumorigenesis, which could provide a better insight into the evolution of the tumor dynamics during treatment and disease progression. Improvements in isolation technologies, based on a higher grade of purification of CTCs, exosomes, and ctDNA, will provide a better characterization of biomarkers and give rise to a wide range of clinical applications, such as early detection of diseases, and the prediction of treatment responses due to the discovery of personalized tumor-related biomarkers. PMID- 30248979 TI - The Effect of Commercially Available Endodontic Cements and Biomaterials on Osteogenic Differentiation of Dental Pulp Pluripotent-Like Stem Cells. AB - The aim of this study is to compare the osteogenic differentiation capacity of the dental pulp pluripotent-like stem cells (DPPSCs) using conditional media pretreated with ProRoot-MTA, Biodentine (BD) or the newly manufactured pure Portland cement Med-PZ (MZ). DPPSCs, isolated from human third molars, are the most relevant cell model to draw conclusions about the role of biomaterials on dental tissue regeneration. Cytotoxicity, alkaline phosphatase (ALP) activity, and calcium deposition analysis were evaluated at different differentiation time points. Gene expression of key osteogenic markers (RUNX2, Collagen I and Osteocalcin) was determined by qRT-PCR analysis. The osteogenic capacity of cells cultured in conditioned media prepared from MZ or MTA cements was comparable. BD conditioned media supported cell proliferation but failed to induce osteogenesis. Relative to controls and other cements, high osteogenic gene expression was observed in cultures pre-treated with the novel endodontic cement MZ. In conclusion, the in vitro behavior of a MZ- endodontic cement was evaluated, showing similar enhanced cell proliferation compared to other commercially available cements but with an enhanced osteogenic capacity with prospective potential as a novel cement for endodontic treatments. PMID- 30248978 TI - 'Sustainable' Rather Than 'Subsistence' Food Assistance Solutions to Food Insecurity: South Australian Recipients' Perspectives on Traditional and Social Enterprise Models. AB - South Australian (SA) food charity recipients' perspectives were sought on existing services and ideas for improvement of food assistance models to address food insecurity. Seven focus groups were conducted between October and November 2017 with 54 adults. Thematically analysed data revealed five themes: (1) Emotional cost and consequences of seeking food relief; (2) Dissatisfaction with inaccessible services and inappropriate food; (3) Returning the favour-a desire for reciprocity; (4) Desiring help beyond food; and, (5) "It's a social thing", the desire for social interaction and connection. Findings revealed that some aspects of the SA food assistance services were disempowering for recipients. Recipients desired more empowering forms of food assistance that humanise their experience and shift the locus of control and place power back into their hands. Some traditional models, such as provision of supermarket vouchers, empower individuals by fostering autonomy and enabling food choice in socially acceptable ways. Improvement in the quality of existing food assistance models, should focus on recipient informed models which re-dress existing power relations. Services which are more strongly aligned with typical features of social enterprise models were generally favoured over traditional models. Services which are recipient centred, strive to empower recipients and provide opportunities for active involvement, social connection and broader support were preferred. PMID- 30248977 TI - The Multifaceted Role of Pectin Methylesterase Inhibitors (PMEIs). AB - Plant cell walls are complex and dynamic structures that play important roles in growth and development, as well as in response to stresses. Pectin is a major polysaccharide of cell walls rich in galacturonic acid (GalA). Homogalacturonan (HG) is considered the most abundant pectic polymer in plant cell walls and is partially methylesterified at the C6 atom of galacturonic acid. Its degree (and pattern) of methylation (DM) has been shown to affect biomechanical properties of the cell wall by making pectin susceptible for enzymatic de-polymerization and enabling gel formation. Pectin methylesterases (PMEs) catalyze the removal of methyl-groups from the HG backbone and their activity is modulated by a family of proteinaceous inhibitors known as pectin methylesterase inhibitors (PMEIs). As such, the interplay between PME and PMEI can be considered as a determinant of cell adhesion, cell wall porosity and elasticity, as well as a source of signaling molecules released upon cell wall stress. This review aims to highlight recent updates in our understanding of the PMEI gene family, their regulation and structure, interaction with PMEs, as well as their function in response to stress and during development. PMID- 30248980 TI - A Novel PAA Derivative with Enhanced Drug Efficacy in Pancreatic Cancer Cell Lines. AB - Nanoparticles have been shown to be effective drug carriers in cancer therapy. Pancreatic cancer forms dense tumours which are often resistant to drug molecules. In order to overcome such multidrug resistance, new drug entities, novel delivery systems and combination therapy strategies are being explored. In this paper, we report the design and synthesis of a poly(allylamine)-based amphiphile modified with hydrophobic naphthalimido pendant groups. Bisnaphthalimide compounds have been shown to possess anticancer activity. The potential of this polymer to encapsulate, solubilize and enhance drug (5 fluorouricil and bis-(naphthalimidopropyl)-diaminooctane) cytotoxicity in BxPC-3 cells was evaluated. Our studies showed that the insoluble drugs could be formulated up to 4.3 mg mL-1 and 2.4 mg mL-1 inside the amphiphiles, respectively. Additionally, the novel poly(allylamine)-naphthalimide carrier resulted in an amplification of cytotoxic effect with drug treatment after 24 h, and was capable of reduction of 50% cell population at concentrations as low as 3 MUg mL-1. PMID- 30248981 TI - Systematic Approach to the Diagnosis and Treatment of Lyme Carditis and High Degree Atrioventricular Block. AB - Lyme carditis (LC) is a manifestation of the early disseminated stage of Lyme disease and often presents as high-degree atrioventricular (AV) block. High degree AV block in LC can be treated with antibiotics, usually resolving with a highly favorable prognosis, thus preventing the unnecessary implantation of permanent pacemakers. We present a systematic approach to the diagnosis and management of LC that implements the Suspicious Index in Lyme Carditis (SILC) risk stratification score. PMID- 30248982 TI - A Pilot Study for the Detection of Cyclic Prolyl-Hydroxyproline (Pro-Hyp) in Human Blood after Ingestion of Collagen Hydrolysate. AB - Levels of short linear hydroxyproline (Hyp)-containing peptides, such as prolyl hydroxyproline (Pro-Hyp), increase in human blood after the ingestion of collagen hydrolysate, which has been associated with beneficial effects for human skin and joints. The present study demonstrates the presence of a novel food-derived collagen peptide, cyclic Pro-Hyp, in human blood after the ingestion of collagen hydrolysate. The cyclic Pro-Hyp levels in plasma samples were estimated by liquid chromatography mass spectrometry (LC-MS). Cyclic Pro-Hyp levels significantly increased in the plasma after ingestion of collagen hydrolysate, reaching a maximum level after 2 h and then decreasing. The maximum level of cyclic Pro-Hyp in plasma ranged from 0.1413 to 0.3443 nmol/mL, representing approximately 5% of linear Pro-Hyp in plasma after ingestion of collagen hydrolysate. Addition of cyclic Pro-Hyp in medium at 7 nmol/mL significantly enhanced the growth rate of mouse skin fibroblasts on collagen gel more extensively compared to linear Pro Hyp. PMID- 30248983 TI - Hysteretic Photochromic Switching (HPS) in Doubly Doped GaN(Mg):Eu-A Summary of Recent Results. AB - Europium is the most-studied and least-well-understood rare earth ion (REI) dopant in GaN. While attempting to increase the efficiency of red GaN light emitting diodes (LEDs) by implanting Eu+ into p-type GaN templates, the Strathclyde University group, in collaboration with IST Lisbon and Unipress Warsaw, discovered hysteretic photochromic switching (HPS) in the photoluminescence spectrum of doubly doped GaN(Mg):Eu. Our recent work, summarised in this contribution, has used time-, temperature- and light-induced changes in the Eu intra-4f shell emission spectrum to deduce the microscopic nature of the Mg-Eu defects that form in this material. As well as shedding light on the Mg acceptor in GaN, we propose a possible role for these emission centres in quantum information and computing. PMID- 30248984 TI - A Polarization-Independent Fiber-Optic SPR Sensor. AB - Fiber-optic surface plasmon resonance (SPR) sensors possess the advantages of small size, flexible, allowing for a smaller sample volume, easy to be integrated, and high sensitivity. They have been intensively developed in recent decades. However, the polarizing nature of the surface plasmon waves (SPWs) always hinders the acquisition of SPR spectrum with high signal-noise ratio in wavelength modulation unless a polarizer is employed. The addition of polarizer complicates the system and reduces the degree of compactness. In this work, we propose and demonstrate a novel, polarization-independent fiber-optic SPR sensor based on a BK7 bi-prism with two incident planes orthogonal to each other. In the bi-prism, TM-polarized components of non-polarized incident lights excite SPWs on the first sensing channel, meanwhile the TE components and the remaining TM components are reflected, then the reflected TE components serve as TM components of incident lights for the second sensing channel to excite SPWs. Simulations show the proposed SPR structure permit us to completely eliminate the polarization dependence of the plasmon excitation. Experimental results agree well with the simulations. This kind of devices can be considered an excellent option for development of simple and compact SPR chemical sensors. PMID- 30248986 TI - Field Distortion and Optimization of a Vapor Cell in Rydberg Atom-Based Radio Frequency Electric Field Measurement. AB - Highly excited Rydberg atoms in a room-temperature vapor cell are promising for developing a radio-frequency (RF) electric field (E-field) sensor and relevant measurement standards with high accuracy and sensitivity. The all-optical sensing approach is based on electromagnetically-induced transparency and Autler-Townes splitting induced by the RF E-field. Systematic investigation of measurement uncertainty is of great importance for developing a national measurement standard. The presence of a dielectric vapor cell containing alkali atoms changes the magnitude, polarization, and spatial distribution of the incident RF field. In this paper, the field distortion of rubidium vapor cells is investigated, in terms of both field strength distortion and depolarization. Full-wave numerical simulation and analysis are employed to determine general optimization solutions for minimizing such distortion and validated by measuring the E-field vector distribution inside different vapor cells. This work can improve the accuracy of atom-based RF E-field measurements and contributes to the development of related RF quantum sensors. PMID- 30248988 TI - A Meta-Analysis of the Clinical Use of Curcumin for Irritable Bowel Syndrome (IBS). AB - Irritable bowel syndrome (IBS) remains a prevalent and difficult-to-manage gastrointestinal condition. There is growing interest in the use of traditional medicine to manage IBS. In particular, curcumin, a biologically active phytochemical, has demonstrated anti-inflammatory and anti-oxidant properties and mucosal protective effects in rat models of colitis. This meta-analysis thus aimed to investigate the hypothesis that curcumin improves IBS symptoms. Using the keywords (curcumin OR turmeric OR Indian saffron OR diferuloylmethane OR curcuminoid) AND (irritable bowel syndrome OR IBS), a preliminary search on the PubMed, Medline, Embase, PsychINFO, Web of Science, and Google Scholar databases yielded 1080 papers published in English between 1 January 1988 and 1 May 2018. Five randomized, controlled trials were systematically reviewed and 3 were included in the final meta-analysis. Random-effects meta-analysis based on three studies and 326 patients found curcumin to have a beneficial albeit not statistically significant effect on IBS symptoms (pooled standardized mean difference from baseline IBS severity rating -0.466, 95% CI: -1.113 to 0.182, p = 0.158). This is the first meta-analysis to examine the use of curcumin in IBS. With its unique anti-oxidant and anti-inflammatory activities and ability to modulate gut microbiota, curcumin is a potentially useful addition to our armamentarium of agents for IBS. It also appears safe and well-tolerated, with no adverse events reported in the available trials. However, current findings are based on a considerably limited evidence base with marked heterogeneity. More robust clinical trials involving a standardized curcumin preparation and larger sample sizes should be encouraged. PMID- 30248987 TI - Ingestion of Insect Protein Isolate Enhances Blood Amino Acid Concentrations Similar to Soy Protein in A Human Trial. AB - BACKGROUND: Increased amino acid availability stimulates muscle protein synthesis (MPS), which is critical for maintaining or increasing muscle mass when combined with training. Previous research suggests that whey protein is superior to soy protein in regard to stimulating MPS and muscle mass. Nevertheless, with respect to a future lack of dietary protein and an increasing need for using eco-friendly protein sources it is of great interest to investigate the quality of alternative protein sources, like insect protein. OBJECTIVE: Our aim was to compare the postprandial amino acid (AA) availability and AA profile in the blood after ingestion of protein isolate from the lesser mealworm, whey isolate, and soy isolate. DESIGN: Six healthy young men participated in a randomized cross-over study and received three different protein supplementations (25 g of crude protein from whey, soy, insect or placebo (water)) on four separate days. Blood samples were collected at pre, 0 min, 20 min, 40 min, 60 min, 90 min, and 120 min. Physical activity and dietary intake were standardized before each trial, and participants were instructed to be fasting from the night before. AA concentrations in blood samples were determined using 1H NMR spectroscopy. RESULTS: A significant rise in blood concentration of essential amino acids (EAA), branched-chain amino acids (BCAA) and leucine was detected over the 120 min period for all protein supplements. Nevertheless, the change in AA profile was significantly greater after ingestion of whey than soy and insect protein (p < 0.05). Area under the curve (AUC) analysis and AA profile revealed comparable AA concentrations for soy and insect protein, whereas whey promoted a ~97% and ~140% greater AUC value than soy and insect protein, respectively. A tendency towards higher AA concentrations beyond the 120 min period was observed for insect protein. CONCLUSION: We report that ingestion of whey, soy, and insect protein isolate increases blood concentrations of EAA, BCAA, and leucine over a 120 min period (whey > insect = soy). Insect protein induced blood AA concentrations similar to soy protein. However, a tendency towards higher blood AA concentrations at the end of the 120 min period post ingestion was observed for insect protein, which indicates that it can be considered a "slow" digestible protein source. PMID- 30248989 TI - Double Notched Long-Period Fiber Grating Characterization for CO2 Gas Sensing Applications ?. AB - In this study, we applied a double-sided inductively coupled plasma (ICP) process to nanostructure long-period fiber grating (LPFG) in order to fabricate a double notched LPFG (DNLPFG) sensor with a double-sided surface corrugated periodic grating. Using the sol-gel method, we also added thymol blue and ZnO to form a gas sensing layer, thus producing a DNLPFG CO2 gas sensor. The resulting sensor is the first double-sided etching sensor used to measure CO2. The experimental results showed that as the CO2 concentration increased, the transmission loss increased, and that the smaller the fiber diameter, the greater the sensitivity and the greater the change in transmission loss. When the diameter of the fiber was 32 MUm (and the period was 570 MUm) and the perfusion rate of CO2 gas was 15%, the maximum loss variation of up to 3.881 dB was achieved, while the sensitivity was 0.2146 dB/% and the linearity was 0.992. These results demonstrate that the DNLPG CO2 gas sensor is highly sensitive. PMID- 30248985 TI - Role of COX-2/PGE2 Mediated Inflammation in Oral Squamous Cell Carcinoma. AB - A significant amount of research indicates that the cyclooxygenase/prostaglandin E2 (PGE2) pathway of inflammation contributes to the development and progression of a variety of cancers, including squamous cell carcinoma, or the oral cavity and oropharynx (OSCC). Although there have been promising results from studies examining the utility of anti-inflammatory drugs in the treatment of OSCC, this strategy has been met with only variable success and these drugs are also associated with toxicities that make them inappropriate for some OSCC patients. Improved inflammation-targeting therapies require continued study of the mechanisms linking inflammation and progression of OSCC. In this review, a synopsis of OSCC biology will be provided, and recent insights into inflammation related mechanisms of OSCC pathobiology will be discussed. The roles of prostaglandin E2 and cluster of differentiation factor 147 (CD147) will be presented, and evidence for their interactions in OSCC will be explored. Through continued investigation into the protumourigenic pathways of OSCC, more treatment modalities targeting inflammation-related pathways can be designed with the hope of slowing tumour progression and improving patient prognosis in patients with this aggressive form of cancer. PMID- 30248990 TI - Metallic Nanoparticles: General Research Approaches to Immunological Characterization. AB - Our immunity is guaranteed by a complex system that includes specialized cells and active molecules working in a spatially and temporally coordinated manner. Interaction of nanomaterials with the immune system and their potential immunotoxicity are key aspects for an exhaustive biological characterization. Several assays can be used to unravel the immunological features of nanoparticles, each one giving information on specific pathways leading to immune activation or immune suppression. Size, shape, and surface chemistry determine the surrounding corona, mainly formed by soluble proteins, hence, the biological identity of nanoparticles released in cell culture conditions or in a living organism. Here, we review the main laboratory characterization steps and immunological approaches that can be used to understand and predict the responses of the immune system to frequently utilized metallic or metal-containing nanoparticles, in view of their potential uses in diagnostics and selected therapeutic treatments. PMID- 30248993 TI - Phytotoxicity of Essential Oils on Selected Weeds: Potential Hazard on Food Crops. AB - The chemical composition of winter savory, peppermint, and anise essential oils, and in vitro and in vivo phytotoxic activity against weeds (Portulaca oleracea, Lolium multiflorum, and Echinochloa crus-galli) and food crops (maize, rice, and tomato), have been studied. Sixty-four compounds accounting for between 97.67 99.66% of the total essential oils were identified by Gas Chromatography-Mass Spectrometry analysis. Winter savory with carvacrol (43.34%) and thymol (23.20%) as the main compounds produced a total inhibitory effect against the seed germination of tested weed. Menthol (48.23%), menthone (23.33%), and iso-menthone (16.33%) from peppermint only showed total seed germination inhibition on L. multiflorum, whereas no significant effects were observed with trans-anethole (99.46%) from anise at all concentrations (0.125-1 uL/mL). Low doses of peppermint essential oil could be used as a sustainable alternative to synthetic agrochemicals to control L. multiflorum. The results corroborate that in vivo assays with a commercial emulsifiable concentrate need higher doses of the essential oils to reproduce previous in vitro trials. The higher in vivo phytotoxicity of winter savory essential oil constitutes an eco-friendly and less pernicious alternative to weed control. It is possible to achieve a greater in vivo phytotoxicity if less active essential oil like peppermint is included with other active excipients. PMID- 30248991 TI - Oral Microbes, Biofilms and Their Role in Periodontal and Peri-Implant Diseases. AB - Despite many discoveries over the past 20 years regarding the etio-pathogenesis of periodontal and peri-implant diseases, as well as significant advances in our understanding of microbial biofilms, the incidence of these pathologies still continues to rise. This review presents a general overview of the main protagonists and phenomena involved in oral health and disease. A special emphasis on the role of certain keystone pathogens in periodontitis and peri implantitis is underlined. Their capacity to bring a dysregulation of the homeostasis with their host and the microbial biofilm lifestyle are also discussed. Finally, the current treatment principles of periodontitis and peri implantitis are presented and their limits exposed. This leads to realize that new strategies must be developed and studied to overcome the shortcomings of existing approaches. PMID- 30248994 TI - Anxiety in Rural Chinese Children and Adolescents: Comparisons across Provinces and among Subgroups. AB - China's competitive education system has produced notably high learning outcomes, but they may be costly. One potential cost is high levels of anxiety. China has launched several initiatives aimed at improving student mental health. However, little is known about how effective these programs and policies are. The goal of this paper was to examine anxiety levels among children and adolescents in rural China, and to identify which subpopulations were particularly vulnerable to anxiety. Data were aggregated from 10 different school-level surveys conducted in rural areas of five provinces between 2008 and 2015. In total, 50,361 students were evaluated using the 100-item, nine-subcategory Mental Health Test (a variation of the Children's Manifest Anxiety Scale). Seven percent of students were at risk for overall anxiety. However, over half of students were at risk for at least one subcategory of anxiety. Students at higher risk for anxiety included students from poorer counties and families, female students, secondary school students, and students with lower levels of academic performance. Many students in rural China are at risk for anxiety, and certain student subpopulations are particularly vulnerable. We suggest that China's government review and update student mental health programs and policies. PMID- 30248995 TI - The Chameleon-Like Properties of Psychoactive Drugs: Examinations with HR LC MS/MS Technology of Patients Presenting at the Emergency Department Following the Use of Synthetic Cannabinoids: A Case Series and Literature Review. AB - The chameleon can disguise itself in nature by taking on different colors and forms. As synthetic cannabinoids (SC) have clinically similar effects to those of several psychoactive agents, they are one of the most difficult intoxications to diagnose. The reasons for this are due to clinical variations throughout the world and the differences in symptoms having not been determined due to their similarity to the intoxication of several other drugs. The aim of this study was to obtain prospective data of patients presenting at the Emergency Department (ED) with suspected SC intoxication, and as a result of prospective examination of samples, to determine a new generation of SC use, SC types, clinical findings, and treatments. Method: A total of a 15 patients with suspected SC intoxication who presented at the ED of the Health Sciences University Kayseri Training and Research Hospital between January 2017 and January 2018 were examined. Samples taken prospectively from patients who were followed-up for a diagnosis of SC intoxication were examined with the HR LC-MS/MS method; SC were determined, and the test results of other psychoactive agents that were used concurrently were examined. Conclusions: Three significant findings emerged as a result of this study. Firstly, due to the different clinical forms of presentation at ED associated with SC use and the range of intoxications that cannot be diagnosed, advanced laboratory tests are required, in addition to routine tests for the determination of SC. Secondly, those diagnosed as having taken SC were also determined to have used it concurrently with substances that have a high potential for addiction, such as amphetamines and quetiapine. Thirdly, in regard to examples of cases presented in the literature, anti-psychotics, fluid hydration, and anxiolytics can be used as treatment options for those diagnosed with SC use. PMID- 30248996 TI - Immunizing the Immune: Can We Overcome Influenza's Most Formidable Challenge? AB - The first human influenza virus was isolated more than 85 years ago, and several vaccine candidates were developed and tested soon after. Yet, controlling infections mediated by this respiratory pathogen continues to present a formidable challenge. Development of an effective influenza vaccine has been undermined by the dynamic nature of influenza viruses: these viruses have the unique capacity to escape pre-existing immunity. In this perspective, I highlight pre-existing immunity as a different, but related, hurdle that may actually lessen the effectiveness of influenza vaccine-induced immune responses. Specifically, I discuss the impact of pre-existing immunity on the generation of de novo B cell responses to influenza vaccination. As the influenza virus changes its major antigenic determinants, it creates new ones in the process. Our immune system adapts by targeting the new determinants. However, pre-existing antibodies and memory B cells interfere with the generation of de novo responses against these newly formed epitopes, rendering vaccines less effective. Overcoming such interference is essential for the development of more effective influenza vaccines. PMID- 30248997 TI - Smart Bandage Based on Molecularly Imprinted Polymers (MIPs) for Diclofenac Controlled Release. AB - The aim of the present study was the development of a "smart bandage" for the topical administration of diclofenac, in the treatment of localized painful and inflammatory conditions, incorporating Molecularly Imprinted Polymers (MIPs) for the controlled release of this anti-inflammatory drug. For this purpose, MIP spherical particles were synthesized by precipitation polymerization, loaded with the therapeutic agent and incorporated into the bandage surface. Batch adsorption binding studies were performed to investigate the adsorption isotherms and kinetics and the selective recognition abilities of the synthesized MIP. In vitro diffusion studies were also carried out using Franz cells and the obtained results were reported as percentage of the diffused dose, cumulative amount of diffused drug, steady-state drug flux and permeability coefficient. Moreover, the biocompatibility of the developed device was evaluated using the EPISKINTM model. The Scatchard analysis indicated that the prepared MIP is characterized by the presence of specific binding sites for diclofenac, which are not present in the corresponding non-imprinted polymer, and the obtained results confirmed both the ability of the prepared bandage to prolong the drug release and the absence of skin irritation reactions. Therefore, these results support the potential application of the developed "smart bandage" as topical device for diclofenac sustained release. PMID- 30248992 TI - Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier. AB - For glioblastoma, the tumor microenvironment (TME) is pivotal to support tumor progression and therapeutic resistance. TME consists of several types of stromal, endothelial and immune cells, which are recruited by cancer stem cells (CSCs) to influence CSC phenotype and behavior. TME also promotes the establishment of specific conditions such as hypoxia and acidosis, which play a critical role in glioblastoma chemoresistance, interfering with angiogenesis, apoptosis, DNA repair, oxidative stress, immune escape, expression and activity of multi-drug resistance (MDR)-related genes. Finally, the blood brain barrier (BBB), which insulates the brain microenvironment from the blood, is strongly linked to the drug-resistant phenotype of glioblastoma, being a major physical and physiological hurdle for the delivery of chemotherapy agents into the brain. Here, we review the features of the glioblastoma microenvironment, focusing on their involvement in the phenomenon of chemoresistance; we also summarize recent advances in generating systems to modulate or bypass the BBB for drug delivery into the brain. Genetic aspects associated with glioblastoma chemoresistance and current immune-based strategies, such as checkpoint inhibitor therapy, are described too. PMID- 30248998 TI - Characterization and Antioxidant and Angiotensin I-Converting Enzyme (ACE) Inhibitory Activities of Gelatin Hydrolysates Prepared from Extrusion-Pretreated Milkfish (Chanos chanos) Scale. AB - Fish gelatin hydrolysates have been shown to possess various biological activities due to their unique Gly-Pro-Y and Gly-X-Hyp sequences. In the current study, fish gelatin was extracted from non-extruded milkfish scale (FSG1) or extrusion-pretreated milkfish scale (FSG2); extracted gelatins were hydrolyzed with different combinations of Flavourzyme and Alcalase to give four different hydrolysates, namely: FSGH1 (FSG1 hydrolyzed with Flavourzyme), FSGH2 (FSG1 hydrolyzed with Alcalase + Flavourzyme), FSGH3 (FSG2 hydrolyzed with Flavourzyme), and FSGH4 (FSG2 hydrolyzed with Alcalase + Flavourzyme). The extrusion-pretreatment process enhanced the extraction yield of gelatin from fish scale. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Fourier transform infrared (FTIR) analyses showed the extracts FSG1 and FSG2 possessed characteristics of gelatin. Moreover, the physicochemical characteristics of FSGH1-FSGH4 were examined by analyses of their degree of hydrolysis, amino acid composition, UV spectrum, FTIR spectrum, molecular weight, and RP-HPLC profile. Additional biological functional analyses showed that all of the studied gelatin hydrolysates FSGH1-FSGH4 possessed antioxidant activity dose dependently as revealed by DPPH scavenging, ABTS scavenging, and reducing power analyses. In addition, FSGH2 and FSGH4 showed higher angiotensin-I-converting enzyme (ACE)-inhibitory activity as compared to FSGH1 and FSGH3. Taken together, FSGH2 and FSGH4 showed high antioxidant activity and potent anti-ACE activity. Due to the potential antioxidant and antihypertensive properties of FSGH2 and FSGH4, further research is needed to explore their possible use as natural supplementary raw materials in food and nutraceutical products. PMID- 30249000 TI - Comparative Analysis of Mechanical Properties and Metal-Ceramic Bond Strength of Co-Cr Dental Alloy Fabricated by Different Manufacturing Processes. AB - Cobalt-chromium (Co-Cr) alloy is a widely used base material for dental fixed prostheses. These restorations can be produced through casting technique, subtractive or additive manufacturing technologies. However, limited information is available regarding the influence of manufacturing techniques on the properties of Co-Cr alloy since most studies used different chemical compositions of Co-Cr alloy for different manufacturing methods. This study compares the mechanical properties, metal-ceramic bond strength, and microstructures of specimens produced by casting, milling, and selective laser melting (SLM) from one single Co-Cr alloy composition. The mechanical properties of the alloy were investigated by tensile and Vickers hardness tests, and metal-ceramic bond strength was determined by three-point bending. Scanning electron microscopy (SEM) with backscattered electron (BSE) images and optical microphotographs were used to analyze the surface microstructures. Compared with the casting and milling techniques, SLM Co-Cr alloy specimens indicated enhanced mechanical properties and comparable metal-ceramic bond strength. Besides, the microstructures of the SLM specimens showed finer grains with more second phase particles than the casting and milling specimens. The results of our study indicate that SLM might be superior to traditional techniques for the manufacturing of fixed dental restorations. PMID- 30248999 TI - Development of an In Vitro Screening Platform for the Identification of Partial PPARgamma Agonists as a Source for Antidiabetic Lead Compounds. AB - Type 2 diabetes (T2D) is a metabolic disorder where insulin-sensitive tissues show reduced sensitivity towards insulin and a decreased glucose uptake (GU), which leads to hyperglycaemia. Peroxisome proliferator-activated receptor (PPAR)gamma plays an important role in lipid and glucose homeostasis and is one of the targets in the discovery of drugs against T2D. Activation of PPARgamma by agonists leads to a conformational change in the ligand-binding domain, a process that alters the transcription of several target genes involved in glucose and lipid metabolism. Depending on the ligands, they can induce different sets of genes that depends of their recruitment of coactivators. The activation of PPARgamma by full agonists such as the thiazolidinediones leads to improved insulin sensitivity but also to severe side effects probably due to their behavior as full agonists. Partial PPARgamma agonists are compounds with diminished agonist efficacy compared to full agonist that may exhibit the same antidiabetic effect as full agonists without inducing the same magnitude of side effects. In this review, we describe a screening platform for the identification of partial PPARgamma agonists from plant extracts that could be promising lead compounds for the development of antidiabetic drugs. The screening platform includes a series of in vitro bioassays, such as GU in adipocytes, PPARgamma mediated transactivation, adipocyte differentiation and gene expression as well as in silico docking for partial PPARgamma agonism. PMID- 30249001 TI - Food Byproducts as Sustainable Ingredients for Innovative and Healthy Dairy Foods. AB - The valorization of food wastes and byproducts has become a major subject of research to improve the sustainability of the food chain. This narrative review provides an overview of the current trends in the use of food byproducts in the development of dairy foods. We revised the latest data on food loss generation, the group of byproducts most used as ingredients in dairy product development, and their function within the food matrix. We also address the challenges associated with the sensory properties of the new products including ingredients obtained from byproducts, and consumers' attitudes towards these sustainable novel dairy foods. Overall, 50 studies supported the tremendous potential of the application of food byproducts (mainly those from plant-origin) in dairy foods as ingredients. There are promising results for their utilization as food additives for technological purposes, and as sources of bioactive compounds to enhance the health-promoting properties of dairy products. However, food technologists, nutritionists and sensory scientists should work together to face the challenge of improving the palatability and consumer acceptance of these novel and sustainable dairy foods. PMID- 30249002 TI - Chronic Insulin Infusion Down-Regulates Circulating and Urinary Nitric Oxide (NO) Levels Despite Molecular Changes in the Kidney Predicting Greater Endothelial NO Synthase Activity in Mice. AB - Insulin therapy is often needed to overcome insulin receptor resistance in type 2 diabetes; however, the impact of providing additional insulin to already hyperinsulinemic subjects is not clear. We infused male TALLYHO/Jng (TH) mice (insulin resistant) with insulin (50 U/kg.bw/d) or vehicle (control) by osmotic minipump for 14 days. One group of insulin-infused mice was switched to 4% NaCl diet (high-sodium diet, HSD) in the second week. Blood chemistry revealed a significantly higher anion gap and blood sodium concentrations with insulin infusion, i.e., relative metabolic acidosis. Systolic BP and heart rate were slightly (~5 mm Hg) higher in insulin-infused versus control mice. HSD resulted in a modest and transient rise in mean arterial blood pressure (BP), relative to control or insulin-infused, normal-NaCl-fed mice. In kidney, insulin infusion: (1) increased total and phosphorylated (serine-1177) endothelial nitric oxide synthase (eNOS) band densities; (2) reduced band density of the uncoupled form of eNOS; and (3) increased renal homogenate nitric oxide synthase (NOS) activity. Despite this, plasma and urine levels of nitrates plus nitrites (NOx) fell with insulin infusion, by day 14 (40-50%) suggesting worsening of resistance. Overall, insulin infusion ramps up the cellular means in kidney to increase vasodilatory and natriuretic NO, but in the long term may be associated with worsening of insulin receptor resistance. PMID- 30249003 TI - The Synergistic Effects of Resveratrol combined with Resistant Training on Exercise Performance and Physiological Adaption. AB - The comprehensive studies done on resveratrol (RES) support that this polyphenol has multiple bioactivities and is widely accepted for dietary supplementation. Furthermore, regular exercise is known to have benefits on health and is considered as a form of preventive medicine. Although the vast majority of prior studies emphasize the efficacy of aerobic exercise in promoting physiological adaptions, other types of exercise, such as resistance exercise and high intensity interval training (HIIT), may achieve similar or different physiological outcomes. Few studies have looked into the effectiveness of a combinational, synergistic approach to exercise using a weight-loading ladder climbing animal platform. In this study, ICR mice were allocated randomly to the RES and training groups using a two-way ANOVA (RES * Training) design. Exercise capacities, including grip strength, aerobic performance, and anaerobic performance, were assessed and the physiological adaptions were evaluated using fatigue-associated indexes that were implemented immediately after the exercise intervention. In addition, glycogen levels, muscular characteristics, and safety issues, including body composition, histopathology, and biochemistry, were further elucidated. Synergistic effects were observed on grip strength, anaerobic capacities, and exercise lactate, with significant interaction effects. Moreover, the training or RES may have contributed significantly to elevating aerobic capacity, tissue glycogen, and muscle hypertrophy. Toxic and other deleterious effects were also considered to evaluate the safety of the intervention. Resistance exercise in combination with resveratrol supplementation may be applied in the general population to achieve better physiological benefits, promote overall health, and promote participation in regular physical activities. PMID- 30249005 TI - Cell-Based Methods for Determination of Efficacy for Candidate Therapeutics in the Clinical Management of Cancer. AB - Determination of therapeutic efficacy is a major challenge in developing treatment options for cancer. Prior to in vivo studies, candidate therapeutics are evaluated using cell-based in vitro methods to assess their anti-cancer potential. This review describes the utility and limitations of evaluating therapeutic efficacy using human tumor-derived cell lines. Indicators for therapeutic efficacy using tumor-derived cell lines include cell viability, cell proliferation, colony formation, cytotoxicity, cytostasis, induction of apoptosis, and cell cycle arrest. Cell panel screens, 3D tumor spheroid models, drug-drug/drug-radiation combinatorial analysis, and invasion/migration assays reveal analogous in vitro information. In animal models, cellular assays can assess tumor micro-environment and therapeutic delivery. The utility of tumor derived cell lines for efficacy determination is manifest in numerous commercially approved drugs that have been applied in clinical management of cancer. Studies reveal most tumor-derived cell lines preserve the genomic signature of the primary tumor source and cell line-based data is highly predictive of subsequent clinical studies. However, cell-based data often disregards natural system components, resulting in cell autonomous outcomes. While 3D cell culture platforms can counter such limitations, they require additional time and cost. Despite the limitations, cell-based methods remain essential in early stages of anti-cancer drug development. PMID- 30249004 TI - Epidemiology of Moderate Alcohol Consumption and Breast Cancer: Association or Causation? AB - Epidemiological studies have been used to show associations between modifiable lifestyle habits and the incidence of breast cancer. Among such factors, a history of alcohol use has been reported in multiple studies and meta-analyses over the past decades. However, associative epidemiological studies that were interpreted as evidence that even moderate alcohol consumption increases breast cancer incidence have been controversial. In this review, we consider the literature on the relationship between moderate or heavy alcohol use, both in possible biological mechanisms and in variations in susceptibility due to genetic or epigenetic factors. We argue that there is a need to incorporate additional approaches to move beyond the associations that are reported in traditional epidemiological analyses and incorporate information on molecular pathologic signatures as a requirement to posit causal inferences. In particular, we point to the efforts of the transdisciplinary field of molecular pathological epidemiology (MPE) to evaluate possible causal relationships, if any, of alcohol consumption and breast cancer. A wider application of the principles of MPE to this field would constitute a giant step that could enhance our understanding of breast cancer and multiple modifiable risk factors, a step that would be particularly suited to the era of "personalized medicine". PMID- 30249006 TI - A Disturbance in the Force: Cellular Stress Sensing by the Mitochondrial Network. AB - As a highly dynamic organellar network, mitochondria are maintained as an organellar network by delicately balancing fission and fusion pathways. This homeostatic balance of organellar dynamics is increasingly revealed to play an integral role in sensing cellular stress stimuli. Mitochondrial fission/fusion balance is highly sensitive to perturbations such as loss of bioenergetic function, oxidative stress, and other stimuli, with mechanistic contribution to subsequent cell-wide cascades including inflammation, autophagy, and apoptosis. The overlapping activity with m-AAA protease 1 (OMA1) metallopeptidase, a stress sensitive modulator of mitochondrial fusion, and dynamin-related protein 1 (DRP1), a regulator of mitochondrial fission, are key factors that shape mitochondrial dynamics in response to various stimuli. As such, OMA1 and DRP1 are critical factors that mediate mitochondrial roles in cellular stress-response signaling. Here, we explore the current understanding and emerging questions in the role of mitochondrial dynamics in sensing cellular stress as a dynamic, responsive organellar network. PMID- 30249009 TI - Historical and Contemporary Perspectives on the Microbiological Aspects of Endodontics. AB - The microbiota of the oral cavity plays a significant role in pulpal and periapical diseases. Historically, 100 years ago little was known on microbiota, but after a century of investigations, only now can many of the intimate secrets of microbial growth, expansion, persistence, communal activities, and virulence be revealed. However, with the capabilities of the microbiota for mutation, quorum sensing, and information transference, researchers are hard-pressed to keep up with both the changes and challenges that an amazingly wide range of bacterial species pose for both the scientist and clinician. Fortunately, the development and expansion of a vast array of molecular biological investigative techniques have enabled dentistry and its associated medical fields to attempt to keep pace with the wide and fascinating world of oral microbiology. PMID- 30249007 TI - Electromagnetic Shielding by MXene-Graphene-PVDF Composite with Hydrophobic, Lightweight and Flexible Graphene Coated Fabric. AB - MXene and graphene based thin, flexible and low-density composite were prepared by cost effective spray coating and solvent casting method. The fabricated composite was characterized using Raman spectroscopy, X-ray diffraction (XRD), scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS) and energy dispersive X-ray (EDX). The prepared composites showed hydrophobic nature with higher contact angle of 126 degrees , -43 mN.m-1 wetting energy, -116 mN.m-1 spreading Coefficient and 30 mN.m-1 lowest work of adhesion. The composites displayed excellent conductivity of 13.68 S.cm-1 with 3.1 Omega.sq-1 lowest sheet resistance. All the composites showed an outstanding thermal stability and constrain highest weight lost until 400 degrees C. The MXene-graphene foam exhibited excellent EMI shielding of 53.8 dB (99.999%) with reflection of 13.10 dB and absorption of 43.38 dB in 8-12.4 GHz. The single coated carbon fabric displayed outstanding absolute shielding effectiveness of 35,369.82 dB.cm2.g-1. The above results lead perspective applications such as aeronautics, radars, air travels, mobile phones, handy electronics and military applications. PMID- 30249010 TI - First Order Reversal Curve Study of SmFe2 Melt-Spun Ribbons. AB - First-order reversal curves (FORC) and the FORC distribution provide a detailed characterization of the relative proportions of reversible and irreversible components of the magnetization of a material, revealing the dominant interactions in the system. Alloys with the nominal composition SmFe2 were obtained by melt-spinning with a cooper wheel velocity of 30 m/s. X-ray powder diffraction analysis showed a greater part consisting of an amorphous phase and a very small amount of SmFe2 crystalline phase with an average crystallite size of 8 nm. A constant acceleration Mossbauer spectrum, measured at room temperature in transmission mode, was fitted to a continuous distribution of effective fields at the nucleus of the amorphous phase (about 84% of the total area), plus two sextets for the non-equivalent sites of Fe in the SmFe2 crystalline phase. 91 first-order reversal curves were collected in a Quantum Design PPMS-VSM with reversal fields from -800 mT to +800 mT and using a calibration field of 850 mT. The obtained FORC diagrams showed a combined effect of a local interaction field and a mean interaction field, and showed that the reversible magnetization is a function of both, the applied magnetic field and the irreversible magnetization. PMID- 30249011 TI - Perioperative Serum Calcium and Phosphorus Levels are Associated with Hospital Costs and Length of Stay after Major Abdominal Surgery. AB - This study aimed to identify an association between serum calcium (Ca) and phosphate (P) levels, tested during the pre- and postoperative period, with hospital costs and length of hospital stay (LOS) of patients who underwent major abdominal surgery. This retrospective cohort study analyzed the medical records of patients who underwent major abdominal surgery. A total of 3893 patients were included in the analysis, and multivariable linear regression analysis was performed. For a 1 mg/dL increase in preoperative Ca, total hospital costs decreased by 3997.9 dollars (coefficient: -3997.9, 95% confidence interval (CI): 4900.5, -30,953; p-value < 0.01), and for a 1 mg/dL increase in postoperative P, total hospital costs decreased by 702.5 dollars (coefficient: -702.5, 95% CI: 1274.5, -67.3; p-value = 0.03). Furthermore, for a 1 mg/dL increase in preoperative Ca, LOS decreased by 2.9 days (coefficient: -2.9, 95% CI: -3.7, 2.1; p-value < 0.01). For a 1 mg/dL increase in postoperative P, LOS decreased by 3.4 days (coefficient: -3.4, 95% CI: -4.2, -2.6; p-value < 0.01). This study suggested preoperative Ca and postoperative P could be useful indicators for the reduction of hospital costs and decrease in LOS from the perspective of enhanced recovery after surgery. PMID- 30249008 TI - Multifaceted Interweaving Between Extracellular Matrix, Insulin Resistance, and Skeletal Muscle. AB - The skeletal muscle provides movement and support to the skeleton, controls body temperature, and regulates the glucose level within the body. This is the core tissue of insulin-mediated glucose uptake via glucose transporter type 4 (GLUT4). The extracellular matrix (ECM) provides integrity and biochemical signals and plays an important role in myogenesis. In addition, it undergoes remodeling upon injury and/or repair, which is also related to insulin resistance (IR), a major cause of type 2 diabetes (T2DM). Altered signaling of integrin and ECM remodeling in diet-induced obesity is associated with IR. This review highlights the interweaving relationship between the ECM, IR, and skeletal muscle. In addition, the importance of the ECM in muscle integrity as well as cellular functions is explored. IR and skeletal muscle ECM remodeling has been discussed in clinical and nonclinical aspects. Furthermore, this review considers the role of ECM glycation and its effects on skeletal muscle homeostasis, concentrating on advanced glycation end products (AGEs) as an important risk factor for the development of IR. Understanding this complex interplay between the ECM, muscle, and IR may improve knowledge and help develop new ideas for novel therapeutics for several IR-associated myopathies and diabetes. PMID- 30249012 TI - Relevance of the Glycemic Index and Glycemic Load for Body Weight, Diabetes, and Cardiovascular Disease. AB - Despite initial enthusiasm, the relationship between glycemic index (GI) and glycemic response (GR) and disease prevention remains unclear. This review examines evidence from randomized, controlled trials and observational studies in humans for short-term (e.g., satiety) and long-term (e.g., weight, cardiovascular disease, and type 2 diabetes) health effects associated with different types of GI diets. A systematic PubMed search was conducted of studies published between 2006 and 2018 with key words glycemic index, glycemic load, diabetes, cardiovascular disease, body weight, satiety, and obesity. Criteria for inclusion for observational studies and randomized intervention studies were set. The search yielded 445 articles, of which 73 met inclusion criteria. Results suggest an equivocal relationship between GI/GR and disease outcome. The strongest intervention studies typically find little relationship among GI/GR and physiological measures of disease risk. Even for observational studies, the relationship between GI/GR and disease outcomes is limited. Thus, it is unlikely that the GI of a food or diet is linked to disease risk or health outcomes. Other measures of dietary quality, such as fiber or whole grains may be more likely to predict health outcomes. Interest in food patterns as predictors of health benefits may be more fruitful for research to inform dietary guidance. PMID- 30249013 TI - Tuning Nanopore Diameter of Titanium Surfaces to Improve Human Gingival Fibroblast Response. AB - The aim of this study was to determine the optimal nanopore diameter of titanium nanostructured surfaces to improve human gingival fibroblast (hGF) response, with the purpose of promoting gingiva integration to dental implant abutments. Two TiO2 nanoporous groups with different diameters (NP-S ~48 nm and NP-B ~74 nm) were grown on Ti foils using an organic electrolyte containing fluoride by electrochemical oxidation, varying the applied voltage and the interelectrode spacing. The surfaces were characterized by scanning electron microscope (SEM), atomic force microscopy (AFM), and contact angle. The hGF were cultured onto the different surfaces, and metabolic activity, cytotoxicity, cell adhesion, and gene expression were analyzed. Bigger porous diameters (NP-B) were obtained by increasing the voltage used during anodization. To obtain the smallest diameter (NP-S), apart from lowering the voltage, a lower interelectrode spacing was needed. The greatest surface area and number of peaks was found for NP-B, despite these samples not being the roughest as defined by Ra. NP-B had a better cellular response compared to NP-S. However, these effects had a significant dependence on the cell donor. In conclusion, nanoporous groups with a diameter in the range of 74 nm induce a better hGF response, which may be beneficial for an effective soft tissue integration around the implant. PMID- 30249014 TI - Upregulation of Myocardial and Vascular Phosphodiesterase 9A in A Model of Atherosclerotic Cardiovascular Disease. AB - Atherosclerosis is strongly associated with cardiac dysfunction and heart failure. Besides microvascular dysfunction and diminishment of the cardiac nitric oxide-Protein Kinase G (NO-PKG) pathway, recent evidence suggests that phosphodiesterase 9A (PDE9A) enzyme has an unfavorable role in pathological changes. Here, we characterized a rabbit model that shows cardiac dysfunction as a result of an atherogenic diet, and examined the myocardial PDE9A signaling. Rabbits were divided into Control (normal diet) and HC (atherogenic diet) groups. Cardiac function was evaluated by echocardiography. Vascular function was assessed, along with serum biomarkers. Histological stains were conducted, expression of selected proteins and cyclic guanosine monophosphate (cGMP) levels were determined. Signs of diastolic dysfunction were shown in HC animals, along with concentric hypertrophy and interstitial fibrosis. Endothelial function was diminished in HC rabbits, along with marked reduction in the aortic lumen, and increased left ventricle outflow tract (LVOT) pressures. A significant increase was shown in myocardial PDE9A levels in HC animals with unchanged vasodilator stimulated phosphoprotein (VASP) phosphorylation and cGMP levels. Upregulation of PDE9A may be associated with early stage of cardiac dysfunction in atherosclerotic conditions. Since PDE9A is involved in cGMP degradation and in deactivation of the cardioprotective PKG signaling pathway, it may become an encouraging target for future investigations in atherosclerotic diseases. PMID- 30249015 TI - Bioactive Peptides from Germinated Soybean with Anti-Diabetic Potential by Inhibition of Dipeptidyl Peptidase-IV, alpha-Amylase, and alpha-Glucosidase Enzymes. AB - Functional foods containing peptides offer the possibility to modulate the absorption of sugars and insulin levels to prevent diabetes. This study investigates the potential of germinated soybean peptides to modulate postprandial glycaemic response through inhibition of dipeptidyl peptidase IV (DPP-IV), salivary alpha-amylase, and intestinal alpha-glucosidases. A protein isolate from soybean sprouts was digested by pepsin and pancreatin. Protein digest and peptide fractions obtained by ultrafiltration (<5, 5-10 and >10 kDa) and subsequent semipreparative reverse phase liquid chromatography (F1, F2, F3, and F4) were screened for in vitro inhibition of DPP-IV, alpha-amylase, maltase, and sucrase activities. Protein digest inhibited DPP-IV (IC50 = 1.49 mg/mL), alpha-amylase (IC50 = 1.70 mg/mL), maltase, and sucrase activities of alpha glucosidases (IC50 = 3.73 and 2.90 mg/mL, respectively). Peptides of 5-10 and >10 kDa were more effective at inhibiting DPP-IV (IC50 = 0.91 and 1.18 mg/mL, respectively), while peptides of 5-10 and <5 kDa showed a higher potency to inhibit alpha-amylase and alpha-glucosidases. Peptides in F1, F2, and F3 were mainly fragments from beta-conglycinin, glycinin, and P34 thiol protease. The analysis of structural features of peptides in F1-F3 allowed the tentative identification of potential antidiabetic peptides. Germinated soybean protein showed a promising potential to be used as a nutraceutical or functional ingredient for diabetes prevention. PMID- 30249016 TI - Serpentinization: Connecting Geochemistry, Ancient Metabolism and Industrial Hydrogenation. AB - Rock-water-carbon interactions germane to serpentinization in hydrothermal vents have occurred for over 4 billion years, ever since there was liquid water on Earth. Serpentinization converts iron(II) containing minerals and water to magnetite (Fe3O4) plus H2. The hydrogen can generate native metals such as awaruite (Ni3Fe), a common serpentinization product. Awaruite catalyzes the synthesis of methane from H2 and CO2 under hydrothermal conditions. Native iron and nickel catalyze the synthesis of formate, methanol, acetate, and pyruvate intermediates of the acetyl-CoA pathway, the most ancient pathway of CO2 fixation. Carbon monoxide dehydrogenase (CODH) is central to the pathway and employs Ni0 in its catalytic mechanism. CODH has been conserved during 4 billion years of evolution as a relic of the natural CO2-reducing catalyst at the onset of biochemistry. The carbide-containing active site of nitrogenase-the only enzyme on Earth that reduces N2-is probably also a relic, a biological reconstruction of the naturally occurring inorganic catalyst that generated primordial organic nitrogen. Serpentinization generates Fe3O4 and H2, the catalyst and reductant for industrial CO2 hydrogenation and for N2 reduction via the Haber-Bosch process. In both industrial processes, an Fe3O4 catalyst is matured via H2-dependent reduction to generate Fe5C2 and Fe2N respectively. Whether serpentinization entails similar catalyst maturation is not known. We suggest that at the onset of life, essential reactions leading to reduced carbon and reduced nitrogen occurred with catalysts that were synthesized during the serpentinization process, connecting the chemistry of life and Earth to industrial chemistry in unexpected ways. PMID- 30249018 TI - A Multi-Objective Demand Response Optimization Model for Scheduling Loads in a Home Energy Management System. AB - Demand Response (DR) aims to motivate end consumers to change their energy consumption patterns in response to changes in electricity prices or when the reliability of the electrical power system (EPS) is compromised. Most of the proposals found in the literature only aim at reducing the cost for end consumers. However, this article proposes a home energy management system (HEMS) that aims to schedule the use of each home appliance based on the price of electricity in real-time (RTP) and on the consumer satisfaction/comfort level in order to guarantee the stability and the safety of the EPS. Thus, this paper presents a multi-objective DR optimization model which was formulated as a multi objective nonlinear programming problem subjected to a set of constraints and was solved using the Non-Dominated Sorted Genetic Algorithm (NSGA-II), in order to determine the scheduling of home appliances for the time horizon. The multi objective DR optimization model not only to minimize the cost of electricity consumption but also to reduce the level of inconvenience for residential consumers. Moreover, a priori, it is expected to obtain a more uniform demand with fewer peaks in the system and, potentially, achieving a more reliable and safer EPS operation. Thus, the energy management controller (EMC) within the HEMS determines an optimized schedule for each home appliance through the multi objective DR model presented in this article, and ensures a more economic scenario for end consumers. In this paper, a performance evaluation of HEMS in 15 Brazilian families between 1 January and 31 December 2016 is presented with different electric energy consumption patterns in the cities of Belem-PA, Teresina-PI, Cuiaba-MT, Florianopolis-SC and Sao Paulo-SP, with three families per city, located in the regions north, northeast, central west, south and the southeast of Brazil, respectively. In addition, a total of 425 home appliances were used in the simulations. The results show that the HEMS achieved reductions in the cost of electricity for all the Scenarios used while minimally affecting the satisfaction/comfort of the end consumers as well as taking into account all the restrictions. The largest reduction in the total cost of electricity occurred for the couple without children, resident in the city of Teresina-PI; with a drop from US$ 99.31 to US$ 90.72 totaling 8.65% savings in the electricity bill. Therefore, the results confirm that the proposed HEMS effectively improves the operating efficiency of home appliances and reduces electricity costs for end consumers. PMID- 30249017 TI - HIC1 and RassF1A Methylation Attenuates Tubulin Expression and Cell Stiffness in Cancer. AB - Cell stiffness is a potential biomarker for monitoring cellular transformation, metastasis, and drug resistance development. Environmental factors relayed into the cell may result in formation of inheritable markers (e.g., DNA methylation), which provide selectable advantages (e.g., tumor development-favoring changes in cell stiffness). We previously demonstrated that targeted methylation of two tumor suppressor genes, hypermethylated in cancer 1 (HIC1) and Ras-association domain family member 1A (RassF1A), transformed mesenchymal stem cells (MSCs). Here, transformation-associated cytoskeleton and cell stiffness changes were evaluated. Atomic force microscopy (AFM) was used to detect cell stiffness, and immunostaining was used to measure cytoskeleton expression and distribution in cultured cells as well as in vivo. HIC1 and RassF1A methylation (me_HR) transformed MSCs developed into tumors that clonally expanded in vivo. In me_HR transformed MSCs, cell stiffness was lost, tubulin expression decreased, and F actin was disorganized; DNA methylation inhibitor treatment suppressed their tumor progression, but did not fully restore their F-actin organization and stiffness. Thus, me_HR-induced cell transformation was accompanied by the loss of cellular stiffness, suggesting that somatic epigenetic changes provide inheritable selection markers during tumor propagation, but inhibition of oncogenic aberrant DNA methylation cannot restore cellular stiffness fully. Therefore, cell stiffness is a candidate biomarker for cells' physiological status. PMID- 30249020 TI - Diet and Physical Activity as Determinants of Lifestyle Chosen by Women from Southern Poland. AB - The aim of the study was to assess the relationship between the lifestyle of Polish women (characterized by the quality of diets and levels of reported physical activity) and their characteristics such as age, place of residence, physical activity at work or school, reported health status, and BMI. The sample consisted of 882 women from Southern Poland. Diet quality and the level of physical activity were evaluated by the Nutrition Beliefs Questionnaire established by the Polish Academy of Sciences. The lifestyle category (healthy, moderate, or unhealthy) was based on "Prohealthy Diet Index-10" and participant's self-assessed physical activity during their leisure-time. The lifestyle category was significantly associated with age, BMI, physical activity at work/school, and health. Moderate lifestyle (high or moderate levels of physical activity combined with low prohealthy diet) was the most commonly found classification in examined women. Age (>35 years old) and overweight are the main factors determining unhealthy lifestyle behavior. Healthy lifestyle is more often chosen by the women from big cities. More intensive efforts should be undertaken to increase the knowledge and awareness of the health benefits of a healthy lifestyle. The main goal should be concentrated on increasing the level of physical activity, especially in leisure time, and promoting the tenets of a well-balanced diet. PMID- 30249021 TI - Noninvasive Glucose Monitoring with a Contact Lens and Smartphone. AB - Diabetes has become a chronic metabolic disorder, and the growing diabetes population makes medical care more important. We investigated using a portable and noninvasive contact lens as an ideal sensor for diabetes patients whose tear fluid contains glucose. The key feature is the reversible covalent interaction between boronic acid and glucose, which can provide a noninvasive glucose sensor for diabetes patients. We present a phenylboronic acid (PBA)-based HEMA contact lens that exhibits a reversible swelling/shrinking effect to change its thickness. The difference in thickness can be detected in a picture taken with a smartphone and analyzed using software. Our novel technique offers the following capabilities: (i) non-enzymatic and continuous glucose detection with the contact lens; (ii) no need for an embedded circuit and power source for the glucose sensor; and (iii) the use of a smartphone to detect the change in thickness of the contact lens with no need for additional photo-sensors. This technique is promising for a noninvasive measurement of the glucose level and simple implementation of glucose sensing with a smartphone. PMID- 30249019 TI - The Role of Stroma in Cholangiocarcinoma: The Intriguing Interplay between Fibroblastic Component, Immune Cell Subsets and Tumor Epithelium. AB - Cholangiocarcinoma (CCA) is a severe and mostly intractable adenocarcinoma of biliary epithelial cells. A typical feature of CCA is its highly desmoplastic microenvironment containing fibrogenic connective tissue and an abundance of immune cells (T lymphocytes, Natural Killer (NK) cells, and macrophages) infiltrating tumor epithelium. This strong desmoplasia is orchestrated by various soluble factors and signals, suggesting a critical role in shaping a tumor growth permissive microenvironment that is responsible for CCA poor clinical outcome. Indeed stroma not only provides an abundance of factors that facilitate CCA initiation, growth and progression, but also a prejudicial impact on therapeutic outcome. This review will give an overview of tumor-stroma signaling in a microenvironment critically regulating CCA development and progression. Identification of CCA secreted factors by both the fibroblast component and immune cell subsets might provide ample opportunities for pharmacological targeting of this type of cancer. PMID- 30249023 TI - Association between Fasting Glucose Concentration, Lipid Profile and 25(OH)D Status in Children Aged 9-11. AB - BACKGROUND: The aim of this study was to assess the relationship between vitamin D status and the prevalence of dyslipidemia and impaired fasting glucose (IFG) in children. Methods and Summary: 284 children (150 boys and 134 girls) aged 9-11 were included in the study. Children with deficient 25(OH)D (25 hydroxycholecalciferol) levels <=20 ng/mL (50 nmol/L) were characterized by a more frequent occurrence of impaired fasting glucose (IFG) (Odd ratios (OR) = 1.966, 95% confidence interval (CI): 1.055-3.663; p = 0.033) when compared to children with 25(OH)D >20 ng/mL. Serum 25(OH)D with concentration lower by 1 ng/mL (2.5 nmol/L) was linked to higher fasting glucose (by 0.25 mg/dL, 0.013 mmol/L; p = 0.017), higher total cholesterol (TC) by almost 1 mg/dL (0.96 mg/dL, 0.25 mmol/L; p = 0.006) and higher high-density lipoprotein cholesterol (HDL-C) (by 0.57 mg/dL, 0.015 mmol/L; p < 0.001). CONCLUSION: 25(OH)D deficiency may negatively affect fasting glucose and total cholesterol concentration in children aged 9-11. Vitamin D-deficient children are twice as likely to develop prediabetes as reflected by impaired fasting glucose when compared to those with a 25(OH)D level above 20 ng/mL (50 nmol/L). PMID- 30249022 TI - Immunological Heterogeneity of Healthy Peripheral Blood Stem Cell Donors-Effects of Granulocyte Colony-Stimulating Factor on Inflammatory Responses. AB - Interleukin-6 (IL-6) contributes to the development of immune-mediated complications after allogeneic stem cell transplantation. However, systemic IL-6 levels also increase during granulocyte colony-stimulating factor (G-CSF) mobilization of hematopoietic stem cells in healthy donors, but it is not known whether this mobilization alters systemic levels of other IL-6 family cytokines/receptors and whether such effects differ between donors. We examined how G-CSF administration influenced C-reactive protein (CRP) levels (85 donors) and serum levels of IL-6 family cytokines/receptors (20 donors). G-CSF increased CRP levels especially in elderly donors with high pretherapy levels, but these preharvesting levels did not influence clinical outcomes (nonrelapse mortality, graft versus host disease). The increased IL-6 levels during G-CSF therapy normalized within 24 h after treatment. G-CSF administration did not alter serum levels of other IL-6-familly mediators. Oncostatin M, but not IL-6, showed a significant correlation with CRP levels during G-CSF therapy. Clustering analysis of mediator levels during G-CSF administration identified two donor subsets mainly characterized by high oncostatin M and IL-6 levels, respectively. Finally, G-CSF could increase IL-6 release by in vitro cultured monocytes, fibroblasts, and mesenchymal stem cells. In summary, G-CSF seems to induce an acute phase reaction with increased systemic IL-6 levels in healthy stem cell donors. PMID- 30249024 TI - Domain Correction Based on Kernel Transformation for Drift Compensation in the E Nose System. AB - This paper proposes a way for drift compensation in electronic noses (e-nose) that often suffers from uncertain and unpredictable sensor drift. Traditional machine learning methods for odor recognition require consistent data distribution, which makes the model trained with previous data less generalized. In the actual application scenario, the data collected previously and the data collected later may have different data distributions due to the sensor drift. If the dataset without sensor drift is treated as a source domain and the dataset with sensor drift as a target domain, a domain correction based on kernel transformation (DCKT) method is proposed to compensate the sensor drift. The proposed method makes the distribution consistency of two domains greatly improved through mapping to a high-dimensional reproducing kernel space and reducing the domain distance. A public benchmark sensor drift dataset is used to verify the effectiveness and efficiency of the proposed DCKT method. The experimental result shows that the proposed method yields the highest average accuracies compared to other considered methods. PMID- 30249025 TI - In-Line UV-Vis Spectroscopy as a Fast-Working Process Analytical Technology (PAT) during Early Phase Product Development Using Hot Melt Extrusion (HME). AB - This paper displays the potential of an in-line PAT system for early phase product development during pharmaceutical continuous manufacturing following a Quality by Design (QbD) framework. Hot melt extrusion (HME) is used as continuous manufacturing process and UV-Vis spectroscopy as an in-line monitoring system. A sequential design of experiments (DoE) (screening, optimisation and verification) was used to gain process understanding for the manufacture of piroxicam (PRX)/Kollidon(r) VA64 amorphous solid dispersions. The influence of die temperature, screw speed, solid feed rate and PRX concentration on the critical quality attributes (CQAs) absorbance and lightness of color (L*) of the extrudates was investigated using multivariate tools. Statistical analysis results show interaction effects between concentration and temperature on absorbance and L* values. Solid feed rate has a significant effect on absorbance only and screw speed showed least impact on both responses for the screening design. The optimum HME process conditions were confirmed by 4 independent studies to be 20% w/w of PRX, temperature 140 degrees C, screw speed 200 rpm and feed rate 6 g/min. The in-line UV-Vis system was used to assess the solubility of PRX in Kollidon(r) VA64 by measuring absorbance and L* values from 230 to 700 nm. Oversaturation was observed for PRX concentrations higher than 20% w/w. Oversaturation can be readily identified as it causes scattering in the visible range. This is observed by a shift of the baseline in the visible part of the spectrum. Extrudate samples were analyzed for degradation using off-line High Performance Liquid Chromatography (HPLC) standard methods. Results from off-line experiments using differential scanning calorimetry (DSC), and X-ray diffraction (XRD) are also presented. PMID- 30249026 TI - Exposure of Breast and Lung Cancer Cells to a Novel Estrone Analog Prior to Radiation Enhances Bcl-2-Mediated Cell Death. AB - Following exposure of cells to gamma-radiation, a cascade of intracellular consequences may be observed in a semitemporal manner. This includes deoxyribonucleic acid (DNA) damage and reactive oxygen species (ROS) accumulation initially, with consequent signaling for DNA repair and facilitative regulation of the cell cycle. Failure to rectify the damage or ROS levels leads to induction of senescence or apoptosis. 2-Ethyl-3-O-sulfamoyl-estra-1,3,5(10),15-tetraen-17 ol (ESE-15-ol), a 2-methoxyestradiole analog designed in silico for superior pharmacokinetics, was investigated for its potential to enhance apoptotic signaling and decrease the long-term survival of cells exposed to radiation. Sequential early intracellular effects within radiation-treated MCF-7 breast- and A549 lung cancer cells pre-exposed to low-dose ESE-15-ol were investigated using various flow cytometric protocols, spectrophotometry, and microscopy. Long-term cellular survival and proliferation was examined using clonogenic studies, which demonstrated a significant decrease in the presensitized cells. Combination treated cells exhibited increased superoxide formation, and decreased Bcl-2 expression and -phosphorylation. Induction of apoptosis and elevation of the sub G1 phase was evident in the pre-exposed MCF-7 cells, although only minimally in the A549 cells at 48-h. These results indicate that low-dose ESE-15-ol may increase tumor response to radiation. Future studies will investigate the effect of ESE-15-ol pre-exposure on radiation-induced DNA damage and repair mechanisms. PMID- 30249027 TI - Comparison of Antioxidant Activities of Different Grape Varieties. AB - Grapes are widely consumed in the world, and different grape varieties could exhibit distinctly different antioxidant activities. In this study, the free radical-scavenging and antioxidant activities of lipophilic, hydrophilic, and insoluble-bound fractions from 30 grape varieties were evaluated by ferric reducing antioxidant powers (FRAP), Trolox equivalent antioxidant capacities (TEAC), total phenolic contents (TPC), and total flavonoid contents (TFC). The results indicated that the 30 grape varieties exhibited diverse FRAP values (1.289-11.767 MUmol Fe(II)/g FW), TEAC values (0.339-4.839 MUmol Trolox/g FW), TPC values (0.294-1.407 mg GAE/g FW) and TFC values (0.082-0.132 mg QE/g FW). Several grapes, such as Pearl Black Grape (Xinjiang), Summer Black Grape (Shaanxi), Pearl Green Grape (Xinjiang), Seedless Green Grape (Xinjiang), and Seedless Red Grape (Yunnan), exhibited strong free radical-scavenging and antioxidant activities, which could be consumed as good sources of natural antioxidants to prevent several diseases induced by oxidative stress, such as cardiovascular disease and cancer. Furthermore, several antioxidants were identified and quantified, including caffeic acid, catechin gallate, epicatechin, gallic acid, protocatechuic acid and rutin, which could contribute to the antioxidant activities of grapes. PMID- 30249028 TI - Marine Peroxy Sesquiterpenoids Induce Apoptosis by Modulation of Nrf2-ARE Signaling in HCT116 Colon Cancer Cells. AB - Our current study demonstrated that the marine peroxy sesquiterpenoids isolated from the Okinawan soft coral Sinularia sp. have an antitumor activity in human colon cancer cell (HCT) 116 colon cancer cells with their induction of apoptosis due to H2O2 production derived from the compounds. This study clarified that peroxy sesquiterpenoids (1 and 2) inhibited anti-apoptosis proteins, such as B cell lymphoma-extra large (Bcl-xL) and phosphoAkt (pAkt). In addition, the heme oxygenase-1 (HO-1), nuclear factor-erythroid-2-related factor (Nrf2), and phosphoNrf2 (pNrf2) proteins related to the cell survival regulation signal of Nrf2-ARE (antioxidant response element) were also suppressed in the presence of these compounds. While the cells treated with the compounds and trolox as an antioxidant expressed the inhibited proteins, such as HO-1, Nrf2, and Bcl-xL, it was suggested that the H2O2 involving free radical reactions derived from the molecule would be a trigger of apoptosis with the modulation of Nrf2-ARE signaling in the cells. PMID- 30249030 TI - KMUP-1, a GPCR Modulator, Attenuates Triglyceride Accumulation Involved MAPKs/Akt/PPARgamma and PKA/PKG/HSL Signaling in 3T3-L1 Preadipocytes. AB - Xanthine-based KMUP-1 was shown to inhibit phosphodiesterases (PDEs) and modulate G-protein coupled receptors (GPCRs) to lower hyperlipidemia and body weight. This study further investigated whether KMUP-1 affects adipogenesis and lipolysis in 3T3-L1 preadipocytes. KMUP-1 (1-40 uM) concentration-dependently attenuated Oil Red O (ORO) staining and decreased triglyceride (TG) accumulation, indicating adipogenesis inhibition in 3T3-L1 cells. In contrast, the beta-agonist ractopamine increased ORO staining and TG accumulation and adipogenesis. KMUP-1 (1-40 uM) also reduced MAPKs/Akt/PPARgamma expression, PPARgamma1/PPARgamma2 mRNA, and p-ERK immunoreactivity at the adipogenesis stage, but enhanced hormone sensitive lipase (HSL) immunoreactivity at the lipolysis stage. Addition of protein kinase A (PKA) or protein kinase G (PKG) antagonist (KT5720 or KT5728) to adipocytes did not affect HSL immunoreactivity. However, KMUP-1 did increase HSL immunoreactivity and the effect was reduced by PKA or PKG antagonist. Simvastatin, theophylline, caffeine, and sildenafil, like KMUP-1, also enhanced HSL immunoreactivity. Phosphorylated HSL (p-HSL) was enhanced by KMUP-1, indicating increased lipolysis in mature 3T3-L1 adipocytes. Decreases of MAPKs/Akt/PPARgamma during adipogenesis contributed to inhibition of adipocyte differentiation, and increases of PKA/PKG at lipolysis contributed to HSL activation and TG hydrolysis. Taken together, the data suggest that KMUP-1 can inhibit hyperadiposity in 3T3-L1 adipocytes. PMID- 30249032 TI - Formamide Adsorption at the Amorphous Silica Surface: A Combined Experimental and Computational Approach. AB - Mineral surfaces have been demonstrated to play a central role in prebiotic reactions, which are understood to be at the basis of the origin of life. Among the various molecules proposed as precursors for these reactions, one of the most interesting is formamide. Formamide has been shown to be a pluripotent molecule, generating a wide distribution of relevant prebiotic products. In particular, the outcomes of its reactivity are strongly related to the presence of mineral phases acting as catalysts toward specific reaction pathways. While the mineral-products relationship has been deeply studied for a large pool of materials, the fundamental description of formamide reactivity over mineral surfaces at a microscopic level is missing in the literature. In particular, a key step of formamide chemistry at surfaces is adsorption on available interaction sites. This report aims to investigate the adsorption of formamide over a well-defined amorphous silica, chosen as a model mineral surface. An experimental IR investigation of formamide adsorption was carried out and its outcomes were interpreted on the basis of first principles simulation of the process, adopting a realistic model of amorphous silica. PMID- 30249031 TI - Genetic Association between Serum 25-Hydroxyvitamin D Levels and Lung Function in Korean Men and Women: Data from KNHANES 2011-2012. AB - The association between single-nucleotide polymorphisms (SNPs) in the vitamin D metabolic pathway and lung function is unknown. We examined the association between five SNPs on DHCR7, GC, CYP2R1, and CYP24A1 along with serum 25 hydroxyvitamin D (25(OH)D) levels and lung function in older Korean men (n = 758) and women (n = 837). Lung function was determined by forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) from the data in the Korea Nutrition and Health Examination Survey 2011-2012. Genetic risk score (GRS) was calculated by the number of 25(OH)D-decreasing alleles of the five SNPs. Our results showed that increases in GRS were associated with reduced 25(OH)D levels (p < 0.05 for both sexes). In the entire population, FVC and FEV1 were associated with both GRS and 25(OH)D levels. In women, FVC and FEV1 were negatively associated with GRS (beta-coefficient (95% CI): -0.022 (-0.039, -0.005) and -0.020 (-0.035, -0.005), respectively; both p < 0.05), but not with 25(OH)D. However, in men, FVC and FEV1 were positively associated with 25(OH)D (beta-coefficient (95% CI): 0.008 (0.001, 0.016) and 0.008 (0.002, 0.015), respectively; both p < 0.05), but not with GRS. In conclusion, lung function was associated with genetic variation in Korean women and with 25(OH)D in Korean men. PMID- 30249029 TI - Eradicating Suicide at Its Roots: Preclinical Bases and Clinical Evidence of the Efficacy of Ketamine in the Treatment of Suicidal Behaviors. AB - Despite the continuous advancement in neurosciences as well as in the knowledge of human behaviors pathophysiology, currently suicide represents a puzzling challenge. The World Health Organization (WHO) has established that one million people die by suicide every year, with the impressive daily rate of a suicide every 40 s. The weightiest concern about suicidal behavior is how difficult it is for healthcare professionals to predict. However, recent evidence in genomic studies has pointed out the essential role that genetics could play in influencing person's suicide risk. Combining genomic and clinical risk assessment approaches, some studies have identified a number of biomarkers for suicidal ideation, which are involved in neural connectivity, neural activity, mood, as well as in immune and inflammatory response, such as the mammalian target of rapamycin (mTOR) signaling. This interesting discovery provides the neurobiological bases for the use of drugs that impact these specific signaling pathways in the treatment of suicidality, such as ketamine. Ketamine, an N-methyl d-aspartate glutamate (NMDA) antagonist agent, has recently hit the headlines because of its rapid antidepressant and concurrent anti-suicidal action. Here we review the preclinical and clinical evidence that lay the foundations of the efficacy of ketamine in the treatment of suicidal ideation in mood disorders, thereby also approaching the essential question of the understanding of neurobiological processes of suicide and the potential therapeutics. PMID- 30249033 TI - Seroprevalence and Determinants Associated with Mumps Antibodies after 20 Years of MMR Vaccination in Urban Area of Shanghai, China. AB - A resurgence of the mumps epidemic in highly vaccinated populations has occurred in recent years in many countries. This study aimed to evaluate the seroprevalence to mumps in urban areas of Shanghai, where a measles-mumps-rubella (MMR) vaccination had been implemented for 20 years. Mumps IgG antibodies were tested in 2662 residual sera from all ages in an urban area of Shanghai. A linear regression method was performed to assess the persistence of mumps antibodies after MMR vaccination. A logistic regression method was used to analyze the variables associated with seronegative sera. The overall age- and gender-adjusted seroprevalence of mumps antibodies reached 90% (95% CI: 90.0-90.2). The antibody concentration declined significantly in the first eight years after the second dose of MMR. The multivariate analysis identified that males, age groups, especially 17-19 years and no dose of vaccination, as well as one dose of vaccination, as factors associated with an increased risk of seronegative sera. A high seroprevalence to mumps has been achieved in the urban areas of Shanghai. A declining antibody level of mumps after the second dose of MMR may put a potential risk of recurrence of mumps. The two-dose MMR vaccine schedule is superior to one-dose schedule for mumps control. PMID- 30249034 TI - The Pro-Oxidant Activity of Pheomelanin is Significantly Enhanced by UVA Irradiation: Benzothiazole Moieties Are More Reactive than Benzothiazine Moieties. AB - It is generally considered that eumelanin (EM) is photoprotective while pheomelanin (PM) is phototoxic. A recent study using a mouse model demonstrated that PM produces reactive oxygen species (ROS) that cause DNA damage and eventually lead to melanomagenesis. A biochemical study showed that PM possesses a pro-oxidant activity. PM consists of benzothiazine (BT) and benzothiazole (BZ) moieties, BT moieties being transformed to BZ moieties by heat or light. In this study, we compared the effects of ultraviolet A (UVA) irradiation using synthetic PMs with different BT to BZ ratios and using various coat color mouse hairs. We found that UVA irradiation of BZ-PM increased glutathione (GSH) depletion and generated more H2O2 than UVA irradiation of BT-PM. Non-irradiated controls did not exhibit strong pro-oxidant activities. Upon UVA irradiation, yellow mouse hairs oxidized GSH and produced H2O2 faster than black or albino mouse hairs. Next, to examine the mechanism of the pro-oxidant activity of BT-PM and BZ-PM, we examined the pro-oxidant activities of 7-(2-amino-2-carboxyethyl)-dihydro-1,4 benzothiazine-3-carboxylic acid (DHBTCA) and 6-(2-amino-2-carboxyethyl)-4 hydroxybenzothiazole (BZ-AA) as BT and BZ monomers, respectively. Their pro oxidant activities were similar, but a large difference was seen in the effects of ROS scavengers, which suggests that the redox reactions may proceed via singlet oxygen in BZ-AA and via superoxide anions in DHBTCA. These results show that UVA enhances the pro-oxidant activity of PM, in particular BZ-PM. PMID- 30249036 TI - Embryonal Tumors of the Central Nervous System in Children: The Era of Targeted Therapeutics. AB - Embryonal tumors (ET) of the central nervous system (CNS) in children encompass a wide clinical spectrum of aggressive malignancies. Until recently, the overlapping morphological features of these lesions posed a diagnostic challenge and undermined discovery of optimal treatment strategies. However, with the advances in genomic technology and the outpouring of biological data over the last decade, clear insights into the molecular heterogeneity of these tumors are now well delineated. The major subtypes of ETs of the CNS in children include medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and embryonal tumors with multilayered rosettes (ETMR), which are now biologically and clinically characterized as different entities. These important developments have paved the way for treatments guided by risk stratification as well as novel targeted therapies in efforts to improve survival and reduce treatment burden. PMID- 30249035 TI - Surface-Plasmon-Resonance-Based Optical-Fiber Micro-Displacement Sensor with Temperature Compensation. AB - Micro-displacement measurements play a crucial role in many industrial applications. Aiming to address the defects of existing optical-fiber displacement sensors, such as low sensitivity and temperature interference, we propose and demonstrate a novel surface plasmon resonance (SPR)-based optical fiber micro-displacement sensor with temperature compensation. The sensor consists of a displacement-sensing region (DSR) and a temperature-sensing region (TSR). We employed a graded-index multimode fiber (GI-MMF) to fabricate the DSR and a hetero-core structure fiber to fabricate the TSR. For the DSR, we employed a single-mode fiber (SMF) to change the radial position of the incident beam as displacement. The resonance angle in the DSR is highly sensitive to displacement; thus, the resonance wavelength of the DSR shifts. For the TSR, we employed polydimethylsiloxane (PDMS) as a temperature-sensitive medium, whose refractive index is highly sensitive to temperature; thus, the resonance wavelength of the TSR shifts. The displacement and temperature detection ranges are 0-25 MUm and 20 60 degrees C; the displacement and temperature sensitivities of the DSR are 4.24 nm/MUm and -0.19 nm/ degrees C, and those of the TSR are 0.46 nm/MUm and -2.485 nm/ degrees C, respectively. Finally, by means of a sensing matrix, the temperature compensation was realized. PMID- 30249037 TI - Overview on the Application of Modern Methods for the Extraction of Bioactive Compounds from Marine Macroalgae. AB - Marine macroalgae represent a rich source of bioactive compounds that can be implemented in various food, cosmetic, and pharmaceutical products for health improvement. It has been proven that these bioactive compounds, such as polyphenols, polysaccharides, carotenoids, and omega-3 fatty acids possess bioactivity. For the extraction of these compounds, modern methods (Supercritical Fluid Extraction (SFE), Subcritical Water Extraction (SWE), Ultrasound-Assisted Extraction (UAE), and Microwave-Assisted Extraction (MAE)) have been used due to their advantages over the conventional methods. The process parameters of each method must be optimized for obtaining the extracts with the targeted bioactive compounds. In distinction from the existing reviews, the present review provides novelty with respect to: (a) presenting systematically the selected process parameters of SFE (temperature, time, pressure, use of co-solvents), SWE (temperature, time, pressure, solid-solvent ratio), UAE (temperature, time, frequency, power, solid-solvent ratio), and MAE (temperature, time, frequency, power, solvent type) applied for the extractions of marine macroalgae; (b) reporting the major groups or individual compounds extracted with their biological activities (if determined); and, PMID- 30249038 TI - Association between the Dietary Inflammatory Index and Risk of Frailty in Older Individuals with Poor Nutritional Status. AB - Both inflammation and poor nutritional status are major risk factors of frailty, and the dietary inflammatory index (DII) has been suggested as being associated with the risk of frailty. The present study aimed to investigate whether DII scores were positively associated with the risk of frailty in older individuals, particularly those with poor nutritional status. In total, 321 community-dwelling older individuals aged 70-85 years were recruited and categorized as non-frail, pre-frail, and frail according to the Cardiovascular Health Study index. DII scores were calculated based on 24-h dietary recall, and nutritional status was assessed using the Mini Nutritional Assessment. Multinomial logistic regression analysis showed that DII scores were positively associated with the risk of frailty in older individuals (odds ratio, OR 1.64, 95% confidence interval, 95% CI 1.25-2.17), particularly those with poor nutritional status (OR 1.68, 95% CI 1.21-2.34). Among the frailty criteria, weight loss (OR 1.29, 95% CI 1.03-1.60), low walking speed (OR 1.33, 95% CI 1.10-1.61), and low grip strength (OR 1.34, 95% CI 1.13-1.60) were associated with DII scores. In addition, the optimal DII cut-off score for frailty was >=0.93 (sensitivity 71%; specificity: 72%; area under the receiver operating characteristic curve, AUC = 0.792). The present study showed that a pro-inflammatory diet was associated with increased risk of frailty, particularly in older individuals with poor nutritional status. Future randomized controlled trials with a low DII diet for the prevention of frailty are needed to confirm our finding. PMID- 30249039 TI - The Impact of Uremic Toxicity Induced Inflammatory Response on the Cardiovascular Burden in Chronic Kidney Disease. AB - Uremic toxin (UT) retention in chronic kidney disease (CKD) affects biological systems. We aimed to identify the associations between UT, inflammatory biomarkers and biomarkers of the uremic cardiovascular response (BUCVR) and their impact on cardiovascular status as well as their roles as predictors of outcome in CKD patients. CKD patients stages 3, 4 and 5 (n = 67) were recruited and UT (indoxyl sulfate/IS, p-cresil sulfate/pCS and indole-3-acetic acid/IAA); inflammatory biomarkers [Interleukin-6 (IL-6), high sensitivity C reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM 1) and soluble Fas (sFas)] and BUCVRs [soluble CD36 (sCD36), soluble receptor for advanced glycation end products (sRAGE), fractalkine] was measured. Patients were followed for 5.2 years and all causes of death was used as the primary outcome. Artery segments collected at the moment of transplantation were used for the immunohistochemistry analysis in a separate cohort. Estimated glomerular filtration rate (eGFR), circulating UT, plasma biomarkers of systemic and vascular inflammation and BUCVR were strongly interrelated. Patients with plaque presented higher signs of UT-induced inflammation and arteries from CKD patients presented higher fractalkine receptor (CX3CR1) tissue expression. Circulating IS (p = 0.03), pCS (p = 0.007), IL-6 (p = 0.026), sFas (p = 0.001), sCD36 (p = 0.01) and fractalkine (p = 0.02) were independent predictors of total mortality risk in CKD patients. Our results reinforce the important role of uremic toxicity in the pathogenesis of cardiovascular disease (CVD) in CKD patients through an inflammatory pathway. PMID- 30249041 TI - Detection of Chloroalkanes by Surface-Enhanced Raman Spectroscopy in Microfluidic Chips. AB - Optofluidics, a research discipline combining optics with microfluidics, currently aspires to revolutionize the analysis of biological and chemical samples, e.g., for medicine, pharmacology, or molecular biology. In order to detect low concentrations of analytes in water, we have developed an optofluidic device containing a nanostructured substrate for surface enhanced Raman spectroscopy (SERS). The geometry of the gold surface allows localized plasmon oscillations to give rise to the SERS effect, in which the Raman spectral lines are intensified by the interaction of the plasmonic field with the electrons in the molecular bonds. The SERS substrate was enclosed in a microfluidic system, which allowed transport and precise mixing of the analyzed fluids, while preventing contamination or abrasion of the highly sensitive substrate. To illustrate its practical use, we employed the device for quantitative detection of persistent environmental pollutant 1,2,3-trichloropropane in water in submillimolar concentrations. The developed sensor allows fast and simple quantification of halogenated compounds and it will contribute towards the environmental monitoring and enzymology experiments with engineered haloalkane dehalogenase enzymes. PMID- 30249043 TI - A Secure Multi-Tier Mobile Edge Computing Model for Data Processing Offloading Based on Degree of Trust. AB - Current mobile devices need to run applications with high computational demands and critical response times. The mobile edge computing (MEC) paradigm was developed to improve the performance of these devices. This new computation architecture allows for the mobile devices to execute applications on fog nodes at the network edge; this process is called data processing offloading. This article presents a security model for the externalization of application execution in multi-tier MEC environments. The principal novelty of this study is that the model is able to modify the required security level in each tier of the distributed architecture as a function of the degree of trust associated with that tier. The basic idea is that a higher degree of trust requires a lower level of security, and vice versa. A formal framework is introduced that represents the general environment of application execution in distributed MEC architectures. An architecture is proposed that allows for deployment of the model in production environments and is implemented for evaluation purposes. The results show that the security model can be applied in multi-tier MEC architectures and that the model produces a minimal overhead, especially for computationally intensive applications. PMID- 30249040 TI - Cancer Vaccine Immunotherapy with RNA-Loaded Liposomes. AB - Cancer vaccines may be harnessed to incite immunity against poorly immunogenic tumors, however they have failed in therapeutic settings. Poor antigenicity coupled with systemic and intratumoral immune suppression have been significant drawbacks. RNA encoding for tumor associated or specific epitopes can serve as a more immunogenic and expeditious trigger of anti-tumor immunity. RNA stimulates innate immunity through toll like receptor stimulation producing type I interferon, and it mediates potent adaptive responses. Since RNA is inherently unstable, delivery systems have been developed to protect and deliver it to intended targets in vivo. In this review, we discuss liposomes as RNA delivery vehicles and their role as cancer vaccines. PMID- 30249042 TI - Erianin against Staphylococcus aureus Infection via Inhibiting Sortase A. AB - With continuous emergence and widespread of multidrug-resistant Staphylococcus aureus infections, common antibiotics have become ineffective in treating these infections in the clinical setting. Anti-virulence strategies could be novel, effective therapeutic strategies against drug-resistant bacterial infections. Sortase A (srtA), a transpeptidase in gram-positive bacteria, can anchor surface proteins that play a vital role in pathogenesis of these bacteria. SrtA is known as a potential antivirulent drug target to treat bacterial infections. In this study, we found that erianin, a natural bibenzyl compound, could inhibit the activity of srtA in vitro (half maximal inhibitory concentration-IC50 = 20.91 +/- 2.31 MUg/mL, 65.7 +/- 7.2 MUM) at subminimum inhibitory concentrations (minimum inhibitory concentrations-MIC = 512 MUg/mL against S. aureus). The molecular mechanism underlying the inhibition of srtA by erianin was identified using molecular dynamics simulation: erianin binds to srtA residues Ile182, Val193, Trp194, Arg197, and Ile199, forming a stable bond via hydrophobic interactions. In addition, the activities of S. aureus binding to fibronectin and biofilm formation were inhibited by erianin, when co-culture with S. aureus. In vivo, erianin could improve the survival in mice that infected with S. aureus by tail vein injection. Experimental results showed that erianin is a potential novel therapeutic compound against S. aureus infections via affecting srtA. PMID- 30249045 TI - Defective Vagal Innervation in Murine Tbx1 Mutant Hearts. AB - Haploinsufficiency of the T-box transcription factor TBX1 is responsible for many features of 22q11.2 deletion syndrome. Tbx1 is expressed dynamically in the pharyngeal apparatus during mouse development and Tbx1 homozygous mutants display numerous severe defects including abnormal cranial ganglion formation and neural crest cell defects. These abnormalities prompted us to investigate whether parasympathetic (vagal) innervation of the heart was affected in Tbx1 mutant embryos. In this report, we used an allelic series of Tbx1 mouse mutants, embryo tissue explants and cardiac electrophysiology to characterise, in detail, the function of Tbx1 in vagal innervation of the heart. We found that total nerve branch length was significantly reduced in Tbx1+/- and Tbx1neo2/- mutant hearts expressing 50% and 15% levels of Tbx1. We also found that neural crest cells migrated normally to the heart of Tbx1+/-, but not in Tbx1neo2 mutant embryos. In addition, we showed that cranial ganglia IXth and Xth were fused in Tbx1neo2/- but neuronal differentiation appeared intact. Finally, we used telemetry to monitor heart response to carbachol, a cholinergic receptor agonist, and found that heart rate recovered more quickly in Tbx1+/- animals versus controls. We speculate that this condition of decreased parasympathetic drive could result in a pro-arrhythmic substrate in some 22q11.2DS patients. PMID- 30249044 TI - Intestinal Phosphorus Absorption in Chronic Kidney Disease. AB - Chronic kidney disease (CKD) affects approximately 10% of adults worldwide. Dysregulation of phosphorus homeostasis which occurs in CKD leads to development of CKD-Mineral Bone Disorder (CKD-MBD) and contributes to increased morbidity and mortality in these patients. Phosphorus is regulated by multiple hormones (parathyroid hormone (PTH), 1,25-dihyxdroxyvitamin D (1,25D), and fibroblast growth factor 23 (FGF23)) and tissues (kidney, intestine, parathyroid glands, and bone) to maintain homeostasis. In health, the kidneys are the major site of regulation for phosphorus homeostasis. However, as kidney function declines, the ability of the kidneys to adequately excrete phosphorus is reduced. The hormonal changes that occur with CKD would suggest that the intestine should compensate for impaired renal phosphorus excretion by reducing fractional intestinal phosphorus absorption. However, limited studies in CKD animal models and patients with CKD suggest that there may be a break in this homeostatic response where the intestine fails to compensate. As many existing therapies for phosphate management in CKD are aimed at reducing absolute intestinal phosphorus absorption, better understanding of the factors that influence fractional and absolute absorption, the mechanism by which intestinal phosphate absorption occurs, and how CKD modifies these is a much-needed area of study. PMID- 30249047 TI - Mouse Gamma Herpesvirus MHV-68 Induces Severe Gastrointestinal (GI) Dilatation in Interferon Gamma Receptor-Deficient Mice (IFNgammaR-/-) That Is Blocked by Interleukin-10. AB - Inflammatory bowel disease (IBD) and Clostridium difficile infection cause gastrointestinal (GI) distension and, in severe cases, toxic megacolon with risk of perforation and death. Herpesviruses have been linked to severe GI dilatation. MHV-68 is a model for human gamma herpesvirus infection inducing GI dilatation in interleukin-10 (IL-10)-deficient mice but is benign in wildtype mice. MHV-68 also causes lethal vasculitis and pulmonary hemorrhage in interferon gamma receptor deficient (IFNgammaR-/-) mice, but GI dilatation has not been reported. In prior work the Myxomavirus-derived anti-inflammatory serpin, Serp-1, improved survival, reducing vasculitis and pulmonary hemorrhage in MHV-68-infected IFNgammaR-/- mice with significantly increased IL-10. IL-10 has been investigated as treatment for GI dilatation with variable efficacy. We report here that MHV-68 infection produces severe GI dilatation with inflammation and gut wall degradation in 28% of INFgammaR-/- mice. Macrophage invasion and smooth muscle degradation were accompanied by decreased concentrations of T helper (Th2), B, monocyte, and dendritic cells. Plasma and spleen IL-10 were significantly reduced in mice with GI dilatation, while interleukin-1 beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNFalpha) and INFgamma increased. Treatment of gamma herpesvirus-infected mice with exogenous IL-10 prevents severe GI inflammation and dilatation, suggesting benefit for herpesvirus-induced dilatation. PMID- 30249049 TI - Probing Downstream Olive Biophenol Secoiridoids. AB - Numerous bioactive biophenol secoiridoids (BPsecos) are found in the fruit, leaves, and oil of olives. These BPsecos play important roles in both the taste of food and human health. The main BPseco bioactive from green olive fruits, leaves, and table olives is oleuropein, while olive oil is rich in oleuropein downstream pathway molecules. The aim of this study was to probe olive BPseco downstream molecular pathways that are alike in biological and olive processing systems at different pHs and reaction times. The downstream molecular pathway were analyzed by high performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI/MS) and typed neglected of different overlap (TNDO) computational methods. Our study showed oleuropein highest occupied molecular orbital (HOMO) and HOMO-1 triggered the free radical processes, while HOMO-2 and lowest unoccupied molecular orbital (LUMO) were polar reactions of glucoside and ester groups. Olive BPsecos were found to be stable under acid and base catalylic experiments. Oleuropein aglycone opened to diales and rearranged to hydroxytyrosil-elenolate under strong reaction conditions. The results suggest that competition among olive BPseco HOMOs could induce glucoside hydrolysis during olive milling due to native olive beta-glucosidases. The underlined olive BPsecos downstream molecular mechanism herein could provide new insights into the olive milling process to improve BPseco bioactives in olive oil and table olives, which would enhance both the functional food and the nutraceuticals that are produced from olives. PMID- 30249046 TI - Molecular Mechanisms of H. pylori-Induced DNA Double-Strand Breaks. AB - Infections contribute to carcinogenesis through inflammation-related mechanisms. H. pylori infection is a significant risk factor for gastric carcinogenesis. However, the molecular mechanism by which H. pylori infection contributes to carcinogenesis has not been fully elucidated. H. pylori-associated chronic inflammation is linked to genomic instability via reactive oxygen and nitrogen species (RONS). In this article, we summarize the current knowledge of H. pylori induced double strand breaks (DSBs). Furthermore, we provide mechanistic insight into how processing of oxidative DNA damage via base excision repair (BER) leads to DSBs. We review recent studies on how H. pylori infection triggers NF kappaB/inducible NO synthase (iNOS) versus NF-kappaB/nucleotide excision repair (NER) axis-mediated DSBs to drive genomic instability. This review discusses current research findings that are related to mechanisms of DSBs and repair during H. pylori infection. PMID- 30249048 TI - Viruses.STRING: A Virus-Host Protein-Protein Interaction Database. AB - As viruses continue to pose risks to global health, having a better understanding of virus-host protein-protein interactions aids in the development of treatments and vaccines. Here, we introduce Viruses.STRING, a protein-protein interaction database specifically catering to virus-virus and virus-host interactions. This database combines evidence from experimental and text-mining channels to provide combined probabilities for interactions between viral and host proteins. The database contains 177,425 interactions between 239 viruses and 319 hosts. The database is publicly available at viruses.string-db.org, and the interaction data can also be accessed through the latest version of the Cytoscape STRING app. PMID- 30249050 TI - Band Ratios Matrix Transformation (BRMT): A Sedimentary Lithology Mapping Approach Using ASTER Satellite Sensor. AB - Remote sensing imagery has become an operative and applicable tool for the preparation of geological maps by reducing the costs and increasing the precision. In this study, ASTER satellite remote sensing data were used to extract lithological information of Deh-Molla sedimentary succession, which is located in the southwest of Shahrood city, Semnan Province, North Iran. A robust and effective approach named Band Ratio Matrix Transformation (BRMT) was developed to characterize and discriminate the boundary of sedimentary rock formations in Deh-Molla region. The analysis was based on the forward and continuous division of the visible-near infrared (VNIR) and the shortwave infrared (SWIR) spectral bands of ASTER with subsequent application of principal component analysis (PCA) for producing new transform datasets. The approach was implemented to ASTER spectral band ratios for mapping dominated mineral assemblages in the study area. Quartz, carbonate, and Al, Fe, Mg -OH bearing altered minerals such as kaolinite, alunite, chlorite and mica were appropriately mapped using the BRMT approach. The results match well with geology map of the study area, fieldwork data and laboratory analysis. Accuracy assessment of the mapping result represents a reasonable kappa coefficient (0.70%) and appropriate overall accuracy (74.64%), which verified the robustness of the BRMT approach. This approach has great potential and capability for mapping sedimentary succession with diverse local-geological-physical characteristics around the world. PMID- 30249052 TI - Priorization of River Restoration by Coupling Soil and Water Assessment Tool (SWAT) and Support Vector Machine (SVM) Models in the Taizi River Basin, Northern China. AB - Identifying priority zones for river restoration is important for biodiversity conservation and catchment management. However, limited data due to the difficulty of field collection has led to research to better understand the ecological status within a catchment and develop a targeted planning strategy for river restoration. To address this need, coupling hydrological and machine learning models were constructed to identify priority zones for river restoration based on a dataset of aquatic organisms (i.e., algae, macroinvertebrates, and fish) and physicochemical indicators that were collected from 130 sites in September 2014 in the Taizi River, northern China. A process-based model soil and water assessment tool (SWAT) was developed to model the temporal-spatial variations in environmental indicators. A support vector machine (SVM) model was applied to explore the relationships between aquatic organisms and environmental indicators. Biological indices among different hydrological periods were simulated by coupling SWAT and SVM models. Results indicated that aquatic biological indices and physicochemical indicators exhibited apparent temporal and spatial patterns, and those patterns were more evident in the upper reaches compared to the lower reaches. The ecological status of the Taizi River was better in the flood season than that in the dry season. Priority zones were identified for different hydrological seasons by setting the target values for ecological restoration based on biota organisms, and the results suggest that hydrological conditions significantly influenced restoration prioritization over other environmental parameters. Our approach could be applied in other seasonal river ecosystems to provide important preferences for river restoration. PMID- 30249051 TI - Cellular Mechanisms Responsible for Success and Failure of Bone Substitute Materials. AB - Bone grafts, i.e., autologous, allogeneic or synthetic bone substitute materials play an increasing role in reconstructive orthopedic surgery. While the indications and materials differ, it is important to understand the cellular mechanisms regarding their integration and remodeling, which are discussed in this review article. Osteoconductivity describes the new bone growth on the graft, while osteoinductivity represents the differentiation of undifferentiated cells into bone forming osteoblasts. The best case is that both mechanisms are accompanied by osteogenesis, i.e., bone modeling and remodeling of the graft material. Graft incorporation is mediated by a number of molecular pathways that signal the differentiation and activity of osteoblasts and osteoclasts (e.g., parathyroid hormone (PTH) and receptor activator of nuclear factor kappabeta ligand (RANKL), respectively). Direct contact of the graft and host bone as well as the presence of a mechanical load are a prerequisite for the successful function of bone grafts. Interestingly, while bone substitutes show good to excellent clinical outcomes, their histological incorporation has certain limits that are not yet completely understood. For instance, clinical studies have shown contrasting results regarding the complete or incomplete resorption and remodeling of allografts and synthetic grafts. In this context, a foreign body response can lead to complete material degradation via phagocytosis, however it may also cause a fibrotic reaction to the bone substitute. Finally, the success of bone graft incorporation is also limited by other factors, including the bone remodeling capacities of the host, the material itself (e.g., inadequate resorption, toxicity) and the surgical technique or preparation of the graft. PMID- 30249053 TI - HoPE: Horizontal Plane Extractor for Cluttered 3D Scenes. AB - Extracting horizontal planes in heavily cluttered three-dimensional (3D) scenes is an essential procedure for many robotic applications. Aiming at the limitations of general plane segmentation methods on this subject, we present HoPE, a Horizontal Plane Extractor that is able to extract multiple horizontal planes in cluttered scenes with both organized and unorganized 3D point clouds. It transforms the source point cloud in the first stage to the reference coordinate frame using the sensor orientation acquired either by pre-calibration or an inertial measurement unit, thereby leveraging the inner structure of the transformed point cloud to ease the subsequent processes that use two concise thresholds for producing the results. A revised region growing algorithm named Z clustering and a principal component analysis (PCA)-based approach are presented for point clustering and refinement, respectively. Furthermore, we provide a nearest neighbor plane matching (NNPM) strategy to preserve the identities of extracted planes across successive sequences. Qualitative and quantitative evaluations of both real and synthetic scenes demonstrate that our approach outperforms several state-of-the-art methods under challenging circumstances, in terms of robustness to clutter, accuracy, and efficiency. We make our algorithm an off-the-shelf toolbox which is publicly available. PMID- 30249055 TI - Metabolomics of Two Pecan Varieties Provides Insights into Scab Resistance. AB - UHPLC-MS-based non-targeted metabolomics was used to investigate the biochemical basis of pecan scab resistance. Two contrasting pecan varieties, Kanza (scab resistant) and Pawnee (scab-susceptible), were profiled and the metabolomics data analyzed using multivariate statistics. Significant qualitative and quantitative metabolic differences were observed between the two varieties. Both varieties were found to have some unique metabolites. Metabolites that were only present or more abundant in Kanza relative to Pawnee could potentially contribute to the scab resistance in Kanza. Some of these metabolites were putatively identified as quercetin derivatives using tandem mass spectrometry. This suggests that quercetin derivatives could be important to pecan scab resistance. PMID- 30249054 TI - Bee Collected Pollen with Enhanced Health Benefits, Produced by Fermentation with a Kombucha Consortium. AB - The bioavailability of pollen bioactive compounds for humans is limited. In this study, our aim was to enhance the health-related benefits of pollen by fermentation with a Kombucha/SCOBY (symbiotic culture of bacteria and yeasts) consortium. We performed the fermentation of pollen suspended from the beginning with SCOBY on sweetened green tea or on Kombucha vinegar, by adding pollen after 20 days of Kombucha fermentation. We analyzed: formation of bioactive compounds (anti-oxidant polyphenols, soluble silicon, hydroxy-acids, short chain fatty acids-SCFA); parameters related to Kombucha fermentation (dynamics of lactic acid bacteria-LAB, formation of organic acids, soluble sugar evolution on Kombucha vinegar); the influence of Kombucha fermentation on pollen morphology and ultrastructure; in vitro cytotoxic and antitumoral effects of the Kombucha fermented pollen. The pollen addition increases LAB proportion in the total number of SCOBY microbial strains. SEM images highlight the adhesion of the SCOBY bacteria to pollen. Ultrastructural analysis reveals the release of the pollen content. The content of bioactive compounds (polyphenols, soluble silicon species and SCFA) is higher in the fermented pollen and the product shows a moderate antitumoral effect on Caco-2 cells. The health benefits of pollen are enhanced by fermentation with a Kombucha consortium. PMID- 30249056 TI - A Study of Strain-Driven Nucleation and Extension of Deformed Grain: Phase Field Crystal and Continuum Modeling. AB - The phase-field-crystal (PFC) method is used to investigate migration of grain boundary dislocation and dynamic of strain-driven nucleation and growth of deformed grain in two dimensions. The simulated results show that the deformed grain nucleates through forming a gap with higher strain energy between the two sub-grain boundaries (SGB) which is split from grain boundary (GB) under applied biaxial strain, and results in the formation of high-density ensembles of cooperative dislocation movement (CDM) that is capable of plastic flow localization (deformed band), which is related to the change of the crystal lattice orientation due to instability of the orientation. The deformed grain stores the strain energy through collective climbing of the dislocation, as well as changing the orientation of the original grain. The deformed grain growth (DGG) is such that the higher strain energy region extends to the lower strain energy region, and its area increase is proportional to the time square. The rule of the time square of the DGG can also be deduced by establishing the dynamic equation of the dislocation of the strain-driven SGB. The copper metal is taken as an example of the calculation, and the obtained result is a good agreement with that of the experiment. PMID- 30249057 TI - Data-Driven Exploration of Selectivity and Off-Target Activities of Designated Chemical Probes. AB - Chemical probes are of central relevance for chemical biology. To unambiguously explore the role of target proteins in triggering or mediating biological functions, small molecules used as probes should ideally be target-specific; at least, they should have sufficiently high selectivity for a primary target. We present a thorough analysis of currently available activity data for designated chemical probes to address several key questions: How well defined are chemical probes? What is their level of selectivity? Is there evidence for additional activities? Are some probes "better" than others? Therefore, highly curated chemical probes were collected and their selectivity was analyzed on the basis of publicly available compound activity data. Different selectivity patterns were observed, which distinguished designated high-quality probes. PMID- 30249059 TI - Further Enhancement of Mechanical Properties of Conducting Rubber Composites Based on Multiwalled Carbon Nanotubes and Nitrile Rubber by Solvent Treatment. AB - Post-treatment removal of dispersion agents from carbon nanotube/rubber composites can greatly enhance the mechanical properties by increasing the filler matrix interaction. In this study, multiwall carbon nanotubes (MWNT) were dispersed in water by sonication and nonionic surfactant, octyl-phenol-ethoxylate was used as a dispersion agent. The dispersed MWNTs were incorporated in thermo reactive acrylonitrile butadiene rubber (NBR) latex and nanocomposite films were prepared by solution casting. As a post-treatment, the surfactant was removed with acetone and films were dried in air. Dispersion quality of the colloid before casting was determined, and mechanical, electrical and thermal properties of the composites before and after the acetone post-treatment were studied. It was found that removal of dispersion agent increased the storage modulus of films between 160-300% in all samples. Relative enhancement was greater in samples with better dispersion quality, whereas thermal conductivity changed more in samples with smaller dispersion quality values. Electrical properties were not notably affected. PMID- 30249058 TI - Chlorogenic Acid Targeting of the AKT PH Domain Activates AKT/GSK3beta/FOXO1 Signaling and Improves Glucose Metabolism. AB - Chlorogenic acid (CGA), a bioactive component in the human diet, is reported to exert beneficial effects on the regulation of glucose metabolism. This study was designed to investigate the specific target of CGA, and explore its underlying mechanisms. Beneficial effects of CGA in glucose metabolism were confirmed in insulin-treated human hepatocarcinoma HepG2 cells. Protein fishing, via CGA modified functionalized magnetic microspheres, demonstrated the binding of CGA with protein kinase B (AKT). Immunofluorescence using a CGA molecular probe further demonstrated the co-localization of CGA with AKT. A competitive combination test and hampering of AKT membrane translocation showed that CGA might bind to the pleckstrin homology (PH) domain of AKT. The specific binding did not lead to the membrane translocation to phosphatidylinositol (3,4,5) trisphosphate (PIP3), but directly activated the phosphorylation of AKT on Ser 473, induced the phosphorylation of the downstream molecules, glycogen synthase kinase 3beta (GSK3beta) and forkhead box O1 (FOXO1), and improved glucose metabolism. Collectively, our data demonstrate that CGA exerts regulatory effects on glucose metabolism via direct targeting the PH domain of AKT. This study clarifies the mechanism of the potential benefits of nutrients containing CGA in the complementary therapy of glucose metabolism disorders. PMID- 30249060 TI - Granulocyte-Colony-Stimulating Factor Alters the Proteomic Landscape of the Ventral Tegmental Area. AB - Cocaine addiction is characterized by aberrant plasticity of the mesolimbic dopamine circuit, leading to dysregulation of motivation to seek and take drug. Despite the significant toll that cocaine use disorder exacts on society, there are currently no available pharmacotherapies. We have recently identified granulocyte-colony stimulating factor (G-CSF) as a soluble cytokine that alters the behavioral response to cocaine and which increases dopamine release from the ventral tegmental area (VTA). Despite these known effects on behavior and neurophysiology, the molecular mechanisms by which G-CSF affects brain function are unclear. In this study mice were treated with repeated injections of G-CSF, cocaine or a combination and changes in protein expression in the VTA were examined using an unbiased proteomics approach. Repeated G-CSF treatment resulted in alterations in multiple signaling pathways related to synaptic plasticity and neuronal morphology. While the treatment groups had marked overlap in their effect, injections of cocaine and the combination of cocaine and G-CSF lead to distinct patterns of significantly regulated proteins. These experiments provide valuable information as to the molecular pathways that G-CSF activates in an important limbic brain region and will help to guide further characterization of G-CSF function and evaluation as a possible translational target. PMID- 30249061 TI - Overlay Virtualized Wireless Sensor Networks for Application in Industrial Internet of Things: A Review. AB - In recent times, Wireless Sensor Networks (WSNs) are broadly applied in the Industrial Internet of Things (IIoT) in order to enhance the productivity and efficiency of existing and prospective manufacturing industries. In particular, an area of interest that concerns the use of WSNs in IIoT is the concept of sensor network virtualization and overlay networks. Both network virtualization and overlay networks are considered contemporary because they provide the capacity to create services and applications at the edge of existing virtual networks without changing the underlying infrastructure. This capability makes both network virtualization and overlay network services highly beneficial, particularly for the dynamic needs of IIoT based applications such as in smart industry applications, smart city, and smart home applications. Consequently, the study of both WSN virtualization and overlay networks has become highly patronized in the literature, leading to the growth and maturity of the research area. In line with this growth, this paper provides a review of the development made thus far concerning virtualized sensor networks, with emphasis on the application of overlay networks in IIoT. Principally, the process of virtualization in WSN is discussed along with its importance in IIoT applications. Different challenges in WSN are also presented along with possible solutions given by the use of virtualized WSNs. Further details are also presented concerning the use of overlay networks as the next step to supporting virtualization in shared sensor networks. Our discussion closes with an exposition of the existing challenges in the use of virtualized WSN for IIoT applications. In general, because overlay networks will be contributory to the future development and advancement of smart industrial and smart city applications, this review may be considered by researchers as a reference point for those particularly interested in the study of this growing field. PMID- 30249063 TI - Proteases Shape the Chlamydomonas Secretome: Comparison to Classical Neuropeptide Processing Machinery. AB - The recent identification of catalytically active peptidylglycine alpha-amidating monooxygenase (PAM) in Chlamydomonas reinhardtii, a unicellular green alga, suggested the presence of a PAM-like gene and peptidergic signaling in the last eukaryotic common ancestor (LECA). We identified prototypical neuropeptide precursors and essential peptide processing enzymes (subtilisin-like prohormone convertases and carboxypeptidase B-like enzymes) in the C.reinhardtii genome. Reasoning that sexual reproduction by C. reinhardtii requires extensive communication between cells, we used mass spectrometry to identify proteins recovered from the soluble secretome of mating gametes, and searched for evidence that the putative peptidergic processing enzymes were functional. After fractionation by SDS-PAGE, signal peptide-containing proteins that remained intact, and those that had been subjected to cleavage, were identified. The C. reinhardtii mating secretome contained multiple matrix metalloproteinases, cysteine endopeptidases, and serine carboxypeptidases, along with one subtilisin like proteinase. Published transcriptomic studies support a role for these proteases in sexual reproduction. Multiple extracellular matrix proteins (ECM) were identified in the secretome. Several pherophorins, ECM glycoproteins homologous to the Volvox sex-inducing pheromone, were present; most contained typical peptide processing sites, and many had been cleaved, generating stable N- or C-terminal fragments. Our data suggest that subtilisin endoproteases and matrix metalloproteinases similar to those important in vertebrate peptidergic and growth factor signaling play an important role in stage transitions during the life cycle of C.reinhardtii. PMID- 30249062 TI - Inhibitory Effect of Methotrexate on Rheumatoid Arthritis Inflammation and Comprehensive Metabolomics Analysis Using Ultra-Performance Liquid Chromatography Quadrupole Time of Flight-Mass Spectrometry (UPLC-Q/TOF-MS). AB - Rheumatoid arthritis (RA) is a common autoimmune disease. The inflammation in joint tissue and system endanger the human health seriously. Methotrexate have exhibited a satisfactory therapeutic effect in clinical practice. The aim of this research was to establish the pharmacological mechanism of methotrexate on RA therapy. Collagen induced arthritic rats were used to identify how methotrexate alleviates inflammation in vivo. Lipopolysaccharide-induced inflammatory proliferation in macrophages was also be detected in vitro. The activation level of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and Nucleotide binding domain and leucine-rich repeat pyrin 3 domain (NLRP3)/Caspase 1 and related cytokines were examined by real-time PCR and western blotting or quantified with the enzyme-linked immunosorbent assay. Comprehensive metabolomics analysis was performed to identify the alteration of metabolites. Results showed that treating with methotrexate could alleviate the inflammatory condition, downregulate the activation of NF-kappaB and NLRP3/Caspase-1 inflammatory pathways and reduce the level of related cytokines. Docking interaction between methotrexate and caspase-1 was visualized as six H-bonds indicating a potential inhibitory effect. Metabolomics analysis reported three perturbed metabolic inflammation related pathways including arachidonic acid, linoleic acid and sphingolipid metabolism. These findings indicated that methotrexate could inhibit the onset of inflammation in joint tissue by suppressing the activation of NF kappaB and NLRP3/Caspase-1 pathways and regulating the inflammation related metabolic networks. PMID- 30249064 TI - Development and Psychometric Properties of The Delayed Childbearing Questionnaire (DCBQ-55). AB - The comprehensive assessment of delayed childbearing needs a valid and reliable instrument. Therefore, the aim of the present study was to develop an instrument to evaluate factors influencing delayed childbearing among women and to assess its psychometric properties. The current methodological study was performed in two phases of (i) qualitative instrument development, and (ii) quantitative psychometric assessment of the developed instrument. Face and content validity of the instrument was assessed by eligible women and a panel of experts. Construct validity was assessed using the exploratory factor analysis (EFA). For reliability, internal consistency reliability and intra-rater reliability analysis were used. The initial instrument developed from the qualitative phase consisted of 60 items, which were reduced to 55 items after the face and content validity processes. EFA (n = 300) using the Kaiser criteria (Eigenvalues > 1) and the scree plot led to a six-factor solution accounting for 61.24% of the observed variance. The Cronbach's alpha coefficient, Spearman's correlation, test-retest and intra-class correlation coefficients for the whole instrument were reported as 0.83, 0.86 and 0.81, respectively. The final instrument entitled the delayed childbearing questionnaire (DCBQ-55) included 50 items with six domains of 'readiness for childbearing', 'stability in the partner relationship', 'awareness about the adverse outcomes of pregnancy in advanced maternal age', 'attitude toward delayed childbearing', 'family support', and 'social support' on a five point Likert scale. The DCBQ-55 as a simple, valid and reliable instrument can assess factors influencing delayed childbearing. It can be used by reproductive healthcare providers and policy makers to understand factors influencing delayed childbearing and devise appropriate strategies. PMID- 30249065 TI - Effects of Pr and Yb Dual Doping on the Thermoelectric Properties of CaMnO3. AB - There has been research on CaMnO3 with natural abundance, low toxicity, and low cost as promising candidates for n-type thermoelectric (TE) materials. In this paper, Ca1-2xPrxYbxMnO3 with different Pr and Yb contents (x = 0, 0.01, 0.02, 0.03, 0.04 and 0.05) were synthesized by means of coprecipitation. With X-ray diffraction (XRD), scanning electron microscopy (SEM), and high-resolution transmission electron microscopy (HRTEM), researchers characterized the phase structure and morphology of all the samples. The oxidation states of manganese were determined by X-ray photoemission spectroscopy (XPS). The role of Ca-site dual doping in the TE properties was also investigated. Increasing the Pr and Yb contents leads to decreases in the electrical resistivity and Seebeck coefficient, leading to a power factor of 3.48 * 10-4 W.m-1.K-2 for x = 0.04 at 773 K, which is its maximum. Furthermore, the thermal conductivity (kappa) decreases with increasing x, and kappa = 1.26 W m-1.K-1 is obtained for x = 0.04 at 973 K. Ca0.92Pr0.04Yb0.04MnO3 exhibit a ZT (thermoelectric figure of merit) value of 0.24 at 973 K, approximately 3 times more than that of the pristine CaMnO3. Thus, the reported method is a new strategy to enhance the TE performance of CaMnO3. PMID- 30249066 TI - Efficient Suzuki-Miyaura C-C Cross-Couplings Induced by Novel Heterodinuclear Pd bpydc-Ln Scaffolds. AB - An easy access to a series of previously unreported heterodinuclear Pd-Ln compounds, Pd-bpydc-La, Pd-bpydc-Ce and Pd-bpydc-Nd (bpydc = 2,2'-bipyridine-5,5' dicarboxylate) has been developed. The Pd-Ln hybrid networks were effectively applied as catalysts in Suzuki-Miyaura C-C cross-coupling reactions of 4 bromoanisole and 4-bromobenzonitrile with phenylboronic acid, under mild conditions. A systematic investigation revealed Pd-bpydc-Nd as the most active catalyst. In all cases, reaction yields varied with the base, catalyst loading and substantially augmented with temperature (from 30 to 60 degrees C). Substituent effects were operative when changing from 4-bromoanisole to 4 bromobenzonitrile. The key role played by the lanthanides, aromatic substrate and base, in modulating the Pd-catalytic cycle has been highlighted. Importantly, the new catalysts proved to be stable in air and vs. functionalities and are quite efficient in Suzuki-Miyaura carbon-carbon bond formation conducted in protic solvents. PMID- 30249068 TI - External morphology of Xyleborus ferrugineus (Fabr.) (Coleoptera: Scolytidae). I. Head and prothorax of adult males and females. AB - The overall body dimensions and external morphology of the head, head appendages, prothorax, and prothoracic legs of the adult haploid male and diploid female Xyleborus ferrugineus (Fabricius) were examined by scanning electron microscopy and light microscopy, and analyzed for variation. The female is significantly larger (1.26 X) than the male. The length/width ratio of both the pronotum and elytron, and the pronotum-length/elytron-length ratio are significantly different in the male and female. These findings indicate a distinct sexual dimorphism in general body form. There is significantly greater variability in pronotal length and width in the male than the female. There are sexual differences in setal patterns and setal size variabilities on the dorsal pronotum and the terminus of the antennae. PMID- 30249069 TI - Sense organs on the antennal flagellum of mayflies (Ephemeroptera). AB - A few very small sensory pegs with the characteristics of chemoreceptors are present in both males and females on the antennal flagellum of the mayflies, Stenacron interpunctatum (Say) Stenacron interpunctatum (Say) is Stenonema interpunctatum (Say) of earlier literature. and Cloeon sp. They are situated near the proximal end of the flagellum on its ventro-lateral surface and have escaped the attention of earlier investigators. PMID- 30249067 TI - HS-SPME-GC-MS Analyses of Volatiles in Plant Populations-Quantitating Compound * Individual Matrix Effects. AB - Headspace solid-phase microextraction (HS-SPME) coupled to gas chromatography mass spectrometry (GC-MS) is widely employed for volatile analyses of plants, including mapping populations used in plant breeding research. Studies often employ a single internal surrogate standard, even when multiple analytes are measured, with the assumption that any relative changes in matrix effects among individuals would be similar for all compounds, i.e., matrix effects do not show Compound * Individual interactions. We tested this assumption using individuals from two plant populations: an interspecific grape (Vitis spp.) mapping population (n = 140) and a tomato (Solanum spp.) recombinant inbred line (RIL) population (n = 148). Individual plants from the two populations were spiked with a cocktail of internal standards (n = 6, 9, respectively) prior to HS-SPME-GC-MS. Variation in the relative responses of internal standards indicated that Compound * Individual interactions exist but were different between the two populations. For the grape population, relative responses among pairs of internal standards varied considerably among individuals, with a maximum of 249% relative standard deviation (RSD) for the pair of [U13C]hexanal and [U13C]hexanol. However, in the tomato population, relative responses of internal standard pairs varied much less, with pairwise RSDs ranging from 8% to 56%. The approach described in this paper could be used to evaluate the suitability of using surrogate standards for HS-SPME-GC-MS studies in other plant populations. PMID- 30249070 TI - Morphology of the thoracic skeleton and muscles of the mosquito, Culiseta inornata (Williston), (Diptera: Culicidae). AB - The objectives of this research were to investigate the morphology of the thoracic skeleton and muscles of the mosquito, Culiseta inornata (Williston). The results are presented in 25 text figures and descriptions of each skeletal part and muscle. Undescribed exoskeletal structures are the postmediotergite, intersegmental cleft on the caudal margin of the metapleuron, and the parascutellar process. This process is considered a homologue of the fourth axillary. The acrotergite 2 and subalifer were identified. The prescutum has been called the paratergite by previous authors. The morphological basis for self amputation of legs is described. Undescribed parts of the endoskeleton are: lateral arm of sternal apophysis 1 and its socket on the mesal surface of coxa 1, furcopleural apodeme on sternal apophysis 1, precoxal and postcoxal apodemes arising from the ventral pleural arm, upper and lower laterotergite apodemes on the postnotum, and the pleural and intersegmental apodemes for attachment of halter muscles. Seventy-two muscles are illustrated with their attachments and the origin, insertion, and action of each is described. Ten of the muscles are newly described for the mosquito. There are no muscles inserted on the subalare, second axillary, or third axillary. PMID- 30249071 TI - Fine structural changes in the mandibular gland of the male spider crab, Libinia emarginata (L). Following eyestalk ablation. AB - Mandibular glands from destalked male spider crabs were fixed in glutaraldehyde paraformaldehyde, post-fixed in 1% osmium in phosphate buffer, dehydrated in acetone and embedded in Spurr's low-viscosity medium ('69). The glands hypertrophy and several changes occur in the subcellular cytoarchitecture following eyestalk ablation. These include loss of most of the smooth endoplasmic reticulum or its appearance as lamallae, appearance of numerous polysomes and a change in mitochondrial structure. Large vesicles with ribosomes spaced at intervals along their membranes are apparently formed by blebbing of the outer nuclear membrane and appear throughout the cytoplasm. Banded structures consisting of alternate granular and flocculent materials are found within the nucleus. PMID- 30249072 TI - The diversity of neurosecretory cell types in the cave tick Ornithodoros tholozani. AB - Neurosecretory cells are arranged in 16 NSC centers in the different regions of the brain of O. tholozani. The component cells belong to 13 different types, of which five types are paraldehyde fuchsin positive and the remaining types are negative. Three of these cell types are here described for the first time. Some of these NSC show an affinity to certain localities inside the brain. Cells comprising a neurohaemal organ were found near the exit of the esophagus. PMID- 30249073 TI - Fine structure of the tracheoles of the lantern of a photurid firefly. AB - The lantern tracheoles of the firefly, Photuris, are unusual in that their walls are reinforced by cuticular bars. The tracheoles are stiff and resist collapse under conditions which flatten more typical tracheoles. This reinforcement and the structural resemblance of the tracheal end cell to cells considered to be active in moving ions and fluid is taken as evidence suggesting that the flash may be turned on and off by control of the oxygen supply and that said control may involve some sort of osmotic mechanism. PMID- 30249074 TI - Postembryonic ontogeny and functional anatomy of the ligamentum mandibulo hyoideum and the ligamentum interoperculo-mandibulare, with notes on the opercular bones and some other cranial elements in Salmo gairdneri Richardson, 1836 (Teleostei: Salmonidae). AB - This study deals with the development of the opercular bones the ligamentum mandibulo-hyoideum, the ligamentum interoperculo-mandibulare and with some aspects of the development of the ceratohyale and the cartilago meckeli during postembryonic ontogeny of Salmo gairdneri (rainbow trout). It is stated that the ligamentum mandibulo-hyoideum is present from hatching onward, while the development of the ligamentum interoperculo-mandibulare appears during the period of active feeding. Some functional reasons are proposed to explain these facts. It is further suggested that the opercular bones develop under influence of the opercular muscles. PMID- 30249075 TI - Spermatozoa of Ciona intestinalis and analysis of ascidian fertilization. AB - The complex array of vestments which surrounds the ascidian oocyte indicates that spermatozoa of these urochordates may be highly modified to effect penetration through the egg-envelopes and to achieve successful fusion with the female gamete. Examination of the spermatozoa of Ciona intestinalis reveals, however, that they lack an acrosomal vesicle and do not possess detectable amounts of actin. Furthermore, the spermatozoa do not undergo observable morphological alterations when exposed to ammoniated seawater, a treatment known to produce aggregation and an acrosome reaction in other organisms. Ciona spermatozoa do contain significant quantities of proteases. It is hypothesized that the localization of these enzymes may be related to the ridge-like surface ornamentation which is observed as a component of the head region of Ciona spermatozoa. PMID- 30249076 TI - Studies on the gill ciliation of the American oyster Crassostrea virginica (Gmelin). AB - Latero-frontal, para-latero-frontal, and frontal ciliary tracts on the gill filaments of Crassostrea virginica (Gmelin) were studied with light microscopy and scanning electron microscopy. Latero-frontal cirri are complex structures composed of varying numbers of paired cilia. The multiple pairs of cilia which constitute a single cirrus are closely appressed for a portion of their length; they then branch laterally from the central axis in a plume-like fashion. Latero frontal cirri of adjacent gill filaments create a filtration sieve which should be capable of retaining particles smaller than 1 MUm in diameter. Para-latero frontal cilia are short, closely spaced cilia arranged as a staggered row along the frontal side of each tract of latero-frontal cirri. Latero-frontal cirri and para-latero-frontal cilia occur on ordinary, principal, and transitional gill filaments. Frontal ciliary tracts of ordinary filaments are divided into a central, ventrally directed coarse tract, flanked on either side by a dorsally directed fine ciliary tract. The coarse tract is covered by cirri which are comprised of five to eight cilia, while the fine frontal tracts are made up of individually functioning cilia. The frontal ciliary tracts of principal and transitional filaments bear only dorsally directed fine cilia. The unique direction of effective beat of the coarse frontal cirri of ordinary filaments, in combination with the action of fine frontal cilia and the strategic location of mucus producing cells, is used to describe a possible mechanism for the sorting of filtered particles. PMID- 30249077 TI - Some correlates of cranial and cervical morphology with predatory modes in snakes. AB - Dissection of the cervical and basicranial regions in three species of snakes indicates that compared to Crotalus viridis and Lichanura roseofusca, Masticophis flagellum possesses relatively high numbers of compound axial muscle insertions on the atlas-axis and vertebrae numbers 3-5. It is suggested that the condition in Masticophis facilitates its vertical-neck-horizontal-head foraging posture and has allowed axial muscles inserting on the dorsocaudal braincase in this snake to generate vertical and lateral head movements more effectively. PMID- 30249078 TI - Action of surfactants on the mammal epidermal skin barrier. AB - BACKGROUND: Daily skin washing routines can promote undesirable effects on skin barrier function. The stratum corneum (SC) lipid matrix is crucial for skin barrier function. Skin cleansing products are mostly composed of surfactants: surface-active molecules that interact with skin lipids in several ways. The main aim of this work was to investigate the effect produced by surfactants on skin barrier permeability. Porcine skin is a well-accepted and readily available model of the human skin barrier. The effect of two cleansing formulations (based on different surfactant mixtures) on the barrier properties of mammalian skin were evaluated. METHODS: Water sorption/desorption (DVS) experiments were used to measure skin permeability. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and confocal Raman were useful to study SC lipid organization. RESULTS: The results showed that while anionic surfactants (SLS) had a negative impact on the skin barrier, with a clear increase of alkyl chain disorder; co- surfactants present in the shampoo formulation diminished the detrimental effect of their primary ionic surfactant, inducing less modification on lipid intramolecular chain disorder. CONCLUSIONS: The obtained results confirmed that the mild cleansing formulations studied had gentle interaction with skin. The capacity to discriminate between detergent systems was clearly established with both DVS and spectroscopy techniques. PMID- 30249079 TI - Microcystic adnexal carcinoma of the skin in atypical site (pubic region): clinical and dermatoscopic features. PMID- 30249080 TI - Could Terra firma-forme dermatosis induce eczematous halo dermatitis? An hypothesis. PMID- 30249081 TI - Peristomal allergic contact dermatitis caused by ostoma pastes and role of Gantrez ES-425. AB - BACKGROUND: Peristomal allergic contact dermatitis is an emerging problem and contact sensitization is probably more common than previously thought. Our objective was to identify sensitization to the most common topical equipment for ostomy in patients with history of peristomal dermatitis. METHODS: 26 patients with suspected peristomal contact dermatitis were patch tested with our standard series and with products for stoma care (adhesive pastes, powders, adhesive skin barriers). 13 patients and 20 volunteers were also patch tested with Gantrez ES 425, which is a common component of adhesive pastes. RESULTS: 18 patients showed one or more positive reactions, 12 to one or more of the most commonly used adhesive pastes. 10 out of 13 patients tested to Gantrez ES-425 had a positive reaction. CONCLUSIONS: Allergic contact dermatitis of the peristomal area is probably more common than previously reported. Patch testing is the method of choice to determine sensitization to products for stoma care, and Gantrez ES-425 should be considered for patch testing. PMID- 30249082 TI - Clinical evaluation of an antiperspirant for hyperhidrosis. AB - BACKGROUND: Hyperhidrosis is a fairly common condition characterized by excessive sweating, usually in axillary areas. Although not involving major health problems, it is a significant psychological distress to those affected, compromising their social life. The first line of defense used to address this problem are antiperspirants, usually containing aluminum salts, capable of blocking the excessive sweating. METHODS: We made a clinical trial to test the deodorant effectiveness and anti-bacterial activity of an antiperspirant product, based on Agaricine, Aluminum hydrochloride and Silver Citrate, in a panel of 20 subjects following a single laboratory application under controlled conditions. Later, the same product has been tested for skin compatibility, effectiveness and cosmetic quality after repeated home applications under normal conditions of use for 14 consecutive days. RESULTS: After 6 and 24 hours from the application, the microbial load observed in treated axilla was inferior in a statistically significant way compared to the untreated axilla. There was not found the presence of pathogenic bacteria on any of the two armpits. The tested product has shown an excellent anti-bacterial activity. CONCLUSIONS: Overall, the product has been highly appreciated by the volunteers for its effectiveness and its cosmetic qualities, particularly because it has a good deodorant activity, its deodorant activities persist throughout the day, it does not stain clothes, and it has a practical package. PMID- 30249083 TI - An oral supplementation based on myo-inositol, folic acid and liposomal magnesium may act synergistically with antibiotic therapy and can improve metabolic profile in patients affected by Hidradenitis Suppurativa: our experience. AB - BACKGROUND: Over recent years, the link between obesity, metabolic syndrome and Hidradenitis Suppurativa (HS) has been explored. It has been demonstrated that HS patients have a high prevalence of the metabolic syndrome and an increased frequency of insulin resistance. The objective of our study is to estimate the effectiveness of an oral supplementation based on myo- inositol (MI), folic acid and liposomal magnesium (LEVIGON(r)) on the clinical and metabolic profile of patients affected by HS. METHODS: 20 subjects with HS and an impaired glucose metabolism were enrolled. Group A: 10 subjects received for 6 months MI 2000 mg, liposomal magnesium and folic acid associated to topical antibiotic therapy (clindamycin gel 1%), systemic antibiotic therapy (clindamycin 300 mg b.i.d. and rifampicin 600 mg daily for 6 weeks) and a normocaloric diet Group B: 10 subjects received topical and systemic antibiotic therapy associated to a normocaloric diet for 6 months. RESULTS: After 6 months group A patients showed an average reduction of Sartorius Score from 38.3 +/- 7.75 to 27.3 +/- 13.53 (p-value <0.04) while in the control group there was a reduction of the Sartorius from 38.4 +/- 7.88 to 31.1 +/- 8.02 (p-value = 0.55). Moreover in group A Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was significantly reduced from 2.43 +/ 0.35 to 2.1 +/- 0.31 (p <0.01) whereas in group B HOMA-IR did not significantly decrease (2.51 +/- 0.65 at T0 at 2.40 +/- 0.67 at T1). CONCLUSIONS: Our study underlines the importance of the evaluation of metabolic profile in patients with HS. Moreover it suggests that the supplementation of MI, folic acid and liposomal magnesium in HS can improve the efficacy of concomitant therapies and the metabolic profile. PMID- 30249084 TI - Early detection of IgH monoclonal rearrangenent in follicular spicules of the nose preceding multiple myeloma diagnosis. Case report and review of the literature. PMID- 30249085 TI - Risk of incident melanoma in patients with inflammatory disease treated with anti TNF: the Turin experience. PMID- 30249086 TI - Generalized parthenium dermatitis with deck-chair sign. PMID- 30249087 TI - Improvement of severe facial seborrheic dermatitis following low-dose isotretinoin therapy. PMID- 30249088 TI - Acne mechanica in a child with a motor tic. PMID- 30249089 TI - Safety and long-term efficacy of partial matricectomy and phenolization for the treatment of pyogenic granuloma-like lesions induced by epidermal growth factor receptor inhibitors. PMID- 30249090 TI - Design of Bifunctional Dendritic 5-Aminolevulinic Acid and Hydroxypyridinone Conjugates for Photodynamic Therapy. AB - Iron chelators have recently attracted interest in the field of photodynamic therapy (PDT) owing to their role in enhancement of intracellular protoporphyrin IX (PpIX) generation induced by 5-aminolevulinic acid (ALA) via the biosynthetic heme cycle. Although ALA is widely used in PDT, cellular uptake of ALA is limited by its hydrophilicity. In order to improve ALA delivery and enhance the PpIX production, several dendrimers incorporating both ALA and 3-hydroxy-4-pyridinone (HPO) were synthesized. The ability of the dendrimers to enter cells and be metabolized to the PpIX photosensitizer was studied in several human cancer cell lines. The dendrimers were found to be significantly more efficient than ALA alone in PpIX production. The higher intracellular PpIX levels showed a clear correlation with enhanced cellular phototoxicity following light exposure. Dendritic derivatives are therefore capable of efficiently delivering both ALA and HPO, which act synergistically to amplify in vitro PpIX levels and enhance PDT efficacy. PMID- 30249091 TI - Current emissions and future mitigation pathways of coal-fired power plants in China from 2010 to 2030. AB - As the largest energy infrastructure in China, power sector consumed approximately half of China's coal over the past decade and threatened air quality and greenhouse gas (GHG) abatement target. In this work, we assessed the evolution of coal-fired power plants and associated emissions in China during 2010-2030 by using a unit-based emission projection model which integrated the historical power plants information, turnover of the future power plant fleet, and the evolution of end-of-pipe control technologies. We found that, driven by the stringent environmental legislation, SO2, NO x, and PM2.5 emissions from coal fired power plants decreased by 49%, 45%, and 24% respectively during 2010-2015, comparing to 15% increase in CO2 emissions. In contrast to ever-increasing CO2 emissions until 2030 under current energy development planning, we found aggressive energy development planning could curb CO2 emissions from the peak before 2030. Owing to the implementation of "near zero" emission control policy, we projected emissions of air pollutants will significantly decrease during 2016 2030. Early retirement of small and low-efficient power plants would further reduce air pollutants and CO2 emissions. Our study explored various mitigation pathways for China's coal-fired power plants, which could reduce coal consumptions, air pollutants and CO2 emissions, and improve the energy efficiency. PMID- 30249092 TI - Unique Flavanol-Anthocyanin Condensed Forms in Apache Red Purple Corn. AB - Anthocyanin pigments from purple corn are being explored as a potential alternative to artificial colorants and for their health-promoting properties. However, all pericarp-pigmented corn varieties examined to date primarily contain cyanidin-derived anthocyanins, which produce bluish-red or pink extracts. Here we describe the first pelargonidin-dominant pericarp-pigmented corn lines from the landrace Apache Red (AR). Anthocyanins were characterized from six AR families using high-performance liquid chromatography-mass spectrometry (HPLC-MS). From this, we identified two new flavanol-anthocyanin condensed forms in corn: catechin-(4,8)-pelargonidin 3,5-diglucoside and afzelechin-(4,8)-pelargonidin 3,5 diglucoside, which were subsequently confirmed with NMR. Additionally, several apigenin-derived C-glycosyl flavones were identified in abundance. With a diverse flavonoid profile containing an array of different anthocyanin species and flavones, Apache Red will be an important line in which to study control of the flavonoid biosynthesis pathway. PMID- 30249093 TI - Tuning Oxygen Vacancy Diffusion through Strain in SrTiO3 Thin Films. AB - Understanding diffusion of oxygen vacancies in oxides under different external stimuli is crucial for the design of ion-based electronic devices, improvement of catalytic performance, and so forth. In this manuscript, using an external electric field produced by an atomic force microscopy tip, we obtain the room temperature diffusion coefficient of oxygen-vacancies in thin films of SrTiO3 under compressive/tensile epitaxial strain. Tensile strain produces a substantial increase of the diffusion coefficient, facilitating the mobility of vacancies through the film. Additionally, the effect of tip bias, pulse time, and temperature on the local concentration of vacancies is investigated. These are important parameters of control in the production and stabilization of nonvolatile states in ion-based devices. Our findings show the key role played by strain for the control of oxygen vacancy migration in thin-film oxides. PMID- 30249094 TI - Mechanistic Insights into Cyclopropenes-Involved Carbonylative Carbocyclization Catalyzed by Rh(I) Catalyst: A DFT Study. AB - Computational studies were carried out to provide mechanistic insights into the Rh(I)-catalyzed activation of cyclopropenes and the detailed mechanistic pathways of [3+2+1] carbonylative carbocyclization of tethered ene- and yne-cyclopropenes. Computational results suggest that it is more favorable for the cyclopropene moiety of tethered ene-cyclopropenes to initially undergo heterolytic cleavage of a C-C sigma-bond to form a vinyl Rh(I) carbenoid intermediate than to proceed through homolytic C-C sigma-bond cleavage to generate a rhodacyclobutene intermediate. The yielded vinyl Rh(I) carbenoid intermediate could undergo cyclization to generate a Rh(III) metallacyclobutene intermediate, which could further lead to a thermodynamically more stable six-coordinated Rh(III) metallacycle intermediate in the presence of additional CO. Afterward, it is more feasible for the yielded six-coordinated Rh(III) metallacycle to sequentially undergo CO migratory insertion, cyclization, and reductive elimination to furnish the final cyclohexenone product. The origin of stereoselectivity of the product was also discussed. The proposed mechanistic pathway can also be applied to the Rh(I)-catalyzed carbonylative carbocyclization of tethered yne-cyclopropenes and vinyl cyclopropenes to produce phenol derivatives. The main mechanistic difference for the vinyl cyclopropene substrate is that the conversion of Rh(I) carbenoid intermediate to the Rh(III) metallacycle proceeds via intramolecular 6pi electrocyclization. PMID- 30249096 TI - In Nano, Volume 12, Issue 9. PMID- 30249097 TI - Nano in Boston and Beyond. PMID- 30249095 TI - Sensing Ocean Plastics with an Airborne Hyperspectral Shortwave Infrared Imager. AB - Here, we present a proof-of-concept on remote sensing of ocean plastics using airborne shortwave infrared (SWIR) imagery. We captured red, green, and blue (RGB) and hyperspectral SWIR imagery with equipment mounted on a C-130 aircraft surveying the "Great Pacific Garbage Patch" at a height of 400 m and a speed of 140 knots. We recorded the position, size, color, and type (container, float, ghost net, rope, and unknown) of every plastic piece identified in the RGB mosaics. We then selected the top 30 largest items within each of our plastic type categories (0.6-6.8 m in length) to investigate SWIR spectral information obtained with a SASI-600 imager (950-2450 nm). Our analyses revealed unique SWIR spectral features common to plastics. The SWIR spectra obtained ( N = 118 items) were quite similar both in magnitude and shape. Nonetheless, some spectral variability was observed, likely influenced by differences in the object optical properties, the level of water submersion, and an intervening atmosphere. Our simulations confirmed that the ~1215 and ~1732 nm absorption features have potential applications in detecting ocean plastics from spectral information. We explored the potential of SWIR remote sensing technology for detecting and quantifying ocean plastics, thus provide relevant information to those developing better monitoring solutions for ocean plastic pollution. PMID- 30249098 TI - Engineered systems to study the synergistic signaling between integrin-mediated mechanotransduction and growth factors (Review). AB - While tremendous leaps in knowledge into cellular signaling and control have been achieved over the last few decades, there is still more to learn in how different signaling pathways act synergistically. A better understanding and control of cells in vitro and in vivo is important to enable more successful and safe applications of tissue engineering and stem cell therapy. This review is focused on two central ways cells sense their surroundings, namely, integrin-mediated mechanotransduction and growth factor signaling. Specifically, the authors explore how engineered interfaces have been applied to learn more about these processes, and how these important signaling pathways interact synergistically. PMID- 30249099 TI - Controlling the surface structure of electrospun fibers: Effect on endothelial cells and blood coagulation. AB - The influence of nano- or micron-sized structures on polymer films as well as the impact of fiber diameter of electrospun membranes on endothelial cell (EC) and blood response has been studied for vascular tissue engineering applications. However, the influence of surface structures on micron-sized fibers on endothelial cells and blood interaction is currently not known. In this work, electrospun membranes with distinct fiber surface structures were designed to study their influence on the endothelial cell viability and thrombogenicity. The thermodynamically derived Hansen-solubility-parameters model accurately predicted the formation of solvent dependent fiber surface structured poly(caprolactone) membranes. The electrospun membranes composed of microfibers (MF) or structured MF were of similar fiber diameter, macroscopic roughness, wettability, and elastic modulus. In vitro evaluation with ECs demonstrated that cell proliferation and morphology were not affected by the fiber surface structure. Similarly, investigating the blood response to the fiber meshes showed comparable fibrin network formation and platelet activation on MF and structured MF. Even though the presented results provide evidence that surface structures on MF appear neither to affect EC viability nor blood coagulation, they shed light on the complexity and challenges when studying biology-material interactions. They thereby contribute to the understanding of EC and blood-material interaction on electrospun membranes. PMID- 30249100 TI - AJCC 8th Edition (2017) versus AJCC 7th Edition (2010) in thin melanoma staging. AB - In comparison with the 7th Edition, the 8th Edition of the American Joint Committee on Cancer (AJCC) staging system no longer considers the mitotic count in the a or b T1 categorization for melanoma, but it adopts a sub-stratification based on the Breslow's depth. Today, the death burden of thin melanoma is still severe, despite of attempts for early screening. We believe that a bio histological implementation may explain this evidence. It is generally accepted that melanoma progression includes two subsequent phases: the radial growth phases (RGP) and the vertical growth phase (VGP). If left untreated, RGP is able to move towards VGP. In this second phase, melanoma grows as a malignant, mitotically active, tumor with invasive and metastatic capacities. By our experience, thin melanoma includes three bio-histological subtypes: the non tumorigenic micro-invasive RGP without significant regression, the micro-invasive RGP with regression of uncertain tumorigenic potential at diagnosis, due to the extensive presence (> 75%) of regression which could contain a VGP clone, and the micro-invasive tumorigenic VGP. Therefore, we are prone to support that the prognosis of thin melanoma is correlated with the type of growth phase inside it. PMID- 30249101 TI - Identification of critical microRNAs in gastrointestinal stromal tumor patients treated with Imatinib. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Imatinib mesylate was considered to be a breakthrough drug in clinical treatment of GIST, but GIST patients showed resistance against it. We aimed to identify critical microRNAs (miRNAs) related to imatinib resistance in imatinib-treated GIST patients. Microarray datasets under the accession number of GSE63159 and GSE45901 were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed miRNAs (DEMs) that are related to imatinib resistance were identified. GO function and KEGG pathway enrichment analyses were performed, and lncRNA-miRNA-target gene regulatory networks were constructed. Finally, the critical miRNAs and their target genes that are related to imatinib resistance or sensitivity were identified. In total, 20 DEMs in the GSE63159 dataset (7 significantly up regulated and 13 down-regulated) and 23 DEMs in the GSE45901 dataset (8 up regulated and 15 down-regulated) were identified. In lncRNA-miRNA-target gene regulatory networks, five critical miRNAs and 109 target genes were identified. GO function and KEGG pathway enrichment analysis showed that the target genes of DEMs were mainly involved in several signaling pathways, such as focal adhesion and the GnRH signaling pathway. Among the five miRNAs, the overexpression of hsa miR-28-5p and hsa-miR-125a-5p had significant correlation to imatinib resistance or imatinib sensitivity in GIST patients. Hsa-miR-28-5p and hsa-miR-125a-5p may be involved in the development and progression of GIST, and they may be able to serve as prognostic markers for imatinib-response in GIST patients. PMID- 30249102 TI - Long non-coding RNA EPB41L4A-AS2 inhibited non-small cell lung cancer proliferation, invasion and promoted cell apoptosis. AB - The aim of the research was to investigate the expression of lncRNA EPB41L4A-AS2 in non-small cell lung cancer (NSCLC) and evaluate its influence on the proliferation, invasion and apoptosis of NSCLC. A total of 56 NSCLC tissues and its corresponding adjacent tissues were collected. Quantitative Reverse transcription polymerase chain reaction (qRT-PCR) was performed to evaluate the lncRNA EPB41L4A-AS2 expression level in tissues and cell lines. Proliferating cell nuclear antigen (PCNA) protein level was determined by western blot assay. CCK8 assay, EdU assay, flow cytometry (FCM) and transwell assay were performed to access cell proliferation, apoptosis and invasion. EPB41L4A-AS2 expression was significantly downregulated in cancer tissues and cells compared with the adjacent tissues and normal cells (P<0.05). After cells were transfected with pcDNA3.1-EPB41L4A-AS2, cell viability and PCNA protein level was decreased, and cells were arrested in the G0/G1 phase with higher apoptosis rate. Transwell assay showed that over-expressed EPB41L4A-AS2 could reduce cells invasion ability. Expression of low levels of EPB41L4A-AS2 is associated with poor survival in NSCLC and the over-expression of lncRNA EPB41L4A-AS2 inhibits NSCLC cell proliferation, invasion and promote cell apoptosis. PMID- 30249103 TI - Ku70 N-terminal lysines acetylation/deacetylation is required for radiation induced DNA-double strand breaks repair. AB - Ku70 protein in hetero-trimeric complex with Ku80 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) represents a critical component of the nonhomologous-end-joining (NHEJ), the major machinery of DSBs repair in mammalian cells. It has been previously shown that modulation of Ku70 acetylation by histone deacetylases (HDAC) inhibitors induced sensitization of cancer cells to chemotherapeutic agents. However, the effects of such modulation on the repair of Ionizing Radiation (IR)-induced DSBs and the importance of dynamic equilibrium of acetylation/deacetylation have not been studied in details. To address these questions aceto-blocking and aceto-mimicking mutants were designed by replacing Ku70 lysine residues K317, K331 and K338 with arginine and glutamine respectively via site-directed mutagenesis. Transformed human embryonic lung fibroblasts MRC5VA were transfected to create stables cells lines over-expressing Ku70 mutant proteins. Clonogenic survival and gamma-H2AX foci assays were performed to study the impact of these mutants on DNA repair proficiency of MRC5VA cells in response to IR. We report here that both Ku70 aceto-blocking and aceto-mimicking mutants rendered MRC5VA cells more susceptible to IR in terms of clonogenic survival and gammaH2AX foci. Moreover, modelling the possible interactions and structural impact of these aceto-blocking and aceto-mimicking mutants with DNA substrate showed that mimicking acetylation/deacetylation of K331 and K338 could directly compromise KU-DNA interactions, whereas K317 may have a more subtle role via forming a salt bridge with E330 thus optimising the positioning of the helix containing both K331 and K338 residues on the DNA. Our data indicates that dynamic equilibrium of acetylation/deacetylation of Ku70 lysine residues K317, K331 and K338 is critical for optimal repair of IR-induced DSBs, and may offer a novel therapeutic approach for cancer treatment. PMID- 30249104 TI - MiR-365a-3p suppresses proliferation and invasion of Hep-2 cells through targeting ten-eleven translocation 1 (TET1). AB - miRNAs are among the most important factors that regulate gene expression. According to bioinformatic analysis, miR-365a-3p was predicted to interact with the TET1 mRNA. We predicted that it might affect tumor biological processes through TET1. TET1 interference and miR-365a-3p inhibitor constructs were generated. qRT-PCR was used to verify the expression level of miR-365a-3p and TET1 in Hep-2 and BESB-2B cells. qRT-PCR and Western blot were used to confirm the TET1 expression level in Hep-2 and miR-365a-3p inhibitor cells. Cell proliferation, cell cycle progression and cell invasion were further studied to identify the relationship between TET1 and miR-365a-3p. Luciferase reporter gene assays were used to find the binding site of miR-365a-3p in the 3'-UTR (3' untranslated region) of the TET1 mRNA. TET1 was weakly expressed in Hep-2 cells and highly expressed in BESB-2B cells, while miR-143-3p and miR-365a-3p were highly expressed in Hep-2 cells and lowly expressed in BESB-2B cells. Inhibiting miR-365a-3p could up-regulate the expression of TET1. The negative effects of miR 365a-3p on cell proliferation, cell cycle progression and cell invasion could be abolished by TET1 interference. The binding site of miR-365a-3p was in the 3'-UTR of the TET1 mRNA. TET1 is one of the targets of miR-365a-3p. miR-365a-3p regulates the biological behavior of laryngeal cancer by down-regulating TET1. PMID- 30249105 TI - MiR-589-5p is a potential prognostic marker of hepatocellular carcinoma and regulates tumor cell growth by targeting MIG-6. AB - MicroRNAs (miRNAs) are small noncoding RNAs approximately with 22 nucleotides. Accumulating evidence indicates that microRNAs are involved in carcinogenesis and tumor progression. Some recent investigations have also reported that several microRNAs could act as biomarkers in cancer diagnosis and prognosis. MicroRNA-589 5p (miR-589-5p) is a less studied microRNA, in this study, we explored its roles in hepatocellular carcinoma (HCC). We analyzed miR-589-5p expression in HCC tissues by sequencing data and proved the expression in liver cancer cell lines by quantitative real-time PCR (qRT-PCR). We studied the effect of miR-589-5p on the growth of liver cancer cells by MTT assay, colony formation and flow cytometry, and identified its target gene by luciferase reporter assay. We found that miR-589-5p was commonly overexpressed in HCC specimens. High expression of miR-589-5p was a risk factor for HCC patient (Hazard ratio [HR] = 1.434; 95% confidence intervals [CI] = 1.006-2.044; p = 0.046). We also found miR-589-5p had higher expression in hepatocarcinoma cell lines HepG2 and HuH-7 than did in normal hepatocyte Lo-2. We identified that suppression of miR-589-5p inhibited cell proliferation and cell cycle progression by loss-of-function studies. Furthermore, we found mitogen-inducible gene 6 (MIG-6) to be a target of miR-589 5p. Our study demonstrated that miR-589-5p facilitated the growth of liver cancer cells by targeting MIG-6 and could be a prognosis biomarker for HCC. Suppression of miR-589-5p may be a feasible approach for inhibiting HCC progress. PMID- 30249106 TI - TMEM45B is a novel predictive biomarker for prostate cancer progression and metastasis. AB - It is urgently needed to explore the clinical relevance of TMEM45B expression and Prostate cancer(PCa), and determine the predictive significance of TMEM45B as a biomarker for PCa patients.Patient-derived xenograft (PDX) model of PCa with different metastatic potential (LTL-418, LTL-313B, LTL-313H and LTL-331) were developed. The gene expression microarray of LTL-313H and LTL-313B, which derived from a single PCa patient, was performed to identify the candidate biomarker gene, TMRM45B. MSKCC and TCGA PCa patient cohorts were introduced to analyzed the clinical significance of TMEM45B expression. Quantitative Real-Time PCR (qRT-PCR) revealed that there was a significant increase of TMEM45B expression in high metastatic potential tumor lines LTL-313H and LTL-331 compared with the other two low metastatic potential tumor lines(LTL-418, LTL-313B). In MSKCC PCa cohort, the mRNA level of TMEM45B in patients with metastasis was significantly higher than that in primary PCa (P=0.001) and begin prostate hyperplasia (BPH) patients (P<0.001). In addition, the increased TMEM45B expression was positively related with a higher possibility of biochemical recurrence (P=0.016), distant metastasis occurrence(P<0.001) and overall patient survival (P=0.07). Moreover, TMEM45B expression was considered as an independent risk factor for metastasis of PCa based on multivariate logistic regression. Kaplan-Meier analysis showed that patients with elevated TMEM45B had a shorter biochemical recurrence free survival (RFS). For primary PCa patients, subgroup analysis showed that there was a significant association between TMEM45B expression and clinical features in primary PCa cohort. Meanwhile, cases with elevated TMEM45B were more likely to develop metastasis compared to the normal group among N0 primary PCa patients (P=0.010). Primary PCa patient cohort TCGA was used to validate the results, and an obvious relationship was found between TMEM45B and clinical characteristic of PCa (T/N stage, Gleason score, Recurrence / Progress). Furthermore, a significant poor disease free survival (DFS) was investigated in high-level of TMEM45B patients compared with the other remaining cases (P=0.007). Taken together, the increased expression of TMEM45B appears to be significantly associated with prostate carcinoma progression and metastasis which provide a new prognostic biomarker for predicting metastatic potential of PCa patients, especially for primary PCa. PMID- 30249107 TI - MiRNA-500a-3p inhibits cell proliferation and invasion by targeting lymphocyte antigen 6 complex locus K (LY6K) in human non-small cell lung cancer. AB - LY6K (lymphocyte antigen 6 complex locus K) is an anti-gene in non-small cell lung cancer (NSCLC) and miR-500a-3p promotes the progression of cancers. Evidence shows that the increase of miR-500a-3p caused LY6K to be suppressed. Here we hypothesized that miR-500a-3p may take part in the progression of NSCLC through targeting LY6K. miR-500a-3p expression levels in NSCLC specimens and cell lines were detected by quantitative real-time PCR (qRT-PCR). The mRNA and protein expression levels of LY6K in NSCLC specimens and cell lines were examined by qRT PCR, immunohistochemistry and western blotting. Dual-luciferase reporter assay was carried out to assess miR-500a-3p binding to LY6K gene. The functions of miR 500a-3p and LY6K in proliferation/invasion and lung metastasis formation were assessed by CCK8, Transwell assay and subcutaneous tumor model in nude mice, respectively. Statistical analysis was performed to explore the clinical correlation between miR-500a-3p/LY6K expression and clinicopathological features. miR-500a-3p was substantially decreased in NSCLC tissues and cell lines. LY6K protein and mRNA level expressions were increased in NSCLC patients. Clinical analysis indicated that miR-500a-3p and LY6K were related to tumor differentiation, lymph node metastasis and TNM staging in NSCLC patients. MiR 500a-3p suppresses cell proliferation, invasion and metastasis formation in vivo by targeting the LY6K. miR-500a-3p acts as a tumor suppressor in NSCLC partially via down-regulation of LY6K expression and for NSCLC intervention and suggests a potential therapeutic target for NSCLC intervention. PMID- 30249108 TI - Reply from the authors. When and how to start exercise training after heart failure decompensation? Still more questions than answers. PMID- 30249109 TI - Video-assisted thoracoscopic surgery for lung cancer after induction therapy. AB - Background Although thoracoscopic surgery is widely performed for early-stage lung cancer, only a few small studies have evaluated the role of video-assisted thoracoscopic surgery in patients with locally advanced lung cancer who had received preoperative chemotherapy. Methods Among 1655 patients who underwent anatomical lung resection for lung cancer between January 2009 and December 2014 in our institution, we retrospectively examined the short- and long-term outcomes of 110 (6.6%) who had undergone induction therapy. Thoracoscopic surgery was performed in 79 of these patients and thoracotomy in 31. Results In the thoracoscopic group, conversion to a thoracotomy was required in 4 patients. More combined resections were included in the thoracotomy group, and combined resection of large vessels or the carina was carried out only via a thoracotomy. Postoperative complications of grade 3 or above were found in 15 (13.6%) patients, and there was no significant difference in the incidence of postoperative complications between the 2 groups. The 3- and 5-year survival rates for the patients overall were 58.6% and 50.3%, respectively. Although there was no significant difference in overall outcome between the 2 groups, the patients with postoperative ypN2 status in the thoracoscopic group had a significantly better outcome than those in the thoracotomy group. Conclusion Although video-assisted thoracoscopic surgery was not suitable for central advanced lung cancer requiring angioplasty or carinal resection, it seems to be useful for patients with locally advanced lung cancer who had undergone induction therapy, especially patients with peripheral lung cancer and mediastinal lymph node metastasis. PMID- 30249110 TI - Surgical management of a free-floating thrombus in the ascending aorta. AB - The ascending aorta is an uncommon site of noninfective thrombus. We describe the case of a 63-year-old woman who was admitted to our department with acute myocardial infarction. Coronary angiography showed occlusion of a small diagonal vessel, likely related to a distal embolization event. A transthoracic echocardiogram revealed a free-floating mass in the proximal ascending aorta. Two and 3-dimensional transesophageal echocardiography studies were performed, and after a multidisciplinary heart team discussion, surgical removal of the mass was planned and successfully performed through a median sternotomy on cardiopulmonary bypass. PMID- 30249111 TI - Hand-sewn trileaflet valve in the right ventricular outflow tract. AB - A 4-year-old girl with pulmonary regurgitation after complete repair of tetralogy of Fallot, underwent an alternative surgical repair for pulmonary valve replacement. Hand-sewn trileaflet valve reconstruction using expanded polytetrafluoroethylene membrane is a feasible method for pulmonary regurgitation in such a young child in whom a large-sized bioprosthetic valve cannot be implanted. PMID- 30249112 TI - Low-dose non-contrast examination of the temporal bone using volumetric 320-row computed tomography. AB - Background 320-row volume computed tomography (CT) allows CT dose to be reduced while maintaining image quality. Purpose To evaluate image quality of low-dose non-contrast temporal bone CT using single volumetric 320-row multidetector CT technique. Material and Methods A total of 125 patients were included in our study. Two low-dose protocols, including 135 kV tube voltage with 5 mAs tube current and 80 kV tube voltage with 5 mAs tube current, were chosen based on results of present phantom study. For evaluating subjective image quality, conspicuity of anatomic landmarks were assigned a score using a five-point scale. Objective image quality analysis was performed by analyzing regions of interest on axial soft-tissue and bone reconstructions. Effective dose was calculated from dose-length product. Results Mean effective radiation dose for 120 kV and 75 mAs protocol (control group) was 0.29 +/- 0.04 mSv; for 135 kV and 5 mAs protocol (study group A), this value was 0.02 +/- 0. 003 mSv; and for 80 kV and 5 mAs protocol (study group B), this value was 0.005 +/- 0. 0009 mSv. Mean effective radiation doses of study group A and B were significantly lower than the control group ( P < 0.001). Study group A and control group images showed no significant difference in image quality except for some anatomic landmarks. Study group B images had lower image quality than control group images. Conclusions Temporal bone CT with 135 kVp and 5 mAs can be performed at very low radiation exposure while maintaining high image quality. PMID- 30249113 TI - The relationship between calcium (water) density and age distribution in adult women with spectral CT: initial result compared to bone mineral density by dual energy X-ray absorptiometry. AB - Background Calcium (water) density (DCa(Wa)) of gemstone spectral imaging by spectral computed tomography (CT) is a new method of evaluating bone structures. Purpose To investigate age-related change of DCa(Wa) of a chosen lumbar vertebra in adult women with spectral CT and the correlation between the DCa(Wa) and bone mineral density (BMD) of dual-energy X-ray absorptiometry (DXA). Material and Methods A total of 305 adult women underwent spectral CT, 127 of whom simultaneously underwent DXA. All the patients were divided into 11 subgroups based on age. DCa(Wa) and BMD were measured at the second lumbar vertebra on the calcium (water)-based material decomposition images of spectral CT and DXA, respectively. A one-way analysis of variance (ANOVA) was performed for the difference of the measurements among adjacent age subgroups. Pearson correlation was used to assess the association between age and DCa(Wa), age and BMD, as well as DCa(Wa) and BMD. Results There was a significant negative correlation between DCa(Wa) and age (r = -0.719) as well as BMD and age(r = -0.851). The mean DCa(Wa) of L2 vertebral body was significantly different between the 40-44- and 45-49-, 45-49- and 50-54-, 55-59- and 60-64-, 65-69- and 70-74-year-old age subgroups. BMD was significantly different between the 35-39- and 40-44-, 45-49- and 50-54-, and 65-69- and 70-74-year-old age subgroups. There was a significant positive correlation between DCa(Wa) and BMD. Conclusions The DCa(Wa) of lumbar vertebra by spectral CT demonstrated similar age distribution as BMD of DXA and could be used as a method of measuring the vertebral bone mineral density in adult women. PMID- 30249114 TI - Dementia-Related Results of "Costs of Medication in Older Patients: Before and After Comprehensive Geriatric Assessment". AB - Changes in the pharmacokinetics and pharmacodynamics of drugs in the presence of certain comorbidities and geriatric syndromes and reduced tolerability of potential drug side effects due to physiological changes with aging lead to difficulties in planning treatments in elderly adults, especially patients with dementia. The Comprehensive Geriatric Assessment has an important role in assessing polypharmacy and optimizing potentially inappropriate medications and potentially prescribing omissions in these patients. For this reason, we intend to reexamine our new study titled " Costs of medication in older patients: before and after comprehensive geriatric assessment," because most of these results are also very important for dementia practice. PMID- 30249115 TI - Seeing the Patient and Family Through: Nurses and Physicians Experiences With Withdrawal of Life-Sustaining Therapy in the ICU. AB - Withdrawal of life-sustaining therapy at the end of life is a complex phenomenon. Intensive care nurses and physicians are faced with caring for patients and supporting families, as these difficult decisions are made. The purpose of this study was to explore and describe the experience of critical care nurses and physicians participating in the process of withdrawal of life-sustaining therapy. A hermeneutic phenomenological approach was used to guide this qualitative investigation. Interviews were conducted with critical care nurses and physicians from 2 medical centers. An inductive approach to data analysis was used to understand similarities between the nurses and the physicians' experiences. Methodological rigor was established, and data saturation was achieved. The main categories that were inductively derived from the data analysis included from novice to expert, ensuring ethical care, uncertainty to certainty, facilitating the process, and preparing and supporting families. The categories aided in understanding the experiences of nurses and physicians, as they worked individually and together to see patients and families through the entire illness experience, withdrawal of life-sustaining therapy decision-making process and dying process. Understanding the perspectives of health-care providers involved in the withdrawal of life-sustaining therapy process will help other health-care providers who are striving to provide quality care to the dying and to their families. PMID- 30249116 TI - Encapsulated sour cherry pomace extract: Effect on the colour and rheology of cookie dough. AB - In this study, the effect of encapsulated sour cherry pomace extract on the physical characteristics of the cookie dough (colour, textural and rheological properties) was investigated. Sour cherry pomace extract encapsulated in whey (WE) and soy proteins (SE) was incorporated in cookie dough, replacing 10% (WE10 and SE10) and 15% (WE15 and SE15) of wheat flour. The dough samples containing encapsulates had the grey-blue colour ( b* values significantly decreased compared to control sample). Due to the presence of anthocyanins, a* values of the dough colour increased significantly with the addition of encapsulates. The addition of soy protein encapsulate increased hardness, resistance to extension and viscosity of cookie dough and decreased deformation compliance ( J), while the addition of whey encapsulate caused dough softness, higher deformation compliance and lower values of viscosity compared to control sample. Values of storage and loss modulus, G' and G", significantly decreased when wheat flour was replaced with WE and increased when the flour was replaced with soy protein encapsulate. The addition of soy protein encapsulate resulted in higher cookie hardness. PMID- 30249117 TI - Updated meta-analysis of prevention of cardiovascular mortality by regular physical activity. PMID- 30249118 TI - An Unusual Presentation of Cutaneous Leishmaniasis in 2 Canadian Patients: A Case Report. PMID- 30249119 TI - Perceptions of Rural African American Adults About the Role of Family in Understanding and Addressing Risk Factors for Cardiovascular Disease. AB - PURPOSE: African Americans (AAs) in rural south and southeast regions of the United States have among the highest prevalence of cardiovascular disease (CVD) in the country. The purpose of this qualitative, exploratory study is to understand family influences on CVD-related knowledge and health-related behaviors among rural AA adults. DESIGN: Qualitative descriptive study design using a community-based participatory research approach. SETTING: Two rural North Carolina counties. PARTICIPANTS: Eligible participants were AA adults (at least 21 years of age), who self-reported either CVD diagnosis or selected CVD risk factor(s) for themselves or for an adult family member (N = 37). METHOD: Directed content analysis of semistructured interviews by community and academic partners. RESULTS: Family health history and familial norms and preferences influenced participants' CVD-related knowledge, beliefs, and health-related behaviors. Participants reported their families were helpful for increasing motivation for and overcoming barriers to healthy behaviors, including hard-to-access community resources and physical challenges. Conversely, and to a lesser extent, participants also reported that family members hindered or had little influence (positive or negative) on their engagement in healthy behaviors. CONCLUSION: Family played an important role in helping individuals overcome personal and community-related challenges. Efforts to reduce CVD burden among rural AAs should seek to understand the family-related facilitators, barriers, and processes associated with CVD knowledge and risk-reduction behaviors. PMID- 30249120 TI - Regulatory Trends in Drug Development in Asia Pacific. AB - The Asia Pacific (AP) region is diverse and dynamic. It comprises over 40 economies, with about 24 markets that are relatively more active in terms of promulgating and implementing regulations that impact the biopharmaceutical industry and advance drug development. Although many country- and territory specific regulations, often driven by the local economy and market dynamics, exist, the overall trend in the AP region is toward international harmonization and global convergence. More markets are now participating in the International Council on Harmonization (ICH), and there is growing interest in identifying and incorporating best practices from competent regulatory agencies. These include expedited pathways to speed access to new medicines, and incentives and other means to encourage innovation. In this paper, we provide a summary of recent activities in select AP markets. PMID- 30249121 TI - Effects of Listening to Live Singing in Patients Undergoing Hemodialysis: A Randomized Controlled Crossover Study. AB - BACKGROUND: Participation in music therapy is associated with improved psychological and physical indices among chronically ill patients. Listening to music during hemodialysis treatments positively affects patients' hemodynamics, laboratory values, quality of life, and physical symptoms. The effect of live singing during hemodialysis treatments, however, has not previously been studied. METHODS: A total of 24 participants with a diagnosis of end-stage kidney disease participated in the study. The vocalist was a musically trained dialysis nurse. Twelve of the patients listened to 15 min of live singing during 6 consecutive hemodialysis sessions, while the other 12 underwent standard hemodialysis. After a washout period of 2 days, the two groups were reversed. RESULTS: Listening to live music was associated with improvements in systolic and diastolic blood pressure, better quality of sleep, fewer cramps, and reduced anxiety/depression, pain, and itching ( p < .05, all values). CONCLUSIONS: Listening to live music during hemodialysis is an effective and potentially low-cost therapy for the dialysis care team to employ during hemodialysis treatments. PMID- 30249123 TI - The Role of Mobile Phone Technology in Understanding and Preventing Suicidal Behavior. PMID- 30249124 TI - Plant synthetic biology could drive a revolution in biofuels and medicine. AB - Population growth, climate change, and dwindling finite resources are amongst the major challenges which are facing the planet. Requirements for food, materials, water, and energy will soon exceed capacity. Green biotechnology, fueled by recent plant synthetic biology breakthroughs, may offer solutions. This review summarizes current progress towards robust and predictable engineering of plants. I then discuss applications from the lab and field, with a focus on bioenergy, biomaterials, and medicine. Impact statement The plant synthetic biology field has exploded in the last five years, in part driven by techniques such as CRISPR and cheap DNA synthesis. This review summarizes the current state of research in plant synthetic biology, and how it is being applied to two topics: renewable fuels and chemicals, and medicine. PMID- 30249125 TI - Developing a clinical trial governance framework for pharmaceutical industry funded clinical trials. AB - Rising concerns relating to pharmaceutical sponsor bias in the conduct of clinical trials have compelled the need to develop a clinical trial governance framework. This article describes the development of the Conflict of Interest in Research (COIR), a clinical trial governance framework. The COIR, consisting of three process phases (initiation, concurrent, and ongoing), developed following a needs assessment, using a four-stage methodology, and evaluated against the International Conference on Harmonization--Good Clinical Practice (ICH-GCP) guidelines. The Conflict of Interest Resolution algorithm, the backbone of COIR, enables constant surveillance to detect/resolve conflicts at all stages of the clinical trial life-cycle. COIR promotes interaction between the regulatory system and the sponsors, independent of individuals. COIR enables rapid detection of scientific and financial conflicts, to prevent subject harm and, to assure optimal funds utilization, the latter feature helped to reduce a significant burden for the ethics committee, as it lacks financial expertise. COIR is a semi automated Oracle system, requires manpower, and is affected by human expertise and subjectivity. Complete automation to overcome this limitation will still need human expertise to scale changing trial regulations. Nevertheless, the COIR has won the distinction of the "most favored site" from pharmaceutical sponsors and is anticipated to be adopted by other clinical trial sites. PMID- 30249127 TI - JAPA Prizes for 2017. PMID- 30249126 TI - Protective Behavioral Strategies and Hazardous Drinking Among College Students: The Moderating Role of Psychological Distress. AB - There is increasing evidence that mental health problems may attenuate the relationship between protective behavioral strategies (PBS) and alcohol outcomes. However, psychological distress may also affect these relationships. Further, it appears that different types of PBS have differential relationships with alcohol outcomes. The current study examined the degree to which psychological distress moderated the associations PBS subtypes had with hazardous drinking and alcohol related negative consequences. Participants were 632 traditional-age undergraduate students ( M = 20.04, standard deviation = 1.48) who had consumed alcohol within the past 30 days and completed online self-report measures designed to assess PBS use, level of psychological distress, hazardous drinking patterns, and alcohol-related negative consequences. Serious harm reduction PBS were associated with less hazardous drinking and less alcohol-related negative consequences, and these associations were strengthened for those experiencing greater psychological distress. Controlled consumption PBS were associated with less hazardous drinking, but this association was not moderated by psychological distress. These findings highlight the potential benefit of teaching serious harm reduction PBS to college students experiencing elevated levels of psychological distress. PMID- 30249129 TI - Laplanche on Apres-Coup: Translation, Time, and Trauma Apres-coup . By Laplanche Jean . Translated by House Jonathan and Thurston Luke . New York : The Unconscious in Translation , 2017 , xviii + 253 pp., $55.00 hardcover, $39.50 paperback. PMID- 30249130 TI - Poster Summary from the 2018 Poster Session of the American Psychoanalytic Association: Will a Video-Based Psychoanalytic Outreach Effort Engage a Young Audience? The Freudalicious Mind Project. PMID- 30249131 TI - Playing in the Darkness: Use of the Object and Use of the Subject. AB - Play in the context of the patient's sense of absence, loss, and compromised capacities for symbolization can be a link between unsymbolized experience and greater capacities for representation. Winnicott's concepts of play evolved as one of the ways that analysts translate unconscious and unrepresented experience. For many patients who have experienced absence, the analyst and the analytic setting are subjected to the patient's unconscious efforts to destroy and negate meaning and relatedness. For the analyst to be "used" as an object to be destroyed and to survive destruction, he must become a subject in the mind of the patient and in his own mind as analyst within the intersubjective field. The analyst's work with his own resistance is vital to becoming a changing subject and an object available for play in the psychoanalytic process. PMID- 30249132 TI - Boundaries and Representation in The Mexico-Texas Borderland: Reflections on Geography, Culture, and Identity. PMID- 30249133 TI - Memory Slip: Stage Fright and Performing Musicians. AB - This paper discusses stage fright as seen primarily in classical music performers. A confluence of narcissistic sensitivities, developmental issues, shame dynamics, physical injury and pain, and terrors pertaining to both psychic and bodily disintegration can fuel anxiety reactions in many people but hold particular relevance for the performing musician. Two classical music performers who struggled with stage fright are discussed: one was in treatment with the author; the other is the author herself, reflecting on her own performance anxiety as revealed through her analysis and her countertransference to her patient. PMID- 30249134 TI - Spatial Translation and Regression in Dreams: The Nicholas Young Phenomenon. AB - The Nicholas Young phenomenon involves an immediate shift in dreams to more regressive mental functioning whenever, in the manifest ideational content, the dreamer or protagonist crosses a topographical boundary or threshold (spatial translation). This phenomenon thus furthers the regression typical in dreams. Eight examples of the Young phenomenon are presented. An attempt to explain this highly specialized phenomenon addresses dreams in series, or dream sections in series, and refers to Scherner's Law, which covers their sequential trend toward regression. Referring to the mind's self-observing capacity, Silberer's "symbolism of the threshold" is invoked to explain the spatial translation of the Young phenomenon. PMID- 30249135 TI - Assembling Justice: Reviving Nonhuman Subjectivities to Examine Institutional Betrayal Around Sexual Misconduct. AB - While some colleges have adopted bystander intervention and restorative justice practices to address sexual misconduct as a community issue, psychoanalytic institutes facing crises of sexual misconduct have typically relied on the tried and-true tactic of identifying the neoliberal individual as the sole site of trouble. Successful strategies used in colleges can be applied to the psychoanalytic setting by focusing on institutional betrayal. This systemic, community-based approach decenters not only individual bodies but human subjectivities. Here institutions become not just containers for group or networked affect, as if affect itself emanates from individuals into an institution. Agency and affect emerge through networks, not individual bodies, and institutions are active agents in violent betrayal. Acknowledging the ways the nonhuman and the human co-emerge creates the space to hold the vitalities and agencies of both, including multiple potentialities for (re)traumatization, resistance, and transformation. PMID- 30249136 TI - Emotional Regulation in Women with Chronic Fatigue Syndrome and Depression: Internal Representations and Adaptive Defenses. AB - Chronic fatigue syndrome (CFS) presents challenges in differential diagnosis and treatment. Complicating diagnosis is that its symptoms overlap with those of depression. This study applies psychoanalytic concepts to understand emotional regulation (ER) in women with CFS and/or depression. One hundred eighty-six women were assigned to four groups and compared: (a) CFS plus high er depression (CFS HD); (b) CFS plus lower depression (CFS-LD); (c) depressive disorder (DD); and (d) healthy controls (HC). ER was operationalized by measures of capacity to form internal representations and adaptive defenses. The study's premise was that difficulties metabolizing emotions psychologically would be associated with their greater somatic expression. Some support was found for the hypothesis that CFS participants would exhibit more impairment in representing emotions and in adaptive defenses compared to the DD and HC groups, but this held only for the CFS-HD group. Although CFS-LD participants were expected to be more purely somatizing than the CFS-HD group, they instead showed more sophisticated capacities for ER than that group and recalled less distressing early relationships, revealing more resilience. Still, however, we found support for somatization in some CFS sufferers: Within both the CFS-HD and the CFS-LD groups, weaknesses in representing emotions and in defensive functioning were associated with more severe physical symptoms. Clinically, the heterogeneity of CFS and those who suffer from it indicates the need for individual assessment and depression treatment. PMID- 30249137 TI - Serum caveolin-1 levels in patients with preeclampsia. AB - AIM: The expressions of caveolin-1 have only been examined in the placental tissue of patients with preeclampsia and were reported to be low. Therefore, we decided to investigate the maternal serum levels of caveolin-1 in patients with preeclampsia. MATERIAL AND METHODS: This cross-sectional study was conducted including 87 pregnant women; 32 with normal pregnancy and 55 with preeclampsia. Maternal serum levels of caveolin-1 were measured by using enzyme-linked immunosorbent assay kit (ELISA). RESULTS: The mean serum caveolin-1 level was significantly lower in women with preeclampsia (PE) compared with the control group (11.48 +/- 0.92 versus 12.94 +/- 1.36 ng/ml) and being lowest in the early onset PE group (11.24 +/- 0.74 ng/ml). Serum caveolin-1 concentrations did not correlate with maternal age and BMI. However, caveolin-1 concentrations were negatively correlated with systolic blood pressure (r = -0.467, p = .001) and diastolic blood pressure (r = -0.441, p = .001) as well as with umbilical artery resistance index (r = -0.275, p = .01). CONCLUSION: Maternal serum caveolin-1 levels are significantly lower in patients with PE than controls. The serum caveolin-1 levels inversely correlate with blood pressure and umbilical artery Doppler parameters. PMID- 30249138 TI - Association between maternal/newborn genetic variants, placental pathology and spontaneous preterm birth risk: a Romanian population-based study. AB - OBJECTIVE: The objective of this study was to determine the association between maternal/newborn single-nucleotide polymorphisms (SNPs) in three candidate genes, placental pathology and the risk of spontaneous preterm birth (SPTB) in a Romanian population. METHODS: We performed a prospective case-control study in a tertiary maternity in Romania, including 79 mother-newborn pairs with SPTB and 81 mother-newborn pairs with term delivery. Using real-time Polymerase Chain Reaction (PCR), three SNPs rs8192282 A > G, rs2277698 C > T and rs34003 A > C located on interleukin 6 receptor (IL6R), tissue inhibitor of matrix metalloproteinase-2 (TIMP2) and fibroblast growth factor 1 (FGF1) genes were assessed. The minor allele and genotype frequencies were compared between groups. Multilocus genetic association analyses were performed. From pathology reports, the morphological and histopathological examination of the placentas were extracted. RESULTS: The rs34003 C/C genotype frequency in newborns FGF1 gene was significantly higher in the spontaneous preterm birth (SPTB) group compared to the control group (p = .045). In single-locus analyses, C/C genotype was associated with an increased risk of spontaneous preterm birth (OR = 2.59, 95%CI: 1.02-6.58). Additionally, this homozygote genotype was correlated with the presence of placental pathology, especially with the inflammatory and vascular lesions (p < .01). The prediction model based on rs34003 C/C genotype - placental pathology joint influence had a statistically significant regression coefficient (p < .01, OR = 7.76, 95%CI: 4.03-14.93). Single nucleotide polymorphisms related to IL6R gene in maternal samples and FGF1 gene in newborns were associated with spontaneous preterm delivery in multilocus genetic association analyses (p = .028, OR of 2.375). CONCLUSIONS: Our results indicate that rs34003 C/C genotype in newborns FGF1gene is correlated with the occurrence of placental pathological lesions and with an increased SPTB risk. The association of two SNPs in maternal and fetal genes doubled the risk of spontaneous preterm birth in our population. PMID- 30249141 TI - A special issue of SFRR Asia: Cross talk between free radicals and mitochondria in health and disease. PMID- 30249140 TI - Questions healthcare boards should ask senior leaders about risk. AB - Drawing on strong ethical and evidence-based principles, Healthcare Insurance Reciprocal of Canada, in collaboration with healthcare leaders, has developed guiding questions to help boards of healthcare organizations carry out a critical governance function-the oversight of key organizational risks. The resulting list of 21 questions is the first of its kind for healthcare and focuses on the core mandate of healthcare organizations which is providing high-quality care. Recommended practices accompany each question. PMID- 30249142 TI - Assessing the impact of retraction on the citation of randomized controlled trial reports: an interrupted time-series analysis. AB - Objectives To assess the impact of retraction on the citation of randomized controlled trials. Methods We used an interrupted time-series with matched controls. PubMed, CINHAL, Google and the Retraction Watch Database were searched. We identified retracted publications reporting the results of randomized controlled trials involving human participants with two years of available data before and after retraction. We obtained monthly citation counts across all articles for the 24 months before and after retraction, from Web of Science. We used a Poisson segmented regression to detect changes in the level and trend of citation following retraction. We also undertook a matched control analysis of unretracted randomized controlled trials and a sensitivity analysis to account for cases of large-scale, well-advertised fraud. Results We identified 387 retracted randomized controlled trial reports, of which 218 (56.3%) were included in the interrupted time-series analysis. A reduction of 22.9% (95% CI 4.0% to 38.2%, p = 0.02) was observed in the number of citations in the month after retraction, and a further reduction of 1.9% (95% CI 0.4% to 3.5%, p = 0.02) per month in the following 24 months, relative to the expected trend. There was no evidence of a statistically significant reduction among the matched controls. Authors with a large number of retractions saw a 48.2% reduction at the time of retraction (95% CI 17.7% to 67.3%, p = 0.01). Other cases had a more gradual reduction with no change at the time of retraction and a 1.8% reduction per month in the following 24 months (95% CI 0.2% to 3.4%, p = 0.03). Conclusions Retractions of randomized controlled trial reports can be effective in reducing citations. Other factors, such as the scale of the retractions and media attention, may play a role in the effectiveness of the reduction. PMID- 30249143 TI - Fluorescent probes for G-protein-coupled receptor drug discovery. AB - INTRODUCTION: G-protein-coupled receptors (GPCRs) mediate the effects of approximately 33% of all marketed drugs. The development of tools to study GPCR pharmacology is urgently needed as it can lead to the discovery of safer and more effective medications. Fluorescent GPCR ligands represent highly sensitive and safe small-molecule tools for real-time exploration of the life of the receptor, cellular signaling, and ligand-/receptor-receptor interactions in cellulo and/or in vivo. Areas covered: This review summarizes relevant information from published literature and provides critical insights into the design of successful small-molecule fluorescent probes for Class A GPCRs as potential major targets for drug development. Expert opinion: Considering the rapid progress of fluorescence technologies, effective small-molecule fluorescent probes represent valuable pharmacological tools for studying GPCRs. However, the design and development of such probes are challenging, largely due to the low affinity/specificity of the probe for its target, inadequate photophysical properties, extensive non-specific binding, and/or low signal-to-noise ratio. Generally speaking, fluorescent and luminescent small-molecule probes, receptors, and G proteins in combination with FRET and BRET technologies hold great promise for studying kinetic profiles of GPCR signaling. PMID- 30249139 TI - Novel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group acting as human carbonic anhydrase IX inhibitors. AB - A small collection of 26 structurally novel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group, were synthesised and tested in enzyme inhibition assays against the tumour-associated hCA IX enzyme. Inhibition constants in the lower micromolar region (KI < 25 MUM) have been measured for 17 of the 26 compounds. Even though the KI values are relatively weak, the fact that they do not contain a sulphonamide moiety suggests that these compounds do not interact with the active site zinc ion. Therefore, docking studies and molecular dynamics simulations have been performed to suggest binding poses for these structurally novel inhibitors. PMID- 30249145 TI - The comparative performance of the Canadian and Australian health systems. AB - Using three data sets, each providing an overview of health service delivery in high-income countries, this article provides a high-level comparative analysis of health system performance against specified key performance indicators in two jurisdictions: Canada and Australia. Several variations, nuances, and points of comparison between delivery and organization of care are discussed. The article examines three policy and structural differences that may help explain the comparatively superior performance of the Australian system on most indicators, and two key areas of improvement for the Canadian system were illuminated: a stronger central government role and a national pharmaceutical plan. It is hoped that this article will empower health leaders to take action in these areas. PMID- 30249144 TI - The severity of lung injury and metabolic disorders induced by ambient PM2.5 exposure is associated with cumulative dose. AB - Lots of epidemiological and experimental studies have found that ambient fine particulate matter (PM2.5) exposure is associated with the development of cardiopulmonary diseases, obesity and diabetes. This study focused on the effects of cumulative PM2.5 exposure on pulmonary and systemic inflammation and insulin resistance. Thirty-two 6-week-old male Balb/c mice were randomly divided into four groups (FA, PM, WEEK and DAY groups) and were continuously or intermittently exposed to concentrated PM2.5 or filtered air (FA) for four weeks using Shanghai Meteorological and Environmental Animal Exposure System ("Shanghai-METAS"). The levels of IL-6 and TNF-alpha in serum, bronchoalveolar lavage fluid (BALF), lung tissues and white adipose tissue (WAT) were measured. Meanwhile, the expression of NF-kappaB and phosphor-NF-kappaB in lung tissue was detected by Western blot. Glucose tolerance and insulin resistance were also determined at the end of exposure. The results found that the mice in PM group displayed moderate inflammatory cell infiltration in lung, whereas the mice in WEEK and DAY groups displayed slight inflammatory cell infiltration in lung. Compared with the mice in FA group, the mRNA expressions of IL-6 and TNF-alpha in lung tissue and WAT significantly increased in the mice of PM group. Importantly, IL-6 and TNF-alpha mRNA expressions in PM group were higher than those in WEEK and DAY groups. The protein expression of phospho-NF-kappaB in lung tissue showed that PM group showed the activation of NF-kappaB, which was higher than that in the WEEK and DAY groups. Meanwhile, the mice in PM group showed more severe glucose tolerance and insulin resistance than that in the WEEK and DAY groups. The results suggested that the reduction of PM2.5 cumulative exposure may alleviate pulmonary and adipose inflammation, insulin resistance and glucose tolerance impairment. The results provided a clue that the interruption of ambient PM2.5 exposures by systems such as indoor air purification could be of benefit to people's health. PMID- 30249146 TI - Syntactic Cues Take Precedence Over Distributional Cues in Native and Non-Native Speech Segmentation. AB - This study investigates whether syntactic cues take precedence over distributional cues in native and non-native speech segmentation by examining native and non-native speech segmentation in potential French-liaison contexts. Native French listeners and English-speaking second-language learners of French completed a visual-world eye-tracking experiment. Half the stimuli contained the pivotal consonant /t/, a frequent word onset but infrequent liaison consonant, and half contained /z/, a frequent liaison consonant but rare word onset. In the adjective-noun condition (permitting liaison), participants heard a consonant initial target (e.g., le petit tatoue; le fameux zele) that was temporarily ambiguous at the segmental level with a vowel-initial competitor (e.g., le petit [t]athee; le fameux [z]elu); in the noun-adjective condition (not permitting liaison), they heard a consonant-initial target (e.g., le client tatoue; le Francais zele) that was not temporarily ambiguous with a vowel-initial competitor (e.g., le client [*t]athee; le Francais [*z]elu). Growth-curve analyses revealed that syntactic context modulated both groups' fixations (noun-adjective > adjective-noun), and pivotal consonant modulated both groups' fixations (/t/ > /z/) only in the adjective-noun condition, with the effect of the consonant decreasing in more proficient French learners. These results suggest that syntactic cues override distributional cues in the segmentation of French words in potential liaison contexts. PMID- 30249147 TI - Uterocervical angle: an ultrasound screening tool to predict satisfactory response to labor induction. AB - BACKGROUND: A wide uterocervical angle >95 degrees detected during the second trimester was associated with an increased risk for spontaneous preterm birth. OBJECTIVE: We aimed to determine whether an ultrasonographic marker, uterocervical angle, correlates with satisfactory response to labor induction. STUDY DESIGN: We conducted a prospective cohort study from May 2016 through December 2017 of singleton term gestations undergoing transvaginal ultrasound for cervical length screening and uterocervical angle measurement. Uterocervical angle was measured between the lower uterine segment and the cervical canal. Latent phase duration >720 min was accepted to be a prolonged latent phase. The primary outcome was a prediction of satisfactory response to labor induction (latent phase duration <720 min). RESULTS: Both anterior uterocervical angle (AUC = 0.802, p < .001) and the cervical length (AUC = 0.679, p < .05) significantly predicted satisfactory response to labor induction. Optimal cutoff value was obtained at the value of 97 degrees (64% sensitivity, 91% specificity) for anterior uterocervical angle and 27 mm (64% sensitivity, 64% specificity) for the cervical length. Kaplan-Meier survival analysis showed that duration from labor induction to delivery was significantly higher in a group with longer cervical length (p = .04), additionally labor induction to delivery time was significantly higher in a group with lower UCA (p = .04). CONCLUSIONS: Both the cervical length and anterior uterocervical length were predictors for the satisfactory response to labor induction, and both parameters were found to be significantly associated with time from induction to delivery in survival analysis. PMID- 30249148 TI - Toward a Common Understanding of Diet-Exercise Strategies to Manipulate Fuel Availability for Training and Competition Preparation in Endurance Sport. AB - From the breakthrough studies of dietary carbohydrate and exercise capacity in the 1960s through to the more recent studies of cellular signaling and the adaptive response to exercise in muscle, it has become apparent that manipulations of dietary fat and carbohydrate within training phases, or in the immediate preparation for competition, can profoundly alter the availability and utilization of these major fuels and, subsequently, the performance of endurance sport (events >30 min up to ~24 hr). A variety of terms have emerged to describe new or nuanced versions of such exercise-diet strategies (e.g., train low, train high, low-carbohydrate high-fat diet, periodized carbohydrate diet). However, the nonuniform meanings of these terms have caused confusion and miscommunication, both in the popular press and among the scientific community. Sports scientists will continue to hold different views on optimal protocols of fuel support for training and competition in different endurance events. However, to promote collaboration and shared discussions, a commonly accepted and consistent terminology will help to strengthen hypotheses and experimental/experiential data around various strategies. We propose a series of definitions and explanations as a starting point for a more unified dialogue around acute and chronic manipulations of fat and carbohydrate in the athlete's diet, noting philosophies of approaches rather than a single/definitive macronutrient prescription. We also summarize some of the key questions that need to be tackled to help produce greater insight into this exciting area of sports nutrition research and practice. PMID- 30249149 TI - Response of mouse bone marrow mesenchymal stem cells to graphene-containing grid like bioactive glass scaffolds produced by robocasting. AB - In the study, three-dimensional, grid-like silicate-based bioactive glass scaffolds were manufactured using a robotic deposition technique. Inks were prepared by mixing 13-93 bioactive glass particles in Pluronic(r) F-127 solution. After deposition, scaffolds were dried at room temperature and sintered at 690 degrees C for 1 h. The surface of the sintered scaffolds was coated with graphene nanopowder (1, 3, 5, 10 wt%) containing poly(epsilon-caprolactone) solution. The in vitro mineralization ability of the prepared composite scaffolds was investigated in simulated body fluid. The surface of the simulated body fluid treated scaffolds was analyzed using scanning electron microscopy to investigate the hydroxyapatite formation. Mechanical properties were tested under compression. Results revealed that graphene coating has no detrimental effect on the hydroxyapatite forming ability of the prepared glass scaffolds. On the other hand, it decreased the compression strength of the scaffolds at high graphene concentrations. The prepared grid-like bioactive glass-based composite scaffolds did not show toxic response to bone marrow mesenchymal stem cells. It was shown that stem cells seeded onto the scaffolds attached and proliferated well on the surface. Cells seeded on the scaffolds surface also demonstrated osteogenic differentiation under in vitro conditions in the absence of transforming growth factors. PMID- 30249150 TI - The Effects of Medicare Accountable Organizations on Inpatient Mortality Rates. AB - Studies have linked Accountable Care Organizations (ACOs) to improved primary care, but there is little research on how ACOs affect care in other settings. We examined whether Medicare ACOs have improved hospital quality of care, specifically focusing on preventable inpatient mortality. We used 2008-2014 Healthcare Cost and Utilization Project hospital discharge data from 34 states' Medicare ACO and non-ACO hospitals in conjunction with data from the American Hospital Association Annual Survey and the Survey of Care Systems and Payment. We estimated discharge-level logistic regression models that measured the relationship between ACO affiliation and mortality following admissions for acute myocardial infarction, abdominal aortic aneurysm (AAA) repair, coronary artery bypass grafting, and pneumonia, controlling for patient demographic mix, hospital, and year. Our results suggest that, on average, Medicare ACO hospitals are not associated with improved mortality rates for the studied IQI conditions. Stakeholders may potentially consider providing ACOs with incentives or designing new programs for ACOs to target inpatient mortality reductions. PMID- 30249151 TI - Investigating the association between post-term birth and long term cognitive, developmental and educational impacts: a systematic review and Meta-analysis. AB - PURPOSE: Infants who remain in-utero after their due date are exposed to increasing risk of infection, late stillbirth and delivery complications. Much of the current literature on post-term outcomes is based on short term observations and the impacts may be substantially greater in the long term. The aim of this work is to perform a systematic review and meta-analysis to quantify the cognitive or educational impacts of post term delivery. METHODS: Systematic review was performed by the two authors using Medline database (1960-2017). A title search was performed to identify likely relevant literature. Exposure terms were clarified to identify papers where the exposure was related to delivery after the infants' due date. Primary outcome was cognitive score. A quality assessment and data extraction pro forma was completed by both reviewers for all studies deemed to satisfy the inclusion and exclusion criteria. Meta-analysis used adjusted results where available. Small-study bias was assessed visually using a funnel plot and then formally tested using Egger's regression asymmetry test. RESULTS: Medline was searched on the 4 July 2018; and produced a list of 1318 publications. Of these, 43 abstracts were screened, and of these a total of 10 full-text papers were reviewed. A further three papers were identified during this review and contributed to a total of 13 papers. The publications dated from 1969 to 2017. Two studies presented a binary outcome for cognitive measures and combined estimates found that the risk of a low cognitive score was higher in post-term infants compared to term infants (odds ratio [OR] 1.06 [1.04-1.08]). Four papers presented the association with mean cognitive measures and post-term delivery, and all demonstrated a mean reduction in scores in the post-term group. A combined estimate showed strong evidence of a reduction in cognitive scores across the four studies (-1.90 [-3.50 to -0.31]). There was little evidence of heterogeneity in the studies which reported cognitive outcomes (other p-values >.2). CONCLUSION: This meta-analysis has found that post term birth (>41 + 6 weeks) is associated with small but significant negative effects on cognitive outcomes when compared with delivery at, or around term. The effect, while small, is compounded by a common exposure and appears consistent in the studies identified. Less evidence was found for a measurable impact on early developmental measures or educational outcomes. This may further help inform the debate on the timing of otherwise uncomplicated pregnancies and further trials in this area. PMID- 30249152 TI - Bacillus subtilis exhibits MnmC-like tRNA modification activities. AB - The MnmE-MnmG complex of Escherichia coli uses either ammonium or glycine as a substrate to incorporate the 5-aminomethyl or 5-carboxymethylaminomethyl group into the wobble uridine of certain tRNAs. Both modifications can be converted into a 5-methylaminomethyl group by the independent oxidoreductase and methyltransferase activities of MnmC, which respectively reside in the MnmC(o) and MnmC(m) domains of this bifunctional enzyme. MnmE and MnmG, but not MnmC, are evolutionarily conserved. Bacillus subtilis lacks genes encoding MnmC(o) and/or MnmC(m) homologs. The glycine pathway has been considered predominant in this typical gram-positive species because only the 5-carboxymethylaminomethyl group has been detected in tRNALysUUU and bulk tRNA to date. Here, we show that the 5 methylaminomethyl modification is prevalent in B. subtilis tRNAGlnUUG and tRNAGluUUC. Our data indicate that B. subtilis has evolved MnmC(o)- and MnmC(m) like activities that reside in non MnmC homologous protein(s), which suggests that both activities provide some sort of biological advantage. PMID- 30249153 TI - Artificial Intelligence-Driven Designer Drug Combinations: From Drug Development to Personalized Medicine. AB - Artificial intelligence holds great promise in transforming how drugs are designed and patients are treated. In a study recently published in Science Translational Medicine, a unique artificial intelligence platform makes efficient use of small experimental datasets to design new drug combinations as well as identify the best drug combinations for specific patient samples. This quadratic phenotypic optimization platform (QPOP) does not rely on previous assumptions of molecular mechanisms of disease, but rather uses system-specific experimental data to determine the best drug combinations for a specific disease model or a patient sample. In this commentary, we explore how QPOP was applied toward multiple myeloma in the study. We also discuss how this study demonstrates the potential for applications of QPOP toward improving therapeutic regimen design and personalized medicine. PMID- 30249154 TI - Financial impact from in-office dispensing of oral chemotherapy. AB - Background Oral chemotherapy agents are being prescribed more frequently in many cancer types. In-office dispensing of oral chemotherapy agents has demonstrated clinical benefits and also shown financial benefit to third-party payers. A previous publication estimated over $200,000 in cost savings annually from in office dispensing solely from medications returned to stock for credit. However, pharmacists in the in-office setting perform many other interventions that may affect financial outcomes. Objective Assess financial impact of oral chemotherapy in-office dispensing by a clinic-based oral chemotherapy program serving five outpatient cancer centers in Southern Idaho. Outcomes include calculated monetary waste and cost avoidance of oral chemotherapy prescriptions from in-office dispensing and mail-order pharmacies. Methods Prescriptions received by the clinic-based oral chemotherapy program for filling through in-office dispensing and mail-order pharmacies were monitored for monetary waste and cost avoidance events from December 2016 through May 2017. Information was collected on the number of returned medications, therapy discontinuations, and dose adjustments. Monetary outcomes were calculated using average wholesale price. Results During the six-month evaluation, prescriptions filled through in-office dispensing had a total cost avoidance of $1,020,193 ( n = 154) and total waste of $154,985 ( n = 36) resulting in an estimated net cost avoidance annually of $1,730,416. Prescriptions filled through mail-order had a total cost avoidance of $20,497 ( n = 4) and a total waste of $80,394 ( n = 15) resulting in an estimated $119,794 net annual waste. Conclusions In-office dispensing of oral chemotherapy provided significant cost savings to third-party payers compared to mail-order pharmacy dispensing. Continued evaluation may help further justify the importance and value of in-office dispensing. PMID- 30249155 TI - Polymyalgia rheumatica due to pembrolizumab therapy. AB - Pembrolizumab is a humanized anti-programmed cell death 1 antibody used for the therapy of several malignancies. While autoimmune adverse events are not uncommon with this agent, they are typically mild and self-limiting. Severe autoimmunity is rare but can be life-threatening. Herein, we describe a unique case of severe proximal muscle weakness and joint pain shortly after beginning therapy with pembrolizumab. Work-up revealed elevated pro-inflammatory markers leading to the diagnosis of polymyalgia rheumatica. Steroids allowed for resolution of the joint pain. We call for awareness of this rare autoimmune toxicity with pembrolizumab. PMID- 30249156 TI - An Exploratory Correlational Study in the Use of Mobile Technology Among Adult Kidney Transplant Recipients. AB - INTRODUCTION:: Rapidly growing use of mobile technology provides a platform for self-management of care support for those with chronic conditions. Few studies have explored the characteristics or access patterns of kidney transplant recipients who use mHealth applications (apps) for self-management of care. RESEARCH QUESTIONS:: The primary aim of this study was to describe demographics, use, barriers, and perceptions of mobile apps for self-management of care among adult kidney transplants recipients. The secondary aim was to compare blood urea nitrogen, glomerular filtration rate, and number of hospitalizations among mHealth app users, other app users, and non-app users. METHODS:: A cross sectional design was used to administer the Mobile Application Use among Kidney Transplant Recipients Questionnaire. Descriptive statistics, chi2 statistics, and analysis of variance were used for the primary aim and linear regression was used for the secondary aim. RESULTS:: The sample included mostly African American males (n = 123, 75.5%) with a mean age of 50 (13.2) years. Knowledge was the greatest barrier reported by the non-app users (mHealth app users 9%, other app users 12%, non-app users, 49%, P < .001). Significantly fewer hospitalizations were found in the mHealth app users compared to other app users (regression coefficient b = -1.2, standard error [SE] = 0.5) and non-app users ( b = -0.9, SE = 0.6), adjusting for patient demographic and clinical characteristics. DISCUSSION:: Findings suggest a relationship may exist between mHealth app use and a decrease in the number of hospitalizations following kidney transplantation. PMID- 30249157 TI - Reliability of the current newborn screening action value for beta thalassaemia disease detection in England: A prospective study. AB - Objective Beta thalassaemias are a group of hereditary red cell disorders resulting in a reduced or absent production of the main adult haemoglobin, adult haemoglobin. In England, the NHS Sickle Cell & Thalassaemia Screening Programme recommends reporting newborn beta thalassaemia disease as an incidental finding when detected whilst screening for sickle cell disease. The current action value to initiate further investigations is 1.5% adult haemoglobin, using high performance liquid chromatography or capillary electrophoresis. We examined the reliability of this action value. Methods A 44-month country-wide prospective study using data from 13 newborn screening laboratories in England. Results There were 81 cases reported with an adult haemoglobin of 1.5% or less at first-line screen, of which nine were lost to follow-up. The six false-positive results were all of 32 weeks' gestation or less. Of the 66 true-positives, 36 had confirmatory molecular results (11 of these cases also have results from tandem mass spectrometry), 19 had clinical confirmation and 11 had the results of both parents available which were consistent with the screening result. There was one false-negative, a confirmed beta thalassaemia major case with an adult haemoglobin of 1.7%, above the action value at first-line screen but known to be at risk from parental results and therefore referred into clinical care by the laboratory. Conclusions This study demonstrates a positive predictive value of 91.7%, with a specificity of 99.9% and a sensitivity of 98.5%. These results confirm the reliability of the current action value. PMID- 30249158 TI - Cancer worries and uptake of breast, cervical, and colorectal cancer screening: A population-based survey in England. AB - Objective Some degree of general worry about cancer may facilitate screening participation, but specific worries about the potential consequences (e.g. treatment, death) may act as deterrents. No studies have examined these associations in the same sample. We assessed associations between general versus specific cancer worries and cancer screening participation. Methods In 2016, a population-based cross-sectional survey of adults living in England was carried out. This paper reports analyses of a subsample (n = 1694). Measures included (i) frequency of general cancer worry, (ii) specific worries about the emotional and physical consequences of a cancer diagnosis, and (iii) specific worries about the social consequences of a cancer diagnosis. Logistic regression analyses examined their association with self-reported screening uptake among participants eligible for cervical (n = 671), breast (n = 323), and colorectal (n = 368) cancer screening. Results Frequency of general cancer worry was not associated with screening participation. Specific worry about the emotional and physical consequences increased the odds of participants reporting regular uptake of colorectal screening (OR 1.41, 95% CI 1.04-1.90). Specific worry about the social consequences of diagnosis was negatively associated with regular attendance for cervical and breast screening in unadjusted analyses only. In adjusted models, the associations were no longer statistically significant for cervical (OR 0.82, 95% CI 0.65-1.03) or breast (OR 0.69, 95% CI 0.45-1.04) screening. Conclusions Specific worries about cancer may be differentially associated with participation across screening programmes. Further research is needed, as interventions to optimise informed participation may be improved if the specific worries associated with low participation in each programme are understood. PMID- 30249159 TI - Current Knowledge on Skin Cancer Prevention in Liver Transplant Recipients. AB - The improved survival of liver transplant recipients (LTRs) has been accompanied by a concomitant rise in long-term liver transplantation complications, including skin cancer. A recent study found that the prevalence of skin cancer among LTRs is 13.5%, a rate equivalent to that observed among kidney transplant recipients. Given the morbidity associated with skin cancer in LTRs, an individualized, multidisciplinary approach to skin cancer prevention that incorporates patient education, encourages consistent use of primary prevention methods, and ensures routine dermatologic screening should be universally adopted in this population. Chemopreventative measures should be considered in LTRs with a high skin cancer burden. Furthermore, additional studies should be performed in order to systematize these recommendations. PMID- 30249160 TI - Personal Prejudice, Other Guilt: Explicit Prejudice Toward Black People Predicts Guilty Verdicts for White Officers Who Kill Black Men. AB - Across the United States, acquittals of White police officers who have killed Black men have spurred clashes between those who see such situations as manifestations of racism and those who see them as race-irrelevant acts of officer self-defense. In this research, we explore the relationship between participants' racial prejudice and construal of an event that leads to the death of a Black man. In Study 1, we found that participants' racial prejudice predicts lower perceived guilt for a White officer who killed a Black man. In Study 2, we found evidence that the relationship between racial prejudice and guilt judgments is driven by increased perceptions that the officer was in danger and decreased perceived relevance of officer prejudice. Finally, Study 3 demonstrated that these patterns hold when the victim is Black, but not White. We conclude that racial prejudice shapes perceptions of legal responsibility for lethal interactions with Black men. PMID- 30249161 TI - A Systematic Review of Reviews of the Outcome of Noninstitutional Child Maltreatment. AB - The aim of the systematic review described in this article was to synthesize available high-quality evidence on the outcomes of noninstitutional child maltreatment across the life span. A systematic review of previous systematic reviews and meta-analyses was conducted. Ten databases were searched. One hundred eleven papers which met stringent inclusion and exclusion criteria were selected for review. Papers were included if they reported systematic reviews and meta analyses of longitudinal or cross-sectional controlled studies, or single-group cohort primary studies of the outcomes of child maltreatment in the domains of physical and mental health and psychosocial adjustment of individuals who were children lived mainly with their families. Using AMSTAR criteria, selected systematic reviews and meta-analyses were found to be of moderate or high quality. Searches, study selection, data extraction, and study quality assessments were independently conducted by two researchers, with a high degree of interrater reliability. The 111 systematic reviews and meta-analyses reviewed in this article covered 2,534 independent primary studies involving 30,375,962 participants, of whom more than 518,022 had been maltreated. The magnitude and quality of this evidence base allow considerable confidence to be placed in obtained results. Significant associations were found between a history of child maltreatment and adjustment in the domains of physical health, mental health, and psychosocial adjustment in a very wide range of areas. The many adverse outcomes associated with child maltreatment documented in this review highlight the importance of implementing evidence-based child protection policies and practices to prevent maltreatment and treat child abuse survivors. PMID- 30249162 TI - Investigation of the biogas production potential from algal wastes. AB - In recent years, researchers focused their attention on biogas production more than ever to meet the energy demand. Especially, biogas obtained from algal wastes has become a trending research area owing to the high content of volatile solids in algae. The main purpose of this study is to determine the biogas production potential from algal wastes and examine the effect of temperature and particle size parameters on biogas yield. A comparison was made between the biogas production potential of microalgal wastes, obtained after oil extraction, and macroalgal wastes collected from coastal areas. It was found that algal biogas yield is directly proportional to temperature and inversely proportional to particle size. Optimal conditions for biogas production from algal wastes were determined as the temperature of 55 degrees C, a particle size of 200 MUm, a residence time of 30 days and an alga-inoculum ratio of 1:4 (w:w). Highest biogas yield obtained under these conditions was found as 342.59 cm3 CH4 g-1 VS with Ulva lactuca. Under thermophilic conditions, both micro- and macroalgal biogas yields were comparable. It can be concluded that algal biomass is a good source for biogas production, although further research is needed to increase biogas yield and quality. PMID- 30249163 TI - Recycle of resin-based analogue material for geo-mechanical model test. AB - Analogue materials are widely used to simulate prototype rocks in geo-mechanical model tests. The large amounts of solid waste generated by a large-scale model test has always posed problems for studies. The re-use of analogue materials can significantly reduce the cost of geo-mechanical model tests and the resulting environmental problems. However, despite the environmental and economic benefits, there have been few reports on the re-use of analogue materials. In this work, a recycling method for a resin-based analogue material is studied experimentally. More than 300 samples were prepared and tested. By adding a certain amount of resin in solution form to the recycled material, regenerated samples with properties consistent with those of the samples prior to recycling were obtained. Based on a comparative analysis of the test data, an equation is proposed for the calculation of the appropriate amount of resin addition in the recycling process. Thus, a simple and effective recycling method is established for a resin-based analogue material. Verification was performed by independent tests on three group samples with different proportions, and the possibility of repeated recycling was also confirmed. The proposed recycling method makes the cyclic utilization of resin-based analogue material possible and is helpful for reducing the cost and pollution of geo-mechanical model tests. PMID- 30249164 TI - Precarious Manhood and Its Effects on Aggression: The Role of Cultural Script. AB - The present study tests the precariousness of manhood and the impact of precarious manhood on aggression. In total, 50 undergraduates (25 girls, 25 boys) participated in this experiment. It was found that the male participants used more verbs in the "A man should__" sentence string than in the "One woman should__" sentence string, and similar language patterns were found even after controlling for gender stereotypes. Individuals were found to more often attribute the individual behavior caused by cultural scripts to external situational factors; that is, if individuals agreed that another male's aggression was due to threatened manhood, this behavior was seen to be because of the male cultural script and was due to external circumstances. To test this view, a total of 56 college students participated in this experiment. In total, 25 college students (11 males, 14 females) took part in the attribution evaluation of two male fighters, and 31 college students (15 males, 16 females) participated in the attribution evaluation of two female fighters. It was found that the male participants believed that other male physical aggression that threatened their manhood was induced by situational factors rather than the internal characteristics of the attacker. The differences between the female participants were not significant, indicating that it was part of the male cultural script for men (rather than women) to defend or restore precarious manhood through aggression. PMID- 30249165 TI - Utilisation of poultry industry wastes for liquid biofuel production via thermal and catalytic fast pyrolysis. AB - The objective of this study was to examine the potential of poultry wastes to be used as feedstock in non-catalytic and catalytic fast pyrolysis processes, which is a continuation of our previous research on their conversion into biofuel via slow pyrolysis and hydrothermal conversion. Both poultry meal and poultry litter were examined, initially in a fixed bed bench-scale reactor using ZSM-5 and MgO as catalysts. Pyrolysis of poultry meal yielded high amounts of bio-oil, while pyrolysis of poultry litter yielded high amounts of solid residue owing to its high ash content. MgO was found to be more effective for the deoxygenation of bio oil and reduction of undesirable compounds, by converting mainly the acids in the pyrolysis vapours of poultry meal into aliphatic hydrocarbons. ZSM-5 favoured the formation of both aromatic compounds and undesirable nitrogenous compounds. Overall, all bio-oil samples from the pyrolysis of poultry wastes contained relatively high amounts of nitrogen compared with bio-oils from lignocellulosic biomass, ca. 9 wt.% in the case of poultry meal and ca. 5-8 wt.% in the case of poultry litter. This was attributed to the high nitrogen content of the poultry wastes, unlike that of lignocellulosic biomass. Poultry meal yielded the highest amount of bio-oil and was selected as optimum feedstock to be scaled-up in a semi pilot scale fluidised bed biomass pyrolysis unit with the ZSM-5 catalyst. Pyrolysis in the fluidised bed reactor was more efficient for deoxygenation of the bio-oil vapours, as evidenced from the lower oxygen content of the bio-oil. PMID- 30249166 TI - European Survey Study Among Plastic/Breast Surgeons on the Use of and Opinion Toward Autologous Fat Transfer: With Emphasis on Breast Surgery. AB - OBJECTIVE: The aim of this study is to examine the experience of European surgeons on autologous fat transfer (AFT) and highlight differences between countries and levels of experience. BACKGROUND DATA: The popularity of AFT causes an increase in sophisticated scientific research and clinical implementation. While results from the former are well-documented, important aspects of the latter are far less recognized. METHODS: An international survey study about surgeon background, besides AFT familiarity, technique, and opinion, was distributed among surgeons from 10 European countries. The differences between countries and levels of experience were analyzed using a logistic regression model. RESULTS: The mean respondent age, out of the 358 completed questionnaires, was 46 years. Ninety-seven percent of the respondents were plastic surgeons, who practiced AFT mostly in breast surgery and considered themselves experienced with the technique. The thigh and abdomen were less favored harvest locations by the Belgium and French respondents, respectively, and both the French and Austrian respondents preferred manual aspiration over liposuction in harvesting the fat. Despite minor differences between countries and experience, the intraglandular space was injected in all subgroups. CONCLUSIONS: The expanding use of AFT in Europe will lead to more experience and heterogeneity regarding the technique. However, despite an obvious adherence to Coleman's method, deviations thereof become more apparent. An important example of such a deviation is the ongoing practice of intraglandular AFT despite being a contraindication in various European guidelines. These unsafe practices should be avoided until scientific clarification regarding oncological safety is obtained and should therefore be the focus of surgeon education in Europe. PMID- 30249167 TI - The Dual-Mode Imaging of Nanogold-Labeled Cells by Photoacoustic Microscopy and Fluorescence Optical Microscopy. AB - Photoacoustic microscopy is dominantly sensitive to the endogenous optical absorption, while a fluorescence optical microscopy can detect the fluorescence emission to obtain the image of a sample. To some extent, the physical processes of the 2 methods are opposite, one is absorption and another is emission, but both can be used to image cells. In this article, a simultaneous dual-mode imaging system of photoacoustic microscopy and fluorescence optical microscopy is set up to image tobacco cells. Furthermore, gold nanoparticles, which have a large absorption coefficient and enough fluorescence emission with wavelength of 512 nm, are used to label certain drugs and added to the tobacco cells. Then based on the simultaneous dual-mode microscopy imaging system, the photoacoustic microscopy and fluorescence optical microscopy images of gold nanoparticle labeled tobacco cells are obtained. The final purpose of this experimental research is to detect if the labeled drugs can enter the cells by the positions of the gold nanoparticles. This will help the experts to deliver organic pesticide more accurately and effectively. The experimental results show that by gold nanoparticle labeling technology, the imaging quality of photoacoustic microscopy and fluorescence optical microscopy can be improved, which indicates that the drugs probably enter the tobacco cells successfully. PMID- 30249169 TI - Nintedanib in the management of idiopathic pulmonary fibrosis: clinical trial evidence and real-world experience. AB - Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease associated with significant morbidity and mortality. Previously, IPF has been managed using immunosuppressive therapy; however, it has been shown that this is associated with increased mortality. In the last 5 years, two disease-modifying agents have been licensed for use in IPF, namely pirfenidone and nintedanib. Nintedanib is a tyrosine kinase inhibitor with antifibrotic properties that has also been shown to significantly reduce the progression of the disease. The scientific evidence shows that nintedanib is effective and well tolerated for the treatment of IPF in mild, moderate and severe stages of the disease. Real-world experiences also support the findings of previously conducted clinical trials and show that nintedanib is effective for the management of IPF and is associated with reducing disease progression. Gastrointestinal events, mainly diarrhoea, are the main adverse events caused by the treatment. Recent real-word studies also suggest that nintedanib stabilizes lung function till lung transplantation, with no increased surgical complications or postoperative mortality after lung transplantation. In this review, we will discuss the clinical trial evidence and real-world experience for nintedanib in the management of IPF. PMID- 30249170 TI - Nivolumab for the treatment of Japanese patients with advanced metastatic non small cell lung cancer: a review of clinical trial evidence for efficacy and safety. AB - Programmed cell death (PD)-1 immune checkpoint inhibitors have emerged as promising options for the treatment of multiple cancer types. Nivolumab is a fully human immunoglobulin G4 monoclonal antibody, which inhibits the PD-1 receptor and has been approved in the United States, Europe, and Asia for the treatment of advanced NSCLC. This review focuses on nivolumab's efficacy and safety in the treatment of NSCLC patients in Japan. PMID- 30249168 TI - An Integrative Model Accounting for the Symptom Cluster Triggered After an Acoustic Shock. AB - Acoustic shocks and traumas sometimes result in a cluster of debilitating symptoms, including tinnitus, hyperacusis, ear fullness and tension, dizziness, and pain in and outside the ear. The mechanisms underlying this large variety of symptoms remain elusive. In this article, we elaborate on the hypothesis that the tensor tympani muscle (TTM), the trigeminal nerve (TGN), and the trigeminal cervical complex (TCC) play a central role in generating these symptoms. We argue that TTM overuse (due to the acoustic shock), TTM overload (due to muscle tension), and ultimately, TTM injury (due to hypoxia and "energy crisis") lead to inflammation, thereby activating the TGN, TCC, and cortex. The TCC is a crossroad structure integrating sensory inputs coming from the head-neck complex (including the middle ear) and projecting back to it. The multimodal integration of the TCC may then account for referred pain outside the ear when the middle ear is inflamed and activates the TGN. We believe that our model proposes a synthetic and explanatory framework to explain the phenomena occurring postacoustic shock and potentially also after other nonauditory causes. Indeed, due to the bidirectional properties of the TCC, musculoskeletal disorders in the region of the head-neck complex, including neck injury due to whiplash or temporomandibular disorders, may impact the middle ear, thereby leading to otic symptoms. This previously unavailable model type is experimentally testable and must be taken as a starting point for identifying the mechanisms responsible for this particular subtype of tinnitus and its associated symptoms. PMID- 30249171 TI - Hearing Aids Benefit Recognition of Words in Emotional Speech but Not Emotion Identification. AB - Vocal emotion perception is an important part of speech communication and social interaction. Although older adults with normal audiograms are known to be less accurate at identifying vocal emotion compared to younger adults, little is known about how older adults with hearing loss perceive vocal emotion or whether hearing aids improve the perception of emotional speech. In the main experiment, older hearing aid users were presented with sentences spoken in seven emotion conditions, with and without their own hearing aids. Listeners reported the words that they heard as well as the emotion portrayed in each sentence. The use of hearing aids improved word-recognition accuracy in quiet from 38.1% (unaided) to 65.1% (aided) but did not significantly change emotion-identification accuracy (36.0% unaided, 41.8% aided). In a follow-up experiment, normal-hearing young listeners were tested on the same stimuli. Normal-hearing younger listeners and older listeners with hearing loss showed similar patterns in how emotion affected word-recognition performance but different patterns in how emotion affected emotion-identification performance. In contrast to the present findings, previous studies did not find age-related differences between younger and older normal hearing listeners in how emotion affected emotion-identification performance. These findings suggest that there are changes to emotion identification caused by hearing loss that are beyond those that can be attributed to normal aging, and that hearing aids do not compensate for these changes. PMID- 30249174 TI - Factors associated with knowledge and awareness of HIV/AIDS among married women in Bangladesh: evidence from a nationally representative survey. AB - Women in Bangladesh share a greater risk of Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) infection compared to men. Levels of knowledge and awareness largely contribute to the prevalence of the HIV epidemic and its consequences. So, it is required to conduct studies based on most recent data to explore the determinants of HIV awareness. Therefore, we aimed to find the awareness level and factors influencing HIV related awareness among the married women in Bangladesh. We used data from 2014 Bangladesh Demographic and Health Survey (BDHS). About two-third of total respondents who heard about the HIV/AIDS were selected and interviewed successfully (n = 12,593) about 11 basic questions related to individual's awareness. A score of the respondent's knowledge and awareness was determined based on these questions. We used logistic regression models for analysing the data. We found about 62% of the respondents had an adequate knowledge and consciousness about the HIV/AIDS. Respondents' education status, mass-media access, place of living, and working status played significant role on the awareness. As expected, respondents with higher education were more aware than those with no education (odds ratio (OR) = 3.56, 95% confidence interval (CI): 2.99-4.23). Moreover, respondents who had access to the mass media were more likely to be aware compared to those who did not have the access (OR = 1.14, 95% CI: 1.04-1.26). Although a sizeable proportion of women had an adequate knowledge and awareness regarding the HIV/AIDS, we recommend implementing educational programmes related to HIV/AIDS in the curriculum to ensure a standard level of awareness throughout the nation. Since the respondents from rural areas scored significantly lower than the urban areas, awareness through mass media, particularly in rural areas, is of prime concern for raising awareness. PMID- 30249173 TI - Safety and Efficacy of Inferior Vena Cava Reconstruction During Hepatic Resection. AB - BACKGROUND AND AIMS: Patients with liver tumors involving the inferior vena cava have a poor outcome without surgery. Liver resection en bloc with inferior vena cava resection and reconstruction is now performed in many centers. The purpose of this study is to investigate the safety and efficacy of inferior vena cava reconstruction during hepatic resection. MATERIALS AND METHODS: A review of 12 centers reporting 240 patients with combined hepatectomy and inferior vena cava resection and reconstruction for malignant tumors was performed. Sample size, patient characteristics, histological type of the tumor, method of reconstruction, complications, and long-term survival (1-, 2-, and 5-year survival) were evaluated. RESULTS: A total of 240 patients from 12 institutions (male 58%) with mean age 54 years underwent combined liver resection and inferior vena cava resection and reconstruction for colorectal liver metastases (43%), cholangiocarcinomas (26%), hepatocellular carcinomas (19%), leiomyosarcomas (4%), and other tumors (7.9%). Reconstruction included primary closure (35.8%), patch repair (13.3%), or interposition graft (50.8%) In-hospital mortality was 6.25% and overall morbidity was 42.1%. 1- and 10-year survival rates were 79.7% and 28.9%, respectively. CONCLUSION: Tumors arising in or extending to inferior vena cava that require liver resection should be considered for surgery as it can be performed with an acceptable mortality and morbidity in centers with liver transplantation and hepato-pancreato-biliary facilities. PMID- 30249175 TI - Editorial. PMID- 30249172 TI - The Pupil Dilation Response to Auditory Stimuli: Current State of Knowledge. AB - The measurement of cognitive resource allocation during listening, or listening effort, provides valuable insight in the factors influencing auditory processing. In recent years, many studies inside and outside the field of hearing science have measured the pupil response evoked by auditory stimuli. The aim of the current review was to provide an exhaustive overview of these studies. The 146 studies included in this review originated from multiple domains, including hearing science and linguistics, but the review also covers research into motivation, memory, and emotion. The present review provides a unique overview of these studies and is organized according to the components of the Framework for Understanding Effortful Listening. A summary table presents the sample characteristics, an outline of the study design, stimuli, the pupil parameters analyzed, and the main findings of each study. The results indicate that the pupil response is sensitive to various task manipulations as well as interindividual differences. Many of the findings have been replicated. Frequent interactions between the independent factors affecting the pupil response have been reported, which indicates complex processes underlying cognitive resource allocation. This complexity should be taken into account in future studies that should focus more on interindividual differences, also including older participants. This review facilitates the careful design of new studies by indicating the factors that should be controlled for. In conclusion, measuring the pupil dilation response to auditory stimuli has been demonstrated to be sensitive method applicable to numerous research questions. The sensitivity of the measure calls for carefully designed stimuli. PMID- 30249176 TI - Machine Learning for detection of viral sequences in human metagenomic datasets. AB - BACKGROUND: Detection of highly divergent or yet unknown viruses from metagenomics sequencing datasets is a major bioinformatics challenge. When human samples are sequenced, a large proportion of assembled contigs are classified as "unknown", as conventional methods find no similarity to known sequences. We wished to explore whether machine learning algorithms using Relative Synonymous Codon Usage frequency (RSCU) could improve the detection of viral sequences in metagenomic sequencing data. RESULTS: We trained Random Forest and Artificial Neural Network using metagenomic sequences taxonomically classified into virus and non-virus classes. The algorithms achieved accuracies well beyond chance level, with area under ROC curve 0.79. Two codons (TCG and CGC) were found to have a particularly strong discriminative capacity. CONCLUSION: RSCU-based machine learning techniques applied to metagenomic sequencing data can help identify a large number of putative viral sequences and provide an addition to conventional methods for taxonomic classification. PMID- 30249177 TI - An effort toward molecular biology of food deprivation induced food hoarding in gonadectomized NMRI mouse model: focus on neural oxidative status. AB - BACKGROUND: Environmental uncertainty, such as food deprivation, may alter internal milieu of nervous system through various mechanisms. In combination with circumstances of stress or aging, high consumption of unsaturated fatty acids and oxygen can make neural tissues sensitive to oxidative stress (OS). For adult rats, diminished level of gonadal steroid hormones accelerates OS and may result in special behavioral manifestations. This study was aimed to partially answer the question whether OS mediates trade-off between food hoarding and food intake (fat hoarding) in environmental uncertainty (e.g., fluctuations in food resource) within gonadectomized mouse model in the presence of food deprivation-induced food hoarding behavior. RESULTS: Hoarding behavior was not uniformly expressed in all male mice that exposed to food deprivation. Extended phenotypes including hoarder and non-hoarder mice stored higher and lower amounts of food respectively as compared to that of low-hoarder mice (normal phenotype) after food deprivation. Results showed that neural oxidative status was not changed in the presence of hoarding behavior in gonadectomized mice regardless of tissue type, however, glutathione levels of brain tissues were increased in the presence of hoarding behavior. Decreased superoxide dismutase activity in brain and spinal cord tissues and increased malondialdehyde in brain tissues of gonadectomized mice were also seen. CONCLUSIONS: Although, food deprivation-induced hoarding behavior is a strategic response to food shortage in mice, it did not induce the same amount of hoarding across all colony mates. Hoarding behavior, in this case, is a response to the environmental uncertainty of food shortage, therefore is not an abnormal behavior. Hoarding behavior induced neural OS with regard to an increase in brain glutathione levels but failed to show other markers of neural OS. Decreased superoxide dismutase activity in brain and spinal cord tissues and increased malondialdehyde levels in brain tissues of gonadectomized mice could be a hallmark of debilitated antioxidative defense and more lipid peroxidation due to reduced amount of gonadal steroid hormones during aging. PMID- 30249178 TI - Bi-specific and tri-specific antibodies- the next big thing in solid tumor therapeutics. AB - Antibody-based therapy has revitalized the world of cancer therapeutics since rituximab was first approved for the treatment of Non-Hodgkin's Lymphoma. Monoclonal antibodies against cancer antigens have been successful strategies for only a handful of cancer types due to many reasons including lack of antibody specificity and complex nature of tumor milieu which interfere with antibody efficacy. Polyspecific antibodies are promising class of anti-cancer agents which can be directed at multiple tumor antigens to eradicate tumor cells more precisely and effectively. They may overcome some of these limitations and have already changed treatment landscape for some malignancies such as B cell acute lymphoblastic leukemia. Pre-clinical studies and early phase clinical trials have demonstrated that this approach may be an effective strategy even for solid tumors. This review focuses on the development of bispecific and trispecific antibody therapy for the treatment of solid tumor malignancies and highlights the potential they hold for future therapies to come. PMID- 30249179 TI - Molecular dynamics and structure function analysis show that substrate binding and specificity are major forces in the functional diversification of Eqolisins. AB - BACKGROUND: Eqolisins are rare acid proteases found in archaea, bacteria and fungi. Certain fungi secrete acids as part of their lifestyle and interestingly these also have many eqolisin paralogs, up to nine paralogs have been recorded. This suggests a process of functional redundancy and diversification has occurred, which was the subject of the research we performed and describe here. RESULTS: We identified eqolisin homologs by means of iterative HMMER analysis of the NR database. The identified sequences were scrutinized for which new hallmarks were identified by molecular dynamics simulations of mutants in highly conserved positions, using the structure of an eqolisin that was crystallized in the presence of a transition state inhibitor. Four conserved glycines were shown to be important for functionality. A substitution of W67F is shown to be accompanied by the L105W substitution. Molecular dynamics shows that the W67 binds to the substrate via a pi-pi stacking and a salt bridge, the latter being stronger in a virtual W67F/L105W double mutant of the resolved structure of Scytalido-carboxyl peptidase-B (PDB ID: 2IFW). Additional problematic mutations are discussed. Upon sequence scrutiny we obtained a set of 233 sequences that was used to reconstruct a Bayesian phylogenetic tree. We identified 14 putative specificity determining positions (SDPs) of which four are explained by mere structural explanations and nine seem to correspond to functional diversification related with substrate binding and specificity. A first sub-network of SDPs is related to substrate specificity whereas the second sub-network seems to affect the dynamics of three loops that are involved in substrate binding. CONCLUSION: The eqolisins form a small superfamily of acid proteases with nevertheless many paralogs in acidic fungi. Functional redundancy has resulted in diversification related to substrate specificity and substrate binding. PMID- 30249180 TI - De novo assembly of middle-sized genome using MinION and Illumina sequencers. AB - BACKGROUND: The plastid acquisition by secondary endosymbiosis is a driving force for the algal evolution, and the comparative genomics was required to examine the genomic change of symbiont. Therefore, we established a pipeline of a de novo assembly of middle-sized genomes at a low cost and with high quality using long and short reads. RESULTS: We sequenced symbiotic algae Chlorella variabilis using Oxfofrd Nanopore MinION as the long-read sequencer and Illumina HiSeq 4000 as the short-read sequencer and then assembled the genomes under various conditions. Subsequently, we evaluated these assemblies by the gene model quality and RNA-seq mapping rate. We found that long-read only assembly could not be suitable for the comparative genomics studies, but with short reads, we could obtain the acceptable assembly. On the basis of this result, we established the pipeline of de novo assembly for middle-sized algal genome using MinION. CONCLUSIONS: The genomic change during the early stages of plastid acquisition can now be revealed by sequencing and comparing many algal genomes. Moreover, this pipeline offers a solution for the assembly of various middle-sized eukaryotic genomes with high quality and ease. PMID- 30249181 TI - Fast design of arbitrary length loops in proteins using InteractiveRosetta. AB - BACKGROUND: With increasing interest in ab initio protein design, there is a desire to be able to fully explore the design space of insertions and deletions. Nature inserts and deletes residues to optimize energy and function, but allowing variable length indels in the context of an interactive protein design session presents challenges with regard to speed and accuracy. RESULTS: Here we present a new module (INDEL) for InteractiveRosetta which allows the user to specify a range of lengths for a desired indel, and which returns a set of low energy backbones in a matter of seconds. To make the loop search fast, loop anchor points are geometrically hashed using C alpha-C alpha and C beta-C beta distances, and the hash is mapped to start and end points in a pre-compiled random access file of non-redundant, protein backbone coordinates. Loops with superposable anchors are filtered for collisions and returned to InteractiveRosetta as poly-alanine for display and selective incorporation into the design template. Sidechains can then be added using RosettaDesign tools. CONCLUSIONS: INDEL was able to find viable loops in 100% of 500 attempts for all lengths from 3 to 20 residues. INDEL has been applied to the task of designing a domain-swapping loop for T7-endonuclease I, changing its specificity from Holliday junctions to paranemic crossover (PX) DNA. PMID- 30249182 TI - Rhodoliths holobionts in a changing ocean: host-microbes interactions mediate coralline algae resilience under ocean acidification. AB - BACKGROUND: Life in the ocean will increasingly have to contend with a complex matrix of concurrent shifts in environmental properties that impact their physiology and control their life histories. Rhodoliths are coralline red algae (Corallinales, Rhodophyta) that are photosynthesizers, calcifiers, and ecosystem engineers and therefore represent important targets for ocean acidification (OA) research. Here, we exposed live rhodoliths to near-future OA conditions to investigate responses in their photosynthetic capacity, calcium carbonate production, and associated microbiome using carbon uptake, decalcification assays, and whole genome shotgun sequencing metagenomic analysis, respectively. The results from our live rhodolith assays were compared to similar manipulations on dead rhodolith (calcareous skeleton) biofilms and water column microbial communities, thereby enabling the assessment of host-microbiome interaction under climate-driven environmental perturbations. RESULTS: Under high pCO2 conditions, live rhodoliths exhibited positive physiological responses, i.e. increased photosynthetic activity, and no calcium carbonate biomass loss over time. Further, whereas the microbiome associated with live rhodoliths remained stable and resembled a healthy holobiont, the microbial community associated with the water column changed after exposure to elevated pCO2. CONCLUSIONS: Our results suggest that a tightly regulated microbial-host interaction, as evidenced by the stability of the rhodolith microbiome recorded here under OA-like conditions, is important for host resilience to environmental stress. This study extends the scarce comprehension of microbes associated with rhodolith beds and their reaction to increased pCO2, providing a more comprehensive approach to OA studies by assessing the host holobiont. PMID- 30249183 TI - Bacterial contamination of human skin allografts and antimicrobial resistance: a skin bank problem. AB - BACKGROUND: Bacterial contamination remains the major problem in skin banks, even after antimicrobial treatment, and results in high rates of tissue discarding. This study aimed to analyze bacterial contamination in 32 human skin allografts from the skin bank of Dr. Roberto Correa Chem from the Hospital Complex Santa Casa de Misericordia de Porto Alegre. These samples were already discarded due to microbial contamination. The identification of the bacteria isolated from skin allografts was performed by matrix assisted laser desorption ionization-time of flight. The antimicrobial susceptibility of the isolates to six different classes of antimicrobials was determined using the disk-diffusion agar method, and the evaluation of the inhibitory potential was determined by the minimal inhibitory concentration (50/90) of antimicrobials already used in the skin bank and those that most isolates were susceptible to. RESULTS: A total of 21 (65.6%) skin samples were contaminated with Gram-positive bacteria: 1 (4.7%) with Paenibacillus sp., 12 (61.9%) with Bacillus sp., 6 (28.5%) with Staphylococcus sp., and 2 (9.5%) with Bacillus sp. and Staphylococcus sp. Several resistance profiles, including multiresistance, were found among the isolates. Most of the isolates were susceptible to at least one of the antimicrobials used in the skin bank. All isolates were susceptible to amikacin, gentamicin, and tetracycline, which demonstrated the best inhibitory activities against the isolates and were considered as potential candidates for new antimicrobial treatments. CONCLUSIONS: Bacillus, Paenibacillus, and Staphylococcus were isolated from the skin allografts, thus demonstrating the predominance of Gram-positive bacteria contamination. Other factors not related to the resistance phenotype may also be involved in the persistence of bacterial isolates in the skin allografts after antibiotic treatment. Gentamicin, amikacin, and tetracycline can be considered as an option for a more effective treatment cocktail. PMID- 30249184 TI - Characterization of the bacterial communities on recent Icelandic volcanic deposits of different ages. AB - BACKGROUND: Basalt is the most common igneous rock on the Earth's surface covering. Basalt-associated microorganisms drive the cycling and sequestration of different elements such as nitrogen, carbon and other nutrients, which facilitate subsequent pioneer and plant development, impacting long-term regulation of the Earth's temperature and biosphere. The initial processes of colonization and subsequent rock weathering by microbial communities are still poorly understood and relatively few data are available on the diversity and richness of the communities inhabiting successive and chronological lava flows. In this study, the bacterial communities present on lava deposits from different eruptions of the 1975-84 Krafla Fires (32-, 35- and 39-year old, respectively) at the Krafla, Iceland, were determined. RESULTS: Three sites were sampled for each deposit (32 , 35- and 39-year old), two proximal sites (at 10 m distance) and one more distant site (at 100 m from the two other sites). The determined chemical composition and metal concentrations were similar for the three basalt deposits. No significant differences were observed in the total number of cells in each flow. 16S rRNA gene amplicon sequencing showed that the most abundant classified phylum across the 3 flows was Proteobacteria, although predominance of Acidobacteria, Actinobacteria and Firmicutes was observed for some sampling sites. In addition, a considerable fraction of the operational taxonomic units remained unclassified. Alpha diversity (Shannon, inverse Simpson and Chao), HOMOVA and AMOVA only showed a significant difference for Shannon between the 32- and 39-year old flow (p < 0.05). Nonmetric multidimensional scaling (NMDS) analysis showed that age significantly (p = 0.026) influenced the leftward movement along NMDS axis 1. CONCLUSIONS: Although NMDS indicated that the (relatively small) age difference of the deposits appeared to impact the bacterial community, this analysis was not consistent with AMOVA and HOMOVA, indicating no significant difference in community structure. The combined results drive us to conclude that the (relatively small) age differences of the deposits do not appear to be the main factor shaping the microbial communities. Probably other factors such as spatial heterogeneity, associated carbon content, exogenous rain precipitations and wind also affect the diversity and dynamics. PMID- 30249186 TI - Comparative transcriptome analysis of Eimeria maxima (Apicomplexa: Eimeriidae) suggests DNA replication activities correlating with its fecundity. AB - BACKGROUND: Chicken coccidiosis, caused by the infection of Eimeria species, leads to important economic losses to the poultry industry. Vaccination with attenuated live parasites seems to be the best way to control this disease. Attenuated eimerian parasites with shortened prepatent times show great changes in intracellular development compared to their parent strains but the mechanisms involved in these biological differences are still unclear. RESULTS: In this study, we obtained a precocious line of E. maxima by sequential selection of 22 generations of early shed oocysts in chickens and performed a comparative transcriptome analysis of three different developmental stages of the precocious line and its parent strain using Illumina high-throughput sequencing. Our E. maxima precocious line showed decreased pathogenicity, reduced fecundity and a greatly shorted prepatent time of only 98 h. We found that typical gene changes in the stage development from unsporulated to sporulated oocyst and from sporulated oocyst to merozoite were marked by upregulated organelle genes and protein translation related genes, respectively. Additionally, major differences between the precocious line and its parent strain were detected in the merozoite stage, characterized by downregulated genes involved in protein cleavage and DNA replication activities. CONCLUSIONS: Our study generated and characterized an E. maxima precocious line, illustrating gene expression landscapes during parasite development by transcriptome analysis. We also show that the suppressed DNA replication progress in the merozoite stage in the precocious line may result in its reduced fecundity. These results provide the basis for a better understanding of the mechanism of precocity in Eimeria species, which can be useful in studies in early gametocytogenesis in apicomplexan parasites. PMID- 30249185 TI - Nitric oxide contributes to methane-induced osmotic stress tolerance in mung bean. AB - BACKGROUND: Osmotic stress is a major abiotic stress limiting crop production by affecting plant growth and development. Although previous reports discovered that methane (CH4) has a beneficial effect on osmotic stress, the corresponding downstream signal(s) is still elusive. RESULTS: Polyethylene glycol (PEG) treatment progressively stimulated the production of CH4 in germinating mung bean seeds. Exogenous CH4 and sodium nitroprusside (SNP) not only triggered nitric oxide (NO) production in PEG-stressed plants, but also alleviated the inhibition of seed germination. Meanwhile, amylase activity was activated, thus accelerating the formation of reducing sugar and total soluble sugar. Above responses could be impaired by NO scavenger(s), suggesting that CH4-induced stress tolerance was dependent on NO. Subsequent tests showed that CH4 could reestablish redox balance in a NO-dependent fashion. The addition of inhibitors of the nitrate reductase (NR) and NO synthase in mammalian (NOS), suggested that NR and NOS-like protein might be partially involved in CH4-alleviated seed germination inhibition. In vitro and scavenger tests showed that NO-mediated S-nitrosylation might be associated with above CH4 responses. CONCLUSIONS: Together, these results indicated an important role of endogenous NO in CH4-enhanced plant tolerance against osmotic stress, and NO-regulated redox homeostasis and S-nitrosylation might be involved in above CH4 action. PMID- 30249187 TI - The key genes and pathways related to male sterility of eggplant revealed by comparative transcriptome analysis. AB - BACKGROUND: Male sterility (MS) is an effective tool for hybrid production. Although MS has been widely reported in other plants, such as Arabidopsis and rice, the molecular mechanism of MS in eggplant is largely unknown. To understand the mechanism, the comparative transcriptomic file of MS line and its maintainer line was analyzed with the RNA-seq technology. RESULTS: A total of 11,7695 unigenes were assembled and 19,652 differentially expressed genes (DEGs) were obtained. The results showed that 1,716 DEGs were shared in the three stages. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that these DEGs were mainly involved in oxidation-reduction, carbohydrate and amino acid metabolism. Moreover, transcriptional regulation was also the impact effector for MS and anther development. Weighted correlation network analysis (WGCNA) showed two modules might be responsible for MS, which was similar to hierarchical cluster analysis. CONCLUSIONS: A number of genes and pathways associated with MS were found in this study. This study threw light on the molecular mechanism of MS and identified several key genes related to MS in eggplant. PMID- 30249188 TI - Evolutionary insights from comparative transcriptome and transcriptome-wide coalescence analyses in Tetrastigma hemsleyanum. AB - BACKGROUND: Tetrastigma hemsleyanum is of great medicinal importance and used as a model system to address the evolutionary history of warm-temperate evergreen (WTE) forest biomes in East Asia over Neogene time scales. However, further studies on the neutral and adaptive divergence processes of T. hemsleyanum are currently impeded by a lack of genomic resources. In this study, we de novo assembled and annotated a reference transcriptome for two cpDNA lineages (Central South-East vs. Southwest) of T. hemsleyanum. We further used comparative genomic and multilocus coalescent approaches to investigate the tempo and mode of lineage diversification in T. hemsleyanum. RESULTS: A total of 52,838 and 65,197 unigenes with an N50 of 1,667 and 1,841 bp for Central-South-East (CSE) and Southwest (SW) lineages, respectively, were recovered, and 6,692 putative orthologs were identified between the two lineages. Estimation of Ka/Ks ratios for these orthologs revealed that ten genes had Ka/Ks values significantly greater than 0.5 (P < 0.05), whereas 2,099 (Ka/Ks < 0.5, P < 0.05) were inferred to be under purifying selection. Based on three bioinformatic strategies, we identified a total of 1,018 single-copy nuclear genes (SCNGs) from the orthologs. We successfully designed eight nuclear gene primer pairs with high intraspecific variation (e.g. hT = 0.923, piT = 1.68*10-3), when surveyed across a subset of T. hemsleyanum individuals. Concordant with the previous cpDNA data, the haplotype networks constructed for most nuclear gene loci clearly identified the two lineages. A multilocus coalescence analysis suggested that the separation between the two lineages appears to have occurred during the mid-Pliocene. Despite their ancient divergence, both lineages experienced expansion at rather localized scales and have continued to exchange genes at a low rate. CONCLUSIONS: This study demonstrated the utility of transcriptome sequencing as a basis for SCNG development in non-model species and the advantages of integrating multiple nuclear loci for phylogeographic and phylogenetic studies. PMID- 30249190 TI - Noncontrast magnetic resonance imaging versus ultrasonography for hepatocellular carcinoma surveillance (MIRACLE-HCC): study protocol for a prospective randomized trial. AB - BACKGROUND: Biannual ultrasound (US)-with or without alpha-fetoprotein (AFP)-is recommended by current guidelines for the surveillance of hepatocellular carcinoma (HCC). However, the inadequate sensitivity of US has been a concern. Magnetic resonance imaging (MRI) is known to have high sensitivity in detecting hepatic malignancies, even without contrast enhancement. The purpose of our study is to compare US with noncontrast (unenhanced) MRI for HCC surveillance of high risk patients. METHODS/DESIGN: MIRACLE-HCC (usefulness of noncontrast MagnetIc Resonance imAging versus nonContrast ultrasonography for surveiLlancE of HepatoCellular Carcinoma) is a prospective, single-center, nonblinded, balanced randomized, parallel-group study. This study was approved by our institutional review board, and informed consent will be obtained from all participating patients. All patients with compensated liver cirrhosis will undergo noncontrast US or MRI, with serum AFP testing every 6 months. If a suspicious lesion is newly detected, or if the serum AFP level is elevated in an increasing trend for two consecutive tests, dynamic contrast-enhanced imaging will be performed to confirm the diagnosis. The primary endpoints are detection rates of very early or early stage HCC, stage distribution at the initial diagnosis, and false positive referral rates, which will be compared using Fisher's exact or chi-square tests. The study will include 416 patients in a tertiary academic medical center in South Korea. DISCUSSION: MIRACLE-HCC is the first prospective randomized trial to compare the effectiveness of noncontrast MRI and noncontrast US in the surveillance of HCC in at-risk patients. The results of this trial will show whether noncontrast MRI surveillance is superior to noncontrast US surveillance in the early detection of HCC. The trial will also determine whether there are fewer false referrals with noncontrast MRI than with noncontrast US and, eventually, whether there is improvement in the overall survival of HCC patients. TRIAL REGISTRATION: The date of trial registration (ClincalTrials.gov: NCT02514434 ) for this study is July 23, 2015. Enrollment of participants was finished in November 2017. No authors have relationships, conditions, or circumstances that present potential conflicts of interest. PMID- 30249189 TI - Comparative transcriptome analysis of the wild-type model apomict Hieracium praealtum and its loss of parthenogenesis (lop) mutant. AB - BACKGROUND: Asexual seed formation (apomixis) has been observed in diverse plant families but is rare in crop plants. The generation of apomictic crops would revolutionize agriculture, as clonal seed production provides a low cost and efficient way to produce hybrid seed. Hieracium (Asteraceae) is a model system for studying the molecular components of gametophytic apomixis (asexual seed reproduction). RESULTS: In this study, a reference transcriptome was produced from apomictic Hieracium undergoing the key apomictic events of apomeiosis, parthenogenesis and autonomous endosperm development. In addition, transcriptome sequences from pre-pollination and post-pollination stages were generated from a loss of parthenogenesis (lop) mutant accession that exhibits loss of parthenogenesis and autonomous endosperm development. The transcriptome is composed of 147,632 contigs, 50% of which were annotated with orthologous genes and their probable function. The transcriptome was used to identify transcripts differentially expressed during apomictic and pollination dependent (lop) seed development. Gene Ontology enrichment analysis of differentially expressed transcripts showed that an important difference between apomictic and pollination dependent seed development was the expression of genes relating to epigenetic gene regulation. Genes that mark key developmental stages, i.e. aposporous embryo sac development and seed development, were also identified through their enhanced expression at those stages. CONCLUSION: The production of a comprehensive floral reference transcriptome for Hieracium provides a valuable resource for research into the molecular basis of apomixis and the identification of the genes underlying the LOP locus. PMID- 30249191 TI - Preventing adverse events of chemotherapy by educating patients about the nocebo effect (RENNO study) - study protocol of a randomized controlled trial with gastrointestinal cancer patients. AB - BACKGROUND: Patients undergoing chemotherapy are highly burdened by side effects. These may be caused by the pharmacodynamics of the drug or be driven by psychological factors such as negative expectations or pre-conditioning, which reflect nocebo effects. As such, negative pre-treatment expectations or prior experiences might exacerbate the burden of chemotherapy side effects. Educating patients about this nocebo effect has been put forward as a potential strategy to optimize patients' pre-treatment expectations. In this study, we evaluate whether a briefing about the nocebo effect is efficacious in reducing side effects. METHODS: In this exploratory study, a total number of n = 100 outpatients with newly diagnosed gastrointestinal cancers are randomized 1:1 to an information session about the nocebo effect (nocebo-education) or an attention control group (ACG) with matching interaction time. Assessments take place before the intervention (T1 pre), post-intervention (T1 post), and 10 days (T2) and 12 weeks (T3) after the initial chemotherapy. The primary outcomes are the patient-rated number and intensity of side effects at 10-days and at 12-weeks follow-up. Secondary outcomes include coping with side effects, tendency to misattribute symptoms, compliance intention, attitude towards the chemotherapy, co-medication to treat side effects and the clinician-rated severity of toxicity. Further analyses are conducted to investigate whether a potential beneficial effect is mediated by a change of expectations before and after the intervention. DISCUSSION: Informing patients about the nocebo effect might be an innovative and feasible intervention to reduce the burden of side effects and strengthen patients' perceived control over adverse symptoms. TRIAL REGISTRATION: The trial is registered at the German Clinical Trials Register (ID: DRKS00009501 ; retrospectively registered on March 27, 2018). The first patient was enrolled on September 29, 2015. PMID- 30249192 TI - A similar effect of P16 hydroxymethylation and true-methylation on the prediction of malignant transformation of oral epithelial dysplasia: observation from a prospective study. AB - BACKGROUND: Total P16 methylation (P16M), including P16 hydroxymethylation (P16H) and true-P16M, correlates with malignant transformation of oral epithelial dysplasia (OED). Both true-P16M and P16H are early events in carcinogenesis. The aim of this study is to prospectively determine if discrimination of true-P16M from P16H is necessary for prediction of cancer development from OEDs. METHODS: Patients (n = 265) with mild or moderate OED were recruited into the double blind two-center cohort. Total-P16M and P16H were analyzed using the 115-bp MethyLight, TET-assisted bisulfite (TAB) methylation-specific PCR (MSP), and TAB-sequencing. Total-P16M-positive and P16H-negative samples were defined as true-P16M-positive. Progression of OEDs was monitored for a minimum 24 months follow-up period. RESULTS: P16H was detected in 23 of 73 (31.5%) total-P16M-positive OEDs. Follow up information was obtained from 247 patients with an ultimate compliance rate of 93.2%. OED-derived squamous cell carcinomas were observed in 13.0% (32/247) patients during follow-up (median, 41.0 months). The cancer progression rate for total-P16M-positive patients was significantly increased when compared to total P16M-negative patients [23.3% vs 8.6%; adjusted odds ratio = 2.67 (95% CI: 1.19 5.99)]. However, the cancer progression rates were similar between P16H- and true P16M-positive OEDs [26.1% (6/23) vs 22.0% (11/50); odds ratio = 0.80 (95% CI: 0.22-2.92)]. The cancer-free survival was also similar for these patients. CONCLUSION: P16H and true-P16M are similar biomarkers for determining malignant potential of OEDs. Discrimination of P16H from true-P16M, at least in OED, may be not necessary in clinical applications. TRIAL REGISTRATION: This study is registered prospectively in the U.S. National Institutes of Health Clinical Trials Protocol Registration System (trial number NCT02967120, available at https://ClinicalTrials.gov/ct2/show/NCT02967120 ). PMID- 30249194 TI - Spontaneously induced prophages are abundant in a naturally evolved bacterial starter culture and deliver competitive advantage to the host. AB - BACKGROUND: In complex microbial ecosystems such as the marine environment, the gastrointestinal tract, but also in mixed culture fermentations, bacteriophages are frequently found to be a part of the microbial community. Moreover, prophages or prophage-like elements are frequently identified in sequenced bacterial genomes. The mixed undefined starter cultures represent an ecosystem which is shaped by long term evolution under relatively defined environmental conditions and provides an interesting model to study co-evolution of phages and their hosts as well as the impact of diversity on microbial community stability. RESULTS: In the present study we investigated the presence, identity and behaviour of prophages in lactococci being part of a complex cheese starter culture. Genome analysis of representative strains of the 7 genetic lineages of Lactococcus lactis constituting the culture indicated the presence of prophages in all strains. Exposure of potential lysogens to mitomycin C confirmed the release of ~ 1010.ml- 1 phage particles from all tested strains. Furthermore, phages were also released in substantial amounts due to spontaneous induction: more than 108.ml- 1 phage particles were present in cultures under non-inducing conditions. This observation suggests continuous release of phage particles by the lactococci. The released bacteriophages exhibited an unusual morphology. For most strains tested, tailless icosahedral phage heads were found. The competitive advantage of lysogens compared to their cured derivatives and their high abundance in the culture suggests that the released tailless bacteriophages play an important role in the ecosystem. CONCLUSIONS: The results of this study indicate that chromosomal genetic elements are active participants in the stable complex microbial community of the starter culture. We show that prophages are abundant in such a community, are produced continuously in large amounts and, despite the huge metabolic burden imposed on the cells by phage particle production, provide a selective advantage to the host. PMID- 30249193 TI - Iron deficiency among low income Canadian toddlers: a cross-sectional feasibility study in a Community Health Centre and non-Community Health Centre sites. AB - BACKGROUND: Iron deficiency in early childhood has been associated with poor developmental outcomes. Little is known about the nutritional health of young children receiving care at Canadian Community Health Centres (CHCs). Our objectives were to describe iron deficiency among toddlers at an Ontario CHC, to compare young children attending CHCs and non-CHCs, and assess the feasibility of conducting research on children in CHC settings. METHODS: One CHC, Kingston Community Health Centres (CHC) with two clinical sites and one community programming site was added to the nine non-CHC pediatric and primary care clinics in the existing TARGet Kids! research network. A cross-sectional feasibilitystudy was conducted.and. Healthy children, ages 12-36 months were Enrolled. iron deficiency without inflammation (ferritin< 14 MUg/L and CRP < 10 mg/L) and serum ferritin were assessed. Adjusted multivariable regression analyses were used to evaluate an association between CHC enrolment and iron status. RESULTS: The CHC cohort (n = 31) was older, had lower household income, lower maternal education, higher nutrition risk scores, higher cow's milk intake, shorter breastfeeding duration and higher prevalence of unhealthy weights compared with the non-CHC cohort (n = 875). There was no association between CHC status and serum ferritin (difference in median serum ferritin 4.78 MUg/L, 95% confidence interval [CI] 2.5, 14.3, p = 0.22) or iron deficiency (OR 0.55, 95% CI 0.11, - 2.73, p = 0.46) using multivariable linear and logistic regression, respectively. CONCLUSION: Despite differences in sociodemographic variables, we did not detect a difference in iron status between toddlers enrolled at CHCs compared to non-CHC settings. Further research is needed to understand the health effects of poverty generally, and iron deficiency specifically among children receiving care at CHCs. PMID- 30249195 TI - Clinical trial protocol of the ASTER trial: a double-blind, randomized, placebo controlled phase III trial evaluating the use of acetylsalicylic acid (ASA) for enhanced early detection of colorectal neoplasms. AB - : ?: Immunochemical fecal occult blood tests (iFOBTs) are increasingly used for colorectal cancer (CRC) screening. In our preceding observational study, sensitivity for detecting advanced colorectal neoplasms by iFOBT was 70.8% among users of low-dose acetylsalicylic acid compared with 35.9% among non-users (p = 0.001), whereas there were only very small differences in specificity. In receiver operating characteristics (ROC) analyses, the area under the curve (AUC) was much higher for acetylsalicylic acid users than for non-users, with particularly strong differences in men (0.87 versus 0.68, p = 0.003). These findings suggested that use of acetylsalicylic acid before conduct of iFOBT might be a promising approach to improve non-invasive screening for CRC. METHODS/DESIGN: In this randomized, double-blind, placebo-controlled trial, the diagnostic performance of two iFOBTs for detecting advanced colorectal neoplasms after a single low-dose of acetylsalicylic acid (300 mg) compared to placebo is evaluated. Acetylsalicylic acid or placebo is administered at least 5 days before a planned, study-independent colonoscopic screening in 2400 participants aged 40 to 80 years. Stool samples are obtained before and on three different days after the single dose of acetylsalicylic acid or placebo. In addition, optional blood samples are taken for future biomarker analyses. The diagnostic performance of the iFOBTs will be compared to the results of the colonoscopy as a gold standard for the diagnosis of colorectal neoplasms. Additionally, gender-specific performance of the tests and gain in diagnostic performance by test application on multiple days will be evaluated. DISCUSSION: If the findings from our preceding observational study will be confirmed in this large trial, the proposed low-risk, inexpensive intervention would considerably improve the diagnostic accuracy of iFOBTs and thus lead to enhanced early detection of colorectal neoplasms. Thus, the results of this trial may have a large public health impact. TRIAL REGISTRATION: This trial was registered before recruitment of the participants in www.clinicaltrialsregister.eu on the 30th of May 2012: EudraCT No.: 2011-005603-32 and in www.drks.de on 13th of March 2012: German Clinical Trials Register DRKS-ID: DRKS00003252 . PMID- 30249196 TI - Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections among pregnant women and eye colonization of their neonates at birth time, Shiraz, Southern Iran. AB - BACKGROUND: Chlamydia trachomatis and Neisseria gonorrhoeae are the two common transmissible pathogens from pregnant women to their neonates. Given the lack of routine screening and treatment of pregnant women in some areas, the possibility of transmission rises. This study seeks to determine the prevalence of C. trachomatis and N. gonorrhoeae in the pregnant women with no clinical symptoms and the vertical transmission rate to their neonates. METHODS: The study was conducted on endocervical and eye swab samples of 239 pregnant women and their neonates. Identification was based on PCR method. RESULTS: The prevalence rates of C.trachomatis in women and neonates were 37/239 (15.5%) and 28/239 (11.7%), and for N. gonorrhoeae 3/239 (1.3%), 1/239 (0.4%), respectively. The vertical transmission rates to the neonates were 28/37(75.6%) for C. trachomatis and 1/3 for N. gonorrhoeae. CONCLUSIONS: In the areas with a high prevalence of chlamydial or gonococcal infections, and in the absence of screening and treatment of the pregnant women, ocular prophylaxis with antibiotics is suggested as a part of routine neonatal care program for the prevention of chlamydial and gonococcal ophthalmia. PMID- 30249197 TI - Outcomes of STEMI patients with chronic kidney disease treated with percutaneous coronary intervention: the Malaysian National Cardiovascular Disease Database - Percutaneous Coronary Intervention (NCVD-PCI) registry data from 2007 to 2014. AB - BACKGROUND: Patients with renal impairment often left out from most major clinical trials assessing the optimal treatment for ST-elevation myocardial infarction (STEMI). Large body of evidence from various cardiovascular registries reflecting more 'real-world' experience might contribute to the knowledge on how best to treat this special cohort. We aim to analyze the outcomes of Malaysian STEMI patients with renal impairment treated with coronary angioplasty. METHODS: Utilizing the Malaysian National Cardiovascular Disease Database-Percutaneous Coronary Intervention (NCVD-PCI) registry data from 2007 to 2014, STEMI patients treated with percutaneous coronary intervention (PCI) were stratified into presence (GFR < 60 mls/min/1.73m2) or absence (GFR >= 60 mls/min/1.73m2) of chronic kidney disease (CKD). Patient's demographics, extent of coronary artery disease, procedural data, discharge medications, short (in-hospital) and long (1 year) term outcomes were critically assessed. RESULTS: A total of 6563 patients were included in the final analysis. STEMI CKD cohort was predominantly male (80%) with mean age of 61.02 +/- 9.95 years. They had higher cardiovascular risk factors namely diabetes mellitus (54.6%), hypertension (79.2%) and dyslipidemia (68.8%) in contrast to those without CKD. There were notably higher percentage of CKD patients presented with Killip class 3 and 4; 24.9 vs 8.7%. Thrombolytic therapy remained the most commonly instituted treatment regardless the status of kidney function. Furthermore, our STEMI CKD cohort also was more likely to receive less of evidence-based treatment upon discharge. In terms of outcomes, patients with CKD were more likely to develop in-hospital death (OR: 4.55, 95% CI 3.11-6.65), MACE (OR: 3.42, 95% CI 2.39-4.90) and vascular complications (OR: 1.88, 95% CI 0.95-3.7) compared to the non-CKD patients. The risk of death at 1 year post PCI in STEMI CKD patients was also reported to be high (HR: 3.79, 95% CI 2.84-5.07). CONCLUSION: STEMI and CKD is a deadly combination, proven in our cohort, adding on to the current evidence in the literature. We noted that our STEMI CKD patients tend to be younger than the Caucasian with extremely high prevalence of diabetes mellitus. The poor outcome mainly driven by immediate or short term adverse events peri-procedural, therefore suggesting that more efficient treatment in this special group is imperative. PMID- 30249198 TI - Vaginal birth after caesarean birth in Italy: variations among areas of residence and hospitals. AB - BACKGROUND: The rates of caesarean section (CS) are increasing globally. CS rates are one of the most frequently used indicators of health care quality. Vaginal Birth After Caesarean (VBAC) could be considered a reasonable and safe option for most women with a previous CS. Despite this fact, in some European countries, many women who had a previous CS will have a routine CS subsequently and VBAC rates are extremely variable across countries. VBAC use is inversely related to caesarean use. The objective of the present study was to analyze VBAC rates with respect to caesarean rates and the variations among areas of residence, hospitals and hospital ownership types in Italy. METHODS: This study was based on information from the Hospital Information System (HIS). We collected data from all deliveries in Italy from January 1, 2010 to December 31, 2014 and we considered only deliveries with a previous caesarean section. Applying multivariate logistic regression analysis, the adjusted proportions of VBAC for each Local Health Units (LHU), each hospital and by hospital ownership types were calculated. Cross-classified logistic multilevel models were performed to analyze within geographic, hospitals and hospital ownership types variations. RESULTS: We studied a total of 77,850 deliveries with a previous caesarean section in Italy between January 1, 2010 and December 31, 2014. The proportion of VBAC in Italy slightly increased in the last few years, from 5.8% in 2010 to 7.5% in 2014. Proportions of VBAC ranged from 0.29 to 50.05% in Italian LHUs. The LHUs with lower proportions of VBAC deliveries were characterized by higher values for primary caesarean deliveries. Private hospitals showed the lowest mean of crude VBAC proportions but the highest variation among hospitals, ranging from 0 to 47.1%. CONCLUSIONS: Hospital rates of caesarean section for women with at least one previous caesarean section vary widely, and only some of the variation can be explained by case-mix and hospital-level factors, suggesting that additional factors influence practices. Identifying disparities in VBAC may have important implications for health services planning and targeted efforts to reduce overall rates of caesarean deliveries. PMID- 30249199 TI - Association between cognitive function and life-space mobility in older adults: results from the FReLE longitudinal study. AB - BACKGROUND: Cross-sectional and longitudinal studies show conflicting results regarding the association between cognition and life-space mobility, and little is known regarding the mediators and moderators of the association. The aim of this study was to investigate the association between cognition and life-space mobility in older adults, as well as the intervening variables modifying the relationship. METHODS: Community-dwelling older adults aged 65 years and older (N = 1643) were assessed at three time points over a period of 2 years. Growth mixture models with mediation and moderation analysis were utilised to investigate association between cognitive function and life-space mobility. The potential mediators and moderators were depressive symptoms, locus of control, gait speed and grip strength. Analysis was controlled for age, sex, education, annual income, number of chronic illnesses, and living site. RESULTS: The direct association between initial scores of cognitive function and life-space was mediated by initial scores of depressive symptoms and gait speed, and moderated by initial scores of grip strength. No direct association between change in cognitive function and change in life-space mobility was found; the scores were mediated by change in depressive symptoms. CONCLUSIONS: We conclude that the relationship between change in cognitive function and life-space mobility in older adults is not well-defined over an observation period of 2 years. PMID- 30249200 TI - A mixed methods case study exploring the impact of membership of a multi activity, multicentre community group on social wellbeing of older adults. AB - BACKGROUND: Social wellbeing factors such as loneliness and social support have a major impact on the health of older adults and can contribute to physical and mental wellbeing. However, with increasing age, social contacts and social support typically decrease and levels of loneliness increase. Group social engagement appears to have additional benefits for the health of older adults compared to socialising individually with friends and family, but further research is required to confirm whether group activities can be beneficial for the social wellbeing of older adults. METHODS: This one-year longitudinal mixed methods study investigated the effect of joining a community group, offering a range of social and physical activities, on social wellbeing of adults with a mean age of 70. The study combined a quantitative survey assessing loneliness and social support (n = 28; three time-points, analysed using linear mixed models) and a qualitative focus group study (n = 11, analysed using thematic analysis) of members from Life Activities Clubs Victoria, Australia. RESULTS: There was a significant reduction in loneliness (p = 0.023) and a trend toward an increase in social support (p = 0.056) in the first year after joining. The focus group confirmed these observations and suggested that social support may take longer than 1 year to develop. Focus groups also identified that group membership provided important opportunities for developing new and diverse social connections through shared interest and experience. These connections were key in improving the social wellbeing of members, especially in their sense of feeling supported or connected and less lonely. Participants agreed that increasing connections was especially beneficial following significant life events such as retirement, moving to a new house or partners becoming unwell. CONCLUSIONS: Becoming a member of a community group offering social and physical activities may improve social wellbeing in older adults, especially following significant life events such as retirement or moving-house, where social network changes. These results indicate that ageing policy and strategies would benefit from encouraging long-term participation in social groups to assist in adapting to changes that occur in later life and optimise healthy ageing. PMID- 30249201 TI - Association among handgrip strength, body mass index and decline in cognitive function among the elderly women. AB - BACKGROUND: The association between handgrip strength combined with body mass index (BMI) and cognitive impairment has not been thoroughly examined. We aimed to investigate whether the relationship between handgrip strength and risk of cognitive impairment is altered by the presence of obesity in older women. METHODS: A total of 544 older women aged over 65 years without cognitive impairment from the Korean Longitudinal Study of Aging (KLoSA) were included in the study. Handgrip strength was classified in a binary manner (weak or strong) or in tertiles and obesity was defined as a BMI >= 25 kg/m2, in accordance with the Asia-Pacific World Health Organization criteria. Incident cognitive impairment was defined as a Korean Mini-mental State Examination (K-MMSE) score of less than 24 after eight years of follow-up. RESULTS: Strong handgrip strength was associated with reduced likelihood of developing cognitive impairment compared to weak handgrip strength in obese women (adjusted odds ratio, aOR 0.23, 95% confidence interval, CI 0.08-0.66). The highest tertile of handgrip strength was associated with reduced risk of incident cognitive impairment (aOR 0.16, 95% CI 0.04-0.70), compared to the lowest tertile of handgrip strength in obese women, with a significant linear trend (p for trend = 0.016). Furthermore, the highest tertile of handgrip strength was significantly associated with smaller decline in K-MMSE scores compared to the lowest tertile of handgrip strength in obese women (p value = 0.009). There was no association between handgrip strength and incident cognitive impairment in non-obese women. CONCLUSIONS: Strong handgrip strength was associated with reduced risk of cognitive impairment among obese women, but not in non-obese women. Handgrip strength may be a simple and useful marker for predicting future cognitive impairment among obese women. PMID- 30249202 TI - Pregnancy risk factors associated with birthweight of infants born to Australian Aboriginal women in an urban setting - a retrospective cohort study. AB - BACKGROUND: A key focus of the Closing the Gap campaign is to reduce low birthweight in Aboriginal babies. Limited research exists on factors affecting Aboriginal birthweight in urban areas. METHODS: Retrospective cohort analysis of 38,382 births (38,167 non-Aboriginal, 215 Aboriginal) at the Royal Women's Hospital in Melbourne from January 2010 to December 2015. Aboriginal status was defined by mothers who identified themselves and their baby as Aboriginal or Torres Strait Islander. The aim was to examine the association of maternal health risk behaviours and obstetric complications with birthweight of infants born to Australian Aboriginal women birthing in an urban setting. RESULTS: Aboriginal babies had a lower mean birthweight than non-Aboriginal babies (mean difference 290 g; 95% confidence interval [CI] -413, - 166 g), but when accounting for gestational age and sex there was little difference (mean difference 5 g; 95% CI 53, 6 g). Aboriginal babies were significantly more likely to be delivered preterm < 37 weeks (23.3% vs 7.9%, odds ratio [OR] 3.58; 95% CI 2.58, 4.95) and be of low birthweight < 2500 g (22.3% vs 6.7%, OR 4.03; 95% CI 2.90, 5.60) or very low birthweight < 1500 g (9.8% vs 1.8%, OR 5.81; 95% CI 3.67, 9.16). Aboriginal mothers were significantly more likely to be teenage mothers (9.8% vs 1.6%, OR 5.72; 95% CI 3.54, 9.24), smoke cigarettes throughout the pregnancy (53.8% vs 5.6%, OR 17.2; 95% CI 12.8, 23.0), and use drugs (26.5% vs 2.4%, OR 14.3; 95% CI 10.4, 19.6) during pregnancy, all of which were associated with lower birthweight. Aboriginal mothers were also more likely to have a mental health diagnosis (49.5% vs 18.8%, OR 3.77; 95% CI 2.86, 4.97), be overweight (59.9% vs 42.6%, OR 1.88; 95% CI 1.39, 2.56) and have diabetes (15.3% vs 7.3%, OR 2.31; 95% CI 1.59, 3.35) which were all associated with higher birthweight. CONCLUSIONS: Aboriginal babies born in metropolitan Melbourne are more likely to be of low birthweight compared with non-Aboriginal babies, which in turn was related to higher rates of prematurity and not to being small for gestational age. PMID- 30249204 TI - Quality of randomized controlled trials of new generation antidepressants and antipsychotics identified in the China National Knowledge Infrastructure (CNKI): a literature and telephone interview study. AB - BACKGROUND: We are witnessing an exponential increase in the number of randomized controlled trials (RCTs) reported from mainland China. The increase is particularly notable in the field of new generation antidepressants and antipsychotics. Several previous studies have raised doubts regarding their quality. However, the quality of most recent RCTs published in China may have improved. METHODS: We searched RCTs that examined new generation antidepressants and antipsychotics published between 2013 and 2016 in the China National Knowledge Infrastructure (CNKI), the largest database of scientific publications in China. We interviewed the authors of a random subset of the identified references. We assessed the methodological rigor of each study based on the published reports and telephone interviews with the authors using six methodological domains adapted from the Cochrane's risk of bias tool. RESULTS: The final sample consisted of 138 studies, for which we interviewed 58 authors; the authors of 51 studies declined the interview, and the authors of 29 studies could not be contacted. The 51 studies with refused interviews were significantly less likely to be reported from university-affiliated hospitals and were less likely to be published in Chinese core journals. Based on the published reports, most of the 58 studies were assessed to be at unclear risk of bias in most methodological domains. After the interview, only 10 studies were assessed to be at low risk of bias for sequence generation and allocation concealment. Assuming that the studies for which the authors declined interviews had an unclear risk, the proportion of RCTs at low risk of bias in both sequence generation and allocation concealment was 9.2% (10/109, 95% confidence interval [CI]: 5.0 to 16.2). The interviews indicated that the studies were at high risk of bias for most of the other domains. CONCLUSION: In general, RCTs that evaluate new generation antidepressants or antipsychotics and are indexed in the CNKI continue to be of low quality. When conducting systematic reviews and meta-analyses in this field, it would be wise to include a specialist from China as a coresearcher to help assess the risk of bias in the identified studies. PMID- 30249203 TI - Rationale and design of a pragmatic clinical trial to assess the impact of self monitoring blood pressure at home and self-titration of antihypertensive medication in poorly controlled hypertension: the ADAMPA study protocol. AB - BACKGROUND: Lack of control of hypertension is one of the most prevalent problems encountered by general practitioners (GPs). Self-measured blood pressure monitoring at home (SMBP) and self-titration of medication could be a good strategy to improve hypertension management, however, evidence is limited and not conclusive. We aimed to assess the effectiveness, in the primary care setting, of an intervention that includes educational components, SMBP and self-titration of antihypertensive medication to decrease systolic blood pressure compared to usual care, in a population with poorly controlled hypertension, during a 12-month period. METHODS: Pragmatic, controlled, randomized, unblinded clinical trial with two parallel groups assigned in a ratio of 1:1 to self-management (which includes educational components, SBMP and self-titration of antihypertensive medication based on a patient's GP's pre-established adjustment plan) or to usual care (with educational components too). DISCUSSION: If the data from this trial show positive results, the study may contribute to a change of strategy in the treatment of hypertension, focusing on the patient as the main actor to achieve blood pressure control. Furthermore, this approach might contribute to the financial sustainability of the National Health Service. TRIAL REGISTRATION: This trial has been registered in the database with reference number EudraCT: 2016 003986-25. Registered 05 May 2017, https://www.clinicaltrialsregister.eu/ctr search/search?query=2016-003986-25. PMID- 30249205 TI - Comparison of analgesic effect of oxycodone and morphine on patients with moderate and advanced cancer pain: a meta-analysis. AB - BACKGROUND: Morphine and oxycodone are considered as wide-spreadly used opioids for moderate/severe cancer pain. However, debate exists about the evidence regarding their relative tolerability and underlying results. METHODS: A systematic search of online electronic databases, including PubMed, Embase, Cochrane library updated on October 2017 were conducted. The meta-analysis was performed including the studies that were designed as randomized controlled trials. RESULTS: In total, seven randomized clinical trials met our inclusion criteria. No statistical differences in analgesic effect between oxycodone and morphine were observed. Both the pooled analysis of API (MD =0.01, 95% CI -0.22 - 0.23; p = 0.96) and WPI (MD = - 0.05, 95% CI -0.21 - 0.30; p = 0.72) demonstrated clinical non-inferiority of the efficacy of morphine compared with oxycodone, respectively. Additionally, no significant difference in PRR response was observed in either oxycodone or morphine that were used in patients (MD =0.99, 95% CI -0.88 - 1.11; p = 0.87). With the pooled result of AEs indicating the comparable safety profiles between the 2 treatment groups, the meta-analysis on the nausea (OR = 1.20, 95% CI 0.90-1.59; p = 0.22), vomiting (OR = 1.33, 95% CI 0.75-2.38; p = 0.33), somnolence (OR = 1.35, 95% CI 0.95-1.93; p = 0.10), diarrhea (OR = 1.01, 95% CI 0.60-1,67; p = 0.98), and constipation (OR = 1.04, 95% CI 0.77-1.41; p = 0.79) was conducted, respectively. CONCLUSIONS: In the current study, no remarkable difference was identified either in analgesic efficacy or in tolerability of oxycodone and morphine as the first-line therapy for patients with moderate to severe cancer pain. Thus, no sufficient clinical evidence on the superior effects of oxycodone to morphine was provided in this experimental hypothesis. PMID- 30249206 TI - Genome-wide diversity in temporal and regional populations of the betabaculovirus Erinnyis ello granulovirus (ErelGV). AB - BACKGROUND: Erinnyis ello granulovirus (ErelGV) is a betabaculovirus infecting caterpillars of the sphingid moth E. ello ello (cassava hornworm), an important pest of cassava crops (Manihot esculenta). In this study, the genome of seven field isolates of the virus ErelGV were deep sequenced and their inter- and intrapopulational sequence diversity were analyzed. RESULTS: No events of gene gain/loss or translocations were observed, and indels were mainly found within highly repetitive regions (direct repeats, drs). A naturally occurring isolate from Northern Brazil (Acre State, an Amazonian region) has shown to be the most diverse population, with a unique pattern of polymorphisms. Overall, non synonymous substitutions were found all over the seven genomes, with no specific gathering of mutations on hotspot regions. Independently of their sizes, some ORFs have shown higher levels of non-synonymous changes than others. Non-core genes of known functions and structural genes were among the most diverse ones; and as expected, core genes were the least variable genes. We observed remarkable differences on diversity of paralogous genes, as in multiple copies of p10, fgf, and pep. Another important contrast on sequence diversity was found on genes encoding complex subunits and/or involved in the same biological processes, as late expression factors (lefs) and per os infectivity factors (pifs). Interestingly, several polymorphisms in coding regions lie on sequences encoding specific protein domains. CONCLUSIONS: By comparing and integrating information about inter- and intrapopulational diversity of viral isolates, we provide a detailed description on how evolution operates on field isolates of a betabaculovirus. Our results revealed that 35-41% of the SNPs of ErelGV lead to amino acid changes (non-synonymous substitutions). Some genes, especially non core genes of unknown functions, tend to accumulate more mutations, while core genes evolve slowly and are more conserved. Additional studies would be necessary to understand the actual effects of such gene variations on viral infection and fitness. PMID- 30249208 TI - Knockdown long non-coding RNA ANRIL inhibits proliferation, migration and invasion of HepG2 cells by down-regulation of miR-191. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with high fatality rate. Recent studies reported that up-regulation of long non-coding RNA antisense non-coding RNA in the INK4 locus (lncRNA ANRIL) was found in HCC tissues, and which could affect HCC cells biological processes. However, the potential molecular mechanism of ANRIL in HCC is still unclear. The study aimed to uncover the effect of ANRIL on HepG2 cells growth, migration and invasion. METHODS: The knockdown expression vectors of ANRIL were transfected into HepG2 cells, and qRT-PCR, CCK-8, flow cytometry, Transwell and western blot assays were performed to analyze the effect of ANRIL on cell proliferation, apoptosis, migration and invasion. The relative expression of miR-191 was then examined in ANRIL knockdown vector transfected cells. These experiments were repeated again for exploring the effect of miR-191 on HepG2 cells. NF-kappaB and Wnt/beta catenin signaling pathways were examined by using western blot assay. RESULTS: Knockdown of ANRIL inhibited proliferation, induced apoptosis, meanwhile suppressed migration and invasion of HepG2 cells. Additionally, the results showed that the expression level of miR-191 was down-regulated by ANRIL knockdown in HepG2 cells. Importantly, overexpression of miR-191 reversed the anti-tumor effect of ANRIL on cell proliferation, apoptosis, migration and invasion in HepG2 cells. Besides, we found that ANRIL knockdown inactivated NF-kappaB and Wnt/beta catenin pathways by regulating miR-191. CONCLUSIONS: These data demonstrated that ANRIL knockdown suppressed proliferation, migration, invasion, and promoted apoptosis in HepG2 cells by down-regulating miR-191 and inactivating NF-kappaB and Wnt/beta-catenin signaling pathways. PMID- 30249209 TI - Embedding of lamellar hole-associated epiretinal proliferation combined with internal limiting membrane inversion for the treatment of lamellar macular hole: a case report. AB - BACKGROUND: We recently reported that lamellar macular hole (LMH) with lamellar hole-associated epiretinal proliferation (LHEP) can be effectively treated by embedding the LHEP into the retinal cleavage to improve foveal contour and visual acuity. Here, we report a case of LMH with LHEP for which we performed embedding of the LHEP combined with internal limiting membrane (ILM) inversion. We then evaluated the effects of this surgery on macular morphology and visual functions. CASE PRESENTATION: A 62-year-old man presented with visual disturbance (20/29) and metamorphopsia in his right eye. B-scan optical coherence tomography (OCT) imaging revealed the presence of both partial-thickness defect of the macula with degenerative retinal cleavage and LHEP at the surface of the retina. En face OCT imaging showed the absence of retinal fold. We performed phacoemulsification with intraocular lens implantation, vitrectomy, embedding of LHEP into the retinal cleavage, and ILM inversion. Three months after the surgery, both foveal contour and visual acuity (20/20) were improved and metamorphopsia was reduced. CONCLUSION: Embedding of the LHEP combined with ILM inversion may be an effective treatment for LMH with LHEP. PMID- 30249207 TI - Analysis of Drosophila melanogaster testis transcriptome. AB - BACKGROUND: The formation of matured and individual sperm involves a series of molecular and spectacular morphological changes of the developing cysts in Drosophila melanogaster testis. Recent advances in RNA Sequencing (RNA-Seq) technology help us to understand the complexity of eukaryotic transcriptomes by dissecting different tissues and developmental stages of organisms. To gain a better understanding of cellular differentiation of spermatogenesis, we applied RNA-Seq to analyse the testis-specific transcriptome, including coding and non coding genes. RESULTS: We isolated three different parts of the wild-type testis by dissecting and cutting the different regions: 1.) the apical region, which contains stem cells and developing spermatocytes 2.) the middle region, with enrichment of meiotic cysts 3.) the basal region, which contains elongated post meiotic cysts with spermatids. Total RNA was isolated from each region and analysed by next-generation sequencing. We collected data from the annotated 17412 Drosophila genes and identified 5381 genes with significant transcript accumulation differences between the regions, representing the main stages of spermatogenesis. We demonstrated for the first time the presence and region specific distribution of 2061 lncRNAs in testis, with 203 significant differences. Using the available modENCODE RNA-Seq data, we determined the tissue specificity indices of Drosophila genes. Combining the indices with our results, we identified genes with region-specific enrichment in testis. CONCLUSION: By multiple analyses of our results and integrating existing knowledge about Drosophila melanogaster spermatogenesis to our dataset, we were able to describe transcript composition of different regions of Drosophila testis, including several stage-specific transcripts. We present searchable visualizations that can facilitate the identification of new components that play role in the organisation and composition of different stages of spermatogenesis, including the less known, but complex regulation of post-meiotic stages. PMID- 30249210 TI - Antibiotic resistance in Vietnam: moving towards a One Health surveillance system. AB - BACKGROUND: The international community strongly advocates the implementation of multi-sectoral surveillance policies for an effective approach to antibiotic resistance, in line with the One Health concept. To comply with these international recommendations, the Vietnamese government has issued an inter ministerial surveillance strategy for antibiotic resistance, including an integrated surveillance system. However, one may question the ability and willingness of surveillance stakeholders to implement the collaborations required. To assess the feasibility of operationalising this strategy within the national context, we explored the role of key stakeholders in the strategy, as well as their abilities to comply with it. METHODS: We conducted a qualitative approach based on an iterative stakeholder mapping and analysis, in three distinct steps: (1) a description of the structure of the national surveillance strategy (literature review, key informant interviews); (2) an analysis of the key stakeholders' positions regarding the strategy (semi-structured interviews); (3) the identification of factors influencing the operationalisation of the collaborative surveillance strategy (comparison of data collected at the first and second steps). RESULTS: The mapping of the surveillance system, as well as the characterisation of key stakeholders according to organisational and functional attributes, underlined that inter-sectoral surveillance initiatives do exist, but that the organisation of the national surveillance system remains highly silo-oriented. Based on stakeholder perspectives, we identified seven factors that may influence the implementation of the One Health strategy at national level: governance and operational frameworks, divergence of institutional cultures, level of knowledge, technical capacities, allocation of resources, conflicting commercial interests and influence of international partners. CONCLUSIONS: The study suggests that the operationalisation of the collaborative surveillance strategy requires the full adhesion of stakeholders and the provision of appropriate resources. Based on these findings, we have proposed a guidance framework together with recommendations to move towards a more suitable governance and operational model for One Health surveillance of antibiotic resistance in Vietnam. To lever and promote successful inter-sectoral collaboration, a participatory "learning by doing" process could be applied to guide, frame and mentor stakeholders through the identification of appropriate levels of collaboration, depending on the expected positive impacts on the value of surveillance. PMID- 30249211 TI - Phase II study of neoadjuvant checkpoint blockade in patients with surgically resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. AB - BACKGROUND: Soft tissue sarcomas are a heterogeneous and rare group of solid tumors of mesenchymal origin that can arise anywhere in the body. Although surgical resection is the mainstay of treatment for patients with localized disease, disease recurrence is common and 5-year overall survival is poor (~ 65%). Both radiation therapy and conventional chemotherapy are used to reduce local and distant recurrence. However, the utility of radiation therapy is often limited by disease location (in the case of retroperitoneal sarcomas, for instance) while systemic therapy with conventional lines of chemotherapy offer limited efficacy and are often poorly tolerated and associated with significant toxicity. Within the past decade, major advances have been made in the treatment of other malignancies including melanoma, renal cell carcinoma, and non-small cell lung carcinoma with the advent of immune-checkpoint inhibitors such as ipilimumab (anti-CTLA4), pembrolizumab (anti-PD1), and nivolumab (anti-PD1). The recently published SARC028 (NCT02301039), an open label, phase II, multicenter trial of pembrolizumab in patients with advanced bone and soft tissue sarcomas reported promising activity in select histologic subtypes of advanced STS, including undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. METHODS: There is a clear need for novel and effective adjuncts in the treatment of STS. We hypothesize that immune checkpoint blockade will be effective in patients with surgically resectable primary or locally recurrent dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma when administered in the neoadjuvant setting. The primary aim of this phase II, single-center, open label, randomized non-comparative trial is to determine the pathologic response to neoadjuvant nivolumab monotherapy and combination nivolumab/ipilimumab in patients with resectable dedifferentiated liposarcoma of the retroperitoneum or undifferentiated pleomorphic sarcoma of the trunk or extremity treated with concurrent standard of care neoadjuvant radiation therapy. DISCUSSION: This study will help define the role of single agent anti-PD1 and combination anti-CTLA4 and anti-PD1 therapy in patients with surgically resectable dedifferentiated liposarcoma and undifferentiated pleomorphic sarcoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT03307616 , registered October 12, 2017. PMID- 30249212 TI - Metabolic memory in mitochondrial oxidative damage triggers diabetic retinopathy. AB - BACKGROUND: Diabetic retinopathy (DR) is a microvascular complication induced by high blood glucose. This study was conducted to investigate the effect of metabolic memory on mitochondrial oxidative damage-induced DR. METHODS: Rat retinal endothelial cells (rRECs) were isolated from SD rats and treated with high glucose (20 mM) for various times and then cultured in normal glucose (5.6 mM) medium for 2 days. The cells were assayed for the expression of respiratory chain complexes cytochrome c oxidase subunit 1 (CO1) and NADPH-1 using RT-PCR, mitochondrial membrane potentials and reactive oxygen species (ROS) production using flow cytometry and apoptosis using Annexin V/PI flow cytometry. RESULTS: rRECs displayed like short spindles after cultured for 9-10 days and reached 100% confluency. Compared with the control grown in normal glucose (5.6 mM) medium, rRECs exposed to high glucose medium for 3, 12 and 24 h had significantly increased mRNA levels of CO1 and NAPDH-1 even after being shifted back to normal glucose medium. They also had lower mitochondrial membrane potential (89.13% vs 78.21%, p < 0.05), cytochrome C level (1 in control vs 0.25 after 24 h exposure to high glucose, p < 0.05 and higher ROS production (2.77% in control vs 9.00% after 12 h exposure to high glucose, p < 0.05) and apoptosis (7.15% in control vs and 29.91% after 24 h exposure to high glucose, p < 0.05). CONCLUSION: It is likely that mitochondrial oxidative damage triggers metabolic memory via ROS overproduction, leading to diabetic retinopathy. PMID- 30249213 TI - Meaningful connections in dementia end of life care in long term care homes. AB - BACKGROUND: Most persons with dementia die in long term care (LTC) homes, where palliative approaches are appropriate. However, palliative approaches have not been widely implemented and there is limited understanding of staff and family experiences of dying and bereavement in this context. METHOD: This descriptive qualitative study explored family and staff experiences of end of life and end of life care for persons with dementia in LTC homes. Eighteen focus groups were conducted with 77 staff members and 19 relatives of persons with dementia at four LTC homes in four Canadian provinces. RESULTS: Three themes emerged: knowing the resident, the understanding that they are all human beings, and the long slow decline and death of residents with dementia. DISCUSSION: Intimate knowledge of the person with dementia, obtained through longstanding relationships, was foundational for person-centred end of life care. Health care aides need to be included in end of life care planning to take advantage of their knowledge of residents with dementia. There were unmet bereavement support needs among staff, particularly health care aides. Persons with dementia were affected by death around them and existing rituals for marking deaths in LTC homes may not fit their needs. Staff were uncomfortable answering relatives' questions about end of life. CONCLUSIONS: Longstanding intimate relationships enhanced end of life care but left health care aides with unmet bereavement support needs. Staff in LTC homes should be supported to answer questions about the trajectory of decline of dementia and death. Further research about residents' experiences of deaths of other residents is needed. PMID- 30249214 TI - Tractional Descemet's membrane detachment after ocular alkali burns: case reports and review of literature. AB - BACKGROUND: Descemet's membrane detachment (DMD) is a rare complication after ocular chemical injury and its pathogenesis remains unclear. In this study, we reported two cases of DMD with traction demonstrated on Anterior segment optical coherence tomography (AS-OCT). CASE PRESENTATION: Two patients sustained ocular chemical injury with 50% sodium hydroxide. In both cases, AS-OCT revealed detached Descemet's membrane that was adherent to the underlying iris tissue in the inferior quadrant at 45 days and 34 days after the injury respectively. The first case received intracameral tamponade with 12% C3F8 gas and the second case received corticosteroid and sodium chloride 5% eye drops. However, DMD persisted in both cases. CONCLUSIONS: The atypical features of DMD on anterior segment optical coherence tomography in our cases suggested the presence of an inflammatory component caused adhesions and traction of iris to Descemet's membrane and prevented reattachment of DMD even with gas tamponade. PMID- 30249215 TI - Febrile neutropenia (FN) occurrence outside of clinical trials: occurrence and predictive factors in adult patients treated with chemotherapy and an expected moderate FN risk. Rationale and design of a real-world prospective, observational, multinational study. AB - BACKGROUND: Febrile neutropenia (FN) is a common occurrence during chemotherapy. Granulocyte colony-stimulating factors (G-CSFs) can significantly reduce the risk of FN. International guidelines recommend G-CSF for patients receiving chemotherapy with FN risk of >=20% or 10% to 20% with defined risk factors. Prophylaxis is not typically recommended for FN risk of < 10%; however, few studies have investigated FN incidence in lower-risk patients in real-world settings and tried to identify higher-risk subgroups. METHODS: This real-world prospective, observational, multinational study aims to estimate the rate of development of FN with a chemotherapy line expected to be associated with a 10% to 20% risk of FN. Eligible patients (> 18 years of age) will have a solid tumour or Hodgkin/non-Hodgkin lymphoma and a planned chemotherapy regimen with expected risk of FN of 10% to 20% (according to published guidelines). Patients will be observed for the duration of the chemotherapy line (first cycle administered without FN prophylaxis). Primary endpoint is incidence of FN after the first chemotherapy cycle. Secondary outcomes include: FN-associated morbidity and mortality; time to first FN occurrence; other FN risk factors and impact of FN on quality of life. A risk model using occurrence of FN as a binary outcome will be developed. Data will be stratified by age, comorbidities and other risk factors. DISCUSSION: This study will provide insight into the real FN risk for common chemotherapy regimens and predictive factors for FN, including patients generally excluded from randomised clinical trials, from which reported FN rates have been variable. This study builds on knowledge of predictive factors from other research and will provide information on patients with 10% to 20% FN risk. PMID- 30249217 TI - Use of biologically-based complementary medicine in breast and gynecological cancer patients during systemic therapy. AB - BACKGROUND: Biologically-based complementary medicines (BB-CAM) including herbs and nutritional supplements are frequently taken by breast- and gynecological cancer patients undergoing systemic therapy. The aim of this study was to analyze the use of these natural CAM methods under systemic therapy. METHODS: From September 2014 to December 2014 and February 2017 to May 2017 all patients (n= 717) undergoing systemic therapy at the day care unit, Department of Gynecology and Obstetrics, Technical University Munich, Germany, with breast- and/or gynecological cancer were included in this survey. The self-administered 8-item questionnaire was developed to obtain information on complementary medication intake during systemic therapy. RESULTS: Among 448 respondents 74.1% reported to use complementary medication simultaneous to their systemic therapy. The most frequently applied methods during therapy were vitamins and minerals supplements (72.3%), medicinal teas (46.7%), phytotherapy (30.1%), and mistletoe (25.3%). The analysis showed that various patients-, disease- and therapy characteristics like receiving chemotherapy (p= 0.002), and younger age (younger than 60 years; p=0.017) are significantly associated with BB-CAM use. CONCLUSIONS: Our data suggest that female cancer patients undergoing systemic therapy frequently use BB CAM medicine. Therefore, it is indispensable to implement counseling and evidence based complementary treatments into clinical routine of cancer centers. A counseling service for integrative medicine concepts and an outpatient program (ZIGG) was therefore implemented in our cancer center in 2013. Further research on the CAM intake of cancer patients is needed in order to verify drug interactions and implement specific guidelines for integrative medication concepts. PMID- 30249218 TI - Hospital utilization rates following antipsychotic dose reductions: implications for tardive dyskinesia. AB - BACKGROUND: Data are limited on the benefits and risks of dose reduction in managing side effects associated with antipsychotic treatment. As an example, antipsychotic dose reduction has been recommended in the management of tardive dyskinesia (TD), yet the benefits of lowering doses are not well studied. However, stable maintenance treatment is essential to prevent deterioration and relapse in schizophrenia. METHODS: A retrospective cohort study was conducted to analyze the healthcare burden of antipsychotic dose reduction in patients with schizophrenia. Medical claims from six US states spanning a six-year period were analyzed for >=10% or >= 30% antipsychotic dose reductions compared with those from patients receiving a stable dose. Outcomes measured were inpatient admissions and emergency room (ER) visits for schizophrenia, all psychiatric disorders, and all causes, and TD claims. RESULTS: A total of 19,556 patients were identified with >=10% dose reduction and 15,239 patients with >=30% dose reduction. Following a >= 10% dose reduction, the risk of an all-cause inpatient admission increased (hazard ratio [HR] 1.17; 95% confidence interval [CI] 1.11, 1.23; P < 0.001), and the risk of an all-cause ER visit increased (HR 1.09; 95% CI 1.05, 1.14; P < 0.001) compared with controls. Patients with a >= 10% dose reduction had an increased risk of admission or ER visit for schizophrenia (HR 1.27; 95% CI 1.19, 1.36; P < 0.001) and for all psychiatric disorders (HR 1.16; 95% CI 1.10, 1.23; P < 0.001) compared with controls. A dose reduction of >=30% also led to an increased risk of admission for all causes (HR 1.23; 95% CI 1.17, 1.31; P < 0.001), and for admission or ER visit for schizophrenia (HR 1.31; 95% CI 1.21, 1.41; P < 0.001) or for all psychiatric disorders (HR 1.21; 95% CI 1.14, 1.29; P < 0.001) compared with controls. Dose reductions had no significant effect on claims for TD. CONCLUSION: Patients with antipsychotic dose reductions showed significant increases in both all-cause and mental health-related hospitalizations, suggesting that antipsychotic dose reductions may lead to increased overall healthcare burden in some schizophrenia patients. This highlights the need for alternative strategies for the management of side effects, including TD, in schizophrenia patients that allow for maintaining effective antipsychotic treatment. PMID- 30249216 TI - Effectiveness of targeting fathers for breastfeeding promotion: systematic review and meta-analysis. AB - BACKGROUND: Further research gaps exist in relation to the promotion of breastfeeding. Robust scientific evidence obtained by a meta-analysis would provide objectively summarized data while enabling the assessment of consistency of findings. This review includes the first documented meta-analysis done on the effectiveness of targeting fathers for promoting breastfeeding (BF). Assessments have been done for a primary outcome and for six more secondary outcomes. METHODS: PubMed, EMBASE, Google Scholar, CENTRAL databases and unpublished researches were searched. Selections of randomized-controlled trials and quasi experimental studies were done in three rounds. Heterogeneity and potential publication bias were assessed. Eight studies were included in meta-analysis and others in narrative synthesis of the outcomes. Pooling was done with the Mental- Haenszel method using risk ratio (RR). Summary-of-Findings table was composed by Review-Manager (version 5.3) and GRADEproGDT applications. Subsequent sensitivity analysis was done. RESULTS: Selected eight interventional studies included 1852 families. Exclusive BF at six months was significantly higher (RR = 2.04, CI = 1.58-2.65) in the intervention groups. The RR at 4 months was 1.52 (CI = 1.14 to 2.03). Risk of full-formula-feeding (RR = 0.69, CI = 0.52-0.93) and the occurrence of lactation-related problems were lower in the intervention groups (RR = 0.24, CI = 0.10-0.57). More likelihood of rendering support in BF-related issues was seen in intervention groups (RR = 1.43, CI = 1.22-1.68). Increase of maternal knowledge and favorable attitudes on BF were higher in the intervention groups (P <=; 0.001). The quality of evidence according to GRADE was "low" (for one outcome), "moderate" (for four outcomes), and "high" (for two outcomes). CONCLUSIONS: Targeting fathers in promotion of BF has provided favorable results for all seven outcomes with satisfactory quality of evidence. This review was registered in the PROSPERO-registry (ID: 2017-CRD42017076163) prior to its commencement. PMID- 30249219 TI - Risk patterns of lung cancer mortality in northern Thailand. AB - BACKGROUND: Over the past decade, lung cancers have exhibited a disproportionately high mortality and increasing mortality trend in Thailand, especially in the northern region, and prevention strategies have consequently become more important in this region. Spatial analysis studies may be helpful in guiding any strategy put in place to respond to the risk of lung cancer mortality in specific areas. The aim of our study was to identify risk patterns for lung cancer mortality within the northern region of Thailand. METHODS: In the spatial analysis, the relative risk (RR) was used as a measure of the risk of lung cancer mortality in 81 districts of northern Thailand between 2008 and 2017. The RR was estimated according to the Besag-York-Mollie autoregressive spatial model performed using the OpenBUGS routine in the R statistical software package. We presented the overall and gender specific lung cancer mortality risk patterns of the region using the Quantum Geographic Information System. RESULTS: The overall risk of lung cancer mortality was the highest in the west of northern Thailand, especially in the Hang Dong, Doi Lo, and San Pa Tong districts. For both genders, the risk patterns of lung cancer mortality indicated a high risk in the west of northern Thailand, with females being at a higher risk than males. CONCLUSIONS: There was distinct geographical variation in risk patterns of lung cancer mortality in Thailand. Differences could be related to differences in risk factors such as ground-based radon and air pollution. This study provides a starting point for estimating the spatial pattern of the risk of lung cancer mortality and for examining associations between geographic risk factors and lung mortality for further studies. PMID- 30249220 TI - Suicidal ideation in primary care patients suffering from panic disorder with or without agoraphobia. AB - BACKGROUND: Suicidal ideation is common in patients suffering from panic disorder. The present study investigated rates of suicidal ideation and risk factors for suicidal ideation in a sample of primary care patients suffering from panic disorder with or without agoraphobia. METHODS: A total of N = 296 patients [n = 215 (72.6%) women; age: M = 43.99, SD = 13.44] were investigated. Anxiety severity, anxiety symptoms, avoidance behavior, comorbid depression diagnosis, severity of depression, age, sex, employment status, living situation and frequency of visits at the general practitioner were considered as risk factors of suicidal ideation. RESULTS: Suicidal ideation was experienced by 25% of the respondents. In a logistic regression analysis, depression diagnosis and depression severity emerged as significant risk factors for suicidal ideation. Anxiety measures were not associated with suicidal ideation. CONCLUSION: Suicidal ideation is common in primary care patients suffering from panic disorder with or without agoraphobia. Individuals with greater burden of mental illness in terms of mood disorder comorbidity and depressive symptomatology are especially likely to suffer from suicidal ideation. PMID- 30249222 TI - Regulatory effect of Phikud Navakot extract on HMG-CoA reductase and LDL-R: potential and alternate agents for lowering blood cholesterol. AB - BACKGROUND: For decades, various cardiovascular symptoms have been relieved by the use of Ya-Hom Navakot, which is a formulation comprising 54 herbal medicines. The Thailand Ministry of Public Health listed Ya-Hom Navakot's nine active principle and nomenclative herbal ingredients and termed them 'Phikud Navakot' (PN). Several reports have confirmed that PN has cardiovascular benefits similar to Ya-Hom Navakot. However, whether PN facilitates lipid-lowering activity remains unclear. METHODS: The present study investigated an in vitro model for examining the gene expression levels of 3-hydroxyl-3-methylglutaryl-CoA reductase (HMGCR) and low-density lipoprotein receptor (LDL-R) in HepG2 cells using qRT PCR. The ethanol and water extractions of Ya-Hom Navakot, PN and Ya-Hom Navakot without PN were compared. RESULTS: One mg/ml of both NYEF and NYWF were found to significantly lower cholesterol by either the up-regulation of LDL-R or down regulation of HMGCR compared with negative controls and 1 mg/ml simvastatin (p < 0.05). PNEF also up-regulated LDL-R gene expression, even more than NYEF (p < 0.05). In addition, the ethanol and water extracts of PN significantly down regulated HMGCR gene expression compared with those of Ya-Hom Navakot without PN (p < 0.05). CONCLUSION: The use of Ya-Hom Navakot or PN may provide an alternative treatment to lower cholesterol through HMGCR gene inhibition and LDL R gene enhancement. PMID- 30249221 TI - Developing a digital communication training tool on information-provision in oncology: uncovering learning needs and training preferences. AB - BACKGROUND: Adequate information-provision forms a crucial component of optimal cancer care. However, information-provision is particularly challenging in an oncology setting. It is therefore imperative to help oncological health care practitioners (HCP) optimise their information-giving skills. New forms of online education, i.e. e-learning, enable safe and time and location independent ways of learning, enhancing access to continuous learning for HCP. As part of a user centred approach to developing an e-learning to improve information-giving skills, this study aims to: 1) uncover the learning needs of oncological healthcare providers related to information- provision, and 2) explore their training preferences in the context of clinical practice. METHODS: Focus groups and interviews were organised with oncological HCP (medical specialists and clinical nurse specialists) addressing participants' learning needs concerning information- provision and their training preferences with respect to a new digital training tool on this issue. All sessions were audiorecorded and transcribed verbatim. Using an inductive approach, transcripts were independently coded by three researchers and discussed to reach consensus. Main themes were summarised and discussed. RESULTS: Four focus group sessions (total n = 13) and three interviews were conducted. The first theme concerned the patient outcomes HCP try to achieve with their information. We found HCP to mainly strive to promote patients' understanding of information. The second theme concerned HCP reported strategies and challenges when trying to inform their patients. These entailed tailoring of information to patient characteristics, structuring of information, and dealing with patients' emotions. Regarding HCP training preferences, an e-learning should be neatly connected to clinical practice. Moreover, participants desired a digital training to allow for feedback on their own (videotaped) information-giving skills from peers, communication experts, and/or patients; to monitor their progress and to tailored the training to individual learning needs. CONCLUSIONS: An e-learning for improvement of information-giving skills of oncological HCP should be aimed at the transfer of skills to clinical practice, rather than at enhancing knowledge. Moreover, an e learning is probably most effective when the facilitates individual learning needs, supports feedback on competence level and improvement, and allows input from significant others (experts, peers, or patients). PMID- 30249223 TI - Predictors of male condom use among sexually active heterosexual young women in South Africa, 2012. AB - BACKGROUND: In South Africa, young women are at disproportionate risk of HIV infection with about 2363 new infections per week in 2015. Proper condom use is one of the most effective HIV/AIDS prevention strategies among sexually active persons. Understanding factors associated with male condom use in this key population group is important to curb the spread of HIV. This study determined practices and predictors of male condom use among sexually active young women in South Africa. METHODS: The 2012 National HIV Communication Survey measured the extent of exposure to communication activities for HIV prevention among men and women aged 16-55 years in South Africa. We performed a secondary data analysis on a subset of this survey, focussing on 1031 women aged 16-24 years who reported having had sex in the past 12 months. We determined predictors of male condom use using the unconditional multivariable logistic regression model. RESULTS: Of the 1031 young women, 595 (57.8%) reported using a male condom at last sex, 68.4% in women aged 16-19 years and 54.5% in women aged 20-24 years (p < 0.001). Delayed sexual debut [20 years or above] (Adjusted Odds Ratio [aOR] 2.1, 95% CI: 1.2 to 3.7, p = 0.006); being a student (aOR 1.6, 95% CI: 1.2 to 2.3, p = 0.005); and exposure to HIV communication programmes (aOR 3.1, 95% CI: 1.2 to 8.6, p = 0.025) were significantly associated with male condom use at last sex. CONCLUSION: Male condom use was a common practice among young women and was associated with delayed sexual debut and exposure to HIV communication programmes. Behavioral interventions and HIV communication programmes should therefore encourage young women to delay initiation of sex and promote usage of male condoms. PMID- 30249224 TI - Public health response to large influx of asylum seekers: implementation and timing of infectious disease screening. AB - BACKGROUND: Infectious disease screening of migrants at increased risk is a feature of national infection prevention and control measures. Asylum seekers in Finland are offered screening of tuberculosis (TB), hepatitis B, human immunodeficiency virus infection (HIV) and syphilis based on individual risk assessment. We aimed to evaluate the public health response to a large influx of asylum seekers to Finland in 2015-2016 with respect to national guidelines on initial health services and infectious disease screening. METHODS: We used immigration and healthcare procurement data for all 38,134 asylum seekers to Finland during 2015-2016 to assess the implementation, timing and yields of infectious disease screening. RESULTS: The coverage of pulmonary TB screening was 71.6% [95% CI 71.1-72.0%] and that of hepatitis B, HIV or syphilis 60.6% [60.1 61.1%] among those eligible for screening. The estimated average delay from arrival to pulmonary TB screening was 74 days for adults and 43 days for children. Delay to hepatitis B, HIV and syphilis screening was 91 days for adults and 47 days for children. The seroprevalence of hepatitis B surface antigen positivity was 1.4% [95% CI 1.3-1.6%], HIV 0.3% [95% CI 0.1-0.4%] and Treponema pallidum specific antibodies 1.0% [95% CI 0.8-1.1%]. Data did not allow assessment of yields of pulmonary TB screening. CONCLUSIONS: Up to one third of asylum seekers were not reached by screening and screenings were delayed from target timeframes. Children, as a vulnerable population, were screened earlier than adults. To ensure higher screening coverage, infectious disease risks should be reassessed and screening completed at contacts to healthcare during the post asylum phase of integration. The large influx of asylum seekers to Finland in 2015-2016 tested the country's public health preparedness. After action reviews of the public health response to the large migrant influx such as screening implementation can be used for evidence-based improvement of public health preparedness and guidelines for initial health services and infectious disease screening. PMID- 30249225 TI - Negative pressure wound therapy and split thickness skin graft aided in the healing of extensive perineum necrotizing fasciitis without faecal diversion: a case report. AB - BACKGROUND: Perineum necrotizing fasciitis, also known as Fournier gangrene (FG), is a rare but highly mortal infectious necrotizing fasciitis with or without involvement of the underlying muscle. Evidence exists that negative pressure wound therapy (NPWT) combined with a split thickness skin graft (STSG) can help to heal wounds with FG. However, when the wound spreads to the anal area, it can easily be contaminated by faeces, causing a more extensive wounds; thus, faecal diversion is considered. Here, we report a case of extensive perineum necrotizing fasciitis that spread to near the anus; NPWT combined with STSGs was used to help heal the wound without faecal diversion. CASE PRESENTATION: A 47-year-old male patient was admitted with extensive perineum fascia necrosis caused by Pseudomonas aeruginosa that rapidly spread to near the anus. After comprehensive therapy completed wound bed preparation, STSGs from the scalp were grafted to the wound, and NPWT was applied to improve STSGs survival and seal the anus without faecal diversion. After treatment, graft take was 95%, and the exposed testicular and residual wounds were repaired with a local skin flap. At discharge, the wound had decreased to two pea-sized areas. The patient received conventional moist gauze therapy to close the residual wound at the local hospital. A follow-up by telephone 1 month later showed that both wounds had healed and that the patient was satisfied with the outcome. CONCLUSION: NPWT use combined with STSGs to cover the whole wound and the anus without faecal diversion is a safe and effective method to help with wound healing and avoid contamination with excrement. PMID- 30249226 TI - Increased expression of immediate early response gene 3 protein promotes aggressive progression and predicts poor prognosis in human bladder cancer. AB - BACKGROUND: Immediate early response gene 3 (IER3) is a stress-inducible gene, which exerts diverse effects in regulating cell apoptosis and cell cycle. Growing evidence shows that IER3 functions either as an oncogene or a tumor suppressor in various human cancers with a cancer type-dependent manner. However, the involvement of IER3 in human bladder cancer (BCa) has not been elucidated. In the current study, we aimed to investigate the expression pattern and the clinical significance of IER3 in BCa. METHODS: We performed immunohistochemistry analysis to examine the subcellular localization and the expression levels of IER3 protein in 88 BCa specimens obtained from Department of Pathology in Massachusetts General Hospital. The associations of IER3 protein expression with various clinicopathological features and patients' overall survival were statistically evaluated. RESULTS: IER3 protein was mainly expressed in the cytoplasm in bladder cancer cell. Of 88 BCa tissue specimens, 39 (44.3%) showed high expression of IER3 protein and 49 (55.7%) showed low expression. High IER3 protein expression was significantly associated with high pathologic nodal stage (p = 0.018). Kaplan Meier analysis revealed that the overall survival of BCa patients with overexpression of IER3 protein was shorter than that with low expression (p < 0.01). Multivariate analysis by Cox regression further identified IER3 as an independent prognostic factor of BCa patients (p = 0.010). CONCLUSIONS: Our findings suggest for the first time that the increased expression of IER3 protein may promote the aggressive progression of BCa. Importantly, IER3 may be a potential prognostic marker for BCa patients. PMID- 30249228 TI - Men's awareness of cervical cancer: a qualitative study. AB - BACKGROUNDS: As HPV is a sexually transmitted virus, men are crucial in the prevention of cervical cancer, but research about men's awareness on cervical cancer is limited. Therefore, in this study, we investigated men's awareness toward women's cervical cancer, to thoroughly understand the viewpoints of men, and to emphasize the centrality of the role of men in the prevention of cervical cancer. METHODS: A qualitative descriptive design was chosen to explore men's awareness of women's cervical cancer. Twelve men aged 20-58 were interviewed. Snowball sampling was conducted to recruit participants. RESULTS: Most participants stated that they were not interested in women's health, and that they did not have much knowledge about cause and prevention of cervical cancer. They acknowledged that cervical cancer was different from other cancers, based on cause and prognosis of disease. The recognition of cervical cancer in participants varied widely depending on their relationship with women. Respondents' recognition of cervical cancer was classified into four types based on a Situational Awareness (SA) model including individual factors (knowledge about cervical cancer, interest in women's health) and system/task factors (relationship with women, men's responsibility). CONCLUSION: This study is one of the few studies describing men's awareness on cervical cancer. Korean men's awareness level was low, and their concern and knowledge were not good. Some participants thought that cervical cancer can be treated, can be prevented, and is recognized as a disease of a female with men intervening. Our participants perceived that the role of men is necessary for the prevention of cervical cancer. Therefore, a strategy is needed to develop the awareness and knowledge of men on cervical cancer prevention. When planning cervical cancer education for men, phase and type-specific approaches are required, depending on perception level. PMID- 30249227 TI - Cyclic bisphosphonate therapy reduces pain and improves physical functioning in children with osteogenesis imperfecta. AB - BACKGROUND: Children with osteogenesis imperfecta (OI) experience pain and impaired physical functioning. The longitudinal effect of cyclic bisphosphonate treatment on these symptoms has not been described. We serially evaluated pain and functioning in pediatric patients with OI treated with intravenous bisphosphonate therapy. METHODS: Pain and physical functioning were assessed at multiple time-points over two infusion cycles in 22 OI patients (median age 10 years [range 2-21 years]; 8 girls) receiving cyclic intravenous bisphosphonate therapy. Pain was assessed using the FACES(r) visual analogue scale; physical functioning, including self-care, was assessed using the PedsQLTM Generic Core inventory. RESULTS: Pain scores decreased significantly immediately following infusion and remained reduced at 4 weeks post-infusion, increasing before and decreasing again after subsequent infusion (F = 25.00, p < 0.001). Physical functioning scaled scores improved 4 weeks after infusion and declined before subsequent infusion across patients (F = 10.87, p = 0.007). Exploratory analyses indicated significantly different effects between mild and moderate-severe OI types for pain, but not for physical functioning. No fractures occurred during the study. CONCLUSION: In children with OI, cyclic intravenous bisphosphonate therapy transiently reduces pain and improves functional abilities. Pain relief occurs immediately following infusion with functional improvements observed 4 weeks later. Both pain and physical functioning return to pretreatment levels by the subsequent infusion. PMID- 30249229 TI - Developing internal medicine subspecialty fellows' teaching skills: a needs assessment. AB - BACKGROUND: For academic physicians, teaching represents an essential skill. The proliferation of educator training programs aimed at residents and medical students signals the increasing commitment of training programs to develop teaching skills in their trainees as early as possible. However, clinical fellowships represent an important opportunity to advance training as educators. In addition to enriching the pipeline of future teachers, developing fellows as teachers augments the training experience for more junior trainees and may impact patient care. Fellows' needs for programs to improve teaching skills have been largely unexplored. METHODS: We conducted a multi-institutional needs assessment of internal medicine (IM) subspecialty fellows to gauge interest in teaching and improvement of teaching skills. We surveyed IM subspecialty fellows at three academic medical centers about their access to fellow-as-teacher programs and other mechanisms to improve their teaching skills during fellowship. We also elicited their attitudes towards teaching and interest in training related to teaching skills. RESULTS: One hundred eighty-three fellows representing 20 programs and nine different subspecialties responded to the survey (48% response rate). The majority of participants (67%) reported having no specific training focused on teaching skills and only 12% reported receiving regular feedback about their teaching during their fellowship. Seventy-nine percent of fellows anticipated teaching to be part of their careers, and 22% planned to participate in medical education scholarship. Fellows reported a strong interest in teaching and programs aimed at improving their teaching skills. CONCLUSIONS: The majority of fellows reported a lack of mechanisms to advance their teaching skills as fellows, despite anticipating teaching to be an important aspect of their future careers and having strong interest in such programs. Our findings at three academic medical centers confirm a lost opportunity among subspecialty fellowships to accelerate teaching skills development for future educators. PMID- 30249230 TI - Associations among IGF-1, IGF2, IGF-1R, IGF-2R, IGFBP-3, insulin genetic polymorphisms and central precocious puberty in girls. AB - BACKGROUND: Insulin and insulin-like growth factor (IGF)-1 coupled with growth hormone helps control timing of sexual maturation. Mutations and variants in multiple genes are associated with development or reduced risk of central precocious puberty (CPP). METHODS: We assessed single nucleotide polymorphisms (SNPs) in the IGF-1, IGF-2, IGF-3, IGF-1 receptor (IGF1R), IGF-2 receptor (IGF2R), and IGF -binding protein 3 (IGFBP-3) genes, and their association with demographics and metabolic proteins in girls with CPP. Z-scores of height, weight, and body mass index (BMI) were calculated with the WHO reference growth standards for children. RESULTS: IGF-1 serum levels of CPP group exhibited a higher correlation with bone age, z-scores of height and weight, and luteinizing hormone (LH) than those of control group, regardless of BMI adjustment. In the CPP group, height was associated with IGF-2(3580), an adenine to guanine (A/G) SNP at position + 3580. BMI in the CPP group was associated with IGF-2(3580), IGF1R, and the combinations of [IGF-2(3580) + IGF2R], and [IGF-2(3580) + IGFBP 3]. Body weight in the CPP group was associated with the combination of [IGF 2(3580) + IGFBP-3] (p = 0.024). Weight and BMI were significantly associated with the combination of [IGF-2(3580) + IGF2R + IGFBP-3] in the CPP group. These associations were not significantly associated with z-scores of weight, height, or BMI. The distribution of these genotypes, haplotypes, and allele frequencies were similar between control and CPP groups. CONCLUSIONS: These known SNPs of these IGF-1 axis genes appear to play minor roles in the risk for development of CPP. PMID- 30249231 TI - The Erlangen test of activities of daily living in persons with mild dementia or mild cognitive impairment (ETAM) - an extended validation. AB - BACKGROUND: The ability to perform activities of daily living (ADLs) is a central marker in the diagnosis and progression of the dementia syndrome. ADLs can be identified as basic ADLs (BADLs), which are fairly easy to perform, or instrumental ADLs (IADLs), which involve more complex activities. Presently, the only performance-based assessment of IADL capabilities in persons with cognitive impairment is the Erlangen Test of Activities of Daily Living in Persons with Mild Dementia or Mild Cognitive Impairment (ETAM). The aim of the present study was to revalidate the ETAM in persons with mild cognitive impairment (MCI) or mild dementia and to analyze its application to persons with moderate dementia. METHODS: We used baseline data from a cluster randomized controlled trial involving a sample of 443 users of 34 day-care centers in Germany. We analyzed groups of persons with MCI, mild dementia, and moderate dementia, categorized on the basis of the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). An item analysis was performed, and new discriminant validities were calculated. We computed a confirmatory factor analysis (CFA) to examine the postulated theoretical model of the ETAM with all six items loading on a single IADL factor. This was the first time that the ETAM's sensitivity to change was analyzed after a time period of 6 months. RESULTS: The overall sample scored on average 17.3 points (SD = 7.2) on the ETAM (range: 0-30 points). Persons with MCI scored on average 23.2 points, persons with mild dementia scored 18.4 points, and persons with moderate dementia scored 12.9 points, p < .001 (ANOVA). The item analysis yielded good difficulty indices and discrimination powers. The CFA indicated a good fit between the model and the observed data. After 6 months, both the ETAM score at baseline and the change in MMSE score (t0 t1) were significant predictors of the ETAM score at t1. CONCLUSIONS: The ETAM is a valid and reliable instrument for assessing IADL capabilities in persons with MCI or mild dementia. It is sensitive to changes in cognitive abilities. The test parameters confirm its application to persons with moderate dementia. TRIAL REGISTRATION: Identifier: ISRCTN16412551 (Registration date: 30 July 2014, registered retrospectively). PMID- 30249232 TI - Correction to: Full title: peripheral venous catheter complications in children: predisposing factors in a multicenter prospective cohort study. AB - Following publication of the original article [1], one of the authors flagged that the title of the article was submitted (incorrectly) with "Full title:" at the beginning. PMID- 30249233 TI - An exploratory study of knowledge, attitudes, and beliefs related to tobacco use and secondhand smoke among women in Aleta Wondo, Ethiopia. AB - BACKGROUND: By 2030, the Sub-Saharan African region is projected to be the epicenter of the tobacco epidemic. While smoking prevalence is currently low among women (< 2%), the prevalence among men (7.7% overall and up to 27% depending on region) makes exposure to secondhand smoke a pressing concern for women and children. To prevent the uptake of smoking among women and address tobacco-related risks, including secondhand smoke exposure, a greater understanding of women's related perceptions is needed. The purpose of this study was to explore Ethiopian women's knowledge, attitudes, and beliefs related to tobacco use and secondhand smoke exposure, and the potential influence of contextual factors including; khat use, exposure to pro- and anti-tobacco messaging, and religious affiliation. METHODS: A cross-sectional study using a systematic household sampling technique and an adapted interviewer-administered survey was conducted in Southern Ethiopia. The survey was administered to 353 women, 18-55 years of age, in Aleta Wondo town and surrounding districts between August-October 2014 (95.2% cooperation rate). RESULTS: General awareness of harm associated with personal tobacco use and exposure to secondhand smoke was high (> 94%); however, specific knowledge of associated health-risks was limited. More than 96% perceived female tobacco use as socially unacceptable. At the same time, more than 70% were able to name potential benefits of using tobacco for both personal consumption and non-personal use. Respondents reported greater experimentation with khat versus tobacco and 73% reported that their religion significantly influenced their tobacco-related attitudes. Overall, there were higher reports of exposure to anti-tobacco (70%) versus pro-tobacco (49%) messaging, in the last 30 days. CONCLUSIONS: The high level of awareness of health risks associated with tobacco use and SHS exposure and the high exposure to anti-tobacco messaging are community-level strengths that can proactively be built on to prevent the projected disease burden associated with tobacco. Findings have implications for the development of contextualized gender-specific tobacco control interventions, particularly in relation to the promotion of smoke free homes. PMID- 30249234 TI - Bronchial thermoplasty reduces gas trapping in severe asthma. AB - BACKGROUND: In randomized controlled trials, bronchial thermoplasty (BT) has been proven to reduce symptoms in severe asthma, but the mechanisms by which this is achieved are uncertain as most studies have shown no improvement in spirometry. We postulated that BT might improve lung mechanics by altering airway resistance in the small airways of the lung in ways not measured by FEV1. This study aimed to evaluate changes in measures of gas trapping by body plethysmography. METHODS: A prospective cohort of 32 consecutive patients with severe asthma who were listed for BT at two Australian university hospitals were evaluated at three time points, namely baseline, and then 6 weeks and 6 months post completion of all procedures. At each evaluation, medication usage, symptom scores (Asthma Control Questionnaire, ACQ-5) and exacerbation history were obtained, and lung function was evaluated by (i) spirometry (ii) gas diffusion (KCO) and (iii) static lung volumes by body plethysmography. RESULTS: ACQ-5 improved from 3.0 +/- 0.8 at baseline to 1.5 +/- 0.9 at 6 months (mean +/- SD, p < 0.001, paired t-test). Daily salbutamol usage improved from 8.3 +/- 5.6 to 3.5 +/- 4.3 puffs per day (p < 0.001). Oral corticosteroid requiring exacerbations reduced from 2.5 +/- 2.0 in the 6 months prior to BT, to 0.6 +/- 1.3 in the 6 months after BT (p < 0.001). The mean baseline FEV1 was 57.8 +/- 18.9%predicted, but no changes in any spirometric parameter were observed after BT. KCO was also unaltered by BT. A significant reduction in gas trapping was observed with Residual Volume (RV) falling from 146 +/- 37% predicted at baseline to 136 +/- 29%predicted 6 months after BT (p < 0.005). Significant improvements in TLC and FRC were also observed. These changes were evident at the 6 week time period and maintained at 6 months. The change in RV was inversely correlated with the baseline FEV1 (r = 0.572, p = 0.001), and in patients with a baseline FEV1 of < 60%predicted, the RV/TLC ratio fell by 6.5 +/- 8.9%. CONCLUSION: Bronchial thermoplasty improves gas trapping and this effect is greatest in the most severely obstructed patients. The improvement may relate to changes in the mechanical properties of small airways that are not measured with spirometry. PMID- 30249235 TI - Environmental causes of between-population difference in growth rate of a high altitude lizard. AB - BACKGROUND: Ectothermic animals living in cold (high latitude or high elevation) regions are predicted to grow slower due to limited thermal opportunities for activity and food resources than those living in warm regions. However, the Qinghai toad-headed lizards (Phrynocephalus vlangalii) grow faster and reach a larger adult size at a high-elevation site than at a low-elevation site. In this study, we aimed to identify the genetic and environmental causes of this between population difference in growth rate by conducting mark-recapture and common garden experiments on juvenile growth rate, and investigating the thermal environment, lizard body temperature, potential prey availability at the two elevation sites. RESULTS: Compared with low-elevation individuals, high-elevation juvenile lizards had higher growth rates in the field, but grew at similar rates in the laboratory. High-elevation lizards had higher active body temperatures than low-elevation lizards despite similar air temperatures in the period of field investigation. The high-elevation site had relatively more and larger preys than the low-elevation site. CONCLUSIONS: Inter-population difference in growth rate of P. vlangalii may primarily result from developmental plasticity in response to the difference in environmental resources, rather than genetic differentiation. The higher growth rate of high-elevation lizards is likely associated with higher potential food availability and higher active body temperatures. PMID- 30249236 TI - Pseudothrombophlebitis syndrome in a rheumatoid arthritis patient with swollen calf and persistent itching: a case report. AB - BACKGROUND: Baker's cyst is a benign lesion that results from degenerative or inflammatory diseases of the knee joint. When Baker's cyst ruptures, it may simulate deep vein thrombosis known as Pseudothrombophlebitis syndrome with calf pain, swelling and redness. Pseudothrombophlebitis syndrome without thrombus in popliteal veins has distinct treatment choice than deep vein thrombus. CASE PRESENTATION: In this report, we presented a 47 year-old male rheumatoid arthritis patient with complaints of redness, pain and swelling on his right calf. Pseudothrombophlebitis syndrome was diagnosed due to ruptured Baker's cyst. CONCLUSIONS: We used musculoskeletal ultrasound for both differential diagnosis and treatment of pseudothrombophlebitis syndrome. Ultrasonography revealed massive fluid collection within muscle layers. 280 cc inflammatory fluid was aspirated simultaneously. We also emphasized the importance of ultrasonography in diagnosis and treatment of Pseudothrombophlebitis syndrome with this report. PMID- 30249237 TI - Gillespie syndrome in a South Asian child: a case report with confirmation of a heterozygous mutation of the ITPR1 gene and review of the clinical and molecular features. AB - BACKGROUND: Gillespie syndrome is a rare, congenital, neurological disorder characterized by the association of partial bilateral aniridia, non-progressive cerebellar ataxia and intellectual disability. Homozygous and heterozygous pathogenic variants of the ITPR1 gene encoding an inositol 1, 4, 5- triphosphate- responsive calcium channel have been identified in 13 patients recently. There have been 22 cases reported in the literature by 2016, mostly from the western hemisphere with none reported from Sri Lanka. CASE PRESENTATION: A 10-year-old girl born to healthy non-consanguineous parents with delayed development is described. She started walking unaided by 9 years with a significantly unsteady gait and her speech was similarly delayed. Physical examination revealed multiple cerebellar signs. Slit lamp examination of eyes revealed bilateral partial aniridia. Magnetic resonance imaging of brain at the age of 10 years revealed cerebellar (mainly vermian) hypoplasia. Genetic testing confirmed the clinical suspicion and demonstrated a heterozygous pathogenic variant c.7786_7788delAAG p.(Lys2596del) in the ITPR1 gene. CONCLUSION: The report of this child with molecular confirmation of Gillespie syndrome highlights the need for careful evaluation of ophthalmological and neurological features in patients that enables correct clinical diagnosis. The availability of genetic testing enables more accurate counseling of the parents and patients regarding recurrence risks to other family members. PMID- 30249239 TI - Burden of gluteal fibrosis and post-injection paralysis in the children of Kumi District in Uganda. AB - BACKGROUND: The purpose of this study was to estimate the prevalence of postinjection paralysis (PIP) and gluteal fibrosis (GF) among children treated in a rural Ugandan Hospital. METHODS: We conducted a retrospective cohort study by reviewing the musculoskeletal clinic and community outreach logs for children (age < 18 yrs) diagnosed with either PIP or GF from Kumi Hospital in Kumi, Uganda between 2013 and 2015. We estimated the prevalence as a ratio of the number of children seen with each disorder over the total population of children seen for any musculoskeletal complaint in musculoskeletal clinic and total population of children seen for any medical complaint in the outreach clinic. RESULTS: Of 1513 children seen in the musculoskeletal clinic, 331 (21.9% (95% CI 19.8-24.1%)) had PIP and another 258 (17.1% (95% CI 15.2-19.0%)) had GF as their diagnosis. Of 3339 children seen during outreach for any medical complaint, 283 (8.5% (95% CI 7.6-9.5%)) had PIP and another 1114 (33.4% (95% CI 31.8-35.0%)) had GF. Of patients with GF, 53.9% were male with a median age of 10 years (50% between 7 and 12 years old). Of patients with PIP, 56.7% were male with a median age of 5 years (50% between 2 and 8 years old). CONCLUSION: PIP and GF comprise over 30% of clinical visits for musculoskeletal conditions and 40% of outreach visits for any medical complaint in this area of Uganda. The high estimated prevalence in these populations suggest a critical need for research, treatment, and prevention. PMID- 30249238 TI - E-learning for self-management support: introducing blended learning for graduate students - a cohort study. AB - BACKGROUND: E-learning allows delivery of education in many diverse settings and researchers have demonstrated it can be as effective as learning conducted in traditional face-to-face settings. However, there are particular practices and skills needed in the area of providing patient self-management support (SMS), that may not be achievable online. The aim of this study was to compare three approaches in the training of university students regarding the preparation of a Chronic Condition Self-Management Care Plan: 1) traditional face-to-face delivery of SMS training, 2) an e-learning approach and 3) a blended approach (combining e learning and face-to-face teaching). METHODS: Graduate entry physiotherapy students and medical students at Flinders University were recruited. Depending on the cohort, students were either exposed to traditional face-to-face training, e learning or a blended model. Outcomes were compared between the three groups. We measured adherence to care plan processes in the preparation of an assessment piece using the Flinders Program Chronic Care Self Management tools. A total of 183 care plans were included (102 traditional, 52 blended, 29 e-learning,). All students submitted the Flinders Program Chronic Care Plan for university assessment and these were later assessed for quality by researchers. The submission was also assigned a consumer engagement score and a global competence score as these are integral to successful delivery of SMS and represent the patient perspective. RESULTS: The blended group performed significantly better than the traditional group in quality use of the Flinders Program tools: Problem and Goals (P < 0.0001). They also performed significantly better in the total care plan score (P < 0.0001) and engagement score (P < 0.0001). There was no significant difference between the groups for the Partners in Health tool. CONCLUSIONS: In this pilot study, the blended learning model was a more effective method for teaching self-management skills than the traditional group, as assessed in the development of a chronic condition self-management care plan. We anticipate that future research with identical groups of students would yield similar results but in the meantime, academics can have confidence that blended learning is at least as effective as traditional learning methods. PMID- 30249240 TI - Atherosclerosis of the right posterior hepatic artery in a patient with hilar cholangiocarcinoma undergoing left trisectionectomy: a case report of a therapeutic pitfall. AB - BACKGROUND: We experienced a rare case of benign arterial stricture of the right posterior hepatic artery (RPHA) caused by atherosclerosis in a patient with hilar cholangiocarcinoma. CASE PRESENTATION: A 75-year-old man was referred to our hospital for the detailed investigation of serum hepatobiliary enzyme elevation. The patient had a history of hypertension, type 2 diabetes mellitus, and an operative history of coronary artery bypass grafting 10 years before. Endoscopic retrograde cholangiography found strictures of the right and left hepatic ducts with involvement of right anterior and posterior bile ducts. Adenocarcinoma was evident by brush cytology. We diagnosed these findings as hilar cholangiocarcinoma and planned left trisectionectomy including bile duct reconstruction. Although the tumor and RPHA were not adjacent, preoperative multidetector computed tomography revealed a stricture of the RPHA that was 5.6 mm in length. We suspected that atherosclerosis caused the stricture, and we performed digital subtraction angiography and intravascular ultrasonography that showed stricture of the RPHA accompanied by thick plaques in the arterial wall. We placed a bare-metal stent in the RPHA and then performed left trisectionectomy. Since this patient developed bile leakage postoperatively, percutaneous drainage was performed. The bile leakage was successfully controlled, and the patient was discharged 3 months after surgery. Unfortunately, 4 months after hepatectomy, he was re-hospitalized with multiple pyogenic liver abscesses. We performed intensive multimodal treatment for the liver abscesses and stabilized the disease; however, we eventually lost this patient due to liver failure 14 months after surgery. CONCLUSION: To the best of our knowledge, there is no previous literature on atherosclerosis of the RPHA, which was evident preoperatively in our case. Because arterial complications may lead to critical biliary complications in patients who undergo left trisectionectomy, we first performed prophylactic arterial stent placement. We speculate that existing chronic microscopic injury of the peribiliary plexus might have caused the liver abscesses. We successfully diagnosed atherosclerosis of the RPHA preoperatively. However, further investigation of patients is warranted to determine if left trisectionectomy is contraindicated in these patients. PMID- 30249241 TI - Using behaviour change theory and preliminary testing to develop an implementation intervention to reduce imaging for low back pain. AB - BACKGROUND: Imaging is overused in the management of low back pain (LBP). Interventions designed to decrease non-indicated imaging have predominantly targeted practitioner education alone; however, these are typically ineffective. Barriers to reducing imaging have been identified for both patients and practitioners. Interventions aimed at addressing barriers in both these groups concurrently may be more effective. The Behaviour Change Wheel provides a structured framework for developing implementation interventions to facilitate behavioural change. The aim of this study was to develop an implementation intervention aiming to reduce non-indicated imaging for LBP, by targeting both general medical practitioner (GP) and patient barriers concurrently. METHODS: The Behaviour Change Wheel was used to identify the behaviours requiring change, and guide initial development of an implementation intervention. Preliminary testing of the intervention was performed with: 1) content review by experts in the field; and 2) qualitative analysis of semi-structured interviews with 10 GPs and 10 healthcare consumers, to determine barriers and facilitators to successful implementation of the intervention in clinical practice. Results informed further development of the implementation intervention. RESULTS: Patient pressure on the GP to order imaging, and the inability of the GP to manage a clinical consult for LBP without imaging, were determined to be the primary behaviours leading to referral for non-indicated imaging. The developed implementation intervention consisted of a purpose-developed clinical resource for GPs to use with patients during a LBP consult, and a GP training session. The implementation intervention was designed to provide GP and patient education, remind GPs of preferred behaviour, provide clinical decision support, and facilitate GP-patient communication. Preliminary testing found experts, GPs, and healthcare consumers were supportive of most aspects of the developed resource, and thought use would likely decrease non-indicated imaging for LBP. Suggestions for improvement of the implementation intervention were incorporated into a final version. CONCLUSIONS: The developed implementation intervention, aiming to reduce non-indicated imaging for LBP, was informed by behaviour change theory and preliminary testing. Further testing is required to assess feasibility of use in clinical practice, and the effectiveness of the implementation intervention in reducing imaging for LBP, before large-scale implementation can be considered. PMID- 30249242 TI - Comparative single-dose pharmacokinetics of sildenafil after oral and rectal administration in healthy beagle dogs. AB - BACKGROUND: Sildenafil citrate, a highly selective phosphodiesterase type 5 inhibitor, is used to treat pulmonary hypertension (PH) in veterinary medicine. The objective of this study was to investigate pharmacokinetic profiles by oral administration of orally disintegrating film (ODF) and film coated tablet (FCT) formulations and rectal administration of ODF formulation in healthy dogs. Twelve healthy beagle dogs were administered four separate doses of sildenafil: FCT formulation 2 mg/kg orally, ODF formulation 2 mg/kg orally, ODF formulation 2 mg/kg rectally, and ODF formulation 10 mg/kg rectally. For 24 hours following administration, blood samples were collected and the plasma concentrations of sildenafil were assayed by liquid chromatography-tandem mass spectrometry. RESULTS: There were no significant differences in all the pharmacokinetic parameters between FCT and ODF formulations when administrated orally. Cmax at the time of rectal administration was lower when the same dose was given as that orally administered. No serious systemic adverse events (AEs) were observed. CONCLUSIONS: These findings suggest that sildenafil ODF formulation can be used as an alternative to FCT formulation in the treatment of canine PH patients; additionally, rectal administration of sildenafil ODF may be a beneficial treatment option for canine patients who are unable to receive medication orally. PMID- 30249244 TI - Evaluating hospital websites in Kuwait to improve consumer engagement and access to health information: a cross-sectional analytical study. AB - BACKGROUND: Current advances in information and communication technology have made accessing and obtaining health-related information easier than ever before. Today, many hospital websites use a patient-centric approach to promote engagement and encourage learning for better health-related decision making. However, little is known about the current state of hospital websites in the State of Kuwait. This study aims to evaluate hospital websites in Kuwait and offer recommendations to improve patient engagement and access to health information. METHODS: This study employs a cross-sectional analytical approach to evaluate hospital websites in Kuwait in 2017. The websites of hospitals that provide in-patient services were identified through a structured search. Only active websites that were available in either English or Arabic were considered. The evaluation of the websites involved a combination of automated and expert- based evaluation methods and was performed across four dimensions: Accessibility, Usability, Presence, and Content. RESULTS: Nine hospitals met the inclusion criteria. Most of the websites fell short in all four dimensions. None of the websites passed the accessibility guidelines. The usability of websites varied between hospitals. Overall, the majority of hospitals in Kuwait have rudimentary online presence and their websites require careful reassessment with respect to design, content, and user experience. The websites focus primarily on promoting services provided by the hospital rather than engaging and communicating with patients or providing evidence-based information. CONCLUSIONS: Healthcare organization and website developers should follow best-practices to improve their websites taking into consideration the quality, readability, objectivity, coverage and currency of the information as well as the design of their websites. Hospitals should leverage social media to gain outreach and better engagement with consumers. The websites should be offered in additional languages commonly spoken by people living in Kuwait. Efforts should be made to ensure that health information on hospital websites are evidence-based and checked by healthcare professionals. PMID- 30249245 TI - Assessment of quality of life using the EQ-5D-3L instrument for hospitalized patients with femoral fracture in Brazil. AB - BACKGROUND: Quality of life has become a key outcome in assessing the effectiveness of treatments and interventions in health. METHODS: Accordingly, this research study aimed to measure quality of life using the EQ-5D-3L instrument for patients from the Jamil Haddad National Institute of Traumatology and Orthopedics (Instituto Nacional de Traumatologia e Ortopedia Jamil Haddad - INTO) with femoral fractures, hospitalized between 11/2015 and 10/2016. RESULTS: A total of 165 orthopedic trauma patients with femoral fractures, aged 18 years or older, who were hospitalized and operated upon in the INTO were assessed. The assessment instruments were applied at admission and in the first and second follow-up visits to the outpatient clinic. Most study subjects were women and older than 60 years. Proximal femoral fracture was the most commonly found fracture. The Visual Analog Scale (VAS) assessments over the study period showed an increasing gain in self-assessed quality of life. Similarly, the EQ-5D-3L showed significant improvements in quality of life assessed in the five dimensions of the instrument: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. CONCLUSION: This type of assessment may help in decision-making and cost-utility assessments related to orthopedic trauma. PMID- 30249243 TI - Histone variants H2A.Z and H3.3 coordinately regulate PRC2-dependent H3K27me3 deposition and gene expression regulation in mES cells. AB - BACKGROUND: The hierarchical organization of eukaryotic chromatin plays a central role in gene regulation, by controlling the extent to which the transcription machinery can access DNA. The histone variants H3.3 and H2A.Z have recently been identified as key regulatory players in this process, but the underlying molecular mechanisms by which they permit or restrict gene expression remain unclear. Here, we investigated the regulatory function of H3.3 and H2A.Z on chromatin dynamics and Polycomb-mediated gene silencing. RESULTS: Our ChIP-seq analysis reveals that in mouse embryonic stem (mES) cells, H3K27me3 enrichment correlates strongly with H2A.Z. We further demonstrate that H2A.Z promotes PRC2 activity on H3K27 methylation through facilitating chromatin compaction both in vitro and in mES cells. In contrast, PRC2 activity is counteracted by H3.3 through impairing chromatin compaction. However, a subset of H3.3 may positively regulate PRC2-dependent H3K27 methylation via coordinating depositions of H2A.Z to developmental and signaling genes in mES cells. Using all-trans retinoic acid (tRA)-induced gene as a model, we show that the dynamic deposition of H2A.Z and H3.3 coordinately regulates the PRC2-dependent H3K27 methylation by modulating local chromatin structure at the promoter region during the process of turning genes off. CONCLUSIONS: Our study provides key insights into the mechanism of how histone variants H3.3 and H2A.Z function coordinately to finely tune the PRC2 enzymatic activity during gene silencing, through promoting or impairing chromosome compaction respectively. PMID- 30249246 TI - Factors associated with self-care practice among adult diabetes patients in West Shoa Zone, Oromia Regional State, Ethiopia. AB - BACKGROUND: Diabetes, a rising global health problem, requires continuous self care practice to prevent acute and chronic complications. However, studies show that few diabetes patients practice the recommended self-care in Ethiopia. The aim of this study was to assess factors associated with self-care practice among adult diabetes patients in public hospitals of West Shoa Zone, Oromia Regional State, Ethiopia. METHODS: In this cross-sectional study, 257 diabetes patients (mean age 42.9 +/- 14.6 years, 54.1% male) completed the survey in Afan Oromo and Amharic languages. A questionnaire consisting standardized tools was used to collect the data. Descriptive and logistic regression analyses were conducted using SPSS version 21. RESULTS: The mean score for diabetes self-care was 39.8 +/ 9.5 and 45.5% of the participants scored below the mean. Multiple logistic regression analysis revealed that having higher diabetes knowledge (AOR = 2.42, 95% CI = 1.22, 4.80), self-efficacy (AOR = 3.30, 95% CI = 1.64, 6.62), social support (AOR = 2.86, 95% CI = 1.37, 5.96), secondary school education (AOR = 6.0, 95% CI = 1.90, 18.85), and longer duration of diabetes (AOR = 5.55, 95% CI = 2.29, 13.44) were important predictors of good diabetes self-care practice. CONCLUSION: The diabetes education programs should use strategies that enhance patients' diabetes knowledge, self-efficacy, and social support. Patients with recent diabetes diagnosis need special attention as they may relatively lack knowledge and skills in self-care. Further studies are needed to elucidate pathways through which diabetes knowledge, self-efficacy, social support, and health literacy affect diabetes self-care. PMID- 30249248 TI - Research topics and trends in medical education by social network analysis. AB - BACKGROUND: As studies analyzing the networks and relational structures of research topics in academic fields emerge, studies that apply methods of network and relationship analysis, such as social network analysis (SNA), are drawing more attention. The purpose of this study is to explore the interaction of medical education subjects in the framework of complex systems theory using SNA and to analyze the trends in medical education. METHODS: The authors extracted keywords using Medical Subject Headings terms from 9,379 research articles (162,866 keywords) published in 1963-2015 in PubMed. They generated an occurrence frequency matrix, calculated relatedness using Weighted Jaccard Similarity, and analyzed and visualized the networks with Gephi software. RESULTS: Newly emerging topics by period units were identified as historical trends, and 20 global-level topic clusters were obtained through network analysis. A time-series analysis led to the definition of five historical periods: the waking phase (1963-1975), the birth phase (1976-1990), the growth phase (1991-1996), the maturity phase (1997 2005), and the expansion phase (2006-2015). CONCLUSIONS: The study analyzed the trends in medical education research using SNA and analyzed their meaning using complex systems theory. During the 53-year period studied, medical education research has been subdivided and has expanded, improved, and changed along with shifts in society's needs. By analyzing the trends in medical education using the conceptual framework of complex systems theory, the research team determined that medical education is forming a sense of the voluntary order within the field of medicine by interacting with social studies, philosophy, etc., and establishing legitimacy and originality. PMID- 30249247 TI - Musculoskeletal conditions may increase the risk of chronic disease: a systematic review and meta-analysis of cohort studies. AB - BACKGROUND: Chronic diseases and musculoskeletal conditions have a significant global burden and frequently co-occur. Musculoskeletal conditions may contribute to the development of chronic disease; however, this has not been systematically synthesised. We aimed to investigate whether the most common musculoskeletal conditions, namely neck or back pain or osteoarthritis of the knee or hip, contribute to the development of chronic disease. METHODS: We searched CINAHL, Embase, Medline, Medline in Process, PsycINFO, Scopus and Web of Science to February 8, 2018, for cohort studies reporting adjusted estimates of the association between baseline musculoskeletal conditions (neck or back pain or osteoarthritis of the knee or hip) and subsequent diagnosis of a chronic disease (cardiovascular disease, cancer, diabetes, chronic respiratory disease or obesity). Two independent reviewers performed data extraction and assessed study quality. Adjusted hazard ratios were pooled using the generic inverse variance method in random effect models, regardless of the type of musculoskeletal condition or chronic disease. PROSPERO: CRD42016039519. RESULTS: There were 13 cohort studies following 3,086,612 people. In the primary meta-analysis of adjusted estimates, osteoarthritis (n = 8 studies) and back pain (n = 2) were the exposures and cardiovascular disease (n = 8), cancer (n = 1) and diabetes (n = 1) were the outcomes. Pooled adjusted estimates from these 10 studies showed that people with a musculoskeletal condition have a 17% increase in the rate of developing a chronic disease compared to people without (hazard ratio 1.17, 95% confidence interval 1.13-1.22; I2 52%, total n = 2,686,113 people). CONCLUSIONS: This meta-analysis found that musculoskeletal conditions may increase the risk of chronic disease. In particular, osteoarthritis appears to increase the risk of developing cardiovascular disease. Prevention and early treatment of musculoskeletal conditions and targeting associated chronic disease risk factors in people with long standing musculoskeletal conditions may play a role in preventing other chronic diseases. However, a greater understanding about why musculoskeletal conditions may increase the risk of chronic disease is needed. PMID- 30249249 TI - Magnetic motor evoked potentials of cervical muscles in horses. AB - BACKGROUND: When surgical treatment of cervical vertebral malformation is considered, precise localization of compression sites is essential, but remains challenging. Magnetic motor evoked potentials (mMEP) from paravertebral muscles are useful in localizing spinal cord lesions, but no information about cervical muscle mMEP in horses is available yet. Therefore, the aim of this study was to determine the possibility, normal values, inter- and intra-observer agreement and factors that have an effect on cervical mMEP in healthy horses. METHODS: Transcranial magnetic stimulation was performed on 50 normal horses and 4 (2 left, 2 right) muscle responses were recorded at the middle of each cervical vertebra (C1-C7) and additionally just caudal to C7 to evaluate cervical nerves (Cn) Cn1 to Cn8. Latency time and amplitude of the recorded mMEP were defined by both an experienced and an unexperienced operator. RESULTS: Latency increased gradually from 14.2 +/- 1.38 ms for Cn3 to 17.7 +/- 1.36 ms for Cn8, was significantly influenced by cervical nerve (P < 0.01), gender (P = 0.02) and height (P = 0.03) and had a good intra-observer agreement. The smallest mean amplitude (4.35 +/- 2.37 mV) was found at Cn2, the largest (5.99 +/- 2.53 mV) at Cn3. Amplitude was only significantly influenced by cervical nerve (P < 0.01) and had a low intra-observer agreement. No significant effect of observer on latency (P = 0.88) or amplitude (P = 0.99) measurements was found. CONCLUSION: mMEP of cervical muscles in normal horses are easy to collect and to evaluate with limited intra- and inter-observer variation concerning amplitude and should be investigated in future studies in ataxic horses to evaluate its clinical value. PMID- 30249250 TI - Impact of nutrition on inflammation, tauopathy, and behavioral outcomes from chronic traumatic encephalopathy. AB - BACKGROUND: Repetitive mild traumatic brain injuries (rmTBI) are associated with cognitive deficits, inflammation, and stress-related events. We tested the effect of nutrient intake on the impact of rmTBI in an animal model of chronic traumatic encephalopathy (CTE) to study the pathophysiological mechanisms underlying this model. We used a between group design rmTBI closed head injuries in mice, compared to a control and nutrient-treated groups. METHODS: Our model allows for controlled, repetitive closed head impacts to mice. Briefly, 24-week-old mice were divided into five groups: control, rmTBI, and rmTBI with nutrients (2% of NF 216, NF-316 and NF-416). rmTBI mice received four concussive impacts over 7 days. Mice were treated with NutriFusion diets for 2 months prior to the rmTBI and until euthanasia (6 months). Mice were then subsequently euthanized for macro- and micro-histopathologic analysis for various times up to 6 months after the last TBI received. Animals were examined behaviorally, and brain sections were immunostained for glial fibrillary acidic protein (GFAP) for astrocytes, iba-1 for activated microglia, and AT8 for phosphorylated tau protein. RESULTS: Animals on nutrient diets showed attenuated behavioral changes. The brains from all mice lacked macroscopic tissue damage at all time points. The rmTBI resulted in a marked neuroinflammatory response, with persistent and widespread astrogliosis and microglial activation, as well as significantly elevated phospho-tau immunoreactivity to 6 months. Mice treated with diets had significantly reduced inflammation and phospho-tau staining. CONCLUSIONS: The neuropathological findings in the rmTBI mice showed histopathological hallmarks of CTE, including increased astrogliosis, microglial activation, and hyperphosphorylated tau protein accumulation, while mice treated with diets had attenuated disease process. These studies demonstrate that consumption of nutrient-rich diets reduced disease progression. PMID- 30249251 TI - Effect of levothyroxine supplementation on pregnancy outcomes in women with subclinical hypothyroidism and thyroid autoimmuneity undergoing in vitro fertilization/intracytoplasmic sperm injection: an updated meta-analysis of randomized controlled trials. AB - BACKGROUND: Evidence suggests that subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes. This systematic review and meta-analysis was conducted to determine whether levothyroxine (LT4) supplementation would improve pregnancy outcomes among infertile women with SCH and/or TAI who underwent in vitro fertilization (IVF) or intracytoplastic sperm injection (ICSI). METHODS: We searched databases of PubMed, EMBASE, Web of Science, Cochrane Controlled Trials Register databases, and Clinicaltrials.gov up to April 2018 to identify eligible studies. Studies that focused on the treatment effect of LT4 on pregnancy outcomes of women with SCH and/or TAI who underwent IVF/ICSI were included in the data synthesis. We only included randomized controlled trials (RCTs). Relative risks (RR) and 95% confidence intervals (CI) were calculated using a random-effects model to assess the results of pregnancy outcomes, including clinical pregnancy rate, miscarriage rate, live birth rate and preterm birth rate. RESULTS: Four published RCTs including 787 infertile couples undergoing IVF/ICSI were included in this meta analysis. Notably, the study observed no significant associations of LT4 treatment with the clinical pregnancy rate (RR = 1.46, 95% CI: 0.86-2.48), live birth rate (RR = 2.05, 95% CI: 0.96-4.36), or preterm birth rate (RR = 1.13, 95% CI: 0.65-1.96). However, patients receiving LT4 supplementation had a significantly decreased miscarriage rate relative to those receiving a placebo or no treatment (RR = 0.51, 95% CI: 0.32-0.82). A further sub-group analysis showed that LT4 supplementation did not improve the miscarriage rates among patients with SCH (RR = 0.67, 95% CI: 0.39-1.15) or TAI (RR = 0.28, 95% CI: 0.07-1.06). CONCLUSIONS: Given its potential to reduce the miscarriage rate, LT4 supplementation is recommended for infertile women with SCH and/or TAI who are undergoing IVF/ICSI. However, additional population-based RCTs are needed to confirm this recommendation. PMID- 30249253 TI - "If I had known, I would have applied": poor communication, job dissatisfaction, and attrition of rural health workers in Sierra Leone. AB - BACKGROUND: Sierra Leone's health outcomes rank among the worst in the world. A major challenge is the shortage of primary healthcare workers (HCWs) in rural areas due to especially high rates of attrition. This study was undertaken to determine the drivers of job dissatisfaction and poor retention among Sierra Leone's rural HCWs. METHODS: Interviews were conducted with 58 rural and 32 urban primary HCWs in Sierra Leone's public health sector, complemented by key informant discussions and review of national policy documents. HCW interviews included (1) semi-structured discussion, (2) questionnaire, (3) card sort about HCW priorities, and (4) free-listing of most pressing challenges and needs. Sampling for HCW interviews was stratified purposive, emphasizing rural HCWs. RESULTS: Among 90 HCWs interviewed, 67% were dissatisfied with their jobs (71% rural vs 52% urban) and 61% intended to leave their post (75% rural vs 38% urban). While working and living conditions and remuneration were significant factors, a major reason for rural HCW disenchantment was their inability to access worker rights, benefits, and advancement opportunities. This was caused by HCWs' lack of knowledge about human resource (HR) policies and procedures, as well as ambiguity in many policies and inequitable implementation. HCWs reported feeling neglected and marginalized and perceived a lack of transparency. These issues can be attributed to the absence of systems for regular two-way communication between the Ministry of Health and HCWs; lack of official national documents with up-to-date, clear HR policies and procedures for HCWs; pay statements that do not provide a breakdown of financial allowances and withholdings; and lack of HCW induction. CONCLUSIONS: HCWs in Sierra Leone lacked accurate information about entitlements, policies, and procedures, and this was a driver of rural HCW job dissatisfaction and attrition. System-oriented, low-cost initiatives can address these underlying structural causes in Sierra Leone. These issues likely apply to other countries facing HCW retention challenges and should be considered in development of global HCW retention strategies. PMID- 30249252 TI - Ruminant meat flavor influenced by different factors with special reference to fatty acids. AB - Ruminant meat flavor is an important quality and sensory parameter which relays mainly on the organoleptic characteristics of meat. Meat flavor is vital factor for the palatability and acceptability of meat by the consumers. There are various intrinsic and extrinsic factors that influence eating quality of meat. Among these factors, flavor is the major contributor. Fat and low-molecular weight water-soluble compounds are the most important precursor components in meat, responsible for the meat flavor. The present review focus on the different pre and post-harvest factors that influences the ruminant meat flavor. Raw meat has little flavor but cooking adds value in flavor due to different temperature and cooking methods. The volatile flavoring compounds which are responsible for cooked meat flavor are produced thermally by the Maillard's reaction itself or interaction with lipid oxidation products and vitamin degradation. In nutshell, this review provides perception into previous literature on flavor that affected by various factors particularly the fatty acids and cooking methods. PMID- 30249254 TI - Towards a more integrated and gender-sensitive care delivery for victims of sexual assault: key findings and recommendations from the Belgian sexual assault care centre feasibility study. AB - BACKGROUND: Sexual assault remains a major threat to public health, affecting every gender, gender identity and sexual orientation. Following the Belgian ratification of the Istanbul Convention in 2016, the feasibility of a Belgian sexual assault centre model was investigated, aiming to provide more integrated and patient-centred health and judiciary services to victims of sexual assault. By actively involving health professionals, police and judiciary system representatives, as well as victims themselves, this feasibility study eventually fed into the Belgian Sexual Assault Care Centre model. In this process, this paper assessed current Belgian health services and the degree to which the implementation of this model could contribute to both a more integrated and gender-sensitive care delivery. Findings from this study and the subsequent recommendations aim to contribute to similar reforms in other countries that have already taken or are about to take steps towards an integrated, multi-agency support framework for victims of sexual assault. METHODS: A qualitative, descriptive analysis of the survey response of 60 key health professionals (N = 60) representing 15 major Belgian hospitals was first conducted. Comparing their approach with the international guidelines and standards, a Strengths Weaknesses Opportunities and Threats analysis of the current sexual assault health services and their potential transition to the Sexual Assault Care Centre model was then executed. RESULTS: Despite adequate equipment, the clear fragmentation of health services and limited follow-up hamper an integrated care delivery in most hospitals. Only three hospitals differentiated their sexual assault care protocol based on the victim's gender, gender identity and sexual orientation. A striking unawareness among health professionals of sexual assault in male victims, as well as in gender and sexual minorities further hampers a gender-sensitive care delivery. CONCLUSIONS: The Sexual Assault Care Centre model aims to counter most of the current sexual assault health services' weaknesses and threats hampering an integrated care for victims of sexual assault. Further research and training of health professionals are however required in order to tune this integrated form of care to sexuality and gender-based differences in victims' already multi faceted healthcare needs. PMID- 30249255 TI - Understanding the business versus care paradox in gambling venues: a qualitative study of the perspectives from gamblers, venue staff and counsellors. AB - BACKGROUND: In recent years, greater emphasis has been placed on gambling venues to identify potential problem gamblers, respond appropriately and refer to treatment. In seeking the perspectives of problem gamblers, venue staff and treatment providers, this qualitative study investigates how problem gamblers experience being identified and referred for treatment by venue staff. METHODS: A semi-structured interview guide focusing on experiences and perceptions of problem gambling identification and referral for treatment in gaming venues was used to conduct 4 focus groups and 9 semi-structured in-depth interviews. Participants comprised 22 problem gamblers, 10 gambling venue staff and 8 problem gambling counsellors. Audio recordings were transcribed verbatim, and an interpretive phenomenological analysis was conducted. RESULTS: 'Role conflict' was identified as a considerable source of stress for venue staff who described conflicting priorities in responding to problem gamblers whilst maintaining employer profit margins. Problem gamblers described offers of help from venue staff as hypocritical and disingenuous. Venue staff also described reluctance to make moral judgements through the identification of and engagement with problem gamblers, and gamblers described resentment in being singled out and targeted as a problem gambler. Being approached and offered referral to a counselling service was a rare occurrence among problem gamblers. This corresponded with reports by gambling counsellors. CONCLUSIONS: Role conflict experienced by gambling venue staff and patrons alike inhibits effective referral of potential problem gamblers into treatment. Reducing the need for gambling venue staff to make a perceived moral judgement about the gambling behaviours of specific patrons may improve the reception of responsible gambling information and promote help-seeking. PMID- 30249256 TI - Significant predictors of medically diagnosed chronic obstructive pulmonary disease in patients with preserved ratio impaired spirometry: a 3-year cohort study. AB - BACKGROUND: Preserved ratio impaired spirometry (PRISm) is an incompletely understood respiratory condition. We investigated the incidence and significant predictive factors of chronic obstructive pulmonary disease (COPD) in PRISm patients. METHODS: From 11,922 subjects registered in the Korea National Health and Nutrition Examination Survey, never or light smokers, young subjects, and those already medically diagnosed with COPD (defined by ICD-10 code and prescribed medication) were excluded. The 2666 remaining subjects were categorized into PRISm (normal forced expiratory volume in the first second [FEV1]/force vital capacity [FVC] [>= 0.7] and low FEV1 (< 80%); n = 313); normal (n = 1666); and unrevealed COPD groups (FEV1/FVC ratio < 0.7; n = 687). These groups were compared using matched Health Insurance Review and Assessment Service data over a 3-year follow-up. RESULTS: COPD incidence in PRISm patients (17/1000 person-year [PY]) was higher than that in normal subjects (4.3/1000 PY; P < 0.001), but lower than that in unrevealed COPD patients (45/1000 PY; P < 0.001). PRISm patients visited hospitals, took COPD medication, and incurred hospitalization costs more frequently than normal subjects, but less frequently than unrevealed COPD patients. In the overall sample, age, FVC, FEV1, dyspnea, and wheezing were significant predictors of COPD, but in PRISm patients, only age (OR, 1.14; P = 0.002) and wheezing (OR, 4.56; P = 0.04) were significant predictors. CONCLUSION: PRISm patients are likely to develop COPD, and should be monitored carefully, especially older patients and those with wheezing, regardless of lung function. PMID- 30249257 TI - Relation of arterial stiffness to left ventricular structure and function in healthy women. AB - BACKGROUND: Interactions between the left ventricular (LV) and the arterial system, (ventricular-arterial coupling) are key determinants of cardiovascular function. However, most of studies covered multiple cardiovascular risk factors, which also contributed to the morphological and functional changes of LV. The aim of this study was to examine the relationship between arterial stiffness and LV structure and function in healthy women with a low burden of risk factors. METHODS: Healthy women from the Twins UK cohort (n = 147, mean age was 54.07 +/- 11.90 years) were studied. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (cf-PWV). LV structure and function were assessed by two dimensional speckle tracking echocardiography. RESULTS: cf-PWV was significantly associated with most measures of LV geometry and function, including relative wall thickness (RWT), E/e' ratio, global circumferential and radial strain, apical rotation and LV twist (each p < 0.05), but bore no relation to global longitudinal strain. After adjustment for age, body mass index, blood pressure and heart rate, cf-PWV was significantly correlated with RWT, global circumferential strain, apical rotation and LV twist (beta = 0.011, - 0.484, 1.167 and 1.089, respectively, each p <= 0.05). CONCLUSIONS: In healthy women with a low burden of risk factors, elevated arterial stiffness was intimately interwoven with increased LV twisting even before LV dysfunction becomes clinically evident. PMID- 30249258 TI - First retrospective studies with etiological confirmation of porcine transmissible gastroenteritis virus infection in Argentina. AB - BACKGROUND: In 2014, a notification of porcine transmissible gastroenteritis virus (TGEV) was made by the National Services of Animal Health of Argentina (SENASA) to the World Organization of Animal Health (OIE). The notification was based on a serological diagnosis in a small farm with a morbidity rate of 2.3% without enteric clinical signs. In order to determine if TGEV was circulating before the official report, a retrospective study on cases of neonatal diarrhea was performed. The selection criteria was a sudden increase in mortality in 1- to 21-day-old piglets with watery diarrhea that did not respond to antibiotics. Based on these criteria, three clinical cases were identified during 2010-2015. RESULTS: All animals that were evaluated presented histological lesions consistent with enteric viral infection. The feces and ultrathin sections of intestine that were evaluated by electron microscopy confirmed the presence of round particles of approximately 80 nm in size and characterized by finely granular electrodense nucleoids consistent with complete particles of coronavirus. The presence of the TGEV antigen was confirmed by monoclonal specific immunohistochemistry, and final confirmation of a metabolically-active virus was performed by in situ hybridization to detect a TGE mRNA encoding spike protein. All sections evaluated in this case were negative for PEDV and rotavirus A. CONCLUSIONS: This is the first case series describing neonatal mortality with etiological confirmation of TGEV in Argentina. The clinical diagnosis of TGEV infections in endemic regions is challenging due to the epidemiological distribution and coinfection with other enteric pathogens that mask the clinical presentation. PMID- 30249259 TI - A circulating cell population showing both M1 and M2 monocyte/macrophage surface markers characterizes systemic sclerosis patients with lung involvement. AB - BACKGROUND: Systemic sclerosis (SSc) is a disorder characterized by immune system alterations, vasculopathy and fibrosis. SSc-related interstitial lung disease (ILD) represents a common and early complication, being the leading cause of mortality. Monocytes/macrophages seem to have a key role in SSc-related ILD. Interestingly, the classically (M1) and alternatively (M2) activated monocyte/macrophage phenotype categorization is currently under revision. Our aim was to evaluate if circulating monocyte/macrophage phenotype could be used as biomarker for lung involvement in SSc. To this purpose we developed a wide phenotype characterization of circulating monocyte/macrophage subsets in SSc patients and we evaluated possible relations with lung involvement parameter values. METHODS: A single centre cross-sectional study was performed in fifty five consecutive SSc patients, during the year 2017. All clinical and instrumental tests requested for SSc follow up and in particular, lung computed tomography (CT) scan, pulmonary function tests (PFTs), Doppler echocardiography with systolic pulmonary artery pressure (sPAP) measurement, blood pro-hormone of brain natriuretic peptide (pro-BNP) evaluation, were performed in each patient in a maximum one-month period. Flow cytometry characterization of circulating cells belonging to the monocyte/macrophage lineage was performed using specific M1 (CD80, CD86, TLR2 and TLR4) and M2 surface markers (CD204, CD163 and CD206). Non parametric tests were used for statistical analysis. RESULTS: A higher percentage of circulating CD204+CD163+CD206+TLR4+CD80+CD86+ and CD14+CD206+CD163+CD204+TLR4+CD80+CD86+ mixed M1/M2 monocyte/macrophage subsets, was identified to characterize patients affected by SSc-related ILD and higher systolic pulmonary artery pressure. Mixed M1/M2 monocyte/macrophage subset showed higher percentages in patients positive for anti-topoisomerase antibody, a known lung involvement predictor. CONCLUSIONS: The present study shows for the first time, through a wide flow cytometry surface marker analysis, that higher circulating mixed M1/M2 monocyte/macrophage cell percentages are associated with ILD, sPAP and anti-topoisomerase antibody positivity in SSc, opening the path for research on their possible role as pathogenic or biomarker elements for SSc lung involvement. PMID- 30249260 TI - Frozen blood clots can be used for the diagnosis of distinct Plasmodium species in man and non-human primates from the Brazilian Atlantic Forest. AB - BACKGROUND: Zoonotic infections with epidemic potential, as non-human primate malaria and yellow fever (YF), can overlap geographically. Optimizing a small blood sample for diagnosis and surveillance is of great importance. Blood are routinely collected for YF diagnosis and blood clots usually discarded after serum obtention. Aiming to take sample advantage, the sensitivity of a PCR using extracted DNA from long-term frozen clots from human and non-human primates for detection of Plasmodium spp. in low parasitaemia conditions was assayed. RESULTS: Malaria diagnosis with DNA extracted from blood clots generated results in agreement with samples obtained with whole blood, including mixed Plasmodium vivax/simium and Plasmodium malariae/brasilianum infections. CONCLUSION: Blood clots from human and non-human primates may be an important and low cost source of DNA for malaria surveillance in the Atlantic Forest. PMID- 30249261 TI - Malaria parasitaemia, anaemia and malnutrition in children less than 15 years residing in different altitudes along the slope of Mount Cameroon: prevalence, intensity and risk factors. AB - BACKGROUND: Malaria, anaemia and malnutrition are frequently co-existing diseases that cause significant morbidity and mortality particularly among children. This study measured the prevalence, intensity and evaluated risk factors for malaria parasitaemia, anaemia and malnutrition among children living at low versus high altitude settings in the Mount Cameroon area. METHODS: A cross-sectional community based survey involving 828 children aged 6 months to 14 years was conducted between July and November 2017. Malaria parasitaemia was confirmed by light microscopy, haemoglobin concentration was measured using an auto haematology analyser, nutritional status was determined from the anthropometric measurements collected, and socioeconomic status related variables by the use of questionnaire. Anaemia and malnutrition were defined according to World Health Organization standards. Associations between predictor variables and primary outcomes were assessed using logistic regression analysis. RESULTS: Malaria parasite and anaemia were prevalent in 41.7% and 56.2% of the children, respectively while, malnutrition prevalence was 34.8% with wasting, underweight and stunting occurring in 25.7%, 19.9% and 23.7% of them respectively. Overall malaria parasite geometric mean density was 413/uL of blood (range 100-27,060). The odds of having malaria parasitaemia was highest in children 5-9 years of age [odd ratio (OR) = 1.69, P = 0.006], living in lowland (OR = 1.48, P = 0.008) as well as those whose domestic water was collected from an open source (streams/springs) (OR = 1.81, P = 0.005) than their counterparts. Being < 5 years (OR = 3.15, P = < 0.001) or 5-9 years (OR = 2.20, P < 0.001) of age, having malaria parasite (OR = 2.07, P = < 0.001) and fever in the past 2 days (OR = 1.52, P < 0.04) were identified as significant risk factors of anaemia while the age group < 5 years was the only significant risk (OR = 3.09, P = < 0.001) associated with malnutrition. CONCLUSION: While age specific attention should be given in the control of malaria (5-9 years), anaemia (< 10 years) and malnutrition (< 5 years), the existing malaria control programmes should be revised to integrate anaemia and malnutrition control strategies so as to improve upon the health of the children. PMID- 30249262 TI - The barriers and facilitators to the implementation of National Clinical Programmes in Ireland: using the MRC framework for process evaluations. AB - BACKGROUND: A major healthcare reform agenda in Ireland is underway which underpins the establishment of a series of National Clinical Programmes (NCPs), which aim to take an evidence based approach to improve quality, access and value. The current study aimed to determine the enablers and barriers to implementation of the NCPs. METHODS: A qualitative methodology advocated by the Medical Research Council (MRC) framework on conducting process evaluations of complex interventions guided this research. Purposive sampling techniques were used to recruit participants from seven NCPs across both acute and chronic healthcare domains, comprised of orthopaedics, rheumatology, elective surgery, emergency medicine, paediatrics, diabetes and chronic obstructive pulmonary disease. A total of 33 participants were interviewed using a semi-structured interview guide. Participants included current and previous Clinical Leads, Programme Managers, Health Service Executive management, hospital Chief Executive Officers, representatives of General Practice, and a Nursing and a Patient representative. Thematic analyses was conducted. RESULTS: A range of factors of different combinations and co-occurrence were highlighted across a total of six themes, including (i) positive leadership, governance and clinical networks of the NCPs, (ii) the political and social context in which the NCPs operate, (iii) constraints on resources, (iv) a passive attitudinal resistance to change borne from poor consultation and communication, (v) lack of data and information technology, (vi) forces outside of the NCPs such as the general practitioner contract thwarting change of the model of care. CONCLUSIONS: The MRC framework proved a useful tool to conduct this process evaluation. Results from this research provide real world experiences and insight from the people charged with implementing large-scale health system improvement initiatives. The findings highlight the need for measured responses that acknowledge both direct and non direct challenges and opportunities for successful change. Combined, it is recommended that these elements be considered in the planning and implementation of large-scale initiatives across healthcare delivery systems, both in Ireland and internationally. PMID- 30249264 TI - Cytokine release syndrome: grading, modeling, and new therapy. AB - Genetically modified T cells that express a chimeric antigen receptor (CAR) are opening a new frontier in cancer immunotherapy. CAR T cells currently are in clinical trials for many cancer types. Cytokine release syndrome (CRS) and neurotoxicities (CAR-related encephalopathy syndrome, CRES) are major adverse events limiting wide deployment of the CAR T cell treatment. Major efforts are ongoing to characterize the pathogenesis and etiology of CRS and CRES. Mouse models have been established to facilitate the study of pathogenesis of the major toxicities of CAR T cells. Myeloid cells including macrophages and monocytes, not the CAR T cells, were found to be the major cells mediating CRS and CRES by releasing IL-1 and IL-6 among other cytokines. Blocking IL-1 or depletion of monocytes abolished both CRS and CRES, whereas IL-6 blocker can ameliorate CRS but not CRES. Therefore, both IL-1 and IL-6 are major cytokines for CRS, though IL-1 is responsible for CRES. It was also demonstrated in the mouse models that blocking CRS does not interfere with the CAR T cell antitumor functions. We summarized new developments in the grading, modeling, and possible new therapeutic approaches for CRS and CRES in this review. PMID- 30249263 TI - Left atrium remodeling predicts late recurrence of paroxysmal atrial fibrillation after second generation cryoballoon ablation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia worldwide. Nowadays, AF ablation is a valuable treatment option. It has been shown that the left atrium (LA) diameter is a predictor of AF recurrence after cryoballoon ablation (CBA). Since it does not reflect the true LA size, we compared the role of different LA anatomical parameters using echocardiography for the prediction of AF recurrence after CBA. METHODS: We retrospectively included 209 patients (mean age 56.1 +/- 13.6 years, male 62%) with paroxysmal AF undergoing CBA. A transthoracic echocardiography was performed in all patients. RESULTS: At a mean follow-up of 16.9 +/- 6.3 months, AF recurred in 25.4% of the patients. LA anterior - posterior diameter (LAD), LA minimum volume (LAmin) and early AF recurrence were independent predictors of recurrence. Based on receiver operating characteristics, cut - off values for LAD and, LAmin were 41 mm, 23.69 mL, respectively. The negative predictive values for recurrence were 73% and 87.3% respectively. In patients with AF recurrence, a significant proportion (30.2%) showed LA longitudinal remodeling (LA superior - inferior diameter) even though classically measured LAD was normal. CONCLUSIONS: Longitudinal LA remodeling plays an additional role for predicting AF recurrence after CBA, in patients without LAD dilation. Moreover, LAmin had a high negative predictive value and was an independent predictor of AF recurrence. Therefore, a more complete LA anatomical assessment allows a better prediction of AF recurrences after CBA. PMID- 30249265 TI - Proteomic profiling of the plasma of Gambian children with cerebral malaria. AB - BACKGROUND: Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection. A number of pathological findings have been correlated with pediatric CM including sequestration, platelet accumulation, petechial haemorrhage and retinopathy. However, the molecular mechanisms leading to death in CM are not yet fully understood. METHODS: A shotgun plasma proteomic study was conducted using samples form 52 Gambian children with CM admitted to hospital. Based on clinical outcome, children were assigned to two groups: reversible and fatal CM. Label-free liquid chromatography-tandem mass spectrometry was used to identify and compare plasma proteins that were differentially regulated in children who recovered from CM and those who died. Candidate biomarkers were validated using enzyme immunoassays. RESULTS: The plasma proteomic signature of children with CM identified 266 proteins differentially regulated in children with fatal CM. Proteins from the coagulation cascade were consistently decreased in fatal CM, whereas the plasma proteomic signature associated with fatal CM underscored the importance of endothelial activation, tissue damage, inflammation, haemolysis and glucose metabolism. The concentration of circulating proteasomes or PSMB9 in plasma was not significantly different in fatal CM when compared with survivors. Plasma PSMB9 concentration was higher in patients who presented with seizures and was significantly correlated with the number of seizures observed in patients with CM during admission. CONCLUSIONS: The results indicate that increased tissue damage and hypercoagulability may play an important role in fatal CM. The diagnostic value of this molecular signature to identify children at high risk of dying to optimize patient referral practices should be validated prospectively. PMID- 30249267 TI - Changes in heart rate variability with respect to exercise intensity and time during treadmill running. AB - BACKGROUND: Heart rate variability (HRV) arises from the complex interplay of sympathetic and parasympathetic autonomic regulation of heart rate. Ultra-low frequency (ULF) and very-low frequency (VLF) components of HRV play a crucial role in automatic HR controllers, but these frequency bands have hitherto largely been neglected in HRV studies. The aim of this work was to investigate changes in ULF and VLF heart rate variability with respect to exercise intensity and time during treadmill running. METHODS: RR intervals were determined by ECG in 21 healthy male participants at rest, and during moderate and vigorous-intensity treadmill running; each of these three tests had a duration of 45 min. Time dependence of HRV was investigated for moderate and vigorous running intensities by dividing the constant-speed stages into three consecutive windows of equal duration ([Formula: see text] 14 min), denoted [Formula: see text], [Formula: see text] and [Formula: see text]. ULF and VLF power were computed using Lomb-Scargle power spectral density estimates. RESULTS: For both the ULF and VLF frequency bands, mean power was significantly different between the resting, moderate and vigorous intensity levels (overall [Formula: see text]): mean power was lower for moderate vs. rest ([Formula: see text]), for vigorous vs. rest ([Formula: see text]), and for vigorous vs. moderate ([Formula: see text]). For both ULF and VLF and moderate intensity, mean power was significantly different between the three time windows (overall [Formula: see text] for ULF, overall [Formula: see text] for VLF): for ULF, mean power was lower for [Formula: see text] vs. [Formula: see text] ([Formula: see text]) and for [Formula: see text] vs. [Formula: see text] ([Formula: see text]); for VLF, mean power was lower for [Formula: see text] vs. [Formula: see text] ([Formula: see text]). For ULF and vigorous intensity, there was no significant difference in mean power between the three time windows (overall [Formula: see text]). For VLF and vigorous intensity, mean power was significantly different between [Formula: see text], [Formula: see text] and [Formula: see text] (overall [Formula: see text]): mean power was lower for [Formula: see text] vs. [Formula: see text] ([Formula: see text]) and for [Formula: see text] vs. [Formula: see text] ([Formula: see text]). CONCLUSIONS: The degree of HRV in terms of ULF and VLF power was found to decrease with increasing intensity of exercise. HRV was also observed to decrease over time, but it remains to clarify whether these changes are due to time itself or to increases in HR related to cardiovascular drift. For feedback control applications, attention should be focused on meeting performance targets at low intensity and during the early stages of exercise. PMID- 30249266 TI - Are women in Uganda gaining adequate gestational weight? A prospective study in low income urban Kampala. AB - BACKGROUND: Pre-pregnancy weight and weight gained during pregnancy significantly influence maternal and infant health. Little information is available regarding optimal gestational weight gain (GWG) in relation to pre-pregnancy body mass index (BMI) in Uganda. The study aimed at determining gestational weight gain (GWG) in women pregnant for the first and second time. METHODS: The study was prospective cohort study which included 221 HIV negative women pregnant for the first or second time. It was conducted in the antenatal clinic of the directorate of gynecology and obstetrics, Mulago hospital and women were recruited at <=18 weeks of gestation by dates. Follow up measurements were done at 26 and 36 weeks gestation. Measured maternal height and reported pre-pregnancy weight were used to calculate BMI. Depending on BMI category, GWG was categorized as inadequate, adequate and excessive based on the Uganda Ministry of Health guidelines. RESULTS: The participants' mean +/- standard deviation (Sd) age was 20.9 +/- 2.7 years and mean +/- Sd BMI was 21.40 +/- 2.73 kg/m2. None of the participants was obese and 68.8% (n = 132) were pregnant for the first time. The mean +/- Sd GWG at time of delivery was 10.58 +/- 2.44 kg. Inadequate GWG was recorded in 62.5% (n = 120/192) while only 3.1% (n = 6/192) of the participants gained excessive weight during pregnancy. CONCLUSION: About 62% of pregnant women in Kampala did not gain adequate weight during their first/second pregnancy. We recommend that studies be carried out to assess whether the Uganda Ministry of Health recommendations for weight gain during are appropriate for preventing adverse pregnancy outcomes across populations in Uganda. PMID- 30249268 TI - Quality of occlusal outcome following space closure in cases of lower second premolar aplasia using lingual orthodontic molar mesialization without maxillary counterbalancing extraction. AB - BACKGROUND: Controlled space closure in cases of isolated lower second premolar aplasia (ILSPA) without maxillary counterbalancing extraction is challenging. Anterior anchorage loss may occur during space closure resulting in compromised occlusal results in terms of an absence of proper canine guidance during laterotrusive mandible movements. In order to evaluate the effectiveness of Herbst telescope anchorage in combination with double-cable, pull mechanics and a completely customized lingual appliance for orthodontic space management in cases of ILSPA, we tested the null hypothesis that there is a significant deterioration in the sagittal canine relationship towards an Angle-Class-II occlusion expressed as a loss of anterior anchorage following space closure with molar mesialization. METHODS: Twenty-five consecutively de-bonded subjects (female / male 17 / 8; aged at T0 (start of MB Tx) 12.3 to 20.6 years; mean age 15.0 / SD 1.7 years) were included in this retrospective analysis using the inclusion criteria of least of one lower second premolar aplasia; completed treatment with a totally customized lingual appliance (CCLA) in combination with Herbst telescopes. Exclusion criteria were the absence of counterbalancing maxillary extractions, as well as additional tooth aplasia other than lower second premolars. A total of 33 single, lower premolar aplasia space closures (right / left sided 17 / 16) were assessed using plaster casts and intra-oral photographs scaled to the plaster casts, at bonding (T0), Herbst insertion (T1), following gap closure (T2) and de-bonding (T3). Parallelism of roots was controlled by panoramic x-rays at T3. RESULTS: The mean aplasia space at T0 was 7.5 mm (SD 2.6). Complete space closure was achieved in all 33 situations. The null hypothesis was rejected. There was a significant improvement in the initial canine relationships (mean 3.5 mm distal occlusion at T0) to a mean 0.1 mm at T3. When evaluated against the individual treatment plan, the following amounts of planned improvements were achieved: space closure 100%, canine relationship 97.5%, overjet 93.9%, overbite 96.4%, parallel roots in space closure site 93.9%. CONCLUSION: Herbst telescope anchorage in combination with double-cable pull mechanics and a CCLA for orthodontic space closure can deliver predictable, high-quality treatment results. PMID- 30249271 TI - The disposable male- the ultimate emancipation of females? AB - Sexual reproduction is costly compared to asexual reproduction, in particular because males generally contribute little to offspring. Research published today in BMC Biology shows that some populations of a termite species have disposed of males altogether. However, this need not necessarily be seen as a victory for the females, since males in most termite societies are active colony members that contribute their fair share to colony tasks. PMID- 30249269 TI - Loss of males from mixed-sex societies in termites. AB - BACKGROUND: Sexual reproduction is the norm in almost all animal species, and in many advanced animal societies, both males and females participate in social activities. To date, the complete loss of males from advanced social animal lineages has been reported only in ants and honey bees (Hymenoptera), whose workers are always female and whose males display no helping behaviors even in normal sexual species. Asexuality has not previously been observed in colonies of another major group of social insects, the termites, where the ubiquitous presence of both male and female workers and soldiers indicate that males play a critical role beyond that of reproduction. RESULTS: Here, we report asexual societies in a lineage of the termite Glyptotermes nakajimai. We investigated the composition of mature colonies from ten distinct populations in Japan, finding six asexual populations characterized by a lack of any males in the reproductive, soldier, and worker castes of their colonies, an absence of sperm in the spermathecae of their queens, and the development of unfertilized eggs at a level comparable to that for the development of fertilized eggs in sexual populations of this species. Phylogenetic analyses indicated a single evolutionary origin of the asexual populations, with divergence from sampled sexual populations occurring about 14 million years ago. Asexual colonies differ from sexual colonies in having a more uniform head size in their all-female soldier caste, and fewer soldiers in proportion to other individuals, suggesting increased defensive efficiencies arising from uniform soldier morphology. Such efficiencies may have contributed to the persistence and spread of the asexual lineage. Cooperative colony foundation by multiple queens, the single-site nesting life history common to both the asexual and sexual lineages, and the occasional development of eggs without fertilization even in the sexual lineage are traits likely to have been present in the ancestors of the asexual lineage that may have facilitated the transition to asexuality. CONCLUSIONS: Our findings demonstrate that completely asexual social lineages can evolve from mixed-sex termite societies, providing evidence that males are dispensable for the maintenance of advanced animal societies in which they previously played an active social role. PMID- 30249270 TI - The experience of interpreter access and language discordant clinical encounters in Australian health care: a mixed methods exploration. AB - BACKGROUND: Current evidence highlights that language discordant clinical encounters seriously compromise patient quality of care and health outcomes. We aimed to characterise patterns of interpreter service use in medical inpatient wards use and explore clinician experience of language discordance. METHODS: Participants included medical students, residents, attending physicians, nursing and allied health professionals working in General Internal Medicine wards across two tertiary referral hospitals servicing a large Australian health care area. This study involved a retrospective electronic medical record audit of interpreter use. Six focus groups were conducted with 32 participants. Data were analysed using an inductive thematic approach with constant comparison. RESULTS: Allied health professionals were identified as the largest users of interpreter services, followed by medical doctors. Distinct themes emerged regarding clinician experiences of language discordant encounters including: (1) Negotiating care when unable to get an accurate assessment; (2) Over servicing to fill in the gaps; (3) Using family members instead of professional interpreters: a vexed solution; (4) Disparities in care provision; and (5) Communication drought: broken by a flood. CONCLUSIONS: Patients with low English proficiency are at risk of being less informed of care processes, and having a very large volume of information given in a shorter period of time when an interpreter is present. There is a need for systematic and transformative change that addresses utilisation of professional interpreters as well as embedded healthcare culture and practices leading to less interaction with patients with limited English proficiency and reliance on family members as informal interpreters. PMID- 30249272 TI - Grouping of nanomaterials to read-across hazard endpoints: from data collection to assessment of the grouping hypothesis by application of chemoinformatic techniques. AB - BACKGROUND: An increasing number of manufactured nanomaterials (NMs) are being used in industrial products and need to be registered under the REACH legislation. The hazard characterisation of all these forms is not only technically challenging but resource and time demanding. The use of non-testing strategies like read-across is deemed essential to assure the assessment of all NMs in due time and at lower cost. The fact that read-across is based on the structural similarity of substances represents an additional difficulty for NMs as in general their structure is not unequivocally defined. In such a scenario, the identification of physicochemical properties affecting the hazard potential of NMs is crucial to define a grouping hypothesis and predict the toxicological hazards of similar NMs. In order to promote the read-across of NMs, ECHA has recently published "Recommendations for nanomaterials applicable to the guidance on QSARs and Grouping", but no practical examples were provided in the document. Due to the lack of publicly available data and the inherent difficulties of reading-across NMs, only a few examples of read-across of NMs can be found in the literature. This manuscript presents the first case study of the practical process of grouping and read-across of NMs following the workflow proposed by ECHA. METHODS: The workflow proposed by ECHA was used and slightly modified to present the read-across case study. The Read-Across Assessment Framework (RAAF) was used to evaluate the uncertainties of a read-across within NMs. Chemoinformatic techniques were used to support the grouping hypothesis and identify key physicochemical properties. RESULTS: A dataset of 6 nanoforms of TiO2 with more than 100 physicochemical properties each was collected. In vitro comet assay result was selected as the endpoint to read-across due to data availability. A correlation between the presence of coating or large amounts of impurities and negative comet assay results was observed. CONCLUSION: The workflow proposed by ECHA to read-across NMs was applied successfully. Chemoinformatic techniques were shown to provide key evidence for the assessment of the grouping hypothesis and the definition of similar NMs. The RAAF was found to be applicable to NMs. PMID- 30249273 TI - Cerebral influx of Na+ and Cl- as the osmotherapy-mediated rebound response in rats. AB - BACKGROUND: Cerebral edema can cause life-threatening increase in intracranial pressure. Besides surgical craniectomy performed in severe cases, osmotherapy may be employed to lower the intracranial pressure by osmotic extraction of cerebral fluid upon intravenous infusion of mannitol or NaCl. A so-called rebound effect can, however, hinder continuous reduction in cerebral fluid by yet unresolved mechanisms. METHODS: We determined the brain water and electrolyte content in healthy rats treated with osmotherapy. Osmotherapy (elevated plasma osmolarity) was mediated by intraperitoneal injection of NaCl or mannitol with inclusion of pharmacological inhibitors of selected ion-transporters present at the capillary lumen or choroidal membranes. Brain barrier integrity was determined by fluorescence detection following intravenous delivery of Na+-fluorescein. RESULTS: NaCl was slightly more efficient than mannitol as an osmotic agent. The brain water loss was only ~ 60% of that predicted from ideal osmotic behavior, which could be accounted for by cerebral Na+ and Cl- accumulation. This electrolyte accumulation represented the majority of the rebound response, which was unaffected by the employed pharmacological agents. The brain barriers remained intact during the elevated plasma osmolarity. CONCLUSIONS: A brain volume regulatory response occurs during osmotherapy, leading to the rebound response. This response involves brain accumulation of Na+ and Cl- and takes place by unresolved molecular mechanisms that do not include the common ion transporting mechanisms located in the capillary endothelium at the blood-brain barrier and in the choroid plexus epithelium at the blood-CSF barrier. Future identification of these ion-transporting routes could provide a pharmacological target to prevent the rebound effect associated with the widely used osmotherapy. PMID- 30249274 TI - Reduction in low-dose to normal tissue with the addition of deep inspiration breath hold (DIBH) to volumetric modulated arc therapy (VMAT) in breast cancer patients with implant reconstruction receiving regional nodal irradiation. AB - BACKGROUND: Despite dosimetric benefits of volumetric modulated arc therapy (VMAT) in breast cancer patients with implant reconstruction receiving regional nodal irradiation (RNI), low dose to the thoracic structures remains a concern. Our goal was to report dosimetric effects of adding deep inspiration breath hold (DIBH) to VMAT in left-sided breast cancer patients with tissue expander (TE)/permanent implant (PI) reconstruction receiving RNI. METHODS: Ten consecutive breast cancer patients with unilateral or bilateral TE/PI reconstruction who were treated with a combination of VMAT and DIBH to the left reconstructed chest wall and regional nodes were prospectively identified. Free breathing (FB) and DIBH CT scans were acquired for each patient. VMAT plans for the same arc geometry were compared for FB versus DIBH. Prescription dose was 50 Gy in 25 fractions. Dosimetric differences were tested for statistical significance. RESULTS: For comparable coverage and target dose homogeneity, the mean dose to the heart reduced on average by 2.9 Gy (8.2 to 5.3 Gy), with the addition of DIBH (p < 0.05). The maximum dose to the left anterior descending (LAD) artery was reduced by 9.9 Gy (p < 0.05), which related closely to the reduction in the maximum heart dose (9.4 Gy). V05 Gy to the heart, ipsilateral lung, contralateral lung and total lung (p < 0.05) decreased on average by 29.6%, 5.8%, 15.4% and 10.8% respectively. No significant differences were seen in the ipsilateral lung V20 Gy or mean dose as well as in the mean contralateral breast/implant dose. However, V04 Gy and V03 Gy of the contralateral breast/implant were respectively reduced by 13.2% and 18.3% using DIBH (p < 0.05). CONCLUSION: Combination of VMAT and DIBH showed significant dosimetric gains for low dose to the heart, lungs and contralateral breast/implant. Not surprisingly, the mean and maximum dose to the heart and to the LAD were also reduced. DIBH should be considered with the use of VMAT in breast cancer patients with implant reconstructions receiving RNI. PMID- 30249275 TI - Linking gut microbiota, metabolic syndrome and economic status based on a population-level analysis. AB - BACKGROUND: The metabolic syndrome (MetS) epidemic is associated with economic development, lifestyle transition and dysbiosis of gut microbiota, but these associations are rarely studied at the population scale. Here, we utilised the Guangdong Gut Microbiome Project (GGMP), the largest Eastern population-based gut microbiome dataset covering individuals with different economic statuses, to investigate the relationships between the gut microbiome and host physiology, diet, geography, physical activity and socioeconomic status. RESULTS: At the population level, 529 OTUs were significantly associated with MetS. OTUs from Proteobacteria and Firmicutes (other than Ruminococcaceae) were mainly positively associated with MetS, whereas those from Bacteroidetes and Ruminococcaceae were negatively associated with MetS. Two hundred fourteen OTUs were significantly associated with host economic status (140 positive and 74 negative associations), and 157 of these OTUs were also MetS associated. A microbial MetS index was formulated to represent the overall gut dysbiosis of MetS. The values of this index were significantly higher in MetS subjects regardless of their economic status or geographical location. The index values did not increase with increasing personal economic status, although the prevalence of MetS was significantly higher in people of higher economic status. With increased economic status, the study population tended to consume more fruits and vegetables and fewer grains, whereas meat consumption was unchanged. Sedentary time was significantly and positively associated with higher economic status. The MetS index showed an additive effect with sedentary lifestyle, as the prevalence of MetS in individuals with high MetS index values and unhealthy lifestyles was significantly higher than that in the rest of the population. CONCLUSIONS: The gut microbiome is associated with MetS and economic status. A prolonged sedentary lifestyle, rather than Westernised dietary patterns, was the most notable lifestyle change in our Eastern population along with economic development. Moreover, gut dysbiosis and a Western lifestyle had an additive effect on increasing MetS prevalence. PMID- 30249277 TI - A phase Ib study to assess the efficacy and safety of vismodegib in combination with ruxolitinib in patients with intermediate- or high-risk myelofibrosis. AB - BACKGROUND: The JAK inhibitor (JAKi) ruxolitinib is standard treatment for myelofibrosis (MF), but some patients are unresponsive. Pre-clinical and clinical data suggest that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve response. Vismodegib is an HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study assessed the safety and efficacy of combining ruxolitinib with vismodegib in ruxolitinib-naive patients with MF and characterized the pharmacokinetics (PK) of vismodegib in this setting. METHODS: In this phase Ib study, ten patients with intermediate- or high-risk primary or secondary MF received open-label vismodegib (150 mg/day orally) and ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study for comparison with other patient populations. Efficacy outcomes at week 24 included spleen response (>= 35% reduction in volume by imaging) and improvement in bone marrow fibrosis by central and investigator assessment, symptom response (>= 50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom score), and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment revised response criteria). RESULTS: As of November 17, 2017, eight patients had completed 48 weeks of treatment with vismodegib and ruxolitinib; two discontinued treatment early. At week 24 (+/- 1 week), three patients experienced a spleen response by central review and no patients showed a 1-grade improvement in bone marrow fibrosis by central review. Five patients experienced symptom response at week 24, and no patients experienced an anemia response. The most common adverse events were muscle spasm (100% of patients), alopecia (70%), dysgeusia (50%), thrombocytopenia (50%), and nausea (40%); these events were predominantly grade 1/2. Three patients experienced a total of six serious adverse events. CONCLUSIONS: The combination of vismodegib and ruxolitinib was tolerable and no new safety signals were seen, but there was no evidence that the addition of vismodegib to ruxolitinib improved any of the efficacy outcome measures assessed. Further evaluation of this combination will not be pursued. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02593760 . Registered November 2, 2015. PMID- 30249276 TI - Agents of change: establishing quality improvement collaboratives to improve adherence to Australian clinical guidelines for dementia care. AB - BACKGROUND: Dissemination of clinical practice guidelines alone is insufficient to create meaningful change in clinical practice. Quality improvement collaborative models have potential to address the evidence-practice gap in dementia care because they capitalise on known knowledge translation enablers and incorporate optimal approaches to implementation. Non-pharmacological interventions focused on promoting independence are effective and favoured by people with dementia and their carers but are not routinely implemented. The objective of this translational project is to assess the impact of quality improvement collaboratives (QICs) on adherence to non-pharmacological recommendations from the Clinical Practice Guidelines for Dementia in Australia. METHODS: This project will employ an interrupted time-series design with process evaluation to assess the impact, uptake, feasibility, accessibility, cost, and sustainability of the QICs over 18 months. Thirty clinicians from across Australia will be invited to join the QICs to build their capacity in leading innovation in dementia care. Clinicians will participate in a training program and be supported to develop and implement a quality improvement project unique to their service context using plan-do-study-act cycles. Regular online meetings with their peers in the QIC will facilitate benchmarking and problem-solving. Clinicians will describe their practice via monthly checklists, and guideline adherence will be determined against a set of defined criteria. Phone interviews with up to 180 client dyads will be used to assess satisfaction with care and client outcomes. Clinician interviews and field note data will be used to explore implementation and costs. Involvement of people with dementia and carers will be embedded in the study design, conduct, and reporting, in addition to clinical and industry expertise. DISCUSSION: The quality of dementia care in Australia is largely dependent on the clinician involved and the extent to which they apply best available evidence in their practice. This study will determine the elements of this multifaceted implementation strategy that contributed to guideline adherence and client outcomes. The findings will inform future translational approaches to improving care and outcomes for people with dementia and their carers. TRIAL REGISTRATION: Registered with the Australian New Zealand Clinical Trials Registry 21 February 2018 ( ACTRN12618000268246 ). PMID- 30249278 TI - Long noncoding RNA MLK7-AS1 promotes ovarian cancer cells progression by modulating miR-375/YAP1 axis. AB - BACKGROUND: Long noncoding RNAs (LncRNAs) have been reported to be abnormally expressed in human ovarian cancer and associated with the proliferation and metastasis of cancer cells. The objective of this study was to investigate the role and the underlying mechanisms of LncRNA MAP3K20 antisense RNA 1 (MLK7-AS1) in ovarian cancer. METHODS: The expression level of MLK7-AS1 was investigated in human ovarian cancer tissues and cell lines. The effects of MLK7-AS1 knockdown on ovarian cancer cell proliferation, migration, invasion and apoptosis were evaluated in vitro using MTT, colony formation assays, wound healing assays, transwell assays and flow cytometry. Furthermore, the in vivo effects were determined using the immunodeficient NSG female mice. Luciferase reporter assays were employed to identify interactions among MLK7-AS1 and its target genes. RESULTS: In the current study, MLK7-AS1 was specifically upregulated in ovarian cancer tissues and cell lines. Knockdown of MLK7-AS1 inhibited the ability of cell migration, invasion, proliferation, colony formation and wound healing, whereas promoted cell apoptosis in vitro. By using online tools and mechanistic analysis, we demonstrated that MLK7-AS1 could directly bind to miR-375 and downregulate its expression. Besides, MLK7-AS1 reversed the inhibitory effect of miR-375 on the growth of ovarian cancer cells, which might be involved in the upregulation of Yes-associated protein 1 (YAP1) expression. Moreover, knockdown MLK7-AS1 expression inhibited primary tumor growth in ovary and metastatic tumors in multiple peritoneal organs including liver and spleen in vivo, which were partly abolished by miR-375 inhibition. Mechanically, we found that MLK7-AS1 modulated the epithelial-mesenchymal transition (EMT) process by interacting with miR-375/YAP1 both in vivo and vitro, which promoted the expression of Slug. CONCLUSIONS: Taken together, our study showed for the first time that MLK7-AS1 interacted with miR-375 to promote proliferation, metastasis, and EMT process in ovarian cancer cells through upregulating YAP1. PMID- 30249279 TI - MySafeRx: a mobile technology platform integrating motivational coaching, adherence monitoring, and electronic pill dispensing for enhancing buprenorphine/naloxone adherence during opioid use disorder treatment: a pilot study. AB - BACKGROUND: While buprenorphine/naloxone (B/N) is approved for opioid use disorder treatment, effective delivery of B/N comes with significant challenges. Most notably, many patients do not take medication daily as prescribed; this non adherence worsens treatment outcomes, increases healthcare costs, and leads to persistent worries of diversion among providers and policymakers. The present study examines the feasibility, usability, and acceptability of MySafeRx-a mobile technology platform integrating motivational coaching, adherence monitoring, and electronic pill dispensing designed to address the challenges of office-based opioid treatment (OBOT) with B/N. METHODS: The MySafeRx platform integrates electronic pill dispensers, text-messaging, and videoconferencing to provide supervised self-administration of medication and daily motivational coaching through an Android app interface. High-risk early adults (18-39 years old) who were enrolled in OBOT with B/N and had documented illicit opioid use in the past month during opioid agonist therapy (n = 12) participated in a 28-day single-arm observational study of the MySafeRx platform in addition to standard care. RESULTS: Two-thirds of participants who completed the study achieved an average of > 5 days per week of supervised B/N self-administration. Visual confirmation of medication adherence was demonstrated for an average of 72% of study days among all participants. All participants achieved platform technical proficiency within 60 min, reporting good levels of usability and acceptability. Illicit opioid abstinence rates confirmed by urine toxicology increased by 53% during MySafeRx but fell 43% within 3 weeks post-intervention. CONCLUSION: The MySafeRx medication adherence and remote coaching mobile platform is acceptable and can be feasibly implemented in real-world opioid use disorder treatment settings during high-risk periods (i.e., initial stabilization, after illicit opioid lapse), resulting in reduced illicit opioid use; however, the effect did not last after intervention completion, suggesting longer duration or extended taper of program may be needed. ClinicalTrials.Gov NCT02942199 10/24/16 https://clinicaltrials.gov/ct2/show/NCT02942199. PMID- 30249280 TI - Evaluating the current state of Mendelian randomization studies: a protocol for a systematic review on methodological and clinical aspects using neurodegenerative disorders as outcome. AB - BACKGROUND: Mendelian randomization (MR) is fast becoming a popular method to judge causality from routinely conducted observational studies. However, stringent underlying statistical assumptions, missing biological information, and high sample size requirement might make it prone to misuse. Furthermore, rapidly updating methodologies and increasingly available datasets to researchers are making the interpretations of heterogeneous results even more complicated. In this protocol, we provide our design for a multifaceted systematic review on MR studies using neurodegenerative disease as an example outcome. The planned systematic review which has already passed the pilot stage will help to develop an in-depth understanding of how various MR methods have been applied, what has been achieved, and what can be done in future for to arrive at true causal risk factors. METHODS: During the pilot phase of this systematic review, several versions of questionnaires and frequent consultations between reviewers helped us to finalize a comprehensive list of questions. This will be used to extract information on systematically searched MR articles investigating causality underlying neurodegenerative diseases. A literature search of the electronic databases (Embase, MEDLINE, Web of Science, Scopus, and databases listed in the Cochrane library) will be conducted. The search strategy will include terms related to MR and the spectrum of neurodegenerative diseases. Two independent reviewers will screen the studies, and three will extract the data. The included studies will be further judged by two reviewers for accuracy and completeness of available information. We will perform descriptive and quantitative synthesis using sensitivity analyses of causal association by study design, selection of genetic instrument, validity of MR assumptions, MR method, and sensitivity analysis based on exclusion of potential pleiotropic variants. The quality of conduct as well as quality of reporting in the included studies will be assessed and reported. A meta-analysis will be conducted, if effect estimates on identical genetic instruments are available for both exposure and outcome in the studies using data from participants from ethnically similar populations. DISCUSSION: This systematic review protocol utilizes a unique comprehensive data abstraction tool based on recent methodological advancements in the field of MR. The planned systematic review will further integrate information on methodological details with clinical findings in latest available large-scale genome-wide association study datasets. Our findings aim to help raising awareness and promoting transparent reporting of MR studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018091434 . PMID- 30249281 TI - Analytic and clinical validity of thyroid nodule mutational profiling using droplet digital polymerase chain reaction. AB - BACKGROUND: Recent guidelines for the management of thyroid nodules incorporate mutation testing as an adjunct for surgical decision-making, however current tests are costly with limited accuracy. Droplet digital PCR (ddPCR) is an ultrasensitive method of nucleic acid detection that is particularly useful for identifying gene mutations. This study aimed to assess the analytic and clinical validity of RAS and BRAF ddPCR mutational testing as a diagnostic tool for thyroid fine needle aspirate biopsy (FNAB). METHODS: Patients with thyroid nodules meeting indication for FNAB were prospectively enrolled from March 2015 to September 2017. In addition to clinical protocol, an additional FNAB was obtained for ddPCR. Optimized ddPCR probes were used to detect mutations including HRASG12 V, HRASQ61K, HRASQ61R, NRASQ61R, NRASQ61K and BRAFV600E. The diagnostic performance of BRAF and RAS mutations was assessed individually or in combination with Bethesda classification against final surgical pathology. RESULTS: A total of 208 patients underwent FNAB and mutational testing with the following Bethesda cytologic classification: 26.9% non-diagnostic, 55.2% benign, 5.3% FLUS/AUS, 2.9% FN/SPN, 2.4% SFM and 7.2% malignant. Adequate RNA was obtained from 91.3% (190) FNABs from which mutations were identified in 21.1% of HRAS, 11.5% of NRAS and 7.4% of BRAF. Malignant cytology or BRAFV600E was 100% specific for malignancy. Combining cytology with ddPCR BRAF600E mutations testing increased the sensitivity of Bethesda classification from 41.7 to 75%. Combined BRAFV600E and Bethesda results had a positive predictive value (PPV) of 100% and negative predictive value (NPV) of 89.7% for thyroid malignancy in our cohort. CONCLUSIONS: DdPCR offers a novel and ultrasensitive method of detecting RAS and BRAF mutations from thyroid FNABs. BRAFV600E mutation testing by ddPCR may serve as a useful adjunct to increase sensitivity and specificity of thyroid FNAB. PMID- 30249282 TI - Novel in-frame deletion in MFSD8 gene revealed by trio whole exome sequencing in an Iranian affected with neuronal ceroid lipofuscinosis type 7: a case report. AB - BACKGROUND: The neuronal ceroid lipofuscinoses are a group of neurodegenerative, lysosomal storage disorders. They are inherited as an autosomal recessive pattern with the exception of adult neuronal ceroid lipofuscinosis, which can be inherited in either an autosomal recessive or an autosomal dominant manner. The neuronal ceroid lipofuscinoses are characterized by accumulation of autofluorescent lipopigments in the cells and one of the most important pathological manifestations is ceroid accumulation in the lysosomes. Various types of neuronal ceroid lipofuscinoses are categorized based on the clinical manifestations and the genes involved. Accumulatively, 15 different genes have been found so far to be implicated in the pathogenesis of at least nine different types of neuronal ceroid lipofuscinoses, which result in similar pathological and clinical manifestations. CASE PRESENTATION: A 5-year-old Iranian boy affected by a neurodegenerative disorder with speech problems, lack of concentration, walking disability at age of 4 years leading to quadriplegia, spontaneous laughing, hidden seizure, clumsiness, psychomotor delay, and vision deterioration at age of 5 years, which could be the consequence of macular dystrophy, was referred to us for genetic testing. Trio whole exome sequencing, Sanger validation, and segregation analysis discovered a novel in-frame small deletion c.325_339del (p.Val109_Ile113del) in MFSD8 gene associated with neuronal ceroid lipofuscinosis type 7. CONCLUSIONS: The deletion found in this patient affects the exon 5 of this gene which is the region encoding transmembrane domain. Sequencing analysis in this family has shown that the index is homozygous for 15 base pairs in-frame deletion, his uncle has normal homozygous, and his parents are heterozygous. This pattern of mutation inheritance and the signs and symptoms observed in the affected male of this family are compatible with what is described in the literature for neuronal ceroid lipofuscinosis type 7 and, therefore, suggest that the MFSD8 gene deletion found in this study is most probably the cause of disease in this family. PMID- 30249284 TI - A novel candidate species of Anaplasma that infects avian erythrocytes. AB - BACKGROUND: Anaplasma spp. are Gram-negative obligate intracellular bacteria transmitted by ticks. Even though numerous studies have detected DNA from Anaplasma spp. in the blood of birds, thus far mammals were the only vertebrates demonstrated to serve as competent hosts to these organisms. We report a novel candidate species of Anasplasma that was associated with cytoplasmic inclusions in the erythrocytes of an African penguin (Spheniscus demersus) in South Africa. METHODS: Cytoplasmic inclusions were morphologically characterized from freshly produced blood smears, and phylogenetic analysis of 16S rRNA and groEL genes were used to evaluate the evolutionary relationships of the organism to other Anaplasmataceae. RESULTS: Dark-purple round or oval inclusions consistent with Anaplasmataceae morulae were observed in the cytoplasm of erythrocytes. Phylogenetic trees produced using different methods agreed that the organism detected in this study belongs to the genus Anaplasma, and suggested that it is most closely related to the cluster comprising A. centrale, A. capra, A. marginale and A. ovis. We propose provisionally naming the strain detected in this study as "Candidatus Anaplasma sphenisci". CONCLUSIONS: This is the first species of Anaplasma shown to produce cytoplasmic inclusions in avian cells, opening the possibility that cytoplasmic inclusions in avian erythrocytes that had previously been attributed to Aegyptianella sp. might in fact correspond to Anaplasma. Further studies on the molecular biology of avian-infecting Anaplasmataceae will be valuable to provide insight into the evolution and epidemiology of these organisms. PMID- 30249286 TI - Is nodding syndrome in northern Uganda linked to consumption of mycotoxin contaminated food grains? AB - OBJECTIVE: Nodding syndrome (NS) is a type of epilepsy characterized by repeated head-nodding seizures that appear in previously healthy children between 3 and 18 years of age. In 2012, during a WHO International Meeting on NS in Kampala, Uganda, it was recommended that fungal contamination of foods should be investigated as a possible cause of the disease. We therefore aimed to assess whether consumption of fungal mycotoxins contributes to NS development. RESULTS: We detected similar high levels of total aflatoxin and ochratoxin in mostly millet, sorghum, maize and groundnuts in both households with and without children with NS. Furthermore, there was no significant association between concentrations of total aflatoxin, ochratoxin and doxynivalenol and the presence of children with NS in households. In conclusion, our results show no supporting evidence for the association of NS with consumption of mycotoxins in contaminated foods. PMID- 30249285 TI - Cardiorespiratory fitness attenuates age-associated aggregation of white matter hyperintensities in an at-risk cohort. AB - BACKGROUND: Age is the cardinal risk factor for Alzheimer's disease (AD), and white matter hyperintensities (WMH), which are more prevalent with increasing age, may contribute to AD. Higher cardiorespiratory fitness (CRF) has been shown to be associated with cognitive health and decreased burden of AD-related brain alterations in older adults. Accordingly, the aim of this study was to determine whether CRF attenuates age-related accumulation of WMH in middle-aged adults at risk for AD. METHODS: One hundred and seven cognitively unimpaired, late-middle aged adults from the Wisconsin Registry for Alzheimer's Prevention underwent 3 T magnetic resonance imaging and performed graded maximal treadmill exercise testing from which we calculated the oxygen uptake efficiency slope (OUES) as our measure of CRF. Total WMH were quantified using the Lesion Segmentation Tool and scaled to intracranial volume. Linear regression adjusted for APOE4 carriage, family history, body mass index, systolic blood pressure, and sex was used to examine relationships between age, WMH, and CRF. RESULTS: As expected, there was a significant association between age and WMH (p < .001). Importantly, there was a significant interaction between age and OUES on WMH (p = .015). Simple main effects analyses revealed that the effect of age on WMH remained significant in the Low OUES group (p < .001) but not in the High OUES group (p = .540), indicating that higher CRF attenuates the deleterious age association with WMH. CONCLUSIONS: Higher CRF tempers the adverse effect of age on WMH. This suggests a potential pathway through which increased aerobic fitness facilitates healthy brain aging, especially among individuals at risk for AD. PMID- 30249287 TI - The complete genomic sequence of Sugarcane mosaic virus from Canna spp. in China. AB - BACKGROUND: Sugarcane mosaic virus (SCMV) is the prevalent virus inducing maize dwarf mosaic and sugarcane mosaic diseases in China. According to the phylogenetic results of the complete genomic and coat protein gene sequences, SCMV was divided into four or five molecular groups, respectively. Previously, we detected SCMV isolates of group SO from Canna spp. in Ji'nan, Shandong province, China. FINDINGS: In this study, we collected two SCMV isolates infecting Canna spp. in Ji'nan (Canna-Ji'nan) and Tai'an (Canna-Tai'an) of Shandong, China. Their complete genome sequences had genome of 9576 nucleotides and contained a large open reading frame encoding a polyprotein of 3063 amino acids. The phylogenetic analysis showed that the both Canna-Ji'nan and Canna-Tai'an were clustered into an independent group based on the complete genome sequence. CONCLUSION: In this study, we report the complete genome sequences of SCMV infecting Canna spp. from Ji'nan and Tai'an. This is the first report on SCMV belonging to SO group. PMID- 30249288 TI - Extensile lateral versus sinus tarsi approach for displaced, intra-articular calcaneal fractures: a meta-analysis. AB - BACKGROUND: Operative management of displaced, intra-articular calcaneal fractures is associated with improved functional outcomes but associated with frequent complications due to poor soft tissue healing. The use of a minimally invasive sinus tarsi approach to the fixation of these fractures may be associated with a lower rate of complications and therefore provide superior outcomes without the associated morbidity of operative intervention. METHODS: We reviewed four prospective and seven retrospective trials that compared the outcomes from the operative fixation of displaced intra-articular calcaneal fractures via either an extensile lateral approach or minimally invasive fixation via a sinus tarsi approach. RESULTS: Patients managed with a sinus tarsi approach were less likely to suffer complications (OR = 2.98, 95% CI = 1.62-5.49, p = 0.0005) and had a shorter duration of surgery (OR = 44.29, 95% CI = 2.94-85.64, p = 0.04). CONCLUSION: In displaced intra-articular calcaneal fractures, a minimally invasive sinus tarsi approach is associated with a lower complication rate and quicker operation duration compared to open reduction and internal fixation via an extensile lateral approach. PMID- 30249290 TI - Morphine-induced supraventricular tachycardia in near-term fetus. AB - BACKGROUND: Fetal supraventricular tachycardia (SVT), characterized by fetal heart rate between 220 and 260 bpm, is a rare but most commonly encountered fetal cardiac arrhythmia in pregnancy that may be associated with adverse perinatal outcome. CASE PRESENTATION: We describe a 36/6 week near term fetus who presented morphine-induced SVT after maternal treatment of a renal colic. Following emergency cesarean section, the neonate had resolution of symptoms. CONCLUSIONS: The pathophysiology of morphine-related SVT, previously documented in experimental animal models, and for the first time reported in the human fetus, is presented. PMID- 30249289 TI - SPAG5 promotes hepatocellular carcinoma progression by downregulating SCARA5 through modifying beta-catenin degradation. AB - BACKGROUND: The sperm-associated antigen 5 (SPAG5) plays a key role in controlling various cellular phenomena, including cell cycle progression and proliferation. However, the role of SPAG5 in hepatocellular carcinoma (HCC) remains unknown. METHODS: This study investigated the function and clinical significance of SPAG5 protein expression in hepatocellular carcinoma. We analyzed SPAG5 expression in surgical specimens from 136 HCC patients. The correlation between the clinical characteristics and prognosis was also determined. Furthermore, the SPAG5 was overexpressed in HCC cell and silenced with shRNA in HCC cells. Moreover, cell proliferation and apoptosis were measured using Edu assay and flow cytometry and a molecular mechanism of SPAG5 promotes HCC progression was explored. RESULTS: Herein, our study showed that upregulation of SPAG5 was detected frequently in primary HCC tissues, and was associated with significantly worse survival among the HCC patients. Multivariate analyses revealed that high SPAG5 expression was an independent predictive marker for the poor prognosis of HCC. SPAG5 silence effectively abolished the proliferation abilities of SPAG5 in vivo and in vitro, while induced apoptosis in HCC cells. Furthermore, our results indicate that SPAG5 promoted cell progression by decreasing SCARA5 expression, which has been reported to control the progression of HCC, and our data demonstrated that SCARA5 is crucial for SPAG5-mediated HCC cell progression in vitro and in vivo. Moreover, we found that the expression of SPAG5 and SCARA5 are inversely correlated in HCC tissues. In addition, we demonstrated that SPAG5 promoted progression in HCC via downregulating SCARA5 depended on the beta-catenin/TCF4 signaling pathway. Interestingly, the underlying mechanism is which SPAG5 regulates SCARA5 expression by modulating beta-catenin degradation. CONCLUSIONS: Taken together, our data provide a novel evidence for the biological and clinical significance of SPAG5 as a potential biomarker, and we demonstrate that SPAG5-beta-catenin-SCARA5 might be a novel pathway involved in HCC progression. PMID- 30249283 TI - Inflammation: the link between comorbidities, genetics, and Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder, most cases of which lack a clear causative event. This has made the disease difficult to characterize and, thus, diagnose. Although some cases are genetically linked, there are many diseases and lifestyle factors that can lead to an increased risk of developing AD, including traumatic brain injury, diabetes, hypertension, obesity, and other metabolic syndromes, in addition to aging. Identifying common factors and trends between these conditions could enhance our understanding of AD and lead to the development of more effective treatments. Although the immune system is one of the body's key defense mechanisms, chronic inflammation has been increasingly linked with several age-related diseases. Moreover, it is now well accepted that chronic inflammation has an important role in the onset and progression of AD. In this review, the different inflammatory signals associated with AD and its risk factors will be outlined to demonstrate how chronic inflammation may be influencing individual susceptibility to AD. Our goal is to bring attention to potential shared signals presented by the immune system during different conditions that could lead to the development of successful treatments. PMID- 30249291 TI - Determinants of drug-related problems among ambulatory type 2 diabetes patients with hypertension comorbidity in Southwest Ethiopia: a prospective cross sectional study. AB - OBJECTIVE: The aim of this study was to assess drug-related problems and its determinants in type 2 diabetes patients with hypertension co-morbidity. RESULTS: A total of 300 type 2 diabetes patients with hypertension co-morbidity were studied. The majority of participants, 194 (64.7%), were males. Mean age of the participants was 54.44 +/- 11.68 years. The mean durations of diabetes and hypertension were 5.37 +/- 4.79 and 5.15 +/- 4.65 years respectively. The most commonly prescribed antidiabetic medications were metformin in 200 (66.7%) and insulin 126 (42%) of the participants. Enalapril was the most commonly prescribed antihypertensive medication; 272 (90.7%). Aspirin was prescribed to 182 (60.7%) participants. Statins were prescribed to one-third (65.67%) of the participants. Eighty-five (28.3%) participants had diabetes related complications other than hypertension. A total of 494 drug related problems were identified. The mean number of drug related problems was 1.65 +/- 1.05. The most common drug related problems were need for additional drug therapy (29.35%), ineffective drug (27.94%) and dose too low (15.8%). Independent predictors of drug related problems were age 41-60 years (AOR = 6.87, 95% CI 2.63-17.93), age > 60 years (AOR = 5.85, 95% CI 2.15-15.93) and the presence of comorbidity (AOR = 3.0, 95% CI 1.11-8.16). PMID- 30249292 TI - Completion rates and psychosocial intervention effectiveness in an Australian substance use therapeutic community. AB - BACKGROUND: Program attrition is a major problem in substance use treatment. It is not clear which client and treatment variables are related to successful completion. This study aimed to identify client variables associated with Therapeutic Community (TC) completion. A secondary aim was to investigate changes in entry and exit scores on psychosocial outcome measures. METHODS: Retrospective quantitative analysis of data collected from 193 Australian TC residents, over 3.5 years. Variables measured included: demographics; Depression, Anxiety, Stress Score (DASS-21) and World Health Organisation Quality of Life 8 questions (WHOQOL 8). RESULTS: Completion rates were 30.6%. High Money WHOQOL-8 scores, suggestive of minimal financial stressors, positively predicted completion. Multivariate analyses showed that negative predictors of completion were: amphetamine being primary substance of concern, aggression, high Relationship WHOQOL-8 scores, suggestive of positive relationships, and younger or older age. Those in the program demonstrated clinically significant psychological improvement and significant improvement in all quality of life scores over time. The degree of psychometric improvement was most pronounced in those who completed the course, with the exception of depression, stress, and money problems. CONCLUSION: The findings provide an understanding of specific predictors of program completion which may help to identify high-risk clients and inform program improvement. Early attrition rates may be reduced by monitoring and supporting high-risk clients. Overall, psychometric improvement occurred amongst both completers and non-completers overtime but is most prominent amongst course completers, with the exception of depression, stress, and money problems. Future research could potentially focus on amphetamine users and shortened TC programs, focusing on acute psychosocial intervention. PMID- 30249294 TI - Process evaluation of a social franchising model to improve maternal health: evidence from a multi-methods study in Uttar Pradesh, India. AB - BACKGROUND: A prominent strategy to engage private sector health providers in low and middle-income countries is clinical social franchising, an organisational model that applies the principles of commercial franchising for socially beneficial goals. The Matrika programme, a multi-faceted social franchise model to improve maternal health, was implemented in three districts of Uttar Pradesh, India, between 2013 and 2016. Previous research indicates that the intervention was not effective in improving the quality and coverage of maternal health services at the population level. This paper reports findings from an independent external process evaluation, conducted alongside the impact evaluation, with the aim of explaining the impact findings. It focuses on the main component of the programme, the "Sky" social franchise. METHODS: We first developed a theory of change, mapping the key mechanisms through which the programme was hypothesised to have impact. We then undertook a multi-methods study, drawing on both quantitative and qualitative primary data from a wide range of sources to assess the extent of implementation and to understand mechanisms of impact and the role of contextual factors. We analysed the quantitative data descriptively to generate indicators of implementation. We undertook a thematic analysis of the qualitative data before holding reflective meetings to triangulate across data sources, synthesise evidence, and identify the main findings. Finally, we used the framework provided by the theory of change to organise and interpret our findings. RESULTS: We report six key findings. First, despite the franchisor achieving its recruitment targets, the competitive nature of the market for antenatal care meant social franchise providers achieved very low market share. Second, all Sky health providers were branded but community awareness of the franchise remained low. Third, using lower-level providers and community health volunteers to encourage women to attend franchised antenatal care services was ineffective. Fourth, referral linkages were not sufficiently strong between antenatal care providers in the franchise network and delivery care providers. Fifth, Sky health providers had better knowledge and self-reported practice than comparable health providers, but overall, the evidence pointed to poor quality of care across the board. Finally, telemedicine was perceived by clients as an attractive feature, but problems in the implementation of the technology meant its effect on quality of antenatal care was likely limited. CONCLUSIONS: These findings point towards the importance of designing programmes based on a strong theory of change, understanding market conditions and what patients value, and rigorously testing new technologies. The design of future social franchising programmes should take account of the challenges documented in this and other evaluations. PMID- 30249293 TI - Culturally tailored, peer-based sleep health education and social support to increase obstructive sleep apnea assessment and treatment adherence among a community sample of blacks: study protocol for a randomized controlled trial. AB - BACKGROUND: Compared to whites, blacks are at increased risk for obstructive sleep apnea (OSA) yet less likely to adhere to physician-recommended sleep assessment and treatment. Poor OSA health literacy and lack of social support to navigate the current healthcare system are two potential barriers to adequate OSA care. This study is designed to address these barriers by evaluating the effectiveness of a peer-based sleep health education program on adherence to OSA assessment and treatment among blacks at risk for OSA. METHOD/DESIGN: In a two arm, randomized controlled trial, we will ascertain the effectiveness of peer based sleep health education and social support in increasing OSA evaluation and treatment rates among 398 blacks at low to high OSA risk. Participants at risk of OSA will receive quality controlled, culturally, and linguistically tailored peer education based on Motivational Enhancement principles over a period of 12 months. During this 12-month period, participants are encouraged to participate in a sleep home study to determine risk of OSA and, if found to be at risk, they are invited to undergo a diagnostic sleep assessment at a clinic. Participants who are diagnosed with OSA and who are prescribed continuous positive airway pressure treatment will be encouraged, through peer-based education, to adhere to recommended treatment. Recruitment for the project is ongoing. DISCUSSION: The use of a culturally tailored sleep health education program, peer health educators trained in sleep health, and home-based sleep assessment are novel approaches in improving OSA assessment and treatment adherence in blacks who are significantly at risk for OSA. Empirical evidence from this trial will provide clinical and population level solutions on how to improve and increase assessment and treatment of OSA among blacks. TRIAL REGISTRATION: NCT02427815 . Registered on 20 April 2015. ClinicalTrials.gov title: Sleep Health Education and Social Support Among Blacks With OSA. PMID- 30249295 TI - PATCH: posture and mobility training for care staff versus usual care in care homes: study protocol for a randomised controlled trial. AB - BACKGROUND: Residents of care homes have high levels of disability and poor mobility, but the promotion of health and wellbeing within care homes is poorly realised. Residents spend the majority of their time sedentary which leads to increased dependency and, coupled with poor postural management, can have many adverse outcomes including pressure sores, pain and reduced social interaction. The intervention being tested in this project (the Skilful Care Training Package) aims to increase the awareness and skills of care staff in relation to poor posture in the older, less mobile adult and highlight the benefits of activity, and how to skilfully assist activity, in this group to enable mobility and reduce falls risk. Feasibility work will be undertaken to inform the design of a definitive cluster randomised controlled trial. METHODS: This is a cluster randomised controlled feasibility trial, aiming to recruit at least 12-15 residents at each of 10 care homes across Yorkshire. Care homes will be randomly allocated on a 1:1 basis to receive either the Skilful Care Training Package alongside usual care or to continue to provide usual care alone. Assessments will be undertaken by blinded researchers with participating residents at baseline (before care home randomisation) and at three and six months post randomisation. Data relating to changes in physical activity, mobility, posture, mood and quality of life will be collected. Data at the level of the home will also be collected and will include staff experience of care and changes in the numbers and types of adverse events residents experience (for example, hospital admissions, falls). Details of NHS service usage will be collected to inform the economic analysis. An embedded process evaluation will explore intervention delivery and its acceptability to staff and residents. DISCUSSION: Participant uptake, engagement and retention are key feasibility outcomes. Exploration of barriers and facilitators to intervention delivery will inform intervention optimisation. Study results will inform progression to a definitive trial and add to the body of evidence for good practice in care home research. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN50080330 . Registered on 27 March 2017. PMID- 30249296 TI - The cost-effectiveness and cost-utility of at-home infrared temperature monitoring in reducing the incidence of foot ulcer recurrence in patients with diabetes (DIATEMP): study protocol for a randomized controlled trial. AB - BACKGROUND: Home monitoring of foot temperatures in high-risk diabetes patients proves to be a promising approach for early recognition and treatment of pre signs of ulceration, and thereby ulcer prevention. Despite previous studies demonstrating its efficacy, it is currently not widely applied in (Dutch) health care. METHODS: In a multicenter, outcome-assessor-blinded, randomized controlled trial, 304 patients with diabetes mellitus types I or II, loss of protective sensation based on peripheral neuropathy, and a history of foot ulceration in the preceding 4 years or a diagnosis of Charcot neuro-osteoarthropathy will be included. Enhanced therapy will consist of usual care and additional at-home daily measurement of foot temperatures at six to eight predefined locations on the foot. If a contralateral foot temperature difference of > 2.2 degrees C is found on two consecutive days, the participant is instructed to contact their podiatrist for further foot diagnosis or treatment, and to reduce ambulatory activity by 50% until temperatures are normalized. Enhanced therapy will be compared to usual care. The primary outcomes are the cost (savings) per patient without a foot ulcer (i.e., cost-effectiveness) and per quality-adjusted life year gained (i.e., cost-utility). The primary clinical outcome in the study is the proportion of patients with foot ulcer recurrence on the plantar foot, apical surfaces of the toes, the interdigital spaces or medial and lateral forefoot surfaces during 18-month follow-up. DISCUSSION: Confirmation of the efficacy of at-home foot temperature monitoring in ulcer prevention, together with assessing its usability, cost-effectiveness and cost-utility, could lead to implementation in Dutch health care, and in many settings across the world. TRIAL REGISTRATION: Netherlands Trial Registration: NTR5403 . Registered on 8 September 2015. PMID- 30249299 TI - Correction to: preserving prion strain identity upon replication of prions in vitro using recombinant prion protein. AB - Figure 6 of the original publication [1] contained an error in the Wavenumber in panels B and C. The wavenumbers 1616 (Cm-1) in panels B and C should have been 1516 (cm-1). The updated figure has been published in this correction article; the original article has been updated. PMID- 30249298 TI - A novel taping therapy for pain after arthroscopic shoulder surgery: study protocol for a randomised controlled pilot trial. AB - BACKGROUND: In recent years, the number of arthroscopic shoulder surgeries has increased given that the intervention is minimally invasive. However, postoperative pain is one of the most common symptoms of patients who undergo arthroscopic surgery. Although pharmacological treatments and brachial plexus blocks for reducing pain are currently used, the adherence rate of interventions is low, and adverse effects often occur. Chimsband, made up of silver and optic fibres, is a novel taping therapy that stimulates patients' acupoints and is expected to relieve pain with few adverse effects. The aim of this study is to explore the effectiveness of Chimsband to relieve pain following arthroscopic shoulder surgery. METHODS/DESIGN: This is a randomised, parallel, controlled, exploratory clinical trial. Thirty participants who undergo arthroscopic shoulder surgery will be randomly allocated to an intervention or a control group. Both groups will receive 10 sessions of interferential current therapy within a period of 2 weeks, while the intervention group will additionally receive taping therapy after undergoing physical therapy. Two follow-up visits will be scheduled after the last treatment session. The primary outcome variable will be the difference in the visual analogue scale (VAS) scores between baseline and first follow-up evaluation after the end of 10 treatment sessions. The secondary outcomes will be VAS at the end of the second week, shoulder pain and disability index, range of motion, VAS while sleeping, questionnaire of blood stasis pattern identification at two follow-up visits, and number of bands used per visit. Outcomes will be evaluated at baseline, 2 weeks from visit 1 (+ within 6 days) after commencement, and at 4 weeks from visit 1 (+ within 6 days) follow-up. DISCUSSION: This study will be the first clinical trial to explore the effect and safety of Chimsband on postoperative shoulder pain. It would provide clinical evidence to conduct further taping therapy studies for relieving musculoskeletal pain. TRIAL REGISTRATION: Korean Clinical Trial Registry, KCT0002355 . Registered on 13 June 2017. PMID- 30249297 TI - Alzheimer's associated amyloid and tau deposition co-localizes with a homeostatic myelin repair pathway in two mouse models of post-stroke mixed dementia. AB - The goal of this study was to determine the chronic impact of stroke on the manifestation of Alzheimer's disease (AD) related pathology and behavioral impairments in mice. To accomplish this goal, we used two distinct models. First, we experimentally induced ischemic stroke in aged wildtype (wt) C57BL/6 mice to determine if stroke leads to the manifestation of AD-associated pathological beta amyloid (Abeta) and tau in aged versus young adult wt mice. Second, we utilized a transgenic (Tg) mouse model of AD (hAPP-SL) to determine if stroke leads to the worsening of pre-existing AD pathology, as well as the development of pathology in brain regions not typically expressed in AD Tg mice. In the wt mice, there was delayed motor recovery and an accelerated development of cognitive deficits in aged mice compared to young adult mice following stroke. This corresponded with increased brain atrophy, increased cholinergic degeneration, and a focal increase of Abeta in areas of axonal degeneration in the ipsilateral hemisphere of the aged animals. By contrast, in the hAPP-SL mice, we found that ischemia induced aggravated behavioral deficits in conjunction with a global increase in Abeta, tau, and cholinergic pathology compared to hAPP-SL mice that underwent a sham stroke procedure. With regard to a potential mechanism, in both models, we found that the stroke-induced Abeta and tau deposits co-localized with increased levels of beta-secretase 1 (BACE1), along with its substrate, neuregulin 1 (NGR1) type III, both of which are proteins integral for myelin repair. Based on these findings, we propose that the chronic sequelae of stroke may be ratcheting-up a myelin repair pathway, and that the consequent increase in BACE1 could be causing an inadvertent cleavage of its alternative substrate, AbetaPP, resulting in greater Abeta seeding and pathogenesis. PMID- 30249300 TI - The susceptibility of cochlear outer hair cells to cyclodextrin is not related to their electromotile activity. AB - Niemann-Pick Type C1 (NPC1) disease is a fatal neurovisceral disorder caused by dysfunction of NPC1 protein, which plays a role in intracellular cholesterol trafficking. The cholesterol-chelating agent, 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD), is currently undergoing clinical trials for treatment of this disease. Though promising in alleviating neurological symptoms, HPbetaCD causes irreversible hearing loss in NPC1 patients and outer hair cell (OHC) death in animal models. We recently found that HPbetaCD-induced OHC death can be significantly alleviated in a mouse model lacking prestin, an OHC-specific motor protein required for the high sensitivity and sharp frequency selectivity of mammalian hearing. Since cholesterol status is known to influence prestin's electromotility, we examined how prestin contributes to HPbetaCD-induced OHC death in the disease context using the NPC1 knockout (KO) mouse model (NPC1-KO). We found normal expression and localization of prestin in NPC1-KO OHCs. Whole cell patch-clamp recordings revealed a significant depolarization of the voltage operating point of prestin in NPC1-KO mice, suggesting reduced levels of cholesterol in the lateral membrane of OHCs that lack NPC1. OHC loss and elevated thresholds were found for high frequency regions in NPC1-KO mice, whose OHCs retained their sensitivity to HPbetaCD. To investigate whether prestin's electromotile function contributes to HPbetaCD-induced OHC death, the prestin inhibitor salicylate was co-administered with HPbetaCD to WT and NPC1-KO mice. Neither oral nor intraperitoneal administration of salicylate mitigated HPbetaCD induced OHC loss. To further determine the contribution of prestin's electromotile function, a mouse model expressing a virtually nonelectromotile prestin protein (499-prestin) was subjected to HPbetaCD treatment. 499-prestin knockin mice showed no resistance to HPbetaCD-induced OHC loss. As 499-prestin maintains its ability to bind cholesterol, our data imply that HPbetaCD-induced OHC death is ascribed to the structural role of prestin in maintaining the OHC's lateral membrane, rather than its motor function. PMID- 30249301 TI - Metabolomic alterations associated with Behcet's disease. AB - BACKGROUND: The diagnosis of Behcet's disease (BD) remains challenging due to the lack of diagnostic biomarkers. This study aims to identify potential serum metabolites associated with BD and its disease activity. METHODS: Medical records and serum samples of 24 pretreated BD patients, 12 post-treated BD patients, and age-matched healthy controls (HC) were collected for metabolomics and lipidomics profiling using UPLC-QTOF-MS and UPLC-QTOF-MSE approaches. Additionally, serum samples from an independent cohort of BD patients, disease controls including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Takayasu's arteritis (TA), Crohn's disease (CD) patients, and HC were collected for further validation of two potential biomarkers using UPLC-QTOFMS analysis. RESULTS: Unsupervised principal component analysis (PCA) showed a clear separation of metabolomics profiles of BD patients from HC. Statistical analysis of the data revealed differential metabolites between BD patients and HC. The serum levels of some phosphatidylcholines (PCs) were found to be significantly lower in BD patients, while the levels of several polyunsaturated fatty acids (PUFAs) were increased markedly in the BD group compared with HC. Furthermore, the serum level of two omega-6 PUFAs, linoleic acid (LA) and arachidonic acid (AA), were dramatically decreased in patients with remission. A validation cohort confirmed that the serum LA and AA levels in BD patients were significantly higher than those in HC and patients with RA, SLE, TA, and CD. In addition, receiver operating characteristic (ROC) analysis indicated good sensitivity and specificity. CONCLUSIONS: The serum metabolomics profiles in BD patients are altered. Serum LA and AA are promising diagnostic biomarkers for BD. PMID- 30249302 TI - Radiation oncology resident training in patient safety and quality improvement: a national survey of residency program directors. AB - BACKGROUND: Physicians and physicists are expected to contribute to patient safety and quality improvement (QI) in Radiation Oncology (RO), but prior studies suggest that training for this may be inadequate. RO and medical physics (MP) program directors (PDs) were surveyed to better understand the current patient safety/QI training in their residency programs. METHODS: PDs were surveyed via email in January 2017. Survey questions inquired about current training, curriculum elements, and barriers to development and/or improvement of safety and QI training. RESULTS: Eighty-nine RO PDs and 84 MP PDs were surveyed, and 21 RO PDs (28%) and 31 MP PDs (37%) responded. Both RO and MP PDs had favorable opinions of current safety and QI training, and used a range of resources for program development, especially safety and QI publications. Various curriculum elements were reported. Curriculum elements used by RO and MP PDs were similar, except RO were more likely than MP PDs to implement morbidity and mortality (M&M) conference (72% vs. 45%, p < 0.05). RO and MP PDs similarly cited various barriers, but RO PDs were more likely to cite lack of experience than MP PDs (40% vs. 16%, p < 0.05). PDs responded similarly independent of whether they reported using a departmental incident learning system (ILS) or not. CONCLUSIONS: PDs view patient safety/QI as an important part of resident education. Most PDs agreed that residents are adequately exposed to patient safety/QI and prepared to meet the patient safety/QI expectations of clinical practice. This conflicts with other independent studies that indicate a majority of residents feel their patient safety/QI training is inadequate and lacks formal exposure to QI tools. PMID- 30249303 TI - Neurodegeneration in SCA14 is associated with increased PKCgamma kinase activity, mislocalization and aggregation. AB - Spinocerebellar ataxia type 14 (SCA14) is a subtype of the autosomal dominant cerebellar ataxias that is characterized by slowly progressive cerebellar dysfunction and neurodegeneration. SCA14 is caused by mutations in the PRKCG gene, encoding protein kinase C gamma (PKCgamma). Despite the identification of 40 distinct disease-causing mutations in PRKCG, the pathological mechanisms underlying SCA14 remain poorly understood. Here we report the molecular neuropathology of SCA14 in post-mortem cerebellum and in human patient-derived induced pluripotent stem cells (iPSCs) carrying two distinct SCA14 mutations in the C1 domain of PKCgamma, H36R and H101Q. We show that endogenous expression of these mutations results in the cytoplasmic mislocalization and aggregation of PKCgamma in both patient iPSCs and cerebellum. PKCgamma aggregates were not efficiently targeted for degradation. Moreover, mutant PKCgamma was found to be hyper-activated, resulting in increased substrate phosphorylation. Together, our findings demonstrate that a combination of both, loss-of-function and gain-of function mechanisms are likely to underlie the pathogenesis of SCA14, caused by mutations in the C1 domain of PKCgamma. Importantly, SCA14 patient iPSCs were found to accurately recapitulate pathological features observed in post-mortem SCA14 cerebellum, underscoring their potential as relevant disease models and their promise as future drug discovery tools. PMID- 30249304 TI - Development of a novel method for rapid cloning of shRNA vectors, which successfully knocked down CD44 in mesenchymal triple-negative breast cancer cells. PMID- 30249306 TI - Blood donation practice and associated factors among health professionals in Tigray regional state public hospitals, northern Ethiopia. AB - OBJECTIVE: The demand for blood and blood products are increasing in all part of the globe, especially in the developing nations. However, there is limited information on the level of blood donation practice and their related factors. Therefore, assessing the level of blood donation practice and its determinant factors among health professionals have a paramount importance in designing an effective strategy for sustaining adequate and safe blood provision in the hospitals. RESULTS: Out of 556 health professionals, 266 (47.8%) had ever donated blood in their life time. Age above 30 years (AOR = 2.756 95% CI 1.055-7.197), married health professionals (AOR = 1.729 95% CI 1.091-2.739), health professionals' knowledge of blood donation (AOR = 3.403 95% CI 2.296-5.044), health professionals' attitude towards blood donation (AOR = 3.41 95% CI 2.320 5.041) and health professionals who attend degree education (AOR = 0.315 95% CI 0.104-0.950) were significantly associated with blood donation behavior of health professionals. The magnitude of blood donation practice was found low. Therefore, the Ethiopian Red Cross Society and ministry of health should continue increasing the attitude and knowledge of health professionals toward blood donation practices are the key avenues interventions. PMID- 30249307 TI - Hand hygiene opportunities on Canadian acute-care inpatient units: A multicenter observational study. AB - In this multicenter observational study, medical and surgical inpatient rooms were randomized to receive 1 hour of continuous direct observation to determine hand hygiene opportunities (HHOs). After multivariable adjustment, HHOs were similar across inpatient units and hospitals. This estimate could serve to calibrate electronic hand hygiene monitoring systems for Canadian medical and surgical units. PMID- 30249308 TI - Childhood maltreatment affects adolescent sensitivity to parenting and close friendships in predicting growth in externalizing behavior. AB - Childhood maltreatment robustly predicts adolescent externalizing behaviors (EB; e.g., violence, delinquency, substance use) and may crystalize patterns of EB by influencing sensitivity to the social environment (e.g., parenting, friendships). In a nationally representative sample of 9,421 adolescents, we modeled latent growth curves of EB from age 13 to 32 years. Next, we explored whether maltreated youth differed from nonmaltreated youth in their sensitivity to parental closeness, friendship involvement, and polymorphisms from dopamine genes linked to EB (dopamine receptors D2 and D4, dopamine transporter). Overall, maltreated youth had significantly higher levels of EB across adolescence and adulthood; however, maltreated and nonmaltreated youth showed similar patterns of EB change over time: violent behavior decreased in adolescence before stabilizing in adulthood, whereas nonviolent delinquency and substance use increased in adolescence before decreasing in the transition to adulthood. Maltreatment reduced sensitivity to parental closeness and friendship involvement, although patterns varied based on type of EB outcome. Finally, none of the environmental effects on EB were significantly moderated by the dopamine polygenic risk score after accounting for multiple testing. These findings underline the enduring effects of early maltreatment and implicate that maltreatment may contribute to long-term risk for EB by influencing children's sensitivity to social relationship factors in adolescence. PMID- 30249309 TI - Food processing: criteria for dietary guidance and public health? AB - The NOVA food categorisation recommends 'avoiding processed foods (PF), especially ultra-processed foods (UPF)' and selecting minimally PF to address obesity and chronic disease. However, NOVA categories are drawn using non traditional views of food processing with additional criteria including a number of ingredients, added sugars, and additives. Comparison of NOVA's definition and categorisation of PF with codified and published ones shows limited congruence with respect to either definition or food placement into categories. While NOVA studies associate PF with decreased nutrient density, other classifications find nutrient-dense foods at all levels of processing. Analyses of food intake data using NOVA show UPF provide much added sugars. Since added sugars are one criterion for designation as UPF, such a proof demonstrates a tautology. Avoidance of foods deemed as UPF, such as wholegrain/enriched bread and cereals or flavoured milk, may not address obesity but could decrease intakes of folate, calcium and dietary fibre. Consumer understanding and implementation of NOVA have not been tested. Neither have outcomes been compared with vetted patterns, such as Dietary Approaches to Stop Hypertension, which base food selection on food groups and nutrient contribution. NOVA fails to demonstrate the criteria required for dietary guidance: understandability, affordability, workability and practicality. Consumers' confusion about definitions and food categorisations, inadequate cooking and meal planning skills and scarcity of resources (time, money), may impede adoption and success of NOVA. Research documenting that NOVA can be implemented by consumers and has nutrition and health outcomes equal to vetted patterns is needed. PMID- 30249310 TI - Further Investigation of Screening for Anxiety and Depression in Epilepsy. PMID- 30249311 TI - Tularemia transmission to humans: a multifaceted surveillance approach. AB - Tularemia has sustained seroprevalence in Eurasia, with estimates as high as 15% in endemic regions. The purpose of this report is to characterise the current epidemiology of Francisella tularensis subspecies holarctica in Georgia. Three surveillance activities are summarised: (1) acute infections captured in Georgia's notifiable disease surveillance system, (2) infectious disease seroprevalence study of military volunteers, and (3) a study of seroprevalence and risk factors in endemic regions. Descriptive analyses of demographic, exposure and clinical factors were conducted for the surveillance studies; bivariate analyses were computed to identify risk factors of seropositivity using likelihood ratio chi2 tests or Fisher's exact tests. Of the 19 incident cases reported between 2014 and August 2017, 10 were confirmed and nine met the presumptive definition; the estimated annual incidence was 0.12/100 000. The first cases of tularemia in Western Georgia were reported. Seroprevalences of antibodies for F. tularensis were 2.0% for military volunteers and 5.0% for residents in endemic regions. Exposures correlated with seropositivity included work with hay and contact with multiple types of animals. Seroprevalence studies conducted periodically may enhance our understanding of tularemia in countries with dramatically underestimated incidence rates. PMID- 30249312 TI - Operationalizing Neuroimaging for Disorders of Consciousness in the Canadian Context. PMID- 30249313 TI - Homotypic and heterotypic continuity of internalizing and externalizing symptoms from ages 3 to 12: The moderating role of diurnal cortisol. AB - Psychological symptoms that arise in early childhood can follow a multitude of patterns into adolescence, including homotypic continuity (i.e., similar symptoms over time) and heterotypic continuity (i.e., a shift in symptoms over time). However, we know very little about the factors that distinguish homotypic vs. heterotypic continuity of early internalizing and externalizing symptoms over development. In a separate line of research, diurnal cortisol has been shown to predict later internalizing and externalizing problems. In the current study, we tested whether diurnal cortisol patterns moderated the course of internalizing and externalizing symptoms from preschool to early adolescence. 554 children (54% male) and parents participated in a longitudinal study. Parents reported on their children's internalizing and externalizing symptoms at ages 3 and 12, and children collected diurnal saliva samples at age 9. Results showed that a steeper cortisol decline at age 9 combined with high internalizing or externalizing problems at age 3 predicted higher internalizing problems at age 12. A more blunted cortisol decline combined with early internalizing or externalizing problems predicted higher externalizing problems in early adolescence. These results illustrate the moderating role of stress system functioning in homotypic and heterotypic patterns of psychopathology from preschool to early adolescence. PMID- 30249305 TI - Quality control of B-lines analysis in stress Echo 2020. AB - BACKGROUND: The effectiveness trial "Stress echo (SE) 2020" evaluates novel applications of SE in and beyond coronary artery disease. The core protocol also includes 4-site simplified scan of B-lines by lung ultrasound, useful to assess pulmonary congestion. PURPOSE: To provide web-based upstream quality control and harmonization of B-lines reading criteria. METHODS: 60 readers (all previously accredited for regional wall motion, 53 B-lines naive) from 52 centers of 16 countries of SE 2020 network read a set of 20 lung ultrasound video-clips selected by the Pisa lab serving as reference standard, after taking an obligatory web-based learning 2-h module ( http://se2020.altervista.org ). Each test clip was scored for B-lines from 0 (black lung, A-lines, no B-lines) to 10 (white lung, coalescing B-lines). The diagnostic gold standard was the concordant assessment of two experienced readers of the Pisa lab. The answer of the reader was considered correct if concordant with reference standard reading +/-1 (for instance, reference standard reading of 5 B-lines; correct answer 4, 5, or 6). The a priori determined pass threshold was 18/20 (>= 90%) with R value (intra class correlation coefficient) between reference standard and recruiting center) > 0.90. Inter-observer agreement was assessed with intra-class correlation coefficient statistics. RESULTS: All 60 readers were successfully accredited: 26 (43%) on first, 24 (40%) on second, and 10 (17%) on third attempt. The average diagnostic accuracy of the 60 accredited readers was 95%, with R value of 0.95 compared to reference standard reading. The 53 B-lines naive scored similarly to the 7 B-lines expert on first attempt (90 versus 95%, p = NS). Compared to the step-1 of quality control for regional wall motion abnormalities, the mean reading time per attempt was shorter (17 +/- 3 vs 29 +/- 12 min, p < .01), the first attempt success rate was higher (43 vs 28%, p < 0.01), and the drop-out of readers smaller (0 vs 28%, p < .01). CONCLUSIONS: Web-based learning is highly effective for teaching and harmonizing B-lines reading. Echocardiographers without previous experience with B-lines learn quickly. PMID- 30249314 TI - Pre-sleep protein in casein supplement or whole-food form has no impact on resting energy expenditure or hunger in women. AB - The purpose of this study was to determine the effect of a whole-food protein (cottage cheese, CC) consumed before sleep on next-morning resting energy expenditure (REE), RER and appetite compared with an isoenergetic/isonitrogenous casein protein (CP) supplement and placebo (PL) in active women. In a beverage blinded, randomised, cross-over design, ten active women (age, 23.1 (sd 1.9) years; body fat, 22.0 (sd 4.6) %) consumed pre-sleep CC (30 g of protein, 10 g of carbohydrate and 0 g of fat) or energy- and protein-matched liquid CP or PL (0 kJ). Participants arrived at 18.00 hours for an overnight stay in the laboratory. At 30-60 min before normal bed time (2 h post standard meal), participants consumed CC, CP or PL before measurement of REE. Upon waking (05.00-08.00 hours), REE was repeated and subjective appetite was recorded. Statistical analyses were conducted using repeated-measures ANOVA (SPSS). Significance was accepted at P<=0.05. There were no significant differences in acute REE (CC, 7217 (sd 1368); CP, 7188 (SD 895); PL, 7075 (sd 1108) kJ/d, P=0.95), acute RER (0.79 (sd 0.05), P=0.56), morning REE (CC, 5840 (sd 1225); CP, 5694 (sd 732); PL, 5991 (sd 903) kJ/d, P=0.79) or morning RER (0.77 (sd 0.03), P=0.52). Subjective measures of appetite were not different between groups. In active women, pre-sleep consumption of CC does not alter REE or RER more than a CP or PL beverage. These data suggest that the metabolic response from whole-food protein do not differ from the metabolic response of liquid protein. PMID- 30249315 TI - Deficient auditory predictive coding during vocalization in the psychosis risk syndrome and in early illness schizophrenia: the final expanded sample. AB - BACKGROUND: During vocalization, efference copy/corollary discharge mechanisms suppress the auditory cortical response to self-generated sounds. Previously, we found attenuated vocalization-related auditory cortical suppression in psychosis and a similar trend in the psychosis risk syndrome. Here, we report data from the final sample of early illness schizophrenia patients (ESZ), individuals at clinical high risk for psychosis (CHR), and healthy controls (HC). METHODS: Event related potentials (ERP) were recorded from ESZ (n = 84), CHR (n = 71), and HC (n = 103) participants during a vocalization paradigm. The N1 ERP component was elicited during production (Talk) and playback (Listen) of vocalization. Age effects on N1 suppression (Talk-Listen), Talk N1, and Listen N1 were compared across groups. N1 measures were adjusted for normal aging before testing for group differences. RESULTS: Both ESZ and CHR groups showed reduced Talk-Listen N1 suppression relative to HC, but did not differ from each other. Listen N1 was reduced in ESZ, but not in CHR, relative to HC. Deficient Talk-Listen N1 suppression was associated with greater unusual thought content in CHR individuals. N1 suppression increased with age in HC (12-36 years), and while CHR individuals showed a similar age-related increase, no such relationship was evident in ESZ. CONCLUSIONS: Putative efference copy/corollary discharge-mediated auditory cortical suppression during vocalization is deficient in ESZ and precedes psychosis onset, particularly in CHR individuals with greater unusual thought content. Furthermore, this suppression increases from adolescence through early adulthood, likely reflecting the effects of normal brain maturation. This maturation effect is disrupted in ESZ, presumably due to countervailing illness effects. PMID- 30249316 TI - Cost and anonymity as factors for the effective implementation of pre-exposure prophylaxis: an observational study among gay, bisexual and other men who have sex with men in Singapore. AB - : Background HIV pre-exposure prophylaxis (PrEP) is currently offered by several public and private clinics at unsubsidised prices in Singapore, but to date, no information is available on the effect of these services. This study sought to assess the knowledge and uptake of, and willingness to use PrEP among gay, bisexual and other men who have sex with men (GBMSM) in Singapore. METHODS: Recruitment was conducted through Grindr(r), a geosocial networking application for GBMSM. Results were quantitatively analysed through descriptive statistics and multivariate Poisson regression models, while open-ended responses were qualitatively coded and categorised. RESULTS: Of the 1339 participants who responded, 1098 participants who indicated their knowledge and use of PrEP were included in the analytic sample. Overall, 15.0% (n=154) had taken PrEP, 66.2% (n=678) had heard of but not taken PrEP, while 18.8% (n=193) had never heard of PrEP. Of those who had ever taken PrEP, 59.6% (n=90) had obtained PrEP from overseas or other unofficial sources. Of those who had heard of but never taken PrEP, 73.3% (n=486) reported that they would consider taking PrEP. Those who had taken PrEP were older and had higher educational attainment. CONCLUSIONS: The gap between the willingness to use PrEP and its uptake may be attributed to the cost of PrEP and issues of anonymity at healthcare settings in Singapore. National financing schemes are needed to expand access to PrEP if it is to make a meaningful effect to the Singapore HIV/AIDS response. PMID- 30249317 TI - Princess PrEP program: the first key population-led model to deliver pre-exposure prophylaxis to key populations by key populations in Thailand. AB - : Background No data are available on the feasibility of pre-exposure prophylaxis (PrEP) delivered by trained key population (KP) community health workers. Herein we report data from the KP-led Princess PrEP program serving men who have sex with men (MSM) and transgender women (TGW) in Thailand. METHODS: From January 2016 to December 2017, trained MSM and TGW community health workers delivered same-day PrEP service in community health centres, allowing clients to receive one PrEP bottle to start on the day of HIV-negative testing. Visits were scheduled at Months 1 and 3, and every 3 months thereafter. Uptake, retention and adherence to PrEP services and changes in risk behaviours over time are reported. RESULTS: Of 1467 MSM and 230 TGW who started PrEP, 44.1% had had condomless sex in the past 3 months. At Months 1, 3, 6, 9 and 12, retention was 74.2%, 64.0%, 56.2%, 46.7% and 43.9% respectively (lower in TGW than MSM at all visits; P<0.001), with adherence to at least four PrEP pills per week self-reported by 97.4%, 96.8%, 96.5%, 97.5% and 99.5% of respondents respectively (no difference between MSM and TGW). Logistic regression analysis identified age >25 years, being MSM and having at least a Bachelors degree significantly increased retention. Condomless sex did not change over the 12-month period (from 47.2% to 45.2%; P=0.20). New syphilis was diagnosed in 4.9% and 3.0% of PrEP clients at Months 6 and 12 (cf. 7.0% at baseline; P=0.007). Among PrEP adherers and non adherers, there were one and six HIV cases of seroconversion respectively, which resulted in corresponding HIV incidence rates (95% confidence interval) of 0.27 (0.04-1.90) and 1.36 (0.61-3.02) per 100 person-years. CONCLUSION: Our KP-led PrEP program successfully delivered PrEP to MSM and TGW. Innovative retention supports are needed, especially for TGW and those who are young or with lower education levels. To scale-up and sustain KP-led PrEP programs, strong endorsement from international and national guidelines is necessary. PMID- 30249318 TI - Evolution of a pre-exposure prophylaxis (PrEP) service in a community-located sexual health clinic: concise report of the PrEPxpress. AB - Screening and treatment of sexually transmissible infections, including HIV, are free in the UK nations; pre-exposure prophylaxis (PrEP) became free in England in October 2017 through the PrEP Impact trial. Doctor-led PrEP clinics started at 56 Dean Street in September 2015, with the drug purchased privately at full price. The service was expanded to other staff to support initiation and monitoring of increasing numbers of attendees purchasing PrEP from online pharmacies. Nonetheless, when the clinic was given a target of 1700 for the PrEP Impact trial, it was clear this could not be achieved in a timely manner through 56 Dean Street alone. To prepare for the trial, all staff with HIV testing competencies were trained in good clinical practice and trial-specific procedures, and a patient group directive was approved to facilitate nurse prescribing and dispensing. Electronic pro formas to capture eligibility for starting or continuing PrEP were adapted for the Dean Street Express clinic, with some information collected directly from service users using touch screens. These interventions, together with an update to the 2016 information leaflet developed by the community, enabled enrolment and follow-up of 1700 participants in 4 months. PrEP advice and monitoring were easily accommodated in the 56 Dean Street sexual health service, but did require additional training and approval for nurse prescribing and dispensing drug in order to achieve the target, which still fell short of the demand. PMID- 30249319 TI - Prospects of using nanotechnology for food preservation, safety, and security. AB - The rapid development of nanotechnology has transformed many domains of food science, especially those that involve the processing, packaging, storage, transportation, functionality, and other safety aspects of food. A wide range of nanostructured materials (NSMs), from inorganic metal, metal oxides, and their nanocomposites to nano-organic materials with bioactive agents, has been applied to the food industry. Despite the huge benefits nanotechnology has to offer, there are emerging concerns regarding the use of nanotechnology, as the accumulation of NSMs in human bodies and in the environment can cause several health and safety hazards. Therefore, safety and health concerns as well as regulatory policies must be considered while manufacturing, processing, intelligently and actively packaging, and consuming nano-processed food products. This review aims to provide a basic understanding regarding the applications of nanotechnology in the food packaging and processing industries and to identify the future prospects and potential risks associated with the use of NSMs. PMID- 30249320 TI - Nanoparticle-based laser desorption/ionization mass spectrometric analysis of drugs and metabolites. AB - Nanoparticle-assisted laser desorption/ionization mass spectrometry (LDI-MS) is a powerful tool for the analysis of a wide range of molecules. Many of the drawbacks in the matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) can be avoided with the application of nanomaterials as matrices as well as substrates for the LDI-MS to achieve a low background noise in low m/z region and high reproducibility. Surface-assisted LDI (SALDI)-MS, especially the nanoparticle-based LDI-MS, has emerged as a promising technique for the analysis of trace amounts of substances in various biological samples due to their high surface area for analyte enrichment, efficient desorption/ionization, and homogeneous crystallization of sample. Therefore, it is highly useful in clinical, forensic, medical, food and drug analyses, disease diagnosis, and various other fields. In this review, we briefly discuss the application of various nanomaterials, which include metal-based, carbon-based, silicon-based nanomaterials and nanocomposites, as matrices and substrates for LDI-MS based drug and metabolite analyses and possible detection strategies. Also, we discuss the idea of using "mass tag" for signal amplification for drug and metabolite detection using nanoparticle assisted LDI-MS. PMID- 30249321 TI - Kinetics of lactose fermentation in milk with kombucha starter. AB - The aim of this research was to investigate the effect of new, non-conventional starter culture on the kinetics of the lactose transformation during milk fermentation by kombucha, at pH 5.8; 5.4; 5.1; 4.8; and 4.6, at two different temperatures 37 degrees C and 42 degrees C. Milk fermentation at 42 degrees C lasted significantly shorter (about 5 h, 30 min) compared to the fermentation at 37 degrees C. Changes of lactose concentration at the both temperatures are consisting of two retaining stages and very steep decline in-between. The analysis of the rate curves showed that the reaction rate passes through the maximum after 9 h, 30 min at 37 degrees C and after 4 h at 42 degrees C. The sigmoidal saturation curve indicates a complex kinetics of lactose fermentation by kombucha starter. PMID- 30249323 TI - Effect of Phyllanthus emblica L. fruit on methionine and choline-deficiency diet induced nonalcoholic steatohepatitis. AB - Phyllanthus emblica L. fruit contains abundant bioactive components and exhibits a variety of biological activities. In this study, the hepatoprotective effect of water extract of P. emblica (WEPE) on nonalcoholic steatohepatitis (NASH) was evaluated. C57BL/6 mice were fed methionine and choline-deficiency diet (MCD diet) for 4 or 8 weeks to induce NASH. Results showed that administration of WEPE could significantly reduce serum AST and ALT as compared to MCD diet-alone group. Administration of WEPE could significantly decrease lipid peroxidation and CYP2E1 mRNA expression, and elevate the antioxidant activities in mice livers. In addition, administration of WEPE after 8 weeks could significantly decrease the mRNA expressions of TNF-alpha and IL-1beta in mice livers, but have less improving effect of hepatic steatosis and mononuclear cell infiltration. Taken together, MCD diet might cause serious hepatic steatosis and mild inflammation in mice livers, but administration of WEPE could ameliorate the rapid progression of NASH. PMID- 30249322 TI - Profiles of commensal and opportunistic bacteria in human milk from healthy donors in Taiwan. AB - Recent studies indicate that milk from healthy mothers may harbor potential probiotics. Nonetheless, the distribution of bacterial profiles in human milk samples in Taiwan is not fully understood. Therefore, with the aim to address this question, in this study, milk samples were collected from 33 healthy mothers (D1 to D33) visiting our hospital during a 6-month period. The milk microbiota was analyzed by a molecular approach (Illumina MiSeq sequencing). The results indicate that the milk samples have a unique profile and patterns of bacterial abundance levels. Moreover, in colostrum and transitional-milk samples, we detected 154 and 127 bacterial species, respectively, and these sets shared 42.6% of the bacterial species. The most common bacterial species among all milk samples were Staphylococcus epidermidis, Streptococcus lactarius, and Staphylococcus hominis, suggesting that the skin contamination route plays an important role in the composition of the milk microbiota. Nevertheless, four Lactobacillus species, Lactobacillus helveticus, Lactobacillus iners, Lactobacillus zeae, and Lactobacillus gasseri, were present in only 7 samples (21% prevalence), and bifidobacterial species were quite rare taxa among the present samples. The Staphylococcus aureus was detected in a total of 15 samples (45% prevalence), suggesting that this species may be commonly present in milk samples. In conclusion, each milk sample revealed a unique profile and patterns of bacterial abundance levels, and our data do not support the idea that lactobacilli and bifidobacteria are common and abundant in modern milk samples. Because none of the donors of the milk samples showed mastitis or any discomfort during the sampling process or at follow-up inspection, the microbiota of these milk samples is not likely to negatively affect its host. This study provides new information on the proportions of commensal bacteria in human milk in Taiwan. PMID- 30249324 TI - Curculigoside and polyphenol-rich ethyl acetate fraction of Molineria latifolia rhizome improved glucose uptake via potential mTOR/AKT activated GLUT4 translocation. AB - Adipose tissue is one of the major organs responsible for rapid restoration of postprandial glucose fluxes. Being the major isoform of glucose transporter in adipose tissue, regulations of insulin-dependent GLUT4 trafficking have always been of research interest. The present study aimed to examine the molecular mechanisms underlying the efficacy of curculigoside and polyphenol-rich ethyl acetate fraction (EAF) of Molineria latifolia rhizome in triggering glucose uptake. We assessed the adipogenic potential and glucose uptake stimulatory activity of curculigoside and EAF by employing a murine 3T3-L1 adipocyte model. The transcriptional and translational expressions of selected intermediates in the insulin signalling pathway were evaluated. While curculigoside neither promoted adipogenesis nor activated peroxisome proliferator activated receptor gamma, treatment with polyphenol-rich EAF resulted otherwise. However, both treatments enhanced insulin-stimulated uptake of glucose. This was coupled with increased availability of GLUT4 at the plasma membrane of the differentiated adipocytes although the total GLUT4 protein level was unaffected. In addition, the treatment increased the phosphorylation of both AKT and mTOR, which have been reported to be associated with GLUT4 translocation. The present findings proposed that curculigoside and EAF increased glucose transport activity of 3T3-L1 adipocytes via GLUT4 translocation as a result of potential mTOR/AKT activation. The more potent efficacy observed with EAF suggested potential synergistic and multi-targeted action. PMID- 30249325 TI - Benefits of combination low-dose pioglitazone plus fish oil on aged type 2 diabetes mice. AB - The elderly patients with type 2 diabetes suffer more adverse drug events than young adults due to pharmacokinetic and pharmacodynamic changes associated with aging. Reducing the risks of these medication-related problems are equally important for the clinical care of older type 2 diabetes patients. Pioglitazone is used for treating type 2 diabetes as an oral antidiabetic drug. Despite pioglitazone is used helpful insulin sensitizers, the accumulation of subcutaneous fat is considered a major adverse effect of pioglitazone therapy. We investigated to reduce the adverse effect of pioglitazone by combination with fish oil rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in aged diabetic KK mice. The accumulation of subcutaneous fat associated with high dose pioglitazone is reduced by fish oil, suppressing lipogenesis and stimulating fatty acid beta-oxidation in the liver. Our data suggest that adding fish oil to low-dose pioglitazone results in antidiabetic efficacy similar to that of the high-dose without concomitant body weight gain. PMID- 30249326 TI - Comparison of anti-inflammatory effect and protein profile between the water extracts from Formosan sambar deer and red deer. AB - Velvet antler (VA), the unossified antler from members of the family Cervidae, has been used in traditional Chinese medicines and health foods for over 2000 years in enhancement of kidney function and treatment or prevention of cardiovascular, immunological and gynaecological disease. The aim of this study was to investigate the anti-inflammatory effect of velvet antler water extracts from Formosan sambar deer (Rusa unicolor swinhoei, SVAE) and red deer (Cervus elaphus, RVAE). Results indicated that both SVAE and RVAE significantly reduced the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) productions in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells at concentrations above 200 MUg mL-1. SVAE seems to demonstrate a better anti-inflammatory effect than that of RVAE in vitro. Both SVAE and RAVE also enhanced the anti-inflammatory cytokine IL-10 production in LPS-stimulated RAW 264.7 cells. The results of MTT assay indicated that SVAE and RVAE did not exhibit any cytotoxicity in LPS-stimulated RAW 264.7 cells. Two-dimensional (2D) gel electrophoresis analysis revealed that the levels of 6 specific proteins were different between these two velvet antlers samples. Furthermore, the storage period was the major factor affecting the anti-inflammatory activity of SAVE. In this study, we demonstrated the difference of anti-inflammatory effect and the protein profile between SVAE and RVAE. SVAE showed better anti-inflammatory potential than RVAE. In the future, the anti-inflammatory active components and their related mechanisms should be further investigated. PMID- 30249327 TI - Development and validation of a Fast gas chromatography/mass spectrometry method for the determination of cannabinoids in Cannabis sativa L. AB - A routine method for determining cannabinoids in Cannabis sativa L. inflorescence, based on Fast gas chromatography coupled to mass spectrometry (Fast GC/MS), was developed and validated. To avoid the decarboxylation of carboxyl group of cannabinoids, different derivatization approaches, i.e. silylation and esterification (diazomethane-mediated), reagents and solvents (pyridine or ethyl acetate), were tested. The methylation significantly increased the signal-to-noise ratio of all carboxylic cannabinoids, except for cannabigerolic acid (CBGA). Since diazomethane is not commercially available, is considered a hazardous reactive and requires 1-day synthesis by specialized chemical staff, silylation was used along the whole validation of a routine method. The method gave a fast (total analysis time < 7.0 min) and satisfactory resolution (R > 1.1), with a good repeatability (intraday < 8.38%; interday < 11.10%) and sensitivity (LOD < 11.20 ng/mL). The Fast GC/MS method suitability for detection of cannabinoids in hemp inflorescences, was tested; a good repeatability (intraday < 9.80%; interday < 8.63%), sensitivity (LOD < 58.89 ng/mg) and robustness (<9.52%) was also obtained. In the analyzed samples, the main cannabinoid was cannabidiolic acid (CBDA, 5.19 +/- 0.58 g/100 g), followed by cannabidiol (CBD, 1.56 +/- 0.03 g/100 g) and CBGA (0.83 g/100 g). Delta9 tetrahydrocannabivarine (THCV) was present at trace level. Therefore, the developed routine Fast GC/MS method could be a valid alternative for a fast, robust and high sensitive determination of main cannabinoids present in hemp inflorescences. PMID- 30249328 TI - Antioxidant activity, neuroprotective properties and bioactive constituents analysis of varying polarity extracts from Eucalyptus globulus leaves. AB - Eucalyptus globulus is employed as herbal tea and therapeutical purposes. In this work, it is investigated for first time the neuroprotective activities, based on antioxidant properties, of varying polarity extracts (acetone, ethanol and methanol) from E. globulus leaves and elucidate their main bioactive constituents. Methanol and acetone extracts contained the highest phenolic compounds amount and chlorogenic acid was the major compound identified by UPLC ESI-MS/MS. Moreover, the three tested extracts showed significant antioxidant properties, varying their potency depending on the in vitro technique used. Furthermore, E.globulus extracts were effective in ameliorating H2O2-induced oxidative stress by increasing cell viability, GSH levels and antioxidant enzymes activity and, by decreasing ROS production and lipid peroxidation levels in SH SY5Y cells. Taken together, E.globulus leaves extracts could be used as raw material for food and pharmaceutical supplements for their high content in antioxidant compounds with health benefits properties against oxidative stress. PMID- 30249329 TI - A novel micro-extraction strategy for extraction of bisphosphonates from biological fluids using zirconia nanoparticles coupled with spectrofluorimetry and high performance liquid chromatography. AB - Extraction of bisphosphonates from biological fluids is important and time consuming step in sample preparation procedure. This paper describes a simple and green sample preparation technique for dispersive micro solid phase extraction (DMSPE) of alendronate sodium (ALS) from urine and serum samples prior to direct spectrofluorimetry (DSFL) and high performance liquid chromatography with fluorescence detection (HPLC-FLD), respectively. The DMSPE strategy is based on the selective chemisorption of ALS on zirconia nanoparticles (ZNPs) as an adsorbent followed by derivatization of the eluted analyte using o-phthalaldehyde (OPA) in the presence of 2-mercaptoethanol (2ME) at basic medium to form fluorescent species. The chemical and instrumental influencing parameters on DMSPE and measuring methods were optimized for the efficient extraction and determination of ALS. The presented methods were capable of extracting ALS from human urine and serum samples and determining over the wide ranges of 5-1000 and 5-2500 MUg L-1 with limits of detection (LOD) of 1.5 and 1.4 MUg L-1 for DSFL and HPLC methods, respectively. The relative recoveries for the three spiked standard levels of ALS in urine and serum samples ranged from 89.0% to 107.0%, and the intra-day relative standard deviations (%RSDs) were in the range of 2.9-7.9%. PMID- 30249331 TI - Corrigendum. PMID- 30249332 TI - September 2014 (vol. 211, no. 3, page 288). PMID- 30249330 TI - Application of food description to the food classification system: Evidence of risk assessment from Taiwan as Acrylamide of grain products. AB - Harmonization of national consumption data for international comparison is an important but challenging work, yet to date there is a lack of comparable food classification system that incorporates food description in Taiwan. In 2015, European Food Safety Authority (EFSA) released a new standardized food classification and description system called FoodEx2, which provides a flexible combination of classifications and descriptions. Based on FoodEx2 and a unique data set of daily food consumption offered by Taiwan Food Consumption Database, this study aims to provide a harmonized, food description incorporated, food classification system (HFDFC system) that captures all the useful details of food groups in exposure assessments. The HFDFC system was built according to six risk assessment-related facets including food sources, processed products, cooking methods, manufacturers (brand), food additives and specialty foods. The HFDFC system includes 199 foods in the core list and 131 foods in the extended list. This study also compared the Acrylamide hazard index estimated under the HFDFC system with that under the National Food Consumption Database in Taiwan (NFCDT). The findings indicated that the HFDFC system provides useful and detailed information that helps the users to quickly identify food information in a harmonized manner and to reduce estimation bias. The HFDFC system is expected to facilitate global comparisons in the food risk assessment because it is built based upon EU Foodex2. PMID- 30249333 TI - The Microglial Response to Neurodegenerative Disease. AB - Microglia are a subset of tissue macrophages that constitute the major immune cell type of the central nervous system. These cells have long been known to change their morphology and functions in response to various neurological insults. Recently, a plethora of unbiased transcriptomics studies have revealed that across a broad spectrum of neurodegeneration-like disease models, microglia adopt a similar activation signature and perform similar functions. Despite these commonalities in response, the role of microglia has been described as both positive and negative in different murine disease models. In humans, genetic association studies have revealed strong connections between microglia genes and various neurodegenerative diseases, and mechanistic investigations of these mutations have added another layer of complexity. Here, we provide an overview of studies that have built a case for a common microglial response to neurodegeneration and discuss pathways that may be important to initiate and sustain this response; delineate the multifaceted functions of activated microglia spanning different diseases; and discuss insights from studying genes associated with disease in humans. We argue that strong evidence causally links activated microglia function to neurodegeneration and discuss what seems to be a conflict between mouse models and human genetics. PMID- 30249334 TI - The First B-Cell Tolerance Checkpoint in Mice and Humans: Control by AID. AB - Activation-induced cytidine deaminase (AID) expression in the germinal center response drives the immunoglobulin class-switch recombination and V(D)J hypermutation necessary for efficacious, high-affinity antibody responses. That AID is expressed in developing lymphocytes is less well known, but represents an evolutionarily conserved pattern of lymphocyte development that is represented in all vertebrate species. Here we review the role of early, developmentally regulated AID expression in mice and humans and its role in establishing the first B-cell tolerance checkpoint. This newly recognized component of central tolerance requires coordinate signaling by poly- or autoreactive B-cell antigen receptors and endosomal Toll-like receptors. These signals synergize to upregulate AID expression in immature and transitional B cells to levels that approach that of germinal center B cells with the result of caspase 3-mediated cell death. In this review, we discuss the origins and mechanism of this interesting collaboration between adaptive and innate receptors to purge the primary B-cell repertoire of self-reactivity and how it may be related to receptor editing, the other major mechanism for central tolerance. PMID- 30249335 TI - RAG Chromatin Scanning During V(D)J Recombination and Chromatin Loop Extrusion are Related Processes. AB - An effective adaptive immune system depends on the ability of developing B and T cells to generate diverse immunoglobulin (Ig) and T cell receptor repertoires, respectively. Such diversity is achieved through a programmed somatic recombination process whereby germline V, D, and J segments of antigen receptor loci are assembled to form the variable region V(D)J exons of Ig and TCRs. Studies of this process, termed V(D)J recombination, have provided key insights into our understanding of a variety of general gene regulatory and DNA repair processes over the last several decades. V(D)J recombination is initiated by the RAG endonuclease which generates DNA double-stranded breaks at the borders of V, D, and J segments. In this review, we cover recent work that has elucidated RAG structure and work that revealed that RAG has a novel chromatin scanning activity, likely mediated by chromatin loop extrusion, that contributes to its ability to locate V, D, J gene segment substrates within large chromosomal loop domains bounded by CTCF-binding elements (CBEs). This latter function, coupled with the role CBE-based chromatin loop domains and subdomains within them play in focusing V(D)J recombination activity within antigen receptor loci, provide mechanistic explanations for long-standing questions regarding V(D)J segment usage diversification and in limiting potentially deleterious off-target RAG initiated recombination events genome-wide. This review will focus mainly on studies of the mouse Ig heavy chain locus, but the principles described also apply to other Ig loci and to TCR loci in mice and humans. PMID- 30249336 TI - The business of educating the next generation of surgeons. AB - Surgical education community needs to be informed about how education is funded and how it is threatened. In order to explore these issues the Association of Surgical Education convened a panel with significant experience in managing surgery departments to discuss the business of surgical education. They specifically addressed methods to recognize and reward faculty, educate residents on safety, quality and cost, and increase departmental revenue. This information is important in the current educational environment where there is an increased need for institutions to find alternate revenue streams to sustain graduate medical education. It is also important to find additional revenue streams to fund new residency slots to accommodate the greater number medical students who have been admitted to medical schools in response to meet the projected shortage of physicians. PMID- 30249337 TI - Stereotype threat and working memory among surgical residents. AB - BACKGROUND: Stereotype threat is a situational threat in which a member of a stereotyped group fears conforming to a negative stereotype. In this study, we examined the impact of stereotype threat on surgical performance and working memory among surgical residents. METHODS: Residents at one institution were randomized to either the threat condition or the no-threat condition. We administered the Vandenberg Mental Rotation Test and the reading span task to assess residents' mental rotation and working memory, respectively. RESULTS: 102 residents participated in this study (response rate 61%). In multivariable analysis, we found significant gender differences. Men outperformed women in mental rotation, and women outperformed men in working memory. There was no effect of condition on performance on the mental rotation or working memory test. CONCLUSIONS: No effect of condition on either test suggests that high-achieving women may be less susceptible to stereotype threat. This could be due to self selection or adapted resilience, or women in this context may be more qualified to reach the same level of achievement as their male colleagues. PMID- 30249339 TI - Timeout: A look to the left. PMID- 30249338 TI - Automatic registration of MRI-based joint models to high-speed biplanar radiographs for precise quantification of in vivo anterior cruciate ligament deformation during gait. AB - Understanding in vivo joint mechanics during dynamic activity is crucial for revealing mechanisms of injury and disease development. To this end, laboratories have utilized computed tomography (CT) to create 3-dimensional (3D) models of bone, which are then registered to high-speed biplanar radiographic data captured during movement in order to measure in vivo joint kinematics. In the present study, we describe a system for measuring dynamic joint mechanics using 3D surface models of the joint created from magnetic resonance imaging (MRI) registered to high-speed biplanar radiographs using a novel automatic registration algorithm. The use of MRI allows for modeling of both bony and soft tissue structures. Specifically, the attachment site footprints of the anterior cruciate ligament (ACL) on the femur and tibia can be modeled, allowing for measurement of dynamic ACL deformation. In the present study, we demonstrate the precision of this system by tracking the motion of a cadaveric porcine knee joint. We then utilize this system to quantify in vivo ACL deformation during gait in four healthy volunteers. PMID- 30249340 TI - Evidence on on-pump versus off-pump in Taiwan accepts a critical insight! PMID- 30249341 TI - Open surgery for descending thoracic aortic disease: "Pride and prejudice". PMID- 30249342 TI - Novel regulatory Th17 cells and regulatory B cells in modulating autoimmune diseases. AB - Pathogenic lymphocytes aberrantly recognize and mount an immune response against self-antigens, leading to the destruction of healthy cells, tissues and organs. Recent studies have shown that both B and T lymphocytes contribute to the development, prevention and modulation of various autoimmune diseases. Regulatory T and B cell subsets appear to play a prominent role in the prevention of autoimmune diseases. The recent identification of novel regulatory Th17 cells, termed as Treg17 cells, has expanded the scope of regulatory T lymphocytes (Treg cells) in the prevention of autoimmune diseases. Similarly, novel regulatory B cell subsets, termed as Breg cells, acting on their own or by inducing Treg cells have extended the role of B lymphocytes in the prevention and regulation of autoimmune diseases. We suggest that Treg17 cells and Breg cells have an important immunoregulatory role in autoimmune diseases. PMID- 30249343 TI - Adenosine receptor activation in the Th17 autoimmune responses of experimental autoimmune uveitis. AB - Th17-type autoreactive T cells contribute to pathogenicity in autoimmune diseases, including autoimmune uveitis. However, the mechanisms of regulation of Th17 cell activities remain unsolved and are likely to be tissue- and disease specific. In this review, we have summarized our studies from the murine model of experimental autoimmune uveitis (EAU). The resultsdemonstrate that gammadelta T cells have a regulatory effect on Th17 response. The regulatory effects of gammadelta T cells depend on their action state. Activated gammadelta T cells express significantly high levels of adenosine receptor A2 (A2AR) but low CD73. Both molecules are crucially involved in adenosine generation, thus modifying T cell responses. While the increased expression of A2AR-allows activated gammadelta T cells to bind adenosine more effectively than other immune cells, the decreased CD73 restricts their ability to convert AMP to adenosine. Adenosine affects Th1 and Th17 autoimmune responses differently. Its activation of gammadelta T cells shifts the Th1/Th17 balance towards the Th17 autoreactivity. PMID- 30249345 TI - Management of an Acute Exacerbation of Chronic Neuropathic Pain in the Emergency Department: A Case to Support Ultrasound-Guided Forearm Nerve Blocks. AB - BACKGROUND: Acute on chronic neuropathic pain is often refractory to analgesics and can be challenging to treat in the emergency department (ED). In addition, systemic medications such as opiates and nonsteroidal inflammatory drugs have risks, including hypotension and kidney injury, respectively. Difficulties in managing pain in patients with neuropathy can lead to prolonged ED stays, undesired admissions, and subsequent increased health care costs. CASE REPORT: We describe the case of a 51-year-old woman who presented to the ED on two separate occasions for left forearm pain secondary to chronic ulnar neuropathy. During her first ED visit, the patient received multiple rounds of intravenous opiates and required hospital admission, which was complicated by opiate-induced hypotension. During her second visit, she underwent an ultrasound-guided ulnar nerve block performed by the emergency physician; her pain resolved and she was discharged home. WHY SHOULD EMERGENCY PHYSICIANS BE AWARE OF THIS?: Ultrasound-guided nerve blocks are an effective, safe, and relatively inexpensive alternative to opioids. Our case demonstrates that emergency providers may be able to perform ultrasound guided regional anesthesia to treat an acute exacerbation of chronic neuropathic pain. PMID- 30249344 TI - Pathological Laughter as a Symptom of Middle Cerebral Artery Stroke. AB - BACKGROUND: Pathological laughter is defined as uncontrollable and inappropriate laughter unrelated to an emotion or a mood. This symptom can reveal a stroke. CASE REPORT: We described the case of a 57-year-old patient who presented to the emergency department 2 h after a sudden onset of left hemiparesis preceded by pathological laughter. The left motor weakness was very discrete and underestimated because of severe behavioral changes, that is, laughter, joviality, and motor restlessness. Despite abnormal brain imaging results, symptoms were considered as atypical to evoke a stroke. The patient did not receive intravenous thrombolysis. Brain magnetic resonance imaging performed 2 days after admission confirmed the diagnosis of stroke. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians are at the forefront of stroke management. They should be aware that the initial symptom of a stroke can be atypical and lead to misunderstanding the diagnosis. Because the treatment of stroke requires the fastest care, it is important for emergency physicians to know that sudden behavioral troubles and pathological laughter can reveal strokes. PMID- 30249346 TI - Intussusception Mimicking Acute Appendicitis in an Adult. PMID- 30249347 TI - Effect of ESA as a modifier of radiotherapy in curative intended treatment of squamous cell carcinoma of the head and neck (HNSCC). PMID- 30249349 TI - [The incorporation of community health in the planning and transformation of the urban environment. SESPAS Report 2018]. AB - Urbanized and built-up environments are determinants of health as well as community health. Therefore, we intend to analyze the influence of urban development on both public and community health, from the perspective of gender, citizen participation in urban planning projects, and accessibility. From a bibliographic review and narrative analysis, based on the experience of the authors, we found several urban transformation projects focusing, in particular, on four large areas: school centres and playgrounds, empty urban spaces and disused buildings, pedestrian pathways, and various housing interventions. The participatory processes (driven by institutions and/or citizens) developed within the framework of urban diagnostic projects and the preparation of plans and projects, constitute a double opportunity to work on community health: on the one hand, considering them as an objective, and on the other, as a tool to design environments that promote the well-being of the community. The incorporation of citizens and the collaboration of all the agents involved, taking their diversity into account, are essential, and this is a shared responsibility between local/supra-local administration, and citizenship. Regulation must be designed to facilitate the processes and when it is applied must allow the population to take a central role in the transformation of environments that will promote well-being and health. PMID- 30249348 TI - Influence of PD-L1 expression in immune cells on the response to radiation therapy in patients with oropharyngeal squamous cell carcinoma. AB - BACKGROUND AND PURPOSE: To investigate influences of proteins involved with tumor immunity on outcomes of radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC). MATERIAL AND METHODS: We performed immunohistochemical staining to examine expressions of p16 and proteins involved with tumor immunity in 92 OPSCC patients treated with radiotherapy. RESULTS: Patients with abundant infiltrating CD8-positive cells had the significantly better overall survival (OS) rate than patients with fewer CD8-positive cells (p = 0.026). Patients with higher PD-L1 expression in tumor cells (TC 1-3) had a better outcome than those with low PD-L1 expression in tumor cells (TC 0) for both OS (p = 0.019) and progression-free survival (PFS) rate (p = 0.032). Patients with high PD-L1 expression in infiltrating immune cells (IC 3) showed significantly better OS (p = 0.009) and PFS (p = 0.011) than those with low PD-L1 expression (IC 0-2). Patients with p16 negative and IC 3 showed similar OS to patients with p16-positive and IC 0-2. P16 positive tumors had a significantly higher CD8-positive cell infiltration and PD L1 expression in tumor cells than p16-negative tumors. CONCLUSIONS: In addition to tumor p16 expression, PD-L1 expression in TC and IC can be useful for predicting the response of OPSCC to radiotherapy. PMID- 30249350 TI - [Training in community health: challenges, threats and opportunities. SESPAS Report 2018]. AB - Incorporating community health teaching in the undergraduate nursing and medicine curriculum and postgraduate training programmes contributes to enhance the quality, rigour and sustainability of health-promoting community interventions. In this article, we discuss the failure of Spanish Medical Universities to include family and community medicine and primary health care as integrated and cross-cutting disciplines on the undergraduate curriculum. During specialized medical and nursing training, community health teaching varies widely depending on the qualification, priorities and motivation of the primary health care workers, teaching units and trainees. Growing job instability and current nurse and medical recruitment systems, are hindering learning being put into practice, as well as the development of health-promoting community activities and the strengthening of training networks and facilities. Amid such adversity, there are initiatives that provide quality training on community health and should, accordingly, be fostered and acknowledged. PMID- 30249351 TI - Gel dosimetry for three dimensional proton range measurements in anthropomorphic geometries. AB - Proton beams used for radiotherapy have potential for superior sparing of normal tissue, although range uncertainties are among the main limiting factors in the accuracy of dose delivery. The aim of this study was to benchmark an N vinylpyrrolidone based polymer gel to perform three-dimensional measurement of geometric proton beam characteristics and especially to test its suitability as a range probe in combination with an anthropomorphic phantom. For single proton pencil beams as well as for 3*3cm2 mono-energy layers depth dose profiles, lateral dose distribution at different depths and proton range were evaluated in simple cubic gel phantoms at different energies from 75 to 115MeV and different dose levels. In addition, a 90MeV mono-energetic beam was delivered to an anthropomorphic 3D printed head phantom, which was filled with gel. Subsequently, all phantoms underwent magnetic resonance imaging using an axial pixel size of 0.68-0.98mm and with slice thicknesses of 2 or 3mm to derive a 3-dimensional distribution of the T2 relaxation time, which correlates with radiation dose. Indices describing lateral dose distribution and proton range were compared against predictions from a treatment planning system (TPS, for cubic and head phantoms) and Monte Carlo simulations (MC, for the head phantom) after manual rigid co-registration with the T2 relaxation time datasets. For all pencil beams, the FWHM agreement with TPS was better than 1mm or 7%. For the mono-energetic layer, the agreement with TPS in this respect was even better than 0.3mm in each case. With respect to range, results from gel measurements differed no more than 0.9mm (1.6%) from values predicted by TPS. In case of the anthropomorphic phantom, deviations with respect to a nominal range of about 61mm as well as in FWHM were slightly higher, namely within 1.0mm and 1.1mm respectively. Average deviations between gel and TPS/MC were similar (-0.3mm+/-0.4mm/-0.2+/-0.5mm). In conclusion, polymer gel dosimetry was found to be a valuable tool to determine geometric proton beam properties three-dimensionally and with high spatial resolution in simple cubic as well as in a more complex anthropomorphic phantom. Post registration range errors of the order of 1mm could be achieved. The additional registration uncertainty (95%) was 1mm. PMID- 30249352 TI - Non-adherence to cardiovascular drugs in older patients with depression: A population-based cohort study. AB - BACKGROUND: Depression is common among patients with cardiovascular disease and has been associated with both drug non-adherence and increased mortality. Non adherence can occur because of non-initiation, suboptimal implementation, or non persistence. We aimed to determine if depression increased the risk of any of these components of non-adherence among older patients prescribed cardiovascular drugs in primary care. METHODS: A longitudinal analysis of routine primary care data from the Nivel Primary Care Database was performed using data for 2011-2013. A total of 1512 patients aged >=60 years diagnosed with depression in 2012 were compared with age- and sex-matched groups with either other psychological diagnoses (N = 1457) or mentally healthy controls (N = 1508), resulting in the inclusion of 4477 patients. Non-adherence was classified as non-initiation, suboptimal implementation, or non-persistence. Regression analyses were performed to determine the association between mental health status and non-initiation, suboptimal implementation, and non-persistence. RESULTS: Mixed-effects logistic regression analyses showed increased odds for suboptimal implementation of beta blockers among depressed patients (2.18; 95% CI 1.29-3.69). For non-persistence, a clustered Cox regression analysis demonstrated that, compared with controls, there was an increased hazard ratio for depressed patients to discontinue beta blockers (2.31; 95% CI 1.58-3.37) and calcium antagonists (1.74; 95% CI 1.23 2.46). CONCLUSIONS: It is likely that older patients in primary care diagnosed with depression are at increased risk of non-persistence with cardiovascular drug therapy. Because non-adherence is associated with increased cardiovascular mortality, it is important that physicians ensure that older depressed patients persevere with therapy. PMID- 30249353 TI - Case Study: Providing Nutritional Support to an Ultraendurance Runner in Preparation for a Self-Sufficient Multistage Ultramarathon: Rationed Versus Full Energy Provisions. AB - To assess the impact of rationed versus full estimated energy provisions on markers of physiological strain in response to a simulated 250 km multistage ultramarathon (MSUM), on two separate occasions, the ultraendurance runner performed a laboratory simulated MSUM, with rationed (RP: 3303+/-75 kcal?day-1) and full (FP: 7156+/-359 kcal?day-1) provisions. Total daily energy expenditure was determined using dual-method indirect calorimetry. Resting metabolic rate, iDXA, and body water were measured at baseline, day 3, and post-MSUM. Blood, urine, and feces were collected, and mood state was measured, d 1 to 5 (before and after running) to determine various physiological strain indices. Heart rate, RPE, thermal comfort, gastrointestinal symptoms, and non-protein oxidation rates were measured every 30 min during running. Data were analyzed using single subject design analysis and interpreted using Cohen's effect size. Energy expenditure was lower on RP (6943+/-145 kcal?day-1) than FP (7486+/-143 kcal?day 1) (Cohen's delta=-3.1). More pronounced exertional strain (RPE delta=1.2, thermal conform delta=0.6, rectal temperature delta=1.0, and plasma cortisol concentration delta=1.7) was observed on RP as the MSUM progressed. Total carbohydrate and fat oxidation during running decreased (0.76 vs. 1.82 g?min-1; delta=-3.9) and increased (0.91 vs. 0.54 g?min-1; delta=3.7), respectively, more profoundly on RP as the MSUM progressed. Gastrointestinal symptoms were modestly lower in RP (delta=-0.26). Exercise-induced leukocytosis, cytokinaemia, and neutrophil responses were higher on RP. Iron status markers were trivial. Higher mood disturbance and fatigue were reported on RP. The ultraendurance runner presented greater physiological and psychophysiological disturbances, in response to a laboratory simulated MSUM, on rationed energy provisions, despite the lighter pack-weight. PMID- 30249354 TI - Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease. AB - The discovery and lead optimisation of a novel series of SYK inhibitors is described. These were optimised for SYK potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials. PMID- 30249355 TI - Somatic Mutation in Pediatric Neurological Diseases. PMID- 30249356 TI - Children and Fear of the "Other". PMID- 30249357 TI - Long-term pulmonary function after lobectomy for congenital pulmonary airway malformation: is thoracoscopic approach really better than open? AB - INTRODUCTION: Congenital pulmonary airway malformation (CPAM) is the most common lung pathology diagnosed antenatally. Thoracoscopic lobectomy has shown increasing popularity, but the long-term result is still lacking. In this study we compared long -term pulmonary function after thoracoscopic and open lobectomy. METHODS: All CPAM patients with lobectomy between 2000 and 2008 were recruited into the study. Pulmonary function test (PFT) was performed at least 7 years after operation. Demographic data and PFT results were analyzed. Comparison was made between the thoracoscopic and open group. RESULTS: Twelve patients were included in each group. PFT was performed at a mean age of 9.8 (thoracoscopic) and 12.2 years (open), respectively (p = 0.17). The thoracoscopic group showed better performance in forced vital capacity (FVC) (98.9 vs 84.3% predicted, p = 0.03), forced expiratory volume in 1 s (FEV1) (88.5 vs 76.1% predicted, p = 0.04), and alveolar volume adjusted diffusion capacity of carbon monoxide (106.4 vs 91.4% predicted, p = 0.03). FEV1 to FVC ratio, total lung capacity, and residual volume showed no statistical difference. CONCLUSION: The long term PFT result following thoracoscopic lobectomy is better than open lobectomy. This may be due to impaired respiratory musculature after thoracotomy. Further study with larger sample size is necessary to determine this hypothesis. LEVEL-OF-EVIDENCE: III. PMID- 30249358 TI - Surgical resection of infantile hemangiomas following medical treatment with propranolol versus corticosteroids. AB - PURPOSE: There has been a paradigm shift from corticosteroid to propranolol treatment for infantile hemangiomas (IHs), with surgical resection reserved for complicated or persistent IHs. The purpose of this study was to determine if propranolol treatment was associated with decreased utilization of surgical resection compared to corticosteroids. METHODS: A single center retrospective chart review of all corticosteroid or propranolol treated IHs between 2005 and 2014 was performed. Demographic and clinical data were collected. Both univariate and multivariate analyses were performed with the primary outcome of requiring surgical intervention. RESULTS: Of 652 patients with IH, 52 were treated with oral corticosteroids and 195 with propranolol only. Surgical intervention was required in 14 (27%) of steroid patients vs 18 (9%) of propranolol patients (p < .001). On multivariable analysis patients treated with steroids had 3.3 the odds of requiring surgery when compared to propranolol patients (p = .001). Prematurity (<37 weeks) was also associated with increased odds of surgery (OR = 2.8, p = .003). CONCLUSION: Patients treated with propranolol required significantly fewer surgical interventions than those treated with corticosteroids suggesting a more efficacious treatment paradigm. Prematurity increases the need for surgical intervention regardless of the modality of medical treatment. LEVEL OF EVIDENCE: Level III, treatment study. PMID- 30249359 TI - Half-life of alpha-fetoprotein in neonatal sacrococcygeal teratoma. AB - BACKGROUND: Alpha-fetoprotein (AFP) is useful as a tumor marker for sacrococcygeal teratoma (SCT). We investigated the half-life of AFP in SCT. METHODS: Neonates who underwent surgical treatment for SCT between 1997 and 2016 were included in the study, whereas patients who died before or after surgery or had malignant germ cell tumors were excluded. RESULTS: Fifty-five non-recurrent SCT patients (M:F = 18:37) were enrolled. They underwent surgery on average 7.4 +/- 4.1 days after birth. Serum AFP was measured an average 4.25 +/- 2.07 times per patient. We obtained 165 half-lives following the formula (M = Mo * (1/2) Deltat/T). A positive correlation was observed between half-life and patient age using the formula T1/2 = 0.0597 * days +6.1643 (p < 0.001). It was different from recurrent SCT (T1/2 = 0.1196 * days -0.0633) (p < 0.05). Half-life was different between mature SCT (T1/2 = 0.0671 * days +4.3912) and immature SCT (T1/2 = 0.0433 * days +8.9339) (p < 0.05). CONCLUSION: The half-life of AFP in neonatal patients with SCT was prolonged in proportion to the age, and it was getting longer in recurrent tumor than non-recurrent tumor. The half-life of AFP was longer in immature teratoma than in mature teratoma. LEVEL OF EVIDENCE: IV. PMID- 30249360 TI - Dysphagia in Nursing Home Residents: Management and Outcomes. AB - OBJECTIVES: To define the prevalence of dysphagia and its associated factors and to investigate the influence of dysphagia and nutritional therapies performed in dysphagic subjects on clinical outcomes, including nutritional status, pressure ulcers, hospitalization, and mortality. DESIGN: A prospective observational study. SETTING AND PARTICIPANTS: Thirty-one Italian nursing homes participating in the ULISSE project and 1490 long-stay nursing home residents, older than 65 years, assessed at baseline and reassessed after 6 and 12 months. MEASURES: All participants underwent a standardized comprehensive assessment using the Italian version of the nursing home Minimum Data Set. The activities of daily living Long Form scale was used to evaluate functional status. Health care professionals assessed dysphagia by means of clinical evaluation. Nutritional status was assessed using the information on weight loss. RESULTS: The prevalence of dysphagia was 12.8%, and 16% of the subjects were treated with artificial nutrition. The mortality rate in subjects with dysphagia was significantly higher compared with that of nondysphagic subjects (27.7% vs 16.8%; P = .0001). The prevalence of weight loss and pressure ulcers was also higher in dysphagic subjects. At variance, dysphagia was not associated with a higher hospitalization risk. CONCLUSION/IMPLICATIONS: Dysphagia is common in nursing home residents, and it is associated with higher mortality. Therefore, early diagnosis and optimal management of dysphagia should become a priority issue in nursing homes. PMID- 30249361 TI - Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: Clinical gene panels versus genome-wide approaches to molecular diagnosis. AB - Charcot-Marie-Tooth (CMT) disease type 1 is an inherited peripheral neuropathy characterized by demyelination and reduced nerve conduction velocities. We present a multi-generational family with peripheral neuropathy in whom clinical CMT panel testing failed to conclude a molecular diagnosis. We found a PMP2 pathogenic variant c.155T > C, p.(Ile52Thr) that segregates with disease suggesting that PMP2 variants should be considered in patients with neuropathy and that it may be prudent to include in clinical CMT gene panels. PMID- 30249362 TI - Sarcopenia and Hip-Structure Analysis Variables in Korean Elderly Population. AB - The purpose of this study is comparing the hip-structure analysis (HSA) variables with the skeletal muscle index (SMI) in elderly patients with sarcopenia using nationwide representative data on the Republic of Korea (ROK). The survey data were collected from household interviews and direct standardized physical examinations conducted in specially equipped mobile examination centers. The data were collected in 2008 from 9744 participants. Patients under 65years of age who were without data on the skeletal-muscle-mass and HSA variables were excluded. After these exclusions, a total of 744 participants (293 men and 451 women) were ultimately analyzed. The HSA measurements of the hip-bone geometry were analyzed using dual-energy X-ray absorptiometry. The appendicular SMI is defined as the sum of the arm and leg SMIs. Sarcopenia is defined according to the criteria for the Asia Working Group for Sarcopenia as SMIs of less than 5.4 kg/m2 and 7.0 kg/m2 for women and men, respectively. In the entire population, SMI was found to be positively correlated to HSA variables. After adjusting for age, body mass index, and energy intake in both the women and men groups, a statistically significant difference became evident in all variables between the SMI and the HSA. The present study suggests that skeletal-muscle loss negatively affects hip bone-strength indices in elderly sarcopenia patients. Implementing strategies to increase SMI in the elderly population may be useful for reducing the vulnerability to hip fracture. PMID- 30249363 TI - [Gender violence: when the aggressor is a patient with dementia. About clinical case]. PMID- 30249364 TI - [Cardiac rehabilitation in adults with congenital heart diseases]. AB - The great advances in the medical and surgical management of congenital heart diseases have allowed many children to reach adulthood with often a good hemodynamic result. Nevertheless most of these adults have a limitation of their functional capacity. This limitation is more or less important, penalizes them in their daily life and alters their quality of life. The origin of this limitation is generally multifactorial. It is linked, of course, to the severity of the heart disease and the quality of the operative result. But there is very often a physical deconditioning. It can be secondary to the heart disease but is often secondary to a lack of physical activity. It is the parents, sometimes overprotective, but frequently the doctors who imposed, often wrongly, this restriction. It is essential to take this dimension into account in view of the important benefits expected for health and quality of life. Cardiac rehabilitation is a privileged tool for providing advice in a suitable environment. This requires close collaboration between cardiac rehabilitators and congenital cardiologists to offer appropriate care. We bring here some reflections and the basic elements to guide the re-training of these patients. PMID- 30249365 TI - Probing the benzofuroquinolinium derivative as a potent antibacterial agent through the inhibition of FtsZ activity. AB - A benzofuroquinolinium derivative that exhibits excellent cell division inhibitory effect was discovered through cell-based screening approach. This compound possesses potent antimicrobial activity against both Gram-positive and Gram-negative bacteria including the drug-resistant strains. In addition, this compound is able to restore MRSA susceptibility to beta-lactam antibiotics. The biochemical results suggest that the compound inhibits bacterial cell division through the disruption of GTPase activity and the polymerization of FtsZ, which is probably the mechanism of antibacterial activity. PMID- 30249366 TI - Pharmacokinetic Interactions Between Gemigliptin and Metformin, and Potential Differences in the Pharmacokinetic Profile of Gemigliptin Between the Mexican and Korean Populations: A Randomized, Open-label Study in Healthy Mexican Volunteers. AB - PURPOSE: The aim of this study was to assess the pharmacokinetic interactions between a newly developed dipeptidyl peptidase (DPP)-4 inhibitor, gemigliptin, and metformin in healthy Mexican male volunteers, and the differences in the pharmacokinetic profile of gemigliptin between Korean and Mexican healthy volunteers. METHODS: This was a multiple-dose, randomized, open-label, 3-way, 3 period crossover study. Subjects were randomized to 1 of 3 treatment sequences and received gemigliptin 50mg once a day, metformin1000mg BID, or both drugs during a 7-day treatment period, and underwent sampling for pharmacokinetic analysis and tolerability assessments. Point estimates and 90% CIs of Cmax,ss and AUCtau,ss least squares mean (LSM) ratios of the concurrent administration of gemigliptin + metformin to the administration of monotherapy with either drug were obtained, and the pharmacokinetic profile of gemigliptin observed was compared with that in healthy Korean volunteers studied during the initial development of gemigliptin. FINDINGS: The coadministration of gemigliptin + metformin did not affect the pharmacokinetic characteristics of gemigliptin (LSM ratio [90% CI] for Cmax,ss and AUCtau,ss: 0.98 [0.87-1.10] and 0.94 [0.91-0.98], respectively) or metformin (LSM ratio [90% CI] for Cmax,ss and AUCtau,ss: 0.97 [0.88-1.08] and 1.02 [0.93-1.12], respectively) when administered as monotherapy and was well tolerated. In contrast with Korean healthy volunteers, Mexican subjects showed a modestly higher gemigliptin exposure (LSM ratio [90% CI] for AUCtau,ss: 1.22 [1.14-1.31]). IMPLICATIONS: The results of this study support, in ethnically different populations, the absence of drug-drug interactions between gemigliptin and metformin previously shown in Korean healthy volunteers. Considering the flat effect-concentration curve and wide therapeutic range of gemigliptin, the pharmacokinetic profile of gemigliptin observed in healthy Mexican and Korean subjects suggests that gemigliptin use in Mexican patients may be associated with outcomes, in terms of efficacy and tolerability, similar to those observed in the Korean population. ClinicalTrials.gov identifier: NCT03310749. PMID- 30249367 TI - Feel good, do good? Subjective well-being and sharing behavior among children. AB - The current study examined the association between children's subjective well being (SWB) and their sharing behavior. School children (second and fifth graders) were interviewed in private and had an opportunity to share candy with a recipient under one of two between-participants conditions: Perceived-High Obligation (a recipient in poverty) and Perceived-Low Obligation (a temporarily needy recipient). Results provide initial evidence of an increased association between SWB and sharing decisions with age; whereas SWB was not significantly correlated with the incidence of sharing by younger children (second graders), it was a positive predictor of sharing behavior among fifth graders. Manipulating the perceived obligation to share (by emphasizing the causes beyond the recipient's need), we found that higher levels of SWB were linked to sharing only in the Perceived-Low Obligation condition. Children with lower SWB behaved as expected by the norm and shared to a similar degree as children with higher SWB when sharing felt obligatory. However, when sharing was less obligatory, higher levels of SWB were linked to higher levels of sharing. PMID- 30249368 TI - Reprint of: Pathologic manifestations of Immunoglobulin(Ig)G4-related lung disease. AB - Immunoglobulin(Ig)G4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect virtually any organ and usually presents as tumefactive lesions involving multiple sites. Characteristic histopathology of IgG4-RD consists of dense lymphoplasmacytic infiltrate, fibrosis (often in storiform pattern), and obliterative phlebitis, accompanied by tissue infiltration of IgG4-positive plasma cells with or without elevation of serum IgG4 level. Despite a general similarity in the morphologic manifestations of IgG4-RD, site-specific unique morphologic features have been described in some organs including the lung. Compared with other sites, pulmonary involvement by IgG4-RD has been recognized more recently, and lung biopsy interpretation for this condition is often challenging, as both a relative paucity of pathognomonic features and a plethora of overlapping findings with other fibroinflammatory processes of the lung. This review is focused on the morphologic spectrum of IgG4-related lung disease documented in the current literature and on the pertinent issues in the differential diagnoses with other conditions encountered in the lung. PMID- 30249369 TI - Reprint of: Unusual non-neoplastic lesions of the lung. AB - Many nonneoplastic conditions that may affect the lung are in reality rare or unusual manifestations of metabolic processes, inflammatory conditions, or unknown etiology. Because of their rarity, they can often be confused with malignant neoplasms. Familiarity with these conditions not only will expedite further treatment for these patients but also will avoid the process of more tests or unnecessary surgical procedures. The nomenclature for some of those conditions is still controversial. The clinical outcome of these conditions can be quite variable, with some patients surviving a long number of years and others eventually succumbing to the disease. We will limit our discussion in this review to four of these conditions, including inflammatory pseudotumor (inflammatory myofibroblastic tumor), placental transmogrification of lung, alveolar microlithiasis, and metastatic calcification. Although these lesions are not part of the gamut of neoplastic conditions affecting the lung, they are nonetheless important to recognize, as their outcome may not necessarily be an innocuous one. PMID- 30249370 TI - Reprint of: Nonspecific interstitial pneumonia: pathologic features and clinical implications. AB - Nonspecific interstitial pneumonia (NSIP) is a form of chronic interstitial pneumonia that should be separated from the other idiopathic interstitial pneumonias, including most importantly, usual interstitial pneumonia (UIP). Diagnosis is predicated on identification of characteristic findings in a surgical lung biopsy in the appropriate clinical and radiological context. Affected patients may have a variety of underlying or associated conditions, although most have a form of idiopathic lung disease associated with a more favorable prognosis than UIP/idiopathic pulmonary fibrosis (IPF). Keys to distinguishing NSIP from UIP include absence of heterogeneous lung involvement, architectural distortion in the form of fibrotic scarring and/or honeycomb change, and fibroblast foci in NSIP. PMID- 30249372 TI - Achieving mainstream nitrogen removal via the nitrite pathway from real municipal wastewater using intermittent ultrasonic treatment. AB - Achieving mainstream nitrogen removal via the nitrite pathway (NH4+ -> NO2- -> N2) is highly beneficial for energy neutral/positive wastewater treatment. Our previous batch assays revealed that ultrasonic treatment can suppress nitrite oxidizing bacteria (NOB) while enhancing the activity of ammonia-oxidizing bacteria (AOB). Based on this concept, this study investigated the feasibility of applying ultrasonication to achieve the nitrite pathway in mainstream wastewater treatment. Two lab-scale sequencing batch reactors were set-up in parallel and fed with real municipal wastewater. With 100% of the sludge treated every 12 h at a treatment energy input of 0.066 kJ per mg mixed liquor suspended solids, the nitrite pathway was rapidly (within two weeks) established in the experimental reactor with stable effluent nitrite accumulation ratio (NO2-/(NO2- + NO3-)) of above 80% and significantly decreased NOB population. In comparison, the control reactor always possessed the conventional nitrification and denitrification pathway. Economic analysis indicated that energy consumption is too high for practical applications. However, this technology may be used in conjunction with other technologies, whereby this ultrasonic treatment can be used infrequently (e.g. once every few months) when the nitrite pathway becomes unstable. PMID- 30249371 TI - Ultrasound-assisted preparation of flaxseed oil nanoemulsions coated with alginate-whey protein for targeted delivery of omega-3 fatty acids into the lower sections of gastrointestinal tract to enrich broiler meat. AB - Flaxseed oil is one of the richest sources of alpha-linolenic acid (ALA). However, the susceptibility of ALA to oxidation and also lack of the convenient methods to deliver these invaluable compound into the lower sections of gastrointestinal tract (GIT) are still unknown. The objective of the current study was to establish a method for ALA targeted delivery into the lower sections of GIT to enrich broiler meat. An in vitro study was performed to use ultrasound to produce oil-in-water nanoemulsions of flaxseed oil stabilized by different wall materials for controlled release of ALA in GIT. The fabricated nanoemulsions were assessed in terms of particle size distribution, zeta-potential, encapsulation efficiency, field emission scanning electron microscopy (FESEM), and in vitro gastric and intestinal digestions. Results indicated that the nanoemulsions coated by a combination of whey protein-sodium alginate (WP/SA) had a relatively uniform distribution and all particles distributed in less than 1000 nm. The values of zeta-potential for nanoemulsions stabilized by whey protein (WP), sodium alginate (SA) and WP/SA were -31.4, -29.3 and -45.5 mV, respectively. The wall combination of WP/SA showed the best encapsulation efficiency followed by WP. The FESEM results indicated spherical and non aggregated structures for three types of nanoemulsions. The nanoemulsions stabilized by WP/SA showed a high resistance to in vitro gastric digestion but a relatively rapid release during intestinal digestion. An in vivo study was conducted to enrich broiler meat with ALA, using the best wall material from the in vitro study. In total, 300 one-day-old broilers (Ross, 308) were assigned into 5 experimental treatments including: basal diet (BD), basal diet plus flaxseed oil (BD + FO, 1 mL/kg body weight), basal diet plus ultrasonicated flaxseed oil nanoemulsions stabilized by WP/SA (BD + FON, 1 mL/kg body weight), basal diet plus flaxseed oil and vitamin E (BD + FO + E, 1 mL/kg body weight and 200 mg/kg diet vitamin E) and basal diet plus ultrasonicated flaxseed oil nanoemulsions stabilized by WP/SA and vitamin E (BD + FON + E, 1 mL/kg body weight of nanoemulsion and 200 mg/kg diet vitamin E). Each experimental treatment included 4 replicates in a completely randomized design. Results showed a better feed conversion ratio (FCR) in birds treated with dietary treatments compared with those received basal diet. A greater incorporation of ALA and total poly unsaturated fatty acids (PUFA) omega-3 were observed in thigh and breast meat of birds fed by ultrasonicated flaxseed oil nanoemulsions. In comparison to birds fed with BD, a favourably lower PUFA omega-6/omega-3 ratio was observed in birds received nanoemulsions of flaxseed oil. In general, the current study showed that using ultrasound to produce nanoemulsions stabilized by WP/SA has potential to protect ALA of flaxseed oil from gastric digestion and could be used as delivery carriers of ALA omega-3 fatty acid to the posterior sections of chicken GIT. Moreover, ultrasonic fabrication of nanoemulsion has potential to enrich broiler meat by ALA fatty acid. PMID- 30249373 TI - Winter picoplankton diversity in an oligotrophic marginal sea. AB - Marine picoplankton, unicellular organisms with cell sizes up to 3 MUm in diameter, numerically dominate marine ecosystems, encompassing Archaea, Bacteria, Eukarya (protists and fungi) as well as viruses. Autotrophic and heterotrophic picoplankton abundance and community composition with a focus on picoeukaryotes (PEs) were investigated in the winter of 2016 at three stations along a coast-to offshore transect in the southern Adriatic Sea. Abundances were estimated by flow cytometry, while community composition by Illumina High-Throughput Sequencing (HTS) of 16S and 18S rRNA genes. The photosynthetic picoplankton diversity was also investigated by High-Performance Liquid Chromatography (HPLC) of liposoluble pigments. Heterotrophic bacteria and cyanobacteria (Prochlorococcus and Synechococcus) accounted for up to 7 * 105; 2.3 * 104 and 2.5 * 104 cells mL-1, respectively, while photosynthetic picoeukaryotes peaked with 3 * 103 cells mL-1. Prokaryotes, as revealed by HTS were dominated by Alphaproteobacteria (mainly SAR11, 44.91% of total 16S sequence reads), followed by Gammaproteobacteria (Oceanospirillales and Pseudomonadales, 14.96%), Bacteroidetes (mainly Flavobacteriales, 13%), Cyanobacteria (Prochlorococcus and Synechococcus, 9.52%), Marinimicrobia (SAR406, 7.97%), Deltaproteobacteria (SAR324, 3.83%), Actinobacteria (2.24%) and Chloroflexi (SAR202, 1.90%). Photosynthetic pigment concentrations were very low (12.12 MUgL-1 at the most) and taxonomic pigments could be attributed to Prochlorococcus, Synechococcus, Prymnesiophyceae, Bacillariophyceae, Chrysophyceae, and Prasinophyceae. HTS data revealed that PEs were dominated by heterotrophs, such as Syndiniophyceae, parasitic dinoflagellates (79.67% of total 18S sequence reads), Dinophyceae (8.7%) and the radiolarians Collodaria belonging to Sphaerozoidae (22.1%) and Spumellaria (5.0%). On the other hand, photoautotrophs, including Chlorophyta (Mamiellophyceae, Prasinophyceae, Trebouxiophyceae, and Ulvophyceae), Stramenopiles (Bacillariophyta, Chrysophyceae, Dictyochophyceae, Pelagophyceae), photoautotrophic Cryptophyta and some Haptophyta (Prymnesiophyceae), did not exceed 5% of total sequence reads. This study provides the first snapshot of the PEs diversity in oligotrophic euphotic waters of the southern Adriatic Sea, hence setting the stage for large-scale surveying and characterization of the eukaryotic diversity in the entire basin. PMID- 30249374 TI - Differential effects of postoperative oral corticosteroid on eosinophilic vs. non eosinophilic CRSwNP subtypes. AB - PURPOSE: The efficacy of postoperative oral corticosteroids on surgical outcomes in chronic rhinosinusitis with nasal polyps (CRSwNP) patients following endoscopic sinus surgery (ESS) remains controversial. This study evaluated the potential benefits of postoperative oral corticosteroids on surgical outcomes in CRSwNP patients and investigated the differential effects on eosinophilic CRSwNP (ECRSwNP) and noneosinophilic CRSwNP (NECRSwNP). MATERIALS AND METHODS: Patients with bilateral CRSwNP who underwent ESS were enrolled and randomized to receive either oral prednisolone (30 mg/day) or placebo for 2 weeks after surgery. Visual analog scale (VAS) and Sino-Nasal Outcome Test 22 (SNOT-22) scores were chosen as the subjective outcomes, evaluated at preoperative baseline and 1, 3, and 6 months postoperatively. Lund-Kennedy Endoscopic Scores (LKESs) were used as the objective outcome, evaluated at preoperative baseline and at 2 weeks and 2, 3, and 6 months postoperatively. RESULTS: In total, 100 patients with bilateral CRSwNP were enrolled, of whom only 82 completed the 6-month follow-up. The subjective outcomes showed no significant difference at each follow-up points. Of the objective outcomes, the corticosteroid group reporting a trend of improvement in LKESs at 6 months postoperatively (p = 0.05). After stratification by tissue eosinophils, only patients with NECRSwNP (<10 eosinophils/HPF) demonstrated a significant improvement in LKESs at 3 months postoperatively (p = 0.03). CONCLUSIONS: Postoperative oral corticosteroids did not provide additional improvements in VAS and SNOT-22 scores; nevertheless, a trend of LKES improvement was noted at 6 months postoperatively. After stratification by tissue eosinophils, this effect was significant only among NECRSwNP patients at 3 months follow-up. PMID- 30249375 TI - Interspinalis-longissimus mid-line approach for thoracic and thoracolumbar minimally invasive fixation: Technical note. AB - The authors present a new minimally invasive posterior thoracic and upper lumbar spinal approach, using midline-staged incision with bilateral dissection via the natural muscular cleavage plane between the spinalis and longissimus muscles for pedicle fixation. The aim was to clarify anatomy and compare results between this technique and the conventional paraspinal approach. An anatomic MRI study determined the position of the superficial aponeurosis of the spinalis longissimus intermuscular cleavage plane with respect to the midline. The surgical procedure is described. A radiological and clinical study evaluated 24 patients divided into two comparative groups, operated on via the medial intermuscular or the paraspinal approach, for isolated A3 and B2 Magerl fracture between T2 and L2, without neurologic involvement. Pain, postoperative complications, reduction quality and esthetic satisfaction were assessed. MRI located the cleavage plane, which was consistently 11.01+/-0.9mm (range, 9.4 12.3mm) from the midline. In the "medial approach" group, hospital stay was significantly shorter, by 3 days, at 4+/-1.9 (range, 2-8 days) (p: 0.005); pain on VAS was 2 points lower at postoperative day 1 (2.1+/-1.4; range,<=1-4; p:0.032), and lower at discharge (0.3+/-0.6; range, 0-1; p: 0.001). The scar was considered esthetically very satisfactory. This easily performed and reproducible medial intermuscular approach showed low iatrogenesis, significantly improving postoperative course. PMID- 30249376 TI - Cardiac sarcoidosis: Diagnosis confirmation by bronchoalveolar lavage and lung biopsy. AB - INTRODUCTION: The diagnosis of cardiac sarcoidosis (CS) is difficult to ascertain due to the insensitivity of endomyocardial biopsy. Current diagnostic criteria require a positive endomyocardial biopsy or extra-cardiac biopsy with clinical features suggestive of CS. Common tests for diagnosis of pulmonary sarcoidosis include bronchoalveolar lavage (BAL), lung and mediastinal lymph node (MLN) biopsies. Our objective was to determine the diagnostic utility of these tests in patients with suspected CS and without prior history of pulmonary involvement. METHODS: This retrospective cohort study included 37 patients without history of extra-cardiac sarcoidosis referred for suspected CS. All patients underwent chest computed tomography (CT) staged using the modified Scadding criteria, and had BAL, and/or lung or MLN biopsy. BAL cellular analyses with lymphocytes>15% and/or CD4/CD8 ratio>= 4 were considered suggestive of sarcoidosis. The number of positive biopsies and BALs were compared between normal CT (Scadding stage 0) and abnormal CT (Scadding stage 1-4) groups. RESULTS: A definitive diagnosis of sarcoidosis was ascertained in 18/31 (58%) patients undergoing lung or lymph node biopsy, and a potential diagnosis in 18/27 (67%) patients with BAL CD4/CD8>4 or lymphocytes>15%. Of the 12 patients in the normal CT group, 4/10 (40%) had positive lung biopsies, and 9/12 (75%) patients had either positive biopsy or BAL criteria. CONCLUSIONS: In suspected cardiac sarcoidosis, a diagnosis of extra cardiac sarcoidosis was ascertained in a majority of patients irrespective of degree of lung involvement on chest CT. Our results support referral for pulmonary biopsy/bronchoalveolar lavage in suspected CS to confirm the diagnosis of sarcoidosis. PMID- 30249377 TI - The delicate choice of optimal basic therapy for multimorbid older adults: A cross-sectional survey. AB - BACKGROUND: Clinical practice guidelines are useful to suggest pharmacological therapies for the treatment of single chronic diseases. However, there is little guidance for multimorbidity, and specific quality measures for people with multimorbidity that can be used at a population level are lacking. OBJECTIVE: To describe what pharmacists and geriatricians consider to be an optimal basic pharmacological therapy for an older individual with type 2 diabetes (DM), chronic obstructive pulmonary disease (COPD) and heart failure (HF). METHODS: An online cross-sectional survey among 162 pharmacists and geriatricians, in Quebec, Canada, was performed. Participants were invited to choose, from a list of 32 medications or classes, the optimal basic therapy for an individual aged 65-75 years with the 3 chronic diseases. Descriptive statistics were used to calculate the median number of medications chosen and the proportions of participants who chose each medication, according to the participant's specialty. A Kruskall Wallis test was performed to detect whether there were differences in the median number of medications recommended according to speciality. RESULTS: There was little consensus on the optimal basic pharmacological therapy for this hypothetical multimorbid individual, with 157 different combinations provided by the 162 participants. Nevertheless, 5 classes were chosen by at least 75% of the participants: metformin, long-acting anticholinergic agents, angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), beta blockers, and short-acting beta-agonists. The median number of recommended medications was 10 (interquartile range [IQR]: 6-13). There was a statistically significant difference between specialties (p = 0.0396). Geriatricians recommended the lower median number of medications, 7 (IQR: 5-10). CONCLUSIONS: At least half of the participants considered polypharmacy (>=10 medications) inevitable for an optimal basic treatment of DM, COPD and HF. The heterogeneity of responses raises issues when considering quality indicators in population based studies. PMID- 30249378 TI - Ultrasonographic study of intestinal Doppler blood flow in infantile non-IgE mediated gastrointestinal food allergy. AB - BACKGROUND: Although non-IgE-mediated gastrointestinal food allergy has increased rapidly in Japan, a small number of reports has evaluated B-mode and Doppler ultrasonographic findings in the acute phase of infantile gastrointestinal milk allergy. The aim of the present study was to compare the diagnostic utility of ultrasonographic findings and laboratory allergic data in non-IgE-mediated infantile gastrointestinal milk allergy. METHODS: Sixteen cases of active non-IgE mediated infantile gastrointestinal milk allergy, diagnosed by food elimination tests and oral food challenge tests (OFCTs) (group A), 15 cases of acute viral gastroenteritis (AGE) (group B), and 15 controls (group C) were enrolled. 1) B mode abdominal ultrasound findings, 2) laboratory allergic data including eosinophil counts (Eos), serum IgE, and the antigen-specific lymphocyte proliferation test (ALPT) against milk protein, and 3) vessel density (VD) indirectly quantified by gastrointestinal Doppler flow at jejunum, ileum, and sigmoid colonic mucosae were evaluated and compared among the groups. RESULTS: In the small intestine, wall thickening, dilation, mesenteric thickening, and poor peristalsis were found in 100%, 62.5%, 93.7%, and 100%, respectively, in group A. Eos, IgE, ALPT, and VD were positive in 25.0%, 0%, 87.5%, and 100%, respectively, in group A. Small intestinal VD was significantly greater in group A than in groups B (jejunum p < .001; ileum p < .001) and C (jejunum p < .001; ileum p < .001), with no significant differences between groups B and C (jejunum: p = .74; ileum: p = .73). CONCLUSIONS: Abdominal Doppler ultrasonography and small intestinal VD at symptomatic state can support the diagnosis and evaluation of non-IgE-mediated infantile gastrointestinal milk allergy with symptoms of vomiting, diarrhea, and failure to thrive. PMID- 30249379 TI - Stem cell factor suppressed IL-33-induced MHC class II expression in murine bone marrow-derived mast cells. PMID- 30249380 TI - Reply to: Letter to the editor: Evaluation of anatomical and round breast implant aesthetics and preferences in Dutch young lay and plastic surgeon cohortBy Fengrui Cheng; Ying Cen. PMID- 30249381 TI - Isolated superior mesenteric artery dissection in the emergency department: A rare cause of abdominal pain. AB - Acute onset abdominal pain constitutes a significant proportion of emergency department visits, but only a small fraction of these cases are attributable to vascular pathologies (Bauersfeld, 1947 [1]). In this case, report, we present an incidental diagnosis of Spontaneous Isolated Superior Mesenteric Artery Dissection (SISMAD). A 69-year-old man was admitted to the emergency department complaining of fever, loss of appetite, vague epigastric pain, dysuria, and a productive cough for several days. A lower extremity venous Doppler ultrasound was performed, and a deep venous thrombosis (DVT) was identified in the left main femoral vein and in the proximal segment of the superficial vein. The patient also had no blood flow in the distal part of left external iliac vein. A contrast enhanced computerized tomography angiography of the thorax and abdomen was performed to detect pulmonary embolism and the etiology of the abdominal pain. No pulmonary embolism was found; however, multiple metastatic nodules were identified in both lungs, as well as infiltration on the posterobasal field of the right lung, metastases on the liver, focal dilatation, and an intimal flap on the middle-distal part of the superior mesenteric artery (SMA) at 2 cm, with a segment that was compatible with isolated dissection. There was a contrast passage on the distal part of SMA, and no sign of bowel ischemia. PMID- 30249382 TI - Diagnostic performance of high sensitive troponin in non-ST elevation acute coronary syndrome. AB - OBJECTIVE: To assess the diagnostic performance of high-sensitivity troponin T (hs-TnT) in patients with suspected non-ST elevation acute coronary syndrome (NSTE-ACS); confirm whether it shortens the time to diagnosis; and analyze the clinical consequences derived from its use. METHOD: A prospective, longitudinal observational study was carried out in 5 emergency care departments. Patients seen for chest pain with suspected of NSTE-ACS were consecutively included. Patient care followed the internal protocols of the center, based on the consensus guidelines of the European Society of Cardiology. Serial conventional cardiac troponin (cTn) and hs-TnT determinations were made. RESULTS: A total of 351 patients were included in the study. A final diagnosis of acute myocardial infarction (AMI) was established in 77 patients, with unstable angina in 102, and no acute coronary syndrome in 172 patients. The hs-TnT values were above percentile 99% in a large number of patients without AMI. In the initial determination, the diagnostic sensitivity of the hs-TnT was significantly greater than that of cTn (87.0% vs. 42.9%), which led to a negative predictive value of 95.1%. CONCLUSIONS: High-sensitivity troponin T improves diagnostic performance compared with conventional troponin assay, shortens the time to diagnosis, and identifies a larger number of patients with smaller myocardial infarctions. PMID- 30249383 TI - Modest contribution of JAK2 V617F allele burden to the occurrence of major thrombosis in polycthemia vera and essential thrombocythemia. PMID- 30249385 TI - Measuring fluorescence-lifetime and bio-impedance sensors for cell based assays using a network analyzer integrated circuit. AB - Cell culture assays for therapeutic drug screening today are fully automated. Vitality of the cells is monitored by different sensors. For such a system, we propose a new reader unit, which is capable of reading two different fluorescent sensors and electrical impedance in 24-well-plates. Main goals are to reduce cost, complexity and size while achieving a similar performance as the existing reader unit. To achieve this, measurement electronics and signal paths for frequency domain fluorescence and bio-impedance measurement are combined. Central component is an integrated circuit for impedance spectroscopy. A new compact and economic optical setup is developed to read two different sensor spots on the bottom of the well. Measurement errors introduced by different components like DFT leakage, and frequency dependent signal delays are evaluated and compensated. A set of commercially available fluorescence sensor spots is used to verify the read out performance. The results are usable, with noise slightly higher than commercial readers. To verify the impedance measurement accuracy, measurements of known resistances are conducted. In the relevant impedance and frequency range for biological applications a suitable accuracy is achieved. Due to the higher sampling rate of the new reader, the higher noise can be reduced through averaging. The new system is significantly smaller and cheaper to manufacture than commercially available devices. PMID- 30249384 TI - Evaluation of the activity levels of rat FVIII and human FVIII delivered by adeno associated viral vectors both in vitro and in vivo. AB - The development of a novel coagulation factor VIII (FVIII) expression cassette with an enhanced activity for gene therapy of hemophilia A (HA) is essential. The biological properties of several non-human FVIII sequences, such as porcine and canine, have been evaluated. Here, we compared the activity level of rat FVIII (rFVIII) and human FVIII (hFVIII) by using single-chain and dual-chain strategies in 293 T cells and the HA mice. In both in vitro and hydrodynamic injection studies, the activity of rFVIII detected by the activated partial thromboplastin time assay was higher than that of hFVIII both by single-chain (~2.96-fold and ~1.72-fold, respectively) and dual-chain (~7.69-fold and ~2.35-fold, respectively). Moreover, the dual chain exerted a potentially higher delivery efficacy compared with the single chain (~4.96-fold and ~2.99-fold, respectively). The blood loss of HA mice administrated with rFVIII was less than those with hFVIII. AAV-delivered rFVIII and hFVIII also exerted long-term therapeutic effects on HA mice and caused a transient ALT elevation. These data might help to the development of novel, optimized FVIII expression cassettes based on the amino acid difference between rFVIII and hFVIII. These data indicate that the dual-chain strategy would likely enhance the delivery efficiency of the AAV-mediated FVIII gene therapy. PMID- 30249386 TI - Dilemma of elevated CA 19-9 in biliary pathology. AB - Carbohydrate antigen 19-9 (CA 19-9) is a tumor marker which has been extensively evaluated and widely utilized primarily in diagnosing and prognosticating pancreaticobiliary malignancies. Levels may be significantly influenced and elevated in cases of benign biliary conditions however, especially in obstructive jaundice, thereby posing difficulty in distinguishing between benign and malignant cholestasis. A myriad of studies have focused on elucidating proper use and interpretation of CA 19-9 in pancreatic cancer as well as in the setting of cholestasis. These studies have demonstrated that many factors influence CA 19-9 values and various methods for interpreting CA 19-9 in obstructive jaundice have been proposed. With improvements in diagnostic imaging, advancements in endoscopic modalities, and likelihood that management will not change based on the results of the test, clinicians should be cautious when ordering CA 19-9 and consider the reasons for measuring the tumor marker. PMID- 30249387 TI - Multiple cerebral syphilitic gummas mimicking brain tumor in a non-HIV-infected patient: A case report. AB - We present a unique case of symptomatic early neurosyphilis in a non-HIV-infected patient. A 47-year-old man with a history of diabetes mellitus presented with generalized seizures. He did not manifest any neurological deficits. At first, multiple brain tumors were suspected based on findings from magnetic resonance imaging of the brain. However, serological and cerebrospinal fluid tests for syphilis yielded positive results, and the masses were reduced using amoxicillin. Multiple cerebral syphilitic gummas were therefore diagnosed. High-dose penicillin therapy was initiated and syphilitic gummas disappeared after five months. Treponema pallidum could invade the central nervous system at an early phase, and sometimes may be difficult to distinguish from malignant brain tumor. If intracranial lesions are identified in a syphilis-infected patient, cerebral syphilitic gumma should be considered as a differential diagnosis. PMID- 30249389 TI - Improvement in Parameters of Hematologic and Immunologic Function and Patient Well-being in the Phase III RESONATE Study of Ibrutinib Versus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. AB - BACKGROUND: Ibrutinib compared with ofatumumab significantly improves progression free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). PATIENTS AND METHODS: Measures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization. RESULTS: With up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on ofatumumab (P < .0001). Higher rates of clinically meaningful improvement were demonstrated with ibrutinib versus ofatumumab for FACIT-F and EORTC global health. Greater improvement was observed in disease-related weight loss, fatigue, night sweats, and abdominal discomfort with ibrutinib versus ofatumumab. Hospitalizations in the first 30 days occurred less frequently with ibrutinib than ofatumumab (0.087 vs. 0.184 events/patient; P = .0198). New-onset diarrhea was infrequent with ibrutinib after the first 6 months (47% at <=6 months vs. 5% at 12-18 months). With ibrutinib, grade >= 3 hypertension occurred in 6%, grade >= 3 atrial fibrillation in 4%, major hemorrhage in 2%, and tumor lysis syndrome in 1% of patients. CONCLUSION: Ibrutinib led to significant improvements in hematologic function and disease symptomatology versus ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL. PMID- 30249390 TI - Patterns of seasonal influenza activity in U.S. core based statistical areas, described using prescriptions of oseltamivir in Medicare claims data. AB - Using Medicare claims data on prescriptions of oseltamivir dispensed to people 65 years old and older, we present a descriptive analysis of patterns of influenza activity in the United States for 579 core based statistical areas (CBSAs) from the 2010-2011 through the 2015-2016 influenza seasons. During this time, 1,010,819 beneficiaries received a prescription of oseltamivir, ranging from 45,888 in 2011-2012 to 380,745 in 2014-2015. For each season, the peak weekly number of prescriptions correlated with the total number of prescriptions (Pearson's r >= 0.88). The variance in peak timing decreased with increasing severity (p < 0.0001). Among these 579 CBSAs, neither peak timing, nor relative timing, nor severity of influenza seasons showed evidence of spatial autocorrelation (0.02 <= Moran's I <= 0.23). After aggregating data to the state level, agreement between the seasonal severity at the CBSA level and the state level was fair (median Cohen's weighted kappa = 0.32, interquartile range = 0.26 0.39). Based on seasonal severity, relative timing, and geographic place, we used hierarchical agglomerative clustering to join CBSAs into influenza zones for each season. Seasonal maps of influenza zones showed no obvious patterns that might assist in predicting influenza zones for future seasons. Because of the large number of prescriptions, these data may be especially useful for characterizing influenza activity and geographic distribution during low severity seasons, when other data sources measuring influenza activity are likely to be sparse. PMID- 30249391 TI - Pathologic Grading of Malignant Pleural Mesothelioma: An Evidence-Based Proposal. AB - INTRODUCTION: A pathologic grading system (PGS) for malignant pleural mesothelioma (MPM) is warranted to better identify different risk categories of patients, plan therapeutic options, and activate clinical trials. METHODS: A series of 940 patients with MPM (328 in a training set and 612 in a validation set) that was diagnosed between October 1980 and June 2015 at the participant institutions was retrospectively assembled. A PGS was constructed by attributing to each histologic parameter, independent at multivariate analysis with excellent reproducibility (kappa > 0.75), different scores based on the increase in corresponding hazard ratios. The relevant PGS score thus ranged from 0 to 8 points for individual patients with MPM. CONCLUSIONS: The PGS was constructed by taking into consideration the histological subtyping of MPM (epithelioid/biphasic = 0 points; sarcomatoid = 2 points), necrosis (absent = 0 points versus present = 1 point), mitotic count per 1 mm2 (cutoffs as follows: 1-2 = 0 points, 3-5 = 1 point, 6-9 = 2 points, or >=10 = 4 points), and Ki-67 labeling index based on 2000 cells (<30% = 0 points versus >=30 = 1 point), all of which are independent factors in both patient sets after adjustment for stage and age at diagnosis. No heterogeneity was seen across the validation centers (p = 0.19). Epithelioid/biphasic MPM patterning and biopsy versus resection did not affect survival, whereas the PGS outperformed mitotic count and Ki-67 LI in both the training (area under the curve receiver operating characteristic = 0.76) and validation sets (area under the curve receiver operating characteristic = 0.73) (p < 0.01). Patient survival progressively deteriorated from a score of 0 (median times of 26.3 and 26.9 months) to a score 1 to 3 (median times of 12.8 and 14.4 months) and a score of 4 to 8 (median times of 3.7 and 7.7 months) in both sets of patients, with the hazard ratio for a 1-point increase in score being 1.46 (95% confidence interval: 1.36-1.56) in the training set and 1.28 (95% confidence interval: 1.22-1.34) in the validation set (after adjustment for age and [when available] tumor stage). The PGS was effective even in subgroup analysis (epithelioid, biphasic, and sarcomatoid tumors). DISCUSSION: A simple and reproducible multiparametric PGS effectively predicted survival in patients with MPM. PMID- 30249388 TI - HIV-Specific, Ex Vivo Expanded T Cell Therapy: Feasibility, Safety, and Efficacy in ART-Suppressed HIV-Infected Individuals. AB - Adoptive T cell therapy has had dramatic successes in the treatment of virus related malignancies and infections following hematopoietic stem cell transplantation. We adapted this method to produce ex vivo expanded HIV-specific T cells (HXTCs), with the long-term goal of using HXTCs as part of strategies to clear persistent HIV infection. In this phase 1 proof-of-concept study (NCT02208167), we administered HXTCs to antiretroviral therapy (ART)-suppressed, HIV-infected participants. Participants received two infusions of 2 * 107 cells/m2 HXTCs at a 2-week interval. Leukapheresis was performed at baseline and 12 weeks post-infusion to measure the frequency of resting cell infection by the quantitative viral outgrowth assay (QVOA). Overall, participants tolerated HXTCs, with only grade 1 adverse events (AEs) related to HXTCs. Two of six participants exhibited a detectable increase in CD8 T cell-mediated antiviral activity following the two infusions in some, but not all, assays. As expected, however, in the absence of a latency reversing agent, no meaningful decline in the frequency of resting CD4 T cell infection was detected. HXTC therapy in ART suppressed, HIV-infected individuals appears safe and well tolerated, without any clinical signs of immune activation, likely due to the low residual HIV antigen burden present during ART. PMID- 30249392 TI - Downregulated miR-1247-5p associates with poor prognosis and facilitates tumor cell growth via DVL1/Wnt/beta-catenin signaling in breast cancer. AB - The abnormal expression of microRNAs is a key hallmark of breast cancer. Nevertheless, the biological roles of miR-1247-5p in breast cancer remain unknown. In this study, we revealed that miR-1247-5p expression was markedly decreased in breast cancer. It was a valuable diagnostic biomarker for breast cancer with the area under the curve of more than 0.80. Reduced miR-1247-5p expression was significantly correlated with patient age, tumor size, and poor prognosis in The Cancer Genome Atlas cohort including 839 breast cancer patients. Multivariate Cox regression analysis demonstrated that miR-1247-5p was an independent prognostic indicator for overall survival (hazard radio [HR] = 1.683, 95% confidence interval [CI] = 1.087-2.606, p = 0.020) and recurrence-free survival (HR = 2.496, 95% CI = 1.576-3.951, p < 0.001). Moreover, functional studies showed that overexpression of miR-1247-5p inhibited proliferation and induced apoptosis in breast cancer cells. Bioinformatics analysis and mechanistic investigations revealed that Dishevelled 1 (DVL1) was a direct target of miR-1247 5p. Inhibition of DVL1 by miR-1247-5p resulted in the suppression of Wnt/beta catenin signaling, whereas overexpression of DVL1 abrogated the miR-1247-5p mediated effect. These data reveal that miR-1247-5p, as an oncosuppressor in breast cancer, may be a promising prognostic biomarker and therapeutic target. PMID- 30249394 TI - Exploring the role of methionine residues on the oligomerization and neurotoxic properties of DOPAL-modified alpha-synuclein. AB - The dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is believed to play a central role in Parkinson's disease neurodegeneration by stabilizing potentially toxic oligomers of the presynaptic protein alpha-Synuclein (aSyn). Besides the formation of covalent DOPAL-Lys adducts, DOPAL promotes the oxidation of Met residues of aSyn, which is also a common oxidative post-translational modification found in the protein in vivo. Herein we set out to address the role of Met residues on the oligomerization and neurotoxic properties of DOPAL modified aSyn. Our data indicate that DOPAL promotes the formation of two distinct types of aSyn oligomers: large and small (dimer and trimers) oligomers, which seem to be generated by independent mechanisms and cannot be interconverted by using denaturing agents. Interestingly, H2O2-treated aSyn monomer, which exhibits all-four Met residues oxidized to Met-sulfoxide, exhibited a reduced ability to form large oligomers upon treatment with DOPAL, with no effect on the population of small oligomers. In this context, triple Met-Val mutant M5V/M116V/M127V exhibited an increased population of large aSyn-DOPAL oligomers in comparison with the wild-type protein. Interestingly, the stabilization of large rather than small oligomers seems to be associated with an enhanced toxicity of DOPAL-aSyn adducts. Collectively, these findings indicate that Met residues may play an important role in modulating both the oligomerization and the neurotoxic properties of DOPAL-derived aSyn species. PMID- 30249393 TI - Hsa_circRNA_103809 regulated the cell proliferation and migration in colorectal cancer via miR-532-3p / FOXO4 axis. AB - Circular RNAs(circRNAs) are a class of non-coding RNAs that are widely expressed in a variety of cell species. The role they play in cancers is poorly understood, especially in colorectal cancer (CRC). Hsa_circRNA_103809 (hsa_circ_0072088, circZFR)has been demonstrated to be lowly expressed in colorectal cancer tissues and is associated with stage and lymph node metastasis of cancer tissues. Real time quantitative PCR (qRT-PCR) was used to verify the relationship of hsa_circRNA_103809 between colorectal cancer and paired adjacent tissue in clinical tissue samples. Then, the proliferative capacity, migration ability, cell cycle, and apoptosis were measured using wound-healing assay, CCK8, transwell assay, flow cytometry, and the like, when hsa_circRNA_103809 expression in SW620 and COCA-2. The qRT-PCR, western bolt and other experiments verify that the expression of hsa_circRNA_103809 can regulate the expression of miR-532-3P and FOXO4. Hsa_circRNA_103809 was found to be significantly down regulated in CRC tissues and cell lines and compared with paired adjacent non-tumorous tissues and normal FHC cells. Hsa_circRNA_103809 participates in the regulation of biological functions through the miR-532-3P/FOXO4 axis in the CRC. Hsa_circRNA_103809 may be a potential novel gene target for the diagnosis and treatment of CRC. PMID- 30249395 TI - Hydroxysafflor yellow A attenuates high glucose-induced pancreatic beta-cells oxidative damage via inhibiting JNK/c-jun signaling pathway. AB - Pancreatic beta-cells apoptosis and dysfunction induced by glucose toxicity were attributed to the formation of excess oxidative damage. Some studies have found that hydroxysafflor yellow A has strong effects to scavenge oxidative stress and inhibit apoptosis. In order to explore the influence of HSYA on oxidative stress induced by high glucose and the potential mechanisms, we set up a high glucose damage model and induced oxidative stress in INS-1 rat insulinoma cells. N acetylcysteine was added as a group of oxidative stress scavenger. After 72 h of cultivation, the related indexes of oxidative stress (reactive oxygen species, catalase, glutathione peroxidase, lipid peroxidation, and superoxide dismutase), apoptosis (caspase3, parp) and the function of glucose stimulated insulin secretion were determined. In addition, the signaling pathway proteins of C-Jun NH2 -terminal kinases (JNK), phosphorylated JNK, C-jun, phosphorylated C-jun were evaluated. Fluorescence microscopy, qRT-PCR, western blotting were the main methods used in the experiment. Our results showed that hydroxysafflor yellow A reduced pancreatic beta-cells apoptosis by attenuating oxidative damage, and JNK/c-Jun signaling pathway was involved. It indicated a significant mechanism for the positive impacts of HSYA on oxidative stress induced by high glucose, and provide important basis for using HSYA in diabetic prevention and therapy. PMID- 30249396 TI - Administration of ubiquitin-activating enzyme UBA1 inhibitor PYR-41 attenuates angiotensin II-induced cardiac remodeling in mice. AB - Pathological cardiac hypertrophy is the main risk factor for heart diseases. The ubiquitin-proteasome system (UPS) is the major intracellular protein degradation system involved in the development of cardiac hypertrophic remodeling. Ubiquitin activating enzyme E1, a key component of the UPS, catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation via proteasome. However, the functional role of E1 (UBA1) in regulation of hypertrophic remodeling in angiotensin II (Ang II)-infused mice remains unknown. In this study, male wild-type mice were treated with UBA1 inhibitor PYR-41 at two doses of 5 and 10 mg and infused with Ang II (1000 ng/kg/min) for 14 days. Systolic blood pressure was detected by using tail-cuff system. Cardiac function was assessed by echocardiography. Hypertrophic remodeling was analyzed examined by histological examinations. The expressions of genes and proteins were detected by quantitative real-time PCR and immunoblotting analysis. After 14 days, Ang II infusion significantly increased UBA1 expression at both mRNA and protein levels in the hearts. Furthermore, Ang II-infused mice showed a significant increase in systolic blood pressure compensatory cardiac function, hypertrophy, interstitial fibrosis, inflammation and oxidative stress compared with saline-treated controls, whereas these effects were dose-dependently attenuated in PYR-41 treated mice. These beneficial actions were associated mainly with inhibition of PTEN degradation and multiple downstream mediators (AKT, ERK1/2, STAT3, TGF beta/Smad2/3 and NF-kB(p65)). In conclusion, these results indicate that inhibition of UBA1 suppresses Ang II-induced hypertrophic remodeling, and suggest that administration of low dose PYR-41 may be a new potential therapeutic approach for treating hypertensive heart diseases. PMID- 30249397 TI - miR-20a inhibits the killing effect of natural killer cells to cervical cancer cells by downregulating RUNX1. AB - BACKGROUND: NK cells are presented in tumor microenvironments and acts as an essential defense line against multiple malignancies. Recently, miRNAs are reported to involve in the development of natural killer (NK) cells via negatively regulating gene expression. Here, we aim to explore the function and mechanism underlying how miR-20a modulated the killing effect of NK cells to cervical cancer cells. METHODS: Abundances of miR-20a and runt-related transcription factor 1 (RUNX1) in NK cells from cervical cancer patients and healthy donors were detected by qRT-PCR and western blot. The releases of IFN gamma and TNF-alpha were determined by ELISA. The cytotoxicity of NK cells against cervical cancer cells was measured by CytoTox 96 non-radioactive cytotoxicity assay. Luciferase reporter, western blot, and RNA immunoprecipitation (RIP) assays were performed to assess the interaction between miR-20a and RUNX1. RESULT: miR-20a was upregulated while RUNX1 was downregulated in NK cells from cervical cancer patients compared to healthy donors. IL-2 stimulated the releases of IFN-gamma and TNF-alpha, and the killing effect of NK cells to cervical cancer cells, which was overturned by miR-20a introduction. RUNX1 was identified to be a target of miR-20a. Restoration of RUNX1 abolished the inhibitory effects of miR-20a on the secretions of IFN-gamma and TNF-alpha, as well as the killing effect of NK cells to colorectal cancer cells. CONCLUSION: miR-20a attenuated the killing effect of NK cells to cervical cancer cells by directly targeting RUNX1. PMID- 30249398 TI - Nucleolar localization signal and histone methylation reader function is required for SPIN1 to promote rRNA gene expression. AB - Spindlin1 (SPIN1), a histone modification reader protein, was enriched in the cell nucleolus and facilitated rRNA expression. However, how SPIN1 localizes to the nucleolus and its functional role in rRNA gene expression remain unresolved. Here, we identified a nucleolar localization signal in the N-terminal region of SPIN1 that is essential for its enrichment and function in the nucleolus. We also discovered that, in addition to its H3K4me3 recognizing activity, the H3R8me2a recognizing capacity of SPIN1 is also indispensable for stimulating rRNA expression. Chromatin immunoprecipitation results indicated that SPIN1 is required for the association or assembly of selective factor 1 (SL1) complex, probably facilitating the initiation of rDNA transcription through its H3 K4me3 R8me2a reader function. PMID- 30249399 TI - Detecting phospholipase activity with the amphipathic lipid packing sensor motif of ArfGAP1. AB - The amphipathic lipid packing sensor (ALPS) motif of ArfGAP1 brings this GTPase activating protein to membranes of high curvature. Phospholipases are phospholipid-hydrolyzing enzymes that generate different lipid products that alter the lateral organization of membranes. Here, we evaluate by fluorescence microscopy how in-situ changes of membrane lipid composition driven by the activity of different phospholipases promotes the binding of ALPS. We show that the activity of phospholipase A2, phospholipase C and phospholipase D drastically enhances the binding of ALPS to the weakly-curved membrane of giant liposomes. Our results suggest that the enzymatic activity of phospholipases can modulate the ArfGAP1-mediated intracellular traffic and that amphiphilic peptides such as the ALPS motif can be used to study lipolytic activities at lipid membranes. PMID- 30249400 TI - Ca2+ and Myosin Cycle States Work as Allosteric Effectors of Troponin Activation. AB - In cardiac muscle, troponin (Tn) and tropomyosin inhibit actin and myosin interactions through the steric blocking of myosin binding to F-actin. Ca2+ binding to Tn C modulates this inhibition. Thin filaments become activated upon Ca2+ binding, which enables strong binding of myosin with a concomitant release of ATP hydrolysis products and level arm swinging responsible for force generation. Despite this level of description, the current cross-bridge cycle model does not fully define the structural events that take place within Tn during combinatorial myosin and Ca2+ interventions. Here, we studied conformational changes within Tn bound to F-actin and tropomyosin by fluorescence lifetime imaging combined with Forster resonance energy transfer. Fluorescent dye molecules covalently bound to the Tn C C-lobe and Tn I C-terminal domain report Ca2+- and myosin-induced activation of Tn. Reconstituted thin filaments were deposited on a myosin-coated surface similar to an in vitro motility assay setup without filament sliding involved. Under all the tested conditions, Ca2+ was responsible for the most significant changes in Tn activation. Rigor myosin activated Tn at subsaturated Ca2+ conditions but not to the degree seen in thin filaments with Ca2+. ATP-gamma-S did not affect Tn activation significantly; however, blebbistatin induced significant activation at subsaturating Ca2+ levels. The relation between the extent of Tn activation and its conformational flexibility suggests that active/inactive Tn states coexist in different proportions that depend on the combination of effectors. These results satisfy an allosteric activation model of the thin filament as a function of Ca2+ and the myosin catalytic cycle state. PMID- 30249401 TI - Mechanics of Virus-like Particles Labeled with Green Fluorescent Protein. AB - Nanoindentation with an atomic force microscope was used to investigate the mechanical properties of virus-like particles (VLPs) derived from the avian pathogen infectious bursal disease virus, in which the major capsid protein was modified by fusion with enhanced green fluorescent protein (EGFP). These VLPs assemble as ~70-nm-diameter T = 13 icosahedral capsids with large cargo space. The effect of the insertion of heterologous proteins in the capsid was characterized in the elastic regime, revealing that EGFP-labeled chimeric VLPs are more rigid than unmodified VLPs. In addition, nanoindentation measurements beyond the elastic regime allowed the determination of brittleness and rupture force limit. EGFP incorporation results in a complex shape of the indentation curve and lower critical indentation depth of the capsid, rendering more brittle particles as compared to unlabeled VLPs. These observations suggest the presence of a complex and more constrained network of interactions between EGFP and the capsid inner shell. These results highlight the effect of fluorescent protein insertion on the mechanical properties of these capsids. Because the physical properties of the viral capsid are connected to viral infectivity and VLP transport and disassembly, our results are relevant to design improved labeling strategies for fluorescence tracking in living cells. PMID- 30249403 TI - MicroRNAs: Novel Molecular Targets and Response Modulators of Statin Therapy. AB - Cardiovascular disease (CVD) is a major cause of death globally. Addressing cardiovascular risk factors, particularly dyslipidemia, represents the most robust clinical strategy towards reducing the CVD burden. Statins inhibit 3 hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and represent the main therapeutic approach for lowering cholesterol and reducing plaque formation/rupture. The protective effects of statins extend beyond lowering cholesterol. MicroRNAs (miRNAs or miRs), small noncoding regulatory RNAs, likely mediate the positive pleiotropic effects of statins via modulation of lipid metabolism, enhancement of endothelial function, inhibition of inflammation, improvement of plaque stability, and immune regulation. miRNAs are implicated in statin-related interindividual variations in therapeutic response, directly via HMG-CoA reductase, or indirectly through targeting cytochrome P450 3A (CYP3A) functionality and proprotein convertase subtilisin/kexin type9 (PCSK9) biology. PMID- 30249404 TI - Emergency Department Visits Within Thirty Days of Discharge After Primary Total Hip Arthroplasty: A Hidden Quality Measure. AB - BACKGROUND: Thirty-day hospital readmissions following total hip arthroplasty (THA) have received increasing scrutiny by policy makers and hospitals. Emergency department (ED) visits may not necessarily result in an inpatient readmission but can be a measure of performance and can incur costs to the health system. The purpose of this study is to describe the following: (1) the frequency and subsequent disposition; (2) patient characteristics; (3) reasons; and (4) potential risk factors for ED visits that did not result in a readmission within 30 days of discharge after THA. METHODS: All primary THAs performed at a large healthcare system between 2013 and 2015 were identified. Patients who received unplanned hospital services for complications within 30 days following surgery were identified and analyzed. A multiple regression analysis was utilized to identify risk factors predisposing for returning to the ED without readmission. RESULTS: From a total of 6270 primary THAs, 440 patients (7%) had an unplanned return to the hospital within 30 days. Of those, 227 (3.6%) patients presented to the ED and were not readmitted. Higher percentage of African Americans was noted among patients who returned to the ED versus those who did not (20.2% vs 9.8%, P < .01). The most common medical diagnoses were nonspecific medical symptoms (24.8%) followed by minor gastrointestinal problems (10.5%). The most common surgery-related diagnoses were pain and swelling (35%), followed by wound complications (12%) and hip dislocations (7.3%). Nearly 50% of wound complications and 40% of hip dislocations were managed and discharged from the ED without a readmission. Both African Americans (odds ratio 2.28, 95% confidence interval 1.55-3.36) and home discharge (odds ratio 1.90, 95% confidence interval 1.28-2.82) were independent risk factors for return to the ED without readmission. CONCLUSION: ED visits that do not result in hospital readmissions, many of which may be due to serious complications, are more frequent than inpatient readmission. This is extremely relevant to policy makers and quality metrics, especially as comprehensive and bundled payment initiatives become more prevalent. PMID- 30249402 TI - Insights into the Cooperative Nature of ATP Hydrolysis in Actin Filaments. AB - Actin filaments continually assemble and disassemble within a cell. Assembled filaments "age" as a bound nucleotide ATP within each actin subunit quickly hydrolyzes followed by a slower release of the phosphate Pi, leaving behind a bound ADP. This subtle change in nucleotide state of actin subunits affects filament rigidity as well as its interactions with binding partners. We present here a systematic multiscale ultra-coarse-graining approach that provides a computationally efficient way to simulate a long actin filament undergoing ATP hydrolysis and phosphate-release reactions while systematically taking into account available atomistic details. The slower conformational changes and their dependence on the chemical reactions are simulated with the ultra-coarse-graining model by assigning internal states to the coarse-grained sites. Each state is represented by a unique potential surface of a local heterogeneous elastic network. Internal states undergo stochastic transitions that are coupled to conformations of the underlying molecular system. The model reproduces mechanical properties of the filament and allows us to study whether conformational fluctuations in actin subunits produce cooperative filament aging. We find that the nucleotide states of neighboring subunits modulate the reaction kinetics, implying cooperativity in ATP hydrolysis and Pi release. We further systematically coarse grain the system into a Markov state model that incorporates assembly and disassembly, facilitating a direct comparison with previously published models. We find that cooperativity in ATP hydrolysis and Pi release significantly affects the filament growth dynamics only near the critical G-actin concentration, whereas far from it, both cooperative and random mechanisms show similar growth dynamics. In contrast, filament composition in terms of the bound nucleotide distribution varies significantly at all monomer concentrations studied. These results provide new insights, to our knowledge, into the cooperative nature of ATP hydrolysis and Pi release and the implications it has for actin filament properties, providing novel predictions for future experimental studies. PMID- 30249405 TI - No Difference in Total Episode-of-Care Cost Between Staged and Simultaneous Bilateral Total Joint Arthroplasty. AB - BACKGROUND: Due to concerns about higher complication rates, surgeons debate whether to perform simultaneous bilateral total joint arthroplasty (BTJA), particularly in the higher-risk Medicare population. Advances in pain management and rehabilitation protocols have called into question older studies that found an overall cost benefit for simultaneous procedures. The purpose of this study was to compare 90-day episode-of-care costs between staged and simultaneous BTJA among Medicare beneficiaries. METHODS: We retrospectively reviewed a consecutive series of 319 simultaneous primary TJAs and 168 staged TJAs (336 procedures) at our institution between 2015 and 2016. We recorded demographics, comorbidities, readmission rates, and 90-day episode-of-care costs based upon Centers for Medicare and Medicaid Services claims data. To control for confounding variables, we performed a multivariate regression analysis to identify independent risk factors for increased costs. RESULTS: Simultaneous patients had decreased inpatient facility costs ($19,402 vs $23,025, P < .001), increased post-acute care costs ($13,203 vs $10,115, P < .001), and no difference in total episode-of care costs ($35,666 vs $37,238, P = .541). Although there was no difference in readmissions (8% vs 9%, P = .961), simultaneous bilateral patients were more likely to experience a thromboembolic event (2% vs 0%, P = .003). When controlling for demographics, procedure, and comorbidities, a simultaneous surgery was not associated with an increase in episode-of-care costs (P = .544). Independent risk factors for increased episode-of-care costs following BTJA included age ($394 per year increase, P < .001), cardiac disease ($4877, P = .025), history of stroke ($14,295, P = .010), and liver disease ($12,515, P = .016). CONCLUSION: In the Medicare population, there is no difference in 90-day episode-of-care costs between simultaneous and staged BTJA. Surgeons should use caution in performing a simultaneous procedure on older patients or those with a history of stroke, cardiac, or liver disease. PMID- 30249406 TI - ECMO for all? Challenging traditional ECMO contraindications. PMID- 30249407 TI - Long-term neurodevelopmental outcome after perinatal arterial ischemic stroke and periventricular venous infarction. AB - BACKGROUND: Long-term follow-up data after different vascular types of ischemic perinatal stroke is sparse. Our aim was to study neurodevelopmental outcomes following neonatal and presumed perinatal ischemic middle cerebral artery territory stroke (arterial ischemic stroke, AIS) and periventricular venous infarction (PVI). METHODS: A prospective consecutive cohort of 40 term-born children with perinatal stroke (21 AIS, 19 PVI) was identified through the Estonian Paediatric Stroke Database. While 48% of the children with AIS were diagnosed during the neonatal period, all the children with PVI had presumed perinatal stroke. Outcomes based on the Paediatric Stroke Outcome Measure (PSOM) and Kaufman Assessment Battery for Children - Second Edition (K-ABC-II), in relation to extent and laterality of stroke, were defined. RESULTS: At a median age of 7 years 6 months (range 3.6-13y), there was a trend towards worse neurodevelopmental outcome in participants with AIS when compared to PVI (mean total PSOM scores 3.1 and 2.2, respectively; p = 0.06). Combined deficits of motor, language and cognitive/behavioural functions were significantly more common among children with AIS (90%) when compared to children with PVI (53%, p = 0.007). General cognitive ability (by K-ABC-II) was significantly lower in the AIS subgroup (mean 79.6; 95% CI 72.3-87.0), but children with PVI (91.6; 95% CI 85.5-97.8) also had poorer performance than the age-equivalent normative mean. Large extent of stroke was associated with poorer neurodevelopmental outcome and lower cognitive performance in children following AIS but not in PVI. CONCLUSION: In this national cohort, poor long-term neurodevelopmental outcome after perinatal ischemic stroke was seen irrespective of the vascular type or time of diagnosis of stroke. However, the spectrum of neurological deficits is different after perinatal AIS and PVI, with combined deficits more common among children following AIS. PMID- 30249408 TI - Gadolinium Deposition in the Brain: A Systematic Review of Existing Guidelines and Policy Statement Issued by the Canadian Association of Radiologists. AB - Emerging evidence has confirmed that, following administration of a gadolinium based contrast agent (GBCA), very small amounts of gadolinium will deposit in the brain of humans with intact blood-brain barriers. The literature is evolving rapidly and the degree to which gadolinium will deposit for a particular GBCA or class of GBCAs remains undetermined. Several studies suggest that linear GBCAs deposit more gadolinium in the brain compared with macrocyclic GBCAs; however, our understanding of the molecular composition of deposited gadolinium is preliminary, and the clinical significance of gadolinium deposition remains unknown. To date, there is no conclusive evidence linking gadolinium deposition in the brain with any adverse patient outcome. A panel of radiologists representing the Canadian Association of Radiologists was assembled to assist the Canadian medical imaging community in making informed decisions regarding the issue of gadolinium deposition in the brain. The objectives of the working group were: 1) to review the evidence from animal and human studies; 2) to systematically review existing guidelines and position statements issued by other organizations and health agencies; and 3) to formulate an evidence-based position statement on behalf of the Canadian Association of Radiologists. Based on our appraisal of the evidence and systematic review of 9 guidelines issued by other organizations, the working group established the following consensus statement. GBCA administration should be considered carefully with respect to potential risks and benefits, and only used when required. Standard dosing should be used and repeat administrations should be avoided unless necessary. Gadolinium deposition is one of several issues to consider when prescribing a particular GBCA. Currently there is insufficient evidence to recommend one class of GBCA over another. The panel considered it inappropriate to withhold a linear GBCA if a macrocyclic agent is unavailable, if hepatobiliary phase imaging is required, or if there is a history of severe allergic reaction to a macrocyclic GBCA. Further study in this area is required, and the evidence should be monitored regularly with policy statements updated accordingly. PMID- 30249409 TI - Radiation Dose Reduction With a Low-Tube Voltage Technique for Pediatric Chest Computed Tomographic Angiography Based on the Contrast-to-Noise Ratio Index. AB - INTRODUCTION: The aim of this study was to evaluate the radiation dose and image quality at low tube-voltage pediatric chest computed tomographic angiography (CTA) that applies the same contrast-to-noise ratio (CNR) index as the standard tube voltage technique. MATERIALS AND METHODS: Contrast-enhanced chest CTA scans of 100 infants were acquired on a 64-row multidetector computed tomography (MDCT) scanner. In the retrospective study, we evaluated 50 images acquired at 120 kVp; the image noise level was set at 25 Hounsfield units. In the prospective study, we used an 80-kVp protocol; the image noise level was 40 Hounsfield units because the iodine contrast was 1.6 times higher than on 120-kVp scans; the CNR was as in the 120-kVp protocol. We compared the CT number, image noise, CT dose index volume (CTDIvol), and the dose-length product on scans acquired with the 2 protocols. A diagnostic radiologist and a pediatric cardiologist visually evaluated all CTA images. RESULTS: The mean CTDIvol and the mean dose-length product were 0.5 mGy and 7.8 mGy-cm for 80- and 1.2 mGy and 20.8 mGy-cm for 120 kVp scans, respectively (P < .001). The mean CTDIvol was 42% lower at 80 kVp than at 120 kVp, and there was no significant difference in the visual scores assigned to the CTA images (P = .28). CONCLUSIONS: With the CNR index being the same at 80 kVp and 120-kVp imaging, the radiation dose delivered to infants subjected to chest CTA can be reduced without degradation of the image quality. PMID- 30249410 TI - Referral Patterns for Dual-Energy Computed Tomography in Diagnosis and Management of Gout: Ten-Year Experience at a Canadian Institution. AB - PURPOSE: To analyze the utilization, indications, and outcomes of dual-energy computed tomography (DECT) gout imaging in clinical practice. METHODS: This retrospective study was ethics approved. Radiology reports of DECT gout scans between 2007 and 2016 were analyzed for trends of utilization, referral pattern, indication, and diagnosis. RESULTS: DECT gout referrals increased substantially (2007: 37; 2008: 72; 2016: 385; total: 1877). The largest number of referrals were from rheumatology (1160), emergency medicine (283), and family medicine (177). Most referrals (92%) were requested to aid an initial diagnosis of gout. Other reasons included estimating the disease burden (6%) or monitoring disease progression and effectiveness of treatment (2%). Rheumatology accounted for most referrals for the latter two reasons (81% and 97%). Imaging findings of urate presence were similar in referrals from rheumatology (62%), family medicine (62%), and other medical specialties (62%). The urate positive rates were slightly lower in referrals from emergency medicine (47%) and surgical specialties (41%). The most common differential diagnoses by referring specialties were calcium pyrophosphate dihydrate crystal deposition disease (CPPD) and other inflammatory or erosive arthritides (rheumatology, family medicine), CPPD and infections (other medical specialties), infections and fractures (emergency medicine), neoplasm and infections (surgical specialties). CONCLUSIONS: The increasing utilization of DECT for gout imaging validates its clinical value. Varying clinical presentation could explain differences of urate positive rates among specialties. Our results support a multispecialty collaborative approach to the diagnosis and management of gout, with direct access to DECT gout imaging provided to various physician specialties. PMID- 30249411 TI - Phosphorylation meets DNA mismatch repair. AB - DNA mismatch repair (MMR) is a highly conserved process and ensures the removal of mispaired DNA bases and insertion-deletion loops right after replication. For this, a MutSalpha or MutSbeta protein complex recognizes the DNA damage, MutLalpha nicks the erroneous strand, exonuclease 1 removes the wrong nucleotides, DNA polymerase delta refills the gap and DNA ligase I joins the fragments to seal the nicks and complete the repair process. The failure to accomplish these functions is associated with higher mutation rates and may lead to cancer, which highlights the importance of MMR by the maintenance of genomic stability. The post-replicative MMR implies that involved proteins are regulated at several levels, including posttranslational modifications (PTMs). Phosphorylation is one of the most common and major PTMs. Suitable with its regulatory force phosphorylation was shown to influence MMR factors thereby adjusting eukaryotic MMR activity. In this review, we summarized the current knowledge of the role of phosphorylation of MMR process involved proteins and their functional relevance. PMID- 30249412 TI - The hidden face of Wilson's disease. AB - In brief, the classic form of Wilson's disease (WD) is an autosomal-recessive condition with hepatic, neurologic, psychiatric and systemic manifestations. However, the diagnosis should not be excluded because of a family history consistent with autosomal-dominant transmission. The latest next-generation sequencing (NGS) studies have demonstrated a gap between phenotype and genetic prevalences, and also suggest that WD may still be underdiagnosed. In a majority of WD patients, early recognition and appropriate treatment can result in resolution of symptoms and/or improved quality of life. Thus, finding WD in patients aged>40 years or with thrombocytopenia, hemolytic anemia, unexplained bone pain, amenorrhea, repeated spontaneous abortion or renal lithiasis is of major importance. These symptoms can all be found on their own or in association with mild-to-incapacitating neurological and/or neuropsychiatric manifestations. While brain lesions of the lenticular, midbrain and dentate nuclei are classic, white-matter changes and cortical lesions may also be observed: these are often asymmetrical with frontal lobe predilection and, when extensive, associated with a poor prognosis. These lesions are due mainly to copper deposition, but may also be related to focal accumulation of other metals, such as iron and manganese. A new biological marker called 'relative exchangeable copper' (REC) facilitates diagnosis and familial screening. Patient monitoring is important to ensure treatment adherence, efficacy and tolerability, and to detect rare complications such as copper deficiency induced by chronic copper chelation and hepatocarcinoma in patients with cirrhosis. Currently used treatments are copper chelators and zinc salts. Therapeutic perspectives are liver transplantation, new copper chelators as tetrathiomolybdate, hepatocyte/tissue transfer and gene therapy. PMID- 30249414 TI - Factors related to patient propensity to receive adjuvant chemotherapy and outcomes in stage III gastric cancer cases after D2 surgery. AB - BACKGROUND: Radical gastrectomy and extended lymph node (D2) dissection followed by adjuvant chemotherapy is the optimal treatment for patients with stage III gastric cancer in Asian population. The clinical factors associated with patient propensity to receive adjuvant chemotherapy and outcomes were analyzed. METHODS: In total, 509 patients with stage III gastric cancer who had undergone D2 surgery between 2007 and 2017 at a single medical center in Taiwan were analyzed. The patients' preoperative clinical characteristics relevant to adjuvant chemotherapy adherence were analyzed using multivariate regression. Significant variables were analyzed using recursive partitioning analysis (RPA) for identifying specific patient groups with the lowest and highest probabilities of adjuvant chemotherapy adherence. RESULTS: After surgery, 361 (70.9%) patients in the cohort had received adjuvant chemotherapy. All patients were categorized into five probability groups with adherence to adjuvant chemotherapy according to age, Eastern Cooperative Oncology Group (ECOG) performance status grade, and American Society of Anesthesiologists (ASA) class, which were discovered to be independent factors in the RPA-based probability prediction. In general, adjuvant chemotherapy improved survival across broad categories of stage III gastric cancer patients (overall survival hazard ratio: 0.53-0.75 and disease-free survival hazard ratio: 0.47-0.76). CONCLUSIONS: Our study identified that age, ECOG grade, and ASA class were independent clinical factors associated with patient propensity to receive adjuvant chemotherapy in stage III gastric cancer. Knowledge of the clinical factors of patients may help clinicians identify and encourage specific patients to receive the adjuvant chemotherapy. PMID- 30249415 TI - Role of cell-secreted extracellular matrix formation in aggregate formation and stability of human induced pluripotent stem cells in suspension culture. AB - Clinical and industrial applications require large quantities of human induced pluripotent stem cells (hiPSCs); however, little is known regarding the mechanisms governing aggregate formation and stability in suspension culture. To address this, we determined differences in growth processes among hiPSC lines in suspension culture. Using an hiPSC aggregate suspension culture system, hiPSCs from different lines formed multicellular aggregates classified as large compact or small loose based on their size and morphology. Time-lapse observation of the growth processes of two different hiPSC lines revealed that the balance between cell division and the extent of subsequent cell death determined the final size and morphology of aggregates. Comparison of the cell survival and death of two hiPSC lines showed that the formation of small, loose aggregates was due to continued cell death during the exponential phase of growth, with apoptotic cells extruded from growing hiPSC aggregates by the concerted contraction of their neighbors. Western blot and immunofluorescent staining revealed that aggregate morphology and proliferative ability relied to a considerable extent upon secretion of the extracellular matrix (ECM). hiPSCs forming large compact and stable aggregates showed enhanced production of collagen type I in suspension culture at 120 h. Furthermore, these aggregates exhibited higher expression of E cadherin and proliferation marker Ki-67 as compared with levels observed in small and loose aggregates at 120 h. These findings indicated that differences in both aggregate formation and stability in suspension culture among hiPSC lines were caused by differences in ECM secretion capacity. PMID- 30249413 TI - Development of the human penis and clitoris. AB - The human penis and clitoris develop from the ambisexual genital tubercle. To compare and contrast the development of human penis and clitoris, we used macroscopic photography, optical projection tomography, light sheet microscopy, scanning electron microscopy, histology and immunohistochemistry. The human genital tubercle differentiates into a penis under the influence of androgens forming a tubular urethra that develops by canalization of the urethral plate to form a wide diamond-shaped urethral groove (opening zipper) whose edges (urethral folds) fuse in the midline (closing zipper). In contrast, in females, without the influence of androgens, the vestibular plate (homologue of the urethral plate) undergoes canalization to form a wide vestibular groove whose edges (vestibular folds) remain unfused, ultimately forming the labia minora defining the vaginal vestibule. The neurovascular anatomy is similar in both the developing human penis and clitoris and is the key to successful surgical reconstructions. PMID- 30249416 TI - Randomized controlled trial of transcranial magnetic stimulation in pregnant women with major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) affects 10% of pregnancies. Because transcranial magnetic stimulation (TMS) is a nonmedication option, psychiatric patients who do not tolerate or prefer to avoid antidepressants are good candidates for TMS. METHOD: In a randomized controlled trial of twenty-two women with MDD in the second or third trimester of pregnancy, subjects were randomized to active TMS (n=11) or sham TMS (n=11). This study took place at a single academic center. Subjects received 20 sessions of TMS to the right dorsolateral prefrontal cortex at 1 Hz as a single train of 900 pulses per session at 100% motor threshold. Estradiol and progesterone and were measured before session 1 and after session 20. RESULTS: Results demonstrated significantly decreased Hamilton Depression Rating Scale (HDRS-17) scores for the active compared to the sham group (p=0.003). Response rates were 81.82% for the active and 45.45% for the sham coil (p=0.088). Remission rates were 27.27% for the active 18.18% for the sham coil (p=0.613). Late preterm birth (PTB) occurred in three women receiving active TMS. All other maternal and delivery outcomes were normal. CONCLUSIONS: Right-sided, low frequency TMS was effective in reducing depressive symptoms in this sample of pregnant women. There may be a possibility that TMS is associated with late PTB although a larger sample size would be needed for adequate power to detect a true difference between groups. This study demonstrated that TMS is low risk during pregnancy although larger trials would provide more information about the efficacy and safety of TMS in this population. This trial shows that an RCT of a biologic intervention in pregnant women with psychiatric illness can be conducted. PMID- 30249418 TI - Retraction notice to "Correlations between peroxisome proliferator activator receptor gamma, Cystatin C, or advanced oxidation protein product, and atherosclerosis in diabetes patients" [Pathology - Research and Practice 211/3 (2014) 235-239]. PMID- 30249417 TI - Neurostimulation in tardive dystonia/dyskinesia: A delayed start, sham stimulation-controlled randomized trial. AB - INTRODUCTION: Growing evidence suggests that pallidal deep brain stimulation represents a potential new therapeutic avenue in tardive dystonia/dyskinesia, but controlled and blinded randomized studies (RCT) are missing. The present RCT compares dystonia/dyskinesia severity of pallidal neurostimulation in patients with tardive dystonia using a delayed-start design paradigm. METHODS: Dystonia/dyskinesia severity was assessed via blinded videos following pallidal neurostimulation at 3 (blinded phase) and 6 months (open extension phase). Primary endpoint was the percentage change of dystonia severity (Burke-Fahn Marsden-Dystonia-Rating-Scale, BFMDRS) at 3 months between active vs. sham neurostimulation using blinded-video assessment. Secondary endpoints comprised clinical rating scores for movement disorders. Clinicaltrials.gov NCT00331669. RESULTS: Twenty-five patients were randomized (1:1) to active (n = 12) or sham neurostimulation (n = 13). In the intention-to-treat analyses the between group difference of dystonia severity (BFMDRS) between active vs. sham stimulation was not significant at 3 months. Three months post-randomisation dystonia severity improved significantly within the neurostimulation by 22.8% and non-significantly within the sham group (12.0%) compared to their respective baseline severity. During the open-label extension with both groups being actively treated, significant and pronounced improvements of 41.5% were observed via blinded evaluation. Adverse events (n = 10) occurred in 10/25 of patients during the 6 months, mostly related to surgical implantation of the device; all resolved without sequelae. CONCLUSION: The primary endpoint of this randomized trial was not significant, most likely due to incomplete recruitment. However, pronounced improvements of most secondary endpoints at 3 and 6 months provide evidence for efficacy and safety of pallidal neurostimulation in tardive dystonia. PMID- 30249419 TI - Urine Sediment Examination in the Diagnosis and Management of Kidney Disease: Core Curriculum 2019. AB - Automated urine technology and centralized laboratory testing are becoming the standard for providing urinalysis data to clinicians, including nephrologists. This trend has had the unintended consequence of making examination of urine sediment by nephrologists a relatively rare event. In addition, the nephrology community appears to have lost interest in and forgotten the utility of provider performed urine microscopy. However, it is critical to remember that urine sediment examination remains a time-honored test that provides a wealth of information about the patient's underlying kidney disease. This test performs very favorably as a urinary "biomarker" for a number of acute kidney diseases. When used properly, urine sediment findings alert health care providers to the presence of kidney disease, while also providing diagnostic information that often identifies the compartment of kidney injury. Urine sediment findings may also guide therapy and assist in prognostication. In this review of the role of urine sediment examination in the diagnosis and management of kidney disease, we seek to help experienced nephrologists maintain their competency in performing this test and encourage ongoing training of nephrology fellows and others less experienced in such analyses. PMID- 30249420 TI - Using All Longitudinal Data to Define Time to Specified Percentages of Estimated GFR Decline: A Simulation Study. AB - RATIONALE & OBJECTIVE: The standard method to calculate time to the event of a specified percentage decline in estimated glomerular filtration rate (eGFR) uses 2 eGFR assessments, 1 at baseline and 1 at the event time. However, event times may be inaccurate due to eGFR variability and restriction of events to study visit times. We propose a novel method for calculating time to a specified percentage decline in eGFR that uses all available longitudinal eGFR assessments. STUDY DESIGN: Simulation study and comparison of methods in 2 observational cohorts. SETTINGS & PARTICIPANTS: Simulation data and study participants in the Nephrotic Syndrome Study Network (NEPTUNE) and Clinical Phenotyping and Resource Biobank Core (C-PROBE). EXPOSURE: Analytical method for calculating time to a specified percentage decline in eGFR: standard 2-point method versus a regression method incorporating all available longitudinally assessed eGFR assessments. OUTCOME: Time to percentage decline in eGFR. ANALYTIC APPROACH: A 2-point method used only the baseline eGFR and first eGFR below the decline threshold. The comparison method used ordinary linear regression incorporating all longitudinal eGFR assessments to define the baseline measure and 40% decline threshold. Time to a 40% decline in eGFR was defined as the time when the regression line crossed the decline threshold. The 2 outcome calculation methods were compared using simulations to assess the accuracy of estimated event times and power to detect event time differences between groups. Comparison of event times calculated using each method was also implemented using data from NEPTUNE and C-PROBE. RESULTS: The regression method incorporating all eGFR assessments was more accurate than the 2-point method in estimating event times in simulation analyses, particularly when eGFR variability was high, there was a greater correlation among successive eGFR values, or there were more missing data. This method was also more powerful in detecting differences between groups. Using NEPTUNE and C-PROBE data, the standard method estimated a more rapid rate of events, some likely representing transient reductions in kidney function, and was less likely to give accurate estimates in the presence of nonlinear eGFR trajectories. LIMITATIONS: Computations required for our proposed method currently limit its use to research rather than clinical applications. CONCLUSIONS: A regression method using all longitudinal eGFR values to estimate time to a percentage decline in eGFR increases accuracy and power over traditional methods, representing a potential improvement in the ability to discover treatment or biomarker effects on kidney disease progression. PMID- 30249421 TI - Introduction to the Special Section: Applications/Implications of the National Institute of Mental Health Research Domain Criteria for Conceptualizing, Assessing, and Treating Mental Disorders in Youth. PMID- 30249422 TI - The concept of severe hypertriglyceridemia and its implications in clinical practice. PMID- 30249423 TI - Effectiveness of varying number of doses and timing between doses of quadrivalent HPV vaccine against severe cervical lesions. AB - BACKGROUND: Based on immunogenicity studies, a 2 dose HPV vaccination-schedule was recently recommended for girls younger than 15 years. We aimed to investigate the effectiveness of quadrivalent HPV (qHPV) vaccination against CIN2 or worse (CIN2+), by age at vaccination, number of doses, and to test whether optimal timing of 2 doses of qHPV vaccine can confer the same level of protection as the originally recommended three dose-schedule. METHODS: A population-based cohort of all women aged 13-30 years, living in Denmark or Sweden during 2006-2013, was followed for qHPV vaccination status and first occurrence of CIN2+. RESULTS: The study cohort comprised 2,253,561 women, of which 33% were vaccinated during follow-up, and 1.7% were diagnosed with CIN2+. Vaccination at ages 13-16 and 17 19 was associated with a reduced risk of CIN2+ after 3 doses (IRR = 0.23, 95% CI 0.11-0.49, and IRR = 0.65, 95% CI 0.41-1.03, respectively), compared to being unvaccinated. After 1 and 2 doses there was a reduced risk, but not statistically significant. Women vaccinated ages 13-16 with 2 doses, where time between first and second dose was 5 months or longer showed no difference in risk compared to 3 doses. CONCLUSIONS: Women vaccinated with 3 doses of qHPV showed a reduced risk of CIN2+ if they were vaccinated before age 20, with a further reduced risk if vaccinated before age 17. Vaccination with 2 doses, with the second dose 5 months or longer after the first dose, did not yield an increased risk of CIN2+, compared to 3 doses. PMID- 30249424 TI - Safety and immunogenicity of inactivated poliovirus vaccine made from Sabin strains: A phase II, randomized, dose-finding trial. AB - BACKGROUND: In order to completely eradicate polio caused by wild poliovirus infection as well as vaccine-associated paralytic polio (VAPP), Sabin inactivated poliovirus vaccine (sIPV) should be developed to meet the requirements for biosafety and affordable strategy in the developing countries. METHOD: A randomized, double-blinded clinical trial was conducted to compare the immunogenicity and safety among infants aged 2 months (60-90 days) receiving five different vaccination regimens: the test groups (A, B, and C) received three doses of sIPV with high, medium, and low D antigen content, respectively, on the month 0, 1, 2 schedule; two control groups (D and E) received three doses of conventional IPV (cIPV) or sIPV (CAMS), respectively, on the same schedule as that of test groups. Serum samples were collected immediately before the 1st dose and 30 days after the 3rd dose vaccination to assess the immunogenicity. Adverse events occurring within 30 days after each dose were collected to assess the safety. RESULTS: After three doses, seroconversion rates in groups A-E were 100%, 98.2%, 100%, 100%, and 100%, respectively, for type 1; 99.1%, 100%, 98.1%, 100%, and 97.1%, respectively, for type 2; and 100%, 100%, 100%, 100%, and 99.0%, respectively, for type 3. The seropositive rates (>=1:8) of groups A-E for all types were nearly 100%. The GMTs in the target dose group (group B) were 4635, 342, and 2218 for type 1-3, respectively. The most common injection-site and systemic adverse reactions were swelling and fever respectively. The swelling (4.2%, P = 0.0075) and fever (58.3%, P = 0.0188) frequency of group A were statistically significantly higher than any other groups. CONCLUSION: The test sIPV generally demonstrated good safety and immunogenicity. The medium-D antigen dose would be a preferred choice for the further phase III clinical trial in consideration of its high immunogenicity for all serotypes and the satisfying tolerance. CLINICAL TRIALS REGISTRATION: NCT02985320. PMID- 30249425 TI - Cost of herpes zoster and herpes zoster-related complications among immunocompromised individuals. AB - Herpes zoster (HZ) is a painful dermatomal rash caused by reactivation of latent varicella-zoster virus. The incidence of HZ is increased for immunocompromised (IC) individuals. The objective of this study is to assess the healthcare costs incurred by IC individuals who develop HZ with or without associated complications. We conducted a retrospective case-control study across the US over a 5-year period, based on health insurance claims data for individuals aged >=50 years identified as IC by disease or immunosuppressive treatment. A cohort of 30,107 IC individuals who experienced HZ was matched to a cohort of 113,875 IC individuals without HZ. Average all-cause healthcare costs over 18 months were calculated and compared between IC individuals with and without HZ. In addition, the costs of HZ in IC individuals with HZ-related complications were compared to the costs of those with uncomplicated HZ. During the year following HZ onset, IC individuals with HZ had on average total unadjusted costs that were US$3879 higher than the controls. After adjusting costs, controlling for comorbidities and healthcare costs before the onset of HZ, the average annual costs for HZ cases and controls without HZ were similar. HZ-related complications led to increases in average adjusted annual costs compared to uncomplicated HZ ranging from US$612 for eye complications to US$4535 for neurologic complications. In conclusion, in IC individuals, episodes of HZ lead to substantially increased unadjusted annual healthcare costs. HZ-related complications add considerably to adjusted annual healthcare costs compared to uncomplicated HZ. PMID- 30249426 TI - The impact of family centred care interventions in a neonatal or paediatric intensive care unit on parents' satisfaction and length of stay: A systematic review. AB - OBJECTIVE: To explore the impact of family centred care interventions on parents' satisfaction and length of stay for patients admitted to a paediatric intensive care unit or a neonatal intensive care unit. METHODS: A systematic review was conducted. Searches have been done in Cinahl, Cochrane, Embase and PubMed from February 2016 till October 2017. All included studies were quality appraised. Due to the heterogeneity of interventions findings were narratively reviewed. RESULTS: Seventeen studies were included in this review of which 12/17 studies investigated parents' satisfaction and 7/17 length of stay. For this review two types of interventions were found. Interventions improving parents-professional collaboration which increased parents' satisfaction, and interventions improving parents' involvement which decreased length of stay. Overall quality of the included studies was weak to good. CONCLUSIONS: Strong evidence was found for a significant decrease in length of stay when parents where participating in caring for their infant in a neonatal intensive care unit. Moderate evidence was found in parents' satisfaction, which increased when collaboration between parents and professionals at a neonatal intensive care unit improved. Studies performed in a paediatric intensive care setting were of weak to moderate quality and too few to show evidence regarding parents satisfaction and length of stay. PMID- 30249428 TI - Stoma without rod (or stoma with spur). PMID- 30249427 TI - The impact of bilingualism on brain structure and function in Huntington's disease. AB - INTRODUCTION: Bilingualism exerts neuroprotective effects against neurodegeneration. In Huntington's disease (HD), the systems involved in bilingual control show early compromise, but the effect of bilingualism on the course of HD is unknown. METHODS: We addressed the impact of livelong use of bilingualism on the clinical features, brain structure and function in 30 early mild stage HD patients. Using voxel-wise regression analysis, we explored the effect of levels of use of bilingualism on grey-matter volume (GMV) and 18F-FDG metabolism. RESULTS: Higher use of bilingualism was associated with better performance in inhibitory control and set-shifting independently of age and education and with higher GMV in the inferior frontal gyrus. 18F-FDG data revealed a significant effect on multiple fronto-temporal regions, specifically, in the dorsal anterior cingulate cortex, the anterior insula, the ventromedial orbital prefrontal cortex and the inferior frontal gyrus. These changes contributed to better inhibitory control and set-shifting and to more preserved motor and functional capacity. CONCLUSION: In HD, lifelong use of bilingualism is associated with structural and metabolic brain changes that have an impact on cognition, movement and functionality. These findings highlight the importance of stimulating cognitive and brain reserve in HD and in other neurodegenerative conditions. PMID- 30249429 TI - Chronic radiation enteritis. AB - Radiation enteritis is an iatrogenic disease of the intestines caused by radiation therapy. Two entities, chronic and acute radiation enteritis, are described. The acute symptoms (abdominal pain, loss of appetite, diarrhea) develop within the first hours or days after radiation therapy and can be treated medically. Chronic radiation enteritis leads to a chronic sub-obstructive and/or malabsorption syndrome developing at least two months after the end of radiation therapy. Cases occurring 30 post-radiation are reported. Treatment is surgical with extended resection of all involved elements of the digestive tract and ileocolonic anastomosis in healthy zones. The diagnosis is confirmed by the anatomopathology report of fibrous intestinal lesions associated with obliterating arterial lesions. PMID- 30249430 TI - Pneumatosis cystoides intestinalis: Not uncommon cause of free air in acute abdomen. AB - Pneumatosis cystoides intestinalis is generally benign in course and sometimes, if cysts ruptured, behave as the not uncommon cause of free air in acute abdomen. In our case, we illustrate ruptured isolated cysts of pneumatosis cystoides intestinalis are responsible for pneumoperitoneum in a 94-year-old male patient. Laparotomy with gastrotomy for decompression of intraluminal aeropressure was performed, with an uneventful recovery. This paper presents with preoperative and intraoperative images of high educational value for this, often underdiagnosed, clinical entity. PMID- 30249431 TI - USAID: Current support for global surgery and implications of reform. PMID- 30249432 TI - Should the duration of primary hyperparathyroidism impact guidelines for evaluation and treatment? PMID- 30249433 TI - Hepatic regeneration by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is feasible but attenuated in rat liver with thioacetamide-induced fibrosis. AB - BACKGROUND: The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure promotes the proliferation of the future liver remnant, but evidence to support the feasibility of ALPPS in livers with fibrosis is needed. Therefore the aim of this study was to establish a fibrotic ALPPS model in the rat to compare the capacity of regeneration in the remnant liver with or without fibrosis. METHODS: In our study we first established a thioacetamide-induced fibrotic ALPPS model in rats. Then the ALPPS-induced regenerative capacities of normal and fibrotic liver were compared in this animal model. In addition, markers of regeneration, including the proliferative index and cyclin D1 and proliferating cell nuclear antigen levels, as well as various indicators of liver function were determined to evaluate the quality of the hepatic regeneration. RESULTS: Compared with that of the sham group (opening of the peritoneal cavity with no further operative manipulation), the proliferation of the future liver remnant in fibrotic rat liver after the ALPPS procedure was increased on postoperative days 1, 2, and 5 (P < .039 each). In addition, the proliferative response was greater in the ALPPS group than in the ligation group subjected only to portal vein ligation of the left lateral, left middle, right, and caudate lobes (P = .099, P = .006, and P = .020 on postoperative days 1, 2, and 5, respectively). In contrast, the ALPPS-induced regenerative capacity in the fibrotic rat livers was attenuated compared with that in the normal liver on postoperative days 1, 2, and 5 (P < .031 for each) after stage I and on postoperative day 5 after stage II of the ALPPS procedure (P < .005). This attenuated the recovery of liver function, and the greater mortality rate indicated that functional proliferation was either delayed or not as extensive in the fibrotic rat livers. CONCLUSION: Through establishing a rat model of thioacetamide-induced liver fibrosis, we found that ALPPS-derived liver regeneration was present and feasible in fibrotic livers, but this effect was attenuated compared with that in normal liver. PMID- 30249434 TI - Factors predicting outcome after anterior neurectomy in patients with chronic abdominal pain due to anterior cutaneous nerve entrapment syndrome (ACNES). AB - BACKGROUND: Chronic abdominal pain due to anterior cutaneous nerve entrapment syndrome may require surgery to provide long-term pain relief in up to 70% of patients. Factors predicting outcome after an anterior neurectomy are unknown. The aim of the study is to identify factors associated with treatment failure to possibly allow for optimizing patient counselling and selection. METHODS: Characteristics of anterior cutaneous nerve entrapment syndrome patients who were unresponsive to nonsurgical therapies and underwent an anterior neurectomy in a tertiary referral center from 2011 to 2016 were analyzed. Treatment failure was defined as <50% pain reduction using a numeric pain rating scale (numeric pain rating score 0-10) approximately 2 months postoperatively. A prediction model based on a multivariate regression analysis was tested for its discriminative value. RESULTS: A total of 495 patients (78% female, median age 40 years, range 8 83) undergoing an anterior neurectomy were eligible for analysis. Pain medication use (odds ratio 1.84, P = .027, confidence interval 1.07-3.17), abdominal surgery in the past (odds ratio 1.85, P = .026, confidence interval 1.08-3.18), the presence of paravertebral tender points at exit points of intercostal nerves (odds ratio 2.58, P = .003, confidence interval 1.39-4.80), and failure to favorably respond to a diagnostic rectus sheath block (odds ratio 3.74, P = .000, confidence interval 3.74 - 7.10) were identified as factors predicting surgical failure. However, a prediction model including these 4 factors had poor accuracy with an area under the curve of 0.64 (confidence interval 0.58-0.70). CONCLUSION: The present study identified risk factors associated with treatment failure that are useful in counseling anterior cutaneous nerve entrapment syndrome patients prior to a surgical intervention. PMID- 30249435 TI - The effect of hospital clown nurse on children's compliance to burn dressing change. AB - BACKGROUND AND AIM: Pediatric burn injury is a traumatic experience which affects the child both physically and psychologically. Following the burn injury, repetitive dressing changes are one of the main problems, and to manage the level of distress caused this procedure, various distraction strategies are being used. However, the effect of hospital clown during burn dressing change among children has not been studied before. Therefore, the present study aimed to investigate the effect of hospital clown-nurse on children's compliance to burn dressing change. METHODS: This randomized controlled experimental study was conducted with 50 children between 3-7years. There were 25 children in the experimental group and 25 children in the control group. In the intervention group, clown-nurse accompanied the child during burn dressing change while the children in the control group received standard care without hospital clown. Children's behavioral reactions were observed during dressing change. CONCLUSIONS: Children in the intervention group had better compliance to burn dressing change, in other words, they cried and/or yelled less, they were more active, had better mood, better communication and interaction with the accompanying parent and the nurse. In addition, older children in the experimental group had better compliance to the burn dressing change. PMID- 30249436 TI - Chondroblastoma: An evaluation of the recurrences and functional outcomes following treatment. AB - OBJECTIVE: Chondroblastoma is a benign aggressive tumor which needs surgical treatment and has a recurrence rate up to 35%. Extended (aggressive) curettage is the mainstay of treatment and local adjuvants have been reported to decrease the recurrence rate. METHODS: The recurrence rates and the functional results of 14 patients who were treated in our institution and 2 other patients who were treated elsewhere between the years 2004-2016 were evaluated. Seventeen cases (13 male, 3 female; mean age: 17.1 [range: 13 to 32] years) who had been diagnosed, treated and followed up in our hospital between 2004 and 2016 were evaluated in terms of recurrence rates and functional outcomes. The average follow-up period was 41.6 (range: 12 to 132) months. RESULTS: Five cases of recurrence were observed. Two cases had undergone their primary treatment in another institution. Seven cases were performed curettage alone whereas nine others were administered adjuvant treatments. One of the five recurrence patients was advised to undergo disarticulation. Another was treated with curettage and grafting and the remaining three patients with curettage and cementing. No recurrence was observed in their follow-up period. Their mean MSTS score was 27.3 (range: 4 to 30) over a maximum of 30 points and their functional results were good. CONCLUSION: Chondroblastoma is a tumor with high recurrence rates in the post-treatment period. However, good functional outcomes can be achieved with early diagnosis and appropriate treatment even after recurrence. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 30249437 TI - Role of physical therapists in the weaning and extubation procedures of pediatric and neonatal intensive care units: a survey. AB - BACKGROUND: Weaning a patient from mechanical ventilation is a complex procedure that involves clinical and contextual aspects. Mechanical ventilation also depends on the characteristics of health professionals who work in intensive care. OBJECTIVE: This study described the organizational aspects associated with the physical therapist's performance in the weaning procedure from mechanical ventilation and extubation in neonatal, pediatric and mixed (neonatal and pediatric) intensive care units in Brazil. METHODS: In order to identify the existing intensive care units in Brazil, data from the National Health Facilities Census was used to enable the researchers to obtain information about registered units. A cross-sectional survey was carried out by sending an electronic questionnaire to 298 neonatal, pediatric and mixed intensive care units in Brazil. RESULTS: This study assessed questionnaires from 146 intensive care units (49.3% neonatal, 35.6% pediatric and 15.1% mixed). A total of 57.5% of these units applied mechanical ventilation weaning protocols, and a physical therapist frequently conducted this procedure (66.7%). However, the clinician responsible for conducting the weaning and deciding when to do extubation varied regardless of ICU patient age profile. Regardless of the type of hospital or the type of units, most of these had a dedicated physical therapist. However, physical therapy care 24h/7 days per week was predominantly in pediatric intensive care units (56.0%), and in public hospitals (45.9%). Moreover, when the physical therapist was available 24h/7 days per week, (s)he was responsible for the mechanical ventilation extubation decision and patients were successfully extubated on the first attempt. CONCLUSION: In this survey, intensive care units using physical therapy assistance 24h/7 days per week were associated with the use of a mechanical ventilation weaning protocol, an extubation decision and success commonly on the first attempt of extubation. PMID- 30249438 TI - Translation of the short version of the Smartphone Addiction Scale into Brazilian Portuguese: cross-cultural adaptation and testing of measurement properties. AB - BACKGROUND: Smartphone use has been constantly increasing. Smartphone addiction can lead to changes in the emotional state and musculoskeletal system of users. To identify smartphone addicts, the Smartphone Addiction Scale-Short Version was developed; however, this scale has not been translated into Brazilian Portuguese and tested for its measurement properties. OBJECTIVE: To translate and cross culturally adapt the Smartphone Addiction Scale-Short Version into Brazilian Portuguese; to assess the internal consistency, reliability and construct validity of the scale among university students. METHODS: The cross-cultural adaptation was performed following the guidelines for cross-cultural adaptation of self-report measures, and data were collected via online surveys administered to 59 university students over 18 years of age for test-retest. To test the measurement properties of the final version of the Smartphone Addiction Scale Short Version, a convenience sample including 130 university students was used. RESULTS: The Smartphone Addiction Scale-Short Version showed good reliability for test-retest scores (ICC3,1=0.82; 95% CI=0.70-0.89) and good internal consistency considering all 10 items (Cronbach's alpha=0.95). The construct validity was calculated comparing the Smartphone Addiction Scale-Short Version score to data from a questionnaire prepared by the authors of this study, including frequency per day (r=0.35; p<0.001), leisure time on the smartphone (r=0.33; p<0.001), and time working on the smartphone (r=0.18; p=0.04) that were significantly positively associated with higher Smartphone Addiction Scale-Short Version scores. The results show a high prevalence of smartphone addiction among university students (33.1%). CONCLUSION: It can be concluded that the Brazilian Portuguese version of the Smartphone Addiction Scale-Short Version is a reliable and valid tool for screening smartphone addiction in university students. PMID- 30249440 TI - Why Do We Need Yet Another Left Atrial Appendage Occluder Device? PMID- 30249439 TI - Percutaneous Left Atrial Appendage Closure With the Ultraseal Device: Insights From the Initial Multicenter Experience. AB - OBJECTIVES: This study sought to evaluate the feasibility, safety, and efficacy of the Ultraseal device for left atrial appendage closure (LAAC) (Cardia, Eagan, Minnesota) in patients with nonvalvular atrial fibrillation at high bleeding risk. BACKGROUND: The Ultraseal device is a novel bulb-and-sail designed LAAC device, with an articulating joint enabling conformability to heterogeneous angles and shapes of appendage anatomy. METHODS: This was a multicenter study including consecutive patients undergoing LAAC with the Ultraseal device at 15 Canadian and European sites. Periprocedural and follow-up events were systematically collected, and transesophageal echocardiography at 45 to 180 days post-procedure was routinely performed in all centers but 3. RESULTS: A total of 126 patients (mean age 75 +/- 8 years; mean CHA2DS2-VASc score 5 +/- 2; mean HAS BLED score 4 +/- 1) were included. The device was successfully implanted in 97% of patients. A major periprocedural adverse event occurred in 3 (2.4%) patients (clinically relevant pericardial effusion [n = 1], stroke [n = 1], device embolization [n = 1]). Ninety percent of patients were discharged on single or dual antiplatelet therapy. Follow-up transesophageal echocardiography was available in 89 (73%) patients, with no cases of large (>5 mm) residual leak and 5 (5.6%) cases of device-related thrombosis (all successfully treated with anticoagulation therapy). At a median follow-up of 6 (interquartile range: 3 to 10) months, the rates of stroke and transient ischemic attack were 0.8% and 0.8%, respectively, with no systemic emboli. None of the events occurred in patients with device-related thrombosis. CONCLUSIONS: In this initial multicenter experience, LAAC with the Ultraseal device was associated with a high implant success rate and a very low incidence of periprocedural complications. There were no late device-related clinical events and promising efficacy results were observed regarding thromboembolic prevention at midterm follow-up. Larger studies are further warranted to confirm the long-term safety and efficacy of this novel device. PMID- 30249441 TI - Multilayer Myocardial Mechanics in Genotype-Positive Left Ventricular Hypertrophy Negative Patients With Hypertrophic Cardiomyopathy. AB - It is unknown whether the presence of a sarcomeric mutation alone is sufficient to result in abnormal myocardial force generation, or whether additional changes in myocardial architecture (hypertrophy, disarray, and fibrosis) are required to impair systolic function. Speckle tracking echocardiography allows quantification of global strain/strain rates, twist, and dyssynchrony. In the present study we sought to further elucidate early abnormalities of myocardial mechanics in sarcomeric mutation carriers without evidence of clinical disease. Sixty genotype positive left ventricular hypertrophy-negative (G+left ventricular hypertrophy [LVH]-) patients and 60 normal controls were studied. Velocity vector imaging was applied retrospectively to echocardiographic images to quantify global longitudinal and circumferential strain/strain rate, and rotation parameters. The G+LVH- group demonstrated both smaller left ventricular diastolic cavity dimensions (4.5 +/- 0.6 cm vs 4.8 +/- 0.4 cm) and a higher LVEF (66 +/- 6% vs 60 +/- 5%) compared with controls. An increase in circumferential subendocardial systolic strain (-30 +/- 5 vs -27 +/- 3%) and both systolic and diastolic subendocardial strain rate was seen in the G+LVH- group. Peak rotation angles were higher at the base and apex, with an increase in total twist (9.0 +/- 3.8 vs 6.9 +/- 2.9). In the control group, global and average segmental strain were similar, suggesting no/minimal dyssynchrony (global mechanical synchrony index [GMSi] 0.97-0.98). In the G+LVH- group GMSi was significantly lower (subendocardial GMSi 0.95; subepicardial GMSi 0.60), suggesting increasing subendocardial to subepicardial dyssynchrony. In conclusion, utilizing multilayer strain analysis, we demonstrate that G+LVH- subjects have enhanced subendocardial systolic strain rate and twist, as well as mechanical dyssynchrony within the left ventricular myocardium. These results demonstrate that abnormalities in myocardial mechanics precede the development of clinical hypertrophy. PMID- 30249442 TI - Regular and irregular inflection in down syndrome - New evidence from German. AB - The study aims to explore whether regular inflectional morphology is affected in children/adolescents with Down syndrome (DS). German past participle forms were elicited for ten regular and ten irregular inflected verbs as well as for five novel verbs. Data were collected from a group of 21 monolingual German children and adolescents with DS (chronological age M = 11;03 years) and a group of 21 typically developing monolingual German children (chronological age M = 4;03 years) matched in chronological age to the nonverbal mental age of the DS group (mental age DS group M = 4;05 years). Data analysis indicated that eight children/adolescents with DS displayed a deficit in acquiring the regular participle marker -t and in applying it as default inflection in German participle formation. In contrast, a group of 13 individuals with DS performed similar to the typically developing control children. They had successfully acquired the regular participle affix -t and readily applied it as default inflection to produce participles for irregular verbs and novel verbs. The data indicate that the acquisition of regular inflectional morphology is not outside the scope of individuals with DS and succeeded in many affected individuals. However, a substantial number of individuals with DS displayed a selective deficit with regular default inflection. The occurrence of a selective deficit with regular default inflection in individuals with DS supports dualistic views to inflection, according to which two different cognitive components are involved in regular and irregular inflection that can be selectively affected in language disorders. PMID- 30249444 TI - Anesthesia Safety in Otolaryngology. AB - This article highlights the important relationship between the otolaryngologist and anesthesiologist, focusing on intraoperative patient safety for otolaryngologic surgery. In addition, consideration of preoperative history, physical examination, and potential postoperative complications helps guide the otolaryngologist and anesthesiologist in formulating an appropriate and collaborative management strategy. PMID- 30249445 TI - Patient Safety and Quality for Office-Based Procedures in Otolaryngology. AB - Office-based procedures have increased in frequency with the recent changes in the current health care climate prioritizing improved efficiency and greater value in the care that is delivered. This article focuses on patient safety and quality issues that are specific to procedures in the office setting of an Otolaryngologist. Specific topics are categorized into preprocedure planning, procedural execution, and postprocedure follow-up. Several best practice recommendations are included to promote and simplify the integration of these quality and safety measures into every office setting. PMID- 30249446 TI - Simulation Saves the Day (and Patient). AB - Surgeons can use simulation to improve the safety of the systems they work within, around, because of, and despite. Health care is a complex adaptive system that can never be completely knowable; simulation can expose aspects of patient care delivery that are not necessarily evident prospectively, during planning, or retrospectively, during investigations or audits. The constraints of patient care processes and adaptive capacity of health care providers may become most evident during simulations conducted "in situ" using real teams and real equipment, in actual patient care locations. PMID- 30249443 TI - Glucose and lipid-related biomarkers and the antidepressant response to infliximab in patients with treatment-resistant depression. AB - The tumor necrosis factor (TNF) antagonist infliximab was previously found to reduce depressive symptoms in patients with treatment-resistant major depression (TRD) who exhibited high baseline inflammation, as reflected by plasma C-reactive protein (CRP) >5 mg/L. Further predictors of antidepressant response to infliximab included differential expression of peripheral blood gene transcripts that were related not only to inflammation but also to glucose and lipid metabolism. To determine whether plasma biomarkers of glucose and lipid metabolism were similarly associated with antidepressant response to infliximab and with relevant gene transcripts, we measured concentrations of glucose, insulin, and protein hormones that regulate glucose homeostasis and metabolism (leptin, resistin, and adiponectin), as well as cholesterols, triglycerides, and non-esterified fatty acids (NEFA), in medically-stable TRD outpatients at baseline and 2 weeks after the first infusion of infliximab (n = 26) or placebo (n = 26). Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. We found that baseline cholesterol (total, low-density lipoprotein [LDL], and non-high-density lipoprotein [non-HDL]), triglycerides and NEFA were elevated in patients who exhibited an antidepressant response to infliximab (all p < 0.05) but not placebo (all p > 0.299). HDL and non-HDL cholesterol concentrations also correlated with two lipid-related gene transcripts that were predictive of antidepressant response (r = 0.33 to 0.39, p < 0.05). Although not associated with response to infliximab, resistin correlated with numerous glucose-related transcripts (r = -0.32 to 0.37, p < 0.05) and was higher at 2 weeks post-infusion in patients treated with infliximab compared to placebo (p = 0.028). Concentrations of cholesterol (total, LDL, HDL, non-HDL) were also lower at 2 weeks in patients treated with infliximab compared to placebo, but only in those patients with CRP >5 mg/L at baseline (all p < 0.05). These results are consistent with previous work showing that high inflammation in patients with depression is associated with metabolic alterations, which together predict response to both traditional and experimental antidepressant therapies. Additionally, our findings suggest a causal relationship between increased inflammation and high cholesterol in depression, as a single infusion of infliximab reduced cholesterol in TRD patients with high CRP compared to placebo. PMID- 30249447 TI - Understanding inter-organizational trust among integrated care service provider networks: A perspective on organizational asymmetries. AB - OBJECTIVE: To explore the factors that influence trust among the integrated healthcare service provider network in the context of seeking combined health and care services in the UK. DATA SOURCES/STUDY SETTING: Primary data were collected from three regional integrated care service provider networks from March 2016 to October 2017. STUDY DESIGN: Explorative qualitative study and inductive methods from emerging findings. DATA COLLECTION/EXTRACTION METHODS: We conducted qualitative semi-structured interviews in three care networks and collected organizational documents from local integration boards from 2016 to 2017. Thematic analysis was performed in three large care networks with hospital staff, local councils, integration boards, and community and voluntary organizations under the NHS England Better Care Fund. PRINCIPAL FINDINGS: Our findings reveal that trust among integrated care service provider networks is influenced by the following factors on various asymmetries: 1) recognition and knowledge asymmetries among care service partners of each other's skills, expertise and capabilities; 2) capacity and financial imbalances within the network; and 3) organizational differences in management, culture and attitudes toward change. CONCLUSION: There is a need to improve competence recognition and capacity imbalances and to foster open minds toward change within networks to build trust to overcome divisions and facilitate integrated services among health and care organizations. PMID- 30249448 TI - A new approach to preferred provider selection in health care. AB - In January 2015 Zilveren Kruis, the largest health insurer in The Netherlands, engaged in a new three-year, unlimited volume contract with five carefully selected providers of cataract surgery. Zilveren Kruis used a novel method, designed to identify the top expert providers in a certain discipline. This procedure for provider selection uses the principles of Best Value Procurement (BVP), and puts the provider in charge of defining key performance indicators for health care quality. The procedure empowers the professional and acknowledges that the provider, not the purchaser, is the true expert in defining what is high quality care. This new approach focuses purely on provider selection and is thus complementary to innovations in health care reimbursement, such as value-based hospital purchasing or outcome-based financing. We describe this novel approach to preferred provider selection and show how it makes affordable quality the core topic in negotiations with providers. PMID- 30249449 TI - An undetectable serum prealbumin measurement led to a diagnosis of monoclonal gammopathy: two cases of spurious results in the setting of paraproteinaemia. PMID- 30249450 TI - Interleukin-10 as a predictor of major adverse cardiovascular events in a racially and ethnically diverse population: Multi-Ethnic Study of Atherosclerosis. AB - PURPOSE: To understand if baseline levels of the anti-inflammatory cytokine interleukin-10 (IL-10) are associated with either subclinical atherosclerosis or risk for adverse cardiovascular (CV) events. METHODS: The study included 930 adults from the Multi-Ethnic Study of Atherosclerosis (MESA) ancillary Stress Study. Participants, age 48-90 years at enrollment, were followed for an average of 10.2 years. IL-10 level was measured at the initial Stress Study visit. Cardiovascular outcomes were defined as composite CV death, myocardial infarction, stroke, stroke death, and resuscitated cardiac arrest. Coronary calcification was determined by Agatston coronary artery calcium (CAC) score. The association between IL-10 level and CV event risk was evaluated by Cox proportional hazard modeling, while that of IL-10 level and CAC presence and amount was determined with prevalence risk ratio (PRR) and linear regression modeling, respectively. Models were adjusted for CV risk factors and proinflammatory biomarkers. RESULTS: After full adjustment, IL-10 level did not predict CV events (HR 1.19, 95%CI 0.89, 1.60) and was not associated with CAC prevalence (PRR 1.00, 95%CI 0.94, 1.07), nor amount of CAC in those with nonzero CAC (beta -0.01, 95%CI -0.23, 0.21). CONCLUSION: In individuals without clinical heart disease, baseline IL-10 level appears unrelated to risk of CV events and is a poor marker of subclinical coronary atherosclerosis. PMID- 30249451 TI - Anaphylaxis to beta-lactam antibiotics at pediatric age: Six-year survey. AB - INTRODUCTION: Beta-lactams are the most frequently used antibiotics in pediatric age. Anaphylactic reactions may occur and need to be properly studied, but studies in children are scarce. OBJECTIVE: Characterization of case reports of anaphylaxis in children referred to an allergy department with suspected beta lactams hypersensitivity. MATERIALS AND METHODS: Retrospective analysis of all children referred to our Drug Allergy Center with suspected beta-lactams hypersensitivity between January 2011 and December 2016. Description of the drug allergy work-up performed studied according to standardized diagnostic procedures of ENDA/EAACI, including specific-IgE assay, skin prick and intradermal tests and diagnostic/alternative drug challenge tests. RESULTS: 146 children with suspected beta-lactams hypersensitivity were studied, and in 21 (14.4%) the diagnosis was confirmed. In all of them, except for three children, an alternative beta-lactam was found. In seven children (33.3% of those with confirmed beta-lactams hypersensitivity) anaphylaxis was confirmed, and all of them described reactions with cutaneous and respiratory or gastrointestinal involvement. The culprit drug was amoxicillin in six and flucloxacillin in one. In this sample, we also performed oral challenge with cefuroxime, being negative in all cases. Almost all cases of confirmed anaphylaxis (six from seven cases) were IgE mediated, with positive skin tests despite negative serum specific-IgE. CONCLUSIONS: Allergic reactions to beta-lactams, although rare in children, require a detailed clinical history and a specialized drug allergy work-up to allow a correct diagnosis as well as to avoid the possibility of a potential life-threatening reaction and provide alternative drugs. PMID- 30249453 TI - Role of office hysteroscopic morcellation and 3-dimensional transvaginal ultrasound in conservative management of retained placenta accreta. PMID- 30249452 TI - CD8+ T cells modulate autosomal dominant polycystic kidney disease progression. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited nephropathy. To date, therapies alleviating the disease have largely focused on targeting abnormalities in renal epithelial cell signaling. ADPKD has many hallmarks of cancer, where targeting T cells has brought novel therapeutic interventions. However, little is known about the role and therapeutic potential of T cells in ADPKD. Here, we used an orthologous ADPKD model, Pkd1 p.R3277C (RC), to begin to define the role of T cells in disease progression. Using flow cytometry, we found progressive increases in renal CD8+ and CD4+ T cells, correlative with disease severity, but with selective activation of CD8+ T cells. By immunofluorescence, T cells specifically localized to cystic lesions and increased levels of T-cell recruiting chemokines (CXCL9/CXCL10) were detected by qPCR/in situ hybridization in the kidneys of mice, patients, and ADPKD epithelial cell lines. Importantly, immunodepletion of CD8+ T cells from one to three months in C57Bl/6 Pkd1RC/RC mice resulted in worsening of ADPKD pathology, decreased apoptosis, and increased proliferation compared to IgG-control, consistent with a reno-protective role of CD8+ T cells. Thus, our studies suggest a functional role for T cells, specifically CD8+ T cells, in ADPKD progression. Hence, targeting this pathway using immune-oncology agents may represent a novel therapeutic approach for ADPKD. PMID- 30249454 TI - [Unilateral congenital exophthalmia revealing an unusual complication of a vacuum extractor delivery (a case report)]. PMID- 30249455 TI - Seasonal ecology in ice-covered Arctic seas - Considerations for spill response decision making. AB - Due to retreating sea ice and predictions of undiscovered oil and gas resources, increased activity in Arctic shelf sea areas associated with shipping and oil and gas exploration is expected. Such activities may accidentally lead to oil spills in partly ice-covered ocean areas, which raises issues related to oil spill response. Net Environmental Benefit Analysis (NEBA) is the process that the response community uses to identify which combination of response strategies minimises the impact to environment and people. The vulnerability of Valued Ecosystem Components (VEC's) to oil pollution depends on their sensitivity to oil and the likelihood that they will be exposed to oil. As such, NEBA requires a good ecological knowledge base on biodiversity, species' distributions in time and space, and timing of ecological events. Biological resources found at interfaces (e.g., air/water, ice/water or water/coastline) are in general vulnerable because that is where oil can accumulate. Here, we summarize recent information about the seasonal, physical and ecological processes in Arctic waters and evaluate the importance these processes when considering in oil spill response decision making through NEBA. In spring-time, many boreal species conduct a lateral migration northwards in response to sea ice retraction and increased production associated with the spring bloom. However, many Arctic species, including fish, seabirds and marine mammals, are present in upper water layers in the Arctic throughout the year, and recent research has demonstrated that bioactivity during the Arctic winter is higher than previously assumed. Information on the seasonal presence/absence of less resilient VEC's such as marine mammals and sea birds in combination with the presence/absence of sea ice seems to be especially crucial to consider in a NEBA. In addition, quantification of the potential impact of different, realistic spill sizes on the energy cascade following the spring bloom at the ice-edge would provide important information for assessing ecosystem effects. PMID- 30249456 TI - How including ecological realism impacts the assessment of the environmental effect of oil spills at the population level: The application of matrix models for Arctic Calanus species. AB - For oil spill responses, assessment of the potential environmental exposure and impacts of a spill is crucial. Due to a lack of chronic toxicity data, acute data is used together with precautionary assumptions. The effect on the Arctic keystone (copepod) species Calanus hyperboreus and Calanus glacialis populations is compared using two approaches: a precautionary approach where all exposed individuals die above a defined threshold concentration and a refined (full-dose response) approach. For this purpose a matrix population model parameterised with data from the literature is used. Population effects of continuous exposures with varying durations were modelled on a range of concentrations. Just above the chronic No Observed Effect Concentration (which is field relevant) the estimated population recovery duration of the precautionary approach was more than 300 times that of the refined approach. With increasing exposure concentration and duration, the effect in the refined approach converges to the maximum effect assumed in the precautionary approach. PMID- 30249457 TI - Short-term variation of abundance of the purple sea urchin, Paracentrotus lividus (Lamarck, 1816), subject to harvesting in northern Portugal. AB - Paracentrotus lividus is a common and intensely harvested sea urchin at several European locations, including the Mediterranean Sea and the Atlantic coast of the Iberian Peninsula. The increasing human pressure on this resource due to the growing demand and market value of sea urchin gonads as seafood raises concerns on the ecological sustainability of present fisheries, which are showing a technological improvement and an expansion towards previously non-harvested areas. We examined the abundance of P. lividus of both commercial and non commercial size before, during and after the harvesting season (from October to April) in the rocky shallow subtidal habitat along the northern Portuguese coast. The abundance of commercial (>=50 mm in test diameter) P. lividus individuals increased in the harvesting season, but drastically dropped by about 90% in the after-harvesting period. Such a pattern was consistent among three rocky shores spanning about 65 km of coast. The multivariate population structure and most size classes of non-commercial sea urchins did not differ depending on the period. The only exception was Class 4 (test diameter between 30 and 40 mm), which was more abundant in the harvesting than in the before- and, further, the after-harvesting period, but only at one shore. Very small (Class 1, test diameter below 10 mm) urchins were never found. The present findings suggest that human harvesting may cause considerable reductions in the abundance of target P. lividus, but that such an effect would not be evident concomitantly with harvesting, but in the subsequent period. Even if just under a precautionary principle, protection strategies focused on sea urchin populations and the harvesting period are advisable to contribute to maintain a sustainable local fishery of P. lividus populations that are likely to be negatively affected also by other natural and anthropogenic perturbations. PMID- 30249458 TI - Functional links on coral reefs: Urchins and triggerfishes, a cautionary tale. AB - Urchins are ubiquitous components of coral reefs ecosystems, with significant roles in bioerosion and herbivory. By controlling urchin densities, triggerfishes have been identified as keystone predators. However, the functional linkages between urchins and triggerfishes, in terms of distributional patterns and concomitant effects on ecosystem processes, are not well understood, especially in relatively unexploited systems. To address this we censused urchins and triggerfishes on two cross-shelf surveys on the Great Barrier Reef (GBR) at the same times and locations. We also evaluated the role of urchins in bioerosion. Although urchin abundance and triggerfish biomass varied by 80% and nearly 900% across sites, respectively, this variability was driven primarily by shelf position with no evidence of top-down control on urchins by triggerfishes. Low urchin abundances meant urchins only played a minor role in bioerosion. We highlight the potential variability in functional links, and contributions to ecosystem processes, among regions. PMID- 30249459 TI - 1.5mile run time and body mass predict 8mile loaded march performance, irrespective of sex. AB - OBJECTIVES: To develop a statistical model to predict 8mile Loaded March (LM) performance and quantify differences in physical characteristics for men and women British Army Personnel. DESIGN: 135 trained soldiers (87 men; 48 women) completed two sessions, seven days apart. METHODS: Session 1: Participants' stature, body mass, Fat Free Mass (FFM) [by dual-energy X-ray absorptiometry], Single Lift (SL), Water Can Carry (WCC), and 1.5mile run performance were measured. Session 2: Participants completed an 8mile LM, carrying 25kg (4miles paced and 4miles individual best effort). Sex differences were compared using independent samples t-tests and 8mile LM performance time was predicted using various multiple linear regression analysis: hierarchical forced entry multiple ordinary least squares, principal component and ordinary least products. RESULTS: A combination of 1.5mile run time and body mass were the strongest predictors of 8mile LM time (R2=0.71; SEE=4.17min; p<0.001). Including stature, FFM, sex, SL score, or WCC score did not further improve predictions (p>0.05). Compared to women, men had faster mean 1.5mile run and LM times, greater body mass and total FFM and higher SL and WCC scores (p<0.001), however some women outperformed men. CONCLUSION: 1.5mile run time and body mass predict 8mile LM performance with no further improvement gained in the model by including sex as a variable. PMID- 30249460 TI - Mucormycosis outbreak due to Rhizopus microsporus after arthroscopic anterior cruciate ligament reconstruction surgery evaluated by RAPD and MALDI-TOF Mass spectrometry. AB - BACKGROUND: Rhizopus microsporus is one of the main causative agents of mucormycosis. These mycoses are mostly described as isolated cases involving uncontrolled diabetes mellitus or immunosuppressed patients. In this work we report a nosocomial outbreak of mucormycosis due to R. microsporum involving three young immunocompetent patients whom underwent arthroscopic anterior cruciate ligament reconstruction surgery in a seven-month time span. PROCEDURES: During the outbreak period, a total of 32 surgeries of this type were performed in the clinic (mucormycosis prevalence of 9.375%). The three patients presented healthcare-associated Mucormycosis comprising the bone surrounding one of the fixation screws (femoral or tibial). In addition to these three strains, another three R. microsporus strains isolated in the medical center during the same period of time were included in the study. One of these fungi was isolated from a skin lesion of a kidney transplant patient while the other two strains were isolated from environmental sources. Classical, mass spectrometry-based (MALDI TOFF) and molecular identification were performed. Genetic relatedness was established by Rep-PCR (RAPD variant) and by single-linkage cluster analysis mass spectra. Cluster analysis was performed by unweighed pair group method with arithmetic mean (UPGMA). MAIN FINDINGS: All the strains were identified as R. microsporum by the used phenotypic and genetic tools. Clinical strains fell into 2 different clusters separating the renal transplant recipient strain from the three strains isolated post ACLR surgery, which clustered together. CONCLUSIONS: The established genetic/mass spectra relatedness between the three post-surgery isolates suggests that these cases may be considered a healthcare-associated mucormycosis outbreak. PMID- 30249461 TI - Global maternal mortality rate declines-Except in America. PMID- 30249462 TI - 5-Year Outcomes of Self-Expanding Transcatheter Versus Surgical Aortic Valve Replacement in High-Risk Patients. AB - BACKGROUND: The CoreValve U.S. Pivotal High Risk Trial was the first randomized trial to show superior 1-year mortality of transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve replacement (SAVR) among high operative mortality-risk patients. OBJECTIVES: The authors sought to compare TAVR to SAVR for mid-term 5-year outcomes of safety, performance, and durability. METHODS: Surgical high-risk patients were randomized (1:1) to TAVR with the self expanding bioprosthesis or SAVR. VARC-1 (Valve Academic Research Consortium I) definitions were applied. Severe hemodynamic structural valve deterioration was defined as a mean gradient >=40 mm Hg or a change in gradient >=20 mm Hg or new severe aortic regurgitation. Five-year follow-up was planned. RESULTS: A total of 797 patients were randomized at 45 U.S. centers, of whom 750 underwent an attempted implant (TAVR = 391, SAVR = 359). The overall mean age was 83 years, and the STS score was 7.4%. All-cause mortality rates at 5 years were 55.3% for TAVR and 55.4% for SAVR. Subgroup analysis showed no differences in mortality. Major stroke rates were 12.3% for TAVR and 13.2% for SAVR. Mean aortic valve gradients were 7.1 +/- 3.6 mm Hg for TAVR and 10.9 +/- 5.7 mm Hg for SAVR. No clinically significant valve thrombosis was observed. Freedom from severe SVD was 99.2% for TAVR and 98.3% for SAVR (p = 0.32), and freedom from valve reintervention was 97.0% for TAVR and 98.9% for SAVR (p = 0.04). A permanent pacemaker was implanted in 33.0% of TAVR and 19.8% of SAVR patients at 5 years. CONCLUSIONS: This study shows similar mid-term survival and stroke rates in high risk patients following TAVR or SAVR. Severe structural valve deterioration and valve reinterventions were uncommon. (Safety and Efficacy Study of the Medtronic CoreValve(r) System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902). PMID- 30249463 TI - Background parenchymal enhancement in breast magnetic resonance imaging: A review of current evidences and future trends. AB - Background parenchymal enhancement (BPE) on breast magnetic resonance imaging (MRI) is a dynamic process, which varies among women and within the same woman over time due to different factors. BPE has profound implications for women with or at risk of breast cancer. Breast radiologist should be aware of factors that could potentially influence BPE and have to be familiar with its typical appearance. Marked BPE could indeed affect the diagnostic accuracy of breast MRI, but this shortcoming can be minimized through evaluation by dedicated radiologists, in order to correctly interpret and properly manage the additional findings. BPE shows promise as an imaging biomarker but many issues need to be addressed before it can be used either to determine screening strategy or the value of risk-reducing interventions. This review analyzes the clinical influence of BPE on breast MRI interpretation, breast cancer staging and surgical outcome and discusses current available evidences about BPE as an imaging biomarker. PMID- 30249465 TI - Critical periods for language: Comment on "Rethinking foundations of language from a multidisciplinary perspective" by T. Gong et al. PMID- 30249464 TI - Notch signaling regulates cell density-dependent apoptosis of NIH 3T3 through an IL-6/STAT3 dependent mechanism. AB - Apoptosis is a physiological process that plays a critical maintenance role in cellular homeostasis. Previous reports have demonstrated that cells undergo apoptosis in a cell density-dependent manner, which is regulated, in part, by signal transducers and activators of transcription (STAT) 3. The molecular mechanisms regulating cell density-dependent apoptosis, however, has not been thoroughly investigated to date. Since Notch signaling is activated via direct cell-to-cell contact and plays a pivotal role in cell fate decisions, we examined the role of Notch signaling in cell density-dependent apoptosis of mouse embryonic fibroblasts NIH 3T3 cells. With the increase in cell density, IL-6 expression was induced, which was necessary for STAT3 activation as well as apoptosis regulation. Notch signaling was also activated in a cell-density dependent manner. Blocking Notch signaling either through siRNA-mediated targeting of Jagged1 expression or gamma-secretase inhibitor treatment demonstrated that Notch signaling activation was necessary for IL-6 induction. Constitutive activation of Notch signaling via the overexpression of Notch1 intracellular domain was sufficient for the induction of IL-6, which was mediated via direct transcriptional activation. Taken together, our study indicates that Notch signaling regulates cell density-dependent apoptosis through IL-6/STAT3 dependent mechanism. Consequently, Notch signaling might represent a novel therapeutic target in diseases characterized by dysregulated apoptosis. PMID- 30249466 TI - The mucous cyst, a rare and delayed complication after rhinoplasty. AB - INTRODUCTION: Rhinoplasty is frequently performed worldwide, and patients and surgeons both expect good cosmetic results without any deformity recurrence. We report a rare case of mucous cyst occurred after post-traumatic rhinoseptoplasty. OBSERVATION: A 27-year old woman presented a median mass of the nose root 7 years after prior rhinoseptoplasty. Investigations showed a subcutaneous lesion of 10.5*24.5mm. The surgery consisted on an external rhinoplasty allowing cyst removal, bilateral osteotomies and reconstruction of the nasal dorsum by deep temporal fascia graft. Histological examination confirmed the diagnosis of begnin mucous cyst. No recurrence was observed at 1-year follow-up. DISCUSSION: Mucous cyst post rhinoplasty is rare and is probably due to accidental mucosal material implantation into the subcutaneous plane during rhinoplasty. This complication can be avoided by adequate infiltration and hydrodissection, careful dissection, and avoidance of unnecessary trauma during osteotomies. PMID- 30249467 TI - Coronary and Abdominal Aortic Aneurysms. PMID- 30249468 TI - TEVARs to the North, FEVARs to the South; Here we are, Stuck in the Mid-Term With you .... PMID- 30249469 TI - Extended Petticoat Strategy in Aortic Dissection: when Is It Too Much, or Not Enough? PMID- 30249470 TI - Metabolic abnormalities and low dietary Omega 3 are associated with symptom severity and worse functioning prior to the onset of psychosis: Findings from the North American Prodrome Longitudinal Studies Consortium. AB - OBJECTIVE: Patients with schizophrenia have a high prevalence of metabolic disorders and cardiovascular mortality. It is possible that a vulnerability to metabolic abnormalities is associated with risk for psychosis, symptoms and functionality. In this study, we evaluate demographic information, cardiometabolic indices, symptoms and functioning in an antipsychotic free cohort at Clinical High Risk (CHR) for psychosis from the NAPLS Omega 3 fatty acid clinical trial. METHOD: Subjects received physical exams and metabolic monitoring prior to randomization into the Omega 3 versus Placebo trial. Anthropometrical measures, vital signs, glucose, and lipids were assessed along with symptoms, functioning, dietary Omega 3 fatty acids, erythrocyte polyunsaturated fatty acid content and a measure of lipid peroxidation (TBARS, Thiobarbituric acid-reactive substances). RESULTS: The sample included 113 CHR subjects (42.1% female; 17.5% Latino) ages 12-29. The mean BMI was 24.3 with a trend toward higher BMI and a higher incidence of metabolic syndrome in Latino subjects; 36% of the sample was obese/overweight; 37.6% met criteria for prehypertension/hypertension; 4.2% met criteria for prediabetes/diabetes; 9.6% showed evidence of insulin resistance and 44.7% had dyslipidemia. The TBARS was elevated at 9.8 MUM +/- 6.1 (normal 1.86 3.94 MUM). Metabolic parameters and a diet low in Omega 3 rich foods were significantly associated with prodromal symptoms and poor functioning. CONCLUSIONS: CHR subjects show a high percentage of metabolic abnormalities prior to exposure to antipsychotic medication. These findings reinforce that early detection of metabolic disturbances and food insecurity is crucial since these factors are modifiable with the potential for significant gains in terms of quality of life, physical and mental health. PMID- 30249471 TI - Left prefrontal high-frequency rTMS may improve movement disorder in schizophrenia patients with predominant negative symptoms - A secondary analysis of a sham-controlled, randomized multicenter trial. PMID- 30249472 TI - Comparison of drop jump landing biomechanics and asymmetry among adolescents with hamstring, patellar and quadriceps tendon autografts for anterior cruciate ligament reconstruction. AB - BACKGROUND: Adolescent anterior cruciate ligament reconstruction (ACLR) commonly utilizes hamstring (HT), patellar (PT) or quadriceps (QT) tendon autografts, but consensus is lacking regarding optimal graft choice. This study compared landing biomechanics and asymmetries among ACLR patients with HT, PT and QT grafts and uninjured controls. METHODS: This retrospective study included 61 adolescents with unilateral ACLR (27 HT, 20 PT, 14 QT; four to 12 months post-surgery, mean 6.4; age 15.4, SD 1.4 years) and 27 controls (14.6, SD 0.9 years) who were evaluated during drop jump landings. Lower extremity 3D biomechanics and asymmetries were compared. RESULTS: Compared to controls, all operative limbs exhibited 1) greater hip flexion and lower dorsiflexion angles; 2) higher hip and lower knee and ankle flexion moments; 3) higher energy absorption at the hip (HT and QT only) and lower at the knee and ankle; and 4) higher knee abduction moments. Asymmetries observed in all ACLR groups included 1) lower knee and ankle flexion angles; 2) lower knee and ankle flexion moments; 3) lower energy absorption at the knee and ankle; and 4) higher hip and knee abduction moments on the operative side. The PT and QT groups demonstrated greater asymmetry in hip and knee flexion moments compared to HT. CONCLUSIONS: While adolescent ACLR limbs offloaded the knee and ankle, patients with PT or QT grafts demonstrated greater deficiencies during rehabilitation than those reconstructed with HT. Graft choice in ACLR should remain patient-specific and aim to optimize biomechanics with the ultimate goal of minimizing graft re-tear and donor site morbidity. PMID- 30249474 TI - Unusual array of neural communications in the infratemporal fossa: Useful for skull base surgery. AB - Variations in the branching pattern of the mandibular nerve frequently accounts for failure to obtain adequate local anesthesia in routine oral and dental procedures, and also for unexpected injury to the nerves during surgery. The knowledge of the neurovascular relationships of the infratemporal region is relevant in odontostomatology practice. In this article we present a rare case of atypical communication between the inferior alveolar nerve and lingual nerve and the mylohyoid and lingual nerves. Further, the clinical implications of these communications on the development of the supplementary innervation and their possible role in anesthesia is discussed in detail. The communication between mylohyoid and lingual nerve was found in this case near the submandibular ganglion after the lingual nerve passes in close relation to third molar tooth, which makes it more susceptible to injury during third molar extractions. The communicating branch between the mylohyoid nerve and lingual nerve may also innervate the tongue, and surgeons should be aware of this variation to avoid post- operative complcations after oral surgeries. Thus the precise anatomy of structures of infratemporal region and its variations may prove beneficial to clinicians, especially to oral and maxillofacial surgeons. PMID- 30249473 TI - Cryopreservation of female reproductive potential. AB - Storing female reproductive potential can offer enhanced prospects for future conception in women whose fertility is threatened by cytotoxic therapies. Human female reproductive potential can be cryopreserved and stored at very low temperatures as embryos or gametes. Gamete (oocyte) cryopreservation circumvents potential issues associated with ownership when future use is being considered and may, therefore, be more generally acceptable as an approach. Advances in the technology, in particular the clinical application of vitrification, have significantly improved the outcomes from mature oocyte cryopreservation, which are now comparable to those from embryo cryopreservation. In cases where mature oocyte cryopreservation is not feasible, ovarian cortex containing primordial follicles can be cryopreserved, and over 100 births have now been reported following grafting of stored ovarian tissue. Ovarian tissue cryopreservation is now an established approach to preserve future fertility for young women; however, the efficiency is difficult to determine particularly for the prepubertal tissue with a scarcity of data. PMID- 30249475 TI - Genotoxic damage in end-stage renal disease. AB - End-stage renal disease (ESRD) patients are at increased risk for cardiovascular events and cancer, possibly due to genomic instability associated with renal disease and/or its therapy. Prognostic biomarkers of genomic instability may prove useful for initiating appropriate intervention strategies. We conducted a case-control study, performing the single-cell gel electrophoresis assay (circulating leukocytes) and the micronucleus cytome assay (buccal epithelial cells). Cases (ESRD patients; n = 55) were on weekly/fortnightly dialysis therapy and controls (n = 39) were healthy adults. The patients had significantly elevated levels of DNA damage and micronucleated cells. DNA damage showed higher validity and sensitivity than did chromosome damage, for discriminating patients from controls. The patient group showed significant increases in cell proliferation, cytokinetic defects, and cell death, and a decrease in repair index. Correlations were seen between genetic damage and both time-on-medication and time-on-dialysis; between condensed chromatin cells and sex; and between pyknotic cells and dietary pattern. Following stratification by age, gender, and dialysis frequency, significantly elevated DNA damage and MN frequency were seen in the fortnightly dialysis patients, perhaps due to accumulated uremic toxicants. DNA and chromosome damage may be useful prognostic biomarkers for initiating timely interventions against co-morbidities in ESRD patients. PMID- 30249476 TI - Small-for-pregnancy-age rats submitted to exercise: DNA damage in mothers and newborns, measured by the comet assay. AB - BACKGROUND: Fetal impairment caused by a deleterious intrauterine environment may have long-term consequences, such as oxidative stress and genetic damage. Rats born as small-for-gestational-age (SPA) were submitted to exercise (swimming) before and during pregnancy. The animals exhibited glucose intolerance, reduced general adiposity, and increased maternal and offspring organ weight, showing the benefit of exercise for these rats. We hypothesised that regular exercise in SPA during gestation could prevent DNA damage in these animals and in their offspring, contributing to altered fetal programming of metabolism in the offspring. Severe diabetes was induced by streptozotocin treatment, to obtain SPA newborns. At adulthood, pregnant SPA rats were randomly distributed into two groups: exercised (SPAex - submitted to swimming program) or not-exercised (SPA - sedentary rats). Post-partum, blood was collected for analysis of DNA damage (comet assay) and oxidative stress. SPAex rats presented lower DNA damage levels, decreased lipid peroxidation, and a lower rate of newborns classified as large for-pregnancy-age. DNA damage was also lower in SPAex newborns. We conclude that swimming applied to SPA pregnant rats contributes to decreased DNA damage and lipid peroxidation in the dams, and decreased DNA damage and macrosomia in their offspring. PMID- 30249477 TI - DNA damaging agents trigger the expression of the HML silent mating type locus in Saccharomyces cerevisiae. AB - Many DNA damaging agents also react with RNA and protein, and could thus cause epigenetic as well as genotoxic changes. To investigate which DNA damaging agents alter epigenetic states, we studied the chemical-induced changes in expression of the yeast silent mating type locus HMLalpha, which can be triggered by inhibiting yeast Sir2. We observed that the alkylating agent methyl methane sulfonate (MMS) can result in HMLalpha expression, using a colony sector assay that results from expression of a HML-positioned cre gene. Using single-cell imaging we also observed that alkylating agents, including MMS and methyl-3-nitro-1 nitrosoguanidine (MNNG), as well as short-wave UV, also decreased HML silencing. We suggest that chemical-induced alterations in heterochromatin structure could confer transient phenotypic changes that affect the cellular responses to DNA damaging agents. PMID- 30249478 TI - Hunter syndrome: Long-term idursulfase treatment does not protect patients against DNA oxidation and cytogenetic damage. AB - Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is an inborn error of metabolism characterized by the accumulation of glycosaminoglycans (GAG) in lysosomes. Enzyme replacement therapy (ERT) can reduce GAG storage, ameliorate symptoms, and slow disease progression. Oxidative damages may contribute to the MPS II pathophysiology, and treatment with ERT might reduce the effects of oxidative stress. We evaluated levels of DNA damage (including oxidative damage) and chromosome damage in leukocytes of long-term-treated MPS II patients, by applying the buccal micronucleus cytome assay. We observed that, despite long term ERT, MPS II patients had higher levels of DNA damage and higher frequencies of micronuclei and nuclear buds than did control. These genetic damages are presumably due to oxidation: we also observed increased levels of oxidized guanine species in MPS II patients. Therapy adjuvant to ERT should be considered, in order to decrease oxidative damage and cytogenetic alterations. PMID- 30249479 TI - Bacterial mutagenicity of selected procarcinogens in the presence of recombinant human or rat cytochrome P4501A1. AB - Cytochrome P4501A1 (CYP1A1) is an important enzyme of procarcinogen activation. We have studied bacterial (Ames test) mutagenicity resulting from mutagen activation by recombinant human or rat CYP1A1. Mutagenicity depends on both the chemical group and species-specific activation: polycyclic aromatic hydrocarbons showed higher (5-7-fold) mutagenic activity when activated by the human enzyme, whereas heterocyclic amines were more mutagenic (5-75-fold) in the presence of the rat enzyme. With regard to the two aromatic amines tested, only 2 aminoanthracene showed a clear species preference, activated 3-fold more effectively by human than by rat CYP1A1. We also analyzed in silico the binding of these compounds to the human and rat enzyme catalytic sites, identifying residues expected to participate in ligand recognition. A phenylalanine residue was involved in CYP-mutagen stabilization through pi-pi stacking. Variations in the three-dimensional conformations and distances to the heme groups may contribute to differences between human and rat CYP-substrate interactions. In conclusion, CYP1A1 shows significant differences between species, in terms of mutagen activation, which should be considered in the context of human risk assessment. PMID- 30249480 TI - Buccal micronucleus cytome biomarkers in Algerian couples with idiopathic infertility. AB - The buccal micronucleus cytome (BMCyt) assay is a useful and a minimally invasive cytogenetic method for measuring genomic damage. The aim of the present study is to evaluate the extent of chromosomal damage in couples with idiopathic infertility using a BMCyt. This study included 54 patients (27 couples) with idiopathic infertility and 30 fertile subjects (15 couples). When evaluated by individual (each subject from the couple is considered separately), the frequencies of micronucleated cells (MNC), total micronuclei (TMN), nuclear buds (NBUD), and binucleated cells (BN) were significantly higher in the infertile individuals than in the fertile ones (p = 0.009, p = 0.009, p = 0.003 and p < 0.0001, respectively). Among the cells reflecting cell death events, condensed chromatin (CC), karyorrhectic (KHC) and pyknotic (PYK) cells were significantly higher in the infertile individuals (p = 0.0001, p = 0.003, p = 0.001, respectively). Identical results were obtained when data were analysed by couple (female + male). The frequencies of MNC, TMN, NBUD, and BN cells were significantly higher in the infertile couples (p = 0.019, p = 0.021, p = 0.013, and p < 0.0001, respectively). Likewise, CC, KHC and PYK cells were significantly higher in the infertile couples (p = 0.002, p = 0.034, p = 0.008, respectively). BN cells showed the most pronounced difference between the fertile and infertile groups. The basal (BAS) and karyolitic (KYL) cells did not show a significant difference. In conclusion, this study showed that, in comparison to controls, couples with idiopathic infertility had significantly higher frequencies of DNA damage biomarkers (MN and NBUD), biomarkers of cytokinesis-failure or arrest (BN cells) and cell death biomarkers (CC, KHC and PYK cells). These results suggest a possible role of chromosomal damage in idiopathic infertility that may be due to an imbalance between DNA damage rates and DNA repair mechanisms. PMID- 30249481 TI - Perspective on Wheat Yield and Quality with Reduced Nitrogen Supply. AB - Wheat is an important cereal crop with a high demand for nitrogen (N) fertilizer to enable the grain protein accumulation that is necessary for baking and processing quality. Here, perspectives for the development of improved wheat genotypes with higher yield stability, better grain quality, and improved N use efficiency to lower environmental impacts are discussed. The development of improved wheat genotypes, for example, genotypes that lack storage proteins that do not contribute to baking quality (e.g., by genome editing), in combination with appropriate N fertilizer management to prevent N losses into the environment underpins a novel approach to improving N use efficiency. This approach may be particularly applicable to wheats grown for animal feed, which have lower quality and functionality requirements. PMID- 30249482 TI - Three-dimensional evaluation of mandibular midline distraction: A systematic review. AB - OBJECTIVE: To provide a literature overview on mandibular midline distraction (MMD) using three-dimensional (3D) imaging analysis techniques. Regarding different distractor types, the focus was on changes in position and/or morphology of the mandibular condyle and temporomandibular joint (TMJ), skeletal effects, dental effects, soft tissue effects, and biomechanical and masticatory effects, specifically on the mandible and TMJ. METHODS: Studies up to March 27 2017 were included, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines, using Embase, Medline OvidSP, Web-of-science, Scopus, Cochrane, and Google Scholar. RESULTS: Thirty-one full-text papers were assessed for eligibility and 15 met the inclusion criteria: prospective (2), retrospective (2), case-report (1) and computational analysis (10). All included studies were graded low (level 4-5) for quality of evidence, using the Oxford Centre for Evidence-Based Medicine criteria. CONCLUSION: There is a limited number of studies available, with low levels of evidence and small sample sizes. Bone-borne distraction seems preferable when taking skeletal effects into account. Tooth-borne distraction leads to significant dental tipping. Hybrid distractors combined with parasymphyseal step osteotomy seem to be the most stable under functional masticatory loads. The effects of chewing appeared to be marginal during the latency period. No permanent TMJ symptoms were reported, and little is known about soft tissue effects. SYSTEMATIC REVIEW REGISTRATION: International Prospective Register of Systematic Reviews, PROSPERO CRD42014010010. PMID- 30249483 TI - Efficacy of viscosupplementation with hyaluronic acid in temporomandibular disorders: A systematic review. AB - OBJECTIVE: To perform a systematic review of the viscosupplementation effectiveness with hyaluronic acid (HA) in the articular Temporomandibular Dysfunctions (TMDs) clinical management. METHOD: Electronic searches were performed in the following databases: MEDLINE (via PubMed), Scopus, Web of Science, Cochrane Library, EMBASE, LILACS, BBO, SIGLE (System for Information on Grey Literature in Europe), ClinicalTrials.gov, and the Brazilian Clinical Trials Registry (ReBec). Only randomized clinical trials that evaluated the intra articular administration of HA or its derivatives in osteoarthritis and/or anterior displacement of the temporomandibular joint (TMJ) disc were included. The primary outcomes evaluated were patients' self-report of pain and/or discomfort in the TMJ. Each study was assessed for the risk of bias, using the Cochrane collaboration's risk of bias tool. RESULTS: A total of 640 studies were obtained in the electronic search. After the application of the eligibility criteria, manual search, and duplicate removal, 21 articles were included. Five articles classified their volunteers with internal derangements of the TMJ, in 4 articles the treatment was directed to participants with disc displacement with reduction and the other articles evaluated HA therapy in osteoarthritis. The protocols presented heterogeneity, varying in the form of application, associated or not with arthrocentesis, number of applications, molecular weight, dose and concentration. Nine studies presented high risk of bias. CONCLUSION: Due to the heterogeneity and methodological inconsistencies of the studies evaluated, it was not possible to establish the efficacy of HA in articular TMDs. PMID- 30249484 TI - Nomogram model to predict postoperative relapse after mandibular osteoradionecrosis surgery. AB - PURPOSE: Osteoradionecrosis of the mandible (ORNM) is one of the most devastating complications following radiotherapy. Postoperative relapse (POR) occurs with high incidence even if a radical resection is performed. The current investigation was designed to identify prognostic factors for POR and to establish a nomogram model to estimate the risk for the onset of POR of ORNM. MATERIALS AND METHODS: A retrospective study was conducted in ORNM patients during the period from 2003 to 2016. Predictive factors for POR were preliminarily filtered by Kaplan-Meier analysis and were further confirmed by Cox regression model. A nomogram model was established to predict the risk for the onset of POR, and the performance was estimated by receiver operating characteristic (ROC) and calibration curve. POR was defined as the primary outcome variable and was measured using univariate and multivariate analyses. RESULTS: A total of 213 patients were analyzed, and the total incidence of POR was 24.4% (52/213). In the Cox regression analysis, radiation doses >=80 Gy (versus<80 Gy, OR = 3.528, P<0.001, 95% CI: 1.759-7.076), location of ORNM (lesion only in mandibular body versus that involving mandibular body, angulus and ramus versus, OR = 2.900, P = 0.007, 95% CI: 1.345-6.253), S classification (S2 versus S0, OR = 8.926, P = 0.001, 95% CI: 2.487-32.036), and surgical treatment (sequestretomy versus ER + reconstruction, OR = 3.299, P = 0.012, 95% CI: 1.294-8.411) were significantly associated with POR. The current nomogram model can effectively evaluate the hazard risk and survival rate of POR. The discrimination capability was tested by the ROC curve with an area under the curve of 0.813, revealing highly predictive abilities. The calibration curve showed sufficient fitness. CONCLUSION: The current nomogram model was effective in predicting the risk of POR in ORNM patients. PMID- 30249485 TI - Aberrant expression of the innate restriction factor bone marrow stromal antigen 2 in primary Sjogren's syndrome. AB - OBJECTIVE: The objective of this study was to analyze bone marrow stromal antigen 2 (BST-2) levels in labial glands, total peripheral blood mononuclear cells (PBMCs) and PBMC subpopulations from primary Sjogren's syndrome (pSS) patients and determine the correlation between BST-2 expression and clinical characteristics. MATERIALS AND METHODS: PBMC subsets were positively separated using magnetic microbeads. BST-2 mRNA levels in labial glands, total PBMCs and PBMC subsets of 30 pSS and 30 healthy control (HC) subjects were investigated using real-time polymerase chain reaction (RT-PCR). Distribution of BST-2 positive cells in the labial glands was assessed by immunohistochemistry. RESULTS: BST-2 was significantly increased in pSS labial glands and was positively correlated with the VAS value for parotid gland swelling and rheumatoid factor and beta2-microglobulin serum levels. BST-2 levels were statistically different between pSS patients with positive and negative expression of anti-SSA antibody. Positive focal infiltrating lymphocytes and adjacent ductal epithelial cells were observed in labial glands from pSS patients, while there were a few scattered positive ductal epithelial cells in controls. BST-2 was also up-regulated in CD19+ B cells and the remaining CD4-CD8 CD19- PBMCs. CONCLUSION: BST-2 was aberrantly expressed in pSS patients, and expression in labial glands was positively correlated with important clinical characteristics; thus, it may be a potential biomarker of pSS activity. PMID- 30249486 TI - Long-term survival of teeth in the posterior region after apical surgery. AB - Oftentimes the discussion of long-term success rates and treatment modalities becomes a central issue in consultations with patients. The aim of this study was to retrospectively evaluate survival rates of teeth after apicoectomy in an established private practice for Oral and Maxillofacial Surgery in Kiel, Germany. All teeth treated with apicoectomy between 2001 and 2006 were included. Treatment success was previously defined as preservation of the tooth. Putative influence factors on success as kind and quality of endodontic treatment, additional intraoperative endodontic filling, inflammatory status, tooth mobility, and pre- and postoperative X-rays were further evaluated. A total of 149 teeth could be included. The mean observation period was 6.3 (SD: 4.4) years. In all, 48.3% of these teeth could be retained after a 10-year period. Teeth that received an additional retrograde root canal filling during surgery resulted in a significantly higher success rate (p = 0.0237) compared to those with orthograde root canal fillings or without additional endodontic treatment. The quality of endodontic treatment had no impact (p = 0.125). Our results suggest that apical surgery is a reliable procedure to treat and ensure the survival of symptomatic teeth in the posterior region for several years. A significant improvement was further determined for a retrograde filling. PMID- 30249487 TI - Prevalence of dental anomalies in French orthodontic patients: A retrospective study. AB - OBJECTIVES: To investigate the prevalence and gender distributions of dental anomalies in French orthodontic patients. MATERIAL AND METHODS: A retrospective review of the dental files of orthodontic patients was conducted to investigate the frequencies of dental anomalies. Pretreatment intraoral photographs and panoramic radiographs were analyzed. The occurrence rates of various dental anomalies (as determined by the numbers, shapes, structures, exfoliations, and eruptions of teeth) were calculated as percentages and differences in gender distribution using Chi2 and Fisher tests. RESULTS: Five hundred fifty-one patients receiving orthodontic treatment between 2003 and 2013 at a French hospital were included in the study: 45.74% of the patients (n=252) presented at least one dental anomaly. Taurodontism was the most common (15.06%), followed by ectopic eruption (11.43%). Odontoma, macrodontia, fusion, gemination, talon cusp, dentinogenesis imperfecta, regional odontodysplasia, premature tooth eruption, and premature exfoliation were not found. No statistically significant correlations were found between gender and the occurrence of dental anomalies. CONCLUSION: French orthodontic patients exhibit a high rate of dental anomalies, indicating that dental anomalies should be carefully considered in the orodental management of French patients. PMID- 30249488 TI - Risk analysis in pediatric inpatients. AB - The complexity and vulnerability of the pediatric population make them unique to risk management. Risk analysis is particularly demanding here and requires comprehensive identification of hazardous situations. Few data are published on methods to prevent medication errors in pediatric inpatients, reducing the possibility for healthcare institutions to prioritize the actions to take. This paper summarizes the proactive risk analysis methods described in the literature, the failures identified, and the corrective actions applied to reduce the risks in pediatrics. PMID- 30249489 TI - Neonatal fever: A puzzling case. AB - Toxoplasmosis is a potentially serious fetal infection associated with maternal seroconversion of toxoplasmosis during pregnancy. Follow-up and treatment vary between different countries. We present a case of congenital toxoplasmosis with unusual physiopathology and symptomatology. The mother was immunized before the beginning of pregnancy but immunosuppressive treatments for Crohn disease maintained during the pregnancy could explain toxoplasmosis reactivation in the mother and congenital toxoplasmosis. The baby presented reversible B lymphopenia and hypogammaglobulinemia. PMID- 30249490 TI - SPINA classification of cleft lip and palate: A suggestion for a complement. AB - Spina's classification uses the incisive foramen as an anatomic reference to define groups I, II, and III. In some cases, the morphological manifestation of the cleft arises simultaneously pre- and postforamen, but without communicating. Considering that group I refers to isolated clefts of the primary palate and group III includes isolated clefts of the secondary palate, the authors suggest the classification group IIa for the association of these two occurrences in the same patient, thus associating two classifications. The original structure proposed by Spina is maintained and simply complemented and updated to Spina-A classification. PMID- 30249491 TI - Enzyme-replacement therapy in perinatal hypophosphatasia: Case report and review of the literature. AB - Hypophosphatasia (HPP) is a rare disease resulting from alterations of the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Perinatal HPP is mainly characterized by bone hypomineralization and severe respiratory insufficiency. We describe a full-term boy diagnosed with perinatal HPP after birth, showing dramatic improvement after treatment with Asfotase Alfa, an enzyme replacement therapy (ERT) prescribed in HPP cases. He initially presented with respiratory insufficiency due to bone hypomineralization, and severe pulmonary hypoplasia that required tracheostomy and invasive ventilation for 8 months. He was taken off ventilation at 41 weeks of age. He also presented complications including hypercalcemia, craniosynostosis, nephrocalcinosis, hypotonia, and a severe feeding disorder. He is still alive at 30 months of age, and his respiratory status and tonus is steadily improving. This case reflects the progression of HPP patients with specific therapy added to symptomatic management. Some aspects of the disease are now well known, such as nephrocalcinosis and craniosynostosis, related to the natural course of the disease, which persisted despite the ERT. The long-term prognosis and outcome for this newborn child remain unknown. PMID- 30249492 TI - Sudden death by arrythmia in a 4-year-old boy. AB - Cardiac arrhythmia with sudden death is rare in children but mainly due to ventricular tachycardia. In case of pulseless ventricular tachycardia, prehospital treatment is crucial with immediate cardiopulmonary resuscitation and external electrical cardioversion. We report the case of pulseless ventricular tachycardia in a child with no past medical history. Sinus rhythm was obtained after 12min of cardiorespiratory resuscitation and three external electrical shocks. An exhaustive diagnostic approach allow us to find its origin. The clinical progression was marked by a severe encephalopathy. The authors discuss different etiologies and treatment of arrhythmia in children, reviewing the pediatric algorithm for shockable rhythm. PMID- 30249493 TI - Hand injury without any deficit: Is systematic surgical exploration justified? AB - : Out of 100,000 inhabitants, 700 to 4000 suffer a hand wound each year. Numerous hand wounds that may not have a clinically evaluated deficit, actually have damage to a major structure after surgical exploration in the operating room (OR). The aim of our study was to evaluate the incidence of major structure damage within a population of patients presenting a hand wound with no deficit on the clinical examination. Every patient older than 12 years, consulting for a wound deeper than the dermis with no clinical signs of major structure damage underwent surgical treatment and exploration of the wound under regional anesthesia in the OR. After each surgery, the surgeon filled out an anonymous study form describing the wound characteristics and the potential findings of major structure damage. Of the 145 wounds with normal clinical examination, we found that 58.6% had a major structure damaged. Given that damage to any major structure in the hand can lead to functional sequela, and the fact that a well conducted clinical examination by a qualified hand surgeon is not sufficient to eliminate major structure damage, we recommend systematic surgical exploration of hand wounds, even when no clinical deficit is evident. LEVEL OF EVIDENCE III: Type of sudy: diagnostic study. PMID- 30249494 TI - Novel 4-(2-pyrimidinylamino)benzamide derivatives as potent hedgehog signaling pathway inhibitors. AB - A series of novel hedgehog signaling pathway inhibitors have been designed and synthesized based on our previously reported scaffold of 4-(2 pyrimidinylamino)benzamide. The Hh signaling pathway inhibitory activities were evaluated by Gli-luciferase reporter method and most compounds showed more potent inhibitory activities than vismodegib. Three compounds were picked out to evaluated in vivo for their PK properties, and compound 23b bearing a 2-pyridyl A ring and (morpholin-4-yl)methylene at 3-position of D-ring demonstrated satisfactory PK properties. This study suggested the 4-(2 pyrimidinylamino)benzamides were a series of potent Hh signaling pathway inhibitors, deserving to further structural optimization. PMID- 30249495 TI - Development of matrix metalloproteinase-13 inhibitors - A structure activity/structure-property relationship study. AB - A structure-activity/structure-property relationship study based on the physicochemical as well as in vitro pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (2) was undertaken. After systematic variation of inhibitor 2, compound 31 was identified which exhibited microsomal half-life higher than 20 min, kinetic solubility higher than 20 MUM, and a permeability coefficient greater than 20 * 10-6 cm/s. Compound 31 also showed excellent in vivo PK properties after IV dosing (Cmax = 56.8 MUM, T1/2 (plasma) = 3.0 h, Cl = 0.23 mL/min/kg) and thus is a suitable candidate for in vivo efficacy studies in an OA animal model. PMID- 30249496 TI - Identification of N-(5-(phenoxymethyl)-1,3,4-thiadiazol-2-yl)acetamide derivatives as novel protein tyrosine phosphatase epsilon inhibitors exhibiting anti-osteoclastic activity. AB - Cytosolic protein tyrosine phosphatase epsilon (cyt-PTPepsilon) plays a central role in controlling differentiation and function of osteoclasts, whose overactivation causes osteoporosis. Based on our previous study reporting a number of cyt-PTPepsilon inhibitory chemical compounds, we carried out a further and extended analysis of our compounds to examine their effects on cyt-PTPepsilon mediated dephosphorylation and on osteoclast organization and differentiation. Among five compounds showing target selectivity to cyt-PTPepsilon over three other phosphatases in vitro, two compounds exhibited an inhibitory effect against the dephosphorylation of cellular Src protein, the cyt-PTPepsilon substrate. Moreover, these two compounds caused destabilization of the podosome structure that is necessary for the bone-resorbing activity of osteoclasts, and also attenuated cellular differentiation of monocytes into osteoclasts, without affecting cell viability. Therefore, these findings not only verified anti osteoclastic effects of our cyt-PTPepsilon inhibitory compounds, but also showed that cyt-PTPepsilon expressed in osteoclasts could be a putative therapeutic target worth considering. PMID- 30249497 TI - A truncated RHAMM protein for discovering novel therapeutic peptides. AB - The receptor for hyaluronan mediated motility (RHAMM, gene name HMMR) belongs to a group of proteins that bind to hyaluronan (HA), a high-molecular weight anionic polysaccharide that has pro-angiogenic and inflammatory properties when fragmented. We propose to use a chemically synthesized, truncated version of the protein (706-767), 7 kDa RHAMM, as a target receptor in the screening of novel peptide-based therapeutic agents. Chemical synthesis by Fmoc-based solid-phase peptide synthesis, and optimization using pseudoprolines, results in RHAMM protein of higher purity and yield than synthesis by recombinant protein production. 7 kDa RHAMM was evaluated for its secondary structure, ability to bind the native ligand, HA, and its bioactivity. This 62-amino acid polypeptide replicates the HA binding properties of both native and recombinant RHAMM protein. Furthermore, tubulin-derived HA peptide analogues that bind to recombinant RHAMM and were previously reported to compete with HA for interactions with RHAMM, bind with a similar affinity and specificity to the 7 kDa RHAMM. Therefore, in terms of its key binding properties, the 7 kDa RHAMM mini-protein is a suitable replacement for the full-length recombinant protein. PMID- 30249498 TI - Novel autophagy modulators: Design and synthesis of (+)-epogymnolactam analogues and structure-activity relationship. AB - (+)-Epogymnolactam (1) was discovered as a novel autophagy inducer from a culture of Gymnopus sp. in our laboratory. To determine structure-activity relationships among (+)-epogymnolactam analogues comparing with cerulenin (2), we synthesized 5 analogues including (-)-epogymnolactam (3) having each different functional group, and 3 analogues with different side-chain lengths. Five analogues, 3, 4, 5, 6, and 7 did not significantly increase the ratio of LC3-II to LC3-I as an autophagy marker in NIH3T3 cells. These results suggest that presence and stereochemistry of (2R,3S)-epoxy group and cyclic syn-form (1b) of 1 are important for the activity as autophagy inducer. Hexyl analogue (8) as well as 1 having butyl side-chain dose-dependently increased the ratio of LC3-II to LC3-I, whereas octyl analogue (9) and 2 rather decreased the ratio. Decyl analogue (10) did not give a change in the ratio. Although 8 seemed to be an excellent autophagy inducer, it dose-dependently increased SQSTM1 (p62) as in the case of 2, whereas 1 showed a slight dose-dependent decrease of p62 as an index of autophagic protein degradation. These observations suggest that 8 is an autophagy modulator with different molecular target from 1 or 2. PMID- 30249499 TI - Glass ionomer cements with milled, dry chlorhexidine hexametaphosphate filler particles to provide long-term antimicrobial properties with recharge capacity. AB - OBJECTIVE: Glass ionomer cements (GICs) are a versatile material, offering the opportunity for ion exchange with the oral environment. The aim of this study was to develop a GIC that delivers a controlled, rechargeable dose of chlorhexidine (CHX) over an extended period without compromising mechanical properties. METHODS: GICs were supplemented with finely milled particles of chlorhexidine hexametaphosphate (CHX-HMP). CHX release into artificial saliva was measured over 660 days, and recharge with CHX and CHX-HMP was investigated. Mechanical properties were investigated, and an agar diffusion test was carried out to assess antimicrobial properties using Streptococcus mutans and Scardovia wiggsiae. RESULTS: Dose-dependent CHX release was observed, and this was ongoing at 660 days. Compared with related studies of GICs containing CHX-HMP, the fine, dry particles resulted in fewer adverse effects on mechanical properties, including tensile, compressive and biaxial flexural strength, with 1% CHX-HMP GICs indistinguishable from control specimens. The GICs could be recharged with CHX using both a conventional CHX digluconate solution comparable to commercial mouthrinses, and a suspension of CHX-HMP of equivalent concentration. Recharging with CHX digluconate increased subsequent CHX release by 50% compared with no recharge, and recharging with CHX-HMP increased subsequent CHX release by 100% compared with no recharge. The GICs inhibited growth of St. mutans and Sc. wiggsiae in a simple agar diffusion model. SIGNIFICANCE: These materials, which provide sustained CHX release over clinically relevant timescales, may find application as a restorative material intended to inhibit secondary caries as well as in temporary restorations and fissure sealants. PMID- 30249500 TI - Endoscopic findings and esophageal cancer incidence among Fanconi Anemia patients participating in an endoscopic surveillance program. AB - BACKGROUND AND AIMS: The primary clinical characteristics of Fanconi Anemia (FA) include typical physical features, progressive bone marrow failure, and an increased incidence of neoplasms, including esophageal carcinoma. Currently, there are no data regarding endoscopic findings or the interval time to malignancy in these patients. Data about the contribution of Human Papilloma Virus (HPV) to esophageal carcinoma is conflicting. Our objective is to document the upper gastrointestinal (GI) findings at baseline, document cancer incidence, and evaluate the role of HPV among these cancers. METHODS: We reviewed endoscopic and clinical data of FA subjects who participated in active surveillance before cancer diagnosis. Incident esophageal cancers were stained for HPV p16 protein. RESULTS: Eight FA patients were included (men 62.5%; median age at first endoscopy 20 years, median endoscopies number: 5.5). At baseline, 8/8 had endoscopic evidence for reflux esophagitis. In 3/8 the reflux esophagitis was mild and in 5/8 it was moderate or severe. During the follow up time (median time 4.5 years 2/8 developed Barrett's esophagus and 2/8 patients had incident esophageal squamous cell carcinoma during follow up, at intervals of eight and eighteen months from the previous upper endoscopy. Both cancers stained negative for HPV P16. CONCLUSIONS: FA subjects have both an extremely high risk for esophageal cancer within short intervals and a very high prevalence of reflux esophagitis with various severities. Active surveillance programs in specialized centers including annual upper endoscopies should be considered in these patients. PMID- 30249501 TI - Reply to "Reconsidering Sham in Transcutaneous Vagus Nerve Stimulation studies". PMID- 30249502 TI - A study detection of the ROS1 gene fusion by FISH and ROS1 protein expression by IHC methods in patients with ovarian malignant or borderline serous tumors. AB - OBJECTIVE: ROS1 is an orphan receptor protein tyrosine kinase which is supposed to undergo genetic rearrangement in carcinogenesis. In the current study, we aimed to investigate the frequency and clinicopathologic features associated with ROS1 gene fusion and ROS1 protein expression in patients with ovarian serous carcinoma or serous borderline tumors. MATERIALS AND METHODS: Tissue samples of 102 patients with high or low grade serous carcinoma and borderline serous tumors were selected randomly from the archives of Department of Gyneco-pathology, and analyzed for ROS1 gene expression. (Fluorescence in situ hybridization (FISH) method was used to assess ROS1 gene rearrangement, while ROS1 protein expression was analyzed using immunohistochemistry. RESULTS: The study consisted of 94 cases of high-grade serous carcinoma (92.1%), 2 cases of low-grade serous carcinoma (%2) and 6 cases of serous borderline tumor (5.9%). ROS1 gene rearrangement analysis revealed that 4 patients (3.9%) were FISH-positive; whereas the immunohistochemical analysis yielded only 1 patient (0.9%) exhibiting faint positive expression of ROS1 protein. Given the low incidences of ROS1 gene rearrangement and protein expression, their relationships with clinicopathologic parameters could not be statistically analyzed. CONCLUSION: Although rare, patients with ovarian serous carcinoma or serous borderline tumor may exhibit ROS1 gene rearrangement and ROS1 protein expression. Further large-scale studies are necessary to explore the clinicopathologic significance of ROS1 gene expression in ovarian serous carcinoma. PMID- 30249503 TI - Polymorphism of MMP-9 gene is not associated with the risk of urinary cancers: Evidence from an updated meta-analysis. AB - OBJECTIVE: Matrix metalloproteinases 9 (MMP-9) is a zinc-dependent gelatinase, which could decrease the expression of extracellular matrix proteins and influence the metastatic behavior of tumors. In order to draw a comprehensive and precise result about the relationship of MMP-9 and urinary cancers, we presented the current meta-analysis. METHODS: We searched the PubMed, EMbase, Web of Science, CBM, CNKI and Wanfang databases, the cited references were also manually searched again, covering all the papers published until August 2018. Quality assessment was conducted using the Newcastle-Ottawa Scale. All the meta-analysis was conducted with Stata version 12.0 software to assess the strength of the association. Linkage disequilibrium (LD) analyses of gene polymorphisms and in silico analysis of MMP-9 expression were also conducted to illustrate the relationship. RESULTS: 17 case-control studies comprise of more than 6154 cases and 6330 controls were enrolled and analyzed. After analyzed, we found that there is no significant association between rs3918241, rs2250889, rs17576 and rs17577 of MMP-9 and urinary cancers. LD analysis uncovered a significant LD between rs3918241 and rs17577 in CEU, CHB&CHS, ESN, and JPT populations (CEU: r2 = 1.0; CHB&CHS: r2 = 1.0; ESN: r2 = 0.74; JPT: r2 = 0.77), as well as a remarkable LD between rs17576 and rs2250889 in CHB&CHS and JPT populations (CHB&CHS: r2 = 0.81; JPT: r2 = 0.82). Furthermore, in-silico results indicated that the expression of MMP-9 in cancer tissue was higher than that in normal tissue in prostate cancer (Transcripts Per Kilobase Million (TPM) = 7.14 vs. 1.36, P < 0.001), bladder cancer (TPM = 14.2 vs. 2.47, P < 0.001), kidney renal clear cell carcinoma (TPM = 7.43 vs. 1.61, P < 0.001), kidney renal papillary cell carcinoma (TPM = 5.52 vs. 1.74, P = 0.002). CONCLUSIONS: rs3918241, rs2250889, rs17576 and rs17577 polymorphisms of MMP-9 are not associated with altered risk of urinary cancer. More studies with large sample size focused on the combined effect of two or more polymorphisms of MMP-9 are necessary in the future. PMID- 30249504 TI - miR-23 regulates cell proliferation and apoptosis of vascular smooth muscle cells in coronary heart disease. AB - BACKGROUND: Aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) play an important role in the pathogenesis of cardiovascular diseases including coronary heart disease (CHD). MicroRNAs has reported play critical roles in VSMCs function. The present study was to investigate the effects of microRNA-23 (miR-23) on VSMCs and uncover its potential mechanism. METHODS: Cell viability was detected by CCK-8 assay. Cell apoptosis was measured by flow cytometry. Dual luciferase reporter assay was conducted to verify whether BCL2L11 is a target gene of miR-23. The protein levels of BCL2L11 and caspase-3 were detect by quantitative real time PCR and western blot. RESULTS: Our results showed that the expression of miR-23 was upregulated in peripheral blood of CHD patients compared with controls. Overexpression of miR-23 promoted VSMCs proliferation and inhibited VSMCs apoptosis. Downregulation of miR-23 suppressed VSMCs proliferation and promoted VSMCs apoptosis. In addition, we identified BCL2L11 was a direct gene of miR-23. Overexpression of miR-23 decreased the levels of BCL2L11 and caspase-3, and downregulate of miR-23 increased the levels of BCL2L11and caspase-3 in VSMCs. CONCLUSION: Our findings suggest that miR-23 plays a crucial role in controlling VSMCs proliferation and apoptosis by targeting BCL2L11. PMID- 30249505 TI - The PD-1 rs36084323 A > G polymorphism decrease cancer risk in Asian: A meta analysis. AB - The rs36084323 A > G polymorphism in programmed cell death-1(PD-1) gene has been reported to be associated with cancer risk. However, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to identify the potential association, by searching the PubMed, EMBASE, Cochrane Library, and the Chinese CNKI, WANFANG and CBM databases. Data were extracted and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the strength of the association. A total of 10 relevant studies involving 4445 cancer cases and 5126 controls were recruited. Overall, the results indicated that the PD-1 rs36084323 A > G polymorphism was not statistically associated with cancer risk. However, stratified analysis revealed that there was a statistically reduced cancer risk in Asians(G vs. A, OR = 0.89, 95%CI:0.81-0.97, P = 0.008, I2 = 48.8%; GG vs. AA, OR = 0.79, 95% CI:0.66-0.94, P = 0.008, I2 = 48.7%; GG/AG vs. AA, OR = 0.87, 95%CI:0.76-0.98, P = 0.017, I2 = 34.9%; GG vs. AG/AA, OR = 0.85, 95%CI:0.75 0.97, P = 0.027, I2 = 40%) and in the patients with EOC(AG vs. AA, OR = 0.69, 95%CI:0.54-0.90, P = 0.005, I2 = 0%; GG/AG vs. AA, OR = 0.67, 95%CI:0.52-0.85, P = 0.001, I2 = 0). Meta-regression showed that ethnicity (P = 0.029) but not cancer types (P = 0.792), source of controls (P = 0.207) or ample size (P = 0.585) were the sources of heterogeneity. This meta-analysis demonstrates the PD 1 rs36084323 A > G polymorphism is associated with decreased cancer risk in Asian, and suggests it could potentially serve as a biomarker to screen high-risk individuals. Large-scale and well-designed case-control studies are needed to enrich the evidence of this result. PMID- 30249506 TI - 10 years after the Commission on Social Determinants of Health: social injustice is still killing on a grand scale. PMID- 30249508 TI - Ustekinumab: a promising new drug for SLE? PMID- 30249507 TI - Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. AB - BACKGROUND: Ustekinumab is a monoclonal antibody targeting interleukin (IL)-12 and IL-23 and is approved for the treatment of plaque psoriasis, psoriatic arthritis, and Crohn's disease. IL-12 and IL-23 have been implicated in systemic lupus erythematosus. We aimed to assess the efficacy and safety of ustekinumab for the treatment of systemic lupus erythematosus in patients with moderate-to severe disease activity despite conventional treatment. METHODS: This was a multicentre, double-blind, phase 2, randomised, controlled trial of adult patients with active, seropositive systemic lupus erythematosus, done at 44 private practices and academic centres in Argentina, Australia, Germany, Hungary, Mexico, Poland, Spain, Taiwan, and the USA. Eligible adults were aged 18-75 years, weighed at least 35 kg, and had a diagnosis of systemic lupus erythematosus at least 3 months before the first administration of study drug. Eligible patients were randomly assigned (3:2) to the ustekinumab or placebo group using an interactive web response system with stratification by skin biopsy, lupus nephritis presence, baseline systemic lupus erythematosus medications and systemic lupus erythematosus disease activity index 2000 (SLEDAI 2K) score combined factor, site, region, and race. Patients and investigators were masked to treatment allocation. Patients received an intravenous infusion of ustekinumab (260 mg for patients weighing 35-55 kg, 390 mg for patients weighing >55 kg and <=85 kg, and 520 mg for patients weighing >85 kg) followed by subcutaneous injections of ustekinumab 90 mg every 8 weeks or intravenous infusion of placebo at week 0 followed by subcutaneous injections of placebo every 8 weeks, both in addition to standard-of-care therapy. The primary endpoint was the proportion of patients achieving a SLEDAI-2K responder index-4 (SRI-4) response at week 24. Efficacy analyses were done in a modified intention-to-treat population of patients who received at least one dose (partial or complete, intravenous or subcutaneous) of their randomly assigned study treatment. Safety analyses were done in all patients who received at least one dose of study treatment, regardless of group assignment. This study is registered at ClinicalTrials.gov, number NCT02349061. FINDINGS: Between Oct 6, 2015, and Nov 30, 2016, 166 patients were screened, of whom 102 were randomly assigned to receive ustekinumab (n=60) or placebo (n=42). At week 24, 37 (62%) of 60 patients in the ustekinumab group and 14 (33%) of 42 patients in the placebo group achieved an SRI-4 response (percentage difference 28% [95% CI 10-47], p=0.006). Between week 0 and week 24, 47 (78%) of 60 patients in the ustekinumab group and 28 (67%) of 42 patients in the placebo group had at least one adverse event. Infections were the most common type of adverse event (27 [45%] in the ustekinumab group vs 21 [50%] in the placebo group). No deaths or treatment emergent opportunistic infections, herpes zoster, tuberculosis, or malignancies occurred between weeks 0-24. INTERPRETATION: The addition of ustekinumab to standard-of-care treatment resulted in better efficacy in clinical and laboratory parameters than placebo in the treatment of active systemic lupus erythematosus and had a safety profile consistent with ustekinumab therapy in other diseases. The results of this study support further development of ustekinumab as a novel treatment in systemic lupus erythematosus. FUNDING: Janssen Research & Development, LLC. PMID- 30249509 TI - A systematic review and meta-analysis of the aetiology of acute pancreatitis. AB - BACKGROUND: Gallstones and alcohol are currently the most frequent aetiologies of acute pancreatitis (AP). The aim of this study is to quantify these aetiologies worldwide, by geographic region and by diagnostic method. METHODS: A systematic review of observational studies published from January 2006 to October 2017 was performed. The studies provided objective criteria for establishing the diagnosis and aetiology of AP for at least biliary and alcoholic causes. A random-effects meta-analysis was used to assess the frequency of biliary (ABP), alcoholic (AAP) and idiopathic AP (IAP) worldwide and to perform 6 subgroup analyses: 2 compared diagnostic methods for AP aetiology and the other 4 compared geographic regions. RESULTS: Forty-six studies representing 2,341,007 patients of AP in 36 countries were included. The global estimate of proportion (95% CI) of aetiologies was 42 (39-44)% for ABP, 21 (17-25)% for AAP and 18 (15-22)% for IAP. In studies that used discharge code diagnoses and in those from the US, IAP was the most frequent aetiology. ABP was more frequent in Latin America than in other regions. CONCLUSION: Gallstones represent the main aetiology of AP globally, and this aetiology is twice as frequent as the second most common aetiology. PMID- 30249510 TI - Postoperative adjuvant transcatheter arterial chemoembolization should be considered selectively in patients who have hepatocellular carcinoma with microvascular invasion. AB - BACKGROUND: Microvascular invasion (MVI) is a powerful predictor of recurrence in patients who undergo liver resection for hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy of postoperative adjuvant transarterial chemoembolization (PA-TACE) in HCC patients with MVI, and further select potential patients benefitting from PA-TACE. METHODS: Patients who had HCC with MVI and underwent liver resection between September 2004 and December 2015 were identified for further analysis. Overall survival (OS) and disease-free survival (DFS) were compared between patients treated with and without PA-TACE. Propensity score matching analysis was used to minimize inter-group differences. RESULTS: A total of 176 patients with HCC and MVI were included. In both the entire and propensity-matched cohorts, OS and DFS were higher in PA-TACE group than non-TACE group (all P < 0.05). In subgroup analyses, PA-TACE showed efficacy in improving OS and DFS in HCC patients at early stage beyond Milan criteria and intermediate stage, but not in patients within Milan criteria. Multivariable analysis identified PA-TACE as a significantly favorable factor of OS and DFS for patients beyond Milan criteria, but not for those within Milan criteria. CONCLUSION: PA TACE could be beneficial for patients who have HCC with MVI beyond Milan criteria, but not for those within Milan criteria. PMID- 30249512 TI - Relationship of lipoprotein-associated apolipoprotein C-III with lipid variables and coronary artery disease risk: The EPIC-Norfolk prospective population study. AB - BACKGROUND: Plasma apolipoprotein C-III (apoC-III) levels are associated with coronary artery disease (CAD) risk. OBJECTIVE: To assess whether lipoprotein associated apoC-III levels predict risk of CAD events. METHODS: apoC-III associated with apoB, apoAI, and Lp(a) (apoCIII-apoB, apoCIII-apoAI, and apoCIII Lp(a), respectively) were measured using high-throughput chemiluminescent enzyme linked immunoassays in 2711 subjects (1879 controls and 832 cases with CAD) in the European Prospective Investigation into Cancer and Nutrition-Norfolk prospective population study with 7.4 years of follow-up. These measures were correlated with a variety of lipid measurements and the presence of CAD. The indices of "total apoCIII-apoB" and "total apoCIII-apoAI" were derived by multiplying plasma apoB and apoAI, respectively. RESULTS: apoCIII-apoB (P = .001), apoCIII-Lp(a) (P < .001), apoCIII-apoAI (P = .005) were higher in cases vs controls; tended to correlate positively with body mass index, hsCRP, apoC-III, low-density lipoprotein (LDL) cholesterol, triglycerides, remnant cholesterol, very low density lipoprotein, LDL and high-density lipoprotein particle number and very low density lipoprotein size; but negatively with LDL and high-density lipoprotein particle size (P < .001 for all). apoCIII-apoB, apoCIII-apoAI, apoCIII-Lp(a), total apoCIII-Lp(a), and total apoCIII-apoB were predictors of CAD after adjustment of age, sex, body mass index, smoking, diabetes, hypertensive and lipid-lowering drug use, but they lost their significance after further adjustment of lipid and lipoprotein variables. CONCLUSIONS: This study suggests that enzyme-linked immunoassay-measured lipoprotein-associated apoC-III markers reflect atherogenic lipid particles but do not independently predict risk of CAD events. PMID- 30249511 TI - Risk factors for cervical lymph node metastasis in endoscopically resected superficial hypopharyngeal cancers. AB - OBJECTIVE: Hypopharyngeal cancer is a head and neck cancer with a poor prognosis, and most cases show metastases on diagnosis. Cervical lymph node (LN) metastasis is a poor prognostic factor in hypopharyngeal cancer patients. The identification of risk factors for LN metastasis can help guide surgical treatment strategies for these patients. METHODS: This retrospective study included 93 superficial hypopharyngeal cancer patients with 109 histopathologically examined lesions treated by endoscopic resection between January 2007 and December 2017. Tumor thickness quantification, quantification of budding nests, immunostaining and other histopathological analyses in paraffin-embedded, formalin-fixed tissue sections (3-MUm) of surgical specimens were performed by a certified pathologist. RESULTS: Cervical LN metastasis was positive in 18 out of 93 cases (19.3%) and 18 out of 109 lesions (16.5%). No differences were detected in patient characteristics between LN-positive and LN-negative cases, except for tumor thickness, which was significantly larger in LN-positive cases (3119.4+/-602.2MUm vs. 1015.5+/-129.6MUm, respectively; p<0.0001). Univariate analysis showed that tumor thickness >=1000MUm (odds ratio: 5.559, p=0.003), lesions with high budding grade (odds ratio: 5.188, p=0.01) and vascular invasion (odds ratio: 12.710, p=0.007) were significantly associated with cervical LN metastasis. Multivariate analysis revealed tumor thickness>=1000MUm as the most significant risk factor for cervical LN metastasis in superficial hypopharyngeal cancer (odds ratio: 3.639, p=0.04). CONCLUSIONS: We demonstrate for the first time that high budding grade may serve as powerful predictors of LN metastasis and tumor thickness >=1000MUm is a significant risk factor for LN metastasis of superficial hypopharyngeal cancer. These results should be further examined in future larger scale studies. PMID- 30249513 TI - Prevalence of Haemophilus influenzae with alteration of PBP 3 sequence over a 1 year period in a French hospital: focus on a clinical failure after ceftriaxone treatment. AB - Among 547 Haemophilus influenzae isolates recovered in our center, 45 displayed a phenotype of loss of PBP 3 affinity (8.2%). Two isolates with 6 substitutions in PBP 3 showed decreased susceptibility to third-generation cephalosporins. Clinical data revealed clinical failure after ceftriaxone treatment in a context of bronchitis in a patient with pulmonary sarcoidosis. PMID- 30249515 TI - Transfer of Skills From Simulation Lab to Surgical Services: Impact of a Decade Long Laparoscopic Urology Surgical Course. AB - OBJECTIVE: To investigate the impact of decade-long dedicated laparoscopic urology surgical skills course on the successful implementation of surgical services by the participants. METHODS: A prospective database was maintained for all the participants in urological laparoscopic courses run by a single dedicated unit between January 2016 and December 2016. Data on various variables were collected using a follow-up validated questionnaire exploring speciality of clinical practice, challenges and need for additional training to establish clinical services, improvement in quality and frequency of laparoscopic courses. A subset of participants reported data of their outcomes in a national database available publically. RESULTS: One hundred sixty one delegates were drawn from 18 countries attended laparoscopic skills courses during the study period of 10years. Data were available for 154 (95.65%) participants. There were only 20 (20/154; 12.9%) responses to online website questionnaires despite 3 reminders. Further, follow-up through websites/telephonic contact/organizational contacts improved the response rate to 93% (143/154). Of the participants, 95% (135/143) felt that these courses should be continued, and they agreed to recommend them to their trainees in the future. More than 50% (81/143; 56.6%) of the participants performed laparoscopic/robotic surgery at various centers. Sixty two (62/143; 43.3%) did not pursue laparoscopic surgery as a career choice. Fifty six (56/81; 69%) participants were established laparoscopic surgeons were from the UK, and of them, 30 (30/56; 53.57%: 30/81; 37.04%) were established surgeons that contributed to publishing their results through professional organizations with the outcomes of all of these within normal ranges of their peers. CONCLUSIONS: A dedicated laparoscopic urological surgery course run over a decade had a significant impact on the skills of participants, and most participants were able to establish clinical practice catering to a large proportion of the UK population as well as a few centers internationally. PMID- 30249514 TI - Tell Me Straight: Teaching Residents to Disclose Adverse Events in Surgery. AB - OBJECTIVE: The purpose of this effort was to create an educational experience that provided learners a realistic disclosure experience and improved resident confidence discussing an adverse outcome with a patient and family. DESIGN: Residents practiced disclosing a surgical complication to a patient/family with simulated patients (SPs). We paired professional SPs with former patient SPs to present a realistic case. Junior residents were given extra training time before their disclosure of a laparoscopic cholecystectomy conversion to an open procedure; senior residents disclosed a bile duct injury. Residents rated pre and post-module confidence levels, and skills performance using the Disclosure of a Complication Checklist. SETTING: 900-bed tertiary care hospital with surgical residency program and simulation center. PARTICIPANTS: General surgery residents (PGY 1-5). RESULTS: Eighteen residents participated in the disclosure module. Analysis of the medians and interquartile ranges of pre and post-module confidence scores showed significant improvement for each individual item and mean score of learners. Residents assessed their completion rates of individual Checklist tasks positively. For example, 94% self-endorsed completion of "explanation of facts," 89% self-endorsed "took responsibility," and 78% self endorsed "apologized sincerely." Self-rated competence scores from the Checklist were low: 7% indicated they would be "extremely comfortable" entrusting their loved one's care to themselves, 11% rated their ability to explain the facts as "outstanding," and 12% felt they were "outstanding" in their "ability to disclose a complication in a professional manner." CONCLUSION: Residents received important skills practice in our disclosure training; disclosure confidence increased after participation. Residents scored high on completion of disclosure tasks and low on comfort and proficiency of those tasks. The Checklist provided a useful set of tasks to review and complete in the exercise. Separating residents by PGY level enabled senior residents to experience a more complex scenario and junior residents extra time to practice. PMID- 30249516 TI - Current Trends in Training in the Surgical Management of Acute Appendicitis at a Veteran Affairs Hospital. AB - INTRODUCTION: An open appendectomy used to be one of the most common cases performed by interns and physical exam dictated operative intervention. We hypothesized that the management of acute appendicitis has drastically changed from these previous practices. METHODS: A retrospective, single institution study was performed at the VA North Texas Health Care System between July 2005 to June 2017 for all patients who underwent an appendectomy. Using postgraduate year (PGY)-level (PGY 1-3 and PGY 4-5) as a dependent variable, univariate analyses, and multiple logistic regression analyses were performed. All statistical tests were 2-sided, and the statistical significance level was set at a p <= 0.05. RESULTS: Only patients with acute appendicitis were included (n = 257; male = 90.7%; age = 45.4 +/- 15.6 year old; body mass index = 30.3 +/- 6.3 Kg/m2). Of these, only 8 were performed by interns, 25 by PGY-2, 147 by PGY-3, 22 by PGY-4, and 55 by PGY-5. On presentation, 92.2% of patients had a computed tomography scan and 90.7% underwent a laparoscopic appendectomy. Conversion rate was 4.7%. There were 20 complications (7.8%) and length of hospital stay was 2.2+/-3.7 days. Comparing patients operated by senior (PGY-4 and 5) to junior (PGY-1 to -3) residents: patients were of similar age, gender, body mass index, American Society of Anesthesiologists (ASA), and had similar WBC and blood pressure on initial presentation (all p's > 0.05); but were more likely to have diabetes mellitus, hypertension or pulmonary disease. Complication rate was the same (7.8%) for both senior and junior residents. CONCLUSIONS: At the VA North Texas Health Care System, most patients presenting with suspected appendicitis undergo a computed tomography scan. Most cases are performed laparoscopically mainly by PGY >= 3 residents. The rate of post-operative complications was similar between junior and senior residents. PMID- 30249517 TI - Magnetic Resonance Imaging White Matter Hyperintensity as a Predictor of Stroke Recurrence in Patients with Embolic Stroke of Undetermined Source. AB - BACKGROUND AND PURPOSE: This study aimed to investigate factors associated with stroke recurrence and new-onset atrial fibrillation (AF) in patients with embolic stroke of undetermined source (ESUS). METHODS: Between January 2005 and March 2012, a total of 1514 consecutive patients were admitted to our hospital with a diagnosis of acute ischemic stroke within 7 days after onset. Of these, 236 patients met the diagnostic criteria for ESUS. A retrospective analysis was performed of the following characteristics of these ESUS patients: medical history, comorbidities, and magnetic resonance imaging (MRI) findings including the deep and subcortical white matter hyperintensity (DSWMH) grade, drugs used for preventing recurrence, and clinical information such as NIH Stroke Scale scores on admission and outcomes evaluated by modified Rankin scale. The rate of recurrence after discharge and the frequency of new-onset AF were also determined. RESULTS: There were 236 ESUS patients (141 men, mean age 70.2 +/- 12.1 years). During the follow-up period, ranging from 7 days to 12.9 years (median 54.3 months), 32 (13.6%) and 44 (18.6%) of these patients had a recurrent ischemic stroke and new-onset AF, respectively. The most prevalent subtype of recurrent ischemic stroke was ESUS itself; this type of stroke occurred in 19 (59.3%) patients. AF was observed at stroke recurrence, but only 2 patients were diagnosed with cardioembolism. Multivariate analysis with a Cox proportional hazard model demonstrated that DSWMH grade greater than or equal to 3 was significantly associated with both recurrent ischemic stroke (hazard ratio 3.66, 95% confidence interval 1.69-7.92, P = .001) and new-onset AF (2.00, 1.03-3.90, .04). CONCLUSIONS: MRI classification of white matter hyperintensity could be effectively used as a predictor for recurrent ischemic stroke and new-onset AF in patients with ESUS. PMID- 30249518 TI - Safety and Feasibility of Argatroban, Recombinant Tissue Plasminogen Activator, and Intra-Arterial Therapy in Stroke (ARTSS-IA Study). AB - BACKGROUND: A randomized trial of concurrent recombinant tissue-type plasminogen activator (r-tPA) + thrombin-inhibition with Argatroban in stroke patients recently demonstrated safety and signal of efficacy compared to r-tPA alone, but patients having endovascular therapy (EVT) were excluded. The current study intended to study feasibility and safety of concurrent r-tPA and Argatroban in patients undergoing EVT. METHODS: We conducted a single-arm, feasibility, and safety study of patients that received standard-dose r-tPA, had intracranial large vessel occlusions, and underwent EVT within 6 hours of stroke onset. During r-tPA, a 100 MUg/kg Argatroban bolus, followed by 12-hour infusion, targeted an activated Partial Thromboplastin Time (aPTT) 2.25 timesbaseline. Feasibility was defined as ability to combine treatments without EVT time-metric delays, compared to cotemporaneous r-tPA + EVT treatments. Safety was incidence of symptomatic intracerebral hemorrhage (sICH), systemic hemorrhage, or EVT complications. RESULTS: All preplanned 10 patients were enrolled. Arterial occlusions were middle cerebral artery (n = 8), internal carotid artery (n = 1), and posterior cerebral artery (n = 1). All received Argatroban before EVT and completed infusions. There were no delays in time-metrics compared to nonstudy patients during the same period. Nine patients achieved excellent angiographic reperfusion (Thrombolysis In Cerebral Ischemia [TICI] >=2b); with 7 complete (TICI = 3). There were no sICH, systemic hemorrhage, or EVT complications. At 90 days, 6 (60%) patients had a modified Rankin Scale of 0-2 and none died. CONCLUSIONS: In patients treated with r-tPA and EVT, concomitant Argatroban is feasible, does not delay EVT provision, produces high rates of recanalization, is probably safe, and warrants further study. PMID- 30249519 TI - The impact of age at the time of radiotherapy for localized prostate cancer on the development of second primary malignancies. AB - PURPOSE: There is a known increased risk of second primary malignancy (SPM) in patients with prostate cancer (CaP) treated with radiotherapy (RT). It is unclear how age at diagnosis influences the risk of SPMs. MATERIALS AND METHODS: Using the 1973 to 2013 Surveillance, Epidemiology, and End Results Program, we studied the impact of age on SPMs (defined as a bladder or rectal tumor) after localized CaP treatment with radical prostatectomy (RP) or RT. SPM risk was compared using inverse probability of treatment weighting (IPTW)-adjusted cumulative incidence function and competing-risk proportional hazard models. Overall survival (OS) in patients with SPM was compared using Kaplan Meier and Cox regression analyses. RESULTS: A total of 579,608 patients met inclusion criteria, and 51.8% of the cohort was treated with RT. The 10- and 20-year cumulative incidences of competing risk (IPTW adjusted) of SPMs were 1.9% (95%CI = 1.8-1.9%) and 3.6% (95%CI = 3.4-3.7%) after RP vs. 2.7% (95%CI = 2.6-2.8%) and 5.4%(95%CI = 5.3 5.6%) after RT. IPTW-adjusted competing risk hazard ratio (HR) of SPM after RT compared to RP was increased in the entire cohort (HR 1.46; 95%CI = 1.39-1.53, P < 0.001) and was highest in the youngest patients: Age <55 HR = 1.83 (95% confidence interval [CI] = 1.49-2.24, P<0.001), Age 55 to 64 HR = 1.66 (95%CI = 1.54-1.79, P < 0.001), Age 65-74 HR = 1.41 (95%CI = 1.33-1.48, P < 0.001), Age >=75 HR = 1.14 (95%CI = 0.97-1.35, P = 0.112). At 10 years, SPM-specific mortality occurred in 28.9% of patients treated with RT, though OS with SPM was worse in the youngest patients: Age <55 HR = 1.88 (95%CI = 1.25-2.81, P = 0.002), Age 55-64 HR = 1.60 (95%CI = 1.42-1.81, P < 0.001), Age 65-74 HR = 1.40 (95%CI = 1.30-1.52, P < 0.001), Age >= 75 HR = 1.27 (95%CI = 1.06-1.53, P = 0.009). All of the age categories had similar median follow-up times. CONCLUSION: At 10 years there is a 1.8% increased incidence of SPM after RT compared to RP, of which <30% of RT-treated patients with an SPM die as a result of a SPM. However, the risk of SPMs was greatest among younger men treated with RT for localized CaP, and this relationship could not be explained solely by follow-up time, latency time, or life expectancy. An improved understanding of those at the highest risk of SPMs may help tailor treatment and surveillance strategies. PMID- 30249521 TI - An Assessment of Perceived Barriers to Farmers' Market Access. AB - OBJECTIVE: To explore whether Supplemental Nutrition Assistance Program-Education (SNAP-Ed) stakeholders (individuals involved in work to increase access to farmers' markets [FMs] for low-income populations) perceive the same barriers to shopping at FMs as those reported by SNAP participants in Washington State. DESIGN: Descriptive study; data included a stratified clustered random sample of SNAP participants and stakeholder interviews. SETTING: Washington State. PARTICIPANTS: A total of 400 SNAP participants and 51 SNAP-Ed stakeholders. MAIN OUTCOME MEASURES: The SNAP participants' reported barriers to accessing FMs and the SNAP-Ed stakeholders' perceptions of FM access barriers. ANALYSIS: Thematic content analysis, descriptive statistics, 2-sample tests of proportion, and Pearson chi-square tests (P < .025). RESULTS: A majority of SNAP participants reported they did not shop at an FM because it is inconvenient (n = 193; 51%) and not financially viable (n = 84; 22%). Moreover, 9% of SNAP participants (n = 34) stated that they experienced no barriers. The SNAP-Ed stakeholders placed increased emphasis on transportation and cost barriers compared with the SNAP participants. CONCLUSIONS AND IMPLICATIONS: Comprehensive, multilevel strategies that reflect the perspectives of SNAP participants could increase SNAP use at FMs. Opening FMs in diverse locations at variable operating times may address convenience barriers while engaging the targeted populations' communities to promote FMs, and FM incentive programs may address financial and awareness barriers. PMID- 30249520 TI - Malignant testicular germ cell tumors in children and adolescents: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) protocol. AB - OBJECTIVES: We report the results of an Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) study on the treatment of testicular germ cell tumors (TGCT) with a pediatric PEB (pPEB) regimen (cisplatin 25 mg/m2 daily on days 1-4; etoposide 100 mg/m2 daily on days 1-4; bleomycin 15 mg/m2 on day 2, once per cycle). METHODS AND MATERIALS: Male patients under 18 years old with malignant TGCT were enrolled for a second national prospective protocol. All patients underwent orchiectomy at diagnosis. Those with Stage I received no chemotherapy; those with Stage II-III disease received three cycles of pPEB; and those with Stage IV received four cycles. After chemotherapy, resection of radiologically-evident residual disease was recommended. The main study end points were overall survival and relapse-free survival. RESULTS: Ninety-nine boys from 0.5 to 17.8 years old (median 15.4 years) were evaluable, and staged as follows: 58 Stage I (59%), 7 Stage II (7%), 14 Stage III (14%), and 20 Stage IV (20%). With a median follow-up of 59 months (range 4-165 months), 5-year relapse free survival (95% CI) was 73% (65%-83%) for the whole sample, 65% (53%-79%) for Stage I patients, and 86% (75%-98%) for Stage II-IV patients. Five-year overall survival (95% CI) was 99% (97%-100%). CONCLUSIONS: We confirmed a good prognosis for malignant TGCT in children and adolescents. Reducing the number of chemotherapy cycles for Stage II-III disease does not seem to negatively affect survival outcomes. PMID- 30249522 TI - Psychometric Testing of a Policy, Systems, and Environmental (PSE)-Focused SNAP Ed Evaluation Tool. AB - OBJECTIVES: To validate the Healthy Youth Environment Survey, a pre-then-post survey completed by teachers to capture nutrition and physical activity-related changes in the classroom and school environment. METHODS: Analysis included 679 pretest surveys. A factor analysis was conducted to establish construct validity and Cronbach alpha was established to assess internal consistency reliability. RESULTS: The factor analysis extracted 10 main factors, with 97% of variables loading (>= +0.30 factor loading) onto appropriate factors. After deleting one question, 6 of the 10 factors demonstrated acceptable internal reliability (Cronbach alpha >= 0.70). CONCLUSIONS AND IMPLICATIONS: After revision and subsequent retesting of construct validity, internal reliability, along with cognitive testing, The Healthy Youth Environment Survey may be suitable for use by other SNAP-Ed agencies implementing multi-level policy, systems, and environmental (PSE) interventions within youth education settings. PMID- 30249523 TI - Barriers to Food Literacy: A Conceptual Model to Explore Factors Inhibiting Proficiency. AB - Food literacy research typically conceptualizes food-related knowledge and skills as contributing to improved health and nutrition; however, there is limited research examining the process that leads to this improvement. This article reviews the literature reporting barriers to food literacy proficiency in order to examine the relationship between food-related knowledge, attitudes, and behaviors. Informed by these barrier types, its central objective is to develop a model of food literacy proficiency that highlights the relationship between nutrition education and health-related outcomes. This model will help researchers, educators, and nutrition professionals implement effective interventions with enhanced capacity to change food-related behaviors. PMID- 30249524 TI - Robust erythroid differentiation system for rhesus hematopoietic progenitor cells allowing preclinical screening of genetic treatment strategies for the hemoglobinopathies. AB - BACKGROUND AIMS: gamma-globin expression can be induced by various gene modification strategies, which could be beneficial for hemoglobin (Hb) disorders. To translate promising ideas into clinics, large animal models have proven valuable to evaluate safety and efficacy of the approaches; however, in vitro erythroid differentiation methods have not been established to determine whether they can be modeled in nonhuman primates. METHODS: We optimized erythroid differentiation culture to produce high-level adult Hb from rhesus hematopoietic progenitor cells by using low (LC) or high cytokine concentration (HC) protocols with or without feeder cells. In addition, we established rhesus globin protein analysis using reverse-phase high performance liquid chromatography and mass spectrometry. RESULTS: Robust adult Hb production at protein levels was observed in the LC protocol when feeder cells were used, whereas the HC protocol resulted in higher baseline fetal Hb levels (P < 0.01). We then compared lentiviral transduction of rhesus cells between serum-containing LC media and serum-free StemSpan-based differentiation media, revealing 100-fold more efficient transduction in serum-free differentiation media (P < 0.01). Finally, rhesus CD34+ cells were transduced with lentiviral vectors encoding artificial zinc finger proteins (ZF-Ldb1), which can reactivate gamma-globin expression via tethering the transcriptional co-regulator Ldb1 to gamma-globin promoters, and were differentiated in the optimized erythroid differentiation method. This resulted in marked increases of gamma-globin levels compared with control groups (P < 0.01). DISCUSSION: In conclusion, we developed an efficient rhesus erythroid differentiation protocol from hematopoietic progenitor cells with low fetal and high adult Hb production. Further studies are warranted to optimize gene modification and transplantation of rhesus hematopoietic progenitor cells. PMID- 30249525 TI - Duplex nested-PCR for detection of small ruminant lentiviruses. AB - Small ruminant lentiviruses (SRLV) have high genetic variability which results in different viral strains around the world. This create a challenge to design sensible primers for molecular diagnosis in different regions. This work proposes a protocol of duplex nested-PCR for the precise diagnosis of SRLV. The technique was designed and tested with the control strains CAEV Co and MVV 1514. Then, field strains were submitted to the same protocol of duplex nested-PCR. Blood samples of sheep and goats were tested with AGID and nested PCR with specific primers for pol, gag and LTR. The AGID results showed low detection capacity of positive animals, while the nested PCR demonstrated a greater capacity of virus detection. Results demonstrated that LTR-PCR was more efficient in detecting positive sheep samples, whereas gag-PCR allowed a good detection of samples of positive goats and positive sheep. In addition, pol-PCR was more efficient with goat samples than for sheep. Duplex nested PCR performed with standard virus samples and field strains demonstrated that the technique is more efficient for the detection of multiple pro-viral DNA sequences. This study demonstrated a successful duplex nested PCR assay allowing a more accurate diagnosis of SRLV. PMID- 30249526 TI - METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition. AB - OBJECTIVE: As the most prevalent internal modification in mammalian messenger RNA, N6-methyladenosine (m6A) plays an important role in posttranscriptional gene regulation. METTL3 is a key component of the m6A methyltransferase complex and has recently been shown to play important roles in cancer development and progression. The current study was aimed to explore the function and underlying mechanism of METTL3 in ovarian cancer. METHODS: METTL3 expression was assessed by immunohistochemistry in 162 ovarian carcinoma patients. Stable cell lines with METTL3 gene overexpression or knockdown were established to investigate the function of METTL3 in ovarian cancer in vitro and in vivo. RESULTS: METTL3 was frequently upregulated in ovarian carcinoma and that a high level of METTL3 was significantly associated with tumor grade (P = 0.001), pT status (P = 0.002), pN/pM status (P < 0.001), FIGO stage (P < 0.001), and overall survival rate (P < 0.001). Stable overexpression of METTL3 in the OVCAR3 and COV504 cell lines significantly increased cellular proliferation, focus formation, motility, invasion, and tumor formation in nude mice. Silencing METTL3 expression in the SKOV3 and HO-8910 cell lines with short hairpin RNA effectively inhibited its oncogenic function. Further study found that METTL3 promoted epithelial mesenchymal transition (EMT) by upregulating the receptor tyrosine kinase AXL. CONCLUSION: Our findings suggest that METTL3 plays very important oncogenic roles in ovarian carcinoma development and/or aggressiveness by stimulating AXL translation and EMT and that METTL3 may serve as a novel prognostic and/or therapeutic target of interest in ovarian cancer. PMID- 30249527 TI - It's time to warm up to hyperthermic intraperitoneal chemotherapy for patients with ovarian cancer. AB - The peritoneal spread of ovarian cancer makes it a potential target for hyperthermic intraperitoneal chemotherapy (HIPEC). Intraperitoneal delivery exposes the tumor to concentrations of cytotoxic drugs much greater than with intravenous delivery, and in vitro studies have also shown that combining hyperthermia and platinum leads to an additive cytotoxic effect. Pharmacokinetic analyses have confirmed very high concentrations of cytotoxic drugs in the peritoneal cavity, with minimal systemic exposure and toxicity. The majority of historical data evaluating HIPEC in ovarian cancer are based on retrospective research, which included heterogeneous groups of patients and drugs used for HIPEC. Recent publications on the findings of prospective studies, including the first randomized trial in which the only difference in intervention was the addition of HIPEC with cisplatin to interval debulking surgery in stage III patients, have shown a benefit in favor of HIPEC. Yet, a recent prospective study from Korea did not find a benefit. Opponents of HIPEC have cited higher rates of complications with this approach, yet most of the serious adverse events observed are likely related to the surgery itself, and are comparable to the rates reported in studies evaluating cytoreductive surgery without HIPEC. Findings from a recent randomized controlled trial showed no delays in initiation or completion of postoperative chemotherapy in patients treated with HIPEC. A growing body of evidence is indicating that it might be time to seriously consider HIPEC as a complementary treatment at the time of cytoreductive surgery for patients with advanced-stage ovarian cancer in the setting of an experienced center. Yet, more research is needed to identify the population of patients who gain the most benefit from this therapy. PMID- 30249528 TI - Enhanced recovery after surgery program in older patients undergoing gynaecologic oncological surgery is feasible and safe. AB - BACKGROUND: Enhanced Recovery After Surgery Programs (ERP) include multimodal approaches of perioperative patient's clinical pathways designed to achieve early recovery after surgery and a decreased length of hospital stay (LOS). By allowing patients to return rapidly to their everyday surroundings, older patients are those who could take the greatest benefit from ERP. This is the first study to date to assess feasibility and safety of ERP on older patients undergoing gynaecologic oncological surgery. METHODS: Data were prospectively collected between December 2015 and September 2017 at the Institut Paoli-Calmettes, a French comprehensive cancer centre. All the patients included in the study were referred for hysterectomy and/or pelvic or para-aortic lymphadenectomy for gynaecological cancer. The primary objective was to achieve similar LOS in patients >=70 years old compared to younger patients without increasing the proportion of complications and readmission rates. A binary (LOS < or >= 2 days) logistic regression was built, including age, Charlson score, BMI, ASA score, oncological indication, surgical procedures and surgical approaches. G8 score was estimated for all the >=70 years old patients. RESULTS: Of a total of 329 patients, 75 were >=70 years old and 254 were <70. Except a disparity in oncological indications with a higher proportion of endometrial cancer in the >=70 years old group (56% vs. 27%; p < 0.01), there were no differences in patient's characteristics and surgical procedures. Age >= 70 years was associated with a longer LOS (means, 3.88 vs. 3.11 days; p = 0.024) only in univariate analysis. Considering the logistic regression, age was no longer associated with LOS. Total hysterectomy with pelvic lymphadenectomy and ASA score >= 3 were independently associated with longer LOS while mini-invasive techniques were associated with a shorter LOS. Morbidities and readmissions occurred respectively in 23% and 8% of the total population without any difference between the two groups. In the >=70 years old population, G8 score was not predictive of LOS, morbidities or readmissions. CONCLUSION: Although it is already widely accepted that ERP improves early recovery, our study shows that ERP for patients over 70 years of age undergoing gynaecologic oncological surgery is as safe and feasible as on younger patients. PMID- 30249529 TI - Use of paracetamol, low-dose aspirin, or non-aspirin non-steroidal anti inflammatory drugs and risk of ovarian borderline tumors in Denmark. AB - OBJECTIVE: Few studies have examined ovarian borderline tumor (BOT) risk associated with analgesics, and with inconclusive findings. The aim was to examine serous borderline tumor (SBT) or mucinous borderline tumor (MBT) risk associated with use of paracetamol, low-dose aspirin, or non-aspirin non steroidal anti-inflammatory drugs (NSAIDs). METHODS: We identified all women with SBTs or MBTs in the Danish Pathology Data Bank, 1997-2015. Using risk-set sampling, we randomly selected 15 controls per case. We excluded women with previous cancer (except non-melanoma skin cancer) and controls with bilateral oophorectomy/salpingo-oophorectomy. Information on redeemed prescriptions of medications/confounders was identified from nationwide registries. We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We observed a decreased MBT risk among recent paracetamol users (OR = 0.77; 95% CI: 0.60-0.98), but no association with SBTs. Regarding non-aspirin NSAIDs, we found an increased SBT risk with recent (OR = 1.29; 95% CI: 1.11-1.51) and former use (OR = 1.19; 95% CI: 1.04-1.37), and an elevated MBT risk with recent use (OR = 1.14; 95% CI: 0.97-1.33). Low-dose aspirin use did not seem related with SBT risk, and the association with MBTs was unclear. CONCLUSIONS: No strong associations between the examined medications and BOTs were observed. However, our nationwide case-control study may suggest that recent paracetamol use could have a chemopreventive effect on MBTs, whereas neither low-dose aspirin nor non-aspirin NSAIDs use seem to protect against SBTs or MBTs. Larger studies are needed to firmly establish a potential association between these medications and BOT risk. PMID- 30249530 TI - Forensic science needs both the 'hedgehog' and the 'fox'. AB - Forensic science faces many challenges, some high profile and others that are less visible. It is argued that a holistic understanding of the complex matrix of forensic science is critical to robust and transparent forensic reconstruction approaches. This paper explores the value of incorporating the contrasting approaches to complexity of the 'hedgehog' and the 'fox', by illustrating their comparative strengths. The value of such collaboration in the context of a holistic understanding of the complex interactions that exist within forensic science, offers insights for developing approaches that can be taken to address the visible and less visible challenges at their root cause. PMID- 30249531 TI - Effect of postremission high dose cytarabine-based consolidation chemotherapy before allogenic stem cell transplantation in outcomes of acute myeloid leukemia patients. AB - BACKGROUND AND AIM: This is a retrospective study aiming to investigate the effect of the number of high dose cytarabine-based chemotherapy (HiDAC) courses in patients with acute myeloid leukemia before allogenic stem cell transplantation (ASCT). MATERIALS AND METHODS: A total of 110 patients with acute myeloid leukemia who received ASCT between 2001 and 2018 were included in the study. RESULTS: Of the 110 patients, 25 (23%) patients received one course of HiDAC, 42 (38%) patients received two courses of HiDAC, 34 (31%) patients received three courses of HiDAC and 9 (8%) patients received four courses of HiDAC. Median follow-up for survivors was 71 months (range 4-186) for all patients. The 3-year overall survival for patients who received one course of HiDAC and patients who received more than one course of HiDAC were 49% and 70%, respectively (p = 0.29). The 3-year disease free survival (DFS) for patients who received one course of HiDAC and patients who received more than one course of HiDAC were 38% and 66%, respectively (p = 0.05). There was no statistically significant difference in OS between patients who received one or more than one consolidation chemotherapy. But there was nearly a statistically significant difference between patients who received one or more than one consolidation chemotherapy in DFS. CONCLUSION: In conclusion, the administration of more than one consolidation chemotherapy may provide longer DFS, however the number of consolidation chemotherapy is not associated with statistically significant differences in overall outcomes. PMID- 30249532 TI - Apheresis education and certification for nurses. AB - Hematopoietic stem cell transplantation requires a wide-range of expertise and procedural competence, in which nurses play important roles throughout, including stem cell mobilization and collection by apheresis. Little is published about post-licensure nursing education in apheresis, which suggests that it proceeds at the discretion of individual institutions, supplemented with practical training by equipment manufacturers. Information can be obtained on a small number of apheresis training courses for nurses in Australia, Canada, Indonesia, Italy, The Netherlands, Sweden and Turkey, and on nurse certification systems in Turkey and the United States. There seems to be no certification officially linked to institutional accreditation or medical insurance reimbursement related to apheresis, except in Turkey. Because apheresis is associated with various adverse events, including citrate toxicity and vasovagal reactions, the Japan Society of Transfusion Medicine and Cell Therapy, in cooperation with 3 other speciality societies, started a "Qualified Apheresis Nurse" certification in 2010, when the Japan Marrow Donor Program officially added circulating stem cell collection to bone marrow harvest from unrelated donors as a source of hematopoietic stem cells. Questionnaire surveys, collected when nurses must renew or surrender their 5-year certification, show that our system matches nurses' learning desire and can be an objective and motive of their learning, thus leading to safer and more effective apheresis practice. We dare to imagine that an internationally standardized curriculum might emerge, to which we would contribute, and from which we would learn. PMID- 30249533 TI - Promising utilization areas of therapeutic plasmapheresis in cardiovascular surgery practice. AB - OBJECTIVE: Apheresis is performed for treatment of numerous diseases by removing auto-antibodies, antigen-antibody complexes, allo-antibodies, paraproteins, non Ig proteins, toxins, exogenous poisons. In current study, we present our experience of using therapeutic plasma exchange (TPE) in patients with different types of clinical scenarios. METHODS: Between January 2013 and May 2016, we retrospectively presented the results of 64 patients in whom postoperative TPE was performed in ICU setting after cardiac surgery. Patients were grouped into four as; 1-sepsis (n = 26), 2-hepatorenal syndrome(n = 24), 3-antibody mediated rejection(AMR) following heart transplantation(n = 4) and 4-right heart failure(RHF) after left ventricular asist device(LVAD)(n = 10). Hemodynamic parameters were monitored constantly, pre- and post-procedure peripheral blood tests including renal and liver functions and daily complete blood count (CBC), sedimentation, C-reactive protein and procalcitonin (ng/ml) levels were studied. RESULTS: The mean age was 61 +/- 17.67 years old and 56.25% (n = 36) were male. Mean Pre TPE left ventricular ejection fraction (LVEF) (%), central venous pressure (CVP)(mmHg) pulmonary capillary wedge pressure (PCWP)(mmHg) and pulmonary arterial pressure (PAP)(mmHg) were measured as 41.8 +/- 8.1, 15.5 +/- 4.4, 17.3 +/- 3.24 and 39.9 +/- 5.4, respectively. Procalcitonin (ng/ml) level of patients undergoing TPE due to sepsis was significantly reduced from 873 +/- 401 ng/ml to 248 +/- 132 ng/ml. Seventeen (26.5%) patients died in hospital during treatment, mean length of intensive care unit (ICU) stay(days) was 13.2 +/- 5.1. CONCLUSION: This study shows that TEP is a safe and feasible treatment modality in patients with different types of complications after cardiac surgery and hopefully this study will lead to new utilization areas. PMID- 30249534 TI - Isolated gluteal metastasis 3years after sufficiently treated oral squamous cell carcinoma: Case report and literature review. AB - Metastases from oral squamous cell carcinoma usually occur in the cervical lymph nodes. Distant skeletal muscle metastases are exceedingly rare and have been reported only in sporadic cases. A 70-year-old male patient was diagnosed with nonmetastatic oral squamous cell carcinoma (pT4a, N0, M0). The patient underwent successful surgical treatment involving tumor resection and selective neck dissection of both sides, including adjuvant radiotherapy. After 3years of uneventful course, with no clinical or radiographic evidence for local recurrence or metastasis, an isolated distant metastasis in the gluteal muscles was diagnosed. The patient died 7 months after diagnosis despite further surgical resection and adjuvant chemotherapy. Distant metastases are mostly accompanied by systemic spread of tumor cells. Thus, the prognosis is generally very poor. The therapeutic concept of surgical tumor resection and adjuvant chemotherapy failed to significantly improve the patient's prognosis in the present case. PMID- 30249535 TI - Prevalence, initiating factor, and treatment outcome of medication-related osteonecrosis of the jaw-a 4-year prospective study. AB - OBJECTIVES: Medication-related osteonecrosis of the jaw (MRONJ) has a wide range of prevalence, and a standard therapy has not yet been established. The aim of this study was to analyze the prevalence and initiating factors of MRONJ and the outcomes of surgical therapy. STUDY DESIGN: In a prospective cohort study, all patients diagnosed with MRONJ in the Region of Skane, in Sweden, were included. Predictor variables (comorbidity, site, stage, gender) and initiating factors (tooth extraction, periodontitis) were recorded. Surgical treatment was sequestrectomy or block resection, and the outcome variable was healing after 2 months. To estimate the prevalence, data on the use of bisphosphonate and denosumab were used. RESULTS: Fifty-five patients with MRONJ were identified. The prevalence of MRONJ was 0.043% among patients treated with oral bisphosphonates, 1.03% among those on intravenous bisphosphonates and 3.64% in those on high-dose denosumab. Periodontal disease preceded development of MRONJ in 41 patients. Fifty patients were treated surgically and followed up for at least 2 months. Remission or healing occurred in 80% of patients treated with sequestrectomy and in 92.5% of patients treated with block resection. CONCLUSIONS: The prevalence of MRONJ in Sweden is low. Periodontitis is the most common initiating factor. The outcome of treatment of MRONJ is healing in most patients treated surgically. PMID- 30249536 TI - Feasibility of a combination of intraoral UHFUS and CBCT in the study of peri implantitis. AB - OBJECTIVES: The aim of this study was to investigate the combination of intraoral ultra-high-frequency ultrasonography (UHFUS) and cone beam computed tomography (CBCT) in the evaluation of hard and soft tissues in a case of peri-implantitis. STUDY DESIGN: A 57-year-old patient was referred for pain and numbness of the chin after implant placement and the subsequent guided bone regeneration (GBR) procedure. Clinical examination revealed hard tumefaction of the mandibular mucosa, with mild mobility of the implants. Assessment with UHFUS was undertaken for the study of the width, degree of tissue alteration, and vascularity of the swollen mucosa, and CBCT was used to evaluate the bone surrounding the implants and the possible impingement of the inferior alveolar nerve. RESULTS: A combination of CBCT and UHFUS was effective in the evaluation of GBR complications in peri-implantitis, revealing alterations in the periosteum secondary to suboptimal GBR treatment. This was the first study to use UHFUS to evaluate the characteristics of oral soft tissues. CONCLUSIONS: UHFUS is a promising tool for the diagnosis of complicated soft tissue diseases. When used with CBCT, it can provide useful information on oral and maxillofacial diseases involving hard and soft tissue in a noninvasive way, with reduced radiation dose exposure. PMID- 30249537 TI - Longitudinal morphometric analysis of dental arch of children with cleft lip and palate: 3D stereophotogrammetry study. AB - OBJECTIVE: This study aimed to perform a longitudinal morphometric analysis of the alterations of the maxillary dental arches in children with cleft lip and palate before and after primary lip and/or palate surgeries using a 3-dimensional stereophotogrammetry system. STUDY DESIGN: The sample consisted of dental casts of 60 children with complete unilateral cleft lip (UCL) and complete unilateral cleft lip and palate (UCLP). Dental arches were evaluated before cheiloplasty (T1), after cheiloplasty (T2), and 1 year after palatoplasty (T3). Independent t test and Mann-Whitney U test were used for intergroup comparisons, and paired t test, Wilcoxon's test, and repeated-measures analysis of variance (ANOVA), followed by Tukey's test, were used for intragroup comparisons. RESULTS: At T1, the intercanine and intertuberosity distances in the UCLP group were statistically greater than those in the UCL group. At T2, the maxillary dimensions significantly increased, except for the intertuberosity distance in UCL. Between T1 and T3, the intercanine distance and the anterior length decreased significantly, whereas the intertuberosity distance and the total length of the palate increased significantly. CONCLUSIONS: Our results indicated that the primary lip surgery altered the development of dental arches, evidently in children with UCLP. The primary palate surgery interfered in the growth of the anterior palatal region in the UCLP group. Children with UCLP had more restricted development of the maxillary dental arch compared with children with UCL. PMID- 30249538 TI - A 48-year-old female with an exophytic nodule in the buccal mucosa. PMID- 30249539 TI - IL-7R-mediated signaling in T-cell acute lymphoblastic leukemia: An update. AB - Interleukin 7 (IL-7) and its receptor (IL-7R, a heterodimer of IL-7Ralpha and gammac) are essential for normal lymphoid development. In their absence, severe combined immunodeficiency occurs. By contrast, excessive IL-7/IL-7R-mediated signaling can drive lymphoid leukemia development, disease acceleration and resistance to chemotherapy. IL-7 and IL-7R activate three main pathways: STAT5, PI3K/Akt/mTOR and MEK/Erk, ultimately leading to the promotion of leukemia cell viability, cell cycle progression and growth. However, the contribution of each of these pathways towards particular functional outcomes is still not completely known and appears to differ between normal and malignant states. For example, IL 7 upregulates Bcl-2 in a PI3K/Akt/mTOR-dependent and STAT5-independent manner in T-ALL cells. This is a 'symmetric image' of what apparently happens in normal lymphoid cells, where PI3K/Akt/mTOR does not impact on Bcl-2 and regulates proliferation rather than survival. In this review, we provide an updated summary of the knowledge on IL-7/IL-7R-mediated signaling in the context of cancer, focusing mainly on T-cell acute lymphoblastic leukemia, where this axis has been more extensively studied. PMID- 30249540 TI - Nuclear phosphoinositides and phase separation: Important players in nuclear compartmentalization. AB - Nuclear phosphoinositides are recognized as regulators of many nuclear processes including chromatin remodeling, splicing, transcription, DNA repair and epigenetics. These processes are spatially organized in different nuclear compartments. Phase separation is involved in the formation of various nuclear compartments and molecular condensates separated from surrounding environment. The surface of such structures spatiotemporally coordinates formation of protein complexes. PI(4,5)P2 (PIP2) integration into phase-separated structures might provide an additional step in their spatial diversification by attracting certain proteins with affinity to PIP2. Our laboratory has recently identified novel membrane-free PIP2-containing structures, so called Nuclear Lipid Islets (NLIs). We provide an evidence that these structures are evolutionary conserved in different organisms. We hypothesize that NLIs serve as a scaffolding platform which facilitates the formation of transcription factories, thus participating in the formation of nuclear architecture competent for transcription. In this review we speculate on a possible role of NLIs in the integration of various processes linked to RNAPII transcription, chromatin remodeling, actin-myosin interaction, alternative splicing and lamin structures. PMID- 30249542 TI - Rib fractures: elusive, but important. PMID- 30249541 TI - Chest radiographs versus CT for the detection of rib fractures in children (DRIFT): a diagnostic accuracy observational study. AB - BACKGROUND: Internationally, chest radiography is the standard investigation for identifying rib fractures in suspected physical abuse in infants. Several small observation studies in children have found that chest CT can provide greater accuracy than radiography for fracture detection, potentially aiding medicolegal proceedings in abuse cases; however, to our knowledge, this greater accuracy has not been comprehensively evaluated. We aimed to determine differences in rib fracture detection rates between post-mortem chest radiographs and chest CT images, using forensic autopsy as the reference standard. METHODS: In this retrospective diagnostic accuracy study, we searched the Great Ormond Street Hospital (London, UK) radiology information system for all children aged 0-16 years who had a post-mortem skeletal survey (ie, full-body radiography), CT, and full autopsy between Jan 1, 2012, and Jan 1, 2017, for a purpose of death investigation. Cases were excluded if the imaging was done for a reason other than a forensic investigation or if image quality was suboptimal. Radiologists were recruited as reporters on a voluntary basis via membership databases from international radiology and post-mortem imaging societies with no specific inclusion or exclusion criteria. Reporters were sent a set of chest radiographs on a password protected and encrypted USB flash drive or via a secure filesharing website and independently reported on the presence of rib fractures, fracture location, and the confidence level of their interpretation. They were masked to the clinical information of the images. 1 month later, the same reporters were sent CTs for the same cases in a random order and asked to report on the same features. The primary objective was to compare the accuracy of detection of rib fractures by use of post-mortem chest radiographs and CTs, with autopsy data as reference standard. Accuracy was assessed by comparison of diagnostic statistics, calculated using random-intercept multilevel logistic models with reporter and patient included as cross-classified random-effects. FINDINGS: 25 cases of children (aged 1 month to 7 years), with 136 rib fractures at autopsy with paired post-mortem chest radiographs and CTs, were selected for analysis. 38 radiologists were recruited as reporters from 23 international centres; 12 (32%) were consultants, median experience of 14.5 years (range 6-27), and 26 (68%) were registrars, median experience of 4 years (range 2-9). Across all radiologists, three times as many rib fractures were correctly detected by use of chest CTs compared with chest radiography (sensitivity 44.9% [95% CI 31.7-58.9] vs 13.5% [8.1-21.5]; difference 31.4% [23.3-37.8; p<0.001]). Sensitivity for detection on the correct rib was higher by use of CT than by use of radiography (62.4% [95% CI 44.9-77.1] vs 23.1% [12.9-37.8]; difference 39.3% [31.9-42.2; p<0.001]), as was diagnosis of a patient with any rib fracture or fractures (81.5% [75.8-86.0] vs 64.7% [57.3-71.4]; difference 16.7% [11.5-22.2; p<0.001]). Radiologist confidence was higher when using CT images than radiographs (highest confidence rating given on 3317 [63.6%] of 5218 fractures for CT vs 1518 [46.6%] of 3303 on radiographs) and was a predictor for accurate fracture detection. INTERPRETATION: Chest CT provides greater accuracy than conventional chest radiography for post-mortem rib fracture detection, irrespective of radiologist experience or fracture location, although both methods detected a substantial number of false positives. The diagnostic accuracy of CT should be studied further in live children ideally in a multicentre trial to assess the applicability of our results. FUNDING: Great Ormond Street Children's Charity, Medical Research Council, Royal College of Radiologists, Research Councils UK, National Institute for Health Research. PMID- 30249543 TI - Histone deacetylase inhibitor suberoylanilide hydroxamic acid alleviates liver fibrosis by suppressing the transforming growth factor-beta1 signal pathway. AB - BACKGROUND: Histone deacetylases (HDACs) inhibitors are new anti-fibrotic drugs that inhibit the activity of hepatic stellate cells. The present study focused on the anti-fibrotic function of HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) by suppressing transforming growth factor-beta1 (TGF-beta1) signaling. METHODS: Male Sprague-Dawley rats were used to induce liver fibrosis with carbon tetrachloride (CCl4) and LX2 cell (human hepatic stellate cell line) was stimulated by TGF-beta1. Both animals and cells were treated with SAHA. The Smad7 and connective tissue growth factor (CTGF) mRNA levels were detected by real-time polymerase chain reaction (PCR). Western blotting was used to examine the protein levels of CTGF, Histone H3 (H3), Smad7, Smad2/3, Acetyl-Histone H3 (AH3), HDAC2, alpha-smooth muscle actin (alpha-SMA), HDAC6, p-Smad2/3 and HDAC8. In addition, the TGF-beta1 and liver enzyme levels from rat serum were detected. Histopathological changes were examined by hematoxylin and eosin (HE), Sirius red and Masson trichrome staining. The alpha-SMA expression was detected by immumohistochemical staining. RESULTS: Compared with control group, the TGF-beta1 and liver enzyme levels from rat serum, together with the mRNA levels of CTGF and protein levels of CTGF, HDAC2, alpha-SMA, HDAC6, p-Smad2/3 and HDAC8 were elevated in fibrotic rats (P < 0.01). But the Smad7 mRNA and AH3 protein levels were notably suppressed in the fibrotic rats (P < 0.01). Pathological examination showed the typical changes of liver fibrosis in the fibrotic rats. After the treatment with SAHA, the levels of liver enzymes, TGF-beta1, CTGF, HDAC2, alpha SMA, HDAC6, p-Smad2/3 and HDAC8 were reduced (P < 0.01) and Smad7 and AH3 protein contents were elevated in liver fibrotic rats (P < 0.01). Moreover, immumohistochemistry showed that SAHA significantly suppressed the alpha-SMA protein content in fibrotic liver (P < 0.01). CONCLUSION: The HDAC inhibitor SAHA alleviated liver fibrosis by suppressing the TGF-beta1 signaling. PMID- 30249544 TI - Nerve growth factor as a new treatment for testosterone deficiency? PMID- 30249545 TI - Increased risk of depression in non-depressed HIV infected men with sleep disturbance: Prospective findings from the Multicenter AIDS Cohort Study. AB - OBJECTIVE: Sleep disturbance is a known risk factor for depression, but it is not known whether sleep disturbance contributes to greater risk of depression in those infected with human immunodeficiency virus (HIV+) as compared to those uninfected with HIV (HIV-). METHODS: Using data from the Multicenter AIDS Cohort Study, a population-based prospective study of men who have sex with men (MSM), self-reported sleep disturbance (>2 weeks) and depressive symptoms (Clinical Epidemiologic Scale for Depression, CES-D) were assessed every 6 months over 12 years of follow-up. Adjusted mixed effects logistic regression analyses tested whether sleep disturbance predicted depression (CES-D >= 16) at the immediate subsequent visit, and so on over 12 years, in non-depressed HIV+(N = 1054; 9556 person-visits) and non-depressed HIV- (N = 1217; 12,680 person-visits). In HIV+ vs. HIV- MSM, linearly estimated average incidence of depression and normalized cumulative rate of depression over 12 years were compared. RESULTS: In the HIV+ MSM, sleep disturbance was associated with a significant increase in depression 6 months later (OR = 1.6; 95% CI, 1.30, 1.96), which was significantly greater (P < .05) than in HIV- MSM (OR = 1.16; 95% CI, 0.94, 1.44). HIV status and sleep disturbance interacted (P < .001), such that incidence of depression and normalized cumulative rate of depression were greater in HIV+ with sleep disturbance than in HIV+ without sleep disturbance and HIV- groups (all P's < 0.001). CONCLUSIONS: HIV+ persons who report sleep disturbance represent a high risk group to be monitored for depression, and possibly targeted for insomnia treatment to prevent depression. FUND: National Institute of Allergy and Infectious Diseases. PMID- 30249547 TI - Latex Allergy Risks Live On. AB - Reduction in the prevalence of IgE-mediated allergy to latex proteins from gloves in patients may lead to lax attention by health care personnel to avoid use of latex products in latex-allergic subjects. Recent evidence from the Pennsylvania Patient Safety Reporting System shows an alarming continuation of adverse events mostly from latex urinary catheters. We are strongly advocating that health care personnel must continue to pay close attention to avoidance of latex in patients with a history of latex allergy. PMID- 30249546 TI - Impact of a single HLA-A*24:02-associated escape mutation on the detrimental effect of HLA-B*35:01 in HIV-1 control. AB - BACKGROUND: HLA-B*35 is an HLA allele associated with rapid progression to AIDS. However, a mechanism underlying the detrimental effect of HLA-B*35 on disease outcome remains unknown. Recent studies demonstrated that most prevalent subtype HLA-B*35:01 is a detrimental allele in HIV-1 clade B-infected individuals. We here investigated the effect of mutations within the epitopes on HLA-B*35:01 restricted CD8+ T cells having abilities to suppress HIV-1 replication. METHODS: We analyzed 16 HLA-B*35:01-restricted epitope-specific T cells in 63 HIV-1 clade B-infected Japanese B*35:01+ individuals and identified HLA-B*35:01-restricted CD8+ T cells having abilities to suppress HIV-1 replication. We further analyzed the effect of HLA-associated mutations on the ability of these T cells. FINDINGS: The breadth of T cell responses to 4 epitopes was inversely associated with plasma viral load (pVL). However, the accumulation of an Y135F mutation in NefYF9 out of the 4 epitopes, which is selected by HLA-A*24:02-restricted T cells, affected the ability of YF9-specific T cells to suppress HIV-1 replication. HLA B*35:01+ individuals harboring this mutation had much higher pVL than those without it. YF9-specific T cells failed to suppress replication of the Y135F mutant in vitro. These results indicate that this mutation impairs suppression of HIV-1 replication by YF9-specific T cells. INTERPRETATION: These findings indicate that the Y135F mutation is a key factor underlying the detrimental effect of HLA-B*35:01 on disease outcomes in HIV-1 clade B-infected individuals. FUND: Grants-in-aid for AIDS Research from AMED and for scientific research from the Ministry of Education, Science, Sports, and Culture, Japan. PMID- 30249548 TI - COVERING THE COVER. PMID- 30249549 TI - Serum biomarkers for the evaluation of liver fibrosis: The need for better tests. PMID- 30249550 TI - Does Helicobacter pylori infection influence the major postoperative complication rate after sleeve gastrectomy? A retrospective cohort study in an endemic region. AB - BACKGROUND/AIMS: Helicobacter pylori infection is very common in Eastern countries. Little is known about the impact this infection has on bariatric surgery outcomes. This retrospective cohort study conducted on obese Turkish adults who underwent sleeve gastrectomy at a single center aimed to determine the prevalence of H. pylori infection and the effect of this infection on the rate of early major postoperative complications. MATERIALS AND METHODS: All consecutive patients who underwent sleeve gastrectomy for obesity between 2014 and 2015 and who had complete data were enrolled. A single surgeon performed all procedures. All resected specimens were sent to pathology for analysis. RESULTS: Of the 460 patients who met the eligibility criteria, 326 (71%) were female. The average (+/ standard deviation) age and body mass index were 37.5+/-10.0 years and 42.7+/-7.7 kg/m2, respectively. Histology revealed that 150 (33%) patients had H. pylori infection. The H. pylori-infected group developed two complications (leakage and intra-abdominal collection). The uninfected group developed three complications (all bleeding related). The two groups did not differ significantly regarding postoperative complication rates (1.3% vs. 1.0%; p=0.717). CONCLUSION: H. pylori infection did not affect the rate of early complications after sleeve gastrectomy. This suggests that H. pylori screening or eradication policy is not essential for asymptomatic candidates who have undergone sleeve gastrectomy. PMID- 30249551 TI - Does the number of mucosal immune cells differ in irritable bowel syndrome and its subtypes? AB - BACKGROUND/AIMS: Recently, mucosal inflammation has been proposed to be one of the mechanisms underlying the pathophysiology of irritable bowel syndrome (IBS); however, there are controversial results regarding this hypotheses. Our aim was to evaluate immune cell infiltration in rectal and ileal biopsy specimens of patients with IBS and to compare it with those of healthy controls. MATERIALS AND METHODS: In total, 36 patients with IBS (15 with diarrhea and 21 with constipation) and 16 healthy volunteers were enrolled. Ileocolonoscopy and ileal/rectal biopsies were performed. Rectal and terminal ileal biopsy specimens were evaluated for mucosal immune cell infiltration using immunohistochemical analysis. Serotonin positivity as well as counts of intraepithelial lymphocytes (IEL) and CD4+, CD8+, CD20+, and CD3+ cells were determined by a single pathologist who is an expert in the gastrointestinal system. RESULTS: CD3+ and CD4+ cell counts in rectal and terminal ileal biopsy specimens were lower in the IBS group than in the controls. Conversely, there was no statistically significant difference between the IBS and control groups in terms of serotonin positivity as well as counts of IEL and CD20+ and CD8+ cells. Comparison between the IBS subgroups revealed a higher number of IEL in rectal biopsy specimens of the diarrhea dominant group. In the IBS subgroups, immune cell counts in terminal ileal and rectal biopsy specimens showed a positive correlation. CONCLUSION: IBS and its subgroups showed lower immune cell counts than the controls in our study. These results indicate that there is no significant mucosal inflammation in homogeneous groups of patients with IBS. Rectal biopsies may be sufficient for the evaluation of inflammation in IBS. PMID- 30249552 TI - Detection and clinical significance of DNA repair gene ERCC8 tag SNPs in gastric cancer. AB - BACKGROUND/AIMS: Excision repair cross-complementing group 8 (ERCC8) is one of the members of the nucleotide excision repair pathway. This study aimed to explore the association between ERCC8 tag single nucleotide polymorphisms (SNPs) and gastric cancer. MATERIALS AND METHODS: Totally, 120 patients with gastric cancer treated from March 2010 to March 2011 were selected as the observation group and 120 healthy individuals were selected as the control group during the same period. The Sequenom MassARRAY system was used to identify genotypes in these samples. The genetic locus of ERCC8 tag SNPs and the relevance of gastric cancer risk to the different ERCC8 genotypes alone or in combination with Helicobacter pylori infection were observed and analyzed. The AA, GA, and GG genotypes on rs158572 and rs158916 in the observation and control groups were compared. RESULTS: The results showed that the odds ratio of the different ERCC8 rs158572 and rs158916 genotypes was not significantly increased in the observation group compared with that in the control group. By contrast, in patients with H. pylori infection, the ERCC8 rs158572 GA/GG and rs158916 TT genotypes showed a 7.921-fold and 8.021-fold [95% confidence interval (CI)=4.022 15.921, p=0.029 and 95% CI=3.021-15.092, p=0.021, respectively] increased risk of gastric cancer than the AA and CT/CC genotypes, respectively. CONCLUSION: Helicobacter pylori infection combined with ERCC8 rs158572 and rs158916 can be used as a predictive index of gastric cancer occurrence. PMID- 30249553 TI - Diagnostic accuracy of fecal calprotectin for screening patients with colorectal cancer: A meta-analysis. AB - BACKGROUND/AIMS: Fecal calprotectin (FC) is reported to have a broad diagnostic accuracy for colorectal cancer (CRC). Therefore, we explored the diagnostic value of FC for CRC using meta-analytical techniques to substantiate the assertion. MATERIALS AND METHODS: An electronic search of the MEDLINE and Embase databases was conducted to identify studies that assessed the diagnostic accuracy of FC for CRC. The sensitivities and specificities of the eligible studies were summarized using a bivariable random-effects model. RESULTS: In total, 20 studies were included in the final analysis. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of FC for CRC detection were 0.83 (95% confidence interval CI, 0.77-0.88), 0.61 (95% CI, 0.54-0.68), 2.15 (95% CI, 1.82-2.55), and 0.28 (95% CI, 0.21-0.37), respectively. The overall diagnostic odds ratio of FC for CRC was 7.76 (95% CI, 5.41-11.12) with an area under the curve of 0.81 (95% CI, 0.77-0.84), whereas the diagnostic value of FC for colorectal adenoma was relatively inferior (area under the curve, 0.55; 95% CI, 0.51-0.59; diagnostic odds ratio, 1.27; 95% CI, 0.91-1.78). CONCLUSION: The results imply that the FC test, as currently implemented, cannot be recommended for CRC detection. PMID- 30249554 TI - Predictive parameters of early postoperative complications in Crohn's disease: Single team experience. AB - BACKGROUND/AIMS: Most of the patients with Crohn's disease (CD) may require at least one surgical procedure over their lifetime. However, these patients tend to have a high incidence of postoperative complications. The aim of this retrospective study was to investigate the predictive parameters of postoperative complications in CD. MATERIALS AND METHODS: All consecutive patients with CD between March 2001 and March 2016 who underwent bowel resection were included to this study. Postoperative complications were divided as; major complications including anastomotic leakage, ostomy complications, acute mechanical intestinal obstruction and hemorrhage, and minor complications including wound infection. RESULTS: A total of 147 patients (74 females, 73 males) with a mean age of 36+/ 11.9 years met the inclusion criteria. Behaviors of CD were stricturing in 90 (62%), fistulizing in 45 (30%) and inflammatory in 12 (8%) patients. Minimally invasive approach was applied in 35% (n=51) of the patients. Twentysix (17%) patients had early (<=30 days) postoperative surgical complications including anastomotic leak (n=10), intra-abdominal bleeding (n=2), complications related to ostomy (n=2), acute mechanical intestinal obstruction (n=1) and wound infection (n=11). Only fistulizing disease behavior was associated with early postoperative complications (p=0.014). CONCLUSION: This study suggests that postoperative complications are still more common in fistulizing CD. Surgical approach did not affect the complication rate. The decision should be individualized according to the prominent risk factors and surgeons' preference. PMID- 30249555 TI - Real world survival data of a rare malignancy: Anal cancer results in HIV negative patients from Turkey. AB - BACKGROUND/AIMS: An organ preservation approach using chemoradiotherapy has been established for anal cancer. This retrospective cohort study aimed to define the clinico-demographic characteristics and outcomes of cases of human immunodeficiency virus (HIV)-negative anal carcinoma during a period of 20 years in a single comprehensive cancer institute. MATERIALS AND METHODS: This was a single-center retrospective cohort study of patients who were treated between January 1995 and January 2015. The primary outcome measures that were investigated included overall survival (OS), progression-free survival (PFS), colostomy rates, and colostomy-free survival (CFS). RESULTS: A total of 28 patients who were principally treated with standard 5-fluorouracil + mitomycin combination chemoradiotherapy were eligible for analysis. The 3- and 5-year PFS rates were 92.4% and 63%, respectively. The lower T stage was found to be associated with a prolonged PFS (p=0.001). The 3- and 5-year CFS rates were 84.3% and 74.9%, respectively. A longer CFS was observed with lower T stages (p=0.05). At the last follow-up, 75% of the patients with anal cancer were alive, and 71.4% of the patients were disease free. The median OS was not reached with a median follow-up of 54 months (range, 6-115 months). The 3- and 5-year OS rates were 82% and 71.1%, respectively. No late toxicity was observed during the follow-up period. DISCUSSION: The short- and long-term prognoses of HIV-negative patients with anal squamous cell carcinoma were good, and low-grade toxicity was rare, thereby demonstrating that these patients can be successfully treated in a real life setting with favorable outcomes. PMID- 30249556 TI - Physicians' attitude and perception regarding celiac disease: A questionnaire based study. AB - BACKGROUND/AIMS: Despite its high prevalence, affecting about 1% of the general population, celiac disease (CD) remains heavily underdiagnosed. Among the reasons for underdiagnosis, awareness among medical professionals has been little studied. The aim of this survey was to determine physicians' knowledge in regard to CD in adult patients. MATERIALS AND METHODS: An 18-items questionnaire pointing out general features, clinical presentation, diagnosis and management of CD patients was addressed to physicians from different medical specialties, in training or board-certified, from one universitary center. RESULTS: Altogether 153 physicians were invited to complete the survey (69.3% female, 35.9% gastroenterologists). Overall, 69.9% of the physicians questioned considered CD as a rare disorder. Lymphoma increased risk was highlighted in significant higher proportion by gastroenterologists when compared with physicians of other medical specialty. Chronic diarrhea, weight loss, iron-deficiency anemia, and abdominal pain were the first four conditions recognized as associated with CD, by 94.1%, 76.5%, 61.4%, and 54.2% study participants, respectively. About one-third of respondents (34.5%) affirmed to perform total serum IgA testing in all patients tested for CD. Intestinal biopsy confirmation of a positive celiac serology was reported by 65.4% physicians, with a higher proportion among gastroenterologists: 81.5% versus 56.6%. In regard to CD management, both groups concluded that referral to specialized centers should be recommended. CONCLUSION: This study highlights poor awareness among the physicians' in regard to important CD features and diagnostic recommendations in adult patients. More efforts are warranted to improve awareness on CD features among physicians of different medical specialties. PMID- 30249557 TI - Potential role of chromatin remodeling factor genes in atrophic gastritis/gastric cancer risk. AB - BACKGROUND/AIMS: Atrophic gastritis (AG), intestinal metaplasia (IM), and Helicobacter pylori (HP) are the risk factors for the development of gastric cancer (GC). Chromatin remodeling is one of the epigenetic mechanisms involved in the carcinogenesis of GC. The purpose of this study was to investigate the expression profiles of defined chromatin remodeling genes in gastric mucosal samples and their values as gastric carcinogenesis biomarkers. MATERIALS AND METHODS: In total, 95 patients were included in the study. Patients were divided into 3 groups as: GC group (n=34), AG group (n=36), and control group (n=25). AG group was further divided into subgroups based on the presence of HP and IM in gastric mucosa. Chromatin remodeling gene expressions were analyzed using real time PCR (RT-PCR) array in all groups. Data were evaluated using the RT-qPCR primer assay data analysis software. RESULTS: EED, CBX3, and MTA1 were more overexpressed, whereas ARID1A, ING5, and CBX7 were more underexpressed in the AG and GC groups compared with the controls. No significant differences were observed between the AG and GC groups concerning the expression of these 6 genes, although the fold change levels of these genes in the GC group were well above than in the AG group. EED, CBX3, and MTA1 were significantly more overexpressed in HP- and IM-positive AG subgroup compared with the HP- or IM-negative AG subgroup. CONCLUSION: In conclusion, our results provide an evidence of epigenetic alterations in AG. Expressions of EED, CBX3, MTA1, ARID1A, ING5, and CBX7 may be considered as promising markers to be used in GC screening for patients with AG. PMID- 30249558 TI - Lesion size determines diagnostic yield of EUS-FNA with onsite cytopathologic evaluation for upper gastrointestinal subepithelial lesions. AB - BACKGROUND/AIMS: The aim of this study was to determine the diagnostic yield and factors influencing the diagnostic yield of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for upper gastrointestinal (GI) subepithelial lesions (SELs) with rapid onsite cytopathologic evaluation. MATERIALS AND METHODS: This is a single-center, retrospective study. RESULTS: Among 22 patients who underwent EUS-FNA, a cytopathological diagnosis was reached in 16 (72.7%) patients. The EUS FNA results were as follows: seven GISTs (31.8%), six leiomyomas (27.2%), four non-diagnostics (18%), two duplication cysts (9%), two spindle cell tumor (9%), and one ectopic pancreas (4.5%). The long-axis size was > 20 mm in 12 patients (average size: 31.3 +/-9.3 mm) and < 20 mm (average size: 16.6 +/-2.5 mm) in 10 patients. Diagnostic accuracy of EUS-FNA from lesions < 20 mm was 50% (5/10 lesions), and of lesions > 20 mm was 91.6% (11/12 lesions) (Fisher's exact test; p=0.028). Six patients underwent surgical resection. Surgical pathology results of five lesions (four GIST, one leiomyoma) were consistent with cytopathology results (83.3%). CONCLUSION: The diagnostic yield of EUS-FNA of the upper GI SELs with an onsite cytopathologic interpretation was 72.7%. Lesion size < 2 cm significantly reduces the diagnostic yield of EUS-FNA for the upper GI SELs. PMID- 30249560 TI - Safety and effectiveness of midazolam for cirrhotic patients undergoing endoscopic variceal ligation. AB - BACKGROUND/AIMS: Endoscopic variceal ligation (EVL) is an established treatment for esophageal variceal bleeding. Midazolam (MDZ) is most commonly used for sedation during endoscopic procedures. However, adverse events (AEs) may occur more frequently in patients with cirrhosis due to altered MDZ metabolism. MATERIALS AND METHODS: We retrospectively reviewed the records of 325 patients with cirrhosis who received EVL. RESULTS: No significant differences were found in treatment outcome and procedure time among 151 patients in the MDZ group and 169 patients in the non-MDZ group. Desaturation (23.2% vs. 7.7%, p<0.01), bradycardia (22.5% vs. 17.2%, p=0.03), and hepatic encephalopathy (HE) (6.6% vs. 0.6%, p<0.01) were more common in the MDZ group than in the non-MDZ group. Logistic regression analyses revealed that an Eastern Cooperative Oncology Group (ECOG) score of >=2 (p<0.01) and the use of MDZ (p<0.01) were associated with the development of overall AEs. An ECOG score of >=2 (p=0.01), high serum creatinine level (p=0.02), and the use of MDZ (p<0.01) were significant risk factors for HE. CONCLUSION: Extreme caution should be taken when sedating patients with cirrhosis receiving EVL due to the AEs associated with the use of MDZ. PMID- 30249559 TI - Hepatic fine-needle aspiration cytology: The role of rapid on-site evaluation in the assessment of hepatic lesions. AB - BACKGROUND/AIMS: Radiologically guided fine-needle aspiration cytology (FNAC) of internal organs is not cost-effective. Rapid on-site evaluation (ROSE) of smears by a cytopathologist can improve the diagnostic yield of FNACs and save time and money by reducing the need for repeat procedure/biopsy. To determine the role of ROSE in the diagnostic outcome of hepatic lesions by comparative analysis of FNAC with and without ROSE by a cytopathologist. MATERIALS AND METHODS: Hepatic FNACs were retrospectively analyzed over two separate time periods from January 2011 to June 2013 and from January 2015 to July 2016. Smears from 2015-2016 were subjected to ROSE by a cytopathologist after staining with toluidine blue for 1 min to assess adequacy of the material. Final report was given after hematoxylin and eosin, May Grunwald Giemsa, and Papanicolaou staining were performed. Chi square test (non-parametric) was used to determine if there was a statistically significant increase in the diagnostic yield with ROSE. RESULTS: During 2011 2013, of the 160 radiologically guided FNACs for hepatic lesions, 22 were non diagnostic, whereas during 2015-2016, of 142 radiologically guided hepatic FNACs, only six were non-diagnostic. With the application of ROSE, there was a statistically significant increase in the diagnostic yield of hepatic FNACs from 86.25% to 95.8% (p=0.015). CONCLUSION: ROSE performed by a cytopathologist using toluidine blue can increase the diagnostic yield of hepatic FNACs and reduce the cost of healthcare by eliminating the need for a repeat procedure. PMID- 30249561 TI - The role of acoustic radiation force impulse elastography in the differentiation of benign and malignant focal liver masses. AB - BACKGROUND/AIMS: The aim of this study was to evaluate elasticity of benign and malign focal liver lesions and surrounding parenchyma as measured by acoustic radiation force impulse (ARFI). MATERIALS AND METHODS: 34 hemangiomas, 4 focal nodular hyperplasia (FNH), 10 hepatocellular carcinoma (HCC) and 22 metastatic lesions from a total of 62 patients were examined with ARFI elastography. ARFI measurements for each tumor type were expressed as mean +/- standard deviation for liver mass and surrounding parenchyma. ARFI values were compared between tumor types and surrounding parencyhma. RESULTS: The mean stiffness values were 2.15+/-0.73 m/s for hemangiomas (n=34), 3.22+/-0.18 m/s for FNH (n=4), 2.75+/ 0.53 m/s for HCC (n=10) and 3.59+/-0.51 m/s for metastasis (n=22). Although there was not a significant difference between hemangiomas and HCC lesions in ARFI values (p>0.05), hemangiomas showed significantly different ARFI values from FNH and metastases (p<0.05). Also, there were significant differences in ARFI values between malignant and benign masses. The area under the receiver-operating characteristics curves for discriminating the malignant from benign liver masses was 0.826 (p<0.001). An ARFI value of 2.32 m/s was selected as cut-off value to differentiate malignant liver masses from benign ones (sensitivity: 0.93, specificity: 0.60). CONCLUSION: Although currently ARFI is not a definitive method for the primary diagnosis of focal solid liver lesions, it provides additional important information non-invasively for differential diagnosis. PMID- 30249562 TI - Diagnostic value of combined serum biomarkers for the evaluation of liver fibrosis in chronic hepatitis C infection: A multicenter, noninterventional, observational study. AB - BACKGROUND/AIMS: The hepatitis C virus (HCV) infection is important cause of chronic hepatitis. Liver biopsy is considered the gold standard for assessment of fibrosis but this procedure is an invasive procedure. We aimed to evaluate the diagnostic efficiency of non-invasive serum biomarkers, separately and in combinations, on liver fibrosis in treatment-naive chronic hepatitis C (CHC) patients. MATERIALS AND METHODS: Two hundred and sixteen treatment-naive CHC patients were enrolled from 32 locations across Turkey in this open-labelled, non interventional prospective observational study. FibroTest(r), aspartate aminotransferase-to-platelet ratio index(APRI), aspartate aminotransferase and alanine aminotransferase ratio (AAR), fibrosis index based on four factors (FIB 4), Age-platelet(AP) index and Forns index were measured and compared with Metavir scores got from liver biopsies. RESULTS: Data from 182 patients with baseline liver biopsy were suitable for analysis. One hundred and twenty patients (65.9%) had F0-F1 fibrosis and 62 patients (34.1%) had F2-F4 fibrosis. APRI 0.732 area under the curve(AUC) indicated advanced fibrosis with 69% sensitivity and 77% specificity. FIB-4 0.732 AUC and FibroTest 0.715 AUC indicated advanced fibrosis with 69% and 78.4% sensitivity, and 75% and 71.4% specificity, respectively. The combined use of tests also led to an increase in AUC and specificity. Combinations of FibroTest with APRI and/or FIB-4, and FIB-4 with APRI were optimal for the evaluation of liver fibrosis. CONCLUSION: Fibrotest, FIB-4, APRI, AP index and Forns index exhibit good diagnostic performance for determining liver fibrosis in CHC patients, and the use of at least two tests together will increase their diagnostic value still further. PMID- 30249563 TI - Clinical outcomes of colorectal endoscopic submucosal dissection and risk factors associated with piecemeal resection. AB - BACKGROUND/AIMS: We aimed to investigate the factors associated with piecemeal resection of colorectal neoplasia (CRN), in spite of endoscopic submucosal dissection (ESD). MATERIALS AND METHODS: We analyzed the retrospective data for colorectal ESD cases from January 2005 to April 2014. We also reviewed the piecemeal endoscopic mucosal resection (EMR) for CRNs >=20 mm, performed over the same period. RESULTS: En bloc resection was possible in 648 (85.7%) of 756 lesions in 740 patients. Multivariate analysis showed that hybrid ESD (odds ratio (OR), 29.07; 95% confidence interval (CI), 15.46-54.65; p<0.01) and mild or severe submucosal fibrosis (OR, 3.62; 95% CI, 1.94-6.76; p<0.01) were independently associated with piecemeal ESD. The en bloc ESD group showed higher histologic complete resection rate than the piecemeal ESD group (80.4% vs. 56.5%; p<0.01), and the piecemeal ESD group showed higher recurrence rate than in the en bloc ESD group (5.6% [4/72] vs. 0.7% [3/450]; p<0.01). Overall recurrence rate was 1.3% (7/522). CONCLUSION: Hybrid ESD and submucosal fibrosis are independently associated with piecemeal ESD. Piecemeal ESD cases recurred more frequently than en bloc ESD cases. PMID- 30249564 TI - Endoscopic small-capacity forceps increase the pathological diagnosis of gastric indefinite neoplasia. AB - BACKGROUND/AIMS: A definitive biopsy-based diagnosis of gastric cancer is sometimes difficult, and some cases are pathologically diagnosed as gastric indefinite neoplasia (GIN). The most appropriate forceps size for gastric biopsy has yet to be determined. In this study, we investigated the relation between the forceps size and the frequency of GIN diagnosis. MATERIALS AND METHODS: The records of patients from two historical groups were reviewed. The first group comprised patients evaluated during the period when standard biopsy forceps (StF) were used (April 2010-March 2011), and the second group comprised patients evaluated during the period when small biopsy forceps (SmF) were used (April 2011 March 2013). Patients in whom GIN lesions were diagnosed with biopsy were identified, and pertinent data were compared between the two groups of patients. RESULTS: Among the 8,420 patients who underwent esophagogastroduodenoscopy (EGD) during the first period, 2,584 (30.7%) underwent gastric biopsy with StF. Among the 15,968 patients who underwent EGD during the second period, 4,204 (26.3%) underwent gastric biopsy with SmF. GIN was diagnosed in a significantly greater number of patients in the SmF group than in the StF group (52 [1.25%] vs. 19 [0.73%]; p=0.048). The mean minor-axis lengths of the biopsy samples were 1.50+/ 0.50 mm and 1.38+/-0.40 mm in the StF group and the SmF group, respectively, with the SmF group samples tending to be shorter (p=0.088). CONCLUSION: Because the SmF use may increase the rate of GIN diagnosis, the use of SmF with a standard caliber endoscope should be avoided. PMID- 30249565 TI - Thrombin activatable fibrinolysis inhibitor as an indicator of the severity of acute pancreatitis. AB - BACKGROUND/AIMS: Thrombin Activatable Fibrinolysis Inhibitor (TAFI), in addition to suppressing fibrinolysis, can be involved as a natural anti-inflammatory molecule in the inflammatory process in acute pancreatitis (AP). The goal of this study was to discover the significance of early determination of the values of TAFI in the assessment of the severity of AP. MATERIALS AND METHODS: The prospective study included 92 patients with AP. In accordance with the revised Atlanta classification, we divided all patients into 3 groups (I-mild AP, II- moderate AP and III-severe AP). All patients were further classified into group A (mild AP) and group B (moderate and severe AP) with the aim of separating the patients with complicated and potentially bad prognosis. Biochemical markers, inflammatory biomarkers, coagulation parameters and TAFI were analyzed in all patients. RESULTS: The level of TAFI were significantly higher among the patients with the complicated form (group B) of AP (p=0.002). The analysis of the ROC curve in regard to the inflammatory biomarkers (fibronectin and CRP) has shown that TAFI possesses the best discriminatory ability for complicated forms of AP (AUC=0.724, p=0.013), with the sensitivity of 83.30% and the specificity of 56.00%. CONCLUSION: The level of TAFI in plasma is higher in patients with moderate or severe AP. Determining the level of TAFI as a single parameter has a greater significance in the early estimation of the severity of AP than inflammatory biomarkers that we have analyzed. PMID- 30249566 TI - Beneficial effect of synbiotics on experimental colon cancer in rats. AB - BACKGROUND/AIMS: The aim of this study was to investigate the influence of a synbiotic preparation (a mixture of six probiotics and a prebiotic) on aberrant crypt foci (ACF) formation, dysplasia, inflammation, and colitis-like lesions in experimental colon cancer in rats. MATERIALS AND METHODS: Sixty male rats were categorized into three groups of 20 animals each. Group A was administered 1,2 dimethylydrazine, 15 mg/kg body weight (BW), once a week for 2 weeks. Group B was administered 1,2-dimethylydrazine at the same dose plus synbiotic, started after the second dose of carcinogen and lasted for 5 weeks. Group C was administered synbiotic plus carcinogen from the beginning of the experiment and lasted for 7 weeks. Animals were killed at the end of week 7. RESULTS: At the end of the experiment, the animals that received carcinogen plus the synbiotic had 100%, whereas the animals that received only carcinogen has 70% survival. Animals of groups B and C had significantly lower percentage of inflammation, colitis-like lesions, and ACF dysplasia than animals of group A, whereas those of group C had the least pathological lesions. CONCLUSION: Synbiotics seem to protect against the appearance of preneoplastic colon lesions in rats. The results of this experimental study suggest that treatment with a synbiotic preparation exerts significant antimutagenic properties against the development of preneoplastic lesions in rats. PMID- 30249567 TI - Comparison of two porcine benign esophageal stricture models using radiofrequency ablation and endoscopic submucosal tunnel dissection. AB - BACKGROUND/AIMS: Large-animal benign esophageal stricture (BES) models are needed for the development of new endoscopic therapies and related devices. This study was undertaken to develop and compare swine BES models produced by radiofrequency ablation (RFA) or endoscopic submucosal tunnel dissection (ESTD). MATERIALS AND METHODS: RFA and ESTD were each performed on three pigs. Follow-up endoscopy and esophagography were performed immediately after the procedures and then 2, 3, and 4 weeks later. Four weeks after the procedures, all animals were sacrificed, and gross and histologic examinations were performed. RESULTS: BES was successfully achieved in both the RFA and ESTD groups, and all animals survived without any serious adverse events during the 4-week follow-up period. Mean procedural times were 9.3 min for RFA and 89.3 min for ESTD. ESTD caused long segment strictures whose average length was 4.5 cm, whereas RFA produced short strictures whose average length was 1.4 cm. BES began to form 2 weeks after both procedures. Degrees of strictures were similar at 3 and 4 weeks in the ESTD group; however, it started deteriorating over time in the RFA group. Histologic examinations showed that ESTD caused inflammation and fibrosis in the submucosal layer, whereas RFA induced extensive inflammation in the submucosal and muscularis propria layers. CONCLUSION: BES was successfully achieved using RFA or ESTD in swine without serious complications. The methods have different characteristics; therefore, researchers should choose the method more appropriate for their purposes. PMID- 30249568 TI - Abnormal growth. PMID- 30249569 TI - Endoscopic ultrasound-guided choledochoduodenostomy using a lumen apposing metal stent for acute cholangitis. AB - We present the case of a 51-year-old woman with a history of uterine cancer who presented to the emergency room with a clinical picture of acute cholangitis. An abdominal ultrasound and a computed tomography scan were performed, revealing a gigantic lymphadenopathy mass compressing the common bile duct and the duodenum. After failure to perform an endoscopic retrograde cholangiopancreatography (ERCP) due to a modified anatomy, we performed an endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) and placed a Hot AXIOS 10Fr/10 mm stent with efficient biliary drainage. In addition, we inserted a duodenal uncoated 120/22 mm expandable metallic stent. EUS-CDS presents a valid alternative in patients with failed ERCP and should be considered as an important option for rapid biliary decompression in patients with acute cholangitis. PMID- 30249570 TI - In extremis diagnosis of celiac disease and concomitant wheat allergy. AB - Celiac disease (CD) and concomitant wheat allergy are not commonly described in the literature. Both can have almost the same treatment consisting of a gluten free or wheat-free diet. On the other hand, they are based on totally different pathogenetic mechanisms and can be easily underdiagnosed, particularly CD. We describe a peculiar case of a young female patient affected by wheat allergy whose serological and histological data were not diagnostic for CD. Organ culture system successfully detected specific antibodies for CD in duodenal biopsy supernatant, supporting the diagnosis of CD. PMID- 30249571 TI - A rare cause of hepatomegaly in the childhood: Lysosomal acid lipase deficiency. PMID- 30249572 TI - Capillary hemangioma in the ileum: Obscure small-bowel bleeding in an elderly person. PMID- 30249573 TI - The coexistence of neurofibromatosis type I and celiac disease in a child. PMID- 30249574 TI - Effect of cumulative time of Helicobacter pylori infection on gastric precancerous lesions? PMID- 30249575 TI - Experience With the Use of an Online Community on Facebook for Brazilian Patients With Gestational Trophoblastic Disease: Netnography Study. AB - BACKGROUND: The term gestational trophoblastic disease (GTD) includes both complete and partial moles, which are uncommon nonviable pregnancies with the potential to evolve into a malignancy known as gestational trophoblastic neoplasia. While highly curable, the potential for malignancy associated with molar pregnancies worries the patients, leading them to seek information on the internet. A Facebook page headed by Brazilian specialized physicians in GTD was created in 2013 to provide online support for GTD patients. OBJECTIVE: The objective of our study was to describe the netnography of Brazilian patients with GTD on Facebook (FBGTD) and to evaluate whether their experiences differed depending on whether they received care in a Brazilian gestational trophoblastic disease reference center (BRC) or elsewhere. METHODS: This was a cross-sectional study using G Suite Google Platform. The members of FBGTD were invited to participate in a survey from March 6 to October 5, 2017, and a netnographic analysis of interactions among the members was performed. RESULTS: The survey was answered by 356 Brazilian GTD patients: 176 reference center patients (RCP) treated at a BRC and 180 nonreference center patients (NRCP) treated elsewhere. On comparing the groups, we found that RCP felt safer and more confident at the time of diagnosis of GTD (P=.001). RCP were more likely to utilize FBGTD subsequent to a referral by health assistants (P<.001), whereas NRCP more commonly discovered FBGTD through Web searches (P<.001). NRCP had higher educational levels (P=.009) and were more commonly on FBGTD for >= 6 months (P=.03). NRCP were more likely to report that doctors did not adequately explain GTD at diagnosis (P=.007), had more doubts about GTD treatment (P=.01), and were less likely to use hormonal contraception (P<.001). Overall, 89% (317/356) patients accessed the internet preferentially from home and using mobile phones, and 98% (349/354) patients declared that they felt safe reading the recommendations posted by FBGTD physicians. CONCLUSIONS: This netnographic analysis of GTD patients on FBGTD shows that an Web-based doctor-patient relationship can supplement the care for women with GTD. This resource is particularly valuable for women being cared for outside of established reference centers. PMID- 30249577 TI - The Effectiveness of Near-Field Communication Integrated with a Mobile Electronic Medical Record System: Emergency Department Simulation Study. AB - BACKGROUND: Improved medical practice efficiency has been demonstrated by physicians using mobile device (mobile phones, tablets) electronic medical record (EMR) systems. However, the quantitative effects of these systems have not been adequately measured. OBJECTIVE: This study aimed to determine the effectiveness of near-field communication (NFC) integrated with a mobile EMR system regarding physician turnaround time in a hospital emergency department (ED). METHODS: A simulation study was performed in a hospital ED. Twenty-five physicians working in the ED participated in 2 scenarios, using either a mobile device or personal computer (PC). Scenario A involved randomly locating designated patients in the ED. Scenario B consisted of accessing laboratory results of an ED patient at the bedside. After completing the scenarios, participants responded to 10 questions that were scored using a system usability scale (SUS). The primary metric was the turnaround time for each scenario. The secondary metric was the usability of the system, graded by the study participants. RESULTS: Locating patients from the ED entrance took a mean of 93.0 seconds (SD 34.4) using the mobile scenario. In contrast, it only required a mean of 57.3 seconds (SD 10.5) using the PC scenario (P<.001). Searching for laboratory results of the patients at the bedside required a mean of only 25.2 seconds (SD 5.3) with the mobile scenario, and a mean of 61.5 seconds (SD 11.6) using the PC scenario (P<.001). Sensitivity analysis comparing only the time for login and accessing the relevant information also determined mobile devices to be significantly faster. The mean SUS score of NFC-mobile EMR was 71.90 points. CONCLUSIONS: NFC integrated with mobile EMR provided for a more efficient physician practice with good usability. PMID- 30249576 TI - Longitudinal Validity and Reliability of Brief Smartphone Self-Monitoring of Diet, Stress, and Physical Activity in a Diverse Sample of Mothers. AB - BACKGROUND: Multiple strategies can be used when self-monitoring diet, physical activity, and perceived stress, but no gold standards are available. Although self-monitoring is a core element of self-management and behavior change, the success of mHealth behavioral tools depends on their validity and reliability, which lack evidence. African American and Latina mothers in the United States are high-priority populations for apps that can be used for self-monitoring of diet, physical activity, and stress because the body mass index (BMI) of mothers typically increases for several years after childbirth and the risks of obesity and its' sequelae diseases are elevated among minority populations. OBJECTIVE: To examine the intermethod reliability and concurrent validity of smartphone-based self-monitoring via ecological momentary assessments (EMAs) and use of daily diaries for diet, stress, and physical activity compared with brief recall measures, anthropometric biomeasures, and bloodspot biomarkers. METHODS: A purposive sample (n=42) of primarily African American (16/42, 39%) and Latina (18/42, 44%) mothers was assigned Android smartphones for using Ohmage apps to self-monitor diet, perceived stress, and physical activity over 6 months. Participants were assessed at 3- and 6-month follow-ups. Recall measures included brief food frequency screeners, physical activity assessments adapted from the National Health and Nutrition Examination Survey, and the nine-item psychological stress measure. Anthropometric biomeasures included BMI, body fat, waist circumference, and blood pressure. Bloodspot assays for Epstein-Barr virus and C reactive protein were used as systemic load and stress biomarkers. EMAs and daily diary questions assessed perceived quality and quantity of meals, perceived stress levels, and moderate, vigorous, and light physical activity. Units of analysis were follow-up assessments (n=29 to n=45 depending on the domain) of the participants (n=29 with sufficient data for analyses). Correlations, R2 statistics, and multivariate linear regressions were used to assess the strength of associations between variables. RESULTS: Almost all participants (39/42, 93%) completed the study. Intermethod reliability between smartphone-based EMAs and diary reports and their corresponding recall reports was highest for stress and diet; correlations ranged from .27 to .52 (P<.05). However, it was unexpectedly low for physical activity; no significant associations were observed. Concurrent validity was demonstrated for diet EMAs and diary reports on systolic blood pressure (r=-.32), C-reactive protein level (r=-.34), and moderate and vigorous physical activity recalls (r=.35 to.48), suggesting a covariation between healthy diet and physical activity behaviors. EMAs and diary reports on stress were not associated with Epstein-Barr virus and C-reactive protein level. Diary reports on moderate and vigorous physical activity were negatively associated with BMI and body fat (r=-.35 to -.44, P<.05). CONCLUSIONS: Brief smartphone-based EMA use may be valid and reliable for long-term self-monitoring of diet, stress, and physical activity. Lack of intermethod reliability for physical activity measures is consistent with prior research, warranting more research on the efficacy of smartphone-based self-monitoring of self-management and behavior change support. PMID- 30249578 TI - Digital Health in Melanoma Posttreatment Care in Rural and Remote Australia: Systematic Review. AB - BACKGROUND: The melanoma incidence and mortality rates in rural and remote communities are exponentially higher than in urban areas. Digital health could be used to close the urban/rural gap for melanoma and improve access to posttreatment and support care services. OBJECTIVE: The aim of this review was to understand how digital health is currently used for melanoma posttreatment care and determine the benefits for Australian rural and remote areas. METHODS: A systematic search of PubMed, Medline, PsycINFO, and Scopus was conducted in March 2018. Findings were clustered per type of intervention and related direct outcomes. RESULTS: Five studies met the inclusion criteria, but none investigated the benefits of digital health for melanoma posttreatment care in rural and remote areas of Australia. Some empirical studies demonstrated consumers' acceptance of digital intervention for posttreatment care. The findings did not take into consideration individual, psychological, and socioeconomic factors, even though studies show their significant impacts on melanoma quality of aftercare. CONCLUSIONS: Digital interventions may be used as an adjunct service by clinicians during melanoma posttreatment care, especially in regions that are less-resourced by practitioners and health infrastructure, such as rural and remote Australia. Technology could be used to reduce the disparity in melanoma incidence, mortality rates, and accessibility to posttreatment care management between urban and rural/remote populations. PMID- 30249579 TI - A Patient-Facing Diabetes Dashboard Embedded in a Patient Web Portal: Design Sprint and Usability Testing. AB - BACKGROUND: Health apps and Web-based interventions designed for patients with diabetes offer novel and scalable approaches to engage patients and improve outcomes. However, careful attention to the design and usability of these apps and Web-based interventions is essential to reduce the barriers to engagement and maximize use. OBJECTIVE: The aim of this study was to apply design sprint methodology paired with mixed-methods, task-based usability testing to design and evaluate an innovative, patient-facing diabetes dashboard embedded in an existing patient portal and integrated into an electronic health record. METHODS: We applied a 5-day design sprint methodology developed by Google Ventures (Alphabet Inc, Mountain View, CA) to create our initial dashboard prototype. We identified recommended strategies from the literature for using patient-facing technologies to enhance patient activation and designed a dashboard functionality to match each strategy. We then conducted a mixed-methods, task-based usability assessment of dashboard prototypes with individual patients. Measures included validated metrics of task performance on 5 common and standardized tasks, semistructured interviews, and a validated usability satisfaction questionnaire. After each round of usability testing, we revised the dashboard prototype in response to usability findings before the next round of testing until the majority of participants successfully completed tasks, expressed high satisfaction, and identified no new usability concerns (ie, stop criterion was met). RESULTS: The sample (N=14) comprised 5 patients in round 1, 3 patients in round 2, and 6 patients in round 3, at which point we reached our stop criterion. The participants' mean age was 63 years (range 45-78 years), 57% (8/14) were female, and 50% (7/14) were white. Our design sprint yielded an initial patient-facing diabetes dashboard prototype that displayed and summarized 5 measures of patients' diabetes health status (eg, hemoglobin A1c). The dashboard used graphics to visualize and summarize health data and reinforce understanding, incorporated motivational strategies (eg, social comparisons and gamification), and provided educational resources and secure-messaging capability. More than 80% of participants were able to successfully complete all 5 tasks using the final prototype. Interviews revealed usability concerns with design, the efficiency of use, and content and terminology, which led to improvements. Overall satisfaction (0=worst and 7=best) improved from the initial to the final prototype (mean 5.8, SD 0.4 vs mean 6.7, SD 0.5). CONCLUSIONS: Our results demonstrate the utility of the design sprint methodology paired with mixed-methods, task-based usability testing to efficiently and effectively design a patient-facing, Web-based diabetes dashboard that is satisfying for patients to use. PMID- 30249580 TI - Exploration of Users' Perspectives and Needs and Design of a Type 1 Diabetes Management Mobile App: Mixed-Methods Study. AB - BACKGROUND: With the popularity of mobile phones, mobile apps have great potential for the management of diabetes, but the effectiveness of current diabetes apps for type 1 diabetes mellitus (T1DM) is poor. No study has explored the reasons for this deficiency from the users' perspective. OBJECTIVE: The aims of this study were to explore the perspectives and needs of T1DM patients and diabetes experts concerning a diabetes app and to design a new T1DM management mobile app. METHODS: A mixed-methods design combining quantitative surveys and qualitative interviews was used to explore users' needs and perspectives. Experts were surveyed at 2 diabetes conferences using paper questionnaires. T1DM patients were surveyed using Sojump (Changsha ran Xing InfoTech Ltd) on a network. We conducted semistructured, in-depth interviews with adult T1DM patients or parents of child patients who had ever used diabetes apps. The interviews were audio recorded, transcribed, and coded for theme identification. RESULTS: The expert response rate was 63.5% (127/200). The respondents thought that the reasons for app invalidity were that patients did not continue using the app (76.4%, 97/127), little guidance was received from health care professionals (HCPs; 73.2%, 93/127), diabetes education knowledge was unsystematic (52.8%, 67/127), and the app functions were incomplete (44.1%, 56/127). A total of 245 T1DM patient questionnaires were collected, of which 21.2% (52/245) of the respondents had used diabetes apps. The reasons for their reluctance to use an app were limited time (39%, 20/52), complicated operations (25%, 13/52), uselessness (25%, 13/52), and cost (25%, 13/52). Both the experts and patients thought that the most important functions of the app were patient-doctor communication and the availability of a diabetes diary. Two themes that were useful for app design were identified from the interviews: (1) problems with patients' diabetes self management and (2) problems with current apps. In addition, needs and suggestions for a diabetes app were obtained. Patient-doctor communication, diabetes diary, diabetes education, and peer support were all considered important by the patients, which informed the development of a prototype multifunctional app. CONCLUSIONS: Patient-doctor communication is the most important function of a diabetes app. Apps should be integrated with HCPs rather than stand-alone. We advocate that doctors follow up with their patients using a diabetes app. Our user-centered method explored comprehensively and deeply why the effectiveness of current diabetes apps for T1DM was poor and what T1DM patients needed for a diabetes app and provided meaningful guidance for app design. PMID- 30249581 TI - Health and Fitness Apps for Hands-Free Voice-Activated Assistants: Content Analysis. AB - BACKGROUND: Hands-free voice-activated assistants and their associated devices have recently gained popularity with the release of commercial products, including Amazon Alexa and Google Assistant. Voice-activated assistants have many potential use cases in healthcare including education, health tracking and monitoring, and assistance with locating health providers. However, little is known about the types of health and fitness apps available for voice-activated assistants as it is an emerging market. OBJECTIVE: This review aimed to examine the characteristics of health and fitness apps for commercially available, hands free voice-activated assistants, including Amazon Alexa and Google Assistant. METHODS: Amazon Alexa Skills Store and Google Assistant app were searched to find voice-activated assistant apps designated by vendors as health and fitness apps. Information was extracted for each app including name, description, vendor, vendor rating, user reviews and ratings, cost, developer and security policies, and the ability to pair with a smartphone app and website and device. Using a codebook, two reviewers independently coded each app using the vendor's descriptions and the app name into one or more health and fitness, intended age group, and target audience categories. A third reviewer adjudicated coding disagreements until consensus was reached. Descriptive statistics were used to summarize app characteristics. RESULTS: Overall, 309 apps were reviewed; health education apps (87) were the most commonly occurring, followed by fitness and training (72), nutrition (33), brain training and games (31), and health monitoring (25). Diet and calorie tracking apps were infrequent. Apps were mostly targeted towards adults and general audiences with few specifically geared towards patients, caregivers, or medical professionals. Most apps were free to enable or use and 18.1% (56/309) could be paired with a smartphone app and website and device; 30.7% (95/309) of vendors provided privacy policies; and 22.3% (69/309) provided terms of use. The majority (36/42, 85.7%) of Amazon Alexa apps were rated by the vendor as mature or guidance suggested, which were geared towards adults only. When there was a user rating available, apps had a wide range of ratings from 1 to 5 stars with a mean of 2.97. Google Assistant apps did not have user reviews available, whereas most of Amazon Alexa apps had at least 1 9 reviews available. CONCLUSIONS: The emerging market of health and fitness apps for voice-activated assistants is still nascent and mainly focused on health education and fitness. Voice-activated assistant apps had a wide range of content areas but many published in the health and fitness categories did not actually have a clear health or fitness focus. This may, in part, be due to Amazon and Google policies, which place restrictions on the delivery of care or direct recording of health data. As in the mobile app market, the content and functionalities may evolve to meet growing demands for self-monitoring and disease management. PMID- 30249582 TI - Exploring Genetic Data Across Individuals: Design and Evaluation of a Novel Comparative Report Tool. AB - BACKGROUND: The growth in the availability of personal genomic data to nonexperts poses multiple challenges to human-computer interaction research; data are highly sensitive, complex, and have health implications for individuals and families. However, there has been little research on how nonexpert users explore their genomic data. OBJECTIVE: We focus on how to support nonexperts in exploring and comparing their own personal genomic report with those of other people. We designed and evaluated CrossGenomics, a novel tool for comparing personal genetic reports, which enables exploration of shared and unshared genetic variants. Focusing on communicating comparative impact, rarity, and certainty, we evaluated alternative novel interactive prototypes. METHODS: We conducted 3 user studies. The first focuses on assessing the usability and understandability of a prototype that facilitates the comparison of reports from 2 family members. Following a design iteration, we studied how various prototypes support the comparison of genetic reports of a 4-person family. Finally, we evaluated the needs of early adopters-people who share their genetic reports publicly for comparing their genetic reports with that of others. RESULTS: In the first study, sunburst- and Venn-based comparisons of two genomes led to significantly higher domain comprehension, compared with the linear comparison and with the commonly used tabular format. However, results show gaps between objective and subjective comprehension, as sunburst users reported significantly lower perceived understanding and higher levels of confusion than the users of the tabular report. In the second study, users who were allowed to switch between the different comparison views presented higher comprehension levels, as well as more complex reasoning than users who were limited to a single comparison view. In the third study, 35% (17/49) reported learning something new from comparing their own data with another person's data. Users indicated that filtering and toggling between comparison views were the most useful features. CONCLUSIONS: Our findings (1) highlight features and visualizations that show strengths in facilitating user comprehension of genomic data, (2) demonstrate the value of affording users the flexibility to examine the same report using multiple views, and (3) emphasize users' needs in comparison of genomic data. We conclude with design implications for engaging nonexperts with complex multidimensional genomic data. PMID- 30249583 TI - Web-Based Cognitive Behavioral Therapy Blended With Face-to-Face Sessions for Major Depression: Randomized Controlled Trial. AB - BACKGROUND: Meta-analyses of several randomized controlled trials have shown that cognitive behavioral therapy (CBT) has comparable efficacy to antidepressant medication, but therapist availability and cost-effectiveness is a problem. OBJECTIVE: This study aimed to evaluate the effectiveness of Web-based CBT blended with face-to-face sessions that reduce therapist time in patients with major depression who were unresponsive to antidepressant medications. METHODS: A 12-week, assessor-masked, parallel-group, waiting- list controlled, randomized trial was conducted at 3 medical institutions in Tokyo. Outpatients aged 20-65 years with a primary diagnosis of major depression who were taking >=1 antidepressant medications at an adequate dose for >=6 weeks and had a 17-item GRID-Hamilton Depression Rating Scale (HAMD) score of >=14 were randomly assigned (1:1) to blended CBT or waiting-list groups using a computer allocation system, stratified by the study site with the minimization method, to balance age and baseline GRID-HAMD score. The CBT intervention was given in a combined format, comprising a Web-based program and 12 45-minute face-to-face sessions. Thus, across 12 weeks, a participant could receive up to 540 minutes of contact with a therapist, which is approximately two-thirds of the therapist contact time provided in the conventional CBT protocol, which typically provides 16 50-minute sessions. The primary outcome was the alleviation of depressive symptoms, as measured by a change in the total GRID-HAMD score from baseline (at randomization) to posttreatment (at 12 weeks). Moreover, in an exploratory analysis, we investigated whether the expected positive effects of the intervention were sustained during follow-up, 3 months after the posttreatment assessment. Analyses were performed on an intention-to-treat basis, and the primary outcome was analyzed using a mixed-effects model for repeated measures. RESULTS: We randomized 40 participants to either blended CBT (n=20) or waiting list (n=20) groups. All patients completed the 12-week treatment protocol and were included in the intention-to-treat analyses. Participants in the blended CBT group had significantly alleviated depressive symptoms at week 12, as shown by greater least squares mean changes in the GRID-HAMD score, than those in the waiting list group (-8.9 points vs -3.0 points; mean between-group difference= 5.95; 95% CI -9.53 to -2.37; P<.001). The follow-up effects within the blended CBT group, as measured by the GRID-HAMD score, were sustained at the 3-month follow-up (week 24) and posttreatment (week 12): posttreatment, 9.4 (SD 5.2), versus follow-up, 7.2 (SD 5.7); P=.009. CONCLUSIONS: Although our findings warrant confirmation in larger and longer term studies with active controls, these suggest that a combined form of CBT is effective in reducing depressive symptoms in patients with major depression who are unresponsive to antidepressant medications. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000009242; https://upload.umin.ac.jp/cgi-open bin/ctr_e/ctr_view.cgi?recptno=R000010852 (Archived by WebCite at http://www.webcitation. org/729VkpyYL). PMID- 30249584 TI - A Cloud-Based Virtual Outpatient Clinic for Patient-Centered Care: Proof-of Concept Study. AB - BACKGROUND: Most electronic health (eHealth) interventions offered to patients serve a single purpose and lack integration with other tools or systems. This is problematic because the majority of patients experience comorbidity and chronic disease, see multiple specialists, and therefore have different needs regarding access to patient data, communication with peers or providers, and self monitoring of vital signs. A multicomponent digital health cloud service that integrates data sharing, collection, and communication could facilitate patient centered care in combination with a hospital patient portal and care professionals. OBJECTIVE: This study aimed to assess the feasibility and functionality of a new cloud-based and multicomponent outpatient clinic, the "Virtual Outpatient Clinic" (VOC). METHODS: The VOC consists of 6 digital tools that facilitate self-monitoring (blood pressure, weight, and pain) and communication with peers and providers (chat and videoconferencing) connected to a cloud-based platform and the hospital patient portal to facilitate access to (self-collected) medical data. In this proof-of-concept study, 10 patients from both Departments of Internal Medicine and Dermatology (N=20) used all options of the VOC for 6 weeks. An eNurse offered support to participants during the study. We assessed the feasibility, usage statistics, content, adherence, and identified technical issues. Moreover, we conducted qualitative interviews with all participants by following a standard interview guide to identify user experiences, including barriers, facilitators, and potential effects. RESULTS: Most participants successfully used all options of the VOC and were positive about different tools and apps and the integral availability of their information. The adherence was 37% (7/19) for weight scale, 58% (11/19) for blood pressure monitor, and 70% (14/20) and 85% (17/20) for pain score and daily questions, respectively. The adherence for personal health record was 65% (13/20) and 60% (12/20) for the patient portal system. Qualitative data showed that performance and effort expectancy scored high among participants, indicating that using the VOC is convenient, easy, and time-saving. CONCLUSIONS: The VOC is a promising integrated Web-based technology that combines self-management, data sharing, and communication between patients and professionals. The system can be personalized by connecting various numbers of components, which could make it a relevant tool for other patient groups. Before a system, such as the VOC, can be implemented in daily practice, prospective studies focused on evaluating outcomes, costs, and patient-centeredness are needed. PMID- 30249586 TI - Assessment of Google Glass for Photographic Documentation in Veterinary Forensic Pathology: Usability Study. AB - BACKGROUND: Google Glass is a head-mounted device designed in the shape of a pair of eyeglasses equipped with a 5.0-megapixel integrated camera and capable of taking pictures with simple voice commands. OBJECTIVE: The objective of our study was to determine whether Google Glass is fit for veterinary forensic pathology purposes. METHODS: A total of 44 forensic necropsies of 2 different species (22 dogs and 22 cats) were performed by 2 pathologists; each pathologist conducted 11 necropsies of each species and, for each photographic acquisition, the images were taken with a Google Glass device and a Nikon D3200 digital single-lens reflex (DSLR) camera. The pictures were collected, divided into 3 groups (based on the external appearance of the animal, organs, and anatomical details), and evaluated by 5 forensic pathologists using a 5-point score system. The parameters assessed were overall color settings, region of interest, sharpness, and brightness. To evaluate the difference in mean duration between necropsies conduced with Google Glass and DSLR camera and to assess the battery consumption of the devices, an additional number of 16 necropsies were performed by the 2 pathologists. In these cases, Google Glass was used for photographic reports in 8 cases (4 dogs and 4 cats) and a Nikon D3200 reflex camera in the other 8 cases. Statistical evaluations were performed to assess the differences in ratings between the quality of the images taken with both devices. RESULTS: The images taken with Google Glass received significantly lower ratings than those acquired with reflex camera for all 4 assessed parameters (P<.001). In particular, for the pictures of Groups A and B taken with Google Glass, the sum of frequency of ratings 5 (very good) and 4 (good) was between 50% and 77% for all 4 assessed parameters. The lowest ratings were observed for the pictures of Group C, with a sum of frequency of ratings 5 and 4 of 21.1% (342/1602) for region of interest, 26% (421/1602) for sharpness, 35.5% (575/1602) for overall color settings, and 61.4% (995/1602) for brightness. Furthermore, we found a significant reduction in the mean execution time for necropsy conduced with the Google Glass with respect to the reflex group (P<.001). However, Google Glass drained the battery very quickly. CONCLUSIONS: These findings suggest that Google Glass is usable in veterinary forensic pathology. In particular, the image quality of Groups A and B seemed adequate for forensic photographic documentation purposes, although the quality was lower than that with the reflex camera. However, in this step of development, the high frequency of poor ratings observed for the pictures of Group C suggest that the device is not suitable for taking pictures of small anatomical details or close-ups of the injuries. PMID- 30249585 TI - User-Driven Comments on a Facebook Advertisement Recruiting Canadian Parents in a Study on Immunization: Content Analysis. AB - BACKGROUND: More people are searching for immunization information online and potentially being exposed to misinformation and antivaccination sentiment in content and discussions on social media platforms. As vaccination coverage rates remain suboptimal in several developed countries, and outbreaks of vaccine preventable diseases become more prevalent, it is important that we build on previous research by analyzing themes in online vaccination discussions, including those that individuals may see without actively searching for information on immunization. OBJECTIVE: The study aimed to explore the sentiments and themes behind an unsolicited debate on immunization in order to better inform public health interventions countering antivaccination sentiment. METHODS: We analyzed and quantified 117 user-driven open-ended comments on immunization posted in the Comments section of a Facebook advertisement that targeted Canadian parents for recruitment into a larger study on immunization. Then, 2 raters coded all comments using content analysis. RESULTS: Of 117 comments, 85 were posted by unique commentators, with most being female (65/85, 77%). The largest proportion of the immunization comments were positive (51/117, 43.6%), followed by negative (41/117, 35.0%), ambiguous (20/117, 17.1%), and hesitant (5/117, 4.3%). Inaccurate knowledge (27/130, 20.8%) and misperceptions of risk (23/130, 17.7%) were most prevalent in the 130 nonpositive comments. Other claims included distrust of pharmaceutical companies or government agencies (18/130, 13.8%), distrust of the health care system or providers (15/130, 11.5%), past negative experiences with vaccination or beliefs (10/130, 7.7%), and attitudes about health and prevention (10/130, 7.7%). Almost 40% (29/74, 39%) of the positive comments communicated the risks of not vaccinating, followed by judgments on the knowledge level of nonvaccinators (13/74, 18%). A total of 10 positive comments (10/74, 14%) specifically refuted the link between autism and vaccination. CONCLUSIONS: The presence of more than 100 unsolicited user-driven comments on a platform not intended for discussion, nor providing any information on immunization, illustrates the strong sentiments associated with immunization and the arbitrariness of the online platforms used for immunization debates. Health authorities should be more proactive in finding mechanisms to refute misinformation and misperceptions that are propagating uncontested online. Online debates and communications on immunization need to be identified by continuous monitoring in order for health authorities to understand the current themes and trends, and to engage in the discussion. PMID- 30249588 TI - Robotic Services Acceptance in Smart Environments With Older Adults: User Satisfaction and Acceptability Study. AB - BACKGROUND: In Europe, the population of older people is increasing rapidly. Many older people prefer to remain in their homes but living alone could be a risk for their safety. In this context, robotics and other emerging technologies are increasingly proposed as potential solutions to this societal concern. However, one-third of all assistive technologies are abandoned within one year of use because the end users do not accept them. OBJECTIVE: The aim of this study is to investigate the acceptance of the Robot-Era system, which provides robotic services to permit older people to remain in their homes. METHODS: Six robotic services were tested by 35 older users. The experiments were conducted in three different environments: private home, condominium, and outdoor sites. The appearance questionnaire was developed to collect the users' first impressions about the Robot-Era system, whereas the acceptance was evaluated through a questionnaire developed ad hoc for Robot-Era. RESULTS: A total of 45 older users were recruited. The people were grouped in two samples of 35 participants, according to their availability. Participants had a positive impression of Robot Era robots, as reflected by the mean score of 73.04 (SD 11.80) for DORO's (domestic robot) appearance, 76.85 (SD 12.01) for CORO (condominium robot), and 75.93 (SD 11.67) for ORO (outdoor robot). Men gave ORO's appearance an overall score higher than women (P=.02). Moreover, participants younger than 75 years understood more readily the functionalities of Robot-Era robots compared to older people (P=.007 for DORO, P=.001 for CORO, and P=.046 for ORO). For the ad hoc questionnaire, the mean overall score was higher than 80 out of 100 points for all Robot-Era services. Older persons with a high educational level gave Robot Era services a higher score than those with a low level of education (shopping: P=.04; garbage: P=.047; reminding: P=.04; indoor walking support: P=.006; outdoor walking support: P=.03). A higher score was given by male older adults for shopping (P=.02), indoor walking support (P=.02), and outdoor walking support (P=.03). CONCLUSIONS: Based on the feedback given by the end users, the Robot-Era system has the potential to be developed as a socially acceptable and believable provider of robotic services to facilitate older people to live independently in their homes. PMID- 30249587 TI - Use of Simulator-Based Teaching to Improve Medical Students' Knowledge and Competencies: Randomized Controlled Trial. AB - BACKGROUND: Simulator-based teaching for coronary angiography (CA) is an attractive educational tool for medical students to improve their knowledge and skills. Its pedagogical impact has not been fully evaluated yet. OBJECTIVE: The aim of this study was to compare traditional face-to-face teaching with a simulator-based teaching for the acquisition of coronary anatomy knowledge and CAs interpretation. METHODS: A total of 118 medical school students in their fourth to sixth year were prospectively randomized in 2 groups: (1) a control teaching group (n=59, CONT group) and (2) a simulator group (using the Mentice VIST-Lab CA simulator; n=59, SIM group). The CONT group received a PowerPoint based course, whereas the SIM group received a simulator-based course including the same information. After the course, all students were evaluated by 40 multiple choice questions (maximum of 100 points), including questions on coronary anatomy (part 1), angiographic projections (part 2), and real CAs interpretation (part 3). Satisfaction of the students was also evaluated by a simple questionnaire. RESULTS: Student characteristics were identical in both the groups: 62/118 (52.5%) were female and age was 22.6 (SD 1.4) years. Moreover, 35.6% (42/118) were in their fourth year, 35.6% (42/118) were in the fifth year, and 28.8% (34/118) in the sixth year. During the evaluation, SIM students had higher global scores compared with CONT students, irrespective of their year of medical school (59.5 [SD 10.8] points vs 43.7 [SD 11.3] points, P<.001). The same observations were noted for each part of the test (36.9 [SD 6.6] points vs 29.6 [SD 6.9] points, P<.001; 5.9 [SD 3.0] points vs 3.1 [SD 2.8] points, P<.001; and 16.8 [SD 6.9] points vs 10.9 [SD 6.5] points, P<.001; for parts 1, 2, and 3, respectively). Student satisfaction was higher in the SIM group compared with the CONT group (98% vs 75%, P<.001). CONCLUSIONS: This study suggests that simulator based teaching could potentially improve students' knowledge of coronary anatomy, angiography projections, and interpretation of real clinical cases, suggesting better clinical skills. These results should encourage further evaluation of simulator-based teaching in other medical specialties and how they can translate into clinical practice. PMID- 30249589 TI - Improving Prediction of Risk of Hospital Admission in Chronic Obstructive Pulmonary Disease: Application of Machine Learning to Telemonitoring Data. AB - BACKGROUND: Telemonitoring of symptoms and physiological signs has been suggested as a means of early detection of chronic obstructive pulmonary disease (COPD) exacerbations, with a view to instituting timely treatment. However, algorithms to identify exacerbations result in frequent false-positive results and increased workload. Machine learning, when applied to predictive modelling, can determine patterns of risk factors useful for improving prediction quality. OBJECTIVE: Our objectives were to (1) establish whether machine learning techniques applied to telemonitoring datasets improve prediction of hospital admissions and decisions to start corticosteroids, and (2) determine whether the addition of weather data further improves such predictions. METHODS: We used daily symptoms, physiological measures, and medication data, with baseline demography, COPD severity, quality of life, and hospital admissions from a pilot and large randomized controlled trial of telemonitoring in COPD. We linked weather data from the United Kingdom meteorological service. We used feature selection and extraction techniques for time series to construct up to 153 predictive patterns (features) from symptom, medication, and physiological measurements. We used the resulting variables to construct predictive models fitted to training sets of patients and compared them with common symptom-counting algorithms. RESULTS: We had a mean 363 days of telemonitoring data from 135 patients. The two most practical traditional score counting algorithms, restricted to cases with complete data, resulted in area under the receiver operating characteristic curve (AUC) estimates of 0.60 (95% CI 0.51-0.69) and 0.58 (95% CI 0.50-0.67) for predicting admissions based on a single day's readings. However, in a real-world scenario allowing for missing data, with greater numbers of patient daily data and hospitalizations (N=57,150, N+=55, respectively), the performance of all the traditional algorithms fell, including those based on 2 days' data. One of the most frequently used algorithms performed no better than chance. All considered machine learning models demonstrated significant improvements; the best machine learning algorithm based on 57,150 episodes resulted in an aggregated AUC of 0.74 (95% CI 0.67-0.80). Adding weather data measurements did not improve the predictive performance of the best model (AUC 0.74, 95% CI 0.69-0.79). To achieve an 80% true-positive rate (sensitivity), the traditional algorithms were associated with an 80% false positive rate: our algorithm halved this rate to approximately 40% (specificity approximately 60%). The machine learning algorithm was moderately superior to the best symptom-counting algorithm (AUC 0.77, 95% CI 0.74-0.79 vs AUC 0.66, 95% CI 0.63-0.68) at predicting the need for corticosteroids. CONCLUSIONS: Early detection and management of COPD remains an important goal given its huge personal and economic costs. Machine learning approaches, which can be tailored to an individual's baseline profile and can learn from experience of the individual patient, are superior to existing predictive algorithms and show promise in achieving this goal. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number ISRCTN96634935; http://www.isrctn.com/ISRCTN96634935 (Archived by WebCite at http://www.webcitation.org/722YkuhAz). PMID- 30249590 TI - The Remote Food Photography Method and SmartIntake App for the Assessment of Alcohol Use in Young Adults: Feasibility Study and Comparison to Standard Assessment Methodology. AB - BACKGROUND: Heavy drinking is prevalent among young adults and may contribute to obesity. However, measurement tools for assessing caloric intake from alcohol are limited and rely on self-report, which is prone to bias. OBJECTIVE: The purpose of our study was to conduct feasibility testing of the Remote Food Photography Method and the SmartIntake app to assess alcohol use in young adults. Aims consisted of (1) quantifying the ability of SmartIntake to capture drinking behavior, (2) assessing app usability with the Computer System Usability Questionnaire (CSUQ), (3) conducting a qualitative interview, and (4) comparing preference, usage, and alcohol use estimates (calories, grams per drinking episode) between SmartIntake and online diet recalls that participants completed for a parent study. METHODS: College students (N=15) who endorsed a pattern of heavy drinking were recruited from a parent study. Participants used SmartIntake to send photographs of all alcohol and food intake over a 3-day period and then completed a follow-up interview and the CSUQ. CSUQ items range from 1-7, with lower scores indicating greater usability. Total drinking occasions were determined by adding the number of drinking occasions captured by SmartIntake plus the number of drinking occasions participants reported that they missed capturing. Usage was defined by the number of days participants provided food/beverage photos through the app, or the number of diet recalls completed. RESULTS: SmartIntake captured 87% (13/15) of total reported drinking occasions. Participants rated the app as highly usable in the CSUQ (mean 2.28, SD 1.23). Most participants (14/15, 93%) preferred using SmartIntake versus recalls, and usage was significantly higher with SmartIntake than recalls (42/45, 93% vs 35/45, 78%; P=.04). Triple the number of participants submitted alcohol reports with SmartIntake compared to the recalls (SmartIntake 9/15, 60% vs recalls 3/15, 20%; P=.06), and 60% (9/15) of participants reported drinking during the study. CONCLUSIONS: SmartIntake was acceptable to college students who drank heavily and captured most drinking occasions. Participants had higher usage of SmartIntake compared to recalls, suggesting SmartIntake may be well suited to measuring alcohol consumption in young adults. However, 40% (6/15) did not drink during the brief testing period and, although findings are promising, a longer trial is needed. PMID- 30249592 TI - They Don't Care About Us! Care Personnel's Perspectives on Ambient Assisted Living Technology Usage: Scenario-Based Survey Study. AB - BACKGROUND: Demographic change represents enormous burdens for the care sectors, resulting in high proportions of (older) people in need of care and a lack of care staff. Ambient Assisted Living (AAL) technologies have the potential to support the bottlenecks in care supply but are not yet in widespread use in professional care contexts. OBJECTIVE: The objective of our study was to investigate professional caregivers' AAL technology acceptance and their perception regarding specific technologies, data handling, perceived benefits, and barriers. In particular, this study focuses on the perspectives on AAL technologies differing between care professionals working in diverse care contexts to examine the extent to which the care context influences the acceptance of assistive technologies. METHODS: A Web-based survey (N=170) was carried out focusing on professional caregivers including medical, geriatric, and disabled people's caregivers. Based on a scenario, the participants were asked for their perceptions concerning specific technologies, specific types of gathered data, and potential benefits of and barriers to AAL technology usage. RESULTS: The care context significantly impacted the evaluations of AAL technologies (F14,220=2.514; P=.002). Professional caregivers of disabled people had a significantly more critical attitude toward AAL technologies than medical and geriatric caregivers, indicated (1) by being the only caregiver group that rejected evaluations of AAL technology acceptance (F2,118=4.570; P=.01) and specific technologies (F2,118=11.727; P<.001) applied for gathering data and (2) by the comparatively lowest agreements referring to the evaluations of data types (F2,118=4.073, P=.02) that are allowed to be gathered. CONCLUSIONS: AAL technology acceptance is critical because of technology implementation reasons, especially in the care of people with disabilities. AAL technologies in care contexts have to be tailored to care professional's needs and concerns ("care about us"). The results contribute to a broader understanding of professional caregivers' needs referring to specific data and technology configurations and enclose major differences concerning diverse care contexts. Integrating these findings into user group-tailored technology concepts and communication strategies will support a sustainable adoption of AAL systems in professional care contexts. PMID- 30249591 TI - Development of a Path to Home Mobile App for the Geriatric Rehabilitation Program at Bruyere Continuing Care: Protocol for User-Centered Design and Feasibility Testing Studies. AB - BACKGROUND: As the population ages, the need for appropriate geriatric rehabilitation services will also increase. Pressures faced by hospitals to reduce length of stay and reduce costs have driven the need for more complex care being delivered in the home or community setting. As a result, a multifaceted approach that can provide geriatric rehabilitation patients with safe and effective person- and family-centered care during transitions from hospital to home is required. We hypothesize that a technology-supported person- and family centered care transition could empower geriatric rehabilitation patients, engage them in shared decision making, and ultimately help them to safely manage their personalized needs during care transitions from hospital to home. OBJECTIVE: The purpose of this study is to design and test the feasibility of a novel Path to Home mobile app to manage the personalized needs of geriatric rehabilitation patients during their transitions from hospital to home. METHODS: This study will consist of (1) codesigning a patient- and provider-tailored mobile app, and (2) feasibility pilot testing of the mobile app to manage the needs of geriatric rehabilitation patients when leaving the hospital. In phase 1, we will follow a user-centered design process integrated with a modern agile software development methodology to iteratively codesign the personalized care transition Path to Home mobile app. In phase 2, we will conduct a single-arm feasibility pilot test with geriatric rehabilitation patients using the personalized care transition Path to Home mobile app to manage their needs during the transition from hospital to home. RESULTS: The project was funded in May 2018, and enrollment and data analysis are underway. First results are expected to be submitted for publication in 2019. CONCLUSIONS: Our findings will help validate the use of this technology for geriatric rehabilitation patients discharged from the hospital to home. Future research will more rigorously evaluate the health and economic benefits to inform wide-scale adoption of the technology. REGISTERED REPORT IDENTIFIER: RR1 10.2196/11031. PMID- 30249594 TI - Modified T Cells Home to Brain Tumors. AB - In a recent study, researchers investigated why brain cancers are impervious to T cells, and used their findings to create reengineered T cells that are better able to move into tumors. Their "homing system" could improve CAR T-cell therapies for brain cancers, including glioblastoma and medulloblastoma. PMID- 30249593 TI - Use and Effects of Patient Access to Medical Records in General Practice Through a Personal Health Record in the Netherlands: Protocol for a Mixed-Methods Study. AB - BACKGROUND: In the Dutch health care system, general practitioners hold a central position. They store information from all health care providers who are involved with their patients in their electronic health records. Web-based access to the summary record in general practice through a personal health record (PHR) may increase patients' insight into their medical conditions and help them to be involved in their care. OBJECTIVE: We describe the protocol that we will use to investigate the utilization of patients' digital access to the summary of their medical records in general practice through a PHR and its effects on the involvement of patients in their care. METHODS: We will conduct a multilevel mixed-methods study in which the PHR and Web-based access to the summary record will be offered for 6 months to a random sample of 500 polypharmacy patients, 500 parents of children aged <4 years, and 500 adults who do not belong to the former two groups. At the patient level, a controlled before-after study will be conducted using surveys, and concurrently, qualitative data will be collected from focus group discussions, think-aloud observations, and semistructured interviews. At the general practice staff (GP staff) level, focus group discussions will be conducted at baseline and Q-methodology inquiries at the end of the study period. The primary outcomes at the patient level are barriers and facilitators for using the PHR and summary records and changes in taking an active role in decision making and care management and medication adherence. Outcomes at the GP staff level are attitudes before and opinions after the implementation of the intervention. Patient characteristics and changes in outcomes related to patient involvement during the study period will be compared between the users and nonusers of the intervention using chi-square tests and t tests. A thematic content analysis of the qualitative data will be performed, and the results will be used to interpret quantitative findings. RESULTS: Enrollment was completed in May 2017 and the possibility to view GP records through the PHR was implemented in December 2017. Data analysis is currently underway and the first results are expected to be submitted for publication in autumn 2019. CONCLUSIONS: We expect that the findings of this study will be useful to health care providers and health care organizations that consider introducing the use of PHR and Web-based access to records and to those who have recently started using these. TRIAL REGISTRATION: Netherlands Trial Registry NTR6395; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6395 (Archived by WebCite at http://www.webcitation.org/71nc8jzwM). REGISTERED REPORT IDENTIFIER: RR1-10.2196/10193. PMID- 30249597 TI - Harmful drug shortages will worsen after Brexit, doctors warn. PMID- 30249595 TI - USP14 inhibition corrects an in vivo model of impaired mitophagy. AB - Mitochondrial autophagy or mitophagy is a key process that allows selective sequestration and degradation of dysfunctional mitochondria to prevent excessive reactive oxygen species, and activation of cell death. Recent studies revealed that ubiquitin-proteasome complex activity and mitochondrial membrane rupture are key steps preceding mitophagy, in combination with the ubiquitination of specific outer mitochondrial membrane (OMM) proteins. The deubiquitinating enzyme ubiquitin-specific peptidase 14 (USP14) has been shown to modulate both proteasome activity and autophagy. Here, we report that genetic and pharmacological inhibition of USP14 promotes mitophagy, which occurs in the absence of the well-characterised mediators of mitophagy, PINK1 and Parkin. Critical to USP14-induced mitophagy is the exposure of the LC3 receptor Prohibitin 2 by mitochondrial fragmentation and mitochondrial membrane rupture. Genetic or pharmacological inhibition of USP14 in vivo corrected mitochondrial dysfunction and locomotion behaviour of PINK1/Parkin mutant Drosophila model of Parkinson's disease, an age-related progressive neurodegenerative disorder that is correlated with diminished mitochondrial quality control. Our study identifies a novel therapeutic target that ameliorates mitochondrial dysfunction and in vivo PD-related symptoms. PMID- 30249598 TI - The Epidemiology of Deafness. AB - Hearing loss is the most common sensory deficit worldwide. It affects ~5% of the world population, impacts people of all ages, and exacts a significant personal and societal cost. This review presents epidemiological data on hearing loss. We discuss hereditary hearing loss, complex hearing loss with genetic and environmental factors, and hearing loss that is more clearly related to environment. We also discuss the disparity in hearing loss across the world, with more economically developed countries having overall lower rates of hearing loss compared with developing countries, and the opportunity to improve diagnosis, prevention, and treatment of this disorder. PMID- 30249596 TI - A role for Mog1 in H2Bub1 and H3K4me3 regulation affecting RNAPII transcription and mRNA export. AB - Monoubiquitination of histone H2B (to H2Bub1) is required for downstream events including histone H3 methylation, transcription, and mRNA export. The mechanisms and players regulating these events have not yet been completely delineated. Here, we show that the conserved Ran-binding protein Mog1 is required to sustain normal levels of H2Bub1 and H3K4me3 in Saccharomyces cerevisiae Mog1 is needed for gene body recruitment of Rad6, Bre1, and Rtf1 that are involved in H2B ubiquitination and genetically interacts with these factors. We provide evidence that the absence of MOG1 impacts on cellular processes such as transcription, DNA replication, and mRNA export, which are linked to H2Bub1. Importantly, the mRNA export defect in mog1Delta strains is exacerbated by the absence of factors that decrease H2Bub1 levels. Consistent with a role in sustaining H2Bub and H3K4me3 levels, Mog1 co-precipitates with components that participate in these modifications such as Bre1, Rtf1, and the COMPASS-associated factors Shg1 and Sdc1. These results reveal a novel role for Mog1 in H2B ubiquitination, transcription, and mRNA biogenesis. PMID- 30249599 TI - Stem Cells and the Bird Cochlea-Where Is Everybody? AB - In sharp contrast to the adult mammalian cochlea, which lacks regenerative ability, the mature avian cochlea, or basilar papilla (BP) is capable of complete recovery from hearing loss after damage. Avian sensory hair cell regeneration relies on rousing quiescent supporting cells to proliferate or transdifferentiate after hair cell death. Unlike mammalian cochlear supporting cells, which have clearly defined subtypes, avian BP supporting cells are deceptively indistinguishable and molecular markers have yet to be identified. Despite the importance of supporting cells as the putative stem cells in avian regeneration, it is unknown whether all supporting cells possess equal capability to give rise to a hair cell or if a specialized subpopulation exists. In this perspective, we reinvigorate the concept of a stem cell in the BP, and form comparisons to other regenerating tissues that show cell-cycle reentry after damage. Special emphasis is given to the structure of the BP and how anatomy informs both the potential, intrinsic heterogeneity of the supporting cell layer as well as the choice between mitotic and nonmitotic regenerative strategies. PMID- 30249600 TI - Use of Bioelectronics in the Gastrointestinal Tract. AB - Gastrointestinal (GI) motility disorders are major contributing factors to functional GI diseases that account for >40% of patients seen in gastroenterology clinics and affect >20% of the general population. The autonomic and enteric nervous systems and the muscles within the luminal GI tract have key roles in motility. In health, this complex integrated system works seamlessly to transport liquid, solid, and gas through the GI tract. However, major and minor motility disorders occur when these systems fail. Common functional GI motility disorders include dysphagia, gastroesophageal reflux disease, functional dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, postoperative ileus, irritable bowel syndrome, functional diarrhea, functional constipation, and fecal incontinence. Although still in its infancy, bioelectronic therapy in the GI tract holds great promise through the targeted stimulation of nerves and muscles. PMID- 30249601 TI - Electromagnetic Regulation of Cell Activity. AB - The ability to observe the effects of rapidly and reversibly regulating cell activity in targeted cell populations has provided numerous physiologic insights. Over the last decade, a wide range of technologies have emerged for regulating cellular activity using optical, chemical, and, more recently, electromagnetic modalities. Electromagnetic fields can freely penetrate cells and tissue and their energy can be absorbed by metal particles. When released, the absorbed energy can in turn gate endogenous or engineered receptors and ion channels to regulate cell activity. In this manner, electromagnetic fields acting on external nanoparticles have been used to exert mechanical forces on cell membranes and organelles to generate heat and interact with thermally activated proteins or to induce receptor aggregation and intracellular signaling. More recently, technologies using genetically encoded nanoparticles composed of the iron storage protein, ferritin, have been used for targeted, temporal control of cell activity in vitro and in vivo. These tools provide a means for noninvasively modulating gene expression, intracellular organelles, such as endosomes, and whole-cell activity both in vitro and in freely moving animals. The use of magnetic fields interacting with external or genetically encoded nanoparticles thus provides a rapid noninvasive means for regulating cell activity. PMID- 30249602 TI - Small Heat Shock Proteins, Amyloid Fibrils, and Nicotine Stimulate a Common Immune Suppressive Pathway with Implications for Future Therapies. AB - The alpha7 nicotinic acetylcholine receptor (alpha7nAChR) is central to the anti inflammatory function of the vagus nerve in a physiological mechanism termed the inflammatory reflex. Studies on the inflammatory reflex have been instrumental for the current development of the field of bioelectronic medicine. An independent investigation of the biological role of alphaB-crystallin (HspB5), the most abundant gene transcript present in active multiple sclerosis lesions in human brains, also led to alpha7nAChR. Induction of experimental autoimmune encephalomyelitis (EAE) in HspB5-/- mice results in greater paralytic signs, increased levels of proinflammatory cytokines, and T-lymphocyte activation relative to wild-type animals. Administration of HspB5 was therapeutic in animal models of multiple sclerosis, retinal and cardiac ischemia, and stroke. Structure activity studies established that residues 73-92 were as potent as the parent protein, but only when it formed amyloid fibrils. Amyloid fibrils and small heat shock proteins (sHsps) selectively bound alpha7nAChR on peritoneal macrophages (MPhis) and B lymphocytes, converting the MPhis to an immune suppressive phenotype and mobilizing the migration of both cell types from the peritoneum to secondary lymph organs. Here, we review multiple aspects of this work, which may be of interest for developing future therapeutic approaches for multiple sclerosis and other disorders. PMID- 30249604 TI - Chronic heart failure in adults: summary of updated NICE guidance. PMID- 30249605 TI - Lost in clocks: non-canonical circadian oscillation discovered in Drosophila cells. PMID- 30249606 TI - Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants. AB - Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases. Most tumor-relevant IDH1 mutations are deficient in the normal oxidization of isocitrate to alpha-ketoglutarate (alphaKG), but gain the neomorphic activity of reducing alphaKG to D-2-hydroxyglutarate (D2HG), which drives tumorigenesis. We found previously that IDH1 mutants exhibit one of two reactivities: deficient alphaKG and moderate D2HG production (including commonly observed R132H and R132C) or moderate alphaKG and high D2HG production (R132Q). Here, we identify a third type of reactivity, deficient alphaKG and high D2HG production (R132L). We show that R132Q IDH1 has unique structural features and distinct reactivities towards mutant IDH1 inhibitors. Biochemical and cell-based assays demonstrate that while most tumor-relevant mutations were effectively inhibited by mutant IDH1 inhibitors, R132Q IDH1 had up to a 16 300-fold increase in IC50 versus R132H IDH1. Only compounds that inhibited wild-type (WT) IDH1 were effective against R132Q. This suggests that patients with a R132Q mutation may have a poor response to mutant IDH1 therapies. Molecular dynamics simulations revealed that near the NADP+/NADPH-binding site in R132Q IDH1, a pair of alpha-helices switches between conformations that are more wild-type-like or more mutant-like, highlighting mechanisms for preserved WT activity. Dihedral angle changes in the dimer interface and buried surface area charges highlight possible mechanisms for loss of inhibitor affinity against R132Q. This work provides a platform for predicting a patient's therapeutic response and identifies a potential resistance mutation that may arise upon treatment with mutant IDH inhibitors. PMID- 30249607 TI - Effects of discontinuation of chronic medication in primary care: a systematic review of deprescribing trials. AB - BACKGROUND: Polypharmacy is becoming more prevalent and evaluation of appropriateness of medication use is increasingly important. The primary care physician often conducts the deprescribing process; however, there are several barriers to implementing this. AIM: To examine the feasibility and safety of discontinuation of medication, with a focus on studies that have been conducted in the community, that is, primary care (or general practice) and nursing homes. DESIGN AND SETTING: This systematic review included randomised controlled trials published in 2005-2017, which studied withdrawal of long-term drugs prescribed in primary care settings and compared continuing medication with discontinuing. METHOD: PubMed and EMBASE searches were conducted and the extracted data included the number of patients who successfully stopped medication and the number of patients who experienced relapse of symptoms or restarted medication. RESULTS: A total of 27 studies reported in 26 papers were included in this review. The number of participants in the studies varied from 20 to 2471 and the mean age of participants ranged from 50.3 years to 89.2 years. The proportion of patients who successfully stopped their medication varied from 20% to 100%, and the range of reported relapse varied from 1.9% to 80%. CONCLUSION: Only a few studies have examined the success rate and safety of discontinuing medication in primary care, and these studies are very heterogeneous. Most studies show that deprescribing and cessation of long-term use seem safe; however, there is a risk of relapse of symptoms. More research is needed to advise physicians in making evidence-based decisions about deprescribing in primary care settings. PMID- 30249608 TI - Prevalence of drug-herb and drug-supplement interactions in older adults: a cross sectional survey. AB - BACKGROUND: Polypharmacy is common among older adults, with increasing numbers also using prescription drugs with herbal medicinal products (HMPs) and dietary supplements. There is no reliable evidence from the UK on concurrent use of HMPs and dietary supplements with prescription drugs in older adults. AIM: To establish prevalence of concurrent prescription drugs, HMPs, and dietary supplements among UK community-dwelling older adults and identify potential interactions. DESIGN AND SETTING: Cross-sectional survey of older adults registered at two general practices in South East England. METHOD: A questionnaire asking about prescription medications, HMPs, and sociodemographic information was posted to 400 older adults aged >=65 years, identified as taking >=1 prescription drug. RESULTS: In total 155 questionnaires were returned (response rate = 38.8%) and the prevalence of concurrent HMPs and dietary supplements with prescriptions was 33.6%. Females were more likely than males to be concurrent users (43.4% versus 22.5%; P = 0.009). The number of HMPs and dietary supplements ranged from 1 to 8, (mean = 3, median = 1; standard deviation = 1.65). The majority of concurrent users (78.0%) used dietary supplements with prescription drugs. The most commonly used dietary supplements were cod liver oil, glucosamine, multivitamins, and vitamin D. Others (20.0%) used only HMPs with prescription drugs. Common HMPs were evening primrose oil, valerian, and Nytol Herbal(r) (a combination of hops, gentian, and passion flower). Sixteen participants (32.6%) were at risk of potential adverse drug interactions. CONCLUSION: GPs should routinely ask questions regarding herbal and supplement use, to identify and manage older adults at potential risk of adverse drug interactions. PMID- 30249609 TI - Management of treatment-resistant depression in primary care: a mixed-methods study. AB - BACKGROUND: Non-response to antidepressant medication is common in primary care. Little is known about how GPs manage patients with depression that does not respond to medication. AIM: To describe usual care for primary care patients with treatment-resistant depression (TRD). DESIGN AND SETTING: Mixed-methods study using data from a UK primary care multicentre randomised controlled trial. METHOD: In total, 235 patients with TRD randomised to continue with usual GP care were followed up at 3-month intervals for a year. Self-report data were collected on antidepressant medication, number of GP visits, and other treatments received. In addition, 14 semi-structured face-to-face interviews were conducted with a purposive sample after the 6-month follow-up and analysed thematically. RESULTS: Most patients continued on the same dose of a single antidepressant between baseline and 3 months (n = 147/186 at 3 months, 79% (95% confidence interval [CI] = 73 to 85%)). Figures were similar for later follow-ups (for example, 9-12 months: 72% (95% CI = 63 to 79%). Medication changes (increasing dose; switching to a different antidepressant; adding a second antidepressant) were uncommon. Participants described usual care mainly as taking antidepressants, with consultations focused on other (physical) health concerns. Few accessed other treatments or were referred to secondary care. CONCLUSION: Usual care in patients with TRD mainly entailed taking antidepressants, and medication changes were uncommon. The high prevalence of physical and psychological comorbidity means that, when these patients consult, their depression may not be discussed. Strategies are needed to ensure the active management of this large group of patients whose depression does not respond to antidepressant medication. PMID- 30249603 TI - Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by beta2 adrenergic receptor/PKA and Ca2+/CaMKII signaling. AB - The synapse transmits, processes, and stores data within its tiny space. Effective and specific signaling requires precise alignment of the relevant components. This review examines current insights into mechanisms of AMPAR and NMDAR localization by PSD-95 and their spatial distribution at postsynaptic sites to illuminate the structural and functional framework of postsynaptic signaling. It subsequently delineates how beta2 adrenergic receptor (beta2 AR) signaling via adenylyl cyclase and the cAMP-dependent protein kinase PKA is organized within nanodomains. Here, we discuss targeting of beta2 AR, adenylyl cyclase, and PKA to defined signaling complexes at postsynaptic sites, i.e., AMPARs and the L-type Ca2+ channel Cav1.2, and other subcellular surface localizations, the role of A kinase anchor proteins, the physiological relevance of the spatial restriction of corresponding signaling, and their interplay with signal transduction by the Ca2+ and calmodulin-dependent kinase CaMKII How localized and specific signaling by cAMP occurs is a central cellular question. The dendritic spine constitutes an ideal paradigm for elucidating the dimensions of spatially restricted signaling because of their small size and defined protein composition. PMID- 30249610 TI - Releasing GP capacity with pharmacy prescribing support and New Ways of Working: a prospective observational cohort study. AB - BACKGROUND: General practice in the UK is experiencing a workforce crisis. However, it is unknown what impact prescribing support teams may have on freeing up GP capacity and time for clinical activities. AIM: To release GP time by providing additional prescribing resources to support general practices between April 2016 and March 2017. DESIGN AND SETTING: Prospective observational cohort study in 16 urban general practices that comprise Inverclyde Health and Social Care Partnership in Scotland. METHOD: GPs recorded the time they spent dealing with special requests, immediate discharges, outpatient requests, and other prescribing issues for 2 weeks prior to the study and for two equivalent periods during the study. Specialist clinical pharmacists performed these key prescribing activities to release GP time and Read coded their activities. GP and practice staff were surveyed to assess their expectations at baseline and their experiences during the final data-collection period. Prescribing support staff were also surveyed during the study period. RESULTS: GP time spent on key prescribing activities significantly reduced by 51% (79 hours, P<0.001) per week, equating to 4.9 hours (95% confidence interval = 3.4 to 6.4) per week per practice. The additional clinical pharmacist resource was well received and appreciated by GPs and practices. As well as freeing up GP capacity, practices and practitioners also identified improvements in patient safety, positive effects on staff morale, and reductions in stress. Prescribing support staff also indicated that the initiative had a positive impact on job satisfaction and was considered sustainable, although practice expectations and time constraints created new challenges. CONCLUSION: Specialist clinical pharmacists are safe and effective in supporting GPs and practices with key prescribing activities in order to directly free GP capacity. However, further work is required to assess the impact of such service developments on prescribing cost-efficiency and clinical pharmacist medication review work. PMID- 30249611 TI - GPs' experiences and perceptions of early detection of liver disease: a qualitative study in primary care. AB - BACKGROUND: The incidence of liver disease is increasing in the UK and primary care is a key setting where improvement in the detection and management of liver disease is required. Little is known about GPs' understanding and confidence in detecting liver disease. AIM: To explore GPs' experiences of liver disease with a focus on early detection and interpretation of liver function tests (LFTs). DESIGN AND SETTING: A qualitative study employing semi-structured interviews of a purposive sample of GPs from five UK primary care study sites. METHOD: Telephone and face-to-face interviews of GPs were undertaken. Data were analysed thematically, using a constant comparative approach. RESULTS: From a total of 25 GP interviews (N = 25), four themes were identified from the data: test requesting behaviour, confidence and challenges in diagnosing disease, access to specialist tests, and guidance and education. Participants' descriptions of how they request and interpret LFTs varied widely. Concern over missing diagnoses was a common reason for requesting blood tests; patients with mildly abnormal LFTs and those at risk of non-alcoholic fatty liver disease (NAFLD) were a particular cause of concern. GPs saw themselves as generalists, with a reluctance to take on specialist investigations. Guidelines promoted confidence for some clinicians, but others felt that liver disease was too complex to be amenable to simple instructions. Most felt that they did not have access to relevant, focused education on liver disease. CONCLUSION: Liver disease is not perceived as a priority in primary care. If GPs are to take on a greater role in identification and management of liver disease, support is needed to promote awareness, knowledge, and confidence. PMID- 30249612 TI - Concomitant diagnosis of asthma and COPD: a quantitative study in UK primary care. AB - BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) share many characteristics and symptoms, and the differential diagnosis between the two diseases can be difficult in primary care. This study explored potential overlap between both diseases in a primary care environment. AIM: To quantify how commonly patients with COPD have a concomitant diagnosis of asthma, and how commonly patients with asthma have a concomitant diagnosis of COPD in UK primary care. Additionally, the study aimed to determine the extent of possible misdiagnosis and missed opportunities for diagnosis. DESIGN AND SETTING: Patients with validated asthma and patients with validated COPD in primary care were identified from the UK Clinical Practice Research Datalink (CPRD) in separate validation studies, and the diseases were confirmed by review of GP questionnaires. METHOD: The prevalence of concurrent asthma and COPD in validated cases of either disease was examined based on CPRD coding, GP questionnaires, and requested additional information. RESULTS: In total, 400 patients with COPD and 351 patients with asthma in primary care were identified. Of the patients with validated asthma, 15% (n = 52) had previously received a diagnostic COPD Read code, although COPD was only likely in 14.8% (95% confidence interval [CI] = 11.3 to 19.0) of patients with validated asthma. More than half (52.5%, n = 210) of patients with validated COPD had previously received a diagnostic asthma Read code. However, when considering additional evidence to support a diagnosis of asthma, concurrent asthma was only likely in 14.5% (95% CI = 11.2 to 18.3) of patients with validated COPD. CONCLUSION: A concurrent asthma and COPD diagnosis appears to affect a relative minority of patients with COPD (14.5%) or asthma (14.8%). Asthma diagnosis may be over-recorded in people with COPD. PMID- 30249614 TI - Homogeneous, Real-Time NanoBRET Binding Assays for the Histamine H3 and H4 Receptors on Living Cells. AB - Receptor-binding affinity and ligand-receptor residence time are key parameters for the selection of drug candidates and are routinely determined using radioligand competition-binding assays. Recently, a novel bioluminescence resonance energy transfer (BRET) method utilizing a NanoLuc-fused receptor was introduced to detect fluorescent ligand binding. Moreover, this NanoBRET method gives the opportunity to follow fluorescent ligand binding on intact cells in real time, and therefore, results might better reflect in vivo conditions as compared with the routinely used cell homogenates or purified membrane fractions. In this study, a real-time NanoBRET-based binding assay was established and validated to detect binding of unlabeled ligands to the histamine H3 receptor (H3R) and histamine H4 receptor on intact cells. Obtained residence times of clinically tested H3R antagonists were reflected by their duration of H3R antagonism in a functional receptor recovery assay. PMID- 30249613 TI - Betacellulin (BTC) Biases the EGFR To Dimerize with ErbB3. AB - There are 13 known endogenous ligands for the epidermal growth factor receptor (EGFR) and its closely related ErbB receptor family members. We previously reported that betacellulin (BTC) is more efficacious than epidermal growth factor (EGF) in mediating corneal wound healing, although the molecular basis for this difference was unknown. For the most part, differences between ligands can be attributed to variability in binding properties, such as the unique rate of association and dissociation, pH sensitivity, and selective binding to individual ErbB family members of each ligand. However, this was not the case for BTC. Despite being better at promoting wound healing via enhanced cell migration, BTC has reduced receptor affinity and weaker induction of EGFR phosphorylation. These data indicate that the response of BTC is not due to enhanced affinity or kinase activity. Receptor phosphorylation and proximity ligation assays indicate that BTC treatment significantly increases ErbB3 phosphorylation and EGFR-ErbB3 heterodimers when compared with EGF treatment. We observed that EGFR-ErbB3 heterodimers contribute to cell migration, because the addition of an ErbB3 antagonist (MM-121) or RNA interference-mediated knockdown of ErbB3 attenuates BTC-stimulated cell migration compared with EGF. Thus, we demonstrate that, despite both ligands binding to the EGFR, BTC biases the EGFR to dimerize with ErbB3 to regulate the biologic response. PMID- 30249615 TI - Challenges of independent assessment of potential harms of HPV vaccines. PMID- 30249616 TI - Molecular determinants of alpha-conotoxin potency for inhibition of human and rat alpha6beta4 nicotinic acetylcholine receptors. AB - Nicotinic acetylcholine receptors (nAChRs) containing alpha6 and beta4 subunits are expressed by dorsal root ganglion neurons and have been implicated in neuropathic pain. Rodent models are often used to evaluate the efficacy of analgesic compounds, but species differences may affect the activity of some nAChR ligands. A previous candidate alpha-conotoxin-based therapeutic yielded promising results in rodent models, but failed in human clinical trials, emphasizing the importance of understanding species differences in ligand activity. Here, we show that human and rat alpha6/alpha3beta4 nAChRs expressed in Xenopus laevis oocytes exhibit differential sensitivity to alpha-conotoxins. Sequence homology comparisons of human and rat alpha6beta4 nAChR subunits indicated that alpha6 residues forming the ligand-binding pocket are highly conserved between the two species, but several residues of beta4 differed, including a Leu-Gln difference at position 119. X-ray crystallography of alpha conotoxin PeIA complexed with the Aplysia californica acetylcholine-binding protein (AChBP) revealed that binding of PeIA orients Pro13 in close proximity to residue 119 of the AChBP complementary subunit. Site-directed mutagenesis studies revealed that Leu119 of human beta4 contributes to higher sensitivity of human alpha6/alpha3beta4 nAChRs to alpha-conotoxins, and structure-activity studies indicated that PeIA Pro13 is critical for high potency. Human and rat alpha6/alpha3beta4 nAChRs displayed differential sensitivities to perturbations of the interaction between PeIA Pro13 and residue 119 of the beta4 subunit. These results highlight the potential significance of species differences in alpha6beta4 nAChR pharmacology that should be taken into consideration when evaluating the activity of candidate human therapeutics in rodent models. PMID- 30249619 TI - Legalise illicit drugs to protect health, say former heads of state. PMID- 30249617 TI - Functional metagenomics identifies an exosialidase with an inverting catalytic mechanism that defines a new glycoside hydrolase family (GH156). AB - Exosialidases are glycoside hydrolases that remove a single terminal sialic acid residue from oligosaccharides. They are widely distributed in biology, having been found in prokaryotes, eukaryotes, and certain viruses. Most characterized prokaryotic sialidases are from organisms that are pathogenic or commensal with mammals. However, in this study, we used functional metagenomic screening to seek microbial sialidases encoded by environmental DNA isolated from an extreme ecological niche, a thermal spring. Using recombinant expression of potential exosialidase candidates and a fluorogenic sialidase substrate, we discovered an exosialidase having no homology to known sialidases. Phylogenetic analysis indicated that this protein is a member of a small family of bacterial proteins of previously unknown function. Proton NMR revealed that this enzyme functions via an inverting catalytic mechanism, a biochemical property that is distinct from those of known exosialidases. This unique inverting exosialidase defines a new CAZy glycoside hydrolase family we have designated GH156. PMID- 30249620 TI - Science and politics of disaster death tolls. PMID- 30249618 TI - Coadministration of Chemokine Receptor Antagonists with Morphine Potentiates Morphine's Analgesic Effect on Incisional Pain in Rats. AB - Crossdesensitization between opioid and chemokine receptors and involvement of chemokines in pain modulation are well established. We investigated if coadministration of chemokine receptor antagonists (CRAs) with morphine would enhance the analgesic potency of morphine on incisional pain in rats. Animals underwent incisional surgery on the left hind paw and pain responses were evaluated using von Frey filaments at various time points postsurgery between 15 and 360 minutes and daily between 24 and 72 hours. Dose-response curves for morphine, maraviroc (a CCR5 antagonist), and AMD3100 (a CXCR4 antagonist) alone were established. While morphine significantly reduced pain in a time- and dose dependent manner, maraviroc and AMD3100 had no effect by themselves. Coadministration of either maraviroc or AMD3100 with morphine significantly increased morphine's analgesic effect on incisional pain, shifting the dose response curve to the left 2.3- and 1.8-fold, respectively. Coadministration of both CRAs with morphine significantly shifted further the morphine dose-response curve to the left 3.3-fold. The effect of treatments on mRNA levels in the draining popliteal lymph node for a panel of chemokines and cytokines showed that message for many of these mediators was upregulated by the incision, and the combination of morphine with the CRAs markedly downregulated them. The data show that combining morphine with CRAs potentiates morphine's analgesic effect on incisional pain. Thus, the same analgesic effect of morphine alone can be achieved with lower doses of morphine when combined with CRAs. Using morphine in lower doses could reduce unwanted side effects and possibly block development of tolerance and dependence. PMID- 30249621 TI - Is Breast Still Best From a Bottle? PMID- 30249622 TI - The Teen Driver. AB - For many teenagers, obtaining a driver's license is a rite of passage, conferring the ability to independently travel to school, work, or social events. However, immaturity, inexperience, and risky behavior put newly licensed teen drivers at risk. Motor vehicle crashes are the most common cause of mortality and injury for adolescents and young adults in developed countries. Teen drivers (15-19 years of age) have the highest rate of motor vehicle crashes among all age groups in the United States and contribute disproportionately to traffic fatalities. In addition to the deaths of teen drivers, more than half of 8- to 17-year-old children who die in car crashes are killed as passengers of drivers younger than 20 years of age. This policy statement, in which we update the previous 2006 iteration of this policy statement, is used to reflect new research on the risks faced by teen drivers and offer advice for pediatricians counseling teen drivers and their families. PMID- 30249623 TI - Childhood Seizures After Phototherapy. AB - : : media-1vid110.1542/5804915133001PEDS-VA_2018-0648Video Abstract BACKGROUND AND OBJECTIVES: In a recent Danish study, researchers found an increased risk of childhood epilepsy after phototherapy but only in boys. We investigated this association in a Kaiser Permanente Northern California cohort. METHODS: From 499 642 infants born at >=35 weeks' gestation in 1995-2011 followed for >=60 days, we excluded 1773 that exceeded exchange transfusion thresholds and 1237 with seizure diagnoses at <60 days. We ascertained phototherapy, covariates, and outcomes from electronic records and existing databases. Our primary outcome was >=1 encounter with a seizure diagnosis plus >=1 prescription for an antiepileptic drug. We used Cox and Poisson models to adjust for bilirubin levels and other confounding variables. RESULTS: A total of 37 683 (7.6%) infants received any phototherapy. The mean (SD) follow-up time was 8.1 (5.2) years. The crude incidence rate per 1000 person-years of the primary outcome was 1.24 among phototherapy-exposed children and 0.76 among those unexposed (rate ratio: 1.63; 95% confidence interval [CI]: 1.44 to 1.85). The adjusted hazard ratio (aHR) was 1.22 (95% CI: 1.05 to 1.42; P = .009). Boys were at higher risk of seizures overall (aHR = 1.18; 95% CI: 1.10 to 1.27) and had a higher aHR for phototherapy (1.33; 95% CI: 1.10 to 1.61) than girls (1.07; 95% CI: 0.84 to 1.37), although effect modification by sex was not statistically significant (P = .17). The adjusted 10 year excess risks per 1000 were 2.4 (95% CI: 0.6 to 4.1) overall, 3.7 (95% CI: 1.2 to 6.1) in boys, and 0.8 (95% CI: -1.7 to 3.2) in girls. CONCLUSIONS: Phototherapy in newborns is associated with a small increased risk of childhood seizures, even after adjusting for bilirubin values, and the risk is more significant in boys. PMID- 30249624 TI - Infant Feeding and Weight Gain: Separating Breast Milk From Breastfeeding and Formula From Food. AB - OBJECTIVES: Studies addressing breastfeeding and obesity rarely document the method of breast milk feeding, type of supplementation, or feeding in hospital. We investigated these practices in the CHILD birth cohort. METHODS: Feeding was reported by mothers and documented from hospital records. Weight and BMI z scores (BMIzs) were measured at 12 months. Analyses controlled for maternal BMI and other confounders. RESULTS: Among 2553 mother-infant dyads, 97% initiated breastfeeding, and the median breastfeeding duration was 11.0 months. Most infants (74%) received solids before 6 months. Among "exclusively breastfed" infants, 55% received some expressed breast milk, and 27% briefly received formula in hospital. Compared with exclusive direct breastfeeding at 3 months, all other feeding styles were associated with higher BMIzs: adjusted beta: +.12 (95% confidence interval [CI]: .01 to .23) for some expressed milk, +.28 (95% CI: .16 to .39) for partial breastfeeding, and +.45 (95% CI: .30 to .59) for exclusive formula feeding. Brief formula supplementation in hospital did not alter these associations so long as exclusive breastfeeding was established and sustained for at least 3 months. Formula supplementation by 6 months was associated with higher BMIzs (adjusted beta: +.25; 95% CI: .13 to .38), whereas supplementation with solid foods was not. Results were similar for weight gain velocity. CONCLUSIONS: Breastfeeding is inversely associated with weight gain velocity and BMI. These associations are dose dependent, partially diminished when breast milk is fed from a bottle, and substantially weakened by formula supplementation after the neonatal period. PMID- 30249625 TI - Phototherapy and Seizures: Should We Change Practice? PMID- 30249626 TI - Mantra meditation programme for emergency department staff: a qualitative study. AB - OBJECTIVES: Rates of burnout and stress in healthcare practitioners are steadily increasing. Emergency department (ED) staff are particularly susceptible to such poor outcomes. Mantra meditation (MM) may contribute to increased well-being. The primary aim of this study was to obtain indepth qualitative feedback on ED staff's experience of a MM programme. A secondary objective was to harness staff's perception of the ED working environment. DESIGN: Qualitative study. SETTING: ED in St James' Hospital, Dublin, Ireland. PARTICIPANTS: Doctors, nurses, allied health professionals and administrative staff (n=10, eight women, mean age 35.6 years) working in the ED who attended a MM programme. METHODS: Semistructured interviews were conducted by a trained independent researcher. Interviews were transcribed and thematically analysed. RESULTS: Five main themes and six subthemes were identified: work pressure and perceived stress; perceived benefits of meditation (with subthemes of increased attention/awareness, improved emotion regulation and new coping mechanisms, relaxation and sleep quality); conflicting attitudes to practice; barriers to meditation practice (with subthemes of schedule, length of practice and individual differences); and facilitators to practice. CONCLUSION: ED staff in this study described the demands of their work and voiced a need for a workplace well-being programme. Our findings suggest that MM might represent a viable tool to develop attention and awareness, improve emotion regulation and improve their capacity to cope with stress, which may impact their workplace well-being, wider health service, patient safety and quality of care. Support from the organisation is considered to be integral to embedding of a workplace well-being programme, such as the practice of meditation into their daily lives. PMID- 30249628 TI - Lessons learnt during the implementation of a web-based triage tool for Dutch intensive care follow-up clinics. AB - OBJECTIVES: Screening for symptoms of postintensive care syndrome is based on a long list of questionnaires, filled out by the intensive care unit (ICU) survivor and manually reviewed by the health professional. This is an inefficient and time consuming process. The aim of this study was to evaluate the feasibility of a web based triage tool and to compare the outcomes from web-based questionnaires to those from paper-based questionnaires. DESIGN: A mixed-methods study. SETTING: Nine Dutch ICU follow-up clinics. PARTICIPANTS: 221 ICU survivors and 14 health professionals. INTERVENTIONS: A web-based triage tool was implemented by nine ICU follow-up clinics. End users, that is, health professionals were interviewed in order to evaluate the feasibility of the triage tool. ICU survivors were invited to fill out web-based questionnaires 3 months after hospital discharge. PRIMARY OUTCOMES: Outcomes of the questionnaires were merged with clinical data from a national quality registry to assess the differences in outcomes between paper based and web-based questionnaires. RESULTS: 221 ICU survivors received an invitation to fill out questionnaires, 93 (42.1%) survivors did not respond to the invitation. Respondents to the web-based questionnaires (n=54) were significantly younger and had a significantly longer ICU stay than those who preferred the paper-based questionnaires (n=74). The prevalence of mental, physical and nutritional problems was high, although comparable between the groups. Health professionals' interviews revealed that the software was complex to use (n=8) and although emailing survivors is very convenient, not all survivors have an email address (n=7). CONCLUSIONS: Web-based screening software has major benefits compared with paper-based screening. However, implementation has shown to be rather difficult and there are important barriers to consider. Although different in age, the health status is comparable between the users of the web-based questionnaire and paper-based questionnaire. PMID- 30249629 TI - Role of supplementary material in biomedical journal articles: surveys of authors, reviewers and readers. AB - OBJECTIVE: Many journals permit authors to submit supplementary material for publication alongside the article. We explore the value, use and role of this material in biomedical journal articles from the perspectives of authors, peer reviewers and readers. DESIGN AND SETTING: We conducted online surveys (November December 2016) of corresponding authors and peer reviewers at 17 BMJ Publishing Group journals in a range of specialities. PARTICIPANTS: Participants were asked to respond to one of three surveys: as authors, peer reviewers or readers. RESULTS: We received 2872/20340 (14%) responses: authors 819/6892 (12%), peer reviewers 1142/6682 (17%) and readers 911/6766 (14%). Most authors submitted (711/819, 87%) and 80% (724/911) of readers reported reading supplementary material with their last article, while 95% (1086/1142) of reviewers reported seeing these materials sometimes. Additional data tables were the most common supplementary material reported (authors: 74%; reviewers: 89%; readers: 67%). A majority in each group indicated additional tables were most useful to readers (61%-77%); 20%-36% and 3%-4% indicated they were most useful to peer reviewers and journal editors, respectively. Checklists and reporting guidelines showed the opposite: higher proportions of each group regarded these as most useful to journal editors. All three groups favoured the publication of additional tables and figures on the journal's website (80%-83%), with <4% of each group responding that these do not need to be available. Approximately one-fifth (16%-23%) responded that raw study data should be available on the journal's website, while 24%-33% said that these materials should not be made available anywhere. CONCLUSIONS: Authors, peer reviewers and readers agree that supplementary materials are useful. Supplementary tables and figures were favoured over reporting checklists or raw data for reading but not for study replication. Journals should consider the roles, resource costs and strategic placement of supplementary materials to ensure optimal usage and minimise waste. TRIAL REGISTRATION NUMBER: NCT02961036. PMID- 30249627 TI - Prevalence of depression in patients with type 2 diabetes mellitus in Spain (the DIADEMA Study) : results from the MADIABETES cohort. AB - OBJECTIVE: To estimate the prevalence of depression in patients diagnosed with type 2 diabetes mellitus (T2DM), and to identify sociodemographic, clinical and psychological factors associated with depression in this population. Additionally, we examine the annual incidence rate of depression among patients with T2DM. METHODS: We performed a large prospective cohort study of patients with T2DM from the Madrid Diabetes Study. The first recruitment drive included 3443 patients. The second recruitment drive included 727 new patients. Data have been collected since 2007 (baseline visit) and annually during the follow-up period (since 2008). RESULTS: Depression was prevalent in 20.03% of patients (n=592; 95% CI 18.6% to 21.5%) and was associated with previous personal history of depression (OR 6.482; 95% CI 5.138 to 8.178), mental health status below mean (OR 1.423; 95% CI 1.452 to 2.577), neuropathy (OR 1.951; 95% CI 1.423 to 2.674), fair or poor self-reported health status (OR 1.509; 95% CI 1.209 to 1.882), treatment with oral antidiabetic agents plus insulin (OR 1.802; 95% CI 1.364 to 2.380), female gender (OR 1.333; 95% CI 1.009 to 1.761) and blood cholesterol level (OR 1.005; 95% CI 1.002 to 1.009). The variables inversely associated with depression were: being in employment (OR 0.595; 95% CI 0.397 to 0.894), low physical activity (OR 0.552; 95% CI 0.408 to 0.746), systolic blood pressure (OR 0.982; 95% CI 0.971 to 0.992) and social support (OR 0.978; 95% CI 0.963 to 0.993). In patients without depression at baseline, the incidence of depression after 1 year of follow-up was 1.20% (95% CI 1.11% to 2.81%). CONCLUSIONS: Depression is very prevalent among patients with T2DM and is associated with several key diabetes-related outcomes. Our results suggest that previous mental status, self-reported health status, gender and several diabetes-related complications are associated with differences in the degree of depression. These findings should alert practitioners to the importance of detecting depression in patients with T2DM. PMID- 30249630 TI - Efficacy and tolerability of novel triple combination therapy in drug-naive patients with type 2 diabetes from the TRIPLE-AXEL trial: protocol for an open label randomised controlled trial. AB - INTRODUCTION: Patients with type 2 diabetes are at risk of microvascular and macrovascular complications. Intensive glycaemic control, especially in patients with short duration of diabetes, is the mainstay of management of type 2 diabetes to lower the risk of complications. However, despite the improvement in the understanding of the pathophysiology of type 2 diabetes and development of novel glucose-lowering agents, long-term durable glycaemic control remains a difficult goal to achieve. Several challenging clinical trials proved that an early combination therapy with a variety of glucose-lowering agents had a more favourable effect than conventional stepwise therapy in terms of glycaemic control. We aim to evaluate the efficacy and tolerability of a novel, initial triple combination therapy with metformin, sodium glucose cotransporter 2 inhibitor (dapagliflozin) and dipeptidyl peptidase-4 inhibitor (saxagliptin) compared with conventional stepwise add-on therapy in drug-naive patients with recent-onset type 2 diabetes. METHODS AND ANALYSIS: This study is a multicentre, prospective, randomised, open-label, parallel group, comparator-controlled trial. A total of 104 eligible participants will be randomised to either the initial combination therapy group or the conventional stepwise add-on therapy group for 104 weeks. The primary endpoint is the proportion of patients who achieved haemoglobin A1c level<6.5% without hypoglycaemia, weight gain or discontinuation due to adverse events at 104 weeks. This trial will determine whether a novel triple combination therapy with metformin, dapagliflozin and saxagliptin has a beneficial effect on durable glycaemic control compared with conventional therapy in drug-naive patients with type 2 diabetes. ETHICS AND DISSEMINATION: This study protocol was approved by the local institutional review boards and independent ethics committees over the recruitment sites. Results of this study will be disseminated in scientific journals and scientific conferences. TRIAL REGISTRATION NUMBER: NCT02946632; Pre-results. PMID- 30249631 TI - AIDS Therapy Evaluation in the Netherlands (ATHENA) national observational HIV cohort: cohort profile. AB - PURPOSE: In 1998, the AIDS Therapy Evaluation in the Netherlands (ATHENA) national observational HIV cohort was established to demonstrate the lifesaving effectiveness of triple combination antiretroviral therapy, including HIV protease inhibitors, that had recently been made available for clinical use. Subsequently, the HIV Monitoring Foundation was established by the Dutch Ministry of Health, Welfare and Sport to continue ATHENA as an open cohort in order to continue the registration and monitoring of all HIV-positive people as an integral part of HIV care in all 26 HIV treatment centres in the Netherlands. PARTICIPANTS: To date, a total of 25 036 participants have been enrolled in the cohort, with 263 600 person-years of follow-up. As of 1 January 2017, 19 035 HIV 1-positive participants were known to be in care: 18 824 adults (81% men and 19% women) and 211 children (47% boys and 53% girls). The remaining 6001 participants had either died (46%), were lost to care (29%) or had moved abroad (25%). FINDINGS TO DATE: Today, with over 20 years of follow-up, the ATHENA cohort has provided extensive knowledge on HIV treatment, comorbidities and coinfections and created insight into the transmission dynamics of the HIV epidemic. FUTURE PLANS: ATHENA continues to enrol and monitor HIV positive people entering HIV care in the Netherlands. Future research will continue to provide tangible input into HIV care and prevention policies in the Netherlands and internationally. PMID- 30249632 TI - Effectiveness and acceptability of myo-inositol nutritional supplement in the prevention of gestational diabetes (EMmY): a protocol for a randomised, placebo controlled, double-blind pilot trial. AB - INTRODUCTION: Gestational diabetes increases maternal and offspring complications in pregnancy and cardiovascular complications in the long term. The nutritional supplement myo-inositol may prevent gestational diabetes; however, further evaluation is required, especially in multiethnic high-risk mothers. Our pilot trial on myo-inositol to prevent gestational diabetes will evaluate trial processes, assess acceptability to mothers and obtain preliminary estimates of effect and cost data prior to a large full-scale trial. METHODS AND ANALYSIS: EMmY is a multicentre, placebo-controlled, double-blind, pilot, randomised trial, with qualitative evaluation. We will recruit pregnant women at 12-15+6 weeks' gestation, with gestational diabetes risk factors, from five maternity units in England between 2018 and 2019. We will randomise 200 women to take either 2 g of myo-inositol powder (intervention) or placebo, twice daily until delivery. We will assess rates of recruitment, randomisation, adherence to intervention and follow-up. Gestational diabetes will be diagnosed at 24-28 weeks as per the National Institute for Health and Care Excellence (NICE) criteria (fasting plasma glucose: >=5.6 mmol/L and 2-hour plasma glucose: >=7.8 mmol/L). We will assess the effects of myo-inositol on glycaemic indices at 28 weeks and on other maternal, fetal and neonatal outcomes at postnatal discharge. Qualitative evaluation will explore the acceptability of the trial and the intervention among women and healthcare professionals. Cost data and health-related quality of life measures will be captured. We will summarise feasibility outcomes using standard methods for proportions and other descriptive statistics, and where appropriate, report point estimates of effect sizes (eg, mean differences and relative risks) and associated 95% CIs. ETHICS AND DISSEMINATION: Ethical approval was obtained through the London Queen Square Research Ethics Committee (17/LO/1741). Study findings will be submitted for publication in peer-reviewed journals. Newsletters will be made available to participants, healthcare professionals and members of Katie's Team (a patient and public advisory group) to disseminate. TRIAL REGISTRATION NUMBER: ISRCTN48872100. PROTOCOL VERSION AND DATE: Version 4.0, 15 January 2018. PMID- 30249633 TI - Acceptability of a German multicentre healthcare research study: a survey of research personnels' attitudes, experiences and work load. AB - OBJECTIVES: The DACAPO study as a multicentre nationwide observational healthcare research study investigates the influence of quality of care on the quality of life in patients with acute respiratory distress syndrome. The aim of this study was to investigate the acceptability to the participating research personnels by assessing attitudes, experiences and workload associated with the conduct of the DACAPO study. DESIGN, SETTING AND PARTICIPANTS: A prospective anonymous online survey was sent via email account to 169 participants in 65 study centres. The questionnaire included six different domains: (1) training for performing the study; (2) obtaining informed consent; (3) data collection; (4) data entry using the online documentation system; (5) opinion towards the study and (6) personal data. Descriptive data analysis was carried out. RESULTS: A total of 78 participants took part (46%) in the survey, 75 questionnaires (44%) could be evaluated. 51% were senior medical specialists. 95% considered the time frame of the training as appropriate and the presentation was rated by 93% as good or very good. Time effort for obtaining consent, data collection and entry was considered by 41% as a burden. Support from the coordinating study centre was rated as good or very good by more than 90% of respondents. While the DACAPO study was seen as scientifically relevant by 81%, only 45% considered the study results valuable for improving patient care significantly. CONCLUSION: Collecting feedback on the acceptability of a large multicentre healthcare research study provided important insights. Recruitment and data acquisition was mainly performed by physicians and often regarded as additional time burden in clinical practice. Reducing the amount of data collection and simplifying data entry could facilitate the conduct of healthcare research studies and could improve motivation of researchers in intensive care medicine. TRIAL REGISTRATION NUMBER: NCT02637011; Pre-results. PMID- 30249634 TI - Trehalose 6-Phosphate Positively Regulates Fatty Acid Synthesis by Stabilizing WRINKLED1. AB - WRINKLED1 (WRI1), the transcriptional activator of fatty acid synthesis, was recently identified as a target of KIN10, a catalytic alpha-subunit of the SUCROSE-NON-FERMENTING1-RELATED PROTEIN KINASE1 (SnRK1). We tested the hypothesis that trehalose 6-phosphate (T6P), a signal of cellular sucrose status, can regulate fatty acid synthesis by inhibiting SnRK1. Incubation of Brassica napus suspension cells in medium containing T6P, or overexpression of the Escherichia coli T6P synthase, OtsA, in Nicotiana benthamiana, significantly increased T6P levels, WRI1 levels, and fatty acid synthesis rates. T6P directly bound to purified recombinant KIN10 with an equilibrium dissociation constant (K d) of 32 +/- 6 MUM based on microscale thermophoresis. GEMINIVIRUS REP-INTERACTING KINASE1 (GRIK1) bound to KIN10 (K d 19 +/- 3 MUM) and activated it by phosphorylation. In the presence of T6P, the GRIK1-KIN10 association was weakened by more than 3-fold (K d 68 +/- 9.8 MUM), which reduced both the phosphorylation of KIN10 and its activity. T6P-dependent inhibition of SnRK1 activity was reduced in extracts of individual Arabidopsis thaliana grik1 and grik2 mutants relative to the wild type, while SnRK1 activity in grik1 grik2 extracts was enhanced by T6P. These results indicate that the T6P sensitivity of SnRK1 in vivo is GRIK1/GRIK2 dependent. Based on our findings, we propose a mechanistic model that links sugar signaling and fatty acid homeostasis. PMID- 30249635 TI - Glyphosate perturbs the gut microbiota of honey bees. AB - Glyphosate, the primary herbicide used globally for weed control, targets the 5 enolpyruvylshikimate-3-phosphate synthase (EPSPS) enzyme in the shikimate pathway found in plants and some microorganisms. Thus, glyphosate may affect bacterial symbionts of animals living near agricultural sites, including pollinators such as bees. The honey bee gut microbiota is dominated by eight bacterial species that promote weight gain and reduce pathogen susceptibility. The gene encoding EPSPS is present in almost all sequenced genomes of bee gut bacteria, indicating that they are potentially susceptible to glyphosate. We demonstrated that the relative and absolute abundances of dominant gut microbiota species are decreased in bees exposed to glyphosate at concentrations documented in the environment. Glyphosate exposure of young workers increased mortality of bees subsequently exposed to the opportunistic pathogen Serratia marcescens Members of the bee gut microbiota varied in susceptibility to glyphosate, largely corresponding to whether they possessed an EPSPS of class I (sensitive to glyphosate) or class II (insensitive to glyphosate). This basis for differences in sensitivity was confirmed using in vitro experiments in which the EPSPS gene from bee gut bacteria was cloned into Escherichia coli All strains of the core bee gut species, Snodgrassella alvi, encode a sensitive class I EPSPS, and reduction in S. alvi levels was a consistent experimental result. However, some S. alvi strains appear to possess an alternative mechanism of glyphosate resistance. Thus, exposure of bees to glyphosate can perturb their beneficial gut microbiota, potentially affecting bee health and their effectiveness as pollinators. PMID- 30249636 TI - Neural basis of location-specific pupil luminance modulation. AB - Spatial attention enables us to focus visual processing toward specific locations or stimuli before the next fixation. Recent evidence has suggested that local luminance at the spatial locus of attention or saccade preparation influences pupil size independent of global luminance levels. However, it remains to be determined which neural pathways produce this location-specific modulation of pupil size. The intermediate layers of the midbrain superior colliculus (SC) form part of the network of brain areas involved in spatial attention and modulation of pupil size. Here, we demonstrated that pupil size was altered according to local luminance level at the spatial location corresponding to a microstimulated location in the intermediate SC (SCi) map of monkeys. Moreover, local SCi inactivation through injection of lidocaine reversed this local luminance modulation. Our findings reveal a causal role of the SCi in preparing pupil size for local luminance conditions at the next saccadic goal. PMID- 30249638 TI - A new clade of basal Early Cretaceous pygostylian birds and developmental plasticity of the avian shoulder girdle. AB - Early members of the clade Pygostylia (birds with a short tail ending in a compound bone termed "pygostyle") are critical for understanding how the modern avian bauplan evolved from long-tailed basal birds like Archaeopteryx However, the currently limited known diversity of early branching pygostylians obscures our understanding of this major transition in avian evolution. Here, we describe a basal pygostylian, Jinguofortis perplexus gen. et sp. nov., from the Early Cretaceous of China that adds important information about early members of the short-tailed bird group. Phylogenetic analysis recovers a clade (Jinguofortisidae fam. nov.) uniting Jinguofortis and the enigmatic basal avian taxon Chongmingia that represents the second earliest diverging group of the Pygostylia. Jinguofortisids preserve a mosaic combination of plesiomorphic nonavian theropod features such as a fused scapulocoracoid (a major component of the flight apparatus) and more derived flight-related morphologies including the earliest evidence of reduction in manual digits among birds. The presence of a fused scapulocoracoid in adult individuals independently evolved in Jinguofortisidae and Confuciusornithiformes may relate to an accelerated osteogenesis during chondrogenesis and likely formed through the heterochronic process of peramorphosis by which these basal taxa retain the scapulocoracoid of the nonavian theropod ancestors with the addition of flight-related modifications. With wings having a low aspect ratio and wing loading, Jinguofortis may have been adapted particularly to dense forest environments. The discovery of Jinguofortis increases the known ecomorphological diversity of basal pygostylians and highlights the importance of developmental plasticity for understanding mosaic evolution in early birds. PMID- 30249637 TI - Identity and novelty in the avian syrinx. AB - In its most basic conception, a novelty is simply something new. However, when many previously proposed evolutionary novelties have been illuminated by genetic, developmental, and fossil data, they have refined and narrowed our concept of biological "newness." For example, they show that these novelties can occur at one or multiple levels of biological organization. Here, we review the identity of structures in the avian vocal organ, the syrinx, and bring together developmental data on airway patterning, structural data from across tetrapods, and mathematical modeling to assess what is novel. In contrast with laryngeal cartilages that support vocal folds in other vertebrates, we find no evidence that individual cartilage rings anchoring vocal folds in the syrinx have homology with any specific elements in outgroups. Further, unlike all other vertebrate vocal organs, the syrinx is not derived from a known valve precursor, and its origin involves a transition from an evolutionary "spandrel" in the respiratory tract, the site where the trachea meets the bronchi, to a target for novel selective regimes. We find that the syrinx falls into an unusual category of novel structures: those having significant functional overlap with the structures they replace. The syrinx, along with other evolutionary novelties in sensory and signaling modalities, may more commonly involve structural changes that contribute to or modify an existing function rather than those that enable new functions. PMID- 30249640 TI - Correction for Taylor et al., Origins of equine dentistry. PMID- 30249639 TI - Genomic blueprint of a relapsing fever pathogen in 15th century Scandinavia. AB - Louse-borne relapsing fever (LBRF) is known to have killed millions of people over the course of European history and remains a major cause of mortality in parts of the world. Its pathogen, Borrelia recurrentis, shares a common vector with global killers such as typhus and plague and is known for its involvement in devastating historical epidemics such as the Irish potato famine. Here, we describe a European and historical genome of B recurrentis, recovered from a 15th century skeleton from Oslo. Our distinct European lineage has a discrete genomic makeup, displaying an ancestral oppA-1 gene and gene loss in antigenic variation sites. Our results illustrate the potential of ancient DNA research to elucidate dynamics of reductive evolution in a specialized human pathogen and to uncover aspects of human health usually invisible to the archaeological record. PMID- 30249641 TI - Sediment starvation destroys New York City marshes' resistance to sea level rise. AB - New York City (NYC) is representative of many vulnerable coastal urban populations, infrastructures, and economies threatened by global sea level rise. The steady loss of marshes in NYC's Jamaica Bay is typical of many urban estuaries worldwide. Essential to the restoration and preservation of these key wetlands is an understanding of their sedimentation. Here we present a reconstruction of the history of mineral and organic sediment fluxes in Jamaica Bay marshes over three centuries, using a combination of density measurements and a detailed accretion model. Accretion rate is calculated using historical land use and pollution markers, through a wide variety of sediment core analyses including geochemical, isotopic, and paleobotanical analyses. We find that, since 1800 CE, urban development dramatically reduced the input of marsh-stabilizing mineral sediment. However, as mineral flux decreased, organic matter flux increased. While this organic accumulation increase allowed vertical accumulation to outpace sea level, reduced mineral content causes structural weakness and edge failure. Marsh integrity now requires mineral sediment addition to both marshes and subsurface channels and borrow pits, a solution applicable to drowning estuaries worldwide. Integration of marsh mineral/organic accretion history with modeling provides parameters for marsh preservation at specific locales with sea level rise. PMID- 30249642 TI - Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections. AB - The increased prevalence of drug-resistant human pathogenic fungal diseases poses a major threat to global human health. Thus, new drugs are urgently required to combat these infections. Here, we demonstrate that acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway, is a promising new target for antifungal drug discovery. First, we show that several AHAS inhibitors developed as commercial herbicides are powerful accumulative inhibitors of Candida albicans AHAS (K i values as low as 800 pM) and have determined high-resolution crystal structures of this enzyme in complex with several of these herbicides. In addition, we have demonstrated that chlorimuron ethyl (CE), a member of the sulfonylurea herbicide family, has potent antifungal activity against five different Candida species and Cryptococcus neoformans (with minimum inhibitory concentration, 50% values as low as 7 nM). Furthermore, in these assays, we have shown CE and itraconazole (a P450 inhibitor) can act synergistically to further improve potency. Finally, we show in Candida albicans-infected mice that CE is highly effective in clearing pathogenic fungal burden in the lungs, liver, and spleen, thus reducing overall mortality rates. Therefore, in view of their low toxicity to human cells, AHAS inhibitors represent a new class of antifungal drug candidates. PMID- 30249643 TI - Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium. AB - Retinal degenerative diseases are generally characterized by a permanent loss of light-sensitive retinal neurons known as photoreceptors, or their support cells, the retinal pigmented epithelium (RPE). Metabolic dysfunction has been implicated as a common mechanism of degeneration. In this study, we used the drug metformin in a gain-of-function approach to activate adenosine monophosphate-activated protein kinase (AMPK). We found that treatment protected photoreceptors and the RPE from acute injury and delayed inherited retinal degeneration. Protection was associated with decreased oxidative stress, decreased DNA damage, and increased mitochondrial energy production. To determine whether protection was a local or a systemic effect of metformin, we used AMPK retinal knockout mice and found that local expression of AMPK catalytic subunit alpha2 was required for metformin induced protection. Our data demonstrate that increasing the activity of AMPK in retinal neurons or glia can delay or prevent degeneration of photoreceptors and the RPE from multiple types of cell-death triggers. PMID- 30249644 TI - Parallel reaction pathways and noncovalent intermediates in thymidylate synthase revealed by experimental and computational tools. AB - Thymidylate synthase was one of the most studied enzymes due to its critical role in molecular pathogenesis of cancer. Nevertheless, many atomistic details of its chemical mechanism remain unknown or debated, thereby imposing limits on design of novel mechanism-based anticancer therapeutics. Here, we report unprecedented isolation and characterization of a previously proposed intact noncovalent bisubstrate intermediate formed in the reaction catalyzed by thymidylate synthase. Free-energy surfaces of the bisubstrate intermediates interconversions computed with quantum mechanics/molecular mechanics (QM/MM) methods and experimental assessment of the corresponding kinetics indicate that the species is the most abundant productive intermediate along the reaction coordinate, whereas accumulation of the covalent bisubstrate species largely occurs in a parallel nonproductive pathway. Our findings not only substantiate relevance of the previously proposed noncovalent intermediate but also support potential implications of the overstabilized covalent intermediate in drug design targeting DNA biosynthesis. PMID- 30249645 TI - Profile of Jonathan D. G. Jones. PMID- 30249648 TI - Origin and significance of Si and O isotope heterogeneities in Phanerozoic, Archean, and Hadean zircon. AB - Hydrosphere interactions and alteration of the terrestrial crust likely played a critical role in shaping Earth's surface, and in promoting prebiotic reactions leading to life, before 4.03 Ga (the Hadean Eon). The identity of aqueously altered material strongly depends on lithospheric cycling of abundant and water soluble elements such as Si and O. However, direct constraints that define the character of Hadean sedimentary material are absent because samples from this earliest eon are limited to detrital zircons (ZrSiO4). Here we show that concurrent measurements of Si and O isotope ratios in Phanerozoic and detrital pre-3.0 Ga zircon constrain the composition of aqueously altered precursors incorporated into their source melts. Phanerozoic zircon from (S)edimentary-type rocks contain heterogeneous delta18O and delta30Si values consistent with assimilation of metapelitic material, distinct from the isotopic character of zircon from (I)gneous- and (A)norogenic-type rocks. The delta18O values of detrital Archean zircons are heterogeneous, although yield Si isotope compositions like mantle-derived zircon. Hadean crystals yield elevated delta18O values (vs. mantle zircon) and delta30Si values span almost the entire range observed for Phanerozoic samples. Coupled Si and O isotope data represent a constraint on Hadean weathering and sedimentary input into felsic melts including remelting of amphibolites possibly of basaltic origin, and fractional addition of chemical sediments, such as cherts and/or banded iron formations (BIFs) into source melts. That such sedimentary deposits were extensive enough to change the chemical signature of intracrustal melts suggests they may have been a suitable niche for (pre)biotic chemistry as early as 4.1 Ga. PMID- 30249647 TI - MAVS deficiency induces gut dysbiotic microbiota conferring a proallergic phenotype. AB - Prominent changes in the gut microbiota (referred to as "dysbiosis") play a key role in the development of allergic disorders, but the underlying mechanisms remain unknown. Study of the delayed-type hypersensitivity (DTH) response in mice contributed to our knowledge of the pathophysiology of human allergic contact dermatitis. Here we report a negative regulatory role of the RIG-I-like receptor adaptor mitochondrial antiviral signaling (MAVS) on DTH by modulating gut bacterial ecology. Cohousing and fecal transplantation experiments revealed that the dysbiotic microbiota of Mavs -/- mice conferred a proallergic phenotype that is communicable to wild-type mice. DTH sensitization coincided with increased intestinal permeability and bacterial translocation within lymphoid organs that enhanced DTH severity. Collectively, we unveiled an unexpected impact of RIG-I like signaling on the gut microbiota with consequences on allergic skin disease outcome. Primarily, these data indicate that manipulating the gut microbiota may help in the development of therapeutic strategies for the treatment of human allergic skin pathologies. PMID- 30249649 TI - Two-dimensional dry ices with rich polymorphic and polyamorphic phase behavior. AB - Both carbon dioxide (CO2) and water (H2O) are triatomic molecules that are ubiquitous in nature, and both are among the five most abundant gases in the Earth's atmosphere. At low temperature and ambient pressure, both CO2 and H2O form molecular crystals--dry ice I and ice I h Because water possesses distinctive hydrogen bonds, it exhibits intricate and highly pressure-dependent phase behavior, including at least 17 crystalline ice phases and three amorphous ice phases. In contrast, due to its weak van der Waals intermolecular interactions, CO2 exhibits fewer crystalline phases except at extremely high pressures, where nonmolecular ordered structures arise. Herein, we show the molecular dynamics simulation results of numerous 2D polymorphs of CO2 molecules in slit nanopores. Unlike bulk polymorphs of CO2, 2D CO2 polymorphs exhibit myriad crystalline and amorphous structures, showing remarkable polymorphism and polyamorphism. We also show that depending on the thermodynamic path, 2D solid-to solid phase transitions can give rise to previously unreported structures, e.g., wave-like amorphous CO2 structures. Our simulation also suggests intriguing structural connections between 2D and 3D dry ice phases (e.g., Cmca and PA-3) and offers insights into CO2 polyamorphic transitions through intermediate liquid or amorphous phases. PMID- 30249646 TI - Small molecule inhibits alpha-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons. AB - Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of alpha-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit alpha-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild type alpha-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of alpha synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature alpha-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing alpha-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by alpha-synuclein. SynuClean-D-treated worms show decreased alpha synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from alpha synuclein-induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson's disease. PMID- 30249650 TI - Correction for Sargent et al., Anthropogenic and biogenic CO2 fluxes in the Boston urban region. PMID- 30249652 TI - QnAs with Sang Yup Lee. PMID- 30249653 TI - Use of scenario ensembles for deriving seismic risk. AB - High death tolls from recent earthquakes show that seismic risk remains high globally. While there has been much focus on seismic hazard, large uncertainties associated with exposure and vulnerability have led to more limited analyses of the potential impacts of future earthquakes. We argue that as both exposure and vulnerability are reducible factors of risk, assessing their importance and variability allows for prioritization of the most effective disaster risk reduction (DRR) actions. We address this through earthquake ensemble modeling, using the example of Nepal. We model fatalities from 90 different scenario earthquakes and establish whether impacts are specific to certain scenario earthquakes or occur irrespective of the scenario. Our results show that for most districts in Nepal impacts are not specific to the particular characteristics of a single earthquake, and that total modeled impacts are skewed toward the minimum estimate. These results suggest that planning for the worst-case scenario in Nepal may place an unnecessarily large burden on the limited resources available for DRR. We also show that the most at-risk districts are predominantly in rural western Nepal, with ~9.5 million Nepalis inhabiting districts with higher seismic risk than Kathmandu. Our proposed approach provides a holistic consideration of seismic risk for informing contingency planning and allows the relative importance of the reducible components of risk (exposure and vulnerability) to be estimated, highlighting factors that can be targeted most effectively. We propose this approach for informing contingency planning, especially in locations where information on the likelihood of future earthquakes is inadequate. PMID- 30249651 TI - Rapid stimulation of human dentate gyrus function with acute mild exercise. AB - Physical exercise has beneficial effects on neurocognitive function, including hippocampus-dependent episodic memory. Exercise intensity level can be assessed according to whether it induces a stress response; the most effective exercise for improving hippocampal function remains unclear. Our prior work using a special treadmill running model in animals has shown that stress-free mild exercise increases hippocampal neuronal activity and promotes adult neurogenesis in the dentate gyrus (DG) of the hippocampus, improving spatial memory performance. However, the rapid modification, from mild exercise, on hippocampal memory function and the exact mechanisms for these changes, in particular the impact on pattern separation acting in the DG and CA3 regions, are yet to be elucidated. To this end, we adopted an acute-exercise design in humans, coupled with high-resolution functional MRI techniques, capable of resolving hippocampal subfields. A single 10-min bout of very light-intensity exercise (30%[Formula: see text]) results in rapid enhancement in pattern separation and an increase in functional connectivity between hippocampal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an individual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possibly by increasing DG/CA3 neocortical functional connectivity. PMID- 30249654 TI - Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle. AB - Nebulin is a giant sarcomeric protein that spans along the actin filament in skeletal muscle, from the Z-disk to near the thin filament pointed end. Mutations in nebulin cause muscle weakness in nemaline myopathy patients, suggesting that nebulin plays important roles in force generation, yet little is known about nebulin's influence on thin filament structure and function. Here, we used small angle X-ray diffraction and compared intact muscle deficient in nebulin (using a conditional nebulin-knockout, Neb cKO) with control (Ctrl) muscle. When muscles were activated, the spacing of the actin subunit repeat (27 A) increased in both genotypes; when converted to thin filament stiffness, the obtained value was 30 pN/nm in Ctrl muscle and 10 pN/nm in Neb cKO muscle; that is, the thin filament was approximately threefold stiffer when nebulin was present. In contrast, the thick filament stiffness was not different between the genotypes. A significantly shorter left-handed (59 A) thin filament helical pitch was found in passive and contracting Neb cKO muscles, as well as impaired tropomyosin and troponin movement. Additionally, a reduced myosin mass transfer toward the thin filament in contracting Neb cKO muscle was found, suggesting reduced cross-bridge interaction. We conclude that nebulin is critically important for physiological force levels, as it greatly stiffens the skeletal muscle thin filament and contributes to thin filament activation and cross-bridge recruitment. PMID- 30249656 TI - Desert ants possess distinct memories for food and nest odors. AB - The desert ant Cataglyphis fortis inhabits the North African saltpans where it individually forages for dead arthropods. Homing ants rely mainly on path integration, i.e., the processing of directional information from a skylight compass and distance information from an odometer. Due to the far-reaching foraging runs, path integration is error-prone and guides the ants only to the vicinity of the nest, where the ants then use learned visual and olfactory cues to locate the inconspicuous nest entrance. The learning of odors associated with the nest entrance is well established. We furthermore know that foraging Cataglyphis use the food-derived necromone linoleic acid to pinpoint dead insects. Here we show that Cataglyphis in addition can learn the association of a given odor with food. After experiencing food crumbs that were spiked with an innately neutral odor, ants were strongly attracted by the same odor during their next foraging journey. We therefore explored the characteristics of the ants' food-odor memory and identified pronounced differences from their memory for nest associated odors. Nest odors are learned only after repeated learning trials and become ignored as soon as the ants do not experience them at the nest anymore. In contrast, ants learn food odors after a single experience, remember at least 14 consecutively learned food odors, and do so for the rest of their lives. As an ant experiences many food items during its lifetime, but only a single nest, differentially organized memories for both contexts might be adaptive. PMID- 30249655 TI - Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model. AB - HERV-K HML-2 (HK2) has been proliferating in the germ line of humans at least as recently as 250,000 years ago, with some integrations that remain polymorphic in the modern human population. One of the solitary HK2 LTR polymorphic integrations lies between exons 17 and 18 of RASGRF2, a gene that affects dopaminergic activity and is thus related to addiction. Here we show that this antisense HK2 integration (namely RASGRF2-int) is found more frequently in persons who inject drugs compared with the general population. In a Greek HIV-1-positive population (n = 202), we found RASGRF2-int 2.5 times (14 versus 6%) more frequently in patients infected through i.v. drug use compared with other transmission route controls (P = 0.03). Independently, in a United Kingdom-based hepatitis C virus positive population (n = 184), we found RASGRF2-int 3.6 times (34 versus 9.5%) more frequently in patients infected during chronic drug abuse compared with controls (P < 0.001). We then tested whether RASGRF2-int could be mechanistically responsible for this association by modulating transcription of RASGRF2 We show that the CRISPR/Cas9-mediated insertion of HK2 in HEK293 cells in the exact RASGRF2 intronic position found in the population resulted in significant transcriptional and phenotypic changes. We also explored mechanistic features of other intronic HK2 integrations and show that HK2 LTRs can be responsible for generation of cis-natural antisense transcripts, which could interfere with the transcription of nearby genes. Our findings suggest that RASGRF2-int is a strong candidate for dopaminergic manipulation, and emphasize the importance of accurate mapping of neglected HERV polymorphisms in human genomic studies. PMID- 30249659 TI - Stable Frank-Kasper phases of self-assembled, soft matter spheres. AB - Single molecular species can self-assemble into Frank-Kasper (FK) phases, finite approximants of dodecagonal quasicrystals, defying intuitive notions that thermodynamic ground states are maximally symmetric. FK phases are speculated to emerge as the minimal-distortional packings of space-filling spherical domains, but a precise measure of this distortion and how it affects assembly thermodynamics remains ambiguous. We use two complementary approaches to demonstrate that the principles driving FK lattice formation in diblock copolymers emerge directly from the strong-stretching theory of spherical domains, in which a minimal interblock area competes with a minimal stretching of space-filling chains. The relative stability of FK lattices is studied first using a diblock foam model with unconstrained particle volumes and shapes, which correctly predicts not only the equilibrium sigma lattice but also the unequal volumes of the equilibrium domains. We then provide a molecular interpretation for these results via self-consistent field theory, illuminating how molecular stiffness increases the sensitivity of the intradomain chain configurations and the asymmetry of local domain packing. These findings shed light on the role of volume exchange on the formation of distinct FK phases in copolymers and suggest a paradigm for formation of FK phases in soft matter systems in which unequal domain volumes are selected by the thermodynamic competition between distinct measures of shape asymmetry. PMID- 30249657 TI - FUS interacts with ATP synthase beta subunit and induces mitochondrial unfolded protein response in cellular and animal models. AB - FUS (fused in sarcoma) proteinopathy is a group of neurodegenerative diseases characterized by the formation of inclusion bodies containing the FUS protein, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Previous studies show that mitochondrial damage is an important aspect of FUS proteinopathy. However, the molecular mechanisms by which FUS induces mitochondrial damage remain to be elucidated. Our biochemical and genetic experiments demonstrate that FUS interacts with the catalytic subunit of mitochondrial ATP synthase (ATP5B), disrupts the formation of ATP synthase complexes, and inhibits mitochondrial ATP synthesis. FUS expression activates the mitochondrial unfolded protein response (UPRmt). Importantly, down-regulating expression of ATP5B or UPRmt genes in FUS transgenic flies ameliorates neurodegenerative phenotypes. Our data show that mitochondrial impairment is a critical early event in FUS proteinopathy, and provide insights into the pathogenic mechanism of FUS-induced neurodegeneration. PMID- 30249658 TI - Anatomical and microstructural determinants of hippocampal subfield functional connectome embedding. AB - The hippocampus plays key roles in cognition and affect and serves as a model system for structure/function studies in animals. So far, its complex anatomy has challenged investigations targeting its substructural organization in humans. State-of-the-art MRI offers the resolution and versatility to identify hippocampal subfields, assess its microstructure, and study topographical principles of its connectivity in vivo. We developed an approach to unfold the human hippocampus and examine spatial variations of intrinsic functional connectivity in a large cohort of healthy adults. In addition to mapping common and unique connections across subfields, we identified two main axes of subregional connectivity transitions. An anterior/posterior gradient followed long-axis landmarks and metaanalytical findings from task-based functional MRI, while a medial/lateral gradient followed hippocampal infolding and correlated with proxies of cortical myelin. Findings were consistent in an independent sample and highly stable across resting-state scans. Our results provide robust evidence for long-axis specialization in the resting human hippocampus and suggest an intriguing interplay between connectivity and microstructure. PMID- 30249660 TI - Role for ERK1/2-dependent activation of FCHSD2 in cancer cell-selective regulation of clathrin-mediated endocytosis. AB - Clathrin-mediated endocytosis (CME) regulates the uptake of cell-surface receptors as well as their downstream signaling activities. We recently reported that signaling can reciprocally regulate CME in cancer cells and that this crosstalk can contribute to cancer progression. To further explore the nature and extent of the crosstalk between signaling and CME in cancer cell biology, we analyzed a panel of oncogenic signaling kinase inhibitors for their effects on CME across a panel of normal and cancerous cells. Inhibition of several kinases selectively affected CME in cancer cells, including inhibition of ERK1/2, which selectively inhibited CME by decreasing the rate of clathrin-coated pit (CCP) initiation. We identified an ERK1/2 substrate, the FCH/F-BAR and SH3 domain containing protein FCHSD2, as being essential for the ERK1/2-dependent effects on CME and CCP initiation. Our data suggest that ERK1/2 phosphorylation activates FCHSD2 and regulates EGF receptor (EGFR) endocytic trafficking as well as downstream signaling activities. Loss of FCHSD2 activity in nonsmall cell lung cancer (NSCLC) cells leads to increased cell-surface expression and altered signaling downstream of EGFR, resulting in enhanced cell proliferation and migration. The expression level of FCHSD2 is positively correlated with higher NSCLC patient survival rates, suggesting that FCHSD2 can negatively affect cancer progression. These findings provide insight into the mechanisms and consequences of the reciprocal regulation of signaling and CME in cancer cells. PMID- 30249661 TI - Single-stranded telomere-binding protein employs a dual rheostat for binding affinity and specificity that drives function. AB - ssDNA, which is involved in numerous aspects of chromosome biology, is managed by a suite of proteins with tailored activities. The majority of these proteins bind ssDNA indiscriminately, exhibiting little apparent sequence preference. However, there are several notable exceptions, including the Saccharomyces cerevisiae Cdc13 protein, which is vital for yeast telomere maintenance. Cdc13 is one of the tightest known binders of ssDNA and is specific for G-rich telomeric sequences. To investigate how these two different biochemical features, affinity and specificity, contribute to function, we created an unbiased panel of alanine mutations across the Cdc13 DNA-binding interface, including several aromatic amino acids that play critical roles in binding activity. A subset of mutant proteins exhibited significant loss in affinity in vitro that, as expected, conferred a profound loss of viability in vivo. Unexpectedly, a second category of mutant proteins displayed an increase in specificity, manifested as an inability to accommodate changes in ssDNA sequence. Yeast strains with specificity-enhanced mutations displayed a gradient of viability in vivo that paralleled the loss in sequence tolerance in vitro, arguing that binding specificity can be fine-tuned to ensure optimal function. We propose that DNA binding by Cdc13 employs a highly cooperative interface whereby sequence diversity is accommodated through plastic binding modes. This suggests that sequence specificity is not a binary choice but rather is a continuum. Even in proteins that are thought to be specific nucleic acid binders, sequence tolerance through the utilization of multiple binding modes may be a broader phenomenon than previously appreciated. PMID- 30249663 TI - Three pillars of sustainability in fisheries. AB - Sustainability of global fisheries is a growing concern. The United Nations has identified three pillars of sustainability: economic development, social development, and environmental protection. The fisheries literature suggests that there are two key trade-offs among these pillars of sustainability. First, poor ecological health of a fishery reduces economic profits for fishers, and second, economic profitability of individual fishers undermines the social objectives of fishing communities. Although recent research has shown that management can reconcile ecological and economic objectives, there are lingering concerns about achieving positive social outcomes. We examined trade-offs among the three pillars of sustainability by analyzing the Fishery Performance Indicators, a unique dataset that scores 121 distinct fishery systems worldwide on 68 metrics categorized by social, economic, or ecological outcomes. For each of the 121 fishery systems, we averaged the outcome measures to create overall scores for economic, ecological, and social performance. We analyzed the scores and found that they were positively associated in the full sample. We divided the data into subsamples that correspond to fisheries management systems with three categories of access-open access, access rights, and harvest rights-and performed a similar analysis. Our results show that economic, social, and ecological objectives are at worst independent and are mutually reinforcing in both types of managed fisheries. The implication is that rights-based management systems should not be rejected on the basis of potentially negative social outcomes; instead, social considerations should be addressed in the design of these systems. PMID- 30249662 TI - l-Serine-modified polyamidoamine dendrimer as a highly potent renal targeting drug carrier. AB - Effective delivery of drug carriers selectively to the kidney is challenging because of their uptake by the reticuloendothelial system in the liver and spleen, which limits effective treatment of kidney diseases and results in side effects. To address this issue, we synthesized l-serine (Ser)-modified polyamidoamine dendrimer (PAMAM) as a potent renal targeting drug carrier. Approximately 82% of the dose was accumulated in the kidney at 3 h after i.v. injection of 111In-labeled Ser-PAMAM in mice, while i.v. injection of 111In labeled unmodified PAMAM, l-threonine modified PAMAM, and l-tyrosine modified PAMAM resulted in kidney accumulations of 28%, 35%, and 31%, respectively. Single photon emission computed tomography/computed tomography (SPECT/CT) images also indicated that 111In-labeled Ser-PAMAM specifically accumulated in the kidneys. An intrakidney distribution study showed that fluorescein isothiocyanate-labeled Ser-PAMAM accumulated predominantly in renal proximal tubules. Results of a cellular uptake study of Ser-PAMAM in LLC-PK1 cells in the presence of inhibitors [genistein, 5-(N-ethyl-N-isopropyl)amiloride, and lysozyme] revealed that caveolae-mediated endocytosis, micropinocytosis, and megalin were associated with the renal accumulation of Ser-PAMAM. The efficient renal distribution and angiotensin-converting enzyme (ACE) inhibition effect of captopril (CAP), an ACE inhibitor, was observed after i.v. injection of the Ser-PAMAM-CAP conjugate. These findings indicate that Ser-PAMAM is a promising renal targeting drug carrier for the treatment of kidney diseases. Thus, the results of this study demonstrate efficient renal targeting of a drug carrier via Ser modification. PMID- 30249664 TI - Interferometric plasmonic imaging and detection of single exosomes. AB - Exosomes play an important role in numerous cellular processes. Fundamental study and practical use of exosomes are significantly constrained by the lack of analytical tools capable of physical and biochemical characterization. In this paper, we present an optical approach capable of imaging single exosomes in a label-free manner, using interferometric plasmonic microscopy. We demonstrate monitoring of the real-time adsorption of exosomes onto a chemically modified Au surface, calculating the image intensity, and determining the size distribution. The sizing capability enables us to quantitatively measure the membrane fusion activity between exosomes and liposomes. We also report the recording of the dynamic interaction between exosomes and antibodies at the single-exosome level, and the tracking of hit-stay-run behavior of exosomes on an antibody-coated surface. We anticipate that the proposed method will contribute to clinical exosome analysis and to the exploration of fundamental issues such as the exosome antibody binding kinetics. PMID- 30249666 TI - Critical role for the Ly49 family of class I MHC receptors in adaptive natural killer cell responses. AB - Adaptive natural killer (NK) cell memory represents a new frontier in immunology. Work over the last decade has discovered and confirmed the existence of NK cells with antigen-specific memories, which had previously been considered a unique property of T and B cells. These findings have shown that antigen-specific NK cells gain their specificity without the use of RAG proteins, representing a novel mechanism for generating antigen specificity, but the details of this mechanism have remained a mystery. We have discovered that members of the Ly49 family of surface receptors are critically involved in both the sensitization and the challenge phases of an NK cell memory response, as is antigen presentation from their binding partner, the class I MHC. Moreover, we demonstrate that the Ly49-interacting component of a presented antigen dictates the specificity of the NK cell memory response, implicating Ly49 receptors themselves in antigen specific recognition. Finally, we demonstrate that adaptive NK cell memories can protect against an otherwise lethal melanoma without T cell or B cell support. These findings offer insight into the mechanism behind NK cell antigen specificity and demonstrate the clinical potential of this adaptive immune cell. PMID- 30249665 TI - Mutations of mitochondrial DNA are not major contributors to aging of fruit flies. AB - Mammals develop age-associated clonal expansion of somatic mtDNA mutations resulting in severe respiratory chain deficiency in a subset of cells in a variety of tissues. Both mathematical modeling based on descriptive data from humans and experimental data from mtDNA mutator mice suggest that the somatic mutations are formed early in life and then undergo mitotic segregation during adult life to reach very high levels in certain cells. To address whether mtDNA mutations have a universal effect on aging metazoans, we investigated their role in physiology and aging of fruit flies. To this end, we utilized genetically engineered flies expressing mutant versions of the catalytic subunit of mitochondrial DNA polymerase (DmPOLgammaA) as a means to introduce mtDNA mutations. We report here that lifespan and health in fruit flies are remarkably tolerant to mtDNA mutations. Our results show that the short lifespan and wide genetic bottleneck of fruit flies are limiting the extent of clonal expansion of mtDNA mutations both in individuals and between generations. However, an increase of mtDNA mutations to very high levels caused sensitivity to mechanical and starvation stress, intestinal stem cell dysfunction, and reduced lifespan under standard conditions. In addition, the effects of dietary restriction, widely considered beneficial for organismal health, were attenuated in flies with very high levels of mtDNA mutations. PMID- 30249668 TI - What's happening in Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 30249670 TI - Resident & Fellow Rounds. PMID- 30249669 TI - Late Lyme neuroborreliosis with chronic encephalomyelitis. PMID- 30249667 TI - VEGF-B is a potent antioxidant. AB - VEGF-B was discovered a long time ago. However, unlike VEGF-A, whose function has been extensively studied, the function of VEGF-B and the mechanisms involved still remain poorly understood. Notwithstanding, drugs that inhibit VEGF-B and other VEGF family members have been used to treat patients with neovascular diseases. It is therefore critical to have a better understanding of VEGF-B function and the underlying mechanisms. Here, using comprehensive methods and models, we have identified VEGF-B as a potent antioxidant. Loss of Vegf-b by gene deletion leads to retinal degeneration in mice, and treatment with VEGF-B rescues retinal cells from death in a retinitis pigmentosa model. Mechanistically, we demonstrate that VEGF-B up-regulates numerous key antioxidative genes, particularly, Gpx1 Loss of Gpx1 activity largely diminished the antioxidative effect of VEGF-B, demonstrating that Gpx1 is at least one of the critical downstream effectors of VEGF-B. In addition, we found that the antioxidant function of VEGF-B is mediated mainly by VEGFR1. Given that oxidative stress is a crucial factor in numerous human diseases, VEGF-B may have therapeutic value for the treatment of such diseases. PMID- 30249672 TI - Editors' note: Core cerebrospinal fluid biomarker profile in cerebral amyloid angiopathy: A meta-analysis. PMID- 30249671 TI - Mystery Case: Spinal tuberculosis masquerading lung malignancy. PMID- 30249673 TI - Reader response: Core cerebrospinal fluid biomarker profile in cerebral amyloid angiopathy: A meta-analysis. PMID- 30249674 TI - Author response: Core cerebrospinal fluid biomarker profile in cerebral amyloid angiopathy: A meta-analysis. PMID- 30249676 TI - Reader response: Education Research: Difficult conversations in neurology: Lessons learned from medical students. PMID- 30249675 TI - Editors' note: Difficult conversations in neurology: Lessons learned from medical students. PMID- 30249677 TI - Author response: Education Research: Difficult conversations in neurology: Lessons learned from medical students. PMID- 30249678 TI - Midregional proatrial natriuretic peptide improves risk stratification after ischemic stroke: Association with mortality and cardioembolic etiology. PMID- 30249679 TI - Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production. PMID- 30249680 TI - Clinical Reasoning: A 58-year-old woman with systemic scleroderma and progressive cervical cord compression. PMID- 30249682 TI - Teaching NeuroImages: Myotonic dystrophy type 1. PMID- 30249681 TI - Clinical Reasoning: Ventriculomegaly detected on 20-week anatomic fetal ultrasound. PMID- 30249683 TI - Pregnancy, anti-seizure medications, and seizures. PMID- 30249684 TI - Origin, Composition, and Structure of the Supernumerary B Chromosome of Drosophila melanogaster. AB - The number of chromosomes carried by an individual species is one of its defining characteristics. Some species, however, can also carry supernumerary chromosomes referred to as B chromosomes. B chromosomes were recently identified in a laboratory stock of Drosophila melanogaster-an established model organism with a wealth of genetic and genomic resources-enabling us to subject them to extensive molecular analysis. We isolated the B chromosomes by pulsed-field gel electrophoresis and determined their composition through next-generation sequencing. Although these B chromosomes carry no known euchromatic sequence, they are rich in transposable elements and long arrays of short nucleotide repeats, the most abundant being the uncharacterized AAGAT satellite repeat. Fluorescent in situ hybridization on metaphase chromosome spreads revealed this repeat is located on chromosome 4, strongly suggesting the origin of the B chromosomes is chromosome 4 Cytological and quantitative comparisons of signal intensity between chromosome 4 and the B chromosomes supports the hypothesis that the structure of the B chromosome is an isochromosome. We also report the identification of a new B chromosome variant in a related laboratory stock. This B chromosome has a similar repeat signature as the original but is smaller and much less prevalent. We examined additional stocks with similar genotypes and did not find B chromosomes, but did find these stocks lacked the AAGAT satellite repeat. Our molecular characterization of D. melanogaster B chromosomes is the first step toward understanding how supernumerary chromosomes arise from essential chromosomes and what may be necessary for their stable inheritance. PMID- 30249686 TI - Site-Directed Mutagenesis of the 1,3-beta-Glucan Synthase Catalytic Subunit of Pneumocystis jirovecii and Susceptibility Assays Suggest Its Sensitivity to Caspofungin. AB - The echinocandin caspofungin inhibits the catalytic subunit Gsc1 of the enzymatic complex synthesizing 1,3-beta-glucan, an essential compound of the fungal wall. Studies with rodents showed that caspofungin is effective against Pneumocystis asci. However, its efficacy against asci of Pneumocystis jirovecii, the species infecting exclusively humans, remains controversial. The aim of this study was to assess the sensitivity to caspofungin of the P. jirovecii Gsc1 subunit, as well as of those of Pneumocystis carinii and Pneumocystis murina infecting, respectively, rats and mice. In the absence of an established in vitro culture method for Pneumocystis species, we used functional complementation of the Saccharomyces cerevisiae gsc1 deletant. In the fungal pathogen Candida albicans, mutations leading to amino acid substitutions in Gsc1 confer resistance to caspofungin. We introduced the corresponding mutations into the Pneumocystis gsc1 genes using site-directed mutagenesis. In spot dilution tests, the sensitivity to caspofungin of the complemented strains decreased with the number of mutations introduced, suggesting that the wild-type enzymes are sensitive. The MICs of caspofungin determined by Etest and YeastOne for strains complemented with Pneumocystis enzymes (respectively, 0.125 and 0.12 MUg/ml) were identical to those upon complementation with the enzyme of C. albicans, for which caspofungin presents low MICs. However, they were lower than the MICs upon complementation with the enzyme of the resistant species Candida parapsilosis (0.19 and 0.25 MUg/ml). Sensitivity levels of Gsc1 enzymes of the three Pneumocystis species were similar. Our results suggest that P. jirovecii is sensitive to caspofungin during infections, as are P. carinii and P. murina. PMID- 30249687 TI - Investigating Sulfoxide-to-Sulfone Conversion as a Prodrug Strategy for a Phosphatidylinositol 4-Kinase Inhibitor in a Humanized Mouse Model of Malaria. AB - The in vivo antimalarial efficacies of two phosphatidylinositol 4-kinase (PI4K) inhibitors, a 3,5-diaryl-2-aminopyrazine sulfoxide and its corresponding sulfone metabolite, were evaluated in the NOD-scid IL2Rgammanull (NSG) murine malaria disease model of Plasmodium falciparum infection. We hypothesized that the sulfoxide would serve as a more soluble prodrug for the sulfone, which would lead to improved drug exposure with oral dosing. Both compounds had similar efficacy (90% effective dose [ED90], 0.1 mg kg-1 of body weight) across a quadruple-dose regimen. Pharmacokinetic profiling revealed rapid sulfoxide clearance via conversion to sulfone, with sulfone identified as the major active metabolite. When the sulfoxide was dosed, the exposure of the sulfone achieved was as much as 2.9-fold higher than when the sulfone was directly dosed, thereby demonstrating that the sulfoxide served as an effective prodrug for the treatment of malaria. PMID- 30249685 TI - A Large, Refractory Nosocomial Outbreak of Klebsiella pneumoniae Carbapenemase Producing Escherichia coli Demonstrates Carbapenemase Gene Outbreaks Involving Sink Sites Require Novel Approaches to Infection Control. AB - Carbapenem-resistant Enterobacteriaceae (CRE) represent a health threat, but effective control interventions remain unclear. Hospital wastewater sites are increasingly being highlighted as important potential reservoirs. We investigated a large Klebsiella pneumoniae carbapenemase (KPC)-producing Escherichia coli outbreak and wider CRE incidence trends in the Central Manchester University Hospital NHS Foundation Trust (CMFT) (United Kingdom) over 8 years, to determine the impact of infection prevention and control measures. Bacteriology and patient administration data (2009 to 2017) were linked, and a subset of CMFT or regional hospital KPC-producing E. coli isolates (n = 268) were sequenced. Control interventions followed international guidelines and included cohorting, rectal screening (n = 184,539 screens), environmental sampling, enhanced cleaning, and ward closure and plumbing replacement. Segmented regression of time trends for CRE detections was used to evaluate the impact of interventions on CRE incidence. Genomic analysis (n = 268 isolates) identified the spread of a KPC-producing E. coli outbreak clone (strain A, sequence type 216 [ST216]; n = 125) among patients and in the environment, particularly on 2 cardiac wards (wards 3 and 4), despite control measures. ST216 strain A had caused an antecedent outbreak and shared its KPC plasmids with other E. coli lineages and Enterobacteriaceae species. CRE acquisition incidence declined after closure of wards 3 and 4 and plumbing replacement, suggesting an environmental contribution. However, ward 3/ward 4 wastewater sites were rapidly recolonized with CRE and patient CRE acquisitions recurred, albeit at lower rates. Patient relocation and plumbing replacement were associated with control of a clonal KPC-producing E. coli outbreak; however, environmental contamination with CRE and patient CRE acquisitions recurred rapidly following this intervention. The large numbers of cases and the persistence of bla KPC in E. coli, including pathogenic lineages, are of concern. PMID- 30249688 TI - A Hyperactive Form of the Zinc Cluster Transcription Factor Stb5 Causes YOR1 Overexpression and Beauvericin Resistance in Candida albicans. AB - Gain-of-function mutations in the zinc cluster transcription factors Mrr1, Tac1, and Upc2, which result in constitutive overexpression of their target genes, are a frequent cause of fluconazole resistance in the pathogenic yeast Candida albicans In this study, we show that an activated form of another zinc cluster transcription factor, Stb5, confers resistance to the natural compound beauvericin via the overexpression of YOR1, encoding an efflux pump of the ATP binding cassette transporter superfamily. Beauvericin was recently shown to potentiate the activity of azole drugs against C. albicans Although Yor1 did not contribute to fluconazole resistance when C. albicans cells were treated with the drug alone, Stb5-mediated YOR1 overexpression diminished the synergistic effect of the fluconazole-beauvericin combination, thereby enhancing fluconazole resistance in beauvericin-treated C. albicans cells. Stb5-mediated YOR1 overexpression also suppressed the inhibition of hyphal growth, an important virulence trait of C. albicans, by beauvericin. Therefore, activating mutations in Stb5, which result in constitutive YOR1 overexpression, may enable C. albicans to acquire resistance to beauvericin and thereby overcome both the sensitization to azole drugs and the inhibition of morphogenesis caused by this compound. PMID- 30249689 TI - Rifampin Resistance in Staphylococci after Rifaximin Intake for Surgical Prophylaxis in Elective Colorectal Surgery. AB - The aim of our study was to determine whether rifampin resistance emerges in human skin staphylococci after oral intake of rifaximin for surgical prophylaxis. Rifampin-resistant staphylococci appeared on the skin of 32 out of 74 patients (43.2%) two weeks after prophylactic treatment with rifaximin. In all cases, the resistant strains were coagulase-negative staphylococci. The resistance completely reverted after three months. This study shows the emergence of transient resistance to rifampin after rifaximin intake. PMID- 30249690 TI - In Vitro Activity of Ceftazidime-Avibactam and Aztreonam-Avibactam against OXA-48 Carrying Enterobacteriaceae Isolated as Part of the International Network for Optimal Resistance Monitoring (INFORM) Global Surveillance Program from 2012 to 2015. AB - Enterobacteriaceae producing the Ambler class D OXA-48 carbapenemase, combined with additional resistance mechanisms, such as permeability defects or cocarriage of class A, B, or C beta-lactamases, can become highly resistant to most beta lactams currently in use, including carbapenems. A total of 45,872 Enterobacteriaceae clinical isolates collected in 39 countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance study in 2012 to 2015 were tested for susceptibility to beta-lactams and comparator agents using the Clinical and Laboratory Standards Institute broth microdilution methodology and screened for the presence of beta-lactamases. The bla OXA-48 and bla OXA-48-like genes were detected in 333 isolates across 14 species of Enterobacteriaceae collected in 20 countries across the globe. Few agents tested were effective in vitro against the overall collection of OXA-48 producers (n = 265), with tigecycline (MIC90, 2 ug/ml; 92.5% susceptible), ceftazidime-avibactam (MIC90, 4 ug/ml; 92.5% susceptible), and aztreonam avibactam (MIC90, 0.5 ug/ml; 99.6% of isolates with MIC <=8 ug/ml) demonstrating the greatest activity. Similarly, colistin (MIC90, 1 ug/ml; 94.2% susceptible), tigecycline (MIC90, 2 ug/ml; 92.6% susceptible), ceftazidime-avibactam (MIC90, >128 ug/ml; 89.7% susceptible), and aztreonam-avibactam (MIC90, 4 ug/ml; 100% of isolates with MIC <=8 ug/ml) were most active against OXA-48-like-positive isolates (n = 68). The in vitro activity of ceftazidime-avibactam was improved against the subset of metallo-beta-lactamase (MBL)-negative, OXA-48- and OXA-48 like-positive isolates (99.2% and 100% susceptible, respectively). The data reported here support the continued investigation of ceftazidime-avibactam and aztreonam-avibactam for the treatment of infections caused by carbapenem resistant Enterobacteriaceae carrying OXA-48 and OXA-48-like beta-lactamases in combination with serine- or metallo-beta-lactamases. PMID- 30249691 TI - In Silico Investigation of the Decline in Clinical Efficacy of Artemisinin Combination Therapies Due to Increasing Artemisinin and Partner Drug Resistance. AB - Antimalarial treatment currently relies on an artemisinin derivative and a longer acting partner drug. With the emergence of resistance to the artemisinin derivatives and the potential pressure this exerts on the partner drugs, the impact of resistance to each drug on efficacy needs to be investigated. An in silico exploration of dihydroartemisinin-piperaquine and mefloquine-artesunate, two artemisinin-based combination therapies that are commonly used in Southeast Asia, was performed. The percentage of treatment failures was simulated from a within-host pharmacokinetic-pharmacodynamic (PKPD) model, assuming that parasites developed increasing levels of (i) artemisinin derivative resistance or (ii) concomitant resistance to both the artemisinin derivative and the partner drug. Because the exact nature of how resistant Plasmodium falciparum parasites respond to treatment is unknown, we examined the impact on treatment failure rates of artemisinin resistance that (i) reduced the maximal killing rate, (ii) increased the concentration of drug required for 50% killing, or (iii) shortened the window of parasite stages that were susceptible to artemisinin derivatives until the drugs had no effect on the ring stages. The loss of the ring-stage activity of the artemisinin derivative caused the greatest increase in the treatment failure rate, and this result held irrespective of whether partner drug resistance was assumed to be present or not. To capture the uncertainty regarding how artemisinin derivative and partner drug resistance affects the assumed concentration-killing effect relationship, a variety of changes to this relationship should be considered when using within-host PKPD models to simulate clinical outcomes to guide treatment strategies for resistant infections. PMID- 30249692 TI - In Vivo Efficacy of Ellagic Acid against Candida albicans in a Drosophila melanogaster Infection Model. AB - The aim of this study was to evaluate the antifungal activity and the toxicity of ellagic acid (EA) using a Drosophila melanogaster model. Candida albicans bacteria were inoculated into Toll heterozygous flies. Survival curves were obtained for the evaluation of the antimicrobial effect and toxicity of EA. A protective effect of EA against fungal infection in Drosophila melanogaster was observed at nontoxic concentrations. This study showed that EA is a promising tool for the treatment of candidiasis. PMID- 30249693 TI - Activity of Moxifloxacin against Mycobacterium tuberculosis in Acid Phase and Nonreplicative-Persister Phenotype Phase in a Hollow-Fiber Infection Model. AB - A major goal for improving tuberculosis therapy is to identify drug regimens with improved efficacy and shorter treatment durations. Shorter therapies improve patient adherence to the antibiotic regimens, which, in turn, decreases resistance emergence. Mycobacterium tuberculosis exists in multiple metabolic states. At the initiation of therapy, the bulk of the population is in log-phase growth. Consequently, it is logical to focus initial therapy on those organisms. Moxifloxacin has good early bactericidal activity against log-phase bacteria and is a logical component of initial therapy. It would be optimal if this agent also possessed activity against acid-phase and nonreplicative-persister (NRP) phenotype organisms. In our hollow-fiber infection model, we studied multiple exposures to moxifloxacin (equivalent to 200 mg to 800 mg daily) against strain H37Rv in the acid phase and against strain 18b in streptomycin starvation, which is a model for NRP-phase organisms. Moxifloxacin possesses good activity against acid-phase organisms, generating cell killing of 3.75 log10(CFU/ml) (200 mg daily) to 5.16 log10(CFU/ml) (800 mg daily) over the 28 days of the experiment. Moxifloxacin also has activity against streptomycin-starved strain 18b. The 400- to 800-mg daily regimens achieved extinction at day 28, while the no-treatment control still had 1.96 log10(CFU/ml) culturable. The lowest dose (200 mg daily) still had 0.7 log10(CFU/ml) measurable at day 28, a net kill of 1.26 log10(CFU/ml). Moxifloxacin is an attractive agent for early therapy, because it possesses activity against three metabolic states of M. tuberculosis. PMID- 30249694 TI - Microbiological Analysis from a Phase 2 Randomized Study in Adults Evaluating Single Oral Doses of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria gonorrhoeae. AB - We evaluated microbiological correlates for the successful treatment of Neisseria gonorrhoeae isolates from a phase 2 study of gepotidacin, a novel triazaacenaphthylene antibacterial, for therapy of uncomplicated urogenital gonorrhea. Culture, susceptibility testing, genotypic characterization, and frequency of resistance (FoR) were performed for selected isolates. Microbiological success was defined as culture-confirmed eradication of N. gonorrhoeae Against 69 baseline urogenital isolates, gepotidacin MICs ranged from <=0.06 to 1 ug/ml (MIC90 = 0.5 ug/ml). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to the MIC (fAUC/MIC) was associated with therapeutic success. Success was 100% (61/61) at fAUC/MICs of >=48 and decreased to 63% (5/8) for fAUC/MICs of <=25. All 3 isolates from microbiological failures were ciprofloxacin resistant, had a baseline gepotidacin MIC of 1 ug/ml, and carried a preexisting ParC D86N mutation, a critical residue for gepotidacin binding. In a test-of-cure analysis, the resistance to gepotidacin emerged in 2 isolates (MICs increased >=32-fold) with additional GyrA A92T mutations, also implicated in gepotidacin binding. Test-of-cure isolates had the same sequence type as the corresponding baseline isolates. For 5 selected baseline isolates, all carrying a ParC D86N mutation, the in vitro FoR to gepotidacin was low (10-9 to 10-10); the resistant mutants had the same A92T mutation as the 2 isolates in which resistance emerged. Five participants with isolates harboring the ParC D86N mutation were treatment successes. In summary, fAUC/MICs of >=48 predicted 100% microbiological success, including 3 isolates with the ParC D86N mutation (fAUC/MICs >= 97). Pharmacokinetic/pharmacodynamic determinations may help to evaluate new therapies for gonorrhea; further study of gepotidacin is warranted. (This study has been registered at ClinicalTrials.gov under identifier NCT02294682.). PMID- 30249695 TI - Detection of Carbapenemase-Producing Enterobacteriaceae in Positive Blood Culture Using an Immunochromatographic RESIST-4 O.K.N.V. Assay. AB - We evaluated the performance of the RESIST-4 O.K.N.V. assay (Coris) with 98 isolates to detect OXA-48-like and KPC-, NDM-, and VIM-type carbapenemases directly on positive human blood cultures. OXA-48-like and KPC-type isolates were correctly detected, but the detection of NDM- and VIM-type carbapenemases was weak and variable. We show that repeating the test on a 4-h subculture improves the detection of NDM- and VIM-type carbapenemases to 100%. PMID- 30249696 TI - Electrocardiographic Safety of Repeated Monthly Dihydroartemisinin-Piperaquine as a Candidate for Mass Drug Administration. AB - Mass drug administration (MDA) of sequential rounds of antimalarial drugs is being considered for use as a tool for malaria elimination. As an effective and long-acting antimalarial, dihydroartemisinin-piperaquine (DHA-PQP) appears to be suitable as a candidate for MDA. However, the absence of cardiac safety data following repeated administration hinders its use in the extended schedules proposed for MDA. We conducted an interventional study in Lihir Island, Papua New Guinea, using healthy individuals age 3 to 60 years who received a standard 3-day course of DHA-PQP on 3 consecutive months. Twelve-lead electrocardiography (ECG) readings were conducted predose and 4 h after the final dose of each month. The primary safety endpoint was QT interval correction (QTc using Fridericia's correction [QTcF]) prolongation from baseline to 4 h postdosing. We compared the difference in prolongations between the third course postdose and the first course postdose. Of 84 enrolled participants, 69 (82%) participants completed all treatment courses and ECG measurements. The average increase in QTcF was 19.6 ms (standard deviation [SD], 17.8 ms) and 17.1 ms (SD, 17.1 ms) for the first-course and third-course postdosing ECGs risk difference, -2.4 (95% confidence interval [95% CI], -6.9 to 2.1; P = 0.285), respectively. We recorded a QTcF prolongation of >60 ms from baseline in 3 (4.3%) and 2 (2.9%) participants after the first course and third course (P = 1.00), respectively. No participants had QTcF intervals of >500 ms at any time point. Three consecutive monthly courses of DHA PQP were as safe as a single course. The absence of cumulative cardiotoxicity with repeated dosing supports the use of monthly DHA-PQP as part of malaria elimination strategies. PMID- 30249697 TI - Predicting the Outcomes of New Short-Course Regimens for Multidrug-Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modeling. AB - Short-course regimens for multidrug-resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug bedaquiline (BDQ) may have the potential to shorten MDR-TB treatment to less than 6 months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modeling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ containing regimens. Our modeling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (4 months) while still maintaining a very high treatment success rate (100% for daily BDQ for 2 weeks, or 95% for daily BDQ for 1 week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes, then we anticipate clear cost savings and a subsequent improvement in the efficiency of national TB programs. PMID- 30249698 TI - Assessment of Quality Indicators for Appropriate Antibiotic Use. AB - One of the critical elements of antimicrobial stewardship programs is the ability to measure the quality of antibiotic prescriptions. The aims of the present study were to evaluate the performance properties of a set of previously developed quality indicators (QIs) and to identify the potential room for improvement in antibiotic use in our setting. A monthly cross-sectional point prevalence survey was conducted in a 400-bed acute care teaching hospital, from June to November 2015. All adult patients treated for >=24 hours with antibiotic therapy for a suspected hospital- or community-acquired bacterial infection were included. Performance scores (adherence, room for improvement, interobserver reliability, and applicability) were calculated for 8 QIs. A total of 362 patients were evaluated. Adherence to the whole set of QIs was accomplished for 14.1% of evaluable patients. The QIs with greater room for improvement were adequate request for blood cultures (60.6%), therapeutic drug monitoring (TDM) (59.1%), sequential antibiotic therapy within 72 hours (48.2%), and empirical antibiotic therapy according to local guidelines (30.4%). The percentage of patients receiving unnecessary antibiotic treatment in the absence of clinical or microbiological evidence of infection after 5 days was 12.2%. All indicators scored kappa values of >=0.6, suggesting good interobserver reliability. Low applicability (6.1% of reviewed patients) was found only for the TDM QI. The QIs analyzed were found to be applicable, showed good interobserver reliability, and were useful tools to identify areas with potential room for improvement in antibiotic use. PMID- 30249699 TI - Enterobacter cloacae Complex Sequence Type 171 Isolates Expressing KPC-4 Carbapenemase Recovered from Canine Patients in Ohio. AB - Companion animals are likely relevant in the transmission of antimicrobial resistant bacteria. Enterobacter xiangfangensis sequence type 171 (ST171), a clone that has been implicated in clusters of infections in humans, was isolated from two dogs with clinical disease in Ohio. The canine isolates contained IncHI2 plasmids encoding bla KPC-4 Whole-genome sequencing was used to put the canine isolates in phylogenetic context with available human ST171 sequences, as well as to characterize their bla KPC-4 plasmids. PMID- 30249700 TI - The Combination of Fosfomycin plus Meropenem Is Synergistic for Pseudomonas aeruginosa PAO1 in a Hollow-Fiber Infection Model. AB - Treating high-density bacterial infections is a challenging clinical problem. We have a paucity of new agents that can address this problem. Pseudomonas aeruginosa is a particularly difficult pathogen to treat effectively because of the plethora of resistance mechanisms it carries. Fosfomycin is an agent discovered circa 40 years ago. Recently, it has been resurrected in the United States and studied for intravenous therapy. We hypothesized that, to maximize its utility, it would require combination chemotherapy when used in a clinical circumstance in high-bacterial-burden infections. We chose to examine the combination of meropenem plus fosfomycin. These agents were studied in the hollow fiber infection model. We utilized a fully factorial study design, looking at 2 doses of meropenem alone (1 and 2 g 8-hourly) and two doses of fosfomycin alone (6 and 8 g 8-hourly), as well as all possible combinations plus a no-treatment control. We used a high-dimensional model of 5 inhomogeneous differential equations with 5 system outputs to analyze all data simultaneously. Combination therapy outperformed all monotherapy regimens, with all combinations driving >6 log10 CFU/ml of bacterial killing. Combination therapy was able to counterselect resistance emergence (meropenem mutants being killed by the combination, as well as fosfomycin mutants being killed by the combination) in all regimens studied. The analysis demonstrated that the combination was significantly synergistic for bacterial cell killing and resistance suppression. Meropenem plus fosfomycin is a promising combination for therapy of high-burden Pseudomonas aeruginosa infections and requires further study. PMID- 30249702 TI - Getting Our Fingers on the Pulse of Slow-Growing Bacteria in Hard-To-Reach Places. AB - Chronic infections with slow-growing pathogens have plagued humans throughout history. However, assessing the identities and growth rates of bacteria in an infection has remained an elusive goal. Neubauer et al. (J. Bacteriol. 200:e00365 18, 2018, https://doi.org/10.1128/JB.00365-18) combine two cutting-edge approaches to make progress on both fronts: probing specific RNA molecules to assess the identity of actively transcribing microbes and measuring growth rates through incorporation of stable isotope labels. They found that growth rates of pathogens were relatively stable during antibacterial therapy. The article delves into a basic and unanswered question that gets to the heart of understanding infection: what are the microbial growth rates? PMID- 30249701 TI - Coenzyme F420-Dependent Glucose-6-Phosphate Dehydrogenase-Coupled Polyglutamylation of Coenzyme F420 in Mycobacteria. AB - Coenzyme F420 plays a key role in the redox metabolisms of various archaea and bacteria, including Mycobacterium tuberculosis In M. tuberculosis, F420-dependent reactions have been linked to several virulence factors. F420 carries multiple glutamate residues in the side chain, forming F420-n species (n, number of glutamate residues), and the length of this side chain impacts cellular physiology. M. tuberculosis strains with F420 species carrying shorter side chains exhibit resistance to delamanid and pretomanid, two new tuberculosis (TB) drugs. Thus, the process of polyglutamylation of F420 is of great interest. It has been known from genetic analysis that in mycobacteria an F420-0 gamma glutamyl ligase (FbiB) introduces up to seven glutamate residues into F420 However, purified FbiB of M. tuberculosis (MtbFbiB) is either inefficient or incapable of incorporating more than two glutamates. We found that, in vitro, MtbFbiB synthesized side chains containing up to seven glutamate residues if F420 was presented to the enzyme in a two-electron reduced state (F420H2). Our genetic analysis in Mycobacterium bovis BCG and Mycobacterium smegmatis and an analysis of literature data on M. tuberculosis revealed that in these mycobacteria the polyglutamylation process requires the assistance of F420-dependent glucose-6 phosphate dehydrogenase (Fgd) which reduces F420 to F420H2 We hypothesize that, starting with F420-0H2, the amino-terminal domain of FbiB builds F420-2H2, which is then transferred to the carboxy-terminal domain for further glutamylation; F420-2H2 modifies the carboxy-terminal domain structurally to accommodate longer glutamyl chains. This system is analogous to folylpolyglutamate synthase, which introduces more than one glutamate residue into folate only after this vitamin is reduced to tetrahydrofolate.IMPORTANCE Coenzyme F420-dependent reactions of Mycobacterium tuberculosis, which causes tuberculosis, potentially contributes to the virulence of this bacterium. The coenzyme carries a glutamic acid-derived tail, the length of which influences the metabolism of M. tuberculosis Mutations that eliminate the production of F420 with longer tails make M. tuberculosis resistant to two new tuberculosis drugs. This report describes that the synthesis of longer glutamyl tails of F420 requires concerted actions of two enzymes, one of which reduces the coenzyme prior to the action of the other, which catalyzes polyglutamylation. This knowledge will help to develop more effective tuberculosis (TB) drugs. Remarkably, the introduction of multiple glutamate residues into the sidechain of folate (vitamin B9) requires similar concerted actions, where one enzyme reduces the vitamin to tetrahydrofolate and the other catalyzes polyglutamylation; folate is required for DNA and amino acid synthesis. Thus, the reported research has also revealed a key similarity between two important cellular systems. PMID- 30249703 TI - DNA Methylation by Restriction Modification Systems Affects the Global Transcriptome Profile in Borrelia burgdorferi. AB - Prokaryote restriction modification (RM) systems serve to protect bacteria from potentially detrimental foreign DNA. Recent evidence suggests that DNA methylation by the methyltransferase (MTase) components of RM systems can also have effects on transcriptome profiles. The type strain of the causative agent of Lyme disease, Borrelia burgdorferi B31, possesses two RM systems with N6 methyladenosine (m6A) MTase activity, which are encoded by the bbe02 gene located on linear plasmid lp25 and bbq67 on lp56. The specific recognition and/or methylation sequences had not been identified for either of these B. burgdorferi MTases, and it was not previously known whether these RM systems influence transcript levels. In the current study, single-molecule real-time sequencing was utilized to map genome-wide m6A sites and to identify consensus modified motifs in wild-type B. burgdorferi as well as MTase mutants lacking either the bbe02 gene alone or both bbe02 and bbq67 genes. Four novel conserved m6A motifs were identified and were fully attributable to the presence of specific MTases. Whole genome transcriptome changes were observed in conjunction with the loss of MTase enzymes, indicating that DNA methylation by the RM systems has effects on gene expression. Genes with altered transcription in MTase mutants include those involved in vertebrate host colonization (e.g., rpoS regulon) and acquisition by/transmission from the tick vector (e.g., rrp1 and pdeB). The results of this study provide a comprehensive view of the DNA methylation pattern in B. burgdorferi, and the accompanying gene expression profiles add to the emerging body of research on RM systems and gene regulation in bacteria.IMPORTANCE Lyme disease is the most prevalent vector-borne disease in North America and is classified by the Centers for Disease Control and Prevention (CDC) as an emerging infectious disease with an expanding geographical area of occurrence. Previous studies have shown that the causative bacterium, Borrelia burgdorferi, methylates its genome using restriction modification systems that enable the distinction from foreign DNA. Although much research has focused on the regulation of gene expression in B. burgdorferi, the effect of DNA methylation on gene regulation has not been evaluated. The current study characterizes the patterns of DNA methylation by restriction modification systems in B. burgdorferi and evaluates the resulting effects on gene regulation in this important pathogen. PMID- 30249704 TI - The Di-iron RIC Protein (YtfE) of Escherichia coli Interacts with the DNA-Binding Protein from Starved Cells (Dps) To Diminish RIC Protein-Mediated Redox Stress. AB - The RIC (repair of iron clusters) protein of Escherichia coli is a di-iron hemerythrin-like protein that has a proposed function in repairing stress-damaged iron-sulfur clusters. In this work, we performed a bacterial two-hybrid screening to search for RIC-protein interaction partners in E. coli As a result, the DNA binding protein from starved cells (Dps) was identified, and its potential interaction with RIC was tested by bacterial adenylate cyclase-based two-hybrid (BACTH) system, bimolecular fluorescence complementation, and pulldown assays. Using the activity of two Fe-S-containing enzymes as indicators of cellular Fe-S cluster damage, we observed that strains with single deletions of ric or dps have significantly lower aconitase and fumarase activities. In contrast, the ric dps double mutant strain displayed no loss of aconitase and fumarase activity with respect to that of the wild type. Additionally, while complementation of the ric dps double mutant with ric led to a severe loss of aconitase activity, this effect was no longer observed when a gene encoding a di-iron site variant of the RIC protein was employed. The dps mutant exhibited a large increase in reactive oxygen species (ROS) levels, but this increase was eliminated when ric was also inactivated. Absence of other iron storage proteins, or of peroxidase and catalases, had no impact on RIC-mediated redox stress induction. Hence, we show that RIC interacts with Dps in a manner that serves to protect E. coli from RIC protein-induced ROS.IMPORTANCE The mammalian immune system produces reactive oxygen and nitrogen species that kill bacterial pathogens by damaging key cellular components, such as lipids, DNA, and proteins. However, bacteria possess detoxifying and repair systems that mitigate these deleterious effects. The Escherichia coli RIC (repair of iron clusters) protein is a di-iron hemerythrin like protein that repairs stress-damaged iron-sulfur clusters. E. coli Dps is an iron storage protein of the ferritin superfamily with DNA-binding capacity that protects cells from oxidative stress. This work shows that the E. coli RIC and Dps proteins interact in a fashion that counters RIC protein-induced reactive oxygen species (ROS). Altogether, we provide evidence for the formation of a new bacterial protein complex and reveal a novel contribution for Dps in bacterial redox stress protection. PMID- 30249705 TI - Novel Metabolic Pathways and Regulons for Hexuronate Utilization in Proteobacteria. AB - We used comparative genomics to reconstruct D-galacturonic and D-glucuronic acid catabolic pathways and associated transcriptional regulons involving the tripartite ATP-independent periplasmic (TRAP) family transporters that bind hexuronates in Proteobacteria. The reconstructed catabolic network involves novel transcription factors, catabolic enzymes, and transporters for utilization of both hexuronates and aldarates (D-glucarate, meso-galactarate). The reconstructed regulons for a novel GntR-family transcription factor, GguR, include the majority of hexuronate/aldarate utilization genes in 47 species from the Burkholderiaceae, Comamonadaceae, Halomonadaceae, and Pseudomonadaceae families. GudR, GulR, and UdhR are additional local regulators of some hexuronate/aldarate utilization genes in some of the above species. The predicted DNA binding motifs of GguR and GudR regulators from Ralstonia pickettii and Polaromonas sp. were validated by in vitro binding assays. Genes from the GulR- and GguR-controlled loci were differentially expressed in R. pickettii grown on hexuronates and aldarates. By a combination of bioinformatics and experimental techniques we identified a novel variant of the oxidative pathway for hexuronate utilization including two previously uncharacterized subfamilies of lactone hydrolases (UxuL and UxuF). The genomic context of respective genes and reconstruction of associated pathways suggest that both enzymes catalyze the conversion of D-galactaro- and D-glucaro 1,5-lactones to the ring opened aldarates. The activities of the purified recombinant enzymes, UxuL and UxuF from four Proteobacterial species were directly confirmed and kinetically characterized. The inferred novel aldarate specific transporter from the tripartite tricarboxylate transporter (TTT) family TctC was confirmed to bind D-glucarate in vitro This study expands our knowledge of bacterial carbohydrate catabolic pathways by identifying novel families of catabolic enzymes, transcriptional regulators, and transporters.IMPORTANCE Hexuronate catabolic pathways and their transcriptional networks are highly variable among different bacteria. We identified novel transcriptional regulators that control the hexuronate and aldarate utilization genes in four families of Proteobacteria. By regulon reconstruction and genome context analysis we identified several novel components of the common hexuronate/aldarate utilization pathways including novel uptake transporters and catabolic enzymes. Two novel families of lactonases involved in the oxidative pathway of hexuronate catabolism were characterized. Novel transcriptional regulons were validated via in vitro binding assays and gene expression studies in Polaromonas and Ralstonia species. The reconstructed catabolic pathways are interconnected with each other metabolically and co-regulated via the GguR regulons in Proteobacteria. PMID- 30249706 TI - Planktonic Interference and Biofilm Alliance between Aggregation Substance and Endocarditis- and Biofilm-Associated Pili in Enterococcus faecalis. AB - Like many bacteria, Enterococcus faecalis encodes a number of adhesins involved in colonization or infection of different niches. Two well-studied E. faecalis adhesins, aggregation substance (AS) and endocarditis- and biofilm-associated pili (Ebp), both contribute to biofilm formation on abiotic surfaces and in endocarditis, suggesting that they may be expressed at the same time. Because different regulatory pathways have been reported for AS and Ebp, here, we examined if they are coexpressed on the same cells and what is the functional impact of coexpression on individual cells and within a population. We found that while Ebp are only expressed on a subset of cells, when Ebp and AS are expressed on the same cells, pili interfere with AS-mediated clumping and impede AS mediated conjugative plasmid transfer during planktonic growth. However, when the population density increases, horizontal gene transfer rates normalize and are no longer affected by pilus expression. Instead, at higher cell densities during biofilm formation, Ebp and AS differentially contribute to biofilm development and structure, synergizing to promote maximal biofilm formation.IMPORTANCE Most bacteria express multiple adhesins that contribute to surface attachment and colonization. However, the network and relationships between the various adhesins of a single bacterial species are less well understood. Here, we examined two well-characterized adhesins in Enterococcus faecalis, aggregation substance and endocarditis- and biofilm-associated pili, and found that they exhibit distinct functional contributions depending on the growth stage of the bacterial community. Pili interfere with aggregation substance-mediated clumping and plasmid transfer under planktonic conditions, whereas the two adhesins structurally complement one another during biofilm development. This study advances our understanding of how E. faecalis, a ubiquitous member of the human gut microbiome and an opportunistic pathogen, uses multiple surface structures to evolve and thrive. PMID- 30249707 TI - Role and Function of Class III LitR, a Photosensor Homolog from Burkholderia multivorans. AB - The LitR/CarH protein family is an adenosyl B12 (AdoB12)-dependent photoreceptor family with DNA-binding activity, and its homologs are widely distributed in the genomes of diverse bacterial genera. Here, we studied the role and functions of a LitR homolog from a gram-negative soil bacterium Burkholderia multivorans, which does not possess an AdoB12-binding domain. Transcriptome analysis indicated the existence of 19 light-induced genes including folE2, cfaB, litS, a photolyase gene phrB2, and cryB located in the region flanking litR Disruption of litR caused constitutive expression of all the light-inducible genes, while mutation in the light-induced sigma factor gene, litS, abolished the transcription of the phrB2 operon and the cfa operon, indicating that LitR and LitS play a central role in light-inducible transcription. A gel-shift assay showed that a recombinant protein LitR specifically binds to the promoter regions of litR and the folE2 operon, and its binding was weakened by on UV-A illumination. LitR absorbs light at maximally near 340 nm and exhibited a photocyclic response and light-dependent dissociation of multimer into tetramer. The litR mutant produced a 20-fold higher intracellular level of folate compared to the wild-type strain. Thus, the evidence suggests that LitR light-dependently regulates the transcription of litR itself and the folE2 operon, resulting in the production of folate, and then the expressed RNA polymerase complex containing sigmaLitS directs the transcription of the phrB2 operon and the cfa operon. These light dependent characteristics suggest that class III LitR, in complex with a UV-A absorbing molecule, follows a novel light-sensing mechanism.Importance Members of the LitR/CarH family are adenosyl B12-based photosensory transcriptional regulator involved in light-inducible carotenoid production in non-phototrophic bacteria. Our study provides the first evidence of the involvement of a class III LitR, which lacks an adenosyl B12-binding domain in light-response of Burkholderia multivorans belonging to beta-proteobacteria. Our biochemical analysis suggests that class III LitR protein exhibits features as a photosensor including absorption of light at UV-A region (lambdamax = ca. 340 nm), photocyclic response, and light-dependent dissociation. This suggests that class III LitR associates with a UV-A absorbing molecule, and it has a distinguishable photosensing mechanism from that of B12-based type. PMID- 30249709 TI - Role of Acetyltransferase PG1842 in Gingipain Biogenesis in Porphyromonas gingivalis. AB - Porphyromonas gingivalis, the major etiologic agent in adult periodontitis, produces large amounts of proteases that are important for its survival and pathogenesis. Activation/maturation of gingipains, a major protease, in P. gingivalis involves a complex network of processes which are not yet fully understood. VimA, a putative acetyltransferase and virulence modulating protein in P. gingivalis, is known to be involved in gingipains biogenesis. P. gingivalis FLL92, a vimA-defective isogenic mutant (vimA::ermF-ermAM) showed late onset gingipain activity at stationary phase indicating the likelihood of a complimentary functional VimA homolog in that growth phase. This study is aimed at identifying functional homolog(s) that may activate the gingipains in absence of VimA at stationary phase. Bioinformatics analysis showed five putative GNAT acetyltransferases in the P. gingivalis genome that are structurally related to VimA. Allelic exchange mutagenesis was used to make deletion mutants in these acetyltransferases in the P. gingivalis vimA-defective mutant FLL102 (DeltavimA::ermF) genetic background. One of the mutants, designated P. gingivalis FLL126 (DeltavimA-DeltaPG1842), did not show any late onset gingipain activity at stationary phase as compared to parent strain P. gingivalis FLL102. Western blot analysis of stationary phase extracellular fractions using anti gingipain antibodies showed immunoreactive bands that were similar in size to the pro-gingipain species present only in the DeltavimA-DeltaPG1842 isogenic mutant compared to the DeltavimA strain. Both, recombinant VimA and PG1842, proteins acetylated Y230, K247 and K248 residues in the pro-RgpB substrate. Collectively, these findings indicate that PG1842 may play a significant role in activation/maturation of gingipains in P. gingivalisImportanceGingipain proteases are key virulence factors secreted by P. gingivalis that cause periodontal tissue damage and degradation of the host immune system proteins. Gingipains are translated as an inactive zymogen to restrict intracellular proteolytic activity before secretion. Post-translational processing converts the inactive proenzyme to a catalytically active protease. Gingipain biogenesis, including secretion and activation, is a complex process which is still not fully understood. One recent study reported acetylated lysine residues in the three gingipains RgpA, RgpB and Kgp, thus indicating a role for acetylation in gingipain biogenesis. Here, we show that the acetyltransferases, VimA and PG1842, can acetylate the pro-RgpB gingipain species. These findings further confirm acetylation as a potential mechanism in the gingipain activation/maturation pathway in P. gingivalis. PMID- 30249708 TI - A subset of exoribonucleases serve as degradative enzymes for pGpG in c-di-GMP signaling. AB - Cyclic-di-GMP (c-di-GMP) is a bacterial second messenger that regulates processes such as biofilm formation and virulence. During degradation, c-di-GMP is first linearized to pGpG and subsequently hydrolyzed to two GMPs by a previously unknown enzyme, which was recently identified in Pseudomonas aeruginosa as the 3' to 5' exoribonuclease Oligoribonuclease (Orn). Mutants of orn accumulated pGpG, which inhibited linearization of c-di-GMP. This product inhibition led to elevated c-di-GMP levels, resulting in increased aggregate and biofilm formation. Thus, the hydrolysis of pGpG is crucial to maintenance of c-di-GMP homeostasis. How species that utilize c-di-GMP signaling but lack an orn ortholog hydrolyze pGpG remains unknown. Because Orn is an exoribonuclease, we asked whether pGpG hydrolysis can be carried out by genes that encode protein domains found in exoribonucleases. From a screen of these genes from Vibrio cholerae and Bacillus anthracis, we found only enzymes known to cleave oligoribonucleotides (orn and nrnA), rescued the P. aeruginosa Deltaorn phenotypes to wild-type. Thus, we tested addtional RNases with demonstrated activity against short oligoribonucleotides. These experiments show that only exoribonucleases previously reported to degrade short RNAs (nrnA, nrnB, nrnC and orn) can also hydrolyze pGpG. A B. subtilis nrnA and nrnB mutant had elevated c-di-GMP, suggesting that these two genes serve as the primary enzymes to degrade pGpG. These results indicate that the requirement for pGpG hydrolysis to complete c-di GMP signaling is conserved across species. The final steps of RNA turnover and c di-GMP turnover appear to converge at a subset of RNases specific for short oligoribonucleotides.Importance The bacterial cyclic-di-GMP (c-di-GMP) signaling molecule regulates complex processes such as biofilm formation. C-di-GMP is degraded in two-steps: linearization into pGpG and subsequently cleavage to two GMPs. The 3' to 5' exonuclease oligoribonuclease (Orn) serves as the enzyme that degrades pGpG in Pseudomonas aeruginosa Many phyla contain species that utilize c di-GMP signaling but lack an Orn homolog and the protein that functions to degrade pGpG remains uncharacterized. Here, systematic screening of genes encoding proteins containing domains found in exoribonucleases revealed a subset of genes encoded within the genomes of Bacillus anthracis and Vibrio cholerae that degrade pGpG to GMP and are functionally analogous to Orn. Feedback inhibition by pGpG is a conserved process as strains lacking these genes accumulate c-di-GMP. PMID- 30249710 TI - Refining the Application of Microbial Lipids as Tracers of Staphylococcus aureus Growth Rates in Cystic Fibrosis Sputum. AB - Chronic lung infections in cystic fibrosis (CF) could be treated more effectively if the effects of antimicrobials on pathogens in situ were known. Here, we compared changes in the microbial community composition and pathogen growth rates in longitudinal studies of seven pediatric CF patients undergoing intravenous antibiotic administration during pulmonary exacerbations. The microbial community composition was determined by counting rRNA with NanoString DNA analysis, and growth rates were obtained by incubating CF sputum with heavy water and tracing incorporation of deuterium into two branched-chain ("anteiso") fatty acids (a C15:0 and a-C17:0) using gas chromatography-mass spectrometry (GC/MS). Prior to this study, both lipids were thought to be specific for Staphylococcaceae; hence, their isotopic enrichment was interpreted as a growth proxy for Staphylococcus aureus Our experiments revealed, however, that Prevotella is also a relevant microbial producer of a-C17:0 fatty acid in some CF patients; thus, deuterium incorporation into these lipids is better interpreted as a more general pathogen growth rate proxy. Even accounting for a small nonmicrobial background source detected in some patient samples, a-C15:0 fatty acid still appears to be a relatively robust proxy for CF pathogens, revealing a median generation time of ~1.5 days, similar to prior observations. Contrary to our expectation, pathogen growth rates remained relatively stable throughout exacerbation treatment. We suggest two straightforward "best practices" for application of stable-isotope probing to CF sputum metabolites: (i) parallel determination of microbial community composition in CF sputum using culture-independent tools and (ii) assessing background levels of the diagnostic metabolite.IMPORTANCE In chronic lung infections, populations of microbial pathogens change and mature in ways that are often unknown, which makes it challenging to identify appropriate treatment options. A promising tool to better understand the physiology of microorganisms in a patient is stable-isotope probing, which we previously developed to estimate the growth rates of S. aureus in cystic fibrosis (CF) sputum. Here, we tracked microbial communities in a cohort of CF patients and found that anteiso fatty acids can also originate from other sources in CF sputum. This awareness led us to develop a new workflow for the application of stable-isotope probing in this context, improving our ability to estimate pathogen generation times in clinical samples. PMID- 30249711 TI - Chest wall mass: what lies beneath? AB - CLINICAL INTRODUCTION: A 24-year-old Filipino man attended the ED with a 1-month history of a discrete swelling over his upper anterior chest wall that was rapidly increasing in size and tenderness. He denied any other symptoms. His medical history was unremarkable.Examination revealed a tender, 7 cm * 6 cm mass over the upper part of the sternum (figure 1). The surface was smooth, it was immobile, non-compressible and the overlying skin was normothermic but mildly erythematous. Cervical lymphadenopathy was present. His vital signs were normal.emermed;35/10/586/F1F1F1Figure 1Chest wall mass. QUESTION: What is the most likely diagnosis?LipomaChondrosarcomaLymphoma Mycobacterium tuberculosis (TB). PMID- 30249712 TI - BET 1: In paracetamol overdose, is oral N-acetylcysteine as effective as intravenous N-acetylcysteine? AB - A short-cut review was carried out to establish whether oral N-acetylcysteine is as effective as intravenous N-acetylcysteine in the management of paracetamol overdose. Seven studies were directly relevant to the question. The author, year and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that oral N-acetylcysteine is a safe alternative in patients for whom the intravenous route is not an option. PMID- 30249714 TI - BET 2: CT versus MRI for occult hip fractures. AB - A short-cut review was carried out to establish whether CT or MRI is better at detecting an occult hip fracture. Six studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that CT is a valid first-line investigation for a suspected plain X-ray occult hip fracture. If clinical suspicion remains after a negative CT scan, then MRI should be used. PMID- 30249715 TI - Is Alternate-Day Therapeutic Drug Monitoring in the Intensive Care Unit Not Intensive Enough? PMID- 30249716 TI - Reply to Sorooshian and Snow, "Is Alternate-Day Therapeutic Drug Monitoring in the Intensive Care Unit Not Intensive Enough?" PMID- 30249717 TI - Erratum for Yew et al., "Oxidative Stress and First-Line Antituberculosis Drug Induced Hepatotoxicity". PMID- 30249718 TI - Correction for Trokter and Waksman, "Translocation through the Conjugative Type IV Secretion System Requires Unfolding of Its Protein Substrate". PMID- 30249719 TI - Will research preprints improve healthcare for patients? PMID- 30249720 TI - Editor's Note: Inactivation of AR/TMPRSS2-ERG/Wnt Signaling Networks Attenuates the Aggressive Behavior of Prostate Cancer Cells. PMID- 30249721 TI - Minimally invasive glaucoma surgery - coming of age. PMID- 30249722 TI - The relationship between habitual dietary sodium intake and RAAS blockade on circulating microparticle levels in type two diabetes. AB - OBJECTIVE: Low sodium intake is paradoxically associated with adverse cardiovascular outcomes in individuals with type 2 diabetes mellitus (T2D), possibly from renin-angiotensin-aldosterone system (RAAS) activation, leading to endothelial dysfunction. In the present study, we investigated the associations between habitual sodium intake and RAAS blockade on endothelial function by measuring circulating microparticles (MPs) in individuals with T2D. METHODS: We conducted a prospective, cross-sectional study in 74 individuals with T2D. Habitual dietary sodium intake was estimated by using the mean of three corrected 24-h urine sodium excretion measurements (24hUNa). MP subtypes in platelet-free plasma were quantitated using flow cytometry. RESULTS: No associations between 24hUNa with levels of endothelial MPs were observed. Instead, a trend toward higher diabetes related CD36+/CD235a+ MP levels was associated with lower 24hUNa (rho = -0.23, P=0.05). When stratified according to tertiles of 24hUNa, platelet derived CD42b+/CD41+ and CD42+/CD41+/Annexin V+ MPs were higher in the lowest tertile (24hUNa < 157 mmol/24 h) (P=0.02 respectively). Despite RAAS blockade being associated with lower levels of most MP subsets, it was not associated with lower MPs, in the setting of low sodium intake. CONCLUSION: Lower sodium intake is associated with higher circulating procoagulant MPs, but not with evidence of endothelial dysfunction in individuals with T2D. PMID- 30249724 TI - Primary tonsillar tuberculosis. AB - Upper aerodigestive tract involvement with tuberculosis is relatively rare and may be seen in up to 2% of patients with pulmonary tuberculosis. Isolated tonsil involvement with tuberculosis is not commonly seen in clinical practice. We report a case of a 22-year-old postpartum mother who presented with odynophagia, fever, loss of weight and submandibular swelling of 3 months' duration. Clinical examination revealed a submandibular node, and oropharyngeal examination revealed necrotic slough overlying an enlarged left tonsil. Fine-needle aspiration cytology of the node and histopathological examination of the left tonsillectomy specimen revealed necrotising epithelioid cell granulomas, and stain for acid fast bacilli was positive in the latter. She was diagnosed with tonsillar tuberculosis and was started on antituberculous treatment following which she improved clinically. This case serves to demonstrate an uncommon presentation of primary tuberculosis and reminds us to consider tuberculosis also as a microbiological aetiology for tonsillitis. PMID- 30249725 TI - Barriers to healthcare for female patients in Papua New Guinea. AB - A 25-year-old woman presented to hospital in the remote highlands of Papua New Guinea (PNG) with a 3-year history of increasing abdominal distension, amenorrhoea and syncope. Ultrasound showed a large unilocular ovarian cyst. During her work-up, she was found to be HIV positive. She was treated with antiretroviral therapy, and once her CD4 count improved, she underwent a laparotomy and removal of the ovarian cyst with immediate improvement in symptoms. PNG has high levels of HIV particularly in young women and children.1 This is partly due to a lack of screening and treatment facilities and partly due to significant gender discrimination. PNG is considered one of the most dangerous places in the world for females; women are treated as second-class citizens with few human rights or access to services such as healthcare.2 Rape, sexual assault and domestic violence are common, and their lives are dictated to them by their husbands or male relatives.2 3 The lack of healthcare resources and significant levels of gender discrimination meant that this patient had a delayed presentation resulting in potentially grave complications. PMID- 30249723 TI - GTP hydrolysis promotes disassembly of the atlastin crossover dimer during ER fusion. AB - Membrane fusion of the ER is catalyzed when atlastin GTPases anchored in opposing membranes dimerize and undergo a crossed over conformational rearrangement that draws the bilayers together. Previous studies have suggested that GTP hydrolysis triggers crossover dimerization, thus directly driving fusion. In this study, we make the surprising observations that WT atlastin undergoes crossover dimerization before hydrolyzing GTP and that nucleotide hydrolysis and Pi release coincide more closely with dimer disassembly. These findings suggest that GTP binding, rather than its hydrolysis, triggers crossover dimerization for fusion. In support, a new hydrolysis-deficient atlastin variant undergoes rapid GTP dependent crossover dimerization and catalyzes fusion at an initial rate similar to WT atlastin. However, the variant cannot sustain fusion activity over time, implying a defect in subunit recycling. We suggest that GTP binding induces an atlastin conformational change that favors crossover dimerization for fusion and that the input of energy from nucleotide hydrolysis promotes complex disassembly for subunit recycling. PMID- 30249726 TI - Mast cell deposition and activation may be a new explanation for epiploic appendagitis. AB - Epiploic appendagitis is as an acute painful condition of the fat on the outside of the intestine. Thus far, there have been no publications to our knowledge that appendagitis can be caused by mast cells or can be associated with chronic pain. A patient with multisystemic disorders suffered with both chronic and acute attacks of abdominal pain for a year. The worst attack led to surgical resection of an enlarged sigmoid colon epiploic appendage. Careful review of her complex medical history and mast cell stains of gastrointestinal biopsies led to the diagnosis of mast cell activation syndrome. Re-examination of the resected appendage using an immunohistochemical stain demonstrated a high mast cell density which is a new histopathological finding. Treatment of mast cell activation syndrome and other related syndromes led to marked improvement in her health, including all types of chronic abdominal pain. PMID- 30249727 TI - External auditory canal lesion: colorectal metastatic adenocarcinoma. AB - The patient presented to the ear, nose and throat clinic with failed conservative treatment of persistent right otitis externa. On examination, the roof of the right ear canal was polypoid and the tympanic membrane could not be visualised. There was a fragile mass noted in the external auditory canal (EAC) which on microsuction started to bleed. CT internal auditory meatus and MRI internal auditory meatus identified soft tissue mass in the EAC. The patient underwent urgent examination under anaesthetic of the ear and biopsies were taken. He had a background of ascending colon cancer; Duke's C1, pT4, N1 M0, R0 resection and had undergone laparoscopic right hemicolectomy with adjuvant chemotherapy, in the previous year. The biopsy results proved that the mass in the EAC was due to metastatic deposit of colorectal primary tumour. The patient also had a full body CT which revealed other new metastases. The patient is being treated with palliative chemotherapy. PMID- 30249728 TI - Uncommon cause of pelvic inflammatory disease leading to toxic shock syndrome. AB - A 44-year-old Caucasian female with a history of endometriosis is admitted to the intensive care unit due to severe left lower quadrant abdominal pain, nausea and vomiting. With patients' positive chandelier sign on pelvic examination, leucocytosis, elevated erythrocyte sedimentation rate and elevated C-reactive protein indicated that she had pelvic inflammatory disease (PID). PCR tests were negative for Neisseria gonorrhoeae and Chlamydia trachomatis; however, her blood and urine cultures grew Group A streptococci (GAS) with a negative rapid Streptococcus throat swab and no known exposure to Streptococcus On further review, patient met criteria for GAS toxic shock syndrome based on diagnostic guidelines. The patient was promptly treated with intravenous antibiotics and supportive care, and she acutely recovered. This case demonstrates a rare cause of PID and an atypical aetiology of severe sepsis. It illuminates the importance of considering PID as a source of infection for undifferentiated bacteraemia. PMID- 30249729 TI - Expand the differential...think beyond rheumatoid arthritis. AB - A 31-year-old male patient with severe, migratory arthralgias presented to our academic medical centre after being erroneously diagnosed and treated for rheumatoid arthritis for over 1 year. Multiple immunomodulatory therapies for rheumatoid arthritis were attempted with no relief of symptoms. Eventually, the pain was so bothersome that the patient became bedridden for 1 month prior to presenting to our facility. Our assessment revealed that the patient met the diagnostic criteria, known as the Yamaguchi criteria, needed to diagnose adult onset Still's disease. Yamaguchi criteria include migratory inflammatory arthritis, quotidian fevers, leucocytosis and a salmon-coloured maculopapular rash. These signs and symptoms may go unnoticed or overlooked if adult-onset Still's disease is not considered. The patient was treated with anakinra (a recombinant human IL-1 receptor antagonist) and had rapid improvement in his symptoms, with the restoration of mobility. PMID- 30249730 TI - Varicella causing remission of Cushing's disease. AB - An 18-year-old male with Cushing's disease presented with generalised skin eruptions and backache. He was diagnosed with varicella infection. During the course of the illness, he developed persistent vomiting. Hormonal evaluation suggested adrenal insufficiency. MRI of brain showed features of pituitary apoplexy. Initially, he required hydrocortisone replacement. Later on his hypothalamic-pituitary-adrenal axis recovered and he is currently asymptomatic without any treatment. PMID- 30249731 TI - Delusional infestation in the treatment of ADHD with atomoxetine. AB - The case describes an adult diagnosed with attention deficit hyperactivity disorder and treated with atomoxetine who quickly developed a florid case of delusional infestation. The patient described very distressing experiences that were significantly impacting her daily life. The symptoms improved with the withdrawal of atomoxetine and resolved completely with antipsychotic medications. Atomoxetine is proposed as the putative causative agent in this case. PMID- 30249732 TI - On a knife-edge: clinical uncertainty with an extensive knife blade in situ in the craniofacial region. AB - A 25-year-old man presented to the trauma department following a penetrating stab wound to his left infraorbital margin with retained knife blade causing superoposterior displacement of the globe. Plain skull X-ray revealed an extensive retained blade with subsequent CT imaging revealing the tip of the blade had reached the right styloid process with no neurovascular compromise. Initial concern was primarily for the left eye leading to ophthalmology being the first specialty requested to review the patient. However, once the extent of the injury was established, ophthalmology requested further review from maxillofacial, ENT and neurosurgery. This resulted in an 84 hours wait between the initial injury and the removal of the knife blade. Incredibly, the patient had no initial sequelae from such an extensive injury and had an unremarkable recovery with no further complications aside from a laceration to the left inferior rectus muscle that was conservatively managed. PMID- 30249733 TI - Novel mutation in the CHST14 gene causing musculocontractural type of Ehlers Danlos syndrome. AB - Musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) is a recently recognised connective tissue disorder. MC-EDS is caused by homozygous or compound heterozygous mutation in the carbohydrate sulfotransferase 14 (CHST14) gene on chromosome 15q15. Herein, we report a case of a 3-year-old boy with MC-EDS in whom a novel mutation in the CHST14 gene was discovered. Besides being the second report of this rare disorder from India, the child till 3 years has not had any bleeding tendency as described in the earlier reports of this disorder. PMID- 30249734 TI - Extreme scoliosis from CKD-MBD resulting in respiratory failure and death. PMID- 30249735 TI - Posterior urethral valve associated with a foreign body in posterior urethra: a first of its kind report. AB - Posterior urethral valve and foreign body are among the important causes of male urethral obstruction. Although one is congenital and the other is acquired, both entities are rare in children with only a few reported cases. Because of myriad of symptoms associated with both conditions, a conclusive diagnosis requires both physical examination and radiological imaging. We report a first of its kind association of posterior urethral valve with foreign body in the posterior urethra in a 6-year-old male child which was eventually managed by endoscopic intervention. PMID- 30249736 TI - Spontaneous resolution of a 'ping-pong' fracture at birth. AB - 'Ping-pong' fractures are depressed skull fractures in newborn infants that occur as inward buckling of the calvarial bones, forming a cup shape. These fractures are often associated with maintenance of bone continuity. These fractures may occur spontaneously during the intrauterine period or secondary to birth trauma. Currently, there is no standard protocol for the management of depressed skull fractures. Neurosurgical or non-surgical approaches may be administered depends on the severity of the fracture. Most untreated ping-pong fractures resolve spontaneously within 6 months. Therefore, it is recommended to reserve surgical elevation or non-surgical techniques for infants not demonstrating spontaneous resolution during this period. In addition, neurosurgical interventions are usually considered for cases with intracranial pathology or neurological deficits or for infants who do not respond to conservative treatment. Herein, we report a case of a newborn infant with a spontaneous intrauterine ping-pong fracture, which spontaneously resolved, without surgical or non-surgical intervention. PMID- 30249737 TI - Management of C-shaped root canal configuration in mandibular second molar. PMID- 30249738 TI - Skin metastasis: a rare presentation in testicular germ cell tumour. AB - A 35-year-old man presented with a history of cough, haemoptysis, weight loss for 2 months along with ulceroproliferative lesions on the chin and the scalp. On evaluation he was found to have non-seminomatous germ cell tumour, stage 3 c, poor risk with Eastern Cooperative Oncology Group Performance Status of 4. The skin lesions were proven to be metastasis by fine-needle aspiration cytology. He showed significant improvement with a 3-day protocol of abbreviated etoposide and cisplatin chemotherapy and is planned for 4 cycles of VIP. This case describes an uncommon presentation of germ cell tumour in the form of skin metastasis with excellent response to chemotherapy. PMID- 30249739 TI - Over-the-counter drug-induced lung injuries with both diffuse alveolar haemorrhage and diffuse alveolar damage. PMID- 30249740 TI - Chronic cutaneous lupus erythematosus and topical clindamycin. PMID- 30249741 TI - The genomic architecture and molecular evolution of ant odorant receptors. AB - The massive expansions of odorant receptor (OR) genes in ant genomes are notable examples of rapid genome evolution and adaptive gene duplication. However, the molecular mechanisms leading to gene family expansion remain poorly understood, partly because available ant genomes are fragmentary. Here, we present a highly contiguous, chromosome-level assembly of the clonal raider ant genome, revealing the largest known OR repertoire in an insect. While most ant ORs originate via local tandem duplication, we also observe several cases of dispersed duplication followed by tandem duplication in the most rapidly evolving OR clades. We found that areas of unusually high transposable element density (TE islands) were depauperate in ORs in the clonal raider ant, and found no evidence for retrotransposition of ORs. However, OR loci were enriched for transposons relative to the genome as a whole, potentially facilitating tandem duplication by unequal crossing over. We also found that ant OR genes are highly AT-rich compared to other genes. In contrast, in flies, OR genes are dispersed and largely isolated within the genome, and we find that fly ORs are not AT-rich. The genomic architecture and composition of ant ORs thus show convergence with the unrelated vertebrate ORs rather than the related fly ORs. This might be related to the greater gene numbers and/or potential similarities in gene regulation between ants and vertebrates as compared to flies. PMID- 30249742 TI - Genome-scale analysis of Acetobacterium bakii reveals the cold adaptation of psychrotolerant acetogens by post-transcriptional regulation. AB - Acetogens synthesize acetyl-CoA via CO2 or CO fixation, producing organic compounds. Despite their ecological and industrial importance, their transcriptional and post-transcriptional regulation has not been systematically studied. With completion of the genome sequence of Acetobacterium bakii (4.28 Mb), we measured changes in the transcriptome of this psychrotolerant acetogen in response to temperature variations under autotrophic and heterotrophic growth conditions. Unexpectedly, acetogenesis genes were highly up-regulated at low temperatures under heterotrophic, as well as autotrophic, growth conditions. To mechanistically understand the transcriptional regulation of acetogenesis genes via changes in RNA secondary structures of 5'-untranslated regions (5'-UTR), the primary transcriptome was experimentally determined, and 1379 transcription start sites (TSS) and 1100 5'-UTR were found. Interestingly, acetogenesis genes contained longer 5'-UTR with lower RNA-folding free energy than other genes, revealing that the 5'-UTRs control the RNA abundance of the acetogenesis genes under low temperature conditions. Our findings suggest that post-transcriptional regulation via RNA conformational changes of 5'-UTRs is necessary for cold adaptive acetogenesis. PMID- 30249743 TI - A comparative analysis of the capacity of the Candida species to elicit vaginal immunopathology. AB - The human fungal pathogen Candida albicans is the major etiological agent of vulvovaginal candidiasis (VVC). Despite this fact, other non-albicans Candida (NAC) species have frequently been reported as well. Despite their presence in the vaginal environment, little is known about their capacity to elicit immune responses classically associated with C. albicans-mediated immunopathology, including neutrophil recruitment and pro-inflammatory cytokine signaling. Therefore, using a combination of in vitro and in vivo approaches, we undertook a comparative analysis to determine whether a representative panel of NAC species could colonize, induce immunopathological markers, or cause damage at the vaginal mucosa. Using a murine model of VVC, C. albicans was found to induce robust immunopathology (neutrophils, IL-1beta) and elicit mucosal damage. However, all NAC species tested (including C. dubliniensis, C. tropicalis, C. parapsilosis, C. krusei, C. glabrata, andC. auris) induced significantly less damage and neutrophil recruitment, despite achieving similar early colonization levels as C. albicans These results largely correlated with notable lack of the NAC species (C. dubliniensis and C. tropicalis included) to form hyphae both in vitro and in vivo. Furthermore, both C. dubliniensis and C. tropicalis induced significantly less expression of the ECE1 gene encoding for Candidalysin, a key fungal virulence determinant driving VVC immunopathology. In order to determine the relative capacity of these species to elicit inflammasome-dependent IL-1beta release, both WT and NLRP3-/- THP-1 cells were challenged in vitro. While most species tested elicited only modest amounts of IL-1beta, challenge with C. albicans led to significantly elevated levels that were largely NLRP3-dependent. Collectively, our findings demonstrate that although NAC species are increasingly reported as causative agents of VVC, C. albicans appears to be exceedingly vaginopathogenic, exhibiting robust immunopathology, hypha formation and Candidalysin expression. Thus, this study provides mechanistic insight as to why C. albicans is overwhelmingly the major pathogen reported during VVC. PMID- 30249745 TI - Glucose metabolism by Escherichia coli inhibits Vibrio cholerae intestinal colonization of zebrafish. AB - The V. cholerae O1 serogroup is responsible for pandemic cholera and is divided into the classical and El Tor biotypes. Classical V. cholerae produces acid when using glucose as a carbon source, whereas El Tor V. cholerae produces the neutral product acetoin when using glucose as a carbon source. An earlier study demonstrated that Escherichia coli strains that metabolize glucose to acidic by products drastically reduced the survival of V. cholerae strains in vitro. In the present study, zebrafish were fed 1% glucose and inoculated with single V. cholerae or E. coli strains or co-infected with both V. cholerae and E. coli A significant decrease in classical biotype colonization was observed after glucose feeding due to acid production in the zebrafish intestine. El Tor colonization was unaffected by glucose alone. However, the El Tor strain exhibited significantly lower colonization of the zebrafish when either of the acid producing E. coli was co-inoculated in the presence of glucose. An E. coli sugar transport mutant had no effect on V. cholerae colonization even in presence of glucose. Glucose and E. coli produced a prophylactic effect on El Tor colonization in zebrafish when E. coli was inoculated before V. cholerae infection. Thus, the probiotic feeding of E. coli inhibits V. cholerae colonization in a natural host. This suggests that a similar inhibitory effect could be seen in cholera patients, especially if glucose-based oral rehydration solution (ORS) is administered in combination with probiotic E. coli during cholera treatment. PMID- 30249744 TI - Ascaris Larval Infection and Lung Invasion Directly Induce Severe Allergic Airway Disease in Mice. AB - Ascaris lumbricoides (roundworm) is the most common helminth infection globally and a cause of lifelong morbidity that may include allergic airway disease, an asthma phenotype. We hypothesize that Ascaris larval migration through the lungs leads to persistent airway hyperresponsiveness (AHR) and type 2 inflammatory lung pathology despite resolution of infection that resembles allergic airway disease. Mice were infected with Ascaris by oral gavage. Lung AHR was measured by plethysmography and histopathology with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) stains, and cytokine concentrations were measured by using Luminex Magpix. Ascaris-infected mice were compared to controls or mice with allergic airway disease induced by ovalbumin (OVA) sensitization and challenge (OVA/OVA). Ascaris-infected mice developed profound AHR starting at day 8 postinfection (p.i.), peaking at day 12 p.i. and persisting through day 21 p.i., despite resolution of infection, which was significantly increased compared to controls and OVA/OVA mice. Ascaris-infected mice had a robust type 2 cytokine response in both the bronchoalveolar lavage (BAL) fluid and lung tissue, similar to that of the OVA/OVA mice, including interleukin-4 (IL-4) (P < 0.01 and P < 0.01, respectively), IL-5 (P < 0.001 and P < 0.001), and IL-13 (P < 0.001 and P < 0.01), compared to controls. By histopathology, Ascaris-infected mice demonstrated early airway remodeling similar to, but more profound than, that in OVA/OVA mice. We found that Ascaris larval migration causes significant pulmonary damage, including AHR and type 2 inflammatory lung pathology that resembles an extreme form of allergic airway disease. Our findings indicate that ascariasis may be an important cause of allergic airway disease in regions of endemicity. PMID- 30249746 TI - Candida albicans Ras1 Inactivation Increases Resistance to Phagosomal Killing by Human Neutrophils. AB - Host phagocytic cells are crucial players in initial defense against Candida albicans infection. C. albicans utilizes MAP kinases and Ras1 stress response signaling pathways to protect itself from killing by immune cells. In this study, we tested the importance of these pathways in C. albicans phagocytosis by neutrophils and subsequent phagosomal survival. Phagocytosis was influenced by C. albicans morphology, so hyphal length of >10 MUm reduced the phagocytic index (PI) 2- to 3-fold in human neutrophils. Primary human neutrophils killed 81% of phagocytosed C. albicans, while primary mouse neutrophils killed 63% of yeasts. We found that both the C. albicans Cek1 and Hog1 pathways were required for survival of phagocytosed yeast, whereas deletion of C. albicans RAS1 resulted in an 84% increase in survival within neutrophils compared to that of the wild type (WT). The absence of Ras1 did not alter reactive oxygen species (ROS) production by C. albicans; however, phagocytosed C. albicans Delta/Deltaras1 cells reduced ROS release by neutrophils by 86%. Moreover, C. albicans Delta/Deltaras1 cells had increased resistance to hydrogen peroxide as a result of high levels of catalase activity. This phenotype was specific to Ras1, since these effects were not observed in the absence of its partner Cyr1 or with its downstream target Efg1. In addition, C. albicans Delta/Deltaras1 cells had a significantly increased resistance to nonoxidative killing by human neutrophil peptide 1 (HNP 1) that was reversed by restoring cellular cAMP levels. These data show that C. albicans Ras1 inactivation leads to fungal resistance to both oxidative and nonoxidative mechanisms of neutrophil phagosomal killing. PMID- 30249747 TI - Heterogeneity of Ly6G+ Ly6C+ Myeloid-Derived Suppressor Cell Infiltrates during Staphylococcus aureus Biofilm Infection. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature monocytes and granulocytes. While neutrophils (polymorphonuclear leukocytes [PMNs]) are classically identified as highly differentiated cells specialized for antimicrobial defense, our laboratory has reported minor contributions of PMNs to the immune response during Staphylococcus aureus biofilm infection. However, these two cell types can be difficult to differentiate because of shared surface marker expression. Here we describe a more refined approach to distinguish MDSCs from PMNs utilizing the integrin receptor CD11b combined with conventional Ly6G and Ly6C expression. This approach separated the Ly6G+ Ly6C+ population that we previously identified in a mouse model of S. aureus orthopedic implant infection into two subsets, namely, CD11bhigh Ly6G+ Ly6C+ MDSCs and CD11blow Ly6G+ Ly6C+ PMNs, which was confirmed by characteristic nuclear morphology using cytospins. CD11bhigh Ly6G+ Ly6C+ MDSCs suppressed T cell proliferation throughout the 28-day infection period, whereas CD11blow Ly6G+ Ly6C+ PMNs had no effect early (day 3 postinfection), although this population acquired suppressive activity at later stages of biofilm development. To further highlight the distinctions between biofilm-associated MDSCs and PMNs versus monocytes, transcriptional profiles were compared by transcriptome sequencing (RNA-Seq). A total of 6,466 genes were significantly differentially expressed in MDSCs versus monocytes, whereas only 297 genes were significantly different between MDSCs and PMNs. A number of genes implicated in cell cycle regulation were identified, and in vivo ethynyldeoxyuridine (EdU) labeling revealed that approximately 50% of MDSCs proliferated locally at the site of S. aureus biofilm infection. Based on their similar transcriptomic profiles to those of PMNs, biofilm-associated MDSCs are of a granulocytic lineage and can be classified as granulocytic MDSCs (G-MDSCs). PMID- 30249748 TI - Improved Tolerability of a Salmonella enterica Serovar Typhimurium Live Attenuated Vaccine Strain Achieved by Balancing Inflammatory Potential with Immunogenicity. AB - A notable proportion of Salmonella-associated gastroenteritis in the United States is attributed to Salmonella enterica serovar Typhimurium. We have previously shown that live-attenuated S Typhimurium vaccine candidate CVD 1921 (I77 DeltaguaBA DeltaclpP) was safe and immunogenic in rhesus macaques but was shed for an undesirably long time postimmunization. In mice, occasional mortality postvaccination was also noted (approximately 1 in every 15 mice). Here we describe a further attenuated vaccine candidate strain harboring deletions in two additional genes, htrA and pipA We determined that S Typhimurium requires pipA to elicit fluid accumulation in a rabbit ileal loop model of gastroenteritis, as an S Typhimurium DeltapipA mutant induced significantly less fluid accumulation in rabbit loops than the wild-type strain. New vaccine strain CVD 1926 (I77 DeltaguaBA DeltaclpP DeltapipA DeltahtrA) was assessed for inflammatory potential in an organoid model of human intestinal mucosa, where it induced less inflammatory cytokine production than organoids exposed to the precursor vaccine, CVD 1921. To assess vaccine safety and efficacy, mice were given three doses of CVD 1926 (109 CFU/dose) by oral gavage, and at 1 or 3 months postimmunization, mice were challenged with 700 or 100 LD50 (50% lethal doses), respectively, of wild-type strain I77. CVD 1926 was well tolerated and exhibited 47% vaccine efficacy following challenge with a high inoculum and 60% efficacy after challenge with a low inoculum of virulent S Typhimurium. CVD 1926 is less reactogenic yet equally as immunogenic and protective as previous iterations in a mouse model. PMID- 30249750 TI - Treatment of Dextran Sulfate Sodium-Induced Colitis with Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Inhibitor MI-2 Is Associated with Restoration of Gut Immune Function and the Microbiota. AB - Disruption of the healthy intestinal microbiome and homeostasis of the intestinal immune system, which are closely interactive, are two key factors for ulcerative colitis. Here, we show that MI-2, a selective inhibitor of mucosa-associated lymphoid tissue lymphoma translocation-1 (MALT1), alleviated excessive inflammatory responses and was associated with restoration of healthy intestinal microbiome in mice suffering from dextran sulfate sodium (DSS)-induced colitis. We found that the diversity of intestinal microbiome of mice with DSS-induced colitis was significantly lower than that of healthy mice. However, MI-2 treatment in mice with DSS-induced colitis resulted in restored microbially diverse populations. To understand the possibility of the beneficial effect of the restored microbially diverse populations of MI-2-treated mice with DSS induced colitis, we showed that inserting fecal microbiota from MI-2-treated mice with DSS-induced colitis and healthy control mice into mice with DSS-induced colitis could alleviate symptoms of colitis. The possibility of MI-2 treatment in DSS-induced colitis, associated with restoration of healthy microbially diverse populations in addition to reshaping host immune modulating capacity by reducing inflammatory cytokines (tumor necrosis factor alpha, interleukin-1beta [IL 1beta], IL-17alpha, and IL-22), may be considered therapeutic for ulcerative colitis. PMID- 30249749 TI - Autoinducer 2 (AI-2) Production by Nontypeable Haemophilus influenzae 86-028NP Promotes Expression of a Predicted Glycosyltransferase That Is a Determinant of Biofilm Maturation, Prevention of Dispersal, and Persistence In Vivo. AB - Nontypeable Haemophilus influenzae (NTHi) is an extremely common human pathobiont that persists on the airway mucosal surface within biofilm communities, and our previous work has shown that NTHi biofilm maturation is coordinated by the production and uptake of autoinducer 2 (AI-2) quorum signals. To directly test roles for AI-2 in maturation and maintenance of NTHi biofilms, we generated an NTHi 86-028NP mutant in which luxS transcription was under the control of the xylA promoter (NTHi 86-028NP luxS xylA::luxS), rendering AI-2 production inducible by xylose. Comparison of biofilms under inducing and noninducing conditions revealed a biofilm defect in the absence of xylose, whereas biofilm maturation increased following xylose induction. The removal of xylose resulted in the interruption of luxS expression and biofilm dispersal. Measurement of luxS transcript levels by real-time reverse transcription-PCR (RT-PCR) showed that luxS expression peaked as biofilms matured and waned before dispersal. Transcript profiling revealed significant changes following the induction of luxS, including increased transcript levels for a predicted family 8 glycosyltransferase (NTHI1750; designated gstA); this result was confirmed by real-time RT-PCR. An isogenic NTHi 86-028NP gstA mutant had a biofilm defect, including decreased levels of sialylated matrix and significantly altered biofilm structure. In experimental chinchilla infections, we observed a significant decrease in the number of bacteria in the biofilm population (but not in effusions) for NTHi 86 028NP gstA compared to the parental strain. Therefore, we conclude that AI-2 promotes NTHi biofilm maturation and the maintenance of biofilm integrity, due at least in part to the expression of a probable glycosyltransferase that is potentially involved in the synthesis of the biofilm matrix. PMID- 30249751 TI - Ade2 Functions in the Drosophila Fat Body To Promote Sleep. AB - Metabolic state is a potent modulator of sleep and circadian behavior, and animals acutely modulate their sleep in accordance with internal energy stores and food availability. Across phyla, hormones secreted from adipose tissue act in the brain to control neural physiology and behavior to modulate sleep and metabolic state. Growing evidence suggests the fat body is a critical regulator of complex behaviors, but little is known about the genes that function within the fat body to regulate sleep. To identify molecular factors functioning in non neuronal tissues to regulate sleep, we performed an RNAi screen selectively knocking down genes in the fat body. We found that knockdown of Phosphoribosylformylglycinamidine synthase/Pfas (Ade2), a highly conserved gene involved the biosynthesis of purines, sleep regulation and energy stores. Flies heterozygous for multiple Ade2 mutations are also short sleepers and this effect is partially rescued by restoring Ade2 to the Drosophila fat body. Targeted knockdown of Ade2 in the fat body does not alter arousal threshold or the homeostatic response to sleep deprivation, suggesting a specific role in modulating baseline sleep duration. Together, these findings suggest Ade2 functions within the fat body to promote both sleep and energy storage, providing a functional link between these processes. PMID- 30249752 TI - Biopanning of allergens from wasp sting patients. AB - OBJECTIVE: Wasp venom is a potentially important natural drug, but it can cause hypersensitivity reactions. The purpose of the present study was to systematically study the epitopes of wasp venom. METHODS: Using a random 12 peptide phage library, we performed antibody-binding epitope panning on ten serum samples from wasp sting victims at 3 h and 4 days after the sting. The panning epitopes were identified by high-throughput sequencing and matched with wasp venom proteins by BLAST. The panned antibody-binding epitopes were verified by ELISA. RESULTS: A total of 35 specific potential wasp venom epitopes in 4 days were identified. Amongst them, twelve peptide epitopes were matched with nine wasp venom proteins, namely, vitellogenin precursor, hexamerin 70b precursor, venom carboxylesterase-6 precursor, MRJP5, major royal jelly protein 8 precursor, venom acid phosphatase Acph-1 precursor, phospholipase A2, venom serine protease 34 precursor, and major royal jelly protein 9 precursor. The changes in serum IgM antibodies induced by wasp venom were confirmed by ELISA based on the 12 peptide epitopes. CONCLUSION: The nine wasp venom proteins are potential allergens, which should be excluded or modified in the potential biomedical applications of wasp venom. PMID- 30249754 TI - Inhibition of glycogen synthase kinase-3beta is involved in cardioprotection by alpha7nAChR agonist and limb remote ischemic postconditionings. AB - The present study was designed to determine whether glycogen synthase kinase 3beta (GSK-3beta) was involved in the cardioprotection by alpha7 nicotinic acetylcholine receptor (alpha7nAChR) agonist and limb remote ischemic postconditionings. Forty male Sprague-Dawley rats were randomly divided equally into control (C), alpha7nAChR agonist postconditioning (P), limb remote ischemic postconditioning (L), combined alpha7nAChR agonist and limb remote ischemic postconditioning (P+L) groups. At the end of experiment, serum cTnI, creatine kinase-MB (CK-MB), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), high mobility group protein (HMGB1) and interleukin-10 (IL-10) levels were measured; infarct size (IS), myocardial expressions of GSK-3beta, p-GSK-3beta (Ser9), nuclear factor-kappaB (NF-kappaB) and p-NF-kappaB (Ser536) in the ischemic area were assessed. The results showed that compared with group C, IS, serum cTnI and CK-MB levels obviously decreased in groups P, L and P+L. Compared with groups P and L, IS, serum cTnI and CK-MB levels significantly decreased in group P+L. Compared with group C, serum TNF-alpha, IL-6 and HMGB1 levels, and myocardial expression of p-NF-kappaBp65 (Ser536) evidently decreased, and myocardial expression of p-GSK-3beta (Ser9) obviously increased in groups P, L and P+L. Compared with group P, serum TNF-alpha, IL-6 and HMGB1 levels and myocardial expression of p-NF-kappaBp65 (Ser536) significantly increased, and myocardial expression of p-GSK-3beta (Ser9) evidently decreased in group L. Compared with group L, serum TNF-alpha, IL-6, HMGB1 levels, and myocardial expression of p-NF-kappaBp65 (Ser536) significantly decreased, and myocardial expression of p-GSK-3beta (Ser9) obviously increased in group P+L. In conclusion, our findings indicate that inhibition of GSK-3beta to decrease NF-kappaB transcription is one of cardioprotective mechanisms of alpha7nAChR agonist and limb remote ischemic postconditionings by anti-inflammation, but improved cardioprotection by combined two interventions is not completely attributable to an enhanced anti-inflammatory mechanism. PMID- 30249753 TI - Effects of FM0807, a novel curcumin derivative, on lipopolysaccharide-induced inflammatory factor release via the ROS/JNK/p53 pathway in RAW264.7 cells. AB - Purpose: Sepsis is a systemic inflammatory response caused by infection. Curcumin is known to have antioxidant and anti-inflammatory activities. FM0807, a curcumin derivative, was investigated in the present study to determine its effect on cytokines and the possible molecular mechanism. Main methods: The experiments were carried out in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Cell viability was measured by MTT assay. ELISA, Griess assays, fluorescence-based quantitative PCR, flow cytometric analysis, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) experiments, and Western blotting were carried out to assess the potential effects of FM0807 on LPS-induced RAW 264.7 cells. Significant findings: FM0807 had no cytotoxic effects on RAW 264.7 cells. Furthermore, pretreatment with FM0807 inhibited the inflammatory factor tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 1beta (IL-1beta), IL-6, and inducible nitric oxide synthase (iNOS) at the protein and gene levels. FM0807 also inhibited the production of reactive oxygen species (ROS) and apoptosis. In addition, the activation of the ROS/JNK (c-jun NH2-terminal kinase)/p53 signaling pathway was inhibited by FM0807 in RAW 264.7 cells in vitro Conclusion: FM0807 has anti inflammatory activity in vitro, which suggests a potential clinical application in sepsis. The anti-inflammatory activity of FM0807 may be mediated by the ROS/JNK/p53 signaling pathway. PMID- 30249755 TI - FOXF2 inhibits proliferation, migration, and invasion of Hela cells by regulating Wnt signaling pathway. AB - This article was aimed to study the FOXF2 effects on cervical cancer. Tumor tissues and adjacent tissues of 41 cervical cancer patients were collected. Human endometrial epithelial cells (hEEC) and Hela cells were cultured. FOXF2 expression vector and its empty vector were transfected into Hela cells, and named as pcDNA 3.1-FOXF2 group and Vector group, respectively. Hela cells without any treatment were set as Blank group. qRT-PCR was used to detect mRNA expression. Nude mouse xenograft assay was performed to test Hela cells proliferation ability in vivo FOXF2 and beta-catenin positive cell numbers were detected by immunohistochemistry. Protein expression was analyzed by Western blot. Cells migration and invasion were conducted by Transwell. Tumor tissues and Hela cells FOXF2 expression were lower than that in adjacent tissues and hEEC (P<0.01). Low FOXF2 expression predicted poor outcomes of cervical cancer patients. Compared with Blank group and Vector group, Hela cells of pcDNA 3.1 FOXF2 group were with higher FOXF2 expression, lower OD495 value, migrated and invaded cells, higher E-cadherin expression, lower Vimentin and Snail expression, smaller tumor volume in nude mice, lower c-Myc, CyclinDl, MMP9, Lgr5, and nuclear beta-catenin expression (all P<0.01). FOXF2 inhibits Hela cells proliferation, migration, and invasion through regulating Wnt signaling pathway. PMID- 30249756 TI - Down-regulation of lncRNA snaR is correlated with postoperative distant recurrence of HPV-negative cervical squamous cell carcinoma. AB - Long non-coding RNAs (lncRNAs) snaR is a newly identified lncRNA with known functionality only in colon cancer. Our study was carried out to investigate the involvement of lncRNA snaR in human papillomaviruses (HPV)-negative cervical squamous cell carcinoma (CSCC). In the present study, plasma levels of lncRNA snaR in 108 patients with HPV-negative CSCC at stage I and II, and 35 healthy female controls were detected by real-time quantitative PCR. ROC curve analysis was performed to evaluate the diagnostic value of lncRNA snaR for HPV-negative CSCC. All patients were subjected to surgical resection and followed-up for 5 years to record cancer recurrence. lncRNA snaR expression vectors were transfected into HPV-negative CSCC cells. Cell migration and invasion ability were evaluated by Transwell migration and invasion assay, respectively. Expression levels of TGF-beta1 were determined by Western blot. It was observed that lncRNA snaR was down-regulated in HPV-negative CSCC patients comparing with healthy controls. Down-regulation of lncRNA snaR effectively distinguished HPV negative CSCC patients from healthy controls. lncRNA snaR was further down regulated in patients with distant recurrence (DR) but not in patients with local recurrence or without recurrence. lncRNA snaR overexpression decreased TGF-beta1 expression in CSCC cells, while exogenous TGF-beta1 treatment showed no significant effects on lncRNA snaR expression. lncRNA snaR overexpression inhibited cancer cell migration and invasion, while TGF-beta1 treatment attenuated the inhibitory effect of lncRNA snaR overexpression on cancer cell migration and invasion. We therefore conclude that down-regulation of lncRNA snaR may induce postoperative DR of HPV-negative CSCC possibly through the interactions with TGF-beta1. PMID- 30249757 TI - Managing frailty in primary care: evidence gaps cannot be ignored. PMID- 30249760 TI - Myasthenia gravis. PMID- 30249758 TI - Care setting and 30-day hospital readmissions among older adults: a population based cohort study. AB - BACKGROUND: Despite the fact that many older adults receive home or long-term care services, the effect of these care settings on hospital readmission is often overlooked. Efforts to reduce hospital readmissions, including capacity planning and targeting of interventions, require clear data on the frequency of and risk factors for readmission among different populations of older adults. METHODS: We identified all adults older than 65 years discharged from an unplanned medical hospital stay in Ontario between April 2008 and December 2015. We defined 2 preadmission care settings (community, long-term care) and 3 discharge care settings (community, home care, long-term care) and used multinomial regression to estimate associations with 30-day readmission (and death as a competing risk). RESULTS: We identified 701 527 individuals (mean age 78.4 yr), of whom 414 302 (59.1%) started in and returned to the community. Overall, 88 305 in dividuals (12.6%) were re admitted within 30 days, but this proportion varied by care setting combination. Relative to individuals returning to the community, those discharged to the community with home care (adjusted odds ratio [OR] 1.43, 95% confidence interval [CI] 1.39-1.46) and those returning to long-term care (adjusted OR 1.35, 95% CI 1.27-1.43) had a greater risk of readmission, whereas those newly admitted to long-term care had a lower risk of readmission (adjusted OR 0.68, 95% CI 0.63-0.72). INTERPRETATION: In Ontario, about 40% of older people were discharged from hospital to either home care or long-term care. These discharge settings, as well as whether an individual was admitted to hospital from long-term care, have important implications for understanding 30-day readmission rates. System planning and efforts to reduce readmission among older adults should take into account care settings at both admission and discharge. PMID- 30249761 TI - Extramammary Paget disease of the glans penis. PMID- 30249759 TI - Identification and management of frailty in the primary care setting. PMID- 30249762 TI - Adopt US recommendation on vision screening in older adults. PMID- 30249763 TI - Not another consultation process: a critique of the implementation of Bill C-277 Framework on Palliative Care in Canada. PMID- 30249764 TI - Students tidy online presence before applying to medical school and residency. PMID- 30249765 TI - Ontario health providers protest pause on overdose prevention. PMID- 30249766 TI - Telemedicine on the rise but lagging in Canada. PMID- 30249767 TI - Elastin modulation and modification by homocysteine: a key factor in the pathogenesis of Pseudoexfoliation syndrome? AB - BACKGROUND: Pseudoexfoliation syndrome (PXF) is an idiopathic, elastogenesis associated systemic disease characterised by amyloid-like material aggregates in the eye. Elevated plasma and aqueous humour (aqH) homocysteine (Hcy) is reportedly associated with PXF. This study is aimed to probe Hcy-mediated alterations in elastin expression. METHODOLOGY: Lens level of Hcy (total Hcy (tHcy)), mRNA expression of Eln, CBS and MTR in lens capsule, protein expression of elastin in aqH were estimated by enzyme immunoassay, quantitative PCR and western blot, respectively in PXF, PXF with glaucoma (PXF-G) cases, in comparison with cataract-alone disease controls. Human lens epithelial cells (hLECs) were exposed to Hcy and homocysteine thiolactone (HCTL) to evaluate elastin expression in vitro. Furthermore, elastin recombinant protein was incubated with Hcy and HCTL to assess secondary and tertiary structural modifications based on circular dichroism spectroscopy, spectrophotometric and SEM studies. RESULTS: The lens tHcy was significantly high in PXF (p=0.02) and PXF-G (p=0.009). Eln expression was elevated in PXF and PXF-G (p=0.0007). Elastin level in aqH was elevated in PXF (p=0.01) and PXF-G (p=0.002). Hcy (200 uM) and HCTL (1 uM) promoted elastin expression at mRNA level by 36-fold (p=0.02) and 10-fold (p=0.05), respectively, and at protein level by nearly two-fold in cultured hLECs. Secondary structure changes in elastin protein caused by Hcy were evident from 34.11% drop in alpha helix and 6.17% gain in beta-sheet. Fluorescence, spectral assays and SEM analyses showed aggregation and amyloid formation of elastin with homocysteinylation. CONCLUSION: The study reveals that lens accumulation of Hcy associated with hyperhomocysteinaemia is characteristic of PXF that augments elastin expression. Hcy causes structural changes promoting elastin aggregation, thereby contributing to defective elastin in PXF and PXF-G. PMID- 30249768 TI - Mechanics of development. PMID- 30249769 TI - Blocking mechanosensitive ion channels eliminates the effects of applied mechanical loading on chick joint morphogenesis. AB - Abnormalities in joint shape are increasingly considered a critical risk factor for developing osteoarthritis in life. It has been shown that mechanical forces during prenatal development, particularly those due to fetal movements, play a fundamental role in joint morphogenesis. However, how mechanical stimuli are sensed or transduced in developing joint tissues is unclear. Stretch-activated and voltage-gated calcium ion channels have been shown to be involved in the mechanoregulation of chondrocytes in vitro In this study, we analyse, for the first time, how blocking these ion channels influences the effects of mechanical loading on chick joint morphogenesis. Using in vitro culture of embryonic chick hindlimb explants in a mechanostimulation bioreactor, we block stretch-activated and voltage-gated ion channels using, respectively, gadolinium chloride and nifedipine. We find that the administration of high doses of either drug largely removed the effects of mechanical stimulation on growth and shape development in vitro, while neither drug had any effect in static cultures. This study demonstrates that, during joint morphogenesis, mechanical cues are transduced-at least in part-through mechanosensitive calcium ion channels, advancing our understanding of cartilage development and mechanotransduction.This article is part of the Theo Murphy meeting issue 'Mechanics of development'. PMID- 30249770 TI - Smooth muscle: a stiff sculptor of epithelial shapes. AB - Smooth muscle is increasingly recognized as a key mechanical sculptor of epithelia during embryonic development. Smooth muscle is a mesenchymal tissue that surrounds the epithelia of organs including the gut, blood vessels, lungs, bladder, ureter, uterus, oviduct and epididymis. Smooth muscle is stiffer than its adjacent epithelium and often serves its morphogenetic function by physically constraining the growth of a proliferating epithelial layer. This constraint leads to mechanical instabilities and epithelial morphogenesis through buckling. Smooth muscle stiffness alone, without smooth muscle cell shortening, seems to be sufficient to drive epithelial morphogenesis. Fully understanding the development of organs that use smooth muscle stiffness as a driver of morphogenesis requires investigating how smooth muscle develops, a key aspect of which is distinguishing smooth muscle-like tissues from one another in vivo and in culture. This necessitates a comprehensive appreciation of the genetic, anatomical and functional markers that are used to distinguish the different subtypes of smooth muscle (for example, vascular versus visceral) from similar cell types (including myofibroblasts and myoepithelial cells). Here, we review how smooth muscle acts as a mechanical driver of morphogenesis and discuss ways of identifying smooth muscle, which is critical for understanding these morphogenetic events.This article is part of the Theo Murphy meeting issue 'Mechanics of Development'. PMID- 30249771 TI - Tissue self-organization underlies morphogenesis of the notochord. AB - The notochord is a conserved axial structure that in vertebrates serves as a hydrostatic scaffold for embryonic axis elongation and, later on, for proper spine assembly. It consists of a core of large fluid-filled vacuolated cells surrounded by an epithelial sheath that is encased in extracellular matrix. During morphogenesis, the vacuolated cells inflate their vacuole and arrange in a stereotypical staircase pattern. We investigated the origin of this pattern and found that it can be achieved purely by simple physical principles. We are able to model the arrangement of vacuolated cells within the zebrafish notochord using a physical model composed of silicone tubes and water-absorbing polymer beads. The biological structure and the physical model can be accurately described by the theory developed for the packing of spheres and foams in cylinders. Our experiments with physical models and numerical simulations generated several predictions on key features of notochord organization that we documented and tested experimentally in zebrafish. Altogether, our data reveal that the organization of the vertebrate notochord is governed by the density of the osmotically swelling vacuolated cells and the aspect ratio of the notochord rod. We therefore conclude that self-organization underlies morphogenesis of the vertebrate notochord.This article is part of the Theo Murphy meeting issue on 'Mechanics of development'. PMID- 30249773 TI - The first digestive movements in the embryo are mediated by mechanosensitive smooth muscle calcium waves. AB - Peristalsis enables transport of the food bolus in the gut. Here, I show by dynamic ex vivo intra-cellular calcium imaging on living embryonic gut explants that the most primitive form of peristalsis that occurs in the embryo is the result of inter-cellular, gap-junction-dependent calcium waves that propagate in the circular smooth muscle layer. I show that the embryonic gut is an intrinsically mechanosensitive organ, as the slightest externally applied mechanical stimulus triggers contractile waves. This dynamic response is an embryonic precursor of the 'law of the intestine' (peristaltic reflex). I show how characteristic features of early peristalsis such as counter-propagating wave annihilation, mechanosensitivity and nucleation after wounding all result from known properties of calcium waves. I finally demonstrate that inter-cellular mechanical tension does not play a role in the propagation mechanism of gut contractile waves, unlike what has been recently shown for the embryonic heartbeat. Calcium waves are a ubiquitous dynamic signalling mechanism in biology: here I show that they are the foundation of digestive movements in the developing embryo.This article is part of the Theo Murphy meeting issue on 'Mechanics of development'. PMID- 30249772 TI - Mechanics of cortical folding: stress, growth and stability. AB - Cortical folding, or gyrification, coincides with several important developmental processes. The folded shape of the human brain allows the cerebral cortex, the thin outer layer of neurons and their associated projections, to attain a large surface area relative to brain volume. Abnormal cortical folding has been associated with severe neurological, cognitive and behavioural disorders, such as epilepsy, autism and schizophrenia. However, despite decades of study, the mechanical forces that lead to cortical folding remain incompletely understood. Leading hypotheses have focused on the roles of (i) tangential growth of the outer cortex, (ii) spatio-temporal patterns in the birth and migration of neurons, and (iii) internal tension in axons. Recent experimental studies have illuminated not only the fundamental cellular and molecular processes underlying cortical development, but also the stress state, mechanical properties and spatio temporal patterns of growth in the developing brain. The combination of mathematical modelling and physical measurements has allowed researchers to evaluate hypothesized mechanisms of folding, to determine whether each is consistent with physical laws. This review summarizes what physical scientists have learned from models and recent experimental observations, in the context of recent neurobiological discoveries regarding cortical development. Here, we highlight evidence of a combined mechanism, in which spatio-temporal patterns bias the locations of primary folds (i), but tangential growth of the cortical plate induces mechanical instability (ii) to propagate primary and higher-order folds.This article is part of the Theo Murphy meeting issue 'Mechanics of development'. PMID- 30249774 TI - From mechanobiology to developmentally inspired engineering. AB - The field of mechanobiology emerged based on the recognition of the central role that physical forces play in development and physiology. In this article, which is based on a lecture I presented at the 2018 Royal Society meeting on Mechanics of Development, I review work from my laboratory carried out over the 40 years which helped to birth this field. I will also describe how we are leveraging the fundamental design principles that govern mechanoregulation to develop new experimental tools and organ-engineering approaches as well as novel mechanotherapeutics.This article is part of the Theo Murphy meeting issue 'Mechanics of development'. PMID- 30249775 TI - Embryo movements regulate tendon mechanical property development. AB - Tendons transmit forces from muscles to bones to enable skeletal motility. During development, tendons begin to bear load at the onset of embryo movements. Using the chick embryo model, this study showed that altered embryo movement frequency led to changes in elastic modulus of calcaneal tendon. In particular, paralysis led to decreased modulus, whereas hypermotility led to increased modulus. Paralysis also led to reductions in activity levels of lysyl oxidase (LOX), an enzyme that we previously showed is required for cross-linking-mediated elaboration of tendon mechanical properties. Additionally, inhibition of LOX activity abrogated hypermotility-induced increases in modulus. Taken together, our findings suggest embryo movements are critical for tendon mechanical property development and implicate LOX in this process. These exciting findings expand current knowledge of how functional tendons form during development and could guide future clinical approaches to treat tendon defects associated with abnormal mechanical loading in uteroThis article is part of the Theo Murphy meeting issue 'Mechanics of development'. PMID- 30249777 TI - The same but different: cell intercalation as a driver of tissue deformation and fluidity. AB - The ability of cells to exchange neighbours, termed intercalation, is a key feature of epithelial tissues. Intercalation is predominantly associated with tissue deformations that drive morphogenesis. More recently, however, intercalation that is not associated with large-scale tissue deformations has been described both during animal development and in mature epithelial tissues. This latter form of intercalation appears to contribute to an emerging phenomenon that we refer to as tissue fluidity-the ability of cells to exchange neighbours without changing the overall dimensions of the tissue. Here, we discuss the contribution of junctional dynamics to intercalation governing both morphogenesis and tissue fluidity. In particular, we focus on the relative roles of junctional contractility and cell-cell adhesion as the driving forces behind intercalation. These two contributors to junctional mechanics can be used to simulate cellular intercalation in mechanical computational models, to test how junctional cell behaviours might regulate tissue fluidity and contribute to the maintenance of tissue integrity and the onset of disease.This article is part of the Theo Murphy meeting issue 'Mechanics of development'. PMID- 30249778 TI - Investigating the mechanistic basis of biomechanical input controlling skeletal development: exploring the interplay with Wnt signalling at the joint. AB - Embryo movement is essential to the formation of a functional skeleton. Using mouse and chick models, we previously showed that mechanical forces influence gene regulation and tissue patterning, particularly at developing limb joints. However, the molecular mechanisms that underpin the influence of mechanical signals are poorly understood. Wnt signalling is required during skeletal development and is altered under reduced mechanical stimulation. Here, to explore Wnt signalling as a mediator of mechanical input, the expression of Wnt ligand and Fzd receptor genes in the developing skeletal rudiments was profiled. Canonical Wnt activity restricted to the developing joint was shown to be reduced under immobilization, while overexpression of activated beta-catenin following electroporation of chick embryo limbs led to joint expansion, supporting the proposed role for Wnt signalling in mechanoresponsive joint patterning. Two key findings advance our understanding of the interplay between Wnt signalling and mechanical stimuli: first, loss of canonical Wnt activity at the joint shows reciprocal, coordinated misregulation of BMP signalling under altered mechanical influence. Second, this occurs simultaneously with increased expression of several Wnt pathway component genes in a territory peripheral to the joint, indicating the importance of mechanical stimulation for a population of potential joint progenitor cells.This article is part of the Theo Murphy meeting issue 'Mechanics of Development'. PMID- 30249776 TI - New functions for the proprioceptive system in skeletal biology. AB - Muscle spindles and Golgi tendon organs (GTOs) are two types of sensory receptors that respond to changes in length or tension of skeletal muscles. These mechanosensors have long been known to participate in both proprioception and stretch reflex. Here, we present recent findings implicating these organs in maintenance of spine alignment as well as in realignment of fractured bones. These discoveries have been made in several mouse lines lacking functional mechanosensors in part or completely. In both studies, the absence of functional spindles and GTOs produced a more severe phenotype than that of spindles alone. Interestingly, the spinal curve phenotype, which appeared during peripubertal development, bears resemblance to the human condition adolescent idiopathic scoliosis. This similarity may contribute to the study of the disease by offering both an animal model and a clue as to its aetiology. Moreover, it raises the possibility that impaired proprioceptive signalling may be involved in the aetiology of other conditions. Overall, these new findings expand considerably the scope of involvement of proprioception in musculoskeletal development and function.This article is part of the Theo Murphy meeting issue 'Mechanics of development'. PMID- 30249779 TI - Quantifying blood flow dynamics during cardiac development: demystifying computational methods. AB - Blood flow conditions (haemodynamics) are crucial for proper cardiovascular development. Indeed, blood flow induces biomechanical adaptations and mechanotransduction signalling that influence cardiovascular growth and development during embryonic stages and beyond. Altered blood flow conditions are a hallmark of congenital heart disease, and disrupted blood flow at early embryonic stages is known to lead to congenital heart malformations. In spite of this, many of the mechanisms by which blood flow mechanics affect cardiovascular development remain unknown. This is due in part to the challenges involved in quantifying blood flow dynamics and the forces exerted by blood flow on developing cardiovascular tissues. Recent technologies, however, have allowed precise measurement of blood flow parameters and cardiovascular geometry even at early embryonic stages. Combined with computational fluid dynamics techniques, it is possible to quantify haemodynamic parameters and their changes over development, which is a crucial step in the quest for understanding the role of mechanical cues on heart and vascular formation. This study summarizes some fundamental aspects of modelling blood flow dynamics, with a focus on three dimensional modelling techniques, and discusses relevant studies that are revealing the details of blood flow and their influence on cardiovascular development.This article is part of the Theo Murphy meeting issue 'Mechanics of development'. PMID- 30249783 TI - California law requires doctors to disclose serious misconduct probation to patients. PMID- 30249780 TI - Three-dimensional microscopy and image analysis methodology for mapping and quantification of nuclear positions in tissues with approximate cylindrical geometry. AB - Organogenesis involves extensive and dynamic changes of tissue shape during development. It is associated with complex morphogenetic events that require enormous tissue plasticity and generate a large variety of transient three dimensional geometries that are achieved by global tissue responses. Nevertheless, such global responses are driven by tight spatio-temporal regulation of the behaviours of individual cells composing these tissues. Therefore, the development of image analysis tools that allow for extraction of quantitative data concerning individual cell behaviours is central to study tissue morphogenesis. There are many image analysis tools available that permit extraction of cell parameters. Unfortunately, the majority are developed for tissues with relatively simple geometries such as flat epithelia. Problems arise when the tissue of interest assumes a more complex three-dimensional geometry. Here, we use the endothelium of the developing zebrafish dorsal aorta as an example of a tissue with cylindrical geometry and describe the image analysis routines developed to extract quantitative data on individual cells in such tissues, as well as the image acquisition and sample preparation methodology.This article is part of the Theo Murphy meeting issue 'Mechanics of development'. PMID- 30249782 TI - CCGs win right to offer patients Avastin for wet AMD. PMID- 30249781 TI - The mechanical impact of col11a2 loss on joints; col11a2 mutant zebrafish show changes to joint development and function, which leads to early-onset osteoarthritis. AB - Collagen is the major structural component of cartilage, and mutations in the genes encoding type XI collagen are associated with severe skeletal dysplasias (fibrochondrogenesis and Stickler syndrome) and early-onset osteoarthritis (OA). The impact of the lack of type XI collagen on cell behaviour and mechanical performance during skeleton development is unknown. We studied a zebrafish mutant for col11a2 and evaluated cartilage, bone development and mechanical properties to address this. We show that in col11a2 mutants, type II collagen is made but is prematurely degraded in maturing cartilage and ectopically expressed in the joint. These changes are correlated with increased stiffness of both bone and cartilage; quantified using atomic force microscopy. In the mutants, the skeletal rudiment terminal region in the jaw joint is broader and the interzone smaller. These differences in shape and material properties impact on joint function and mechanical performance, which we modelled using finite element analyses. Finally, we show that col11a2 heterozygous carriers reach adulthood but show signs of severe early-onset OA. Taken together, our data demonstrate a key role for type XI collagen in maintaining the properties of cartilage matrix; which when lost leads to alterations to cell behaviour that give rise to joint pathologies.This article is part of the Theo Murphy meeting issue 'Mechanics of development'. PMID- 30249785 TI - Distinct patterns of clonal evolution in patients with concurrent myelo- and lymphoproliferative neoplasms. PMID- 30249784 TI - Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. AB - The introduction of novel agents has led to major improvements in clinical outcomes for patients with multiple myeloma. To shorten evaluation times for new treatments, health agencies are currently examining minimal residual disease (MRD) as a surrogate end point in clinical trials. We assessed the prognostic value of MRD, measured during maintenance therapy by next-generation sequencing (NGS). MRD negativity was defined as the absence of tumor plasma cell within 1 000 000 bone marrow cells (<10-6). Data were analyzed from a recent clinical trial that evaluated the role of transplantation in newly diagnosed myeloma patients treated with lenalidomide, bortezomib, and dexamethasone (RVD). MRD negativity was achieved at least once during maintenance in 127 patients (25%). At the start of maintenance therapy, MRD was a strong prognostic factor for both progression-free survival (adjusted hazard ratio, 0.22; 95% confidence interval, 0.15-0.34; P < .001) and overall survival (adjusted hazard ratio, 0.24; 95% confidence interval, 0.11-0.54; P = .001). Patients who were MRD negative had a higher probability of prolonged progression-free survival than patients with detectable residual disease, regardless of treatment group (RVD vs transplant), cytogenetic risk profile, or International Staging System disease stage at diagnosis. These results were similar after completion of maintenance therapy. Our findings confirm the value of MRD status, as determined by NGS, as a prognostic biomarker in multiple myeloma, and suggest that this approach could be used to adapt treatment strategies in future clinical trials. PMID- 30249786 TI - Hyper N-glycosylated SAMD14 and neurabin-I as driver CNS autoantigens of PCNSL. AB - To address the role of chronic antigenic stimulation in PCNSL we searched for auto-antigens and identified SAMD-14 and neurabin-I as auto-antigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases SAMD14 and neurabin-I were atypically hyper-N-glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277) explaining their auto-immunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14 and neurabin-I reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to a truncated Pseudomonas exotoxin killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified CNS driver auto antigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism and provide the basis for a novel specific treatment approach. PMID- 30249787 TI - SKI controls MDS-associated chronic TGF-beta signaling, aberrant splicing, and stem cell fitness. AB - The transforming growth factor beta (TGF-beta) signaling pathway controls hematopoietic stem cell (HSC) behavior in the marrow niche; however, TGF-beta signaling becomes chronic in early-stage myelodysplastic syndrome (MDS). Although TGF-beta signaling normally induces negative feedback, in early-stage MDS, high levels of microRNA-21 (miR-21) contribute to chronic TGF-beta signaling. We found that a TGF-beta signal-correlated gene signature is sufficient to identify an MDS patient population with abnormal RNA splicing (eg, CSF3R) independent of splicing factor mutations and coincident with low HNRNPK activity. Levels of SKI messenger RNA (mRNA) encoding a TGF-beta antagonist are sufficient to identify these patients. However, MDS patients with high SKI mRNA and chronic TGF-beta signaling lack SKI protein because of miR-21 activity. To determine the impact of SKI loss, we examined murine Ski -/- HSC function. First, competitive HSC transplants revealed a profound defect in stem cell fitness (competitive disadvantage) but not specification, homing, or multilineage production. Aged recipients of Ski -/- HSCs exhibited mild phenotypes similar to phenotypes in those with macrocytic anemia. Second, blastocyst complementation revealed a dramatic block in Ski -/- hematopoiesis in the absence of transplantation. Similar to SKI-high MDS patient samples, Ski -/- HSCs strikingly upregulated TGF-beta signaling and deregulated expression of spliceosome genes (including Hnrnpk). Moreover, novel single-cell splicing analyses demonstrated that Ski -/- HSCs and high levels of SKI expression in MDS patient samples share abnormal alternative splicing of common genes (including those that encode splicing factors). We conclude that miR-21 mediated loss of SKI activates TGF-beta signaling and alternative splicing to impair the competitive advantage of normal HSCs (fitness), which could contribute to selection of early-stage MDS-genic clones. PMID- 30249788 TI - N-terminal mutation of apoA-I and interaction with ABCA1 reveal mechanisms of nascent HDL biogenesis. AB - ApoA-I and the ATP-binding cassette transporter A1 (ABCA1) play important roles in nascent HDL (nHDL) biogenesis, the first step in the pathway of reverse cholesterol transport that protects against cardiovascular disease. On the basis of the crystal structure of a C-terminally truncated form of apoA-IDelta;[185 243]) determined in our laboratory, we hypothesized that opening the N-terminal helix bundle would facilitate lipid binding. To that end, we structurally designed a mutant (L38G/K40G) to destabilize the N-terminal helical bundle at the first hinge region. Conformational characterization of this mutant in solution revealed minimally reduced alpha-helical content, a less-compact overall structure, and increased lipid-binding ability. In solution-binding studies, apoA I and purified ABCA1 also showed direct binding between them. In ABCA1 transfected HEK293 cells, L38G/K40G had a significantly enhanced ability to form nHDL, which suggests that a destabilized N-terminal bundle facilitates nHDL formation. The total cholesterol efflux from ABCA1-transfected HEK293 cells was unchanged in mutant versus wild-type apoA-I, though, which suggests that cholesterol efflux and nHDL particle formation might be uncoupled events. Analysis of the particles in the efflux media revealed a population of apoA-I free lipid particles along with nHDL. This model improves knowledge of nHDL formation for future research. PMID- 30249789 TI - A53T Mutant Alpha-Synuclein Induces Tau-Dependent Postsynaptic Impairment Independently of Neurodegenerative Changes. AB - Abnormalities in alpha-synuclein are implicated in the pathogenesis of Parkinson's disease (PD). Because alpha-synuclein is highly concentrated within presynaptic terminals, presynaptic dysfunction has been proposed as a potential pathogenic mechanism. Here, we report novel, tau-dependent, postsynaptic deficits caused by A53T mutant alpha-synuclein, which is linked to familial PD. We analyzed synaptic activity in hippocampal slices and cultured hippocampal neurons from transgenic mice of either sex expressing human WT, A53T, and A30P alpha synuclein. Increased alpha-synuclein expression leads to decreased spontaneous synaptic vesicle release regardless of genotype. However, only those neurons expressing A53T alpha-synuclein exhibit postsynaptic dysfunction, including decreased miniature postsynaptic current amplitude and decreased AMPA to NMDA receptor current ratio. We also found that long-term potentiation and spatial learning were impaired by A53T alpha-synuclein expression. Mechanistically, postsynaptic dysfunction requires glycogen synthase kinase 3beta-mediated tau phosphorylation, tau mislocalization to dendritic spines, and calcineurin dependent AMPA receptor internalization. Previous studies reveal that human A53T alpha-synuclein has a high aggregation potential, which may explain the mutation's unique capacity to induce postsynaptic deficits. However, patients with sporadic PD with severe tau pathology are also more likely to have early onset cognitive decline. Our results here show a novel, functional role for tau: mediating the effects of alpha-synuclein on postsynaptic signaling. Therefore, the unraveled tau-mediated signaling cascade may contribute to the pathogenesis of dementia in A53T alpha-synuclein-linked familial PD cases, as well as some subgroups of PD cases with extensive tau pathology.SIGNIFICANCE STATEMENT Here, we report mutation-specific postsynaptic deficits that are caused by A53T mutant alpha-synuclein, which is linked to familial Parkinson's disease (PD). The overexpression of WT, A53T, or A30P human alpha-synuclein leads to decreased spontaneous synaptic vesicle release. However, only those neurons expressing A53T alpha-synuclein exhibit tau phosphorylation-dependent postsynaptic dysfunction, which is characterized by decreased miniature postsynaptic current amplitude and decreased AMPA to NMDA receptor current ratio. The mutation-specific postsynaptic effects caused by human A53T alpha-synuclein will help us better understand the neurobiological basis of this specific form of familial PD. The differential effects of exogenous human WT, A53T, A30P, and E46K alpha-synuclein on glutamatergic synaptic responses will help to explain the clinical heterogeneity of sporadic and familial PD. PMID- 30249791 TI - Inhibitory Connectivity Dominates the Fan Cell Network in Layer II of Lateral Entorhinal Cortex. AB - Fan cells in layer II of the lateral entorhinal cortex (LEC) form a main component of the projection to the dentate gyrus, CA3 and CA2 of the hippocampal formation. This projection has a counterpart originating from stellate cells in layer II of the medial entorhinal cortex (MEC). Available evidence suggests that the two pathways carry different information, exemplified by a difference in spatial tuning of cells in LEC and MEC. The grid cell, a prominent position modulated cell type present in MEC, has been postulated to derive its characteristic hexagonal firing pattern from dominant disynaptic inhibitory connections between hippocampal-projecting stellate cells. Given that grid cells have not been described in LEC, we aim to describe the local synaptic connectivity of fan cells, to explore whether the network architecture is similar to that of the MEC stellate cell. Using a combination of in vitro multicell electrophysiological and optogenetic approaches in acute slices from rodents of either sex, we show that excitatory connectivity between fan cells is very sparse. Fan cells connect preferentially with two distinct types of inhibitory interneurons, suggesting disynaptic inhibitory coupling as the main form of communication among fan cells. These principles are similar to those reported for stellate cells in MEC, indicating an overall comparable local circuit architecture of the main hippocampal-projecting cell types in the lateral and medial entorhinal cortex.SIGNIFICANCE STATEMENT Our data provide the first description of the synaptic microcircuit of hippocampal-projecting layer II cells in the lateral entorhinal cortex. We show that these cells make infrequent monosynaptic connections with each other, and that they preferentially communicate through a disynaptic inhibitory network. This is similar to the microcircuit of hippocampal-projecting stellate cells in layer II of the medial entorhinal cortex, but dissimilar to the connectivity observed in layer 2 of neocortex. In medial entorhinal cortex, the observed network structure has been proposed to underlie the firing pattern of grid cells. This opens the possibility that layer II cells in lateral entorhinal cortex exhibit regular firing patterns in an unexplored domain. PMID- 30249790 TI - Representation of Real-World Event Schemas during Narrative Perception. AB - Understanding movies and stories requires maintaining a high-level situation model that abstracts away from perceptual details to describe the location, characters, actions, and causal relationships of the currently unfolding event. These models are built not only from information present in the current narrative, but also from prior knowledge about schematic event scripts, which describe typical event sequences encountered throughout a lifetime. We analyzed fMRI data from 44 human subjects (male and female) presented with 16 three-minute stories, consisting of four schematic events drawn from two different scripts (eating at a restaurant or going through the airport). Aside from this shared script structure, the stories varied widely in terms of their characters and storylines, and were presented in two highly dissimilar formats (audiovisual clips or spoken narration). One group was presented with the stories in an intact temporal sequence, while a separate control group was presented with the same events in scrambled order. Regions including the posterior medial cortex, medial prefrontal cortex (mPFC), and superior frontal gyrus exhibited schematic event patterns that generalized across stories, subjects, and modalities. Patterns in mPFC were also sensitive to overall script structure, with temporally scrambled events evoking weaker schematic representations. Using a Hidden Markov Model, patterns in these regions predicted the script (restaurant vs airport) of unlabeled data with high accuracy and were used to temporally align multiple stories with a shared script. These results extend work on the perception of controlled, artificial schemas in human and animal experiments to naturalistic perception of complex narratives.SIGNIFICANCE STATEMENT In almost all situations we encounter in our daily lives, we are able to draw on our schematic knowledge about what typically happens in the world to better perceive and mentally represent our ongoing experiences. In contrast to previous studies that investigated schematic cognition using simple, artificial associations, we measured brain activity from subjects watching movies and listening to stories depicting restaurant or airport experiences. Our results reveal a network of brain regions that is sensitive to the shared temporal structure of these naturalistic situations. These regions abstract away from the particular details of each story, activating a representation of the general type of situation being perceived. PMID- 30249794 TI - Neural Classifiers with Limited Connectivity and Recurrent Readouts. AB - For many neural network models in which neurons are trained to classify inputs like perceptrons, the number of inputs that can be classified is limited by the connectivity of each neuron, even when the total number of neurons is very large. This poses the problem of how the biological brain can take advantage of its huge number of neurons given that the connectivity is sparse. One solution is to combine multiple perceptrons together, as in committee machines. The number of classifiable random patterns would then grow linearly with the number of perceptrons, even when each perceptron has limited connectivity. However, the problem is moved to the downstream readout neurons, which would need a number of connections as large as the number of perceptrons. Here we propose a different approach in which the readout is implemented by connecting multiple perceptrons in a recurrent attractor neural network. We prove analytically that the number of classifiable random patterns can grow unboundedly with the number of perceptrons, even when the connectivity of each perceptron remains finite. Most importantly, both the recurrent connectivity and the connectivity of downstream readouts also remain finite. Our study shows that feedforward neural classifiers with numerous long-range afferent connections can be replaced by recurrent networks with sparse long-range connectivity without sacrificing the classification performance. Our strategy could be used to design more general scalable network architectures with limited connectivity, which resemble more closely the brain neural circuits that are dominated by recurrent connectivity.SIGNIFICANCE STATEMENT The mammalian brain has a huge number of neurons, but the connectivity is rather sparse. This observation seems to contrast with the theoretical studies showing that for many neural network models the performance scales with the number of connections per neuron and not with the total number of neurons. To solve this dilemma, we propose a model in which a recurrent network reads out multiple neural classifiers. Its performance scales with the total number of neurons even when each neuron of the network has limited connectivity. Our study reveals an important role of recurrent connections in neural systems like the hippocampus, in which the computational limitations due to sparse long-range feedforward connectivity might be compensated by local recurrent connections. PMID- 30249793 TI - Regulation of the Natriuretic Peptide Receptor 2 (Npr2) by Phosphorylation of Juxtamembrane Serine and Threonine Residues Is Essential for Bifurcation of Sensory Axons. AB - cGMP signaling elicited by activation of the transmembrane receptor guanylyl cyclase Npr2 (also known as guanylyl cyclase B) by the ligand CNP controls sensory axon bifurcation of DRG and cranial sensory ganglion (CSG) neurons entering the spinal cord or hindbrain, respectively. Previous studies have shown that Npr2 is phosphorylated on serine and threonine residues in its kinase homology domain (KHD). However, it is unknown whether phosphorylation of Npr2 is essential for axon bifurcation. Here, we generated a knock-in mouse line in which the seven regulatory serine and threonine residues in the KHD of Npr2 were substituted by alanine (Npr2-7A), resulting in a nonphosphorylatable enzyme. Real time imaging of cGMP in DRG neurons with a genetically encoded fluorescent cGMP sensor or biochemical analysis of guanylyl cyclase activity in brain or lung tissue revealed the absence of CNP-induced cGMP generation in the Npr27A/7A mutant. Consequently, bifurcation of axons, but not collateral formation, from DRG or CSG in this mouse mutant was perturbed at embryonic and mature stages. In contrast, axon branching was normal in a mouse mutant in which constitutive phosphorylation of Npr2 is mimicked by a replacement of all of the seven serine and threonine sites by glutamic acid (Npr2-7E). Furthermore, we demonstrate that the Npr27A/7A mutation causes dwarfism as described for global Npr2 mutants. In conclusion, our in vivo studies provide strong evidence that phosphorylation of the seven serine and threonine residues in the KHD of Npr2 is an important regulatory element of Npr2-mediated cGMP signaling which affects physiological processes, such as axon bifurcation and bone growth.SIGNIFICANCE STATEMENT The branching of axons is a morphological hallmark of virtually all neurons. It allows an individual neuron to innervate different targets and to communicate with neurons located in different regions of the nervous system. The natriuretic peptide receptor 2 (Npr2), a transmembrane guanylyl cyclase, is essential for the initiation of bifurcation of sensory axons when entering the spinal cord or the hindbrain. By using two genetically engineered mouse lines, we show that phosphorylation of specific serine and threonine residues in juxtamembrane regions of Npr2 are required for its enzymatic activity and for axon bifurcation. These investigations might help to understand the regulation of Npr2 and its integration in intracellular signaling systems. PMID- 30249792 TI - A Druggable Genome Screen Identifies Modifiers of alpha-Synuclein Levels via a Tiered Cross-Species Validation Approach. AB - Accumulation of alpha-Synuclein (alpha-Syn) causes Parkinson's disease (PD) as well as other synucleopathies. alpha-Syn is the major component of Lewy bodies and Lewy neurites, the proteinaceous aggregates that are a hallmark of sporadic PD. In familial forms of PD, mutations or copy number variations in SNCA (the alpha-Syn gene) result in a net increase of its protein levels. Furthermore, common risk variants tied to PD are associated with small increases of wild-type alpha-Syn levels. These findings are further bolstered by animal studies which show that overexpression of alpha-Syn is sufficient to cause PD-like features. Thus, increased alpha-Syn levels are intrinsically tied to PD pathogenesis and underscore the importance of identifying the factors that regulate its levels. In this study, we establish a pooled RNAi screening approach and validation pipeline to probe the druggable genome for modifiers of alpha-Syn levels and identify 60 promising targets. Using a cross-species, tiered validation approach, we validate six strong candidates that modulate alpha-Syn levels and toxicity in cell lines, Drosophila, human neurons, and mouse brain of both sexes. More broadly, this genetic strategy and validation pipeline can be applied for the identification of therapeutic targets for disorders driven by dosage-sensitive proteins.SIGNIFICANCE STATEMENT We present a research strategy for the systematic identification and validation of genes modulating the levels of alpha-Synuclein, a protein involved in Parkinson's disease. A cell-based screen of the druggable genome (>7,500 genes that are potential therapeutic targets) yielded many modulators of alpha-Synuclein that were subsequently confirmed and validated in Drosophila, human neurons, and mouse brain. This approach has broad applicability to the multitude of neurological diseases that are caused by mutations in genes whose dosage is critical for brain function. PMID- 30249795 TI - Pathway-Specific Asymmetries between ON and OFF Visual Signals. AB - Visual processing is largely organized into ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways exhibit natural pairings based on morphological and physiological similarities, such as ON and OFF alpha-ganglion cells in the mammalian retina. Several studies have noted asymmetries in the properties of ON and OFF pathways. For example, the spatial receptive fields (RFs) of OFF alpha-cells are systematically smaller than ON alpha-cells. Analysis of natural scenes suggests that these asymmetries are optimal for visual encoding. To test the generality of ON/OFF asymmetries, we measured the spatiotemporal RF properties of multiple RGC types in rat retina. Through a quantitative and serial classification, we identified three functional pairs of ON and OFF RGCs. We analyzed the structure of their RFs and compared spatial integration, temporal integration, and gain across ON and OFF pairs. Similar to previous results from the cat and primate, RGC types with larger spatial RFs exhibited briefer temporal integration and higher gain. However, each pair of ON and OFF RGC types exhibited distinct asymmetric relationships between RF properties, some of which were opposite to the findings of previous reports. These results reveal the functional organization of six RGC types in the rodent retina and indicate that ON/OFF asymmetries are pathway specific.SIGNIFICANCE STATEMENT Circuits that process sensory input frequently process increments separately from decrements, so-called ON and OFF responses. Theoretical studies indicate that this separation, and associated asymmetries in ON and OFF pathways, may be beneficial for encoding natural stimuli. However, the generality of ON and OFF pathway asymmetries has not been tested. Here we compare the functional properties of three distinct pairs of ON and OFF pathways in the rodent retina and show that their asymmetries are pathway specific. These results provide a new view on the partitioning of vision across diverse ON and OFF signaling pathways. PMID- 30249797 TI - The Subprimary Range of Firing Is Present in Both Cat and Mouse Spinal Motoneurons and Its Relationship to Force Development Is Similar for the Two Species. AB - In the motor system, force gradation is achieved by recruitment of motoneurons and rate modulation of their firing frequency. Classical experiments investigating the relationship between injected current to the soma during intracellular recording and the firing frequency (the I-f relation) in cat spinal motoneurons identified two clear ranges: a primary range and a secondary range. Recent work in mice, however, has identified an additional range proposed to be exclusive to rodents, the subprimary range (SPR), due to the presence of mixed mode oscillations of the membrane potential. Surprisingly, fully summated tetanic contractions occurred in mice during SPR frequencies. With the mouse now one of the most popular models to investigate motor control, it is crucial that such discrepancies between observations in mice and basic principles that have been widely accepted in larger animals are resolved. To do this, we have reinvestigated the I-f relation using ramp current injections in spinal motoneurons in both barbiturate-anesthetized and decerebrate (nonanesthetized) cats and mice. We demonstrate the presence of the SPR and mixed mode oscillations in both species and show that the SPR is enhanced by barbiturate anesthetics. Our measurements of the I-f relation in both cats and mice support the classical opinion that firing frequencies in the higher end of the primary range are necessary to obtain a full summation. By systematically varying the leg oil pool temperature (from 37 degrees C to room temperature), we found that only at lower temperatures can maximal summation occur at SPR frequencies due to prolongation of individual muscle twitches.SIGNIFICANCE STATEMENT This work investigates recent revelations that mouse motoneurons behave in a fundamentally different way from motoneurons of larger animals with respect to the importance of rate modulation of motoneuron firing for force gradation. The current study systematically addresses the proposed discrepancies between mice and larger species (cats) and demonstrates that mouse motoneurons, in fact, use rate modulation as a mechanism of force modulation in a similar manner to the classical descriptions in larger animals. PMID- 30249796 TI - Parkinson's Disease-Linked LRRK2-G2019S Mutation Alters Synaptic Plasticity and Promotes Resilience to Chronic Social Stress in Young Adulthood. AB - The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a prevalent cause of late-onset Parkinson's disease, producing psychiatric and motor symptoms, including depression, that are indistinguishable from sporadic cases. Here we tested how this mutation impacts depression-related behaviors and associated synaptic responses and plasticity in mice expressing a Lrrk2-G2019S knock-in mutation. Young adult male G2019S knock-in and wild-type mice were subjected to chronic social defeat stress (CSDS), a validated depression model, and other tests of anhedonia, anxiety, and motor learning. We found that G2019S mice were highly resilient to CSDS, failing to exhibit social avoidance compared to wild type mice, many of which exhibited prominent social avoidance and were thus susceptible to CSDS. In the absence of CSDS, no behavioral differences between genotypes were found. Whole-cell recordings of spiny projection neurons (SPNs) in the nucleus accumbens revealed that glutamatergic synapses in G2019S mice lacked functional calcium-permeable AMPARs, and following CSDS, failed to accumulate inwardly rectifying AMPAR responses characteristic of susceptible mice. Based on this abnormal AMPAR response profile, we asked whether long-term potentiation (LTP) of corticostriatal synaptic strength was affected. We found that both D1 receptor (D1R)- and D2R-SPNs in G2019S mutants were unable to express LTP, with D2R-SPNs abnormally expressing long-term depression following an LTP-induction protocol. Thus, G2019S promotes resilience to chronic social stress in young adulthood, likely reflecting synapses constrained in their ability to undergo experience-dependent plasticity. These unexpected findings may indicate early adaptive coping mechanisms imparted by the G2019S mutation.SIGNIFICANCE STATEMENT The G2019S mutation in LRRK2 causes late-onset Parkinson's disease (PD). LRRK2 is highly expressed in striatal neurons throughout life, but it is unclear how mutant LRRK2 affects striatal neuron function and behaviors in young adulthood. We addressed this question using Lrrk2-G2019S knock-in mice. The data show that young adult G2019S mice were unusually resilient to a depression-like syndrome resulting from chronic social stress. Further, mutant striatal synapses were incapable of forms of synaptic plasticity normally accompanying depression-like behavior and important for supporting the full range of cognitive function. These data suggest that in humans, LRRK2 mutation may affect striatal circuit function in ways that alter normal responses to stress and could be relevant for treatment strategies for non-motor PD symptoms. PMID- 30249798 TI - A Dual Noradrenergic Mechanism for the Relief of Neuropathic Allodynia by the Antidepressant Drugs Duloxetine and Amitriptyline. AB - In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. Despite the widespread use of these drugs, the mechanism underlying their therapeutic action in this pain context remains partly elusive. The present study combined data collected in male and female mice from a model of neuropathic pain and data from the clinical setting to understand how antidepressant drugs act. We show two distinct mechanisms by which the selective inhibitor of serotonin and noradrenaline reuptake duloxetine and the tricyclic antidepressant amitriptyline relieve neuropathic allodynia. One of these mechanisms is acute, central, and requires descending noradrenergic inhibitory controls and alpha2A adrenoceptors, as well as the mu and delta opioid receptors. The second mechanism is delayed, peripheral, and requires noradrenaline from peripheral sympathetic endings and beta2 adrenoceptors, as well as the delta opioid receptors. We then conducted a transcriptomic analysis in dorsal root ganglia, which suggested that the peripheral component of duloxetine action involves the inhibition of neuroimmune mechanisms accompanying nerve injury, including the downregulation of the TNF-alpha-NF-kappaB signaling pathway. Accordingly, immunotherapies against either TNF-alpha or Toll-like receptor 2 (TLR2) provided allodynia relief. We also compared duloxetine plasma levels in the animal model and in patients and we observed that patients' drug concentrations were compatible with those measured in animals under chronic treatment involving the peripheral mechanism. Our study highlights a peripheral neuroimmune component of antidepressant drugs that is relevant to their delayed therapeutic action against neuropathic pain.SIGNIFICANCE STATEMENT In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. However, the mechanism by which antidepressant drugs can relieve neuropathic pain remained in part elusive. Indeed, preclinical studies led to contradictions concerning the anatomical and molecular substrates of this action. In the present work, we overcame these apparent contradictions by highlighting the existence of two independent mechanisms. One is rapid and centrally mediated by descending controls from the brain to the spinal cord and the other is delayed, peripheral, and relies on the anti-neuroimmune action of chronic antidepressant treatment. PMID- 30249801 TI - Unique Mapping of Structural and Functional Connectivity on Cognition. AB - The unique mapping of structural brain connectivity (SC) and functional brain connectivity (FC) on cognition is currently not well understood. It is not clear whether cognition is mapped via a global connectome pattern or instead is underpinned by several sets of distributed connectivity patterns. Moreover, we also do not know whether the spatial distributions of SC and FC that underlie cognition are overlapping or distinct. Here, we study the relationship between SC and FC and an array of psychological tasks in 609 subjects (males, 269; females, 340) from the Human Connectome Project. We identified several sets of connections that each uniquely map onto cognitive function. We found a small number of distributed SCs and a larger set of corticocortical and corticosubcortical FCs that express this association. Importantly, the SC and FC each show unique and distinct patterns of variance across subjects as they relate to cognition. The results suggest that a complete understanding of connectome underpinnings of cognition calls for a combination of the two modalities.SIGNIFICANCE STATEMENT Structural connectivity (SC), the physical white-matter inter-regional pathways in the brain, and functional connectivity (FC), the temporal coactivations between the activity of the brain regions, have each been studied extensively. Little is known, however, about the distribution of variance in connections as they relate to cognition. Here, in a large sample of subjects (N = 609), we showed that two sets of brain-behavior patterns capture the correlations between SC and FC with a wide range of cognitive tasks, respectively. These brain behavior patterns reveal distinct sets of connections within the SC and the FC network and provide new evidence that SC and FC each provide unique information for cognition. PMID- 30249800 TI - The Avian Basal Ganglia Are a Source of Rapid Behavioral Variation That Enables Vocal Motor Exploration. AB - The basal ganglia (BG) participate in aspects of reinforcement learning that require evaluation and selection of motor programs associated with improved performance. However, whether the BG additionally contribute to behavioral variation ("motor exploration") that forms the substrate for such learning remains unclear. In songbirds, a tractable system for studying BG-dependent skill learning, a role for the BG in generating exploratory variability, has been challenged by the finding that lesions of Area X, the song-specific component of the BG, have no lasting effects on several forms of vocal variability that have been studied. Here we demonstrate that lesions of Area X in adult male zebra finches (Taeniopygia gutatta) permanently eliminate rapid within-syllable variation in fundamental frequency (FF), which can act as motor exploration to enable reinforcement-driven song learning. In addition, we found that this within syllable variation is elevated in juveniles and in adults singing alone, conditions that have been linked to enhanced song plasticity and elevated neural variability in Area X. Consistent with a model that variability is relayed from Area X, via its cortical target, the lateral magnocellular nucleus of the anterior nidopallium (LMAN), to influence song motor circuitry, we found that lesions of LMAN also eliminate within-syllable variability. Moreover, we found that electrical perturbation of LMAN can drive fluctuations in FF that mimic naturally occurring within-syllable variability. Together, these results demonstrate that the BG are a central source of rapid behavioral variation that can serve as motor exploration for vocal learning.SIGNIFICANCE STATEMENT Many complex motor skills, such as speech, are not innately programmed but are learned gradually through trial and error. Learning involves generating exploratory variability in action ("motor exploration") and evaluating subsequent performance to acquire motor programs that lead to improved performance. Although it is well established that the basal ganglia (BG) process signals relating to action evaluation and selection, whether and how the BG promote exploratory motor variability remain unclear. We investigated this question in songbirds, which learn to produce complex vocalizations through trial and error. In contrast with previous studies that did not find effects of BG lesions on vocal motor variability, we demonstrate that the BG are an essential source of rapid behavioral variation linked to vocal learning. PMID- 30249802 TI - Interactive Repression of MYRF Self-Cleavage and Activity in Oligodendrocyte Differentiation by TMEM98 Protein. AB - Myelin sheath formed by oligodendrocytes (OLs) is essential for the rapid propagation of action potentials in the vertebrate CNS. Myelin regulatory factor (MYRF) is one of the critical factors that control OL differentiation and myelin maintenance. Previous studies showed that MYRF is a membrane-bound transcription factor associated with the endoplasmic reticulum (ER). After self-cleavage, the N fragment of MYRF is released from the ER and translocated into the nucleus where it functions as a transcription factor to activate myelin gene expression. At present, it remains unknown whether MYRF self-cleavage and functional activation can be regulated during OL differentiation. Here, we report that TMEM98, an ER associated transmembrane protein, is capable of binding to the C-terminal of MYRF and inhibiting its self-cleavage and N-fragment nuclear translocation. In the developing CNS, TMEM98 is selectively expressed in early maturing OLs in mouse pups of either sex. Forced expression of TMEM98 in embryonic chicken spinal cord of either sex suppresses endogenous OL differentiation and MYRF-induced ectopic expression of myelin genes. These results suggest that TMEM98, through inhibiting the self-cleavage of MYRF, functions as a negative feedback regulator of MYRF in oligodendrocyte differentiation and myelination.SIGNIFICANCE STATEMENT MYRF protein is initially synthesized as an ER-associated membrane protein that undergoes autoproteolytic cleavage to release the N-fragment, which is then transported into the nucleus and activates the transcription of myelin genes. To date, the molecular mechanisms that regulate the self-cleavage and function of MYRF in regulating oligodendrocyte differentiation have remained unknown. In this study, we present the molecular and functional evidence that TMEM98 membrane protein physically interacts with MYRF in the ER and subsequently blocks its self cleavage, N-terminal nuclear translocation, and functional activation of myelin gene expression. To our knowledge, this is the first report on the regulation of MYRF self-proteolytic activity and function by an interacting protein, providing new insights into the molecular regulation of OL differentiation and myelinogenesis. PMID- 30249803 TI - The Motor Network Reduces Multisensory Illusory Perception. AB - Observing mouth movements has strikingly effects on the perception of speech. Any mismatch between sound and mouth movements will result in listeners perceiving illusory consonants (McGurk effect), whereas matching mouth movements assist with the correct recognition of speech sounds. Recent neuroimaging studies have yielded evidence that the motor areas are involved in speech processing, yet their contributions to multisensory illusion remain unclear. Using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) in an event-related design, we aimed to identify the functional roles of the motor network in the occurrence of multisensory illusion in female and male brains. fMRI showed bilateral activation of the inferior frontal gyrus (IFG) in audiovisually incongruent trials. Activity in the left IFG was negatively correlated with occurrence of the McGurk effect. The effective connectivity between the left IFG and the bilateral precentral gyri was stronger in incongruent than in congruent trials. The McGurk effect was reduced in incongruent trials by applying single-pulse TMS to motor cortex (M1) lip areas, indicating that TMS facilitates the left IFG-precentral motor network to reduce the McGurk effect. TMS of the M1 lip areas was effective in reducing the McGurk effect within the specific temporal range from 100 ms before to 200 ms after the auditory onset, and TMS of the M1 foot area did not influence the McGurk effect, suggesting topographical specificity. These results provide direct evidence that the motor network makes specific temporal and topographical contributions to the processing of multisensory integration of speech to avoid illusion.SIGNIFICANCE STATEMENT The human motor network, including the inferior frontal gyrus and primary motor cortex lip area, appears to be involved in speech perception, but the functional contribution to the McGurk effect is unknown. Functional magnetic resonance imaging revealed that activity in these areas of the motor network increased when the audiovisual stimuli were incongruent, and that the increased activity was negatively correlated with perception of the McGurk effect. Furthermore, applying transcranial magnetic stimulation to the motor areas reduced the McGurk effect. These two observations provide evidence that the motor network contributes to the avoidance of multisensory illusory perception. PMID- 30249804 TI - Opposite Roles in Short-Term Plasticity for N-Type and P/Q-Type Voltage-Dependent Calcium Channels in GABAergic Neuronal Connections in the Rat Cerebral Cortex. AB - Neurotransmitter release is triggered by Ca2+ influx through voltage-dependent Ca2+ channels (VDCCs). Distinct expression patterns of VDCC subtypes localized on the synaptic terminal affect intracellular Ca2+ dynamics induced by action potential-triggered Ca2+ influx. However, it has been unknown whether the expression pattern of VDCC subtypes depends on each axon terminal or neuronal subtype. Furthermore, little information is available on how these VDCC subtypes regulate the release probability of neurotransmitters. To address these questions, we performed multiple whole-cell patch-clamp recordings from GABAergic neurons in the insular cortex of either the male or the female rat. The paired pulse ratio (PPR; 50 ms interstimulus interval) varied widely among inhibitory connections between GABAergic neurons. The PPR of unitary IPSCs was enhanced by omega-conotoxin GVIA (CgTx; 3 MUm), an N-type VDCC blocker, whereas blockade of P/Q-type VDCCs by omega-agatoxin IVA (AgTx, 200 nm) decreased the PPR. In the presence of CgTx, application of 4 mm [Ca2+]o or of roscovitine, a P/Q-type activator, increased the PPR. These results suggest that the recruitment of P/Q type VDCCs increases the PPR, whereas N-type VDCCs suppress the PPR. Furthermore, we found that charybdotoxin or apamin, blockers of Ca2+-dependent K+ channels, with AgTx increased the PPR, suggesting that Ca2+-dependent K+ channels are coupled to N-type VDCCs and suppress the PPR in GABAergic neuronal terminals. Variance-mean analysis with changing [Ca2+]o showed a negative correlation between the PPR and release probability in GABAergic synapses. These results suggest that GABAergic neurons differentially express N-type and/or P/Q-type VDCCs and that these VDCCs regulate the GABA release probability in distinct manners.SIGNIFICANCE STATEMENT GABAergic neuronal axons target multiple neurons and release GABA triggered by Ca2+ influx via voltage-dependent Ca2+ channels (VDCCs), including N-type and P/Q-type channels. Little is known about VDCC expression patterns in GABAergic synaptic terminals and their role in short-term plasticity. We focused on inhibitory synaptic connections between GABAergic neurons in the cerebral cortex using multiple whole-cell patch-clamp recordings and found different expression patterns of VDCCs in the synaptic terminals branched from a single presynaptic neuron. Furthermore, we observed facilitative and depressive short-term plasticity of IPSCs mediated by P/Q-type and N-type VDCCs, respectively. These results suggest that VDCC expression patterns regulate distinctive types of synaptic transmission in each GABAergic axon terminal even though they are branched from a common presynaptic neuron. PMID- 30249799 TI - Specificity of Primate Amygdalar Pathways to Hippocampus. AB - The amygdala projects to hippocampus in pathways through which affective or social stimuli may influence learning and memory. We investigated the still unknown amygdalar termination patterns and their postsynaptic targets in hippocampus from system to synapse in rhesus monkeys of both sexes. The amygdala robustly innervated the stratum lacunosum-moleculare layer of cornu ammonis fields and uncus anteriorly. Sparser terminations in posterior hippocampus innervated the radiatum and pyramidal layers at the prosubicular/CA1 juncture. The terminations, which were larger than other afferents in the surrounding neuropil, position the amygdala to influence hippocampal input anteriorly, and its output posteriorly. Most amygdalar boutons (76-80%) innervated spines of excitatory hippocampal neurons, and most of the remaining innervated presumed inhibitory neurons, identified by morphology and label with parvalbumin or calretinin, which distinguished nonoverlapping neurochemical classes of hippocampal inhibitory neurons. In CA1, amygdalar axons innervated some calretinin neurons, which disinhibit pyramidal neurons. By contrast, in CA3 the amygdala innervated both calretinin and parvalbumin neurons; the latter strongly inhibit nearby excitatory neurons. In CA3, amygdalar pathways also made closely spaced dual synapses on excitatory neurons. The strong excitatory synapses in CA3 may facilitate affective context representations and trigger sharp-wave ripples associated with memory consolidation. When the amygdala is excessively activated during traumatic events, the specialized innervation of excitatory neurons and the powerful parvalbumin inhibitory neurons in CA3 may allow the suppression of activity of nearby neurons that receive weaker nonamygdalar input, leading to biased passage of highly charged affective stimuli and generalized fear.SIGNIFICANCE STATEMENT Strong pathways from the amygdala targeted the anterior hippocampus, and more weakly its posterior sectors, positioned to influence a variety of emotional and cognitive functions. In hippocampal field CA1, the amygdala innervated some calretinin neurons, which disinhibit excitatory neurons. By contrast, in CA3 the amygdala innervated calretinin as well as some of the powerful parvalbumin inhibitory neurons and may help balance the activity of neural ensembles to allow social interactions, learning, and memory. These results suggest that when the amygdala is hyperactive during emotional upheaval, it strongly activates excitatory hippocampal neurons and parvalbumin inhibitory neurons in CA3, which can suppress nearby neurons that receive weaker input from other sources, biasing the passage of stimuli with high emotional import and leading to generalized fear. PMID- 30249806 TI - NHS makes good progress on sustainability, report shows. PMID- 30249805 TI - Nature and Nurture: Brain Region-Specific Inheritance of Sleep Neurophysiology in Adolescence. AB - Sleep-specific oscillations of spindles and slow waves are generated through thalamocortical and corticocortical loops, respectively, and provide a unique opportunity to measure the integrity of these neuronal systems. Understanding the relative contribution of genetic factors to sleep oscillations is important for determining whether they constitute useful endophenotypes that mark vulnerability to psychiatric illness. Using high-density sleep EEG recordings in human adolescent twin pairs (n = 60; 28 females), we find that over posterior regions 80-90% of the variance in slow oscillations, slow wave, and spindle activity is due to genes. Surprisingly, slow (10-12 Hz) and fast (12-16 Hz) anterior spindle amplitude and sigma power are largely driven by environmental factors shared among the twins. To our knowledge this is the first example of a neural phenotype that exhibits a strong influence of nature in one brain region, and nurture in another. Overall, our findings highlight the utility of the sleep EEG as a reliable and easy to measure endophenotype during adolescence. This measure may be used to measure disease risk in development before the onset of a psychiatric disorder; the location within the brain of deficits in sleep neurophysiology may suggest whether the ultimate cause is genetic or environmental.SIGNIFICANCE STATEMENT Two cardinal oscillations of sleep, slow waves and sleep spindles, play an important role in the core functions of sleep including memory consolidation, synaptic plasticity, and the recuperative function of sleep. In this study, we use a behavioral genetics approach to examine the heritability of sleep neurophysiology using high-density EEG in a sample of early adolescent twins. Our findings reveal a strong influence of both environmental and genetic factors in shaping these oscillations, dependent on brain region. Thus, during a developmental period when brain structure and function is in flux, we find that the sleep EEG is among the most heritable of human traits over circumscribed brain regions. PMID- 30249807 TI - High-Resolution Genetic and Phenotypic Analysis of KIR2DL1 Alleles and Their Association with Pre-Eclampsia. AB - Killer-cell Ig-like receptor (KIR) genes are inherited as haplotypes. They are expressed by NK cells and linked to outcomes of infectious diseases and pregnancy in humans. Understanding how genotype relates to phenotype is difficult because of the extensive diversity of the KIR family. Indeed, high-resolution KIR genotyping and phenotyping in single NK cells in the context of disease association is lacking. In this article, we describe a new method to separate NK cells expressing allotypes of the KIR2DL1 gene carried by the KIR A haplotype (KIR2DL1A) from those expressing KIR2DL1 alleles carried by the KIR B haplotype (KIR2DL1B). We find that in KIR AB heterozygous individuals, different KIR2DL1 allotypes can be detected in both peripheral blood and uterine NK cells. Using this new method, we demonstrate that both blood and uterine NK cells codominantly express KIR2DL1A and KIR2DL1B allotypes but with a predominance of KIR2DL1A variants, which associate with enhanced NK cell function. In a case-control study of pre-eclampsia, we show that KIR2DL1A, not KIR2DL1B, associates with increased disease risk. This method will facilitate our understanding of how individual KIR2DL1 allelic variants affect NK cell function and contribute to disease risk. PMID- 30249808 TI - Perforin-2 Breaches the Envelope of Phagocytosed Bacteria Allowing Antimicrobial Effectors Access to Intracellular Targets. AB - Perforin-2, the product of the MPEG1 gene, limits the spread and dissemination of bacterial pathogens in vivo. It is highly expressed in murine and human phagocytes, and macrophages lacking Perforin-2 are compromised in their ability to kill phagocytosed bacteria. In this study, we used Salmonella enterica serovar Typhimurium as a model intracellular pathogen to elucidate the mechanism of Perforin-2's bactericidal activity. In vitro Perforin-2 was found to facilitate the degradation of Ags contained within the envelope of phagocytosed bacteria. In contrast, degradation of a representative surface Ag was found to be independent of Perforin-2. Consistent with our in vitro results, a protease-sensitive, periplasmic superoxide dismutase (SodCII) contributed to the virulence of S. Typhimurium in Perforin-2 knockout but not wild-type mice. In aggregate, our studies indicate that Perforin-2 breaches the envelope of phagocytosed bacteria, facilitating the delivery of proteases and other antimicrobial effectors to sites within the bacterial cell. PMID- 30249810 TI - Augmentation of Human Monocyte Responses to Lipopolysaccharide by the Protein S and Mer/Tyro3 Receptor Tyrosine Kinase Axis. AB - Resolution of the inflammatory response requires coordinated regulation of pro- and anti-inflammatory mediator production, together with clearance of recruited inflammatory cells. Many different receptors have been implicated in phagocytosis of apoptotic cells (efferocytosis), including Mer, a receptor tyrosine kinase that can mediate recognition and subsequent internalization of apoptotic cells. In this manuscript, we examine the expression and function of the Tyro3/Axl/Mer (TAM) family of receptors by human monocytes. We demonstrate that the Mer ligand, protein S, binds to the surface of viable monocytes via phosphatidylserine dependent and -independent mechanisms. Importantly, we have identified a novel role for receptor tyrosine kinase signaling in the augmentation of monocyte cytokine release in response to LPS. We propose that low-level phosphatidylserine exposure on the plasma membrane of viable monocytes allows protein S binding that leads to TAM-dependent augmentation of proinflammatory cytokine production. Our findings identify a potentially important role for TAM-mediated signaling during the initiation phase of inflammation. PMID- 30249812 TI - In vitro evaluation of phytochemical loaded electrospun gelatin nanofibers for application in bone and cartilage tissue engineering. AB - Wattakaka volubilis, a medicinal plant, is known to exhibit various potential health benefits and has traditionally been used in Ayurveda for various medicinal applications. In the present study, phytochemicals hexadecanoic acid, octadecanoic acid and N,N-Diisopropyl(2,2,3,3,3-pentafluoropropyl)amine isolated from W. volubilis leaf extract were co-electrospun with gelatin nanofibers for meniscus and osteoblast cell attachment and proliferation. The electrospun nanofibers were characterized using suitable techniques such as a scanning electron microscope and Fourier transform infrared spectroscopy. The mechanical property of electrospun gelatin nanofibers and phytochemicals incorporated gelatin nanofibers were tensile tested. Both the control and phytochemical loaded nanofiber exhibited a similar stress-strain trend. The average diameter of the control and phytocompound loaded gelatin nanofiber was found to be 300 +/- 5.5 nm and 483 +/- 12 nm, respectively. The rate of biodegradation of the control and phytochemical loaded nanofiber was analyzed in a simulated body fluid. The cell attachment and proliferation were monitored using a fluorescence microscope after appropriate staining. The cell viability, DNA content, extracellular secretion confirmed that the phytocompound loaded gelatin nanofibers were non-toxic and enhanced the meniscus and osteoblast cell growth and proliferation. This phytocompound loaded gelatin matrix may be used as a potential scaffold for cartilage and bone tissue engineering applications. PMID- 30249813 TI - Multivessel coronary artery ectasia and severe calcification in a patient with pheochromocytoma: a case report. AB - Multivessel coronary artery ectasia with severe calcification is rare among patients with coronary artery disease. A 74-year-old Chinese woman suffered from acute myocardial infarction on a background of 50 years of poorly controlled hypertension secondary to pheochromocytoma, which was surgically removed in June 2012 prior to the presentation. Coronary angiography revealed total occlusion of the proximal left anterior descending artery, and multiple ectasias with severe calcification in the left main, circumflex and right coronary artery. After an aspiration thrombectomy and balloon angioplasty, grade 3 coronary flow was restored in the left descending coronary artery. No cardiac events were found in the 12-month follow-up. We conclude that multivessel coronary artery ectasia and severe calcification may be present in patients with a long-standing history of hypertension secondary to pheochromocytoma. PMID- 30249811 TI - Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy. AB - The combined inhibition of histone deacetylases (HDAC) and the proteins of the bromodomain and extraterminal (BET) family have recently shown therapeutic efficacy against melanoma, pancreatic ductal adenocarcinoma, testicular, and lymphoma cancers in murine studies. However, in such studies, the role of the immune system in therapeutically controlling these cancers has not been explored. We sought to investigate the effect of the HDAC inhibitor romidepsin (RMD) and the BET inhibitor IBET151, both singly and in combination, on vaccine-elicited immune responses. C57BL/6 mice were immunized with differing vaccine systems (adenoviral, protein) in prime-boost regimens under treatment with RMD, IBET151, or RMD+IBET151. The combined administration of RMD+IBET151 during vaccination resulted in a significant increase in the frequency and number of Ag-specific CD8+ T cells. RMD+IBET151 treatment significantly increased the frequency of vaccine-elicited IFN-gamma+ splenic CD8+ T cells and conferred superior therapeutic and prophylactic protection against B16-OVA melanoma. RNA sequencing analyses revealed strong transcriptional similarity between RMD+IBET151 and untreated Ag-specific CD8+ T cells except in apoptosis and IL-6 signaling-related genes that were differentially expressed. Serum IL-6 was significantly increased in vivo following RMD+IBET151 treatment, with recombinant IL-6 administration replicating the effect of RMD+IBET151 treatment on vaccine-elicited CD8+ T cell responses. IL-6 sufficiency for protection was not assessed. Combined HDAC and BET inhibition resulted in greater vaccine-elicited CD8+ T cell responses and enhanced therapeutic and prophylactic protection against B16-OVA melanoma. Increased IL-6 production and the differential expression of pro- and anti apoptotic genes following RMD+IBET151 treatment are likely contributors to the enhanced cancer vaccine responses. PMID- 30249809 TI - Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus. AB - We have produced Csf1r-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of Csf1r in macrophage differentiation, there was a loss of peripheral blood monocytes, microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice. Csf1r-/- rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development, organogenesis, and homeostasis. PMID- 30249814 TI - Computer-aided identification of protein targets of four polyphenols in Alzheimer's disease (AD) and validation in a mouse AD model. AB - Natural polyphenols are a large class of phytochemicals with neuroprotective effects. Four polyphenolic compounds: hesperidin, icariin, dihydromyricetin and baicalin were selected to evaluate their effects on Alzheimer's disease (AD). We analyzed by an inverse docking procedure (INVDOCK) the potential protein targets of these polyphenols within the KEGG AD pathway. Consequently, their therapeutic effects were evaluated and compared in a transgenic APP/PS1 mouse model of AD. These polyphenols were docked to several targets, including APP, BACE, PSEN, IDE, CASP, calpain and TNF-alpha, suggesting potential in vivo activities. Five month old transgenic mice were treated with these polyphenols. Icariin and hesperidin restored behavioral deficits and ameliorated Abeta deposits in both the cortex and hippocampus while baicalin and dihydromyricetin showed no substantial effects. Our findings suggest that hesperidin and icariin could be considered potential therapeutic candidates of human AD. PMID- 30249815 TI - A novel technique for sacropelvic fixation using image-guided sacroiliac screws: a case series and biomechanical study. AB - In this study, we sought to assess the safety and accuracy of sacropelvic fixation performed with image-guided sacroiliac screw placement using postoperative computed tomography and X-rays. The sacroiliac screws were placed with navigation in five patients. Intact specimens were mounted onto a six degrees-of-freedom spine motion simulator. Long lumbosacral constructs using bilateral sacroiliac screws and bilateral S1 pedicle and iliac screws were tested in seven cadaveric spines. Nine sacroiliac screws were well-placed under an image guidance system (IGS); one was placed poorly without IGS with no symptoms. Both fixation techniques significantly reduced range of motion (P<0.05) at L5-S1. The research concluded that rigid lumbosacral fixation can be achieved with sacroiliac screws, and image guidance improves its safety and accuracy. This new technique of image-guided sacroiliac screw insertion should prove useful in many types of fusion to the sacrum, particularly for patients with poor bone quality, complicated anatomy, infection, previous failed fusion and iliac harvesting. PMID- 30249816 TI - Association of serum lipids and severity of epithelial ovarian cancer: an observational cohort study of 349 Chinese patients. AB - While obesity and fat intake have been associated with the risk and prognosis of epithelial ovarian cancer, the association between the lipid levels and epithelial ovarian cancer phenotype remains controversial. We conducted a retrospective study of 349 epithelial ovarian cancer patients who received treatment at Jiangsu Cancer Hospital, China between 2011 and 2017. We analyzed age at diagnosis, blood pressure, plasma glucose content, body mass index (BMI), lipid levels and clinical parameters. Severity of epithelial ovarian cancer was classified according to the International Federation of Gynecology and Obstetrics (FIGO) grading system. Univariate analysis of the clinical factors according to the severity of epithelial ovarian cancer was followed by logistic regression analysis to identify clinical factors significantly associated with epithelial ovarian cancer severity. Univariate analysis indicated that age, BMI, triglyceride (TG), and high density lipoproteins (HDL) differed significantly among different stages of epithelial ovarian cancer (P<0.05). In the logistic regression model, elevated TG (OR: 1.883; 95% CI= 1.207-2.937), and low HDL (OR: 0.497; 95% CI= 0.298-0.829) levels were significantly associated with the high severity epithelial ovarian cancer. Our data indicate that high TG and low HDL levels correlate with a high severity of epithelial ovarian cancer. These data provide important insight into the potential relationship between the lipid pathway and epithelial ovarian cancer phenotype and development. PMID- 30249817 TI - Is Collaborative Ocular Melanoma Study (COMS) still relevant? PMID- 30249818 TI - Living Legend in Ophthalmology - Dr Bradley R Straatsma, MD, JD. PMID- 30249819 TI - Precision medicine and clinical ophthalmology. PMID- 30249820 TI - Tackling the cataract backlog - An initiative by the Maharashtra State, India. PMID- 30249821 TI - Conjunctival chemosis or not? PMID- 30249822 TI - Mortality after deferral of treatment or no treatment for choroidal melanoma. AB - Purpose: To report mortality of patients who were eligible for enrollment in the Collaborative Ocular Melanoma Study (COMS) clinical trials of medium-sized choroidal melanoma or large-sized choroidal melanoma but chose to defer treatment or receive no melanoma treatment. Design: Prospective nonrandomized multicenter cohort study as an adjunct to COMS randomized clinical trials. Methods: Patient follow-up procedures included examinations, correspondence, telephone contacts, and National Death Index searches. Primary outcome was patient death measured by all-cause mortality. Secondary outcomes were melanoma treatment and melanoma metastasis. Results: Of 77 patients eligible for COMS clinical trials who chose to defer or receive no melanoma treatment, 61 were appropriate candidates and 45 (74%) enrolled in the natural history study (NHS). In all, 42 patients (42 eyes) had medium melanoma, and the median follow-up was 5.3 years (range, 4-10.7 years). In all, 22 patients (52%) had subsequent melanoma treatment, and 20 (48%) had no melanoma treatment. For the 42 patients, Kaplan-Meier estimate of 5-year mortality was approximately 30% [95% confidence interval (CI), 18%-47%]. For COMS medium melanoma trial, 5-year mortality was 18% (95% CI, 16%-20%), not statistically significantly different from the NHS patients. After adjusting for differences in age and longest basal diameter, the 5-year risk of death for NHS patients versus COMS trial patients was 1.54 (95% CI, 0.93-2.56). Three patients had large melanoma. Melanoma metastasis was confirmed or suspected in 8 (42%) of 19 deaths. Conclusion: Greater mortality and higher risk of death for NHS patients are probative but not conclusive evidence of a beneficial, life extending effect of medium melanoma treatment. PMID- 30249824 TI - Association of the severity of meibomian gland dysfunction with dyslipidemia in Indian population. AB - Purpose: To correlate the severity of meibomian gland dysfunction (MGD) with the serum lipoprotein levels. Methods: The study was conducted as a prospective observational study over a period of 18 months. Ninety patients diagnosed with MGD were enrolled after they gave their informed consent according to the inclusion-exclusion criteria. Meibomian gland status was evaluated by meibum quality, expressibility, and numerical scoring. Lipid profile was done from an overnight fasting blood sample and evaluated for total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TGs). Results: Patients with higher stages of MGD more often had serum TGs >150 mg/dL, total cholesterol >200 mg/dL, an LDL >130 mg/dL, and serum HDL >40 mg/dL, and there exists an association between increasing stage of MGD, and age, female sex, and increasing values of all the lipid profile components. Conclusion: A very strong association exists between increasing age and increasing severity of stage of MGD. A positive association exists between female sex and increasing severity of stage of MGD. A positive association exists between increasing severity of MGD and increasing levels of all the components of lipid profiles, namely LDL, HDL, total cholesterol, and triglycerides. PMID- 30249823 TI - Cataract surgery in diabetes mellitus: A systematic review. AB - India is considered the diabetes capital of the world, and a significant proportion of patients undergoing cataract surgery are diabetic. Considering this, we reviewed the principles and guidelines of managing cataract in patients with diabetes. The preoperative, intraoperative, and postoperative factors are of paramount importance in the management of diabetic cataract patients. Particularly, the early recognition and treatment of diabetic retinopathy or maculopathy before cataract surgery influence the final visual outcome and play a major role in perioperative decision-making. Better understanding of various factors responsible for favorable outcome of cataract surgery in diabetic patients may guide us in better overalll management of these patients and optimizing the results. PMID- 30249825 TI - Comparative studies between longitudinal and torsional modes in phacoemulsification, using active fluidics technology along with the intrepid balanced tip. AB - Purpose: To compare and report the intra- and postoperative outcomes of phacoemulsification between longitudinal (LPKE) and torsional (TPKE) mode, using active fluidics along with the intrepid balanced tip. Methods: This single center prospective randomized comparative study comprised a total 108 consecutive eyes of 108 patients having senile cataract subdivided into nuclear opalescence (NO) grades II-IV according to the lens opacities classification system III (LOCS III). Cataracts of each grade were randomly assigned to two groups LPKE (n = 54) and TPKE (n = 54) mode, who were operated on by the same surgeon using same machine (Centurion(r) Alcon Laboratories, Inc., USA) having features of both active fluidics and intrepid balanced tip. Pre-, intra-, and postoperative evaluations were done independently by a different author, who was masked to the surgical procedures. Patients were evaluated on the postoperative days (PODs) 1, 7, 15, and 28. Intraoperative outcome measures were cumulative dissipated energy (CDE) and ultrasound time (UST). Postoperative outcome measures were endothelial cell loss (ECL), central corneal thickness (CCT), and best-corrected visual acuity (BCVA). Results: Age, gender, and NO-grade distribution among two modes were comparable (P > 0.05). Difference of CDE and UST between modes were found to be significant (P < 0.001) in favor of TPKE with all NO-grades. TPKE mode performs better than LPKE mode with regard to ECL, CCT-change, and BCVA-change, although the differences were found to be insignificant (P > 0.05). Conclusion: When using active fluidics along with the intrepid balanced tip, TPKE mode appeared to be a more efficient mode of PKE with reduced mean UST and CDE across all NO-grades, as compared to LPKE mode. However, ECL, CCT-change, and BCVA change were seemed to be comparable between the two modes. PMID- 30249826 TI - Comparative evaluation of two toric intraocular lenses for correcting astigmatism in patients undergoing phacoemulsification. AB - Purpose: To compare the efficacy of AT-TORBI plate haptic toric intraocular lens (IOL) (Carl Zeiss Meditec AG, Jena, Germany) and AcrySof loop haptic toric IOL (Alcon Laboratories, Inc., Fort Worth, TX, USA) for correcting preexisting astigmatism of >=1 diopters (D) in patients undergoing phacoemulsification and to compare the rotational stability of these two toric IOLs. Methods: In this prospective randomized controlled trial. Forty-two eyes of 42 cataract patients with preexisting astigmatism of 1 D or more were randomized to receive plate haptic toric (AT TORBI) or loop haptic toric (AcrySof) IOLs, with 21 in each group. Postoperative evaluation was done at day 1, 1 week, 1 month, and 3 months. Uncorrected distance visual acuity (UDVA), best corrected visual acuity (VA), and IOL position were noted in both the groups. Results: At 3 months postoperatively, the mean log MAR UDVA was 0.23 +/- 0.20 and 0.20 +/- 0.13 in Groups I and II, respectively (P = 0.7), the mean residual cylindrical refractive error in plate haptic toric group was 0.40 +/- 0.31 D and in loop haptic group was 0.45 +/- 0.33 D (P = 0.64). The mean IOL rotation at 3 months follow-up in plate haptic group was found to be 3.52 +/- 3.84 degrees and in loop haptic group was 2.05 +/- 2.56 degrees (P = 0.25). Conclusion: Both types of toric IOLs were equally efficacious for attaining good uncorrected VA and correcting preexisting astigmatism between 1-5 D. Both of them were rotationally stable at 3 months follow-up. PMID- 30249827 TI - Trabeculectomy with subconjunctival collagen implant in Indian eyes: Long-term results. AB - Purpose: To report long-term safety and efficacy of trabeculectomy with collagen implant in Indian population. Methods: All cases of trabeculectomy with Ologen(r) Collagen Matrix implant performed over a 7-year period from May 2008 through April 2015 at a tertiary referral institute were reviewed. A total of 30 eyes of 28 patients were included in the study with two patients undergoing bilateral trabeculectomy. Outcomes measured included intraocular pressure (IOP) control, number of antiglaucoma medications used, bleb morphology, and complications/reoperations. Results: Trabeculectomy resulted in reduction in IOP from 36.46 to 11.65 mm Hg in the immediate postoperative period (day 1), a 68% decrease to 15.18 mm Hg at 84 months (58% decrease). The mean IOP reduction decreased over time from 63% in the first year to 55% after 5 years of follow-up. Fourteen eyes attained a follow-up of 5 years and eight eyes a follow-up of >=7 years. No sight-threatening complication such as hypotony, bleb leak, and bleb related endophthalmitis was observed in our series, and only intervention required was 5-fluorouracil needling in one case. Conclusion: Ologen-augmented trabeculectomy is effective in controlling IOP over a long-term follow up from minimal 3 to maximal 7 years. No untoward events jeopardizing bleb safety were noted at any time. This modality is a viable alternative for patients with contraindications to use of antimetabolites. PMID- 30249828 TI - Role of hyperhomocysteinemia in proliferative diabetic retinopathy: A case control study. AB - Purpose: Hyperhomocysteinemia has been postulated as a potential risk factor for the development and progression of diabetic retinopathy. The aim of this study was to determine the association of hyperhomocysteinemia with proliferative diabetic retinopathy (PDR). Methods: This was a hospital-based, case-control study, conducted at a tertiary care ophthalmic center in South India. Thirty-nine patients with proliferative diabetic retinopathy were enrolled as cases, and 39 age- and gender-matched patients with no diabetic retinopathy (No DR) were enrolled as controls. Fasting serum homocysteine estimation, as well as baseline investigations, were done in all participants. Data regarding demographic profile and risk factors were documented. Data were analyzed using Chi-square test and independent t-test, as appropriate. Results: The prevalence of hyperhomocysteinemia was higher in PDR (59%) compared to "No DR" (48.7%); however, this difference was not statistically significant (P = 0.36). Similarly, the mean serum homocysteine level in cases was higher than in controls, but this was not statistically significant (17.98 + 6.26 MUmol/L vs. 17.71 + 8.17 MUmol/L; P = 0.87). Longer duration of diabetes, hypertension, anemia, and renal dysfunction were found to be significantly associated with PDR. Conclusion: The prevalence of hyperhomocysteinemia as well as the mean serum levels of homocysteine were found to be higher in the cases with PDR, compared to the controls with No DR, although the difference was not statistically significant. Longer duration of diabetes, hypertension, anemia, and renal dysfunction were significantly associated with PDR. PMID- 30249829 TI - Commentary: Role of hyperhomocysteinemia in proliferative diabetic retinopathy: A case-control study. PMID- 30249830 TI - An experimental study to evaluate safety/toxicity of intravitreal natalizumab. AB - Purpose: The purpose of this prospective experimental study was to evaluate the safety/toxicity of alpha4beta1 integrin blockade in rabbit retina using its monoclonal antibody (Natalizumab). Methods: Twelve New Zealand albino rabbits were divided into three groups (n = 4). Unilateral intravitreal injections of three different concentrations of natalizumab were performed in every rabbit of each group (Group A: 0.625 mg, Group B: 1.25 mg, and Group C: 2.5 mg). Baseline electroretinogram (ERG) and fundus photography were performed prior to injection. At days 1, 7, and 21 postinjection, ERG and fundus photography of each eye were performed. At last follow-up, Group C animals with highest drug concentration were sacrificed and the enucleated eyes were evaluated for retinal toxicity using transmission electron microscopy (TEM). Results: No difference in ERG responses was observed in eyes injected with low and intermediate concentration of natalizumab between day 0 and day 21. Furthermore, rabbits injected intravitreally with highest dose showed reduction in amplitude of "a" wave (P = 0.0017) and a reduction in amplitude of "b" wave of ERG at day 21 (P = 0.0117). TEM revealed changes in the outer plexiform layer and inner nuclear layer, suggestive of toxicity primarily to the photoreceptor synaptic terminals and bipolar cells. Conclusion: Low-dose (0.625 mg) and intermediate-dose (1.25 mg) intravitreal injection of natalizumab appears safe for rabbit retina. However, functional and anatomical changes were observed in rabbit retina following a high dose (2.5 mg) intravitreal injection of a monoclonal antibody blocking alpha4beta1 integrin. PMID- 30249831 TI - Allergic reactions to atropine eye drops for retardation of progressive myopia in children. AB - Purpose: To report clinical manifestations of ocular allergy to atropine eye drops used for retardation of progressive myopia in children. Methods: Myopic children, who developed bothersome itching that subsided promptly after cessation of atropine eye drops, were included. History of systemic or ocular allergy, preexisting ocular conditions, and clinical features of allergy were noted. Results: Six children, age 5-15 years, were included. Four developed allergy to 1% atropine sulfate eye drops and two to 0.01% concentration of atropine sulfate. The onset of allergy was within a month to as late as 4 years after using atropine eye drops. The severity of allergy was higher with 1% concentration. The most common symptoms of atropine allergy were itching and burning. The most common signs were lid swelling and hyperemia. The allergic manifestations promptly reversed with the stoppage of eye drops. Reintroduction was possible in three patients, either by reducing the concentration of atropine or using benzalkonium free formulation. Conclusion: Allergy to atropine eye drops in children may develop within a few weeks or after many years of usage. Prompt cessation followed by a reintroduction and continuation of therapy may be possible in few patients. PMID- 30249832 TI - Subsequent strabismus surgeries in patients with no prior medical records. AB - Purpose: To investigate subsequent strabismus surgeries in patients with no prior medical record and to evaluate discrepancies between surgical findings and preoperative presumptions made based on patient self-reporting and clinical findings. Methods: The medical records of patients who underwent a subsequent strabismus surgery between January 1992 and October 2017 were retrospectively reviewed. Patients with no available medical records were included in analyses. Discrepancies between preoperative presumptions and surgical findings were investigated. Original ocular alignment and previous surgical details were presumed using alternative methods, including patient self-reporting, review old photographs of patient, and checking conjunctival scarring. Results: Eleven consecutive patients (4 females, 7 males) met the inclusion criteria. The mean age at subsequent surgery was 47.7 years (range, 23-69). Seven patients had exotropia and four patients had esotropia before the subsequent surgery. Seven patients reported originally having exotropia and four patients reported originally having esotropia. However, findings from surgical exploration did not agree with preoperative presumptions from patient self-reporting in 7 of 11 patients (7/11, 63.6%). These discrepancies included errors in the original type of strabismus (7/11, 63.6%), which eye was previously operated on (1/11, 9.1%), and number of prior surgeries (1/11, 9.1%). Conclusion: When planning a subsequent strabismus surgery in patients with no prior medical record, information obtained from the patient should be used with caution. This includes the original type of strabismus and previous surgical details. PMID- 30249833 TI - Clinical profile of childhood blindness and inappropriate enrolment of children in schools for visually impaired in Uttar Pradesh, India. AB - Purpose: To assess major causes of severe visual impairment (SVI)/blindness (BL) in children studying in schools for the blind in western Uttar Pradesh, India and the extent of inappropriate enrolment of children in blind schools. Methods: Students of five schools for the blind were examined in a tertiary care eye hospital. The anatomical sites and etiology for SVI/BL were recorded using the World Health Organization/Prevention of Blindness standard reporting form. Categorical variable were summarized using frequencies and percentages. Results: A total of 93 students were examined. Male/Female ratio was 3.4:1. The most common anatomical sites of SVI/BL were the whole globe (40.3%) and the cornea (26.4%). Postnatal or childhood causes were noted in 13.8% cases. Forty-one (56.9%) students had hereditary diseases which was most likely caused by chromosomal abnormalities. Three students were having an associated disability, one was deaf and mute, one was physically handicapped, and one was intellectually challenged. Fifty-four (58%) children were blind and 21 (22.6%) children had no visual impairment but were studying in schools for the blind. Conclusion: Schools for the blind should be screened routinely to reduce the incidence of misdiagnosed visual impairment. This will prevent inappropriate enrolment and will definitely help in reducing the social and economic burden of society and of the schools of blind too. PMID- 30249834 TI - Commentary: Childhood blindness in India: Regional variations. PMID- 30249835 TI - Surgical removal of subfoveal perfluorocarbon liquid using combined flute needle and vacuum aspiration in silicone oil-filled eyes: A novel technique to remove subfoveal PFCL. AB - We report a procedure using a pressure-controllable flute needle to remove subfoveal retention of perfluorocarbon liquid (PFCL) under silicone oil. With a two-port pars plana approach, we used a 27-gauge dental injection needle to create a retinotomy at the farthest edge of the PFCL bubble from the fovea. A 27 gauge flute needle was then inserted into the edge of the subfoveal PFCL to aspirate it with vacuum pressure. Three patients with subfoveal retained PFCL were treated by this procedure within silicone oil tamponade 1 month after the first operation. They promptly underwent successful removal of the PFCL with postoperative retinal reattachment and good visual outcome. This procedure allows safe and early treatment for subfoveal retained PFCL. Many medical institutions around the world could implement this procedure using common dental injection needles and flute needles. PMID- 30249836 TI - Oval sign: A retained bee stinger. PMID- 30249838 TI - Commentary: Discerning the porhyrias! PMID- 30249837 TI - Scleritis in congenital erythropoietic porphyria - infective or inflammatory? PMID- 30249839 TI - Corneal hydrops. PMID- 30249840 TI - Pigment sheet on lens surface. PMID- 30249841 TI - Posterior lentiglobus. PMID- 30249842 TI - Fluorescein cap: Fluorescein angiographic feature of retinal cavernous hemangioma. PMID- 30249843 TI - Atypical superior iris and retinochoroidal coloboma. PMID- 30249844 TI - Ocular chemical burns from accidental exposure to topical dermatological medicinal agent. AB - We report a case of accidental ocular chemical injury by self-medication with a single application of a topical ayurvedic medication containing salicylic acid, phenol, and tincture iodine, which is being used in developing countries for treatment of various dermatological conditions. PMID- 30249845 TI - Infectious crystalline keratopathy post-Descemet stripping endothelial keratoplasty. AB - We report a case of a 46-year-old female who developed infectious crystalline keratopathy (ICK) after Descemet's stripping endothelial keratoplasty (DSEK). She underwent DSEK for pseudophakic corneal edema in her left eye. Ten weeks after the procedure, the patient presented with complaints of blurred vision, redness in eye, and ocular pain. Slit lamp examination revealed white nonsuppurative branching deep stromal infiltrate. Microscopic examination of the Gram-stained smear showed gram-positive cocci. Streptococcus viridans was isolated on cultures. Isolated organism was sensitive to linezolid. Based on antibiotic sensitivity report, fortified linezolid (0.2%) eye drop was started on hourly basis. After 10 weeks of topical fortified linezolid (0.2%) therapy, complete resolution of infiltrate with significant corneal scarring and vascularization was seen. Infectious crystalline keratopathy can occur after DSEK. PMID- 30249846 TI - A rare case of persistent pupillary membrane: Case-based approach and management. AB - Persistent pupillary membranes (PPMs) are a common congenital anomaly seen in 95% of neonates. Extensive PPMs, occluding the visual axis and resulting in reduced visual acuity, are relatively uncommon. We describe a case of bilateral total PPM in a 36-year-old female who presented with complaints of blurred vision in both the eyes. Dense pupillary membranes obscuring the visual axis need early surgical treatment. It is essential that the lens status remains clear along the visual axis both before and after pupilloplasty. PMID- 30249847 TI - Uveitis in sporadic Blau syndrome: Long-term follow-up of a refractory case treated successfully with adalimumab. AB - The classic entity of autosomal dominant Blau syndrome (BS) consists of arthritis, dermatitis, and uveitis, occurring as a result of mutations in the NOD2 gene pattern recognition receptor. Sporadic cases are those in which no known gene mutation is identifiable. Uveitis in BS can be refractory to conventional therapy. We report a case of sporadic Blau uveitis managed with adalimumab monotherapy after failing to respond to topical steroids, systemic steroids, methotrexate, and infliximab therapy sequentially. Uveitis resolved completely with adalimumab and the patient has had a disease-free period over a 2 year follow-up with bi-monthly injections for arthritis control. PMID- 30249848 TI - Anatomical and functional outcomes of pars plana vitrectomy for inflammatory epiretinal membrane surgery in healed toxoplasmosis infection. AB - Epiretinal membrane over macula secondary to toxoplasmosis compromises vision. We describe the outcome of pars plana vitrectomy and epiretinal membrane removal after adequate treatment of acute infection. The average age of all four male patients was 36 years (range 20-60 years). Following surgery there was an average three or more lines visual acuity improvement, restoration of foveal contour with reduction in central macular thickness. One patient developed choroidal neovascular membrane postsurgery and was effectively treated with intravitreal bevacizumab. Surgery for ERM secondary to healed toxoplasmosis infection has good anatomical outcome and reasonable visual improvement, when the surgery is done in a quiet eye. PMID- 30249849 TI - Commentary: Ocular toxoplasma: From bench-side to clinical practice! PMID- 30249850 TI - Retinitis as the presenting feature of subacute sclerosing panencephalitis in an Indian male: A case report. AB - Measles virus is a rare but important cause for acute retinitis as it can eventually lead to the fulminant complication of SSPE. We report a case of a young Indian male with acute viral retinitis who subsequently developed SSPE. It is of paramount importance to consider measles virus and SSPE as a cause in an immunocompetent young adult with necrotizing viral retinitis. PMID- 30249851 TI - Dramatic response to intravitreal Bevacizumab in hypertensive retinopathy. AB - Hypertensive retinopathy is seen frequently in patients with systemic hypertension and is usually asymptomatic. An acute rise in blood pressure may lead to exudative changes in the form of macular edema, hemorrhages, and serous macular detachment that can lead to visual decline. The authors report prompt resolution of exudative changes in a case of hypertensive retinopathy following intravitreal bevacizumab. PMID- 30249852 TI - A case of Leber's miliary aneurysms with diffuse peripheral retinal vascular sheathing. AB - A 30-year-old female presented with macular edema and discoid exudation at the posterior pole. Diffuse vascular sheathing was observed at the peripheral retina. Fluorescein angiography revealed multiple microaneurysms at the posterior pole and leakage from the peripheral vessels. Two monthly intravitreal bevacizumab led to minimal improvement, and resolution of macular edema was achieved by an additional intravitreal triamcinolone. The findings at the posterior pole resembled those of Leber's miliary aneurysm. However, this case also demonstrated a peculiar vascular sheathing at the periphery and showed response to triamcinolone, which are evidences for an inflammatory condition. PMID- 30249853 TI - Bilateral combined central retinal artery and vein occlusion in a 3-year-old child with nephrotic syndrome. AB - Nephrotic syndrome (NS) is a common disease of childhood but ophthalmic manifestations are seldom reported. We report a rare occurrence of bilateral combined central retinal artery and vein occlusion in a 3-year-old with NS. The child presented with bilateral painless loss of vision, central pallid retinae with cherry red spots, vascular tortuosity, and retinal hemorrhages. There was delayed filling of the arteriolar circulation and a delay in arteriovenous transit time on angiography and increased central retinal thickening on optical coherence tomography. She was treated with oral steroids, subcutaneous low molecular weight heparin, and oral acetylsalicylic acid. The central retinae showed resolution of the hemorrhages, tortuosity, edema, and pallor within 3 weeks. Visual acuity recovered bilaterally to 20/360, 20/190, and 20/40 at 1, 3, and 6 weeks, respectively. We discuss the possible reasons for good recovery in our patient. Though bilateral combined central retinal artery and vein occlusion is rare in pediatric NS, the treating physician should be aware of this entity as it can be successfully managed. PMID- 30249854 TI - Measurement of size of pigmented choroidal nevus: Superiority of multicolor imaging compared to conventional color fundus photography. AB - Choroidal nevi are benign fundus lesions that require regular follow with documentation. Conventional color fundus photography (CFP) has traditionally been used to images these lesions. Multicolor imaging (MCI) available on Spectralis spectral domain optical coherence tomography system is increasingly been tested vis-a-vis conventional CFP in various retinal diseases. We present data of the right eye of a 59-year-old gentleman with choroidal nevus who underwent conventional CFP as well as MCI. Nevus appeared orange red on MCI and its size appeared larger than the same measured on conventional CFP. We also report infrared reflectance and near infrared autofluorescence features of choroidal nevus. PMID- 30249856 TI - Masquerades less known: Case report of benign hair follicle tumors. AB - Benign eyelid tumors derived from hair follicles are rare and frequently misdiagnosed as basal-cell carcinoma when evaluation is based on clinical evidence alone. The discrepancy between the clinical aspect and the histological diagnosis can be as high as 30-40%, even for experienced clinicians. Unfortunately, this masquerade is not only clinical but also histological. Patients may be subjected to unnecessarily extensive surgery. We present a case report of three patients clinically diagnosed as malignancy but histopathologically proven as benign hair follicle tumors. PMID- 30249855 TI - A young woman with sudden visual field shimmering: A case report. AB - Clomiphene citrate is a common drug used for the treatment of chronic anovulation, especially in polycystic ovary syndrome (PCOS) patients. The drug potentially has systemic and ocular side effects. Here, we present ocular side effects in a PCOS patient and emphasize the need to pay attention to visual complaints during treatment course with clomiphene citrate. PMID- 30249858 TI - A challenging case of a large intraorbital foreign body perforating the nasal septum in a child. AB - A 5 year old boy with a history of fall from a height of about 4 feet, presented after one week with swelling, watering and discharge of the right eye. He had severe conjunctival chemosis with superior displacement of the globe. Computed Tomography (CT) showed a linear low attenuation tract in the right orbit extending from the inferolateral wall up to the left uncinate process of the ethmoid bone with increasing Hounsfield unit after 10 days. The parents did not agree for early exploration. After 10 days an exploration was done and a large linear and irregular wooden foreign body (FB) measuring 4.5 x 1.5 cm2 was removed from the right orbit and a smaller one from the nasal cavity. Four weeks post surgery, his vision was 6/9 in the right eye with the eyeball in the normal position. This case was challenging because of the late presentation, parents not agreeing for early exploration, difficulty in diagnosing by CT and a large and very deep penetrating FB. PMID- 30249857 TI - A rare case of hypereosinophilic syndrome presenting with unilateral proptosis and torticollis. AB - Hypereosinophilic syndrome (HES) is a spectrum of myeloproliferative disorder, which is characterized by persistent and marked blood eosinophilia and damage to multiple organs due to eosinophilic infiltration. Idiopathic HES is identified after ruling out all other causes of eosinophilia. Poor prognosis is usually associated with cardiac involvement and malignant transformation of blood cells. We report a rare case of HES in an 8-year-old boy who presented with unilateral proptosis and torticollis. The patient responded well to corticosteroid therapy with reduction of proptosis and torticollis and normalization of serum eosinophil count. PMID- 30249859 TI - Necrotizing fungal infection due to Saksenaea erythrospora: A case report and review of literature. AB - Mucormycosis caused by Saksenaea erythrospora is an emerging infection seen with soil contamination, burns and/or nosocomial infections. PCR amplification and internal transcribed spacer sequencing is gold standard for its identification. Here, we report a case of necrotizing fungal orbital infection by S. erythrospora in an immunocompetent child. PMID- 30249860 TI - Ophthalmology training and teaching in India: How these young ophthalmologists can become leaders of tomorrow? PMID- 30249861 TI - Is pediatric eye screening compulsory and if so when? PMID- 30249862 TI - July 1 is National Doctors' Day: How to regain the lost public trust in healthcare - A different perspective. PMID- 30249863 TI - Comment on: Continuous intraoperative optical coherence tomography-guided shield ulcer debridement with tuck in multilayered amniotic membrane transplantation. PMID- 30249864 TI - Response to comment on: Continuous intraoperative optical coherence tomography guided shield ulcer debridement with tuck in multilayered amniotic membrane transplantation. PMID- 30249865 TI - Comment on: Rebound inflammation after an intravitreal injection in Vogt-Koyanagi Harada syndrome. PMID- 30249866 TI - Response to comment on: Rebound inflammation after an intravitreal injection in Vogt-Koyanagi-Harada syndrome. PMID- 30249867 TI - Effects of Shenfu injection on chemotherapy-induced adverse effects and quality of life in patients with advanced nonsmall cell lung cancer: A systematic review and meta-analysis. AB - Objective: To investigate the efficacy of Shenfu injection (SFI) in reducing chemotherapy-induced adverse effects in nonsmall cell lung cancer (NSCLC) patients by conducting a meta-analysis. Methods: A systematic review of Cochrane Library, PubMed, Embase, CNKI, Chinese Biomedical Literature Database, VIP, and Wanfang Database was performed from their inception to December 2015. Eligible studies were randomized controlled trials (RCTs) comparing chemotherapy with or without SFI for patients with NSCLC. The main outcomes were improvement in chemotherapy-induced grade 3/4 marrow suppression (leukopenia, neutropenia, anemia, and thrombocytopenia) or gastrointestinal toxicities (nausea and vomiting, diarrhea, and constipation), quality of life, and T-lymphocytes subsets. Results: Sixteen RCTs involving 948 patients were identified. Compared with chemotherapy alone, SFI plus chemotherapy had lower 3/4 grade toxicity for leukopenia (risk ratio [RR] 0.34; 95% confidence intervals [95% CIs] 0.21-0.55), thrombocytopenia (RR 0.36; 95% CI 0.19-0.71), anemia (RR 0.39; 95% CI 0.16-0.99), nausea and vomiting (RR 0.29; 95% CI 0.14-0.58), and diarrhea (RR 0.21; 95% CI 0.07-0.63), Moreover, SFI plus chemotherapy significantly increased Karnofsky Performance Status (weighted mean difference 11.34; 95% CI 7.26-15.42). Conclusions: Adjuvant treatment with SFI improves the quality of life, attenuates the chemotherapy-induced gastrointestinal toxicities and bone marrow suppression, thus improving compliance to chemotherapy in patients with NSCLC. As for limited English literature about SFI and NSCLC, only trials publishing in the Chinese were included in the meta-analysis. More well-designed multicenter RCTs are needed before a definitive conclusion can be drawn. PMID- 30249868 TI - Prognostic value of NM23 in patients with gastric cancer: A systematic review and meta-analysis. AB - Aim of Study: NM23, as a possible biomarker of prognosis in malignant tumors, has generated remarkable interest in this critical period of the high morbidity and mortality of malignancies. Thus, we launched this meta-analysis to investigate the predictive value of NM23 expression in patients with gastric cancer. Materials and Methods: We searched PubMed, Embase, and Web of Science for relevant articles. The pooled odds ratios (ORs) and corresponding 95% confidence interval (CI) were calculated to evaluate the prognostic value of NM23 expression in patients with gastric cancer and the association between NM23 expression and clinicopathological factors. We also performed subgroup analyses to find the source of heterogeneity. Results: Exactly, 2674 patients were pooled from 19 available studies in total. The incorporative OR combined by 11 studies with overall survival (OS) showed no significance (OR = 0.90, 95% CI: 0.51-1.58, P = 0.71). Although we failed to find any significance in N status and tumor node metastasis (TNM) staging (P = 0.23 and P = 0.74, respectively), elevated NM23 expression was related to well tumor differentiation (OR = 0.62, 95% CI: 0.41 0.95, P = 0.03). However, in the subgroup analyses, we could not find any potential source of heterogeneity. Conclusion: The results showed that statistically significant association was found between NM23 expression and the tumor differentiation of patients with gastric cancer, but no significance was found in OS, N status, and TNM staging. More and further researches should be conducted to reveal the prognostic value of NM23. PMID- 30249869 TI - The change in peripheral blood monocyte count: A predictor to make the management of chemotherapy-induced neutropenia. AB - Purpose: The occurrence of neutropenia following chemotherapy makes the management of myelosuppression important. The main objective of this study was to evaluate whether the decrease of peripheral blood monocytes was a potential indicator to predict the occurrence of neutropenia. Patients and Methods: We retrospectively reviewed the medical records of 103 chemotherapy patients who underwent neutropenia. A paired sample t-test was used to assess whether the number of days when monocyte initial decrease/are in nadir/final increase was significantly less than that of the neutrophils. The baseline of monocyte percentage and the decrease rate of neutrophil were analyzed by the bivariate correlation (two-tailed). Moreover, the grade of neutropenia and the baseline of monocyte percentage (divided into <5% and >=5%) were examined by the Chi-square test for correlations. Results: Our study showed that the change trend of monocyte count was the same as that of neutrophil count and that the number of days when monocytes initial decrease/are in nadir/final increase was significantly less than that of neutrophils, respectively. The time of initial decrease in monocyte count was 1.39 days earlier; the nadir in monocyte count occurred 3.81 days earlier, and the final increase in monocyte count was 2.36 days earlier than that in neutrophil count. In addition, there was an inverse correlation between the decrease rate of neutrophil and the baseline of monocyte percentage according to the analysis of bivariate correlation (Pearson correlation = -0.241, P = 0.0142). Unfortunately, there was no significant correlation between the baseline of monocyte percentage and the grade of neutropenia examined with the Chi-square test (P = 0.7401). Conclusion: Our study shows the increase or decrease in monocyte count is a significant potential indicator to predict the occurrence of neutropenia, and it is also a predictor to guide the next monitoring time of neutrophil count and the treatment of granulocyte-colony stimulating factor. PMID- 30249870 TI - Asthma and the risk of prostate cancer. AB - Objective: The association between asthma and the risk of prostate cancer remains elusive. We aimed to evaluate the relationship between asthma and the onset of prostate cancer. Methods: We searched PubMed, Embase, and Cochrane databases for articles that assessed the association of asthma with the risk of prostate cancer through October 2015. We extracted odds ratio (OR) and calculated the corresponding 95% confidence interval (CI). We used random-effects models to calculate a pooled association between asthma and the risk of prostate cancer. Results: Fourteen studies were involved in the assessment of the association between asthma and prostate cancer risk. Asthma was not associated with the risk of prostate cancer in overall populations (OR 0.994, 95% CI 0.836-1.182), Caucasians (OR 0.922, 95% CI 0.825-1.030), and Asians (OR 5.022, 95% CI 0.415 60.793). The cumulative analysis also suggested a lack association between asthma and the risk of prostate cancer. Exclusion of any single study did not change the results significantly. No evidence of marked publication bias was observed. Conclusions: Our investigation indicated that asthma was not associated with prostate cancer risk in overall populations, Caucasians, and Asians. PMID- 30249871 TI - Trichostatin A induces apoptosis in oral squamous cell carcinoma cell lines independent of hyperacetylation of histones. AB - Aim of Study: To investigate the apoptotic event of trichostatin A (TSA) and its associated mechanism in oral squamous cell carcinoma (OSCC) lines. Materials and Methods: HSC-3 and Ca9.22 cell lines were evaluated using a trypan blue exclusion assay, histone isolation, soft agar assay, live/dead assay, 4%,6-diamidino-2 phenylindole staining, JC-1 mitochondrial membrane potential (MMP) assay, and Western blot analysis to demonstrate the anticancer activity of TSA. Results: TSA decreased OSCC cell viability and proliferation without affecting the histone acetylation. TSA-induced caspase-dependent or -independent apoptosis according to cell types, TSA enhanced the expression levels of Bim protein by dephosphorylating ERK1/2 pathway in HSC-3 cells. TSA also damaged MMP and increased cytosolic apoptosis-inducing factor (AIF) in Ca9.22 cells. Conclusion: The present study suggests that TSA may be a potential anticancer drug candidate for the treatment of OSCC through the induction of apoptosis. PMID- 30249872 TI - The clinical importance of serum galectin-3 levels in breast cancer patients with and without metastasis. AB - Objective: Studies have investigated expression status of galectin-3 (Gal-3), but very little is known about the importance of circulating Gal-3 in patients with breast cancer (BC). The purpose of the study was to investigate the clinical significance and potential diagnostic value of plasma Gal-3 levels in patients with BC. Materials and Methods: Fifty-two patients with BC and 35 age-matched healthy controls were enrolled. Levels of Gal-3 were investigated in BC patients and healthy controls. Gal-3 levels were determined using ELISA method. Results: Serum Gal-3 levels were significantly higher in BC patients than in controls (P = 0.002). Gal-3 levels did not significantly differ according to patients' statuses of lymph node involvement, hormone receptor, lymphovascular invasion, e-cadherin, menopausal, stage, serum hemostatic markers (prothrombin time, partial thromboplastin time, and international normalized ratio), platelet counts, mean platelet volume, lactate dehydrogenase, carcinoembryonic antigen, and carbohydrate antigen 15-3 values (P > 0.05 for all). A cut-off value of Gal-3 to predict BC was determined at >=3.17 ng/ml with a sensitivity of 75.0%, a specificity of 65.71%, a positive and negative predictive values of 76.5 and 63.9%, respectively (area under the curve: 0.705 [95% confidence interval, 0.598 0.798], P = 0.0002). Conclusion: Serum Gal-3 levels were significantly higher in BC patients and did not significantly differ according to clinical and tumoral characteristics of patients. Furthermore, there was no difference in Gal-3 levels between BC patients with and without metastatic disease. Serum Gal-3 levels can be used as an adjunct to other diagnostic or screening tests for BC regardless of clinical and tumoral characteristics of patients. PMID- 30249873 TI - Meta-analysis on the performance of p16/Ki-67 dual immunostaining in detecting high-grade cervical intraepithelial neoplasm. AB - Aim: Although routine screening contributes to substantial reductions in cervical cancer morbidity and mortality, the low specificity of HPV detection and limited sensitivity of cervical cytology necessitates the application of more optimized markers, such as the newly-introduced p16/Ki-67 dual-staining method. Here we reviewed several studies to evaluate the performance of this method in cervical cancer screening. Methods: An electronic database search was performed on PubMed, Web of Science, CNKI and Wanfang Database for studies assessing p16/Ki-67 dual immunostaining in the diagnosis of high-grade cervical intraepithelial neoplasm (HGCIN) with abnormal cytological morphologies. Two reviewers screened literatures, extracted data and assessed the quality of the included studies independently. Meta-analysis was performed using ReV. Man 5.2 and Meta-DiSc 1.2 software packages. Results: The absolute sensitivity of p16/Ki-67 dual staining for diagnosing HGCIN ranged from 80% to 94%, while the sensitivity of triage method with hrHPV testing ranged from 78% to 96%. The specificity of p16/Ki-67 testing and hrHPV detection for predicting absence of CIN2+ ranged from 39% to 79% and 15% to 44%, respectively. Quantitative meta-analysis showed that the pooled sensitivity of p16/ki-67 dual staining is 0.88 [95'CI (0.86-0.90)], the pooled specificity is 0.58 [95'CI (0.56-0.60)]. For hrHPV testing, the pooled sensitivity and pooled specificity is 0.94 [95'CI (0.93-0.96)] and 0.32 [95'CI (0.29-0.34)], respectively. Conclusions: p16/Ki-67 dual immunostaining had comparable sensitivity and improved specificity in screening HGCIN or CC when compared with hrHPV detection. Further studies may be beneficial to assess the efficacy of this novel biomarker, which can be potentially used as one of the initial screening assays. PMID- 30249874 TI - Deglycosylation of wogonoside enhances its anticancer potential. AB - Introduction: Scutellaria baicalensis is commonly used in Asia as an herbal medicine to treat a variety of ailments, including cancer. Wogonoside, one major constituent of S. baicalensis, can be primarily converted to wogonin through deglycosylation via enteric microbiome metabolism. Materials and Methods: The antiproliferative effects of the glycoside (wogonoside) and its deglycosylated compound (wogonin) on a panel of human cancer cell lines from the most common solid tumors were evaluated using the MTS colorimetric assay. Cell cycle and apoptosis were determined using flow cytometry. Enzymatic activities of caspases were measured, and the interactions of wogonin and caspases were explored by a docking analysis. Results: Wogonoside did not have obvious antiproliferative effects on the cancer cells. In contrast, wogonin showed significant antiproliferative activities on all the tested cancer cells. Wogonin arrested the cells in the G1 phase and significantly induced cell apoptosis. The compound also activated the expression of caspases 3 and 9. The docking results suggest that the compound forms hydrogen bonds with Phe250 and Ser251, and pi-pi interactions with Phe256 in caspase 3, and with Asp228 in caspase 9. Conclusions: After wogonoside deglycosylation, wogonin significantly enhanced its anticancer potential as a potent anticancer compound derived from S. baicalensis. PMID- 30249875 TI - Acupuncture for the relief of hot flashes in breast cancer patients: A systematic review and meta-analysis of randomized controlled trials and observational studies. AB - Objective: To critically assess the effectiveness and safety of acupuncture for treating hot flashes (HFs) among breast cancer (BC) patients, and to get much more highly compelling evidence then to guide clinical practice. Methods: Comprehensive systematic literature searches were carried out for identifying randomized controlled trials and observational studies (OSs) published before January 2015. The meta-analysis (MA) was performed by Review Manager 5 software if data could be merged routinely, if not descriptions would be given. Results: A total of 18 studies were eligible ultimately. With respect to HFs frequency, the MA during treatment showed a significant difference (MD = -1.78, 95% confidence intervals [95% CIs]: -3.42--0.14), but no statistical differences were observed when posttreatment or follow-up period. While electroacupuncture versus applied relaxation, they both helped to promote HFs markedly but did not reveal statistically significance between them. Referring to Kupperman's index, all the treatment brought out great assistance when compared with baseline conditions, and there was significant difference between real acupuncture sham acupuncture (posttreatment: MD = -4.40, 95% CI: -6.77--2.03; follow-up: MD = -4.30, 95% CI: 6.52--2.08). In terms of OS, 7 prospective single arm studies focused on exploring the efficacy of traditional acupuncture, and all revealed moderate or great benefit for BC patients suffering from HFs. Conclusions: Acupuncture still appeared to be an efficacious therapeutic strategy, especially for the less/no side effects. Because of its widespread acceptance and encouraging effectiveness for improving HFs, much more high-quality studies are in need urgently. PMID- 30249876 TI - Soybean (Glycine max) prevents the progression of breast cancer cells by downregulating the level of histone demethylase JMJD5. AB - Background: Breast cancer is the first noticeable disease in female patients. Long-term use of soybean (Glycine max) may prevent the progression of cancer. However, the molecular mechanism for the functions of soybean remains unclear. Histone demethylase JMJD5, an important epigenetic molecule, is overexpressed in the progression of breast cancer suggesting that soybean may ameliorate cancer by affecting the expression of JMJD5. Materials and Methods: To test the hypothesis, human breast cancer cell lines MCF-7 and MDA-MB-231 were treated with different concentrations of soybean and/or transfected with the plasmids pcDNA3.1-JMJD5 and pTZU6 + 1-shRNA-JMJD5. The growth rate was measured using xCELLigence real-time cell analysis. The level of JMJD5 was measured by using quantitative reverse transcription-polymerase chain reaction and Western blot. Results: Soybean showed significant inhibitory effects on the growth rates ofMCF-7 and MDA-MB-231 cells in a concentration-dependent way (P < 0.05). Meanwhile, the levels of JMJD5 were reduced with the increase of soybean concentration (P < 0.05). JMJD5 transfection increased the growth rates of MCF-7 and MDA-MB-231 by 25% and 40%. In contrast, the growth rates of MCF-7 and MDA-MB-231 cells were decreased by 17% and 23% after being transfected with JMJD5 shRNA. Soybean inhibited the growth rate of MCF-7 and MDA-MB-231 cells when they were transfected by JMJD5 gene but no for the cells transfected with JMJD5 shRNA. Conclusion: The complicated compositions of soybean will be beneficial to the therapy of breast cancer since its causes may be involved in multiple aspects. Soybean represses breast cancer development by downregulating the level of JMJD5. PMID- 30249877 TI - Pyruvate kinase M2 inhibits the progression of bladder cancer by targeting MAKP pathway. AB - Purpose: Pyruvate kinase M2 (PKM2) was found overexpressed in tumor cells and played a significant role in tumor formation and growth. We sought to explore the correlation of PKM2 expression with cell proliferation, invasion, and apoptosis in bladder cancer cell line. Materials and Methods: Real-time polymerase chain reaction and Western blot were performed to determine the expression level of PKM2 at mRNA and protein level. MTT and flow cytometry were respectively used to explore the proliferation, invasion, and apoptosis in bladder cancer cell line in vitro. Results: The results suggested that suppression of PKM2 significantly decreased the proliferation rate, invasive cell number, and migration ability of bladder cancer cells compared with blank group. Moreover, proteins such as MMP2 and MMP9 as well as P38 expression were also affected by the PKM2 expression changes. These results proved that PKM2 could be involved in the progression of bladder cancer by mitogen-activated protein kinases signaling pathway. Conclusion: The data presented in this study revealed that PKM2 up-regulation may promote the development and metastasis of bladder cancer through promoting cell proliferation, migration and invasion via MAPK signal pathway. PMID- 30249878 TI - Identification of potential transcription factors, long noncoding RNAs, and microRNAs associated with hepatocellular carcinoma. AB - Aim: This study aimed to investigate the key transcription factors (TFs), long noncoding RNAs (lncRNAs), and microRNAs (miRNAs) associated with hepatocellular carcinoma (HCC). Materials and Methods: The datasets GSE31383 and GSE54238 were downloaded from Gene Expression Omnibus data repository. GSE31383 was used to screen differentially expressed miRNAs, and GSE54238 was used to screen differentially expressed messenger RNAs (mRNAs) and lncRNAs. ChipBase was used to identify TF-miRNA pairs. StarBase was selected to identify miRNA-mRNA and lncRNA miRNA interactions. Kyoto Encyclopedia of Genes and Genomes pathway analysis was also conducted using Database for Annotation, Visualization, and Integrated Discovery tool. Results: A total of 2065 mRNAs, 1050 lncRNAs, and 26 miRNAs were identified to be divergently expressed in HCC compared with normal tissues. There were 338 miRNA-mRNA and 65 lncRNA-miRNA pairs with reverse expression trend. Besides 249 TF-miRNA relationships including differentially expressed miRNA were isolated. Among them, 11 TF-miRNA had the same expression trend. Furthermore, lncRNA-miRNA-mRNA and TF-miRNA-mRNA regulatory networks were constructed. hsa-miR 497, hsa-miR-195, and hsa-miR-424 were identified as hub nodes in these two networks. Hub TFs, such as TATA box binding protein-associated factor 1 (TAF1) and hepatocyte nuclear factor 4, alpha (HNF4alpha), and lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) were also screened out in the network. Conclusions: Our findings highlight the regulatory networks among TFs, lncRNAs, miRNAs, and mRNAs in HCC. Several key molecules, such as hsa-miR 195, lncRNA MALAT1 and TFs TAF1 and HNF4alpha, may contribute to the progression of HCC. PMID- 30249879 TI - Liver abscess following transarterial chemoembolization for the treatment of hepatocellular carcinoma: A retrospective analysis of 23 cases. AB - Objective: To investigate the incidence, management, and outcome of a liver abscess after transarterial embolization/chemoembolization (TAE/TACE) therapy for hepatocellular carcinoma (HCC). Materials and Methods: From May 2007 to May 2014, all patients complicated with liver abscess following TAE/TACE for HCC were identified and analyzed at four medical centers. Results: During the study period, a total of 6984 TAE/TACE procedures were performed among 3129 patients, and a total of 23 patients developed liver abscess with the incidence of 0.33% (23/6984) per procedure. There were 21 males and 2 females, and mean age of 52.1 +/- 12.1 years. The mean interval from last TAE/TACE procedure to the diagnosis of liver abscess was 12.9 +/- 6.6 days. All the patients received intravenous antibiotics, with ten patients had a percutaneous drain, one each for percutaneous aspiration and surgery. Complications related to the liver abscess were hepatorrhexis and pleural effusion (n = 1), pleural effusion (n = 1), and obstructive jaundice (n = 1), all of which were resolved after conservative treatments. The serum alpha-fetoprotein (AFP) levels were significantly reduced at 6 months after treatment (P < 0.01) in 15 patients whose AFP > 400 ng/mL preprocedure. Complete or partial tumor response at 6 months after TAE/TACE was achieved in three and twenty patients, respectively; and 6 months survival was 100%. Conclusions: The incidence of a liver abscess after TAE/TACE is low; antibiotics therapy along was successful in about half patients, and percutaneous abscess aspiration/drainage were necessary in large size abscess and severely symptomatic patients; the outcomes are benign without worsening of the progression of underlying HCC. PMID- 30249880 TI - Knockdown of alpha-fetoprotein expression inhibits HepG2 cell growth and induces apoptosis. AB - Aims: To explore the biological roles of alpha-fetoprotein (AFP), a tumor associated antigen in human hepatocellular carcinoma (HCC). Materials and Methods: After knockdown of AFP in HepG2 cells by transfection of specific StealthTM RNAi, the expression of AFP were detected by reverse transcription polymerase chain reaction at mRNA level and by enzyme-linked immunosorbent assay at the protein level. Then, the effect of silenced AFP on cell proliferation was assessed by dimethylthiazolyl-2,5-diphenyl-tetrazolium bromide assay, and apoptosis assessment with Hoechst33258 and flow cytometry (double stain with fluorescein isothiocyanate/propidium iodide), the roles of AFP in the cell cycle regulation were assessed by flow cytometry. We also detected the expression of some key proteins related to apoptosis pathway by Western immunoblot analysis. Results: After the transfection for 48 h, the expression of AFP gene was almost abolished, the cell proliferation was inhibited by 47.61%, the number of cells undergoing early apoptosis was significantly increased to 59.47%; cell cycle was arrested with the increase of G0/G1 phase cells from 45.3% to 58.4%. Inhibition of AFP expression also results in decreasing of transforming growth factor-beta (TGF-beta), mutant P53 expression, and increasing of Bax/Bcl-2 ratio, activation of caspase-3. Conclusions: The results suggest that AFP may positively regulate cell proliferation by enhancing the apoptosis resistance via effect on TGF-beta and p53/Bax/caspase-3 signaling pathway in HepG2 cells. As such, the knockdown of AFP gene should be further investigated in vivo as a novel approach to HCC treatment. PMID- 30249881 TI - Diabetes mellitus might be a protective factor of glioma. AB - Aims: Several studies suggested that diabetes mellitus (DM) was associated with the risk of glioma. However, other studies did not confirm the result. Therefore, I conducted this meta-analysis. Materials and Methods: I retrieved the PubMed, Embase, and Web of Science database, by adopting keywords "glioma," and "diabetes," "DM." The strength of the associations between DM and the risk of glioma was measured by odds ratios (ORs) with 95% confidence intervals (95% CIs). Results: Ten relevant studies were identified in the final analysis. A statistically significant association between DM and glioma risk was fond (OR = 0.84; 95% CI, 0.73-0.97; P = 0.02). In the subgroup analysis of age group, young population with DM showed decreased glioma risk (OR = 0.83; 95% CI, 0.70-0.98; P = 0.02), whereas old population with DM did not show a significant association (OR = 0.87; 95% CI, 0.65-1.16; P = 0.34). In the subgroup analysis of gender, male patients with DM showed decreased glioma risk (OR = 0.82; 95% CI, 0.68-0.99; P = 0.04), whereas female population with DM did not show a significant association (OR = 0.93; 95% CI, 0.70-1.24; P = 0.63). Conclusions: This meta analysis suggested that DM may be associated with the reduced glioma risk. PMID- 30249882 TI - X-linked inhibitor of apoptosis protein inhibitor Embelin induces apoptosis via PI3K/Akt pathway and inhibits invasion in osteosarcoma cells. AB - Background: Embelin is an active compound identified as a novel X-linked inhibitor of apoptosis protein (XIAP) inhibitor from the Embelia ribes that exhibits various medicinal effects including anti-inflammatory and anticancer activities. However, the therapeutic effect of Embelin to human osteosarcoma is not yet determined. Objectives: In this study, we evaluated the sensitizing potential of Embelin on promoting apoptosis to cause osteosarcoma cell death and inhibiting its invasion. Methods: We uesd 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide to detect the survival rates of osteosarcoma cells, Western blot to detect the expression of proteins in U-2 OS and MG63 cells, and fluorescence microscope to observe the morphology of apoptotic cells. Results: The survival of osteosarcoma cells decreased, When Embelin was used. Obvious condensed and flared fluorescence was observed, when used high-dose Embelin. There was an increase of caspase-3, cleaved caspase-3, caspase-8, and caspase-9 in Embelin group, while PI3K, AKt, p-AKt, X-linked inhibitor of apoptosis protein, and MMP-9 were downregulated. The invasion of Embelin application was significantly lower than that of the control application. Conclusion: Embelin promoted apoptosis via XIAP and PI3K/Akt signaling pathway. XIAP inhibitor Embelin inducing apoptosis could cause osteosarcoma cell death and inhibit its invasion. PMID- 30249883 TI - Factors potentially associated with gemcitabine-based chemotherapy-induced thrombocytopenia in Chinese patients with nonsmall cell lung cancer. AB - Objective: To investigate the prevalence and characteristics of gemcitabine-based chemotherapy-induced thrombocytopenia in Chinese patients with nonsmall cell lung cancer (NSCLC). Materials and Methods: Medical records of 197 patients with histologically proven NSCLC received gemcitabine-based chemotherapy from June 2011 to June 2013 in our hospital were collected. The relative risk factors were identified and evaluated by univariate and multivariate analyses. Results: The incidence of gemcitabine-based chemotherapy-induced thrombocytopenia in these NSCLC patients was 85.8%. Between thrombocytopenia and nonthrombocytopenia patients, in patients with thrombocytopenia and thrombocytopenia, we found Stage III/IV patients got more probabilities for thrombocytopenia (P < 0.01). In addition, patients who received gemcitabine and cisplatin (GP) regimen resulted in more thrombocytopenia than gemcitabine and carboplatin (GC) and other regimens (P < 0.001). In addition, majority of the thrombocytopenia patients presented thrombocytopenia in their first cycle (P < 0.001). Whereas, other potential risk factors such as age, gender, performance status value, diabetes mellitus or not, and other underlying disease (hypertension and hepatopathy) were not showed such significance in this study. Further, the multivariate analysis revealed that stage (odds ratio [OR] 7.113, P < 0.01) and chemotherapy cycles (OR 0.543, P < 0.01) were also statistically significant independent risk factors for gemcitabine-based chemotherapy-induced thrombocytopenia. Conclusion: This study shows that thrombocytopenia is common in Chinese NSCLC patients receiving gemcitabine-based regimens. Chemotherapy cycles and stage might be the important factors influencing the occurrence of gemcitabine-based regimens-induced thrombocytopenia. PMID- 30249884 TI - 2-fluoro-2-deoxy-D-glucose positron emission tomography versus conventional imaging for the diagnosis of breast cancer and lymph node metastases. AB - Context: Proper preoperative staging is vital in the treatment of breast cancer patients. Fluorine-18-labeled 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT) and conventional diagnostic modalities including ultrasonography (US), mammography (MG), and magnetic resonance imaging (MRI) play a greater role. Aims: To evaluate the diagnostic accuracy of FDG-PET in detecting primary breast cancer as compared with US, MG, and MRI, and in axillary lymph nodes (ALNs) staging in Chinese women. Settings and Design: It is a study of diagnostic accuracy. Subjects and Methods: Thirty one female patients, with biopsy established breast carcinoma, were recruited and analyzed retrospectively. All patients underwent 18F-FDG-PET, MG, US, and MRI. FDG-PET/CT for the diagnosis of primary breast cancer and detecting ALNs metastases were compared with MG, US, and MRI. Statistical Analysis Used: Sensitivity, specificity, positive-predictive value (PPV), and negative predictive value (NPV) of FDG-PET imaging for primary breast cancers and ALN staging were analyzed using standard statistical analyses. Results: In 31 patients with cytologically established invasive breast carcinoma, the sensitivities of US, MG, MRI, and FDG-PET/CT were 90% (28/31), 84% (26/31), 97% (30/31), and 94% (29/31), respectively. The sensitivity, specificity, overall accuracy, PPV, and NPV of US, MRI, and FDG-PET/CT in ALN staging (maximum standardized uptake value cutoff at 1.5) were 80%, 86%, 84%, 80%, and 90%; 90%, 95%, 94%, 90%, and 95%; and 90%, 86%, 87%, 90%, and 95%, respectively. Conclusions: US and MRI should remain the first line for the diagnosis of breast cancer. Both MRI and FDG-PET/CT could accurately diagnose the primary breast cancer and stage the axilla lymph nodes, but further large population study is needed. PMID- 30249885 TI - Association of serum annexin A1 with treatment response and prognosis in patients with esophageal squamous cell carcinoma. AB - Objective: Annexin A1 (ANXA1), a calcium-dependent phospholipid binding protein, is known to be regulated by microRNA-196a (miR-196a) in esophageal adenocarcinoma, and its high expression in tumor tissue is correlated with the poor prognosis of esophageal squamous cell carcinoma (ESCC). However, the role of ANXA1 in the serum of patients with ESCC remains unclear. Materials and Methods: In this study, we used enzyme-linked immunosorbent assay to evaluate the levels of ANXA1 and real-time polymerase chain reaction to detect the expression of miR 196a in the serum of ESCC patients (healthy donors as controls) and evaluated the relationship between ANXA1 and clinical outcomes. Results: The results showed that the level of serum ANXA1 in ESCC patients was significantly lower than that in controls (P = 0.001) but increased after chemoradiotherapy (P = 0.001). There was no correlation between the baseline level of serum ANXA1 and the short-term efficacy of treatment (P = 0.26) as well as the 1-year progression-free survival (PFS) (P = 0.094). However, there existed a significant correlation between the increases of serum ANXA1 expression and the 1-year PFS (P = 0.04). A higher increase (>2-fold of baseline) in the serum ANXA1 levels was correlated with a poorer PFS (hazard ratio = 3.096, 95% confidence interval 1.239-7.861). There was an inverse correlation between the expressions of miR-196a and ANXA1 in serum (Pearson's correlation of -0.54, P = 0.021). Conclusion: Our data revealed that the expression of serum ANXA1 in ESCC patients increases after chemoradiotherapy and the increased fold change in serum ANXA1 confers independent negative prognostic impact in ESCC. The higher the increase in serum ANXA1 levels, the poorer the outcome. PMID- 30249886 TI - Identification of genes correlated with oral squamous cell carcinoma. AB - Objectives: The objective was to study the mechanisms of oral squamous cell carcinoma (OSCC). Materials and Methods: We analyzed microarrays of GSE23558 and GSE25103. GSE23558 and GSE25103 were downloaded from Gene Expression Omnibus. GSE23558 included 27 OSCC samples, 4 independent and 1 pooled normal samples. GSE25103 included 112 OSCC samples and ten normal samples. The differentially expressed genes (DEGs) and the risk single nucleotide polymorphisms (SNPs) separately were obtained by limma package and plink software. Then, candidate disease genes were screened from the common genes of the genes carrying SNPs and the DEGs using Fisher's combination method. Using TargetMine online tool, potential functions of the candidate disease genes were analyzed by functional and pathway enrichment analyses. Besides, protein-protein interaction (PPI) network of these genes was constructed by STRING and Cytoscape software. Furthermore, modules of PPI network were screened by the ClusterONE. Results: We screened 2353 DEGs and 35635 risk SNPs in OSCC samples compared with normal samples. Moreover, CA9 was the most significant upregulated genes. There were 754 candidate disease genes, including 299 upregulated (e.g., VEGFC and FAT1) and 455 downregulated genes. For the candidate disease genes, the enriched functions were mainly in biological process categories. Importantly, FN1 (degree = 42) and CCNA2 (degree = 38) had high degrees in the PPI network. Furthermore, FN1 and CCNA2 were separately involved in module 1 and module 2 of the PPI network. FN1, CCNA2, CA9, VEGFC, and FAT1 might affect OSCC. Conclusion: In general, our study obtained important genes implicated in OSCC. PMID- 30249887 TI - Cigarette smoke condensate could promote human bronchial epithelial BEAS-2B cell migration through shifting neprilysin trafficking. AB - Aim of Study: Recent studies have suggested neprilysin (NEP) play a key role in cigarette smoke-induced nonsmall-cell lung carcinoma; however, the detailed mechanism was still unclear. Here, we employed in vitro human bronchial epithelial BEAS-2B cells to investigate whether and how NEP involved in cigarette smoke condensate (CSC)-induced cancer occurrence. Materials and Methods: In vitro MTT and transwell assay was applied. Live cell imaging and staining were also employed. Results: In vitro data showed that CSC could increase BEAS-2B cell migration while NEP shRNA could block CSC-induced BEAS-2B cell hypermigration. By biotination and live cell staining, we found that after CSC treatment, cell surface NEP was increased while internalization trafficking was shifted from late endosome/lysosome pathway to recycling pathway. Finally, we found that surface NEP could bind to p120 catenin (p120ctn) for lysosome destination turnover while CSC treatment could change p120ctn membrane/cytosome distribution. Loss of p120ctn will subsequently change NEP trafficking and finally, increase its membrane distribution with a phenocopy manner as CSC. Conclusion: These data indicated under CSC treatment; losing of membrane p120ctn could upregulate surface NEP protein level and thus facilitate BEAS-2B cell migration. PMID- 30249888 TI - Proteinuria: Associated with poor outcome in patients with small cell lung cancer. AB - Objective: Although proteinuria has been increasingly reported in lung cancers, especially small cell lung cancer (SCLC), its clinical impact in patients with SCLC remains unknown. Materials and Methods: We analyzed patients with newly diagnosed SCLC confirmed by clinical, radiological, and pathological features over a 7-year period. Pretreatment proteinuria was assessed by quantitative analysis of 24-h urine before receiving chemotherapy. The demographic, laboratory characteristics and its impact on survival outcome were evaluated. Results: There were 140 SCLC patients with the mean age of 70.2 years, extensive stage (89.3%), and male predominance (81.4%). Significant proteinuria (>300 mg/day) occurred in 17.4% (24/140) patients. Patients with proteinuria had significant higher serum blood urea nitrogen, lower total calcium, total protein, albumin levels, and lower creatinine clearance (Ccr) (24-h Ccr). Daily protein excretion was negatively correlated with serum total protein, albumin, and Ccr. Using a multivariable Cox proportional hazard model, proteinuria (hazard ratio, 1.943, 95% confidence interval 1.148-3.259, P = 0.010), along with poor performance status and serum albumin, were independent risk factors of all-cause mortality. Proteinuria was also associated with poor survival status (6.08 vs. 11.88 months, P < 0.001), especially in those who had severe proteinuria (>2 g/day). Conclusions: Proteinuria is not uncommon and associated with all-cause mortality in patients with SCLC. PMID- 30249889 TI - Utilizing multiple pathway cross-talk networks reveals hub pathways in primary mediastinal B-cell lymphoma. AB - Objective: The objective of this paper was to reveal hub pathways in primary mediastinal B-cell lymphoma (PMBL) based on multiple pathway crosstalk networks (PCNs) and give insight for its pathological mechanism. Materials and Methods: Based on gene expression data, pathway data and protein-protein interaction data, background PCN (BPCN) and tumor PCN (TPCN) of PMBL were constructed. The rank product algorithm was implemented to identify hub pathways of BPCN and TPCN. Finally, topological properties (degree, closeness, betweenness, and transitivity) of hub pathways were analyzed. Results: For BPCN, there were three hundred nodes and 42,239 edges, and the pathway pairs had great overlaps. TPCN was composed of 281 nodes and 12,700 cross-talks. A total of five hub pathways were identified, nonalcoholic fatty liver disease (NAFLD), tuberculosis, human T lymphotropic virus type-I (HTLV-I) infection, hepatitis B, and Epstein-Barr virus infection. The topological properties for them were different from each other, further between PMBL and normal controls. Conclusion: We have identified five hub pathways for PMBL, such as NAFLD, HTLV-I infection, and Hepatitis B, which might be potential biomarkers for target therapy for PMBL. PMID- 30249890 TI - The impact of perioperative blood transfusion on survival and recurrence after radical prostatectomy for prostate cancer: A systematic review and meta-analysis. AB - Objective: Conflicting data have been reported regarding the association between perioperative blood transfusion (PBT) and clinical outcomes for prostate cancer patients. We conducted a systematic review and meta-analysis to evaluate the impact of PBT on cancer survival and recurrence for patients who underwent radical prostatectomy (RP). Methods: A systematic review of PubMed, EMBASE, and Cochrane libraries was performed to identify all eligible studies that evaluate the association between PBT and clinical outcomes for prostate cancer patients undergoing RP. The analyzed outcomes were overall survival (OS) and recurrence free survival (RFS) at 3, 5, and 10 years. Results: A total of eight articles met our criteria. Meta-analysis indicated that prostate cancer patients with PBT had decreased OS (hazard ratio [HR] =1.51, 95% confidence interval [CI], 1.22-1.85, P < 0.01; HR = 1.57, 95% CI, 1.33-1.85, P < 0.01; HR = 1.55, 95% CI, 1.03-2.33, P = 0.04) and RFS (HR = 1.67, 95% CI, 1.37-2.04, P < 0.01; HR = 1.42, 95% CI, 1.23 1.63, P < 0.01; HR = 1.37, 95% CI, 1.03-1.83, P = 0.03) at 3, 5, and 10 years after surgery compared with those without PBT. Conclusions: The findings from the current meta-analysis demonstrate that PBT was associated with adverse survival and recurrence outcomes for prostate cancer patients undergoing RP. PMID- 30249891 TI - The analysis of deregulated expression of the timeless genes in gliomas. AB - Context: Results from recent molecular epidemiologic studies suggest that the timeless genes play a role in tumorigenesis, possibly by influencing cell cycle or other pathways relevant to cancer. Aims: The aim of this study was to explore the expression level of the timeless gene in human glioma. Subjects and Methods: Using immunohistochemical staining, methylation-specific polymerase chain reaction techniques, we examined the expression of the timeless gene in 94 gliomas. Statistical Analysis Used: The association between tumor grade and expression of the investigated proteins was assessed using the Spearman, Chi square test, and two-sample t-test, included in the Statistical Package for the Social Science, version 13.0. Results: The expression levels of timeless mRNA in high-grade glioma were significantly different from the surrounding nontumor tissues (P < 0.01). The difference in the expression of timeless in low-grade gliomas and the surrounding nonglioma tissues was insignificant (P > 0.05). The intensity of immunoactivity for TIMELESS in high-grade gliomas was significantly higher than that of low-grade gliomas (r = -0.403, P = 0.012 < 0.05), nontumor tissues around high-grade gliomas (r = -0.376, P = 0.027 < 0.05), whereas there was no difference in the intensity of immunoactivity for TIMELESS between low grade gliomas and the surrounding nontumor tissues (P > 0.05). Conclusions: The expression of timeless in high-grade gliomas was significantly higher than that of the low-grade gliomas and nonglioma. Therefore, we suggest that disturbances in timeless expression may result in the disruption of the control of normal circadian rhythm, thus benefiting the survival of glioma cells and promoting carcinogenesis. PMID- 30249892 TI - Overexpression of Tat-interacting protein 30 inhibits the proliferation, migration, invasion and promotes apoptosis in bladder cancer cells. AB - Aims: Tat-interacting protein 30 (TIP30), a transcriptional repressor, possesses antitumor effect in different cancer cells. However, little is known about the function of TIP30 in bladder cancer till now. Materials and Methods: A TIP30 overexpressing plasmid was transfected into the bladder cancer cells (T24). The cell cycle and apoptosis were detected by flow cytometry. The cell proliferation was analyzed using the cell counting kit-8 assay. The migrative and invasive abilities of T24 cells were measured by the transwell assay. The expression of TIP30, cell cycle proteins, migration-related proteins, and cell apoptosis related proteins was assessed by Western blotting. Results: The cell proliferation, migration, and invasion of T24 cells were inhibited by overexpression of TIP30. Moreover, the rate of cell apoptosis was increased by the overexpression of TIP30. The expression of cell cycle proteins, phosphorylated EGFR, p-Akt, Bcl-2, cyclin D, cyclin E), migration-related proteins (matrix metalloproteinases 2 [MMP2], MMP6, MMP9), were downregulated, and cell apoptosis-related proteins (bax, cleaved caspase3) were upregulated. Conclusions: These results suggest that TIP30, as a tumor suppressor in the bladder cancer, might be served as a target in cancer therapies in the future. PMID- 30249893 TI - Survivin expression as an independent predictor of overall survival in pancreatic adenocarcinoma. AB - Context: Survivin is an antiapoptotic protein with a role in tumorigenesis and suggested prognostic value in several proliferative diseases. Aims: This study aimed to examine the role of survivin as a prognostic marker in pancreatic adenocarcinoma (PDAC). Settings and Design: Fifty-one specimens of PDAC were assessed for survivin expression by immunohistochemistry. Subjects and Methods: Overall survival and 1-, 3-, and 5-year survival were retrieved retrospectively. Statistical Analysis Used: Bivariate analysis was conducted using Chi-square and Mann-Whitney U tests, while survival analysis was conducted using Kaplan-Meier statistics. Results: Of the 51 assessed cases, 49% were positive for survivin. Survivin expression was significantly correlated 1-year survival and overall survival, particularly in bcl-2 positive cases. Conclusions: Survivin may be implicated in the bcl-2 and p53 pathways and therefore in the biology of PDAC. Its potential use as a survival predictor and therapeutic target represent a promising field. PMID- 30249894 TI - Safety and feasibility of enhanced recovery after surgery in the patients underwent distal pancreatectomy for pancreatic cancer. AB - Purpose: This study assessed whether our enhanced recovery after surgery (ERAS) program for distal pancreatectomy (DP) is safe and feasible. Patients and Methods: The subjects were patients who underwent consecutive DP between 2012 and 2014 at the Department of Gastrointestinal Surgery, Kanagawa Cancer Center. They received perioperative care according to ERAS program. All data were retrieved retrospectively. Outcome measures included postoperative mortality, morbidity, hospitalization, and 30-day readmission rate. Our ERAS program included 12 elements (4 preoperative elements, 3 intraoperative elements, and 5 postoperative elements). Results: A total of 44 patients were studied. The overall incidence of morbidity was 29.5%, the incidence of mortality was 0%, and the incidence of readmission was 0%. Four preoperative elements and 3 intraoperative elements seemed feasible. Among the 5 postoperative elements, 4 elements seemed feasible, accounting 90%< performance rate however the early removal of catheters and drain seemed not feasible. The median postoperative hospital stay was 14 days (range: 8 39 days). The median postoperative hospital stay was 13 days (range: 8-27 days) in patients without postoperative complications while the median postoperative hospital stay was 26 days (range: 14-39 days) in patients with postoperative complications. Conclusion: This study results suggested that our ERAS program is safe and feasible in patients who undergo DP. However, achieving compliance on the postoperative element, especially the removal of catcher and drain, was more challenging. PMID- 30249895 TI - Evaluation of the use of nab-paclitaxel and gemcitabine in clinical practice. AB - Context: Pancreatic cancer in a common tumor in our country for which there are various treatment alternatives. Objective: Evaluate the effectiveness and safety of nab-paclitaxel and gemcitabine in everyday clinical practice. Settings and Design: Observational, retrospective study at a tertiary university hospital. Subjects and Methods: We included patients diagnosed of metastatic or locally advanced pancreatic cancer that were being treated with nab-paclitaxel and gemcitabine. We recorded response, progression-free survival (PFS), and overall survival (OS) rates together with toxicities. Statistical Analysis Used: We used SPSS program for Windows. We conducted descriptive statistics using averages, medians, standard deviations or ranges, and percentages. Results: We included 15 patients. At 3 months, there were no complete responses; 20% showed partial responses, and in 60% of patients, the disease stabilized. The median PFS was 8.9 months and the OS was 9.6. The most important adverse reactions were neutropenia, fatigue, and nausea/vomiting. Conclusions: The treatment regimen leads to increased survival in these patients with an acceptable toxicity profile. PMID- 30249896 TI - Capecitabine-cisplatin versus 5-fluorouracil/leucovorin in combination with radiotherapy for adjuvant therapy of lymph node positive locally advanced gastric cancer. AB - Aim of the Study: Although surgery is considered to be curative treatment, recurrence rates are high in gastric cancer. Adjuvant 5-fluorouracil (5-FU) based chemoradiotherapy has been shown to improve the prognosis. We compared tolerability and efficacy of the two different chemotherapy regimens; 5 FU/leucovorin (LV) versus cisplatin with capecitabine (XP) combined with radiotherapy (RT) in the adjuvant therapy of the lymph node positive locally advanced gastric cancer. Materials and Methods: Totally, 104 patients who underwent curative surgery with lymph node resection were evaluated, respectively. Patients were stratified two group based on the adjuvant chemoradiotherapy regimen. Group 1 (n = 46) received XP followed capecitabine with RT (XRT) then XP. Group 2 (n = 58) received 5-FU/LV combined with RT postoperatively. Two groups were compared based on clinicopathological parameters. Factors related with disease-free survival (DFS) and overall survival (OS) were analyzed. Results: Totally, 32 patients had recurrent disease, and there was no difference between two groups. While peritoneal metastasis was more common in XP arm, distant metastasis was commonly seen in 5-FU/LV arm. There was no significant difference between two groups in regard of Grade 3/4 toxicitis; hematologic toxicities were more in 5-FU/LV group than XP arm. In addition, dose modification because of toxicities were more frequent in 5-FU/LV arm (P = 0.003). For all groups, lymph node dissection type was related with DFS, surgical margin and recurrence were important for OS. Conclusion: XP-XRT regimen is well tolerated with lower toxicity compared the standard 5-FU/LV-RT. Although there is no difference with respect to outcome, patients with XP arm without the necessity of intravenous catheter admitted hospital less frequent than bolus5-FU/LV arm. PMID- 30249897 TI - Advanced signet-ring cell carcinoma of the stomach: Clinicopathological characteristics of patients and efficacy of the modified docetaxel, cisplatin, and fluorouracil regimen. AB - Background: The aim of this retrospective study was to investigate the clinicopathological characteristics of patients with signet-ring cell carcinoma (SRCC) of the stomach, and the efficacy of the modified docetaxel, cisplatin, and fluorouracil (mDCF) chemotherapy regimen. Patients and Methods: Sixty-five patients diagnosed with metastatic or recurrent SRCC and treated with at least one course of mDCF regimen as the first-line treatment at our hospital July 2007 and January 2015, were included in this study. The mDCF protocol comprised docetaxel at 60 mg/m2/day (day 1), cisplatin at 60 mg/m2/day (day 1), and 5 fluorouracil at 600 mg/m2/day (days 1-5) for every 3 weeks. Results: The median age was 53 years (range, 25-69 years). The most frequent sites of metastasis were the peritoneum (50.8%) and liver (21.5%). The median number of chemotherapy courses was six. In assessing 61 patients for response evaluation, one patient (1.6%) achieved a complete response, and 36 (59.0%) achieved a partial response. Fifteen patients (24.6%) had stable disease and nine (14.8%) had progressive disease. Grades 3-4 hematological toxicity revealed anemia in three (4.6%) patients, thrombocytopenia in two (3.1%), and neutropenia in five (7.7%). Grades 3-4 nonhematological side effects revealed nausea and vomiting in four (6.1%) patients and mucositis in one (1.5%). The overall survival (OS) and progression free survival (PFS) were 10.4 months (95% confidence interval [95% CI], 8.9-12.0) and 6.1 months (95% CI, 5.1-7.0), respectively. Multivariate analysis showed that Eastern Cooperative Oncology Group (ECOG) performance score of 2 and a high pretreatment carcinoembryonic antigen level were statistically significant. Conclusions: mDCF is an effective regimen in patients with SRCC of the stomach who have ECOG performance score of 0-1 when the PFS, OS, and tumor response rate are considered. Further prospective studies including more patients should be conducted on this subject. PMID- 30249898 TI - Human colorectal cancer antigen GA733-2-Fc fused to endoplasmic reticulum retention motif KDEL enhances its immunotherapeutic effects. AB - Objective: The aim of this is to compare the immunotherapeutic effects of human colorectal cancer antigen GA733-2 fused to the Fc fragment of antibody (GA733-2 Fc) and to Fc and endoplasmic reticulum (ER) retention motif KDEL (GA733-2-Fc KDEL). Materials and Methods: Recombinant GA733-2-Fc and GA733-2-Fc-KDEL were produced from infiltrated Nicotiana benthamiana leaves and purified by affinity chromatography. Glycan structures were determined by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. The allergic and immunogenic responses of recombinant GA733-2-Fc and GA733-2-Fc-KDEL were estimated in an intraperitoneally immunized mouse. The tumor regression effect of recombinant GA733-2-Fc and GA733-2-Fc-KDEL was examined using a colorectal carcinoma CT-26 animal model. Results: Recombinant GA733-2-Fc contained plant specific glycan structures including beta(1,2)-xylose and alpha(1,3)-fucose whereas recombinant GA733-2-Fc-KDEL contained oligomannose type glycan structures. Mice immunized intraperitoneally with recombinant GA733-2-Fc and GA733-2-Fc-KDEL elicited strong GA733-2-Fc-specific immunoglobulin G (IgG) and IgA serum antibody responses. Recombinant GA733-2-Fc-KDEL reduced the production of GA733-2-Fc-specific IgE. Recombinant GA733-2-Fc-KDEL increased the production of interferon-gamma. Intraperitoneal preimmunization with recombinant GA733-2-Fc and GA733-2-Fc-KDEL regressed tumor growth in a colorectal carcinoma CT-26 animal model. The tumor regression effect induced by recombinant GA733-2-Fc-KDEL was greater than that induced by recombinant GA733-2-Fc. The human and mouse colorectal carcinoma cell binding activities of recombinant GA733-2-Fc-KDEL immunized sera were higher than those of recombinant GA733-2-Fc. Conclusions: Our results suggest that GA733-2-Fc conjugated to ER-retention motif KDEL is a more efficient antigen to prevent tumor growth induced by colorectal carcinoma and minimize an allergic response. PMID- 30249899 TI - Clinical significance of interleukin-6 in diagnosis of lung, oral, esophageal, and gall bladder carcinomas. AB - Introduction: Chronic inflammation predisposes to cancer. Cytokines play an essential role in cancer pathogenesis. Interleukin-6 (IL-6) is a pleiotropic cytokine that enables growth and differentiation of tumors. The effects of IL-6 are mediated by signal transducers and activators of transcription 3 (STAT3). STAT3 deficiency reduced tumor incidence and growth while STAT3 hyperactivation has an opposite effect; also it negatively regulates p53 gene. IL-6/STAT3 signaling is crucial in carcinogenesis linked to inflammation. Increased IL-6 levels are observed in cancer. Studies investigating the role of IL-6 is limited. Aim: This study aims at determining IL-6 levels in lung, oral, esophageal, and gallbladder cancer patients. Materials and Methods: Subjects consisted of 175 patients with lung, oral, gall bladder, and esophageal cancers. The patients included 68 females and 107 males with an average age of 52 years. Fifty healthy individuals served as controls. IL-6 was detected by electrochemiluminescent immunoassay principle. Results: IL-6 values were determined in 175 (21 lung, 55 oral, 17 esophageal and 82 gallbladder) cancer patients. Of these, 147/175 (18 lung, 43 oral, 13 esophageal and 73 gallbladder) cancer patients (84%) showed higher IL-6 levels as compared to control group (normal range: <7 pg/ml). Conclusion: This indicates a significant correlation between IL-6 overexpression and cancer development, highlighting the significance of IL-6 in oral, lung, esophageal, and gallbladder carcinomas. IL-6 may be used as a tumor marker for cancer diagnosis. It may be a clinically significant predictor and may represent a target for cancer treatment. However, to definitely conclude this, further extensive studies would be required. PMID- 30249900 TI - A randomized phase III study of hepatic arterial infusion chemotherapy with 5 fluorouracil and subsequent systemic chemotherapy versus systemic chemotherapy alone for colorectal cancer patients with curatively resected liver metastases (Japanese Foundation for Multidisciplinary Treatment of Cancer 32). AB - Aim: This randomized phase III trial compared hepatic arterial infusion (HAI) chemotherapy with 5-fluorouracil (5-FU) followed by uracil/tegafur (UFT) and leucovorin (LV) versus UFT/LV alone for patients with curatively resected liver metastases from colorectal cancer (CRC). Methods: The study was designed to include 280 patients to be randomized to receive either HAI with 5-FU followed by UFT/LV (Arm A) or UFT/LV alone (Arm B) to assess whether HAI chemotherapy improved disease-free survival (DFS). Results: Forty-four patients were randomized. Three-year DFS was relatively worse in the experimental arm although this difference was not statistically significant (43.5% in Arm A vs. 58% in Arm B; hazard ratio [HR], 1.304; P = 0.534). The experimental arm also tended to have a worse 3-year overall survival rate (80.2% in Arm A vs. 85.2% in Arm B; HR, 2.255; P = 0.192). There was no significant difference in the frequency of Grade 3 or higher toxicities between the two arms. Conclusion: Although this study was limited by a small sample size after early study termination, our analysis found that HAI with 5-FU followed by UFT/LV did not improve the DFS of patients with curatively resected liver metastases from CRC compared with UFT/LV alone. The future studies are necessary to evaluate the survival benefit of HAI in combination with newer systemic chemotherapeutic agents for patients with resectable liver metastases from CRC. PMID- 30249901 TI - Four-and-a-half LIM protein 1 promotes paclitaxel resistance in hepatic carcinoma cells through the regulation of caspase-3 activation. AB - Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Aim: To investigate the mechanisms of paclitaxel resistance in hepatocellular carcinoma cells and find promising molecular target for HCC therapy. Materials and Methods: To investigate the effects of FHL1 on chemo resistance in HCC cells, we generated FHL1 knock-down stable cell lines with HepG2 and SMMC7721 cells. Cell viability assay, colony formation and xenograft experiments assay were performed to detect effect of FHL1 on Paclitaxel or Oxaliplatin resistance in vitro and in vivo. Caspase activity assay was performed to explore the activation of caspase-3 and caspase-9 in paclitaxel treated FHL1 knockdown HepG2 cells. Result: In the present study we have investigated that four-and-a-half LIM protein 1 (FHL1), which plays an important role in the development of cancer, is associated with both the chemo resistance of hepatocellular carcinomas cells in vitro and in vivo. Knockdown of FHL1 significantly enhanced the sensitivity of paclitaxel, but had no effects on sensitivity of oxaliplatin. Moreover, knockdown of FHL1 promoted the activation of caspase-3 and caspase-9, which were induced by paclitaxel. Interestingly, FHL1 negatively regulates the chemo resistance of HCC in xenografted nude mice. Conclusion: FHL1 promote paclitaxel resistance in hepatocellular carcinomas cells through regulating apoptosis induced by paclitaxel, suggesting that FHL1 may be a promising molecular target for HCC therapy. PMID- 30249902 TI - Hepatitis B and C rates are significantly increased in certain solid tumors: A large retrospective study. AB - Objective: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with significant morbidity and mortality among cancer patients who received cytotoxic chemotherapy. The aim of current study was to elucidate the prevalence of HBV and HCV among large population of solid cancers and lymphoma and to compare them with large number of control group. Patients and Methods: Between 2000 and 2014, 8322 cancer patients who were admitted to Oncology Departments were evaluated retrospectively and 3890 patients in whom hepatitis serology were available were included in this study. Their results were compared with control group that consisted of 96,000 subjects. Results: In control groups, hepatitis B surface antigen (HBsAg) positivity rate was 3.3% and anti-HCV positivity rate was 0.84%. In cancer patients, HBsAg positivity rate was 3.65% and anti-HCV positivity rate was 1.2%. Neither HBsAg positivity rate nor anti-HCV positivity rate was statistically significant between groups (P = 0.12 and P = 0.09, respectively). HBsAg positivity rates of head and neck cancer (5.88%; P = 0.02), rectum (5.6%; P = 0.025), and gastric and esophagus cancer (5.88%; P = 0.025) were significantly higher than control groups. Anti-HCV positivity rate (2.5%; P = 0.0016) was significantly higher in lung cancer when compared with control group. Conclusion: The current study elucidated the prevalence of HBV and HCV among large population of solid cancers and lymphoma and we showed that hepatitis B and C positivity rates are significantly increased in certain solid tumors. Our findings should also be clarified with large prospective studies. PMID- 30249903 TI - Preventive effect of ethanolic extract of cactus (Opuntia ficus-indica) cladodes on methotrexate-induced oxidative damage of the small intestine in Wistar rats. AB - Context: Methotrexate (MTX) is a cytotoxic chemotherapeutic element for various inflammatory diseases. The cytotoxic effect of MTX is also seen in normal tissues having a high proliferation rate including gastrointestinal and bone marrow. Aims: The aim of this study was to find out whether oxidative damage could be relevant for MTX-induced toxicity in vivo using Wistar rats and to investigate the preventive potential of cactus cladodes. Materials and Methods: Adult and healthy male Wistar rats (200-250 g) were pretreated by ethanol fraction of cactus cladodes. Following a single dose of MTX (20 mg/kg), either vehicle (saline) or ethanolic (400 mg/kg) was administered intraperitoneally. All animals were killed 24 h after the intraperitoneal injection of MTX. Small intestine samples were collected for malondialdehyde (MDA) level, protein carbonyl generation, and peroxidase and catalase (CAT) activity measurement. The small intestine was also collected for histopathology analysis. Statistical Analysis Used: Each experiment was conducted in triplicate separately. Values were presented as a mean +/- standard deviation. Differences were considered significant at P < 0.05. Results: Our results showed that MTX-induced significant alterations in oxidative stress markers noticed in the form of intestinal tissues damage, MDA level increased and protein carbonyls generation. CAT and peroxidase activities decreased with MTX administration. The combined treatment of MTX with cactus extracts showed a reduction of MTX-induced oxidative damage. Conclusions: It could be concluded that cactus cladodes extract was effective in protecting the small intestine against MTX-induced damage. PMID- 30249904 TI - Primary large cell neuroendocrine carcinoma of the prostate in a hormone naive patient: A case report from Taiwan. AB - Large cell neuroendocrine carcinoma (LCNEC) of the prostate is extremely rare. Previously reported cases in the literature were almost exclusively developed in men receiving androgen deprivation therapy for prostate adenocarcinoma. We herein present a case of de novo LCNEC: A 66-year-old male was incidentally diagnosed as LCNEC after he underwent transurethral resection of prostate. The stage was T4N1M1. Therefore, the patient was treated with 6 cycles of cisplatin and etoposide in the following 6 months, which achieved a partial remission. He gave up the chance to eradicate the residual mass. Three months later, the tumor progressed rapidly. In conclusion, LCNEC is a rare prostate cancer. Our experience shows that chemotherapy with etoposide and cisplatin is effective to achieve a significant remission. However, LCNEC is highly malignant in nature, postchemotherapy surgery for the residual mass should be considered. PMID- 30249905 TI - Bevacizumab and stereotactic radiosurgery achieved complete response for pediatric recurrent medulloblastoma. AB - Recurrent medulloblastoma has a very poor prognosis in children regardless of the treatment employed. We report the case of a 3-year-old child with recurrent refractory medulloblastoma who was treated with both bevacizumab and stereotactic radiosurgery (SRS). The boy was found to harbor a tumor in the cerebral posterior fossa in November 2010. Craniotomy was performed to remove the tumor completely. Postoperative pathological examination showed desmoplastic medulloblastoma. Craniospinal radiotherapy and chemotherapy were performed. Three years later, the boy suffered from constant headache again. Magnetic resonance imaging showed seeding of medulloblastoma in the posterior fossa as four masses with diameter ranging from 2 cm to 3 cm. To avoid overdose radiation, we used SRS and anti angiogenesis therapy. Bevacizumab was given at 10 mg/kg for four times with an interval of 1 month. Gamma Knife (Leksell Gamma Knife(r), Elekta Instruments, Stockholm, Sweden) was used targeting at one lesion each time and performed for consecutive two times with bevacizumab therapy. Following this combined treatment, the lesions targeted with radiosurgery showed complete response with minimal toxicity in <1 month successively. The combined use of bevacizumab and SRS may represent a novel treatment against medulloblastoma in patients who are not surgical candidates, and should be investigated further. This is the first documented case of medulloblastoma treated with bevacizumab and SRS. Further clinical trials should be considered to evaluate the effectiveness of this strategy. PMID- 30249906 TI - Pancreatic primitive neuroectodermal tumor: Focus on radiological features and differential diagnosis - A case report and literature review. AB - Primitive neuroectodermal tumor (PNET) is an exceedingly rare type of malignant tumor. The diagnosis of pancreatic PNET is usually challenging for radiologists and surgeons, especially when an accurate preoperative diagnosis is needed. Herein, we report a case of a 36-year-old patient with a mass diagnosed as PNET in the head of the pancreas and present a literature review. Compared to previous literature reports, there were some imaging features observed by computed tomography (CT) in our case that might be helpful for a relatively accurate preoperative diagnosis. PNET should be considered preoperatively for soft-tissue neoplasms of the pancreas when the diagnosis of more common pancreatic tumors is not favored by signs in CT, especially in pediatric and adolescent populations. This case is the 20th case of pancreatic PNET reported in literature. PMID- 30249907 TI - Low-grade myofibroblastic sarcoma of the pancreas: A case report and literature review. AB - Low-grade myofibroblastic sarcoma (LGMS) is a malignant tumor with myofibroblastic differentiation, which frequently occurs in the oral cavity and extremities. Here, we report a case of LGMS of the pancreas in a 44-year-old female presented to our hospital with recurrent upper abdominal pain. Computed tomography revealed a low-density solid tumor at the body of the pancreas. Distal pancreatectomy combined with splenectomy was performed. LGMS of the pancreas was diagnosed by the histological features together with immunohistochemical findings. The patient received adjuvant chemotherapy after surgery and remained asymptomatic for 5 years. Previous studies and our experience suggested that surgical excision with wide margins is the reasonable treatment of LGMS and adjuvant therapy may improve its prognosis. PMID- 30249908 TI - Trisomy 3 as an acquired cytogenetic abnormality in primary acute megakaryoblastic leukemia. AB - Acute myeloid leukemia has a rare subtype in French-American-British classification as M7 or acute megakaryoblastic leukemia. Chromosome abnormalities in cases with acute megakaryoblastic leukemia can affect their prognosis. Evaluation of these abnormalities and their impact are not fully elucidated. This case presentation is about 16 months female who has a rare abnormality (trisomy 3) alongside acute megakaryoblastic leukemia. The remarkable point is that her malignancy is as primary or non-Down syndrome acute megakaryoblastic leukemia. The author's suggestion through this case presentation is the necessity of drawing a cytogenetic profile, especially in cases with acute megakaryoblastic leukemia for better treatment strategies. PMID- 30249909 TI - Successful management of a patient with radiological presentation of choriocarcinoma syndrome before induction chemotherapy. AB - Choriocarcinoma syndrome is a life-threatening lysis syndrome caused by blood vessel rupture and subsequent tumor bleeding. We describe a case of pretreatment choriocarcinoma syndrome that developed in a 27-year-old man. He underwent a high orchiectomy at a local hospital and was diagnosed with metastatic testicular tumor given the high serum human chorionic gonadotropin levels (943,601 mIU/mL). Thus, he was referred to our institution. Although he had bulky lung metastases and alveolar bleeding, we were able to administer full-dose chemotherapy with etoposide and cisplatin. On day 3 of chemotherapy, he presented with severe hypoxia and worsening of alveolar bleeding. Thus, he underwent tracheal intubation at the Intensive Care Unit. Full-dose chemotherapy was continued, and the patient was extubated upon improvement. He is currently alive and continuing treatment at another hospital. PMID- 30249910 TI - Renin-producing germ cell tumor in the pineal apparatus and mediastinum: A rare case report. AB - Ectopic extrarenal renin-producing tumor is a rare disease with approximately 30 case reports in English literature. We herein present the first case of renin producing germ cell tumors in the pineal apparatus and mediastinum. A 26-year-old man who had undergone craniotomy for the treatment of pineal tumor was found to have hypertension at a regular visit postoperatively. Laboratory findings revealed high plasma levels of renin activity and that of aldosterone concentration. Chest computed tomography demonstrated a large tumor in the mediastinum. The pathological findings revealed the mediastinal germ cell tumor positive for renin. The present case suggests that for young patients presenting with hypertension with a mediastinal tumor, the possibility of a renin-producing tumor should be considered. PMID- 30249911 TI - Hemangioma of rib masquerading a malignancy. AB - Hemangioma of bone is a rare bone tumor accounting for <1% of all osseous tumors. Hemangiomas are common in skull and vertebrae but uncommon in rib. Rib hemangiomas may increase in size over a period and may cause symptoms due to increasing size. Preoperative diagnosis is not always possible due to overlapping radiological features between benign and malignant lesions. Use of preoperative aspiration and biopsy has their own risks and benefit. Excision of rib in case of monostotic rib lesions is the treatment of choice due to low risk of recurrence and no reported postoperative complications. We report a case of rib hemangioma which mimicked a malignancy preoperatively. PMID- 30249912 TI - Sinonasal paraganglioma and Cushing's syndrome: A rare association. AB - In general, paragangliomas are symptomatic tumors, which may be clinically taken for other tumors, benign or malignant lesions. Paragangliomas of the nasal cavity and paranasal sinuses are an extremely rare entity and what is even rarer is its association with ectopic adrenocorticotropic hormone production. We report this very rare case to highlight the rare association of Cushing's syndrome with nasal paraganglioma and the importance of total surgical resection in its treatment. PMID- 30249913 TI - Malignant melanoma metastasizing to tonsil: A rare presentation. AB - Malignant melanoma (MM) has a high potential of lymphatic and hematogeneous spread, and metastatic disease is always incurable with a high mortality. We present a rare phenomenon of MM metastasizing to the palatine tonsil. PMID- 30249915 TI - Contraception, opisthorchiasis, and cholangiocarcinoma. PMID- 30249914 TI - Sunitinib-induced acute severe hypothyroidism in a case of metastatic gastrointestinal stromal tumor: A case report. AB - Thyroid abnormalities are found nearly 70% cases receiving sunitinib therapy. Mostly, patients suffer transient hypothyroidism rarely presents with overt acute symptoms requiring levothyroxine replacement. Onset is variable in published literature. We report a case of metastatic gastrointestinal stromal tumor receiving sunitinib with normal baseline thyroid function. The patient developed symptoms of acute severe hypothyroidism with high thyroid stimulating hormone level on the 4th week of therapy. The patient responded with oral levothyroxine. clinical and biochemical parameter resolved rapidly. Patient receiving sunitinib warns baseline and subsequent surveillance of thyroid function (both clinical and biochemical). This rare dreadful condition reverts promptly with thyroxine replacement. PMID- 30249916 TI - Tian Xian Liquid: Is it a really effective anticancer dietary supplement? PMID- 30249917 TI - Phenotype and Prognosis of the Lamin A/C Gene (LMNA) Mutation Carriers in Japan. PMID- 30249918 TI - Application of Awake Surgery for Epilepsy in Clinical Practice. AB - Epilepsy surgery aims to control epilepsy by resecting the epileptogenic region while preserving function. In some patients with epileptogenic foci in and around functionally eloquent areas, awake surgery is implemented. We analyzed the surgical outcomes of such patients and discuss the clinical application of awake surgery for epilepsy. We examined five consecutive patients, in whom we performed lesionectomy for epilepsy with awake craniotomy, with postoperative follow-up > 2 years. All patients showed clear lesions on magnetic resonance imaging (MRI) in the right frontal (n = 1), left temporal (n = 1), and left parietal lobe (n = 3). Intraoperatively, under awake conditions, sensorimotor mapping was performed; primary motor and/or sensory areas were successfully identified in four cases, but not in one case of temporal craniotomy. Language mapping was performed in four cases, and language areas were identified in three cases. In one case with a left parietal arteriovenous malformation (AVM) scar, language centers were not identified, probably because of a functional shift. Electrocorticograms (ECoGs) were recorded in all cases, before and after resection. ECoG information changed surgical strategy during surgery in two of five cases. Postoperatively, no patient demonstrated neurological deterioration. Seizure disappeared in four of five cases (Engel class 1), but recurred after 2 years in the remaining patient due to tumor recurrence. Thus, for patients with epileptogenic foci in and around functionally eloquent areas, awake surgery allows maximal resection of the foci; intraoperative ECoG evaluation and functional mapping allow functional preservation. This leads to improved seizure control and functional outcomes. PMID- 30249920 TI - The Method for Placement of an Intraoperative Continuous Facial Nerve Stimulating Electrode in Acoustic Neuroma Surgery: Technical Note. AB - Preservation of facial nerve (FN) function is the most important goal in acoustic neuroma (AN) surgery. We have been using intraoperative continuous facial nerve monitoring (ICFNm) of evoked electromyography during AN surgery. ICFNm is very useful, and we can identify the real-time functions of the FN. Some surgeons have experienced difficulty with placing the ICFN stimulating electrode (SE). We therefore show how to place the ICFN SE. We mostly perform AN surgery with a retrosigmoid approach (RSA). A craniotomy with four burr holes is performed. We dissect the arachnoid membrane along the accessory nerve from the cisterna magna to the glossopharyngeal nerve. When we are able to identify the root exit zone (REZ) of the FN near the brainstem, we place the ICFN SE on it. However, when a large tumor covers the REZ, we have to debulk the tumor to create a space between the tumor and the glossopharyngeal nerve. After that, we can place the SE on the REZ. A method for placement of the ICFN SE is needed for some techniques of AN surgery. Once we learn how to place the SE, we can identify continuous FN function during AN surgery. This method is useful for the preservation of postoperative FN function in AN surgery. PMID- 30249921 TI - Perioperative Sildenafil Therapy in Pediatric Congenital Cardiac Disease Patients. AB - Sildenafil is a pulmonary artery hypertension (PH)-targeted drug that finds an increased indiscriminate use in children with PH secondary to congenital heart disease (CHD).We performed a meta-analysis to evaluate the effects of sildenafil on pediatric patients with PH secondary to CHD during perioperative period.PubMed, EMBASE, the Cochrane Library, and the Google Scholar were searched up to May 2016 for randomized controlled trials (RCTs) assessing the perioperative treatment of sildenafil in pediatric patients with PH secondary to CHD. Major clinical outcomes were mortality before discharge, length of ICU stay, and length of hospitalization. The outcomes were analyzed as continuous and dichotomized variables by using fixed or random effect model, and we computed the pooled RR and MD with 95% confidence interval.Five RCTs involving 238 pediatric patients with PH experienced CHD operation were included. Sildenafil was used in all trials. We observed no differences in mortality before discharge (RR 0.35; 95% CI 0.06-2.10; chi2 = 1.31, I2 = 0.24, P = 0.25) and length of hospitalization (MD -0.50; 95% CI -1.60 to 0.60; chi2 = 5.29, I2 = 62%, P = 0.38). There was a decrease in the length of ICU stay (MD -18.18; 95% CI -24.68 to -11.67; chi2 = 12.61, I2 = 84%, P < 0.00001), which had a high heterogeneity. The findings were robust after the sensitivity analyses.The perioperative treatment of sildenafil for CHD pediatric patients is a potential method to reduce the length of ICU stay. We observed no differences with the use of it in the mortality before discharge and the length of hospitalization. PMID- 30249922 TI - Renoprotective Transcatheter Aortic Valve Implantation Without Contrast Media. AB - The therapeutic role of transcatheter aortic valve implantation (TAVI) in high surgical risk or inoperable cases has been established. Most of the candidates for TAVI are elderly and have multiple comorbidities including chronic kidney disease. However, contrast-enhanced computed tomography and coronary angiography, both of which require iodine contrast media, are essential for pre-procedural planning. In addition, TAVI could have adverse effects on kidney function including contrast media-induced nephrotoxicity. Acute kidney injury following TAVI has been reported to be related to poor prognosis. In a case with advanced renal dysfunction, we successfully avoided post-procedural acute kidney injury by performing pre-procedural evaluation using minimal contrast and TAVI without contrast media. If anatomical conditions and experiences of the heart team are adequate, renoprotective TAVI should be a favorable therapy for patients with aortic stenosis complicated by renal dysfunction. PMID- 30249919 TI - Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma. AB - Glioblastoma (GBM) is a highly malignant type of primary brain tumor with a high mortality rate. Although the current standard therapy consists of surgery followed by radiation and temozolomide (TMZ), chemotherapy can extend patient's post-operative survival but most cases eventually demonstrate resistance to TMZ. O6-methylguanine-DNA methyltransferase (MGMT) repairs the main cytotoxic lesion, as O6-methylguanine, generated by TMZ, can be the main mechanism of the drug resistance. In addition, mismatch repair and BER also contribute to TMZ resistance. TMZ treatment can induce self-protective autophagy, a mechanism by which tumor cells resist TMZ treatment. Emerging evidence also demonstrated that a small population of cells expressing stem cell markers, also identified as GBM stem cells (GSCs), contributes to drug resistance and tumor recurrence owing to their ability for self-renewal and invasion into neighboring tissue. Some molecules maintain stem cell properties. Other molecules or signaling pathways regulate stemness and influence MGMT activity, making these GCSs attractive therapeutic targets. Treatments targeting these molecules and pathways result in suppression of GSCs stemness and, in highly resistant cases, a decrease in MGMT activity. Recently, some novel therapeutic strategies, targeted molecules, immunotherapies, and microRNAs have provided new potential treatments for highly resistant GBM cases. In this review, we summarize the current knowledge of different resistance mechanisms, novel strategies for enhancing the effect of TMZ, and emerging therapeutic approaches to eliminate GSCs, all with the aim to produce a successful GBM treatment and discuss future directions for basic and clinical research to achieve this end. PMID- 30249925 TI - Incidence and Clinical Course of Limb Dysfunction Post Cardiac Catheterization - A Systematic Review. AB - BACKGROUND: We systematically reviewed the available literature on limb dysfunction after transradial access (TRA) or transfemoral access (TFA) cardiac catheterization. Methods and Results: MEDLINE and EMBASE were searched for studies evaluating any transradial or transfemoral procedures and limb function outcomes. Data were extracted and results were narratively synthesized with similar treatment arms. The TRA group included 15 studies with 3,616 participants and of these 3 reported nerve damage with a combined incidence of 0.16% and 4 reported sensory loss, tingling and numbness with a pooled incidence of 1.61%. Pain after TRA was the most common form of limb dysfunction (7.77%) reported in 3 studies. The incidence of hand dysfunction defined as disability, grip strength change, power loss or neuropathy was low at 0.49%. Although radial artery occlusion (RAO) was not a primary endpoint for this review, it was observed in 3.57% of the participants in a total of 8 studies included. The TFA group included 4 studies with 15,903,894 participants; the rates of peripheral neuropathy were 0.004%, sensory neuropathy caused by local groin injury and retroperitoneal hematomas were 0.04% and 0.17%, respectively, and motor deficit caused by femoral and obturator nerve damage was 0.13%. CONCLUSIONS: Limb dysfunction post cardiac catheterization is rare, but patients may have nonspecific sensory and motor complaints that resolve over a period of time. PMID- 30249926 TI - LINC-PINT Activates the Mitogen-Activated Protein Kinase Pathway to Promote Acute Myocardial Infarction by Regulating miR-208a-3p. AB - BACKGROUND: This study is performed to explore the differential expression of long intergenic non-coding-p53 induced non-coding transcript, miR-208a-3p and JUN in acute myocardial infarction (AMI) and their potential mechanisms. Methods and Results: Gene Expression Omnibus, R software, Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analysis were used for analyzing the differentially expressed genes (DEGs) and pathways. The differential expressions of LINC-PINT and miR-208a-3p were examined by qRT-PCR. The expressions of JUN and the mitogen-activated protein kinase (MAPK) pathway-related proteins were analyzed by Western blot. The triphenyltetrazolium chloride (TTC) staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining methods were used to measure the myocardial infarction size and tissue apoptosis respectively. The targeted relationships between miR 208a-3p and LINC-PINT or JUN were confirmed using a dual luciferase reporter assay. DEGs were significantly enriched in the MAPK signaling pathway. LINC-PINT could sponge miR-208a-3p, which targeted and regulated JUN. LINC-PINT and JUN were confirmed to be overexpressed in AMI tissues. Silencing LINC-PINT and JUN could exert a protective influence against AMI. The expression of miR-208a-3p was significantly decreased in AMI tissues, and miR-208a-3p reduced myocardial ischemia-reperfusion injury and apoptosis. Downregulation of LINC-PINT facilitated miR-208a-3p expression and suppressed the protein level of JUN, contributing to the inactivation of the MAPK pathway in the AMI tissues and thus generating protective effects. CONCLUSIONS: Knockdown of LINC-PINT inactivated the MAPK pathway by releasing miR-208a-3p and suppressing the JUN, protecting the injury during the process of AMI. PMID- 30249927 TI - Collection and frozen storage of semen for artificial insemination in red foxes (Vulpes vulpes). AB - This study was conducted on red foxes to determine the appropriate voltage in electroejaculation for semen collection from stud males, and to confirm whether frozen semen with bovine semen extender can be used for artificial insemination. The proper load voltage for electroejaculation was 3-4 V based on semen collection rates and concentrations of spermatozoa. Frozen semen was prepared according to the known procedure for cows. In frozen-thawed semen, a relatively high conception rate (81.3%) was obtained in vixens, in which the optimum insemination time was detected by vaginal electrical resistance. These findings demonstrate that the restricted condition for semen collection by electroejaculation with cryopreservation of semen using bovine semen extender can be applied to artificial insemination of red foxes. PMID- 30249928 TI - Primary cardiac lymphoma in a 10-week-old dog. AB - A 10-week-old miniature dachshund presented with acute onset of weakness. Electrocardiography showed sustained ventricular tachycardia, and thoracic and abdominal radiography revealed pleural and peritoneal effusion. Echocardiography revealed severely hypokinetic left and right ventricles. Thoracocentesis and abdominocentesis and subsequent transfer to an oxygen chamber yielded no clinical improvement, and the dog died about 1 hr after admission. Gross examination of a longitudinal section through the entire heart revealed poorly demarcated focal or patchy areas of grayish-white tissue infiltrating extensively into the myocardium. Histologically, these lesions were consistent with infiltrative proliferation of neoplastic lymphoid cells. Immunohistochemical staining confirmed the diagnosis of primary cardiac lymphoma (PCL) of T-cell origin. There have been no previous reports of such young dogs with PCL. PMID- 30249929 TI - Towards Green Titration: Downscaling Sequential Injection Analysis Lab-at-valve Titration System with Stepwise Addition of Titrant. PMID- 30249930 TI - Comparison of 0.1 M Stable CsCl and 1 M NH4NO3 as an Extraction Reagent to Evaluate Cs-137 Mobility in Soils. PMID- 30249931 TI - Green Synthesis of Blue Fluorescent P-doped Carbon Dots for Selective Determination of Picric Acid in Aqueous Medium. PMID- 30249932 TI - Improving the job-retention strategies in multiple sclerosis workers: the role of occupational physicians. AB - Several studies evaluated whether a person with multiple sclerosis is employed or not and investigated the main symptoms that hinder the job performance. However, despite occupational physicians are fundamental in managing disabled subjects, there is a serious lack of data regarding their role in improving employability of these workers. In this regard, we assessed occupational physicians' professional activity and training/updating needs in order to identify and develop management tools, operative procedures and training programs helpful to support and implement adequate job-retention strategies. 403 Italian occupational physicians compiled a self-administered questionnaire to evaluate individual demographics, health surveillance system, fitness for work and training needs. Our findings confirmed the suitability to adopt environmental adjustments at workplace (particularly referring to the ergonomics of workstation, the typology of occupational risk factors and the working time) to accommodate individual's needs in order to improve working ability among multiple sclerosis workers. Moreover, training events discussing operational guidelines and standardized instruments and/or methodologies to adequately manage the disable workers should be fostered. Therefore, in this regard, occupational physicians could play a key role but they need more high-quality training especially concerning the different tools that are currently available to assess the work issues in multiple sclerosis patients. PMID- 30249933 TI - A large-scale study of treatment methods for foreign bodies in the maxillary sinus. AB - Recently, reports regarding a foreign body in the maxillary sinus have considerably increased, with the majority being iatrogenic cases resulting from dental treatment. This study involves an extensive review of the Japanese literature, including 112 papers from 1978 to 2017. These papers documented total 407 cases of a foreign body in the maxillary sinus. Among the 392 cases for which treatment details were available, the Caldwell-Luc approach was used for 216, the alveolar approach for 116, extraction using nasal endoscopy for 15, and extraction using oral endoscopy for eight. Spontaneous passage occurred in 19 cases, follow-up with medication was used in 17, and "other" was noted in one. This study determined that surgical removal remains the most common method for treating both tooth roots and other foreign bodies and that the Caldwell-Luc approach is used in majority of the surgeries. No marked differences were noted among the removal methods used in relation to the foreign body type. PMID- 30249934 TI - Effect of age on pulpal blood flow in human teeth during orthodontic movement. AB - We aimed to assess the relationship between age, pulpal blood flow (PBF), and orthodontic treatment outcomes. Decreased blood supply to pulp cells commonly occurs with age and can change the response of pulp to orthodontic tooth movement. This study was conducted in 28 human subjects divided into 2 groups according to age. A laser Doppler flowmeter was used to record blood flow to the teeth prior to and during the course of orthodontic treatment (days 1, 3, and 7; week 3; and month 1). Data were analyzed using Wilcoxon signed-rank and Mann Whitney U tests. Mean PBF values were significantly higher in the young group compared to the old group at all time points (P < 0.001). The decreased PBF in response to tooth movement was more severe in the old group and was also of longer duration. Pulp in younger patients had significantly higher blood flow values compared to that in older patients at baseline and throughout the course of the study. PMID- 30249935 TI - p53- and ROS-mediated AIF pathway involved in TGEV-induced apoptosis. AB - We previously demonstrated that transmissible gastroenteritis virus (TGEV) could induce apoptosis through caspase signaling. However, apoptosis was not completely prevented by caspases inhibitors, suggesting that there may be a caspase independent pathway involved in TGEV-induced cell apoptosis. In this study, we investigated the regulation of apoptosis-inducing factor (AIF) on TGEV-induced apoptotic pathway. Results indicated that AIF translocated from the mitochondria to nucleus during TGEV infection, and the AIF inhibitor, N-phenylmaleimide (NP), significantly attenuated the apoptosis. In addition, the translocation of AIF was inhibited by Veliparib (ABT-888), an inhibitor of poly (ADP-ribose) polymerase (PARP). And the reactive oxygen species (ROS) scavenger, pyrrolidinedithiocarbamic (PDTC), redistributed AIF in the mitochondria and nucleus in TGEV-infected cells. Moreover, the protein levels in nucleus and the mRNA levels of AIF were inhibited in the presence of the p53 inhibitor, pifithrin alpha (PFT-alpha) or in TGEV-infected p53-/-cells. Furthermore, TGEV-induced apoptosis was blocked by combination of three or more inhibitors, such as pan caspase inhibitor Z-VAD-FMK, NP, ABT-888, PDTC, PFT-alpha, to treat PK-15 cells. Taken together, these results suggest that the p53- and ROS-mediated AIF pathway and caspase-dependent pathway were involved in TGEV-induced apoptosis. PMID- 30249936 TI - Effects of cilostazol on the heart rate in healthy dogs. AB - Appropriate dosages of cilostazol have not been studied in veterinary patients, and the degrees of heart rate (HR) increase have not been studied in dogs administered cilostazol. Therefore, this study aimed to investigate the degrees of HR increase in healthy dogs administered cilostazol. Thirty healthy beagle dogs (15 males and 15 females; age, 5-8 years) were divided into 3 groups of 10 dogs each and orally administered 2.5, 5, or 10 mg/kg cilostazol (twice a day at 8:00 AM and 8:00 PM for 10 days). Higher HR increases were seen in the 5 mg/kg group than in the 2.5 mg/kg group at all time points except 7:00 AM, 9:00 AM, 1:00 PM, and 4:00 PM (P<0.01). Higher HR increases were also observed in the 10 mg/kg group than in the 2.5 mg/kg group at all time points except 4:00 PM (P<0.01). The 10 mg/kg group showed higher HR increases than the 5 mg/kg group at all time points except 6:00 AM, 7:00 AM, 6:00 PM, and 7:00 PM (P<0.05 for 4:00 PM and 5:00 PM; P<0.01 for the other time points). These results together show that the HR of healthy dogs increased in a dose-dependent manner after cilostazol administration twice a day at doses of 5 to 10 mg/kg. These results provide a useful basis for choosing cilostazol in the treatment of bradyarrhythmia in dogs. PMID- 30249937 TI - Prevalence of Vibrio parahaemolyticus in seafood and water environment in the Mekong Delta, Vietnam. AB - A total of 449 samples including 385 seafood and 64 water samples in the Mekong Delta of Vietnam collected in 2015 and 2016 were examined. Of 385 seafood samples, 332 (86.2%) samples were contaminated with Vibrio parahaemolyticus and 25 (6.5%) samples were pathogenic V. parahaemolyticus carrying tdh and/or trh genes. The tdh gene positive V. parahaemolyticus strains were detected in 22 (5.7%) samples and trh gene positive V. parahaemolyticus strains were found in 5 (1.3%) samples. Of 25 pathogenic V. parahaemolyticus strains, two strains harbored both tdh and trh genes and the other 23 strains carried either tdh or trh gene. Of 64 water samples at aquaculture farms, 50 (78.1%) samples were contaminated with V. parahaemolyticus. No tdh gene positive V. parahaemolyticus strains were detected; meanwhile, trh gene positive V. parahaemolyticus strain was detected in 1 (1.6%) sample. Twenty-six pathogenic V. parahaemolyticus strains isolated were classified into 6 types of O antigen, in which the serotype O3:K6 was detected in 4 strains. All pathogenic strains were group-specific PCR negative except for 4 O3:K6 strains. The result of antimicrobial susceptibility test indicated that pathogenic strains showed high resistance rates to streptomycin (84.6%), ampicillin (57.7%) and sulfisoxazole (57.7%). These findings can be used for understanding microbiological risk of seafood in the Mekong Delta, Vietnam. PMID- 30249938 TI - Inverse Relationship between Baseline Serum Albumin Levels and Risk of Mild Cognitive Impairment in Elderly: A Seven-Year Retrospective Cohort Study. AB - Mild cognitive impairment (MCI) is the prophase of dementia. MCI patients have a high risk of developing dementia. Relatively low serum albumin levels are associated with the development of several geriatric diseases, including stroke and poor cognitive performance. However, the potential relationship between serum albumin levels and MCI risk has not been fully elucidated. In the present study, we explored this relationship to increase our understanding of the pathogenesis of MCI, the finding of which may provide new ideas for the controlling of dementia. A total of 1,800 subjects who had normal cognitive function at their first health examinations (seven years ago) were retrospectively analyzed from a health database in Tianjin Medical University General Hospital. They were over 60 years old at baseline, and the follow-up period was 7 years. At the time of data collection (seven years after), 196 subjects suffered from MCI, diagnosed by symptoms and Mini-Mental State Examination. The remaining 1,604 subjects were still cognitively normal. Multivariate COX regression analysis showed that relatively low serum albumin levels at baseline (< 40.5 g/L) were associated with the increased risk of MCI (HR: 2.18, 95% CI: 1.67-2.82). Moreover, the effect of low serum albumin on the risk of MCI was further enhanced among the subjects with hypertension, diabetes, hyperlipemia, cardiovascular disease, cerebrovascular disease, high serum levels of C-reactive protein, or relatively low levels of uric acid or total bilirubin. In conclusion, relatively low serum concentrations of albumin may be an independent risk factor for MCI in elderly. PMID- 30249939 TI - Function of alkyl hydroperoxidase AhpD in resistance to oxidative stress in Corynebacterium glutamicum. AB - Alkyl hydroperoxidase reductase AhpD, which is functionally equivalent to the bacterial flavin-containing disulfide reductase AhpF, acts as a proton donor for the organic peroxide-scavenging alkyl hydroperoxidase AhpC. Although AhpD has long been demonstrated in Mycobacterium tuberculosis, its physiological and biochemical functions remain largely unknown in other actinobacteria, including Corynebacterium glutamicum, Streptomyces, Mycobacterium smegmatis. Here, we report that C. glutamicum AhpD contributed to regenerate a variety of thiol dependent peroxidase in the decomposition of peroxide by linking a dihydrolipoamide dehydrogenase (Lpd)/dihydrolipoamide succinyltransferase (SucB)/NADH system through the cyclization of their own active site dithiol to the oxidized disulphide. The CXXC motif of AhpD was essential to maintain the peroxides reduction activity of thiol-dependent peroxidase. DeltaahpD1DeltaahpD2 mutants exhibited significantly decreased resistance to adverse stress conditions and obviously increased the accumulation of reactive oxygen species (ROS). The physiological roles of AhpD in resistance to adverse stresses, were corroborated by their induced expression under various stresses and their direct regulation under the stress-responsive ECF-sigma factor SigH. C. glutamicum AhpDs were disulfide oxidoreductases behaving like thioredoxin (Trx) in regenerating thiol dependent peroxidase for stress response, which provides the theoretical basis for an in-depth study of the reduction system in ahpC-lacking bacteria. PMID- 30249940 TI - Low Baseline High-Sensitive C-Reactive Protein is Associated with Coronary Atherosclerosis Regression: Insights from the MILLION Study. AB - AIM: The prospective, randomized, multicenter Myocardial Ischemia Treated with Percutaneous Coronary Intervention and Plaque Regression by Lipid Lowering & Blood Pressure Controlling assessed by Intravascular Ultrasonography (MILLION) study demonstrated that combined treatment with atorvastatin and amlodipine enhanced coronary artery plaque regression. Although the baseline high-sensitive C-reactive protein (hs-CRP) reportedly plays an important role in atherogenesis, few data exist regarding the relationship between hs-CRP and plaque regression in patients receiving a combined atorvastatin and amlodipine therapy. METHODS: A total of 68 patients (male, 55; mean age, 64.2 years) with baseline and follow-up 3-dimensional intravascular ultrasound examinations in the MILLION study were stratified by baseline hs-CRP level quartiles. The serial measurements of lipid, blood pressure, and percentage changes in the plaque volume were compared between the groups, and the factors associated with the percentage change in the plaque volume were assessed. RESULTS: There were no significant between-group differences in the extent of change in low-density lipoprotein cholesterol (LDL C) or systolic and diastolic blood pressure after 18-24 months of treatment. The percentage change in the plaque volume showed a linear association with the baseline hs-CRP (p for trend <0.05); however, there was no correlation with changes in LDL-C or systolic and diastolic blood pressure. In the multiple regression analysis, the baseline hs-CRP level was independently associated with the percentage change in the plaque volume (beta=0.29, p=0.022). CONCLUSIONS: Coronary plaque regression was associated with the baseline hs-CRP level in patients treated with a combined lipid- and blood pressure-lowering therapy. PMID- 30249941 TI - Inflammatory Mediators Across the Spectrum of Ankle-Brachial Index. AB - AIM: Peripheral artery disease (PAD) is a manifestation of atherosclerosis with poor prognosis. It is generally complicated by vascular calcification, which is located either in the intima as patchy infiltrates; or circumferentially in the media, also known as medial arterial calcification (MAC). Obstructive PAD is reflected by low anklebrachial index (ABI <= 0.9), whereas MAC is revealed by high ABI (ABI >1.4). Considering the increase in cardiovascular mortality at both ends of the ABI spectrum, this study aimed to explore the underlying pathology through cytokines with established prognostic significance; namely pentraxin 3(PTX3), high sensitivity C-reactive protein (hsCRP), copeptin, soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), NT-proBNP, and neopterin. METHODS: We categorized 180 patients with previous multivessel coronary artery bypass grafting surgery into three groups based on their ABI measurements; 60 patients with ABI <= 0.9, 60 patients with ABI within 0.91 and 1.4 normal ABI, and 60 patients with ABI >1.4 constituted the "PAD," "normal," "MAC" groups, respectively. The circulating levels of the biochemical markers were determined. RESULTS: In the PAD group, the cytokine levels with predominantly proatherogenic actions such as PTX3, hsCRP, copeptin, and sTREM-1 were increased and these cytokine levels declined as the ABI increased. In the MAC group, the cytokine concentrations with pleiotropic actions such as NT-proBNP and neopterin increased and; NT-proBNP and neopterin concentrations decreased as ABI decreased. The linear regression analysis revealed that neopterin (beta=0.72), PTX3 (beta=-0.32), and copeptin (beta=-0.48) were independent predictors of ABI. CONCLUSIONS: These findings suggest that different inflammatory pathways influence the pathology at the opposing ends of the ABI spectrum. Consequently, we suggest that PTX3, copeptin, and neopterin are promising biomarkers for future research. PMID- 30249942 TI - Optimal Criteria and Diagnostic Ability of Serum Pepsinogen Values for Helicobacter pylori Infection. AB - BACKGROUND: Practical criteria for the use of serum pepsinogen (PG) values in diagnosing Helicobacter pylori infection have not yet been determined. METHODS: The results of gastric endoscopies, H. pylori infection tests, and PG values were retrospectively reviewed. Subjects were assigned to groups, including never infected (with neither infection nor gastric mucosal atrophy), infected (with atrophy or findings indicating infection in endoscopy and positive infection tests except for antibody tests), and ex-infected (with gastric mucosal atrophy and negative infection tests, except for antibody tests). The optimal criteria with combined use of the PG II concentrations and the PG I/PG II ratio were investigated separately for PG measurements obtained with the chemiluminescent magnetic particle immunoassay (CLIA) and latex agglutination (LA) methods, such that the specificity was greater than 70% and the sensitivity was no less than 95% among the never-infected and infected subjects. Similar analyses were performed by combining the data from ex-infected and infected subjects. RESULTS: For the CLIA (LA) method, the optimal criterion among 349 (397) never-infected and 748 (863) infected subjects was a PG II value of at least 10 (12) ng/mL or a PG I/PG II ratio no more than 5.0 (4.0), which produced 96.3% (95.1%) sensitivity and 82.8% (72.8%) specificity. When 172 (236) ex-infected subjects were included, the optimal criterion was the same, and the sensitivity was 89.1% (86.9%). CONCLUSIONS: The above criteria may be practical for clinical use, and PG tests using these criteria might prevent unnecessary endoscopic examinations for never infected subjects. PMID- 30249943 TI - Physical Activity Earlier in Life Is Inversely Associated With Insulin Resistance Among Adults in Japan. AB - BACKGROUND: It is known that physical activity affects glucose metabolism. However, there have been no reports on the influence of physical activity earlier in life on subsequent glucose metabolism. Therefore, we analyzed the influence of physical activity in earlier decades of life on insulin resistance in middle aged and older residents in Japan. METHODS: The subjects were 6,883 residents of Okazaki City between the ages of 40 and 79 years who underwent physical examinations at the Okazaki City Medical Association Public Health Center from April 2007 through August 2011. They gave informed consent for participation in the study. Data on individual characteristics were collected via a questionnaire and from the health examination records. Fasting blood glucose and insulin levels were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR). HOMA-IR >1.6 was considered to indicate insulin resistance for the purpose of logistic regression models. RESULTS: The study sample included 3,683 men and 3,200 women for whom complete information was available. For those who exercised regularly throughout their teens to their 30s-40s, the odds ratio for having insulin resistance was 0.75 (95% confidence interval [CI], 0.58-0.96) for men and 0.76 (95% CI, 0.58-0.99) for women after adjusting for other variables, including age, body mass index, and present physical activity. A linear trend was also observed in both men and women. CONCLUSIONS: Subjects who have exercised regularly in the early decades of life are less likely to have insulin resistance later in life. PMID- 30249944 TI - Associations of Daily Walking Time With Pneumonia Mortality Among Elderly Individuals With or Without a Medical History of Myocardial Infarction or Stroke: Findings From the Japan Collaborative Cohort Study. AB - BACKGROUND: The association between daily walking and pneumonia mortality, stratified by the presence of disease conditions, such as myocardial infarction (MI) or stroke, was investigated. METHODS: The study participants were 22,280 Japanese individuals (9,067 men and 13,213 women) aged 65-79 years. Inverse propensity weighted competing risk model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for pneumonia mortality. RESULTS: After a median of 11.9 years of follow-up, 1,203 participants died of pneumonia. Participants who did not have a history of MI or stroke and who walked for 1 hour/day or more were less likely to die from pneumonia (HR 0.90; 95% CI, 0.82 0.98) than those walked for 0.5 hours/day. A similar inverse association of pneumonia and walking (0.5 hours/day) was observed among participants with a history of MI (HR 0.66; 95% CI, 0.48-0.90). Among the participants with a history of stroke, those who walked for 0.6-0.9 hours/day were less likely to die because of pneumonia (HR 0.65; 95% CI, 0.43-0.98). CONCLUSIONS: Regular walking for >=1 hour/day may reduce the risk of pneumonia mortality in elderly individuals with or without cardiovascular disease history. PMID- 30249945 TI - Prevalence of Congenital Anomalies in the Japan Environment and Children's Study. AB - BACKGROUND: The aims of the present report were to estimate the prevalence of congenital anomalies (CAs) among infants in Japan using data from the Japan Environment and Children's Study (JECS) and to evaluate the validity of CA classification within JECS. METHODS: Data on CAs were collected at delivery and at age 1 month from the medical records of 101,825 infants at 15 regional centers. The analyses focused on 61 CAs, selected on the basis of reported associations with environmental exposure. Prevalence per 10,000 pregnancies (including miscarriages, stillbirths, and live births) was stratified according to four reporting patterns (at delivery, at age 1 month, at either, and at both). To evaluate the accuracy of observed CA prevalence, the medical records of 179 cases from a single JECS regional center underwent independent, retrospective re evaluation. RESULTS: The prevalence of major CAs in four reporting patterns (at delivery, at age 1 month, at either, and at both) was 2.4, 2.6, 3.5, and 1.4 for myelomeningocele/spina bifida; 4.3, 4.2, 5.3, and 3.2 for cleft palate; 18.1, 17.4, 19.5, and 15.1 for cleft lip with or without cleft palate; 73.4, 100.3, 120.8, and 52.8 for congenital heart disease; and 10.5, 14.1, 15.0, and 9.6 for Down's syndrome, respectively. In the subsample re-evaluation, CA diagnoses were confirmed for 92.7%, 93.3%, 90.5%, and 97.8% of cases in the four reporting patterns (at delivery, at age 1 month, at either, and at both), respectively. CONCLUSIONS: The present report generated reliable data concerning the prevalence of major CAs in JECS. PMID- 30249946 TI - Household income relationship with health services utilization and healthcare expenditures in people aged 75 years or older in Japan: A population-based study using medical and long-term care insurance claims data. AB - BACKGROUND: This study aimed to determine whether there are disparities in healthcare services utilization according to household income among people aged 75 years or older in Japan. METHODS: We used data on medical and long-term care (LTC) insurance claims and on LTC insurance premiums and needs levels for people aged 75 years or older in a suburban city. Data on people receiving public welfare were not available. Participants were categorized according to household income level using LTC insurance premiums data. The associations of low income with physician visit frequency, length of hospital stay (LOS), and medical and LTC expenditures were evaluated and adjusted for the five-year age group and LTC needs level. RESULTS: The study analyzed 12,852 men and 18,020 women, among which 13.3% and 41.5% were respectively categorized as low income. Participants with low income for both genders were more likely to be functionally dependent. In the adjusted analyses, lower income was associated with fewer physician visits (incidence rate ratio: 0.90 (95% confidence interval 0.87-0.92) for men and 0.97 (0.95-0.99) for women), longer LOS (1.98 (1.54-2.56) and 1.42 (1.20-1.67)), and higher total expenditures (1.09 (1.01-1.18) and 1.09 (1.05-1.14)). CONCLUSIONS: This study suggests older people with lower income had fewer consultations with physicians but an increased use of inpatient services. The income categorization used in this study may be an appropriate proxy of socioeconomic status. PMID- 30249948 TI - [PITFALLS IN MEDICAL STATISTICS FOR CLINICAL RESEARCHES]. PMID- 30249947 TI - Geographical Variation in Psychiatric Admissions Among Recipients of Public Assistance. AB - BACKGROUND: Understanding the area-specific resource use of inpatient psychiatric care is essential for the efficient use of the public assistance system. This study aimed to assess the geographical variation in psychiatric admissions and to identify the prefecture-level determinants of psychiatric admissions among recipients of public assistance in Japan. METHODS: We identified all recipients of public assistance who were hospitalized in a psychiatric ward in May 2014, 2015, or 2016 using the Fact-finding Survey on Medical Assistance. The age- and sex-standardized number of psychiatric admissions was calculated for each of the 47 prefectures, using direct and indirect standardization methods. RESULTS: A total of 46,559 psychiatric inpatients were identified in May 2016. The number of psychiatric admissions per 100,000 population was 36.6. We found a 7.1-fold difference between the prefectures with the highest (Nagasaki) and lowest (Nagano) numbers of admissions. The method of decomposing explained variance in the multiple regression model showed that the number of psychiatric beds per 100,000 population and the number of recipients of public assistance per 1,000 population were the most important determinants of the number of psychiatric admissions (R2 = 28% and R2 = 23%, respectively). The sensitivity analyses, using medical cost as the outcome and data from different survey years and subgroups, showed similar findings. CONCLUSIONS: We identified a large geographical variation in the number and total medical cost of psychiatric admissions among recipients of public assistance. Our findings should encourage policy makers to assess the rationale for this variation and consider strategies for reducing it. PMID- 30249949 TI - [GENETIC FACTORS FOR THE DEVELOPMENT OF ALLERGIC DISORDERS]. PMID- 30249950 TI - [CLINICAL EFFICACY OF SUBLINGUAL IMMUNOTHERAPY IN A LARGE AMOUNT OF POLLEN DISPARSAL AND IT'S IMPACT OF TREATMENT YEAR]. AB - BACKGROUND: It past 4 years in 2018 after the first treatment of sublingual immunotherapy (SLIT) for Japanese cedar pollinosis. The purpose of this study is to clear the clinical efficacy of SLIT in a large amount of pollen dispersal in 2018 (total 5041 grain). METHODS: The subjects were 270 SLIT (83 forth year of treatment, 72 third year, 48 second year, 67 first year), 320 primary pharmacotherapy that started therapies before pollen dispersal, and 424 untreated. The clinical efficacy was evaluated with symptom scores of Japanese rhinoconjuctivitis quality of life questionnaire No1, medication scores and combined total nasal symptom-medication scores, and visual analog scale of nose, eye and total symptoms. RESULTS: Each SLIT was significantly better than untreated in all assessments, and better than primary pharmacotherapy in assessments of total symptom. SLITs of third and forth year of treatment were also better than primary pharmacotherapy in nasal symptoms. SLIT patients, whose symptom scores of nose and eye were 0 and 1 point without any rescue drugs, accounted for 41.0%, 31.9%, 18.8%, 20.9% in the order from the fourth year to the first year. Of them, patients with score 0 occupied 12.0%, 12.5%, 4.2%, 4.5%, in order. There was no patient who needs treatments for adverse events. CONCLUSION: SLIT was significantly effective compared with primary pharmacotherapy or untreated group in a large amount of pollen dispersal. It was better to treat at least for 4 years. PMID- 30249951 TI - [EVALUATION OF DRUG ERUPTION RELATED HELICOBACTER PYLORI ERADICATION THERAPY]. AB - OBJECTIVES AND METHODS: The number of patients who undergo Helicobacter pylori (HP) eradication therapy has been increasing since it became covered by insurance in Japan. As such, an increasing number of patients develop drug eruption as a result of HP eradication therapy. In the present study, we describe the clinical course of 28 patients who were treated at our hospital for drug eruption following HP eradication therapy between April 2008 and March 2016. RESULTS AND DISCUSSION: The majority of the patients were women (21 women, 7 men). The average length of time from the start of treatment to the onset of eruption was 7.6 days. A drug-induced lymphocyte stimulation test (DLST) was performed in 10 patients. Amoxicillin was the most common cause of eruption, with 6 patients testing positive. Patients who were considered likely to have developed sensitivity prior to the treatment required the systemic administration of steroids. On the other hand, symptoms were relieved with topical steroids in some of the patients who were considered likely to have developed sensitivity during the course of treatment. CONCLUSION: Since penicillin antibiotics have long been used, some patients may have become sensitized without being aware of this. Our findings highlight the need for the careful management of patients developing sensitivity prior to treatment as they require the systemic administration of steroids. PMID- 30249953 TI - ? PMID- 30249952 TI - [POLLEN FOOD ALLERGY SYNDROME IN A FIVE-YEAR-OLD BOY AFTER MOVING HOUSE AT THE FOOT OF THE MOUNTAIN: A CASE REPORT]. AB - We report the case of a boy with a history of atopic dermatitis starting in infancy. At the age of four, his family moved into a newly built house at the foot of a mountain. One year later, he was diagnosed with Japanese Cedar pollinosis. During the same year, in March, he began to experience oral symptoms, hoarseness, and coughing, after eating multiple types of fruits and vegetables, like soybeans, apples, etc. His tests for Bet v1 and the pathogenesis-related protein-10 (PR-10) of the corresponding foods were positive; accordingly, he was diagnosed with Pollen Food Allergy Syndrome (PFAS). In order to investigate the relationship between pollen and food allergies, we counted the pollen grains dispersed at the patient's house during a period of one year and measured his specific IgE titers for pollen and food allergens every three months. We found a large amount of Japanese cedar, cypress, oak, and various other species of pollen dispersed at the patient's house. All counts were higher than the average pollen counts in the city of Fukuoka. After the seasonal dispersal of oak pollen, the patient's specific IgE antibody titers against Alder, Oak, Bet v1, Gly m4, and PR 10 protein group of fruits increased, although alder pollen was not detected. We thus inferred that the patient had developed PFAS by exposure to a large amount of Fagales species pollen, including oak. PMID- 30249955 TI - ? PMID- 30249954 TI - ? PMID- 30249956 TI - ? PMID- 30249957 TI - [BIOMARKER FOR ATOPIC DERMATITIS IN CHILDREN:FOCUSING ON TARC AND NOVEL SCCA2]. PMID- 30249958 TI - [MECHANISMS OF ALLERGEN IMMUNOTHERAPY FOR INHALED ALLERGENS AND CLINICAL BIOMARKERS]. PMID- 30249959 TI - [CLINICAL ALLERGY WILL GET MORE INTERESTING IF YOU UNDERSTAND MOLECULAR ALLERGOLOGY]. PMID- 30249960 TI - Characteristics of Biofilms Formed by Co-Culture of Listeria monocytogenes with Pseudomonas aeruginosa at Low Temperatures and Their Sensitivity to Antibacterial Substances. AB - We assessed the properties of biofilms (BFs) formed by mono- and co-cultures of Listeria monocytogenes and Pseudomonas aeruginosa (L+P-BF) at low temperatures and examined their sensitivity to several antibacterial substances. L. monocytogenes viable counts comprised only 1-10% of total L+P-BF viable counts at 10C and 15C, indicating the significant prevalence of P. aeruginosa in co cultures. L+P-BF formed at 10C and 15C showed very high resistance to antibiotics and NaClO. Examination of the effects of nattokinase and nisin, natural food additives with antibacterial properties, showed that their application alone failed to inhibit L+P-BF development at 10C and 15C. However, a combined treatment with nisin and ethylenediaminetetraacetic acid, a food additive that can be used as a permeabilizing agent, suppressed the formation of L+P-BF at 10C and 15C. Microscopy observations of L+P-BF did not reveal pronounced morphological changes in bacterial cell morphology. We also noted that P. aeruginosa resistance to the action of nisin during BF formation was higher when it was maintained in co-culture with L. monocytogenes. The results of the present study are an important step toward developing a safe formulation of acceptable food additives that could be used for suppression of BFs formed by pathogenic bacteria during food storage. PMID- 30249961 TI - Inhibitory Effect of Spice Powders on the Development of Heated and Irradiated Bacillus subtilis Spores as Evaluated by Calorimetry. AB - Inhibitory effects of the powders of paprika, red pepper, black pepper, sage, oregano and thyme in a solid medium after heat treatment and gamma-irradiation on the development from spore of Bacillus subtilis were examined using calorimetry. Based on the f(t) curve (Antoce et al., 1996) from the thermogram obtained, two parameters, the growth rate constant and the growth retardation time, were used to evaluate the inhibitory effect. The inhibitory effects of paprika and red pepper powders were enhanced by the spore pretreatment with heat, but not significantly with irradiation. The inhibitory enhancement by preheating depended upon the kind of spices used. Sage, oregano and thyme powders per se inhibited the development from spores completely even at a low concentration of 0.04 g/ml. Inhibitory effects of paprika and red pepper powders were obviously observed with heat treatment but not with irradiation. With black pepper powder, by contrast, substantial enhancement was neither observed with heat treatment nor gamma irradiation. The results suggested that the addition of those spice powders might be useful in the thermal inactivation process of solid foods contaminated with Bacillus subtilis spores. PMID- 30249962 TI - Antibacterial Activity of Epoxy Resins Mixed with Polyelectrolyte/Silver Nanoparticle Composite Filler. AB - In this study, antibacterial polyelectrolyte/silver nanoparticle (Ag NP) composite powder was mixed with epoxy resins as fillers to impart antibacterial activity. Either an anhydride-type or a polyamideamine-type curing agent was applied to a bisphenol A-type base compound to prepare the epoxy resins. Antibacterial assays of these resins against Escherichia coli were performed using the shake tube technique; suppression of antibacterial activity was found for the anhydride-type resin, although the polyamideamine-type resin did exhibit antibacterial activity. The anhydride-type resin is considered to have suppressed antibacterial activity because carboxylate ions derived from unreacted anhydride in aqueous medium can induce chemical adsorption of silver ions and/or charge repulsion of E. coli. PMID- 30249963 TI - Thermotolerant Yeast Kluyveromyces marxianus Reveals More Tolerance to Heat Shock than the Brewery Yeast Saccharomyces cerevisiae. AB - The thermotolerant yeast Kluyveromyces marxianus, growing at high temperature (45C) , showed stronger survival under heat shock at 50C than the brewing yeast Saccharomyces cerevisiae, which was unable to grow at 45C. The survival rate of K. marxianus decreased to 10% during heat shock at 50C for 20 min, and to less than 0.01% at 60C for 20 min. Cells with damaged cellular membranes were infrequently observed at 50C and had decreased significantly from heat shock at 60C. The metabolic activity of K. marxianus was retained at 50C, whereas that of S. cerevisiae was not. The trehalose content of K. marxianus was approximately two times that of S. cerevisiae. These results suggest that K. marxianus protects itself from heat shock-induced damage through the use of trehalose (a protective molecule in S. cerevisiae) as well as other different factors. PMID- 30249964 TI - Behavior of Nitrate-Nitrogen and Nitrite-Nitrogen in Drinking Water. AB - Nitrate-nitrogen (NO3-N) and nitrite-nitrogen (NO2-N) are constituents of the nitrogen cycle. NO3-N is toxic to humans, primarily due to its reduction to NO2 N. In Japan, NO3-N and NO2-N levels in tap water must not exceed 10 mg/L and only NO2-N alone not 0.04 mg/L, respectively. In this study, we verified the effect of microorganisms and ultraviolet (UV) to increase of NO2-N in water. First, all tested drinking-waters including tap water and commercial mineral water in PET bottles had < 2 mg/L NO3-N and undetectable levels (< 0.01 mg/L) of NO2-N. However, we found that NO2-N was generated in tap water left to stand at room temperature for several days, leading to increases in CF and TC counts and reduction of NO3-N. We also demonstrated that direct UV and sunlight irradiation of NO3-N-containing drinking water generated NO2-N in 1-2 h, with NO2-N reaching > 0.04 mg/mL by 4-6 h. On the other hand, NO3-N and NO2-N were undetectable in commercially purified water. PMID- 30249965 TI - Eligibility of Feline Calicivirus for a Surrogate of Human Norovirus in Comparison with Murine Norovirus, Poliovirus and Coxsackievirus. AB - Feline calicivirus (FCV) is frequently used as a surrogate of human norovirus. We investigated eligibility of FCV for anti-viral assay by investigating the stability of infectivity and pH sensitivity in comparison with other viruses. We found that infectivities of FCV and murine norovirus (MNV) are relatively unstable in infected cells compared with those of coxsackievirus (CoV) and poliovirus (PoV) , suggesting that FCV and MNV have vulnerability. Western blotting indicated that inactivation of FCV was not due to viral protein degradation. We also demonstrated sensitivity of FCV to low pH, the 50% inhibitory pH value being ca. 3.9. Since human norovirus is thought to persist longer, in infectivity and to be a resistant virus, CoV, which is robust and not restrained in use as PoV, may be more appropriate as a test virus for disinfectants, rather than FCV and MNV. PMID- 30249966 TI - Discovery of Terbinafine Low Susceptibility Trichophyton rubrum strain in Japan. AB - This is the first confirmed report of terbinafine low susceptibility Trichophyton rubrum, BGUTR13, in Japan collected from the whole sole of the elderly over 65s with cotton swab sampling method at the special nursing care-home in 2016. We revealed BGUTR13 showed low susceptibility (MIC, >128 MUg/mL) against terbinafine. But, BGUTR13 exhibited normal susceptibility to itraconazole, did not showed cross-resistance. Also, the squalene epoxidase gene of terbinafine low susceptibility strain BGUTR13 which is the target of terbinafine contained newly confirmed one mismatch. We suggested the possibility that the resistance mechanism of terbinafine low susceptibility strains is due to the loss of sensitivity of squalene epoxidase inhibitors and does not affect antifungal drugs with other different mechanisms of action. PMID- 30249967 TI - Control of Aliivibrio fischeri Luminescence and Decrease in Bioluminescence by Fungicides. AB - Studies have reported that cell density, ultraviolet (UV) irradiation, and redox reactions, can induce bioluminescence in bacteria. Conversely, the relationship between seawater components and luminescence is not well understood. The efficacy of marine luminous bacteria as biosensors, and their reactivity to fungicides (for example postharvest pesticides) are also unknown. Therefore, we studied the relationship between the luminescence of Aliivibrio fischeri and the composition of artificial seawater media and analyzed the toxicity of fungicides using A. fischeri grown only with the elements essential to induce luminescence. Luminescence was activated in the presence of KCl, NaHCO3, and MgSO4. In addition, we cultivated A. fischeri with other compounds, including K+, HCO3-, and SO42- ions. These results suggested that A. fischeri requires K+, HCO3-, and SO42- ions to activate cell density-independent luminescence. Additionally, A. fischeri cultured in 2.81% NaCl solutions containing KCl, NaHCO3, and MgSO4 exhibited a decrease in luminescence in the presence of sodium orthophenylphenol at >10 ppm. This result suggests that A. fischeri can be used as a biosensor to detect the presence of sodium ortho-phenylphenol. PMID- 30249968 TI - Antibacterial Properties of Silicone Membranes after a Simple Two-Step Immersion Process in Iodine and Silver Nitrate Solutions. AB - Silicone is widely used in packing materials, medical equipment, and separation membranes. Since microbial cells easily adhere to the surface of silicone materials and form biofilms, techniques for incorporating antimicrobial activity into silicone materials are in high demand. This study describes the preparation of silver (Ag)/silicone composite membranes through a simple two-step immersion process, utilizing an iodine solution followed by a silver nitrate solution at room temperature. Scanning electron microscopy (SEM) observations revealed that particles with sizes of several nanometers to several tens of nanometers were present on the silicone membrane surface; these particles were identified as silver iodide using energy-dispersive X-ray spectroscopy (EDS) . The Ag/silicone membrane possessed excellent antibacterial efficacy against Escherichia coli and Staphylococcus aureus, and the antibacterial efficacy (R) against both types of bacteria was R > 4, even after stomacher treatment or acidic treatment of pH 2-6 for 24 h. The mechanical strength of the silicone membrane was also maintained after antibacterial treatment, with Young's modulus values of 7.9+/-1.2 MPa and 8.3+/-1.5 MPa for the untreated membrane and Ag/silicone membrane, respectively (p > 0.05) . In addition, the reduction in permeation performance of the Ag/silicone membrane was only 20%, despite the antibacterial treatment on the membrane surface. This antibacterial treatment method of silicone membranes can be conducted at room temperature (25C) without special equipment, and may be applied to other types of silicone materials. PMID- 30249969 TI - Galectin-3 Interacts with Vascular Cell Adhesion Molecule-1 to Increase Cardiovascular Mortality in Hemodialysis Patients. AB - BACKGROUND: Interactions and joint effects of galectin-3 and vascular cell adhesion molecule 1 (VCAM-1) on risks of all-cause and cardiovascular (CV) mortality remain unclear in patients with maintenance hemodialysis (MHD). METHODS: Unadjusted and adjusted hazard ratios (aHRs) of mortality risks were analyzed between higher and lower concentration groups of serum galectin-3 and VCAM-1. The modification effect between serum galectin-3 and VCAM-1 on mortality risk was investigated using an interaction product term. RESULTS: During follow up, galectin-3 and VCAM-1 were associated with incremental risks of all-cause mortality (aHR: 1.038 (95% confidence interval (CI): 1.001-1.077) and 1.002 (95% CI: 1.001-1.003), respectively). Nonetheless, VCAM-1 but not galectin-3 predicted CV mortality (aHR: 1.043 (95% CI: 0.993-1.096) and 1.002 (95% CI: 1.001-1.003), respectively). In the interaction analysis, patients with combined higher galectin-3 (>29.5 ng/mL) and VCAM-1 (>1546.9 ng/mL) were at the greatest risk of all-cause and CV mortality (aHR: 4.6 (95% CI: 1.6-13.4), and 4.2 (95% CI: 1.3 14.4), respectively). The interactions between galectin-3 and VCAM-1 with respect to all-cause and CV mortality were statistically significant (p < 0.01 and < 0.05, respectively). CONCLUSION: Galectin-3 and VCAM-1 could serve as a promising dual biomarker for prognostic assessment, considering their joint effects on pathogenesis of leukocyte trafficking and atherothrombosis. PMID- 30249970 TI - Measurement of Atmospheric Dimethyl Sulfide with a Distributed Feedback Interband Cascade Laser. AB - This paper presents a mid-infrared dimethyl sulfide (CH3SCH3, DMS) sensor based on tunable laser absorption spectroscopy with a distributed feedback interband cascade laser to measure DMS in the atmosphere. Different from previous work, in which only DMS was tested and under pure nitrogen conditions, we measured DMS mixed by common air to establish the actual atmospheric measurement environment. Moreover, we used tunable laser absorption spectroscopy with spectral fitting to enable multi-species (i.e., DMS, CH4, and H2O) measurement simultaneously. Meanwhile, we used empirical mode decomposition and greatly reduced the interference of optical fringes and noise. The sensor performances were evaluated with atmospheric mixture in laboratory conditions. The sensor's measurement uncertainties of DMS, CH4, and H2O were as low as 80 ppb, 20 ppb, and 0.01% with an integration time 1 s, respectively. The sensor possessed a very low detection limit of 9.6 ppb with an integration time of 164 s for DMS, corresponding to an absorbance of 7.4 * 10-6, which showed a good anti-interference ability and stable performance after optical interference removal. We demonstrated that the sensor can be used for DMS measurement, as well as multi-species atmospheric measurements of DMS, H2O, and CH4 simultaneously. PMID- 30249972 TI - The Role of Vitamin E in the Treatment of NAFLD. AB - There has been a growing interest in the role of vitamin E supplementation in the treatment and/or prevention of nonalcoholic fatty liver (NAFLD). We performed a systematic review of the medical literature from inception through 15 June 2018 by utilizing PubMed and searching for key terms such as NAFLD, vitamin E, alpha tocopherol, and nonalcoholic steatohepatitis (NASH). Data from studies and medical literature focusing on the role of vitamin E therapy in patients with NAFLD and nonalcoholic steatohepatitis (NASH) were reviewed. Most studies assessing the impact of vitamin E in NAFLD were designed to evaluate patients with NASH with documented biochemical and histological abnormalities. These studies demonstrated improvement in biochemical profiles, with a decline in or normalization of liver enzymes. Furthermore, histological assessment showed favorable outcomes in lobular inflammation and hepatic steatosis following treatment with vitamin E. Current guidelines regarding the use of vitamin E in the setting of NAFLD recommend that vitamin E-based treatment be restricted to biopsy-proven nondiabetic patients with NASH only. However, some concerns have been raised regarding the use of vitamin E in patients with NASH due to its adverse effects profile and lack of significant improvement in hepatic fibrosis. In conclusion, the antioxidant, anti-inflammatory, and anti-apoptotic properties of vitamin E accompanied by ease-of-use and exceptional tolerability have made vitamin E a pragmatic therapeutic choice in non-diabetic patients with histologic evidence of NASH. Future clinical trials with study design to assess vitamin E in combination with other anti-fibrotic agents may yield an additive or synergistic therapeutic effect. PMID- 30249971 TI - Recombination Located over 2A-2B Junction Ribosome Frameshifting Region of Saffold Cardiovirus. AB - Here we report the nearly full-length genome of a recombinant Saffold virus strain (SAFV-BR-193) isolated from a child with acute gastroenteritis. Evolutionary analysis performed using all available near-full length Saffold picornavirus genomes showed that the breakpoint found in the Brazilian strain (SAFV-BR-193) is indeed a recombination hotspot. Notably, this hotspot is located just one nucleotide after the ribosomal frameshift GGUUUUU motif in the SAFV genome. Empirical studies will be necessary to determine if this motif also affects the binding affinity of RNA-dependent RNA-polymerase (RdRp) and therefore increases the changes of RdRp swap between molecules during the synthesis of viral genomes. PMID- 30249973 TI - An Introduction to the Toxins Special Issue on the Adenylate Cyclase Toxin. PMID- 30249974 TI - A Non-Linear Filtering Algorithm Based on Alpha-Divergence Minimization. AB - A non-linear filtering algorithm based on the alpha-divergence is proposed, which uses the exponential family distribution to approximate the actual state distribution and the alpha-divergence to measure the approximation degree between the two distributions; thus, it provides more choices for similarity measurement by adjusting the value of alpha during the updating process of the equation of state and the measurement equation in the non-linear dynamic systems. Firstly, an alpha -mixed probability density function that satisfies the normalization condition is defined, and the properties of the mean and variance are analyzed when the probability density functions p ( x ) and q ( x ) are one-dimensional normal distributions. Secondly, the sufficient condition of the alpha-divergence taking the minimum value is proven, that is when alpha >= 1 , the natural statistical vector's expectations of the exponential family distribution are equal to the natural statistical vector's expectations of the alpha -mixed probability state density function. Finally, the conclusion is applied to non linear filtering, and the non-linear filtering algorithm based on alpha divergence minimization is proposed, providing more non-linear processing strategies for non-linear filtering. Furthermore, the algorithm's validity is verified by the experimental results, and a better filtering effect is achieved for non-linear filtering by adjusting the value of alpha . PMID- 30249975 TI - Early Evaluation of Copper Radioisotope Production at ISOLPHARM. AB - The ISOLPHARM (ISOL technique for radioPHARMaceuticals) project is dedicated to the development of high purity radiopharmaceuticals exploiting the radionuclides producible with the future Selective Production of Exotic Species (SPES) Isotope Separation On-Line (ISOL) facility at the Legnaro National Laboratories of the Italian National Institute for Nuclear Physics (INFN-LNL). At SPES, a proton beam (up to 70 MeV) extracted from a cyclotron will directly impinge a primary target, where the produced isotopes are released thanks to the high working temperatures (2000 degrees C), ionized, extracted and accelerated, and finally, after mass separation, only the desired nuclei are collected on a secondary target, free from isotopic contaminants that decrease their specific activity. A case study for such project is the evaluation of the feasibility of the ISOL production of 64Cu and 67Cu using a zirconium germanide target, currently under development. The producible activities of 64Cu and 67Cu were calculated by means of the Monte Carlo code FLUKA, whereas dedicated off-line tests with stable beams were performed at LNL to evaluate the capability to ionize and recover isotopically pure copper. PMID- 30249976 TI - A Concurrent and Hierarchy Target Learning Architecture for Classification in SAR Application. AB - This article discusses the issue of Automatic Target Recognition (ATR) on Synthetic Aperture Radar (SAR) images. Through learning the hierarchy of features automatically from a massive amount of training data, learning networks such as Convolutional Neural Networks (CNN) has recently achieved state-of-the-art results in many tasks. To extract better features about SAR targets, and to obtain better accuracies, a new framework is proposed: First, three CNN models based on different convolution and pooling kernel sizes are proposed. Second, they are applied simultaneously on the SAR images to generate image features via extracting CNN features from different layers in two scenarios. In the first scenario, the activation vectors obtained from fully connected layers are considered as the final image features; in the second scenario, dense features are extracted from the last convolutional layer and then encoded into global image features through one of the commonly used feature coding approaches, which is Fisher Vectors (FVs). Finally, different combination and fusion approaches between the two sets of experiments are considered to construct the final representation of the SAR images for final classification. Extensive experiments on the Moving and Stationary Target Acquisition and Recognition (MSTAR) dataset are conducted. Experimental results prove the capability of the proposed method, as compared to several state-of-the-art methods. PMID- 30249978 TI - Prognostic Factors in Merkel Cell Carcinoma: A Retrospective Single-Center Study in 90 Patients. AB - Merkel Cell Carcinoma (MCC) is a rare but highly aggressive neuroendocrine neoplasm of the skin. This study aimed at describing characteristics, treatment, and prognosis of a series of consecutive cases of MCC patients, in order to contribute to the investigation of this rare malignancy and provide better patient care. This is a retrospective cohort study including all 90 patients diagnosed and/or treated for MCC between 1991 and 2018 at the Veneto Institute of Oncology in Padua (Italy). Patient and tumor characteristics, treatment, and immunohistochemical data were extracted from a prospectively collected local database. There were 68 primary (76%) and 22 non-primary (15 occult primary, three metastatic, four recurrence) tumors (24%). CK20 expression was associated with reduced overall (HR 2.92, 95% CI 1.04-8.16) and disease-specific (HR 4.62, 95% CI 1.31-16.28) survival. Immunomodulatory regimens for treatment of other comorbidities were associated with reduced disease-specific ((HR 2.15, 95% CI 1.06-4.36) and recurrence-free (HR 3.08, 95% CI 1.44-6.57) survival. Iatrogenic immunomodulation resulted as the main factor associated with impaired prognosis. Lack of CK20 expression was associated with better survival. PMID- 30249979 TI - The Salt Content of Lunch Meals Eaten at Danish Worksites. AB - Monitoring levels of sodium (salt) in meals consumed out-of-home is needed to support effective implementation of salt-reduction strategies. The objective of the study was to examine lunch salt intake at 15 worksite canteens and to compare with results from a comparable study conducted 10 years before. A duplicate portion-technique with subsequent chemical analysis was used to quantify 240 customers' lunch salt intake. Estimated mean salt intake was 2.6 g/meal (95% Cl: 2.2 to 3.0 g/meal) and 0.78 g/100 g (95% Cl: 0.69 to 0.88 g/100 g). Salt intake measured both as g per meal and per 100 g was found to be significantly higher for male compared with female participants (+0.10 g/100 g, 95% Cl: +0.02 to +0.17 g/100 g, p = 0.011). Compared with the study conducted 10 years before, there was a significantly lower estimated salt intake of 0.5 g/meal (95% CI: -0.8 to -0.2 g/meal, p = 0.001), suggesting a possible reduction in canteen lunch salt intake during a 10-year period. Still, 40% of the meals exceeded the Nordic Keyhole label requirements of maximum 0.8 g salt per 100 g for ready meals. A further reduction of salt intake is warranted to comply with salt reduction targets. PMID- 30249980 TI - Judicious Use of Lipid Lowering Agents in the Management of NAFLD. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world. NAFLD encompasses a spectrum of histological features, including steatosis, steatohepatitis with balloon degeneration, and hepatic fibrosis leading to cirrhosis. In patients with advanced liver damage, NAFLD is associated with an increased risk of hepatocellular carcinoma. Diabetes mellitus, hypertension, and dyslipidemia are components of metabolic syndrome and are commonly associated with NAFLD. Cardiovascular disease is the leading cause of mortality in patients with NAFLD. Therefore, it is important to pre-emptively identify and proactively treat conditions like hyperlipidemia in an effort to favorably modify the risk factors associated with cardiovascular events in patients with NAFLD. The management of hyperlipidemia has been shown to reduce cardiovascular mortality and improve histological damage/biochemical abnormalities associated with non-alcoholic steatohepatitis (NASH), a subset of NAFLD with advance liver damage. There are no formal guidelines available regarding the use of anti-hyperlipidemic drugs, as prospective data are lacking. The focus of this article is to discuss the utility of lipid-lowering drugs in patients with NAFLD. PMID- 30249977 TI - Autophagy in Metabolic Age-Related Human Diseases. AB - Autophagy is a highly conserved homeostatic cellular mechanism that mediates the degradation of damaged organelles, protein aggregates, and invading pathogens through a lysosome-dependent pathway. Over the last few years, specific functions of autophagy have been discovered in many tissues and organs; however, abnormal upregulation or downregulation of autophagy has been depicted as an attribute of a variety of pathologic conditions. In this review, we will describe the current knowledge on the role of autophagy, from its regulation to its physiological influence, in metabolic age-related disorders. Finally, we propose to discuss the therapeutic potential of pharmacological and nutritional modulators of autophagy to treat metabolic diseases. PMID- 30249981 TI - Effect of Acute Exercise Mode on Serum Brain-Derived Neurotrophic Factor (BDNF) and Task Switching Performance. AB - Previous studies have consistently reported a positive effect of acute exercise on cognition, particularly on executive function. However, most studies have focused on aerobic and resistant forms of exercise. The purpose of this study was to compare the effect of 'open-skill' with 'closed-skill' exercise (defined in terms of the predictability of the performing environment) on brain-derived neurotrophic factor (BDNF) production and task switching performance. Twenty young adult males participated in both closed (running) and open (badminton) skill exercise sessions in a counterbalanced order on separate days. The exercise sessions consisted of 5 min of warm up exercises followed by 30 min of running or badminton. The exercise intensity was set at 60% (+/-5%) of the heart rate reserve level (HRR) with HR being monitored by a wireless heart rate monitor. Blood samples were taken and participation in a task-switching paradigm occurred before and after each exercise session. Results showed no differences in serum BDNF or task-switching performance at the pre-test stage, however, badminton exercise resulted in significantly higher serum BDNF levels (a proxy for levels of BDNF in the brain) and near significant smaller global switching costs relative to running. This study has provided preliminary evidence in support the relative benefits of open-skills exercises on BDNF and executive function. PMID- 30249982 TI - Experience Applying the Guidelines for Reporting Reliability and Agreement Studies (GRRAS) Indicated Five Questions Should Be Addressed in the Planning Phase from a Statistical Point of View. AB - The Guidelines for Reporting Reliability and Agreement Studies (GRRAS) were proposed in 2011 to support transparent and accurate reporting. These studies may be conducted with the primary aim of estimating reliability and/or agreement itself, but are more often than not part of larger diagnostic accuracy studies, clinical trials, or epidemiological studies. As such, the study design may be compromised in terms of practicability issues, preventing the collection of sufficient results. We presented an example from a consultancy with a difficult mission and discussed five questions that concern the very nature of such a study (agreement vs. reliability; intra- vs. interrater), the rater population, explanatory factors in a multivariable model, and the statistical analysis strategy. Discussion of such basic methodological and statistical questions must take place before an investigation is started in order to ensure adequate data collection, to predict possible complications in the study, to plan sufficient statistical analyses, and to request timely assistance from an experienced statistician. GRRAS and its accompanying checklist of 15 items proved to be most helpful. Hopefully, our commentary will help improve the planning of agreement and reliability studies, which, in turn, will then be more focused, more appropriate, and more easily reported using GRRAS. PMID- 30249983 TI - Applications of Magnetotactic Bacteria, Magnetosomes and Magnetosome Crystals in Biotechnology and Nanotechnology: Mini-Review. AB - Magnetotactic bacteria (MTB) biomineralize magnetosomes, which are defined as intracellular nanocrystals of the magnetic minerals magnetite (Fe3O4) or greigite (Fe3S4) enveloped by a phospholipid bilayer membrane. The synthesis of magnetosomes is controlled by a specific set of genes that encode proteins, some of which are exclusively found in the magnetosome membrane in the cell. Over the past several decades, interest in nanoscale technology (nanotechnology) and biotechnology has increased significantly due to the development and establishment of new commercial, medical and scientific processes and applications that utilize nanomaterials, some of which are biologically derived. One excellent example of a biological nanomaterial that is showing great promise for use in a large number of commercial and medical applications are bacterial magnetite magnetosomes. Unlike chemically-synthesized magnetite nanoparticles, magnetosome magnetite crystals are stable single-magnetic domains and are thus permanently magnetic at ambient temperature, are of high chemical purity, and display a narrow size range and consistent crystal morphology. These physical/chemical features are important in their use in biotechnological and other applications. Applications utilizing magnetite-producing MTB, magnetite magnetosomes and/or magnetosome magnetite crystals include and/or involve bioremediation, cell separation, DNA/antigen recovery or detection, drug delivery, enzyme immobilization, magnetic hyperthermia and contrast enhancement of magnetic resonance imaging. Metric analysis using Scopus and Web of Science databases from 2003 to 2018 showed that applied research involving magnetite from MTB in some form has been focused mainly in biomedical applications, particularly in magnetic hyperthermia and drug delivery. PMID- 30249984 TI - Inferring microRNA-Environmental Factor Interactions Based on Multiple Biological Information Fusion. AB - Accumulated studies have shown that environmental factors (EFs) can regulate the expression of microRNA (miRNA) which is closely associated with several diseases. Therefore, identifying miRNA-EF associations can facilitate the study of diseases. Recently, several computational methods have been proposed to explore miRNA-EF interactions. In this paper, a novel computational method, MEI-BRWMLL, is proposed to uncover the relationship between miRNA and EF. The similarities of miRNA-miRNA are calculated by using miRNA sequence, miRNA-EF interaction, and the similarities of EF-EF are calculated based on the anatomical therapeutic chemical information, chemical structure and miRNA-EF interaction. The similarity network fusion is used to fuse the similarity between miRNA and the similarity between EF, respectively. Further, the multiple-label learning and bi-random walk are employed to identify the association between miRNA and EF. The experimental results show that our method outperforms the state-of-the-art algorithms. PMID- 30249985 TI - Cancer Health Literacy and Willingness to Participate in Cancer Research and Donate Bio-Specimens. AB - Although it has been well documented that poor health literacy is associated with limited participation in cancer clinical trials, studies assessing the relationships between cancer health literacy (CHL) and participation in research among diverse populations are lacking. In this study, we examined the relationship between CHL and willingness to participate in cancer research and/or donate bio-specimens (WPRDB) among African Americans, Latinos, and Whites. Participants completed the Cancer Health Literacy Test and the Multidimensional Cancer Literacy Questionnaire. Total-scale and subscale scores, frequencies, means, and distributions were computed. Analyses of variance, the Bonferroni procedure, and the Holm method were used to examine significant differences among groups. Cronbach's alphas estimated scales' internal consistency reliability. Significant interactions were found between race/ethnicity, gender, and CHL on WPRDB scales and subscale scores, even after education and age were taken into account. Our study confirms that CHL plays an important role that should be considered and researched further. The majority of participants were more willing to participate in non-invasive research studies (surveys, interviews, and training) or collection of bio-specimens (saliva, check cells, urine, and blood) and in studies led by their own healthcare providers, and local hospitals and universities. However, participants were less willing to participate in more invasive studies requiring them to take medications, undergo medical procedures or donate skin/tissues. We conclude that addressing low levels of CHL and using community-based participatory approaches to address the lack of knowledge and trust about cancer research among diverse populations may increase not only their willingness to participate in research and donate bio-specimens, but may also have a positive effect on actual participation rates. PMID- 30249987 TI - Recognition of Sedentary Behavior by Machine Learning Analysis of Wearable Sensors during Activities of Daily Living for Telemedical Assessment of Cardiovascular Risk. AB - With the recent advancement in wearable computing, sensor technologies, and data processing approaches, it is possible to develop smart clothing that integrates sensors into garments. The main objective of this study was to develop the method of automatic recognition of sedentary behavior related to cardiovascular risk based on quantitative measurement of physical activity. The solution is based on the designed prototype of the smart shirt equipped with a processor, wearable sensors, power supply and telemedical interface. The data derived from wearable sensors were used to create feature vector that consisted of the estimation of the user-specific relative intensity and the variance of filtered accelerometer data. The method was validated using an experimental protocol which was designed to be safe for the elderly and was based on clinically validated short physical performance battery (SPPB) test tasks. To obtain the recognition model six classifiers were examined and compared including Linear Discriminant Analysis, Support Vector Machines, K-Nearest Neighbors, Naive Bayes, Binary Decision Trees and Artificial Neural Networks. The classification models were able to identify the sedentary behavior with an accuracy of 95.00% +/- 2.11%. Experimental results suggested that high accuracy can be obtained by estimating sedentary behavior pattern using the smart shirt and machine learning approach. The main advantage of the developed method to continuously monitor patient activities in a free living environment and could potentially be used for early detection of increased cardiovascular risk. PMID- 30249986 TI - Momordica charantia Ethanol Extract Attenuates H2O2-Induced Cell Death by Its Antioxidant and Anti-Apoptotic Properties in Human Neuroblastoma SK-N-MC Cells. AB - Oxidative stress, which is induced by reactive oxygen species (ROS), causes cellular damage which contributes to the pathogenesis of neurodegenerative diseases. Momordica charantia (MC), a traditional medicinal plant, is known to have a variety of health benefits, such as antidiabetic, anti-inflammatory, and antioxidant effects. However, it is unknown whether MC has protective effects against oxidative stress-induced neuronal cell death. The aim of this study was to investigate the potential action of MC on oxidative stress induced by H2O2. First, we tested whether the pretreatment of Momordica charantia ethanol extract (MCEE) attenuates H2O2-induced cell death in human neuroblastoma SK-N-MC cells. MCEE pretreatment significantly improved cell viability and apoptosis that deteriorated by H2O2. Further, MCEE ameliorated the imbalance between intracellular ROS production and removal through the enhancement of the intracellular antioxidant system. Intriguingly, the inhibition of apoptosis was followed by the blockage of mitochondria-dependent cell death cascades and suppression of the phosphorylation of the mitogen-activated protein kinase signaling (MAPKs) pathway by MCEE. Taken together, MCEE was shown to be effective in protecting against H2O2-induced cell death through its antioxidant and anti apoptotic properties. PMID- 30249988 TI - Antimelanogenic Effects of Polygonum tinctorium Flower Extract from Traditional Jeju Fermentation via Upregulation of Extracellular Signal-Regulated Kinase and Protein Kinase B Activation. AB - This study was carried out to investigate the antimelanogenic effects of a Polygonum tinctorium flower extract obtained using red nuruk, a traditional Jeju barley-based fermentation starter. We also studied the mechanism of action of the P. tinctorium fermented flower extract (PTFFE) in mouse melanoma cells (B16F10). Cells were treated with various concentrations (62.5, 125 and 250 MUg/mL) of PTFFE and the results showed that PTFFE significantly decreased the melanin content and tyrosinase activity without being cytotoxic. In addition, PTFFE strongly inhibited the expression of tyrosinase and tyrosinase-related protein 2 by decreasing the expression of the microphthalmia-associated transcription factor, as shown by a western blot assay. Furthermore, PTFFE inhibited melanogenesis via upregulation of the phosphorylation of extracellular signal regulated kinase (ERK) and protein kinase B, also known as AKT. We also used inhibitors such as PD98059 (a specific ERK inhibitor) or LY294002 (an AKT inhibitor) to determine whether the signaling pathways are involved. High performance liquid chromatography fingerprinting showed the presence of a quercetin glucoside (isoquercitrin) and quercetin in PTFFE. To test the potential for PTFFE application as a cosmetic material, we also performed a primary skin irritation test on human skin. In this assay, PTFFE did not induce any adverse reactions at the treatment dose. Based on these results, we suggest that PTFFE may be considered a potential antimelanogenesis candidate for topical applications. PMID- 30249989 TI - Key Parameters to Promote Granularization of Lath-Like Bainite/Martensite in FeNiC Alloys during Isothermal Holding. AB - The stability of lath-like microstructures during low-temperature isothermal ageing was analyzed in a Fe5Ni0.33C (in wt %) steel. The microstructures were characterized using Scanning Electron Microscopy (SEM) coupled with Electron Backscatter Diffraction (EBSD). Advanced orientation data processing was applied to quantify the hierarchical and multiscale organization of crystallographic variants subdividing Prior Austenite Grains (PAG) into packets/blocks/sub-blocks. The result shows that ferrite laths of martensite or lower bainite are stable, whatever the ageing temperature (up to 380 degrees C). On the contrary, a granularization process is triggered when microstructures contain a fraction of upper bainite. This metallurgical evolution corresponds to a rapid and significant change of the ferrite matrix involving a disappearance of 60 degrees disoriented blocks. The phenomenon affects in turn the mechanical properties. The final microstructures obtained after isothermal holding look like granular bainite, which raises some questions about the classification of bainite. PMID- 30249990 TI - Methodology for Simulating 5G and GNSS High-Accuracy Positioning. AB - This paper focuses on the exploitation of fifth generation (5G) centimetre-wave (cmWave) and millimetre-wave (mmWave) transmissions for high-accuracy positioning, in order to complement the availability of Global Navigation Satellite Systems (GNSS) in harsh environments, such as urban canyons. Our goal is to present a representative methodology to simulate and assess their hybrid positioning capabilities over outdoor urban, suburban and rural scenarios. A novel scenario definition is proposed to integrate the network density of 5G deployments with the visibility masks of GNSS satellites, which helps to generate correlated scenarios of both technologies. Then, a generic and representative modeling of the 5G and GNSS observables is presented for snapshot positioning, which is suitable for standard protocols. The simulations results indicate that GNSS drives the achievable accuracy of its hybridisation with 5G cmWave, because non-line-of-sight (NLoS) conditions can limit the cmWave localization accuracy to around 20 m. The 5G performance is significantly improved with the use of mmWave positioning with dominant line-of-sight (LoS) conditions, which can even achieve sub-meter localization with one or more base stations. Therefore, these results show that NLoS conditions need to be weighted in 5G localization, in order to complement and outperform GNSS positioning over urban environments. PMID- 30249991 TI - Epidural Analgesia and Neonatal Morbidity: A Retrospective Cohort Study. AB - (1) Background: Epidural analgesia (EA), at the present time, is one of the most effective methods to reduce labor pain. In recent years its use has increased, being used between 20-70% of all deliveries; (2) Methods: Historical cohort on a total of 2947 deliveries during the years 2012-2016 at the "Mancha-Centro Hospital" of Alcazar de San Juan. The main outcome variables were four neonatal morbidity (NM) criteria: umbilical artery pH of <7.10, Apgar score at 5 min < 7, need for advanced resuscitation and composite morbidity. We used the multivariate analysis to control confounding bias. (3) Results: No statistical relationship between EA and the second stage of labor duration with none of the four criteria of NM used (p > 0.005). However, the type of delivery was associated with three criteria (pH, resuscitation, and composite morbidity). The instrumental delivery presented an OR of pH < 7.10 of 2.68 95% CI [1.15, 6.27], an OR of advanced resuscitation of 2.44 95% CI [1.17, 5.08] and OR of composite morbidity of 2.86 95% CI [1.59, 5.12]; (4) Conclusions: The EA and the second stage of labor duration are not related to the NM. While the instrumental delivery doubles the risk of NM compared to the normal vaginal delivery. PMID- 30249992 TI - Excellent Infrared Nonlinear Optical Crystals BaMO(IO3)5 (M = V, Ta) Predicted by First Principle Calculations. AB - Two nonlinear optical crystals, BaVO(IO3)5 and BaTaO(IO3)5, are designed by substituting Nb with V and Ta, respectively, in BaNbO(IO3)5, which is itself a recently synthesized infrared nonlinear optical (NLO) material. The designs of BaVO(IO3)5 and BaTaO(IO3)5 from BaNbO(IO3)5 are based on the following motivation: BaVO(IO3)5 should have a larger second-harmonic generation (SHG) coefficient than BaNbO(IO3)5, as V will result in a stronger second-order Jahn Teller effect than Nb due to its smaller ion radius; at the same time, BaTaO(IO3)5 should have a larger laser-damage threshold, due to the fact that Ta has a smaller electronegativity leading to a greater band-gap. Established on reliable first-principle calculations, it is demonstrated that BaVO(IO3)5 has a much larger SHG coefficient than BaNbO(IO3)5 (23.42 * 10-9 vs. 18.66 * 10-9 esu); and BaTaO(IO3)5 has a significantly greater band-gap than BaNbO(IO3)5 (4.20 vs. 3.55 eV). Meanwhile, the absorption spectra and birefringences of both BaVO(IO3)5 and BaTaO(IO3)5 are acceptable for practice, suggesting that these two crystals can both be expected to be excellent infrared NLO materials. PMID- 30249993 TI - Pd-Free Activation Pretreatment for Electroless Ni-P Plating on NiFe2O4 Particles. AB - A Pd-free activation pretreatment process was developed for electroless Ni-P plating on NiFe2O4 particles. The main influencing factors, including NiCl2.6H2O concentration, pH of electroless bath and temperature, were investigated. Microstructures of the coating layers were characterized by scanning electron microscopy. It was found that a more uniform and compact Ni-P coating layer was successfully formed by electroless plating via Pd-free activation pretreatment than Pd as sited plating. The coating layers plated by Pd-free activation pretreatment were thicker than those by the sensitization and activation pretreatment on average (9 vs. 5 MUm). The new process did not need conventional sensitization or activation pretreatments, because the Ni particles dispersed uniformly on the NiFe2O4 substrate became catalytic activation sites for nickel electroless plating. Such improvement was beneficial to shortening the preparation process and reducing the production costs with the use of noble metal Pd. PMID- 30249994 TI - Explorative Data Analysis of Drosophila suzukii Trap Catches from a Seven-Year Monitoring Program in Southwest Germany. AB - Over the last decade, Drosophila suzukii Matsumura, an invasive pest of soft skinned fruits, gradually established itself in Europe, often resulting in significant economic losses. In 2011, when D. suzukii was first described for Germany, the Julius Kuhn Institut (JKI) started a monitoring program in southwest Germany to study the occurrence and activity of the fly. Capture data from late 2011-early 2018 from 100 traps were analyzed for the effect of weather and immediate habitat on trap captures at different times of the year. We identified five phases in the annual population development cycle of D. suzukii. We found that the mild winter of 2013/2014 helped the thorough establishment of D. suzukii in Germany. Habitat types in the immediate vicinity of the trap and local weather conditions had a strong influence on trap captures. Forest borders and hedges were found to provide adequate overwintering shelter for the flies. Trap captures in forests and hedges were generally higher than those of vineyards and orchards, even during the fruiting seasons. Summer capture rates were correlated with the number of heat days and precipitation. We also discuss briefly the limitations of using trap captures as representative of fly density in the field. PMID- 30249996 TI - Highly Efficient and Low-Temperature Preparation of Plate-Like ZrB2-SiC Powders by a Molten-Salt and Microwave-Modified Boro/Carbothermal Reduction Method. AB - To address the various shortcomings of a high material cost, energy-intensive temperature conditions and ultra-low efficiency of the conventional boro/carbothermal reduction method for the industrial preparation of ZrB2-SiC powders, a novel molten-salt and microwave-modified boro/carbothermal reduction method (MSM-BCTR) was developed to synthesize ZrB2-SiC powders. As a result, phase pure ZrB2-SiC powders can be obtained by firing low-cost zircon (ZrSiO4), amorphous carbon (C), and boron carbide (B4C) at a reduced temperature of 1200 degrees C for only 20 min. Such processing conditions are remarkably milder than not only that required for conventional boro/carbothermal reduction method to prepare phase pure ZrB2 or ZrB2-SiC powders (firing temperature of above 1500 degrees C and dwelling time of at least several hours), but also that even with costly active metals (e.g., Mg and Al). More importantly, the as-obtained ZrB2 particles had a single crystalline nature and well-defined plate-like morphology, which is believed to be favorable for enhancing the mechanical properties, especially toughness of their bulk counterpart. The achievement of a highly efficient preparation of such high-quality ZrB2-SiC powders at a reduced temperature should be mainly attributed to the specific molten-salt and microwave modified boro/carbothermal reduction method. PMID- 30249995 TI - Corrosion Behavior of the As-Cast and As-Solid Solution Mg-Al-Ge Alloy. AB - The corrosion behavior of Mg-3Al-xGe (x = 1, 3, 5) alloy in as-cast and as-solid was investigated by virtue of microstructure, corrosion morphology observation, and electrochemical measurement. Among the as-cast alloys, the corrosion rate of Mg-3Al-1Ge with a discontinuous bar-morphology was the highest, which was 101.7 mm.a-1; the corrosion rate of Mg-3Al-3Ge with a continuous network distribution was the lowest, which was 23.1 mm.a-1; and the corrosion rate of Mg-3Al-5Ge of Ge enriched phase with sporadic distribution was in-between, which was 63.9 mm.a-1. It is suggested that the morphology of the Mg2Ge phase changes with a change in Ge content, which affects the corrosion performance of the alloy. After solid solution treatment, the corrosion rate of the corresponding solid solution alloy increased-Mg-3Al-1Ge to 140.5 mm.a-1, Mg-3Al-3Ge to 52.9 mm.a-1, and Mg-3Al-5Ge to 87.3 mm.a-1, respectively. After investigation of the microstructure, it can be suggested that solid solution treatment dissolves the Mg17Al12 phase, which changes the phase composition of the alloy and also affects its microstructure, thus affecting its corrosion performance. PMID- 30249997 TI - Geographic Variation in the Chemical Composition and Antioxidant Properties of Phenolic Compounds from Cyclocarya paliurus (Batal) Iljinskaja Leaves. AB - Cyclocarya paliurus has been widely used as an ingredient in functional foods in China. However, the antioxidant properties of phenolic compounds and the effect of the plant origin remain unclear. The present study evaluated the geographical variation of this plant in term of its phenolic composition and antioxidant activities based on leaf materials collected from five regions. high-performance liquid chromatography (HPLC) analysis showed that there are three major components, quercetin-3-O-glucuronide, kaempferol-3-O-glucuronide, and kaempferol 3-O-rhamnoside, and their contents varied significantly among sampling locations. The investigated phenolic compounds showed substantial antioxidant activities, both in vitro and in vivo, with the highest capacity observed from Wufeng and Jinzhongshan. Correlation analysis revealed that quercetin and kaempferol glycosides might be responsible for the antioxidant activities. Our results indicate the importance of geographic origin, with sunny hours and temperature as the main drivers affecting the accumulation of C. paliurus phenolics and their antioxidant properties. PMID- 30250000 TI - Thermochemical Measurements of Alkali Cation Association to Hexatantalate. AB - Ion association is an important process in aqueous dissolution, precipitation, and crystallization of ionic inorganic, organic, and biological materials. Polyoxometalates (POMs) are good model compounds for understanding the complex relationships between lattice energy, ion-pairing in solution, and salt solubility. Here we perform calorimetric measurements to elucidate trends in cluster stability, lattice energy, and ion-pairing behavior studies of simple hexatantalate salts in neat water, parent hydroxide solutions, and molybdate melts, extending previous studies on the isostructural hexaniobates. High temperature calorimetry of alkali salts of hexatantalate reveals that the enthalpies of formation from oxides of the K, Rb, and Cs salts are more similar to each other than they are for their niobate analogues and that the tantalate cluster is energetically less stable than hexaniobate. Aqueous dissolution calorimetry reveals that the cesium salt of hexatantalate has a similar concentration dependence on its dissolution enthalpy to that of hexaniobate. However, unlike rubidium hexaniobate, rubidium hexatantalate also exhibits increased concentration dependence, indicating that hextantalate can undergo increased ion-pairing with alkali salts other than cesium, despite the dilute environments studied. Dissolution enthalpies of POM salts in the parent alkali hydroxides shows that protonation of clusters stabilizes lattices even more than the strongly associating heavy alkali cations do. Additionally, neither weak nor strong lattice ion associations necessarily correlates with respectively high or low aqueous solubility. These studies illuminate the importance of considering ion-pairing among the interrelated processes in the aqueous dissolution of ionic salts that can be extended to serving as a model of cation association to metal oxide surfaces. PMID- 30249999 TI - A Review on the Use of Hydroxyapatite-Carbonaceous Structure Composites in Bone Replacement Materials for Strengthening Purposes. AB - Biomedical materials constitute a vast scientific research field, which is devoted to producing medical devices which aid in enhancing human life. In this field, there is an enormous demand for long-lasting implants and bone substitutes that avoid rejection issues whilst providing favourable bioactivity, osteoconductivity and robust mechanical properties. Hydroxyapatite (HAp)-based biomaterials possess a close chemical resemblance to the mineral phase of bone, which give rise to their excellent biocompatibility, so allowing for them to serve the purpose of a bone-substituting and osteoconductive scaffold. The biodegradability of HAp is low (Ksp ~ 6.62 * 10-126) as compared to other calcium phosphates materials, however they are known for their ability to develop bone like apatite coatings on their surface for enhanced bone bonding. Despite its favourable bone regeneration properties, restrictions on the use of pure HAp ceramics in high load-bearing applications exist due to its inherently low mechanical properties (including low strength and fracture toughness, and poor wear resistance). Recent innovations in the field of bio-composites and nanoscience have reignited the investigation of utilising different carbonaceous materials for enhancing the mechanical properties of composites, including HAp based bio-composites. Researchers have preferred carbonaceous materials with hydroxyapatite due to their inherent biocompatibility and good structural properties. It has been demonstrated that different structures of carbonaceous material can be used to improve the fracture toughness of HAp, as they can easily serve the purpose of being a second phase reinforcement, with the resulting composite still being a biocompatible material. Nanostructured carbonaceous structures, especially those in the form of fibres and sheets, were found to be very effective in increasing the fracture toughness values of HAp. Minor addition of CNTs (3 wt.%) has resulted in a more than 200% increase in fracture toughness of hydroxyapatite-nanorods/CNTs made using spark plasma sintering. This paper presents a current review of the research field of using different carbonaceous materials composited with hydroxyapatite with the intent being to produce high performance biomedically targeted materials. PMID- 30249998 TI - Interplay between Cellular Metabolism and Cytokine Responses during Viral Infection. AB - Metabolism and immune responses are two fundamental biological processes that serve to protect hosts from viral infection. As obligate intracellular pathogens, viruses have evolved diverse strategies to activate metabolism, while inactivating immune responses to achieve maximal reproduction or persistence within their hosts. The two-way virus-host interaction with metabolism and immune responses choreograph cytokine production via reprogramming metabolism of infected cells/hosts. In return, cytokines can affect the metabolism of virus infected and bystander cells to impede viral replication processes. This review aims to summarize our current understanding of the cross-talk between metabolic reprogramming and cytokine responses, and to highlight future potential research topics. Although the focus is placed on viral pathogens, relevant findings from other microbes are integrated to provide an overall picture, particularly when corresponding information on viral infection is lacking. PMID- 30250001 TI - Enhanced Electrochemical Properties of Gel Polymer Electrolyte with Hybrid Copolymer of Organic Palygorskite and Methyl Methacrylate. AB - Gel polymer electrolyte (GPE) is widely considered as a promising safe lithium ion battery material compared to conventional organic liquid electrolyte, which is linked to a greater risk of corrosive liquid leakage, spontaneous combustion, and explosion. GPE contains polymers, lithium salts, and liquid electrolyte, and inorganic nanoparticles are often used as fillers to improve electrochemical performance. However, such composite polymer electrolytes are usually prepared by means of blending, which can impact on the compatibility between the polymer and filler. In this study, the hybrid copolymer poly (organic palygorskite-co-methyl methacrylate) (poly(OPal-MMA)) is synthesized using organic palygorskite (OPal) and MMA as raw materials. The poly(OPal-MMA) gel electrolyte exhibits an ionic conductivity of 2.94 * 10-3 S/cm at 30 degrees C. The Li/poly(OPal-MMA) electrolyte/LiFePO4 cell shows a wide electrochemical window (approximately 4.7 V), high discharge capacity (146.36 mAh/g), and a low capacity-decay rate (0.02%/cycle). PMID- 30250002 TI - Artificial Heme Enzymes for the Construction of Gold-Based Biomaterials. AB - Many efforts are continuously devoted to the construction of hybrid biomaterials for specific applications, by immobilizing enzymes on different types of surfaces and/or nanomaterials. In addition, advances in computational, molecular and structural biology have led to a variety of strategies for designing and engineering artificial enzymes with defined catalytic properties. Here, we report the conjugation of an artificial heme enzyme (MIMO) with lipoic acid (LA) as a building block for the development of gold-based biomaterials. We show that the artificial MIMO@LA can be successfully conjugated to gold nanoparticles or immobilized onto gold electrode surfaces, displaying quasi-reversible redox properties and peroxidase activity. The results of this work open interesting perspectives toward the development of new totally-synthetic catalytic biomaterials for application in biotechnology and biomedicine, expanding the range of the biomolecular component aside from traditional native enzymes. PMID- 30250003 TI - An Efficient Algorithm for Sensitively Detecting Circular RNA from RNA-seq Data. AB - Circular RNA (circRNA) is an important member of non-coding RNA family. Numerous computational methods for detecting circRNAs from RNA-seq data have been developed in the past few years, but there are dramatic differences among the algorithms regarding the balancing of the sensitivity and precision of the detection and filtering strategies. To further improve the sensitivity, while maintaining an acceptable precision of circRNA detection, a novel and efficient de novo detection algorithm, CIRCPlus, is proposed in this paper. CIRCPlus accurately locates circRNA candidates by identifying a set of back-spliced junction reads by comparing the local similar sequence of each pair of spanning junction reads. This strategy, thus, utilizes the important information provided by unbalanced spanning reads, which facilitates the detection especially when the expression levels of circRNA are unapparent. The performance of CIRCPlus was tested and compared to the existing de novo methods on the real datasets as well as a series of simulation datasets with different configurations. The experiment results demonstrated that the sensitivities of CIRCPlus were able to reach 90% in common simulation settings, while CIRCPlus held balanced sensitivity and reliability on the real datasets according to an objective assessment criteria based on RNase R-treated samples. The software tool is available for academic uses only. PMID- 30250004 TI - A Practical Data-Gathering Algorithm for Lossy Wireless Sensor Networks Employing Distributed Data Storage and Compressive Sensing. AB - Reliability and energy efficiency are two key considerations when designing a compressive sensing (CS)-based data-gathering scheme. Most researchers assume there is no packets loss, thus, they focus only on reducing the energy consumption in wireless sensor networks (WSNs) while setting reliability concerns aside. To balance the performance-energy trade-off in lossy WSNs, a distributed data storage (DDS) and gathering scheme based on CS (CS-DDSG) is introduced, which combines CS and DDS. CS-DDSG utilizes broadcast properties to resist the impact of packet loss rates. Neighboring nodes receive packets with process constraints imposed to decrease the volume of both transmissions and receptions. The mobile sink randomly queries nodes and constructs a measurement matrix based on received data with the purpose of avoiding measuring the lossy nodes. Additionally, we demonstrate how this measurement matrix satisfies the restricted isometry property. To analyze the efficiency of the proposed scheme, an expression that reflects the total number of transmissions and receptions is formulated via random geometric graph theory. Simulation results indicate that our scheme achieves high precision for unreliable links and reduces the number of transmissions, receptions and fusions. Thus, our proposed CS-DDSG approach effectively balances energy consumption and reconstruction accuracy. PMID- 30250006 TI - Bilateral Wilms Tumor: A Surgical Perspective. AB - Historically, the management of bilateral Wilms tumor (BWT) was non-standardized and suffered from instances of prolonged chemotherapy and inconsistent surgical management which resulted in suboptimal renal and oncologic outcomes. Because of the risk of end-stage renal disease associated with the management of BWT, neoadjuvant chemotherapy and nephron-sparing surgery have been adopted as the guiding management principles. This management strategy balances acceptable oncologic outcomes against the risk of end-stage renal disease. A recent multi institutional Children's Oncology Group study (AREN0534) has confirmed the benefits of standardized 3-drug neoadjuvant chemotherapy and the utilization of nephron-sparing surgery in BWT patients; however, less than 50% of patients underwent bilateral nephron-sparing surgery. The coordination of neoadjuvant chemotherapy and the timing and implementation of bilateral nephron-sparing surgery are features of BWT management that require collaboration between oncologists and surgeons. This review discusses the surgical management strategy in the context of BWT disease biology, with an emphasis on timepoints during therapy at which surgical decision making can greatly impact this disease and minimize long-term toxicities. PMID- 30250005 TI - Acetylene in Organic Synthesis: Recent Progress and New Uses. AB - Recent progress in the leading synthetic applications of acetylene is discussed from the prospect of rapid development and novel opportunities. A diversity of reactions involving the acetylene molecule to carry out vinylation processes, cross-coupling reactions, synthesis of substituted alkynes, preparation of heterocycles and the construction of a number of functionalized molecules with different levels of molecular complexity were recently studied. Of particular importance is the utilization of acetylene in the synthesis of pharmaceutical substances and drugs. The increasing interest in acetylene and its involvement in organic transformations highlights a fascinating renaissance of this simplest alkyne molecule. PMID- 30250007 TI - Pioglitazone Protects Mesenchymal Stem Cells against P-Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1. AB - Mesenchymal stem cells (MSC) could be a candidate for cell-based therapy in chronic kidney disease (CKD); however, the uremic toxin in patients with CKD restricts the therapeutic efficacy of MSCs. To address this problem, we explored the effect of pioglitazone as a measure against exposure to the uremic toxin P cresol (PC) in MSCs. Under PC exposure conditions, apoptosis of MSCs was induced, as well as PC-induced dysfunction of mitochondria by augmentation of mitofusion, reduction of mitophagy, and inactivation of mitochondrial complexes I and IV. Treatment of MSCs with pioglitazone significantly inhibited PC-induced apoptosis. Pioglitazone also prevented PC-induced mitofusion and increased mitophagy against PC exposure through up-regulation of phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK-1). Furthermore, pioglitazone protected against PC-induced mitochondrial dysfunction by increasing the cytochrome c oxidase subunit 4 (COX4) level and activating complexes I and IV, resulting in enhancement of proliferation. In particular, activation of nuclear factor kappa light-chain-enhancer of activated B cells (NF-kappaB) regulated the pioglitazone mediated up-regulation of PINK-1. These results indicate that pioglitazone protects MSCs against PC-induced accumulated mitochondrial dysfunction via the NF kappaB-PINK-1 axis under P-cresol exposure conditions. Our study suggests that pioglitazone-treated MSCs could be a candidate for MSC-based therapy in patients with CKD. PMID- 30250008 TI - Current Disease-Targets for Oleocanthal as Promising Natural Therapeutic Agent. AB - The broad number of health benefits which can be obtained from the long-term consumption of olive oil are attributed mainly to its phenolic fraction. Many olive oil phenolics have been studied deeply since their discovery due to their bioactivity properties, such as Hydroxytyrosol. Similarly, in the last decade, the special attention of researchers has been addressed to Oleocanthal (OC). This olive oil phenolic compound has recently emerged as a potential therapeutic agent against a variety of diseases, including cancer, inflammation, and neurodegenerative and cardiovascular diseases. Recently, different underlying mechanisms of OC against these diseases have been explored. This review summarizes the current literature on OC to date, and focuses on its promising bioactivities against different disease-targets. PMID- 30250009 TI - Does Location of Tonic Pain Differentially Impact Motor Learning and Sensorimotor Integration? AB - Recent work found that experimental pain appeared to negate alterations in cortical somatosensory evoked potentials (SEPs) that occurred in response to motor learning acquisition of a novel tracing task. The goal of this experiment was to further investigate the interactive effects of pain stimulus location on motor learning acquisition, retention, and sensorimotor processing. Three groups of twelve participants (n = 36) were randomly assigned to either a local capsaicin group, remote capsaicin group or contralateral capsaicin group. SEPs were collected at baseline, post-application of capsaicin cream, and following a motor learning task. Participants performed a motor tracing acquisition task followed by a pain-free retention task 24-48 h later while accuracy data was recorded. The P25 (p < 0.001) SEP peak significantly decreased following capsaicin application for all groups. Following motor learning acquisition, the N18 SEP peak decreased for the remote capsaicin group (p = 0.02) while the N30 (p = 0.002) SEP peaks increased significantly following motor learning acquisition for all groups. The local, remote and contralateral capsaicin groups improved in accuracy following motor learning (p < 0.001) with no significant differences between the groups. Early SEP alterations are markers of the neuroplasticity that accompanies acute pain and motor learning acquisition. Improved motor learning while in acute pain may be due to an increase in arousal, as opposed to increased attention to the limb performing the task. PMID- 30250010 TI - Characterization of Properties and Transglycosylation Abilities of Recombinant alpha-Galactosidase from Cold-Adapted Marine Bacterium Pseudoalteromonas KMM 701 and Its C494N and D451A Mutants. AB - A novel wild-type recombinant cold-active alpha-d-galactosidase (alpha-PsGal) from the cold-adapted marine bacterium Pseudoalteromonas sp. KMM 701, and its mutants D451A and C494N, were studied in terms of their structural, physicochemical, and catalytic properties. Homology models of the three dimensional alpha-PsGal structure, its active center, and complexes with D galactose were constructed for identification of functionally important amino acid residues in the active site of the enzyme, using the crystal structure of the alpha-galactosidase from Lactobacillus acidophilus as a template. The circular dichroism spectra of the wild alpha-PsGal and mutant C494N were approximately identical. The C494N mutation decreased the efficiency of retaining the affinity of the enzyme to standard p-nitrophenyl-alpha-galactopiranoside (pNP alpha-Gal). Thin-layer chromatography, matrix-assisted laser desorption/ionization mass spectrometry, and nuclear magnetic resonance spectroscopy methods were used to identify transglycosylation products in reaction mixtures. alpha-PsGal possessed a narrow acceptor specificity. Fructose, xylose, fucose, and glucose were inactive as acceptors in the transglycosylation reaction. alpha-PsGal synthesized -alpha(1->6)- and -alpha(1->4)-linked galactobiosides from melibiose as well as -alpha(1->6)- and -alpha(1->3)-linked p nitrophenyl-digalactosides (Gal2-pNP) from pNP-alpha-Gal. The D451A mutation in the active center completely inactivated the enzyme. However, the substitution of C494N discontinued the Gal-alpha(1->3)-Gal-pNP synthesis and increased the Gal alpha(1->4)-Gal yield compared to Gal-alpha(1->6)-Gal-pNP. PMID- 30250011 TI - An Anti-Inflammatory Azaphenothiazine Inhibits Interferon beta Expression and CXCL10 Production in KERTr Cells. AB - An azaphenothiazine derivative, 6-chloroethylureidoethyldiquino[3,2-b;2',3' e][1,4]thiazine (DQT), has recently been shown to exhibit immunosuppressive activities in mouse models. It also inhibited the expression of CXCL10 at the protein level, at non-toxic concentrations, in the culture of KERTr cells treated with double-stranded RNA, poly(I:C). In this report, we demonstrated that DQT inhibits the transcription of the CXCL10 gene. Although CXCL10 is an IFNgamma inducible protein, we found that the CXCL10 protein was induced without the detectable release of IFNgamma or IkappaB degradation. Hence, we concluded that IFNgamma or NFkappaB was not involved in the regulation of the CXCL10 gene in KERTr cells transfected with poly(I:C), nor in the inhibitory activity of DQT. On the other hand, we found that IFNbeta was induced under the same conditions and that its expression was inhibited by DQT. Kinetic analysis showed that an increase in IFNbeta concentrations occurred 4-8 h after poly(I:C) treatment, while the concentration of CXCL10 was undetectable at that time and started to increase later, when IFNbeta reached high levels. Therefore, DQT may be regarded as a new promising inhibitor of IFNbeta expression and IFNbeta-dependent downstream genes and proteins, e.g., CXCL10 chemokine, which is implicated in the pathogenesis of autoimmune diseases. PMID- 30250012 TI - Bioprocessing of Functional Ingredients from Flaxseed. AB - Flaxseeds (Linum usitatissimum L.) are oilseeds endowed with nutritional constituents such as lignans, lipids, proteins, fibre, carbohydrates, and micronutrients. Owing to their established high nutritional profile, flaxseeds have gained an established reputation as a dietary source of high value functional ingredients. Through the application of varied bioprocessing techniques, these essential constituents in flaxseeds can be made bioavailable for different applications such as nutraceuticals, cosmetics, and food industry. However, despite their food and health applications, flaxseeds contain high levels of phytotoxic compounds such as linatine, phytic acids, protease inhibitors, and cyanogenic glycosides. Epidemiological studies have shown that the consumption of these compounds can lead to poor bioavailability of essential nutrients and/or health complications. As such, these components must be removed or inactivated to physiologically undetectable limits to render flaxseeds safe for consumption. Herein, critical description of the types, characteristics, and bioprocessing of functional ingredients in flaxseed is presented. PMID- 30250014 TI - Recurrent Seizures in 2 Patients with Magnesium Sulfate-Treated Eclampsia at a Secondary Hospital. AB - BACKGROUND Recurrent seizure in patients with magnesium sulfate-treated eclampsia is very rare and requires meticulous management due to poor prognosis. The development of eclamptic convulsions is considered a preventable obstetric situation. Magnesium sulfate has been the drug of choice in such cases. However, some cases are persistent and need more aggressive treatment. CASE REPORT First case: A 20-year-old, nulliparous woman was referred from a private midwifery practice with history of convulsion, 40 weeks of gestational age (GA), and in the active phase of labor. She had been treated with magnesium sulfate and nifedipine beforehand. Her fetus was tachycardic, so an emergency caesarean section was done and placental abruption was found. The day after the surgery, the patient had recurrent seizures despite receiving a maintenance dose of magnesium sulfate. The patient then received thiopental sodium and remained stable. Second case: A 19 year-old, nulliparous woman came to the hospital with 40 weeks of GA, prolonged premature rupture of the membrane (PROM), preeclampsia, and cephalopelvic disproportion (CPD). An emergency caesarean section was performed. Eighteen hours after surgery, the patient had convulsions despite receiving magnesium sulfate maintenance therapy. We repeated the loading dose of 2 g magnesium sulfate, but the seizures persisted. Hence, midazolam was given and the seizures remained controlled. Both babies were delivered without any significant complications. CONCLUSIONS We report 2 cases of GIP0-0 women with 40 weeks GA who had magnesium sulfate-resistant eclampsia and needed additional anticonvulsant drugs. These cases show the importance of comprehensive management and the need for alternative drugs in eclampsia. PMID- 30250015 TI - Liver Transplantation for Progressive Familial Intrahepatic Cholestasis. AB - BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that disrupts the genes for bile formation. Liver transplantation (LT) is the only effective treatment for PFIC patients with end stage liver disease. We describe our experience in terms of clinical characteristics, complications, and outcome of LT for PFIC. CASE REPORT The data of 5 pediatric PFIC patients recipients (3 PFIC1, 1 PFIC2, and 1 PFIC3) who received LT at our Liver Transplant Center from June 2013 to February 2017 were retrospectively analyzed. Four patients received liver transplantation from donation after cardiac death (DCD) donors. One patient received a living donor liver transplantation (LDLT). All the LT recipients received an immunosuppressive regimen of tacrolimus (FK 506) + methylprednisolone + mycophenolate mofetil (MMF). Diarrhea did not improve in 2 PFIC1 patients after LT, and they both developed steatohepatitis several months after LT. The other PFIC1 patient received ABO blood group incompatible LT and developed biliary complications and a severe Epstein-Barr virus infection; this patient underwent endoscopic retrograde cholangiopancreatography. She recovered after treatment with ganciclovir and reduction of tacrolimus dosage. The PFIC2 patient had abnormal liver function 19 months after LT, and recovered after administration of increased dosage of immunosuppressant agents. Liver function in the PFIC3 patient was normal during 2-year follow-up. CONCLUSIONS Liver transplantation is an effective treatment in PFIC patients. However, PFIC1 patients may develop aggravated diarrhea and steatohepatitis after LT. PFIC2 and PFIC3 patients have good outcomes after LT. PMID- 30250016 TI - Tumor Growth Assessment by Computed Tomography Perfusion Imaging (CTPI), Perfusion-Weighted Imaging (PWI), and Diffusion-Weighted Imaging (DWI) in a Rabbit Pleural Squamous Cell Carcinoma VX2-Implanted Model. AB - BACKGROUND Computed tomography perfusion imaging (CTPI) and perfusion-weighted imaging (PWI) are non-invasive technologies that can quantify tumor vascularity and blood flow. This study explored the blood flow information, tumor cell viability, and hydrothoraces in a rabbit pleural VX2-implanted model through use of CTPI, PWI, and DWI. MATERIAL AND METHODS A pleural VX2-implanted model was established in 58 New Zealand white rabbits. CTPI, PWI, and DWI were applied with a 16-slice spiral CT and an Archival 1.5 T dual-gradient MRI. RESULTS Compared with muscle tissue, PV, PEI, and BV of parietal and visceral pleural tumor implantation rabbits showed significant differences. The t values of PV, PEI, and BV between parietal and visceral pleura were 2.08, 2.29, and 2.88, respectively. Compared with muscle tissue, WIR, WOR, and MAXR of parietal and visceral pleural tumor implantation rabbits showed significant differences. In parietal pleural tumor implantation rabbits, the section surface of lesion tissues was 5.2+/-2.7 cm2. Hydrothorax appeared 6.0+/-2.0 days after tumor implantation. The mean value of ADC was 1.5+/-0.6. In visceral pleural tumor implantation rabbits, the section surface of lesion tissues was 1.6+/-0.8 cm2. Hydrothorax appeared 7.0+/-3.0 days after tumor implantation. The mean value of ADC was 1.4+/-0.5. The t values of the above 3 indices for the parietal and visceral pleura were 1.85, 1.83, and 1.76, respectively (P<0.05). CONCLUSIONS The combined application of CTPI, PWI, and DWI accurately and visually reflects the blood perfusion of tumor tissues and quantitatively analyzes blood flow information and the mechanism underlying hydrothorax generation in tumor tissues. PMID- 30250017 TI - [Impact of place of residence on the presentation of cardiovascular events and all-cause mortality in a cohort with metabolic syndrome]. AB - OBJECTIVE: In order to clarify the relation between deprivation and morbillity and mortality, in function of different residence places, we design this study. Main objective is to analyze the influence of place of residence on the incidence of cardiovascular events (CVD) and general mortality from any cause, in a cohort with metabolic syndrome. METHODS: Prospective study to determine the incidence of CVD according to the place of residence (rural, urban) in individuals with different combinations of clinical features of Metabolic Syndrome (MS). Setting: Primary Care, Catalonia (Spain). Subjects: between 35-75 years of age fulfilling SM criteria, without CVD at the beginning of follow-up (2009). The population was stratified according to the MEDEA index in rural, and within urban areas in 5 subcategories (urban1 - urban5), according to their level of deprivation. We performed descriptive statistics, variance analysis and survival curves (Kaplan Meier and Cox methods) in order to contrast data from different categories. RESULTS: We analyzed 401,743 subjects with MS (17.2% of the Catalan population); 20.1% resided in rural areas. Their average age ranged between 60.5 + 9.6 years in urban area 1 (most favored) and 59.6 + 10.4 years in urban area 5 (the most precarious). After 5 years of follow-up, the global incidence of CVD was 5.5%, being slightly lower in rural areas (5%) than in urban areas (between 5.5% 5.8%). On the other hand, mortality was higher in the rural area (859 deaths/100000 inhabitants-year) - than in the rest of the areas (minimum value in urban-3 (736 deaths/100000 inhabitants-year)). CONCLUSIONS: The place of residence is a risk marker, which is associated with the incidence of CVD but above all, with higher mortality from all causes in patients with MS. Undoubtedly and leaving aside the possible confounding factors, in the socioeconomically most disadvantaged areas, mortality is increased. PMID- 30250018 TI - Endothelial cell activation on 3D-matrices derived from PDGF-BB-stimulated fibroblasts is mediated by Snail1. AB - Carcinomas, such as colon cancer, initiate their invasion by rescuing the innate plasticity of both epithelial cells and stromal cells. Although Snail is a transcriptional factor involved in the Epithelial-Mesenchymal Transition, in recent years, many studies have also identified the major role of Snail in the activation of Cancer-Associated Fibroblast (CAF) cells and the remodeling of the extracellular matrix. In CAFs, Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant. High expression of both SNAI1 and PDGF receptors is associated with poor prognosis in cancer patients, but the mechanism(s) that underlie these connections are not understood. In this study, we demonstrate that PDGF-activated fibroblasts stimulate extracellular matrix (ECM) fiber remodeling and deposition. Furthermore, we describe how SNAI1, through the FAK pathway, is a necessary factor for ECM fiber organization. The parallel-oriented fibers are used by endothelial cells as "tracks", facilitating their activation and the creation of tubular structures mimicking in vivo capillary formation. Accordingly, Snail1 expression in fibroblasts was required for the co-adjuvant effect of these cells on matrix remodeling and neoangiogenesis when co-xenografted in nude mice. Finally, in tumor samples from colorectal cancer patients a direct association between stromal SNAI1 expression and the endothelial marker CD34 was observed. In summary, our results advance the understanding of PDGF/SNAI1-activated CAFs in matrix remodeling and angiogenesis stimulation. PMID- 30250020 TI - SIRT1 suppresses the migration and invasion of gastric cancer by regulating ARHGAP5 expression. AB - Gastric cancer (GC) ranks among the top five malignant tumors worldwide by the incidence and mortality rate. However, the mechanisms underlying its progression are poorly understood. In this study, we investigated the role of SIRT1, a class III deacetylase, in the invasion and metastasis of GC. Here, we found that knockdown of SIRT1 promoted GC cell migration and invasion in vitro and metastasis in vivo. Forced expression of SIRT1 in GC cells had the opposite effects. Then, we used mRNA microarray to identify the target genes that are regulated by SIRT1 and found that ARHGAP5 was downregulated by SIRT1. The results of the mRNA microarray were confirmed in several GC cell lines. Furthermore, SIRT1 inhibited the expression of ARHGAP5 by physically associating with transcription factor c-JUN and deacetylating and inhibiting the transcriptional activity of c-JUN. Then the expression dynamics and clinical significance of ARHGAP5 were analyzed using clinical samples and database. The expression of ARHGAP5 was increased in GC, and positively correlated with tumor size, tumor infiltration, lymph node metastasis, and clinical stage. And multivariate analyses indicated that ARHGAP5 served as an independent prognostic marker of GC. In addition, the biological effects of ARHGAP5 in SIRT1-mediated inhibition of GC migration and invasion were investigated using both in vitro and in vivo models. Silencing of ARHGAP5 considerably inhibited the migration and invasion of GC, and ARHGAP5 was found to be involved in the SIRT1-mediated inhibition of GC migration and invasion. Our results indicate that SIRT1 suppresses migration and invasion of GC by downregulating ARHGAP5 through an interaction with c-JUN, and these phenomena represent a novel mechanism of the antitumor action of SIRT1. PMID- 30250019 TI - Rapamycin and fasting sustain autophagy response activated by ischemia/reperfusion injury and promote retinal ganglion cell survival. AB - Autophagy, the cellular process responsible for degradation and recycling of cytoplasmic components through the autophagosomal-lysosomal pathway, is fundamental for neuronal homeostasis and its deregulation has been identified as a hallmark of neurodegeneration. Retinal hypoxic-ischemic events occur in several sight-treating disorders, such as central retinal artery occlusion, diabetic retinopathy, and glaucoma, leading to degeneration and loss of retinal ganglion cells. Here we analyzed the autophagic response in the retinas of mice subjected to ischemia induced by transient elevation of intraocular pressure, reporting a biphasic and reperfusion time-dependent modulation of the process. Ischemic insult triggered in the retina an acute induction of autophagy that lasted during the first hours of reperfusion. This early upregulation of the autophagic flux limited RGC death, as demonstrated by the increased neuronal loss observed in mice with genetic impairment of basal autophagy owing to heterozygous ablation of the autophagy-positive modulator Ambra1 (Ambra1+/gt). Upregulation of autophagy was exhausted 24 h after the ischemic event and reduced autophagosomal turnover was associated with build up of the autophagic substrate SQSTM-1/p62, decreased ATG12-ATG5 conjugate, ATG4 and BECN1/Beclin1 expression. Animal fasting or subchronic systemic treatment with rapamycin sustained and prolonged autophagy activation and improved RGC survival, providing proof of principle for autophagy induction as a potential therapeutic strategy in retinal neurodegenerative conditions associated with hypoxic/ischemic stresses. PMID- 30250021 TI - Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer. AB - Estrogen receptor alpha (ERalpha) is expressed in ~67% of breast cancers and is critical to their proliferation and progression. The expression of ERalpha is regarded as a major prognostic marker, making it a meaningful target to treat breast cancer (BCa). However, hormone receptor-positive BCa was sometimes irresponsive or even resistant to classic anti-hormonal therapies (e.g., fulvestrant and tamoxifen). Hence, novel anti-endocrine therapies are urgent for ERalpha+ BCa. A phase II study suggested that bortezomib, an inhibitor blocking the activity of 20 S proteasomes, intervenes in cancer progression for anti endocrine therapy in BCa. Here we report that proteasome-associated deubiquitinases (USP14 and UCHL5) inhibitors b-AP15 and platinum pyrithione (PtPT) induce growth inhibition in ERalpha+ BCa cells. Further studies show that these inhibitors induce cell cycle arrest and apoptosis associated with caspase activation, endoplasmic reticulum (ER) stress and the downregulation of ERalpha. Moreover, we suggest that b-AP15 and PtPT block ERalpha signaling via enhancing the ubiquitin-mediated degradation of ERalpha and inhibiting the transcription of ERalpha. Collectively, these findings demonstrate that proteasome-associated deubiquitinases inhibitors b-AP15 and PtPT may have the potential to treat BCa resistant to anti-hormonal therapy. PMID- 30250013 TI - Curcumin, Cardiometabolic Health and Dementia. AB - Current research indicates curcumin [diferuloylmethane; a polyphenolic compound isolated from the rhizomes of the dietary spice turmeric (Curcuma longa)] exerts a beneficial effect on health which may be partly attributable to its anti oxidative and anti-inflammatory properties. The aim of this review is to examine potential mechanisms of the actions of curcumin in both animal and human studies. Curcumin modulates relevant molecular target pathways to improve glucose and lipid metabolism, suppress inflammation, stimulate antioxidant enzymes, facilitate insulin signalling and reduce gut permeability. Curcumin also inhibits Abeta and tau accumulation in animal models and enhances mitochondria and synaptic function. In conclusion, in high-dose animal studies and in vitro, curcumin exerts a potential beneficial effect on cardiometabolic disease. However, human studies are relatively unconvincing. More intervention studies should be conducted with the new curcumin formulation with improved oral bioavailability. PMID- 30250022 TI - SP1-induced lncRNA-ZFAS1 contributes to colorectal cancer progression via the miR 150-5p/VEGFA axis. AB - Increasing long non-coding RNAs (lncRNAs) have been reported to play key roles in the development and progression of various malignancies. ZNFX1 antisense RNA1 (ZFAS1) has been reported to be aberrant expression and suggested as a tumor suppressor or oncogene in many cancers. However, the biological role and underlying molecular mechanism of ZFAS1, especially the miRNA sponge role of which in CRC remain largely unknown. We found that ZFAS1 expression was higher in CRC tissues, where it was associated with poor overall survival (OS), we also showed that ZFAS1 upregulation was induced by nuclear transcription factor SP1. Moreover, ZFAS1 and VEGFA are both targets of miR-150-5p, while ZFAS1 binds to miR-150-5p in an AGO2-dependent manner. Additionally, ZFAS1 upregulation markedly promoted as well as ZFAS1 knockdown significantly suppressed CRC cell proliferation, migration, invasion and angiogenesis, and the inhibitory effect caused by ZFAS1 knockdown could be reversed by antagomiR-150-5p. Lastly, we demonstrated that ZFAS1 knockdown inhibited EMT process and inactivated VEGFA/VEGFR2 and downstream Akt/mTOR signaling pathway in CRC. Our data demonstrated that SP1-induced ZFAS1 contributed to CRC progression by upregulating VEGFA via competitively binding to miR-150-5p, which acts as a tumor suppressor by targeting VEGFA in CRC. PMID- 30250023 TI - Linc02527 promoted autophagy in Intrahepatic cholestasis of pregnancy. AB - LncRNA plays a crucial role in human disease. However, the expression and function of LncRNA in ICP(Intrahepatic cholestasis of pregnancy) is still not fully elucidated. In this study, we found Linc02527 was increased expression in placenta and serum of ICP patients. Ectopically expression of Linc02527 promoted autophagy and proliferate in HTR8 cells. Silencing Linc02527 suppressed the autophagy and proliferate in HTR8 cells. Mechanically study revealed that Linc02527 regulated the expression of ATG5 and ATG7 by sponging miR-3185. Linc02527 directly binding to YBX1 and activated P21. The growth of C57 mouse was retarded when autophagy was activated. In normal condition, inhibited autophagy using chloroquine did not affect the growth of C57 mouse. However, in the condition of autophagy was activated, inhibited autophagy using chloroquine can improve the growth of C57 mouse. Overall, the results of this study identified Linc02527 as a candidate biomarker in ICP and a potential target for ICP therapy. Chloroquine was a potential drug for ICP therapy. PMID- 30250024 TI - SIRT3 deficiency leads to induction of abnormal glycolysis in diabetic kidney with fibrosis. AB - The regulation of aberrant glucose metabolism in diabetes associated-kidney fibrosis is not well known. In this study we found the suppression of SIRT3 protein level in diabetic kidney, displays responsibility in fibrogenic programming associated with aberrant glycolysis and such abnormal glycolysis is the therapeutic target in diabetes associated-kidney fibrosis. When analyzing different strains of streptozotocin-induced diabetic mice model (fibrotic model: CD-1, less fibrotic model: C57Bl6), we found SIRT3 suppression was associated with kidney fibrosis in fibrotic CD-1; further SIRT3 suppression by systemic administration of SIRT3 siRNA in the diabetic mice, showed profound fibrogenic phenotype in the kidney. Such suppression in SIRT3 was associated with the induction of transforming growth factor-beta (TGF-beta)/smad signaling, higher level of HIF1alpha accumulation and PKM2 dimer formation; these alterations subsequently led to abnormal glycolysis and linked abnormal mesenchymal transformations in vivo and in vitro. Inhibition of such aberrant glycolysis suppressed fibrogenic programming and restored SIRT3 level as well. Such aberrant glycolysis was confirmed in the KK/Ta-Ins2Akita mouse, the mouse model of progressive diabetic kidney disease. These data demonstrate that SIRT3 deficiency promotes abnormal glycolysis which is responsible for the fibrogenic pathway in diabetic kidney. Restoration of SIRT3 could be an alternative strategy in combating diabetes associated-kidney fibrosis via inhibition of aberrant glycolysis. PMID- 30250025 TI - Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells. AB - Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 activator. Our data demonstrated that UBCS039 induced a time-dependent activation of autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate autophagy. At the molecular level, SIRT6-mediated autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced autophagy, suggesting that ROS burst had a key role in upstream events leading to autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an autophagy inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 activator, thereby providing a proof of principle that modulation of the enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death. PMID- 30250026 TI - 'Brain Fogginess' and D-Lactic Acidosis: Probiotics Are Not the Cause. PMID- 30250027 TI - Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy. AB - Diabetes cardiomyopathy (DCM) is a critical complication of long-term chronic diabetes mellitus and is characterized by myocardial fibrosis and myocardial hypertrophy. It has been suggested that DCM is related to pyroptosis, a programmed cell death associated with inflammation. The long non-coding RNA Kcnq1ot1 is involved in different pathophysiological mechanisms of multiple diseases, including acute myocardial damage and arrhythmia. Our previous study found that Kcnq1ot1 was elevated in left ventricular tissue of diabetic mice. However, whether Kcnq1ot1 is capable of regulating pyroptosis and fibrosis in high glucose-treated cardiac fibroblasts remains unknown. The aim of the study was to investigate the mechanisms of Kcnq1ot1 in DCM. Our study revealed that silencing Kcnq1ot1 by a lentivirus-shRNA improved cardiac function and fibrosis, ameliorated pyroptosis, and inhibited TGF-beta1/smads pathway in C57BL/6 mice. In vitro, experiments revealed that Kcnq1ot1 and pyroptosis were activated in cardiac fibroblasts treated with 30 mmol/l glucose. Furthermore, Kcnq1ot1 knockdown by a small interfering RNA decreased caspase-1 expression. Bioinformatic prediction and luciferase assays showed that Kcnq1ot1 functioned as a competing endogenous RNA to regulate the expression of caspase-1 by sponging miR-214-3p. In addition, silencing Kcnq1ot1 promoted gasdermin D cleavage and the secretion of IL-1beta, thus repressing the TGF-beta1/smads pathway in high glucose-treated cardiac fibroblasts through miR-214-3p and caspase-1. Therefore, Kcnq1ot1/miR-214-3p/caspase-1/TGF-beta1 signal pathway presents a new mechanism of DCM progression and could potentially be a novel therapeutic target. PMID- 30250028 TI - OCP-FRP protein complex topologies suggest a mechanism for controlling high light tolerance in cyanobacteria. AB - In cyanobacteria, high light photoactivates the orange carotenoid protein (OCP) that binds to antennae complexes, dissipating energy and preventing the destruction of the photosynthetic apparatus. At low light, OCP is efficiently deactivated by a poorly understood action of the dimeric fluorescence recovery protein (FRP). Here, we engineer FRP variants with defined oligomeric states and scrutinize their functional interaction with OCP. Complemented by disulfide trapping and chemical crosslinking, structural analysis in solution reveals the topology of metastable complexes of OCP and the FRP scaffold with different stoichiometries. Unable to tightly bind monomeric FRP, photoactivated OCP recruits dimeric FRP, which subsequently monomerizes giving 1:1 complexes. This could be facilitated by a transient OCP-2FRP-OCP complex formed via the two FRP head domains, significantly improving FRP efficiency at elevated OCP levels. By identifying key molecular interfaces, our findings may inspire the design of optically triggered systems transducing light signals into protein-protein interactions. PMID- 30250029 TI - Eosinophil recruitment is dynamically regulated by interplay among lung dendritic cell subsets after allergen challenge. AB - Eosinophil infiltration, a hallmark of allergic asthma, is essential for type 2 immune responses. How the initial eosinophil recruitment is regulated by lung dendritic cell (DC) subsets during the memory stage after allergen challenge is unclear. Here, we show that the initial eosinophil infiltration is dependent on lung cDC1s, which require nitric oxide (NO) produced by inducible NO synthase from lung CD24-CD11b+ DC2s for inducing CCL17 and CCL22 to attract eosinophils. During late phase responses after allergen challenge, lung CD24+ cDC2s inhibit eosinophil recruitment through secretion of TGF-beta1, which impairs the expression of CCL17 and CCL22. Our data suggest that different lung antigen presenting cells modulate lung cDC1-mediated eosinophil recruitment dynamically, through secreting distinct soluble factors during the memory stage of chronic asthma after allergen challenge in the mouse. PMID- 30250030 TI - Neurogenetic profiles delineate large-scale connectivity dynamics of the human brain. AB - Experimental and modeling work of neural activity has described recurrent and attractor dynamic patterns in cerebral microcircuits. However, it is still poorly understood whether similar dynamic principles exist or can be generalizable to the large-scale level. Here, we applied dynamic graph theory-based analyses to evaluate the dynamic streams of whole-brain functional connectivity over time across cognitive states. Dynamic connectivity in local networks is located in attentional areas during tasks and primary sensory areas during rest states, and dynamic connectivity in distributed networks converges in the default mode network (DMN) in both task and rest states. Importantly, we find that distinctive dynamic connectivity patterns are spatially associated with Allen Human Brain Atlas genetic transcription levels of synaptic long-term potentiation and long term depression-related genes. Our findings support the neurobiological basis of large-scale attractor-like dynamics in the heteromodal cortex within the DMN, irrespective of cognitive state. PMID- 30250031 TI - Gas-solid reaction based over one-micrometer thick stable perovskite films for efficient solar cells and modules. AB - Besides high efficiency, the stability and reproducibility of perovskite solar cells (PSCs) are also key for their commercialization. Herein, we report a simple perovskite formation method to fabricate perovskite films with thickness over 1 MUm in ambient condition on the basis of the fast gas-solid reaction of chlorine incorporated hydrogen lead triiodide and methylamine gas. The resultant thick and smooth chlorine-incorporated perovskite films exhibit full coverage, improved crystallinity, low surface roughness and low thickness variation. The resultant PSCs achieve an average power conversion efficiency of 19.1 +/- 0.4% with good reproducibility. Meanwhile, this method enables an active area efficiency of 15.3% for 5 cm * 5 cm solar modules. The un-encapsulated PSCs exhibit an excellent T80 lifetime exceeding 1600 h under continuous operation conditions in dry nitrogen environment. PMID- 30250032 TI - Solution-processed perovskite light emitting diodes with efficiency exceeding 15% through additive-controlled nanostructure tailoring. AB - Organometal halide perovskites (OHP) are promising materials for low-cost, high efficiency light-emitting diodes. In films with a distribution of two-dimensional OHP nanosheets and small three-dimensional nanocrystals, an energy funnel can be realized that concentrates the excitations in highly efficient radiative recombination centers. However, this energy funnel is likely to contain inefficient pathways as the size distribution of nanocrystals, the phase separation between the OHP and the organic phase. Here, we demonstrate that the OHP crystallite distribution and phase separation can be precisely controlled by adding a molecule that suppresses crystallization of the organic phase. We use these improved material properties to achieve OHP light-emitting diodes with an external quantum efficiency of 15.5%. Our results demonstrate that through the addition of judiciously selected molecular additives, sufficient carrier confinement with first-order recombination characteristics, and efficient suppression of non-radiative recombination can be achieved while retaining efficient charge transport characteristics. PMID- 30250033 TI - Autism, Early Psychosis, and Social Anxiety Disorder: a transdiagnostic examination of executive function cognitive circuitry and contribution to disability. AB - The disability burden in clinical cohorts with social impairment is significant, leading to poor functional outcomes. Some of this impairment has been linked to executive dysfunction. In this study, a transdiagnostic approach was taken to identify executive function (EF) processes in young adults that may underpin social impairment and to evaluate their contribution to disability. Comparisons were made between three prominent disorders that are characterized by social impairments, Autism Spectrum Disorder (ASD), Early Psychosis (EP) and Social Anxiety Disorder (SAD), as well as a neurotypically developing group (TYP). We examined whether overall disability could be predicted by neuropsychological and self-report assessments of EF. Our study showed that ASD participants demonstrated impaired performance on most domains of EF compared to the TYP group (mental flexibility, sustained attention and fluency) while the EP group showed impairment on sustained attention and attentional shifting. The SAD participants showed EF impairment on self-report ratings, even though their objective performance was intact. Self-reports of EF explained a significant percentage (17%) of disability in addition to the variance explained by other predictors, and this was particularly important for ASD. This is the first study to compare EF measures across clinical groups of social impairment and suggests unique cognitive-circuitry that underpins disability within groups. Impairments in EF were broad in ASD and predicted disability, EP impairments were specific to attentional processes and SAD impairments likely relate to negative self monitoring. Self-report, as opposed to performance-based EF, provided best capacity to predict disability. These findings contribute to transdiagnostic circuitry models and intervention strategies. PMID- 30250034 TI - Association Between Type 2 Diabetes Mellitus, HbA1c and the Risk for Spontaneous Bacterial Peritonitis in Patients with Decompensated Liver Cirrhosis and Ascites. AB - INTRODUCTION: Type 2 diabetes mellitus (DM) is a frequent comorbidity among patients with liver cirrhosis. However, data regarding the impact of DM on spontaneous bacterial peritonitis (SBP) are quite limited. Our aim was to analyze the impact of DM and HbA1c values on the incidence of SBP and mortality in patients with liver cirrhosis and ascites. METHODS: A number of 475 consecutive patients with liver cirrhosis and ascites were analyzed. Presence of DM as well as HbA1c was assessed at the time of the first paracentesis. Patients were followed up for a mean of 266 days. Primary endpoints were SBP development and mortality. RESULTS: Overall, 118 (25%) patients were diagnosed with DM. DM patients had an increased risk for developing a SBP during follow-up (HR: 1.51; p = 0.03). SBP incidence was particularly high in DM patients with HbA1c values >=6.4%, significantly higher than in DM patients with HbA1c values <6.4% (HR: 4.21; p = 0.0002). Of note, DM patients with HbA1c <6.4% at baseline had a similar risk for SBP as those without DM (HR: 0.93; p = 0.78, respectively). After excluding all patients who were eligible for secondary antibiotic prophylaxis, HbA1c >=6.4% but neither bilirubin nor ascites protein level were associated with primary SBP development in the multivariate analysis (p = 0.003). CONCLUSIONS: Individuals with liver cirrhosis and concomitant DM have a higher risk for developing a SBP. HbA1c values may be useful to further stratify the risk for SBP among DM patients, which may help to identify those who benefit from antibiotic prophylaxis. PMID- 30250035 TI - Identification of Quantitative Trait Loci and Candidate Genes for Maize Starch Granule Size through Association Mapping. AB - Starch is an important nutrient component of maize kernels, and starch granule size largely determines kernel waxiness, viscosity, and other physiochemical and processing properties. To explore the genetic basis of maize starch granule size, 266 tropical, subtropical, and temperate inbred lines were subjected to genome wide association analyses with an array of 56,110 random single nucleotide polymorphisms (SNPs). In the present panel, the kernel starch granule size ranged from 7-15.8 um long and 6.8-14.3 um wide. Fourteen significant SNPs were identified as being associated with the length of starch granules and 9 with their width. One linkage disequilibrium block flanking both sides of a significant SNP was defined as a quantitative trait locus (QTL) interval, and seven QTLs were mapped for both granule length and width. A total of 79 and 88 candidate genes associated with starch length and width, respectively, were identified as being distributed on QTL genomic regions. Among these candidate genes, six with high scores were predicted to be associated with maize starch granule size. A candidate gene association analysis identified significant SNPs within genes GRMZM2G419655 and GRMZM2G511067, which could be used as functional markers in screening starch granule size for different commercial uses. PMID- 30250036 TI - A two-step DNA barcoding approach for delimiting moth species: moths of Dongling Mountain (Beijing, China) as a case study. AB - DNA barcoding, based on a fragment of cytochrome c oxidase I (COI) mtDNA, is as an effective molecular tool for identification, discovery, and biodiversity assessment for most animals. However, multiple gene markers coupled with more sophisticated analytical approaches may be necessary to clarify species boundaries in cases of cryptic diversity or morphological plasticity. Using 339 moths collected from mountains surrounding Beijing, China, we tested a pipeline consisting of two steps: (1) rapid morphospecies sorting and screening of the investigated fauna with standard COI barcoding approaches; (2) additional analyses with multiple molecular markers for those specimens whose morphospecies and COI barcode grouping were incongruent. In step 1, 124 morphospecies were delimited into 116 barcode units, with 90% of the conflicts being associated with specimens identified to the genus Hypena. In step 2, 55 individuals representing all 12 Hypena morphospecies were analysed using COI, COII, 28S, EF-1a, Wgl sequences or their combinations with the BPP (Bayesian Phylogenetics and Phylogeography) multigene species delimitation method. The multigene analyses supported the delimitation of 5 species, consistent with the COI analysis. We conclude that a two-step barcoding analysis pipeline is able to rapidly characterize insect biodiversity and help to elucidate species boundaries for taxonomic complexes without jeopardizing overall project efficiency by substantially increasing analytical costs. PMID- 30250037 TI - Identifying the missing link in catalyst transfer polymerization. AB - Nickel-catalyzed catalyst transfer polycondensation (CTP) of thiophenes is an efficient strategy for the controlled synthesis of polythiophenes. However, a detailed view of its reaction mechanism has remained elusive with unresolved questions regarding the geometry and bonding of critical Ni(0) thiophene intermediates. Herein, we provide experimental and computational evidence of structurally characterized square planar eta2-Ni(0)-thiophene species and their relevance to the mechanism of CTP. These results confirm the viability of C,C eta2 bound intermediates in CTP of thiophenes, providing an electronic rationale for the stability of such species, and thus that such processes can proceed as living polymerizations. We further show that C,S-kappa2 species may also be relevant in nickel-catalyzed CTP of thiophenes, providing new avenues for exploitation and optimization. PMID- 30250038 TI - Novel role for receptor dimerization in post-translational processing and turnover of the GRalpha. AB - Glucocorticoids (GCs), acting via the glucocorticoid receptor (GRalpha), remain the mainstay therapeutic choice for the treatment of inflammation. However, chronic GC use, aside from generating undesirable side-effects, results in GRalpha down-regulation, often coupled to a decrease in GC-responsiveness, which may culminate in acquired GC resistance. The current study presents evidence for a novel role of the dimerization state of the GRalpha in mediating GC-mediated GRalpha turnover. Through comparing the effects of dimerization promoting GCs on down-regulation of a transfected human wild type GRalpha (hGRwt) or a dimerization deficient GRalpha mutant (hGRdim), we established that a loss of receptor dimerization restricts GRalpha turnover, which was supported by the use of the dimerization abrogating Compound A (CpdA), in cells containing endogenous GRalpha. Moreover, we showed that the dimerization state of the GRalpha influenced the post-translational processing of the receptor, specifically hyper phosphorylation at Ser404, which influenced the interaction of GRalpha with the E3 ligase, FBXW7alpha, thus hampering receptor turnover via the proteasome. Lastly, the restorative effects of CpdA on the GRalpha pool, in the presence of Dex, were demonstrated in a combinatorial treatment protocol. These results expand our understanding of factors that contribute to GC-resistance and may be exploited clinically. PMID- 30250039 TI - Functional characterization of TBR1 variants in neurodevelopmental disorder. AB - Recurrent de novo variants in the TBR1 transcription factor are implicated in the etiology of sporadic autism spectrum disorders (ASD). Disruptions include missense variants located in the T-box DNA-binding domain and previous work has demonstrated that they disrupt TBR1 protein function. Recent screens of thousands of simplex families with sporadic ASD cases uncovered additional T-box variants in TBR1 but their etiological relevance is unclear. We performed detailed functional analyses of de novo missense TBR1 variants found in the T-box of ASD cases, assessing many aspects of protein function, including subcellular localization, transcriptional activity and protein-interactions. Only two of the three tested variants severely disrupted TBR1 protein function, despite in silico predictions that all would be deleterious. Furthermore, we characterized a putative interaction with BCL11A, a transcription factor that was recently implicated in a neurodevelopmental syndrome involving developmental delay and language deficits. Our findings enhance understanding of molecular functions of TBR1, as well as highlighting the importance of functional testing of variants that emerge from next-generation sequencing, to decipher their contributions to neurodevelopmental disorders like ASD. PMID- 30250041 TI - Author Correction: Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30250040 TI - Transcriptional Regulatory Networks in Hepatitis C Virus-induced Hepatocellular Carcinoma. AB - Understanding the transcriptional regulatory elements that influence the progression of liver disease in the presence of hepatitis C virus (HCV) infection is critical for the development of diagnostic and therapeutic approaches. Systems biology provides a roadmap by which these elements may be integrated. In this study, a previously published dataset of 124 microarray samples was analyzed in order to determine differentially expressed genes across four tissue types/conditions (normal, cirrhosis, cirrhosis HCC, and HCC). Differentially expressed genes were assessed for their functional clustering and those genes were annotated with their potential transcription factors and miRNAs. Transcriptional regulatory networks were constructed for each pairwise comparison between the 4 tissue types/conditions. Based on our analysis, it is predicted that the disruption in the regulation of transcription factors such as AP-1, PPARgamma, and NF-kappaB could contribute to the liver progression from cirrhosis to steatosis and eventually to HCC. Whereas the condition of the liver digresses, the downregulation of miRNAs' (such as miR-27, Let-7, and miR-106a) expression makes the transition of the liver through each pathological stage more apparent. This preliminary data can be used to guide future experimental work. An understanding of the transcriptional regulatory attributes acts as a road map to help design interference strategies in order to target the key regulators of progression of HCV induced HCC. PMID- 30250042 TI - Malic Enzyme 1 (ME1) is pro-oncogenic in ApcMin/+ mice. AB - Cytosolic Malic Enzyme (ME1) provides reduced NADP for anabolism and maintenance of redox status. To examine the role of ME1 in tumor genesis of the gastrointestinal tract, we crossed mice having augmented intestinal epithelial expression of ME1 (ME1-Tg mice) with ApcMin/+ mice to obtain male ApcMin/+/ME1-Tg mice. ME1 protein levels were significantly greater within gut epithelium and adenomas of male ApcMin/+/ME1-Tg than ApcMin/+ mice. Male ApcMin/+/ME1-Tg mice had larger and greater numbers of adenomas in the small intestine (jejunum and ileum) than male ApcMin/+ mice. Male ApcMin/+/ME1-Tg mice exhibited greater small intestine crypt depth and villus length in non-adenoma regions, correspondent with increased KLF9 protein abundance in crypts and lamina propria. Small intestines of male ApcMin/+/ME1-Tg mice also had enhanced levels of Sp5 mRNA, suggesting Wnt/beta-catenin pathway activation. A small molecule inhibitor of ME1 suppressed growth of human CRC cells in vitro, but had little effect on normal rat intestinal epithelial cells. Targeting of ME1 may add to the armentarium of therapies for cancers of the gastrointestinal tract. PMID- 30250044 TI - Identification of RSPO2 Fusion Mutations and Target Therapy Using a Porcupine Inhibitor. AB - Cancers are driven by a variety of somatic gene mutations and identifying these mutations enables the development of novel target drugs. We have sought to identify abnormalities in Wnt pathway-related genes that are sensitive to Wnt inhibitor treatment. We examined Patient Derived Xenograft (PDX) RNA samples and found new R-Spondin 2 (RSPO2) transcript fusions with the EMC2, PVT1 or HNF4G genes. These fusion events were identified in about 1.4% of the digestive system cancer samples. We then examined the oncogenic effects of the RSPO2-EMC2 fusion gene and confirmed that it can drive oncogenesis, sustain tumor growth and promote metastasis. Finally, we used a Wnt pathway Porcupine inhibitor CGX1321 to treat PDX mouse models containing RSPO2 fusion genes. All the RSPO2 fusion tumors responded to the treatment and stopped progression. Our data show that Wnt pathway inhibition could provide an effective treatment for cancers containing RSPO2 fusion. The RSPO2 fusion will serve as a good biomarker for screening patients to support clinical treatment of digestive system cancers using Wnt pathway inhibitors. PMID- 30250043 TI - CcpA Coordinates Growth/Damage Balance for Streptococcus pyogenes Pathogenesis. AB - To achieve maximum fitness, pathogens must balance growth with tissue damage, coordinating metabolism and virulence factor expression. In the gram-positive bacterium Streptococcus pyogenes, the DNA-binding transcriptional regulator Carbon Catabolite Protein A (CcpA) is a master regulator of both carbon catabolite repression and virulence, suggesting it coordinates growth/damage balance. To examine this, two murine models were used to compare the virulence of a mutant lacking CcpA with a mutant expressing CcpA locked into its high-affinity DNA-binding conformation (CcpAT307Y). In models of acute soft tissue infection and of long-term asymptomatic mucosal colonization, both CcpA mutants displayed altered virulence, albeit with distinct growth/damage profiles. Loss of CcpA resulted in a diminished ability to grow in tissue, leading to less damage and early clearance. In contrast, constitutive DNA-binding activity uncoupled the growth/damage relationship, such that high tissue burdens and extended time of carriage were achieved, despite reduced tissue damage. These data demonstrate that growth/damage balance can be actively controlled by the pathogen and implicate CcpA as a master regulator of this relationship. This suggests a model where the topology of the S. pyogenes virulence network has evolved to couple carbon source selection with growth/damage balance, which may differentially influence pathogenesis at distinct tissues. PMID- 30250045 TI - Identification of mesothelioma-specific sialylated epitope recognized with monoclonal antibody SKM9-2 in a mucin-like membrane protein HEG1. AB - The anti-mesothelioma mAb SKM9-2 recognizes the sialylated protein HEG homolog 1 (HEG1). HEG1 is a 400 kDa mucin-like membrane protein found on mesothelioma. SKM9 2 can detect mesothelioma more specifically and sensitively than other antibodies against current mesothelioma markers; therefore, SKM9-2 would be likely useful for the precise detection and diagnosis of malignant mesothelioma. In the present study, we investigated the epitope of SKM9-2. We analyzed the binding of SKM9-2 to truncated HEG1 and candidate epitope-fused glycosylphosphatidylinositol-anchor proteins. The epitope of SKM9-2 was identified as an O-glycosylated region, 893 SKSPSLVSLPT-903, in HEG1. An alanine scanning assay of the epitope showed that SKM9-2 bound to a simple epitope in HEG1, and the SKxPSxVS sequence within the epitope was essential for SKM9-2 recognition. Mass spectrometry analysis and lectin binding analysis of soluble epitope peptides indicated that the SKM9-2 epitope, in which Ser897 was not glycosylated, contained two disialylated core 1 O-linked glycan-modified serine residues, Ser893 and Ser900. Neuraminidase treatment analysis also confirmed that the epitope in mesothelioma cells contained a similar glycan modification. The specific detection of mesothelioma with SKM9-2 can thus be performed by the recognition of sialylated glycan modification in the specific region of HEG1. PMID- 30250046 TI - Skin alpha-synuclein deposits differ in clinical variants of synucleinopathy: an in vivo study. AB - : We aimed to characterize in vivo alpha-synuclein (alpha-syn) aggregates in skin nerves to ascertain: 1) the optimal marker to identify them; 2) possible differences between synucleinopathies that may justify the clinical variability. We studied multiple skin nerve alpha-syn deposits in 44 patients with synucleinopathy: 15 idiopathic Parkinson's disease (IPD), 12 dementia with Lewy Bodies (DLB), 5 pure autonomic failure (PAF) and 12 multiple system atrophy (MSA). Ten healthy subjects were used as controls. Antibodies against native alpha-syn, C-terminal alpha-syn epitopes such as phosphorylation at serine 129 (p syn) and to conformation-specific for alpha-syn mature amyloid fibrils (syn-F1) were used. We found that p-syn showed the highest sensitivity and specificity in disclosing skin alpha-syn deposits. In MSA abnormal deposits were only found in somatic fibers mainly at distal sites differently from PAF, IPD and DLB displaying alpha-syn deposits in autonomic fibers mainly at proximal sites. PAF and DLB showed the highest p-syn load with a widespread involvement of autonomic skin nerve fibers. IN CONCLUSION: 1) p-syn in skin nerves was the optimal marker for the in vivo diagnosis of synucleinopathies; 2) the localization and load differences of aggregates may help to identify specific diagnostic traits and support a different pathogenesis among synucleinopathies. PMID- 30250047 TI - Future scenarios of marine resources and ecosystem conditions in the Eastern Mediterranean under the impacts of fishing, alien species and sea warming. AB - Using a temporal-dynamic calibrated Ecosim food web model, we assess the effects of future changes on marine resources and ecosystem conditions of the Israeli Mediterranean continental shelf. This region has been intensely invaded by Indo Pacific species. The region is exposed to extreme environmental conditions, is subjected to high rates of climate change and has experienced intense fishing pressure. We test the impacts of a new set of fishing regulations currently being implemented, a continued increase in sea temperatures following IPCC projections, and a continued increase in alien species biomass. We first investigate the impacts of the stressors separately, and then we combine them to evaluate their cumulative effects. Our results show overall potential future benefits of fishing effort reductions, and detrimental impacts of increasing sea temperature and increasing biomass of alien species. Cumulative scenarios suggest that the beneficial effects of fisheries reduction may be dampened by the impact of increasing sea temperature and alien species when acting together. These results illustrate the importance of including stressors other than fisheries, such as climate change and biological invasions, in an ecosystem-based management approach. These results support the need for reducing local and regional stressors, such as fishing and biological invasions, in order to promote resilience to sea warming. PMID- 30250048 TI - Analysis of the role of GSK3 in the mitotic checkpoint. AB - The mitotic checkpoint ensures proper chromosome segregation; defects in this checkpoint can lead to aneuploidy, a hallmark of cancer. The mitotic checkpoint blocks progression through mitosis as long as chromosomes remain unattached to spindle microtubules. Unattached kinetochores induce the formation of a mitotic checkpoint complex (MCC) composed of Mad2, BubR1, Bub1 and Bub3 which inhibits anaphase onset. Spindle toxins induce prolonged mitotic arrest by creating persistently unattached kinetochores which trigger MCC formation. We find that the multifunctional ser/thr kinase, glycogen synthase kinase 3 (GSK3) is required for a strong mitotic checkpoint. Spindle toxin-induced mitotic arrest is relieved by GSK3 inhibitors SB 415286 (SB), RO 318220 (RO) and lithium chloride. Similarly, targeting GSK3beta with knockout or RNAi reduced mitotic arrest in the presence of Taxol. GSK3 was required for optimal localization of Mad2, BubR1, and Bub1 at kinetochores and for optimal assembly of the MCC in spindle toxin arrested cells. The WNT- and PI3K/Akt signaling pathways negatively regulate GSK3beta activity. Inhibition of WNT and PI3K/Akt signaling, in the presence of Taxol, induced a longer mitotic arrest compared to Taxol alone. Our observations provide novel insight into the regulation of the mitotic checkpoint and its connection to growth-signaling pathways. PMID- 30250050 TI - Lath formation mechanisms and twinning as lath martensite substructures in an ultra low-carbon iron alloy. AB - Lath martensite is the dominant microstructural feature in quenched low-carbon Fe C alloys. Its formation mechanism is not clear, despite extensive research. The microstructure of an Fe-0.05 C (wt.%) alloy water-quenched at various austenitizing temperatures has been investigated using transmission electron microscopy and a novel lath formation mechanism has been proposed. Body-centered cubic {112}<111>-type twin can be retained inside laths in the samples quenched at temperatures from 1050 degrees C to 1200 degrees C. The formation mechanism of laths with a twin substructure has been explained based on the twin structure as an initial product of martensitic transformation. A detailed detwinning mechanism in the auto-tempering process has also been discussed, because auto tempering is inevitable during the quenching of low-carbon Fe-C alloys. The driving force for the detwinning is the instability of omega-Fe(C) particles, which are located only at the twinning boundary region. The twin boundary can move through the omega <-> bcc transition in which the omega phase region represents the twin boundary. PMID- 30250051 TI - Wastewater treatment plant resistomes are shaped by bacterial composition, genetic exchange, and upregulated expression in the effluent microbiomes. AB - Wastewater treatment plants (WWTPs) are implicated as hotspots for the dissemination of antibacterial resistance into the environment. However, the in situ processes governing removal, persistence, and evolution of resistance genes during wastewater treatment remain poorly understood. Here, we used quantitative metagenomic and metatranscriptomic approaches to achieve a broad-spectrum view of the flow and expression of genes related to antibacterial resistance to over 20 classes of antibiotics, 65 biocides, and 22 metals. All compartments of 12 WWTPs share persistent resistance genes with detectable transcriptional activities that were comparatively higher in the secondary effluent, where mobility genes also show higher relative abundance and expression ratios. The richness and abundance of resistance genes vary greatly across metagenomes from different treatment compartments, and their relative and absolute abundances correlate with bacterial community composition and biomass concentration. No strong drivers of resistome composition could be identified among the chemical stressors analyzed, although the sub-inhibitory concentration (hundreds of ng/L) of macrolide antibiotics in wastewater correlates with macrolide and vancomycin resistance genes. Contig based analysis shows considerable co-localization between resistance and mobility genes and implies a history of substantial horizontal resistance transfer involving human bacterial pathogens. Based on these findings, we propose future inclusion of mobility incidence (M%) and host pathogenicity of antibiotic resistance genes in their quantitative health risk ranking models with an ultimate goal to assess the biological significance of wastewater resistomes with regard to disease control in humans or domestic livestock. PMID- 30250049 TI - Neural correlates of multi-day learning and savings in sensorimotor adaptation. AB - In the present study we evaluated changes in neural activation that occur over the time course of multiple days of sensorimotor adaptation, and identified individual neural predictors of adaptation and savings magnitude. We collected functional MRI data while participants performed a manual adaptation task during four separate test sessions over a three-month period. This allowed us to examine changes in activation and associations with adaptation and savings at subsequent sessions. Participants exhibited reliable savings of adaptation across the four sessions. Brain activity associated with early adaptation increased across the sessions in a variety of frontal, parietal, cingulate, and temporal cortical areas, as well as various subcortical areas. We found that savings was positively associated with activation in several striatal, parietal, and cingulate cortical areas including the putamen, precuneus, angular gyrus, dorsal anterior cingulate cortex (dACC), and cingulate motor area. These findings suggest that participants may learn how to better engage cognitive processes across days, potentially reflecting improvements in action selection. We propose that such improvements may rely on action-value assignments, which previously have been linked to the dACC and striatum. As correct movements are assigned a higher value than incorrect movements, the former are more likely to be performed again. PMID- 30250052 TI - Clinical Characteristics and Outcomes in the Very Elderly Patients Hospitalized for Acute Heart Failure: Importance of Pharmacologic Guideline Adherence. AB - The prognostic factors and pharmacological effects of the very elderly patients (aged >=80 years) with acute heart failure (AHF) remain unclear. The study, therefore, investigated the prognostic impacts of the guideline-recommended pharmacological therapy in these patients. A cohort of 1297 very elderly patients [85.1 +/- 4.0 years, 69.7% male, 32.6% heart failure with reduced left ventricular ejection fraction (LVEF), HFrEF], hospitalized for AHF, was studied. The percentage of the recommended prescription for HFrEF at discharge, including renin-angiotensin system inhibitors, beta-blockers, and mineralocorticoid receptor antagonists, was calculated as guideline adherence indicator (GAI). Among the 1233 survivors at discharge, 495 subjects (40.1%) died during a mean follow-up of 27.1 +/- 23.9 months. Mean GAIs in HFrEF and HFpEF were 70.6 +/- 34.9% and 64.1 +/- 35.9%, respectively. A higher GAI was associated with less overall mortality [hazard ratio and 95% confidence interval per-1SD: 0.781, 0.655 0.930] and cardiovascular death (0.718, 0.558-0.925), independent of age, gender, diabetes, hypertension, mean blood pressure, LVEF, eGFR, sodium, and NT-proBNP. A GAI of 100% was associated with a better survival in both HFrEF and HFpEF. A prescription of the three recommended medications for HFrEF to the very elderly AHF patients was associated with a better survival after discharge. PMID- 30250054 TI - Stereocilin gene variants associated with episodic vertigo: expansion of the DFNB16 phenotype. AB - Vestibular disorders comprise a heterogeneous group of diseases with transient or permanent loss of vestibular function. Vestibulopathy is in most cases associated with migraine, Meniere disease, hereditary ataxias, or sensorineural hearing loss. We identified two brothers and their first cousin affected by hearing loss and episodic vertigo. The brothers were homozygous STRC nonsense variant [c.4027 C > T, p.(Q1343*)], whereas their first cousin was compound heterozygous for the STRC nonsense variant and a 97 kb deletion spanning the entire STRC gene. Clinical investigations confirmed pathological vestibular responses in addition to a characteristic DFNB16 hearing loss. The STRC gene encodes Stereocilin in the cochlea and in the vestibular organ where it ensheathes the kinocilium of the otolithic membranes. Stereocilin is associated with the gel overlaying the vestibular kinocilia, suggesting a role for the protein in sensing balance and spatial orientation. Our findings support such a function for Stereocilin in the vestibular organ and expand the phenotype associated with DFNB16. PMID- 30250053 TI - Transcriptomic insights into the blue light-induced female floral sex expression in cucumber (Cucumis sativus L.). AB - In cucurbitaceous crops, sex differentiation of flower buds is a crucial developmental process that directly affects fruit yield. Here we showed that the induction of female flower was the highest in the blue light-treated monoecious cucumber plants compared with that in other light qualities (white, green and red). High-throughput RNA-Seq analysis of the shoot apexes identified a total of 74 differently-expressed genes (DEGs), in which 52 up-regulated and 22 down regulated under the blue light compared with that in white light. The DEGs were mainly involved in metabolic pathways, biosynthesis of secondary metabolites, plant hormone signal transduction, starch and sucrose metabolism and phenylpropanoid biosynthesis. While the ethylene and gibberellins synthesis and signaling related genes were down-regulated, the abscisic acid and auxin signal transduction pathways were up-regulated by the blue light treatment. Furthermore, the blue light treatment up-regulated the transcription of genes relating to photosynthesis, starch and sucrose metabolism. Meanwhile, the blue light suppressed the GA3 concentration but promoted the concentrations of auxin and photosynthetic pigments. Taken together, the results suggest that the blue light induced female floral sex expression is closely associated with the blue light induced changes in abscisic acid, auxin, gibberellins, photosynthesis, starch and sucrose metabolism pathways, which is potentially different from the traditional ethylene-dependent pathway. PMID- 30250055 TI - Effectiveness of endothelial progenitor cell culture under microgravity for improved angiogenic potential. AB - Endothelial progenitor cell (EPC) transplantation is beneficial for ischemic diseases such as critical limb ischemia and ischemic heart disease. The scarcity of functional EPCs in adults is a limiting factor for EPC transplantation therapy. The quality and quantity culture (QQc) system is an effective ex vivo method for enhancing the number and angiogenic potential of EPCs. Further, microgravity environments have been shown to enhance the functional potential of stem cells. We therefore hypothesized that cells cultured with QQc under microgravity may have enhanced functionality. We cultured human peripheral blood mononuclear cells using QQc under normal (E), microgravity (MG), or microgravity followed by normal (ME) conditions and found that ME resulted in the most significant increase in CD34+ and double positive Dil-Ac-LDL-FITC-Ulex-Lectin cells, both EPC markers. Furthermore, angiogenic potential was determined by an EPC-colony forming assay. While numbers of primitive EPC-colony forming units (pEPC-CFU) did not change, numbers of definitive EPC-CFU colonies increased most under ME conditions. Gene-expression profiling also identified increases in angiogenic factors, including vascular endothelial growth factor, under MG and ME conditions. Thus, QQc along with ME conditions could be an efficient system for significantly enhancing the number and angiogenic potential of EPCs. PMID- 30250057 TI - Deep generative models of genetic variation capture the effects of mutations. AB - The functions of proteins and RNAs are defined by the collective interactions of many residues, and yet most statistical models of biological sequences consider sites nearly independently. Recent approaches have demonstrated benefits of including interactions to capture pairwise covariation, but leave higher-order dependencies out of reach. Here we show how it is possible to capture higher order, context-dependent constraints in biological sequences via latent variable models with nonlinear dependencies. We found that DeepSequence ( https://github.com/debbiemarkslab/DeepSequence ), a probabilistic model for sequence families, predicted the effects of mutations across a variety of deep mutational scanning experiments substantially better than existing methods based on the same evolutionary data. The model, learned in an unsupervised manner solely on the basis of sequence information, is grounded with biologically motivated priors, reveals the latent organization of sequence families, and can be used to explore new parts of sequence space. PMID- 30250056 TI - Reducing effects of particle adsorption to the air-water interface in cryo-EM. AB - Most protein particles prepared in vitreous ice for single-particle cryo-electron microscopy (cryo-EM) are adsorbed to air-water or substrate-water interfaces, which can cause the particles to adopt preferred orientations. By using a rapid plunge-freezing robot and nanowire grids, we were able to reduce some of the deleterious effects of the air-water interface by decreasing the dwell time of particles in thin liquid films. We demonstrated this by using single-particle cryo-EM and cryo-electron tomography (cryo-ET) to examine hemagglutinin, insulin receptor complex, and apoferritin. PMID- 30250058 TI - Speckle tracking-derived bi-atrial strain before and after eleven weeks of training in elite rowers. AB - The left (LA) and right (RA) atria undergo adaptive remodeling in response to hemodynamic stress not only induced by endurance exercise but also as part of several cardiovascular diseases thereby confounding differential diagnosis. Echocardiographic assessment of the atria with novel speckle tracking (STE) derived variables broadens the diagnostic spectrum compared to conventional analyses and has the potential to differentiate physiologic from pathologic changes. The purpose of this study was to assess and categorize baseline values of bi-atrial structure and function in elite rowers according to recommended cutoffs, and to assess the cardiac changes occurring with endurance training. Therefore, fifteen elite rowers underwent 2D-echocardiographic analysis of established variables of cardiac structure and function as well as STE-derived variables of bi-atrial function. Measurements were performed at baseline and after eleven weeks of extensive training. 40% of athletes displayed mildly enlarged LA and 47% mildly enlarged RA at baseline, whereas no athlete fell below the lower reference values of LA and RA reservoir strain. Average power during a 2000 m ergometer rowing test (P2000 m) improved from 426 +/- 39 W to 442 +/- 34 W (p = 0.010) but there were no changes of echocardiographic variables following training. In elite rowers, longitudinal bi-atrial strain assessment indicates normal resting function of structurally enlarged atria and thereby may assist to differentiate between exercise-induced versus disease-associated structural cardiac changes in which function is commonly impaired. PMID- 30250059 TI - Simple separation of good quality bovine oocytes using a microfluidic device. AB - We fabricated a simple microfluidic device for separation of bovine oocytes based on the oocyte quality to improve the conception rate of in vitro fertilization (IVF) by using good quality oocytes. The microfluidic device separates oocytes based on sedimentation rate differences in a sucrose buffer, which is dependent on oocyte quality. The microfluidic device has a 700 um width, 1 mm height, and 10 mm long separation channel. Oocytes were injected from the upper half of the separation channel, and they flowed while sinking. The outlets of the separation channel were divided into upper and lower chambers. Good quality oocytes settled faster than poor quality oocytes in sucrose buffer; therefore, good quality oocytes were collected from the lower outlet. We performed IVF after the microfluidic separation of oocytes. The developmental rate to blastocysts of oocytes collected from the lower outlet was significantly higher than those collected from the upper outlet (36.0% vs. 14.1%). This result was comparable to that in the BCB staining method performed as a comparison method (BCB+ : 35.7%, BCB-: 15.4%). These findings indicate that our microfluidic device could be applied to oocyte separation and contribute to improvement of in vitro embryo production system. PMID- 30250060 TI - Direct induction of microtubule branching by microtubule nucleation factor SSNA1. AB - Microtubules are central elements of the eukaryotic cytoskeleton that often function as part of branched networks. Current models for branching include nucleation of new microtubules from severed microtubule seeds or from gamma tubulin recruited to the side of a pre-existing microtubule. Here, we found that microtubules can be directly remodelled into branched structures by the microtubule-remodelling factor SSNA1 (also known as NA14 or DIP13). The branching activity of SSNA1 relies on its ability to self-assemble into fibrils in a head to-tail fashion. SSNA1 fibrils guide protofilaments of a microtubule to split apart to form daughter microtubules. We further found that SSNA1 localizes at axon branching sites and has a key role in neuronal development. SSNA1 mutants that abolish microtubule branching in vitro also fail to promote axon development and branching when overexpressed in neurons. We have, therefore, discovered a mechanism for microtubule branching and implicated its role in neuronal development. PMID- 30250061 TI - Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. AB - Actin-based protrusions are reinforced through positive feedback, but it is unclear what restricts their size, or limits positive signals when they retract or split. We identify an evolutionarily conserved regulator of actin-based protrusion: CYRI (CYFIP-related Rac interactor) also known as Fam49 (family of unknown function 49). CYRI binds activated Rac1 via a domain of unknown function (DUF1394) shared with CYFIP, defining DUF1394 as a Rac1-binding module. CYRI depleted cells have broad lamellipodia enriched in Scar/WAVE, but reduced protrusion-retraction dynamics. Pseudopods induced by optogenetic Rac1 activation in CYRI-depleted cells are larger and longer lived. Conversely, CYRI overexpression suppresses recruitment of active Scar/WAVE to the cell edge, resulting in short-lived, unproductive protrusions. CYRI thus focuses protrusion signals and regulates pseudopod complexity by inhibiting Scar/WAVE-induced actin polymerization. It thus behaves like a 'local inhibitor' as predicted in widely accepted mathematical models, but not previously identified in cells. CYRI therefore regulates chemotaxis, cell migration and epithelial polarization by controlling the polarity and plasticity of protrusions. PMID- 30250063 TI - A mitochondria-paraspeckle crosstalk. PMID- 30250062 TI - Single-fluorophore biosensors for sensitive and multiplexed detection of signalling activities. AB - Unravelling the dynamic molecular interplay behind complex physiological processes such as neuronal plasticity requires the ability to both detect minute changes in biochemical states in response to physiological signals and track multiple signalling activities simultaneously. Fluorescent protein-based biosensors have enabled the real-time monitoring of dynamic signalling processes within the native context of living cells, yet most commonly used biosensors exhibit poor sensitivity (for example, due to low dynamic range) and are limited to imaging signalling activities in isolation. Here, we address this challenge by developing a suite of excitation ratiometric kinase activity biosensors that offer the highest reported dynamic range and enable the detection of subtle changes in signalling activity that could not be reliably detected previously, as well as a suite of single-fluorophore biosensors that enable the simultaneous tracking of as many as six distinct signalling activities in single living cells. PMID- 30250064 TI - Genome-wide screening of NEAT1 regulators reveals cross-regulation between paraspeckles and mitochondria. AB - The long noncoding RNA NEAT1 (nuclear enriched abundant transcript 1) nucleates the formation of paraspeckles, which constitute a type of nuclear body with multiple roles in gene expression. Here we identify NEAT1 regulators using an endogenous NEAT1 promoter-driven enhanced green fluorescent protein reporter in human cells coupled with genome-wide RNAi screens. The screens unexpectedly yield gene candidates involved in mitochondrial functions as essential regulators of NEAT1 expression and paraspeckle formation. Depletion of mitochondrial proteins and treatment of mitochondrial stressors both lead to aberrant NEAT1 expression via ATF2 as well as altered morphology and numbers of paraspeckles. These changes result in enhanced retention of mRNAs of nuclear-encoded mitochondrial proteins (mito-mRNAs) in paraspeckles. Correspondingly, NEAT1 depletion has profound effects on mitochondrial dynamics and function by altering the sequestration of mito-mRNAs in paraspeckles. Overall, our data provide a rich resource for understanding NEAT1 and paraspeckle regulation, and reveal a cross-regulation between paraspeckles and mitochondria. PMID- 30250065 TI - AIMP3 depletion causes genome instability and loss of stemness in mouse embryonic stem cells. AB - Aminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3) is a component of the multi-aminoacyl-tRNA synthetase complex and is involved in diverse cellular processes. Given that AIMP3 deficiency causes early embryonic lethality in mice, AIMP3 is expected to play a critical role in early mouse development. To elucidate a functional role of AIMP3 in early mouse development, we induced AIMP3 depletion in mouse embryonic stem cells (mESCs) derived from blastocysts of AIMP3f/f; CreERT2 mice. In the present study, AIMP3 depletion resulted in loss of self-renewal and ability to differentiate to three germ layers in mESCs. AIMP3 depletion led to accumulation of DNA damage by blocking double-strand break repair, in particular homologous recombination. Through microarray analysis, the p53 signaling pathway was identified as being activated in AIMP3-depleted mESCs. Knockdown of p53 rescued loss of stem cell characteristics by AIMP3 depletion in mESCs. These results imply that AIMP3 depletion in mESCs leads to accumulation of DNA damage and p53 transactivation, resulting in loss of stemness. We propose that AIMP3 is involved in maintenance of genome stability and stemness in mESCs. PMID- 30250066 TI - Enah overexpression is correlated with poor survival and aggressive phenotype in gastric cancer. AB - Enabled homolog (Enah), which is a member of the Ena/VASP family that also includes VASP (vasodilator-stimulated phosphoprotein) and Ena/VASP like, is a mammalian ortholog of Drosophila Enabled (Ena). An increasing number of studies demonstrated Enah overexpression is involved in human colorectal carcinomas, breast cancers and hepatocellular carcinoma. However, the significance of Enah expression in gastric cancer (GC) is poorly elucidated. Here, we demonstrate that Enah is upregulated in GC and associated with AJCC stage, depth of invasion and poor overall survival (OS). Knockdown of Enah inhibited GC cell proliferation and metastasis and vice versa. Further experiments suggested that p-Erk1/2, p-AKT, p p65, Vimentin and Fibronectin were downregulated and E-cadherin was upregulated after Enah silencing, implicating altered functions in GC proliferation and metastasis. Thus, our study suggests that Enah is a harmful factor for GC and a novel target for GC treatment. PMID- 30250068 TI - Moonage daydreams of space rock. PMID- 30250069 TI - Diamond sculpting pushes extremes. PMID- 30250067 TI - PAXX and its paralogs synergistically direct DNA polymerase lambda activity in DNA repair. AB - PAXX is a recently identified component of the nonhomologous end joining (NHEJ) DNA repair pathway. The molecular mechanisms of PAXX action remain largely unclear. Here we characterise the interactomes of PAXX and its paralogs, XLF and XRCC4, to show that these factors share the ability to interact with DNA polymerase lambda (Pol lambda), stimulate its activity and are required for recruitment of Pol lambda to laser-induced DNA damage sites. Stimulation of Pol lambda activity by XRCC4 paralogs requires a direct interaction between the SP/8 kDa domain of Pol lambda and their N-terminal head domains to facilitate recognition of the 5' end of substrate gaps. Furthermore, PAXX and XLF collaborate with Pol lambda to promote joining of incompatible DNA ends and are redundant in supporting Pol lambda function in vivo. Our findings identify Pol lambda as a novel downstream effector of PAXX function and show XRCC4 paralogs act in synergy to regulate polymerase activity in NHEJ. PMID- 30250070 TI - Shedding light on black titania. PMID- 30250071 TI - Slippery in every direction. PMID- 30250072 TI - Ultrafast water harvesting and transport in hierarchical microchannels. AB - Various natural materials have hierarchical microscale and nanoscale structures that allow for directional water transport. Here we report an ultrafast water transport process in the surface of a Sarracenia trichome, whose transport velocity is about three orders of magnitude faster than those measured in cactus spine and spider silk. The high velocity of water transport is attributed to the unique hierarchical microchannel organization of the trichome. Two types of ribs with different height regularly distribute around the trichome cone, where two neighbouring high ribs form a large channel that contains 1-5 low ribs that define smaller base channels. This results in two successive but distinct modes of water transport. Initially, a rapid thin film of water is formed inside the base channels (Mode I), which is followed by ultrafast water sliding on top of that thin film (Mode II). This two-step ultrafast water transport mechanism is modelled and experimentally tested in bio-inspired microchannels, which demonstrates the potential of this hierarchal design for microfluidic applications. PMID- 30250073 TI - Materials for space exploration and settlement. PMID- 30250074 TI - Across the Universe. PMID- 30250076 TI - Apoptosis and necroptosis in the liver: a matter of life and death. AB - Cell death represents a basic biological paradigm that governs outcomes and long term sequelae in almost every hepatic disease condition. Acute liver failure is characterized by massive loss of parenchymal cells but is usually followed by restitution ad integrum. By contrast, cell death in chronic liver diseases often occurs at a lesser extent but leads to long-term alterations in organ architecture and function, contributing to chronic hepatocyte turnover, the recruitment of immune cells and activation of hepatic stellate cells. These chronic cell death responses contribute to the development of liver fibrosis, cirrhosis and cancer. It has become evident that, besides apoptosis, necroptosis is a highly relevant form of programmed cell death in the liver. Differential activation of specific forms of programmed cell death might not only affect outcomes in liver diseases but also offer novel opportunities for therapeutic intervention. Here, we summarize the underlying molecular mechanisms and open questions about disease-specific activation and roles of programmed cell death forms, their contribution to response signatures and their detection. We focus on the role of apoptosis and necroptosis in acute liver injury, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and liver cancer, and possible translations into clinical applications. PMID- 30250075 TI - Sensitizing non-small cell lung cancer to BCL-xL-targeted apoptosis. AB - Lung cancer is the leading cause of death in the United States, with non-small cell lung cancers (NSCLC) accounting for 85% of all cases. By analyzing the expression profile of the pro-apoptotic and anti-apoptotic proteins, we have assigned NSCLCs into two distinct groups. While single agent treatment with the BCL-2/BCL-xL/BCL-w inhibitor ABT-263 (navitoclax) did not trigger apoptosis in either group, cells with a moderate to high level of MCL-1 expression were sensitive to ABT-263 treatment when MCL-1 expression was suppressed with a gene specific siRNA. In contrast, those with a low MCL-1 expression did not undergo apoptosis upon combination treatment with ABT-263 and MCL-1 siRNA. Further studies revealed that cells with a low MCL-1 expression had low mitochondrial priming, and treatment with the chemotherapy drug docetaxel raised the mitochondrial priming level and consequently sensitized cells to ABT-263. These results establish a rationale for molecular profiling and a therapeutic strategy to treat NSCLC patients with pro-apoptotic anti-cancer drugs based on their MCL-1 expression level. PMID- 30250077 TI - Towards exact molecular dynamics simulations with machine-learned force fields. AB - Molecular dynamics (MD) simulations employing classical force fields constitute the cornerstone of contemporary atomistic modeling in chemistry, biology, and materials science. However, the predictive power of these simulations is only as good as the underlying interatomic potential. Classical potentials often fail to faithfully capture key quantum effects in molecules and materials. Here we enable the direct construction of flexible molecular force fields from high-level ab initio calculations by incorporating spatial and temporal physical symmetries into a gradient-domain machine learning (sGDML) model in an automatic data-driven way. The developed sGDML approach faithfully reproduces global force fields at quantum-chemical CCSD(T) level of accuracy and allows converged molecular dynamics simulations with fully quantized electrons and nuclei. We present MD simulations, for flexible molecules with up to a few dozen atoms and provide insights into the dynamical behavior of these molecules. Our approach provides the key missing ingredient for achieving spectroscopic accuracy in molecular simulations. PMID- 30250079 TI - Giant reversible elongation upon cooling and contraction upon heating for a crosslinked cis poly(1,4-butadiene) system at temperatures below zero Celsius. AB - Polymers with reversible elongation upon cooling (EUC) and contraction upon heating (CUH) enabled applications in actuators, fasteners, dampers, grippers, swimmers, sealants, etc. With the current working temperature being limited to mainly above zero Celsius, applications for subzero Celsius environments are obstructed. In addition, current reversible actuation needs a constant tensile load, or for the best case, under zero tensile load. Reversible EUC and CUH under compressive load is almost impossible and has not been explored. In this work, a cis poly(1,4-butadiene) based system has been developed. Actuated below zero Celsius, 69% EUC occurred under a tensile load; and 6.2% EUC and 17.9% CUH occurred under 0.05 MPa compressive load. The reversible actuation was driven by both entropy and enthalpy, which was validated by a series of characterization tools. PMID- 30250078 TI - Reversible Human Immunodeficiency Virus Type-1 Latency in Primary Human Monocyte Derived Macrophages Induced by Sustained M1 Polarization. AB - We have reported that short-term stimulation of primary human monocyte-derived macrophages (MDM) with interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha), i.e. M1 polarization, leads to a significant containment of virus replication. Here we show that M1-MDM restimulation with these cytokines 7 days after infection (M12 MDM) promoted an increased restriction of HIV-1 replication characterized by very low levels of virus production near to undetectable levels. In comparison to control and M1-MDM that were not restimulated, M12 MDM showed a stronger reduction of both total and integrated HIV DNA as well as of viral mRNA expression. M12 MDM were characterized by an upregulated expression of restriction factors acting at the level of reverse transcription (RT), including apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A (APOBEC3A) and APOBEC3G, but not SAM domain and HD domain containing protein 1 (SAMHD1). M12 MDM also showed an increased expression of Class II Transactivator (CIITA) and Tripartite Motif22 (TRIM22), two negative regulators of proviral transcription, whereas expression and phosphorylation of transcriptional inducers of HIV-1, such as nuclear factor kB (NF-kB) and signal transducer and activator of transcription 1 (STAT1), were not impaired in these cells. The almost quiescent state of the infection in M12 MDM was promptly reversed by coculture with mitogen-stimulated leukocytes or cell incubation with their filtered culture supernatant. M12 MDM harbored replication-competent HIV-1 as virus spreading following cell stimulation was fully prevented by the RT inhibitor lamivudine/3TC. Selective reactivation of proviral expression in M12 MDM, but not in control or in M1-MDM that were not restimulated, was confirmed in cells infected with single round Vesicular Stomatitis Virus-G-pseudotyped HIV-1. Thus, M12 MDM represent an in vitro model of reversible, almost quiescent HIV-1 infection of primary human macrophages that could be further exploited for "Cure" related investigations. PMID- 30250080 TI - Comparing passive measures of fatigue-like behavior in mice. AB - Fatigue is a very common and costly symptom associated with various diseases and disorders. Nonetheless, understanding the pathobiology and developing of therapies for fatigue have been difficult, partly because of a lack of consensus on the measures to phenotype this behavior, both in clinical settings and in animal studies. Here, we describe a fatigue-like behavior induced in mice by abdominal irradiation and compare three different methods of measuring changes in physical activity over time: running wheels, video home cage monitoring, and telemetry. These methods collect data passively and continuously, requiring no disruption of animals' normal home cage behavior. In our experiments, all three methods reported a fatigue-like behavior, exhibited by a reduction in physical activity following abdominal irradiation. Video tracking showed the largest fatigue effect size (Cohen's D = 1.78) over four days of monitoring, and was the only method showing a significant decrease in activity during the light period. Telemetry and running wheels showed a similar effect size (D = 1.68 and 1.65, respectively), but running wheels showed different circadian patterns of physical activity. In addition, we conducted rotarod and inverted grid suspension tests, which suggested that fatigue-like behavior was not the result of gross motor abnormalities. PMID- 30250082 TI - Determining standards of adequate veterinary care. PMID- 30250081 TI - October Updates: People and Places. PMID- 30250084 TI - What is happening at Lab Animal. AB - Introducing a new online platform for the journal, new types of content, and a new Chief Editor. PMID- 30250083 TI - The importance of direct and frequent communication. PMID- 30250085 TI - Better communication is advised. PMID- 30250086 TI - Updates on Animal Care guidance documents. PMID- 30250088 TI - Home sweet home cage. PMID- 30250087 TI - Flipping the switch off. PMID- 30250089 TI - Worms expressing themselves. PMID- 30250090 TI - To link zinc to adenylates. PMID- 30250091 TI - Boning up on turnover. PMID- 30250092 TI - Less methionine means more health. PMID- 30250093 TI - Behavior tracking cuts deep. PMID- 30250095 TI - The fly's stable symbionts. PMID- 30250094 TI - How the sparrow got its house. PMID- 30250096 TI - Aquatic acoustic trauma. PMID- 30250097 TI - Meal time & mouse rhythms. PMID- 30250098 TI - A mouse sleep database for systems genetics. PMID- 30250100 TI - Response to May Protocol Review. PMID- 30250099 TI - Incorrect citation. PMID- 30250101 TI - Stop and smell the geosmin. PMID- 30250102 TI - A word from USDA. PMID- 30250105 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Welcome Address. AB - Sponsorship Statement: Publication of this supplement is sponsored by the European Society for Blood and Marrow Transplantation. PMID- 30250106 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Lectures. PMID- 30250104 TI - A new ESI-LC/MS approach for comprehensive metabolic profiling of phytocannabinoids in Cannabis. AB - Most clinical studies of Cannabis today focus on the contents of two phytocannabinoids: (-)-Delta9-trans-tetrahydrocannabinol (Delta9-THC) and cannabidiol (CBD), regardless of the fact that the plant contains over 100 additional phytocannabinoids whose therapeutic effects and interplay have not yet been fully elucidated. This narrow view of a complex Cannabis plant is insufficient to comprehend the medicinal and pharmacological effects of the whole plant. In this study we suggest a new ESI-LC/MS/MS approach to identify phytocannabinoids from 10 different subclasses, and comprehensively profile the identified compounds in diverse medical Cannabis plants. Overall, 94 phytocannabinoids were identified and used for profiling 36 of the most commonly used Cannabis plants prescribed to patients in Israel. In order to demonstrate the importance of comprehensive phytocannabinoid analysis before and throughout medical Cannabis clinical trials, treatments, or experiments, we evaluated the anticonvulsant effects of several equally high-CBD Cannabis extracts (50% w/w). We found that despite the similarity in CBD contents, not all Cannabis extracts produced the same effects. This study's approach for phytocannabinoid profiling can enable researchers and physicians to analyze the effects of specific Cannabis compositions and is therefore critical when performing biological, medical and pharmacological-based research using Cannabis. PMID- 30250107 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Reviewers. PMID- 30250108 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Van Bekkum Awards. PMID- 30250110 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: QUALITY MANAGEMENT GROUP - ORAL SESSION. PMID- 30250109 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Data Management Group-Poster Session. PMID- 30250111 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Nurses Oral Session. PMID- 30250112 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Organising Committee. PMID- 30250113 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians Award Winners. PMID- 30250114 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Working Parties. PMID- 30250115 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: STATISTICAL SYMPOSIUM - POSTER SESSION. PMID- 30250116 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Nurses Group - Poster Session. PMID- 30250117 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: QUALITY MANAGEMENT GROUP - POSTER SESSION. PMID- 30250118 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians Oral Session. AB - Sponsorship Statement: Publication of this supplement is sponsored by the European Society for Blood and Marrow Transplantation. PMID- 30250119 TI - Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand. AB - Inhibition of epidermal growth factor receptor (EGFR) signaling by small molecule kinase inhibitors and monoclonal antibodies has proven effective in the treatment of multiple cancers. In contrast, metastatic breast cancers (BC) derived from EGFR-expressing mammary tumors are inherently resistant to EGFR-targeted therapies. Mechanisms that contribute to this inherent resistance remain poorly defined. Here, we show that in contrast to primary tumors, ligand-mediated activation of EGFR in metastatic BC is dominated by STAT1 signaling. This change in downstream signaling leads to apoptosis and growth inhibition in response to epidermal growth factor (EGF) in metastatic BC cells. Mechanistically, these changes in downstream signaling result from an increase in the internalized pool of EGFR in metastatic cells, increasing physical access to the nuclear pool of STAT1. Along these lines, an EGFR mutant that is defective in endocytosis is unable to elicit STAT1 phosphorylation and apoptosis. Additionally, inhibition of endosomal signaling using an EGFR inhibitor linked to a nuclear localization signal specifically prevents EGF-induced STAT1 phosphorylation and cell death, without affecting EGFR:ERK1/2 signaling. Pharmacologic blockade of ERK1/2 signaling through the use of the allosteric MEK1/2 inhibitor, trametinib, dramatically biases downstream EGFR signaling toward a STAT1-dominated event, resulting in enhanced EGF-induced apoptosis in metastatic BC cells. Importantly, combined administration of trametinib and EGF also facilitated an apoptotic switch in EGFR-transformed primary tumor cells, but not normal mammary epithelial cells. These studies reveal a fundamental distinction for EGFR function in metastatic BC. Furthermore, the data demonstrate that pharmacological biasing of EGFR signaling toward STAT1 activation is capable of revealing the apoptotic function of this critical pathway. PMID- 30250120 TI - Agmatine modulates spontaneous activity in neurons of the rat medial habenular complex-a relevant mechanism in the pathophysiology and treatment of depression? AB - The dorsal diencephalic conduction system connects limbic forebrain structures to monaminergic mesencephalic nuclei via a distinct relay station, the habenular complexes. Both habenular nuclei, the lateral as well as the medial nucleus, are considered to play a prominent role in mental disorders like major depression. Herein, we investigate the effect of the polyamine agmatine on the electrical activity of neurons within the medial habenula in rat. We present evidence that agmatine strongly decreases spontaneous action potential firing of medial habenular neurons by activating I1-type imidazoline receptors. Additionally, we compare the expression patterns of agmatinase, an enzyme capable of inactivating agmatine, in rat and human habenula. In the medial habenula of both species, agmatinase is similarly distributed and observed in neurons and, in particular, in distinct neuropil areas. The putative relevance of these findings in the context of depression is discussed. It is concluded that increased activity of the agmatinergic system in the medial habenula may strengthen midbrain dopaminergic activity. Consequently, the habenular-interpeduncular axis may be dysregulated in patients with major depression. PMID- 30250121 TI - Functional Studies of Anodic Oxidized beta-Ti-28Nb-11Ta-8Zr Alloy for Mechanical, In-vitro and Antibacterial Capability. AB - We developed an osseocompatible beta-type Ti-28Nb-11Ta-8Zr (TNTZ) alloy that displays the excellent elastic modulus, cellular response, corrosion resistance and antibacterial capability demanded for bone-mimetic materials. The TNTZ alloy exhibited an elastic modulus of 49 GPa, which approximates that of human bones and prevent stress shielding effects. A further anodic oxidation and subsequent post-annealing modification formed a crystalline nanoporous TNTZ oxide layer (NPTNTZO(c)) on the alloy surface, potentially promoting interlocking with the extracellular matrix of bone cells and cell proliferation. Osteoblast viability tests also verified that NPTNTZO(c) enhanced cell growth more significantly than that of flat TNTZ. In addition, potentiodynamic polarization tests in Hanks' balanced salt solution (HBSS) revealed that both TNTZ and NPTNTZO(c) exhibited better corrosion resistance than commercial pure titanium. Finally, NPTNTZO(c) reinforced with silver nanoparticles (NPTNTZO PMID- 30250123 TI - Revisiting signatures of neutral tumor evolution in the light of complexity of cancer genomic data. PMID- 30250122 TI - Co-occurrence of Asthma and the Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis. AB - BACKGROUND: Inflammatory bowel diseases (IBD) and asthma share genetic and environmental risk factors. Consequently, several observational studies have explored an association between IBD and asthma. We systematically reviewed and summarized the literature on the co-occurrence of asthma and IBD. METHODS: MEDLINE and EMBASE (to April 2017) were searched to identify observational studies on the association between asthma and IBD. Relative risks (RR) were pooled using random effects models. Heterogeneity was assessed using the I2 and Cochran Q statistics. Meta-regression based on study design, source of patients (population-based vs. tertiary-care center) and study location was conducted to explain between-study heterogeneity. RESULTS: Eighteen studies were identified (15 Crohn's disease, 15 ulcerative colitis (UC)). Asthma was associated with both Crohn's disease (pooled RR 1.30, 95% confidence interval (CI) 1.16-1.47, I2 = 88%) and UC (RR 1.34, 95% CI 1.24-1.44, I2 = 93%). The study design and source of patients and study location explained between-study heterogeneity in Crohn's disease, but not UC. CONCLUSION: Asthma is associated with both Crohn's disease and UC. Additional research is needed to determine if one disease influences the risk of developing the other or if the frequent co-occurrence of these diseases result from shared genetic, environmental, and microbial risk factors. PMID- 30250124 TI - Organization of the genome sequence of the polyploid crop species Brassica juncea. PMID- 30250125 TI - Reply to 'Revisiting signatures of neutral tumor evolution in the light of complexity of cancer genomic data'. PMID- 30250127 TI - Author Correction: The genome sequence of allopolyploid Brassica juncea and analysis of differential homoeolog gene expression influencing selection. AB - Following publication of this article, the authors have corrected 426 chimeric scaffolds in this genome (total scaffold number 10,684). The genome assembly has now been improved as V1.5, and the updated genome assembly is available to be downloaded from http://brassicadb.org/brad/datasets/pub/Genomes/Brassica_juncea/V1.5/ . PMID- 30250126 TI - Individual variations in cardiovascular-disease-related protein levels are driven by genetics and gut microbiome. AB - Despite a growing body of evidence, the role of the gut microbiome in cardiovascular diseases is still unclear. Here, we present a systems-genome-wide and metagenome-wide association study on plasma concentrations of 92 cardiovascular-disease-related proteins in the population cohort LifeLines-DEEP. We identified genetic components for 73 proteins and microbial associations for 41 proteins, of which 31 were associated to both. The genetic and microbial factors identified mostly exert additive effects and collectively explain up to 76.6% of inter-individual variation (17.5% on average). Genetics contribute most to concentrations of immune-related proteins, while the gut microbiome contributes most to proteins involved in metabolism and intestinal health. We found several host-microbe interactions that impact proteins involved in epithelial function, lipid metabolism, and central nervous system function. This study provides important evidence for a joint genetic and microbial effect in cardiovascular disease and provides directions for future applications in personalized medicine. PMID- 30250129 TI - Reply to: 'Organization of the genome sequence of the polyploid crop species Brassica juncea'. PMID- 30250128 TI - Parallel selection on a dormancy gene during domestication of crops from multiple families. AB - Domesticated species often exhibit convergent phenotypic evolution, termed the domestication syndrome, of which loss of seed dormancy is a component. To date, dormancy genes that contribute to parallel domestication across different families have not been reported. Here, we cloned the classical stay-green G gene from soybean and found that it controls seed dormancy and showed evidence of selection during soybean domestication. Moreover, orthologs in rice and tomato also showed evidence of selection during domestication. Analysis of transgenic plants confirmed that orthologs of G had conserved functions in controlling seed dormancy in soybean, rice, and Arabidopsis. Functional investigation demonstrated that G affected seed dormancy through interactions with NCED3 and PSY and in turn modulated abscisic acid synthesis. Therefore, we identified a gene responsible for seed dormancy that has been subject to parallel selection in multiple crop families. This may help facilitate the domestication of new crops. PMID- 30250130 TI - Protecting quantum resources via frequency modulation of qubits in leaky cavities. AB - Finding strategies to preserve quantum resources in open systems is nowadays a main requirement for reliable quantum-enhanced technologies. We address this issue by considering structured cavities embedding qubits driven by a control technique known as frequency modulation. We first study a single qubit in a lossy cavity to determine optimal modulation parameters and qubit-cavity coupling regime allowing a gain of four orders of magnitude concerning coherence lifetimes. We relate this behavior to the inhibition of the qubit effective decay rate rather than to stronger memory effects (non-Markovianity) of the system. We then exploit these findings in a system of noninteracting qubits embedded in separated cavities to gain basic information about scalability of the procedure. We show that the determined modulation parameters enable lifetimes of quantum resources, such as entanglement, discord and coherence, three orders of magnitude longer than their natural (uncontrolled) decay times. We discuss the feasibility of the system within the circuit-QED scenario, typically employed in the current quantum computer prototypes. These results provide new insights towards efficient experimental strategies against decoherence. PMID- 30250132 TI - Pontin/Tip49 acts as a novel regulator of JNK pathway. PMID- 30250131 TI - Microfluidic deposition for resolving single-molecule protein architecture and heterogeneity. AB - Scanning probe microscopy provides a unique window into the morphology, mechanics, and structure of proteins and their complexes on the nanoscale. Such measurements require, however, deposition of samples onto substrates. This process can affect conformations and assembly states of the molecular species under investigation and can bias the molecular populations observed in heterogeneous samples through differential adsorption. Here, we show that these limitations can be overcome with a single-step microfluidic spray deposition platform. This method transfers biological solutions to substrates as microdroplets with subpicoliter volume, drying in milliseconds, a timescale that is shorter than typical diffusion times of proteins on liquid-solid interfaces, thus avoiding surface mass transport and change to the assembly state. Finally, the single-step deposition ensures the attachment of the full molecular content of the sample to the substrate, allowing quantitative measurements of different molecular populations within heterogeneous systems, including protein aggregates. PMID- 30250134 TI - Exercise training and/or diet on reduction of intra-abdominal adipose tissue and risk factors for cardiovascular disease. AB - BACKGROUND/OBJECTIVES: To test the effects of weight loss with and without exercise training (aerobic or resistance) on intra-abdominal adipose tissue (IAAT) and risk factors for cardiovascular disease (CVD). Additionally, CVD risk factors was evaluated before and after weight loss using previously established IAAT cut-points. SUBJECTS/METHODS: One hundred twenty-two overweight premenopausal women were randomly assigned to one of three groups: (1) diet only (Diet); (2) diet and aerobic training (Diet + AT); or (3) diet and resistance training (Diet + RT); until a BMI of < 25 kg/m2 was reached. Computerized tomography was used to measure IAAT and blood lipids were measured by assay. Evaluations were made before and after weight loss. RESULTS: Though no group-by time effects were found after weight loss, we observed significant time effects for: IAAT (-38.0%, P < 0.001), total cholesterol (TC) (-2.2%, P = 0.008), low density lipoprotein cholesterol (LDL-C) (-4.8%, P < 0.001), high-density lipoprotein cholesterol (HDL-C) (+20.2%, P < 0.001), triglycerides (-18.7%, P < 0.001), TC/HDL-C (-16.3%, P < 0.001), and LDL-C/HDL-C (-18.0%, P < 0.001). Following weight loss, 40.2% of all participants reduced IAAT to < 40 cm2 (IAAT associated with low CVD risk). Furthermore, only 2.5% of participants had an IAAT > 110 cm2 (IAAT associated with high CVD risk) after weight loss. We also observed that decreases of IAAT were associated with decreased CVD risk factors after weight loss independent of race, changes in %fat mass and changes in maximal oxygen uptake. CONCLUSIONS: Caloric restriction leading to significant weight loss with or without exercise training appears to be equally effective for reducing IAAT and CVD risk factors. PMID- 30250133 TI - Maternal glycemic index and glycemic load in pregnancy and offspring metabolic health in childhood and adolescence-a cohort study of 68,471 mother-offspring dyads from the Danish National Birth Cohort. AB - BACKGROUND: High glycemic index (GI) and glycemic load (GL) as indicators of carbohydrate quality and quantity have been found to increase risk of metabolic outcomes in adults. Whether carbohydrate quality may influence metabolic programming already in early life is unknown. We examined the association of maternal GI and GL with offspring body mass index (BMI) in the first 7 years of life among 68,471 mother-offspring dyads from the Danish National Birth Cohort (DNBC). In a sub-cohort of offspring with clinical data (n = 1234) that included 608 dyads exposed to gestational diabetes mellitus (GDM), we also examined the relation to metabolic health at 9-16 years. METHODS: Maternal GI and GL were quantified using a mid-pregnancy food frequency questionnaire. We used birth weight and length to calculate offspring's ponderal index. Age- and sex-specific BMI z scores at 5 mo, 12 mo, and 7 y were standardized against WHO reference data. In the clinical cohort, we quantified body composition, HOMA-IR, and HOMA B. We used multivariable mixed linear and Poisson regression to model the associations. RESULTS: Median (IQR) of GI and GL were 83 (63-111) and 241 (180 333) g/day, respectively. We found that GI (Q4 vs. Q1:1.09, 95%CI: 1.03, 1.15) and GL (Q4 vs. Q1:1.10, 95%CI: 1.05, 1.16) modestly increased the relative risk of large-for gestational age (LGA). In the clinical sub-cohort, we observed a potential increase in offspring HOMA-IR, adiposity, and metabolic syndrome z score with higher maternal GI and GI. These associations were stronger among the GDM-exposed offspring, but the CI included the null value. CONCLUSION: We found associations of GI and GL in pregnancy with offspring LGA. Potential long-term benefits to offspring exposed to GDM need to be confirmed in larger, well-powered studies. PMID- 30250135 TI - Genome guided investigation of antibiotics producing actinomycetales strain isolated from a Macau mangrove ecosystem. AB - Actinomycetes are a heterogeneous group of gram positive filamentous bacteria that have been found to produce a wide range of valuable bioactive secondary metabolites, particularly antibiotics. Moreover, actinomycetes isolated from unexplored environments show an unprecedented potential to generate novel active compounds. Hence, in order to search for novel antibiotics, we isolated and characterized actinomycetes strains from plant samples collected from a mangrove in Macau. Within the class of actinobacteria, fourteen actinomycetes isolates have been isolated and identified belonging to the genus of Streptomyces, Micromonospora, Mycobacterium, Brevibacterium, Curtobacterium and Kineococcus based on their 16S rRNA sequences. Further whole genome sequencing analysis of one of the isolated Streptomyces sp., which presented 99.13% sequence similarity with Streptomyces parvulus strain 2297, showed that it consisted of 118 scaffolds, 8,348,559 base pairs and had a 72.28% G + C content. In addition, genome-mining revealed that the isolated Streptomyces sp. contains 109 gene clusters responsible for the biosynthesis of known and/or novel secondary metabolites, including different types of terpene, T1pks, T2pks, T3pks, Nrps, indole, siderophore, bacteriocin, thiopeptide, phosphonate, lanthipeptide, ectoine, butyrolactone, T3pks-Nrps, and T1pks-Nrps. Meanwhile, the small molecules present in ethyl acetate extract of the fermentation broth of this strain were analyzed by LC-MS. Predicted secondary metabolites of melanin and desferrioxamine B were identified and both of them were firstly found to be produced by the Streptomyces parvulus strain. Our study highlights that combining genome mining is an efficient method to detect potentially promising natural products from mangrove-derived actinomycetes. PMID- 30250136 TI - Regulation of the terminal maturation of iNKT cells by mediator complex subunit 23. AB - Invariant natural killer T cells (iNKT cells) are a specific subset of T cells that recognize glycolipid antigens and upon activation rapidly exert effector functions. This unique function is established during iNKT cell development; the detailed mechanisms of this process, however, remain to be elucidated. Here the authors show that deletion of the mediator subunit Med23 in CD4+CD8+ double positive (DP) thymocytes completely blocks iNKT cell development at stage 2. This dysregulation is accompanied by a bias in the expression of genes related to the regulation of transcription and metabolism, and functional impairment of the cells including the loss of NK cell characteristics, reduced ability to secrete cytokines and attenuated recruitment capacity upon activation. Moreover, Med23 deficient iNKT cells exhibit impaired anti-tumor activity. Our study identifies Med23 as an essential transcriptional regulator that controls iNKT cell differentiation and terminal maturation. PMID- 30250137 TI - Integrative metabolic and transcriptomic profiling of prostate cancer tissue containing reactive stroma. AB - Reactive stroma is a tissue feature commonly observed in the tumor microenvironment of prostate cancer and has previously been associated with more aggressive tumors. The aim of this study was to detect differentially expressed genes and metabolites according to reactive stroma content measured on the exact same prostate cancer tissue sample. Reactive stroma was evaluated using histopathology from 108 fresh frozen prostate cancer samples gathered from 43 patients after prostatectomy (Biobank1). A subset of the samples was analyzed both for metabolic (n = 85) and transcriptomic alterations (n = 78) using high resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS MRS) and RNA microarray, respectively. Recurrence-free survival was assessed in patients with clinical follow-up of minimum five years (n = 38) using biochemical recurrence (BCR) as endpoint. Multivariate metabolomics and gene expression analysis compared low (<=15%) against high reactive stroma content (>=16%). High reactive stroma content was associated with BCR in prostate cancer patients even when accounting for the influence of Grade Group (Cox hazard proportional analysis, p = 0.013). In samples with high reactive stroma content, metabolites and genes linked to immune functions and extracellular matrix (ECM) remodeling were significantly upregulated. Future validation of these findings is important to reveal novel biomarkers and drug targets connected to immune mechanisms and ECM in prostate cancer. The fact that high reactive stroma grading is connected to BCR adds further support for the clinical integration of this histopathological evaluation. PMID- 30250139 TI - Crystal structures of multicopper oxidase CueO G304K mutant: structural basis of the increased laccase activity. AB - The multicopper oxidase CueO is involved in copper homeostasis and copper (Cu) tolerance in Escherichia coli. The laccase activity of CueO G304K mutant is higher than wild-type CueO. To explain this increase in activity, we solved the crystal structure of G304K mutant at 1.49 A. Compared with wild-type CueO, the G304K mutant showed dramatic conformational changes in methionine-rich helix and the relative regulatory loop (R-loop). We further solved the structure of Cu soaked enzyme, and found that the addition of Cu ions induced further conformational changes in the R-loop and methionine-rich helix as a result of the new Cu-binding sites on the enzyme's surface. We propose a mechanism for the enhanced laccase activity of the G304K mutant, where movements of the R-loop combined with the changes of the methionine-rich region uncover the T1 Cu site allowing greater access of the substrate. Two of the G304K double mutants showed the enhanced or decreased laccase activity, providing further evidence for the interaction between the R-loop and the methionine-rich region. The cuprous oxidase activity of these mutants was about 20% that of wild-type CueO. These structural features of the G304K mutant provide clues for designing specific substrate-binding mutants in the biotechnological applications. PMID- 30250141 TI - Meeting brain-computer interface user performance expectations using a deep neural network decoding framework. AB - Brain-computer interface (BCI) neurotechnology has the potential to reduce disability associated with paralysis by translating neural activity into control of assistive devices1-9. Surveys of potential end-users have identified key BCI system features10-14, including high accuracy, minimal daily setup, rapid response times, and multifunctionality. These performance characteristics are primarily influenced by the BCI's neural decoding algorithm1,15, which is trained to associate neural activation patterns with intended user actions. Here, we introduce a new deep neural network16 decoding framework for BCI systems enabling discrete movements that addresses these four key performance characteristics. Using intracortical data from a participant with tetraplegia, we provide offline results demonstrating that our decoder is highly accurate, sustains this performance beyond a year without explicit daily retraining by combining it with an unsupervised updating procedure3,17-20, responds faster than competing methods8, and can increase functionality with minimal retraining by using a technique known as transfer learning21. We then show that our participant can use the decoder in real-time to reanimate his paralyzed forearm with functional electrical stimulation (FES), enabling accurate manipulation of three objects from the grasp and release test (GRT)22. These results demonstrate that deep neural network decoders can advance the clinical translation of BCI technology. PMID- 30250140 TI - Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia. AB - Spinal sensorimotor networks that are functionally disconnected from the brain because of spinal cord injury (SCI) can be facilitated via epidural electrical stimulation (EES) to restore robust, coordinated motor activity in humans with paralysis1-3. Previously, we reported a clinical case of complete sensorimotor paralysis of the lower extremities in which EES restored the ability to stand and the ability to control step-like activity while side-lying or suspended vertically in a body-weight support system (BWS)4. Since then, dynamic task specific training in the presence of EES, termed multimodal rehabilitation (MMR), was performed for 43 weeks and resulted in bilateral stepping on a treadmill, independent from trainer assistance or BWS. Additionally, MMR enabled independent stepping over ground while using a front-wheeled walker with trainer assistance at the hips to maintain balance. Furthermore, MMR engaged sensorimotor networks to achieve dynamic performance of standing and stepping. To our knowledge, this is the first report of independent stepping enabled by task-specific training in the presence of EES by a human with complete loss of lower extremity sensorimotor function due to SCI. PMID- 30250138 TI - Comparative assessment of autochthonous bacterial and fungal communities and microbial biomarkers of polluted agricultural soils of the Terra dei Fuochi. AB - Organic and inorganic xenobiotic compounds can affect the potential ecological function of the soil, altering its biodiversity. Therefore, the response of microbial communities to environmental pollution is a critical issue in soil ecology. Here, a high-throughput sequencing approach was used to investigate the indigenous bacterial and fungal community structure as well as the impact of pollutants on their diversity and richness in contaminated and noncontaminated soils of a National Interest Priority Site of Campania Region (Italy) called "Terra dei Fuochi". The microbial populations shifted in the polluted soils via their mechanism of adaptation to contamination, establishing a new balance among prokaryotic and eukaryotic populations. Statistical analyses showed that the indigenous microbial communities were most strongly affected by contamination rather than by site of origin. Overabundant taxa and Actinobacteria were identified as sensitive biomarkers for assessing soil pollution and could provide general information on the health of the environment. This study has important implications for microbial ecology in contaminated environments, increasing our knowledge of the capacity of natural ecosystems to develop microbiota adapted to polluted soil in sites with high agricultural potential and providing a possible approach for modeling pollution indicators for bioremediation purposes. PMID- 30250142 TI - Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo. AB - Mutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNAAla mouse. Through application of a programmable nuclease therapy approach, using systemically administered, mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus, we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes. These findings constitute proof of principle that mtDNA heteroplasmy correction using programmable nucleases could provide a therapeutic route for heteroplasmic mitochondrial diseases of diverse genetic origin. PMID- 30250143 TI - MitoTALEN reduces mutant mtDNA load and restores tRNAAla levels in a mouse model of heteroplasmic mtDNA mutation. AB - Mutations in the mitochondrial DNA (mtDNA) are responsible for several metabolic disorders, commonly involving muscle and the central nervous system1. Because of the critical role of mtDNA in oxidative phosphorylation, the majority of pathogenic mtDNA mutations are heteroplasmic, co-existing with wild-type molecules1. Using a mouse model with a heteroplasmic mtDNA mutation2, we tested whether mitochondrial-targeted TALENs (mitoTALENs)3,4 could reduce the mutant mtDNA load in muscle and heart. AAV9-mitoTALEN was administered via intramuscular, intravenous, and intraperitoneal injections. Muscle and heart were efficiently transduced and showed a robust reduction in mutant mtDNA, which was stable over time. The molecular defect, namely a decrease in transfer RNAAla levels, was restored by the treatment. These results showed that mitoTALENs, when expressed in affected tissues, could revert disease-related phenotypes in mice. PMID- 30250144 TI - Author Correction: Regional variation limits applications of healthy gut microbiome reference ranges and disease models. AB - In the version of this article originally published, in the sentence "Applying the same approach to obesity (Fig. 2b), MetS (Fig. 2c) and fatty liver (Fig. 2d) yielded similar results," two figure panels were cited incorrectly. The data for obesity are in Fig. 2c, and the data for MetS are in Fig. 2b. The sentence has been updated with the correct citations in the print, PDF and HTML versions of the article. PMID- 30250145 TI - The Fab fragment of anti-IgE Cepsilon2 domain prevents allergic reactions through interacting with IgE-FcepsilonRIalpha complex on rat mast cells. AB - Immunoglobulin E (IgE) plays a central role in the pathogenesis of Type I hypersensitivity through interaction with a high-affinity receptor (FcepsilonRIalpha). For therapeutic applications, substantial attention has been focused recently on the blockade of the IgE interaction with FcepsilonRIalpha. While exploring better options for preventing allergic diseases, we found that the Fab fragment of the rat anti-murine IgE antibody (Fab-6HD5) strongly inhibited passive cutaneous anaphylaxis (PCA) in vivo, as well as spleen tyrosine kinase (Syk) activity and beta-hexosaminidase release from basophilic leukemia cells in vitro. The in vivo effects of Fab-6HD5 pre-administration were maintained over a long period of time for at least 10 days. Using flow cytometry analysis, we also found that Fab-6HD5 did not recognize the IgE Cepsilon3 domain containing specific binding sites for FcepsilonRIalpha. Furthermore, deletion mapping studies revealed that Fab-6HD5 recognized conformational epitopes on the Cepsilon2 domain of IgE. Given that the Cepsilon2 domain plays a key role in stabilizing the interaction of IgE with FcRIalpha, our results suggest that the specific binding of Fab-6HD5 to the Cepsilon2 domain prevents allergic reactions through destabilizing the preformed IgE-FcepsilonRIalpha complex on rat mast cells. Although the present study was performed using animal models, these findings support the idea that a certain antibody directed against IgE CH domains may contribute to preventing allergic diseases through interacting with IgE FcepsilonRIalpha complex. PMID- 30250147 TI - Effect of transition metal alloying elements on the deformation of Ti-44Al-8Nb 0.2B-0.2Y alloys. AB - A series of beta-gamma Ti-44Al-8Nb-0.2B-0.2Y alloys have been modified with 0.5 to 2.0 at.% of the beta-stabilizing elements Mn, Cr, Mo and V. Additions of Cr and Mo alone result in a decrease in the flow stress, whereas the opposite effect was observed for additions of V. For alloys with Mn additions, a minimum value of the flow stress was achieved in the alloy with 1.5% Mn. For alloys with combined additions, optimum hot deformation behavior was obtained for the alloy with 1.5% Mn and 1.0% Cr. PMID- 30250146 TI - Enrichment and detection of bone disseminated tumor cells in models of low tumor burden. AB - Breast cancer cells frequently home to the bone, but the mechanisms controlling tumor colonization of the bone marrow remain unclear. We report significant enrichment of bone-disseminated estrogen receptor positive human MCF7 cells by 17 beta-estradiol (E2) following intracardiac inoculation. Using flow cytometric and quantitative PCR approaches, tumor cells were detected in >80% of MCF7 tumor inoculated mice, regardless of E2, suggesting that E2 is not required for MCF7 dissemination to the bone marrow. Furthermore, we propose two additional models in which to study prolonged latency periods by bone-disseminated tumor cells: murine D2.0R and human SUM159 breast carcinoma cells. Tumor cells were detected in bone marrow of up to 100% of D2.0R and SUM159-inoculated mice depending on the detection method. These findings establish novel models of bone colonization in which to study mechanisms underlying tumor cell seeding to the marrow and prolonged latency, and provide highly sensitive methods to detect these rare events. PMID- 30250148 TI - Association between SLCO1B1 T521C polymorphism and risk of statin-induced myopathy: a meta-analysis. AB - Numerous studies have illustrated the relationship between SLCO1B1 T521C polymorphism and statin-induced myopathy risk; however, this association is not consistent. Three electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched from inception to October 2017 to identify potential studies. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated from different genetic models by using a random-effects model. Fourteen studies comprising 3265 myopathy patients and 7743 controls were included. The summary ORs suggested that 521CC (OR: 2.31; 95% CI: 1.15-4.63; P = 0.019), 521TC (OR: 1.34; 95% CI: 1.02-1.76; P = 0.034), and 521CC + TC (OR: 1.82; 95% CI: 1.32-2.51; P < 0.001) were associated with a greater risk of statin-induced myopathy than 521TT. The higher incidence of statin-induced myopathy was found to be significantly correlated with the C allele compared with the T allele (OR: 1.89; 95% CI: 1.36-2.62; P < 0.001). In addition, we observed that 521CC + TC was associated with an increased risk of myopathy in individuals who received simvastatin (OR: 2.35; 95% CI: 1.08-5.12; P = 0.032) or rosuvastatin (OR: 1.69; 95% CI: 1.07-2.67; P = 0.024) when compared with 521TT. The 521C allele was associated with a greater risk of cerivastatin-induced myopathy than the T allele (OR: 1.95; 95% CI: 1.47-2.57; P < 0.001). The findings of this study indicated that SLCO1B1 T521C was associated with a significantly higher risk of statin induced myopathy, especially for simvastatin, rosuvastatin, and cerivastatin. Future studies should be conducted in subjects receiving specific types of drugs, and any potential adverse events need to be explored. PMID- 30250149 TI - Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults. AB - Adverse drug reactions (ADRs) contribute to hospitalization but data on its economic burden is scant. Pre-emptive pharmacogenetic (PGx) testing can potentially reduce ADRs and its associated costs. The objectives of this study were to quantify the economic burden of ADRs and to estimate the breakeven cost of pre-emptive PGx testing in Singapore. We collected itemized costs for 1000 random non-elective hospitalizations of adults admitted to a tertiary-care general hospital in Singapore. The presence of ADRs at admission and their clinical characteristics were reported previously. The economic burden of ADRs was assessed from two perspectives: (1) Total cost and (2) incremental costs. The breakeven cost of PGx testing was estimated by dividing avoidable hospitalization costs for ADRs due to selected drugs by the number of patients taking those drugs. The total cost of 81 admissions caused by ADRs was US$570,404. Costs were significantly higher for bleeding/elevated international normalized ratio (US$9906 vs. US$2251, p = 6.58 * 10-3) compared to other ADRs, and for drugs acting on the blood coagulation system (US$9884 vs. US$2229, p = 4.41 * 10-3) compared to other drug classes. There were higher incremental laboratory costs due to ADRs causing or being present at admission. The estimated breakeven cost of a pre-emptive PGx test for patients taking warfarin, clopidogrel, chemotherapeutic and neuropsychiatric drugs was US$114 per patient. These results suggest that future studies designed to directly measure the clinical and cost impact of a pre-emptive genotyping program will help inform clinical practice and health policy decisions. PMID- 30250151 TI - Swap outdated authorship listings for contributorship credit. PMID- 30250150 TI - Transfer and Integration of Breast Milk Stem Cells to the Brain of Suckling Pups. AB - Beside its unique nutritional content breast milk also contains live cells from the mother. Fate of these cells in the offspring has not been adequately described. In this study, we aimed to detect and identify maternal cells in the suckling's blood and the brain. Green fluorescent protein expressing transgenic female mice (GFP+) were used as foster mothers to breastfeed wildtype newborn pups. One week and two months after the birth, blood samples and brains of the sucklings were analyzed to detect presence of GFP+ cells by fluorescence activated cell sorting, polymerase chain reaction and immunohistochemistry on the brain sections and optically cleared brains. The tests confirmed that maternal cells were detectable in the blood and the brain of the pups and that they differentiated into both neuronal and glial cell types in the brain. This phenomenon represents breastfeeding - induced microchimerism in the brain with functional implications remain to be understood. PMID- 30250152 TI - How do natural hazards cascade to cause disasters? PMID- 30250153 TI - Machine learning gets to grips with plankton challenge. PMID- 30250154 TI - Molecular clocks provide little information to date methanogenic Archaea. PMID- 30250155 TI - Reply to 'Molecular clocks provide little information to date methanogenic Archaea'. PMID- 30250156 TI - Ecosystem scale trade-off in nitrogen acquisition pathways. AB - The nitrogen (N) cycle in terrestrial ecosystems is strongly influenced by resorption before litter fall and by mineralization after litter fall. Although both resorption and mineralization make N available to plants and are influenced by climate, their linkage in a changing environment remains largely unknown. Here, our synthesis study shows that, at the global scale, increasing N resorption efficiency negatively affects the N-mineralization rate. As temperature and precipitation increase, the increasing rates of N cycling closely correspond to a shift from the more conservative resorption pathway to the mineralization pathway. Furthermore, ecosystems with faster N-cycle rates support plant species that have higher foliar N:P ratios and microbial communities with lower fungi:bacteria ratios. Our study shows an ecosystem scale trade-off in N acquisition pathways. We propose that incorporating the dynamic interaction between N resorption and N mineralization into Earth system models will improve the simulation of nutrient constraints on ecosystem productivity. PMID- 30250158 TI - Macroevolutionary shift in the size of amphibian genomes and the role of life history and climate. AB - The evolution and great diversity of genome size has been of long-standing interest to biologists, but has seldom been investigated on a broad phylogenetic scale. Here we present a comparative quantitative analysis of factors shaping genome size evolution in amphibians, the extant class of vertebrates with the largest variation in genome size. We find that amphibian genomes have undergone saltations in size, although these are rare and the evolutionary history of genome size in amphibians has otherwise been one of gradual, time-dependent variation (that is, Brownian motion). This macroevolutionary homogeneity is remarkable given the evolutionary and ecological diversity of most other aspects of the natural history of amphibians. Contrary to previous claims, we find no evidence for associations between life cycle complexity and genome size despite the high diversity of reproductive modes and the multiple events of independent evolution of divergent life cycles in the group. Climate (temperature and humidity) affects genome size indirectly, at least in frogs, as a consequence of its effect on premetamorphic developmental period, although directionality of the relationship between developmental period and genome size is not unequivocal. PMID- 30250157 TI - Divergence and plasticity shape adaptive potential of the Pacific oyster. AB - The interplay between divergence and phenotypic plasticity is critical to our understanding of a species' adaptive potential under rapid climate changes. We investigated divergence and plasticity in natural populations of the Pacific oyster Crassostrea gigas with a congeneric oyster Crassostrea angulata from southern China used as an outgroup. Genome re-sequencing of 371 oysters revealed unexpected genetic divergence in a small area that coincided with phenotypic divergence in growth, physiology, heat tolerance and gene expression across environmental gradients. These findings suggest that selection and local adaptation are pervasive and, together with limited gene flow, influence population structure. Genes showing sequence differentiation between populations also diverged in transcriptional response to heat stress. Plasticity in gene expression is positively correlated with evolved divergence, indicating that plasticity is adaptive and favoured by organisms under dynamic environments. Divergence in heat tolerance-partly through acetylation-mediated energy depression-implies differentiation in adaptive potential. Trade-offs between growth and survival may play an important role in local adaptation of oysters and other marine invertebrates. PMID- 30250159 TI - PYK2 negatively regulates the Hippo pathway in TNBC by stabilizing TAZ protein. AB - The tumor suppressor Hippo pathway negatively regulates the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) to inhibit cell growth and control organ size, whereas activation of YAP and TAZ is implicated in tumorigenesis and cancer metastasis. Here, we report that the nonreceptor tyrosine kinase PYK2 positively regulates TAZ and YAP transcriptional activity in triple-negative breast cancer (TNBC). We found that inhibition of PYK2 expression or its kinase activity substantially affects the steady-state level of TAZ and markedly facilitates its proteasomal degradation. This effect was specific to PYK2 inhibition and was not obtained by inhibition of FAK. Destabilization of TAZ was associated with profound effect of PYK2 inhibition on cell growth at low-density concomitant with reduced expression of TAZ-target genes and induction of cell apoptosis. We further show that PYK2 enhances the tyrosine phosphorylation of both TAZ and LATS1/2 and concomitantly TAZ stability, and that PYK2 protein level correlates with the level of TAZ protein in primary breast tumors. Together these observations suggest that PYK2 is an important regulator of the Hippo pathway, and its tyrosine kinase activity has a striking effect on TAZ stabilization and activation in TNBC. PMID- 30250160 TI - Modulating the hierarchical fibrous assembly of Au nanoparticles with atomic precision. AB - The ability to modulate nanoparticle (NP) assemblies with atomic precision is still lacking, which hinders us from creating hierarchical NP organizations with desired properties. In this work, a hierarchical fibrous (1D to 3D) assembly of Au NPs (21-gold atom, Au21) is realized and further modulated with atomic precision via site-specific tailoring of the surface hook (composed of four phenyl-containing ligands with a counteranion). Interestingly, tailoring of the associated counterion significantly changes the electrical transport properties of the NP-assembled solids by two orders of magnitude due to the altered configuration of the interacting pi-pi pairs of the surface hooks. Overall, our success in atomic-level modulation of the hierarchical NP assembly directly evidences how the NP ligands and associated counterions can function to guide the 1D, 2D, and 3D hierarchical self-assembly of NPs in a delicate manner. This work expands nanochemists' skills in rationally programming the hierarchical NP assemblies with controllable structures and properties. PMID- 30250161 TI - Development of a genome-informed loop-mediated isothermal amplification assay for rapid and specific detection of Xanthomonas euvesicatoria. AB - Bacterial spot (BS), caused by Xanthomonas euvesicatoria, X. vesicatoria, X. gardneri and X. perforans, is an economically important bacterial disease of tomato and pepper. Symptoms produced by all four species are nearly indistinguishable. At present, no point-of-care diagnostics exist for BS. In this research, we examined genomes of X. euvesicatoria, X. vesicatoria, X. gardneri, X. perforans and other species of Xanthomonas; the unique gene recG was chosen to design primers to develop a loop-mediated isothermal amplification (LAMP) assay to rapidly and accurately identify and differentiate X. euvesicatoria from other BS causing Xanthomonas sp. using a field-deployable portable BioRangerTM instrument. Specificity of the developed assay was tested against 39 strains of X. euvesicatoria and 41 strains of other species in inclusivity and exclusivity panels, respectively. The assay detection limit was 100 fg (~18 genome copies) of genomic DNA and 1,000 fg in samples spiked with tomato DNA. The assay unambiguously detected X. euvesicatoria in infected tomato plant samples. Concordant results were obtained when multiple operators performed the test independently. No false positives and false negatives were detected. The developed LAMP assay has numerous applications in diagnostics, biosecurity and disease management. PMID- 30250164 TI - Bongani Mawethu Mayosi. PMID- 30250162 TI - Enrichment of gut-derived Fusobacterium is associated with suboptimal immune recovery in HIV-infected individuals. AB - We explored the gut microbiota profile among HIV-infected individuals with diverse immune recovery profiles following long-term suppressive ART and investigated the relationship between the altered bacteria with markers of immune dysfunction. The microbiota profile of rectal swabs from 26 HIV-infected individuals and 20 HIV-uninfected controls were examined. Patients were classified as suboptimal responders, sIR (n = 10, CD4 T-cell <350 cells/ul) and optimal responders, oIR (n = 16, CD4 T-cell >500 cells/ul) after a minimum of 2 years on suppressive ART. Canonical correlation analysis(CCA) and multiple regression modelling were used to explore the association between fecal bacterial taxa abundance and immunological profiles in optimal and suboptimal responders. We found Fusobacterium was significantly enriched among the HIV-infected and the sIR group. CCA results showed that Fusobacterium abundance was negatively correlated with CD4 T-cell counts, but positively correlated with CD4 T-cell activation and CD4 Tregs. Multiple linear regression analysis adjusted for age, baseline CD4 T-cell count, antibiotic exposure and MSM status indicated that higher Fusobacterium relative abundance was independently associated with poorer CD4 T-cell recovery following ART. Enrichment of Fusobacterium was associated with reduced immune recovery and persistent immune dysfunction following ART. Modulating the abundance of this bacterial taxa in the gut may be a viable intervention to improve immune reconstitution in our setting. PMID- 30250165 TI - Ticagrelor not superior to DAPT after PCI. PMID- 30250163 TI - Intermediate predator naivete and sex-skewed vulnerability predict the impact of an invasive higher predator. AB - The spread of invasive species continues to reduce biodiversity across all regions and habitat types globally. However, invader impact prediction can be nebulous, and approaches often fail to integrate coupled direct and indirect invader effects. Here, we examine the ecological impacts of an invasive higher predator on lower trophic groups, further developing methodologies to more holistically quantify invader impact. We employ functional response (FR, resource use under different densities) and prey switching experiments to examine the trait- and density-mediated impacts of the invasive mosquitofish Gambusia affinis on an endemic intermediate predator Lovenula raynerae (Copepoda). Lovenula raynerae effectively consumed larval mosquitoes, but was naive to mosquitofish cues, with attack rates and handling times of the intermediate predator unaffected by mosquitofish cue-treated water. Mosquitofish did not switch between male and female prey, consistently displaying a strong preference for female copepods. We thus demonstrate a lack of risk-reduction activity in the presence of invasive fish by L. raynerae and, in turn, high susceptibility of such intermediate trophic groups to invader impact. Further, we show that mosquitofish demonstrate sex-skewed predator selectivity towards intermediate predators of mosquito larvae, which may affect predator population demographics and, perversely, increase disease vector proliferations. We advocate the utility of FRs and prey switching combined to holistically quantify invasive species impact potential on native organisms at multiple trophic levels. PMID- 30250166 TI - Prevention of atherothrombotic events in patients with diabetes mellitus: from antithrombotic therapies to new-generation glucose-lowering drugs. AB - Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. This situation might be caused, at least in part, by the prothrombotic status observed in patients with diabetes. Therefore, contemporary antithrombotic strategies, including more potent agents or drug combinations, might provide greater clinical benefit in patients with diabetes than in those without diabetes. In this Consensus Statement, our Working Group explores the mechanisms of platelet and coagulation activity, the current debate on antiplatelet therapy in primary cardiovascular disease prevention, and the benefit of various antithrombotic approaches in secondary prevention of cardiovascular disease in patients with diabetes. While acknowledging that current data are often derived from underpowered, observational studies or subgroup analyses of larger trials, we propose antithrombotic strategies for patients with diabetes in various cardiovascular settings (primary prevention, stable coronary artery disease, acute coronary syndromes, ischaemic stroke and transient ischaemic attack, peripheral artery disease, atrial fibrillation, and venous thromboembolism). Finally, we summarize the improvements in cardiovascular outcomes observed with the latest glucose-lowering drugs, and on the basis of the available evidence, we expand and integrate current guideline recommendations on antithrombotic strategies in patients with diabetes for both primary and secondary prevention of cardiovascular disease. PMID- 30250167 TI - GRP75 modulates oncogenic Dbl-driven endocytosis derailed via the CHIP-mediated ubiquitin degradation pathway. AB - Chaperone-assisted proteasome degradation of oncogenic protein acts as an upstream signal controlling tumorigenesis and progression. The understanding of the co-regulation of chaperone and oncoprotein of endocytosis pathways is extremely limited. In this study, we showed for the first time that proto-Dbl (dbl proto-oncogene product) is co-enriched with mitochondrial chaperone GRP75 in endocytosis vesicles from ovarian cancer cells. onco-Dbl, produced by oncogenic mutation/degradation of proto-Dbl, markedly enhanced cellular macropinocytosis but suppressed clathrin-mediated endocytosis and clathrin-independent endocytosis pathways, presenting a derailed endocytosis phenotype. GRP75 was associated with proto-Dbl inside cells and modulated Dbl-driven endocytosis derailed by a co regulatory mode. In spite of not being a component of the Hsc70/Hsp90/proto-Dbl complex, the degradation of proto-Dbl was promoted by GRP75 through the CHIP mediated ubiquitin-proteasome pathway, of which GRP75 acts as a cooperator with CHIP but also acts as a competitor to Hsc70 and Hsp90 in the multiple chaperones assisted pro-folding/pro-degradation machinery. Knockdown or inhibition of GRP75 attenuated proto-Dbl degradation and reduced the onco-Dbl level, which differentially impaired Rho GTPases activation and therefore shifted the endocytosis-derailed phenotype. Our data uncovered a novel GRP75-Dbl endocytosis regulatory axis and provided an alternative using chaperone inhibitor to shut down the oncoprotein-driven endocytosis derailment mechanism. PMID- 30250168 TI - BRWD1 orchestrates epigenetic landscape of late B lymphopoiesis. AB - Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. Here we show that in small pre-B cells, the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 regulates over 7000 genes to repress proliferative and induce differentiation programs. However, BRWD1 does not regulate the expression of TFs required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations have B-cell transcriptional profiles and enhancer landscapes similar to those observed in Brwd1-/- mice. These data indicate that, in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B-cell development. PMID- 30250169 TI - Long non-coding RNA CCAL/miR-149/FOXM1 axis promotes metastasis in gastric cancer. AB - Early evidence indicates that the long non-coding RNA CCAL plays a critical role in cancer progression and metastasis. However, the overall biological role and clinical significance of CCAL in gastric tumourigenesis and progression remain largely unknown. We observed that CCAL was upregulated in gastric cancer tissues and was associated with the tumour-node-metastasis stage. Functional experiments showed that CCAL promoted gastric cancer cell proliferation and metastasis in vitro and in vivo. Luciferase reporter assay indicated that CCAL directly bind to miR-149. Moreover, knockdown of CCAL significantly reduced the expression of FOXM1, a direct target of miR-149. We also showed that FOXM1 suppression by miR 149 could be partially rescued by CCAL overexpression. In addition, we identified a negative correlation between the mRNA expression of CCAL and miR-149 in gastric cancer tissues. Furthermore, we observed a negative correlation between the expression of miR-149 and FOXM1 and a positive correlation between CCAL and FOXM1 levels. These results demonstrated that the CCAL/miR-149/FOXM1 axis functions as a key regulator in gastric cancer metastasis and CCAL potentially represents a biomarker for diagnosis and potential target for therapy in the future. PMID- 30250171 TI - Crystal structure of FlgL and its implications for flagellar assembly. AB - Bacteria move toward attractants and away from repellants by rotating their flagellum. The bacterial flagellum assembles through the ordered organization of more than 30 different proteins. Among the diverse flagellar proteins, FlgL forms the junction between the hook and the filament in the flagellum together with FlgK and provides a structural base where flagellin, a filament-forming protein, is inserted for the initiation of filament elongation. However, the functional and structural information available for FlgL is highly limited. To provide structural insights into the cross-linkage between the FlgL junction and the flagellin filament, we determined the crystal structures of FlgL from gram positive Bacillus cereus (bcFlgL) and gram-negative Xanthomonas campestris (xcFlgL). bcFlgL contains one domain (D1), whereas xcFlgL adopts a two-domain structure that consists of the D1 and D2 domains. The constant D1 domain of FlgL adopts a rod structure that is generated by four longitudinal segments. This four segment structure is recapitulated in filament and junction proteins but not in hook and rod proteins, allowing us to propose a junction-filament assembly mechanism based on a quasi-homotypic interaction. The D2 domain of xcFlgL resembles that of another junction protein, FlgK, suggesting the structural and functional relatedness of FlgL and FlgK. PMID- 30250172 TI - Comparison of two different ecological floating bio-reactors for pollution control in hyper-eutrophic freshwater. AB - The use of ecological floating beds (EFBs) to control water pollution has been increasingly reported worldwide due to the severe situation of eutrophication in water bodies. In this study, two kinds of EFBs were set up under similar condition to compare their purification efficiency in hyper-eutrophic water. The conventional ecological floating bed (CEFB) was made of polystyrene foam board, and the enhanced ecological floating bio-reactor (EEFB) was designed as an innovative hollow, thin floating bed integrated with substrates of zeolite and limestone. The results showed that the EEFB increased treatment efficiency of total nitrogen (TN), total phosphate (TP), and ammonia nitrogen (NH4+-N) to 63.5%, 59.3%, and 68.0%, respectively. Plant accumulation was the main pathway for TN and TP removal in the CEFB. Microbial degradation played an increasingly important role in TN and TP removal in the EEFB. A higher concentration of nitrogen cycling bacteria was recorded in the EEFB than the CEFB (P < 0.05), suggesting that the substrates might enhanced the removal efficiency of the EEFB by promoting the growth of microorganisms rather than their absorption effect. PMID- 30250173 TI - Morphological Evaluation of Meta-stable Oligomers of alpha-Synuclein with Small Angle Neutron Scattering. AB - Amyloidogenesis of alpha-synuclein (alphaS) is considered to be a pathological phenomenon related to Parkinson's disease (PD). As a key component to reveal the fibrillation mechanism and toxicity, we have investigated an oligomeric species of alphaS capable of exhibiting the unit-assembly process leading to accelerated amyloid fibril formation. These oligomers previously shown to exist in a meta stable state with mostly disordered structure and unable to seed the fibrillation were converted to either temperature-sensitive self-associative oligomers or NaCl induced non-fibrillating oligomeric species. Despite their transient and disordered nature, the structural information of meta-stable alphaS oligomers (Meta-alphaS-Os) was successfully evaluated with small-angle neutron scattering (SANS) technique. By fitting the neutron scattering data with polydisperse Gaussian Coil (pGC) model, Meta-alphaS-O was analyzed as a sphere with approximate diameter of 100 A. Its overall shape altered drastically with subtle changes in temperature between 37 degrees C and 43 degrees C, which would be responsible for fibrillar polymorphism. Based on their bifurcating property of Meta-alphaS-Os leading to either on-pathway or off-pathway species, the oligomers could be suggested as a crucial intermediate responsible for the oligomeric diversification and multiple fibrillation processes. Therefore, Meta-alphaS-Os could be considered as a principal target to control the amyloidogenesis and its pathogenesis. PMID- 30250170 TI - Griffithsin carrageenan fast dissolving inserts prevent SHIV HSV-2 and HPV infections in vivo. AB - Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) strategies with proven in vivo efficacy rely on antiretroviral drugs, creating the potential for drug resistance and complicated treatment options in individuals who become infected. Moreover, on-demand products are currently missing from the PrEP development portfolio. Griffithsin (GRFT) is a non-antiretroviral HIV entry inhibitor derived from red algae with an excellent safety profile and potent activity in vitro. When combined with carrageenan (CG), GRFT has strong activity against herpes simplex virus-2 (HSV-2) and human papillomavirus (HPV) in vitro and in vivo. Here, we report that GRFT/CG in a freeze-dried fast dissolving insert (FDI) formulation for on-demand use protects rhesus macaques from a high dose vaginal SHIV SF162P3 challenge 4 h after FDI insertion. Furthermore, the GRFT/CG FDI also protects mice vaginally against HSV-2 and HPV pseudovirus. As a safe, potent, broad-spectrum, on-demand non-antiretroviral product, the GRFT/CG FDI warrants clinical development. PMID- 30250174 TI - Identification of a limb enhancer that is removed by pathogenic deletions downstream of the SHOX gene. AB - Haploinsufficiency of the human SHOX gene causes Leri-Weill dyschondrosteosis (LWD), characterized by shortening of the middle segments of the limbs and Madelung deformity of the wrist. As many as 35% of LWD cases are caused by deletions of non-coding sequences downstream of SHOX that presumably remove an enhancer or enhancers necessary for SHOX expression in developing limbs. We searched for these active sequences using a transgenic mouse assay and identified a 563 basepair (bp) enhancer with specific activity in the limb regions where SHOX functions. This enhancer has previously escaped notice because of its poor evolutionary conservation, although it does contain 100 bp that are conserved in non-rodent mammals. A primary cell luciferase assay confirmed the enhancer activity of the conserved core sequence and demonstrated that putative HOX binding sites are required for its activity. This enhancer is removed in most non coding deletions that cause LWD. However, we did not identify any likely pathogenic variants of the enhancer in a screen of 124 LWD individuals for whom no causative mutation had been found, suggesting that only larger deletions in the region commonly cause LWD. We hypothesize that loss of this enhancer contributes to the pathogenicity of deletions downstream of SHOX. PMID- 30250176 TI - Golden single-atomic-site platinum electrocatalysts. AB - Bimetallic nanoparticles with tailored structures constitute a desirable model system for catalysts, as crucial factors such as geometric and electronic effects can be readily controlled by tailoring the structure and alloy bonding of the catalytic site. Here we report a facile colloidal method to prepare a series of platinum-gold (PtAu) nanoparticles with tailored surface structures and particle diameters on the order of 7 nm. Samples with low Pt content, particularly Pt4Au96, exhibited unprecedented electrocatalytic activity for the oxidation of formic acid. A high forward current density of 3.77 A mgPt-1 was observed for Pt4Au96, a value two orders of magnitude greater than those observed for core shell structured Pt78Au22 and a commercial Pt nanocatalyst. Extensive structural characterization and theoretical density functional theory simulations of the best-performing catalysts revealed densely packed single-atom Pt surface sites surrounded by Au atoms, which suggests that their superior catalytic activity and selectivity could be attributed to the unique structural and alloy-bonding properties of these single-atomic-site catalysts. PMID- 30250175 TI - MyD88 signaling causes autoimmune sialadenitis through formation of high endothelial venules and upregulation of LTbeta receptor-mediated signaling. AB - Autoimmune sialadenitis (AS), chronic inflammation of the salivary glands (SGs) with focal lymphocyte infiltration, appears in autoimmune diseases such as Sjogren's syndrome. The pathological role of MyD88-dependent innate immune signaling in autoimmune diseases including AS has been studied using mouse models, such as NOD mice. Although AS development in NOD mice was reported to be suppressed by Myd88 deficiency, its specific role remains unclear. Here, we determined the potent suppressive effects of Myd88 deficiency on AS development in lupus-prone B6/lpr mice, which have lymphoproliferation abnormalities, and also in NOD mice, which have no lymphoproliferation abnormalities. This indicates that MyD88 signaling triggers AS through both lymphoproliferation-dependent and independent mechanisms. To address the MyD88-dependent lymphoproliferation independent AS manifestation, SGs from C57BL/6 mice were analyzed. Remarkable upregulation of Glycam1 and high endothelial venule (HEV)-associated changes were unexpectedly found in Myd88+/+ mice, compared with Myd88-/- mice. MyD88-dependent HEV-associated changes were also observed in NOD mice. Additionally, Lta, Ltb, and Ltbr in SGs of NOD mice were lowered by Myd88 deficiency. Interestingly, LTbetaR-induced HEV-associated gene expression in cultured cells was impaired by Myd88 deficiency. Our findings highlight novel roles for MyD88 in AS development, which imply the existence of MyD88-dependent HEV formation in ectopic lymphoid neogenesis. PMID- 30250178 TI - Bleeding anti-inflammatory. PMID- 30250177 TI - Large electrostrictive response in lead halide perovskites. AB - Lead halide perovskites have demonstrated outstanding performance in photovoltaics, photodetectors, radiation detectors and light-emitting diodes. However, the electromechanical properties, which are the main application of inorganic perovskites, have rarely been explored for lead halide perovskites. Here, we report the discovery of a large electrostrictive response in methylammonium lead triiodide (MAPbI3) single crystals. Under an electric field of 3.7 V um-1, MAPbI3 shows a large compressive strain of 1%, corresponding to a mechanical energy density of 0.74 J cm-3, comparable to that of human muscles. The influences of piezoelectricity, thermal expansion, intrinsic electrostrictive effect, Maxwell stress, ferroelectricity, local polar fluctuation and methylammonium cation ordering on this electromechanical response are excluded. We speculate, using density functional theory, that electrostriction of MAPbI3 probably originates from lattice deformation due to formation of additional defects under applied bias. The discovery of large electrostriction in lead iodide perovskites may lead to new potential applications in actuators, sonar and micro-electromechanical systems and aid the understanding of other field dependent material properties. PMID- 30250179 TI - Viral exploitation of mTOR. PMID- 30250180 TI - Anti-tumor role of metformin. PMID- 30250181 TI - TB prognostic marker. PMID- 30250182 TI - Iron strength. PMID- 30250183 TI - A more human mouse. PMID- 30250184 TI - Sex-hormone-driven innate antibodies protect females and infants against EPEC infection. AB - Females have an overall advantage over males in resisting Gram-negative bacteremias, thus hinting at sexual dimorphism of immunity during infections. Here, through intravital microscopy, we observed a sex-biased difference in the capture of blood-borne bacteria by liver macrophages, a process that is critical for the clearance of systemic infections. Complement opsonization was indispensable for the capture of enteropathogenic Escherichia coli (EPEC) in male mice; however, a faster complement component 3-independent process involving abundant preexisting antibodies to EPEC was detected in female mice. These antibodies were elicited predominantly in female mice at puberty in response to estrogen regardless of microbiota-colonization conditions. Estrogen-driven antibodies were maternally transferrable to offspring and conferred protection during infancy. These antibodies were conserved in humans and recognized specialized oligosaccharides integrated into the bacterial lipopolysaccharide and capsule. Thus, an estrogen-driven, innate antibody-mediated immunological strategy conferred protection to females and their offspring. PMID- 30250185 TI - The identity and function of microglia in neurodegeneration. AB - The predominant type of immune cell in the brain is the microglia, a type of tissue-resident macrophage. In a variety of neurodegenerative settings, microglia alter their transcriptional profile, morphology and function in similar ways; thus, these activated cells have been called 'degeneration- or disease-associated microglia' (DAM). These activated microglia can perform different functions and exert both positive effects and negative effects in different mouse disease models. In humans, mutations in genes expressed in microglia are linked to various neurodegenerative diseases. Here we provide an overview of the common microglial response to neurodegeneration and key contributing pathways; delineate the multifaceted functions of activated microglia spanning various diseases; and discuss insights from the study of human disease-associated genes. We argue that strong evidence from both mouse models and human genetics causally links the function of activated microglia to neurodegeneration. PMID- 30250186 TI - Infection perturbs Bach2- and Bach1-dependent erythroid lineage 'choice' to cause anemia. AB - Elucidation of how the differentiation of hematopoietic stem and progenitor cells (HSPCs) is reconfigured in response to the environment is critical for understanding the biology and disorder of hematopoiesis. Here we found that the transcription factors (TFs) Bach2 and Bach1 promoted erythropoiesis by regulating heme metabolism in committed erythroid cells to sustain erythroblast maturation and by reinforcing erythroid commitment at the erythro-myeloid bifurcation step. Bach TFs repressed expression of the gene encoding the transcription factor C/EBPbeta, as well as that of its target genes encoding molecules important for myelopoiesis and inflammation; they achieved the latter by binding to their regulatory regions also bound by C/EBPbeta. Lipopolysaccharide diminished the expression of Bach TFs in progenitor cells and promoted myeloid differentiation. Overexpression of Bach2 in HSPCs promoted erythroid development and inhibited myelopoiesis. Knockdown of BACH1 or BACH2 in human CD34+ HSPCs impaired erythroid differentiation in vitro. Thus, Bach TFs accelerate erythroid commitment by suppressing the myeloid program at steady state. Anemia of inflammation and myelodysplastic syndrome might involve reduced activity of Bach TFs. PMID- 30250188 TI - CCL19 suppresses angiogenesis through promoting miR-206 and inhibiting Met/ERK/Elk-1/HIF-1alpha/VEGF-A pathway in colorectal cancer. AB - The mechanisms underlying the role of chemokines in tumor angiogenesis is still not fully understood. In this study, we detected the influence of CCL19 on colorectal cancer (CRC) angiogenesis. The expression of CCL19 and CD31 in CRC tissues were detected by immunohistochemistry. Human CRC cell lines SW1116 and SW620 stably transfected with CCL19 lentivirus and CCL19 shRNA, and HUVEC stably transfected with CCR7 shRNA were used in our study. Our study showed that CCL19 was significantly low-expressed in CRC tissues and positively related to highly tumor microvessel density. In vitro, we observed that CCL19 high-expressed SW1116 supernatant was able to inhibit proliferation, migration, and sprouting responses of HUVEC, whereas CCL19 low-expressed SW620 supernatant can promote HUVEC angiogenesis. Additionally, we further demonstrated that these functions maybe achieved through promoting miR-206 thus inhibiting Met/ERK/Elk-1/HIF-1alpha/VEGF A pathway in a CCR7-dependent manner. Mice angiogenesis model also confirmed that elevated expression of CCL19 inhibit the angiogenesis of CRC in vivo. In summary, our results supported that CCL19 can inhibit CRC angiogenesis through promoting miR-206 thus inhibiting Met/ERK/Elk-1/HIF-1alpha/VEGF-A pathway. This may be a novel therapeutic option for anti-vascular treatment in CRC. PMID- 30250187 TI - NIK signaling axis regulates dendritic cell function in intestinal immunity and homeostasis. AB - Dendritic cells (DCs) play an integral role in regulating mucosal immunity and homeostasis, but the signaling network mediating this function of DCs is poorly defined. We identified the noncanonical NF-kappaB-inducing kinase (NIK) as a crucial mediator of mucosal DC function. DC-specific NIK deletion impaired intestinal immunoglobulin A (IgA) secretion and microbiota homeostasis, rendering mice sensitive to an intestinal pathogen, Citrobacter rodentium. DC-specific NIK was required for expression of the IgA transporter polymeric immunoglobulin receptor (pIgR) in intestinal epithelial cells, which in turn relied on the cytokine IL-17 produced by TH17 cells and innate lymphoid cells (ILCs). NIK activated noncanonical NF-kappaB induced expression of IL-23 in DCs, contributing to the maintenance of TH17 cells and type 3 ILCs. Consistent with the dual functions of IL-23 and IL-17 in mucosal immunity and inflammation, NIK deficiency also ameliorated colitis induction. Thus, our data suggest a pivotal role for the NIK signaling axis in regulating DC functions in intestinal immunity and homeostasis. PMID- 30250189 TI - Atom-hybridization for synthesis of polymetallic clusters. AB - The chemistry of metal clusters on the sub-nanometer scale is not yet well understood because metal clusters, especially multimetallic clusters, are difficult to synthesize with control over size and composition. The template synthesis of multimetallic sub-nanoclusters is achieved using a phenylazomethine dendrimer as a macromolecular template. Its intramolecular potential gradient allows the precise uptake of metal precursor complexes containing up to eight elements on the template. The usefulness of this method is demonstrated by synthesizing multimetallic sub-nanoclusters composed of five elements (Ga1In1Au3Bi2Sn6). The size and composition of this cluster can be precisely controlled and the metals involved are alloyed with each other. This approach provides the ability to easily blend different metals in various combinations to create new materials on the sub-nanometer scale, which will lead to the development of a new area in the field of chemistry. PMID- 30250190 TI - VDAC2 interacts with PFKP to regulate glucose metabolism and phenotypic reprogramming of glioma stem cells. AB - Plastic phenotype convention between glioma stem cells (GSCs) and non-stem tumor cells (NSTCs) significantly fuels glioblastoma heterogeneity that causes therapeutic failure. Recent progressions indicate that glucose metabolic reprogramming could drive cell fates. However, the metabolic pattern of GSCs and NSTCs and its association with tumor cell phenotypes remain largely unknown. Here we found that GSCs were more glycolytic than NSTCs, and voltage-dependent anion channel 2 (VDAC2), a mitochondrial membrane protein, was critical for metabolic switching between GSCs and NSTCs to affect their phenotypes. VDAC2 was highly expressed in NSTCs relative to GSCs and coupled a glycolytic rate-limiting enzyme platelet-type of phosphofructokinase (PFKP) on mitochondrion to inhibit PFKP mediated glycolysis required for GSC maintenance. Disruption of VDAC2 induced dedifferentiation of NSTCs to acquire GSC features, including the enhanced self renewal, preferential expression of GSC markers, and increased tumorigenicity. Inversely, enforced expression ofVDAC2 impaired the self-renewal and highly tumorigenic properties of GSCs. PFK inhibitor clotrimazole compromised the effect of VDAC2 disruption on glycolytic reprogramming and GSC phenotypic transition. Clinically, VDAC2 expression inversely correlated with glioma grades (Immunohistochemical staining scores of VDAC2 were 4.7 +/- 2.8, 3.2 +/- 1.9, and 1.9 +/- 1.9 for grade II, grade III, and IV, respectively, p < 0.05 for all) and the patients with high expression of VDAC2 had longer overall survival than those with low expression of VDAC2 (p = 0.0008). In conclusion, we demonstrate that VDAC2 is a new glycolytic regulator controlling the phenotype transition between glioma stem cells and non-stem cells and may serves as a new prognostic indicator and a potential therapeutic target for glioma patients. PMID- 30250191 TI - A novel human IL-2 mutein with minimal systemic toxicity exerts greater antitumor efficacy than wild-type IL-2. AB - IL-2 is critical to the activation, growth, and survival of T cells and NK cells, and maintains the delicate balance between auto-immunity and anti-neoplasm surveillance. High IL-2 doses have clear antitumor capabilities, but also have severe side effects that limit its clinical use. Side effects include the vascular leak syndrome (VLS), which results in lung edema and liver damage. Therefore, a new version of IL-2 that does not induce organ toxicity would improve IL-2-based immunotherapy. We conducted a systematic screening by changing one amino acid at a time at the interaction area of IL-2 with its receptor IL-2R to select one particular mutant IL-2, FSD13, in which the proline at position 65 was substituted by lysine (P65L). FSD13 had a greater ability than wild-type IL-2 in stimulating CD4+ T, CD8+ T, and NK cell proliferation, enhancing the expression of CD69, CD183, CD44, and CD54 in these cells, and triggering cancer cell apoptosis. FSD13 had three-time lower than wild-type IL-2 in inducing CD4+ T to Tregs. Compared with wild-type IL-2, FSD13 greatly limited the growth, invasion into adjacent tissues, and metastasis of melanoma metastatic into the lung. In contrast to wild-type IL-2, high dose of FSD3 did not alter structures and induce any pathogenic changes in the liver and lung. Thus, we generated a novel the IL-2 mutant, FSD13, by targeting a different area than previously reported. FSD13 surpasses the wild-type IL-2's ability in stimulating the antitumor immune cell functions, but exerts much less systemic toxicity. PMID- 30250192 TI - Contrasting effects on deep convective clouds by different types of aerosols. AB - Convective clouds produce a significant proportion of the global precipitation and play an important role in the energy and water cycles. We quantify changes of the convective cloud ice mass-weighted altitude centroid (ZIWC) as a function of aerosol optical thickness (AOT). Analyses are conducted in smoke, dust and polluted continental aerosol environments over South America, Central Africa and Southeast Asia, using the latest measurements from the CloudSat and CALIPSO satellites. We find aerosols can inhibit or invigorate convection, depending on aerosol type and concentration. On average, smoke tends to suppress convection and results in lower ZIWC than clean clouds. Polluted continental aerosol tends to invigorate convection and promote higher ZIWC. The dust aerosol effects are regionally dependent and their signs differ from place to place. Moreover, we find that the aerosol inhibition or invigoration effects do not vary monotonically with AOT and the variations depend strongly on aerosol type. Our observational findings indicate that aerosol type is one of the key factors in determining the aerosol effects on convective clouds. PMID- 30250193 TI - Restoration of GLP-1 secretion by Berberine is associated with protection of colon enterocytes from mitochondrial overheating in diet-induced obese mice. AB - OBJECTIVE: L-cell dysfunction is reported for GLP-1 reduction in type 2 diabetes. However, the mechanism of dysfunction remains unknown. In this study, we examined mitochondrial function in the mechanistic study in diet-induced obese (DIO) mice. SUBJECTS: C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks to establish the DIO model for GLP-1 reduction. The mice were then treated with berberine (BBR) (100 mg/kg/day) for 8 weeks to test the impact on GLP-1 expression. Mitochondrial activities of the colon enterocytes were compared among three groups of mice (lean, DIO, and DIO + BBR) at the end of treatment. Gut microbiota and short-chain fatty acids (SCFAs) were examined to understand the mitochondrial responses. A cellular model treated with palmitic acid (PA) was used in the mechanism study. RESULTS: A reduction in GLP-1 expression was observed in DIO mice with mitochondrial stress responses in the colon enterocytes. The mitochondria exhibited cristae loss, membrane rupture, and mitochondrial swelling, which was observed with an increase in ATP abundance, complex I activity, and deficiency in the activities of complexes II and IV. Those changes were associated with dysbiosis and a reduction in SCFAs in the colon of DIO mice. In the cellular model, an increase in ATP abundance, loss of mitochondrial potential, and elevation of apoptosis were induced by PA. All of the alterations in DIO mice and the cellular model were attenuated by BBR. CONCLUSION: The mitochondrial stress responses were observed in the colon enterocytes of DIO mice for GLP-1 reduction. The stress was prevented by BBR in the restoration of GLP-1 expression, in which BBR may act through direct and indirect mechanisms. PMID- 30250194 TI - The proline-arginine repeat protein linked to C9-ALS/FTD causes neuronal toxicity by inhibiting the DEAD-box RNA helicase-mediated ribosome biogenesis. AB - A GGGGCC repeat expansion in the C9ORF72 gene has been identified as the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeat expansion undergoes unconventional translation to produce dipeptide repeat (DPR) proteins. Although it has been reported that DPR proteins cause neurotoxicity, the underlying mechanism has not been fully elucidated. In this study, we have first confirmed that proline-arginine repeat protein (poly PR) reduces levels of ribosomal RNA and causes neurotoxicity and found that the poly-PR-induced neurotoxicity is repressed by the acceleration of ribosomal RNA synthesis. These results suggest that the poly-PR-induced inhibition of ribosome biogenesis contributes to the poly-PR-induced neurotoxicity. We have further identified DEAD-box RNA helicases as poly-PR-binding proteins, the functions of which are inhibited by poly-PR. The enforced reduction in the expression of DEAD box RNA helicases causes impairment of ribosome biogenesis and neuronal cell death. These results together suggest that poly-PR causes neurotoxicity by inhibiting the DEAD-box RNA helicase-mediated ribosome biogenesis. PMID- 30250195 TI - Phosphoglycerate dehydrogenase inhibition induces p-mTOR-independent autophagy and promotes multilineage differentiation in embryonal carcinoma stem-like cells. AB - Cancer cells with a less differentiated stem-like phenotype are more resistant to therapeutic manipulations than their differentiated counterparts, and are considered as one of the main causes of cancer persistence and relapse. As such, induction of differentiation in cancer stem-like cells (CSLCs) has emerged as an alternative strategy to enhance the efficacy of anticancer therapies. CSLCs are metabolically distinct from differentiated cells, and any aberration from the intrinsic metabolic state can induce differentiation of CSLCs. Therefore, metabolism-related molecular targets, with a capacity to promote differentiation within CSLCs, are of therapeutic importance. Here, we demonstrate that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme catalyzing the synthesis of amino acid serine, is important for maintaining the poorly differentiated, stem-like state of CSLCs. Our data shows that PHGDH deficiency impairs the tumorsphere formation capacity in embryonal carcinoma stem-like cells (ECSLCs), breast cancer stem-like cells (BCSLCs) and patient-derived brain tumor initiating cells (BTICs), which is accompanied by the reduced expression of characteristic stemness-promoting factors, such as Oct4, Nanog, Sox-2, and Bmi-1. Mechanistically, PHGDH deficiency in ECSLCs promotes differentiation to various lineages via degradation of Oct4 and by increasing the stability of differentiation marker beta3-tubulin. Furthermore, PHGDH inhibition promotes p mTOR independent but Beclin-1-dependent autophagy, independent of apoptosis. When studied in combination, the inhibition of both PHGDH and p-mTOR in ECSLCs causes further augmentation of autophagy, and additionally promotes apoptosis, demonstrating the clinical applicability of PHGDH-based manipulations in cancer therapies. Recapitulating these in vitro findings in CSLC models, the intratumoral PHGDH expression in patient-derived tumors is positively correlated with the mRNA levels of stemness factors, especially Oct4, and cancer patients co expressing high levels of PHGDH and Oct4 display significantly lower survival than those with low PHGDH/Oct4 co-expression. Altogether, this study identifies a clinically-relevant role for PHGDH in the regulation of stemness-differentiation axis within CSLCs. PMID- 30250196 TI - Author Correction: Direct evidence for microbial-derived soil organic matter formation and its ecophysiological controls. AB - In the originally published version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include support from the NSF Long-term Ecological Research Program (DEB 1637653) at the Kellogg Biological Station and from Michigan State University AgBioResearch. PMID- 30250197 TI - RIPK1 is a critical modulator of both tonic and TLR-responsive inflammatory and cell death pathways in human macrophage differentiation. AB - In this study, we took advantage of human-induced pluripotent stem cells (hiPSC) and CRISPR/Cas9 technology to investigate the potential roles of RIPK1 in regulating hematopoiesis and macrophage differentiation, proinflammatory activation, and cell death pathways. Knock-out of RIPK1 in hiPSCs demonstrated that this protein is not required for erythro-myeloid differentiation. Using a well-established macrophage differentiation protocol, knock-out of RIPK1 did not block the differentiation of iPSC-derived macrophages, which displayed a similar phenotype to WT hiPSC-derived macrophages. However, knock-out of RIPK1 leads to a TNFalpha-dependent apoptotic death of differentiated hiPSC-derived macrophages (iPS-MPhi) and progressive loss of iPS-MPhi production irrespective of external pro-inflammatory stimuli. Live video analysis demonstrated that TLR3/4 activation of RIPK1 KO hiPSC-derived macrophages triggered TRIF and RIPK3-dependent necroptosis irrespective of caspase-8 activation. In contrast, TLR3/4 activation of WT macrophages-induced necroptosis only when caspases were inhibited, confirming the modulating effect of RIPK1 on RIPK3-mediated necroptosis through the FADD, Caspase-8 pathway. Activation of these inflammatory pathways required RIPK3 kinase activity while RIPK1 was dispensable. However, loss of RIPK1 sensitizes macrophages to activate RIPK3 in response to inflammatory stimuli, thereby exacerbating a potentially pathological inflammatory response. Taken together, these results reveal that RIPK1 has an important role in regulating the potent inflammatory pathways in authentic human macrophages that are poised to respond to external stimuli. Consequently, RIPK1 activity might be a valid target in the development of novel therapies for chronic inflammatory diseases. PMID- 30250199 TI - E4BP4 promotes thyroid cancer proliferation by modulating iron homeostasis through repression of hepcidin. AB - Iron homeostasis is critical to mammals, and dysregulation in iron homeostasis usually leads to severe disorders including various cancers. Massive hepcidin secretion is an indicator of thyroid cancer, but the molecular mechanisms responsible for this dysregulation are unknown. Hepcidin secretion from thyroid cancer cells also leads to decreased expression of the iron exporter, ferroportin (FPN), and increased intracellular iron retention, which promote cancer proliferation. In this study, we examined the role of hepcidin in thyroid cancer (TC) and the molecular bases of its signaling. Synthesis of hepcidin is regulated by the BMP4/7 agonist SOSTDC1, which was downregulated in TC; SOSTDC1 downregulation was correlated with G9a-mediated hypermethylation in its promoter. The binding of G9a to the SOSTDC1 promoter requires E4BP4, which interacts with G9a to form a multi-molecular complex that contributes to SOSTDC1 silencing. Silencing of E4BP4 or G9a has similar effects to SOSTDC1 overexpression, which suppresses secretion of hepcidin and inhibits TC cell proliferation. Furthermore, our in vivo xenograft data indicated that depletion of E4BP4 also inhibits cancer growth, reduces hepcidin secretion, and reduces G9a nuclear transportation. Iron homeostasis and tumor growth in TC may be regulated by an E4BP4-dependent epigenetic mechanism. These findings suggest a new mechanism of cellular iron dysfunction through the E4BP4/G9a/SOSTDC1/hepcidin pathway, which is an essential link in TC. PMID- 30250200 TI - Mitochondrial DNA keeps you young. PMID- 30250198 TI - Loperamide, pimozide, and STF-62247 trigger autophagy-dependent cell death in glioblastoma cells. AB - Autophagy is a well-described degradation mechanism that promotes cell survival upon nutrient starvation and other forms of cellular stresses. In addition, there is growing evidence showing that autophagy can exert a lethal function via autophagic cell death (ACD). As ACD has been implicated in apoptosis-resistant glioblastoma (GBM), there is a high medical need for identifying novel ACD inducing drugs. Therefore, we screened a library containing 70 autophagy-inducing compounds to induce ATG5-dependent cell death in human MZ-54 GBM cells. Here, we identified three compounds, i.e. loperamide, pimozide, and STF-62247 that significantly induce cell death in several GBM cell lines compared to CRISPR/Cas9 generated ATG5- or ATG7-deficient cells, pointing to a death-promoting role of autophagy. Further cell death analyses conducted using pharmacological inhibitors revealed that apoptosis, ferroptosis, and necroptosis only play minor roles in loperamide-, pimozide- or STF-62247-induced cell death. Intriguingly, these three compounds induce massive lipidation of the autophagy marker protein LC3B as well as the formation of LC3B puncta, which are characteristic of autophagy. Furthermore, loperamide, pimozide, and STF-62247 enhance the autophagic flux in parental MZ-54 cells, but not in ATG5 or ATG7 knockout (KO) MZ-54 cells. In addition, loperamide- and pimozide-treated cells display a massive formation of autophagosomes and autolysosomes at the ultrastructural level. Finally, stimulation of autophagy by all three compounds is accompanied by dephosphorylation of mammalian target of rapamycin complex 1 (mTORC1), a well known negative regulator of autophagy. In summary, our results indicate that loperamide, pimozide, and STF-62247 induce ATG5- and ATG7-dependent cell death in GBM cells, which is preceded by a massive induction of autophagy. These findings emphasize the lethal function and potential clinical relevance of hyperactivated autophagy in GBM. PMID- 30250202 TI - A room-temperature sodium-sulfur battery with high capacity and stable cycling performance. AB - High-temperature sodium-sulfur batteries operating at 300-350 degrees C have been commercially applied for large-scale energy storage and conversion. However, the safety concerns greatly inhibit their widespread adoption. Herein, we report a room-temperature sodium-sulfur battery with high electrochemical performances and enhanced safety by employing a "cocktail optimized" electrolyte system, containing propylene carbonate and fluoroethylene carbonate as co-solvents, highly concentrated sodium salt, and indium triiodide as an additive. As verified by first-principle calculation and experimental characterization, the fluoroethylene carbonate solvent and high salt concentration not only dramatically reduce the solubility of sodium polysulfides, but also construct a robust solid-electrolyte interface on the sodium anode upon cycling. Indium triiodide as redox mediator simultaneously increases the kinetic transformation of sodium sulfide on the cathode and forms a passivating indium layer on the anode to prevent it from polysulfide corrosion. The as-developed sodium-sulfur batteries deliver high capacity and long cycling stability. PMID- 30250201 TI - Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination. AB - The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anti-cancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM gammaH2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer. PMID- 30250203 TI - GWAS and eQTL analysis identifies a SNP associated with both residual feed intake and GFRA2 expression in beef cattle. AB - Residual feed intake (RFI), a measure of feed efficiency, is an important economic and environmental trait in beef production. Selection of low RFI (feed efficient) cattle could maintain levels of production, while decreasing feed costs and methane emissions. However, RFI is a difficult and expensive trait to measure. Identification of single nucleotide polymorphisms (SNPs) associated with RFI may enable rapid, cost effective genomic selection of feed efficient cattle. Genome-wide association studies (GWAS) were conducted in multiple breeds followed by meta-analysis to identify genetic variants associated with RFI and component traits (average daily gain (ADG) and feed intake (FI)) in Irish beef cattle (n = 1492). Expression quantitative trait loci (eQTL) analysis was conducted to identify functional effects of GWAS-identified variants. Twenty-four SNPs were associated (P < 5 * 10-5) with RFI, ADG or FI. The variant rs43555985 exhibited strongest association for RFI (P = 8.28E-06). An eQTL was identified between this variant and GFRA2 (P = 0.0038) where the allele negatively correlated with RFI was associated with increased GFRA2 expression in liver. GFRA2 influences basal metabolic rates, suggesting a mechanism by which genetic variation may contribute to RFI. This study identified SNPs that may be useful both for genomic selection of RFI and for understanding the biology of feed efficiency. PMID- 30250204 TI - Mapping of histone-binding sites in histone replacement-completed spermatozoa. AB - The majority of histones are replaced by protamines during spermatogenesis, but small amounts are retained in mammalian spermatozoa. Since nucleosomes in spermatozoa influence epigenetic inheritance, it is important to know how histones are distributed in the sperm genome. Conflicting data, which may result from different conditions used for micrococcal nuclease (MNase) digestion, have been reported: retention of nucleosomes at either gene promoter regions or within distal gene-poor regions. Here, we find that the swim-up sperm used in many studies contain about 10% population of sperm which have not yet completed the histone-to-protamine replacement. We develop a method to purify histone replacement-completed sperm (HRCS) and to completely solubilize histones from cross-linked HRCS without MNase digestion. Our results indicate that histones are retained at specific promoter regions in HRCS. This method allows the study of epigenetic status in mature sperm. PMID- 30250205 TI - Circuit quantum electrodynamics of granular aluminum resonators. AB - Granular aluminum (grAl) is a promising high kinetic inductance material for detectors, amplifiers, and qubits. Here we model the grAl structure, consisting of pure aluminum grains separated by thin aluminum oxide barriers, as a network of Josephson junctions, and we calculate the dispersion relation and nonlinearity (self-Kerr and cross-Kerr coefficients). To experimentally study the electrodynamics of grAl thin films, we measure microwave resonators with open boundary conditions and test the theoretical predictions in two limits. For low frequencies, we use standard microwave reflection measurements in a low-loss environment. The measured low-frequency modes are in agreement with our dispersion relation model, and we observe self-Kerr coefficients within an order of magnitude from our calculation starting from the grAl microstructure. Using a high-frequency setup, we measure the plasma frequency of the film around 70 GHz, in agreement with the analytical prediction. PMID- 30250207 TI - Sleep Disturbance and Related Factors in Patients with Nasopharyngeal Carcinoma and Their Family Caregivers Prior to the Initiation of Treatment. AB - Sleep disturbance is a common complaint in cancer patients. However, less is known about the parameters of sleep in patients with nasopharyngeal cancer (NPC) and their family caregivers (FCs) when they are about to begin treatment. We investigated the sleep quality in patients with NPC and their FCs before treatment and determined the related factors that predict sleep disturbance in these patients before therapy. A total of 101 patient-FC dyads were recruited. They completed the Pittsburgh Sleep Quality Index (PSQI) prior to treatment. No differences were found in sleep disturbance between patients (38.6%) and their FCs (31.7%). Patients reported significantly higher rates of short sleep duration than their FCs (P = 0.011). Logistic regression analyses showed that older patients were more prone to suffer from poor sleep quality before treatment (OR = 1.06, 95% CI = 1.01-1.10, P = 0.008), while patients with a higher BMI were less likely to experience sleep disturbance (OR = 0.83, 95% CI = 0.71-0.96, P = 0.012). Sleep disturbance is a significant problem in patients with NPC and their FCs before therapy. Older patients and those with a lower BMI appear to be more inclined to suffer from poor sleep before treatment. PMID- 30250206 TI - Dendritic cell maturation in the corneal epithelium with onset of type 2 diabetes is associated with tumor necrosis factor receptor superfamily member 9. AB - Type 2 diabetes mellitus is characterized by a low-grade inflammation; however, mechanisms leading to this inflammation in specific tissues are not well understood. The eye can be affected by diabetes; thus, we hypothesized that inflammatory changes in the eye may parallel the inflammation that develops with diabetes. Here, we developed a non-invasive means to monitor the status of inflammatory dendritic cell (DC) subsets in the corneal epithelium as a potential biomarker for the onset of inflammation in type 2 diabetes. In an age-matched cohort of 81 individuals with normal and impaired glucose tolerance and type 2 diabetes, DCs were quantified from wide-area maps of the corneal epithelial sub basal plexus, obtained using clinical in vivo confocal microscopy (IVCM). With the onset of diabetes, the proportion of mature, antigen-presenting DCs increased and became organized in clusters. Out of 92 plasma proteins analysed in the cohort, tumor necrosis factor receptor super family member 9 (TNFRSF9) was associated with the observed maturation of DCs from an immature to mature antigen presenting phenotype. A low-grade ocular surface inflammation observed in this study, where resident immature dendritic cells are transformed into mature antigen-presenting cells in the corneal epithelium, is a process putatively associated with TNFRSF9 signalling and may occur early in the development of type 2 diabetes. IVCM enables this process to be monitored non-invasively in the eye. PMID- 30250208 TI - Maternal gut and breast milk microbiota affect infant gut antibiotic resistome and mobile genetic elements. AB - The infant gut microbiota has a high abundance of antibiotic resistance genes (ARGs) compared to adults, even in the absence of antibiotic exposure. Here we study potential sources of infant gut ARGs by performing metagenomic sequencing of breast milk, as well as infant and maternal gut microbiomes. We find that fecal ARG and mobile genetic element (MGE) profiles of infants are more similar to those of their own mothers than to those of unrelated mothers. MGEs in mothers' breast milk are also shared with their own infants. Termination of breastfeeding and intrapartum antibiotic prophylaxis of mothers, which have the potential to affect microbial community composition, are associated with higher abundances of specific ARGs, the composition of which is largely shaped by bacterial phylogeny in the infant gut. Our results suggest that infants inherit the legacy of past antibiotic consumption of their mothers via transmission of genes, but microbiota composition still strongly impacts the overall resistance load. PMID- 30250209 TI - Direct electric field imaging of graphene defects. AB - Material properties are sensitive to atomistic structure defects such as vacancies or impurities, and it is therefore important to determine not only the local atomic configuration but also their chemical bonding state. Annular dark field scanning transmission electron microscopy (STEM) combined with electron energy-loss spectroscopy has been utilized to investigate the local electronic structures of such defects down to the level of single atoms. However, it is still challenging to two-dimensionally map the local bonding states, because the electronic fine-structure signal from a single atom is extremely weak. Here, we show that atomic-resolution differential phase-contrast STEM imaging can directly visualize the anisotropy of single Si atomic electric fields in monolayer graphene. We also visualize the atomic electric fields of Stone-Wales defects and nanopores in graphene. Our results open the way to directly examine the local chemistry of the defective structures in materials at atomistic dimensions. PMID- 30250210 TI - Enhanced Prediction of Hot Spots at Protein-Protein Interfaces Using Extreme Gradient Boosting. AB - Identification of hot spots, a small portion of protein-protein interface residues that contribute the majority of the binding free energy, can provide crucial information for understanding the function of proteins and studying their interactions. Based on our previous method (PredHS), we propose a new computational approach, PredHS2, that can further improve the accuracy of predicting hot spots at protein-protein interfaces. Firstly we build a new training dataset of 313 alanine-mutated interface residues extracted from 34 protein complexes. Then we generate a wide variety of 600 sequence, structure, exposure and energy features, together with Euclidean and Voronoi neighborhood properties. To remove redundant and irrelevant information, we select a set of 26 optimal features utilizing a two-step feature selection method, which consist of a minimum Redundancy Maximum Relevance (mRMR) procedure and a sequential forward selection process. Based on the selected 26 features, we use Extreme Gradient Boosting (XGBoost) to build our prediction model. Performance of our PredHS2 approach outperforms other machine learning algorithms and other state-of-the-art hot spot prediction methods on the training dataset and the independent test set (BID) respectively. Several novel features, such as solvent exposure characteristics, second structure features and disorder scores, are found to be more effective in discriminating hot spots. Moreover, the update of the training dataset and the new feature selection and classification algorithms play a vital role in improving the prediction quality. PMID- 30250211 TI - Neuronal MAP kinase p38alpha inhibits c-Jun N-terminal kinase to modulate anxiety related behaviour. AB - Modulation of behavioural responses by neuronal signalling pathways remains incompletely understood. Signalling via mitogen-activated protein (MAP) kinase cascades regulates multiple neuronal functions. Here, we show that neuronal p38alpha, a MAP kinase of the p38 kinase family, has a critical and specific role in modulating anxiety-related behaviour in mice. Neuron-specific p38alpha knockout mice show increased levels of anxiety in behaviour tests, yet no other behavioural, cognitive or motor deficits. Using CRISPR-mediated deletion of p38alpha in cells, we show that p38alpha inhibits c-Jun N-terminal kinase (JNK) activity, a function that is specific to p38alpha over other p38 kinases. Consistently, brains of neuron-specific p38alpha-knockout mice show increased JNK activity. Inhibiting JNK using a specific blood-brain barrier-permeable inhibitor reduces JNK activity in brains of p38alpha-knockout mice to physiological levels and reverts anxiety behaviour. Thus, our results suggest that neuronal p38alpha negatively regulates JNK activity that is required for specific modulation of anxiety-related behaviour. PMID- 30250212 TI - Biallelic mutations in FDXR cause neurodegeneration associated with inflammation. AB - Mitochondrial dysfunction lies behind many neurodegenerative disorders, owing largely to the intense energy requirements of most neurons. Such mitochondrial dysfunction may work through a variety of mechanisms, from direct disruption of the electron transport chain to abnormal mitochondrial biogenesis. Recently, we have identified biallelic mutations in the mitochondrial flavoprotein "ferredoxin reductase" (FDXR) gene as a novel cause of mitochondriopathy, peripheral neuropathy, and optic atrophy. In this report, we expand upon those results by describing two new cases of disease-causing FDXR variants in patients with variable severity of phenotypes, including evidence of an inflammatory response in brain autopsy. To investigate the underlying pathogenesis, we examined neurodegeneration in a mouse model. We found that Fdxr mutant mouse brain tissues share pathological changes similar to those seen in patient autopsy material, including increased astrocytes. Furthermore, we show that these abnormalities are associated with increased levels of markers for both neurodegeneration and gliosis, with the latter implying inflammation as a major factor in the pathology of Fdxr mutations. These data provide further insight into the pathogenic mechanism of FDXR-mediated central neuropathy, and suggest an avenue for mechanistic studies that will ultimately inform treatment. PMID- 30250215 TI - Why patients receive treatments that are minimally effective? PMID- 30250213 TI - Occurrence of cagA+ vacA s1a m1 i1 Helicobacter pylori in farm animals in Egypt and ability to survive in experimentally contaminated UHT milk. AB - Cases of human gastric cancer due to Helicobacter pylori have been reported worldwide and animals might act as a reservoir of infection in certain circumstances. The recent few decades showed a rapid decline in the incidence of gastric cancer, which was mainly due to the decrease in H. pylori infection. The aims of the present study were to determine the prevalence of H. pylori among livestock and investigate whether the animal isolates can be transmitted through contaminated milk causing gastric infection. Feces and milk samples were collected from apparently healthy cows, buffaloes, and sheep, and were examined by nested PCR and genotyping. The PCR positive samples were further subjected to bacterial culture followed by partial 16s sequencing of the isolates. Twenty-nine percent of the animals showed the presence of H. pylori, mainly the virulent cagA+vacA+s1a m1 i1 genotype, which is known to be associated with serious diseases in humans. The spiral viable culturable form (SVCF) of this strain was inoculated into UHT (ultra-high temperature) milk and remained viable for up to 10 days at 4 degrees C. Increasing period of storage and or temperature led to a decrease in the number of the SVCF and occurrence of the coccoid viable non culturable form (CVNCF). The infectivity of the survived forms was determined by feeding healthy groups of laboratory mice with the contaminated UHT milk containing SVCF or CVNCF for 40 days. The gastric mucosa of the two mice groups showed similar levels of H. pylori load. This highlights that H. pylori can persist in contaminated milk by entering a non-culturable state, which can induce gastric infection. PMID- 30250214 TI - Noise-robust quantum sensing via optimal multi-probe spectroscopy. AB - The dynamics of quantum systems are unavoidably influenced by their environment, but in turn observing a quantum system (probe) can allow one to measure its environment: Measurements and controlled manipulation of the probe such as dynamical decoupling sequences as an extension of the Ramsey interference measurement allow to spectrally resolve a noise field coupled to the probe. Here, we introduce fast and robust estimation strategies for the characterization of the spectral properties of classical and quantum dephasing environments. These strategies are based on filter function orthogonalization, optimal control filters maximizing the relevant Fisher Information and multi-qubit entanglement. We investigate and quantify the robustness of the schemes under different types of noise such as finite-precision measurements, dephasing of the probe, spectral leakage and slow temporal fluctuations of the spectrum. PMID- 30250216 TI - Pleomorphic xanthoastrocytomas of adults: MRI features, molecular markers, and clinical outcomes. AB - Fifty adult patients with pathologically-confirmed pleomorphic xanthoastrocytomas (PXAs) were retrospectively analyzed. Adult PXAs appeared as a single lesion in 47 patients and multiple lesions in 3 patients. Temporal lobe was the most common location (17/50). Twenty-two cases were superficial with obvious meningeal contact and 9 were closely adjacent to lateral ventricles. Three imaging patterns were differentiated, including a predominantly solid mass with or without cystic changes (n = 33), a predominantly cystic mass with an obvious mural nodule (n = 14), and a predominantly cystic mass with an uneven wall thickness (n = 3). The mean tumoral apparent diffusion coefficient (ADC) was 0.83 +/- 0.17 * 10-3 mm2/s, and the mean ADC ratio was 1.02 +/- 0.22. The V-raf murine sarcoma viral oncogenes homolog B1 (BRAF)V600E mutation was found in 12 of 29 patients. In 36 patients with isocitrate dehydrogenases 1 and 2 (IDH1/2) data, only one had IDH1 mutation and no patient had IDH2 mutation. Anaplastic features were common (24/50) and significantly associated with high rates of recurrence or progression (P < 0.001). In conclusion, this study expands our knowledge on the MRI features, molecular markers, and clinical outcomes of adult PXAs, to some extent different from pediatric PXAs. PMID- 30250217 TI - Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants. AB - PURPOSE: Genetic testing in pediatric cholestasis can be very informative but genetic causes have not been fully characterized. METHODS: Exome sequencing and positional mapping in seven families with cholestatic liver disease and negative clinical testing for known disease genes. RESULTS: KIF12, which encodes a microtubule motor protein with a tentative role in cell polarity, was found to harbor three homozygous likely deleterious variants in three families with sclerosing cholangitis. KIF12 expression is dependent on HNF-1beta, deficiency which is known to cause bile duct dysmorphogenesis associated with loss of KIF12 expression. In another extended family, we mapped an apparently novel syndrome of sclerosing cholangitis, short stature, hypothyroidism, and abnormal tongue pigmentation in two cousins to a homozygous variant in PPM1F (POPX2), a regulator of kinesin-mediated ciliary transport. In the fifth family, a syndrome of normal gamma glutamyltransferase (GGT) cholestasis and hearing loss was found to segregate with a homozygous truncating variant in USP53, which encodes an interactor with TJP2. In the sixth family, we mapped a novel syndrome of transient neonatal cholestasis, intellectual disability, and short stature to a homozygous variant in LSR, an important regulator of liver development. In the last family of three affected siblings, a novel syndrome of intractable itching, hypercholanemia, short stature, and intellectual disability was mapped to a single locus that contains a homozygous truncating variant in WDR83OS (C19orf56), known to interact with ATP13A2 and BSEP. CONCLUSION: Our results expand the genetic heterogeneity of pediatric cholestatic liver disease and highlight the vulnerability of bile homeostasis to a wide range of molecular perturbations. PMID- 30250218 TI - Flexible Learning-Free Segmentation and Reconstruction of Neural Volumes. AB - Imaging is a dominant strategy for data collection in neuroscience, yielding stacks of images that often scale to gigabytes of data for a single experiment. Machine learning algorithms from computer vision can serve as a pair of virtual eyes that tirelessly processes these images, automatically detecting and identifying microstructures. Unlike learning methods, our Flexible Learning-free Reconstruction of Imaged Neural volumes (FLoRIN) pipeline exploits structure specific contextual clues and requires no training. This approach generalizes across different modalities, including serially-sectioned scanning electron microscopy (sSEM) of genetically labeled and contrast enhanced processes, spectral confocal reflectance (SCoRe) microscopy, and high-energy synchrotron X ray microtomography (MUCT) of large tissue volumes. We deploy the FLoRIN pipeline on newly published and novel mouse datasets, demonstrating the high biological fidelity of the pipeline's reconstructions. FLoRIN reconstructions are of sufficient quality for preliminary biological study, for example examining the distribution and morphology of cells or extracting single axons from functional data. Compared to existing supervised learning methods, FLoRIN is one to two orders of magnitude faster and produces high-quality reconstructions that are tolerant to noise and artifacts, as is shown qualitatively and quantitatively. PMID- 30250219 TI - POFUT1 promotes colorectal cancer development through the activation of Notch1 signaling. AB - Copy number variations (CNVs) are key drivers of colorectal cancer (CRC). Our previous studies revealed that protein O-fucosyltransferase 1 (POFUT1) overexpression is driven by CNVs during CRC development. The potential role and underlying mechanisms of POFUT1 in CRC were not investigated. In this study, we analyzed the expression of POFUT1 in CRC from cosmic and TCGA databases and confirmed that POFUT1 is highly expressed in CRC. We used well characterized CRC cell lines, including SW620 and HCT116 to establish a model POFUT1 knockdown cell line. Using these cells, we investigated the role of POFUT1 in CRC. Our data revealed that silencing POFUT1 in CRC cells inhibits cell proliferation, decreases cell invasion and migration, arrests cell cycle progression, and stimulates CRC cell apoptosis in vitro. We further demonstrate that POFUT1 silencing dramatically suppresses CRC tumor growth and transplantation in vivo. We additionally reveal new mechanistic insights into the role of POFUT1 during CRC, through demonstrating that POFUT1 silencing inhibits Notch1 signaling. Taken together, our findings demonstrate that POFUT1 is a tumor activating gene during CRC development, which positively regulates CRC tumor progression through activating Notch1. PMID- 30250220 TI - Unscrambling phylogenetic effects and ecological determinants of chromosome number in major angiosperm clades. AB - As variations in the chromosome number are recognized to be of evolutionary interest but are also widely debated in the literature, we aimed to quantitatively test for possible relationships among the chromosome number, plant traits, and environmental factors. In particular, the chromosome number and drivers of its variation were examined in 801 Italian endemic vascular plants, for a total of 1364 accessions. We estimated phylogenetic inertia and adaptation in chromosome number - based on an Ornstein-Uhlenbeck process - and related chromosome numbers with other plant traits and environmental variables. Phylogenetic effects in chromosome number varied among the examined clades but were generally high. Chromosome numbers were poorly related to large scale climatic conditions, while a stronger relationship with categorical variables was found. Specifically, open, disturbed, drought-prone habitats selected for low chromosome numbers, while perennial herbs, living in shaded, stable environments were associated with high chromosome numbers. Altogether, our findings support an evolutionary role of chromosome number variation, and we argue that environmental stability favours higher recombination rates in comparison to unstable environments. In addition, by comparing the results of models testing for the evolvability of 2n and of x, we provide insight into the presumptive ecological significance of polyploidy. PMID- 30250221 TI - The modification and characterization of thermal-treated sericite by fluorosilicate. AB - In this article, the thermal-treated sericite was modified by both fluorosilicate and the combination of fluorosilicate and nitric acid in order to reduce its layer charge and gain cation exchange capabilities for the preparation of sericite/polymer nanocomposites. After several orthogonal experiments and single factor experiments, the optimal experimental conditions were set up and we found that the combination of nitric acid and fluorosilicate is much more effective than fluorosilicate alone. Chemical composition analysis showed Al3+ was dissolved out from sericite and the dissolving amount is 65 mg/g under optimal experimental conditions. Combining the NMR test, it is considered that the Si/Al ratio in the tetrasheet of the modified product increased from 3.48 to 10. The layer charge reduced and the CEC value increased after fluorosilicate modification, which means the modified sericite is a promising matrix for clay polymer nanocomposites. PMID- 30250222 TI - Circulating microRNAs -192 and -194 are associated with the presence and incidence of diabetes mellitus. AB - We sought to identify circulating microRNAs as biomarkers of prevalent or incident diabetes. In a pilot study of 18 sex- and age-matched patients with metabolic syndrome, nine of whom developed diabetes during 6 years of follow-up, an array of 372 microRNAs discovered significantly elevated serum levels of microRNAs -122, -192, -194, and -215 in patients who developed diabetes mellitus type 2 (T2DM). In two cross-sectional validation studies, one encompassing sex- and age-matched groups of patients with T2DM, impaired fasting glucose (IFG) and euglycemic controls (n = 43 each) and the other 53 patients with type 1 diabetes and 54 age- and BMI-matched euglycemic controls, serum levels of miR-192, miR 194, and mi215 were significantly higher in diabetic subjects than in probands with euglycemia or IFG. In a longitudinal study of 213 initially diabetes-free patients of whom 35 developed diabetes during 6 years of follow-up, elevated serum levels of microRNAs 192 and 194 were associated with incident T2DM, independently of fasting glucose, HbA1c and other risk factors. Serum levels of miR-192 and miR-194 were also elevated in diabetic Akt2 knockout mice compared to wild type mice. In conclusion, circulating microRNAs -192 and -194 are potential biomarkers for risk of diabetes. PMID- 30250223 TI - Enantiomeric Abeta peptides inhibit the fluid shear stress response of PIEZO1. AB - Traumatic brain injury (TBI) elevates Abeta (Abeta) peptides in the brain and cerebral spinal fluid. Abeta peptides are amphipathic molecules that can modulate membrane mechanics. Because the mechanosensitive cation channel PIEZO1 is gated by membrane tension and curvature, it prompted us to test the effects of Abeta on PIEZO1. Using precision fluid shear stress as a stimulus, we found that Abeta monomers inhibit PIEZO1 at femtomolar to picomolar concentrations. The Abeta oligomers proved much less potent. The effect of Abetas on Piezo gating did not involve peptide-protein interactions since the D and L enantiomers had similar effects. Incubating a fluorescent derivative of Abeta and a fluorescently tagged PIEZO1, we showed that Abeta can colocalize with PIEZO1, suggesting that they both had an affinity for particular regions of the bilayer. To better understand the PIEZO1 inhibitory effects of Abeta, we examined their effect on wound healing. We observed that over-expression of PIEZO1 in HEK293 cells increased cell migration velocity ~10-fold, and both enantiomeric Abeta peptides and GsMTx4 independently inhibited migration, demonstrating involvement of PIEZO1 in cell motility. As part of the motility study we examined the correlation of PIEZO1 function with tension in the cytoskeleton using a genetically encoded fluorescent stress probe. Abeta peptides increased resting stress in F-actin, and is correlated with Abeta block of PIEZO1-mediated Ca2+ influx. Abeta inhibition of PIEZO1 in the absence of stereospecific peptide-protein interactions shows that Abeta peptides modulate both cell membrane and cytoskeletal mechanics to control PIEZO1-triggered Ca2+ influx. PMID- 30250225 TI - A tethered-inchworm model of SMC DNA translocation. AB - The DNA loop extrusion model is a provocative new concept explaining the formation of chromatin loops that revolutionizes understanding of genome organization. Central to this model is the structural maintenance of chromosomes (SMC) protein family, which is now thought to function as a DNA motor. In this Perspective, we review and reinterpret the current knowledge of SMC structure and function and propose a novel mechanism for SMC motor activity. PMID- 30250224 TI - High PGAM5 expression induces chemoresistance by enhancing Bcl-xL-mediated anti apoptotic signaling and predicts poor prognosis in hepatocellular carcinoma patients. AB - Hepatocellular carcinoma (HCC) is the one of most common and deadly cancers, and is also highly resistant to conventional chemotherapy treatments. Mitochondrial phosphoglycerate mutase/protein phosphatase (PGAM5) regulates mitochondrial homeostasis and cell death, however, little is known about its roles in cancer. The aim of this study was to explore the clinical significance and potential biological functions of PGAM5 in hepatocellular carcinoma. For the first time, our results show that PGAM5 is significantly upregulated in HCC compared with corresponding adjacent noncancerous hepatic tissues and high PGAM5 expression is an independent predictor of reduced survival times in both univariate and multivariate analyses. Additionally, in vivo and in vitro studies showed that depleting PGAM5 expression inhibited tumor growth and increased the 5 fluorouracil sensitivity of HCC cells. Conversely, restoring PGAM5 expression in PGAM5-knockdown cells dramatically enhanced HCC cell resistance to 5 fluorouracil. Importantly, we demonstrated that the mechanism of 5-fluorouracil resistance conferred to HCC cells by PGAM5 was via inhibiting BAX- and cytochrome C-mediated apoptotic signaling by interacting and stabilizing Bcl-xL. Consistently, in the same cohorts of HCC patient tissues, Bcl-xL expression was positively correlated with PGAM5, and together predicted poor prognoses. In Conclusion, Our data highlight the molecular etiology and clinical significance of PGAM5 in HCC. Targeting the novel signaling pathway mediated by PGAM5/Bcl-xL may represent a new therapeutic strategy to improve the survival outcomes of HCC patients. PMID- 30250227 TI - Kinematic evaluation of thoracic spinal cord sagittal diameter and the space available for cord using weight-bearing kinematic magnetic resonance imaging. AB - STUDY DESIGN: Retrospective kinematic MRI (kMRI) study. OBJECTIVE: To evaluate the dynamic changes of thoracic anterior and posterior space available for cord (SAC), and thoracic spinal cord in the dural sac in three positions. SETTING: Expert MRI, Bellflower California; and University of Southern California, in Los Angeles, USA. METHODS: A total of 118 patients (66 males and 52 females, mean age ( +/- SD) of 45.6 +/- 10.6 years) who underwent thoracic spine kMRI were evaluated from T4-5 to T11-12 in flexion, neutral, and extension positions. The anterior SAC, posterior SAC, and mid-sagittal thoracic cord diameter were measured at each level from T4-5 to T11-12. Inter- and intraobserver agreements were analyzed. RESULTS: The anterior SAC was significantly narrower in flexion position compared with other positions at T8-9 to T11-12 levels (p < 0.01). The T8-9 level had significantly wider posterior SAC in flexion and extension positions compared with the neutral position (p < 0.005). However, the posterior SAC at T9-10 was narrower in extension than the neutral position (p = 0.002). Thoracic spinal cord diameter significantly increased in flexion position when compared with the neutral position at T8-9, T9-10, and T11-12 levels (p < 0.005). CONCLUSIONS: Thoracic spinal cord had dynamic changes with positions. In flexion position, the thoracic cord at T8-9 and below tended to move anteriorly, getting closer to the vertebral body and intervertebral disc. The mid-sagittal diameter of the thoracic cord increased in flexion position at the levels below T8-9. In the presence of lesions in anterior epidural space, the risk of spinal cord compression is higher in flexion position, especially at levels below T8-9. PMID- 30250226 TI - Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration. AB - During liver regeneration, most new hepatocytes arise via self-duplication; yet, the underlying mechanisms that drive hepatocyte proliferation following injury remain poorly defined. By combining high-resolution transcriptome and polysome profiling of hepatocytes purified from quiescent and toxin-injured mouse livers, we uncover pervasive alterations in messenger RNA translation of metabolic and RNA-processing factors, which modulate the protein levels of a set of splicing regulators. Specifically, downregulation of the splicing regulator ESRP2 activates a neonatal alternative splicing program that rewires the Hippo signaling pathway in regenerating hepatocytes. We show that production of neonatal splice isoforms attenuates Hippo signaling, enables greater transcriptional activation of downstream target genes, and facilitates liver regeneration. We further demonstrate that ESRP2 deletion in mice causes excessive hepatocyte proliferation upon injury, whereas forced expression of ESRP2 inhibits proliferation by suppressing the expression of neonatal Hippo pathway isoforms. Thus, our findings reveal an alternative splicing axis that supports regeneration following chronic liver injury. PMID- 30250228 TI - Dot-Matrix Hologram Rendering Algorithm and its Validation through Direct Laser Interference Patterning. AB - The fight against forgery of valuable items demands efficient and reasonably priced solutions. A security tag featuring holographic elements for anti counterfeiting is one of them. However, the content and colours of a diffraction image that would be seen by an observer are often counterintuitive in the design stage. Here, we propose an original algorithm based on the conical diffraction formalism, which can be used to describe the variations of a diffraction image with respect to all aspects of observation. We validate the output of the algorithm by comparing it to test holograms, which we have produced by employing direct laser interference patterning (DLIP) in electrochemically grown nickel foil. We have employed a motorized femtosecond laser system to micro-machine arrays of 65 um * 65 um sized diffraction gratings with a defined orientation and pitch on the order of 1 um. Based on completed diffraction efficiency measurements, we determined optimal ablation parameters, i.e. 57.4 mJ/cm2 fluence per pulse and 1100 pulses/pixel. Furthermore, we show how accurate the proposed algorithm is through measured diffraction spectra as well as captured diffraction images of test holograms produced using the obtained parameters. Finally, we showcase anti-counterfeiting tag prototypes with complex holographic effects, i.e. colour reconstruction, animation effects, and image multiplexing. The proposed algorithm can severely shorten the time between design and production of a holographic tag, especially when realizing it via a competitive origination technology-DLIP. PMID- 30250229 TI - Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA. AB - Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments. PMID- 30250230 TI - Visual salience of the stop signal affects the neuronal dynamics of controlled inhibition. AB - The voluntary control of movement is often tested by using the countermanding, or stop-signal task that sporadically requires the suppression of a movement in response to an incoming stop-signal. Neurophysiological recordings in monkeys engaged in the countermanding task have shown that dorsal premotor cortex (PMd) is implicated in movement control. An open question is whether and how the perceptual demands inherent the stop-signal affects inhibitory performance and their underlying neuronal correlates. To this aim we recorded multi-unit activity (MUA) from the PMd of two male monkeys performing a countermanding task in which the salience of the stop-signals was modulated. Consistently to what has been observed in humans, we found that less salient stimuli worsened the inhibitory performance. At the neuronal level, these behavioral results were subtended by the following modulations: when the stop-signal was not noticeable compared to the salient condition the preparatory neuronal activity in PMd started to be affected later and with a less sharp dynamic. This neuronal pattern is probably the consequence of a less efficient inhibitory command useful to interrupt the neural dynamic that supports movement generation in PMd. PMID- 30250231 TI - PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes. AB - Glucagon-mediated gene transcription in the liver is critical for maintaining glucose homeostasis. Promoting the induction of gluconeogenic genes and blocking that of insulin receptor substrate (Irs)2 in hepatocytes contributes to the pathogenesis of type 2 diabetes. However, the molecular mechanism by which glucagon signalling regulates hepatocyte metabolism is not fully understood. We previously showed that a fasting-inducible signalling module consisting of general control non-repressed protein 5, co-regulator cAMP response element binding protein binding protein/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2, and protein kinase A is required for glucagon-induced transcription of gluconeogenic genes. The present study aimed to identify the downstream effectors of this module in hepatocytes by examining glucagon-induced potential target genes. One of these genes was prolyl hydroxylase domain (PHD)3, which suppressed stress signalling through inhibition of the IkappaB kinase nuclear factor-kappaB pathway in a proline hydroxylase-independent manner to maintain insulin signalling. PHD3 was also required for peroxisome proliferator activated receptor gamma coactivator 1alpha-induced gluconeogenesis, which was dependent on proline hydroxylase activity, suggesting that PHD3 regulates metabolism in response to glucagon as well as insulin. These findings demonstrate that glucagon-inducible PHD3 regulates glucose metabolism by suppressing stress signalling and optimising gluconeogenesis and insulin signalling in hepatocytes. PMID- 30250233 TI - Double-passage ground-state cooling induced by quantum interference in the hybrid optomechanical system. AB - We propose a quantum interference cooling scheme for a nano-mechanical resonator (NAMR) in a hybrid optomechanical system. In our scheme, atoms are trapped in an optomechanical cavity, and this optomechanical cavity interacts both atoms and an optical cavity. Therefore, the absorption of the optomechanical resonator can be modified by quantum interference effects induced by the atom-cavity and cavity cavity couplings. With the modification of the quantum interference, the desired transition for cooling is enhanced, while the undesired transition for heating can be suppressed. As a result, the NAMR vibration can be cooled down to its ground state. Particularly, with the assistance of the atoms, the experimental difficulty can be reduced since the effective decay rate of the cavity can be decreased via the quantum interference for the atom-cavity coupling. PMID- 30250232 TI - Detection and characterization of bacterial nucleic acids in culture-negative synovial tissue and fluid samples from rheumatoid arthritis or osteoarthritis patients. AB - Human intestinal microbes can mediate development of arthritis - Studies indicate that certain bacterial nucleic acids may exist in synovial fluid (SF) and could be involved in arthritis, although the underlying mechanism remains unclear. To characterize potential SF bacterial nucleic acids, we used 16S rRNA gene amplicon sequencing to assess bacterial nucleic acid communities in 15 synovial tissue (ST) and 110 SF samples from 125 patients with rheumatoid arthritis (RA) and 16 ST and 42 SF samples from 58 patients with osteoarthritis (OA). Our results showed an abundant diversity of bacterial nucleic acids in these clinical samples, including presence of Porphyromonas and Bacteroides in all 183 samples. Agrobacterium, Comamonas, Kocuria, Meiothermus, and Rhodoplanes were more abundant in synovial tissues of rheumatoid arthritis (STRA). Atopobium, Phascolarctobacterium, Rhodotorula mucilaginosa, Bacteroides uniformis, Rothia, Megasphaera, Turicibacter, Leptotrichia, Haemophilus parainfluenzae, Bacteroides fragilis, Porphyromonas, and Streptococcus were more abundant in synovial tissues of osteoarthritis (STOA). Veillonella dispar, Haemophilus parainfluenzae, Prevotella copri and Treponema amylovorum were more abundant in synovial fluid of rheumatoid arthritis (SFRA), while Bacteroides caccae was more abundant in the synovial fluid of osteoarthritis (SFOA). Overall, this study confirms existence of bacterial nucleic acids in SF and ST samples of RA and OA lesions and reveals potential correlations with degree of disease. PMID- 30250235 TI - Eye and appearance characteristics of encephalocraniocutaneous lipomatosis. PMID- 30250234 TI - Nod2 Deficiency in mice is Associated with Microbiota Variation Favouring the Expansion of mucosal CD4+ LAP+ Regulatory Cells. AB - Nucleotide-binding Oligomerization Domain-2 (NOD2) mutations are associated with an increased risk to develop Crohn's Disease. In previous studies, we have shown that Nod2-/- mice manifest increased proportion of Lamina Propria (LP) CD4+ LAP+ Foxp3- regulatory cells, when compared with Nod2+/+ mice, while CD4+ Foxp3 + regulatory cells were not affected. Here, we investigated the Nod2 gut microbiota, by 16S rRNA pyrosequencing, at steady state and after TNBS-colitis induction in mice reared separately or in cohousing, correlating the microbial profiles with LP regulatory T cells proportion and tissue cytokines content. We found that enrichment of Rikenella and Alistipes (Rikenellaceae) in Nod2-/- mice at 8 weeks of age reared separately was associated with increased proportion of CD4+ LAP+ Foxp3- cells and less severe TNBS-colitis. In co-housed mice the acquisition of Rickenellaceae by Nod2+/+ mice was associated with increased CD4+ LAP+ Foxp3- proportion and less severe colitis. Severe colitis was associated with enrichment of gram-negative pathobionts (Escherichia and Enterococcus), while less severe colitis with protective bacteria (Barnesiella, Odoribacter and Clostridium IV). Environmental factors acting on genetic background with different outcomes according to their impact on microbiota, predispose in different ways to inflammation. These results open a new scenario for therapeutic attempt to re-establish eubiosis in Inflammatory Bowel Disease patients with NOD2 polymorphisms. PMID- 30250236 TI - Localised corneal haze and scarring following pulsed accelerated collagen cross linking for keratoconus. PMID- 30250237 TI - Optical coherence tomography angiography features of choroidal neovascularization secondary to angioid streaks. AB - PURPOSE: To characterize the features of choroidal neovascularization (CNV) secondary to angioid streaks (AS) with optical coherence tomography angiography (OCT-A) and to assess its sensitivity in CNV detection in this particular context. METHODS: Consecutive patients, both with treatment-naive and recurrent CNV associated with angioid streaks were prospectively analyzed. All patients underwent macular imaging by fluorescein angiography (FA), indocyanine green angiography (ICGA), spectral-domain (SD)-OCT, and OCT-A (AngioVue, Optovue, Optovue Inc., Freemont, CA, USA). OCT-A detection rate of CNV associated to AS was evaluated by two independent observers. We studied the association between OCT-A feature and either exudative or active status using Fisher exact test. RESULTS: A total of 32 eyes of 18 consecutive patients were included in the analysis. OCT-A was able to detect CNV associated with angioid streaks in 87.5 % (28/32) eyes. OCT-A phenotypes of CNV were classified into interlacing pattern in 9 eyes, pruned vascular tree pattern in 7 eyes, and combined pattern in 12 eyes (Interuser agreement: 0.871 +/- 0.071). CNV were not detectable in 4/32 eyes. There was a statistically significant association between the presence in OCT-A of densely ramified networks with both previous treatment status in the last 6 months (p < 0.001) and with exudative signs on SD-OCT (p = 0.014). CONCLUSION: OCT-A appears as a sensitive tool for detection of CNV secondary to AS. The interlacing pattern was significantly associated with active and exudative features. PMID- 30250239 TI - Perceived weight discrimination and risk of incident dementia. AB - Body mass index (BMI) and obesity have a complex relation with risk of dementia that evolves over the lifespan. Research in other domains indicates that the social experience of body weight, not just BMI, is associated with worse health outcomes. The present research uses data from the Health and Retirement Study (N = 12,053) to test whether weight discrimination is associated with increased risk of dementia over an up to 10-year follow-up independent of BMI and other relevant clinical and behavioral risk factors. Participants who reported weight discrimination had a 40% increased risk of incident dementia (Hazard Ratio = 1.40; 95% Confidence Interval = 1.12-1.74), controlling for age, sex, race, ethnicity, and education. The association between weight discrimination and incident dementia held controlling for BMI, diabetes, hypertension, depressive symptoms, smoking, physical activity, and genetic risk status. The present research indicates that the stigma associated with weight is associated with dementia risk independent from obesity. This research highlights that the detrimental effect of obesity on cognitive health in older adulthood may occur through the adverse social experience of body weight in addition to the biological consequences of excess weight. PMID- 30250238 TI - Human hepatic 3D spheroids as a model for steatosis and insulin resistance. AB - Non-alcoholic fatty liver disease (NAFLD) has emerged as a public health concern as reflected in its widespread distribution in the general population. Yet, treatment options are scarce which is at least in part due to lack of reliable human in vitro disease models. Here, we report a human hepatic 3D spheroid system cultured under defined chemical conditions that has the potential to mimic steatotic conditions in a reversible manner, useful for identification of novel drug treatment conditions. Primary human hepatocytes (PHH) from different donors were cultured as spheroid microtissues in physiological in vivo -like culture conditions. Hepatic steatosis was induced over the course of three weeks in culture by supplementing the culture medium with pathophysiological concentrations of free fatty acids, carbohydrates and insulin. Effects of steatosis in the 3D system were evaluated on transcriptional, metabolomic and lipidomic levels. Free fatty acids on one hand as well as a combination of insulin and monosaccharides, promoted lipid accumulation in hepatocytes and increased expression of lipogenic genes, such as fatty acid synthase. This milieu also promoted development of insulin resistance within 2 weeks as manifested by an increase in gluconeogenic and insulin resistance markers, which are observed in type 2 diabetes mellitus and metabolic syndrome. Induced steatosis was reversible after withdrawal of lipogenic substrates and a further reduction in cellular fat content was observed following treatment with different antisteatotic compounds, such as metformin, glucagon, olaparib and antioxidants. Taken together, these results demonstrate that the 3D hepatic spheroids can serve as a valuable, HTS compatible model for the study of liver steatosis and facilitate translational discovery of novel drug targets. PMID- 30250240 TI - Subjective age and adiposity: evidence from five samples. AB - Obesity is a significant public health issue with increasing prevalence among middle-aged and older adults. The present study tested whether subjective age, that is how old or young individuals perceive themselves to be, is related to both BMI and waist circumference in five samples of middle-aged and older adults (total N > 24,000; aged 34 to 105 years). Cross-sectional analyses that accounted for demographic variables revealed that an older subjective age was related to higher BMI and waist circumference in the five samples. Feeling older was related to a 10-20% higher likelihood of BMI >= 30 and a 11-25% higher likelihood of exceeding the obesity-related threshold for waist circumference. For most associations, age felt was more consistently and strongly related to adiposity than chronological age. The overall pattern was confirmed by a meta-analysis of the five samples. The present research adds subjective age to the list of factors related to obesity across adulthood. PMID- 30250241 TI - The effect of brisk walking in the fasted versus fed state on metabolic responses, gastrointestinal function, and appetite in healthy men. AB - OBJECTIVE: To investigate the effect of brisk walking in the fasted versus fed state on gastric emptying rate (GER), metabolic responses and appetite hormone responses. SUBJECTS/METHODS: Twelve healthy men completed two 45 min treadmill walks, fasted (FASTED) and followed consumption of a standardised breakfast (FED). GER of a standardised lunch was subsequently measured for 2 h using the 13C-breath test method. Blood samples were collected at baseline, post-breakfast period, pre-exercise, immediately post exercise, pre-lunch then every 30 min following lunch for 2 h. Circulating concentrations of acylated ghrelin (GHR), glucagon-like peptide-1 (GLP-1), peptide tyrosine tyrosine (PYY), pancreatic polypeptide (PP), glucose, insulin, triglycerides, non-esterified fatty acids (NEFA) and cholesterol were measured. Subjective feelings of appetite were assessed at 15 min intervals throughout. Substrate utilisation was measured every 30 min, and continuously throughout exercise by indirect calorimetry. RESULTS: No differences were observed for GER T1/2 (FASTED 89 +/- 22 vs. FED 89 +/- 24 min, P = 0.868) nor Tlag (FASTED 55 +/- 15 vs. FED 54 +/- 14 min, P = 0.704). NEFA concentrations were higher in FASTED at pre-exercise, post exercise and 30 min post exercise (pre-lunch) (all P < 0.05) but no differences were observed for glucose, cholesterol or triglycerides. Carbohydrate oxidation was greater at all time-points during FED exercise (all P < 0.05). Minimal changes in appetite were observed post lunch ingestion with no differences in PYY or GHR observed between trials. GLP-1 concentrations were greater in FED post-breakfast and pre-exercise (P < 0.05), though no differences were observed after lunch. A greater concentration of PP was observed in FED from pre-exercise to 30 min post lunch consumption (all P < 0.05). Insulin concentrations were higher in FED pre exercise but higher in FASTED 1.5 h post lunch (P < 0.05). CONCLUSION: These findings suggest that gastrointestinal function, hunger and appetite regulatory hormones are not sensitive to low-intensity bouts of physical activity and holds positive implications for weight management practices. PMID- 30250242 TI - Association of body temperature with obesity. The CoLaus study. AB - BACKGROUND AND AIMS: There is conflicting evidence regarding the association between body temperature and obesity. We aimed to assess the associations between body temperature and several adiposity and metabolic markers according to gender and menopausal status in a large population-based sample. METHODS: The data collected between 2009 and 2012 from 4224 participants (mean age 57.3 +/- 10.4 years, 2225 women) of the CoLaus study (Lausanne, Switzerland). Body temperature was measured at the tympanic membrane. RESULTS: Mean body temperature was 36.1 +/ 0.4, 36.4 +/- 0.4 and 36.3 +/- 0.4 degrees C in men, premenopausal, and postmenopausal women, respectively (p < 0.001). In men and postmenopausal women, body temperature was positively and significantly (p < 0.05) associated with body mass index (Spearman correlation coefficients 0.157 and 0.083, respectively), waist (r = 0.163 and r = 0.104), waist to hip ratio (r = 0.187 and r = 0.132), body area (r = 0.094 and r = 0.085), resting heart rate (r = 0.227 and r = 182), glucose (r = 0.104 and r = 0.088) and insulin (r = 0.148 and r = 0.117). Except for body area and BMI in postmenopausal women, all associations remained significant after multivariable adjustment. In premenopausal women, body temperature was positively associated with resting heart rate (r = 0.140) and insulin (r = 0.170), and no significant associations were found after multivariable adjustment. CONCLUSION: Body temperature is strongly associated with obesity markers in men and postmenopausal women. The absence of association in premenopausal women might be due to the influence of the menstrual cycle. PMID- 30250243 TI - Plant neighbor detection and allelochemical response are driven by root-secreted signaling chemicals. AB - Plant neighbor detection and response strategies are important mediators of interactions among species. Despite increasing knowledge of neighbor detection and response involving plant volatiles, less is known about how soil-borne signaling chemicals may act belowground in plant-plant interactions. Here, we experimentally demonstrate neighbor detection and allelopathic responses between wheat and 100 other plant species via belowground signaling. Wheat can detect both conspecific and heterospecific neighbors and responds by increasing allelochemical production. Furthermore, we show that (-)-loliolide and jasmonic acid are present in root exudates from a diverse range of species and are able to trigger allelochemical production in wheat. These findings suggest that root secreted (-)-loliolide and jasmonic acid are involved in plant neighbor detection and allelochemical response and may be widespread mediators of belowground plant plant interactions. PMID- 30250245 TI - Peptidoglycan editing by a specific LD-transpeptidase controls the muramidase dependent secretion of typhoid toxin. AB - Protein secretion mechanisms are essential for the virulence of most bacterial pathogens. Typhoid toxin is an essential virulence factor for Salmonella Typhi, the cause of typhoid fever in humans. This toxin is unique in that it is only produced within mammalian cells, and it must be trafficked to the extracellular space before intoxicating target cells. An essential and poorly understood aspect of this transport pathway is the secretion of typhoid toxin from the bacterium into the S. Typhi-containing vacuole. We show here that typhoid toxin secretion requires its translocation to the trans side of the peptidoglycan layer at the bacterial poles for subsequent release through the outer membrane. This translocation process depends on a specialized muramidase, the activity of which requires the localized editing of peptidoglycan by a specific ld-transpeptidase. These studies describe a protein export mechanism that is probably conserved in other bacterial species. PMID- 30250244 TI - Static and active tactile perception and touch anisotropy: aging and gender effect. AB - Although the human finger is the interface used for the touch process, very few studies have used its properties to provide a description of tactile perception regarding age and gender effects. Age and gender effects on the biophysical properties of the human finger were the main topics of our previous study. Correlating tactile perception with each parameter proved very complex. We expand on that work to assess the static and dynamic touch in addition to the touch gestures. We also investigate the age and gender effects on tactile perception by studying the finger size and the real contact area (static and dynamic) of forty human fingers of different ages and gender. The size of the finger and the real contact area (static and dynamic) define the density of the mechanoreceptors. This density is an image of the number of mechanoreceptors solicited and therefore of tactile perception (static and dynamic). In addition, the touch gestures used to perceive an object's properties differ among people. Therefore, we seek to comprehend the tactile perception of different touch gestures due to the anisotropy of mechanical properties, and we study two different directions (top to bottom and left to right). PMID- 30250246 TI - Strain-level diversity drives alternative community types in millimetre-scale granular biofilms. AB - Microbial communities are often highly diverse in their composition, both at a coarse-grained taxonomic level, such as genus, and at a highly resolved level, such as strains, within species. This variability can be driven by either extrinsic factors such as temperature and or by intrinsic ones, for example demographic fluctuations or ecological interactions. The relative contributions of these factors and the taxonomic level at which they influence community composition remain poorly understood, in part because of the difficulty in identifying true community replicates assembled under the same environmental parameters. Here, we address this problem using an activated granular sludge reactor in which millimetre-scale biofilm granules represent true community replicates. Differences in composition are then expected to be driven primarily by biotic factors. Using 142 shotgun metagenomes of single biofilm granules we found that, at the commonly used genus-level resolution, community replicates varied much more in their composition than would be expected from neutral assembly processes. This variation did not translate into any clear partitioning into discrete community types, that is, distinct compositional states, such as enterotypes in the human gut. However, a strong partition into community types did emerge at the strain level for the dominant organism: genotypes of Candidatus Accumulibacter that coexisted in the metacommunity (the reactor) excluded each other within community replicates (granules). Individual granule communities maintained a significant lineage structure, whereby the strain phylogeny of Accumulibacter correlated with the overall composition of the community, indicating a high potential for co-diversification among species and communities. Our results suggest that due to the high functional redundancy and competition between close relatives, alternative community types are most probably observed at the level of recently differentiated genotypes but not at higher orders of genetic resolution. PMID- 30250247 TI - Anisotropic polarization-induced conductance at a ferroelectric-insulator interface. AB - Coupling between different degrees of freedom, that is, charge, spin, orbital and lattice, is responsible for emergent phenomena in complex oxide heterostrutures1,2. One example is the formation of a two-dimensional electron gas (2DEG) at the polar/non-polar LaAlO3/SrTiO3 (LAO/STO)3-7 interface. This is caused by the polar discontinuity and counteracts the electrostatic potential build-up across the LAO film3. The ferroelectric polarization at a ferroelectric/insulator interface can also give rise to a polar discontinuity8 10. Depending on the polarization orientation, either electrons or holes are transferred to the interface, to form either a 2DEG or two-dimensional hole gas (2DHG)11-13. While recent first-principles modelling predicts the formation of 2DEGs at the ferroelectric/insulator interfaces9,10,12-14, experimental evidence of a ferroelectrically induced interfacial 2DEG remains elusive. Here, we report the emergence of strongly anisotropic polarization-induced conductivity at a ferroelectric/insulator interface, which shows a strong dependence on the polarization orientation. By probing the local conductance and ferroelectric polarization over a cross-section of a BiFeO3-TbScO3 (BFO/TSO) (001) heterostructure, we demonstrate that this interface is conducting along the 109 degrees domain stripes in BFO, whereas it is insulating in the direction perpendicular to these domain stripes. Electron energy-loss spectroscopy and theoretical modelling suggest that the anisotropy of the interfacial conduction is caused by an alternating polarization associated with the ferroelectric domains, producing either electron or hole doping of the BFO/TSO interface. PMID- 30250248 TI - Proscillaridin A exerts anti-tumor effects through GSK3beta activation and alteration of microtubule dynamics in glioblastoma. AB - Glioblastoma (GBM) is characterized by highly aggressive growth and invasive behavior. Due to the highly lethal nature of GBM, new therapies are urgently needed and repositioning of existing drugs is a promising approach. We have previously shown the activity of Proscillaridin A (ProA), a cardiac glycoside inhibitor of the Na(+)/K(+) ATPase (NKA) pump, against proliferation and migration of GBM cell lines. ProA inhibited tumor growth in vivo and increased mice survival after orthotopic grafting of GBM cells. This study aims to decipher the mechanism of action of ProA in GBM tumor and stem-like cells. ProA displayed cytotoxic activity on tumor and stem-like cells grown in 2D and 3D culture, but not on healthy cells as astrocytes or oligodendrocytes. Even at sub-cytotoxic concentration, ProA impaired cell migration and disturbed EB1 accumulation at microtubule (MT) plus-ends and MT dynamics instability. ProA activates GSK3beta downstream of NKA inhibition, leading to EB1 phosphorylation on S155 and T166, EB1 comet length shortening and MT dynamics alteration, and finally inhibition of cell migration and cytotoxicity. Similar results were observed with digoxin. Therefore, we disclosed here a novel pathway by which ProA and digoxin modulate MT-governed functions in GBM tumor and stem-like cells. Altogether, our results support ProA and digoxin as potent candidates for drug repositioning in GBM. PMID- 30250249 TI - Insight into anaerobic methanotrophy from 13C/12C- amino acids and 14C/12C-ANME cells in seafloor microbial ecology. AB - Oceanic methane from global deep-sea sediment is largely consumed through microbially mediated sulfate-coupled oxidation, resulting in 13C-depleted cell biomass of anaerobic methanotrophic archaea (ANME). The general ecological importance of subseafloor ANME has been well recognized in the last two decades. However, the crucial biochemical pathways for the overall anaerobic oxidation of methane (AOM) still remain enigmatic. Here, methanotrophic pathways were analyzed to trace 13C-depleted amino acid biosynthesis in two clades of ANME (ANME-1 and ANME-2) from the Black Sea. Compound-specific analysis of ANME-dominated microbial mats showed a significant 13C-depletion trend in association with increasing carbon numbers in protein-derived amino acid families (e.g., the pyruvate family in the order of alanine, valine, isoleucine and leucine was down to -1140/00). This result indicates a stepwise elongation of 13C-depleted carbon during amino acid biosynthesis. The overall results suggest that intracellular protein amino acids and the most 13C-depleted signature of leucine, which has a specific branched-chain structure, are potentially propagated as isoprenoid precursor molecules into archaeal biosynthesis, resulting in the extremely 13C- and 14C-depleted nature of ANME cells in the deep microbial oasis. PMID- 30250251 TI - Integrated lithium niobate electro-optic modulators operating at CMOS-compatible voltages. AB - Electro-optic modulators translate high-speed electronic signals into the optical domain and are critical components in modern telecommunication networks1,2 and microwave-photonic systems3,4. They are also expected to be building blocks for emerging applications such as quantum photonics5,6 and non-reciprocal optics7,8. All of these applications require chip-scale electro-optic modulators that operate at voltages compatible with complementary metal-oxide-semiconductor (CMOS) technology, have ultra-high electro-optic bandwidths and feature very low optical losses. Integrated modulator platforms based on materials such as silicon, indium phosphide or polymers have not yet been able to meet these requirements simultaneously because of the intrinsic limitations of the materials used. On the other hand, lithium niobate electro-optic modulators, the workhorse of the optoelectronic industry for decades9, have been challenging to integrate on-chip because of difficulties in microstructuring lithium niobate. The current generation of lithium niobate modulators are bulky, expensive, limited in bandwidth and require high drive voltages, and thus are unable to reach the full potential of the material. Here we overcome these limitations and demonstrate monolithically integrated lithium niobate electro-optic modulators that feature a CMOS-compatible drive voltage, support data rates up to 210 gigabits per second and show an on-chip optical loss of less than 0.5 decibels. We achieve this by engineering the microwave and photonic circuits to achieve high electro-optical efficiencies, ultra-low optical losses and group-velocity matching simultaneously. Our scalable modulator devices could provide cost-effective, low power and ultra-high-speed solutions for next-generation optical communication networks and microwave photonic systems. Furthermore, our approach could lead to large-scale ultra-low-loss photonic circuits that are reconfigurable on a picosecond timescale, enabling a wide range of quantum and classical applications5,10,11 including feed-forward photonic quantum computation. PMID- 30250250 TI - The interaction landscape between transcription factors and the nucleosome. AB - Nucleosomes cover most of the genome and are thought to be displaced by transcription factors in regions that direct gene expression. However, the modes of interaction between transcription factors and nucleosomal DNA remain largely unknown. Here we systematically explore interactions between the nucleosome and 220 transcription factors representing diverse structural families. Consistent with earlier observations, we find that the majority of the studied transcription factors have less access to nucleosomal DNA than to free DNA. The motifs recovered from transcription factors bound to nucleosomal and free DNA are generally similar. However, steric hindrance and scaffolding by the nucleosome result in specific positioning and orientation of the motifs. Many transcription factors preferentially bind close to the end of nucleosomal DNA, or to periodic positions on the solvent-exposed side of the DNA. In addition, several transcription factors usually bind to nucleosomal DNA in a particular orientation. Some transcription factors specifically interact with DNA located at the dyad position at which only one DNA gyre is wound, whereas other transcription factors prefer sites spanning two DNA gyres and bind specifically to each of them. Our work reveals notable differences in the binding of transcription factors to free and nucleosomal DNA, and uncovers a diverse interaction landscape between transcription factors and the nucleosome. PMID- 30250252 TI - Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium. AB - Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non selective cation channel that has an essential role in diverse physiological processes such as core body temperature regulation, immune response and apoptosis1-4. TRPM2 is polymodal and can be activated by a wide range of stimuli1 7, including temperature, oxidative stress and NAD+-related metabolites such as ADP-ribose (ADPR). Its activation results in both Ca2+ entry across the plasma membrane and Ca2+ release from lysosomes8, and has been linked to diseases such as ischaemia-reperfusion injury, bipolar disorder and Alzheimer's disease9-11. Here we report the cryo-electron microscopy structures of the zebrafish TRPM2 in the apo resting (closed) state and in the ADPR/Ca2+-bound active (open) state, in which the characteristic NUDT9-H domains hang underneath the MHR1/2 domain. We identify an ADPR-binding site located in the bi-lobed structure of the MHR1/2 domain. Our results provide an insight into the mechanism of activation of the TRPM channel family and define a framework for the development of therapeutic agents to treat neurodegenerative diseases and temperature-related pathological conditions. PMID- 30250254 TI - Publisher Correction: Challenging local realism with human choices. AB - In the HTML version of this Letter, the corresponding author link (M. W. Mitchell; morgan.mitchell@icfo.eu) was missing and the citation file was empty. The list of consortium authors was duplicated, with spurious superscript numbers, in the Acknowledgements (the PDF version was correct). In addition, in Fig. 2a of this Letter, the label '4', which indicates Vienna in the inset, was inadvertently displaced into Siberia in the main panel. These errors have been corrected online. PMID- 30250253 TI - Discovery of a periosteal stem cell mediating intramembranous bone formation. AB - Bone consists of separate inner endosteal and outer periosteal compartments, each with distinct contributions to bone physiology and each maintaining separate pools of cells owing to physical separation by the bone cortex. The skeletal stem cell that gives rise to endosteal osteoblasts has been extensively studied; however, the identity of periosteal stem cells remains unclear1-5. Here we identify a periosteal stem cell (PSC) that is present in the long bones and calvarium of mice, displays clonal multipotency and self-renewal, and sits at the apex of a differentiation hierarchy. Single-cell and bulk transcriptional profiling show that PSCs display transcriptional signatures that are distinct from those of other skeletal stem cells and mature mesenchymal cells. Whereas other skeletal stem cells form bone via an initial cartilage template using the endochondral pathway4, PSCs form bone via a direct intramembranous route, providing a cellular basis for the divergence between intramembranous versus endochondral developmental pathways. However, there is plasticity in this division, as PSCs acquire endochondral bone formation capacity in response to injury. Genetic blockade of the ability of PSCs to give rise to bone-forming osteoblasts results in selective impairments in cortical bone architecture and defects in fracture healing. A cell analogous to mouse PSCs is present in the human periosteum, raising the possibility that PSCs are attractive targets for drug and cellular therapy for skeletal disorders. The identification of PSCs provides evidence that bone contains multiple pools of stem cells, each with distinct physiologic functions. PMID- 30250255 TI - Author Correction: EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors. AB - We wish to correct two mutations in Supplementary Table 4 of this Letter. The NCI H460 cell line was annotated as being mutant for TP53. NCI-H460 has been verified to be TP53 wild type by several sources1. The NCI-H2009 cell line was annotated as being mutant for PIK3CA. As annotated by COSMIC (ref. 24 of the original Letter) and CCLE (ref. 25 of the original Letter), the NCI-H2009 cell line has a mutation in PIK3C3, rather than PIK3CA. The cell line is wild type for PIK3CA. The Supplementary Information of this Amendment contains the corrected Supplementary Table 4. These errors do not affect our conclusions. The original Letter has not been corrected. PMID- 30250256 TI - Publisher Correction: Xenon isotopic constraints on the history of volatile recycling into the mantle. AB - In this Letter, owing to a production error, the arrows in the middle panel of Fig. 1 were wrongly coloured and there were some some typos elsewhere. These errors have been corrected online. PMID- 30250257 TI - Tailoring diamond's optical properties via direct femtosecond laser nanostructuring. AB - We demonstrate a rapid, accurate, and convenient method for tailoring the optical properties of diamond surfaces by employing laser induced periodic surface structuring (LIPSSs). The characteristics of the fabricated photonic surfaces were adjusted by tuning the laser wavelength, number of impinging pulses, angle of incidence and polarization state. Using Finite Difference Time Domain (FDTD) modeling, the optical transmissivity and bandwidth was calculated for each fabricated LIPSSs morphology. The highest transmission of ~99.5% was obtained in the near-IR for LIPSSs structures with aspect ratios of the order of ~0.65. The present technique enabled us to identify the main laser parameters involved in the machining process, and to control it with a high degree of accuracy in terms of structure periodicity, morphology and aspect ratio. We also demonstrate and study the conditions for fabricating spatially coherent nanostructures over large areas maintaining a high degree of nanostructure repeatability and optical performance. While our experimental demonstrations have been mainly focused on diamond anti-reflection coatings and gratings, the technique can be easily extended to other materials and applications, such as integrated photonic devices, high power diamond optics, or the construction of photonic surfaces with tailored characteristics in general. PMID- 30250258 TI - Histopathological Changes Caused by Inflammation and Oxidative Stress in Diet Induced-Obese Mouse following Experimental Lung Injury. AB - Obesity has been identified as a risk factor for adverse outcomes of various diseases. However, information regarding the difference between the response of obese and normal subjects to pulmonary inflammation is limited. Mice were fed with the control or high-fat diet to establish the lean and diet-induced obese (DIO) mice. Escherichia coli was intranasally instilled to reproduce non-fatal acute pneumonia model. After infection, serum samples and lung tissues were obtained at 0, 12, 24, and 72 h. DIO mice exhibited increased serum triglyceride (TG) and total cholesterol (TC) contents as well as pulmonary resistin, IL-6, and leptin levels compared with lean mice. E. coli infection caused an acute suppurative inflammation in the lung with increased lung index and serum TG and TC contents; elevated pulmonary tumor necrosis factor-alpha, interleukin (IL) 1beta, IL-6, IL-8, and leptin levels; and oxidative stress in mice. Interestingly, almost all the above-mentioned parameters peaked at 12 h after infection in the lean-E. coli group but after 12 h in the DIO-E. coli group. These results indicated that the DIO mice presented a delayed inflammatory response and oxidative stress in non-fatal acute pneumonia induced by E. coli infection. PMID- 30250260 TI - Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. AB - A hallmark event in neurodegenerative diseases (NDs) is the misfolding, aggregation, and accumulation of proteins, leading to cellular dysfunction, loss of synaptic connections, and brain damage. Despite the involvement of distinct proteins in different NDs, the process of protein misfolding and aggregation is remarkably similar. A recent breakthrough in the field was the discovery that misfolded protein aggregates can self-propagate through seeding and spread the pathological abnormalities between cells and tissues in a manner akin to the behavior of infectious prions in prion diseases. This discovery has vast implications for understanding the mechanisms involved in the initiation and progression of NDs, as well as for the design of novel strategies for treatment and diagnosis. In this Review, we provide a critical discussion of the role of protein misfolding and aggregation in NDs. Commonalities and differences between distinct protein aggregates will be highlighted, in addition to evidence supporting the hypothesis that misfolded aggregates can be transmissible by the prion principle. We will also describe the molecular basis and implications for prion-like conformational strains, cross-interaction between different misfolded proteins in the brain, and how these concepts can be applied to the development of novel strategies for therapy and diagnosis. PMID- 30250259 TI - Natural variation at XND1 impacts root hydraulics and trade-off for stress responses in Arabidopsis. AB - Soil water uptake by roots is a key component of plant performance and adaptation to adverse environments. Here, we use a genome-wide association analysis to identify the XYLEM NAC DOMAIN 1 (XND1) transcription factor as a negative regulator of Arabidopsis root hydraulic conductivity (Lpr). The distinct functionalities of a series of natural XND1 variants and a single nucleotide polymorphism that determines XND1 translation efficiency demonstrate the significance of XND1 natural variation at species-wide level. Phenotyping of xnd1 mutants and natural XND1 variants show that XND1 modulates Lpr through action on xylem formation and potential indirect effects on aquaporin function and that it diminishes drought stress tolerance. XND1 also mediates the inhibition of xylem formation by the bacterial elicitor flagellin and counteracts plant infection by the root pathogen Ralstonia solanacearum. Thus, genetic variation at XND1, and xylem differentiation contribute to resolving the major trade-off between abiotic and biotic stress resistance in Arabidopsis. PMID- 30250262 TI - Selective vulnerability in neurodegenerative diseases. AB - Neurodegenerative diseases have two general characteristics that are so fundamental we usually take them for granted. The first is that the pathology associated with the disease only affects particular neurons ('selective neuronal vulnerability'); the second is that the pathology worsens with time and impacts more regions in a stereotypical and predictable fashion. The mechanisms underpinning selective neuronal and regional vulnerability have been difficult to dissect, but the recent application of whole-genome technologies, the development of mouse models that reproduce spatial and temporal features of the pathology, and the identification of intrinsic morphological, electrophysiological, and biochemical properties of vulnerable neurons are beginning to shed some light on these fundamental features of neurodegenerative diseases. Here we detail our emerging understanding of the underlying biology of selective neuronal vulnerability and outline some of the areas in which our understanding is incomplete. PMID- 30250264 TI - Deconstructing the synapse. PMID- 30250261 TI - The role of brain vasculature in neurodegenerative disorders. AB - Adequate supply of blood and structural and functional integrity of blood vessels are key to normal brain functioning. On the other hand, cerebral blood flow shortfalls and blood-brain barrier dysfunction are early findings in neurodegenerative disorders in humans and animal models. Here we first examine molecular definition of cerebral blood vessels, as well as pathways regulating cerebral blood flow and blood-brain barrier integrity. Then we examine the role of cerebral blood flow and blood-brain barrier in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. We focus on Alzheimer's disease as a platform of our analysis because more is known about neurovascular dysfunction in this disease than in other neurodegenerative disorders. Finally, we propose a hypothetical model of Alzheimer's disease biomarkers to include brain vasculature as a factor contributing to the disease onset and progression, and we suggest a common pathway linking brain vascular contributions to neurodegeneration in multiple neurodegenerative disorders. PMID- 30250265 TI - Animal models of neurodegenerative diseases. AB - Animal models of adult-onset neurodegenerative diseases have enhanced the understanding of the molecular pathogenesis of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Nevertheless, our understanding of these disorders and the development of mechanistically designed therapeutics can still benefit from more rigorous use of the models and from generation of animals that more faithfully recapitulate human disease. Here we review the current state of rodent models for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. We discuss the limitations and utility of current models, issues regarding translatability, and future directions for developing animal models of these human disorders. PMID- 30250263 TI - Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible. AB - To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we adopted a symptom-to-circuit approach in the Fmr1-knockout (Fmr1-/-) mouse model of Fragile X syndrome. Using a go/no-go task and in vivo two-photon calcium imaging, we find that impaired visual discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons and with a decrease in the activity of parvalbumin interneurons in primary visual cortex. Restoring visually evoked activity in parvalbumin cells in Fmr1-/- mice with a chemogenetic strategy using designer receptors exclusively activated by designer drugs was sufficient to rescue their behavioral performance. Strikingly, human subjects with Fragile X syndrome exhibit impairments in visual discrimination similar to those in Fmr1-/- mice. These results suggest that manipulating inhibition may help sensory processing in Fragile X syndrome. PMID- 30250266 TI - The Stochastic Transport Dynamics of a Conserved Quantity on a Complex Network. AB - The stochastic dynamics of conserved quantities is an emergent phenomena observed in many complex systems, ranging from social and to biological networks. Using an extension of the Ehrenfest urn model on a complex network, over which a conserved quantity is transported in a random fashion, we study the dynamics of many elementary packets transported through the network by means of a master equation approach and compare with the mean field approximation and stochastic simulations. By use of the mean field theory, it is possible to compute an approximation to the ensemble average evolution of the number of packets in each node which, in the thermodynamic limit, agrees quite well with the results of the master equation. However, the master equation gives a more complete description of the stochastic system and provides a probabilistic view of the occupation number at each node. Of particular relevance is the standard deviation of the occupation number at each node, which is not uniform for a complex network. We analyze and compare different network topologies (small world, scale free, Erdos Renyi, among others). Given the computational complexity of directly evaluating the asymptotic, or equilibrium, occupation number probability distribution, we propose a scaling relation with the number of packets in the network, that allows to construct the asymptotic probability distributions from the network with one packet. The approximation, which relies on the same matrix found in the mean field approach, becomes increasingly more accurate for a large number of packets. PMID- 30250267 TI - Effectiveness of monovalent rotavirus vaccine in the Philippines. AB - Rotavirus (RV) is an important cause of diarrheal disease particularly in children aged under 5 years. Monovalent RV vaccine (RVV) was selectively introduced in 2012 in the Philippines and in July 2014 was introduced in the public health program of a province. Two RVV doses are recommended at 6 and 10 weeks of age. We conducted a test negative case-control evaluation to assess the effectiveness of RVV when given in a routine public health program in the Philippines. From September 2014 to August 2017, 967 children aged <5 years were hospitalized with diarrhea and of these, we enrolled 600 who were eligible to have received RVV and provided stool specimens for testing. Among children >=8 months of age who were age-eligible to have received RVV, at least one dose of RVV had an adjusted vaccine effectiveness (VE) against RV hospitalization of 60% (95% confidence interval, CI: 24%, 79%), and against severe rotavirus diarrhea, VE was 64% (95% CI: 11%, 85%). These findings support the introduction of RVV into routine public health use in the Philippines. However, other factors such as costs, cost-effectiveness and operational issues must be considered prior to adoption of the vaccine into the countries' public immunization program. PMID- 30250268 TI - Parkin-mediated mitophagy as a potential therapeutic target for intervertebral disc degeneration. AB - Intervertebral disc degeneration (IDD) is a complicated pathological condition blamed for low back pain. Mitochondrion is of vital importance for cellular homeostasis, and mitochondrial dysfunction is considered to be one of the major causes of cellular damage. Mitophagy is a cellular process to eliminate impaired mitochondria and showed protective effects in various diseases; however, its role in IDD is still not clear. Here, we explore the role of Parkin-mediated mitophagy in IDD. In this study, we found that Parkin was upregulated in degenerative nucleus pulposus (NP) tissues in vivo as well as in TNF-alpha stimulated NP cells in vitro. Knockdown of Parkin by siRNA showed that Parkin is crucial for apoptosis and mitochondrion homeostasis in NP cells. Further study showed that upregulation of Parkin by salidroside may eliminate impaired mitochondria and promote the survival of NP cells through activation of mitophagy in vitro. In in vivo study, we found that salidroside could inhibit the apoptosis of NP cells and ameliorate the progression of IDD. These results suggested that Parkin is involved in the pathogenesis of IDD and may be a potential therapeutic target for IDD. PMID- 30250270 TI - The association between serum sodium concentration, hypertension and primary cardiovascular events: a retrospective cohort study. AB - The mechanisms underlying the adverse cardiovascular effects of increased salt intake are incompletely understood, but parallel increases in serum sodium concentration may be of importance. The aim of this retrospective cohort study was to investigate the relationship between serum sodium, hypertension and incident cardiovascular disease (CVD). Routinely collected primary care data from the Royal College of General Practitioners Research and Surveillance Centre were analysed. A total of 231,545 individuals with a measurement of serum sodium concentration at baseline were included. Exclusion criteria were: age < 40 years; abnormal serum sodium; diabetes mellitus; prior CVD event; stage 5 chronic kidney disease; and liver cirrhosis. The primary outcome was incident CVD (myocardial infarction, acute coronary syndrome, coronary revascularisation, stroke, transient ischaemic attack or new heart failure diagnosis) over 5 years. There was a 'J-shaped' relationship between serum sodium concentration and primary cardiovascular events that was independent of established risk factors, medications and other serum electrolytes. The lowest cardiovascular risk was found with a serum sodium between 141 and 143 mmol/l. Higher serum sodium was associated with increased risk in hypertensive individuals, whereas lower concentrations were associated with increased risk in all individuals. Therefore, alterations in serum sodium concentration may be a useful indicator of CVD risk. Higher serum sodium could have a direct effect on the vasculature, particularly in hypertensive individuals. Lower serum sodium may be a reflection of complex volume and neuroendocrine changes. PMID- 30250269 TI - MARVELD1 depletion leads to dysfunction of motor and cognition via regulating glia-dependent neuronal migration during brain development. AB - The establishment of functional neuronal connectivity is dependent on the neuronal migration and the accurate positioning of neurons in the developing brain. Abnormal neuronal migration can trigger neuronal maturation defects and apoptosis. However, many genetic bases remain unclear in neuronal migration disorders during brain development. In this study, we reported that MARVELD1 defected mice displayed motor and cognitive dysfunction resulting from aberrant neuronal migration during brain development. The laminar organization of the cerebral cortex and cerebellum in MARVELD1 knockout (KO) mice is disrupted, indicating impaired radial neuronal migration. Furthermore, we used the cerebellum as a model to explore the radial neuronal migration processes, and the results demonstrated that the proper neuronal migration depended on MARVELD1 expression in glial cells of the developing brain. MARVELD1 suppressed the expression of ITGB1 and FAK Tyr397 phosphorylation in glia-dependent manner. The inhibition of the MARVELD1/ITGB1/FAK signalling pathway in MARVELD1 KO mice could reverse the defects in neuronal migration in vitro. Our findings revealed that MARVELD1 regulated neuronal migration by mediating the formation of glial fibres and ITGB1/FAK signalling pathway. The depletion of MARVELD1 during mouse brain development led to the abnormity of motor and cognition functions. PMID- 30250271 TI - Microbial niches in marine oxygen minimum zones. AB - In the ocean's major oxygen minimum zones (OMZs), oxygen is effectively absent from sea water and life is dominated by microorganisms that use chemicals other than oxygen for respiration. Recent studies that combine advanced genomic and chemical detection methods are delineating the different metabolic niches that microorganisms can occupy in OMZs. Understanding these niches, the microorganisms that inhabit them, and their influence on marine biogeochemical cycles is crucial as OMZs expand with increasing seawater temperatures. PMID- 30250272 TI - Spatiotemporal dynamics of homologous recombination repair at single collapsed replication forks. AB - Homologous recombination (HR) is a crucial pathway for the repair of DNA double strand breaks. BRCA1/2 breast cancer proteins are key players in HR via their mediation of RAD51 nucleofilament formation and function; however, their individual roles and crosstalk in vivo are unknown. Here we use super-resolution (SR) imaging to map the spatiotemporal kinetics of HR proteins, revealing the interdependent relationships that govern the dynamic interplay and progression of repair events. We show that initial single-stranded DNA/RAD51 nucleofilament formation is mediated by RAD52 or, in the absence of RAD52, by BRCA2. In contrast, only BRCA2 can orchestrate later RAD51 recombinase activity during homology search and resolution. Furthermore, we establish that upstream BRCA1 activity is critical for BRCA2 function. Our analyses reveal the underlying epistatic landscape of RAD51 functional dependence on RAD52, BRCA1, and BRCA2 during HR and explain the phenotypic similarity of diseases associated with mutations in these proteins. PMID- 30250273 TI - On-Demand Design of Tunable Complete Photonic Band Gaps based on Bloch Mode Analysis. AB - The fundamental property of photonic crystals is the band gap effect, which arises from the periodic dielectric modulation of electromagnetic waves and plays an indispensable role in manipulating light. Ever since the first photonic bandgap structure was discovered, the ability to tune its bandgap across a wide wavelength range has been highly desirable. Therefore, obtaining photonic crystals possessing large on-demand bandgaps has been an ever-attractive study but has remained a challenge. Here we present an analytical design method for achieving high-order two-dimensional photonic crystals with tunable photonic band gaps on-demand. Based on the Bloch mode analysis for periodic structures, we are able to determine the geometric structure of the unit cell that will realize a nearly optimal photonic band gap for one polarization between the appointed adjacent bands. More importantly, this method generates a complete bandgap for all polarizations, with frequencies tuned by the number of photonic bands below the gap. The lowest dielectric contrast needed to generate a photonic band gap, as well as conditions for generating complete bandgaps, are investigated. Our work first highlights the systematic approach to complete photonic band gaps design based on Bloch mode analysis. The physical principles behind our work are then generalized to other photonic lattices. PMID- 30250275 TI - Abnormal Stop Band Behavior Induced by Rotational Resonance in Flexural Metamaterial. AB - This paper investigates abnormal stop band behavior of resonance-based flexural elastic metamaterials under the rotational resonance motion. Due to the unique physics of flexural waves, we found that the stop band generated by the rotational resonance motion exhibits peculiar behavior which are quite different from general belief - it is shown that the negativity due to the rotational resonance does not provide any stop bands and the stop band generation due to the rotational resonance is governed by totally different band gap condition. To explain the peculiar behavior, a discrete Timoshenko beam model with both effective mass and rotational inertia as independent variables is introduced, and the wave behaviors of resonance-based flexural elastic metamaterial are precisely and fully described. The unique band gap condition, including the peculiar behavior, is derived with numerical validations. We expect our new model can provide a strong background for various flexural elastic metamaterials which can be effectively applied in various vibration devices. PMID- 30250276 TI - Rediscovering natural flowering. PMID- 30250274 TI - Structure of Type-I Mycobacterium tuberculosis fatty acid synthase at 3.3 A resolution. AB - Tuberculosis (TB) is a devastating and rapidly spreading disease caused by Mycobacterium tuberculosis (Mtb). Therapy requires prolonged treatment with a combination of multiple agents and interruptions in the treatment regimen result in emergence and spread of multi-drug resistant (MDR) Mtb strains. MDR Mtb poses a significant global health problem, calling for urgent development of novel drugs to combat TB. Here, we report the 3.3 A resolution structure of the ~2 MDa type-I fatty acid synthase (FAS-I) from Mtb, determined by single particle cryo EM. Mtb FAS-I is an essential enzymatic complex that contributes to the virulence of Mtb, and thus a prime target for anti-TB drugs. The structural information for Mtb FAS-I we have obtained enables computer-based drug discovery approaches, and the resolution achieved by cryo-EM is sufficient for elucidating inhibition mechanisms by putative small molecular weight inhibitors. PMID- 30250278 TI - How fruit ripening is ENCODEd. PMID- 30250277 TI - Molecular basis of flowering under natural long-day conditions in Arabidopsis. AB - Plants sense light and temperature changes to regulate flowering time. Here, we show that expression of the Arabidopsis florigen gene, FLOWERING LOCUS T (FT), peaks in the morning during spring, a different pattern than we observe in the laboratory. Providing our laboratory growth conditions with a red/far-red light ratio similar to open-field conditions and daily temperature oscillation is sufficient to mimic the FT expression and flowering time in natural long days. Under the adjusted growth conditions, key light signalling components, such as phytochrome A and EARLY FLOWERING 3, play important roles in morning FT expression. These conditions stabilize CONSTANS protein, a major FT activator, in the morning, which is probably a critical mechanism for photoperiodic flowering in nature. Refining the parameters of our standard growth conditions to more precisely mimic plant responses in nature can provide a powerful method for improving our understanding of seasonal response. PMID- 30250280 TI - NPR1 mediates a novel regulatory pathway in cold acclimation by interacting with HSFA1 factors. AB - NON-EXPRESSER OF PATHOGENESIS-RELATED GENES 1 (NPR1) is a master regulator of plant response to pathogens that confers immunity through a transcriptional cascade mediated by salicylic acid and TGA transcription factors. Little is known, however, about its implication in plant response to abiotic stress. Here, we provide genetic and molecular evidence supporting the fact that Arabidopsis NPR1 plays an essential role in cold acclimation by regulating cold-induced gene expression independently of salicylic acid and TGA factors. Our results demonstrate that, in response to low temperature, cytoplasmic NPR1 oligomers release monomers that translocate to the nucleus where they interact with heat shock transcription factor 1 (HSFA1) to promote the induction of HSFA1-regulated genes and cold acclimation. These findings unveil an unexpected function for NPR1 in plant response to low temperature, reveal a new regulatory pathway for cold acclimation mediated by NPR1 and HSFA1 factors, and place NPR1 as a central hub integrating cold and pathogen signalling for a better adaptation of plants to an ever-changing environment. PMID- 30250279 TI - Genome encode analyses reveal the basis of convergent evolution of fleshy fruit ripening. AB - Fleshy fruits using ethylene to regulate ripening have developed multiple times in the history of angiosperms, presenting a clear case of convergent evolution whose molecular basis remains largely unknown. Analysis of the fruitENCODE data consisting of 361 transcriptome, 71 accessible chromatin, 147 histone and 45 DNA methylation profiles reveals three types of transcriptional feedback circuits controlling ethylene-dependent fruit ripening. These circuits are evolved from senescence or floral organ identity pathways in the ancestral angiosperms either by neofunctionalisation or repurposing pre-existing genes. The epigenome, H3K27me3 in particular, has played a conserved role in restricting ripening genes and their orthologues in dry and ethylene-independent fleshy fruits. Our findings suggest that evolution of ripening is constrained by limited hormone molecules and genetic and epigenetic materials, and whole-genome duplications have provided opportunities for plants to successfully circumvent these limitations. PMID- 30250281 TI - High resolution 7T and 9.4T-MRI of human cerebral arterial casts enables accurate estimations of the cerebrovascular morphometry. AB - Quantitative data on the morphology of the cerebral arterial tree could aid in modelling and understanding cerebrovascular diseases, but is scarce in the range between 200 micrometres and 1 mm diameter arteries. Traditional manual measurements are difficult and time consuming. 7T-MRI and 9.4T-MRI of human cerebral arterial plastic casts could proof feasible for acquiring detailed morphological data of the cerebral arterial tree in a time efficient method. One cast of the complete human cerebral arterial circulation embedded in gadolinium containing gelatine gel was scanned at 7T-MRI (0.1 mm isotropic resolution). A small section of another cast was scanned at 9.4T-MRI (30 um isotropic resolution). Subsequent 3D-reconstruction was performed using a semi-automatic approach. Validation of 7T-MRI was performed by comparing the radius calculated using MRI to manual measurements on the same cast. As manual measurement of the small section was not feasible, 9.4T-MRI was validated by scanning the small section both at 7T-MRI and 9.4T MRI and comparing the diameters of arterial segments. Linear regression slopes were 0.97 (R-squared 0.94) and 1.0 (R-squared 0.90) for 7T-MRI and 9.4T-MRI. This data shows that 7T-MRI and 9.4T-MRI and subsequent 3D reconstruction of plastic casts is feasible, and allows for characterization of human cerebral arterial tree morphology. PMID- 30250282 TI - Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma. AB - Osteosarcoma (OS), the most common primary cancer of bone, exhibits a high propensity for local invasion and distant metastasis. This study sought to elucidate the role of S phase kinase-associated protein (Skp2) in osteosarcoma invasion and metastasis and to explore flavokawain A (FKA), a natural chalcone from kava extract, as a potential Skp2 targeting agent for preventing osteosarcoma progression. Skp2 was found to be overexpressed in multiple osteosarcoma cell lines, including 5 standard and 8 primary patient-derived cell lines. Patients whose tumors expressed high levels of Skp2 sustained a significantly worse metastasis-free (p = 0.0095) and overall survival (p = 0.0013) than those with low Skp2. Skp2 knockdown markedly reduced in vitro cellular invasion and in vivo lung metastasis in an orthotopic mouse model of osteosarcoma. Similar to Skp2 knockdown, treatment with FKA also reduced Skp2 expression in osteosarcoma cell lines and blocked the invasion of osteosarcoma cells in vitro and lung metastasis in vivo. Together, our findings suggest that Skp2 is a promising therapeutic target in osteosarcoma, and that FKA may be an effective Skp2-targeted therapy to reduce osteosarcoma metastasis. PMID- 30250283 TI - Rapid Fabrication of Microporous BaTiO3/PDMS Nanocomposites for Triboelectric Nanogenerators through One-step Microwave Irradiation. AB - Even though porous elastomers and elastomeric nanocomposites have shown many advantages for triboelectric nanogenerators (TENGs), their fabrication techniques are relatively complicated, inefficient, and time-consuming. In this work, we introduced a simple, efficient and rapid concept to fabricate porous polydimethylsiloxane (PDMS) nanocomposites. PDMS nanocomposites with various porous structure were produced within a few minutes through just one-step microwave irradiation without any post-processing. Three solvents with different boiling points were selected as sacrificial materials to control porous structure. To fabricate nanocomposites, BaTiO3 (BT) nanoparticles were mixed into the uncured PDMS and sacrificial solvent mixture. Additionally, Ni nanoparticles were also used to understand the effect of embedded material's property on porous structure. The porous BT/PDMS nanocomposites fabricated via microwave irradiation greatly enhanced the electrical performance of TENGs as compared to a pure solid elastomer. The present study provides a simple, rapid and inexpensive approach for fabricating TENGs based on porous elastomeric nanocomposites. PMID- 30250284 TI - Caspase-11-mediated tubular epithelial pyroptosis underlies contrast-induced acute kidney injury. AB - Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients after administration of iodinated contrast media and is associated with a significant high risk for severe renal failure and death due to the wholesale necrosis of the tubules and interstitial inflammation. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in tubular epithelial cell (TEC) death and contrast-induced acute kidney injury. Here we show that systemic exposure to contrast media causes severe tubular epithelial pyroptosis that is mediated by the inflammatory caspases, caspases 4/5 in human TECs, or the murine homolog caspase-11 in mice in vivo and in mouse TECs in vitro. Knockdown of caspase-4/5 preserved human TECs from cell death and reduced the release of mature IL-1beta, and in caspase-11-deficient mice, contrast-induced acute kidney injury was abrogated, indicating a central role for caspase-11 in acute kidney injury. In addition, deletion of caspase-11 in TECs reduced Gsdmd cleavage, which is the key process for execution of pyroptosis. These results establish the requisite role of epithelial pyroptosis in contrast-induced acute kidney injury and suggest that epithelial inflammatory caspases are an important therapeutic target for acute kidney injury. PMID- 30250286 TI - Acute and rapid degradation of endogenous proteins by Trim-Away. AB - Protein depletion is a key approach to understanding the functions of a protein in a biological system. We recently developed the Trim-Away approach in order to rapidly degrade endogenous proteins without prior modification. Trim-Away is based on the ubiquitin ligase and Fc receptor TRIM21, which recognizes antibody bound proteins and targets them for degradation by the proteasome. In a typical Trim-Away experiment, protein degradation is achieved in three steps: first, introduction of an antibody against the target protein; second, recruitment of endogenous or exogenous/overexpressed TRIM21 to the antibody-bound target protein; and third, proteasome-mediated degradation of the target protein, antibody and TRIM21 complex. Protein degradation by Trim-Away is acute and rapid, with half-lives of ~10-20 min. The major advantages of Trim-Away over other protein degradation methods are that it can be applied to any endogenous protein without prior modification; that it uses conventional antibodies that are widely available; and that it can be applied to a wide range of cell types, including nondividing primary human cells, for which other loss-of-function assays are challenging. In this protocol, we describe the detailed procedures for antibody preparation and delivery in mouse oocytes and cultured cells via microinjection and electroporation. In addition, we provide recommendations for antibody selection and validation, and for the generation of TRIM21-overexpressing cell lines for cases in which endogenous TRIM21 is limited. A typical Trim-Away experiment takes just a few hours. PMID- 30250287 TI - Design and operation of reconfigurable two-dimensional DNA molecular arrays. AB - Information relay and cascaded transformation are essential in biology and engineering. Imitation of such complex behaviors via synthetic molecular self assembly at the nanoscale remains challenging. Here we describe the use of structural DNA nanotechnology to realize prescribed, multistep, long-range information relay and cascaded transformation in rationally designed molecular arrays. The engineered arrays provide a controlled platform for studying complex dynamic behaviors of molecular arrays and have a range of potential applications, such as with reconfigurable metamaterials. A reconfigurable array consists of a prescribed number of interconnected dynamic DNA antijunctions. Each antijunction unit consists of four DNA domains of equal length with four dynamic nicking points, which are capable of switching between two stable conformations through an intermediate open conformation. By interconnecting the small DNA antijunctions, one can build custom two-dimensional (2D) molecular 'domino' arrays with arbitrary shapes. More important, the DNA molecular arrays are capable of undergoing programmed, multistep, long-range transformation driven by information relay between neighboring antijunction units. The information relay is initiated by the trigger strands under high temperature or formamide concentration. The array's dynamic behavior can be regulated by external factors such as its shape and size, points of transformation initiation, and/or any engineered information propagation pathways. This protocol provides detailed strategies for designing DNA molecular arrays, as well as procedures for sample production, purification, reconfiguration, and imaging by atomic force microscopy (AFM) and transmission electron microscopy (TEM). The procedure can be completed in 4-7 d. PMID- 30250285 TI - Sharing an environment with sick conspecifics alters odors of healthy animals. AB - Body odors change with health status and the odors of sick animals can induce avoidance behaviors in healthy conspecifics. Exposure to sickness odors might also alter the physiology of healthy conspecifics and modify the odors they produce. We hypothesized that exposure to odors of sick (but non-infectious) animals would alter the odors of healthy cagemates. To induce sickness, we injected mice with a bacterial endotoxin, lipopolysaccharide. We used behavioral odor discrimination assays and analytical chemistry techniques followed by predictive classification modeling to ask about differences in volatile odorants produced by two types of healthy mice: those cohoused with healthy conspecifics and those cohoused with sick conspecifics. Mice trained in Y-maze behavioral assays to discriminate between the odors of healthy versus sick mice also discriminated between the odors of healthy mice cohoused with sick conspecifics and odors of healthy mice cohoused with healthy conspecifics. Chemical analyses paired with statistical modeling revealed a parallel phenomenon. Urine volatiles of healthy mice cohoused with sick partners were more likely to be classified as those of sick rather than healthy mice based on discriminant model predictions. Sickness-related odors could have cascading effects on neuroendocrine or immune responses of healthy conspecifics, and could affect individual behaviors, social dynamics, and pathogen spread. PMID- 30250288 TI - Genetic lineage tracing of resident stem cells by DeaLT. AB - Unraveling the fates of resident stem cells during tissue regeneration is an important objective in clinical and basic research. Genetic lineage tracing based on Cre-loxP recombination provides an effective strategy for inferring cell fate and cell conversion in vivo. However, the determination of the exact fates of resident stem cells or their derivatives in disease states and during tissue regeneration remains controversial in many fields of study, partly because of technical limitations associated with Cre-based lineage tracing, such as, for example, off-target labeling. Recently, we generated a new lineage-tracing platform we named DeaLT (dual-recombinase-activated lineage tracing) that uses the Dre-rox recombination system to enhance the precision of Cre-mediated lineage tracing. Here, we describe as an example a detailed protocol using DeaLT to trace the fate of c-Kit+ cardiac stem cells and their derivatives, in the absence of any interference from nontarget cells such as cardiomyocytes, during organ homeostasis and after tissue injury. This lineage-tracing protocol can also be used to delineate the fate of resident stem cells of other organ systems, and takes ~10 months to complete, from mouse crossing to final tissue analysis. PMID- 30250289 TI - Direct fluorine-18 labeling of heat-sensitive biomolecules for positron emission tomography imaging using the Al18F-RESCA method. AB - Positron emission tomography (PET) is a quickly expanding, non-invasive molecular imaging technology, and there is high demand for new specific imaging probes. Herein, we present a generic protocol for direct radiolabeling of heat-sensitive biomolecules with the positron-emitting radioisotope fluorine-18 (18F) using the aluminum fluoride restrained complexing agent (Al18F-RESCA) method. The Al18F RESCA method combines the chemical advantages of a chelator-based radiolabeling method with the unique physical properties of the radionuclide of choice, fluorine-18. Proteins of interest can be conjugated to RESCA via amine coupling using (+/-)-H3RESCA-TFP, followed by purification using size-exclusion chromatography (SEC). Next, RESCA-derivatized biomolecules can be labeled in one step, at room temperature (~20 degrees C) in an aqueous medium with aluminum fluoride (Al18F). Al18F-labeled proteins can be obtained with moderate (12-17 GBq/umol) to good (80-85 GBq/umol) apparent molar activity, depending on the starting activity of 18F-. In addition, satisfactory radiochemical yields (35 55%, non-decay corrected) and high radiochemical purity (>98%, using gel filtration or solid-phase purification) are obtained. The mild radiolabeling procedure takes 0.5 h to complete and can be used for direct labeling of vector molecules such as peptides, protein scaffolds, and engineered antibody fragments. PMID- 30250290 TI - Synthesis of an ultrasensitive BODIPY-derived fluorescent probe for detecting HOCl in live cells. AB - Hypochlorous acid (HOCl) is a critical member of the reactive oxygen species (ROS) produced by immune cells to fight infections. On the other hand, HOCl in homeostasis causes oxidative damage to biomolecules and is linked to many diseases, including inflammatory, neurodegenerative, and cardiovascular diseases. Herein, we detail a procedure for the preparation of a boron-dipyrromethene (BODIPY)-derived fluorescent probe for HOCl (BClO) and its application as an imaging reagent in living cells. BClO is synthesized in one pot through a four step procedure that is nearly the same as that for conventional BODIPY dye preparation, except for the ratio of starting materials. BClO has an extremely rapid response (saturated within seconds) and is ultrasensitive to HOCl. The detection limit of BClO reaches the subnanomolar range, which is the highest HOCl sensitivity to date. Taking advantage of the ultrasensitive character of BClO, we have previously demonstrated its ability to detect endogenous HOCl generated by macrophages and shown that it can also be used to discriminate cancer cell lines (which show high HOCl production) from non-cancer cell lines (which show low HOCl production). The protocol requires ~2 d for probe synthesis and up to ~18 h for fluorescence imaging and flow cytometry assays. PMID- 30250291 TI - Small-seq for single-cell small-RNA sequencing. AB - Small RNAs participate in several cellular processes, including splicing, RNA modification, mRNA degradation, and translational arrest. Traditional methods for sequencing small RNAs require a large amount of cell material, limiting the possibilities for single-cell analyses. We describe Small-seq, a ligation-based method that enables the capture, sequencing, and molecular counting of small RNAs from individual mammalian cells. Here, we provide a detailed protocol for this approach that relies on standard reagents and instruments. The standard protocol captures a complex set of small RNAs, including microRNAs (miRNAs), fragments of tRNAs and small nucleolar RNAs (snoRNAs); however, miRNAs can be enriched through the addition of a size-selection step. Ready-to-sequence libraries can be generated in 2-3 d, starting from cell collection, with additional days needed to computationally map the sequence reads and calculate molecular counts. PMID- 30250292 TI - Use of the iNo score to discriminate normal from altered nucleolar morphology, with applications in basic cell biology and potential in human disease diagnostics. AB - Ribosome biogenesis is initiated in the nucleolus, a cell condensate essential to gene expression, whose morphology informs cancer pathologists on the health status of a cell. Here, we describe a protocol for assessing, both qualitatively and quantitatively, the involvement of trans-acting factors in the nucleolar structure. The protocol involves use of siRNAs to deplete cells of factors of interest, fluorescence imaging of nucleoli in an automated high-throughput platform, and use of dedicated software to determine an index of nucleolar disruption, the iNo score. This scoring system is unique in that it integrates the five most discriminant shape and textural features of the nucleolus into a parametric equation. Determining the iNo score enables both qualitative and quantitative factor classification with prediction of function (functional clustering), which to our knowledge is not achieved by competing approaches, as well as stratification of their effect (severity of defects) on nucleolar structure. The iNo score has the potential to be useful in basic cell biology (nucleolar structure-function relationships, mitosis, and senescence), developmental and/or organismal biology (aging), and clinical practice (cancer, viral infection, and reproduction). The entire protocol can be completed within 1 week. PMID- 30250293 TI - Mixed-species RNA-seq for elucidation of non-cell-autonomous control of gene transcription. AB - Transcriptomic changes induced in one cell type by another mediate many biological processes in the brain and elsewhere; however, achieving artifact-free physical separation of cell types to study them is challenging and generally allows for analysis of only a single cell type. We describe an approach using a co-culture of distinct cell types from different species that enables physical cell sorting to be replaced by in silico RNA sequencing (RNA-seq) read sorting, which is possible because of evolutionary divergence of messenger RNA (mRNA) sequences. As an exemplary experiment, we describe the co-culture of purified neurons, astrocytes, and microglia from different species (12-14 d). We describe how to use our Python tool, Sargasso, to separate the reads from conventional RNA seq according to species and to eliminate any artifacts borne of imperfect genome annotation (10 h). We show how this procedure, which requires no special skills beyond those that might normally be expected of wet lab and bioinformatics researchers, enables the simultaneous transcriptomic profiling of different cell types, revealing the distinct influence of microglia on astrocytic and neuronal transcriptomes under inflammatory conditions. PMID- 30250294 TI - Astrocytic ATX fuels synaptic phospholipid signaling involved in psychiatric disorders. PMID- 30250295 TI - Publisher Correction: The machineries, regulation and cellular functions of mitochondrial calcium. AB - In the original version of the article, sentences highlighting references 108, 137 and 175 incorrectly refer to other items in the reference list: reference 106, 132 and 169, respectively, which were corrected - in order - to reference 110, 136 and 176. The changes have been made in the HTML and PDF versions of the manuscript. PMID- 30250296 TI - Electrical conductivity and magnetic dynamos in magma oceans of Super-Earths. AB - Super-Earths are extremely common among the numerous exoplanets that have been discovered. The high pressures and temperatures in their interiors are likely to lead to long-lived magma oceans. If their electrical conductivity is sufficiently high, the mantles of Super-Earth would generate their own magnetic fields. With ab initio simulations, we show that upon melting, the behavior of typical mantle silicates changes from semi-conducting to semi-metallic. The electrical conductivity increases and the optical properties are substantially modified. Melting could thus be detected with high-precision reflectivity measurements during the short time scales of shock experiments. We estimate the electrical conductivity of mantle silicates to be of the order of 100 Omega-1 cm-1, which implies that a magnetic dynamo process would develop in the magma oceans of Super Earths if their convective velocities have typical values of 1 mm/s or higher. We predict exoplanets with rotation periods longer than 2 days to have multipolar magnetic fields. PMID- 30250297 TI - Estrogen receptor beta promotes the vasculogenic mimicry (VM) and cell invasion via altering the lncRNA-MALAT1/miR-145-5p/NEDD9 signals in lung cancer. AB - While estrogen receptor beta (ERbeta) may impact the progression of non-small cell lung cancer (NSCLC), its linkage to alteration of the vasculogenic mimicry (VM) formation to influence the NSCLC cell invasion remains unclear. Here, we analyzed immunohistochemistry data from NSCLC tissues and found that ERbeta positive NSCLC female patients had worse survival outcomes than those of ERbeta negative NSCLC female patients. In vitro studies using multiple NSCLC cell lines also revealed that ERbeta could increase the VM formation and cell invasion. Molecular mechanism dissection suggested that ERbeta could increase the lncRNA MALAT1 (MALAT1) expression via directly binding to the estrogen response elements (EREs) located on the promoter of MALAT1, which could then lead to (i) suppressing the miR145-5p and (ii) increasing the NEDD9 protein expression as miR145-5p can directly target the 3'-UTR of NEDD9-mRNA. A preclinical study using the in vivo mouse model further confirmed the in vitro cell lines data. Together, results from the above studies demonstrated that ERbeta can promote NSCLC VM formation and cell invasion via altering the ERbeta/MALAT1/miR145-5p/NEDD9 signaling. Targeting this newly identified signaling pathway with small molecules may help the development of novel therapies to better suppress the NSCLC metastasis. PMID- 30250298 TI - Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2 ALDH1 signaling in the pancreas. AB - The accumulation of prostaglandin E2 (PGE2) during chronic inflammation has been implicated in the progression of several cancers. Cyclooxygenase is the key synthesizing enzyme of PGE2, although the degradation enzyme 15 hydroxyprostaglandin dehydrogenase (15-PGDH) has received considerable attention recently. We investigated the molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) progression via 15-PGDH downregulation. Here, we found that 15-PGDH expression was inversely correlated with ALDH1, an important cancer stem cell-associated marker indicative of poor prognosis in humans. Moreover, we demonstrated that pharmacological inhibition of 15-PGDH enhanced CYP26A1 expression, leading to depletion of all-trans retinoic acid (ATRA) and expansion of the ALDH1-positive subset in both human PDAC cells and tumor cells of KrasLSL G12D/+; Ptf1aCre/+ (KC) mice. Furthermore, genetic deletion of 15-Pgdh in KC mice showed PGE2 accumulation and ATRA depletion in the pancreas, resulting in PDAC with high levels of Aldh1 and Ki-67. Finally, ATRA replacement suppressed 15-PGDH inhibition-induced tumor progression in KC mice, and ATRA treatment attenuated Aldh1 activity in tumor cells isolated from the pancreas of 15-Pgdh-/- KC mice. These findings provide evidence that 15-PGDH inhibition enhances KRAS-driven tumor progression via ATRA depletion in the pancreas. Therefore, ATRA replacement could be a potential strategy for PDAC treatment. PMID- 30250299 TI - Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma. AB - While the two mammalian sphingosine kinases, SK1 and SK2, both catalyze the generation of pro-survival sphingosine 1-phosphate (S1P), their roles vary dependent on their different subcellular localization. SK1 is generally found in the cytoplasm or at the plasma membrane where it can promote cell proliferation and survival. SK2 can be present at the plasma membrane where it appears to have a similar function to SK1, but can also be localized to the nucleus, endoplasmic reticulum or mitochondria where it mediates cell death. Although SK2 has been implicated in cancer initiation and progression, the mechanisms regulating SK2 subcellular localization are undefined. Here, we report that SK2 interacts with the intermediate chain subunits of the retrograde-directed transport motor complex, cytoplasmic dynein 1 (DYNC1I1 and -2), and we show that this interaction, particularly with DYNC1I1, facilitates the transport of SK2 away from the plasma membrane. DYNC1I1 is dramatically downregulated in patient samples of glioblastoma (GBM), where lower expression of DYNC1I1 correlates with poorer patient survival. Notably, low DYNC1I1 expression in GBM cells coincided with more SK2 localized to the plasma membrane, where it has been recently implicated in oncogenesis. Re-expression of DYNC1I1 reduced plasma membrane localized SK2 and extracellular S1P formation, and decreased GBM tumor growth and tumor-associated angiogenesis in vivo. Consistent with this, chemical inhibition of SK2 reduced the viability of patient-derived GBM cells in vitro and decreased GBM tumor growth in vivo. Thus, these findings demonstrate a tumor-suppressive function of DYNC1I1, and uncover new mechanistic insights into SK2 regulation which may have implications in targeting this enzyme as a therapeutic strategy in GBM. PMID- 30250300 TI - Hypoxia-induced TUFT1 promotes the growth and metastasis of hepatocellular carcinoma by activating the Ca2+/PI3K/AKT pathway. AB - Tuftelin1 (TUFT1), an acidic protein constituent of developing and mineralizing tooth tissues, is regulated by hypoxia and the Hedgehog signaling pathway. We investigated the role of TUFT1 in hepatocellular carcinoma (HCC). qRT-PCR, immunohistochemistry and western blot were employed to evaluate TUFT1 level in HCC. MTT, BrdU, 3D culture and Transwell assays were used to assess cell viability, proliferation, in vitro growth, migration, and invasion. Subcutaneous and tail vein injection models were established to investigate in vivo growth and metastasis. Chromatin immunoprecipitation was performed to assess binding of hypoxia-inducible factor 1alpha (HIF-1alpha) to TUFT1 promoter. A microRNA array was used to identify hypoxia-related microRNAs. TUFT1 was elevated in HCC, and correlated with unfavorable clinicopathologic characteristics and poor survival. TUFT1 promoted HCC cell growth, metastasis and epithelial-mesenchymal transition in vitro and in vivo via activation of Ca2+/PI3K/AKT pathway. Hypoxia induced TUFT1 expression in an HIF-1alpha dependent manner, and TUFT1 expression was positively correlated with HIF-1alpha level in HCC tissues. Hypoxiaenhanced TUFT1 expression by downregulating miR-671-5p rather than by directly promoting the binding of HIF-1alpha to TUFT1 promoter. MiR-671-5p interacted with the 3'-UTR of TUFT1 mRNA and subsequently inhibited TUFT1 expression. Consequently, knockdown of TUFT1 blocked the effects of hypoxia in promoting HCC progression. TUFT1 promoted the growth, metastasis and EMT of HCC cells through activating Ca2+/PI3K/AKT pathway. The hypoxic microenvironment increased the expression of TUFT1 via downregulation of miR-671-5p. TUFT1 may function as a potential therapeutic target for the intervention and treatment of HCC. PMID- 30250301 TI - Donor blood remains a source of heavy metal exposure. PMID- 30250302 TI - Prenatal exposure to perfluoroalkyl substances and adipocytokines: the HOME Study. AB - OBJECTIVE: Gestational perfluoroalkyl substances exposure has been associated with decreased birthweight. We determined if gestational perfluoroalkyl substances exposure was associated with fetal metabolic markers using data from the HOME Study, a prospective birth cohort of pregnant women and their children in Cincinnati, Ohio. METHODS: Maternal serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid, and perfluorohexane sulfonic acid were quantified. We measured neonatal adipocytokine (leptin and adiponectin) concentrations in umbilical cord serum, and estimated percent differences with a 2-fold increase in maternal perfluoroalkyl substances concentrations among 230 mother-infant pairs. RESULTS: Median maternal serum PFOA and PFOS concentrations were 5.6 ng/mL and 14 ng/mL, respectively. Leptin was positively correlated with infant birthweight (p < 0.001). There were no statistically significant associations between maternal perfluoroalkyl substances and neonatal adipocytokine concentrations; each 2-fold increase in PFOA was associated with a non-significant increase in leptin (5%; 95% CI: -10, 22) and adiponectin (7%; 95% CI: -4, 19). CONCLUSION: Despite known associations with reduced birthweight, gestational serum perfluoroalkyl substances concentrations were not associated with neonatal adipocytokine concentrations. Further exploration of pathways of perfluoroalkyl substances associated changes in birthweight may help identify biomarkers that could be used to identify at-risk populations and develop interventions. PMID- 30250303 TI - Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months. AB - BACKGROUND: Studies of early childhood outcomes of mild hypoxic-ischemic encephalopathy (HIE) identified in the first 6 h of life are lacking. OBJECTIVE: To evaluate neurodevelopmental outcomes at 18-22 months of PRIME study. STUDY DESIGN: Multicenter, prospective study of mild HIE defined as >=1 abnormality using the modified Sarnat within 6 h of birth and not meeting cooling criteria. Primary outcome was disability with mild: Bayley III cognitive 70-84 or >=85 and either Gross Motor Function Classification System (GMFCS) 1 or 2, seizures, or hearing deficit; moderate: cognitive 70-84 and either GMFCS 2, seizures, or hearing deficit; severe: cognitive <70, GMFCS 3-5. RESULTS: Of the 63 infants enrolled, 51 (81%) were evaluated at 19 +/- 2 months and 43 (68%) completed Bayley III. Of the 43 infants, 7 (16%) were diagnosed with disability, including 1 cerebral palsy and 2 autism. Bayley scores < 85 in either cognition, motor, or language were detected in 17 (40%): 14 (32%) language, 7 (16%) cognitive, and 6 (14%) motor domain. Infants with disability had more abnormalities on discharge examination and brain MRI, with longer hospital stay (p < 0.001). CONCLUSIONS: In this contemporary untreated cohort of mild HIE, disability occurred in 16% of infants at 18-22 months. PMID- 30250304 TI - Intranasal administration of resveratrol successfully prevents lung cancer in A/J mice. AB - Lung cancer is the most lethal cancer in the world. About 80% of lung cancer deaths are linked to tobacco use. As a complement to tobacco control, efficient chemoprevention strategies are needed to tackle lung cancer epidemic. Resveratrol is one of the most studied natural products, notably for its cancer chemoprevention properties. However, its low oral bioavailability has often limited the translation of in vitro activities to in vivo effects. While oral administration of resveratrol effectively inhibited colorectal carcinogenesis, it failed to protect mice from chemically-induced lung carcinogenesis. Therefore, non-invasive parenteral routes must be considered to bring resveratrol to the lungs. In the present study, intranasal administration of a concentrated formulation proved to be a valid method to expose the lungs to a sufficient amount of resveratrol. This formulation was administered three times a week for 25 weeks to A/J mice having 4-[methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone induced lung carcinogenesis. Resveratrol-treated mice showed a 27% decrease in tumour multiplicity, with smaller tumours, resulting in 45% decrease in tumour volume/mouse. In vitro investigations highlighted apoptosis as a potential mechanism of action. This study presents an effective way to overcome resveratrol low oral bioavailability, encouraging a reevaluation of its use in future clinical trials. PMID- 30250305 TI - Familial TGCT: polygenic aetiology advanced. PMID- 30250306 TI - Early-life alcohol intake and high-grade prostate cancer. PMID- 30250307 TI - The evolution of fruit colour: phylogeny, abiotic factors and the role of mutualists. AB - The adaptive significance of fruit colour has been investigated for over a century. While colour can fulfil various functions, the most commonly tested hypothesis is that it has evolved to increase fruit visual conspicuousness and thus promote detection and consumption by seed dispersing animals. However, fruit colour is a complex trait which is subjected to various constraints and selection pressures. As a result, the effect of animal selection on fruit colour are often difficult to identify, and several studies have failed to detect it. Here, we employ an integrative approach to examine what drives variation in fruit colour. We quantified the colour of ripe fruit and mature leaves of 97 tropical plant species from three study sites in Madagascar and Uganda. We used phylogenetically controlled models to estimate the roles of phylogeny, abiotic factors, and dispersal mode on fruit colour variation. Our results show that, independent of phylogeny and leaf coloration, mammal dispersed fruits are greener than bird dispersed fruits, while the latter are redder than the former. In addition, fruit colour does not correlate with leaf colour in the visible spectrum, but fruit reflection in the ultraviolet area of the spectrum is strongly correlated with leaf reflectance, emphasizing the role of abiotic factors in determining fruit colour. These results demonstrate that fruit colour is affected by both animal sensory ecology and abiotic factors and highlight the importance of an integrative approach which controls for the relevant confounding factors. PMID- 30250309 TI - NPC mutations cause SRNS. PMID- 30250308 TI - Untangling the complexity of opioid receptor function. AB - Mu opioid receptor agonists are among the most powerful analgesic medications but also among the most addictive. The current opioid crisis has energized a quest to develop opioid analgesics that are devoid of untoward effects. Since their discovery in the 1970's, there have been major advances in our understanding of the endogenous opioid systems that these drugs target. Yet many questions remain and the development of non-addictive opioid analgesics has not been achieved. However, access to new molecular, genetic and computational tools have begun to elucidate the structural dynamics of opioid receptors, the scaffolding that links them to intracellular signaling cascades, their cellular trafficking and the distinct ways that various opioid drugs modify them. This mini-review highlights some of the chemical and pharmacological findings and new perspectives that have arisen from studies using these tools. They reveal multiple layers of complexity of opioid receptor function, including a spatiotemporal specificity in opioid receptor-induced cellular signaling, ligand-directed biased signaling, allosteric modulation of ligand interactions, heterodimerization of different opioid receptors, and the existence of slice variants with different ligand specificity. By untangling these layers, basic research into the chemistry and pharmacology of opioid receptors is guiding the way towards deciphering the mysteries of tolerance and physical dependence that have plagued the field and is providing a platform for the development of more effective and safer opioids. PMID- 30250310 TI - Sugerencias en torno a medicamentos de efectividad demostrada sin interes comercial para la industria farmaceutica. AB - Varios medicamentos de adecuada eficacia han sido retirados del mercado por razones financieras, ya sea por su reducido precio (la patente ha expirado) o porque han sido sustituidos por nuevos farmacos (con patentes vigentes); otros tantos no han sido desarrollados porque las enfermedades contra las que van dirigidos no son economicamente promisorias debido al tipo de poblacion que las padece (estratos economicamente marginados o sin significacion numerica). Deberan establecerse lineamientos e incentivos para la industria farmaceutica y de biotecnologia. PMID- 30250311 TI - [Medicina supresora y medicina estimulante: una mirada penetrante de la practica medica]. AB - La teoria de la medicina supresora (MS) y la medicina estimulante (ME) destaca dos formas radicalmente distintas de entender la enfermedad y de enfrentarla. Para la MS es un objeto extrano o ajeno al organismo que hay que disminuir o destruir (suprimir); para la ME es un trastorno de la armonia interna que requiere fortalecer o avivar el organismo para restablecerla (estimular). En la medicina moderna, el poder de la industria de la salud favorece el predominio de la MS, por su alta rentabilidad, y la marginacion de las medicinas alternativas (MA), poco rentables que, al igual que la vacunacion o las terapias sustitutivas y regenerativas, son formas de ME. El efecto placebo (EP) inherente a la practica medica, revelador de fuerzas curativas endogenas susceptibles de estimulacion, da sentido a la ME y credibilidad a las MA. La direccion del EP de lo macro (psicosocial) a lo micro (fisico-quimico) explica su alta especificidad y ausencia de efectos secundarios. El efecto farmacologico de lo micro a lo macro, opuesto a las fuerzas endogenas, conlleva indefectiblemente efectos secundarios que requieren ulteriores supresiones y dosis repetidas indefinidamente. Se analizan equivocos de la ciencia con respecto al EP y al imponer a las MA criterios metodicos propios de la MS, que las desvirtua, descalifica y excluye como objetos de conocimiento. Se insiste en la necesidad de reconocer la ME y rescatar las MA para la indagacion, a fin de explorar sinergias, complementos o reemplazos con relacion a la MS en la busqueda del bien vivir. PMID- 30250312 TI - [Experiencia en el tratamiento de la hemorragia uterina anormal en adolescentes con enfermedad renal cronica]. AB - Introduccion: La enfermedad renal cronica (ERC) se asocia con alteraciones menstruales, y el manejo del sangrado uterino suele ser complejo por las condiciones de este grupo de pacientes. El objetivo de este trabajo fue describir la respuesta clinica al tratamiento hormonal de las alteraciones menstruales de adolescentes con ERC. Metodos: Se presentan los datos de una serie de casos de pacientes adolescentes con ERC que cursaron con alteraciones menstruales y que recibieron tratamiento desde el ano 2008 al 2012. Se identificaron las caracteristicas del trastorno menstrual, del tratamiento hormonal recibido y de la respuesta al mismo. El analisis estadistico fue descriptivo. Resultados: Se estudiaron 11 pacientes de sexo femenino con edad promedio de 14.5 anos, que se encontraban en predialisis (n = 1), dialisis peritoneal (n = 7) y hemodialisis (n = 3). Las pacientes presentaron hiperpolimenorrea asociada a la opsomenorrea (n = 3), en su mayoria clasificadas como hemorragia uterina anormal secundaria. El tratamiento, en general, fue con progestagenos de manera inicial (clormadinona con o sin medroxiprogesterona) o bien con anticonceptivos combinados. En la mayoria de las pacientes se obtuvo una respuesta favorable; sin embargo, hubo casos en los que fue necesario modificar la dosis y el tiempo de tratamiento. Conclusiones: La mayor parte de las adolescentes con ERC que han sido tratadas por hemorragia uterina anormal en nuestro estudio tuvieron una respuesta favorable al tratamiento hormonal. Background: Chronic kidney disease (CKD) is associated with menstrual abnormalities and management of uterine bleeding is often complex because of the conditions in this group of patients. The aim of this study was to describe the clinical response to hormonal treatment of menstrual alterations in adolescents with CKD. Methods: We present data of cases of adolescent patients with CKD who had undergone menstrual changes and received treatment during the period 2008 to 2012. The characteristics of the menstrual disorder, hormone treatment received, and response to treatment were evaluated. The statistical analysis aplicated to analyze the results was descriptive. Results: We studied 11 patients with a mean age of 14.5 years, who were in predialysis (n = 1), peritoneal dialysis (n = 7), hemodialysis (n = 3). Patients had hyperpolymenorrhea associated with opsomenorrhea (n = 3), mostly classified as secondary abnormal uterine bleeding. Treatment, in general, was with progestins initially (chlormadinone with or without medroxyprogesterone) or combined contraceptives. In the majority of the patients, a favorable response was obtained; however, there were cases where it was necessary to modify the dose and time of treatment. Conclusions: The majority of adolescents with CKD who have been treated for abnormal uterine bleeding in our study had a favorable response to hormonal treatment. PMID- 30250313 TI - Estudio de variabilidad geografica de las hospitalizaciones potencialmente evitables en Mexico durante tres quinquenios. AB - Introduccion: Las enfermedades que motivan hospitalizacion potencialmente evitable tienen la caracteristica de ser sensibles a la prevencion, diagnostico y control ambulatorio en atencion primaria a la salud. Objetivos: Identificar la tendencia nacional de la hospitalizacion potencialmente evitable entre 2001 y 2015 y analizar el patron geografico a nivel municipal y priorizar municipios. Metodo: Se usaron los egresos hospitalarios de la Secretaria de Salud. Se calcularon tasas de prevalencia nacionales y razones municipales, estandarizadas por edad y sexo. Se emplearon estadisticos de variabilidad para analizar y elaborar mapas. Resultados: De los egresos hospitalarios, 10.39, 9.81 y 9.26 % se clasificaron como hospitalizaciones potencialmente evitables para cada periodo quinquenal. La tasa nacional se incremento en el lapso estudiado: de 36.27 a 47.24 por 10 000 habitantes. La diabetes mellitus, las gastroenteritis y otras enfermedades de las vias respiratorias inferiores fueron las causas de mayor frecuencia. Los patrones geograficos en los tres periodos fueron semejantes. Se identificaron 487 municipios prioritarios, 174 con alto uso y 313 con sobreuso hospitalario, que concentraron 35.83 % de las hospitalizaciones evitables, 8.58 y 27.25 %, respectivamente. Conclusiones: En Mexico existe amplia variabilidad geografica de la hospitalizacion potencialmente evitable con un patron casi inmutable. Introduction: Diseases that motivate potentially preventable hospitalization (PH) have the characteristic of being sensitive to prevention, diagnosis and control on an outpatient basis in primary care. Objectives: To identify the national trend of potentially avoidable hospitalization between 2001 and 2015; to analyze its geographical pattern at the municipal level and prioritize municipalities. Method: Hospital discharge records from the Ministry of Health were used. National prevalence rates and municipal PH ratios, standardized by age and gender, were calculated. Variability statistics were used to analyze and generate maps. Results: Among all hospital discharges, 10.39%, 9.81% and 9.26% were classified as PH for each period. The national PH rate did increase in the studied period: from 36.27 to 47.24 per 10,000 population. Diabetes mellitus, gastroenteritis and other diseases of the lower respiratory tract were the most common causes. Geographic patterns of PH were similar for the three periods. A total of 487 priority municipalities were identified, 174 with hospital high use and 313 with overuse, 35.83 % were avoidable hospitalizations, 8.58% and 27.25%, respectively. Conclusions: In Mexico there is wide geographical variability in PH, with an almost unchanging geographical pattern. PMID- 30250314 TI - Importancia del "diagnostico temprano" en los ninos con cancer para mejorar el pronostico: concepto con poco sustento cientifico. AB - La mortalidad por cancer en ninos mexicanos no ha disminuido a los niveles informados en paises desarrollados. Una explicacion frecuentemente declarada es el alto porcentaje (57.3 %) de pacientes diagnosticados en estadios avanzados (III/IV), atribuible a errores en la sospecha o en la metodologia empleada, consideracion dudosa si se toma en cuenta que el tiempo de diagnostico y la proporcion de estadios avanzados en Mexico son semejantes a los de paises desarrollados. En la mayoria de los ninos con cancer, los dias transcurridos desde el primer sintoma a momento del diagnostico oncologico no correlacionan con el estadio clinico y tampoco con la probabilidad de supervivencia. El exito en la supervivencia depende en gran medida del tratamiento integral (especifico y de la atencion a las complicaciones). Esta vision obliga a estrategias dirigidas principalmente a invertir mas recursos en opciones terapeuticas eficaces y eficientes, capacitacion oncologica integral del equipo de salud (medicos, enfermeras, tecnicos), tecnologias diagnosticas, fomento a la colaboracion interinstitucional e internacional y apoyo socioeconomico a las familias durante el proceso terapeutico. PMID- 30250315 TI - La psoriasis: de la investigacion basica y clinica al desarrollo de nuevos tratamientos. AB - La psoriasis es una enfermedad cutanea incurable que afecta a 2.9 % de la poblacion mexicana, por lo que es trascendente analizar el impacto de la medicina traslacional en el desarrollo de medicamentos antipsoriasicos. En esta revision se discuten conceptos etiopatogenicos de la enfermedad y se analizan articulos publicados entre 2005 y 2017 en torno a medicamentos en desarrollo, ademas, se presenta un analisis critico sobre las perspectivas futuras en el desarrollo de nuevos tratamientos. El uso de estrategias bidireccionales de la medicina traslacional ha permitido incrementar significativamente el numero de tratamientos antipsoriasicos disponibles. Se encontraron 18 nuevos farmacos en exploracion. La caracterizacion de antigenos responsables de la activacion inmunologica, la identificacion de biomarcadores predictivos de eficacia farmacologica, el desarrollo de modelos mas representativos de la enfermedad, asi como la integracion de aspectos farmacogenomicos a estrategias de medicina traslacional fueron identificados como elementos relevantes que deben ser incorporados en el desarrollo de nuevas opciones terapeuticas. PMID- 30250316 TI - Thyroid function in pediatric population with different nutritional status. AB - Background: Thyroid dysfunction has been associated with the development of obesity. There are few studies describing their status in Mexican schoolchildren, in whom obesity and subclinical hypothyroidism (SCH) prevail. Methods: Levels of stimulating thyroid hormone (TSH) and thyroid hormones (TH) were correlated with anthropometric variables as indicators of nutritional status in schoolchildren residents of Mexico City. The thyroid status and prevalences of SCH were compared between all the nutritional conditions, considering the degree of pubertal development. Results: The mean of TSH was 2.96 +/- 1.48 mIU/L, and the prevalence of SCH was 11.30%. TSH levels are higher in prepubertal (5.21 +/-1.24 mIU/L (95% confidence interval [CI]: 3.72-6.69) versus pubertal children (2.96 +/- 1.48 mIU/L [95% CI: 2.61-3.30), as well as in children with obesity (3.5 +/- 1.13 mIU/L [95% CI: 2.98-4.02]) versus normal weight children (2.43 +/- 1.37 mIU/L [95% CI: 1.88 - 2.97]). The TH is similar in the whole population, although triiodothyronine total levels tend to be lower in malnourished children. There is a positive correlation between TSH levels and all anthropometric variables. The prevalences of SCH were higher in groups of children with overweight and obesity. Conclusions: The body fat content is associated with thyroid status in Mexican schoolchildren. In addition, it is relevant to consider the degree of pubertal development for diagnosing hyperthyrotropinemia in children and adolescents. PMID- 30250317 TI - Recomendaciones para la prescripcion segura de opioides en el manejo del dolor cronico no oncologico. AB - El tratamiento del dolor cronico severo es una meta historica de la medicina. Los opioides naturales (como la morfina) se han usado por muchos anos y la aparicion reciente de opioides sinteticos se ha sumado a esta opcion terapeutica, sin embargo, el potencial adictivo de estas sustancias obliga a la reglamentacion de su uso. Las agencias medicas internacionales recomiendan prudencia en el uso terapeutico de opioides. PMID- 30250318 TI - Impacto de la medicina nuclear en el diagnostico y tratamiento del cancer diferenciado de tiroides. AB - Los pacientes afectados por el cancer diferenciado de tiroides habitualmente presentan un curso clinico favorable, ya que la piedra angular del tratamiento es la cirugia; a pesar de esto, algunos pueden desarrollar un ominoso desenlace, debido a las caracteristicas clinico-patologicas de esta enfermedad. El tratamiento optimo aun es controvertido, en especial respecto a la extension de la cirugia, indicaciones de radioyodo y la supresion de la hormona estimulante de la tiroides. La correcta evaluacion de los riesgos, antes y despues de la cirugia, facilita un selectivo enfoque del tratamiento; destacando la relevancia de revisar el impacto de la medicina nuclear en la correcta evaluacion, tratamiento y seguimiento de los pacientes que padecen esta neoplasia. PMID- 30250319 TI - [Hallazgos clinicos y epidemiologicos en la neurofibromatosis tipo 1 y el complejo esclerosis tuberosa en una serie de pacientes pediatricos]. AB - Introduccion: La neurofibromatosis tipo 1 (NF1) es una entidad genetica con una incidencia de 1 entre 2,500 a 3,500 nacimientos. Por su parte, el complejo esclerosis tuberosa (CET) presenta una incidencia de 1 entre 6,000 a 10,000 nacimientos. Ambas entidades neurocutaneas cursan con un patron de herencia autosomico dominante, expresividad variable y la morbimortalidad se encuentra asociada a complicaciones multisistemicas. El objetivo de este trabajo fue exponer las caracteristicas clinicas y epidemiologicas de una serie de pacientes pediatricos con diagnostico de NF1 y CET atendidos en la Unidad de Genetica Medica de la Universidad de Los Andes. Metodos: Este trabajo corresponde a una serie de casos de pacientes menores de 16 anos atendidos en un periodo de 11 anos, que cumplan con los criterios diagnosticos de NF1 y CET segun los consensos para cada entidad. Resultados: Se estudiaron 89 pacientes, 73 con NF1 y 16 con CET. Presentaron dos criterios para NF1, 58 (79.45%) pacientes, y las maculas cafe con leche fueron las mas frecuentes y presentes en todos los casos; 10 pacientes (62.50 %) presentaron dos criterios mayores para el CET, y las maculas hipocromicas estuvieron igualmente presentes en todos los casos. Conclusiones: Este estudio muestra la forma de presentacion clinica de las dos entidades neurocutaneas mas frecuentes. Se discuten los criterios diagnosticos con el objeto de identificarlos a edades mas tempranas y poder brindar una evaluacion medica interdisciplinaria, tratamiento y un oportuno asesoramiento genetico familiar. Background: Neurofibromatosis type 1 (NF1) is a genetic entity with an incidence of 1 in 2,500 to 3,500 births. Tuberous sclerosis complex (TSC) has an incidence between 1 in 6,000 to 10,000 births. Both neurocutaneous entities present an autosomal dominant inheritance pattern, variable expressivity and their morbidity and mortality is associated with multisystemic complications. The aim of this study was to present the clinical and epidemiological characteristics of a series of pediatric patients diagnosed with NF1 and TSC, who were treated in the Medical Genetics Unit of the Universidad of Los Andes. Methods: This work corresponds to a series of cases of patients under 16 years of age served in a period of 11 years, who met the diagnostic criteria of NF1 and CET according to the consensus for each entity. Results: We studied 89 patients, 73 with NF1 and 16 with TSC. 58 (79.45%) of the patients presented two criteria for NF1, with cafe-au-lait macules being the most frequent and present in all cases. 10 (62.50%) of the patients presented two major criteria for TSC; hypochromic macules were equally present in all cases. Conclusions: This study shows the clinical presentation of the two most frequent neurocutaneous entities. Diagnostic criteria are discussed in order to perform them at younger ages and to provide an interdisciplinary medical evaluation, treatment and timely family genetic counseling. PMID- 30250320 TI - Las calcificaciones simetricas y asimetricas de los ganglios basales pueden reflejar enfermedad mitocondrial. PMID- 30250321 TI - Comentarios a "Utilidad del indice de resistencia obtenido por ultrasonido Doppler en nodulos tiroideos de caracteristicas ecograficas malignas". PMID- 30250322 TI - [Histiocitosis de celulas de Langerhans con compromiso vertebral]. AB - Introduccion: La histiocitosis de celulas de Langerhans (HCL) es un trastorno histiocitico raro y su incidencia exacta se mantiene desconocida; se ha diagnosticado en todos los grupos de edad, pero es mas comun en los primeros 3 anos de vida. Se caracteriza por lesiones unicas o multiples de tipo osteolitico causadas por proliferacion clonal de celulas histologicamente similares a las celulas de Langerhans; su presentacion clinica es heterogenea. Caso clinico: Presentamos el caso de una paciente de sexo femenino de 7 anos, con dificultad para la marcha y debilidad progresiva en los miembros inferiores de 5 dias de evolucion. A la exploracion fisica presenta hallazgos concordantes con sindrome piramidal e hipoestesias de miembros inferiores. Se realizo resonancia magnetica (RM) de columna y tomografia computarizada de craneo simple, que descarto patologia intracraneal. En la RM de columna se detecto vertebra plana con extension epidural y paravertebral, por lo que se inicio manejo con esteroides y se indico descompresion quirurgica. Se realizo reseccion parcial y biopsia de la lesion. Debido a los hallazgos histologicos y la presencia de marcadores positivos para CD1a y CD207, se confirmo el diagnostico de HCL. Conclusiones: La HCL es una enfermedad poco frecuente y de dificil diagnostico por su presentacion heterogenea. El granuloma eosinofilico y la vertebra plana como hallazgos imagenologicos pueden orientar el diagnostico, aunque siempre se debe confirmar histologicamente. Background: Langerhans cell histiocytosis (LCH) is a rare disease, more common in the first three years of life. It is characterized by single or multiple osteolytic lesions due to clonal proliferation of cells histologically similar to Langerhans cells; its clinical presentation is heterogeneous. Case report: 7-year-old female patient with 5 days of progressive lower extremity weakness and difficulty to walk. Physical exam findings were consistent with pyramidal syndrome and lower extremities hypoesthesia. Magnetic resonance imaging (MRI) of spine and cranial computed tomography (CT) were performed. Intracranial pathology was ruled out. The MRI findings showed vertebra plana with epidural and paravertebral involvement, so treatment with steroids and surgical decompression initiated. Partial resection and biopsy of the lesion was performed. Due to histological findings and positive CD1a and CD207 markers, diagnosis of LCH was confirmed. Conclusions: LCH is an uncommon disease with a challenging diagnosis due to its heterogeneous clinical presentation. Eosinophilic granuloma and vertebra plana as imaging findings may guide the diagnosis. However, it should always be confirmed with histological evidence. PMID- 30250323 TI - Evaluacion clinica y ultrasonografica de la glandula tiroides en pacientes con artritis reumatoide. AB - Introduccion: Los pacientes con artritis reumatoide pueden desarrollar enfermedad tiroidea autoinmune (ETA), cuyo diagnostico clinico puede ser dificil debido a que ambas comparten sintomas como artralgias, mialgias, rigidez matutina o fatiga. Objetivo: Determinar la prevalencia de ETA en pacientes con artritis reumatoide. Metodo: Estudio transversal que incluyo 78 pacientes con artritis reumatoide y 81 controles clinicamente sanos pareados por edad y sexo. A ambos grupos se realizo cuantificacion de anticuerpos antitiroideos, pruebas de funcion tiroidea, ultrasonido y biopsia de glandula tiroides cuando la puntuacion de Thyroid Imaging Reporting and Data System (TIRADS) fue >= 4. Resultados: 24.4 % de los pacientes con artritis reumatoide presento hipotiroidismo (p = 0.003) y altos titulos de anticuerpos antitiroideos versus controles clinicamente sanos; 53 % de los ultrasonidos tiroideos resulto normal en pacientes hipotiroideos; en pacientes con artritis reumatoide positivos para anticuerpos antitiroideos se encontro perfusion incrementada en 40 %. Los casos clasificados como TIRADS 4 fueron enviados a aspiracion, con resultado histopatologico benigno. Conclusiones: Se demostro el valor clinico agregado de la evaluacion tiroidea en pacientes con artritis reumatoide, conforme a la prevalencia de hipotiroidismo subclinico, positividad de anticuerpos antitiroideos y anomalias en el ultrasonido independientes de la funcion tiroidea normal o alterada. Introduction: Patients with rheumatoid arthritis can develop autoimmune thyroid disease (ATD), the clinical diagnosis of which can be difficult because both entities share symptoms such as arthralgia, myalgia, morning stiffness or fatigue. Objective: To determine the prevalence of ATD in patients with rheumatoid arthritis. Method: Cross-sectional study that included 78 patients with rheumatoid arthritis and 81 clinically healthy controls matched by age and gender. Both groups underwent anti-thyroid antibodies quantification, thyroid function tests, thyroid ultrasound and thyroid gland biopsy when the Thyroid Imaging Reporting and Data System (TIRADS) score was >= 4. Results: Hypothyroidism was found in 24.4% of patients with rheumatoid arthritis (p = 0.003), as well as high titers of anti-thyroid antibodies versus clinically healthy controls; 53% of thyroid ultrasounds were normal in hypothyroid patients, and increased perfusion was found in 40% of rheumatoid arthritis patients who tested positive for anti-thyroid antibodies. Cases classified as TIRADS 4 underwent aspiration with benign histopathological results. Conclusions: Thyroid assessment added clinical value was demonstrated in patients with rheumatoid arthritis, according to the prevalence of subclinical hypothyroidism, anti thyroid antibodies positivity and ultrasound abnormalities, regardless of normal or altered thyroid function. PMID- 30250324 TI - [Fiebre manchada de montanas rocosas: experiencia en 5 anos de vigilancia activa en un hospital pediatrico de segundo nivel en el noreste de Mexico]. AB - Introduccion: La fiebre manchada de las montanas rocosas (FMMR) es causada por Rickettsia rickettsii. En Coahuila, la region de la Comarca Lagunera se considera una zona endemica. No se han reportado casos en la zona sur del estado, especificamente en la ciudad de Saltillo. Metodos: Estudio prospectivo, reporte de casos. Se incluyeron los casos de ninos atendidos en el Hospital del Nino Dr. Federico Gomez Santos en la ciudad de Saltillo, Coah., del mes de septiembre de 2012 a septiembre 2017 con diagnostico confirmado clinicamente y por reaccion en cadena de la polimerasa (PCR) de FMMR. Se presentan los antecedentes epidemiologicos, las caracteristicas clinicas y evolucion de los pacientes. Resultados: Se confirmaron 14 pacientes. La relacion masculino:femenino fue de 1.8:1, la edad promedio de los pacientes fue de 7.6 anos (18 meses a 13 anos). El 42.8% de los pacientes refirio el contacto con perros y el 57.1% afirmo tener contacto con garrapatas. En todos los casos hubo fiebre y exantema purpurico; alrededor del 70% manifestaron mialgias y artralgias; el 28% tuvo sangrado del tubo digestivo, y el 11% alteraciones neurologicas graves. El 64.2% de los casos recibio tratamiento adecuado con doxiciclina. Fallecieron 8 pacientes, con una tasa de letalidad de 57.1%. Conclusiones: La zona sur de Coahuila debe considerarse una zona endemica para FMMR. El retraso en el diagnostico y tratamiento favorecen una mayor letalidad. Background: Rocky Mountain Spotted Fever (RMSF) is caused by Rickettsia rickettsii. In Coahuila, Comarca Lagunera is considered an endemic zone; no cases have been reported in the southern zone of the state, specifically in the city of -Saltillo. Methods: Prospective study, cases report. Children evaluated in the Hospital del Nino Dr. Federico Gomez Santos from September 2012 to September 2017, with clinically and laboratory (by polymerase chain reaction, PCR) confirmed diagnosis of FMMR were included. The epidemiological antecedents, clinical characteristics and patient's evolution are presented. Results: 14 patients were confirmed. The male: female ratio was 1.8: 1, the average age of the patients was 7.6 years (18 months to 13 years). 42.8% reported contact with dogs and 57.1% confirmed contact with ticks. In all cases, there was fever and purpuric rash; around 70% manifested myalgias and arthralgias; 28% presented digestive tract bleeding and 11% had severe neurological alterations. 64.2% of the cases received adequate treatment with doxycycline. Eight patients died with a case fatality rate of 57.1%. Conclusions: The southern zone of Coahuila should be considered an endemic area for FMMR. The delay in diagnosis and treatment favor a greater lethality. PMID- 30250325 TI - La Ciudad de Mexico, cuna del primer estudio radiologico en la Republica Mexicana. AB - En agosto de 1896, el ingeniero Gilberto Crespo y Martinez publico un articulo en el que presento dos radiografias realizadas por Roberto Jofre y Fernando Ferrari Perezen. Correspondieron a las dos primeras radiografias llevadas a cabo en la Republica Mexicana, dos meses antes de las efectuadas en la ciudad de San Luis Potosi el 24 de octubre y la del doctor Tobias Nunez en el Hospital Juarez, el 19 de octubre de ese mismo ano. PMID- 30250326 TI - Tendencias de mortalidad y anos potenciales de vida perdidos por cancer de ovario en Mexico, 2000-2014. AB - Introduccion: En Mexico, el cancer de ovario representa 5.3 % de los diagnosticos de cancer en todos los grupos de edad y 21 % de los canceres ginecologicos; en las ultimas tres decadas ha tenido un aumento constante. Objetivo: Determinar la tendencia de la mortalidad por cancer de ovario y los anos potenciales de vida perdidos (APVP) por estado y region socioeconomica de Mexico entre 2000 y 2014. Metodo: Se obtuvieron los registros de cancer de ovario del Instituto Nacional de Estadistica y Geografia. Se identificaron los codigos de la CIE-10 correspondientes a la causa basica de defuncion por cancer de ovario. Se calcularon las tasas de mortalidad y las tasas de APVP a nivel nacional, por estado y region socioeconomica. Resultados: Entre 2000 y 2014, las tasas ajustadas por edad por 100 000 mujeres se incrementaron de 3.3 a 4.1. Las mayores tasas de mortalidad se identificaron en la region 7, en Chihuahua, Baja California Sur, Colima, Quintana Roo, Zacatecas, Sonora, Coahuila, Aguascalientes, Queretaro. La mayor tasa de APVP por cancer de ovario se registro en las regiones 7, 5 y 6, en Nayarit, Baja California Sur, Zacatecas, Colima, Tlaxcala, Oaxaca, Quintana Roo, Coahuila, Aguascalientes y Queretaro. Conclusiones: La region socioeconomica 7 de Mexico presento las mayores tasas de APVP y de mortalidad por cancer de ovario. Introduction: In Mexico, ovarian cancer accounting for 5.3% of cancer diagnoses in all age groups and 21% of gynecological cancers and it has had a steady increase in the last three decades. Objective: To determine mortality trends from ovarian cancer and potential years of life lost (PYLL) by state and socioeconomic region of Mexico between 2000 and 2014. Method: Records of ovarian cancer were obtained from the National Institute of Statistics and Geography. ICD-10 codes corresponding to ovarian cancer as the basic cause of death were identified. Mortality rates and YPLL rates were calculated by nationwide, states and socioeconomic region. Results: Between 2000 and 2014, age-adjusted rates per 100,000 women increased from 3.3 to 4.1. The highest mortality rates were identified in region 7, in Chihuahua, Baja California Sur, Colima, Quintana Roo, Zacatecas, Sonora, Coahuila, Aguascalientes and Queretaro. The highest rates of PYLL due to ovarian cancer were recorded in regions 7, 5 and 6, Nayarit, Baja California Sur, Zacatecas, Colima, Tlaxcala, Oaxaca, Quintana Roo, Coahuila, Aguascalientes and Queretaro. Conclusions: Mexico's socioeconomic region 7 had the highest rates of PYLL and mortality from ovarian cancer. PMID- 30250327 TI - Sindrome metabolico y aterosclerosis carotidea subclinica en ninos y adolescentes mexicanos con acantosis nigricans. AB - Introduccion: La acantosis nigricans es un marcador de resistencia a la insulina, la cual se asocia con alteraciones metabolicas y cardiovasculares. Objetivo: Investigar la frecuencia de sindrome metabolico y aterosclerosis carotidea subclinica en ninos y adolescentes mexicanos con acantosis nigricans y comparar los resultados entre sexos. Metodo: Estudio transversal. Se incluyeron 30 sujetos masculinos y 30 femeninos con diagnostico de acantosis nigricans, menores de 18 anos. Se investigo sindrome metabolico (criterios de Cook), riesgo cardiovascular (proteina C reactiva ultrasensible [PCRus]) y aterosclerosis carotidea (grosor intima-media). Para el analisis de datos se utilizo estadistica descriptiva e inferencial. Resultados: La frecuencia de sindrome metabolico fue de 43 % (sexo masculino 42 % versus femenino 58 %, p = 0.58). Todos presentaron niveles anormales de PCRus: 67 % fue clasificado con riesgo cardiovascular moderado y 27 % con riesgo alto. Frecuencia de aterosclerosis carotidea 98 % (masculino 49 % versus femenino 51 %, p = 0.45). La severidad de la acantosis nigricans no influyo en los resultados. Conclusiones: La busqueda intencionada de sindrome metabolico y aterosclerosis carotidea subclinica en ninos y adolescentes mexicanos con acantosis nigricans, independientemente del sexo o severidad de la enfermedad, permitira implementar medidas para disminuir la morbimortalidad en la edad adulta. Introduction: Acanthosis nigricans is a marker of insulin resistance that is associated with metabolic and cardiovascular alterations. Objective: To investigate the frequency of metabolic syndrome and subclinical carotid atherosclerosis in children and adolescents with acanthosis nigricans, and to compare the results between genders. Method: Cross-sectional study, where 30 male and 30 female subjects younger than 18 years of age diagnosed with acanthosis nigricans were included. The presence of metabolic syndrome (Cook's criteria), cardiovascular risk (ultrasensitive C-reactive protein and [us-CRP]), and carotid atherosclerosis (intima-media thickness [IMT]) was investigated. Descriptive and inferential statistics was used for data analysis. Results: The frequency of metabolic syndrome was 43% (males 42 % versus females 58%, p = 0.58). All patients showed us-CRP abnormal levels: 67% were classified with moderate cardiovascular risk and 27% with high risk. The prevalence of carotid atherosclerosis was 98% (males 49% versus females 51%, p = 0.45). Acanthosis nigricans severity did not influence on the results. Conclusions: Intentional search for metabolic syndrome and subclinical carotid atherosclerosis in Mexican children and adolescents with acanthosis nigricans, regardless of gender or disease severity, will enable the implementation of measures to decrease the morbidity and mortality seen in adult age. PMID- 30250328 TI - ?Por que surgio Gaceta Medica de Mexico? PMID- 30250329 TI - Acido urico serico como marcador de gravedad clinica y comorbilidad en psoriasis en placas. AB - Introduccion: La hiperuricemia es comun en pacientes con psoriasis. Se ha sugerido que la elevacion de acido urico en psoriasis esta fuertemente asociada con morbilidad cardiovascular. Objetivo: Determinar la relacion entre niveles de acido urico, gravedad clinica medida por Psoriasis Area Severity Index (PASI), Body Surface Area (BSA) y static Physician's Global Assessment (sPGA) en pacientes con psoriasis en placas y comorbilidades ungueales y artritis psoriasica. Metodo: Determinacion de acido urico serico en 45 pacientes con psoriasis en placas y 45 controles pareados por sexo, edad e indice de masa corporal; medicion de indices de gravedad clinica en pacientes y presencia de manifestaciones ungueales y articulares. Resultados: Los pacientes con psoriasis presentaron niveles mas elevados de acido urico (7.03 +/- 1.47 versus 5.32 +/- 1.17, p < 0.01) y mayor prevalencia de hiperuricemia asintomatica (68 versus 17.8 %, p < 0.01) que los controles. Existio correlacion proporcional significativa entre gravedad determinada por PASI y acido urico (r2 = 0.70) y entre manifestaciones articulares e hiperuricemia en pacientes con psoriasis en placas (p < 0.01; RM = 2.85, IC 95 % = 1.52-5.33). Conclusiones: Los niveles sericos de acido urico tuvieron correlacion proporcional con PASI y se asociaron con manifestaciones articulares en pacientes con psoriasis en placas. Introduction: Hyperuricemia is common in patients with psoriasis. Uric acid elevation in psoriasis has been suggested to be strongly associated with cardiovascular morbidity. Objective: To determine the relationship between uric acid levels and clinical severity as measured by the Psoriasis Area Severity Index (PASI), body surface area (BSA) and static Physician's Global Assessment (sPGA) in patients with plaque psoriasis and nail comorbidities and psoriatic arthritis. Method: Determination of serum uric acid in 45 patients with plaque psoriasis and 45 controls matched by gender, age and body mass index; measurement of patient clinical severity indices and presence of nail and joint manifestations. Results: Patients with psoriasis had higher levels of uric acid (7.03 +/- 1.47 versus 5.32 +/- 1.17, p < 0.01), and higher prevalence of asymptomatic hyperuricemia than controls (68% versus 17.8%, p < 0.01). There was significant proportional correlation between PASI-determined severity and uric acid (r2 = 0.70), and between joint manifestations and hyperuricemia in patients with plaque psoriasis (p < 0.01; OR = 2.85, 95% CI = 1.52-5.33). Conclusions: Serum uric acid levels had a proportional correlation with PASI and were associated with joint manifestations in patients with plaque psoriasis. PMID- 30250330 TI - En relacion con la publicacion de reportes de casos. PMID- 30250331 TI - Discurso inaugural del Centesimo Quincuagesimo Quinto Ano de la Academia Nacional de Medicina. PMID- 30250332 TI - [Colestasis por deficiencia de 3b-Delta5-C27-hidroxiesteroide deshidrogenasa en un paciente con alteracion en la sintesis de acidos biliares]. AB - Introduccion: Los errores innatos en la sintesis de acidos biliares son un grupo de defectos geneticos que representan del 1 al 2% de las enfermedades colestasicas cronicas en lactantes, ninos y adolescentes. La deficiencia de 3b Delta5-C27-hidroxiesteroide oxidoreductasa (3b-HSDH) es el defecto mas comunmente reportado. El cuadro clinico caracteristico consiste en hepatitis neonatal, hepatomegalia, esplenomegalia, malabsorcion, desnutricion y enfermedad hepatica de aparicion tardia. Caso clinico: Lactante masculino con antecedente de ictericia en escleras a los 4 meses que se resolvio espontaneamente; posteriormente, a los 18 meses, presento enfermedad colestasica. Durante su abordaje se documento gamma-glutamil transpeptidasa normal, hallazgo que es altamente sugestivo de alteracion en la sintesis de acidos biliares. El diagnostico se realizo con espectrometria de masas en orina. Se inicio tratamiento con acido colico oral, y presento mejoria inmediata. Conclusiones: El resultado en los acidos biliares urinarios es definitivo para el defecto genetico y consistente con mutaciones homocigotas en el gen HSD3B7. Este padecimiento constituye un diagnostico de exclusion en las enfermedades colestasicas de la infancia, particularmente el hallazgo de gamma-glutamil transpeptidasa normal o levemente aumentada, y responde adecuadamente al tratamiento oral, por lo que debe identificarse de forma temprana. Background: Inborn errors in bile acid synthesis are a group of genetic defects accounting for 1 to 2% of chronic cholestatic diseases in infants, children and adolescents. Deficiency of 3b Delta5-C27-hydroxysteroid dehydrogenase (3beta-HSDH) is the most common defect in this disease. Clinical features consist of neonatal hepatitis, hepatomegaly, splenomegaly, malabsorption, malnutrition, and late-onset liver disease. Case report: A male infant who presented jaundice in sclera at 4 months that resolved spontaneously, later presented cholestatic disease at 18 months. During his approach, normal gamma-glutamyl transpeptidase was documented, a finding that is highly suggestive of alteration in the synthesis of bile acids. The diagnosis was made using urine mass spectrometry. Oral colic acid treatment was started, presenting immediate improvement. Conclusions: The result in urinary bile acids is definitive for the genetic defect and consistent with homozygous mutations in the HSD3B7 gene. This condition is a diagnosis of exclusion in childhood cholestatic diseases, particularly in the presence of normal or mildly enlarged gamma-glutamyl transpeptidase, and responds adequately to oral treatment; it should be identified early. PMID- 30250333 TI - Pronostico de pacientes con lupus eritematoso generalizado en una unidad de cuidados intensivos. AB - Introduccion: La identificacion de factores de riesgo para mortalidad ha permitido mejorar el tratamiento de los pacientes criticos con lupus eritematosos generalizado. Objetivo: Describir las caracteristicas clinicas y los pronosticos de pacientes graves con lupus eritematosos generalizado ingresados en una unidad de cuidados intensivos. Metodo: Estudio de cohorte, observacional y descriptivo. Se incluyeron 207 pacientes con lupus eritematosos generalizado enero de 2011 y enero de 2016. Resultados: Durante el periodo del estudio fueron ingresados 3215 pacientes graves a una unidad de cuidados intensivos, 207 (6.4 %) con lupus eritematosos generalizado despues de ser evaluados por un intensivista. La mortalidad fue de 18.4 %. El analisis multivariado identifico la presencia fallas organicas (cardiovascular, hepatica y neurologica) y niveles sericos de lactato > 2 mmol/L al ingreso o durante las primeras 24 horas de estancia en la unidad de cuidados intensivos como los principales factores asociados con incremento de la mortalidad. Conclusiones: Un dato relevante fue que la falla neurologica y la falla hepatica estuvieron asociadas con mayor riesgo de muerte a 28 dias, sin que identificaramos reportes similares a estos hallazgos. Introduction: Identification of risk factors for mortality has enabled improving the treatment of critically ill patients with systemic lupus erythematosus. Objective: To describe clinical characteristics and prognoses of critically ill patients with systemic lupus erythematosus admitted to an intensive care unit. Method: Prospective, observational cohort study. A total of 207 patients with systemic lupus erythematosus admitted between January 2011 and January 2016 were included. Results: During the study period, 3,215 critically ill patients were admitted to the intensive care unit, out of which 207 (6.4%) were identified as having systemic lupus erythematosus after being evaluated by an intensivist. The multivariate analysis identified the presence of organ failure (cardiovascular, liver, neurological) and serum lactate levels > 2 mmoL/L at admission or within the first 24 hours of intensive care unit stay as the main factors associated with increased mortality. Conclusions: A relevant observation was that neurological failure and liver failure were associated with higher mortality risk at 28 days, without reports similar to these findings being identified. PMID- 30250335 TI - ?Por que son felices los dermatologos? PMID- 30250334 TI - Presentacion clinica de la apendicitis aguda en pacientes inmunocomprometidos por diabetes o VIH/sida. AB - Introduccion: Los pacientes inmunocomprometidos presentan respuesta inflamatoria limitada que puede retrasar el diagnostico de la apendicitis aguda (AA). Objetivo: Evaluar si el inmunocompromiso puede afectar el curso clinico y evolucion de la AA. Metodo: Analisis retrospectivo, comparativo, de pacientes sometidos a apendicectomia por AA: con VIH, diabetes mellitus tipo 2 (DM2) y sin otra patologia. Resultados: Se revisaron 128 pacientes con AA intervenidos quirurgicamente (53.6 % del sexo femenino), edad media de 42.5 anos, 15 (11.7 %) tenian diagnostico de VIH, 47 (36.7 %) de DM2 y 66 (51.6 %) no cursaban con otra enfermedad. La proporcion de leucocitosis fue menor en el grupo con VIH (66.7 %; p = 0.007). En los pacientes con VIH y DM2 se registro mayor tiempo de evolucion: 66.9 +/- 61.2y 90.1 +/- 144 horas (p <= 0.001), mayor tiempo de estancia hospitalaria: 11.1 +/- 17.1 y 6.5 +/- 4.1 dias (p <= 0.0001), mayor tasa de complicaciones: 20 y 23.8 % (p = 0.036). La complicacion mas frecuente fue la infeccion del sitio quirurgico superficial y profunda. La hemicolectomia derecha fue mas frecuente en el grupo con VIH (20 %, p = 0.017). No se registro mortalidad. Conclusiones: La inmunodepresion afecta el curso clinico y evolucion de la AA. Introduction: Immunocompromised patients experience limited inflammatory response, which can delay acute appendicitis (AA) diagnosis. Objective: To assess if immunosuppression can affect AA clinical course and evolution. Method: Comparative, retrospective analysis of patients with HIV or type 2 diabetes mellitus (DM2) or with no other pathology who underwent appendectomy for AA. Results: A total of 128 patients with AA who were surgically intervened were assessed (53.6% were of the female gender); mean age was 42.5 years, 15 (11.7%) had been diagnosed with HIV infection, 47 (36.7%) with DM2 and 66 (51.6%) had no other disease. The proportion of leukocytosis was lower in the HIV group (66.7%; p = 0.007). Patients with HIV and DM2 had longer evolution time (HIV 66.9 +/- 61.2, DM2 90.1 +/- 144 hours; p <= 0.001), longer hospital length of stay (HIV 11.1 +/- 17.1, DM2 6.5 +/- 4.1 days; p <= 0.0001), and a higher rate of complications (HIV 20%, DM2 23.8%; p = 0.036). The most common complication was superficial and deep surgical site infection. Right hemicolectomy was more common in the HIV group (20%; p = 0.017). There was no mortality registered. Conclusions: Immunosuppression affects AA clinical course and evolution. PMID- 30250336 TI - ?Publicacion anticipada en medicina clinica? PMID- 30250337 TI - Validacion de un cuestionario para medir la habilidad de la poblacion general para evaluar afirmaciones acerca de tratamientos medicos. AB - Introduccion: Todos los dias, las personas se enfrentan a afirmaciones acerca de tratamientos en medios de comunicacion, redes sociales o por viva voz. Objetivo: Validar un cuestionario en espanol para medir las habilidades de un individuo para evaluar afirmaciones acerca de tratamientos. Metodo: Veintidos preguntas de opcion multiple de la base de datos Claim Evaluation Tools fueron traducidas y aplicadas a 172 ninos y 268 adultos. Mediante un modelo Rasch se exploro el ajuste promedio e individual por reactivo, el potencial comportamiento diferencial del reactivo (basado en el genero, edad y modo de aplicacion), la multidimensionalidad y la independencia local. Resultados: El ajuste promedio por reactivo fue apropiado. Cuatro preguntas de opcion multiple mostraron pobre ajuste. La fiabilidad del cuestionario fue satisfactoria, con un indice de separacion de 0.7. Las preguntas de opcion multiple fueron unidimensionales, y no hubo dependencia especifica. Conclusion: Se obtuvo un conjunto de 18 preguntas de opcion multiple con ajuste satisfactorio. El cuestionario es el primero disponible y validado en espanol para medir las habilidades de los individuos para evaluar afirmaciones acerca de tratamientos. Introduction: Every day, people are faced with claims about treatment effects through mass media, social media, or by word of mouth. Objective: To validate a Spanish-language questionnaire to measure the ability of an individual to assess claims about treatments effects. Method: A set of 22 multiple choice questions taken from the claim evaluation tools database were translated and applied to 172 children and 268 adults. Using a Rasch model, overall and individual item-person fit was explored, as well as the potential item differential functioning (based on gender, age and mode of administration), multidimensionality and local independence. Results: Overall item-person fit was appropriate. Four multiple-choice questions showed a poor fit. Reliability of the questionnaire was satisfactory with a person separation index of 0.7. Multiple-choice questions were unidimensional, and there was no specific dependency. Conclusion: A set of 18 multiple-choice questions with satisfactory fit was obtained. This is the first available questionnaire validated in Spanish to measure individuals' ability to assess claims about treatment effects. PMID- 30250338 TI - Extending the Reach with Social Media. PMID- 30250339 TI - Incidence of Cerebral Microemboli in Single-Dose vs. Multidose Cardioplegia in Adult Cardiac Surgery. AB - Cerebral microemboli have been associated with neurocognitive deficits after cardiac operations using cardiopulmonary bypass (CPB). Interventions by the perfusionist and alterations in blood flow account for a large proportion of previously unexplained microemboli. This study compared the incidence of microemboli during cardiac operations using conventional (multidose) and del Nido (single-dose) cardioplegia delivery. Transcranial Doppler ultrasonography was used to detect microemboli in bilateral middle cerebral arteries of 30 adult patients undergoing cardiac operations using CPB and aortic clamping. Multidose conventional blood cardioplegia (CBC) was used in 15 patients and single-dose del Nido cardioplegia (DNC) in 15. Manual count of microemboli during cross-clamp and during administration of cardioplegia was performed. Baseline preoperative characteristics were similar between groups. There were no differences in the ascending aortic atheroma grade (1.4 +/- .4 CBC vs. 1.6 +/- .7 DNC, p = .44), bypass times (141 +/- 36 minutes CBC vs. 151 +/- 33 minutes DNC, p = .64), and cross-clamp times (118 +/- 32 minutes CBC vs. 119 +/- 45 minutes DNC, p = .95). The use of multidose CBC was associated with a seven-fold increase in the number of microemboli per minute of bypass (1.65 +/- 1 vs. .24 +/- .18 emboli/min DNC, p = .0004). In this prospective pilot study, we found that the use of single-dose cardioplegia strategy led to fewer cerebral microemboli when compared with the traditional multidose approach. Our findings warrant further investigation of various cardioplegia strategies and neurologic outcomes in larger cohorts. PMID- 30250340 TI - Use of Thromboelastography to Predict Thrombotic Complications in Pediatric and Neonatal Extracorporeal Membranous Oxygenation. AB - The objectives of this study were to investigate the correlation between thromboelastography (TEG) and conventional measures of anticoagulation, and to determine optimum values for citrated kaolin TEG R time (TEG RCK) and anti-Xa activity that would minimize both bleeding and thrombotic complications in pediatric and neonatal patients requiring extracorporeal membranous oxygenation (ECMO). A retrospective chart review of patients requiring veno-venous (VV) and venoarterial (VA) ECMO was performed. Combined medical and cardiac ICU within a single-center, tertiary care, freestanding, children's hospital. Non-pregnant patients <18 years and >2 kilograms requiring VV or VA ECMO from July 2013 through July 2015. Anti-Xa (OR = 0.62, 95% CI 0.53-0.72, p < .001) and TEG RCK (OR = 1.19, 95% CI 1.07-1.34, p = .003) were the only independent predictors for a significant thrombotic event. Receiver operating characteristic curves and traditional epidemiological data (sensitivity, specificity, PPV, NPV) were used to determine optimal target Anti-Xa and TEG RCK values. No independent predictors for significant bleeding events were identified in this cohort. A anti-Xa activity of .25 IU/mL (sensitivity = 81%, specificity = 67%, PPV = 81%, NPV = 58%) and TEG RCK time of 17.85 minutes (sensitivity = 84%, specificity = 68%, PPV = 82%, NPV = 59%) were established as the optimal thresholds for preventing thrombotic events. Anti-Xa and TEG RCK were independent predictors of thrombosis in this cohort of pediatric and neonatal ECMO patients. Targeting an anti-Xa activity greater than .25 IU/mL and a TEG RCK greater than 17.85 minutes may minimize the risk of thrombosis in pediatric and neonatal ECMO patients. Future investigation should evaluate targets for anti-Xa and TEG RCK, which additionally minimize the risk of significant bleeding in this patient population. PMID- 30250341 TI - Distal Perfusion Cannulation and Limb Complications in Venoarterial Extracorporeal Membrane Oxygenation. AB - The utility of distal perfusion cannula (DPC) placement for the prevention of limb complications in patients undergoing femoral venoarterial (VA) extracorporeal membrane oxygenation (ECMO) is poorly characterized. Patients undergoing femoral VA ECMO cannulation at two institutions were retrospectively assessed. Patients were grouped into those who did and those who did not receive a DPC at the time of primary cannulation. The primary outcome was any limb complication. Secondary outcomes included successfully weaning ECMO and in hospital mortality. A total of 75 patients underwent femoral cannulation between December 2010 and December 2017. Of those, 65 patients (86.7%) had a DPC placed during primary cannulation and 10 patients (13.3%) did not. Baseline demographics, indications for ECMO, and hemodynamic perturbations were well matched between groups. The rate of limb complications was 14.7% (11/75) for the overall cohort and did not differ between groups (p = .6). Three patients (4%) required a four-compartment fasciotomy for compartment syndrome in the DPC group; no patients without a DPC required fasciotomy. Of the three patients who required a thrombectomy for distal ischemia, two were in the DPC group and one was in the no-DPC group (p = .3). Two patients (2.7%) underwent delayed DPC placement for limb ischemia with resolution of symptoms. The in-hospital morality rate was 59.5% and did not differ between groups (p = .5). Patients in the present study, undergoing femoral VA ECMO without preemptive DPC placement did not experience a higher rate of limb complications. However, the two patients who underwent delayed DPC placement for post-cannulation ischemia experienced resolution of symptoms, suggesting that a DPC may be used as an effective limb salvage intervention. PMID- 30250342 TI - Bivalirudin Anticoagulation Dosing Protocol for Extracorporeal Membrane Oxygenation: A Retrospective Review. AB - Anticoagulation with unfractionated heparin during extracorporeal membrane oxygenation (ECMO) is common, but alternative agents are being evaluated for safety and efficacy. The objective of this analysis was to assess if a comprehensive bivalirudin dosing and monitoring protocol effectively guides dose adjustments and monitoring of bivalirudin in patients during ECMO. Our analysis included 11 patients who received bivalirudin during ECMO therapy and had dosing managed using our hospital derived protocol. Patients treated over a 1-year period were included in this retrospective analysis. Clinical characteristics and changes in activated partial thromboplastin time (aPTT) were evaluated from medical records to determine the efficacy of the dosing protocol. ECMO was initiated for acute respiratory distress syndrome in eight (72.7%) patients and for cardiac arrest in three (27.3%) patients. A total of 178 protocol guided dose adjustments were made during the study. Among the dose adjustments, 56 (31.5%) attained the protocol predicted aPTT level change, 96 (53.9%) of the measured aPTT changes were less than predicted, and 26 (14.6%) of the measured aPTT changes were more than predicted. On average, patients were within their defined therapeutic aPTT target range 66.3% of the time. All patients reached their designated aPTT target range within the first 24 hours of therapy. Significant bleeding was documented in eight (72.7%) patients. No clinically evident thromboembolic events were identified in vivo while cannulated. This analysis suggests that bivalirudin can be managed using a dosing protocol to provide anticoagulation therapy to patients during ECMO and can provide foundational guidance for dose adjustment and monitoring for other institutions. PMID- 30250343 TI - Malposition of the Extracorporeal Membrane Oxygenation Venous Cannula in an Accessory Hepatic Vein. AB - We report a case of a refractory cardiogenic shock secondary to myocardial infarction in a 70-year-old patient requiring femoral venoarterial extracorporeal membrane oxygenation (VA-ECMO). At initial transesophageal echocardiography, the venous cannula tip was seen in the inferior vena cava (IVC), but not in right atrium. On day 8, ultrasonic examination identified that the end of the venous cannula was in the hepatic vein (HV). Despite such malposition, no disturbance in extracorporeal membrane oxygenation (ECMO) venous return was observed. Moving or replacing the cannula was considered a high-risk maneuver potentially resulting in hepatic laceration with hemoperitoneum. Because of adequate venous drainage, allowing sufficient blood flow, venous cannula repositioning was delayed until day 10, when a ventricular defect was repaired and ECMO was weaned off. At the time of VA-ECMO implantation, the venous cannula has to be positioned in the right atrium using real time echo monitoring. Visualization of the guide wire in the IVC but not in the right atrium is insufficient to ensure appropriate venous cannula positioning. Indeed, either accidental catheterization or cannula migration into the HV is possible during ECMO. Health care professionals dealing with ECMO have to be aware of this possible malposition, to correct it and prevent insufficient venous drainage or traumatic complications. PMID- 30250344 TI - Recombinant Factor VIII Measurement in a Hemophilia A Patient Undergoing Cardiopulmonary Bypass-Supported Cardiac Surgery. AB - Patients with hemophilia A (Hem A) requiring cardiopulmonary bypass-supported cardiac surgery pose unique challenges for perioperative hemostatic management. This report describes a staged perioperative approach to clinical hematologic management as applied to an 80-year-old male of O-positive blood type with mild Hem A, who underwent successful, uncomplicated coronary artery bypass graft surgery. Hematologic management primarily consisted of normalization of plasma factor VIII levels followed by standard care. Conventional laboratory methods and point-of-care-testing methods such as thromboelastography and heparin management assays were combined to guide patient care. Minimal blood loss and minimal hemodilution techniques were also used to achieve favorable outcomes. The thorough preparation and execution of care by our multidisciplinary team from perfusion, pathology and laboratory medicine, cardiovascular surgery, transfusion services, nursing, and anesthesia, facilitated a safe, smooth, clinical course and an optimal outcome. PMID- 30250345 TI - The Novel Use of a Low Prime Modified Ultrafiltration Apparatus in a 13-kg Jehovah's Witness Patient: A Case Report. AB - Modified ultrafiltration (MUF) is used in neonates and infants to reduce volume overload and increase oxygen-carrying capacity post cardiopulmonary bypass (CPB). In addition, it decreases edema, attenuates complementation activation and immunogenic response to CPB. Hemodilution in the pediatric patient has always been a challenge, countered in part by miniaturization of CPB circuits. We describe a case in which we maintained an acceptable hematocrit level greater than 24%, considered the nadir below which the adverse effects of hemodilution can become evident. We performed this by the novel use of an intravenous warming device (enFlow, Vyaire Medical, Mettawa, IL) to reduce the prime volume of our MUF circuit by more than 50%. We present the case and discuss the advantages and disadvantages of using a low-prime MUF circuit. We were able to conduct "bloodless" CPB, with the use of acute normovolemic hemodilution, miniaturization of the CPB and MUF circuits. PMID- 30250346 TI - Bloodless Heart Surgery for an 11-kg Infant of the Jehovah's Witness Faith Undergoing Second Repair for Complete Atrioventricular Canal. AB - Bloodless pediatric cardiac surgery is the intent of most surgical centers especially in the Jehovah's Witness population where it is a desire not to administer blood products because of religious belief. It is a tremendous feat, considering that most pediatric cardiovascular prime volumes are more than 20% of the patient's estimated blood volume (EBV). We report on our bloodless strategy for a 2-year old Jehovah's Witness with trisomy 21 and complete atrioventricular canal repair, who underwent atrial septal defect and ventricular septal defect patch closure, pulmonary artery debanding, and pulmonary arterioplasty. We modified our circuit to reduce our prime volume to approximately 10% of the EBV and removed 200 mL of the patient's blood before surgery as acute normovolemic hemodilution. We did not alter our institutional standards for transfusion of blood and blood products. The post cardiopulmonary bypass (CPB) hematocrit was 30%. We conclude that bloodless CPB surgery can be performed safely in Jehovah's Witness patients with a carefully planned interdisciplinary approach. PMID- 30250347 TI - Asanguinous Del Nido Cardioplegia for an Aortic Valve Replacement Patient with Cold Agglutinins. AB - A patient with known cold agglutinins requiring an aortic valve replacement was referred for surgery. Asanguinous, Del Nido cardioplegia was used for myocardial protection. Warm induction followed by cold infusion prevented any agglutination and eliminated the need for subsequent cardioplegia doses. Following the cross clamp period, the heart returned to normal sinus rhythm without need for defibrillation. Postoperative ejection fraction and systolic function were normal. PMID- 30250348 TI - Complete Myocardial Function Recovery with ECMO in a Woman Presenting with Cardiogenic Shock during Peripartum Period. AB - Peripartum cardiomyopathy is a potentially life-threatening cause of heart failure (HF) that affects women toward the end of pregnancy or in months after delivery. Treatment is similar to the treatment for HF with reduced ejection fraction (EF). Most women make full myocardial function recovery within 6 months on conventional HF therapy. In rare instances, catastrophic presentations may occur with hemodynamic instability requiring the use of mechanical support. Because of the small patient population, limited information is available regarding the recovery of myocardial function in women who received mechanical support. We present a case of a woman in her peripartum period who presented with cardiogenic shock and made complete myocardial function recovery after 4 days of extracorporeal membrane oxygenation (ECMO). Our patient's EF at the time of catastrophe was 5-10%, which improved to 60% on day 4 on ECMO. PMID- 30250349 TI - Technique of Complete Heart Isolation with Continuous Cardiac Perfusion During Cardiopulmonary Bypass: New Opportunities for Gene Therapy. AB - Cardiopulmonary bypass (CPB) featuring complete heart isolation and continuous cardiac perfusion is a very promising approach for solving the problem of efficient gene delivery. In the technique presented here, separate pumps are used for the systemic and cardiac circuits. This system permits continuous isolated arrested heart perfusion through optimizing a number of delivery parameters including temperature, flow rate, driving pressure, ionic composition, and exposure time to the cardiac vessels. During complete cardiac isolation, the blood vector concentration trended from 11.51 +/- 1.73 log genome copies (GCs)/cm3 to 9.84 +/- 1.65 log GC/cm3 (p > .05). Despite restructuring a very high concentration to the heart, GCs were detectable in the systemic circuit. These values over time were near negligible by comparison but detectable 1.66 +/- .26 during 20 minutes of recirculation and did not change (p > .05). After the completion of the recirculation interval and subsequent washing procedure, the initial systemic blood vector GC concentration slightly increased to 2.08 +/- .38 log GCs/cm3 (p > .05). During the recirculation period, we supported flow via the cardiac circuit around 300 mL/min. In this technique of heart isolation with continuous cardiac perfusion, >99% of the vector remains in coronary circulation during recirculation period. The animal's non recirculation blood, or that in the system, was routinely tested during and after recirculation to contain much less than 1% of the original dose obtained via logging concentration of therapeutic over time. All of the sheep in this group recovered from anesthesia and received critical postoperative care, including all organ function, in the first 24-36 hours. Twenty-one sheep (84%) survived to euthanasia at 12 weeks. Average CPB time was 107 +/- 19.0 minutes and cross-clamp time was 49 +/- 7.9 minutes. This technology readily provides multiple pass recirculation of genes through the heart with minimal side effects of collateral expression of other organs. PMID- 30250352 TI - An Examination of Parental and Peer Influence on Substance Use and Criminal Offending During the Transition from Adolescence to Adulthood. AB - Although peer behavior and parent-child-conflict have been associated with adolescent and young adults' behavior, prior studies have not adequately controlled for selection effects and other confounders, or examined whether associations change across the transition to adulthood or by race. Using annual data from young men followed from 17-26, within-individual change models examined whether substance use or offending increased in the year after boys began affiliating with friends who engaged in substance use/offending and/or experienced increased parent-son-conflict. Moderation analyses tested whether associations varied by age or race. Alcohol use, marijuana use, and offending (Black participants only) increased in the year after boys began affiliating with more peers who engaged in similar behaviors. Associations were strongest during adolescence for substance use. Parent-son conflict was not associated with the outcomes. Findings underscore the importance of developmental and racialized differences in understanding the role of social influences on young men's substance use and offending. PMID- 30250353 TI - Dynamics of Economic Security among the Aging in Mexico: 2001-2012. AB - Similar to other developing countries, population aging in Mexico has accelerated, raising concerns that economic disparities will widen even more. We use data from the Mexican Health and Aging Study for 2001 and 2012 to derive measures of economic security ? income and its sources, and wealth and its components ? and describe how they changed over time and varied across key characteristics. The database is unique for a developing country: longitudinal and spanning a relatively long time period, and nationally representative of older persons (n=12,400; ages 50+). We conduct descriptive analysis for the full sample, and for sub-samples defined by 'safety net' indicators, health status, and demographic characteristics. Given that this time period included crucial economic and social changes in Mexico, we derive period results, measuring differences across time in two cross-sections; and longitudinal results, capturing changes among individuals as they age. In-depth examination of income and wealth identifies important contributors to old-age economic security in Mexico; we confirm several expected patterns and provide first evidence about others. Older adults with low income and asset values in Mexico have less diverse income sources and asset types; real incomes of older persons decreased substantially, and their income and asset portfolios became less diverse over the period. With older age, Mexicans relied more heavily on transfers and family help, and less on earnings. Overall, limited safety net options and worse health conditions were associated with less robust and deteriorating economic profiles. PMID- 30250354 TI - Hypothesis Tests for Neyman's Bias in Case-Control Studies. AB - Survival bias is a long-recognized problem in case-control studies, and many varieties of bias can come under this umbrella term. We focus on one of them, termed Neyman's bias or "prevalence-incidence bias." It occurs in case-control studies when exposure affects both disease and disease-induced mortality, and we give a formula for the observed, biased odds ratio under such conditions. We compare our result with previous investigations into this phenomenon and consider models under which this bias may or may not be important. Finally, we propose three hypothesis tests to identify when Neyman's bias may be present in case control studies. We apply these tests to three data sets, one of stroke mortality, another of brain tumors, and the last of atrial fibrillation, and find some evidence of Neyman's bias in the former two cases, but not the last case. PMID- 30250355 TI - Novel Geometric Approach for Virtual Coiling. AB - Endovascular coiling is a primary treatment for intra-cranial aneurysm, which deploys a thin and detachable metal wire inside the aneurysm so as to prevent its rupture. Emerging evidence from medical research and clinical practice has suggested that the coil configuration inside the aneurysm plays a vital role in properly treating aneurysm and predicting its outcome. In this paper, we propose a novel virtual coiling technique, called Ball Winding, for generating a coil configuration with ensured blocking ability. It can be used as an automatic tool for virtually simulating coiling before its implantation and thus optimizes such treatments. Our approach is based on integer linear programming and computational geometry techniques, and takes into consideration the packing density and coil distribution as the performance measurements. The resulting coiling is deployable (with the help of coil pre-shaping) and with minimized energy. Experimental results on both random and real aneurysm data suggest that our proposed method yields near optimal solution. PMID- 30250356 TI - Locally Optimal Designs for Some Dose-Response Models With Continuous Endpoints. AB - We consider the problem of constructing static (or non-sequential), approximate optimal designs for a class of dose response models with continuous outcomes. We obtain conditions for a design being D-optimal or c-optimal. The designs are locally optimal in that they depend on the model parameters. The efficiency studies show that these designs have high efficiency when the mis-specification of the initial values of model parameters is not severe. A case study indicates that using an optimal design may result in a significant saving of resources. PMID- 30250357 TI - Modeling Ramp-hold Indentation Measurements based on Kelvin-Voigt Fractional Derivative Model. AB - Interpretation of experimental data from micro- and nano-scale indentation testing is highly dependent on the constitutive model selected to relate measurements to mechanical properties. The Kelvin-Voigt Fractional Derivative model (KVFD) offers a compact set of viscoelastic features appropriate for characterizing soft biological materials. This paper provides a set of KVFD solutions for converting indentation testing data acquired for different geometries and scales into viscoelastic properties of soft materials. These solutions, which are mostly in closed-form, apply to ramp-hold relaxation, load unload and ramp-load creep-testing protocols. We report on applications of these model solutions to macro- and nano-indentation testing of hydrogels, gastric cancer cells and ex vivo breast tissue samples using an Atomic Force Microscope (AFM). We also applied KVFD models to clinical ultrasonic breast data using a compression plate as required for elasticity imaging. Together the results show that KVFD models fit a broad range of experimental data with a correlation coefficient typically R2 > 0.99. For hydrogel samples, estimation of KVFD model parameters from test data using spherical indentation versus plate compression as well as ramp relaxation versus load-unload compression all agree within one standard deviation. Results from measurements made using macro- and nano-scale indentation agree in trend. For gastric cell and ex vivo breast tissue measurements, KVFD moduli are, respectively, 1/3 - 1/2 and 1/6 of the elasticity modulus found from the Sneddon model. In vivo breast tissue measurements yield model parameters consistent with literature results. The consistency of results found for a broad range of experimental parameters suggest the KVFD model is a reliable tool for exploring intrinsic features of the cell/tissue microenvironments. PMID- 30250358 TI - Genetic and phylogenetic analysis of the outer capsid protein genes of Indian isolates of bluetongue virus serotype-16. AB - Aim: The aim of the study was to characterize bluetongue virus serotype 16 (BTV 16), recently isolated from different states of India. The evolutionary relationship of newly isolated BTV-16 and previously reported Indian and global BTV-16 isolates were compared using molecular analysis. Materials and Methods: In the present study, five (n=5) BTV-16 isolates were used to amplify gene segment-2 and segment-6 encoding the outer capsid proteins VP2 and VP5, respectively. The amplified products were purified and sequenced by the Sanger sequencing method. The phylogenetic relationship and nucleotide identity of all five BTV-16 isolates were compared with previously reported Indian and global BTV-16 isolates. Nucleotide sequence data were aligned using the CLUSTAL W algorithm implemented in the MegAlign of DNASTAR program package (MegAlign 5.00, DNASTAR Inc., Madison, USA). Phylogenetic analyses were carried out using MEGA version 6.0 software with the best nucleotide substitution model. Results: Phylogenetic analysis based on the VP2 and VP5 encoding genes, segregates Indian BTV-16 isolates in a distinct cluster with proximity to the Eastern topotype. Indian isolates make a monophyletic cluster with Eastern topotypes with Western topotype BTV-16 (BTV 16/NIG/AJ586694) occupying a separate cluster. Indian isolates were found to share 91.5%-97.5% and 96.5%-98.9% identity at the nucleotide and deduced amino acid (aa) level, respectively, to the global BTV-16 isolates. There is a high degree of variation with the Nigerian isolate with 27.0-27.7% and 26.0-26.9% at the nucleotide and aa sequence level, respectively. These data suggest that Indian BTV-16 isolates might have evolved separately within the Eastern BTV topotype. Conclusion: Phylogenetic analyses and nucleotide identity of BTV-16 isolates at the VP2 and VP5 gene encoded level indicate that isolates used in the present study might have evolved from a common Eastern topotype ancestor. The data presented in this study will be helpful for future selection of reference strains in a serological and molecular epidemiology study. PMID- 30250359 TI - Seroprevalence of brucellosis in small ruminants in organized and unorganized sectors of Gujarat state, India. AB - Aim: The present study aimed to study the seroprevalence of brucellosis in small ruminants of Gujarat state, India, using Rose Bengal Plate test (RBPT) and indirect enzyme-linked immunosorbent assay (iELISA). Materials and Methods: A total of 2444 sera samples (675 sheep and 1769 goat) from unorganized sector and 1310 sera samples (861 sheep and 449 goat) from seven organized farms were collected for brucellosis screening. Results: In unorganized sector, 23.70% sheep (160/675) and 15.99% goat (283/1769) were positive by RBPT and 24.44% sheep (165/675) and 17.24% goat (305/1769) by iELISA. The organized sector samples showed higher seroprevalence in goat (7.79 %, 35/449) than sheep (4.06 %, 35/861) by RBPT. Similarly, in iELISA, goat samples showed a higher seroprevalence (9.35%, 42/449) compared to sheep (7.50%, 65/861). The diagnostic sensitivity and specificity of RBPT with ELISA were 88.69% and 99.65%, respectively, and showed a significant difference (p<=0.0001). The Chi-square analysis revealed a significant difference in seroprevalence between sectors (p<=0.01) and species (p<=0.01). Conclusion: The seroprevalence of brucellosis in small ruminants of Gujarat was investigated and showed a higher prevalence of brucellosis and warrants the implementation of proper preventive measures. PMID- 30250360 TI - Pathogens isolated from clinical cases of urinary tract infection in dogs and their antibiogram. AB - Aim: This study aims to determine the etiology of urinary tract infection (UTI) in dogs and to develop an antibiogram of organisms isolated. Materials and Methods: Urine samples were collected either through catheterization or cystocentesis from 35 dogs suspected of UTI admitted to VCC, LUVAS, Hisar. Bacteria were identified on the basis of cultural characteristics in 22 samples, and all the isolates were subjected to in vitro antimicrobial sensitivity testing. Results: The urine samples found positive for bacteria yielded pure colony growth in 77.27% and mixed growth in 22.73% samples, respectively. Escherichia coli (29.62%) and Streptococcus spp. (29.62%) were the most prevalent microorganisms followed by Staphylococcus spp. (22.22%), Klebsiella spp. (11.11%), Pseudomonas spp. (3.7%), and Bacillus spp. (3.7%). Overall, maximum sensitivity of isolates was found toward ceftriaxone/tazobactam (88.88%) and least toward amoxicillin and cloxacillin (29.62%). Conclusion: E. coli and Streptococcus spp. were the most predominant bacteria isolated from UTI affected dogs. In vitro sensitivity revealed a significant proportion of bacteria to be multidrug resistant. PMID- 30250361 TI - Red flour beetle (Tribolium castaneum): From population genetics to functional genomics. AB - Tribolium castaneum is a small and low maintenance beetle that has emerged as a most suitable insect model for studying developmental biology and functional genetic analysis. Diverse population genetic studies have been conducted using Tribolium as the principal model to establish basic facts and principles of inbreeding experiments and response to the selection and other quantitative genetics fundamentals. The advanced molecular genetic studies presently focused on the use of Tribolium as a typical invertebrate model for higher diploid eukaryotes. After a whole genome sequencing of Tribolium, many areas of functional genomics were unraveled, which enabled the use of it in many technical approaches of genomics. The present text reviews the use of Tribolium in techniques such as RNAi, transgenic studies, immune priming, immunohistochemistry, in situ hybridization, gene sequencing for characterization of microRNAs, and gene editing using engineered endonuclease. In contrast to Drosophila, the T. castaneum holds a robust systemic RNAi response, which makes it an excellent model for comparative functional genetic studies. PMID- 30250362 TI - The effect of cashew leaf extract on small intestine morphology and growth performance of Jawa Super chicken. AB - Aim: This research aimed to study the effect of leaf extract of cashew as a bioactive compound in feed on the morphology of the small intestine in Jawa Super chicken (Gallus gallus domesticus). Materials and Methods: This study used 72 1 day-old Jawa Super chicks reared for a further 16 days. We used a randomized complete design, in which basal feed was supplemented with ethanolic extract of cashew leaves at 0 g/kg feed (control), 1.25 g/kg feed (P1), 2.5 g/kg feed (P2), 5 g/kg feed (P3), 10 g/kg feed (P4), and 20 g/kg feed (P5). Parameters observed included growth performance, chicken morphometry, and morphology of the small intestine, comprising the length and width of the villi, the depth of the crypt, and the number and size of goblet cells in the duodenum, jejunum, and ileum. Data analysis was conducted using one-way ANOVA followed by Duncan's test, with significance defined as p<0.05. Results: Ethanolic extract of cashew leaf significantly increased body weight, feed efficiency, body morphometry, villus length, crypt depth, number of goblet cells, and extent of goblet cell area of the small intestine at 16 days. The morphological results from the small intestine showed that P4 and P5 were significantly better than control. Conclusions: Cashew leaf ethanolic extract mixed with 10 g/kg basal feed is effective as a natural feed supplement for Jawa Super chickens. PMID- 30250363 TI - Investigation of haptoglobin, serum amyloid A, and some biochemical parameters in calves with omphalitis. AB - Aim: In this study, it was aimed to determine the concentration of some important acute phase proteins (APPs) and some biochemical parameters pre-operative and post-operative in calves with omphalitis. Materials and Methods: A total of 20 calves were used in the study and they consist of 10 clinically healthy calves that were used as a control and 10 calves with omphalitis were used as the treatment group. Blood samples were collected from Vena jugularis of animals to tubes with anticoagulant (sodium citrate) and without anticoagulants, pre operative (day 0), and post-operative (day 7). Samples were used to determine the concentration of haptoglobin (Hp), serum amyloid A (SAA), ceruloplasmin (Cp), fibrinogen, glucose, total protein, albumin, urea, total bilirubin, creatinine, calcium, phosphorus, aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) concentrations. Results: While the Hp, SAA, Cp, fibrinogen, urea, creatinine, total bilirubin, ALP, and GGT concentrations were statistically and significantly increasing rather than the control group during the pre-operative period for calves with omphalitis, they decreased to the post-operative period. Moreover, an insignificant increase in the glucose, total protein, and AST concentrations and an insignificant decrease in the albumin, calcium, and phosphorus concentrations were statistically determined. Conclusion: We have the opinion that the assessment of biochemical parameters and especially APP levels in calves with the omphalitis together with the clinical findings may be important in terms of the treatment and prognosis. PMID- 30250364 TI - Post-epidemic awareness and knowledge of Lassa fever among residents in affected community in Ibadan, Oyo State, Nigeria. AB - Aim: An outbreak of Lassa fever occurred in Ibadan with a case fatality rate of 50% in 2012. Awareness creation and sensitization is a known disease prevention and control strategy. An assessment of the awareness level and knowledge of Lassa fever in the affected community and a nearby university community was done to aid the development of effective information, education, and communication (IEC) material adaptable to the affected community. Materials and Methods: A semi structured questionnaire was used to obtain the data about awareness and knowledge of Lassa fever from 130 respondents. Descriptive statistics and statistical differences between categorical variables were done using Fisher's exact test at 5% significant level. Results: Respondents' age was 29.9 +/- 10.9 years. Awareness level in the affected and university communities was 42 (65%) and 55 (85%), respectively (p=0.02). The most reported source of awareness was the television and radio (59.8%). Only 33.1% of all respondents had good knowledge of the clinical symptoms. Most (68.5%) of the respondents knew rat as the reservoir: However, 56.9% and 80.0% of respondents from the affected and university communities, respectively, had this knowledge (p=0.01). About one third (30.0%) of the respondents had good knowledge of preventive measures: 18.5% and 41.5% from affected and university communities, respectively (p=0.01). Conclusion: Knowledge of respondents on Lassa fever symptoms, reservoir, and preventive measures was low in the affected community; the IEC material was developed to address the knowledge gaps. Awareness was also intensified in the affected community. PMID- 30250365 TI - Effectiveness of poultry litter amendments on bacterial survival and Eimeria oocyst sporulation. AB - Aim: Broilers' optimum performance in response to their genetic potential depends on litter environment which is ideal for bacterial survival and coccidian oocyst sporulation. An in vitro evaluation was conducted for the effectiveness of superphosphate, meta-bisulfide, and charcoal litter amendments in minimizing Escherichia coli O157:H7 and Salmonella Typhimurium survival, Eimeria oocyst count, and sporulation. Materials and Methods: Three groups of 16 litter trays were prepared and inoculated with E. coli O157:H7, S. Typhimurium, and Eimeria non-sporulated oocyst. A set of four trays in each group was designed for each one of the chemical amendments. A total of 720 litter samples were collected and examined for bacterial counts, Eimeria oocyst count, and sporulation during the experimental period (35 days). Results: Litter moisture and pH revealed a highly significant (p<0.001) reduction in all treated litter trays compared to control. Total bacterial count (TBC), total Enterobacteriaceae count, and S. Typhimurium count showed a highly significant (p<0.001) reduction in meta-bisulfide-treated trays compared to other amendments and positive control. Meanwhile, Eimeria oocyst count and sporulation revealed a highly significant (p<0.001) reduction in superphosphate, meta-bisulfide, and charcoal-treated trays, respectively. Temperature revealed a highly significant (p<0.001) weak positive correlation with pH of all inoculated trays, a highly significant (p<0.001) weak negative correlation with moisture percentage of E. coli O157:H7 and S. Typhimurium inoculated trays, and a highly significant (p<0.001) weak negative correlation with TBC. Meanwhile, relative humidity revealed significant (p<=0.005) weak positive correlation with moisture percentage of E. coli O157:H7 inoculated trays. Conclusion: The study concluded that regular usage with periodical reapplication of litter amendments as meta-bisulfide or superphosphate in poultry farms is one of the indispensable managemental and preventive measures for minimizing bacterial survival and inhibiting Eimeria oocyst maturation and sporulation. PMID- 30250366 TI - Sources of contamination, prevalence, and antimicrobial resistance of thermophilic Campylobacter isolated from turkeys. AB - Aim: Sources of contamination, prevalence, and antimicrobial susceptibility of thermophilic Campylobacter isolated from turkey samples were determined. Materials and Methods: A total of 300 samples were collected from 3 farms (fecal droppings) and 4 poultry slaughterhouses (neck skins and ceca) located in the middle area of Algeria (Algiers, Boumerdes, and Bouira). After detection, an antibiogram was realized only for slaughterhouses samples. Results: Samples from cecum (90.0%, 90/100; 95% confidence interval (CI)=84.1-95.9%), fecal dropping (68.0%, 68/100; 95% CI=58.9-77.1%), and neck skin (55.0%, 55/100; 95% CI=45.2 64.8%) were positive for thermophilic Campylobacter (p<0.05). Contamination rate of turkey carcasses was higher in modern slaughterhouse (96.7%) than in traditional slaughterhouses (37.1%) (p<0.05). Isolated strains were resistant to nalidixic acid (NA) (87.5%), tetracycline (TE) (81.3%), ciprofloxacin (CIP) (75.0%), ampicillin (AM) (65.6%), and erythromycin (25.0%) (p<0.05). 96.9% (124/128) of the isolates were multiresistant and 18 drug resistance patterns were registered. The predominant one (43.0%) was AM, NA, CIP, and TE. Conclusions: Potential sources of contamination of this fastidious bacterium were noticed in farms and slaughterhouses. Modern slaughterhouse allowed contamination of turkey carcasses more than a traditional slaughterhouse. However, the scalding step could not represent a source of contamination. The most tested strains exhibited resistance to erythromycin and/or CIP. It is worrisome because these molecules are considered as first-choice antibiotics for human campylobacteriosis. PMID- 30250367 TI - Antimicrobial resistance genes in pathogenic Escherichia coli isolated from diseased broiler chickens in Egypt and their relationship with the phenotypic resistance characteristics. AB - Aim: The aim of this study was to determine the relationship between phenotypic resistance and genotypic resistance of isolated serotyped pathogenic Escherichia coli isolates from the clinically diseased broiler. Materials and Methods: A total of 160 samples (heart, liver, kidney, and lung) were collected from 18 to 34 days old clinically diseased broiler from 40 broiler farms (3-5 birds/farm) reared in Giza and Kaluobaia Governorates for the isolation of pathogenic E. coli. Various E. coli isolates were tested for the pathogenicity based on Congo red (CR) dye binding assay. The obtained CR-positive E. coli isolates were subjected to serological identification using slide agglutination test. Disc diffusion test was used to study the sensitivity pattern of E. coli isolates to available 12 antibiotics. Polymerase chain reaction was performed for the detection of antimicrobial resistance genes in the studied pathogenic E. coli isolates. Results: The results revealed that 56 samples (35 %) were positive for E. coli. The results of the CR assay indicates that 20 isolates of 56 (35.7%) were positive and 36 isolates (64.3%) were negative. Identified E. coli serotypes of CR-positive isolates were 1 (O24), 2 (O44), 2 (O55), 5 (O78), 2 (O86), 1 (124), 3 (O127), 1 (O158), and 3 untyped. Resistance rate in disc diffusion test was 85% to oxytetracycline and kanamycin; 80% to ampicillin (AMP), clindamycin, and streptomycin (S); 75% to enrofloxacin; 65% to chloramphenicol; 55% to cefotaxime and gentamicin (CN); 45% to trimethoprim+sulfamethoxazole; 35% to erythromycin (ERI); and 30% to oxacillin. All strains are multidrug-resistant (MDR). Antibacterial resistance genes CITM, ere, aac (3)-(IV), tet(A), tet(B), dfr(A1), and aad(A1) were detected in 14 (70%), 12 (60%), 12 (60%), 8 (40%), 11 (55%), 8 (40%), and 9 (45%) of tested 20 isolates, respectively. Multidrug resistance was detected in the form of resistance to 42%-83.3% of tested 12 antibiotics. Three isolates (15%) of 20 tested isolates showed a relationship between phenotype and genotype and 17 (85%) showed irregular relation. Strains are sensitive and show resistant gene (P-G+) presented in three isolates for AMP (beta-lactam), one for ERI (Macrolide), as well as five isolates for trimethoprim (pyrimidine inhibitor). E. coli isolates had resistance and lacked gene (P+ G-) reported meanly in one isolate for CN (aminoglycoside), two isolates for tetracycline, four isolates for ERI, seven isolates for trimethoprim, and eight isolates for S (aminoglycoside). Conclusion: The study demonstrates that E. coli is still a major pathogen responsible for disease conditions in broiler. E. coli isolates are pathogenic and MDR. Responsible gene was detected for six antibiotics in most of the isolates, but some do not show gene expression, this may be due to few numbers of resistance genes tested or other resistance factors not included in this study. PMID- 30250368 TI - Determination of hematological and serum biochemical reference values for indigenous sheep (Ovies aries) in Dhaka and Chittagong Districts of Bangladesh. AB - Aim: The study was aimed to determine the reference values of most commonly used hematological and biochemical parameters of indigenous sheep, reared under semi intensive backyard farms in Dhaka and Chittagong district, Bangladesh. Materials and Methods: A total of 41 blood samples were collected from indigenous sheep (Ovis aries) from June to December 2016 from Dhaka and Chittagong Districts of Bangladesh. Hematological and serum biochemical parameters such as hemoglobin (Hb), packed cell volume (PCV), erythrocyte sedimentation rate (ESR), total erythrocyte count (TEC), total leukocyte count (TLC), neutrophil, eosinophil, basophil, monocyte, lymphocyte, urea, triglyceride, cholesterol, glucose, albumin, total protein (TP), alanine aminotransferase (ALT), and aspartate transaminase (AST) were determined by biochemical analyzer. 90% reference intervals were calculated for all parameters. Results: The hematologica and serum biochemical profiles of indigenous sheep showed wide range and variation. The results were categorized according to sex and age of the sheep for comparison. Young sheep had significantly higher PCV, eosinophil, triglyceride, and TP level than that of adult (p<0.05), whereas the urea and albumin level was higher in adult than that of juvenile (p<0.05). Most of the values of the parameters are close to each other for both male and female except TEC, urea, cholesterol, triglyceride, glucose, and AST. However, a significant difference was found only for albumin and basophil level between male and female sheep. Conclusion: Hematological and biochemical parameters in Bangladeshi indigenous sheep showed a wide range and variation implicating future study for the prophylaxis of ovine diseases. PMID- 30250369 TI - A cross-sectional study of the welfare of calves raised in smallholder dairy farms in Meru, Kenya, 2017. AB - Aim: This study was aimed at describing calf comfort and determining the individual and pen level factors that affect comfort status (in particular, calf leg hygiene scores) of smallholder dairy farms in Meru County, Kenya. Materials and Methods: A cross-sectional study was carried out on 52 calves that were up to 1 year old in 38 dairy farms (mean+/-standard deviation: Herd size=1.71+/-0.7 milking cows and milk production=6.7+/-3.1 L/day) in Meru, Kenya, in 2017, with the intention to describe their comfort and determine the factors associated with leg hygiene as a critical parameter for calf comfort assessment. Calves' biodata, health status, and leg hygiene were assessed, along with pen characteristics such as area, hygiene, and knee impact and knee wetness scores, while a questionnaire was administered to the farmers to gather information regarding calf housing management practices in the farm. Results: The calves had a mean body weight of 85.2+/-32.8 kg and average daily weight gain of 0.50+/-0.45 kg per day. 71% of calves had a good body condition score (>=2.5), and the mean space allowance per calf was 2.52+/-1.56 m2. Approximately 75% of the calves (39/52) were kept in pens, and the rest were reared outdoors. For 39 calves kept indoors, 26% (10/39) of them had wooden or concrete floors while 74% (29/39) had dirt floors. Nearly two-thirds (62%) of indoor calves (26/39) were reared in pens with bedding, and 23% (9/39) and 33% (13/39) of the calves reared indoors were kept in pens displaying a failed knee impact test and failed knee wetness test. Indoor housed calves had an increased probability of having dirty calf legs (cleanliness score of >2.5) by 8.6 times (p=0.031), compared to outdoor-housed calves. In the final multivariable logistic regression model of 39 calves in pens, concrete or wood floors (odds ratio [OR]=7.9, p=0.047), poor body condition (OR=17.1, p=0.020) and use of bedding (OR=12.5, p=0.046) appeared to be positively correlated with dirtiness of calf legs, compared to dirt floors, good body condition, and no bedding, respectively. Conclusion: Overall, some calf comfort aspects were covered for the majority of calves examined, but 69% of the pens were categorized as dirty, especially those with wooden or concrete floors and poor bedding management. Smallholder dairy farmers in Kenya should be trained on calf housing management to improve calf comfort and productivity. PMID- 30250370 TI - Prevalence and risk factors for Salmonella spp. contamination in broiler chicken farms and slaughterhouses in the northeast of Algeria. AB - Aim: The aim of this study was to provide information on the prevalence of Salmonella serotypes and to identify risk factors for Salmonella spp. contamination in broiler chicken farms and slaughterhouses in the northeast of Algeria. Materials and Methods: This study was conducted on 32 poultry farms and five slaughterhouses in the province of Skikda (northeastern Algeria). A questionnaire was answered by the poultry farmers and slaughterhouses' managers. Biological samples (cloacal swabs, droppings, caeca, livers, and neck skins) and environmental ones (water, feed, surface wipes, rinsing water, and sticking knife swabbing) were taken to assess the Salmonella contamination status. Results: Nearly 34.37% of the poultry farms and all the slaughterhouses were contaminated with Salmonella. The isolated Salmonella strains belonged to two major serotypes: Kentucky and Heidelberg followed by Enteritidis, Virginia, and Newport. There was an evident heterogeneous distribution of serotypes in poultry farms and slaughterhouses. Only one factor (earth floor) was significantly associated with Salmonella contamination in poultry houses (p<0.05). Conclusion: A high prevalence rate of Salmonella contamination was found in poultry farms and slaughterhouses in Skikda region. These results showed the foremost hazardous role of poultry production in the spread and persistence of Salmonella contamination in the studied region. PMID- 30250371 TI - Molecular and immunological characterization of Hyalomma dromedarii and Hyalomma excavatum (Acari: Ixodidae) vectors of Q fever in camels. AB - Background and Aim: Q fever Coxiella burnetii is a worldwide zoonotic disease, and C. burnetii was detected in mammals and ticks. Ticks play an important role in the spread of C. burnetii in the environment. Therefore, the aims of this study were to detect Q fever C. burnetii in camels and ixodid ticks by molecular tools and identification of Hyalomma dromedarii and Hyalomma excavatum using molecular and immunological assays. Materials and Methods: A total of 113 blood samples from camels and 190 adult ticks were investigated for the infection with C. burnetii by polymerase chain reaction (PCR) and sequencing the targeting IS30A spacer. The two tick species H. dromedarii and H. excavatum were characterized molecularly by PCR and sequencing of 16S ribosomal RNA (16S rRNA) and cytochrome oxidase subunit-1 (CO1) genes and immunologically by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and western blot. Results: A total of 52 camels (46%) were positive for Q fever infection. Only 10 adult ticks of H. dromedarii were infected with C. burnetii. The IS30A sequence was around 200 bp in length for C. burnetii in H. dromedarii ticks with a similarity of 99% when compared with reference data in GenBank records. The length of 16S rDNA and CO1 was 440 and 850 bp, respectively, for both H. dromedarii and H. excavatum. The phylogenetic status of H. dromedarii was distant from that of H. excavatum. SDS PAGE revealed seven different bands in the adult antigens of either H. dromedarii or H. excavatum with molecular weights ranged from 132.9 to 17.7 KDa. In western blot analyses, the sera obtained from either infested camel by H. dromedarii or infested cattle by H. excavatum recognized four immunogenic bands (100.7, 49.7, 43.9, and 39.6 kDa) in H. dromedarii antigen. However, the infested camel sera identified two immunogenic bands (117 and 61.4 kDa) in H. excavatum antigen. Furthermore, the sera collected from cattle infested by H. excavatum recognized three immunogenic bands (61.4, 47.3, and 35 kDa) in H. excavatum antigen. Conclusion: Molecular analyses indicated that both camels and ticks could be sources for infection of animals and humans with Q fever. Furthermore, the molecular analyses are more accurate tools for discriminating H. dromedarii and H. excavatum than immunological tools. PMID- 30250372 TI - Genetic and phenotypic characterization of the native rabbits in Middle Egypt. AB - Aim: Native rabbits in smallholder system are considered as important genetic resources, and the present study was aimed to study the genetic and phenotypic characterization and detection of the maternal origin of the native rabbit populations located at the Middle of Egypt. Materials and Methods: A survey of native rabbit populations was conducted in three governorates (Fayum [FY], Beni Suef [BN], and El Menia [MN]). The phenotypic characterization of rabbits included the profile body of the head, ears, eyes, neck, and legs and the coat colors. The blood samples were collected for genetic characterization based on mitochondrial (cytochrome b) and the microsatellite markers. Results: The phenotypic characterization of the body parts in the three populations was almost similar. The body weight of the mature rabbits in MN Government was significantly heaviest, and the measurements for the main body parts (body length, chest circumference, and abdominal girth) were the highest compared to the two populations. The results of mitochondrial (cytochrome b) analysis revealed that the rabbits from the three governments belonged to lineage A except one animal was recorded as lineage G from MN's rabbit population. The results of the microsatellite markers revealed that the genetic diversity between the three populations showed genetic interferences; however, a closer genetic relationship was observed between BN and MN than FY. The majority of the genetic diversity was the individual variability. Conclusion: The mitochondrial lineage A is the major lineage in rabbit populations in the area of the Middle Egypt understudy. The genetic populations' structure is the interferences among the three populations. A large-scale survey should be done on native rabbit populations for the sustainable management and conservation of the local breeds' genetic resources. PMID- 30250373 TI - Potency of lactic acid bacteria isolated from balinese bovine (Bos sondaicus) intestinal waste from slaughterhouse to improve nutrient content of wheat pollard as animal feedstuff by fermentation process. AB - Aim: The purpose of this study was to know the genetic and biochemical identification of isolated lactic acid bacteria (LAB) from Balinese bovine (Bos sondaicus) intestinal waste, acidity, and ox bile salts and to inhibit the growth pathogen of Staphylococcus aureus and Escherichia coli and the potential of those isolated to improve nutrient value of wheat pollard as animal feed ingredient by fermentation process. Materials and Methods: This research was divided into three stages. The first stage, isolated LAB were obtained from the bovine intestines at a slaughterhouse in Indonesia. Small intestinal samples were collected from 10 healthy Balinese beef cattle (B. sondaicus). The isolated LAB were identified by VITEK 2, polymerase chain reaction, and 16S rDNA. The basic local alignment search tool (BLAST) was performed to determine the phylogenetic tree. The second stage, the LAB were screened for their tolerance at pH 2, 3, and 4; bile salt, and antagonistic to enteric pathogen. In the third stage, to determine the potency of this isolate to increase nutrient content of wheat pollard by facultative anaerobe fermentation for 3 and 5 days. Results: The result of the first stage showed that the isolate could be identified as Lactobacilluscasei WPL 315. The result of the second stage showed that the isolate tolerance to low pH (pH 2, pH 3, and pH4) for 90 min and 24 h, and this isolate had viability tolerance in 0.3% bile salt. The isolate can inhibit S. aureus and E. coli. The result of the third stage by proximate analysis showed that crude protein increased by 23.08% after fermentation, while crude fiber decreased by 61.24% on the level 0.5% L. casei subsp. WPL 315 in the 3-day fermentation. Conclusion: Based on the results, it showed that L. casei WPL 315 derived from indigenous intestinal Balinese beef cattle (B. sondaicus) has tolerant characteristic on acidity and ox bile salts, has antagonistic effect against E. coli and S. aureus, and has the ability to increase crude protein and decrease crude fiber content of wheat pollard. It would be interesting to determine whether the strain has a probiotic candidate. PMID- 30250374 TI - Seasonal changes of rumen and intestine morphology of the Qinghai yak (Bos grunniens). AB - Aim: The aim of the current study was to investigate the effects of seasonal changes in grass quality on the ruminal and intestinal morphology of male Qinghai yaks. Materials and Methods: A total of four male yaks with the same age of 4 years old from each season (summer and winter) were randomly selected and slaughtered to determine the effect of different season on intestinal morphology of yak in the Qinghai-Tibetan Plateau. Results: The histological analysis shows that male yak has the longer and wider papillae in rumen in green season. The height of villi in duodenum and jejunum was significantly higher in green season, and the width of villi on duodenum, jejunum, ileum, and rectum was significantly wider in green season. Surface area of villi and crypt depth in duodenum, jejunum, and ileum was significantly larger and deeper in green season. Submucosa thickness of duodenum, jejunum, ileum, and rectum was significantly thicker in green season. The muscular thickness of jejunum, cecum, and rectum was significantly thicker in green season. Conclusion: According to this research, we found that the seasonal changes of ruminal and intestinal morphology of yak showed different length and width papillae, villi, crypt, and submucosa. This fact was confirmed the functional advantages resulting from the ability to successfully adapt to a dry climate and diets, flat, open, and cold grassland may allow yak to overcome both water shortage and energy deficiency in winter. PMID- 30250375 TI - Slaughter of pregnant goats for meat at Nsukka slaughterhouse and its economic implications: A public health concern. AB - Aim: This study was conducted to determine the incidence rate of the slaughter of pregnant goats in Nsukka slaughterhouse, which has become a major cruel occurrence in Nigeria, as well as it's economic and public health implications. Materials and Methods: All the goats slaughtered at Nsukka slaughterhouse over a period of 3 months (February-April, 2017) were screened. The data collected were: total number of goats slaughtered, age, breed and sex of goats slaughtered, pregnancy status of the goats, and sex of the fetuses observed, and gestational age of the fetuses estimated by crown-rump length. Results: In the 3-month study, a total of 684 goats were slaughtered, of which 617 (90.2%) were females. 364 (59%) of the females slaughtered were pregnant, and more than 80% of the gestations were in the second and third trimesters. Of 661 fetuses recorded, 320 (48.3%) were males, and 341 (51.7%) were females with 438 (66.3%) predominantly twins. At the cost of ? 6,000 ($16) and ? 8,000 ($20) for male and female kids, respectively, a total of ? 4,648,000 ($11,620) was lost in just one slaughterhouse in 3 months. Conclusion: This study shows that there is a high rate of slaughter of pregnant goats in Nsukka slaughterhouse with a tremendous economic loss, and most chevon sold in Nsukka are unwholesome and of low meat quality. PMID- 30250376 TI - Isolation and identification of bacteria from fresh guava (Psidium guajava) sold at local markets in Mymensingh and their antibiogram profile. AB - Aim: The study was conducted for the isolation, identification, and antibiogram of bacteria obtained from fresh guava (Psidium guajava). Materials and Methods: A total of 25 fresh guavas were collected from five markets located in Mymensingh city. Guava samples were cultured onto various selective media such as eosin methylene blue, xylose lysine deoxycholate, thiosulfate-citrate-bile salts sucrose, blood agar, and mannitol salt agar for the isolation of bacteria. Biochemical tests (dextrose, maltose, lactose, sucrose, mannitol, methyl red, Voges-Proskauer, and indole) were performed to identify the bacteria. Results: Total viable counts of guava were ranged between log 6.56 colony-forming unit (cfu)/ml and 6.62 cfu/ml. A total of 106 bacterial isolates belonged to five genera (Escherichia coli, Salmonella spp., Vibrio spp., Bacillus spp., and Staphylococcus spp.) were identified. Salmonella spp. (23.6%) was the most prevalent, followed by E. coli (22.64%), Bacillus spp. (19.81%), Staphylococcus spp. (17.92%), and Vibrio spp. (16.03%). The results of antibiotic sensitivity test showed that Salmonella spp., Bacillus spp., and E. coli were sensitive to chloramphenicol, ciprofloxacin, and gentamicin and resistant to ampicillin and cephalexin. Vibrio spp. was sensitive to chloramphenicol and gentamicin, intermediately sensitive to ciprofloxacin and ampicillin and resistant to cephalexin. Conclusion: The results of this study indicate that fresh guava contains multidrug-resistant bacteria which might pose a public health risk. PMID- 30250377 TI - Sporadic cases of lumpy skin disease among cattle in Sharkia province, Egypt: Genetic characterization of lumpy skin disease virus isolates and pathological findings. AB - Background and Aim: Lumpy skin disease (LSD) is a highly infectious viral disease upsetting cattle, caused by LSD virus (LSDV) within the family Poxviridae. Sporadic cases of LSD have been observed in cattle previously vaccinated with the Romanian sheep poxvirus (SPPV) vaccine during the summer of 2016 in Sharkia province, Egypt. The present study was undertaken to perform molecular characterization of LSDV strains which circulated in this period as well as investigate their phylogenetic relatedness with published reference capripoxvirus genome sequences. Materials and Methods: A total of 82 skin nodules, as well as 5 lymph nodes, were collected from suspect LSD cases, and the virus was isolated in embryonated chicken eggs (ECEs). LSD was confirmed by polymerase chain reactions amplification of the partial and full-length sequences of the attachment and G protein-coupled chemokine receptor (GPCR) genes, respectively, as well as a histopathological examination of the lesions. Molecular characterization of the LSDV isolates was conducted by sequencing the GPCR gene. Results: Characteristic skin nodules that covered the whole intact skin, as well as lymphadenopathy, were significant clinical signs in all suspected cases. LSDV isolation in ECEs revealed the characteristic focal white pock lesions dispersed on the chorioallantoic membranes. Histopathologic examination showed characteristic eosinophilic intracytoplasmic inclusion bodies within inflammatory cell infiltration. Phylogenetic analysis revealed that the LSDV isolates were clustered together with other African and European LSDV strains. In addition, the LSDV isolates have a unique signature of LSDVs (A11, T12, T34, S99, and P199). Conclusion: LSDV infections have been detected in cattle previously vaccinated with Romanian SPPV vaccine during the summer of 2016 and making the evaluation of vaccine efficacy under field conditions necessary. PMID- 30250378 TI - Morphologic and morphometric characteristics of ascaroid worm, Ophidascaris piscatori in Xenochrophis piscator snake in Sidoarjo, Indonesia. AB - Aim: The study was conducted to describe the morphology and morphometry of nematode worm in the stomach of Xenochrophis piscator snake macroscopically and microscopically using light and scanning electron microscopy (SEM). Materials and Methods: The sample was 40 nematode worms that have been collected from 60 snakes which slaughtered at snake slaughterhouses in Sidoarjo, Indonesia. The worms (10 male and 10 female) were stained with carmine, and the others were sent to Indonesian Science Institute for ultrastructure observation by SEM. Some of the female worms were immersed in physiological NaCl and incubated to collect the worm eggs. Results: Nematode worm in this study had three lips with almost the same size and it had papillae, so it was included in ascaridoid. The mouth of ascaridoids has three lips, the dorsal bearing two large outer papillae and the each lateroventral with one papilla. The body length and width of the male worm were 70-105 mm and 0.92-1.32, respectively, with head diameter of 0.22-0.28 mm. Dorsal and ventrolateral lips almost have the same size that was 0.10-0.12*0.11 0.13 mm. The length of interlabia was 0.06-0.08 mm, esophagus was 3.21-4 mm, tail was 0.17-0.23 mm, and spicule was 2.12-3.36 mm. The body length and width of the female worm were 85-130 mm and 1.28-1.71 mm, respectively. The head diameter was 0.29-0.38 mm. Dorsal and ventrolateral lips almost have the same size that was 0.13-0.16*0.15-0.19 mm. The interlabial length was 0.08-0.10 mm, esophagus was 3.04-4.67 mm, and tail was 0.22-0.31 mm. The distance of the vulva from the anterior edge was 56-88 mm with an average of 67.35 mm. The eggs have conspicuously pitted with length 0.08-0.09 mm and width 0.07-0.08 mm. Conclusion: Based on the characteristics of morphology and morphometry, the ascaroid worms found on X. piscator snake from Sidoarjo, Indonesia, were O. piscatori. PMID- 30250379 TI - An epidemiological investigation on occurrence of enterohemorrhagic Escherichia coli in raw milk. AB - Aim: The aim of the present investigation was to study the epidemiology of enterohemorrhagic Escherichia coli (EHEC) in raw milk and molecular characterization of isolates using multiplex polymerase chain reaction (PCR). Materials and Methods: A total of 125 raw milk samples were subjected to isolation, identification, and confirmation of virulence-associated genes by multiplex PCR (mPCR). The samples were collected from a milk cooperative society of Thrissur district, Kerala. For further epidemiological investigation, samples such as dung (126), hair coat of cow (60), udder swab (60), udder wash (60), milking utensil wash (36), Milker's hand wash (36), water (36), soil (36), and feed (36) were collected from the households from which the raw milk tested positive for EHEC. Results: The occurrence of EHEC in individual raw milk samples was found to be 8.8%. The major source of contamination to raw milk was found to be dung (19.84%) followed by udder swab (16.67%), hair coat of cow (15%), Milker's hand and milking utensils and water (11.11% each), and udder wash and soil (8.33% each). For identification of virulence genes, all the isolates were subjected to mPCR, of 75 isolates 73.33% of isolates harbored stx 2 gene while 53.33, 36, and 36% of isolates were encoded by stx 1, eae A, and hly A genes, respectively. On epidemiological survey, the multiple risk factors accountable for occurrence of EHEC in raw milk were found to be the quality of water used, improper and inadequate udder preparation, unhygienic hands of Milker's, use of insufficiently cleaned milking utensils, and using common utensil for washings of udder and milking purposes. Conclusion: The result of the present study signifies that raw milk was contaminated with EHEC and possesses a high public health threat. As dairy cattle and its environment serve as a potential niche for EHEC, hygienic milking practices should be adopted to curb the occurrence of EHEC in raw milk. PMID- 30250380 TI - Serosurveillance of Brucella antibody in food animals and role of slaughterhouse workers in spread of Brucella infection in Southeast Nigeria. AB - Aim: The study was carried out to determine the seroprevalence of Brucella antibody in slaughter cattle and goats; and the role of slaughterhouse workers (SHWs) in spread of Brucella infection during slaughterhouse operations in Enugu State, Southeast Nigeria. Materials and Methods: Rose Bengal plate test was used to screen for Brucella antibody in 484 cattle and 340 goats slaughtered for human consumption in the state. Structured and pretested questionnaire was used to elicit information from randomly selected SHWs, on socioeconomic characteristics, awareness of brucellosis and involvement in practices that aid dissemination of Brucella infection during slaughterhouse operations. Results: Suspected seroprevalence of 2.5% and 4.1% were recorded for Brucella antibody in cattle and goats respectively. There was poor awareness of brucellosis (32.1%) among the workers surveyed. Slaughterhouse practices that aid acquisition or spread of Brucella infection and percentage of SHWs engaged in the practices are: non-use of personal protective clothing during slaughterhouse operations (70.8%), discharge of eviscerated fetuses or pregnant uterine contents by open-air dump method of refuse disposal (64.9%) and illegal sell of eviscerated fetuses or gravid uterine contents for human consumption (59.9%) or preparation of dog food (71.5%). Conclusion: The 4.1% suspected seroprevalence of Brucella antibodies in goats represents 128% increase from 1.8% seroprevalence earlier reported in the same species and study area in 2009. Significant amounts of Brucella antibody was detected in the food animals screened. Slaughterhouse workers played significant roles in spread of Brucella infection by their involvement in risk practices and behaviours that facilitate pathogen transmission. Therefore, massive awareness campaign and coordinated brucellosis control program in Enugu State are imperative to forestall the zoonotic and economic consequences associated with brucellosis. PMID- 30250381 TI - Intestinal parasites among migrant barn swallows (Hirundo rustica) in the central region of Mazandaran Province, Northern Iran. AB - Aim: Swallows are a family of migratory birds found worldwide except Antarctica. Annually, a number of species of swallows migrate to Iran. As they make their nests close to human living places, this may be a potential risk for public health. Conversely, no study has been conducted on intestinal parasitic infections of these birds so far. Therefore, the objective of this study was to determine the prevalence of intestinal parasites in migratory swallows (Hirundo rustica) in the central region of Mazandaran Province, Northern Iran. Materials and Methods: In this cross-sectional study, 205 feces samples from two districts (Sari and Qaemshahr) in the central region of Mazandaran were randomly collected during the summer and spring sessions of 2016-2017. The collected samples were examined using the routine direct fecal examination and formalin-ethyl acetate concentration. In addition, the samples were examined by cold acid-fast staining method to detect possible Cryptosporidium oocysts. Results: The results of this study indicated that 38 samples (18.5%) were infected with intestinal parasites. Among the helminthic parasites, eight genera and species were identified as follows: Ascaridia galli, Syngamus trachea, Raillietina, Toxocara spp., Choanotaenia, Taenia spp., Ascaridia spp., and Moniezia spp. In addition, among protozoan parasites, only the Coccidia spp. oocysts were identified. Conclusion: Our findings showed a relatively high prevalence of parasitic infections in migratory barn swallows in Mazandaran Province. Given the presence of zoonotic parasites in the samples, further investigations are needed to identify all parasites fauna, particularly zoonotic species among swallows in the region. PMID- 30250382 TI - Assessment of antibody assay methods in determination of prevalence of infectious bursal disease among local chickens and guinea fowls in Kwara state, North Central Nigeria. AB - Aim: This study aimed to assess available assay methods for infectious bursal disease (IBD) diagnosis and seromonitoring in local birds. It also sought to know the prevalence of IBD antibodies among local chickens and guinea fowls in Kwara state, North Central Nigeria. Materials and Methods: Sera were obtained from local chickens and guinea fowls and IBD virus (IBDV) antibodies were assayed using enzyme-linked immunosorbent assay (ELISA), indirect hemagglutination (IHA) test, and agar gel immunodiffusion (AGID) test. Results: A total of 265 sera were obtained from local birds during dry and wet seasons. ELISA recorded the highest prevalence of 81.1% (215/265) while IHA and AGID detected IBDV antibodies in 183 (69.1%) and 122 (46%) birds, respectively. Significant differences were established for IBD-positive sera based on the assay method used, bird species, and seasons. Conclusion: This study indicated that ELISA is the most sensitive and reliable assay method while AGID is the least. It also showed that there is a high prevalence of IBDV antibodies among local birds which were not vaccinated, and this implies a high IBDV activity among these bird species in the study area. This may have significant epidemiological implications on the spread of the virus to exotic bird reared in the rural areas on a commercial scale. Thus, this study suggests continuous surveillance, awareness campaign, and advocacy for vaccination of indigenous birds against IBD. PMID- 30250383 TI - Mixing two different propolis samples potentiates their antimicrobial activity and wound healing property: A novel approach in wound healing and infection. AB - Aim: The study aimed to investigate whether mixing two different propolis samples can potentiate their biological activity. This hypothesis was tested by studying the effect of mixed propolis on microbial growth and wound healing and compared with the effect of each propolis individually. Materials and Methods: The effect of mixing two different propolis extracts (A and B) collected from different locations in Iraq on Escherichia coli, Staphylococcus aureus, and Candida albicans was studied by minimum inhibitory concentration assessment and compared with the effect of each propolis. Wound healing effect of the mixed propolis was studied. Twenty-four rabbits were used for the experiment, and they were assigned to four groups. Wounds were created on the dorsum of each rabbit and treated by topical application of 1 mL of either mixed propolis, propolis A, or propolis B extracts or were kept without treatment as a control. Macroscopic wound evaluation was performed with an assessment of wound size, wound recovery, redness, edema, discharge, granulation tissue, and epithelialization. Results: Propolis A was more potent than propolis B extracts to inhibit the growth of E. coli, S. aureus, and C. albicans (p<0.05). However, mixed propolis showed a higher antimicrobial activity toward all the pathogens than propolis A or propolis B extract individually (p<0.05). Furthermore, propolis A and propolis B extracts showed favorable effects on wound healing which was more pronounced with propolis A extract. Interestingly, mixed propolis accelerated wound healing faster than propolis A or propolis B extracts, and it shortened the time of reepithelialization (p<0.05). Conclusion: This study demonstrates for the first time that mixing different propolis samples possesses a higher antimicrobial activity and higher wound healing property than individual propolis. This approach could pave the way for the development of more effective antimicrobials and wound healing agents. PMID- 30250384 TI - Amino acid sequence based on Cytochrome b gene in Kejobong goat and its genetic relationships among several local goats in Asia. AB - Aim: This study aimed to analyze the amino acid sequence of Cytochrome b (Cyt b) gene in Kejobong goat and its genetic relationships with local goats located in Asia. Materials and Methods: A total of 28 heads of Kejobong goat were purposively sampled. The deoxyribonucleic acid (DNA) was extracted from blood using gSYNC DNA mini kit (Geneaid Biotech Ltd.). Cyt b gene was amplified using polymerase chain reaction (PCR) method with CytbCapF and CytbCapR primers. The amplified PCR products were sequenced for further analysis. Results: There were a total 377 amino acid sequences translated from 1140 base pair (bp) of Cyt b gene, 99.20% of it were monomorphic, amino acid alterations were found at site 16th, 121st, and 231st, and Kejobong goat was in the same cluster with Southeast Asian local goats. Conclusion: Most of the amino acid sequence on Cyt b gene in Kejobong goat is monomorphic (99.20%), only a few nucleotide mutations were found that causing amino acid alteration in three sites (0.80%). Kejobong goat has a close genetic relationship to several local goats in Southeast Asian. PMID- 30250385 TI - New ways of understanding brain neurocircuitry. AB - Inside the brain, neural regions dynamically interact at multiple spatial and temporal scales through a highly structured and adaptive neurocircuitry. Comprehensive maps of brain connectivity have led to the emerging field of connectomics. Graph theory methods are interesting tools to improve our understanding of the brain as a complex interconnected system. PMID- 30250386 TI - Data-driven approaches for identifying links between brain structure and function in health and disease. AB - Brain imaging technology provides a powerful tool to visualize the living human brain, provide insights into disease mechanisms, and potentially provide a tool to assist clinical decision-making. The brain has a very specific structural substrate providing a foundation for functional information; however, most studies ignore the very interesting and complex relationships between brain structure and brain function. While a variety of approaches have been used to study how brain structure informs function, the study of such relationships in living humans in most cases is limited to noninvasive approaches at the macroscopic scale. The use of data-driven approaches to link structure and function provides a tool which is especially important at the macroscopic scale at which we can study the human brain. This paper reviews data-driven approaches, with a focus on independent component analysis approaches, which leverage higher order statistics to link together macroscopic structural and functional MRI data. Such approaches provide the benefit of allowing us to identify links which do not necessarily correspond spatially (eg, structural changes in one region related to functional changes in other regions). They also provide a "network level" perspective on the data, by enabling us to identify sets of brain regions that covary together. This also opens up the ability to evaluate both within and between network relationships. A variety of examples are presented, including several showing the potential of such approaches to inform us about mental illness, particularly about schizophrenia. PMID- 30250387 TI - Connectome development and a novel extension to the neurodevelopmental model of schizophrenia. AB - The brain is the ultimate adaptive system, a complex network organized across multiple levels of spatial and temporal resolution that is sculpted over several decades via its interactions with the environment. This review sets out to examine how fundamental biological processes in early and late neurodevelopment, in interaction with environmental inputs, guide the formation of the brain's network and its ongoing reorganization throughout the course of development. Moreover, we explore how disruptions in these processes could lead to abnormal brain network architecture and organization and thereby give rise to schizophrenia. Arguing that the neurodevelopmental trajectory leading up to the manifestation of psychosis may best be understood from the sequential trajectory of connectome formation and maturation, we propose a novel extension to the neurodevelopmental model of the illness that posits that schizophrenia is a disorder of connectome development. PMID- 30250388 TI - Graph theory methods: applications in brain networks. AB - Network neuroscience is a thriving and rapidly expanding field. Empirical data on brain networks, from molecular to behavioral scales, are ever increasing in size and complexity. These developments lead to a strong demand for appropriate tools and methods that model and analyze brain network data, such as those provided by graph theory. This brief review surveys some of the most commonly used and neurobiologically insightful graph measures and techniques. Among these, the detection of network communities or modules, and the identification of central network elements that facilitate communication and signal transfer, are particularly salient. A number of emerging trends are the growing use of generative models, dynamic (time-varying) and multilayer networks, as well as the application of algebraic topology. Overall, graph theory methods are centrally important to understanding the architecture, development, and evolution of brain networks. PMID- 30250390 TI - The frontoparietal network: function, electrophysiology, and importance of individual precision mapping. AB - The frontoparietal network is critical for our ability to coordinate behavior in a rapid, accurate, and flexible goal-driven manner. In this review, we outline support for the framing of the frontoparietal network as a distinct control network, in part functioning to flexibly interact with and alter other functional brain networks. This network coordination likely occurs in a 4 Hz to 73 Hz theta/alpha rhythm, both during resting state and task state. Precision mapping of individual human brains has revealed that the functional topography of the frontoparietal network is variable between individuals, underscoring the notion that group-average studies of the frontoparietal network may be obscuring important typical and atypical features. Many forms of psychopathology implicate the frontoparietal network, such as schizophrenia and attention deficit/hyperactivity disorder. Given the interindividual variability in frontoparietal network organization, clinical studies will likely benefit greatly from acquiring more individual subject data to accurately characterize resting state networks compromised in psychopathology. PMID- 30250389 TI - Rich-club neurocircuitry: function, evolution, and vulnerability. AB - Over the past decades, network neuroscience has played a fundamental role in the understanding of large-scale brain connectivity architecture. Brains, and more generally nervous systems, can be modeled as sets of elements (neurons, assemblies, or cortical chunks) that dynamically interact through a highly structured and adaptive neurocircuitry. An interesting property of neural networks is that elements rich in connections are central to the network organization and tend to interconnect strongly with each other, forming so-called rich clubs. The ubiquity of rich-club organization across different species and scales of investigation suggests that this topology could be a distinctive feature of biological systems with information processing capabilities. This review surveys recent neuroimaging, computational, and cross-species comparative literature to offer an insight into the function and origin of rich-club architecture in nervous systems, discussing its relevance to human cognition and behavior, and vulnerability to brain disorders. PMID- 30250391 TI - Evolving a new neuropsychiatry. AB - Clinical neuroscience struggles with poor scientific validity of neuropsychiatric diagnosis and its negative impact on management. Sydenham's ancient conformity of type approach to nosology with its assumption that the symptom cluster and course of a disorder are due to a common etiology, has proven no match for the complicated comorbidities faced in neuropsychiatry. In the absence of accurate pathological biomarkers there is a challenge in finding a solid foundation for modern neuropsychiatry. We find standard psychiatric nosology to be of limited benefit at the general hospital bedside in evaluating and treating neuropsychiatric disorders. Consequently, we have developed over the years a neuro-circuitry-based training for our psychosomatic medicine fellows. In this commentary, we will introduce a strategy for understanding patients with neuropsychiatric disorders that may advance our ability to diagnose and treat them in accordance with neuroscientific evidence anchored in evolutionary neurocircuitry and attachment neurobehavior. PMID- 30250392 TI - Optimisation of a serum albumin removal protocol for use in a proteomic study to identify the protein biomarkers for silent gastric ulceration in horses. AB - Silent gastric ulceration occurs without evidence of clinical signs and is common in horses. There is currently no a simple and effective method to diagnose this disease. Proteomics can be used to identify serum biomarkers, but the most abundant serum protein, albumin, could conceal candidate biomarkers. Therefore, it is recommended to remove albumin before a proteomic study; however, there is no specific albumin depletion kit or standard protocol available for horse samples. The objectives of this study were to optimise a protocol to remove equine serum albumin and to use albumin-depleted serum to identify the protein biomarkers for silent gastric ulceration. Gastroscopy was used to identify gastric ulceration, and serum was obtained from horses with either a healthy gastric mucosa or gastric ulceration. Serum albumin was removed using the trichloroacetic acid (TCA) protein precipitation method, and this protocol was optimised by varying the concentration of TCA, type of organic solvents, ratio of serum to protein precipitation solution, and incubation times. Electrophoresis and image analysis were used to compare the amounts of albumin, immunoglobulins G (IgG), and protein degradation before and after TCA precipitation. The best protocol was chosen to remove albumin for a proteomic study (electrophoresis and mass spectrometry). The results revealed that protocol 2 (ratio of serum to solution 1:5, 10% TCA in acetone, and 90 min incubation) was the most efficient protocol to remove albumin (98%) and IgG heavy (80%) and light (98%) chains without degrading other proteins. After electrophoresis and mass spectrometry analysis, KRT1, KRT6A and KRT18 were identified as potential markers for silent gastric ulceration. PMID- 30250393 TI - Changes of lying behavior in Thoroughbred foals influenced by age, pasturing time, and weather conditions. AB - The lying behavior of Thoroughbred foals on breeding farms was continuously measured using triaxial accelerometers. Accelerometers were attached on the side of the hind limb cannon and under the halter of six foals to record triaxial angle data every 10 sec for a period of 24 hr. Lying behavior was divided into sternal lying and lateral lying based on head angle. Sampling was performed for two consecutive days each week until weaning. Sampling periods were divided into two periods on the basis of pasturing time: daytime pasturing (period A: 7-hr pasturing period, 2-60 days of age) and overnight pasturing (period B: 19-hr pasturing period, 32-152 days of age). Lying duration and frequency were longer and higher, respectively, in period A (44.6% of the time and 26.8 +/- 7.4 times per day) than those in period B (27.7% of the time and 15.3 +/- 4.2 times per day). In addition, foals spent more time laterally in period A (48.1% of total lying time) than in period B (38.9% of total lying time). Foals lie down longer in stalls than in pastures (Period A, 56.3 vs. 16.0%; Period B, 52.5 vs. 21.1%). Lateral lying was also longer in the stall than in the pasture. Lying duration and frequency changed with age in period A. Wet weather prevented lying behavior in the pasture. These results suggested that age, weather, and pasturing time affected the lying behavior of Thoroughbred foals under management at a breeding farm. Triaxial accelerometers may be useful for monitoring equine lying behavior. PMID- 30250394 TI - Ranking quarter horse sires via models of offspring performance. AB - The 2016 Equibase data set of American Quarter Horse starts in North America was analyzed, with the purpose of ranking the sires of the racehorses. A speed z score derived from the race times and distances was used as a racing performance measure. Mixed effects models were used on various subsets of the data based on race distance and sire offspring number. The sire categorical variable was considered as a random effect. Various statistical criteria were used to optimize the model. The constructed models were then varied in terms of the random and fixed effects included, and the conditional modes of the sire effects were extracted from these models. The benefit of the sire ranking that comes from this analysis is that it is controlled for track, jockey, trainer, weather, and several other variables that can impact speed. Sires are typically valued for high rankings for offspring earnings and winners. Yet a sire with a low stud fee may still produce offspring with a high ranking using our z-score model. The offspring of this bargain sire have the potential to produce fast offspring that could pay a dividend on a relatively low cost investment. The model sire ranking approach described in this paper is clearly bringing a new approach to the field of sire rankings. PMID- 30250395 TI - Comparison of oxidative stress under different propofol administration protocols in Thoroughbred racehorses by bOS and bAP assessment. AB - It is desirable to reduce surgery-induced oxidative stress (OS) because it can cause immune suppression and delayed wound healing. Propofol is known to have antioxidant potential and to reduce OS in humans, but there have been no studies of this issue in horses. This study was conducted to evaluate OS under three different propofol administration protocols in Thoroughbred racehorses undergoing arthroscopic surgery with sevoflurane anesthesia. Blood oxidative stress (bOS) and blood antioxidant power (bAP) were used as OS biomarkers. Both bOS and bAP significantly decreased after surgery in all groups, but no differences in these reductions were found among them. Different propofol administration protocols with sevoflurane anesthesia did not cause a difference in OS in Thoroughbred racehorses that underwent arthroscopic surgery. PMID- 30250396 TI - Evaluating continuous blood coagulopathy in assessing the severity of acute colitis in Thoroughbred racehorses. AB - Although severe blood coagulopathy in horses with acute colitis causes multiple organ failure, which may be fatal, few studies have focused on the correlation between the fluctuations of coagulation parameters and severity of colitis. In this study, we evaluated the fluctuations of coagulation parameters in 14 Thoroughbred racehorses with acute colitis for 5 days from the day of hospitalization and compared them between 5 survivors and 9 non-survivors. Noteworthy features in the non-survivors were that antithrombin activity and fibrin degradation products continuously decreased and increased, respectively, for 4 days or more and that thrombin-antithrombin complexes increased in the last 2 days before death. Thus, these parameters should be continuously monitored to observe these fluctuations in assessing the severity of acute colitis. PMID- 30250397 TI - Access to primaquine in the last mile: challenges at the service delivery points in pre-elimination era, Myanmar. AB - Background: Alongside monitoring of the disease burden, the successful move towards malaria elimination relies on the readiness of the health care delivery system. However, there is a lack of evidence in the gap of existing National Guidelines and access to low dose primaquine in real practice under varying degrees of antimalarial resistance in the pre-elimination phase in Myanmar. Therefore, this study addressed the essential information from the service delivery points (SDPs) of public and private sectors on the availability and the use of primaquine in both supply and demand side. Concomitantly, the study aimed to underscore challenges in health system infrastructure to promote the sustained flow in rolling out primaquine in line with National Guidelines for malaria elimination. Methods: A cross-sectional study conducted from September 2017 to February 2018 included six townships of three states/regions. The team used an observation checklist for documenting primaquine supplies at SDPs. Semi structured interviews, key informant, and in-depth interviews focused both public and private sectors including staff from the Vector-Borne Diseases Control (VBDC) teams in each state/region and rural health centers (n = 25), those from the non governmental organizations (NGOs), general practitioners and drug sellers (n = 11), and recently infected malaria patients (n = 11). Triangulation of quantitative and qualitative data provided meaningful interpretations. Results: Public sector staff reported an adequate stock of primaquine, but it was unavailable at the general practitioners' clinics without any connection to NGOs and also at the unlicensed drug shops. Health care providers of the public sector experienced challenges in poor compliance of malaria patients to primaquine treatment in conjunction with an artemisinin-based combination therapy, loss-to follow-ups especially in conflict areas, and delays in timely substitution of new batches of primaquine. Respondents from the private sector demanded for the refresher training course on updated antimalarial treatment guidelines. Conclusion: Monitoring compliance and safety of primaquine treatment was found as a barrier especially among mobile migrant workers and those who were in conflict areas. An alternative strategy by the NMCP could enable to prevent the underutilization of primaquine in vivax malaria to reach the malaria elimination targets. PMID- 30250398 TI - Human infection with Plasmodium knowlesi on the Laos-Vietnam border. AB - Background: Border malaria in the Greater Mekong region of Southeast Asia poses a serious threat to the health of the ethnic minority populations of the region. Traditionally thought to be caused primarily by the malaria parasites Plasmodium falciparum and Plasmodium vivax, recently a zoonotic parasite, Plasmodium knowlesi, has been identified in some countries of the region. The presence of this parasite poses a challenge to malaria control programmes, as it is maintained in a zoonotic reservoir of forest-dwelling macaque monkeys. Methods: A cross-sectional malaria parasite species prevalence survey was conducted along the Laos-Vietnam border in the central part of the two countries. Human blood samples were collected from Savannakhet in Laos and Quang Tri in Vietnam between August and October 2010 and assayed for the presence of human malaria parasite species and P. knowlesi. A PCR targeting the 18S small subunit ribosomal RNA gene and circumsporozoite protein gene was used for Plasmodium species identification. Results: Nine cases of P. knowlesi were detected by PCR in blood samples from the Laos side and three from the Vietnam side. All P. knowlesi infections were found in co-infection with P. vivax, with some triple infections of P. knowlesi, P. vivax and P. falciparum detected in Laos. Phylogenetic analysis of these parasites suggests that P. knowlesi is circulating in the Laos-Vietnam border region. Conclusion: This report shows that P. knowlesi is transmited on both sides of the Vietnam-Laos border. Continued monitoring of the range and prevalence of P. knowlesi on both the sides of Laos-Vietnam border is of importance to the National Malaria Control Programmes of both countries. PMID- 30250399 TI - LncRNA SNHG5 promotes the progression of osteosarcoma by sponging the miR-212 3p/SGK3 axis. AB - Background: Long non-coding RNA (lncRNA) SNHG5 has been found to play an important role in tumors. Nevertheless, the function and mechanism of lncRNA SNHG5 in osteosarcoma (OS) remains unclear. The purpose of this study was to investigate whether lncRNA SNHG5 can regulate the occurrence and development of OS cells. Methods: We performed quantitative real time PCR to detect the expression of lncRNA SNHG5 in OS cells. 143B, MG63 (knockdown) and U2OS, U2R (overexpression) cell lines were chosen for the function study of SNHG5. The effect of SNHG5, miR-212-3p, and SGK3 in OS cells was explored by MTT assays, clony formation, flow cytometry, transwell assays, wound healing assays, and cell spreading assays. Quantitative real-time PCR, Western blot analysis and luciferase assays were used to detect the interaction between lncRNA SNHG5 and miR-212-3p. Results: In this study, knockdown of lncRNA SNHG5 suppressed the growth and metastasis of OS cells, whereas the overexpression of SNHG5 produced an opposite result. Mechanistically, lncRNA SNHG5 functions as a sponger against miR-212-3p and suppresses the miR-212-3p/SGK3 signaling pathway. Introduction of miR-212-3p mimics or inhibitors reverses SNHG5 overexpression or silences the exerted tumor promoting or suppressing effect. In addition, our results showed that the function of SNHG5 can be rescued by miR-212-3p and can regulate the growth and metastasis of OS cells via SGK3, the downstream target of miR-212-3p. Conclusions: In summary, our study demonstrated that lncRNA SNHG5 can regulate the proliferation and metastasis of OS cells through the miR-212-3p/SGK3 axis. This axis may provide a new target for future clinical treatment. PMID- 30250400 TI - Long noncoding RNA ROR promotes breast cancer by regulating the TGF-beta pathway. AB - Background: Breast cancer is the leading cause of oncological mortality among women. Efficient detection of cancer cells in an early stage and potent therapeutic agents targeting metastatic tumors are highly needed to improve survival rates. Emerging evidence indicates that lncRNAs (long noncoding RNAs) are critical regulators of fundamental cellular processes in a variety of tumors including breast cancer. The functional details of these regulatory elements, however, remain largely unexplored. Methods: In this study, lncRNA ROR (linc-ROR) was examined by real-time PCR in different breast cancer cell lines and breast tumor tissues/non-tumor tissues were collected from both breast cancer patients and healthy controls. Linc-ROR was knockdown in breast cancer cell lines and the effects on cell proliferation, migration and invasion were tested both in vitro and in vivo tumor model. Effects of linc-ROR knockdown on TGF-beta signaling pathway were investigated by Western blot. Results: Our studies have suggested that linc-ROR, a critical factor for embryonic stem cell maintenance, probably acts as an oncogenic factor in breast cancer cells, causing poor prognostic outcomes. Overexpression of linc-ROR seems to be responsible for promoting proliferation and invasion of cancer cells as well as tumor growth in nude mice. The regulatory action of linc-ROR can affect the activity of the TGF-beta signaling pathway, which has been proven critical for mammary development and breast cancer. Conclusions: The results have highlighted the potential importance of linc-ROR in the progression of advanced breast cancer, and thus will stimulate efforts in the development of novel diagnostic and therapeutic strategies. PMID- 30250401 TI - LncRNA DLX6-AS1 promoted cancer cell proliferation and invasion by attenuating the endogenous function of miR-181b in pancreatic cancer. AB - Background: Pancreatic cancer, one of the most aggressive malignancies, ranks the fourth cause of cancer-related death worldwide. Aberrantly expressed long non coding RNAs (lncRNAs) functioned as oncogenes or tumor suppressors in pancreatic cancer. This study aimed to determine the expression of lncRNA DLX6 antisense RNA 1 (DLX6-AS1) in pancreatic cancer tissues and to explore the DLX6-AS1-related pathway in pancreatic cancer. Materials and methods: The gene expression levels were determined by quantitative real-time PCR, and protein expression levels were determined by western blot assay. CCK-8 assay, colony formation assay and Transwell migration and invasion assays were used to examine cell proliferation, migration and invasion. Luciferase reporter assay was used to confirm the binding between DLX6-AS1and its potential targets. In vivo study used the mouse xenograft model to test the anti-tumor effect of DLX6-AS1 knockdown. Results: The high expression of DLX6-AS1 was observed in pancreatic cancer tissues, and high expression of DLX6-AS1 was positively correlated with larger tumor size, advanced TNM stage and lymph node metastasis. Knockdown of DLX6-AS1 dramatically impaired cancer cell proliferation, migration and invasion. MiR-181b was the downstream target of DLX6-AS1. Knockdown of miR-181b reversed the suppression of cell viability, migration and invasion abilities caused by DLX6-AS1 knockdown. MiR 181b was found to target Zinc finger E-box-binding homeobox 2 and to modulate epithelial-mesenchymal transition. Furthermore, DLX6-AS1 knockdown inhibited tumor growth and tumor metastasis in vivo. Conclusion: Collectively, our data suggested that DLX6-AS1 promotes cancer cell proliferation and invasion by attenuating the endogenous function of miR-181b in pancreatic cancer. PMID- 30250402 TI - Decreased RIG-I expression is associated with poor prognosis and promotes cell invasion in human gastric cancer. AB - Background: Retinoic acid-induced protein I (RIG-I), known as a cytoplastic pattern recognition receptor, can recognize exogenous viral RNAs, and then initiate immune response. Recently, numerous studies also showed that RIG-I play an important role in oncogenesis and cancer progression as well. As of now, the expression pattern and the role of RIG-I in gastric cancer still remain largely unexplored. In this study, we investigated the clinical associations of RIG-I expression in human gastric cancer tissues and further explore its important contribution in the regulation of malignant phenotype of gastric cancer cells. Methods: Immunohistochemistry was performed to study the correlation between patients' clinical parameters and RIG-I expression in gastric cancer tissues. Knockdown of RIG-I was achieved by RNAi technology to examine the contribution of RIG-I in the regulation of biological functions in the cell lines of human gastric cancer. The Affymetrix GeneChip was performed to figure out the differential gene expression profile between RIG-I wild type and RIG-I knockdown cell lines of gastric cancer. Results: Immunohistochemistry result demonstrated that the expression of RIG-I in gastric cancer tissues significantly correlated with pathological stage and patients' prognoses. Furthermore, decreased RIG-I expression in human gastric cancer cell lines could significantly increase the cell migration, cell viability, and the ratio of cells in G2/M phase. Our microarray analysis also revealed that the differentially expressed gene profiles were enriched in related signal pathways or biological processes in KEGG or GO analysis respectively. Conclusions: Our present findings showed that the decreased RIG-I expression significantly correlated with patients' prognoses, and such down-regulation could promote the cell invasion in this malignancy. PMID- 30250403 TI - The lncRNA CCAT1 upregulates TGFbetaR1 via sponging miR-490-3p to promote TGFbeta1-induced EMT of ovarian cancer cells. AB - Background: Ovarian cancer is the fifth leading cause of cancer deaths in women worldwide. LncRNACCAT1 was reported to play a critical role in cell metastasis of ovarian cancer. However, little is known about the detailed mechanism of how CCAT1 enhances TGFbeta1-induced EMT of ovarian cancer cells. Methods: We used RT qPCR to examine the level of miR-490-3p and CCAT1 and western blot to detect the protein level of TGFbetaR1 and EMT-associated markers. We utilized luciferase reporter assay to confirm the direct interaction of CCAT1 or TGFbeta1 with miR 490-3p. Wound healing and invasion assay were employed to investigate the role of CCAT1 and miR-490-3p in the TGFbeta1-induced migration and cell invasion of ovarian cancer cells, respectively. Results: TGFbeta1 stimulated the expression of CCAT1. And CCAT1 knockdown decreased cell migration, invasion and EMT associated markers expression of ovarian cancer cells treated with TGFbeta1. CCAT1 directly targeted and downregulated miR-490-3p, then increasing TGFbetaR1 level. miR-490-3p was shown to regulate cell invasion, migration and EMT markers expression via TGFbetaR1. In addition, we also observed that miR-490-3p was essential for TGFbeta1-induced tumor cell invasion and migration influenced by CCAT1. CCAT1 level was significantly higher in tumors than adjacent normal tissue, in contrast, miR-490-3p level was lower in ovarian tumors. Conclusion: Here, we reveal that CCAT1 contributes to TGFbeta1-induced EMT of ovarian tumor cells through miR-490-3p/TGFR1 axis. These findings will provide deep insights into the mechanism by which CCAT1 exerts its oncogenic role in ovarian cancer progression and facilitate developing novel therapeutical therapies for treating ovarian cancer. PMID- 30250404 TI - The roles of IL-19 and IL-20 in the inflammation of degenerative lumbar spondylolisthesis. AB - Background: Degenerative lumbar spondylolisthesis (DLS) is a major cause of spinal canal stenosis and is often related to lower back pain. IL-20 is emerging as a potent angiogenic, chemotactic, and proinflammatory cytokine related to several chronic inflammatory bone disorders likes intervertebral disc herniation, rheumatoid arthritis (RA), osteoporosis, and bone fracture. IL-19 also acts as a proinflammatory cytokine in RA. The aim of the present study was to investigate whether IL-19 and IL-20 are involved in DLS and compare three different tissues including disc, facet joint, and ligamentum flavum of patients with DLS to verify which tissue is affected more by inflammation. Methods: Disc, facet joint and ligamentum flavum from 13 patients with DLS was retrieved, and the expression pattern of IL-19, IL-20, IL-20R1, IL-20R2, TNF-alpha, IL-1beta, and MCP-1 was evaluated using immunohistochemical staining with specific antibodies. The disc cells were isolated and incubated with IL-19 and IL-20 under CoCl2-mimicked hypoxic conditions to analyze the proinflammatory cytokine expression pattern using real-time quantitative PCR with specific primers. Results: IL-19 and IL-20 were positively stained and accompanied by abundant expression of TNF-alpha, IL 1beta, and MCP-1 in facet joints of DLS patients. IL-19 and IL-20's receptors (IL 20R1 and IL-20R2) were expressed on chondrocytes and fibrocytes/fibroblasts in facet joint and ligamentum flavum tissues from patients with DLS. There was a significant correlation between the expression of IL-20 and IL-1beta in facet joint. In vitro assay, IL-19 and IL-20 upregulated the expression of IL-1beta, IL 6, TNF-alpha, IL-8, VEGF, and MCP-1 in primary cultured DLS disc cells under CoCl2-mimicked hypoxic conditions. Conclusions: IL-19, IL-20, and their receptors as well as proinflammatory cytokines (TNF-alpha, IL-1beta, and MCP-1) were expressed more in facet joints than the other tissues in patients with DLS; therefore, the etiology of inflammation might be more facet-centric. IL-19 and IL 20 induced proinflammatory cytokine expression in disc cells and might play a role in the pathogenesis of DLS. PMID- 30250405 TI - A Novel Autonomous 5-D Hyperjerk RC Circuit with Hyperbolic Sine Function. AB - A novel autonomous 5-D hyperjerk RC circuit with hyperbolic sine function is proposed in this paper. Compared to some existing 5-D systems like the 5-D Sprott B system, the 5-D Lorentz, and the Lorentz-like systems, the new system is the simplest 5-D system with complex dynamics reported to date. Its simplicity mainly relies on its nonlinear part which is synthetized using only two semiconductor diodes. The system displays only one equilibrium point and can exhibit both periodic and chaotic dynamical behavior. The complex dynamics of the system is investigated by means of bifurcation analysis. In particular, the striking phenomenon of multistability is revealed showing up to seven coexisting attractors in phase space depending solely on the system's initial state. To the best of author's knowledge, this rich dynamics has not yet been revealed in any 5 D dynamical system in general or particularly in any hyperjerk system. Pspice circuit simulations are performed to verify theoretical/numerical analysis. PMID- 30250406 TI - Corrigendum to "Immunocompetent Mice Model for Dengue Virus Infection". AB - [This corrects the article DOI: 10.1100/2012/525947.]. PMID- 30250407 TI - Occupational Therapy in Complex Patients: A Pilot Randomized Controlled Trial. AB - Introduction: To determine effect size and feasibility of experimental occupational therapy (OT) intervention in addition to standard care in a population of complex patients undergoing rehabilitation in a hospital-home-based setting. Method: 40 complex patients admitted to the rehabilitation ward of the Local Health Authority-Research Institute of Reggio Emilia (Italy) were randomized in a parallel-group, open-label controlled trial. Experimental OT targeting occupational needs in the areas of self-care, productivity, and leisure was delivered by occupational therapists. Standard care consisted of task oriented rehabilitation delivered by a multiprofessional team. Results: The experimental OT intervention was completed by 75% of patients assigned to this group. The average changes in the Canadian Occupational Performance Measure (COPM) performance score significantly and clinically favored experimental OT [ 3,06 (-4.50; -1.61); delta > 2 points, resp.]. Similar trends were detected for COPM satisfaction and independence in instrumental activities of daily living (ADL). At follow-up, level of social participation was higher for patients treated with experimental OT (p = 0.043) than for controls. Conclusions: Experimental OT was feasible in complex patients in a hospital-home-based setting. It ameliorated both patients' performance and satisfaction in carrying out relevant activities and improved independence in instrumental ADL. The trial is registered with ClinicalTrials.gov NCT02677766. PMID- 30250408 TI - Proteomic analysis identifies highly expressed plasma membrane proteins for detection and therapeutic targeting of specific breast cancer subtypes. AB - In recent years, there has been an emphasis on personalizing breast cancer treatment in order to avoid the debilitating side effects caused by broad spectrum chemotherapeutic drug treatment. Development of personalized medicine requires the identification of proteins that are expressed by individual tumors. Herein, we reveal the identity of plasma membrane proteins that are overexpressed in estrogen receptor alpha-positive, HER2-positive, and triple negative breast cancer cells. The proteins we identified are involved in maintaining protein structure, intracellular homeostasis, and cellular architecture; enhancing cell proliferation and invasion; and influencing cell migration. These proteins may be useful for breast cancer detection and/or treatment. PMID- 30250409 TI - Plasma lipoproteome in Alzheimer's disease: a proof-of-concept study. AB - Background: Although total plasma lipoproteome consists of proteins that have shown promises as biomarkers that can identify Alzheimer's disease (AD), effect sizes are modest. The objective of this study is to provide initial proof-of concept that the plasma lipoproteome more likely differ between AD cases and controls when measured in individual plasma lipoprotein fractions than when measured as total in immunodepleted plasma. Methods: We first developed a targeted proteomics method based on selected reaction monitoring (SRM) and liquid chromatography and tandem mass spectrometry for measurement of 120 tryptic peptides from 79 proteins that are commonly present in plasma lipoproteins. Then in a proof-of concept case-control study of 5 AD cases and 5 sex- and age-matched controls, we applied the targeted proteomic method and performed relatively quantification of 120 tryptic peptides in plasma lipoprotein fractions (fractionated by sequential gradient ultracentrifugation) and in immunodepleted plasma (of albumin and IgG). Unadjusted p values from two-sample t-tests and overall fold change was used to evaluate a peptide relative difference between AD cases and controls, with lower p values (< 0.05) or greater fold differences (> 1.05 or < 0.95) suggestive of greater peptide/protein differences. Results: Within-day and between-days technical precisions (mean %CV [SD] of all SRM transitions) of the targeted proteomic method were 3.95% (2.65) and 9.31% (5.59), respectively. Between-days technical precisions (mean % CV [SD]) of the entire plasma lipoproteomic workflow including plasma lipoprotein fractionation was 27.90% (14.61). Ten tryptic peptides that belonged to 5 proteins in plasma lipoproteins had unadjusted p values < 0.05, compared to no peptides in immunodepleted plasma. Furthermore, 27, 32, 17, and 20 tryptic peptides in VLDL, IDL, LDL and HDL, demonstrated overall peptide fold differences > 1.05 or < 0.95, compared to only 6 tryptic peptides in immunodepleted plasma. The overall comparisons, therefore, suggested greater peptide/protein differences in plasma lipoproteome when measured in individual plasma lipoproteins than as total in immunodepleted plasma. Specifically, protein complement C3's peptide IHWESASLLR, had unadjusted p values of 0.00007, 0.00012, and 0.0006 and overall 1.25, 1.17, 1.14-fold changes in VLDL, IDL, and LDL, respectively. After positive False Discovery Rate (pFDR) adjustment, the complement C3 peptide IHWESASLLR in VLDL remained statistically different (adjusted p value < 0.05). Discussion: The findings may warrant future studies to investigate plasma lipoproteome when measured in individual plasma lipoprotein fractions for AD diagnosis. PMID- 30250410 TI - Serologic Survey and Risk Factors for Coxiella burnetii Infection among Dairy Cattle Farmers in Korea. AB - Background: The zoonotic disease Q fever is caused by Coxiella burnetii and usually affects high-risk human populations. We conducted a serological survey of dairy cattle farmers in Korea to determine seroreactivity and identify risk factors for C. burnetii infection. Methods: This cross-sectional study included 1,824 of 7,219 dairy cattle farms (25.3%) in the study region. The selected dairy cattle farmers visited the nearest public health centers or branches with completed questionnaires. Serum samples from the farmers were tested using an indirect immunofluorescence assay to detect phase II C. burnetii immunoglobulin (Ig) G or M antibodies. Results: A total of 1,222 dairy cattle farmers from 784 dairy cattle farms (43.0%) participated in this study, and 11.0% (134/1,222) exhibited seroreactivity, defined as a phase II antigen IgG or IgM titer >= 1:16. In the multivariate analysis, male sex, residence in Gyeonggi Province, a larger herd size, and ocular/oral contact with birth products during calf delivery were significantly associated with a higher risk of C. burnetii infection. Furthermore, the risk was significantly lower among farmers who always wore protective gloves while cleaning cattle excretion, compared to those who sometimes or rarely wore protective gloves. Conclusion: Dairy cattle farmers should exercise caution by avoiding ocular/oral contact with birth products during calf delivery and by using protective equipment (including gloves). PMID- 30250412 TI - Evaluation of Methicillin-Resistance Rates among Community-associated Staphylococcus aureus Infections in Korean Military Personnel. AB - To evaluate methicillin-resistance (MR) rates among community-associated (CA) Staphylococcus aureus infections in the Korean military, we screened electronic medical records of 223 patients with S. aureus infection in a military referral hospital from 2012 to 2017. During the study period, MR rates did not change annually, and were not different between officers and conscripted personnel. Among conscripted personnel, MR rates in CA S. aureus infections did not increase with longer duration of military service, both in trend analysis and multivariate analysis. In conclusion, MR rates among CA S. aureus infections did not increase during military service in Korea. PMID- 30250411 TI - The Relationship between Emotional Labor and Job Stress among Hospital Workers. AB - Background: We divided hospital workers into two groups according to whether one was an interpersonal service worker (ISW) or was not (non-ISW). We then explored differences between these groups in job stress and emotional labor type and investigated the mediating factors influencing their relationships. Methods: Our participants included both ISW (n = 353) and non-ISW (n = 71) hospital workers. We administered the Korean Standard Occupational Stress Scale Short Form to measure job stress and the Emotional Labor Scale to indicate both emotional labor type and characteristics. We also administered the Beck Depression Inventory-II to indicate the mediating factors of depressive symptoms, the Beck Anxiety Inventory to indicate the mediating factors of anxiety, and the State Anger Subscale of the State-Trait Anger Expression inventory to indicate the mediating factors of anger. Results: The ISW group showed more severe job stress than the non-ISW group over a significantly longer duration, with greater intensity, and with higher level of surface acting. The ISW group showed a significant positive correlation between surface acting and job stress and no significant correlation between deep acting and job stress. Parallel mediation analysis showed that for ISWs surface acting was directly related to increased job stress, indirectly related to depression, and unrelated to anxiety and anger. Conclusion: The ISW group displayed more surface acting and job stress in its emotional labor than the non-ISW group. In the ISW group, surface acting during emotional labor was positively correlated with job stress. Depression partially mediated their relationship. PMID- 30250413 TI - Atrial Innervation Patterns of Intrinsic Cardiac Autonomic Nerves. AB - Background: Although ganglionated plexi (GPs) are important in the pathogenesis of arrhythmia, their patterns of atrial innervation have remained unclear. We investigated patterns of GP innervation to cardiac atria and the neuroanatomical interconnections among GPs in an animal model. Methods: Atrial innervation by GPs was evaluated in 10 mongrel dogs using a retrograde neuronal tracer (cholera toxin subunit B [CTB] conjugated with fluorescent dyes). In Experiment 1, CTB was injected into the atria. In Experiment 2, CTB was injected into the major GP, including the anterior right GP (ARGP), inferior right GP (IRGP), superior left GP (SLGP), and ligament of Marshall (LOM). After 7 days, the GPs were examined for the presence of tracer-positive neurons. Results: GPs in either right or left side were innervating to both the same and opposite sides of the atrium. In quantitative analysis, right-sided GPs, especially ARGP, showed numerical predominance in atrial innervation. Based on the proportion of CTB-labeled ganglion in each GP, atrial innervation by GPs showed a tendency of laterality. In Experiment 2, CTB that was injected to a particular GP widely distributed in different GP. ARGP projected the largest number of innervating neurons to the IRGP, SLGP and LOM. Conclusion: This study demonstrated that GPs project axons widely to both the same and opposite sides of atria. ARGP played a dominant role in atrial innervation. Furthermore, there were numerous neuroanatomical interconnections among GPs. These findings about neuronal innervation and interconnections of GPs could offer useful information for understanding intrinsic cardiac nervous system neuroanatomy. PMID- 30250414 TI - Analysis of Patients with Acute Toxic Exposure between 2009 and 2013: Data from the Korea Health Insurance Review and Assessment Service and the National Emergency Department Information System. AB - Background: According to domestic studies, patients visiting the emergency departments (ED) with acute toxic exposure comprise 0.68%-5.5% of all ED patients, with various causes and motives. The purpose of this study is to investigate the clinical and social characteristics of patients with toxic exposure visiting the ED. Methods: This study spanned a period of five years, from January 1, 2009 to December 31, 2013. The data were extracted using the National Emergency Department Information System (NEDIS) and The Korea Health Insurance Review and Assessment Service (HIRA). Results: From the HIRA database, during the study period (2009-2013); 310,159 (2009), 289,829 (2010), 288,906 (2011), 285,514 (2012), and 279,575 (2013) patients, respectively, visited EDs with diagnoses related to exposure to toxic substances. The number of patients who presented with acute toxic exposure compared to all ED visits significantly decreased consistently (7.8%, 6.9%, 6.0%, 5.0%, 4.1%) over 5 years. Regarding the cause of toxic exposure, substances other than drugs accounted for the largest percentage, and increased annually. Acetylcysteine was the most commonly prescribed antidote, and patients in their 40s and 50s showed the most frequent visits. The monthly distribution was highest in July-September, and higher in January than in other months. Conclusion: This study found that the percentage of patients visiting the ED is decreasing, the exposure to quasi-drugs was the most common, and the exposure to antipsychotic drugs was the most frequent. PMID- 30250415 TI - Towards More Influential Research in Acute Poisoning from Toxic Materials. PMID- 30250417 TI - Web Usability and Database Connectivity How to Use them in the Laboratory. PMID- 30250416 TI - Prevalence and treatment of sexually transmitted infections in men followed by urologists in Germany - a cross sectional study with 347,090 men. AB - Aim: The goal of this retrospective analysis was to study the prevalence and treatment of the most common sexually transmitted infections (STI) in men followed by urologists in Germany. Methods: This study included a total of 347,090 men followed in 71 urology practices in Germany between 2013 and 2015. The first outcome was the prevalence of individuals diagnosed with STI between 2013 and 2015. The following eight types of STI infections were included in the analysis: chlamydial infection, gonococcal infection, anogenital warts, anogenital herpes infection, trichomoniasis, ulcus molle, phthiriasis, and syphilis. The second outcome was the prevalence of individuals with STI who received an appropriate therapy within 90 days of their initial STI diagnosis. Results: The most frequent STI was anogenital warts (0.64%), whereas the least frequent STI was syphilis (0.03%). The median age at diagnosis ranged from 30.3 years for chlamydia infection to 47.5 years for trichomoniasis. The proportion of individuals receiving treatment was the highest for trichomoniasis (90.6%) and the lowest for anogenital warts (49.9%). Conclusions: Overall, approximately 1.25% of men followed in urology practices in Germany between 2013 and 2015 were diagnosed with at least one STI. Further research is needed to gain a better understanding of the factors potentially associated with the risk of being diagnosed with STI in this setting in Germany. Moreover, there is a need for enabling higher rates of diagnosis and thus treatment of infected persons. PMID- 30250418 TI - Telemedicine and Fictional views of the e-Laboratory for Better Care Decisions. PMID- 30250419 TI - One-Armed Economists and The Invisible Hand: An Introduction to Economics. AB - The need for leaders and managers to have a basic understanding of elementary economics is demonstrated. The limited retrospective view of the accountant must be supplemented by the broader, prospective view of the economist. The limits and scope of economics are defined. The First and Second Fundamental Theorems of Welfare Economics are introduced. The mythology behind the mechanism of action of Adam Smith's Invisible Hand is dissected; and the mechanism of the free market is explained in terms of the effect of marginal cost on net market efficiency. The apparently simple case of the effect of legislating a minimum wage upon a free market is discussed. This provides an example of the real-world complexity of economies and of applying economic concepts to the business world. "Common sense is what tells you that a ten pound weight falls ten times as fast as a one pound weight". Anon"Common sense is the collection of prejudices acquired by age eighteen.", Albert Einstein. PMID- 30250420 TI - International Federation of Clinical Chemistry and Laboratory Medicine: SCIENTIFIC DIVISIONCOMMITTEE ON NOMENCLATURE, PROPERTIES AND UNITS (C-NPU) and INTERNATIONAL UNION OF PURE AND APPLIED CHEMISTRY CHEMISTRY AND HUMAN HEALTH DIVISION(VII) Project number 2001-059-1-700:PROPERTIES AND UNITS FOR TRANSFUSION MEDICINE AND IMMUNOHAEMATOLOGY (Technical report) (IFCC-IUPAC 2003). PMID- 30250421 TI - Telehealth and Telebiology Making Healthcare Accessible in Emerging Countries. PMID- 30250422 TI - Paradigm Shift in Sensorimotor Control Research and Brain Machine Interface Control: The Influence of Context on Sensorimotor Representations. AB - Neural activity in the primary motor cortex (M1) is known to correlate with movement related variables including kinematics and dynamics. Our recent work, which we believe is part of a paradigm shift in sensorimotor research, has shown that in addition to these movement related variables, activity in M1 and the primary somatosensory cortex (S1) are also modulated by context, such as value, during both active movement and movement observation. Here we expand on the investigation of reward modulation in M1, showing that reward level changes the neural tuning function of M1 units to both kinematic as well as dynamic related variables. In addition, we show that this reward-modulated activity is present during brain machine interface (BMI) control. We suggest that by taking into account these context dependencies of M1 modulation, we can produce more robust BMIs. Toward this goal, we demonstrate that we can classify reward expectation from M1 on a movement-by-movement basis under BMI control and use this to gate multiple linear BMI decoders toward improved offline performance. These findings demonstrate that it is possible and meaningful to design a more accurate BMI decoder that takes reward and context into consideration. Our next step in this development will be to incorporate this gating system, or a continuous variant of it, into online BMI performance. PMID- 30250423 TI - Iron and Alzheimer's Disease: From Pathogenesis to Therapeutic Implications. AB - As people age, iron deposits in different areas of the brain may impair normal cognitive function and behavior. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, and ultimately leads to cell death. There is an imbalance in iron homeostasis in Alzheimer's disease (AD). Excessive iron contributes to the deposition of beta-amyloid and the formation of neurofibrillary tangles, which in turn, promotes the development of AD. Therefore, iron-targeted therapeutic strategies have become a new direction. Iron chelators, such as desferoxamine, deferiprone, deferasirox, and clioquinol, have received a great deal of attention and have obtained good results in scientific experiments and some clinical trials. Given the limitations and side effects of the long-term application of traditional iron chelators, alpha-lipoic acid and lactoferrin, as self-synthesized naturally small molecules, have shown very intriguing biological activities in blocking Abeta-aggregation, tauopathy and neuronal damage. Despite a lack of evidence for any clinical benefits, the conjecture that therapeutic chelation, with a special focus on iron ions, is a valuable approach for treating AD remains widespread. PMID- 30250424 TI - A DNA Methylation Signature of Addiction in T Cells and Its Reversal With DHEA Intervention. AB - Previous studies in animal models of cocaine craving have delineated broad changes in DNA methylation profiles in the nucleus accumbens. A crucial factor for progress in behavioral and mental health epigenetics is the discovery of epigenetic markers in peripheral tissues. Several studies in primates and humans have associated differences in behavioral phenotypes with changes in DNA methylation in T cells and brain. Herein, we present a pilot study (n = 27) showing that the T cell DNA methylation profile differentiates persons with a substance use disorder from controls. Intervention with dehydroepiandrosterone (DHEA), previously shown to have a long-term therapeutic effect on human addicts herein resulted in reversal of DNA methylation changes in genes related to pathways associated with the addictive state. PMID- 30250425 TI - Clinical Impact of Spontaneous Hyperactivity in Degenerating Retinas: Significance for Diagnosis, Symptoms, and Treatment. AB - Hereditary retinal degenerations result from varied pathophysiologic mechanisms, all ultimately characterized by photoreceptor dysfunction and death. Hence, much research on these diseases has concentrated on the outer retina. Over the past decade or so increasing attention has focused on concomitant changes in complex inner retinal neural circuits that process visual signals for transmission to the brain. One striking abnormality develops before the ultimately profound anatomic disruption of the inner retina. Highly elevated spontaneous activity was first demonstrated in central nervous system visual centers in vivo by Drager and Hubel (1978), and subsequently has been confirmed in vitro, now in multiple animal models and by multiple investigators (see other contributions to this Research Topic). What evidence exists that this phenomenon occurs in human patients with retinal degeneration, and what is the ultimate effect of spontaneous hyperactivity in the output neurons, the retinal ganglion cells? Here I summarize abnormalities of visual perception among patients with retinal degeneration that may arise from hyperactivity. Next, I consider the disruption of neural encoding and anatomic connectivity that may result within the retina and in downstream visual centers of the brain. I then consider how specific characteristics of hyperactivity may distinguish various forms or stages of retinal degeneration, potentially helping in the near future to refine diagnosis and/or treatment choices for different patients. Finally, I review how consideration of these features may help optimize pharmacologic, gene, stem cell, prosthetic or other therapies to forestall visual loss or restore sight. PMID- 30250426 TI - Cue-Polarized Transport of beta-actin mRNA Depends on 3'UTR and Microtubules in Live Growth Cones. AB - Guidance cues trigger fast responses in axonal growth cones such as directional turning and collapse that require local protein synthesis. An attractive cue gradient, such as Netrin-1, triggers de novo synthesis of beta-actin localized to the near-side compartment of the growth cone that promotes F-actin assembly and attractive steering. How this precise spatial asymmetry in mRNA translation arises across the small expanse of the growth cone is poorly understood. Pre localized mRNAs in the vicinity of activated receptors could be selectively translated and/or new mRNAs could be trafficked into the area. Here we have performed live imaging of fluorescent-tagged beta-actin mRNA to investigate mRNA trafficking dynamics in Xenopus retinal ganglion cell (RGC) axons and growth cones in response to Netrin-1. A Netrin-1 gradient was found to elicit the transport of beta-actin mRNA granules to the near-side of growth cones within a 4 7 min window. This polarized mRNA trafficking depended on the 3' untranslated region (UTR) since mRNA-Delta3'UTR mutant failed to exhibit cue-induced localization. Global application of Netrin-1 significantly increased the anterograde movement of beta-actin mRNA along axons and also promoted microtubule dependent mRNA excursions from the central domain of the growth cone into the periphery (filopodia and lamellipodia). Dual channel imaging revealed beta-actin mRNA riding behind the microtubule plus-end tracking protein, EB1, in movements along dynamic microtubules into filopodia. The mRNA-EB1 movements were unchanged by a Netrin-1 gradient indicating the dynamic microtubules themselves do not underlie the cue-induced polarity of RNA movement. Finally, fast-moving elongated "worm-like" trains of Cy3-RNA, distinct from mitochondria, were seen transporting RNA along axons in vitro and in vivo suggesting the existence of a novel transport organelle. Overall, the results provide evidence that the axonal trafficking of beta-actin mRNA can be regulated by the guidance cue Netrin-1 to transduce the polarity of an extracellular stimulus and that the 3'UTR is essential for this cue-induced regulation. PMID- 30250428 TI - Neural Field Theory of Corticothalamic Prediction With Control Systems Analysis. AB - Neural field theory is used to model and analyze realistic corticothalamic responses to simple visual stimuli. This yields system transfer functions that embody key features in common with those of engineering control systems, which enables interpretation of brain dynamics in terms of data filters. In particular, these features assist in finding internal signals that represent input stimuli and their changes, which are exactly the types of quantities used in control systems to enable prediction of future input signals, and adjustment of gains which is argued to be the analog of attention in control theory. Corticothalamic dynamics are shown to be analogous to the classical proportional-integral derivative (PID) filters that are widely used in engineering. PMID- 30250427 TI - Investigating Stimulation Protocols for Language Mapping by Repetitive Navigated Transcranial Magnetic Stimulation. AB - Navigated transcranial magnetic stimulation (nTMS) is increasingly applied to map human language functions. However, studies on protocol comparisons are mostly lacking. In this study, 20 healthy volunteers (25.7 +/- 3.8 years, 12 females) underwent left-hemispheric language mapping by nTMS, combined with an object naming task, over a cortical spot with reproducible naming errors within the triangular or opercular part of the inferior frontal gyrus (trIFG, opIFG: anterior stimulation) and the angular gyrus or posterior part of the superior temporal gyrus (anG, pSTG: posterior stimulation), respectively. Various stimulation intensities [80, 100, and 120% of the resting motor threshold (rMT)], frequencies (2, 5, 10, and 20 Hz), and coil orientations (in steps of 45 degrees ) were evaluated, and the adjustments leading to the highest error rates (ERs), combined with low occurrences of errors due to muscle stimulation, were considered optimal. Regarding anterior stimulation, 100% rMT, 5 Hz, and a coil orientation of 90 degrees or 270 degrees in relation to the respective stimulated gyrus resulted in optimal results. For posterior stimulation, 100% rMT, 10 Hz, and coil orientations of 90 degrees or 270 degrees were considered optimal. Errors due to facial muscle stimulation only played a considerable role during analyses of high-intensity (120% rMT) or high-frequency stimulation (20 Hz). In conclusion, this is one of the first studies to systematically investigate different stimulation protocols for nTMS language mapping, including detailed analyses of the distribution of ERs in relation to various coil orientations considered during neuronavigated stimulation. Mapping with 100% rMT, combined with 5 Hz (anterior stimulation) or 10 Hz (posterior stimulation) and a coil orientation perpendicular to the respective stimulated gyrus can be recommended as optimal adjustments. PMID- 30250429 TI - Neural Correlates of Conscious Motion Perception. AB - The nature of the proper neural signature of conscious perception remains a topic of active debate. Theoretical support from integrative theories of consciousness is consistent with such signature being P3b, one of the main candidates in the literature. Recent work has also put forward a mid-latency and more localized component, the Visual Awareness Negativity (VAN), as a proper Neural Correlate of Consciousness (NCC). Early local components like P1 have also been proposed. However, experiments exploring visual NCCs are conducted almost exclusively using static images as the content to be consciously perceived, favoring ventral stream processing, therefore limiting the scope of the NCCs that have been identified. Here we explored the visual NCCs isolating local motion, a dorsally processed feature, as the primary feature being consciously perceived. Physical equality between Seen and Unseen conditions in addition to a minimal contrast difference between target and no-target displays was employed. In agreement with previous literature, we found a P3b with a wide centro-parietal distribution that strongly correlated with the detection of the stimuli. P3b magnitude was larger for Seen vs. Unseen conditions, a result that was consistently observed at the single subject level. In contrast, we were unable to detect VAN in our data, regardless of whether the subject perceived or not the stimuli. In the 200-300 ms time window we found a N2pc component, consistent with the high attentional demands of our task. Early components like P1 were not observed in our data, in agreement with their proposed role in the processing of visual features, but not as proper NCCs. Our results extend the role of P3b as a content independent NCC to conscious visual motion perception. PMID- 30250430 TI - Reduced Regional Cerebral Blood Flow Relates to Poorer Cognition in Older Adults With Type 2 Diabetes. AB - Type 2 diabetes mellitus (T2DM) increases risk for dementia, including Alzheimer's disease (AD). Many previous studies of brain changes underlying cognitive impairment in T2DM have applied conventional structural magnetic resonance imaging (MRI) to detect macrostructural changes associated with cerebrovascular disease such as white matter hyperintensities or infarcts. However, such pathology likely reflects end-stage manifestations of chronic decrements in cerebral blood flow (CBF). MRI techniques that measure CBF may (1) elucidate mechanisms that precede irreversible parenchymal damage and (2) serve as a marker of risk for cognitive decline. CBF measured with arterial spin labeling (ASL) MRI may be a useful marker of perfusion deficits in T2DM and related conditions. We examined associations among T2DM, CBF, and cognition in a sample of 49 well-characterized nondemented older adults. Along with a standard T1-weighted scan, a pseudocontinuous ASL sequence optimized for older adults (by increasing post-labeling delays to allow more time for the blood to reach brain tissue) was obtained on a 3T GE scanner to measure regional CBF in FreeSurfer derived regions of interest. Participants also completed a neuropsychological assessment. Results showed no significant differences between individuals with and without T2DM in terms of cortical thickness or regional brain volume. However, adjusting for age, sex, comorbid vascular risk factors, and reference CBF (postcentral gyrus) older adults with T2DM demonstrated reduced CBF in the hippocampus, and inferior temporal, inferior parietal, and frontal cortices. Lower CBF was associated with poorer memory and executive function/processing speed. When adjusting for diabetes, the significant associations between lower regional CBF and poorer executive function/processing speed remained. Results demonstrate that CBF is reduced in older adults with T2DM, and suggest that CBF alterations likely precede volumetric changes. Notably, relative to nondiabetic control participants, those with T2DM showed lower CBF in predilection sites for AD pathology (medial temporal lobe and inferior parietal regions). Findings augment recent research suggesting that perfusion deficits may underlie cognitive decrements frequently observed among older adults with T2DM. Results also suggest that CBF measured with ASL MRI may reflect an early and important marker of risk of cognitive impairment in T2DM and related conditions. PMID- 30250431 TI - Current Standards and Recent Advances in Biomarkers of Major Endocrine Tumors. AB - The complexity of endocrine tumor diagnosis stems from its variable symptoms and presentation that may mimic many other disease states, or display asymptomatic properties for a prolonged amount of time. Early and accurate disease identification is needed for better patient prognosis. The key to this may be in using validated biomarkers with enhanced sensitivity and specificity. Several biomarkers are consistently used across various endocrine tumor types, possibly indicating a deeper pathophysiological mechanism behind endocrine cancer genesis and development. For example, carbohydrate antigen (CA) is measured in both pancreatic adenocarcinoma as well as ovarian cancer for diagnosis, surveillance, and risk stratification. The discovery of measuring miRNAs that are highly expressed in malignant tumors is also a novel strategy across multiple endocrine tumor types, and is propelling the future advancement of biomarker development. This review introduces currently utilized biomarkers in some of the commonly known endocrine tumors, including thyroid, adrenal, pituitary, pancreatic, and gonadal carcinoma, as well as future research directions. PMID- 30250432 TI - Annexin A12-26 Treatment Improves Skin Heterologous Transplantation by Modulating Inflammation and Angiogenesis Processes. AB - Skin graft successful depends on reduction of local inflammation evoked by the surgical lesion and efficient neovascularization to nutrition the graft. It has been shown that N-terminal portion of the Annexin A1 protein (AnxA1) with its anti-inflammatory properties induces epithelial mucosa repair and presents potential therapeutic approaches. The role of AnxA1 on wound healing has not been explored and we investigated in this study the effect of the peptide Ac2-26 (N terminal AnxA1 peptide Ac2-26; AnxA12-26) on heterologous skin scaffolds transplantation in BALB/c mice, focusing on inflammation and angiogenesis. Treatment with AnxA12-26, once a day, from day 3-60 after scaffold implantation improved the take of the implant, induced vessels formation, enhanced gene and protein levels of the vascular growth factor-A (VEGF-A) and fibroblast influx into allograft tissue. It also decreased pro- while increasing anti-inflammatory cytokines. The pro-angiogenic activity of AnxA12-26 was corroborated by topical application of AnxA12-26 on the subcutaneous tissue of mice. Moreover, treatment of human umbilical endothelial cells (HUVECs) with AnxA12-26 improved proliferation, shortened cycle, increased migration and actin polymerization similarly to those evoked by VEGF-A. The peptide treatment instead only potentiated the tube formation induced by VEGF-A. Collectively, our data showed that AnxA12-26 treatment favors the tissue regeneration after skin grafting by avoiding exacerbated inflammation and improving the angiogenesis process. PMID- 30250433 TI - Delay-Dependent Impairments in Memory and Motor Functions After Acute Methadone Overdose in Rats. AB - Methadone is used as a substitution drug for the treatment of opioid dependence and chronic pain. Despite its widespread use and availability, there is a serious concern with respect to the relative safety of methadone. The purpose of this study was to characterize how acute methadone overdose affects the cognitive and motor performance of naive healthy rats. The methadone overdose was induced by administering an acute toxic dose of methadone (15 mg/kg; ip; the equivalent dose of 80% of LD50) to adolescent rats. Resuscitation using a ventilator pump along with a single dose of naloxone (2 mg/kg; ip) was administered following the occurrence of apnea. The animals which were successfully resuscitated divided randomly into three apnea groups that evaluated either on day 1, 5, or 10 post resuscitation (M/N-Day 1, M/N-Day 5, and M/N-Day 10 groups) in the Y-maze and novel object memory recognition tasks as well as pole and rotarod tests. The data revealed that a single toxic dose of methadone had an adverse effect on spontaneous behavior. In addition, Recognition memory impairment was observed in the M/N-Day 1, 5, and 10 groups after methadone-induced apnea. Further, descending time in the M/N-Day 5 group increased significantly in comparison with its respective Saline control group. The overall results indicate that acute methadone-overdose-induced apnea produced delay-dependent cognitive and motor impairment. We suggest that methadone poisoning should be considered as a possible cause of delayed neurological disorders, which might be transient, in some types of memory or motor performance in naive healthy rats. PMID- 30250434 TI - Behavioral Inhibition and Activation Systems, and Emotional Regulation in Individuals With Chronic Musculoskeletal Pain. AB - Gray's Reinforcement Sensitivity Theory postulates two distinct neurophysiological systems that underlie thoughts, emotions, and behavior: the Behavioral Inhibition System (BIS) and the Behavioral Approach System (BAS). Preliminary research suggests that both systems may play relevant roles in the adjustment of individuals with chronic pain. However, there is a lack of research on the extent to which emotional regulation (i.e., cognitive reappraisal and expressive suppression) mediates the associations between BIS and BAS activation and emotional responses in individuals with chronic pain. The aim of this study was to test a model of the associations between the BIS and BAS, cognitive reappraisal and expressive suppression, and positive and negative affect in individuals with chronic musculoskeletal pain. In total, 516 participants were interviewed. Structural Equation Modeling was used to estimate the associations between variables. The empirical model showed a good fit to the data (chi2/df = 1.95; RMSEA = 0.04; GFI = 0.99; AGFI = 0.98; CFI = 0.99). The hypothesized model received partial support. The BIS was associated with cognitive reappraisal and expressive suppression; cognitive reappraisal was associated with negative and positive affect; expressive suppression was positively associated with affect; and the BAS was not associated with the emotional regulation strategies assessed. However, the BIS and BAS were both directly associated with negative and positive affect. The results suggest that individuals with chronic pain with higher BIS activation appear to use greater expressive suppression. Cognitive reappraisal strongly mediated the BIS-negative affect association. The results also suggest that BAS activation may have a weak or inconsistent association with emotional regulation approaches in individuals with chronic pain. These data provide new and relevant information on the potential role of the BIS and BAS as predictors of psychological functioning in individuals with chronic pain. They suggest that the BIS-BAS model of chronic pain may need to be modified to take into account the potential negative effects of BAS activation. The findings suggest that treatments for emotional regulation could potentially reduce the negative impact of chronic pain via BIS. PMID- 30250435 TI - Episodic Ethanol Exposure in Adolescent Rats Causes Residual Alterations in Endogenous Opioid Peptides. AB - Adolescent binge drinking is associated with an increased risk of substance use disorder, but how ethanol affects the central levels of endogenous opioid peptides is still not thoroughly investigated. The aim of this study was to examine the effect of repeated episodic ethanol exposure during adolescence on the tissue levels of three different endogenous opioid peptides in rats. Outbred Wistar rats received orogastric (i.e., gavage) ethanol for three consecutive days per week between 4 and 9 weeks of age. At 2 h and 3 weeks, respectively, after the last exposure, beta-endorphin, dynorphin B and Met-enkephalin-Arg6Phe7 (MEAP) were analyzed with radioimmunoassay. Beta-endorphin levels were low in the nucleus accumbens during ethanol intoxication. Remaining effects of adolescent ethanol exposure were found especially for MEAP, with low levels in the amygdala, and high in the substantia nigra and ventral tegmental area three weeks after the last exposure. In the hypothalamus and pituitary, the effects of ethanol on beta endorphin were dependent on time from the last exposure. An interaction effect was also found in the accumbal levels of MEAP and nigral dynorphin B. These results demonstrate that repeated episodic exposure to ethanol during adolescence affected opioid peptide levels in regions involved in reward and reinforcement as well as stress response. These alterations in opioid networks after adolescent ethanol exposure could explain, in part, the increased risk for high ethanol consumption later in life. PMID- 30250436 TI - Bridging Exercise Science, Cognitive Psychology, and Medical Practice: Is "Cognitive Fatigue" a Remake of "The Emperor's New Clothes"? AB - Fatigue is such a multifaceted construct it has sprouted specific research fields and experts in domains as different as exercise physiology, cognitive psychology, human factors and engineering, and medical practice. It lacks a consensus definition: it is an experimental concept, a symptom, a risk, a cause (e.g., of performance decrement) and a consequence (e.g., of sleep deprivation). This fragmentation of knowledge leads to slower dissemination of novel insights, and thus to a poorer research. Indeed, what may seem as a novel result in one field, may very well be old news in another, hence leading to this "innovation" being a scientific equivalent to the emperor's new clothes. The current paper aims to describe the common denominator in the different areas of expertise where fatigue is investigated. Indeed, rather than focusing on the differences in semantics and conceptualization, we hope that identifying common concepts may be inductive of easier multidisciplinary research. Considering the vastness of fatigue research in all areas identified as relevant-cognitive science, exercise physiology, and medical practice, this analysis has not the ambition to be an exhaustive review in all domains. We have reviewed the fatigue concepts and research in these areas and report the ones that are used to describe the proposed common model to be further investigated. The most promising common feature to cognitive science, exercise physiology and clinical practice is the notion of "perceived effort." This allows to account for interindividual differences, as well as for the situational variations in fatigue. It is applicable to both mental and physical constructs. It integrates motivational and emotional dimensions. It overcomes current polemics in various research fields, and it does not draw on any semantic ambiguity. We thus suggest a new model of fatigue and performance, whether this performance is mental or physical; and whether it is in a clinical range or relates to optimal functioning. PMID- 30250437 TI - Interacting Timescales in Perspective-Taking. AB - Through theoretical discussion, literature review, and a computational model, this paper poses a challenge to the notion that perspective-taking involves a fixed architecture in which particular processes have priority. For example, some research suggests that egocentric perspectives can arise more quickly, with other perspectives (such as of task partners) emerging only secondarily. This theoretical dichotomy-between fast egocentric and slow other-centric processes-is challenged here. We propose a general view of perspective-taking as an emergent phenomenon governed by the interplay among cognitive mechanisms that accumulate information at different timescales. We first describe the pervasive relevance of perspective-taking to cognitive science. A dynamical systems model is then introduced that explicitly formulates the timescale interaction proposed. This model illustrates that, rather than having a rigid time course, perspective taking can be fast or slow depending on factors such as task context. Implications are discussed, with ideas for future empirical research. PMID- 30250440 TI - Predictors of Bribe-Taking: The Role of Bribe Size and Personality. AB - Laboratory studies allow studying the predictors of bribe-taking in a controlled setting. However, presently used laboratory tasks often lack any connection to norm violation or invite participants to role-play. A new experimental task for studying the decision to take a bribe was designed in this study to overcome these problems by embedding the opportunity for bribe-taking in an unrelated task that participants perform. Using this new experimental task, we found that refraining from harming a third party by taking a bribe was associated with lower offered bribes and higher scores of the participants on the honesty-humility scale from the HEXACO personality inventory. A trial-level analysis showed that response times were longer for trials with bribes and even longer for trials in which bribes were accepted. These results suggest that taking a bribe may require overcoming automatic honest response and support the validity of the honesty humility scale in predicting moral behavior. PMID- 30250438 TI - Can Mindfulness Address Maladaptive Eating Behaviors? Why Traditional Diet Plans Fail and How New Mechanistic Insights May Lead to Novel Interventions. AB - Emotional and other maladaptive eating behaviors develop in response to a diversity of triggers, from psychological stress to the endless external cues in our modern food environment. While the standard approach to food- and weight related concerns has been weight-loss through dietary restriction, these interventions have produced little long-term benefit, and may be counterproductive. A growing understanding of the behavioral and neurobiological mechanisms that underpin habit formation may explain why this approach has largely failed, and pave the way for a new generation of non-pharmacologic interventions. Here, we first review how modern food environments interact with human biology to promote reward-related eating through associative learning, i.e., operant conditioning. We also review how operant conditioning (positive and negative reinforcement) cultivates habit-based reward-related eating, and how current diet paradigms may not directly target such eating. Further, we describe how mindfulness training that targets reward-based learning may constitute an appropriate intervention to rewire the learning process around eating. We conclude with examples that illustrate how teaching patients to tap into and act on intrinsic (e.g., enjoying healthy eating, not overeating, and self-compassion) rather than extrinsic reward mechanisms (e.g., weighing oneself), is a promising new direction in improving individuals' relationship with food. PMID- 30250439 TI - Differential Effects of Transcranial Direct Current Stimulation (tDCS) Depending on Previous Musical Training. AB - Previous studies have shown that transcranial direct current stimulation (tDCS) facilitates motor performance, but individual differences such as baseline performance seem to influence this effect. Accordingly, musicians offer an inter individual differences model due to anatomical and functional variances displayed among the motor cortex regions. The aim of the present work was to study if the baseline motor skill predicts whether tDCS can enhance motor learning. For that objective, we administered anodal (n = 20) or sham (n = 20) tDCS on the right primary motor cortex region of 40 right-handed healthy participants, who were divided into four groups: musicians (tDCS/sham) and non-musicians (tDCS/sham). We measured the skill index (SI) presented in the sequential finger-tapping task (SEQTAP) at baseline, during three 20 min/2 mA stimulation sessions, and in follow-up tests after 20 min and 8 days. Depending on the normality of the data distribution, statistical differences were estimated by ANOVA and Bonferroni post hoc test or Kruskal-Wallis and U Mann-Whitney. Results showed that musicians scored higher in baseline performance than non-musicians. The non-musicians who received tDCS scored higher than the sham group in the first and second stimulation session. This effect was extended to the 20 min and 8 days follow-up test. In musicians, there was no effect of tDCS. The present method seems to be suitable for the achievement of positive and consolidated tDCS effects on motor learning in inexperienced participants, but not in musicians. These data may have an implication for the rehabilitation of motor impairments, contributing to more individualized stimulation protocols. PMID- 30250442 TI - Studying the Efficacy of Psychodrama With the Hermeneutic Single Case Efficacy Design: Results From a Longitudinal Study. AB - Throughout the last decades, scientific and therapeutic communities have made common efforts to collect reliable information concerning the efficacy of psychotherapies. One of these initiatives has, recently, involved the psychodrama community and its desire to achieve progress in the validation of this therapy. Based on Robert Elliott's Hermeneutic Single Case Efficacy Design, we followed five participants (three women, two men, aged 27-48 years) of a psychodrama group over the course of their therapeutic process, which ranged from 24 months to 5 years. For the single case study, we selected the participant who had the longest data collecting record, including one follow-up. Participants generally reported improvement in their personal therapeutic goals, decrease in symptoms and life problems, and some showed a marked increase in spontaneity levels. In the single case, these results are confirmed, and following decision criteria it is possible to assert that the participant improved in all the variables assessed and that therapy is the main cause of these changes. Furthermore, the participant frequently rated psychodrama sessions as being helpful and stated they had a transformational impact on his life. This research contributes toward validating psychodrama as an efficient therapeutic method, hopefully stimulating practitioners to integrate therapy and research-which, for years, were considered independent and incompatible-and to facilitate their use in a complementary way. PMID- 30250441 TI - Hormonal Correlates of Exploratory and Play-Soliciting Behavior in Domestic Dogs. AB - Exploration and play are considered to be crucial behaviors during mammalian development. Even though the relationship between glucocorticoids and exploratory behavior, stress, and anxiety is well described in the literature, very little is known about their role in play behavior in non-rodents. Likewise, the functional role of the "social hormone" oxytocin in exploration, play, stress, and anxiety is still unknown. The present work addresses this literature gap by studying plasma hormone profiles for cortisol (CORT) and oxytocin (OT) of domestic dogs exposed to a novel arena containing two unfamiliar trainers who did not interact with the dogs. We provide evidence suggesting a functional relationship between hormonal measures of cortisol and oxytocin and adaptive behavior (play-soliciting and exploration) in freely behaving domestic dogs. We have taken into account several possible factors in our analyses and interpretations, from the nature and quality of the measurements to demographic factors to statistical robustness. Our results indicate that reduced CORT levels are associated with increments of both play-soliciting behavior frequency and exploratory behavior duration. Furthermore, taken together, our data and our simulations suggest a relationship between OT and the enactment of play-soliciting behaviors by freely behaving domestic dogs that must be further investigated. Future studies should consider naturalistic structured and semi-structured experimental approaches linking behavior with (neuro) physiological measures, taking into account demographic factors such as age and relevant interphase factors such as the sex of the dog; and socio-historic factors such as the playfulness of the dog, history of interaction with young humans, among others, to take full account of interaction between humans and animals in comparative studies (Parada and Rossi, 2018). PMID- 30250443 TI - Nature as a Commodity: What's Good for Human Health Might Not Be Good for Ecosystem Health. PMID- 30250444 TI - Calculation of Average Mutual Information (AMI) and False-Nearest Neighbors (FNN) for the Estimation of Embedding Parameters of Multidimensional Time Series in Matlab. AB - Using the method or time-delayed embedding, a signal can be embedded into higher dimensional space in order to study its dynamics. This requires knowledge of two parameters: The delay parameter tau, and the embedding dimension parameter D. Two standard methods to estimate these parameters in one-dimensional time series involve the inspection of the Average Mutual Information (AMI) function and the False Nearest Neighbor (FNN) function. In some contexts, however, such as phase space reconstruction for Multidimensional Recurrence Quantification Analysis (MdRQA), the empirical time series that need to be embedded already possess a dimensionality higher than one. In the current article, we present extensions of the AMI and FNN functions for higher dimensional time series and their application to data from the Lorenz system coded in Matlab. PMID- 30250445 TI - Quantifying Contextual Information For Cognitive Control. PMID- 30250446 TI - Corrigendum: Recurrent Convolutional Neural Networks: A Better Model of Biological Object Recognition. AB - [This corrects the article DOI: 10.3389/fpsyg.2017.01551.]. PMID- 30250447 TI - Cerebrovascular Insult as Presenting Symptom of Neurofibromatosis Type 2 in Children, Adolescents, and Young Adults. AB - Background and Purpose: Neurofibromatosis Type 2 (NF2) is an autosomal-dominant tumor-prone disorder characterized by the manifestations of central nervous system lesions. However, the first clinical signs of disease are often non tumorous. Cerebrovascular insults are known in NF2, however, not yet described as first symptom in young NF2 patients. Methods: Magnetic resonance image scans of 298 NF2 patients treated in our neurofibromatosis center in Tubingen from 2003 to 2017 were retrospectively evaluated focusing on presence of aneurysms and ischemic stroke. Clinical data were used to clarify whether or not ischemic stroke or aneurysm rupture were the first presentation of disease. Blood of the patients were subjected to genetic screening for constitutional NF2 mutations. Results: We identified 5 cases under age of 25 years with aneurysms or ischemic stroke. Among them three had ischemic strokes of the brain stem and one aneurysmal subarachnoid hemorrhage as the first symptom of the disease. Incidental finding of 2 intracranial aneurysm occurred in one patient. All aneurysms were clipped. Patients with ischemia suffered from dysarthria, gait disturbances, dizziness, and hemiparesis. Residual signs of hemiparesis and dysarthria persisted in one patient. All others fully recovered from the cerebrovascular insult. Bilateral vestibular schwannomas and intracranial meningiomas were found in all five patients. Conclusions: A cerebrovascular insult in the vertebrobasilar territory may occur as first symptom of disease in young NF2 patients. The brain stem seems to be especially prone to ischemic stroke. Multicenter studies on large NF2 cohorts are needed to determine the prevalence and pattern of cerebrovascular insults and disease in NF2 patients. PMID- 30250448 TI - Simultaneous Presentation of Definite Vestibular Migraine and Definite Meniere's Disease: Overlapping Syndrome of Two Diseases. AB - Objectives: To review the clinical records of patients that exhibited the clinical features of both vestibular migraine (VM) and Meniere's disease (MD) during each episodic vertigo attack and to discuss the possible pathophysiology of such combination of symptoms. Subjects: Ten patients that were selected according to criteria based on a combination of the diagnostic criteria for definite MD and VM (9 females and one male, age: 22-54 years) were enrolled. They were required to show features of both diseases in each vertigo attack. Methods: The patients' medical histories and pure-tone audiometry, cervical vestibular evoked myogenic potential (cVEMP), video head-impulse test (vHIT), and caloric test results were examined. cVEMP was recorded using 500 and 1,000 Hz short tone bursts (125dBSPL, air-conducted), 500 Hz-1,000 Hz cVEMP slope, an index of endolymphatic hydrops in the saccule was calculated using normalized amplitudes of p13-n23. For performing vHIT, each subject was seated 1.5 m in front of a target and asked to keep watching it as their head was passively rotated by the examiner. Their eye movements were evaluated using video-oculography while their head movements were recorded using inertial sensors. Results: The patients were predominantly female. On average, the onset of migrainous headaches occurred 9 years earlier than the onset of vertigo attacks. All of the patients but one had migraines with auras. Five of the 10 patients had a family history of vertigo attacks accompanied by both migrainous and auditory symptoms. The patients mainly displayed hearing loss at low frequencies. Nine patients exhibited 500-1,000 Hz cVEMP slope < -19.9, which was suggestive of endolymphatic hydrops. None of the patients who underwent vHIT showed abnormal canal function. One patient showed unilaterally decreased caloric responses. Conclusions: These patients presented with simultaneous MD and VM signs/symptoms might be referred to "VM/MD overlapping syndrome (VM/MD-OS)" as a new clinical syndrome. PMID- 30250449 TI - Neuroanatomical Basis of State-Dependent Activity of Upper Airway Muscles. AB - Obstructive Sleep Apnea (OSA) is a common sleep-related respiratory disorder that is associated with cognitive, cardiovascular, and metabolic morbidities. The major cause of OSA is the sleep-related reduction of upper airway muscle tone that leads to airway obstructions in individuals with anatomically narrow upper airway. This reduction is mainly due to the suppressant effect of sleep on hypoglossal motoneurons that innervate upper airway muscles. The hypoglossal motoneurons have state-dependent activity, which is decreased during the transition from wakefulness to non-rapid eye movement sleep and is further suppressed during rapid eye movement sleep. Multiple neurotransmitters and their receptors have been implicated in the control of hypoglossal motoneuron activity across the sleep-wake states. However, to date, the results of the rigorous testing show that withdrawal of noradrenergic excitation and cholinergic inhibition essentially contribute to the depression of hypoglossal motoneuron activity during sleep. The present review will focus on origins of noradrenergic and cholinergic innervation of hypoglossal motoneurons and the functional role of these neurons in the state-dependent activity of hypoglossal motoneurons. PMID- 30250450 TI - Patient Benefit Following Bimodal CI-provision: Self-reported Abilities vs. Hearing Status. AB - Objectives: Patient-reported outcomes gain importance for the assessment of auditory abilities in cochlear implant users and for the evaluation of auditory rehabilitation. Aims of the study were to explore the interrelation of self reported improvements in auditory ability with improvements in speech comprehension and to identify factors other than audiological improvement that affect self-reported auditory ability. Study Design: Explorative prospective analysis using a within-subjects repeated measures design. Setting: Academic tertiary care center. Participants: Twenty-seven adult participants with bilateral sensorineural hearing loss who received a HiRes 90K CI and continued use of a HA at the non-implanted ear (bimodal hearing). Intervention: Cochlear implantation. Main Outcome Measures: Self-reported auditory ability/disability assessed by the comparative version of the Speech, Spatial and Qualities of Hearing Scale (SSQ-B), and monosyllable as well as sentence comprehension in quiet and within speech modulated noise from different directions assessed pre- as well as 3 and 6 months post-implantation. Results: Data of 17 individuals were analyzed. At the endpoint of the study, improvement of self-reported auditory ability was significant. Regarding audiometric measures, significant improvement was seen for CI-aided pure tone thresholds, for monaural CI-assisted and bimodal sentence comprehension in quiet and in speech-modulated noise that was presented from the same source or at the side of the HA-ear. Correlations between self reported and audiometric improvements remained weak, with the exception of the improvement seen for monaural CI-aided sentence comprehension in quiet and self perceived improvement of sound quality. Considerable correlations existed between self-reported improvements and current level of depression and anxiety, and with general self-efficaciousness. Regression analyses substantiated a positive influence of self-efficaciousness on self-reported improvement in speech comprehension and between the improvement of monaural CI-aided sentence comprehension in quiet and perceived sound quality as well as a negative influence of anxiety on self-reported improvement in spatial hearing. Self reported improvements were significantly better in the subgroup with intensive as compared to regular rehabilitation. Conclusions: Self-reported auditory ability/disability represents an important measure for the success of bimodal CI provision. It is influenced by personal and mental health factors that may improve CI-rehabilitation results if addressed during rehabilitation. PMID- 30250451 TI - Phase 2 Randomized, Placebo-Controlled Clinical Trial of Recombinant Human Growth Hormone (rhGH) During Rehabilitation From Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a major cause of death and disability, but there are currently no therapies with proven efficacy for optimizing regeneration of repair during rehabilitation. Using standard stimulation tests, as many as 40-50% of survivors of severe TBI have deficiency of one or more pituitary hormones. Of these, the somatotropic axis is the most commonly affected, with Growth Hormone (GH) deficiency affecting ~20% of persons with severe TBI. Treatment with recombinant human Growth Hormone (rhGH) is generally effective in reversing the effects of acquired GH deficiency, but there is no evidence documenting functional or neurocognitive improvement after GH replacement in TBI patients. As a consequence, screening for GH deficiency and GH replacement when deficiency is found is not routinely performed as part of the rehabilitation of TBI survivors. Given that most of the recovery after TBI occurs within the first 6-12 months after injury and IGF-1 and GH are part of a coordinated restorative neurotrophic system, we hypothesized that patients will optimally benefit from GH therapy during the window of maximal neuroregenerative activity. We performed a Phase IIa, randomized, double-blind, placebo-controlled feasibility trial of recombinant human Growth Hormone (rhGH), starting at discharge from an inpatient rehabilitation unit, with follow up at 6 and 12 months. Our primary hypothesis was that treatment with rhGH in the subacute period would result in improved functional outcomes 6 months after injury. Our secondary hypothesis proposed that treatment with rhGH would increase IGF-1 levels and be well tolerated. Sixty three subjects were randomized, and 40 completed the trial. At baseline, there was no correlation between IGF-1 levels and peak GH levels after L-arginine stimulation. IGF-1 levels increased after rhGH treatment, but it took longer than 1 month for levels to be higher than for placebo-treated patients. rhGH therapy was well-tolerated. The rhGH group was no different from placebo in the Disability Rating Scale, Glasgow Outcome Scale-Extended, or neuropsychological function. However, a trend toward greater improvement from baseline in Functional Independence Measure (FIM) was noted in the rhGH treated group. Future studies should include longer treatment periods, faster titration of rhGH, and larger sample sizes. PMID- 30250452 TI - Nutrient-Driven O-GlcNAcylation at Promoters Impacts Genome-Wide RNA Pol II Distribution. AB - Nutrient-driven O-GlcNAcylation has been linked to epigenetic regulation of gene expression in metazoans. In C. elegans, O-GlcNAc marks the promoters of over 800 developmental, metabolic, and stress-related genes; these O-GlcNAc marked genes show a strong 5', promoter-proximal bias in the distribution of RNA Polymerase II (Pol II). In response to starvation or feeding, the steady state distribution of O-GlcNAc at promoters remain nearly constant presumably due to dynamic cycling mediated by the transferase OGT-1 and the O-GlcNAcase OGA-1. However, in viable mutants lacking either of these enzymes of O-GlcNAc metabolism, the nutrient responsive GlcNAcylation of promoters is dramatically altered. Blocked O-GlcNAc cycling leads to a striking nutrient-dependent accumulation of O-GlcNAc on RNA Pol II. O-GlcNAc cycling mutants also show an exaggerated, nutrient-responsive redistribution of promoter-proximal RNA Pol II isoforms and extensive transcriptional deregulation. Our findings suggest a complex interplay between the O-GlcNAc modification at promoters, the kinase-dependent "CTD-code," and co factors regulating RNA Pol II dynamics. Nutrient-responsive O-GlcNAc cycling may buffer the transcriptional apparatus from dramatic swings in nutrient availability by modulating promoter activity to meet metabolic and developmental needs. PMID- 30250453 TI - Stress, Glucocorticoids and Bone: A Review From Mammals and Fish. AB - Glucocorticoids (GCs) are the final effector products of a neuroendocrine HPA/HPI axis governing energy balance and stress response in vertebrates. From a physiological point of view, basal GC levels are essential for intermediary metabolism and participate in the development and homeostasis of a wide range of body tissues, including the skeleton. Numerous mammalian studies have demonstrated that GC hormones exert a positive role during bone modeling and remodeling as they promote osteoblastogenesis to maintain the bone architecture. Although the pharmacological effect of the so-called stress hormones has been widely reported, the role of endogenous GCs on bone mineral metabolism as result of the endocrine stress response has been largely overlooked across vertebrates. In addition, stress responses are variable depending on the stressor (e.g., starvation, predation, and environmental change), life cycle events (e.g., migration and aging), and differ among vertebrate lineages, which react differently according to their biological, social and cognitive complexity (e.g., mineral demands, physical, and psychological stress). This review intends to summarize the endogenous GCs action on bone metabolism of mammals and fish under a variety of challenging circumstances. Particular emphasis will be given to the regulatory loop between GCs and the parathyroid hormone (PTH) family peptides, and other key regulators of mineral homeostasis and bone remodeling in vertebrates. PMID- 30250455 TI - Comparison of the Mitochondrial Genome Sequences of Six Annulohypoxylon stygium Isolates Suggests Short Fragment Insertions as a Potential Factor Leading to Larger Genomic Size. AB - Mitochondrial DNA (mtDNA) is a core non-nuclear genetic material found in all eukaryotic organisms, the size of which varies extensively in the eumycota, even within species. In this study, mitochondrial genomes of six isolates of Annulohypoxylon stygium (Lev.) were assembled from raw reads from PacBio and Illumina sequencing. The diversity of genomic structures, conserved genes, intergenic regions and introns were analyzed and compared. Genome sizes ranged from 132 to 147 kb and contained the same sets of conserved protein-coding, tRNA and rRNA genes and shared the same gene arrangements and orientation. In addition, most intergenic regions were homogeneous and had similar sizes except for the region between cytochrome b (cob) and cytochrome c oxidase I (cox1) genes which ranged from 2,998 to 8,039 bp among the six isolates. Sixty-five intron insertion sites and 99 different introns were detected in these genomes. Each genome contained 45 or more introns, which varied in distribution and content. Introns from homologous insertion sites also showed high diversity in size, type and content. Comparison of introns at the same loci showed some complex introns, such as twintrons and ORF-less introns. There were 44 short fragment insertions detected within introns, intergenic regions, or as introns, some of them located at conserved domain regions of homing endonuclease genes. Insertions of short fragments such as small inverted repeats might affect or hinder the movement of introns, and these allowed for intron accumulation in the mitochondrial genomes analyzed, and enlarged their size. This study showed that the evolution of fungal mitochondrial introns is complex, and the results suggest short fragment insertions as a potential factor leading to larger mitochondrial genomes in A. stygium. PMID- 30250454 TI - Weight-Independent Mechanisms of Glucose Control After Roux-en-Y Gastric Bypass. AB - Roux-en-Y gastric bypass results in large and sustained weight loss and resolution of type 2 diabetes in 60% of cases at 1-2 years. In addition to calorie restriction and weight loss, various gastro-intestinal mediated mechanisms, independent of weight loss, also contribute to glucose control. The anatomical re-arrangement of the small intestine after gastric bypass results in accelerated nutrient transit, enhances the release of post-prandial gut hormones incretins and of insulin, alters the metabolism and the entero-hepatic cycle of bile acids, modifies intestinal glucose uptake and metabolism, and alters the composition and function of the microbiome. The amelioration of beta cell function after gastric bypass in individuals with type 2 diabetes requires enteric stimulation. However, beta cell function in response to intravenous glucose stimulus remains severely impaired, even in individuals in full clinical diabetes remission. The permanent impairment of the beta cell may explain diabetes relapse years after surgery. PMID- 30250456 TI - Recent Advances on the Multiplex Molecular Detection of Plant Viruses and Viroids. AB - Plant viruses are still one of the main contributors to economic losses in agriculture. It has been estimated that plant viruses can cause as much as 50 billion euros loss worldwide, per year. This situation may be worsened by recent climate change events and the associated changes in disease epidemiology. Reliable and early detection methods are still one of the main and most effective actions to develop control strategies for plant viral diseases. During the last years, considerable progress has been made to develop tools with high specificity and low detection limits for use in the detection of these plant pathogens. Time and cost reductions have been some of the main objectives pursued during the last few years as these increase their feasibility for routine use. Among other strategies, these objectives can be achieved by the simultaneous detection and (or) identification of several viruses in a single assay. Nucleic acid-based detection techniques are especially suitable for this purpose. Polyvalent detection has allowed the detection of multiple plant viruses at the genus level. Multiplexing RT polymerase chain reaction (PCR) has been optimized for the simultaneous detection of more than 10 plant viruses/viroids. In this short review, we provide an update on the progress made during the last decade on techniques such as multiplex PCR, polyvalent PCR, non-isotopic molecular hybridization techniques, real-time PCR, and array technologies to allow simultaneous detection of multiple plant viruses. Also, the potential and benefits of the powerful new technique of deep sequencing/next-generation sequencing are described. PMID- 30250457 TI - A Requirement for Global Transcription Factor Lrp in Licensing Replication of Vibrio cholerae Chromosome 2. AB - The human pathogen, Vibrio cholerae, belongs to the 10% of bacteria in which the genome is divided. Each of its two chromosomes, like bacterial chromosomes in general, replicates from a unique origin at fixed times in the cell cycle. Chr1 initiates first, and upon duplication of a site in Chr1, crtS, Chr2 replication initiates. Recent in vivo experiments demonstrate that crtS binds the Chr2 specific initiator RctB and promotes its initiator activity by remodeling it. Compared to the well-defined RctB binding sites in the Chr2 origin, crtS is an order of magnitude longer, suggesting that other factors can bind to it. We developed an in vivo screen to identify additional crtS-binding proteins and identified the global transcription factor, Lrp, as one such protein. Studies in vivo and in vitro indicate that Lrp binds to crtS and facilitates RctB binding to crtS. Chr2 replication is severely defective in the absence of Lrp, indicative of a critical role of the transcription factor in licensing Chr2 replication. Since Lrp responds to stresses such as nutrient limitation, its interaction with RctB presumably sensitizes Chr2 replication to the physiological state of the cell. PMID- 30250458 TI - Genomic and Proteomic Analyses of Salmonella enterica Serovar Enteritidis Identifying Mechanisms of Induced de novo Tolerance to Ceftiofur. AB - With the alarming proliferation of antibiotic resistance, it is important to understand the de novo development of bacterial adaptation to antibiotics in formerly susceptible lineages, in the absence of external genetic input from existing resistance pools. A strain of ceftiofur susceptible Salmonella enterica serovar Enteritidis ABB07-SB3071 (MIC = 1.0 MUg/ml) was successively exposed to sub-MIC of ceftiofur to allow its adaptation for tolerance to a concentration of 2.0 MUg/ml of this antibiotic. Genomic and proteomic comparative analyses of the parental strain and induced tolerant derived lineages were performed to characterize underlying mechanisms of de novo adaptation (tolerance). Expression and localization of specific drug-, heme-, sugar-, amino acid-, and sulfate transporters were altered, as was the localization of the cell membrane stabilizing protein OsmY in the tolerant strains adapted to 2.0 MUg/ml compared to the parental isolate lines. This redistribution of existing transporters acts to minimize the concentrations of ceftiofur in the periplasm, by decreasing facilitated import and increasing active efflux and cytosolic sequestration as determined by high performance liquid chromatography quantification of residual total and extracellular ceftiofur after growth. Genetic, subcellular localization, and abundance changes of specific regulators of transcription, translation, and post-translational dynamics in the derived ceftiofur tolerant lineages decrease metabolic strain on cell walls and enhance periplasmic envelop stability against stress. This produces slower growing, more tolerant populations, which deplete free ceftiofur concentrations significantly more than susceptible parental populations (P < 0.05), as measured by recoverable levels of ceftiofur from cultures of equivalent cellular density incubated with equal ceftiofur concentrations. Genetic and abundance changes to specific carbon and nitrogen metabolism enzymes, not traditionally associated with beta-lactam metabolism, establish an enzymatic framework with the potential to detoxify/degrade ceftiofur, while mutations and changes in subcellular localization in specific cell surface factors enhance the stability of the Gram negative cell envelop despite the compromising effect of ceftiofur. The observed changes highlight generalizable mechanisms of de novo tolerance without horizontal gene transfer, and thus can inform policies to combat antibiotic tolerance and minimize induction of de novo tolerance. PMID- 30250459 TI - Antagonistic Potential of Fluorescent Pseudomonads Colonizing Wheat Heads Against Mycotoxin Producing Alternaria and Fusaria. AB - Natural control of phytopathogenic microorganisms is assumed as a priority function of the commensal plant microbiota. In this study, the suitability of fluorescent pseudomonads in the phyllosphere of crop plants as natural control agents was evaluated. Under field conditions, ears of winter wheat were found to be colonized with high consistency and at a high density by pseudomonads at the late milk dough stage. Isolates of these bacteria were evaluated for their potential to protect the plants from phytopathogenic Alternaria and Fusarium fungi. More Pseudomonas isolates were antagonistically active against alternaria than against fusaria in the dual culture test. The alternaria responded species specifically and more sensitively to bacterial antagonism than the strain specific reacting fusaria. A total of 110 randomly selected Pseudomonas isolates were screened for genes involved in the biosynthesis of the antibiotics 2,4 diacetylphloroglucinol, phenazine-1-carboxylic acid, pyoluteorin, and pyrrolnitrin. The key gene for production of the phloroglucinol was found in none of these isolates. At least one of the genes, encoding the biosynthesis of the other antibiotics was detected in 81% of the isolates tested. However, the antagonistic effect found in the dual culture assay was not necessarily associated with the presence of these antibiotic genes. Wheat grains as natural substrate were inoculated with selected antagonistic Pseudomonas isolates and Alternaria and Fusarium strains, respectively. The fungal growth was only slightly delayed, but the mycotoxin production was significantly reduced in most of these approaches. In conclusion, the distribution of phytopathogenic fungi of the genera Alternaria and Fusarium in the field is unlikely to be inhibited by naturally occurring pseudomonads, also because the bacterial antagonists were not evenly distributed in the field. However, pseudomonads can reduce the production of Alternaria and Fusarium mycotoxins in wheat grains and thus have the potential to improve the crop quality. PMID- 30250460 TI - Escherichia coli Cells Exposed to Lethal Doses of Electron Beam Irradiation Retain Their Ability to Propagate Bacteriophages and Are Metabolically Active. AB - Reports in the literature suggest that bacteria exposed to lethal doses of ionizing radiation, i.e., electron beams, are unable to replicate yet they remain metabolically active. To investigate this phenomenon further, we electron beam irradiated Escherichia coli cells to a lethal dose and measured their membrane integrity, metabolic activity, ATP levels and overall cellular functionality via bacteriophage infection. We also visualized the DNA double-strand breaks in the cells. We used non-irradiated (live) and heat-killed cells as positive and negative controls, respectively. Our results show that the membrane integrity of E. coli cells is maintained and that the cells remain metabolically active up to 9 days post-irradiation when stored at 4 degrees C. The ATP levels in lethally irradiated cells are similar to non-irradiated control cells. We also visualized extensive DNA damage within the cells and confirmed their cellular functionality based on their ability to propagate bacteriophages for up to 9 days post irradiation. Overall, our findings indicate that lethally irradiated E. coli cells resemble live non-irradiated cells more closely than heat-killed (dead) cells. PMID- 30250461 TI - Characterization of an Oleaginous Unicellular Green Microalga, Lobosphaera incisa (Reisigl, 1964) Strain K-1, Isolated From a Tidal Flat in the Yellow Sea, Republic of Korea. AB - Microalgae are considered as sustainable resources for biofuel production. However, recently the focus on microalgal research has shifted toward the investigation of high-value metabolites for potential pharmaceutical and nutritional applications. Herein, we report the identification of a novel oleaginous green microalga isolated from the Yellow Sea in Korea. We also describe the morphological, molecular, and biochemical characteristics of this microalga. On the basis of microscopic and genetic analyses, the isolate was classified as Lobosphaera incisa (the strain was designated as K-1), and molecular phylogeny revealed that the isolate distinctly differed from the other known L. incisa strains. The microalga could be cultivated in various commercial culture media under a relatively broad range of pH and temperature conditions. We also did a rough and detailed estimation of the different cellular components in the microalga. The composition of arachidonic acid (C20:4omega6) in the lipids of L. incisa strain K-1 was relatively high, similar to that in other strains, however, the K-1 strain had higher proportions of the omega3 series of fatty acids (FAs), including alpha-linolenic acid (C18:3omega3) and eicosapentaenoic acid (C20:5omega3), highlighting its uniqueness and strong potential for biotechnological application. To the best of our knowledge, this is the first report on the isolation of L. incisa from Korea as well as from a marine environment; this novel strain might be useful for the production of high-value omega3 and omega6 polyunsaturated fatty acids (PUFAs). PMID- 30250462 TI - Microbiome Interaction Networks and Community Structure From Laboratory-Reared and Field-Collected Aedes aegypti, Aedes albopictus, and Culex quinquefasciatus Mosquito Vectors. AB - Microbial interactions are an underappreciated force in shaping insect microbiome communities. Although pairwise patterns of symbiont interactions have been identified, we have a poor understanding regarding the scale and the nature of co occurrence and co-exclusion interactions within the microbiome. To characterize these patterns in mosquitoes, we sequenced the bacterial microbiome of Aedes aegypti, Ae. albopictus, and Culex quinquefasciatus caught in the field or reared in the laboratory and used these data to generate interaction networks. For collections, we used traps that attracted host-seeking or ovipositing female mosquitoes to determine how physiological state affects the microbiome under field conditions. Interestingly, we saw few differences in species richness or microbiome community structure in mosquitoes caught in either trap. Co-occurrence and co-exclusion analysis identified 116 pairwise interactions substantially increasing the list of bacterial interactions observed in mosquitoes. Networks generated from the microbiome of Ae. aegypti often included highly interconnected hub bacteria. There were several instances where co-occurring bacteria co excluded a third taxa, suggesting the existence of tripartite relationships. Several associations were observed in multiple species or in field and laboratory reared mosquitoes indicating these associations are robust and not influenced by environmental or host factors. To demonstrate that microbial interactions can influence colonization of the host, we administered symbionts to Ae. aegypti larvae that either possessed or lacked their resident microbiota. We found that the presence of resident microbiota can inhibit colonization of particular bacterial taxa. Our results highlight that microbial interactions in mosquitoes are complex and influence microbiome composition. PMID- 30250463 TI - Contribution of Fluorescence Techniques in Determining the Efficiency of the Non thermal Plasma Treatment. AB - We have recently developed a non-thermal plasma (NTP) equipment intended to sterilize fragile medical devices and maintain the sterile state of items downstream the treatment. With traditional counts on agar plate a six log reduction of Staphylococcus aureus viability was obtained within 120 min of O2, Ar, or N2 NTP treatments. However to determine the best NTP process, we studied the different physiological states of S. aureus by flow cytometry (FC) and confocal laser scanning microscopy (CLSM) focusing on the esterasic activity and membrane integrity of the bacteria. Two fluorochromes, 5-(and-6)-carboxy-2',7' dichlorofluorescein diacetate and propidium iodide were used in order to distinguish three sub-populations: metabolically active, permeabilized, and damaged bacteria that can be in the viable but nonculturable state. FC and CLSM highlight that O2 and Ar NTP treatments were the most attractive processes. Indeed, a 5 min of Ar NTP generated a high destruction of the structure of bacteria and a 120 min of O2 NTP treatment led to the higher decrease of the total damaged bacteria population. SEM observations showed that in presence of clusters, bacteria of upper layers are easily altered compared to bacteria in the deeper layers. In conclusion, the plate counting method is not sufficient by itself to determine the best NTP treatment. FC and CLSM represent attractive indicator techniques to select the most efficient gas NTP treatment generating the lowest proportion of viable bacteria and the most debris. PMID- 30250464 TI - Cell Signaling of Caenorhabditis elegans in Response to Enterotoxigenic Escherichia coli Infection and Lactobacillus zeae Protection. AB - Enterotoxigenic Escherichia coli (ETEC) infection causes the death of Caenorhabditis elegans, which can be prevented by certain Lactobacillus isolates. The host response of C. elegans to ETEC infection and its regulation by the isolates are, however, largely unclear. This study has revealed that, in agreement with the results of life-span assays, the expression of the genes encoding p38 mitogen-activated protein kinase (MAPK) pathway (nsy-1, sek-1, and pmk-1), insulin/insulin-like growth factor (DAF/IGF) pathway (daf-16), or antimicrobial peptides (lys-7, spp-1, and abf-3) and other defensing molecules (abf-2, clec-85) was upregulated significantly when the wild-type nematode (N2) was subjected to ETEC infection. This upregulation was further enhanced by the pretreatment with Lactobacillus zeae LB1, but not with L. casei CL11. Mutants defective in the cell signaling of C. elegans were either more susceptible (defective in NSY-1, SEK-1, PMK-1, or DAF16) or more resistant (defective in AGE 1, DBL-1, SKN-1, or SOD-3) to ETEC infection compared with the wild-type. Mutants defective in antimicrobial peptides (LYS-7, SPP1, or ABF-3) were also more susceptible. In addition, mutants that are defective in NSY-1, SEK-1, PMK-1, DAF16, ABF-3, LYS-7, or SPP1 showed no response to the protection from L. zeae LB1. The expression of the genes encoding antimicrobial peptides (lys-7, spp-1, and abf-3) and other defensing molecules (abf-2, clec-60, and clec-85) were almost all upregulated in AGE-1- or DBL-1-defective mutant compared with the wild type, which was further enhanced by the pretreatment of L. zeae LB1. The expression of these genes was, however, mostly downregulated in NSY-1- or DAF-16 defective mutant. These results suggest that L. zeae LB1 regulates C. elegans signaling through the p38 MAPK and DAF/IGF pathways to control the production of antimicrobial peptides and defensing molecules to combat ETEC infection. PMID- 30250465 TI - 4-1BB Signaling Promotes Alveolar Macrophages-Mediated Pro-Fibrotic Responses and Crystalline Silica-Induced Pulmonary Fibrosis in Mice. AB - Silicosis is caused by exposure to crystalline silica (CS). We have previously shown that blocking 4-1BB signaling attenuated CS-induced inflammation and pulmonary fibrosis. However, the cells that express 4-1BB, which plays a vital role in promoting fibrosis, are still unknown. In this study, we demonstrated that the expression of 4-1BB is elevated in alveolar macrophages (AMs) in the lungs of CS-injured mice. CS exposure also markedly enhanced the expression of 4 1BB in macrophage-like, MH-S cells. In these cells, activation of the 4-1BB signaling with an agonist antibody led to upregulated secretion of pro-fibrotic mediators. Consistently, blocking 4-1BB downstream signaling or genetic deletion of 4-1BB alleviated pro-fibrotic responses in vitro, while treatment with a 4-1BB fusion protein promoted pro-fibrotic responses. In vivo experiments showed that blocking 4-1BB signaling decreased the expressions of pro-fibrotic mediators and fibrosis. These data suggest that 4-1BB signaling plays an important role in promoting AMs-mediated pro-fibrotic responses and pulmonary fibrosis. Our findings may provide a potential molecular target to reduce CS-induced fibrotic responses in occupational lung disease. PMID- 30250466 TI - Treating Influenza Infection, From Now and Into the Future. AB - Influenza viruses (IVs) are a continual threat to global health. The high mutation rate of the IV genome makes this virus incredibly successful, genetic drift allows for annual epidemics which result in thousands of deaths and millions of hospitalizations. Moreover, the emergence of new strains through genetic shift (e.g., swine-origin influenza A) can cause devastating global outbreaks of infection. Neuraminidase inhibitors (NAIs) are currently used to treat IV infection and act directly on viral proteins to halt IV spread. However, effectivity is limited late in infection and drug resistance can develop. New therapies which target highly conserved features of IV such as antibodies to the stem region of hemagglutinin or the IV RNA polymerase inhibitor: Favipiravir are currently in clinical trials. Compared to NAIs, these treatments have a higher tolerance for resistance and a longer therapeutic window and therefore, may prove more effective. However, clinical and experimental evidence has demonstrated that it is not just viral spread, but also the host inflammatory response and damage to the lung epithelium which dictate the outcome of IV infection. Therapeutic regimens for IV infection should therefore also regulate the host inflammatory response and protect epithelial cells from unnecessary cell death. Anti inflammatory drugs such as etanercept, statins or cyclooxygenase enzyme 2 inhibitors may temper IV induced inflammation, demonstrating the possibility of repurposing these drugs as single or adjunct therapies for IV infection. IV binds to sialic acid receptors on the host cell surface to initiate infection and productive IV replication is primarily restricted to airway epithelial cells. Accordingly, targeting therapies to the epithelium will directly inhibit IV spread while minimizing off target consequences, such as over activation of immune cells. The neuraminidase mimic Fludase cleaves sialic acid receptors from the epithelium to inhibit IV entry to cells. While type III interferons activate an antiviral gene program in epithelial cells with minimal perturbation to the IV specific immune response. This review discusses the above-mentioned candidate anti-IV therapeutics and others at the preclinical and clinical trial stage. PMID- 30250467 TI - Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers. AB - Background: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in CTLA4 can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown. Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled. Results: Among the 184 CTLA4 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected CTLA4 mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated. Conclusion: Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected CTLA4 mutation carriers. PMID- 30250469 TI - Dominant Negative FADD/MORT1 Inhibits the Development of Intestinal Intraepithelial Lymphocytes With a Marked Defect on CD8alphaalpha+TCRgammadelta+ T Cells. AB - Intestinal intraepithelial lymphocytes (IELs) play a critical role in mucosal immune system, which differ from thymus-derived cells and develop locally in gut. Although the development of IELs has been studied in some detail, the molecular cues controlling their local development remain unclear. Here, we demonstrate that FADD, a classic adaptor protein required for death-receptor-induced apoptosis, is a critical regulator of the intestinal IEL development. The mice with a dominant negative mutant of FADD (FADD-DN) display an abnormal development of intestinal IELs with a marked reduction in the numbers of CD8alphaalpha+TCRgammadelta+ T cells. As a precursor for CD8alphaalpha+ development, lamina propria lymphocytes in lin-negative expression (lin- LPLs) were analyzed and the massive accumulation of IL-7R-lin- LPLs was observed in FADD-DN mice. As IL-7R is one of Notch1-target genes, we further observed that the level of Notch1 expression was lower in Lin- LPLs from FADD-DN mice compared with normal mice. The downregulation of Notch1 expression induced by FADD-DN overexpression was also confirmed in Jurkat T cells. Considering that IL-7 and its receptor IL7-R play a differentiation inducing role in the development of intestinal IELs, the influence of FADD via its DD domain on Notch1 expression might be a possible molecular signal involved in the early IELs development. In addition, loss of gammadelta T-IELs in FADD-DN mice aggravates DSS-induced colitis, suggesting that FADD is a relevant contribution to the field of mucosal immunology and intestinal homeostasis. PMID- 30250468 TI - Cerebral Malaria in Mouse and Man. AB - Cerebral malaria (CM) is an acute encephalopathy caused by the malaria parasite Plasmodium falciparum, which develops in a small minority of infected patients and is responsible for the majority of deaths in African children. Despite decades of research on CM, the pathogenic mechanisms are still relatively poorly defined. Nevertheless, many studies in recent years, using a combination of animal models, in vitro cell culture work, and human patients, provide significant insight into the pathologic mechanisms leading to CM. In this review, we summarize recent findings from mouse models and human studies on the pathogenesis of CM, understanding of which may enable development of novel therapeutic approaches. PMID- 30250470 TI - Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses. AB - About 8% of our genome is composed of sequences with viral origin, namely human Endogenous Retroviruses (HERVs). HERVs are relics of ancient infections that affected the primates' germ line along the last 100 million of years, and became stable elements at the interface between self and foreign DNA. Intriguingly, HERV co-evolution with the host led to the domestication of activities previously devoted to the retrovirus life cycle, providing novel cellular functions. For example, selected HERV envelope proteins have been coopted for pregnancy-related purposes, and proviral Long Terminal Repeats participate in the transcriptional regulation of various cellular genes. Given the HERV persistence in the host genome and its basal expression in most healthy tissues, it is reasonable that human defenses should prevent HERV-mediated immune activation. Despite this, HERVs and their products (including RNA, cytosolic DNA, and proteins) are still able to modulate and be influenced by the host immune system, fascinatingly suggesting a central role in the evolution and functioning of the human innate immunity. Indeed, HERV sequences had been major contributors in shaping and expanding the interferon network, dispersing inducible genes that have been occasionally domesticated in various mammalian lineages. Also the HERV integration within or near to genes encoding for critical immune factors has been shown to influence their activity, or to be responsible for their polymorphic variation in the human population, such as in the case of an HERV-K(HML10) provirus in the major histocompatibility complex region. In addition, HERV expressed products have been shown to modulate innate immunity effectors, being therefore often related on the one side to inflammatory and autoimmune disorders, while on the other side to the control of excessive immune activation through their immunosuppressive properties. Finally, HERVs have been proposed to establish a protective effect against exogenous infections. The present review summarizes the involvement of HERVs and their products in innate immune responses, describing how their intricate interplay with the first line of human defenses can actively contribute either to the host protection or to his damage, implying a subtle balance between the persistence of HERV expression and the maintenance of a basal immune alert. PMID- 30250471 TI - Targeting Checkpoint Receptors and Molecules for Therapeutic Modulation of Natural Killer Cells. AB - Among the most promising therapeutic modalities for cancer treatment is the blockade of immune checkpoint pathways, which are frequently co-opted by tumors as a major mechanism of immune escape. CTLA-4 and PD-1 are the representative examples, and their blockade by therapeutic antibodies leads to enhanced anti tumor immunity with durable clinical responses, but only in a minority of patients. This has highlighted the need to identify and target additional immune checkpoints that can be exploited to further enhance immune responses to refractory cancers. These emerging targets include natural killer (NK) cell directed checkpoint receptors (KIR and CD94/NKG2A) as well as the NK- and T cell expressed checkpoints TIM-3, TIGIT, CD96, and LAG-3. Interestingly, the potentiation of anti-tumor immunity by checkpoint blockade relies not only on T cells but also on other components of the innate immune system, including NK cells. NK cells are innate lymphoid cells that efficiently kill tumor cells without MHC specificity, which is complementary to the MHC-restricted tumor lysis mediated by cytotoxic T cells. However, the role of these immune checkpoints in modulating the function of NK cells remains unclear and somewhat controversial. Unraveling the mechanisms by which these immune checkpoints function in NK cells and other immune cells will pave the way to developing new therapeutic strategies to optimize anti-tumor immunity while limiting cancer immune escape. Here, we focus on recent findings regarding the roles of immune checkpoints in regulating NK cell function and their potential application in cancer immunotherapy. PMID- 30250472 TI - Therapeutic Potential of the Gut Microbiota in the Prevention and Treatment of Sepsis. AB - Alongside advances in understanding the pathophysiology of sepsis, there have been tremendous strides in understanding the pervasive role of the gut microbiota in systemic host resistance. In pre-clinical models, a diverse and balanced gut microbiota enhances host immunity to both enteric and systemic pathogens. Disturbance of this balance increases susceptibility to sepsis and sepsis-related organ dysfunction, while restoration of the gut microbiome is protective. Patients with sepsis have a profoundly distorted composition of the intestinal microbiota, but the impact and therapeutic potential of the microbiome is not well-established in human sepsis. Modulation of the microbiota consists of either resupplying the pool of beneficial microbes by administration of probiotics, improving the intestinal microenvironment to enhance the growth of beneficial species by dietary interventions and prebiotics, or by totally recolonizing the gut with a fecal microbiota transplantation (FMT). We propose that there are three potential opportunities to utilize these treatment modalities over the course of sepsis: to decrease sepsis incidence, to improve sepsis outcome, and to decrease late mortality after sepsis. Exploring these three avenues will provide insight into how disturbances of the microbiota can predispose to, or even perpetuate the dysregulated immune response associated with this syndrome, which in turn could be associated with improved sepsis management. PMID- 30250473 TI - Stochastically Timed Competition Between Division and Differentiation Fates Regulates the Transition From B Lymphoblast to Plasma Cell. AB - In response to external stimuli, naive B cells proliferate and take on a range of fates important for immunity. How their fate is determined is a topic of much recent research, with candidates including asymmetric cell division, lineage priming, stochastic assignment, and microenvironment instruction. Here we manipulate the generation of plasmablasts from B lymphocytes in vitro by varying CD40 stimulation strength to determine its influence on potential sources of fate control. Using long-term live cell imaging, we directly measure times to differentiate, divide, and die of hundreds of pairs of sibling cells. These data reveal that while the allocation of fates is significantly altered by signal strength, the proportion of siblings identified with asymmetric fates is unchanged. In contrast, we find that plasmablast generation is enhanced by slowing times to divide, which is consistent with a hypothesis of competing timed stochastic fate outcomes. We conclude that this mechanistically simple source of alternative fate regulation is important, and that useful quantitative models of signal integration can be developed based on its principles. PMID- 30250474 TI - Clarithromycin Enhances the Antibacterial Activity and Wound Healing Capacity in Type 2 Diabetes Mellitus by Increasing LL-37 Load on Neutrophil Extracellular Traps. AB - Background: Type 2 diabetes mellitus (T2D) is characterized by susceptibility to bacterial infections and impaired wound healing. Neutrophil extracellular traps (NETs) and the cathelicidin antimicrobial peptide LL-37 have been implicated both in defense against bacterial infections and in wound healing process. Recently, it was shown that macrolide antibiotic clarithromycin induces the release of LL 37-bearing NETs. In T2D there has not been identified any link between NETs and LL-37 and the effect of clarithromycin in neutrophils/NETs is unknown yet. Methods: Peripheral blood neutrophils were obtained from treatment-naive hyperglycemic T2D patients (naive), normoglycemic T2D patients under antidiabetic treatment (well-controlled) and healthy donors (controls). NET release and NET proteins were studied. Co-culture systems of NET structures with E. coli NCTC 9001 and primary skin fibroblasts were deployed to examine the in vitro antibacterial and fibrotic NET properties, respectively. The effect of clarithromycin was also investigated. Analysis was performed using immunofluorescence confocal microscopy, myeloperoxidase-DNA complex and LL-37 ELISA, immunoblotting and qRT-PCR. Results: NETs were characterized by the presence of LL-37, however they lacked antibacterial activity, in both groups of T2D patients. Clarithromycin significantly increased the externalization of LL-37 on NETs generated from well-controlled T2D neutrophils, thus restoring NET antibacterial capacity and promoting the wound healing process via fibroblast activation and differentiation. Conclusion: This study suggests that clarithromycin may add further advantage to well-controlled T2D patients, by enhancing their antibacterial defense and improving wound healing capacity of fibroblasts, through upregulation of LL-37 on NET structures. PMID- 30250476 TI - Prospective of Essential Oils of the Genus Mentha as Biopesticides: A Review. AB - Mentha is a genus from the family Lamiaceae, whose essential oils has long been used in various forms such as in management of plant pathogens and insect pests, in traditional medicine as well as in culinary and cosmetics. Its major chemical components such as menthol, carvone have now been successfully commercialized in the industry as antimicrobials/insecticidal agents. Current review focuses on chemical composition of essential oils of some Mentha species from different geographical regions with their insecticidal (repellent, antifeedant, and ovicidal) and antimicrobial efficacies against bacterial, fungal plant pathogens and insects of stored products. Reports of the researchers on chemical analysis of essential oils of Mentha species revealed that most of the oils being rich in pulegone, menthon, menthol, carvone, 1, 8-cineole, limonene and beta caryophyllene. Reviewed literature revealed that, essential oils from different Mentha species possess potential antimicrobial activity against plant pathogens and have insecticidal activity against stored product insects. Thus, antimicrobial and insecticidal properties of essential oils of Mentha species offer the prospect of using them as natural pesticides with a commercial value, having social acceptance due to its sustainability and being environment friendly. PMID- 30250475 TI - Microscopic and Proteomic Analysis of Dissected Developing Barley Endosperm Layers Reveals the Starchy Endosperm as Prominent Storage Tissue for ER-Derived Hordeins Alongside the Accumulation of Barley Protein Disulfide Isomerase (HvPDIL1-1). AB - Barley (Hordeum vulgare) is one of the major food sources for humans and forage sources for animal livestock. The average grain protein content (GPC) of barley ranges between 8 and 12%. Barley hordeins (i.e., prolamins) account for more than 50% of GPC in mature seeds and are important for both grain and flour quality. Barley endosperm is structured into three distinct cell layers: the starchy endosperm, which acts essentially as storage tissue for starch; the subaleurone, which is characterized by a high accumulation of seed storage proteins (SSPs); and the aleurone, which has a prominent role during seed germination. Prolamins accumulate in distinct, ER-derived protein bodies (PBs) and their trafficking route is spatio-temporally regulated. The protein disulfide isomerase (PDI) has been shown to be involved in PB formation. Here, we unravel the spatio-temporal proteome regulation in barley aleurone, subaleurone, and starchy endosperm for the optimization of end-product quality in barley. We used laser microdissection (LMD) for subsequent nanoLC-MS/MS proteomic analyses in two experiments: in Experiment One, we investigated the proteomes of dissected barley endosperm layers at 12 and at >=20 days after pollination (DAP). We found a set of 10 proteins that were present in all tissues at both time points. Among these proteins, the relative protein abundance of D-hordein, B3-hordein and HvPDIL1-1 significantly increased in starchy endosperm between 12 and >=20 DAP, identifying the starchy endosperm as putative major storage tissue. In Experiment Two, we specifically compared the starchy endosperm proteome at 6, 12, and >=20 DAP. Whereas the relative protein abundance of D-hordein and B3-hordein increased between 6 and >=20 DAP, HvPDIL1-1 increased between 6 and 12 DAP, but remained constant at >=20 DAP. Microscopic observations showed that these relative protein abundance alterations were accompanied by additional localization of hordeins at the periphery of starch granules and a partial re-localization of HvPDIL1-1 from PBs to the periphery of starch granules. Our data indicate a spatio-temporal regulation of hordeins and HvPDIL1-1. These results are discussed in relation to the putative role of HvPDIL1-1 in end-product quality in barley. PMID- 30250477 TI - Arbuscular Mycorrhizas: A Promising Component of Plant Production Systems Provided Favorable Conditions for Their Growth. AB - Arbuscular mycorrhizal (AM) fungi have become an attractive target as biostimulants in agriculture due to their known contributions to plant nutrient uptake and abiotic stress tolerance. However, inoculation with AM fungi can result in depressed, unchanged, or stimulated plant growth, which limits security of application in crop production systems. Crop production comprises high diversity and variability in atmospheric conditions, substrates, plant species, and more. In this review, we emphasize that we need integrative approaches for studying mycorrhizal symbioses in order to increase the predictability of growth outcomes and security of implementation of AM fungi into crop production. We briefly review known mechanisms of AM on nutrient uptake and drought tolerance of plants, on soil structure and soil hydraulic properties. We carve out that an important factor for both nutrient availability and drought tolerance is yet not well understood; the AM effects on soil hydraulic properties. We gave special emphasis to circular references between atmospheric conditions, soil hydraulic properties and plant nutrient and water uptake. We stress that interdisciplinary approaches are needed that account for a variability of atmospheric conditions and, how this would match to mycorrhizal functions and demands in a way that increased plant nutrient and water uptake can be effectively used for physiological processes and ultimately growth. Only with integrated analyses under a wide range of growing conditions, we will be able to make profound decisions whether or not to use AM in particular crop production systems or can adjust culture conditions in ways that AM plants thrive. PMID- 30250478 TI - Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice. AB - We previously determined that repeated binge ethanol drinking produced sex differences in the regulation of signaling downstream of Group 1 metabotropic glutamate receptors in the nucleus accumbens (NAc) of adult C57BL/6J mice. The purpose of the present study was to characterize RNA expression differences in the NAc of adult male and female C57BL/6J mice following 7 binge ethanol drinking sessions, when compared with controls consuming water. This binge drinking procedure produced high intakes (average >2.2 g/kg/30 min) and blood ethanol concentrations (average >1.3 mg/ml). Mice were euthanized at 24 h after the 7th binge session, and focused qPCR array analysis was employed on NAc tissue to quantify expression levels of 384 genes in a customized Mouse Mood Disorder array, with a focus on glutamatergic signaling (3 arrays/group). We identified significant regulation of 50 genes in male mice and 70 genes in female mice after 7 ethanol binges. Notably, 14 genes were regulated in both males and females, representing common targets to binge ethanol drinking. However, expression of 10 of these 14 genes was strongly dimorphic (e.g., opposite regulation for genes such as Crhr2, Fos, Nos1, and Star), and only 4 of the 14 genes were regulated in the same direction (Drd5, Grm4, Ranbp9, and Reln). Interestingly, the top 30 regulated genes by binge ethanol drinking for each sex differed markedly in the male and female mice, and this divergent neuroadaptive response in the NAc could result in dysregulation of distinct biological pathways between the sexes. Characterization of the expression differences with Ingenuity Pathway Analysis was used to identify Canonical Pathways, Upstream Regulators, and significant Biological Functions. Expression differences suggested that hormone signaling and immune function were altered by binge drinking in female mice, whereas neurotransmitter metabolism was a central target of binge ethanol drinking in male mice. Thus, these results indicate that the transcriptional response to repeated binge ethanol drinking was strongly influenced by sex, and they emphasize the importance of considering sex in the development of potential pharmacotherapeutic targets for the treatment of alcohol use disorder. PMID- 30250479 TI - Evidence for Introgression Among Three Species of the Anastrepha fraterculus Group, a Radiating Species Complex of Fruit Flies. AB - Introgression should no longer be considered as rare a phenomenon as once thought, since several studies have recently documented gene flow between closely related and radiating species. Here, we investigated evolutionary relationships among three closely related species of fruit flies of the Anastrepha fraterculus group (Anastrepha fraterculus, A. obliqua and A. sororcula). We sequenced a set of 20 genes and implemented a combined populational and phylogenetic inference with a model selection approach by an ABC framework in order to elucidate the demographic history of these species. The phylogenetic histories inferred from most genes showed a great deal of discordance and substantial shared polymorphic variation. The analysis of several population and speciation models reveal that this shared variation is better explained by introgression rather than convergence by parallel mutation or incomplete lineage sorting. Our results consistently showed these species evolving under an isolation with migration model experiencing a continuous and asymmetrical pattern of gene flow involving all species pairs, even though still showed a more closely related relationship between A. fraterculus and A. sororcula when compared with A. obliqua. This suggests that these species have been exchanging genes since they split from their common ancestor ~2.6 MYA ago. We also found strong evidence for recent population expansion that appears to be consequence of anthropic activities affecting host crops of fruit flies. These findings point that the introgression here found may have been driven by genetic drift and not necessary by selection, which has implications for tracking and managing fruit flies. PMID- 30250480 TI - Role of Microbes in the Development of Alzheimer's Disease: State of the Art - An International Symposium Presented at the 2017 IAGG Congress in San Francisco. AB - This article reviews research results and ideas presented at a special symposium at the International Association of Gerontology and Geriatrics (IAGG) Congress held in July 2017 in San Francisco. Five researchers presented their results related to infection and Alzheimer's disease (AD). Prof. Itzhaki presented her work on the role of viruses, specifically HSV-1, in the pathogenesis of AD. She maintains that although it is true that most people harbor HSV-1 infection, either latent or active, nonetheless aspects of herpes infection can play a role in the pathogenesis of AD, based on extensive experimental evidence from AD brains and infected cell cultures. Dr. Miklossy presented research on the high prevalence of bacterial infections that correlate with AD, specifically spirochete infections, which have been known for a century to be a significant cause of dementia (e.g., in syphilis). She demonstrated how spirochetes drive senile plaque formation, which are in fact biofilms. Prof. Balin then described the involvement of brain tissue infection by the Chlamydia pneumoniae bacterium, with its potential to use the innate immune system in its spread, and its initiation of tissue damage characteristic of AD. Prof. Fulop described the role of AD-associated amyloid beta (Abeta) peptide as an antibacterial, antifungal and antiviral innate immune effector produced in reaction to microorganisms that attack the brain. Prof. Barron put forward the novel hypothesis that, according to her experiments, there is strong sequence-specific binding between the AD associated Abeta and another ubiquitous and important human innate immune effector, the cathelicidin peptide LL-37. Given this binding, LL-37 expression in the brain will decrease Abeta deposition via formation of non-toxic, soluble Abeta/LL-37 complexes. Therefore, a chronic underexpression of LL-37 could be the factor that simultaneously permits chronic infections in brain tissue and allows for pathological accumulation of Abeta. This first-of-its-kind symposium opened the way for a paradigm shift in studying the pathogenesis of AD, from the "amyloid cascade hypothesis," which so far has been quite unsuccessful, to a new "infection hypothesis," or perhaps more broadly, "innate immune system dysregulation hypothesis," which may well permit and lead to the discovery of new treatments for AD patients. PMID- 30250481 TI - Comparative Transcriptome Profiling of mRNA and lncRNA Related to Tail Adipose Tissues of Sheep. AB - The Lanzhou Fat-Tail sheep (LFTS, long fat-tailed sheep) is an endangered sheep breed in China with a fat tail compared to the traditional local varieties, Small Tail Han sheep (STHS, thin-tailed sheep) with a small tail, and Tibetan sheep (TS, short thin-tailed sheep) with a little tail. However, little is known regarding how tail fat deposition is regulated by long noncoding RNA (lncRNA). To evaluate the lncRNA and mRNA associated with tail fat deposition and development among these breeds, high-throughput RNA sequencing of three individuals each of LFTS, STHS, and TS were performed and analyzed in this study. RNA sequencing data from these three groups revealed 10 differentially expressed genes (DEGs) and 37 differentially expressed lncRNAs between the LFTS and STHS groups, 390 DEGs and 59 differentially expressed lncRNAs between the LFTS and TS groups, and 80 DEGs and 16 differentially expressed lncRNAs between the STHS and TS groups (p-value < 0.05 and fold change >= 2), respectively. Gene Ontology and pathway analysis of DEGs and target genes of differentially expressed lncRNAs revealed enrichment in fatty acid metabolism and fatty acid elongation-related pathways that contribute to fat deposition. Subsequently, the expression of 14 DEGs and 6 differentially expressed lncRNAs was validated by quantitative real-time PCR. Finally, two co expression networks of differentially expressed mRNA and lncRNAs were constructed. The results suggested that some differentially expressed lncRNAs (TCONS_00372767, TCONS_00171926, TCONS_00054953, and TCONS_00373007) may play crucial roles as core lncRNAs in tail fat deposition processes. In summary, the present study extends the sheep tail fat lncRNA database and these differentially expressed mRNA and lncRNAs may provide novel candidate regulators for future genetic and molecular studies on tail fat deposition of sheep. PMID- 30250482 TI - mTOR Signaling, Translational Control, and the Circadian Clock. AB - Almost all cellular processes are regulated by the approximately 24 h rhythms that are endogenously driven by the circadian clock. mRNA translation, as the most energy consuming step in gene expression, is temporally controlled by circadian rhythms. Recent research has uncovered key mechanisms of translational control that are orchestrated by circadian rhythmicity and in turn feed back to the clock machinery to maintain robustness and accuracy of circadian timekeeping. Here I review recent progress in our understanding of translation control mechanisms in the circadian clock, focusing on a role for the mammalian/mechanistic target of rapamycin (mTOR) signaling pathway in modulating entrainment, synchronization and autonomous oscillation of circadian clocks. I also discuss the relevance of circadian mTOR functions in disease. PMID- 30250484 TI - Comparison of Preoperative Assessment of Patient's Metabolic Equivalents (METs) Estimated from History versus Measured by Exercise Cardiac Stress Testing. AB - Background: Preoperative anesthetic evaluations of patients before surgery traditionally involves assessment of a patient's functional capacity to estimate perioperative risk of cardiovascular complications and need for further workup. This is typically done by inquiring about the patient's physical activity, with the goal of providing an estimate of the metabolic equivalents (METs) that the patient can perform without signs of myocardial ischemia or cardiac failure. We sought to compare estimates of patients' METs between preoperative assessment by medical history with quantified assessment of METs via the exercise cardiac stress test. Methods: A single-center retrospective chart review from 12/1/2005 to 5/31/2015 was performed on 492 patients who had preoperative evaluations with a cardiac stress test ordered by a perioperative anesthesiologist. Of those, a total of 170 charts were identified as having a preoperative evaluation note and an exercise cardiac stress test. The METs of the patient estimated by history and the METs quantified by the exercise cardiac stress test were compared using a Bland-Altman plot and Cohen's kappa. Results: Exercise cardiac stress test quantified METs were on average 3.3 METS higher than the METs estimated by the preoperative evaluation history. Only 9% of patients had lower METs quantified by the cardiac stress test than by history. Conclusions: The METs of a patient estimated by preoperative history often underestimates the METs measured by exercise stress testing. This demonstrates that the preoperative assessments of patients' METs are often conservative which errs on the side of patient safety as it lowers the threshold for deciding to order further cardiac stress testing for screening for ischemia or cardiac failure. PMID- 30250483 TI - On the Evolution and Function of Plasmodium vivax Reticulocyte Binding Surface Antigen (pvrbsa). AB - The RBSA protein is encoded by a gene described in Plasmodium species having tropism for reticulocytes. Since this protein is antigenic in natural infections and can bind to target cells, it has been proposed as a potential candidate for an anti-Plasmodium vivax vaccine. However, genetic diversity (a challenge which must be overcome for ensuring fully effective vaccine design) has not been described at this locus. Likewise, the minimum regions mediating specific parasite-host interaction have not been determined. This is why the rbsa gene's evolutionary history is being here described, as well as the P. vivax rbsa (pvrbsa) genetic diversity and the specific regions mediating parasite adhesion to reticulocytes. Unlike what has previously been reported, rbsa was also present in several parasite species belonging to the monkey-malaria clade; paralogs were also found in Plasmodium parasites invading reticulocytes. The pvrbsa locus had less diversity than other merozoite surface proteins where natural selection and recombination were the main evolutionary forces involved in causing the observed polymorphism. The N-terminal end (PvRBSA-A) was conserved and under functional constraint; consequently, it was expressed as recombinant protein for binding assays. This protein fragment bound to reticulocytes whilst the C-terminus, included in recombinant PvRBSA-B (which was not under functional constraint), did not. Interestingly, two PvRBSA-A-derived peptides were able to inhibit protein binding to reticulocytes. Specific conserved and functionally important peptides within PvRBSA-A could thus be considered when designing a fully-effective vaccine against P. vivax. PMID- 30250485 TI - Thyroid Function in Korean Adolescents with Obesity: Results from the Korea National Health and Nutrition Examination Survey VI (2013-2015). AB - Purpose: In this study, we investigated the status of thyroid function and its association with metabolic risk factors in Korean adolescents. Methods: Among 2679 subjects aged 10-19 years who participated in the Korea National Health and Nutrition Examination Survey VI (2013-2015), 1067 adolescents (M = 559, F = 508) with available data on free T4 (FT4) and thyroid-stimulating hormone (TSH) were included. Study participants were classified into normal weight [body mass index (BMI) below 85th percentile, 80.7%], overweight (85th <= BMI< 95th percentile, 8.7%), and obesity (BMI >= 95th percentile, 10.6%). Results: With increasing levels of BMI category, the means of TSH increased (2.73 +/- 0.06, 2.77 +/- 0.02, and 3.24 +/- 0.22 mIU/L, P = 0.031) and FT4 decreased (1.30 +/- 0.01, 1.26 +/- 0.02, and 1.25 +/- 0.02 ng/mL, P = 0.001). Positive linear associations were observed between TSH and BMI z-score (P = 0.031), waist circumference (P = 0.013), waist-height ratio (P = 0.002), systolic blood pressure (P = 0.001), total cholesterol (P = 0.008), and triglyceride (P = 0.002) after adjusting for age and sex. With per-unit increase in TSH, the odds ratios of having abdominal obesity (OR = 1.18, 95% CI, 1.01-1.38) and triglyceride >= 150 mg/dL (OR = 1.18, 95% CI, 1.04-1.34) were significantly increased after adjusting for age, sex, and BMI. Conclusions: In adolescents with obesity, TSH was higher and FT4 was lower than in adolescents with normal weight. Hyperthyrotropinemia was associated with abnormal metabolic risk factors including abdominal obesity and elevated triglyceride. PMID- 30250486 TI - Nano-TiO2 Doped Chitosan Scaffold for the Bone Tissue Engineering Applications. AB - The present focus is on the synthesis of highly effective, porous, biocompatible, and inert scaffold by using ceramic nanoparticles and natural polymer for the application in tissue engineering. Freeze-drying method was used to fabricate nano-TiO2 doped chitosan sample scaffold. Nano-TiO2/chitosan scaffold can considered as an effective solution for damaged tissue regeneration. The interaction between chitosan (polysaccharide) and nano-TiO2 makes it highly porous and brittle that could be an effective substitute for bone tissue engineering. The TiO2 nanoparticles have a great surface area and inert properties while chitosan is highly biocompatible and antibacterial. The physiochemical properties of TiO2 nanoparticles and scaffold are evaluated by XRD and FTIR. The nanoparticles doped scaffold has given improved density (1.2870g/cm3) that is comparatively relevant to the dry bone (0.8 - 1.2 gm/cm3). The open and closed porosity of sample scaffold were measured by using Brunauer Emmett-Teller analyzer (BET) and scanning electron microscopy (SEM). The mechanical properties are examined by stable microsystem (Texture Analyzer). The in vitro degradation of scaffold is calculated in PBS containing lysozyme at pH 7.4. Electron and fluorescence microscopy are used to study morphological characteristics of the scaffolds and TiO2 nanoparticles. The growth factor and drug-loaded composites can improve osteogenesis and vascularization. PMID- 30250487 TI - Treatment Outcomes of Patients with Squamous Cell Carcinoma of the Vulva: The Largest Series from a Tertiary Care Hospital. AB - Objective: To evaluate the outcomes of squamous cell carcinoma (SCCA) of the vulva treated at our tertiary care center. Methods: The medical records of SCCA patients treated between January 2006 and December 2015 were retrospectively reviewed. Results: One hundred forty-five patients met the criteria with the median age of 57 years old, and 58.6% had an underlying disease. The distribution of stages was as follows: IA 6.2%, IB 21.4%, II 26.2%, IIIA 14.5%, IIIB 6.2%, IIIC 9.7%, IVA 9.0%, and IVB 6.9%. One hundred and nine patients underwent surgical intervention and radical local excision with bilateral groin node dissection as the most frequent procedure. Approximately half of the patients received combined treatment with surgery followed by radiation with or without chemotherapy. Recurrence developed in 127 patients after the median follow-up time of one year with the common sites in the groin and vulva region. However, no significant difference in survival occurred in patients with and without groin node recurrence (15 vs. 28 months, P=0.109). The five-year overall survival was 50.8%. Conclusions: The survival of patients with SCCA vulvar cancer was modest. The common failure sites were groin and vulva regions with unfavorable outcomes. PMID- 30250488 TI - Characterization of Human Mesenchymal Stem Cells Isolated from the Testis. AB - Mesenchymal stem cells hold great promise for regenerative medicine as they can be easily isolated from different sources such as adipose tissue, bone marrow, and umbilical cord blood. Spontaneously arising pluripotent stem cells can be obtained in culture from murine spermatogonial stem cells (SSCs), while the pluripotency of the human counterpart remains a matter of debate. Recent gene expression profiling studies have demonstrated that embryonic stem cell- (ESC-) like cells obtained from the human testis are indeed closer to mesenchymal stem cells (MSCs) than to pluripotent stem cells. Here, we confirm that colonies derived from human testicular cultures, with our isolation protocol, are of mesenchymal origin and do not arise from spermatogonial stem cells (SSCs). The testis, thus, provides an important and accessible source of MSCs (tMSCs) that can be potentially used for nephrotoxicity testing in vitro. We further demonstrate, for the first time, that tMSCs are able to secrete microvesicles that could possibly be applied to the treatment of various chronic diseases, such as those affecting the kidney. PMID- 30250489 TI - Editorial focus: entering into the non-coding RNA era. AB - Recent developments in high-throughput genotyping technologies have revealed the existence of several new classes of RNA that do not encode proteins but serve other cellular roles. To date, these non-coding RNAs (ncRNAs) have been shown to modulate both gene expression and genome remodeling, thus contributing to the control of both normal and disease-related cellular processes. The attraction of this research topic can be seen in the increasing number of submissions on ncRNAs to molecular biology journals, including Cellular Molecular Biology Letters (CMBL). As researchers attempt to deepen the understanding of the role of ncRNAs in cell biology, it is worth discussing the broader importance of this research. PMID- 30250490 TI - R-Limonene Enhances Differentiation and 2-Deoxy-D-Glucose Uptake in 3T3-L1 Preadipocytes by Activating the Akt Signaling Pathway. AB - Adipocyte is an important place for lipid storage. Defects in lipid storage in adipocytes can lead to lipodystrophy and lipid accumulation in muscle, liver, and other organs. It is the condition of mixed dyslipidemia which may favor the development of insulin resistance via lipotoxic mechanisms. Our objective of the study was to investigate the potential role of R-limonene (LM) on differentiation, lipid storage, and 2-deoxy-D-glucose (2DG) uptake in 3T3-L1 preadipocytes. Genes and proteins associated with differentiation, lipid accumulation, 2DG uptake and its signaling pathways in the adipocytes were analyzed using qPCR and western blot methods. LM treatment increased differentiation, lipid accumulation, and the expression of adipogenic and lipogenic markers such as C/EBP-alpha, C/EBP-beta, PPARgamma, SREBP-1, RXR, FAS, and adiponectin. However, the LM concentration at 10MUM decreased (p < 0.05) adipogenesis and lipogenesis via regulating key transcriptional factors. LM treatment increased activation of Akt by increasing its phosphorylation, but p44/42 activation was not altered. MK-2206, an Akt specific inhibitor, reduced the activation of Akt phosphorylation whereas LM treatment aborted the MK-2206 mediated inhibition of Akt activation. LM enhanced glucose uptake in differentiated adipocytes. Overall data suggested that LM treatment favored lipid storage and glucose uptake in adipocytes via activation of key transcriptional factors through activation of Akt phosphorylation in 3T3-L1 adipocytes. PMID- 30250491 TI - Aging and sex affect soluble alpha klotho levels in bonobos and chimpanzees. AB - Background: Throughout life, physiological homeostasis is challenged and the capacity to cope with such challenges declines with increasing age. In many species, sex differences exist in life expectancy. Sex-specific differences have been related to extrinsic factors like mate competition and/or intrinsic proximate mechanisms such as hormonal changes. In humans, an intrinsic factor related to aging is soluble alpha klotho (alpha-Kl). Both sexes show an age related decline in alpha-Kl, but throughout life women have higher levels than men of the same age. Sex differences in alpha-Kl have been linked to a shorter lifespan, as well as to specific morbidity factors such as atherosclerosis and arteries calcifications. In non-human animals, information on alpha-Kl levels is rare and restricted to experimental work. Our cross-sectional study is the first on alpha-Kl levels in two long-lived species: bonobos (Pan paniscus) and chimpanzees (Pan troglodytes). As in most mammals, female bonobos and chimpanzees have longer life expectancy than males. Methods: We measured serum alpha-Kl levels of 140 subjects from 16 zoos with an ELISA to examine if alpha-Kl levels reflect this difference in life expectancy. Results: In both species and in both sexes, alpha-Kl levels declined with age suggesting that this marker has potential for aging studies beyond humans. We also found species-specific differences. Adult female bonobos had higher alpha-Kl levels than males, a difference that corresponds to the pattern found in humans. In chimpanzees, we found the opposite: males had higher alpha-Kl levels than females. Conclusion: We suggest that contrasting sex differences in adult alpha-Kl levels mirror the dominance relations between females and males of the two Pan species; and that this might be related to corresponding sex differences in their exposure to stress. In humans, higher cortisol levels were found to be related to lower alpha Kl levels. We conclude that there is great potential for studying aging processes in hominoids, and perhaps also in other non-human primates, by measuring alpha-Kl levels. To better understand the causes for sex differences in this aging marker, consideration of behavioural parameters such as competition and stress exposure will be required as well as other physiological markers. PMID- 30250492 TI - Psychometric properties of the Chinese version of the empathy quotient among Chinese minority college students. AB - Background: When the minority college students from the ethnic minority communities come to study in Chinese Han region, they encounter adapting difficulties of culture and socio-psychology, in which empathy plays a crucial role. Current instruments used to measure empathy have many limited effectiveness. The empathy quotient (EQ) scale which has been validated in many countries was explicitly designed for clinical applications and was intended to be sensitive to a lack of empathy. This study is to develop a complete Chinese version of the EQ scale and to assess its reliability and validity among Chinese minority college students in the Han Chinese region. Methods: A total of 1638 Chinese minority college students in the Han region were selected and were randomly divided into two groups. One group of 818 students took part in the implementation of the exploratory factor analysis while the other group of 820 students participated in the confirmatory factor analysis. Results: Twenty-nine items of the EQ were retained based on the factor analysis and four factors were extracted: self-awareness, cognitive empathy, social skills, and emotional reactivity, which can explain 51.793% of the total variance. The factors of the EQ scale were significantly correlated with each other, with the correlation coefficient ranging from 0.316 to 0.563. The coefficient of internal consistency (Cronbach's alpha) was 0.824 for the total scale and ranged from 0.640 to 0.818 for the subscales. Confirmatory factor analysis proved that the measured data fitted well with the hypothesized four-factor model. All of the items in the scale fitted the model well, and the point-measure correlation coefficient had acceptable consistency. Conclusions: The refined 29-item Chinese version of the EQ possesses good reliability and validity, and can be applied in assessing empathy among Chinese minority college students. PMID- 30250493 TI - A method for real-time classification of insect vectors of mosaic and brown streak disease in cassava plants for future implementation within a low-cost, handheld, in-field multispectral imaging sensor. AB - Background: The paper introduces a multispectral imaging system and data processing approach for the identification and discrimination of morphologically indistinguishable cryptic species of the destructive crop pest, the whitefly Bemisia tabaci. This investigation and the corresponding system design, was undertaken in two phases under controlled laboratory conditions. The first exploited a prototype benchtop variant of the proposed sensor system to analyse four cryptic species of whitefly reared under similar conditions. The second phase, of the methodology development, employed a commercial high-precision laboratory hyperspectral imager to recover reference data from five cryptic species of whitefly, immobilized through flash freezing, and taken from across four feeding environments. Results: The initial results, for the single feeding environment, showed that a correct species classification could be achieved in 85 95% of cases, utilising linear Partial Least Squares approaches. The robustness of the classification approach was then extended both in terms of the automated spatial extraction of the most pertinent insect body parts, to assist with the spectral classification model, as well as the incorporation of a non-linear Support Vector Classifier to maintain the overall classification accuracy at 88 98%, irrespective of the feeding and crop environment. Conclusion: This study demonstrates that through an integration of both the spatial data, associated with the multispectral images being used to separate different regions of the insect, and subsequent spectral analysis of those sub-regions, that B. tabaci viral vectors can be differentiated from other cryptic species, that appear morphologically indistinguishable to a human observer, with an accuracy of up to 98%. The implications for the engineering design for an in-field, handheld, sensor system is discussed with respect to the learning gained from this initial stage of the methodology development. PMID- 30250496 TI - DINOSARC: Color Features Based on Selective Aggregation of Chromatic Image Components for Wireless Capsule Endoscopy. AB - Wireless Capsule Endoscopy (WCE) is a noninvasive diagnostic technique enabling the inspection of the whole gastrointestinal (GI) tract by capturing and wirelessly transmitting thousands of color images. Proprietary software "stitches" the images into videos for examination by accredited readers. However, the videos produced are of large length and consequently the reading task becomes harder and more prone to human errors. Automating the WCE reading process could contribute in both the reduction of the examination time and the improvement of its diagnostic accuracy. In this paper, we present a novel feature extraction methodology for automated WCE image analysis. It aims at discriminating various kinds of abnormalities from the normal contents of WCE images, in a machine learning-based classification framework. The extraction of the proposed features involves an unsupervised color-based saliency detection scheme which, unlike current approaches, combines both point and region-level saliency information and the estimation of local and global image color descriptors. The salient point detection process involves estimation of DIstaNces On Selective Aggregation of chRomatic image Components (DINOSARC). The descriptors are extracted from superpixels by coevaluating both point and region-level information. The main conclusions of the experiments performed on a publicly available dataset of WCE images are (a) the proposed salient point detection scheme results in significantly less and more relevant salient points; (b) the proposed descriptors are more discriminative than relevant state-of-the-art descriptors, promising a wider adoption of the proposed approach for computer-aided diagnosis in WCE. PMID- 30250495 TI - Colloidal aggregation: from screening nuisance to formulation nuance. AB - It is well known that small molecule colloidal aggregation is a leading cause of false positives in early drug discovery. Colloid-formers are diverse and well represented among corporate and academic screening decks, and even among approved drugs. Less appreciated is how colloid formation by drug-like compounds fits into the wider understanding of colloid physical chemistry. Here we introduce the impact that colloidal aggregation has had on early drug discovery, and then turn to the physical and thermodynamic driving forces for small molecule colloidal aggregation, including the particulate nature of the colloids, their critical aggregation concentration-governed formation, their mechanism of protein adsorption and subsequent inhibition, and their sensitivity to detergent. We describe methods that have been used extensively to both identify aggregate formers and to study and control their physical chemistry. While colloidal aggregation is widely recognized as a problem in early drug discovery, we highlight the opportunities for exploiting this phenomenon in biological milieus and for drug formulation. PMID- 30250497 TI - Reduced Urban Heat Island intensity under warmer conditions. AB - The Urban Heat Island (UHI), the tendency for urban areas to be hotter than rural regions, represents a significant health concern in summer as urban populations are exposed to elevated temperatures. A number of studies suggest that the UHI increases during warmer conditions, however there has been no investigation of this for a large ensemble of cities. Here we compare urban and rural temperatures in 54 US cities for 2000-2015 and show that the intensity of the urban heat island, measured here as the differences in daily-minimum or daily-maximum temperatures between urban and rural stations or DeltaT, in fact tends to decrease with increasing temperature in most cities (38/54). This holds when investigating daily variability, heat extremes, and variability across climate zones and is primarily driven by changes in rural areas. We relate this change to large-scale or synoptic weather conditions, and find that the lowest DeltaT nights occur during moist weather conditions. We also find that warming cities have not experienced an increasing urban heat island effect. PMID- 30250494 TI - The functional diversity of Aurora kinases: a comprehensive review. AB - Aurora kinases are serine/threonine kinases essential for the onset and progression of mitosis. Aurora members share a similar protein structure and kinase activity, but exhibit distinct cellular and subcellular localization. AurA favors the G2/M transition by promoting centrosome maturation and mitotic spindle assembly. AurB and AurC are chromosome-passenger complex proteins, crucial for chromosome binding to kinetochores and segregation of chromosomes. Cellular distribution of AurB is ubiquitous, while AurC expression is mainly restricted to meiotically-active germ cells. In human tumors, all Aurora kinase members play oncogenic roles related to their mitotic activity and promote cancer cell survival and proliferation. Furthermore, AurA plays tumor-promoting roles unrelated to mitosis, including tumor stemness, epithelial-to-mesenchymal transition and invasion. In this review, we aim to understand the functional interplay of Aurora kinases in various types of human cells, including tumor cells. The understanding of the functional diversity of Aurora kinases could help to evaluate their relevance as potential therapeutic targets in cancer. PMID- 30250498 TI - Posterior Tibial Neuropathy Secondary to Pseudoaneurysm of the Proximal Segment of the Anterior Tibial Artery with Delayed Onset. AB - Anterior tibial artery is a nonvital artery which is one of the three arteries of the leg. This artery has a short proximal l segment in the popliteal region and a long segment in the anterior compartment of the leg designated as distal segment. With consideration of the deep location of the proximal segment in the popliteal fossa, it is less susceptible to trauma and subsequent formation of an aneurysm. On the contrary, the superficial long distal segment is more susceptible to trauma with high chance of pseudoaneurysm formation at the site of unrecognized injury. In this article, a 38-year-old military man being manifested about a decade after a trivial missile fragment injury with progressive posterior tibial neuropathy is presented. A giant pseudoaneurysm arising from the proximal segment of the anterior tibial artery was confirmed with angiography and the exact size of this pathology was documented with contrasted computed tomographic scan. The aneurysmal sac removal was accomplished after ligation of the corresponding artery proximal and distal to the sac followed by tibial nerve neurolysis which result in full recovery. In careful review we found that neither pseudoaneurysm arising from the proximal tibial artery nor posterior tibial neuropathy due to the compressive effect of the aneurysmal sac of this segment has been reported previously. Our primary purpose for reporting this case is not to describe the rarity of pseudoaneurysm formation at proximal segment of this artery but rather to describe delayed-onset posterior tibial vascular compressive neuropathy due to such an aneurysm. Eventually due to the potential sequel of a pseudoaneurysm, it is important for the surgeons to have high index of suspicion to prevent a missed or delayed diagnosis. PMID- 30250500 TI - Mental health and psychosocial problems among conflict-affected children in Kachin State, Myanmar: a qualitative study. AB - Background: In Kachin State, Myanmar, collapse of a ceasefire in 2011 has resulted in widespread exposure to conflict and ongoing internal displacement. Such exposures are known risk factors for mental health and psychosocial (MHPS) problems, yet mental health services for children and youth are typically scarce in such circumstances. Following evaluation of a mental health treatment for adult trauma survivors on the Thailand-Myanmar border, our study team received requests to support the development of a similar intervention for displaced children in Kachin State. To inform this work, we conducted a brief qualitative needs assessment to explore priority MHPS problems among this population. Methods: Data were collected in internally displaced persons camps in Kachin State during July and August, 2016. Free list interviews with a convenience sample of 28 adolescents and 12 adults produced a list of problems affecting children and adolescents in this area. Four problems were further explored in key informant interviews with a convenience sample of 26 adolescents and 4 adults. Data analysis was conducted by the local interview team. Results: Priority problems included: behavior problems, substance use, effects of war, and feeling sad/depressed/hopeless. Descriptions emphasized the interconnectedness between the problems. Overall, most problems were related to specific events that suggest that the symptoms themselves are responses to unusual situations; however, the problems were also linked to current psychosocial stressors such as poverty, poor nutrition, and discrimination. Effects of war were described primarily as a constellation of social and economic problems rather than a list of mental health symptoms, although descriptions of these problems did include post-traumatic stress symptoms. Conclusions: Findings fit well within explanatory models of distress that include both direct trauma exposure and exacerbation of daily stressors. Results of this study have been used to inform intervention adaptation and evaluation, but also contribute to the literature on the needs of young people in situations of protracted conflict. PMID- 30250499 TI - Traditional medicinal plants used for respiratory disorders in Pakistan: a review of the ethno-medicinal and pharmacological evidence. AB - Respiratory disorders are a common cause of malady and demise in Pakistan due to its remoteness, cold and harsh climatic conditions as well as scarce health care facilities. The people rely upon the indigenous plant resources to cure various respiratory disorders. The primary objective of this review was to assemble all available ethno-medicinal data of plants used for respiratory disorders in Pakistan. Pharmacological activity of these plants (based upon published scientific research), distribution, diversity, use, preparation methods, economical value, conservation status and various available herbal products of some plants have also been explored. This study scrutinized various electronic databases for the literature on medicinal plants used in Pakistan to treat respiratory disorders. A total of 384 species belonging to 85 families used to treat respiratory disorders in Pakistan has been documented. Cough was the disorder treated by the highest number of species (214) followed by asthma (150), cold (57) and bronchitis (56). Most of the plants belongs to Asteraceae (32) and Solanaceae family (32) followed by moraceae (17), Poaceae (13), and Amaranthaceae (13) with their habit mostly of herb (219) followed by Shrub (112) and tree (69). Traditional healers in the region mostly prepare ethno medicinal recipes from leaves (24%) and roots (11%) in the form of decoction. Among the reported conservation status of 51 plant species, 5 were endangered, 1 critically endangered, 11 vulnerable, 14 rare, 16 least concern, 3 infrequent and 1 near threatened. We found only 53 plants on which pharmacological studies were conducted and 17 plants being used in herbal products available commercially for respiratory disorders. We showed the diversity and importance of medicinal plants used to treat respiratory disorders in the traditional health care system of Pakistan. As such disorders are still causing several deaths each year, it is of the utmost importance to conduct phytochemical and pharmacological studies on the most promising species. It is also crucial to increase access to traditional medicine, especially in rural areas. Threatened species need special attention for traditional herbal medicine to be exploited sustainably. PMID- 30250501 TI - Prevalence and correlates of post-traumatic stress disorder among survivors of road traffic accidents in Ethiopia. AB - Background: Post-traumatic stress disorder is the most common mental disorders occurring among survivors of road traffic accident. However, research into post traumatic stress disorder and correlates in low and middle-income countries is limited. To the best of our knowledge, there is no published study of the post traumatic stress disorder and associated factors conducted in Ethiopia. Therefore, this study aimed to determine the prevalence of post-traumatic stress disorder and associated factors among survivors of road traffic accident. Methods: Institution based cross-sectional study was conducted in May 2016. Data were collected using a pretested, structured, standardized post-traumatic stress disorder Checklist-Specific version (PCL-S) questionnaire. Systematic sampling technique was used to select the study participants. Binary logistic regression analysis was used to identify associated factors. Odds ratio with 95% CI was computed to assess the strength of associations. Results: The prevalence of post traumatic stress disorder was found to be 22.8% (CI 19.2, 26.6) among survivors of road traffic accident. In the multivariable analysis, Being female [AOR = 2.23, 95% CI 1.40, 3.56], having poor social support [AOR = 2.1, 95% CI 1.34, 3.46], duration since accident (1-3 months) [AOR = 1.72, 95% CI 1.07, 2.76] and having depression [AOR = 3.46, 95% CI 1.99, 5.99] were significantly associated with PTSD among survivors of road traffic accident. Conclusion: In the current study the magnitude of post-traumatic stress disorder was high. Being female, poor social support, duration since the accident (1-3 months) and depression were found to be significant predictors of post-traumatic stress disorders. The finding suggests a need for early screening for post-traumatic disorder among survivors of road traffic accidents. PMID- 30250502 TI - Mechanical Design and Assessment of a Low-Cost 7-DOF Prosthetic Arm for Shoulder Disarticulation. AB - This work presents the design of a low-cost prosthetic device for shoulder disarticulation. A proper design of the mechanisms has been addressed to obtain a prototype that presents 7 degrees of freedom. Shoulder movement is achieved by means of a spherical parallel manipulator, elbow movement is performed by a six bar mechanism, and the wrist movement is implemented by a spherical parallel manipulator. A set of dynamic simulations was performed in order to assess the functionality of the design. The prototype was built using 3D printing techniques and implementing low-cost actuators. An experimental evaluation was carried out to characterize this device. The result of this work is a prototype that weighs 1350 g that is able to perform movements related to activities of daily living. PMID- 30250503 TI - A Study on Influence of Minivan Front-End Design and Impact Velocity on Pedestrian Thorax Kinematics and Injury Risk. AB - Thoracic injuries occur frequently in minivan-to-pedestrian impact accidents and can cause substantial fatalities. The present research work investigates the human thoracic responses and injury risks in minivan-to-pedestrian impacts, when changing the minivan front-end design and the impact velocity, by using computational biomechanics model. We employed three typical types of minivan model of different front-end designs that are quite popular in Chinese market and considered four impact velocities (20, 30, 40, and 50 km/h). The contact time of car to thorax region (CTCTR), thorax impact velocity, chest deformation, and thoracic injury risks were extracted for the investigation. The results indicate that the predicted pedestrian kinematics, injury responses, and thoracic injury risks are strongly affected by the variation of the minivan front-end design and impact velocity. The pedestrian thoracic injury risks increase with the increasing vehicle impact velocity. It is also revealed that the application of the extra front bumper is beneficial for reducing the thoracic injury risk, and a relatively flatter minivan front-end design gives rise to a higher thoracic injury risk. This study is expected to be served as theoretical references for pedestrian protection design of minivans. PMID- 30250504 TI - Exploitation of novel wild type solventogenic strains for butanol production. AB - Butanol has been regarded as an important bulk chemical and advanced biofuel; however, large scaling butanol production by solventogenic Clostridium sp. is still not economically feasible due to the high cost of substrates, low butanol titer and yield caused by the toxicity of butanol and formation of by-products. Renewed interests in biobutanol as biofuel and rapid development in genetic tools have spurred technological advances to strain modifications. Comprehensive reviews regarding these aspects have been reported elsewhere in detail. Meanwhile, more wild type butanol producers with unique properties were also isolated and characterized. However, few reviews addressed these discoveries of novel wild type solventogenic Clostridium sp. strains. Accordingly, this review aims to comprehensively summarize the most recent advances on wild type butanol producers in terms of fermentation patterns, substrate utilization et al. Future perspectives using these native ones as chassis for genetic modification were also discussed. PMID- 30250505 TI - A dynamic model of lignin biosynthesis in Brachypodium distachyon. AB - Background: Lignin is a crucial molecule for terrestrial plants, as it offers structural support and permits the transport of water over long distances. The hardness of lignin reduces plant digestibility by cattle and sheep; it also makes inedible plant materials recalcitrant toward the enzymatic fermentation of cellulose, which is a potentially valuable substrate for sustainable biofuels. Targeted attempts to change the amount or composition of lignin in relevant plant species have been hampered by the fact that the lignin biosynthetic pathway is difficult to understand, because it uses several enzymes for the same substrates, is regulated in an ill-characterized manner, may operate in different locations within cells, and contains metabolic channels, which the plant may use to funnel initial substrates into specific monolignols. Results: We propose a dynamic mathematical model that integrates various datasets and other information regarding the lignin pathway in Brachypodium distachyon and permits explanations for some counterintuitive observations. The model predicts the lignin composition and label distribution in a BdPTAL knockdown strain, with results that are quite similar to experimental data. Conclusion: Given the present scarcity of available data, the model resulting from our analysis is presumably not final. However, it offers proof of concept for how one may design integrative pathway models of this type, which are necessary tools for predicting the consequences of genomic or other alterations toward plants with lignin features that are more desirable than in their wild-type counterparts. PMID- 30250506 TI - Correction to: High-value biomass from microalgae production platforms: strategies and progress based on carbon metabolism and energy conversion. AB - [This corrects the article DOI: 10.1186/s13068-018-1225-6.]. PMID- 30250507 TI - Genetic repertoires of anaerobic microbiomes driving generation of biogas. AB - Background: Biogas production is an attractive technology for a sustainable generation of renewable energy. Although the microbial community is fundamental for such production, the process control is still limited to technological and chemical parameters. Currently, most of the efforts on microbial management system (MiMaS) are focused on process-specific marker species and community dynamics, but a practical implementation is in its infancy. The high number of unknown and uncharacterized microorganisms in general is one of the reasons hindering further advancements. Results: A Biogas Metagenomics Hybrid Assembly (BioMETHA) database, derived from microbiomes of biogas plants, was generated using a dedicated assembly strategy for different metagenomic datasets. Long reads from nanopore sequencing (MinION) were combined with short, more accurate second-generation sequencing reads (Illumina). The hybrid assembly resulted in 231 genomic bins each representing a taxonomic unit with an average completeness of 47%. Functional annotation identified 13,190 non-redundant genes covering roughly 207 k coding sequences. Mapping rates of metagenomics DNA derived from diverse biogas plants and laboratory reactors increased up to 73%. In addition, an EC (enzyme commission) reference sequence collection (ERSC) was generated whose genes are crucial for biogas-related processes, consisting of 235 unique EC numbers organized in 52 metabolic modules. Mapping rates of metatranscriptomic data to this ERSC revealed coverages of up to 93%. Process parameters and imbalances of laboratory reactors could be reconstructed by evaluating abundance of biogas-specific metabolic modules using metatranscriptomic data derived from various fermenter systems. Conclusion: This newly established metagenomic hybrid assembly in combination with an EC reference sequence collection might help to shed light on the microbial dark matter of biogas plants by contributing to the development of a reference for biogas plant microbiome-specific gene sequences. Considering a biogas microbiome as a complex meta-organism expressing a meta transcriptome, the approach established here could lay the foundation for a function-based microbial management system. PMID- 30250508 TI - Biorefining of protein waste for production of sustainable fuels and chemicals. AB - To mitigate the climate change caused by CO2 emission, the global incentive to the low-carbon alternatives as replacement of fossil fuel-derived products continuously expands the need for renewable feedstock. There will be accompanied by the generation of enormous protein waste as a result. The economical viability of the biorefinery platform can be realized once the surplus protein waste is recycled in a circular economy scenario. In this context, the present review focuses on the current development of biotechnology with the emphasis on biotransformation and metabolic engineering to refine protein-derived amino acids for production of fuels and chemicals. Its scope starts with the explosion of potential feedstock sources rich in protein waste. The availability of techniques is applied for purification and hydrolysis of various feedstock proteins to amino acids. Useful lessons are leaned from the microbial catabolism of amino acids and lay a foundation for the development of the protein-based biotechnology. At last, the future perspective of the biorefinery scheme based on protein waste is discussed associated with remarks on possible solutions to overcome the technical bottlenecks. PMID- 30250510 TI - Intraoperative angioedema induced by angiotensin II receptor blocker: a case report. AB - Background: Angiotensin II receptor blockers are a class of antihypertensive agent that is developed to exclude the adverse effects of angiotensin converting enzyme inhibitors. However, as angiotensin II receptor blockers have begun to be more widely prescribed, cases of angiotensin II receptor blocker-induced angioedema have been reported. Rare cases of angioedema following surgery in patients using angiotensin converting enzyme inhibitors have been published. Case presentation: A 38-year-old man with past history of hypertension was admitted for an elective lumbosacral spine surgery. He had been taking Valsartan 160 mg a day for the past 4 years.At the end of the surgical procedure and turning the patient into supine position, we noticed severe swelling in the neck and the face with.an edematous tongue, floor of the mouth, glottis, and supraglottic areas. A diagnosis of drug induced angioedema was made and intravenous dexamethasone, diphenhydramine and ranitidine were given. The patient remained intubated and was transferred to the intensive care unit. The valsartan was suspected to be the precipitating factor for the angioedema and was therefore discontinued.The swelling started to regress after 2 h, and resolved completely by the third day. Conclusion: The precise mechanism of angiotensin II receptor blocker-induced angioedema is still unknown and should be thoroughly investigated. This report demonstrates a unique case of intraoperative angiotensin II receptor blocker induced angioedema. Potential differential diagnoses of postoperative facial edema are discussed in detail, including the prolonged prone positioning for posterior spine surgery. Anesthesiologists should be aware of such rare, but potentially dangerous, perioperative adverse reaction that can occur with angiotensin II receptor blockers use. PMID- 30250509 TI - Stacking of a low-lignin trait with an increased guaiacyl and 5-hydroxyguaiacyl unit trait leads to additive and synergistic effects on saccharification efficiency in Arabidopsis thaliana. AB - Background: Lignocellulosic biomass, such as wood and straw, is an interesting feedstock for the production of fermentable sugars. However, mainly due to the presence of lignin, this type of biomass is recalcitrant to saccharification. In Arabidopsis, lignocellulosic biomass with a lower lignin content or with lignin with an increased fraction of guaiacyl (G) and 5-hydroxyguaiacyl (5H) units shows an increased saccharification efficiency. Here, we stacked these two traits and studied the effect on the saccharification efficiency and biomass yield, by combining either transaldolase (tra2), cinnamate 4-hydroxylase (c4h-3), or 4 coumarate:CoA ligase (4cl1-1) with caffeic acid O-methyltransferase (comt-1 or comt-4) mutants. Results: The three double mutants (tra2 comt-1, c4h-3 comt-4, and 4cl1-1 comt-4) had a decreased lignin amount and an increase in G and 5H units in the lignin polymer compared to wild-type (WT) plants. The tra2 comt-1 double mutant had a better saccharification efficiency compared to the parental lines when an acid or alkaline pretreatment was used. For the double mutants, c4h 3 comt-4 and 4cl1-1 comt-4, the saccharification efficiency was significantly higher compared to WT and its parental lines, independent of the pretreatment used. When no pretreatment was used, the saccharification efficiency increased even synergistically for these mutants. Conclusion: Our results show that saccharification efficiency can be improved by combining two different mutant lignin traits, leading to plants with an even higher saccharification efficiency, without having a yield reduction of the primary inflorescence stem. This approach can help improve saccharification efficiency in bio-energy crops. PMID- 30250511 TI - 13q mosaic deletion including RB1 associated to mild phenotype and no cancer outcome - case report and review of the literature. AB - Background: The 13q deletion syndrome is a rare chromosome disorder associated with wide phenotypic spectrum, which is related to size and location of the deleted region and includes intellectual disability, growth retardation, craniofacial dysmorphisms, congenital malformations, and increased risk of retinoblastoma. Case presentation: Here, we report on a teenage boy with a mild phenotype characterized by obesity, hyperactivity, dysphagia, dysgraphia, sleep disturbance, and minor dysmorphic features (round face, bushy eyebrows, and stubby hands). Array Comparative Genomic Hybridization on blood identified a mosaic 13q14.13-13q31.1 deletion, with a mosaicism rate around 40%, which was confirmed by quantitative PCR and interphase Fluorescent In Situ Hybridization (iFISH) on both blood genomic DNA and cultured/uncultured blood lymphocytes, respectively. Conversely, karyotype analysis on blood estimated a mosaicism rate of 24% and iFISH on buccal smears revealed a borderline value of 0.4%, suggesting the absence of 13q deletion in this cell line. Conclusions: The comparison with previous patients carrying similar deletions informed that the proband clinical presentation is the mildest reported to date, thus supporting the burden of mosaicism in modulating the phenotype also in case of large chromosomal rearrangements. Characterization of further cases by in-depth mosaicism rate in tissues with different embryonic origins might contribute in the future to a better definition of genotype-phenotype correlation, including tumor risk. PMID- 30250512 TI - Politics of Respectability, Colorism, and the Terms of Social Exchange in Family Research. AB - In this article, we consider the utility of social exchange theory when centering the material and cultural realities of people and families of color. We draw on critical race and intersectionality scholarship to argue that this work challenges some of the core assumptions of social exchange theory (while reifying others) and offers novel avenues of inquiry and expanded foci for family researchers employing a social exchange framework. We illustrate our points by focusing on existing research and offering new empirical evidence on African Americans, yet we note that our revisioning has broader relevance for relationships between and within other groups and positionalities. PMID- 30250513 TI - Genome characterization of bile-isolated Shewanella algae ACCC. AB - Background: Shewanella algae has been recognized as an emerging human pathogen. However, not much is known about the mechanism of its pathogenesis and its adaptation to a special niche such as the hepatobiliary tract. Results: In this study, we isolated the S. algae ACCC strain from human bile and performed whole genome sequencing. S. algae ACCC consists of a circular 4,743,354-bp chromosome with a GC content of 53.08%, within 4080 protein coding sequences. The genome of strain ACCC contains a number of candidate genes which have been reported to be associated with bile adaption, including htpB, exbBD, wecA, galU, adeFGH and phoPQ regulon. Conclusions: Our results highlight the association of S. algae with a rare disease profile. Further studies are needed to shed light on the evolution of pathogenesis and the niche adaptation of S. algae. PMID- 30250514 TI - Antimicrobial resistance in Enterobacteriaceae from healthy broilers in Egypt: emergence of colistin-resistant and extended-spectrum beta-lactamase-producing Escherichia coli. AB - Background: Poultry remains one of the most important reservoir for zoonotic multidrug resistant pathogens. The global rise of antimicrobial resistance in Gram-negative bacteria is of reasonable concern and demands intensified surveillance. Methods: In 2016, 576 cloacal swabs were collected from 48 broiler farms located in five governorates in northern Egypt. Isolates of Enterobacteriaceae could be cultivated on different media and were identified by MALDI-TOF MS and PCR. Escherichia coli isolates were genotyped by DNA-microarray based assays. The antimicrobial susceptibility to 14 antibiotics was determined and resistance-associated genes were detected. The VITEK-2 system was applied for phenotypical confirmation of extended-spectrum beta-lactamase-producing isolates. The determination of colistin resistance was carried out phenotypically using E test and genotypically using PCR for detection of the mcr-1 gene. Results: Out of 576 samples, 72 representatives of Enterobacteriaceae were isolated and identified as 63 E. coli (87.5%), 5 Enterobacter cloacae (6.9%), 2 Klebsiella pneumoniae (2.8%) and 2 Citrobacter spp. (2.8%). Seven out of 56 cultivated E. coli (12.5%) were confirmed as ESBL-producing E. coli and one isolate (1.8%) as ESBL/carbapenemase-producing E. coli. Five out of 63 E. coli isolates (7.9%) recovered from different poultry flocks were phenotypically resistant to colistin and harboured mcr-1 gene. Conclusions: This is the first study reporting colistin resistance and emergence of multidrug resistance in Enterobacteriaceae isolated from healthy broilers in the Nile Delta region, Egypt. Colistin-resistant E. coli in poultry is of public health significance. The global rise of ESBL- and carbapenemase-producing Gram-negative bacteria demands intensified surveillance. ESBL-producing E. coli in poultry farms in Egypt are of major concern that emphasizes the possibility of spread of such strains to humans. The results also reinforce the need to develop strategies and to implement specific control procedures to reduce the use of antibiotics. PMID- 30250515 TI - Fibroblast growth factor receptor 1 antagonism attenuates lipopolysaccharide induced activation of hepatic stellate cells via suppressing inflammation. AB - Activated hepatic stellate cells (HSCs) serve key roles in hepatic fibrosis by producing excessive extracellular matrix (ECM) components. Lipopolysaccharide (LPS) has been found to be associated with hepatic fibrogenesis through direct interactions with HSCs. Recently, the fibroblast growth factor receptor 1 (FGFR1) signalling system was identified as a key player in the process of liver fibrosis. In the present study it was evaluated whether FGFR1 mediated LPS induced HSCs activation. In cultured cells, FGFR1 was inhibited by either siRNA silencing or by a small-molecule inhibitor in LPS-stimulated HSCs. The blockade of FGFR1 decreased LPS-induced nuclear factor-kappaB (NF-kappaB) activation, inflammatory cytokine release, fibrosis, and cell proliferation in HSCs. It was further indicated that LPS triggered FGFR1 phosphorylation via TLR4/c-Src. These findings confirmed the detrimental effect of FGFR1 activation in the pathogenesis of LPS-related HSC activation and revealed that FGFR1 may be an ideal therapeutic target for LPS-induced liver fibrosis. PMID- 30250516 TI - Potential use of compounds from sea cucumbers as MDM2 and CXCR4 inhibitors to control cancer cell growth. AB - Ineffectiveness of cancer therapy may originate in the incompatibility of the treatment with various mutations in the cancer cells. Finding novel anticancer treatments that work efficiently for varying types of cancer cells remains challenging. Previous studies have identified that compounds in sea cucumbers are capable of inhibiting the growth of cancer cells and inducing apoptosis. However, information on the underlying mechanisms controlling cancer cell growth at a molecular level remains limited. The current study analyzed the potential of colochiroside A, ds-echinoside A, philinopside E, sphingosine and stichoposide C as inhibitors for anticancer target proteins, including mouse double minute 2 homolog (MDM2) and C-X-C chemokine receptor type 4 (CXCR4). Inhibition of MDM2 triggers apoptosis through regulation of tumor protein 53 and CXCR4 inhibition may prevent cancer cell proliferation and growth by affecting the Janus kinase 2/3 signal transducer and activator of transcription signaling pathway and protein tyrosine kinase 2. The results of a binding affinity analysis using molecular docking revealed that philinopside E and ds-echinoside A may inhibit MDM2 and CXCR4. The data suggested that these active compounds may be promising inhibitors of cell growth by binding to two targets simultaneously. Furthermore, stichoposide C and colochiroside A were predicted to inhibit CXCR4. Additional research is needed to validate the in vitro activity of the aforementioned compounds. PMID- 30250517 TI - MicroRNA-663b promotes cell proliferation and epithelial mesenchymal transition by directly targeting SMAD7 in nasopharyngeal carcinoma. AB - MicroRNAs (miRs) serve important roles in the development of various types of human cancer, including nasopharyngeal carcinoma (NPC). In the present study, the expression levels of miR-663b in NPC were investigated and its role and underlying mechanisms were examined. Reverse transcription-quantitative polymerase chain reaction was performed to assess miR-663b expression levels in NPC tissues and C666-1 cells. TargetScan was applied to predict the putative targets of miR-663b and the dual luciferase reporter assay was used to confirm the predictions. To investigate the role of miR-663b in NPC, the NPC C666-1 cell line was transfected with miR-663b mimics, miR-663b inhibitors or negative control. The Cell Counting kit-8 assay was performed for cell proliferation detection and western blot analysis was applied to determine the expression levels of epithelial mesenchymal transition (EMT)-associated proteins. Results indicated that when compared with the adjacent normal tissues and the normal nasopharyngeal epithelial cells, miR-663b expression levels were significantly upregulated in the NPC tissues and the NPC cells (P<0.01). Notably, SMAD7 is a target gene of miR-663b and may be inhibited by miR-663b. Results indicated that NPC cell proliferation was significantly promoted by miR-663b mimics and significantly inhibited by miR-663b inhibitors (P<0.05 and P<0.01). In addition, the results indicated that, when compared with the negative control group the expression levels of E-cadherin were significantly decreased, whereas the expression levels of N-cadherin, Vimentin and matrix metalloproteinase-9 were significantly increased in the cells of the miR-663b mimics group (P<0.05 and P<0.01). However, cells in the miR-663b inhibitors group exhibited the opposite effects. In conclusion, the results of the present study indicated that miR-663b functions as a tumor promoter in NPC via promoting NPC cell proliferation and EMT by directly targeting SMAD7. PMID- 30250518 TI - Establishment and characterization of McA-RH7777 cells using virus-mediated stable overexpression of enhanced green fluorescent protein. AB - Hepatocellular carcinoma (HCC), the most common primary tumor of the liver, has a poor prognosis, rapid progression. The aim of the current study was to establish a stable lentiviral expression vector for enhanced green fluorescent protein (EGFP) and to evaluate biological characteristics on HCC growth and migration following transfection of HCC cells with EGFP. McA-RH7777 cells were transfected with EGFP overexpression lentiviral vector. Cell activity and mobility were monitored with a Cell-IQ Analyzer. Transwell assays were performed to detect invasiveness and flow cytometry was performed for cell cycle analysis. A subcutaneous tumor rat model was established to analyze the stability of fluorescent protein expression. The result suggested no significant differences between wild-type and EGFP-overexpressing McA-RH7777 cells with regards to cell proliferation, activity, mobility, invasiveness and cell cycle. Green fluorescence was detected over 108 days of culturing. The subcutaneous tumor rat model demonstrated that EGFP expression had no influence on tumor growth and long term expression was stable. The stable EGFP expression of the HCC transplanted tumor rat model may share biological characteristics with human liver cancer. The model established in the current study may be suitable for various applications, including research focusing on liver cancer metastasis and recurrence, interventional therapy, imaging diagnosis and drug screenings. PMID- 30250519 TI - Echinocandins for Pneumocystis jirovecii pneumonia in non-HIV patients: A case report. AB - For the past two decades, echinocandins have shown prophylactic and therapeutic efficacy in patients with Pneumocystis jirovecii pneumonia (PJP), due to their ability to inhibit the synthesis of beta-1, 3-glucan, a major component of the cell wall of P. jirovecii. The present study reported two cases of human immunodeficiency virus (HIV)-negative patients who received echinocandins as a salvage therapy at Peking Union Medical College Hospital (Beijing, China), both of whom exhibited good responses to treatment. In both cases, polymerase chain reaction of sputum or bronchoalveolar lavage specimens became negative following treatment. The present study also performed a literature search to identify non HIV patients with PJP who previously received echinocandins. The results of the present study suggested that echinocandins maybe promising therapeutic agents in the treatment of non-HIV patients with PJP, particularly in combination with trimethoprim-sulfamethoxazole. Therefore, the results warrant a randomized controlled trial. PMID- 30250521 TI - Sericin enhances the insulin-PI3K/AKT signaling pathway in the liver of a type 2 diabetes rat model. AB - The aim of the current study was to investigate the regulatory effect of sericin on the hepatic insulin-phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in a type 2 diabetes rat model. Male Sprague Dawley rats were randomly divided into four groups: Control group, diabetic model group, high-dose sericin group and low-dose sericin group, with 12 rats in each group. Fasting blood glucose was detected by the glucose oxidase method, and hepatic glycogen was determined by periodic acid-Schiff staining. The morphology of the liver was observed by hematoxylin and eosin staining. Immunohistochemical staining, western blotting and reverse transcription-quantitative polymerase chain reaction were used to determine the protein and mRNA expression levels of insulin receptor (IR), IR substrate-1 (IRS-1), PI3K and AKT. Compared with the control group, the blood glucose of the diabetic model group was significantly increased (P<0.05). The glycogen content and the expression levels of IR, IRS-1, PI3K and AKT in the diabetic model group were significantly lower (P<0.05), and the liver morphological structure of the diabetic model group exhibited obvious pathological changes compared with the control group. Compared with the diabetic model group, the blood glucose of the high- and low-dose sericin groups was significantly reduced, while the glycogen content and the expression levels of IR, IRS-1, PI3K and AKT in the sericin treatment groups were significantly increased (P<0.05). Additionally, the liver pathological changes of high-dose and low-dose sericin groups were markedly reduced. Sericin may enhance the signaling transduction effect of insulin by upregulating the expression levels of key factors (IR, IRS-1, PI3K and AKT) in the liver insulin-PI3K/AKT signaling pathway, thus promoting glucose transport and liver glycogen synthesis, and further reducing blood glucose. PMID- 30250520 TI - Oxidative status of cardinal ligament in pelvic organ prolapse. AB - Pelvic organ prolapse (POP) is a common and distressing health problem in adult women, but the pathophysiological mechanism is yet to be fully elucidated. Previous studies have indicated that oxidative stress may be associated with POP. Thus, the aim of the present study was to investigate the oxidative status of pelvic supportive tissue in POP and further demonstrate that oxidative stress is associated with the pathogenesis of POP. A total of 60 samples were collected from females undergoing hysterectomy for POP or cervical intraepithelial neoplasia (CIN). This included 16 females with POP II, 24 females with POP III-IV (according to the POP-Q system) and 20 females with CIN II-III as the control group. Immunohistochemistry was utilized to measure the expression of oxidative biomarkers, 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxynonenal (4-HNE). Major antioxidative enzymes, mitochondrial superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPx1) were measured through reverse transcription-quantitative polymerase chain reaction, western blotting and enzyme activity assays. The results demonstrated that in the cardinal ligament, the expression of 8-OHdG and 4-HNE was higher in the POP III-IV group compared with the POP II group and control group. The MnSOD and GPx1 protein level and enzyme activity were lower in the POP III-IV group compared with the POP II or the control group, while the mRNA expression level of MnSOD and GPx1 was increased. In conclusion, oxidative damage is increased in the pelvic supportive ligament of female patients with POP and the antioxidative defense capacity is decreased. These results support previous findings that oxidative stress is involved in the pathogenesis of POP. PMID- 30250522 TI - Local injection of dexamethasone helping to prevent lower back pain after epidural delivery analgesia. AB - This report aims to retrospectively analyze the clinical effect of local pretreatment with dexamethasone (DXMS) on lower back pain after epidural labor analgesia. Patients with epidural labor analgesia treated in People's Hospital of Rizhao from January 2014 to December 2016 were studied. All 368 cases involved were pregnant primipara with full-term single birth. Parturient received injection of DXMS and lidocaine mixture around the epidural puncture point was the observation group (n=188), and parturient received injection of 0.9% sodium chloride and lidocaine mixture around the epidural puncture point was the control group (n=180). The incidence and degree of lower back pain postoperatively in the two groups were evaluated by pain visual analogue scale method. The incidence of lower back pain at 48 h, 72 h after operation in observation group was significantly lower than that in control group (p<0.05). Among patients undergoing one puncture and more than one puncture, the incidence of postoperative lower back pain in the observation group was significantly lower than that in the control group (59.26%) (p<0.05). Among the parturient with spontaneous delivery, the incidence of postoperative lower back pain in the observation group was significantly lower than that in the control group (p=0.028). Among the cesarean section patients, the incidence of pain in observation group was significantly lower than that in control group (p=0.019). At 48 and 72 h after operation, severe pain in the observation group was significantly less than that in the control group (p<0.05). DXMS local pretreatment can significantly reduce the incidence of postoperative lower back pain and the degree of pain after epidural delivery analgesia. DXMS pretreatment in epidural analgesia deserved to be widely used clinically. PMID- 30250523 TI - Establishment and evaluation of a Beagle model of grade III pancreatic trauma. AB - Pancreatic trauma (PT) is a severe abdominal injury that is often combined with multiple organ injury. It is a severe disease that is difficult to diagnose and has a high mortality rate, particularly for grade III PT. The pathogenesis, disease progress and complications have not been fully investigated due to the lack of a reliable animal model. To address this, a Beagle model of grade III PT was established in the present study using a procedure involving rupture of the main pancreatic duct. Peripancreatic effusions and the degree of pancreatic damage were examined by routine ultrasound and contrast-enhanced ultrasound (CEUS). Also, ascites were collected for the examination of amylase and lipase levels, and whole blood samples were collected for the analysis of amylase, lipase, C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha levels in the serum. Urine samples were also collected for the examination of trypsinogen activation peptide (TAP). In addition, the pancreas was sectioned and stained with hematoxylin and eosin. In comparison with routine ultrasound, CEUS showed a large area of focal trauma, with a depth greater than half of the anteroposterior diameter of the pancreas, with a clear boundary, clear capsular rupture and trauma induced by active bleeding. The volume of ascites peaked at 48 h post-trauma and decreased thereafter. Amylase and lipase levels in the ascites were elevated at 24 h post-trauma and significantly decreased at 48 and 72 h post-trauma (P<0.01). In addition, serum amylase and lipase levels increased to peak levels at 48 h post-trauma and then decreased (P<0.05), while serum CRP, IL-6 and TNF-alpha levels peaked at 24 h post-trauma and then decreased (P<0.05). Urinary TAP levels also peaked at 24 h post-trauma and subsequently decreased (P<0.05). At 72 h post-trauma, the pancreatic cells were loosely distributed, with damaged acini, hyperchromatic nuclei and severe inflammatory cell invasion. These results indicated that the Beagle model of grade III PT was satisfactorily established, and that CEUS is potentially useful as an auxiliary diagnosis method for PT. This animal model may be useful for studying the pathogenesis, disease progress and complications of PT. PMID- 30250524 TI - Comprehensive analysis of gene expression profiles associated with proliferative diabetic retinopathy. AB - Proliferative diabetic retinopathy (PDR) is characterized by neovascularization on the surface of the retina or the optic disc, which is associated with environmental and genetic factors. However, its regulatory mechanism remains to be fully elucidated, particularly at a multiomics level. In the present study, a comprehensive analysis was performed of the gene expression profile of fibrovascular membranes (FVMs) associated with PDR, including an analysis of differentially expressed genes, functional enrichment, and regulation of transcription factors (TFs). As a result, novel marker genes of PDR were identified, including flavin containing monooxygenase 2. Furthermore, several common or specific genes, pathways and TFs have been recovered for active and inactive FVMs. In the present study, lymphoid enhancer binding factor 1 (LEF1) was identified as an upregulator in active and inactive FVMs, which is capable of activating or repressing target genes, including claudin 2, secreted phosphoprotein 1 (SPP1), and aristaless-like homeobox 4. It was demonstrated that the Wnt/beta-catenin effector LEF1 regulating SPP1 is potentially important in PDR. The results of the present study may provide novel insights into the molecular mechanisms underlying the pathophysiology of PDR. PMID- 30250525 TI - Clinical treatment of traumatic optic neuropathy in children: Summary of 29 cases. AB - Clinical features and treatments for traumatic optic neuropathy (TON) in children are reported. Twenty-nine children were enrolled in the Affiliated Hospital of Qingdao University from April 1999 to May 2015 for retrospective analysis. Of these 29 patients, 5 received drug therapy, and 24 received drug therapy combined with surgical therapy. Among the patients who received surgical therapy, 23 received nasal endoscopic optic decompression under general anaesthesia, and 1 received nasal endoscopic orbital decompression under general anaesthesia. All the patients were followed up for at least 6 months. In 29 cases, 48.28% (14/29) had visual improvement. Of the 5 patients who received drug therapy, 3 showed improvement (60%). Of the 24 cases who received drug and surgical therapy, 11 showed improvement (45.83%). Of the 22 patients who lost visual sensitivity, 10 showed improvement (45.45%). Of the 7 cases with visual acuity above basic light sensitivity, 4 showed improvement (57.14%). In conclusion, TON in children can lead to poor diagnosis and prognosis because of the difficulty of examining children and their limited language expression ability. Early ophthalmologic examination is therefore essential for children with craniofacial injuries, and proper treatment should be undertaken as soon as possible. PMID- 30250526 TI - Intrapancreatic accessory spleen: Evaluation with CT and MRI. AB - The aim of the present study was to evaluate the characteristics of computed tomography (CT) and magnetic resonance imaging (MRI), particularly diffusion weighted imaging (DWI), in the imaging of intrapancreatic accessory spleen (IPAS). The clinical and pathological records of 9 patients, including 8 patients with IPAS and 1 patient with splenosis, were reviewed. The patients had undergone plain and triple-phase enhanced CT scanning (n=9) and MRI scanning (n=8). The lesions of the 8 IPAS patients were located in the pancreatic tail, and were round (n=3), oval (n=4) or triangular (n=1) in shape. The CT and/or MRI densities, signal intensities and dynamic enhanced patterns of the lesions were similar to those of the orthotopic spleen. In DWI images (n=5), the IPAS regions presented high signal intensity (SI), and no significant difference in the apparent diffusion coefficient determined using a b-value of 600 sec/mm2 was identified between the IPAS and orthotopic spleen (P>0.05). One patient with splenosis complicated with cirrhosis had a nodule located in the pancreatic tail with an unenhanced CT value of 65 HU. In MRI examination, with the exception of the dynamic enhancement pattern, the T1-weighted, T2-weighted and DWI signals of splenosis were inconsistent with those of the normal spleen. In conclusion, in pre-contrast and post-contrast-enhanced CT and MRI images, IPAS exhibits similar characteristics to the orthotopic spleen. CT and MRI used in combination with DWI are important in the diagnosis of IPAS. PMID- 30250527 TI - Effect of transient ulnar artery compression on radial artery diameter. AB - The transradial approach is widely preferred in coronary procedures. A small radial artery diameter (RAD) is the most important factor affecting successful access. Various maneuvers and medications have been used to increase the RAD and thereby facilitate RA cannulation. Ulnar artery compression (UAC) for 30 min has been indicated to be effective in increasing the RAD and facilitating RA access. The aim of the present preliminary study was to assess the effect of transient UAC for 1 min on the RAD. A total of 151 patients were included in the present study. RA ultrasonography was performed at the level of the wrist. The UA was compressed for 1 min. The RAD was measured at baseline, at the end of UAC and at 1 min thereafter. The results indicated that the RAD was significantly smaller in diabetic vs. non-diabetic patients (2.35+/-0.43 vs. 2.50+/-0.39 mm, P=0.024) and in women vs. men (2.25+/-0.38 vs. 2.56+/-0.38 mm, P<0.001). At the end of UAC, the RAD was increased compared with that at baseline (2.45+/-0.41 vs. 2.62+/-0.41 mm, P<0.001), but it started to decrease thereafter, and the RAD measured at 1 min after stopping UAC was significantly smaller (2.62+/-0.41 vs. 2.55+/-0.40 mm, P<0.001), while remaining significantly larger than that at baseline (P<0.001). The RA peak systolic flow velocity also increased significantly during UAC (35.3+/-8.9 vs. 60.3+/-19.2 cm/sec; P<0.001). In conclusion, Transient UAC for 1 min significantly increased the RAD and the peak systolic flow velocity. Further studies with clinical endpoints are required for further exploration of the feasibility of this approach. PMID- 30250528 TI - The role of interleukin-6-STAT3 signalling in glioblastoma. AB - Glioblastoma is the most common type of malignant brain tumor among adults and is currently a non-curable disease due primarily to its highly invasive phenotype, and the lack of successful current therapies. Despite surgical resection and post surgical treatment patients ultimately develop recurrence of the tumour. Several signalling molecules have been implicated in the development, progression and aggressiveness of glioblastoma. The present study reviewed the role of interleukin (IL)-6, a cytokine known to be important in activating several pro oncogenic signaling pathways in glioblastoma. The current study particularly focused on the contribution of IL-6 in recurrent glioblastoma, with particular focus on glioblastoma stem cells and resistance to therapy. PMID- 30250529 TI - A meta-analysis and bioinformatics exploration of the diagnostic value and molecular mechanism of miR-193a-5p in lung cancer. AB - Lung cancer is a leading cause of mortality worldwide and despite recent improvements in lung cancer treatments patient mortality remains high. miR-193a 5p serves a crucial role in the initiation and development of cancer; it is necessary to understand the underlying molecular mechanisms of miR-193a-5p in lung cancer, which may enable the development of improved clinical diagnoses and therapies. The present study investigated the diagnostic value of peripheral blood and tissue miR-193a-5p expression using a microarray meta-analysis. Peripheral blood miR-193a-5p was revealed to be upregulated in patients with lung cancer. The pooled area under the curve (AUC) was 0.67, with a sensitivity and specificity of 0.74 and 0.56, respectively. Conversely, the peripheral tissue miR 193a-5p expression in patients with lung cancer was significantly downregulated. The pooled AUC was 0.83, and the sensitivity and specificity were 0.65 and 0.89, respectively. Through bioinformatics analysis, three Kyoto Encyclopedia of Genes and Genomes (KEGG) terms, pathways in cancer, prostate cancer and RIG-I-like receptor signaling pathway, were identified as associated with miR-193a-5p in lung cancer. In addition, in lung cancer, six key miR-193a-5p target genes, receptor tyrosine-protein kinase erbB-2 (ERBB2), nuclear cap-binding protein subunit 2 (NCBP2), collagen alpha-1(I) chain (COL1A1), roprotein convertase subtilisin/kexin type 9 (PCSK9), casein kinase II subunit alpha (CSNK2A1) and nucleolar transcription factor 1 (UBTF), were identified, five of which were significantly upregulated (ERBB2, NCBP2, COL1A1, CSNK2A1 and UBTF). The protein expression of ERBB2, NCBP2, COL1A1, CSNK2A1 and UBTF was also upregulated. NCBP2 and CSNK2A1 were negatively correlated with miR-193a-5p. The results demonstrated that miR-193a-5p exhibited opposite expression patterns in peripheral blood and tissue. Upregulated peripheral blood miR-193a-5p and downregulated tissue miR 193a-5p may be promising diagnostic biomarkers in lung cancer. In addition, the KEGG terms pathways in cancer, prostate cancer and RIG-I-like receptor signaling pathway may suggest which pathways serve vital roles in lung cancer by regulating miR-193a-5p. In addition, six genes, ERBB2, COL1A1, PCSK9, UBTF and particularly NCBP2 and CSNK2A1, may be key target genes of miR-193a-5p in lung cancer. PMID- 30250530 TI - Regulation of miR-155 affects the invasion and migration of gastric carcinoma cells by modulating the STAT3 signaling pathway. AB - Studies investigating the effects of microRNA (miR)-155 on the behavior of tumor cells have concentrated primarily on proliferation and apoptosis. The aim of the present study was to investigate the effect of miR-155 inhibitor on the metastatic and invasive ability of gastric carcinoma cells and whether this effect is mediated via the signal transduction and activators of transcription 3 (STAT3) signaling pathway. The miR-155 inhibitor and miR-155 negative control (NC) were transfected into the AGs and MKN-45 cell lines. The migratory and invasive abilities of the cells were analyzed. The level of phosphorylated (p )STAT3 and the expression levels of matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF) and suppressor of cytokine signaling 1 (SOCS1) were also detected. For the AGS cell line, the cell counts (mean +/- standard deviation) for the Transwell migration assay were 98.99+/-9.13 in the miR-155 NC group and 45.32+/-4.32 in the miR-155 inhibitor group (P<0.01). For the MKN-45 cell line, the cell counts for the migration assay were 129.99+/-10.12 and 50.36+/-5.2 in the miR-155 NC and miR-155 inhibitor groups, respectively (P<0.01). The cell counts of the AGS cell line for the invasion assay were 70.25+/-7.94 in the miR-155 NC group and 40.68+/-4.73 in the miR-155 inhibitor group (P<0.05). For the MKN-45 cell line, the cell counts for the invasion assay were 84.63+/-8.12 and 40.35+/-4.29 in the miR-155 NC and miR-155 inhibitor groups, respectively (P<0.05). Transfection with the miR-155 inhibitor was able to significantly decrease the level of p-STAT3 in the AGS and MKN-45 cell lines compared with the negative control group (all P<0.05). The levels of MMP2 and MMP9 expression were decreased following transfection with miR-155 in AGS and MKN 45 cells (both P<0.05). Notably, transfection with the miR-155 inhibitor was able to decrease the level of VEGF expression, whilst increasing the SOCS1 expression level compared with the negative control group (both P<0.05). Additionally, the downregulation of miR-155 expression in gastric carcinoma cell lines was able to significantly decrease the expression of VEGF, MMP2 and MMP9, thereby inhibiting the invasion and metastasis of gastric carcinoma cells. PMID- 30250531 TI - Identification of six key miRNAs associated with breast cancer through screening large-scale microarray data. AB - Breast Cancer (BC) is one of the most common primary malignant tumors, which is life threatening. Previous studies have demonstrated that microRNAs (miRNA) may regulate or affect the incidence of BC. However, results of these studies are inconsistent, due to factors including the different sequencing platforms and sample selection methods used. To explore the key miRNAs involved in the pathogenesis of BC, and to use these miRNAs to monitor the tumor progression of BC, a systematic review was performed on the previous studies examining BC miRNA; the function of the target genes that were modulated by these key miRNAs were also analyzed. A total of 8 representative miRNA datasets examining the pathogenesis of BC were selected. Key miRNAs were identified by comparing the overlap between these datasets. Then, the target genes of these key miRNAs were predicted through TargetScan. Furthermore, functional enrichment analysis of target genes and transcription factor (TF) binding analysis was also performed using the Database for Annotation, Visualization and Integrated Discovery and Tfacts database, respectively. A total of 6 key miRNAs were identified by comparing the differentially expressed miRNAs datasets in the pathogenesis of BC. Compared with normal tissues, 3 miRNAs were upregulated: Hsa-miR-21b; hsa-miR 29b; and hsa-miR-155; and 3 miRNAs were downregulated: Hsa-miR-10b; hsa-miR-125; and hsa-miR-145. The target genes regulated by the up- and downregulated miRNAs were significantly enriched in the biological processes of 'transcriptional regulation', and these target genes depended on RNA polymerase II promoter and DNA template, respective to the up- and downregulated genes. The downregulated key miRNAs were specifically enriched in the biological processes of 'ephrin receptor signaling pathway' (GO: 0048013) and 'axon guidance' (GO: 0007411). TF analysis of the key miRNA target genes revealed that 104 TFs interacted with the 319 target genes of the upregulated miRNAs, while the 92 TFs interacted with the 254 target genes of the downregulated miRNAs. In total, there were 133 TFs and 63 (47.3%) TFs shared by the 2 types (up- and downregulated) of target genes. In summary, 6 key miRNAs in BC were identified by systematic review; the corresponding target genes and TFs that bind to these target genes were also identified, and the potential functions of target genes were revealed. These data may be beneficial to increasing the accuracy of BC treatment through monitoring miRNA. PMID- 30250532 TI - miR-204 enhances p27 mRNA stability by targeting Brd4 in head and neck squamous cell carcinoma. AB - The present study aimed to explore the function of microRNA (miR)-204 in modulating cyclin-dependent kinase inhibitor 1B (p27) mRNA stability in head and neck squamous cell carcinoma (HNSCC). Briefly, reverse transcription quantitative polymerase chain reaction and western blot analysis were used to detect miR-204 and Brd4 level. Cell viability, cell cycle and cell apoptosis were used to investigate the effects of miR-204. Additional luciferase reporter and mRNA stability assays were used to explore the mechanisms contributing to miR-204 effects. Here, miR-204 was downregulated in HNSCC tissues compared with the adjacent normal tissues. The expression levels of miR-204 and bromodomain containing protein 4 (Brd4) were negatively associated in HNSCC tissues. Ectopic expression of miR-204 inhibited HNSCC cell proliferation, promoted cell cycle arrest at the G1/S phase and promoted cell apoptosis compared with control cells. Additionally, upregulation of miR-204 expression levels enhanced p27 mRNA stability. Notably, Brd4 was identified as a target of miR-204, and the co expression of Brd4 with miR-204 mimics attenuated the inhibitory effects of miR 204 on cell proliferation and enhanced p27 mRNA stability compared with control cells. Thus, it was concluded that miR-204 functions as a tumor suppressor by enhancing p27 mRNA stability through targeting Brd4 in HNSCC. PMID- 30250533 TI - Identification of key pathways and genes in lung carcinogenesis. AB - The present study aimed to identify key pathways and genes in the pathogenesis of lung cancer. The GSE10072 dataset was downloaded from the Gene Expression Omnibus database. Protein-protein interaction data were collected from Human Protein Reference Database, and 201 pathways were downloaded from the Kyoto Encyclopedia of Genes and Genomes database. Signaling network impact analysis was performed to identify enriched pathways, followed by the construction of a pathway-pathway crosstalk network. Benzopyrene was used to treat normal human lung cells at concentrations of 0.01, 0.1, 1 and 10 uM, and cell viability was measured. Furthermore, growth arrest and DNA damage inducible beta (GADD45B), p53, cyclin B, Akt and nuclear factor (NF)-kappaB protein levels were also measured via western blotting. Impact analysis identified 11 enriched lung cancer-associated KEGG pathways, including 'complement and coagulation cascades', 'ECM-receptor interaction', 'P53 signaling pathway', 'cell adhesion molecules' and 'focal adhesion'. In addition, cell cycle, 'drug metabolism-cytochrome P450', 'metabolic pathways', 'pathways in cancer', 'focal adhesion' and 'antigen processing and presentation' were central in the pathway-pathway cross-talk network. Furthermore, the upregulated gene GADD45B was associated with three of the pathways, including an activated pathway ('MAPK signaling pathway') and two repressed pathways ('cell cycle' and 'P53 pathway'). Western blotting demonstrated that the expression of NF-kappaB, Akt and GADD45B increased over time in lung cells treated with benzopyrene, whereas the expression levels of cyclin B and P53 decreased. In conclusion, GADD45B may contribute to lung carcinogenesis via affecting the MAPK, P53 signaling and cell cycle pathways. PMID- 30250534 TI - Role of gastroscopic biopsy of gastric ulcer margins and healed sites in the diagnosis of early gastric cancer: A clinical controlled study of 513 cases. AB - The present case study aimed to evaluate the effect of gastroscopic biopsy of gastric ulcer margins and healed sites in the diagnosis of early gastric cancer. A total of 513 patients who were diagnosed with gastric ulcers using gastroscopy between January 1999 and December 2013 were included in the present study and were divided into either the experimental or the control group. In the control group, samples were only taken from the ulcer margin, whereas in the experimental group samples were taken from the ulcer margin and from the ulcer base. In the experimental group, a routine biopsy of the ulcer margin was performed on first examination, and recheck by gastroscopy was performed from the second week. For ulcers that remained unhealed, a biopsy of the ulcer margin was subsequently conducted; however, for healed or almost healed ulcers, a biopsy of the ulcer base was conducted. The duration of follow-up by gastroscopy ranged between 1 week and 24 months. For the control group, a biopsy of the ulcer margin was conducted using the conventional method. The detection rate of the experimental group was 3.88% (9/232), with 4 cases of gastric cancer confirmed from examinations of the ulcer base. The detection rate of the control group was 1.07% (3/281), which was significantly decreased compared with that of the experimental group (P=0.0345). Overall, patients who underwent regular follow-up gastroscopy following treatment exhibited a markedly increased detection rate of early gastric cancer, suggesting that early cancer may occur in healed gastric ulcer sites. PMID- 30250535 TI - Specific miRNA expression profile in the blood serum of cardiac myxoma patients. AB - The profile of differentially expressed microRNAs (miRNAs) in the serum of patients with cardiac myxoma (CM) (n=30) and healthy people (n=30) was studied using miRNA microarray analysis. The expression of the candidate miRNAs was validated by reverse transcription-quantitative polymerase chain reaction (RT qPCR) in the serum of 30 CM patients and 30 healthy control individuals. TargetScan, PicTar and miRanda were used to predict the possible target gene of miR-320a. The Gene Ontology database and Kyoto Encyclopedia of Genes and Genomes database were used to enrich the functions and signaling pathways of the target genes, respectively. The results showed that 4 differentially expressed miRNAs were identified, the expression levels of miR-320a and miR-1249-5p were upregulated, and those of miR-634 and miR-6870-3p were downregulated in CM patients (P<0.05). The expression levels of miR-320a and miR-634 selected for verification by RT-qPCR were in high concordance with the results of microarray analysis. Through bioinformatics, we identified 487 target genes predicted from miR-320a, that were mostly enriched in the bone morphogenetic protein signaling pathway, nicotinamide adenine dinucleotide pathway and de novo ceramide biosynthetic pathway. In our study, we reported for the first time the circulating miRNA profile of CM patients and suggested that miR-320a may participate in CM development through the ceramide signaling pathway. PMID- 30250536 TI - Real-time assessment of platinum sensitivity of primary culture from a patient with ovarian cancer with extensive metastasis and the platinum sensitivity enhancing effect by metformin. AB - The aim of the present study was to perform a rapid evaluation of the efficiency of commonly used platinum-based chemotherapy regimens for patients with ovarian cancer with extensive metastases using an in vitro method combined with culturing primary cells and real-time monitoring, and to further explore the enhanced effect of metformin on susceptibility of ovarian cancer cells to platinum-based chemotherapy. The primary omental metastatic (OM) cells were isolated from the omentum metastasis of a surgical patient with stage IIIc ovarian carcinoma. Drug sensitivity was evaluated using the xCELLigence system, and screening of the most effective platinum chemotherapy was performed through analysis of cell susceptibility to cisplatin, carboplatin, nedaplatin and paclitaxel or docetaxel alone or in combination. At the same time, this system was used to determine whether metformin was able to increase the sensitivity of cancer cells to platinum chemotherapy. The results revealed that nedaplatin exhibited the most marked cytotoxic effect on the OM cells, followed by those of carboplatin and cisplatin. The addition of docetaxel enhanced the cytotoxic effect, and the combination of platinum and paclitaxel also enhanced the effect. Metformin rapidly increased the sensitivity of cells to platinum-based chemotherapy, and this effect was dose-dependent. The sensitivity of OM cells to different platinum based regimens was varied. The effect of metformin on chemotherapeutic sensitization of cancer cells is clear in vitro, and the real-time cell analyzer assay has the potential to assist in determining individualized drug regimens for patients with metastatic ovarian cancer. PMID- 30250537 TI - miRNA-21 inhibition inhibits osteosarcoma cell proliferation by targeting PTEN and regulating the TGF-beta1 signaling pathway. AB - The present study aimed to investigate the role of microRNA (miRNA)-21 in the growth of osteosarcoma. A total of 46 patients with osteosarcoma and 20 healthy controls were included in the study. The expression of miRNA-21 was detected by reverse transcription-quantitative polymerase chain reaction in tumor tissues and adjacent healthy tissues from patients with osteosarcoma, as well as the serum of patients with osteosarcoma and the healthy controls was. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic values of serum miRNA-21 for osteosarcoma at different T stages. Survival curves plotted using the Kaplan-Meier method were used to evaluate the prognostic value. miRNA 21 knockdown osteosarcoma cell lines were established and their effects on cell proliferation were explored using a Cell Counting Kit-8 assay. The effect of miRNA-21 knockdown on the protein expression of phosphatase and tensin homolog (PTEN) and transforming growth factor (TGF)-beta1 was detected by western blot analysis. The expression levels of miRNA-21 in tumor tissues were significantly higher compared with the adjacent healthy tissues in the majority of patients with osteosarcoma. The serum miRNA-21 increased as the T-stage of osteosarcoma increased. Serum miRNA-21 may be used to effectively diagnose osteosarcoma and predict the prognosis of the disease. miRNA-21 knockdown inhibited the proliferation of osteosarcoma and promoted the expression of PTEN and TGF-beta1 proteins in the osteosarcoma cells. However, TGF-beta1 inhibitor treatment reduced the inhibitory effects of miRNA-21 knockdown on osteosarcoma cell proliferation. In conclusion, miRNA-21 inhibition may inhibit osteosarcoma cell proliferation by targeting PTEN and regulating the TGF-beta1 signaling pathway. PMID- 30250538 TI - A quantitative analysis of the potential biomarkers of non-small cell lung cancer by circulating cell-free DNA. AB - The study was conducted to ascertain whether the quantification of circulating cell-free DNA (cfDNA) in serum has value as a diagnostic or for monitoring the progression of non-small cell lung cancer (NSCLC). The serum/plasma cfDNA concentration was quantified by absolute qPCR of long interspersed nuclear element-1 (LINE1) in 60 NSCLC patients and 68 controls in good health. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic utility and cut-off levels of cfDNA, CEA, and CYFRA21-1 in NSCLC patients. Correlations between cfDNA and age, sex, tumour stage and progression free survival (PFS) were analysed. A follow-up study was conducted on 4 NSCLC patients, and serum cfDNA, CEA, and CYFRA21-1 were quantified throughout disease progression. Serum cfDNA levels were significantly higher in NSCLC patients than those in normal controls. Elevated serum cfDNA concentration was also significantly associated with advanced tumour stage. Serum cfDNA had a ROC area under the curve comparable to that of CEA and CYFRA21-1 for the diagnosis of NSCLC, and the combined cfDNA/CEA/CYFRA21-1 indicator had the highest diagnostic efficiency. Moreover, increased serum cfDNA levels were strongly correlated with tumour progression and poor PFS. This study preliminarily confirmed that cfDNA can monitor disease progression in NSCLC patients, and the lead time was 1-7 months compared with clinical medical imaging. Serum cfDNA may be useful in monitoring NSCLC progression, suggesting that the non-invasive quantification of serum cfDNA by LINE1 qPCR is a viable option for predicting progression and disease severity when repeated invasive tissue biopsy is not possible. PMID- 30250539 TI - Comprehensive analysis of marker gene detection and computed tomography for the diagnosis of human lung cancer. AB - Non-small cell lung cancer (NSCLC) is one of leading causes of cancer-associated mortality, with a high number of cases caused by metastasis. The early diagnosis of cancer contributes to the successful treatment of patients with lung cancer. The aim of the present study was to analyze the efficacy of marker gene detection and computed tomography (CT) in diagnosing human lung cancer. Lung cancer marker genes, including carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), tissue polypeptide antigen (TPA), pro-gastrin-releasing peptide (ProGRB), cytokeratin fragment 21-1 (Cyfra21-1) and neuron-specific enolase (NSE), were analyzed in patients with lung cancer. The tumor size was evaluated using CT, and the association between lung serum levels of marker gene protein expression and tumor size was investigated. A total of 328 patients with lung cancer were identified, including 204 adenocarcinoma, 75 large cell carcinoma and 49 squamous cell carcinoma cases. All patients were indicated to have a high serum level of CEA, CA125, TPA, ProGRB, Cyfra21-1 and NSE, compared with the normal range. Immunohistochemistry demonstrated higher expression levels of CEA, CA125, TPA, ProGRB, Cyfra21-1 and NSE in lung tumor tissues, compared with the normal range. Results indicated that CT was able to diagnose tumor size for patients with lung cancer. The CEA and CA125 expression levels were associated with CT-diagnosed adenocarcinoma tumor size. Large cell carcinoma tumor size was associated with serum levels of CEA, TPA and ProGRB. Results indicated that Cyfra21-1 and NSE were associated with the squamous cell carcinoma cases, as demonstrated using CT. In conclusion, these results indicated that comprehensive analysis of marker gene detection and CT results may be used to diagnose human lung cancer. PMID- 30250540 TI - Galectin-7 is elevated in endometrioid (type I) endometrial cancer and promotes cell migration. AB - Endometrial cancer (EC) is the most commonly diagnosed gynecological malignancy in Australian women. Notably, its incidence and mortality rate is increasing. Despite this, there are limited treatment options for EC. Galectin-7 regulates tumorigenesis in numerous epithelial cancer types, but the role of galectin-7 has not been investigated in EC. It was hypothesized that galectin-7 expression would be altered in EC and contribute to the development of EC. Galectin-7 levels in EC and benign endometrium were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and ELISA. The effect of recombinant galectin 7 (1 ug/ml) on cell adhesion, proliferation, apoptosis (xCELLigence and flow cytometry), migration (wound healing assay) and gene expression (RT-qPCR) was investigated using three human EC cell lines (Ishikawa, HEC1A and AN3CA). Galectin-7 gene and protein expression was significantly elevated in Grade 3 EC, compared with benign tissues. Galectin-7 was almost undetectable in Ishikawa and AN3CA cells, but highly expressed by HEC1A cells. Recombinant galectin-7 had no significant effect on cell proliferation or apoptosis in any cell line, but significantly reduced cell adhesion in Ishikawa (at 4 and 6 h) and AN3CA (at 2, 3, 4 and 6 h). Galectin-7 significantly promoted Ishikawa migration and significantly elevated collagen type IV alpha 1 chain and intercellular adhesion molecule 1 (ICAM1) gene expression during wound healing. The present study demonstrated that galectin-7 production increased in EC with increasing cancer grade; therefore, galectin-7 may promote the metastasis of EC by reducing cell cell adhesion and enhancing cell migration. PMID- 30250541 TI - Monitoring of platelet function parameters and microRNA expression levels in patients with prostate cancer treated with volumetric modulated arc radiotherapy. AB - Radiotherapy (RT) may result in platelet activation and thrombosis development. To the best of our knowledge, the potential effect of volumetric-modulated arc therapy (VMAT), a novel radiotherapy technique, on platelet function and microRNA (miRNA/miR) expression has not been previously investigated. The present study aimed to determine the effect of VMAT on the alterations in platelet function parameters and miRNA expression levels. A total of 25 patients with prostate cancer and 25 healthy subjects were included in the present study. Blood samples were collected from the patient group on the day prior to RT (pre-RT), the day RT was completed (post-RT day 0), and 40 days following the end of therapy (post-RT day 40). Platelet count, mean platelet volume (MPV) value, platelet aggregation, plasma P-selectin, thrombospondin-1, platelet factor 4, plasma miR-223 and miR 126 expression levels were measured. A significant decrease in platelet count in the post-RT day 0 group was measured in comparison with the pre-RT and the post RT day 40 groups. Pre-RT MPV values were higher than those of the post-RT day 0 and the post-RT day 40 groups. No significant differences were observed in the levels of platelet activation markers or miR-223 and miR-126 expression levels between the RT groups. Although RT may result in a reduction in platelet and MPV counts, the results of the present study indicate that platelet activation markers are not affected by VMAT. Therefore, it is possible that no platelet activation occurs during VMAT, owing to the conformal dose distributions, improved target volume coverage and the sparing of normal tissues from undesired radiation. PMID- 30250542 TI - Leptin induces epithelial-to-mesenchymal transition via activation of the ERK signaling pathway in lung cancer cells. AB - Previous studies revealed that leptin induces the growth and proliferation and inhibits the apoptosis of lung cancer cells. However, the effect of leptin on epithelial-to-mesenchymal transition (EMT) is not yet clear. In the present study, the effect of leptin on EMT was investigated as well as its underlying mechanisms in A549 cells. The ability of leptin to induce EMT was investigated by microscopic examination and western blotting. The impacts of leptin on cell migration, invasion and tumorigenesis were evaluated by wound healing, Transwell and colony formation assays, respectively. It was demonstrated that leptin induced EMT-associated morphological changes, namely a decrease in cell-cell contact and a more elongated morphological shape. Leptin decreased the expression levels of epithelial phenotype markers E-cadherin and keratin, increased the expression of mesenchymal phenotype marker Vimentin, and raised the expression of EMT-induced transcription factor ZEB-1. In addition, leptin activated the extracellular signal regulated kinase (ERK) signaling pathway and did not affect the activation of the protein kinase B signaling pathway in A549 cells. Leptin also promoted EMT-induced migration, invasion and tumorigenesis in vitro in A549 cells. The present study provides evidence that leptin induced EMT via the activation of the ERK signaling pathway and increased EMT-induced tumor phenotypes in lung cancer cells. These findings suggest that leptin may be a promising target for lung cancer treatment through the regulation of EMT. PMID- 30250543 TI - Erratum: The association between inflammation, the microbiome and urethane induced pulmonary adenocarcinoma. AB - [This corrects the article DOI: 10.3892/ol.2018.8167.]. PMID- 30250545 TI - Analysis of feasibility, safety and effectiveness of ultrasound-guided percutaneous microwave ablation of splenic neoplasm. AB - The present study aimed to analyze the feasibility, safety and effectiveness of ultrasound-guided percutaneous microwave ablation of splenic neoplasm. A total of 62 patients with splenic neoplasm admitted to Second People's Hospital of Liaocheng between January 2009 and December 2012 were selected, and randomly divided into the observation group (n=31) and control group (n=31). The control group was treated with open ablation, while the observation group was treated with ultrasound-guided percutaneous microwave ablation. The splenic hemodynamics and ablation effects of patients after treatment were detected via color Doppler ultrasound. The changes in peripheral blood cell count before treatment, and at 3, 7 and 14 days after treatment were monitored. The side effects and complications were compared between the two groups. Patients were followed up for 5 years to observe the survival rates of the two groups. At 1 week after treatment, the peak velocity of splenic artery in observation group was significantly lower than that in control group, and the diameter, velocity and flow of splenic vein were significantly lower than those in control group (P<0.05). After treatment, the white blood cell and platelet counts in both groups were significantly increased compared with those before treatment, and the counts in observation group were obviously higher than those in control group (P<0.05). There were no significant changes in the red blood cell counts in both groups before and after treatment (P>0.05). The ablation volume, ablation ratio and 1-week shrink ratio in both groups had no significant differences (P>0.05). The incidence rates of side effects and complications in observation group were significantly lower than those in control group (P<0.05). The 5-year survival rates of both groups were >50%, and the survival time and survival rate were not significantly different (P<0.05). The curative effects of open ablation and ultrasound-guided percutaneous microwave ablation in the treatment of splenic neoplasm were significant, and the 5-year survival rate of patients was higher; compared with open ablation. The ultrasound-guided percutaneous microwave ablation is characterized by the small trauma, lower incidence rates of adverse reactions and complications and better safety, which can increase the peripheral blood cell count, and improve the splenic blood flow and coagulation function, playing a role in the regulation of the patient's body status. PMID- 30250544 TI - Transforming growth factor-beta signaling in head and neck squamous cell carcinoma: Insights into cellular responses. AB - Head and neck squamous cell carcinoma (HNSCC) arises in the oral cavity, salivary glands, larynx, pharynx, nasal cavity and paranasal sinuses, and is characterized by high morbidity and metastasis rates. Transforming growth factor-beta (TGF beta) is a homodimeric protein known to be a multifunctional regulator in target cells and to serve a pivotal role in numerous types of cancer, including HNSCC. The role of TGF-beta signaling in carcinogenesis can change from tumor suppressing to tumor-promoting. In addition, TGF-beta induces epithelial mesenchymal transition and restrains immune surveillance on malignant cells. In the present review, the effects of TGF-beta signaling at a cellular level were discussed, which includes the regulation of tumor cells, immune cells and other stromal cells, as well as the possible mechanisms underlying the conversion from a tumor suppressor to a tumor promoter in HNSCC. Further research is required to improve the understanding on how this network is involved in carcinogenesis, progression and metastases in HNSCC. PMID- 30250546 TI - Growth inhibition and chemo-radiosensitization of esophageal squamous cell carcinoma by survivin-shRNA lentivirus transfection. AB - Esophageal cancer is one of the most common types of cancer worldwide, and it has a poor prognosis. Chemo-radiotherapy resistance and cancer relapse are among the most difficult issues in its treatment. Identifying the underlying molecular mechanisms is critical for developing novel therapies. Survivin has been previously suggested to be overexpressed in esophageal cancer cells. The present study identified that down-regulation of survivin sensitized esophageal cancer cells to chemo-radiotherapy. Consistent with previous studies, the present study indicated that survivin was overexpressed in 4 esophageal squamous carcinoma cell lines. Short hairpin RNA delivered by lentivirus successfully knocked down survivin in these cancer cell lines. Consequently, down-regulation of survivin impaired their colony-forming, migratory and invasive capabilities, while the overexpression of survivin in normal human esophagus epithelial cells improved their resistance to cisplatin, paclitaxel and radiation. Survivin knockdown induced apoptosis in esophageal cancer KYSE-150 and ECA-109 cell lines when exposed to the aforementioned chemo-radiotherapy treatments. These results indicate that survivin expression sustains growth in esophageal cancer cells, and confers resistance to chemo-radiotherapy. Targeted survivin ablation may be a promising strategy against esophageal tumor relapse and chemo-radioresistance. PMID- 30250547 TI - Increased MALAT1 expression contributes to cisplatin resistance in non-small cell lung cancer. AB - Cisplatin-based chemotherapy is commonly used for the clinical treatment of patients with non-small cell lung cancer (NSCLC). However, the anti-tumor efficacy of cisplatin is limited by poor clinical response and the development of chemoresistance. At present, the underlying mechanism for cisplatin resistance remains unclear. In the present study, it was identified that metastasis associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA that has been demonstrated to function as an oncogene, was increased in tumor tissues from patients with cisplatin-resistant NSCLC. In addition, the MALAT1 level was increased in A549rCDDP cells compared with the parental A549 cells. Silencing of MALAT1 sensitized A549rCDDP cells to cisplatin treatment, while overexpression of MALAT1 in A549 cells decreased their sensitivity towards cisplatin. Through analysis of the gene expression in patient samples, a decrease in miR-145 and an increase in Kruppel-like factor 4 (KLF4) in tumor tissues compared with adjacent normal tissues was observed. A negative association between MALAT1 and miR-145 was also identified in A549 cells and A549rCDDP cells. Furthermore, reverse transcription quantitative polymerase chain reaction and western blotting identified that KLF4 was positively and negatively regulated by MALAT1 and miR 145, respectively. The direct regulatory association between MALAT1 and miR-145 and the target gene KLF4 was additionally confirmed using a luciferase reporter assay. Knockdown of MALAT1 reversed cisplatin resistance in A549rCDDP cells. Taken together, these data indicated that MALAT1 decreased the sensitivity of NSCLC to cisplatin via the regulation of miR-145 and KLF4. PMID- 30250548 TI - Caveolin-1 facilitated KCNA5 expression, promoting breast cancer viability. AB - Potassium voltage-gated channel subfamily A member 5 (KCNA5) is a voltage-gated potassium channel protein encoded by the KCNA5 gene. A large number of studies have shown that KCNA5 is associated with the survival of malignant tumors, including breast cancer, but the detailed mechanism remains inconclusive. Our previous study found that KCNA5 is co-expressed with a scaffolding protein, caveolin-1 in MCF-10A-neoT non-tumorigenic epithelial cell. In the present study, KCNA5 and caveolin-1 were expressed in breast cancer tissues and cell lines. Exposing MCF-10A-neoT to 2 mM of methyl-beta-cyclodextrin, an agent to disrupt caveolae and lipid rafts led to a downregulation of caveolin-1 that reduced the expression of KCNA5. Furthermore, following caveolin-1 knockdown, the expression of KCNA5 was decreased in MDA-MB-231 human breast cancer and MCF-10A-neoT non tumorigenic epithelial cell lines. In subsequent experiments, the MTT assay showed that increased caveolin-1 and KCNA5 expression promoted the survival of MCF-7 human breast cancer cells, but cell survival was not affected following KCNA5 overexpression alone. Using small interfering RNA technology, KCNA5 silenced MCF-10A-neoT cells were established and a decreased level of phosphorylated-AKT serine/threonine kinase (AKT) was observed in the cells compared with the parental cells. Overall, these results suggested that caveolin 1 facilitated KCNA5 expression and may be associated with AKT activation. PMID- 30250549 TI - Interleukin-15 suppresses gastric cancer liver metastases by enhancing natural killer cell activity in a murine model. AB - Interleukin (IL)-15 is a promising cytokine for cancer immunotherapy as it is a critical factor for the proliferation and activation of natural killer (NK) cells. Previous studies have suggested critical roles of IL-15 in tumor invasion and metastasis. However, the association between IL-15 and liver metastasis of gastric cancer (LMGC) remains unknown. The present study investigated the therapeutic efficacy of recombinant mouse IL-15 (rmIL-15) in murine LMGC models, in which stable green fluorescent protein (GFP)-expressing MKN45 cells (MKN45-GFP cells) were injected into the spleen parenchyma of mice for liver metastasis. At different treatments (high dose group: 2.5 ug of rmIL-15; low dose group: 0.2 ug of rmIL-15; control group: PBS), it was found that rmIL-15 decreased the formation of liver metastasis sites. Additionally, this treatment lead to improved survival of mice following tumor cell transplantation. Treatment with a high dose of rmIL-15 provided greater therapeutic efficacy by prolonged survival of the mice compared with low dose group and control group. It was found that NK cells isolated from the liver that received the high dose of rmIL-15 showed stronger cytotoxic activity compared with the other two groups on the target cells. These findings hold significant importance for the use of IL-15 as a potential adjuvant/therapeutic for liver metastasis from gastric cancer. PMID- 30250550 TI - Piperidine nitroxide Tempol enhances cisplatin-induced apoptosis in ovarian cancer cells. AB - A nitroxide radical, Tempol (Tempol, TPL), is usually used as an antioxidative agent clinically, whereas the mechanism underlying its pro-oxidative effect has not been thoroughly investigated. The present study investigated the pro oxidative effect of TPL on the inhibition of cellular proliferation and its role in enhancing the effect of anticancer drug cisplatin (DDP) on the induction of apoptosis in ovarian cancer cells. Cell viability and proliferation were evaluated by MTT assay. Cell apoptosis was analyzed by flow cytometry (FCM) following staining with Annexin V/propidium iodide. Western blot analysis was performed to determine the expression levels of anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) and pro-apoptotic protein Bcl-2-associated X protein (Bax), and the Bcl-2:Bax expression ratio. Cellular reactive oxygen species (ROS) were labeled with dichlorofluorescin-diacetate and analyzed by FCM. The results revealed that cell viabilities of OVCAR3 and SKOV3 cells were decreased by TPL in dose-dependent manner at concentrations of 2 to 10 mM after 48 h incubation. The cell proliferation rates of OVCAR3 and SKOV3 cells were suppressed by TPL at lower toxic concentrations of 1.5 and 1 mM, respectively, compared with the control group. The MTT assay indicated that the combination therapy significantly inhibited the cell proliferation of OVCAR3 cells compared with treatment with DDP alone. FCM demonstrated that the combination treatment increased the proportion of early apoptotic cells in OVCAR3 cells compared with single DDP treatment. Western blot analysis revealed that the combination treatment markedly decreased the Bcl-2:Bax expression ratio compared with treatment with DDP alone. Detection of cellular ROS expression levels demonstrated that the combination therapy significantly increased cellular ROS generation compared with the DDP-only therapy. These data indicated that TPL increased the effect of DDP on inducing apoptosis in OVCAR3 cells. PMID- 30250551 TI - Expression of Smo in pancreatic cancer CD44+CD24+cells and construction of a lentiviral expression vector to silence Smo. AB - The present study focused on the roles of members of the Hedgehog (Hh) signaling pathway in the maintenance of malignant biological characteristics, such as tumorigenesis, similar to that of pancreatic tumor cells. Cluster of differentiation (CD)44+CD24+/CD44-CD24- cells were isolated from three different pancreatic cancer cell lines by flow cytometry. Among the three pancreatic cancer cell lines, the SW1990 cell line exhibited the highest percentage of CD44+CD24+ cells, which accounted for 39.9% of the total. The expression of members of the Hh signaling pathway in CD44+CD24+/CD44-CD24- cells was detected using reverse transcription-polymerase chain reaction and western blot analysis. The results demonstrated that members of the Hh signaling pathway were differentially expressed in CD44+CD24+ cells compared with CD44-CD24-, normal pancreatic duct cells and unsorted SW1990 cells. In addition, lentiviral expression vectors expressing Smoothened (Smo) small interfering RNA (siRNA) were constructed. Following transfection with the lentiviral expression vectors, Smo expression was markedly reduced in CD44+CD24+ cells. The present study represents a preliminary investigation into the biological characteristics of CD44+CD24+ pancreatic cancer cells. PMID- 30250552 TI - Landscape of somatic mutations in gastric cancer assessed using next-generation sequencing analysis. AB - Gastric cancer is a highly heterogeneous disease and the second leading cause of cancer-associated mortality. However, the genomic basis of gastric cancer is not completely understood and the underlying genetic heterogeneity has not been well studied. In the present study, 1,021 genes were sequenced and the somatic mutations of 45 formalin-fixed, paraffin-embedded gastric adenocarcinoma samples were assessed using next-generation sequencing technologies. In the present study, a median sequencing coverage depth of 708-fold was achieved. Somatic genomic alterations were detected in 37/45 patients (82.4%) and the most frequent genetic alterations identified were tumor protein P53 (TP53) gene mutations. Mutations in MLL4, ERBB3, FBXW7, MLL3, MTOR, NOTCH1, PIK3CA, KRAS, ERBB4 and EGFR were also detected. Patients with TP53 mutations had a higher number of somatic mutations, and the total number of somatic mutations was weakly correlated with patient age. These results provided data on the intratumoral heterogeneity of gastric cancer and may be used in order to develop personalized cancer therapy. PMID- 30250553 TI - Identification of potential functional genes in papillary thyroid cancer by co expression network analysis. AB - Interactions between multiple genes are involved in the development of complex diseases. However, there are few analyses of gene interactions associated with papillary thyroid cancer (PTC). Weighted gene co-expression network analysis (WGCNA) is a novel and powerful method that detects gene interactions according to their co-expression similarities. In the present study, WGCNA was performed in order to identify functional genes associated with PTC using R package. First, differential gene expression analysis was conducted in order to identify the differentially expressed genes (DEGs) between PTC and normal samples. Subsequently, co-expression networks of the DEGs were constructed for the two sample groups, respectively. The two networks were compared in order to identify a poorly preserved module. Concentrating on the significant module, validation analysis was performed to confirm the identified genes and combined functional enrichment analysis was conducted in order to identify more functional associations of these genes with PTC. As a result, 1062 DEGs were identified for network construction. A brown module containing 118 highly related genes was selected as it exhibited the lowest module preservation. After validation analysis, 61 genes in the module were confirmed to be associated with PTC. Following the enrichment analysis, two PTC-related pathways were identified: Wnt signal pathway and transcriptional misregulation in cancer. LRP4, KLK7, PRICKLE1, ETV4 and ETV5 were predicted to be candidate genes regulating the pathogenesis of PTC. These results provide novel insights into the etiology of PTC and the identification of potential functional genes. PMID- 30250554 TI - Preoperative platelet-lymphocyte ratio is an independent prognostic factor in ampullary carcinoma following pancreaticoduodenectomy. AB - The objective of the present study was to evaluate whether preoperative platelet lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) could predict the prognosis for curative resected ampullary carcinoma. A total of 94 patients were retrospectively included over a 6-year period in which consecutive cases underwent pancreaticoduodenectomy for ampullary malignancy. Preoperative blood results were available in the 94 cases of resected ampullary carcinoma. Preoperative PLR and NLR cut-off values of 226.8 and 2.58 were determined to represent the optimal cut-off values in the cases for survival analysis. PLR remained a significant independent predictor of survival in multivariate analysis (Cox, P<0.001) in addition to tumor differentiation (P<0.001), nodal status (P<0.001) and stage (P<0.001). While NLR failed to serve as a prognostic factor in univariate (P=0.0637) and multivariate (P=0.164) survival analysis. Furthermore, the nodal involvement rate was higher in high PLR group (74.2 vs. 19.05%, P<0.001). Preoperative PLR and NLR merit further evaluation as a prognostic index in curative resected ampullary carcinoma. Additionally, it is a candidate predictor for the lymph node metastasis. PMID- 30250555 TI - miR-199b-5p inhibits triple negative breast cancer cell proliferation, migration and invasion by targeting DDR1. AB - Triple negative breast cancer (TNBC) has received increasing attention from oncologists worldwide due to its poor prognosis and paucity of targeted therapies. MicroRNAs (miRs) are a group of small non-coding RNAs that are responsible for the post-transcriptional regulation of various target genes. The present study demonstrated that the expression of miR-199b-5p in breast cancer tissue was significantly reduced compared with that in normal breast tissues by reverse transcription-quantitative polymerase chain reaction. In addition, western blot analysis and luciferase reporter assays revealed that miR-199b-5p in TNBC cells inhibited discoidin domain receptor tyrosine kinase 1 expression by directly targeting its 3'-untranslated region. Furthermore, miR-199b-5p markedly suppressed the proliferation and invasion of TNBC cells, as demonstrated by using wound-healing, migration, invasion and proliferation assays. Collectively, these results indicate that miR-199b-5p may be a novel alternative therapeutic target for TNBC. PMID- 30250556 TI - Clinicopathological characteristics and prognostic factors of gastrointestinal stromal tumors in Chinese patients. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms in the gastrointestinal tract, exhibiting wide variability in their biological behavior. The aim of the present study was to investigate the clinicopathological characteristics and prognostic factors of GISTs in Chinese patients. All GIST cases (n=182) retrieved from the pathology database and the archived files in Shanghai Changzheng Hospital between January 2011 and December 2014 were reviewed. The clinical symptoms, preoperative investigations, treatments, pathological characteristics and follow-up data of these patients were reviewed, and univariate and multivariate survival analyses were performed. A total of 73.1% of the GISTs were located in the stomach, and the most common three symptoms included abdominal pain (30.2%), dyspepsia (23.1%) and gastrointestinal bleeding (21.4%). Univariate analysis revealed that larger tumor size (P<0.001), higher mitotic rate (P<0.001), aggressive behavior (P<0.001), negative smooth muscle actin expression (P=0.009) and palliative resection (P<0.001) contributed toward poor overall survival (OS). In addition, non-gastric disease location (P<0.001), larger tumor size (P<0.001), higher mitotic rate (P=0.004), aggressive behavior (P<0.001) and palliative resection (P<0.001) were associated with poor relapse-free survival (RFS). Multivariate analysis indicated that mitotic rate [hazard ratio (HR=3.761, P=0.015)] and aggressive behavior (HR=3.916, P=0.010) were independent risk factors for OS, while non-gastric location (HR=4.740, P=0.002) and aggressive behavior (HR=4.009, P=0.004) were independent risk factors for RFS. The present study provided information on the clinicopathological characteristics and epidemiology of GISTs in the Chinese population. Non-gastric disease location, higher mitotic rate and tumor metastasis or local invasion prior to treatment were identified as predictors of a poor prognosis. PMID- 30250557 TI - Endoscopic ultrasound-guided fine-needle aspiration biopsy for diagnosis of gastric linitis plastica with negative malignant endoscopy biopsies. AB - The value of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsy in the gastric linitis plastica (GLP) with negative malignant endoscopy biopsies was investigated. Forty-six patients with linitis plastica who had undergone EUS FNA were retrospectively studied, and their clinicopathological data were examined. Among the 46 eligible patients, 38 cases were diagnosed clearly by EUS FNA. There were 24 cases with lymph node metastasis in the 38 patients. Both the lymph nodes and gastric lesions were punctured by EUS-FNA in the 24 cases. We compared the diagnostic accuracy in different sites, and the results showed that the diagnostic accuracy in lymph nodes was significantly higher than that in gastric lesions (P<0.05). Among them, 16 patients underwent surgical resection, and the accuracy of the pathological diagnosis by EUS-FNA was 87.5% (14/16). The preoperative diagnostic accuracy of T and N staging by endoscopic ultrasound (EUS) were both 75%. Neither severe hemorrhage nor perforation occurred in any patient. In conclusion, EUS-FNA is a safe and effective procedure for the diagnosis of indefinite linitis plastica, and puncturing metastatic lymph nodes can improve the diagnostic accuracy. PMID- 30250558 TI - Inhibition of histamine receptor H3R suppresses prostate cancer growth, invasion and increases apoptosis via the AR pathway. AB - Histamine h3 receptor (H3R) is expressed in numerous types of tumor and is associated with tumor cell proliferation, migration and invasion. However, whether H3R is expressed in prostate cancer remains unknown. Therefore, the expression and function of H3R in prostate cancer was investigated. Immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blotting all indicated overexpression of H3R in prostate cancer. Cell counting kit-8 (CCK-8), migration and invasion assays demonstrated that overexpressed H3R is associated with cell proliferation, migration and invasion. Inhibition of H3R induced cell apoptosis, however, androgen receptor protein expression was decreased. Overall, the results suggest that H3R is overexpressed in prostate cancer and associated with cell proliferation, migration and invasion. These results may broaden our understanding of the underlying pathological mechanisms of prostate cancer and aid the discovery of novel treatments for prostate cancer. These findings suggest that inhibition of H3R may have favorable application prospects in the treatment of prostate cancer. PMID- 30250559 TI - An analysis of the expression and function of myeloid differentiation factor 88 in human osteosarcoma. AB - The aim of the present study was to investigate the expression and function of myeloid differentiation factor 88 (MyD88) in osteosarcoma. Immunohistochemical staining was used to detect MyD88 protein in osteosarcoma tissues and matched normal bone tissues. The association between MyD88 expression and the clinical characteristics of patients with osteosarcoma was analyzed. Furthermore, survival analysis of patients with osteosarcoma was performed to study the association between MyD88 expression and patient prognosis. Finally, the effect of the MyD88 inhibitor, ST2825, on the proliferation and apoptosis of the human osteosarcoma cell line U2OS was examined. Additionally, cell proliferation, invasion and apoptosis were examined using an MTT assay, Transwell assay and Annexin V fluorescein isothiocyanate staining kit, respectively. The expression of proteins associated with the NF-kappaB signaling pathway was analyzed by western blotting. The positive expression rate of MyD88 in osteosarcoma and normal bone tissues was 71.4 and 6.1%, respectively. Statistical analysis demonstrated that MyD88 was not associated with gender, age, histological type or tumor location, but that it was associated with Enneking stage and tumor metastasis (P<0.05). According to the survival analysis, patients with osteosarcoma in the high MyD88 expression group displayed a reduced overall survival rate (P<0.05). Furthermore, inhibition of MyD88 by ST2825 in U2OS cells resulted in a marked decrease in cellular proliferation and migration, and an increase in the rate of apoptosis (P<0.05). Notably, ST2825 significantly decreased cyclin D1, matrix metallopeptidase-9 and nucleus p65 expression, but increased cleaved-caspase 3 expression in ST2825 treated U2OS cells (P<0.05). The results of the present study indicated that MyD88 expression is associated with the progression of osteosarcoma and may be a potential therapeutic target for the treatment of osteosarcoma. PMID- 30250560 TI - Differential expressions of integrin-linked kinase, beta-parvin and cofilin 1 in high-fat diet induced prostate cancer progression in a transgenic mouse model. AB - High-fat diet induced obesity was associated with more aggressive prostate cancer. Recent research has demonstrated that integrin-linked kinase (ILK), beta parvin and downstream cofilin 1 jointly affected cancer progression. Meanwhile, these proteins were also involved in energy metabolism. Therefore, the present study was conducted to investigate the potential function of ILK, beta-parvin and cofilin 1 in the high-fat diet-induced progression of prostate cancer. Transgenic mice with prostate cancer were employed, fed with different diets and sacrificed at 20 and 28 weeks. Tumor differentiation, extracapsular extension and metastasis were compared between the groups. Expression levels of ILK, beta-parvin and cofilin 1 in prostate were evaluated by immunohistochemical analysis and determined by an immunoreactivity score. Public databases were applied for analysis and validation. It was detected that high-fat diet feeding promoted cancer progression in transgenic mice with prostate cancer, with increased expressions of beta-parvin (P=0.038) and cofilin 1 (P=0.018). Higher expressions of ILK, beta-parvin and cofilin 1 were also associated with poorer cancer differentiation. Additionally, higher mRNA levels of CFL1 were correlated with a worse disease-free survival in patients of certain subgroups from The Cancer Genome Atlas database. Further studies were warranted in discussing the potential roles of ILK, beta-parvin and cofilin 1 in high-fat diet feeding induced progression of prostate cancer. PMID- 30250561 TI - Comparison between open partial laryngectomy with tube-free tracheostomy and total laryngectomy for hypopharyngeal cancer with cartilage invasion. AB - The present study aimed to identify a feasible treatment strategy for hypopharyngeal cancer (HPC) with non-extensive invasion of the thyroid and/or cricoid cartilage. Between June 2008 and December 2014, patients with previously untreated HPC invading cartilage who had received either open partial laryngectomy (OPL) with tube-free tracheostomy or total laryngectomy (TL) with permanent tracheostomy and an artificial larynx (pneumatic tube) were retrospectively reviewed. The patients with extensive cartilage invasion and those with inoperable or T4b disease were excluded for OPL. Outcomes and quality of life were compared between the two treatment modalities. A total of 44 patients were included. The survival rates, complications, and Dysphagia Score were compared between the two treatment modalities. The outcome of the Voice Handicap Index (P=0.032), understandability of speech (P<0.001), normalcy of diet (P=0.041), senses (P=0.006), speech (P<0.001) and social contact (P=0.004) were significantly improved in the group receiving OPL compared with the group receiving TL. Therefore, OPL with tube-free tracheostomy may be a feasible option to treat patients with HPC with non-extensive invasion of the thyroid and/or cricoid cartilage. PMID- 30250562 TI - WTX inhibits gastric cancer migration through the reversal of epithelial mesenchymal transition. AB - The aim of the present study was to investigate whether the expression of Wilms' tumor gene on X chromosome (WTX) affected the epithelial-mesenchymal transition (EMT) process and migration of gastric cancer cells. Stable WTX-overexpressing AGS cells (AGS.W) were established and analyzed by flow cytometry. The efficiency of the overexpression was verified by fluorescence microscopy, reverse transcription-quantitative polymerase chain reaction and western blotting. To analyze the expression of EMT-associated proteins, western blotting and immunofluorescence assays were performed. The migratory capability of the cells was detected by Transwell wound-healing assays, respectively. Compared with that of the control cells (AGS.veh), WTX expression was notably increased at mRNA (P<0.05) and protein levels (P<0.05) in the AGS.W gastric cancer cells. Morphological observations indicated that AGS.W cells transformed into spindle shapes, compared to AGS.veh cells, which maintained round or oval shapes. Furthermore, western blotting and immunofluorescence validated that the expression level of the epithelial marker epithelial-cadherin was significantly increased, whereas the expression levels of the mesenchymal markers neural cadherin, beta-catenin and vimentin were significantly decreased in the AGS.W cells compared with those in the AGS.veh cells. In addition, the overexpression of WTX decreased the migratory ability of AGS.W cells compared with AGS.veh cells. Exogenous expression of WTX inhibited gastric cancer cell migration by reversing EMT. The results of the present study describe a molecular feature that may be a promising target for future gastric cancer therapy strategies. PMID- 30250563 TI - SLC6A1-miR133a-CDX2 loop regulates SK-OV-3 ovarian cancer cell proliferation, migration and invasion. AB - The present study assessed the expression of solute carrier 6 member 1 (SLC6A1) in ovarian cancer (OC) tissues and evaluated the effect of silencing SLC6A1 or caudal type homeobox 2 (CDX2) on the proliferation, migration, and invasion of SK OV-3 OC cells. The levels of caudal type homeobox 2 (CDX2) and SLC6A1 mRNA were also examined in OC SK-OV-3, OVCAR3 and A2780 cell lines. The mRNA levels of CDX2 and SLC6A1 in SK-OV-3 OC cells were assessed following transection with microRNA (miR) 133a mimics; the mRNA and protein levels of SLC6A1 were determined following the silencing of CDX2, and the mRNA expression of CDX2 was gauged following the silencing of SLC6A1. A luciferase reporter assay was performed to assess the effect of miR133a on the CDX2 and SLC6A1 3'-untranslated regions (3'UTRs). The proliferation, migration and invasion rate of SK-OV-3 cells were then examined following the silencing of CDX2 or SLC6A1. The expression of SLC6A1 was increased in OC compared with adjacent tissue. The expression of CDX2 and SLC6A1 in SK-OV-3 and OVCAR3 cells was increased compared with A2780 cells (P<0.05). The level of CDX2 and SLC6A1 mRNA in SK-OV-3 cells decreased when the cells were transected with the miR133a mimics, compared with a negative control (P<0.05). Transfection with the miR133a mimics significantly reduced the luciferase activity of reporter plasmids with the SLC6A1 or CDX2 3'UTRs (P<0.05). The mRNA level of CDX2 was decreased subsequent to the silencing of SLC6A1; the mRNA and protein level of SLC6A1 were decreased when CDX2 was silenced (P<0.05). The proliferation, migration, and invasion of SK-OV-3 cells were significantly reduced following the silencing of CDX2 or SLC6A1 (P<0.05). CDX2 may therefore be inferred to promote the proliferation, migration and invasion in SK-OV-3 OC cells, acting as a competing endogenous RNA. PMID- 30250565 TI - Silencing of heart and neural crest derivatives expressed transcript 2 attenuates transforming growth factor-beta1-enhanced apoptosis of human bronchial epithelial cells. AB - Human bronchial epithelial (HBE) cells form the first protective barrier of the airway to protect patients from pulmonary diseases. The present study was performed to illustrate the mechanism underlying the effect of silencing heart and neural crest derivatives expressed transcript 2 (HAND2) on attenuating the transforming growth factor (TGF)-beta1-enhanced apoptosis of HBE cells. TGF-beta1 (10 ug/ml) was applied to HBE cells, and the HBE cells were transfected with small interfering RNA targeting HAND2 or were transfected with non-specific sequence. Subsequently, cell proliferation was measured using a Cell Counting kit 8 assay, whereas cell cycle and apoptosis status were measured using a flow cytometer. Reverse transcription-quantitative polymerase chain reaction and western blot analyses were performed to detect the expression levels of cell cycle- and apoptosis-related factors. Western blot analysis was also used to detect the phosphorylation levels of extracellular signal-regulated kinase (ERK), P38 and c-Jun-N-terminal kinase (JNK) of mitogen-activated protein kinase (MAPK) pathways. The results showed that TGF-beta1 decreased HBE cell proliferation ability, arrested cell cycle at the G2 phase and promoted cell apoptosis with statistical significance. The expression levels of P21 and Cyclin D1 were inhibited, and those of caspase-3, caspase-8 and caspase-9 were promoted by TGF beta1. The phosphorylation levels of ERK, P38 and JNK were increased by TGF beta1. HAND2-silencing significantly alleviated the above functions of TGF-beta1 on the HBE cells. In conclusion, the silencing of HAND2 attenuated the TGF-beta1 stimulated apoptosis of HBE cells through regulating cell cycle, apoptosis related factors and ERK/P38/JNK MAPK pathways. This may provide a novel treatment strategy for pulmonary disease, with HAND2 as the novel gene target. PMID- 30250564 TI - Precision medicine based on tumorigenic signaling pathways for triple-negative breast cancer. AB - As a clinically heterogeneous subtype of breast cancer, triple-negative breast cancer (TNBC) is associated with a poor clinical outcome and a high relapse rate. Conventional chemotherapy and radiotherapy are effective treatments for patients with TNBC. However, the prognosis of TNBC remains unsatisfactory. Therefore, a large volume of research has explored the molecular markers and oncogenic signaling pathways associated with TNBC, including the cell cycle, DNA damage response and androgen receptor (AR) signaling pathways, to identify more efficient targeted therapies. However, whether these predicted pathways are effective targets has yet to be confirmed. In the present review, potentially carcinogenic signaling pathways in TNBCs from previous reports were considered, and ultimately five tumorigenic signaling pathways were selected, specifically receptor tyrosine kinases and downstream signaling pathways, the epithelial-to mesenchymal transition and associated pathways, the immunoregulatory tumor microenvironment, DNA damage repair pathways, and AR and coordinating pathways. The conclusions of the preclinical and clinical trials of each pathway were then consolidated. Although a number of signaling pathways in TNBC have been considered in preclinical and clinical trials, the aforementioned pathways account for the majority of the malignant behaviors of TNBC. Identifying the alterations to different carcinogenic signaling pathways and their association with the heterogeneity of TNBC may facilitate the development of optimal precision medical approaches for patients with TNBC, potentially improving the efficiency of anticancer therapy. PMID- 30250566 TI - Erianin inhibits human cervical cancer cell through regulation of tumor protein p53 via the extracellular signal-regulated kinase signaling pathway. AB - Erianin, a natural bibenzyl compound, is present in Dendrobium chrysotoxum Lindl. (commonly known as Shihu in China), which is used as an antipyretic and analgesic in traditional Chinese medicine, and has been reported to exert inhibitory effects on cancer cells in vitro. Cervical cancer is the third-most common cancer in women worldwide, and has the highest morbidity rate of gynecological malignancies. Thus, the identification of effective chemotherapeutical agents to treat this disease is urgent. The aim of the present study was to elucidate the biological functions and molecular mechanism of erianin on HeLa cells. Cellular proliferation was assessed using an MTT assay and flow cytometry assay with propidium iodide (PI) staining. Apoptosis rates were observed using a high content screening system via annexin V-fluorescein isothiocyanate/PI double staining, and measured by flow cytometry. The protein levels of tumor protein p53, extracellular signal-regulated kinase 1/2 (ERK1/2), caspase-3, B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X (Bax) were assessed by western blot analysis. Erianin inhibited the growth of HeLa cells and induced apoptosis in a dose- and time-dependent manner, inducing cell cycle arrest at the G2/M stage. Erianin treatment also increased the expression of Bax and caspase-3, but decreased levels of Bcl-2 and phosphorylated-ERK1/2. Cells treated with paclitaxel were regarded as the positive group. Together, the results of the present study indicated that erianin could be considered as an effective drug candidate; in HeLa cells it inhibited cellular proliferation and promoted apoptosis via regulation of the ERK1/2 signaling and mitochondrial-based apoptosis pathways. Thus, erianin has the promise to be developed further for cervical cancer therapy. PMID- 30250567 TI - Cytotoxic chemotherapy reduces T cell trafficking to the spleen by downregulating the expression of C-C motif chemokine ligand 21 and C-C motif chemokine ligand 19. AB - T cells serve an important role in the destruction of tumor cells and clearing of foreign pathogens. Previous studies have suggested that the T cell immune response of tumor-bearing patients is significantly lower than that of healthy people, and the principal reason for this is lymphocytopenia, which is caused by repeated cycles of chemotherapy. In addition to lymphocytopenia, the present study revealed that cytotoxic chemotherapy also weakens the homing ability of T cells to the T-cell zone of the spleen, which decreases the possibility of encounters between antigen-specific T cells and dendritic cells presenting the appropriate antigen, thereby weakening the immune response of T cells. These changes are attributed to the lower expression of C-C motif chemokine ligand 21 (CCL21) and C-C motif chemokine ligand 19 (CCL19) in the spleen of secondary lymphoid organs (SLOs). Finally, the present study identified that chemotherapy affects the function and survival of fibroblastic reticular cells in SLOs, which are the main source of CCL21 and CCL19. These observations aid us in further understanding the mechanism that is responsible for the decreased T cell immune response following repeated cycles of chemotherapy. PMID- 30250568 TI - Liriodenine enhances radiosensitivity in esophageal cancer ECA-109 cells by inducing apoptosis and G2/M arrest. AB - At present, chemotherapy and radiotherapy represent the primary modalities of treatment for patients with unresectable esophageal squamous cell carcinoma (ESCC). However, the outcome of patients remains poor owing to radioresistance. The present study aimed to determine the radiosensitizing effect of liriodenine, an aporphine alkaloid derived from Enicosanthellum pulchrum, and investigating the underlying mechanisms in ESCC, using the esophageal cancer ECA-109 cell line. Cellular proliferation was evaluated using the Cell Counting kit-8 assay. Colony formation assay was performed to characterize the radiosensitive effects of liriodenine on ECA-109 cells, and flow cytometry was used to detect the percentage of cells undergoing apoptosis. An immunofluorescence assay was utilized to evaluate the DNA damage repair ability. Western blotting was used to assess the protein levels of caspase-3, B cell lymphoma-2 (Bcl-2) and Bcl-2 associated X (Bax). Liriodenine dose-dependently inhibited ECA-109 cell viability. The clonogenic survival assay demonstrated that liriodenine increased the radiosensitivity of ESCC cells, with a sensitization enhancement ratio of 1.11-1.69. The results of flow cytometry demonstrated that liriodenine induced apoptosis and G2/M arrest. The immunofluorescence assay revealed that liriodenine delays DNA damage repair. The upregulation of Bax and Caspase-3, and the suppression of Bcl-2 confirmed that apoptosis was occurring. Liriodenine radiosensitizes ECA-109 cells by inducing apoptosis and G2/M arrest. The findings of the present study indicated that liriodenine may represent an anticancer agent with promising potential for the treatment of ESCC. PMID- 30250569 TI - Inhibitory effects of miR-25 targeting HMGB1 on macrophage secretion of inflammatory cytokines in sepsis. AB - High mobility group box 1 (HMGB1) can promote the migration of macrophages and the release of inflammatory cytokines, functions associated with the occurrence of sepsis. The role of microRNA (miR)-25 in the targeted regulation of HMGB1 expression and the release of macrophage inflammatory cytokines remains uncharacterized. The present study investigated the association between miR-25, HMGB1 and sepsis by analyzing the expression of miR-25 and HMGB1 in patients with sepsis. The present study also investigated whether miR-25 serves a role in targeting the regulation of HMGB1 expression and macrophage inflammatory factor release. Patients with sepsis were selected from the Intensive Care Unit, and serum levels of HMGB1. The expression of miR-25 and HMGB1 in serum and peripheral blood mononuclear cells (PBMCs) was compared. Macrophages were cultured in vitro and divided into 5 groups following treatment with lipopolysaccharide (LPS). The expression levels of miR-25, HMGB1, phosphorylated (p-)p65, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and HMGB-1 were compared, and the migration ability of cells was investigated by Transwell assays. Compared with the healthy controls, patients with sepsis exhibited elevated expression of HMGB1 and decreased expression of miR-25 in serum and PBMCs. Following treatment with LPS, the expression of HMGB1 and p-p65 was elevated, and the expression of miR-25 was decreased in macrophages compared with untreated cells. Following transfection with miR-25 mimics and/or short interfering RNA-HMGB1, the expression of HMGB1 in macrophages decreased significantly, the expression of p p65, HMGB-1, TNF-alpha and IL-6 in the culture solution were also decreased, and the migration ability of macrophages was attenuated. The present study suggests that miR-25 attenuated the induction of HMGB1 by LPS, decreased the activity of nuclear factor-kappaB and the transcriptional activation of TNF-alpha and IL-6, and suppressed the migration of macrophages. Inhibiting expression of miR-25 may serve a role in upregulating HMGB1 expression, promoting the secretion of inflammatory cytokines and resulting in sepsis. PMID- 30250570 TI - Photodynamic therapy reduces the inhibitory effect of osteosarcoma cells on dendritic cells by upregulating HSP70. AB - Osteosarcoma is the most common primary bone tumor and predominantly affects children and adolescents. The prognosis for patients with osteosarcoma is poor. Therefore, the development of novel treatments for osteosarcoma is required. Photodynamic therapy (PDT) is a disease site-specific treatment that utilizes a photosensitizing agent along with light to kill cancer cells. This agent only works following activation by certain wavelengths of light. After the agent is absorbed by the cancer cells, light is then applied to the area to be treated. The light causes the drug to react with oxygen, which produces radical and reactive oxygen species that kill the cells. However, the immune reaction that occurs following PDT remains unknown. The present study demonstrated that the necrosis of osteosarcoma cells inhibited the function of dendritic cells. However, treatment of osteosarcoma cells with PDT restored the function of dendritic cells by upregulating heat shock protein 70. Taken together, the results of the present study provided insight into the subsequent molecular reaction following PDT treatment of osteosarcoma at the molecular level. PMID- 30250571 TI - Dextran sulfate inhibition on human gastric cancer cells invasion, migration and epithelial-mesenchymal transformation. AB - The objective of the present study was to observe the influence of dextran sulfate (DS) on the proliferation, invasion and migration of AGS, BGC-23, GES-1, MGC-803 and SGC-7901 cells. Additionally, the possible inhibition mechanism of DS on BGC-823 cells epithelial-mesenchymal transition (EMT) was explored. The cells in the control and experimental group were treated with PBS and DS respectively. The effect of DS on the invasion and migration of these five types of cells were investigated using Transwell invasion and migration assays. Immunocytochemistry, western blotting and reverse transcription-polymerase chain reaction (RT-PCR) assays were used to measure gene and protein expression of hypoxia-inducible factor 1alpha (HIF1-a) and EMT associated factors [Twist, E-cadherin, N-cadherin and beta-catenin] of BGC-823 cells. According to the results of CCK-8, DS significantly decreased the proliferation of AGS, SGC-7901 and BGC-823 cells to different extents, but there were no notable differences for MGC-803 cells. Transwell migration and invasion results demonstrated that, compared with the control group, DS reduced the migration and invasion of every types of cells to different extents, and the inhibition to BGC-823 cells invasion is the most notably. Immunofluorescence, RT-PCR and western blot analysis results indicated that HIF-1alpha, Twist and N-cad expressions levels had different degrees of reduction in the experimental group following DS treatment; however, the expression level of E-cad had increased. In conclusion, DS inhibited the proliferation of AGS, BGC-823, SGC-7901 and GES-1 cells, the inhibition degree may be associated with the differentiation degree of every cancer cell, the higher the differentiation degree, the stronger the inhibition. DS inhibited migration and invasion of the five types of gastric cancer cells in different degree. DS may inhibit EMT of BGC-823 by inhibiting Wnt signaling. PMID- 30250572 TI - Impact of local tumor lesion treatments and preoperative indicators on the survival of patients with small hepatocellular carcinomas. AB - The prognosis for small hepatocellular carcinomas (SHCC) remains uncertain. The aim of the present study was to compare three local tumor lesion treatments and identify the prognostic factors in patients with SHCC by analyzing preoperative indicators. A retrospective study was performed using data from 206 patients with SHCC from 2006-2015. All of the patients had undergone transarterial chemoembolization (TACE) alone, TACE plus percutaneous microwave coagulation therapy (PMCT) or surgical resection (SR). The Kaplan-Meier method was used to calculate the survival rates. Multivariate analysis was conducted using Cox regression analysis. The median survival time of patients with SHCC was 27 (range, 14-49) months in the TACE group, 29.5 (range, 16-52) months in the TACE PMCT group and 36.5 (range, 26-52) months in the SR group (P=0.091). The 1, 3 and 5-year survival rates for patients with SHCC were 82.4, 64.9 and 46.8% in the TACE group; 89.0, 72.6 and 58.3% in the TACE-PMCT group and 88.8, 72.3 and 58.6% in the SR group (P=0.181), respectively. Analysis from the Cox regression model demonstrated that preoperative alpha-fetoprotein (AFP; <400 ng/ml vs. >=400 ng/ml; HR=0.548; P=0.036) was an independent predictor of the survival time of patients with SHCC. Analysis of patients with preoperative AFP levels of >=400 ng/ml revealed that the median survival time in the SR group was 36 (range, 28.25 52) months, significantly longer than the TACE (17 months; range, 12-44 months) and TACE-PMCT group (27 months; range, 14-55 months; P=0.035). The 1, 2 and 3 year survival rates for patients with SHCC with >=400 ng/ml AFP were: 70.8, 55.5 and 49.9% in the TACE group; 83.7, 68.0 and 60.8% in the TACE-PMCT group; and 90.9, 81.8 and 61.0% in SR group, respectively (P=0.664). However, there was no significant difference among the three groups in the survival time of patients with SHCC with <400 ng/ml preoperative AFP. The observations indicated that SR is not significantly different for overall survival time in the patients with SHCC between the two groups; this method can be employed for patients with SHCC. This was based on the median survival time of patients with >=400 ng/ml AFP in the SR group who had a longer survival time and a higher survival rate than in the TACE and TACE-PMCT group. PMID- 30250573 TI - Src kinase inhibitor PP2 regulates the biological characteristics of A549 cells via the PI3K/Akt signaling pathway. AB - Lung cancer is one of the most prevalent types of cancer worldwide, with a poor prognosis for patients and a concomitant financial burden on society. There are a number of different pathological subtypes, with non-small cell lung cancer (NSCLC) being the primary subtype. Although anticancer therapy has led to a marked improvement in the survival rate of patients in recent years, the survival rate remains poor. Potential reasons for this include a lack of early diagnosis and drug resistance, which is considered to be associated with mutations in components of signaling pathways, tumor suppressors and epidermal growth factor receptor, and certain other complex mechanisms to a certain extent. It is therefore imperative to develop novel therapies. In the present study, the pyrazolopyrimidine compound PP2 was used to inhibit Src family protein tyrosine kinases in A549 cells. It was demonstrated that PP2 was able to suppress cell viability, migration and invasion, and promote apoptosis via regulating the phosphoinositide 3-kinase/protein kinase B/B-cell lymphoma 2/caspase-3 signaling pathway. PP2 may therefore be useful in anti-NSCLC therapy in the future. PMID- 30250574 TI - Smokeless tobacco extract inhibits proliferation and promotes apoptosis in oral mucous fibroblasts. AB - The consumption of smokeless tobacco extract (STE) is growing rapidly, and it has been implicated in several human diseases including diabetes, inflammation and a number of types of cancer. The toxicity of STE requires evaluation, as it is known to induce numerous public health issues. To investigate whether STE serves a role in cultured human oral mucosa fibroblasts (hOMFs), the present study examined HOMF morphology with inverted microscopy and immunofluorescence staining. The cell viability was measured with MTT assays, which detected the cell apoptosis rate via flow cytometry. The activities of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were measured via flow cytometry and commercial kits, subsequent to exposing the cells to various concentrations of STE. Reverse transcription quantitative polymerase chain reaction and western blot analyses were used to demonstrate that the mRNA and the protein expression levels of cell cycle-associated genes (cyclin dependent kinase inhibitor 1 and cyclin D1), apoptosis-associated genes [B cell lymphoma 2 (Bcl-2) and Bcl-2-associatied X protein], tumor protein (p53), nuclear factor kappa light chain enhancer of activated B cells (NF-kappaB)-transcription factor (p65) signaling pathways, NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H: quinoneoxidoreductase1 (NQO1). The results indicated that the hOMF cells were positive for cytokeratin staining. STE induced G1-S cell cycle progression and cell apoptosis by regulating the cell cycle or apoptosis associated proteins. STE treatment increased the concentrations of ROS and MDA, and decreased the concentrations of SOD and CAT. STE unregulated phosphorylated p53, NF-kappaB p65, Nrf2, HO-1, and NQO1 expression levels in the hOMF cells. The present study demonstrated that STE appears to promote oral disease. PMID- 30250575 TI - MicroRNA-153 suppresses human laryngeal squamous cell carcinoma migration and invasion by targeting the SNAI1 gene. AB - Human laryngeal squamous cell carcinoma (LSCC) is a malignant cancer type. Epithelial-mesenchymal transition marker Snail family transcriptional repressor 1 (SNAI1) is associated with the occurrence, development, invasion and metastasis of numerous tumor types, such as lung, liver and ovarian cancer. Previous studies have indicated that microRNA-153 (miR-153) may serve as a novel tumor suppressor, which is involved in tumor metastasis; however, the role and clinical significance of miR-153 in LSCC are not fully understood. The aim of the present study was to determine the role of miR-153 in the growth and aggressiveness of LSCC cells. Bioinformatics prediction method, western blot analysis, Matrigel invasion assay and immunofluorescence were used to analyze whether SNAI1 can be regulated and controlled by miR-153 in LSCC cells. An inverse association between miR-153 and SNAI1 was observed in LSCC tissues. It was demonstrated that SNAI1 is a direct target of miR-153 in LSCC. In addition, the results indicated that miR 153 knockdown inhibited PCI-13 cell migration and invasion by targeting SNAI1, which may be a potential marker that can reflect the degree of malignancy in patients with LSCC. Furthermore, miR-153 knockdown decreased Twist family BHLH transcription factor 1 and metastasis-associated 1 family member 3 expression in LSCC cells. In conclusion, these data indicated that miR-153 regulates LSCC migration via the targeting of SNAI1 gene, which may be a potential predictor for patients with LSCC. PMID- 30250576 TI - Correlation between DCE-MRI radiomics features and Ki-67 expression in invasive breast cancer. AB - The aim of the present study was to investigate the association between Ki-67 expression and radiomics features of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with invasive breast cancer. A total of 53 cases with low-Ki-67 expression (Ki-67 proliferation index <14%) and 106 cases with high-Ki-67 expression (Ki-67 proliferation index >14%) were investigated. A systematic approach was applied that focused on the automated segmentation of lesions and extraction of radiomics features. For each lesion 5 morphology, 4 gray-scale histogram and 6 texture features were obtained, and statistical analyzes were performed to assess the differences in these features between the low- and high-Ki-67 expressions. One morphology metric (area), 3 gray-scale histogram indexes (standard deviation, skewness and kurtosis) and 3 texture features (contrast, homogeneity and inverse differential moment) demonstrated a significant difference (P<0.05), with low-Ki-67 expression lesions tending to be smaller, clearer and heterogeneous when compared with the high-Ki-67 expressed cases. These results may provide a noninvasive means to better understand the proliferation of breast cancer. PMID- 30250577 TI - Spindle cell melanoma: Incidence and survival, 1973-2017. AB - Spindle cell melanoma (SCM) is a rare morphological subtype of melanoma, which is relatively uncharacterized. The aim of the present study was to investigate the incidence of SCM, its general demographics, basic clinico-pathologic features, treatment outcomes and disease-specific prognostic factors. SCM cases were sampled from the Surveillance, Epidemiology and End Results (SEER) Program (1973 2017). A total of 4761 SCM cases were identified, with a median age of 66 years. The female:male ratio was 0.62:1. Statistically significant overall survival (OS) and disease-specific survival (DSS) rate differences were identified depending on age, sex, ethnicity, tumor location, T stage, N stage, M stage, pathological grade, AJCC stage, SEER stages and surgical treatment (P<0.05). Multivariate Cox regression analysis revealed that age >66 years, T3+T4 stage disease, positive N stage and SEER historic stage of regional and distant metastasis tumor were associated with poor DSS and OS rates. In summary, SCM was most common in Caucasian people of 60~80 years of age with a predominance in males. Patient's age, ethnicity, T stage, N stage, and SEER historic stage were identified as independent prognostic factors of SCM in terms of DSS and OS. PMID- 30250578 TI - Intravoxel incoherent motion magnetic resonance imaging for breast cancer: A comparison with benign lesions and evaluation of heterogeneity in different tumor regions with prognostic factors and molecular classification. AB - The objective of the present study was to compare the differentiation between breast cancer and benign breast lesions and study regional distribution characteristics in various subtypes of breast cancer using intravoxel incoherent motion (IVIM) parameters. This retrospective study involved 119 patients with breast cancer and 22 patients with benign breast lesions, who underwent 3.0T breast magnetic resonance imaging examinations. The apparent diffusion coefficient (ADC) and IVIM parameters (slow ADC, fast ADC and fraction of fast ADC) were obtained from patients with breast cancer and benign lesions using diffusion-weighted imaging (DWI) with b-values of 0, 50, 100, 150, 200, 400, 500, 1,000 and 1,500 sec/mm2. Compared with patients with benign breast lesions, patients with breast cancer exhibited decreased ADC (P<0.001), slow ADC (P<0.001) and fast ADC (P<0.001) values, and higher fraction of fast ADC (P<0.001) values. Tumors with metastatic axillary lymph nodes demonstrated increased fraction of fast ADC values (P<0.001) and decreased slow ADC values (P<0.001) compared with tumors without metastatic axillary lymph nodes. The Fast ADC values of tumor tissues in estrogen receptor (ER) and progesterone receptor (PR) negative groups were higher than in positive groups (P<0.001), and the slow ADC values of tumor tissues were lower in ER and PR negative groups than positive groups (P<0.001). Luminal B (HER2- negative) tumor (P<0.001) and peritumor (P<0.001) tissues exhibited decreased fraction of fast ADC values, in comparison with other subtypes. Triple-negative breast cancer (TNBC) tumor tissue exhibited increased fast ADC (P<0.001) and fraction of fast ADC values (P<0.001), and decreased slow ADC values (P<0.001), when compared with other subtypes. The TNBC tumor edge tissues had increased fraction of fast ADC values compared with other subtypes (P<0.01) and TNBC tumor tissues (P<0.05). Therefore, the IVIM parameters of tumor, tumor edge and peritumor tissues in various subtypes of breast cancer may be useful for differentiation of breast cancer subtypes and to assess the invasive extent of the tumors. PMID- 30250579 TI - Bone morphogenetic protein and activin membrane-bound inhibitor suppress bone cancer progression in MG63 and SAOS cells via regulation of the TGF-beta-induced EMT signaling pathway. AB - Bone cancer is one of the most common tumor types that occurs in bones and their affiliated tissues. The prognosis remains poor due to the limited number of effective therapeutic targets. Downregulation of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) has been observed in human cancer cells and BAMBI reconstitution can inhibit growth and metastasis of human cancer cells. In the present study, a potential mechanism mediated by BAMBI in osteosarcoma cells was investigated. The data demonstrated that BAMBI reconstitution suppressed the cell growth, migration and invasion of the osteosarcoma cell lines SAOS2 and MG63. Alterations to the epithelial-to-mesenchymal transition (EMT) marker expression were observed in BAMBI-treated osteosarcoma SAOS2 and MG63 cells. The apoptosis rate of SAOS2 and MG63 cells induced by cisplatin were increased in BAMBI-treated osteosarcoma SAOS2 and MG63 cells via downregulation of the anti-apoptosis genes P16, P21 and B-cell lymphoma 2. The potential mechanism investigated indicated that BAMBI administration downregulated the transforming growth factor-beta (TGF-beta) signaling pathway, whilst knockdown of BAMBI upregulated the TGF-beta signaling pathway in SAOS2 and MG63 cells. Reconstitution of BAMBI in SAOS2 and MG63 cells resulted in a notable reduction of TGF-beta-induced EMT, cell growth, migration and invasion in vitro. In conclusion, the results demonstrated that BAMBI reconstitution inhibited growth and invasiveness of osteosarcoma, as well as promoted the apoptotic sensibility, which indicated that the TGF-beta-induced EMT signaling pathway may be regarded as a potential target for osteosarcoma therapy. PMID- 30250580 TI - Positive expression of ZNF689 indicates poor prognosis of hepatocellular carcinoma. AB - The objective of the present study was to investigate the association between zinc finger protein (ZNF) 689 expression and the clinicopathological features and prognosis of hepatocellular carcinoma (HCC). A total of 102 paired HCC and paired non-cancerous tissues, and 16 normal liver tissues were collected. ZNF689 expression was examined in HCC tissues, paired-noncancerous tissues, and normal liver tissues using RT-qPCR and immunohistochemistry analysis, and the association between ZNF689 expression and HCC prognosis was analyzed using the Kaplan-Meier method. ZNF689 expression was not significantly different between HCC tissues and paired-noncancerous tissues (P=0.61). ZNF689 expression in HCC and paired-noncancerous tissues was significantly increased compared with that in normal liver tissues (P<0.01). Positive expression of ZNF689 protein in HCC was significantly associated with a tumor size of >=10 cm, tumor capsule infiltration, and microvascular invasion (P<0.05). Positive expression of ZNF689 was a prognostic factor for overall survival time [hazard ratio (HR):1.961; P=0.048] and progression-free survival time (HR:1.902; P=0.041). ZNF689 maybe a novel predictor for prognosis of patients with HCC. PMID- 30250581 TI - MiR-1260b inhibitor enhances the chemosensitivity of colorectal cancer cells to fluorouracil by targeting PDCD4/IGF1. AB - Colorectal cancer (CRC) is the most common malignant tumor type and has become resistant to 5-fluorouracil (5-FU) in recent decades, which is one of the most popular therapies. Recently, microRNA (miRNA or miR) has been investigated as a potential therapeutic strategy for CRC. However, there has been little investigation of the underlying mechanism of the association between expression of miRNA and chemosensitivity. The present study aimed to investigate the effect of miR-1260b inhibitor on CRC cells, and their chemosensitivity to 5-FU, by treating them with the miR-1260b inhibitor. miR-1260b inhibitor was demonstrated to significantly promote the proliferation and invasion of the CRC cell line, HCT116, and to increase the apoptotic rate. Furthermore, it was validated that programmed cell death 4 (PDCD4) was a direct target of miR-1260b inhibitor in CRC with bioinformatics tools and a luciferase assay. Western blot analysis revealed that miR-1260b inhibitor could significantly decrease PDCD4 expression, and downregulate the expression of phosphorylated-Akt (p-Akt) and phosphorylated extracellular-signal-regulated kinase (p-ERK). In conclusion, it was confirmed that the anti-tumor effect of the miR-1260b inhibitor was conducted by blocking the phosphorylated 3-kinase/Akt pathway as dysregulated protein expression induced by miR-1260b inhibitor was rescued by insulin-like growth factor. Notably, miR-1260b inhibitor could significantly enhanced the chemoresponse of HCT116 cells to 5-FU via reduced proliferation, increased apoptosis, and downregulation of PDCD4, p-Akt and p-ERK protein expression. In summary, the present study may provide a novel direction for future clinical therapy to enhance the chemosensitivity of tumor cells. PMID- 30250582 TI - Downregulation of lncRNA PVT1 expression inhibits proliferation and migration by regulating p38 expression in prostate cancer. AB - Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) has been reported to be overexpressed in prostate cancer cells and associated with tumorigenesis in various types of cancer. However, the biological function of lncRNA PVT1 remains largely unknown. The aim of the present study was to investigate the effect of lncRNA PVT1 expression on the proliferation and migration of prostate cancer cells. Stably transfected prostate cancer cells with downregulated expression of lncRNA PVT1 were constructed by an efficient siRNA fragment, followed by confirmation by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Proliferation was assessed using CCK-8, colony formation and xenograft assays, and cell migration was evaluated using a wound healing assay. The PathScan(r) Intracellular Signaling Array kit was utilized to explore the underlying molecular mechanisms of lncRNA PVT1 expression in prostate cancer cells. RT-qPCR results confirmed that the lncRNA PVT1 expression level was successfully knocked down in prostate cancer cells. When lncRNA PVT1 expression was downregulated in prostate cancer cells, proliferation and migration were significantly inhibited, compared with the control lncRNA PVT1 group. Furthermore, PVT1 knockdown decreased the phosphorylation of p38 in DU145 cells. Therefore, the present study demonstrated that lncRNA PVT1 downregulation inhibits the proliferation and migration of prostate cancer cells, and is associated with p38 phosphorylation. PMID- 30250583 TI - A novel EXT2 frameshift mutation identified in a family with multiple osteochondromas. AB - Multiple osteochondromas (MO) is an autosomal inherited disease that is characterized by benign bone tumors. However, the underlying mechanism of MO at a molecular level requires further investigation. The majority of mutations associated with MO occur in the exostosin glycosyltransferase genes (EXT)1 or EXT2. In the present study, the genetic causes of the disease were investigated. Polymerase chain reaction amplification, followed by DNA sequencing of the complete EXT1 and EXT2 coding regions, were conducted in a family with MO (n=5). A novel frameshift mutation in exon 3 of EXT2 (c.660delG) was detected. The production of a defective EXT2 protein, lacking 450 C-terminal amino acid residues is predicted to be caused by the c.660delG mutation, located within the exostosin domain of EXT2. The missing residues contain the exostosin and glycosyltransferase family 64 domains, which are critical for the function of EXT2. The novel c.660delG frameshift mutation in the EXT2 gene extends the etiological understanding of MO and may provide an effective reference for genetic counseling and prenatal diagnosis in this family. PMID- 30250584 TI - D Rhamnose beta-Hederin against human breast cancer by reducing tumor-derived exosomes. AB - D Rhamnose beta-hederin (DRbeta-H), a novel oleanane-type triterpenoid saponin isolated from the traditional Chinese medicinal plant Clematis ganpiniana, has been demonstrated to be effective against various types of tumor. However, the exact role of DRbeta-H on breast cancer remains largely unresolved. In the present study, it was observed that DRbeta-H exhibited anti-proliferative and pro apoptotic activity in human breast cancer cells (MCF-7/S). DRbeta-H was able to inhibit exosome secretion, and the level of exosomes was positively associated with cell growth after absorption and internalization by target breast cancer cells. By analyzing the miRNA profiles of exosomes and MCF-7/S, it was identified that several miRNAs were detected exclusively in exosomes. Knockdown of the top five exosomal miRNAs and an MCF-7/S proliferation assay indicated that exosomal miR-130a and miR-425 may enhance MCF-7/S cell viability. Target gene prediction and pathway analysis revealed the involvement of miR-130a and miR-425 in pathways associated with malignant cell proliferation. These results demonstrated that DRbeta-H inhibited MCF-7/S cell growth through reducing exosome release. PMID- 30250585 TI - Characterization of an orthotopic gastric cancer mouse model with lymph node and organ metastases using bioluminescence imaging. AB - Lymph node (LN) metastasis of gastric cancer (GC) is the strongest prognostic indicator for this disease; however, the majority of the LN metastasis profiles of GC remain unknown, which notably hinders the therapeutic efficacy in clinic. In the present study, an orthotopic model of human GC was established for investigation of time-dependent LN metastasis patterns in mice. Luciferase expressing NCI-N87 human GC cells were injected into the subserosa of the gastric body, resulting in a tumor formation rate of 100%. LN metastasis at four different anatomical positions in the abdomen were characterized until week 10 after tumor cell injection using sensitive bioluminescence imaging and histopathological analyses. Skip LN metastases were observed at later stages (weeks 8-10) of the experiment. Metastases in other major organs, including liver, spleen and lung, were also examined. Characterization of this orthotopic GC model and metastasis patterns in LNs and major organs should aid in the preclinical GC research regarding the metastatic mechanism and drug development. PMID- 30250586 TI - A study of the application of TAP combined with transvaginal ultrasound in the diagnosis of early-stage endometrial cancer. AB - The aim of the study was to investigate the application of tumor abnormal protein (TAP) combined with transvaginal ultrasound in the diagnosis of early-stage endometrial cancer. A total of 248 patients with suspected endometrial cancer who were admitted to the Gynecology Department of the Second People's Hospital of Liaocheng from September 2013 to September 2015 were selected and randomly divided into the control (n=124) and the observation group (n=124). The control group received conventional ultrasound examination, while the observation, underwent TAP combined with conventional ultrasound examination. Differences in the definite diagnostic results of the two diagnostic methods and curettage were compared, and the application of TAP combined with transvaginal ultrasound in the diagnosis of early-stage endometrial cancer was studied. Among 248 patients receiving hysteroscopy and diagnostic curettage examination, there were 75 patients with early-stage endometrial cancer, and 173 benign patients. The total diagnostic accordance rate of conventional ultrasound for endometrial lesions was 87.90% (n=218), and the accordance rate for early-stage endometrial carcinoma was 90.67% (n=68); the total diagnostic accordance rate of TAP combined with vaginal ultrasound for endometrial lesions was 94.35% (n=234), and for early-stage endometrial cancer was 94.67% (n=71); of TAP combined with conventional ultrasound for endometrial lesions and endometrial cancer were higher than those of simple conventional ultrasound (P<0.05). The area under the curve (AUC) of conventional ultrasound in the diagnosis of endometrial cancer was 0.754 [95% confidence interval (CI): 0.211-2.534]. The AUC of TAP combined with vaginal ultrasound in the diagnosis of endometrial cancer was 0.814 (95% CI: 0.517 0.932), and a comparison between the two groups was statistically significant (P=0.011). The accuracy rate of TAP combined with transvaginal ultrasound in the diagnosis of early-stage endometrial cancer is relatively high, and it is worthy promoting and applying in clinical practice. PMID- 30250587 TI - The synergistic effect of propofol and ulinastatin suppressed the viability of the human lung adenocarcinoma epithelial A549 cell line. AB - Ulinastatin and propofol (PPF) are recognized for their anticancer properties. The aim of the present study was to evaluate the synergistic antitumor effect of PPF followed by ulinastatin against A549 cells. In MTT assays, PPF (10, 20 and 30 uM) followed by 200 U/ml ulinastatin was more effective at inhibiting A549 cell viability compared with PPF (10, 20 and 30 uM) or 200 U/ml ulinastatin. PPF (10, 20 and 30 uM) followed by 200 U/ml ulinastatin treatments synergistically increased the number of S cells and synergistically reduced the number of G2/M cells associated with PPF stimulation in a dose-dependent manner. Western blot analysis demonstrated that the antitumor effect of PPF followed by 200 U/ml ulinastatin treatments were associated with the downregulated expression of extracellular signal-regulated kinase 1 and 2 phosphorylation (p-ERK1/2) and matrix metalloproteinases 2 (MMP-2). In conclusion, these data demonstrated that PPF (20 and 30 uM) followed by 200 U/ml ulinastatin treatments synergistically stimulated a significant proportion of A549 cells in S phase. Furthermore, the combination synergistically reduced a significant proportion of A549 cells in G2/M phase and synergistically suppressed the viability of A549 cells, which was possibly related regulation of the expression of p-ERK1/2 and MMP-2 in A549 cells. PMID- 30250588 TI - Identification of potential biomarkers in cervical cancer with combined public mRNA and miRNA expression microarray data analysis. AB - Cervical cancer is the fourth most prevalent malignancy in females worldwide. Early diagnosis is key to improving survival rates. Molecular biomarkers are an important method for diagnosing a number of types of cancer, including cervical cancer. The present study utilized public data from three mRNA microarray datasets and one microRNA dataset to analyze the key genes involved in cervical cancer. The mRNA and microRNA expression profile datasets (GSE9750, GSE46857, GSE67522 and GSE30656) were downloaded from the Gene Expression Omnibus database (GEO). Differentially expressed genes (DEGs) and microRNAs (DEMs) were screened using the online tool GEO2R. By using the DEGs consistent across the three mRNA datasets, a functional and pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery. A protein protein interaction (PPI) network was constructed and module analysis performed using the Search Tool for the Retrieval of Interacting Genes. Validated target genes of the DEMs were identified using the miRecords website. Using the identified target genes of the DEMs, a survival analysis was performed using the OncoLnc online tool. A total of 73 DEGs and 19 DEMs were screened from the microarray expression profile datasets. 'Integrin-mediated', 'proteolysis' and 'phosphoinositide 3 kinase-protein kinase 3' signaling pathways were the most enriched in the DEGs. Three of the DEGs, including Ras homolog family member B (RhoB), stathmin 1 (STMN1) and cyclin D1 (CCNB1) were validated DEM target genes. The OncoLnc survival analysis identified that RhoB was associated with a significantly longer overall survival, whereas STMN1 was associated with a significantly reduced overall survival time in patients with cervical cancer. Finally, data from The Cancer Genome Atlas revealed an association between the mRNA expression levels of RhoB and STMN1, and the overall survival time for patients with cervical cancer. In conclusion, RhoB and STMN1 were identified as key genes that may provide potential targets for cervical cancer diagnosis and treatment. PMID- 30250589 TI - Comparison of diagnostic values between ultrasound elastography and ultrasound guided thyroid nodular puncture in thyroid nodules. AB - Diagnostic value between ultrasound elastography and ultrasound-guided fine needle puncture biopsy in thyroid nodules was compared to provide reference for the selection of thyroid nodule (TN) diagnostic mode. A total of 194 patients with TN, admitted from June 2014 to June 2015, were selected to be treated with ultrasound elastography and ultrasound-guided fine needle puncture biopsy. The ultrasonic elasticity score and results of ultrasound-guided TN puncture were compared with diagnostic results of surgical or ultrasound follow-up for 12 months, and the sensitivity, specificity and accuracy of differentiating and diagnosing TN of the two methods were calculated to compare the clinical diagnostic values. A total of 194 patients were diagnosed with TN 217, including 129 benign and 88 malignant lesions. All the nodules were obtained by effective ultrasound elastography and ultrasound-guided fine needle puncture cytological pathological specimens, and it was diagnosed by ultrasound elastography that there were 75 benign nodules and 142 malignant nodules. It was diagnosed by ultrasound-guided fine needle puncture that there were 112 benign, 78 malignant and 27 uncertain nodules. The specificity and accuracy of ultrasound-guided fine needle puncture in the diagnosis of TN were higher than that of ultrasound elastography and the differences were statistically significant (P<0.05), while there was no statistically significant difference between the sensitivity of ultrasound elastography and ultrasound-guided fine needle puncture biopsy in the diagnosis of TN (P>0.05). Ultrasound elastography in the diagnosis of TN has a low specificity and the diagnosis of ultrasound-guided fine needle puncture biopsy may have uncertain results. There are some defects in the two diagnostic schemes and their combined application can complement each other's advantages and improve the early diagnostic efficiency of TN. PMID- 30250590 TI - Prognostic impact of programmed cell death ligand 1 expression on long-term oncologic outcomes in colorectal cancer. AB - The present study evaluated the association between programmed cell death ligand 1 (PD-L1) expression and long-term oncologic outcomes in colorectal cancer (CRC). PD-L1 expression was evaluated using immunohistochemistry in 175 patients who underwent surgical resection for CRC between September 1999 and August 2004. Patients were grouped according to PD-L1 expression, with 82 (46.9%) and 93 (53.1%) in the low and high PD-L1 expression groups, respectively. The overall survival (OS) and disease-free survival (DFS) rates were significantly better in the high expression group compared with in the low expression group (OS: 48.2 vs. 32.9%, P=0.047; DFS: 43.3 vs. 32.9%, P=0.021). According to the Tumor-Node Metastasis stage subgroups, the OS rates in the low and high expression groups, respectively, were 66.7 and 60.0% in stage I (P=0.715), 51.8 and 46.7% in stage II (P=0.789), 19.6 and 51.1% in stage III (P=0.011) and 9.1 and 0% in stage IV (P=0.005). The DFS rates in the low and high expression groups, respectively, were 66.7 and 60.0% in stage I (P=0.715), 51.8 and 46.7% in stage II (P=0.857), 19.6 and 38.3% in stage III (P=0.006) and 9.1 and 0% in stage IV (P=0.700). The systemic recurrence rate was significantly higher in the low expression group compared with in the high expression group (42.7 vs. 12.9%, respectively, P=0.030). Low PD-L1 expression was significantly associated with tumor relapse and poor prognosis in stage III CRC. PMID- 30250591 TI - Value of ultrasonography in the diagnosis of primary hepatic carcinoma and thyroid carcinoma. AB - The present study explored the value of ultrasonography in the diagnosis of primary hepatic carcinoma (PHC) and thyroid carcinoma (TC) by assessing their sonographic features. A total of 426 patients diagnosed with liver space occupying lesions by ultrasonic examination admitted to Liaocheng People's Hospital from March 2014 to October 2017 were enrolled in this study. These patients were divided into two groups: A total of 226 patients with 237 foci in the PHC group and 200 patients with 216 foci in the benign liver lesion group. During the same period, 367 patients diagnosed with thyroid nodules (382 nodules) by ultrasonic examination were also enrolled in this study. These patients were divided into further two groups: A total of 193 patients with 203 nodules in the TC group and 174 patients with 179 nodules in the benign thyroid nodule group. Two-dimensional and color Doppler ultrasonography were performed on all the patients in the four groups. Differences in the sonographic features such as focus morphology, focus size, internal echo, halo and blood flow distribution were statistically significant between patients in the PHC and the benign liver lesion group (p<0.001). Differences in the sonographic features such as nodule boundary, nodule size, internal echo, microcalcification, lymph node status and blood flow were statistically significant between patients in the TC and the benign thyroid nodule group (p<0.01). PHC can be differentiated from benign liver lesions by evaluation of focus morphology, focus size, internal echo, halo, and blood flow. TC can be differentiated from benign thyroid nodules by evaluation of nodule boundary, nodule size, internal echo, microcalcification, lymph node status, and blood flow. Ultrasonic diagnosis of PHC and TC is not only accurate, but also convenient, fast, cost-efficient and non-invasive. Thus, application of ultrasonography in the diagnosis of PHC and TC should be expanded for the benefits of patients. PMID- 30250592 TI - ATPase inhibitory factor 1 inhibition improves the antitumor of YC-1 against hepatocellular carcinoma. AB - YC-1 is a synthetic compound, which serves as a hypoxia-inducible factor 1-alpha inhibitor or sensitizer to enhance the effect of chemotherapy. Previous studies have revealed the anti-cancer effects of YC-1 in various types of cancer, including hepatocellular carcinoma (HCC). ATPase inhibitory factor 1 (IF1) is upregulated in a number of human carcinomas and regulates mitochondrial bioenergetics and structure. However, whether IF1 is involved in the antitumor effects of YC-1 against HCC remains unclear. The present study examined the function of IF1 in HCC and its potential role in YC-1 effects within HCC cells. MTT, colony formation and Transwell assays revealed that IF1 overexpression promoted proliferation, colony formation and invasion of HCC cells, while IF1 downregulation had the opposite effects. Overexpression of IF1 reversed the inhibitory effects of YC-1 on Huh7 cell growth and invasion activities, while downregulation of IF1 increased the sensitivity of HCCLM3 cells to YC-1. YC-1 treatment of HCCLM3 and Huh7 cells reduced the levels of phosphorylated (p-) signal transducer and activator of transcription 3 (STAT3) and IF1, and increased the expression of E-cadherin. IF1 knockdown resulted in decreased p-STAT3 levels and increased E-cadherin expression, while IF1 overexpression increased p-STAT3 levels and reduced the expression of E-cadherin. The present study demonstrated that the inhibition of IF1 improves the antitumor effects of YC-1 in HCC cells. These findings support the clinical strategy of combining YC-1 and an IF1 inhibitor for the treatment of HCC. PMID- 30250593 TI - MicroRNA-409-3p suppresses cell proliferation and cell cycle progression by targeting cyclin D2 in papillary thyroid carcinoma. AB - MicroRNAs (miRs) function as tumor suppressors or oncogenes in tumor development and progression. The present study reported that miR-409-3p was significantly downregulated in human papillary thyroid carcinoma (PTC) tissues and cell lines. Overexpression of miR-409-3p suppressed cell proliferation and induced cell cycle G0/G1 phase arrest in PTC cells. Further study revealed that the transcriptional regulator cyclin D2 was a target of miR-409-3p, as miR-409-3p bound directly to its 3'-untranslated region and the miR-409-3p mimic reduced the protein expression levels of cyclin D2. In addition, restoration of cyclin D2 expression reversed the inhibitive effect of miR-409-3p on PTC cells. To the best of our knowledge, these findings demonstrate for the first time that miR-409-3p functions as a tumor suppressor in PTC and could serve as an efficient agent for therapy of PTC. PMID- 30250594 TI - Oct3/4 is potentially useful for the suppression of the proliferation and motility of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) cells are immature compared with healthy mature hepatocytes. Transcription factors serve a role in hepatocyte differentiation. The expression levels of transcription factors in HCC cell lines have been investigated to determine potential therapeutic targets. In the present study, the HLE, HLF, PLC/PRF/5, Huh-7, Hep3B, Huh-6 and HepG2 HCC cell lines were subjected to reverse-transcription polymerase chain reaction (RT-PCR) of transcription factors, including NANOG, Oct3/4, GATA binding protein 4 (GATA4), GATA6 and hematopoietically expressed homeobox (HHEX). In addition, these cell lines were analyzed using RT-quantitative PCR (RT-qPCR) of NANOG and Oct3/4. The 201B7 human induced pluripotent stem cells were evaluated as a model of pluripotent cells. The HLF cells were transfected with Oct3/4 small interfering RNA (siRNA) and used in an MTS colorimetric assay and a scratch assay. NANOG was not expressed in any of the cell lines. However, GATA4, GATA6 and HHEX were expressed in the majority of the HCC cell lines. In addition, NANOG and Oct3/4 were expressed in 201B7 cells. Oct3/4 was expressed in HLE, HLF and Hep3B cells; however, its expression levels were significantly reduced compared with those in 201B7 cells. RT-qPCR demonstrated that the expression of Oct3/4 siRNA suppressed the proliferation and motility of HLF cells. Oct3/4 siRNA may be a potentially effective therapy for the suppression of the proliferation and motility of HCC cells. PMID- 30250595 TI - Triple primary cancer of the head and neck, skin and prostate: A case report and literature review. AB - Second primary cancer (SPC) is an important prognostic factor for patients with head and neck cancer (HNC); therefore, the association between the prognosis and development of SPC has been well-reported. The use of 2-[18F]-fluoro-2-deoxy-D glucose-positron emission tomography (FDG-PET) is valuable to examine cancer stage, evaluate treatment responses and investigate suspected relapses or metastases. In the present study, the case of a male patient who was diagnosed with three primary cancer types, including well to moderately differentiated squamous cell carcinoma (SCC) of the mandible, axillary cutaneous poorly differentiated SCC and prostate adenocarcinoma, was described. Among these, mandible cancer was the first diagnosed when the patient was 70 years of age. Synchronous skin and prostate cancer (PRC) types then developed 3 years later. To the best of our knowledge, this is the first report of the aforementioned combination of cancer types. Postoperative FDG-PET was not performed as no lesions of recurrence or metastases of mandible cancer were found. Three years later, the PRC was asymptomatic and was incidentally detected by FDG-PET performed for a preoperative evaluation of skin cancer. It was indicated that FDG PET could be utilized in patients with HNC due to there being no accurate FDG-PET protocol to detect SPC over a long-term follow-up. PMID- 30250596 TI - Expression of vasohibin-1 and -2 predicts poor prognosis among patients with squamous cell carcinoma of the esophagus. AB - Vasohibin (VASH) -1 and -2 are novel angiogenic regulators. The aim of the present study was to assess the prognostic values of VASH1 expression and VASH2 expression in esophageal squamous cell carcinoma (ESCC). A total of 209 patients with ESCC were investigated. Resected tumor specimens were immunostained using anti-CD34 antibody, anti-VASH1 antibody and anti-VASH2 antibody. The ratio of the microvessels density and the VASH1 density as the VASH1-positive ratio were defined and the patients were divided into two groups (a high VASH1 group and a low VASH1 group) according to the average value. The patients were also divided into two groups (a high VASH2 group and a low VASH2 group) according to VASH2 expression upon immunostaining. The clinical outcomes of these two groups were then evaluated. The high VASH1 group contained 106 patients (50.7%). The high VASH2 group contained 48 patients (23.0%). Long-term survival was significantly poorer in the high VASH1 group compared with that in the low VASH1 group. A slight correlation between VASH1 expression and VASH2 expression was observed. The low VASH1/low VASH2 group had a better prognosis than the other three groups with different combinations of VASH1 and VASH2 expression levels. The present study showed that high VASH1 expression and high VASH2 expression may be novel independent predictors of a poor prognosis in patients with ESCC and that a slight correlation between VASH1 and VASH2 expression existed. The present findings suggest that combined evaluation of VASH1 and VASH2 expression should provide an improved understanding of their clinicopathological features. PMID- 30250597 TI - Effects of cisplatin on surgically induced endometriosis in a rat model. AB - Research has strongly suggested that the features of endometriosis serve as a precursor lesion of ovarian cancer. Cisplatin (CDDP) is the preferred drug against these cancer types. The present study investigated the effects of CDDP on surgically induced endometriosis in a rat model. Endometriosis was surgically induced by the autologous transplantation of endometrial tissue. A total of 36 model rats were randomly divided into three groups. The rats in Group 1 (control group, n=12) received no medication. The rats in Group 2 (n=12) and Group 3 (n=12) were administered 35 mg/m2 CDDP and 70 mg/m2 CDDP, respectively, every four days. All rats were treated for a total of 24 days. The growth and histologic scores of the implants were calculated. The expression of protein markers, including vascular endothelial growth factor (VEGF), aromatase P450 (P450arom), transforming growth factor-beta (TGF-beta) and matrix metalloproteinase (MMP)-2, were assessed using immunohistochemistry, an enzyme linked immunosorbent assay and western blot analysis. Following CDDP treatment, the mean implant sizes were significantly reduced in Groups 2 and 3 compared with the control group (P=0.01). The mean histologic scores were also significantly lower in Groups 2 and 3. Furthermore, the protein expression of VEGF, P450arom, TGF-beta and MMP-2 was significantly lower in Groups 2 and 3 when compared with the control group. A loss of hair was observed in 4 rats, which only occurred in Group 3. A dose-dependent effect was observed in the two CDDP-treated groups. In conclusion, the expression of proliferation- and angiogenesis-associated proteins was significantly lower following treatment with CDDP. CDDP caused a significant regression in the size of the endometriotic implants and induced atrophy of these lesions in rats. PMID- 30250598 TI - miR-27a in serum acts as biomarker for prostate cancer detection and promotes cell proliferation by targeting Sprouty2. AB - Prostate cancer (PCa) exhibits a high incidence among men, but there is no effective and non-invasive biomarker for the diagnosis of PCa, and the pathogenesis of PCa remains unclear. The present study identified that miR-27a was significantly overexpressed in the tumor tissues and sera of patients with PCa. In addition, high serum levels of miR-27a were correlated with poor survival in patients with PCa. Receiver-operating characteristic curves analysis demonstrated that the serum levels of miR-27a exhibited a high area under the curve value. Furthermore, miR-27a mimics or inhibitors significantly promoted or repressed the proliferation of PCa cells, respectively. In addition, it was identified that the expression of Sprouty2 (SPRY2) was inversely correlated with the expression of miR-27a in PCa tissues. The knockdown or overexpression of SPRY2 promoted or suppressed the proliferation of PCa cells, respectively, and the overexpression of SPRY2 inhibited the increased proliferation and cell cycle distribution of PCa cells mediated by miR-27a mimics. Taken together, these data indicated that the serum levels of miR-27a may be a novel and non-invasive biomarker for the diagnosis and prognosis of patients with PCa, and miR-27a/SPRY2 may be a therapeutic target for the treatment of PCa. PMID- 30250599 TI - Osteopontin promotes hepatocellular carcinoma progression via the PI3K/AKT/Twist signaling pathway. AB - The epithelial-mesenchymal transition (EMT) serves critical roles in the migration, invasion and metastasis of human cancer cells. This process is initiated by regulation of E-cadherin expression by the major inducers of EMT. Previous studies reported that osteopontin (OPN) is essential for hepatocellular carcinoma (HCC) metastasis as it facilitates the EMT in HCC. However, the role and clinical significance of OPN as an EMT regulator in HCC remains unknown. The present study revealed that OPN regulated the expression of Twist by activating RAC serine/threonine-protein kinase (Akt), a critical EMT regulator. Interfering with the phosphoinositide 3-kinase (PI3K)/Akt pathway may suppress the expression of Twist enhanced by OPN. Increased Twist levels in HCC were associated with poor survival and tumor recurrence in patients with HCC following surgery. A significant association was observed between OPN expression and Twist levels in HCC, and a combination of these two parameters was revealed to be a more powerful predictor of poor patient prognosis. The findings of the present study indicate that Twist serves an notable role in OPN-mediated metastasis of HCC through activation of the PI3K/Akt pathway. Twist may be a potential therapeutic target for the prevention of HCC metastasis in patients exhibiting high OPN expression. PMID- 30250600 TI - Hsp27 regulates epithelial mesenchymal transition, metastasis and proliferation in colorectal carcinoma. AB - The primary factor associated with poor survival rate in patients with colorectal carcinoma (CRC) is the presence of metastasis. The underlying molecular mechanisms of CRC metastasis are yet to be fully elucidated. The present study investigated the function of heat shock protein 27 (Hsp27) on the invasion and proliferation of CRC cells. The clinical significance of Hsp27 was evaluated using tissue microarray analysis (n=81). Invasion and metastasis assays were used to determine the function of Hsp27 in CRC metastasis in vitro and in vivo using RNA interference and the ectopic expression of Hsp27. The upregulation of Hsp27 has been frequently identified in CRC tissues. Patients with CRC and a high expression level of Hsp27 have a reduced overall survival rate. Silencing Hsp27 inhibited the growth and invasion of CRC cells in vitro and in vivo, whereas ectopic overexpression of Hsp27 promoted the proliferation and invasion of CRC cells in vitro. Furthermore, depletion of Hsp27 expression inhibited the epithelial-to-mesenchymal transition (EMT), whilst ectopic overexpression of Hsp27 induced EMT. The results of the present study indicated that Hsp27 serves an important function in the aggressiveness of CRC through inducing EMT. Hsp27 suppression may represent a potential therapeutic option for the suppression of CRC progression. PMID- 30250601 TI - Long non-coding RNA TUG1 promotes the proliferation of colorectal cancer cells through regulating Wnt/beta-catenin pathway. AB - The long non-coding RNA taurine up-regulated gene 1 (TUG1) has been shown to be dysregulated in various types of malignant cancer; however, its underlying mechanism of action has not been fully elucidated. The present study aimed to investigate the biological role and clinical significance of TUG1 in the progression of colorectal cancer (CRC). A reverse transcription-quantitative polymerase chain reaction assay was used to evaluate TUG1 expression in tissues from patients with CRC. The effect of TUG1 on cell viability of CRC cells using MTT assay. The influence of TUG1 on tumorigenesis was monitored using an in vivo xenograft model. The status of the Wnt/beta-catenin signaling pathway was evaluated using immunofluorescence, western blotting and luciferase reporter assays. The results demonstrated that the expression of TUG1 was positively associated with the pathological grade and clinical stage of CRC patients. Knockdown of TUG1 inhibited the proliferation of CRC cells and attenuated the activity of Wnt/beta-catenin pathway in CRC cells. In addition, TUG1 knockdown inhibited the tumorigenicity in the in vivo CRC xenograft model, as well as the nuclear localization of beta-catenin and downstream gene transcription. Taken together, the data of the present study highlighted the pivotal role of the TUG1 Wnt/beta-catenin signaling pathway in CRC, which could be targeted to improve the therapeutic efficacy of CRC. PMID- 30250602 TI - Fanconi anemia in twins with neutropenia: A case report. AB - Fanconi anemia (FA) is a rare inherited disease caused by mutations in genes that are primarily involved in DNA damage response or repair. The disease is often characterized by congenital malformations, progressive bone marrow failure, abnormal skin pigmentation patterns and susceptibility to cancer. The present study describes a pair of 4-year-old male twins, both of whom had been suffering from upper respiratory tract infections for >2 years. There was no indication of discomfort including fever, coughing, bleeding or fatigue from either child when the upper respiratory tract infection disappeared. Physical examination of the twins did not reveal anything significant, and no external anomalies were observed. In order to obtain additional diagnostic evidence, next-generation gene sequencing, chromosome breakage analysis and comet assays were performed. The results revealed double heterozygous mutations in the Fanconi Anemia Complementation Group D2 gene of the twins, therefore providing a conclusive diagnosis of FA. The case highlights how difficulties in clinical diagnosis may be overcome by including genetic screening tests into the range of diagnostic tests, which may also reveal unexpected results. PMID- 30250603 TI - MicroRNA-324-5p suppresses the migration and invasion of MM cells by inhibiting the SCFbeta-TrCP E3 ligase. AB - Multiple myeloma (MM) is a cytogenetically heterogeneous malignancy of plasma cells in bone marrow. Among the cytogenetic abnormalities of MM, del(17p) is a well-recognized high-risk genetic lesion associated with the late stage and progression of the disease. MicroRNA (miR)-324-5p, located at 17p13.1, was identified to be involved in the dysregulation of a number of types of malignant disease. However, whether miR-324-5p is associated with the development and progression of MM remains unknown. In the present study, the expression status of miR-324-5p in MM, and its effect on the migratory and invasive ability of MM cells were investigated. Using ubiquitination pathway polymerase chain reaction array, the inhibitory effect of miR-324-5p on the ubiquitinated proteins was investigated. It was identified that miR-324-5p levels were decreased in samples from patients with MM and MM cell lines. Increased expression of miR-324-5p by transfection of miR-324-5p mimic suppressed the proliferative, migratory and invasive abilities of MM.1R cells. Furthermore, increased expression of miR-324 5p in MM.1R cells inhibited the ubiquitination pathway and decreased the levels of ubiquitination-associated proteins, particularly the Skp1-Cullin1-F-box beta transducin repeat-containing protein (SCFbeta-TrCP) E3 ligase. In addition, the results of the present study demonstrated that the SCFbeta-TrCP E3 ligase may contribute to the suppression of MM cell motility by inhibiting the expression of metastasis-associated genes, including metastasis suppressor 1. In conclusion, the results of the present study suggested that miR-324-5p may act as a tumor suppressor by impairing the motility of MM cells by suppressing the ubiquitination pathway. PMID- 30250604 TI - Fenretinide targeting of human colon cancer sphere cells through cell cycle regulation and stress-responsive activities. AB - Cancer stem cells (CSCs) are considered to be the main cause of chemoresistance and the resultant low survival rate of patients with cancer. N-(4-hydroxyphenyl) retinamide, known as fenretinide or 4HPR, is a synthetic derivative of all-trans retinoic acid. It is a promising anticancer agent, has minimal side effects and synergizes with other anticancer agents to reinforce their anticancer efficacy. The present study investigated whether fenretinide eliminated colon sphere cells. HT29 and HCT116 cells incubated in low-serum culture medium were more sensitive to fenretinide treatment than those incubated in full-serum medium. Colon spheres formed in serum-free medium demonstrated stem-like characteristics. The percentage of cluster of differentiation (CD) 44+ cells was significantly higher in sphere cells compared with parental cells. Sphere cells also demonstrated increased tumorigenic ability in non-obese diabetic/severe combined immunodeficiency mice. Fenretinide inhibited the formation of colon spheres in HT29 and HCT116 cells. Microarray, cell cycle and reverse transcription quantitative polymerase chain reaction analysis revealed that fenretinide induced genes associated with cell cycle regulation and the stress response in fenretinide-treated HT29 sphere cells. To the best of our knowledge, the present study was the first to investigate the effect of fenretinide on colon stem cells. Fenretinide was demonstrated to preferentially target colon sphere cells, which may possess certain stem-like characteristics. These results are an important addition to the current knowledge concerning fenretinide, and provide a foundation for its clinical application in the treatment of cancer. PMID- 30250605 TI - A novel small inhibitor, LLL12, targets STAT3 in non-small cell lung cancer in vitro and in vivo. AB - Lung cancer is the leading cause of cancer-associated mortality worldwide. Despite the development of novel molecular therapies, the prognosis for patients with locally advanced or metastatic lung cancer remains poor. Therefore, the identification of novel therapeutic approaches is required. In numerous types of cancer, the constitutive activation of signal transducer and activator of transcription 3 (STAT3) signaling serves as a potent therapeutic target. The present study aimed to characterize the suppressive role of LLL12, a STAT3 small molecule inhibitor, in lung cancer cell proliferation and tumor growth. The mechanism of STAT3 signaling modulation by LLL12 was also investigated. The antitumor activity of LLL12 was revealed to take place via inhibition of lung cancer cell proliferation and migration in vitro. High and low doses of LLL12 significantly reduced tumor volume and weight in xenograft mice compared with that in the control group. Furthermore, LLL12 was demonstrated to reduce the level of STAT3 phosphorylation. These results suggested that LLL12 inhibited the proliferation and migration of A549 cells, and the increase in tumor volume in nude mice with lung cancer. This may be associated with the inhibitory effect of STAT3 phosphorylation and the expression of STAT3. The results of the present study suggest that constitutive STAT3 signaling is required for lung cancer cell survival and migration, and tumor growth in vivo. It is also indicated that LLL12 has clinical potential as a novel targeted therapy. PMID- 30250606 TI - MicroRNA-99b promotes Helicobacter pylori-induced autophagyand suppresses carcinogenesis by targeting mTOR. AB - The regulatory mechanism of Helicobacter pylori-induced gastric carcinogenesis remains unclear. Autophagy has previously been identified as an effective method of regulating carcinogenesis. In the present study, microRNA (miR)-99b levels increased in H. pylori-infected gastric cancer tissues and the BGC-823 gastric cancer cell line. Overexpression of miR-99b significantly enhanced autophagy, decreased intracellular bacterial loads and blocked cell proliferation. The effect on autophagy was demonstrated to be triggered by mammalian target of rapamycin inhibition. These results indicate that miR-99b expression serves a key role in preventing H. pylori-associated gastric cancer formation and this may provide potential targets for the future treatment of H. pylori-associated diseases. PMID- 30250607 TI - Preclinical evaluation of 99mTc direct labeling ZHER2:V2 for HER2 positive tumors imaging. AB - The present study aimed to label ZHER2:V2 with technetium-99m (99mTc) using a simple method and to evaluate its clinical potential as a diagnostic probe for human epidermal growth factor receptor type 2 (HER2)-positive tumors. The ZHER2:V2 (Affibody molecule of ZHER2:2395-C, which is based on the ZHER2:342 binding sequence with C-terminal engineered cysteine) with C-terminal chelating sequence GGGC was designed and labeled with 99mTc. The 99mTc-ZHER2:V2 labeling efficiency was analyzed. The cellular uptake, retention and binding affinity, and the stability of the probe were examined in vitro. 99mTc-ZHER2:V2 biodistribution analysis and imaging were performed in BALB/c nude mice bearing SKOV3 (HER2 overexpression) xenografts. Furthermore, imaging of the probe was performed in MCF-7 (HER2 low-expression) xenografts. The 99mTc-ZHER2:V2 labeling efficiency was identified as 98.99+/-0.99% (n=6), and was stable in physiological saline and fresh human serum at 37 degrees C in vitro. The cellular uptake peak of SKOV3 cells at 24 h was 6.15+/-0.18%, the cellular retention ratio of the probe was 48.58+/-4.52% at 6 h following interrupted incubation, and ~70% of 99mTc-ZHER2:V2 was membrane bound following 24 h. 99mTc-ZHER2:V2 was blocked by excess amounts of unlabeled ZHER2:V2 in SKOV3 cells. 99mTc-ZHER2:V2 exhibited high distribution (10.07% ID/g) in SKOV3 *enografts at 6 h following injection. The single photon emission computed tomography (SPECT) imaging revealed clear localization of 99mTc ZHER2:V2 in the SKOV3 *enografts at 4 h. However, there was low uptake in MCF-7 tumors on the SPECT images. The SKOV3 *enograft imaging could be blocked by excess amounts unlabelled ZHER2:V2. 99mTc-ZHER2:V2 is an easy and quick labeling method, with high labeling yields, and radiochemical purity. 99mTc-ZHER2:V2 is a promising probe for the diagnosis of HER2-overexpression tumors and the monitoring of therapy response. PMID- 30250608 TI - PSA response following the 'steroid switch' in patients with castration-resistant prostate cancer treated with abiraterone: A case report. AB - A 69-year-old man presented initially with back pain and incomplete bilateral lower limb paralysis. The level of prostate-specific antigen (PSA) in the patient was elevated to 167.0 ng/ml, and multiple bone metastases were detected. Thoracic laminectomy was performed in an emergency due to spinal decompression. Subsequently, the patient was diagnosed with prostate cancer from an examination of resected bone specimens. Combined androgen blockade with degarelix and bicalutamide was initiated in October 2013. Consequently, the serum PSA level decreased to <1.0 ng/ml, but thereafter gradually increased. Subsequent bicalutamide withdrawal response was not observed, and switch of anti-androgen therapy to flutamide also resulted in a poor response. Then, abiraterone (1,000 mg daily) in combination with prednisolone (10 mg daily) was initiated when the level of PSA increased to 35.9 ng/ml in June 2015. The level of PSA decreased to the lowest point of 4 ng/ml; however, PSA level increased again to 21.7 ng/ml in April 2016. Consequently, a 'steroid switch' was attempted. Abiraterone therapy was continued, but concomitant corticosteroid was switched from prednisone to dexamethasone (1.0 mg per day). Fortunately, serum PSA level decreased promptly to the lowest point of 0.6 ng/ml. In the present case report, a review of recent literature was presented and potential explanations of the mechanism underlying the 'steroid switch' were described. Pharmacokinetic differences between dexamethasone and prednisolone may partially explain why the 'steroid switch' occurs. Other mechanisms may include the activation of the glucocorticoid receptor, mineralocorticoid receptor and/or mutant androgen receptor. Corticosteroids accelerate a number of transcription factors, cellular growth factors and cytokines, which may also be potential mechanisms. The 'steroid switch' at PSA progression might be a feasible option for therapy, which may delay the development of the disease. Although the underlying mechanisms require further study, clinicians should pay attention to this phenomenon. PMID- 30250609 TI - Recruitment and significance of Th22 cells and Th17 cells in malignant ascites. AB - T helper (Th)22 and Th17 cells are implicated in the pathogenesis of a number of types of cancer. However, the function of Th22 and Th17 cells in malignant ascites (MA) remains unknown. The present study aimed at examining the distribution, phenotypes, recruitment, and prognostic value of Th22 and Th17 cells in MA from patients with hepatocellular carcinoma (HCC). A total of 26 patients with HCC with MA and 15 healthy controls were included in the present study. The proportion of Th22 cells, Th17 cells, C-C motif chemokine receptor (CCR)4, CCR6 and CCR10 were examined using flow cytometry. Interleukin (IL-)22, IL-17, C-C motif chemokine ligand (CCL)20, CCL22 and CCL27 were investigated using ELISA. In addition, the chemoattractant activity of chemokines for Th22 and Th17 cells in vitro were examined via a chemotaxis assay. The results of the present study demonstrated that Th22 cells, Th17 cells, IL-22 and IL-17 were significantly increased in MA compared with the corresponding blood and peripheral blood from healthy controls. Additionally, Th22 cells expressed increased concentrations of CCR6, CCR4 and CCR10, and Th17 cells expressed increased concentrations of CCR4 and CCR6 in MA compared with the corresponding blood. The chemotaxis assay revealed that CCL20/CCR6, CCL22/CCR4 and CCL27/CCR10 were responsible for the recruitment of Th22 cells into MA, whereas CCL22/CCR4 was responsible for the recruitment of Th17 cells. Furthermore, the patients with an increased number of Th17 cells exhibited an increased survival time compared with patients with a limited number of Th17 cells. Th22 and Th17 cells serve an important function in the development of MA, and the accumulation of Th22 and Th17 cells in MA may be due to a local increase in proinflammatory cytokines and chemokines. Increased Th17 cell numbers in MA may indicate the improvement of patient survival. PMID- 30250610 TI - High expression of S100A12 on intratumoral stroma cells indicates poor prognosis following surgical resection of hepatocellular carcinoma. AB - The S100 protein family is widely involved in the pathological process of various types of cancer. However, the prognostic value of the S100 protein family member S100A12 in hepatocellular carcinoma (HCC) remains unknown. A total of 139 patients undergoing curative surgical resection for HCC from December 2005 to June 2006 were investigated. Immunohistochemistry of S100A12 tissue was performed and expression was classified according to the total positive staining area. Co expression of S100A12 with cluster of differentiation (CD)11B, CD15 and CD68 was evaluated using immunofluorescence. Associations between S100A12 expression and preoperative clinicopathological parameters were assessed using a chi2 test or independent sample Student's t-test. Kaplan-Meier estimator survival analysis and multivariate Cox's proportional hazard regression model were used to evaluate the prognostic value of S100A12 expression. The expression of S100A12 was restricted exclusively to stroma cells, primarily to myeloid-derived immune cells, CD15 positive neutrophils and CD68-positive macrophages in particular. A total positive staining area of 1,600 um2 was selected as the threshold between high and low S100A12 expression. There was a statistically significant association between intratumoral S100A12 expression and tumor differentiation (P=0.010). High expression of S100A12 on intratumoral stroma cells was an independent prognostic factor for the overall (P=0.002) and disease-free survival (P=0.007) rates of HCC following curative surgical resection. No significant association was identified between peritumoral S100A12 expression and HCC prognosis. The results of the present study demonstrated that high expression of S100A12 on intratumoral stroma cells is associated with poor HCC prognosis following curative resection, which may serve as a potential target for an adjuvant therapy. PMID- 30250611 TI - Association between IDH1/2 mutations and brain glioma grade. AB - Isocitrate dehydrogenase 1/2 (IDH)1/2 mutations are frequently detected in glioma. The aim of the present study was to investigate the association between IDH1/2 mutations and glioma grades. The current study was retrospective and used samples from 206 patients with brain glioma and 9 patients with spinal cord glioma as a control. Patients were diagnosed and graded according to the World Health Organization classification of tumors of the central nervous system. The association of patient age with glioma grade was evaluated, and IDH1/2 mutations were also examined and analyzed in different grades. On average, brain glioma grade tended to increase with increasing patient age; patients with grade IV (primary) gliomas had a significantly higher mean age than those with grades I and II (P<0.05), and patients with grade II glioma had a significantly lower mean age than those with grade III (P<0.05). The majority of brain gliomas with mutations in IDH1/2 in grade II, II-III and III occurred in adults, rather than adolescents. IDH1/2 mutations occurred most frequently in grade II, II-III and III gliomas, and these mutation frequencies differed significantly between brain glioma grades (P<0.001). In summary, mutations in IDH1/2 were associated with grade II, II-III and III brain gliomas, and possibly with the progression of brain glioma from grade II to grade III. PMID- 30250612 TI - Expression levels of the long noncoding RNA steroid receptor activator promote cell proliferation and invasion and predict patient prognosis in human cervical cancer. AB - Long noncoding RNAs (lncRNAs) are involved in developmental processes and diseases and function as critical regulators of a number of different cancer types. Previous research has revealed that lncRNAs affect cervical cancer development. Steroid receptor activator (SRA), an lncRNA, serves as a critical regulator of gynecologic cancer. However, the association between SRA expression and cervical cancer remains unclear. In the present study, the SRA expression levels in patients with cervical cancer were examined and the association between SRA expression and clinicopathological factors was determined. SRA expression was observed in cervical cancer tissues (n=100) and corresponding normal tissues (n=22) using reverse transcription-quantitative polymerase chain reaction, and its associations with clinical parameters and prognosis were analyzed. SRA expression was significantly greater in tissues from patients with cervical cancer compared with in control patients (P<0.001). Multivariate analysis revealed that high SRA expression was an independent prognostic factor of overall survival (hazard ratio=3.714, P=0.031). The present study additionally investigated the biofunctional consequences of SRA overexpression in vitro using Cell Counting kit-8, wound healing migration and Matrigel invasion assays. The results demonstrated that SRA overexpression enhanced cell proliferation, migration and invasion in vitro. Furthermore, SRA overexpression induced the epithelial-mesenchymal transition (EMT). Therefore, SRA may promote tumor aggressiveness through the upregulation of EMT-associated genes. These results indicated that SRA may represent a novel biomarker for predicting recurrence and prognosis and serve as a promising therapeutic target in cervical cancer. PMID- 30250613 TI - Overexpression of RECQL4 is associated with poor prognosis in patients with gastric cancer. AB - The present study aimed to investigate the expression, clinical association, and prognosis of RecQ protein-like 4 (RECQL4) protein in human gastric cancers (GCs). The expression levels and prognostic value of RECQL4 were initially predicted by using bioinformatics. GC specimens and matched normal gastric tissues were evaluated by immunohistochemistry (IHC), and patient clinicopathological parameters and survival times were analyzed. Multivariate Cox analysis was used to determine the prognostic role of RECQL4 expression. The Oncomine database predicted that RECQL4 mRNA expression levels were significantly increased in GCs as compared with those in normal gastric tissues (P<0.05) and that patients with increased RECQL4 mRNA expression levels had significantly lower overall survival (OS) (P<0.001). The results of IHC showed that the positive rate of RECQL4 in the GC samples was significantly higher than that in the normal gastric mucosa specimens (P<0.05). RECQL4 expression was positively associated with depth of invasion and TNM (P<0.05). High RECQL4 expression in GC samples was significantly associated with poor OS (P=0.024). Positive RECQL4 expression, depth of invasion, lymphatic invasion, and TNM staging were independent factors for predicting worse OS rates by using multivariate analysis. Compared with expression levels in normal gastric tissues, RECQL4 was significantly overexpressed in GC samples, and increased RECQL4 expression was an independent predictor of poor prognosis in GC patients. PMID- 30250614 TI - Dipeptide gamma-secretase inhibitor treatment enhances the anti-tumor effects of cisplatin against gastric cancer by suppressing cancer stem cell properties. AB - The gamma-secretase inhibitor blocks Notch activity by preventing its cleavage at the cell surface. In the present study, the effect of the gamma-secretase inhibitor on the viability of gastric cancer cells when administered in combination with cisplatin was investigated, with particular focus on CD44highLgr 5high cancer cells. The four gastric cancer cell lines, MKN45, MKN74, SC-6-JCK and SH-10-TC, were used for the experiments. In the MTT assay, treatment with 25 uM dipeptide gamma-secretase inhibitor (DAPT) alone did not affect cell proliferation in any of the four cell lines. Gastric cancer cells subjected to combination treatment with DAPT and cisplatin exhibited decreased viability when compared with those treated with cisplatin alone. Flow cytometry was performed to evaluate the expression of cluster of differentiation (CD)-44 and leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr-5), two cancer stem cell markers in gastric cancers. Treatment with cisplatin alone significantly increased the proportion of CD44highLgr-5high cells. However, the addition of DAPT to cisplatin reduced the CD44highLgr-5high fraction, suggesting that DAPT reduced the number of gastric cancer cells. In conclusion, the present study demonstrated the synergistic effects of DAPT in combination with cisplatin by decreasing the survival of gastric cancer cells. In addition, combination treatment with DAPT reduced the number of CD44highLgr-5high cells, which are thought to exhibit cancer stem cell properties. These results highlight the therapeutic potential of DAPT in gastric cancer treatment. PMID- 30250615 TI - Plasma omega-3 and omega-6 fatty acids in thyroid diseases. AB - The incidences of nodular goiter (NG), thyroid adenoma (TA), and thyroid cancer (TC) are increasing rapidly; however, the etiologies of these diseases remain unclear. The present study aimed to evaluate the differences in plasma fatty acids among these three thyroid diseases to facilitate etiological research. Four omega-3 and seven omega-6 polyunsaturated fatty acids were measured from 97 TC, 14 TA and 11 NG patient plasma samples with gas chromatography-flame ionization detector. Fatty acids levels were expressed as the percentage of each fatty acid out of the total fatty acids evaluated. The present study identified that the level of 22:6n-3 [median, interquartile range (IQR)] was significantly increased in TA (5.2%, 4.3-6.4%) compared with NG (3.6%, 3.1-4.6%) and TC patients (4.2%, 3.2-4.8%). Though not statistically significant, the levels of 20:5n-3 and 22:5n 3 demonstrated a similar pattern. The level of 22:4n-6 expressed (median, IQR) was significantly increased in NG patients (0.21%, 0.18-0.26%) compared with TA (0.16%, 0.15-0.18%) and TC (0.17%, 0.14-0.22%) patients. Furthermore the fatty acids 18:3n-6, 20:2n-6, 20:3n-6, 20:4:6, and 22:5n-6 demonstrated a similar but statistically insignificant pattern. This suggests that different fatty acids exhibit various etiological roles in NG, TA and TC and warrant further study. PMID- 30250616 TI - Identification of a novel splice variant of the human musashi-1 gene. AB - Musashi-1 (Msi1) is an evolutionarily conserved RNA-binding protein that has been reported to be the key regulator in malignancies and with involvement in cancer stemness. In the present study, a novel Msi1 transcript variant generated by alternative splicing was identified and termed Msi1 variant 2. This variant was observed to be ubiquitously expressed in cancerous and non-cancerous cells compared with its wild-type variant, which is preferentially expressed in cancer cells. Notably, the expression levels of Msi1 variant 2 were inversely associated with the protein expression levels of Msi1 in various cancer cells. This naturally truncated variant contains 899 nucleotides and a skipping event of exons 3 and 4, which leads to the emergence of a premature TGA stop codon in exon 5. The present results also demonstrated that hypoxia increased the resistance of H460 cells to cisplatin by suppressing the exon 3 and 4 skipping event of Msi1. In summary, the present study identified a novel splice variant of Msi1 lacking two complete RNA recognition motifs, and revealed the role of exon 3 and 4 skipping of Msi1 pre-mRNA in regulating cisplatin resistance under hypoxia. These observations indicate that targeting Msi1 alternative splicing could represent a valuable strategy to repress Msi1 signaling in tumors overexpressing this RNA binding protein. PMID- 30250617 TI - Unfolded protein response, a link between endometrioid ovarian carcinoma and endometriosis: A pilot study. AB - The aim of the present study was to analyze the expression profile of unfolded protein response (UPR) genes in endometrioid ovarian carcinoma and to evaluate its possible involvement in the neoplastic progression of endometriosis. An experimental retrospective pilot study was conducted on women with a diagnosis of endometrioid ovarian carcinoma at FIGO stage IA, ovarian endometriotic cysts or healthy subjects without a previous diagnosis of endometriosis. The expression profiles of UPR genes (ATF6, GRP78, CHOP and XBP1) were compared among ovaries with endometrioid ovarian cancer, endometriotic ovarian cysts, healthy contralateral ovaries and eutopic and healthy endometrial tissues. A significantly higher expression of ATF6 and GRP78 was detected in the affected ovaries in comparison with the healthy contralateral ovaries, while CHOP and XBP1 exhibited a significantly lower expression. XBP1 was overexpressed in endometrial tissues and its expression gradually decreased in endometriosis cysts and endometrioid ovarian carcinoma. These results support the hypothesis that alterations in the UPR genes CHOP and XBP1 are involved in the neoplastic progression of endometrioid ovarian cancer and are acquired following ovarian localization of ectopic endometrial cells. PMID- 30250618 TI - Left ventricle primary cardiac fibroma in an adult: A case report. AB - There is a very low prevalence of cardiac fibroma in the adult population. Cardiac fibromas arise from heart fibroblasts, and these tumors are primarily located in the ventricles or in the interventricular septum. Symptomatic tumors are treated by resection. By contrast, asymptomatic tumors require a long-term follow-up or surgical resection as a preventive measure to avoid complications. The present study reports the case of a 43-year-old man, who presented with a cough and shortness of breath for 2 months. Echocardiogram and cardiac magnetic resonance imaging indicated a large mass located in the left ventricular lateral wall. The patient underwent surgical excision of the tumor, and histopathological examination confirmed the mass to be a fibroma. The patient had a good postoperative recovery and was discharged on day 9 post-surgery. PMID- 30250619 TI - Survivin expression modulates the sensitivity of A549 lung cancer cells resistance to vincristine. AB - Lung cancer is the leading cause of cancer-associated mortalities worldwide. Chemotherapeutic drug vincristine is widely used to treat lung cancer; however, the acquisition of drug resistance is the major limitation of chemotherapy, and it is thus important to determine the mechanism underlying vincristine resistance in lung cancer. Survivin has been reported to be associated with the development of drug resistance and be involved in the progression of non-small cell lung cancer. In the present study, a vincristine-resistant lung cancer cell line, A549/VCR, was used to investigate the possible involvement of survivin in the acquisition of vincristine resistance. Western blot analysis demonstrated that survivin protein expression level was markedly higher in A549/VCR cells compared with in control A549 cells, whereas p53 expression level was lower in A549/VCR cells compared with in A549 cells. Thus, wild-type p53 was overexpressed in A549/VCR cells and it reversed vincristine resistance of A549/VCR cells via the inhibition of survivin expression. Furthermore, survivin was knocked down by small interfering RNA technology and the effects on viability and apoptosis of resistant cells were investigated. MTT, Annexin V-fluorescein isothiocyanate/propidium iodide and caspase-3 activity assays indicated that survivin silencing significantly inhibited cell viability and enhanced apoptosis induced by vincristine treatment in A549/VCR cells compared with non-silenced A549/VCR cells. These results suggested that survivin expression regulated by p53 may serve an important role in drug resistance in A549/VCR cells and may be a potential target for enhancing vincristine sensitivity in A549 lung cancer cells. Additionally, the present study revealed that A549/VCR cells exhibited cross resistance to methotrexate (MTX) and survivin silencing re-sensitized A549/VCR cells to MTX, indicating the crucial role of survivin in regulating A549 cells sensitivity to anticancer drugs. The results of the present study are significant for determining the underlying mechanism of vincristine resistance in lung cancer. PMID- 30250620 TI - Wee1 kinase inhibitor MK-1775 induces apoptosis of acute lymphoblastic leukemia cells and enhances the efficacy of doxorubicin involving downregulation of Notch pathway. AB - Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy affecting pediatric and adult populations. Although the outcomes of ALL in children have improved markedly in previous years, limited treatment strategies are available at present for adult patients with ALL. Wee1 is a crucial cell cycle checkpoint kinase of G2/M that regulates cell cycle progression and maintains chromatin integrity. MK-1775, a selective inhibitor of Wee1 has recently been identified to be able to induce apoptosis of tumor cells by abrogating G2/M checkpoint. The present study investigated the anti-leukemic activity of MK-1775 alone and in combination with doxorubicin (Adriamycin(r); ADM) in various human ALL cell lines. MK-1775 treatment induced apoptosis of ALL cells, accompanied by unscheduled mitotic entry and downregulation of Notch pathway. The anti-leukemic activity of MK-1775 was in a concentration- and time dependent manner. The data also indicated that it decreased the half-maximal inhibitory concentration (IC50) of ADM compared with the control group. The combination of MK-1775 and ADM induced an increased apoptotic rate compared with each agent alone. In addition, the human bone marrow stromal cell HS-5 cell line was detected to exhibit an increased IC50 value of MK-1775 treatment in contrast to ALL cell lines. It indicates that the hematopoietic supportive capability may remain intact during the treatment of MK-1775. Taken together, the Wee1 inhibitor MK-1775 may be an attractive agent in the treatment of patients with ALL. PMID- 30250621 TI - Troglitazone inhibits the migration and invasion of PC-3 human prostate cancer cells by upregulating E-cadherin and glutathione peroxidase 3. AB - Troglitazone (TGZ) is a synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) ligand that exhibits potential antitumor effects on a number of cancer subtypes, including prostate cancer. However, little is known about the effect of TGZ on metastasis in prostate cancer. The aim of the present study was to determine the inhibitory effect and mechanism underlying TGZ on cell growth, migration and invasion using the prostate cancer PC-3 cell line. Cellular migration and invasion were evaluated by performing a wound healing assay and Matrigel assay, respectively. The expression levels of mRNA and protein were determined by reverse transcription-quantitative polymerase chain reaction and western blotting. The results demonstrated that TGZ dose-dependently inhibited cell migration and invasion of PC-3 cells. The present study also revealed that TGZ increased the mRNA and protein levels of E-cadherin and glutathione peroxidase 3 (GPx3) in human prostate cancer PC-3 cells. In addition, GW9662, a PPARgamma antagonist, attenuated the increased mRNA and protein levels of E cadherin and GPx3, suggesting that the PPARgamma-dependent signaling pathway was involved. Taken together, these results suggested that the anti-migration and anti-invasion effect of TGZ on PC-3 prostate cancer cells is, at least in part, mediated via upregulation of E-cadherin and GPx3. The present study also concluded that PPARgamma may be used as a potential remedial target for the prevention and treatment of prostate cancer cell invasion and metastasis. PMID- 30250622 TI - Overexpression of MARCKS indicates a poor prognosis of oral squamous cell carcinoma. AB - Myristoylated alanine-rich C kinase substrate (MARCKS) is a protein kinase C substrate functioning in different physiological and pathological mechanisms. Previous studies have suggested that MARCKS is capable of influencing tumorigenesis and progression. However, a limited number of studies are available regarding the role of MARCKS in oral squamous cell carcinoma (OSCC). The present study primarily examined MARCKS expression in the OSCC tissues. Furthermore, increased expression of MARCKS was confirmed in the majority of OSCC tissues. Increased MARCKS expression was correlated with more advanced tumor stages, lymphatic metastasis and a poorer overall patient survival. Further molecular mechanistic examinations revealed that downregulated MARCKS expression inhibited the proliferation and migration of OSCC cells in vitro through interruption of MARCKS expression. In addition, the present study demonstrated that MARCKS aggravated OSCC progression via the phosphoinositide 3-kinase/protein kinase B pathway. Accordingly, the present study considered MARCKS to be a promoter of OSCC tumorigenesis and progression, with the potential utility as a biomarker of a poor prognosis. PMID- 30250623 TI - Association of IRS2 overexpression with disease progression in intrahepatic cholangiocarcinoma. AB - Insulin receptor substrate 2 (IRS2) is a candidate driver oncogene frequently amplified in cancer and is positively associated with IRS2 expression. The overexpression of IRS2 has been suggested to promote tumor metastasis. However, its function in intrahepatic cholangiocarcinoma (iCCA) has not been investigated extensively. The present study examined 86 cases of iCCA to analyze IRS2 expression and its correlation with clinicopathological characteristics using immunohistochemical assays. Three stable cell lines overexpressing IRS2 were established. The mobility potential of cells was compared in the basal condition and following manipulation using cell migration and invasion assays. Epithelial mesenchymal transition (EMT)-associated proteins were assessed by western blotting. IRS2 was overexpressed in 29 iCCA cases (33.7%) and was significantly more frequent in cases with large tumor size (P=0.033), classified as an advanced stage by the American Joint Committee on Cancer (P=0.046). In comparison with the control cells, the three IRS2-overexpressing iCCA cell lines exhibited a statistically significant increase in mobility potential. Expression analysis of EMT markers demonstrated decreased epithelial marker levels and increased mesenchymal marker levels in IRS2-overexpressing cells compared with their corresponding control cells. The results of the present study indicate that IRS2 overexpression is characterized by a large tumor size and advanced tumor stage in iCCA, and that it may increase tumor mobility potential by regulating EMT pathways. Therefore, it is a valuable predictive indicator of metastasis and may provide a novel direction for targeted therapy in iCCA. PMID- 30250624 TI - Personality development in psychotherapy: a synergetic model of state-trait dynamics. AB - Theoretical models of psychotherapy not only try to predict outcome but also intend to explain patterns of change. Studies showed that psychotherapeutic change processes are characterized by nonlinearity, complexity, and discontinuous transitions. By this, theoretical models of psychotherapy should be able to reproduce these dynamic features. Using time series derived from daily measures through internet-based real-time monitoring as empirical reference, we earlier presented a model of psychotherapy which includes five state variables and four trait variables. In mathematical terms, the traits modulate the shape of the functions which define the nonlinear interactions between the variables (states) of the model. The functions are integrated into five coupled nonlinear difference equations. In the present paper, we model how traits (dispositions or competencies of a person) can continuously be altered by new experiences and states (cognition, emotion, behavior). Adding equations that link states to traits, this model not only describes how therapeutic interventions modulate short-term change and fluctuations of psychological states, but also how these can influence traits. Speaking in terms of Synergetics (theory of self organization in complex systems), the states correspond to the order parameters and the traits to the control parameters of the system. In terms of psychology, trait dynamics is driven by the states-i.e., by the concrete experiences of a client-and creates a process of personality development at a slower time scale than that of the state dynamics (separation of time scales between control and order parameter dynamics). PMID- 30250625 TI - Examining stability of independent component analysis based on coefficient and component matrices for voxel-based morphometry of structural magnetic resonance imaging. AB - Independent component analysis (ICA) on group-level voxel-based morphometry (VBM) produces the coefficient matrix and the component matrix. The former contains variability among multiple subjects for further statistical analysis, and the latter reveals spatial maps common for all subjects. ICA algorithms converge to local optimization points in practice and the mostly applied stability investigation approach examines the stability of the extracted components. We found that the practically stable components do not guarantee to produce the practically stable coefficients of ICA decomposition for the further statistical analysis. Consequently, we proposed a novel approach including two steps: (1), the stability index for the coefficient matrix and the stability index for the component matrix were examined, respectively; (2) the two indices were multiplied to analyze the stability of ICA decomposition. The proposed approach was used to study the sMRI data of Type II diabetes mellitus group and the healthy control group (HC). Group differences in VBM were found in the superior temporal gyrus. Besides, it was revealed that the VBMs of the region of the HC group were significantly correlated with Montreal Cognitive Assessment (MoCA) describing the level of cognitive disorder. In contrast to the widely applied approach to investigating the stability of the extracted components for ICA decomposition, we proposed to examine the stability of ICA decomposition by fusion the stability of both coefficient matrix and the component matrix. Therefore, the proposed approach can examine the stability of ICA decomposition sufficiently. PMID- 30250627 TI - An oscillatory neural network model that demonstrates the benefits of multisensory learning. AB - Since the world consists of objects that stimulate multiple senses, it is advantageous for a vertebrate to integrate all the sensory information available. However, the precise mechanisms governing the temporal dynamics of multisensory processing are not well understood. We develop a computational modeling approach to investigate these mechanisms. We present an oscillatory neural network model for multisensory learning based on sparse spatio-temporal encoding. Recently published results in cognitive science show that multisensory integration produces greater and more efficient learning. We apply our computational model to qualitatively replicate these results. We vary learning protocols and system dynamics, and measure the rate at which our model learns to distinguish superposed presentations of multisensory objects. We show that the use of multiple channels accelerates learning and recall by up to 80%. When a sensory channel becomes disabled, the performance degradation is less than that experienced during the presentation of non-congruent stimuli. This research furthers our understanding of fundamental brain processes, paving the way for multiple advances including the building of machines with more human-like capabilities. PMID- 30250626 TI - Electrophysiological and neuropsychological outcomes of severe obstructive sleep apnea: effects of hypoxemia on cognitive performance. AB - Obstructive sleep apnea syndrome (OSAS) is a sleep disorder characterized with upper airway obstructions. Some studies showed cognitive and electrophysiological changes in patients with OSAS; however, contradictory results were also reported. The purpose of the present study was twofold: (1) to investigate cognitive changes in severe OSAS patients by using neuropsychological tests and electrophysiological methods together, (2) to investigate influence of hypoxemia levels on cognition. Fifty-four severe OSAS patients and 34 age-, gender- and education matched healthy subjects were participated. OSAS patients were further divided into two subgroups according to minimum oxygen saturation levels. All participants underwent a detailed neuropsychological test battery. A classical visual oddball task was used to elicit ERP P300 and mean P300 amplitudes were measured from Fz, Cz and Pz electrode sites. OSAS patients showed reduced mean P300 amplitudes up to 43-51% on all electrode sites compared to healthy controls. Subgroup analysis revealed significant differences in neuropsychological test scores between healthy controls and high hypoxemia OSAS group, as well as between low and high hypoxemia groups. Moreover, both low and high hypoxemia OSAS groups had lower P300 amplitudes compared with healthy controls. P300 amplitudes showed a gradual decline in parallel with increasing hypoxemia severity; however, the difference between high and low hypoxemia OSAS groups did not reach significance. Moderate correlations were found between sleep parameters, neuropsychological test scores and P300 amplitudes. These results suggest that electrophysiological measures could be better indicators of cognitive changes than neuropsychological tests in OSAS, particularly in mildly affected patients. PMID- 30250628 TI - The informational entropy endowed in cortical oscillations. AB - A two-dimensional shadow may encompass more information than its corresponding three-dimensional object. Indeed, if we rotate the object, we achieve a pool of observed shadows from different angulations, gradients, shapes and variable length contours that make it possible for us to increase our available information. Starting from this simple observation, we show how informational entropies might turn out to be useful in the evaluation of scale-free dynamics in the brain. Indeed, brain activity exhibits a scale-free distribution that leads to the variations in the power law exponent typical of different functional neurophysiological states. Here we show that modifications in scaling slope are associated with variations in Renyi entropy, a generalization of Shannon informational entropy. From a three-dimensional object's perspective, by changing its orientation (standing for the cortical scale-free exponent), we detect different two-dimensional shadows from different perception angles (standing for Renyi entropy in different brain areas). We show how, starting from known values of Renyi entropy (easily detectable in brain fMRIs or EEG traces), it is feasible to calculate the scaling slope in a given moment and in a given brain area. Because changes in scale-free cortical dynamics modify brain activity, this issue points towards novel approaches to mind reading and description of the forces required for transcranial stimulation. PMID- 30250629 TI - Vibrational resonance in a randomly connected neural network. AB - A randomly connected network is constructed with similar characteristics (e.g., the ratio of excitatory and inhibitory neurons, the connection probability between neurons, and the axonal conduction delays) as that in the mammalian neocortex and the effects of high-frequency electrical field on the response of the network to a subthreshold low-frequency electrical field are studied in detail. It is found that both the amplitude and frequency of the high-frequency electrical field can modulate the response of the network to the low-frequency electric field. Moreover, vibrational resonance (VR) phenomenon induced by the two types of electrical fields can also be influenced by the network parameters, such as the neuron population, the connection probability between neurons and the synaptic strength. It is interesting that VR is found to be related with the ratio of excitatory neurons that are under high-frequency electrical stimuli. In summary, it is suggested that the interaction of excitatory and inhibitory currents is also an important factor that can influence the performance of VR in neural networks. PMID- 30250630 TI - An observational learning task using Barnes maze in rats. AB - Observational learning, which modulates one's own behavior by observing the adaptive behavior of others, is crucial for behaving efficiently in social communities. Although many behavioral experiments have reported observational learning in monkeys and humans, its neural mechanisms are still unknown. In order to conduct neuroscientific researches with recording neural activities, we developed an observational learning task for rats. We designed the task using Barnes circular maze and then tested whether rats (observers) could actually improve their learning by observing the behavior of other rats (models) that had already acquired the task. The result showed that the observer rats, which were located in a metal wire mesh cylinder at the center of the maze and allowed to observe model rats escaping to the goal in the maze, demonstrated significantly faster escape behavior than the model rats. Thus, the present study confirmed that rats can efficiently learn the behavioral task by observing the behavior of other rats; this shows that it is conceivable to elucidate the neural mechanisms of social interaction by analyzing neural activity in observer rats performing the observational learning task. PMID- 30250631 TI - Usefulness of Nonvalved Spacers for Administration of Inhaled Steroids in Young Children with Recurrent Wheezing and Risk Factors for Asthma. AB - Background: In vitro and scintigraphic studies have suggested that effectiveness of metered-dose inhalers (MDI) with nonvalved spacers (NVS) is similar to that of MDI with valved holding chambers (VHC). Nevertheless, there are no clinical studies that compare these techniques in long-term treatment with inhaled steroids in young children with recurrent wheezing and risk factors for asthma. Objective: To compare the efficacy of a long-term treatment with Fluticasone Propionate administered by an MDI through both type of spacers, with and without valves, in young children with recurrent wheezing and risk factors for asthma. Patients and Methods: Outpatient children (6 to 20 months old) with recurrent wheezing and risk factors for asthma were randomized to receive a 6-month treatment with metered-dose inhaler (MDI) of Fluticasone Propionate 125 mcg BID through an NVS or through a VHC. Parents recorded daily their child's respiratory symptoms and rescue medication use. Results: 46 patients of 13.4 +/- 5 months old were studied. During the study period, the NVS group (n=25) experienced 3.9 +/- 2.4 obstructive exacerbations, and the VHC group (n=21) had 2.6 +/- 1.6 (p=0.031). The NVS group had 17.4 +/- 14% of days with respiratory symptoms, and the VHC group had 9.7 +/- 7% (p=0.019). The NVS group spent 29.8 +/- 22 days on albuterol while the VHC group spent 17.9 +/- 11 days (p=0.022). Conclusion: Long term treatment with inhaled steroids administered by MDI and NVS is less effective than such treatment by MDI and VHC in infants with recurrent wheezing and risk factors for asthma. PMID- 30250632 TI - Increase and Redistribution of Sex Hormone Receptors in Premenopausal Women Are Associated with Varicose Vein Remodelling. AB - In chronic venous insufficiency of the lower limbs, data show that the clinical manifestation is varicose veins (VVs), and VV epidemiology suggests that sex hormones directly influence disease development through intracellular receptors. This study aimed to determine the presence and localization of oestrogen receptors (ERs), progesterone receptors (PRs), and androgen receptors (ARs) in both healthy and VV wall cells and their relationship with gender. In this study, samples from patients without a history of venous disease (CV) (n = 18) and with VV (n = 40) were used. The samples were divided by gender: CV women (CVw) = 6, CV men (CVm) = 12, VV women (VVw) = 25, and VV men (VVm) = 15. RT-qPCR and immunohistochemical techniques were performed, and increased ER and PR protein expression was found in VVw in all tunica layers. ARs were localized to the adventitial layer in the CV and were found in the neointima in VVs. mRNA expression was increased for ER and PR in VVw. AR gene expression was significantly decreased in VVm. The increase in the number of these receptors and their redistribution through the wall reinforces the role of sex hormones in varicose vein development. PMID- 30250634 TI - Complete genome sequence of the Robinia pseudoacacia L. symbiont Mesorhizobium amorphae CCNWGS0123. AB - Mesorhizobium amorphae CCNWGS0123 was isolated in 2006, from effective nodules of Robinia pseudoacacia L. grown in lead-zinc mine tailing site, in Gansu Province, China. M. amorphae CCNWGS0123 is an aerobic, Gram-negative, non-spore-forming rod strain. This paper characterized M. amorphae CCNWGS0123 and presents its complete genome sequence information and genome annotation. The 7,374,589 bp long genome which encodes 7136 protein-coding genes and 63 RNA coding genes, contains one chromosome and four plasmids. Moreover, a chromosome with no gaps was assembled. PMID- 30250633 TI - Dexmedetomidine Ameliorates Acute Stress-Induced Kidney Injury by Attenuating Oxidative Stress and Apoptosis through Inhibition of the ROS/JNK Signaling Pathway. AB - Acute stress induces tissue damage through excessive oxidative stress. Dexmedetomidine (DEX) reportedly has an antioxidant effect. However, protective roles and related potential molecular mechanisms of DEX against kidney injury induced by acute stress are unknown. Herein, rats were forced to swim 15 min followed by restraint stress for 3 h with/without DEX (30 MUg/kg). Successful model establishment was validated by an open-field test. Assessment of renal function (creatinine, urea nitrogen), histopathology, oxidative stress (malondialdehyde, glutathione, and superoxide dismutase), and apoptosis (transferase-mediated dUTP nick end labeling) was performed. Localization of apoptosis was determined by immunohistochemistry of cleaved caspase 3 protein. In addition, key proteins of the death receptor-mediated pathway, mitochondrial pathway, endoplasmic reticulum stress (ERS) pathway, and ROS/JNK signaling pathway were measured by Western blot. We found that DEX significantly improved renal dysfunction, ameliorated kidney injury, reduced oxidative stress, and alleviated apoptosis. DEX also inhibited the release of norepinephrine (NE), decreased the production of reactive oxygen species (ROS), and inhibited JNK phosphorylation. Additionally, DEX downregulated the expression of Bax, cytochrome C, cleaved caspase 9, and cleaved caspase 3 proteins in mitochondria dependent pathways. In summary, DEX protects against acute stress-induced kidney injury in rats by reducing oxidative stress and apoptosis via inhibition of the ROS/JNK pathway. PMID- 30250635 TI - Adolescent Alcohol Use: The Effects of Parental Knowledge, Peer Substance Use, and Peer Tolerance of Use. AB - Objective: Parents and peers exert significant influence on a young person's decision to consume alcohol. This study examines the relationship between parental monitoring and adolescent alcohol consumption and tests whether peer substance use and tolerance of use mediates the relationship between monitoring and drinking. Method: Participants included 116 adolescents (53.5% female; Mage = 15.6). All participants reported drinking alcohol in the past 6 months, and 96 participants had been previously admitted to a hospital emergency department for an alcohol-related event. Mediation analyses were used to test the study hypotheses. Results: The total effect of baseline parental monitoring on 6-month alcohol use was -1.15 (p < .01), with higher monitoring related to less use. Controlling for peer use and tolerance of use, the effect of parental monitoring was reduced to .46, leaving an indirect effect of .69 (p < .01). Peer use and tolerance of use had no effect on participant alcohol use when controlling for parental monitoring. Conclusions: Study findings extend current knowledge about the interactive effects of parental supervision and peer influence on the drinking patterns of adolescents. Results underscore the importance of addressing both parental monitoring and peer influence in interventions that target adolescent alcohol use, recognizing peer factors as a potential mechanism of the effect that parental monitoring has on adolescent drinking. PMID- 30250636 TI - JAK inhibitors for refractory lymphoma. PMID- 30250637 TI - Combination of ATO with FLT3 TKIs eliminates FLT3/ITD+ leukemia cells through reduced expression of FLT3. AB - Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. Arsenic trioxide (ATO, As2O3) has been proven effective in treating acute promyelocytic leukemia (APL) and has shown activity in some cases of refractory and relapsed AML and other hematologic malignances. We explored the feasibility of combining FLT3 TKIs with ATO in the treatment of FLT3/ITD+ leukemias. The combination of FLT3 TKIs with ATO showed synergistic effects in reducing proliferation, viability and colony forming ability, and increased apoptosis in FLT3/ITD+ cells and primary patient samples. In contrast, no cooperativity was observed against wild-type FLT3 leukemia cells. ATO reduced expression of FLT3 RNA and its upstream transcriptional regulators (HOXA9, MEIS1), and induced poly ubiquitination and degradation of the FLT3 protein, partly through reducing its binding with USP10. ATO also synergizes with FLT3 TKIs to inactivate FLT3 autophosphorylation and phosphorylation of its downstream signaling targets, including STAT5, AKT and ERK. Furthermore, ATO combined with sorafenib, a FLT3 TKI, in vivo reduced growth of FLT3/ITD+ leukemia cells in NSG recipients. In conclusion, these results suggest that ATO is a potential candidate to study in clinical trials in combination with FLT3 TKIs to improve the treatment of FLT3/ITD+ leukemia. PMID- 30250638 TI - A new drug combination significantly reduces kidney tumor progression in kidney mouse model. AB - Tuberous sclerosis complex (TSC) disease is associated with tumors in many organs, particularly angiomyolipoma (AML) in the kidneys. Loss or inactivation of TSC1/2 results in high levels of HIF-alpha activity and VEGF expression. mTOR inhibitor (rapamycin) and the AMPK activator 5-aminoimidazole-4-carboxamide (AICA)-riboside (AICAR) are currently used separately to treat cancer patients. Here, we investigated the effect of a novel combination of rapamycin and AICAR on tumor progression. Our data show that treatment of AML human cells with drug combinations resulted in 5-7-fold increase in cell apoptosis compared to each drug alone. In addition, drug combinations resulted in 4-5-fold decrease in cell proliferation compared to each drug alone. We found that drug combinations abolished Akt and HIF activity in AML cells. The drug combinations resulted in decrease in cell invasion and cell immigration by 70% and 84%, respectively in AML cells. The combined drugs also significantly decreased the VEGF expression compare to each drug alone in AML cells. Drug combinations effectively abolished binding of HIF-2alpha to the putative Akt site in the nuclear extracts isolated from AML cells. Treatment TSC mice with drug combinations resulted in 75% decrease in tumor number and 88% decrease in tumor volume compared to control TSC mice. This is first evidence that drug combinations are effective in reducing size and number of kidney tumors without any toxic effect on kidney. These data will provide evidence for initiating a new clinical trial for treatment of TSC patients. PMID- 30250639 TI - Lipolysis-stimulated lipoprotein receptor overexpression is a novel predictor of poor clinical prognosis and a potential therapeutic target in gastric cancer. AB - The prognosis of patients with advanced gastric cancer (GC) remains poor despite the recent advances in molecular targeted therapies, and the search for biomarkers that can predict prognosis and additional new agents with acceptable toxicity profiles are needed. Lipolysis-stimulated lipoprotein receptor (LSR) is a lipoprotein receptor that binds to triglyceride-rich lipoproteins and related to some malignancies. Herein, we examined the association between LSR expression and the prognosis of patients with GC, and investigated the antitumor effect of a previously developed anti-human LSR monoclonal antibody (#1-25). We first performed immunohistochemical analysis of LSR protein expression in GC and normal tissues, and then examined its association with the prognosis of 110 patients with GC. LSR was overexpressed in most of primary GC and metastatic tumors, but not in normal tissues. Patients with strong LSR expression (N = 80, 72.7%) had significantly poorer overall survival (OS) than those with weak expression (P = 0.017). Multivariate analysis identified strong LSR (as well as pT) as independent and significant prognostic factors for OS. Next, we demonstrated that very low density lipoprotein (VLDL) treatment increases cell proliferation in LSR expressing GC cell lines in vitro; LSR inhibition using #1-25 inhibited VLDL induced proliferation by suppressing JAK/STAT and PI3K signaling. In vivo, we demonstrated a marked antitumor effect of #1-25 in 2 distinct GC cell line xenograft mice models. Our findings suggest that LSR plays a key functional role in GC development, and that this antigen can be therapeutically targeted to improve GC treatment. PMID- 30250640 TI - Coriolus versicolor biomass increases dendritic arborization of newly-generated neurons in mouse hippocampal dentate gyrus. AB - Brain cognitive reserve refers to the ability of the brain to manage different challenges that arise throughout life, making it resilient to neuropathology. Hippocampal adult neurogenesis has been considered to be a relevant contributor for brain cognitive reserve and brain plasticity. Coriolus versicolor (CV), a common healthful mushroom, has been receiving increasing attention by its antitumoral, anti-inflammatory, antioxidant, antibacterial, and immunomodulatory properties, including in the hippocampus. Herein, we evaluated whether CV biomass oral administration for 2.5 months enhances hippocampal neurogenic reserve under normal/physiological conditions, by quantifying hippocampal dentate gyrus (DG) granular cell layer (GCL) and subgranular zone (SGZ) volumes, proliferation, number and dendritic complexity features of hippocampal newly-generated neurons. We also analyzed beta-catenin levels in DG newly-generated immature neurons, because it plays a major role in neurogenesis. Although no differences were observed in the volume of GCL and SGZ layers, in proliferation and in the number of newly-generated neurons of controls and CV-administered mice, we found that CV administration promotes a significant increase in dendritic length and branching and total dendritic volume of immature neurons, suggesting a positive effect of oral CV administration in the hippocampal neurogenic reserve. We also observed that beta-catenin levels are increased both in the nucleus and cytoplasm of DG immature neurons, suggesting that Wnt/beta-catenin signalling may play an important role in the CV positive effect on the differentiation of these cells. These data unveil a so far unexplored neurogenic potential of CV supplementation, which emerges as a possible preventive strategy for different neurological conditions. PMID- 30250641 TI - Combination of resveratrol and 5-flurouracil enhanced anti-telomerase activity and apoptosis by inhibiting STAT3 and Akt signaling pathways in human colorectal cancer cells. AB - Colorectal cancer is one of the leading causes for mortalities worldwide. The most common cause of colorectal cancer mortality is hepatic metastasis. There has been a limited advancement in the targeted-therapies for metastatic colorectal cancer. Conventional chemotherapeutic agent 5-fluorouracil has been used for various cancer treatments including colorectal cancer. Development of drug resistance and severe toxicity are major hurdles for its use in clinical setting. Resveratrol is a natural polyphenolic compound which has protective effects against aging-related diseases. In this study, we have tested whether combined treatments of resveratrol and 5-FU enhanced inhibitory effects against colorectal cancer cell growth. We herein showed that resveratrol and 5-FU combination treatments caused the anti-cancer activities by simultaneously inhibiting STAT3 and Akt signaling pathways. Resveratrol treatment induced S-phase specific cell cycle arrest, and when combined with 5-FU, it showed further increase in colorectal cancer cell apoptosis. Combined treatments of resveratrol and 5-FU inhibited epithelial-mesenchymal transition. Notably, resveratrol showed anti inflammatory effects by downregulating inflammatory biomarkers, pSTAT3 and pNFkappaB. Resveratrol and 5-FU treatments inhibited STAT3 phosphorylation and its binding to the promoter region of human telomerase reverse transcriptase (hTERT). Our data provide the first evidence that resveratrol can enhance anti telomeric and pro-apoptotic potentials of 5-FU in colorectal cancer, hence lead to re-sensitization to chemotherapy. PMID- 30250642 TI - MAP17 (PDZK1IP1) and pH2AX are potential predictive biomarkers for rectal cancer treatment efficacy. AB - Rectal cancer represents approximately 10% of cancers worldwide. Preoperative chemoradiotherapy increases complete pathologic response and local control, although it offers a poor advantage in survivorship and sphincter saving compared with that of radiotherapy alone. After preoperative chemoradiotherapy, approximately 20% of patients with rectal cancer achieve a pathologic complete response to the removed surgical specimen; this response may be related to a better prognosis and an improvement in disease-free survival. However, better biomarkers to predict response and new targets are needed to stratify patients and obtain better response rates. MAP17 (PDZK1IP1) is a small, 17 kDa non glycosylated membrane protein located in the plasma membrane and Golgi apparatus and is overexpressed in a wide variety of human carcinomas. MAP17 has been proposed as a predictive biomarker for reactive oxygen species, ROS, inducing treatments in cervical tumors or laryngeal carcinoma. Due to the increase in ROS, MAP17 is also associated with the marker of DNA damage, phosphoH2AX (pH2AX). In the present manuscript, we examined the values of MAP17 and pH2AX as surrogate biomarkers of the response in rectal tumors. MAP17 expression after preoperative chemoradiotherapy is able to predict the response to chemoradiotherapy, similar to the increase in pH2AX. Furthermore, we explored whether we can identify molecular targeted therapies that could help improve the response of these tumors to radiotherapy. In this sense, we found that the inhibition of DNA damage with olaparib increased the response to radio- and chemotherapy, specifically in tumors with high levels of pH2AX and MAP17. PMID- 30250643 TI - COPD-Type lung inflammation promotes K-ras mutant lung cancer through epithelial HIF-1alpha mediated tumor angiogenesis and proliferation. AB - Chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, is an independent risk factor for lung cancer. Lung tissues obtained from human smokers with COPD and lung cancer demonstrate hypoxia and up-regulated hypoxia inducible factor-1 (HIF-1). HIF-1 activation is the central mechanism for controlling the cellular response to hypoxia during inflammation and tumor development. These facts suggest a link between COPD-related airway inflammation, HIF-1, and lung cancer. We have previously established a mouse model of COPD-like airway inflammation that promotes lung cancer in a K-ras mutant mouse model (CC LR). Here we show that tumors in the CC-LR model have significantly elevated levels of HIF-1alpha and HIF-1 activity. To determine the tumor-promoting functions of HIF-1 in CC-LR mice, the gene Hif1a which encodes HIF-1alpha and is required for HIF-1 activity, was disrupted in the lung epithelium of CC-LR animals. Airway epithelial specific HIF-1alpha deficient mice demonstrated significant reductions in lung surface tumor numbers, tumor angiogenesis, and tumor cell proliferation in the absence or presence of COPD-like airway inflammation. In addition, when CC-LR mice were bred with transgenic animals that overexpress a constitutively active mutant form of human HIF-1alpha in the airway epithelium, both COPD- and adenocarcinoma-like phenotypes were observed. HIF 1alpha overexpressing CC-LR mice had significant emphysema, and they also showed potentiated tumorigenesis, angiogenesis, and cell proliferation accompanied by an invasive metastatic phenotype. Our gain and loss of function studies support a key role for HIF-1alpha in the promotion of lung cancer by COPD-like inflammation. PMID- 30250644 TI - Increased plasma levels of galectin-1 in pancreatic cancer: potential use as biomarker. AB - Pancreatic ductal adenocarcinoma (PDA) is the most frequent type of pancreatic cancer and one of the deadliest diseases overall. New biomarkers are urgently needed to allow early diagnosis, one of the only factors that currently improves prognosis. Here we analyzed whether the detection of circulating galectin-1 (Gal 1), a soluble carbohydrate-binding protein overexpressed in PDA tissue samples, can be used as a biomarker for PDA. Gal-1 levels were determined by ELISA in plasma from healthy controls and patients diagnosed with PDA, using three independent cohorts. Patients with chronic pancreatitis (CP) were also included in the study to analyze the potential of Gal-1 to discriminate between cancer and inflammatory process. Plasma Gal-1 levels were significantly increased in patients with PDA as compared to controls in all three cohorts. Gal-1 sensitivity and specificity values were similar to that of the CA19-9 biomarker (the only FDA approved blood test biomarker for PDA), and the combination of Gal-1 and CA19-9 significantly improved their individual discriminatory powers. Moreover, high levels of Gal-1 were associated with lower survival in patients with non-resected tumors. Collectively, our data indicate a strong potential of using circulating Gal-1 levels as a biomarker for detection and prognostics of patients with PDA. PMID- 30250645 TI - Panobinostat mediated cell death: a novel therapeutic approach for osteosarcoma. AB - Osteosarcoma is an aggressive cancer with a poor long term prognosis. Neo adjuvant poly-chemotherapy followed by surgical resection remains the standard treatment, which is restricted by multi-drug resistance. If first-line therapy fails, disease control and patient survival rate drop dramatically. We aimed to identify alternative apoptotic mechanisms induced by the histone deacetylase inhibitor panobinostat in osteosarcoma cells. Saos-2, MG63 and U2-OS osteosarcoma cell lines, the immortalized human osteoblast line hFOB and the mouse embryo osteoblasts (MC3T3-E1) were treated with panobinostat. Real time viability and FACS confirmed the cytotoxicity of panobinostat. Cell stress/death related factors were analysed by RT-qPCR and western blot. Cell morphology was assessed by electron microscopy. 10 nM panobinostat caused cell viability arrest and death in all osteosarcoma and osteoblast cells. P21 up-regulation was observed in osteosarcoma cells, while over-expression of p73 was restricted to Saos-2 (TP53-/ ). Survivin and Bcl-2 were suppressed by panobinostat. Endoplasmic reticulum (ER) stress markers BiP, CHOP, ATF4 and ATF6 were induced in osteosarcoma cells. The un-spliced Xbp was no further detectable after treatment. Autophagy players Beclin1, Map1LC3B and UVRAG transcripts over-expressed after 6 hours. Protein levels of Beclin1, Map1LC3B and p62 were up-regulated at 72 hours. DRAM1 was stable. Electron micrographs revealed the fragmentation and the disappearance of the ER and the statistically significant increase of autophagosome vesiculation after treatment. Panobinostat showed a synergistic suppression of survival and promotion of cell death in osteosarcoma cells. Panobinostat offers new perspectives for the treatment of osteosarcoma and other malignant bone tumours. PMID- 30250646 TI - Constitutive activation and overexpression of NF-kappaB/c-Rel in conjunction with p50 contribute to aggressive tongue tumorigenesis. AB - Tongue squamous cell carcinoma (TSCC) is a most aggressive head and neck cancer often associated with a poor survival rate. Yet, it always shows better prognosis in presence of HPV16 infection. NF-kappaB plays a pivotal role in carcinogenesis and chemo-radio resistance of cancer but its role in tongue cancer is not yet explored. In this study, a total of hundred tongue tissue biopsies comprising precancer, cancer and adjacent normal controls including two tongue cancer cell lines (HPV+/-ve) were employed to examine expression and transactivation of NF kappaB proteins, their silencing by siRNA and invasion assays to understand their contributions in tongue carcinogenesis. An exclusive prevalence (28%) of HR-HPV type 16 was observed mainly in well differentiated tumors (78.5%). Increased DNA binding activity and differential expression of NF-kappaB proteins was observed with p50 and c-Rel being the two major DNA binding partners forming the functional NF-kappaB complex that increased as a function of severity of lesions in both HPV+/-ve tumors but selective participation of p65 in HPV16+ve TSCCs induced well differentiation of tumors resulting in better prognosis. siRNA treatment against c-Rel or Fra-2 led to upregulation of p27 but strong inhibition of c-Rel, c-Jun, c-myc, HPVE6/E7 and Fra-2 which is exclusively overexpressed in HPV-ve aggressive tumors. In conclusion, selective participation of c-Rel with p50 that in cross-talk with AP-1/Fra-2 induced poor differentiation and aggressive tumorigenesis mainly in HPV-ve smokers while HPV infection induced expression of p65 and p27 leading to well differentiation and better prognosis preferably in non-smoking TSCC patients. PMID- 30250647 TI - Synergistic combination of flavopiridol and carfilzomib targets commonly dysregulated pathways in adrenocortical carcinoma and has biomarkers of response. AB - Drug repurposing is an effective approach to identify active drugs with known toxicity profiles for rare cancers such as ACC. The objective of this study was to determine the anticancer activity of combination treatment for ACC from previously identified candidate agents using quantitative high-throughput screening (qHTS). In this study, we evaluated the anticancer activity of flavopiridol and carfilzomib in three ACC cell lines in vitro and in vivo. Human ACC samples were analyzed for drug-target analysis, and cancer-related pathway arrays were used to identify biomarkers of treatment response. Because flavopiridol is a potent cyclin-dependent kinase (CDK) inhibitor, we found significantly higher CDK1 and CDK2 mRNA expression in three independent cohorts human ACC (p<0.01) and CDK1 protein by immunohistochemistry (p<0.01) in human ACC samples. In vitro treatment with flavopiridol and carfilzomib in all three ACC cell lines resulted in a dose-dependent, anti-proliferative effect, and the combination had synergistic activity as well as in three-dimensional tumor spheroids. We observed increased G2M cell-cycle arrest and apoptosis with combination treatment compared to other groups in vitro. The combination treatment decreased XIAP protein expression in ACC cell lines. Mice with human ACC xenografts treated with flavopiridol and carfilzomib had significantly lower tumor burden, compared to other groups (p<0.05). We observed increased cleaved caspase expression and decreased XIAP in tumor xenografts of mice treated with combined agents. Our preclinical data supports the evaluation of combination therapy with flavopiridol and carfilzomib in patients with advanced ACC. PMID- 30250648 TI - Immune-related adverse events and atypical radiological response with checkpoint inhibitor immunotherapy in an elderly patient with high PD-L1 expressing lung adenocarcinoma. AB - Advances in immunotherapy have changed the therapeutic landscape of non-small cell lung cancer (NSCLC), extending overall survival over standard chemotherapy. However, by removing the protection against autoimmunity, immunotherapy can increase immune-related adverse events (irAEs). In addition, new patterns of radiological response have been observed in patients treated with immune checkpoint inhibitors (ICIs). We report the case of a 77 year-old patient with advanced lung adenocarcinoma, who presented three consecutive different irAEs (nephritis, hepatitis, and pneumonitis) and an atypical radiological response (partial response, dissociated response, and "disease flare") in relation to treatment with the PD-1 inhibitor nivolumab. The role of ICIs in elderly patients, the incidence of consecutive irAEs, and the new patterns of radiological response, are also reviewed. PMID- 30250649 TI - Correction: Prosopis juliflora (Sw.), DC induces apoptosis and cell cycle arrest in triple negative breast cancer cells: in vitro and in vivo investigations. AB - [This corrects the article DOI: 10.18632/oncotarget.25717.]. PMID- 30250650 TI - Lack of pain relief during labor is blamable for the increase in the women demands towards cesarean delivery: a cross-sectional study. AB - Background: This study aims to assess knowledge, attitude and acceptance of antenatal women for pain relief methods during labor and to know the effect of presumed availability of pain relief methods during labor on the attitude of women towards the mode of delivery. Materials and Methods: A cross sectional study was conducted at a tertiary hospital between January and December 2016. A structured interview questionnaire had been administered including data related to current pregnancy, knowledge, attitude and previous experience of pain, labor analgesia, women's attitude toward the mode of delivery and its relation to the availability of adequate analgesia during labor. Visual analog scale (VAS) was used to assess pregnant women's attitude towards pain in general and that related to the process of labor (past and expected experience). Results: Eight hundred and fourteen women were included in the study. The majority of our participants (82.9%) were unaware about the availability of labor analgesia. Sixty of the study participants preferred cesarean section (CS) to avoid labor pain. Availability of adequate pain relief during labor could decrease the women decision of CS by more than 50% in women expecting moderate and severe pain during labor compared to non-availability of pain relief (9.6% vs. 22.7% and 8.2% vs. 28.1% respectively). Conclusion: There is a great lack of knowledge regarding the availability of pain relief during labor. Lack of pain relief during labor can be responsible for more than half of women's intention to prefer CS as a mode of delivery. PMID- 30250651 TI - The Belgian Obstetric Surveillance System to monitor severe maternal morbidity. AB - Background: In 2011 the Belgian Obstetric Surveillance System (B.OSS) was set up to monitor severe maternal morbidity in Belgium. Aim: The aim of B.OSS is to get an accurate picture of the obstetric complications under investigation and secondly, to improve the quality and safety of obstetric care in Belgium by practical recommendations based on the results. Methodology: Data are obtained through prospective active collection of cases by a monthly call according to the principle of nothing-to-report, along with data collection forms that confirm the diagnosis and gather detailed information. Data-collection occurs web-based since August 2013 through www.b-oss.be. Results: B.OSS achieves excellent participation rates and response rates. The results of the first registration round are gradually brought out by means of scientific publications and presentations, biennial reports, newsletters and the website. The international comparison of results within the International Network of Obstetric Survey Systems (INOSS) gives important added value. No alternative mandatory data sources are appropriate to check for underreporting. Conclusions: B.OSS is successful in monitoring severe maternal morbidity thanks to the willingness of the Belgian OB GYNs. The results of the first studies suggest the need to develop nationally adopted guidelines. Furthermore, the results invite to critically evaluate the current organisation of obstetric health care in Belgium. B.OSS aims to monitor the impact on patient safety in future surveys, when guidelines and recommendations are put into practice. PMID- 30250652 TI - Ethnic disparities and morbidity in the Province of Antwerp, Belgium. AB - Objective: This study aims to identify geographical disparities in perinatal mortality and morbidity in the province of Antwerp, Belgium. We performed a retrospective cohort study from an existing database. Data included from 1 January , 2000 to 31 December, 2009 and including all deliveries in the Province of Antwerp, Belgium. Collected outcome measures : fetal death, early and late neonatal death, preterm birth, low birth weight. Outcomes were analyzed according to postal code of the pregnant women's address. Results: A total of 167.246 deliveries in sixty postal codes were analyzed and statistically significant differences (p<0.001) between postal codes for all outcome measures except for early and late neonatal death were detected. Generally postal codes tend to have either high or low prevalences for all perinatal outcomes and two postal code zones had a significantly worse perinatal outcome on all fields. Major differences in perinatal outcome exist within the well-defined area of the relatively small province of Antwerp, Belgium. Conclusion: Perinatal outcome is strongly influenced by maternal postal code even within a relatively affluent European region demonstrating persistent health inequalities and suggesting further research is necessary to explain these differences and create interventions to diminish inequalities. PMID- 30250653 TI - The impact of single versus double blastocyst transfer on pregnancy outcomes: A prospective, randomized control trial. AB - Objective: To determine if elective single blastocyst transfer (e-SBT) compromises pregnancy outcomes compared to double blastocyst transfer (DBT) in patients with favorable reproductive potential. Methods: This Randomized Control Trial included 50 patients with SBT (Group 1) and 50 patients with DBT (Group 2). All women were <35 years and had favorable reproductive potential. Randomization criterion was two good quality blastocysts on day 5. Patients who did not get pregnant or who miscarried underwent subsequent frozen cycles with transfer of two blastocysts (if available) in both groups. Results: No significant difference was observed in the majority of the demographic data, infertility etiology, ovarian stimulation characteristics and embryology data between the two groups. There was a significantly lower clinical pregnancy (61.2% vs 80.0%), and delivery (49.0% vs 70.0%) rates, but no difference in implantation (59.2% vs 54.0%), miscarriage, or ectopic pregnancy rates between Group 1 and Group 2, respectively. There was a significantly higher multiple pregnancy rate in Group 2 (35.0%) compared to Group 1 (0%) [P=0.000]. When fresh and first frozen cycles were combined, there was a significantly lower cumulative clinical pregnancy (77.6% vs 96.0%, P=0.007) and delivery (65.3% vs 86.0%, P=0.016) rates in Group 1 compared to Group 2 respectively. Conclusions: In patients with favorable reproductive potential, although e-SBT appears to reduce clinical pregnancy and live-birth rates, excellent pregnancy outcomes are achieved. Clinicians must weigh the benefits of DBT against the risk associated with multiple pregnancies in each specific patient before determining the number of blastocysts to be transferred. PMID- 30250654 TI - The value of postpartum ultrasound for the diagnosis of retained products of conception: A systematic review. AB - Background: The goal of this review is to evaluate the value of ultrasound for detection of retained products of conception (RCOP) after delivery. Methods: A systematic search was performed using 'postpartum', 'retained placenta', 'retained products' and 'ultrasound' resulting 82 publications, after screening titles and abstracts, 30 remained. Results: On gray scale ultrasound, one must be focus on a thickened endometrial echo complex (EEC) with a cut off value of 10 mm and on an intracavitary mass. If these features are not visible, RPOC is rare. However, these findings are neither specific nor conclusive for RPOC and can even be seen in a normal postpartum uterus. Detection of hypervascularity in a thickened EEC or intracavitary mass with color Doppler ultrasound is very sensitive for RPOC but still not specific nor can it exclude RPOC. MRI seems best in differentiating RPOC, arteriovenous malformations and gestational trophoblastic disease. Conclusion: There is no consensus on a standardised method for postpartum ultrasound. More research and standardization are necessary to differentiate of normal and pathological findings in the postpartum uterus. PMID- 30250655 TI - External factors affecting fertility, and how to correct their impact. AB - Fertility of both men and women has been negatively influenced by external factors and life style in recent decennia. Mechanisms of hormone disruption, oxidative damage, and epigenetic DNA changes play a pivotal role in this process. In Belgium, strict regulations have been imposed to reduce the exposure to xeno estrogens, which has resulted in a partial recovery of sperm quality. At the other hand, more couples require in vitro fertilisation (IVF) whereby ovarian stimulation may be associated with epigenetic DNA hyper-methylation of follicular cells, and increased risk of carcinogenesis among offspring. In order to reduce the health risks for the offspring it is recommended to optimize the oxidative, epigenetic and metabolic situation of both parents by means of lifestyle adaptation, and the use of appropriate food supplementation before conception and during pregnancy. PMID- 30250656 TI - Prenatal diagnosis of multiple large subchorionic placental cysts with intracystic hemorraghe. AB - Subchorionic placental cysts occur in up to 5% of pregnancies. Large and numerous placental cysts increase the risk for intrauterine growth restriction. We describe a case with large multiple subchorionic placental cysts complicated by intracystic hemorraghe and fetal growth restriction. PMID- 30250657 TI - The Patient in Precision Medicine: A Systematic Review Examining Evaluations of Patient-Facing Materials. AB - Precision medicine (PM) has the potential to tailor healthcare to the individual patient by using their genetic information to guide treatment choices. However, this process is complex and difficult to understand for patients and providers alike. With a recent push in the healthcare community to understand the patient experience and engage patients in their care, it is important to give patients the opportunity to learn about PM. We performed a systematic review to identify previous work assessing the quality of patient-facing PM materials from 2008 to July 2018. Ten studies were identified, which used varying methods and measures. A qualitative assessment was conducted to compare key elements of the studies, including study design, characteristics of the participant population, what measurements were used to assess the PM materials, understandability, preference, psychological reactions, and the type of PM materials being assessed. The studies identified provide important groundwork by highlighting consistent aspects of design that aid in comprehension. Eight of the ten studies focused on the content and organization of genomic test results, while the remaining two assessed educational tools. Two main design elements that appeared across the studies were appropriately designed visual aids and simplified language. The studies identified were limited by the participant populations that were used, which were primarily white and well educated. Only one study attempted to oversample patient populations typically underrepresented in this type of research. Through our systematic review, it is evident that the breadth of knowledge in this field is limited in scope and that more work must be done to ensure that patients can engage in their care when faced with PM. PMID- 30250658 TI - Open transcatheter aortic valve implantation on a degenerated bioprosthetic valve conduit. AB - The degeneration of bioprosthetic aortic Conduit with hemodynamic dysfunction mostly requires a re-do surgery, which is associated with an increased perioperative risk. Considering this, an open implantation of a transcatheter aortic bioprothesis (TAVI) after resection of the degenerated valve leaflets could be of great benefit, reducing cross-clamp and cardiopulmonary bypass duration, especially in combined surgery in high-risk patients. This is a case of a high-risk female (78 years, EuroScore 59%) treated with an open TAVI as an alternative to conventional valve or aortic conduit replacement for degenerative aortic valve due to endocarditis lente, 2 years following a bio-Bentall procedure. PMID- 30250659 TI - Power, pitfalls, and potential for integrating computational literacy into undergraduate ecology courses. AB - Environmental research requires understanding nonlinear ecological dynamics that interact across multiple spatial and temporal scales. The analysis of long-term and high-frequency sensor data combined with simulation modeling enables interpretation of complex ecological phenomena, and the computational skills needed to conduct these analyses are increasingly being integrated into graduate student training programs in ecology. Despite its importance, however, computational literacy-that is, the ability to harness the power of computer technologies to accomplish tasks-is rarely taught in undergraduate ecology classrooms, representing a major gap in training students to tackle complex environmental challenges. Through our experience developing undergraduate curricula in long-term and high-frequency data analysis and simulation modeling for two environmental science pedagogical initiatives, Project EDDIE (Environmental Data-Driven Inquiry and Exploration) and Macrosystems EDDIE, we have found that students often feel intimidated by computational tasks, which is compounded by the lack of familiarity with software (e.g., R) and the steep learning curves associated with script-based analytical tools. The use of prepackaged, flexible modules that introduce programming as a mechanism to explore environmental datasets and teach inquiry-based ecology, such as those developed for Project EDDIE and Macrosystems EDDIE, can significantly increase students' experience and comfort levels with advanced computational tools. These types of modules in turn provide great potential for empowering students with the computational literacy needed to ask ecological questions and test hypotheses on their own. As continental-scale sensor observatory networks rapidly expand the availability of long-term and high-frequency data, students with the skills to manipulate, visualize, and interpret such data will be well-prepared for diverse careers in data science, and will help advance the future of open, reproducible science in ecology. PMID- 30250660 TI - Population-level manipulations of field vole densities induce subsequent changes in plant quality but no impacts on vole demography. AB - Grazing-induced changes in plant quality have been suggested to drive the negative delayed density dependence exhibited by many herbivore species, but little field evidence exists to support this hypothesis. We tested a key premise of the hypothesis that reciprocal feedback between vole grazing pressure and the induction of anti-herbivore silicon defenses in grasses drives observed population cycles in a large-scale field experiment in northern England. We repeatedly reduced population densities of field voles (Microtus agrestis) on replicated 1-ha grassland plots at Kielder Forest, northern England, over a period of 1 year. Subsequently, we tested for the impact of past density on vole life history traits in spring, and whether these effects were driven by induced silicon defenses in the voles' major over-winter food, the grass Deschampsia caespitosa. After several months of density manipulation, leaf silicon concentrations diverged and averaged 22% lower on sites where vole density had been reduced, but this difference did not persist beyond the period of the density manipulations. There were no significant effects of our density manipulations on vole body mass, spring population growth rate, or mean date for the onset of spring reproduction the following year. These findings show that grazing by field voles does induce increased silicon defenses in grasses at a landscape scale. However, at the vole densities encountered, levels of plant damage appear to be below those needed to induce changes in silicon levels large and persistent enough to affect vole performance, confirming the threshold effects we have previously observed in laboratory-based studies. Our findings do not support the plant quality hypothesis for observed vole population cycles in northern England, at least over the range of vole densities that now prevail here. PMID- 30250661 TI - eDNA metabarcoding as a new surveillance approach for coastal Arctic biodiversity. AB - Because significant global changes are currently underway in the Arctic, creating a large-scale standardized database for Arctic marine biodiversity is particularly pressing. This study evaluates the potential of aquatic environmental DNA (eDNA) metabarcoding to detect Arctic coastal biodiversity changes and characterizes the local spatio-temporal distribution of eDNA in two locations. We extracted and amplified eDNA using two COI primer pairs from ~80 water samples that were collected across two Canadian Arctic ports, Churchill and Iqaluit, based on optimized sampling and preservation methods for remote regions surveys. Results demonstrate that aquatic eDNA surveys have the potential to document large-scale Arctic biodiversity change by providing a rapid overview of coastal metazoan biodiversity, detecting nonindigenous species, and allowing sampling in both open water and under the ice cover by local northern-based communities. We show that DNA sequences of ~50% of known Canadian Arctic species and potential invaders are currently present in public databases. A similar proportion of operational taxonomic units was identified at the species level with eDNA metabarcoding, for a total of 181 species identified at both sites. Despite the cold and well-mixed coastal environment, species composition was vertically heterogeneous, in part due to river inflow in the estuarine ecosystem, and differed between the water column and tide pools. Thus, COI-based eDNA metabarcoding may quickly improve large-scale Arctic biomonitoring using eDNA, but we caution that aquatic eDNA sampling needs to be standardized over space and time to accurately evaluate community structure changes. PMID- 30250662 TI - Disentangling effects of air and soil temperature on C allocation in cold environments: A 14C pulse-labelling study with two plant species. AB - Carbon cycling responses of ecosystems to global warming will likely be stronger in cold ecosystems where many processes are temperature-limited. Predicting these effects is difficult because air and soil temperatures will not change in concert, and will affect above and belowground processes differently. We disentangled above and belowground temperature effects on plant C allocation and deposition of plant C in soils by independently manipulating air and soil temperatures in microcosms planted with either Leucanthemopsis alpina or Pinus mugo seedlings. Daily average temperatures of 4 or 9 degrees C were applied to shoots and independently to roots, and plants pulse-labelled with 14 CO 2. We traced soil CO 2 and 14 CO 2 evolution for 4 days, after which microcosms were destructively harvested and 14C quantified in plant and soil fractions. In microcosms with L. alpina, net 14C uptake was higher at 9 degrees C than at 4 degrees C soil temperature, and this difference was independent of air temperature. In warmer soils, more C was allocated to roots at greater soil depth, with no effect of air temperature. In P. mugo microcosms, assimilate partitioning to roots increased with air temperature, but only when soils were at 9 degrees C. Higher soil temperatures also increased the mean soil depth at which 14C was allocated. Our findings highlight the dependence of C uptake, use, and partitioning on both air and soil temperature, with the latter being relatively more important. The strong temperature-sensitivity of C assimilate use in the roots and rhizosphere supports the hypothesis that cold limitation on C uptake is primarily mediated by reduced sink strength in the roots. We conclude that variations in soil rather than air temperature are going to drive plant responses to warming in cold environments, with potentially large changes in C cycling due to enhanced transfer of plant-derived C to soils. PMID- 30250663 TI - Development of on-shore behavior among polar bears (Ursus maritimus) in the southern Beaufort Sea: inherited or learned? AB - Polar bears (Ursus maritimus) are experiencing rapid and substantial changes to their environment due to global climate change. Polar bears of the southern Beaufort Sea (SB) have historically spent most of the year on the sea ice. However, recent reports from Alaska indicate that the proportion of the SB subpopulation observed on-shore during late summer and early fall has increased. Our objective was to investigate whether this on-shore behavior has developed through genetic inheritance, asocial learning, or through social learning. From 2010 to 2013, genetic data were collected from SB polar bears in the fall via hair snags and remote biopsy darting on-shore and in the spring from captures and remote biopsy darting on the sea ice. Bears were categorized as either on-shore or off-shore individuals based on their presence on-shore during the fall. Levels of genetic relatedness, first-order relatives, mother-offspring pairs, and father offspring pairs were determined and compared within and between the two categories: on-shore versus off-shore. Results suggested transmission of on-shore behavior through either genetic inheritance or social learning as there was a higher than expected number of first-order relatives exhibiting on-shore behavior. Genetic relatedness and parentage data analyses were in concurrence with this finding, but further revealed mother-offspring social learning as the primary mechanism responsible for the development of on-shore behavior. Recognizing that on-shore behavior among polar bears was predominantly transmitted via social learning from mothers to their offspring has implications for future management and conservation as sea ice continues to decline. PMID- 30250664 TI - Long-distance pollen and seed dispersal and inbreeding depression in Hymenaea stigonocarpa (Fabaceae: Caesalpinioideae) in the Brazilian savannah. AB - Hymenaea stigonocarpa is a neotropical tree that is economically important due to its high-quality wood; however, because it has been exploited extensively, it is currently considered threatened. Microsatellite loci were used to investigate the pollen and seed dispersal, mating patterns, spatial genetic structure (SGS), genetic diversity, and inbreeding depression in H. stigonocarpa adults, juveniles, and open-pollinated seeds, which were sampled from isolated trees in a pasture and trees within a forest fragment in the Brazilian savannah. We found that the species presented a mixed mating system, with population and individual variations in the outcrossing rate (0.53-1.0). The studied populations were not genetically isolated due to pollen and seed flow between the studied populations and between the populations and individuals located outside of the study area. Pollen and seed dispersal occurred over long distances (>8 km); however, the dispersal patterns were isolated by distance, with a high frequency of mating occurring between near-neighbor trees and seeds dispersed near the parent trees. The correlated mating for individual seed trees was higher within than among fruits, indicating that fruits present a high proportion of full-sibs. Genetic diversity and SGS were similar among the populations, but offspring showed evidence of inbreeding, mainly originating from mating among related trees, which suggests inbreeding depression between the seed and adult stages. Selfing resulted in a higher inbreeding depression than mating among relatives, as assessed through survival and height. As the populations are not genetically isolated, both are important targets for in situ conservation to maintain their genetic diversity; for ex situ conservation, seeds can be collected from at least 78 trees in both populations separated by at least 250 m. PMID- 30250665 TI - Plastome phylogeny and lineage diversification of Salicaceae with focus on poplars and willows. AB - Phylogenetic relationships and lineage diversification of the family Salicaceae sensu lato (s.l.) remain poorly understood. In this study, we examined phylogenetic relationships between 42 species from six genera based on the complete plastomes. Phylogenetic analyses of 77 protein coding genes of the plastomes produced good resolution of the interrelationships among most sampled species and the recovered clades. Of the sampled genera from the family, Flacourtia was identified as the most basal and the successive clades comprised both Itoa and Poliothyrsis, Idesia, two genera of the Salicaceae sensu stricto (s.s.) (Populus and Salix). Five major subclades were recovered within the Populus clade. These subclades and their interrelationships are largely inconsistent with morphological classifications and molecular phylogeny based on nuclear internal transcribed spacer sequence variations. Two major subclades were identified for the Salix clade. Molecular dating suggested that species diversification of the major subclades in the Populus and Salix clades occurred mainly within the recent Pliocene. In addition, we found that the rpl32 gene was lost and the rps7 gene evolved into a pseudogene multiple times in the sampled genera of the Salicaceae s.l. Compared with previous studies, our results provide a well-resolved phylogeny from the perspective of the plastomes. PMID- 30250666 TI - Tritrophic interactions between a fungal pathogen, a spider predator, and the blacklegged tick. AB - The blacklegged tick Ixodes scapularis is the primary vector for the bacterium causing Lyme disease in eastern North America and for other medically important pathogens. This species is vulnerable to attack by fungal pathogens and arthropod predators, but the impacts of interactions between biocontrol agents have not been examined. The biocontrol agent Met52(r), containing the entomopathogenic fungus Metarhizium brunneum (=M. anisopliae), controls blacklegged ticks with efficacy comparable to chemical acaricides. The brush-legged wolf spider Schizocosa ocreata is a predator of I. scapularis that reduces their survival under field conditions. We conducted a field microcosm experiment to assess the compatibility of Met52 and S. ocreata as tick biocontrol agents. We compared the fits of alternative models in predicting survival of unfed (flat) and blood-fed (engorged) nymphs. We found the strongest support for a model that included negative effects of Met52 and S. ocreata on flat nymph survival. We found evidence for interference between biocontrol agents, with Met52 reducing spider survival, but we did not find a significant interaction effect between the two agents on nymph survival. For engorged nymphs, low recovery rates resulted in low statistical power to detect possible effects of biocontrol agents. We found that nymph questing activity was lower when the spider was active above the leaf litter than when the spider was unobserved. This provides the first evidence that predation cues might affect behavior important for tick fitness and pathogen transmission. This study presents field microcosm evidence that the biopesticide Met52 and spider Schizocosa ocreata each reduced survival of blacklegged ticks Ixodes scapularis. Met52 reduced spider survival. Potential interference between Met52 and the spider should be examined at larger scales, where overlap patterns may differ. Ticks were more likely to quest when the spider was inactive, suggesting the ticks changed their behavior to reduce danger. PMID- 30250668 TI - Quaternary climate instability is correlated with patterns of population genetic variability in Bombus huntii. AB - Climate oscillations have left a significant impact on the patterns of genetic diversity observed in numerous taxa. In this study, we examine the effect of Quaternary climate instability on population genetic variability of a bumble bee pollinator species, Bombus huntii in western North America. Pleistocene and contemporary B. huntii habitat suitability (HS) was estimated with an environmental niche model (ENM) by associating 1,035 locality records with 10 bioclimatic variables. To estimate genetic variability, we genotyped 380 individuals from 33 localities at 13 microsatellite loci. Bayesian inference was used to examine population structure with and without a priori specification of geographic locality. We compared isolation by distance (IBD) and isolation by resistance (IBR) models to examine population differentiation within and among the Bayesian inferred genetic clusters. Furthermore, we tested for the effect of environmental niche stability (ENS) on population genetic diversity with linear regression. As predicted, high-latitude B. huntii habitats exhibit low ENS when compared to low-latitude habitats. Two major genetic clusters of B. huntii inhabit western North America: (a) a north genetic cluster predominantly distributed north of 28 degrees N and (b) a south genetic cluster distributed south of 28 degrees N. In the south genetic cluser, both IBD and IBR models are significant. However, in the north genetic cluster, IBD is significant but not IBR. Furthermore, the IBR models suggest that low-latitude montane populations are surrounded by habitat with low HS, possibly limiting dispersal, and ultimately gene flow between populations. Finally, we detected high genetic diversity across populations in regions that have been climatically unstable since the last glacial maximum (LGM), and low genetic diversity across populations in regions that have been climatically stable since the LGM. Understanding how species have responded to climate change has the potential to inform management and conservation decisions of both ecological and economic concerns. PMID- 30250667 TI - Population structure of a vector of human diseases: Aedes aegypti in its ancestral range, Africa. AB - Aedes aegypti, the major vector of dengue, yellow fever, chikungunya, and Zika viruses, remains of great medical and public health concern. There is little doubt that the ancestral home of the species is Africa. This mosquito invaded the New World 400-500 years ago and later, Asia. However, little is known about the genetic structure and history of Ae. aegypti across Africa, as well as the possible origin(s) of the New World invasion. Here, we use ~17,000 genome-wide single nucleotide polymorphisms (SNPs) to characterize a heretofore undocumented complex picture of this mosquito across its ancestral range in Africa. We find signatures of human-assisted migrations, connectivity across long distances in sylvan populations, and of local admixture between domestic and sylvan populations. Finally, through a phylogenetic analysis combined with the genetic structure analyses, we suggest West Africa and especially Angola as the source of the New World's invasion, a scenario that fits well with the historic record of 16th-century slave trade between Africa and Americas. PMID- 30250669 TI - Lake regionalization and diatom metacommunity structuring in tropical South America. AB - Lakes and their topological distribution across Earth's surface impose ecological and evolutionary constraints on aquatic metacommunities. In this study, we group similar lake ecosystems as metacommunity units influencing diatom community structure. We assembled a database of 195 lakes from the tropical Andes and adjacent lowlands (8 degrees N-30 degrees S and 58-79 degrees W) with associated environmental predictors to examine diatom metacommunity patterns at two different levels: taxon and functional (deconstructed species matrix by ecological guilds). We also derived spatial variables that inherently assessed the relative role of dispersal. Using complementary multivariate statistical techniques (principal component analysis, cluster analysis, nonmetric multidimensional scaling, Procrustes, variance partitioning), we examined diatom environment relationships among different lake habitats (sediment surface, periphyton, and plankton) and partitioned community variation to evaluate the influence of niche- and dispersal-based assembly processes in diatom metacommunity structure across lake clusters. The results showed a significant association between geographic clusters of lakes based on gradients of climate and landscape configuration and diatom assemblages. Six lake clusters distributed along a latitudinal gradient were identified as functional metacommunity units for diatom communities. Variance partitioning revealed that dispersal mechanisms were a major contributor to diatom metacommunity structure, but in a highly context-dependent fashion across lake clusters. In the Andean Altiplano and adjacent lowlands of Bolivia, diatom metacommunities are niche assembled but constrained by either dispersal limitation or mass effects, resulting from area, environmental heterogeneity, and ecological guild relationships. Topographic heterogeneity played an important role in structuring planktic diatom metacommunities. We emphasize the value of a guild-based metacommunity model linked to dispersal for elucidating mechanisms underlying latitudinal gradients in distribution. Our findings reveal the importance of shifts in ecological drivers across climatic and physiographically distinct lake clusters, providing a basis for comparison of broad-scale community gradients in lake-rich regions elsewhere. This may help guide future research to explore evolutionary constraints on the rich Neotropical benthic diatom species pool. PMID- 30250670 TI - Host specificity of parasitoids (Encyrtidae) toward armored scale insects (Diaspididae): Untangling the effect of cryptic species on quantitative food webs. AB - Host specificity of parasitoids may be measured by various specialization indices to assess the variation of interaction strength among species and the structure of the wider interaction network. However, the conclusions from analyses at the species and network levels may differ, which remains poorly explored. In addition, the recovery of cryptic species of hosts and parasitoids with molecular data may affect the structure of inferred interaction links. We quantified host specificity of hymenopteran parasitoids (family Encyrtidae) on armored scale insects (Hemiptera: Diaspididae) from a wide geographic sampling range across the Chinese Mainland based on both morphological and molecular species delimitation. Mitochondrial COI and nuclear 28S markers detected high cryptic species diversity in the encyrtids and to a lesser degree in the diaspidids, which divided generalist morphospecies into complexes of specialists and generalists. One-to one reciprocal host-parasite links were increased in the molecular data set, but different quantitative species-level indices produced contrasting estimates of specificity from various one-to-multiple and multiple-to-multiple host-parasite links. Network indices calculated from DNA-based species, compared to morphology based species definitions, showed lower connectance and generality, but greater specialization and compartmentalization of the interaction network. We conclude that a high degree of cryptic species in host-parasitoid systems refines the true network structure and may cause us overestimating the stability of these interaction webs. PMID- 30250671 TI - Expected impacts of climate change threaten the anuran diversity in the Brazilian hotspots. AB - We performed Ecological Niche Models (ENMs) to generate climatically suitable areas for anurans in the Brazilian hotspots, the Atlantic Forest (AF), and Cerrado (CER), considering the baseline and future climate change scenarios, to evaluate the differences in the alpha and beta diversity metrics across time. We surveyed anuran occurrence records and generated ENMs for 350 and 155 species in the AF and CER. The final predictive maps for the baseline, 2050, and 2070 climate scenarios, based on an ensemble approach, were used to estimate the alpha (local species richness) and beta diversity metrics (local contribution to beta diversity index and its decomposition into replacement and nestedness components) in each ~50 * 50 km grid cell of the hotspots. Climate change is not expected to drastically change the distribution of the anuran richness gradients, but to negatively impact their whole extensions (i.e., cause species losses throughout the hotspots), except the northeastern CER that is expected to gain in species richness. Areas having high beta diversity are expected to decrease in northeastern CER, whereas an increase is expected in southeastern/southwestern CER under climate change. High beta diversity areas are expected to remain in the same AF locations as the prediction of the baseline climate, but the predominance of species loss under climate change is expected to increase the nestedness component in the hotspot. These results suggest that the lack of similar climatically suitable areas for most species will be the main challenge that species will face in the future. Finally, the application of the present framework to a wide range of taxa is an important step for the conservation of threatened biomes. PMID- 30250672 TI - Assessing the role of ontogenetic movement in maintaining population structure in fish using otolith microchemistry. AB - Identifying the mechanisms maintaining population structure in marine fish species with more than a single dispersing life stage is challenging because of the difficulty in tracking all life stages. Here, a two-stage otolith microchemistry approach to examining life-stage movement was adopted, tracking a year-class from the juvenile to adult stage and inferring larval sources from clustering, in order to consider the mechanisms maintaining population structuring in North Sea cod. Clustering of near-core chemistry identified four clusters, two of which had either a southern or northern affinity and were similar to juvenile edge chemistry. The other two clusters, common to the central North Sea, had intermediate chemical composition and may have reflected either larval mixing in this region or a lack of geographic heterogeneity in the elemental signature. From the comparison of whole juvenile and the corresponding component of adult otoliths, adults from the southern North Sea mostly recruited from adjacent nursery grounds. In contrast, many adults in the northern North Sea had a juvenile chemistry consistent with the Skagerrak and juveniles from the northern Skagerrak site had a near-core chemistry consistent with the northern North Sea. Similarities in otolith chemistry were consistent with retention of early life stages at a regional level and also juvenile and adult fidelity. The links between the northern North Sea and Skagerrak indicate natal homing, which when considered in the context of genetic evidence is suggestive of philopatry. The approach used here should be useful in exploring the mechanisms underlying population structuring in other species with multiple dispersive life stages and calcified hard parts. PMID- 30250673 TI - Local trampling disturbance effects on alpine plant populations and communities: Negative implications for climate change vulnerability. AB - Global change is modifying species communities from local to landscape scales, with alterations in the abiotic and biotic determinants of geographic range limits causing species range shifts along both latitudinal and elevational gradients. An important but often overlooked component of global change is the effect of anthropogenic disturbance, and how it interacts with the effects of climate to affect both species and communities, as well as interspecies interactions, such as facilitation and competition. We examined the effects of frequent human trampling disturbances on alpine plant communities in Switzerland, focusing on the elevational range of the widely distributed cushion plant Silene acaulis and the interactions of this facilitator species with other plants. Examining size distributions and densities, we found that disturbance appears to favor individual Silene growth at middle elevations. However, it has negative effects at the population level, as evidenced by a reduction in population density and reproductive indices. Disturbance synergistically interacts with the effects of elevation to reduce species richness at low and high elevations, an effect not mitigated by Silene. In fact, we find predominantly competitive interactions, both by Silene on its hosted and neighboring species and by neighboring (but not hosted) species on Silene. Our results indicate that disturbance can be beneficial for Silene individual performance, potentially through changes in its neighboring species community. However, possible reduced recruitment in disturbed areas could eventually lead to population declines. While other studies have shown that light to moderate disturbances can maintain high species diversity, our results emphasize that heavier disturbance reduces species richness, diversity, as well as percent cover, and adversely affects cushion plants and that these effects are not substantially reduced by plant plant interactions. Heavily disturbed alpine systems could therefore be at greater risk for upward encroachment of lower elevation species in a warming world. PMID- 30250674 TI - Stage duration distributions in matrix population models. AB - Matrix population models are a standard tool for studying stage-structured populations, but they are not flexible in describing stage duration distributions. This study describes a method for modeling various such distributions in matrix models. The method uses a mixture of two negative binomial distributions (parametrized using a maximum likelihood method) to approximate a target (true) distribution. To examine the performance of the method, populations consisting of two life stages (juvenile and adult) were considered. The juvenile duration distribution followed a gamma distribution, lognormal distribution, or zero-truncated (over-dispersed) Poisson distribution, each of which represents a target distribution to be approximated by a mixture distribution. The true population growth rate based on a target distribution was obtained using an individual-based model, and the extent to which matrix models can approximate the target dynamics was examined. The results show that the method generally works well for the examined target distributions, but is prone to biased predictions under some conditions. In addition, the method works uniformly better than an existing method whose performance was also examined for comparison. Other details regarding parameter estimation and model development are also discussed. PMID- 30250676 TI - Variation in context-dependent foraging behavior across pollinators. AB - Pollinator foraging behavior has direct consequences for plant reproduction and has been implicated in driving floral trait evolution. Exploring the degree to which pollinators exhibit flexibility in foraging behavior will add to a mechanistic understanding of how pollinators can impose selection on plant traits. Although plants have evolved suites of floral traits to attract pollinators, flower color is a particularly important aspect of the floral display. Some pollinators show strong innate color preference, but many pollinators display flexibility in preference due to learning associations between rewards and color, or due to variable perception of color in different environments or plant communities. This study examines the flexibility in flower color preference of two groups of native butterfly pollinators under natural field conditions. We find that pipevine swallowtails (Battus philenor) and skippers (family Hesperiidae), the predominate pollinators of the two native Texas Phlox species, Phlox cuspidata and Phlox drummondii, display distinct patterns of color preferences across different contexts. Pipevine swallowtails exhibit highly flexible color preferences and likely utilize other floral traits to make foraging decisions. In contrast, skippers have consistent color preferences and likely use flower color as a primary cue for foraging. As a result of this variation in color preference flexibility, the two pollinator groups impose concordant selection on flower color in some contexts but discordant selection in other contexts. This variability could have profound implications for how flower traits respond to pollinator-mediated selection. Our findings suggest that studying dynamics of behavior in natural field conditions is important for understanding plant-pollinator interactions. PMID- 30250675 TI - CHIIMP: An automated high-throughput microsatellite genotyping platform reveals greater allelic diversity in wild chimpanzees. AB - Short tandem repeats (STRs), also known as microsatellites, are commonly used to noninvasively genotype wild-living endangered species, including African apes. Until recently, capillary electrophoresis has been the method of choice to determine the length of polymorphic STR loci. However, this technique is labor intensive, difficult to compare across platforms, and notoriously imprecise. Here we developed a MiSeq-based approach and tested its performance using previously genotyped fecal samples from long-term studied chimpanzees in Gombe National Park, Tanzania. Using data from eight microsatellite loci as a reference, we designed a bioinformatics platform that converts raw MiSeq reads into locus specific files and automatically calls alleles after filtering stutter sequences and other PCR artifacts. Applying this method to the entire Gombe population, we confirmed previously reported genotypes, but also identified 31 new alleles that had been missed due to sequence differences and size homoplasy. The new genotypes, which increased the allelic diversity and heterozygosity in Gombe by 61% and 8%, respectively, were validated by replicate amplification and pedigree analyses. This demonstrated inheritance and resolved one case of an ambiguous paternity. Using both singleplex and multiplex locus amplification, we also genotyped fecal samples from chimpanzees in the Greater Mahale Ecosystem in Tanzania, demonstrating the utility of the MiSeq-based approach for genotyping nonhabituated populations and performing comparative analyses across field sites. The new automated high-throughput analysis platform (available at https://github.com/ShawHahnLab/chiimp) will allow biologists to more accurately and effectively determine wildlife population size and structure, and thus obtain information critical for conservation efforts. PMID- 30250677 TI - Annual flower strips support pollinators and potentially enhance red clover seed yield. AB - Ecological intensification provides opportunity to increase agricultural productivity while minimizing negative environmental impacts, by supporting ecosystem services such as crop pollination and biological pest control. For this we need to develop targeted management solutions that provide critical resources to service-providing organisms at the right time and place. We tested whether annual strips of early flowering phacelia Phacelia tanacetifolia support pollinators and natural enemies of seed weevils Protapion spp., by attracting and offering nectar and pollen before the crop flowers. This was expected to increase yield of red clover Trifolium pratense seed. We monitored insect pollinators, pests, natural enemies and seed yields in a total of 50 clover fields along a landscape heterogeneity gradient, over 2 years and across two regions in southern Sweden. About half of the fields were sown with flower strips of 125-2,000 m2. The clover fields were pollinated by 60% bumble bees Bombus spp. and 40% honey bees Apis mellifera. The clover seed yield was negatively associated with weevil density, but was unrelated to bee species richness and density. Flower strips enhanced bumble bees species richness in the clover fields, with the strongest influence in heterogeneous landscapes. There were few detectable differences between crop fields with and without flower strips. However, long-tongued bumble bees were redistributed toward field interiors and during phacelia bloom honey bees toward field edges. Clover seed yield also increased with increasing size of the flower strip. We conclude that annual flower strips of early flower resources can support bumble bee species richness and, if sufficiently large, possibly also increase crop yields. However, clover seed yield was mainly limited by weevil infestation, which was not influenced by the annual flower strips. A future goal should be to design targeted measures for pest control. PMID- 30250678 TI - Phylogeography of two closely related species of Allium endemic to East Asia: Population evolution in response to climate oscillations. AB - This study investigated the effects of climate oscillations on the evolution of two closely related Allium species, A. neriniflorum and A. tubiflorum. We sequenced three cp DNA (cpDNA) fragments (rps16, rpl32-trnL, and trnD-trnT, together approximately 2,500 bp in length) of two closely related Allium species, with samples from 367 individuals in 47 populations distributed across the total range of these species. The interspecific and intraspecific divergence times of the two species were in the Quaternary glaciation. The population divergence was high for the cpDNA variation, suggesting a significant phylogeographic structure (NST = 0.844, GST = 0.798, p < 0.05). Remarkable ecological differentiation was also revealed by Niche models and statistical analyses. Our results suggest the speciation event of the two species was triggered by violent climatic changes during the Quaternary glaciation. PMID- 30250679 TI - Genome-wide SNP analysis unveils genetic structure and phylogeographic history of snow sheep (Ovis nivicola) populations inhabiting the Verkhoyansk Mountains and Momsky Ridge (northeastern Siberia). AB - Insights into the genetic characteristics of a species provide important information for wildlife conservation programs. Here, we used the OvineSNP50 BeadChip developed for domestic sheep to examine population structure and evaluate genetic diversity of snow sheep (Ovis nivicola) inhabiting Verkhoyansk Range and Momsky Ridge. A total of 1,121 polymorphic SNPs were used to test 80 specimens representing five populations, including four populations of the Verkhoyansk Mountain chain: Kharaulakh Ridge-Tiksi Bay (TIK, n = 22), Orulgan Ridge (ORU, n = 22), the central part of Verkhoyansk Range (VER, n = 15), Suntar Khayata Ridge (SKH, n = 13), and Momsky Ridge (MOM, n = 8). We showed that the studied populations were genetically structured according to a geographic pattern. Pairwise FST values ranged from 0.044 to 0.205. Admixture analysis identified K = 2 as the most likely number of ancestral populations. A Neighbor Net tree showed that TIK was an isolated group related to the main network through ORU. TreeMix analysis revealed that TIK and MOM originated from two different ancestral populations and detected gene flow from MOM to ORU. This was supported by the f3 statistic, which showed that ORU is an admixed population with TIK and MOM/SKH heritage. Genetic diversity in the studied groups was increasing southward. Minimum values of observed (Ho) and expected (He) heterozygosity and allelic richness (Ar) were observed in the most northern population-TIK, and maximum values were observed in the most southern population SKH. Thus, our results revealed clear genetic structure in the studied populations of snow sheep and showed that TIK has a different origin from MOM, SKH, and VER even though they are conventionally considered a single subspecies known as Yakut snow sheep (Ovis nivicola lydekkeri). Most likely, TIK was an isolated group during the Late Pleistocene glaciations of Verkhoyansk Range. PMID- 30250680 TI - Cattle selectivity by leopards suggests ways to mitigate human-leopard conflict. AB - Addressing widespread livestock losses to carnivores requires information on which livestock categories are preferentially selected. We analyzed an individual based database of cattle grazing in forest (n = 932) and having been killed (n = 70) by leopards (Panthera pardus) in the Hyrcanian forest, Iran. We calculated Jacobs' selectivity index for cattle age, sex, and coloration across four scales: the study area as a whole, three sites, nine villages, and 60 cattle owners. Naturally colored cattle were significantly preferred by leopards at all scales in comparison with black and black-and-white cattle, and there was also a preference for males and juveniles at the study area level. More research is needed to see whether cattle losses would decrease if the share of naturally colored individuals in local holdings was reduced and males and juveniles had limited access to forest. We conclude that phenotypic and biologic characteristics of livestock can affect depredation and appeal for more research in this direction, particularly within the predator-prey framework. PMID- 30250681 TI - Latitudinal variation in biophysical characteristics of avian eggshells to cope with differential effects of solar radiation. AB - Solar radiation is an important driver of animal coloration, not only because of the effects of coloration on body temperature but also because coloration may protect from the deleterious effects of UV radiation. Indeed, dark coloration may protect from UV, but may increase the risk of overheating. In addition, the effect of coloration on thermoregulation should change with egg size, as smaller eggs have higher surface-volume ratios and greater convective coefficients than larger eggs, so that small eggs can dissipate heat quickly. We tested whether the reflectance of eggshells, egg spottiness, and egg size of the ground-nesting Kentish plover Charadrius alexandrinus is affected by maximum ambient temperature and solar radiation at breeding sites. We measured reflectance, both in the UV and human visible spectrum, spottiness, and egg size in photographs from a museum collection of plover eggshells. Eggshells of lower reflectance (darker) were found at higher latitudes. However, in southern localities where solar radiation is very high, eggshells are also of dark coloration. Eggshell coloration had no significant relationship with ambient temperature. Spotiness was site-specific. Small eggs tended to be light-colored. Thermal constraints may drive the observed spatial variation in eggshell coloration, which may be lighter in lower latitudes to diminish the risk of overheating as a result of higher levels of solar radiation. However, in southern localities with very high levels of UV radiation, eggshells are of dark coloration likely to protect embryos from more intense UV radiation. Egg size exhibited variation in relation to coloration, likely through the effect of surface area-to-volume ratios on overheating and cooling rates of eggs. Therefore, differential effects of solar radiation on functions of coloration and size of eggshells may shape latitudinal variations in egg appearance in the Kentish plover. PMID- 30250682 TI - Genetic structuring in a Neotropical palm analyzed through an Andean orogenesis scenario. AB - Andean orogenesis has driven the development of very high plant diversity in the Neotropics through its impact on landscape evolution and climate. The analysis of the intraspecific patterns of genetic structure in plants would permit inferring the effects of Andean uplift on the evolution and diversification of Neotropical flora. In this study, using microsatellite markers and Bayesian clustering analyses, we report the presence of four genetic clusters for the palm Oenocarpus bataua var. bataua which are located within four biogeographic regions in northwestern South America: (a) Choco rain forest, (b) Amotape-Huancabamba Zone, (c) northwestern Amazonian rain forest, and (d) southwestern Amazonian rain forest. We hypothesize that these clusters developed following three genetic diversification events mainly promoted by Andean orogenic events. Additionally, the distinct current climate dynamics among northwestern and southwestern Amazonia may maintain the genetic diversification detected in the western Amazon basin. Genetic exchange was identified between the clusters, including across the Andes region, discarding the possibility of any cluster to diversify as a distinct intraspecific variety. We identified a hot spot of genetic diversity in the northern Peruvian Amazon around the locality of Iquitos. We also detected a decrease in diversity with distance from this area in westward and southward direction within the Amazon basin and the eastern Andean foothills. Additionally, we confirmed the existence and divergence of O. bataua var. bataua from var. oligocarpus in northern South America, possibly expanding the distributional range of the latter variety beyond eastern Venezuela, to the central and eastern Andean cordilleras of Colombia. Based on our results, we suggest that Andean orogenesis is the main driver of genetic structuring and diversification in O. bataua within northwestern South America. PMID- 30250683 TI - Parsing propagule pressure: Number, not size, of introductions drives colonization success in a novel environment. AB - Predicting whether individuals will colonize a novel habitat is of fundamental ecological interest and is crucial to conservation efforts. A consistently supported predictor of colonization success is the number of individuals introduced, also called propagule pressure. Propagule pressure increases with the number of introductions and the number of individuals per introduction (the size of the introduction), but it is unresolved which process is a stronger driver of colonization success. Furthermore, their relative importance may depend upon the environment, with multiple introductions potentially enhancing colonization of fluctuating environments. To evaluate the relative importance of the number and size of introductions and its dependence upon environmental variability, we paired demographic simulations with a microcosm experiment. Using Tribolium flour beetles as a model system, we introduced a fixed number of individuals into replicated novel habitats of stable or fluctuating quality, varying the number of introductions through time and size of each introduction. We evaluated establishment probability and the size of extant populations through seven generations. We found that establishment probability generally increased with more, smaller introductions, but was not affected by biologically realistic fluctuations in environmental quality. Population size was not significantly affected by environmental variability in the simulations, but populations in the microcosms grew larger in a stable environment, especially with more introduction events. In general, the microcosm experiment yielded higher establishment probability and larger populations than the demographic simulations. We suggest that genetic mechanisms likely underlie these differences and thus deserve more attention in efforts to parse propagule pressure. Our results highlight the importance of preventing further introductions of undesirable species to invaded sites and suggest conservation efforts should focus on increasing the number of introductions or reintroductions of desirable species rather than increasing the size of those introduction events into harsh environments. PMID- 30250685 TI - Spawning behavior of Arctic charr (Salvelinus alpinus): Spawning synchrony, vibrational communication, and mate guarding. AB - A mismatch in synchrony between male and female gamete release in external fertilizers can result in reduced or failed fertilization, sperm competition, and reduced paternity. In Arctic charr (Salvelinus alpinus), males can adopt either a guard or sneak tactic resulting in both pre- and postcopulatory competition between males with alternative reproduction tactics. Here, spawning behavior of free-living Arctic charr was video-recorded, and their reproductive behavior was analyzed. From evaluating 157 spawning events, we observed that females mainly spawned with a guarding male and that the female and the guarding male synchronized timing of gamete release under sperm competition. Although sneakers spawned with higher synchrony than the guarding male in single-male spawning events, the average sneaker released his milt less synchronized with the female than the guarding male under sperm competition. Approximately 50% of the recorded spawning events occurred under sperm competition, where each event included an average of 2.7 males. Additionally, sneakers were more exposed to sperm competition than guarding males. An influx of males, in close proximity to the female, occurred during the behavioral sequences leading up to egg release, but this influx seemed not dependent on egg release, suggesting that something else than gonadal product attracts sneaker males to the spawning female. Just before and during the actual release of gametes, the spawning couple vibrates their bodies in close contact and it seems likely that this vibrational communication between the spawning couple, which results in a larger amplitude sound wave than seen under regular courting, reveals time of gamete release to sneaker males. Thus, vibrational communication may enable synchrony between the guarding male and the female, and this might be traded against the cost of higher detectability from surrounding sneaker males, eavesdropping in close proximity. PMID- 30250684 TI - A subset of chemosensory genes differs between two populations of a specialized leaf beetle after host plant shift. AB - Due to its fundamental role in shaping host selection behavior, we have analyzed the chemosensory repertoire of Chrysomela lapponica. This specialized leaf beetle evolved distinct populations which shifted from the ancestral host plant, willow (Salix sp., Salicaceae), to birch (Betula rotundifolia, Betulaceae). We identified 114 chemosensory candidate genes in adult C. lapponica: 41 olfactory receptors (ORs), eight gustatory receptors, 17 ionotropic receptors, four sensory neuron membrane proteins, 32 odorant binding proteins (OBPs), and 12 chemosensory proteins (CSP) by RNA-seq. Differential expression analyses in the antennae revealed significant upregulation of one minus-C OBP (Clap OBP27) and one CSP (Clap CSP12) in the willow feeders. In contrast, one OR (Clap OR17), four minus-C OBPs (Clap OBP02, 07, 13, 20), and one plus-C OBP (Clap OBP32) were significantly upregulated in birch feeders. The differential expression pattern in the legs was more complex. To narrow down putative ligands acting as cues for host discrimination, the relative abundance and diversity of volatiles of the two host plant species were analyzed. In addition to salicylaldehyde (willow-specific), both plant species differed mainly in their emission rate of terpenoids such as (E,E)-alpha-farnesene (high in willow) or 4,8-dimethylnona-1,3,7-triene (high in birch). Qualitatively, the volatiles were similar between willow and birch leaves constituting an "olfactory bridge" for the beetles. Subsequent structural modeling of the three most differentially expressed OBPs and docking studies using 22 host volatiles indicated that ligands bind with varying affinity. We suggest that the evolution of particularly minus-C OBPs and ORs in C. lapponica facilitated its host plant shift via chemosensation of the phytochemicals from birch as novel host plant. PMID- 30250686 TI - Considerations for monitoring population trends of colonial waterbirds using the effective number of breeders and census estimates. AB - Detecting trends in population size fluctuations is a major focus in ecology, evolution, and conservation biology. Populations of colonial waterbirds have been monitored using demographic approaches to determine annual census size (Na). We propose the addition of genetic estimates of the effective number of breeders (Nb) as indirect measures of the risk of loss of genetic diversity to improve the evaluation of demographics and increase the accuracy of trend estimates in breeding colonies. Here, we investigated which methods of the estimation of Nb are more precise under conditions of moderate genetic diversity, limited sample sizes and few microsatellite loci, as often occurs with natural populations. We used the wood stork as a model species and we offered a workflow that researchers can follow for monitoring bird breeding colonies. Our approach started with simulations using five estimators of Nb and the theoretical results were validated with empirical data collected from breeding colonies settled in the Brazilian Pantanal wetland. In parallel, we estimated census size using a corrected method based on counting active nests. Both in simulations and in natural populations, the approximate Bayesian computation (ABC) and sibship assignment (SA) methods yielded more precise estimates than the linkage disequilibrium, heterozygosity excess, and molecular coancestry methods. In particular, the ABC method performed best with few loci and small sample sizes, while the other estimators required larger sample sizes and at least 13 loci to not underestimate Nb. Moreover, according to our Nb/Na estimates (values were often <=0.1), the wood stork colonies evaluated could be facing the loss of genetic diversity. We demonstrate that the combination of genetic and census estimates is a useful approach for monitoring natural breeding bird populations. This methodology has been recommended for populations of rare species or with a known history of population decline to support conservation efforts. PMID- 30250687 TI - Selective constraints in cold-region wild boars may defuse the effects of small effective population size on molecular evolution of mitogenomes. AB - Spatial range expansion during population colonization is characterized by demographic events that may have significant effects on the efficiency of natural selection. Population genetics suggests that genetic drift brought by small effective population size (Ne) may undermine the efficiency of selection, leading to a faster accumulation of nonsynonymous mutations. However, it is still unknown whether this effect might be balanced or even reversed by strong selective constraints. Here, we used wild boars and local domestic pigs from tropical (Vietnam) and subarctic region (Siberia) as animal model to evaluate the effects of functional constraints and genetic drift on shaping molecular evolution. The likelihood-ratio test revealed that Siberian clade evolved significantly different from Vietnamese clades. Different datasets consistently showed that Siberian wild boars had lower Ka/Ks ratios than Vietnamese samples. The potential role of positive selection for branches with higher Ka/Ks was evaluated using branch-site model comparison. No signal of positive selection was found for the higher Ka/Ks in Vietnamese clades, suggesting the interclade difference was mainly due to the reduction in Ka/Ks for Siberian samples. This conclusion was further confirmed by the result from a larger sample size, among which wild boars from northern Asia (subarctic and nearby region) had lower Ka/Ks than those from southern Asia (temperate and tropical region). The lower Ka/Ks might be due to either stronger functional constraints, which prevent nonsynonymous mutations from accumulating in subarctic wild boars, or larger Ne in Siberian wild boars, which can boost the efficacy of purifying selection to remove functional mutations. The latter possibility was further ruled out by the Bayesian skyline plot analysis, which revealed that historical Ne of Siberian wild boars was smaller than that of Vietnamese wild boars. Altogether, these results suggest stronger functional constraints acting on mitogenomes of subarctic wild boars, which may provide new insights into their local adaptation of cold resistance. PMID- 30250688 TI - Sea-level rise, habitat loss, and potential extirpation of a salt marsh specialist bird in urbanized landscapes. AB - Sea-level rise (SLR) impacts on intertidal habitat depend on coastal topology, accretion, and constraints from surrounding development. Such habitat changes might affect species like Belding's savannah sparrows (Passerculus sandwichensis beldingi; BSSP), which live in high-elevation salt marsh in the Southern California Bight. To predict how BSSP habitat might change under various SLR scenarios, we first constructed a suitability model by matching bird observations with elevation. We then mapped current BSSP breeding and foraging habitat at six estuarine sites by applying the elevation-suitability model to digital elevation models. To estimate changes in digital elevation models under different SLR scenarios, we used a site-specific, one-dimensional elevation model (wetland accretion rate model of ecosystem resilience). We then applied our elevation suitability model to the projected digital elevation models. The resulting maps suggest that suitable breeding and foraging habitat could decline as increased inundation converts middle- and high-elevation suitable habitat to mudflat and subtidal zones. As a result, the highest SLR scenario predicted that no suitable breeding or foraging habitat would remain at any site by 2100 and 2110. Removing development constraints to facilitate landward migration of high salt marsh, or redistributing dredge spoils to replace submerged habitat, might create future high salt marsh habitat, thereby reducing extirpation risk for BSSP in southern California. PMID- 30250689 TI - High levels of multiple paternity in a spermcast mating freshwater mussel. AB - Multiple paternity is an important characteristic of the genetic mating system and common across a wide range of taxa. Multiple paternity can increase within population genotypic diversity, allowing selection to act on a wider spectre of genotypes, and potentially increasing effective population size. While the genetic mating system has been studied in many species with active mating behavior, little is known about multiple paternity in sessile species releasing gametes into the water. In freshwater mussels, males release sperm into the water, while eggs are retained and fertilized inside the female (spermcast mating). Mature parasitic glochidia are released into the water and attach to the gills of fish where they are encapsulated until settling in the bottom substrate. We used 15 microsatellite markers to detect multiple paternity in a wild population of the freshwater pearl mussel (Margaritifera margaritifera). We found multiple paternity in all clutches for which more than two offspring were genotyped, and numbers of sires were extremely high. Thirty-two sires had contributed to the largest clutch (43 offspring sampled). This study provides the first evidence of multiple paternity in the freshwater pearl mussel, a species that has experienced dramatic declines across Europe. Previous studies on other species of freshwater mussels have detected much lower numbers of sires. Multiple paternity in freshwater pearl mussels may be central for maintaining genetic variability in small and fragmented populations and for their potential to recover after habitat restoration and may also be important in the evolutionary arms race with their fish host with a much shorter generation time. PMID- 30250690 TI - Fire rather than nitrogen addition affects understory plant communities in the short term in a coniferous-broadleaf mixed forest. AB - Increasing fire risk and atmospheric nitrogen (N) deposition have the potential to alter plant community structure and composition, with consequent impacts on biodiversity and ecosystem functioning. This study was conducted to examine short term responses of understory plant community to burning and N addition in a coniferous-broadleaved mixed forest of the subtropical-temperate transition zone in Central China. The experiment used a pair-nested design, with four treatments (control, burning, N addition, and burning plus N addition) and five replicates. Species richness, cover, and density of woody and herbaceous plants were monitored for 3 years after a low-severity fire in the spring of 2014. Burning, but not N addition, significantly stimulated the cover (+15.2%, absolute change) and density (+62.8%) of woody species as well as herb richness (+1.2 species/m2, absolute change), cover (+25.5%, absolute change), and density (+602.4%) across the seven sampling dates from June 2014 to October 2016. Light availability, soil temperature, and prefire community composition could be primarily responsible for the understory community recovery after the low-severity fire. The observations suggest that light availability and soil temperature are more important than nutrients in structuring understory plant community in the mixed forest of the subtropical-temperate transition zone in Central China. Legacy woody and herb species dominated the understory vegetation over the 3 years after fire, indicating strong resistance and resilience of forest understory plant community and biodiversity to abrupt environmental perturbation. PMID- 30250691 TI - Latitudinal effects on crown shape evolution. AB - Large variations in crown shape are observed across the globe, from plants with wide and deep crowns to those with leaves clustered at the top. While there have been advances in the large-scale monitoring of forests, little is known about factors driving variations in crown shape with environmental conditions. Previous theoretical research suggests a gradient in crown shape with latitude, due to the effects of sun angle. Yet, it remains unclear whether such changes are also predicted under competition. Using a size-structured forest-growth model that incorporates self-shading from plants and competitive shading from their neighbors, we investigate how changes in site productivity and sun angle shape crown evolution. We consider evolution in two traits describing the top-heaviness and width-to-height ratio of crowns, shaped by trade-offs reflecting the costs and benefits of alternative architectures. In top-heavy trees, most of the leaves are at the top half of the trunk. We show that, contrary to common belief, the angle of sun beams per se has only a weak influence on crown shapes, except at low site productivity. By contrast, reduced site productivity has a strong effect, with trees growing in less productive sites keeping their leaves closer to the ground. The crown width-to-height ratio is generally higher at a lower site productivity, but this trait is not strongly influenced by any environmental factor. This theoretical analysis brings into question established beliefs about the effects of latitude on crown shapes. By introducing geometry-related growth constraints caused by shading from both the surrounding forest and the tree on itself, and costs for constructing and maintaining a three-dimensional crown, our analysis suggests crown shapes may vary with latitude, mostly via effects on overall site productivity, and less because of the angle of the sun. PMID- 30250692 TI - Color vision models: Some simulations, a general n-dimensional model, and the colourvision R package. AB - The development of color vision models has allowed the appraisal of color vision independent of the human experience. These models are now widely used in ecology and evolution studies. However, in common scenarios of color measurement, color vision models may generate spurious results. Here I present a guide to color vision modeling (Chittka (1992, Journal of Comparative Physiology A, 170, 545) color hexagon, Endler & Mielke (2005, Journal Of The Linnean Society, 86, 405) model, and the linear and log-linear receptor noise limited models (Vorobyev & Osorio 1998, Proceedings of the Royal Society B, 265, 351; Vorobyev et al. 1998, Journal of Comparative Physiology A, 183, 621)) using a series of simulations, present a unified framework that extends and generalize current models, and provide an R package to facilitate the use of color vision models. When the specific requirements of each model are met, between-model results are qualitatively and quantitatively similar. However, under many common scenarios of color measurements, models may generate spurious values. For instance, models that log-transform data and use relative photoreceptor outputs are prone to generate spurious outputs when the stimulus photon catch is smaller than the background photon catch; and models may generate unrealistic predictions when the background is chromatic (e.g. leaf reflectance) and the stimulus is an achromatic low reflectance spectrum. Nonetheless, despite differences, all three models are founded on a similar set of assumptions. Based on that, I provide a new formulation that accommodates and extends models to any number of photoreceptor types, offers flexibility to build user-defined models, and allows users to easily adjust chromaticity diagram sizes to account for changes when using different number of photoreceptors. PMID- 30250693 TI - Regional and local patterns of genetic variation and structure in yellow-necked mice - the roles of geographic distance, population abundance, and winter severity. AB - The goal of this study, conducted in seven large woodlands and three areas with small woodlots in northeastern Poland in 2004-2008, was to infer genetic structure in yellow-necked mouse Apodemus flavicollis population and to evaluate the roles of environmental and population ecology variables in shaping the spatial pattern of genetic variation using 768 samples genotyped at 13 microsatellite loci. Genetic variation was very high in all studied regions. The primal genetic subdivision was observed between the northern and the southern parts of the study area, which harbored two major clusters and the intermediate area of highly admixed individuals. The probability of assignment of individual mice to the northern cluster increased significantly with lower temperatures of January and July and declined in regions with higher proportion of deciduous and mixed forests. Despite the detected structure, genetic differentiation among regions was very low. Fine-scale structure was shaped by the population density, whereas higher level structure was mainly shaped by geographic distance. Genetic similarity indices were highly influenced by mouse abundance (which positively correlated with the share of deciduous forests in the studied regions) and exhibited the greatest change between 0 and 1 km in the forests, 0 and 5 km in small woodlots. Isolation by distance pattern, calculated among regions, was highly significant but such relationship between genetic and geographic distance was much weaker, and held the linearity at very fine scale (~1.5 km), when analyses were conducted at individual level. PMID- 30250694 TI - Grazing effect on grasslands escalated by abnormal precipitations in Inner Mongolia. AB - Grazing effects on arid and semi-arid grasslands can be constrained by aridity. Plant functional groups (PFGs) are the most basic component of community structure (CS) and biodiversity & ecosystem function (BEF). They have been suggested as identity-dependent in quantifying the response to grazing intensity and drought severity. Here, we examine how the relationships among PFGs, CS, BEF, and grazing intensity are driven by climatic drought. We conducted a manipulative experiment with three grazing intensities in 2012 (nondrought year) and 2013 (drought year). We classified 62 herbaceous plants into four functional groups based on their life forms. We used the relative species abundance of PFGs to quantify the effects of grazing and drought, and to explore the mechanisms for the pathway correlations using structural equation models (SEM) among PFGs, CS, and BEF directly or indirectly. Grazers consistently favored the perennial forbs (e.g., palatable or nutritious plants), decreasing the plants' relative abundance by 23%-38%. Drought decreased the relative abundance of ephemeral plants by 42 +/ 13%; and increased perennial forbs by 20 +/- 7% and graminoids by 80 +/- 31%. SEM confirmed that annuals and biennials had negative correlations with the other three PFGs, with perennial bunchgrasses facilitated by perennial rhizome grass. Moreover, the contributions of grazing to community structure (i.e., canopy height) were 1.6-6.1 times those from drought, whereas drought effect on community species richness was 3.6 times of the grazing treatment. Lastly, the interactive effects of grazing and drought on BEF were greater than either alone; particularly, drought escalated grazing damage on primary production. Synthesis. The responses of PFGs, CS, and BEF to grazing and drought were identity dependent, suggesting that grazing and drought regulation of plant functional groups might be a way to shape ecosystem structure and function in grasslands. PMID- 30250695 TI - Sibling rivalry: Males with more brothers develop larger testes. AB - When females mate with multiple partners in a reproductive cycle, the relative number of competing sperm from rival males is often the most critical factor in determining paternity. Gamete production is directly related to testis size in most species, and is associated with both mating behavior and perceived risk of competition. Deer mice, Peromyscus maniculatus, are naturally promiscuous and males invest significantly more in sperm production than males of P. polionotus, their monogamous sister-species. Here, we show that the larger testes in P. maniculatus are retained after decades of enforced monogamy in captivity. While these results suggest that differences in sperm production between species with divergent evolutionary histories can be maintained in captivity, we also show that the early rearing environment of males can strongly influence their testis size as adults. Using a second-generation hybrid population to increase variation within the population, we show that males reared in litters with more brothers develop larger testes as adults. Importantly, this difference in testis size is also associated with increased fertility. Together, our findings suggest that sperm production may be both broadly shaped by natural selection over evolutionary timescales and also finely tuned during early development. PMID- 30250696 TI - The effect of habitat fragmentation on the bee visitor assemblages of three Australian tropical rainforest tree species. AB - Tropical forest loss and fragmentation can change bee community dynamics and potentially interrupt plant-pollinator relationships. While bee community responses to forest fragmentation have been investigated in a number of tropical regions, no studies have focused on this topic in Australia. In this study, we examine taxonomic and functional diversity of bees visiting flowers of three tree species across small and large rainforest fragments in Australian tropical landscapes. We found lower taxonomic diversity of bees visiting flowers of trees in small rainforest fragments compared with large forest fragments and show that bee species in small fragments were subsets of species in larger fragments. Bees visiting trees in small fragments also had higher mean body sizes than those in larger fragments, suggesting that small-sized bees may be less likely to persist in small fragments. Lastly, we found reductions in the abundance of eusocial stingless bees visiting flowers in small fragments compared to large fragments. These results suggest that pollinator visits to native trees living in small tropical forest remnants may be reduced, which may in turn impact on a range of processes, potentially including forest regeneration and diversity maintenance in small forest remnants in Australian tropical countryside landscapes. PMID- 30250697 TI - Linking microbial co-occurrences to soil ecological processes across a woodland grassland ecotone. AB - Ecotones between distinct ecosystems have been the focus of many studies as they offer valuable insights into key drivers of community structure and ecological processes that underpin function. While previous studies have examined a wide range of above-ground parameters in ecotones, soil microbial communities have received little attention. Here we investigated spatial patterns, composition, and co-occurrences of archaea, bacteria, and fungi, and their relationships with soil ecological processes across a woodland-grassland ecotone. Geostatistical kriging and network analysis revealed that the community structure and spatial patterns of soil microbiota varied considerably between three habitat components across the ecotone. Woodland samples had significantly higher diversity of archaea while the grassland samples had significantly higher diversity of bacteria. Microbial co-occurrences reflected differences in soil properties and ecological processes. While microbial networks were dominated by bacterial nodes, different ecological processes were linked to specific microbial guilds. For example, soil phosphorus and phosphatase activity formed the largest clusters in their respective networks, and two lignolytic enzymes formed joined clusters. Bacterial ammonia oxidizers were dominant over archaeal oxidizers and showed a significant association (p < 0.001) with potential nitrification (PNR), with the PNR subnetwork being dominated by Betaproteobacteria. The top ten keystone taxa comprised six bacterial and four fungal OTUs, with Random Forest Analysis revealing soil carbon and nitrogen as the determinants of the abundance of keystone taxa. Our results highlight the importance of assessing interkingdom associations in soil microbial networks. Overall, this study shows how ecotones can be used as a model to delineate microbial structural patterns and ecological processes across adjoining land-uses within a landscape. PMID- 30250698 TI - Multiple stages of tree seedling recruitment are altered in tropical forests degraded by selective logging. AB - Tropical forest degradation is a global environmental issue. In degraded forests, seedling recruitment of canopy trees is vital for forest regeneration and recovery. We investigated how selective logging, a pervasive driver of tropical forest degradation, impacts canopy tree seedling recruitment, focusing on an endemic dipterocarp Dryobalanops lanceolata in Sabah, Borneo. During a mast fruiting event in intensively logged and nearby unlogged forest, we examined four stages of the seedling recruitment process: seed production, seed predation, and negative density-dependent germination and seedling survival. Our results suggest that each stage of the seedling recruitment process is altered in logged forest. The seed crop of D. lanceolata trees in logged forest was one-third smaller than that produced by trees in unlogged forest. The functional role of vertebrates in seed predation increased in logged forest while that of non-vertebrates declined. Seeds in logged forest were less likely to germinate than those in unlogged forest. Germination increased with local-scale conspecific seed density in unlogged forest, but seedling survival tended to decline. However, both germination and seedling survival increased with local-scale conspecific seed density in logged forest. Notably, seed crop size, germination, and seedling survival tended to increase for larger trees in both unlogged and logged forests, suggesting that sustainable timber extraction and silvicultural practices designed to minimize damage to the residual stand are important to prevent seedling recruitment failure. Overall, these impacts sustained by several aspects of seedling recruitment in a mast-fruiting year suggest that intensive selective logging may affect long-term population dynamics of D. lanceolata. It is necessary to establish if other dipterocarp species, many of which are threatened by the timber trade, are similarly affected in tropical forests degraded by intensive selective logging. PMID- 30250699 TI - RAD sequencing resolved phylogenetic relationships in European shrub willows (Salix L. subg. Chamaetia and subg. Vetrix) and revealed multiple evolution of dwarf shrubs. AB - The large and diverse genus Salix L. is of particular interest for decades of biological research. However, despite the morphological plasticity, the reconstruction of phylogenetic relationships was so far hampered by the lack of informative molecular markers. Infrageneric classification based on morphology separates dwarf shrubs (subg. Chamaetia) and taller shrubs (subg. Vetrix), while previous phylogenetic studies placed species of these two subgenera just in one largely unresolved clade. Here we want to test the utility of genomic RAD sequencing markers for resolving relationships at different levels of divergence in Salix. Based on a sampling of 15 European species representing 13 sections of the two subgenera, we used five different RAD sequencing datasets generated by ipyrad to conduct phylogenetic analyses. Additionally we reconstructed the evolution of growth form and analyzed the genetic composition of the whole clade. The results showed fully resolved trees in both ML and BI analysis with high statistical support. The two subgenera Chamaetia and Vetrix were recognized as nonmonophyletic, which suggests that they should be merged. Within the Vetrix/Chamaetia clade, a division into three major subclades could be observed. All species were confirmed to be monophyletic. Based on our data, arctic-alpine dwarf shrubs evolved four times independently. The structure analysis showed five mainly uniform genetic clusters which are congruent in sister relationships observed in the phylogenies. Our study confirmed RAD sequencing as a useful genomic tool for the reconstruction of relationships on different taxonomic levels in the genus Salix. PMID- 30250700 TI - Top-down control by an aquatic invertebrate predator increases with temperature but does not depend on individual behavioral type. AB - Variation in behavioral traits among individuals within a population can have implications for food webs and ecosystems. Temperature change also alters food web structure and function, but potential interactions between warming and intraspecific behavioral variation are largely unexplored. We aimed to test how increased temperature, individual activity level of a predatory backswimmer (Anisops assimilis), and their interaction influenced the strength of top-down control of zooplankton and phytoplankton. We used stable isotopes to support our assumption that the study population of A. assimilis is zooplanktivorous, and behavioral trials to confirm that activity level is a repeatable trait. We established freshwater microcosms to test for effects of warming, backswimmer presence, and backswimmer behavioral type on zooplankton density, zooplankton composition, and phytoplankton chlorophyll a. Top-down control was present and was generally stronger at increased temperature. There was no indication that predator behavioral type influenced the strength of top-down control either on its own or interactively with temperature. Predator behavioral type may not be associated with ecologically important function in this species at the temporal and spatial scales addressed in this study, but the links between behavior, temperature, and food web processes are worthy of broader exploration. PMID- 30250701 TI - Sexual and temporal variations in floral scent in the subdioecious shrub Eurya japonica Thunb. AB - In many flowering plants, floral scents are a significant trait for visitors, playing an important role in attracting pollinators and/or detracting herbivores. The evolution of flowering plants from hermaphroditism to dioecy is often accompanied by sexual dimorphism in floral scent. In this study, floral scents emitted by different sexual morphs of the subdioecious shrub Eurya japonica Thunb. were collected using a dynamic headspace method, and sexual and temporal variations were evaluated by gas chromatography-mass spectrometry (GC-MS). Two volatiles, alpha-pinene and linalool, were identified as the major components of floral scents in females, hermaphrodites, and males. The males emit higher amounts of floral scents, particularly alpha-pinene, compared to females or hermaphrodites. Floral scents emitted by males generally decrease as flowers enter senescence, whereas those from females or hermaphrodites do not significantly differ. Intraspecific variations in floral scents of subdioecious species provided by this study would contribute to better understanding of sexual dimorphism in floral scent. PMID- 30250702 TI - Gastropods alien to South Africa cause severe environmental harm in their global alien ranges across habitats. AB - Alien gastropods have caused extensive harm to biodiversity and socioeconomic systems like agriculture and horticulture worldwide. For conservation and management purposes, information on impacts needs to be easily interpretable and comparable, and the factors that determine impacts understood. This study aimed to assess gastropods alien to South Africa to compare impact severity between species and understand how they vary between habitats and mechanisms. Furthermore, we explore the relationship between environmental and socioeconomic impacts, and both impact measures with life-history traits. We used the Environmental Impact Classification for Alien Taxa (EICAT) and Socio-Economic Impact Classification for Alien Taxa (SEICAT) to assess impacts of 34 gastropods alien to South Africa including evidence of impact from their entire alien range. We tested for correlations between environmental and socioeconomic impacts per species, and with fecundity and native latitude range using Kendall's tau tests. Kruskal-Wallis tests were used to compare impact magnitude among mechanisms and habitats, respectively. This study presents the first application of EICAT and SEICAT for invertebrates. There was no correlation between environmental impacts and socioeconomic impacts. Habitats did not differ regarding the severity of impacts recorded, but impacts via disease transmission were lower than other mechanisms. Neither fecundity nor native range latitude was correlated with impact magnitude. Despite gastropods being agricultural and horticultural pests globally, resilience of socioeconomic systems makes high impacts uncommon. Environmental systems may be vulnerable to gastropod impacts across habitats, having experienced multiple local extinctions of wetland island snail fauna. South Africa stands out as the only continental country that follows this trend. The knowledge gained on severity and nature of gastropod impacts is useful in risk assessment, which can aid conservation management. To make impact assessments more realistic, we suggest alternative ways of reporting impacts classified under EICAT and SEICAT. PMID- 30250703 TI - Time-lapse cameras reveal latitude and season influence breeding phenology durations in penguins. AB - Variation in the phenology of avian taxa has long been studied to understand how a species reacts to environmental changes over both space and time. Penguins (Sphenicidae) serve as an important example of how biotic and abiotic factors influence certain stages of seabird phenology because of their large ranges and the extreme, dynamic conditions present in their Southern Ocean habitats. Here, we examined the phenology of gentoo (Pygoscelis papua) and chinstrap penguins (Pygoscelis antarctica) at 17 sites across the Scotia arc, including the first documented monitoring of phenology on the South Sandwich Islands, to determine which breeding phases are intrinsic, or rather vary across a species range and between years. We used a novel method to measure seabird breeding phenology and egg and chick survival: time-lapse cameras. Contrary to the long-standing theory that these phases are consistent between colonies, we found that latitude and season had a predominant influence on the length of the nest establishment, incubation, and guard durations. We observe a trend toward longer incubation times occurring farther south, where ambient temperatures are colder, which may indicate that exposure to cold slows embryo growth. Across species, in colonies located farther south, parents abandoned nests later when eggs were lost or chicks died and the latest record of eggs or chicks in the nest occurred earlier during the breeding period. The variation in both space and time observed in penguin phenology provides evidence that the duration of phases within the annual cycle of birds is not fundamental, or genetic, as previously understood. Additionally, the recorded phenology dates should inform field researchers on the best timing to count colonies at the peak of breeding, which is poorly understood. PMID- 30250704 TI - Predicting the potential geographical distribution of parasitic natural enemies of the Dubas bug (Ommatissus lybicus de Bergevin) using geographic information systems. AB - The Dubas bug (Ommatissus lybicus de Bergevin) is a pest species whose entire life cycle occurs on date palms, Phoenix dactylifera L, causing serious damage and reducing date palm growth and yield. Pseudoligosita babylonica Viggiani, Aprostocetus nr. Beatus, and Bocchus hyalinus Olmi are very important parasitic natural enemies of Ommatissus lybicus in northern Oman. In this study, random farms were selected to (a) model the link between occurrences of the Pseudoligosita babylonica, Aprostocetus nr beatus, and Bocchus hyalinus (dependent variables) with environmental, climatological, and Dubas bug infestation levels (the independent variables), and (b) produce distribution and predictive maps of these natural enemies in northern Oman. The multiple R2 values showed the model explained 63%, 89%, and 94% of the presence of P. babylonica, A. nr beatus, and Bocchus hyalinus, respectively. However, the distribution of each species appears to be influenced by distinct and geographically associated climatological and environmental factors, as well as habitat characteristics. This study reveals that spatial analysis and modeling can be highly useful for studying the distribution, the presence or absence of Dubas bugs, and their natural enemies. It is anticipated to help contribute to the reduction in the extent and costs of aerial and ground insecticidal spraying needed in date palm plantations. PMID- 30250705 TI - Genomic divergence between Spanish Littorina saxatilis ecotypes unravels limited admixture and extensive parallelism associated with population history. AB - The rough periwinkle, Littorina saxatilis, is a model system for studying parallel ecological speciation in microparapatry. Phenotypically parallel wave adapted and crab-adapted ecotypes that hybridize within the middle shore are replicated along the northwestern coast of Spain and have likely arisen from two separate glacial refugia. We tested whether greater geographic separation corresponding to reduced opportunity for contemporary or historical gene flow between parallel ecotypes resulted in less parallel genomic divergence. We sequenced double-digested restriction-associated DNA (ddRAD) libraries from individual snails from upper, mid, and low intertidal levels of three separate sites colonized from two separate refugia. Outlier analysis of 4256 SNP markers identified 34.4% sharing of divergent loci between two geographically close sites; however, these sites each shared only 9.9%-15.1% of their divergent loci with a third more-distant site. STRUCTURE analysis revealed that genotypes from only three of 166 phenotypically intermediate mid-shore individuals appeared to result from recent hybridization, suggesting that hybrids cannot be reliably identified using shell traits. Hierarchical AMOVA indicated that the primary source of genomic differentiation was geographic separation, but also revealed greater similarity of the same ecotype across the two geographically close sites than previously estimated with dominant markers. These results from a model system for ecological speciation suggest that genomic parallelism is affected by the opportunity for historical or contemporary gene flow between populations. PMID- 30250706 TI - Landscape genetics identifies streams and drainage infrastructure as dispersal corridors for an endangered wetland bird. AB - Anthropogenic alterations to landscape structure and composition can have significant impacts on biodiversity, potentially leading to species extinctions. Population-level impacts of landscape change are mediated by animal behaviors, in particular dispersal behavior. Little is known about the dispersal habits of rails (Rallidae) due to their cryptic behavior and tendency to occupy densely vegetated habitats. The effects of landscape structure on the movement behavior of waterbirds in general are poorly studied due to their reputation for having high dispersal abilities. We used a landscape genetic approach to test hypotheses of landscape effects on dispersal behavior of the Hawaiian gallinule (Gallinula galeata sandvicensis), an endangered subspecies endemic to the Hawaiian Islands. We created a suite of alternative resistance surfaces representing biologically plausible a priori hypotheses of how gallinules might navigate the landscape matrix and ranked these surfaces by their ability to explain observed patterns in genetic distance among 12 populations on the island of O'ahu. We modeled effective distance among wetland locations on all surfaces using both cumulative least-cost-path and resistance-distance approaches and evaluated relative model performance using Mantel tests, a causal modeling approach, and the mixed-model maximum-likelihood population-effects framework. Across all genetic markers, simulation methods, and model comparison metrics, surfaces that treated linear water features like streams, ditches, and canals as corridors for gallinule movement outperformed all other models. This is the first landscape genetic study on the movement behavior of any waterbird species to our knowledge. Our results indicate that lotic water features, including drainage infrastructure previously thought to be of minimal habitat value, contribute to habitat connectivity in this listed subspecies. PMID- 30250707 TI - The evolution of chemical defenses along invasion routes: Harmonia axyridis Pallas (Coccinellidae: Coleoptera) as a case study. AB - The evolution of increased competitive ability (EICA) hypothesis (Blossey & Notzold, 1995) postulates that escaping from coevolved enemies increases invaders fitness by energy reallocation from defenses and immunity to growth and reproduction. In this context, we evaluated the evidence of evolutionary change in invasive populations of Harmonia axyridis Pallas (Coccinellidae: Coleoptera). We measured egg defenses-cocktail of hydrocarbons on the egg's surface flagging egg toxicity and the concentration of the main alkaloid harmonine-in individuals from three populations along the invasion route (Japan: native, United States: introduced more than 30 years ago, South Africa: introduced in the early 2000s) in a common garden experiment. Our results support the EICA hypothesis: We found changes along the invasion route in the profiles of the hydrocarbons coating the eggs' surface and a decrease in the concentration of harmonine in eggs from the most recent invasive South African population compared to the long established in the United States and the native Japanese ones. PMID- 30250708 TI - River ecosystem resilience to extreme flood events. AB - Floods have a major influence in structuring river ecosystems. Considering projected increases in high-magnitude rainfall events with climate change, major flooding events are expected to increase in many regions of the world. However, there is uncertainty about the effect of different flooding regimes and the importance of flood timing in structuring riverine habitats and their associated biotic communities. In addition, our understanding of community response is hindered by a lack of long-term datasets to evaluate river ecosystem resilience to flooding. Here we show that in a river ecosystem studied for 30 years, a major winter flood reset the invertebrate community to a community similar to one that existed 15 years earlier. The community had not recovered to the preflood state when recurrent summer flooding 9 years later reset the ecosystem back to an even earlier community. Total macroinvertebrate density was reduced in the winter flood by an order of magnitude more than the summer flood. Meiofaunal invertebrates were more resilient to the flooding than macroinvertebrates, possibly due to their smaller body size facilitating greater access to in-stream refugia. Pacific pink salmon escapement was markedly affected by the winter flood when eggs were developing in redds, compared to summer flooding, which occurred before the majority of eggs were laid. Our findings inform a proposed conceptual model of three possible responses to flooding by the invertebrate community in terms of switching to different states and effects on resilience to future flooding events. In a changing climate, understanding these responses is important for river managers to mitigate the biological impacts of extreme flooding effects. PMID- 30250709 TI - Northern range shift may be due to increased competition induced by protection of species rather than to climate change alone. AB - Few long-term, large-scale studies have been conducted about the factors likely to explain changes in species abundance and distribution in winter. Range shifts are generally attributed to the climate change or land use. This study shows that other factors such as species protection and the ensuing increasing numbers of individuals and competition could be involved. It details the progressive conquest of France, the most important European wintering area for great cormorant, in three decades as its legal protection by the EU Birds Directive. It is based on 13 exhaustive national counts. Cormorants first occupied the farthest areas (Atlantic and Mediterranean lagoons, then larger rivers) from the main-core European breeding area, with only progressive occupancy of the northeastern part later. This strategy mainly resulted from competition for optimal available feeding areas. Suboptimal areas (smaller wetlands harboring smaller night roosts, colder northeastern French areas) and progressive fragmentation of large night roosts into smaller, better located ones minimized flight costs. The coldest areas were occupied last, once other areas were saturated. Their occupancy was favored locally by the global climate change, but it played a minor role in these strategies. Both factors induced only a small NNE shift of the weighted centroid range of the wintering population (2.6 km/year) which mainly resulted from competition (buffer effect). Only the 2009 cold wave decreased the total number of wintering cormorants at the national scale, once the population had probably reached the carrying capacity of the country, while the previous cold waves had a minor effect. Comparatively, there was a greater SSE range shift of the weighted centroid of the breeding population (4.66 km/year). Range shifts of other recently protected species have been attributed to the sole climate change in the literature, but competition due to the saturation of usual wintering or breeding areas should be considered too. PMID- 30250710 TI - Compound-specific isotope analysis of benthic foraminifer amino acids suggests microhabitat variability in rocky-shore environments. AB - The abundance and biomass of benthic foraminifera are high in intertidal rocky shore habitats. However, the availability of food to support their high biomass has been poorly studied in these habitats compared to those at seafloor covered by sediments. Previous field and laboratory observations have suggested that there is diversity in the food preferences and modes of life among rocky-shore benthic foraminifera. In this study, we used the stable nitrogen isotopic composition of amino acids to estimate the trophic position, trophic niche, and feeding strategy of individual foraminifera species. We also characterized the configuration and structure of the endobiotic microalgae in foraminifera using transmission electron microscopy, and we identified the origin of endobionts based on nucleotide sequences. Our results demonstrated a large variation in the trophic positions of different foraminifera from the same habitat, a reflection of endobiotic features and the different modes of life and food preferences of the foraminifera. Foraminifera did not rely solely on exogenous food sources. Some species effectively used organic matter derived from endobionts in the cell cytoplasm. The high biomass and species density of benthic foraminifera found in intertidal rocky-shore habitats are thus probably maintained by the use of multiple nitrogen resources and by microhabitat segregation among species as a consequence. PMID- 30250711 TI - Laboulbeniales hyperparasites (Fungi, Ascomycota) of bat flies: Independent origins and host associations. AB - The aim of this study was to explore the diversity of ectoparasitic fungi (Ascomycota, Laboulbeniales) that use bat flies (Diptera, Hippoboscoidea) as hosts. Bat flies themselves live as ectoparasites on the fur and wing membranes of bats (Mammalia, Chiroptera); hence this is a tripartite parasite system. Here, we collected bats, bat flies, and Laboulbeniales, and conducted phylogenetic analyses of Laboulbeniales to contrast morphology with ribosomal sequence data. Parasitism of bat flies by Laboulbeniales arose at least three times independently, once in the Eastern Hemisphere (Arthrorhynchus) and twice in the Western Hemisphere (Gloeandromyces, Nycteromyces). We hypothesize that the genera Arthrorhynchus and Nycteromyces evolved independently from lineages of ectoparasites of true bugs (Hemiptera). We assessed phylogenetic diversity of the genus Gloeandromyces by considering the LSU rDNA region. Phenotypic plasticity and position-induced morphological adaptations go hand in hand. Different morphotypes belong to the same phylogenetic species. Two species, G. pageanus and G. streblae, show divergence by host utilization. In our assessment of coevolution, we only observe congruence between the Old World clades of bat flies and Laboulbeniales. The other associations are the result of the roosting ecology of the bat hosts. This study has considerably increased our knowledge about bats and their associated ectoparasites and shown the necessity of including molecular data in Laboulbeniales taxonomy. PMID- 30250712 TI - Food quality and quantity are more important in explaining foraging of an intermediate-sized mammalian herbivore than predation risk or competition. AB - During times of high activity by predators and competitors, herbivores may be forced to forage in patches of low-quality food. However, the relative importance in determining where and what herbivores forage still remains unclear, especially for small- and intermediate-sized herbivores. Our objective was to test the relative importance of predator and competitor activity, and forage quality and quantity on the proportion of time spent in a vegetation type and the proportion of time spent foraging by the intermediate-sized herbivore European hare (Lepus europaeus). We studied red fox (Vulpes vulpes) as a predator species and European rabbit (Oryctolagus cuniculus) as a competitor. We investigated the time spent at a location and foraging time of hare using GPS with accelerometers. Forage quality and quantity were analyzed based on hand-plucked samples of a selection of the locally most important plant species in the diet of hare. Predator activity and competitor activity were investigated using a network of camera traps. Hares spent a higher proportion of time in vegetation types that contained a higher percentage of fibers (i.e., NDF). Besides, hares spent a higher proportion of time in vegetation types that contained relatively low food quantity and quality of forage (i.e., high percentage of fibers) during days that foxes (Vulpes vulpes) were more active. Also during days that rabbits (Oryctolagus cuniculus) were more active, hares spent a higher proportion of time foraging in vegetation types that contained a relatively low quality of forage. Although predation risk affected space use and foraging behavior, and competition affected foraging behavior, our study shows that food quality and quantity more strongly affected space use and foraging behavior than predation risk or competition. It seems that we need to reconsider the relative importance of the landscape of food in a world of fear and competition. PMID- 30250713 TI - Lactation and resource limitation affect stress responses, thyroid hormones, immune function, and antioxidant capacity of sea otters (Enhydra lutris). AB - Lactation is the most energetically demanding stage of reproduction in female mammals. Increased energetic allocation toward current reproduction may result in fitness costs, although the mechanisms underlying these trade-offs are not well understood. Trade-offs during lactation may include reduced energetic allocation to cellular maintenance, immune response, and survival and may be influenced by resource limitation. As the smallest marine mammal, sea otters (Enhydra lutris) have the highest mass-specific metabolic rate necessitating substantial energetic requirements for survival. To provide the increased energy needed for lactation, female sea otters significantly increase foraging effort, especially during late lactation. Caloric insufficiency during lactation is reflected in the high numbers of maternal deaths due to End-Lactation Syndrome in the California subpopulation. We investigated the effects of lactation and resource limitation on maternal stress responses, metabolic regulation, immune function, and antioxidant capacity in two subspecies of wild sea otters (northern: E. l. nereis and southern: E. l. kenyoni) within the California, Washington, and Alaska subpopulations. Lactation and resource limitation were associated with reduced glucocorticoid responses to acute capture stress. Corticosterone release was lower in lactating otters. Cortisol release was lower under resource limitation and suppression during lactation was only evident under resource limitation. Lactation and resource limitation were associated with alterations in thyroid hormones. Immune responses and total antioxidant capacity were not reduced by lactation or resource limitation. Southern sea otters exhibited higher concentrations of antioxidants, immunoglobulins, and thyroid hormones than northern sea otters. These data provide evidence for allocation trade-offs during reproduction and in response to nutrient limitation but suggest self-maintenance of immune function and antioxidant defenses despite energetic constraints. Income breeding strategists may be especially vulnerable to the consequences of stress and modulation of thyroid function when food resources are insufficient to support successful reproduction and may come at a cost to survival, and thereby influence population trends. PMID- 30250715 TI - Sixty years of community change in the prairie-savanna-forest mosaic of Wisconsin. AB - Biodiversity loss is a global concern, and maintaining habitat complexity in naturally patchy landscapes can help retain regional diversity. A mosaic of prairie, savanna, and forest historically occurred across central North America but currently is highly fragmented due to human land conversion. It is unclear how each habitat type now contributes to regional diversity. Using legacy data, we resurveyed savanna plant communities originally surveyed in the 1950s to compare change in savannas to that in remnant forests and prairies. Savanna community structure and composition changed substantially over the past 60 years. Tree canopy density nearly doubled and many prairie and savanna specialist species were replaced by forest and non-native species. All three habitats gained and lost many species since the 1950s, resulting in large changes in community composition from local colonizations and extinctions. Across all three habitats, regional species extinctions matched that of regional colonization resulting in no net change in regional species richness. Synthesis-Despite considerable species turnover within savannas, many species remain within the broader prairie savanna-forest mosaic. Both regional extinctions and colonizations were high over the past 60 years, and maintaining the presence of all three community types prairie, savanna and forest-on the landscape is critical to maintaining regional biodiversity. PMID- 30250714 TI - Individual behavioral variation reflects personality divergence in the upcoming model organism Nothobranchius furzeri. AB - In the animal kingdom, behavioral variation among individuals has often been reported. However, stable among-individual differences along a behavioral continuum-reflective of personality variation-have only recently become a key target of research. While a vast body of descriptive literature exists on animal personality, hypothesis-driven quantitative studies are largely deficient. One of the main constraints to advance the field is the lack of suitable model organisms. Here, we explore whether N. furzeri could be a valuable model to bridge descriptive and hypothesis-driven research to further unravel the causes, function and evolution of animal personality. As a first step toward this end, we perform a common garden laboratory experiment to examine if behavioral variation in the turquoise killifish Nothobranchius furzeri reflects personality divergence. Furthermore, we explore if multiple behavioral traits are correlated. We deliver "proof of principle" of personality variation among N. furzeri individuals in multiple behavioral traits. Because of the vast body of available genomic and physiological information, the well-characterized ecological background and an exceptionally short life cycle, N. furzeri is an excellent model organism to further elucidate the causes and implications of behavioral variation in an eco-evolutionary context. PMID- 30250716 TI - Effects of increased N and P availability on biomass allocation and root carbohydrate reserves differ between N-fixing and non-N-fixing savanna tree seedlings. AB - In mixed tree-grass ecosystems, tree recruitment is limited by demographic bottlenecks to seedling establishment arising from inter- and intra-life-form competition, and disturbances such as fire. Enhanced nutrient availability resulting from anthropogenic nitrogen (N) and phosphorus (P) deposition can alter the nature of these bottlenecks by changing seedling growth and biomass allocation patterns, and lead to longer-term shifts in tree community composition if different plant functional groups respond differently to increased nutrient availability. However, the extent to which tree functional types characteristic of savannas differ in their responses to increased N and P availability remains unclear. We quantified differences in above- and belowground biomass, and root carbohydrate contents in seedlings of multiple N-fixing and non-N-fixing tree species characteristic of Indian savanna and dry forest ecosystems in response to experimental N and P additions. These parameters are known to influence the ability of plants to compete, as well as survive and recover from fires. N-fixers in our study were co-limited by N and P availability, while non-N-fixers were N limited. Although both functional groups increased biomass production following fertilization, non-N-fixers were more responsive and showed greater relative increases in biomass with fertilization than N-fixers. N-fixers had greater baseline investment in belowground resources and root carbohydrate stocks, and while fertilization reduced root:shoot ratios in both functional groups, root carbohydrate content only reduced with fertilization in non-N-fixers. Our results indicate that, even within a given system, plants belonging to different functional groups can be limited by, and respond differentially to, different nutrients, suggesting that long-term consequences of nutrient deposition are likely to vary across savannas contingent on the relative amounts of N and P being deposited in sites. PMID- 30250717 TI - Diversity and abundance of macro-invertebrates on abandoned cattle kraals in a semi-arid savanna. AB - Abandoned cattle (Bos taurus) kraals are sources of habitat heterogeneity in dystrophic semi-arid African savannas with a strong positive effect on soil nutrients and plant productivity. However, little is known regarding how macro invertebrate assemblages vary between abandoned kraals and the surrounding savanna matrix. We tested whether herbaceous biomass and basal and aerial covers and soil nutrients have an effect on aboveground and belowground macro invertebrate assemblages. Twelve abandoned kraals were contrasted with their paired control plots for soil characteristics, herbaceous productivity, and macro invertebrate assemblages in Save Valley Conservancy, Zimbabwe. Abandoned kraals had significantly higher concentrations of soil nitrogen (N), phosphorus (P), potassium (K), and calcium (Ca) as well as herbaceous biomass and basal and aerial covers than control plots. Both aboveground and belowground macro invertebrate species richness were higher on abandoned kraals. However, only belowground macro-invertebrate diversity (Shannon H' and Hill number 1) was significantly higher on abandoned kraals. Soil nutrients and herbaceous productivity had positive and significant correlations with the dominant taxa (Coleoptera, Hymenoptera, Hemiptera, Isoptera, and Myriapoda) on abandoned kraals. These results add to the growing body of evidence that abandoned kraals exert significant effects on savanna spatial heterogeneity years later, with implications on ecosystem processes and functioning. PMID- 30250718 TI - Flyway structure in the circumpolar greater white-fronted goose. AB - Dispersal and migratory behavior are influential factors in determining how genetic diversity is distributed across the landscape. In migratory species, genetic structure can be promoted via several mechanisms including fidelity to distinct migratory routes. Particularly within North America, waterfowl management units have been delineated according to distinct longitudinal migratory flyways supported by banding data and other direct evidence. The greater white-fronted goose (Anser albifrons) is a migratory waterfowl species with a largely circumpolar distribution consisting of up to six subspecies roughly corresponding to phenotypic variation. We examined the rangewide population genetic structure of greater white-fronted geese using mtDNA control region sequence data and microsatellite loci from 23 locales across North America and Eurasia. We found significant differentiation in mtDNA between sampling locales with flyway delineation explaining a significant portion of the observed genetic variation (~12%). This is concordant with band recovery data which shows little interflyway or intercontinental movements. However, microsatellite loci revealed little genetic structure suggesting a panmictic population across most of the Arctic. As with many high-latitude species, Beringia appears to have played a role in the diversification of this species. A common Beringian origin of North America and Asian populations and a recent divergence could at least partly explain the general lack of structure at nuclear markers. Further, our results do not provide strong support for the various taxonomic proposals for this species except for supporting the distinctness of two isolated breeding populations within Cook Inlet, Alaska (A. a. elgasi) and Greenland (A. a. flavirostris), consistent with their subspecies status. PMID- 30250719 TI - Changing environmental gradients over forty years alter ecomorphological variation in Guadalupe Bass Micropterus treculii throughout a river basin. AB - Understanding the degree of intraspecific variation within and among populations is a key aspect of predicting the capacity of a species to respond to anthropogenic disturbances. However, intraspecific variation is usually assessed at either limited temporal, but broad spatial scales or vice versa, which can make assessing changes in response to long-term disturbances challenging. We evaluated the relationship between the longitudinal gradient of changing flow regimes and land use/land cover patterns since 1980 and morphological variation of Guadalupe Bass Micropterus treculii throughout the Colorado River Basin of central Texas. The Colorado River Basin in Texas has experienced major alterations to the hydrologic regime due to changing land- and water-use patterns. Historical collections of Guadalupe Bass prior to rapid human-induced change present the unique opportunity to study the response of populations to varying environmental conditions through space and time. Morphological differentiation of Guadalupe Bass associated with temporal changes in flow regimes and land use/land cover patterns suggests that they are exhibiting intraspecific trait variability, with contemporary individuals showing increased body depth, in response to environmental alteration through time (specifically related to an increase in herbaceous land cover, maximum flows, and the number of low pulses and high pulses). Additionally, individuals from tributaries with increased hydrologic alteration associated with urbanization or agricultural withdrawals tended to have a greater distance between the anal and caudal fin. These results reveal trait variation that may help to buffer populations under conditions of increased urbanization and sprawl, human population growth, and climate risk, all of which impose novel selective pressures, especially on endemic species like Guadalupe Bass. Our results contribute an understanding of the adaptability and capacity of an endemic population to respond to expected future changes based on demographic or climatic projection. PMID- 30250720 TI - Repeated range expansion and niche shift in a volcanic hotspot archipelago: Radiation of C4 Hawaiian Euphorbia subgenus Chamaesyce (Euphorbiaceae). AB - Woody perennial plants on islands have repeatedly evolved from herbaceous mainland ancestors. Although the majority of species in Euphorbia subgenus Chamaesyce section Anisophyllum (Euphorbiaceae) are small and herbaceous, a clade of 16 woody species diversified on the Hawaiian Islands. They are found in a broad range of habitats, including the only known C4 plants adapted to wet forest understories. We investigate the history of island colonization and habitat shift in this group. We sampled 153 individuals in 15 of the 16 native species of Hawaiian Euphorbia on six major Hawaiian Islands, plus 11 New World close relatives, to elucidate the biogeographic movement of this lineage within the Hawaiian island chain. We used a concatenated chloroplast DNA data set of more than eight kilobases in aligned length and applied maximum likelihood and Bayesian inference for phylogenetic reconstruction. Age and phylogeographic patterns were co-estimated using BEAST. In addition, we used nuclear ribosomal ITS and the low-copy genes LEAFY and G3pdhC to investigate the reticulate relationships within this radiation. Hawaiian Euphorbia first arrived on Kaua'i or Ni'ihau ca. 5 million years ago and subsequently diverged into 16 named species with extensive reticulation. During this process Hawaiian Euphorbia dispersed from older to younger islands through open vegetation that is disturbance-prone. Species that occur under closed vegetation evolved in situ from open vegetation of the same island and are only found on the two oldest islands of Kaua'i and O'ahu. The biogeographic history of Hawaiian Euphorbia supports a progression rule with within-island shifts from open to closed vegetation. PMID- 30250722 TI - Unexpected prey of juvenile spotted scat (Scatophagus argus) near a wharf: The prevalence of fouling organisms in stomach contents. AB - A knowledge of fish diets can contribute to revealing the trophic role and ecological function of species in aquatic ecosystems. At present, however, there are no efficient or comprehensive methods for analyzing fish diets. In this study, we investigated the diets of juvenile Scatophagus argus collected near a wharf in Daya Bay, China, by dissection and high-throughput sequencing (HTS) using the 18S rDNA V4 region. Microscopy disclosed large amounts of bryozoans and unrecognizable detritus. In contrast, HTS analysis indicated that the fish diets were considerably more diverse than visual inspection suggested. After eliminating fish sequences, approximately 17,000 sequences from taxa in nine phyla (Ciliophora, Bryozoa, Annelida, Bacillariophyta, Chlorophyta, Arthropoda, Dinoflagellata, Tunicata, and Phaeophyta) were identified from the analysis of stomach contents. Twenty-one food categories were identified, most of which (95.2%) were benthic fouling organisms that could easily be collected around wharfs. These consisted of bryozoans (31.9%), ciliates (45.7%), polychaetes (14.6%), and green algae (3.0%). Therefore, to adapt to anthropogenic habitat modification, the fish had probably shifted from planktonic to benthic feeding. The prevalence of fouling organisms in the stomachs of juvenile S. argus indicates that the fish have responded to habitat changes by widening their food spectrum. This adaptation may have increased their chances of survival. The fouling organisms that inhabit highly perturbed coastal ecosystems could represent a food source for animals at higher trophic levels. Our results accordingly suggest that human activity might significantly influence fish feeding behavior and material transfer along the food chain. PMID- 30250721 TI - A new tool for studying waterfowl immune and metabolic responses: Molecular level analysis using kinome profiling. AB - Here, we describe the design of an Anas-specific kinome peptide array that can be used to study the immunometabolic responses of mallard and American black duck to pathogens, contaminants, and environmental stress. The peptide arrays contain 2,642 unique phosphorylate-able peptide sequences representing 1,900 proteins. These proteins cover a wide array of metabolic and immunological processes, and 758 Gene Ontology Biological processes are statistically significantly represented on the duck peptide array of those 164 contain the term "metabolic" and 25 "immune." In addition, we conducted a comparison of mallard to American black duck at a genetic and proteomic level. Our results show a significant genomic and proteomic overlap between these two duck species, so that we have designed a cross-reactive peptide array capable of studying both species. This is the first reported development of a wildlife species-specific kinome peptide array. PMID- 30250723 TI - Sharing the same slope: Behavioral responses of a threatened mesocarnivore to motorized and nonmotorized winter recreation. AB - Winter recreation is a widely popular activity and is expected to increase due to changes in recreation technology and human population growth. Wildlife are frequently negatively impacted by winter recreation, however, through displacement from habitat, alteration of activity patterns, or changes in movement behavior. We studied impacts of dispersed and developed winter recreation on Canada lynx (Lynx canadensis) at their southwestern range periphery in Colorado, USA. We used GPS collars to track movements of 18 adult lynx over 4 years, coupled with GPS devices that logged 2,839 unique recreation tracks to provide a detailed spatial estimate of recreation intensity. We assessed changes in lynx spatial and temporal patterns in response to motorized and nonmotorized recreation, as well as differences in movement rate and path tortuosity. We found that lynx decreased their movement rate in areas with high-intensity back-country skiing and snowmobiling, and adjusted their temporal patterns so that they were more active at night in areas with high-intensity recreation. We did not find consistent evidence of spatial avoidance of recreation: lynx exhibited some avoidance of areas with motorized recreation, but selected areas in close proximity to nonmotorized recreation trails. Lynx appeared to avoid high intensity developed ski resorts, however, especially when recreation was most intense. We conclude that lynx in our study areas did not exhibit strong negative responses to dispersed recreation, but instead altered their behavior and temporal patterns in a nuanced response to recreation, perhaps to decrease direct interactions with recreationists. However, based on observed avoidance of developed recreation, there may be a threshold of human disturbance above which lynx cannot coexist with winter recreation. PMID- 30250724 TI - Root exudation rate as functional trait involved in plant nutrient-use strategy classification. AB - Plants adopt a variety of life history strategies to succeed in the Earth's diverse environments. Using functional traits which are defined as "morphological, biochemical, physiological, or phonological" characteristics measurable at the individual level, plants are classified according to their species' adaptative strategies, more than their taxonomy, from fast growing plant species to slower-growing conservative species. These different strategies probably influence the input and output of carbon (C)-resources, from the assimilation of carbon by photosynthesis to its release in the rhizosphere soil via root exudation. However, while root exudation was known to mediate plant microbe interactions in the rhizosphere, it was not used as functional trait until recently. Here, we assess whether root exudate levels are useful plant functional traits in the classification of plant nutrient-use strategies and classical trait syndromes? For this purpose, we conducted an experiment with six grass species representing along a gradient of plant resource-use strategies, from conservative species, characterized by low biomass nitrogen (N) concentrations and a long lifespans, to exploitative species, characterized by high rates of photosynthesis and rapid rates of N acquisition. Leaf and root traits were measured for each grass and root exudate rate for each planted soil sample. Classical trait syndromes in plant ecology were found for leaf and root traits, with negative relationships observed between specific leaf area and leaf dry matter content or between specific root length and root dry matter content. However, a new root trait syndrome was also found with root exudation levels correlating with plant resource-use strategy patterns, specifically, between root exudation rate and root dry matter content. We therefore propose root exudation rate can be used as a key functional trait in plant ecology studies and plant strategy classification. PMID- 30250725 TI - Rainfall seasonality and drought performance shape the distribution of tropical tree species in Ghana. AB - Tree species distribution in lowland tropical forests is strongly associated with rainfall amount and distribution. Not only plant water availability, but also irradiance, soil fertility, and pest pressure covary along rainfall gradients. To assess the role of water availability in shaping species distribution, we carried out a reciprocal transplanting experiment in gaps in a dry and a wet forest site in Ghana, using 2,670 seedlings of 23 tree species belonging to three contrasting rainfall distributions groups (dry species, ubiquitous species, and wet species). We evaluated seasonal patterns in climatic conditions, seedling physiology and performance (survival and growth) over a 2-year period and related seedling performance to species distribution along Ghana's rainfall gradient. The dry forest site had, compared to the wet forest, higher irradiance, and soil nutrient availability and experienced stronger atmospheric drought (2.0 vs. 0.6 kPa vapor pressure deficit) and reduced soil water potential (-5.0 vs. -0.6 MPa soil water potential) during the dry season. In both forests, dry species showed significantly higher stomatal conductance and lower leaf water potential, than wet species, and in the dry forest, dry species also realized higher drought survival and growth rate than wet species. Dry species are therefore more drought tolerant, and unlike the wet forest species, they achieve a home advantage. Species drought performance in the dry forest relative to the wet forest significantly predicted species position on the rainfall gradient in Ghana, indicating that the ability to grow and survive better in dry forests and during dry seasons may allow species to occur in low rainfall areas. Drought is therefore an important environmental filter that influences forest composition and dynamics. Currently, many tropical forests experience increase in frequency and intensity of droughts, and our results suggest that this may lead to reduction in tree productivity and shifts in species distribution. PMID- 30250726 TI - Increase in CO2 concentration could alter the response of Hedera helix to climate change. AB - Increasing CO 2 concentration ([CO 2]) is likely to affect future species distributions, in interaction with other climate change drivers. However, current modeling approaches still seldom consider interactions between climatic factors and the importance of these interactions therefore remains mostly unexplored. Here, we combined dendrochronological and modeling approaches to study the interactive effects of increasing [CO 2] and temperature on the distribution of one of the main European liana species, Hedera helix. We combined a classical continent-wide species distribution modeling approach with a case study using H. helix and Quercus cerris tree rings, where we explored the long-term influence of a variety of climate drivers, including increasing [CO 2], and their interactions, on secondary growth. Finally, we explored how our findings could influence the model predictions. Climate-only model predictions showed a small decrease in habitat suitability for H. helix in Europe; however, this was accompanied by a strong shift in the distribution toward the north and east. Our growth ring data suggested that H. helix can benefit from high [CO 2] under warm conditions, more than its tree hosts, which showed a weaker response to [CO 2] coupled with higher cavitation risk under high temperature. Increasing [CO 2] might therefore offset the negative effects of high temperatures on H. helix, and we illustrate how this might translate into maintenance of H. helix in warmer areas. Our results highlight the need to consider carbon fertilization and interactions between climate variables in ecological modeling. Combining dendrochronological analyses with spatial distribution modeling may provide opportunities to refine predictions of how climate change will affect species distributions. PMID- 30250727 TI - Floral traits of mammal-pollinated Mucuna macrocarpa (Fabaceae): Implications for generalist-like pollination systems. AB - Floral traits are adapted by plants to attract pollinators. Some of those plants that have different pollinators in different regions adapt to each pollinator in each region to maximize their pollination success. Mucuna macrocarpa (Fabaceae) limits the pollinators using its floral structure and is pollinated by different mammals in different regions. Here, we examine the relationships between floral traits of M. macrocarpa and the external morphology of mammalian pollinators in different regions of its distribution. Field surveys were conducted on Kyushu and Okinawajima Island in Japan, and in Taiwan, where the main pollinators are the Japanese macaque Macaca fuscata, Ryukyu flying fox Pteropus dasymallus, and red bellied squirrel Callosciurus erythraeus, respectively. We measured the floral shapes, nectar secretion patterns, sugar components, and external morphology of the pollinators. Results showed that floral shape was slightly different among regions and that flower sizes were not correlated with the external morphology of the pollinators. Volume and sugar rate of nectar were not significantly different among the three regions and did not change throughout the day in any of the regions. However, nectar concentration was higher in Kyushu than in the other two regions. These results suggest that the floral traits of M. macrocarpa are not adapted to each pollinator in each region. Although this plant limits the number of pollinators using its flower structure, it has not adapted to specific mammals and may attract several species of mammals. Such generalist-like pollination system might have evolved in the Old World. PMID- 30250728 TI - Decaying trees improve nesting opportunities for cavity-nesting birds in temperate and boreal forests: A meta-analysis and implications for retention forestry. AB - Many studies have dealt with the habitat requirements of cavity-nesting birds, but there is no meta-analysis on the subject and individual study results remain vague or contradictory. We conducted a meta-analysis to increase the available evidence for nest-site selection of cavity-nesting birds. Literature was searched in Web of Science and Google Scholar and included studies that provide data on the habitat requirements of cavity-nesting birds in temperate and boreal forests of varying naturalness. To compare nest and non-nest-tree characteristics, the following data were collected from the literature: diameter at breast height (DBH) and its standard deviation (SD), sample size of trees with and without active nest, amount of nest and available trees described as dead or with a broken crown, and amount of nest and available trees that were lacking these characteristics. Further collected data included bird species nesting in the cavities and nest-building type (nonexcavator/excavator), forest type (coniferous/deciduous/mixed), biome (temperate/boreal), and naturalness (managed/natural). From these data, three effect sizes were calculated that describe potential nest trees in terms of DBH, vital status (dead/alive), and crown status (broken/intact). These tree characteristics can be easily recognized by foresters. The results show that on average large-diameter trees, dead trees, and trees with broken crowns were selected for nesting. The magnitude of this effect varied depending primarily on bird species and the explanatory variables forest type and naturalness. Biome had lowest influence (indicated by DeltaAIC). We conclude that diameter at breast height, vitality, and crown status can be used as tree characteristics for the selection of trees that should be retained in selectively harvested forests. PMID- 30250729 TI - Heterogeneity of ecological patterns, processes, and funding of marine manipulative field experiments conducted in Southeastern Pacific coastal ecosystems. AB - Ecological manipulative experiments conducted in marine coastal ecosystems have substantially improved ecological theory during the last decades and have provided useful knowledge for the management and conservation of coastal ecosystems. Although different studies report global trends in ecological patterns worldwide, Southeastern Pacific coastal ecosystems have been poorly considered. Given that the SE Pacific coast encompasses diverse coastal ecosystems, consideration of studies conducted along this range can shed light on the heterogeneity of processes regulating coastal communities. We reviewed the biotic interactions and habitat type considered, as well as the complexity in terms of spatial and temporal extent of manipulative field experimental studies conducted along the SE Pacific coast from 0 degrees S to 56 degrees S (Ecuador to Chile). We test the effect of funding reported by different studies as a main factor limiting experimental complexity. From field ecological studies published from 1970 to 2016, we found that 81 studies were truly manipulative, in which one or multiple factors were "manipulated." Around 77% of these studies were located between 21 degrees S and 40 degrees S, and conducted in intertidal rocky habitats. An increase in experimental studies was observed between 2010 and 2015, especially focused on herbivore-alga interactions, although we found that both the temporal extent and spatial extent of these studies have shown a decrease in recent decades. Funding grant amount reported had a positive effect on elapsed time of field experiments, but no effect was observed on spatial extent or in the biotic interactions considered. Elapsed time of experiments was different among the main biotic interactions considered, that is, herbivory, predation, and competition. We suggest that to further progress in applied ecological knowledge, it will be necessary to consider pollution and urbanization processes explicitly using a field experimental framework. This information could improve our understanding of how ecosystems present along the SE Pacific coast respond to climate change and increased levels of human interventions. PMID- 27158454 TI - The ICR142 NGS validation series: a resource for orthogonal assessment of NGS analysis. AB - To provide a useful community resource for orthogonal assessment of NGS analysis software, we present the ICR142 NGS validation series. The dataset includes high quality exome sequence data from 142 samples together with Sanger sequence data at 704 sites; 416 sites with variants and 288 sites at which variants were called by an NGS analysis tool, but no variant is present in the corresponding Sanger sequence. The dataset includes 293 indel variants and 247 negative indel sites, and thus the ICR142 validation dataset is of particular utility in evaluating indel calling performance. The FASTQ files and Sanger sequence results can be accessed in the European Genome-phenome Archive under the accession number EGAS00001001332. PMID- 29067164 TI - A case series report of cancer patients undergoing group body psychotherapy. AB - Background: Disturbances in bodily wellbeing represent a key source of psychosocial suffering and impairment related to cancer. Therefore, interventions to improve bodily wellbeing in post-treatment cancer patients are of paramount importance. Notably, body psychotherapy (BPT) has been shown to improve bodily wellbeing in subjects suffering from a variety of mental disorders. However, how post-treatment cancer patients perceive and subjectively react to group BPT aiming at improving bodily disturbances has, to the best of our knowledge, not yet been described. Methods: We report on six patients undergoing outpatient group BPT that followed oncological treatment for malignant neoplasms. The BPT consisted of six sessions based on a scientific embodiment approach, integrating body-oriented techniques to improve patients' awareness, perception, acceptance, and expression regarding their body. Results: The BPT was well accepted by all patients. Despite having undergone different types of oncological treatment for different cancer types and locations, all subjects reported having appreciated BPT and improved how they perceived their bodies. However, individual descriptions of improvements showed substantial heterogeneity across subjects. Notably, most patients indicated that sensations, perceptions, and other mental activities related to their own body intensified when proceeding through the group BPT sessions. Conclusion: The findings from this case series encourage and inform future studies examining whether group BPT is efficacious in post treatment cancer patients and investigating the related mechanisms of action. The observed heterogeneity in individual descriptions of perceived treatment effects point to the need for selecting comprehensive indicators of changes in disturbances of bodily wellbeing as the primary patient-reported outcome in future clinical trials. While increases in mental activities related to their own body are commonly interpreted as important mechanisms of therapeutic action in BPT, follow-up assessments are needed to evaluate intended and unintended consequences of these changes in cancer patients. PMID- 30135730 TI - Major histocompatibility complex (MHC) fragment numbers alone - in Atlantic cod and in general - do not represent functional variability. AB - This correspondence concerns a publication by Malmstrom et al. in Nature Genetics in October 2016. Malmstrom et al. made an important contribution to fish phylogeny research by using low-coverage genome sequencing for comparison of 66 teleost (modern bony) fish species, with 64 of those 66 belonging to the species rich clade Neoteleostei, and with 27 of those 64 belonging to the order Gadiformes. For these 66 species, Malmstrom et al. estimated numbers of genes belonging to the major histocompatibility complex (MHC) class I lineages U and Z and concluded that in teleost fish these combined numbers are positively associated with, and a driving factor of, the rates of establishment of new fish species (speciation rates). They also claimed that functional genes for the MHC class II system molecules MHC IIA, MHC IIB, CD4 and CD74 were lost in early Gadiformes. Our main criticisms are (1) that the authors did not provide sufficient evidence for presence or absence of intact functional MHC class I or MHC class II system genes, (2) that they did not discuss that an MHC subpopulation gene number alone is a very incomplete measure of MHC variance, and (3) that the MHC system is more likely to reduce speciation rates than to enhance them. Furthermore, their use of the Ornstein-Uhlenbeck model is a typical example of overly naive use of that model system. In short, we conclude that their new model of MHC class I evolution, reflected in their title "Evolution of the immune system influences speciation rates in teleost fish", is unsubstantiated, and that their "pinpointing" of the functional loss of the MHC class II system and all the important MHC class II system genes to the onset of Gadiformes is preliminary, because they did not sufficiently investigate the species at the clade border. PMID- 30250733 TI - Relationship between endotoxin core, staphylococcal and varicella antibody levels and outcome following aortic valve replacement surgery: a prospective observational study. AB - Background: Morbidity and mortality following cardiac valve surgery is high. Immunity is an important contributor to outcome. This study examines the relationship of staphylococcal and endotoxin antibody levels to outcome following cardiac surgery. Methods: Using enzyme-linked immunosorbent assays (ELISA), we measured pre-operative levels of antibodies to endotoxin core (EndoCAb); 3 common staphylococcal epitopes and varicella on saved serum of 60 adult patients scheduled to undergo elective primary surgical aortic valve replacement (AVR). Primary outcome measure was post-operative length of stay (LOS) in hospital with secondary outcomes being development of infective complications, length of stay on the intensive care unit (ICU) and 30-day mortality. Patients were quartiled according to antibody levels and outcomes compared between the quartile groups using Mann-Whitney tests for length of stay and Fisher's test for development of infection. Results: Sixty patients (34 M, 26 F) were recruited with mean age 73 years (IQR 66-78), mean body mass index (BMI) 27.7 (IQR 25-31) and EuroSCORE II 1.44 (0.95-1.99). Those patients in the lower quartile for pre-operative antibody level had a longer post-operative stay than the upper quartile. EndoCAb (median IgG level Q1 42.2 MU/ml vs Q4 256 MU/ml) 9 vs 6 days, p = 0.025; alpha-toxin (median IgG level Q1 63 U vs Q4 558 U) 10 vs 7 days, p = 0.034; teichoic acid (median IgG level Q1 14 U vs Q4 419 U) 10 vs 8 days, p = 0.441; staphylococcal enterotoxin A (median IgG level Q1 55 U vs Q4 427 U) 9 vs 7 days, p = 0.865; varicella zoster (median IgG level Q1 1.325 U vs Q4 2.54 U) 8 vs 7 days, p = 1.0; and combined antibody levels 10 vs 6 days, p = 0.017. There were no differences in the number developing post-operative infections for each antibody type. The combined antibody analysis suggested a reduction in proportion of individuals developing infection from the upper vs lower quartile: 0 vs 0.33, p = 0.042. Conclusions: This study again suggests the inverse relationship between endotoxin core antibody levels and outcome following aortic valve surgery as well as suggesting a similar relationship with antibodies to staphylococcus. There is no such relationship for antibody levels against an organism not providing a peri operative threat. Understanding this relationship may enable therapeutic manipulation of immune status, re-evaluation of risk and further investigation of the low immune state. Trial registration: The patients in this study are a sub group of the RELIEF AS study.ClinicalTrials.gov identifier NCT02174471. PMID- 30250734 TI - View point: gaps in the current guidelines for the prevention of Methicillin resistant Staphylococcus aureus surgical site infections. AB - The authors advocate the addition of two preventative strategies to the current United State's guidelines for the prevention of surgical site infections. It is known that Staphylococcus aureus, including Methicillin-resistant Staphylococcus aureus (MRSA), carriers are at a higher risk for the development of infections and they can easily transmit the organism. The carriage rate of Staph. aureus in the general population approximates 33%. The CDC estimates the carriage rate of MRSA in the United States is approximately 2%. The first strategy is preoperative screening of surgical patients for Staph. aureus, including MRSA. This recommendation is based upon the growing literature which shows a benefit in both prevention of infections and guidance in preoperative antibiotic selection. The second is performing MRSA active surveillance screening on healthcare workers. The carriage rate of MRSA in healthcare workers approximates 5% and there are concerns of transmission of this pathogen to patients. MRSA decolonization of healthcare workers has been reported to approach a success rate of 90%. Healthcare workers colonized with dangerous pathogens, including MRSA, should be assigned to non-patient contact work areas. In addition, there needs to be implemented a safety net for both the worker's economic security and healthcare. Finally, a reporting system for the healthcare worker acquisition and infections with dangerous pathogens needs to be implemented. These recommendations are needed because Staph. aureus including MRSA is endemic in the United States. Policies regarding endemic pathogens which are to be implemented only upon the occurrence of a facility defined "outbreak" have to be questioned, since absence of infections does not mean absence of transmission. Optimizing these policies will require further research but until then we should error on the side of patient safety. PMID- 30250738 TI - The 1918 influenza pandemic: Ecological, historical, and evolutionary perspectives. PMID- 30250735 TI - Migrant and refugee populations: a public health and policy perspective on a continuing global crisis. AB - The 2015-2017 global migratory crisis saw unprecedented numbers of people on the move and tremendous diversity in terms of age, gender and medical requirements. This article focuses on key emerging public health issues around migrant populations and their interactions with host populations. Basic needs and rights of migrants and refugees are not always respected in regard to article 25 of the Universal Declaration of Human Rights and article 23 of the Refugee Convention. These are populations with varying degrees of vulnerability and needs in terms of protection, security, rights, and access to healthcare. Their health status, initially conditioned by the situation at the point of origin, is often jeopardised by adverse conditions along migratory paths and in intermediate and final destination countries. Due to their condition, forcibly displaced migrants and refugees face a triple burden of non-communicable diseases, infectious diseases, and mental health issues. There are specific challenges regarding chronic infectious and neglected tropical diseases, for which awareness in host countries is imperative. Health risks in terms of susceptibility to, and dissemination of, infectious diseases are not unidirectional. The response, including the humanitarian effort, whose aim is to guarantee access to basic needs (food, water and sanitation, healthcare), is gripped with numerous challenges. Evaluation of current policy shows insufficiency regarding the provision of basic needs to migrant populations, even in the countries that do the most. Governments around the world need to rise to the occasion and adopt policies that guarantee universal health coverage, for migrants and refugees, as well as host populations, in accordance with the UN Sustainable Development Goals. An expert consultation was carried out in the form of a pre-conference workshop during the 4th International Conference on Prevention and Infection Control (ICPIC) in Geneva, Switzerland, on 20 June 2017, the United Nations World Refugee Day. PMID- 30250737 TI - Association between self-reported hearing impairment and diabetes: a Brazilian population-based study: Association between self-reported hearing impairment and diabetes in adults. AB - Background: Some studies have already explored the relationship between diabetes and hearing loss; however, this relationship has still not been well established, especially due to methodological limitations related to lack of control for confounders. The aim of this study was to analyze the association between self reported hearing impairment and diabetes among adults in Brazil, controlling for sociodemographic and occupational exposure to ototoxic agents. Methods: This is a cross-sectional study based on data collected by the National Health Survey of 2013 in Brazil. A total of 60,202 individuals aged>=18 years were interviewed. Crude and adjusted prevalence ratios were calculated using the Poisson regression model with robust estimation of the variance. All analyzes were performed considering the appropriated weights imposed by the complex sample design. Results: Hearing loss prevalence was 2.56% (95%CI: 2.34-2.79). It was higher in males, older age groups, white and individuals with lower levels of schooling. Diabetes was positively and significantly associated with hearing loss in the crude analysis (PRcrude = 2.92; 95%CI: 2.75-3.11) and also in the analysis adjusted for gender, age, skin color, schooling, smoking, alcohol consumption and occupational exposure (PRadj = 1.46; 95%CI: 1.32-1.61). Conclusions: The present results suggest that individuals with diabetes have higher prevalence of hearing impairment. There is the need of longitudinal studies to investigate if diabetes is a risk factor to hearing impairment. PMID- 30250736 TI - Residual feed intake phenotype and gender affect the expression of key genes of the lipogenesis pathway in subcutaneous adipose tissue of beef cattle. AB - Background: Feed accounts for up to 75% of costs in beef production systems, thus any improvement in feed efficiency (FE) will benefit the profitability of this enterprise. Residual feed intake (RFI) is a measure of FE that is independent of level of production. Adipose tissue (AT) is a major endocrine organ and the primary metabolic energy reservoir. It modulates a variety of processes related to FE such as lipid metabolism and glucose homeostasis and thus measures of inter animal variation in adiposity are frequently included in the calculation of the RFI index. The aim of this study was to determine the effect of phenotypic RFI status and gender on the expression of key candidate genes related to processes involved in energy metabolism within AT. Dry matter intake (DMI) and average daily gain (ADG) were measured over a period of 70 d for 52 purebred Simmental heifers (n = 24) and bulls (n = 28) with an initial BW+/-SD of 372+/-39.6 kg and 387+/-50.6 kg, respectively. Residual feed intake was calculated and animals were ranked within gender by RFI into high (inefficient; n = 9 heifers and n = 8 bulls) and low (efficient; n = 9 heifers and n = 8 bulls) groups. Results: Average daily gain +/-SD and daily DMI +/-SD for heifers and bulls were 1.2+/-0.4 kg and 9.1+/-0.5 kg, and 1.8+/-0.3 kg and 9.5+/-1 kg respectively. High RFI heifers and bulls consumed 10% and 15% more (P < 0.05) than their low RFI counterparts, respectively. Heifers had a higher expression of all genes measured than bulls (P < 0.05). A gender * RFI interaction was detected for HMGCS2(P < 0.05) in which high RFI bulls tended to have lower expression of HMGCS2 than low RFI bulls (P < 0.1), whereas high RFI heifers had higher expression than low RFI heifers (P < 0.05) and high RFI bulls (P < 0.05). SLC2A4 expression was consistently higher in subcutaneous AT of low RFI animals across gender. Conclusion: The findings of this study indicate that low RFI cattle exhibit upregulation of the molecular mechanisms governing glucose metabolism in adipose tissue, in particular, glucose clearance. The decreased expression of SLC2A4 in the inefficient cattle may result in less efficient glucose metabolism in these animals. We conclude that SLC2A4 may be a potential biomarker for RFI in cattle. PMID- 30250739 TI - Capturing foraging and resting behavior using nested multivariate Markov models in an air-breathing marine vertebrate. AB - Background: Matching animal movement with the behaviors that shape life history requires a rigorous connection between the observed patterns of space use and inferred behavioral states. As animal-borne dataloggers capture a greater diversity and frequency of three dimensional movements, we can increase the complexity of movement models describing animal behavior. One challenge in combining data streams is the different spatial and temporal frequency of observations. Nested movement models provide a flexible framework for gleaning data from long-duration, but temporally sparse, data sources. Results: Using a two-layer nested model, we combined geographic and vertical movement to infer traveling, foraging and resting behaviors of Humpback whales off the West Antarctic Peninsula. This approach refined previous work using only geographic data to delineate coarser behavioral states. Our results showed increased intensity in foraging activity in late season animals as the whales prepared to migrate north to tropical calving grounds. Our model also suggests strong diel variation in movement states, likely linked to daily changes in prey distribution. Conclusions: Using a combination of two-dimensional and three dimensional movement data, we highlight the connection between whale movement and krill availability, as well as the complex spatial pattern of whale foraging in productive polar waters. PMID- 30250741 TI - The impact of helicobacter pylori eradication on platelet counts of adult patients with idiopathic thrombocytopenic purpura. AB - Background: Idiopathic (immune) thrombocytopenic purpura (ITP) is an acquired disorder characterized by autoantibodies against platelet membrane antigens. Several studies found an association between Helicobacter Pylori infection and the incidence of ITP. So far, It is still unclear whether H. pylori eradication will increase platelet counts in adult ITP patients. We conduct this study to investigate platelet recovery in ITP patients after H. pylori eradication. Methods: This is a prospective study. The diagnostic criterion for Idiopathic thrombocytopenic purpura is: isolated thrombocytopenia, with no evidence of any underlying causes like drugs, TTP, SLE, hepatitis, HIV,CLL and... etc. We examined blood smears of all patients. We have diagnosed Helicobacter pylori infection by histological examination of several biopsies obtained from stomach and duodenum by esophagogastroduodenoscopy (EGD). If EGD was not applicable due to patient's poor situation or platelet count, H.pylori infection was diagnosed by the positivity of serum antibodies or respiratory urease test. We treated infected patients with triple therapy (omeprazole 40 mg once daily, amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily) for 14 days. Uninfected patients did not receive any treatment. We did platelet quantification at the beginning of the study, at the end of the first month, at the end of the third month and at the end of the sixth month. Results: This study involved 50 patients with chronic ITP, 29 males (58%) and 21 females (42%). Participants ages range between18 and 51 years (mean age = 28.60 years). We diagnosed H. pylori in 36 patients (72%), who were treated with triple therapy. At the end of the sixth month, 10 of them (27.77%) showed complete response, and 18 of them (50%) showed partial response. The 14 uninfected patients, who did not receive any treatment, did not show neither complete nor partial response. Patient sex and age were not associated with achieving response, while baseline platelet count and H.pylori infection did. Conclusion: Helicobacter pylori eradication significantly increases platelet counts in adult ITP patients. PMID- 30250742 TI - Asymptomatic hepatosplenomegaly in chronic myeloid leukemia. AB - A 39-year-old male diagnosed as chronic myeloid leukemia, had no abdominal symptoms. However, his physical examination revealed apparent abdominal fullness. His liver and spleen were palpable. His abdominal CT revealed that a narrow space to pass intestinal digestive contents. Asymptomatic hepatosplenomegaly is somewhat typical in these chronic type hematological diseases. PMID- 30250740 TI - Borderline personality disorder and substance use disorders: an updated review. AB - For decades, clinicians and researchers have recognized that borderline personality disorder (BPD) and substance use disorders (SUDs) are often diagnosed within the same person (e.g., (Gunderson JG. Borderline personality disorder: A clinical guide. Washington, D.C.: American Psychiatric Press, 2001; Leichsenring et al., Lancet 377:74-84, 2011; Paris J. Borderline personality disorder: A multidimensional approach. American Psychiatric Pub, 1994; Trull et al., Clin Psychol Rev 20:235-53, 2000)). Previously, we documented the extent of this co occurrence and offered a number of methodological and theoretical explanations for the co-occurrence (Trull et al., Clin Psychol Rev 20:235-53, 2000). Here, we provide an updated review of the literature on the co-occurrence between borderline personality disorder (BPD) and substance use disorders (SUDs) from 70 studies published from 2000 to 2017, and we compare the co-occurrence of these disorders to that documented by a previous review of 36 studies over 15 years ago (Trull et al., Clin Psychol Rev 20:235-53, 2000). PMID- 30250743 TI - Pseudomyxoma pleurii and peritonei secondary to sigmoid colon adenocarcinoma: a rare clinico-pathologico-radiological presentation. AB - Pseudomyxoma peritonei (PMP) is a rare condition resulting from mucin-producing tumors that have disseminated into intraperitoneal implants and mucinous ascites. The extra-abdominal spread of PMP is exceptionally rare, with few reported cases in the medical literature. Pseudomyxoma pleurii is an infrequently encountered clinical syndrome characterized by transdiaphragmatic pleural extension and spread of PMP. The disease is highly fatal. We hereby report a case of 58 years old woman who presented with an abdominal distension and shortness of breath of 2 months duration. Histopathology confirmed the diagnosis of large mucin-producing rectosigmoid adenomatous polypoid lesion with malignant transformation and PMP that had spread to the right pleural space. PMP from colon tumor is uncommon and its transdiaphragmatic pleural extension is very unusual complicated by management challenge and high mortality rate. PMID- 30250744 TI - Post-exposure prophylaxis with isavuconazole after occupational exposure to Rhizopus. AB - Invasive mucormycosis is typically seen in patients with hematological malignancies, diabetes and other conditions that affect the immune system. However, locally invasive disease can also be seen in both immunocompromised and immunocompetent hosts after trauma and direct inoculation. Since historically post-exposure prophylaxis with lipid-based amphotericin B compounds has not been feasible because of a high toxicity profile, there is no experience regarding the role of post-exposure prophylaxis after injuries contaminated with agents of mucormycosis. We describe the first case of a patient with occupational exposure to Rhizopus that received post-exposure prophylaxis with oral isavuconazole. PMID- 30250745 TI - Multi-system bleeding risk with a cutaneous angiosarcoma at an arteriovenous fistula site. AB - We present a case of angiosarcoma at an arteriovenous fistula site in a non immunocompromised patient presenting as a soft tissue swelling with associated findings suggestive of lung malignancy, metastases and bleeding diathesis. This patient died of an otherwise unexplained subdural haematoma. Given the ability of this tumour to metastasise early and the poor prognosis of angiosarcoma without adequate resection, this needs to be considered early in any differential diagnosis of soft tissue masses near an arteriovenous fistula. PMID- 30250746 TI - A case report of melioidosis complicated by infective sacroiliitis in Sri Lanka. AB - Background: Melioidosis is an infection caused by a facultative intracellular Gram-negative bacterium, Burkholderia pseudomallei. It can present as septicemia, localized infection with/without septicemia, asymptomatic infections, ulcers, pneumonia, visceral abscesses, neurological infection, musculoskeletal infections and can involve any organ. Case presentation: A 56 year old Sri Lankan diabetic female presented with fever, chills and rigors for 2 weeks. She also had malaise and loss of appetite, but no other features. On examination, she was febrile (temperature was 101.4 0 F) and rest of the examination was unremarkable. Her blood culture was positive for Burkholderia pseudomallei and she was started on IV antibiotics, on day 3. During her 2nd week of hospital stay, she developed right sided low back pain with buttock pain, right hip joint pain and restricted hip joint movements suggestive of right sacroiliitis. CE CT and MRI scans confirmed the diagnosis of right iliopsoas abscesses and right sacroiliitis.Incision and drainage was performed and a pigtail catheter was left in place for continuous drainage of abscesses. Her intensive phase was initiated with IV ceftazidime 2 g every 6 h for 12 days, then changed over to IV meropenem 2 g every 8 h together with oral co-trimoxazole. 2 weeks later, oral co trimoxazole was replaced by oral doxycycline for another 6 weeks (due to transient pancytopaenia). She made a complete and uneventful recovery with oral co-trimoxazole for another 6 months, in her eradication phase.We report this case to show the importance in early diagnosis of melioidosis, and to consider it in the differential diagnosis of multiple abscesses and to emphasize the importance in suspecting melioidosis as a causative agent in infective sacroiliitis. Discussion: Melioidosis can have 2 major presentations; acute infection (symptoms lasting less than 2 months) and chronic infection (symptoms lasting more than 2 months). Musculoskeletal melioidosis is a well-recognized manifestation of the disease, which can manifest as soft tissue abscesses, septic arthritis, spondylitis, sacroiliitis and osteomyelitis.Management of melioidosis consists of 2 phases. The intensive phase and the eradication phase. These are aimed at the importance of rapidly treating the septicemia, the need of eradication of the persistent disease and the prevention of recurrent infections or relapses. The intensive phase consists of minimum 10-14 days of IV antibiotics: IV ceftazidime or IV carbapenem (meropenem/ imipenem). Eradication phase should be followed by 3 6 months of oral co-trimoxazole alone or in combination with oral doxycycline/ oral amoxiciliin-clavulanic acid. PMID- 30250747 TI - Detection of Cystoisospora suis in faeces of suckling piglets - when and how? A comparison of methods. AB - Background: Cystoisospora suis is the causative agent of porcine neonatal coccidiosis, a diarrheal disease which affects suckling piglets in the first weeks of life. Detection of oocysts in the faeces of infected animals is frequently hampered by the short individual excretion period and the high fat content of faecal samples. We analysed oocyst excretion patterns of infected piglets, evaluated different detection methods for their detection limit and reproducibility, and propose a sampling scheme to improve the diagnosis of C. suis in faecal samples from the field using a protocol for reliable parasite detection. Results: Based on a hypothesized model of the course of infection on a farm, three samplings (days of life 7-14-21 or 10-15-20) should be conducted including individual samples of piglets from each sampled litter. Samples can be examined by a modified McMaster method (lower detection limit: 333 oocysts per gram of faeces, OpG), by examining faecal smears under autofluorescence (lower detection limit: 10 OpG) or after carbol-fuchsin staining (lower detection limit: 100 OpG). Reproducibility and inter-test correlations were high with (R2 > 0.8). A correlation of oocyst excretion with diarrhoea could not be established so samples with different faecal consistencies should be taken. Pooled samples (by litter) should be comprised of several individual samples from different animals. Conclusions: Since oocyst excretion by C. suis-infected piglets is usually short the right timing and a sufficiently sensitive detection method are important for correct diagnosis. Oocyst detection in faecal smears of samples taken repeatedly is the method of choice to determine extent and intensity of infection on a farm, and autofluorescence microscopy provides by far the lowest detection limit. Other methods for oocyst detection in faeces are less sensitive and/or more labour- and cost intensive and their usefulness is restricted to specific applications. PMID- 30250748 TI - Factors associated with contraceptive use among young women in Malawi: analysis of the 2015-16 Malawi demographic and health survey data. AB - Background: Although Malawi is one of the countries with highest Contraceptive Prevalence Rate (CPR) in Sub-Saharan Africa, pregnancies and fertility among young women remain high. This suggests low up take of contraceptives by young women. The aim of this study was to investigate the factors associated with contraceptive use among young women in Malawi. Methods: This is a secondary analysis of household data for 10,422 young women aged 15-24 years collected during the 2015-16 Malawi Demographic and Health Survey (MDHS). The sample was weighted to ensure representativeness. Descriptive statistics, bivariate and multivariate logistic regressions were performed to assess the demographic, social - economic and other factors that influence contraceptive use among young women. Crude Odds Ratio (COR) and Adjusted Odds Ratio (AOR) with their corresponding 95% confidence intervals (95% CI) were computed using the Statistical Package for the Social Sciences version 22.0. Results: Of the 10,422 young women, 3219 used contraception representing a prevalence of 30.9%. The findings indicate that age, region of residence, marital status, education, religion, work status, a visit to health facility, and knowledge of the ovulatory cycle are significant predictors of contraceptive use among young women in Malawi. Women who were in the age group 20-24 years (AOR = 1.93; 95% CI = 1.73 2.16), working (AOR = 1.26; 95% CI = 1.14-1.39), currently married (AOR = 6.26; 95% CI = 5.46-7.18), knowledgeable about their ovulatory cycle (AOR = 1.75; 95% CI = 1.50-2.05), and those with primary education (AOR = 1.47; 95% CI = 1.18 1.83) were more likely to use contraceptives than their counterparts. Conclusion: This study has demonstrated that several social demographic and economic factors are associated with contraceptive use among young women in Malawi. These findings should be considered and reflected in public health policies to address issues that could be barriers to the use of contraception by young women. Strengthening access to family planning information and services for young women is highly recommended to reduce pregnancies among young women in Malawi. PMID- 30250749 TI - A novel photic entrainment mechanism for the circadian clock in an insect: involvement of c-fos and cryptochromes. AB - Background: Entrainment to the environmental light cycle is an essential property of the circadian clock. Although the compound eye is known to be the major photoreceptor necessary for entrainment in many insects, the molecular mechanisms of photic entrainment remain to be explored. Results: We found that cryptochromes (crys) and c-fos mediate photic entrainment of the circadian clock in a hemimetabolous insect, the cricket Gryllus bimaculatus. We examined the effects of RNA interference (RNAi)-mediated knockdown of the cry genes, Gb'cry1 and Gb'cry2, on photic entrainment, and light-induced resetting of the circadian locomotor rhythm. Gb'cry2 RNAi accelerated entrainment for delay shifts, while Gb'cry1/ Gb'cry2 double RNAi resulted in significant lengthening of transient cycles in both advance and delay shifts, and even in entrainment failure in some crickets. Double RNAi also strongly suppressed light induced resetting. The Gb'cry-mediated phase shift or resetting of the rhythm was preceded by light induced Gb'c-fosB expression. We also found that Gb'c-fosB, Gb'cry2 and Gb'period (Gb'per) were likely co-expressed in some optic lobe neurons. Conclusion: Based on these results, we propose a novel model for photic entrainment of the insect circadian clock, which relies on the light information perceived by the compound eye. PMID- 30250750 TI - Eplerenone in the treatment of central serous chorioretinopathy: a review of the literature. AB - Purpose: The purpose of this review is to examine the role of eplerenone in the treatment of central serous chorioretinopathy (CSCR). Methods: A comprehensive search of the PubMed database has been conducted regarding eplerenone for CSCR, while studies using spironolactone were excluded. Articles and book chapters cited in the reference lists of articles obtained by this method were reviewed and included when considered appropriate, while the retrieved articles were filtered manually to exclude duplicates. Results: Oral eplerenone at a dose of 25 50 mg/day has been found to be effective and well-tolerated for the treatment of chronic CSCR. The published studies have shown significant improvement in visual acuity and decrease or total absorption of subretinal fluid in patients with CSCR treated with oral eplerenone. However, it should be noted that the majority of studies were retrospective with limited number of patients and short follow-up. On the other hand, patients presenting widespread retinal pigment epithelium changes are less likely to benefit from eplerenone treatment, which may argue for an earlier intervention. Conclusions: CSCR is a challenging disease to understand and treat, since its pathogenesis remains elusive and multifactorial. Pharmacologic approaches, like eplerenone, are intriguing, as they target several pathophysiological pathways and may lead to visual acuity improvement and more rapid recovery. PMID- 30250751 TI - Inferring the age difference in HIV transmission pairs by applying phylogenetic methods on the HIV transmission network of the Swiss HIV Cohort Study. AB - Age-mixing patterns are of key importance for understanding the dynamics of human immunodeficiency virus (HIV)-epidemics and target public health interventions. We use the densely sampled Swiss HIV Cohort Study (SHCS) resistance database to study the age difference at infection in HIV transmission pairs using phylogenetic methods. In addition, we investigate whether the mean age difference of pairs in the phylogenetic tree is influenced by sampling as well as by additional distance thresholds for including pairs. HIV-1 pol-sequences of 11,922 SHCS patients and approximately 240,000 Los Alamos background sequences were used to build a phylogenetic tree. Using this tree, 100 per cent down to 1 per cent of the tips were sampled repeatedly to generate pruned trees (N = 500 for each sample proportion), of which pairs of SHCS patients were extracted. The mean of the absolute age differences of the pairs, measured as the absolute difference of the birth years, was analyzed with respect to this sample proportion and a distance criterion for inclusion of the pairs. In addition, the transmission groups men having sex with men (MSM), intravenous drug users (IDU), and heterosexuals (HET) were analyzed separately. Considering the tree with all 11,922 SHCS patients, 2,991 pairs could be extracted, with 954 (31.9 per cent) MSM-pairs, 635 (21.2 per cent) HET-pairs, 414 (13.8 per cent) IDU-pairs, and 352 (11.8 per cent) HET/IDU-pairs. For all transmission groups, the age difference at infection was significantly (P < 0.001) smaller for pairs in the tree compared with randomly assigned pairs, meaning that patients of similar age are more likely to be pairs. The mean age difference in the phylogenetic analysis, using a fixed distance of 0.05, was 9.2, 9.0, 7.3 and 5.6 years for MSM-, HET-, HET/IDU-, and IDU-pairs, respectively. Decreasing the cophenetic distance threshold from 0.05 to 0.01 significantly decreased the mean age difference. Similarly, repeated sampling of 100 per cent down to 1 per cent of the tips revealed an increased age difference at lower sample proportions. HIV-transmission is age-assortative, but the age difference of transmission pairs detected by phylogenetic analyses depends on both sampling proportion and distance criterion. The mean age difference decreases when using more conservative distance thresholds, implying an underestimation of age-assortativity when using liberal distance criteria. Similarly, overestimation of the mean age difference occurs for pairs from sparsely sampled trees, as it is often the case in sub-Saharan Africa. PMID- 30250753 TI - Prevalence and Predictors of Overweight and Obesity among Somalis in Norway and Somaliland: A Comparative Study. AB - Background and Aim: The knowledge about the health status of Somalis in Norway and Somaliland is limited. This paper reports the results of a comparative study on the prevalence and predictors of overweight/obesity among Somalis in Norway and Somaliland. Method: We conducted two cross-sectional studies using the same tools and procedures, between 2015 and 2016. The study population was adults aged 20-69 years (n=1110 (Somaliland) and n=220 (Norway)). Results: The prevalence of obesity (body mass index (BMI) >=30 kg/m2) was 44% and 31% in women in Norway and Somaliland, respectively. In contrast, the prevalence of obesity was low in men (9% in Norway; 6% in Somaliland). Although the prevalence of high BMI was higher in Somali women in Norway than women in Somaliland, both groups had the same prevalence of central obesity (waist circumference (WC) >= 88 cm). In men, the prevalence of central obesity (WC >= 102 cm) was lower in Somaliland than in Norway. For women in Somaliland, high BMI was associated with lower educational level and being married. Conclusion: The prevalence of overweight and obesity is high among Somali immigrants in Norway, but also among women in Somaliland. The high prevalence of overweight and obesity, particularly among women, calls for long-term prevention strategies. PMID- 30250752 TI - The changing forms and expectations of peer review. AB - The quality and integrity of the scientific literature have recently become the subject of heated debate. Due to an apparent increase in cases of scientific fraud and irreproducible research, some have claimed science to be in a state of crisis. A key concern in this debate has been the extent to which science is capable of self-regulation. Among various mechanisms, the peer review system in particular is considered an essential gatekeeper of both quality and sometimes even integrity in science. However, the allocation of responsibility for integrity to the peer review system is fairly recent and remains controversial. In addition, peer review currently comes in a wide variety of forms, developed in the expectation they can address specific problems and concerns in science publishing. At present, there is a clear need for a systematic analysis of peer review forms and the concerns underpinning them, especially considering a wave of experimentation fuelled by internet technologies and their promise to improve research integrity and reporting. We describe the emergence of current peer review forms by reviewing the scientific literature on peer review and by adding recent developments based on information from editors and publishers. We analyse the rationale for developing new review forms and discuss how they have been implemented in the current system. Finally, we give a systematisation of the range of discussed peer review forms. We pay detailed attention to the emergence of the expectation that peer review can maintain 'the integrity of science's published record', demonstrating that this leads to tensions in the academic debate about the responsibilities and abilities of the peer review system. PMID- 30250754 TI - Transcutaneous Puncture of an Undeflatable Coronary Angioplasty Balloon Catheter. AB - This case report describes a quick and safe method to successfully retrieve an undeflatable angioplasty balloon via the transradial access site. The article also presents potential mechanisms of contrast media entrapment and bench tests of guidewire-assisted balloon puncture. After successful stent implantation in the proximal right coronary artery in a 74-year-old female patient referred for acute coronary syndrome, the balloon catheter became undeflatable for an unknown reason. Several attempts to burst the balloon in the guide catheter and the aorta failed. After a pullback into the radial artery, the still inflated balloon became stuck again and was unable to be retrieved through the sheath. Finally, transcutaneous puncture and aspiration of contrast media with a 23 gauge syringe needle through the skin in the right forearm allowed deflation and successful removal the balloon. PMID- 30250756 TI - Cardiothoracic Area Ratio Predicts Lethal Pulmonary Venous Obstruction in Patients with Single Ventricle and Total Anomalous Pulmonary Venous Connection. AB - Background and Objectives When single ventricle (SV) is complicated with total anomalous pulmonary venous connection (TAPVC), the pulmonary vein obstruction (PVO) occurs at a high rate. There are some patients who died from the lethal PVO (l-PVO) which needed PVO release dead due to severe desaturation within 24 hours after birth. The purpose of this study was to find a predictive marker for l-PVO during the fetal period. Methods We enrolled 21 patients diagnosed with SV associated with TAPVC in the antenatal period. Ten patients had supracardiac, five had cardiac, five had infracardiac, and one had mixed TAPVC. We reviewed fetal echocardiography and measured cardiothoracic area ratio (CTAR) and total cardiac dimension (TCD). We divided 21 cases into l-PVO group (6) and non-l-PVO group (15) and compared the fetal echocardiography findings and postnatal prognoses between the groups. Results CTAR at the final fetal echocardiography was 16 to 29% (median: 21) in the l-PVO group and 22 to 38% (median: 28) in the non-l-PVO group ( p = 0.01). TCD/week at the final echocardiography was 0.67 to 1.0 (median: 0.77) in the l-PVO group and 0.78 to 1.2 (median: 0.96) in the non-l PVO group ( p = 0.02). Conclusion Reduced CTAR in the antenatal period is a good predictor of l-PVO after birth. PMID- 30250757 TI - A Novel Approach to Serial Amnioinfusion in a Case of Premature Rupture of Membranes Near the Limit of Viability. AB - Prelabor rupture of the membranes (PROM) near the limit of viability is associated with significant risks for both mother and fetus. Preterm labor, intra amniotic infection, and placental abruption are the immediate risks to the pregnancy; however, the fetus incurs additional risks related to the sequela of persistent oligohydramnios. Transabdominal intra-amniotic infusions have been studied. Results, suggesting that this intervention may prolong the latency period, and potentially, decrease pulmonary hypoplasia in surviving neonates without evidence of increasing risk of intra-amniotic infection. To our knowledge, the use of antibiotic-infused fluid has not been reported in this clinical scenario. Therefore, we present a case of a patient with PROM before the limit of viability who underwent serial transabdominal amnioinfusions with oxacillin-containing normal saline, which resulted in membrane resealing and neonatal survival with no additional maternal morbidity. PMID- 30250755 TI - Nickel(I) Aryl Species: Synthesis, Properties, and Catalytic Activity. AB - In this work, Ni(I) aryl species that are directly relevant to cross-coupling have been synthesized. Transmetalation of (dppf)NiIX (dppf = 1,1' bis(diphenylphosphino)-ferrocene, X = Cl, Br) with aryl Grignard reagents or aryl boronic acids in the presence of base produces Ni(I) aryl species of the form (dppf)NiI(Ar) (Ar = Ph, o-tolyl, 2,6-xylyl, 2,4,6-mesityl, 2,4,6-iPr3C6H2). The stability of the Ni(I) aryl species is inversely correlated to the steric bulk on the aryl ligand. The most unstable Ni(I) aryl species are the most active precatalysts for Suzuki-Miyaura reactions because they rapidly decompose to generate the active Ni(0) catalyst. This study shows that Ni(I) aryl species are initially formed in the activation of Ni(I) halide precatalysts for Suzuki Miyaura reactions and establishes their stoichiometric and catalytic reactivity profile. PMID- 30250758 TI - Uterine Monitoring Techniques from Patients' and Users' Perspectives. AB - Objective To evaluate preferences from patients and users on 3 uterine monitoring techniques, during labor. Study Design Women in term labor were simultaneously monitored with the intrauterine pressure catheter, the external tocodynamometer, and the electrohysterograph. Postpartum, these women filled out a questionnaire evaluating their preferences and important aspects. Nurses completed a questionnaire evaluating users' preferences. Results Of all 52 participating women, 80.8% preferred the electrohysterograph, 17.3% the intrauterine pressure catheter and 1.9% the external tocodynamometer. For these women, the electrohysterograph scored best regarding application and presence during labor ( p < 0.001). Most important aspects were "least likely to harm" and "least discomfort". Of 57 nurses, 40.4% preferred the electrohysterograph, 35.1% the external tocodynamometer, and 24.6% had no preference, or replied that their preference is subject to situation and patient. Conclusion Patients prefer the electrohysterograph over the external tocodynamometer and the intrauterine pressure catheter, while healthcare providers report ambiguous results. PMID- 30250759 TI - Monitoring of Blood Pressure is not Enough to Avoid Neonatal Postoperative Encephalopathy. AB - Background Neonatal encephalopathy with seizures after general anesthesia not occurring in infants undergoing cardiac or major neurosurgery is very uncommon. An ischemic origin due to cerebral hypoperfusion from perioperative hypotension has been suggested, but there is a lack of a consensus definition for intraoperatory hypotension in neonates. Case Report We report the first case of neonatal encephalopathy with seizures in a neonate with anorectal malformation. He underwent a colostomy with caudal anesthesia combined with light general anesthesia. Intraoperative systolic blood pressure and mean blood pressure values were considered normal. Thirty-two hours after the intervention, the patient presented electroclinical seizures. Diffusion-weighted imaging showed bilateral involvement with reduced diffusivity in the watershed areas of the middle cerebral artery and posterior cerebral artery. Conclusion Perioperative monitoring of blood pressure is not enough in neonatal surgery. Cerebral magnetic resonance imaging should be considered in infants with noncardiac congenital anomalies after neonatal surgery and long-term follow-up is required. PMID- 30250761 TI - Breast Cancer Risk Among Women in Jail. AB - Over 200,000 women are diagnosed with breast cancer each year, and incarcerated women face unique risks associated with poor access to healthcare. Regular mammography can diagnose breast cancer early, giving the patient the best chance of survival. The objective of this study was to determine the proportion of jail incarcerated women who have received a mammogram and were up-to-date based on the most recent United States Preventive Services Task Force recommendations. This was a secondary analysis of data collected among jailed women who participated in a cervical cancer literacy program. Rates of mammography were calculated for the group overall and for those women 50 years or older. Subgroups were compared using chi-squared tests. Two hundred sixty-one women were included in the analysis, of which 42.1% (N = 110) had ever had a mammogram. Of women 50 years old or older (N = 28), 75.0% had ever received a mammogram, yet only 39.3% were up-to-date (within the past 2 years). Factors associated with up-to-date mammography included being up-to-date on cervical cancer screening (76.9%) compared with women who were not up-to-date on cervical cancer screening (12.5%), p < 0.01, and women experiencing intimate partner violence (IPV) in the past year (71.4%) compared with women with no IPV in the past year (14.2%), p = 0.02. The low rates of up-to-date mammography highlight the need for more breast cancer prevention programming among women with criminal justice histories. PMID- 30250762 TI - Longitudinal Relations Between Depressive Symptoms and Executive Functions From Adolescence to Early Adulthood: A Twin Study. AB - Depression is associated with deficits in executive functions (EFs)-cognitive control abilities that regulate goal-directed thoughts and actions-but the etiology of these associations is unclear. We examined the relations between depressive symptoms and multiple EF latent variables in a population-based sample of 439 twin pairs assessed at mean ages 12, 17, and 23 years. Greater depressive symptoms negatively related to a Common EF factor capturing shared variance across response inhibition, working memory updating, and mental set shifting tasks, and also negatively related to an Updating-Specific factor, but not a Shifting-Specific factor. Cross-lagged panel models suggested that the Common EF correlations reflected within-wave associations rather than prospective effects, whereas the Updating-Specific correlations reflected associations of earlier depression levels with later Updating-Specific ability. Twin models were consistent with a model in which Common EF and Updating-Specific abilities relate to depression through correlated genetic risk, with no significant environmental correlations. PMID- 30250763 TI - Knowledge, Attitudes, and Practices Among Nurses in Pakistan Towards Diabetic Foot. AB - Introduction Diabetic foot ulcers are a pressing complication of diabetes mellitus. Wound care requires a significant proportion of healthcare resources. It is imperative, therefore, for healthcare professionals to possess sound knowledge of the disease along with a positive attitude to ensure better clinical practice. Our literature search revealed a scarcity of data pertaining to diabetic foot ulcers. Therefore, this study aims to evaluate the knowledge and attitudes of nurses regarding diabetic foot care. Methods A cross-sectional study design was employed, a pre-validated and pre-tested questionnaire was used to collect data from a sample size of 250 nurses working at two tertiary care hospitals in Karachi, Pakistan. The study was conducted over a period of three months (January to March 2018) and included all nurses who possessed at least one year of clinical experience in diabetic ulcer care. The statistical software employed was SPSS version 19 (IBM Corp., Armonk, NY, US). Non-parametric tests and descriptive statistics were used for data analysis and statistical significance was assumed at a p-value of less than 0.5. Results Only 54% of the nurses in our study possessed adequate knowledge of diabetic foot ulcers. The mean score of knowledge was 74.9 (+/-9.5). Macdonald's standard criteria for learning outcomes was used to gauge the knowledge levels of our study population. Nurses performed best in the domain of ulcer care with 65.3% of the participants possessing good knowledge of the topic. The overall attitude of nurses towards patients with diabetic ulcers was positive. Conclusion This study highlights important gaps in nurses' knowledge and sheds light on the lack of evidence-based practice. Poor knowledge can compromise healthcare standards, even with the presence of positive attitudes. Hence, a comprehensive revision of nursing curricula across local tertiary hospitals for allowing nurses to update their knowledge is warranted. PMID- 30250764 TI - Post-traumatic Cavernous Carotid Pseudoaneurysm with Delayed Epistaxis. AB - Cavernous carotid aneurysms (CCAs) pose considerable dilemmas in management. Delayed post-traumatic epistaxis is a rare presentation of CCA. Clinically, the symptomatic triad of unilateral blindness, orbital fractures, and massive epistaxis is pathognomonic for internal carotid artery (ICA) pseudoaneurysm. The epistaxis is usually profound, intermittent, and life-threatening in nature. As most of these cases are initially seen by a physician, a high index of suspicion is essential during its early identification. Traumatic aneurysms are pseudoaneurysms with a fibrous wall that rupture and cause massive epistaxis resulting from disruption through the sphenoid sinus wall. We report a young adult who presented with the triad and severe anemia four months following head injury. He was treated with ligation of the carotid artery and a high-flow extracranial-intracranial (EC-IC) bypass. In the era of endovascular coiling and flow diverters, EC-IC bypass still has a role in the treatment of complex giant aneurysms with comparable results. PMID- 30250765 TI - Osteoma Cutis and Tonsillolith: A Cone Beam Computed Tomography Study. AB - In this study, we report a rare case of osteoma cutis (OC) and tonsillolith, diagnosed using cone beam computed tomography. The dystrophic calcifications in the face and tonsils were incidentally found during examination of the patient's scan with no relation to the main chief complaint. The diagnosis was OC, combined with dystrophic calcification of the tonsils. It is important to mention that OC is a rare soft-tissue ossification of cutaneous tissue, typically on the face and clinically asymptomatic. It may be primary but the majority of cases are secondary. Incidental finding of OC and tonsilloliths on a two-dimensional dental radiograph does not provide sufficient information concerning the location of these calcifications. Thus, cone beam computed tomography (CBCT) provides critical information for the diagnosis of asymptomatic OC lesions not available through any other means of clinical detection. PMID- 30250760 TI - Mechanisms for estrogen receptor expression in human cancer. AB - Estrogen is a steroid hormone that has critical roles in reproductive development, bone homeostasis, cardiovascular remodeling and brain functions. However, estrogen also promotes mammary, ovarian and endometrial tumorigenesis. Estrogen antagonists and drugs that reduce estrogen biosynthesis have become highly successful therapeutic agents for breast cancer patients. The effects of estrogen are largely mediated by estrogen receptor (ER) alpha and ERbeta, which are members of the nuclear receptor superfamily of transcription factors. The mechanisms underlying the aberrant expression of ER in breast cancer and other types of human tumors are complex, involving considerable alternative splicing of ERalpha and ERbeta, transcription factors, epigenetic and post-transcriptional regulation of ER expression. Elucidation of mechanisms for ER expression may not only help understand cancer progression and evolution, but also shed light on overcoming endocrine therapy resistance. Herein, we review the complex mechanisms for regulating ER expression in human cancer. PMID- 30250766 TI - Idiopathic Hyperprolactinemia Presenting as Polycystic Ovary Syndrome in Identical Twin Sisters: A Case Report and Literature Review. AB - This case report describes 15-year-old identical twin sisters, who presented to us with features of polycystic ovary syndrome (PCOS). A biochemical workup revealed hyperinsulinemia and androgen excess with elevated prolactin levels. The possible etiologies for hyperprolactinemia were excluded with a detailed evaluation and it was labeled as idiopathic. Considering the fact that androgen excess could be caused by either insulin resistance or hyperprolactinemia, we decided to treat one sister with insulin sensitizer metformin and other with dopamine agonist cabergoline. While cabergoline treatment resulted in normalization of prolactin levels and androgen excess, no significant biochemical or clinical improvement occurred with metformin treatment. Hyperprolactinemia was therefore considered to be the cause of androgen excess in both and cabergoline therapy initiated in the other sister as well. Through the report, we conclude that diagnosis of PCOS should be made only after exclusion of alternative causes like hyperprolactinemia and detailed evaluation should be sought for any significant, unexplained prolactin elevation. Although rare, hyperprolactinemia can lead to androgen excess by increasing adrenal androgen secretion, which improves with dopamine agonist therapy. PMID- 30250767 TI - Erythroderma: A Rare Complication of Dyshidrotic Eczema. AB - A 47-year-old man with a history of dyshidrotic eczema presented to the emergency department with diffuse erythema, chills and pruritus of three weeks' duration. The patient had received two injections of methotrexate in the preceding two weeks, both of which had failed to improve his whole-body erythema and pruritus. In the emergency department, the patient was evaluated for infection and admitted for the dermatology consultation. After being seen on the general medical floor by the dermatology service the diagnosis of erythroderma was made and the patient was treated with intravenous (IV) cyclosporine therapy, with which his rash dramatically improved over three days. This case report summarizes the presentation and differential of erythroderma, and highlights the importance of having a high index of suspicion for this potentially fatal disease. PMID- 30250768 TI - Early Versus Delayed Double J Stent Removal in Deceased Donor Renal Transplant Recipients: A Prospective Comparative Study. AB - INTRODUCTION: Prophylactic ureteric stents have been commonly employed to reduce the incidence of ureteric obstruction and anastomotic leaks following renal transplantation. There are very few studies on the duration of ureteric stenting in deceased donor renal transplantation (DDRT). We performed a prospective study to compare early and late double J stent removal in DDRT. AIMS AND METHODS: The aim of this study was to compare the early and delayed removal of ureteric stents after DDRT. We performed 80 DDRTs at our center from August 2012 to December 2016, which were included in the study. However, we enrolled 48 patients as the remaining had to be excluded based on the high-risk factors. The recipients were allocated on the 14th postoperative day to two groups. Group 1 underwent early stent removal on the fourteenth postoperative day and in group 2, the stent was removed in the sixth postoperative week. The two groups were followed up for six months and the incidence of urological complications and urinary tract infections (UTI) was compared. RESULTS: The incidence of UTI during the follow-up period of six months was significantly lower in the early stent removal group (two out of 24) than in delayed stent removal group (eight out of 24) (p=0.016). Asymptomatic bacteriuria occurred in six out of 24 (25%) in group 1 and 10 out of 24 (41.6%) in group 2 (p=0.120). There was no significant difference in the incidence of urinary leak, hematuria, or ureteric obstruction between the two groups (p=0.900). However, stent-related symptoms were significantly more in the delayed stent removal group (three in group 1 versus 18 in group 2) (p=0.001). CONCLUSION: Prolonged stenting is associated with an increased risk of UTI and stent-related symptoms in immunosuppressed renal transplant recipients. The early removal of double J stents can be done in carefully selected patients to reduce stent-related complications in DDRT. PMID- 30250769 TI - Neisseria cinerea in a Post-splenectomy Patient: A Rare Potentially Fatal Bacteremia. AB - Neisseria cinerea is a commensal which usually resides in the human respiratory tract. Very rarely, the organism finds its way into the bloodstream causing severe bacteremia. So far, very few cases of Neisseria bacteremia have been reported. We report a case of a 78-year-old male, post-splenectomy, who presented with high fever, cough and shortness of breath. The patient was initially managed for septic shock with fluid resuscitations, vasopressors and broad-spectrum antibiotics. Later, the blood cultures grew gram-negative coccobacilli, Neisseria cinerea. The patient was successfully treated with intravenous ceftriaxone. This is the first case ever of Neisseria cinerea bacteremia in a post-splenectomy patient and ninth case overall. This case illustrates that the physicians should maintain heightened awareness for Neisseria cinerea bacteremia in post splenectomy patients. PMID- 30250770 TI - Intra-articular Large Ossicle Associated to Osgood-Schlatter Disease. AB - Osgood-Schlatter disease (OSD) is known as a self-limiting condition but surgical excision of the ossicles may be required in adults resistant to conservative treatments. The ossicle associated to OSD is generally small and located outside the joint near the tibial tubercle; however, large or intra-articular ossicle has been reported rarely. Here, we report an unusual case of OSD with a separated, large-sized ossicle that protruded into the knee joint and treated by arthroscopy assisted excision of the ossicle. PMID- 30250772 TI - Flexibility of the "rigid" classics or rugged bottom of the folding funnels of myoglobin, lysozyme, RNase A, chymotrypsin, cytochrome c, and carboxypeptidase A1. AB - The abilities to crystalize of a globular protein and to solve its crystal structure seem to represent triumph of the lock-and-key model of protein functionality, where the presence of unique 3D structure resembling aperiodic crystal is considered as a prerequisite for a given protein to possess specific biologic activity. The history of protein crystallography has its roots in first crystal structures of myoglobin, lysozyme, RNase A, chymotrypsin, cytochrome c, and carboxypeptidase A1 solved more than 50 y ago. This article briefly considers extensive structural information currently available for these proteins and shows that the bottoms of their folding funnels (i.e., the lowest parts of their potential energy landscapes) are not smoothed but rugged. In other words, these crystallization classics are characterized by significant conformational flexibility and are not rigid (immobile) crystal-like entities. PMID- 30250774 TI - A Convolutional Neural Network Smartphone App for Real-Time Voice Activity Detection. AB - This paper presents a smartphone app that performs real-time voice activity detection based on convolutional neural network. Real-time implementation issues are discussed showing how the slow inference time associated with convolutional neural networks is addressed. The developed smartphone app is meant to act as a switch for noise reduction in the signal processing pipelines of hearing devices, enabling noise estimation or classification to be conducted in noise-only parts of noisy speech signals. The developed smartphone app is compared with a previously developed voice activity detection app as well as with two highly cited voice activity detection algorithms. The experimental results indicate that the developed app using convolutional neural network outperforms the previously developed smartphone app. PMID- 30250771 TI - Paradoxes and wonders of intrinsic disorder: Stability of instability. AB - This article continues a series of short comments on the paradoxes and wonders of the protein intrinsic disorder phenomenon by introducing the "stability of instability" paradox. Intrinsically disordered proteins (IDPs) are characterized by the lack of stable 3D-structure, and, as a result, have an exceptional ability to sustain exposure to extremely harsh environmental conditions (an illustration of the "you cannot break what is already broken" principle). Extended IDPs are known to possess extreme thermal and acid stability and are able either to keep their functionality under these extreme conditions or to rapidly regain their functionality after returning to the normal conditions. Furthermore, sturdiness of intrinsic disorder and its capability to "ignore" harsh conditions provides some interesting and important advantages to its carriers, at the molecular (e.g., the cell wall-anchored accumulation-associated protein playing a crucial role in intercellular adhesion within the biofilm of Staphylococcus epidermidis), supramolecular (e.g., protein complexes, biologic liquid-liquid phase transitions, and proteinaceous membrane-less organelles), and organismal levels (e.g., the recently popularized case of the microscopic animals, tardigrades, or water bears, that use intrinsically disordered proteins to survive desiccation). PMID- 30250773 TI - How accurate are your simulations? Effects of confined aqueous volume and AMBER FF99SB and CHARMM22/CMAP force field parameters on structural ensembles of intrinsically disordered proteins: Amyloid-beta42 in water. AB - Amyloid-beta42 (Abeta42) is an intrinsically disordered peptide intimately related to the pathogenesis of several neurodegenerative diseases. Molecular dynamics (MD) simulations are extensively utilized in the characterization of the structures and conformational dynamics of intrinsically disordered proteins (IDPs) including Abeta42, with AMBER and CHARMM parameters being commonly used in these studies. Recently, comparison of the effects of force field parameters on the Abeta42 structures has started to gain significant attention. In this study, the structures of Abeta42 are simulated using AMBER FF99SB and CHARMM22/CMAP parameters via replica exchange MD simulations utilizing a widely used clustering algorithm. These analyses show that the structural properties (extent and positioning of the elements of secondary and tertiary structure), radius of gyration values, number and position of salt bridges are extremely dependent on the chosen force field parameters notably with the usage of clustering algorithms. For example, predicted secondary structure elements, which are of the great importance for better understanding of the molecular mechanisms of neurodegenerative diseases, deviate enormously in models generated using currently available force field parameters for proteins. Based on the derived models, chemical shift values are calculated and compared to the experimentally determined data. This comparison revealed that although both force field parameters yield results in agreement with experiments, the obtained structural properties were rather different using a clustering algorithm. In other words, these results show that the predicted structures depend heavily on the force field parameters. Importantly, since none of the force field parameters currently utilized in MD studies were developed specifically taking into account the disordered nature of IDPs, these findings clearly indicate that new force field parameters have to be developed for IDPs considering their rapid flexibility and dynamics with high amplitude. Furthermore, molecular simulations of IDPs are typically conducted using one water volume. We show that the confined aqueous volume impacts the predicted structural properties of Abeta42 in water. Although up to date, confined aqueous volume effects have been ignored in the MD simulations of IDPs in water, our data indicate that these effects have to be taken into account in predicting the structural and thermodynamic properties of disordered proteins in solution. PMID- 30250775 TI - Influence of various parameters in the replica-exchange molecular dynamics method: Number of replicas, replica-exchange frequency, and thermostat coupling time constant. AB - The replica-exchange molecular dynamics (REMD) method has been used for conformational sampling of various biomolecular systems. To maximize sampling efficiency, some adjustable parameters must be optimized. Although it is agreed that shorter intervals between the replica-exchange attempts enhance traversals in the temperature space, details regarding the artifacts caused by these short intervals are controversial. In this study, we revisit this problem by performing REMD simulations on an alanine octapeptide in an implicit solvent. Fifty different sets of conditions, which are a combination of five replica-exchange periods, five different numbers of replicas, and two thermostat coupling time constants, were investigated. As a result, although short replica-exchange intervals enhanced the traversals in the temperature space, they led to artifacts in the ensemble average of the temperature, potential energy, and helix content. With extremely short replica-exchange intervals, i.e., attempted at every time step, the ensemble average of the temperature deviated from the thermostat temperature by ca. 7 K. Differences in the ensembles were observed even for larger replica-exchange intervals (between 100 and 1,000 steps). In addition, the shorter thermostat coupling time constant reduced the artifacts found when short replica-exchange intervals were used, implying that these artifacts are caused by insufficient thermal relaxation between the replica-exchange events. Our results will be useful to reduce the artifacts found in REMD simulations by adjusting some key parameters. PMID- 30250777 TI - Plant-Based Antioxidant Nanoparticles without Biological Toxicity. AB - Here, we present a function to derive non-deteriorated nanoparticulated lignin as an antioxidant without biological toxicity that is supplied through the simultaneous enzymatic saccharification and comminution of plants. The lignin exhibits an oxygen radical absorption capacity, even in its macromolecular nature. The non-deteriorated lignin nanoparticles never inhibit the biological activity of living things, despite their antioxidant nature. The oxygen radical absorption capacity of lignin is dependent on its botanical origin and monomeric structure. A stable organic radical in lignin is responsible for the antioxidant nature of non-deteriorated lignin. The organic radical of non-deteriorated lignin, which yields a distinct signal on electron spin resonance spectra, serves as a spin trap reagent that detects the emergence of short lifespan radicals as the change of radical concentration of the lignin. The presented discovery of non deteriorated lignin will induce not only the industrial utilization of plant biomass polymers in pharmaceuticals and reagents, but also advance our scientific understanding of the antioxidant function of native lignin. PMID- 30250776 TI - Novel insight into an energy transduction mechanism of the bacterial flagellar type III protein export. AB - Type III secretion system (T3SS) is a protein translocator complex family including pathogenic injectisome or bacterial flagellum. The inejectisomal T3SS serves to deliver virulence proteins into host cell and the flagellar T3SS constructs the flagellar axial structure. Although earlier studies have provided many findings on the molecular mechanism of the Type III protein export, they were not sufficient to reveal energy transduction mechanism due to difficulties in controlling measurement conditions in vivo. Recently, we developed an in vitro flagellar Type III protein transport assay system using inverted membrane vesicles (IMVs), and analyzed protein export by using the in vitro method. We reproduced protein export of the flagellar T3SS, hook assembly and substrate specificity switch in IMV to a similar extent to what is seen in living cell. Furthermore, we demonstrated that ATP-hydrolysis energy can drive protein transport even in the absence of proton-motive force (PMF). In this mini-review, we will summarize our new in vitro Type III transport assay method and our findings on the molecular mechanism of Type III protein export. PMID- 30250778 TI - Simultaneous Suppression of the Dendrite Formation and Shuttle Effect in a Lithium-Sulfur Battery by Bilateral Solid Electrolyte Interface. AB - Although the reversible and inexpensive energy storage characteristics of the lithium-sulfur (Li-S) battery have made it a promising candidate for electrical energy storage, the dendrite growth (anode) and shuttle effect (cathode) hinder its practical application. Here, it is shown that new electrolytes for Li-S batteries promote the simultaneous formation of bilateral solid electrolyte interfaces on the sulfur-host cathode and lithium anode, thus effectively suppressing the shuttle effect and dendrite growth. These high-capacity Li-S batteries with new electrolytes exhibit a long-term cycling stability, ultrafast charge/slow-discharge rates, super-low self-discharge performance, and a capacity retention of 94.9% even after a 130 d long storage. Importantly, the long cycle stability of these industrial grade high-capacity Li-S pouch cells with new electrolytes will provide the basis for creating robust energy dense Li-S batteries with an extensive life cycle. PMID- 30250779 TI - Solution-Processed Bilayer Dielectrics for Flexible Low-Voltage Organic Field Effect Transistors in Pressure-Sensing Applications. AB - Flexible pressure sensors based on organic field-effect transistors (OFETs) have emerged as promising candidates for electronic-skin applications. However, it remains a challenge to achieve low operating voltages of hysteresis-free flexible pressure sensors. Interface engineering of polymer dielectrics is a feasible strategy toward sensitive pressure sensors based on low-voltage OFETs. Here, a novel type of solution-processed bilayer dielectrics is developed by combining a thick polyelectrolyte layer of polyacrylic acid (PAA) with a thin poly(methyl methacrylate) (PMMA) layer. This bilayer dielectric can provide a vertical phase separation structure from hydrophilic interface to hydrophobic interface which adjoins well to organic semiconductors, leading to improved stability and remarkably reduced leakage currents. Consequently, OFETs using the PMMA/PAA dielectrics reveal greatly suppressed hysteresis and improved mobility compared to those with a pure PAA dielectric. Using the optimized PMMA/PAA dielectric, flexible OFET-based pressure sensors that show a record high sensitivity of 56.15 kPa-1 at a low operating voltage of -5 V, a fast response time of less than 20 ms, and good flexibility are further demonstrated. The salient features of high capacitance, good dielectric performance, and excellent reliability of the bilayer dielectrics promise a bright future of flexible sensors based on low voltage OFETs for wearable electronic applications. PMID- 30250780 TI - Coordination-Responsive Longitudinal Relaxation Tuning as a Versatile MRI Sensing Protocol for Malignancy Targets. AB - Biomarkers (e.g., acidity, H2O2, hypoxia, and specific molecules) as one primary component of tumor microenvironments are closely associated with occurrence, invasion, and metastasis of malignancy, thus can act as biological targets. However, their monitoring remains a challenging task. Herein, a coordination dependent longitudinal relaxation tuning (CLRT) that occurs between a Mn2+ "donor" and a Mn2+ "acceptor" is established to enable biological target sensing. Relying on the differences of coordination ability and spatial structure between donors and acceptors, the biological targets as Mn2+ acceptor can take Mn2+ away from the donors (i.e., modified ligands) in nanoscale probes, which consequently varies T1-weighted (T1W) magnetic resonance imaging (MRI) signal. The coordination ability and spatial structure of the modified Mn2+ "donor" and the pore diameter of donor carrier are demonstrated to determine the feasibility, specificity, and generality of CLRT. With CLRT, this MRI-based ruler is demonstrated for the successful specific detection of biological targets (i.e., hyaluronic acid and glutathione) of malignancy, and its potential in quantitative measurement of hyaluronic acid is further demonstrated. CLRT can serve as a novel and general sensing principle to augment the exploration of a wide range of biological systems. PMID- 30250781 TI - Chemically Propelled Motors Navigate Chemical Patterns. AB - Very small synthetic motors that use chemical reactions to drive their motion are being studied widely because of their potential applications, which often involve active transport and dynamics on nanoscales. Like biological molecular machines, they must be able to perform their tasks in complex, highly fluctuating environments that can form chemical patterns with diverse structures. Motors in such systems can actively assemble into dynamic clusters and other unique nonequilibrium states. It is shown how chemical patterns with small characteristic dimensions may be utilized to suppress rotational Brownian motions of motors and guide them to move along prescribed paths, properties that can be exploited in applications. In systems with larger pattern length scales, domains can serve as catch basins for motors through chemotactic effects. The resulting collective motor dynamics in such confining domains can be used to explore new aspects of active particle collective dynamics or promote specific types of active self-assembly. More generally, when chemically self-propelled motors operate in far-from-equilibrium active chemical media the variety of possible phenomena and the scope of their potential applications are substantially increased. PMID- 30250782 TI - A Novel On-Chip Method for Differential Extraction of Sperm in Forensic Cases. AB - One out of every six American women has been the victim of a sexual assault in their lifetime. However, the DNA casework backlog continues to increase outpacing the nation's capacity since DNA evidence processing in sexual assault casework remains a bottleneck due to laborious and time-consuming differential extraction of victim's and perpetrator's cells. Additionally, a significant amount (60-90%) of male DNA evidence may be lost with existing procedures. Here, a microfluidic method is developed that selectively captures sperm using a unique oligosaccharide sequence (Sialyl-LewisX), a major carbohydrate ligand for sperm egg binding. This method is validated with forensic mock samples dating back to 2003, resulting in 70-92% sperm capture efficiency and a 60-92% reduction in epithelial fraction. Captured sperm are then lysed on-chip and sperm DNA is isolated. This method reduces assay-time from 8 h to 80 min, providing an inexpensive alternative to current differential extraction techniques, accelerating identification of suspects and advancing public safety. PMID- 30250783 TI - Robust Sandwich-Structured Nanofluidic Diodes Modulating Ionic Transport for an Enhanced Electrochromic Performance. AB - Biomimetic solid-state nanofluidic diodes have attracted extensive research interest due to the possible applications in various fields, such as biosensing, energy conversion, and nanofluidic circuits. However, contributions of exterior surface to the transmembrane ionic transport are often ignored, which can be a crucial factor for ion rectification behavior. Herein, a rational design of robust sandwich-structured nanofluidic diode is shown by creating opposite charges on the exterior surfaces of a nanoporous membrane using inorganic oxides with distinct isoelectric points. Potential-induced changes in ion concentration within the nanopores lead to a current rectification; the results are subsequently supported by a theoretical simulation. Except for providing surface charges, functional inorganic oxides used in this work are complementary electrochromic materials. Hence, the sandwich-structured nanofluidic diode is further developed into an electrochromic membrane exhibiting a visual color change in response to redox potentials. The results show that the surface-charge governed ionic transport and the nanoporous structure facilitate the migration of Li+ ions, which in turn enhance the electrochromic performance. It is envisioned that this work will create new avenues to design and optimize nanofluidic diodes and electrochromic devices. PMID- 30250784 TI - Independent Band Modulation in 2D van der Waals Heterostructures via a Novel Device Architecture. AB - Benefiting from the technique of vertically stacking 2D layered materials (2DLMs), an advanced novel device architecture based on a top-gated MoS2/WSe2 van der Waals (vdWs) heterostructure is designed. By adopting a self-aligned metal screening layer (Pd) to the WSe2 channel, a fixed p-doped state of the WSe2 as well as an independent doping control of the MoS2 channel can be achieved, thus guaranteeing an effective energy-band offset modulation and large through current. In such a device, under specific top-gate voltages, a sharp PN junction forms at the edge of the Pd layer and can be effectively manipulated. By varying top-gate voltages, the device can be operated under both quasi-Esaki diode and unipolar-Zener diode modes with tunable current modulations. A maximum gate coupling efficiency as high as ~90% and a subthreshold swing smaller than 60 mV dec-1 can be achieved under the band-to-band tunneling regime. The superiority of the proposed device architecture is also confirmed by comparison with a traditional heterostructure device. This work demonstrates the feasibility of a new device structure based on vdWs heterostructures and its potential in future low-power electronic and optoelectronic device applications. PMID- 30250785 TI - A Modular Assembly of Spinal Cord-Like Tissue Allows Targeted Tissue Repair in the Transected Spinal Cord. AB - Tissue engineering-based neural construction holds promise in providing organoids with defined differentiation and therapeutic potentials. Here, a bioengineered transplantable spinal cord-like tissue (SCLT) is assembled in vitro by simulating the white matter and gray matter composition of the spinal cord using neural stem cell-based tissue engineering technique. Whether the organoid would execute targeted repair in injured spinal cord is evaluated. The integrated SCLT, assembled by white matter-like tissue (WMLT) module and gray matter-like tissue (GMLT) module, shares architectural, phenotypic, and functional similarities to the adult rat spinal cord. Organotypic coculturing with the dorsal root ganglion or muscle cells shows that the SCLT embraces spinal cord organogenesis potentials to establish connections with the targets, respectively. Transplantation of the SCLT into the transected spinal cord results in a significant motor function recovery of the paralyzed hind limbs in rats. Additionally, targeted spinal cord tissue repair is achieved by the modular design of SCLT, as evidenced by an increased remyelination in the WMLT area and an enlarged innervation in the GMLT area. More importantly, the pro-regeneration milieu facilitates the formation of a neuronal relay by the donor neurons, allowing the conduction of descending and ascending neural inputs. PMID- 30250786 TI - Origin, Genetic Diversity, and Evolutionary Dynamics of Novel Porcine Circovirus 3. AB - Porcine circovirus 3 (PCV3) is a novel virus associated with acute PDNS (porcine dermatitis and nephropathy syndrome)-like clinical signs identified by metagenomic sequencing from swine. Its high occurrence may pose a potential threat to the swine industry worldwide. The processes resulting in the emergence and spread of PCV3 remain poorly understood. Herein, the possible origin, genotypes, and evolutionary dynamics of PCV3 based on available genomic sequences are determined. The closest ancestor of PCV3 is found to be within the clade 1 bat CVs. Using different phylogenetic methods, two major genotypes are identified, PCV3a and PCV3b. It is found that the effective population size of PCV3 increased rapidly during late 2013 to early 2014 and this is associated with the diversification of PCV3a and PCV3b. A relatively high effective reproductive number (Re) value and higher evolutionary rate were found compared to other single-stranded DNA viruses, and positive selection on codons 122 and 320 (24 of ORF2) is identified. It is hypothesized that this, together with the prediction of a potential change of an antigenic epitope at position 320, might have allowed PCV3 to escape from the host immune response. Overall, this study has important implications for understanding the ongoing PCV3 cases worldwide and will guide future efforts to develop effective preventive and control measures. PMID- 30250787 TI - Origin and Perspectives of the Photochemical Activity of Nanoporous Carbons. AB - Even though, owing to the complexity of nanoporous carbons' structure and chemistry, the origin of their photoactivity is not yet fully understood, the recent works addressed here clearly show the ability of these materials to absorb light and convert the photogenerated charge carriers into chemical reactions. In many aspects, nanoporous carbons are similar to graphene; their pores are built of distorted graphene layers and defects that arise from their amorphicity and reactivity. As in graphene, the photoactivity of nanoporous carbons is linked to their semiconducting, optical, and electronic properties, defined by the composition and structural defects in the distorted graphene layers that facilitate the exciton splitting and charge separation, minimizing surface recombination. The tight confinement in the nanopores is critical to avoid surface charge recombination and to obtain high photochemical quantum yields. The results obtained so far, although the field is still in its infancy, leave no doubts on the possibilities of applying photochemistry in the confined space of carbon pores in various strategic disciplines such as degradation of pollutants, solar water splitting, or CO2 mitigation. Perhaps the future of photovoltaics and smart-self-cleaning or photocorrosion coatings is in exploring the use of nanoporous carbons. PMID- 30250790 TI - Fluorination-Enhanced Ambient Stability and Electronic Tolerance of Black Phosphorus Quantum Dots. AB - The environmental instability and uneliminable electronic trap states in black phosphorus quantum dots (BPQDs) limit the optoelectronics and related applications of BPQDs. Here, fluorinated BPQDs (F-BPQDs) are successfully synthesized by using a facile electrochemical exfoliation and synchronous fluorination method. The F-BPQDs exhibit robust ambient stability and limited fluorination capability, showing a nonstoichiometric fluorination degree (DF) maximum of ~0.68. Density functional theory calculations confirm that due to the edge etching effect of fluorine adatoms, the simulated F-BPQDs become structurally unstable when DF surpasses the limit. Furthermore, the trap states of BPQDs can be effectively eliminated via fluorination to obtain a coordination number of 3 or 5 for fluorinated and unfluorinated phosphorus atoms. The results reveal that the air-stable F-BPQDs exhibit fluorine defect-enhanced electronic tolerance, which is crucial for nanophotonics and nanoelectronics applications. PMID- 30250789 TI - 3D Nanofabrication of High-Resolution Multilayer Fresnel Zone Plates. AB - Focusing X-rays to single nanometer dimensions is impeded by the lack of high quality, high-resolution optics. Challenges in fabricating high aspect ratio 3D nanostructures limit the quality and the resolution. Multilayer zone plates target this challenge by offering virtually unlimited and freely selectable aspect ratios. Here, a full-ceramic zone plate is fabricated via atomic layer deposition of multilayers over optical quality glass fibers and subsequent focused ion beam slicing. The quality of the multilayers is confirmed up to an aspect ratio of 500 with zones as thin as 25 nm. Focusing performance of the fabricated zone plate is tested toward the high-energy limit of a soft X-ray scanning transmission microscope, achieving a 15 nm half-pitch cut-off resolution. Sources of adverse influences are identified, and effective routes for improving the zone plate performance are elaborated, paving a clear path toward using multilayer zone plates in high-energy X-ray microscopy. Finally, a new fabrication concept is introduced for making zone plates with precisely tilted zones, targeting even higher resolutions. PMID- 30250788 TI - Fiber-Type Solar Cells, Nanogenerators, Batteries, and Supercapacitors for Wearable Applications. AB - Wearable electronic devices represent a paradigm change in consumer electronics, on-body sensing, artificial skins, and wearable communication and entertainment. Because all these electronic devices require energy to operate, wearable energy systems are an integral part of wearable devices. Essentially, the electrodes and other components present in these energy devices should be mechanically strong, flexible, lightweight, and comfortable to the user. Presented here is a critical review of those materials and devices developed for energy conversion and storage applications with an objective to be used in wearable devices. The focus is mainly on the advances made in the field of solar cells, triboelectric generators, Li-ion batteries, and supercapacitors for wearable device development. As these devices need to be attached/integrated with the fabric, the discussion is limited to devices made in the form of ribbons, filaments, and fibers. Some of the important challenges and future directions to be pursued are also highlighted. PMID- 30250791 TI - Red Organic Light-Emitting Diode with External Quantum Efficiency beyond 20% Based on a Novel Thermally Activated Delayed Fluorescence Emitter. AB - A novel thermally activated delayed fluorescence (TADF) emitter 12,15-di(10H phenoxazin-10-yl)dibenzo[a,c]dipyrido[3,2-h:2',3'-j]phenazine (DPXZ-BPPZ) is developed for a highly efficient red organic light-emitting diode (OLED). With rigid and planar constituent groups and evident steric hindrance between electron donor (D) and electron-acceptor (A) segments, DPXZ-BPPZ realizes extremely high rigidity to suppress the internal conversion process. Meanwhile, the highly twisted structure between D and A segments will also lead to an extremely small singlet-triplet energy split to DPXZ-BPPZ. Therefore, DPXZ-BPPZ successfully realizes an efficient fluorescent radiation transition and reverse intersystem crossing process, and possesses an extremely high photoluminescence quantum efficiency of 97.1 +/- 1.1% under oxygen-free conditions. The OLED based on DPXZ BPPZ shows red emission with a peak at 612 nm and a Commission Internationale de L'Eclairage (CIE) coordinate of (0.60, 0.40), and it achieves high maximum forward-viewing efficiencies of 20.1 +/- 0.2% (external quantum efficiency), 30.2 +/- 0.6 cd A-1 (current efficiency), and 30.9 +/- 1.3 lm W-1 (power efficiency). The prepared OLED has the best performance among the reported red TADF OLEDs. These results prove that DPXZ-BPPZ is an ideal candidate for red TADF emitters, and the designing approach is valuable for highly efficient red TADF emitters. PMID- 30250792 TI - In Situ Formed Protective Barrier Enabled by Sulfur@Titanium Carbide (MXene) Ink for Achieving High-Capacity, Long Lifetime Li-S Batteries. AB - Sulfur (S) is an attractive cathode material with advantages including high theoretical capacity and low cost. However, issues such as the lithium polysulfide shuttle effect and its insulating properties greatly limit the future applications of lithium-sulfur (Li-S) batteries. Here, a viscous aqueous ink with nanoscale S uniformly decorated on the polar, metallically conductive titanium carbide MXene nanosheets (S@Ti3C2T x ) is reported to address these issues. Importantly, it is observed that the conductive Ti3C2T x mediator efficiently chemisorbs the soluble polysulfides and converts them into thiosulfate/sulfate. The in situ formed sulfate complex layer acts as a thick protective barrier, which significantly retards the shuttling of polysulfides upon cycling and improves the sulfur utilization. Consequently, the binder-free, robust, highly electrically conductive composite film exhibits outstanding electrochemical performance, including high capacities (1244-1350 mAh g-1), excellent rate handling, and impressive cycling stability (0.035-0.048% capacity loss per cycle), surpassing the best MXene-S batteries known. The fabrication of a pouch cell based on the freestanding S@Ti3C2T x film is also reported. The prototype device showcases high capacities and excellent mechanical flexibility. Considering the broad family of MXenes and their unique roles in immobilizing the polysulfides, various S@MXene composites can be similarly fabricated with promising Li+ storage capability and long lifetime performance. PMID- 30250793 TI - Oscillatory Strain Promotes Vessel Stabilization and Alignment through Fibroblast YAP-Mediated Mechanosensitivity. AB - Endothelial cells form the interior layer of blood vessels and, as such, are constantly exposed to shear stress and mechanical strain. While the impact of shear stress on angiogenesis is widely studied, the role of mechanical strain is less understood. To this end, endothelial cells and fibroblasts are cocultured under oscillatory strain to create a vessel network. The two cell types show distinctly different sensitivities to the mechanical stimulation. The fibroblasts, sense the stress directly, and respond by increased alignment, proliferation, differentiation, and migration, facilitated by YAP translocation into the nucleus. In contrast, the endothelial cells form aligned vessels by tracking fibroblast alignment. YAP inhibition in constructs under mechanical strain results in vessel destruction whereas less damage is observed in the YAP inhibited static control. Moreover, the mechanical stimulation enhances vessel development and stabilization. Additionally, vessel orientation is preserved upon implantation into a mouse dorsal window chamber and promotes the invading host vessels to orient in the same manner. This study sheds light on the mechanisms by which mechanical strain affects the development of blood vessels within engineered tissues. This can be further utilized to engineer a more organized and stable vasculature suitable for transplantation of engineered grafts. PMID- 30250794 TI - Bifunctionality from Synergy: CoP Nanoparticles Embedded in Amorphous CoOx Nanoplates with Heterostructures for Highly Efficient Water Electrolysis. AB - Hydrogen production from renewable electricity relies upon the development of an efficient alkaline water electrolysis device and, ultimately, upon the availability of low cost and stable electrocatalysts that can promote oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). Normally, different electrocatalysts are applied for HER and OER because of their different reaction intermediates and mechanisms. Here, the synthesis of a heterostructured CoP@a-CoOx plate, which constitutes the embedded crystalline cobalt phosphide (CoP) nanoclusters and amorphous cobalt oxides (CoOx) nanoplates matrix, via a combined solvothermal and low temperature phosphidation route is reported. Due to the presence of synergistic effect between CoP nanoclusters and amorphous CoOx nanoplates in the catalyst, created from the strong nanointerfaces electronic interactions between CoP and CoOx phases in its heterostructure, this composite displays very high OER activity in addition to favorable HER activity that is comparable to the performance of the IrO2 OER benchmark and approached that of the Pt/C HER benchmark. More importantly, an efficient and stable alkaline water electrolysis operation is achieved using CoP@a-CoOx plate as both cathode and anode as evidenced by the obtainment of a relatively low potential of 1.660 V at a 10 mA cm-2 current density and its marginal increase above 1.660 V over 30 h continuous operation. PMID- 30250796 TI - Toward Perceptive Soft Robots: Progress and Challenges. AB - In the past few years, soft robotics has rapidly become an emerging research topic, opening new possibilities for addressing real-world tasks. Perception can enable robots to effectively explore the unknown world, and interact safely with humans and the environment. Among all extero- and proprioception modalities, the detection of mechanical cues is vital, as with living beings. A variety of soft sensing technologies are available today, but there is still a gap to effectively utilize them in soft robots for practical applications. Here, the developments in soft robots with mechanical sensing are summarized to provide a comprehensive understanding of the state of the art in this field. Promising sensing technologies for mechanically perceptive soft robots are described, categorized, and their pros and cons are discussed. Strategies for designing soft sensors and criteria to evaluate their performance are outlined from the perspective of soft robotic applications. Challenges and trends in developing multimodal sensors, stretchable conductive materials and electronic interfaces, modeling techniques, and data interpretation for soft robotic sensing are highlighted. The knowledge gap and promising solutions toward perceptive soft robots are discussed and analyzed to provide a perspective in this field. PMID- 30250795 TI - Design and Synthesis of Layered Na2Ti3O7 and Tunnel Na2Ti6O13 Hybrid Structures with Enhanced Electrochemical Behavior for Sodium-Ion Batteries. AB - A novel complementary approach for promising anode materials is proposed. Sodium titanates with layered Na2Ti3O7 and tunnel Na2Ti6O13 hybrid structure are presented, fabricated, and characterized. The hybrid sample exhibits excellent cycling stability and superior rate performance by the inhibition of layered phase transformation and synergetic effect. The structural evolution, reaction mechanism, and reaction dynamics of hybrid electrodes during the sodium insertion/desertion process are carefully investigated. In situ synchrotron X-ray powder diffraction (SXRD) characterization is performed and the result indicates that Na+ inserts into tunnel structure with occurring solid solution reaction and intercalates into Na2Ti3O7 structure with appearing a phase transition in a low voltage. The reaction dynamics reveals that sodium ion diffusion of tunnel Na2Ti6O13 is faster than that of layered Na2Ti3O7. The synergetic complementary properties are significantly conductive to enhance electrochemical behavior of hybrid structure. This study provides a promising candidate anode for advanced sodium ion batteries (SIBs). PMID- 30250797 TI - Ultrastretchable Fiber Sensor with High Sensitivity in Whole Workable Range for Wearable Electronics and Implantable Medicine. AB - Fast progress in material science has led to the development of flexible and stretchable wearable sensing electronics. However, mechanical mismatches between the devices and soft human tissue usually impact the sensing performance. An effective way to solve this problem is to develop mechanically superelastic and compatible sensors that have high sensitivity in whole workable strain range. Here, a buckled sheath-core fiber-based ultrastretchable sensor with enormous stain gauge enhancement is reported. Owing to its unique sheath and buckled microstructure on a multilayered carbon nanotube/thermal plastic elastomer composite, the fiber strain sensor has a large workable strain range (>1135%), fast response time (~16 ms), high sensitivity (GF of 21.3 at 0-150%, and 34.22 at 200-1135%), and repeatability and stability (20 000 cycles load/unload test). These features endow the sensor with a strong ability to monitor both subtle and large muscle motions of the human body. Moreover, attaching the sensor to a rat tendon as an implantable device allowes quantitative evaluation of tendon injury rehabilitation. PMID- 30250798 TI - A Dual-Salt Gel Polymer Electrolyte with 3D Cross-Linked Polymer Network for Dendrite-Free Lithium Metal Batteries. AB - Lithium metal batteries show great potential in energy storage because of their high energy density. Nevertheless, building a stable solid electrolyte interphase (SEI) and restraining the dendrite growth are difficult to realize with traditional liquid electrolytes. Solid and gel electrolytes are considered promising candidates to restrain the dendrites growth, while they are still limited by low ionic conductivity and incompatible interphases. Herein, a dual salt (LiTFSI-LiPF6) gel polymer electrolyte (GPE) with 3D cross-linked polymer network is designed to address these issues. By introducing a dual salt in 3D structure fabricated using an in situ polymerization method, the 3D-GPE exhibits a high ionic conductivity (0.56 mS cm-1 at room temperature) and builds a robust and conductive SEI on the lithium metal surface. Consequently, the Li metal batteries using 3D-GPE can markedly reduce the dendrite growth and achieve 87.93% capacity retention after cycling for 300 cycles. This work demonstrates a promising method to design electrolytes for lithium metal batteries. PMID- 30250799 TI - Advancing the Pharmaceutical Potential of Bioinorganic Hybrid Lipid-Based Assemblies. AB - Bioinspired lipid assemblies that mimic the elaborate architecture of natural membranes have fascinated researchers for a long time. These lipid assemblies have gone from being just an imperative platform for biophysical research to a pharmaceutical delivery system for biomedical applications. Despite success, these organized nanosystems are often subject to the mechanical instability and limited theranostic capability without adding any inconvenient modifications. To reach their advanced pharmaceutical potential, various bioinorganic hybrid lipid based assembles, which provide new opportunities to synergistically complement and improve therapeutic/diagnostic potential of existing lipid-based nanomedicine with distinct mechanisms containing inorganic embedded surfactants, have recently been developed. PMID- 30250800 TI - Heavy Doping by Bromine to Improve the Thermoelectric Properties of n-type Polycrystalline SnSe. AB - Single crystal tin selenide (SnSe) has attracted much attention for its excellent thermoelectric performance. However, polycrystalline SnSe exhibits unsatisfactory figure-of-merit due to the inferior electrical properties, especially for n-type SnSe. In this work, a high concentration of Br doping (6-12 atm%) on the Se site effectively increases the Hall carrier concentration from 1.6 * 1017 cm-3 (p type) in undoped SnSe to 1.3 * 1019 cm-3 (n-type) in Br-doped SnSe0.88Br0.12, leading to an increased electrical conductivity close to that of a single crystal. Combined with the decreased lattice thermal conductivity due to the enhanced phonon scattering by composition fluctuation and dislocations, a peak ZT of ~1.3 at 773 K, together with the enhanced average ZT is obtained in SnSe0.9Br0.1 along the hot pressing direction. PMID- 30250801 TI - MnS Incorporation into Higher Manganese Silicide Yields a Green Thermoelectric Composite with High Performance/Price Ratio. AB - Thermoelectric materials that can directly convert heat to electrical energy offer a viable solution for reducing the usage of fossil energy by harvesting waste heat resources. Higher manganese silicide (HMS) is a naturally abundant, eco-friendly, and low-cost p-type thermoelectric semiconductor with high power factor (PF); however, its figure of merit (ZT) is limited by intrinsically high thermal conductivity (kappa). For effectively enhancing the thermoelectric performance of HMS and avoiding the use of expensive or toxic elements, such as Re, Te, or Pb, a green p-type MnS with high Seebeck coefficient (S) and low kappa is incorporated into the HMS matrix to form MnS/HMS composites. The incorporation of MnS leads to a 31% reduction of kappa and a 10% increase of S. The ZT value increases by ~48% from 0.40 to 0.59 at 823 K. Correspondingly, performance/price ratio is first proposed to evaluate the practical value of thermoelectric materials, which is higher than those of the vast majority of current thermoelectric materials. This study provides an overview of enhancing ZT of HMS and reducing costs, which may also be applicable to other thermoelectric materials. PMID- 30250802 TI - Adaptable Fast Relaxing Boronate-Based Hydrogels for Probing Cell-Matrix Interactions. AB - Hydrogels with tunable viscoelasticity hold promise as materials that can recapitulate many dynamic mechanical properties found in native tissues. Here, covalent adaptable boronate bonds are exploited to prepare hydrogels that exhibit fast relaxation, with relaxation time constants on the order of seconds or less, but are stable for long-term cell culture and are cytocompatible for 3D cell encapsulation. Using human mesenchymal stem cells (hMSC) as a model, the fast relaxation matrix mechanics are found to promote cell-matrix interactions, leading to spreading and an increase in nuclear volume, and induce yes-associated protein/PDZ binding domain nuclear localization at longer times. All of these effects are exclusively based on the hMSCs' ability to physically remodel their surrounding microenvironment. Given the increasingly recognized importance of viscoelasticity in controlling cell function and fate, it is expected that the synthetic strategies and material platform presented should provide a useful system to study mechanotransduction on and within viscoelastic environments and explore many questions related to matrix biology. PMID- 30250803 TI - MaxMIF: A New Method for Identifying Cancer Driver Genes through Effective Data Integration. AB - Identification of a few cancer driver mutation genes from a much larger number of passenger mutation genes in cancer samples remains a highly challenging task. Here, a novel method for distinguishing the driver genes from the passenger genes by effective integration of somatic mutation data and molecular interaction data using a maximal mutational impact function (MaxMIF) is presented. When evaluated on six somatic mutation datasets of Pan-Cancer and 19 datasets of different cancer types from TCGA, MaxMIF almost always significantly outperforms all the existing state-of-the-art methods in terms of predictive accuracy, sensitivity, and specificity. It recovers about 30% more known cancer genes in 500 top-ranked candidate genes than the best among the other tools evaluated. MaxMIF is also highly robust to data perturbation. Intriguingly, MaxMIF is able to identify potential cancer driver genes, with strong experimental data support. Therefore, MaxMIF can be very useful for identifying or prioritizing cancer driver genes in the increasing number of available cancer genomic data. PMID- 30250805 TI - Caging Na3V2(PO4)2F3 Microcubes in Cross-Linked Graphene Enabling Ultrafast Sodium Storage and Long-Term Cycling. AB - Sodium-ion batteries are widely regarded as a promising supplement for lithium ion battery technology. However, it still suffers from some challenges, including low energy/power density and unsatisfactory cycling stability. Here, a cross linked graphene-caged Na3V2(PO4)2F3 microcubes (NVPF@rGO) composite via a one-pot hydrothermal strategy followed by freeze drying and heat treatment is reported. As a cathode for a sodium-ion half-cell, the NVPF@rGO delivers excellent cycling stability and rate capability, as well as good low temperature adaptability. The structural evolution during the repeated Na+ extraction/insertion and Na ions diffusion kinetics in the NVPF@rGO electrode are investigated. Importantly, a practicable sodium-ion full-cell is constructed using a NVPF@rGO cathode and a N doped carbon anode, which delivers outstanding cycling stability (95.1% capacity retention over 400 cycles at 10 C), as well as an exceptionally high energy density (291 Wh kg-1 at power density of 192 W kg-1). Such micro-/nanoscale design and engineering strategies, as well as deeper understanding of the ion diffusion kinetics, may also be used to explore other micro-/nanostructure materials to boost the performance of energy storage devices. PMID- 30250804 TI - Highly Multiplexed Single-Cell Protein Profiling with Large-Scale Convertible DNA Antibody Barcoded Arrays. AB - Highly multiplexed detection of proteins secreted by single cells is always challenging. Herein, a multiplexed in situ tagging technique based on single stranded DNA encoded microbead arrays and multicolor successive imaging for assaying single-cell secreted proteins with high throughput and high sensitivity is presented. This technology is demonstrated to be capable of increasing the multiplexity exponentially. Upon integration with polydimethylsiloxane microwells, this platform is applied to detect ten immune effector proteins from differentiated single macrophages stimulated with lipopolysaccharide. Significant heterogeneity is observed when the derived human primary macrophages are analyzed. This versatile technology is expected to open new opportunities in systems biology, immune regulation studies, signaling analysis, and molecular diagnostics. PMID- 30250806 TI - Phototunable Biomemory Based on Light-Mediated Charge Trap. AB - Phototunable biomaterial-based resistive memory devices and understanding of their underlying switching mechanisms may pave a way toward new paradigm of smart and green electronics. Here, resistive switching behavior of photonic biomemory based on a novel structure of metal anode/carbon dots (CDs)-silk protein/indium tin oxide is systematically investigated, with Al, Au, and Ag anodes as case studies. The charge trapping/detrapping and metal filaments formation/rupture are observed by in situ Kelvin probe force microscopy investigations and scanning electron microscopy and energy-dispersive spectroscopy microanalysis, which demonstrates that the resistive switching behavior of Al, Au anode-based device are related to the space-charge-limited-conduction, while electrochemical metallization is the main mechanism for resistive transitions of Ag anode-based devices. Incorporation of CDs with light-adjustable charge trapping capacity is found to be responsible for phototunable resistive switching properties of CDs based resistive random access memory by performing the ultraviolet light illumination studies on as-fabricated devices. The synergistic effect of photovoltaics and photogating can effectively enhance the internal electrical field to reduce the switching voltage. This demonstration provides a practical route for next-generation biocompatible electronics. PMID- 30250807 TI - Near-Infrared-Plasmonic Energy Upconversion in a Nonmetallic Heterostructure for Efficient H2 Evolution from Ammonia Borane. AB - Plasmonic metal nanostructures have been widely used to enhance the upconversion efficiency of the near-infrared (NIR) photons into the visible region via the localized surface plasmon resonance (LSPR) effect. However, the direct utilization of low-cost nonmetallic semiconductors to both concentrate and transfer the NIR-plasmonic energy in the upconversion system remains a significant challenge. Here, a fascinating process of NIR-plasmonic energy upconversion in Yb3+/Er3+-doped NaYF4 nanoparticles (NaYF4:Yb-Er NPs)/W18O49 nanowires (NWs) heterostructures, which can selectively enhance the upconversion luminescence by two orders of magnitude, is demonstrated. Combined with theoretical calculations, it is proposed that the NIR-excited LSPR of W18O49 NWs is the primary reason for the enhanced upconversion luminescence of NaYF4:Yb-Er NPs. Meanwhile, this plasmon-enhanced upconversion luminescence can be partly absorbed by the W18O49 NWs to re-excite its higher energy LSPR, thus leading to the selective enhancement of upconversion luminescence for the NaYF4:Yb-Er/W18O49 heterostructures. More importantly, based on this process of plasmonic energy transfer, an NIR-driven catalyst of NaYF4:Yb-Er NPs@W18O49 NWs quasi-core/shell heterostructure, which exhibits a ~35-fold increase in the catalytic H2 evolution from ammonia borane (BH3NH3) is designed and synthesized. This work provides insight on the development of nonmetallic plasmon-sensitized optical materials that can potentially be applied in photocatalysis, optoelectronic, and photovoltaic devices. PMID- 30250808 TI - Multilevel Data Encryption Using Thermal-Treatment Controlled Room Temperature Phosphorescence of Carbon Dot/Polyvinylalcohol Composites. AB - Thermal-treatment controlled room temperature phosphorescence is realized by embedding either originally synthesized carbon dots (CDs) or 200 degrees C thermal-treated CDs into a polyvinylalcohol (PVA) matrix through post-synthetic thermal annealing at 200 or 150 degrees C. The thermal-treatment controlled phosphorescence is attributed to the transfer of photoexcitation from the excited singlet state to the triplet state through intersystem crossing, followed by radiative transition to the ground state, which is due to decrease of quenchers (oxygen) in the CDs and suppression of the vibrational dissipations through the chemical bonding of CDs in the PVA matrix. Multilevel fluorescence/phosphorescence data encryption is demonstrated based on the thermal treatment controlled phosphorescence from CD@PVA composites. PMID- 30250809 TI - An Intravascular Magnetic Catheter Enables the Retrieval of Nanoagents from the Bloodstream. AB - The clinical adoption of nanoscale agents for targeted therapy is still hampered by the quest for a balance between therapy efficacy and side effects on healthy tissues, due to nanoparticle biodistribution and undesired drug accumulation issues. Here, an intravascular catheter able to efficiently retrieve from the bloodstream magnetic nanocarriers not contributing to therapy, thus minimizing their uncontrollable dispersion and consequently attenuating possible side effects, is proposed. The device consists of a miniature module, based on 27 permanent magnets arranged in two coaxial series, integrated into a clinically used 12 French catheter. This device can capture ~94% and 78% of the unused agents when using as carriers 500 and 250 nm nominal diameter superparamagnetic iron oxide nanoparticles, respectively. This approach paves the way to the exploitation of new "high-risk/high-gain" drug formulations and supports the development of novel therapeutic strategies based on magnetic hyperthermia or magnetic microrobots. PMID- 30250810 TI - Morphology-Controlled Aluminum-Doped Zinc Oxide Nanofibers for Highly Sensitive NO2 Sensors with Full Recovery at Room Temperature. AB - Room-temperature (RT) gas sensitivity of morphology-controlled free-standing hollow aluminum-doped zinc oxide (AZO) nanofibers for NO2 gas sensors is presented. The free-standing hollow nanofibers are fabricated using a polyvinylpyrrolidone fiber template electrospun on a copper electrode frame followed by radio-frequency sputtering of an AZO thin overlayer and heat treatment at 400 degrees C to burn off the polymer template. The thickness of the AZO layer is controlled by the deposition time. The gas sensor based on the hollow nanofibers demonstrates fully recoverable n-type RT sensing of low concentrations of NO2 (0.5 ppm). A gas sensor fabricated with Al2O3-filled AZO nanofibers exhibits no gas sensitivity below 75 degrees C. The gas sensitivity of a sensor is determined by the density of molecules above the minimum energy for adsorption, collision frequency of gas molecules with the surface, and available adsorption sites. Based on finite-difference time-domain simulations, the RT sensitivity of hollow nanofiber sensors is ascribed to the ten times higher collision frequency of NO2 molecules confined inside the fiber compared to the outer surface, as well as twice the surface area of hollow nanofibers compared to the filled ones. This approach might lead to the realization of RT sensitive gas sensors with 1D nanostructures. PMID- 30250811 TI - Encapsulation of CoS x Nanocrystals into N/S Co-Doped Honeycomb-Like 3D Porous Carbon for High-Performance Lithium Storage. AB - A honeycomb-like 3D N/S co-doped porous carbon-coated cobalt sulfide (CoS, Co9S8, and Co1-x S) composite (CS@PC) is successfully prepared using polyacrylonitrile (PAN) as the nitrogen-containing carbon source through a facile solvothermal method and subsequent in situ conversion. As an anode for lithium-ion batteries (LIBs), the CS@PC composite exhibits excellent electrochemical performance, including high reversible capacity, good rate capability, and cyclic stability. The composite electrode delivers specific capacities of 781.2 and 466.0 mAh g-1 at 0.1 and 5 A g-1, respectively. When cycled at a current density of 1 A g-1, it displays a high reversible capacity of 717.0 mAh g-1 after 500 cycles. The ability to provide this level of performance is attributed to the unique 3D multi level porous architecture with large electrode-electrolyte contact area, bicontinuous electron/ion transport pathways, and attractive structure stability. Such micro-/nanoscale design and engineering strategies may also be used to explore other nanocomposites to boost their energy storage performance. PMID- 30250812 TI - High-Mobility Two-Dimensional Electron Gas at InGaN/InN Heterointerface Grown by Molecular Beam Epitaxy. AB - Due to the intrinsic spontaneous and piezoelectric polarization effect, III nitride semiconductor heterostructures are promising candidates for generating 2D electron gas (2DEG) system. Among III-nitrides, InN is predicted to be the best conductive-channel material because its electrons have the smallest effective mass and it exhibits large band offsets at the heterointerface of GaN/InN or AlN/InN. Until now, that prediction has remained theoretical, due to a giant gap between the optimal growth windows of InN and GaN, and the difficult epitaxial growth of InN in general. The experimental realization of 2DEG at an InGaN/InN heterointerface grown by molecular beam epitaxy is reported here. The directly probed electron mobility and the sheet electron density of the InGaN/InN heterostructure are determined by Hall-effect measurements at room temperature to be 2.29 * 103 cm2 V-1 s-1 and 2.14 * 1013 cm-2, respectively, including contribution from the InN bottom layer. The Shubnikov-de Haas results at 3 K confirm that the 2DEG has an electron density of 3.30 * 1012 cm-2 and a quantum mobility of 1.48 * 103 cm2 V-1 s-1. The experimental observations of 2DEG at the InGaN/InN heterointerface have paved the way for fabricating higher-speed transistors based on an InN channel. PMID- 30250813 TI - Bis-Tridentate Iridium(III) Phosphors with Very High Photostability and Fabrication of Blue-Emitting OLEDs. AB - Sky-blue and blue-emitting, carbazolyl functionalized, bis-tridentate Ir(III) phosphors Cz-1-Cz-3 with bright emission and short radiative lifetime are successfully synthesized in a one-pot manner. They exhibit very high photostability against UV-vis irradiation in degassed toluene, versus both green and true-blue-emitting reference compounds, i.e., fac-[Ir(ppy)3] and mer [Ir(pmp)3]. Organic light-emitting diodes (OLEDs) based on Cz-2 exhibit maximum external quantum efficiency (EQE) of 21.6%, EQE of 15.1% at 100 cd m-2, and with CIE x,y coordinates of (0.17, 0.25). This study provides a conceptual solution to the exceedingly stable and efficient blue phosphor. It is promising that long lifespan blue OLED based on these emitters can be attained with further engineering of devices suitable for commercial application. PMID- 30250814 TI - DeepScreen: An Accurate, Rapid, and Anti-Interference Screening Approach for Nanoformulated Medication by Deep Learning. AB - Accuracy of current efficacy judgment methods for nanoformulated drug remains unstable due to the interference of nanocarriers. Herein, DeepScreen, a drug screening system utilizing convolutional neural network based on flow cytomerty single-cell images, is introduced. Compared to existing experimental approaches, the high-throughput system has superior precision, rapidity, and anti interference, and is cost-cutting with high accuracy. First, it can resist most disturbances from manual factors of complicated evaluation progress. In addition, class activation maps generated from DeepScreen indicate that it may identify and locate the tiny variation from cell apoptosis and slight changes of cellular period caused by drug or even nanoformulated drug action at very early stages. More importantly, the excellent performance of assessment on two types of nanoformulations and fluorescent drug proves the fine generality and anti interference of this novel system. All these privileged performances make DeepScreen a very smart and promising system for drug detection. PMID- 30250815 TI - Enhanced CO2/CH4 Separation Performance of a Mixed Matrix Membrane Based on Tailored MOF-Polymer Formulations. AB - Membrane-based separations offer great potential for more sustainable and economical natural gas upgrading. Systematic studies of CO2/CH4 separation over a wide range of temperatures from 65 degrees C (338 K) to as low as -40 degrees C (233 K) reveals a favorable separation mechanism toward CO2 by incorporating Y fum-fcu-MOF as a filler in a 6FDA-DAM polyimide membrane. Notably, the decrease of the temperature from 308 K down to 233 K affords an extremely high CO2/CH4 selectivity (~130) for the hybrid Y-fum-fcu-MOF/6FDA-DAM membrane, about four fold enhancement, with an associated CO2 permeability above 1000 barrers. At subambient temperatures, the pronounced CO2/CH4 diffusion selectivity dominates the high permeation selectivity, and the enhanced CO2 solubility promotes high CO2 permeability. The differences in adsorption enthalpy and activation enthalpy for diffusion between CO2 and CH4 produce the observed favorable CO2 permeation versus CH4. Insights into opportunities for using mixed-matrix membrane-based natural gas separations at extreme conditions are provided. PMID- 30250816 TI - Comparison of the Success Rate of Intubation Between the LMA Fastrach and AirQ ILA Methods in Patients Undergoing Elective Surgery During General Anaesthesia. AB - Background: Rapid placement of a reliable airway is the most important task in anesthesia practice. Airway management is a critical skill to provide safe anesthesia since morbidity. In addition, mortality due to anesthesia could be linked to difficulty or failure in airway management. In this study, intubation success was compared between two methods, AirQ-ILA and LMAfastrach, among candidates for elective surgery under general anesthesia. Methods: In this clinical trial, patients, who were candidates for elective surgery under general anesthesia at Firoozgar and Rasoul Akram Hospitals, were randomly divided into LMAfastrach and AirQ-ILA groups. Heart rate before and after induction and intubation, diastolic blood pressure, systolic blood pressure, duration of device insertion, intubation time, number of attempts until successful device insertion and trachea intubation, and success or failure in the insertion of the device and the tube were recorded; as for statistical analysis, SPSS version 21 was considered. Results: In comparison with the LMAfastrach group, the device insertion time and intubation time were significantly longer in the AirQ-ILA group (P < 0.05). However, the groups showed no significant difference regarding the number of device and tube insertion attempts (P > 0.05). Moreover, no significant difference was observed in the success of device insertion and intubation in either LMAfastrach or AirQ-ILA group (P > 0.05). Conclusions: The LMAfastrach and AirQ-ILA methods were not significantly different regarding the success of airway instrument application and intubation, while the device insertion time and intubation time were significantly longer in the AirQ-ILA group in comparison with the LMAfastrach group. PMID- 30250817 TI - The Association Between Constipation or Stool Consistency and Pain Severity in Patients With Chronic Pain. AB - Background: Bacteria can influence a variety of gut functions. Some studies showed that stool consistency and constipation were associated with gut microbiome (GM) composition, and enterotype, dysbiosis. Growing evidence indicates the significant role of GM in the homeostatic function of the host body. The GM may regulate multiple neurochemical and neurometabolic pathways. Chronicity of the pain is actively modulated at the molecular to the network level by means of several neurotransmitters. The GM to some extent can affect pain perception. Objectives: The current study aimed at investigating the relationship between constipation state or usual stool form and pain severity of patients with chronic pain. Methods: The current study was conducted on 365 patients with chronic pain. The participants were evaluated on their stool form (the Bristol stool form scale; BSFS), constipation state (the Cleveland clinic constipation score; CCCS), body mass index (BMI), and usual pain severity (numerical rating scale; NRS). In addition, the participants were assigned into five groups according to the pain region (i e, low back and/or lower limb, whole body, neck and/or upper back and/or upper limb, head and/or face, chest and/or abdominal). Results: The CCS showed a significant and positive association with the pain severity of the total patients and patients with low back and/or lower limb pain. Simultaneous multiple linear regression analyses revealed that a predictor of the pain severity was the CCS for the total patients and patients with low back and/or lower limb, whole body pain. Conclusions: Constipation displayed a significant and positive association with the pain severity of the total patients and patients with low back and/or lower limb pain, whole body. PMID- 30250818 TI - The Effects of Pre-Spinal Anesthesia Administration of Crystalloid and Colloid Solutions on Hypotension in Elective Cesarean Section. AB - Background: Spinal anesthesia is an appropriate alternative for general anesthesia in many operations, particularly in cesarean section. However, the induced hypotension is the main drawback of this method. Therefore, the current study aimed at comparing the effects of crystalloid and colloid solutions used as the preload on the post-spinal hypotension and its complications in females who are candidate for elective cesarean section. Methods: The current randomized, controlled, double-blind study was conducted on the female candidate of elective cesarean section (n = 96; age range: 20 to 40 years). The patients were in their 37 to 42 weeks of gestational age during the experiments. The systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) variation, amount of injected ephedrine during surgery, Apgar score at birth, total solution infused after spinal anesthesia, urine output, nausea, and vomiting were comparatively assessed between the two groups. Results: The percentages of reduction in SBP and DBP variables in the crystalloid solution were higher than those of the colloid group and the differences were statistically significant (P = 0.042 and P = 0.008, respectively). Average percentage of HR changes was more significant in the crystalloid than the colloid group (P = 0.032). In contrary, administration of the two types of solutions did not result in significant differences in the Apgar scores. The prevalence of nausea and vomiting in the colloid group subjects was lower than those of the crystalloid solution group; however, the differences were not significant. Conclusions: The current study findings recommend colloid solution to prevent hemodynamic instability after spinal anesthesia. However, the costs and availability of the solution and recommendation of anesthesiologist should be considered. Conduction of further clinical trials with larger sample sizes is recommended. PMID- 30250819 TI - An Evaluation of the Adding Magnesium Sulfate to Ropivacaine on Ultrasound-Guided Transverse Abdominis Plane Block After Abdominal Hysterectomy. AB - Background: Post-hysterectomy pain is extremely annoying and using transverse abdominis plane (TAP) block can be a useful method to manage postoperative pain, but its duration of effect is challenging. Magnesium sulfate increases, in some cases, the effects of local anesthetics on the peripheral nerve blocks. Objectives: The current study aimed at investigating the effects of adding magnesium sulfate to ropivacaine in the transverse abdominis plane block after hysterectomy. Methods: The current randomized, double blind, clinical trial, to manage postoperative pain, was conducted on a total of 60 patients, 30 - 60 years old, ASA (American Society of Anesthesiologists) class I-II undergone elective abdominal hysterectomy candidates to receive ultrasound-guided bilateral transverse abdominis abdominis plane (TAP) blocks. Patients with coagulation disorders, infection, history of any addiction, sensitivity to the local anesthetics and magnesium sulfate were excluded. The subjects were equally allocated into two groups, the control group, ropivacaine plus normal saline (R), and the study group, ropivacaine plus magnesium sulfate (RM). The injection contained 19 mL ropivacaine 0.2% plus 1 mL normal saline in the group R, and 19 mL ropivacaine 0.2% plus 1 mL magnesium sulfate 50% in the RM group on each side. As well as the patients' characteristics, the level of pain score (visual analogue scale = VAS), rescue analgesic demand (diclofenac suppository), and possible adverse effects were evaluated at 1, 2, 6, 12, and 24 hours after the operation in the two groups. Results: The mean pain scores of the patients at the first hour after surgery were 5.7 +/- 0.9 and 5.9 +/- 1.1 in R and RM groups, respectively. The scores reached 2.9 +/- 0.5 and 2.7 +/- 0.4 at the second hour after surgery (the first post-block measurement) and 3.1 +/- 0.7 and 2.8 +/- 0.7 within the next 24 hours, respectively. Although the pain scores were generally lower at all hours in the RM group, none was statistically significant. The rescue analgesic consumption gradually increased in the two groups, and it was less in the study group than in the control group in the first hours after the block (second hour after surgery); however, it was not statistically significant. No adverse effects were observed in the two groups. Conclusions: Results of the current study suggested that the addition of magnesium sulfate to ropivacaine in TAP block does not affect the post-hysterectomy pain. PMID- 30250820 TI - Comparison of Three Techniques on Facility of Bag-Mask Ventilation: Thenar Eminence, E-O and E-C. AB - Background: Rapid and secure management of airway is an important lifesaving intervention in critically ill patients at emergency wards. Training undergraduate students about airway management must be regarded as a priority in their education period. The aim of the present study was to compare the quality of three ventilation techniques with a bag and mask among two groups of undergraduate students (Novices) and senior group (Experienced) in Tabriz University of Medical Sciences. Methods: This study was a mannequin type research that was carried out in the faculty of medicine, Tabriz University of Medical Sciences. The study population consisted of two elementary groups (Novices) and senior group (Experienced). The number of participants included 100 individuals. Ventilation quality by bag and mask in two groups was recorded based on the rise of lungs and two reviewers' opinions who gave a score from 1 as weak to 4 as excellent using three techniques of E-C, E-O, and Thenar Eminence. In the E-C technique, index fingers and thumbs form two "C"s facing each other while the remaining fingers lift the mandible and form two "E"s. In E-O techniques, the web between thumb and index finger is used to form a circle around the neck of the mask while other fingers perform a chin lift. In thenar eminence techniques, the thenar eminence and thumb are placed on the top of the mask while other fingers perform jaw thrust. Results: In our study, 27% of undergraduate participants and 59% of seniors were male and the others were female. The mean of age of elementary and seniors were 24 and 33.5, respectively (P < 0.05). E-O technique was well done by the novices group. Conclusions: Based on our results, it was concluded that the elementary group performed E-O bag and mask ventilation technique appropriately. Therefore, it can be suggested that training of this technique will be placed in educational curriculum of undergraduate students. PMID- 30250821 TI - The Effect of Adding Dexmedetomidine as an Adjuvant to Lidocaine in Forearm Fracture Surgeries by Supraclavicular Block Procedure Under Ultrasound-Guided. AB - Background: To improve the brachial plexus block (BPB) performance, different compounds have been used as adjuvants to local analgesics. Objectives: The aim of the present study was to investigate the effects of adding DEX to lidocaine on effectiveness of nerve block, and postoperative pain in forearm fracture surgery by supraclavicular BPB undergoing ultrasound-guided. Methods: This was a double blinded randomized clinical trial conducted on 72 patients with ASA classes I and II, which were candidates for forearm fracture surgery. In group A, patients received 3 mg/kg of lidocaine 2%. In group B, patients received 3 mg/kg of lidocaine 2% and DEX (1 ug/kg). The ultrasound-guided supraclavicular BPB was performed in all patients. The onset of sensory and motor blocks were evaluated with pin prick test and modified Bromage scale, respectively. The sensory and motor block moment was recorded as the onset of the block. The first analgesic request time, total consumed analgesic, adverse effect, and hemodynamic parameters of patients were recorded. A visual analog scale (VAS) was used for recording the severity of pain. Results: The two groups showed no significant difference in the demographic variables. The onset of sensory and motor block in the DEX groups was shorter. The duration of sensory and motor block, and analgesic request was significantly longer than the control groups. Total analgesic consumption 24 hours after surgery in the DEX groups was significantly lower. Moreover, hemodynamic status of patients in both groups was stable and no significant difference was observed between groups. This study showed that DEX, as an adjuvant to lidocaine, improve the characteristics of supraclavicular BPB and decrease the postoperative pain. PMID- 30250822 TI - C-reactive Protein Level on Postoperative Day One is Associated with Chronic Postsurgical Pain After Mastectomy. AB - Background: C-reactive protein (CRP) is an acute phase reactant released in response to inflammation or tissue injury. Inflammation is one of the pathogenic factors related to transition from acute postsurgical pain (APSP) to chronic postsurgical pain (CPSP). Although several risk factors are reportedly associated with CPSP, the effects of CRP levels on CPSP have not been examined. Objectives: The present study investigated the relationship between perioperative risk factors, including CRP levels on postoperative day one and CPSP, in patients undergoing mastectomy. Methods: Preoperative anxiety and depression levels were evaluated in female patients undergoing mastectomy under general anesthesia, with or without peripheral nerve block. Patients with chronic preoperative pain and/or preoperative breast pain were excluded. The intensity of postoperative pain was prospectively examined one and six days, and three and twelve months after surgery using a numerical rating scale (NRS). Results: The current researchers conducted univariate and multivariate linear regression analyses to explore risk factors for CPSP in 36 patients. Patient demographics, preoperative psychological states, and anesthetic managements showed no relationship with CPSP. On the other hand, pain intensity of APSP and CRP levels on postoperative day one was significantly associated with the pain intensity of CPSP. Conclusions: Postoperative CRP level is likely to be associated with the development of CPSP after mastectomy. PMID- 30250823 TI - Cancer Immunotherapy in Diffuse Large B-Cell Lymphoma. AB - Remarkable progress has been made in the field of cancer immunotherapy in the past few years. Immunotherapy has become a standard treatment option for patients with various cancers, including melanoma, lymphoma, and carcinomas of the lungs, kidneys, bladder, and head and neck. Promising immunotherapy approaches, such as chimeric antigen receptor (CAR) T cell therapy and therapeutic blockade of immune checkpoints, in particular cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 pathway (PD-1/PD-L1), have boosted the development of new therapeutic regimens for patients with cancer. Immunotherapeutic strategies for diffuse large B-cell lymphoma (DLBCL) include monoclonal anti-CD20 antibody (rituximab), monoclonal anti-PD-1 antibodies (nivolumab and pembrolizumab), monoclonal anti-PD-L1 antibodies (avelumab, durvalumab, and atezolizumab) and chimeric antigen receptor (CAR) T cell therapy. In this review, we outline the latest highlights and progress in using immunotherapy to treat patients with DLBCL, with a focus on the therapeutic blockade of PD-1/PD-L1 and CAR T cell therapy in DLBCL. We also discuss current clinical trials of PD-1/PD-L1 and CAR T cell therapy and review the challenges and opportunities of using immunotherapy for the treatment of DLBCL. PMID- 30250824 TI - Multiple Myeloma Exemplifies a Model of Cancer Based on Tissue Disruption as the Initiator Event. AB - The standard model of multiple myeloma (MM) oncogenesis is based on the genetic instability of MM cells and presents its evolution as the emergence of clones with more and more aggressive genotypes, giving them surviving and proliferating advantage. The micro-environment has a passive role. In contrast, many works have shown that the progression of MM is also characterized by the selection of clones with extended phenotypes able to destroy bone trabeculae, suggesting a major role for early micro-environmental disruption. We present a model of MM oncogenesis in which genetic instability is the consequence of the disruption of normal interactions between plasma cells and their environment, the bone remodeling compartment. These interactions, which normally ensure the stability of the genotypes and phenotypes of normal plasma cells could be disrupted by many factors as soon as the early steps of the disease (MGUS, pre-MGUS states). Therapeutical implications of the model are presented. PMID- 30250826 TI - The Prevalence of Rhesus-Negative Blood Group Among Patient With Small Cell Lung Cancer and Analysis of Its Effect on Overall Survival. AB - A higher incidence of Rhesus group D (RHD)-negative blood group among patients with Small Cell Cancer of the lung (SCLC) had been previously reported but reproducibility was not confirmed, and clinical relevance is undefined. We tested 1,090 (SCLC; Adenocarcinoma: Squamous = 202:536:352) cases of lung cancer over a 3-year period at a single institution and noted a higher frequency RHD negative status among SCLC cases (19/89) compared with non-SCLC (61/480) that could not be explained by differences in ethnic background in the patient population. While we confirmed poor ECOG functional status, advanced stage, elevated alkaline phosphatase, and low albumin levels as independent and significant factors for reduced overall survival (OS), we did not detect any clinical outcome correlations with RHD status in our dataset. Patients with SCLC rarely undergo surgical resection resulting in limited data for blood group analyses. We have now detected a higher rate of RHD-negative status in patients with SCLC compared with all other subtypes of lung cancer. The clinical and biological basis for this observation is undefined and we feel that this may be explained by variations in ethnic background. PMID- 30250825 TI - Transforming Growth Factor-beta-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis. AB - The Transforming Growth Factor-beta (TGF-beta) family plays relevant roles in the regulation of different cellular processes that are essential for tissue and organ homeostasis. In the case of the liver, TGF-beta signaling participates in different stages of disease progression, from initial liver injury toward fibrosis, cirrhosis and cancer. When a chronic injury takes place, mobilization of lymphocytes and other inflammatory cells occur, thus setting the stage for persistence of an inflammatory response. Macrophages produce profibrotic mediators, among them, TGF-beta, which is responsible for activation transdifferentiation- of quiescent hepatic stellate cells (HSC) to a myofibroblast (MFB) phenotype. MFBs are the principal source of extracellular matrix protein (ECM) accumulation and prominent mediators of fibrogenesis. TGF beta also mediates an epithelial-mesenchymal transition (EMT) process in hepatocytes that may contribute, directly or indirectly, to increase the MFB population. In hepatocarcinogenesis, TGF-beta plays a dual role, behaving as a suppressor factor at early stages, but contributing to later tumor progression, once cells escape from its cytostatic effects. As part of its potential pro tumorigenic actions, TGF-beta induces EMT in liver tumor cells, which increases its pro-migratory and invasive potential. In parallel, TGF-beta also induces changes in tumor cell plasticity, conferring properties of a migratory tumor initiating cell (TIC). The main aim of this review is to shed light about the pleiotropic actions of TGF-beta that explain its effects on the different liver cell populations. The cross-talk with other signaling pathways that contribute to TGF-beta effects, in particular the Epidermal Growth Factor Receptor (EGFR), will be presented. Finally, we will discuss the rationale for targeting the TGF-beta pathway in liver pathologies. PMID- 30250827 TI - The Tumor Vascular Endothelium as Decision Maker in Cancer Therapy. AB - Genetic and pathophysiologic criteria prearrange the uncontrolled growth of neoplastic cells that in turn initiates new vessel formation, which is prerequisite for further tumor growth and progression. This first endothelial lining is patchy, disordered in structure and thus, angiogenic tumor vessels were proven to be functionally inferior. As a result, tumors were characterized by areas with an apparent oversupply in addition to areas with an undersupply of vessels, which complicates an efficient administration of intravenous drugs in cancer therapy and might even lower the response e.g. of radiotherapy (RT) because of the inefficient oxygen supply. In addition to the vascular dysfunction, tumor blood vessels contribute to the tumor escape from immunity by the lack of response to inflammatory activation (endothelial anergy) and by repression of leukocyte adhesion molecule expression. However, tumor vessels can remodel by the association with and integration of pericytes and smooth muscle cells which stabilize these immature vessels resulting in normalization of the vascular structures. This normalization of the tumor vascular bed could improve the efficiency of previously established therapeutic approaches, such as chemo- or radiotherapy by a more homogenous drug and oxygen distribution, and/or by overcoming endothelial anergy. This review highlights the current investigations that take advantage of a proper vascular function for improving cancer therapy with a special focus on the endothelial-immune system interplay. PMID- 30250829 TI - Antimicrobial stewardship in Spain: Programs for Optimizing the use of Antibiotics (PROA) in Spanish hospitals. PMID- 30250828 TI - Antimicrobial Activity of Gallium Compounds on ESKAPE Pathogens. AB - ESKAPE bacteria are a major cause of multidrug-resistant infections, and new drugs are urgently needed to combat these pathogens. Given the importance of iron in bacterial physiology and pathogenicity, iron uptake and metabolism have become attractive targets for the development of new antibacterial drugs. In this scenario, the FDA-approved iron mimetic metal Gallium [Ga(III)] has been successfully repurposed as an antimicrobial drug. Ga(III) disrupts ferric iron dependent metabolic pathways, thereby inhibiting microbial growth. This work provides the first comparative assessment of the antibacterial activity of Ga(NO3)3 (GaN), Ga(III)-maltolate (GaM), and Ga(III)-protoporphyrin IX (GaPPIX), belonging to the first-, second- and third-generation of Ga(III) formulations, respectively, on ESKAPE species, including reference strains and multidrug resistant (MDR) clinical isolates. In addition to the standard culture medium Mueller Hinton broth (MHB), iron-depleted MHB (DMHB) and RPMI-1640 supplemented with 10% human serum (HS) (RPMI-HS) were also included in Ga(III)-susceptibility tests, because of their different nutrient and iron contents. All ESKAPE species were resistant to all Ga(III) compounds in MHB and DMHB (MIC > 32 MUM), except Staphylococcus aureus and Acinetobacter baumannii, which were susceptible to GaPPIX. Conversely, the antibacterial activity of GaN and GaM was very evident in RPMI-HS, in which the low iron content and the presence of HS better mimic the in vivo environment. In RPMI-HS about 50% of the strains were sensitive (MIC < 32) to GaN and GaM, both compounds showing a similar spectrum of activity, although GaM was more effective than GaN. In contrast, GaPPIX lost its antibacterial activity in RPMI-HS likely due to the presence of albumin, which binds GaPPIX and counteracts its inhibitory effect. We also demonstrated that the presence of multiple heme-uptake systems strongly influences GaPPIX susceptibility in A. baumannii. Interestingly, GaN and GaM showed only a bacteriostatic effect, whereas GaPPIX exerted a bactericidal activity on susceptible strains. Altogether, our findings raise hope for the future development of Ga(III)-based compounds in the treatment of infections caused by multidrug-resistant ESKAPE pathogens. PMID- 30250830 TI - Incidence of methicillin resistant Staphylococcus aureus (MRSA) in burn intensive care unit: a systematic review. AB - Background: Burn victims admitted in burn intensive care units (ICU) are at a high risk of nosocomial infections generated by methicillin resistant Staphylococcus aureus (MRSA). This systematic review aims to estimate the incidence of MRSA among burn patients admitted to the ICU setting, with an emphasis on the incidence rate and antibiotic resistance profile of the MRSA strains. Methods: A systematic literature search was performed in five electronic databases limited to publication dates from 1st January 2000 until 31st August 2017. After screening n=481 articles, n=21 were found to meet the inclusion criteria of this systematic review. Results: Results from the meta-analysis revealed that the risk for MRSA isolates in the burn ICU was 55.0% higher (OR 0.55, 95%CI 0.32-0.94). Therefore, timely testing, appropriate hygiene practice and suggested wound care must be practiced while handling such patients. Conclusion: Further studies are needed to identify the risk factors of MRSA infections among burn patients and to develop new antimicrobial agents for MRSA infections. PMID- 30250831 TI - High frequency of Mycoplasma pneumoniae among patients with atypical pneumonia in Tehran, Iran. AB - Introduction: Mycoplasma pneumoniae is a major cause of atypical community acquired pneumonia (CAP) with a prevalence range of 15-20% and up to 40% in adults and children, respectively. In Iran, the recorded frequency ranges between 1-6.15%. We aimed to investigate the frequency of M. pneumoniae among patients with atypical pneumonia acquired from the community. Methods: Over a period of 5 months between January and June 2017, 520 patients with suspected CAP, who had been to the hospital outpatient clinics of Tehran University, were enrolled in this study. Throat swab specimens were obtained from 110 outpatients who presented with symptoms of atypical pneumonia. M. pneumoniae was identified via culture and biochemical tests, such as fermentation of glucose and arginine, hemolysis, and hemadsorption. For confirmation, PCR was performed to amplify the gene fragment coding for p1 adhesin. Results: The major and minor clinical signs of the patients were dyspnea (67.3%) and nausea (15.5%), respectively. Out of 110 specimens, 25 (22.7%) and 29 (26.4%) isolates were identified to be M. pneumoniae via culture and molecular assay, respectively. Comparing the results of the two methods, the PCR showed better sensitivity and rapidity for the detection of M. pneumoniae. There was a high congruence between culture and the PCR assay; kappa level was 'almost perfect' (kappa=0.90). Conclusion: This is the first report of high frequency of M. pneumoniae in our region. This finding can serve as baseline information for further investigation and confirmation of the potential epidemics of M. pneumoniae pneumonia in our community. PMID- 30250832 TI - Vancomycin resistance among Staphylococcus aureus isolates in a rural setting, Egypt. AB - Introduction: With the increased occurrence of methicillin resistant S. aureus (MRSA), the consumption of vancomycin, the drug of choice, has also increased. As a consequence, strains of S. aureus resistant to vancomycin have started to emerge. This study aimed to evaluate the level of vancomycin resistance among clinical and nasal S. aureus isolates in a rural town in Egypt. Methods: This cross-sectional study was held in the general hospital at the rural town of Kafr Eldawar in Egypt, during the period from January 2013 to January 2014. S. aureus isolates were collected from clinical samples and from nasal swabs. Results: Two hundred S. aureus isolates were collected, 80 (40%) from clinical samples and 120 (60%) from nasal carriage samples. Vancomycin resistant S. aureus (VRSA) was only detected in clinical samples, all collected from the outpatient clinic. Eleven VRSA isolates (13.8% of total S. aureus clinical isolates) and one strain of vancomycin-intermediate S. aureus (from nasal carriage) were detected. VRSA isolates were most resistant to ciprofloxacin (90.9%) and erythromycin (81.8%). Five isolates were resistant to all tested antibiotics: ciprofloxacin, clindamycin, erythromycin, linezolid, oxacillin, penicillin and trimethoprim sulfamethoxazole. MRSA was found to constitute 43.8% of clinical S. aureus isolates. The MRSA colonization rate among community individuals was 43.6%, 42.9% among healthcare workers and 51.4% among patients. Conclusion: The prevalence of VRSA was high in clinical samples suggesting that there is a high level of VRSA strains in Egypt that goes undetected since most laboratories only use disk diffusion for detection of vancomycin resistance. PMID- 30250834 TI - Carbapenem resistance among clinical and environmental Gram-negative isolates recovered from hospitals in Gaza strip, Palestine. AB - Background: The world is threatened by the ongoing emergence of carbapenem resistant organisms, which are contributing to increasing morbidity and mortality rates. The main objective of this study was to highlight carbapenem resistance among clinical and environmental Gram-negative bacteria (GNB) isolates. Methods: A cross-sectional study wherein 210 clinical isolates, 150 environmental swabs, and 110 air samples were collected from three major hospitals in Gaza strip: Al Shifa, AlNaser and the European Gaza hospitals. The study lasted for seven months (September 2016 to March 2017). All isolates/samples were cultured and identified using conventional bacteriological methods. All GNB isolates were tested for their antimicrobial susceptibility using the disk diffusion method. Modified Hodge Test (MHT) was performed to investigate carbapenemases production. Results: The overall percentage of carbapenem resistance among GNB was (30/247) 12.1%. Resistance to imipenem was (20/247) 8.1% while resistance to ertapenem and meropenem was (8/226) 3.5% and (2/247) 0.8%, respectively. The intensive care units exhibited the highest resistance rate 9/17 (52.9%). Carbapenem resistance among Enterobacteriaceae was (30/226) 13.2% while in Pseudomonas it was (0/21) 0%. Klebsiella spp. was the most resistant to carbapenems 13/90 (14.4%), followed by E. coli (9/91) 9.8%. Seven isolates out of 30 (23.3%) were positive for MHT. All Enterobacteriaceae isolates had a multiple antibiotic resistance (MAR) index higher than 0.2, while those of Pseudomonas had an average of 0.2. GNB were isolated from 19/110 (17.2%) and 21/150 (14%) of air and environmental samples, respectively. Conclusion: The resistance found, after a recent introduction of carbapenem use in Gaza, shows the need for policies to prevent misuse and overuse of carbapenems, the need for infection control procedures and screening policies for carbapenem resistance on a routine basis. PMID- 30250833 TI - Hypervirulent Klebsiella pneumoniae as a hospital-acquired pathogen in the intensive care unit in Mansoura, Egypt. AB - Introduction: Hypervirulent Klebsiella pneumoniae (hvKP) are variants of K. pneumoniae that come up worldwide. hvKP is known in community-acquired infections but little is known about its role in hospital-acquired (HA) infections. The aim of this study was to evaluate the frequency of hvKP among HA K. pneumoniae infections in the intensive care unit (ICU) and to compare virulence and antibiotic susceptibility between hvKP and classical K. pneumoniae (cKP). Methods: String test, biofilm formation, serum bactericidal assay, capsular polysaccharide genes (K1, K2, K5, K20, K54, K57), virulence genes: rmpA, rmpA2, iucA, iroB and antimicrobial susceptibility were assessed in HA K. pneumoniae strains isolated from the ICU in Mansoura, Egypt. Results: Probable hvKP represented 4 out of 65 (6.2%) K. pneumoniae. K1 and K2 genes were present in 2 and 1 isolate respectively in probable hvKP. rmpA genes were significantly associated with hvKP; at the same time biofilm production and serum resistance were not significantly associated with the hypervirulent group. There was no significant difference between hvKP and cKP strains in terms of resistance pattern. Conclusion: hvKP in critically ill patients from the ICU may form a new threat especially in the presence of antibiotic resistance. Although the validity of the string test in detecting metastatic Klebsiella is questionable, it is a simple and easy test that can be done in any laboratory indicating the presence of this organism. Serotypes and genomic background may provide helpful and confirmatory tools to diagnose hvKP. PMID- 30250835 TI - Soil contamination by Toxocara canis and human seroprevalence in the Attica region, Greece. AB - Background: Toxocara canis is one of the most widespread public health and economically important zoonotic parasitic infections humans share with canids, mainly dogs. Human infection occurs by the accidental ingestion of embryonated eggs or larvae from a range of wild and domestic paratenic hosts. The aim of the present study was to examine the soil contamination of public places by the parasitic ova and to estimate serologically the prevalence of T. canis human infection in the Attica region, Greece. Methods: In this region, public areas are permanently inhabited by dogs, mostly stray dog population that is hardly kept down to a manageable level. A total of 1,510 soil samples were collected from 33 public places of six regional units of Attica from March 2014 to April 2014 and ova were detected using a microscopic assay. In addition, sera were collected from 250 residents, routinely active in the sampled areas, and tested for T. canis IgG antibodies using an enzyme immunoassay. Results: T. canis eggs were isolated from 31 (94%) of the examined public areas. Of the total samples, T. canis ova were recovered from 258 samples, suggesting an overall T. canis ova contamination of 17.2%. The areas of higher socioeconomic status presented lower percentages of soil contamination in a statistically significant level, compared to the areas of lower socioeconomic status. T. canis IgG seropositivity was detected in 40 (16%) serum samples. Similar rates were established among T. canis seropositivity and soil contamination within the same geographical areas. The proportion of seropositive samples in the group of children was significantly higher compared to the proportion of adults (48% versus 8%, p<0.001). Conclusion: The level of environmental T. canis contamination as well as human infection found in the Attica region calls for a greater awareness towards this public issue. Preventing measures should be implemented to control the spread of this parasitic infection. PMID- 30250836 TI - Diversity of Human Milk Oligosaccharides and Effects on Early Life Immune Development. AB - One of the well-known features of human milk, is the capacity to protect against the risk and impact of neonatal infections, as well as to influence the onset of allergic and metabolic disease manifestations. The major objective of this review is to provide a detailed overview regarding the role of human milk, more specifically the diversity in human milk oligosaccharides (HMOS), on early life immune development. Novel insights in immune modulatory effects of HMOS obtained by in vitro as well as in vivo studies, adds to the understanding on how early life nutrition may impact immune development. Extensive description and analysis of single HMOS contributing to the diversity within the composition provided during breastfeeding will be discussed with specific emphasis on immune development and the susceptibility to neonatal and childhood infections. PMID- 30250837 TI - Pediatric ECMO Research: The Case for Collaboration. AB - The use of extracorporeal membrane oxygenation (ECMO) in the pediatric age has increased considerably in the last decade, as has the complexity of cases and the variety of indications outside of the neonatal age. However, no randomized controlled trials have been attempted to date to test ECMO as an intervention in non-neonatal pediatric patients with critical illness. In this review, we provide a brief overview of the history of clinical research in pediatric ECMO and discuss methodological challenges including heterogeneity of ages and diagnoses in the pediatric ECMO population, rapid advances in technology and clinical practice related to ECMO, feasibility of enrolling critically ill children on ECMO in clinical research studies, and variability in ECMO management across institutions and countries. Lastly, we discuss opportunities and existing infrastructure for future multicenter, multi-network research collaborations for pediatric ECMO studies. PMID- 30250838 TI - Sedentariness and Health: Is Sedentary Behavior More Than Just Physical Inactivity? AB - Sedentary behavior refers to certain activities in a reclining, seated, or lying position requiring very low energy expenditure. It has been suggested to be distinct from physical inactivity and an independent predictor of metabolic risk even if an individual meets current physical activity guidelines. Over the past decades, a shift in the activity profile of individuals has been observed with vigorous physical activity and sleep being partly replaced by cognitive work, a potential neurogenic stress component considering its hormonal and neurophysiological effects, leading to various impacts on health. Mental work, for instance, may significantly increase glycemic instability leading to an increase in the desire to eat and thus, higher energy intakes. Furthermore, screen-based leisure activities (e.g., television watching) and screen-based work activities (e.g., computer use for work purposes) have often been considered together while they may not trigger the same stress response and/or use of substrate. Thus, the problems of sedentariness may not only be attributed to a lack of movement, but also to the stimulation provided by replacing activities. The objective of this review is to discuss the (1) recent evidence and current state of knowledge regarding the health impact of sedentary behaviors on health; (2) potential neurogenic effects of cognitive work as a sedentary behavior; (3) link between sedentary behaviors and the diet; (4) resemblance between sedentary behaviors and the inadequate sleeper; and (5) potential solutions to reduce sedentary behaviors and increase physical activity. PMID- 30250839 TI - Raman Spectroscopy for Pharmaceutical Quantitative Analysis by Low-Rank Estimation. AB - Raman spectroscopy has been widely used for quantitative analysis in biomedical and pharmaceutical applications. However, the signal-to-noise ratio (SNR) of Raman spectra is always poor due to weak Raman scattering. The noise in Raman spectral dataset will limit the accuracy of quantitative analysis. Because of high correlations in the spectral signatures, Raman spectra have the low-rank property, which can be used as a constraint to improve Raman spectral SNR. In this paper, a simple and feasible Raman spectroscopic analysis method by Low-Rank Estimation (LRE) is proposed. The Frank-Wolfe (FW) algorithm is applied in the LRE method to seek the optimal solution. The proposed method is used for the quantitative analysis of pharmaceutical mixtures. The accuracy and robustness of Partial Least Squares (PLS) and Support Vector Machine (SVM) chemometric models can be improved by the LRE method. PMID- 30250840 TI - Construction of Fused Tropone Systems Through Intramolecular Rh(I)-Catalyzed Carbonylative [2+2+2+1] Cycloadditon of Triynes. AB - "Tropone" is a non-benzenoid aromatic skeleton that can be found in a variety of natural products. This cyclohepta-2,4,6-trien-1-one skeleton appears simple, but there have been no straightforward ways to construct this molecular architecture. It is conceivable that this molecule can be constructed via a higher order cycloaddition of three acetylene units and CO, but such process was not known until we have discovered that the carbonylative [2+2+2+1] cycloaddition of triynes can take place in the presence of a Rh complex catalyst and CO. However, this highly challenging process is naturally accompanied by ordinary [2+2+2] cyclotrimization products, i.e., benzenes, as side products. A mechanistic study led to two competing processes wherein the critical CO insertion occurs either to a rhodacyclopentadiene intermediate (Path A) or a rhodacycloheptatriene intermediate (Path B). The DFT analysis of those two pathways disclosed that the Path A should be the one that yields the carbonylative [2+2+2+1] cycloaddition products, i.e., fused tricyclic tropones. A further substrate design, inspired by colchicine structure, led to the almost exclusive formation of a fused tetracyclic tropone from a triyne bearing 1,2-disubstituted benzene moiety in a single step and excellent yield. PMID- 30250841 TI - Combined Multistate and Kohn-Sham Density Functional Theory Studies of the Elusive Mechanism of N-Dealkylation of N,N-Dimethylanilines Mediated by the Biomimetic Nonheme Oxidant FeIV(O)(N4Py)(ClO4)2. AB - The oxidative C-H bond activation mediated by heme and nonheme enzymes and related biomimetics is one of the most interesting processes in bioinorganic and oxidative chemistry. However, the mechanisms of these reactions are still elusive and controversy due to the involvement of highly reactive metal-oxo intermediates with multiple spin states, despite extensive experimental efforts, especially for the N-dealkylation of N,N-dialkyalinines. In this work, we employed multistate density functional theory (MSDFT) and the Kohn-Sham DFT to investigate the mechanism of N-demethylation of N,N-dimethyalinines oxidized by the reaction intermediate FeIV(O)(N4Py)(ClO4)2. The Kohn-Sham DFT study demonstrated that the reaction proceeds via a rate-limiting hydrogen atom transfer (HAT) step and a subsequent barrier-free oxygen rebound step to form the carbinol product. The MSDFT investigation on the first C-H activation further showed that this step is an initial hydrogen atom abstraction that is highly correlated between CEPT and HAT, i.e., both CEPT and HAT processes make significant contributions to the mechanism before reaching the diabatic crossing point, then the valence bond character of the adiabatic ground state is switched to the CEPT product configuration. The findings from this work may be applicable to other hydrogen abstraction process. PMID- 30250842 TI - Light-Mediated Growth of Noble Metal Nanostructures (Au, Ag, Cu, Pt, Pd, Ru, Ir, Rh) From Micro- and Nanoscale ZnO Tetrapodal Backbones. AB - Micro- and nanoscale ZnO tetrapods provide an attractive support for metallic nanostructures since they can be inexpensively produced using the flame transport method and nanoparticle synthesis schemes can take advantage of a coupled response facilitated by the formation of a semiconductor-metal interface. Here, we present a light-mediated solution-based growth mode capable of decorating the surface of ZnO tetrapods with nanostructures of gold, silver, copper, platinum, palladium, ruthenium, iridium, and rhodium. It involves two coupled reactions that are driven by the optical excitation of electron-hole pairs in the ZnO semiconductor by ultraviolet photons where the excited electrons are used to reduce aqueous metal ions onto the ZnO tetrapod as excited holes are scavenged from the surface. For the most part, the growth mode gives rise to nanoparticles with a roundish morphology that are uniformly distributed on the tetrapod surface. Larger structures with irregular shapes are, however, obtained for syntheses utilizing aqueous metal nitrates as opposed to chlorides, a result that suggests that the anion plays a role in shape determination. It is also demonstrated that changes to the molarity of the metal ion can influence the nanostructure nucleation rate. The catalytic activity of tetrapods decorated with each of the eight metals is assessed using the reduction of 4-nitrophenol by borohydride as a model reaction where it is shown that those decorated with Pd, Ag, and Rh are the most active. PMID- 30250844 TI - From Early Immunomodulatory Triggers to Immunosuppressive Outcome: Therapeutic Implications of the Complex Interplay Between the Wavebands of Sunlight and the Skin. AB - Phototherapy is an efficient treatment for many cutaneous diseases that involve the activation of inflammatory pathways or the overgrowth of cells with aberrant phenotype. In this review, we discuss recent advances in photoimmunology, focusing on the effects of UV-based therapies currently used in dermatology. We describe the molecular responses to the main forms of photo(chemo)therapy such as UVB, UVA-1, and PUVA that include the triggering of apoptotic or immunosuppressive pathways and help to clear diseased skin. The early molecular response to UV involves DNA photoproducts, the isomerization of urocanic acid, the secretion of biophospholipids such as platelet activating factor (PAF), the activation of aryl hydrocarbon receptor and inflammasome, and vitamin D synthesis. The simultaneous and complex interaction of these events regulates the activity of the immune system both locally and systemically, resulting in apoptosis of neoplastic and/or benign cells, reduction of cellular infiltrate, and regulation of cytokines and chemokines. Regulatory T-cells and Langerhans cells, among other skin-resident cellular populations, are deeply affected by UV exposure and are therefore important players in the mechanisms of immunomodulation and the therapeutic value of UV in all its forms. We weigh the contribution of these cells to the therapeutic application of UV and how they may participate in transferring the direct impact of UV on the skin into local and systemic immunomodulation. Moreover, we review the therapeutic mechanisms revealed by clinical and laboratory animal investigations in the most common cutaneous diseases treated with phototherapy such as psoriasis, atopic dermatitis, vitiligo, and cutaneous T-cell lymphoma. Better understanding of phototherapeutic mechanisms in these diseases will help advance treatment in general and make future therapeutic strategies more precise, targeted, personalized, safe, and efficient. PMID- 30250845 TI - Polymorphic Light Eruption: What's New in Pathogenesis and Management. AB - Polymorphic light eruption is the commonest photosensitive disorder, characterized by an intermittent eruption of non-scarring erythematous papules, vesicles or plaques that develop within hours of ultraviolet radiation exposure of patient skin. Together with the lesions, a terrible itch starts and increases with the spreading of the disease, sometimes aggravated by a sort of burning sensation. Clinical picture and symptoms can improve during the rest of the summer with further solar exposures. In the last years many advances have been performed in the knowledge of its pathogenesis and some news have been proposed as preventive, as well as therapeutic options. All this has been discussed in the current mini review. PMID- 30250843 TI - Hypoxia and Selective Autophagy in Cancer Development and Therapy. AB - Low oxygen availability, a condition known as hypoxia, is a common feature of various pathologies including stroke, ischemic heart disease, and cancer. Hypoxia adaptation requires coordination of intricate pathways and mechanisms such as hypoxia-inducible factors (HIFs), the unfolded protein response (UPR), mTOR, and autophagy. Recently, great effort has been invested toward elucidating the interplay between hypoxia-induced autophagy and cancer cell metabolism. Although novel types of selective autophagy have been identified, including mitophagy, pexophagy, lipophagy, ERphagy and nucleophagy among others, their potential interface with hypoxia response mechanisms remains poorly understood. Autophagy activation facilitates the removal of damaged cellular compartments and recycles components, thus promoting cell survival. Importantly, tumor cells rely on autophagy to support self-proliferation and metastasis; characteristics related to poor disease prognosis. Therefore, a deeper understanding of the molecular crosstalk between hypoxia response mechanisms and autophagy could provide important insights with relevance to cancer and hypoxia-related pathologies. Here, we survey recent findings implicating selective autophagy in hypoxic responses, and discuss emerging links between these pathways and cancer pathophysiology. PMID- 30250846 TI - Dicarbonyl Stress and Glyoxalase-1 in Skeletal Muscle: Implications for Insulin Resistance and Type 2 Diabetes. AB - Glyoxalase-1 (GLO1) is a ubiquitously expressed cytosolic protein which plays a role in the natural maintenance of cellular health and is abundantly expressed in human skeletal muscle. A consequence of reduced GLO1 protein expression is cellular dicarbonyl stress, which is elevated in obesity, insulin resistance and type 2 diabetes (T2DM). Both in vitro and pre-clinical models suggest dicarbonyl stress per se induces insulin resistance and is prevented by GLO1 overexpression, implicating a potential role for GLO1 therapy in insulin resistance and type 2 diabetes (T2DM). Recent work has identified the therapeutic potential of novel natural agents as a GLO1 inducer, which resulted in improved whole-body metabolism in obese adults. Given skeletal muscle is a major contributor to whole body glucose, lipid, and protein metabolism, such GLO1 inducers may act, in part, through mechanisms in skeletal muscle. Currently, investigations examining the specificity of dicarbonyl stress and GLO1 biology in human skeletal muscle are lacking. Recent work from our lab indicates that dysregulation of GLO1 in skeletal muscle may underlie human insulin resistance and that exercise training may impart therapeutic benefits. This minireview will summarize the existing human literature examining skeletal muscle GLO1 and highlight the emerging therapeutic concepts for GLO1 gain-of-function in conditions such as insulin resistance and cardiometabolic disease. PMID- 30250848 TI - Uterine Fibroids: From Molecular Oncology to Reproduction. PMID- 30250847 TI - Submucous Fibroids, Fertility, and Possible Correlation to Pseudocapsule Thickness in Reproductive Surgery. AB - Background and Objectives: Fibroids are related to infertility. Fibroid pseudocapsule is a neurovascular bundle surrounding leiomyomas rich of neurofibers involved in myometrial biology. Authors evaluated, by a case-control study, the fibroid pseudocapsule (FP) thickness by ultrasound (US) and the histological measurements, according to uterine location of fibroids. Methods: 137 consecutive patients undergoing hysterectomy for uterine myomas were enrolled and 200 myomas were evaluated. Before surgery, patients underwent an ultrasound (US) investigation to evaluate the number, the size, and the location of fibroids. After surgery, myoma-pseudocapsule-myometrium specimens were measured and evaluated by a single expert pathologist. Both US and histological data were collected and statistically analyzed. Results: Our results confirm the relevant difference of FP thickness, particularly represented under the endometrium for submucous LMs. FPs near the endometrial cavity were considerably thicker than those of both intramural fibroids and subserous fibroids measured by US (P=0.0001) and histology (P=0.0001). A clear cut-off measurement at 2 mm (P=0.0001) was found between endometrial FPs and all other FPs for either US or histology measurements. Conclusion: The thickness of FP is considerably higher near the endometrial cavity when compared to those of both intramural and subserous LMs, suggesting a potential role either in fertility or in myometrial healing. PMID- 30250849 TI - Obesity-Linked Gut Microbiome Dysbiosis Associated with Derangements in Gut Permeability and Intestinal Cellular Homeostasis Independent of Diet. AB - This study aimed to determine the association between non-high-fat diet-induced obesity- (non-DIO-) associated gut microbiome dysbiosis with gut abnormalities like cellular turnover of intestinal cells, tight junctions, and mucin formation that can impact gut permeability. We used leptin-deficient (Lepob/ob) mice in comparison to C57BL/6J control mice, which are fed on identical diets, and performed comparative and correlative analyses of gut microbiome composition, gut permeability, intestinal structural changes, tight junction-mucin formation, cellular turnover, and stemness genes. We found that obesity impacted cellular turnover of the intestine with increased cell death and cell survival/proliferation gene expression with enhanced stemness, which are associated with increased intestinal permeability, changes in villi/crypt length, and decreased expression of tight junctions and mucus synthesis genes along with dysbiotic gut microbiome signature. Obesity-induced gut microbiome dysbiosis is also associated with abnormal intestinal organoid formation characterized with decreased budding and higher stemness. Results suggest that non-DIO-associated gut microbiome dysbiosis is associated with changes in the intestinal cell death versus cell proliferation homeostasis and functions to control tight junctions and mucous synthesis-regulating gut permeability. PMID- 30250850 TI - The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice. AB - The haptoglobin (Hp) genotype (1-1 and 2-2) is a major determinant of nephropathy progression in diabetes mellitus patients. Hp 2-2 diabetic mice have impaired Hb clearance and increased iron deposits and oxidative stress in the proximal tubules (PCT), leading to increased renal injury. However, the precise mechanism of the PCT injury in diabetic nephropathy (DN) remains elusive. In the kidney, 1,25(OH)2D3 suppresses the inflammatory response to renal tubular injury and requires normal renal expression of the alpha-klotho protein. In this study, we set out to test the hypothesis that the increased renal iron deposits in the PCT of Hp 2-2 DN affect the alpha-klotho-vitamin D receptor (VDR) axis and thereby exacerbates the PCT injury generated by the iron deposits. Immunohistochemical analysis of human and mouse kidney biopsies along with western blot analysis showed that the increased iron deposits in the PCT of the Hp 2-2 genotype were accompanied with significantly decreased alpha-klotho and VDR renal expression but significantly increased 1-alpha-hydroxylase renal expression. In conclusion, the iron-klotho-VDR axis is a major player in the mechanism contributing to iron mediated PCT injury in diabetic Hp 2-2 mice and patients. Targeting this axis may open the way for new ideas regarding the pathogenesis and treatment of DN. PMID- 30250852 TI - A Modified Small-Incision Lenticule Intrastromal Keratoplasty (sLIKE) for the Correction of High Hyperopia: A Description of a New Surgical Technique and Comparison to Lenticule Intrastromal Keratoplasty (LIKE). AB - Patients with high hyperopia are generally confined to either spectacle wear or contact lenses as a primary means of refractive correction. For this patient population, the surgical corrective methods, such as hyperopic laser assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) are imperfect options due to induction of higher-order aberrations, optical regression, and loss of best corrected distance visual acuity. Recently, there has been growing interest in lenticule implantation underneath a flap via lenticule intrastromal keratoplasty (LIKE) for high hyperopia correction (+3 diopters to +10 diopters). We instead propose a modified surgical technique (small-incision lenticule intrastromal keratoplasty, sLIKE), in which the lenticule is implanted inside an intrastromal pocket thereby causing less injury to the subbasal nerve plexus injury, less postoperative dry eye symptoms, less reduction in biomechanical strength, and lower chances for epithelial ingrowth. We provide an overview of these novel surgical techniques to treat high hyperopia, and compare the associated advantages and disadvantages. In addition, we will discuss the enhancement options and methods of optimization for both surgical techniques. PMID- 30250853 TI - Teleophthalmology Support for Primary Care Diagnosis and Management. AB - This study was performed to evaluate a healthcare strategy based on teleophthalmology for diagnosis and management of primary healthcare users. A descriptive cross-sectional study was conducted to review the medical records of patients from January 2013 to December 2014 from primary care units in the city of Sao Paulo. The units referred patients, who had diabetes or high blood pressure, and were users of chloroquine compounds, for a fundus examination. The images were sent to a reading center for review, diagnosis, and patient referrals. From 9173 analyzed patients, 570 (6.2%) were excluded because of poor image quality. Of the remaining patients, 4933 (57.3%) had diabetes, 7242 (84,2%) systemic hypertension, and 113 (1.3%) used chloroquine. Of these, 989 (11.5%) patients needed ophthalmologic treatment. The most frequently prescribed treatments were cataract extraction in 692 (70%) of 989 and photocoagulation in 245 (24.8%) of 989 cases. Overall, cataract extraction was indicated in 692 (8%) of 8603 cases and photocoagulation in 245 (2.8%) of 8603 cases. When only patients with diabetes were considered, the indication for photocoagulation increased to 4.5%.The results showed that non-medical professionals could produce good-quality ocular images for screening of ocular diseases in most cases; only 6.2% of ocular images did not meet quality requirements. Most patients referred for fundus examination did not need a specific treatment, indicating that this system could be an inexpensive and reliable tool for use in developing countries. PMID- 30250851 TI - Skeletal Status, Body Composition, and Glycaemic Control in Adolescents with Type 1 Diabetes Mellitus. AB - Background: Disturbed bone turnover, osteoporosis, and increased fracture risk are late complications of insulin-dependent diabetes mellitus. Little is known about how far and to what extent can glycaemic control of type 1 diabetes mellitus (T1DM) prevent disturbances of bone health and body composition during the growth and maturation period. Objective: The aim of this cross-sectional study was to compare the skeletal status outcomes and body composition between patients stratified by glycaemic control (1-year HbA1c levels) into well- and poorly-controlled subgroups in a population of T1DM adolescents, that is, <8% and >=8%, respectively. Subjects and Methods: Skeletal status and body composition were evaluated in 60 adolescents with T1DM (53.3% female; mean aged: 15.1 +/- 1.9 years; disease duration: 5.1 +/- 3.9 years) using dual energy X-ray absorptiometry (GE Prodigy). The results were compared to age- and sex-adjusted reference values for healthy controls. The calculated Z-scores of different metabolic control subgroups were compared. Clinical data was also assessed. Results: As evidenced by Z-scores, patients with T1DM revealed a significantly lower TBBMD (total body bone mineral density), TBBMC (total body bone mineral content), S24BMD (bone mineral density of lumbar spine L2-L4), and TBBMC/LBM ratio (total body bone mineral content/lean body mass), but higher FM (fat mass) and FM/LBM ratio (fat mass/lean body mass) values compared to an age- and sex adjusted general population. The subset (43.3% patients) with poor metabolic control (HbA1c >= 8%) had lower TBBMD, TBBMC, and LBM compared to respective values noted in the HbA1c < 8% group, after adjusting for confounders (mean Z scores: -0.74 vs. -0.10, p = 0.037; -0.67 vs. +0.01, p = 0.026; and -0.45 vs. +0.20, p = 0.043, respectively). Additionally, we found a significant difference in the TBBMC/LBM ratio (relative bone strength index) between the metabolic groups (-0.58 vs. -0.07; p = 0.021). A statistically significant negative correlation between 1-year HbA1c levels and Z-scores of TBBMD, TBBMC, and LBM was also observed. In patients with longer disease duration, a significant negative correlation was established only for TBBMD, after adjusting for confounders. The relationships between densitometric values and age at onset of T1DM and sex were not significant and showed no relation to any of the analysed parameters of the disease course. Conclusion: Findings from this study of adolescents with T1DM indicate that the lower Z-scores of TBBMD, TBBMC, and LBM as well as the TBBMC/LBM ratio are associated with increased HbA1c levels. Their recognition can be crucial in directing strategies to optimise metabolic control and improve diabetes management for bone development and maintenance in adolescents with T1DM. PMID- 30250854 TI - Short-Term Results of Sutureless Scleral Tunnel Trabeculectomy Using Adjunctive Topical Bevacizumab. AB - This study was performed to assess the short-term effect of sutureless scleral tunnel trabeculectomy procedure with and without topical bevacizumab. Thirty patients with Primary Open-Angle Glaucoma (POAG) were enrolled and randomly divided to two groups. Patients in the first group (15 patients) underwent sutureless trabeculectomy without topical bevacizumab and patients in the second group (15 patients) underwent sutureless trabeculectomy with 1.25 mg of topical bevacizumab. Intraocular Pressure (IOP) of both groups was measured by an expert ophthalmologist, without awareness of the patient's study group before the operation and six months post-operatively. Out of 30 patients in this study, six females (40%) and nine males (60%) underwent the sutureless trabeculectomy procedure (group A) as well as seven females (46.7%) and eight males (53.3%) underwent sutureless trabeculectomy with topical bevacizumab (group B). The mean age of the patients was not significantly different between the two groups (P = 0.91). A statistically significant difference in time variation of IOP was found between the two groups (P < 0.001). Mean IOP was 18.4 +/- 4.35 mmHg in the sutureless group without bevacizumab and 11.73 +/- 2.12 mmHg in the sutureless group with bevacizumab, six months post-surgically. No statistical significant differences were found in the baseline IOP between the two groups (P = 0.28). However, IOP changed significantly in group A and B from baseline to six months post-operatively (P = 0.004 and P < 0.001 respectively). According to the current findings, the sutureless trabeculectomy procedure is an effective surgical method for reduction of IOP. Addition of a single dose of 1.25 mg topical bevacizumab was more effective in reduction of IOP compared to sutureless trabeculectomy alone. PMID- 30250855 TI - Corneal Biomechanical Properties and Thickness in Primary Congenital Glaucoma and Normal Eyes: A Comparative Study. AB - The correct estimation of Intraocular Pressure (IOP) is the most important factor in the management of various types of glaucoma. Primary congenital glaucoma is a type of glaucoma that can cause blindness in the absence of control of the IOP. In this retrospective observational study, 95 eyes, including 48 healthy eyes and 47 eyes with Primary Congenital Glaucomatous (PCG) were studied. Two groups were matched for age, gender, and Goldman Applanation Tonometry (GIOP). Corneal Hysteresis (CH), Corneal Resistance Factor (CRF), and Goldman intraocular pressure were measured by ORA (IOPg), and corneal compensated Intraocular Pressure (IOPcc) was measured for each patient using the Ocular Response Analyzer (ORA). Central Corneal Thickness (CCT) was measured by ultrasonic pachymetry. For each patient, one eye was selected randomly. Student's t-test and analytical regression were used for statistical analysis. The two groups were matched for age (P = 0.34), gender (P = 0.47), and GIOP (P = 0.17). Corneal hysteresis and CRF were significantly lower in PCG than in normal eyes (P < 0.0001), yet CCT was significantly thicker in PCG than normal eyes (P < 0.0001). The regression equation on the effect of CH, CRF, and CCT on GIOP in the PCG group showed that CH and CRF (P-value = 0.001 and P-value<0.0001) also had a significant effect yet CCT did not (P-value = 0.691). A significant decrease in CH and CRF was found in the PCG group compared to the normal controls. In the PCG group, the CCT was greater than normal. These results showed the usefulness of biomechanical properties (CH, CRF) in order to interpret IOP measurements. Furthermore, GIOP measurement may not be confined to consideration of CCT alone. A low CH and CRF value could be responsible for under-estimation of GIOP in the PCG group, in comparison to the normal controls. PMID- 30250856 TI - Reoperation in Horizontal Strabismus and its Related Risk Factors. AB - This study was performed to determine the surgical outcomes and the related risk factors of second operation in patients with residual horizontal deviations. In this interventional case series study, a total of 119 patients with a history of reoperation were included (39 exotropia and 80 esotropia). Cases with consecutive strabismus, muscular palsy, systemic disease, lack of ocular fixation, and those, who had vertical deviation and Dissociated Vertical Deviation (DVD)>5 Prism Diopters (pd) were excluded. Medial Rectus (MR) resection in residual Exotropia (XT) and Lateral Rectus (LR) resection in residual Esotropia (ET) were performed. Unilateral or bilateral operations were considered if the preoperative residual deviation was < 20 pd or > 20 pd, respectively. Success of the reoperation was considered if the postoperative angle of deviation was <= 10 pd. Unilateral and bilateral MR resection was performed in 26% and 74% of patients with XT, respectively, with greater dose response in unilateral cases (2.8 versus 2.6 mm/pd). Successful surgical outcomes were observed in 94.9% of patients with XT. Unilateral and bilateral LR resection was also performed in patients with residual ET, each in 50% of patients. Unilateral cases showed greater dose response compared to bilateral ones (2.6 versus 2 mm/pd) and successful surgical outcomes were observed in 83.8% of patients with ET. No variable was found as a risk factor of reoperation in both groups. In conclusion, both LR and MR resection are easy and predictable surgical approaches with high success rate in patients with residual ET and XT. Generally, MR resection is more effective than LR resection. Unilateral operation is less recommended in the residual exotropic group, due to its lower success compared to the bilateral operation. Unfortunately, none of the mentioned variables were found to be the risk factor of reoperation in the sampled patients. PMID- 30250857 TI - Combined Lateral Rectus Myectomy and Maximal Medial Rectus Resection in Complete Third Cranial Nerve Palsy. AB - This study was performed to describe lateral rectus myectomy and maximal medial rectus resection for correction of eye deviation in complete third cranial nerve palsy. A retrospective review of thirteen patients (fourteen eyes) with complete third cranial nerve palsy, who underwent lateral rectus myectomy and maximal medial rectus resection, was performed. These procedures were combined with superior oblique tendon transposition in nine patients with a large angle of exotropia (more than 60 prism diopters [?]), or significant hypotropia (more than 5 ?). Preoperative deviations were exotropia of 50 to 120 ? in thirteen cases and hypotropia of 5 to 25 ? in eight cases. Six months after the surgery, eleven patients were within 10 ? of orthotropia in primary position. Revision surgery was performed for two patients, eight and 18 months after the first operation. Eventually, five patients (38%) achieved orthotropia in the primary position, and seven patients (54%) had < 11 ? exotropia and < 6 ? vertical deviation. In conclusion, this procedure can be considered as an acceptable approach for treatment of strabismus in complete third cranial nerve palsy. This procedure is simple and can be easily performed even in very young children. PMID- 30250858 TI - The Effect of Artificial Tear Preparations with Three Different Ingredients on Contrast Sensitivity in Patients with Dry Eye Syndrome. AB - This study was conducted to investigate the effects of Artificial Tear Preparations (ATP) with three different ingredients on contrast sensitivity in patients with dry eye syndrome. Contrast sensitivity measurements were obtained before and 5, 15, 30, 60, and 90 minutes after administering three different ATPs, containing dextran 70, hydroxypropyl methylcellulose (ATP-1), polyvinyl alcohol-povidone (ATP-2) and carbomer (ATP-3) to one eye of 20 patients with dry eye syndrome, who had been divided to three groups. Contrast sensitivity measurements were obtained at 1.5, 3, 6, 12, and 18 spatial frequencies (cpd). Compared with the baseline measurements, ATP-1 provided a significant increase of 1.5 and 3 cpd at the 15th minute, 12 cpd at the 60th minute, and 18 cpd at the 30th minute, ATP-2 significantly increased contrast sensitivity compared with the baseline at the 15th, 30th, 60th, and 90th minute measurements, recorded as 1.5, 3, 12, and 18 cpd, and ATP-3 provided significant increases of 18 cpd at 60th and 90th minute measurements compared with the baseline. In conclusion, while ATP-2 increased the majority of contrast sensitivity measurements both at early, mid, and late terms, the ATP-1 and ATP-3 were found to be effective on mid-term and late-term contrast sensitivity measurements, respectively. PMID- 30250859 TI - Somatosensory and auditory deviance detection for outcome prediction during postanoxic coma. AB - Objective: Prominent research in patients with disorders of consciousness investigated the electrophysiological correlates of auditory deviance detection as a marker of consciousness recovery. Here, we extend previous studies by investigating whether somatosensory deviance detection provides an added value for outcome prediction in postanoxic comatose patients. Methods: Electroencephalography responses to frequent and rare stimuli were obtained from 66 patients on the first and second day after coma onset. Results: Multivariate decoding analysis revealed an above chance-level auditory discrimination in 25 patients on the first day and in 31 patients on the second day. Tactile discrimination was significant in 16 patients on the first day and in 23 patients on the second day. Single-day sensory discrimination was unrelated to patients' outcome in both modalities. However, improvement of auditory discrimination from first to the second day was predictive of good outcome with a positive predictive power (PPV) of 0.73 (CI = 0.52-0.88). Analyses considering the improvement of tactile, auditory and tactile, or either auditory or tactile discrimination showed no significant prediction of good outcome (PPVs = 0.58-0.68). Interpretation: Our results show that in the acute phase of coma deviance detection is largely preserved for both auditory and tactile modalities. However, we found no evidence for an added value of somatosensory to auditory deviance detection function for coma-outcome prediction. PMID- 30250860 TI - Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross-sectional diffusion tensor imaging study. AB - Objective: We aimed to investigate mutation-specific white matter (WM) integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72,MAPT, and GRN mutations by use of diffusion-weighted imaging within the Genetic Frontotemporal dementia Initiative (GENFI) study. Methods: One hundred and forty mutation carriers (54 C9orf72, 30 MAPT, 56 GRN), 104 presymptomatic and 36 symptomatic, and 115 noncarriers underwent 3T diffusion tensor imaging. Linear mixed effects models were used to examine the association between diffusion parameters and years from estimated symptom onset in C9orf72,MAPT, and GRN mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left-right asymmetry analyses on GRN mutation carriers versus noncarriers. Results: Diffusion changes in C9orf72 mutation carriers are present significantly earlier than both MAPT and GRN mutation carriers - characteristically in the posterior thalamic radiation and more posteriorly located tracts (e.g., splenium of the corpus callosum, posterior corona radiata), as early as 30 years before estimated symptom onset. MAPT mutation carriers showed early involvement of the uncinate fasciculus and cingulum, sparing the internal capsule, whereas involvement of the anterior and posterior internal capsule was found in GRN. Restricting analyses to presymptomatic mutation carriers only, similar - albeit less extensive - patterns were found: posteriorly located WM tracts (e.g., posterior thalamic radiation, splenium of the corpus callosum, posterior corona radiata) in presymptomatic C9orf72, the uncinate fasciculus in presymptomatic MAPT, and the internal capsule (anterior and posterior limbs) in presymptomatic GRN mutation carriers. In GRN, most tracts showed significant left-right differences in one or more diffusion parameter, with the most consistent results being found in the UF, EC, RPIC, and ALIC. Interpretation: This study demonstrates the presence of early and widespread WM integrity loss in presymptomatic FTD, and suggests a clear genotypic "fingerprint." Our findings corroborate the notion of FTD as a network based disease, where changes in connectivity are some of the earliest detectable features, and identify diffusion tensor imaging as a potential neuroimaging biomarker for disease-tracking and -staging in presymptomatic to early-stage familial FTD. PMID- 30250861 TI - Pre-amyloid stage of Alzheimer's disease in cognitively normal individuals. AB - Objective: To study risk factors for decreasing abeta1-42 concentrations in cerebrospinal fluid (CSF) in cognitively unimpaired individuals with initially normal amyloid and tau markers, and to investigate whether such abeta1-42 decreases are associated with subsequent decline in cognition and other biomarkers of Alzheimer's disease. Methods: Cognitively normal subjects (n = 83, 75 +/- 5 years, 35(42%) female) with normal CSF abeta1-42 and tau and repeated CSF sampling were selected from ADNI. Subject level slopes of abeta1-42 decreases were estimated with mixed models. We tested associations of baseline APP processing markers (BACE1 activity, abeta1-40, abeta1-38 and sAPP beta) and decreasing abeta1-42 levels by including an interaction term between time and APP marker. Associations between decreasing abeta1-42 levels and clinical decline (i.e., progression to mild cognitive impairment or dementia, MMSE, memory functioning) and biological decline (tau, hippocampal volume, glucose processing and amyloid PET) over a time period of 8-10 years were assessed. Results: Abeta1 42 levels decreased annually with -4.6 +/- 1 pg/mL. Higher baseline BACE1 activity (beta(se) = -0.06(0.03), P < 0.05), abeta1-40 (beta(se)= -0.11(.03), P < 0.001), and abeta1-38 levels (beta(se) = -0.11(0.03), P < 0.001) predicted faster decreasing abeta1-42. The fastest tertile of decreasing abeta1-42 rates was associated with subsequent pathophysiological processes: 11(14%) subjects developed abnormal amyloid levels after 3 +/- 1.7 years, showed increased risk for clinical progression (Hazard Ratio[95CI] = 4.8[1.1-21.0]), decreases in MMSE, glucose metabolism and hippocampal volume, and increased CSF tau and amyloid aggregation on PET (all P < 0.05). Interpretation: Higher APP processing and fast decreasing abeta1-42 could be among the earliest, pre-amyloid, pathological changes in Alzheimer's disease. PMID- 30250862 TI - Transient ischemia facilitates neuronal chloride accumulation and severity of seizures. AB - Objective: Preceding oxygen glucose deprivation (OGD) and ongoing seizures have both been reported to increase neuronal chloride concentration ([Cl-]i), which may contribute to anticonvulsant failure by reversing the direction of chloride currents at inhibitory GABAA synapses. Methods: The effects of OGD on [Cl-]i, seizure activity, and anticonvulsant efficacy were studied in a chronically epileptic in vitro preparation. Results: Seizures initially increased during OGD, followed by suppression. On reperfusion, seizure frequency and [Cl-]i progressively increased, and phenobarbital efficacy was reduced. Bumetanide (10 MUmol/L) and furosemide (1 mmol/L) prevented or reduced the OGD induced [Cl-]i increase. Phenobarbital efficacy was enhanced by bumetanide (10 MUmol/L). Furosemide (1 mmol/L) suppressed recurrent seizures. Interpretation: [Cl-]i increases after OGD and is associated with worsened seizure activity, reduced efficacy of GABAergic anticonvulsants, and amelioration by antagonists of secondary chloride transport. PMID- 30250863 TI - Physiological and pathological high frequency oscillations in focal epilepsy. AB - Objective: This study investigates high-frequency oscillations (HFOs; 65-600 Hz) as a biomarker of epileptogenic brain and explores three barriers to their clinical translation: (1) Distinguishing pathological HFOs (pathHFO) from physiological HFOs (physHFO). (2) Classifying tissue under individual electrodes as epileptogenic (3) Reproducing results across laboratories. Methods: We recorded HFOs using intracranial EEG (iEEG) in 90 patients with focal epilepsy and 11 patients without epilepsy. In nine patients with epilepsy putative physHFOs were induced by cognitive or motor tasks. HFOs were identified using validated detectors. A support vector machine (SVM) using HFO features was developed to classify tissue under individual electrodes as normal or epileptogenic. Results: There was significant overlap in the amplitude, frequency, and duration distributions for spontaneous physHFO, task induced physHFO, and pathHFO, but the amplitudes of the pathHFO were higher (P < 0.0001). High gamma pathHFO had the strongest association with seizure onset zone (SOZ), and were elevated on SOZ electrodes in 70% of epilepsy patients (P < 0.0001). Failure to resect tissue generating high gamma pathHFO was associated with poor outcomes (P < 0.0001). A SVM classified individual electrodes as epileptogenic with 63.9% sensitivity and 73.7% specificity using SOZ as the target. Interpretation: A broader range of interictal pathHFO (65-600 Hz) than previously recognized are biomarkers of epileptogenic brain, and are associated with SOZ and surgical outcome. Classification of HFOs into physiological or pathological remains challenging. Classification of tissue under individual electrodes was demonstrated to be feasible. The open source data and algorithms provide a resource for future studies. PMID- 30250865 TI - Flupirtine derivatives as potential treatment for the neuronal ceroid lipofuscinoses. AB - Objective: Neuronal Ceroid Lipofuscinoses (NCL) are fatal inherited neurodegenerative diseases with established neuronal cell death and increased ceramide levels in brain, hence, a need for disease-modifying drug candidates, with potential to enhance growth, reduce apoptosis and lower ceramide in neuronal precursor PC12 cells and human NCL cell lines using enhanced flupirtine aromatic carbamate derivatives in vitro. Methods: Aromatic carbamate derivatives were tested by establishing growth curves under pro-apoptotic conditions and activity evaluated by trypan blue and JC-1 staining, as well as a drop in pro-apoptotic ceramide in neuronal precursor PC12 cells following siRNA knockdown of the CLN3 gene, and CLN1-/CLN2-/CLN3-/CLN6-/CLN8 patient-derived lymphoblasts. Ceramide levels were determined in CLN1-/CLN2-/CLN3-/CLN6-/CLN8 patient-derived lymphoblasts before and after treatment. Expression of BCL-2, ceramide synthesis enzymes (CERS2/CERS6/SMPD1/DEGS2) and Caspases 3/8/9 levels were compared in treated versus untreated CLN3-deficient PC12 cells by qRT-PCR. Results: Retigabine, the benzyl-derivatized carbamate and an allyl carbamate derivative were neuroprotective in CLN3-defective PC12 cells and rescued CLN1-/CLN2-/CLN3 /CLN6-/CLN8 patient-derived lymphoblasts from diminished growth and accelerated apoptosis. All drugs decreased ceramide in CLN1-/CLN2-/CLN3-/CLN6-/CLN8 patient derived lymphoblasts. Increased BCL-2 and decreased ceramide synthesis enzyme expression were established in CLN3-derived PC12 cells treated with the benzyl and allyl carbamate derivatives. They down-regulated Caspase 3/Caspase 8 expression. Caspase 9 expression was reduced by the benzyl-derivatized carbamate. Interpretation: These findings establish that compounds analogous to flupirtine demonstrate anti-apoptotic activity with potential for treatment of NCL disease and use of ceramide as a marker for these diseases. PMID- 30250864 TI - A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome. AB - Introduction: Both Delta9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects. Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy. Primary objective was to establish dosing and tolerability of TIL-TC150 - a cannabis plant extract produced by Tilray(r), containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life. Methods: Twenty children received add-on therapy with TIL-TC150. The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC. Patients were monitored for tolerability and adverse events, and secondary objectives. Results: Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%. Conclusions: TIL TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC containing cannabinoid preparations. PMID- 30250866 TI - Seizures, periodic and rhythmic patterns in primary intraventricular hemorrhage. AB - Objective: Primary intraventricular hemorrhage (pIVH) uncommonly presents with seizures. There are no prior data regarding the frequency of seizures, periodic and rhythmic patterns on continuous electroencephalography (EEG), (cEEG) in these patients. Methods: We retrospectively assessed frequency of seizures, periodic discharges, and rhythmic patterns in pIVH patients undergoing cEEG monitoring. We reviewed indications for cEEG, demographics, GCS at presentation and during cEEG, modified Graeb score (mGS), presence of hydrocephalus, cEEG duration, findings and use of antiseizure medications (ASM). cEEG patterns were classified according to location and morphology. All patterns were considered "hyperexcitable" except GRDA. The ictal-interictal continuum (IIC) was defined as LRDA, PDs, and/or SW >1 Hz but <2.5 Hz, not meeting criteria for definite electrographic seizures. Results: Eleven patients had pIVH with median age of 81 (46-87) years and median mGS of 15 (9-23). Hydrocephalus was present in 7 (63.6%) and all underwent external ventricular drain (EVD) placement. Median cEEG recording was 19 (12-156) hours. Periodic or rhythmic EEG patterns were seen in 7 of 11 (64%), 5 of which were "hyperexcitable". For the 5 patients with pIVH, EVDs, and hyperexcitable patterns, 4 (80%) were lateralized contralateral to the EVD and 1 (20%) was generalized to the EVD. The only significant difference between the hyperexcitable and non-hyperexcitable group was duration of cEEG monitoring (P = 0.007). Interpretation: Hyperexcitable patterns were common in our cases. Further research is warranted to assess prevalence of hyperexcitable patterns, their risk factors, underlying pathophysiology, and association with neuronal injury in pIVH. PMID- 30250867 TI - Caffeine for apnea of prematurity and brain development at 11 years of age. AB - Objective: Caffeine therapy for apnea of prematurity has been reported to improve brain white matter microstructure at term-equivalent age, but its long-term effects are unknown. This study aimed to investigate whether caffeine affects (1) brain structure at 11 years of age, and (2) brain development from term equivalent age to 11 years of age, compared with placebo. Methods: Preterm infants born <=1250 g were randomly allocated to caffeine or placebo. Magnetic resonance imaging (MRI) was performed on 70 participants (33 caffeine, 37 placebo) at term-equivalent age and 117 participants (63 caffeine, 54 placebo) at 11 years of age. Global and regional brain volumes and white matter microstructure were measured at both time points. Results: In general, there was little evidence for differences between treatment groups in brain volumes or white matter microstructure at age 11 years. There was, however, evidence that the caffeine group had a smaller corpus callosum than the placebo group. Volumetric brain development from term-equivalent to 11 years of age was generally similar between treatment groups. However, there was evidence that caffeine was associated with slower growth of the corpus callosum, and slower decreases in axial, radial, and mean diffusivities in the white matter, particularly at the level of the centrum semiovale, over time than placebo. Interpretation: This study suggests any benefits of neonatal caffeine therapy on brain structure in preterm infants weaken over time and are not clearly detectable by MRI at age 11 years, although caffeine may have long-term effects on corpus callosum development. PMID- 30250868 TI - FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei. AB - Mutations in FARS2, the gene encoding the mitochondrial phenylalanine-tRNA synthetase (mtPheRS), have been linked to a range of phenotypes including epileptic encephalopathy, developmental delay, and motor dysfunction. We report a 9-year-old boy with novel compound heterozygous variants of FARS2, presenting with a pure spastic paraplegia syndrome associated with bilateral signal abnormalities in the dentate nuclei. Exome sequencing identified a paternal nonsense variant (Q216X) lacking the catalytic core and anticodon-binding regions, and a maternal missense variant (P136H) possessing partial enzymatic activity. This case confirms and expands the phenotype related to FARS2 mutations with regards to clinical presentation and neuroimaging findings. PMID- 30250869 TI - Combined respiratory training in an individual with C9orf72 amyotrophic lateral sclerosis. AB - This case study examined the impact of a respiratory strength training program targeting inspiratory and expiratory musculature in an individual with C9orf72 amyotrophic lateral sclerosis (ALS). The individual tolerated 24 months of respiratory training completed at home, 50 repetitions per day, and 5 days per week. Significant increases in maximum inspiratory pressure (from 71 to 134 centimeters of water), maximum expiratory pressure (from 108 to 197 centimeters of water) and peak cough flow (from 331 to 655 Liters per minute) were noted and forced vital capacity remained unchanged. A moderate intensity respiratory strength training program applied early in the disease progression improved function in this C9orf72 ALS individual. PMID- 30250870 TI - Comment on: Zika virus and Guillain-Barre syndrome in Bangladesh. PMID- 30250871 TI - Reply to: Comment on: Zika virus and Guillain-Barre syndrome in Bangladesh. PMID- 30250872 TI - Erratum: EUS-guided gastroenterostomy in management of benign gastric outlet obstruction. AB - [This corrects the article DOI: 10.1055/s-0043-123468.]. PMID- 30250873 TI - Targeting the KEAP1/NRF2 pathway to manipulate the expression of oncogenic and oncosuppressive miRNAs in human leukemia. AB - The Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor E2-related factor 2 (NRF2L2, best known as NRF2) pathway plays a pivotal cytoprotective role in the regulation of cellular responses to oxidative stress. We report that NRF2 modulates the expression of microRNA-125B and microRNA-29B in acute myeloid leukemia. The regulation of microRNA in leukemia can now be added to the growing list of prosurvival functions of NRF2. PMID- 30250874 TI - A new mechanism for LKB1 activation. AB - Liver kinase B1 (LKB1, also known as serine/threonine kinase 11, STK11) has been thought to be a constitutively active tumor suppressor that is activated by forming an active complex. Very recently, a new post-translational modification on LKB1 was identified that can regulate LKB1 activation and LKB1-mediated cancer cell survival under energy stress. PMID- 30250875 TI - The roles of NANOG in tumorigenesis. AB - The pluripotency factor Nanog is highly expressed in pluripotent stem cells and certain adult stem cells, but is not expressed in normal adult cells. However, Nanog is frequently overexpressed in human cancers. Here, we discuss the distinct oncogenic roles of Nanog at various stages of tumorigenesis. PMID- 30250877 TI - Linking SLAMF1 to autophagy and sensitivity to therapy in chronic lymphocytic leukemia. AB - We recently reported that expression of the costimulatory molecule and microbial sensor SLAMF1 (signaling lymphocytic activation molecule family 1, also known as CD150) is lost in chronic lymphocytic leukemia (CLL) patients characterized by a shorter overall survival. SLAMF1 modulates CLL responses to chemokines and regulates autophagy. Loss of SLAMF1 renders CLL cells relatively unresponsive to autophagy-inducing drugs, including B-cell CLL/lymphoma 2 (BCL2) inhibitors. PMID- 30250876 TI - Crosstalk between p53 modifiers at PML bodies. AB - Tumor protein p53 (TP53, best known as p53), the most frequently mutated tumor suppressor in cancer, plays a central role in cell fate decisions induced by DNA damage. Regulation of p53 activity by post-translational modifications has been linked to promyelocytic leukemia nuclear bodies (PML-NBs), where p53 encounters many of its regulators. Recent evidence implies that crosstalk between p53 regulators at the PML-NB shapes post-translational modifications and function of p53. PMID- 30250878 TI - The Cohesion complex maintains genome stability by preventing end joining of distant DNA ends in S phase. AB - Genome instability is a hallmark of cancer cells. The joining of distant DNA double-strand ends (DSEs) ineluctably leads to genome rearrangements. We found that the cohesion complex maintains genome stability by repressing the joining of distant DSEs specifically in the S phase, i.e., the main phase producing one ended DSEs. PMID- 30250879 TI - Cellular differentiation: Potential insight into butyrate paradox? AB - We recently demonstrated that cellular responses to butyrate depend on the differentiation status of the colonic epithelium. Here, we apply the implications of these findings to cancer biology and discuss discrepancies in the effects of butyrate on cancer progression. PMID- 30250880 TI - Aggressive leukemia driven by MLL-AF9. AB - We recently showed that cellular origin impacts the aggressiveness and the phenotype of acute myeloid leukemia (AML). Direct induction of the MLL-AF9 fusion in various hematopoietic compartments in vivo using a doxycycline (DOX) regulated mouse model (iMLL-AF9) led to an invasive chemoresistant AML expressing several genes known to be involved in epithelial to mesenchymal transition (EMT) in solid cancers. Many of these genes play important roles in migration and invasion and are significantly associated with poor overall survival in AML patients. PMID- 30250881 TI - Dual targeting of EGFR and glutaminase in lung cancer. AB - We have recently demonstrated that targeted inhibition of epidermal growth factor receptor (EGFR) signaling and glutaminase led to metabolic crisis in EGFR mutant lung adenocarcinomas and significant tumor regression in mouse xenograft models. Combining targeted therapies that restrict the metabolic activity and growth of tumors represents a therapeutic strategy that holds promise for clinical translation. PMID- 30250882 TI - Nutrient availability dictates the regulation of metabolism by the ribosomal protein-MDM2-p53 pathway. AB - Nutrient availability alters ribosomal biogenesis, causing ribosomal proteins to act as secondary messengers of nutrient response by binding to MDM2 and activating p53. Recent work suggests that the ribosomal protein (RP)-MDM2-p53 pathway responds to the deficiency or overabundance of nutrients through seemingly contradictory mechanisms; however, both of these responses promote organism survival. PMID- 30250883 TI - Moving nuclear receptor Nur77 to damaged mitochondria for clearance by mitophagy. AB - Selective clearance of damaged mitochondria can reverse pathological status in chronic inflammatory diseases. We recently identified a critical role of nuclear receptor Nur77 and celastrol in priming inflamed mitochondria for autophagy through its mitochondrial targeting and interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2) and the autophagic adaptor p62/SQSTM1. PMID- 30250884 TI - Insidious communication amongst cancer cells. AB - The tumor microenvironment is home to various types of cognate and non-cognate cell interactions. Here we comment on a newly discovered form of intercellular communication, which is based on endoplasmic reticulum stress signaling. Through this mechanism transmitter cancer cells impart receiver cancer cells with resistance to secondary metabolic, pharmacologic and genotoxic stress, providing survival advantage. The implications of this finding are briefly discussed. PMID- 30250885 TI - Loss of histone acetylation and H3K4 methylation promotes melanocytic malignant transformation. AB - Epigenetic mechanisms play essential roles in biological processes such as cell maintenance, differentiation, proliferation and apoptosis. A recent report from our laboratory showed that the loss of histone acetylation and H3K4 (Histone H3 Lysine 4) methylation in the proximal regions of cancer regulatory genes promote tumorigenesis. PMID- 30250886 TI - Tumor-suppressive or tumor-supportive: For p53, that is the question. AB - We have recently reported a TP53 (known as p53) regulated long noncoding RNA named TRINGS (Tp53-regulated inhibitor of necrosis under glucose starvation). With the aid of TRINGS, p53 was shown to prevent cancer cells against necroptosis under glucose starvation. Our findings suggest that p53 may act as an oncogenic player in metabolic reprogramming. PMID- 30250887 TI - ARF-NRF2: A new checkpoint for oxidative stress responses? AB - NRF2 (nuclear factor erythroid 2-related factor 2) is a transcription factor which plays a major role in oxidative stress responses by regulating antioxidant gene expression. We have recently identified the ARF tumor suppressor as a key regulator of NRF2. ARF can significantly inhibit NRF2 transcriptional activities, and the ARF-NRF2 interaction may function as a novel checkpoint for oxidative stress responses. PMID- 30250888 TI - An unexpected tumor suppressor role for VAV1a. AB - RHO GDP/GTP exchange factors, including VAV1, are considered key protumorigenic factors. Against this paradigm, we have found that VAV1 plays tumor suppressor roles by buffering NOTCH1 signals in thymocytes. The silencing of this pathway contributes to the pathogenesis of T cell acute lymphoblastic leukemia of the early cortical, TLX+ subtype. PMID- 30250889 TI - Escaping NK cells and recruiting neutrophils: How Morgana/NF-kappaB signaling promotes metastasis. AB - Cancer cells escape immune surveillance and induce immune cell aberrant activation to support tumour growth and progression. We recently reported that Morgana/NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling in breast cancer cells is responsible for NK (Natural Killer) cell inactivation and neutrophil recruitment in the primary tumour and in the lung pre-metastatic niche. PMID- 30250890 TI - ADHFE1 is a MYC-linked oncogene that induces metabolic reprogramming and cellular de-differentiation in breast cancer. AB - The oncometabolite, D-2-hydroxyglutarate, accumulates in various cancers because of acquired mutations in isocitrate dehydrogenase 1 & 2. Here, we describe a new mechanism for D-2-hydroxyglutarate accumulation in breast cancer. It involves c Myc signaling and alcohol dehydrogenase, iron-containing protein 1 (ADHFE1) and leads to metabolic reprogramming, de-differentiation, and increased mammary tumorigenesis. PMID- 30250891 TI - Targeting kinases with precision. AB - Cancer genomics and mechanistic studies have revealed that heterogeneous mutations within a single kinase can result in a variety of activation mechanisms. The challenge has been to match these insights with tailored drug discovery strategies to yield potent, highly selective drugs. With optimized drugs in hand, physicians could apply the principles of personalized medicine with an increasing number of options to treat patients with improved precision according to their tumor's molecular genotype. PMID- 30250892 TI - Targeting endosomal pH for cancer chemotherapy. AB - Altered pH homeostasis in cancer cells has been linked with essentially all classical hallmarks of cancer, including chemoresistance. We recently identified a conceptually novel mechanism for how dysregulated pH in hypoxic cells causes chemoresistance which is based on the aberrant cellular distribution of the endosomal pH regulator, the sodium/hydrogen exchanger 6 (NHE6). PMID- 30250893 TI - Cisd2 haploinsufficiency: A driving force for hepatocellular carcinoma. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is the major risk factor leading to hepatocellular carcinoma (HCC). Cisd2 haploinsufficiency in mice causes NAFLD by disrupting Ca2+ homeostasis, indicating that CISD2 is a molecular target for the treatment of NAFLD and the prevention of HCC. PMID- 30250894 TI - The histone variant macroH2A1 is a splicing-modulated caretaker of genome integrity and tumor growth. AB - The macroH2A1.2 histone variant facilitates the response to replication stress with implications for genome maintenance and cell growth. A mutually exclusive splice variant, macroH2A1.1, has opposing effects on DNA repair outcome and proliferation. Here we discuss the potential impact of splicing-modulated macroH2A1 chromatin organization for cell function and malignant transformation. PMID- 30250895 TI - AMPK lifts the PRC2-implemented gene repression. AB - The crosstalk between cellular energy status and epigenetic modifications remains largely elusive. We recently uncovered that upon energy restriction, AMP activated protein kinase (AMPK) phosphorylates enhancer of zeste homolog 2 (EZH2), which disrupts the integrity of the polycomb repressive complex 2 (PRC2), thus inhibiting PRC2 oncogenic functions in ovarian and breast cancer cells. PMID- 30250896 TI - Asparagine, a critical limiting metabolite during glutamine starvation. AB - A challenge of targeting glutamine metabolism in cancer is that tumor cells develop various strategies to adapt to glutamine limitation. We found that asparagine plays a critical role in supporting protein synthesis during glutamine starvation, highlighting a possible approach to optimize the therapeutic efficacy of targeting glutamine metabolism in cancer. PMID- 30250897 TI - Cell fate in colon cancer stem cells: To GLI or not to GLI? AB - Colon cancer is a heterogeneous tumor driven by subpopulations of cancer stem cells (CSCs). We recently used patient-derived organoids (PDOs) to demonstrate that CSC survival is regulated by autocrine non-canonical Hedgehog signaling, which acts as a positive regulator of Wnt signaling to block CSC differentiation. PMID- 30250898 TI - Autophagy-independent effects of autophagy-related-5 (Atg5) on exosome production and metastasis. AB - Autophagy-related-5 (Atg5) and Autophagy-related-16-Like-1 (Atg16L1) canonically participate in autophagy. Recent research demonstrates that apart from this, they also control production of extracellular vesicles called exosomes by regulating acidification of late endosomes. Atg5-mediated exosome production increased migration and metastasis of breast cancer cells suggesting exosomes may perform some functions ascribed to autophagy. PMID- 30250899 TI - EXD2: A new regulator of mitochondrial translation and potential target for cancer therapy. AB - In recent work we identified Exonuclease 3'-5' domain-containing protein 2 (EXD2) as an RNase required for efficient mitochondrial translation. Here I describe in brief the cellular phenotypes caused by EXD2 deficiency and make the case that EXD2 inhibitors could be valuable agents for cancer therapy. PMID- 30250900 TI - CHMP4C: A novel regulator of the mitotic spindle checkpoint. AB - The mitotic spindle checkpoint delays anaphase onset until all chromosomes have achieved stable kinetochore-microtubule attachments. Here, we discuss recent findings showing that CHMP4C, a component of the endosomal sorting complex required for transport (ESCRT) machinery, protects human cells against chromosome missegregation by promoting localisation of the ROD-ZW10-ZWILCH (RZZ) spindle checkpoint complex to unattached kinetochores. PMID- 30250901 TI - Single cell RNA-seq highlights a role for a partial EMT in head and neck cancer. AB - Studies in single cell transcriptomics have significantly expanded our understanding of tumor biology, including recent analyses in head and neck squamous cell carcinoma. Here, we focus on the role of a partial epithelial-to mesenchymal (EMT) program in these tumors, with discussion of its dynamics, regulation, and implications for diagnostic and therapeutic approaches. PMID- 30250902 TI - LPCAT2 controls chemoresistance in colorectal cancer. AB - Lipid droplets (LD) are now-well recognized as playing a role in cancer progression, however their potential role in chemoresistance remains largely unknown, particularly in colorectal cancer (CRC). We recently highlighted that LD accumulate in CRC cells under the control of lysophosphatidylcholine acyltransferase 2 (LPCAT2) enzyme expression. We also showed that chemotherapy induced LD accumulation counteracts intrinsic and extrinsic cancer cell death activation. PMID- 30250904 TI - JAK3 mutations and HOXA9 expression are important cooperating events in T-cell acute lymphoblastic leukemia. AB - Sequencing data from large cohorts of T-cell acute lymphoblastic leukemia patients identified a significant association between the presence of JAK3 mutations and ectopic HOXA9 expression. Mouse models using a constitutive or novel inducible retroviral expression vector to express the JAK3(M511I) mutant and HOXA9 led to the development of an aggressive leukemia in vivo, with shorter latency than JAK3(M511I) or HOXA9 alone. This was primarily due to the co-binding of STAT5 and HOXA9 to the same genomic loci leading to increased oncogenic JAK STAT signaling. PMID- 30250903 TI - A novel mechanism for the prevention of transcription replication conflicts. AB - Transcription and replication complexes can coincide in space and time. Such coincidences may result in collisions that trigger genomic instability. The phosphorylation of Mrc1 by different signaling kinases is part of a general mechanism that serves to delay replication in response to different stresses that trigger a massive transcriptional response in S phase. This mechanism prevents Transcription-Replication Conflicts and maintains genomic integrity in response to unscheduled massive transcription during S phase. PMID- 30250905 TI - Feedback regulation of mitochondrial homeostasis via Wnt/beta-catenin signaling. AB - Cellular abundance of mitochondria is dynamically regulated. We could recently show that dysfunctional mitochondria release the phosphatase PGAM family member 5 (PGAM5) into the cytosol, where it interacts with the Wnt signaling-component AXIN1 and dephosphorylates AXIN1-bound beta-catenin (CTNNB1) thereby activating Wnt/beta-catenin signaling. Because Wnt/beta-catenin signaling induces mitochondrial biogenesis dysfunctional mitochondria trigger their own replacement by releasing PGAM5. PMID- 30250906 TI - The decisive role of fumarase: Responsive signaling to glucose deficiency. AB - Our recent study shows that AMPK normally phosphorates fumarase (FH) at Ser75 under glucose deprivation, resulting in FH-ATF2 complex formation that facilitates transcription for cell growth arrest. Meanwhile, O-GlcNAc transferase can compete with AMPK to O-GlcNAcylate FH. In tumor cells, FH is highly O GlcNAcylated and is proinhibited from AMPK-ATF2 signaling. PMID- 30250907 TI - Does the BCL-2 family member BIK control lung carcinogenesis? AB - Hyperplastic airway epithelial cells may be the cause for increased risk for lung cancer in patients with chronic lung diseases. The B-cell lymphoma 2 (Bcl-2) family member, Bcl-2-interacting killer (BIK), triggers cell death specifically in these hyperplastic cells because of adequate presence of Death-associated Protein Kinase 1 (DAPk1), BCL-2 Antagonist Killer (BAK), and Extracellular Signal regulated Kinase 1/2 (ERK1/2). Therefore, BIK may be a useful tool to control the development of lung cancer in patients with chronic diseases. PMID- 30250908 TI - Another one bites the dust; ARTS enables degradation of Bcl-2 by XIAP. AB - ARTS (Sept4_i2) is a pro-apoptotic mitochondrial tumor suppressor protein which binds to and causes degradation of XIAP (X-linked inhibitor of apoptosis). We recently showed that ARTS brings XIAP into close proximity to Bcl-2, creating a complex which enables degradation of both these major anti-apoptotic proteins and promotes apoptosis. The possible therapeutic implications are discussed here. PMID- 30250909 TI - Complex role of SIRT6 in NF-kappaB pathway regulation. AB - The NF-kappaB pathway regulates cell physiology under stress conditions. We have recently described a novel NF-kappaB regulatory mechanism, by which SIRT6 induces cysteine monoubiquitination of the methyltransferase SUV39H1. This causes SUV39H1 dissociation from the gene encoding the NF-kappaB inhibitor IkappaBalpha, increasing its expression and leading to NF-kappaB pathway inactivation. PMID- 30250910 TI - A Case of mistaken identity: Rhabdomyosarcoma development from endothelial progenitor cells. AB - Rhabdomyosarcoma (RMS) histologically resembles developing skeletal muscle and is thought to solely originate from a differentiation block in muscle progenitors. We demonstrate that RMS can arise from endothelial progenitor cells following reprogramming and myogenic transdifferentiation. These results highlight how tumors with identical morphological features can arise from different cell types and offer insight into RMS formation in non-myogenic tissue. PMID- 30250911 TI - FAK family kinases: The Yin and Yang of cancer cell invasiveness. AB - Proline-rich tyrosine kinase 2 (PYK2, also known as Pyk2) and its closely related focal adhesion kinase (FAK) modulate cancer cell invasion by coordinating the balance between focal adhesion-mediated migration and invadopodia-dependent extracellular matrix invasion. Our recent findings present Pyk2 and FAK as novel mediators of breast cancer invasiveness and as potential targets for blocking breast cancer metastasis. PMID- 30250912 TI - Mediating the death of dormant tumor cells. AB - How immunological cues trigger cancer cell-intrinsic signaling pathways for their entering dormancy remains an enigma. In out recent studies, we found that IFN beta induces tumor-repopulating cells (TRC) into dormancy by activating Indoleamine-pyrrole 2,3-dioxygenase (IDO)-Kynurenine-aryl hydrocarbon receptor (AhR)-cyclin-dependent kinase inhibitor 1B (p27) pathway, while blocking this pathway leads dormant TRCs to apoptosis by switching to STAT3-cellular tumor antigen p53 (p53) pathway. PMID- 30250913 TI - EnABLing Cathepsin-Driven Melanoma Metastasis. AB - Metastatic melanoma remains incurable for many due to its aggressive nature. Secreted cathepsins promote metastasis by cleaving matrix and activating pro invasive proteases. We reported that ABL kinases induce cathepsin secretion and subsequent metastasis by activating ETS1, SP1, and RELA pathways, indicating that ABL inhibitors may serve as novel anti-cathepsin agents. PMID- 30250914 TI - PTPN2 as a promoter of colon carcinoma via reduction of inflammasome activation. AB - We have recently demonstrated that macrophage-specific loss of Protein tyrosine phosphatase non-receptor type 2 (PTPN2) promotes inflammasome activation, resulting in protection from colorectal cancer. Here we place these findings in context with the role of inflammasomes in colorectal carcinoma, and with a recent study indicating that PTPN2-silencing promotes anti-cancer immunotherapy. PMID- 30250915 TI - Ewing sarcoma fusion oncogene: At the crossroads of transcription and DNA damage response. PMID- 30250916 TI - RIPK1-dependent mitophagy: A novel mechanism to eliminate cells detached from the extracellular matrix. AB - For cancer cells to survive during extracellular matrix (ECM)-detachment, they must inhibit anoikis and rectify metabolic deficiencies that lead to the induction of non-apoptotic cell death. Here, we highlight and discuss our recent study implicating receptor-interacting protein kinase-1 (RIPK1) in the induction of mitophagy, the production of reactive oxygen species (ROS) and the consequent elimination of ECM-detached cells. PMID- 30250917 TI - Killing two birds with one stone: Blocking the mitochondrial pyruvate carrier to inhibit lactate uptake by cancer cells and radiosensitize tumors. AB - Lactate-based metabolic symbiosis between glycolytic and oxidative cancer cells is known to facilitate tumor growth. We have recently demonstrated that 7ACC2 blocks extracellular lactate uptake via the inhibition of mitochondrial pyruvate carrier. 7ACC2 also prevents compensatory glucose oxidation, induces tumor reoxygenation and potentiates radiotherapy, making it a promising anticancer drug. PMID- 30250918 TI - One gene to rule them all...and in the darkness bind them. AB - Pharmaceutical inhibition of the Human Epidermal growth factor Receptor 2 (HER2) oncogene has dramatically improved outcomes in HER2-amplified breast cancers. However, monotherapy HER2 inhibitors are not effective. We have recently reported that a co-amplified microRNA within the HER2 amplicon, leads to activation of the oncogene Myeloid Cell Leukemia-1 (MCL-1), tempering cell death responses to HER2 inhibitors. Importantly, HER2 inhibitors are sensitized to cell death by the addition of pharmacological MCL-1 inhibitors, which are entering clinical trials. PMID- 30250920 TI - Revisiting glucose metabolism in cancer: lessons from a PKM knock-in model. AB - Isoform selection of pyruvate kinase M (PKM), a glycolytic enzyme, influences fates of glucose-derived carbons in cellular metabolic networks. We recently developed novel mouse lines to study PKM isoform function and identified PKM1 as a potential target in a subset of human lung cancers. This work provides new insight into cancer metabolism. PMID- 30250919 TI - DDR1 inhibition as a new therapeutic strategy for colorectal cancer. AB - The clinical management of metastatic colorectal cancer (mCRC) is still a major challenge. Recently, we discovered that nilotinib, an approved treatment for chronic myeloid leukaemia, inhibits invasive and metastatic properties of CRC cells by targeting the kinase activity of receptor for collagens DDR1 (Discoidin Domain Receptor tyrosine kinase 1), suggesting that nilotinib could be an effective strategy to treat mCRC. PMID- 30250921 TI - PSPC1 potentiates TGF-beta-dependent metastatic dissemination. AB - Metastatic reprogramming toward malignant tumor progression relies on the activation of oncogenic regulators, yet the cellular determinants remain elucidated. Through identification of aberrant prognostic cancer genes, we identified paraspeckle component 1 (PSPC1) functions as a master activator of metastatic reprogramming by activating epithelial-to-mesenchymal transition (EMT), stemness and TGF-beta1 pro-metastatic switch. PMID- 30250922 TI - What a dog transmissible tumor can teach us about cancer regression. AB - The canine transmissible venereal tumor (CTVT) is one of the few clonally transmissible cancers in nature and the only one that fully regresses following treatment with vincristine. The molecular signature of CTVT regression has been described in a recent paper published in Cancer Cell, revealing some fundamental insights into cancer regression. PMID- 30250923 TI - Starving PTEN-deficient prostate cancer cells thrive under nutrient stress by scavenging corpses for their supper. AB - Our recent work demonstrates that inactivating mutations in phosphatase and tensin homolog (PTEN) are sufficient to drive macropinocytosis in the context of AMP-activated protein kinase (AMPK) activation. Given that blocking macropinocytosis limits PTEN-deficient prostate tumor growth, AMPK or phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitors could have therapeutic value in castration-resistant prostate cancer patients, particularly when used in combination with standard of care therapies. Abbreviations: ATG5: autophagy related 5; NHE: Na(+)/H(+) exchanger; PAK1: p21-activated kinase 1; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; PIP3: phosphatidylinositol (3,4,5)-trisphosphate; PIP2: phosphatidylinositol (4,5)-bisphosphate; RAC1: Rac family small GTPase 1. PMID- 30250924 TI - ZMYND8 is a primary HIF coactivator that mediates breast cancer progression. AB - Epigenetic regulator plays a pivotal role in breast cancer progression. We recently demonstrated that the epigenetic reader zinc finger MYND-type containing 8 (ZMYND8) mediates breast cancer progression and metastasis by activating hypoxia-inducible factor (HIF). This discovery provides new insights into the molecular mechanism underlying HIF activation and breast cancer progression. PMID- 30250926 TI - Calorie restriction for human aging: is there a potential benefit for cancer? AB - Caloric restriction in non-obese humans improves metabolic efficiency and reduces oxidative damage markers which may decrease cancer incidence and progression. PMID- 30250925 TI - Examination of Hypoxanthine Guanine Phosphoribosyltransferase as a biomarker for colorectal cancer patients. AB - The aim of this study is to investigate these enzymes as possible biomarkers in two colorectal cancer cell lines: HT29, SW480, SW620, and Colo205. With 1,168,929 individuals currently diagnosed with colorectal cancer in the United States, there remains a need to find biomarkers to improve diagnosis and expand treatment options for patients. Due to their role in proliferation and cell cycle regulation, we hypothesized an increase in salvage pathway enzyme (APRT, DCK, and HPRT) expression and possible presentation within colon cancer cells. Enzyme surface localization was assessed utilizing confocal microscopy, flow cytometry, and scanning electron microscopy. General protein expression was evaluated utilizing immunohistochemistry and Western blot analysis. While we found no statistically significant presence of either APRT or DCK on the membranes of SW620, Colo205, and HT29 cells, but found significant expression of HPRT on the surface of HT29, SW480, and SW620 cells. The average population fluorescence increased by 28%, 58%, and 40% in HT29, SW620, and SW480 cells, respectively, when compared to isotype controls. Confocal microscopy images revealed direct overlap between SW620 cells stained with a membrane dye and anti-HPRT antibody, indicating co-localization on the plasma membrane. In addition, cells treated with gold labelled HPRT antibody experienced significant changes in gold weight percentage on both SW620 and HT29 cells when compared to isotype controls. When evaluating expression within normal tissue, there was insignificant levels of HPRT binding. These data collectively suggest that HPRT may be a possible biomarker target for the identification and treatment of colorectal cancer. PMID- 30250927 TI - LSD1 inhibitors disrupt the GFI1 transcription repressor complex. AB - Pharmacologic inhibition of KDM1A (Lysine Demethylase 1A) induces differentiation in certain subtypes of acute myeloid leukemia. Our recent studies reveal this is dependent upon drug-induced disruption of the GFI1 (Growth Factor Independent 1) transcription repressor complex, leading to activation of enhancers distributed close to genes controlling monocytic lineage differentiation. PMID- 30250928 TI - CDC25 as a common therapeutic target for triple-negative breast cancer - the challenges ahead. AB - The dual phosphatase CDC25 has recently been identified as a target for diverse triple-negative breast cancers including RB1/PTEN/P53-deficient tumors. Moreover, CDC25 inhibitors effectively synergize with PI3K inhibitors to suppress tumor growth. We discuss these findings and the challenges that lie ahead in bringing CDC25 inhibitors to the clinic. PMID- 30250929 TI - Exiting the dark side: A vital role for Caspase-3 in Yap signaling. AB - Caspase-3 is known to play a critical function in the process of apoptosis. Recently, we have discovered a non-apoptotic role of Caspase-3 as a key regulator of cell proliferation and organ size. Caspase-3 cleaves alpha-Catenin, which sequesters Yes-associated protein 1 (Yap1) in the cytoplasm, thus facilitating the activation and nuclear translocation of Yap1. These findings reveal that the apoptotic machinery can be refocused to regulate cell proliferation and organ size. PMID- 30250930 TI - GRASP55 facilitates autophagosome maturation under glucose deprivation. AB - Under growth condition, the Golgi reassembly-stacking protein of 55 kDa (GRASP55)/GORASP2 serves as the "glue" to hold adjacent Golgi cisternae into stacks by forming trans-oligomers. Upon glucose starvation, GRASP55 is de-O GlcNAcylated and functions as a membrane tether to facilitate autophagosome lysosome fusion through the interactions with LC3-II and LAMP2. PMID- 30250931 TI - A novel function for the mitotic checkpoint protein Mad2p in translation. AB - MAD2L1 (Mitotic Arrest Deficient 2 Like 1), a member of the mitotic checkpoint, maintains the genomic stability by insuring the proper segregation of the sister chromatids. Deregulation of MAD2L1 protein expression is a recurrent feature in cancer cells. In our recent publication, we uncovered a role for its yeast homolog, Mad2p, in protein synthesis during S-phase. PMID- 30250932 TI - Itraconazole perturbs colorectal cancer dormancy through SUFU-mediated WNT inhibition. AB - Cancer cell dormancy is an important source of treatment failure. We studied the molecular characteristics and functional behaviour of dormant colorectal cancer cells finding them to be a differentiated yet plastic population. Organoid drug screening identified itraconazole perturbs dormancy through non-canonical hedgehog signalling effects on the WNT pathway. PMID- 30250933 TI - T-cell leukemogenesis is an inappropriate lineage decision-making process: implications for precision oncology. AB - Genetic lineage tracing in cell type-specific mouse models of T-cell acute lymphoblastic leukemia (T-ALL) have revealed that tumor cell identity is imposed by expression of the oncogene Lim Domain Only 2 (LMO2), rather than by the target cell phenotype. This approach allowed to identify that secondary genomic alterations, like Notch1 mutations, appeared late and only took place within the thymus during T-ALL development. These concepts are therefore critical for the development of modern therapies aimed at curing T-ALL. PMID- 30250934 TI - SETD2 in MLL-rearranged leukemia - a complex case. AB - Oncogenic MLL-fusion proteins often hijack essential molecular mechanisms during leukemogenesis. The histone methyltransferase SETD2 was implicated in the regulation of transcription, DNA damage and other cellular processes. Recent studies identified a critical role for SETD2 in MLL-rearranged leukemia. These results may help to unravel important functions of SETD2 in hematopoiesis. PMID- 30250935 TI - Renal Papillary Hyperplasia as a Cause of Persistent Asymptomatic Microhematuria. AB - Asymptomatic microscopic hematuria (AMH) is incidentally found during routine health screenings. In the clinical evaluation of persistent AMH imaging modalities, CT urography, MR urography, and retrograde pyelography are of diagnostic importance. In case of pathologic findings (e.g., contrast-filling defects), endoscopic evaluation is mostly performed. To our knowledge, we report the first case of a patient with persistent AMH caused by biopsy-proven renal papillary hyperplasia. PMID- 30250938 TI - Editorial. PMID- 30250939 TI - Can Ultrasound Alone Predict Papillary Thyroid Carcinoma with Desmoid-Type Fibromatosis? A Retrospective Analysis of 13 Cases, Focusing on the Stromal Area. AB - Purpose: Papillary thyroid carcinoma with desmoid-type fibromatosis (PTC-DTF) is extremely rare. So far, only 4 cases describing the ultrasound findings of this variant have been reported. Here, we describe the ultrasound findings of 13 cases of PTC-DTF, focusing especially on the DTF area. Materials and Methods: We retrospectively analyzed the clinical reports, ultrasound reports, and ultrasound photographs obtained from medical records at Kuma Hospital. Results: The patients included 8 women and 5 men with a mean age of 47.9 years. The widest dimension of the nodules ranged from 16 to 79 mm (mean: 37.5 mm). The original ultrasound reports classified the nodules as either intermediate suspicion or high suspicion. A diagnosis of PTC was suspected in 12 nodules, and anaplastic carcinoma was suspected in 1 nodule. PTC-DTF presented with an irregularly shaped nodule (100%), taller-than-wide sign (84.6%), heterogeneous echogenicity (100%), no microcalcification (76.9%), and no or mild flow signal on Doppler (75.0%). The DTF area was identified in the ultrasound photographs of 8 nodules. DTF areas were generally heterogeneous (62.5%) and more hypoechoic (71.4%) than PTC areas. Microcalcification was not observed in the DTF areas. All of the DTF areas revealed no or mild flow signal. On ultrasound elastography, the DTF areas were not stiff, and they were more elastic than the PTC areas. Conclusion: It is difficult to predict PTC-DTF using ultrasound alone, and B-mode ultrasonography is more reliable than ultrasound elastography in the ultrasound diagnosis of malignant thyroid nodules. PMID- 30250937 TI - Navigating Systemic Therapy in Advanced Thyroid Carcinoma: From Standard of Care to Personalized Therapy and Beyond. AB - Thyroid cancer, with the exception of anaplastic thyroid cancer, typically has very favorable outcomes with the standard therapy. However, those that persist, recur, or metastasize are associated with a worse prognosis. Targeted therapy with kinase inhibitors has shown promise in advanced cases of thyroid cancer, and currently five drug regimens are approved for use in clinical practice in the treatment of differentiated, medullary, and anaplastic thyroid cancer, with more options in the pipeline. However, one of the greatest dilemmas is when and how to initiate one of these drugs, and this is discussed herein. PMID- 30250936 TI - The genetics of retinopathy of prematurity: a model for neovascular retinal disease. AB - TOPIC: Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease in premature infants, and is a major cause of childhood blindness worldwide. In addition to known clinical risk factors such as low birth weight and gestational age, there is a growing body of evidence supporting a genetic basis for ROP. CLINICAL RELEVANCE: While comorbidities and environmental factors have been identified as contributing to ROP outcomes in premature infants, most notably gestational age and oxygen, some infants progress to severe disease despite absence of these clinical risk factors. The contribution of genetic factors may explain these differences and allow better detection and treatment of infants at risk for severe ROP. METHODS: To comprehensively review genetic factors that potentially contribute to the development and severity of ROP, we conducted a literature search focusing on the genetic basis for ROP. Terms related to other heritable retinal vascular diseases like "familial exudative vitreoretinopathy", as well as to genes implicated in animal models of ROP, were also used to capture research in diseases with similar pathogenesis to ROP in humans with known genetic components. RESULTS: Contributions across several genetic domains are described including vascular endothelial growth factor, the Wnt signaling pathway, insulin-like growth factor 1, inflammatory mediators, and brain-derived neurotrophic factor. CONCLUSIONS: Most candidate gene studies of ROP have limitations such as inability to replicate results, conflicting results from various studies, small sample size, and differences in clinical characterization. Additional difficulty arises in separating the contribution of genetic factors like Wnt signaling to ROP and prematurity. Although studies have implicated involvement of multiple signaling pathways in ROP, the genetics of ROP have not been clearly elucidated. Next-generation sequencing and genome-wide association studies have potential to expand future understanding of underlying genetic risk factors and pathophysiology of ROP. PMID- 30250940 TI - Calcifications in Thyroid Tumors on Ultrasonography: Calcification Types and Relationship with Histopathological Type. AB - Purpose: The purpose of the study is to clarify the prevalence of calcifications within thyroid tumors on ultrasonography as well as the relationship between the calcification and histopathological types. Materials and Methods: Calcifications were classified into 6 (or 8) types according to their shape, size, and region. The prevalence of calcifications and types were investigated in new outpatients and patients who underwent thyroid surgery. Results: Among 2,902 nodules in 2,678 new outpatients, 747 nodules (26%) had calcifications. The types showed a wide distribution. Among 941 patients with papillary carcinoma (PC), 725 patients (77%) had calcifications, and the types showed a wide distribution. 18 patients with the diffuse sclerosing variant of PC only showed punctate microcalcifications in the parenchyma (100%), 32 patients with the cyst-forming type of PC mostly fragmentary and massive types (100%), and 161 metastatic lymph nodes from PC mostly punctate microcalcifications and fragmentary types (48%). Among 337 patients with follicular carcinoma, 79 patients (23%) had calcifications, and the types were mostly fragmentary, massive, and egg-shell types. Among 41 patients with undifferentiated carcinoma, 33 patients (80%) presented with calcifications, which were mostly the massive and egg-shell types. Among 137 patients with medullary carcinoma, 99 patients (72%) had calcification, and the types showed a wide distribution. None of 173 patients with primary thyroid lymphoma had calcifications (0%). Conclusion: Calcifications on ultrasonography can be one of the characteristic findings and a full understanding of the prevalence of calcifications and types will markedly contribute to the ultrasonic diagnosis of thyroid tumors. PMID- 30250941 TI - Influencing Factors of 2D Shear Wave Elastography of the Muscle - An Ex Vivo Animal Study. AB - Objective: To evaluate measurement confounders on 2D shear wave elastography (2D SWE) elastography of muscle. Materials and Methods: Ex vivo , porcine muscle was examined with a GE LOGIQ E9 ultrasound machine with a 9 L linear (9 MHz) and C1-6 convex probe (operating at 2.5 or 6 MHz). The influence of different confounders on mean shear wave velocity (SWVmean) was analyzed: probes, pressure applied by probe, muscle orientation, together with the impact of different machine settings such as frequency, placement depth and size of region of interest (ROI). The mean of twelve repeated SWVmean measurements (m/s) and coefficient of variation (CV; standard deviation/mean in %) were assessed for each test configuration. Results: Reproducibility (CV) and maximum possible tissue depth of the linear probe were inferior to the convex probe. With the linear probe, there was a linear decrease of SWVmean with placement depth from 4.56 m/s to 1.81 m/s. A significant increase of SWVmean (p<0.001) was observed for larger ROI widths (range 3.96 m/s to 6.8 m/s). A change in the machine operation mode ('penetration' instead of 'general') led to a significant increase of SWVmean (p=0.04). SWVmean in the longitudinal direction of muscle was significantly higher than in cross section (p<0.001) (e. g. 4.56 m/s versus 3.42 m/s). An increase of linear probe pressure significantly increased muscle SWVmean from 5.29 m/s to 7.21 m/s (p<0.001). Conclusions: 2D-SWE of muscle is influenced by a wealth of parameters. Therefore, standardization of measurement is advisable before application in clinical research studies and routine patient assessment. PMID- 30250942 TI - Atherosclerotic Lesions in the Superficial Femoral Artery (SFA) Characterized with Velocity Ratios using Vector Velocity Ultrasound. AB - Purpose: Atherosclerotic arteries are challenging to evaluate quantitatively using spectral Doppler ultrasound because of the turbulent flow conditions that occur in relation to the atherosclerotic stenoses. Vector velocity ultrasound is angle independent and provides flow information, which could potentially improve the diagnosis of arterial stenoses. The purpose of the study is to distinguish significant stenoses in the superficial femoral artery (> 50% diameter reduction) from non-significant stenoses based on velocity ratios derived from the commercially available vector velocity ultrasound technique Vector Flow Imaging (VFI). Materials and Methods: Velocity ratios (intrastenotic blood flow velocity divided by pre- or poststenotic velocity) from a total of 16 atherosclerotic stenoses and plaques in the superficial femoral artery of 11 patients were obtained using VFI. The stenosis degree, expressed as percentage diameter reduction of the artery, was determined from digital subtraction angiography and compared to the velocity ratios. Results: A velocity ratio of 2.5 was found to distinguish clinically relevant stenoses with>50% diameter reduction from clinically non-relevant stenoses with<50% diameter reduction and the difference was statistically significant. Conclusion: The study indicates that VFI is a potential future tool for the evaluation of arterial stenoses. PMID- 30250943 TI - Ultrasound Evaluation of Testicular Volume in Patients with Testicular Microlithiasis. AB - Purpose: Ultrasonography is a useful tool to measure testicular volume. According to the European Society of Urogenital Radiology, the combination of testicular atrophy and testicular microlithiasis (TML) is a risk factor for testicular cancer. Testicular atrophy is defined as a volume of less than 12 ml. The aim of this study was to compare testicular volume in patients with TML to patients with normal testicular tissue. Materials and Methods: From 2013 to 2015 we included a total of 91 adult patients with TML, and 91 adult patients with normal testicular tissue as a control group. All patients underwent scrotal B-mode ultrasound investigation including measurement of width, length and height in both testicles. Testicular volume was calculated using the formula pi/6*length*height*width. Results: The median age for patients with TML was 48 years (range: 19-94 years), and 48 years (range: 20-75 years) in patients with normal tissue. No statistically significant difference was found between total testicular volume (both testes) >30 ml in patients with TML compared to patients without (OR 0.77 (95% CI 0.43-1.38, p=0.37). However, patients with TML tended to have lower testicular volume compared to patients without TML, when investigating testicular volume below 12 ml. Conclusion: Overall, no association was found between testicular volume and TML, but there was a trend indicating that severe atrophy is often seen in patients with TML compared to patients without TML. However, a significant difference was only found in testicular volume <=8 ml. PMID- 30250944 TI - Caffeine Treatment for Apnea of Prematurity and the Influence on Dose-Dependent Postnatal Weight Gain Observed Over 15 Years. AB - Background and Aim: To analyze the influence on weight gain of infants exposed to two dosage regimens of oral caffeine citrate (CC) for apnea of prematurity. Methods: Retrospective descriptive observational study of an eligible very low birth weight cohort over a 15-year period in an Irish University hospital. Data were analyzed between two distinct postnatal ages: 14-28 and 29-56 days. Results: During the 15-year study, 457 infants were prescribed caffeine. Among the 14-28 day group, after applying exclusion criteria, 418 infants qualified. Two hundred forty-eight infants received 5 mg/(kg.day) and 170 received 10 mg/(kg.day) of CC. Among the 29-56-day group, 362 infants were identified and after applying exclusions, 332 fulfilled entry criteria [214 on 5 mg/(kg.day) and 118 on 10 mg/(kg.day) regimen]. Baseline characteristics of infants were comparable between groups without statistically significant differences. Mean daily weight gain (MDWG) in grams from day 14 to 28 showed a higher rate of increase for the 5 mg/(kg.day) group compared with the 10 mg/(kg.day) group (17.2 +/- 12 g vs. 13.0 +/- 10.2 g [p = 0.04]). From day 29 to 56, also MDWG was higher among infants on 5 mg/(kg.day) of CC compared with 10 mg/(kg.day) group (15.6 +/- 10.8 g vs. 10.2 +/- 9.8 g [p = 0.011]). Conclusion: While a variety of measures are optimized to promote postnatal weight gain of premature infants close to an ideal intrauterine growth curve, not paying sufficient attention to one of the most widely used catabolic agents in neonatology is questionable and warrants vigilance. Additional nutritional measures could be offered to those with prolonged caffeine exposure. PMID- 30250945 TI - Correlates of Alcohol Mixed with Energy Drink Use Among First Year College Students: Clinical and Research Implications. AB - Background: Alcohol mixed with energy drink (AmED) use among college students is associated with specific adverse effects (e.g., sexual assault, driving while intoxicated). This study offered the opportunity to evaluate correlates of past year AmED use in a large sample of college students. Methods: In autumn 2010, emails were sent to all first year students (n = 29,536) at 11 colleges and universities in North Carolina and Virginia, inviting them to participate in a brief web-based survey to be used to establish a cohort for the parent tobacco use study; 10,340 (35%) students responded to the web-based survey, which elicited items on demographics, past year use of AmED, and other health behaviors. Results: Past year of AmED was reported by 29.4% of students. Logistic regression analysis revealed that female gender (adjusted odds ratios [AOR] = 1.28, 95% confidence interval [CI] = 1.16-1.42); ever use of smokeless tobacco (AOR = 3.51, 95% CI = 3.00-4.10); current smoking (AOR = 4.97, 95% CI = 4.34 5.69); 2 or fewer days of physical activity per week (AOR = 1.16, 95% CI = 1.04 1.28); and 7 or 8 hours of sleep per day (AOR = 1.12, 95% CI = 1.02-1.24) predicted risk of past year use of AmED. Conclusions: Nearly a third of first year college students reported past year use of AmED. Our finding of increased past year use of AmED use among women is new and might reflect the changing epidemiology of female college alcohol use. Of additional concern, such use might also reflect targeted marketing to women by the energy drink industry. Findings can guide future research as well as substance counseling to college students. PMID- 30250946 TI - Live imaging of cell membrane-localized MT1-MMP activity on a microfluidic chip. AB - We designed an enzyme-activatable probe for real time in situ tracking of MT1-MMP activity. The MT1-MMP responses of endothelial cells were investigated under the regulation of shear stress and biochemical factor on a microfluidic chip. This strategy can be beneficial to evaluate membrane protein responses to external stimuli and to engineer cells for basic and clinical research. PMID- 30250947 TI - Influence of conjugation length on ultrafast electronic tunneling in organic semiconductor thin films. AB - Electron delocalization in conjugated organic molecules is a rate-limiting step in maximizing the charge generation efficiency of next generation photovoltaics and molecular electronics. In particular, ultrafast (<50 fs) delocalization is an important aspect that has been beyond the scope of traditional optical experiments. In this work, we use resonant photoemission spectroscopy to probe electron delocalization timescales as a function of conjugation length by examining an oligothiophene chemical series containing 4-, 5- and 6-mers. We find that above a certain photon energy threshold, the 5-mer, quinquenthiophene, displays the largest ultrafast tunneling rates, roughly three times faster than the 6-mer, sexithiophene. We argue that differences in thin-film molecular packing cannot satisfactorily explain our results, and we speculate that the differences in ultrafast electron dynamics may be a manifestation of the odd/even effect. PMID- 30250948 TI - A tetrameric perylene diimide non-fullerene acceptor via unprecedented direct (hetero)arylation cross-coupling reactions. AB - This study reports on the synthesis of an indancenodithiophene perylene diimide tetramer via unique direct (hetero)arylation reactivity. The thiophene based core structure is shown to be easily functionalized with four perylene diimides at the four active C-H positions. This new reactivity provides a simple synthetic pathway towards tetrameric perylene diimides which have emerged as one of the best classes of electron acceptors for organic solar cells. PMID- 30250949 TI - The effect of graphene on surface plasmon resonance of metal nanoparticles. AB - Two transparent graphene-metal nanoparticle (NP) hybrid schemes, namely Au NPs covered by graphene layers and Au NPs encapsulated by graphene layers, are presented and the effect of graphene on the localized surface plasmon resonance of metal NPs is systematically investigated. For both schemes, the direct contact of graphene with Au NPs would strongly tune the resonant frequency due to the electron transfer from Au NPs to graphene. Such electron transfer is demonstrated by comparing the absorption spectra of Au NPs with different free electron densities between calculation results via FDTD simulation and experimental results, comparing Raman properties of graphene between pure graphene and the Au NP/graphene hybrid nanostructure, correlating the electron doping concentration in graphene with the electron density change in Au NPs, and ruling out the possible mechanism of the change of the effective refractive index of Au NPs. Such an effective tuning of the resonant frequency may shed light on the future applications of 2D based materials in plasmonic devices. PMID- 30250950 TI - Activated barrier crossing dynamics of a Janus particle carrying cargo. AB - We numerically study the escape kinetics of a self-propelled Janus particle, carrying a cargo, from a meta-stable state. We assume that the cargo is attached to the Janus particle by a flexible harmonic spring. We take into account the effect of the velocity field created in the fluid due to movements of the dimer's components, by considering a space-dependent diffusion tensor (Oseen tensor). Our simulation results show that the synchronization between barrier crossing events and the rotational relaxation process can enhance the escape rate to a large extent. Also, the load carrying capability of a Janus particle is largely controlled by its rotational dynamics and self-propulsion velocity. Moreover, the hydrodynamic interaction, conspicuously, enhances the escape rate of the Janus cargo dimer. The most important features in escape kinetics have been justified based on analytic arguments. PMID- 30250951 TI - Metalation and coordination reactions of 2H-meso-trans-di(p-cyanophenyl)porphyrin on Ag(111) with coadsorbed cobalt atoms. AB - We investigated the metalation and coordination reactions of Co with 2H-5,15 bis(para-cyanophenyl)-10,20-bisphenylporphyrin (2HtransDCNPP) on a Ag(111) surface by scanning tunneling microscopy. At room temperature (RT), 2HtransDCNPPs self-assemble into a supramolecular structure stabilized by intermolecular hydrogen bonding. The metalation of 2HtransDCNPP is achieved either by depositing Co atoms onto the supramolecular structure at RT, or, alternatively, by depositing the molecules onto a submonolayer Co-precovered Ag(111) surface with a subsequent heating to 500 K. In addition, the molecules coordinate to Co atoms through the N atoms in the peripheral cyano groups with a preference of isolated 4-fold coordination motifs at RT. PMID- 30250952 TI - Ternary semiconductor ZnxAg1-xS nanocomposites for efficient photocatalytic degradation of organophosphorus pesticides. AB - The construction of ternary semiconductor nanostructures has attracted much attention in photocatalysis by virtue of their tunable elemental composition and band structure. Here, ternary semiconductor ZnxAg1-xS (0 <= x <= 1) composites were successfully prepared by a simple and low-cost hydrothermal method without using any surfactant. Combined analyses using XRD, N2 sorption, SEM, TEM and UV vis DRS revealed that the ternary composite semiconductor materials exhibited well-developed crystalline frameworks, large surface areas of 15-70 m2 g-1, sizes of 10-30 nm, and outstanding UV light absorption properties. Data from XRD and TEM indicate that photocatalysis might contribute to the formation of the strong interfacial interaction between ZnS and Ag2S nanoparticles. The photocatalytic activities were investigated via the degradation of organophosphorus pesticides, including malathion (MLT), monocrotophos (MCP) and chlorpyrifos (CPS), using the ZnxAg1-xS composites under UV light irradiation. The toxicity of MLT, MCP, and CPS was reduced by photocatalysis and photolysis; however, photocatalysis had a greater impact. Superior photocatalytic performance was exhibited by the Zn0.5Ag0.5S catalyst owing to its large surface area and the presence of Ag0 with improved charge transfer in comparison with that of bare ZnS and Ag2S. Assays of stability and reusability indicated that the Zn0.5Ag0.5S composite retained more than 85% of its activity after five cycles of use. On the basis of the results, a possible photocatalytic mechanism of the prepared samples was proposed. This study indicates a potential application of the ternary semiconductor materials in the efficient UV light-driven photocatalytic degradation of other pollutants that may cause environmental pollution. PMID- 30250953 TI - Temperature dependence of photophysical properties of a dinuclear C^N cyclometalated Pt(ii) complex with an intimate Pt-Pt contact. Zero-field splitting and sub-state decay rates of the lowest triplet. AB - The temperature dependence (1.7 K < T < 100 K) of emission decay is reported for the first time for a type of di-nuclear Pt complex featuring a metal-metal-to ligand charge transfer (MMLCT) lowest energy transition that arises from a strong Pt-Pt interaction. The effect of local variation of the host/guest cage in a polymer matrix upon the phosphorescence decay time constants is characterized by the Kohlrausch-Williams-Watts function. The temperature dependence of the average decay time constants is fit by a Boltzmann-type expression to obtain the average zero-field splittings and individual sublevel decay rates of the photoluminescent triplet excited state. PMID- 30250954 TI - Flow and fracture near the sol-gel transition of silica nanoparticle suspensions. AB - We analyze the evolution of the mechanical response of a colloidal suspension to an external tensile stress, from fracture to flow, as a function of the distance from the sol-gel transition. We cease to observe cracks at a finite distance from the transition. In an intermediate region where the phenomenon is clearly hysteretic, we observe the coexistence of both flow and fracture. Even when cracks are observed, the material in fact flows over a distance that increases in the vicinity of the transition. PMID- 30250955 TI - Contribution of the in situ release of endogenous cations from xenograft bone driven by fluoride incorporation toward enhanced bone regeneration. AB - Xenograft, namely bone-derived biological apatite (BAp), is widely recognized as a favorable biomaterial in bone tissue engineering owing to its biodegradability, biocompatibility, and osteoconductive properties. Substitutions of endogenous trace ions are thought to improve the osteogenic capacity of xenograft compared with synthetic hydroxyapatite (HAp). In order to modify the physicochemical and biological properties of apatite, different approaches to induce trace ion incorporation have been widely considered. In this study, we demonstrated that the incorporation of fluoride ions into porcine bone-derived biological apatite (pBAp) contributes to altered crystal morphology of the apatite, the sustained release of fluoride, and the in situ release of endogenous trace ions (e.g., magnesium and calcium) into the peripheral tissue microenvironment. This ionic balanced perimaterial microenvironment not only led to superior proliferation and osteogenic differentiation of rat bone mesenchymal stem cells (rBMSCs), but also accelerated new bone formation of the calvarial defect on a rat model via the activation of Wnt/beta-catenin signaling. These promising observations may be attributed to the controlled release of endogenous trace ions from the xenograft to the peripheral tissue microenvironment driven by fluoride ion incorporation. Lastly, this study may provide a new insight to strengthen the osteogenicity of xenografts for clinical applications in the future. PMID- 30250956 TI - Interactions between acid and proteins under in vitro gastric condition - a theoretical and experimental quantification. AB - The gastric digestion of proteins is influenced by the pH and the gastric pH fluctuates after food consumption. However, the dynamics of gastric pH still need to be quantitatively understood. Proteins in food strongly influences the gastric pH. Therefore, we studied the interaction between acid and proteins, including the buffer reaction and the acid diffusion in protein gels. The buffer capacity of proteins stems from its content of ionizable amino acid side groups. Based on this, we set up a model and method to parameterize the buffer capacity of proteins. Moreover, the liberated carboxyl and amino groups during enzymatic hydrolysis of protein can also contribute to the buffer capacity. While we expected protons to diffuse faster than pepsin, we found that the penetration distance of acid is comparable to that of pepsin. The buffer reaction caused the acid to concentrate tenfold in the gel compared to the bulk acid concentration. Therefore, we postulated that the buffer reaction reduces acid diffusivity in gels. PMID- 30250957 TI - Dimethylamine adducts of allylic triorganoboranes as effective reagents for Petasis-type homoallylation of primary amines with formaldehyde. AB - Dimethylamine adducts of triallyl-, triprenyl- and trans-cinnamyl(dipropyl)borane are effective reagents for mild homoallylation of primary amines with aqueous formaldehyde in MeOH without an inert atmosphere. A new concept is proposed for the explanation of the high stability of allylborane-amine adducts in aqueous MeOH. PMID- 30250958 TI - A degradable fluorinated surfactant for emulsion polymerization of vinylidene fluoride. AB - An original degradable fluorinated surfactant, 3-hydroxy-2 (trifluoromethyl)propanoic acid (MAF-OH), was applied for the emulsion polymerization of vinylidene fluoride (VDF) to yield a latex of PVDF, consisting of typically 100 nm particle diameters. This surfactant was shown to be easily decomposed in subcritical water, releasing fluoride anions. The % reversed head to head (H-H) addition is greatly minimized (2.4%) in the PVDF, prepared in the presence of MAF-OH surfactant. PMID- 30250959 TI - Surface organometallic chemistry in heterogeneous catalysis. AB - The broad challenges of energy and environment have become a main focus of research efforts to develop more active and selective catalytic systems for key chemical transformations. Surface organometallic chemistry (SOMC) is an established concept, associated with specific tools, for the design, preparation and characterization of well-defined single-site catalysts. The objective is to enter a catalytic cycle through a presumed catalytic intermediate prepared from organometallic or coordination compounds to generate well defined surface organometallic fragments (SOMFs) or surface coordination fragments (SCFs). These notions are the basis of the "catalysis by design" strategy ("structure-activity" relationship) in which a better understanding of the mechanistic aspects of the catalytic process led to the improvement of catalyst performances. In this review the application of SOMC strategy for the design and preparation of catalysts for industrially relevant processes that are crucial to the energy and environment is discussed. In particular, the focus will be on the conversion of energy-related feedstocks, such as methane and higher alkanes that are primary products of the oil and gas industry, and of their product of combustion, CO2, whose efficient capture and conversion is currently indicated as a top priority for the environment. Among the main topics related to energy and environment, catalytic oxidation is also considered as a key subject of this review. PMID- 30250960 TI - Cyanomethyl anion transfer reagents for diastereoselective Corey-Chaykovsky cyclopropanation reactions. AB - A readily available and bench-stable cyanomethyl sulfonium salt was used in highly diastereoselective Corey-Chaykovsky cyclopropanation reactions of electron poor olefins. This efficient method provides a rapid route to access densely functionalized cyclopropyl nitriles. PMID- 30250961 TI - The Importance of Achieving Clear or Almost Clear Skin for Patients: Results from the Nordic Countries of the Global Clear about Psoriasis Patient Survey. AB - Psoriasis is a stigmatizing chronic skin condition in which impairment of quality of life is associated with visibility of skin lesions, disease activity and severity. The ultimate goal of treatment is complete clearance of skin symptoms. The worldwide "Clear About Psoriasis" survey explored patients' perspectives on clear/almost clear skin and the impact of psoriasis on daily life. We report here results from the Nordic countries (n = 609). Of respondents, 44% achieved clear/almost clear skin with their current treatment, of which 71% were comfortable discussing this expectation with their physician, compared with only 46% of patients who had not achieved clear/almost clear skin. Of patients who achieved clear/almost clear skin, 85% reported treatment satisfaction vs. 39% who had not. Psoriasis profoundly affected daily life, with 88% of respondents reporting discrimination/humiliation and 61% reporting an impact on their professional life. This report highlights stigmatization among Nordic patients with psoriasis and the potential to improve physician-patient communication. PMID- 30250962 TI - Pulse-Daylight-Photodynamic Therapy in Combination with Corticosteroid and Brimonidine Tartrate for Multiple Actinic Keratoses: A Randomized Clinical Trial. PMID- 30250963 TI - Increase in Vitamin D but not Regulatory T Cells following Ultraviolet B Phototherapy of Patients with Atopic Dermatitis. AB - This study investigated serum 25-hydroxyvitamin D (25(OH)D) concentrations and circulating regulatory T cells in patients with atopic dermatitis receiving narrow-band ultraviolet B (nbUVB) phototherapy. Thirty adult patients with atopic dermatitis were included. Blood samples were collected at baseline and at weeks 2 and 4 of nbUVB phototherapy. Skin biopsies were taken at baseline and at week 4. Serum 25(OH)D concentrations increased significantly following nbUVB phototherapy (estimate of change from baseline to week 2: 32.00 nmol/l, confidence interval (CI) 20.48-43.52, p < 0.0001, n = 25; and from baseline to week 4: 50.30 nmol/l, CI 37.28-63.33, p < 0.0001, n = 18). This increase was independent of the filaggrin gene FLG loss-of-function mutation status. Flow cytometry showed no significant change in regulatory T cells or cytokine profiles of T cells in blood. Real-time quantitative PCR showed no change in skin cytokine levels. In conclusion, nbUVB phototherapy was associated with increased serum 25(OH)D concentrations, but not changes in circulating regulatory T cells in patients with atopic dermatitis. PMID- 30250964 TI - Systematic review of mobile phone-based teledermatology. AB - Teledermatology is an expanding field within dermatology that has grown and become more clinically accepted by both patients and doctors. With approximately 260 million mobile phone users in the US and 4-6 billion worldwide with access to mobile phones, teledermatology serves as a potentially useful tool for diagnosis and management (Samkange-Zeeb and Blettner in Emerg Health Threats J, https://doi.org/10.3134/ehtj.09.005 , 2009). In this review, we provide a detailed overview of mobile phone technology and the accumulating evidence for its incorporation into dermatology. Key questions addressed include accuracy and concordance between mobile teledermatology and face-to-face dermatology for the diagnosis of skin conditions. Similarly, accuracy and concordance were compared for the management of skin conditions. To track the development of mobile phone technology, we also assessed how data were captured, stored, and displayed in teledermatology studies. PMID- 30250965 TI - [What is certain in the treatment of glomerulonephritis?] AB - Glomerulonephritides essentially all belong to the rare diseases; however, they are the most common cause of end-stage renal disease in young adults. Besides obtaining a specific diagnosis via a renal biopsy, assessing the prognosis constitutes the other essential step in the work-up, since this enables a decision to be made on whether supportive care with relatively few adverse effects is sufficient or whether additional immunosuppressive therapy is required. The latter is discussed focusing on the most common European types of glomerulonephritis: immunoglobulin A nephropathy, membranous glomerulonephritis, minimal change nephropathy and focal segmental glomerulosclerosis. PMID- 30250966 TI - [Low-dose prophylactic oral isotretinoin treatment for 18 years in a patient with epidermodysplasia verruciformis and numerous squamous cell carcinomas]. AB - Epidermodysplasia verruciformis (also known as Lewandowsky-Lutz dysplasia) is an extremely rare autosomal recessive genodermatosis, in which the skin is unusually sensitive to human papilloma viruses (HPV). It is associated with a high risk of developing non-melanocytic skin tumors. Treatment with keratolytic retinoids is currently considered to be the most effective therapy. Retinoids have a broad spectrum of activity and inhibit the growth of squamous cell carcinoma and other malignant tumors. We report the case of an 81-year-old woman who had been receiving prophylactic treatment with oral isotretinoin at a daily dose of 1.0 0.33 mg/kg bodyweight for about 18 years because of her epidermodysplasia verruciformis (HPV types 9 & 57 detected). We observed a reduction of the incidence of squamous cell carcinomas of the skin and presume a causal relationship between the treatment with this retinoid and the reduction of squamous cell carcinomas of the skin in this patient. PMID- 30250967 TI - Involvement of butyrate in electrogenic K+ secretion in rat rectal colon. AB - Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are synthesized from dietary carbohydrates by colonic bacterial fermentation. These SCFAs supply energy, suppress cancer, and affect ion transport. However, their roles in ion transport and regulation in the intracellular environment remain unknown. In order to elucidate the roles of SCFAs, we measured short-circuit currents (ISC) and performed RT-PCR and immunohistochemical analyses of ion transporters in rat rectal colon. The application of 30 mM butyrate shifted ISC in a negative direction, but did not attenuate the activity of epithelial Na+ channels (ENaC). The application of bumetanide, a Na+-K+-2Cl- cotransporter inhibitor, to the basolateral side reduced the negative ISC shift induced by butyrate. The application of XE991, a KCNQ-type K+ channel inhibitor, to the apical side decreased the ISC shift induced by butyrate in a dose-dependent manner. The ISC shift was independent of HCO3- and insensitive to ibuprofen, an SMCT1 inhibitor. The mucosa from rat rectal colon expressed mRNAs of H+-coupled monocarboxylate transporters (MCT1, MCT4, and MCT5, also referred to as SLC16A1, SLC16A3, and SLC16A4, respectively). RT-PCR and immunofluorescence analyses demonstrated that KCNQ2 and KCNQ4 localized to the apical membrane of surface cells in rat rectal colon. These results indicate that butyrate, which may be transported by H+-coupled monocarboxylate transporters, activates K+ secretion through KCNQ-type K+ channels on the apical membrane in rat rectal colon. KCNQ type K+ channels may play a role in intestinal secretion and defense mechanisms in the gastrointestinal tract. PMID- 30250968 TI - Artificial Pancreas or Novel Beta-Cell Replacement Therapies: a Race for Optimal Glycemic Control? AB - PURPOSE OF REVIEW: New treatment strategies are needed for patients with type 1 diabetes (T1D). Closed loop insulin delivery and beta-cell replacement therapy are promising new strategies. This review aims to give an insight in the most relevant literature on this topic and to compare the two radically different treatment modalities. RECENT FINDINGS: Multiple clinical studies have been performed with closed loop insulin delivery devices and have shown an improvement in overall glycemic control and time spent in hypoglycemia. Beta-cell transplantation has been shown to normalize or greatly improve glycemic control in T1D, but the donor organ shortage and the necessity to use immunosuppressive agents are major drawbacks. Donor organ shortage may be solved by the utilization of stem cell-derived beta cells, which has shown great promise in animal models and are now tested in clinical studies. Immunosuppression may be avoided by encapsulation. Closed loop insulin delivery devices are promising treatment strategies and are likely to be used in clinical practice in the short term. But this approach will always suffer from delays in glucose measurement and insulin action preventing it from normalizing glycemic control. In the long term, stem cell-derived beta cell transplantation may be able to achieve this, but wide implementation in clinical practice is still far away. PMID- 30250969 TI - Influence of suture technique on anastomotic leakage rate-a retrospective analyses comparing interrupted-versus continuous-sutures. AB - PURPOSE: While many hospitals consider a continuous sutured colonic anastomosis with monofilamental fiber the current state of the art, others have advocated for interrupted sutures as the gold standard. The aim of the study was to evaluate the influence of suture technique on leakage rate (primary endpoint), wound infections, postoperative stay, and mortality. METHODS: Retrospective analyses of 347 patients (273 elective, 74 urgent) over 6 years with a handsewn colonic anastomosis (190 interrupted, 157 continuous), excluding sigma and rectum anastomosis. Demographic and surgical baseline characteristics were used as competing predictors. RESULTS: Overall leakage rate was 9% but strongly dependent on suture technique (interrupted: 16%; continuous: 2.5%; p = 0.001) yielding an odds ratio of 5.10 [95% CI: 2.55, 6.71] (relative risk of leakage). No other variable showed a significant influence on leakage rate. Postoperative stay was prolonged in the interrupted suture group (23 +/- 15 vs. 16 +/- 11 days; p = 0.000, attributable effect 7.5 days [4.7, 10.3]). CONCLUSIONS: Our results indicate a highly significant reduction of anastomotic leakage rate and postoperative stay that generalize to the underlying population by continuous sutures in handsewn colonic anastomosis. In the absence of randomized prospective studies, the current results provide the yet strongest evidence for the superiority of continuous sutures. PMID- 30250970 TI - Assessment of Trace Metal and Metalloid Accumulation and Human Health Risk from Vegetables Consumption through Spinach and Coriander Specimens Irrigated with Wastewater. AB - This study focused on evaluating the metal and metalloid contamination and associated risks in the two vegetables crops, coriander (Coriandrum sativum) and spinach (Spinacia oleracea) treated with three water regimes, canal water, groundwater and municipal wastewater. These vegetables are widely consumed by people and are also used in traditional medicine for treating various disorders. Metal and metalloid accumulation (Zn, Pb, Se, Cu, As, Mo, Fe, Ni) was found higher in vegetables treated with wastewater. Wastewater treated soil had high pollution load index. Fe, Zn, As and Pb had higher values in water, soil and vegetables as compared to other studied metals. Overall, metal correlation for soil and vegetables was significant and positive except for Fe and Cu in spinach. The highest value for daily metal intake was estimated for Fe while Se had the lowest value for the same index. It was thus concluded that trace metal and metalloid accumulation was a major health concern for the public consuming these vegetables. PMID- 30250971 TI - Acute Toxicity and Hazardous Concentrations of Zinc to Native Freshwater Organisms Under Different pH Values in China. AB - Zinc bioavailability to aquatic organisms varies greatly under different pH values. In the present study, five native species in China and four common international test species were selected to investigate the influence of changing pH on acute zinc toxicity. The results showed that the higher trophic levels exhibited increasing sensitivity to zinc as pH decreased. However, when the pH value was between 8 and 11, the acute toxicity of zinc was relatively constant. In addition, by using a species-sensitivity distribution (SSD) method, the short term hazardous concentrations of zinc at different pH values (based on the 5th percentiles of the pH-specific SSDs) were determined to be 17.26 ug/L (pH 4), 48.31 ug/L (pH 5), 80.34 ug/L (pH 6) and 230.6 ug/L (pH 7), respectively. The present study provides useful information for deriving water quality criteria and assessing the risks of metals in the near future. PMID- 30250973 TI - Bone marrow-derived mesenchymal stem cells ameliorate liver injury in a rat model of sepsis by activating Nrf2 signaling. AB - Sepsis is a fatal condition that leads to serious systemic inflammation and multiple organ dysfunction syndromes. This study was designed to investigate the possible therapeutic effect of bone marrow-derived mesenchymal stem cells (BMSCs) on sepsis-induced liver injury. We also aimed to examine the role of Nrf2 activation in modulating the response to sepsis following BMSCs treatment. Twenty four adult male albino rats were assigned to: control, lipopolysaccharide (LPS) and LPS-stem cell groups. Liver samples were processed for light and electron microscope examinations. Immunohistochemical localization of BAX, proliferating cell nuclear antigen and nuclear factor-erythroid 2-related factor 2 (Nrf2) was carried out. Liver homogenates were prepared for assessment of reduced glutathione, glutathione peroxidase, tumor necrosis factor-alpha and interleukin 6 and also real-time PCR analysis of Nrf2 expression. BMSCs treatment improved the histopathological changes of the liver, enhanced tissue regeneration and decreased apoptosis following sepsis. We reported highly significant enhancement in Nrf2 expressions at mRNA and protein levels in the LPS-stem cell group compared with the LPS group. The up regulation of Nrf2 was probably implicated in decreasing inflammatory cytokine levels and counteracting oxidative stress induced by sepsis. Thus, BMSCs therapies could be a viable approach to treat sepsis-induced liver damage by activating Nrf2 signaling. PMID- 30250972 TI - Monoamines in the enteric nervous system. AB - Recent advances in neurogastroenterology have extended and refined our knowledge on the roles monoamines play in physiology and pathophysiology of the gastrointestinal tract. The catecholamine noradrenaline, as the primary transmitter of postganglionic sympathetic neurons, orchestrates motility and secretory reflexes and controls arterial perfusion as well as immune functions. The catecholamine dopamine is produced by a subpopulation of enteric neurons which possibly use it as transmitter. Serotonin, largely produced by enterochromaffin cells and to a small extent by enteric neurons profoundly affects gut motility, enteric neuron development and is also involved in immunomodulation. However, its mode of action and the relative contribution of non-neuronal versus neuronal serotonin was recently subject to debate again. Histamine, although entirely of non-neuronal origin, is pivotal for gastrointestinal neuroimmunomodulation besides its paracrine effect in gastric HCl production. PMID- 30250974 TI - Effects of N-cadherin on neuronal migration during chicken optic tectum development. AB - N-cadherin, a member of the cadherin family, plays an important role in neural development. In addition, N-cadherin has been reported to be crucial in neuronal migration, axonal outgrowth, and axonal path-finding. However, the mechanism underlying the effects of N-cadherin in neuronal migration is not entirely clear. In this study, we investigated the overexpression or knockdown of N-cadherin in the optic tectum during chicken embryo development, and then analyzed the effect of N-cadherin on neuronal migration. The results showed that compared with the control group, in the N-cadherin knockdown group, the neuronal migration of the optic tectum was significantly affected and could not arrive at destination. The stratum griseum central layer of the optic tectum mainly includes multipolar neurons, which could not be formed after the knockdown of N-cadherin, and more neurons form the bipolar or monopolar neurons compared with the control group. Compared with the control group, more cells stayed in the neuroepithelium layer. The axonal length in the optic tectum was significantly (P < 0.001) shorter in the N-cadherin knockdown group than in the control group. These results reveal that the knockdown of N-cadherin mainly affects the length of axons and formation of multipolar neurons in the development of the chicken optic tectum, which eventually results in the inhibition of neuronal migration. PMID- 30250975 TI - Changes in ephrin gene expression during bone healing identify a restricted repertoire of ephrins mediating fracture repair. AB - To identify the repertoire of ephrin genes that might regulate endochondral bone fracture repair, we examined changes in ephrin ligand and receptor (Eph) gene expression in fracture callus tissues during bone fracture healing. Ephrin and Eph proteins were then localized in the fracture callus tissues present when changes in gene expression were observed. Ephrin gene expression was widespread in fracture tissues, but the repertoire of ephrin genes with significant changes in expression that might suggest a regulatory role in fracture callus development was restricted to the ephrin A family members Epha4, Epha5 and the ephrin B family member Efnb1. After 3 weeks of healing, Epha4 fracture expression was downregulated from 1.3- to 0.8-fold and Epha5 fracture expression was upregulated from 1.2- to 1.5-fold of intact contralateral femur expression, respectively. Efnb1 expression was downregulated from 1.5- to 1.2-fold after 2 weeks post fracture. These ephrin proteins were localized to fracture callus prehypertrophic chondrocytes and osteoblasts, as well as to the periosteum and fibrous tissues. The observed positive correlation between mRNA levels of EfnB1 with Col10 and Epha5 with Bglap, together with colocalized expression with their respective proteins, suggest that EfnB1 is a positive mediator of prehypertrophic chondrocyte development and that Epha5 contributes to osteoblast-mediated mineralization of fracture callus. In contrast, mRNA levels of Epha4 and Efnb1 correlated negatively with Bglap, thus suggesting a negative role for these two ephrin family members in mature osteoblast functions. Given the number of family members and widespread expression of the ephrins, a characterization of changes in ephrin gene expression provides a basis for identifying ephrin family members that might regulate the molecular pathways of bone fracture repair. This approach suggests that a highly restricted repertoire of ephrins, EfnB1 and EphA5, are the major mediators of fracture callus cartilage hypertrophy and ossification, respectively, and proposes candidates for additional functional study and eventual therapeutic application. PMID- 30250976 TI - Enzymatic hydrolysis of PET: functional roles of three Ca2+ ions bound to a cutinase-like enzyme, Cut190*, and its engineering for improved activity. AB - Cut190 from Saccharomonospora viridis AHK190 (Cut190) is the only cutinase that exhibits inactive (Ca2+-free) and active (Ca2+-bound) states, although other homologous cutinases always maintain the active states (Ca2+-free and bound). The X-ray crystallography of the S176A mutant of Cut190* (Cut190_S226P/R228S) showed that three Ca2+ ions were bound at sites 1-3 of the mutant. We analyzed the roles of three Ca2+ ions by mutation and concluded that they play different roles in Cut190* for activation (sites 1 and 3) and structural and thermal stabilization (sites 2 and 3). Based on these analyses, we elucidated the mechanism for the conformational change from the Ca2+-free inactive state to the Ca2+-bound active state, proposing the novel Ca2+ effect on structural dynamics of protein. The introduction of a disulfide bond at Asp250 and Glu296 in site 2 remarkably increased the melting temperatures of the mutant enzymes by more than 20-30 degrees C (while Ca2+-bound) and 4-14 degrees C (while Ca2+-free), indicating that a disulfide bond mimics the Ca2+ effect. Replacement of surface asparagine and glutamine with aspartic acid, glutamic acid, or histidine increased the melting temperatures. Engineered mutant enzymes were evaluated by an increase in melting temperatures and kinetic values, based on the hydrolysis of poly(butylene succinate-co-adipate) and microfiber polyethylene terephthalate (PET). A combined mutation, Q138A/D250C-E296C/Q123H/N202H, resulted in the highest thermostability, leading to the maximum degradation of PET film (more than 30%; approximately threefold at 70 degrees C, compared with that of Cut190* at 63 degrees C). PMID- 30250977 TI - Efforts toward optimization of aerobic biohydrogen reveal details of secondary regulation of biological nitrogen fixation by nitrogenous compounds in Azotobacter vinelandii. AB - Biological nitrogen fixation (BNF) through the enzyme nitrogenase is performed by a unique class of organisms known as diazotrophs. One interesting facet of BNF is that it produces molecular hydrogen (H2) as a requisite by-product. In the absence of N2 substrate, or under conditions that limit access of N2 to the enzyme through modifications of amino acids near the active site, nitrogenase activity can be redirected toward a role as a dedicated hydrogenase. In free living diazotrophs, nitrogenases are tightly regulated to minimize BNF to meet only the growth requirements of the cell, and are often accompanied by uptake hydrogenases that oxidize the H2 by-product to recover the electrons from this product. The wild-type strain of Azotobacter vinelandii performs all of the tasks described above to minimize losses of H2 while also growing as an obligate aerobe. Individual alterations to A. vinelandii have been demonstrated that disrupt key aspects of the N2 reduction cycle, thereby diverting resources and energy toward the production of H2. In this work, we have combined three approaches to override the primary regulation of BNF and redirect metabolism to drive biological H2 production by nitrogenase in A. vinelandii. The resulting H2 producing strain was further utilized as a surrogate to study secondary, post transcriptional regulation of BNF by several key nitrogen-containing metabolites. The improvement in yields of H2 that were achieved through various combinations of these three approaches was compared and is presented along with the insights into inhibition of BNF by several nitrogen compounds that are common in various waste streams. The findings indicate that both ammonium and nitrite hinder BNF through this secondary inhibition, but urea and nitrate do not. These results provide essential details to inform future biosynthetic approaches to yield nitrogen products that do not inadvertently inhibit BNF. PMID- 30250978 TI - Functional expression of monomeric streptavidin and fusion proteins in Escherichia coli: applications in flow cytometry and ELISA. AB - Monomeric streptavidin (mSA) offers a combination of structural and binding properties that are useful in many applications, including a small size and monovalent biotin binding. Because mSA contains a structurally important disulfide bond, the molecule does not fold correctly when expressed inside the cell. We show that mSA can be expressed in a functional form in Escherichia coli by fusing the OmpA signal sequence at the amino terminus. Expressed mSA is exported to the periplasm, from which the molecule leaks to the medium under vigorous shaking. Purified mSA can be conjugated with FITC and used to label microbeads and yeast cells for analysis by flow cytometry, further expanding the scope of mSA-based applications. Some applications require recombinant fusion of mSA with another protein. mSA fused to EGFP cannot be secreted to the medium but was successfully expressed in an engineered cell line that supports oxidative folding in the cytoplasm. Purified mSA-EGFP and mSA-mCherry bound biotin with high affinity and were successfully used in conventional flow cytometry and imaging flow cytometry. Finally, we demonstrate the use of mSA in ELISA, in which horseradish peroxidase-conjugated mSA and biotinylated secondary antibody are used together to detect primary antibody captured on an ELISA plate. Engineering mSA to introduce additional lysine residues can increase the reporter signal above that of wild-type streptavidin. Together, these examples establish mSA as a convenient reagent with a potentially unique role in biotechnology. PMID- 30250979 TI - Morphology dependent optical response tuning in planar square-shaped array of sodium nanoparticles. AB - Among the plasmonic nanostructures, ordered arrangement of metal nanoparticles with inter-particle gap distances in the nanometer scale is becoming increasingly important due to their ability to confine huge electromagnetic fields and tunable optical properties. Using time dependent density functional theory calculations, we study the optical response evolution in a planar square-shaped array of Sodium nanoparticles via morphology deformation. To this aim, we vary the inter-particle gap distance in the range of 2 to 30 A separately along one and two directions. We compare and cross-examine the optical response evolution for both deformation process, and we find that the interaction between sodium nanoparticles in an ordered arrangement can be controlled to a large extent by simple deformation process. We believe that our theoretical results will be useful for designing ultra-small and tunable plasmonic devices that utilize quantum effects. PMID- 30250981 TI - Bartonella quintana and Bartonella vinsonii subsp. vinsonii bloodstream co infection in a girl from North Carolina, USA. AB - The genus Bartonella consists of globally distributed and highly diverse alpha proteobacteria that infect a wide-range of mammals. Medically, Bartonella spp. constitute emerging, vector-borne, zoonotic, intravascular organisms that induce long-lasting bacteremia in reservoir-adapted (passive carrier of a microorganism) hosts. At times, these bacteria are accidentally transmitted by animal scratches, bites, needles sticks or vectors to animal or human hosts. We report the first documented human case of blood stream infection with Bartonella vinsonii subsp. vinsonii in a girl from North Carolina, USA, who was co-infected with Bartonella quintana. Limitations of Bartonella spp. serology and the challenges of microbiological culture and molecular diagnostic confirmation of co-infection with more than one Bartonella spp. are discussed. When and where these infections were acquired is unknown; however, exposure to rodents, fleas and cats in the peri-equestrian environment was a suspected source for transmission of both organisms. PMID- 30250980 TI - Drivers of Physicians' Engagement in Addressing Eco-health Problems. AB - Physicians are in a unique position to be first-hand observers of the effects of environmental factors on population health. As a source of information which is highly trusted, they are also well-suited to raise awareness about the linkages between ecosystem and population health. Yet, current clinical practice in many parts of the world rarely includes environmental health assessments and patient education. The empirical evidence on the reasons for this lack of engagement is limited by the small number of studies published, its narrow geographical scope and the dearth of multivariate statistical analysis. This study used a mixed methods approach to investigate the determinants of whether physicians at selected hospitals in Thailand assess the environmental history of their patients and provide environmental health advice. Using an ordered logistic regression model, it was found that physicians' engagement was associated with their knowledge, personal motivation, perception of being supported by senior staff and ability to discuss with colleagues. According to key informants, possible remedies for the observed lack of physicians' engagement include revisions of the medical school curriculum, clear strategies for addressing eco-health linkages in the clinical context at the national and hospital level, and better cooperation between relevant government institutions in Thailand. PMID- 30250982 TI - The effect of the volume of supra-inguinal injected solution on the spread of the injectate under the fascia iliaca: a preliminary study. AB - The fascia iliaca compartment is the compartment confined by the fascia iliaca (FI) and a muscular layer formed by the iliac- and psoas muscle. This compartment creates a virtual tunnel that contains the femoral nerve (FN), the obturator nerve (ON), and the lateral femoral cutaneous nerve (LFCN) of the lumbar plexus. In this pilot study, we aimed to determine the suggested volume needed to reach the three target nerves of the lumbar plexus (FN, ON, and LFCN) with a single injection ultrasound-guided supra-inguinal fascia iliaca compartment (S-FICB). A computer tomography (CT scan)-guided step-up/step-down sequence was used to determine the suggested injection volume to target all three nerves. Subsequently, an anatomist blinded for the injected volume and CT findings, dissected the cadavers, and evaluated the spread of dye underneath the fascia iliaca. In total, seven pelvic areas of four cadavers were evaluated on CT scan and dissected. Distribution of dye underneath the FI in relation to the FN, ON, and the LFCN was recorded in all dissected cadavers. Combining CT and dissection findings, the suggested volume to reach the FN, ON, and LFCN with an S-FICB was 40 mL. PMID- 30250983 TI - Natural concentrations and reference values of heavy metals in sedimentary soils in the Brazilian Amazon. AB - The soils of the Brazilian Amazon exhibit large geochemical diversity reflecting the different soil formation processes in an area covering 49% of the Brazilian territory. Soil contamination by heavy metals is one of the threats to the sustainability of this Biome but establishing quality reference values (QRVs) for the region is a challenging owing to the immense territorial area of the Amazon. This study aimed to determine the natural background of heavy metals in soils from the southwestern Brazilian Amazon in order to propose QRVs for Ba, Cd, Cr, Cu, Fe, Mn, Ni, Pb, Sb, and Zn for alluvial sedimentary soils. One hundred and twenty-eight soil samples were collected at a depth of 0.0-0.2 m in sites with minimal anthropogenic interference. Soil sample digestion was based on the EPA 3051A method and metal concentrations were determined by ICP-OES. QRVs calculated for the southwestern Brazilian Amazon are among the lowest recorded in Brazil (mg kg-1): Ba (16.5), Cd (0.1), Cr (6.9), Cu (2.8), Fe (15.4), Mn (13.4), Ni (1.7), Pb (4.4), Sb (0.9), and Zn (5.7). The low metal concentration is likely a result of the sedimentary origin of the soils. The results of this study can serve as a basis for defining public policies to investigate the environmental impacts resulting from changes in land use in areas of the Brazilian Amazon. PMID- 30250986 TI - Short-term evaluation of photobiomodulation therapy on the proliferation and undifferentiated status of dental pulp stem cells. AB - The aim of this in vitro study was to analyze the effect of photobiomodulation therapy (PBMT) on the proliferation and undifferentiating status of stem cell from human exfoliated deciduous teeth (SHEDs). PBMT was carried out with an aluminum gallium indium phosphide (InGaAlP) diode laser in contact and punctual mode (continuous wave, 660 nm, 20 mW, 0.028 cm2, and average energy densities of 1 (1 s), 3 (4 s), 5 (7 s), 10 (14 s), 15 (21 s), or 20 (28 s) J/cm2 per point). The immunoprofile of the SHEDs was analyzed using flow cytometry. Cell proliferation was assessed by the MTT reduction assay. Gene expressions of mesenchymal stem cell markers (OCT4, Nestin, CD90, and CD105) were assessed by RT qPCR 48 h after PBMT. Data were compared by analysis of variance (ANOVA) and Tukey's test (p <= 0.05). Cells cultured under nutritional deficit and treated with PBMT at 5 J/cm2 presented similar cell growth than those of positive control group. Cell growth was significantly higher than those of other groups. Mesenchymal stem cell gene markers were still expressed after PBMT at 5 J/cm2. In a short-term analysis, PBMT increases the number of stem cells with no interference in the undifferentiated state of the irradiated cells, which opens wide possibilities for application in tissue regeneration. PMID- 30250984 TI - The World of Melanoma: Epidemiologic, Genetic, and Anatomic Differences of Melanoma Across the Globe. AB - PURPOSE OF REVIEW: As cancer remains an increasing problem in industrial countries, the incidence of melanoma has risen rapidly in many populations during the last decades and still continues to rise. Current strategies aiming to control the disease have largely focused on improving the understanding of the interplay of causal factors for this cancer. RECENT FINDINGS: Cutaneous melanoma shows clear differences in incidence, mortality, genomic profile, and anatomic presentation, depending on the country of residence, ethnicity, and socioeconomic status. Known risk factors are multiple atypical nevi, positive family and/or personal history, immune suppressive diseases or treatments, and fair skin phenotype. Besides new adjuvant therapeutic options, changed attitude toward leisure and sun exposure, primary prevention, and early detection are major contributors to disease control. Melanoma is a disease of multifactorial causality and heterogeneous presentation. Its subtypes differ in origin, anatomical site, role of UV radiation, and mutational profile. Better understanding of these differences may improve prevention strategies and therapeutic developments. PMID- 30250987 TI - Factors affecting diagnosis of primary pediatric central nervous system neoplasias in a developing country. AB - PURPOSE: Understand the variables that could interfere with diagnosis and prompt treatment in CNS childhood cancer in Brazil, a developing country with continental dimensions. METHODS: From 2005 to 2010, we retrospectively evaluated factors, which could represent a negative influence on the time period elapsing from the onset of symptoms until the diagnosis of the central nervous system (CNS) neoplasia in children and adolescents attended in our service. RESULTS: Two hundred seventeen records were analyzed retrospectively. Factors of the households were evaluated, and this data was related to the time period elapsing from presentation of the first symptoms until the diagnosis of CNS neoplasia. The average time elapsed from the onset of the symptoms until seeking medical assistance was 96 days, and from medical assistance to patient referral to a reference service was 33 days. The symptoms which most contributed to a shorter delay in diagnosis were changes in gait and paresis, mother's occupation, father's education level, patient gender, and living in the state of Sao Paulo. Besides that, variables such as male gender, mother's education level, and lower patient age were associated with an early diagnosis time. CONCLUSION: There is great difficulty in performing early diagnosis of CNS tumors, partly due to parent's inability to recognize signs and symptoms, and in part due to an educational deficit among healthcare professionals. Identification of measures that can minimize these causes of delay is fundamental to increasing the chance of cure and survival of these patients. PMID- 30250985 TI - Contribution of the clock gene DEC2 to VEGF mRNA upregulation by modulation of HIF1alpha protein levels in hypoxic MIO-M1 cells, a human cell line of retinal glial (Muller) cells. AB - PURPOSE: Clock genes are components of the molecular clock. Their malfunction is thought to increase the risk of numerous diseases, including cancer. Vascular endothelial growth factor (VEGF) has a pivotal role in angiogenesis, and its expression levels are controlled by clock genes in tumor cells. Ophthalmic diseases such as age-related macular degeneration, proliferative diabetic retinopathy, and neovascular glaucoma are also associated with abnormal angiogenesis followed by upregulation of VEGF in the eye. In the present study, we aimed to uncover the relationship between clock genes and VEGF in the eye. STUDY DESIGN: Laboratory investigation METHODS: Oxygen-induced retinopathy (OIR) mice were prepared to mimic hypoxic conditions in the eye. Deferoxamine (DFO) was used to mimic hypoxic conditions in human Muller cell line MIO-M1 cells. Expression levels of mRNA and protein were quantified by quantitative reverse transcription polymerase chain reaction and Western blot analysis, respectively. RESULTS: In the retinas of OIR mice, the expression levels of Vegf and the clock gene Dec2 increased transiently, and their temporal profiles were correlated. Knockdown of DEC2 resulted in a significant (26.7%) reduction of VEGF expression in MIO-M1 cells under hypoxia-mimicking conditions induced by DFO (P < .05). Levels of HIF1alpha protein were also reduced significantly, by 60.2%, in MIO-M1 cells treated with siRNA against the DEC2 gene (P < .05). Moreover, HIF1alpha levels showed a significant (2.5-fold) increase in MIO-M1 cells overexpressing DEC2 (P < .05). CONCLUSION: DEC2 could upregulate retinal VEGF gene expression through modulation of HIF1alpha levels under hypoxic conditions. PMID- 30250988 TI - Carbon budgets of potential tropical perennial grass cropping scenarios for bioenergy feedstock production. AB - BACKGROUND: The environmental costs of fossil fuel consumption are globally recognized, opening many pathways for the development of regional portfolio solutions for sustainable replacement fuel and energy options. The purpose of this study was to create a baseline carbon (C) budget of a conventionally managed sugarcane (Saccharum officinarum) production system on Maui, Hawaii, and compare it to three different future energy cropping scenarios: (1) conventional sugarcane with a 50% deficit irrigation (sugarcane 50%), (2) ratoon harvested napiergrass (Pennisetum purpureum Schumach.) with 100% irrigation (napier 100%), and (3) ratoon harvested napiergrass with a 50% deficit irrigation (napier 50%). RESULTS: The differences among cropping scenarios for the fossil fuel-based emissions associated with agricultural inputs and field operations were small compared to the differences associated with pre-harvest burn emissions and soil C stock under ratoon harvest and zero-tillage management. Burn emissions were nearly 2000 kg Ceq ha-1 year-1 in the conventional sugarcane; whereas soil C gains were approximately 4500 kg Ceq ha-1 year-1 in the surface layer of the soil profile for napiergrass. Further, gains in deep soil profile C were nearly three times greater than in the surface layer. Therefore, net global warming potential was greatest for conventional sugarcane and least for napier 50% when deep profile soil C was included. Per unit of biomass yield, the most greenhouse gas (GHG) intensive scenario was sugarcane 50% with a GHG Index (GHGI, positive values imply a climate impact, so a more negative value is preferable for climate change mitigation) of 0.11 and the least intensive was napiergrass 50% when a deep soil profile was included (GHGI = - 0.77). CONCLUSION: Future scenarios for energy or fuel production on former sugarcane land across the Pacific Basin or other volcanic islands should concentrate on ratoon-harvested crops that maintain yields under zero-tillage management for long intervals between kill harvest and reduce costs of field operations and agricultural input requirements. For napiergrass on Maui and elsewhere, deficit irrigation maximized climate change mitigation of the system and reduced water use should be part of planning a sustainable, diversified agricultural landscape. PMID- 30250989 TI - Does Measurement of First-Order and Heterogeneity Parameters Improve Response Assessment of Bone Metastases in Breast Cancer Compared to SUVmax in [18F]fluoride and [18F]FDG PET? AB - PURPOSE: To establish whether first-order statistical features from [18F]fluoride and 2-deoxy-2-[18F] fluoro-D-glucose ([18F]FDG) positron emission tomography/x ray computed tomography (PET/CT) demonstrate incremental value in skeletal metastasis response assessment compared with maximum standardised uptake value (SUVmax). PROCEDURES: Sixteen patients starting endocrine treatment for de novo or progressive breast cancer bone metastases were prospectively recruited to undergo [18F]fluoride and [18F]FDG PET/CT scans before and 8 weeks after treatment. Percentage changes in SUV parameters, metabolic tumour volume (MTV), total lesion metabolism (TLM), standard deviation (SD), entropy, uniformity and absolute changes in kurtosis and skewness, from the same <= 5 index lesions, were measured. Clinical response to 24 weeks, assessed by two experienced oncologists blinded to PET/CT imaging findings, was used as a reference standard and associations were made between parameters and progression free and overall survival. RESULTS: [18F]fluoride PET/CT: In four patients (20 lesions) with progressive disease (PD), TLM and kurtosis predicted PD better than SUVmax on a patient basis (4, 4 and 3 out of 4, respectively) and TLM, entropy, uniformity and skewness on a lesion basis (18, 16, 16, 18 and 15 out of 20, respectively). Kurtosis was independently associated with PFS (p = 0.033) and OS (p = 0.008) on Kaplan-Meier analysis. [18F]FDG PET: No parameter provided incremental value over SUVmax in predicting PD or non-PD. TLM was significantly associated with OS (p = 0.041) and skewness with PFS (p = 0.005). Interlesional heterogeneity of response was seen in 11/16 and 8/16 patients on [18F]fluoride and [18F]FDG PET/CT, respectively. CONCLUSION: With [18F]fluoride PET/CT, some first-order features, including those that take into account lesion volume but also some heterogeneity parameters, provide incremental value over SUVmax in predicting clinical response and survival in breast cancer patients with bone metastases treated with endocrine therapy. With [18F]FDG PET/CT, no first-order parameters were more accurate than SUVmax although TLM and skewness were associated with OS and PFS, respectively. Intra-patient heterogeneity of response occurs commonly between metastases with both tracers and most parameters. PMID- 30250991 TI - Whole Body PET Imaging with a Norepinephrine Transporter Probe 4 [18F]Fluorobenzylguanidine: Biodistribution and Radiation Dosimetry. AB - PURPOSE: 4-[18F]Fluorobenzylguanidine ([18F]PFBG) is a positron emission tomography (PET) probe for non-invasive targeting of the norepinephrine transporter. The aim of this study was to assess uptake and distribution characteristics of this PET probe. PROCEDURES: Three cynomolgus monkeys were injected with 269 +/- 51 MBq (7.3 +/- 1.4 mCi) of [18F]PFBG and 21 whole body PET scans were acquired over 165 min. s around organs to generate time-activity curves. The absorbed doses to individual organs and the effective dose to the whole body were estimated. RESULTS: Favorable distribution of [18F]PFBG was noted with a fast wash-in and wash-out of radioactivity from several tissues. [18F]PFBG rapidly distributed in the heart, liver, kidneys, and adrenal glands. The uptake presented as %ID in the brain, lung, and spleen was 1.06 +/- 0.45, 6.28 +/- 0.33, and 1.39 +/- 0.35 at 1 min and decreased to 0.29 +/- 0.02, 1.78 +/- 0.31, and 0.66 +/- 0.22 by 112 min. In general, a two- to fourfold reduction was noted from peak radioactivity levels. Rapid uptake and significant retention of radioactivity was noted in the heart and the septal wall was distinctly visible by 20 min. Fast wash-in and washout kinetics for [18F]PFBG resulted in shorter residence times. The residence time for the liver, lungs, kidneys, and spleen were 28.01 +/- 7.73 min, 2.97 +/- 0.56 min, 6.04 +/- 3.41 min, and 1.09 +/- 0.33 min, respectively. The mean effective dose for the 70-kg male was 0.04 +/- 0.00 mSv/MBq. The organs receiving the highest radiation dose in the 70-kg male model were the testes (0.11 +/- 0.02 mGy/MBq), adrenals (0.08 +/- 0.01 mGy/MBq), and urinary bladder wall (0.08 +/- 0.01 mGy/MBq). CONCLUSIONS: [18F]PFBG shows a favorable biodistribution pattern. Rapid and persistent uptake was noted in innervated organs. Renal clearance was the major path for elimination of [18F]PFBG. The estimated radiation burden from [18F]PFBG was significantly lower than that from [124I]MIBG. PMID- 30250992 TI - Perceived Candidacy for Pre-exposure Prophylaxis (PrEP) Among Men Who Have Sex with Men in Paris, France. AB - Low perception of HIV risk is a challenge to PrEP implementation. We analyzed associations between perceptions of PrEP candidacy, behavioral indications for PrEP, and sexual behaviors. We recruited a sample of 580 MSM from a geosocial networking smartphone application in Paris, France. A modified Poisson regression model was conducted to examine associations between perceived candidacy for PrEP and behavioral indications for PrEP, and relationships among engagement in group sex, transactional sex, HIV test history, and indications for PrEP. Adjusted risk ratios (aRR) and 95% confidence intervals (CIs) were calculated. For the outcome of perceived candidacy for PrEP, a multinomial logistic regression was performed, and adjusted relative risk ratios (aRRR) were calculated. Multivariate analyses were adjusted for socio-demographics. Respondents who considered themselves PrEP candidates were more likely to meet PrEP eligibility criteria compared to those who did not consider themselves candidates (aRR 1.65; 95% CI 1.34-2.03). Those who had engaged in group or transactional sex were more likely to have behavioral indications for PrEP (aRR 1.27; 95% CI 1.07-1.50, aRR 1.32; 95% CI 1.13-1.56, respectively), whereas HIV test history was not significantly associated with behavioral indications for PrEP. Respondents who had engaged in group sex or transactional sex were more likely to perceive themselves as candidates for PrEP (aRRR 2.24; 95% CI 1.21-4.16, aRRR 2.58; 95% CI 1.09-6.13, respectively), although those never tested for HIV were less likely to perceive themselves as candidates for PrEP (aRRR 0.18; 95% CI 0.03-0.91). The elucidation of candidacy perceptions and risk behaviors is key to furthering the effective implementation of PrEP engagement interventions. PMID- 30250990 TI - Current and Emerging Preclinical Approaches for Imaging-Based Characterization of Atherosclerosis. AB - Atherosclerotic plaques can remain quiescent for years, but become life threatening upon rupture or disruption, initiating clot formation in the vessel lumen and causing acute myocardial infarction and ischemic stroke. Whether and how a plaque ruptures is determined by its macroscopic structure and microscopic composition. Rupture-prone plaques usually consist of a thin fibrous cap with few smooth muscle cells, a large lipid core, a dense infiltrate of inflammatory cells, and neovessels. Such lesions, termed high-risk plaques, can remain asymptomatic until the thrombotic event. Various imaging technologies currently allow visualization of morphological and biological characteristics of high-risk atherosclerotic plaques. Conventional protocols are often complex and lack specificity for high-risk plaque. Conversely, new imaging approaches are emerging which may overcome these limitations. Validation of these novel imaging techniques in preclinical models of atherosclerosis is essential for effective translational to clinical practice. Imaging the vessel wall, as well as its biological milieu in small animal models, is challenging because the vessel wall is a small structure that undergoes continuous movements imposed by the cardiac cycle as it is adjacent to circulating blood. The focus of this paper is to provide a state-of-the-art review on techniques currently available for preclinical imaging of atherosclerosis in small animal models and to discuss the advantages and limitations of each approach. PMID- 30250993 TI - Expression profiles of histone modification genes in gastric cancer progression. AB - Gastric cancer (GC) development can be attributed to several risk factors including atrophic gastritis (AG), intestinal metaplasia (IM), and the presence of Helicobacter pylori (HP). Also, histone modification is an epigenetic mechanism that plays a pivotal role in GC carcinogenesis. In this preliminary study, we aimed to describe the expression profiles of histone modification in the AG, IM, and GC patient groups. A total of 80 patients with AG (n = 27), IM (n = 25), and GC (n = 28) with an additional 20 control subjects were included in the study. Expression profiles of three histone phosphorylation genes (PAK1, NEK6, and AURKA) and five histone deacetylation genes (HDACs 1, 2, 3, 5, and 7) were examined based on the results of Real Time qPCR method. It was observed that AURKA and HDAC2 genes were significantly overexpressed in all groups compared to the control (P < 0.05). In GC patients, overexpression of HDAC2 gene was detected in the absence of metastasis, and overexpression of AURKA, HDAC2, and NEK6 genes was detected in the presence of metastasis. When cancer involvements were compared, significant overexpression of the HDAC2 gene was noted in overall and corpus involvements (P < 0.05). In addition, overexpression of AURKA, NEK6, HDAC1, and HDAC2 genes and underexpression of HDAC5 gene were detected in the antrum involvement (P < 0.05). In conclusion, decreased expression of HDAC5 in GC is reported for the first time in this study, while supporting the existing literature in AURKA, NEK6, HDAC1, and HDAC2 up regulations during GC development. PMID- 30250994 TI - Fibroblast growth factor 10 (FGF10) promotes the adipogenesis of intramuscular preadipocytes in goat. AB - Fibroblast growth factor 10 (FGF10) is an adipokine that is found to participate in the regulation of adipogenesis. However, its function remains to be elucidated in intramuscular fat (IMF) deposition of goat. The purpose of this study was to explore the role of FGF10 in goat IMF deposition. Here, we investigated the expression of FGF10 in goat intramuscular adipocytes inducing 0, 2, 4, 6 and 8 days. Effect of FGF10 on adipogenesis was investigated by gaining and losing function of FGF10 in vitro. And then, we examined several lipid metabolism related genes, including peroxisome proliferator activated receptor gamma (PPARgamma), sterol regulatory element binding protein 1 (SREBP1), preadipocyte factor-1 (Pref-1), CCAAT/enhancer binding protein-alpha (C/EBPalpha) and CCAAT/enhancer binding protein-beta (C/EBPbeta), as well as, Kruppel-like factor (KLF) family. We found that the sharp expression of FGF10 appeared at 2 days. Overexpression of FGF10 mediated by adenovirus promotes lipid accumulation, accompanied by up-regulating of LPL and C/EBPalpha with the down-regulating of C/EBPbeta. Conversely, the expression of LPL, C/EBPalpha and SREBP1 was significantly decreased by the siRNAs of FGF10. Meanwhile, we showed that FGF10 regulated the expression of many KLFs members and interacted synergistically or antagonistically with them. Thus, our results demonstrated a key role of FGF10 as a positively factor in the regulation of adipogenic differentiation of intramuscular preadipocyte in goat. PMID- 30250995 TI - Changes in the expression level of IL-17A and p53-fibrinolytic system in smokers with or without COPD. AB - COPD is a chronic airway inflammatory disease characterized mainly by neutrophil airway infiltrations. The neutrophil airway inflammation is mainly mediated through a key player like the pro-inflammatory cytokine IL-17A which is involved in the modulation of p53-fibrinolytic system. This study was undertaken to examine the molecular changes for the expressions of IL-17A and p53-fibrinolytic system in smokers with or without COPD. Blood and serum samples were collected from ten patients of smokers having COPD and ten samples from smokers without COPD and ten healthy control subjects. Western blot analyses were performed to evaluate the expressions of IL-17A, p53 and PAI-1. Apoptosis was assessed by immunoblot for cleaved caspase-3. In addition, FEV% was also determined of these patients. qRT-PCR was done to detect the gene expression study from the blood samples on p53-fibrinolytic components. A significant difference was found in the expression levels of IL-17A in smokers with COPD patient when compared to smokers without COPD and the control subjects. Similarly the smokers with COPD showed significant increase in the fibrinolytic component PAI-1 as well as in expression levels of p53 when compared to smokers without COPD and normal subjects. Increased cleaved caspase-3 may also promote apoptosis.The expression pattern of the IL-17A in chronic obstructive pulmonary distress syndrome samples was increased as compared of those of normal samples, and their main role in the regulation of and p53-fibrinolytic system makes these components as a predictive prominent component in smokers with COPD. PMID- 30250997 TI - Elemental enrichment of sediments in an unprotected shallow groundwater of Lagos and Ogun States, Nigeria. AB - Sediments quality is a good indicator of pollution in a water body where various elements were concentrated. Limited information is available on sediments from hand-dug wells. The present study evaluates sediment samples collected from groundwater of Lagos and Ogun States, Southwest Nigeria. Twenty sediment samples were collected from shallow groundwater, and ten rock samples were also collected from the vicinity of recently dug wells. Trace elements were determined in both the sediments and the rock samples using inductively coupled plasma-mass spectrometry. The enrichment factor was calculated for different elements using Fe, Ti, Mn and Cu as normalizing elements. The order of sediment contamination with each normalizing elements are Cu > Mn > Ti > Fe. The geo-accumulation (Igeo) indexes for Cr, Pb, Cu and Ni are 1.31, 1.05, 1.94 and 1.85, respectively. The Igeo for Lagos sediments is in the order Cr > Pb > Ni > Cu, while in Ogun sediments the order is Cu > Ni > Cr > Pb. The results were compared with Canadian Council of Ministers of Environment values of threshold effect level and probable effect level, which shows the sediments are not toxic. The pollution load index and ecological risk index values are 2.463 and 0.0014, respectively, which further indicates the sediments are not toxic in nature. The major source of most elements in sediments is the host rocks found in the vicinity of the groundwater while high level of some elements recorded in sediments are from the anthropogenic sources. PMID- 30250996 TI - Expression patterns and bioinformatic analysis of miR-1260a and miR-1274a in Prostate Cancer Tunisian patients. AB - Currently, microRNAs (miRs) represent great biomarkers in cancer due to their stability and their potential role in diagnosis, prognosis and therapy. This study aims to evaluate the expression levels of miRs-1260 and -1274a in prostate cancer (PC) samples and to identify their eventual targets by using bioinformatic analysis. In this project, we evaluated the expression status of miRs-1260 and 1274a in 86 PC patients and 19 controls by using real-time quantitative PCR and 2 DeltaDeltaCt method. Moreover, we retrieved validated and predicted targets of miRs from several datasets by using the "multiMir" R/Bioconductor package. We have found that miRs-1260 and -1274a were over-expressed in PC patients compared to controls (p < 1 * 10-5). Moreover ROC curve for miRs-1260 and 1274a showed a good performance to distinguish between controls group and PC samples with an area under the ROC curve of 0.897 and 0.784 respectively. However, no significant association could be shown between these two miRs and clinical parameters such as PSA levels, Gleason score, tumor stage, D'Amico classification, lymph node metastasis statues, tumor recurrence, metastasis status and progression after a minimum of 5 years follow-up. Finally, a bioinformatic analysis revealed the association between these two miRs and several targets implicated in prostate cancer initiation pathways. PMID- 30250998 TI - Device updates successfully reduce T-wave oversensing and inappropriate shocks in subcutaneous ICD patients. AB - AIMS: To analyse the impact of device and software updates on the prevention of T wave oversensing (TWOS) and inappropriate shocks (IS) in subcutaneous ICD (S-ICD) patients. BACKGROUND: TWOS is a feared complication after implantation. It may lead to harmful IS. To date, specific strategies to reduce these events are lacking. METHODS: In this retrospective single-centre trial we analysed 146 S-ICD patients who were implanted between 2010 and 2016. In all eligible consecutive patients (n = 139), follow-up of at least 6 weeks was studied. The incidence of TWOS/IS was analysed in patients receiving a 2nd generation S-ICD (Emblem-S-ICD) between 2014 and 2016 (Emblem). Their outcome was compared with a control group (SQ) treated with the SQ1010 device between 2010 and 2014, who were followed up for a maximum of 2 years. Furthermore, to test if the software update SMR8 reduces inappropriate shocks in the SQ1010-S-ICD population, the incidence of TWOS/IS was evaluated before and after update installation. RESULTS: Basic characteristics and indications for S-ICD implantation were similar in both groups. However, the cumulative incidence of TWOS/IS was significantly decreased in Emblem vs. SQ (SQ: 15.4%, n = 14/91 vs. Emblem 4.2%, n = 2/48; p = 0.049). Furthermore, with regards to the SQ population we also observed a trend towards a significant reduction of TWOS/IS after installation of the software update SMR8 in 2014 (before update: 13.4%, n = 11/82 vs. after update: 4.6%, 3/65, p = 0.07). CONCLUSION: 2nd generation devices but probably also the SMR8 software update reduce the incidence of TWOS/IS in S-ICD patients. PMID- 30250999 TI - The use of a custom-made virtual template for corrective surgeries of asymmetric patients: proof of principle and a multi-center end-user survey. AB - AIM: To evaluate the utility of an individualized template for corrective surgeries for patients suffering from mandibular asymmetry. MATERIALS AND METHOD: Twenty patients with history of favorable clinical outcome of the correction of their mandibular asymmetry were chosen. CBCTs were taken before and 6 weeks postoperative using NewTom 3G. Each volume is mirrored and registered on the cranial base. Surface models for the mandible and its registered mirror were used to compute a template using deformable fluid registration. Surgery was simulated based of the resulting template. A multi-center survey using "Qualtrics" was conducted to gain clinical feedback of 20 surgeons/orthodontists comparing treatment outcomes. RESULTS: Twenty-three clinicians participated. More clinicians rated simulated outcome to be "Good," whereas the actual surgical outcomes were rated as "fair" and "poor." This was true for regional appraisal for the chin, Rami, and body of the mandible as well as the overall assessment of the outcome of surgeries. The gains of computer-assisted simulation tend to be greater for difficult cases especially for the body of the mandible, then the chin, and then the Ramus correction. CONCLUSIONS: This approach has the potential to optimize and increase the predictability of the outcome of craniofacial corrective surgeries for asymmetric patients. PMID- 30251000 TI - Honor and Violence : An Account of Feuds, Duels, and Honor Killings. AB - We present a theory of honor violence as a form of costly signaling. Two types of honor violence are identified: revenge and purification. Both types are amenable to a signaling analysis whereby the violent behavior is a signal that can be used by out-groups to draw inferences about the nature of the signaling group, thereby helping to solve perennial problems of social cooperation: deterrence and assurance. The analysis shows that apparently gratuitous acts of violence can be part of a system of norms that are Pareto superior to alternatives without such signals. For societies that lack mechanisms of governance to deter aggression or to enforce contracts, norms of honor can be a rational means of achieving these functions. The theory also suggests that cultures can become trapped in inefficient equilibria owing to path-dependent phenomena. In other words, costly signals of honor may continue to be sent even when they are no longer providing useful information. PMID- 30251001 TI - Pairs of Genetically Unrelated Look-Alikes : Further Tests of Personality Similarity and Social Affiliation. AB - Relationships of physical resemblance to personality similarity and social affiliation have generated considerable discussion among behavioral science researchers. A "twin-like" experimental design (involving genetically unrelated look-alikes, U-LAs) explores associations among resemblance in appearance, the Big Five personality traits, self-esteem, and social attraction within an evolutionary framework. The Personality for Professionals Inventory (PfPI), NEO/NEO-FFI-3, Rosenberg Self-Esteem Scale, and a Social Relationship Survey were variously completed by 45 U-LA pairs, identified from the "I'm Not a Look-Alike" project, Mentorn Media, and personal referrals. The mean U-LA intraclass correlations were negligible for all Big Five personality traits on the PfPI and NEO/NEO-FFI-3 (ri = -.02 and - .04, respectively). In contrast, mean ri values of .53 and .15 for monozygotic (MZA) and dizygotic (DZA) reared-apart twins, respectively, have been reported for these personality measures. The U-LA self esteem correlation (ri = -.18) was also below the correlations reported for MZ and DZ reared-together twins (ri = .31 and .13, respectively). Finally, far fewer U-LAs expressed close social relationships (20%) than MZA (80%) and DZA (65%) twins. The present study extends earlier findings indicating that appearance is not meaningfully related to personality similarity and social relatedness. The criticism that MZ twins are alike in personality because their matched looks invite similar treatment by others is refuted. A more judicious interpretation is reactive genotype-environment correlation, namely that MZ twins' similar personalities evoke similar reactions from others. MZ twins' close social relations most likely derive from their perceptions of genetically based within pair similarities that are lacking in U-LAs. PMID- 30251002 TI - Risk factor analysis of cerebral infarction and clinicopathological characteristics of left upper pulmonary vein stump thrombus after lobectomy. AB - OBJECTIVE: We aimed to analyze the risk factors of postoperative cerebral infarction (CI) and thrombus formation in the left upper pulmonary vein (PV) stump after lobectomy. METHODS: We retrospectively investigated 1670 patients who underwent lobectomy or more intervention, and analyzed the risk factors of postoperative CI. Furthermore, postoperative contrast-enhanced computed tomography (CE-CT) were reviewed in patients who underwent left upper lobectomy (LUL), and risk factors of the thrombus formation in the left upper PV stump were evaluated. Chi-square test or unpaired t test was used to compare the factors. RESULTS: Cerebral infarction was observed in 10 (0.60%) patients, being more significant in patients with left side lesions (90%) who underwent LUL (50%). Eighty percent of the CI cases occurred by day 4 postoperative. CI was found in 1.47% after LUL. Among 339 patients who underwent LUL, CE-CT was performed in 137 (40%) postoperatively. Among them, left upper PV stump thrombus was found in 16 (11.7%), which was statistically significant in higher age and p stage II or more disease (= 0.003, 0.040). In contrast, preoperative histories including anticoagulant administration, atrial fibrillation, diabetes mellitus, several surgical procedures or intraoperative factors were not associated statistically with thrombus formation. CONCLUSION: Postoperative CI occurred in the very early phase after lobectomy, and the incidence was significantly higher in patients undergoing LUL. Because left upper PV stump thrombus was frequently found retrospectively, a prospective observation study would be required to investigate the real incidence of PV stump thrombus after lobectomy. PMID- 30251003 TI - [Winners of globalization: dengue viruses and Japanese encephalitis virus Diseases in neurology]. AB - Arboviruses are transmitted by arthropods, more than 100 of them are human pathogens and many of the arboviruses have neurotropic characteristics such as dengue viruses (DENV) and Japanese encephalitis virus (JE-V). Both DENV and JE-V belong to the genus Flavivirus. Climatic changes, food imports from the tropics and travel behavior have also increased the number of cases of diseases caused by tropical or subtropical viruses in Europe. Due to the close degree of relationship of the flaviviruses, coinfections with several arboviruses can occur. The DENV and JE-V are mosquito-borne infections caused by the genus Aedes spp. In cases of involvement of the central nervous system, the virus often reaches the brain via the blood-brain barrier. The DENV is a single-stranded RNA positive virus with four known serotypes, DENV-1 to DENV-4. The DENV infections are usually asymptomatic and are known as classical dengue fever, the more severe courses are dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), usually with fatal outcome. Both DHF and DSS are classical second infections. A vaccination is not approved in Germany but has been approved for endemic regions since 2015. The course of an infection with JE-V initially runs characteristically and it is only characterized by encephalitis a few days later. For the JE-V a vaccine is approved even in Germany. PMID- 30251004 TI - Improved Production of Spores and Bioactive Metabolites from Bacillus amyloliquefaciens in Solid-state Fermentation by a Rapid Optimization Process. AB - A dipicolonic acid fluorimetry assay was used instead of plate counting for the assessment of spore yields for enhanced optimization efficiency. The associated parameters, including the ratio of solid substrates, composition of liquid substrates, and cultivation conditions, were systematically optimized in a shake flask culture. The maximum spore yield of 7.24 * 1010 CFU/g of wet substrate was achieved. The optimization process produced a 25.7-fold increase in spore yields compared with those before optimization. In addition, the maximum release of bioactive metabolites during spore accumulation was subsequently obtained with 573.0 U/g of protease, 188.8 U/g of amylase, 186.8 U/g of cellulase, and 3.45 mg/g of acid-soluble protein. The experiment provides a methodological basis for the rapidly optimized production of Bacillus spores in pure solid-state fermentation. PMID- 30251005 TI - Correction to: "Using machine learning to detect events in eye-tracking data". AB - It has come to our attention that the section "Post-processing: Labeling final events" on page 167 of "Using Machine Learning to Detect Events in Eye-Tracking Data" (Zemblys, Niehorster, Komogortsev, & Holmqvist, 2018) contains an erroneous description of the process by which post-processing was performed. PMID- 30251006 TI - The joint contribution of participation and performance to learning functions: Exploring the effects of age in large-scale data sets. AB - Large-scale data sets from online training and game platforms offer the opportunity for more extensive and more precise investigations of human learning than is typically achievable in the laboratory. However, because people make their own choices about participation, any investigation into learning using these data sets must simultaneously model performance-that is, the learning function-and participation. Using a data set of 54 million gameplays from the online brain training site Lumosity, we show that learning functions of participants are systematically biased by participation policies that vary with age. Older adults who are poorer performers are more likely to drop out than older adults who perform well. Younger adults show no such effect. Using this knowledge, we can extrapolate group learning functions that correct for these age related differences in dropout. PMID- 30251007 TI - Concealed correlations meta-analysis: A new method for synthesizing standardized regression coefficients. AB - The synthesis of standardized regression coefficients is still a controversial issue in the field of meta-analysis. The difficulty lies in the fact that the standardized regression coefficients belonging to regression models that include different sets of covariates do not represent the same parameter, and thus their direct combination is meaningless. In the present study, a new approach called concealed correlations meta-analysis is proposed that allows for using the common information that standardized regression coefficients from different regression models contain to improve the precision of a combined focal standardized regression coefficient estimate. The performance of this new approach was compared with that of two other approaches: (1) carrying out separate meta analyses for standardized regression coefficients from studies that used the same regression model, and (2) performing a meta-regression on the focal standardized regression coefficients while including an indicator variable as a moderator indicating the regression model to which each standardized regression coefficient belongs. The comparison was done through a simulation study. The results showed that, as expected, the proposed approach led to more accurate estimates of the combined standardized regression coefficients under both random- and fixed-effect models. PMID- 30251008 TI - Atypical haemolytic uremic syndrome: when multiple etiologies meet. PMID- 30251009 TI - Characteristics and risk factors of postoperative acute kidney injury in ICU patients. PMID- 30251010 TI - Clinical trial of the effects of coenzyme Q10 supplementation on glycemic control and markers of lipid profiles in diabetic hemodialysis patients. AB - PURPOSE: The current study was conducted to determine the effects of coenzyme Q10 (CoQ10) supplementation on glycemic control and markers of lipid profiles risk in diabetic hemodialysis (HD) patients. METHODS: This randomized, double blind, placebo-controlled clinical trial was performed among 60 diabetic HD patients. Subjects were randomly allocated into two groups to take either 120 mg/day of CoQ10 supplements or placebo (n = 30 each group) for 12 weeks. RESULTS: After 12 weeks of intervention, CoQ10 supplementation, compared with the placebo, resulted in a significant decrease in serum insulin concentrations (- 2.5 +/- 4.0 vs. + 2.8 +/- 5.3 uIU/mL, P < 0.001), homeostasis model of assessment-estimated insulin resistance (- 0.9 +/- 2.1 vs. + 1.2 +/- 3.0, P = 0.002), and significant increase in the quantitative insulin sensitivity check index (+ 0.009 +/- 0.01 vs. - 0.02 +/- 0.05, P = 0.003). In addition, a trend toward a greater decrease in serum triglycerides (- 5 +/- 53 vs. + 17 +/- 44, P = 0.078) and VLDL-cholesterol levels (- 0.9 +/- 10 vs. + 3 +/- 9, P = 0.078) was observed in the CoQ10 group compared to the placebo group. We did not observe any significant effect of CoQ10 supplementation on fasting glucose, HbA1c and other lipid profiles compared with the placebo. CONCLUSIONS: Overall, our study supported that CoQ10 supplementation to diabetic HD patients for 12 weeks had beneficial effects on markers of insulin metabolism, but did not affect fasting glucose, HbA1c, and lipid profiles. Clinical registration http://www.irct.ir : IRCT2016081811763N30. PMID- 30251012 TI - Transient expression of intron-containing transgenes generates non-spliced aberrant pre-mRNAs that are processed into siRNAs. AB - MAIN CONCLUSION: In this study, we show that aberrant pre-mRNAs from non-spliced and non-polyadenylated intron-containing transgenes are channelled to the RNA silencing pathway. In plants, improperly processed transcripts are called aberrant RNAs (ab-RNAs) and are eliminated by either RNA silencing or RNA decay mechanisms. Ab-RNAs transcribed from intronless genes are copied by RNA-directed RNA polymerases (RDRs) into double-stranded RNAs which are subsequently cleaved by DICER-LIKE endonucleases into small RNAs (sRNAs). In contrast, ab-RNAs from intron-containing genes are suggested to be channelled post-splicing to exonucleolytic degradation. Yet, it is not clear how non-spliced aberrant pre mRNAs are eliminated. We reasoned that transient expression of agroinfiltrated intron-containing transgenes in Nicotiana benthamiana would allow us to study the steady-state levels of non-spliced pre-mRNAs. SRNA deep sequencing of the agroinfiltrated transgenes revealed the presence of sRNAs mapping to the entire non-spliced pre-mRNA suggesting that RDRs (most likely RDR6) processed aberrant non-spliced pre-mRNAs. Primary and secondary sRNAs with lengths of 18-25 nucleotides (nt) were detected, with the most prominent sRNA size class of 22 nt. SRNAs also mapped to the terminator sequence, indicating that RDR substrates also comprised read-through transcripts devoid of polyadenylation tail. Importantly, the occurring sRNAs efficiently targeted cognate mRNA for degradation but failed to cleave the non-spliced pre-mRNA, corroborating the notion that sRNAs are not triggering RNA cleavage in the nucleus. PMID- 30251013 TI - Proton-pump inhibitor-induced fundic gland polyps with hematemesis. AB - Fundic gland polyps (FGPs) are generally considered benign. Proton-pump inhibitors (PPIs) are used worldwide as first-line therapy for gastroesophageal reflux disease and nonsteroidal anti-inflammatory drug-induced ulcer treatment. Long-term use of PPIs increases the risk of FGP development. We report an extremely rare case of PPI-induced FGPs with hematemesis. A 37-year-old woman taking daily rabeprazole presented to the hospital with a complaint of hematemesis and tarry stools. Esophagogastroduodenoscopy (EGD) revealed > 20 pedunculated polyps in the gastric body and fundus. Histological examination showed multiple fragments of fundic gland mucosa with dilated glands. Based on these findings and the clinical history, FGPs were diagnosed. Rabeprazole use was discontinued. Repeat EGD performed 9 months later showed a significant decrease in the number and size of the polyps. FGPs are small polyps typically located in the gastric corpus and fundus. They are commonly reported in patients in their 60s and predominantly in females. We conclude that PPI use is a risk factor for the development of FGPs and hematemesis. PMID- 30251014 TI - Identity Structure and Processes in Adolescence: Examining the Directionality of Between- and Within-Person Associations. AB - Developing a stable and coherent identity structure (i.e., a synthesized sense of self that can support self-directed decision making) represents a lifelong task. A person's identity structure is continually revised through ongoing processes of identity exploration and commitment. However, longitudinal studies linking identity structure to identity processes are largely lacking. The present three wave longitudinal study among 530 Flemish high school students [50.6% female; Mage = 15; SD = 1.85; age range = 11-19 years] examined the directionality of both between- and within-person associations linking identity synthesis and confusion to identity exploration and commitment processes. Between-person cross lagged models indicated that adolescents who scored high on identity synthesis relative to their peers also scored high on proactive exploration and commitment processes, and low on ruminative exploration one year later, again relative to their peers. Adolescents who scored high on identity confusion relative to their peers also scored high on ruminative exploration one year later, again relative to their peers. With respect to effects of identity processes on identity structure, adolescents who scored high on identification with commitment relative to their peers also scored low on identity confusion one year later. Within person cross-lagged models indicated that, when adolescents scored high on identity synthesis relative to their own average score, they reported increased proactive exploration processes one year later. In general, reaching a degree of identity synthesis appears to represent a prerequisite for proactive identity exploration at both the between- and within-person levels. PMID- 30251011 TI - Acute renal infarction in Turkey: a review of 121 cases. AB - PURPOSE: Renal infarction is a clinical condition which is caused by renal artery occlusion and leads to permanent renal parenchymal damage. In the literature, there are generally case reports on this subject, and few studies that include a large group of patients. Therefore, we aimed to present the data of a large group of patients who were diagnosed with acute renal infarction in our country in this retrospective study. METHODS: The data of patients who were diagnosed with acute renal infarction according to clinical and radiological findings in Turkey in the last 3 years were examined. For this purpose, we contacted with more than 40 centers in 7 regions and obtained support from clinically responsible persons. Demographic data of patients, laboratory data at the time of diagnosis, tests performed for etiologic evaluation, given medications, and patients' clinical status during follow-up were obtained from databases and statistical analysis was performed. RESULTS: One-hundred and twenty-one patients were included in the study. The mean age was 53 +/- 1.4 (19-91) years. Seventy-one (58.7%) patients were male, 18 (14.9%) had diabetes, 53 (43.8%) had hypertension, 36 (30%) had atrial fibrillation (AF), and 6 had a history of lupus + antiphospholipid syndrome (APS). Forty-five patients had right renal infarction, 50 patients had left renal infarction, and 26 (21.5%) patients had bilateral renal infarction. The examinations for the ethiologies revealed that, 36 patients had thromboemboli due to atrial fibrillation, 10 patients had genetic anomalies leading to thrombosis, 9 patients had trauma, 6 patients had lupus + APS, 2 patients had hematologic diseases, and 1 patient had a substance abuse problem. Fifty-seven (57%) patients had unknown. The mean follow-up period was 14 +/- 2 months. The mean creatinine and glomerular filtration rate (GFR) values at 3 months were found to be 1.65 +/- 0.16 mg/dl and 62 +/- 3 ml/min, respectively. The final mean creatinine and GFR values were found to be 1.69 +/- 0.16 mg/dl and 62 +/- 3 ml/min, respectively. CONCLUSIONS: Our study is the second largest series published on renal infarction in the literature. More detailed studies are needed to determine the etiological causes of acute renal infarction occurring in patients. PMID- 30251015 TI - Friends and Education: Identity Patterns across Domains and Associations with Emotion Dysregulation and Identity Disturbance. AB - The task of identity development, which involves distinguishing who one is, and defining and articulating this to others, is a challenging developmental task for most youth. This is made even more challenging when one considers that there are multiple domains of identity development. In the current study, Australia adolescents (N = 336; aged 12-15 years, 46% male) reported their identity status commitment, exploration and reconsideration across two different domains (education and friendship). Cluster analysis was used to evaluate patterns of identity formation within and across domains, and the internalizing symptoms (low self-worth, emotion dysregulation, depressive and anxiety symptoms) and identity disturbance of clusters of youth with different identity status patterns were compared. Results revealed five clusters of committed explorers, committed non explorers, committed reconsiders, uninvolved, and friend identifiers. Cluster comparisons revealed that, across self-worth, emotion dysregulation and identity disturbance, adolescents in the friend identifiers cluster, who reported high commitment to friendship identity and lower commitment to educational identity relative to their peers, fared worse than adolescents reporting higher than average commitment across both domains, and those reporting high reconsideration in both domains. These findings suggest that the benefit of identity commitment for emotional adjustment may depend somewhat on the domain under investigation, and that evaluating the junction and divergence of different identity domains might identify additional adolescents who are experiencing symptoms of maladjustment. PMID- 30251016 TI - Social Withdrawal and Social Surrogacy in Emerging Adulthood. AB - Shyness has been well established as a hindrance to social adjustment and may be problematic for emerging adults attending university, given the high social expectations placed upon students. Previous studies suggest emerging adults high in shyness recruit their friends to act as social surrogates in order to help reduce the stress of entering social interactions; yet, whether other less studied forms of social withdrawal (i.e., avoidance, unsociability) are associated with social surrogacy remains uninvestigated. The goal of the present study was to examine differences between subtypes of withdrawal as related to social surrogacy, while considering the roles of social anxiety and social self efficacy. Participants were 961 emerging adults (76% female; 67% Caucasian) between the ages of 18 and 25 (M = 20.15, SD = 1.71). The results indicated that patterns of social surrogacy varied between withdrawal subtypes, such that social surrogacy was positively related to shyness, and negatively related to unsociability, whereas avoidance yielded mixed results. The findings highlight the importance of considering withdrawal motivations in understanding social surrogacy. PMID- 30251017 TI - Effects of probiotics, prebiotics or synbiotics on jawbone in obese-insulin resistant rats. AB - PURPOSE: Chronic high-fat diet (HFD) consumption results in gut dysbiosis, systemic inflammation, obese-insulin resistance, and osteoporosis of the jawbones. The probiotics, prebiotics or synbiotics alleviated gut dysbiosis and the metabolic disturbance in HFD-induced obesity. However, the effects on jawbone properties have not been investigated. This study aimed to investigate the effects of probiotic Lactobacillus paracasei HII01, prebiotic xylooligosaccharide (XOS), and synbiotics on the jawbone properties along with metabolic parameters, gut and systemic inflammation in HFD-fed rats. METHODS: Forty-eight male Wistar rats were fed with either a HFD or normal diet for 12 weeks. Rats in each group were subdivided into four subgroups to be treated with either vehicle, probiotics, prebiotics, or synbiotics for the additional 12 weeks. Blood samples, gut, bone marrows, and jawbones were collected to determine metabolic parameters, inflammation, and bone properties. RESULTS: The HFD-fed rats developed obese insulin resistance, as indicated by increased body weight, dyslipidemia and decreased insulin sensitivity. Serum lipopolysaccharide levels and interleukin-6 mRNA expression in the ileum and bone marrows were elevated. Altered bone metabolism and the impaired jawbone properties were evident as indicated by decreased bone mineral density with increased trabecular separation. Reduced ultimate load and stiffness were observed in HFD-fed rats. Treatments with probiotics, prebiotics or synbiotics in HFD-fed rats improved metabolic parameters and reduced inflammation. However, no alterations in jawbone properties were found in all treatments. CONCLUSION: The osteoporosis of the jawbone occurred in obese-insulin resistance, and treatments with probiotics, prebiotics and synbiotics were not sufficient to improve the jawbone properties. PMID- 30251018 TI - Bifidobacterium pseudocatenulatum CECT 7765 supplementation improves inflammatory status in insulin-resistant obese children. AB - PURPOSE: The relationships between gut microbiota and obesity-related co morbidities have been increasingly recognized. Low-grade inflammation may be the main factor in the pathogenesis of such disorders. We investigated the effect of the potential probiotic Bifidobacterium pseudocatenulatum CECT 7765 on cardiometabolic risk factors, inflammatory cytokines and gut microbiota composition in obese children with insulin resistance. METHODS: The study included 48 obese children (10-15 years old) with insulin resistance. They received dietary advice and were assigned to take the capsules with or without probiotic (109-10 CFU) daily for 13 weeks. Clinical, biochemical and gut microbiome measurements were made at baseline and at the end of the intervention. RESULTS: There was a significant improvement in body mass index in all children after the intervention, suggesting that weight changes are related to the dietary advice. A significant decrease in circulating high-sensitive C-reactive protein (P = 0.026) and monocyte chemoattractant protein-1 (P = 0.032) and an increase in high-density lipoprotein cholesterol (P = 0.035) and omentin-1 (P = 0.023) in children receiving probiotic supplementation were observed compared to the control group. Regarding gut microbiota, probiotic administration significantly increased the proportion of the Rikenellaceae family members, particularly of the Alistipes genus. CONCLUSIONS: The beneficial effects of the intervention on inflammatory markers and lipid profile suggest that B. pseudocatenulatum CECT 7765 intake together with dietary recommendations can improve inflammatory status in children with obesity and insulin resistance. These effects are parallel to increases in bacterial groups associated with a lean phenotype. The modulation of gut microbiota with probiotic supplementation can be considered an effective tool to ameliorate some obesity-related disorders in children. PMID- 30251019 TI - The effectiveness of omega-3 polyunsaturated fatty acid interventions during pregnancy on obesity measures in the offspring: an up-to-date systematic review and meta-analysis. AB - BACKGROUND: The potential role of omega-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy on subsequent risk of obesity outcomes in the offspring is not clear and there is a need to synthesise this evidence. OBJECTIVE: A systematic review and meta-analysis of randomised controlled trials (RCTs), including the most recent studies, was conducted to assess the effectiveness of omega-3 LCPUFA interventions during pregnancy on obesity measures, e.g. BMI, body weight, fat mass in offspring. METHODS: Included RCTs had a minimum of 1-month follow-up post-partum. The search included CENTRAL, MEDLINE, SCOPUS, WHO's International Clinical Trials Reg., E-theses and Web of Science databases. Study quality was evaluated using the Cochrane Collaboration's risk of bias tool. RESULTS: Eleven RCTs, from ten unique trials, (3644 children) examined the effectiveness of omega-3 LCPUFA maternal supplementation during pregnancy on the development of obesity outcomes in offspring. There were heterogeneities between the trials in terms of their sample, type and duration of intervention and follow-up. Pooled estimates did not show an association between prenatal intake of fatty acids and obesity measures in offspring. CONCLUSION: These results indicate that maternal supplementation with omega-3 LCPUFA during pregnancy does not have a beneficial effect on obesity risk. Due to the high heterogeneity between studies along with small sample sizes and high rates of attrition, the effects of omega-3 LCPUFA supplementation during pregnancy for prevention of childhood obesity in the long-term remains unclear. Large high quality RCTs are needed that are designed specifically to examine the effect of prenatal intake of fatty acids for prevention of childhood obesity. There is also a need to determine specific sub-groups in the population that might get a greater benefit and whether different omega-3 LCPUFA, i.e. eicosapentaenoic (EPA) vs. docosahexanoic (DHA) acids might potentially have different effects. PMID- 30251020 TI - Effects of an oral synbiotic on the gastrointestinal immune system and microbiota in patients with diarrhea-predominant irritable bowel syndrome. AB - PURPOSE: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal disorder. Probiotics and synbiotics have been shown to improve symptoms of IBS, although mechanisms of action are currently not understood. METHODS: We investigated the effects of a 4-week oral synbiotic treatment (OMNi-BiOTiC(r) Stress Repair) in ten IBS-D patients on gastrointestinal mucosal and fecal microbiota, mucosa-associated immune cells, and fecal short-chain fatty acids. The upper and lower gastrointestinal tracts were compared before and after a 4-week synbiotic treatment using endoscopic evaluation to collect mucosal specimens for FACS analysis and mucosal 16S rRNA gene analysis. In stool samples, analysis for fecal SCFAs using GC-MS, fecal zonulin using ELISA, and fecal 16S rRNA gene analysis was performed. RESULTS: Synbiotics led to an increased microbial diversity in gastric (p = 0.008) and duodenal (p = 0.025) mucosal specimens. FACS analysis of mucosal immune cells showed a treatment-induced reduction of CD4+ T cells (60 vs. 55%, p = 0.042) in the ascending colon. Short-chain fatty acids (acetate 101 vs. 202 umol/g; p = 0.007) and butyrate (27 vs. 40 umol/g; p = 0.037) were elevated in fecal samples after treatment. Furthermore, treatment was accompanied by a reduction of fecal zonulin concentration (67 vs. 36 ng/ml; p = 0.035) and disease severity measured by IBS-SSS (237 vs. 54; p = 0.002). CONCLUSIONS: Our findings indicate that a short-course oral synbiotic trial may influence the human gastrointestinal tract in IBS-D patients on different levels which are region specific. PMID- 30251021 TI - Second branchial cleft anomalies in children: a literature review. AB - Branchial cleft anomalies are the second most common head and neck congenital lesions in children. It may sometimes be a part of branchio-oto-renal (BOR) syndrome, so in patients with branchial cleft anomalies associated with a complaint of auricular deformity or a similar history and findings in other family members, we should take an additional examination to find the possibility of BOR syndrome. Complete excision is essential for good prognosis. For the management of branchial cleft anomalies, various methods have been reported. Endoscopically assisted dissection technique and transoral robot-assisted surgery were used in the management of fistula and allowed excellent visualization of the pharyngeal component of the lesion and a minimally invasive approach. It is essential for the surgeon to fully comprehend the congenital lesions to attain the correct preoperative diagnosis and plan for an appropriate surgical approach to prevent the most common complication and recurrence in these lesions. The following sections discuss the anatomy, common presentation, auxiliary examination, differential diagnosis, the current principles of surgical treatment and prognosis for second branchial cleft anomalies in children, and discussed the branchio-oto-renal syndrome. PMID- 30251022 TI - ASO Author Reflections: Esophagectomy Versus Nonsurgical Treatment for Resectable Esophageal Cancer. PMID- 30251023 TI - ASO Author Reflections: Single Axillary Incision Endoscopic-Assisted Hybrid Technique for Nipple-Sparing Mastectomy. PMID- 30251024 TI - ASO Author Reflections: Long-Term Outcomes After R0 Resection of Colorectal Peritoneal Metastasis. PMID- 30251025 TI - Compulsory admission is associated with an increased risk of readmission in patients with schizophrenia: a 7-year, population-based, retrospective cohort study. AB - PURPOSE: The aim of this study was to assess the risk of psychiatric readmission in patients with schizophrenia, compare it between patients prescribed compulsory admission and those consenting to voluntary admission, and determine risk factors for psychiatric readmission. METHODS: This 7-year (2007-2013), population-based, cohort study retrospectively compared data of 2038 schizophrenic inpatients who initially underwent compulsory admission (the CA group) and of 8152 matched controls with schizophrenia who initially underwent voluntary admission (the VA group). RESULTS: During the study period, there were 1204 and 3806 readmissions in the CA and VA groups, respectively. Compared with the VA group, the CA group was associated with a greater risk of psychiatric readmission [adjusted hazard ratio (AHR) = 1.765; 95% confidence interval (CI) 1.389-2.243; P < 0.001]. Stratified analyses showed that the CA group was associated with a higher risk of subsequent compulsory (AHR = 1.307; 95% CI 1.029-1.661; P < 0.001) and voluntary (AHR = 1.801; 95% CI 1.417-2.289; P < 0.001) readmissions compared to the VA group. Sensitivity analyses, after excluding data from the first year of observation, also provided significant findings with respect to compulsory and voluntary readmissions. Kaplan-Meier curves revealed that cumulative survival rates of psychiatric readmissions, compulsory and voluntary readmissions were significantly lower in the CA group than in the VA group among patients with schizophrenia (log-rank test, P < 0.001). CONCLUSIONS: CA was associated with higher subsequent psychiatric readmissions, compulsory, and voluntary readmissions. Clinicians would need to focus on patients undergoing CAs to reduce readmissions. PMID- 30251026 TI - Structural and functional identification of two distinct inspiratory neuronal populations at the level of the phrenic nucleus in the rat cervical spinal cord. AB - The diaphragm is driven by phrenic motoneurons that are located in the cervical spinal cord. Although the anatomical location of the phrenic nucleus and the function of phrenic motoneurons at a single cellular level have been extensively analyzed, the spatiotemporal dynamics of phrenic motoneuron group activity have not been fully elucidated. In the present study, we analyzed the functional and structural characteristics of respiratory neuron population in the cervical spinal cord at the level of the phrenic nucleus by voltage imaging, together with histological analysis of neuronal and astrocytic distribution in the cervical spinal cord. We found spatially distinct two cellular populations that exhibited synchronized inspiratory activity on the transversely cut plane at C4-C5 levels and on the ventral surface of the mid cervical spinal cord in the isolated brainstem-spinal cord preparation of the neonatal rat. Inspiratory activity of one group emerged in the central portion of the ventral horn that corresponded to the central motor column, and the other appeared in the medial portion of the ventral horn that corresponded to the medial motor column. We identified by retrogradely labeling study that the anatomical distributions of phrenic and scalene motoneurons coincided with optically detected central and medial motor regions, respectively. Furthermore, we anatomically demonstrated closely located features of putative motoneurons, interneurons and astrocytes in these regions. Collectively, we report that phrenic and scalene motoneuron populations show synchronized inspiratory activities with distinct anatomical locations in the mid cervical spinal cord. PMID- 30251027 TI - Emergency Department (ED) Triage for Transient Ischemic Attack (TIA). AB - PURPOSE OF REVIEW: Patients with transient ischemic attacks (TIAs) have a higher risk for stroke and vascular events. Specialized and organized management, if rapidly initiated in the emergency department (ED), reduces the vascular burden of TIA. This review summarizes the rationale for optimal triage of patients suspected with TIA in the ED, focusing on early diagnosis confirmation, individual risk stratification, and management. RECENT FINDINGS: New evidence is emerging on the yield of integrating clinical scales with advanced neuroimaging of the vessels and brain for improved diagnosis and risk stratification in patients with TIA. The "TIA clinic" model of management is associated with the lowest long-term cardio-cerebrovascular recurrence rate ever reported. TIA are vascular emergencies that require a specialized, systematic evaluation to confirm the diagnosis of an ischemic mechanism, identify high-risk source of brain ischemia and initiate a tailored therapeutic strategy. TIA triage in the ED should organized as part of a "TIA clinic program" that unifies the expedited specialized management of the patient, in collaboration with stroke neurologists. PMID- 30251028 TI - Integrated analysis of transcription factors and targets co-expression profiles reveals reduced correlation between transcription factors and target genes in cancer. AB - Transcription factors are recognized as the key regulators of gene expression. However, the changes in the correlation of transcription factors and their target genes between normal and tumor tissues are usually ignored. In this research, we used mRNA expression profile data from The Cancer Genome Atlas which included 5726 samples across 11 major human cancers to perform co-expression analysis by the Pearson correlation coefficients. Then, integrating 81,357 pairs of transcription factors and target genes from transcription factors databases to find out the changes in the co-expression correlation of these gene pairs from normal to tumor tissues. Based on the changes in the number of co-expressed TF-TG pairs and changes in the level of co-expression, we found the generally reduced correlation between transcription factors and their target genes in cancer. Additionally, we screened out universal and specific transcription factors-target genes pairs which may significant influence particular cancer. Then, we obtained 423 cancer cell line expression profiles from Broad Institute Cancer Cell Line Encyclopedia to verify our results. Some of these pairs like XRCC5-XRCC6 have been reported to involve in multiple cancers, while pairs like IRF1-PSMB9 without any previous articles related to tumor but involve in the biological processes of cancer, which are of great potential to be therapeutic targets. Our research may provide insights to better understand the tumor development mechanisms and find potential therapeutic targets. PMID- 30251029 TI - An insight into the iron acquisition and homeostasis in Aureobasidium melanogenum HN6.2 strain through genome mining and transcriptome analysis. AB - Aureobasidium melanogenum HN6.2 is a unique yeast strain who can produce the siderophore of fusigen under iron starvation to guarantee its survival. However, a comprehensive understanding of mechanisms involved in iron acquisition and homeostasis for it is still vacant. In this study, genome sequencing and mining revealed that A. melanogenum HN6.2 strain was the first yeast species that exclusively possessed all the four known mechanisms for the iron acquisition: (i) the siderophore-mediated iron uptake; (ii) reductive iron assimilation; (iii) low affinity ferrous uptake; and (iv) heme utilization, which suggested its stronger adaptability than Aspergillus fumigatus and Saccharomyces cerevisiae. This HN6.2 strain also employed the vacuolar iron storage for immobilizing the excessive iron to avoid its cellular toxicity. Specially, genome mining indicated that A. melanogenum HN6.2 strain could also synthesize ferricrocin siderophore. Further HPLC and Q-Tof-MS analysis confirmed that the siderophores synthesized by this strain consisted of cyclic fusigen, linear fusigen, ferricrocin, and hydroxyferricrocin and they played parallel roles as both intracellular and extracellular siderophores. Also, the heme utilization for this strain was experimentally verified by the knock-out of heme oxygenase gene. For iron homeostasis, the transcriptome analysis revealed that this strain mainly employed two central regulators of SreA/HapX to tune iron uptake and storage at the transcriptional level. It was also noted that mitogen-activated protein kinase C gene (MpkC) exhibited a transcriptional up-regulation under iron sufficiency, suggesting that it may serve as another factor involved in the repression of siderophore biosynthesis. This is the first genetic blueprint of iron acquisition and homeostasis for A. melanogenum. PMID- 30251030 TI - Moral enhancement and the good life. AB - One approach to defining enhancement is in the form of bodily or mental changes that tend to improve a person's well-being. Such a "welfarist account", however, seems to conflict with moral enhancement: consider an intervention that improves someone's moral motives but which ultimately diminishes their well-being. According to the welfarist account, this would not be an instance of enhancement in fact, as I argue, it would count as a disability. This seems to pose a serious limitation for the account. Here, I elaborate on this limitation and argue that, despite it, there is a crucial role for such a welfarist account to play in our practical deliberations about moral enhancement. I do this by exploring four scenarios where a person's motives are improved at the cost of their well-being. A framework emerges from these scenarios which can clarify disagreements about moral enhancement and help sharpen arguments for and against it. PMID- 30251031 TI - Biomechanical Analysis of Porcine Cartilage Elasticity. AB - Grafting of tissue-engineered cartilage to joints with osteoarthritis has the potential to supersede arthroplasty as the standard of care. However, in order to support the development of functional tissue engineering methods, the subfailure biomechanics of the individual cartilage types that comprise joints must be determined. Current methods for analyzing tissues are based on imaging and are therefore unable to profile the strain dependence of mechanical behaviors within different cartilage types. Recently, an analysis technique based on Optical Fiber Polarimetric Elastography (OFPE) has overcome these challenges. OFPE has been used to characterize the different mechanical behaviors of a range of unprocessed biomaterials and tissues. In the present work, this technique is used to characterize the biomechanics of both articular cartilage and meniscal fibrocartilage within a porcine knee. OFPE testing of the tissue is conducted over a range of physiological loading and unloading values. These results demonstrate the distinctive mechanics of each cartilage type. Due to their different locations within the knee, each cartilage type exhibits distinctly unique biomechanical behavior. Based on the results of OFPE, we correlate the specific buckling, delamination, and bridging events to maxima and minima along the loading and unloading curves. This provides unprecedented detail with regard to the subfailure biomechanics. This information is integral to the design of the next generation of tissue-engineered constructs. Therefore, OFPE will be used across multiple disciplines to rapidly determine the mechanical behavior of tissue-engineered constructs to support functional tissue engineering efforts. PMID- 30251033 TI - Null Cell Adenoma of the Pituitary: Pseudo-rosettes Say It Best When Immunohistochemistry Says Nothing At All! AB - Null cell adenoma is composed of adenohypophyseal cells that show no evidence of any specific cell type differentiation by immunohistochemistry or transcription factors like pituitary-specific positive transcription factor 1 and steroidogenic factor 1. Though rare, pituitary ependymoma and germinoma are also known to occur at sellar region and in such instances, it is challenging to differentiate them from a pituitary null cell adenoma featuring papillary architecture and perivascular pseudo-rosettes. We describe a case of an elderly diabetic lady presenting with headache and blurring of vision for past 3 months due to a sellar tumour. The histology was diagnostically challenging with notable presence of numerous perivascular pseudo-rosettes and negative immunoreactivity for all pituitary hormones. The differential diagnosis and importance of ancillary techniques is discussed. PMID- 30251032 TI - Primary Laryngeal Tuberculosis: A Series of 15 Cases. AB - Tuberculosis usually involves the lungs, but can also involve various other organs. Extra pulmonary tuberculosis is very rarely confined to the larynx in the absence of an associated pulmonary lesion. In this retrospective study, clinicopathological characteristics of patients with final diagnosis of laryngeal tuberculosis (LTB) were reviewed. The diagnosis of LTB was based on: (1) the existence of chronic granulomatous inflammation with caseous necrosis in the histopathology of laryngeal lesions or (2) the presence of laryngeal lesions with atypical histopathology (chronic granulomatous inflammation) which had a complete response to anti-tuberculosis therapy. Fifteen cases with a diagnosis of LTB were collected. The patients' age ranged between 24 and 75 years with a mean of 49 years. On laryngoscopy, 66.6% of cases (10/15) had an ulceroproliferative lesion while the remaining 33.3% of cases (5/15) had an exophytic growth. The pathology of laryngeal lesions revealed chronic granulomatous inflammation with caseous necrosis in nine cases and chronic granulomatous inflammation without necrosis in six cases. Nine out of 15 cases (60%) showed presence of acid-fast bacilli on Ziehl-Neelsen stain. Any evidence of pulmonary tuberculosis was ruled out by chest X-ray findings. The response to anti-tuberculosis therapy was desirable in all patients. Since the introduction of anti-tuberculous therapy, the incidence of LTB has declined. However, with the incidence of TB increasing, the overall incidence of laryngeal involvement may be on the rise. This study highlights the importance to consider the rare possibility of LTB in the presence of non specific clinical and laryngoscopic signs and to confirm this by histological examination. PMID- 30251034 TI - Pregnane glycosides from the bark of Marsdenia cundurango and their cytotoxic activity. AB - Seven new pregnane glycosides (1-7) and eight known compounds (8-15) were isolated from the bark of Marsdenia cundurango (Asclepiadaceae). The structures of 1-7 were determined by spectroscopic analysis, including two-dimension NMR spectroscopy, chemical transformations, and chromatographic analysis of the hydrolyzed products. The isolated compounds 1-15 were evaluated for their cytotoxic activity against HL-60 human leukemia cells, A549 human lung adenocarcinoma cells, and TIG-3 normal human lung cells, including apoptosis inducing activity of a representative pregnane glycoside in HL-60 cells. PMID- 30251035 TI - Effects of photoperiod, temperature and aging on adult diapause termination and post-diapause development in female Asian comma butterflies, Polygonia c-aureum Linnaeus (Lepidoptera: Nymphalidae). AB - Polygonia c-aureum females exhibit photoperiodically induced imaginal diapause, characterized by cessation of ovarian development. Females grown at a short daylength (SD) entered imaginal diapause, whereas those grown at a long daylength (LD) produced eggs rapidly after adult emergence at 21 degrees C. The termination of diapause was influenced by daylength: diapause ended faster at LD than SD. Complete termination of diapause took 30 days in unchilled females reared under LD at 21 degrees C. On the other hand, prompt, synchronized and strong diapause termination occurred at post-chilling periods. Photoperiods at post-chilling periods affected ovarian development, when the length of pre chilling periods or the length of chilling periods was shorter, suggesting that these treatments were not enough to complete diapause development. Ovarian development proceeded earlier in chilled and subsequent warmed females than unchilled females. Wing damage was remarkable at post-chilling periods when females were reared under an adequate length of pre-chilling and chilling periods, especially comparing with females under pre-overwintering conditions without chilling, indicating that post-diapause reproductive development was weak in unchilled females. Thus, exposure to low temperatures is necessary for a strong diapause termination in this butterfly. PMID- 30251037 TI - Reviews arising from the 2017 conference of the Australian Society for Biophysics and the Japanese Society for Biophysics. PMID- 30251036 TI - Independent processing of increments and decrements in odorant concentration by ON and OFF olfactory receptor neurons. AB - A salient feature of the insect olfactory system is its ability to detect and interpret simultaneously the identity and concentration of an odorant signal along with the temporal stimulus cues that are essential for accurate odorant tracking. The olfactory system of the cockroach utilizes two parallel pathways for encoding of odorant identity and the moment-to-moment succession of odorant concentrations as well as the rate at which concentration changes. This separation originates at the peripheral level of the ORNs (olfactory receptor neurons) which are localized in basiconic and trichoid sensilla. The graded activity of ORNs in the basiconic sensilla provides the variable for the combinatorial representation of odorant identity. The antagonistically responding ON and OFF ORNs in the trichoid sensilla transmit information about concentration increments and decrements with excitatory signals. Each ON and OFF ORN adjusts its gain for odorant concentration and its rate of change to the temporal dynamics of the odorant signal: as the rate of change diminishes, both ORNs improve their sensitivity for the rate of change at the expense of the sensitivity for the instantaneous concentration. This suggests that the ON and OFF ORNs are optimized to detect minute fluctuations or even creeping changes in odorant concentration. PMID- 30251038 TI - Comparative study on treatment performance, membrane fouling, and microbial community profile between conventional and hybrid sequencing batch membrane bioreactors for municipal wastewater treatment. AB - A sequencing batch conventional membrane bioreactor (SB-CMBR) and sequencing batch hybrid membrane bioreactor (SB-HMBR) were operated in parallel under two different hydraulic retention times (HRTs) (namely 12 h and 6 h), and their chemical oxygen demand (COD) and nutrient removal performance, membrane fouling behavior, and microbial community characteristics were compared. Both systems exhibited high organic matter (> 95%) and ammonium (> 98%) removal performance regardless of the HRT applied. As the HRT was reduced from 12 to 6 h, total nitrogen removal slightly increased in both reactors, being higher in the carrier based MBR, where anoxic zones may have been established within the biofilm. Conversely, total phosphorus removal improved only in the SB-CMBR at the shorter HRT. Moreover, activity batch assays have shown a faster P uptake rate in the SB CMBR than in the SB-HMBR, a result likely associated with the lower relative abundance of phosphate-accumulating organisms in both adhered and suspended biomass fractions in the hybrid MBR. The results also revealed that more pronounced increases in the transmembrane pressure and, consequently, in the membrane fouling rate at higher COD loading rates were observed in the SB-CMBR, where the soluble microbial products (proteins, polysaccharides, and especially, transparent exopolymer particles), supernatant turbidity, and filamentous bacteria were more significant. Overall, as compared to the conventional MBR, the plastic media-based SB-HMBR showed a lower fouling propensity at all hydraulic conditions tested. PMID- 30251039 TI - Dissipation and residues of fluazinam and dimethomorph in potatoes, potato plants, and soil, determined by QuEChERS ultra-performance liquid chromatography tandem mass spectrometry. AB - Fluazinam and dimethomorph 35% suspension concentrate (SC) is a new combined fungicide formulation introduced in China to improve fungicidal efficacy and decrease the risk of resistance in potatoes. Fluazinam and dimethomorph dissipation and residues in potatoes, potato plants, and soil under field conditions were determined by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Fluazinam and dimethomorph 35% SC was applied at two doses to potatoes and soil in Ningxia Autonomous Region and Anhui Province, China. Fluazinam and dimethomorph dissipation fitted first-order kinetics, and the fluazinam half-lives in potato plants and soil were 3.3-5.4 and 9.4-9.5 days, respectively. The dimethomorph half-lives in potato plants and soil were 2.1-2.6 and 5.9-8.6 days, respectively. Fluazinam and dimethomorph 35% SC was sprayed onto potato plants three or four times at application rates of 420 and 630 g a.i. ha-1 with 7 days between applications. Potato and soil samples were collected at 3, 7, and 14 days after the last application. Potatoes and soil had fluazinam concentrations of < 0.01 and < 0.05-0.183 mg kg-1, respectively, and dimethomorph concentrations of < 0.01 and 0.129-0.677 mg kg-1, respectively. The final fluazinam and dimethomorph concentrations in potatoes were below the EU maximum residue limits (0.02 and 0.05 mg kg-1, respectively) 3 days after application. Fluazinam and dimethomorph can therefore be applied to potatoes at the recommended doses. PMID- 30251040 TI - A novel corrugated wall channel module for external concentration polarization mitigation in forward osmosis process. AB - Much work has been conducted on the topic of forward osmosis (FO), but only a few studies have focused on mitigating external concentration polarization (ECP). This study introduced a simple structure, the corrugated wall channel, to the design of FO module, to induce vortex, and then mitigate ECP. In this study, the corrugated wall channel module (CWCM) was tested under given conditions, with a traditional flat membrane module (FMM) as control. CWCM could mitigate ECP and then enhance water flux. When deionized water was taken as feed solution (FS) and 2-M NaCl solution as draw solution (DS), the water flux enhancement was 16.49 and 18.51% in FO mode (active layer facing FS) and PRO mode (active layer facing DS), respectively. When 0.5-M NaCl solution was taken as FS, the corresponding values were 15.92 and 17.13%, respectively. Computational fluid dynamics (CFD) analysis showed that the CWCM could induce vortex, promote the mixing of the solution in the module, and further contribute to the increase of water flux. The specific shape of CWCM affected its performance on mitigating ECP. Also, the more tortuous CWCM exhibited higher water flux. In addition, CWCM could lessen membrane fouling. PMID- 30251041 TI - Assessing impacts of climate change on habitat suitability of Coregonus ussuriensis and other coldwater fishes in northern China. AB - Climate change seriously affects habitat suitability for coldwater fish. Amur whitefish (Coregonus ussuriensis) is a commercially important coldwater fish species found in northeast China that is particularly sensitive to water temperature. We use water temperature models for Songhua (Harbin to Yilan) and Mayi rivers to predict habitat suitability for Amur whitefish and other coldwater fish species during the months of July and August in 2014 and 2100-2 months during which river temperatures can reach extremes. The predict-results showed that fish habitat was to deteriorate over time, and to be less suitable for survival of coldwater fish species in 2100 than that in 2014. Under scenario RCP4.5 (Representative Concentration Pathway 4.5), the time period during which habitat for Amur whitefish was unsuitable increased continually; under scenario RCP8.5 (Representative Concentration Pathway 8.5), Amur whitefish might even disappear from the river basin. A significant increase in river water temperature will compromise coldwater fish survival and possibly lead to their disappearance. Practical measures to control greenhouse gas emissions and reduce the impact of global warming on aquatic ecosystems must be taken. PMID- 30251042 TI - Grain size analysis of California waterbodies to determine the spatial extent and temporal trends of depositional areas where hydrophobic organic compounds could accumulate. AB - The objective of this study was to summarize the grain size data from 1993 to 2016 from California water bodies and determine the number and percent of sites where sediment samples are primarily depositional sediment (more than 50% silt/clay) or non-depositional sediment (less than 50% silt/clay). Fine grain depositional areas were of interest because these are areas where hydrophobic organic compounds (HOCs) can accumulate if sources exist. Trends analysis of percent silt/clay data were conducted for all nine California Water Board Regions if adequate data for this type of analysis were available. Sediment sampling protocols were reviewed for all the grain size measurements to determine if depositional areas were targeted or random sampling was conducted. Twelve of the 13 sediment sampling protocols targeted depositional areas. Based on 23 years of data from 685 sites (1859 observations) in all 9 California Regions, the summary analysis showed that only 58% of the sites were considered depositional areas even when targeted sampling for depositional areas was used. Since only slightly more than half the sites were reported as depositional areas based on sampling that targets depositional areas, these results would certainly suggest that depositional areas are not dominant. In fact, for the one protocol where random sampling was used, depositional areas were not reported to be dominant. From an ecological risk perspective, the implication of this finding is that HOCs would not be expected to accumulate in the dominant type of sediment found in most California waterbodies. Trends analysis of percent silt/clay data showed mixed results for the various California Regions. PMID- 30251043 TI - Assessment the activity of magnetic KOH/Fe3O4@Al2O3 core-shell nanocatalyst in transesterification reaction: effect of Fe/Al ratio on structural and performance. AB - Recently, biodiesel production using heterogeneous catalysts has been of great concern. However, simple separation of these catalysts from product mixtures is a problem of the process. In this study, series of magnetic KOH/Fe3O4@Al2O3 core shell nanocatalysts were synthesized via the incipient wetness impregnation method and the effect of weight ratio of Fe3O4-to-Al2O3 (0.15-0.35) on the catalytic performance was assessed. The samples were characterized by XRD, FTIR, BET-BJH, VSM, SEM, TEM, and EDX analyses and their basicity was measured by the Hammett indicator method. The results revealed that although the magnetic KOH/Fe3O4@Al2O3 nanocatalyst with 25 wt% of Fe3O4 showed less activity as compared to those with 15 wt% of Fe3O4, it exhibited higher surface area and appropriate magnetic properties. The sample presented superparamagnetic properties with the magnetic strength of 1.25 emu/g that was simply recovered by using an external magnetic field. The nanocatalyst converted 98.8% of canola oil to biodiesel under reflux condition at the best operational conditions of 12 M ratio of methanol/oil, 4 wt% of catalyst and 6 h of reaction time. Moreover, the nanocatalyst showed high reusability such that it was reused several times without appreciable loss of its catalytic activity. PMID- 30251045 TI - Development and evaluation of gene expression biomarkers for chemical pollution in common frog (Rana temporaria) tadpoles. AB - Pollutants have been proposed as one factor in the worldwide declines of amphibian species and populations. Applying gene expression analysis of liver RNA in tadpoles would be a possible approach for biomarker measurements to increase knowledge of ecological health in amphibian populations. The major aim of this study was to explore the relevance of applying gene expression analyses of cytochrome p450 (cyp1a), metallothionein (mt), and vitellogenin (vtg) in Rana temporaria tadpoles. Therefore, tadpoles were exposed for 1 week to beta naphthoflavone (BNF), cadmium chloride (CdCl2), and ethinylestradiol (EE2). Primers were developed for RT-qPCR to analyze gene expression in livers. The result showed that the methods for gene expression analyses of cyp1a, mt, and vtg as well as the reference gene beta-actin (bact) were successful not only in R. temporaria but also in another amphibian, Rana arvalis. The gene expression of cyp1a was induced by BNF and the gene expression of mt was induced by CdCl2 but no significant induction was recorded in vtg expression after exposure to EE2. Gene expressions varied throughout the tadpole metamorphosis development, in particular for vtg. Overall, the use of gene expression of cyp1a and mt as biomarkers in wild tadpoles seems promising while the use of vtg seems less relevant due to high natural variation and low background expression. The study shows that variations in gene expressions between tadpoles of different genetic origin are important to consider when evaluating the data. The present study has thus increased the background knowledge about gene expression applicability as biomarker for tadpoles. PMID- 30251044 TI - The molecular and biochemical insight view of lycopene in ameliorating tramadol induced liver toxicity in a rat model: implication of oxidative stress, apoptosis, and MAPK signaling pathways. AB - The influence of tramadol (TD) on hepatic tissue and the potential efficiency of lycopene to mitigate TD-induced hepatotoxic impacts were determined. Forty male albino rats were allocated into four groups: group I, untreated (placebo); group II, injected with TD (15 mg kg-1) intraperitoneally (i.p.); group III, gastrogavaged with lycopene (10 mg kg-1) per os (p.o.); and group IV received TD with lycopene with the same mentioned doses for 15 days. The results demonstrated that TD induced augmentation in tissue lipid peroxidation biomarker and disturbance in the antioxidant homeostasis and elevated the activity of serum liver injury biomarkers and decreased serum protein, globulin, and albumin. Hepatic glutathione S-transferase (GST), superoxide dismutase (SOD), thioredoxin 1 (Txn-1), and catalase (CAT) activities and gene expression were decreased and glutathione content was reduced in the TD-challenged rats, and these effects were alleviated by lycopene. Furthermore, TD induced apoptosis in liver tissues as shown by DNA fragmentation and upregulation of proapoptotic Bax and Casp-3 while lycopene upregulated the antiapoptotic Bcl-2. The results of Western blot showed that lycopene initiated low expression of mitogen activated protein kinase pathway (MAPK) protein expression in liver tissues of TD-challenged rats. In addition, lycopene reduced fatty degeneration and necrosis of the liver in TD challenged group. Our data demonstrate that lycopene appears to be highly efficient in mitigating the hepatotoxic impacts of TD by preventing lipid peroxidation and initiating modifications in the expression and activity of antioxidant pathways. Surprisingly, lycopene fortified liver tissue by inhibiting DNA fragmentation and apoptosis signaling induced by TD. MAPK activation may be dependent from ROS generation; due to lycopene which possessed antioxidant potential did have a substantial effect on MAPK activity. PMID- 30251046 TI - Utilization of dye-loaded activated carbon as a potential alternative fuel source: a feasibility study through calorific and thermo-gravimetric analysis. AB - The disodium salt of Rose Bengal [4, 5, 6, 7-tetrachloro-2', 4', 5', 7' tetraiodofluorescein] commonly finds application in medical procedures and its removal from aqueous solution is difficult owing to its high molecular weight of 1017.67 g/mol. Activated carbon was prepared from Prosopis juliflora and immobilized into sodium alginate beads and doped with aniline for enhanced adsorption of Rose Bengal. The effect of initial dye concentration, beads' dosage, contact time, and the temperature over the adsorption of Rose Bengal dye were studied. The optimum conditions derived for maximum dye uptake capacity were 4 mg/L of initial dye concentration, contact time of 60 min with the adsorbent dosage of 0.2 g, and temperature of 303 K at neutral pH. The equilibrium data were found to be best fitted for Langmuir -1 model, whereas the kinetics were interpreted through Ho-Mckay's pseudo-second-order equation. The adsorbents were subjected to thermo-gravimetric studies to determine the activation energy under a heating rate of 20 degrees C/min. The activation energy was computed using Broido's plot and was found to be 35.21 +/- 0.84 kJ/mol for the activated carbon, and 16.77 +/- 2.19 kJ/mol for the dye-adsorbed beads. The heat capacity was determined through differential scanning calorimetry and was calculated to be 19.41 J/g degrees C for activated carbon and 39.43 J/g degrees C for beads post adsorption of Rose Bengal dye. PMID- 30251047 TI - Investigating spatial patterns of mercury and rodenticide residues in raptors collected near the Charlotte, NC, USA, metropolitan area. AB - Raptor population growth is dynamic and trends vary across species and by location in the United States. For those species that are declining, it is important to identify potential causes including chemical contaminants. Sampling wild raptors is problematic due to their small population sizes and role as a top predator. Therefore, we obtained liver samples (n = 56) from carcasses of several raptor species, including common species like red-tailed hawks, red-shouldered hawks, barred owls, great horned owls, and osprey that arrived dead or were euthanized from a non-profit rehabilitation center in Charlotte, North Carolina. Raptors were found or collected in South Carolina, North Carolina, and Virginia, but most samples were located near the metropolitan region of Charlotte, NC. We analyzed livers for total mercury residue (mg/kg, dry weight) and five anti coagulant rodenticides (MUg/kg wet weight). Mercury was analyzed using a direct mercury analyzer approach and rodenticides were quantified by LC-MS. Mercury residues were high in piscivorous birds (15.09 mg/kg for osprey and 6.93 mg/kg for great blue herons, dry weight) and relatively high in red-shouldered hawks and one eastern screech owl tested. Six of our samples exceeded a health threshold of 1 mg/kg (wet weight) including three osprey and one each of great blue heron, red-shouldered hawk, and eastern screech owl. Brodifacoum was the only rodenticide consistently detected in our samples. Brodifacoum detections exceeded 75% in barred owls, great horned owls, and red-shouldered hawks. Sixty nine percent of owl samples were within (or exceeded) a threshold of brodifacoum residue associated with a 10-20% risk of acute toxicity. Correlations between residues and human population density were not significant for either mercury or brodifacoum. Our data suggest that mercury residues for most raptors were not of significant concern with the exception of osprey and possibly red-shouldered hawks. Rodenticide exposures associated with a risk of acute toxicity appear to be common and warrant further investigation. PMID- 30251048 TI - Effect of atrazine on growth and production of AFB1 in Aspergillus section Flavi strains isolated from maize soils. AB - Atrazine is one of the most frequently used herbicides in Argentina for controlling broadleaf weeds and annual grasses. Currently, there is limited information on the impact of triazine herbicides on mycotoxin production and growth parameters of toxigenic fungi in maize. The objective of this study was to evaluate the effect of different concentrations of atrazine on the lag phase prior to growth, the growth rate, and on production of aflatoxin B1 (AFB1) of Aspergillus flavus and Aspergillus parasiticus strains, on maize meal extract agar (MMEA) under different water activities (aW) and temperatures. A commercial formulation of atrazine was added to MMEA medium at 0, 5, 10, 50, or 100 mmol/l, adjusted to 0.98, 0.95, and 0.93 aW, and incubated at 28 degrees C and 37 degrees C for 21 days. AFB1 was determined by HPLC after 7, 14, and 21 days of incubation. In the control treatments, a significant increase in the time prior to growth was observed and as the aW decreased, at both temperatures, the growth rate of the strains also decreased. A significant increase in growth rate was observed as the concentration of atrazine in the medium increased, for all aW levels tested. The optimal conditions for the accumulation of AFB1 in the control treatments were 0.98 aW and 28 degrees C, after 7 days of incubation. As the concentration of herbicide increased, AFB1 production also increased (P < 0.05). These results add to the knowledge about consequences with regard to aflatoxin production of the use of excessive atrazine doses in extensive maize culture. PMID- 30251049 TI - The use of hydrogel spacer in men undergoing high-dose prostate cancer radiotherapy: results of a prospective phase 2 clinical trial. AB - PURPOSE: The purpose of this study was to determine whether the degree of prostate to rectal separation using a hydrogel spacer (HS) and its effect on decreasing rectal dose can be reproduced in the community setting. METHODS: Thirty one patients with cT1-3aN0M0 prostate adenocarcinoma receiving radical radiotherapy to 78 Gy were recruited to the study. The primary endpoint was the proportion of patients achieving at least 25% reduction in volume of rectum receiving 70 Gy (rV70). Other endpoints included degree of prostate to rectum separation, HS insertion-related adverse events and the proportion of patients with grade 1 or worse acute or late gastrointestinal (GI) and genitourinary (GU) toxicity. RESULTS: All patients had successful insertion of their HS with no peri operative toxicity. The mean prostate-rectal separation achieved was 10.5 mm. Twenty nine (93.5%) patients achieved a reduction in rV70 of at least 25%. Acute grade 1 GI toxicity was reported in 3 patients. All symptoms had resolved by 3 months post RT. Late grade 1 GI toxicity was reported in one patient (3.2%) with bowel frequency occurring at 6 months and resolving by 12 months post RT. There was no grade 2 or 3 acute or late GI toxicity seen. CONCLUSION: In conclusion, this study illustrates that the application and benefits of HS on reducing GI rectal dose endpoints and toxicities during prostate cancer RT can be reliably replicated in a community setting similar to centres participating in the randomised trial under high quality assurance trial monitoring. PMID- 30251050 TI - A new urethral catheterisation device (UCD) to manage difficult urethral catheterisation. AB - The cost of urethral catheterisation injury (UCI) is significant, but the true incidence of patient care error is difficult to establish in the absence of specific hospital codes recording difficult urethral catheterisation (DUC) and UCI. For many years urologists are familiar passing a non-traumatic hydrophilic guidewire blindly into the bladder to aid urethral catheter insertion in difficult circumstances. However, so far, no purpose-built regulated medical device was available on the market and clinicians had to improvise. Urethrotech filled that gap and developed the Urethral Catheterisation Device (UCD(r)), which integrates a standard hydrophilic Nitinol guidewire into a 3-way 16F Silicone urethral catheter design to enable safe second-line urethral catheterisation when first-line catheterisation with a standard urethral catheter is unsuccessful. The safety and efficacy of UCD(r) catheterisation were evaluated in consecutive cohorts of men undergoing cardiac surgery and compared to the incidence of DUC and UCI with standard Foley catheterisation. A simple new Male Catheterisation Algorithm is proposed that can deliver a safe male urethral catheterisation treatment protocol for all clinical settings of healthcare services, which is easy to implement and integrate into standard catheterisation training programs to manage DUC and avoid UCI, empowering a frontline workforce to deliver better patient care. PMID- 30251051 TI - Urinary neutrophil gelatinase-associated lipocalin as a biomarker to monitor renal function in patients with obstructive ureteral calculi. AB - PURPOSE: Our study aimed to investigate the clinical significance of urinary neutrophil gelatinase-associated lipocalin (NGAL) as an effective real-time monitoring biomarker of renal function in patients with obstructive ureteral calculi presenting renal colic. METHODS: A cohort of 89 first-visit patients with renal colic caused by unilateral ureteral calculi were retrospectively reviewed. 46 of which received double-J ureteral stent placement (group 1) and the remaining 43 treated conservatively with analgesics and hydration (group 2) when diagnosed. Urinary NGAL (uNGAL) values in the baseline, 2 h and 1 day after treatments were recorded. The variation of this parameter over time and the association with patients' characteristics were analyzed. RESULTS: uNGAL levels decreased as time went by for patients receiving double-J ureteral stent placement (47.23 +/- 28.32 ng/mL for baseline, 40.73 +/- 21.86 ng/mL for 2 h and 34.67 +/- 18.00 ng/mL for 1 day after operation; p = 0.0363). Nevertheless, for those treating conservatively, the levels emerged a mild increase (50.63 +/- 32.30 ng/mL, 56.00 +/- 32.01 ng/mL and 60.63 +/- 34.08 ng/mL, correspondingly; p = 0.3708). By analyzing the association between uNGAL variation and patients' characteristics of group 1, operation duration showed the best correlation coefficient (Pearson r = 0.6106, r2 = 0.3728, p < 0.0001). CONCLUSIONS: uNGAL can be used as a biomarker to monitor the renal function effectively when serum creatinine (sCr) was within normal limits. And double-J ureteral stent can be considered as a protective factor to renal function in patients with obstructive ureteral calculi presenting renal colic. PMID- 30251052 TI - Trends in penile prosthesis implantation and analysis of predictive factors for removal. AB - PURPOSE: This study aims to analyze patient demographics, hospital characteristics, and clinical risk factors which predict penile prosthesis removal. We also examine costs of penile prosthesis removal and trends in inflatable versus non-inflatable penile prostheses implantation in the USA from 2003 to 2015. METHODS: Cross-sectional analysis from Premier Perspective Database was completed using data from 2003 to 2015. We compared the relative proportion of inflatable versus non-inflatable penile prostheses implanted. We separated the prosthesis removal group based on indication for removal-Group 1 (infection), Group 2 (mechanical complication), and Group 3 (all explants). All groups were compared to a control group of patients with penile implants who were never subsequently explanted. Multivariate analysis was performed to analyze patient and hospital factors which predicted removal. Cost comparison was performed between the explant groups. RESULTS: There were 5085 penile prostheses implanted with a stable relative proportion of inflatable versus non-inflatable prosthesis over the 13-year study period. There were 3317 explantations. Patient factors associated with prosthesis removal were non-black race, Charlson Comorbidity Index, diabetes, and HIV status. Hospital factors associated with removal included non-teaching status, hospital region, year of removal, and annual surgeon volume. Median hospitalization costs of all explantations were $10,878. Explantations due to infection cost $11,252 versus $8602 for mechanical complications. CONCLUSIONS: This large population-based study demonstrates a stable trend in inflatable versus non-inflatable prosthesis implantation. We also identify patient and hospital factors that predict penile prosthesis removal which has clinical utility for patient risk stratification and counseling. PMID- 30251053 TI - The MAK-commission: finding solutions to society's future challenges. PMID- 30251054 TI - Chronic dietary toxicity and carcinogenicity studies of dammar resin in F344 rats. AB - Dammar resin is a natural food additive and flavoring substance present in many foods and drinks. The present study evaluates the chronic toxicity and carcinogenicity of dietary dammar resin in F344 rats. Dietary concentrations in the 52-week chronic toxicity study were 0, 0.03, 0.125, 0.5, or 2%. The major treatment-related deleterious effects were body weight suppression, increased relative liver weight, and low hemoglobin levels in males and females. Foci of cellular alteration in the liver were observed in the male 2% group, but not in any other group. The no-observed-adverse-effect level for chronic toxicity was 0.125% for males (200.4 mg/kg b.w./day) and females (241.9 mg/kg b.w./day). Dietary concentrations in the 104-week carcinogenicity study were 0, 0.03, 0.5, or 2%. Dammar resin induced hemorrhagic diathesis in males and females, possibly via the inhibition of extrinsic and intrinsic coagulation pathways. Incidences of hepatocellular adenomas and carcinomas were significantly increased in the male 2% group, but not in any other group. In the 4-week subacute toxicity study, the livers of male rat-fed diet-containing 2% dammar resin had increased levels of protein oxidation and increased the expression of two anti-apoptotic and seven cytochrome P450 (CYP) genes. There was also an increased tendency of oxidative DNA damage. These findings demonstrate that dammar resin is hepatocarcinogenic in male F344 rats and underlines the roles of inhibition of apoptosis, induction of CYP enzymes, and oxidative stress in dammar resin-induced hepatocarcinogenesis. PMID- 30251055 TI - Effects of topical applications of porcine acellular urinary bladder matrix and Centella asiatica extract on oral wound healing in a rat model. AB - OBJECTIVES: To evaluate the effects of topical applications of porcine acellular urinary bladder matrix (AUBM) and Centella asiatica extract (CAE) on the healing of tongue wounds in a rat model. MATERIALS AND METHODS: Wounds were made in the tongue using a punch tool in 64 male Sprague-Dawley rats, randomized into four groups (n = 16 per group): group 1 (control), group 2 (CAE), group 3 (AUBM mixed with orabase), and group 4 (orabase). No product was applied in group 1 and groups 2-4 received three daily topical applications. The animals were weighed on day 0 and at the time of euthanasia. Four rats in each group were euthanized at days 2, 7, 14, and 21 and the tongues were processed for: macroscopic morphometric analysis, myeloperoxidase (MPO) and malondialdehyde (MDA) levels, histological wound repair (degree of reepithelialization and inflammation), and CD31 positivity. RESULTS: The animals' weight gain, histological wound repair, and CD31 positivity from greatest to least were: AUBM > CAE > orabase > control. Percentage of tongue occupied by wound, MPO, and MPA levels from least to greatest were: AUBM < CAE < orabase < control, whereby the AUBM group showed significant differences (p <= 0.05) in comparison with the other groups on days 2, 7, 14, and 21 for percentage of tongue occupied by wound and MDA and on days 7, 14, and 21 for MPO. CONCLUSIONS: CAE is effective for oral tissue regeneration, while AUBM is an even more potent means of oral mucosa regeneration. CLINICAL RELEVANCE: AUBM may be beneficial to patients with oral wounds; this finding requires further clinical and laboratory investigation. PMID- 30251056 TI - Morphological framework for attachment and locomotion in several Digenea of the families Microphallidae and Heterophyidae. AB - Digenea usually use ventral sucker for sustainable attachment within intestine of their definitive vertebrate host. However, if the ventral sucker is absent or poorly developed, the means of attachment are unclear. We investigated attachment and locomotion in such digeneans: three species of the family Microphallidae (Microphallus piriformes, M. pygmaeus, and Levinseniella brachysoma) and two species of the family Heterophyidae (Cryptocotyle concava and C. lingua). Their tegumental spines and musculature were described with use of fluorescent actin staining, confocal microscopy, and scanning electron microscopy. Locomotion of living worms was observed and recorded. Wide serrated tegumental spines probably play the main role in attachment. Their firm contact with the host mucosa may be provided by the action of the ventral concavity-when the entire body or its part acts as a sucker. Dorsoventral muscle bundles act like radial musculature of the sucker generating negative pressure in the ventral concavity. The solid layer of longitudinal muscle fibers on the ventral body surface provides support for the bottom of the ventral concavity. In all microphallids, a U-shaped arrangement of body wall musculature (mostly originating from longitudinal fibers) outlines posterior part of the ventral concavity ridge. In all the studied species, tegumental spines, body wall musculature, and dorsoventral muscle bundles are better developed in the forebody which moves more actively than the hindbody. PMID- 30251057 TI - Differences in activities of daily living after hip arthroplasty among hip resurfacing, anterolateral THA, and posterolateral THA: a propensity score matched analysis. AB - The aim was to elucidate the differences in activities of daily living (ADL) after hip arthroplasty among hip resurfacing (HRA), anterolateral total hip arthroplasty (AL-THA), and posterolateral THA (PL-THA) patients after age, sex, body mass index, bilateral/unilateral hip arthroplasty, and postoperative duration were matched using propensity scores. A total of 673 hips from 540 consecutive patients who underwent hip arthroplasty were included. A self completed questionnaire on preoperative and postoperative ADLs was administered during postsurgical visits at least >= 4 years postoperatively. Between HRA and PL-THA patients, the numbers of patients who performed heels-down squatting was significantly more in HRA than in PL-THA. Between AL-THA and PL-THA patients, there were significant differences in postoperative ADLs including bathing in a bathtub, riding on a train/bus, cutting toenails, bowing while straight sitting, heels-up/down squatting, riding on a bicycle, driving a car, and domestic travel. There were no significant differences in postoperative ADLs between >= 36 mm head and <= 32 mm head PL-THA patients, and between AL-THA and HRA patients. This propensity score matched study indicated that AL-THA and HRA patients were more active postoperatively than PL-THA patients. PMID- 30251058 TI - Identify and monitor clinical variation using machine intelligence: a pilot in colorectal surgery. AB - Standardized clinical pathways are useful tool to reduce variation in clinical management and may improve quality of care. However the evidence supporting a specific clinical pathway for a patient or patient population is often imperfect limiting adoption and efficacy of clinical pathway. Machine intelligence can potentially identify clinical variation and may provide useful insights to create and optimize clinical pathways. In this quality improvement project we analyzed the inpatient care of 1786 patients undergoing colorectal surgery from 2015 to 2016 across multiple Ohio hospitals in the Cleveland Clinic System. Data from four information subsystems was loaded in the Clinical Variation Management (CVM) application (Ayasdi, Inc., Menlo Park, CA). The CVM application uses machine intelligence and topological data analysis methods to identify groups of similar patients based on the treatment received. We defined "favorable performance" as groups with lower direct variable cost, lower length of stay, and lower 30-day readmissions. The software auto-generated 9 distinct groups of patients based on similarity analysis. Overall, favorable performance was seen with ketorolac use, lower intra-operative fluid use (< 2000 cc) and surgery for cancer. Multiple sub groups were easily created and analyzed. Adherence reporting tools were easy to use enabling almost real time monitoring. Machine intelligence provided useful insights to create and monitor care pathways with several advantages over traditional analytic approaches including: (1) analysis across disparate data sets, (2) unsupervised discovery, (3) speed and auto-generation of clinical pathways, (4) ease of use by team members, and (5) adherence reporting. PMID- 30251059 TI - The effect of extra-articular manifestations on tumor necrosis factor-alpha inhibitor treatment duration in patients with ankylosing spondylitis: nationwide data from the Korean College of Rheumatology BIOlogics (KOBIO) registry. AB - Tumor necrosis factor-alpha inhibitor (TNFi) therapy has shown to be remarkably effective for treating ankylosing spondylitis (AS); however, nearly 30% of AS patients every year either stop TNFi therapy or switch to a different TNFi due to inefficacy or adverse effects. The goal of this study was to identify predictors of TNFi treatment duration, including extra-articular manifestations, using a nationwide registry in Korea. Data obtained from the Korean College of Rheumatology Biologics (KOBIO) registry, a nationwide, multi-center database representing 58 tertiary care hospitals in Korea. Demographics, clinical features, laboratory findings, disease activity indices (BASDAI, ASDAS-ESR, ASDAS CRP), peripheral arthritis, and extra-articular manifestations (uveitis, enthesitis, dactylitis, psoriasis, and inflammatory bowel disease) were studied in patients with AS during TNFi therapy. We also analyzed treatment duration outcomes for five TNFi agents (etanercept, infliximab, infliximab biosimilar, adalimumab, and golimumab), as well as factors associated with treatment duration, particularly in terms of extra-articular manifestations. Univariable and multivariable Cox regression analyses were performed to verify preliminary results. A total 1482 AS patients starting TNFi drug therapy between Dec. 2012 and Jan. 2017 were included. No differences in demographics, disease activity, or extra-articular manifestations were evident between continued and discontinued TNFi groups at baseline, though baseline differences were detected for gender distribution, CRP, platelet counts, and HLA-B27 positivity. During treatment period, the effects of extra-articular manifestations, including uveitis (unadjusted hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.57 to 1.48, p = 0.74), enthesitis, dactylitis, psoriasis, and inflammatory bowel disease, on TNFi treatment duration were not statistically significant. By contrast, the occurrence of peripheral arthritis was significantly associated with shorter TNFi treatment duration (unadjusted HR 2.21, 95% CI 1.66 to 2.95; adjusted HR 1.38, 95% CI 1.01 to 1.88). Among disease activity indices, higher ASDAS-ESR levels were significantly associated with shortening of the TNFi treatment duration (unadjusted HR 1.87, 95% CI 1.73 to 2.03; adjusted HR 2.23, 95% CI 2.00 to 2.63). Among TNFi drugs, golimumab had a lower discontinuation rate than that of etanercept over a 3-year follow-up period (unadjusted HR 0.46, 95% CI 0.31 to 0.68; adjusted HR 0.65, 95% CI 0.43 to 0.99). In a nationwide KOBIO registry, extra-articular manifestations, including uveitis, were not associated with TNFi treatment duration. Among clinical cofactors, the development of peripheral arthritis during TNFi therapy was associated with a higher risk of TNFi treatment discontinuance in AS patients. PMID- 30251060 TI - TEKT4 Promotes Papillary Thyroid Cancer Cell Proliferation, Colony Formation, and Metastasis through Activating PI3K/Akt Pathway. AB - Thyroid carcinoma is the most common malignancy of the endocrine system worldwide, but its molecular mechanisms remain unclear. Some diseases are associated with TEKT4 gene. However, its role in thyroid carcinoma has yet to be fully examined. This study was designed to investigate the function of TEKT4 in papillary thyroid cancer (PTC). The effect of TEKT4 on aggressive behavior of PTC cell lines, namely, TPC1 and BCPAP, transfected with small interfering RNA was identified through cell proliferation, colony formation, migration, and invasion. Our previous study revealed that TEKT4 may be vital in PTC. In in vitro experiments, TEKT4 downregulation suppressed cell proliferation, colony formation, cell migration, and invasion. Our data also indicated that tumor suppressing role of TEKT4 knockdown in PTC cell lines was associated with the silence of the PI3K/Akt pathway. Our study revealed that TEKT4 shows important biological implications and is worthy of further study. PMID- 30251061 TI - Dose reduction, oral application, and order of intake to preserve aspirin antiplatelet effects in dipyrone co-medicated chronic artery disease patients. AB - BACKGROUND: Dipyrone comedication in aspirin-treated patients is associated with impaired pharmacodynamic response to aspirin (high on-treatment platelet reactivity [HTPR]). Additionally, in small observational studies, an association with impaired outcome has been described. In this uncontrolled, hypothesis generating study, we aimed to investigate strategies to prevent this drug-drug interaction in patients with coronary artery disease (CAD). METHODS: We analyzed pharmacodynamic response to aspirin in 80 dipyrone co-medicated CAD patients. Aspirin antiplatelet effects were measured using arachidonic acid (AA)-induced light-transmission aggregometry (LTA). Platelet reactivity was associated with daily dose, administration form, and frequency. Additionally, we conducted a time series analysis in patients with HTPR to aspirin with re-evaluation of pharmacodynamic response to aspirin after 5 days. RESULTS: Patients' mean age was 75.5 +/- 9.8 years. Forty-three (54%) were male, 22 (27.5%) obese, and 38 (47.5%) diabetics. Baseline characteristics, cardiovascular risk factors, comorbidities, comedication, or laboratory parameters did not differ between patients with or without HTPR. HTPR to aspirin occurred in 34 out of 80 patients (42.5%). The incidence of HTPR was associated with dipyrone daily dose (< 1 g/day: HTPR 20% vs. > 3 g/day: HTPR 50%, p > 0.0001) and form of administration (i.v. 87.5% vs. oral 37.5%; p < 0.0001). A strict order of intake (aspirin 30 min prior to dipyrone) restored aspirin antiplatelet effects in all patients (HTPR before 100% vs. HTPR after 0%, p = 0.0002). CONCLUSION: This study shows that dipyrone should be used with caution in aspirin-treated patients. If dipyrone seems indispensable, the lowest effective dose and a strict order of intake seem favorable. PMID- 30251062 TI - Effects of clotrimazole on tacrolimus pharmacokinetics in patients with heart transplants with different CYP3A5 genotypes. AB - PURPOSE: This study aimed to investigate the effects of clotrimazole on the pharmacokinetics of tacrolimus in Japanese patients with heart transplants with different CYP3A5 genotypes. METHODS: Twenty-six patients who underwent heart transplantation between June 2012 and July 2017 were enrolled in this retrospective study. The CYP3A5 (rs776746; CYP3A5*3) genotype was determined after monitoring and analysing tacrolimus blood concentrations. The pharmacokinetic profile of tacrolimus was examined before and after the discontinuation of clotrimazole and in patients with different CYP3A5 genotypes. RESULTS: The CYP3A5*1/*1, *1/*3 and *3/*3 genotypes were detected in 2, 8 and 16 patients, respectively. After clotrimazole was discontinued, the CYP3A5 expresser (CYP3A5*1/*1 or *1/*3) group had a 3.3-fold median increase in apparent oral clearance of tacrolimus (0.27 vs. 0.89 L/h/kg, P = 0.002) compared with the CYP3A5 non-expresser (CYP3A5*3/*3) group with a 2.2-fold median increase (0.18 vs. 0.39 L/h/kg, P < 0.0001). Significant correlations were observed between C0 and area under the concentration-time curve (AUC0-12) of tacrolimus after the discontinuation of clotrimazole in the CYP3A5 expresser and non-expresser groups, respectively (R2 = 0.49 and 0.42, all P < 0.05), but not before the discontinuation of clotrimazole. CONCLUSION: The effects of clotrimazole on tacrolimus pharmacokinetics in the CYP3A5 expresser patients were significantly greater than those in the CYP3A5 non-expresser patients. In addition, clotrimazole disturbed the correlation between C0 and AUC0-12 of tacrolimus. Careful dose adjustment of tacrolimus based on CYP3A5 genotypes may be beneficial for the patients with heart transplants who are concomitantly treated with clotrimazole. PMID- 30251063 TI - Condensation Product of 4-Methoxybenzaldehyde and Ethylenediamine: "Off-On" Fluorescent Sensor for Cerium(III). AB - The condensation product (L) of 4-methoxybenzaldehyde and ethylenediamine has been synthesised and characterised. L showed a 21 times enhancement in fluorescence intensity on interaction with Ce3+ in CH3OH at lambdamax = 360 nm when excited with 270 nm photons. Metal ions K+, Na+, Al3+, Co2+, Hg2+, Cd2+, Ni2+, Zn2+, Mn2+, Mg2+ and Ca2+ do not interfere. The stoichiometry of binding and the binding constants were determined from spectroscopic data and found to be 1:1 and 104.8 M respectively. The detection limit was found to be 10-5.2 M. The protonation/de-protonation of water molecules coordinated to Ce3+ was found to show interesting behaviour on the fluorescence of L:Ce3+. PMID- 30251064 TI - A Highly Selective Fluorescent Chemosensor for Detecting Indium(III) with a Low Detection Limit and its Application. AB - A highly selective chemosensor BHC ((E)-N-benzhydryl-2-((2-hydroxynaphthalen-1 yl)methylene)hydrazine-1-carbothioamide) for detecting indium(III) was synthesized. Sensor BHC can detect In(III) by a fluorescence turn-on method. The detection limit was analyzed to be 0.89 MUM. Importantly, this value is the lowest among those previously known for fluorescent turn-on In(III) chemosensors. Based on the analytical methods like ESI-mass, Job plot, and theoretical calculations, the detection mechanism for In(III) was illustrated to be chelation enhanced fluorescence (CHEF) effect. Additionally, sensor BHC was successfully applied to test strips. PMID- 30251065 TI - Understanding patient choices regarding breast reconstruction after mastectomy for breast cancer. AB - PURPOSE: In Australia, about 40% of patients undergo mastectomy to treat breast cancer, with negative impacts on body image, sexual function and quality of life. Whilst breast reconstruction is associated with increased patient self-esteem and a greater sense of wholeness and well-being, the national reconstruction rate is low at 18%. This study aimed to compare demographics, treatment factors and information provision about breast reconstruction in women who had and did not have breast reconstruction following mastectomy treatment and identify goals and concerns underpinning women's reconstruction decisions. METHODS: Female patients who had a mastectomy to treat breast cancer between 2010 and 2014 in a culturally and linguistically diverse (CALD) and socially disadvantaged region participated in a cross-sectional study, completing a questionnaire in their language of choice (English, Vietnamese, Chinese or Arabic). RESULTS: Completed surveys were returned by 168 women (42% response rate; 77% English-speaking), of whom only 19.0% (n = 32) reported having had breast reconstruction. Reconstruction rates were significantly lower in women who reported speaking a language other than English at home versus only English (37.5% vs 62.5%, p = 0.03). However, all women expressed a desire for more information about breast reconstruction and more support to make their decision about breast reconstruction. CONCLUSIONS: Patients identified a need for greater information provision on breast reconstruction, highlighting an urgent need for resources specifically about breast reconstruction, particularly for non-English-speaking patients. Greater provision of information prior to mastectomy is critical to underpin breast cancer patients' decisions about breast reconstruction, especially for non English speaking patients. PMID- 30251066 TI - Short and long-term impairments of cardiopulmonary fitness level in previous childhood cancer cases: a systematic review. AB - PURPOSE: To describe the impairments in physical fitness in individuals who were previously diagnosed and treated for childhood cancer. METHODS: Using the PRISMA guidelines, a systematic search was performed in PubMed, Web of Science, and Embase using a combination of the following predefined keywords: "exercise capacity" OR "aerobic capacity" OR "fitness" OR "cardiorespiratory fitness" OR "cardiopulmonary fitness" OR "physical fitness" OR "exercise testing" OR "exercise tolerance" OR "exercise" OR "oxygen consumption" AND "leukemia" OR "childhood cancer" OR "childhood cancer survivors (CCS)". Studies that met our inclusion criteria were reviewed on methodological quality, while the Newcastle Ottawa Scale was used for evidence synthesis. RESULTS: A total of 2644 articles were identified from the database search. After screening based on the eligibility (abstracts) and inclusion (full texts) criteria, 49 articles remained. Even though the risk-of-bias scores in the studies were generally low, yet the results from those with high-quality studies revealed that poor fitness levels were prevalent in individuals with acute lymphoblastic leukemia, brain tumor, and mixed cancer histories, compared to healthy controls. CONCLUSIONS: A global glance at CCS shows poor levels of fitness that is continuous and life long even after active cancer treatment has ended. Nevertheless, the results presented in this review were based on a limited number of high-quality studies suggesting the need to for additional clinical trials in the topic area. PMID- 30251068 TI - Role of kin recognition in oviposition preference and cannibalism by the predatory mite Gynaeseius liturivorus. AB - Animals often select oviposition sites to minimize the predation risk for eggs and juveniles, which are more vulnerable to predation than adults. When females produce eggs in clusters, the eggs and juveniles are likely to suffer from cannibalism. Although cannibalism among siblings is known to be lower than among non-siblings, there have been few investigations into the possibility that females select oviposition sites that reduce the risk of cannibalism for the offspring. To test this possibility, we examined oviposition preference by adult females of the predatory mite Gynaeseius liturivorus in response to the presence of her own eggs and to eggs of other females, offering plastic discs as oviposition substrates. Although females did not clearly show a preference for plastic discs on which they had oviposited, they avoided plastic discs on which other females had oviposited. When eggs of other females were artificially placed on clean plastic discs, adult female mites avoided these discs, suggesting that the eggs were used as cues for oviposition preference. Cannibalism among juvenile siblings was lower than among non-siblings. These observations show that adult females and juveniles of G. liturivorus discriminate kin relationships among conspecific individuals. Therefore, oviposition preference by adult female G. liturivorus may lead to the reduced risk of cannibalism among offspring. PMID- 30251067 TI - Preference and performance of the two-spotted spider mite Tetranychus urticae (Acari: Tetranychidae) on strawberry cultivars. AB - The two-spotted spider mite (TSSM), Tetranychus urticae Koch (Acari: Tetranychidae), is one of the most serious pests of strawberry worldwide. Understanding the preference of TSSM for particular cultivars of strawberry and performance on them helps identify host-plant resistance to this pest mite. In this study, we tested preference, developmental duration, fecundity and population levels of TSSM on 14 strawberry cultivars. TSSM showed strong preference for the Chinese cultivars of Yanxiang, Baixuegongzhu, and Jingtaoxiang. Development of TSSM on the cultivars varied from 32.32 to 36.82 days; it was longest on the cultivars Hongxiutianxiang and Baixuegongzhu, and shortest on Yanxiang, Jingzangxiang, and Darselect as well as on a wild variety (Wuye). TSSM had high fecundity on the cultivars Yanxiang, Taoxun, Hongxiutianxiang, Jingzangxiang, Albion and Baixuegongzhu as well as on Wuye, whereas egg production was lowest on Sweet Charlie, Portola, Akihime, and Benihoppe. After 28 days of plant infestation with 10 pairs of adults, the cultivars Yanxiang, Taoxun, Jingzangxiang, Jingtaoxiang, and Baixuegongzhu had the highest number of mites (> 1000 per plant), whereas mite numbers on Albion and Camarosa were low. The population size of TSSM was correlated with fecundity, but no correlation was found between other preference/performance measures. Our study suggests that a rapid increase of population size of TSSM on cultivars of strawberry is related to high fecundity, and also that there are substantial differences in preference and performance across cultivars. PMID- 30251069 TI - Webbing life type and behavioral response of the date palm mite, Oligonychus afrasiaticus, to webbing residues on leaves and fruits of date palm. AB - The present study examined the webbing life type and behavioral response of date palm mite (DPM) Oligonychus afrasiaticus (McGregor) toward its webbing residues, in presence or absence of immature individuals, on leaves and fruits of date palm. DPM exhibited a complicated web life type on both the leaves and fruits of date palm, which is characterized by the following features: complicated irregular web structure; webbing density on the leaves is medium and on the fruits extremely high; eggs are always laid on the threads of web without web cover; fecal pellets are deposited on the substrate surface (both leaf and fruit); quiescent stages are on the silken web threads; and the preferred site for feeding and walking is under the web. Behavioral observation of DPM females revealed that the midrib of leaves and the base of fruits of date palm were the preferred sites for feeding and web construction. The number and development stage of DPM affected the behavioral response of females on date palm leaves but not on the fruits. DPM spent most time feeding under the web on both the leaves and fruits of date palm. PMID- 30251070 TI - Laparoscopic Surgery for Diverticular Fistulas: Outcomes of 111 Consecutive Cases at a Single Institution. AB - BACKGROUND: The purpose of this study was to review our experience with laparoscopic colectomy and fistula resection, evaluate the frequency of conversion to open, and to compare the perioperative courses of the complete laparoscopic and conversion groups. METHODS: This study is a retrospective analysis of 111 consecutive adult patients with diverticular fistulae diagnosed clinically or radiographically over 11 years at a single institution. Five patients were excluded for preoperative comorbidities. The remaining 106 consecutive patients underwent minimally invasive sigmoid colectomy with primary anastomosis. Preoperative, intraoperative, and postoperative variables were collected from the colorectal surgery service database. A retrospective cohort analysis was performed between laparoscopic and converted groups. RESULTS: Within the group, 47% had colovesical fistulas, followed by colovaginal, coloenteric, colocutaneous, and colocolonic fistulas. The overall conversion rate to laparotomy was 34.7% (n = 37). The most common reason for conversion was dense fibrosis. Mean operative time was similar between groups. Combined postoperative complications occurred in 26.4% of patients (21.4% laparoscopic and 37.8% converted, p = 0.075). Length of stay was significantly shorter in the laparoscopic group (5.8 vs 8.1 days, p = 0.014). There were two anastomotic leaks, both in the open group. There were no 30-day mortalities. CONCLUSIONS: Laparoscopic sigmoid colectomy for diverticular fistula is safe, with complication rates comparable to open sigmoid resection. We identify a conversion rate which allows the majority of patients to benefit from minimally invasive procedures. PMID- 30251071 TI - Nonsteroidal Anti-inflammatory Drugs for Endoscopic Retrograde Cholangiopancreatography Postoperative Pancreatitis Prevention: a Systematic Review and Meta-analysis. AB - BACKGROUND OR PURPOSE: There is controversy regarding the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) for prophylaxis against endoscopic retrograde cholangiopancreatography (ERCP) postoperative pancreatitis. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy of NSAIDs for prophylaxis against post-ERCP pancreatitis (PEP). METHODS: PubMed, EMBASE, and Cochrane library databases were searched for relevant randomized controlled trials (RCTs). Selected RCTs were pooled under a fixed effects model to generate the relative risks (RRs) and their corresponding 95% confidence intervals (CIs). RESULTS: Nineteen RCTs involving a total of 5031 patients (2555 in the intervention group and 2476 in the control group) were selected. Overall, NSAIDs were associated with a significant reduction in risk of PEP (RR = 0.54, 95% CI 0.45 to 0.64, I2 = 40.4%) and moderate to severe PEP (RR = 0.45, 95% CI 0.30 to 0.67, I2 = 0%) compared with the control group. Subgroup analyses were performed according to route of administration (rectal or other), type of NSAIDs (diclofenac, indomethacin, or other), timing of administration (pre-ERCP, post ERCP, or other), and patient population (high risk or general). Subgroup analyses showed difference in clinical efficacy of NSAID prophylaxis regardless of route, timing, or specific type of NSAID. CONCLUSION: NSAIDs were associated with a significant reduction in risk of PEP and moderate to severe PEP compared to the control group. PMID- 30251073 TI - Differentiate the Source and Site of Intracranial Pressure Measurements Using More Precise Nomenclature. AB - BACKGROUND: Intracranial pressure (ICP) monitoring is fundamental for neurocritical care patient management. For many years, ventricular and parenchymal devices have been available for this aim. The purpose of this paper is to review the published literature comparing ICP recordings via an intraventricular catheter or an intraparenchymal (brain tissue) catheter. METHODS: Literature search of Medline, CINAHL, Embase, and Scopus was performed in which manuscripts discussed both ICP monitoring via an intraventricular catheter and ICP monitoring through intraparenchymal (brain tissue) catheter. Keywords and MeSH terms used include critical care, intracranial pressure, ICP, monitoring, epidural catheter, intracranial hypertension, ventriculostomy, ventricular drain, external ventricular drain, and physiologic monitoring. RESULTS: Eleven articles met inclusion criteria. The published literature shows differences in simultaneously recorded ICP between the intraventricular and intraparenchymal sites. CONCLUSIONS: We propose two new terms that more accurately identify the anatomical site of recording for the referenced ICP: intracranial pressure ventricular (ICP-v) and intracranial pressure brain tissue (ICP-bt). Further delineation of the conventional term "ICP" into these two new terms will clarify the difference between ICP-v and ICP-bt and their respective measurement locations. PMID- 30251072 TI - Standards for Neurologic Critical Care Units: A Statement for Healthcare Professionals from The Neurocritical Care Society. AB - Neurocritical care is a distinct subspecialty focusing on the optimal management of acutely ill patients with life-threatening neurologic and neurosurgical disease or with life-threatening neurologic manifestations of systemic disease. Care by expert healthcare providers to optimize neurologic recovery is necessary. Given the lack of an organizational framework and criteria for the development and maintenance of neurological critical care units (NCCUs), this document is put forth by the Neurocritical Care Society (NCS). Recommended organizational structure, personnel and processes necessary to develop a successful neurocritical care program are outlined. Methods: Under the direction of NCS Executive Leadership, a multidisciplinary writing group of NCS members was formed. After an iterative process, a framework was proposed and approved by members of the writing group. A draft was then written, which was reviewed by the NCS Quality Committee and NCS Guidelines Committee, members at large, and posted for public comment. Feedback was formally collated, reviewed and incorporated into the final document which was subsequently approved by the NCS Board of Directors. PMID- 30251074 TI - Third Ventricle Obstruction by Thalamic Intracerebral Hemorrhage Predicts Poor Functional Outcome Among Patients Treated with Alteplase in the CLEAR III Trial. AB - INTRODUCTION: The Clot Lysis: Evaluating Accelerated Resolution of IVH trial examined whether irrigating the ventricular system with alteplase improved functional outcomes in patients with small intracerebral hemorrhage (ICH) and large intraventricular hemorrhage (IVH). Thalamic ICH location was common and was associated with poor outcome. One possible explanation is thalamic ICH-associated mass effect obstructing the third ventricle. We hypothesized that patients with thalamic ICH obstructing the third ventricle would have worse functional outcomes compared to patients without obstructing lesions. METHODS: ICH obstruction of third ventricle was defined as third ventricle compression on 1 or more axial computed tomography slices visually impeding cerebral spinal fluid flow. If the third ventricle was casted with IVH, it was scored as such. Multivariable logistic regression analyses were used to determine whether obstruction of the third ventricle predicts poor functional outcomes defined as modified Rankin score (mRS) 4-6, higher mRS, and mortality at 180 days. Models were adjusted for thalamic ICH location, ICH volume, IVH volume, age, hydrocephalus, baseline Glasgow coma scale, and percentage of low cerebral perfusion pressures during treatment. RESULTS: Among saline-treated patients, obstruction of the third ventricle by IVH was a significant predictor of higher mRS at 180 days (OR 1.87, CI 1.01-3.47) and mortality at 180 days (OR 2.73, CI 1.27-5.87) while obstruction by ICH was not. In contrast, among alteplase-treated patients, obstruction by ICH was a significant predictor of mRS 4-6 (OR 3.20, CI 1.30-7.88) and higher mRS at 180 days (OR 2.33, CI 1.24-4.35), while obstruction by IVH was not. CONCLUSIONS: Poor outcomes were associated with mass-related obstruction of the third ventricle from thalamic ICH in alteplase-treated patients and from IVH in saline treated patients. Once the ventricular system is cleared with alteplase, obstruction of cerebral spinal fluid flow from thalamic ICH might become important in functional recovery. PMID- 30251075 TI - Characterizing the Response to Cerebrospinal Fluid Drainage in Patients with an External Ventricular Drain: The Pressure Equalization Ratio. AB - BACKGROUND: An external ventricular drain (EVD) is the gold standard for measurement of intracranial pressure (ICP) and allows for drainage of cerebrospinal fluid (CSF). Different causes of elevated ICP, such as CSF outflow obstruction or cerebral swelling, respond differently to CSF drainage. This is a widely recognized but seldom quantified distinction. We sought to define an index to characterize the response to CSF drainage in neurocritical care patients. METHODS: We studied consecutive patients admitted to the neurointensive care unit who had an EVD. The EVD was closed for 30 min prior to assessment. We documented pre-drainage ICP, opened EVD to drainage allowing CSF to drain until it ceased, and recorded post-drainage ICP at EVD closure. We calculated the pressure equalization (PE) ratio as the difference between pre-drainage ICP and post drainage ICP divided by the difference between pre-drainage ICP and EVD height. RESULTS: We studied 60 patients (36 traumatic brain injury [TBI], 24 non-TBI). As expected, TBI patients had more signs of cerebral swelling on CT and smaller ventricles. Although TBI patients had significantly higher pre-drainage ICP (26 +/- 10 mm Hg) than non-TBI patients (19 +/- 5 mm Hg, p < 0.001) they drained less CSF (7 cc vs. 4 cc, p < 0.01). PE ratio was substantially higher in non-TBI than in TBI patients (0.86 +/- 0.36 vs. 0.43 +/- 0.31, p < 0.0001), indicating that non-TBI patients were better able to equalize pressure with EVD height than TBI patients. CONCLUSIONS: PE ratio reflects the ability to equalize pressure with the preset height of the EVD and differs substantially between TBI and non-TBI patients. A high PE ratio likely indicates CSF outflow obstruction effectively treated by CSF diversion, while a lower PE ratio occurs when cerebral swelling predominates. Further studies could assess whether the PE ratio would be useful as a surrogate marker for cerebral edema or the state of intracranial compliance. PMID- 30251076 TI - Plasmon Resonance in Photoabsorption of Colloidal Highly Doped ZnO Nanocrystals. AB - A new type of dipole plasmon excitations in colloidal highly doped ZnO nanocrystals has been studied by means of many-body quantum mechanical approach. We demonstrate that in photodoped ZnO nanocrystals, the conduction band electrons are localized close to the surface and the plasmon oscillations are induced by their angular motion. The transition of this plasmon mode from classical to quantum regime is defined by the nanocrystal size. The size dependence of the resonance frequency which results from quantum effects is in remarkable agreement with experimental observations. PMID- 30251077 TI - Training the Twenty-First Century Cancer Epidemiologist. AB - To assess and advance training of twenty-first century cancer epidemiologists, the National Cancer Institute (NCI) sought to obtain a snapshot of the cancer epidemiology training landscape by conducting a survey across academic institutions and cancer centers, focusing on four key training areas driving current cancer epidemiology research ("drivers"): (1) collaboration, (2) novel methods/technologies, (3) multilevel analysis, and (4) knowledge integration. Complementary to the survey, we conducted a portfolio analysis of active NCI funded training grants. In the present report, we provide our findings from this effort and contribute to the on-going conversation regarding the training of next generation cancer epidemiologists. Analyses and insights gained from conversations with leaders/educators across 24 academic institutions/cancer centers and the portfolio analysis of training grants echoed contemporaneous conversation that cancer epidemiology training must adapt to meet the needs of the changing research environment. Currently, with the exception of novel methods/technologies, cancer epidemiology trainees receive the majority of their training in collaboration, multilevel approaches, and knowledge integration/translation either informally, ad hoc, or not at all; exposure to these identified drivers varied considerably by institution, mentor, and other external as well as internal factors. PMID- 30251078 TI - Cost Effectiveness of Quadrivalent Influenza Vaccines Compared with Trivalent Influenza Vaccines in Young Children and Older Adults in Korea. AB - INTRODUCTION: Trivalent influenza vaccines (TIVs) are currently reimbursed for subjects aged >= 65 years and children between 6 and 59 months of age under a national immunization program in South Korea. Quadrivalent influenza vaccines (QIVs) are expected to address the potential problem of influenza B-lineage mismatch for TIVs. OBJECTIVE: The objective of this analysis was to compare the cost effectiveness of QIV versus TIV in children aged 6-59 months and older adults >= 65 years of age in South Korea. METHODS: A 1-year static population model was employed to compare the costs and outcomes of a QIV vaccination program compared with TIV in children aged 6-59 months and older adults >= 65 years of age in South Korea. Influenza-related parameters (probabilities, health resource use, and costs) were derived from an analysis of the National Health Insurance System claims database between 2010 and 2013 under a broad and narrow set of International Classification of Diseases, Tenth Revision (ICD-10) codes used to identify influenza. Other inputs were extracted from published literature. Incremental cost-effectiveness ratios (2016 South Korean Won [KRW] per quality adjusted life-year [QALY] gained) were estimated using a 'limited' societal perspective as per the Korean pharmacoeconomic guidelines. QALYs lost due to premature mortality were discounted at 5% annually. RESULTS: For both age groups combined, under the narrow definition of influenza, QIV is expected to prevent nearly 16,000 (2923 in children and 13,011 in older adults) medically attended influenza cases, nearly 8000 (672 in children, 7048 in older adults) cases of complications, and over 230 (0 in children, 238 in older adults) deaths annually compared with TIV. The impact of using QIV versus TIV in this setting translates into savings of KRW 24 billion (KRW 0.6 billion in children, KRW 23.4 billion in older adults) in annual medical costs, and over 2100 (18 in children, 2084 in older adults) QALYs. Under the broad definition, the corresponding results are over 190,000 (50,697 in children, 140,644 in older adults) influenza cases, over 37,000 (12,623 in children, 24,526 in older adults) complications, 270 deaths (0 in children, 270 in older adults), KRW 94.22 billion (KRW 16 billion in children, KRW 78.2 billion in older adults), and over 3500 QALYs saved (316 in children, 3260 in older adults). CONCLUSION: The use of QIV over TIV was estimated to not be cost effective in children 6-59 months of age, but cost saving in older adults, using the narrow definition of influenza; however, QIV use was cost saving in both age groups using the broad definition. QIV is expected to yield more benefits in older adults >= 65 years of age than in children aged 6-59 months due to higher influenza-related mortality and costs among the older adults. Further analyses considering the indirect effects of influenza vaccination in children are required. PMID- 30251079 TI - Efficacy and safety of 3D-conformal half body irradiation in patients with multiple bone metastases. AB - Half-body irradiation (HBI) represented a standard treatment for multiple painful bone metastases (BMs). However, its use has progressively reduced due to the associated toxicity rates. The aim of this paper was to evaluate HBI delivered by conformal radiotherapy (RT) technique in a large patients population with widespread BMs. HBI was delivered in 3 Gy fractions, bid, >= 6 h apart, on 2 consecutive days (total dose: 12 Gy) using 3-dimensional conformal RT (3D-CRT) box technique. The target included pelvic bones, lumbar-sacral vertebrae and upper third of femurs. Acute and late toxicity was scored based on RTOG and EORTC RTOG scales, respectively. Pain was evaluated using the Pain-Drug scores and the Visual Analog Scale (VAS). One hundred and eighty patients were eligible for inclusion in this retrospective analysis. Grade 3 and 4 acute toxicity rates were 1.1% and 0.0%, respectively. Mean VAS before and after HBI was 5.3 versus 2.7, respectively (p: 0.0001). Based on VAS, 37.5% of patients showed complete pain relief (VAS: 0) while 38.1% had partial response (>= 2-point VAS reduction). Overall, Pain and Drug Score reduction was observed in 76.3% and 50.4% of patients, respectively. 1-, 2-, and 3-year pain progression free survival was 77.0%, 63.4%, and 52.7%, respectively. Thirty patients (16.7%) underwent RT retreatment on the same site with median 15.9 months interval (range 2-126 months). HBI delivered with 3D-CRT technique is safe and effective. It provides long lasting pain control in patients with multiple BMs with negligible rates of relevant toxicity. PMID- 30251080 TI - Beneficial effects of Gelsemium-based treatment against paclitaxel-induced painful symptoms. AB - Chemotherapeutic drugs induce various side effects including painful peripheral neuropathy that represents a major concern. The widely used anticancer drug paclitaxel causes neurological side effects such as burning pain, allodynia, and hyperalgesia. Neuroprotective substances that may effectively counteract paclitaxel-induced neuropathic symptoms are needed. Here, we investigated the potential of Gelsemium sempervirens (GS) to counteract paclitaxel-evoked painful neuropathy in rats. Using the von Frey hair and acetone behavioral tests, we investigated the potential of GS centesimal (C) dilutions 3, 5, and 9C to prevent or to correct paclitaxel-induced cold allodynia and mechanical allodynia/hyperalgesia involved in neuropathic pain. We found that a prophylactic or corrective treatment with GS dilutions prevented or suppressed PAC-evoked cold allodynia and mechanical allodynia/hyperalgesia, by reversing to normal, decreased cold thermal and mechanical pain thresholds of PAC-treated rats. In particular, preventive or corrective treatments with GS dilution 3C counteracted PAC-evoked allodynic and hyperalgesic responses. Also, GS dilution 5C (in a lesser extent than 3C) significantly reduced PAC-induced mechanical allodynia/hyperalgesia while GS dilution 9C was ineffective. PAC-evoked neuropathic symptoms were efficiently reduced after 1 week treatment with GS dilutions 3 or 5C and the beneficial action increased after 2 weeks. GS dilutions, particularly 3C, also counteracted or prevented PAC-induced sciatic nerve axon alterations and decreased the density of intraepidermal nerve fibers. Altogether, these results obtained in the rat preclinical model suggest that GS dilution-based treatment may constitute an interesting option to explore for the long-term management of pain without undesirable effects. PMID- 30251081 TI - Correction to: Enhancing the Relevance and Effectiveness of a Youth Gambling Prevention Program for Urban, Minority Youth: A Pilot Study of Maryland Smart Choices. AB - The article Enhancing the Relevance and Effectiveness of a Youth Gambling Prevention Program for Urban, Minority Youth: A Pilot Study of Maryland Smart Choices, written by Brittany R. Parham, Carl Robertson, Nancy Lever, Sharon Hoover, Tracy Palmer, Phyllis Lee, Kelly Willis and Joanna Prout, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 18 August 2018 with open access. With the author(s)' decision to step back from Open Choice, the copyright of the article changed on 10 September 2018 to (c) Springer Science+Business Media, LLC, part of Springer Nature 2018 and the article is forthwith distributed under the terms of copyright.The original article has been corrected. PMID- 30251084 TI - Authors' Reply to Valenzuela et al: Comment on: "Assessment of Skeletal Muscle Contractile Properties by Radial Displacement: The Case for Tensiomyography". PMID- 30251082 TI - Continuous Exposure to Inorganic Mercury Affects Neurobehavioral and Physiological Parameters in Mice. AB - Contamination with mercury is a real health issue for humans with physiological consequences. The main objective of the present study was to assess the neurotoxicological effect of inorganic mercury: HgCl2. For this, adult mice were exposed prenatally, postnatally, and during the adult period to a low level of the metal, and their behavior and antioxidant status were analyzed. First, we showed that mercury concentrations in brain tissue of treated animals showed significant bioaccumulation, which resulted in behavioral deficits in adult mice. Thus, the treated mice developed an anxiogenic state, as evidenced by open field and elevated plus maze tests. This anxiety-like behavior was accompanied by a decrease in social behavior. Furthermore, an impairment of memory in these treated mice was detected in the object recognition and Y-maze tests. The enzymatic activity of the antioxidant system was assessed in eight brain structures, including the cerebral cortex, olfactory bulb, hippocampus, hypothalamus, mesencephalon, pons, cerebellum, and medulla oblongata. The results show that chronic exposure to HgCl2 caused alterations in the activity of catalase, thioredoxin reductase, glutathione peroxidase, superoxide dismutase, and glutathione S-transferase, accompanied by peroxidation of membrane lipids, indicating a disturbance in intracellular redox homeostasis with subsequent increased intracellular oxidative stress. These changes in oxidative stress were concomitant with a redistribution of essential heavy metals, i.e., iron, copper, zinc, and magnesium, in the brain as a possible response to homeostatic dysfunction following chronic exposure. The alterations observed in overall oxidative stress could constitute the basis of the anxiety-like state and the neurocognitive disorders observed. PMID- 30251083 TI - Survey of coastal inland pollution sources and their influence on seawater quality in Doam bay, Korea. AB - Inland pollution sources of Doam bay were investigated from August to October in 2013. A total of 210 sources including rivers, streams, domestic, agricultural and industrial discharge points were identified along the coast, including 32 sources that had outflow. Agricultural sources were the largest inland pollution sources (139, 66.2%). Fecal coliform concentrations were measured. These data were combined with water discharge data to determine daily loads of pollutants discharged from each source into the bay. Fecal coliform concentrations were the highest in domestic discharges. However, they only had slight influence because their discharge volume was small. The most significant pollution source was Tamjin River (St.85) due to large amount of discharge volume. The influence of St.85 reached almost half of Doam bay. Fecal coliform levels of streams increased after rainfall, but decreased overtime. Domestic pollution sources were not affected upon rain event. PMID- 30251085 TI - Comment on: "Assessment of Skeletal Muscle Contractile Properties by Radial Displacement: The Case for Tensiomyography". PMID- 30251087 TI - Structural Identification and Systematic Comparison of Phorbol Ester, Dioleoylglycerol, Alcohol and Sevoflurane Binding Sites in PKCdelta C1A Domain. AB - Protein kinase C (PKC) is a family of signal transducing enzymes that have been implicated in anesthetic preconditioning signaling cascade. Evidences are emerging that certain exogenous neuromodulators such as n-alkanols and general anesthetics can stimulate PKC activity by binding to regulatory C1A domain of the enzyme. However, the accurate binding sites in C1A domain as well as the molecular mechanism underlying binding-stimulated PKC activation still remain unelucidated. Here, we report a systematic investigation of the intermolecular interaction of human PKCdelta C1A domain with its natural activator phorbol ester (PE) and co-activator dioleoylglycerol (DOG) as well as exogenous stimulators butanol, octanol and sevoflurane. The domain is computationally identified to potentially have three spatially vicinal ligand-binding pockets 1, 2 and 3, in which the pockets 1 and 2 have previously been determined as the binding sites of PE and DOG, respectively. Systematic cross-binding analysis reveals that long chain octanol and DOG are well compatible with the flat, nonpolar pocket 2, where the nonspecific hydrophobic contacts and van der Waals packing are primarily responsible for the binding, while the general anesthetic sevoflurane prefer to interact with the rugged, polar pocket 3 through specific hydrogen bonds and electrostatic forces. Short-chain butanol appears to bind effectively none of the three pockets. In addition, the pocket 1 consists of two angled arms 1 and 2 that are also involved in pockets 2 and 3, respectively. Dynamics characterization imparts that binding of long-chain octanol and DOG to pocket 2 or binding of sevoflurane to pocket 3 can induce a conformational displacement in arm 1 or 2, thus further opening the included angle and enlarging pocket 1, which can improve the pocket 1-PE affinity via an allosteric mechanism, consequently stimulating the PE-induced PKCdelta activation. PMID- 30251088 TI - Pre-operative Very Low Calorie Ketogenic Diet (VLCKD) vs. Very Low Calorie Diet (VLCD): Surgical Impact. AB - BACKGROUND: Pre-operative diet may play an important role as far as patients' fitness for surgery, post-operative outcomes, and successful weight loss. Our aim was to compare surgical outcome and weight loss in two groups of patients who were offered two different pre-operative kinds of diet: very low calorie diet (VLCD) and very low calorie ketogenic diet (VLCKD). METHODS: Patients candidate for bariatric surgery (laparoscopic sleeve gastrectomy) were registered and assessed according to pre- and post-diet BMI, operative time, hospital stay, drainage output, and hemoglobin (Hb) levels. Patients' preference influenced the type of diet. RESULTS: From January to December 2016, 178 patients (139 F and 39 M) were enrolled in this study. The mean age was 43 years. In total, 72 patients were on VLCKD while 106 patients on VLCD. Pre-diet mean BMI was 46.3 +/- 6.3 kg/m2 for VLCKD group and 43.1 +/- 6.9 kg/m2 for VLCD group, while immediately pre-op BMI were 43.9 +/- 5.9 kg/m2 and 41.9 +/- 6.8 kg/m2, respectively. Drainage output and hemoglobin levels after surgery resulted significantly correlated with diet induced BMI reduction (141.2 +/- 75.8 vs. 190.7 +/- 183.6 ml, p = 0.032; 13.1 +/- 1.2 vs. 12.7 +/- 1.5 g/l, p = 0.04). The percentage of patients requiring a hospital stay longer than anticipated (> 3 days) was 2.8% in the VLCKD group and 10.4% in the VLCD group (p = 0.048). CONCLUSIONS: In our experience, VLCKD showed better results than VLCD on surgical outcome, influencing drainage output, post-operative hemoglobin levels, and hospital stay. PMID- 30251086 TI - Athlete's Heart: Diagnostic Challenges and Future Perspectives. AB - Distinguishing between adaptive and maladaptive cardiovascular response to exercise is crucial to prevent the unnecessary termination of an athlete's career and to minimize the risk of sudden death. This is a challenging task essentially due to the substantial phenotypic overlap between electrical and structural changes seen in the physiological athletic heart remodeling and pathological changes seen in inherited or acquired cardiomyopathies. Stress testing is an ideal tool to discriminate normal from abnormal cardiovascular response by unmasking subtle pathologic responses otherwise undetectable at rest. Treadmill or bicycle electrocardiography, transthoracic echocardiography, and cardiopulmonary exercise testing are common clinical investigations used in sports cardiology, specifically among participants presenting with resting electrocardiographic abnormalities, frequent premature ventricular beats, or non sustained ventricular arrhythmias. In this setting, as well as in cases of left ventricular hypertrophy or asymptomatic left ventricular dysfunction, stress imaging and myocardial tissue characterization by cardiovascular magnetic resonance show promise. In this review, we aimed to reappraise current diagnostic schemes, screening strategies and novel approaches that may be used to distinguish adaptive remodeling patterns to physical exercise from early phenotypes of inherited or acquired pathological conditions commanding prompt intervention. PMID- 30251089 TI - Conversions After Sleeve Gastrectomy for Weight Regain: to Single and Double Anastomosis Duodenal Switch and Gastric Bypass at a Single Institution. AB - BACKGROUND: With the increase in popularity of laparoscopic sleeve gastrectomy (LSG), the number of patients experiencing weight regain has increased as well. This study aims to demonstrate the outcomes of LSG conversions to Roux-en-Y gastric bypass (RYGB), double anastomosis duodenal switch (DS), and single anastomosis duodeno-ileal sleeve (SADI-S) due to weight regain. METHODS: A retrospective chart review was performed on 21 patients who underwent a conversion of LSG due to weight regain between March 1, 2013, and April 30, 2017. A longitudinal analysis was performed for the body mass index (BMI) measures, using multilevel model for change. RESULTS: Of 21 patients, 6 underwent a conversion to RYGB, 9 underwent a conversion to SADI-S, and 6 underwent a conversion to double anastomosis DS. Mean percentage of total weight loss was 16.0% at 6 months, 20.1% at 12 months, 18.8% at 24 months, and 21.8% at 36 months after the procedure. The final model suggests that preoperative BMI is the most significant indicator for initial status and the rate of change in BMI. Adjusting for preoperative BMI, type of procedure significantly affected the rate of change in BMI. The rate of decrease was fastest in RYGB patients, adjusting for preoperative BMI. One patient was readmitted 26 days after the conversion for pulmonary embolism and intraabdominal hematoma, and no patient required a reoperation within 30 days after the conversion. CONCLUSION: Conversions of LSG to RYGB, double anastomosis DS, and SADI-S are safe and can provide significant additional weight loss. PMID- 30251090 TI - Clinical Outcomes of Laparoscopic Greater Curvature Plication and Laparoscopic Sleeve Gastrectomy: a Case-Matched Control Study. AB - BACKGROUND: Laparoscopic greater curvature plication (LGCP) is a new bariatric procedure that is similar to laparoscopic sleeve gastrectomy (LSG) in that it uses a restrictive mechanism. Comparative studies between LGCP and LSG were still limited. The aim of this study was to compare the clinical outcomes of the two procedures based on the same clinical conditions. METHODS: From January 2012 to December 2015, 260 patients with morbid obesity underwent LGCP and LSG in a single center. Data on patient demography, operation time, complications, hospital stay, body mass index loss, percentage of excess weight loss (%EWL), and improvement in comorbidities were collected. A propensity-matched analysis, incorporating pre-operative variables, was used to compare the short-term outcomes between LGCP and LSG. RESULTS: Propensity matching produced 48 patients in each group. Patients who underwent LGCP were predominately female (75.5%, 41.1% of the LSG patients were female, p = 0.028). Baseline BMI and excess weight were significantly lower in the LGCP group (p < 0.001). The LSG group showed a greater decrease in excess body weight than the LGCP group (LSG, 47.36 +/- 12.95% in 3 months, 57.97 +/- 19.28% in 6 months, 66.28 +/- 25.42% in 12 months; LGCP, 39.67 +/- 12.58% in 3 months, 47.40 +/- 19.30% in 6 months, 48.02 +/- 20.17% in 12 months, p = 0.008, 0.032, 0.010). Perioperative complications and resolution of obesity-related comorbidities were not significantly different between the two groups. CONCLUSION: LGCP and LSG are both feasible and safe procedures for surgical weight reduction. In short-term follow-ups, LSG demonstrates a better excess body weight reduction while having perioperative complications similar to LGCP. PMID- 30251091 TI - Comparative Effectiveness of Different Bariatric Procedures in Super Morbid Obesity. AB - BACKGROUND: Super obesity (BMI >= 50 kg/m2) is associated with significant morbidity and mortality. The best procedure to treat super obesity is not completely established. Our aim was to compare the effectiveness of bariatric procedures (adjustable gastric band [AGB], Roux-en-Y gastric bypass [RYGB], sleeve gastrectomy [SG]) in super obesity. METHODS: Retrospective observational study of super obese patients who underwent bariatric surgery. Data was assessed preoperatively and in the 1st and 2nd years of follow-up. RESULTS: We evaluated 213 individuals, 77.9% female, age of 43.38 +/- 11.49 years, and preoperative BMI of 54.53 +/- 4.54 kg/m2; 19 submitted to AGB, 127 to RYGB, and 67 to SG. In the pre-surgical assessment, there were no significant differences in age, anthropometric parameters, blood pressure, glycemic profile, and lipid profile between the three surgical groups. The percentage of excess weight loss (%EWL) in the 1st year was 67.58% in RYGB, 58.74% in SG, and 38.71% in AGB (p < 0.001), and the percentage of total weight loss (%TWL) was 36.29%, 31.59%, and 21.07%, respectively (p < 0.001). Two years after surgery (n = 147; follow-up rate of 69%), the %EWL and %TWL were significantly higher in the RYGB group (p < 0.001). RYGB had a higher success rate (%EWL >= 50% and %TWL >= 20%) in both years of follow-up (p < 0.001). In multiple linear regression, after adjusting for other covariates, RYGB was the only strong predictive factor of %EWL and %TWL (p < 0.001). CONCLUSION: RYGB proved to be more effective in super obesity. The beneficial effects in weight loss were evident both 1 and 2 years after the procedure, regardless of pre-surgical anthropometric characteristics. PMID- 30251092 TI - Weight Loss Outcomes of Laparoscopic Adjustable Gastric Band with Plication: a Single Center Experience of 66 Patients with 18-Month Follow-Up. AB - BACKGROUND: Laparoscopic adjustable gastric band with plication (LAGBP) is a novel bariatric procedure, which combines the adjustability of the laparoscopic adjustable gastric band (LAGB) with the restrictive nature of the vertical sleeve gastrectomy (VSG). The addition of plication of the stomach to LAGB should provide better appetite control, more effective weight loss, and greater weight loss potential. The purpose of the study was to analyze the outcomes of LAGBP at 18 months. METHODS: Data from all patients who underwent a primary LAGBP procedure from December 2011 through June 2016 were retrospectively analyzed. Data collected from each patient included age, gender, weight, body mass index (BMI), and excess weight loss (EWL). RESULTS: Sixty-six patients underwent LAGBP. The mean age and BMI were 44.6 +/- 12.7 years and 42.1 +/- 5.1 kg/m2, respectively. The patients lost an average of 49% and 46.8% EWL at 12 months (77.2% follow-up) and 18 months (66.1% follow-up), respectively. The mean band adjustments were 2.1 +/- 1.7 (range, 0-7) per patient in 1 year. The mean additional adjustment volume (infusion and withdrawal of saline) was 0.6 +/- 1 cc. Dysphagia was the most common long-term complication. The band removal rate was 7.5%. The mortality rate was 0%. CONCLUSIONS: LAGBP is a relatively safe and effective bariatric procedure. In light of recent studies demonstrating poor outcomes following LAGB, LAGBP may prove to be the future for patients desiring a bariatric procedure without resection of the stomach. PMID- 30251093 TI - The Relationship Between Histopathologic Findings and Body Mass Index in Sleeve Gastrectomy Materials. AB - OBJECTIVE: For treatment of obesity, which is one of the important health problems of the present time, lifestyle modification, pharmacotherapy, behavioral treatment methods, and surgical procedures are commonly used. Sleeve gastrectomy is widely used among surgical procedures. We aimed to investigate the relationship between histopathologic findings and body mass indices (BMIs) of cases with sleeve gastrectomy in our study. METHODS: Thirty-seven patients were included in our study who underwent sleeve gastrectomy and whose operation materials were examined histopathologically in our hospital. Two pathologists re evaluated all gastrectomy materials. The relationship between BMI and the presence of gastritis, atrophy, intestinal metaplasia (IM), Helicobacter pylori (HPL), and other histopathological findings was investigated. RESULTS: The mean age of patients included in the study was 34.7 + 9.3 years. Of patients, 70.3% were female and 29.7% were male. There was a statistically significant difference between BMI and IM among the evaluated histopathologic parameters. Moreover, IM was significantly more present in patients with type 2 diabetes. CONCLUSIONS: There is no previous study investigating the relationship between gastric histopathological findings and BMI in sleeve gastrectomy patients. We think that the statistically significant difference between BMI and IM that we found in our study may shed light on studies to be performed in the future. PMID- 30251094 TI - Validating Risk Prediction Models of Diabetes Remission After Sleeve Gastrectomy. AB - INTRODUCTION: Many risk prediction models of diabetes remission after bariatric and metabolic surgery have been proposed. Most models have been created using Roux-en-Y gastric bypass cohorts. However, validation of these models in sleeve gastrectomy (SG) is limited. The objective of our study is to validate the performance of risk prediction models of diabetes remission in obese patients with diabetes who underwent SG. METHOD: This retrospective cohort study included 128 patients who underwent SG with at least 1 year follow-up from Dec 2011 to Sep 2016 as the validation cohort. A literature review revealed total 11 models with 2 categories (scoring system and logistic regression), which were validated by our study dataset. Discrimination was evaluated by area under the receiver operating characteristic (AUC) while calibration by Hosmer-Lemeshow test and predicted versus observed remission ratio. RESULTS: At 1 year after surgery, 71.9% diabetes remission (HbA1c < 6.0 off medication) and 61.4% excess weight loss were observed. Individual metabolic surgery, ABCD, DiaRem, Advanced-DiaRem, DiaBetter, Ana et al., and Dixon et al. models showed excellent discrimination power (AUC > 0.8). In calibration, all models overestimated diabetes remission from 5 to 30% but did not lose their goodness of fit. CONCLUSION: This is the first comprehensive external validation of current risk prediction models of diabetes remission at 1 year after SG. Seven models showed excellent predicting power, and scoring models were recommended more because of their easy utility. PMID- 30251095 TI - Outcomes of Reoperation After Laparoscopic Gastric Plication Failure. AB - BACKGROUND: Management of failed laparoscopic gastric plication (LGP), defined as weight regain or inadequate weight loss, is a challenging issue. METHODS: This prospective investigation was conducted in individuals with morbid obesity who had undergone LGP from 2000 to 2016. Patients with weight loss failure, weight regain, and regain-prone cases were indicated for reoperation. Re-plication, laparoscopic one anastomosis gastric bypass (LOAGB), and modified jejunoileal bypass were done as revisional surgery. RESULTS: Revisional surgery was performed in 102 of 124 patients who needed reoperation. Overall, 39 re-plication, 38 LOAGB, and 25 malabsorptive procedures were performed. Re-plication was the shortest surgery and had the shortest length of hospital stay. The percentage of TWL at 6, 12, and 24 months of follow-up was 20.5%, 25%, and 26.8% for re plication; 20.2%, 27%, and 30.5% for LOAGB; and 22.9%, 28.9%, and 32.6% for the malabsorptive procedure, respectively. In addition, the percentage of EWL at 6, 12, and 24 months of follow-up was 62%, 74.6%, and 79.6% for re-plication; 51.6%, 68.2%, and 75.9% for LOAGB; and 55.4%, 70.1%, and 79.1% for malabsorptive procedure, respectively. In long-term follow-up, according to %TWL, LOAGB and malabsorptive procedure had better outcome compared to re-plication, whereas there was no statistically significant difference in %EWL among the three surgical approaches. CONCLUSIONS: In terms of weight loss, reoperation on failed LGP was completely successful and no treatment failure was reported. All three revisional procedures, including re-plication, LOAGB, and malabsorptive procedure showed promising results and provided substantial weight loss. Since there is little information about the long-term efficacy and safety of revisional surgery on failed LGP, we highly recommend further investigations to confirm our results. PMID- 30251096 TI - Pre- and Postbariatric Subtypes and Their Predictive Value for Health-Related Outcomes Measured 3 Years After Surgery. AB - BACKGROUND: Although bariatric surgery is the most effective treatment for severe obesity, a subgroup of patients shows insufficient postbariatric outcomes. Differences may at least in part result from heterogeneous patient profiles regarding reactive and regulative temperament, emotion dysregulation, and disinhibited eating. This study aims to subtype patients based on these aspects before and 2 years after bariatric surgery and tests the predictive value of identified subtypes for health-related outcomes 3 years after surgery. METHODS: Within a prospective multicenter patient registry, N = 229 bariatric patients were examined before bariatric surgery, 2 and 3 years postoperatively via clinical interviews and self-report questionnaires. Pre- and postbariatric subtypes were differentiated by temperament, emotion dysregulation, and disinhibited eating using latent profile analyses (LPA). The predictive value of pre- and postbariatric subtypes for surgery outcomes measured 3 years postoperatively was tested via linear regression analyses. RESULTS: LPA resulted in five prebariatric and three postbariatric subtypes which were significantly associated with different levels of general and eating disorder psychopathology. Post- versus prebariatric subtypes explained more variance regarding eating disorder psychopathology, depression, and quality of life assessed 3 years postoperatively, whereas neither pre- nor postbariatric subtypes predicted postbariatric weight loss. Patients with prebariatric deficits in self- and emotional control had an increased risk for showing these deficits postoperatively. CONCLUSIONS: A re-evaluation of patients' psychological status after bariatric surgery is recommended to detect patients with potential risk for adverse psychological surgery outcomes in the long term. PMID- 30251097 TI - Sleeve Gastrectomy with Bypass of Proximal Small Intestine Provides Better Diabetes Control than Sleeve Gastrectomy Alone Under Postoperative High-Fat Diet. AB - BACKGROUND: Sleeve gastrectomy (SG) plus procedures have been developed to strengthen the effect of SG on diabetes control. The aim of this study was to compare diabetes control after SG plus bypass of the proximal small intestine with SG alone under adverse conditions for diabetes remission. METHODS: SG plus duodenojejunal bypass (SG-DJB), SG plus jejunojejunal bypass (SG-JJB), SG alone, and sham surgeries were performed in diabetic rats. A high-fat diet (HFD) was fed postoperatively to induce diabetes recurrence. Body weight, food intake, glucose tolerance, insulin sensitivity, serum hormones, hepatic function, and lipid profiles were measured postoperatively. RESULTS: SG-DJB, SG-JJB, and SG groups exhibited significant improvement in glucose tolerance and insulin sensitivity compared with the sham-operated group at 2 weeks postoperatively. Postoperative HFD induced obvious diabetes relapse and re-impaired insulin sensitivity at 16 weeks postoperatively. The SG-DJB and SG-JJB groups exhibited superior glucose tolerance and similar insulin sensitivity to SG alone at 16 weeks postoperatively. Compared with the SG alone, the SG-DJB and SG-JJB groups exhibited similar food intake, weight loss, fasting ghrelin, glucose-stimulated insulin secretion, and higher glucose-stimulated GLP-1 secretion. CONCLUSION: SG DJB and SG-JJB provided better diabetes control than SG alone in rats fed a HFD postoperatively. Further clinical studies are expected to confirm the superiority of SG plus bypass of proximal small intestine. PMID- 30251098 TI - Changes in Body Composition, Dietary Intake, and Substrate Oxidation in Patients Underwent Laparoscopic Roux-en-Y Gastric Bypass and Laparoscopic Sleeve Gastrectomy: a Comparative Prospective Study. AB - PURPOSE: Laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) are the most popular procedures to treat morbid obesity among bariatric surgeries. However, only few studies have compared the changes in body composition, dietary intake, and substrate oxidation after LRYGB and LSG. Therefore, the present study was conducted to compare the changes in body composition, dietary intake, and substrate oxidation 6 months postoperatively in obese patients who underwent LRYGB and LSG. MATERIALS AND METHODS: In this prospective study, a total of 43 adult obese patients participated (LRYGB = 22 and LSG = 21). Their body composition was measured by bioelectric impedance analysis. Dietary intake was assessed using 3-day food record. Substrate oxidation was measured by indirect calorimetry. All participants were followed up for 6 months. RESULTS: The percentage of weight loss was 22.8 +/- 4.5 and 23.3 +/ 5.7% in LRYGB and LSG, respectively. Fat mass (FM), fat-free mass (FFM), and percentage of fat mass (PFM) significantly reduced in LRYGB and LSG, while the percentage of fat-free mass (PFFM) significantly increased in both surgeries. Dietary energy intake significantly reduced by 63.5 +/- 30.6% in LRYGB and 66.7 +/- 20.1% in LSG. Dietary intake of protein, carbohydrate, fat, and fiber significantly decreased in each group. The percentage of energy from protein, carbohydrate, and fat did not change in each group. Protein oxidation and carbohydrate oxidation significantly reduced in both procedures postoperatively. Changes in body composition, dietary intake, and substrate oxidation from baseline were equal in LRYGB and LSG. CONCLUSION: Therefore, LRYGB and LSG have similar effect on total and regional FM and FFM, dietary macronutrients intake, and substrate oxidation. PMID- 30251099 TI - The Expression and Cellular Localisation of Neurotrophin and Neural Guidance Molecules in Peritoneal Ectopic Lesions. AB - Endometriosis is a gynaecological disorder characterised by the presence of endometrial-like tissue outside the uterus. It affects 10-15% of women during their reproductive age. The existence of close and complex relationship between chronic pelvic pain and endometriosis are widely recognised. However, the mechanisms of pain generation in women with endometriosis remain poorly understood. Immunohistochemistry was used to assess the density of nerve fibres stained with protein gene product 9.5 (PGP9.5) and the expression of various neurotrophins including glial cell derived neurotrophic factor (GDNF), persephin, neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) and neuronal guidance molecules semaphorin 3E and Slit-2 and their receptors Plexin-D1 and Robo4 in peritoneal ectopic lesions from women with endometriosis and uninvolved peritoneum samples. Neurotrophins and neuronal guidance molecules and their receptors are synthesised in situ within peritoneal ectopic lesion which suggest their role in facilitating and maintaining the growth of nerve fibres. These molecules were found to be overall most highly expressed in the glands of endometriotic peritoneal lesions. In addition, the presence of ectopic lesions within the peritoneal cavity may affect the environment; in turn, the peritoneum altered appeared to play a role in the growth of nerve fibres and their development and maintenance in peritoneal lesions. Through exploring different neuronally active factors in and around ectopic lesions which may be contributing to pain generation, this study provides an insight and better understanding of the pain mechanisms associated with peritoneal endometriosis. PMID- 30251100 TI - Meniscal repair concurrent with anterior cruciate ligament reconstruction restores posterior shift of the medial meniscus in the knee-flexed position. AB - PURPOSE: The purpose of this study was to evaluate the shape and shift of the medial meniscus before and after meniscal repair concurrent with anterior cruciate ligament (ACL) reconstruction using magnetic resonance imaging (MRI) at 90 degrees of knee flexion. METHODS: This study included 18 patients with ACL deficient knees without meniscus tears (group A), 11 patients with medial meniscus tears alone (group M), and 15 patients with ACL-deficient knees complicated with medial meniscus tears (group AM). The posterior segment shape was evaluated using open MRI at 90 degrees of knee flexion preoperatively and at 3 months postoperatively. The length, height, width, and posterior extrusion of the medial meniscus and posterior tibiofemoral distance were measured. These measurements were compared between the three groups. RESULTS: On preoperative MRI, a significant difference was observed in the posterior extrusion of the medial meniscus (group A, 1.2 +/- 0.5 mm; group M, 1.7 +/- 0.3 mm; group AM, 4.1 +/- 1.5 mm, p < 0.001). All parameters did not differ between the three groups on postoperative MRI. In addition, the posterior width and extrusion of the medial meniscus were decreased significantly after meniscal repair concurrent with ACL reconstruction. CONCLUSIONS: This study demonstrated that the medial meniscus shifted posteriorly at 90 degrees of knee flexion in ACL-deficient knees complicated with medial meniscus tears. Medial meniscal repair concurrent with ACL reconstruction improved the deformed morphology and posterior extrusion. MRI measurements of the posterior extrusion at the knee-flexed position may be clinically useful to assess the functional improvement of the medial meniscus following meniscal repair combined with ACL reconstruction. LEVEL OF EVIDENCE: III. PMID- 30251101 TI - Determination of normal KOOS and WOMAC values in a healthy population. AB - PURPOSE: The KOOS questionnaire is used to assess the symptoms and function of patients with traumatic or degenerative knee pathology. The WOMAC score has been validated mainly in the context of knee osteoarthritis. The distribution of these scores in a non-diseased population is not known. The hypothesis was that KOOS and WOMAC scores were influenced by patients' age, sex, and BMI. The primary objective of this study was to describe, for the first time, the distribution of KOOS and WOMAC scores in a healthy population based on age, sex, and BMI. METHODS: This was a pilot (innovative), cross-sectional, international, multicenter, descriptive study. Persons accompanying patients to our clinic were invited to participate in this study by filling out the KOOS questionnaire. These data were also used to calculate the WOMAC score. The study was designed according to guidelines on pilot studies and planned to enroll a minimum of 30 subjects in each age, gender, and BMI group. Expected KOOS and WOMAC scores by age, gender, and BMI were determined using a linear regression model. RESULTS: Seven hundred and fourteen subjects were included: 305 men (42.7%) and 409 women (57.3%). For the KOOS score, as age increases, there was a decrease in the "ADL" (p = 0.0001) and "sport" (p = 0.0001) items and an increase in the "symptoms" (p = 0.0025) and "QOL" items (p = 0.0001). Women had lower scores (p < 0.05) than men on all the KOOS items, except "QOL". For the WOMAC, the "pain", "stiffness", and "function" items varied significantly based on age (p = 0.0203) and sex (p = 0.0121). The "stiffness" item varied significantly based on age (p = 0.0005) and sex (p = 0.0477). The "function" item varied significantly based on age (p = 0.0001) and sex (p = 0.0256). The expected value for the KOOS and WOMAC scores in a healthy population without any knee ailments were determined. CONCLUSIONS: The KOOS and WOMAC scores vary significantly based on age, sex, and BMI in a healthy population. This study also provides KOOS and WOMAC values in a population without any knee issue. These scores can be used, in a daily practice, as a reference to assess functional outcomes after a surgical procedure. LEVEL OF EVIDENCE: IV. PMID- 30251102 TI - Individual performance across motoric self-regulation tasks are not correlated for pet dogs. AB - Inhibitory control, the ability to restrain a prepotent but ineffective response in a given context, is thought to be indicative of a species' cognitive abilities. This ability ranges from "basic" motoric self-regulation to more complex abilities such as self-control. During the current study, we investigated the motoric self-regulatory abilities of 30 pet dogs using four well-established cognitive tasks - the A-not-B Bucket task, the Cylinder task, the Detour task, and the A-not-B Barrier task - administered in a consistent context. One main goal of the study was to determine whether the individual-level performance would correlate across tasks, supporting that these tasks measure similar components of motoric self-regulation. Dogs in our study were quite successful during tasks requiring them to detour around transparent barriers (i.e., the Cylinder and Detour tasks), but were less successful with tasks requiring the production of a new response (i.e., A-not-B Bucket and A-not-B Barrier tasks). However, individual dog performance did not correlate across tasks, suggesting these well established tasks likely measure different inhibitory control abilities, or are strongly influenced by differential task demands. Our results also suggest other aspects such as perseveration or properties of the apparatus may need to be carefully examined in order to better understand canine motoric self-regulation or inhibitory control more generally. PMID- 30251103 TI - Effect of age on discrimination learning, reversal learning, and cognitive bias in family dogs. AB - Several studies on age-related cognitive decline in dogs involve laboratory dogs and prolonged training. We developed two spatial tasks that required a single 1-h session. We tested 107 medium-large sized dogs: "young" (N=41, aged 2.5-6.5 years) and "old" (N=66, aged 8-14.5 years). Our results indicated that, in a discrimination learning task and in a reversal learning task, young dogs learned significantly faster than the old dogs, indicating that these two tasks could successfully be used to investigate differences in spatial learning between young and old dogs. We also provide two novel findings. First, in the reversal learning, the dogs trained based on the location of stimuli learned faster than the dogs trained based on stimulus characteristics. Most old dogs did not learn the task within our cut-off of 50 trials. Training based on an object's location is therefore more appropriate for reversal learning tasks. Second, the contrast between the response to the positive and negative stimuli was narrower in old dogs, compared to young dogs, during the reversal learning task, as well as the cognitive bias test. This measure favors comparability between tasks and between studies. Following the cognitive bias test, we could not find any indication of differences in the positive and negative expectations between young and old dogs. Taken together, these findings do not support the hypothesis that old dogs have more negative expectations than young dogs and the use of the cognitive bias test in older dogs requires further investigation. PMID- 30251105 TI - Domesticated dogs (Canis familiaris) tend to follow repeated deceptive human cues even when food is visible. AB - There is abundant evidence that domestic dogs (Canis familiaris) readily follow pointing and other cues given by humans. But there has been much less research into the question of whether dogs can learn to discriminate between different humans giving repeated honest or dishonest cues as to food location, by ignoring the information imparted by the deceiver. Prior research has demonstrated that even after repeated exposures to deceptive cues with respect to food location, dogs failed to learn to ignore those cues completely. Kundey, De Los Reyes, Arbuthnot, Coshun, Molina, and Royer (2010) found the same outcome in a similar experiment. The purpose of the current experiment was to determine if dogs could learn to discriminate between an honest and a deceptive human by ignoring the deceiver's cues even when it was obvious that the container being pointed at was not baited by using two transparent containers. Eight dogs were tested. On 20 cooperator trials, the experimenter stood behind the baited container and cued the dog, located midway between the containers and 3 m away, to approach it. On 20 deceiver trials, a different experimenter stood behind the empty container and cued the dog to approach that container. Results replicated prior research in that, even though the containers were transparent, the dogs failed to learn to distrust the deceiver completely and went to the empty and indicated container on more than half of the deceiver trials. PMID- 30251106 TI - North American river otters (Lontra canadensis) discriminate between 2D objects varying in shape and color. AB - We investigated the ability of North American river otters (Lontra canadensis) to visually discriminate between 2D objects. The otters learned to discriminate between stimuli using multiple visual features and then were tested with stimuli in which one of the features was eliminated (color or shape). Two adult otters were trained in a two-alternative forced choice task to discriminate between a red circle and a blue triangle. Test sessions included probe trials containing novel shapes, colors, or shape-color combinations. Both otters successfully learned to discriminate between stimuli varying in multiple features. One of the otters was able to successfully discriminate between novel test stimuli when either color or shape were eliminated as salient features. This study was the first to explore the ability of L. canadensis to use different visual features to recognize objects and provides some preliminary evidence for color vision in this species. This research adds to the sparse literature on perceptual and cognitive capabilities in otters and can be used to support future conservation efforts for this species. PMID- 30251108 TI - Lack of Correlation of Carotid Intima-Media Index and Peripheral Artery Disease. AB - INTRODUCTION: Increased carotid intima-media thickness (IMT) measurement is usually seen as a surrogate marker of peripheral artery disease (PAD) but there is scarce cumulated evidence to support this view. AIM: To evaluate prevalence of increased IMT among patients with symptomatic PAD as well as the frequency of some cardiovascular risk factors in these patients. METHODS: They were recruited 230 patients with diagnosis of medium peripheral artery disease in the Vascular Surgery Service outpatient's office. Serum cystatin C, homocysteine, and lipoprotein (a) were measured. GFR was estimated using the CKD-EPI equation and the Larsson one from cystatin C. RESULTS: The global prevalence of increased IMT was 16.5% (n = 38, 95% CI 12.3-21.9). In all the frequency of hyperlipoproteinemia (a) was 34.2% (95% CI 28.4-40.5%). The global prevalence of hyperhomocysteinemia was 61.5% (95% CI 54.6-68.1%) and the proportion of patients with high cystatin C levels was 38.5% (95% CI 32.1-42.5). The prevalence of stage III chronic kidney disease or higher by CKD-EPI formula was much lesser (13.6%, 95% CI 9.7-18.7) as was the frequency obtained by the Larsson equation (28.7%, 95% CI 23.2-34.9). No differences were found between groups. CONCLUSIONS: Increased IMT is not common among PAD patients. Hyperlipoproteinemia (a) and hyperhomocysteinemia are very frequent in these patients. High serum cystatin levels are also very prevalent but reduced GFR is not so frequent. There were no differences in the prevalence of the studied cardiovascular risk factors between those patients with increased IMT and those ones with normal IMT. PMID- 30251104 TI - In what sense are dogs special? Canine cognition in comparative context. AB - The great increase in the study of dog cognition in the current century has yielded insights into canine cognition in a variety of domains. In this review, we seek to place our enhanced understanding of canine cognition into context. We argue that in order to assess dog cognition, we need to regard dogs from three different perspectives: phylogenetically, as carnivoran and specifically a canid; ecologically, as social, cursorial hunters; and anthropogenically, as a domestic animal. A principled understanding of canine cognition should therefore involve comparing dogs' cognition with that of other carnivorans, other social hunters, and other domestic animals. This paper contrasts dog cognition with what is known about cognition in species that fit into these three categories, with a particular emphasis on wolves, cats, spotted hyenas, chimpanzees, dolphins, horses, and pigeons. We cover sensory cognition, physical cognition, spatial cognition, social cognition, and self-awareness. Although the comparisons are incomplete, because of the limited range of studies of some of the other relevant species, we conclude that dog cognition is influenced by the membership of all three of these groups, and taking all three groups into account, dog cognition does not look exceptional. PMID- 30251107 TI - Complement activation is associated with more severe course of diarrhea associated hemolytic uremic syndrome, a preliminary study. AB - Diarrhea-associated hemolytic uremic syndrome is characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury secondary to enteric infection, typically Shiga toxin-producing Escherichia coli. Shiga toxin 2 is able to activate alternative complement pathways; therefore, the aim of the study was to analyze C3 as a predictor of clinical courses in patients with diarrhea associated hemolytic uremic syndrome. We hypothesized that the patients with increased complement activation at admission suffered from a more severe course. We retrospectively analyzed data of 33 pediatric patients between 1999 and 2015 in the Czech Republic. We tested the association of a C3 concentration with biochemical parameters and the clinical data reflecting the severity of the disease. We found significant correlation between the initial C3 and the duration of renal replacement therapy (r = - 0.62, p = 0.0001) and the initial glomerular filtration rate (r = 0.36, p = 0.026). Patients with C3 < 0.825 g/L needed renal replacement therapy and also had significantly more renal complications (p = 0.015).Conclusion: Based on our study, decreased C3 concentrations can be used as one of the risk factors that can help predict the need for acute dialysis and a more severe course of disease in children with diarrhea-associated hemolytic uremic syndrome. What is Known: * Shiga toxin modulates the function of complement regulatory proteins and thus contributes to complement activation in patients with diarrhea-associated hemolytic uremic syndrome. * Risk factors that can predict the need for acute renal replacement therapy and poor outcome in patients with diarrhea-associated hemolytic uremic syndrome are mainly the combination of oligoanuria, dehydration, leukocytosis, high hematocrit > 23%, and neurological involvement. What is New: * A lowered concentration of C3 at the time of initial presentation of diarrhea-associated hemolytic uremic syndrome was associated with more severe renal failure and the need for renal replacement therapy along with the development of more extra renal complications. * Decreased C3 at admission can predict complicated course of diarrhea-associated hemolytic uremic syndrome. PMID- 30251109 TI - Effects on Cardiovascular Risk Scores and Vascular Age After Aerobic Exercise and Nutritional Intervention in Sedentary and Overweight/Obese Adults with Primary Hypertension: The EXERDIET-HTA Randomized Trial Study. AB - INTRODUCTION: The EXERDIET-HTA study was a multi-arm parallel, a randomized, single-blind controlled experimental trial comparing the effects of 16 weeks of different aerobic exercise programs two days per week, and dietary intervention in a hypertensive, overweight/obese and non-physically active population. AIM: To evaluate the influence of diet and aerobic exercise program intervention on cardiovascular risk (CVR) factors and predicted CVR and vascular age (VA) profiles in overweight/obese people with primary hypertension (HTN), and to analyze the potential sex differences in the ability to predict VA and CVR via different methods. METHODS: The CVR and VA determined (n = 167, 53.7 +/- 7.8 years) using the Framingham Risk Score (FRS) and the new equation for the prediction of 10-year atherosclerotic cardiovascular disease (ASCVD) risk, before and after the 16-week intervention period (different aerobic exercise programs + hypocaloric diet). The sex-specific risk factors considered were age, high density lipoprotein cholesterol (HDL-C), total cholesterol, systolic blood pressure (SBP), diabetes mellitus (DM) and smoking status. RESULTS: From baseline to follow-up, participants reduced (p <= 0.001) FRS-CVR score and VA, and SBP. Total cholesterol decreased significantly, but specifically in men (p <= 0.001), and antihypertensive medication (%) in women (p = 0.047). No significant differences over time were observed for HDL-C, smoking, DM overall for either sex. For ASCVD-CVR there was no overall change or for either sex. After the intervention, women had a lower CVR score than men (p <= 0.001), irrespective of the calculation method. CONCLUSIONS: The improvement in CVR factors after 16-week lifestyle changes reduced the risk of suffering a cardiovascular event in overweight/obese adults with HTN through the FRS estimation tool, but not with the ASCVD score. The risk score algorithms could underestimate CVR in women. In contrast, VA could be a useful and easier tool in the management of individuals with CVR factors. PMID- 30251110 TI - Lowering Blood Pressure with the Combination of a Sodium-Glucose Cotransporter 2 Inhibitor and a Glucagon-like Peptide-1 Receptor Agonist in Type 2 Diabetic Patients: A Clinical Evidence. AB - INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) often have numerous cardiovascular risk factors, among which hypertension. AIM: To evaluate the blood pressure variations among patients treated with a combination of a sodium-glucose cotransporter 2 inhibitor (iSGLT-2) and a glucagon-like peptide-1 receptor agonist (GLP-1ra). METHODS: We analyze 17 patients treated with this combination to quantify the changes on blood pressure by ambulatory blood pressure monitoring at baseline and at three and 6 months follow-up. RESULTS: We observed a decrease of HbA1c levels (p = 0.004) at six months follow-up, a decrease in mean 24 h systolic blood pressure [from 124 (11) mmHg to 123 (4.75) mmHg, p = 0.04] and in both, mean waking and sleeping systolic blood pressure, being greater the reduction in the sleeping time [118 (20) mmHg to 111 (20) mmHg, p = 0.004]. CONCLUSION: The effect of a combination therapy of an iSGLT-2 and a GLP-1ra on blood pressure in a real-world setting, may have summative effects especially in SBP. PMID- 30251111 TI - [New support services for the care of young patients with rheumatic diseases]. AB - The transition process from pediatric to adult rheumatological and internistic care is a challenge for patients and medical personnel. Every second patient with a pediatric rheumatic disease has not achieved stable drug-free remission at early adulthood and therefore requires continuing rheumatological care. Approximately one third of young people with rheumatic diseases in Germany discontinue regular specialist care on their way to the adult healthcare setting. Newly developed support services and tools to improve the healthcare of young people with rheumatic diseases in Germany are presented. PMID- 30251112 TI - The pyrimidine biosynthetic pathway and its regulation in Pseudomonas jessenii. AB - The control of the pyrimidine biosynthetic pathway by pyrimidine bases was examined in Pseudomonas jessenii ATCC 700870. The pyrimidine biosynthetic enzymes aspartate transcarbamoylase, dihydroorotase, dihydroorotate dehydrogenase, orotate phosphoribosyltransferase, and orotidine 5'-monophosphate (OMP) decarboxylase activities were found to be higher in the succinate-grown ATCC 700870 cells than the glucose-grown cells. All the enzyme activities were depressed in uracil-supplemented ATCC 700870 glucose-grown cells relative to the unsupplemented cells which was indicative of possible repression of enzyme synthesis by uracil. In the succinate-grown, ATCC 700870 cells, transcarbamoylase, dihydroorotase and dehydrogenase activities were decreased by uracil and orotate supplementation while decarboxylase activity was decreased following uracil addition. A pyrimidine auxotroph was isolated by conventional chemical mutagenesis and resistance to 5-fluoroorotic acid whose pyrimidine requirement was met by uracil or cytosine. The mutant strain was deficient for orotate phosphoribosyltransferase activity. Pyrimidine limitation of the mutant strain cells for 1 or 2 h caused about a two-fold increase in aspartate transcarbamoylase or dihydroorotase activity independent of carbon source relative to excess uracil growth conditions. At the level of enzyme activity, aspartate transcarbamoylase activity in P. jessenii ATCC 700870 was inhibited strongly by pyrophosphate, ATP, UTP, GTP and UMP under saturating substrate concentrations. PMID- 30251114 TI - New FRAX-based intervention and assessment thresholds for the Ecuadorian population. PMID- 30251113 TI - Streptomyces polaris sp. nov. and Streptomyces septentrionalis sp. nov., isolated from frozen soil. AB - Two novel actinomycetes, designated strains ZLN81T and ZLN712T, were isolated from a frozen soil sample which was collected from the Arctic region. Chemotaxonomic and morphological characteristics were found to be typical of members of the genus Streptomyces. Based on 16S rRNA gene sequence analyses, the two strains show high similarity with Streptomyces polygonati NEAU-G9T (99.45%, 99.17%) and Streptomyces yanglinensis 1307T (98.17%, 98.10%). DNA-DNA relatedness between each of the strains and their close phylogenetic neighbours showed that they belonged to distinct species. Multilocus sequence analysis (MLSA) using four housekeeping genes (atpD, gyrB, recA and rpoB) for comparing Streptomyces type strains showed that the MLSA distance of strains ZLN81T and ZLN712T to the closely related species was greater than the 0.007 threshold. The cell wall amino acids of the two strains were identified as alanine, glycine, asparagine, ll diaminopimelic acid and meso-diaminopimelic acid. The whole cell sugars were identified as galactose and glucose for strain ZLN81T and galactose, glucose and xylose for strain ZLN712T. The predominant menaquinones were identified as MK 10(H8), MK-9(H4) and MK-9(H6) for strain ZLN81T and MK-9(H0), MK-10(H8) and MK 9(H6) for strain ZLN712T. The polar lipid profile of strain ZLN81T was found to contain diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannosides and two unidentified phospholipids, while that of strain ZLN712T consisted of diphosphatidylglycerol, phosphatidylethanolamine, a ninhydrin-positive glycophospholipid, phosphatidylinositol mannosides and two unidentified phospholipids. The major fatty acids were identified as iso-C16:0, anteiso-C17:0, C16:0 and anteiso-C15:0 for strain ZLN81T and iso-C16:0, C16:0, anteiso-C15:0 and iso-C14:0 for strain ZLN712T. The DNA G+C contents were found to be 73.96 and 72.77 mol% for strains ZLN81T and ZLN712T, respectively. On the basis of these phenotypic and genotypic data, strains ZLN81T (= CCTCC AA 2018010T = DSM 107255T) and ZLN712T (= CCTCC AA 2018011T = DSM 107266T) are concluded to represent two novel species of the genus Streptomyces, for which the names Streptomyces polaris sp. nov. and Streptomyces septentrionalis sp. nov. are proposed, respectively. PMID- 30251115 TI - Standardization of [F-18]FDG PET/CT for response evaluation by the Radiologic Society of North America-Quantitative Imaging Biomarker Alliance (RSNA-QIBA) profile: preliminary results from the Japan-QIBA (J-QIBA) activities for Asian international multicenter phase II trial. AB - PURPOSE: In an Asian international multicenter phase II trial conducted in patients with peripheral T-cell lymphoma (PTCL), [F-18]FDG-PET/CT was used for evaluation of the therapeutic response. Standardization of the PET/CT scanners was necessary before patient enrollment. We therefore standardized the scanners by phantom tests based on the profile approved by the Quantitative Imaging Biomarkers Alliance (QIBA) of Radiological Society of North America (RSNA). MATERIALS AND METHODS: The tests were conducted on 12 scanners in 12 facilities in compliance with the QIBA Profile and used National Electrical Manufacturers Association (NEMA) International Electrotechnical Commission (IEC) body phantoms. We measured three parameters (standardized uptake value [SUV], resolution and noise) and adjusted the imaging parameter values. The indexes recommended in the Japanese Society of Nuclear Medicine (JSNM) guideline were also evaluated. RESULTS: In a total of 12 facilities, 6 facilities required no change in imaging conditions and 6 facilities required changes in imaging parameters. After revision, the three measurements (SUV, resolution and noise) met QIBA criteria at all sites, but 10 of the 12 scanners did not meet JSNM criteria. CONCLUSION: We standardized imaging conditions using phantoms as required in the RSNA-QIBA profile for response evaluation by [F-18]FDG PET/CT images in a multicenter study. PMID- 30251116 TI - Hereditary colorectal cancer diagnostics in southern Sweden: retrospective evaluation and future considerations with emphasis on Lynch syndrome. AB - Overlapping phenotypes between different hereditary colorectal cancer (CRC) syndromes together with a growing demand for cancer genetic testing and improved sequencing technology call for adjusted patient selection and adapted diagnostic routines. Here we present a retrospective evaluation of family history of cancer, laboratory diagnostic procedure, and outcome for 372 patients tested for Lynch syndrome (LS), i.e., the single most common hereditary cause of CRC. Based on number of affected family members and age at cancer diagnosis in families with genetically confirmed LS, we developed local patient selection criteria for a simplified one-step gene panel mutation screening strategy targeting also less common Mendelian CRC syndromes. Pros and cons of this strategy are discussed. PMID- 30251117 TI - Inhibition of sonic hedgehog and PI3K/Akt/mTOR pathways cooperate in suppressing survival, self-renewal and tumorigenic potential of glioblastoma-initiating cells. AB - Since PI3K/Akt/mTOR and sonic hedgehog (SHH) signaling pathways are highly activated in glioblastoma-initiating cells (GICs), we examined the effects of inhibiting these pathways on GIC characteristics and tumor growth in mice. NVP LDE-225 (inhibitor of Smoothened) inhibited the expression of Gli1, Gli2, Smoothened, Patched1, and Patched2, and induced the expression of SuFu, whereas NVP-BEZ-235 (dual inhibitor of PI3K and mTOR) inhibited the expression of p-PI3K, p-Akt, p-mTOR, and p-p70S6K. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting the self-renewal capacity of GICs, expression of pluripotency maintaining factors (Nanog, c-Myc, Oct4, and Sox2), Musashi1, cyclin D1, and Bcl 2, and transcription and expression of Gli, and in inducing the expression of cleaved caspase-3, cleaved PARP and Bim. Additionally, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting epithelial-mesenchymal transition. Finally, the combination of NVP-LDE-225 and NVP-BEZ-235 was superior in inhibiting tumor growth, regulating the expression of pluripotency promoting factors, stem cell markers, cell cycle, and cell proliferation, and modulating EMT compared to single agent alone. In conclusion, the combined inhibition of PI3K/Akt/mTOR and SHH pathways was superior to single pathway inhibition in suppressing glioblastoma growth by targeting GICs. PMID- 30251118 TI - Leptin-induced cardiomyocyte hypertrophy is associated with enhanced mitochondrial fission. AB - Cardiac pathology including hypertrophy has been associated with an imbalance between mitochondrial fission and fusion. Generally, well-balanced mitochondrial fission and fusion are essential for proper functions of mitochondria. Leptin is a 16-kDa appetite-suppressing protein which has been shown to induce cardiomyocyte hypertrophy. In the present study, we determined whether leptin can influence mitochondrial fission or fusion and whether this can be related to its hypertrophic effect. Cardiomyocytes treated for 24 h with 3.1 nM leptin (50 ng/ml), a concentration representing plasma levels in obese individuals, demonstrated an increase in surface area and a significant 1.6-fold increase in the expression of the beta-myosin heavy chain. Mitochondrial staining with MitoTracker Green dye showed elongated structures in control cells with an average length of 4.5 um. Leptin produced a time-dependent increase in mitochondrial fragmentation with decreasing mitochondrial length. The hypertrophic response to leptin was also associated with increased protein levels of the mitochondrial fission protein dynamin-related protein1 (Drp1) although gene expression of Drp1 was unaffected possibly suggesting post-translational modifications of Drp1. Indeed, leptin treatment was associated with decreased levels of phosphorylated Drp1 and increased translocation of Drp1 to the mitochondria thereby demonstrating a pro-fission effect of leptin. As calcineurin may dephosphorylate Drp1, we determined the effect of a calcineurin inhibitor, FK506, which prevented leptin-induced hypertrophy as well as mitochondrial fission and mitochondrial dysfunction. In conclusion, our data show that leptin induced cardiomyocyte hypertrophy is associated with enhanced mitochondrial fission via a calcineurin-mediated pathway. The ability of leptin to stimulate mitochondrial fission may be important in understanding the role of this protein in cardiac pathology especially that related to mitochondrial dysfunction. PMID- 30251119 TI - Drug checking at an electronic dance music festival during the public health overdose emergency in British Columbia. AB - SETTING: Shambhala is a 5-day electronic dance music (EDM) festival held in rural British Columbia that annually hosts between 15,000 and 18,000 people on a 500 acre ranch. The AIDS Network Outreach & Support Society (ANKORS) has provided harm reduction services throughout the duration of the festival since 2003, including point-of-care drug checking, which allows real-time testing of illicit substances to assess their composition. Drug checking results are provided directly to clients and displayed in aggregate on a screen for all attendees to see. INTERVENTION: In 2017, ANKORS added fentanyl checking to their repertoire of drug checking technologies for festivalgoers. Volunteers used a brief survey to collect information on what clients expected the samples to contain. Volunteers carried out drug checks and subsequently logged test results. ANKORS provided an amnesty bin at the tent for clients who chose to discard their substances. OUTCOMES: Of the 2683 surveys, 2387 included data on both the client's belief and the actual test result. Clients were more likely to discard when the test result differed from their belief (5.16%) than when their belief was confirmed (0.69%). Discarding increased to 15.54% when the test could not clearly identify a substance and to 30.77% if the client did not have a prior belief of the substance. Of 1971 samples tested for fentanyl, 31 tested positive and 16.13% of clients discarded compared to 2.63% in the negative group. IMPLICATIONS: Drug checking services appeal to festivalgoers who, when faced with uncertainty, may discard their substances. This innovative harm reduction service allows for a personalized risk discussion, potentially reaching others via word-of-mouth and early warning systems. PMID- 30251120 TI - Microbial Community Enhances Biodegradation of Bisphenol A Through Selection of Sphingomonadaceae. AB - Bisphenol A (BPA) is a common ingredient in plastic wares and epoxy resins that are essential for our daily life. Despite the obvious benefits, BPA may act as an environmental endocrine disruptor, causing metabolic, reproductive, and/or developmental consequences and diseases in humans and other organisms. Although previous studies have yielded progress toward the microbial breakdown of BPA, the work has primarily been focused on pure cultures rather than complex microbial communities. In this study, we examined microbial communities in bioreactors that control the fate of BPA at various levels (up to 5000 MUg L-1). Microbial communities rapidly increased removal rates of 500-5000 MUg L-1 BPA from 23-29 to 89-99% during the first 2 weeks of the acclimation period, after which > 90% stable removal rates were maintained over 3 months. Biochemical assays demonstrated that BPA was removed by biodegradation, rather than other abiotic removal routes (e.g., adsorption and volatilization). The 16S rRNA gene-based community analysis revealed that 50-5000 MUg L-1 of BPA exposure systematically selected for three Sphingomonadaceae species (Sphingobium, Novosphingobium, and Sphingopyxis). The Sphingomonadaceae-enriched communities acclimated to BPA showed a 7.0-L gVSS-1 day-1 BPA degradation rate constant, which is comparable to that (4.1-6.3) of Sphingomonadaceae isolates and is higher than other potential BPA degraders. Taken together, our results advanced the understanding of how microbial communities acclimate to environmentally relevant levels of BPA, gradually enhancing BPA degradation via selective enrichment of a few Sphingomonadaceae populations with higher BPA metabolic activity. PMID- 30251121 TI - Helicobacter pylori status and risks of metachronous recurrence after endoscopic resection of early gastric cancer: a systematic review and meta-analysis. AB - The impact of different Helicobacter pylori (H. pylori) status (H. pylori negative, H. pylori eradication and H. pylori persistence) on the development of metachronous gastric lesions after endoscopic resection of early gastric cancer is not well defined. Thus, a systematic review and meta-analysis was performed to investigate this relationship. Two authors independently searched the electronic databases (Pubmed, Embase, the Cochrane Library and Web of Science) through March 2018, without language restriction. Pooled risk ratio for metachronous gastric lesions with regard to H. pylori status was calculated using fixed- or random effects models, and heterogeneity and publication bias were also measured. 20 eligible studies were finally identified in systematic review, and 17 out of 20 studies were further included in meta-analysis. H. pylori eradication was associated with overall 50% lower odds of metachronous events (RR = 0.50; 95 % CI 0.41-0.61). Pooled risk ratios for metachronous gastric neoplasm were 0.85 (95 % CI 0.43-1.68) between H. pylori-eradicated and -negative patients, and 0.63 (95 % CI 0.35-1.12) between H. pylori-negative and -persistent patients, respectively. In conclusion, based on the best available evidence, eradication of H. pylori can provide protection against secondary gastric neoplasm, and this quantitative benefit seemed greater than among asymptomatic individuals. Metachronous risk seems comparable between H. pylori-eradicated and -negative population, or between H. pylori-negative and -persistent patients. PMID- 30251122 TI - Precision/Personalized Medicine in Allergic Diseases and Asthma. AB - Like many other chronic diseases, every allergic patient has different characteristics based on clinical course, treatment responsiveness and disease outcomes, which are associated with the genetic and epigenetic control of molecular mechanisms and environment. This variability necessitates the establishment of patient-tailored and precision approaches in handling allergic disorders. Better understanding of the underlying pathophysiological mechanisms for the development of allergic disorders will provide more rationale strategies based on individual cases in controlling and treating these disorders. Endotyping, phenotyping, genotyping and theratyping, and biomarkers are keywords in this area and have been gaining lots of attention in the field of precision medicine, which aims to revolutionize patient care and develop better prevention and treatment strategies. In addition, precision health is a new concept that brings precise approaches to the scene for being healthy and prevention of allergic disease and asthma. The specialty of allergy has a leading role in the field, because allergen-specific immunotherapy started 105 years ago, and is historically a leading personalized/precision medicine approach in all medicine disciplines providing the possibility of cure in an individualized manner instead of conventional symptomatic treatments. PMID- 30251123 TI - Evaluation of the prognostic utility of the hemoglobin-to-red cell distribution width ratio in head and neck cancer. AB - PURPOSE: Hemoglobin is a known prognostic marker in many cancers, including head and neck cancer (HNC). There is some evidence that the red cell distribution width, which is an index of variation in size of red blood cells (RBCs), might be associated with prognosis as well. Recently, a novel prognostic biomarker has been reported-the ratio of the hemoglobin-to-red cell distribution width (Hb/RDW). Our objective was to evaluate the prognostic utility of the pretreatment Hb/RDW in HNC, controlled with known prognostic indices. METHODS: Retrospective cohort study in a tertiary academic hospital setting. Patients diagnosed with HNC treated with curative-intent surgery were eligible. Metastatic disease was excluded. The variables collected were age, sex, BMI, alcohol/tobacco exposure, performance scores, ACE-27, tumor characteristics, adjuvant treatment, and lab values. The primary endpoints were event-free survival (EFS) and overall survival (OS). OS was defined as time from start of treatment to death from any cause, and EFS was defined as time from start of treatment to any progression, recurrence, or death from any cause. Univariate and multivariate survival analysis was performed on the primary endpoints. RESULTS: A total of 205 patients were enrolled from 2010 to 2016. In multivariate analysis, the factors independently associated with EFS were BMI (p = 0.0364), advanced T stage (p = 0.001), and low Hb/RDW ratio (p = 0.017). The factors independently associated with OS were ECOG score (p = 0.042), advanced T stage (p < 0.0001), positive nodes (p = 0.0195), and Hemoglobin (0.0134). CONCLUSION: A low Hb/RDW ratio was associated with poorer EFS (HR = 2.02, 95% CI 1.13-3.61, p = 0.017), but was not associated with OS. This is the first study reporting the prognostic utility of Hb:RDW in head and neck cancer. PMID- 30251124 TI - Resurrection of Nalidixic Acid: Evaluation of Water-Based Nanoformulations as Potential Nanomedicine. AB - Resistance to quinolone antibiotics has been a serious problem ever since nalidixic acid was introduced into clinical medicine. Over time, resistance of pathogenic microbes to nalidixic acid led to the design of novel variants to revive its potential application. In the present work, a series of eight nanoformulations of nalidixic acid-based diacyl and sulfonyl acyl hydrazine derivatives were prepared. All nanoformulations were found to be stable at different storage temperatures. Antibacterial and anticandida activity of the eight nanoformulations presented encouraging results when compared with their non nano parent counterparts. The nanoformulations of chloro, furanyl, and sulfonyl acyl substituted derivatives of nalidixic acid displayed most promising results (MIC ranging from 50 to 100 MUg mL-1) against the tested bacteria and yeast. Among the screened bacteria, Acinetobacter baumannii displayed maximum sensitivity to the above nanoformulations. Biosafety study on the mammalian model wax moth, Galleria mellonella-showed that all eight prepared nanoformulations were absolutely nontoxic to the larvae and subsequent pupae and hence may likely have no or low toxicity against mammalian systems. PMID- 30251126 TI - Conservative treatment of severe defecatory urgency and fecal incontinence: minor strategies with major impact. AB - BACKGROUND: Bowel disturbances have been identified as the most important risk factor for fecal incontinence (FI). However, few studies have evaluated the impact of fiber supplementation. Our aim was to assess the correlation between the improvement in stool consistency by fiber supplementation and the changes in urgency and number of FI episodes and in the QoL of patients with FI. METHODS: Eighty-three patients who came to our institution with FI and/or fecal urgency associated with loose stools or diarrhea were prospectively included in the study The intervention included dietary advice and methylcellulose 500 mg every 8 h for 6 weeks. All assessments were carried out at baseline and 6 weeks after the start of the intervention, and included a Bristol Stool Scale, a 3-week bowel diary, the St Mark's score, the Fecal Incontinence Quality of Life scale (FIQL) and a bowel satisfaction score. RESULTS: Sixty-one patients completed the study. At baseline 50 reported episodes of urge incontinence, while 11 did not report FI episodes because they rarely left home to avoid leakage. The Bristol score improved to normal stools in 65.6% of patients after treatment. Bowel diaries showed a statistically significant reduction in the number of bowel movements, urge episodes, urge fecal incontinence episodes and soiling per week. The St Mark's score and the bowel satisfaction score significantly improved after methylcellulose and overall deferment time also increased. FIQL significantly improved in two subdomains (lifestyle, coping/behavior). Thirty-one patients (51.7%) were discharged with methylcellulose as the only treatment. CONCLUSIONS: FI may significantly improve with methylcellulose in selected cases. Assessment of fecal consistency and initial treatment with methylcellulose could be started at primary care level to reduce the need for specialist referral. PMID- 30251125 TI - Lifestyle Factors Affecting the Gut Microbiota's Relationship with Type 1 Diabetes. AB - PURPOSE OF REVIEW: The incidence of type 1 diabetes (T1D) is rising drastically for the past decades at a rate that cannot be explained by genetic changes alone. Environmental changes are considered to be the main drivers of this change. Recently, the gut microbiota has been suggested as a missing link between known environmental disease modulators and T1D promotion. Lifestyle factors have changed over time and have altered the gut microbiota-host interaction affecting T1D development. The purpose of this review is to discuss recent data emphasizing the modulatory potential of early lifestyle factors on gut microbiota and to elucidate their implication for T1D. RECENT FINDINGS: Recent findings show that lifestyle factors, especially those that affect the early establishment of gut homeostasis and the education of the immune system, are crucial disease modulators. Changing lifestyle factors affecting the early establishment of gut homeostasis are suggested to be key drivers of the rising T1D incidence. PMID- 30251127 TI - Coexistence of Pre-sarcopenia and Metabolic Syndrome in Arab Men. AB - OBJECTIVE: The present single-center observational study determined the prevalence and coexistence of sarcopenia, pre-sarcopenia, and metabolic syndrome (MetS) among apparently healthy Arab men and whether having both conditions present a unique cardiometabolic profile that is distinct than having the conditions separately. METHODS: A total of 471 out of 530 Arab men aged 20-77 years old were included after screening for the presence of pre-sarcopenia (ALM/ht2 < 7.26 kg/m2), sarcopenia (presence of both low muscle mass and low function), and MetS. MetS screening was done using the definition by the NCEP-ATP III. Based on the screening results, the participants were classified as control (normal) group (N = 328), MetS only (N = 73), pre-sarcopenia only (N = 64), and MetS + pre-sarcopenia (N = 6). RESULTS: Pre-sarcopenia without MetS was observed in 64 participants (13.6%), while MetS without pre-sarcopenia was observed in 73 participants (15.5%). MetS + pre-sarcopenia was observed only in 6 participants (1.3%). None of the participants had sarcopenia. Age- and BMI-adjusted comparisons showed that those with MetS + pre-sarcopenia had the highest diastolic blood pressure and triglyceride levels as compared to all groups (p values < 0.001). MetS + pre-sarcopenia group also had the highest levels of glucose and the lowest lean arms-legs/BMI ratio than control and pre-sarcopenia groups (p values < 0.001 and 0.005, respectively). CONCLUSION: The prevalence of pre-sarcopenia + MetS is low among young adult Arab men, but shows a unique cardiometabolic profile that is worse than those having only one of the conditions. Further investigations should be done among Arab women and the elderly. PMID- 30251129 TI - Association between disaster experience and quality of life: the mediating role of disaster risk perception. AB - PURPOSE: Disasters may impair people's quality of life (QoL) indirectly through disaster risk perception. We intended to address this point by analyzing the correlation between disaster experience and QoL with a test of the mediating effects of risk perception at the example of earthquake. METHODS: We employed the 2013 Taiwan Social Change Survey data as the data source (N = 1481). Unadjusted ordinal logistic regression models examined the correlation of disaster experience with QoL and earthquake risk perception at first. Another set of ordinal regressions were conducted to explore the mediating effect of earthquake risk perception between earthquake experience and QoL. RESULTS: Earthquake experience had negative impact on QoL measured by self-reported happiness, general health status, and life satisfaction. People who had earthquake experience perceived higher earthquake risk compared to those who had never experienced an earthquake. Risk perception measured by perceived likelihood of future earthquake as a mediating factor for the impact of earthquake experience on QoL from the dimensions of both self-reported happiness and life satisfaction was confirmed. CONCLUSIONS: Findings are consistent with existing reports about the association between disaster experience and QoL. Research using multi dimensional measures of disaster risk perception and QoL is needed to inform post disaster recovery programs. PMID- 30251128 TI - Use of prognostic factors of rheumatoid arthritis in clinical practice and perception of their predictive capacity before and after exposure to evidence. AB - The aim of the study is to benchmark the use and attributed importance of well established prognostic factors in rheumatoid arthritis (RA) in daily clinical practice, and to contrast the use of factors with their ability to predict outcome. Medline was searched (inception-Sep. 2016) for systematic reviews on factors predicting death, disability, structural damage or remission in RA. All factors identified were compiled in a matrix of factors * outcomes, and scoping reviews for each cell were then performed. A survey to 42 rheumatologists randomly selected explored the use of the list of prognostic factors and inquired about the perceived strength of association with poor prognosis. In a second round, participants were exposed to evidence from the matrix and to responses from other participants. Change on perceived strength of association was evaluated. Rheumatologists report using prognostic factors in clinical practice on a daily basis. Very young onset, joint counts at diagnosis, rheumatoid factor, ACPA, and radiographic erosions are used frequently and correctly recognized as strong predictors. Comorbidities and other associated problems, such as obesity, low bone mineral density, cardiovascular disease, or extra-articular manifestations, are perceived as moderately associated to prognosis but, nevertheless, rheumatologists also use them profusely. Genetic and other biomarkers and osteitis by magnetic resonance are less accessible in daily practice and they obtained better results on second round (probably after knowing the strength of association with prognosis). Rheumatologists use widely most prognostic factors with a strong predictive value. However, factors with low evidence of prognostic value are also used and some factors are not used despite good evidence. PMID- 30251130 TI - Spectroscopic evidence supporting neutral thiol ligation to ferrous heme iron. AB - The binding of neutral thiol (ethanethiol, EtSH) or thioether (tetrahydrothiophene, THT) to two types of heme proteins in their ferrous state has been investigated with UV-visible (UV-Vis) absorption and magnetic circular dichroism spectroscopy. For the second GAF (cGMP-specific phosphodiesterases, adenylyl cyclases, and FhlA) domain from the sensory kinase MsmS (sGAF2), stepwise additions of these respective two sulfur-donor ligands to its dithionite reduced ferrous form generate homogeneous six-coordinate low-spin ferrous complexes at both pHs 7.0 and 5.4. Similar complexes were partially formed for deoxyferrous soybean leghemoglobin with EtSH or THT within their solubility limits in water. The titrations cause significant UV-Vis spectra changes attributable to a five-coordinate to six-coordinate heme iron coordination change. For sGAF2, the resulting spectra are essentially identical for the both ligands, clearly indicating the direct binding of neutral thiol/thioether to ferrous heme iron as the distal ligand. On the other hand, the thiol EtSH binds to ferric sGAF2 in the anionic thiolate form, while thioether THT forms its ferric sGAF2 complex as a neutral ligand. These observations provide compelling evidence that neutral cysteine is a plausible ligand for ferrous heme proteins. PMID- 30251131 TI - Risk of secondary primary malignancies in multiple myeloma patients with or without autologous stem cell transplantation. AB - Outcomes for patients with multiple myeloma (MM) have improved through use of novel treatments, especially lenalidomide combined with autologous stem cell transplantation. However, because of their increased life expectancy, an increased risk of secondary primary malignancies (SPMs) has been observed in MM patients, particularly after lenalidomide maintenance in both transplant-eligible (TE) and transplant-ineligible (TI) patients. To evaluate the incidence and risk factors of developing SPMs, we identified 17 TE-MM and 12 TI-MM patients with SPMs among 211 TE-MM and 280 TI-MM patients, including seven TE-MM and four TI-MM patients with hematological malignancies and ten TE-MM and eight TI-MM patients with non-hematological cancers, respectively. The median follow-up time from diagnosis was > 4 years. Multivariate analysis identified a history of high-dose cyclophosphamide use for peripheral blood stem cell harvest in TE-MM patients and > 65 years of age at diagnosis, or a history of adriamycin, lenalidomide, or thalidomide use in TI-MM patients as independent risk factors for SPMs (P < 0.001). Patients with a history of lenalidomide use had a lower risk of death among both TE-MM (P = 0.0326) and TI-MM (P < 0.001) patients. The survival benefit of receiving lenalidomide outweighed the increased risk of SPMs in both TE-and TI-MM patients. PMID- 30251132 TI - Detection of recurrent pancreatic cancer: value of second-opinion interpretations of cross-sectional images by subspecialized radiologists. AB - PURPOSE: To investigate the value of second-opinion interpretation of cross sectional images by subspecialized radiologists to diagnose recurrent pancreatic cancer after surgery. METHODS: The IRB approved and issued a waiver of informed consent for this retrospective study. Initial and second-opinion interpretations of 69 consecutive submitted MRI or CT follow-up after pancreatic cancer resection between January 1, 2009 and December 31, 2013 were evaluated by one oncologic imaging radiologist, who was blinded to patient's clinical details and histopathologic data. The reviewer was asked to classify each interpretation in reference of the diagnosis of PDAC recurrence. It was also recorded if the radiologic interpretation recommended additional imaging studies to confirm recurrence. The diagnosis of recurrence was determined by pathology when available, otherwise by imaging follow-up, clinical, or laboratory assessments. Cohen's kappa statistic was used to assess agreement between initial and second opinion interpretations. The differences between the initial and second-opinion interpretations were examined using McNemar test or Bowker's test of symmetry. RESULTS: Disagreement on recurrence between the initial report and the second opinion interpretation was observed in 32% of cases (22/69; k = 0.44). Second opinion interpretations had a higher sensitivity and a higher specificity on recurrence compared to the initial interpretations (0.93 vs. 0.75 and 0.90 vs. 0.68, respectively), and the difference in specificity was significant (p = 0.016). Additional imaging studies were recommended more frequently in the initial interpretation (22% vs. 6%, p = 0.006). CONCLUSIONS: Our study shows the second-opinion interpretation by subspecialized radiologists improves the detection of pancreatic cancer recurrence after surgical resection. PMID- 30251134 TI - Succinate and the shortcut to the cure of metformin-induced lactic acidosis. AB - Inhibition of the respiratory chain complex I plays a key role in the pathogenesis of metformin-induced lactic acidosis. In a work recently published in this journal, a novel cell-permeable succinate prodrug (NV118) increased in vitro mitochondrial oxygen consumption coupled with energy production and decreased lactate production in intact human platelets intoxicated with metformin. This result was interpreted in light of a "bypass" strategy. NV118 entered platelets and released succinate in their cytoplasm; succinate in turn donated electrons to complex II and thus reactivated the flow of electrons to the distal part of the respiratory chain independent of complex I. Herein, I will (1) comment on these findings; (2) highlight the potential therapeutic application of succinate in other critical conditions accompanied by complex I inhibition, including sepsis, traumatic brain injury, and inherited neurological disorders; and (3) examine the most important issues that remain to be solved to transfer these observations to the bedside. PMID- 30251133 TI - Transcriptome responses in wheat roots to colonization by the arbuscular mycorrhizal fungus Rhizophagus irregularis. AB - The influence of arbuscular mycorrhizal (AM) colonization on the expression of genes in the roots of wheat (Triticum aestivum L.) at the transcriptome level is largely unknown. A pot experiment was established to study the responses of the transcriptome profile in the roots of wheat to colonization by the AM fungus Rhizophagus irregularis using high through-put sequencing methods. The results indicated that the expression of 11,746 genes was regulated by AM colonization, and 64.7% of them were up-regulated genes. 1106 genes were only expressed in roots colonized by AM fungi, and 108 genes were only expressed in non-mycorrhizal roots. The differentially expressed genes (DEGs) were primarily distributed on the 2B, 3B, 2A, 2D, and 5B chromosomes of wheat. The DEGs (including both up- and down- regulated) mainly located on membranes, and functioned in nucleotide binding and transferase activity during cellular protein modification and biosynthetic processes. The data revealed that AM colonization up-regulated genes involved in the phenylpropanoid biosynthesis pathway and transcription factors which play vital roles in protecting plants from biotic or abiotic stresses. A number of key genes involved in molecular signal biosynthesis and recognition, epidermal cell colonization and arbuscule formation, carbon and nutrients exchange during AM symbiosis were found. All the ammonium transporter (AMT), iron phytosiderophore transporter, boron, zinc, and magnesium transporter genes found in our study were up-regulated DEGs. One new AM-specific induced AMT and three new AM-specific induced nitrate transporter (NRT) genes were found in the roots of wheat colonized by AM fungi, even though a negative growth response of wheat to AM colonization occurred. The present study provided new information which is important for understanding the mechanisms behind the development and function of the symbiosis between wheat and AM fungi. PMID- 30251135 TI - Robotic retro-rectus repair of parastomal hernias. AB - OBJECTIVE: To present our technique of robotic retrorectus parastomal hernia repair. BACKGROUND: Parastomal hernias represent a significant problem with high recurrence and long-term complications. An estimated of 120,000 new stomas are created per year with a prevalence of up to 800,000 patients in the U.S. 40-60% of these ostomies will never be reversed. Parastomal hernias cause skin breakdown and make adherence of ostomy appliances difficult, creating the need for frequent bag exchanges. They can also cause pain, bowel obstruction and bowel incarceration or strangulation. All of these factors affect quality of life and represent a significant burden to our health care system. There is no definitive gold-standard technique to repair parastomal hernias. The use of prosthesis decreases the recurrence rates, yet using prosthetic material can result in long term complications. Surgeons have developed techniques of pre-peritoneal mesh placement to provide long-lasting repairs and at the same time prevent complications associated with the mesh. We believe that a robotic retro-rectus approach provides a secure repair and avoids leaving prosthetic material in the abdominal cavity at the same time. METHODS: A three-arm technique is used, inserting ports opposite to the target anatomy. Hernia contents are reduced protecting the ostomy loop and mesentery. The contralateral retro-rectus space is entered and this space is developed extensively across the midline and around the ostomy. The hernia defect is approximated. Concomitant ventral hernias are also repaired. A polypropylene mesh with a keyhole is used and wide coverage is ensured in all directions. The leaflets of the mesh are stitched together and the mesh is sutured to the abdominal wall. Finally, the retro-rectus space is closed. RESULTS: We have performed this technique in two patients safely and at 1-year follow-up there were no recurrences in either. On conclusion, this is a novel minimally invasive technique to repair parastomal hernias that provides wide coverage of the defect and avoids leaving mesh intraperitoneally. PMID- 30251136 TI - The prevalence of musculoskeletal injuries in bariatric surgeons. AB - OBJECTIVE: To investigate the prevalence of musculoskeletal (MSK) injuries in bariatric surgeons around the world. BACKGROUND: As the popularity of bariatric surgery increases, efforts into improving its patient safety and decreasing its invasiveness have also been on the rise. However, with this shift towards minimal invasiveness, surgeon ergonomic constraints have been imposed, with a recent report showing a 73-88% prevalence of physical complaints in surgeons performing laparoscopic surgeries. METHODS: A web-based survey was designed and sent out to bariatric surgeons around the world. Participants were queried about professional background, primary practice setting, and various issues related to bariatric surgeries and MSK injuries. RESULTS: There were 113 responses returned from surgeons from 34 countries around the world. 68.5% of the surgeons have had more than 10 years of experience in laparoscopic surgery, 65.8% in open, and 0.9% in robotic surgery. 66% of participants reported that they have experienced some level of discomfort/pain attributed to surgical reasons, causing the case load to decrease in 27.2% of the surgeons. It was seen that the back was the most affected area in those performing open surgery, while shoulders and back were equally as affected in those performing laparoscopic, and the neck for those performing robotic, with 29.4% of the surgeons reporting that this pain has affected their task accuracy/surgical performance. A higher percentage of females than males reported pain in the neck, back, and shoulder area when performing laparoscopic procedures. Supine positioning of patients evoked more discomfort in the wrists, while the French position caused more discomfort in the back region. A higher percentage of surgeons who did not exercise experienced more issues in the neck and back region, while those that exercised more than 3 h a week experienced issues in their shoulders and wrists in both open and laparoscopic approaches. Only 57.7% sought medical treatment for their MSK problem, of which 6.35% had to undergo surgery for their issue, of which 55.6% of those felt that the treatment resolved their problem. CONCLUSION: MSK injuries and pain are a common occurrence among the population of bariatric surgeons (66%), and has the ability to hinder performance at work. Therefore, it is of importance to investigate ways in which to improve ergonomics for these surgeons as to improve quality of life. PMID- 30251137 TI - From the dry lab to the operating room: the first transferability study of hysteroscopic skills. AB - OBJECTIVE: The aim of this study is to prove that a short dry lab training prior to the surgery is efficient to acquire basic hysteroscopic skills and that these skills are transferable directly to the operation theater. METHODS: Thirty-nine gynecologists who never attended a training course or practiced hysteroscopy before were evaluated. Participants were randomly divided into trainees (n = 21) and control (n = 18). Trainees attended a short time dry lab prior the exposure to the OR. The controls went directly to the OR. Participants were asked to identify the different landmarks of the uterine cavity and to perform a punch biopsy under the supervision of a gynecologist expert in hysteroscopy. A video recording for all the exercises was done, and showed independently to two expert surgeons in hysteroscopy for evaluation. The experts were also asked to distinguish between the trainees and the control. RESULTS: For both experts, the trainees' performance was statistically better than that of the controls (p < 0.001) for the identification of the uterus land marks and the punch biopsy. The two experts identified 80.9 and 85.7%, respectively, of the trainees. The participants' subgroup ID and the experts' identification were statistically correlated (p < 0.001). CONCLUSION: A short time dry lab is efficient to acquire basic hysteroscopic skills and these skills are transferable directly to the OR. PMID- 30251138 TI - The value of surgical experience: excess costs associated with the Roux-en-Y gastric bypass learning curve. AB - BACKGROUND: Gastric bypass has a steep learning curve that is associated with increased adverse outcomes and these adverse outcomes are associated with increases in cost. This study sought to quantify the effect of cumulative procedure volume on inpatient cost and characterize the excess cost associated with a surgeon's learning curve. METHODS: This was a retrospective study of 29 high-volume surgeons during the first 6 years of performing gastric bypass in a regionalized center of excellence system. Cumulative volume was determined using the procedure date and analyzed in blocks of 25 cases. The main outcomes of interest were inpatient cost for the initial hospital stay in 2014 Canadian dollars as well as prolonged length of stay (>= 3 days). RESULTS: Overall, 11,684 cases were identified from April 2009 to March 2015. After a surgeon's 50th case, the adjusted inpatient cost decreased by $2775 (95% CI $- 4352 to $- 1204 p = 0.001) compared to the first 25 cases. Cost savings were maintained through a surgeon's 400th case. The average cost savings after the 50th case was $2082 (95% CI $- 3194 to $- 962 p < 0.001) and the excess cost attributable to the first 50 cases was $104,077 (95% CI 48,104 to 159,682) per surgeon. Surgeon experience was also associated with a decrease odds of prolonged length of stay. CONCLUSIONS: This study demonstrated the influence of surgeon experience on improved cost efficiencies. We also characterized that the average excess cost per surgeon of implementing gastric bypass was approximately $104,000. This is relevant to future health system planning as well as providing an economic incentive for impactful training interventions. PMID- 30251139 TI - Evaluation of the rate of marginal ulcer formation after bariatric surgery using the MBSAQIP database. AB - BACKGROUND: Marginal ulcer (MU) formation is a known problem after gastric bypass. The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database contains data from all US and Canadian Centers of Excellence including complication rates. We hypothesized that the short-term rate of ulceration is low. METHODS: We queried the MBSAQIP database for the year 2015. We searched patients with primary gastric bypass who developed MU. We then compared preoperative, operative, and postoperative characteristics with patients who did not develop MU. RESULTS: The incidence of MU in the entire cohort of GB patients was 155 of 44,379 (0.35%, 95% CI 0.297%, 0.409%). Among the 155 patients with an ulcer, 88 (57%) patients had only one procedure, 69 had an intervention (therapeutic or diagnostic endoscopy), 16 had readmission, and 3 had reoperation. 65 patients (42%) had two procedures with the majority having both readmissions and endoscopy (n = 59); and two patients (1%) had three procedures. Ulcer formation was most common in the intervention group (11.4%). The occurrence of ulcer formation was associated with unplanned ICU admissions (6.45%), transfusions (5.16%), postoperative UTI (3.87%), sepsis (1.94%), and myocardial infarction (0.65%). Death occurred in 76 patients with no related cases to MUs. The risk of ulcer was associated with increased BMI (OR 1.02, p = 0.01), presence of percutaneous transluminal cardiac catheterization (PTC) (2.17, p = 0.038), histories of DVT (1.72, p = 0.085), and pulmonary embolism (2.84, p = 0.002). CONCLUSIONS: In a nationally reported database, symptomatic MUs rarely occur in the first month. The large majority are diagnosed and treated endoscopically with minimal need for surgical intervention. The risk of anastomotic ulcer was increased with increased BMI, need for PTC, and history of DVT/PE. PMID- 30251140 TI - Routine esophageal manometry is not useful in patients with normal videoesophagram. AB - BACKGROUND: Videoesophagram (VEG) and esophageal manometry (EM) are components of the preoperative evaluation for foregut surgery. EM is able to identify motility disorders and diminished contractility that may alter surgical planning. However, there are no clearly defined criteria to guide this. Reliable manometry is not always easily obtained, and therefore its necessity in routine preoperative evaluation is unclear. We hypothesized that if a patient has normal videoesophagram, manometry does not reveal clinically significant esophageal dysfunction. METHODS: We reviewed patients who underwent protocolized videoesophagram and manometry at our institution. Measures of esophageal motility including the mean distal contractile integral (DCI), mean wave amplitude (MWA), and percent of peristaltic swallows (PPS) were analyzed. The Chicago Classification was used for diagnostic criteria of motility disorders. Normal VEG was defined as stasis of liquid barium on less than three of five swallows. RESULTS: There were 418 patients included. 231 patients (55%) had a normal VEG, and 187 patients (45%) had an abnormal VEG. In the normal VEG group, only 2/231 (0.9%) patients had both abnormal DCI and PPS, 1/231 (0.4%) patients had both abnormal DCI and MWA and no patients had both abnormal MWA and PPS. There were no patients with achalasia or absent contractility and 1 patient with ineffective esophageal motility (IEM) in the normal VEG group. This was significantly different from the abnormal VEG group which included 4 patients with achalasia, 1 with absent contractility and 22 with IEM (p < 0.0001). The negative predictive value of VEG was 99.6% and the sensitivity was 96.4%. CONCLUSIONS: A normal videoesophagram reliably excluded the presence of clinically significant esophageal dysmotility that would alter surgical planning. Routine manometry is not warranted in patients with normal videoesophagram, and should be reserved for patients with abnormal VEG. PMID- 30251142 TI - Endoscopic plombage with polyglycolic acid sheets and fibrin glue for gastrointestinal fistulas. AB - BACKGROUND AND STUDY AIMS: Gastrointestinal (GI) fistulas arise as adverse events of GI surgery and endoscopic treatment as well as secondary to underlying diseases, such as ulceration and pancreatitis. Until a decade ago, they were mainly treated surgically or conservatively. Bioabsorbable polyglycolic acid (PGA) sheets and fibrin glue, which are commonly used in surgical procedures, have also recently been used in endoscopic procedures for the closure of GI defects. However, there have only been few case reports about successful experiences with this approach. There have not been any case-series studies investigating the strengths and weaknesses of such PGA sheet-based treatment. In this study, we evaluated the clinical effectiveness of using PGA sheets to close GI fistulas. PATIENTS AND METHODS: Cases in which patients underwent endoscopic filling with PGA sheets and fibrin glue for GI fistulas at Kobe University Hospital between January 2013 and April 2018 were retrospectively reviewed. RESULTS: A total of 10 cases were enrolled. They included fistulas due to leakage after GI surgery, aortoesophageal/bronchoesophageal fistulas caused by chemoradiotherapy, or severe acute pancreatitis. The fistulas were successfully closed in 7 cases (70%). The unsuccessful cases involved a fistula due to leakage after surgical esophagectomy and bronchoesophageal fistulas due to chemoradiotherapy or severe acute pancreatitis. Unsuccessful treatment was related to fistula epithelization. CONCLUSION: Endoscopic plombage with PGA sheets and fibrin glue could be a promising therapeutic option for GI fistulas. PMID- 30251141 TI - Pure laparoscopic right hepatectomy of living donor is feasible and safe: a preliminary comparative study in China. AB - BACKGROUND: The adoption of laparoscopic techniques for living donor major hepatectomy has been controversial issue. The aim of this study is to present the preliminary experience of laparoscopic right hepatectomy in China. METHODS: All the donors receiving right hepatectomy for adult-to-adult living donor liver transplantation (LDLT) were divided into three groups: pure laparoscopic right hepatectomy (PLRH) group, hand-assisted right hepatectomy (HARH) group and open right hepatectomy (ORH) group. We compared the perioperative data and surgical outcomes of donors and recipients among three groups. RESULTS: From November 2001 to May 2017, 295 donors have received right hepatectomy for LDLT in our center. Among them, 7 donors received PLRH, 26 donors received HARH and 262 donors received ORH. The operation time of PLRH group (509.3 +/- 98.9 min) was longer than that of the HARH group (451.6 +/- 89.7 min) and the ORH group (418.4 +/- 81.1 min, p = 0.003). The blood loss was the least in the PLRH group (378.6 +/- 177.1 mL), compared with that in the HARH group (617.3 +/- 240.4 mL) and that in the ORH group (798.6 +/- 483.7 mL, p = 0.0013). The postoperative hospital stay was shorter in the PLRH group (7, 7-10 days) than that in the HATH group (8.5, 7.5-12 days) and ORH group (11, 9-14 days; p = 0.001). Only one donor had pleural effusion (Grade I) and another one experienced pulmonary infection (Grade II). One recipient (14.3%) in the PLRH group occurred hepatic venous stenosis. CONCLUSIONS: Laparoscopic approaches for right hepatectomy contribute to less blood loss, better cosmetic satisfaction, less severe complications, and faster rehabilitation. PLRH is a safe and feasible procedure, which must be performed in highly specialized centers with expertise of both LDLT and laparoscopic hepatectomy, and requires a hybrid-to-pure stepwise development. PMID- 30251143 TI - Long-term impact of bariatric surgery in diabetic nephropathy. AB - BACKGROUND: Bariatric surgery has been shown to improve and resolve diabetes. However, limited literature about its impact on end-organ complications of diabetes is available. The aim of this study was to examine the long-term effect of bariatric surgery on albuminuria. METHODS: We studied 101 patients with pre operative diabetes and albuminuria [defined as urine albumin:creatinine ratio (uACR) > 30 mg/g] who underwent bariatric surgery at an academic center from 2005 to 2014. RESULTS: Fifty-seven patients (56%) were female with a mean age of 53 (+/- 11) years. The mean pre-operative BMI and glycated hemoglobin (HbA1c) were 43.1 (+/- 7.6) kg/m2 and 8.4 (+/- 1.8)%, respectively. The median pre-operative uACR was 80.0 (45.0-231.0) mg/g. Bariatric procedures included Roux-en-Y gastric bypass (n = 75, 74%) and sleeve gastrectomy (n = 26, 26%). The mean follow-up period was 61 (+/- 29) months. At last follow-up, the mean BMI was 33.8 (+/- 8.3) kg/m2. The overall glycemic control improved after bariatric surgery. At last follow-up, 73% had good glycemic control (HbA1c < 7%) and 27% met diabetes remission criteria. The mean HbA1c at last follow-up was 6.7 (+/- 1.0)% and the median uACR was 30 (IQR 7-94) mg/g. Albuminuria improved in 77% and resolved in 51% of patients at long-term. CONCLUSIONS: Bariatric surgery has a significantly positive impact on albuminuria in patients with obesity and type 2 diabetes. Our data showed almost an 80% improvement in albuminuria at the short- and long-term period after bariatric surgery. PMID- 30251144 TI - Structured cost analysis of robotic TME resection for rectal cancer: a comparison between the da Vinci Si and Xi in a single surgeon's experience. AB - BACKGROUND: Robotic-assisted surgery by the da Vinci Si appears to benefit rectal cancer surgery in selected patients, but still has some limitations, one of which is its high costs. Preliminary studies have indicated that the use of the new da Vinci Xi provides some added advantages, but their impact on cost is unknown. The aim of the present study is to compare surgical outcomes and costs of rectal cancer resection by the two platforms, in a single surgeon's experience. METHODS: From April 2010 to April 2017, 90 robotic rectal resections were performed, with either the da Vinci Si (Si-RobTME) or the da Vinci Xi (Xi-RobTME). Based on CUSUM analysis, two comparable groups of 40 consecutive Si-RobTME and 40 consecutive Xi RobTME were obtained from the prospectively collected database and used for the present retrospective comparative study. Data costs were analysed based on the level of experience on the proficiency-gain curve (p-g curve) by the surgeon with each platform. RESULTS: In both groups, two homogeneous phases of the p-g curve were identified: Si1 and Xi1: cases 1-19, Si2 and Xi2: cases 20-40. A significantly higher number of full RAS operations were achieved in the Xi-RobTME group (p < 0.001). A statistically significant reduction in operating time (OT) during Si2 and Xi2 phase was observed (p < 0.001), accompanied by reduced overall variable costs (OVC), personnel costs (PC) and consumable costs (CC) (p < 0.001). All costs were lower in the Xi2 phase compared to Si2 phase: OT 265 versus 290 min (p = 0.052); OVC 7983 versus 10231.9 (p = 0.009); PC 1151.6 versus 1260.2 (p = 0.052), CC 3464.4 versus 3869.7 (p < 0.001). CONCLUSIONS: Our experience confirms a significant reduction of costs with increasing surgeon's experience with both platforms. However, the economic gain was higher with the Xi with shorter OT, reduced PC and CC, in addition to a significantly larger number of cases performed by the fully robotic approach. PMID- 30251146 TI - A Pilot Study on the Efficacy of Continuous Positive Airway Pressure on the Manifestations of Dysphagia in Patients with Obstructive Sleep Apnea. AB - There is evidence in the literature demonstrating that patients with obstructive sleep apnea (OSA) may present with dysphagia, but few studies have evaluated whether this complaint can be reversed with treatment of OSA. To assess whether findings of dysphagia in patients with OSA can be reversed with the use of continuous positive airway pressure (CPAP) devices. Seventy adult patients (age 18-70 years) with moderate or severe OSA were included in the study. All patients underwent fiberoptic endoscopic evaluation of swallowing (FEES) and completed the SWAL-QOL questionnaire on quality of life in dysphagia. Patients with visible abnormalities on FEES were treated with CPAP and reassessed after 3 months. The prevalence of dysphagia was 27.3% (18 patients). Premature spillage was the main finding. On comparison of groups with and without dysphagia, the SWAL-QOL score was significantly worse in the dysphagia group in domain 2 (eating duration and eating desire, p = 0.015), with no impact on overall score (p = 0.107). Of the 18 patients with dysphagia, 12 were started on CPAP; 11 exhibited satisfactory adherence and remained in the study. Abnormal FEES findings resolved in 81% (n = 9/11) of patients who started CPAP (p = 0.004), and dysphagia-specific quality of life also improved significantly (overall SWAL-QOL score, p = 0.028). In this sample of patients with OSA, the overall prevalence of dysphagia (as demonstrated by premature spillage on FEES) was 27.3%. Treatment of OSA with CPAP was able to reverse the endoscopic findings of swallowing dysfunction and to improve quality of life as measured by the SWAL-QOL. PMID- 30251145 TI - Newborn Screening for Severe Combined Immunodeficiency: Analytic and Clinical Performance of the T Cell Receptor Excision Circle Assay in France (DEPISTREC Study). AB - Severe combined immunodeficiency (SCID) is characterized by a major T cell deficiency. Infants with SCID are asymptomatic at birth but die from infections in the first year of life if not treated. Survival rates are better for early treatment. SCID therefore meets criteria for newborn screening (NBS). T cell receptor excision circle (TREC) quantification is a reliable marker of T cell deficiency and can be performed using Guthrie cards. The DEPISTREC project was designed to study the feasibility, clinical utility, and cost-effectiveness of generalized SCID screening in France. About 200,000 babies from all over the country were screened at birth with a commercial kit. We determined assay performance and proposed a cutoff for classification of results. Our findings suggest that, given clearly established validation rules and decision-making procedures, the TREC assay is a suitably specific and sensitive method for high throughput SCID screening. Clinical Trials: NCT02244450. PMID- 30251147 TI - Effects of Tongue-Hold Swallows on Suprahyoid Muscle Activation According to the Relative Tongue Protrusion Length in the Elderly Individuals. AB - This study investigated differences in suprahyoid muscle activity in elderly adults during tongue-hold swallowing (THS) according to tongue protrusion length to determine the most effective tongue protrusion length during THS. A total of 52 healthy participants (34 females and 18 males) aged 69-92 years were included. Changes in suprahyoid muscle activation during normal swallowing and THS with 1/3rd and 2/3rd tongue protrusions using surface electromyography were observed. Suprahyoid muscle activation significantly increased with the increasing tongue protrusion length (p < 0.05). Depending on the responses of the participants based on tongue protrusion length, participants were categorized into the increase group [increased suprahyoid muscle activity with tongue protrusion, n = 36 (1/3rd THS compared to normal swallowing) or 38 (2/3rd THS compared to normal swallowing)] or decrease group [decreased suprahyoid muscle activity with tongue protrusion, n = 16 (1/3rd THS compared to normal swallowing) or 14 (2/3rd THS compared to normal swallowing)]. The functional reserve of the increase group was significantly higher than that of the decrease group (p < 0.05). Many elderly people were found to have increased activation of the suprahyoid muscle during THS; however, others showed the opposite. Therefore, it is necessary to confirm the degree of suprahyoid muscle activation during THS so that the patient can perform the exercise at the tongue protrusion length that can maximize the effect of the exercise. For individuals who cannot overcome even a small amount of tongue protrusion (e.g., 1/3rd MTPL), replacing THS with another exercise may be considered. PMID- 30251148 TI - Some do and some don't? Accounting for variability of individual difference structures. AB - A prevailing notion in experimental psychology is that individuals' performance in a task varies gradually in a continuous fashion. In a Stroop task, for example, the true average effect may be 50 ms with a standard deviation of say 30 ms. In this case, some individuals will have greater effects than 50 ms, some will have smaller, and some are forecasted to have negative effects in sign-they respond faster to incongruent items than to congruent ones! But are there people who have a true negative effect in Stroop or any other task? We highlight three qualitatively different effects: negative effects, null effects, and positive effects. The main goal of this paper is to develop models that allow researchers to explore whether all three are present in a task: Do all individuals show a positive effect? Are there individuals with truly no effect? Are there any individuals with negative effects? We develop a family of Bayesian hierarchical models that capture a variety of these constraints. We apply this approach to Stroop interference experiments and a near-liminal priming experiment where the prime may be below and above threshold for different people. We show that most tasks people are quite alike-for example everyone has positive Stroop effects and nobody fails to Stroop or Stroops negatively. We also show a case that under very specific circumstances, we could entice some people to not Stroop at all. PMID- 30251149 TI - TRPM2 modulates neutrophil attraction to murine tumor cells by regulating CXCL2 expression. AB - In recent years, immune cells were shown to play critical roles in tumor growth and metastatic progression. In this context, neutrophils were shown to possess both pro- and anti-tumor properties. To exert their anti-tumor effect, neutrophils need to migrate towards, and form physical contact with tumor cells. Neutrophils secrete H2O2 in a contact-dependent mechanism, thereby inducing a lethal Ca2+ influx via the activation of the H2O2-dependent TRPM2 Ca2+ channel. Here, we explored the mechanism regulating neutrophil chemoattraction to tumor cells. Interestingly, we found that TRPM2 plays a role in this context as well, since it regulates the expression of potent neutrophil chemoattractants. Consequently, cells expressing reduced levels of TRPM2 are not approached by neutrophils. Together, these observations demonstrate how tumor cells expressing reduced levels of TRPM2 evade neutrophil cytotoxicity in two interrelated mechanisms-downregulation of neutrophil chemoattractants and blocking of the apoptotic Ca2+-dependent cascade. These observations demonstrate a critical role for TRPM2 in neutrophil-mediated immunosurveillance and identify cells expressing low levels of TRPM2, as a potential target for cancer therapy. PMID- 30251150 TI - Is the number of rib fractures a risk factor for delayed complications? A case control study. AB - AIM: To analyse factors that may predict the appearance of rib fracture complications during the first days of evolution and determine whether the number of fractures is related to these complications. METHOD: Retrospective case control study of patients admitted with a diagnosis of rib fractures between 2010 and 2014. Two groups were established depending on the appearance or not of pleuropulmonary complications in the first 72 h, and the following were compared: age, sex, Charlson comorbidity index (CCI), number and uni- or bilateral involvement, mechanism of trauma, days of hospital stay, haemoglobin on discharge minus haemoglobin on admission, pleuropulmonary complications during admission (pneumothorax, haemothorax or pulmonary contusion) and placement of pleural drainage. RESULTS: One hundred and forty-one cases of rib fractures were admitted in the period mentioned. There were no differences in the patients' baseline characteristics (age, sex and Charlson Comorbidity Index) between the two groups. Differences were found in the number of fractures (2.98 +/- 1.19 in the group without complications vs 3.55 +/- 1.33 in the group with complications, p = 0.05) and in the drop in the level of haemoglobin (0.52 +/- 0.91 mg/dl vs 1.22 +/- 1.29 mg/dl, p = 0.01). The length of hospital stay varied considerably in each group (5.35 +/- 4.05 days vs 7.86 +/- 6.96 days), but without statistical significance (p = 0.11). CONCLUSIONS: The number of fractured ribs that best predicted the appearance of complications (delayed pleuropulmonary complications and greater bleeding) was 3 or more. PMID- 30251151 TI - Blunt splenic injury in children: haemodynamic status key to guiding management, a 5-year review of practice in a UK major trauma centre. AB - PURPOSE: To review the management of children and adolescents (0-18 years), with blunt splenic injury treated at a single UK major trauma centre over a 5-year period, focusing upon efficacy of non-operative management and the use of haemodynamic stability as a guide to planning treatment strategy, rather than radiological injury grading. To produce a treatment pathway for management of blunt splenic injury in children. METHODS: Retrospective, cross-sectional study of all paediatric patients admitted with radiologically proven blunt splenic injury between January 2011 and March 2016. Penetrating injuries were excluded. Follow up was for at least 30 days. RESULTS: 30 Patients were included, mean age was 14.5 (SD 3.6), median injury severity score was 16 (IQR 10-31). 6 Patients (20%) had a splenectomy, whilst 22 patients (73%) were successfully treated non operatively with 100% efficacy at index admission. 5/8 (63%) patients with radiological grade V injuries were managed non-operatively, injury grade was not associated with surgical intervention (p = 1.57). Haemodynamic instability was initially treated with fluid resuscitation leading to successful non-operative management in 5/11 (45%) patients. However, haemodynamic instability is a significant predictor of requirement for surgical intervention (p = 0.03), admission to critical care (p = 0.017), presence of additional injuries (p = 0.015) and increased length of stay (p = 0.038). No such relationships were found to be associated with increased radiological injury grade. CONCLUSIONS: Non operative management should be first-line treatment in the haemodynamically stable child with a blunt splenic injury and may be carried out with a high degree of efficacy. It may also be successfully implemented in those initially showing signs of haemodynamic instability that respond to fluid resuscitation. Radiological injury grade does not predict definitive management, level of care, or length of stay; however, haemodynamic stability may be utilised to produce a treatment algorithm and is key to guiding management. PMID- 30251152 TI - A new tailored protocol based on laparoscopy in the management of abdominal shotgun injuries: a case-series study. AB - PURPOSE: Abdominal shotgun injuries derive their significance from the wide range of injuries they cause. The management of this type of injury has been continuously evolving. Despite the ongoing incorporation of laparoscopy in management of abdominal trauma, there is no definite protocol raising the role of laparoscopy in such injuries. In this study, we outlined a tailored protocol in the management of penetrating abdominal shotgun injuries differing from the previous protocols which comprised either mandatory exploration or non-operative management. PATIENTS AND METHODS: This case-series study included patients who attended to our emergency department with a shotgun injury involving the abdomen between December 2014 and October 2016. Only stable patients with no clinical signs of surgical abdomen, in combination with CT evidence of penetrating intra abdominal pellets, were subjected to laparoscopic exploration in this study. RESULTS: Thirty patients fulfilled the inclusion criteria. During laparoscopy, ten patients were designated as positive for injuries. No missed injuries were identified. Two of the cases identified as positive by laparoscopy needed no further management while the remaining eight patients warranted laparotomy. Only one of these eight patients turned out to have a non-therapeutic exploration. Consequently, laparoscopy in the management of these injuries had an overall accuracy of 96.7%, sensitivity of 100%, specificity of 95.7%, positive predictive value of 87.5% and negative predictive value of 100% with highly significant p value < 0.001. CONCLUSION: A tailored protocol relying on the use of laparoscopy in the management of stable patients with CT evidence of penetrating abdominal shotgun injuries is safe and helps to cut down the number of non-therapeutic laparotomies with consequent decrease of complications. PMID- 30251153 TI - Postoperative complications of intestinal anastomosis after blunt abdominal trauma. AB - BACKGROUND: Intestinal disruption following blunt abdominal trauma (BAT) continues to be associated with significant morbidity and mortality despite the advances in resuscitation and management. We aim to analyze the management and postoperative outcomes of intestinal injuries secondary to blunt abdominal trauma. METHOD: We retrospectively reviewed all adult patients with intestinal injuries who underwent laparotomy for BAT between December 2008 and September 2015 at Level I trauma center. Data included demographics, mechanism of injury, site (small and large intestine), type of repair, (enterorrhaphy and resection with anastomosis), type of anastomosis (hand-sewn or stapled anastomoses), need for damage control laparotomy, postoperative complications, and mortality. Data were analyzed and compared for postoperative complications. RESULTS: A total of 160 patients with bowel injuries were included with mean age of 33 years, and 95.6% were males. Injuries involving small bowel, colon, and combined small and large bowel were found in 57.5%, 33.1%, and 9.4%, respectively, with only two duodenal and one rectal injury cases. There were 46.3% patients underwent debridement and primary closure, while 53.8% required resection with anastomosis. Anastomoses were side-to-side stapled in 79.1%, hand-sewn in 14.0%, and combination in 7.0% of patients. The overall postoperative complications (17.5%) in terms of wound infection (n = 16), intra-abdominal abscess (n = 13), and anastomotic leak (n = 13). There were two deaths occurred because of bowel injury complications. Need for blood transfusion, high serum lactate, number of re laparotomies, and mortality were significantly associated with postoperative complications. On multivariate regression analysis, serum lactate (OR 1.27; 95% CI 1.01-1.60; p = 0.04) was found to be the independent predictor of postoperative complications. CONCLUSION: Repair of traumatic blunt bowel injury remains a surgical challenge. PMID- 30251154 TI - Weight-bearing or non-weight-bearing after surgical treatment of ankle fractures: a multicenter randomized controlled trial. AB - PURPOSE: The goal of this study was to assess if unprotected weight-bearing as tolerated is superior to protected weight-bearing and unprotected non-weight bearing in terms of functional outcome and complications after surgical fixation of Lauge-Hansen supination external rotation stage 2-4 ankle fractures. METHODS: A multicentered randomized controlled trial was conducted in patients ranging from 18 to 65 years of age without severe comorbidities. Patients were randomized to unprotected non-weight-bearing, protected weight-bearing, and unprotected weight-bearing as tolerated. The primary endpoint of the study was the Olerud Molander Ankle Score (OMAS) 12 weeks after randomization. The secondary endpoints were health-related quality of life using the SF-36v2, time to return to work, time to return to sports, and the number of complications. RESULTS: The trial was terminated early as advised by the Data and Safety Monitoring Board after interim analysis. A total of 115 patients were randomized. The O'Brien-Fleming threshold for statistical significance for this interim analysis was 0.008 at 12 weeks. The OMAS was higher in the unprotected weight-bearing group after 6 weeks c(61.2 +/- 19.0) compared to the protected weight-bearing (51.8 +/- 20.4) and unprotected non-weight-bearing groups (45.8 +/- 22.4) (p = 0.011). All other follow-up time points did not show significant differences between the groups. Unprotected weight-bearing showed a significant earlier return to work (p = 0.028) and earlier return to sports (p = 0.005). There were no differences in the quality of life scores or number of complications. CONCLUSIONS: Unprotected weight-bearing and mobilization as tolerated as postoperative care regimen improved short-term functional outcomes and led to earlier return to work and sports, yet did not result in an increase of complications. PMID- 30251155 TI - Identification and characterization of in vivo, in vitro and reactive metabolites of vandetanib using LC-ESI-MS/MS. AB - Vandetanib (Caprelsa tablets, VNT) is an orally inhibitor of vascular endothelial growth factor receptor 2. The current research reports the characterization and identification of in vitro, in vivo and reactive intermediates of VNT. In vitro metabolites of VNT were performed by incubation with rat liver microsomes (RLMs). Extraction of vandetanib and its in vitro metabolites from the incubation mixtures were done by protein precipitation. In vivo metabolism was done by giving one oral dose of vandetanib (30.8 mg/kg) to Sprague Dawley rats in metabolic cages by using oral gavage. Urine was gathered then filtered at certain time intervals (0, 6, 12, 18, 24, 48, 72, 96 and 120 h) from vandetanib dosing. A similar volume of ACN was added to each collected urine sample. Both layers (organic and aqueous) were injected into liquid chromatography electro spray ionization tandem mass spectrometry (LC-ESI-MS/MS) to detect in vivo vandetanib metabolites. N-methyl piperidine ring of vandetanib is considered a cyclic tertiary amine that undergoes metabolism forming iminium intermediates that are very reactive toward nucleophilic macromolecules. Incubation of vandetanib with RLMs in the presence of 1.0 mM KCN was made to check reactive metabolites as it is usually responsible for noticeable idiosyncratic toxicities including phototoxicity and QT interval prolongation. Four in vivo phase I, one in vivo phase II metabolites, six in vitro phase I metabolites and four cyano conjugates of vandetanib were detected by LC-MS/MS. In vitro and in vivo phase I metabolic reactions were N-oxide formation, N-demethylation, alpha-carbonyl formation and alpha-hydroxylation. In vivo phase II metabolic reaction was direct conjugation of vandetanib with glucuronic acid. All metabolic reactions occurred in N-methyl piperidine of vandetanib which causes toxicity and instability of vandetanib. PMID- 30251156 TI - Effect of GnRHa on Th17/Treg cells in peripheral blood of patients with unexplained repeated implantation failure. AB - OBJECTIVE: To investigate the effect and possible mechanism of downregulation of gonadotropin-releasing hormone agonist (GnRHa) on Th17/Treg (regulatory T cell) cells in peripheral blood of patients with unexplained repeated implantation failure (RIF). METHODS: Fifty-two patients who had RIF (>= 3 consecutive transfers of >= 4 high-grade embryos in women under the age of 40 (excluding 40)) of frozen-thawed embryos were studied. Twenty-nine cases receiving simple hormone replacement therapy (HRT) were defined as transfer group, and the remaining 23 cases with HRT combined with GnRHa downregulation were defined as GnRHa downregulation group. In addition, 30 cases of the normal early pregnancy group were selected as control group. RESULTS: Before HRT, the number of Th17 and Treg cells in CD4+ lymphocytes was increased and decreased, respectively, with the ratio of Th17/Treg cells increased in HRT group compared with the control group (p < 0.05). On the day of progesterone conversion, compared with the HRT group, the percentage of Th17 and Treg cells was decreased and increased, respectively, with the ratio of Th17/Treg cells decreased significantly in GnRHa downregulation group (p < 0.05). The estrogen E2 levels of the GnRHa downregulation group were slightly higher than those of the HRT group, with no significant difference between the two groups (p > 0.05). Further, there was no significant difference in the levels of chorionic gonadotropin at the 14th day and the 21st day after transplantation between HRT group and GnRHa downregulation group (p > 0.05). CONCLUSION: There were an increase and a decrease in the number of Th17 and Treg cells, respectively, with Th17/Treg cells imbalanced in unexplained RIF. GnRHa downregulation may play a direct immunomodulatory role in disrupting the imbalance and then improve the endometrial receptivity. These effects did not depend on the E2 levels in peripheral blood, nor affect early embryonic development. PMID- 30251157 TI - Effects of superovulation, in vitro fertilization, and oocyte in vitro maturation on imprinted gene Grb10 in mouse blastocysts. AB - PURPOSE: Grb10 is a key imprinted gene that is suspected to have a role in the adverse outcomes of assisted reproductive technology (ART), but little is known about the effects of ART on it. Primary ART techniques, including superovulation, in vitro fertilization (IVF), and oocyte in vitro maturation (IVM), were analyzed in this study of the effects of ART on embryo quality and Grb10. METHODS: Embryo development rates were determined. Blastocyst cell number and global methylation were analyzed at the single-embryo level, together with Grb10 methylation and mRNA expression of the imprinted genes. RESULTS: Lower blastocyst cell number, higher genome and Grb10 CGI1 methylation, and variable mRNA expression were observed in the ART groups compared with the control group. Whether fertilization was in vivo or in vitro, the changes in the genome and Grb10 CGI1 methylation level and Grb10 and H19 expression were similar in the groups with superovulation and more significant than the IVM group. CONCLUSIONS: These results suggest that superovulation had a greater impact than IVF or IVM on the genome and Grb10 DNA methylation level, and Grb10 and H19 expression. PMID- 30251158 TI - Influence of preadipocyte-conditioned medium on the proliferation and invasive potential of breast cancer cell lines in vitro. AB - PURPOSE: Autologous transplantation of adipose tissue into the breast is commonly performed in clinical practice, but its oncological safety has not been established. METHODS: We conducted an in vitro study to assess the influence of factors released by adipose-derived stem cells (ASCs), from multiple source tissues and harvested using different techniques, on proliferation and invasiveness of two breast cancer cell lines. RESULTS: Fat specimens of 66 donors (57 female, 9 male) were collected and 44 ASC cultures were established. ASC conditioning of the medium (CM) increased the proliferation of MCF-7 cells (178.4 +/- 62.8%; P < 0.001), whereas MDA-MB321 proliferation was decreased (87.3 +/- 15.3%; P = 0.032). We observed increased cell migration (174.0 +/- 62.8%; P = 0.002), but not cell invasion (1.28 +/- 0.51; P = 0.14) in MDA-MB231. Migration and invasion of MCF-7 cells were not affected by exposure to ASC-CM. For MCF-7 cell migration, lower BMI (< 25 kg/m2) was associated with increased migration, both in univariate (P = 0.015) and multivariate (P = 0.039) analyses. Regarding the cytokine secretome, proliferation of MCF-7 was positively correlated with levels of eotaxin 1 and insulin-like growth factor-binding protein 3 in the CM, and inversely correlated with levels of interleukin 1beta and transforming growth factor beta-3. In case of MDA-MB231, granulocyte colony-stimulating factor, angiogenin, eotaxin 1 and 3, neutrophil activating peptide 2, and neurotrophin-3 were positively correlated with proliferation. CONCLUSIONS: We conclude that fat tissue transplantation increases proliferation and migration, but not invasion, of breast cancer cells. These findings are consistent with clinical data regarding the safety of autologous fat transplantation in breast cancer patients. PMID- 30251160 TI - A risk for athletes: when the desire to sleep becomes a nightmare. A brief case report on benzodiazepine addiction. PMID- 30251161 TI - L-Acetylcarnitine as a histone acetylation modulator in psychiatric disorders. PMID- 30251159 TI - Effects of fatty acid amide hydrolase inhibitor URB597 in a rat model of trauma induced long-term anxiety. AB - RATIONALE: The endocannabinoid neurotransmitter, anandamide, has been implicated in the central modulation of stress responses. Previous animal experiments have shown that inhibitors of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), enhance the ability to cope with acute and chronic stress. OBJECTIVES: Here, we investigated the effects of the globally active FAAH inhibitor URB597 in a rat model of predator stress-induced long-term anxiety. RESULTS: Rats exposed to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a chemical constituent of fox feces, developed a persistent anxiety-like state, which was assessed 7 days after exposure using the elevated plus maze (EPM) test. Systemic administration of URB597 [0.03-0.1-0.3 mg/kg, intraperitoneal (ip)] 2 h before testing suppressed TMT-induced behaviors with a median effective dose (IC50) of 0.075 mg/kg. This effect was strongly correlated with inhibition of brain FAAH activity (r2 = 1.0) and was accompanied by increased brain levels of three FAAH substrates: the endocannabinoid anandamide and the endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists, oleoylethanolamide (OEA), and palmitoylethanolamide (PEA). The anxiolytic-like effects of URB597 were blocked by co-administration of the CB1 receptor antagonist rimonabant (1 mg/kg, ip), but not of the PPAR-alpha antagonist GW6471 (1 mg/kg, ip). Finally, when administered 18 h after TMT exposure (i.e., 6 days before the EPM test), URB597 (0.3 mg/kg, ip) prevented the consolidation of anxiety-like behavior in a CB1-dependent manner. CONCLUSIONS: The results support the hypothesis that anandamide-mediated signaling at CB1 receptors serves an important regulatory function in the stress response, and confirm that FAAH inhibition may offer a potential therapeutic strategy for post-traumatic stress disorder. PMID- 30251162 TI - Effects of the T-type calcium channel antagonist Z944 on paired associates learning and locomotor activity in rats treated with the NMDA receptor antagonist MK-801. AB - RATIONALE: Currently available antipsychotics are unsatisfactory given their side effects and limited efficacy for the cognitive symptoms of schizophrenia. Many currently available drugs, such as haloperidol, are T-type calcium channel antagonists in addition to their well-established antagonism of dopamine D2 receptors. Thus, preclinical research into the effects of T-type calcium channel antagonists/blockers in behavioral assays related to schizophrenia may inform novel therapeutic strategies. OBJECTIVES: We explored the effects of a recently developed highly selective T-type calcium channel antagonist, Z944 (2.5, 5.0, 10.0 mg/kg), on the MK-801 (0.15 mg/kg) model of acute psychosis. METHODS: To examine the effects of Z944 on behaviors relevant to schizophrenia, we tested touchscreen-based paired associates learning given its relevance to the cognitive symptoms of the disorder and locomotor activity given its relevance to the positive symptoms. RESULTS: Acute treatment with Z944 failed to reverse the visuospatial associative memory impairments caused by MK-801 in paired associates learning. The highest dose of drug (10.0 mg/kg) given alone produced subtle impairments on paired associates learning. In contrast, Z944 (5.0 mg/kg) blocked the expected increase in locomotion following MK-801 treatment in a locomotor assay. CONCLUSIONS: These experiments provide support that Z944 may reduce behaviors relevant to positive symptoms of schizophrenia, although additional study of its effects on cognition is required. These findings and other research suggest T-type calcium channel antagonists may be an alternative to currently available antipsychotics with less serious side effects. PMID- 30251164 TI - Adult individuals with congenital, untreated, severe isolated growth hormone deficiency have satisfactory muscular function. AB - PURPOSE: While growth hormone (GH) and the insulin-like growth factor type I (IGF I) are known to exert synergistic actions on muscle anabolism, the consequences of prolonged GH deficiency (GHD) on muscle function have not been well defined. We have previously described a large cohort of subjects with isolated GHD (IGHD) caused by a mutation in the GH-releasing hormone receptor gene, with low serum levels of GH and IGF-I. The aim of this study was to assess muscular function in these IGHD subjects. METHODS: A total of 31 GH-naive IGHD (16 males) and 40 control (20 males) subjects, matched by age and degree of daily physical activity, were enrolled. Fat free mass was measured by bioelectrical impedance; muscle strength by dynamometry of handgrip, trunk extension, and knee extension; myoelectric activity and muscle fatigue by fractal dimension; conduction velocity in vastus medialis, rectus femoris, and vastus lateralis muscles by surface electromyography. RESULTS: The IGHD group showed higher knee extension strength both when corrected for weight and fat free mass, and higher handgrip and trunk extension strength corrected by fat free mass. They also exhibit higher conduction velocity of the muscles vastus medialis, rectus femoris, and vastus lateralis, but lower free fat mass and myoelectric activity of the vastus medialis, rectus femoris and vastus lateralis. There were no differences between the two groups in fractal dimension in all studied muscles. CONCLUSION: Individuals with untreated IGHD have better muscle strength parameters adjusted for weight and fat free mass than controls. They also exhibit greater peripheral resistance to fatigue, demonstrating satisfactory muscle function. PMID- 30251163 TI - Conditioned aversive responses produced by delayed, but not immediate, exposure to cocaine and morphine in male Sprague-Dawley rats. AB - RATIONALE: To determine the conditions under which tastes paired with delayed access to experimenter-delivered cocaine and morphine elicit a conditionally aversive affective state. OBJECTIVES AND METHODS: The potential of saccharin paired with immediate access to cocaine (5, 10, 20 mg/kg, sc and ip) and delayed (30 and 10 min) access to cocaine (20 mg/kg, sc and ip) and morphine (10 mg/kg, sc) to elicit a pattern of aversive responding in the taste reactivity test (Grill and Norgren 1978a) was evaluated. Cocaine-induced aversions were compared with those produced by a moderate dose of LiCl (50 mg/kg). Finally, as an independent measure of cocaine withdrawal, the potential of exposure to saccharin paired with delayed access to cocaine to produce anxiogenic-like responding in the Light-Dark Emersion test was evaluated. RESULTS: Immediate access to cocaine did not produce conditioned aversion at any dose. Delayed (30 or 10 min) access to sc cocaine (20 mg/kg) produced robust conditioned aversion and delayed access to ip cocaine (20 mg/kg; 30 min) and to sc morphine (10 mg/kg; 10 min) produced weaker conditioned aversion. Yawning emerged as a potential withdrawal response in rats conditioned with delayed (30 min) access to 20 mg/kg, sc, cocaine. Contextual cues did not produce conditioned aversion when paired with delayed access to sc cocaine (20 mg/kg). Finally, exposure to saccharin paired with delayed access to cocaine produced anxiogenic-like responding in the Light-Dark Emersion test. CONCLUSION: Our results support the contention that a conditioned aversive state develops when a taste cue comes to predict the delayed availability of drugs of abuse. PMID- 30251165 TI - 18F-FDG PET reveals an adrenocortical carcinoma in a bilateral adrenal multinodular disease. PMID- 30251166 TI - Laparoscopic partial liver resection improves the short-term outcomes compared to open surgery for liver tumors in the posterosuperior segments. AB - PURPOSE: The aim of this study was to compare the clinical outcomes between laparoscopic partial liver resection and open partial hepatectomy for tumors in the posterosuperior segments. METHODS: The clinical outcomes of patients who underwent either laparoscopic (n = 20) or open (n = 44) resection in segments 7/8 of the liver were initially evaluated. Because of disparities in the background characteristics, a case-matched study (1:1) was conducted. In addition, a comparative study of the patients who met the institutional criteria for laparoscopic partial hepatectomy was performed. RESULTS: In the case-matched study, the laparoscopic technique required a longer operation time (p = 0.001), but was associated with less intraoperative blood loss (p = 0.021), a lower incidence of major complications (p = 0.014), higher levels of serum albumin on postoperative days 3 and 7 (p = 0.031 and p = 0.035), and earlier discharge (p = 0.001) than open resection. The results of the latter study were similar to those of the case-matched analysis. CONCLUSIONS: Laparoscopic partial hepatectomy was a feasible procedure for treating tumors in the posterosuperior segments without compromising oncological safety and yielded better short-term outcomes than open techniques. In addition, this study provides concrete selection criteria for laparoscopic partial hepatectomy for difficult lesions. PMID- 30251167 TI - Rapid Detection of Rongalite via a Sandwich Lateral Flow Strip Assay Using a Pair of Aptamers. AB - A sandwich lateral flow strip assay (LFSA) using a couple of aptamers functionalized with gold nanoparticles (AuNPs) was designed to assess the presence of rongalite in agrifood products. More specifically, a biotin-labeled primary A09 aptamer immobilized on a streptavidin-coated membrane and a secondary B09 aptamer conjugated with AuNPs were developed as capturing and signaling probes, respectively. This system allows the successful and direct detection of rongalite in food samples with concentrations as low as 1 MUg/mL, simply by observing the color change of LFSA control and test line. PMID- 30251168 TI - Identification of tetragametic human chimerism by routine DNA profiling. AB - Chimerism in humans is defined as the presence of two genetically different cell lines within the same organism. It is usually an acquired condition that is restricted to certain tissues and can be explained by therapeutic interventions such as blood transfusion or the transplantation of allogenic hematopoietic cells. Implications of such patients for forensic DNA testing have been described in the literature. In some rare cases, true inherited chimerism is observed. This so called tetragametic chimerism occurs via the fertilization of the two ova by two spermatozoa, followed by the fusion of early embryos and the development of an organism with intermingled cell lines. Such examples have been found in mice and other mammalian species including humans. We describe a phenotypically normal woman in whom tetragametic chimerism (46,XX/46,XX) was unexpectedly identified by STR typing during routine DNA profiling. Cytogenetic analysis proved to be a valuable tool for both independent confirmation and direct visualization of the two coexisting cell lines. PMID- 30251169 TI - Electronically ascertained extended pedigrees in breast cancer genetic counseling. AB - A comprehensive pedigree, usually provided by the counselee and verified by medical records, is essential for risk assessment in cancer genetic counseling. Collecting the relevant information is time-consuming and sometimes impossible. We studied the use of electronically ascertained pedigrees (EGP). The study group comprised women (n = 1352) receiving HBOC genetic counseling between December 2006 and December 2016 at Landspitali in Iceland. EGP's were ascertained using information from the population-based Genealogy Database and Icelandic Cancer Registry. The likelihood of being positive for the Icelandic founder BRCA2 pathogenic variant NM_000059.3:c.767_771delCAAAT was calculated using the risk assessment program Boadicea. We used this unique data to estimate the optimal size of pedigrees, e.g., those that best balance the accuracy of risk assessment using Boadicea and cost of ascertainment. Sub-groups of randomly selected 104 positive and 105 negative women for the founder BRCA2 PV were formed and Receiver Operating Characteristics curves compared for efficiency of PV prediction with a Boadicea score. The optimal pedigree size included 3 degrees relatives or up to five generations with an average no. of 53.8 individuals (range 9-220) (AUC 0.801). Adding 4 degrees relatives did not improve the outcome. Pedigrees including 3 degrees relatives are difficult and sometimes impossible to generate with conventional methods. Pedigrees ascertained with data from pre-existing genealogy databases and cancer registries can save effort and contain more information than traditional pedigrees. Genetic services should consider generating EGP's which requires access to an accurate genealogy database and cancer registry. Local data protection laws and regulations have to be addressed. PMID- 30251170 TI - Development and pilot testing of a leaflet informing women with breast cancer about genomic testing for polygenic risk. AB - The inclusion of polygenic risk scores in breast cancer risk prediction models provides a more personalised and accurate prediction of breast cancer risk for women with and without breast cancer, who would otherwise receive negative results from traditional testing of moderate- and high-risk genes. This study aimed to develop, and pilot test a leaflet with a sample of women participating in a large prospective cohort study. The leaflet aimed to provide information about polygenic risk to assist women to decide whether or not to learn results from genomic testing for common risk variants associated with breast cancer risk. A prototype of the leaflet was developed based on published literature and with the expertise from a multidisciplinary team. The acceptability of the leaflet was assessed by self-report questionnaire among 29 women participating in the prospective cohort study. More than 80% participants stated that the leaflet was clear, informative and easy to understand and increased their understanding of polygenic risk information. While low to moderate levels of distress/worry were reported around implications of the test results for the next generation, 71% felt reassured and agreed that the information provided in the leaflet had helped them cope. Pilot-test results indicate the leaflet is acceptable to the participants and the revised leaflet can be used as an information tool for women undergoing genomic testing. This educational leaflet will become a useful information source to meet the information needs of women undergoing genomic testing. PMID- 30251172 TI - Patisiran: First Global Approval. AB - Patisiran (ONPATTROTM) is a double-stranded small interfering RNA encapsulated in a lipid nanoparticle for delivery to hepatocytes. By specifically binding to a genetically conserved sequence in the 3' untranslated region of mutant and wild type transthyretin (TTR) messenger RNA, patisiran causes its degradation (via RNA interference) and subsequently a reduction in serum TTR protein levels and tissue TTR protein deposits. Patisiran has been developed by Alnylam Pharmaceuticals; it was recently approved in the USA for the treatment of the polyneuropathy of hereditary TTR-mediated amyloidosis (hATTR) in adults and subsequently approved in the EU for the treatment of hATTR in adults with stage 1 or 2 polyneuropathy. The recommended dosage, administered as a single intravenous infusion over approximately 80 min, is 0.3 mg/kg once every 3 weeks for patients weighing < 100 kg and 30 mg once every 3 weeks for patients weighing >= 100 kg. This article summarizes the milestones in the development of patisiran leading to these approvals. PMID- 30251173 TI - Capsaicin 8% Dermal Patch: A Review in Peripheral Neuropathic Pain. AB - The adhesive capsaicin dermal patch (Qutenza(r)) delivers a high concentration (8% w/w) of synthetic capsaicin, a highly selective agonist of transient receptor potential vanilloid-1 (TRPV-1), directly to the site of pain. The capsaicin 8% dermal patch is indicated in the EU for the treatment of peripheral neuropathic pain (PNP) in adults, either alone or in combination with other medicinal products for pain. In patients with painful diabetic peripheral neuropathy, a single 30-min application of the capsaicin 8% dermal patch provided 12 weeks of pain relief and improved sleep quality compared with placebo. Repeat treatment with the capsaicin 8% dermal patch plus standard of care over 52 weeks provided sustained pain relief, with no negative neurological effects compared with standard of care alone. The capsaicin 8% dermal patch was non-inferior to oral pregabalin in relieving pain in patients with non-diabetic PNP, with a faster onset of action and greater treatment satisfaction. A single 60-min application of the capsaicin 8% dermal patch provided rapid and sustained pain relief in patients with postherpetic neuralgia. Results in patients with HIV-associated neuropathy were equivocal, with a significant improvement in pain intensity observed in one trial, but not in the other. The capsaicin 8% dermal patch was generally well tolerated; transient application-site reactions were the most common adverse events. In conclusion, the capsaicin 8% dermal patch is a useful addition to the treatment options currently available for patients with PNP. PMID- 30251175 TI - Left atrial, ventricular and atrio-ventricular strain in patients with subclinical heart dysfunction. AB - Arterial hypertension (AH) and diabetes mellitus (DM) are the most common causes of heart deterioration because of their high prevalence in the population. The aim of this study was to evaluate peak left atrial (LA), longitudinal strain (PALS), left ventricular (LV), longitudinal strain (LS) and global atrial ventricular strain (GAVS), by speckle-tracking echocardiography (STE), in asymptomatic patients with AH or/and DM and normal LA, LV size and ejection fraction (EF), to analyze their capability to detect early subclinical dysfunction. We enrolled 162 patients affected by AH and/or DM with normal indexed LA volume, LV end-diastolic diameter and a LVEF > 52% (females) or > 54% (males) (60 hypertensives, 52 diabetics and 50 both) and 60 healthy controls. All subjects underwent standard and advanced STE. PALS, LS and GAVS were measured. GAVS was calculated as the algebraic sum of absolute PALS and LS values in four- and two-chambers views. LS, although with lower values in hypertensives, diabetics and both, did not show significant differences between groups. PALS and GAVS were significantly reduced in AH (31.9 +/- 10.3% and 49.7 +/- 11.2%, respectively) and DM (26.2 +/- 7.1% and 42.6 +/- 9.8%) compared to controls, and even more if the two coexisted (20.4 +/- 6.5% and 37.1 +/- 8.4%). PALS had the highest statistical significance and was able to identify subclinical damage independently from LS value. PALS was reduced in patients with AH and/or DM without alteration of standard echo indexes. The value of PALS was independent from LS and was sufficient to identify heart dysfunction in an earlier stage. PMID- 30251176 TI - Left ventricular myocardial T1 mapping and strain analysis evaluate cardiac abnormality in hypothyroidism. AB - Cardiovascular Magnetic Resonance (CMR)-based T1 mapping and Heart Deformation Analysis (CMR-HDA) can assess the myocardial tissue characteristic and strain of cardiomyopathy. Whether they can assess cardiac abnormality of hypothyroidism (HT) is unknown. We aim to analysis left ventricular (LV) T1 values and strain of patients with overt HT (OHT) and subclinical HT (SHT) with CMR-based T1 mapping and HDA. This study prospectively included 32 OHT patients, 23 SHT patients and 27 healthy controls who underwent CMR. LV T1 mapping was obtained with a Modified Look-Locker Inversion Recovery sequence while LV circumferential strain (LVCS) and radial strain (LVRS), LV longitudinal strain (LVLS) were respectively analyzed on the short-axial and four-chamber cines with HDA. LV Eject Fraction among three groups were similar (p = 0.676). LV myocardial T1 correlated with LVCS (r = 0.734, p < 0.001) and LVRS (r = - 0.340, p = 0.011). LV myocardial T1 of OHT patients significantly increased in comparison with SHT patients (t = 5.403, p < 0.001) and normal controls (t = 10.197, p < 0.001), meanwhile, LV myocardial T1 of SHT patients were higher than that of controls (t = 2.629, p = 0.013). Compared with SHT patients (t = 1.925, p = 0.031) and normal controls (t = 2.875, p = 0.006), LVCS of OHT patients reduced while LVCS of SHT patients were lower than that of normal controls (t = 2.451, p = 0.020). LVRS of SHT patients were higher than OHT patients (t = 2.778, p = 0.008), but comparable to normal controls (t = 1.134, p = 0.266). LVLS of SHT and OHT significantly impaired in comparison with normal control. The increased LV myocardial T1 value and reduced strain were found in HT. CMR-based LV myocardial T1 and stain analysis are useful to evaluate myocardial tissue characteristic and mechanics in both overt and subclinical hypothyroidism. PMID- 30251177 TI - Differences in clinical manifestations and prognosis of Chinese giant cell arteritis patients with or without polymyalgia rheumatica. AB - BACKGROUND: The symptoms of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) frequently overlap in the elderly. Whether there are differences in clinical features or prognosis between GCA patients with or without PMR remains unknown. AIMS: To identify differences in clinical manifestation and prognosis between Chinese GCA patients with or without PMR. METHODS: A retrospective study of patients diagnosed with GCA in Peking Union Medical College Hospital (PUMCH) during the last 20 years was conducted. Clinical data was collected and analyzed accordingly, and follow-up was performed. RESULTS: A total of 50 patients had PMR, while 41 patients did not, with no significant differences in age, gender, and disease course between the two groups. GCA patients with PMR presented with higher risks of family history of malignancy (p = 0.048). Patients without PMR had higher proportion of hearing loss (p = 0.006), ANCA positive (p = 0.024), and abnormal imaging findings illustrating the involvement of arteries under aortic arch (p = 0.018). Before treatment, total lymphocyte counts in patients without PMR were lower than those with PMR, and monocyte counts in both groups were higher than normal. Acute phase reactants in patients without PMR were higher than the other group. No significant differences were found in prognosis during follow-up. CONCLUSIONS: GCA patients with or without PMR have different clinical characteristics. Patients with PMR present myalgia or arthralgia more frequently, while those without PMR have higher inflammatory markers, lower lymphocyte counts, and wider involvement of arteries under aortic arch. PMID- 30251178 TI - Dr Eveleen O'Brien (1901-1981). AB - Dr Eveleen O'Brien (1901-1981) was a leading figure in Irish asylum medicine, with a particular interest in the care of patients suffering from epilepsy and the crossover between neurology and psychiatry. From 1933 to 1966, O'Brien worked in Grangegorman Mental Hospital. She was appointed Governor of the Central Mental Hospital, Dundrum in January 1968 and remained in this position until 1971. An enthusiastic researcher, O'Brien published several papers in the Journal of Mental Science, including Ireland's first systematic review of insulin therapy (1939). In 1942, O'Brien obtained a doctorate in medicine (MD or Medicinae Doctor) from the National University of Ireland for a thesis titled "Epilepsy and its theories, results of treatment". O'Brien died in Sutton, North Dublin, on 31 July 1981 at 80 years of age. O'Brien belonged to a remarkable group of Irish women doctors in the early 1900s, each of whom made substantial contributions to the development of Irish medical services and improvement of social conditions, especially for the socially excluded and the mentally ill. PMID- 30251174 TI - Cardiovascular Safety of Antihyperglycemic Agents: "Do Good or Do No Harm". AB - Results from recent cardiovascular outcome trials have ushered in a new era in the management of type 2 diabetes mellitus, moving from a focus on glycemic control to the cardiovascular safety of antihyperglycemic agents. Several new antihyperglycemic drugs have been shown to exert either neutral or cardioprotective effects in patients with diabetes. Among them, the sodium glucose co-transporter-2 (SGLT-2) inhibitors (gliflozins) and selected agents from the incretin mimetics or enhancers, such as the glucagon-like peptide-1 (GLP 1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins), appear to confer cardiovascular safety and/or protection in patients with underlying, or at high risk for, cardiovascular disease. Metformin remains the standard first-line drug treatment for patients with diabetes because of its established effectiveness and cardiovascular safety. However, this initial drug therapy may not prove adequate as this disease appears to be progressive with a decline in function of the pancreatic beta cells, necessitating the addition of other agents to better control rising glucose levels. With the advent of several new classes of antihyperglycemic drugs and the completion of their respective cardiovascular outcome trials, the therapeutic armamentarium against this disease pandemic appears to be greatly expanding and moving closer to the direction of the Hippocratic aphorism "Do Good or Do No Harm". In this review, we discuss all these issues and summarize the contemporary literature on cardiovascular safety and outcomes of the available glucose-lowering agents. PMID- 30251180 TI - Association between red and processed meat with breast cancer: Comment on "Red and processed meat intake and risk of breast cancer: a meta-analysis of prospective studies" by Guo et al. PMID- 30251179 TI - The Impact of Pancreatic Beta Cell Heterogeneity on Type 1 Diabetes Pathogenesis. AB - PURPOSE OF REVIEW: To discuss advances in our understanding of beta-cell heterogeneity and the ramifications of this for type 1 diabetes (T1D) and its therapy. RECENT FINDINGS: A number of studies have challenged the long-standing dogma that the majority of beta cells are eliminated in T1D. As many as 80% are present in some T1D subjects. Why don't these cells function properly to release insulin in response to high glucose? Other findings deploying single-cell "omics" to study both healthy and diseased cells-from patients with both T1D and type 2 diabetes (T2D)-have revealed cell subpopulations and heterogeneity at the transcriptomic/protein level between individual cells. Finally, our own and others' findings have demonstrated the importance of functional beta-cell subpopulations for insulin secretion. Heterogeneity may endow beta cells with molecular features that predispose them to failure/death during T1D. PMID- 30251182 TI - Medial temporal lobe volumes in late-life depression: effects of age and vascular risk factors. AB - Substantial work associates late-life depression with hippocampal pathology. However, there is less information about differences in hippocampal subfields and other connected temporal lobe regions and how these regions may be influenced by vascular factors. Individuals aged 60 years or older with and without a DSM-IV diagnosis of Major Depressive Disorder completed clinical assessments and 3 T cranial MRI using a protocol allowing for automated measurement of medial temporal lobe subfield volumes. A subset also completed pseudo-continuous arterial spin labeling, allowing for the measurement of hippocampal cerebral blood flow. In 59 depressed and 21 never-depressed elders (mean age = 66.4 years, SD = 5.8y, range 60-86y), the depressed group did not exhibit statistically significant volumetric differences for the total hippocampus or hippocampal subfields but did exhibit significantly smaller volumes of the perirhinal cortex, specifically in the BA36 region. Additionally, age had a greater effect in the depressed group on volumes of the cornu ammonis, entorhinal cortex, and BA36 region. Finally, both clinical and radiological markers of vascular risk were associated with smaller BA36 volumes, while reduced hippocampal blood flow was associated with smaller hippocampal and cornu ammonis volumes. In conclusion, while we did not observe group differences in hippocampal regions, we observed group differences and an effect of vascular pathology on the BA36 region, part of the perirhinal cortex. This is a critical region exhibiting atrophy in prodromal Alzheimer's disease. Moreover, the observed greater effect of age in the depressed groups is concordant with past longitudinal studies reporting greater hippocampal atrophy in late-life depression. PMID- 30251181 TI - Predictors of survival in patients with influenza pneumonia-related severe acute respiratory distress syndrome treated with prone positioning. AB - BACKGROUND: Patients with influenza complicated with pneumonia are at high risk of rapid progression to acute respiratory distress syndrome (ARDS). Prone positioning with longer duration and lung-protective strategies might reduce the mortality level in ARDS. The aim of this study is to investigate the survival predictors of prone positioning in patients with ARDS caused by influenza pneumonia. METHODS: This retrospective study was conducted by eight tertiary referral centers in Taiwan. From January 1 to March 31 in 2016, all of the patients in intensive care units with virology-proven influenza pneumonia were collected, while all of those patients with ARDS and receiving prone positioning were enrolled. Demographic data, laboratory examinations, management records, ventilator settings and clinical outcomes were collected for analysis. RESULTS: During the study period, 336 patients with severe influenza pneumonia were screened and 263 patients met the diagnosis of ARDS. Totally, 65 patients receiving prone positioning were included for analysis. The 60-day survivors had lower Acute Physiology and Chronic Health Evaluation (APACHE) II score, pneumonia severity index (PSI), creatinine level and lower rate of receiving renal replacement therapy than non-survivors (22.4 +/- 8.5 vs. 29.2 +/- 7.4, p = 0.003; 106.6 +/- 40.9 vs. 135.3 +/- 48.6, p = 0.019; 1.2 +/- 0.9 mg/dL vs. 3.1 +/- 3.6 mg/dL, p = 0.040; and 4% vs. 42%, p < 0.005). Multivariate Cox regression analysis identified PSI (hazard ratio 1.020, 95% confidence interval 1.009-1.032; p < 0.001), renal replacement therapy (hazard ratio 6.248, 95% confidence interval 2.245-17.389; p < 0.001), and increase in dynamic driving pressure (hazard ratio 1.372, 95% confidence interval 1.095-1.718; p = 0.006) which were independent predictors associated with 60-day mortality. CONCLUSIONS: In the present study, in evaluating the effect of prone positioning in patients with influenza pneumonia-related ARDS, pneumonia severity index, renal replacement therapy and increase in dynamic driving pressure were associated with 60-day mortality in patients with influenza pneumonia-related ARDS receiving prone positioning. PMID- 30251183 TI - [Knowledge of German anesthetists on antibiotic stewardship]. PMID- 30251185 TI - Mechanism of fibrogenesis in submandibular glands in patients with IgG4-RD. AB - The aim of this study was to investigate the mechanisms driving fibrosis in the submandibular glands (SMG) of patients with IgG4-related disease (IgG4-RD). Immunohistochemistry showed that many fibroblast-like cells expressing IL-6, IL 18, TSLP, IL-33, and MMP1 were present in SMG from the affected patients. SMG fibroblasts were derived from patients with or without IgG4-RD and were cultured in vitro. Expression of IL-6, IL-18, TSLP, IL-33 and MMP1, the secretion of IL-6 and G2/M phase were upregulated in the fibroblasts from the affected patients. By treatment with inflammatory cytokines IL-1beta, TNFalpha or TGF-beta after treatment with or without the NF-kappaB inhibitor curcumin, curucumin blocked the production and secretion of IL-6 upregulated by IL-1beta, TNFalpha, or TNFalpha/TGF-beta in all fibroblasts. Wnt1-inducible signaling protein 1 (WISP1), which can enhance fibroblasts proliferation, was also more abundantly expressed in affected fibroblasts, while treatment with IL-6 induced WISP1, treatment with WISP1 increased the G2/M phase, and curucumin inhibited WISP1 induced by TNFalpha/TGF-beta in unaffected fibroblasts. IL-33 in affected fibroblasts was induced by IL-1beta, TNFalpha, or TNFalpha/TGF-beta, while the effect of IL-1beta or TNFalpha/TGF-beta was blocked by curcumin. These results suggest fibrosis in the SMG of affected patients is closely linked to the proliferation of fibroblasts following induction of IL-6 and WISP1 by inflammatory cytokines. The Th2 cytokines TSLP and IL-33 are also upregulated in affected SMG, and thus may cause chronic inflammation and IgG4 accumulation. PMID- 30251186 TI - Anticipation and violated expectation of pain are influenced by trait rumination: An fMRI study. AB - Rumination - as a stable tendency to focus repetitively on feelings related to distress - represents a transdiagnostic risk factor. Theories suggest altered emotional information processing as the key mechanism of rumination. However, studies on the anticipation processes in relation to rumination are scarce, even though expectation in this process is demonstrated to influence the processing of emotional stimuli. In addition, no published study has investigated violated expectation in relation to rumination yet. In the present study we examined the neural correlates of pain anticipation and perception using a fear conditioning paradigm with pain as the unconditioned stimulus in healthy subjects (N = 30). Rumination was assessed with the 10-item Ruminative Response Scale (RRS). Widespread brain activation - extending to temporal, parietal, and occipital lobes along with activation in the cingulate cortex, insula, and putamen - showed a positive correlation with rumination, supporting our hypothesis that trait rumination influences anticipatory processes. Interestingly, with violated expectation (when an unexpected, non-painful stimulus follows a pain cue compared to when an expected, painful stimulus follows the same pain cue) a negative association between rumination and activation was found in the posterior cingulate cortex, which is responsible for change detection in the environment and subsequent behavioral modification. Our results suggest that rumination is associated with increased neural response to pain perception and pain anticipation, and may deteriorate the identification of an unexpected omission of aversive stimuli. Therefore, targeting rumination in cognitive behavioral therapy of chronic pain could have a beneficial effect. PMID- 30251184 TI - The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders. AB - PURPOSE OF REVIEW: There is a growing body of evidence indicating the gut microbiota influence neurodevelopment and behavior. The purposes of this review are to provide an overview of studies analyzing the microbiota and their metabolites in autism spectrum disorders (ASD) and to discuss the possible mechanisms of action involved in microbial influence on the brain and behavior. RECENT FINDINGS: The microbiota-gut-brain (MGB) axis has been extensively studied in animal models, and it is clear that alterations in the composition of microbiota alter neurological and behavioral outcomes. However, findings in human studies are less abundant. Although there are several studies so far showing altered microbiota (dysbiosis) in ASD, the results are heterogeneous and often contradictory. Intervention studies such as fecal microbiota transplant therapies show promise and lend credence to the involvement of the microbiota in ASD. A role for the microbiota in ASD is likely; however, further studies elucidating microbial or metabolomic signatures and mechanisms of action are needed. Future research should focus on intervention studies that can identify specific metabolites and immune mediators that improve with treatment to help identify etiologies and pathological mechanisms of ASD. PMID- 30251187 TI - Human Vestibulo-Ocular Reflex Adaptation Training: Time Beats Quantity. AB - The vestibulo-ocular reflex (VOR) is the main gaze stabilising system during rapid head movements. The VOR is highly plastic and its gain (eye/head velocity) can be increased via training that induces an incrementally increasing retinal image slip error signal to drive VOR adaptation. Using the unilateral incremental VOR adaptation technique and horizontal active head impulses as the vestibular stimulus, we sought to determine the factors important for VOR adaptation including: the total training time, ratio and number of head impulses to each side (adapting and non-adapting sides; the adapting side was pseudo-randomised left or right) and exposure time to the visual target during each head impulse. We tested 11 normal subjects, each over 5 separate sessions and training protocols. The basic training protocol (protocol one) consisted of unilateral incremental VOR adaptation training lasting 15 min with the ratio of head impulses to each side 1:1. Each protocol varied from the basic. For protocol two, the ratio of impulses were in favour of the adapting side by 2:1. For protocol three, all head impulses were towards the adapting side and the training only lasted 7.5 min. For protocol four, all impulses were towards the adapting side and lasted 15 min. For protocol five, all head impulses were to the adapting side and the exposure time to the visual target during each impulse was doubled. We measured the active and passive VOR gains before and after the training. Albeit with small sample size, our data suggest that the total training time and the visual target exposure time for each head impulse affected adaptation, whereas the total number and repetition rate of head impulses did not. These data have implications for vestibular rehabilitation, suggesting that quality and duration of VOR adaptation exercises are more important than rapid repetition of exercises. PMID- 30251188 TI - Setting Up a Heart Failure Program in 2018: Moving Towards New Paradigm(s). AB - PURPOSE OF REVIEW: Heart failure (HF) is the first cause of hospitalization in the elderly in Western countries, generating tremendous healthcare costs. Despite the spread of multidisciplinary post-discharge programs, readmission rates have remained unchanged over time. We review the recent developments in this setting. RECENT FINDINGS: Recent data plead for global reorganization of HF care, specifically targeting patients at high risk for further readmission, as well as a stronger involvement of primary care providers (PCP) in patients' care plan. Besides, tools, devices, and new interdisciplinary expertise have emerged to support and be integrated into those programs; they have been greeted with great enthusiasm, but their routine applicability remains to be determined. HF programs in 2018 should focus on pragmatic assessments of patients that will benefit the most from the multidisciplinary care; delegating the management of low-risk patients to trained PCP and empowering the patient himself, using the newly available tools as needed. PMID- 30251189 TI - Performance of Bacillus subtilis on fibrous biomass sugar hydrolysates in producing biosurfactants and techno-economic comparison. AB - Surfactin and fatty acetyl glutamate (FA-Glu) were produced by Bacillus subtilis in 5-L fermentor. In a previous 50-mL shake flask study, sugar hydrolysates from soy hull, alfalfa and switchgrass were shown to support the growth of Bacillus strains. It was observed that glucose content and availability of hexose and pentose sugars in the hydrolysates played an important role in determining growth and product concentration. Growth, economic efficiency and product concentration of biosurfactants was compared in fermentations conducted in 5-L stirred tank bioreactor, on biomass hydrolysate-based growth media. Highest bacterial growth absorbance for surfactin and FA-Glu producing strains were at 3.5 and 3.3 absorbance units, respectively, for switchgrass hydrolysate media. Highest concentrations of products were observed in soy hull hydrolysate media (2.9 g/L and 0.28 g/L for surfactin and FA-Glu). Techno-economic analysis of the 5-L fermentations on the three biomasses showed surfactin cost estimate to be $6.63/kg for 97% pure product. PMID- 30251190 TI - Towards efficient enzymatic conversion of D-galactose to D-tagatose: purification and characterization of L-arabinose isomerase from Lactobacillus brevis. AB - L-arabinose isomerase (L-AI) (EC 5. 3. 1. 4. L-AI) that mediates the isomerization of D-galactose to D-tagatose was isolated from Lactobacillus brevis (MF 465792), and was further purified and characterized. Pure enzyme with molecular weight of 60.1 kDa was successfully obtained after the purification using Native-PAGE gel extraction method, which was a monomer in solution. The L AI was found to be stable at 45-75 degrees C, and at pH 7.0-9.0. Its optimum temperature and pH was determined as 65 degrees C and 7.0, respectively. Besides, we found that Ca2+, Cu2+, and Ba2+ ions inhibited the enzyme activity, whereas the enzyme activity was significantly enhanced in the presence of Mg2+, Mn2+, or Co2+ ions. The optimum concentration of Mn2+ and Co2+ was determined to be 1 mM. Furthermore, we characterized the kinetic parameters for L-AI and determined the Km (129 mM) and the Vmax (0.045 mM min- 1) values. Notably, L. brevis L-AI exhibited a high bioconversion yield of 43% from D-galactose to D tagatose under the optimal condition, and appeared to be a more efficient catalyst compared with other L-AIs from various organisms. PMID- 30251191 TI - Enhanced biocatalytic activity of immobilized steapsin lipase in supercritical carbon dioxide for production of biodiesel using waste cooking oil. AB - The present work reports covalent immobilization of steapsin lipase (SL) on Immobead-350 support matrix (IMB) to make a robust biocatalytic system to work under supercritical carbon dioxide condition (Sc-CO2). The developed biocatalyst (IMB:SL) was characterized in details and utilized to convert waste cooking sunflower oil (WCSO) into value-added energy chemical (biodiesel) in Sc-CO2. All reaction process parameters were optimized in detail which offered 86.33% yield of biodiesel from WCSO. The developed Sc-CO2 protocol is compared with the solvent-free conventional synthesis, which indicates almost twofold higher yield of biodiesel in Sc-CO2 media as compared to solvent-free condition. To extend the scope, we have tested fresh and waste cooking oils (WCO) from various sources, offering 81-94% yield of biodiesel. The biocatalyst activity was investigated in various parameters of supercritical condition to know the biocatalyst stability in Sc-CO2. Besides this, IMB:SL biocatalyst was effectively reused up to five recycle. PMID- 30251192 TI - Does high hip centre affect dislocation after total hip arthroplasty for developmental dysplasia of the hip? AB - BACKGROUND: To achieve sufficient socket coverage by the native bone, high placement of cementless acetabular cup is often required. We previously reported, using computer simulation, that higher hip centre improved the bone coverage but decreased the range of motion in total hip arthroplasty (THA) for patients with hip dysplasia. However, in a clinical setting, the correlation between the hip centre height and dislocation after primary THA is still unclear. We examined whether a high hip centre affects dislocation after THA. METHODS: A total of 910 patients, with 1079 dysplastic hips, who underwent primary THA were retrospectively reviewed. The age at THA averaged 63.0 years and mean follow-up was 74.3 months. Vertical centre of rotation (V-COR) was defined as the distance from the head centre to the interteardrop line. Uni- and multivariate logistic regression models were applied to identify significant factors affecting dislocation. RESULTS: Ten hips in nine patients (0.9%) had dislocation after THA. In univariate analysis, age at surgery and V-COR were significant risk factors for dislocation. Multivariate analysis identified advanced age at operation (odds ratio [OR] 1.8/5 years), Crowe classification (OR 15.6), V-COR (OR 3.1/5 mm), and femoral head size (OR 11.6) as independent risk factors for dislocation. Receiver operating characteristic curve analysis revealed the cutoff value of the V-COR for dislocation as 23.9 mm. CONCLUSIONS: A higher hip centre with the V-COR > 23.9 mm affected dislocation after THA for DDH. Our results would be useful for reconstruction of the hip centre, particularly with cementless acetabular cups. PMID- 30251193 TI - Real-time surveillance of left atrial appendage thrombus during contrast computed tomography imaging for catheter ablation: THe Reliability of cOMputed tomography Beyond UltraSound in THROMBUS detection (THROMBUS) study. AB - Left atrial contrast computed tomography (LA-CT) as well as transesophageal echocardiography (TEE) can exclude left atrial appendage (LAA) thrombus, but is sometimes unable to evaluate LAA due to incomplete LAA filling. The aim of the current study was to validate the utility of real-time approach of LA-CT with real-time surveillance of LAA-filling defect (FD). We enrolled consecutive 894 patients with LA-CT studies acquired for catheter ablation and compared the diagnostic accuracy in demonstrating LAA-FD between conventional protocol (N = 474) and novel protocol with real-time surveillance of LAA-FD immediately after the initial scanning and, when necessary, adding delayed scanning in the supine or prone position (N = 420). Primary endpoint was severity of LAA-FD classified into the 3 groups: "Grade-0" for complete filling of contrast, "Grade-1" for incomplete filling of contrast, and "Grade-2" for complete FD of contrast. The prevalence of Grade-1 and Grade-2 FD was 17.3% and 11.2% in conventional protocol, whereas there was no patient with Grade-2 FD, and only 1 patient with Grade-1 FD after the additional scanning in novel protocol. In 5 patients with suspected LAA thrombus both by TEE and Grade-2 FD in LA-CT by the conventional protocol, ablation procedure was canceled due to diagnosis of LAA thrombus. Conversely, 4 patients with suspected LAA thrombus by TEE in novel protocol group was proved to have intact LAA by LA-CT with and without additional scanning. This novel approach with real-time surveillance improved the diagnostic accuracy of LA CT in detecting LAA-FD, suggesting potential superiority of LA-CT over TEE in excluding LAA thrombus. PMID- 30251194 TI - Crohn's disease following rituximab treatment in a patient with refractory nephrotic syndrome. AB - Rituximab (RTX) is increasingly used for the treatment of refractory nephrotic syndrome due to its inhibitory effect on B cells which extends the period of remission, while lowering the dose of steroids needed for disease management. However, RTX can lead to various side effects, including Crohn's disease. Herein, we describe a case of a 15-year-old boy with refractory nephrotic syndrome diagnosed at age 9 years who developed Crohn's disease following RTX treatment. RTX was initiated in this patient at the age of 13 years 6 months due to occurrence of 12 relapses of nephrotic syndrome over a 4-year period, despite treatment using cyclosporine, steroid pulse therapy, and mycophenolate mofetil. The patient received 4 doses of RTX over a 2-year period (dose, 375 mg/m2). Although the treatment was effective in extending the disease-free duration up to 6 months, at the age of 15 years 9 months, the patient developed abdominal pain, associated with frequent watery stools and rapid weight loss. Based on clinical and endoscopic findings, he was diagnosed with Crohn's disease and treated using infliximab. Remission of Crohn's disease was achieved with this treatment, with no further relapse of nephrotic syndrome. Infliximab is thought to extend the remission period of nephrotic syndrome. In this case, we propose that Crohn's disease was caused by an abnormal immune tolerance, secondary to the use of RTX, although the exact underlying mechanism remains to be clarified. Therefore, inflammatory bowel disease should be considered if severe abdominal symptoms with weight loss following RTX administration are observed. PMID- 30251195 TI - Snare technique for endovascular retrieval of coil extending to the atrium after embolization of a dural arteriovenous fistula. AB - BACKGROUND: No data exist regarding retrieval of displaced or stretched coil extending to the right atrium after endovascular embolization of cerebrovascular diseases. We describe a snare technique for retrieval of a displaced coil extending to the right atrium after embolization of dural arteriovenous fistula (DAVF). METHODS: A 35-year-old female with a DAVF underwent transjugular coil embolization that failed with displaced coil extending to the right atrium at an outside hospital. After admission to our hospital, Onyx embolization of the DAVF was performed through left facial vein-inner canthus vein-superior ophthalmic vein to the cavernous sinus. Post-embolization angiography showed complete occlusion of the DAVF. Then we attempted to snare the tip of the displaced coil that extended to the right atrium through femoral vein-inferior vena cava approach. However, current snare techniques failed to retrieve the extended coil after several attempts. Then one week later, we used a modified dual microcatheter and microwire technique to retrieve the displaced coil. One suite of microcatheter and microwire was used to produce a handmade snare device (HMD). The other suite of microcatheter and microwire was used to assist the HMD to snare the displaced coil. RESULTS: Through transjugular vein approach, we used our modified dual microcatheter and microwire snare technique (handmade snare device system) to retrieve the extended coil. After several attempts, the extended coil in the atrium was successfully retrieved. Post-procedure angiography and cardiac examinations did not show any signs of abnormality. CONCLUSIONS: For displaced coil extending to the right atrium after transvenous embolization, our method of modified dual microcatheter technique with HMD snare device system is an effective method to retrieve the extending coil. PMID- 30251196 TI - Impaired cerebral compensatory reserve is associated with admission imaging characteristics of diffuse insult in traumatic brain injury. AB - BACKGROUND: Continuous assessment of cerebral compensatory reserve is possible using the moving correlation between pulse amplitude of intra-cranial pressure (AMP) and intra-cranial pressure (ICP), called RAP. Little is known about the behavior and associations of this index in adult traumatic brain injury (TBI). The goal of this study is to evaluate the association between admission cerebral imaging findings and RAP over the course of the acute intensive care unit stay. METHODS: We retrospectively reviewed 358 adult TBI patients admitted to the Addenbrooke's Hospital, University of Cambridge, from March 2005 to December 2016. Only non-craniectomy patients were studied. Using archived high frequency physiologic signals, RAP was derived and analyzed over the first 48 h and first 10 days of recording in each patient, using grand mean, percentage of time above various thresholds, and integrated area under the curve (AUC) of RAP over time. Associations between these values and admission computed tomography (CT) injury characteristics were evaluated. RESULTS: The integrated AUC, based on various thresholds of RAP, was statistically associated with admission CT markers of diffuse TBI and cerebral edema. Admission CT findings of cortical gyral effacement, lateral ventricle compression, diffuse cortical subarachnoid hemorrhage (SAH), thickness of cortical SAH, presence of bilateral contusions, and subcortical diffuse axonal injury (DAI) were all associated with AUC of RAP over time. Joncheere-Terpstra testing indicated a statistically significant increase in mean RAP AUC across ordinal categories of the abovementioned associated CT findings. CONCLUSIONS: RAP is associated with cerebral CT injury patterns of diffuse injury and edema, providing some confirmation of its potential measurement of cerebral compensatory reserve in TBI. PMID- 30251197 TI - Accurate and robust systolic myocardial T1 mapping using saturation recovery with individualized delay time: comparison with diastolic T1 mapping. AB - T1 mapping data are generally acquired in patients' diastolic phase, wherein their myocardium is the thinnest in the cardiac cycle. However, the analysis of the thin myocardium may cause errors in image registrations and settings related to the region of interest. In this study, we validated systolic T1 mapping using the saturation recovery with individualized delay time (SR-IDT) method and compared it with conventional diastolic T1 mapping. Both diastolic and systolic T1 mappings were performed in the mid-ventricular plane in 10 healthy volunteers (35 +/- 9 years, 9 males) and 29 consecutive patients with cardiac diseases (68 +/- 14 years, 19 males). Comparison of the myocardial T1 value at diastole and systole was performed with both the Pearson correlation coefficient (r) and the Bland-Altman analysis. Additionally, the systolic myocardial T1 value was compared between the volunteers and patients by using Tukey's test. Pearson correlation analysis demonstrated a strong positive correlation between diastolic and systolic T1 values (r = 0.88, P < 0.001). The Bland-Altman plot suggested that left ventricular T1 values in the diastole and systole showed high agreement (mean difference and 95% limits of agreement = 17 +/- 104 ms). Further, systolic T1 values with SR-IDT in patients in the late gadolinium enhancement (LGE) group were significantly higher than those in the control group (1585 +/- 118 ms vs 1469 +/- 69 ms; P = 0.024). Therefore, the proposed systolic T1 mapping with the SR-IDT, which was validated with respect to the conventional diastolic method, is a useful clinical tool for the quantitative characterization of the myocardium. PMID- 30251198 TI - Agreement of driving simulator and on-road driving performance in patients with binocular visual field loss. AB - PURPOSE: On-road testing is considered the standard for assessment of driving performance; however, it lacks standardization. In contrast, driving simulators provide controlled experimental settings in a virtual reality environment. This study compares both testing conditions in patients with binocular visual field defects due to bilateral glaucomatous optic neuropathy or due to retro-chiasmal visual pathway lesions. METHODS: Ten glaucoma patients (PG), ten patients with homonymous visual field defects (PH), and 20 age- and gender-matched ophthalmologically normal control subjects (CG and CH, respectively) participated in a 40-min on-road driving task using a dual brake vehicle. A subset of this sample (8 PG, 8 PH, 8 CG, and 7 CH) underwent a subsequent driving simulator test of similar duration. For both settings, pass/fail rates were assessed by a masked driving instructor. RESULTS: For on-road driving, hemianopia patients (PH) and glaucoma patients (PG) showed worse performance than their controls (CH and CG groups): PH 40%, CH 30%, PG 60%, CG 0%, failure rate. Similar results were obtained for the driving simulator test: PH 50%, CH 29%, PG 38%, CG 0%, failure rate. Twenty-four out of 31 participants (77%) showed concordant results with regard to pass/fail under both test conditions (p > 0.05; McNemar test). CONCLUSIONS: Driving simulator testing leads to results comparable to on-road driving, in terms of pass/fail rates in subjects with binocular (glaucomatous or retro-chiasmal lesion-induced) visual field defects. Driving simulator testing seems to be a well-standardized method, appropriate for assessment of driving performance in individuals with binocular visual field loss. PMID- 30251199 TI - Consensus generation of a minimum set of outcome measures for auditing glaucoma surgery outcomes-a Delphi exercise. AB - PURPOSE: To identify the key set of glaucoma surgery outcome measures considered most important and practical to collect by glaucoma specialists. METHODS: One hundred two glaucoma specialists (57 members of the UK and Eire Glaucoma Society (UKEGS) and 45 members of the European Glaucoma society (EGS)) took part in an Online Delphi exercise. The RAND/UCLA appropriateness method was used analyse data from each round and generate a disagreement index. RESULTS: Participants agreed on 13 baseline data points and 12 outcomes that were considered important and practical to collect. For intraocular pressure (IOP) percentage reduction in IOP from baseline (last three IOP readings pre-op) and reduction below a specified target were considered important. For visual fields, change in a global visual field index, e.g. MD, and development of progression as assessed by linear regression were considered important. From a safety perspective, any visual loss resulting in a doubling of the minimal angle of resolution, loss of 5 dB or more of visual field or development of advanced field loss (Hodapp Parrish Anderson Stage 4) was considered important. The importance of routinely using patient reported outcome measures (PROMs) was highlighted. Consensus suggested that outcomes of glaucoma treatments should be reported at 1, 5 and 10 years. CONCLUSIONS: There was broad consensus on a minimum dataset for reporting the outcomes of glaucoma surgery and outcome measurement intervals. PMID- 30251200 TI - Antiplatelet and anticoagulant agents in vitreoretinal surgery: a prospective multicenter study involving 804 patients. PMID- 30251202 TI - View from inside : Living with mitochondrial disease. PMID- 30251201 TI - Factors associated with lamina cribrosa displacement after trabeculectomy measured by optical coherence tomography in advanced primary open-angle glaucoma. AB - PURPOSE: To investigate the relationship of lamina cribrosa displacement to corneal biomechanical properties and visual function after mitomycin C-augmented trabeculectomy. METHOD: Eighty-one primary open-angle eyes were imaged before and after trabeculectomy using an enhanced depth spectral domain optical coherence tomography (SDOCT). Corneal biomechanical properties were measured with the ocular response analyzer before the surgery. The anterior lamina cribrosa (LC) was marked at several points in each of the six radial scans to evaluate LC displacement in response to intraocular pressure (IOP) reduction. A Humphrey visual field test (HVF) was performed before the surgery as well as 3 and 6 months, postoperatively. RESULTS: Factors associated with a deeper baseline anterior lamina cribrosa depth (ALD) were cup-disc ratio (P = 0.04), baseline IOP (P = 0.01), corneal hysteresis (P = 0.001), and corneal resistance factor (P = 0.001). After the surgery, the position of LC became more anterior (negative), posterior (positive), or remained unchanged. The mean LC displacement was - 42 MUm (P = 0.001) and was positively correlated with the magnitude of IOP reduction (regression coefficient = 0.251, P = 0.02) and negatively correlated with age (regression coefficient = - 0.224, P = 0.04) as well as baseline cup-disk ratio (Regression coefficient = - 0.212, P = 0.05). Eyes with a larger negative LC displacement were more likely to experience an HVF improvement of more than a 3 dB gain in mean deviation (P = 0.002). CONCLUSION: A larger IOP reduction and younger age was correlated with a larger negative LC displacement and improving HVF. The correlation between lower SDOCT cup-disc ratio and postoperative negative LC displacement was borderline (P = 0.05). Corneal biomechanics did not predict LC displacement. PMID- 30251204 TI - Asymptomatic Carotid Stenosis: Intervention or Best Medical Therapy? AB - PURPOSE OF REVIEW: Provide a current overview regarding the optimal strategy for managing patients with asymptomatic carotid artery stenosis. RECENT FINDINGS: Carotid endarterectomy (CEA) and carotid artery stenting (CAS) reduce long-term stroke risk in asymptomatic patients. However, CAS is associated with a higher risk of peri-procedural stroke. Improvements in best medical therapy (BMT) have renewed uncertainty regarding the extent to which results from older randomised controlled trials (RCTs) comparing outcomes following carotid intervention can be generalised to modern medical practise. 'Average surgical risk' patients with an asymptomatic carotid artery stenosis of 60-99% and increased risk of late stroke should be considered for either CEA or CAS. In patients deemed 'high risk' for surgery, CAS is indicated. Use of an anti-platelet, anti-hypertensive and statin, with strict glycaemic control, is recommended. Results from ongoing large, multicentre RCTs comparing CEA, CAS and BMT will provide clarity regarding the optimal management of patients with asymptomatic carotid artery stenosis. PMID- 30251205 TI - Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study. AB - We analyzed the clinical significance and genetic features of ASXL2 and ZBTB7A mutations, and the alternatively spliced isoform of the RUNX1-RUNX1T1 transcript, which is also called AML1-ETO9a (AE9a), in Japanese CBF-AML patients enrolled in the JALSG AML201 study. ASXL2 and ZBTB7A genes were sequenced using bone marrow samples of 41 AML patients with t(8;21) and 14 with inv(16). The relative expression levels of AE9a were quantified using the real-time PCR assay in 23 AML patients with t(8;21). We identified ASXL2 (34.1%) and ZBTB7A (9.8%) mutations in only AML patients with t(8;21). ASXL2-mutated patients had a significantly higher WBC count at diagnosis (P = 0.04) and a lower frequency of sex chromosome loss than wild-type patients (33 vs. 76%, respectively, P = 0.01). KIT mutations were the most frequently accompanied with both ASXL2 (36%) and ZBTB7A (75%) mutations. Neither ASXL2 nor ZBTB7A mutations had an impact on overall or event-free survival. Patients harboring cohesin complex gene mutations expressed significantly higher levels of AE9a than unmutated patients (P = 0.03). In conclusion, ASXL2 and ZBTB7A mutations were frequently identified in Japanese AML patients with t(8;21), but not in those with inv(16). Further analysis is required to clarify the detailed biological mechanism of AE9a regulation of the cohesin complex. PMID- 30251206 TI - Local variations in material and structural properties characterize murine thoracic aortic aneurysm mechanics. AB - We recently developed an approach to characterize local nonlinear, anisotropic mechanical properties of murine arteries by combining biaxial extension distension testing, panoramic digital image correlation, and an inverse method based on the principle of virtual power. This experimental-computational approach was illustrated for the normal murine abdominal aorta assuming uniform wall thickness. Here, however, we extend our prior approach by adding an optical coherence tomography (OCT) imaging system that permits local reconstructions of wall thickness. This multimodality approach is then used to characterize spatial variations of material and structural properties in ascending thoracic aortic aneurysms (aTAA) from two genetically modified mouse models (fibrillin-1 and fibulin-4 deficient) and to compare them with those from angiotensin II-infused apolipoprotein E-deficient and wild-type control ascending aortas. Local values of stored elastic energy and biaxial material stiffness, computed from spatial distributions of the best fit material parameters, varied significantly with circumferential position (inner vs. outer curvature, ventral vs. dorsal sides) across genotypes and treatments. Importantly, these data reveal an inverse relationship between material stiffness and wall thickness that underlies a general linear relationship between stiffness and wall stress across aTAAs. OCT images also revealed sites of advanced medial degeneration, which were captured by the inverse material characterization. Quantification of histological data further provided high-resolution local correlations among multiple mechanical metrics and wall microstructure. This is the first time that such structural defects and local properties have been characterized mechanically, which can better inform computational models of aortopathy that seek to predict where dissection or rupture may initiate. PMID- 30251203 TI - Current trends in tendinopathy: consensus of the ESSKA basic science committee. Part II: treatment options. AB - The treatment of painful chronic tendinopathy is challenging. Multiple non invasive and tendon-invasive methods are used. When traditional non-invasive treatments fail, the injections of platelet-rich plasma autologous blood or cortisone have become increasingly favored. However, there is little scientific evidence from human studies supporting injection treatment. As the last resort, intra- or peritendinous open or endoscopic surgery are employed even though these also show varying results. This ESSKA basic science committee current concepts review follows the first part on the biology, biomechanics and anatomy of tendinopathies, to provide a comprehensive overview of the latest treatment options for tendinopathy as reported in the literature. PMID- 30251208 TI - Open Inguinal Hernia Repair: A Network Meta-analysis Comparing Self-Gripping Mesh, Suture Fixation, and Glue Fixation. AB - The most troublesome complications of inguinal hernia repair are recurrent herniation and chronic pain. A multitude of technological products dedicated to abdominal wall surgery, such as self-gripping mesh (SGM) and glue fixation (GF), were introduced in alternative to suture fixation (SF) in the attempt to lower the postoperative complication rates. We conducted an electronic systematic search using MEDLINE databases that compared postoperative pain and short- and long-term surgical complications after SGM or GF and SF in open inguinal hernia repair. Twenty-eight randomized controlled trials totaling 5495 patients met the inclusion criteria and were included in this network meta-analysis. SGM and GF did not show better outcomes in either short- or long-term complications compared to SF. Patients in the SGM group showed significantly more pain at day 1 compared to those in the GF group (VAS score pain mean difference: - 5.2 Crl - 11.0; - 1.2). The relative risk (RR) of developing a surgical site infection (RR 0.83; Crl 0.50-1.32), hematoma (RR 1.9; Crl 0.35-11.2), and seroma (RR 1.81; Crl 0.54 6.53) was similar in SGM and GF groups. Both the SGM and GF had a significantly shorter operative time mean difference (1.70; Crl - 1.80; 5.3) compared to SF. Chronic pain and hernia recurrence did not statistically differ at 1 year (RR 0.63; Crl 0.36-1.12; RR 1.5; Crl 0.52-4.71, respectively) between SGM and GF. Methods of inguinal hernia repair are evolving, but there remains no superiority in terms of mesh fixation. Ultimately, patient's preference and surgeon's expertise should still lead the choice about the fixation method. PMID- 30251207 TI - The Role of Calpain and Proteasomes in the Degradation of Carbonylated Neuronal Cytoskeletal Proteins in Acute Experimental Autoimmune Encephalomyelitis. AB - The present study was designed to investigate the role of calpain and the proteasome in the removal of oxidized neuronal cytoskeletal proteins in myelin basic protein-induced experimental autoimmune encephalomyelitis (EAE). To this end, EAE rats received a single intrathecal injection of calpeptin or epoxomicin at the first sign of clinical disease. Forty-eight hours later, animals were sacrificed and lumbar spinal cord segments were dissected and used for biochemical analyses. The results show that calpain and proteasome activity is specifically, but partially, inhibited with calpeptin and epoxomicin, respectively. Calpain inhibition causes an increase in total protein carbonylation and in the amount of neurofilament proteins (NFPs), beta-tubulin and beta-actin that were spared from degradation, but no changes are seen in the oxidation of any of three NFPs. By contrast, proteasome inhibition has no effect on total protein carbonylation or cytoskeletal protein degradation but increases the amount of oxidized NFH and NFM. These results suggest that while the proteasome may contribute to removal of oxidized NFPs, calpain is the main protease involved in degradation of neuronal cytoskeleton and does not preferentially targets oxidized NFPs species in acute EAE. Different results were obtained in a cell-free system, where calpain inhibition rises the amount of oxidized NFH, and proteasome inhibition fails to change the oxidation state of the NFPs. The later finding suggests that the preferential degradation of oxidized NFH and NFM in vivo by the proteasome occurs via the 26S and not the 20S particle. PMID- 30251209 TI - The impact of a history of poor mental health on health care costs in the perinatal period. AB - The perinatal period is a critical time for mental health and is also associated with high health care expenditure. Our previous work has identified a history of poor mental health as the strongest predictor of poor perinatal mental health. This study aims to examine the impact of a history of poor mental health on health care costs during the perinatal period. Data from the 1973-1978 cohort of the Australian Longitudinal Study on Women's Health (ALSWH) were linked with a number of administrative datasets including the NSW Admitted Patient Data Collection and Perinatal Data Collection, the Medicare Benefits Scheme and the Pharmaceuticals Benefits Scheme between 2002 and 2011. Even when taking birth type and private health insurance status into account, a history of poor mental health resulted in an average increase of over 11% per birth across the perinatal period. These findings indicate that an investment in prevention and early treatment of poor mental health prior to child bearing may result in a cost saving in the perinatal period and a reduction of the incidence of women experiencing poor perinatal mental health. PMID- 30251210 TI - Potential of leaf and seeds of tropical plants in chicken diets: effect on spermatozoa and egg production. AB - The projected human population growth of 9 billion by the year 2050 has placed greater demand on food security. This calls for an increased supply of foods, especially of animal origin in order to prevent food scarcity in the future. Poultry which would have been a solution to this increased demand for foods of animal origin had suffered from the rising costs of conventional feed ingredients, and this emphasizes the interest to develop local feedstuffs. In view of this, there is increased interest by livestock farmers especially in developing countries to harness the potential of leaf and seeds of tropical browse plants. Data abound that leaf and seed meal of tropical plants are rich in beneficial nutrients and phytochemicals. From previous studies, it can be deduced that leaf and seed meal of tropical browse plants improve chicken performance, but their use in animal feed has been limited owing to constraints imposed by antinutrient factors (ANFs). In this review, the biochemistry of leaf and seed meal of tropical plants, mechanism of actions, methodologies for detoxifying their ANFs, and their effect on chicken reproduction is discussed. PMID- 30251211 TI - Magical Potential: Why Magic Performances Should be Used to Explore the Psychological Factors Contributing to Human Belief Formation. AB - Beliefs in supernatural entities are integral parts of both our culturally embedded religions and more individualized magical belief systems (e.g., paranormal beliefs, spirituality). Scholars regularly link the occurrence of beliefs to individuals' cognitive and affective ways of information processing. For magical beliefs in particular, we expect children to endorse them. When reaching adulthood, however, individuals should have abandoned magical beliefs, and become pragmatic, sceptical, critical and rational thinkers. The reality is, a large proportion of the adult population can be described as magical thinkers, or report having had magical experiences, even in the recent past. Moreover, psychological research in adults shows a large range of magical beliefs, which correlate with particular psychological processing biases (e.g., repetition avoidance, seeing signal in noise). Unfortunately, these correlational studies do not tell us whether such psychological processing biases precede magical beliefs or whether they result from these magical beliefs. Knowing the direction of such relationships is key to understand which psychological biases might contribute to adult belief formation (or the persistence of beliefs from childhood). To test such causal relationships, we started to systematically apply an experimental approach in which people are exposed to anomalous events. Such a central event allows before-after comparisons of psychological biases. First empirical results confirmed that the use of magic performances, particularly when of paranormal nature, results in an important amount of paranormal explanations. Pre-existing beliefs enhanced this explanation bias. These results show how easily naive observers can be "tricked" into unsubstantiated beliefs. PMID- 30251212 TI - Extracellular ATP released by copper stress could act as diffusible signal in alleviating the copper stress-induced cell death. AB - In the present work, by using tobacco cell suspension and wheat seedlings, we studied that eATP (extracellular ATP) released by copper (Cu) stress could act as diffusible signal in alleviating the Cu stress-induced cell death. A semipermeable membrane was fixed in the middle of a plastic box to divide the box into two equal compartments (A and B, respectively). This semipermeable membrane can prevent direct cell-to-cell (or seedling-to-seedling) contact and the diffusion of the macromolecules [such as ATPase (adenosine 5'-triphosphatase)] between these two compartments. The cell suspension directly stressed with CuCl2 was placed in compartment A and was incubated with the untreated cell suspension in compartment B. Such treatment significantly increased the levels of cell death and eATP content of the cell suspension in these two compartments. In contrast, addition of ATPase into the cell suspension directly stressed with CuCl2 decreased the eATP level in these two compartments but further increased the level of cell death in compartment B, compared to no addition of ATPase. Similar results were obtained when tobacco cell suspension was replaced by wheat seedlings. These observations indicate that when Cu stress from compartment A induced the plant cell death in compartment B, ATP transferred from compartment A could play a role in alleviating this cell death. Thus, it is suggested that eATP released by copper stress could act as diffusible signal in alleviating the Cu stress-induced cell death. PMID- 30251213 TI - Circumstances Surrounding High-risk Sexual Experiences Among Primary Care Patients Living With and Without HIV. AB - INTRODUCTION: Rates of sexually transmitted infection (STI) are rising in the USA, yet STI risk remains under-addressed by providers, even in HIV care, and with high-risk patients. We interviewed primary care patients living with and without HIV regarding circumstances surrounding sexual risk behavior to identify opportunities for providers to address and reduce STI risk. METHODS: We conducted semi-structured 1:1 interviews with patients living with and without HIV reporting >= 1 sex partner and varying STI exposure risk in the past 12 months from four geographically diverse US HIV and primary care clinics. We audio recorded, transcribed, and coded interviews by circumstance type, using double coding to ensure inter-coder reliability. We used Fisher's exact and T tests to determine associations with demographic/risk factors. RESULTS: Patients (n = 91) identified a mean of 3 of 11 circumstances. These included substance use (54%), desire for physical/emotional intimacy (48%), lack of HIV/STI status disclosure (44%), psychological drivers (i.e., coping, depression; 38%), personal dislike of condoms (22%), partner condom dislike/refusal (19%), receiving payment for sex (13%), and condom unavailability (9%). Higher proportions of those who were high STI-exposure risk patients, defined as those with >= 2 sex partners in the past 3 months reporting never or sometimes using condoms, reported disliking condoms (p = .006); higher proportions of the high-risk and moderate-risk (>= 2 partners and condom use "most of the time") groups reported substance use as a circumstance (p = .04). CONCLUSION: Circumstances surrounding perceived STI exposure risk were diverse, often overlapping, and dependent on internal, environmental, and partner related factors and inadequate communication. Meaningful care-based interventions regarding HIV/STI transmission behavior must address the diversity and interplay of these factors. PMID- 30251214 TI - General Internists in Pursuit of Diagnostic Excellence. PMID- 30251215 TI - Health Coaching to Enhance Psychological Well-being Among Veterans with Suicidal Ideation: a Pilot Study. PMID- 30251216 TI - County and Physician Variation in Benzodiazepine Prescribing to Medicare Beneficiaries by Primary Care Physicians in the USA. AB - BACKGROUND: Physicians widely prescribe benzodiazepines (BZD) despite well recognized harms. OBJECTIVE: To determine county and provider characteristics that predict high-intensity BZD prescribing by primary care physicians (PCPs) to Medicare beneficiaries. DESIGN: Cross-sectional analysis of the 2015 Medicare Part D Public Use Files (PUF). SUBJECTS: n = 122,054 PCPs who prescribed 37.3 billion medication days. MAIN MEASURES: Primary outcome was intensity of BZD prescribing (days prescribed/total medication days) at the county- and physician levels. PCP and county characteristics were derived from the Part D PUF, Area Health Resources Files, and County Health Rankings. Logistic regression determined the characteristics associated with high-intensity (top quartile) BZD prescribing. KEY RESULTS: Beneficiaries were prescribed over 1.2 billion days of BZD in 2015, accounting for 2.3% of all medication days prescribed in Part D. Top quartile counties had 3.1 times higher BZD prescribing than the lowest (3.4% vs. 1.1%; F = 3293.8, df = 3, p < 0.001). Adjusting for county-level demographics and health care system characteristics (including supply of mental health providers), counties with more adults with at least some college had lower odds of high intensity prescribing (per 5% increase, adjusted odds ratio [AOR] 0.80, 99% confidence interval (CI) 0.73-0.87, p < 0.001), as did higher income counties (per US$1000 increase, AOR 0.93, CI 0.91-0.95, p < 0.001). Top quartile PCPs prescribed at 6.5 times the rate of the bottom (3.9% vs. 0.6%; F = 63,910.2, df = 3, p < 0.001). High-intensity opioid prescribing (AOR 4.18, CI 3.90-4.48, p < 0.001) was the characteristic most strongly associated with BZD prescribing. CONCLUSIONS: BZD prescribing appears to vary across counties and providers and is related to non-patient characteristics. Further work is needed to understand how such non-clinical factors drive variation. PMID- 30251217 TI - Chronic Inflammation Contributes to Tumor Growth: Possible Role of L-Selectin Expressing Myeloid-Derived Suppressor Cells (MDSCs). AB - Recent data have demonstrated that chronic inflammation is a crucial component of tumor initiation and progression. We previously reported that immature myeloid derived suppressor cells (MDSCs) with immunosuppressive activity toward effector T cells were expanded in experimental chronic inflammation. We hypothesized that elevated levels of MDSCs, induced by chronic inflammation, may contribute to the progression of tumor growth. Using the Ehrlich carcinoma animal model, we found increased tumor growth in mice with chronic adjuvant arthritis, which was accompanied by a persistent increase in the proportion of splenic monocytic and granulocytic MDSCs expressing CD62L (L-selectin), when compared to tumor mice without adjuvant arthritis. Depletion of inflammation-induced MDSCs resulted in decreased tumor growth. In vitro studies demonstrated that increased expression of CD62L by MDSCs was mediated by TNFalpha, elevated concentrations of which were found in tumor mice subjected to chronic inflammation. Moreover, the addition of exogenous TNFalpha markedly enhanced the suppressive activity of bone marrow derived MDSCs, as revealed by the ability to impair the proliferation of CD8+ T cells in vitro. This study provides evidence that chronic inflammation may promote tumor growth via induction of CD62L expression by MDSCs that can facilitate their migration to tumor and lymph nodes and modulation of their suppressor activity. PMID- 30251218 TI - Saikosaponin B2 Suppresses Inflammatory Responses Through IKK/IkappaBalpha/NF kappaB Signaling Inactivation in LPS-Induced RAW 264.7 Macrophages. AB - Bupleurum falcatum (Umbelliferae) have been widely used to treat inflammatory diseases as traditional medicines in East Asian region. Although saikosaponins are main bioactive molecules of B. falcatum, there is little information on bioactivity of saikosaponin B2 (SSB2). This study was conducted to assess the anti-inflammatory activities and the involved mechanisms of SSB2 in LPS-induced RAW 264.7 macrophages. SSB2 suppressed the releases of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-alpha), interleukins (IL)-6, and IL-1beta by suppressing mRNA levels of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-alpha, IL-1beta, and IL-6 in LPS-induced macrophages. SSB2 blocked LPS-induced DNA binding and nuclear factor kappa B (NF kappaB) transcriptional activity by inhibiting nuclear translocation p65 and p50, inhibitory kappaBalpha (IkappaBalpha) degradation, and IkappaB kinase beta (IKKbeta) phosphorylation and activity. In IKKbeta-overexpressing cells, SSB2 significantly suppressed IKKbeta-dependent NF-kappaB transcriptional activity. Moreover, SSB2 reduced phosphorylation of p38 and extracellular signal-regulated kinase1/2 (ERK1/2). SSB2 effectively inhibits LPS-induced pro-inflammatory mediator releases by interfering with IKKbeta and IkappaBalpha activation, thus preventing NF-kappaB activation. Our data indicates that SSB2 could be a potential therapeutic application for inflammation-associated diseases. PMID- 30251219 TI - The Exosome: a New Player in Diabetic Cardiomyopathy. AB - Diabetic cardiomyopathy (DCM) or diabetes-induced cardiac dysfunction is a direct consequence of uncontrolled metabolic syndrome and occurs worldwide. However, the underlying cellular and molecular mechanisms remain poorly understood. Recently, exosomes have attracted considerable interest for their use as efficient, targeted, and non-immunogenic delivery systems for biological molecules or pharmacotherapies. This review will summarize the fast-developing field of the regulation and function of exosomes in DCM, affording valuable insights and therapeutic opportunities in combatting diabetes-related cardiac disorder for modern human health. PMID- 30251220 TI - The Use of Serum MMP-9 and TIMP-1 in Acute Coronary Syndrome. PMID- 30251221 TI - Quality of Life Gain After Septorhinoplasty: An Analysis of Health Utility and Cost Utility Values Associated with Septorhinoplasty. AB - PURPOSE: Septorhinoplasty is a common procedure performed in rhinology and facial plastic surgery. Despite this, the health benefits associated with the procedure remain controversial. In this study, a health utility assessment of patients undergoing septorhinoplasty was performed. Health gains associated with the procedure, and the cost at which they were acquired, were also determined. METHODS: Sixty-seven patients undergoing septorhinoplasty at a German tertiary level hospital were included in the study. Study participants completed the Short Form 36 (SF-36) and satisfaction questionnaires before and 12 months after septorhinoplasty. The Short Form six-dimensional (SF-6D) instrument was used to acquire quality-adjusted life year (QALY) values from SF-36 responses, thus allowing estimation of pre- and post-operative health utilities. Health utility gains after septorhinoplasty were determined and combined with cost data to estimate cost per QALY gained. RESULTS: Patients undergoing septorhinoplasty reported mean pre-operative health utility values of 0.70 pre-operatively and 0.74 post-operatively resulting in health gains of 0.04 QALYs. Patients satisfied with their procedures had significant health utility gains, while dissatisfied patients did not experience any significant gains. The cost of septorhinoplasty to statutory health insurance was ?3487.69. When compared to the baseline, the incremental utility ratio for septorhinoplasty was ?94,797.30 per QALY gained. CONCLUSIONS: This study successfully estimated the health utilities and gains associated with septorhinoplasty. The findings indicate that the procedure has associated health gains but at a high cost-utility ratio. These values provide a reference point for further much-needed economic evaluations. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30251222 TI - Statin-Associated Muscle Disease: Advances in Diagnosis and Management. AB - Since the first approval of lovastatin in 1987, hydroxy-methyl-glutaryl CoA (HMG CoA) reductase inhibitors, or statins, have been effective and widely popular cholesterol-lowering agents with substantial benefits for the prevention and treatment of cardiovascular disease. Not all patients can tolerate these drugs, however, and statin intolerance is most frequently associated with a range of side effects directed toward skeletal muscle, termed statin-associated muscle symptoms or SAMS. SAMS are particularly difficult to treat because there are no validated biomarkers or tests that can be used to confirm patient self-reports of SAMS, and a number of patients who report SAMS have non-specific muscle pain not attributable to statin therapy. This review summarizes the most recent evidence related to diagnosis and management of SAMS. First, the range of skeletal muscle side effects associated with statin therapy is described. Second, data regarding the incidence and prevalence of SAMS, the most frequently experienced muscle side effect, are presented. Third, the most promising new techniques to confirm diagnosis of SAMS are explored. Finally, the most effective strategies for the clinical management of SAMS are summarized. Better diagnostic and treatment strategies for SAMS will increase the number of patients using these life-saving statins, thereby increasing statin adherence and reducing the costs of avoidable cardiovascular events. PMID- 30251223 TI - Bench Validation of a Compact Low-Flow CO2 Removal Device. AB - BACKGROUND: There is increasing evidence demonstrating the value of partial extracorporeal CO2 removal (ECCO2R) for the treatment of hypercapnia in patients with acute exacerbations of chronic obstructive pulmonary disease and acute respiratory distress syndrome. Mechanical ventilation has traditionally been used to treat hypercapnia in these patients, however, it has been well-established that aggressive ventilator settings can lead to ventilator-induced lung injury. ECCO2R removes CO2 independently of the lungs and has been used to permit lung protective ventilation to prevent ventilator-induced lung injury, prevent intubation, and aid in ventilator weaning. The Low-Flow Pittsburgh Ambulatory Lung (LF-PAL) is a low-flow ECCO2R device that integrates the fiber bundle (0.65 m2) and centrifugal pump into a compact unit to permit patient ambulation. METHODS: A blood analog was used to evaluate the performance of the pump at various impeller rotation rates. In vitro CO2 removal tested under normocapnic conditions and 6-h hemolysis testing were completed using bovine blood. Computational fluid dynamics and a mass-transfer model were also used to evaluate the performance of the LF-PAL. RESULTS: The integrated pump was able to generate flows up to 700 mL/min against the Hemolung 15.5 Fr dual lumen catheter. The maximum vCO2 of 105 mL/min was achieved at a blood flow rate of 700 mL/min. The therapeutic index of hemolysis was 0.080 g/(100 min). The normalized index of hemolysis was 0.158 g/(100 L). CONCLUSIONS: The LF-PAL met pumping, CO2 removal, and hemolysis design targets and has the potential to enable ambulation while on ECCO2R. PMID- 30251224 TI - Desacylghrelin but not acylghrelin is reduced during smoking cessation. AB - This study focused on the acetylation status of ghrelin examining acyl- and desacylghrelin and its effect on craving during 14 days of smoking abstinence. This is the first study demonstrating changes in desacylghrelin plasma levels in smokers compared to non-smokers while there was no difference of acylated ghrelin. Future studies should specifically refer to plasma ghrelin as either desacyl- or acylghrelin since both have different effects on tobacco-seeking behavior and the underlying physiology. PMID- 30251225 TI - Validation of new marker of fluid responsiveness based on Doppler assessment of blood flow velocity in superior vena cava in mechanically ventilated pigs. AB - BACKGROUND: We studied a novel approach for the evaluation and management of volemia: minimally invasive monitoring of respiratory blood flow variations in the superior vena cava (SVC). We performed an experiment with 10 crossbred (Landrace * large white) female pigs (Sus scrofa domestica). METHODS: Hypovolemia was induced by bleeding from a femoral artery, in six stages. This was followed by blood return and then an infusion of 1000 ml saline, resulting in hypervolemia. Flow in the SVC was measured by Flowire (Volcano corp., USA), located in a distal channel of a triple-lumen central venous catheter. The key parameters measured were venous return variation index (VRV)-a new index for fluid responsiveness, calculated from the maximal and minimal velocity time intervals during controlled ventilation-and systolic peak velocity (defined as peak velocity of a systolic wave using the final end-expiratory beat). A Swan Ganz catheter (Edwards Lifesciences, USA) was introduced into the pulmonary artery to measure pulmonary arterial pressure, pulmonary capillary wedge pressure, and continuous cardiac output measurements, using the Vigilance monitor (Edwards Lifesciences, USA). RESULTS: We analyzed 44 VRV index measurements during defined hemodynamic status events. The curves of VRV indexes for volume responders and volume non-responders intersected at a VRV value of 27, with 10% false negativity and 2% false positivity. We compared the accuracy of VRV and pulse pressure variations (PPV) for separation of fluid responders and fluid non responders using receiver operating characteristic (ROC) curves. VRV was better (AUCROC 0.96) than PPV (AUCROC 0.85) for identification of fluid responders. The VRV index exhibited the highest relative change during both hypovolemia and hypervolemia, compared to standard hemodynamic measurement. CONCLUSIONS: The VRV index provides a real-time method for continuous assessment of fluid responsiveness. It combines the advantages of echocardiography-based methods with a direct and continuous assessment of right ventricular filling during mechanical ventilation. PMID- 30251226 TI - Parameters associated with acute morphometric lesion dimensions created by cryocatheters. AB - PURPOSE: Despite the wide use of cryoenergy, there is a paucity of data regarding the impact of certain ablation parameters on lesion size. Specifically, this study sought to evaluate the impact of catheter type, ablation time, heat load, and tip orientation on lesion dimensions using a porcine thigh model with focal cryoablation catheters. METHODS: In 6 pigs, 251 lesions were created on thigh muscle with parameter permutations to compare the acute impact of catheter type (electrode tip sizes 4, 6, and 8 mm), ablation time (2, 2 * 2, 3, 4, and 2 * 4 min), heat load (1 and 2 L/min), and tip orientation (perpendicular or parallel) on lesion dimensions (length, depth, and cross-sectional area) immediately post ablation. As a sub-study to evaluate the importance of tissue contact during the cryoablation procedure, a 1-min freeze was performed without tissue contact until an ice ball formed, followed by an additional 2-3 min freeze. RESULTS: The linear regression model revealed that catheter type (p < 0.0001) and the interaction between catheter orientation and catheter type (p = 0.027) were significantly associated with lesion cross-sectional area. Lesion length and depth, but not cross-sectional area, are significantly impacted by the catheter type (p < 0.0001; p = 0.003) and orientation (p < 0.0001; p < 0.0001), respectively. Compared to parallel catheter placement, lesions created with the perpendicular orientation were deeper using 4-mm (p = 0.136), 6-mm (p = 0.005), and 8-mm tip catheter (p = 0.004). Lesion creation with an ice ball significantly reduced lesion depth compared to lesions made without an ice ball (p < 0.05). In contrast, ablation time (p = 0.097) and heat load (p = 0.467) were not significantly associated with lesion size. Additionally, there was no statistical significant difference in lesion size between 2 * 2 and 4 min ablation times. CONCLUSIONS: The present study demonstrated that lesion size was significantly impacted by catheter type and catheter tip orientation and that maintaining tissue contact prior to applying cryoenergy is essential. PMID- 30251227 TI - Three-dimensional surface presentation of optic nerve head from SPECTRALIS OCT images: observing glaucoma patients. AB - PURPOSE: To propose an innovative three-dimensional surface presentation of the optic nerve head (ONH) from the SPECTRALIS optical coherence tomography (OCT) device. METHOD: A dataset of OCT ONH files from eight glaucoma follow-up patients was obtained. The set consisted of OCT ONH images for 20 right eyes (OD) and 17 left eyes (OS). Preprocessing steps followed with OCT reconstruction procedures were designed. The three-dimensional (3D) surface rendering was generated for all OCT ONH images. A set of eight International Organization for Standardization (ISO) roughness parameters were calculated to assess the disparities in the 3D ONH surface morphology during follow-up visit. RESULTS: The 3D ONH surface presents a new OCT display to ophthalmology; so, the physician can examine the surface morphology of the OCT ONH region. The 3D ONH surface's shape varied noticeably during follow-up visits in glaucoma patients. The percentage disparity of ONH surface roughness's can be as small as 3% or almost zero, but it can be as large as 56% or 100%. CONCLUSIONS: The approximation of OCT ONH 3D surface is feasible; it may possibly be beneficial to ophthalmology. It allows ophthalmologist to perceive the entire changes in the ONH surface morphology during the follow-up attendances; so, it can be used to observe patient health. The ISO roughness measurements are suggestive complementary factors to observe the alterations in the OCT ONH region. PMID- 30251228 TI - Effect of Aqueous Extract of Glycyrrhiza glabra on the Biochemical Changes Induced by Cadmium Chloride in Rats. AB - Twenty four rats were divided into four groups (6 rats/group): 1-control group; 2 licorice (Glycyrrhiza glabra) extract: rats administered with an oral dose of licorice (3 mg/ml/kg/day) using stomach tube for 4 weeks; 3-cadmium chloride group: rats administered with an oral dose of CdCl2 (10 mg/kg/day) using stomach tube for 4 weeks; and 4-licorice extract + CdCl2 group: rats administered orally with both licorice (3 mg/ml/kg/day) and CdCl2 (10 mg/kg/day) using stomach tube for 4 weeks. Administration of CdCl2 induced significant increase in thiobarbituric acid reactive substance (TBARS), paraoxonase-1 (proxon-1), caspase 3 (casp-3) activities, and significant decrease in superoxide dismutase (SOD), catalase (CAT) activities, and glutathione (GSH) content in hepatic tissue. Significant increase in TBARS and kidney injury molecule-1 (KIM-1) and significant decrease in SOD, CAT activities, and GSH content in renal tissue were recorded. Significant increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) activities, urea, creatinine, and significant decrease in butyryl choline esterase (BChE), total triiodothyronine (T3), and total thyroxin (T4) were recorded in serum. Histological investigation of renal cells showed vacuolations of endothelium lining glomerular tuffs and vacuolations of epithelium lining renal tubules. Investigation of ovarian tissue showed dilatation of interstitial blood vessels and congestion of multiple corpus luteum in CdCl2-treated rats. Significant improvements in the biochemical and histological changes were observed in CdCl2 + licorice extract group. It could be concluded that licorice extract alleviates the hazardous effects of cadmium chloride, which may be attributed to its antioxidant properties. PMID- 30251229 TI - Discoid lateral meniscus in children and adolescents: a histological study. AB - BACKGROUND: Discoid lateral meniscus is the most frequent variant of the meniscus. Although the histology of normal menisci in children and in adults has been well described, few studies have focused on the histology of discoid menisci. Furthermore, most of the patients in those studies were adults. The aim of the present study was to report the histological findings of discoid lateral meniscus in a group of children and adolescents, aged between 9 and 18, after arthroscopic partial resection, focusing on cellularity, arrangement of collagen fibers, and vascularity of the excised fragments. Furthermore, to report on MRI findings compared to the histological findings in the same region. METHODS: Six patients (one female and five males) aged 9, 10, 13, 15, 17, and 18, were arthroscopically operated on partial meniscectomy (saucerization) of a discoid lateral meniscus, and the specimens were histologically examined. RESULTS: The extracellular matrix showed a different distribution and characteristics depending on the different side of the meniscus. Irregularly oriented collagen fibers in discoid lateral meniscus were found. There were no blood vessels in the inner part of discoid lateral meniscus in all patients but the 18-year old (in which we observed also endothelials cells, edematous tissue and leaking of erythrocytes in the extracellular matrix). In the discoid lateral menisci analyzed, irregularly oriented collagen fibers with blood vessels were found only in the presence of degenerating tissue. CONCLUSIONS: Discoid lateral meniscus is different from a normal meniscus in terms of vascularity and disorganization of collagen fibers. PMID- 30251230 TI - In Silico Structure-Based Identification and Validation of Key Residues of Vip3Aa Involving in Lepidopteran Brush Border Receptor Binding. AB - The vegetative insecticidal proteins (VIPs) of Bacillus thuringiensis (Bt) have a broad-spectrum insecticidal activity against Lepidopteran pests and no cross resistance with the insecticidal crystal protein Cry protein. So there are great potentials for the control of agricultural pests and the resolution of resistance problems. The structural information of Vip3Aa protein and the predicted key amino acid sites on the C-terminal domain of Vip3Aa were analyzed with the methods of bioinformatics such as homology modeling and molecular docking. Site directed mutagenesis was used to replace these amino acids with alanine, and there was difference in the activities of the mutant protein and Vip3Aa protein. Y619A had improved insecticidal activity against Helicoverpa armigera, but the toxicity of W552A and E627A to Helicoverpa armigera was significantly reduced. The mutants of W552A and E627A had reduced insecticidal activity against Spodoptera exigua. This study demonstrated that the C-terminal domain played an important role in the function of Vip3Aa protein toxin, and the deletion of the side chain of key residues had a significant effect on the activity of the insecticidal protein. This study provides the theoretical basis for revealing the relationship between the structure and function of Vip3Aa protein. PMID- 30251231 TI - Utilization of Grape Seed Flour for Antimicrobial Lipopeptide Production by Bacillus amyloliquefaciens C5 Strain. AB - An endophytic Bacillus amyloliquefaciens strain called C5, able to produce biosurfactant lipopeptides with a broad antibacterial activity spectrum, has been isolated from the roots of olive tree. Optimization of antibacterial activity was undertaken using grape seed flour (GSF) substrate at 0.02, 0.2, and 2% (w/v) in M9 medium. Strain C5 exhibited optimal growth and antimicrobial activity (MIC value of 60 MUg/ml) when incubated in the presence of 0.2% GSF while lipopeptide production culminated at 2% GSF. Thin layer chromatography analysis of lipopeptide extract revealed the presence of at least three active spots at Rf 0.35, 0.59, and 0.72 at 0.2% GSF. Data were similar to those obtained in LB-rich medium. MALDI-TOF/MS analysis of lipopeptide extract obtained from 0.2% GSF substrate revealed the presence of surfactin and bacillomycin D. These results show that GSF could be used as a low-cost culture medium supplement for optimizing the production of biosurfactants by strain C5. PMID- 30251233 TI - Anti-inflammatory effects of Chinese propolis in lipopolysaccharide-stimulated human umbilical vein endothelial cells by suppressing autophagy and MAPK/NF kappaB signaling pathway. AB - This study aimed to investigate the possible benefits of Chinese poplar propolis (CP) in inhibiting inflammation using vascular endothelial cells (VECs) cultured in a nutrient-rich condition exposed to lipopolysaccharide (LPS). Cell proliferation was detected by sulforhodamine B assay and EdU kit. The production of reactive oxygen species (ROS) and level of mitochondrial membrane potential were determined with fluorescent probe DCHF and JC-1, respectively. Protein expression was examined by immunofluorescence staining and western blotting. The results showed that CP (6.25, 12.5, and 25 MUg/mL) significantly reduced LPS induced cytotoxicity, and when challenged with CP substantially suppressed ROS overproduction and protected mitochondrial membrane potential. CP treatment significantly inhibited autophagy by inhibiting LC3B distribution and accumulation, and elevating the p62 level in an mTOR-independent manner but mainly by suppressing the translocation of p53 from the cytoplasm to the nucleus. Furthermore, CP treatment markedly reduced protein levels of TLR4 at 12 and 24 h and significantly suppressed nuclear translocation of NF-kappaB p65 from cytoplasm to nucleus. In addition, CP treatment significantly reduced the phosphorylation of JNK, ERK1/2, and p38 MAPK. Our findings demonstrated that CP protects VECs from LPS-induced oxidative stress and inflammation, which might be associated with depressing autophagy and MAPK/NF-kappaB signaling pathway. The results provided novel insights for the potential use of nutrient-rich propolis against inflammation. PMID- 30251232 TI - Effects of Cilostazol-Based Triple Antiplatelet Therapy Versus Dual Antiplatelet Therapy After Coronary Drug-Eluting Stent Implantation: An Updated Meta-Analysis of the Randomized Controlled Trials. AB - BACKGROUND AND OBJECTIVE: The results of studies on cilostazol-based triple antiplatelet therapy (TAT) after drug-eluting stent (DES) implantation were inconsistent. To assess the effects of TAT compared with dual antiplatelet therapy (DAT) after DES/second-generation DES implantation, we performed a meta analysis of randomized controlled trials (RCTs). METHODS: All relevant studies evaluated were identified by searching the PubMed, EMBASE, Cochrane Library, and ISI Web of Science databases without time and language limitation. Subgroup analyses were performed to evaluate the efficacy and safety of TAT after second generation DES implantation. RESULTS: Eleven RCTs involving a total of 4684 patients were included. The meta-analysis showed TAT was associated with significant beneficial effects on angiographic findings of in-stent restenosis [risk ratio (RR) 0.645, 95% confidence interval (CI) 0.470-0.885; P = 0.007], in segment restenosis (RR 0.606, 95% CI 0.450-0.817; P = 0.001), in-stent late loss (RR - 0.095, 95% CI - 0.136 to - 0.054; P < 0.0001), in-segment late loss (RR - 0.100, 95% CI - 0.139 to - 0.061; P < 0.0001), target lesion revascularization (TLR) (RR 0.570, 95% CI 0.430-0.755; P < 0.0001), and target vessel revascularization (TVR) (RR 0.523, 95% CI 0.380-0.719; P < 0.0001). No significant difference was found in outcomes of all-cause death, cardiac death, definite/probable stent thrombosis (ST), non-fatal myocardial infarction (MI), overall bleeding, and major bleeding between the two groups, as well as some minor adverse effects including palpitations, thrombocytopenia, neutropenia, and hepatic dysfunction. However, the incidence rate of rash, gastrointestinal disorders, and headache was significantly higher in TAT. The second-generation DES subgroup showed similar results, except for the indicators of all-cause death (RR 2.161, 95% CI 1.007-4.635; P = 0.048) and hepatic dysfunction (RR 0.176, 95% CI 0.031-0.995; P = 0.049). CONCLUSIONS: Compared with DAT, cilostazol-based TAT can significantly improve the angiographic findings of in-stent and in-segment late loss, in-stent and in-segment restenosis, TLR, and TVR after DES/second generation DES implantation. However, no benefits were observed in outcomes of all-cause death, cardiac death, ST, and MI. PMID- 30251234 TI - SB5: An Adalimumab Biosimilar. AB - SB5 (Imraldi(r)) is a biosimilar of the reference anti-TNF monoclonal antibody adalimumab. It is approved for use in the following indications for which reference adalimumab is approved: rheumatoid arthritis (RA), juvenile idiopathic arthritis [polyarticular juvenile idiopathic arthritis (pJIA) and enthesitis related arthritis (ERA)], axial spondyloarthritis [ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)], psoriatic arthritis (PsA), psoriasis, pediatric plaque psoriasis, hidradenitis suppurativa (HS), Crohn's disease, pediatric Crohn's disease, ulcerative colitis (UC), and non infectious uveitis. SB5 has similar physicochemical and pharmacodynamic properties to those of reference adalimumab, and the pharmacokinetic similarity of these agents has been shown in healthy volunteers and patients with RA. SB5 demonstrated clinical efficacy considered equivalent to that of reference adalimumab in patients with RA, and was generally well tolerated in this population. The safety and tolerability profile of SB5 was similar to that of reference adalimumab, as was the immunogenicity profile. Switching from reference adalimumab to SB5 had no impact in terms of efficacy, safety or immunogenicity. The role of reference adalimumab in the management of RA, pJIA, ERA, AS, nr axSpA, PsA, psoriasis, pediatric plaque psoriasis, HS, Crohn's disease, UC and non-infectious uveitis is well established and SB5 provides an effective biosimilar alternative for patients requiring adalimumab therapy. PMID- 30251235 TI - An Ethics of the System: Talking to Scientists About Research Integrity. AB - Research integrity and misconduct have recently risen to public attention as policy issues. Concern has arisen about divergence between this policy discourse and the language and concerns of scientists. This interview study, carried out in Denmark with a cohort of highly internationalised natural scientists, explores how researchers talk about integrity and good science. It finds, first, that these scientists were largely unaware of the Danish Code of Conduct for Responsible Conduct of Research and indifferent towards the value of such codes; second, that they presented an image of good science as nuanced and thereby as difficult to manage through abstracted, principle-based codes; and third, that they repeatedly pointed to systemic issues both as triggering misconduct and as ethical problems in and of themselves. Research integrity is framed as a part of wider moves to 'responsibilise' science; understood in these terms, resistance to codes of conduct and the representation of integrity as a problem of science as a whole can be seen as a rejection of a neoliberal individualisation of responsibility. PMID- 30251236 TI - Pseudo-dissection of the internal carotid artery in acute ischemic stroke. PMID- 30251237 TI - Dibenzazepine Agents in Epilepsy: How Does Eslicarbazepine Acetate Differ? AB - Carbamazepine (CBZ), oxcarbazepine (OXC), and eslicarbazepine acetate (ESL) belong to the dibenzazepine family of antiepileptic drugs and are all thought to primarily act as sodium channel blockers (SCBs). However, ESL is structurally distinct from CBZ and OXC, resulting in differences in metabolism, pharmacokinetics, and pharmacodynamics. Despite a lack of direct comparative data, evidence for potential differences in effectiveness and tolerability within the dibenzazepine family has emerged from studies in which patients being treated with one dibenzazepine agent have received adjunctive treatment with another (having achieved insufficient seizure control with the first) or have transitioned from one dibenzazepine agent to another because of lack of effectiveness or poor tolerability. Most of these studies have been conducted in the real-world clinical practice setting. ESL has been shown to be effective as adjunctive therapy in patients who have previously achieved inadequate seizure control with CBZ, indicating that the use of different dibenzazepine agents in combination can provide additive effectiveness benefits, which may reflect underlying differences in their mechanisms of action. Similarly, ESL monotherapy can be effective in patients who have switched from another dibenzazepine, such as CBZ or OXC, because of inadequate efficacy. There is also considerable evidence to demonstrate that patients transitioning from OXC or CBZ to ESL as a result of adverse events experience improvements in tolerability, which may also be associated with improvements in quality of life, alertness, and/or lipid profiles. Current evidence therefore demonstrates that ESL differs from other dibenzazepine agents in terms of effectiveness and tolerability.Funding: Eisai Ltd. PMID- 30251239 TI - Thoracic Endovascular Aortic Repair for Aortoesophageal Fistula after Covered Rupture of Aortic Homograft. AB - A 63-year-old woman underwent replacement of the aortic root, ascending aorta, and partial arch due to Type A aortic dissection. Shortly thereafter, a replacement of the distal aortic arch and descending aorta was performed. Three years later, the patient developed an aortoesophageal fistula (AEF) resulting in re-replacement of the distal aortic arch and proximal descending aorta with a cryopreserved aortic homograft. Six weeks post-discharge, the patient was readmitted due to recurrent AEF. A thoracic endovascular stent graft was implanted to cover the aortic rupture, followed by correction of an esophageal lesion. The patient was monitored closely over time. PMID- 30251238 TI - Genomic prediction ability for beef fatty acid profile in Nelore cattle using different pseudo-phenotypes. AB - The aim of the present study was to compare the predictive ability of SNP-BLUP model using different pseudo-phenotypes such as phenotype adjusted for fixed effects, estimated breeding value, and genomic estimated breeding value, using simulated and real data for beef FA profile of Nelore cattle finished in feedlot. A pedigree with phenotypes and genotypes of 10,000 animals were simulated, considering 50% of multiple sires in the pedigree. Regarding to phenotypes, two traits were simulated, one with high heritability (0.58), another with low heritability (0.13). Ten replicates were performed for each trait and results were averaged among replicates. A historical population was created from generation zero to 2020, with a constant size of 2000 animals (from generation zero to 1000) to produce different levels of linkage disequilibrium (LD). Therefore, there was a gradual reduction in the number of animals (from 2000 to 600), producing a "bottleneck effect" and consequently, genetic drift and LD starting in the generation 1001 to 2020. A total of 335,000 markers (with MAF greater or equal to 0.02) and 1000 QTL were randomly selected from the last generation of the historical population to generate genotypic data for the test population. The phenotypes were computed as the sum of the QTL effects and an error term sampled from a normal distribution with zero mean and variance equal to 0.88. For simulated data, 4000 animals of the generations 7, 8, and 9 (with genotype and phenotype) were used as training population, and 1000 animals of the last generation (10) were used as validation population. A total of 937 Nelore bulls with phenotype for fatty acid profiles (Sum of saturated, monounsaturated, omega 3, omega 6, ratio of polyunsaturated and saturated and polyunsaturated fatty acid profile) were genotyped using the Illumina BovineHD BeadChip (Illumina, San Diego, CA) with 777,962 SNP. To compare the accuracy and bias of direct genomic value (DGV) for different pseudo-phenotypes, the correlation between true breeding value (TBV) or DGV with pseudo-phenotypes and linear regression coefficient of the pseudo-phenotypes on TBV for simulated data or DGV for real data, respectively. For simulated data, the correlations between DGV and TBV for high heritability traits were higher than obtained with low heritability traits. For simulated and real data, the prediction ability was higher for GEBV than for Yc and EBV. For simulated data, the regression coefficient estimates (b(Yc,DGV)), were on average lower than 1 for high and low heritability traits, being inflated. The results were more biased for Yc and EBV than for GEBV. For real data, the GEBV displayed less biased results compared to Yc and EBV for SFA, MUFA, n-3, n-6, and PUFA/SFA. Despite the less biased results for PUFA using the EBV as pseudo-phenotype, the b(Yi,DGV estimates obtained for the different pseudo phenotypes (Yc, EBV and GEBV) were very close. Genomic information can assist in improving beef fatty acid profile in Zebu cattle, since the use of genomic information yielded genomic values for fatty acid profile with accuracies ranging from low to moderate. Considering both simulated and real data, the ssGBLUP model is an appropriate alternative to obtain more reliable and less biased GEBVs as pseudo-phenotype in situations of missing pedigree, due to high proportion of multiple sires, being more adequate than EBV and Yc to predict direct genomic value for beef fatty acid profile. PMID- 30251241 TI - Visualisation of the oblique vein of the left atrium (vein of Marshall) using cardiac computed tomography: is the game worth the candle? AB - BACKGROUND: The vein of Marshall (VoM) is a small vessel that descends obliquely on the back of the left atrium and ends in the coronary sinus near the area where the great cardiac vein continues into the coronary sinus. AIM: The aim of the study was to examine the frequency of occurrence and anatomical aspects as well as the possibility of visualising the VoM, including an evaluation of the quality of the visualisation, on computed tomography (CT). METHODS: Three hundred patients aged 58.8 +/- 11.5 years (111 women) were included into this single centre study. Cardiac CT was performed in all patients. The search for the VoM was performed by two experienced researchers using two- and three-dimensional techniques. A dedicated Likert-based scale was used to evaluate the quality of the visualisations. RESULTS: The VoM was found in 61 (20.33%) of 300 patients. Its average diameter was 1.72 +/- 0.69 mm with no sex-related differences (men: 1.71 +/- 0.69 mm; women: 1.73 +/- 0.57 mm; p = 0.91). The average length of the vessel was 9.24 +/- 7.58 mm. The VoM was more frequently (p = 0.01) visualised in the systolic phases (68.85% of cases) compared to the diastolic phases (27.86% of cases). Occasionally it was visualised in other phases (3.29%). CONCLUSIONS: Although it was possible to visualise the VoM using cardiac CT in about 20% of the population, this method of visualisation requires that special attention be paid to the quality of the images, especially in the systolic phases. Visualisation may be useful before certain electrophysiology procedures. PMID- 30251240 TI - Human carotid bodies as a therapeutic target: new insights from a clinician's perspective. AB - From the physiological point of view, carotid bodies are mainly responsible for the ventilatory response to hypoxia; however, they also take part in the regulation of sympathetic tone. According to preclinical data, these structures likely contribute to the development and progression of sympathetically mediated diseases. Moreover, carotid body deactivation in animal models improved blood pressure control in hypertension and reduced mortality in heart failure, along with reducing sympathetic activity. On this basis, two first-in-man studies have been recently performed to investigate the safety and feasibility of such an approach in humans. In this review we summarise the current knowledge regarding the function of carotid bodies, the prevalence of their abnormalities, and the consequences of their excision in human hypertension and heart failure. PMID- 30251242 TI - Implantable cardioverter-defibrillators in patients with long QT syndrome: a multicentre study. AB - BACKGROUND: Implantable cardioverter-defibrillator (ICD) therapy has been proven effective in prevention of sudden cardiac death (SCD), but data on outcomes for ICD therapy in the young and otherwise healthy Long QT Syndrome (LQTS) population are limited. AIMS: To collect data on appropriate and inappropriate ICD discharges, risk factors, and ICD-related complications. METHODS: All LQTS patients implanted with an ICD in 14 centres were investigated, and demographical, clinical and data on ICD therapy were collected. RESULTS: There were 67 patients (88% female). Median age at ICD implant was 31 years (12-77 years). ICD indication was based on resuscitated cardiac arrest in 46, syncope in 18 and malignant family history in three patients. During a median follow-up of 48 months, 39 patients (58%) received one or more ICD therapy. Time to first appropriate discharge was up to 55 months. Inappropriate therapies were triggered by fast sinus rhythm, atrial fibrillation, and T-wave oversensing. No predictors of inappropriate shocks were identified. Risk factors for appropriate ICD therapy were: (1) recurrent syncope despite beta-blocker treatment before an ICD, (2) pacemaker therapy before ICD, (3) single-chamber ICD and (4) noncompliance to beta-blockers. In 38 (57%) patients, at least 1 complication occurred. CONCLUSIONS: ICD is effective in nearly half the patient population; however, the early and late complication rates are high. Although the number of unnecessary ICD shocks and reimplant procedures may be lowered by modern programming and increased longevity of newer ICD generators, other adverse events are less likely to be reduced. PMID- 30251243 TI - Cardiovascular diseases prevention in Poland: results of WOBASZ and WOBASZ II studies. AB - BACKGROUND: Cardiovascular diseases are the main cause of morbidity and an important cause of disability and premature death in European countries. Current guidelines recommend prevention delivery by physicians during medical consultations. AIM: We sought to evaluate the prevention support offered by Polish physicians in 2013-2014 compared to 2003-2005, and its determinants. METHODS: The data from two population surveys were analysed: WOBASZ (6392 men and 7153 women, aged 20-74 years, screened in 2003-2005) and WOBASZ II (2751 men and 3418 women, aged >= 20 years, screened in 2013-2014). For comparison analysis, the population of WOBASZ II was restricted to persons aged 20-74 years. Prevention delivery was assessed using a questionnaire. RESULTS: Overall, 64% of men and 75% of women screened in 2003-2005 consulted their physicians at least once in the preceding year; 10 years later these rates were 70% and 82%, respectively. In both studies, 70% of respondents recalled having received one piece of prevention advice during a medical consultation. One-third of participants neither received any prevention advice nor had their blood pressure or cholesterol level measured. In WOBASZ II we observed a significant increase in the frequency of counselling regarding smoking cessation, nutrition, and increased physical activity, as well as in the frequency of cholesterol measurements, compared to WOBASZ. The prevention support was related to the health status. CONCLUSIONS: The prevention support in the years 2013-2014 was better than in 2003-2005, but was still insufficient. About one-third of participants did not receive any preventive advice. The prevention support was offered more often to patients with worse health status. PMID- 30251244 TI - Pulmonary artery dilatation during normal pregnancy. AB - BACKGROUND: During pregnancy the cardiovascular system undergoes complex alterations; however, there have been few studies concerning pulmonary artery behaviour during gestation. AIM: The aim of this study was to evaluate changes in the pulmonary artery diameter (PAD) during gestation, with respect to left ventricular (LV) load and remodelling, as well as to systemic vascular resistance (SVR). METHODS: It was a prospective cohort study, which included 69 consecutive healthy outpatient women with a singleton pregnancy. Echocardiography and ultrasonography of the uterine arteries were performed at two visits (V1 and V2) during pregnancy, and only echocardiography at one visit postpartum. RESULTS: Pulmonary artery diameter increased in all women, from 20.0 mm at V1 to 22.7 mm at V2 (p < 0.001), and it returned to the reference range postpartum (19.5 mm; p < 0.001 vs. V2). Echocardiography did not reveal any other abnormalities, including the signs of intracardiac shunt or right ventricular pressure overload. During V2, PAD positively correlated with the following echocardiographic parameters: LV end-diastolic diameter (r = 0.386; p = 0.002), LV end-systolic diameter (r = 0.345 p = 0.006), LV end-diastolic volume (r = 0.308; p = 0.016), LV mass (r = 0.459; p < 0.001), left atrial area (r = 0.334; p = 0.009), LV cardiac output (r = 0.338; p = 0.011), and aortic diameter (r = 0.369; p = 0.003). Furthermore, there was a negative linear correlation between PAD and SVR (r = -0.307; p = 0.025) and pulsatility index (r = -0.318; p = 0.012). CONCLUSIONS: Our study shows pulmonary artery dilatation in healthy pregnant women without any other abnormal echocardiographic findings. These changes in PAD are associated with volume overload and low vascular resistance, and during postpartum they usually subside. PMID- 30251245 TI - Risk stratification in patients with cardiac resynchronisation therapy: the AL FINE CRT risk score. AB - BACKGROUND: Mortality and morbidity in patients with cardiac resynchronisation therapy (CRT) remain very high. Prognostic evaluation of CRT candidates might be useful for the assessment of CRT indications, directing further therapy, counselling, etc. AIM: Our goal was to assess the prognostic value of various parameters in order to construct a risk score that could predict long-term mortality and morbidity during the initial evaluation of CRT candidates. METHODS: This was a retrospective, single-centre, large cohort study involving consecutive heart failure patients who underwent CRT device implantation. In order to build a prediction model, 28 parameters were analysed using uni- and multivariate Cox models and Kaplan-Meier survival curves. RESULTS: Data from 552 patients were used for the long-term outcome assessment. During nine years of follow-up, 232 patients met the primary endpoint of death and 128 patients were hospitalised for heart failure. The strongest and clinically most relevant predictors were selected as the final model. AL-FINE is the acronym for these six predictors: Age ( > 75 years), non-Left bundle branch block morphology (according to Strauss criteria), Furosemide dose ( > 80 mg), Ischaemic aetiology, New York Heart Association class ( > III), and left ventricular Ejection fraction ( < 20%). Depending on the number of AL-FINE score points, overall mortality at seven years was in the range of 28% (0-1 points) to 74% (3-6 points). CONCLUSIONS: A novel, multiparametric CRT risk score was constructed on the basis of simple and recognised clinical, electrocardiographic, and echocardiographic parameters that show a significant add-on effect on mortality in this specific population. PMID- 30251246 TI - Comparison of multivessel percutaneous coronary intervention and coronary artery bypass grafting in patients with severe coronary artery disease presenting with non-ST-segment elevation acute coronary syndromes. AB - BACKGROUND: There are no clinical trials comparing multivessel percutaneous coronary intervention (MV PCI) with coronary artery bypass grafting (CABG) in the non-ST-segment elevation acute coronary syndrome (NSTE-ACS) population. AIM: We sought to compare long-term outcomes of MV PCI and CABG in patients with severe coronary artery disease (CAD) presenting with NSTE-ACS. METHODS: A total of 3166 consecutive patients with NSTE-ACS hospitalised between 2006 and 2014 were analysed. Patients with left main, proximal left anterior descending artery, or triple-vessel CAD were included in further analysis. Finally, 455 patients were enrolled and divided into two groups (MV PCI or CABG group). The Cox proportional hazards model and propensity score analysis were used to assess the effects of the treatment on 36-month outcomes. RESULTS: MV PCI was performed in 335 patients, the remaining 120 patients underwent CABG. After propensity score analysis, 99 well-matched pairs were chosen. At 36 months MV PCI was associated with similar incidence of the composite endpoint (all-cause death, non-fatal myocardial infarction [MI], ACS-driven, revascularisation, or stroke) in both Cox proportional hazards model (hazard ratio [HR] 1.26; 95% confidence interval [CI] 0.75-2.11; p = 0.39) and propensity matched analysis (HR 1.28; 95% CI 0.75-2.21; p = 0.36). Rates of 36-month mortality were also comparable before (HR 0.90; 95% CI 0.46-1.75; p = 0.76) and after matching (HR 0.94; 95% CI 0.47-1.89; p = 0.87). Rates of MI and ACS-driven revascularisation were independently higher in MV PCI than in CABG groups (17.8% vs. 5.5%, p = 0.01, and 20.6% vs. 4.4%, p = 0.003, respectively). CONCLUSIONS: It seems that MV PCI is comparable to CABG in terms of long-term combined endpoint and mortality in patients with severe CAD and NSTE ACS. However, higher rates of MI and ACS-driven revascularisation were observed in the MV PCI group. PMID- 30251247 TI - Current perspectives on the role of bioresorbable scaffolds in the management of coronary artery disease. AB - New-generation drug-eluting stents are recommended as the default option in all clinical conditions and lesion subsets in patients undergoing percutaneous coronary intervention (PCI). On the other hand, despite achieving very good results in the rate of restenosis, permanent delivery of a metallic platform is affected by several drawbacks, such as caging of the vessel, side branch jailing, impairment of vasomotion, and the impossibility of lumen enlargement. Also, the presence of residual foreign material may increase the risk of late and very late stent thrombosis and support the need for long-term dual antiplatelet therapy after PCI. These pending limitations of metallic stents can be addressed by the implantation of bioresorbable scaf-folds (BRSs). At present, there are numerous devices available for preclinical or clinical evaluation. This review discusses the evidence for BRS in the management of patients with coronary artery disease. PMID- 30251248 TI - Hybrid versus traditional cardiac rehabilitation models: A systematic review and meta-analysis. AB - BACKGROUND: The common drawbacks of standard cardiac rehabilitation (CR) models include low participation rate, high cost, and dependence on the on-site exercise sessions. Therefore, hybrid CR protocols have been developed. AIM: In this study, we aimed to test whether hybrid CR models are superior or equivalent to the traditional CR models in patients after myocardial infarction, heart failure, and cardiac surgery using a meta-analysis framework. METHODS: We searched Medline, Scopus, Cochrane Central, and Web of Science for relevant original studies. Data were extracted from these studies and analyzed using the RevMan software (version 5.3 for windows). The standardized mean difference (SMD) was used as a summary effect estimate, along with 95% confidence interval (CI). RESULTS: Based on data from 1195 patients, the summary effect size showed similar functional capacity improvement in hybrid and standard CR programs (SMD=-0.04, 95% CI [-0.18, 0.09], p=0.51). No significant difference was detected between the two models in terms of exercise duration (SMD=-0.14, 95% CI [-0.51, 0.24], p=0.47), systolic (SMD= 0.01, 95% CI [-0.14, 0.12], p=0.91) and diastolic (SMD=-0.03, 95% CI [-0.16, 0.11], p=0.7) blood pressure changes, and health-related quality of life (SMD= 0.08, CI [-0.23, 0.07], p=0.27). In terms of blood lipids, no significant difference was noted between hybrid and traditional CR models in all assessed lipid profile parameters, except for triglycerides (favoring the traditional CR model). CONCLUSION: Hybrid CR protocols showed comparable efficacy to the traditional model. Further well-designed studies are required to establish these findings, especially on the long-term outcomes. PMID- 30251249 TI - Coexistence of pike Esox lucius and brown trout Salmo trutta in Irish lakes. AB - An environmental study of pike Esox lucius recorded their presence in 522 Irish lakes and that they coexisted with brown trout Salmo trutta in 97 of these. Statistical models, accounting for spatial non-independence among lakes, suggested that lakes with greater area, maximum depth and stream connectivity show a higher probability of coexistence. Introductions of E. lucius are likely to have negative effects on S. trutta stocks in small isolated lakes, but coexistence may be possible in larger systems. PMID- 30251250 TI - Balancing presynaptic release and endocytic membrane retrieval at hair cell ribbon synapses. AB - The timely and reliable processing of auditory and vestibular information within the inner ear requires highly sophisticated sensory transduction pathways. On a cellular level, these demands are met by hair cells, which respond to sound waves - or alterations in body positioning - by releasing glutamate-filled synaptic vesicles (SVs) from their presynaptic active zones with unprecedented speed and exquisite temporal fidelity, thereby initiating the auditory and vestibular pathways. In order to achieve this, hair cells have developed anatomical and molecular specializations, such as the characteristic and name-giving 'synaptic ribbons' - presynaptically anchored dense bodies that tether SVs prior to release - as well as other unique or unconventional synaptic proteins. The tightly orchestrated interplay between these molecular components enables not only ultrafast exocytosis, but similarly rapid and efficient compensatory endocytosis. So far, the knowledge of how endocytosis operates at hair cell ribbon synapses is limited. In this Review, we summarize recent advances in our understanding of the SV cycle and molecular anatomy of hair cell ribbon synapses, with a focus on cochlear inner hair cells. PMID- 30251252 TI - Native Chinook salmon Oncorhynchus tshawytscha and non-native brook trout Salvelinus fontinalis prefer similar water temperatures. AB - Preferred water temperatures and acute temperature tolerance limits of two salmonids in California were assessed: juvenile Chinook salmon Oncorhynchus tshawytscha, a native anadromous species, and sub-adult brook trout Salvelinus fontinalis, an introduced game species. These two species preferred similar temperatures across an 18 h temperature preference experiment and showed similar critical thermal tolerance limits, suggesting a substantial thermal habitat overlap in the wild. PMID- 30251251 TI - Association Between Subclinical Brain Infarcts and Functional Decline Trajectories. AB - OBJECTIVES: To test associations between subclinical brain infarcts (SBIs) and functional decline independently of intervening clinical vascular events and other vascular risk factors. DESIGN: Longitudinal follow-up for a mean 7.3 years. Generalized estimating equation models were used to test associations between SBIs, number of perivascular spaces (PVSs), baseline Barthel Index (BI), and change in BI, adjusting for sociodemographic, vascular, and cognitive risk factors and for stroke and myocardial infarction occurring during follow-up. SETTING: Population-based prospective cohort study. PARTICIPANTS: Stroke-free individuals from the racially and ethnically diverse Northern Manhattan Study (N=1,290). MEASUREMENTS: Annual functional assessments using the BI (range 0 100). RESULTS: Mean age was 70.6 +/- 9.0, 40% of participants were male, 66% were Hispanic, 193 (16%) had SBIs, and 508 (42%) had large PVSs. SBIs were not associated with baseline BI. In a fully adjusted model, there was a change in BI of -0.85 points per year (95% confidence interval (CI)=-1.01 to -0.69); those with SBI had an additional change in BI 0f -0.88 points (95% CI=-1.43 to -0.32). There were no associations between PVS and baseline BI or change in BI. CONCLUSION: In a large population-based study, we found a strong and independent association between "subclinical" markers of cerebrovascular injury and important clinical, person-centered functional trajectories. Future research could clarify the evolution of such subclinical markers over time and test strategies to prevent their progression and minimize related disability. J Am Geriatr Soc 66:2144-2150, 2018. PMID- 30251253 TI - Modifying the consistency of food and fluids for swallowing difficulties in dementia. AB - BACKGROUND: People with dementia can have feeding and swallowing difficulties (dysphagia). Modification of the consistency of food or fluids, or both, is a common management strategy. However, diet modification can affect quality of life and may lead to dehydration and malnutrition. Evidence on the benefits and risks of modifying food and fluids is mandatory to improve the care of people with dementia and dysphagia. OBJECTIVES: To determine the effectiveness and adverse effects associated with modifying the consistency of food and fluids in improving oral intake and eliminating aspiration in adults with dysphagia and dementia. SEARCH METHODS: We searched ALOIS (the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group), the Cochrane Library, MEDLINE via Ovid SP, Embase via Ovid SP, PsycINFO via Ovid SP, CINAHL via EBSCOhost, LILACS via BIREME, ClinicalTrials.gov and the World Health Organization (WHO) Portal on 9 May 2018. We also checked the reference lists of relevant articles to identify any additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs and cluster-RCTs published in any language that measured any of the outcomes of interest. We included trials with adults with a clinical diagnosis of dementia with symptoms and signs of dysphagia confirmed on instrumental assessment. We included participants with all types, stages and severities of dementia. Control groups received either no intervention or interventions not involving diet modification or modification to sensory properties of food. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed for inclusion all potential studies identified. Data were extracted independently along with assessment of methodological quality using standard Cochrane methods. We contacted study authors for additional unpublished information. MAIN RESULTS: No trials on modification of food met the inclusion criteria. We included two studies that examined modification to fluids. Both were part of the same large multicentre trial and included people with dementia and people with or without dementia and Parkinson's disease. Participation in the second trial was determined by results from the first trial. With unpublished data supplied by study authors, we examined data from participants with dementia only. The first study, a cross-over trial, investigated the immediate effects on aspiration of two viscosities of liquids (nectar thick and honey thick) compared to regular liquids in 351 participants with dementia using videofluoroscopy. Regular liquids with a chin down head posture, as well as regular liquids without any intervention were also compared. The sequence of interventions during videofluoroscopy may have influenced response to intervention. The second study, a parallel designed RCT, compared the effect of nectar and honey thick liquids with a chin down head posture over a three-month period in a subgroup of 260 participants with dementia. Outcomes were pneumonia and adverse intervention effects. Honey thick liquids, which are more consistent with descriptors for 'spoon thick' or 'extremely thick' liquids, showed a more positive impact on immediate elimination of aspiration during videofluoroscopy, but this consistency showed more adverse effects in the second follow-up study. During the second three-month follow-up trial, there were a greater number of incidents of pneumonia in participants receiving honey thick liquids than those receiving nectar thick liquids or taking regular liquids with a chin down posture. There were no deaths classified as 'definitely related' to the type of fluids prescribed. Neither trial addressed quality of life. Risk of bias for both studies is high. The overall quality of evidence for outcomes in this review is low. AUTHORS' CONCLUSIONS: We are uncertain about the immediate and long-term effects of modifying the consistency of fluid for swallowing difficulties in dementia as too few studies have been completed. There may be differences in outcomes depending on the grade of thickness of fluids and the sequence of interventions trialled in videofluoroscopy for people with dementia. Clinicians should be aware that while thickening fluids may have an immediate positive effect on swallowing, the long-term impact of thickened fluids on the health of the person with dementia should be considered. Further high-quality clinical trials are required. PMID- 30251254 TI - Serum carcinoembryonic antigen as a clinical marker in hypohidrosis. PMID- 30251255 TI - Optimization of Nutrition Therapy with the Use of Calorimetry to Determine and Control Energy Needs in Mechanically Ventilated Critically Ill Patients: The ONCA Study, a Randomized, Prospective Pilot Study. AB - BACKGROUND: Adequate nutrition therapy in critically ill patients poses a challenge because of the variable energy and substrate needs. The objective was to investigate whether nutrition therapy involving indirect calorimetry (IC), instead of equations for assessment of energy needs, could improve the nutrition status of critically ill patients. METHODS: Forty mechanically ventilated patients were randomized into a group in which energy needs were controlled by calorimetry (IC group) and a group treated with a formula-based approach reflecting standard care (SC group). The primary outcome was change in the phase angle (PhA), a bioelectrical impedance parameter related to nutrition status and prognosis. RESULTS: The mean IC-based energy requirement was lower than the formula-based estimate (21.1 +/- 6.4 versus [vs] 25 kcal/kg/d, P < .01). The IC group reached 98% +/- 8% of the energy goal, whereas the SC group reached only 79% +/- 29% (P < 0.05), although mean intake was similar in both groups. The protein intake goal was better met in the IC group (91% +/- 24%) than the SC group (73% +/- 33%). The PhA of the IC group did not change during treatment, whereas that of the SC group tended to decrease by 0.36 degrees +/- 0.86 degrees (P = .077). A shorter length of stay in intensive care was observed in the IC than in the SC group (13 +/- 8 vs 24 +/- 20 days, P < .05). CONCLUSION: Intensified individual nutrition therapy involving IC appears to be useful for improving nutrition status in critically ill patients. PMID- 30251256 TI - Volatile Profile of Grilled Lamb as Affected by Castration and Age at Slaughter in Two Breeds. AB - : The aim of this study was to assess the effect of castration and slaughter age on the volatile profile of cooked meat from Scottish Blackface (SB) and Texel * Scottish Blackface (T * SB) lambs. M. longissimus thoracis et lumborum was sampled at slaughter and subjected to volatile analysis by SPME-GC-MS. Rams had higher relative proportions, expressed as relative abundance (RA), in lipid oxidation products while castrates had higher RA in pyrazines and benzenoid compounds. There was no consistent age effect on the RA of volatiles, although rams in November and January had a different volatile profile to castrates. There were higher proportions of free branched-chain fatty acids in muscle from SB compared to T * SB lambs. Overall, the results showed that production factors affected the volatile profile of cooked lamb meat which may explain differences in lamb flavor. PRACTICAL APPLICATION: Lamb meat has a characteristic flavor which, according to the evidence to date, may be influenced by farm production factors like gender or slaughter age. Our results showed variations in the proportions of some flavor compounds in cooked lamb between rams and castrated lambs while an increase in slaughter age did not have a consistent effect on proportions of compounds. PMID- 30251257 TI - Comment on "The pink salmon invasion: a Norwegian perspective" (Mo et al., 2018). PMID- 30251258 TI - The efficacy of microemulsion-based delivery to improve vitamin E properties: evaluation of the antinociceptive, antioxidant, antidepressant- and anxiolytic like activities in mice. AB - OBJECTIVES: A microemulsion-based delivery system was designed to improve vitamin E (VE) properties, and its antinociceptive, antioxidant, antidepressant- and anxiolytic-like activities in mice were evaluated. METHODS: Male Swiss mice received, by intragastric route, canola oil (20 ml/kg), blank microemulsion (B ME) (20 ml/kg), VE free (VE-F) (200 mg/kg) or VE microemulsion (VE-ME) (200 mg/kg). In acute treatment, a single dose of treatments was administrated and 30 min after behavioural tests were performed. In the subchronic treatment, mice received such treatments, once a day, for 8 days. On the eighth day, behavioural tests were performed. KEY FINDINGS: In the subchronic treatment, VE-ME increased entries and spent time in the open arms in the elevated plus-maze test and decreased the immobility time in the tail suspension test, but no change was found after acute treatment. Acute and subchronic treatments with VE-ME increased response latency to thermal stimulus in the hot-plate test. VE-ME decreased the thiobarbituric acid reactive species levels in the acute and subchronic protocols. Additionally, in subchronic treatment, VE-ME increased renal catalase activity, but VE-F reduced its activity. CONCLUSIONS: Vitamin E-microemulsions showed antioxidant, antinociceptive, antidepressant- and anxiolytic-like actions; thus, ME-based delivery improved pharmacological properties of VE. PMID- 30251259 TI - Effect of implementation of a surgical safety checklist on perioperative and postoperative complications at an academic institution in North America. AB - OBJECTIVE: To evaluate the efficacy of a surgical safety checklist (SSC) in reducing perioperative and postoperative complications. STUDY DESIGN: Before-and after intervention study. ANIMALS: Client-owned dogs (n = 633) and cats (n = 44). METHODS: Consecutive surgeries were enrolled in the study. The "before" phase consisted of 267 surgeries performed without an SSC (SSC- ) followed by 75 SSC- surgeries in which a trained observer was in the operating room to detect possible complications. An SSC was then implemented in the operating rooms during 1 week. The "after" phase consisted of 58 surgeries in which a safety checklist (SSC+ ) and an observer were used and 277 SSC+ surgeries without an observer. Complications were prospectively recorded when witnessed by the observer, and all other perioperative complications were retrospectively recorded from veterinary records and client telephone communication. RESULTS: There were more perioperative and postoperative complications when surgeries were performed without an SSC (140/342 [40.9%; 95% CI, 35.7%-46.4%]) than there were when surgeries were performed with an SSC (98/335 [29.3%; 95% CI, 24.4%-34.4%]; P = .002). Surgical checklist use, presence of an observer, American Society of Anesthesiologists score, and anesthesia time were all independently associated with the odds of complications. CONCLUSION: Implementation of an SSC in an academic teaching hospital decreased the odds of perioperative and postoperative surgical complications. CLINICAL SIGNIFICANCE: This study supports the use of an SSC to prevent surgical complications in veterinary teaching hospitals. PMID- 30251260 TI - Masking a fish's detection of environmental stimuli: application to improving downstream migration. AB - According to Signal Detection Theory, the ability to detect a stimulus (discriminability, d') is inversely related to the magnitude of internal and external noise. In this study, downstream moving brown trout Salmo trutta were used to investigate whether external hydrodynamic noise (in this case turbulence) could mask a signal that induced an unwanted response, such as rejecting accelerating velocity gradients commonly encountered at entrances to fish bypass channels. Salmo trutta behaviour was quantified in the absence (control) or presence of an accelerating velocity gradient created by an unconstricted or constricted channel, respectively, under two levels (low and high) of background turbulent kinetic energy (hydrodynamic noise). Experiments were conducted in an indoor recirculating flume in the dark and a range of passage metrics were quantified. Under the control condition, most (ca. 91%) S. trutta passed, usually oriented downstream (67%), with minimal delay (median 0.13 min). In comparison, fewer S. trutta (ca. 43%) passed under constricted conditions, they tended to orient facing into the flow (ca. 64%) and delay was greater (median > 20 min). When viewed from a coarse-scale perspective, discriminability of the velocity gradient was lower when turbulence was high suggesting masking of the signal occurred. However, the resulting increase in the percentage of fish that passed, decrease in time to pass and reduction in the distance at which S. trutta reacted (switched orientation) was subtle and non-significant. Despite the mixed results obtained, the use of masking to manipulate an animal's perception of environmental stimuli as a fisheries management tool is conceptually valid and the results of this experiment present a useful stepping stone for future research. PMID- 30251261 TI - Unraveling Methodology to Ensure the Search for Optimal Nutrition Quantity in Acute Respiratory Distress Syndrome Remains INTACT. PMID- 30251262 TI - The roles of jasmonate signalling in nitrogen uptake and allocation in rice (Oryza sativa L.). AB - Herbivore damage by chewing insects activates jasmonate (JA) signalling that can elicit systemic defense responses in rice. Few details are known, however, concerning the mechanism, whereby JA signalling modulates nutrient status in rice in response to herbivory. (15 NH4 )2 SO4 labelling experiments, proteomic surveys, and RT-qPCR analyses were used to identify the roles of JA signalling in nitrogen (N) uptake and allocation in rice plants. Exogenous applications of methyl jasmonate (MeJA) to rice seedlings led to significantly reduced N uptake in roots and reduced translocation of recently-absorbed 15 N from roots to leaves, likely occurring as a result of down-regulation of glutamine synthetase cytosolic isozyme 1-2 and ferredoxin-nitrite reductase. Shoot MeJA treatment resulted in a remobilization of endogenous unlabelled 14 N from leaves to roots, and root MeJA treatment also increased 14 N accumulation in roots but did not affect 14 N accumulation in leaves of rice. Additionally, proteomic and RT-qPCR experiments showed that JA-mediated plastid disassembly and dehydrogenases GDH2 up-regulation contribute to N release in leaves to support production of defensive proteins/compounds under N-limited condition. Collectively, our results indicate that JA signalling mediates large-scale systemic changes in N uptake and allocation in rice plants. PMID- 30251263 TI - A Bayesian approach for correcting exposure misclassification in meta-analysis. AB - In observational studies, misclassification of exposure is ubiquitous and can substantially bias the estimated association between an outcome and an exposure. Although misclassification in a single observational study has been well studied, few papers have considered it in a meta-analysis. Meta-analyses of observational studies provide important evidence for health policy decisions, especially when large randomized controlled trials are unethical or unavailable. It is imperative to account properly for misclassification in a meta-analysis to obtain valid point and interval estimates. In this paper, we propose a novel Bayesian approach to filling this methodological gap. We simultaneously synthesize two (or more) meta-analyses, with one on the association between a misclassified exposure and an outcome (main studies), and the other on the association between the misclassified exposure and the true exposure (validation studies). We extend the current scope for using external validation data by relaxing the "transportability" assumption by means of random effects models. Our model accounts for heterogeneity between studies and can be extended to allow different studies to have different exposure measurements. The proposed model is evaluated through simulations and illustrated using real data from a meta-analysis of the effect of cigarette smoking on diabetic peripheral neuropathy. PMID- 30251264 TI - Topical sodium thiosulfate for calcinosis cutis associated with autoimmune connective tissue diseases: the Mayo Clinic experience, 2012-2017. AB - In this case series, we retrospectively identified all patients treated with topical sodium thiosulfate (TST) for calcinosis cutis (CC) associated with underlying autoimmune connective tissue diseases at Mayo Clinic (Rochester, MN, USA) during the period 1 January 2012 to 27 June 2017. Of 28 patients identified (mean age 57.0 years; 96% female), 19 (68%) had clinical improvement of their CC with TST, 7 (25%) had no response and 2 (7%) had unknown response. There were adverse events in three patients: two had skin irritation and the third, who had a zinc allergy, experienced pain with application. Overall, our findings support those of previous case reports that TST appears to be a relatively well-tolerated adjuvant treatment for CC, although future studies with a control group are warranted to assess the true efficacy of TST for the indication of CC. PMID- 30251265 TI - Impact of non-empirically tuning the range-separation parameter of long-range corrected hybrid functionals on ionization potentials, electron affinities, and fundamental gaps. AB - Non-empirically tuning the range-separation parameter (omega) of long-range corrected (LC) hybrid functionals in improving the accuracy of vertical ionization potentials (IPs), vertical electron affinities (EAs), and fundamental gaps (FGs) is investigated. Use of default omega values gives the best overall property predictions employing the Delta self-consistent field (DeltaSCF) approach, if sufficiently large basis set is used. Upon tuning, IP (HOMO) (i.e., the IP estimated from the negative of HOMO energy via DFT Koopmans' theorem) with the IP (DeltaSCF) (i.e., the IP obtained from the DeltaSCF approach) the accuracy of IP (HOMO) significantly improves however a reciprocal phenomenon is not observed. An interesting observation is that EA (LUMO) (i.e., the EA estimated from the negative of LUMO energy) is more accurate than EA (DeltaSCF), if the omega value is in the range of 0.30 to 0.50 bohr-1 . (c) 2018 Wiley Periodicals, Inc. PMID- 30251266 TI - A case of necrotizing infundibular crystalline folliculitis. PMID- 30251267 TI - (-)-Epigallocatechin-3-gallate induces cell apoptosis in chronic myeloid leukaemia by regulating Bcr/Abl-mediated p38-MAPK/JNK and JAK2/STAT3/AKT signalling pathways. AB - Epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent of green tea, possesses remarkable chemopreventive and therapeutic potential against various types of cancer, including leukaemia. However, the molecular mechanism involved in chronic myeloid leukaemia (CML), especially imatinib-resistant CML cells, is not completely understood. In the present study, we investigated the effect of EGCG on the growth of Bcr/Abl+ CML cell lines, including imatinib-resistant cell lines and primary CML cells. The results revealed that EGCG could inhibit cell growth and induce apoptosis in CML cells. The mechanisms involved inhibition of the Bcr/Abl oncoprotein and regulation of its downstream p38-MAPK/JNK and JAK2/STAT3/AKT pathways. In conclusion, we documented the anti-CML effects of EGCG in imatinib-sensitive and imatinib-resistant Bcr/Abl+ cells, especially T315I-mutated cells. PMID- 30251268 TI - Messy Play Therapy in the Treatment of Food Aversion in a Patient With Intestinal Failure: Our Experience. AB - BACKGROUND: Food aversion (FA) is an eating behavior where children refuse solid or fluid intake. FA can compromise the weaning off parenteral nutrition (PN) in children with intestinal failure (IF), reducing their quality of life (QoL). Around 25% of children with IF experience FA, but few data are available on interventions to get over FA. Messy play therapy (MPT) uses sensory activities to provide another meaningful avenue for learning in children by creating a fun way to experience new textures. This study aims to assess the efficacy of MPT in FA. METHODS: Demographic data and MPT intervention were retrospectively recorded between 2004 and 2017. Food was categorized by tastes and textures. Data are expressed as median and interquartile range (25%-75%). RESULTS: Twelve children were identified. MPT was started at 9 (6-16) months with an enrolling time within the program of 10.11 (7.75-12.5) months. MPT was ended after 19.5 (16.75-28.5) months, and all patients achieved tolerance to oral diet. Significant improvement in savory (P = .001), sweet (P = .002), and mixed texture (P = .001) of food intake was reported. Better QoL and mealtimes with family were reported at median follow-up of 39 (24-56) months. CONCLUSIONS: MPT seems to be a positive intervention to overcome FA. In our experience, the children have gone from not tolerating any intake to tolerating an oral diet, which means enjoying their mealtimes. Further studies are needed to evaluate the effectiveness of MPT in a larger scale of patients. PMID- 30251269 TI - Religious delusions in older adults: Diagnoses, combinations, and delusional characteristics. AB - OBJECTIVE: Religious delusions (RDs) tend to occur relatively often in patients with affective or non-affective psychosis. Few studies exist about RDs in later life. The current study explores (1) the distribution of RDs across diagnosis, (2) how RDs relate to other types of delusions, and (3) how RDs relate to several dimensions or characteristics of delusions. METHODS: Inpatients and outpatients in a Geriatric Psychiatry Department in the Netherlands (N = 155; mean age 76.5 years), and who were diagnosed with an affective or non-affective psychotic disorder, participated in semi structured diagnostic interviews, using the Schedules for Clinical Assessement in Neuropsychiatry 2.1. RESULTS: Religious delusions were most common among patients with psychotic depression (47%) and schizophrenia (32%). The RDs frequently co-occurred with other types of delusions. When combined with delusions of grandeur, RDs were more often classified as bizarre and were accompanied by higher levels of positive psychotic symptoms. When combined with delusions of guilt, RDs were associated with higher levels of distress and a shorter disease duration. The delusional characteristics bizarreness, frequency of psychotic symptoms, and degree of distress were more prevalent for RDs than for any other type of delusion. CONCLUSIONS: The current study suggests that the prevalence of RDs in older adults is particularly high in late life psychotic depression. Also, in later life, RDs can be perceived of as independent marker of complex psychotic states, and as a denominator of severe arousal with respect to existential concerns. PMID- 30251270 TI - Optimal maternal and neonatal outcomes and associated hospital characteristics. AB - BACKGROUND: This study aims to examine hospital variation in both maternal and neonatal morbidities and identify institutional characteristics associated with hospital performance in a combined measure of maternal and neonatal outcomes. METHODS: Using the California Linked Birth File containing data from birth certificate and hospital discharge records, we identified 1 322 713 term births delivered at 248 hospitals during 2010-2012. For each hospital, a risk standardized rate of severe maternal morbidities and a risk-standardized rate of severe newborn morbidities were calculated after adjusting for patient clinical risk factors. Hospitals were ranked based on combined information on their maternal and newborn morbidity rates. RESULTS: Risk-standardized severe maternal and severe newborn morbidity rates varied substantially across hospitals (10th to 90th percentile range = 67.5-148.2 and 141.8-508.0 per 10 000 term births, respectively), although there was no significant association between the two (P = 0.15). Government hospitals (non-Federal) were more likely than other hospitals to be in worse rank quartiles (P value for trend = 0.004), whereas larger volume was associated with better rank among hospitals in the first three quartiles (P = 0.004). The most prevalent morbidities that differed progressively across hospital rank quartiles were severe hemorrhage, disseminated intravascular coagulation, and heart failure during procedure/surgery for mothers, and severe infection, respiratory complication, and shock/resuscitation for neonates. CONCLUSIONS: Hospitals with low maternal morbidity rates may not have low neonatal morbidity rates and vice versa, highlighting the importance of assessing joint maternal-newborn outcomes in order to fully characterize a hospital's obstetrical performance. Hospitals with smaller volume and government ownership tend to have less desirable outcomes and warrant additional attention in future quality improvement efforts. PMID- 30251271 TI - Animal maltreatment law: Evolving efforts to protect animals and their forensic mental health implications. AB - Animals have long formed an important part of human communities and served various roles in human activities. Some of the earliest human civilizations developed laws that protected animals for assorted reasons, including their economic value, religious beliefs pertaining to animals, and societal concerns about cleanliness. In the 1800s, Western thinkers began to view animals as having rights of their own and proposed legislation that changed the legal landscape regarding animal maltreatment. In the United States today there are widely varying laws designed to address the various forms of animal maltreatment. Each state's laws are different. Some states have modern statutes designed to identify and punish animal maltreatment, and others are relatively lax in their consideration of what constitutes abuse. The purpose of this article is to review the development of animal maltreatment legislation from ancient civilization to the present day in the United States; to identify current legislative reforms designed to assist in investigating and prosecuting animal abusers; to describe the role that forensic mental health experts may play in evaluating abusers for a variety of related concerns, including violence risk, sexual violence risk, and fitness for guardianship of an animal; and to delineate areas requiring further research to improve the forensic evaluation of animal abusers. PMID- 30251272 TI - Sesquiterpene lactones-enriched fraction of Inula helenium L. induces apoptosis through inhibition of signal transducers and activators of transcription 3 signaling pathway in MDA-MB-231 breast cancer cells. AB - Inula helenium L., commonly known as Elecampane, has been extensively used for many countries in the folk medicine. Its root is a rich source of sesquiterpene lactones, which possess various pharmacological activities. To develop the phytomedicine including sesquiterpene lactones, we prepared hexane fraction from I. helenium (HFIH) and examined the inhibitory effect of HFIH on signal transducers and activators of transcription 3 (STAT3) activation in human breast cancer MDA-MB-231 cells. Additionally, detailed chemical investigation was done to pinpoint the most active sesquiterpene lactones responsible for its anticancer activity. HFIH selectively suppressed STAT3 phosphorylation at tyrosine 705, not affecting its upstream kinases. HFIH downregulated the expression of STAT3 target genes including cyclin D1 , c-myc, and bcl-2 and induced caspase-mediated apoptosis. Moreover, sesquiterpene lactones of HFIH clearly suppressed STAT3 activation. The in vivo results further supported that HFIH inhibits the growth of human breast xenograft tumors. Our results suggest that HFIH possesses potential anticancer activity, which is mainly mediated through STAT3 signaling pathway. These findings provide the potential of HFIH as a promising phytomedicine for the treatment and prevention of triple-negative breast cancer. PMID- 30251273 TI - Correlation between pre-procedural plaque morphology and patterns of in-stent neointimal hyperplasia at 1-year follow-up in patients treated with new generation drug-eluting stents: An optical coherence tomography based analysis. AB - INSTRUCTION: Several factors affect the in-stent intimal healing process after drug-eluting stents (DESs) implantation. We hope to investigate the influence of plaque characteristics on subsequent heterogeneous neointimal hyperplasia (NIH) using optical coherence tomography (OCT). METHODS: The study population consisted 217 patients with single-vessel de novo lesions who underwent both pre-procedural OCT scan and 12-month follow-up OCT examination. NIH is defined as at least five consecutive cross-sectional images with no less than 100um neointimal thickness. According to OCT follow-up, patients were divided into three groups: neointima covered group, homogeneous, and heterogeneous NIH group. RESULTS: 102 patients were categorized in neointima-covered group, 91 and 24 patients in homogeneous and heterogeneous group, respectively. Time interval between OCT scans was similar (P = 0.55). No significant differences in the patients' age, gender, comorbidities, laboratory findings, procedural, and lesion-related findings were found among these three groups. Heterogeneous group tended to have more subjects presented as acute coronary syndrome (ACS) (P = 0.04) and mean macrophage grade was higher in this group (P = 0.01). While no statistically significant difference concerning mean intimal thickness (P = 0.21) or neointimal burden (P = 0.73) was found between homogeneous and heterogeneous group. Multivariate logistic regression analysis showed that mean macrophage grade (OR: 2.26, 95%CI: 1.12 to 4.53, P = 0.02) and initial clinical presentation of ACS (OR: 2.81, 95%CI: 1.03 to 7.72, P = 0.04) were significant independent risk factors for heterogeneous NIH. CONCLUSION: Mean macrophage grade measured by OCT as a semi quantitative morphological risk factor, as well as clinical presentation of ACS, was associated with in-stent neointimal heterogeneity after DES implantation. PMID- 30251274 TI - Manipulating Luminescence of Light Emitters by Photonic Crystals. AB - The modulation of luminescence is essential because unwanted spontaneous-emission modes have a negative effect on the performance of luminescence-based photonic devices. Photonic crystals are promising materials for the control of light emission because of the variation in the local density of optical modes within them. They have been widely investigated for the manipulation of the emission intensity and lifetime of light emitters. Several groups have achieved greatly enhanced emission by depositing emitters on the surface of photonic crystals. Herein, the different modulating effects of photonic crystal dimensions, light emitter positions, photonic crystal structure type, and the refractive index of photonic crystal building blocks are highlighted, with the aim of evaluating the fundamental principles that determine light propagation. The applications of using photonic crystals to manipulate spontaneous emission in light-emitting diodes and sensors are also reviewed. In addition, potential future challenges and improvements in this field are presented. PMID- 30251275 TI - The accuracy of LD Score regression as an estimator of confounding and genetic correlations in genome-wide association studies. AB - To infer that a single-nucleotide polymorphism (SNP) either affects a phenotype or is linkage disequilibrium with a causal site, we must have some assurance that any SNP-phenotype correlation is not the result of confounding with environmental variables that also affect the trait. In this study, we study the properties of linkage disequilibrium (LD) Score regression, a recently developed method for using summary statistics from genome-wide association studies to ensure that confounding does not inflate the number of false positives. We do not treat the effects of genetic variation as a random variable and thus are able to obtain results about the unbiasedness of this method. We demonstrate that LD Score regression can produce estimates of confounding at null SNPs that are unbiased or conservative under fairly general conditions. This robustness holds in the case of the parent genotype affecting the offspring phenotype through some environmental mechanism, despite the resulting correlation over SNPs between LD Scores and the degree of confounding. Additionally, we demonstrate that LD Score regression can produce reasonably robust estimates of the genetic correlation, even when its estimates of the genetic covariance and the two univariate heritabilities are substantially biased. PMID- 30251276 TI - Lung transplantation from brain-dead donors with bacterial meningitis: Proper donor evaluation for successful lung transplantation. PMID- 30251277 TI - Post-radiation vascular lesions of the breast. AB - Post-radiation vascular lesions are a rare complication most commonly seen in patients previously treated for breast cancer. The main two entities include angiosarcoma (AS), which are malignant tumors that have a poor prognosis, and atypical vascular lesions (AVL), which typically behave in a benign manner and only rarely progress to angiosarcoma. The overall incidence of these lesions is low, but it appears to be increasing. Histopathologic distinction of AVL and AS is essential due to different clinical outcomes and treatment. However, due to the occasional existence of overlapping clinical and histopathologic features, it may be sometimes difficult to render a definite diagnosis, particularly in small biopsies. Ancillary techniques are, in general, of little help for separating the borderland cases but, in some instances, immunohistochemical study (IHC) for Ki67 and IHC or fluorescence in situ hybridization analysis for MYC may help in the diagnosis of angiosarcoma. Herein we discuss the clinical characteristics, histopathologic features, management strategies, and outcome of these lesions, with special emphasis on their differential diagnosis. PMID- 30251278 TI - Cognitive-motor interference during goal-directed upper-limb movements. AB - Research and clinical practice have focused on effects of a cognitive dual-task on highly automated motor tasks such as walking or maintaining balance. Despite potential importance for daily life performance, there are only a few small studies on dual-task effects on upper-limb motor control. We therefore developed a protocol for assessing cognitive-motor interference (CMI) during upper-limb motor control and used it to evaluate dual-task effects in 57 healthy individuals and two highly prevalent neurological disorders associated with deficits of cognitive and motor processing (57 patients with Parkinson's disease [PD], 57 stroke patients). Performance was evaluated in cognitive and motor domains under single- and dual-task conditions. Patterns of CMI were explored to evaluate overall attentional capacity and attention allocation. As expected, patients with neurological deficits showed different patterns of CMI compared to healthy individuals, depending on diagnosis (PD or stroke) and severity of cognitive and/or motor symptoms. Healthy individuals experienced CMI especially under challenging conditions of the motor task. CMI was greater in PD patients, presumably due to insufficient attentional capacity in relation to increased cognitive involvement in motor control. Although no general increase of CMI was observed in stroke patients, correlation analyses suggested that especially patients with severe motor dysfunction experienced CMI. Clinical ratings of cognitive and motor function were weakly associated with CMI, suggesting that CMI reflects a different construct than these unidimensional clinical tests. It remains to be investigated whether CMI is an indicator of difficulties with day to-day activities. PMID- 30251279 TI - Identification of botanicals with potential therapeutic use against methicillin resistant Staphylococcus aureus (MRSA) infections. AB - Staphylococcus aureus is an opportunistic pathogen. Over- and improper-use of pharmaceuticals against S. aureus has led to the development of antibiotic resistance, including methicillin-resistant S. aureus (MRSA). This study examined the efficacy of botanical extracts as an alternative form of treatment to S. aureus and MRSA, including penicillin/methicillin-resistant S. aureus (PenR ), and multidrug resistant S. aureus (MDR). Initial screening of botanicals was done via a minimum inhibitory concentration procedure. In addition, a temporal growth curve was performed in order to quantify the growth of the bacteria in the presence of the extracts. Results demonstrated 13 botanicals that had varying activities against S. aureus, PenR , and MDR. These botanicals were separated into mild, moderate, and highly efficacious based on the concentration needed to inhibit bacterial growth. These results propose a comparison of botanical-derived antimicrobial extracts that may be utilized against S. aureus and different antibiotic resistant strains of MRSA. PMID- 30251280 TI - Cyanidin-3-glucoside attenuates the angiogenesis of breast cancer via inhibiting STAT3/VEGF pathway. AB - Angiogenesis plays a pivotal role in breast cancer progression. Cyanidin-3 glucoside (C3G), one of the most widely distributed anthocyanins in edible fruits, shows antioxidative and anti-inflammatory property as well as induction of breast cancer cells apoptosis. However, the effect of C3G on breast cancer induced angiogenesis remains unknown. In the present study, we found that C3G could attenuate breast cancer-induced angiogenesis via inhibiting VEGF, a key cytokine for angiogenesis, expression and secretion. Furthermore, signal transducer and activator of transcription 3 (STAT3) could transcriptionally activate VEGF, and C3G reduced STAT3 expression at both mRNA and protein level. Subsequently, our data showed that C3G induced miR-124 expression. Moreover, miR 124 could directly repress STAT3 expression, and miR-124-mediated STAT3 down regulation was responsible for the inhibition of C3G on VEGF and angiogenesis. Taken together, we supplied more evidence to the anti-breast cancer property of C3G. PMID- 30251281 TI - Fatherhood and psychobiology in the Philippines: Perspectives on joint profiles and longitudinal changes of fathers' estradiol and testosterone. AB - OBJECTIVES: Research on the psychobiology of partnering and fathering has focused on testosterone (T), oxytocin, and prolactin (PRL) as mechanisms that potentially mediate life history trade-offs related to those roles. Less is known about other hormones that might be responsive to life history transitions and implicated in fathering, such as estradiol (E2). We examined how E2 changed during the transition to marriage and fatherhood, its correlation with fathers' caregiving, and its joint within-individual production with other hormones (T, PRL). METHODS: Data were collected from a total of 913 Filipino men (aged 25.9 years +/- 0.3 SD at follow-up) enrolled in a longitudinal cohort study. Morning saliva samples collected at baseline (2005) and follow-up (2009) were assayed for T and E2 (n = 329), dried blood spots from baseline were assayed for PRL. Fathers reported on caregiving in 2009. RESULTS: When compared with men who remained single non fathers over the study period, men who became married residential fathers experienced larger declines in E2. This effect was non-significant when we controlled for longitudinal changes in T. E2 was not significantly related to fathers' caregiving, controlling for T. In cross-sectional analyses for PRL, T, and E2, married residential fathers exhibited within-individual profiles of reduced T and elevated PRL, whereas single non-fathers exhibited the opposite profile of elevated T and reduced PRL. CONCLUSIONS: Our findings point to the need for future research to consider the mutually regulatory dynamics and/or combinatorial implications of multiple physiological axes acting within individuals to underpin life history trade-offs and behavioral strategies. PMID- 30251282 TI - Multinucleate cell angiohistiocytoma: Case report and literature review. AB - Multinucleate cell angiohistiocytoma is a rare, vascular, fibrohistiocytic proliferation that has a benign but progressive course. The clinical presentation is that of grouped red-purple papules and nodules characteristically located on the lower extremities in women. The histopathology shows a proliferation of narrow vessels within thickened collagen bundles associated with multinucleate giant cells. These lesions are probably reactive in nature, and several mechanisms of pathogenesis, including hormonal, have been proposed. Different modalities, including intense pulsed light and pulsed-dye laser, have been used for treatment of these lesions. We report a case of a 74-year-old Caucasian woman with long-standing multinucleate angiohistiocytoma on her bilateral thighs that eluded diagnosis for several years. Upon biopsy and histopathological analysis, the diagnosis was made. Treatment options were entertained, although ultimately not pursued by the patient. We report this case to increase clinical awareness of this rare disease and to contribute to the ongoing literature aimed to further characterize this condition. PMID- 30251283 TI - Contribution of three-dimensional ultrasound and three-dimensional helical computer tomography in the prenatal diagnosis of Stickler Syndrome. AB - The Pierre Robin Sequence can be associated with various different syndromes in which Stickler Syndrome is the most frequent. The prenatal diagnosis of this syndrome is rare, however, early diagnosis would aid the antenatal counselling of such couples thereby allowing them to make an informed choice regarding their further management. Consequently, we propose the use of three-dimensional ultrasound and three-dimensional helical computer tomography for suspected cases of Stickler syndrome to complement standard ultrasound to reach the diagnosis. This case illustrates that both 3D-ultrasound and 3D-HCT enhanced our diagnostic capability of a Stickler syndrome phenotype prior to molecular confirmation. This article is protected by copyright. All rights reserved. PMID- 30251284 TI - Commentary on Socias et al. (2018): Clinical research perspectives on cannabis use in opioid agonist treatment. PMID- 30251285 TI - Stevia rebaudiana tea prevents experimental cirrhosis via regulation of NF kappaB, Nrf2, transforming growth factor beta, Smad7, and hepatic stellate cell activation. AB - Stevia has been shown to prevent oxidative stress and inflammation in carbon tetrachloride-induced cirrhosis models. This study aimed to investigate the ability of an aqueous extract of stevia (AES) to prevent thioacetamide (TAA) induced cirrhosis in rats and to explore its mechanism of action. Liver cirrhosis was established by administering TAA (200 mg/kg by i.p. injections three times a week for 10 weeks); AES was administered (100 mg/kg by gavage daily) during the TAA treatment. Liver damage and fibrosis were evaluated, and the profibrotic pathways were analyzed by western blotting and immunohistochemistry. TAA increased nuclear factor kappa B (NF-kappaB) and pro-inflammatory cytokine production, as well as the malondialdehyde and 4-hydroxynonenal levels, whereas the glutathione/glutathione disulfide and nuclear factor-E2-related factor 2 (Nrf2) levels were decreased. Moreover, TAA increased collagen production, hepatic stellate cell (HSC) activation, and expression of profibrogenic mediators. TAA-treated rats that had been exposed to Mn2+ exhibited altered striatal dopamine turnover, indicating hepatic encephalopathy. AES partially or completely prevented all of these effects. AES showed antioxidant, anti inflammatory, and antifibrotic properties, probably because of its capacity to induce Nrf2 expression, reduce NF-kappaB expression, and block several profibrogenic signaling pathways, subsequently inhibiting HSC activation and preventing fibrosis and dopamine turnover. PMID- 30251286 TI - Birth weight and cardiac function assessed by echocardiography in adolescence: the Avon Longitudinal Study of Parents and Children. AB - OBJECTIVE: Maternal hemodynamics in pregnancy is associated with fetal growth and birth weight, which in turn is associated with offspring cardiovascular disease later in life. We therefore sought to quantify the extent to which birth weight is associated with cardiac structure and function in adolescence. METHODS: Participants (N=1,964, 55% females) from a UK birth cohort were examined with echocardiography at mean age 17.7 years (SD 0.3). Birth weight z-scores for sex and gestational age were used. Linear regression models were adjusted for several potential confounders, including maternal pre-pregnancy body mass index (BMI), maternal age, maternal level of education, and smoking during pregnancy. RESULTS: Higher birth weight was associated with lower E/A (mean difference -0.024, 95% confidence interval (CI); -0.043 to -0.005) and E/e' (-0.05; 95% CI -0.10; 0.0006) and also associated with higher left ventricular mass index (LVMI) (0.38 g/m2.7 ; 95% CI 0.09; 0.67). There was no or inconsistent evidence of associations with relative wall thickness, left atrial diameter, and measurements of systolic function. Further analyses suggested that the association between birth weight and LVMI was mainly driven by an association observed in participants born small for gestational age and it was also abolished when risk factors in adolescence were accounted for. CONCLUSIONS: Higher birth weight adjusted for sex and gestational age was associated with differences in measures of diastolic function in adolescence but the observed associations were small. It remains to be determined the extent to which these associations translate into increased susceptibility to cardiovascular disease later in life. This article is protected by copyright. All rights reserved. PMID- 30251287 TI - Quantification of intraepidermal nerve fiber density using three-dimensional microscopy. AB - Three-dimensional microscopy provides more extended depth of penetration compared with conventional light microscopy and is known to be useful in clinical evaluation of thick biological specimens. Skin nerve biopsy together with the quantification of intraepidermal nerve fibers in multiple thick sections has been widely adopted for evaluating peripheral neuropathies. The aim of the present study was to evaluate the effectivity of three-dimensional microscopy in reducing the required time and inter-rater discrepancies, especially in the case of personnel not familiar with the quantification methods. A total of six cryo sectioned specimens were analyzed for the study and the skin samples were collected from one patient with postherpetic neuralgia who voluntarily participated in the study. Two investigators, a physician and non-physician assessed the intraepidermal nerve fiber densities and required analysis time using three different methods including direct visualization of tissue slides, and analysis with two- and three-dimensional images. Three-dimensional microscopy could produce images that enabled reliable evaluation of intraepidermal nerve fibers; the accuracy of analysis was statistically comparable between the physician and non-physician (p > .05). Three-dimensional microscopy also enabled the non-physician to proceed meaningfully faster evaluation compared with the direct visualization method (p = .03). Three-dimensional microscopy could be one of the useful methods to improve accuracy and convenience of the analysis of intraepidermal nerve fibers especially appropriate for unaccustomed physician or non-physician. RESEARCH HIGHLIGHTS: Three-dimensional microscopy is capable of producing images with more extended depth of penetration compared with conventional light microscopy and has been known to be suitable for clinical evaluation of thick biological specimens. Cutaneous nerve biopsy and the quantification of nerve fibers in thick sections has been widely adopted for evaluating peripheral neuropathies. Three-dimensional microscopy could be especially appropriate for unaccustomed physician or non-physician to improve accuracy and convenience of the analysis of intraepidermal nerve fibers. PMID- 30251288 TI - The influence of lifestyle, diet, and reproductive history on age at natural menopause in Spain: Analysis from the EPIC-Spain sub-cohort. AB - OBJECTIVE: To determinate the role of lifestyle factors, recent diet, menstrual factors, and reproductive history in age at natural menopause in adult Spanish women. METHODS: In total, 12 562 pre-menopausal women were available for analysis from the EPIC-Spain sub-cohort. Women were recruited between 1992 and 1996 in five regions of Spain (Asturias, Granada, Murcia, Navarra, and San Sebastian) and, for these analyses, were followed for 3 years. Questionnaires on diet, lifestyle, anthropometric measurements, and reproductive and exogenous hormones history were collected at baseline. Menopause status was updated at a median of 3 years of follow-up. RESULTS: After a median of 3 years of follow-up 1166 women became postmenopausal. An earlier age at menopause was observed in current smokers (HR: 1.29; 95%CI 1.08-1.55) and in non-users of oral contraceptives (HR: 1.32; 95%CI 1.01-1.57). A later age at menopause was observed in women with irregular menses (HR: 0.71; 95%CI 0.56-0.91) and in women with a higher number of pregnancies (HR: 0.74; 95%CI 0.56-0.94). CONCLUSIONS: Our results confirm that women who smoked had an earlier age at natural menopause, while use of oral contraceptives, higher number of pregnancies, and irregularity of menses were associated with a prolonged reproductive lifespan. No associations were observed for dietary habits assessed after the age of 40 years. PMID- 30251289 TI - Relationships between the digit ratio (2D:4D) and game-related statistics in professional and semi-professional male basketball players. AB - OBJECTIVES: The primary aim of this study was to examine relationships between digit ratio (2D:4D) and game-related statistics in professional and semi professional male basketball players. The secondary aim was to quantify differences in mean 2D:4Ds between starting and reserve players. METHODS: Using a cross-sectional design, 93 male basketball players from the professional Australian National Basketball League and the semi-professional South Australian Premier League were measured in-season for height, mass, and 2D:4D, with game related statistics collected end-season. Linear relationships between right and left 2D:4Ds and game-related statistics were quantified using nonparametric partial correlations, and differences in mean 2D:4Ds between starting and reserve players were quantified using analysis of covariance (ANCOVA). All partial correlations and ANCOVAs were adjusted for playing experience, body size, and competitive standard. RESULTS: 2D:4D was a weak to moderate negative correlate of points scored and assists-to-turnovers ratio, indicating that males with lower 2D:4Ds were generally better offensively as they recorded more points and assists relative to turnovers. The difference in mean 2D:4D between starting and reserve players was negligible. CONCLUSIONS: 2D:4D was favorably correlated with open skill sports performance, as evidenced by the better offensive statistics of male basketball players with lower 2D:4Ds. These results probably reflect the organizational benefits of prenatal testosterone and indicate that 2D:4D may be a useful complement to traditional physical, physiological, skill, and behavioral predictors of basketball success. PMID- 30251290 TI - Comparison of UV protection properties of cotton fabrics treated with aqueous and methanolic extracts of Solanum nigrum and Amaranthus viridis plants. AB - Harmful effects of ultraviolet rays and protection against them have been long discussed. Numerous synthetic dyes, finishes, UV absorbers, and optical brightening agents are present in the market for decades for achieving UV protection through textiles. However, due to environmental impacts of these chemical agents, textile industry is looking for alternatives. In this regard, some natural dyes and plant extracts have shown promising results. However, use of colorless plant extracts as UV protective finishes is still rare. In this study, ultraviolet protection factor (UPF) rating of bleached cotton fabric has been improved by the application of plant extracts with minimal change in fabric's color. For this purpose, two medicinal plants, that is, Solanum nigrum and Amaranthus viridis were selected and bleached cotton fabric was treated with their methanolic and aqueous extracts. Fabrics treated with both extracts exhibited excellent UPF ratings. PMID- 30251291 TI - Selective Synthesis and Properties of Electron-Deficient Hybrid Naphthalene-Based pi-Conjugated Systems. AB - One driving force for advancing the field of semiconducting polymers is to create new pi-conjugated systems as building units. This work reports on a series of electron-deficient hybrid naphthalene-based pi-conjugated systems in which two different units among benzoxadiazole, benzothiadiazole, benzoselenadiazole, and benzopyrazine (quinoxaline) were fused. These pi-conjugated systems were synthesized in excellent yields via the selective one-side ring-opening reaction of corresponding naphthobischalcogenadiazoles using the NaBH4 /CoCl2 reduction reagents, followed by the ring-closing reactions. The electronic structure of these pi-conjugated systems was studied in comparison with their parent systems. Furthermore, thiadiazolonaphthoxadiazole was incorporated into the pi-conjugated polymer backbone. The electronic structure, film structure, and photovoltaic properties of the polymer were studied as well. PMID- 30251292 TI - Quantification of protein markers monitoring the pre-analytical effect of blood storage time before plasma isolation using 15 N metabolically labeled recombinant proteins. AB - In the hospital, blood samples are collected to monitor patients' health states, and thus various protein-based clinical methods have been developed. However, some proteins are found to change in abundances during the process of blood collection and storage. In order to account such pre-analytical effects, we performed LC-MRM-MS on 15 selected proteins in plasma samples prepared by varying storage time and temperature of whole blood prior to plasma isolation. Two cytosolic proteins, PFN1 and TMSB4X were absolutely quantified using 15 N-labeled recombinant proteins spiked externally. The other thirteen proteins were quantified in a relative way compared to the two reference proteins. Triplicated LC-MRM-MS measurements showed that the median CV of MRM peak areas was 5.7%. The amounts of PFN1 and TMSB4X increased rapidly depending on the storage time between blood collection and plasma preparation. It indicates the leakage of cellular components into the plasma fraction. Relative quantification further revealed that five proteins including PFN1, S10A8, S10A9, S10A11, and TMSB4X showed significant difference (P < 0.05). We further monitored PFN1 and TMSB4X on 40 samples collected for protein diagnostics under a typical clinical study condition. Compared to the plasma samples prepared within a day, the level of both PFN1 and TMSB4X increased in the plasma samples prepared from the blood collected the day before and kept overnight at 4 degrees C (0.51 MUg/mL to 3.11 MUg/mL for PFN1 and 0.98 MUg/mL to 5.36 MUg/mL for TMSB4X in average). Our result suggests an effort of assuring plasma quality for accurate protein-based diagnosis or biomarker discovery and validation. PMID- 30251293 TI - No clear evidence for correlations between handgrip strength and sexually dimorphic acoustic properties of voices. AB - OBJECTIVES: Recent research on the signal value of masculine physical characteristics in men has focused on the possibility that such characteristics are valid cues of physical strength. However, evidence that sexually dimorphic vocal characteristics are correlated with physical strength is equivocal. Consequently, we undertook a further test for possible relationships between physical strength and masculine vocal characteristics. METHODS: We tested the putative relationships between White UK (N = 115) and Chinese (N = 106) participants' handgrip strength (a widely used proxy for general upper-body strength) and five sexually dimorphic acoustic properties of voices: fundamental frequency (F0), fundamental frequency's SD (F0-SD), formant dispersion (Df), formant position (Pf), and estimated vocal-tract length (VTL). RESULTS: Analyses revealed no clear evidence that stronger individuals had more masculine voices. CONCLUSIONS: Our results do not support the hypothesis that masculine vocal characteristics are a valid cue of physical strength. PMID- 30251294 TI - Emerging trends of Nipah virus: A review. AB - Since emergence of the Nipah virus (NiV) in 1998 from Malaysia, the NiV virus has reappeared on different occasions causing severe infections in human population associated with high rate of mortality. NiV has been placed along with Hendra virus in genus Henipavirus of family Paramyxoviridae. Fruit bats (Genus Pteropus) are known to be natural host and reservoir of NiV. During the outbreaks from Malaysia and Singapore, the roles of pigs as intermediate host were confirmed. The infection transmitted from bats to pigs and subsequently from pigs to humans. Severe encephalitis was reported in NiV infection often associated with neurological disorders. First NiV outbreak in India occurred in Siliguri district of West Bengal in 2001, where direct transmission of the NiV virus from bats-to human and human-to-human was reported in contrast to the role of pigs in the Malaysian NiV outbreak. Regular NiV outbreaks have been reported from Bangladesh since 2001 to 2015. The latest outbreak of NiV has been recorded in May, 2018 from Kerala, India which resulted in the death of 17 individuals. Due to lack of vaccines and effective antivirals, Nipah encephalitis poses a great threat to public health. Routine surveillance studies in the infected areas can be useful in detecting early signs of infection and help in containment of these outbreaks. PMID- 30251295 TI - Reply: Does Helicobacter pylori infection increase the risk of Barrett's esophagus and esophageal adenocarcinoma? PMID- 30251296 TI - Grouping Effect of Single Nickel-N4 Sites in Nitrogen-Doped Carbon Boosts Hydrogen Transfer Coupling of Alcohols and Amines. AB - As a new type of heterogeneous catalyst with "homogeneous-like" activity, single site transition-metal materials are usually treated as integrated but separate active centers. A novel grouping effect is reported for single Ni-N4 sites in nitrogen-doped carbon (Ni/NC), where an effective ligand-stabilized polycondensation method endows Ni/NC nanocatalysts with a high content of single site Ni up to 9.5 wt %. The enhanced electron density at each single Ni-N4 site promotes a highly efficient hydrogen transfer, which is exemplified by the coupling of benzyl alcohol and aniline into N-benzylaniline with a turnover frequency (TOF) value of 7.0 molN-benzylaniline molmetal -1 h-1 ; this TOF outpaces that of reported stable non-noble-metal-based catalysts by a factor of 2. PMID- 30251299 TI - Positive expiratory pressure breathing speeds recovery of postexercise dyspnea in chronic obstructive pulmonary disease. AB - OBJECTIVES: Faster recovery of postexertional dyspnea might enable chronic obstructive pulmonary disease (COPD) patients to undertake more physical activity. The purpose of this study was to determine whether breathing with a positive expiratory load to reduce dynamic hyperinflation (DH) would hasten recovery. METHODS: Thirteen male COPD patients (59 +/- 7 years; Global Initiative for Obstructive Lung Disease Stages II and III) took part in a randomized cross over trial in which they exercised by self-paced spot marching. Interventions at the end of exercise consisted of six breaths against either a 5-cm H2 O expiratory load (positive expiratory pressure [PEP]) or no load (Sham), with 3-hr rest between interventions. Recovery was followed for the next 10 min. Primary outcome measures were dyspnea during recovery and inspiratory capacity (IC), measured at rest, at the end of exercise and after the intervention; oxygen saturation, end-tidal CO2 , heart rate, and breathing frequency were also monitored. RESULTS: Patients exercised for 5 min reaching a heart rate of 70% age predicted maximum and developed dyspnea of 3-4 on the Modified Borg CR10 scale. Dyspnea recovered significantly faster after the PEP intervention in all patients, taking 2.8 +/- 0.4 min to return to baseline compared with 5.1 +/- 0.6 min for Sham (p < 0.01). IC declined at the end of exercise and was improved by PEP (+270 220-460 ml, median, interquartile range) more than Sham (+100, 40-160 ml). However, PEP was equally effective in reducing dyspnea in all patients irrespective of the degree of DH. Changes in oxygen saturation, end-tidal CO2 , heart rate, and breathing frequency were similar in PEP and Sham. CONCLUSIONS: Positive expiratory pressure breathing is an effective means of reducing postexercise dyspnea and DH in COPD. The benefits were not limited to patients with high DH suggesting PEP may be used to speed recovery and increase the volume of exercise during pulmonary rehabilitation sessions and physical activity at home or work. PMID- 30251300 TI - Do pharmacists contribute to patients' management of symptoms suggestive of cancer: a qualitative study. AB - OBJECTIVES: Limited awareness of cancer symptoms results in patient delay in seeking help and contributes to delay in diagnosis. Few UK studies have investigated the potential for community pharmacists to facilitate earlier detection of cancer. This study aimed to investigate what actions patients take to manage their early cancer symptoms, to identify the extent of current community pharmacy involvement and to consider the potential role for community pharmacists to facilitate appropriate management and appraisal of potential early cancer symptoms. METHODS: Patients diagnosed with lung, colorectal or gastro oesophageal cancer in the preceding 12 months were identified during clinic visits by consultants. Semi-structured interviews were conducted, audio-recorded, transcribed and thematically analysed, using the Framework Approach. KEY FINDINGS: Twenty-five consenting patients were interviewed: two-thirds were male and more than half had lung cancer. Although all had experienced potential cancer symptoms prior to diagnosis, most underestimated seriousness and misattributed causation. Symptoms were managed by lifestyle changes and self-selecting medicines from local shops, supermarkets and pharmacies but without engaging with the pharmacist. CONCLUSIONS: For symptom management, participants self-selected medicines from community pharmacies, but pharmacy staff were rarely involved. Involving community pharmacists or their staff at the point of sale of these medicines might have facilitated earlier cancer diagnosis. Further research is needed to quantify how many patients with symptoms suggestive of cancer present in community pharmacies to understand if a pharmacist's role in facilitating symptom management and appraisal of potential cancer symptoms would be acceptable and effective, before developing any interventions. PMID- 30251298 TI - Alternative methods for virtual heart transplant-Size matching for pediatric heart transplantation with and without donor medical images available. AB - BACKGROUND: Listed pediatric heart transplant patients have the highest solid organ waitlist mortality rate. The donor-recipient body weight (DRBW) ratio is the clinical standard for allograft size matching but may unnecessarily limit a patient's donor pool. To overcome DRBW ratio limitations, two methods of performing virtual heart transplant fit assessments were developed that account for patient-specific nuances. Method 1 uses an allograft total cardiac volume (TCV) prediction model informed by patient data wherein a matched allograft 3-D reconstruction is selected from a virtual library for assessment. Method 2 uses donor images for a direct virtual transplant assessment. METHODS: Assessments were performed in medical image reconstruction software. The allograft model was developed using allometric/isometric scaling assumptions and cross-validation. RESULTS: The final predictive model included gender, height, and weight. The 25th , 50th-, and 75th-percentiles for TCV percentage errors were -13% (over prediction), -1%, and 8% (under-prediction), respectively. Two examples illustrating the potential of virtual assessments are presented. CONCLUSION: Transplant centers can apply these methods to perform their virtual assessments using existing technology. These techniques have potential to improve organ allocation. With additional experience and refinement, virtual transplants may become standard of care for determining suitability of donor organ size for an identified recipient. PMID- 30251301 TI - Aquatic insects rich in omega-3 fatty acids drive breeding success in a widespread bird. AB - Ecologists studying bird foraging ecology have generally focused on food quantity over quality. Emerging work suggests that food quality, in terms of highly unsaturated omega-3 fatty acids (HUFA), can have equally important effects on performance. HUFA, which are present in aquatic primary producers, are all but absent in vascular plants, and HUFA content is also correspondingly higher in aquatic insects. Here, we show that Tree Swallow (Tachycineta bicolor) chicks rapidly accumulate HUFA from food during the nestling period. Using data sampled over 24 years, we also show that Tree Swallow breeding success is positively associated with the availability of HUFA-rich aquatic insects. Variation in aquatic insect biomass during chick development was a strong predictor of fledging success, whereas variation in terrestrial insects had little effect on fledging success. Our results highlight the potential for nutritional mismatches between insectivores and high-quality prey to affect avian reproductive performance. PMID- 30251302 TI - Surgical Menopause and Frailty Risk in Community-Dwelling Older Women: Study of Osteoporotic Fractures. AB - OBJECTIVES: To determine whether women with surgical menopause have a higher risk of frailty than naturally menopausal women. DESIGN: Prospective cohort study with up to 18 years of follow-up. SETTING: Four U.S clinical centers. PARTICIPANTS: Community-dwelling white women aged 65 and older (mean 71.2+/-5.2) enrolled in the Study of Osteoporotic Fractures (N=7,699). MEASUREMENTS: Surgical menopause was based on participant self-report of having undergone bilateral oophorectomy before menopause. The outcome was incident frailty, classified as robust, prefrail, frail, or death at 4 follow-up interviews, conducted 6 to 18 years after baseline. Information on baseline serum total testosterone concentrations was available for 541 participants. RESULTS: At baseline, 12.6% reported surgical menopause. Over the follow-up period, 22.0% died, and 10.1% were classified as frail, 39.7% as prefrail, and 28.3% as robust. Surgically menopausal women had significantly lower total serum testosterone levels (13.2 +/- 7.8 ng/dL) than naturally menopausal women (21.7 +/- 14.8 ng/dL) (p=0.000), although they were not at greater risk of frailty (adjusted odds ratio (aOR)=0.94, 95% confidence interval (CI)=0.72-1.22), prefrailty (aOR=0.96, 95% CI=0.80-1.10), or death (aOR=1.17, 95% CI=0.97-1.42) after adjusting for age, body mass index, and number of instrumental activity of daily living impairments. There was no evidence that oral estrogen use modified these associations. CONCLUSION: In postmenopausal women, surgical menopause was not associated with greater risk for frailty than natural menopause, even in the absence of estrogen therapy. Future prospective studies are needed to investigate hormonal mechanisms involved in development of frailty in older postmenopausal women. J Am Geriatr Soc 66:2172-2177, 2018. PMID- 30251303 TI - Interventional procedures in children and adolescents with chronic non-cancer pain as part of a multidisciplinary pain treatment program. AB - BACKGROUND: Interventional procedures are part of multidisciplinary pain treatment programs to treat chronic non-cancer pain conditions in children and adolescents. However, the real benefit of these interventions remains unclear. AIMS: The aim of this study was to analyze the potential benefits of the interventional procedures in children and adolescents with chronic non-cancer pain in the setting of a multidisciplinary pain treatment program. METHODS: We retrospectively reviewed the charts of 98 children and adolescents receiving 314 diagnostic or therapeutic interventional procedures. We applied the following definitions of efficacy Short-term positive therapeutic effect: block that produced a minimum of 50% reduction in pain intensity for at least 4 weeks. Long term positive therapeutic effect: a patient with a minimum of 50% reduction in pain intensity for at least 6 months Full recovery: a patient free of pain, not taking analgesics with normal physical and role functioning 6 months after the last procedure. RESULTS: Seventy-six of 112 diagnostic blocks (68%) were associated with a 50% reduction in pain intensity for at least 4 weeks after the procedure. One hundred and sixty-six of 202 therapeutics blocks (82%) were associated with a short-term benefit. Seventy-two of 98 patients (73%) referred a 50% reduction in their pain intensity (17%) or had full recovery 6 months after the procedures (56%) and a MPTP. Psychiatric comorbidity and more advanced age were factors associated with failure to respond to interventional procedures. CONCLUSION: The use of interventional procedures may represent a valid therapeutic option, associated with positive clinical outcomes within a multidisciplinary program. PMID- 30251305 TI - Precision medicine for individual patients should use population group averages and larger, not smaller, groups. PMID- 30251304 TI - Use of a Facilitated Group Process to Design and Implement a Group Antenatal and Postnatal Care Program in Rwanda. AB - INTRODUCTION: The government of Rwanda is exploring strategies that may reduce the incidence of prematurity and low birth weight. Large-scale implementation of group antenatal care (ANC) and postnatal care (PNC) within the context of the Rwanda national health care system is under consideration. To launch a cluster randomized controlled trial of group ANC and PNC in 5 districts in Rwanda, the implementation team needed a customized group care model for this context and trained health care workers to deliver the program. PROCESS: Adapting the group ANC and group PNC model for the Rwandan context was accomplished through a group process identical to that which is fundamental to group care. A technical working group composed of 10 Rwandan maternal-child health stakeholders met 3 times over the course of 3 months, for 4 to 8 hours each time. Their objectives were to consider the evidence on group ANC, agree on the priorities and constraints of their ANC delivery system, and ultimately define the content and structure of a combined group ANC and PNC model for implementation in Rwanda. The same group process was employed to train health care workers to act as group ANC facilitators. OUTCOMES: A customized group ANC and PNC model and guidelines for its introduction were developed in the context of a cluster randomized controlled trial in 36 health centers. Descriptions of this model and the implementation plan are included in this article. DISCUSSION: Our experience suggests that the group process fundamental to successful group ANC and PNC is an effective method to customize and implement this innovative health services delivery model in a new context and is instrumental in achieving local ownership. PMID- 30251306 TI - Antiallodynic effect induced by [6]-gingerol in neuropathic rats is mediated by activation of the serotoninergic system and the nitric oxide-cyclic guanosine monophosphate-adenosine triphosphate-sensitive K+ channel pathway. AB - The present study evaluated the possible antiallodynic effect induced by [6] gingerol in rats with L5-L6 spinal nerve ligation (SNL). Moreover, we determined the possible mechanism underlying the antiallodynic effect induced by [6] gingerol in neuropathic rats. The animals underwent L5-L6 SNL for the purpose of developing tactile allodynia. Tactile allodynia was measured with von Frey filaments. Intrathecal administration of [6]-gingerol reversed SNL-induced tactile allodynia. The [6]-gingerol-induced antiallodynic effect was prevented by the intrathecal administration of methiothepin (30 MUg per rat; nonselective 5 hydroxytryptamine [5-HT] antagonist), WAY-100635 (6 MUg per rat; selective 5-HT1A receptor antagonist), SB-224289 (5 MUg per rat; selective 5-HT1B receptor antagonist), BRL-15572 (4 MUg per rat; selective 5-HT1D receptor antagonist), and SB-659551 (6 MUg per rat; selective 5-HT5A receptor antagonist), but naloxone (50 MUg per rat; nonselective opioid receptor antagonist) did not prevent the [6] gingerol-induced antiallodynic effect. Moreover, intrathecal administration of Nomega-nitro-l-arginine methyl ester (100 MUg per rat; nonselective nitric oxide [NO] synthase inhibitor), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 MUg per rat; inhibitor of guanylate cyclase), and glibenclamide (50 MUg per rat; channel blocker of adenosine triphosphate [ATP]-sensitive K+ channels) prevented the [6] gingerol-induced antiallodynic effect. These data suggest that the antiallodynic effect induced by [6]-gingerol is mediated by the serotoninergic system involving the activation of 5-HT1A/1B/1D/5A receptors, as well as the NO-cyclic guanosine monophosphate-ATP-sensitive K+ channel pathway but not by the opioidergic system. PMID- 30251307 TI - Mothers' perception of maternal and child health information disseminated via different modes of ICT in Nigeria. AB - BACKGROUND: A few studies have examined mothers' perception of ICT and maternal and child health (MCH) information promoted using ICT. The effectiveness of different modes of delivery of such information is unclear. OBJECTIVE: To investigate mothers' perceived usefulness of ICT and MCH information disseminated through e-health projects in Nigeria. METHODS: The study was a descriptive survey that was based on the mixed method paradigm. A questionnaire was used to collect data from 1001 mothers involved in ongoing ICT based projects in Nigeria. The mothers were selected using a convenience sampling technique. Four focus group discussion sessions were also organised for thirty mothers. RESULTS: Mobile phones were viewed as useful (35.0%) or very useful (42.2%) and radio as useful (34.8%) or very useful (57.5%%). But they expressed a negative perception towards the use of DVD/TV (Not useful, 66.5%) and the Internet/computer (Not useful 67.7%). Mothers' perception of MCH information disseminated was also positive. They reported the need for more MCH information products in local languages using acceptable ICT. CONCLUSION: Mothers' perception of preferred modes of delivery of maternal and child health information varies according to location. PMID- 30251308 TI - The state of the science in paediatric pain management practices in low-middle income countries: An integrative review. AB - AIM: Examine the state of the science for pain management in children living in low-middle income countries (LMIC). BACKGROUND: Significant challenges exist in pain management for children living in LMIC. METHODS: An integrative review was conducted using PRISMA guidelines for quality of reporting. Literature searches were completed using Medline, PubMed, Scopus, and CINAHL databases for publications between January 2006 and August 2016 using MeSH and primary search terms pain and LMIC. Full text publications were evaluated using GRADE criterion and methodology specific evaluation tools. RESULTS: Of 1510 publications identified, 31 met the criteria for inclusion. Data were categorized into three broad themes: (1) magnitude of the pain problem with subthemes describing the burden of and resources for paediatric pain management; (2) perceptions, experience, and practices for managing pain in children residing in LMIC with subthemes addressing health care providers, parent/caregiver and children, respectively; and (3) pain management practices with pain assessment and treatment strategies as subthemes. CONCLUSION: Current data on paediatric pain management in LMIC are limited with respect to describing the burden of pain, children's pain perceptions and experiences, and pain management practices. Rigorous investigations are needed to expand knowledge and address the pervasive problem of pain for children in LMIC. PMID- 30251309 TI - A qualitative inquiry of old people's health literacy in situations of health uncertainty. AB - BACKGROUND: This paper examines the health literacy of seniors and the strategies they use to deal with health uncertainty in the context of changes in the health system in Israel that have created a need to examine health literacy in this sector of the population who use the health system the most. The oldest were born and grew up in an era when a physician's knowledge was unchallenged; now, they find it difficult to cope with the expectation of patients taking a role in decision making. METHODS: In-depth interviews were carried out with 17 seniors between the ages of 70-87 that focused on their perception of their health and their health literacy. Data were analysed using thematic analysis. FINDINGS: Seniors used different information sources when looking for medical information. Participants reported three coping mechanisms that help them deal with the uncertainty: disregarding the problem, relying on the physician and searching for information. CONCLUSIONS: The study found different levels of health literacy among participants but, overall, participants who lead an active and optimistic lifestyle tend to take more responsibility for their health and have higher health information literacy. PMID- 30251310 TI - Perioperative anesthetic management of children with congenital central hypoventilation syndrome and rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation undergoing thoracoscopic phrenic nerve-diaphragm pacemaker implantation. AB - BACKGROUND: Congenital Central Hypoventilation Syndrome and Rapid-Onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation are rare neurocristopathies characterized by autonomic dysregulation including bradyarrhythmias, abnormal temperature control, and most significantly, abnormal control of breathing leading to tracheostomy and ventilator dependence as life support. Surgical advancements have made phrenic nerve-diaphragm pacemakers available, to eliminate the tether to a mechanical ventilator for 12-15 hours each day. The thoracoscopic approach to implantation has allowed for a less invasive approach which may have implications for pain control and recovery time. However, thoracoscopic implantation of these devices presents several challenges to the anesthesiologist in these complex ventilator-dependent patients, including, but not limited to, sequential lung isolation, prevention of hypothermia, and management of arrhythmias. Postoperative challenges may also include strategies to treat hemodynamic instability, managing the ventilator following lung derecruitment, and providing adequate pain control. AIMS: We aimed to describe the anesthetic management of Congenital Central Hypoventilation Syndrome and Rapid-Onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation patients undergoing thoracoscopic phrenic nerve diaphragm pacemaker implantation and the nature and incidence of perioperative complications. METHODS: A retrospective chart review was performed of 14 children with Congenital Central Hypoventilation Syndrome and Rapid-Onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation undergoing phrenic nerve-diaphragm pacemaker implantation at a single academic pediatric hospital between 2009 and 2017. Demographic information, intraoperative management, and perioperative complications were analyzed from patient records. RESULTS: Twelve of 14 patients (86%) underwent an inhalational induction via tracheostomy. Lung isolation was achieved via fiberoptic guidance of a single lumen endotracheal tube sequentially into the right or left mainstem bronchi for 12 patients (86%). Double lumen endotracheal tubes were utilized in two patients (7%) and bronchial blockers in two patients (7%) for lung isolation. Anesthesia was maintained using a balanced technique of volatile agents (sevoflurane/isoflurane) and opioids (fentanyl). Bradyarrhythmias developed in six patients (43%) during surgery, 5 (36%) responded to anticholinergics and one patient (7%) required backup cardiac pacing using a previously implanted bipolar cardiac pacemaker. Intraoperative hypothermia (<35.5 degrees C) was present in five patients (36%) despite the use of warming devices. Hypercarbia (>50 mm Hg) during lung isolation was present in eight patients (57%) and hemoglobin desaturation (<90%) in four patients (29%). Postoperatively, oxygen desaturation was a common complication with nine patients (64%) requiring supplemental oxygen administration via mechanical ventilator or manual bag ventilation. Opioids via patient-controlled analgesia devices (12 patients, 86%) or intermittent injection (two patients, 14%) were administered to all patients for postoperative pain control. Phrenic nerve-diaphragm pacemaker placement was successful thoracoscopically in all patients with no perioperative mortality. CONCLUSION: The main anesthetic challenges in patients with Congenital Central Hypoventilation Syndrome and Rapid-Onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation include hemodynamic instability, the propensity to develop hypothermia, hypercarbia/hypoxemia, and the need to perform bilateral sequential lung isolation requisite to the thoracoscopic implantation technique. Most anesthetic agents can be used safely in these patients; however, adequate knowledge of the susceptibility to complications, coupled with adequate preparation and understanding of the innate disease characteristics, are necessary to treat anticipated complications. PMID- 30251311 TI - Blood-borne biomarkers of osteosarcoma: A systematic review. AB - Osteosarcoma is the most common type of primary malignant bone tumor in children and young adults. Development of clinically useful biomarkers has the potential to improve treatments. The aim of this review was to investigate the recent literature assessing the utility of biomarkers for osteosarcoma. A detailed literature search was performed, with hand searches for related research publications. The search was limited to publications in English between January 2007 and February 2017. Of 286 studies identified, 24 met the inclusion criteria. There is a wide range of osteosarcoma biomarkers identified which act as clinical prognostic factors in patient outcome. PMID- 30251312 TI - Total flavones of Rhododendron simsii Planch flower protect isolated rat heart from ischaemia-reperfusion injury and its mechanism of UTR-RhoA-ROCK pathway inhibition. AB - OBJECTIVES: Total flavones of Rhododendron simsii Planch flower (TFR) are an effective part extracted from the flower. The present study was designed to investigate the protective effect of TFR in isolated rat heart following global ischaemia-reperfusion and the possible underlying mechanisms. METHODS: Langendorff perfusion apparatus was used to perfuse isolated rat heart which was subjected to global ischaemia-reperfusion. The hemodynamic parameters were continuously monitored. Coronary flow as well as lactate dehydrogenase (LDH), creatine phosphokinase-MB (CK-MB) and cardiac troponin I (cTnI) in coronary effluents was measured. RhoA activity and urotensin receptor (UTR) and Rho related coiled-coil-forming protein kinase (ROCK) protein expressions in rat myocardium were examined, respectively. Cardiac dysfunction was indicated by the alterations of hemodynamic parameters and the reduced coronary flow. KEY FINDINGS: Total flavones of Rhododendron simsii Planch flower significantly improved ischaemia-reperfusion-induced cardiac dysfunction and leakages of LDH, CK-MB and cTnI, and inhibited myocardial ischaemia-reperfusion-increased RhoA activity and UTR, ROCK1 and ROCK2 protein expressions. The improvement of TFR in the cardiac dysfunction and the leakage of LDH, CK-MB and cTnI were markedly attenuated under the UTR blockade and ROCK inhibition. TFR-inhibited RhoA activity was decreased under the UTR blockade. CONCLUSIONS: Total flavones of Rhododendron simsii Planch flower had a protective effect on ischaemia reperfusion injury in isolated rat heart, which may be attributed to the blocking of UTR and subsequent inhibition of the RhoA-ROCK pathway. PMID- 30251313 TI - Immobilization-induced severe hypercalcaemia successfully treated with reduced dose of zoledronate in a maintenance haemodialysis patient. PMID- 30251314 TI - Recurrent oxalosis in a combined liver-kidney transplant patient with primary hyperoxaluria type 1 resulting in graft failure. PMID- 30251315 TI - A Fad Diet Causing Acute Kidney Injury. PMID- 30251316 TI - Epigenetics and Reproductive Medicine: Scientific Impact Paper No. 57. PMID- 30251317 TI - Cosmeceutical potential of geranium and calendula essential oil: Determination of antioxidant activity and in vitro sun protection factor. AB - The present investigation was aimed to find out the sun protection factor (SPF) and antioxidant potential of geranium essential oil (GEO) and calendula essential oil (CEO) because having a combination of these two properties moves up the oils as an active ingredient of various cosmeceutical formulations for their preventive and protective properties. Essential oils were obtained by hydrodistillation of Pelargonium graveolens leaves (GEO) and Calendula officinalis flowers (CEO). The composition and identification of chemical constituents of oils were determined by GCMS analysis. Free radical scavenging activity was measured by nitric oxide scavenging activity and 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical scavenging activity. It was observed that both GEO and CEO have the potential to reduce or prevent oxidative stress and can be used in skin care regimen to slow down skin aging via its antioxidant properties. In vitro SPF was determined by a very simple and rapid spectroscopic method. SPF value of GEO and CEO was found to 6.45 and 8.36, respectively. The SPF of CEO was higher than GEO, and the results of SPF show that these essential oils can be employed in sunscreen formulations to protect the skin from sunburn. From the results, it can be concluded that the combined antioxidant and SPF property of GEO and CEO can provide synergistic photoprotective effect or lift up the additional value of the cosmeceutical formulation. PMID- 30251318 TI - Transition to adult care in sickle cell disease: A longitudinal study of clinical characteristics and disease severity. AB - BACKGROUND: Sickle cell disease (SCD) is a chronic blood disorder in which mortality has increased for adolescents and young adults (AYA). PROCEDURE: A longitudinal analysis of medical records was conducted to describe the clinical course among AYAs (ages 12-27 years) during transition to adult care. Measures included sociodemographic, complications, SCD severity (modified pediatric SCD severity index), comorbidities, and transfer. Group-based trajectory modeling (GBTM) to identify subgroups with distinct severity trajectories and chi-square and unpaired Student t test to explore subgroup differences were used. RESULTS: Overall, 339 AYAs (97% black, 56% male, 69% hemoglobin SS) had 10 848 clinic, 3840 hospital, and 3152 emergency department visits. Complications included vaso occlusive crises (80%) and acute chest syndrome (41%). Comorbidities included depression (19%) and anxiety (14%). Most AYAs transferred to adult care (n = 220) at 19 years. Fourteen AYAs died, 10 within seven years from transfer. GBTM identified both stable and increasing severity trajectory groups: stable-low (n = 31, 23%), stable-medium (n = 61, 46%), stable-high (n = 6, 4.5%), low-increasing (n = 13, 10%), and medium-increasing (n = 22, 17%). AYAs with increasing severity (25%) were older, lived closer to the clinic, and had higher risk for SCD complications and comorbidities. They had fewer pediatric clinic visits; however, they were more likely to transfer and remain longer in adult SCD care. CONCLUSIONS: Whereas most AYAs had stable severity, nearly a quarter had increasing severity, over time. AYAs with increasing severity had more complications, were more likely to transfer to adult care, and demonstrated higher and longer adult SCD care utilization compared with AYAs with stable severity. PMID- 30251319 TI - Cylindrospermopsis raciborskii Virus and host: genomic characterization and ecological relevance. AB - Cylindrospermopsis (Raphidiopsis) raciborskii is an invasive, filamentous, nitrogen-fixing cyanobacterium that forms frequent blooms in freshwater habitats. While viruses play key roles in regulating the abundance, production and diversity of their hosts in aquatic ecosystems, the role(s) of viruses in the ecology of C. raciborskii is almost unexplored. Progress in this field has been hindered by the absence of a characterized virus-host system in C. raciborskii. To bridge this gap, we sequenced the genome of CrV-01T, a previously isolated cyanosiphovirus, and its host, C. raciborskii strain Cr2010. Analyses suggest that CrV-01T represents a distinct clade of siphoviruses infecting, and perhaps lysogenizing, filamentous cyanobacteria. Its genome contains unique features that include an intact CRISPR array and a 12 kb inverted duplication. Evidence suggests CrV-01T recently gained the ability to infect Cr2010 and recently lost the ability to form lysogens. The cyanobacterial host contains a CRISPR-Cas system with CRISPR spacers matching protospacers within the inverted duplication of the CrV-01T genome. Examination of metagenomes demonstrates that viruses with high genetic identity to CrV-01T, but lacking the inverted duplication, are present in C. raciborskii blooms in Australia. The unique genomic features of the CrV/Cr2010 system offers opportunities to investigate in more detail virus-host interactions in an ecologically important bloom-forming cyanobacterium. PMID- 30251320 TI - The influence of maternal height on offspring's birth weight in Merida, Mexico. AB - OBJECTIVES: To analyze the influence of maternal height (MH) on offspring's birth weight (BW) in infants born from January 2016 to May 2017, in Merida, Mexico. METHODS: A total of 3462 singletons born at term in a public hospital were analyzed. Data extracted from hospital records were MH; number of previous births; and infant's sex, BW, and gestational length. MH was divided into 4 categories at quartile points: Q1:129-147, Q2:148-151, Q3:152-155, and Q4:156-180 cm. BW data were transformed to z-score values using the WHO Child Growth Standard. The association between MH and infants' BW was analyzed through a multiple regression model in which gestational length, infant's sex, maternal age, ethnicity, and number of previous birth were included as covariates. RESULTS: Mean values of MH and infants' BW were 151.43 cm (SD = 6.32) and 3172 g (SD = 401) (corresponding to -0.29 SD in BW z-score), respectively. The regression model showed that the shortest quartile of MH was associated with 0.43 (95% CI -0.35 -0.51) SD in infants' BW compared with the highest quartile. The second and third shortest quartiles of MH were associated with -0.24 (95% CI 0.16 -0.32) and -0.17 (95% CI -0.09 -0.25) SD of infants BW, respectively. CONCLUSIONS: MH remains an important factor for infant BW even in the presence of other determinants. The influence of MH on infants' BW in this population is similar to that found in other populations in low-, middle-, and high-income countries. PMID- 30251321 TI - The joint meeting of the 6th ICRBM and the 16th R&S have been held in Potsdam, Germany. AB - This article is protected by copyright. All rights reserved. PMID- 30251322 TI - Choosing the anesthetic and sedative drugs for supraventricular tachycardia ablations: A focused review. AB - This study provides a review of the contemporary literature for the effects of most commonly used anesthetic drugs for sedation and anesthesia during adult electrophysiologic (EP) studies where supraventricular tachycardias (SVT) need to be induced for diagnostic purposes and/or catheter ablation. Some medications may affect cardiac electrophysiology and conduction, altering the ability to induce the arrhythmia, and may have negative impact on mapping and ablation treatment. The objective of the study is to determine the best sedative choice during SVT ablations. The authors searched MEDLINE, PubMed, and Google Scholar databases for published articles within the past 20 years (1998-2018) that have evaluated the effects of common anesthetic drugs during SVT ablations. Further articles were identified through crossreferencing, discussion with electrophysiologists, and hand-searching key electrophysiology and anesthesia journals. Eight review articles, two randomized control trials, six prospective observational studies, one retrospective observational study, and two case reports were included in this review. Seven of the studies focused on the pediatric population. The findings about the effects of the commonly used anesthetics are discussed further in detail. Sevoflurane had no clinically important effects on sinoatrial (SA) node activity, or the normal atrioventricular (AV), or accessory pathway. Midazolam and fentanyl, alone or in combination, neither alter the inducibility of reentrant tachycardia nor have they shown to affect the SA node, refractory periods of AV conduction, or accessory pathways. Similar findings were reported by investigators with propofol, except for ectopic atrial tachycardia in children, which remained un-inducible in one of the studies. Remifentanil and dexmedetomidine lengthened both sinus cycle and AV conduction. Dexmedetomidine increased the atrial refractory period and diminished atrial excitability. Ketamine shortened atrial conduction and successfully returned prolongation of sinus node conduction due to dexmedetomidine. In conclusion, the current literature regarding sedation for SVT studies in the adult population is sparse. Midazolam, propofol, fentanyl, and remifentanil can be used safely in patients undergoing EP studies without significant interference with electrophysiological variables or the inducibility of reentrant tachycardias in usual clinical doses. Low-dose ketamine has potential use as an adjunctive medication in the EP lab and additional studies would be beneficial. The effects of dexmedetomidine on conduction and arrhythmia inducibility during SVT ablation is not as clear as studies have yielded conflicting results, and may not be the best choice for sedation in this patient population. PMID- 30251323 TI - Pressure ulcers in cardiac surgery: Few clinical studies, difficult risk assessment, and profound clinical implications. AB - Pressure ulcers (PUs) are a common complication after cardiac surgery, with almost one third of patients suffering from PUs during hospitalisation. Because of the burden that PUs exert on both the patients and the health care system, prevention is of utmost importance. The first step in successful prevention, however, includes the identification of the main features that render patients prone to PU development. Cardiac surgery population is not adequately addressed in current clinical trials and studies. Few studies focused specifically on cardiac surgery patients, but the majority included cardiac surgery patients within a heterogeneous population of acute or critical care patients. Therefore, additional research is warranted to understand the unique risk profile of patients undergoing cardiac surgery. Intraoperative risk factors that affect tissue tolerance have not been thoroughly investigated but are likely to play an important role, which might explain the epidemiology of a PU. Further research is also needed to better comprehend the risk of PUs among cardiac surgery patients and to design effective and tailored preventative measures with the help of newer tools for risk assessment. PMID- 30251325 TI - A meta-analysis of patients with treatment-resistant macular oedema secondary to retinal vein occlusions following switching to aflibercept. AB - To systematically review anatomical and functional outcomes of switching therapy from bevacizumab and/or ranibizumab to aflibercept in patients with persistent macular oedema secondary to retinal vein occlusions (RVO). A systematic search of aflibercept for the treatment of persistent macular oedema secondary to branch and central RVO was performed in EMBASE, PubMed and Cochrane databases prior to June 2017. The main outcome variables described were best-corrected visual acuity (BCVA) and central macular thickness (CMT). All results were analysed and pooled using random-effects models with 95% confidence intervals (CI). Eight studies met the inclusion criteria with a total of 137 eyes, incorporating both branch and central RVO. Meta-analysis demonstrated a nonsignificant change in BCVA at 6 and 12 months following switch to aflibercept (4.40 letters, 95% CI: -3.10 to 11.90, p = 0.25 and 3.10 letters, 95% CI: -1.74 to 7.94, p = 0.21, respectively). Significant improvement in mean CMT was observed after switch to aflibercept at 6 (-256.00 MUm, 95% CI: -318.00 to -194.00, p < 0.001) but not 12 months (-118.00 MUm, 95% CI: -261.00 to 25.00, p = 0.11). Switching from bevacizumab/ranibizumab to aflibercept may improve persistent macular oedema secondary to RVO. However, there may be a limitation in the potential of visual recovery. PMID- 30251324 TI - The neurosurgical wound and factors that can affect cosmetic, functional, and neurological outcomes. AB - Surgically accessing pathological lesions located within the central nervous system (CNS) frequently requires creating an incision in cosmetic regions of the head and neck. The biggest factors of surgical success typically tend to focus on the middle portion of the surgery, but a vast majority of surgical complications tend to happen towards the end of a case, during closure of the surgical site incisions. One of the most difficult complications for a surgeon to deal with is having to take a patient back to the operating room for wound breakdowns and, even worse, wound or CNS infections, which can negate all the positive outcomes from the surgery itself. In this paper, we discuss the underlying anatomy, pharmacological considerations, surgical techniques and nutritional needs necessary to help facilitate appropriate wound healing. A successful surgery begins with preoperative planning regarding the placement of the surgical incision, being cognizant of cosmetics, and the effects of possible adjuvant radiation therapy on healing incisions. We need to assess patient's medications and past medical history to make sure we can optimise conditions for proper wound reepithelialisation, such as minimizing the amount of steroids and certain antibiotics. Contrary to harmful medications, it is imperative to optimise nutritional intake with adequate supplementation and vitamin intake. The goals of this paper are to reinforce the mechanisms by which surgical wounds can fail, leading to postoperative complications, and to provide surgeons with the reminder and techniques that can help foster a more successful surgical outcome. PMID- 30251326 TI - Bile Infarcts - new insights into the pathogenesis of obstructive cholestasis. AB - Bile infarcts were first accurately described in 1876 by Charcot and Gombault in studies in animals after bile duct ligation. Since that time, the cause of these infarcts known as "Charcot-Gombault necrosis" has been widely debated. Modern hypotheses first suggested that the accumulation of bile acids in hepatocytes is directly responsible for hepatocyte death due to their cytotoxic detergent properties. Subsequent studies suggested that bile acids cause hepatocyte apoptosis. Currently it is believed that bile acids injure hepatocytes not by their detergent properties but by triggering a cytokine-mediated inflammatory response. Although considerable evidence now supports this latter hypothesis (1 3), the sequence of events that lead to bile infarcts and hepatocyte necrosis after BDL remains to be elucidated. This article is protected by copyright. All rights reserved. PMID- 30251327 TI - Virulence-associated protein A from Rhodococcus equi is an intercompartmental pH neutralising virulence factor. AB - Professional phagocytic cells such as macrophages are a central part of innate immune defence. They ingest microorganisms into membrane-bound compartments (phagosomes), which acidify and eventually fuse with lysosomes, exposing their contents to a microbicidal environment. Gram-positive Rhodococcus equi can cause pneumonia in young foals and in immunocompromised humans. The possession of a virulence plasmid allows them to subvert host defence mechanisms and to multiply in macrophages. Here, we show that the plasmid-encoded and secreted virulence associated protein A (VapA) participates in exclusion of the proton-pumping vacuolar-ATPase complex from phagosomes and causes membrane permeabilisation, thus contributing to a pH-neutral phagosome lumen. Using fluorescence and electron microscopy, we show that VapA is also transferred from phagosomes to lysosomes where it permeabilises the limiting membranes for small ions such as protons. This permeabilisation process is different from that of known membrane pore formers as revealed by experiments with artificial lipid bilayers. We demonstrate that, at 24 hr of infection, virulent R. equi is contained in a vacuole, which is enriched in lysosome material, yet possesses a pH of 7.2 whereas phagosomes containing a vapA deletion mutant have a pH of 5.8 and those with virulence plasmid-less sister strains have a pH of 5.2. Experimentally neutralising the macrophage endocytic system allows avirulent R. equi to multiply. This observation is mirrored in the fact that virulent and avirulent R. equi multiply well in extracts of purified lysosomes at pH 7.2 but not at pH 5.1. Together these data indicate that the major function of VapA is to generate a pH neutral and hence growth-promoting intracellular niche. VapA represents a new type of Gram-positive virulence factor by trafficking from one subcellular compartment to another, affecting membrane permeability, excluding proton-pumping ATPase, and consequently disarming host defences. PMID- 30251328 TI - Spleen tyrosine kinase SYK(L) interacts with YY1 and coordinately suppresses SNAI2 transcription in lung cancer cells. AB - Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase with dual properties of an oncoprotein and an oncosuppressor in distinctive cell types. In solid cancers, two isoforms SYK(L) and SYK(S) of SYK were recently identified due to its alternative mRNA splicing. However, the cellular activity and the biological significance of the long isoform of SYK, SYK(L), is still not well defined in human lung cancers. Here, we describe an interaction between SYK(L) and the ubiquitously expressed transcription regulator Yin Yang 1 (YY1) in the nucleus, which suppresses the epithelial-to-mesenchymal transition (EMT) by inactivating SNAI2 (coding transcription factor SLUG) transcription. ChIP indicated that endogenous SYK(L) interacts directly with a YY1 binding cis regulatory element in the SNAI2 promoter. Importantly, knockdown of YY1 activates SYK(L)-dependent EMT suppression in human lung cancer H1155 cells. We also found that the protein level of SYK(L) is markedly upregulated in various types of human lung cancers, and its nuclear localization is strongly correlated with clinical benefits of lung adenocarcinomas. Collectively, our data reveal a SYK(L) dependent transcriptional regulation of EMT through SLUG as a potential biomarker for lung cancer aggressiveness. PMID- 30251329 TI - Resilience and restoration of tropical and subtropical grasslands, savannas, and grassy woodlands. AB - Despite growing recognition of the conservation values of grassy biomes, our understanding of how to maintain and restore biodiverse tropical grasslands (including savannas and open-canopy grassy woodlands) remains limited. To incorporate grasslands into large-scale restoration efforts, we synthesised existing ecological knowledge of tropical grassland resilience and approaches to plant community restoration. Tropical grassland plant communities are resilient to, and often dependent on, the endogenous disturbances with which they evolved - frequent fires and native megafaunal herbivory. In stark contrast, tropical grasslands are extremely vulnerable to human-caused exogenous disturbances, particularly those that alter soils and destroy belowground biomass (e.g. tillage agriculture, surface mining); tropical grassland restoration after severe soil disturbances is expensive and rarely achieves management targets. Where grasslands have been degraded by altered disturbance regimes (e.g. fire exclusion), exotic plant invasions, or afforestation, restoration efforts can recreate vegetation structure (i.e. historical tree density and herbaceous ground cover), but species-diverse plant communities, including endemic species, are slow to recover. Complicating plant-community restoration efforts, many tropical grassland species, particularly those that invest in underground storage organs, are difficult to propagate and re-establish. To guide restoration decisions, we draw on the old-growth grassland concept, the novel ecosystem concept, and theory regarding tree cover along resource gradients in savannas to propose a conceptual framework that classifies tropical grasslands into three broad ecosystem states. These states are: (1) old-growth grasslands (i.e. ancient, biodiverse grassy ecosystems), where management should focus on the maintenance of disturbance regimes; (2) hybrid grasslands, where restoration should emphasise a return towards the old-growth state; and (3) novel ecosystems, where the magnitude of environmental change (i.e. a shift to an alternative ecosystem state) or the socioecological context preclude a return to historical conditions. PMID- 30251330 TI - Effect of tadalafil add-on therapy in patients with persistant storage symptoms refractory to alpha1 -adrenoceptor antagonist monotherapy for benign prostatic hyperplasia: A randomized pilot trial comparing tadalafil and solifenacin. AB - OBJECTIVE: The aim of this study was to investigate the efficacy and safety of tadalafil add-on therapy with alpha1 -adrenoceptor antagonists. METHODS: Patients with persistent storage symptoms refractory to alpha1 -adrenoceptor antagonists for benign prostatic hyperplasia were enrolled in the study. Patients were randomly assigned to either a 5 mg tadalafil or 5 mg solifenacin treatment group for 12 weeks. International Prostate Symptom Score, Overactive Bladder Symptom Score, urinary flow rates, residual urine volume, and blood pressure were measured prospectively before treatment and after 4 and 12 weeks of treatment. Changes from baseline were compared between groups. The rate of treatment discontinuation due to adverse effects was evaluated. RESULTS: Of the 75 patients recruited to the study, 38 and 37 were assigned to the tadalafil and solifenacin groups, respectively. There were no significant difference in baseline characteristics between the two groups. The change in the amount of residual urine volume was significantly larger in the solifenacin- than tadalafil-treated group; other parameters, including lower urinary tract symptoms and uroflowmetry measures, did not differ significantly between the two groups. Seven (18%) and 12 (32%) patients in the tadalafil and solifenacin groups, respectively, discontinued treatment because of adverse events. The main reasons for discontinuation in the tadalafil group were stomach discomfort or nausea and dizziness or vertigo; voiding difficulty and constipation were the main reasons for discontinuation in the solifenacin group. There was no significant difference in blood pressure fluctuations from baseline between the two groups. CONCLUSIONS: Tadalafil add-on therapy was not inferior to solifenacin add-on therapy in terms of effect and safety. Therefore, tadalafil could be an alternative add-on drug for patients with persistent lower urinary tract symptoms refractory to alpha1 adrenoceptor antagonists. PMID- 30251331 TI - Extreme reactive thrombocytosis in an infant: Much ado about nothing? PMID- 30251332 TI - Co-existence of Langerhans cell histiocytosis and reticulohistiocytosis with initial presentation of skull lesions: A case report. AB - Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder resulting from dysregulated clonal proliferation of Langerhans cells. Reticulohistiocytosis (RH) is another rare histiocytosis caused by the proliferation of histiocytes other than Langerhans cells. Co-existence of LCH and RH in different organs and in the same skin area has not been reported. We present the case of a 20-year-old woman who initially had co-existing bone LCH and cutaneous RH. After 1 year of chemotherapy with cytarabine, bone LCH significantly improved but cutaneous LCH developed in the same area where cutaneous RH was, resulting in hybrid LCH and RH of the skin. This unique history provides some evidence to support the theory that LCH and RH originate from the same stem cells and subsequently develop into hybrid LCH and RH of the skin in a cytokine environment influenced by chemotherapy. Repeat skin biopsies may be considered for adjusting treatment regimens in LCH patients whenever pre-existing skin lesions progress. PMID- 30251333 TI - 12(S)-hydroxyeicosatetraenoic acid impairs vascular endothelial permeability by altering adherens junction phosphorylation levels and affecting the binding and dissociation of its components in high glucose-induced vascular injury. AB - AIMS/INTRODUCTION: Diabetes is an important risk factor for atherosclerotic disease. The initiating factor of atherosclerosis is local endothelial cell injury. The arachidonic acid metabolite, 12(S)-hydroxyeicosatetraenoic acid (12[S]-HETE), might be involved in this process. In recent years, some studies have discussed the effect of 12(S)-HETE on vascular endothelial cell function. In the present study, we investigated the effect of 12(S)-HETE on vascular endothelial cell function in high-glucose conditions and the mechanisms involved. MATERIALS AND METHODS: Human umbilical vein endothelial cells were cultured in conventional M199 medium and high-glucose M199 medium. Human umbilical vein endothelial cells were stimulated with 12(S)-HETE and cinnamyl-3,4-dihydroxy alpha-cyanocinnamate (a 12/15-lipoxygenases inhibitor). A type 1 diabetes mellitus model was established in C57BL/6 or 12/15-lipoxygenases knockout mice with streptozotocin. Aortic tissue was harvested for subsequent testing. The transmembrane transport of dextran and human acute monocytic leukaemia cell line (THP-1) cells was measured. The adherens junction protein, IkBalpha, nuclear factor kappa Bp65 (P65), intercellular adhesion molecule 1 and vascular cell adhesion protein 1 expression and phosphorylation, and the binding/dissociation of endothelial cell components were observed. RESULTS: Transendothelial migration of dextran and THP-1 cells was significantly increased by stimulation of human umbilical vein endothelial cell monolayers with high glucose and 12(S)-HETE (P < 0.05). High glucose and 12(S)-HETE altered the vascular endothelial cadherin and beta-catenin phosphorylation level, and promoted the dissociation of beta-catenin and vascular endothelial cadherin. Expression levels of P-Ikbalpha, P-P65, intercellular adhesion molecule 1 and vascular cell adhesion protein 1 were elevated in high glucose and 12(S)-HETE treated cells and diabetic mice compared with controls (P < 0.05). CONCLUSIONS: The lipoxygenases metabolite, 12(S)-HETE, can impair vascular endothelial permeability by altering adherens junction phosphorylation levels, and affecting the binding and dissociation of its components in high-glucose conditions. PMID- 30251334 TI - Influence of corticosteroid therapy on orthodontic tooth movement: A narrative review of studies in animal-models. AB - The aim was to assess the influence of corticosteroid therapy (CST) on orthodontic tooth movement (OTM). A narrative review of studies performed in animal models. Indexed databases were searched up to and including May 2018 to address the following focused question: "Does CST affect OTM?" The following eligibility criteria were imposed: (a) original studies; (b) presence of a control group (OTM without CST); (c) intervention: effect of CST on OTM; and (d) statistical analysis. Quality assessment was performed using the Animal Research Reporting In Vivo Experiment (ARRIVE) guidelines. Case series, case reports, commentaries, historic reviews and letters to the Editor were excluded. Ten studies performed on animal models were included. The experimental duration ranged between 3 and 49 days. Two studies reported that CST decreases the magnitude of OTM, two studies showed no significant influence of CST on OTM, and two studies found that CST increases OTM. Two studies reported CST significantly decreases bone density and increases bone resorption during OTM. In one study, CST significantly decreased orthodontically induced root resorption. The minimum, median and highest scores (out of 20) based on ARRIVE guidelines were 7, 15.5 and 18, respectively. The influence of CST on OTM in animal models remains debatable. PMID- 30251335 TI - Feasibility of high-dose chemotherapy protocols to treat infants with malignant central nervous system tumors: Experience from a middle-income country. AB - BACKGROUND: Results of high-dose chemotherapy (HDCT) protocols for the management of malignant central nervous system (CNS) tumors in infants are mostly reported in high-income countries. We evaluated the feasibility and results of such protocols in a middle-income country (Jordan). METHODS: A retrospective study of infants' charts with CNS tumors between 2006 and 2015 who were treated according to HeadStart (HS) protocols. Data included patients' demographics, chemotherapy complications, and cost. RESULTS: We identified 18 patients with median age 29 months (range, 9-62 months) at diagnosis (12 HS-I and six HS-II). Distribution according to pathology was: atypical teratoid rhabdoid tumors (ATRT) (nine), primitive neuoroectodermal tumors (PNET)/pineoblastoma (five), and medulloblastoma (four). Six patients (33%) had metastatic disease, and 14 (78%) had an incomplete resection. Eleven patients achieved partial or complete remission, two stabilized, and five progressed. Ten patients did not proceed to HDCT due to progression (five), financial reasons (two), failure to collect stem cells (one), and undocumented reasons (two). Seventy-eight chemotherapy cycles were administered (median interval 26 days). Main complications during induction and consolidation were febrile neutropenia (73% and 100%), documented infections (8% and 13%), and mucositis (12% and 88%), respectively. Three patients developed moderate hearing loss. No protocol-related mortality was reported. At the last follow-up, five patients were alive: three with medulloblastoma (19, 29, and 89 months) and two with ATRT (18 and 42 months). Three survivors received focal/craniospinal radiation. The median cost of a complete HS protocol, excluding surgery/radiotherapy, was $103 500 per patient; 39% of the median cost was related to pharmacy expenses. CONCLUSIONS: These protocols were manageable in our context of limited health care resources. However, considering the significant costs and the modest survival rate, better selection criteria need to be used to identify patients likely to benefit from this approach. PMID- 30251337 TI - Dramatic response to trametinib in a male child with neurofibromatosis type 1 and refractory astrocytoma. PMID- 30251336 TI - Long-Term Nasogastric Versus Percutaneous Endoscopic Gastrostomy Tube Feeding in Older Asians With Dysphagia: A Pragmatic Study. AB - BACKGROUND: A barrier to gastrostomy feeding exists among Asian clinicians and caregivers due to negative perceptions regarding complications. We compared clinical and nutrition outcomes in older dysphagic Asian patients with nasogastric (NG) or gastrostomy tube feeding using a pragmatic study design. METHODS: The choice of enteral tube access was determined by managing clinicians and patients/caregivers. Comparisons of tube feeding methods were made during a 4 month period, adjusting statistically for inherent confounders. RESULTS: A total of 102 participants (NG: n = 52, gastrostomy: n = 50) were recruited over 2 years from 2013 to 2015. Subjects on long-term NG tube feeding were older (82.67 +/- 7.15 years vs 76.88 +/- 7.37 years; P < .001) but both groups had similar clinical indications (stroke: 63.5% NG vs 54% gastrostomy; P = .33). After adjustment for confounders, gastrostomy feeding was associated with fewer tube related complications (adjusted odds ratio [aOR] = 0.19; 95% confidence interval [CI] = 0.06-0.60) and better complication-free survival rate (aOR = 0.32; 95% CI = 0.12-0.89) at 4-month follow-up. Anthropometric and biochemical nutrition parameters improved significantly in both groups at 4 months, but no significant differences were observed at the end of the study. CONCLUSION: Gastrostomy feeding is associated with a greater 4-month complication-free survival and lower tube-related complications compared with long-term NG feeding in older Asians with dysphagia. However, no differences in nutrition outcomes were observed between NG and gastrostomy feeding at 4 months. PMID- 30251338 TI - Elevated metabolic rate and skeletal muscle oxidative metabolism contribute to the reduced susceptibility of NF-kappaB p50 null mice to obesity. AB - Mice with a deletion of the p50 subunit of the proinflammatory nuclear factor kappa B pathway (NF-kappaB p50) have reduced weight compared to wild-type control mice. However, the physiological underpinning of this phenotype remains unknown. This study addressed this issue. Compared to littermate controls, lean male p50 null mice (p50-/- ) had an increased metabolic rate (~20%) that was associated with increased skeletal muscle (SkM, ~35%), but not liver, oxidative metabolism. These metabolic alterations were accompanied by decreases in adiposity, and tissue and plasma triglyceride levels (all ~30%). Notably, there was a marked decrease in skeletal muscle, but not liver, DGAT2 gene expression (~70%), but a surprising reduction in muscle PPARalpha and CPT1 (both ~20%) gene expression. Exposure to a high-fat diet accentuated the diminished adiposity of p50-/- mice despite elevated caloric intake, whereas plasma triglycerides and free fatty acids (both ~30%), and liver (~40%) and SkM (~50%) triglyceride accumulation were again reduced compared to WT. Although SkM cytokine expression (IL-6 and TNFalpha, each ~100%) were increased in p50-/- mice, neither cytokine acutely increased SkM oxidative metabolism. We conclude that the reduced susceptibility to diet-induced obesity and dyslipidemia in p50-/- mice results from an increase in metabolic rate, which is associated with elevated skeletal muscle oxidative metabolism and decreased DGAT2 expression. PMID- 30251339 TI - Optimal Piecewise Linear Regression Algorithm for QSAR Modelling. AB - Quantitative Structure-Activity Relationship (QSAR) models have been successfully applied to lead optimisation, virtual screening and other areas of drug discovery over the years. Recent studies, however, have focused on the development of models that are predictive but often not interpretable. In this article, we propose the application of a piecewise linear regression algorithm, OPLRAreg, to develop both predictive and interpretable QSAR models. The algorithm determines a feature to best separate the data into regions and identifies linear equations to predict the outcome variable in each region. A regularisation term is introduced to prevent overfitting problems and implicitly selects the most informative features. As OPLRAreg is based on mathematical programming, a flexible and transparent representation for optimisation problems, the algorithm also permits customised constraints to be easily added to the model. The proposed algorithm is presented as a more interpretable alternative to other commonly used machine learning algorithms and has shown comparable predictive accuracy to Random Forest, Support Vector Machine and Random Generalised Linear Model on tests with five QSAR data sets compiled from the ChEMBL database. PMID- 30251340 TI - Extracellular Matrix Imaging of Breast Tissue Pathologies by MALDI Imaging Mass Spectrometry. AB - PURPOSE: We recently reported a new method accessing proteins from extracellular matrix by imaging mass spectrometry (ECM IMS). ECM IMS was evaluated for use in exploring breast tissue pathologies. EXPERIMENTAL DESIGN: A tissue microarray (TMA) was analyzed that had 176 cores of biopsies and lumpectomies spanning breast pathologies of inflammation, hyperplasia, fibroadenoma, invasive ductal carcinoma and invasive lobular carcinoma and normal adjacent to tumor (NAT). NAT was compared to subtypes by area under the receiver operating curve (ROC) >0.7. A lumpectomy was also characterized for collagen organization by microscopy and stromal protein distribution by IMS. LC-based high-resolution accurate mass (HRAM) proteomics was used to identify proteins from the lumpectomy. RESULTS: TMA analysis showed distinct spectral signatures reflecting a heterogeneous tissue microenvironment. Ninety-four peaks showed a ROC >0.7 compared to NAT; NAT had overall higher intensities. Lumpectomy analysis by IMS visualized a complex central tumor region with distal tumor regions. HRAM LC-based proteomics identified 39 stromal proteins. Accurate mass matches between image data and LC based proteomics demonstrated a heterogeneous collagen type environment in the central tumor. CONCLUSIONS: Data portray the heterogeneous stromal microenvironment of breast pathologies, including alteration of multiple collagen type patterns. ECM IMS is a promising new tool for investigating the stromal microenvironment of breast tissue including cancer. This article is protected by copyright. All rights reserved. PMID- 30251341 TI - Mannose-Functionalized Nanoscaffolds for Targeted Delivery in Biomedical Applications. AB - Targeted drug delivery by nanomaterials has been extensively investigated as an effective strategy to surmount obstacles in the conventional treatment of cancer and infectious diseases, such as systemic toxicity, low drug efficacy, and drug resistance. Mannose-binding C-type lectins, which primarily include mannose receptor (MR, CD206) and dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), are highly expressed on various cancer cells, endothelial cells, macrophages, and dendritic cells (DCs), which make them attractive targets for therapeutic effect. Mannosylated nanomaterials hold great potential in cancer and infection treatment on account of their direct therapeutic effect on targeted cells, modulation of the tumor microenvironment, and stimulation of immune response through antigen presentation. This review presents the recent advances in mannose-based targeted delivery nanoplatforms incorporated with different therapies in the biomedical field. PMID- 30251342 TI - The role of perceived dignity and control in the wish to hasten death among advanced cancer patients: A mediation model. AB - OBJECTIVE: The objective of the study is to test a model in which perceived loss of dignity and control are proposed, along with symptoms of depression and functional impairment, as risk factors for the wish to hasten death (WTHD) in advanced cancer patients. METHODS: This was a cross-sectional study of 193 patients in an oncology unit. Outcome measures included perceived control, performance status, symptoms of depression, perceived dignity, and the WTHD. Structural equation modeling was performed. RESULTS: Structural equation modeling showed that perceived loss of control (-0.402) and functional impairment (-0.21) were risk factors for perceived loss of dignity. Loss of control (-0.385) and functional impairment (-0.283) were also risk factors for symptoms of depression. Perceived loss of dignity and symptoms of depression were the most proximal determinants of the WTHD, on which they had a direct, positive, and significant effect (0.246 and 0.209, respectively). Therefore, both symptoms of depression and perceived loss of dignity independently predicted the WTHD and mediated the effects of perceived loss of control and functional impairment on this wish. CONCLUSIONS: The hypothesized model provides evidence for the impact of the four aforementioned factors on the WTHD. Our results suggest that personalized care plans which are able to enhance the sense of dignity and control among advanced cancer patients could help to reduce the likelihood or intensity of a WTHD. PMID- 30251343 TI - Sulfophenylated Terphenylene Copolymer Membranes and Ionomers. AB - The copolymerization of a prefunctionalized, tetrasulfonated oligophenylene monomer was investigated. The corresponding physical and electrochemical properties of the polymers were tuned by varying the ratio of hydrophobic to hydrophilic units within the polymers. Membranes prepared from these polymers possessed ion exchange capacities ranging from 1.86 to 3.50 meq g-1 and exhibited proton conductivities of up to 338 mS cm-1 (80 degrees C, 95 % relative humidity). Small-angle X-ray scattering and small-angle neutron scattering were used to elucidate the effect of the monomer ratios on the polymer morphology. The utility of these materials as low gas crossover, highly conductive membranes was demonstrated in fuel cell devices. Gas crossover currents through the membranes of as low as 4 % (0.16+/-0.03 mA cm-2 ) for a perfluorosulfonic acid reference membrane were demonstrated. As ionomers in the catalyst layer, the copolymers yielded highly active porous electrodes and overcame kinetic losses typically observed for hydrocarbon-based catalyst layers. Fully hydrocarbon, nonfluorous, solid polymer electrolyte fuel cells are demonstrated with peak power densities of 770 mW cm-2 with oxygen and 456 mW cm-2 with air. PMID- 30251344 TI - Metal-Mediated Functionalization of Natural Peptides and Proteins: Panning for Bioconjugation Gold. AB - Selective modification of natural proteins is a daunting methodological challenge and a stringent test of selectivity and reaction scope. There is a continued need for new reactivity and new selectivity concepts. Transition metals exhibit a wealth of unique reactivity that is orthogonal to biological reactions and processes. As such, metal-based methods play an increasingly important role in bioconjugation. This review examines metal-based methods, reactivity, and selectivity for functionalization of natural proteins and peptides. PMID- 30251345 TI - Responses of Different Cancer Cells to White Tea Aqueous Extract. AB - : White tea from the eastern Chinese province of Fujian is a unique tea variety. Although the health effects of various teas have been investigated in recent years, most studies focused exclusively on green tea varieties. In order to study effects exerted by white tea from eastern Fujian on the viability of cancer cells, we analyzed its main bioactive ingredients. We also evaluated the antioxidant activity of white tea aqueous extract (WTAE) and employed MTT assay to evaluate effects of WTAE on viabilities of Hela and BEL-7402 cancer cell lines. Apoptosis rate detection was also applied to estimate efficacy of cellular apoptotic induction by WTAE in these two cells types. Results revealed that WTAE exhibited high antioxidant activity and inhibited effectively the proliferation of Hela and BEL-7402 cells. The half maximal inhibitory concentration (IC50) of WTAE for Hela cells (0.05 mg/mL) was lower than that for BEL-7402 cells (0.1 mg/mL). Although WTAE induced apoptosis in both cell lines, pro-apoptotic effects were markedly more apparent in Hela cells. Our study demonstrated that WTAE inhibited proliferation of cancer cells via induction of apoptosis and that Hela cells were more sensitive to WTAE than BEL-7402 cells. PRACTICAL APPLICATION: The aim of this study is to provide a new approach toward cancer prevention by consuming white tea, the properties of which may also be helpful in formulating novel anticancer therapeutics. PMID- 30251346 TI - Modeled state-level estimates of hypertension prevalence and undiagnosed hypertension among US adults during 2013-2015. AB - Hypertension affects about one in three US adults, from recent surveillance, or four in nine based on the 2017 ACC/AHA Hypertension Guideline; about half of them have their blood pressure controlled, and nearly one in six are unaware of their hypertension status. National estimates of hypertension awareness, treatment, and control in the United States are traditionally based on measured BP from National Health and Nutrition Examination Survey (NHANES); however, at the state level, only self-reported hypertension awareness and treatment are available from BRFSS. We used national- and state-level representative samples of adults (>=20 years) from NHANES 2011-2014 and BRFSS 2013 and 2015, respectively. The authors generated multivariable logistic regression models using NHANES to predict the probability of hypertension and undiagnosed hypertension and then applied the fitted model parameters to BRFSS to generate state-level estimates. The predicted prevalence of hypertension was highest in Mississippi among adults (42.4%; 95% CI: 41.8-43.0) and among women (42.6%; 41.8-43.4) and highest in West Virginia among men (43.4%; 42.2-44.6). The predicted prevalence was lowest in Utah 23.7% (22.8-24.6), 26.4% (25.0-27.7), and 21.0% (20.0-22.1) for adults, men, and women, respectively. Hypertension predicted prevalence was higher in most Southern states and higher among men than women in all states except Mississippi and DC. The predicted prevalence of undiagnosed hypertension ranged from 4.1% (3.4-4.8; Kentucky) to 6.5% (5.5-7.5; Hawaii) among adults, from 5.0% (4.0-5.9; Kentucky) to 8.3% (6.9-9.7; Hawaii) among men, and from 3.3% (2.5-4.1; Kentucky) to 4.8% (3.4-6.1; Vermont) among women. Undiagnosed hypertension was more prevalent among men than women in all states and DC. PMID- 30251347 TI - Mechanistic/mammalian target of rapamycin: Recent pathological aspects and inhibitors. AB - The mechanistic/mammalian target of rapamycin (mTOR), also known as the mechanistic target of rapamycin, regulates many normal cell processes such as transcription, cell growth, and autophagy. Overstimulation of mTOR by its ligands, amino acids, sugars, and/or growth factors leads to physiological disorders, including cancer and neurodegenerative diseases. In this study, we reviewed the recent advances regarding the mechanism that involves mTOR in cancer, aging, and neurodegenerative diseases. The chemical and biological properties of recently reported small molecules that function as mTOR kinase inhibitors, including adenosine triphosphate-competitive inhibitors and dual mTOR/PI3K inhibitors, have also been reviewed. We focused on the reports published in the literature from 2012 to 2017. PMID- 30251348 TI - Maternal and Child Nutrition Volume 14. PMID- 30251349 TI - PixelDB: Protein-peptide complexes annotated with structural conservation of the peptide binding mode. PMID- 30251351 TI - A Water-Soluble NaCMC/NaPAA Binder for Exceptional Improvement of Sodium-Ion Batteries with an SnO2 -Ordered Mesoporous Carbon Anode. AB - SnO2 @CMK-8 composite, a highly promising anode for Na-ion batteries (NIBs), was incorporated with polyvinylidene difluoride (PVDF), sodium carboxymethylcellulose (NaCMC), sodium polyacrylate (NaPAA), and NaCMC/NaPAA mixed binders to optimize the electrode sodiation/desodiation properties. Synergistic effects between NaCMC and NaPAA led to the formation of an effective protective film on the electrode. This coating layer not only increased the charge-discharge Coulombic efficiency, suppressing the accumulation of solid-electrolyte interphases, but also kept the SnO2 nanoparticles in the CMK-8 matrix, preventing the agglomeration and removal of oxide upon cycling. The adhesion strength and stability towards the electrolyte of the binders were evaluated. In addition, the charge-transfer resistance and apparent Na+ diffusion of the SnO2 @CMK-8 electrodes with various binders were examined and post-mortem analyses were conducted. With NaCMC/NaPAA binder, exceptional electrode capacities of 850 and 425 mAh g-1 were obtained at charge-discharge rates of 20 and 2000 mA g-1 , respectively. After 300 cycles, 90 % capacity retention was achieved. The thermal reactivity of the sodiated electrodes was studied by using differential scanning calorimetry. The binder effects on NIB safety, in terms of thermal runaway, are discussed. PMID- 30251352 TI - Assignment of culpability to animals as a form of abuse: Historical and cultural perspectives. AB - How the law regards animals reflects cultural trends that have varied widely from antiquity to the present. This article argues that cultural views of animals have shaped laws, attitudes, and practices worldwide. Whereas ancient (biblical and Mesopotamian) practices turned on economics, medieval concepts of animal culpability aligned with Christian beliefs of the primacy of humans. In medieval Europe, pets, farm animals, vermin, and insects could be held accountable for damage to persons and property. Considered entitled to due process, they were represented, tried, and punished - sometimes in public executions. Centuries of regarding animals as property subordinated to humans gave way to animal cruelty laws. It was not until the 19th century that respect for animal welfare, apart from economics, assumed legal significance. Presently, animals are not considered capable of criminal intent but can be "executed" for dangerousness. However, they may possess legal standing as civil complainants in animal rights cases. Contemporary trends include animal rights activism and courts conferring legal personhood to animals. The discussion concludes that there will be disparate approaches worldwide, based on prevailing views of animal sentience, spiritually based concepts and values, litigation arguing property and environmental law, and economics. PMID- 30251353 TI - Description of typical personality factors and events that lead to anxiety at induction of anesthesia in French children. AB - BACKGROUND: Preventive strategies are available to reduce preoperative anxiety in children, the ideal time for implementing such strategies remains poorly determined. AIMS: The aim of this study was to determine psychological factors and events involved in the development of preoperative anxiety in children. METHODS: This study consisted of prospective evaluations of anxiety trait and state during the preoperative period. Attendance at a preanesthetic consultation is obligatory for all patients undergoing surgery in France. Anxiety trait and state assessments were quantified in mothers and children before and after the preanesthetic consultation using visual analog and faces numerical scales. Preoperative anxiety in children was assessed immediately before induction of anesthesia using an analog scale. Other data recorded included demographic and medical data and type of hospital stay. Univariate and multivariate logistic regression analyses were used. RESULTS: Overall 111 consecutive patients were included. The following factors emerged leading to anxiety state at induction of anesthesia: maternal anxiety state before the preanesthetic consultation, a feeling of not being reassured by the anesthesiologist, maternal anxiety state after the consultation, and anxiety trait in the child. Logistic regression found this combination of factors (OR = 4 [1.4 -12]) and inpatient stay (OR = 3 [1.4 7]), predicting anxiety with an accuracy of 69%. CONCLUSION: The present study identified a combination of psychological factors and events associated with the development of anxiety at induction of anesthesia in children. Parental anxiety impacts upon children and occurs before the preanesthetic consultation. This result may assist clinicians to prescribe personalized preventive strategies against anxiety. PMID- 30251354 TI - Development of a ssDNA aptamer system with reduced graphene oxide (rGO) to detect nonylphenol ethoxylate in domestic detergent. AB - Endocrine-disrupting chemicals are a major public health problem throughout the world. In the human body, these compounds functionalize the same as sexual hormones, inducing precocious puberty, gynecomastia, etc. To help prevent this occurrence, a simple detection system is needed. In this study, a nonylphenol ethoxylate (NPE)-specific aptamer was selected by reduced graphene oxide systematic evolution of ligands by exponential enrichment. A random ssDNA library was incubated with rGO for adsorption, followed by elution with the target molecule. As a result of screening, a DNA aptamer was found that specifically bounds to the target with high binding affinity (Kd = 100.9 +/- 13.2 nM) and had a low limit of detection (LOD = 696 pM). Furthermore, this NPE-binding aptamer bounds selectively to the target. Characterization of the aptamer was confirmed by measuring the fluorescence signal recovery from rGO. In addition, detection of NPE was performed with several water samples, and the detection accuracy was 100 +/- 10%. From these results, we expect that this aptamer could be applied to an on-site detection system for NPE in industrial sites or domestic fields. PMID- 30251355 TI - How I approach: Previously untreated patients with severe congenital hemophilia A. AB - Previously untreated patients with severe hemophilia A are a vulnerable population at risk for severe bleeding which is currently managed with exogenous clotting factor replacement. The primary burden of current treatment is high titer inhibitor development. Evolving data on current treatment products as well as emerging therapeutics may inform treatment decisions to prevent bleeding and inhibitor formation. Considerations for diagnosis, education, and shared decision making related to product choice and treatment regimen are discussed. PMID- 30251356 TI - Primer on Study Design, Type I and Type II Errors, Power, and Statistical Significance to Ensure Interpretation of Clinical Trial Results Remains Clearly INTACT. AB - We thank Drs. Patel, Martindale, and Heyland1 for their interest in our most recent study2 exploring the role of early exposure to recommended energy delivery in critically ill patients with acute respiratory distress syndrome. Their stated concerns center around 3 major areas: (1) the comparability of the population in our study2 with those of INTACT (Intensive Nutrition in Acute Lung Injury: A Clinical Trial); (2) their confusion on the analysis of the relationship between the likelihood of death with energy exposure (table 1 in our article2 ); and (3) their apparent misunderstanding of type I error, type II error, P-values, and power analysis. Our responses to each of these areas are detailed as follows. PMID- 30251357 TI - Olefin Bifunctionalization: A Visible-light Photoredox-catalyzed Aryl Alkoxylation of Olefins. AB - Olefin bifunctionalization is a facile route to obtain complex molecules from abundant and commercially available olefin feedstocks. Visible light together with a catalytic amount of tris(bipyridine)ruthenium salt catalyzes the aryl alkoxylation of styrenes with aryl diazonium salts in alcohol solvents via a photoredox process. The scope of this proposed reaction with respect to various aryl diazonium salts and styrenes has been investigated. PMID- 30251358 TI - One-year follow-up results of hair removal using an 810 nm diode laser. AB - INTRODUCTION: Laser hair removal is a common light-based aesthetic procedure. Diode lasers and specifically the long-pulse diode laser 810 nm are the most popular preference for hair removal due to the deep penetration and targeting of the hair follicle. In a recently published article, we presented our hair removal clinical evaluation results using an 810 nm scanning diode laser. Three- and six month follow-up hair counts demonstrated an average hair reduction of about 70%. OBJECTIVE: In the current article, we demonstrate long-term follow-up hair removal results of 1 year after last treatment. METHODS: Among 11 out of 14 female patients who received three axillary hair removal treatments, 4-6 weeks apart, returned to the 1-year follow-up visit. Treatment area photographs and hair count of 1-year follow-up visit were compared to baseline. RESULTS: The average hair count reduction of about 70% at 1 year after the last treatment was maintained. CONCLUSIONS: The examined 810 nm diode laser has been proven to be a safe and effective for hair removal. Results sustain not only for 3 or 6 months but also for 1 year after last treatment. PMID- 30251359 TI - Biomarkers for Progenitor and Differentiated Epithelial Cells in the Human Meibomian Gland. AB - The meibomian gland (MG) is a sebaceous gland that secretes through a holocrine process. Because such secretion requires the destruction of MG acinar epithelial cells, they need constant renewal and differentiation. The processes that promote these regenerative events in the human MG are unknown, nor is it known how to distinguish MG progenitor and differentiated cells. We discovered that Lrig1 and DNase2 serve as biomarkers for human MG progenitor and differentiated cells, respectively. Lrig1 is expressed in MG basal epithelial cells in the acinar periphery, a location where progenitor cells originate in sebaceous glands. DNase2 is expressed in the differentiated epithelial cells of the MG central acinus. Furthermore, proliferation stimulates, and differentiation suppresses, Lrig1 expression in human MG epithelial cells. The opposite is true for DNase2 expression. Our biomarker identification may have significant value in clinical efforts to restore MG function and to regenerate MGs after disease-induced dropout. Stem Cells Translational Medicine 2018;7:887-892. PMID- 30251360 TI - Cold flush after dynamic liver preservation protects against ischemic changes upon reperfusion - an experimental study. AB - Ex vivo machine perfusion of the liver after cold storage has found to be most effective if combined with controlled oxygenated rewarming up to (sub) normothermia. On disconnection of the warm graft from the machine, most surgeons usually perform a cold flush of the organ as protection against the second warm ischemia incurred upon implantation. Experimental evidence, however, is lacking and protective effect of deep hypothermia has been challenged for limited periods of liver ischemia in other models. A first systematic test was carried out on porcine livers, excised 30 min after cardiac arrest, subjected to 18 h of cold storage in UW and then machine perfused for 90 min with Aqix-RSI solution. During machine perfusion, livers were gradually rewarmed up to 20 degrees C. One group (n = 6) was then reflushed with 4 degrees C cold Belzer UW solution whereas the second group (n = 6) remained without cold flush. All livers were exposed to 45 min warm ischemia at room temperature to simulate the surgical implantation period. Organ function was evaluated in an established reperfusion model using diluted autologous blood. Cold reflush after disconnection from the machine resulted in a significant increase in bile production upon blood reperfusion, along with a significant reduction in transaminases release alanine aminotransferase and of the intramitochondrial enzyme glutamate dehydrogenase. Interestingly, free radical-mediated lipid peroxidation was also found significantly lower after cold reflush. No differences between the groups could be evidenced concerning histological injury and recovery of hepatic energy metabolism (tissue content of adenosine triphosphate). Post-machine preservation cold reflush seems to be beneficial in this particular setting, even if the organs are warmed up only to 20 degrees C, without notion of adverse effects, and should therefore be implemented in the protocol. PMID- 30251361 TI - Relationship between depression scores and degree of skin perspiration: A novel cross-sectional study. AB - Primary hyperhidrosis (PH) is a common pathological condition related to excessive sweating. It may be associated with depression. Therefore, the main aim of this study was to analyse and compare depression scores between subjects without PH (degree-I) and patients with PH (degrees-II, -III, and -IV). The secondary aim was to describe and compare depression scores among subjects with different PH degrees (I-without perceptible perspiration, II-tolerable perspiration, III-hardly tolerable perspiration, and IV-intolerable perspiration). A sample of 100 subjects with a median age of 23.00 +/- 6.00 years was recruited from an outpatient medical centre, where medical history data were registered. The degree of PH was determined using the Hyperhidrosis Disease Severity Scale from degrees I (mild) to IV (very severe). The depression scores were analysed using the Beck Depression Inventory (BDI). Statistically significant differences (P < 0.001) were observed for higher BDI scores in the patients with PH (degrees II, III, and IV) than in those without PH (degree-I). Kruskal-Wallis tests demonstrated statistically significant differences for BDI scores (P < 0.001), with higher values for degree-III with respect to degree-I and degree-IV with respect to degree-I. Patients with a greater degree (especially III/IV) of PH showed higher BDI scores compared with subjects without PH. PMID- 30251362 TI - Sleep and subjective cognitive decline in cognitively healthy elderly: Results from two cohorts. AB - Subjective cognitive decline may reflect a dementia prodrome or modifiable risk factor such as sleep disturbance. What is the association between sleep and subjective cognitive decline? Cross-sectional design, from two studies of older adults: the WHICAP in the USA and the HELIAD in Greece. A total of 1,576 WHICAP and 1,456 HELIAD participants, without mild cognitive impairment, dementia or severe depression/anxiety, were included. Participants were mostly women, with 12 (WHICAP) and 8 (HELIAD) mean years of education. Sleep problems were estimated using the Sleep Scale from the Medical Outcomes Study. Subjective cognitive decline was assessed using a structured complaint questionnaire that queries for subjective memory and other cognitive symptoms. Multinomial or logistic regression models were used to examine whether sleep problems were associated with complaints about general cognition, memory, naming, orientation and calculations. Age, sex, education, sleep medication, use of medications affecting cognition, co-morbidities, depression and anxiety were used as co-variates. Objective cognition was also estimated by summarizing neuropsychological performance into composite z-scores. Sleep problems were associated with two or more complaints: WHICAP: beta = 1.93 (95% confidence interval: 1.59-2.34), p <= .0001; HELIAD: beta = 1.48 (95% confidence interval: 1.20-1.83), p <= .0001. Sleep problems were associated with complaints in all the cognitive subcategories, except orientation for the WHICAP. The associations were noted regardless of objective cognition. At any given level of objective cognition, sleep disturbance is accompanied by subjective cognitive impairment. The replicability in two ethnically, genetically and culturally different cohorts adds validity to our results. The results have implications for the correlates, and potential aetiology of subjective cognitive decline, which should be considered in the assessment and treatment of older adults with cognitive complaints. PMID- 30251364 TI - Half a century of anesthesia for children: An interview with Dr. Nishan G. 'Nick' Goudsouzian. AB - The career of Dr Nishan Goudsouzian spanned half a century of pediatric anesthesia. His 50 years saw seminal contributions to the use of neuromuscular blocking agents in children, the development of proton beam therapy and magnetic resonance imaging for pediatric cancer, the introduction of the laryngeal mask airway, an explosion in the volume and depth of knowledge about pediatric anesthesia, the expansion of formal training in pediatric anesthesia, and the widening of academic efforts to improve anesthetic care for children worldwide. Based on interviews with Dr Goudsouzian, this article reviews the contributions of this Robert M. Smith Award winner to the development of pediatric anesthesia. PMID- 30251363 TI - An update on semen quality among young Finnish men and comparison with Danish data. AB - BACKGROUND: Finnish men used to have higher semen quality than Danish men. However, recent studies showed that semen quality in Finland has declined, but it has been relatively stable in Denmark. OBJECTIVE: This study aimed to compare new data on semen quality of the young Finnish men to that of Danish men. MATERIALS AND METHODS: In this cross-sectional study, 18- to 19-year-old men residing in Turku, Finland and Copenhagen, Denmark, were invited to participate in 2008-2011. Each man filled in a questionnaire, provided one semen sample and underwent andrological examination. Semen samples were analyzed according to WHO. Multiway ANOVA was used to adjust semen variables for duration of sexual abstinence and age (and time from ejaculation to the start of semen analysis for sperm motility). RESULTS: Altogether 287 Finnish men and 873 Danish men participated in the study. The adjusted median sperm concentrations were 49 and 47 million/mL for Finnish and Danish men, respectively (p = 0.48). The adjusted median total sperm counts were 148 million in Finland and 146 million in Denmark (p = 0.87). The adjusted median percentages of morphologically normal spermatozoa were 6.9% in Finland and 6.5% in Denmark, p = 0.27. Finnish men had higher adjusted median percentages of motile spermatozoa (A+B+C) than Danish men (80% vs. 69%, p < 0.001). The proportion of men who had low semen quality (sperm concentration, percentage of morphologically normal spermatozoa or percentage of progressively motile spermatozoa below WHO reference limits) was lower in Finland (25.4%) than in Denmark (34.6%), p = 0.004. DISCUSSION: Considerable percentage of men in both countries had low semen quality. The deteriorating semen quality in Finland may result in decreasing fecundity, which is a cause of concern. CONCLUSION: The formerly high semen quality in Finland has converged to the lower Danish levels. Our findings demonstrate the importance of continuing surveillance of semen quality. PMID- 30251365 TI - Pseudomonas syringae evades phagocytosis by animal cells via type III effector mediated regulation of actin filament plasticity. AB - Certain animal and plant pathogenic bacteria have developed virulence factors including effector proteins that enable them to overcome host immunity. A plant pathogen, Pseudomonas syringae pv. tomato (Pto) secretes a large repertoire of effectors via a type III secretory apparatus, thereby suppressing plant immunity. Here, we show that Pto causes sepsis in mice. Surprisingly, the effector HopQ1 disrupted animal phagocytosis by inhibiting actin rearrangement via direct interaction with the LIM domain of the animal target protein LIM kinase, a key regulator of actin polymerization. The results provide novel insight into animal host-plant pathogen interactions. In addition, the current study firstly demonstrates that certain plant pathogenic bacteria such as Pto evade phagocytosis by animal cells due to cross-kingdom suppression of host immunity. PMID- 30251366 TI - Hearing loss in children with sickle cell disease: A prospective French cohort study. AB - BACKGROUND: Sickle cell disease (SCD) is the most common genetic disease in France. In developing countries, it is associated with a high incidence of hearing loss. The aim of this study was to determine the prevalence of hearing loss in French children with SCD in order to determine if they need a close audiological follow-up. METHODS: We performed a single-center prospective cross sectional study of children with SCD. The children, without specific hearing symptom, underwent an ear, nose and throat examination with a hearing assessment between 2015 and 2016. RESULTS: Eighty-nine children were included, aged from 5 to 19 years, with 73% of SS or Sbeta0 genotype and 27% of SC or Sbeta+ genotype. Ten children (11.2%) had hearing thresholds higher than 20 dB in at least one ear: one child with subnormal hearing, six otitis media with effusion (OME), and three sensorineural hearing loss. Late age at diagnosis of SCD, a high platelet count and a low hematocrit level were significantly associated with OME; moreover, children with OME had more severe clinical and biological characteristics than children with normal hearing. Furthermore, 12.4% of the children complained of tinnitus. The rate of sudden hearing loss was 2.2%. Finally, 7.1% of patients with normal hearing showed a speech discrimination disorder. CONCLUSIONS: Several causes were identified for hearing loss in children with SCD. They therefore need a close audiological follow-up in order to avoid complications due to curable phenomena and to enable appropriate management for progressive complications. PMID- 30251367 TI - Differences in Risk Scores of Veterans Receiving Community Care Purchased by the Veterans Health Administration. AB - OBJECTIVE: To assess differences in risk (measured by expected costs associated with sociodemographic and clinical profiles) between Veterans receiving outpatient services through two community care (CC) programs: the Fee program ("Fee") and the Veterans Choice Program ("Choice"). DATA SOURCES/STUDY SETTING: Administrative data from VHA's Corporate Data Warehouse in fiscal years (FY) 2014 2015. STUDY DESIGN: We compared the clinical characteristics of Veterans across three groups (Fee only, Choice only, and Fee & Choice). We classified Veterans into risk groups based on Nosos risk scores and examined the relationship between type of outpatient utilization and risk within each CC group. We also examined changes in utilization of VHA and CC in FY14-FY15. We used chi-square tests, t tests, and ANOVAs to identify significant differences between CC groups. PRINCIPAL FINDINGS: Of the 1,400,977 Veterans using CC in FY15, 91.4 percent were Fee-only users, 4.4 percent Choice-only users, and 4.2 percent Fee & Choice users. Mean concurrent risk scores were higher for Fee only and Fee & Choice (1.9, SD = 2.7; 1.8, SD = 2.2) compared to Choice-only users (1.0, SD = 1.2) (p < .0001). Most CC users were "dual users" of both VHA and CC in FY14-FY15. CONCLUSIONS: As care transitions from VHA to CC, VHA should consider how best to coordinate care with community providers to reduce duplication of efforts, improve handoffs, and achieve the best outcomes for Veterans. PMID- 30251368 TI - Diagnostic accuracy of STAF, LADS, and iPAB scores for predicting paroxysmal atrial fibrillation in patients with acute cerebral infarction. AB - BACKGROUND AND OBJECTIVE: The scoring scales scoring system for targeting atrial fibrillation (STAF), left atrial diameter, age, diagnosis of stroke, and smoking status (LADS), and identified by past history of arrhythmia or antiarrhythmic agent use, atrial dilation, and elevation of Brain natriuretic peptide (iPAB) have been proposed for predicting atrial fibrillation in patients with acute cerebral infarction, but their relative accuracies are not clear. This prospective study compared STAF, LADS, and iPAB scores for predicting paroxysmal atrial fibrillation (PAF) in patients with acute cerebral infarction. METHODS: Patients with acute cerebral infarction (n = 744; 495 men, 249 women; aged 65 +/- 12 years) were consecutively enrolled throughout the year 2016 at the Department of Neurology of Huizhou Municipal Central Hospital. Patients were followed for 3 months. The sensitivity, specificity, area under the receiver operating characteristic curve (AUC), and best cutoff points of STAF, LADS, and iPAB scores for predicting PAF were computed. RESULTS: Among the 744 patients, 37 patients had PAF. The AUCs of the STAF, LADS, and iPAB scores for predicting PAF were 0.87, 0.79, and 0.84, respectively, and with a cutoff at four points, the sensitivities were 73%, 70.3%, and 83.8%, and specificities were 92.1%, 82.2%, and 77%. CONCLUSIONS: The STAF, LADS, and iPAB scores could satisfactorily predict PAF in patients with acute cerebral infarction. STAF was superior to the others in diagnostic performance. PMID- 30251370 TI - Blaschkoid distribution of composite syringocystadenoma papilliferum and tubular apocrine adenoma without naevus sebaceous. PMID- 30251369 TI - Pravastatin for Primary Prevention in Older Adults: Restricted Mean Survival Time Analysis. AB - OBJECTIVES: To use restricted mean survival time, which summarizes treatment effects in terms of event-free time over a fixed time period, to evaluate the benefit of pravastatin therapy for primary prevention of cardiovascular disease in older adults. DESIGN: Secondary analysis of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial-Lipid-Lowering Trial (ALLHAT LLT). SETTING: Ambulatory setting. PARTICIPANTS: Individuals aged 65 and older (mean aged 71, 49% female) free of cardiovascular disease (N=2,867). INTERVENTION: Pravastatin 40 mg/d (n=1,467) versus usual care (n=1,400). MEASUREMENTS: We estimated the difference in RMST for total and coronary heart disease (CHD)-free survival between the pravastatin and usual care groups over the 6-year trial period and used parametric survival models to estimate RMST differences projected over 10 years. RESULTS: Over 6 years, individuals treated with pravastatin lived (RMST 2,008.1 days), on average, 33.7 fewer days than those receiving usual care (RMST 2,041.8 days) (difference -33.7 days, 95% confidence interval (CI)=-67.0 to -0.5 days, p=.047). Pravastatin-treated individuals lived RMST 2,088.1 days), on average, 18.7 more days free of CHD over 6 years than those receiving usual care (RMST 2,069.4 days), but this difference was not statistically significant (difference 18.7 days, 95% CI=-10.4-47.8 days, p=.21). The 10-year projection showed that pravastatin-treated individuals would live 108.1 fewer days (95% CI=-204.5 to -14.1, p=.03) than those receiving usual care, although treated individuals would gain 77.9 days (95% CI=3.8-159.6, p=.046) of CHD-free survival. CONCLUSION: RMST provides an intuitive and explicit way to express the effect of pravastatin therapy on CHD-free and overall survival in older adults free of cardiovascular disease. This measure allows a more personalized interpretation than hazard ratios of the benefits and risks of a medical intervention for decision-making. PMID- 30251371 TI - Spinal sensory and motor blockade by intrathecal doxylamine and triprolidine in rats. AB - OBJECTIVES: The aim of this experiment was mainly to examine the effects of intrathecally injected doxylamine and triprolidine, two antihistamine drugs spinal motor and sensory functions. METHODS: After intrathecally injecting the rats with five different doses, the dose-response curves of spinal sensory and motor block with doxylamine and triprolidine were constructed. In comparison with the local anaesthetic mepivacaine, the quality and duration of spinal anaesthesia with doxylamine or triprolidine were conducted. KEY FINDINGS: Doxylamine, mepivacaine and triprolidine elicited spinal motor and sensory (nociception and proprioception) blockades in a dose-dependent fashion. On the ED50 (50% effective dose) basis, the rank order of drug potency was triprolidine > mepivacaine > doxylamine (P < 0.05) at provoking spinal motor, proprioceptive and nociceptive blockades. On the equianaesthetic doses (ED25 , ED50 and ED75 ), the duration of spinal anaesthesia with doxylamine was longer (P < 0.01) than that with mepivacaine or triprolidine. Moreover, doxylamine or triprolidine displayed greater potency (ED50 ) (P < 0.05) and duration (P < 0.05) of sensory block over motor block. CONCLUSIONS: Doxylamine or triprolidine produces a dose-dependent effect of spinal motor and sensory block. Triprolidine with a better nociception selective action over motor block has a better potency than mepivacaine or doxylamine. Doxylamine and triprolidine produce longer durations than mepivacaine. PMID- 30251372 TI - A role for Saccharomyces cerevisiae Centrin (Cdc31) in mitochondrial function and biogenesis. AB - Centrins belong to a family of proteins containing calcium-binding EF-hand motifs that perform well-established roles in centrosome and spindle pole body (SPB) duplication. Yeast encodes a single Centrin protein (Cdc31) that binds components in the SPB. However, further studies revealed a role for Centrins in mRNA export, and interactions with contractile filaments and photoreceptors. In addition, human Centrin-2 can bind the DNA-lesion recognition factor XPC, and improve the efficiency of nucleotide excision repair. Similarly, we reported that yeast Cdc31 binds Rad4, a functional counterpart of the XPC DNA repair protein. We also found that Cdc31 is involved in the ubiquitin/proteasome system, and mutations interfere with intracellular protein turnover. In this report, we describe new findings that indicate a role for Cdc31 in the energy metabolism pathway. Cdc31 and cdc31 mutant proteins showed distinct interactions with proteins in energy metabolism, and mutants showed sensitivity to oxidative stress and poor growth on non-fermentable carbon. Significant alteration in mitochondrial morphology was also detected. Although it is unclear how Cdc31 contributes to so many unrelated mechanisms, we propose that by controlling SPB duplication Centrin proteins might link the cellular responses to DNA damage, oxidative load and proteotoxic stresses to growth control. PMID- 30251373 TI - Development of a quality improvement audit tool for the primary care of children with chronic wet cough using a modified Delphi consensus approach. AB - AIM: In the absence of quality indicators (QIs) for the management of chronic wet cough, our study's aim was to determine whether consensus on QIs reflecting good primary health care, prior to referral for children with chronic wet cough, can be achieved. METHODS: A questionnaire consisting of 10 QIs was developed by a clinical working group based on current evidence and guidelines on the management of chronic wet cough in children. Each indicator reflected the quality of care provided to children with chronic wet cough in primary care prior to referral. A modified Delphi consensus questionnaire was undertaken involving expert paediatric respiratory clinicians and general paediatricians who graded the importance of each indicator for the purposes above. We a priori defined that consensus was considered achieved if >75% agreed on the indicator. RESULTS: Twenty-two specialists (from Brisbane, Melbourne, Perth and Canberra) participated in the survey. The cumulative number of years of their respiratory experience was 324 and that of general clinical practice was 504. Consensus was achieved in all 10 QIs, with 6 reaching 100% agreement. Mean agreement for the 10 items was 97%. CONCLUSION: As complete consensus was achieved on these QIs, it can be used as a provisional clinical audit tool and can guide the development of a robust audit tool for primary care clinical practice to assist with quality improvement initiatives. PMID- 30251374 TI - Does the Geriatric Depression Scale measure depression in Parkinson's disease? AB - : The Geriatric Depression Scale (GDS) is recommended for screening depression in individuals with Parkinson's disease (PD). Empirical evidence, however, is limited regarding its validity and factor structure in PD. Thus, the current study sought to evaluate the convergent and divergent validity of the GDS, as well as the structure and validity of the derived factors. METHOD: Nondemented individuals with PD (n = 158) completed the GDS-30, and items were subjected to a principle component analysis. Geriatric Depression Scale total and factor scores were correlated with depression items from the Movement Disorder Society Unified Parkinson's disease Rating Scale (MDS-UPDRSd) and Hamilton Rating Scale for Depression (HAMDd), as well as with the Apathy Scale (AS), State-Trait Anxiety Inventory (STAI), Modified Fatigue Impact Scale (MFIS), Parkinson's disease Sleep Scale, and a Subjective Cognitive Function composite score. RESULTS: The GDS total score was strongly correlated with divergent neuropsychiatric measures (AS, r = 0.57; STAI, r = 0.66; MFIS, r = 0.60), while only moderately correlated with convergent measures (MDS-UPDRSd, r = 0.36; HAMDd, r = 0.32; Ps < 0.05). Linear regression analyses revealed standardized measures of anxiety, apathy, and fatigue independently predicted the GDS total score, while depression items (MDS UPDRSd and HAMDd) failed to reach significance. Three independent factors were identified: Anxiety, Apathy, and Fatigue. These factors were significantly predicted by their respective convergent measures. CONCLUSIONS: Taken together, our findings suggest that the GDS and its subscales appear to primarily measure anxiety, apathy, and fatigue in PD, or alternatively, these symptom dimensions may be predominant in PD-depression. Future research with clinically diagnosed samples is needed to confirm these initial findings. PMID- 30251375 TI - Lacosamide in bipolar disorder: A 30-day comparison to a retrospective control group treated with other antiepileptics. AB - AIM: Bipolar disorder (BD) is often treated with anticonvulsants. Lacosamide has not been tested in BD. We assessed its effects in a hospital setting in patients with BD without epilepsy. METHODS: We treated 102 consecutive hospitalized patients with acute BD with lacosamide 50-300 mg/day. We compared this sample with a retrospective sample treated with other antiepileptics (OAE). We rated patients after 3, 7, 15, and 30 days of treatment with the Brief Psychiatric Rating Scale, Young Mania Rating Scale, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Clinical Global Impressions - Severity, and Global Assessment of Functioning. RESULTS: Patients receiving lacosamide were significantly younger and had fewer mixed episodes at intake, and less substance use disorder comorbidity than those receiving OAE. Both groups showed positive effects on all measures. The two groups did not differ on any clinical measure at baseline, but from the 3rd day on, lacosamide patients fared better than OAE patients on the Young Mania Rating Scale and Clinical Global Impressions - Severity and worse on the Hamilton Anxiety Rating Scale. From the 15th day, OAE patients scored better on the Brief Psychiatric Rating Scale. Global Assessment of Functioning scores were significantly more improved in the lacosamide patients. Age, substance use disorder comorbidity, episode type, and educational level significantly affected results. No interactions were found amongst these parameters. CONCLUSION: Lacosamide was effective in reducing psychopathology, mania, depression, and anxiety and in improving global functioning in patients with BD-I/II disorder in the short term, with few side-effects. Lacosamide improved mania, clinical severity, and global functioning better than OAE at doses lower than those used in epilepsy. PMID- 30251376 TI - High interindividual variability in plasma clopidogrel active metabolite concentrations in healthy cats is associated with sex and cytochrome P450 2C genetic polymorphism. AB - Clopidogrel response variability has been identified in cats. In humans, evidence suggests that variable clopidogrel active metabolite (CAM) generation is the primary explanation for clopidogrel response variability with differences in body weight, sex, and variable metabolism of clopidogrel primarily due to polymorphisms of the gene encoding cytochrome P450 (CYP) 2C19 as some proposed mechanisms. The aim of this study was to evaluate whether variation in CAM concentrations exists in healthy cats and what the cause of such variation might be. Nineteen healthy cats were given 18.75 mg clopidogrel by mouth. Blood was collected 2 hr later. Plasma CAM concentrations were measured using high performance liquid chromatography and tandem mass spectrometry. Clopidogrel metabolism was estimated by calculating CAM metabolic ratio. DNA was collected, and feline CYP2C genotyping was performed. The cats demonstrated high interindividual variation of plasma CAM concentrations. Approximately 69% of this interindividual variation was primarily explained by differences in clopidogrel metabolism as measured by CAM metabolic ratio with some influence by sex but not by weight. A single nucleotide polymorphism was identified in the feline CYP2C gene that explained in part individual differences in CAM metabolic ratio and CAM plasma concentrations. PMID- 30251377 TI - Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement. AB - Nicotine and alcohol addiction are leading causes of preventable death worldwide and continue to constitute a huge socio-economic burden. Both nicotine and alcohol perturb the brain's mesocorticolimbic system. Dopamine (DA) neurons projecting from the ventral tegmental area (VTA) to multiple downstream structures, including the nucleus accumbens, prefrontal cortex, and amygdala, are highly involved in the maintenance of healthy brain function. VTA DA neurons play a crucial role in associative learning and reinforcement. Nicotine and alcohol usurp these functions, promoting reinforcement of drug taking behaviors. In this review, we will first describe how nicotine and alcohol individually affect VTA DA neurons by examining how drug exposure alters the heterogeneous VTA microcircuit and network-wide projections. We will also examine how coadministration or previous exposure to nicotine or alcohol may augment the reinforcing effects of the other. Additionally, this review briefly summarizes the role of VTA DA neurons in nicotine, alcohol, and their synergistic effects in reinforcement and also addresses the remaining questions related to the circuit function specificity of the dopaminergic system in mediating nicotine/alcohol reinforcement and comorbidity. PMID- 30251378 TI - Characterization of CRISPR-Cas systems in the Ralstonia solanacearum species complex. AB - Clustered regularly interspaced short palindromic repeats (CRISPRs) are composed of an array of short DNA repeat sequences separated by unique spacer sequences that are flanked by associated (Cas) genes. CRISPR-Cas systems are found in the genomes of several microbes and can act as an adaptive immune mechanism against invading foreign nucleic acids, such as phage genomes. Here, we studied the CRISPR-Cas systems in plant-pathogenic bacteria of the Ralstonia solanacearum species complex (RSSC). A CRISPR-Cas system was found in 31% of RSSC genomes present in public databases. Specifically, CRISPR-Cas types I-E and II-C were found, with I-E being the most common. The presence of the same CRISPR-Cas types in distinct Ralstonia phylotypes and species suggests the acquisition of the system by a common ancestor before Ralstonia species segregation. In addition, a Cas1 phylogeny (I-E type) showed a perfect geographical segregation of phylotypes, supporting an ancient acquisition. Ralstoniasolanacearum strains CFBP2957 and K60T were challenged with a virulent phage, and the CRISPR arrays of bacteriophage-insensitive mutants (BIMs) were analysed. No new spacer acquisition was detected in the analysed BIMs. The functionality of the CRISPR-Cas interference step was also tested in R. solanacearum CFBP2957 using a spacer protospacer adjacent motif (PAM) delivery system, and no resistance was observed against phage phiAP1. Our results show that the CRISPR-Cas system in R. solanacearum CFBP2957 is not its primary antiviral strategy. PMID- 30251379 TI - Implantation of bioresorbable vascular scaffold for the treatment of pudendal artery stenosis and erectile dysfunction. AB - Bioresorbable vascular scaffolds (BVS) have been designed to overcome long-term limitations of metallic drug-eluting stents including permanent metallic "caging" that might trigger late coronary adverse events. Here, we report for the first time a case of 72-year gentleman with previous coronary artery disease, treated by successful implantation of BVS (Absorb, Abbott Vascular) due to significant stenosis of internal pudenda artery and erectile dysfunction. After 2 years, BVS completely resorbed and there were no signs of pudendal artery restenosis on CT scan, whereas blood flow and sexual function improved. PMID- 30251381 TI - Maldevelopment of the submandibular gland in a mouse model of apert syndrome. AB - BACKGROUND: Apert syndrome is characterized by craniosynostosis and bony syndactyly of the hands and feet. The cause of Apert syndrome is a single nucleotide substitution mutation (S252W or P253R) in fibroblast growth factor receptor 2 (FGFR2). Clinical experience suggests increased production of saliva by Apert syndrome patients, but this has not been formally investigated. FGFR2 signaling is known to regulate branching morphogenesis of the submandibular glands (SMGs). With the Apert syndrome mouse model (Ap mouse), we investigated the role of FGFR2 in SMGs and analyzed the SMG pathology of Apert syndrome. RESULTS: Ap mice demonstrated significantly greater SMG and sublingual gland (SMG/SLG complex) mass/body weight and percentage of parenchyma per unit area of the SMG compared with control mice. Furthermore, gene expression of Fgf1, Fgf2, Fgf3, Pdgfra, Pdgfrb, Mmp2, Bmp4, Lama5, Etv5, and Dusp6 was significantly higher in the SMG/SLG complex of Ap mice. FGF3 and BMP4 exhibited altered detection patterns. The numbers of macrophages were significantly greater in SMGs of Ap mice than in controls. Regarding functional evaluations of the salivary glands, no significant differences were observed. CONCLUSIONS: These results suggest that the gain-of-function mutation in FGFR2 in the SMGs of Ap mice enhances branching morphogenesis. Developmental Dynamics 247:1175-1185, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30251382 TI - Restoring islands and identifying source populations for introductions. AB - Article impact statement: Structured decision making can be used to identify an optimal source population for conservation introductions. PMID- 30251383 TI - Copper-Catalyzed Ring Opening of Benzofurans and an Enantioselective Hydroamination Cascade. AB - A copper(II) acetate/(R)-DTBM-SEGPHOS-catalyzed ring opening of benzofurans and enantioselective hydroamination cascade with dimethoxymethylsilane (DMMS) and hydroxylamine esters is described. Starting from readily available substituted benzofurans, a series of chiral N,N-dibenzylaminophenols, which are of high interest in pharmaceutical chemistry, were obtained with excellent enantioselectivities (up to 66 % yield, 94 % ee). PMID- 30251380 TI - Association of Hospitalization, Critical Illness, and Infection with Brain Structure in Older Adults. AB - OBJECTIVES: To examine the association between hospitalization, critical illness, and infection occurring during middle- and late-life and structural brain abnormalities in older adults. DESIGN: Prospective cohort study. SETTING: Atherosclerosis Risk in Communities (ARIC) Study. PARTICIPANTS: A community sample of adults who were 44 to 66 years of age at study baseline. MEASUREMENTS: Active surveillance of local hospitals and annual participant contact were used to gather hospitalization information (including International Classification of Diseases, Ninth Revision, codes) on all participants over a 24-year surveillance period. Subsequently, a subset of participants underwent 3-Tesla brain magnetic resonance imaging (MRI) to quantify total and regional brain volumes, white matter hyperintensity (WMH) volume, and white matter microstructural integrity (fractional anisotropy (FA) and mean diffusivity (MD) as measured using diffusion tensor imaging (DTI)). RESULTS: Of the 1,689 participants included (mean age at MRI 76+/-5), 72% were hospitalized, 14% had a major infection, and 4% had a critical illness during the surveillance period. Using covariate-adjusted regression, hospitalization was associated with 0.12-standard deviation (SD) greater WMH volume (95% confidence interval (CI)=0.00-0.24) and poorer white matter microstructural integrity (0.17-SD lower FA, 95% CI=-0.27 to -0.06; 0.16 SD greater MD, 95% CI=0.07-0.25) than no hospitalization. There was a dose dependent relationship between number of hospitalizations, smaller brain volumes, and lower white matter integrity (p-trends <=.048). In hospitalized participants, critical illness was associated with smaller Alzheimer's disease (AD) signature region (-1.64 cm3 , 95% CI=-3.16 to -0.12); major infection was associated with smaller AD signature region (-1.28 cm3 , 95% CI=-2.21 to -0.35) and larger ventricular volume (3.79 cm3 , 95% CI= 0.81-6.77). CONCLUSIONS: Whereas all-cause hospitalization was primarily associated with lower white matter integrity, critical illness and major infection were associated with smaller brain volume, particularly within regions implicated in AD. PMID- 30251384 TI - Benzyl sulforaphane is superior to sulforaphane in inhibiting the Akt/MAPK and activating the Nrf2/ARE signalling pathways in HepG2 cells. AB - OBJECTIVES: Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, has been reported to own anticarcinogenic, antiinflammatory and cancer chemopreventive properties. Benzyl sulforaphane (BSFN) was a derivative of SFN which was designed and synthesized by our laboratory. Here, the cancer prevention and anticancer effects of BSFN on human hepatoma (HepG2) cells were investigated. METHODS: The following effects of BSFN on components of the mitochondrial apoptotic pathway were examined: generation of reactive oxygen species and mitochondrial membrane potential (DeltaPsim) changes by flow cytometry, the expression changes of Bcl-2 family proteins and Akt/MAPK proteins by western blot. The protein levels of Nrf2 and Keap1 were also tested via Western blot. The effects of BSFN on Nrf2 nuclear translocation and ARE-reporter gene activity were examined by fluorescence microscope and multifunctional spectrophotometer. KEY FINDINGS: Benzyl sulforaphane could induce cell apoptosis by mitochondrion-dependent pathway, which inhibited HepG2 cells growth in a manner of time- and concentration -dependent. Furthermore, BSFN could inhibit the Akt/MAPK and activate the Nrf2/ARE pathway in HepG2 cells. CONCLUSIONS: Benzyl sulforaphane was superior to SFN in inhibiting Akt/MAPK and activating Nrf2/ARE signalling pathways in HepG2 cells, which indicated that BSFN could be a safe therapeutic strategy for the prevention and treatment of liver cancer. PMID- 30251385 TI - Diagnosis and Treatment of Primary Headache Disorders in Older Adults. AB - OBJECTIVES: To provide a unique perspective on geriatric headache and a number of novel treatment options that are not well known outside of the headache literature. DESIGN: Review of the most current and relevant headache literature for practitioners specializing in geriatric care. RESULTS: Evaluation and management of headache disorders in older adults requires an understanding of the underlying pathophysiology and how it relates to age-related physiological changes. To treat headache disorders in general, the appropriate diagnosis must first be established, and treatment of headaches in elderly adults poses unique challenges, including potential polypharmacy, medical comorbidities, and physiological changes associated with aging. CONCLUSION: The purpose of this review is to provide a guide to and perspective on the challenges inherent in treating headaches in older adults. PMID- 30251386 TI - (Mid)West Side Story: Acute Hepatitis C Virus Infection and the Opioid Epidemic in the United States. AB - In the February issue of the American Journal of Public Health, Zibbell et al. report on a relationship between increases in acute hepatitis C virus (HCV) infections and the rising opiod injection epidemic in the United States. The authors base their report on acute HCV case data from the National Notifiable Disease Surveillance System (NNDSS) and national substance use disorder (SUD) admissions data from the Substance Abuse and Mental Health Services Administration's (SAMHSA's) Treatment Episode Data Set: Admissions (TEDS-A). This article is protected by copyright. All rights reserved. PMID- 30251387 TI - Antidiabetic potential of Musa spp. inflorescence: a systematic review. AB - OBJECTIVES: Extracts of parts Musa spp. have been used for the treatment of various diseases in traditional medicine. Studies have shown that these extracts have hypoglycaemic properties. The aim of this work was to gather evidence on the antidiabetic effects of Musa spp. inflorescence. METHODS: A systematic review was conducted with searches in three electronic databases, along with manual searches. Studies evaluating the antidiabetic properties of extracts of flower or bract of the genus Musa (in vitro or in vivo) were included. KEY FINDINGS: Overall, 16 studies were found. The reported assays were of hypoglycaemic effects, oral glucose tolerance, inhibitory activities in carbohydrate metabolism and digestive enzymes, enhanced glucose uptake activity and popular use of the extract in patients with diabetes type 2. In vitro studies showed that use of the extract was associated with antidiabetic effects (e.g. increased glucose uptake and inhibition of carbohydrate digestion enzymes). In induced diabetic models, Musa spp. extracts showed dose-dependent glycaemic level reductions compared with pharmacological drugs (P < 0.05). SUMMARY: In general, promising results regarding antidiabetic activity were found for inflorescence of Musa spp., suggesting that this plant could represent a natural alternative therapy for treating diabetes mellitus type 2. PMID- 30251388 TI - Effect of cellular polyanion mimetics on tau peptide aggregation. AB - Tau protein aggregation is believed to be one of the key drivers of Alzheimer's disease. The two hexapeptide amino acid sequences 306 VQIVYK311 and 275 VQIINK280 of the tau protein are responsible for aggregation, and subsequent functional loss leading to Alzheimer's progression. Hence, it is important to understand the factors that promote the self-aggregation of this tau peptide fragments. Cellular microenvironmental polyanions are known to play a major role in tau protein aggregation and loss of function. Previous studies mainly focused on the effect of heparin and heparan sulfate solution on the full tau protein aggregation. Here, we study the effect of cellular polyanion mimetics, glycosaminoglycans (GAGs) in solution and on surface to mimic intracellular and extracellular conditions, and cellular RNA on the aggregation of tau hexapeptide 306 VQIVYK311 , and mutant tau peptide 273 GKVQIIN_KLDL284 found frequently in taupathy. Characterization techniques used for the study include biochemical assays, electron microscopy, and spectroscopy techniques to investigate the aggregation vitro. Results show while all the GAGs in solution form play a role in tau peptides aggregation, heparin, chondroitin sulfate, and dermatan sulfate in particular significantly promote the tau peptides aggregation formation. On the other hand, surface-coated GAGs did not promote significant tau aggregation. As far as cellular RNA is concerned, results show significant increase in tau peptides aggregation and toxicity in neuroblastoma cells. The study on the tau peptides fragments aggregation in the presence of GAGs and cellular RNA could provide novel information on the tau aggregation mechanism and could open ways for developing cellular polyanions modulating therapeutics for treating Alzheimer's disease. PMID- 30251389 TI - Neurobiology of motivated behaviors. PMID- 30251390 TI - Body Composition with Dual-Energy X-Ray Absorptiometry and Bioelectrical Impedance Analysis in Breast Cancer Survivors. AB - BACKGROUND: Because obesity is an independent risk factor for breast cancer recurrence, assessment of body composition is crucial to guide weight management in breast cancer survivors (BCS). This study assessed whether dual-energy x-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA) yield similar results for body composition in BCS. METHODS: Body fat percentage, lean body mass, and fat mass were estimated using DXA and BIA under fasting conditions in 89 BCS. BMI categories included normal (18-24.99 kg/m2 ; n = 28), overweight (25.0-29.9 kg/m2 ; n = 21), obese (>30 kg/m2 ; n = 23), and severely obese BCS (>35 kg/m2 ; n = 17). Agreement between the devices was assessed by Bland-Altman analysis. RESULTS: There was no agreement between the 2 devices for body fat percentage (DXA: 44.2 +/- 6.2% vs BIA: 40.4 +/- 7.8%), lean body mass (DXA: 39.1 +/- 7.6 kg vs BIA: 42.9 +/- 5.9 kg), and fat mass (DXA: 32.4 +/- 10.8 kg vs BIA: 30.6 +/- 11.0 kg; P < .001). These findings were consistent in normal, overweight, and obese BCS. There was agreement between the 2 devices for fat mass (DXA: 48.7 +/- 7.2 kg vs BIA: 47.9 +/- 5.7 kg) in severely obese BCS (P = .102), possibly due to small sample size. CONCLUSIONS: BIA may underestimate body fat percentage and fat mass and overestimate lean body mass, compared with DXA. Future studies are warranted to assess the use of these 2 devices in a larger cohort of BCS within BMI categories. PMID- 30251391 TI - Applicability of Standardized Early Fetal Heart Examination in the Obese Population. AB - OBJECTIVE: This study aimed to evaluate the impact of obesity on early evaluation of fetal cardiac landmarks using a standardized examination method at the time of nuchal translucency scan. METHODS: This was a cross-sectional study of an ongoing prospective cohort at high risk for congenital heart defects. We used a standardized examination protocol using 2-dimensional sonography with power Doppler in the evaluation of fetal cardiac landmarks consisting of 4-chamber view, outflow tract relationship, and transverse arches view. The study population was stratified based on maternal body mass index into nonobese (<30 kg/m2 ) and obese (>=30 kg/m2 ). Groups were compared in terms of satisfactory evaluation of fetal cardiac landmarks, transvaginal sonography use, and scan times required for the evaluations. Subanalysis was performed by further categorizing obesity into nonmorbid obesity (30.0-39.9 kg/m2 ) and morbid obesity (>=40 kg/m2 ). RESULTS: A total of 190 patients were evaluated. Of these, 48.4% (n = 92) were obese. The most common indication for fetal cardiac assessment was maternal pregestational diabetes mellitus (42.6%). Transvaginal sonography was utilized in one nonobese woman (1.4%) and 11 obese women (12%) (P = .002). The satisfactory evaluation of 4-chamber view, outflow tract relationship, transverse arches view, and all views were not significantly different between groups (P > .05). The scan time was about 5 minutes longer in the obese group compared with nonobese group (P = .020). CONCLUSIONS: Obesity does not hamper early evaluation of fetal cardiac landmarks around the time of nuchal translucency scan. However, obese patients are more likely to require transvaginal examinations. PMID- 30251392 TI - Size-by-environment interactions: a neglected dimension of species' responses to environmental variation. AB - In both plant and animal systems, size can determine whether an individual survives and grows under different environmental conditions. However, it is unclear whether and when size-dependent responses to exogenous environmental fluctuations affect population dynamics. Size-by-environment interactions create pathways for environmental fluctuations to influence population dynamics by allowing for negative covariation between sizes within vital rates (e.g. small and large individuals have negatively covarying survival rates) and/or size dependent variability in a vital rate (e.g. survival of large individuals varies less than small individuals through time). Whether these phenomena affect population dynamics depends on how they are mediated by elasticities (they must affect the sizes and vital rates that matter) and their projected impacts will depend on model functional form (the impact of reduced variance depends on the relationship between the environment and vital rate). We demonstrate these ideas with an analysis of fifteen species from five semiarid plant communities. We find that size-by-environment interactions are common but do not impact long-term population dynamics. Size-by-environment interactions may yet be important for other species. Our approach can be applied to species in other ecosystems to determine if and how size-by-environment interactions allow them to cope with, or exploit, fluctuating environments. PMID- 30251393 TI - Prospects for the Use of Induced Pluripotent Stem Cells (iPSC) in Animal Conservation and Environmental Protection. AB - Stem cells are unique cell populations able to copy themselves exactly as well as specialize into new cell types. Stem cells isolated from early stages of embryo development are pluripotent, i.e., can be differentiated into multiple different cell types. In addition, scientists have found a way of reverting specialized cells from an adult into an embryonic-like state. These cells, that are as effective as cells isolated from early embryos, are termed induced pluripotent stem cells (iPSCs). The potency of iPSC technology is recently being employed by researchers aimed at helping wildlife and environmental conservation efforts. Ambitious attempts using iPSCs are being made to preserve endangered animals as well as reanimate extinct species, merging science fiction with reality. Other research to sustain natural resources and promote animal welfare are exploring iPSCs for laboratory grown animal products without harm to animals offering unorthodox options for creating meat, leather, and fur. There is great potential in iPSC technology and what can be achieved in consumerism, animal welfare, and environmental protection and conservation. Here, we discuss current research in the field of iPSCs and how these research groups are attempting to achieve their goals. Stem Cells Translational Medicine 2018. PMID- 30251394 TI - Determinants of prescribing potentially inappropriate medications in a nationwide cohort of community dwellers with dementia receiving a comprehensive geriatric assessment. AB - OBJECTIVE: To identify the prevalence and predictors of prescribing potentially inappropriate medications (PIMs) in a nationwide cohort of community dwellers with dementia requiring complex care needs. METHODS: A cross-matched data of the International Resident Assessment Instrument-Home Care (9.1) (interRAI-HC) and prescribing data obtained from the Pharmaceutical Claims Data Mart (Pharms) extract files for older adults (>=65 y) requiring complex care needs were utilized for this study. The 2015 Beers criteria were applied to identify the prevalence of PIMs in older adults with dementia. Sociodemographic and clinical predictors of PIMs were analysed using a logistic regression model. RESULTS: The study population consisted of 16 568 individuals who had their first interRAI assessment from 1 January 2015 to 31 December 2015. The estimated prevalence of dementia was 13.2% (2190/16 568). 66.9% (1465/2190) of the older adults diagnosed with dementia were prescribed PIMs, of which anticholinergic medications constituted 59.6% (873/1465). Males and individuals who were prescribed a greater number of medications were more likely to be prescribed PIMs. Individuals over 85 years of age, Maori ethnic group of individuals, older adults who were being supervised with respect to their activities of daily living, and individuals who reported good or excellent self-reported health had a lesser likelihood of being prescribed PIMs. CONCLUSION: We found that PIMs are prescribed frequently in older adults with dementia. Comprehensive geriatric assessments can serve as a potential tool to decrease the occurrence of PIMs in vulnerable groups with poor functional and cognitive status. PMID- 30251395 TI - Cytotoxic activity of difluoromethylornithine compared with fenretinide in neuroblastoma cell lines. AB - BACKGROUND: Maintenance therapy with 13-cis-retinoic acid and immunotherapy (given after completion of intensive cytotoxic therapy) improves outcome for high risk neuroblastoma patients. The synthetic retinoid fenretinide (4-HPR) achieved multiple complete responses in relapse/refractory neuroblastoma in early-phase clinical trials, has low systemic toxicity, and has been considered for maintenance therapy clinical trials. Difluoromethylornithine (DFMO, an irreversible inhibitor of ornithine decarboxylase with minimal single-agent clinical response data) is being used for maintenance therapy of neuroblastoma. We evaluated the cytotoxic activity of DFMO and fenretinide in neuroblastoma cell lines. PROCEDURE: We tested 16 neuroblastoma cell lines in bone marrow-level hypoxia (5% O2 ) using the DIMSCAN cytotoxicity assay. Polyamines were measured by HPLC-mass spectrometry and apoptosis by transferase dUTP nick end labeling (TUNEL) using flow cytometry. RESULTS: At clinically achievable levels (100 MUM), DFMO significantly decreased (P < 0.05) polyamine putrescine and achieved modest cytotoxicity (<1 log (90% cytotoxicity). Prolonged exposures (7 days) or culture in 2% and 20% O2 did not enhance DFMO cytotoxicity. However, fenretinide (10 MUM) even at a concentration lower than clinically achievable in neuroblastoma patients (20 MUM) induced >= 1 log cell kill in 14 cell lines. The average IC90 and IC99 of fenretinide was 4.7 +/- 1 MUM and 9.9 +/- 1.8 MUM, respectively. DFMO did not induce a significant increase (P > 0.05) in apoptosis (TUNEL assay). Apoptosis by fenretinide was significantly higher (P < 0.001) compared with DFMO or controls. CONCLUSIONS: DFMO as a single agent has minimal cytotoxic activity for neuroblastoma cell lines. PMID- 30251396 TI - Perceived barriers to psychological treatment in Chinese cancer patients. PMID- 30251397 TI - It is a complex issue: emerging connections between epigenetic regulators in drug addiction. AB - Drug use leads to addiction in some individuals, but the underlying brain mechanisms that control the transition from casual drug use to an intractable substance use disorder (SUD) are not well understood. Gene x environment interactions such as the frequency of drug use and the type of substance used likely to promote maladaptive plastic changes in brain regions that are critical for controlling addiction-related behavior. Epigenetics encompasses a broad spectrum of mechanisms important for regulating gene transcription that are not dependent on changes in DNA base pair sequences. This review focuses on the proteins and complexes contributing to epigenetic modifications in the nucleus accumbens (NAc) following drug experience. We discuss in detail the three major mechanisms: histone acetylation and deacetylation, histone methylation, and DNA methylation. We discuss how drug use alters the regulation of the associated proteins regulating these processes and highlight how experimental manipulations of these proteins in the NAc can alter drug-related behaviors. Finally, we discuss the ways that histone modifications and DNA methylation coordinate actions by recruiting large epigenetic enzyme complexes to aid in transcriptional repression. Targeting these multiprotein epigenetic enzyme complexes - and the individual proteins that comprise them - might lead to effective therapeutics to reverse or treat SUDs in patients. PMID- 30251398 TI - Risk of ischemic stroke after third, fourth, and sixth cranial nerve palsies in type 2 diabetes. AB - BACKGROUND: The aim of this study was to define the risk of ischemic stroke among newly diagnosed type 2 diabetes (T2D) patients who developed ocular motor cranial nerve (CN) palsies. METHODS: From the National Health Insurance Service - National Sample Cohort database (2002-2013) of a random sample of 1 025 340 Koreans, patients with newly diagnosed T2D aged >=20 years were included in the study. The incidence of ocular motor CN palsies was identified using diagnostic codes for third, fourth, and sixth CN palsies. To determine the effect of incident ocular motor CN palsy on subsequent ischemic stroke, covariate Cox regression was used (Model 1 included only ocular motor CN palsy as a time varying covariate; Model 2 included ocular motor CN palsy and demographic information; Model 3 included all variables in Model 2 as well as comorbidity, concomitant medication, and the Charlson comorbidity index score). RESULTS: Of 45 820 T2D patients, 75 developed ocular motor CN palsy and 1411 had ischemic stroke. Four patients experienced ischemic stroke after the development of ocular motor CN palsy. Incident ocular motor CN palsy was associated with the subsequent risk of ischemic stroke in Models 1, 2 and 3 (hazard ratios [95% confidence intervals] 3.74 [1.40-9.98], 3.33 [1.25-8.89], and 2.96 [1.11-7.92], respectively). Male sex, older age, and lower income were associated with an increased risk of ischemic stroke. Among confounders, hypertension, atrial fibrillation, and congestive heart failure were associated with the risk of ischemic stroke. CONCLUSIONS: Physicians should pay more attention to manageable risk factors of ischemic stroke when diabetic patients suffer from ocular motor CN palsies. PMID- 30251400 TI - Evaluation of the accuracy, reliability, efficiency, and acceptability of fast forwarding to score problem behavior. AB - Technological advances have allowed professionals to obtain extended recordings of caregiver-client interactions in natural settings, but scoring recorded video at normal speed to identify instances of low-rate problem behavior is impractical in terms of scoring time. Fast forwarding is a continuous measurement system in which all seconds of an observation are viewed at a speed faster than normal. In Study 1, we evaluated whether three groups of five observers could discriminate problem behavior at three fast-forwarding speeds across 10-min observations. We analyzed the efficiency of using fast forwarding compared to continuous scoring, and interobserver agreement across the fast-forwarding speeds. In Study 2, we compared the accuracy, efficiency, and social acceptability of fast forwarding (3.5x) and momentary time sampling (3.5 s) across 90-min observations. Results support the use of 3.5x fast forwarding as a viable measurement system of improving the practicality of scoring problem behavior from video. PMID- 30251399 TI - Phthalorubines: Fused-Ring Compounds Synthesized from Phthalonitrile. AB - A series of dibenzo[a,f][1,3,5]triazino[2,1,6-cd] pyrrolizine compounds have been synthesized from phthalonitriles by a facile intramolecular cyclization process using "half-phthalocyanine" precursors, and they were characterized by X-ray crystallography, 1 H NMR spectroscopy, UV/Vis, and theoretical calculations. These compounds have spectroscopic profiles similar to phthalocyanines and porphyrins, although their inner-core structures and coordination types are totally different. They can be regarded as a new class of aromatic fused-ring compounds. The low-energy absorption of these new fused-ring compounds are located at around 600 nm. Such a low-energy pi-pi* transition is scarce in aromatic compounds having a similar molecular size. According to the nomenclature of phthalocyanines, these types of compounds have been named phthalorubines (Prs). PMID- 30251401 TI - What happens when the therapist leaves? The impact of therapy transfer on the therapeutic alliance and symptoms. AB - BACKGROUND: The therapeutic alliance is an important factor in psychotherapy, affecting both therapy processes and outcome. Therapy transfers may impair the quality of the therapeutic alliance and increase symptom severity. The aim of this study is to investigate the impact of patient transfers in cognitive behavioural therapy on alliance and symptoms in the sessions after the transfer. METHOD: Patient- and therapist-rated therapeutic alliance and patient-reported symptom severity were measured session-to-session. Differences in the levels of alliance and symptom severity before (i.e., with the original therapist) and after (i.e., with the new therapist) the transfer session were analysed. The development of alliance and symptom severity was explored using multilevel growth models. RESULTS: A significant drop in the alliance was found after the transfer, whereas no differences were found with regard to symptom severity. After an average of 2.93 sessions, the therapeutic alliance as rated by patients reached pretransfer levels, whereas it took an average of 5.05 sessions for therapist rated alliance levels to be at a similar level as before the transfer. Inter individual differences were found with regard to the development of the therapeutic alliance over time. CONCLUSIONS: Therapy transfers have no long lasting negative effects on either symptom impairment or the therapeutic alliance. PMID- 30251402 TI - Feasibility of lung ultrasound to assess pulmonary overflow in congenital heart disease children. AB - BACKGROUND: Pulmonary overflow (PO) is one of the most common complications in congenital heart disease (CHD) children with an incidence of 48-60% approximately. This study explored the feasibility of using lung ultrasound (LUS) to assess pulmonary overcirculation in CHD children and compare the diagnostic performance of LUS and chest radiography (CXR) for the detection of pulmonary overcirculation. METHOD: The upper anterior area, lower anterior area, upper lateral area, and lower posterior area, in each hemithorax were scanned in 59 children in the supine position. A-lines, B-lines in each scanned region were recorded, and the worst LUS abnormality in the video clip was considered to characterize the examined region. Sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of LUS and CXR were compared using computed tomography (CT) as a standard criterion. RESULTS: PO was diagnosed in 53% (31/59), 63% (37/59), and 51% (30/59) children with CT, CXR, and LUS, respectively. The sensitivity, specificity, and diagnostic accuracy of PO were 96%, 94%, and 95% for LUS and 74%, 50%, and 63% for CXR. The percentage of mild, moderate, and severe PO diagnosed via LUS were 31% (18/59), 19% (11/59), and 2% (1/59), respectively. Furthermore, the PO incidence diagnosed by LUS in CHD children less than 1 year old were significantly higher than those beyond 1 year old. CONCLUSION: LUS is a noninvasive and useful tool for the detection and assessment of PO in CHD children at the operating room, and is better than CXR in sensitivity and specificity, comparable to CT. PMID- 30251403 TI - Hydrochlorothiazide vs chlorthalidone, indapamide, and potassium sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta-analysis. AB - Left ventricular hypertrophy develops in 36%-41% of hypertensive patients and independently predicts cardiovascular events and total mortality. Moreover, drug induced reduction in left ventricular mass (LVM) correlates with improved prognosis. The optimal thiazide-type diuretic for reducing LVM is unknown. Evidence regarding potency, cardiovascular events, sodium, and potassium suggested the hypothesis that "CHIP" diuretics (CHlorthalidone, Indapamide, and Potassium-sparing diuretic/hydrochlorothiazide [PSD/HCTZ]) would reduce LVM more than HCTZ. Systematic searches of five databases were conducted. Among the 38 randomized trials, a 1% reduction in systolic blood pressure (SBP) predicted a 1% reduction in LVM, P = 0.00001. CHIP-HCTZ differences in reducing LVM differed across trials (ie, heterogeneity), making interpretation uncertain. However, among the 28 double-blind trials, heterogeneity was undetectable, and HCTZ reduced LVM (percent reduction [95% CI]) by -7.3 (-10.4, -4.2), P < 0.0001. CHIP diuretics surpassed HCTZ in reducing LVM: chlorthalidone -8.2 (-14.7, -1.6), P = 0.015; indapamide -7.5 (-12.7, -2.3), P = 0.005; and all CHIP diuretics combined 7.7 (-12.2, -3.1), P < 0.001. The comparison of PSD/HCTZ with HCTZ had low statistical power but favored PSD/HCTZ: -6.0 (-14.1, +2.1), P = 0.149. Thus, compared to HCTZ, CHIP diuretics had twice the effect on LVM. CHIP diuretics did not surpass HCTZ in reducing systolic or diastolic blood pressure: -0.3 (-5.0, +4.3) and -1.6 (-5.6, +2.4), respectively. The strength of evidence that CHIP diuretics surpass HCTZ for reducing LVM was high (GRADE criteria). In conclusion, these novel results have demonstrated that CHIP diuretics reduce LVM 2-fold more than HCTZ among hypertensive patients. Although generally related to LVM, blood pressure fails to explain the superiority of CHIP diuretics for reducing LVM. PMID- 30251404 TI - Bacteremia in cardiac surgery patients with heparin-induced thrombocytopenia. PMID- 30251405 TI - Prognostic value of JAK2V617F mutation in pseudotumor cerebri associated with cerebral venous sinus thrombosis. AB - OBJECTIVES: To examine the clinical characteristics and prognosis of cerebral venous sinus thrombosis (CVST) that presented as pseudotumor cerebri (PTC) patients with JAK2V617F mutation. METHODS: Medical records of all consecutive patients that presented with PTC and a JAK2V617F mutation who were treated were retrospectively reviewed. Data regarding demographics and ocular presenting symptoms and signs, neurological signs, hematological factors treatment, and prognosis were collected. RESULTS: The most common presenting symptoms were headache (5 patients, 83.3%) and visual obscurations (5 patients, 83.3%). CVST of the sagittal sinus and sigmoid sinus were the most common site of thrombus. Platelet count and hemoglobin count were higher than normal during follow-up. There was significant change in the disk edema degree as well as decline in retinal nerve fiber layer (RNFL) thickness (P < 0.001, P < 0.001, Matched pairs). There was no significant change in visual acuity (VA) or mean deviation (MD) during follow-up (P = 0.95, 0.64, respectively, Matched pairs). CONCLUSIONS: Pseudotumor cerebri resulting from CSVT in our patients with JAK2V617F mutation was frequent in young patients and needed medical and surgical treatment, without improvement in visual functions and in third caused poor visual outcome. Therefore, we believe that a screening test for JAK2V617F mutation should be considered for patients with CVST without known risk factor presenting with PTC, especially when sagittal sinus or sigmoid sinus involvement or thrombocytosis or high hemoglobin are found upon presentation. This might lead to more aggressive management which may improve the visual prognosis of those young patients. PMID- 30251406 TI - The rooting reflex as an infant feeding cue. AB - Experts in infant health and development consider the rooting reflex a cue of a baby's hunger and recommend feeding the infant when this reflex occurs. However, the relation between rooting and infant feeding status has not been well established in the literature. In the current study, seven parents documented the occurrence of their newborns' rooting, crying, and a control reflex (palmar grasp) before, after, and between naturally occurring feedings. For all participants, rooting occurred during a greater percentage of reflex checks prior to feedings, whereas the palmar grasp occurred during a similar percentage of checks across these time periods. These results provide empirical support for the rooting reflex as a feeding cue. However, data for only one dyad suggested a high probability of the rooting reflex occurring without crying during prefeeding checks. Thus, our data do not provide evidence that feeding in response to the rooting reflex would preempt infant crying. PMID- 30251407 TI - Design, synthesis, and biological evaluation of quinazoline derivatives as dual HDAC1 and HDAC6 inhibitors for the treatment of cancer. AB - Fifty-eight quinazoline-based compounds were designed and synthesized based on the structural optimizations from the lead compound 23bb in an attempt to search for more potent dual HDAC1 and HDAC6 inhibitors. Among them, 32c (HDAC1, IC50 = 31.10 +/- 0.37 nM; HDAC6, IC50 = 16.15 +/- 0.62 nM) and 32d (HDAC1, IC50 = 37.00 +/- 0.24 nM; HDAC6, IC50 = 35.00 +/- 0.71 nM) were not only identified as potent dual-acting HDAC1 and HDAC6 inhibitors with over 10-fold selectivity to the other HDACs, but also displayed activities in tubulin acetylation and histone H3 acetylation induction. Importantly, both of them displayed strong antiproliferative activities against various tumor cell lines in vitro with IC50 values less than 40 nM, especially for hematologic tumors cells (U266 and RPMI8226, IC50 < 1 nM), which were even better than 23bb and SAHA. Furthermore, 32c showed a significant tumor growth inhibition (antitumor rate = 63.98%, p < 0.05) in the resistant MCF-7/ADR xenograft model without any obvious body weight changes and abnormal behaviors. Our findings validate that 32c is a potent dual inhibitor of HDAC1/6 that can be an efficacious treatment for breast cancer with Adriamycin resistance. PMID- 30251408 TI - Silver nanoparticles induce Egr-1-dependent psoriasin expression via the ERK and p38 pathways. AB - BACKGROUND: Silver nanoparticles (Ag-NPs) can prevent bacterial infection and improve cutaneous wound healing owing to their antimicrobial activity. However, the mechanism of their antimicrobial activity is poorly understood. AIM: To determine the mechanistic relationship between Ag-NP treatment and expression of psoriasin. METHODS: Human epidermal keratinocytes, neonatal (HEKn) were used. Psoriasin mRNA expression was measured by reverse transcription PCR and real-time PCR. Western blotting was performed to verify expression of early growth response 1 (Egr-1) and psoriasin, and phosphorylation of mitogen-activated protein kinase (MAPK). Psoriasin promoter activity by Egr-1 was detected by a luciferase assay. RESULTS: Treatment of HEKn with Ag-NPs induced psoriasin mRNA and protein expression. Upregulation of psoriasin promoter activity was also observed in the luciferase assay. Ag-NPs increased Egr-1 expression, promoter activity and nuclear translocation in HEKn. Psoriasin luciferase activity was increased in HEKn transfected with Egr-1 pcDNA 3.1. Ag-NPs activated MAPK pathways including the extracellular signal-regulated kinase (ERK), p38, and c-Jun-N-terminal kinase (JNK) pathways. The upregulation of Egr-1 expression by Ag-NP stimulation was inhibited by ERK and p38 inhibitors, but not by a JNK inhibitor. Psoriasin expression was reduced in Egr-1 small interfering RNA-transfected HEKn. CONCLUSIONS: Ag-NP treatment induces upregulation of psoriasin expression through Egr-1 expression. We suggest that the ERK and p38 pathways are involved in Egr-1 dependent psoriasin expression. PMID- 30251409 TI - Can Polymer Solar Cells Open the Path to Sustainable and Efficient Photovoltaic Windows Fabrication? AB - Sunlight is among the most abundant energy sources available on our planet. Finding adequate solutions to properly and efficiently harvest it is of major importance to potentially solve the global energy crisis. Polymer solar cells have been introduced in the late 20th century as low-cost and easily processed alternative to the state-of-the-art silicon photovoltaics. Their power conversion efficiencies, which were initially rather low, are constantly improving and now reach values close to 15 %. As their optical properties can be easily tuned, designing active layer which absorb homogeneously throughout the visible spectrum is relatively simple. These peculiar characteristics enable the possibility to fabricate visibly transparent solar cells with high color rendering indices which can be employed as photovoltaic windows. After reviewing some of the most successful examples of polymer solar cell-based transparent photovoltaic window fabrication, I will discuss the possibility to produce these devices in a sustainable and/or eco-friendly manner while maintaining their performances. PMID- 30251410 TI - Delayed ventricular pacing failure and correlations between pacing thresholds, left ventricular ejection fraction, and QTc values in a male with Takotsubo cardiomyopathy. AB - BACKGROUND: Transient pacing failure caused by transient increased pacing threshold has been reported in patients with transient left ventricular apical dysfunction (Takotsubo cardiomyopathy [TC]). Normal pacing thresholds usually recover after normalization of systolic dysfunction. HYPOTHESIS: Pacing failure correlates with clinics of TC. METHODS: We report the case of a 76-year-old man with a dual chamber pacemaker, admitted for acute chest pain and dyspnea and final diagnosis of TC. One month after index admission, the patient came back complaining again of chest pain. Unexpectedly, admission electrocardiogram showed ventricular pacing failure and an increased pacing threshold. In the following weeks, pacing threshold gradually recovered with left ventricular ejection fraction and QTc values. RESULTS: Ventricular pacing threshold correlated directly to QTc values and inversely to left ventricular ejection fraction over time (P < 0.05). CONCLUSIONS: This is one of the first cases of delayed transient ventricular pacing failure in a male patient with transient left ventricular apical ballooning, in the presence of spared right ventricular function. Given the possibility of acute transient anomalies in myocardial impedance and pacing failure even in the subacute phase of TC several weeks after clinical onset of transient systolic dysfunction, pacing threshold should be carefully monitored in subjects with TC, both during the acute phase of the disease and in first months of follow-up after discharge. Ventricular pacing threshold correlated directly to QTc values and inversely to left ventricular ejection fraction over time. PMID- 30251411 TI - Cell-Based Therapies: The Nonresponder. AB - Cell-based therapies have come of age and several phase III trials are now being conducted. Cell-based therapies, especially involving mesenchymal stem cells (MSCs), have substantial nonresponder rates, as has been reported in some current clinical trials. This high rate is expected as the MSCs are neither tuned for each of the diseases that are being treated nor for the huge variance in the genetics and response characteristics of the individual patients being treated. Such nonresponders might be used as a control group, thus eliminating the need for placebo controls. Stem Cells Translational Medicine 2018;7:762-766. PMID- 30251412 TI - Native and exotic seed dispersal by the stone marten (Martes foina Erxleben, 1777): implications for the regeneration of a relict climactic forest in central Portugal. AB - The stone marten (Martes foina, Erxleben, 1777) is a carnivorous mammal that often consumes fleshy fruits, thus potentially promoting seed dispersion. This study was developed in Bussaco National Forest, central Portugal, and aimed to assess the potential role of the stone marten in dispersing native and exotic plants in different forest landscapes types. Seeds from stone marten scats and fleshy fruits were collected monthly and were thereafter identified and sowed in a nursery, following a randomized experimental setup. Plant emergence was monitored fortnightly. Generalized Linear Models were used to test for differences in time and success of emergence between seeds from scats and fruits of three native species (Rubus ulmifolius, Arbutus unedo, Celtis australis) and one exotic plant species with invasive behaviour (Prunus laurocerasus). Fruit consumption by the stone marten significantly increased and accelerated the germination of the native R. ulmifolius but had no effect on the other two native species or on the invasive species. This suggested that stone martens contribute to gene flow and forest regeneration, by dispersing native plant seeds. However, though the germination was not enhanced in the invasive species, the preference of stone marten for these fruits may potentially contribute to the proliferation of P. laurocerasus. Our study represents a contribution to better understanding the fauna and flora interactions, enabling for a more conscious and effective decision-making in forest management. This article is protected by copyright. All rights reserved. PMID- 30251413 TI - Iron-sulfur cluster carrier proteins involved in the assembly of Escherichia coli NADH:ubiquinone oxidoreductase (complex I). AB - The NADH:ubiquinone oxidoreductase (respiratory complex I) is the main entry point for electrons into the Escherichia coli aerobic respiratory chain. With its sophisticated setup of 13 different subunits and 10 cofactors, it is anticipated that various chaperones are needed for its proper maturation. However, very little is known about the assembly of E. coli complex I, especially concerning the incorporation of the iron-sulfur clusters. To identify iron-sulfur cluster carrier proteins possibly involved in the process, we generated knockout strains of NfuA, BolA, YajL, Mrp, GrxD and IbaG that have been reported either to be involved in the maturation of mitochondrial complex I or to exert influence on the clusters of bacterial complex. We determined the NADH and succinate oxidase activities of membranes from the mutant strains to monitor the specificity of the individual mutations for complex I. The deletion of NfuA, BolA and Mrp led to a decreased stability and partially disturbed assembly of the complex as determined by sucrose gradient centrifugation and native PAGE. EPR spectroscopy of cytoplasmic membranes revealed that the BolA deletion results in the loss of the binuclear Fe/S cluster N1b. PMID- 30251414 TI - The use of human pluripotent stem cells for modelling liver development and disease. AB - The use of pluripotent stem cells has transformed the investigation of liver development and disease. Clinical observations and animal models have provided the foundations of our understanding in these fields. While animal models remain essential research tools, long experimental lead times and low throughput limits the scope of investigations. The ability of pluripotent stem cells to produce large numbers of human hepatocyte-like cells, with a given or modified genetic background, allows investigators to use previously incompatible experimental techniques, such as high-throughput screens, to enhance our understanding of liver development and disease. In this review, we explore how pluripotent stem cells have expedited our understanding of developmental mechanisms and been used to identify new therapeutic options for numerous hepatic diseases. We discuss the future directions of the field, including how to further unlock the potential of the pluripotent stem cell model to make it amenable for use with a broader range of assays and a greater repertoire of diseases. Furthermore, we evaluate the current weaknesses of the pluripotent stem cell model and the directions open to researchers to address these limitations. Conclusion The use of pluripotent stem cells to model human liver disease and development has and will continue to have substantial impact, which is likely to further expand as protocols used to generate hepatic cells are improved. This article is protected by copyright. All rights reserved. PMID- 30251415 TI - Increased risk of severe course of pemphigus in patients with pemphigus associated alopecia: a prospective observational study. AB - BACKGROUND: Pemphigus-associated alopecia is considered rare, and has not been studied in detail. AIM: To evaluate the clinical and immunological characteristics of patients with pemphigus-associated alopecia. METHODS: This prospective observational study included 80 consecutive patients with histopathologically and immunopathologically confirmed pemphigus, of whom 11 (13.8%) were found to have pemphigus-associated alopecia. Alopecia was observed in 11/52 patients with pemphigus and scalp involvement: [0/28 (35.7%) with pemphigus vulgaris and 1/24 (4.2%) with pemphigus foliaceus. The clinical and immunological characteristics of these patients were analysed. RESULTS: Patients with pemphigus-associated alopecia had a significantly higher Pemphigus Disease Area Index total activity score compared with patients who had no pemphigus associated alopecia (21.8 +/- 18.6 and 11.0 +/- 20.5, respectively; P = 0.02). Mean serum anti-desmoglein (Dsg)1 antibody concentration was 141.8 +/- 66.9 U/mL and 60.0 +/- 52.6 U/mL, respectively (P = 0.03), and mean serum anti-Dsg3 concentration was 126.6 +/- 36.7 U/mL and 67.4 +/- 52.5 U/mL, respectively (P = 0.03). The values for achieving serological remission were 10% and 70%, respectively (P = 0.02). CONCLUSIONS: Pemphigus-associated alopecia is a marker of severe disease and a treatment-resistant disease course. PMID- 30251417 TI - Decursin inhibits the growth of HepG2 hepatocellular carcinoma cells via Hippo/YAP signaling pathway. AB - Targeted therapy has a pivotal role for the treatment of liver cancer. The aim of this current study was to examine the effects of decursin on the growth of HepG2 cells and the underlying mechanisms. Our present study showed that treatment of HepG2 cells with decursin significantly inhibited the growth of HepG2 cells by suppressing cell proliferation, cell cycle arresting, and promoting apoptosis in a dose- and time-dependent manner. Most significantly, administration of decursin dramatically impeded in vivo tumor growth in nude mice. Mechanically, it is noteworthy that decursin treatment provoked degradation of YAP by upregulating the expression of phosphorylated LATS1 and betaTRCP. Moreover, apoptosis caused by decursin could be reversed by a selective MST1/2 inhibitor, XMU-MP-1, suggesting that decursin may function through Hippo/YAP signaling. This study has identified that decursin is a potential agent for HCC therapy, and further research should be undertaken to facilitate its therapeutic application. PMID- 30251416 TI - Lymphocytes are a major source of circulating soluble dipeptidyl peptidase 4. AB - Dipeptidyl peptidase 4 (DPP4, CD26) is a serine protease that is expressed constitutively by many haematopoietic and non-haematopoietic tissues. It exists as a membrane-associated protein, as well as in an active, soluble form (herein called sDPP4), present at high concentrations in bodily fluids. Despite the proposed use of sDPP4 as a biomarker for multiple diseases, its cellular sources are not well defined. Here, we report that individuals with congenital lymphocyte immunodeficiency had markedly lower serum concentrations of sDPP4, which were restored upon successful treatment and restoration of lymphocyte haematopoiesis. Using irradiated lymphopenic mice and wild-type to Dpp4-/- reciprocal bone marrow chimeric animals, we found that haematopoietic cells were a major source of circulating sDPP4. Furthermore, activation of human and mouse T lymphocytes resulted in increased sDPP4, providing a mechanistic link between immune system activation and sDPP4 concentration. Finally, we observed that acute viral infection induced a transient increase in sDPP4, which correlated with the expansion of antigen-specific CD8+ T cell responses. Our study demonstrates that sDPP4 concentrations are determined by the frequency and activation state of lymphocyte populations. Insights from these studies will support the use of sDPP4 concentration as a biomarker for inflammatory and infectious diseases. PMID- 30251419 TI - Remembering Uwe Reinhardt. PMID- 30251418 TI - Pelvic abscess: A late complication of abdominal trachelectomy for cervical cancer. AB - AIM: Only a few reports of pelvic abscess as a late complication of trachelectomy have been published to date. To evaluate the cases of pelvic abscess as a late complication of abdominal trachelectomy for cervical cancer. METHODS: In June 2005, we began a clinical trial of abdominal trachelectomy at our institution. Written informed consent was obtained from all patients. We retrospectively reviewed the medical records of patients who underwent trachelectomy and extracted the data of patients who experienced pelvic abscess as a late complication. RESULTS: From June 2005 to September 2017, we performed 181 trachelectomies at our institution. In total, 15 pelvic abscesses occurred in 12 of these patients more than 1 month after trachelectomy. The median postoperative period before the onset of pelvic abscess was 51 months (range, 1-104 months). Among the 15 cases, abscess formed in the uterine adnexa in 12, in a pelvic lymphocyst in two, and in the uterus in one. Abscess drainage was performed in six cases. Three patients underwent laparotomy with salpingo-oophorectomy. CONCLUSION: It is possible that not only surgical removal of the uterine cervix but also the use of nonabsorbable suture in cervical cerclage and placement of an intrauterine device triggered post-trachelectomy infection. Pelvic abscess can occur as a late complication of abdominal trachelectomy. PMID- 30251420 TI - Recognition of lettuce downy mildew effector BLR38 in Lactuca serriola LS102 requires two unlinked loci. AB - Plant-pathogenic oomycetes secrete effector proteins to suppress host immune responses. Resistance proteins may recognize effectors and activate immunity, which is often associated with a hypersensitive response (HR). Transient expression of effectors in plant germplasm and screening for HR has proven to be a powerful tool in the identification of new resistance genes. In this study, 14 effectors from the lettuce downy mildew Bremia lactucae race Bl:24 were screened for HR induction in over 150 lettuce accessions. Three effectors-BLN06, BLR38 and BLR40-were recognized in specific lettuce lines. The recognition of effector BLR38 in Lactuca serriola LS102 did not co-segregate with resistance against race Bl:24, but was linked to resistance against multiple other B. lactucae races. Two unlinked loci are both required for effector recognition and are located near known major resistance clusters. Gene dosage affects the intensity of the BLR38 triggered HR, but is of minor importance for disease resistance. PMID- 30251421 TI - Abstracts of Annual Congress 2018, 26-28 September 2018, Dublin, Ireland. PMID- 30251423 TI - 'Til Death Do Us Part: End-of-Life Experiences of Married Couples in a Nationally Representative Survey. AB - OBJECTIVES: To determine whether end-of-life (EOL) experiences in the first spouse in a marriage are associated with EOL experiences in the other spouse. DESIGN: Nationally representative, longitudinal survey. SETTING: Health and Retirement Study, Waves 1992-2012 linked to Medicare claims PARTICIPANTS: Community-dwelling older adults who died (N=4,558), representing 2,279 married heterosexual couples. MEASUREMENTS: We examined 3 EOL experiences: enrollment in hospice for >3 days before death, lack of advance care planning (ACP) before death, and intensive care unit (ICU) use during the last 30 days of life. We used multiple logistic regression to determine whether the EOL experience of the first spouse was a significant predictor of the EOL experience of the second spouse after adjusting for demographic characteristics, socioeconomic status, health status, and time between the first and second spouses' deaths. RESULTS: First spouses who died were on average 80 years old, and 62% were male; second spouses were on average 85 years old, and 62% were female. After adjustment, second spouses were more likely to use hospice if the first spouse used hospice (odds ratio (OR)=1.68, 95% confidence interval (CI)=1.29-2.20). Second spouses were less likely to have ACP when the first spouse did not have ACP (OR=2.91, 95% CI=2.02-4.21). Hospice and ACP associations were stronger when deaths were closer in time to one another (p-value for interaction < .05). Second spouses were more likely to use ICU services if the first spouse did (OR=1.80, 95% CI=1.27-2.55). CONCLUSIONS: The EOL experiences of older spouses are strongly associated, which may be relevant when framing ACP discussions. PMID- 30251424 TI - Risk of hospitalisation and death related to baclofen for alcohol use disorders: Comparison with nalmefene, acamprosate, and naltrexone in a cohort study of 165 334 patients between 2009 and 2015 in France. AB - PURPOSE: Baclofen is widely used off-label for alcohol use disorders (AUD) in France, despite its uncertain efficacy and safety, particularly at high doses. This study was designed to evaluate the safety of this off-label use compared to the main approved drugs for AUD (acamprosate, naltrexone, nalmefene). METHODS: This cohort study from the French Health Insurance claims database included patients, aged 18 to 70 years, with no serious comorbidity (assessed by the Charlson score) initiating baclofen or approved drugs for AUD between 2009 and 2015. The risk of hospitalisation or death associated with baclofen, at variable doses over time (from low doses <30 mg/day to high doses >=180 mg/day), compared to approved drugs, was evaluated by a Cox model adjusted to sociodemographic and medical characteristics. RESULTS: The cohort included 165 334 patients, 47 614 of whom were exposed to baclofen. Patients exposed to baclofen differed from those treated with approved drugs in terms of sociodemographic and medical characteristics (more females, higher socioeconomic status, fewer hospitalisations for alcohol-related problems), but these differences tended to fade at higher doses of baclofen. Baclofen exposure was significantly associated with hospitalisation (hazard ratio [HR] = 1.13 [95%CI: 1.09-1.17]) and death (HR = 1.31 [95%CI: 1.08-1.60]). The risk increased with dose, reaching 1.46 [1.28 1.65] for hospitalisation and 2.27 [1.27-4.07] for death at high doses. Similar results were in patients with a history of hospitalisation for alcohol-related problems. CONCLUSIONS: This study raises concerns about the safety of baclofen for AUD, particularly at high doses, with higher risks of hospitalisation and mortality than approved drugs. PMID- 30251425 TI - Associations between hypospadias, cryptorchidism and anogenital distance: Systematic review and meta-analysis. AB - Hypospadias and cryptorchidism are potential manifestations of testicular dysgenesis syndrome (TDS) at birth. Anogenital distance (AGD) has been presumed as an indicator related to endocrine disruptors proposed as one of the pathogenetic mechanisms underlying male reproductive disorders. In humans, recent studies have correlated AGD in boys to testicular anomalies. However, the associations between hypospadias, cryptorchidism and AGD remain inconsistent and have not been combined. Hence, we conducted a meta-analysis to assess gradations in the severity of the endocrine disruption in cryptorchidism or hypospadias by using AGD. A total of 2,119 boys from five birth cohort studies and two cross sectional studies were subjected to meta-analysis. Random-effect model was used to calculate the standardised mean difference (SMD) of AGD. Our results reveal that boys with hypospadias or cryptorchidism have shorter AGD ([SMD, -2.63; 95% CI, -4.65 to -0.62] and [SMD, -0.69; 95% CI, -1.36 to -0.02]) respectively. There was no indication of a publication bias either from the result of Egger's test or Begg's test for hypospadias and cryptorchidism. PMID- 30251426 TI - Predictors of positive electrophysiological study in patients with syncope and bundle branch block: PR interval and type of conduction disturbance. AB - BACKGROUND: Electrophysiological study (EPS) is indicated in patients with syncope and bundle branch block (BBB). Data about predictors of positive EPS in these patients is scarce. OBJECTIVE: To assess clinical and electrocardiographic (ECG) predictors of positive EPS in patients with syncope and BBB. METHODS: Observational single-center study that included all consecutive patients with syncope and BBB that underwent EPS from January 2011 to June 2017. Results of EPS were considered positive according to current ESC syncope guidelines. RESULTS: During study period, 271 patients were included (64.9% male, age: 73.9 +/- 12.2 years, number of syncopal episodes: 2.4 +/- 2.5, LVEF: 56.1 +/- 9.9%). Type of BBB: RBBB + LAFB/LPFB in 39.8%, isolated LBBB in 38.7% and isolated RBBB in 18.5% of the patients. Duration of QRS and PR interval were 141.9 +/- 16.7 and 182.8 +/ 52.2 milliseconds. EPS was positive in 41.7% of the patients. In multivariate analysis, conduction disturbance pattern and long PR interval (OR 8.6; 2.9-25; P < 0.0001) were predictors of positive EPS. Conduction disturbance patterns related with positive EPS were: BBB different than isolated RBBB (OR 15.2; 2.2 23.4; P = 0.005), LBBB or RBBB+long PR + left fascicular block (OR 4.5; 1.06 20.01; P < 0.042), and RBBB+left fascicular block compared with LBBB (OR 4.8; 1.2 16.7; P = 0.025). Clinical factors and syncope characteristics were not related with EPS result. CONCLUSIONS: Diagnostic yield of EPS in patients with syncope and BBB is moderate (41%). Type of conduction disturbance pattern and PR interval are associated with the electrophysiological (EP) test result. Patients with LBBB or bifascicular block have the highest rate of positive EP test. Long PR interval increases the proportion of positive EPS in all conduction disturbance patterns. PMID- 30251427 TI - Letter to 'Practical use of C1 esterase inhibitor concentrate for clinical amniotic fluid embolism'. PMID- 30251428 TI - Patients with multiple morphological abnormalities of the sperm flagella harbouring CFAP44 or CFAP43 mutations have a good pregnancy outcome following intracytoplasmic sperm injection. AB - Multiple morphological abnormalities of the sperm flagella (MMAF) are a rare type of male infertility. Mutations in DNAH1, CFAP43 and CFAP44 are the main aetiology of the disorder. Previously, good intracytoplasmic sperm injection (ICSI) outcomes were reported for MMAF patients with DNAH1 mutations. However, the ICSI prognosis for MMAF patients with CFAP43 or CFAP44 mutations was not known. We designed a retrospective cohort study. Molecular genetic testing identified six MMAF patients with biallelic CFAP44 (CFAP44+ group) or CFAP43 mutations and 12 patients with homozygous or compound heterozygous DNAH1 mutations (DNAH1+ group). A control group consisted of age-matched, non-MMAF men. For MMAF patients carrying CFAP44 mutations, the recorded rates of fertilisation, transferable embryos, pregnancy and delivery after ICSI were 76.47%, 88.46%, 50.0% and 50.0% respectively. The fertilisation rate was significantly higher in the CFAP44+ group than in the DNAH1+ group (76.47% vs. 54.5%, p = 0.0196). There were no statistically significant differences in the rates of transferable embryos, implantation, clinical pregnancy and miscarriage between the CFAP44+ group and either the DNAH1+ group or the age-matched control group. Our results support a good ICSI prognosis for MMAF patients carrying CFAP44 or CFAP43 mutations. PMID- 30251429 TI - Taurine is Involved in Energy Metabolism in Muscles, Adipose Tissue, and the Liver. AB - Energy metabolism is a basic and general process, by which the body acquires and uses energy to maintain normal function, and taurine plays a vital role in energy metabolism. Taurine deficiency may cause a weak energy metabolism and energy metabolism dysfunction. Taurine biosynthetic ability is limited, and its supplementation in the diet can strengthen energy metabolism in muscle performance, cardiac function, liver activity, and adipose tissue. Combining taurine with other drugs may have a superior effect in energy metabolism. In many metabolic disorders, taurine, or the combination of taurine with other drugs, also functions as a repair treatment for damaged tissues, and acts as a promoter for the balance of energy metabolism. The present study discusses the potential roles of taurine in energy metabolism. PMID- 30251430 TI - Potential P-glycoprotein-mediated herb-drug interaction of phyllanthin at the intestinal absorptive barrier. AB - OBJECTIVES: This study investigated the absorptive potential of phyllanthin across the polarized Caco-2 monolayers and the potential role of phyllanthin in P glycoprotein (P-gp)-mediated drug interaction. METHODS: The absorptive potential of phyllanthin was predicted from its apparent permeability (Papp ) across the Caco-2 monolayers under the pH gradient condition (pH 6.5AP -7.4BL ) at 37 degrees C. Integrity of paracellular transport was assessed by monitoring transepithelial electrical resistance (TEER) and lucifer yellow (LY) leakage. P gp-mediated interaction was evaluated by transport studies of phyllanthin and rhodamine-123. KEY FINDINGS: The absorptive Papp of phyllanthin (34.90 +/- 1.18 * 10-6 cm/s) was in the same rank order as the high permeable theophylline and antipyrine. Phyllanthin transport in the absorptive and secretive directions was comparable (the efflux ratio (ER) of 1.19 +/- 0.01). Phyllanthin caused no changes in TEER nor LY leakage in the monolayers. However, phyllanthin increased rhodamine-123 ER in a concentration-dependent manner, suggesting its inhibition on P-gp function. In addition, phyllanthin aqueous solubility was <5 MUg/ml at 37 degrees C. CONCLUSIONS: Phyllanthin is a highly permeable compound that could passively diffuse through the absorptive barrier via transcellular pathway with little hindrance from P-gp. Phyllanthin could interfere with transport of P-gp drug substrates, when concomitantly administered. In addition, aqueous solubility could be a limiting factor in phyllanthin absorption. PMID- 30251431 TI - Health-related quality of life following surgical attenuation of congenital portosystemic shunts versus healthy controls. AB - OBJECTIVES: To design a health-related quality of life questionnaire for dogs with congenital portosystemic shunts, use it in a cohort of dogs treated with suture attenuation and compare results with those obtained from a healthy control cohort. MATERIALS AND METHODS: Data were collected from the hospital records of dogs treated with suture ligation of an intrahepatic or extrahepatic congenital portosystemic shunt at two referral centres. Owners were asked to complete a questionnaire assessing their dog's health-related quality of life preoperatively (retrospectively) and at the time of follow-up. Owners of control dogs also completed the questionnaire. RESULTS: One hundred and twenty-eight dogs with congenital portosystemic shunts and 131 control dogs were recruited. Median follow-up time was 64 months (range 19.7 to 157.2). The median long-term health related quality of life score was excellent for both intrahepatic and extrahepatic shunt cases and similar to that of control dogs. The long-term portosystemic shunt clinical sign scores for both intrahepatic and extrahepatic congenital portosystemic shunt dogs were significantly worse than the those of the control group. CLINICAL SIGNIFICANCE: Suture attenuation of congenitial portosystemic shunts is associated with an excellent health-related quality of life score at long-term follow-up. PMID- 30251432 TI - Comparison of the tube test and column agglutination techniques for anti-A/-B antibody titration in healthy individuals. AB - BACKGROUND AND OBJECTIVES: Determination of the anti-A/-B titre pre- and post transplantation is beneficial for treatment selection. Currently, the recommended method for antibody titration is the tube test (TT) assay. Dithiothreitol (DTT) is used for IgM antibody inactivation. Recently, a fully automated antibody titration assay using the column agglutination technique (CAT) was developed (auto-CAT). Our aim was to compare the auto-CAT and TT techniques for ABO antibody titration, to evaluate the effectiveness of DTT-treated plasma for use with auto-CAT and to define the cut-off value for antibody titration by auto-CAT. MATERIALS AND METHODS: We enrolled 30 healthy individuals, including 10 each for blood types A, B and O. We performed antibody titre measurement using the TT technique and auto-CAT simultaneously. Auto-CAT uses the bead column agglutination technology. RESULTS: With the auto-CAT cut-off value set to weak (w)+ with DTT treatment plasma, the concordance rate was 45%, and the weighted kappa value between TT and auto-CAT results was 0.994 in all subjects. Furthermore, there was a significant positive correlation between the anti-A/-B titre results obtained using the TT technique and auto-CAT in all blood types. Moreover, a positive bias (falsely elevated end-points due to agglomeration of A/B cells) was not observed in auto-CAT testing using DTT-treated plasma. CONCLUSION: Our results show that 1+ agglutination using the TT technique is equivalent to w+ agglutination obtained using auto-CAT. We recommend that DTT may be used with auto-CAT to measure antibody titres. Thus, we suggest that auto-CAT is useful for antibody titration in routine examination. PMID- 30251433 TI - Causes and consequences of ontogenetic dietary shifts: a global synthesis using fish models. AB - Ontogenetic dietary shifts (ODSs), the changes in diet utilisation occurring over the life span of an individual consumer, are widespread in the animal kingdom. Understanding ODSs provides fundamental insights into the biological and ecological processes that function at the individual, population and community levels, and is critical for the development and testing of hypotheses around key concepts in trophic theory on model organisms. Here, we synthesise historic and contemporary research on ODSs in fishes, and identify where further research is required. Numerous biotic and abiotic factors can directly or indirectly influence ODSs, but the most influential of these may vary spatially, temporally and interspecifically. Within the constraints imposed by prey availability, we identified competition and predation risk as the major drivers of ODSs in fishes. These drivers do not directly affect the trophic ontogeny of fishes, but may have an indirect effect on diet trajectories through ontogenetic changes in habitat use and concomitant changes in prey availability. The synthesis provides compelling evidence that ODSs can have profound ecological consequences for fish by, for example, enhancing individual growth and lifetime reproductive output or reducing the risk of mortality. ODSs may also influence food-web dynamics and facilitate the coexistence of sympatric species through resource partitioning, but we currently lack a holistic understanding of the consequences of ODSs for population, community and ecosystem processes and functioning. Studies attempting to address these knowledge gaps have largely focused on theoretical approaches, but empirical research under natural conditions, including phylogenetic and evolutionary considerations, is required to test the concepts. Research focusing on inter-individual variation in ontogenetic trajectories has also been limited, with the complex relationships between individual behaviour and environmental heterogeneity representing a particularly promising area for future research. PMID- 30251434 TI - Repair of a pseudoaneurysm compressing the right coronary artery in a patient with Takayasu's arteritis. PMID- 30251435 TI - Sonographically Guided Office Endometrial Sampling: Indications and Results. AB - OBJECTIVES: The purpose of this study was to identify clinical indications in which endometrial sampling was performed under transabdominal ultrasound (US) guidance and to evaluate the outcomes of this approach in an academic practice. METHODS: We retrieved data from the electronic medical record for all patients referred to the gynecologic US unit for transabdominal US-guided endometrial sampling from January 2011 to June 2017. Data retrieved included age, parity, previous cesarean delivery or pelvic surgery, indication for endometrial biopsy, US abnormalities, clinical reasoning for US-guided sampling, and pathologic reports. RESULTS: A total of 113 patients were referred for US-guided sampling between January 2011 and June 2017. We identified the following reasons for US guided biopsy referral: failed blind biopsy attempt, fibroids, uterine position or anomaly, need for targeted sampling, cervical stenosis, and other indications. Ninety-five of the 113 patients (84%) underwent successful US-guided endometrial sampling. Forty of the 113 patients were referred after a failed blind biopsy, with 83% subsequently undergoing successful US-guided endometrial sampling. Of the 30 patients referred for fibroids, 29 (97%) underwent successful US-guided sampling. High success rates were also noted for transabdominal US guidance referrals for the uterine position or anomaly (86%) and the need for targeted sampling (83%). CONCLUSIONS: Our results suggest that endometrial sampling performed under US guidance could be considered for patients with a failed blind approach, fibroids, uterine anomalies, and interest in targeted sampling. In such cases, US-guided sampling could be considered before surgical options. PMID- 30251436 TI - Medial and Lateral Patellofemoral Joint Retinaculum Thickness in People With Patellofemoral Pain: A Case-Control Study. AB - OBJECTIVES: To measure the medial and lateral retinaculum thickness in individuals with and without patellofemoral pain using ultrasound and to assess associations with the symptom duration and function. METHODS: Medial and lateral patellofemoral joint retinaculum thicknesses of 32 knees (16 with patellofemoral pain and 16 asymptomatic) were measured with B-mode ultrasound at 0.5, 1, and 1.5 cm from the patella border. Participants with patellofemoral pain completed a Kujala questionnaire, and both groups underwent a single-leg squat performance assessment. Two-way analyses of variance (site * group) determined the overall effect, and Cohen d values were calculated to describe the magnitude of the difference for each measurement. RESULTS: The groups were matched for age, height, and weight. Compared to controls, participants with patellofemoral pain had thicker lateral (overall effect, P = .03) and medial (overall effect, P < 0.01) retinacula. No correlations between retinaculum thickness and Kujala scores (lateral retinaculum, r = 0.106 [0.5 cm], -0.093 [1 cm], and -0.207 [1.5 cm]; and medial retinaculum, r = 0.059, 0.109, and -0.219), symptom duration (lateral retinaculum, r = 0.001, -0.041, and 0.302; and medial retinaculum, r = -0.027, 0.358, and -0.346), or single-leg squat performance scores (lateral retinaculum, r = 0.051, 0.114, and 0.046; and medial retinaculum, r = -0.119, -0.292, and 0.011) were observed. CONCLUSIONS: Increased lateral and medial retinaculum thickness in individuals with patellofemoral pain compared to controls identifies structural changes that may be associated with the pathogenesis of patellofemoral pain. The absence of a significant correlation between retinaculum thickness and the symptom duration or function further shows a lack of an association between structure and function in individuals with patellofemoral pain. PMID- 30251437 TI - Three-dimensional printing assisted transcatheter closure of atrial septal defect with deficient posterior-inferior rim. AB - OBJECTIVE: Though successful transcatheter closure has been reported in secundum atrial septal defect (ASD) with deficient posterior-inferior rim, it is still difficult to screen the appropriate candidates. Three-dimensional printing (3DP) makes in vitro trial occlusion possible, and might provide a feasible method in the prediction of successful closure. METHODS: Thirty-five consecutive ASD patients (10M/25F, age, 47.7 +/- 11.8 years) with deficient posterior-inferior rim (<=3 mm) were referred for attempted transcatheter closure, and personalized heart model (elastic rubber) was produced based on end-systolic MSCT images. The in vitro measurement and trial occlusion were performed for preoperative evaluation (in vitro successful/unsuccessful group), and the results were compared with postoperative outcomes. RESULTS: Successful in vitro occlusion was achieved in 30 patients (7M/23F), and the size of ASD was 27.1 +/- 4.4 mm. The posterior-inferior rim was 0.95 +/- 1.22 mm (rim defect in 17 patients), and 12 patients were associated with aortic rim deficiency. The subsequent transcatheter closure was performed successfully in 29 patients, and the occluder-diameter was identical to that of in vitro occlusion (35.0 +/- 4.4 mm). The follow-up (1.4 +/- 0.58 years) showed no residual shunt and related-complications. In unsuccessful in vitro group (n = 5), the range of rim deficiency was wider (P = 0.019) and the rim to inferior vena cava was shorter (4.60 +/- 2.07 mm vs. 10.71 +/- 5.28 mm, P = 0.016). Furthermore, transcatheter closure failed in all patients. CONCLUSIONS: In ASD with deficient posterior-inferior rim, 3DP allows accurate determination of the size and surrounding rims of ASD. Based on personalized heart model, in vitro trial occlusion is an effective method to identify the appropriate candidates for transcatheter closure. PMID- 30251438 TI - Course of transforming growth factor beta1 in the systemic and cavernous blood of healthy males through different penile conditions. AB - Studies on erectile dysfunction (ED) have revealed a relationship between smooth muscle atrophy and the accumulation of collagen in the corpus cavernosum (CC). Transforming growth factor beta1 (TGF beta1) is a cytokine which has been proposed to be involved in the fibrotic process in the CC. We aimed to evaluate the course of TGF beta1 in the systemic and cavernous blood of 17 healthy males through different phases of the sexual arousal response (exemplified by the penile conditions flaccidity, tumescence, rigidity and detumescence). An enzyme linked immunoassay was used to measure the concentration of TGF beta1 (ng/ml) in both the systemic and cavernous blood at the stages of flaccidity, tumescence and detumescence. TGF levels were significantly higher in the cavernous compartment than in the systemic blood. A linear decrease was evident in the cavernous blood when the flaccid penis became tumescent (24.3 +/- 14.5 to 13.9 +/- 6.5) and rigid (to 8.7 +/- 3.1). At detumescence, TGF increased to 18.3 +/- 10.4. In contrast, the levels in the systemic circulation remained unchanged. The results are in support of the hypothesis that the concentration of TGF beta1 in the CC is regulated by adequate blood flow and oxygenation. PMID- 30251439 TI - Validation of a diagnostic tool for the diagnosis of lumpy skin disease. AB - BACKGROUND: Lumpy skin disease (LSD) is caused by LSD virus which is a member of the Capripoxvirus (CaPV) genus. Although PCR provides for a rapid and sensitive diagnosis, it has limited use due to its complexity in terms of cost, time and equipment. Loop-mediated isothermal amplification (LAMP) is a simple, specific and cost-effective method with a diagnostic accuracy similar to PCR. OBJECTIVES/HYPOTHESIS: To compare the detection rate (DR) of two LAMP assays versus PCR for the detection of CaPV. ANIMALS: This study used 105 apparently health animals (AHA) and 59 clinically sick animals (CSA). METHODS AND MATERIALS: PCR and LAMP assays (LAMP1 and LAMP 2) were compared for detection of CaPV from AHA and CSA using blood and tissue samples. The detection was confirmed by sequencing of PCR positive samples. Analytical sensitivity and specificity of LAMP assays also were assessed. RESULTS: The DR in CSA was 13.6% for PCR whereas for LAMP it was 39.0% and 25.4% for LAMP 1 and 2 methods, respectively. In AHA, the LAMP assay DR was 14.3% and 1.9% for LAMP 1 and 2, respectively. Phylogenetic tree analysis confirmed the identity of CaPV. Analytic sensitivity showed a detection limit of 8 copies/MUL. The analytic specificity test showed no cross detection with other infectious agents. CONCLUSION AND CLINICAL IMPORTANCE: Good sensitivity and specificity results for LAMP assay support its application in the routine diagnosis of LSD, whereas its ability to detect LSDV in apparently healthy animals shows its usefulness in identifying populations at risk of LSD. PMID- 30251440 TI - Design Rules for Template-Confined DNA-Mediated Nanoparticle Assembly. AB - Template-based strategies are becoming increasingly important for controlling the position of nanoparticle-based (NP-based) structures on surfaces for a wide variety of encoding and device fabrication strategies. Thus, there is an increasing need to understand the behavior of NPs in confined spaces. Herein, a systematic investigation of the diffusion and adsorption properties of DNA modified NPs is presented in lithographically defined, high-aspect-ratio pores using a template-confined, DNA-mediated assembly. Leveraging the sequence specific binding affinity of DNA, it is discovered that although NP adsorption in deep polymer pores follows a traditional Langmuir adsorption model when under thermodynamic control, such NPs kinetically follow Fick's classical law of diffusion. Importantly, these observations allow one to establish design rules for template-confined, DNA-mediated NP assembly on substrates based on pore dimensions, NP size and shape, NP concentration, temperature, and time. As a proof-of-concept example, these design rules are used to engineer a vertical, four-layer assembly consisting of individual octahedral NPs stacked on top of one another, with in-plane positioning defined by pores generated by e-beam lithography. PMID- 30251441 TI - Ruthenium(IV) Intermediates in C-H Activation/Annulation by Weak O-Coordination. AB - Ruthenium(IV) complexes were identified as key intermediates of C-H/O-H activations by weak O-coordination. Thus, the annulations of sulfoxonium ylides by benzoic acids provided expedient access to diversely-decorated isocoumarins with ample scope. Detailed experimental and computational studies provided strong support for a facile BIES-C-H activation, along with cyclometalated ruthenium(IV) intermediates within a versatile ruthenium(II/IV) catalysis regime (BIES=base assisted internal electrophilic substitution). PMID- 30251442 TI - Novel association of Psychrobacter and Pseudomonas with malodour in bloodhound dogs, and the effects of a topical product composed of essential oils and plant derived essential fatty acids in a randomized, blinded, placebo-controlled study. AB - BACKGROUND: The pathogenesis and treatment of cutaneous malodour in dogs have not been investigated previously. Staphylococcus and Corynebacterium spp. are associated with human axillary malodour. HYPOTHESIS: Staphylococcus and Corynebacterium spp. are associated with cutaneous malodour in dogs, and treatment with a topical essential oil-based product will improve malodour and reduce the abundance of odour-causing bacteria. ANIMALS: Twenty seven bloodhound dogs from a south Texas boarding facility were enrolled in this study. METHODS AND MATERIALS: Skin swabs were taken from the axilla and dorsum of 27 dogs at initiation of the study. Mean malodour scores were used to assign dogs to control or malodour groups. The malodourous dogs were randomly assigned to a treatment or placebo group, received four weekly topical applications of the spot-on or placebo, and samples were recollected. Next-generation sequencing (NGS) and real time quantitative PCR (qPCR) were performed on all swabs. RESULTS: Psychrobacter and Pseudomonas spp. were significantly more abundant (P < 0.001, P = 0.006; respectively), and overall bacterial diversity was reduced (P = 0.0384) on the skin of malodourous dogs. Staphylococcus and Corynebacterium spp. were not associated with malodour. The topical essential oil-based product significantly (P = 0.0078) improved malodour in the treatment group and shifted their bacterial community structure. CONCLUSIONS AND CLINICAL IMPORTANCE: A novel association of bacterial genera with malodour in bloodhound dogs, identified by NGS, highlights future targets for odour control. The topical treatment significantly reduced malodour. The interaction between the topical treatment and cutaneous microbiota should be further investigated and may be useful in other dermatological conditions involving microbiota. PMID- 30251443 TI - Understanding the quality of life of family carers of people with dementia: Development of a new conceptual framework. AB - BACKGROUND: Dementia is a major global health and social care challenge, and family carers are a vital determinant of positive outcomes for people with dementia. This study's aim was to develop a conceptual framework for the Quality of Life (QOL) of family carers of people with dementia. METHODS: We studied family carers of people with dementia and staff working in dementia services iteratively using in-depth individual qualitative interviews and focus groups discussions. Analysis used constant comparison techniques underpinned by a collaborative approach with a study-specific advisory group of family carers. RESULTS: We completed 41 individual interviews with 32 family carers and nine staff and two focus groups with six family carers and five staff. From the analysis, we identified 12 themes that influenced carer QOL. These were organised into three categories focussing on person with dementia, carer, and external environment. CONCLUSIONS: For carers of people with dementia, the QOL construct was found to include condition-specific domains which are not routinely considered in generic assessment of QOL. This has implications for researchers, policy makers, and service providers in addressing and measuring QOL in family carers of people with dementia. PMID- 30251444 TI - Associations of white matter hyperintensities with poststroke depression: A 1 year longitudinal study. AB - BACKGROUND: Depression is common in stroke survivors and may lead to a poor prognosis and more severe functional impairment. Although subcortical white matter hyperintensities (WMHs) are associated with late-life depression, few studies have examined the association between depression and WMHs after a stroke. We investigated the associations of periventricular (PVWMH) and deep (DWMH) WMHs with poststroke depression (PSD) at two time points after stroke. METHODS: A total of 408 patients were evaluated 2 weeks after stroke (baseline), and of those, 284 (70%) were followed up 1 year later. Magnetic resonance images were obtained in all subjects at baseline. PVWMHs and DWMHs were rated using the four point modified Fazekas scale and categorized as mild (grades 0 and 1) or severe (grades 2 and 3). Depression was diagnosed according to DSM-IV criteria, and subjects were divided into without PSD, any PSD, and major PSD groups at baseline, and follow-up examinations were conducted according to the severity of depression. Associations of PSD with PVWMHs and DWMHs were assessed using multivariate logistic regression analyses after adjusting for various demographic and clinical characteristics. RESULTS: The adjusted analyses revealed that severe PVWMHs were significantly associated with any PSD at baseline and severe DWMHs were significantly associated with major PSD at follow-up. CONCLUSION: The association between WMH and PSD varies according to type of WMH, and time after stroke, such that early depressive symptoms are associated with PVWMHs, and delayed severe depression is associated with DWMHs. PMID- 30251445 TI - Coronary embolism following Bentall procedure and hemiarch resection for acute Type A aortic dissection. PMID- 30251446 TI - Mutational screen of a panel of tumor genes in a case report of mucoepidermoid carcinoma of the breast from Jordan. PMID- 30251447 TI - Trends in genetic screening referral in breast cancer patients under the age of forty: 2001-2016. PMID- 30251448 TI - Survivin overexpression via adeno-associated virus vector Rh10 ameliorates ischemic damage after middle cerebral artery occlusion in rats. AB - Survivin, a member of the inhibitors of apoptosis protein gene family, inhibits the activity of caspase, leading to a halt of the apoptotic process. Our study focused on the neuroprotective effect of survivin after transient middle cerebral artery occlusion (MCAO) with intraparenchymal administration of an adeno associated virus (AAV) vector. His-tagged survivin was cloned and packaged into the AAV-rh10 vector. Four-week-old Sprague-Dawley rats were injected with 4 * 109 vg of AAV-GFP or AAV-His-survivin into the right striatum and were treated 3 weeks later with transient MCAO for 90 min. Twenty-four hours after MCAO, functional and histological analyses of the rats were performed. The result showed that rats that had been treated with AAV-green fluorescent protein (GFP) and those that had been treated with AAV-His-survivin did not show a significant difference in neurological scores 24 hr after MCAO, however, infarction volume was significantly reduced in the AAV-His-survivin group compared to that in the AAV-GFP group. Although the neutrophil marker myeloperoxidase did not show a significant difference in the ischemic boundary zone, cells positive for active caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling were significantly decreased in the AAV-His survivin group. In conclusion, survivin overexpression in the ischemic boundary zone induced by using an AAV vector has the potential for amelioration of ischemic damage via an antiapoptotic mechanism. PMID- 30251450 TI - Courses and Conferences. PMID- 30251449 TI - HLA-B*56:55:01:02, -C*03:374 and -DPB1*13:01:03 characterized by next-generation sequencing. AB - The new HLA alleles HLA-B*56:55:01:02, -C*03:374 and -DPB1*13:01:03 were characterized by NGS methodology. PMID- 30251451 TI - Oxythiamine improves antifungal activity of ketoconazole evaluated in canine Malassezia pachydermatis strains. AB - BACKGROUND: Malassezia pachydermatis is an opportunistic yeast involved in skin and ear canal infections of dogs and cats. Reports suggest that strains of M. pachydermatis resistant to commonly used antifungal agents may be emerging. Therefore, new therapeutic strategies should be explored. OBJECTIVES: The synergistic effect of oxythiamine (OT) and ketoconazole (KTC) was analysed using a reference strain and field isolates (n = 66) of M. pachydermatis. Hydrogel formulations containing these components also were evaluated. METHODS AND MATERIALS: The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of OT, KTC and their mixtures were determined by a broth macrodilution method. The antifungal effects of hydrogel formulations were determined by a plate diffusion method. RESULTS: The MIC and MFC values of OT were in the range 0.08 * 103 to 10 * 103 mg/L. All M. pachydermatis strains showed higher susceptibility to KTC (MICs and MFCs in the range 0.04-0.32 mg/L). Formulations that combined OT and KTC showed a synergistic effect for all tested isolates (n = 66). Hydrogels that contained OT at a concentration of 10 * 103 or 20 * 103 mg/L and KTC at the concentration of 0.1 * 103 mg/L showed a stronger effect than a commercially available product with KTC alone (20 * 103 mg/L). CONCLUSIONS AND CLINICAL IMPORTANCE: Synergy of these drugs may allow for successful topical treatment which utilizes lower doses of KTC without changing its therapeutic effectiveness. Hydrogel formulations proved to be attractive drug carriers for potential topical use. PMID- 30251452 TI - Illness trajectory of initial infection for patients with hepatitis C: A qualitative study. AB - Little is known about how the initial infection and diagnosis of hepatitis C virus (HCV) impacts a patient's experience of living with and adjusting to the disease. In the present qualitative, descriptive study, we explored the initial experiences of patients in Taiwan diagnosed with HCV. Eighteen participants were recruited from hepatology clinics of a teaching hospital in Taichung, Taiwan by purposive sampling. Data were collected via in-depth face-to-face interviews and analyzed by conventional content analysis. The core theme describing the illness trajectory was "Oasis in the desert". Two main themes described the participants' experiences and adjustment to the diagnosis of hepatitis C: "Getting lost in the journey" and "The calm after the storm". Our findings highlight the need for health-care providers to coordinate interactions between patients and multi disciplinary teams to manage the integration of different treatment options. There is a demand for educational interventions and online information for patients and the general population, which could improve knowledge of HCV. PMID- 30251453 TI - Cognitive-behavioural therapy in patients with inflammatory bowel diseases: A systematic review and meta-analysis. AB - AIMS: This systematic review and meta-analysis aimed to evaluate the effects of cognitive-behavioural therapy in patients with inflammatory bowel diseases. METHODS: Cochrane Library, Web of Science, Pubmed, EMBASE, and CINAHL were searched up to June 2017, as well as grey literature and databases hand searches. Quality assessment, heterogeneity, sensitivity analysis, and publication bias were performed. Stata12.0 software was used for pooled estimates. RESULTS: Seven eligible reports were included in the final analysis. Inflammatory Bowel Disease Questionnaire score was higher in the cognitive-behavioural therapy group than in the control group at the final follow-up in inflammatory bowel disease patients (P = 0.008). There was no statistically significant difference in the Crohn's Disease Activity Index (P = 0.751), Simple Clinical Colitis Activity Index score (P = 0.747), State Anxiety score (P = 0.988), Trait Anxiety score (P = 0.681), and Perceived Stress Questionnaire score (P = 0.936) at the final point of follow up. A funnel plot showed no publication bias (P = 0.98). CONCLUSION: Cognitive behavioural therapy appeared to support higher quality of life in inflammatory bowel disease patients compared with a control group at the final follow-up point but had no effect on disease activity, anxiety, or perceived stress in patients with inflammatory bowel disease. Cognitive-behavioural therapy can be an acceptable adjunctive therapy for inflammatory bowel disease patients, but the effect of cognitive-behavioural therapy is limited. PMID- 30251455 TI - A systematic review of the clinical utility of the concept of self-disgust. AB - This systematic literature review examined the clinical utility of the construct of self-disgust in understanding mental distress. Specifically, the review assessed whether there is a shared conceptual definition of self-disgust, the face and construct validity of the quantitative assessment measures of self disgust, and the predictive validity of self-disgust in formulating the development of a range of psychological difficulties. A systematic database search supplemented by manual searches of references and citations identified 31 relevant papers (27 quantitative, 3 qualitative, and 1 mixed). Analysis of qualitative papers indicated a number of shared features in the definition of self-disgust, including a visceral sense of self-elicited nausea accompanied by social withdrawal and attempts at cleansing or suppressing aspects of the self. Quantitative assessment measures appeared to capture these dimensions and evidenced good psychometric properties, although some measures may have only partially captured the full self-disgust construct. Strong relationships were observed between self-disgust and a range of mental health presentations, in particular, depression, body-image difficulties, and trauma-related difficulties. However, these relationships are smaller when the effects of other negative self referential emotions were controlled, and stronger conclusions about the predictive validity of self-disgust are limited by the cross-sectional nature of many of the studies. PMID- 30251454 TI - Acyclic and Cyclic Alkyl and Ether-Functionalised Sulfonium Ionic Liquids Based on the [TFSI]- and [FSI]- Anions as Potential Electrolytes for Electrochemical Applications. AB - This work provides a study based on acyclic and cyclic sulfonium ionic liquids (ILs) with alkyl and ether-functionality on the cation paired with the bis{(trifluoromethyl)sulfonyl}imide, [TFSI]- , or the bis(fluorosulfonyl)imide, [FSI]- , as the counter anion. Herein, thermophysical characterisation of nine sulfonium-based ILs concerning the density, viscosity and conductivity and thermal properties including phase transition behaviour and decomposition temperature is reported. The electrochemical stability of the ILs was also measured by cyclic voltammetry at a glassy carbon macro-disk electrode. All of the ILs showed low melting point, low viscosity and good conductivity and could serve as potential electrolytes for energy storage devices. PMID- 30251456 TI - Percutaneous removal of benign phyllodes tumor of the breast: An alternative to surgery. AB - We aimed to evaluate the efficacy of vacuum assisted percutaneous excision in the treatment of benign phyllodes tumors of the breast. From 2007 to 2016, a total of 160 benign fibroepithelial nodules were percutaneously removed in our department. Ultrasonographic follow-up was performed 12 months after the procedure to assess recurrence. Out of the 160 nodules excised, 11 lesions corresponded to benign phyllodes tumors. The median patient age was 39.7 years. The average size of the lesion was 16.9 mm. Ultrasound-guided biopsy was performed before the percutaneous removal in eight of them. Six were histopathologically diagnosed as fibroadenomas, one as phyllodes tumor and in one case histological findings were inconclusive. The mean surveillance period was 27.7 months. During the follow-up period, local recurrence was detected in one patient (9%). We conclude that percutaneous excision of benign phyllodes tumors is not associated with greater risk of recurrence than surgery. PMID- 30251458 TI - Secretory breast carcinoma in an 8-year-old girl: A case report and literature review. AB - Secretory breast carcinoma (SBC) is a rare form of breast cancer found in both children and adults, and is the most common breast cancer in the pediatric population. Although SBC usually carries a favorable prognosis, there have been reported cases of axillary and distant metastases. Surgery is the primary mode of treatment, however, there exists variability within the literature surrounding the management of SBC. We report a case of an 8-year-old girl who presented with a firm, mobile, palpable breast mass. Ultrasonography was performed, followed by local excision, with surgical pathology concerning for SBC. The patient was definitively treated with mastectomy and sentinel lymph node (SLN) biopsy. She received no adjuvant therapies and 2 years later, remains disease free. Herein, we review the literature, curate data from 89 reported cases of pediatric and adult SBC, and address some of the controversy surrounding its treatment. From this review we conclude that patients with SBC should be reviewed at multidisciplinary treatment planning conference, undergo surgery with mastectomy or lumpectomy with SLN biopsy, and have long-term postoperative follow-up. PMID- 30251457 TI - PPARalpha-independent action against metabolic syndrome development by fibrates is mediated by inhibition of STAT3 signalling. AB - OBJECTIVES: Metabolic syndrome (MS) is the concurrence of at least three of five medical conditions: obesity, high blood pressure, insulin resistance, high serum triglyceride (TG) and low serum high-density lipoprotein levels. While fibrates are used to treat disorders other than the lowering serum TG, the mechanism by which fibrates decrease MS has not been established. METHODS: In this study, wild type and Ppara-null mice fed a medium-fat diet (MFD) were administered gemfibrozil and fenofibrate for 3 months respectively, to explore the effect and action mechanism. KEY FINDINGS: In Ppara-null mice, MFD treatment increased body weight, adipose tissue, serum TG and impaired glucose tolerance. These phenotypes were attenuated in two groups treated with gemfibrozil and fenofibrate. The STAT3 pathway was activated in adipose and hepatic tissues in positive control, and inhibited in groups treated with gemfibrozil and fenofibrate. The above phenotypes and inflammation were not observed in any wild-type group. In 3T3-L1 adipogenic stem cells treated with high glucose, STAT3 knockdown greatly decreased the number of lipid droplets. CONCLUSIONS: Low dose of clinical fibrates was effective against MS development independent of PPARalpha, and this action was mediated by STAT3 signalling inhibition in adipose tissue and, to a lesser extent, in hepatic tissues. PMID- 30251459 TI - Impact of Hurricane Katrina on healthcare delivery for New Orleans patients, 2005 2014. AB - BACKGROUND AND OBJECTIVES: Hematology/oncology patients have special health needs. To identify barriers to care, we surveyed patients/parents at Children's Hospital of New Orleans 1 year after Hurricane Katrina. We then implemented a "Hurricane Action Plan"-identification of families' evacuation plans at each hurricane season's onset; of hospital(s) and pharmacies in the intended evacuation area; updating roadmaps/treatment plans; giving information to families requiring hematology/oncology services in evacuation areas. Administration of a second survey was initiated 7 years post Katrina to assess the efficacy of the "Hurricane Action Plan." METHODS: Both surveys were conducted on random patients attending Children's Hospital. Survey #1 was performed in 2006, while survey #2 was conducted in 2013-2014. RESULTS: Eighty-nine percent of 124 families left New Orleans during Hurricane Katrina; only 50% had an evacuation plan. Twenty-five percent of families had difficulty physically accessing care; others (13%) could not find a hematology/oncology provider for follow-up and had difficulty reaching their primary provider or making appointments. An additional 25 percent did not have access to medical records. There was no access to mental health services. Eighty- two patients/representatives were surveyed in 2013/2014; 72% of families were evacuated during subsequent hurricane seasons with 78% of families having an evacuation plan. Thirty-six percent of patients had a roadmap/treatment plan with them; 71% had a 2-week medication supply. Ninety-two percent found information given to them by providers helpful. CONCLUSIONS: Interventions instituted to allow greater access to care by our hematology/oncology patients after Hurricane Katrina resulted in better preparedness, easier acquisition of information, and possibly better continuity of care. PMID- 30251460 TI - Reversible Band Gap Narrowing of Sn-Based Hybrid Perovskite Single Crystal with Excellent Phase Stability. AB - An intriguing reversible band gap narrowing behavior of the lead-free hybrid perovskite single crystal DMASnI3 (DMA=CH3 NH2 CH3 + ) from yellow to black is observed without phase transformation. We discuss the transformation mechanism in detail. More interestingly, the transformed samples in black can rapidly self heal into yellow ones when exposed to deionized water (DI water). Contrary to other hybrid perovskites, DMASnI3 crystals exhibit excellent water phase stability. For example, DMASnI3 was immersed in DI water for 16 h and no decomposition was observed. Inspired by its excellent water phase stability, we demonstrate a potential eco-friendly application of DMASnI3 in photo-catalysis for H2 evolution in DI water. We present the first H2 evolution rate of 0.64 MUmol h-1 with good recycling properties for pure DMASnI3 crystals. After the narrowing process, the optical band gap of DMASnI3 can be lowered from 2.48 eV to 1.32 eV. Systematical characterizations are applied to investigate their structures and optoelectronic properties. The reversible band gap narrowing behavior and outstanding electrical properties, such as higher carrier mobility and long carrier lifetime show that DMASnI3 has a great potential for optoelectronic applications. PMID- 30251461 TI - Oxygen saturation or respiratory rate to improve risk stratification in hemodynamically stable patients with acute pulmonary embolism. AB - Essentials In acute pulmonary embolism (PE), risk stratification is essential to drive clinical management. Improving the 2014-ESC risk stratification strategy is crucial in hemodynamically stable patients. Oxygen saturation and respiratory rate improve risk stratification in hemodynamically stable PE. Simple and routine tests improve risk stratification of hemodynamically stable PE. SUMMARY: Background In patients with acute pulmonary embolism (PE), risk stratification for short-term death is recommended to drive clinical management. A risk stratification strategy combining the simplified Pulmonary Embolism Severity Index (PESI), echocardiography and troponin was proposed by the European Society of Cardiology (ESC) in 2014. The identification of hemodynamically stable patients at increased risk of death by this strategy needs improvement. Objective To assess whether further stratification by serial cut-off values of oxygen saturation or respiratory rate improves the accuracy of the ESC risk stratification strategy in hemodynamically stable PE patients. Methods Prospective cohorts of hemodynamically stable patients with PE were merged in a collaborative database. The accuracy of risk stratification for 30-day mortality by the original and a modified 2014 ESC strategy was assessed. Results Overall, 255 patients (27%) were categorized as low, 510 (54%) as intermediate-low and 181 (19%) as intermediate-high risk according to the original 2014 ESC strategy. Thirty-day mortality was 1.2% in low, 10% in intermediate-low and 11% in intermediate-high-risk patients. By adding oxygen saturation in air of < 88%, the discriminatory power of the 2014 ESC model improved for 30-day mortality (c statistics, 0.71; 95% confidence interval [CI], 0.65-0.77 vs. 0.63, 95% CI, 0.56 0.69) and for PE-related death (c-statistics, 0.75; 95% CI, 0.69-0.81 vs. 0.63, 95% CI 0.56-0.69). Conclusions Simple and routine tests, such as oxygen saturation or respiratory rate, could be added to the 2014 ESC strategy for risk stratification to identify hemodynamically stable PE patients at increased risk of death who are potentially candidates for more aggressive treatment. PMID- 30251462 TI - One-Step Plasma Synthesis of Nb2 O5 Nanofibers and their Enhanced Photocatalytic activity. AB - Fiberform nanostructured niobium (Nb) was fabricated by one step helium (He) plasma irradiation. He ion implantation formed He nano-bubbles on a Nb plate and led to formation of protrusions while migrating in Nb matrix; fiberform nanostructures (FN) were grown when the fluence became high (>1026 m-2 ). The necessary conditions for the formation of Nb FN were revealed to be the surface temperature range of 900-1100 K and the incident ion energy higher than 70 eV. The sample was oxidized at 573-773 K in an air atmosphere, and Pt nanoparticles were photo-deposited on the Nb2 O5 samples. The surface was analyzed by scanning electron microscope, transmission electron microscope, x-ray photoelectron spectroscopy, and ultraviolet-visible spectrophotometry. Photocatalytic activity of the fabricated materials was studied using methylene blue (MB) decolorization process. An enhanced photocatalytic performance was identified on FN Nb2 O5 substrate with Pt deposition. PMID- 30251463 TI - Intrahepatic Cholangiocarcinoma: Continuing Challenges and Translational Advances. AB - Intrahepatic cholangiocarcinoma (iCCA) has over the last 10-20 years become the focus of increasing concern largely due to its rising incidence and high mortality rates worldwide. The significant increases in mortality rates from this primary hepatobiliary cancer, particularly over the past decade or so, has coincided with a rapidly growing interest among clinicians, investigators, and patient advocates seeking greater mechanistic insights and more effective biomarker-driven targeted approaches for managing and/or preventing this challenging liver cancer. In addition to discussing challenges posed by this aggressive cancer, this review will emphasize recent epidemiological, basic and translational research findings for iCCA. In particular, we highlight emerging demographic changes and evolving risk factors, the critical role of the tumor microenvironment, extracellular vesicle biomarkers and therapeutics, inter- and intra-tumoral heterogeneity, and current and emerging targeted therapies regarding iCCA. Specifically, recent evidence linking non-bile duct medical conditions, such as non-alcoholic fatty liver disease and nonspecific cirrhosis to intrahepatic cholangiocarcinogenesis, together with geographic and ethnic variation are assessed. Recent developments concerning the roles played by transforming growth factor-beta and platelet derived growth factor-D in driving the recruitment and expansion of cancer-associated myofibroblasts within cholangiocarcinoma stroma, as well as their therapeutic implications are also discussed. In addition, the potential significance of extracellular vesicles as novel bile and serum biomarkers and therapeutic delivery systems for iCCA are described. An integrated systems approach to classifying heterogeneous iCCA sub types is further highlighted, and recent clinical trials and emerging targeted therapies are reviewed, along with recommendations for future translational research opportunities. Established international cholangiocarcinoma networks are now acting to facilitate collaborations aimed at advancing iCCA translational and clinical research. This article is protected by copyright. All rights reserved. PMID- 30251464 TI - Health Care-Related Correlates of Cervical Cancer Screening among Sexual Minority Women: An Integrative Review. AB - INTRODUCTION: Sexual minority women (SMW; lesbian, bisexual, nonheterosexual women) may have lower rates of cervical cancer screening than heterosexual women. Health care-related factors may explain some of the variation in cervical cancer screening rates among SMW. We aimed to synthesize published evidence of health care-related correlates of cervical cancer screening among SMW. METHODS: We searched PubMed, CINAHL, and PsycINFO databases for English-language studies published between January 2000 and March 2017 that 1) assessed sexual identity or the sexual partners of female participants, 2) included cervical cancer screening as a main outcome of interest, and 3) measured at least one health care-related variable in addition to cervical cancer screening. We excluded articles that 1) reported on non-US samples or 2) did not report original research. We reviewed the sample, methods, and findings of 17 studies. We then summarized current knowledge about health care-related factors across 3 categories and generated recommendations for clinical practice and future research. RESULTS: Several health care-related factors such as previous contraception use, having a primary care provider, knowledge of screening recommendations, and disclosing sexual orientation to providers were consistently positively associated with cervical cancer screening. Three groups of factors-previous health care use, health care provider-related factors, and belief-related factors-account for a substantial part of the variation in cervical cancer screening among SMW. DISCUSSION: Several gaps in knowledge remain that could be addressed by recruiting more diverse samples of SMW with improved generalizability. Clinicians and clinical institutions can address factors associated with low rates of screening among SMW by preventing sexual orientation-based discrimination, inviting sexual orientation disclosure, and offering cervical cancer screening to SMW at a variety of health care encounters. Future research should examine how the location of care and health care provider type affect SMW's cervical cancer screening behaviors and should test the effectiveness of health care interventions designed to address sexual orientation-related disparities. PMID- 30251465 TI - X-Ray Scattering and Imaging Studies of Electrode Structure and Dynamics. AB - We will review structures and dynamics of electrode interfaces studied in situ using x-ray scattering and imaging techniques. The examples cover single-crystal and nanocrystal structures relevant to electrocatalytic activities, anodic oxidation and corrosion, aqueous dissolution reactions, surface reconstructions, and surface modifications by under potential deposition. The x-ray techniques include the widely used traditional surface x-ray scattering, such as crystal truncation rods and x-ray reflectivity, as well as recently developed resonance surface scattering, coherent surface x-ray photon correlation spectroscopy, coherent x-ray Bragg diffraction imaging, and surface ptychography. Results relevant to various electrochemical phenomena will be highlighted. PMID- 30251466 TI - Perspective to the Potential Use of Graphene in Li-ion Battery and Supercapacitor. AB - Graphene is a hot star in materials science with various potential application aspects, including in Li-ion battery and supercapacitor. The burst of scientific papers in this area seems to validate the performance of graphene, but also arouses large dispute. Herein, we share our judgment of these trends to all, encouraging the discussion and enhancing the understanding of the structure performance relationship of graphene. PMID- 30251467 TI - Limulus and heart rhythm. AB - Great interest in the comparative physiology of hearts and their functions in Animalia has emerged with classic papers on Limulus polyphemus and mollusks. The recurrent cardiac activity-heart rate-is the most important physiological parameter and when present the kardia (Greek) is vital to the development of entire organs of the organisms in the animal kingdom. Extensive studies devoted to the regulation of cardiac rhythm in invertebrates have revealed that the basics of heart physiology are comparable to mammals. The hearts of invertebrates also beat spontaneously and are supplied with regulatory nerves: either excitatory or inhibitory or both. The distinct nerves and the source of excitation/inhibition at the level of single neurons are described for many invertebrate genera. The vertebrates and a majority of invertebrates have myogenic hearts, whereas the horseshoe crab L. polyphemus and a few other animals have a neurogenic cardiac rhythm. Nevertheless, the myogenic nature of heartbeat is precursor, because the contraction of native and stem-cell-derived cardiomyocytes does occur in the absence of any neural elements. Even in L. polyphemus, the heart rhythm is myogenic at embryonic stages. PMID- 30251468 TI - The face of animal cognition. AB - Animal cognition is currently one of the most exciting fields within animal behaviour as an increasing number of researchers investigate the cognitive abilities of an ever-wider range of animals. Tinbergen would be proud: all four of his approaches are being pursued and we are learning much about how animals collect information and how they use that information to make decisions for their current and future states as well as what animals do not perceive or choose to ignore. Here I provide an overview of this productivity, alighting only briefly on any single example, in order to showcase the diversity of species, of approaches and the sheer mass of research effort currently underway. We are getting closer to understanding the minds of other animals and the evolution of cognition at an increasingly rapid rate. This article is protected by copyright. All rights reserved. PMID- 30251469 TI - Main factors affecting lacertid lizard thermal ecology. AB - The thermal ecology of ectotherms has been studied for almost two centuries, but additional attention is currently being paid to the issue in order to understand how organisms deal with the environment in a climate change context. However, a consensus is still far away, due to the large number of factors involved and their complex interactions. In this context, three analyses in lacertid lizards were carried out: (1) a meta-analysis, to test for differences between body and air temperatures from 71 populations, (2) a meta-analysis concerning correlations between body and air temperatures from 60 populations, and (3) a multimodel inference using thermoregulation effectiveness indices from 45 populations. The importance of different factors, including body size, habitat, insuraliry, altitude, climate, and season, was evaluated in all analyses in order to model the response variables. A strong seasonality effect was observed, with a consistent pattern of less effective thermoregulation in summer compared to other seasons. Altitude was the second most important factor, with a consistent higher thermoregulation effort in populations occurring at high elevations (> 1000 m asl). Other factors, such as insularity or body size, can also be important, but did not exhibit a clear pattern. Finally, thermoregulation was less affected by climate and habitat type. This article is protected by copyright. All rights reserved. PMID- 30251470 TI - Why implantation of bio-loggers may improve our understanding of how animals cope within their natural environment. AB - Bio-loggers are miniaturized autonomous devices that record quantitative data on the state of free-ranging animals (e.g. behavior, position, and physiology) and their natural environment. This is especially relevant for species where direct visual observation is difficult or impossible. Today, ongoing technical development allows the monitoring of numerous parameters in an increasing range of species over extended periods. However, the external attachment of devices might affect various aspects of animal performance (energetics, thermoregulation, foraging as well as social and reproductive behavior), which ultimately affect fitness. External attachment might also increase entanglement risk and the conspicuousness of animals, leaving them more vulnerable to predation. By contrast, implantation of devices can mitigate many of these undesirable effects and might be preferable, especially for long-term studies, provided that the many challenges associated with surgical procedures can be mastered. Implantation may then allow us to gather data that might be impossible to obtain otherwise and thereby may provide new and ecologically relevant insights into the life of wild animals. Here, we (1) discuss the pros and cons of attachment methods, (2) highlight recent field studies that used implanted bio-loggers to address eco physiological questions in a wide range of species, and (3) discuss logger implantation in the light of ethical considerations. This article is protected by copyright. All rights reserved. PMID- 30251471 TI - Close surgical margins after radical prostatectomy: how to make a complex story even more complex. PMID- 30251472 TI - Guidelines vs reality of practice (two sides of the same coin) and lifelong learning! PMID- 30251474 TI - Postoperative intravesical chemotherapy has an important role in reducing subsequent bladder tumours - why is it not routine? PMID- 30251473 TI - Measuring testicular asymmetry in healthy adolescent boys. PMID- 30251475 TI - Reply. PMID- 30251478 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 40/2018. PMID- 30251476 TI - A genome-wide association study identifies a 3'UTR genetic variant of RARB associated with carotid intima-media thickness in rheumatoid arthritis. AB - OBJECTIVE: A genome-wide association study (GWAS) was conducted to shed light into the genetic background influencing the development of cardiovascular (CV) disease in patients diagnosed with rheumatoid arthritis (RA). METHODS: After quality control and imputation, a total of 6,308,944 polymorphisms across the whole genome were analysed in 2,989 RA patients from European origin. Data on subclinical atherosclerosis, obtained by carotid ultrasonography through assessment of carotid intima-media thickness (cIMT) and presence/absence of carotid plaques, were available for 1,355 individuals. RESULTS: A genetic variant of the RARB gene (rs116199914) was associated with cIMT values at the genome-wide level of significance (minor allele (G): beta (beta) coefficient=0.142, P=1.86E 08). Interestingly, rs116199914 overlapped with regulatory elements in tissues related to CV pathophysiology and immune cells. In addition, biological pathway enrichment and predictive protein-protein relationship analyses, including suggestive GWAS signals of potential relevance, revealed a functional enrichment of the collagen biosynthesis network related to the presence/absence of carotid plaques (GO:0032964, PFDR =4.01E-03). Furthermore, our data suggest a potential influence of the previously described candidate CV risk loci NFKB1, MSRA and ZC3HC1 (P=8.12E-04, P=5.94E-04 and P=2.46E-04, respectively). CONCLUSION: Our study strongly suggests that genetic variation within RARB contributes to the development of subclinical atherosclerosis in patients with RA. This article is protected by copyright. All rights reserved. PMID- 30251477 TI - Arthritis prevalence: which case definition should be used for surveillance? Comment on the article by Jafarzadeh and Felson. PMID- 30251479 TI - Diuretics and left ventricular hypertrophy regression: The relationship that we commonly forget. PMID- 30251480 TI - Oestrogenic activity of mimosine on MCF-7 breast cancer cell line through the ERalpha-mediated pathway. AB - Hormone replacement therapy has been a conventional treatment for postmenopausal symptoms in women. However, it has potential risks of breast and endometrial cancers. The aim of this study was to evaluate the oestrogenicity of a plant based compound, mimosine, in MCF-7 cells by in silico model. Cell viability and proliferation, ERalpha-SRC1 coactivator activity and expression of specific ERalpha-dependent marker TFF1 and PGR genes were evaluated. Binding modes of 17beta-oestradiol and mimosine at the ERalpha ligand binding domain were compared using docking and molecular dynamics simulation experiments followed by binding interaction free energy calculation with molecular mechanics/Poisson-Boltzmann surface area. Mimosine showed increased cellular viability (64,450 cells/ml) at 0.1 MUM with significant cell proliferation (120.5%) compared to 17beta oestradiol (135.2%). ER antagonist tamoxifen significantly reduced proliferative activity mediated by mimosine (49.9%). Mimosine at 1 MUM showed the highest ERalpha binding activity through increased SRC1 recruitment at 186.9%. It expressed TFF1 (11.1-fold at 0.1 MUM) and PGR (13.9-fold at 0.01 MUM) genes. ERalpha-mimosine binding energy was -49.9 kJ/mol, and it interacted with Thr347, Gly521 and His524 of ERalpha-LBD. The results suggested that mimosine has oestrogenic activity. PMID- 30251481 TI - The importance of measuring hand and foot function over the disease course in rheumatoid arthritis: An eight-year follow-up study. AB - OBJECTIVE: To assess function using the Signals of Functional Impairment (SOFI) instrument over eight years and to study clinical variables associated with the change. Also to study change over time of the SOFI items. METHODS: Altogether, 1,223 patients with early RA from the BARFOT cohort (mean age 56.9 [SD 15.4] years; 67% women) were included in the analysis. Data from baseline and from one and eight years were studied. SOFI includes measures of range of motion in the hand, shoulder/arm, and lower extremity (0-44, best to worst). The effects of baseline variables (sociodemographic, disease activity, joint destruction, and function) on change in SOFI scores were studied by linear regression analysis. RESULTS: During the first year, there was a mean improvement in SOFI of 2.7 (SD 5.7) (p<0.001). Worse scores in DAS28 and HAQ at baseline were associated with this improvement (r2 <= 0.11). During the next seven years, there was a mean deterioration in SOFI of 1.5 (SD 4.9) (p<0.001). Based on change scores, finger flexion, pincer grip, and toe-standing were the most important items to measure, explaining 58-61% of the total SOFI score and were also associated with radiographic changes at the eight-year follow-up. CONCLUSION: Function as assessed with SOFI improved during the first year in patients with early RA, but it deteriorated slowly thereafter. Impaired hand and foot tasks were associated with joint destruction at the eight-year follow-up. Measures of hand and foot function will complement self-reported and medical data both in clinical work and in long-term research studies. This article is protected by copyright. All rights reserved. PMID- 30251482 TI - Modeling photoacoustic imaging with a scanning focused detector using Monte Carlo simulation of energy deposition. AB - Photoacoustic imaging using a focused, scanning detector in combination with a pulsed light source is a common technique to visualize light-absorbing structures in biological tissue. In the acoustic resolution mode, where the imaging resolution is given by the properties of the transducer, there are various challenges related to the choice of sensors and the optimization of the illumination. These are addressed by linking a Monte Carlo simulation of energy deposition to a time-domain model of acoustic propagation and detection. In this model, the spatial and electrical impulse responses of the focused transducer are combined with a model of acoustic attenuation in a single response matrix, which is used to calculate detector signals from a volumetric distribution of absorbed energy density. Using the radial symmetry of the detector, the calculation yields a single signal in less than a second on a standard personal computer. Various simulation results are shown, comparing different illumination geometries and demonstrating spectral imaging. Finally, simulation results and experimental images of an optically characterized phantom are compared, validating the accuracy of the model. The proposed method will facilitate the design of photoacoustic imaging devices and will be used as an accurate forward model for iterative reconstruction techniques. PMID- 30251483 TI - Noncontact speckle contrast diffuse correlation tomography of blood flow distributions in tissues with arbitrary geometries. AB - A noncontact electron multiplying charge-coupled-device (EMCCD)-based speckle contrast diffuse correlation tomography (scDCT) technology has been recently developed in our laboratory, allowing for noninvasive three-dimensional measurement of tissue blood flow distributions. One major remaining constraint in the scDCT is the assumption of a semi-infinite tissue volume with a flat surface, which affects the image reconstruction accuracy for tissues with irregular geometries. An advanced photometric stereo technique (PST) was integrated into the scDCT system to obtain the surface geometry in real time for image reconstruction. Computer simulations demonstrated that a priori knowledge of tissue surface geometry is crucial for precisely reconstructing the anomaly with blood flow contrast. Importantly, the innovative integration design with one single-EMCCD camera for both PST and scDCT data collection obviates the need for offline alignment of sources and detectors on the tissue boundary. The in vivo imaging capability of the updated scDCT is demonstrated by imaging dynamic changes in forearm blood flow distribution during a cuff-occlusion procedure. The feasibility and safety in clinical use are evidenced by intraoperative imaging of mastectomy skin flaps and comparison with fluorescence angiography. PMID- 30251484 TI - Economical and compact briefcase spectral-domain optical coherence tomography system for primary care and point-of-care applications. AB - Development of low-cost and portable optical coherence tomography (OCT) systems is of global interest in the OCT research community. Such systems enable utility broadly throughout a clinical facility, or in remote areas that often lack clinical infrastructure. We report the development and validation of a low-cost, portable briefcase spectral-domain optical coherence tomography (SD-OCT) system for point-of-care diagnostics in primary care centers and/or in remote settings. The self-contained briefcase OCT contains all associated optical hardware, including light source, spectrometer, hand-held probe, and a laptop. Additionally, this system utilizes unique real-time mosaicking of surface video images that are synchronized with rapid A-scan acquisition to eliminate the need for lateral scanning hardware, and enable the construction of cross-sectional B mode images over extended lateral distances. The entire briefcase system weighs 9 kg and costs ~USD$8000 using off-the-shelf components. System performance was validated by acquiring images of in vivo human skin on the fingertip, palm, and nail fold. The efficiency, portability, and low-cost enable accessibility and utility in primary care centers and low-resource settings. PMID- 30251486 TI - Label-free dynamic segmentation and morphological analysis of subcellular optical scatterers. AB - Imaging without fluorescent protein labels or dyes presents significant advantages for studying living cells without confounding staining artifacts and with minimal sample preparation. Here, we combine label-free optical scatter imaging with digital segmentation and processing to create dynamic subcellular masks, which highlight significantly scattering objects within the cells' cytoplasms. The technique is tested by quantifying organelle morphology and redistribution during cell injury induced by calcium overload. Objects within the subcellular mask are first analyzed individually. We show that the objects' aspect ratio and degree of orientation ("orientedness") decrease in response to calcium overload, while they remain unchanged in untreated control cells. These changes are concurrent with mitochondrial fission and rounding observed by fluorescence, and are consistent with our previously published data demonstrating scattering changes associated with mitochondrial rounding during calcium injury. In addition, we show that the magnitude of the textural features associated with the spatial distribution of the masked objects' orientedness values, changes by more than 30% in the calcium-treated cells compared with no change or changes of less than 10% in untreated controls, reflecting dynamic changes in the overall spatial distribution and arrangement of subcellular scatterers in response to injury. Taken together, our results suggest that our method successfully provides label-free morphological signatures associated with cellular injury. Thus, we propose that dynamically segmenting and analyzing the morphology and organizational patterns of subcellular scatterers as a function of time can be utilized to quantify changes in a given cellular condition or state. PMID- 30251485 TI - Compact and low-cost handheld quasibright-field linear-array probe design in photoacoustic computed tomography. AB - The optimal photoacoustic probe design is the key to obtain highest imaging sensitivity in photoacoustic computed tomography. Two commonly used probe design types are dark- and bright-field designs. We proposed a design for photoacoustic probe called quasibright-field illumination and compared the performance of all three kinds of probes theoretically and experimentally. Our conclusion is that the proposed quasibright-field illumination photoacoustic probe is superior compared to the existing probe designs as demonstrated. However, each type of illumination should still have its own advantages under certain circumstances. The dark-field illumination is capable of minimizing surface interference signals and reducing their contributions to the background of deeper signals. Hence, it should perform better when imaging samples with high optical absorbance at the surface layer. The bright field may perform better under circumstance when phase distortion is less. We also designed and fabricated three kinds of probes using a single multimode optical fiber for laser energy delivery instead of fiber bundle. Single fiber probes are low cost, transmit laser energy efficiently, and are compact for easy handling. Thus, our study not only provides a method for probe design but also a guidance for cost-effective transducer array-based photoacoustic probe design and manufacturing in the future. PMID- 30251487 TI - Investigation of optical properties of dissected and homogenized biological tissue. AB - Knowledge of tissue optical properties, in particular the absorption MUa and the reduced scattering coefficient MUs', is required for diagnostic and therapeutic applications in which the light distribution during treatment has to be known. As it is generally very difficult to obtain this information with sufficient accuracy in vivo, optical properties are often approximately determined on ex vivo tissue samples. In this case, the obtained optical properties may strongly depend on the sample preparation. The extent of the expectable preparation dependent differences was systematically investigated in comparative measurements on dissected and homogenized porcine tissue samples (liver, lung, brain, and muscle). These measurements were performed at wavelengths 520, 635, 660, and 785 nm, using a dual-step reflectance device and at a spectral range of 515 to 800 nm with an integrating sphere setup. In a third experiment, the density of tissue samples (dissected and homogenized) was investigated, as the characteristic of the packaging of internal tissue structures strongly influences the absorption and scattering. The standard errors of the obtained absorption and reduced scattering coefficients were found to be reduced in case of homogenized tissue. Homogenizing the tissues also allows a much easier and faster sample preparation, as macroscopic internal tissue structures are destroyed in the homogenized tissue so that a planar tissue sample with well-defined thickness can easily and accurately be prepared by filling the tissue paste into a cuvette. Consequently, a better reproducibility result was obtained when using homogenized samples. According to the density measurements accomplished for dissected and homogenized tissue samples, all types of tissues, except lung, showed a decrease in the density due to the homogenization process. The presented results are in good agreement for MUs' regardless of the preparation procedure, whereas MUa differs, probably influenced by blood content and dehydration. Because of faster and easier preparation and easier sample positioning, homogenization prior to measurement seems to be suitable for investigating the optical properties ex vivo. Additionally, by means of using the homogenization process, the sample size and thickness do not need to be particularly large, as is the case for most biopsies from the OR. PMID- 30251488 TI - Special Section Guest Editorial: Topical Problems of Biophotonics: from Optical Bioimaging to Clinical Biophotonics. AB - This editorial provides an introductory overview for the Special Section on Topical Problems of Biophotonics. PMID- 30251489 TI - Nonlinear relation between concentration and fluorescence emission of protoporphyrin IX in calibrated phantoms. AB - 5-ALA-induced protoporphyrin IX (PpIX) has shown its relevance in medical assisting techniques, notably in the detection of glioma (brain tumors). Validation of instruments on phantoms is mandatory and a standardization procedure has recently been proposed. This procedure yields phantoms recipes to realize a linear relationship between PpIX concentration and fluorescence emission intensity. The present study puts forward phantoms where this linear relationship cannot be used. We propose a model that considers two states of PpIX, corresponding to two different aggregates of PpIX, with fluorescence spectra peaking at 634 and 620 nm, respectively. We characterize the influence of these two states on PpIX fluorescence emission spectra in phantoms with steady concentration of PpIX and various microenvironment parameters (surfactant, Intralipid or bovine blood concentration, and pH). We show that, with fixed PpIX concentration, a modification of the microenvironment induces a variation of the emitted spectrum, notably a shift in its central wavelength. We show that this modification reveals a variation of proportions of the two states. This establishes phantom microenvironment regimes where the usual single state model is biased while a linear combination of the two spectra enables accurate recovering of any measured spectra. PMID- 30251490 TI - Tool for simulating the focusing of arbitrary vector beams in free-space and stratified media. AB - Vectorial models of focused beams are important to a variety of fields including microscopy, lithography, optical physics, and biomedical imaging. This has led to many models being developed, which calculate how beams of various profiles are focused both in free space and in the presence of stratified media. The majority of existing models begin with a vectorial diffraction formula, often referred to as the Debye-Wolf integral, which must be evaluated partially analytically and partially numerically. The complexity of both the analytic and numerical evaluations increases significantly when exotic beams are modeled, or, a stratified medium is located in the focal region. However, modern-day computing resources permit this integral to be evaluated entirely numerically for most applications. This allows for the development of a vectorial model of focusing in which the focusing itself, interaction with a stratified medium, and incident beam specification are independent, allowing for a model of unprecedented flexibility. We outline the theory upon which this model is developed and show examples of how the model can be used in applications including optical coherence tomography, high numerical aperture microscopy, and the properties of cylindrical vector beams. We have made the computer code freely available. PMID- 30251491 TI - Intraoperative brain tumor resection with indocyanine green using augmented microscopy. AB - Treatment outcomes for brain cancer have seen dismal improvements over the last two decades as evident in available statistical data. Efforts to address this challenge include development of near-infrared contrast agents for improvements in diagnostic and therapeutic modalities. This creates a need for imaging technologies that can support the intraoperative use of such agents. Here, we report implementation of a recently introduced augmented microscope in combination with indocyanine green (ICG), a near-infrared contrast agent, for surgical image guidance of a glioma resection in a rat model. Luc-C6 cells were implanted in rats in the left-frontal lobe and grown for 22 days. Surgical resection was performed by a neurosurgeon using the augmented microscope with ICG contrast. ICG accumulated in the tumor tissue due to enhanced permeation and retention from the compromised blood-brain barrier. Videos and images were acquired to evaluate image quality and resection margins. The augmented microscope highlighted tumor tissue regions via visualization of ICG fluorescence and was capable of guiding the rat glioma resection. PMID- 30251492 TI - [Research progress of micro-electro-mechanical systems micro gas chromatography columns]. AB - The gas chromatography (GC) column is a key component of the gas chromatographic system, which is mainly used for the separation of mixed gas components. Compared with the traditional GC column, the micro GC column based on micro-electro mechanical systems (MEMS) technology has the advantages of lighter weight, smaller volume, lower power consumption, and faster analysis. Furthermore, it can be integrated into a portable instrument, such as a miniaturized GC. The research progress of micro GC columns based on MEMS technology is summarized in this paper. First, the theoretical basis of the MEMS micro GC column is stated. Then, the layout and inner structure of the MEMS micro GC column, the stationary-phase support, and the preparation of the stationary phase are summarized. Finally, trends in the development of MEMS micro GC columns are discussed. PMID- 30251493 TI - [Preparation of magnetic surface molecularly imprinted polymers for melamine and its application in milk samples]. AB - By using melamine (MEL) as the template molecule, magnetic surface molecularly imprinted polymers (MMIPs) were prepared. Methacrylic acid (MAA) was chosen as the functional monomer, and ethyleneglycol dimethacrylate (EGDMA) was chosen as the cross-linker, and Fe3O4@SiO2 was used as the magnetic supporter. Transmission electron microscope (TEM), thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR) analysis and a vibrating sample magnetometer (VSM) were used to characterize the polymers. An imprinted polymer layer was found on the surface of the Fe3O4@SiO2 nanomaterials. MMIPs were applied to extract and enrich melamine in milk samples. The specific recognition capability of the material was confirmed by high performance liquid chromatographic (HPLC) analysis. Thus, a simple and selective method was successfully established using MMIPs as sorbents to detect melamine in milk with satisfactory results. PMID- 30251494 TI - [Synthesis and application of a magnetic spiramycin-templated molecularly imprinted nanoparticle adsorbent]. AB - A magnetic spiramycin-templated molecularly imprinted nanoparticle adsorbent is described. It was synthesized by choosing Fe3O4 nanoparticles as the core, and then modified with acrylic acid, followed by the addition of spiramycin as a template molecule, methacrylic acid as a functional monomer, and ethylene glycol dimethacrylate as a crosslinking agent. Finally, the adsorbent was prepared via surface radical polymerization. The adsorbent demonstrated effective enrichment for four macrolide antibiotics (MA) including spiramycin, josamycin, tilmicosin, and tylosin tartrate, whose enrichment factors were 310, 118, 758, and 72, respectively. Its selectivity toward the trace MA was obviously higher than that of the common C18 adsorbent. In addition, the adsorbent also showed favorable reusability (at least six times). A corresponding analytical method for MA was established by subjecting the adsorbent to high-performance liquid chromatography with ultraviolet absorbance. For the above four model MAs, the limits of detection were in the range of 0.53-2.75 MUg/L, and the limits of quantitation were in the range of 1.78-9.16 MUg/L. The recoveries of the method were in the range of 80.78%-123.02% for three spiked levels of 50, 100 and 150 MUg/L, and the relative standard deviation was less than 15.8% (n=5). The method was used for the determination of the four MAs above in honey. PMID- 30251495 TI - [Simultaneous determination of 11 strobilurin fungicides in different vegetation types of soil by QuEChERS-ultra performance liquid chromatography-tandem mass spectrometry]. AB - A method for the simultaneous determination of the 11 strobilurin fungicides (coumoxystrobin, tricyclopyricarb, picoxystrobin, fluoxastrobin, trifloxystrobin, E-metominostrobin, kresoxim-methyl, dimoxystrobin, orysastrobin, pyraoxystrobin and fenaminstrobin) in different vegetation types of soil by QuEChERS-ultra performance liquid chromatography-tandem mass spectrometry was developed. The strobilurin fungicides were extracted with 0.1% (volume percentage) acetic acid acetonitrile, and cleaned-up with 100 mg primary secondary amine (PSA) and 100 mg C18. The separation was performed on a C18 column with methanol and water as the mobile phases. The strobilurin fungicides were determined in the positive ion mode and multiple reaction monitoring mode. The quantification was carried out by the matrix-matched external standard curve. The results showed good linear relationships for all analytes in the range of 0.1-100 MUg/kg with the correlation coefficients of 0.9805-0.9999. The mean recoveries of strobilurin fungicides in the spiked soil samples were 65.1%-103.9% and the relative standard deviations were 0.082%-14% (n=3) at three spiked levels (5, 10 and 50 MUg/kg). The limits of quantitation were 0.005-2.0 MUg/kg. This method is suitable for the trace determination of the 11 strobilurin fungicides in different vegetation types of soil (black soil, red soil, sandy soil, moisture soil, desert grey soil, and plateau soil). PMID- 30251497 TI - [Rapid determination of fipronil and its metabolite residues in eggs using ultra performance liquid chromatography-tandem mass spectrometry]. AB - A method was developed for the rapid simultaneous determination of fipronil and its metabolite residues in eggs using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The egg samples (2 g) with 2 mL water were extracted with 4 mL acetonitrile. After adding 1 g sodium chloride, the mixture was centrifuged at 9000 r/min for 10 min at 4C. The suspension was diluted and filtered through a 0.22 MUm organic membrane. The analytes were separated on a C18 column (100 mm*2.1 mm, 1.7 MUm), and detected under the multiple reaction monitoring (MRM) mode with a negative ESI source. The average recoveries of fipronil and its metabolites varied from 77.4% to 112.1%, and the relative standard deviations were between 4.0% and 13.6% at three spiked levels. The limits of detection (LODs) ranged from 0.10 MUg/kg to 0.43 MUg/kg. The method is simple, effective, and can be applied to real samples. PMID- 30251496 TI - [Determination of migration of perfluorooctanoic acid and perfluorooctane sulfonic acid from food contact materials by ionic liquid-based dispersive liquid liquid microextraction and ultra-performance liquid chromatography-tandem mass spectrometry]. AB - A new method was developed to determine the migration of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) from food contact materials (FCMs) using ionic liquid-based dispersive liquid-liquid microextraction (IL DLLME) coupled with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). FCM samples were soaked in three food simulants of water, 10% (v/v) aqueous ethanol solution, and 4% (v/v) acetic acid solution for the migration test, and then the migration liquid was extracted and enriched using the IL-DLLME. The key parameters in terms of the type and volume of extractant, vortex time, NaCl concentration, and the speed and time of centrifugation were investigated. The analytes were separated on a Waters ACQUITY UPLC BEH Shield RP18 column (50 mm*2.1 mm, 1.7 MUm), eluted by gradient with acetonitrile and water, and quantified by electrospray ionization mass spectrometry in negative mode using multiple reaction monitoring (MRM). The experimental results showed good linearities (r2>0.99) in their concentration ranges. The limits of detection (LODs) were 0.5 and 1 MUg/L, and the limits of quantitation (LOQs) were 2 and 5 MUg/L for PFOA and PFOS, respectively. The recoveries of PFOA and PFOS ranged from 86.4% to 116.9% at three spiked levels with the relative standard deviations (RSDs) between 4.3% and 14.4% (n=6). The proposed method was demonstrated as accurate, efficient, eco-friendly, and suitable for the determination of the migration of PFOA and PFOS from FCMs. PMID- 30251499 TI - [Determination of 28 exogenous medicines and endogenous components in herbal drink using high performance liquid chromatography]. AB - A high performance liquid chromatographic method for the determination of 28 exogenous medicines and endogenous components in the herbal drink was developed. The samples were extracted ultrasonically with methanol-water (70:30, v/v), and the extracts were separated in a Thermo Accucore C18 column (100 mm*4.6 mm, 2.6 MUm) with methanol-acetonitrile-20 mmol/L ammonium acetate solution (pH 4.2) as the mobile phases by gradient elution. The flow rate was 1.2 mL/min and the column temperature was 35C. The detection wavelengths were 254 nm and 220 nm. Quantification analysis was performed by the external standard method. The result showed the compounds had a good linear relationship in the range of 1-100 mg/L, and the correlation coefficients (r) were not less than 0.999. The limits of detection (LODs) of the 28 compounds were 1-10 mg/kg in the liquid sample and 20 200 mg/kg in the solid sample. The average recoveries of the 28 compounds in the liquid and solid samples were in the ranges of 88.8%-118.6% and 92.7%-112.3% with the relative standard deviations (RSDs) of 0.1%-6.7% and 0.1%-6.4%, respectively. The method was applied to analyze 456 herbal drink samples, and 55 positive samples were found. The positive rate was 12.1%. The developed method was simple and reliable, and it was suitable for the determination of 28 components in the herbal drink. PMID- 30251498 TI - [Simultaneous determination of monepantel and its metabolite residues in cow and sheep milk by solid phase extraction-high performance liquid chromatography tandem mass spectrometry]. AB - A method for the rapid and simultaneous determination of monepantel and its metabolite residues in cow and sheep milk has been developed using high performance liquid chromatography-tandem mass spectrometry. The samples were extracted with acetonitrile to precipitate the proteins and passed through a neutral alumina solid phase extraction (SPE) cartridge. The extracts were separated on an Inertsil C8-3 column (150 mm*4.6 mm, 5 MUm) with a gradient elution program consisting of methanol and ammonium acetate. A triple stage quadrupole mass spectrometer equipped with an electrospray ionization source in negative ion mode was used to detect monepantel and its metabolite residues. The quantification of the analytes was performed by the external standard method. Good linear relationships between the peak areas and mass concentrations of the analytes were obtained in the range of 0.1-5.0 MUg/L with correlation coefficients greater than 0.99 (n=6). The limits of quantification were 2.0 MUg/kg. The recoveries of the analytes in cow and sheep milk at three spiked levels (2.0, 50, and 100 MUg/kg) were in the range of 90.1%-103.3% with relative standard deviations between 2.0% and 6.2% (n=6). This method is fast, accurate, and highly sensitive, exhibits strong anti-interference capability with good recovery and repeatability, and can thus be used to simultaneously determine monepantel and its metabolite residues in cow and sheep milk. PMID- 30251500 TI - [Analysis of traditional Chinese medicine components by high performance liquid chromatography with diode array detection based on double qualitative principles]. AB - The double qualitative principle is a new composite qualitative method based on retention time and the characteristic peaks of the absorption spectra. Using a self-designed and assembled diode array detector (DAD), a high performance liquid chromatography (HPLC) system was constructed. The illegal additive auramine O in six kinds of herbal slices and the active ingredient schisandrin in Jujube kernel Tianma capsules were separated and qualitative analyzed using the HPLC-DAD system. The results showed that there were similar peaks in the chromatograms of pollen typhae and Jujube kernel Tianma capsules when comparing the target analytes. However, the probabilities of the targets were excluded by comparing the absorption spectra. The application results indicated that, based on the double qualitative principle of retention time/absorption spectrum, the interference of impurities in the samples could be well eliminated and the false positives could be avoided. This provides a reference method for the study of traditional Chinese medicine components. PMID- 30251501 TI - [Gas chromatography-mass spectrometry data analysis algorithm based on sparse model and its application in resolving severely overlapped peaks]. AB - A Gas chromatography-mass spectrometry (GC-MS) data analysis algorithm is proposed. The mass spectrum at the top of the chromatographic peak is the spectrum to be solved. A certain amount of related reference spectra is retrieved from the spectral library, then, the equation of the chromatographic response value of each pure component is solved. A step by step strategy is used for the mass spectra retrieval. Firstly, an efficient indexing technology is used for rough selection, then, the "strong peak out with high probability" and the "extrusion" rules are used to exclude more unrelated mass spectra. A regression algorithm based on a sparse model is proposed to solve the equation of the chromatographic response value. Compared with the traditional algorithm, this algorithm can extract the main structure of the spectrum to be solved, and avoid over-fitting. The experimental results show that the proposed algorithm has a higher accuracy and smaller residual reference spectrum set, and the sparse model achieves satisfactory experimental results in the analysis of severely overlapped peaks. The proposed method provides an effective solution for resolving overlapped peaks, especially severely overlapped peaks, in GC-MS data. PMID- 30251502 TI - [Analysis of kerosene-based endothermic hydrocarbon fuel using comprehensive two dimensional gas chromatography coupled to mass spectrometry]. AB - Hydrocarbon fuels are mainly composed of n-alkenes, iso-alkanes, cycloalkanes (primarily single-and double-ring), alkylbenzenes, indans, tetralins, naphthalene, and alkylnaphthalenes. Different hydrocarbon classes impart different properties to a fuel. An identification method of hydrocarbon classes in kerosene-based endothermic hydrocarbon fuel was established using comprehensive two-dimensional gas chromatography coupled to mass spectrometry (GC*GC-MS). Moreover, the corresponding quantitative determination was achieved using the effective carbon number correction factors of GC*GC-FID. The effects of the main chromatographic conditions such as the column system, program heating conditions, and modulation period on the separation of fuels were discussed. Nine hydrocarbon fuels were analyzed. The results showed that the contents of paraffin and cycloalkanes are consistent with the results obtained using the standard test method ASTM D2425. The relative error is within +/-10%. The carbon content calculated using this method has an error of less than 0.5% compared with the elemental analysis method. This method does not require complicated pretreatment, and the sample can be injected directly after dilution. Compared with the traditional GC-MS, the operation is simple, and the differences among various samples can be observed intuitively, which helps in improving the performance of the fuel. PMID- 30251503 TI - [Determination of 16 phthalate acid esters in infant formula by gas chromatography-tandem mass spectrometry]. AB - A method was established for the determination of 16 phthalate acid esters (PAEs) in infant formula by gas chromatography-tandem mass spectrometry (GC-MS/MS). PAEs in infant formula samples were homogenized by deionized water, extracted with acetonitrile, and purified by a solid-phase extraction (SPE) method using primary secondary amine (PSA) sorbents. The separation was performed on a DB-5 MS UI (30 m*0.25 mm*0.25 MUm) capillary column. Effects of different elution solvents on alumina/PSA and PSA SPE columns were investigated. Fair recoveries of 16 PAEs were achieved on the PSA column upon elution by mixed n-hexane-acetone (60:40, v/v). All the 16 PAEs were quantified by matrix-matched isotopic-dilution mass spectrometry (IDMS); the 16 PAEs showed linear relationships in the concentration range of 0.01-2.0 mg/kg with linear coefficients (R2) greater than 0.9996. The limits of detection (LODs) and quantification (LOQs) were in the range of 0.15 2.5 MUg/kg and 0.50-8.33 MUg/kg, respectively. The recoveries of the 16 PAEs, obtained using the IDMS method, were 96.1%-104.0% with relative standard deviations (RSDs) lower than 3.3% (n=5). These results established the method described here as sensitive and precise for the simultaneous determination of 16 PAEs in infant formula, even at trace concentrations. PMID- 30251504 TI - [Determination of 11 synthetic musks in imported seafood by solid phase extraction and gas chromatography-mass spectrometry]. AB - A method has been developed for the simultaneous determination of 11 synthetic musks (cashmeran, celestolide, phantolide, musk ambrette, traseolide, galaxolide, musk xylene, tonalide, musk moskene, musk tibetene, and musk ketone) in imported seafood. The method combines solid phase extraction and gas chromatography-mass spectrometry. Samples were extracted by n-hexane and purified using a Florisil column. Internal standards were used to correct for matrix effects. The calibration curves showed good linearity with correlation coefficients greater than 0.99. The limits of detection (S/N>3) ranged from 0.35 to 2.08 MUg/kg, and the limits of quantification (S/N>10) were between 1.18 and 5.00 MUg/kg. The average recoveries measured at three spiked levels (10, 20, and 30 MUg/kg) were in the range 83.1%-117%, with relative standard deviations ranging from 5.1% to 8.5%. Further, the concentrations of 11 synthetic musks in 30 imported seafood in Shanghai were investigated. Galaxolide was detected in 93.3% of samples analysed, in concentration as high as 3.82 MUg/kg. Musk ambrette and musk moskene were found in concentrations as high as 15.4 MUg/kg and 10.5 MUg/kg, respectively. The established method demonstrates high sensitivity and selectivity for the determination and confirmation of 11 synthetic musks in imported seafood. PMID- 30251505 TI - [Determination of six amphetamine-type stimulants in urine samples using electro enhanced single drop microextraction-gas chromatography]. AB - A method for the simultaneous determination of six amphetamine-type stimulants (ATSs) in urine by electro-enhanced single drop microextraction-gas chromatography (EE-SDME-GC) with a flame ionization detector (FID) was developed. The influences of the EE-SDME parameters on the extraction efficiencies were investigated. The 5 mL-samples at pH 7 were extracted with 2 MUL dichloromethane for 3 min under an applied potential of -2.5 V. The analysis was performed on a HP-5 capillary column (30 m*0.32 mm*0.25 MUm) using a flame ionization detector. The six ATSs were linear in the range of 20-1000 MUg/L with correlation coefficients (r) between 0.989 and 0.997. The limits of detection (S/N=3) of the six ATSs ranged from 3.2 to 7.6 MUg/L. The recoveries of the six ATSs in the spiked urine samples were 91.6%-111.2%, and the relative standard deviations were 2.9%-6.2% (n=3) at three spiked levels of 50, 100 and 500 MUg/L. This method was rapid, sensitive, reliable, easily-operated and environment-friendly for the determination of the ATSs in urine samples. PMID- 30251506 TI - [Screening of 17 cephalosporin residues in infant formula milk powder by ultra high performance liquid chromatography-high resolution mass spectrometry]. AB - A method for the simultaneous determination of 17 cephalosporinsin milk powder by ultra-high performance liquid chromatography-quadrupole/electrostatic field orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) has been developed. After dissolution in water, the homogenized milk powder samples were extracted with acetonitrile to remove impurities such as proteins and the extract was further purified by high-speed centrifugation at low temperature. A C8 chromatographic column was employed to separate the analytes. Quantitative and qualitative analyses were performed in Q Exactive Full-MS/dd-MS2 scan mode. The results revealed an excellent linear correlation over a wide range of analyte mass concentrations (5-200 MUg/L) with coefficients of determination (r2) greater than 0.99 in all cases. The limits of detection (LODs) and quantitation (LOQs) were in the range of 0.0060-0.014 MUg/L and 0.71-4.62 MUg/kg, respectively. The overall average recoveries were 69.6%-101.4% with RSDs<10%. This method presents the advantages of simple operation, good repeatability, and high resolution, being suitable for the qualitative and quantitative screening of 17 cephalosporin residues in infant formula milk powder. PMID- 30251507 TI - [Determination of aminobutanol by high performance liquid chromatography based on charge transfer reaction]. AB - A method was developed for the determination of the content of aminobutanol by high performance liquid chromatography (HPLC) based on charge transfer reaction. Under the condition of a borax-boric acid buffer solution of pH 8.4, aminobutanol and tetra-chloro-benzoquinone reacted at 60C for 60 min, and were analyzed by an HPLC-ultraviolet detector. The charge-transfer complex was separated on an Agilent Extend C18 column (250 mm*4.6 mm, 5 MUm) with 0.001% (v/v) triethylamine and methanol as the mobile phases for gradient elution at a flow rate of 1 mL/min. The limit of quantification of aminobutanol was 0.01 g/L, the linear range was 0.1-0.6 g/L, and the correlation coefficient (R2) was 0.9994. The spiked recoveries of the method were 98.3%-103.6% with relative standard deviations (RSDs) of 0.9%-1.6%. The method is simple and quick, and suitable for the rapid detection of aminobutanol. PMID- 30251508 TI - [Fabrication of conventional ion chromatography-capacitively coupled contactless conductivity detector]. AB - A conventional ion chromatography-capacitively coupled contactless conductivity detector (IC-C4D) was fabricated. The main parameters, such as the electrode length and gap, tube material and inner diameter, excitation frequency, voltage and waveforms, were optimized. The self-made C4D showed comparable performance to that of a commercial contact conductivity detector. Under the suppressed mode, the limits of detection of common inorganic anions (F-, Cl-, NO2-, Br-, NO3-, and SO42-) were 0.02-0.08 MUmol/L. The relative standard deviations (RSDs) for the peak area were less than 1.8% (n=6). The linearities of the six common inorganic anions were achieved in the range of 0.1-10 MUmol/L with correlation coefficients (R2)>0.9950. The advantages of such a C4D in a relatively conventional mode include simple structure, low fabrication cost and no electrode fouling, and it will help extend the application of IC. PMID- 30251509 TI - [Differences of three pretreatment methods for the detection of docosahexaenoic acid, eicosatetraenoic acid, linoleic acid and alpha-linolenic acid in infant formula milk powder]. AB - The differences of three pretreatment methods (acetyl chloro carbinol esterification, acid hydrolysis esterification and alkali hydrolysis esterification) for the detection of four polyunsaturated fatty acids (docosahexaenoic acid, arachidonic acid, linoleic acid and alpha -linolenic acid) in infant formula milk powder were discussed. Acetyl chloro carbinol esterification and acid hydrolysis esterification were found to be significantly better than alkali hydrolysis esterification. The sample digestion and fat methyl esterification were carried out simultaneously in the acetyl chloro carbinol esterification method, where the two processes seemed to enhance each other. This allowed the complete release and methyl esterification of the fats. The accuracy of the methods was determined by investigating the reaction processes and recovery rates. Acid and alkali hydrolysis esterification methods were employed to hydrolyze the samples using a hydrochloric acid solution and an ammonia solution, respectively. Then, the fats were extracted for subsequent methyl esterification. These two methods were compared in terms of the digestion efficiency, extraction efficiency, and methylation efficiency. The results showed that the digestion efficiency is the main factor determining the differences between the acid and alkali hydrolysis methods. The accuracies of acetyl chloro carbinol esterification and acid hydrolysis esterification methods were further verified in the detection of samples, providing a basis for the determination of fatty acids in other foods. PMID- 30251510 TI - [Advances in the hyperbranched and poly amidoamine dendrimers grafting modification methods of chromatographic stationary phase]. AB - With the rapid development of chromatographic stationary-phase preparation technology, various modified methods are becoming increasingly mature, mainly including direct surface chemical reactions, agglomeration, grafting, and hyperbranched modification. Among these methods, hyperbranched modification based on polycondensation has been popular with researchers since it was proposed, and it has been applied to the preparation of various anion exchangers. Dendrimers are a class of three-dimensional, highly ordered dendritic macromolecules with perfect structure, high degree of surface functionality, and unique physicochemical properties. Recently, they have also gradually been applied in various chromatographic stationary-phase modifications and are expected to improve the structure and separation performance of the stationary phase, because its structure is similar to those of hyperbranched polymers. This article mainly summarizes the applications of hyperbranched and poly amidoamine dendrimers using grafted modification methods in the preparation of the chromatographic stationary phase. Finally, the trends and promising prospects of this field are presented. PMID- 30251511 TI - [Tandem technologies in chromatographic analysis]. AB - The acquisition of chemical compounds information from samples depends on the separation as well as detection techniques. Usually, it is difficult to achieve the separation and identification of all components in complex samples by a simple one-dimensional chromatographic method. Thus, tandem technologies, which mainly include column tandem connection techniques, detector tandem connection techniques, and multidimensional chromatography, have aroused widespread interest. In this paper, advances in the three aforementioned tandem techniques (not including chromatography tandem mass spectrometry) since 2010 are discussed. Typical applications for obtaining more comprehensive and accurate information from samples are also reviewed. Finally, the development of chromatographic tandem technologies is summarized and future prospects are examined. PMID- 30251512 TI - [Chromatographic behavior of basic drugs on thioether-embedded benzenesulfonate silica stationary phases]. AB - Mixed-mode chromatography (MMC) has pronounced advantages in the separation and analysis of complex samples. Compared with single-mode chromatography, the solute retention in MMC is controlled by multiple interactions, and the retention mechanism is more complicated. In this work, two thioether-embedded benzenesulfonate silica single-ligand and mixed-ligand stationary phases were prepared by thiol-ene click chemistry. The retention mechanisms of four basic drugs were investigated under various mobile phase compositions (pH, ionic and solvent strength). The results showed that both stationary phases have the mixed retention mechanism of the reverse phase and ion exchange. By changing the salt concentration of the mobile phase, the relationship between the retention factors of basic drugs and the reciprocal of ionic strength were investigated. The results indicate that a three-interaction-form model, containing reversed-phase, pure ion-exchange, and hydrophobically assisted ion-exchange interaction, is more suitable for the mechanism study of MMC. The quantitative results demonstrate that ion-exchange interaction composed of pure ion-exchange and hydrophobically assisted ion-exchange interaction is dominated on two phases. The relative contribution of each mechanism was varied with the solute, mobile phase composition, and ligand type and ratio. In addition, the hydrophobically assisted ion-exchange interaction had a significant impact on the solute retention and separation selectivity. These fundamental studies on the MMC retention mechanism are of great theoretical significance for the novel stationary phase design and the optimization of complex sample separation. PMID- 30251513 TI - [Separation of eicosapentaenoic acid ethyl ester and docosahexaenoic acid ethyl ester by simulated moving bed chromatography]. AB - Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are important omega -3 polyunsaturated fatty acids. Their physiological effects on humans are not exactly the same; therefore, the production of products with high-purity EPA or DHA monomers is significant. In this work, EPA ethyl ester (EPA-EE) and DHA ethyl ester (DHA-EE) were first separated using HPLC with poly(styrene-co divinylbenzene) (PS/DVB) as the stationary phase. The effects of the mobile phase, PS/DVB particle diameter, and column temperature were systematically evaluated. The results showed that methanol is a suitable mobile phase, having a resolution of 2.75. By comparing resolutions, a PS/DVB particle diameter of 10 MU m was chosen; however, when the pressure drop of PS/DVB is considered, PS/DVB with a particle diameter of 20 MU m is more favorable for large-scale preparations. A column temperature of 40C was found to be the most feasible for maintaining efficient separation. Second, eight semi-preparative columns (150 mm*10 mm) of PS/DVB polymer were prepared for the simulated moving bed (SMB) chromatography; the homogeneity of these columns was perfect, with a relative total column porosity error of less than 1%. Finally, an EPA-EE and DHA-EE mixture was separated using the SMB chromatography, and the contents of the extract and the raffinate were determined using GC-FID. The effects of the flow rate of Zone II and Zone III, the flow rate of the feed, and the feed concentration were investigated. Under optimal conditions, EPA-EE and DHA-EE with favorable purities of 91.6% and 93.6%, respectively, were achievable. The recovery of the EPA-EE was 97.0% and the recovery of the DHA-EE was 91.6%. The productivity and solvent requirements were 5.97 g/(L?5h) and 1.52 L/g, respectively. Therefore, SMB chromatography is an attractive technology for the production of high-value products. PMID- 30251514 TI - [Rapid determination of benzidine, picric acid, carbaryl, atrazine, and deltamethrin in surface water by ultra-performance liquid chromatography-tandem mass spectrometry]. AB - A method requiring no pre-treatment steps other than filtration, using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), has been developed and applied for the rapid determination of benzidine, picric acid, carbaryl, atrazine, and deltamethrin residues in surface water. Water samples were filtered with a 0.2-MU m syringe filter for particle removal and injected directly into the UPLC instrument. The separation was performed on a Waters Acquity UPLC HSS T3 column utilizing a gradient elution program of methanol (containing 2 mmol/L ammonium acetate) and water (containing 2 mmol/L ammonium acetate) as the mobile phases at a flow rate of 0.4 mL/min. The detection was accomplished by multiple-reaction monitoring scanning in positive/negative ion switching electrospray ionization mode. Good linearity was observed in the range 0.10-10.0 MU g/L or 1.00-100 MU g/L for different targets with correlation coefficients of 0.996-0.999. The limits of detection (LODs) were 0.01-0.22 MU g/L. The recoveries ranged between 81.4% and 113% at three spiked levels with relative standard deviations (n=6) between 0.84% and 14.0%. The developed method was applied to the analysis of surface waters (river water and reservoir water) from Hangzhou; atrazine and deltamethrin were detected in part of the analyzed samples. This proposed method was characterized by high sensitivity and precision, extensive analytical range, and a high analytical rate, and showed suitability for the analysis of the five named pollutants in surface water. PMID- 30251516 TI - [Determination of 42 veterinary drug residues in common animal derived food by dispersive solid phase extraction coupled with liquid chromatography-tandem mass spectrometry]. AB - A liquid chromatography-tandem mass spectrometry method, coupled with a dispersive solid phase extraction (DSPE) procedure for sample preparation, was developed to determine 13 classes of 42 veterinary drugs in four representative animal-derived foods. The analytes were dispersed with water, extracted with acetonitrile containing 5% (v/v) formic acid, salted out by salts, and purified by DSPE. The analytes were separated on a C18 column (100 mm*2.1 mm, 2 MU m) with gradient elution using the mobile phase containing methanol and 0.1% (v/v) formic acid aqueous solution. Electrospray ionization-mass spectrometry was performed in multiple reaction monitoring mode for analysis of the 42 compounds. The correlation coefficients of the standard calibration curves for the 42 veterinary drugs were all above 0.995. Most recoveries at three spiked levels in the four representative matrixes ranged from 65.8% to 135.5%, with relative standard deviations of 0.5%-14.2% (n=6). The limits of detection (LODs, S/N=3) and the limits of quantification (LOQs, S/N=10) were 0.01-1.68 MU g/kg and 0.01-5.62 MU g/kg, respectively. The method is simple, rapid, sensitive, and suitable for the simultaneous determination of the 42 veterinary drugs in animal-derived food. PMID- 30251515 TI - [Determination of glyphosate, glufosinate, and main metabolite aminomethylphosphonic acid residues in dry tea using ultra-high performance liquid chromatography-tandem mass spectrometry]. AB - A method has been developed for the determination of glyphosate (GLY), glufosinate (GLUF), and the main metabolite aminomethylphosphonic acid (AMPA) residues in dry tea based on ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) coupled with pre-column derivatization. A systematic study of the effects of pretreatment methods including extraction and purification procedures was designed and carried out for the determination of GLY, GLUF, and AMPA. The results indicated that the optimal pretreatment method was as follows:the tea sample was first extracted by water in vortex, and then purified by a cation exchange solid-phase extraction column with the elution of 0.5% (v/v) formic acid aqueous solution. Finally, the eluant was derivatized by 9 fluorenylmethyl chloroformate, and the target compounds were separated on a C18 chromatographic column and analysed by UPLC-MS/MS (ESI+). GLY, GLUF, and AMPA showed good linearity in the range of 1-100 MU g/L, with correlation coefficients above 0.991. The limits of detection and limits of quantification were found to be 0.0160-0.0300 mg/kg and 0.0530-0.100 mg/kg, respectively. The average spiked recoveries of GLY, GLUF, and AMPA varied from 78.3% to 108% at three spiked levels (0.0500, 0.400, and 1.20 mg/kg), while the relative standard deviations ranged from 5.46% to 9.63%. The proposed method was utilized to detect 837 batches of tea samples. The detection ratios of GLY, GLUF, and AMPA were 3.46%, 0.24%, and 4.42%, respectively, while 0.24% of the investigated tea samples had values above maximum residue limits. The developed method is simple, rapid, sensitive, and accurate for the determination of GLY, GLUF, and AMPA in dry tea and may be used for routine analysis. PMID- 30251517 TI - [Simultaneous rapid determination of 12 anti-allergic chemical drugs in Chinese traditional patent medicine and health food by supercritical fluid chromatography tandem mass spectrometry with solid phase extraction]. AB - An analytical method was developed for simultaneous rapid determination of 12 anti-allergic chemical drugs in Chinese traditional patent medicine and health food by supercritical fluid chromatography tandem mass spectrometry with solid phase extraction (SPE-SFC-MS/MS). Samples were extracted with methanol by sonification and then purified by Oasis mixed-model cation exchange SPE. The extracts were separated on a Waters Trefoil CEL1 (150 mm*3.0 mm, 2.5 MU m) column with a mobile phase consisting of carbon dioxide-methanol containing 0.1% (v/v) ammonia water in a gradient elution mode, at a flow rate of 1.2 mL/min. The column temperature was 45C and the back pressure was 12.4*106 Pa. The whole analysis was completed in 10 min. The 12 anti-allergic chemical drugs were detected by an electrospray ion source in positive or negative modes with a multiple reaction monitoring (MRM) mode. The calibration curves of the 12 anti allergic chemical drugs showed good linearities in the range of 5-250 MU g/L with the correlation coefficients (r) >= 0.998. The limits of detection (LODs) were 0.141-0.262 MU g/L, and the limits of quantification (LOQs) were 0.703-1.308 MU g/L. The recoveries of the 12 anti-allergic chemical drugs at spiked levels of 10, 20 and 100 MU g/L were in the range of 76.1%-112.5%, and the relative standard deviations (RSDs) were 1.1%-8.3% (n=6). The method is simple, sensitive and reliable. It has been successfully used for the detection of illegally added anti-allergic chemical drugs in Chinese traditional patent medicine and health food. PMID- 30251518 TI - [Determination of nine phthalate ester metabolites in human urine using ultra high performance liquid chromatography-tandem triple quadrupole mass spectrometry]. AB - A method was developed to determine trace concentrations of phthalate ester (PAE) metabolites in human urine by using ultra high performance liquid chromatography triple quadrupole mass spectrometry. Aliquots (2 mL) of human urine samples were purified using strong anion-exchange solid-phase extraction after enzymatic deconjugation by glucuronidase for 2 h. The separation was performed on a Waters ACQUITY UPLC BEH Phenyl column (100 mm*2.1 mm, 1.7 MU m) with gradient elution by 0.1% (v/v) acetic acid in acetonitrile and 0.1% (v/v) acetic acid aqueous solution. The concentrations of nine PAE metabolites were determined under a multiple reaction monitoring mode by negative electrospray ionization. Eight of the determined metabolites showed good linearities in the range of 0.39-200 MU g/L, and the ninth metabolite showed linearity in the range of 1.17-600 MU g/L with correlation coefficients > 0.995. The limits of detection ranged from 0.06 to 0.85 MU g/L, and the limits of quantification ranged from 0.20 to 2.80 MU g/L. The recovery rates at all three spiked levels ranged from 84.1% to 122% with relative standard deviations between 4.5% and 14.3%. The intra-and inter-day precisions were not more than 10.1% and 9.3%, respectively. The matrix effect and stability were found to be favorable for analysis. This method was utilized for the determination of 50 human urine samples. The detection rates of monocyclohexyl phthalate (MCHP) and monobenzyl phthalate (MBZP) were 0 and 44.0%, and the detection rates of the other seven PAE metabolites was 100%. This method has the advantage of convenient operation and good accuracy and stability, and is suitable for the quantitative determination of the nine PAE metabolites in human urine. PMID- 30251519 TI - [Simultaneous determination of 12 direct dyes in cosmetics by high performance liquid chromatography]. AB - A method was developed for the simultaneous separation and determination of 12 direct dyes in cosmetics by high performance liquid chromatography (HPLC). The analytes were separated on an XB-C18 column with acetonitrile-0.02 mol/L ammonium acetate aqueous solution (pH 9.0) as the mobile phases, and were detected using a diode array detector. The results indicated that the 12 direct dyes had good linearities with correlation coefficients greater than 0.999. The limits of detection were between 0.017 MU g/g and 1.7 MU g/g. The average recoveries ranged from 85.6% to 113.4%, and the relative standard deviations (RSDs) ranged from 1.0% to 7.7%. The intra-and inter-day RSDs were 0.4%-6.5% and 0.2%-7.5%, respectively. The method is simple, rapid, accurate, and is suitable for the determination of direct dyes in cosmetics. PMID- 30251520 TI - [High-aspect-ratio gas chromatography column based on micro-electro-mechanical system technology]. AB - Miniaturization of gas chromatography (GC) columns is one of the key problems associated with microminiaturization of a chromatograph. In this study, a GC column with high-aspect-ratio microchannel based on micro-electro-mechanical system (MEMS) technology has been designed and manufactured. Simulation and analysis by the COMSOL software revealed that the GC column has even velocity field distribution, which is crucial for improving the separation efficiency of the column. The results show that heavy hydrocarbons (C6-C10) and compounds of benzene series can be successfully separated. The number of theoretical plate is 14028 plates/m, and the resolution of C7-C8 is 10.82. Due to its advantages of smaller volume, lower energy consumption, and better separation performance, the GC column can be applied in micro gas chromatography. PMID- 30251521 TI - [Determination of 50 pesticide residues in fruits by gas chromatography-tandem mass spectrometry]. AB - A method for the determination of 50 pesticides in fruits by gas chromatography tandem mass spectrometry (GC-MS/MS) was developed. The three QuEChERS methods (the original one without buffer, the one with acetate buffer and the one with citrate buffer) were compared. The purification effects of primary secondary amine (PSA) and SinChERS-Nano column were also investigated. The results showed that the acetate buffer and the citrate buffer had positive influence on the extraction compared to the original method without buffer, and there was no significant difference between the two methods using buffers. Finally, the QuEChERS method using acetate buffer was chosen as the extraction method. By comparing the purification effect images and the total ion current (TIC) chromatograms, SinChERS-Nano column was revealed to have a better cleaning effect, and was chosen for cleanup. The recoveries of methamidophos, acephate, omethoate, chlorothalonil and dicofol were in ranged of 71.2%-129.2%, the other 45 pesticides were ranged from 79.1% to 122.3%. The limits of detection (LODs) were 0.3-3.0 MU g/kg and the limits of quantification (LOQs) were 1.0-10.0 MU g/kg. The method is rapid and suitable for the screening of the 50 pesticide residues in citrus, grapes and other fruit samples. PMID- 30251522 TI - [Analysis of fatty acid composition in cottonseed by gas chromatography with on line pyrolytic methylation]. AB - A method of on-line pyrolytic methylation-gas chromatography was developed for the analysis of fatty acid composition in cottonseed. Fatty acids in cottonseeds were converted to their corresponding fatty acid methyl esters in the presence of trimethylsulfonium hydroxide at 300C. The major fatty acids were linoleic acid (C18:2), oleic acid (C18:1), palmitic acid (C16:0), stearic acid (C18:0), myristic acid (C14:0), palmitoleic acid (C16:1), arachidic acid (C20:0) and docosanoic acid (C22:0). The unsaturated fatty acid content varied from 66.30% to 72.54%, and linoleic acid content varied from 43.20% to 53.61%. The RSDs of the peak areas of the fatty acids were less than 10% (n=5). The fatty acid compositions in the cottonseed samples, obtained from different growing places and different edible oil samples were compared by statistical analysis. The results showed that fatty acid compositions in cottonseed samples from different regions were similar. The fatty acid composition in cottonseed samples was closest to that of corn oil, and the similarity varied from 0.960 to 0.992. The method is simple, rapid, accurate, and is suitable for the analysis of fatty acid composition in cottonseed. PMID- 30251523 TI - [Uniform and orthogonal designs on experimental design and optimization of micellar electrokinetic capillary chromatographic method for the simultaneous analysis of three nucleoside antivirus drugs in disinfectant and anti/bacteriostatic products]. AB - To prevent the abuse of nucleoside-based antiviral drugs in disinfectant and anti/bacteriostatic products, a new micellar electrokinetic chromatographic (MEKC) method for the simultaneous determination of three nucleoside antiviral drugs (ganciclovir, acyclovir and penciclovir) was established. Three factors and seven levels uniform design and four factors and four levels orthogonal design were used to optimize the concentration of sodium dodecyl sulfate (SDS), sodium dihydrogen phosphate (NaH2PO4) and sodium borate (Na2B4O7) in the running buffer. The three nucleoside antiviral drugs were separated from each other in the shortest time to obtain effective separation through uniform and orthogonal designs on experimental design and optimization. The separation was performed on an uncoated fused-silica capillary with 50 MU m i. d. and a total length of 30.2 cm (effective length:20 cm). An optimized buffer solution consisting of 25 mmol/L NaH2PO4, 10 mmol/L Na2B4O7 (pH 7.41) and 140 mmol/L dodecyl sulfate sodium was used for separation. The applied voltage was 10 kV, the injected pressure and time was at 0.003 Pa for 4 s. The wavelength of the detection was 250 nm. Under the optimum conditions, the corrected area and the concentration had good linearity. The correlation coefficients (r) were not less than 0.9995. The limits of detection were all 2.0 mg/kg. The limits of quantitation were all 7.0 mg/kg. The relative recoveries ranging from 85.4% to 104.1% with RSDs all lower than 8.0%. It showed that the method was suitable for the detection of ganciclovir, acyclovir and penciclovir in disinfectant and anti/bacteriostat products with simplicity and rapidity. PMID- 30251524 TI - [Simultaneous determination of 77 pesticide residues in eight kinds of herbal tea by liquid chromatography-tandem mass spectrometry]. AB - An effective method was developed for the determination of 77 pesticide residues in eight kinds of herbal tea by modified QuEChERS and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The target compounds were extracted with 1% (v/v) acetic acid-acetonitrile and 1 g ammonium acetate, and purified by 4 g MgSO4, 0.05 g C18, 0.50 g primary secondary amine (PSA) sorbent and 0.05 g graphitized carbon black (GCB). The 0.1% (v/v) formic acid aqueous solution and acetonitrile were used as the mobile phases. The extracts were separated on a Venusil MP C18 chromatographic column using a positive electrospray ionization (ESI) and negative ESI source under the selected ion monitoring (SIM) mode. The analytes were quantified by the matrix match standard solutions. The good linearities were obtained in the range of 0.5-100.0 MU g/L, and the correlation coefficients were all greater than 0.995. The average recoveries of the 77 pesticide residues ranged from 70.3% to 110.0%, and RSDs were in the range of 2.6%-9.8%. The limits of detection were 1.0-10.0 MU g/kg. The method is sensitive, accurate and precise, and can meet the requirements for the determination of pesticide residues. PMID- 30251526 TI - Highly Sensitive Detection of MicroRNA-21 with ICPMS via Hybridization Accumulation of Upconversion Nanoparticles. AB - A highly sensitive platform is developed for the determination of microRNA-21 (miRNA-21) with inductively coupled plasma mass spectrometry (ICPMS). It includes the following operations: Hairpin structures DNA H1 and H2 are designed, and DNA H1 is bound to ultrasmall lanthanide upconversion nanoparticles (UCNPs) to produce UCNPs@DNA conjugate probes. Target miRNA triggers a chain reaction for alternating hybridization between DNA H1 (bound on UCNPs@DNA probe) and DNA H2. This leads to UCNPs accumulation and serves as an efficient amplification strategy for UCNPs. The concentration of miRNA-21 is closely correlated to the number of UCNPs; thus, the detection of 89Y by ICPMS provides a promising approach for miRNA quantification. This protocol exhibits high sensitivity to miRNA-21 within 0.1-500 fM, along with a detection limit of 41 aM, which is among the hitherto reported most sensitive procedures. It is worth mentioning that rare earth elements are scarcely present in living systems, which minimizes the background for ICPMS detection and excludes potential interferences from the coexisting species, which is most suited for biological assay. PMID- 30251525 TI - [Kingella kingae as a common cause of arthritis septic in children]. AB - OBJECTIVE: Kingella kingae is a common colonizer of the oropharynx in children that may lead to invasive infection, mainly osteoarticular infections. Invasive infections occur almost exclusively in young children, fundamentally fewer than two years old. K. kingae infections in children are probably underdiagnosed due to the difficulty in growing in routine cultures and the absence of systematic realization of molecular techniques to identify it. It is the most common bacteria involved in childhood osteoarticular infections in recent series and increasingly being recognized in Spain. We report our experience on the epidemiological and clinical characteristics of osteoarticular infections in children in recent years. METHODS: Retrospective analysis of septic arthritis by K. kingae identified by PCR in joint fluid in children during 2010-2016. Epidemiological, clinical and laboratory characteristics are presented. RESULTS: Five arthritis by K. kingae were identified, all of them in <=6 years old children. Median leukocytes, CRP and ESR were 12950 leukocytes/MUL, 4.84 mg/dL and 58 mm/h respectively, and 61,322 leukocytes /MUL in joint fluid. All patients evolved favorably. CONCLUSIONS: Osteoarticular infections by K. kingae in children usually present low increase of inflammatory markers despite being invasive infections. The development of PCR in sterile samples has greatly improved the diagnostic yield of K. kingae infections improving the management of osteoarthritis in children. PMID- 30251528 TI - Photodegradation Rate Constants for Anthracene and Pyrene Are Similar in/on Ice and in Aqueous Solution. AB - Snowpacks contain a variety of chemicals, including organic pollutants such as toxic polycyclic aromatic hydrocarbons (PAHs). While PAHs undergo photodegradation in snow and ice, the rates of these reactions remain in debate. Some studies report that photochemical reactions in snow proceed at rates similar to those expected in a supercooled aqueous solution, but other studies report faster reaction rates, particularly at the air-ice interface (i.e., the quasi liquid layer, or QLL). In addition, one study reported a surprising nonlinear dependence on photon flux. Here we examine the photodegradation of two common PAHs, anthracene and pyrene, in/on ice and in solution. For a given PAH, rate constants are similar in aqueous solution, in internal liquid-like regions of ice, and at the air-ice interface. In addition, we find the expected linear relationship between reaction rate constant and photon flux. Our results indicate that rate constants for the photochemical loss of PAHs in, and on, snow and ice are very similar to those in aqueous solution, with no enhancement at the air-ice interface. PMID- 30251527 TI - Charge-Transfer Modeling and Polarization DRT Analysis of Proton Ceramics Fuel Cells Based on Mixed Conductive Electrolyte with the Modified Anode-Electrolyte Interface. AB - A charge-transfer model considering the mixed conductivities of proton, oxygen ion, and free electron in interface-modified La2Ce2O7 (LCO) electrolyte is designed to analyze the characteristics of proton ceramics fuel cell in the field of the open-circuit voltage, internal short-circuit current, proton-transfer number, discharging curves, oxygen/hydrogen partial pressure, and cell efficiencies. The properties of anode-supported single cells with the modified anode-electrolyte interface containing an in situ formed doped BaCeO3 reaction layer are compared to those of unmodified cells at various temperatures T and H2O partial pressures. Besides, the electrochemical impedance spectroscopies of both cells were investigated by the relaxation time distribution to distinguish different polarization processes. The results indicated that the reaction interface layer can effectively reduce the internal short-circuit current density and increase the proton-transfer number of electrolytes. Importantly, the NiO BaZr0.1Ce0.7Y0.2O3-delta anode can also make more protons transfer from anode to cathode and participate in the cathodic reaction for LCO-based proton ceramics fuel cell. The polarization of the cell decreases with the increase of water partial pressure, which leads to the increase of open-circuit voltage and cell efficiency. PMID- 30251529 TI - A Theory of Enzyme Chemotaxis: From Experiments to Modeling. AB - Enzymes show two distinct transport behaviors in the presence of their substrates in solution. First, their diffusivity enhances with an increasing substrate concentration. In addition, enzymes perform directional motion toward regions with a high substrate concentration, termed as chemotaxis. While a variety of enzymes has been shown to undergo chemotaxis, there remains a lack of quantitative understanding of the phenomenon. Here, we derive a general expression for the active movement of an enzyme in a concentration gradient of its substrate. The proposed model takes into account both the substrate-binding and catalytic turnover step, as well as the enhanced diffusion of the enzyme. We have experimentally measured the chemotaxis of a fast and a slow enzyme: urease under catalytic conditions and hexokinase for both full catalysis and for simple noncatalytic substrate binding. There is good agreement between the proposed model and the experiments. The model is general, has no adjustable parameters, and only requires three experimentally defined constants to quantify chemotaxis: enzyme-substrate binding affinity ( Kd), Michaelis-Menten constant ( KM), and level of diffusion enhancement in the associated substrate (alpha). PMID- 30251530 TI - Self-Organized Formation of Quasi-Regular Ferroelectric Nanodomain Structure on the Nonpolar Cuts by Grounded SPM Tip. AB - The understanding of self-organization processes at the micro- and nanoscale is of fundamental interest and is important to meet the great challenges in further miniaturization of electronic devices to the nanoscale. Here, we report self organized quasi-regular nanodomain structure formation on the nonpolar cut of a ferroelectric lithium niobate single crystal. These structures were formed along the trajectory of grounded scanning probe microscope tip approaching or moving away from the freshly switched region. Detailed analysis of the formed structures revealed internal organization by the length of the needle-like domains, which ranged from uniform to quasi-periodic and even chaotic modes as a function of distance from the switched region. Comprehensive investigations and numerical simulations allowed to attribute explored phenomena to charge injection during the field application and further switching under the action of electric field induced by injected charges near the tip. Self-organization and quasi-periodicity were explained by the effective screening and long-range electrostatic interaction between the individual needle-like domains. PMID- 30251531 TI - Structure Change and Rattling Dynamics in Cu12Sb4S13 Tetrahedrite: an NMR Study. AB - We present a 63Cu and 65Cu NMR study of Cu12Sb4S13, the basis for tetrahedrite thermoelectric materials. In addition to electronic changes observed at the Tc = 88 K metal-insulator transition, we find that locally there are significant structural changes occurring as the temperature extends above Tc, which we associate with Cu atom displacements away from symmetry positions. Spin-lattice relaxation rates (1/ T1) are dominated by a quadrupolar process indicating anharmonic vibrational dynamics both above and below Tc. We used a quasiharmonic approximation for localized anharmonic oscillators to analyze the impact of Cu rattling. The results demonstrate that Cu-atom rattling dynamics extends unimpeded in the distorted structural configuration below Tc and provide a direct measure of the anharmonic potential well. PMID- 30251532 TI - Highly Ordered Macroporous Poly-3,4- ortho-xylendioxythiophene Electrodes as a Sensitive Analytical Tool for Heavy Metal Quantification. AB - Highly ordered macroporous electrodes of the conducting polymer poly-3,4- ortho xylendioxythiophene (PXDOT) are presented as a sensitive analytical tool for heavy metal ion quantification due to a controlled gain in electroactive area. They were designed by using colloidal crystal templates. A direct correlation between the final number of porous layers and the deposition charge ( Qd) employed for electropolymerization is observed. All the electrodes exhibit a surface-templated structure due to an interaction between the radical cation, formed during the electropolymerization, and the surface groups of the silica beads. The voltamperometric response of the macroporous PXDOT electrodes shows a rather fast electron transfer with Delta Ep values between 70 mV and 110 mV. Square wave anodic stripping voltammetric (SWASV) analysis of Cu2+ as a representative heavy metal ion shows a linear response in the subppm range. As a model application, the efficient quantification of Cu2+ in a commercial mezcal sample is validated by the standard addition method and the results correlate adequately with the values obtained by atomic absorption spectroscopy. PMID- 30251533 TI - Conductive and Tough Hydrogels Based on Biopolymer Molecular Templates for Controlling in Situ Formation of Polypyrrole Nanorods. AB - Conductive hydrogels (CHs) have gained significant attention for their wide applications in biomedical engineering owing to their structural similarity to soft tissues. However, designing CHs that combine biocompatibility with good mechanical and electrical properties is still challenging. Herein, we report a new strategy for the fabrication of tough CHs with excellent conductivity, superior mechanical properties, and good biocompatibility by using chitosan framework as molecular templates for controlling conducting polypyrrole (PPy) nanorods in situ formation inside the hydrogel networks. First, polyacrylamide/chitosan (CS) interpenetrating polymer network hydrogel was synthesized by UV photopolymerization; second, hydrophobic and conductive pyrrole monomers were absorbed and fixed on CS molecular templates and then polymerized with FeCl3 in situ inner hydrophilic hydrogel network. This strategy ensured that the hydrophobic PPy nanorods were uniformly distributed and integrated with the hydrophilic polymer phase to form highly interconnected conductive path in the hydrogel, endowing the hydrogel with high conductivity (0.3 S/m). The CHs exhibited remarkable mechanical properties after the chelation of CS by Fe3+ and the formation of composites with the PPy nanorods (fracture energy 12 000 J m-2 and compression modulus 136.3 MPa). The use of a biopolymer molecular template to induce the formation of PPy nanostructures is an efficient strategy to achieve conductive multifunctional hydrogels. PMID- 30251534 TI - Thermal Conductivity of Polyacrylamide Hydrogels at the Nanoscale. AB - A polymer network can imbibe copious amounts of water and swell, and the resulting state is known as a hydrogel. In many potential applications of hydrogels, such as stretchable conductors, ionic cables, and neuroprostheses, the thermal conductivities of hydrogels should be understood clearly. In the present work, we build molecular dynamics (MD) models of random cross-linked polyacrylamide hydrogels with different water volume fractions through a reaction method. On the basis of these models, thermal conductivities of hydrogels at the nanoscale are investigated by a none-equilibrium MD method. This work reveals that when the water fraction of hydrogels is under 85%, the thermal conductivity increases with the water fraction, and can be even higher than the thermal conductivities of both pure polymer networks and pure water because of the influence of the interface between polymer networks and water. However, when the water fraction in hydrogels is bigger than 85%, its thermal conductivity will decrease and get close to the water's conductivity. Accordingly, to explain this abnormal phenomenon, a 2-order-3-phase theoretical model is proposed by considering hydrogel as a 3-phase composite. It can be found that the proposed theory can predict results which agree quite well with our simulated results. PMID- 30251535 TI - Organocatalytic [6+4] Cycloadditions via Zwitterionic Intermediates: Chemo-, Regio-, and Stereoselectivities. AB - The mechanisms and origins of chemo- and stereoselectivities of the organocatalytic [6+4] cycloaddition between 2-cyclopentenone and tropone have been investigated by a combined computational and experimental study. In the presence of a cinchona alkaloid primary amine catalyst and an acid additive, 2 cyclopentenone forms a cross-dienamine intermediate that subsequently undergoes a stepwise [6+4] cycloaddition reaction via a zwitterionic intermediate. The rate determining transition state features a strong hydrogen-bonding interaction between the tropone oxygen atom and the protonated quinuclidine directing the reaction course leading to a highly periselective [6+4] cycloaddition. The importance of the strong hydrogen-bonding interaction is also demonstrated by the influence of the concentration of the acid additive on the yields and enantioselectivities of the reaction. The corresponding [4+2] cycloaddition reaction has a much higher energy barrier. The enantioselectivity of the [6+4] cycloaddition originates from different repulsive hydrogen-hydrogen interactions that distinguish the diastereomeric transition states. PMID- 30251536 TI - Nanogap-Based Electrochemical Measurements at Double-Carbon-Fiber Ultramicroelectrodes. AB - Electrochemical measurements with unprecedentedly high sensitivity, selectivity, and kinetic resolution have been enabled by a pair of electrodes separated by a nanometer-wide gap. The fabrication of nanogap electrodes, however, requires extensive nanolithography or nanoscale electrode positioning, thereby preventing the full exploration of this powerful method in electrode design and application. Herein, we report the simple fabrication of double-carbon-fiber ultramicroelectrodes (UMEs) with nanometer-wide gaps not only to facilitate nanogap-based electrochemical measurements but also to gain high time resolution, signal-to-background ratio, and kinetic selectivity for dopamine against ascorbic acid. Specifically, ~7 MUm-diameter carbon fibers are inserted into a double-bore glass capillary, heat-pulled, and milled by focused ion-beam technology to yield ~50 MUm-long double-cylinder UMEs. The redox cycling of the Ru(NH3)63+/2+ couple across a nanogap between voltammetric generator and amperometric collector electrodes reaches quasi-steady states at fast scan rates of 100 V/s as demonstrated experimentally and even 1000 V/s as predicted theoretically. The transient background of the amperometric collector response is suppressed ~100 times in comparison with that of the voltammetric generator response. Nanogap voltammograms based on the collector response against the cycled generator potential are quantitatively analyzed without background subtraction to reproducibly yield nanogap widths of ~0.18 MUm and a standard electron-transfer rate constant of 0.9 cm/s. Moreover, nanogap-mediated redox cycling can be initiated by dopamine oxidation at the generator electrode to largely improve the dopamine selectivity of the collector response against ascorbic acid, which is also oxidized at the generator electrode to immediately and irreversibly produce a redox-inactive species. PMID- 30251537 TI - Tuning Semiconductor Performance of Nickel Complexes through Crystal Transformation. AB - Crystal transformation between two polymorphs (green, 1-G, and red, 1-R) of the square-planar nickel complex NiL2 (L = 2-ethoxy-6-( N methyliminomethyl)phenolate) and their tuning effect to semiconductor properties were studied both experimentally and theoretically. When 1-G is heated to 413 K, it converts to 1-R, whereas soaking 1-R in several kinds of solvents causes it to revert to 1-G. Crystallographic and PXRD studies reveal the dramatic changes in crystal dimensions due to the changes of packing models. Heating device made from 1-G (D-1-G(298)) at 413 K significantly increases the electrical conductivity from 6.55 * 10-4 S cm-1 for D-1-G(298) to 1.11 * 10-3 S cm-1 for D-1-G(413), showing significant crystal form dependence. Heat-treating D-1-G and D-1-R devices at different temperatures clearly reveals the reason for the conductivity tuning. Thus, the conductivity of NiL2-based devices could be well tuned through crystal transformation by heating or by soaking in solvent. Theoretical calculations clearly revealed the reason for such conductivity changes and also predicted that both polymorphs are good p-type semiconductors with hole mobilities of 1.63 * 10-2 (1-G) and 2.11 * 10-1 cm2 V-1 s-1 (1-R). PMID- 30251538 TI - K2Hg2Te3: Straightforward and Large-Scale Mercury-Flux Synthesis of a Small-Band Gap Photoconducting Material. AB - K2Hg2Te3 was synthesized via a mercury-flux synthesis pathway. Single-crystal and powder X-ray diffraction reveal the compound to be isostructural to its lighter congener K2Hg2Se3, yet exhibiting enhanced photoconductivity and electrical conductivity of (several) orders of magnitude and a decreased thermal conductivity and band gap. In this report, we elaborate on the synthesis and properties of the novel ternary compound. PMID- 30251539 TI - Structural and Biochemical Characterization of the Curcumin-Reducing Activity of CurA from Vibrio vulnificus. AB - Curcumin is a yellow-colored ingredient in dietary spice turmeric ( Curcuma longa Linn). This nontoxic polyphenol has antitumor, anti-inflammatory, apoptotic, and antioxidant activities. The ingested curcumin is reduced to multihydrated forms with more potent therapeutic potentials by the curcumin reductase (CurA) from commensal Escherichia coli. In this study, we demonstrated that Vibrio vulnificus CurA ( VvCurA) with 87% sequence similarity to the E. coli CurA exhibits the curcumin-reducing activity through spectrophotometric detection of NADPH oxidation and high performance liquid chromatographic analysis of curcumin consumption and product generation. Afterward, we determined the crystal structures of VvCurA and the VvCurA/NADPH complex, and made the in silico model of the VvCurA/NADPH/curcumin ternary complex through induced fit docking. Based on structural information, active site residues that play critical roles in catalysis have been identified and characterized by mutational and kinetic studies, leading us to propose the reaction mechanism of CurA. PMID- 30251540 TI - Investigations of Thienoacene Molecules for Classical and Entangled Two-Photon Absorption. AB - Investigations of the optical effects in thienoacene chromophores with different central atoms were performed. These chromophores provide a basis for the comparison of the linear, two-photon, and entangled two-photon properties in organic molecules with varying degrees of dipolar or quadrupolar character. Linear absorption and emission as well as time-dependent density functional theory calculations were performed for the chromophores investigated. Measurements of the classical two-photon absorption (TPA), entangled two-photon absorption (ETPA), as well as entangled two-photon fluorescence were experimentally performed for the four chromophores. Electronic structure calculations were utilized to provide estimates of the classical two-photon absorption coefficients. The results of the measured entangled two-photon cross sections were compared with theoretical estimates for the molecules investigated. It is found that the dipole (transition or permanent) pathway can have an effect on the trends in the entangled photon absorption process in dipolar organic chromophores. This study helps predict the properties of the entangled two-photon effect in chromophores with different dipolar and quadrupolar character. PMID- 30251541 TI - Analyzing the Structure of Pathways and Its Influence on the Interpretation of Biomedical Proteomics Data Sets. AB - Biochemical pathways are commonly used as a reference to conduct functional analysis on biomedical omics data sets, where experimental results are mapped to knowledgebases comprising known molecular interactions collected from the literature. Due to their central role, the content of the functional knowledgebases directly influences the outcome of pathway analyses. In this study, we investigate the structure of the current pathway knowledge, as exemplified by Reactome, discuss the consequences for biological interpretation, and outline possible improvements in the use of pathway knowledgebases. By providing a view of the underlying protein interaction network, we aim to help pathway analysis users manage their expectations and better identify possible artifacts in the results. PMID- 30251542 TI - Near-Infrared Laser-Driven in Situ Self-Assembly as a General Strategy for Deep Tumor Therapy. AB - Nanotherapeutics have encountered some bottleneck problems in cancer therapy, such as poor penetration and inefficient accumulation in tumor site. We herein developed a novel strategy for deep tissue penetration in molecular level and near-infrared (NIR) laser guided in situ self-assembly to solve these challenges. For the proof-of-concept study, we synthesized the polymer-peptide conjugates (PPCs) composed of (i) poly(beta-thioester) as thermoresponsive backbone, (ii) functional peptides (cytotoxic peptide and cell-penetrating peptide), and (iii) the NIR molecule with photothermal property. The PPCs in the molecular level with small size (<10 nm) can penetrate deeply into the interior of the tumor at body temperature. Under the irradiation of NIR laser, the temperature rise induced by photothermal molecules led to the intratumoral self-assembly of thermoresponsive PPCs. The resultant spherical nanoparticles can accumulate in tumor and enter cells effectively, inducing cell apoptosis by destroying mitochondria membrane. Through the site-specific size control, a variety of merits of PPCs are realized including deep tumor penetration, enhanced accumulation, and cellular internalization in vivo. Taking advantage of the NIR guided in situ assembly strategy, numerous polymeric or nanoscaled therapeutics with high anticancer activity can be exploited. PMID- 30251543 TI - Nickel-Catalyzed Synthesis of Benzo[ b]naphtho[1,2- d]azepine via Intramolecular Radical Tandem Cyclization of Alkyl Bromide-Tethered Alkylidenecyclopropanes. AB - A Ni(II)-catalyzed tandem cyclopropane ring opening and radical alkylation of the aromatic ring using unactivated alkyl bromide-tethered alkylidenecyclopropanes (ACPs) have been described in this paper. This ring-forming process exhibits a broad substrate scope with a variety of primary alkyl bromides and aromatic rings, affording diversified benzo[ b]naphtho[1,2- d]azepine derivatives in moderate-to-excellent yields under mild conditions. Plausible reaction mechanisms have been proposed on the basis of several control experiments, including the deuterium labeling examinations. Further derivatization of the obtained polycyclic product has also been performed. PMID- 30251544 TI - Enhancing Treatment Efficacy of 177Lu-PSMA-617 with the Conjugation of an Albumin Binding Motif: Preclinical Dosimetry and Endoradiotherapy Studies. AB - We designed and evaluated a novel albumin-binder-conjugated 177Lu-PSMA-617 derivative, 177Lu-HTK01169, with an extended blood retention time to maximize the radiation dose delivered to prostate tumors expressing prostate-specific membrane antigen (PSMA). PSMA-617 and HTK01169 that contained N-[4-( p iodophenyl)butanoyl]-Glu as an albumin-binding motif were synthesized using the solid-phase approach. Binding affinity to PSMA was determined by in vitro competition-binding assay. 177Lu labeling was performed in acetate buffer (pH 4.5) at 90 degrees C for 15 min. SPECT/CT imaging, biodistribution, and endoradiotherapy studies were conducted in mice bearing PSMA-expressing LNCaP tumor xenografts. Radiation dosimetry was calculated using OLINDA software. Lu PSMA-617 and Lu-HTK01169-bound PSMA with high affinity ( Ki values = 0.24 and 0.04 nM, respectively). SPECT imaging and biodistribution studies showed that 177Lu-PSMA-617 and 177Lu-HTK01169 were excreted mainly via the renal pathway. With fast blood clearance (0.68%ID/g at 1 h postinjection), the tumor uptake of 177Lu-PSMA-617 peaked at 1 h postinjection (15.1%ID/g) and gradually decreased to 7.91%ID/g at 120 h postinjection. With extended blood retention (16.6 and 2.10%ID/g at 1 and 24 h, respectively), the tumor uptake of 177Lu-HTK01169 peaked at 24 h postinjection (55.9%ID/g) and remained at the same level by the end of the study (120 h). Based on dosimetry calculations, 177Lu-HTK01169 delivered an 8.3-fold higher radiation dose than 177Lu-PSMA-617 to LNCaP tumor xenografts. For the endoradiotherapy study, the mice treated with 177Lu-PSMA-617 (18.5 MBq) all reached humane end point (tumor volume >1000 mm3) by Day 73 with a median survival of 58 days. Mice treated with 18.5, 9.3, 4.6, or 2.3 MBq of 177Lu HTK01169 had a median survival of >120, 103, 61, and 28 days, respectively. With greatly enhanced tumor uptake and treatment efficacy compared to 177Lu-PSMA-617 in preclinical studies, 177Lu-HTK01169 warrants further investigation for endoradiotherapy of prostate cancer. PMID- 30251545 TI - Topological Phases in Cove-Edged and Chevron Graphene Nanoribbons: Geometric Structures, [Formula: see text]2 Invariants, and Junction States. AB - Graphene nanoribbons (GNRs) have recently been shown by Cao, Zhao, and Louie [Cao, T.; Zhao, F.; Louie, S. G. Phys. Rev. Lett. 2017, 119, 076401] to possess distinct topological phases in general, characterized by a [Formula: see text]2 invariant. Cove-edged and chevron GNRs moreover are chemically and structurally diverse, quasi-one-dimensional (1D) nanostructures whose structure and electronic properties can be rationally controlled by bottom-up synthesis from precursor molecules. We derive the value of the topological invariant of the different types of cove-edged and chevron GNRs, and we investigate the electronic properties of various junctions formed by these GNRs, as well as such GNRs with the more common armchair or zigzag GNRs. We study the topological junction states at the interface of two topologically distinct segments. For an isolated GNR having two ends of different terminations, topological end states are shown to develop only at the topologically nontrivial end. Our work extends the explicit categorization of topological invariants of GNRs beyond the previously demonstrated armchair GNRs and provides new design rules for novel GNR junctions as well as future GNR-based nanoelectronic devices. PMID- 30251546 TI - Initial experience with a leadless pacemaker (MicraTM) implantation in a low volume center in South East Asia. AB - AIM: The MicraTM Transcatheter Pacing System is a leadless pacemaker that has been introduced recently. We share our experience in a low volume center and the use of right ventricular angiography (RVA) during implantation. MATERIALS & METHODS: Patients underwent Micra implantation and RVA was performed to predetermine the implant site. RESULTS: Nine patients underwent Micra implantation. The most common indication was atrial fibrillation with bradycardia. The device was implanted at apical-septum in seven and mid-septum in two. The procedure time ranged from 30 to 100 min and fluoroscopic time 4-18 min. Pacing parameters remained stable after 1-month follow-up. CONCLUSION: The Micra implantation technique can be easily learnt. RVA was helpful in selecting an appropriate site for the Micra implant. PMID- 30251547 TI - Secondary metabolites isolated from the deep sea-derived fungus Aspergillus sydowii C1-S01-A7. AB - Two novel compounds, 2-hydroxy-6-formyl-vertixanthone (1) and 12-O-acetyl sydowinin A (2), were obtained from the culture of a deep sea-derived fungus Aspergillus sydowii C1-S01-A7, together with twenty-two known compounds (3-24). Their structures were elucidated based on extensive spectroscopic methods. Compounds 4, 8 and 12 showed antibacterial activities against Vibrio rotiferianus and Vibrio vulnificus. Compounds 1, 2, 7, 8, 11 and 12 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus. Remarkably, compound 8 displayed selectively cytotoxic activity against A549 and strongest cytotoxic activities for both A549 and HepG2 in comparison to the remaining compounds. [Figure: see text]. PMID- 30251548 TI - Ponatinib in the treatment of chronic myeloid leukemia and philadelphia chromosome positive acute lymphoblastic leukemia. AB - Philadelphia chromosome, reciprocal translocation between chromosome 9 and 22, leading to a constitutively active fusion protein BCR-ABL1 is the common feature among Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML). The discovery of tyrosine kinase inhibitors (TKIs) has led to significant improvement in the treatment of CML and Ph+ ALL. Ponatinib is a third-generation TKI that is currently approved as per label when no other TKIs are indicated for the treatment of patients with CML and Ph+ ALL after failing treatment with second-generation TKIs or if presence of T315I mutation is discovered. This review summarizes the ponatinib development, approved indications as well as ongoing clinical studies in CML and Ph+ ALL. PMID- 30251549 TI - Using Discrete Event Simulation (DES) To Support Performance-Driven Healthcare Design. AB - AIM: This article aims to provide a description of fundamental elements of discrete event simulation (DES), the process and the values of applying DES in assisting healthcare design and planning decision-making. More importantly, it explores how new technology such as electronic medical records, real-time location services (RTLS), and other simulation methods such as space syntax analysis (SSA) can facilitate and complement DES. BACKGROUND: Healthcare administrators increasingly recognize DES as an effective tool for allocating resources and process improvement. However, limited studies have described specifically how DES can facilitate healthcare design. METHOD: Three case studies were provided to illustrate the value of DES in supporting healthcare design. The first case study used DES to validate a surgical suite design for shorter surgeon walking distance. The second case study used DES to facilitate capacity planning in a clinic through testing the utilization of exam rooms upon various growth scenario. The detailed process data for the current clinic were captured through RTLS tracking. The third case study applied DES in an emergency department for both site selection in master planning and capacity test at various growth scenarios with seasonal volume swing. In addition, SSA was conducted to evaluate the impacts of design on visual surveillance, team communication, and co awareness. CONCLUSIONS: It is recognized that the DES analysis is an effective tool to address the process aspects of healthcare environments and should be combined with post-occupancy evaluation and SSA to address behavioral aspects of operations to provide more solid evidence for future design. PMID- 30251550 TI - Treatment patterns and outcomes for patients with advanced melanoma in US oncology clinical practices. AB - AIM: To describe recent evolution in treatment patterns and outcomes for advanced melanoma (AMel). METHODS: This retrospective observational study analyzed de identified electronic health record data from the Flatiron Health database for 1140 adult patients who initiated first-line therapy for AMel from 1 January 2014 to 30 June 2016 with follow-up through 28 February 2017. RESULTS: The most common first-line regimens were ipilimumab-based therapies (34%), anti-PD1 monotherapy (26%) and BRAF/MEK inhibitor(s) (20%). First-line ipilimumab-based and BRAF inhibitor regimens decreased after the third quarter of 2014 (3Q2014), and by 2Q2016, 55 and 91% of BRAF-mutant and BRAF wild-type cohorts, respectively, received a first-line anti-PD1 regimen. Median overall survival from first-line initiation for all patients was 18.8 months (95% CI: 16.3-23.3). CONCLUSION: Results illustrate changing paradigms of therapy and real-world patient outcomes for AMel. PMID- 30251551 TI - Pharmacokinetics and drug metabolism of antibiotics in the elderly. AB - INTRODUCTION: The number of elderly people is increasing worldwide. The elderly may be at increased risk of bacterial infections compared with younger adults. Dosing adaptation of antibiotics in this population may be difficult due to changes in body composition, decline of renal function and/or drug-drug interactions. Lack of dose adaptation may cause unintentional overdosing with the risk of severe adverse effects. Areas covered: This review is based on a PubMed search of the literature published in English language and concerns pharmacokinetic (PK) studies of antibiotics in the elderly performed between 1971 and 2017. Expert opinion: Appropriateness of drug prescription in the elderly is a major commitment of the health care systems worldwide. This should push more and more clinicians to adjust the dosage of renally cleared antibiotics in relation to renal function estimates. The situation may become even more complex in frail elderly patients who are receiving polypharmacy due to drug-drug interactions. Development of new antibiotics should include within clinical trials adequate representation of patients aged >=75 years to determine age-based dosing. Population PK could be helpful in increasing the knowledge of clinical factors influencing the need for dosing adaptation of the currently available antibiotics in the elderly. PMID- 30251552 TI - Emerging PARP inhibitors for treating breast cancer. AB - INTRODUCTION: Some breast cancers harbor defects in DNA repair pathways, including BRCA1 and BRCA2 mutations, leading to a genomic instability. Compromised DNA-damage repair response is found in 11 to 42% of triple negative breast cancers, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors are a promising strategy in breast cancer exploiting Homologous Deficient Recombination deficiency (HRD) by a synthetic lethal approach. Several PARP inhibitors have currently reached early phase trials with studies on going in the adjuvant, neoadjuvant and metastatic setting. Area covered: Here, we review completed and ongoing trials with PARP inhibitors as well as their mechanisms of activity and acquired resistance. Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance. PMID- 30251553 TI - Comparison of stroke- and bleed-related healthcare resource utilization and costs among patients with newly diagnosed non-valvular atrial fibrillation and newly treated with dabigatran, rivaroxaban, or warfarin. AB - BACKGROUND: This is one of the first head-to-head real-world evidence studies comparing stroke-related and bleed-related healthcare and resource utilization (HCRU) and costs among non-valvular atrial fibrillation (NVAF) patients initiating oral anticoagulants. METHODS: Adult NVAF patients newly diagnosed and treated with dabigatran, rivaroxaban, or warfarin between 10/01/2010 and 12/31/2014 were identified using MarketScan Commercial and Medicare Supplemental databases. Per-patient-per-month stroke and bleed-related HCRU and costs were reported. RESULTS: Dabigatran patients were matched 1:1 to 26,592 rivaroxaban and 33,024 warfarin patients (mean age=68 years). Compared to rivaroxaban, dabigatran patients had lower bleed-related inpatient and outpatient HCRU (0.004 vs. 0.005; 0.099 vs. 0.145) and significantly lower adjusted bleed-related costs ($116 vs. $172), all p <0.05. Compared to warfarin, dabigatran patients had significantly lower stroke-related outpatient visits (0.034 vs. 0.048, p<0.001) and higher bleed-related outpatient visits (0.101 vs. 0.091, p=0.045). Multivariate adjusted bleed-related costs were significantly lower for dabigatran patients than warfarin patients ($94 vs. $138, p<0.001). CONCLUSIONS: The results suggest that dabigatran patients had lower bleed-related HCRU and costs than rivaroxaban patients, and lower outpatient stroke-related HCRU, higher bleed-related outpatient HCRU, and lower bleed-related costs than warfarin patients. It provides valuable stroke-related and bleed-related HCRU and costs information among commercially insured and Medicare patients. PMID- 30251554 TI - Bidirectional Adaptive Signaling between cancer and stromal cells: mechanisms and therapeutics. PMID- 30251555 TI - Evaluation and improvement of QSAR predictions of skin sensitization for pesticides. AB - In vivo skin sensitization assays have to be provided by applicants to the competent authorities in the European Union for the approval of active substances (AS) in pesticides. This study aimed to test the practicability of in silico predictions for AS by freely available (Q)SAR tools to evaluate their use as a time- and cost-effective alternative to animal testing in the context of the 3R concept. Predictions of skin sensitization for 48 selected sensitizing and non sensitizing AS by the software programs CAESAR, Toxtree, OECD (Q)SAR Toolbox, CASE Ultra, Leadscope and SciQSAR were collected and compared. Different data evaluation methodologies (score definition, mean, weighted mean, threshold score definition) were applied to optimize the predictions. The calculation methods were internally cross-validated and further validated with an additional validation set of 80 AS. Although the presented calculation methodologies are not suitable as a stand-alone method, this study has shown weaknesses and strengths of some prominent (Q)SAR programs and diverse combinatorial options in the prediction of skin sensitization by pesticidal AS. The present study will help to foster discussions on in silico alternatives to animal testing in the pesticide area. PMID- 30251556 TI - Design of Genuine Birth Environment: Midwives Intuitively Think in Terms of Evidence-Based Design Thinking. AB - OBJECTIVE: The objective of this study is to investigate a development project initiated and led by midwives. BACKGROUND: The aim was to design an environment that could accommodate the wish to support professionalism while creating better and more cohesive patient treatment, improved patient safety, greater efficiency, higher quality, and stronger focus on the patient. THEORY: The theoretical and analytical account is conducted within the framework of design thinking (DT), replacing the traditional evidence-based design approach with an evidence-based design thinking (EBDT) process underpinning participatory DT and co-creation. METHOD: Based on a longitudinal case study on a participatory design process, interviews are conducted. DT principles are used in the analysis of the interviews. RESULTS: Genuineness arises when all users experience that the physical setting optimally underpins the birthing situation. It is essential to make visible the importance of the physical setting to human behavior in any situation. CONCLUSION: This study shows that midwives intuitively do EBDT. EBDT commands awareness of both research, design, midwifery care, and perspectives on space from women giving birth and their relatives. Collectively, that can provide the genuine scope of a healing birth environment. PMID- 30251557 TI - On Exploring Hidden Structures Behind Cervical Cancer Incidence. AB - Finding new etiological components is of great interest in disease epidemiology. We consider time series version of invariant coordinate selection (tICS) as an exploratory tool in the search of hidden structures in the analysis of population based registry data. Increasing cancer burden inspired us to consider a case study of age-stratified cervical cancer incidence in Finland between the years 1953 and 2014. The latent components, which we uncover using tICS, show that the etiology of cervical cancer is age dependent. This is in line with recent findings related to the epidemiology of cervical cancer. Furthermore, we are able to explain most of the variation of cervical cancer incidence in different age groups by using only two latent tICS components. The second tICS component, in particular, is interesting since it separates the age groups into three distinct clusters. The factor that separates the three clusters is the median age of menopause occurrence. PMID- 30251558 TI - Resection of Inverted Papilloma of the Maxillary Sinus via a Prelacrimal Recess Approach: A Multicenter Retrospective Analysis of Surgical Efficacy. AB - BACKGROUND: The intranasal endoscopic prelacrimal recess approach (PLRA) access to all aspects of the maxillary sinus while preserving the inferior turbinate and nasolacrimal duct and its use have been reported in the treatment of many maxillary sinus and lateral skull base diseases. OBJECTIVE: To retrospectively assess the effectiveness of a 10-year multicenter follow-up for the resection of inverted papilloma of the maxillary sinus (IPMS) via a PLRA. METHODS: A total of 71 patients were admitted and underwent IPMS excision via an intranasal endoscopic PLRA from 2003 to 2013. All patients underwent high-resolution computed tomography scanning of the nasal sinus, and some also underwent magnetic resonance imaging examination. RESULTS: Based on the Krouse staging system, all 71 patients belong to T3 staging. The PLRA was employed to remove IPMS in 71 patients. The postoperative pathological examination of the excised tissue revealed inverted papilloma, and cancerization was identified in 3 patients. The median follow-up time was 37.3 months (range: 13-134 months). Of the 71 patients, reoccurrence was seen in 5 patients (7.04%); 5 patients (7.04%) experienced numbness of the upper lid and the ala of the nose and 4 (5.63%) experienced mild collapse of the ala of the nose. CONCLUSIONS: These multicenter follow-up results demonstrated that the PLRA is a safe and effective method for the excision of primary or recurrent IPMS with lower postoperative complications and recurrent rate. PMID- 30251559 TI - Sarcoidosis: proteomics and new perspectives for improving personalized medicine. AB - INTRODUCTION: Through synergistic approaches integrating biomedical data from omics sciences to the clinical practice, precision medicine aims at more accurate identification of risk factors, characterization of endotypes, patient stratification, establishment of individualized therapy, and prediction of outcomes. Areas covered: This review evaluates the potential role of different omics approaches for the development and application of precision medicine to sarcoidosis patients. This systemic and heterogeneous inflammatory disease is of unknown etiology, affects people of any age, and requires genotypic and phenotypic characterization. The latter can be achieved through the integration of genomic (i.e. information about genes and their mutations potentially involved in sarcoidosis), transcriptomic (reflecting the dynamic state of a cell and measuring the transcribed genes over time), and proteomic data (i.e. proteins in bronchoalveolar lavage, lung tissues, lung cells, serum and immunity system). Expert commentary: Genomic studies have revealed numerous aspects of sarcoidosis; however, for precision medicine, it is necessary to implement genomics with other omic approaches. The improving reliability of omics data, their storage, and their bioinformatics processing represents the next step to recapitulate in silico biological systems, with the final aim to simulate potential molecular pathways involved in the pathology and useful for clinical purposes. PMID- 30251560 TI - Proteomic study of skeletal muscle in obesity and type 2 diabetes: progress and potential. AB - INTRODUCTION: Skeletal muscle is the major site of insulin-stimulated glucose uptake and imparts the beneficial effects of exercise, and hence is an important site of insulin resistance in obesity and type 2 diabetes (T2D). Despite extensive molecular biology-oriented research the molecular mechanisms underlying insulin resistance in skeletal muscle remain to be established. Areas covered: The proteomic capabilities have greatly improved over the last decades. This review summarizes the technical challenges in skeletal muscle proteomics studies as well as the results of quantitative proteomic studies of skeletal muscle in relation to obesity, T2D, and exercise. Expert commentary: Current available proteomic studies contribute to the view that insulin resistance in obesity and T2D is associated with increased glycolysis and reduced mitochondrial oxidative metabolism in skeletal muscle, and that the latter can be improved by exercise. Future proteomics studies should be designed to markedly intensify the identification of abnormalities in metabolic and signaling pathways in skeletal muscle of insulin-resistant individuals to increase the understanding of the pathogenesis of T2D, but more importantly to identify multiple novel targets of treatment of which at least some can be safely targeted by novel drugs to treat and prevent T2D and reduce risk of cardiovascular disease. PMID- 30251561 TI - Relative indoleamine 2,3-dioxygenase transcript level concerning anti-HBs titers in response to HBV vaccination in hemodialysis patients. AB - BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is a negative regulator of the immune system. To approach reasons of variability in the generation of anti-HBs antibodies in response to HBV vaccination among hemodialysis (HD) subjects, we aimed to investigate whether the IDO gene (IDO1) transcript levels are associated with post-vaccination anti-HBs production and IDO1 polymorphic variants. METHODS: The IDO1 transcript was determined by qRT-PCR analysis in 110 HD patients. IDO1 (rs3739319, rs9657182) genotyping was carried out by HRM analysis. RESULTS: The relative IDO1 transcript levels were not associated with IDO1 polymorphic variants. There were 16 non-responders (not able to produce anti-HBs >10 IU/L), 74 patients with anti-HBs 10-999 IU/L, and 20 hyperactive responders (anti-HBs >=1000 IU/L). IDO1 transcript levels were different among these groups (0.832, 0.423-4.373; 1.114, 0.317-6.582; 0.680, 0.164-3.014; respectively, Kruskal-Wallis P = 0.024). Significance in IDO1 transcript was shown between anti-HBs titers 10 999 IU/L and >=1000 IU/L (P = 0.020). IDO1 transcript level <0.743 indicated 3.38 (1.17-9.72) higher probability of hyperactive immunization (adjusted P = 0.005). CONCLUSION: In HD patients, ability to generate anti-HBs is not associated with IDO1 transcript levels. Hyperactive anti-HBs responses occur in patients showing lower IDO1 transcript. The latter cannot be predictable by genotyping IDO1 rs3739319 or rs9657182. PMID- 30251562 TI - Safe and effective exercise training for patients with pulmonary arterial hypertension: putting current evidence into clinical practice. AB - INTRODUCTION: While there have been significant advances in the medical treatment of pulmonary arterial hypertension (PAH), life expectancy, and quality of life remain reduced in this disease. Strenuous exercise may be hazardous for PAH patients; however, several relatively small trials have confirmed that exercise training programs can be used safely and effectively as adjunctive treatment for selected patients. The use of exercise training is now recommended in consensus international PAH treatment algorithms; however, there is no published guideline detailing how this intervention should be carried out. Areas covered: This review describes the evidence available and evaluates its applicability to 'real life' clinical practice. The limitations of current evidence are acknowledged, and we discuss how the existing data can be applied to management of PAH patients in Australia, New Zealand, and countries with similar healthcare systems. Recommendations for PAH exercise training are proposed including patient selection, program structure and duration, training modalities, training intensity, supervision, monitoring, safety precautions, and outcome assessments. Expert commentary: It is recognized that knowledge gaps remain and further research is required into physiological mechanisms associated with improved exercise capacity, optimal outpatient exercise regimen, durability of benefit, and whether there is any disease-modifying effect or impact on long-term prognosis. PMID- 30251563 TI - Application of Cord Blood and Cord Blood-derived Induced Pluripotent Stem Cells for Cartilage Regeneration. AB - Regeneration of articular cartilage is of great interest in cartilage tissue engineering since articular cartilage has a low regenerative capacity. Due to the difficulty in obtaining healthy cartilage for transplantation, there is a need to develop an alternative and effective regeneration therapy to treat degenerative or damaged joint diseases. Stem cells including various adult stem cells and pluripotent stem cells are now actively used in tissue engineering. Here, we provide an overview of the current status of cord blood cells and induced pluripotent stem cells derived from these cells in cartilage regeneration. The abilities of these cells to undergo chondrogenic differentiation are also described. Finally, the technical challenges of articular cartilage regeneration and future directions are discussed. PMID- 30251564 TI - Transplanting Mesenchymal Stem Cells for Treatment of Ischemic Stroke. AB - Stroke is a major disease that leads to high mortality and morbidity. Given the ageing population and the potential risk factors, the prevalence of stroke and socioeconomic burden associated with stroke are expected to increase. During the past decade, both prophylactic and therapeutic strategies for stroke have made significant progress. However, current therapies still cannot adequately improve the outcomes of stroke and may not apply to all patients. One of the significant advances in modern medicine is cell-derived neurovascular regeneration and neuronal repair. Progress in stem cell biology has greatly contributed to ameliorating stroke-related brain injuries in preclinical studies and demonstrated clinical potential in stroke treatment. Mesenchymal stem cells (MSCs) have the differentiating potential of chondrocytes, adipocytes, and osteoblasts, and they have the ability to transdifferentiate into endothelial cells, glial cells, and neurons. Due to their great plasticity, MSCs have drawn much attention from the scientific community. This review will focus on MSCs, stem cells widely utilized in current medical research, and evaluate their effect and potential of improving outcomes in ischemic stroke. PMID- 30251566 TI - Cerebral Small Vessel Disease. AB - Cerebral small vessel disease (CSVD) is composed of several diseases affecting the small arteries, arterioles, venules, and capillaries of the brain, and refers to several pathological processes and etiologies. Neuroimaging features of CSVD include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. The main clinical manifestations of CSVD include stroke, cognitive decline, dementia, psychiatric disorders, abnormal gait, and urinary incontinence. Currently, there are no specific preventive or therapeutic measures to improve this condition. In this review, we will discuss the pathophysiology, clinical aspects, neuroimaging, progress of research to treat and prevent CSVD and current treatment of this disease. PMID- 30251565 TI - Growth Factor-Mediated Tenogenic Induction of Multipotent Mesenchymal Stromal Cells Is Altered by the Microenvironment of Tendon Matrix. AB - Age-related degenerative changes in tendon tissue represent a common cause for acute tendon pathologies. Although the regenerative potential of multipotent mesenchymal stromal cells (MSC) was reported to restore functionality in injured tendon tissue, cellular mechanisms of action remain partly unclear. Potential tenogenic differentiation of applied MSC is affected by various intrinsic and extrinsic factors. The current study presents an in vitro model to evaluate the combined extrinsic effects of decellularized equine tendon matrix, transforming growth factor beta 3 (TGFbeta3) and bone morphogenetic protein 12 (BMP12) on the tenogenic fate of equine adipose tissue-derived MSC. Monolayer MSC cultures supplemented with TGFbeta3 and BMP12 as well as MSC cultured on tendon matrix scaffolds preloaded with the growth factors were incubated for 3 and 5 days. Histological evaluation and real time reverse transcription polymerase chain reaction (RT-PCR) revealed that growth factor-mediated tenogenic induction of MSC was modified by the conditions of the surrounding microenvironment. While the gene expression pattern in monolayer cultures supplemented with TGFbeta3 or TGFbeta3 and BMP12 revealed an upregulation for collagen 1A2, collagen 3A1, tenascin c, scleraxis and mohawk ( p < 0.05 ), the presence of tendon matrix led to an upregulation of decorin and osteopontin as well as to a downregulation of smad8 ( p < 0.05). Preloading of scaffolds with either TGFbeta3, or with TGFbeta3 and BMP12 promoted a tenocyte-like phenotype and improved cell alignment. Furthermore, gene expression in scaffold culture was modulated by TGFbeta3 and/or BMP12, with downregulation of collagen 1A2, collagen 3A1, decorin, scleraxis, smad8 and osteopontin, whereas gene expression of tenascin c was increased. This study shows that growth factor-induced tenogenic differentiation of equine MSC is markedly altered by topographical constraints of decellularized tendon tissue in vitro. While TGFbeta3 represents an effective mediator for tenogenic induction, the role of BMP12 in tenogenesis may be of modulatory character and needs further evaluation. PMID- 30251567 TI - Differentiation of Sendai Virus-Reprogrammed iPSC into beta Cells, Compared with Human Pancreatic Islets and Immortalized beta Cell Line. AB - BACKGROUND: New sources of insulin-secreting cells are strongly in demand for treatment of diabetes. Induced pluripotent stem cells (iPSCs) have the potential to generate insulin-producing cells (ibeta). However, the gene expression profile and secretory function of ibeta still need to be validated in comparison with native beta cells. METHODS: Two clones of human iPSCs, reprogrammed from adult fibroblasts through integration-free Sendai virus, were differentiated into ibeta and compared with donor pancreatic islets and EndoC-betaH1, an immortalized human beta cell line. RESULTS: Both clones of iPSCs differentiated into insulin+ cells with high efficiency (up to 20%). ibeta were negative for pluripotency markers (Oct4, Sox2, Ssea4) and positive for Pdx1, Nkx6.1, Chromogranin A, PC1/3, insulin, glucagon and somatostatin. ibeta basally secreted C-peptide, glucagon and ghrelin and released insulin in response either to increasing concentration of glucose or a depolarizing stimulus. The comparison revealed that ibeta are remarkably similar to donor derived islets in terms of gene and protein expression profile and similar level of heterogeneity. The ability of ibeta to respond to glucose instead was more related to that of EndoC-betaH1. DISCUSSION: We demonstrated that insulin-producing cells generated from iPSCs recapitulate fundamental gene expression profiles and secretory function of native human beta cells. PMID- 30251568 TI - Unintended pregnancies and family planning among women after kidney or liver transplantation. AB - BACKGROUND: To evaluate the incidence of unplanned pregnancies in female organ transplant recipients. METHODS: In a single-center cross-sectional study 252 women aged 18-45 years who underwent kidney or liver transplantation were asked to fill in a survey form. RESULTS: 217 (86%) women were enrolled in the study. Fifty-three percent of women declared 181 pregnancies, of which 30% (54/181) were unplanned. Women more frequently consulted their conception with a doctor post transplantation (74 versus 88%, p = .064). The number of unplanned pregnancies decreased post-transplantation (34 versus 20%, p = .051). The mean time elapsed from an organ transplant to unintended conception was 27.0 +/- 12.5 (3.0-63.0) months. Women with longer (>24 months) rather than shorter (<=24 months) time elapsed from the transplant became pregnant less frequently (38 versus 15%, p = .060). In 70% (38/54) of unplanned pregnancies women did not use any birth control. All cases of conceptions within the post-transplant year were unintentional. Every third woman, who underwent the transplantation up to 1 year before the study enrolment, was unaware of the necessity to prevent the pregnancy. CONCLUSIONS: Although unwanted pregnancies occur more frequently in the early post-transplant period, it seems that women after kidney or liver transplantation seem to plan their pregnancies more carefully. PMID- 30251569 TI - The effect of group prenatal care for women with diabetes on social support and depressive symptoms: a pilot randomized trial. AB - OBJECTIVE: To measure the impact of group prenatal care (GPC) on diabetes specific peer support and depressive symptoms in women with pregnancies complicated by diabetes. MATERIALS AND METHODS: This is a planned secondary analysis of a two-center pilot randomized controlled trial conducted at Denver health (DH) and Washington University in St. Louis (WU) including Spanish (DH) or English (WU) speaking women with type 2 or gestational diabetes. Women were randomized to diabetes GPC or individual prenatal care (IPC) in the resident diabetes clinic. Participants completed an Edinburgh Postnatal Depression Scale (EPDS) at randomization, at 38-week gestation and at 6-12 weeks postpartum. The diabetes support scale (DSS), which includes 12 questions answered on a Likert scale, was administered at 38 weeks. Analysis was by intention to treat (clincaltrials.gov#NCT02444325). RESULTS: A total of 84 women were consented and randomized. Six withdrew consent (two from each cohort) or were lost to follow-up (two from IPC), and three did not complete the 38-week assessment (two from GPC and one from IPC), resulting in primary outcome data available for 75 women: 38 in GPC and 37 in IPC. More women randomized to GPC reported composite positive peer support on the DSS (52.5 versus 26.3%; p < .02). There were no differences in EPDS scores, depression (EPDS >10), or rates of improved EPDS score from baseline to 38 weeks. CONCLUSION: GPC for women with diabetes is associated with improved diabetes-specific peer social support with no significant impact on depressive symptoms. CLINICAL TRIAL REGISTRATION: Clincaltrials.gov NCT02444. PMID- 30251570 TI - Mitochondrial and glycolysis-regulatory gene expression profiles are associated with intrauterine growth restriction. AB - INTRODUCTION: Intrauterine growth restriction (IUGR) is a major pregnancy complication with significant postnatal implications. IUGR is characterized by high placental oxidative stress (OS) and increased mitochondrial DNA (mtDNA) abundance that altogether alter the placental metabolism. Such alterations may be captured by changes in the expression of mitochondrial-encoded oxidative phosphorylation genes and glycolysis-regulatory genes. STUDY DESIGN: We aimed here to determine the association between the placental expression of all 13 protein-coding mitochondrial-encoded genes and seven key nuclear glycolysis regulatory genes, PDK1, PDK2, PDK3, PDK4, PKLR, PKM, OGT, with IUGR, within a case-control study including 50 IUGR and 100 control pregnancies. We additionally assessed placental mtDNA abundance and OS. RESULTS: Three mitochondrial genes, MT ND5, MT-ND6, and MT-ATP6 were found negatively associated with IUGR, while one glycolysis-regulatory gene, PDK1 was positively associated with IUGR. mtDNA abundance and OS were positively associated with IUGR. Our study confirmed the existing data on IUGR inducing increased placental OS and mtDNA abundance. Further, our data highlighted the significant involvement of mitochondria and glucose metabolism in the OS-challenged IUGR placentas, which might modulate the placental expression of genes affecting the OXPHOS and promoting glycolysis. Brief rationale: By using banked placenta samples available at Icahn School of Medicine at Mount Sinai, this study aims at laying the foundation for the characterization of the role of mitochondria epi/genetics in IUGR. IUGR is a highly prevalent pregnancy outcome with long-term effects on the progeny that, at present, has limited tools that can be used for its diagnosis and characterization, thus limiting the efficacy of both clinical and public health interventions. The alterations of mitochondrial copy number, OS and mitochondrial and glycolysis-regulatory gene expression that we detected, together, provide the first evidence that these phenomena are playing an important role in the pathophysiology of IUGR. These findings suggest possible new research paths for the full characterization of mitochondrial biomarkers of IUGR. PMID- 30251571 TI - Stress distribution of different implant connections associated with multiple implant-supported prostheses. AB - In some clinical situations, the clinician may encounter previously installed implants that should be associated with other implants for a proper rehabilitation. The aim of this study was to evaluate the biomechanical behaviour of a multiple prosthesis joined by different implant connections using photoelasticity. Photoelastic models with a screwed fixed prosthesis supported by implants with different connection systems (Morse taper, external hexagon, internal hexagon, and Flexcone), and different combinations among them, were fabricated. Each assembly was placed in a circular polariscope, and axial and oblique (45 degrees ) loads of 100 N were applied on the occlusal surface of the crowns. The fringe patterns were photographed and the analysis was performed by counting the number of high-intensity fringes and also according to the stress distribution region where they appeared. Among implants of the same connection, the external connections obtained a greater number of high intensity fringes when compared to the internal connections. From the biomechanical point of view, the association between different types of connections obtained positive results. PMID- 30251572 TI - Feature extraction of ECG signal. AB - This paper deals with new approaches to analyse electrocardiogram (ECG) signals for extracting useful diagnostic features. Initially, elimination of different types of noise is carried out using maximal overlap discrete wavelet transform (MODWT) and universal thresholding. Next, R-peak fiducial points are detected from these noise free ECG signals using discrete wavelet transform along with thresholding. Then, extraction of other features, viz., Q waves, S waves, P waves, T waves, P wave onset and offset points, T wave onset and offset points, QRS onset and offset points are identified using some rule based algorithms. Eventually, other important features are computed using the above extracted features. The software developed for this purpose has been validated by extensive testing of ECG signals acquired from the MIT-BIH database. The resulting signals and tabular results illustrate the performance of the proposed method. The sensitivity, predictivity and error of beat detection are 99.98%, 99.97% and 0.05%, respectively. The performance of the proposed beat detection method is compared to other existing techniques, which shows that the proposed method is superior to other methods. PMID- 30251573 TI - Differential toxicity of processed and non-processed states of CoCrMo degradation products generated from a hip simulator on neural cells. AB - Physico-chemical characteristics of the CoCrMo degradation products have played an important role in cytotoxicity and clinical complications on the orthopedic patients who have metal implants. Previous studies have limited reflection on the physicochemical characteristics of the degradation products generated in vivo, which are very different from individual metal particles and/or ions obtained from different commercial sources. In this study, we aimed to understand the differences in toxicity induced by the degradation products in as-synthesized form as well as those obtained after post-processing. The degradation products were generated using a hip-simulator by maintaining physiological conditions closer to in vivo and separated into two batches, one with processing by washing and drying called processed degradation products (PDP) and another batch as 'as synthesized' degradation product (DP). We studied the dose-dependent toxicity response by neural cells derived from induced pluripotent stem cells. The results of the study show that as-synthesized DPs are more toxic to neural cells even at lower concentrations studied with evident low TC50 (1-5 MUg/ml) concentrations compared to PDP (25 MUg/ml). Flow cytometric analysis showed a significant (p<.01) increase in uptake of the particles after 24 h and corresponding ROS production in DP-treated cells. RT-PCR analysis of oxidative specific gene expression showed, elevated mRNA levels of NADPH oxidase-1, nuclear transcription factor, superoxide dismutase-2 and glutaredoxin-2 in DP-treated cells after 6 h. The results of the study provided a clear evidence of the differential response of neural cells on the degradation products as a function of concentrations and their chemical nature. PMID- 30251574 TI - A quality improvement study for medical devices usage in an acute healthcare setting. AB - The objectives of this study were, for a large NHS Trust, to (1) Implement a medical devices training information system which connects the medical equipment inventory to the electronic staff record. (2) Monitor the changes in safety related practice in the Trust after implementation (3) Examine the association between training compliance and Trust-wide adverse incident data for high risk medical devices. (4) Identify possible gaps in training course content from adverse incident data. A new system was made available, showing medical devices training records for staff in each location. Relevant staff members were trained on how to set up courses, record training, adjust training requirements and view reports. Training practice, compliance and adverse incidents for high-risk equipment were monitored over 30 months after implementation. Trends and changes in training practice were analysed. The Trust now has monitoring information on medical devices training available that had previously been absent. Training compliance increased from 23% to 59%. The frequency and severity of adverse incidents remained relatively constant throughout and was not associated with the increased uptake of training Trust-wide. Training gaps were identified. A Trust wide system for recording medical devices training has provided training assurance. After implementation changes in practice with training have been identified. It was not possible to show a direct association between increased training compliance and reduced medical device-related incidents Trust-wide. There were specific training courses where changes in content could increase the safe use of medical devices. PMID- 30251576 TI - L1CAM Immunopositivity in Anaplastic Supratentorial Ependymomas: Correlation With Clinical and Histological Parameters. AB - Supratentorial ependymomas (ST EPNs) are molecularly characterized, of which the RELA fusion positive tumors are the most common and aggressive subgroup. Moreover, histologically, anaplastic ST EPN (ST-AE) often mimic other central nervous system primary high-grade tumors resulting in a diagnostic dilemma. We aimed to study a cohort of ST-AE; evaluate the expression of two RELA fusion associated markers-L1CAM and p65 (NF-kappaB); and correlate their expression with clinical and histological parameters. Cases of ST-AE diagnosed in our department from January 2011 to June 2016 (n = 72) were reviewed. A battery of immunohistochemical markers was employed. A total of 65 confirmed ST-AE were included in the study. Age ranged from 9 months to 60 years. There was a slight predominance in the pediatric population (57%). Male-to-female ratio was 1:1.16. Histomorphological features were varied and mimicked other high-grade tumors in several cases. L1CAM immunopositive tumors constituted 26% of cases and were predominantly seen in young children, in the frontoparietal location, and exhibited clear cell morphology with calcification. A consistent pattern of L1CAM immunopositivity was noted in paired primary and recurrent tumor samples. Our study portrays the varied clinical and histomorphological spectrum of ST-AE. The study emphasizes the association of L1CAM immunopositivity with a wide spectrum of histological parameters, literature on which is scant till date. Since ST EPN RELA are tumors with aggressive behavior, such a correlation would be clinically relevant, particularly when there is limited access to molecular testing. PMID- 30251575 TI - Low-Normal Free Triiodothyronine and High Leukocyte Levels in Relation to Stroke Severity and Poor Outcome in Acute Ischemic Stroke with Intracranial Atherosclerotic Stenosis. AB - BACKGROUND: It is uncertain that the effect of free triiodothyronine (FT3) within normal ranges on initial severity and early functional outcomes in acute ischemic stroke (AIS) patients with Intracranial Atherosclerotic Stenosis (ICAS).; The predictive values of white blood cell (WBC) and FT3 are also unclear in symptomatic ICAS (sICAS) patients. METHODS: We consecutively reviewed 848 ischemic stroke patients admitted into Xiangya hospital within 72h after symptom onset. sICAS was defined as AIS patient with degree of intracranial atherosclerotic stenosis >= 50% proved by magnetic resonance angiography (MRA), computed tomography angiography (CTA) or digital subtraction angiography (DSA). WBC and FT3 were assessed within 24h after admission. Neurological severity was evaluated on admission using the National Institutes of Health Stroke Scale (NIHSS). Stroke outcomes were defined by the modified Rankin Scale (mRS) on the 14th day after admission. RESULTS: Logistic regression analysis showed that hypertension, lower FT3 and higher WBC concentrations independently associated with severe stroke [FT3 (odds ratio(OR)=0.543, 95% confidence interval(95% CI): 0.383-0.769); hypertension (OR = 0.436, 95% CI: 0.238-0.800); WBC (OR = 1.17; 95% CI:1.041-1.316]. Besides, lower FT3, higher FT4, higher WBC and higher plasma glucose concentrations independently associated with unfavorable outcomes [FT3 (OR= 0.460; 95% CI: 0.306-0.690); FT4 (OR = 1.151; 95% CI: 1.055-1.255); WBC (OR = 1.178; 95% CI: 1.039-1.334);Plasma glucose(OR = 1.160; 95% CI: 1.002-1.342)]. CONCLUSIONS: Lower FT3 levels within normal ranges and higher WBC count are independently associated with the severity and early poor prognosis of sICAS simultaneously, FT3 and WBC count might be important biomarkers for sICAS patients. PMID- 30251577 TI - Pragmatic clinical trials in the context of regulation of medicines. AB - The pragmatic clinical trial addresses scientific questions in a setting close to routine clinical practice and sometimes using routinely collected data. From a regulatory perspective, when evaluating a new medicine before approving marketing authorization, there will never be enough patients studied in all subgroups that may potentially be at higher risk for adverse outcomes, or sufficient patients to detect rare adverse events, or sufficient follow-up time to detect late adverse events that require long exposure times to develop. It may therefore be relevant that post-marketing trials sometimes have more pragmatic characteristics, if there is a need for further efficacy and safety information. A pragmatic study design may reflect a situation close to clinical practice, but may also have greater potential methodological concerns, e.g. regarding the validity and completeness of data when using routinely collected information from registries and health records, the handling of intercurrent events, and misclassification of outcomes. In a regulatory evaluation it is important to be able to isolate the effect of a specific product or substance, and to have a defined population that the results can be referred to. A study feature such as having a wide and permissive inclusion of patients might therefore actually hamper the utility of the results for regulatory purposes. Randomization in a registry-based setting addresses confounding that could otherwise complicate a corresponding non interventional design, but not any other methodological issues. Attention to methodological basics can help generate reliable study results, and is more important than labelling studies as 'pragmatic'. PMID- 30251578 TI - 2018 Distinguished Service Award Winners. PMID- 30251579 TI - Honorary Guest Lectures 2018. PMID- 30251581 TI - 2018 Honor Award Recipients. PMID- 30251582 TI - Conference Schedule-at-a-Glance. PMID- 30251583 TI - Accreditation Information. PMID- 30251584 TI - 2018 Annual Meeting Program Committee. PMID- 30251586 TI - 2018 President Gavin Setzen, MD. PMID- 30251587 TI - Biobank linked to SWEDEHEART quality registry-routine blood sample collection opens new opportunities for cardiovascular research. AB - High-quality biobanking within routine health services, through the use of existing health-care practices and infrastructure, with respect to safety and integrity of patients in line with the Swedish Biobank Act, enables large-scale collection of biological material at reasonable costs. Complementing the extensive information on myocardial infarction patients from a national registry gives unique opportunities for research focusing on better understanding of cardiovascular disease occurrence and prognosis, developing of new diagnostic methods, and personalized treatments with greater efficacy and fewer side effects. PMID- 30251588 TI - Costs of unintentional injuries among children in an urban slum community in Kampala city, Uganda. AB - Unintentional injuries cause deaths, disabilities, productivity and financial losses and disproportionately affect children in low-income settings yet their cost remains under studied. This study determined the household out-of-pocket expenditure and missed school attendance due to unintentional childhood injuries in a Ugandan slum. We used a cross-sectional household survey design. Data were collected on occurrence and associated costs of unintentional injuries during a one-year period from July 2014 to June 2015. A total of 706 (44.7%) children who had suffered from injuries were reported in the one year period. More male children (N = 415, 58.7%) suffered injuries than females (N = 291, 41.2%). The average out-of-pocket expenditure on treating an injury was US $24.1 [standard deviation (SD) = +/-$62.8] and mean school days lost were 25 days (SD = +/-51.8). Road traffic injuries (RTIs) resulted in higher costs [mean difference was US $51.1 (95% CI: $11.4-$90.8)] compared to injuries that, for example, occurred at school. In a Ugandan slum community, unintentional childhood injuries resulted in high out-of-pocket expenditures and missed school attendance. The costs varied widely depending on external causes of the injury. These findings highlight the need to invest in population level injury prevention interventions to reduce injury costs by households. PMID- 30251589 TI - Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler's Disease, Uppsala University Hospital. AB - AIM: The aim of this retrospective single-centre study was to evaluate whether mutations in the ENG, ACVRL1, and SMAD4 genes were associated with different phenotypes in hereditary haemorrhagic telangiectasia (HHT). METHODS: The case records of 21 HHT patients with verified mutations in ENG, ACVRL1, or SMAD4 genes were reviewed. The numbers of HHT diagnostic criteria fulfilled for the three genotypes were compared, as was the prevalence of complications such as iron deficiency anaemia, gastrointestinal haemorrhage, stroke, and cerebral abscess. RESULTS: Our results indicate that mutations in the ENG (HHT1), ACVRL1 (HHT2), and SMAD4 genes result in different HHT phenotypes. Epistaxis debuts earlier and may be more severe in HHT1 than in HHT2. The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2. One patient with mutations in both ENG and ACVRL1 genes was identified, as were two SMAD4-mutated patients suffering from the overlapping juvenile polyposis-HHT syndrome. Nearly one in five patients in our HHT population has been diagnosed with stroke or cerebral abscess, indicating a high prevalence of cerebral complications. CONCLUSION: Our results showing that ENG and ACVRL1 gene mutations result in different HHT phenotypes confirm the results from other HHT centres worldwide. Cerebral complications of HHT are common, underscoring the importance of regular screening for pulmonary AVMs and early intervention against such AVMs. We have identified an HHT patient with simultaneous mutations in the ENG and ACVRL1 genes. Surprisingly, this patient has had a mild course of the disease. PMID- 30251590 TI - Implementing a method for studying longitudinal DNA methylation variability in association with age. AB - Interindividual variability of DNA methylation is a mechanism of the epigenetic drift in aging. Studies on cross-sectional data have discovered a change in methylation variability in association with age. However, thus far, no method explored DNA methylation variability in longitudinal data, which was the aim of this study. First, we performed a simulation study to explore methods for estimating methylation variability in longitudinal data. Second, an epigenome wide association study (EWAS) on 1011 longitudinal samples (385 individuals followed up to 18 years) was performed to identify age-varying methylation sites using these methods. Following Breusch-Pagan test of heteroscedasticity, we showed that a linear regression model, where the residuals were used in a mixed effect model with a random intercept, properly estimated the change of interindividual variability over time. Our EWAS identified 570 CpG sites where methylation variability was significantly associated with age (P < 1.3 * 10-7). Gene regions of identified loci were enriched in nervous system development functions. In conclusion, we provide a method for analyzing methylation variability in longitudinal data and further identified age-varying methylation loci in a longitudinal analysis using these methods. PMID- 30251591 TI - Electrical Somatosensory Stimulation in Early Rehabilitation of Arm Paresis After Stroke: A Randomized Controlled Trial. AB - BACKGROUND: Arm paresis is present in 48% to 77% of acute stroke patients. Complete functional recovery is reported in only 12% to 34%. Although the arm recovery is most pronounced during the first 4 weeks poststroke, few studies examined the effect of upper extremity interventions during this period. OBJECTIVE: To investigate the effect of electrical somatosensory stimulation (ESS) delivered during early stroke rehabilitation on the recovery of arm functioning. METHODS: A total of 102 patients with arm paresis were randomized to a high-dose or a low-dose ESS group within 7 days poststroke according to our sample size estimation. The high-dose group received 1-hour ESS to the paretic arm daily during hospitalization immediately followed by minimum 15-minute task oriented arm training that was considered a component of the usual rehabilitation. The low-dose group received a placebo ESS followed by identical training. Primary outcome-Box and Block Test (BBT); secondary outcomes-Fugl-Meyer Assessment (FMA), grip strength, pinch strength, perceptual threshold of touch, pain, and modified Rankin Scale (mRS); all recorded at baseline, postintervention and at 6 months poststroke. RESULTS: There were no differences between the high dose and the low-dose groups for any outcome measures at any time points. Improvements ? minimal clinically important difference were observed for FMA, hand grip strength, and mRS in both groups. CONCLUSIONS: Providing the present ESS protocol prior to arm training was equally beneficial as arm training alone. These results are valid for patients with mild-to-moderate stroke and moderate arm impairments. We cannot exclude benefits in patients with other characteristics, in other time intervals poststroke or using a different ESS protocol. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02250365). PMID- 30251592 TI - Pharmacokinetic Evaluation of [11C]CEP-32496 in Nude Mice Bearing BRAFV600E Mutation-Induced Melanomas. AB - CEP-32496, also known as RXDX-105 or Agerafenib, is a new orally active inhibitor for the mutated v-raf murine sarcoma viral oncogene homolog B1 (BRAFV600E), which has attracted considerable attention in clinical trials for the treatment of human cancers. Here, we used carbon-11-labeled CEP-32496 ([11C]CEP-32496) as a positron emission tomography (PET) radiotracer to evaluate its pharmacokinetic properties and explore its potential for in vivo imaging. Following radiotracer synthesis, we performed in vitro binding assays and autoradiography of [11C]CEP 32496 in the A375 melanoma cell line and on tumor tissue sections from mice harboring the BRAFV600E mutation. These were followed by PET scans and biodistribution studies on nude mice bearing subcutaneous A375 cell-induced melanoma. [11C]CEP-32496 showed high binding affinity for BRAFV600E-positive A375 melanoma cells and densely accumulated in the respective tissue sections; this could be blocked by the BRAFV600E selective antagonist sorafenib and by unlabeled CEP-32496. The PET and biodistribution results revealed that [11C]CEP-32496 accumulated continuously but slowly into the tumor within a period of 0 to 60 minutes postinjection in A375-melanoma-bearing nude mice. Metabolite analysis showed high in vivo stability of [11C]CEP-32496 in plasma. Our results indicate that [11C]CEP-32496 has excellent specificity and affinity for the BRAFV600E mutation in vitro, while its noninvasive personalized diagnostic role needs to be studied further. PMID- 30251594 TI - Examining the 'psychopharmacology revolution' (1950-1980) through the advertising of psychoactive drugs in the British Medical Journal. AB - BACKGROUND: Many modern pharmaceutical products were launched during 1950-1980, as reflected in advertisements in the British Medical Journal ( BMJ). One of the first therapeutic areas to benefit from novel effective medications was psychiatry. METHODS: We examined BMJ advertising material between 1950 and 1980, including every other issue over six-month periods (October-March) in 1950/1951, 1955/1956, 1957/1958, 1960/1961, 1962/1963, 1965/1966, 1967/1968, 1970/1971, 1972/1973, 1975/1976, 1980/1981. We recorded numbers of adverts for all pharmaceutical products and for psychiatric drugs; we also recorded trade names, generic names and marketing company. RESULTS: Advertising in BMJ peaked in the 1960s and declined markedly in the 1970s. Adverts for psychiatric drugs as a percentage of total pharmaceutical product advertising was broadly similar during 1955-1980, but with peaks in 1960/1961, 1970/1971 and 1975/1976, reflecting the entry of several novel compounds into the market. The peak marketing of antipsychotic drugs, sedatives and anxiolytic drugs was in 1960 and of antidepressants 1970. The time course of the rise of tricyclics and the switch from barbiturates to benzodiazepines can be seen. Drugs for psychiatry rose from ninth (1955/1956) to fourth (1975/1976) in terms of the number of products in the top 10 therapeutic areas. There is no evidence that they were advertised more aggressively (number of adverts/number of products). CONCLUSIONS: The birth of modern psychopharmacology is reflected in th e advertising of psychiatric drugs in BMJ. Many drugs currently used, or their closely related successors, were launched in the early to mid-1960s. This rise in modern pharmaceuticals preceded several other major therapeutic areas. PMID- 30251595 TI - Quality assessment of Major Trauma Registry of Navarra: completeness and correctness. AB - This study assessed the completeness of the Major Trauma Registry of Navarra (MTR N) data and their concordance with the patients' medical files. It retrospectively reviewed all the MTR-N cases documented in June and July of 2014 and 2015. For each case, 42 parameters' values were taken from the MTR-N. To assess concordance between the MTR-N and medical files, the same variables values were re-recorded. Data completeness was calculated for all cases and data correctness for those documented in the MTR-N, separately for each variable. The overall average completeness rate for all variables was 92.8%. The percentages of completely missing data ranged from 0% (29 variables) to 76.8% (base excess). The overall average rate of correctness was 98.0%. Exact concordance ranged from 93.0% (7 variables) to 100% (22 variables). This study demonstrates the reliability and validity of the MTR-N data and its effectiveness for quality improvement and research in our community. PMID- 30251593 TI - A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus. AB - Virulence mechanisms of the pathogenic fungus Aspergillus fumigatus are multifactorial and depend on the immune state of the host, but little is known about the fungal mechanism that develops during the process of lung invasion. In this study, microarray technology was combined with a histopathology evaluation of infected lungs so that the invasion strategy followed by the fungus could be described. To achieve this, an intranasal mice infection was performed to extract daily fungal samples from the infected lungs over four days post-infection. The pathological study revealed a heavy fungal progression throughout the lung, reaching the blood vessels on the third day after exposure and causing tissue necrosis. One percent of the fungal genome followed a differential expression pattern during this process. Strikingly, most of the genes of the intertwined fumagillin/pseurotin biosynthetic gene cluster were upregulated as were genes encoding lytic enzymes such as lipases, proteases (DppIV, DppV, Asp f 1 or Asp f 5) and chitinase (chiB1) as well as three genes related with pyomelanin biosynthesis process. Furthermore, we demonstrate that fumagillin is produced in an in vitro pneumocyte cell line infection model and that loss of fumagillin synthesis reduces epithelial cell damage. These results suggest that fumagillin contributes to tissue damage during invasive aspergillosis. Therefore, it is probable that A. fumigatus progresses through the lungs via the production of the mycotoxin fumagillin combined with the secretion of lytic enzymes that allow fungal growth, angioinvasion and the disruption of the lung parenchymal structure. PMID- 30251596 TI - Comparisons of the BRIEF parental report and neuropsychological clinical tests of executive function in Fetal Alcohol Spectrum Disorders: data from the UK national specialist clinic. AB - Extant literature is sparse with regards to the relationship between caregiver reports and neuropsychological tests of executive functioning in Fetal Alcohol Spectrum Disorders (FASD). The goal of this paper was determining the clinical utilities of executive functioning measures used in the United Kingdom national FASD clinic. We examined relationships between outcomes on the Behavior Rating Inventory of Executive Function (BRIEF) and the Delis-Kaplan Executive Function System (D-KEFS), as part of an ongoing service evaluation. Profiles of executive functioning measures were reported in order to contribute to delineating a profile of executive dysfunction in FASD. Caregivers of 49 people with FASD completed the Parent BRIEF, and 61 people with FASD were administered the D-KEFS. Pearson's Correlations between all 11 BRIEF scales and the 18 selected D-KEFS subscales showed little relationship. The BRIEF showed a profile of clinically significant elevations in all three Index scores and seven out of the eight Scale scores. Several D-KEFS tests showed below average executive functioning. Both executive function measures have separate clinical utility in demonstrating executive function deficits in FASD. The sample population used in this study also show a similar pattern to FASD populations internationally, suggesting a similar neuropsychological profile is seen in the United Kingdom. However, caregiver reports display little relationship to neuropsychological tests. These measures likely monitor different aspects of executive functioning in different settings. Future research should focus on identifying tests that better relate findings from clinical settings to behavior in daily life. PMID- 30251597 TI - Gender and age distribution of motorcycle crashes in Spain. AB - This study analysed motorcycle crashes in Spain. Ninety-nine thousand three hundred and four motorcycle crash reports filed in the years 2006-2011 were extracted from the Directorate General of Traffic database of crashes with victims. These data were analysed in terms of gender, age groups, trip purpose, type of crash, speed violation, day of the week, harm caused, use of helmet and psychophysical conditions of the driver to study the characteristics of motorcycle crashes in Spain and to assess the differences between male and female motorcycle drivers in these crashes. Significant differences were found in all the variables considered in the study, which implies gender differences in the profile of the injured motorcycle driver. The severity of motorcycle crashes suffered by male drivers is higher than that of women. These results corroborate the need to develop measures differentiated by gender, based on their profile. PMID- 30251598 TI - Effects of aripiprazole on pupillometric parameters related to pharmacokinetics and pharmacogenetics after single oral administration to healthy subjects. AB - BACKGROUND:: Pupillometry is used for the detection of autonomic dysfunction related to numerous diseases and drug administration. Genetic variants in cytochrome P450 ( CYP2D6, CYP3A4), dopamine receptor ( DRD2, DRD3), serotonin receptor ( HTR2A, HTR2C) and ATP-binding cassette subfamily B ( ABCB1) genes were previously associated with aripiprazole response. AIMS:: Our aim was to evaluate if aripiprazole affects pupil contraction and its relationship with pharmacokinetics and pharmacogenetics. METHODS:: Thirty-two healthy volunteers receiving a 10 mg single oral dose of aripiprazole were genotyped for 15 polymorphisms in ABCB1, CYP2D6, DRD2, DRD3, HTR2A and HTR2C genes by reverse transcription polymerase chain reaction. Aripiprazole and dehydro-aripiprazole plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Pupil examination was performed by automated pupillometry. RESULTS:: Aripiprazole caused pupil constriction and reached the peak value at Cmax. HTR2A rs6313 T allele carriers and HTR2C rs3813929 C/T subjects showed higher maximum constriction velocity and maximum pupil diameter. Besides, Gly/Gly homozygotes for DRD3 rs6280 showed significantly lower maximum constriction velocity values. A/G heterozygotes for DRD2 rs6277 showed higher total time taken by the pupil to recover 75% of the initial resting size values. CYP2D6 intermediate metabolisers showed higher area under the curve, Cmax and T1/2 than extensive metabolisers. ABCB1 G2677T/A A/A homozygotes had greater T1/2 in comparison with C/C homozygotes. ABCB1 C3435T T allele carriers and C1236T C/T subjects showed greater area under the curve than C/C homozygotes. CONCLUSIONS:: Aripiprazole affects pupil contraction, which could be a secondary effect through dopamine and serotonin receptors. Pupillometry could be a useful tool to assess autonomic nervous system activity during antipsychotic treatment. PMID- 30251599 TI - A Review of Recent Advances and Research on Drug Target Identification Methods. AB - From a therapeutic viewpoint, understanding how drugs bind and regulate the functions of their target proteins to protect against disease is crucial. The identification of drug targets plays a significant role in drug discovery and in studying the mechanisms of diseases. The development of methods to identify drug targets has become a popular issue in this field of research. Originally, scientists used biological experiments to identify drug targets. However, recently, an increasing number of scientists use computational methods to identify drug targets. Although thousands of drug targets are estimated to exist, only hundreds of these potential targets have been verified. Therefore, in this paper, we systematically review the recent work on identifying drug targets. PMID- 30251600 TI - A Review of Theranostics Applications and Toxicities of Carbon Nanomaterials. AB - BACKGROUND: In last few years, the use of modified carbon nanomaterials (CNMs) for theranostics (therapeutic and diagnosis) applications is a new and rapidly growing area in pharmacy and medical fields. Owing to this, their unique physical and chemical properties like high stability, high drug loading with high surface to volume ratio, low toxicity are mainly responsible to be considered those as smart nanomaterials. OBJECTIVE: This review describes the different sizes, shapes, and dimensions of carbon-based nanocarriers including 0-D fullerene, 1-D CNTs, and 2-D graphene and graphene oxide and their surface modification with different biocompatible and biodegradable molecules via covalent or non-covalent functionalization. The major focus of this article is on the different theranostics applications of carbon-based nanomaterials (CNMs) like targeted drugs and genes delivery, photodynamic therapy, photothermal therapy, bioimaging and biosensing. The therapeutic efficacy of drugs could be enhanced by delivering the drugs directly on specific site using different targeted ligands such as vitamins, peptide, carbohydrates, proteins with its unique intercellular imaging properties. A section of the article discusses the toxicity of the CNMs to the living systems. CONCLUSION: In brief, this review article discusses the numerous theranostics applications and toxicities of CNMs. Biomolecules-functionalized oxygenated GO and CNTs are more efficacious than the other CNMs with abridged cellular toxicity. PMID- 30251601 TI - Influence of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics/Pharmacodynamics of Tacrolimus in pediatric patients. AB - Single nucleotide polymorphisms (SNPs) are the most common variants in many genes, which are also promising markers in relation to drug responses in pharmacogenomics studies. Tacrolimus is a primary immunosuppressant used for the prevention of organ rejection in pediatric organ transplantation. Tacrolimus, transported out of cells via P-glycoprotein (ABCB1), is also a metabolic substrate for cytochrome P450 (CYP) 3A enzymes, especially the CYP3A4 and the CYP3A5. The SNP of these genes have been studied extensively in adult population, but there is no systematic review in children. In this paper, we focus on the impact of CYP3A and ABCB1 SNPs on tacrolimus in children undergoing organ transplantations. Literature searches were performed and all relevant primary research articles were critiqued and summarized. There is no evidence that the CYP3A4 SNP has an effect on the pharmacokinetics/pharmacodynamics of tacrolimus in children. And, the majority of studies have failed to find an association between the ABCB1 SNP and pharmacokinetics of tacrolimus in children. However, although the amount of literature is limited, it does show an association between ABCB1 SNPs and pharmacodynamics of tacrolimus. Despite a strong association between CYP3A5 SNP and tacrolimus pharmacokinetics has been demonstrated, there is no direct evidence to prove the effect of CYP3A5 SNP on pharmacodynamics of tacrolimus. More standardized clinical trials are needed to evaluate the relationship between the CYP3A5 SNP and the pharmacodynamics of tacrolimus, particularly in regard to the outcomes of acute rejection and nephrotoxicity. PMID- 30251602 TI - Replacing GHB with GBL in Recreational Settings: A New Trend in Chemsex. AB - BACKGROUND: Recently, Gamma-hydroxybutyrate (GHB) consumption in the recreational setting has been replaced by that of its prodrug Gamma-butyrolactone (GBL), cheaper and easier to obtain due to several legal industrial applications. OBJECTIVE: The aim of the present paper was to report the most authoritative literature on the pharmacology and toxicology of GBL, dependence and abuse potential and the related public health issues together with the results of the analyses of several illicit liquid preparations containing GHB/GBL generally sold as "G". METHOD: International literature concerning "Gamma-butyrolactone", "GBL" "toxicology", "pharmacology", "abuse", "dependence" and "GHB has been reviewed and liquid preparations containing GHB/GBL analysed by ultra-high performance liquid chromatography coupled to the tandem mass spectrometry validated methodology. RESULTS: GBL for recreational purposes is orally administered in liquid form and rapidly transformed into GHB by lactonase enzymes present in the blood. As GBL shows a higher lipophilicity than GHB, it is absorbed more quickly, its bioavailability is higher and its effects are faster than those of GHB. Studies on rodents have shown that GBL has a low acute toxicity and only central nervous system depression has been highlighted. GBL abuse potential broadly mimics that of GHB, taking into account that it exerts its effects on the only after conversion into GHB. The analysis of 30 illicit preparations generally sold as "G" highlighted the presence of GBL in all of them at a mean concentration of 760.7 +/-91.46 mg/mL (range: 588.5 - 899.3 mg/mL). CONCLUSION: GBL currently represents a growing public health issue since the substance is relatively cheaper and easier to obtain than GHB. Improvement and implementation of laws and policies to place GBL under control are needed to limit its diffusion, the eventual health threat for users and its non -negligible abuse liability and dependence risk. PMID- 30251603 TI - Alzheimer's Disease: Special Focus on the Efficacy of Computer-Based Training Programs - A Mini-Review. AB - BACKGROUND: At present, the number of older people is growing, especially in the developed countries where the living conditions enable a longer life expectancy. However, the higher age may result in the aging diseases such as dementia out which Alzheimer's disease (AD) is the most frequent. Nevertheless, to maintain them both physically and mentally active, more assistance is required. OBJECTIVE: The purpose of this study is to discuss the efficacy of the use of modern information technologies, especially computer-based training programs, on people with Alzheimer's disease (AD). RESULTS: Although the results from the selected studies do not indicate that the computer-based training programs are effective in the delay of cognitive decline is concerned, they suggest that these computerbased training programs are at least appropriate for the improvement of their behavioural symptoms and progression of the disease. CONCLUSION: Generally, these technological devices may contribute to the reduction of patients' and their caregivers' costs and certain flexibility, and thus the improvement of the quality of their life. PMID- 30251604 TI - Assessing Everyday Activities Across the Dementia Spectrum with the Amsterdam IADL Questionnaire. AB - BACKGROUND: Instrumental activities of daily living (IADL) are complex activities which involve multiple cognitive processes, and which are expected to be susceptible to the early effects of cognitive impairment. Informant-based questionnaires are the most common tools used to assess IADL performance in dementia, but must be adjusted for use in early stages of impairment. OBJECTIVE: To investigate the differences in IADL on the continuum of cognitive decline (i.e. no cognitive decline - subjective cognitive decline - mild cognitive impairment- mild dementia - moderate dementia) using the Spanish version of the Amsterdam IADL Questionnaire (A-IADL-Q). METHODS: A total of 500 volunteer participants were included: 88 participants with no signs of cognitive decline, 109 participants with subjective cognitive complaints, 114 participants with mild cognitive impairment (MCI), 81 participants with mild dementia and 108 participants with moderate dementia. IADL was assessed with the A-IADL-Q, a computerized and adaptive questionnaire that calculates scores according to the specific pattern of responses of each participant. The data were examined by ANOVAs and regression analysis. Multinomial logistic regression analysis was used to evaluate the capacity of the A-IADL-Q to distinguish between diagnostic groups. RESULTS: Participants with no cognitive decline and those with subjective cognitive decline obtained higher A-IADL-Q scores than MCI participants, and participants with MCI obtained higher scores than patients with dementia. The A IADL-Q showed excellent discrimination between non-cognitive impairment and dementia, and significant but low discrimination between non-cognitive impairment and MCI. CONCLUSION: A-IADL-Q can discriminate IADL functioning between groups across the dementia spectrum. PMID- 30251605 TI - Global View on Alzheimer's Disease and Diabetes Mellitus: Threats, Risks and Treatment Alzheimer's Disease and Diabetes Mellitus. AB - The incidence of both diabetes and Alzheimer's disease (AD) is increasing and is becoming a social and economic threat worldwide. Recent research studies indicate that both diseases share some pathophysiological features and that specifically, Type 2 Diabetes Mellitus (T2DM) is a risk factor of Alzheimer's disease. The aim of this study is to explore the relationship between diabetes mellitus and AD, explore the efficacy of selected drugs on patients with diabetes and AD, and compare the relative risk of diabetes for Alzheimer's disease within different clinical studies. The method of literature search in several acknowledged databases such as Web of Science, Elsevier Science Direct, PubMed and Scopus in the period from 2000 to 2015 for the following keywords: "Alzheimer's AND disease AND diabetes AND mellitus" was used. The identified studies were divided into two basic groups, based on their focus: efficacy of the selected drugs on patients suffering from AD and diabetes, and a link between diabetes and AD; as diabetes is seen as a risk factor of AD. The findings of this study confirm that there is a close and direct link between diabetes and AD, which indicates that there is a need for early diagnosis of metabolic syndrome, insulin resistance, and T2DM. In fact, the reviewed clinical trials have proved an increase in the risk of AD. However, the values of this risk are relatively low. The results also illustrate that both pharmacological (e.g., the antidiabetic drugs together with insulin dosing) and nonpharmacological (e.g., being intensively engaged in physical activities) treatments can have a positive effect. The results of this study confirm that diabetes and AD are not independent disorders since they share some common pathophysiological mechanisms. In addition, more clinical randomized control trials are needed to explore the efficacy of both pharmacological and non pharmacological approaches to the treatment of T2DM and AD. PMID- 30251606 TI - Do we have a satisfactory cell viability assay? Review of the currently commercially-available assays. AB - Cell-based assays are an important part of the drug discovery process and clinical research. One of the main hurdles is to design sufficiently robust assays with adequate signal to noise parameters while maintaining the inherent physiology of the cells and not interfering with the pharmacology of target being investigated. A plethora of assays that assess cell viability (or cell heath in general) are commercially available and can be classified under different categories according to their concepts and principle of reactions. The assays are valuable tools, however, suffer from a large number of limitations. Some of these limitations can be procedural or operational, but others can be critical as those related to poor concept or the lack of proof of concept of an assay, e.g. those rely on differential permeability of dyes in-and-out of viable versus compromised cell membranes. While the assays can differentiate between dead and live cells, most, if not all, of them can just assess relative performance of cells rather than providing clear distinction between healthy and dying cells. The possible impact of relatively high molecular weight dyes, used in most of the assay, on cell viability has not been addressed. More innovative assays are needed, and until better alternatives are developed, setup of current cell-based studies and data interpretation should be made with the limitations in mind. Negative and positive control should be considered whenever feasible. Also, researchers should use more than one orthogonal method for better assessment of cell health. PMID- 30251607 TI - Role of Cardiac Magnetic Resonance Imaging in Patients with Idiopathic Ventricular Arrhythmias. AB - Ventricular Arrhythmias (VAs) may present with a wide spectrum of clinical manifestations ranging from mildly symptomatic frequent premature ventricular contractions to life-threatening events such as sustained ventricular tachycardia, ventricular fibrillation and sudden cardiac death. Myocardial scar plays a central role in the genesis and maintenance of re-entrant arrhythmias which are commonly associated with SHD such as ischemic heart disease, healed myocarditis and non-ischemic cardiomyopathies. However, the arrhythmogenic substrate may remain unclear in up to 50% of the cases after a routine diagnostic workup comprehensive of 12-lead surface ECG, transthoracic echocardiography and coronary angiography/computed tomography. Whenever any abnormality cannot be identified, VAs are referred as to "idiopathic". In the last decade, cardiac magnetic resonance (CMR) imaging has acquired a growing role in the identification and characterization of myocardial arrhythmogenic substrate, not only being able to accurately and reproducibly quantify biventricular function, but, more importantly, providing information about the presence of myocardial structural abnormalities such as myocardial fatty replacement, myocardial oedema, and necrosis/ fibrosis, which may otherwise remain unrecognized. Moreover, CMR has recently demonstrated to be of great value in guiding interventional treatments, such as radiofrequency ablation, by reliably identifying VA sites of origin and improving long-term outcomes. In the present manuscript, we review the available data regarding the utility of CMR in the workup of apparently "idiopathic" VAs with a special focus on its prognostic relevance and its application in planning and guiding interventional treatments. PMID- 30251608 TI - 2,4-Dichloro-5-[(N-aryl/alkyl)sulfamoyl]benzoic Acid Derivatives: In Vitro Antidiabetic Activity, Molecular Modeling and In silico ADMET Screening. AB - BACKGROUND: Postprandial hyperglycemia can be reduced by inhibiting major carbohydrate hydrolyzing enzymes such as alpha-glucosidase and alpha-amylase which is an effective approach in both preventing and treating diabetes. OBJECTIVE: The aim of this study was to synthesize a series of 2,4-dichloro-5-[(N aryl/alkyl)sulfamoyl]benzoic acid derivatives and evaluate alpha-glucosidase and alpha-amylase inhibitory activity along with molecular docking and in silico ADMET property analysis. METHOD: Chlorosulfonation of 2,4-dichloro benzoic acid and followed by reaction with corresponding anilines/amines yielded 2 ,4-dichloro 5-[(N-aryl/alkyl)sulfamoyl]benzoic acid derivatives. For evaluating their antidiabetic potential alpha-glucosidase and alpha-amylase inhibitory assays were carried out. In silico molecular docking studies of these compounds were performed with respect to these enzymes and a computational study was also carried out to predict the drug-likeness and ADMET properties of the title compounds. RESULTS: Compound 3c (2,4-dichloro-5-[(2-nitrophenyl)sulfamoyl]benzoic acid) was found to be highly active having 3 fold inhibitory potential against alpha-amylase and 5 times inhibitory activity against alpha-glucosidase in comparision to standard drug acarbose. CONCLUSION: Most of the synthesized compounds were highly potent or equipotent to standard drug acarbose for inhibitory potential against alpha-glucosidase and alpha-amylase enzyme and hence this may indicate their antidiabetic activity. The docking study revealed that these compounds interact with active site of enzyme through hydrogen bonding and different pi interactions. PMID- 30251609 TI - Rational design of colchicine derivatives as anti-HIV agents via QSAR and molecular docking. AB - BACKGROUND: Human immunodeficiency virus (HIV) is an infective microorganism that causes an acquired immunodeficiency syndrome (AIDS). Therefore, the rational design of inhibitors for preventing the progression of the disease is required. OBJECTIVE: This study aims to construct quantitative structure-activity relationship (QSAR) models, molecular docking and newly design of colchicine and derivatives with anti-HIV activity. METHOD: A data set of 24 colchicine and derivatives with anti-HIV activity were employed to develop QSAR models using machine learning methods (e.g. multiple linear regression (MLR), artificial neural network (ANN) and support vector machine (SVM)), and to study a molecular docking. RESULTS: The significant descriptors relating to the anti-HIV activity included JGI2, Mor24u, Gm and R8p+ descriptors. The predictive performance of the models gave acceptable statistical qualities as observed by correlation coefficient (Q2) and root mean square error (RMSE) of leave-one out cross validation (LOO-CV) and external sets. Particularly, the ANN method outperformed MLR and SVM methods that displayed and RMSELOO-CV of 0.7548 and 0.5735 for LOO-CV set, and of 0.8553 and RMSEExt of 0.6999 for external validation. In addition, the molecular docking of virus-entry molecule (gp120 envelope glycoprotein) revealed the key interacting residues of the protein (cellular receptor, CD4) and the site-moiety preferences of colchicine derivatives as HIV entry inhibitors for binding to HIV structure. Furthermore, newly rational design of colchicine derivatives using informative QSAR and molecular docking was proposed. CONCLUSION: These findings serve as a guideline for the rational drug design as well as potential development of novel anti-HIV agents. PMID- 30251610 TI - A Novel Amino Acid Sequence-based Computational Approach to Predicting Cell penetrating Peptides. AB - Machine Learning is a useful tool for prediction of cell-penetration compounds as drug candidates. In this study, we developed a novel method for predicting Cell Penetrating Peptides (CPPs) membrane penetrating capability. For this, we used orthogonal encoding to encode amino acid and each amino acid position as one variable. Then a software of IBM spss modeler and a dataset includes 533 CPPs were used for model screening. The results indicated that a machine learning model of Support Vector Machine (SVM) was suitable for membrane penetrating capability predicting. For improvement, the three CPPs with the most length were used to predicting CPPs. The penetration capability can be predicted with an accuracy of close to 95%. All the results indicated that by using amino acid position as variable can be a perspective method for predicting CPPs membrane penetrating capability. PMID- 30251611 TI - A Review of Clinical Data Management Systems Used in Clinical Trials AB - BACKGROUND: Clinical data management system is a software supporting the data management process in clinical trials. In this system, the effective support of clinical data management dimensions leads to the increased accuracy of results and prevention of diversion in clinical trials. The objective of this review article is to investigate the dimensions of data management in clinical data management systems. METHODS: This study was conducted in 2017. The used databases included Web of Science, Scopus, Science Direct, ProQuest, Ovid Medline and PubMed. The search was conducted over a period of 10 years from 2007 to 2017. The initial number of studies was 101 reaching to 19 in the final stage. The final studies were described and compared in terms of the year, country and dimensions of the clinical data management process in clinical trials. RESULTS: The research findings indicated that none of the systems completely supported the data management dimensions in clinical trials. Although these systems were developed for supporting the clinical data management process, they were in many cases similar to electronic data capture systems. The most significant dimensions of data management in such systems were data collection or entry, report, validation, and security maintenance. CONCLUSION: Seemingly, in relation with the performance of data management systems, not sufficient attention was paid to automation all dimensions of the clinical data management process. However, these systems could take positive steps towards changing the manual processes of clinical data management to electronic processes. PMID- 30251613 TI - Design and Fabrication of Ultracapacitor based on Paper substrate and BaTiO3/PEDOT: PSS Separator Film. AB - In this study, the ultracapacitor has been fabricated based on the BaTiO3/PEDOT: PSS separator film and polyvinyl alcohol (PVA) electrolyte. On the paper substrate was coated a film of the graphite nanoparticles (GNPs) as an electrode. The GNPs and surface morphology of the separator, electrolyte and electrode have been characterized using transmission electron microscopy (TEM) and scanning electron microscopy (SEM) respectively. The specific capacitance of the ultracapacitor was measured using cyclic voltammetry and galvanostatic techniques. The specific capacitance of the ultracapacitor using C-V curves was 350 F g-1 at 20 mV/s. Using the electrochemical impedance spectroscopy test the Nyquist and Bode curves of the ultracapacitors have been plotted. From the Nyquist curve, the internal resistance was 80 Omega. The symmetric ultracapacitor based on the GNPs electrode and BaTiO3/PEDOT: PSS separator film represents an advanced type of solid-state flexible ultracapacitor with high performance for energy storage application. PMID- 30251612 TI - Effect of Kangaroo Mother Care on successful breastfeeding: A systematic review and Meta-Analysis of randomised controlled trials. AB - BACKGROUND & AIMS: Evaluating the effect of Kangaroo Mother Care (KMC) on breastfeeding success shows conflicting results. Regarding the importance of breastfeeding and uncertainties about its effect, this study intended to conduct a systematic review and meta-analysis of randomised controlled trials on the effect of KMC on success of breastfeeding. METHODS: In this systematic review and meta-analysis study, required data were collected by searching the following key words: breastfeeding, Breast-Feeding, "skin-to-skin", "Kangaroo Mother Care", randomized clinical trial. The following databases were searched: Google Scholar, PubMed, EMBASE, Scopus, and Cochrane Central Register of Controlled Trials. Two authors independently extracted the data. To estimate the Breast-Feeding outcome variables, CMA2 software was used. The risk of bias of studies was assessed with the criteria developed in the Cochrane Handbook. RESULTS: Twenty articles were included. In the KMC and CNC groups, 1,432 and 1,410 neonates were examined. Breastfeeding success rate was higher in the KMC group within different time slots, however this difference was not statistically significant (RR=1.11(95CI, 0.93-1.34) and RR=1.13(95%CI, 0.92-1.34) based on the time slot and birth weight, respectively). The between-groups difference in the mean scores of Infant Breast Feeding Assessment Tool (IBFAT) statistically significant (P<0.05). Breastfeeding was initiated very sooner in the KMC group, suggesting a statistically significant between-groups difference -0.72(95%CI, from -0.92 to -0.53) (P<0.05). Majority of studies had high risk of bias. CONCLUSION: Findings indicated a superiority of KMC over CNC in terms of breastfeeding success. Assessing the complications and costs of KMC implementation recommended. PMID- 30251614 TI - Nanosponges -A Promising Novel Drug Delivery System. AB - BACKGROUND: Pharmacokinetic issues and poor solubility in water are the most important concern of numerous recently developed chemical entities. OBJECTIVE: The drugs which are poorly soluble in water demonstrate numerous formulating troubles in conventional dosage forms and the low bio-availability is the critical problem linked with it. A nanosponge is an emerging technology which can overcome these problems and precisely control the release rates of controlled drug delivery. METHOD: Nanosponges are tiny mesh-like structures with a size less than 1um. Due to their porous structure and small size; they can easily bind to drugs which are poorly-soluble leading to better bio-availability and solubility of such drugs. Broad range of drugs including both hydrophilic and lipophilic can be easily loaded into nanosponges. RESULTS: These minute sponges can circulate until they reach the definite target site, attach themselves to the surface and initiate the discharge of drugs in a predictable and controlled way. Nanosponges are solid in character and can be developed in various dosage forms such as parenteral, topical, oral or inhalational. Nanosponge drug delivery system has been developed as one of the most capable aspects in the field of pharmaceuticals. CONCLUSION: In this review, attempt has been made to highlight the advantages, characteristics, application, methods of preparation and characterization of nanosponges along with the recent patents on nanosponges. PMID- 30251615 TI - Altered gene expression of muscle satellite cells contributes to age-related sarcopenia in mice. AB - BACKGROUND: During aging, muscle tissue undergoes profound changes which lead to a decline in its functional and regenerative capacity. We utilized global gene expression analysis and gene set enrichment analysis to characterize gene expression changes in aging muscle satellite cells. METHOD: Gene expression data; obtained from Affymetrix Mouse Genome 430 2.0 Array, for 14 mouse muscle satellite cell samples (5 young, 4 middle-aged, and 5 aged), were retrieved from public Gene Expression Omnibus repository. List of differentially expressed genes was generated based on 0.05 multiple-testing-adjusted p-value and 2-fold FC cut off values. Functional profiling of genes was carried out using PANTHER Classification System. RESULTS: We have found several differentially expressed genes in satellite cells derived from aged mice compared to young ones. The gene expression changes increased progressively with time, and the majority of the differentially expressed genes were upregulated during aging. While the downregulated genes could not be correlated with specific biological processes the upregulated ones could be associated with muscle differentiation-, inflammation- or fibrosis-related processes. The latter two processes encompass the senescence-associated secretory phenotype for satellite cells which alters the tissue microenvironment and contributes to inflammation and fibrosis observed in aging muscle. CONCLUSION: Our analysis reveals that by altering gene expression pattern and expressing inflammatory mediators and extracellular matrix components, these cells can directly contribute to muscle wasting in aged mice. PMID- 30251617 TI - Revisiting the Form and Function of Conflict: Neurobiological, Psychological and Cultural Mechanisms for Attack and Defense Within and Between Groups. AB - Conflict can profoundly affect individuals and their groups. Oftentimes, conflict involves a clash between one side seeking change and increased gains through victory, and the other side defending the status quo and protecting against loss and defeat. However, theory and empirical research largely neglected these conflicts between attackers and defenders, and the strategic, social, and psychological consequences of attack and defense remain poorly understood. To fill this void, we model (i) the clashing of attack and defense as games of strategy, reveal that (ii) attack benefits from mismatching its target's level of defense, whereas defense benefits from matching the attacker's competitiveness, suggest that (iii) attack recruits neuro-endocrine pathways underlying behavioral activation and overconfidence, whereas defense invokes neural networks for behavioral inhibition, vigilant scanning and hostile attributions, and show that (iv) people invest less in attack than defense and attack often fails. Finally, we propose that (v) in intergroup conflict out-group attack needs institutional arrangements that motivate and coordinate collective action, whereas in-group defense benefits from endogenously emerging in-group identification. We discuss how games of attack and defense may have shaped human capacities for pro sociality and aggression, and how third parties can regulate such conflicts, and reduce its waste. PMID- 30251616 TI - Individual placement and support for vocational recovery in first-episode psychosis: randomised controlled trial. AB - BACKGROUND: High unemployment is a hallmark of psychotic illness. Individual placement and support (IPS) may be effective at assisting the vocational recoveries of young people with first-episode psychosis (FEP).AimsTo examine the effectiveness of IPS at assisting young people with FEP to gain employment (Australian and Clinical Trials Registry ACTRN12608000094370). METHOD: Young people with FEP (n = 146) who were interested in vocational recovery were randomised using computer-generated random permuted blocks on a 1:1 ratio to: (a) 6 months of IPS in addition to treatment as usual (TAU) or (b) TAU alone. Assessments were conducted at baseline, 6 months (end of intervention), 12 months and 18 months post-baseline by research assistants who were masked to the treatment allocations. RESULTS: At the end of the intervention the IPS group had a significantly higher rate of having been employed (71.2%) than the TAU group (48.0%), odds ratio 3.40 (95% CI 1.17-9.91, z = 2.25, P = 0.025). However, this difference was not seen at 12- and 18-month follow-up points. There was no difference at any time point on educational outcomes. CONCLUSIONS: This is the largest trial to our knowledge on the effectiveness of IPS in FEP. The IPS group achieved a very high employment rate during the 6 months of the intervention. However, the advantage of IPS was not maintained in the long term. This seems to be related more to an unusually high rate of employment being achieved in the control group rather than a gross reduction in employment among the IPS group.Declaration of interestNone. PMID- 30251618 TI - DIFFERENTIATION OF HEALTH-RELATED QUALITY OF LIFE OUTCOMES BETWEEN FIVE DISEASE AREAS: RESULTS FROM AN INTERNATIONAL SURVEY OF PATIENTS. AB - OBJECTIVES: Health-related quality of life (HRQoL) data generated by generic, preference-based instruments (i.e., EQ-5D) are highly demanded in health policy decision making, because they allow for direct comparisons of HRQoL outcomes between disease areas. We aimed to quantify HRQoL outcomes in breast cancer (BC), rheumatoid arthritis (RA), multiple sclerosis (MS), rare cancers (RC), and rare disease (RD) patients and understand the patterns that differentiate HRQoL outcomes between these disease areas, and more specifically between rare and more common disease population groups. METHODS: An international, Web survey of patients measured HRQoL (EQ-5D-5L), self-perceived health (EQ-5D-5L Visual Analogue Scale), and additional QoL dimensions, such as patient disability level. RESULTS: We received 675 completed responses. Average utility loss was 53.5 percent, 32.5 percent, and 33.3 percent for RD, RA, and MS patients, respectively, in contrast to 18.6 percent for BC and RC patients. Statistically significant differences (p < .05) were observed between disease groups in all EQ 5D-5L domain outcomes, apart from that of "Anxiety/Depression." Severe and/or extreme problems were reported in performing usual activities for RD and RC (34 percent and 13 percent of overall problems reported respectively), mobility for MS (18 percent), pain/discomfort for RA (13 percent), and anxiety/depression for BC (7 percent) patients. CONCLUSIONS: We demonstrated significant differences in the dimensions that drive HRQoL outcomes between rare and more common diseases and showcased that the same EQ-5D utility may reflect very different severities depending on the patient population under investigation. Future research should examine whether outcomes in other, critical HRQoL domains not included in generic measures also highlight significant differences across disease areas. PMID- 30251619 TI - Thinking in and about time: A dual systems perspective on temporal cognition. AB - We outline a dual systems approach to temporal cognition, which distinguishes between two cognitive systems for dealing with how things unfold over time - a temporal updating system and a temporal reasoning system - of which the former is both phylogenetically and ontogenetically more primitive than the latter, and which are at work alongside each other in adult human cognition. We describe the main features of each of the two systems, the types of behavior the more primitive temporal updating system can support, and the respects in which it is more limited than the temporal reasoning system. We then use the distinction between the two systems to interpret findings in comparative and developmental psychology, arguing that animals operate only with a temporal updating system and that children start out doing so too, before gradually becoming capable of thinking and reasoning about time. After this, we turn to adult human cognition and suggest that our account can also shed light on a specific feature of our everyday thinking about time that has been the subject of debate in the philosophy of time, which consists in a tendency to think about the nature of time itself in a way that appears ultimately self-contradictory. We conclude by considering the topic of intertemporal choice, and argue that drawing the distinction between temporal updating and temporal reasoning is also useful in the context of characterising two distinct mechanisms for delaying gratification. PMID- 30251620 TI - 'Prescribing' psychotropic medication to our rivers and estuaries. AB - SummaryThe influence of pharmaceuticals on the environment is an increasing concern among environmental toxicologists. It is known that their growing use is leading to detectable levels in wastewater, conceivably causing harm to aquatic ecosystems. Psychotropic medication is one such group of substances, particularly affecting high-income countries. While these drugs have a clear place in therapy, there is debate around the risk/benefit ratio in patients with mild mental health problems. Therefore, it is necessary to evaluate the wider implications as risks could extend beyond the individual to non-target organisms, particularly those in rivers and estuaries.Declaration of interestNone. PMID- 30251621 TI - The slow dynamics of mycoplasma infections in a tortoise host reveal heterogeneity pertinent to pathogen transmission and monitoring. AB - The epidemiology of infectious diseases depends on many characteristics of disease progression, as well as the consistency of these processes across hosts. Longitudinal studies of infection can thus inform disease monitoring and management, but can be challenging in wildlife, particularly for long-lived hosts and persistent infections. Numerous tortoise species of conservation concern can be infected by pathogenic mycoplasmas that cause a chronic upper respiratory tract disease (URTD). Yet, a lack of detailed data describing tortoise responses to mycoplasma infections obscures our understanding of URTDs role in host ecology. We therefore monitored Mycoplasma agassizii infections in 14 captive desert tortoises and characterised clinical signs of disease, infection intensity, pathogen shedding and antibody production for nearly 4 years after initial exposure to donor hosts. Persistent infections established in all exposed tortoises within 10 weeks, but hosts appeared to vary in resistance, which affected the patterns of pathogen shedding and apparent disease. Delays in host immune response and changes to clinical signs and infection intensity over time resulted in inconsistencies between diagnostic tools and changes in diagnostic accuracy throughout the study. We discuss the implications these results have for URTD epidemiology and past and future research assessing disease prevalence and dynamics in tortoise populations. PMID- 30251623 TI - Review: Using physiologically based models to predict population responses to phytochemicals by wild vertebrate herbivores. AB - To understand how foraging decisions impact individual fitness of herbivores, nutritional ecologists must consider the complex in vivo dynamics of nutrient nutrient interactions and nutrient-toxin interactions associated with foraging. Mathematical modeling has long been used to make foraging predictions (e.g. optimal foraging theory) but has largely been restricted to a single currency (e.g. energy) or using simple indices of nutrition (e.g. fecal nitrogen) without full consideration of physiologically based interactions among numerous co ingested phytochemicals. Here, we describe a physiologically based model (PBM) that provides a mechanistic link between foraging decisions and demographic consequences. Including physiological mechanisms of absorption, digestion and metabolism of phytochemicals in PBMs allows us to estimate concentrations of ingested and interacting phytochemicals in the body. Estimated phytochemical concentrations more accurately link intake of phytochemicals to changes in individual fitness than measures of intake alone. Further, we illustrate how estimated physiological parameters can be integrated with the geometric framework of nutrition and into integral projection models and agent-based models to predict fitness and population responses of vertebrate herbivores to ingested phytochemicals. The PBMs will improve our ability to understand the foraging decisions of vertebrate herbivores and consequences of those decisions and may help identify key physiological mechanisms that underlie diet-based ecological adaptations. PMID- 30251622 TI - Structured lifestyle education for people with schizophrenia, schizoaffective disorder and first-episode psychosis (STEPWISE): randomised controlled trial. AB - BACKGROUND: Obesity is a major challenge for people with schizophrenia.AimsWe assessed whether STEPWISE, a theory-based, group structured lifestyle education programme could support weight reduction in people with schizophrenia. METHOD: In this randomised controlled trial (study registration: ISRCTN19447796), we recruited adults with schizophrenia, schizoaffective disorder or first-episode psychosis from ten mental health organisations in England. Participants were randomly allocated to the STEPWISE intervention or treatment as usual. The 12 month intervention comprised four 2.5 h weekly group sessions, followed by 2 weekly maintenance contact and group sessions at 4, 7 and 10 months. The primary outcome was weight change after 12 months. Key secondary outcomes included diet, physical activity, biomedical measures and patient-related outcome measures. Cost effectiveness was assessed and a mixed-methods process evaluation was included. RESULTS: Between 10 March 2015 and 31 March 2016, we recruited 414 people (intervention 208, usual care 206) with 341 (84.4%) participants completing the trial. At 12 months, weight reduction did not differ between groups (mean difference 0.0 kg, 95% CI -1.6 to 1.7, P = 0.963); physical activity, dietary intake and biochemical measures were unchanged. STEPWISE was well-received by participants and facilitators. The healthcare perspective incremental cost effectiveness ratio was L246 921 per quality-adjusted life-year gained. CONCLUSIONS: Participants were successfully recruited and retained, indicating a strong interest in weight interventions; however, the STEPWISE intervention was neither clinically nor cost-effective. Further research is needed to determine how to manage overweight and obesity in people with schizophrenia.Declaration of interestR.I.G.H. received fees for lecturing, consultancy work and attendance at conferences from the following: Boehringer Ingelheim, Eli Lilly, Janssen, Lundbeck, Novo Nordisk, Novartis, Otsuka, Sanofi, Sunovion, Takeda, MSD. M.J.D. reports personal fees from Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, Janssen, Servier, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceuticals International Inc.; and, grants from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, Janssen. K.K. has received fees for consultancy and speaker for Novartis, Novo Nordisk, Sanofi Aventis, Lilly, Servier and Merck Sharp & Dohme. He has received grants in support of investigator and investigator-initiated trials from Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Pfizer, Boehringer Ingelheim and Merck Sharp & Dohme. K.K. has received funds for research, honoraria for speaking at meetings and has served on advisory boards for Lilly, Sanofi-Aventis, Merck Sharp & Dohme and Novo Nordisk. D.Sh. is expert advisor to the NICE Centre for guidelines; board member of the National Collaborating Centre for Mental Health (NCCMH); clinical advisor (paid consultancy basis) to National Clinical Audit of Psychosis (NCAP); views are personal and not those of NICE, NCCMH or NCAP. J.P. received personal fees for involvement in the study from a National Institute for Health Research (NIHR) grant. M.E.C. and Y.D. report grants from NIHR Health Technology Assessment, during the conduct of the study; and The Leicester Diabetes Centre, an organisation (employer) jointly hosted by an NHS Hospital Trust and the University of Leicester and who is holder (through the University of Leicester) of the copyright of the STEPWISE programme and of the DESMOND suite of programmes, training and intervention fidelity framework that were used in this study. S.R. has received honorarium from Lundbeck for lecturing. F.G. reports personal fees from Otsuka and Lundbeck, personal fees and non-financial support from Sunovion, outside the submitted work; and has a family member with professional links to Lilly and GSK, including shares. F.G. is in part funded by the National Institute for Health Research Collaboration for Leadership in Applied Health Research & Care Funding scheme, by the Maudsley Charity and by the Stanley Medical Research Institute and is supported by the by the Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. PMID- 30251624 TI - The Ca2+ transient as a feedback sensor controlling cardiomyocyte ionic conductances in mouse populations. AB - Conductances of ion channels and transporters controlling cardiac excitation may vary in a population of subjects with different cardiac gene expression patterns. However, the amount of variability and its origin are not quantitatively known. We propose a new conceptual approach to predict this variability that consists of finding combinations of conductances generating a normal intracellular Ca2+ transient without any constraint on the action potential. Furthermore, we validate experimentally its predictions using the Hybrid Mouse Diversity Panel, a model system of genetically diverse mouse strains that allows us to quantify inter-subject versus intra-subject variability. The method predicts that conductances of inward Ca2+ and outward K+ currents compensate each other to generate a normal Ca2+ transient in good quantitative agreement with current measurements in ventricular myocytes from hearts of different isogenic strains. Our results suggest that a feedback mechanism sensing the aggregate Ca2+ transient of the heart suffices to regulate ionic conductances. PMID- 30251626 TI - Specific structural elements of the T-box riboswitch drive the two-step binding of the tRNA ligand. AB - T-box riboswitches are cis-regulatory RNA elements that regulate the expression of proteins involved in amino acid biosynthesis and transport by binding to specific tRNAs and sensing their aminoacylation state. While the T-box modular structural elements that recognize different parts of a tRNA have been identified, the kinetic trajectory describing how these interactions are established temporally remains unclear. Using smFRET, we demonstrate that tRNA binds to the riboswitch in two steps, first anticodon recognition followed by the sensing of the 3' NCCA end, with the second step accompanied by a T-box riboswitch conformational change. Studies on site-specific mutants highlight that specific T-box structural elements drive the two-step binding process in a modular fashion. Our results set up a kinetic framework describing tRNA binding by T-box riboswitches, and suggest such binding mechanism is kinetically beneficial for efficient, co-transcriptional recognition of the cognate tRNA ligand. PMID- 30251627 TI - The Additive Value of Pelvic Examinations to History in Predicting Sexually Transmitted Infections for Young Female Patients With Suspected Cervicitis or Pelvic Inflammatory Disease. AB - STUDY OBJECTIVE: We evaluate the additive value of pelvic examinations in predicting sexually transmitted infection for young female patients with suspected cervicitis or pelvic inflammatory disease in a pediatric emergency department (ED). METHODS: This was a prospective observational study of female patients aged 14 to 20 years who presented to an urban academic pediatric ED with a complaint of vaginal discharge or lower abdominal pain. Enrolled patients provided a urine sample for chlamydia, gonorrhea, and trichomonas testing, which served as the criterion standard for diagnosis. A practitioner (pediatric ED attending physician, emergency medicine or pediatric resident, pediatric ED fellow, or advanced practice provider) obtained a standardized history from the patient to assess for cervicitis or pelvic inflammatory disease according to the Centers for Disease Control and Prevention criteria. They then recorded the likelihood of cervicitis or pelvic inflammatory disease on a 100-mm visual analog scale. The same practitioner then performed a pelvic examination and again recorded the likelihood of cervicitis or pelvic inflammatory disease on a visual analog scale with this additional information. Using the results of the urine sexually transmitted infection tests, the practitioner calculated and compared the test characteristics of history alone and history with pelvic examination. RESULTS: Two hundred eighty-eight patients were enrolled, of whom 79 had positive urine test results for chlamydia, gonorrhea, or trichomonas, with a sexually transmitted infection rate of 27.4% (95% confidence interval [CI] 22.6% to 32.8%). The sensitivity of history alone in diagnosis of cervicitis or pelvic inflammatory disease was 54.4% (95% CI 42.8% to 65.5%), whereas the specificity was 59.8% (95% CI 52.8% to 66.4%). The sensitivity of history with pelvic examination in diagnosis of cervicitis or pelvic inflammatory disease was 48.1% (95% CI 36.8% to 59.5%), whereas the specificity was 60.7% (95% CI 53.8% to 67.3%). The information from the pelvic examination changed management in 71 cases; 35 of those cases correlated with the sexually transmitted infection test and 36 did not. CONCLUSION: For young female patients with suspected cervicitis or pelvic inflammatory disease, the pelvic examination does not increase the sensitivity or specificity of diagnosis of chlamydia, gonorrhea, or trichomonas compared with taking a history alone. Because the test characteristics for the pelvic examination are not adequate, its routine performance should be reconsidered. PMID- 30251625 TI - The cargo receptor SURF4 promotes the efficient cellular secretion of PCSK9. AB - PCSK9 is a secreted protein that regulates plasma cholesterol levels and cardiovascular disease risk. Prior studies suggested the presence of an ER cargo receptor that recruits PCSK9 into the secretory pathway, but its identity has remained elusive. Here, we apply a novel approach that combines proximity dependent biotinylation and proteomics together with genome-scale CRISPR screening to identify SURF4, a homologue of the yeast cargo receptor Erv29p, as a primary mediator of PCSK9 secretion in HEK293T cells. The functional contribution of SURF4 to PCSK9 secretion was confirmed with multiple independent SURF4 targeting sgRNAs, clonal SURF4-deficient cell lines, and functional rescue with SURF4 cDNA. SURF4 was found to localize to the early secretory pathway where it physically interacts with PCSK9. Deletion of SURF4 resulted in ER accumulation and decreased extracellular secretion of PCSK9. These findings support a model in which SURF4 functions as an ER cargo receptor mediating the efficient cellular secretion of PCSK9. PMID- 30251628 TI - [Palliative care for children in onco-hematology: Role of a specific home-care team]. AB - BACKGROUND/OBJECTIVE: Our home-care unit (HCU) is specialized for pediatric cancer patients and has a strong palliative care activity. We believe that the introduction of home-care services can influence the place of palliative care and of death as well as the length of hospitalization. We aimed at describing characteristics and care course of patients treated in our HCU, and tried to identify some factors contributing to home care at the end of life. DESIGN/METHODS: We conducted a retrospective, observational, monocentric study about patients in pediatric onco-hematology, treated at least one day in our home care unit, who died between July 1st 2013 and December 31st 2015. Statistical analysis was descriptive and analytic. RESULTS: A total of 74 patients known by our HCU died during study period. Eight were excluded. Forty-three out of 66 patients died at home. During the last 3 months of life, oncology patients have significantly less classical hospitalization, when compared to hematology patients. The implication of general physicians (GP) and nurses and information given to the family increase the possibility for home death. No significant association was found between ages at death, distance between home and hospital, other life conditions and place of death. CONCLUSIONS: Our HCU has a strong palliative care activity and a high rate of children dying at home. Good collaborations between our pediatric onco-hematology team and our HCU as well as between our HCU and caregivers optimize palliative care. PMID- 30251629 TI - Approved Anti-cancer Drugs Target Oncogenic Non-coding RNAs. AB - Potential RNA drug targets for small molecules are found throughout the human transcriptome, yet small molecules known to elicit a pharmacological response by directly targeting RNA are limited to antibacterials. Herein, we describe AbsorbArray, a small molecule microarray-based approach that allows for unmodified compounds, including FDA-approved drugs, to be probed for binding to RNA motif libraries in a massively parallel format. Several drug classes bind RNA including kinase and topoisomerase inhibitors. The latter avidly bound the motif found in the Dicer site of oncogenic microRNA (miR)-21 and inhibited its processing both in vitro and in cells. The most potent compound de-repressed a downstream protein target and inhibited a miR-21-mediated invasive phenotype. The compound's activity was ablated upon overexpression of pre-miR-21. Target validation via chemical crosslinking and isolation by pull-down showed direct engagement of pre-miR-21 by the small molecule in cells, demonstrating that RNAs should indeed be considered druggable. PMID- 30251630 TI - Combined Proteomic and In Silico Target Identification Reveal a Role for 5 Lipoxygenase in Developmental Signaling Pathways. AB - Identification and validation of the targets of bioactive small molecules identified in cell-based screening is challenging and often meets with failure, calling for the development of new methodology. We demonstrate that a combination of chemical proteomics with in silico target prediction employing the SPiDER method may provide efficient guidance for target candidate selection and prioritization for experimental in-depth evaluation. We identify 5-lipoxygenase (5-LO) as the target of the Wnt pathway inhibitor Lipoxygenin. Lipoxygenin is a non-redox 5-LO inhibitor, modulates the beta-catenin-5-LO complex and induces reduction of both beta-catenin and 5-LO levels in the nucleus. Lipoxygenin and the structurally unrelated 5-LO inhibitor CJ-13,610 promote cardiac differentiation of human induced pluripotent stem cells and inhibit Hedgehog, TGF beta, BMP, and Activin A signaling, suggesting an unexpected and yet unknown role of 5-LO in these developmental pathways. PMID- 30251631 TI - Obesity in the fifth quarter: A malignancy in former NFL players significance and potential. PMID- 30251632 TI - Comment on: jejunal long noncoding RNAs are associated with glycemic control via gut-brain axis after bariatric surgery in diabetic mice. PMID- 30251634 TI - AYUSH research for New India: Vision and strategies. PMID- 30251636 TI - Use of Oral Corticosteroids in the Wheezy Toddler. PMID- 30251637 TI - Targeted Hydroxyurea Education after an Emergency Department Visit Increases Hydroxyurea Use in Children with Sickle Cell Anemia. AB - OBJECTIVE: To evaluate the impact of an initiative to increase hydroxyurea use among children with sickle cell anemia (SCA) who presented to the emergency department (ED). STUDY DESIGN: This observational cohort study included children with SCA not taking hydroxyurea who presented to the ED with pain or acute chest syndrome and then attended a Quick-Start Hydroxyurea Initiation Project (Q-SHIP) session. A Q-SHIP session includes a hematologist-led discussion on hydroxyurea, a video of patients talking about hydroxyurea, and a direct offer to start hydroxyurea. RESULTS: Over 64 weeks, 112 eligible patients presented to the ED and 59% (n = 66) participated in a Q-SHIP session a median of 6 days (IQR 2, 20 days) after ED or hospital discharge; 55% of participants (n = 36) started hydroxyurea. After a median follow-up of 49 weeks, 83% (n = 30) of these participants continued hydroxyurea. Laboratory markers of hydroxyurea adherence were significantly increased from baseline: median mean corpuscular volume +8.6 fL (IQR 5.0, 17.7, P < .0001) and median hemoglobin F +5.7% (IQR 2.5, 9.8, P = .0001). Comparing Q-SHIP participants to nonparticipants, 12 weeks after ED visit, participants were more likely to have started hydroxyurea than nonparticipants (53% vs 20%, P = .0004) and to be taking hydroxyurea at last follow-up (50% vs 20%, P = .001). Two years after the implementation of Q-SHIP the overall proportion of eligible patients on hydroxyurea presenting to our ED increased from 56% to 80%, P = .0069. CONCLUSIONS: Participation in a clinic to specifically address starting hydroxyurea after a SCA complication increases hydroxyurea use. PMID- 30251638 TI - A Randomized Controlled Trial of a Barrier Dressing to Reduce Nasal Injury in Preterm Infants Receiving Binasal Noninvasive Respiratory Support. AB - OBJECTIVE: To determine whether the use of a hydrocolloid nasal barrier dressing during binasal continuous positive airway pressure (CPAP) therapy, compared with no barrier dressing, reduces the rate of nasal injury in very preterm and/or very low birth weight infants. STUDY DESIGN: A single-center randomized controlled trial conducted in the neonatal intensive care unit at The Royal Women's Hospital, Melbourne. Eligible infants were born <30 weeks of gestation and/or with birth weight <1250 g, and had received >=4 hours, but <48 hours, of CPAP. Infants were randomly allocated to receive either a hydrocolloid nasal barrier dressing during CPAP (barrier group), or no barrier dressing (no barrier group). The primary outcome was the incidence of any nasal injury during CPAP support, until the infant was both >30 weeks of postmenstrual age and >1250 g, unless CPAP therapy was stopped earlier. Nasal injury was regularly assessed by bedside nurses using a standardized form. RESULTS: A total of 108 preterm infants were enrolled: 53 infants in the barrier group and 55 infants in the no barrier group. Infants in the barrier group had a significantly lower rate of nasal injury compared with the no barrier group: 18 of 53 (34%) vs 31 of 55 (56%), respectively (P = .02), number needed to treat; 5 infants. No significant differences were detected in any secondary respiratory outcomes, or in the rate of common neonatal morbidities. CONCLUSIONS: Prophylactic use of a nasal barrier dressing within 48 hours of commencing treatment with binasal CPAP in very preterm or very low birth weight infants reduces nasal injury. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register ACTRN12616000438459. PMID- 30251639 TI - Preterm Infant Outcomes after Randomization to Initial Resuscitation with FiO2 0.21 or 1.0. AB - OBJECTIVE: To determine rates of death or neurodevelopmental impairment (NDI) at 2 years corrected age (primary outcome) in children <32 weeks' gestation randomized to initial resuscitation with a fraction of inspired oxygen (FiO2) value of 0.21 or 1.0. STUDY DESIGN: Blinded assessments were conducted at 2-3 years corrected age with the Bayley Scales of Infant and Toddler Development, Third Edition or the Ages and Stages Questionnaire by intention to treat. RESULTS: Of the 290 children enrolled, 40 could not be contacted and 10 failed to attend appointments. Among the 240 children for whom outcomes at age 2 years were available, 1 child had a lethal congenital anomaly, 1 child had consent for follow-up withdrawn, and 23 children died. The primary outcome, which was available in 238 (82%) of those randomized, occurred in 47 of the 117 (40%) children assigned to initial FiO2 0.21 and in 38 of the 121 (31%) assigned to initial FiO2 1.0 (OR, 1.47; 95% CI, 0.86-2.5; P = .16). No difference in NDI was found in 215 survivors randomized to FiO2 0.21 vs 1.0 (OR, 1.26; 95% CI, 0.70 2.28; P = .11). In post hoc exploratory analyses in the whole cohort, children with a 5-minute blood oxygen saturation (SpO2) <80% were more likely to die or to have NDI (OR, 1.85; 95% CI, 1.07-3.2; P = .03). CONCLUSIONS: Initial resuscitation of infants <32 weeks' gestation with initial FiO2 0.21 had no significant effect on death or NDI compared with initial FiO2 1.0. Further evaluation of optimum initial FiO2, including SpO2 targeting, in a large randomized controlled trial is needed. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Network Registry ACTRN 12610001059055 and the National Malaysian Research Registry NMRR-07-685-957. PMID- 30251640 TI - Carcinoid Heart Disease in Patients With Bronchopulmonary Carcinoid. AB - INTRODUCTION: The prevalence of carcinoid heart disease (CaHD) in bronchopulmonary carcinoid and its relationship with left-sided valvular disease are unknown. METHODS: All patients with a pathologic diagnosis of bronchopulmonary carcinoid and echocardiography performed at our institution between 2001 and 2016 were retrospectively reviewed. Echocardiograms were reviewed for features of CaHD including valvular leaflet thickening and retraction with resulting regurgitation and/or stenosis. RESULTS: Bronchopulmonary carcinoid was present in 185 patients (age 67 +/- 13 years, 63% female). Carcinoid syndrome was present in 7.7% and liver metastases in 10%. Echocardiographic features of CaHD were present in just 2 (1%) patients. A 62 year-old woman underwent resection of stage 1A bronchopulmonary carcinoid without carcinoid syndrome and also received 7 months dexfenfluramine therapy. During 15 year follow-up, mitral regurgitation decreased and tricuspid regurgitation remained stable, a course more consistent with diet-drug-related valve disease than CaHD. A 71-year-old woman status post-resection of a grade 1 hilar carcinoid tumor with carcinoid syndrome, liver metastases, and elevated 5-hydroxyindole acetic acid had typical thickening and retraction of tricuspid and pulmonary valves with severe regurgitation. The aortic valve was mildly thickened and retracted with mild regurgitation. She underwent tricuspid and pulmonary valve replacement and closure of a patent foramen ovale. Pathologic examination confirmed CaHD. CONCLUSIONS: CaHD occurs in less than 1% of patients with bronchopulmonary carcinoid. Bronchopulmonary carcinoid was associated with neither CaHD in the absence of liver metastases nor left-sided valve involvement in the absence of patent foramen ovale. PMID- 30251641 TI - The effect of time from diagnosis to surgery on oncological outcomes in patients undergoing surgery for colon cancer: A systematic review. AB - : Many countries have implemented cancer pathways with strict time limits dictating the pace of diagnostic testing and treatment. There are concerns that prehabilitation may worsen long-term oncological outcomes if surgery is delayed. We aimed to systematically review the literature investigating the association between increased time between diagnosis of colon cancer and surgical treatment, with special focus on survival outcomes. METHODS: Through a systematic search and analysis of the databases PubMed (1966-2017), EMBASE (1974-2017), CINHAL (1981 2017), and The Cochrane Library performed on June 7th, 2017, the effect of treatment delays on overall survival in colon cancer patients was reviewed. Treatment delay was defined as time from diagnosis to initiation of surgical treatment. All patients included were diagnosed with colon cancer and treated with elective curative surgery without neoadjuvant chemotherapy. This review was prospectively registered on the PROSPERO database of systematic review protocols with registration number CRD42017059774. RESULTS: Five observational studies including 13,514 patients were included. The treatment delay intervals ranged from 1 to >=56 days. Four of the five studies found no association between time elapsed from diagnosis to surgery and reduced overall survival. One study found a clinically insignificant association between longer treatment delays and overall survival. Three studies investigated the effect on disease specific survival and found no negative associations. CONCLUSION: The available data showed no association between treatment delay and reduced overall survival in colon cancer patients. PMID- 30251642 TI - 30-day and long-term outcome following salvage surgery for squamous cell carcinoma of the anus. AB - INTRODUCTION: Squamous cell carcinoma of the anus (SCCA) is a rare condition. First line treatment is combined chemo-radio therapy. As many as a third of patients undergoing CRT will experience recurrence. These patients often undergo salvage surgery with an extended abdominoperineal excision. The aims of this study were 1) to assess and evaluate 30-day postoperative morbidity and mortality after salvage surgery for recurrent SCCA, and furthermore, 2) to examine secondary recurrence and long-term mortality after salvage surgery for recurrent SCCA. MATERIAL AND METHODS: Retrospective evaluation of all patients undergoing salvage surgery for SCCA at Copenhagen University Hospital Herlev between 1st of January 2011 and 31th December 2016. RESULTS: Forty-seven patients were identified. 30-day postoperative mortality was 4%. The most common postoperative complication was perineal wound defects. Within the follow-up period of median 20 (1-80) months, secondary recurrence occurred in 30% of patients. Median disease free survival was 32 months. Secondary recurrence was significantly more frequent in patients with R1 resection and pN >= 1. Within the follow-up period of median 25 (0-80) months, mortality was 40%. Overall median survival was 39 months. Secondary recurrence was associated with a significantly higher risk of death within the follow-up period. CONCLUSION: Salvage surgery for relapse of squamous cell carcinoma of the anus is a safe procedure with a good short-term outcome. Secondary recurrence was more frequent in patients with R1-resection and pN >= 1. More than one third of the patients died within the follow-up period, and mortality was significantly higher in the group of patients with secondary recurrence. PMID- 30251644 TI - Cardiothoracic Surgery in the United Kingdom: Operating Without a Weekend Effect? PMID- 30251643 TI - Triage for selection to colonoscopy? AB - Implementation of population screening for colorectal cancer by direct colonoscopy or follow-up colonoscopy after a positive fecal blood test has challenged the overall capacity of bowel examinations. Certain countries are facing serious colonoscopy capacity constraints, which have led to waiting lists and long-time latency of follow-up examinations. Various options for improvement are considered, including increased cut-off values of the fecal blood tests. Results from major clinical studies of blood-based, cancer-associated biomarkers have led to focus, however, on a triage concept for improved selection to colonoscopy. The triage test may include subject age, concentration of hemoglobin in a feces test and a combination of certain blood-based cancer associated biomarkers. Recent results have indicated that triage may reduce the requirements for colonoscopy by around 30%. Such results may be advantageous for the capacity, the heath budgets and in particular, the subjects, who do not need an unnecessary, unpleasant and risk-associated bowel examination. PMID- 30251645 TI - Multilevel assessments reveal spatially scaled landscape patterns driving coastal fish assemblages. AB - Ecological research, particularly in marine environments, tends to focus on single habitats and often single spatial scales, and thus not account for ecological processes operating at multiple spatial scales. Here we aim to explore how coastal fish assemblages are influenced by landscape patterns integrating multiple spatial scales, to assess the strength of these associations and to identify the most relevant spatial scales at which these associations occur. We use a multiscale approach through multilevel modelling to evaluate the association of landscape metrics with fish assemblages, at three nested spatial scales, in temperate coastal seascapes composed of seagrass meadows, sandy bottoms and rocky reefs. Landscape composition metrics, expressed as cover of vegetated habitats, significantly influenced fish assemblages at small (metres) and intermediate (hundred of metres) scales, while landscape configuration metrics did it at all three scales assessed (from metres to kilometres). Species richness was only influenced by small scale landscape patterns (cover of rocky reefs, positive association), whereas total abundance was associated with landscape patterns measured at small and intermediate scales, encompassing metrics associated with landscape composition (rocky reef cover, positive association), and those indicating landscape heterogeneity (negative association). Similarly, the abundances of different functional groups were influenced by metrics consistent with their mobility and their ecological and behavioural traits at all the spatial scales assessed. These results show how landscape patterns influence coastal fish assemblages, and particularly show that spatially scaled landscape patterns, measured in complex ecological systems as a whole, act simultaneously but not always equally on species assemblages. PMID- 30251646 TI - Seagrass recovery after fish farm relocation in the eastern Mediterranean. AB - Finfish aquaculture has damaged seagrass meadows worldwide as wastes from the farms can kill these habitat-forming plants. In Cyprus, the Mediterranean endemic Posidonia oceanica is at its upper thermal limits yet forms extensive meadows all around the island. Understanding this under-studied isolated population may be important for the long-term survival of the species given that the region is warming rapidly. When fish farming began around Cyprus in the mid-nineties, cages were moored above seagrass beds, but as production expanded they were moved into deeper water further away from the meadows. Here, we monitored the deepest edge of meadows near fish farms that had been moved into deeper waters as well as at a decommissioned farm site. Four P. oceanica monitoring systems were set up using methods developed by the Posidonia Monitoring Network. Seagrass % coverage, shoot density, % of plagiotropic rhizomes, shoot exposure, leaf morphometry, and sediment organic matter content and grain size were monitored at 11 fixed plots within each system, in 2012-2014 and in 2017. Expansion at the lower depth limit of seagrass meadows was recorded at all monitoring sites. Most other P. oceanica descriptors either did not change significantly or declined. Declines were most pronounced at a site that was far from mariculture activities but close to other anthropogenic pressures. The most important predictor affecting P. oceanica was depth. Monitoring using fixed plots allowed direct comparisons of descriptors over time, removes patchiness and intra-meadow variability increasing our understanding of seagrass dynamics and ecosystem integrity. It seems that moving fish farms away from P. oceanica has helped ensure meadow recovery at the deepest margins of their distribution, an important success story given that these meadows are at the upper thermal limits of the species. PMID- 30251647 TI - The effects of low seawater pH on energy storage and heat shock protein 70 expression in a bivalve Limecola balthica. AB - Though biological consequences of CCS (Carbon Capture and Storage) implementation into the marine environment have received substantial research attention, the impact of potential CO2 leakage on benthic infauna in the Baltic Sea remained poorly recognized. This study quantified medium-term (56-day laboratory exposure) effects of CO2-induced seawater acidification (pH 7.7, 7.0 and 6.3) on energetic reserves and heat-shock protein HSP70 expression of adult bivalve Limecola balthica from the southern Baltic. While no clear impact was evident in the most acidic treatment (pH 6.3), moderate seawater hypercapnia (pH 7.0) induced elevated catabolism of high caloric reserves (carbohydrates including glycogen and lipids) in order to provide energy to cover enhanced metabolic requirements for acid-base regulation. Biochemical response did not involve, however, breakdown of proteins, suggesting that they were not utilized as metabolic substrates. As indicated also by subtle variations in the chaperone protein HSP70, the clams demonstrated high CO2 tolerance, presumably through development of efficient defensive/compensatory mechanisms during their larval and/or ontogenic life stages. PMID- 30251648 TI - Extrinsic and intrinsic factors shape the ability of using otolith chemistry to characterize estuarine environmental histories. AB - Reconstructing habitat use and environmental histories of fish via otolith chemistry relies on linking otolith chemical composition to the surrounding environment, as well as disentangling the consequences of ontogenetic or physiological effects that may mask environmental signals. We used multiple linear and linear mixed models to analyse the importance of environmental (temperature, salinity, water chemistry) and individual based (fish size) factors on otolith chemical composition and incorporation (Li, Mg, Mn, Sr, and Ba) of juvenile Dicentrarchus labrax, over their time within an estuarine nursery area. Multi model inference highlighted the importance of ontogeny, as well as the influence of temperature and salinity on otolith chemistry and elemental incorporation, with results indicating that intrinsic effects may potentially outweigh environmental effects. Ultimately, understanding if otolith chemistry accurately reflects fine-scale environmental variation is key to reconstruct environmental histories of juvenile fishes in estuaries and will contribute to determining the impact changing estuarine conditions may have on growth and survival. PMID- 30251649 TI - Corrigendum to "Stormwater runoff plumes in the Southern California Bight: A comparison study with SAR and MODIS imagery" [Mar. Pollut. Bull. 118 (1-2) (2017) 141-154]. PMID- 30251650 TI - Widespread tissue distribution and synthetic pathway of polyunsaturated C24:2 sphingolipids in mammals. AB - Sphingolipids are multifunctional lipids and a major constituent of the cell membranes of eukaryotes. Although the fatty acid (FA) moiety of sphingolipids is usually a saturated or monounsaturated FA, polyunsaturated FA (PUFA)-containing species also exist in mammalian tissues. In the present study, we showed that C24:2 PUFA-containing ceramide is one of the seven major ceramide species in a wide range of tissues. C24:2 ceramide levels were especially high in spleen and small intestine; in the former, it was the fourth most abundant ceramide species. However, both the synthetic pathway and the physiological function of C24:2 ceramide had yet to be identified. Tracer analysis using deuterium-labeled linoleic acid (C18:2) revealed that C24:2 ceramide is produced via elongation of linoleic acid. We also found that the FA elongase ELOVL1 and the ceramide synthase CERS2 were involved in C24:2 ceramide production. Sphingolipids are known to form lipid microdomains in membranes; however, in a detergent-resistant membrane (DRM) assay, we observed a lower proportion of C24:2 sphingomyelin in the DRM fraction than of saturated sphingomyelins, suggesting that C24:2 sphingolipids may act to negatively regulate lipid microdomain formation. Our findings expand our knowledge of sphingolipid diversity, and provide insight into how different sphingolipid molecular species play different functions in biological membranes. PMID- 30251651 TI - Phoenixin-14 stimulates differentiation of 3T3-L1 preadipocytes via cAMP/Epac dependent mechanism. AB - Phoenixin-14 (PNX) is a newly discovered peptide produced by proteolytic cleavage of the small integral membrane protein 20 (Smim20). Previous studies showed that PNX is involved in controlling reproduction, pain, anxiety and memory. Furthermore, in humans, PNX positively correlates with BMI suggesting a potential role of PNX in controlling fat accumulation in obesity. Since the influence of PNX on adipose tissue formation has not been so far demonstrated, we investigated the effects of PNX on proliferation and differentiation of preadipocytes using 3T3-L1 and rat primary preadipocytes. We detected Smim20 and Gpr173 mRNA in 3T3 L1 preadipocytes as well as in rat primary preadipocytes. Furthermore, we found that PNX peptide is produced and secreted from 3T3-L1 and rat primary adipocytes. PNX increased 3T3-L1 preadipocytes proliferation and viability. PNX stimulated the expression of adipogenic genes (Ppargamma, C/ebpbeta and Fabp4) in 3T3-L1 adipocytes. 3T3-L1 preadipocytes differentiated in the presence of PNX had increased lipid content. Stimulation of cell proliferation and differentiation by PNX was also confirmed in rat preadipocytes. PNX failed to induce AKT phosphorylation, however, PNX increased cAMP levels in 3T3-L1 cells. Suppression of Epac signalling attenuated PNX-induced Ppargamma expression without affecting cell proliferation. Our data show that PNX stimulates differentiation of 3T3-L1 and rat primary preadipocytes into mature adipocytes via cAMP/Epac-dependent pathway. In conclusion our data shows that phoenixin promotes white adipogenesis, thereby may be involved in controlling body mass regulation. PMID- 30251652 TI - LMW-PTP modulates glucose metabolism in cancer cells. AB - BACKGROUND: Low Molecular Weight Phosphotyrosine Protein Phosphatase (LMW-PTP) is an enzyme involved not only in tumor onset and progression but also in type 2 diabetes. A recent review shows that LMW-PTP acts on several RTK (receptor tyrosine kinase) such as PDGFR, EGFR, EphA2, Insulin receptor. It is well described also its interaction with cSrc. It is noteworthy that most of these conclusions are based on the use of cell lines expressing low levels of LMW-PTP. The aim of the present study was to discover new LMW-PTP substrates in aggressive human tumors where the over-expression of this phosphatase is a common feature. METHODS: We investigated, by proteomic analysis, the protein phosphorylation pattern of A375 human melanoma cells silenced for LMW-PTP. Two-dimensional electrophoresis (2-DE) analysis, followed by western blot was performed using anti-phosphotyrosine antibodies, in order to identify differentially phosphorylated proteins. RESULTS: Proteomic analysis pointed out that most of the identified proteins belong to the glycolytic metabolism, such as alpha-enolase, pyruvate kinase, glyceraldehyde-3-phosphate dehydrogenase and triosephosphate isomerase, suggesting an involvement of LMW-PTP in glucose metabolism. Assessment of lactate production and oxygen consumption demonstrated that LMW-PTP silencing enhances glycolytic flux and slow down the oxidative metabolism. In particular, LMW-PTP expression affects PKM2 tyrosine-phosphorylation and nuclear localization, modulating its activity. CONCLUSION: All these findings propose that tumor cells are subjected to metabolic reprogramming after LMW-PTP silencing, enhancing glycolytic flux, probably to compensate the inhibition of mitochondrial metabolism. GENERAL SIGNIFICANCE: Our results highlight the involvement of LMW-PTP in regulating glucose metabolism in A375 melanoma cells. PMID- 30251653 TI - Inhibition of amyloid fibril formation in the variable domain of lambda6 light chain mutant Wil caused by the interaction between its unfolded state and epigallocatechin-3-O-gallate. AB - BACKGROUND: Light chains are abnormally overexpressed from disordered monoclonal B-cells and form amyloid fibrils, which are then deposited on the affected organ, leading to a form of systemic amyloidosis known as AL (Amyloid Light chain) amyloidosis. A green tea catechin, epigallocatechin-3-O-gallate (EGCG), which is thought to inhibit various amyloidoses, is a potent inhibitor of amyloid fibril formation in AL amyloidosis. METHODS: An amyloidogenic variable domain in lambda6 light chain mutant, Wil was incubated in the presence of EGCG. The incubation products were analyzed by SDS-PAGE and reverse-phase HPLC. The interaction between Wil and EGCG was observed by using NMR and tryptophan fluorescence. RESULTS: EGCG inhibited the amyloid fibril formation of Wil at pH 7.5 and 42 degrees C. Under these conditions, most Wil populations were in the unfolded state and several chemical reactions, i.e., oxidation and/or covalent bond oligomerization could be induced by auto-oxidated EGCG. Moreover, we found that EGCG bound to the unfolded state of Wil with higher affinity (Kd = 7 MUM). CONCLUSIONS: Inhibition of amyloid fibril formation of Wil was caused by 1) EGCG binding to unfolded state rather than folded state and 2) chemical modifications of Wil by auto oxidation of EGCG. GENERAL SIGNIFICANCE: In the competitive formation of amyloid fibrils and off-pathway oligomers, EGCG produces the latter immediately after it preferentially binds to the unfolded state. It may be general mechanism of EGCG inhibition for amyloidosis. PMID- 30251654 TI - Dynamics of DDB2-DDB1 complex under different naturally-occurring mutants in Xeroderma Pigmentosum disease. AB - BACKGROUND: Xeroderma Pigmentosum (XP) is a disease caused by mutations in the nucleotide excision repair (NER) pathway. Patients with XP exhibit a high propensity to skin cancers and some subtypes of XP can even present neurological impairments. During NER, DDB2 (XPE), in complex with DDB1 (DDB-Complex), performs the DNA lesion recognition. However, not much is known about how mutations found in XP patients affect the DDB2 structure and complex assembly. Thus, we searched for structural evidence associated with the role of three naturally occurring mutations found in XPE patients: R273H, K244E, and L350P. METHODS: Each mutant was individually constructed and submitted to multiple molecular dynamics simulations, done in triplicate for each designed system. Additionally, Dynamic Residue Interaction Networks were designed for each system and analyzed parallel with the simulations. RESULTS: DDB2 mutations promoted loss of flexibility in the overall protein structure, producing a different conformational behavior in comparison to the WT, especially in the region comprising residues 354 to 371. Furthermore, the DDB-complex containing the mutated forms of DDB2 showed distinct behaviors for each mutant: R273H displayed higher structural instability when complexed; L350P affected DDB1 protein-protein binding with DDB2; and K244E, altered the complex binding trough different ways than L350P. CONCLUSIONS: The data gathered throughout the analyses helps to enlighten the structural basis for how naturally occurring mutations found in XPE patients impact on DDB2 and DDB1 function. GENERAL SIGNIFICANCE: Our data influence not only on the knowledge of XP but on the DNA repair mechanisms of NER itself. PMID- 30251655 TI - Opioid and Notch signaling pathways are reciprocally regulated through miR- 29a and miR-212 expression. AB - BACKGROUND: The abuse of opioids, such as morphine and phentanyl or other drugs as heroin is a social and health problem that affects an increasing number of people each year. The activation of the mu opioid receptor triggers several molecular changes that alter the expression of diverse genes, including miRNAs. The dysregulation of these molecules could explain some of the developmental alterations that are induced after drug intake. In addition, the Notch signaling cascade has also been related to alterations on these processes. METHODS: Zebrafish embryos and SH-SY5Y cells were used to assess the effects of opioid and Notch signaling on the expression on miR-29a and miR-212/132 by qPCR and ChIP qPCR. Notch1 expression was analyzed using in situ hybridization on 24 hpf zebrafish embryos. In addition, OPRM1 and NICD levels were measured using western blot on the cultured cells to determine the cross-talk between the two pathways. RESULTS: We have observed changes in the levels of miR-212/132 after administrating DAPT to zebrafish embryos indicating that this pathway could be regulating mu opioid receptor expression. In addition, the ISH experiment showed changes in Notch1 expression after morphine and DAPT administration. Moreover, morphine affects the expression of miR-29a through NF-kappaB, therefore controlling the cleavage and activation of Notch through ADAM12 expression. CONCLUSIONS: This study shows that these two pathways are closely related, and could explain the alterations triggered in the early stages of the development of addiction. GENERAL SIGNIFICANCE: Opioid and Notch pathway are reciprocally regulated by the miRNAs 212/132 and 29a. PMID- 30251656 TI - Plasma protein N-glycan signatures of type 2 diabetes. AB - BACKGROUND: Little is known about enzymatic N-glycosylation in type 2 diabetes, a common posttranslational modification of proteins influencing their function and integrating genetic and environmental influences. We sought to gain insights into N-glycosylation to uncover yet unexplored pathophysiological mechanisms in type 2 diabetes. METHODS: Using a high-throughput MALDI-TOF mass spectrometry method, we measured N-glycans in plasma samples of the DiaGene case-control study (1583 cases and 728 controls). Associations were investigated with logistic regression and adjusted for age, sex, body mass index, high-density lipoprotein-cholesterol, non-high-density lipoprotein-cholesterol, and smoking. Findings were replicated in a nested replication cohort of 232 cases and 108 controls. RESULTS: Eighteen glycosylation features were significantly associated with type 2 diabetes. Fucosylation and bisection of diantennary glycans were decreased in diabetes (odds ratio (OR) = 0.81, p = 1.26E-03, and OR = 0.87, p = 2.84E-02, respectively), whereas total and, specifically, alpha2,6-linked sialylation were increased (OR = 1.38, p = 9.92E-07, and OR = 1.40, p = 5.48E-07). Alpha2,3-linked sialylation of triantennary glycans was decreased (OR = 0.60, p = 6.38E-11). CONCLUSIONS: While some glycosylation changes were reflective of inflammation, such as increased alpha2,6-linked sialylation, our finding of decreased alpha2,3 linked sialylation in type 2 diabetes patients is contradictory to reports on acute and chronic inflammation. Thus, it might have previously unreported immunological implications in type 2 diabetes. GENERAL SIGNIFICANCE: This study provides new insights into N-glycosylation patterns in type 2 diabetes, which can fuel studies on causal mechanisms and consequences of this complex disease. PMID- 30251658 TI - Biochemical characterization of protoporphyrinogen dehydrogenase and protoporphyrin ferrochelatase of Vibrio vulnificus and the critical complex formation between these enzymes. AB - BACKGROUND: Protoporphyrin IX (PPn), an intermediate in the heme biosynthesis reaction, generates singlet oxygen upon exposure to UV light. It has been proposed that PPn is channeled directly to ferrochelatase within a protoporphyrinogen dehydrogenase (PgdH1)-protoporphyrin ferrochelatase (PpfC) complex as a way to avoid this damaging side reaction. However, the PgdH1-PpfC complex has not been characterized, and the question of how heme affects the activities of PgdH1 has not been addressed. METHODS: Protein interactions were explored through pull-down assays and western blotting, and the importance of this complex in vivo was examined using inter-species combinations of the two proteins. The purified PgdH1-PpfC complex was characterized kinetically and used for heme binding studies. RESULTS: In Vibrio vulnificus, PgdH1 and PpfC formed an 8:8 heterohexadecameric complex that was important for maintaining PPn at low levels. PpfC catalyzed PPn efficiently whether or not it was part of the complex. Notably, heme was a noncompetitive inhibitor of V. vulnificus PgdH1, but a competitive inhibitor of the human protoporphyrinogen oxidase PgoX. CONCLUSION: The PdgH1-PpfC complex is important for protective channeling of PPn and for efficient catalysis of free PPn. The production of PPn by PgdH1 is regulated by feedback inhibition by heme. GENERAL SIGNIFICANCE: Both proteobacteria and eukaryotes have evolved mechanisms to prevent the harmful accumulation of the heme biosynthesis intermediate PPn. The data presented here suggest two previously unknown mechanisms: the channeling of PPn through the PgdH1-PpfC complex, and the direct inhibition of PgdH1 activity (PgoX activity as well) by heme. PMID- 30251657 TI - Lysine as a heme iron ligand: A property common to three truncated hemoglobins from Chlamydomonas reinhardtii. AB - BACKGROUND: The nuclear genome of Chlamydomonas reinhardtii encodes a dozen hemoglobins of the truncated lineage. Four of these, named THB1-4, contain a single ~130-residue globin unit. THB1, which is cytoplasmic and capable of nitric oxide dioxygenation activity, uses a histidine and a lysine as axial ligands to the heme iron. In the present report, we compared THB2, THB3, and THB4 to THB1 to gain structural and functional insights into algal globins. METHODS: We inspected properties of the globin domains prepared by recombinant means through site directed mutagenesis, electronic absorption, CD, and NMR spectroscopies, and X ray crystallography. RESULTS: Recombinant THB3, which lacks the proximal histidine but has a distal histidine, binds heme weakly. NMR data demonstrate that the recombinant domains of THB2 and THB4 coordinate the ferrous heme iron with the proximal histidine and a lysine from the distal helix. An X-ray structure of ferric THB4 confirms lysine coordination. THB1, THB2, and THB4 have reduction potentials between -65 and -100 mV, are capable of nitric oxide dioxygenation, are reduced at different rates by the diaphorase domain of C. reinhardtii nitrate reductase, and show different response to peroxide treatment. CONCLUSIONS: Three single-domain C. reinhardtii hemoglobins use lysine as a distal heme ligand in both Fe(III) and Fe(II) oxidation states. This common feature is likely related to enzymatic activity in the management of reactive oxygen species. GENERAL SIGNIFICANCE: Primary structure analysis of hemoglobins has limited power in the prediction of heme ligation. Experimental determination reveals variations in this essential property across the superfamily. PMID- 30251659 TI - Dual blockade of VEGFR1 and VEGFR2 by a novel peptide abrogates VEGF-driven angiogenesis, tumor growth, and metastasis through PI3K/AKT and MAPK/ERK1/2 pathway. AB - BACKGROUND: Neutralization of vascular endothelial growth factor receptor 1 (VEGFR1) and/or VEGFR2 is a widely used means of inhibiting tumor angiogenesis. METHODS: Based on the complex X-ray structures of VEGFA/VEGFR1, VEGFA/VEGFR2, and VEGFB/VEGFR1, a peptide (referred to as VGB) was designed to simultaneously bind to VEGFR1 and VEGFR2, and binding, antiangiogenic and antitumor properties of the peptide was investigated in vitro. RESULTS: VGB bound to both VEGFR1 and VEGFR2 in human umbilical vein endothelial cells (HUVECs) and 4 T1 mammary carcinoma tumor (MCT) cells, and inhibited the proliferation of HUVE, 4 T1 MCT, and U87 glioblastoma cells. Through abrogation of AKT and ERK1/2 phosphorylation, VEGFA stimulated proliferation, migration, and two- and three-dimensional tube formation in HUVECs were inhibited more potently by VGB than by bevacizumab. In a murine 4 T1 MCT model, VGB strongly inhibited tumor growth without causing weight loss, accompanied by inhibition of AKT and ERK1/2 phosphorylation, a significant decrease in tumor cell proliferation (Ki-67 expression), angiogenesis (CD31 and CD34 expression), an increase in apoptosis index (increased TUNEL staining and p53 expression and decreased Bcl-2 expression), and the suppression of systematic spreading of the tumor (reduced NF-kappaB and MMP-9 and increased E-cadherin expression). CONCLUSION: The dual specificity of VGB for VEGFR1 and VEGFR2, through which the PI3K/AKT and MAPK/ERK1/2 signaling pathways can be abrogated and, subsequently, angiogenesis, tumor growth, and metastasis are inhibited. GENERAL SIGNIFICANCE: This study demonstrated that simultaneous blockade of VEGFR1 and VEGFR2 downstream cascades is an effective means for treatment of various angiogenic disorders, especially cancer. PMID- 30251660 TI - Modulation of neurosecretion and approaches for its multistep analysis. AB - BACKGROUND: Neurosecretion is the multistep process occurring in separate spatial and temporal cellular boundaries which complicates its comprehensive analysis. Most of the research are focused on one distinct stage of synaptic vesicle recycling. Here, we describe approaches for complex analysis of synaptic vesicle (SV) endocytosis and separate steps of exocytosis at the level of presynaptic bouton and highly purified SVs. METHODS: Proposed fluorescence-based strategies and analysis of neurotransmitter transport provided the advantages in studies of exocytosis steps. We evaluated SV docking/tethering, their Ca2+-dependent fusion and release of neurotransmitters gamma-aminobutyric acid (GABA) and glutamate in two animal models. RESULTS: Approaches enabled us to study: 1) endocytosis/Ca2+ dependent release of fluorescent carbon nanodots (CNDs) during stimulation of nerve terminals; 2) the action of levetiracetam, modulator of SV glycoprotein SV2, on fusion competence of SVs and stimulated release of GABA and glutamate; 3) impairments of several steps of neurosecretion under vitamin D3 deficiency. CONCLUSIONS: Our algorithm enabled us to verify the method validity for multidimensional analysis of SV turnover. By increasing SV docking and the size of readily releasable pool (RRP), levetiracetam is able to selectively enhance the stimulated GABA secretion in hippocampal neurons. Findings suggest that SV2 regulates RRP through impact on the number of docked/primed SVs. GENERAL SIGNIFICANCE: Methodology can be widely applied to study the stimulated neurosecretion in presynapse, regulation of SV docking, their Ca2+-dependent fusion with target membranes, quantitative analysis of expression of neuron specific proteins, as well as for testing the efficiency of pre-selected designed neuroactive substances. PMID- 30251661 TI - "Pinching" the ammonia tunnel of CTP synthase unveils coordinated catalytic and allosteric-dependent control of ammonia passage. AB - Molecular gates within enzymes often play important roles in synchronizing catalytic events. We explored the role of a gate in cytidine-5'-triphosphate synthase (CTPS) from Escherichia coli. This glutamine amidotransferase catalyzes the biosynthesis of CTP from UTP using either l-glutamine or exogenous NH3 as a substrate. Glutamine is hydrolyzed in the glutaminase domain, with GTP acting as a positive allosteric effector, and the nascent NH3 passes through a gate located at the end of a ~25-A tunnel before entering the synthase domain where CTP is generated. Substitution of the gate residue Val 60 by Ala, Cys, Asp, Trp, or Phe using site-directed mutagenesis and subsequent kinetic analyses revealed that V60 substitution impacts glutaminase activity, nucleotide binding, salt-dependent inhibition, and inter-domain NH3 transport. Surprisingly, the increase in steric bulk present in V60F perturbed the local structure consistent with "pinching" the tunnel, thereby revealing processes that synchronize the transfer of NH3 from the glutaminase domain to the synthase domain. V60F had a slightly reduced coupling efficiency at maximal glutaminase activity that was ameliorated by slowing down the glutamine hydrolysis reaction, consistent with a "bottleneck" effect. The inability of V60F to use exogenous NH3 was overcome in the presence of GTP, and more so if CTPS was covalently modified by 6-diazo-5-oxo-l-norleucine. Use of NH2OH by V60F as an alternative bulkier substrate occurred most efficiently when it was concomitant with the glutaminase reaction. Thus, the glutaminase activity and GTP-dependent activation act in concert to open the NH3 gate of CTPS to mediate inter-domain NH3 transport. PMID- 30251662 TI - Structural basis of phospholipase A2-like myotoxin inhibition by chicoric acid, a novel potent inhibitor of ophidian toxins. AB - BACKGROUND: Specific compounds found in vegetal species have been demonstrated to be efficient inhibitors of snake toxins, such as phospholipase A2-like (PLA2 like) proteins. These particular proteins, present in several species of vipers (Viperidae), induce a severe local myotoxic effect in prey and human victims, and this effect is often not efficiently neutralized by the regular serum therapy. PLA2-like proteins have been functionally and structurally studied since the early 1990s; however, a comprehensive molecular mechanism was proposed only recently. METHODS: Myographic and histological techniques were used to evaluate the inhibitory effect of chicoric acid (CA) against BthTX-I myotoxin. Isothermal titration calorimetry assays were used to measure the affinity between the inhibitor and the toxin. X-ray crystallography was used to reveal details of this interaction. RESULTS: CA prevented the blockade of indirectly evoked muscle contraction and inhibited muscle damage induced by BthTX-I. The inhibitor binds to the toxin with the highest affinity measured for a natural compound in calorimetric assays. The crystal structure and molecular dynamics simulations demonstrated that CA binds at the entrance of the hydrophobic channel of the toxin and binds to one of the clusters that participates in membrane disruption. CONCLUSIONS: CA prevents the myotoxic activity of the toxin, preventing its activation by simultaneous binding with two critical regions. GENERAL SIGNIFICANCE: CA is a potential myotoxic inhibitor to other PLA2-like proteins and a possible candidate to complement serum therapy. PMID- 30251663 TI - Anti-cancer activities of Bharangin against breast cancer: Evidence for the role of NF-kappaB and lncRNAs. AB - Breast cancer remains one of the leading causes of cancer related deaths in women worldwide. Bharangin is a diterpenoid quinonemethide that has demonstrated therapeutic potential against leukemia, lymphoma, and multiple myeloma cells. Whether this diterpenoid exhibit activities against breast cancer cells and the underlying mechanism is largely unknown. Herein, we provide evidence that bharangin suppresses the proliferation of MCF-7, MDA-MB-231, MDA-MB-453, MDA-MB 468 and T-47D breast cancer cells. As examined by AO/PI staining, DAPI staining, sub-G1 analysis, phosphatidylserine externalization, caspase activation, DNA laddering, and poly-ADP ribose polymerase cleavage, the diterpenoid induced apoptosis in breast cancer cells. The growth inhibitory effect of bharangin on breast cancer cells was further confirmed from colony-formation assay. Furthermore, the cancer cell migration was also suppressed by the diterpenoid. Mechanistically, bharangin was found to modulate multiple cancer related cell signalling pathways in breast cancer cells. Bharangin suppressed the expression of cell survival and invasive proteins, and induced Bax and mitochondrial depolarization in breast cancer cells. The diterpenoid also suppressed the activation of pro-inflammatory transcription factor, nuclear factor (NF)-kappaB induced by okadaic acid. Finally, the diterpenoid induced the expression of tumor suppressor lncRNAs (MEG-3, GAS-5), while down-regulating oncogenic H19 expression. Overall, these results suggest that bharangin exhibits anti carcinogenic, anti-proliferative and anti-inflammatory activities against breast cancer cells. The modulation of lncRNA expression and inhibition of NF-kappaB activation by bharangin may contribute to its anti-carcinogenic activities. PMID- 30251664 TI - Cloning and characterisation of the Equilibrative Nucleoside Transporter family of Trypanosoma cruzi: ultra-high affinity and selectivity to survive in the intracellular niche. AB - BACKGROUND: Trypanosoma cruzi, the causative agent of Chagas' disease is unable to synthesise its own purines and relies on salvage from the host. In other protozoa, purine uptake has been shown to be mediated by Equilibrative Nucleoside Transporters (ENTs). METHODS: To investigate the functionality of T. cruzi encoded ENT transporters, its four putative ENT genes (TcrNB1, TcrNB2, TcrNT1 and TcrNT2) were cloned and expressed in genetically adapted Trypanosoma brucei procyclic cells from which the nucleobase transporter locus was deleted. RESULTS: TcrNB1 displayed very high affinity for hypoxanthine (Km 93.8 +/- 4.7 nM for) and guanine, and moderate affinity for adenine. TcrNT1 was found to be a high affinity guanosine/inosine transporter (inosine Km is 1.0 +/- 0.03 MUM; guanosine Ki is 0.92 +/- 0.2 MUM). TcrNT2 encoded a high-affinity thymidine transporter (Km = 223.5 +/- 7.1 nM) with a clear preference for 2'-deoxypyrimidines. TcrNB2, whose activity could not be determined in our system, could be a low-affinity purine nucleobase transporter, given its sequence and predicted structural similarities to Leishmania major NT4. All 4 transporter genes were highly expressed in the amastigote forms, with much lower expression in the non-dividing stages. CONCLUSIONS: The data appear to show that, surprisingly, T. cruzi has a preference for oxopurines over aminopurines and efficiently transports 2' deoxypyrimidines. The T. cruzi ENTs display exceptionally high substrate affinity as an adaptation to their intracellular localisation. GENERAL SIGNIFICANCE: This study reports the first cloning of T. cruzi purine and pyrimidine transporters, including the first gene encoding a pyrimidine-selective protozoan transporter. PMID- 30251665 TI - Revealing the atomistic details behind the binding of B7-1 to CD28 and CTLA-4: A comprehensive protein-protein modelling study. AB - BACKGROUND: CD28 and CTLA-4 are homologous T-cell receptors that bind with B7-1 and produce two opposing immunological signals required for T-cell activation and inactivation, respectively. It has been clinically proven that specific blockade of these key protein-protein interactions at the synapse can offer immunotherapeutic benefits for cancers and autoimmune treatments. Hence, there is a growing interest towards developing anti-CD28 and anti-CTLA-4 small molecule inhibitors. To achieve this goal, it is important to understand unique molecular level fingerprint interactions that stabilize CTLA-4/B7-1 and CD28/B7-1 complexes. However, until recently, the structure of the human CD28/B7-1 complex has not been resolved experimentally, which remains a significant setback in achieving specific inhibitors against CTLA-4 or CD28. METHODS: Here, we employed a combination of advanced molecular modelling and extensive molecular dynamics (MD) simulations to model the CD28/B7-1 complex and characterize the key interactions that stabilize the complex. RESULTS: Ensemble protein-protein docking and MD-based binding-free energy calculations were used to obtain a comprehensive structural model of the CD28/B7-1 complex, which was validated with various mutation-based experimental data from literature. Our CD28/B7-1 model has much weaker binding affinity than the CTLA-4/B7-1 complex, which is in agreement with the results from our binding assay experiments and previous studies. CONCLUSIONS: Per-residue energy decomposition of the binding affinities of the two complexes revealed the unique fingerprint hot-spot sites in CTLA-4/B7-1 and CD28/B7-1 complexes. GENERAL SIGNIFICANCE: The results presented in this work will, on a long-run, be useful to develop new generation of specific CD28 and CTLA-4 inhibitors for targeted immunotherapy. PMID- 30251666 TI - Quantification of kinetic rate constants for transcytosis of polymeric nanoparticle through blood-brain barrier. AB - BACKGROUND: Polymeric nanoparticles (PNP) have received significant amount of interests for targeted drug delivery across the blood-brain barrier (BBB). Experimental studies have revealed that PNP can transport drug molecules from microvascular blood vessels to brain parenchyma in an efficient and non-invasive way. Despite that, very little attention has been paid to theoretically quantify the transport of such nanoparticles across BBB. METHODS: In this study, for the first time, we developed a mathematical model for PNP transport through BBB endothelial cells. The mathematical model is developed based on mass-action laws, where kinetic rate parameters are determined by an artificial neural network (ANN) model using experimental data from in-vitro BBB experiments. RESULTS: The presented ANN model provides a much simpler way to solve the parameter estimation problem by avoiding integration scheme for ordinary differential equations associated with the mass-action laws. Furthermore, this method can efficiently deal with both small and large data set and can approximate highly nonlinear functions. Our results show that the mass-action model, constructed with ANN based rate parameters, can successfully predict the characteristics of the polymeric nanoparticle transport across the BBB. CONCLUSIONS: Our model results indicate that exocytosis of nanoparticles is seven fold slower to endocytosis suggesting that future studies should focus on enhancing the exocytosis process. GENERAL SIGNIFICANCE: This mathematical study will assist in designing new drug carriers to overcome the drug delivery problems in brain. Furthermore, we anticipate that this model will form the basis of future comprehensive models for drug transport across BBB. PMID- 30251667 TI - Multimodal highly fluorescent-magnetic nanoplatform to target transferrin receptors in cancer cells. AB - BACKGROUND: Site-specific multimodal nanoplatforms with fluorescent-magnetic properties have great potential for biological sciences. For this reason, we developed a multimodal nanoprobe (BNPs-Tf), by covalently conjugating an optical magnetically active bimodal nanosystem, based on quantum dots and iron oxide nanoparticles, with the human holo-transferrin (Tf). METHODS: The Tf bioconjugation efficiency was evaluated by the fluorescence microplate assay (FMA) and the amount of Tf immobilized on BNPs was quantified by fluorescence spectroscopy. Moreover, relaxometric and fluorescent properties of the BNPs-Tf were evaluated, as well as its ability to label specifically HeLa cells. Cytotoxicity was also performed by Alamar Blue assay. RESULTS: The FMA confirmed an efficient bioconjugation and the fluorescence spectroscopy analysis indicated that 98% of Tf was immobilized on BNPs. BNPs-Tf also presented a bright fluorescence and a transversal/longitudinal relaxivities ratio (r2/r1) of 65. Importantly, the developed BNPs-Tf were able to label, efficiently and specifically, the Tf receptors in HeLa cells, as shown by fluorescence and magnetic resonance imaging assays. Moreover, this multimodal system did not cause noteworthy cytotoxicity. CONCLUSIONS: The prepared BNPs-Tf hold great promise as an effective and specific multimodal, highly fluorescent-magnetic, nanoplatform for fluorescence analyses and T2-weighted images. GENERAL SIGNIFICANCE: This study developed an attractive and versatile multimodal nanoplatform that has potential to be applied in a variety of in vitro and in vivo studies, addressing biological processes, diagnostic, and therapeutics. Moreover, this work opens new possibilities for designing other efficient multimodal nanosystems, considering other biomolecules in their composition able to provide them important functional properties. PMID- 30251668 TI - Structural properties of the peroxiredoxin AhpC2 from the hyperthermophilic eubacterium Aquifex aeolicus. AB - Peroxiredoxins (Prxs) are thiol peroxidases that scavenge various peroxide substrates such as hydrogen peroxide (H2O2), alkyl hydroperoxides and peroxinitrite. They also function as chaperones and are involved in signal transduction by H2O2 in eukaryotic cells. The genome of Aquifex aeolicus, a microaerophilic, hyperthermophilic eubacterium, encodes four Prxs, among them an alkyl hydroperoxide reductase AhpC2 which was found to be closely related to archaeal 1-Cys peroxiredoxins. We determined the crystal structure of AhpC2 at 1.8 A resolution and investigated its oligomeric state in solution by electron microscopy. AhpC2 is arranged as a toroid-shaped dodecamer instead of the typically observed decamer. The basic folding topology and the active site structure are conserved and possess a high structural similarity to other 1-Cys Prxs. However, the C-terminal region adopts an opposite orientation. AhpC2 contains three cysteines, Cys49, Cys212, and Cys218. The peroxidatic cysteine CP49 was found to be hyperoxidized to the sulfonic acid (SO3H) form, while Cys212 forms an intra-monomer disulfide bond with Cys218. Mutagenesis experiments indicate that Cys212 and Cys218 play important roles in the oligomerization of AhpC2. Based on these structural characteristics, we proposed the catalytic mechanism of AhpC2. This study provides novel insights into the structure and reaction mechanism of 1-Cys peroxiredoxins. PMID- 30251670 TI - Determinative factors in inhibition of aquaporin by different pharmaceuticals: Atomic scale overview by molecular dynamics simulation. AB - The inhibition of water permeation through aquaporins by ligands of pharmaceutical compounds is considered as a method to control the cell lifetime. The inhibition of aquaporin 1 (AQP1) by bacopaside-I and torsemide, was explored and its atomistic nature was elucidated by molecular docking and molecular dynamics (MD) simulation collectively along with Poisson-Boltzmann surface area (PBSA) method. Docking results revealed that torsemide has a lower level of docking energy in comparison with bacopaside-I at the cytoplasmic side. Furthermore, the effect of steric constraints on water permeation was accentuated. Bacopaside-I inhibits the channel properly due to the strong interaction with the channel and larger spatial volume, whereas torsemide blocks the cytoplasmic side of the channel imperfectly. The most probable active sites of AQP1 for the formation of hydrogen bonds between the inhibitor and the channel were identified by numerical analysis of the bonds. Eventually, free energy assessments indicate that binding of both inhibitors is favorable in complex with AQP1, and van der Waals interaction has an important contribution in stabilizing the complexes. PMID- 30251669 TI - Nitric oxide reverses drug resistance by inhibiting ATPase activity of p glycoprotein in human multi-drug resistant cancer cells. AB - BACKGROUND: Development of resistance to chemotherapy drugs is a significant problem in treating human malignancies in the clinic. Overexpression of drug efflux proteins, including P-170 glycoprotein (P-gp), an ATP-dependent efflux protein, is one of the main mechanisms responsible for multi-drug resistance (MDR). Because our previous studies have shown that nitric oxide (NO) or its related species inhibit the ATPase activities of topoisomerase II, we hypothesized that NO should also inhibit the ATPase activity of P-gp and increase drug accumulation in MDR cells, causing a reversal of drug resistance. RESULTS: Cytotoxicity and cellular accumulation studies showed that NO significantly inhibited the ATPase activity of P-gp in isolated membranes and in NCI/ADR-RES tumor cells, causing an increase in drug accumulation and reversals of adriamycin and taxol resistance in the MDR cells. While NO had no effects on topoisomerase II-induced, adriamycin-dependent DNA cleavage complex formation, it significantly inhibited adriamycin-induced DNA double-strand breaks. Electron spin resonance studies showed an increase in adriamycin-dependent hydroxyl radical formation in the presence of an NO-donor. CONCLUSIONS: The reversal of drug resistance is due to inhibition of the ATPase activity by NO, resulting in enhancement of the drug accumulation in the MDR cells. Furthermore, DNA damage was not responsible for this reversal of adriamycin resistance. However, formation of adriamycin dependent toxic free radical species and subsequent cellular damage may be responsible for the increased cytotoxicity of adriamycin by NO in NCI/ADR-RES cells. GENERAL SIGNIFICANCE: Appropriately designed NO donors would be ideal for the treatment of P-gp-overexpressing tumors in the clinic. PMID- 30251672 TI - In vitro neurotoxicity of salsolinol is attenuated by the presynaptic protein alpha-synuclein. AB - BACKGROUND: Salsolinol (SALSO), a product from the reaction of dopamine (DA) with acetaldehyde, is found increased in dopaminergic neurons of Parkinson's disease (PD) patients. The administration of SALSO in rats causes myenteric neurodegeneration followed by the formation of deposits of the protein alpha synuclein (aS), whose aggregation is intimately associated to PD. METHODS: NMR, isothermal titration calorimetry and MS were used to evaluate the interaction of SALSO with aS. The toxicity of SALSO and in vitro-produced aS-SALSO species was evaluated on mesencephalic primary neurons from mice. RESULTS: SALSO, under oxidative conditions, stabilizes the monomeric state besides a minor population of oligomers of aS, resulting in a strong inhibition of the fibrillation process. SALSO does not promote any chemical modification of the protein. Instead, the interaction of SALSO with aS seems to occur via hydrophobic effect, likely mediated by the NAC (non-amyloid component) domain of the protein. aS-SALSO species were found to be innocuous on primary neurons, while SALSO alone induces apoptosis via caspase-3 activation. Importantly, exogenous aS monomer was capable of protecting neurons against SALSO toxicity irrespective whether the protein was co-administered with SALSO or added until 2 h after SALSO, as evidenced by DAPI and cleaved-caspase 3 assays. Similar protective action of aS was found by pre incubating neurons with aS before the administration of SALSO. CONCLUSIONS: Interaction of SALSO with aS leads to the formation of fibril-incompetent and innocuous adducts. SALSO toxicity is attenuated by aS monomer. SIGNIFICANCE: aS could exhibit a protective role against the neurotoxic effects of SALSO in dopaminergic neuron. PMID- 30251673 TI - Metastable states of HYPK-UBA domain's seeds drive the dynamics of its own aggregation. AB - Protein aggregation is a multi-step process that requires sequential structural transitions of monomers during their incorporation into oligomers. Such process involves the formation of various intermediate stages in protein structures. Seed nucleation mediated oligomerization is observed in many aggregation-prone proteins. Understanding of the protein seed's structural features and mechanisms of its transition-state formation are important for knowing the details of post nucleation aggregation process. We have identified the metastable states in the seeds of the Ubiquitin associated (UBA) domain of Huntingtin Interacting Protein K (HYPK). This is studied by monitoring the events of dynamic transitions of metastable seeds to aggregates or monomers through microscopy, biophysical and computational techniques. HYPK-UBA seeds can exist in specific metastable state(s) that show transition from closed to open conformations, thereby reorienting the helix associated hydrophobic patches to cause its self aggregation. Metastable seeds show inter-seed exchange of monomers through simultaneous dissociation-association phenomenon. Monomer release from metastable seeds can cause the dissolution of the aggregates. Like metastable monomers, metastable seeds also show reduction in their secondary structure by altering the molecular contacts and solvent accessible hydrophobic surfaces. Induction of metastable seeds from the ground-state is a slow thermodynamic process and it results from excitable perturbations. Conclusively, we propose the concept that the thermodynamic induction of metastable states in HYPK-UBA seed potentiates the molecule to switch its conformations that increases the protein's self aggregation by the mechanism of hydrophobic patch collapse, while also releasing the monomers from oligomeric seeds due to structural instability. PMID- 30251671 TI - Supramolecular zippers elicit interbilayer adhesion of membranes producing cell death. AB - BACKGROUND: The fluorescent dye 10-N-nonyl acridine orange (NAO) is widely used as a mitochondrial marker. NAO was reported to have cytotoxic effects in cultured eukaryotic cells when incubated at high concentrations. Although the biochemical response of NAO-induced toxicity has been well identified, the underlying molecular mechanism has not yet been explored in detail. METHODS: We use optical techniques, including fluorescence confocal microscopy and lifetime imaging microscopy (FLIM) both in model membranes built up as giant unilamellar vesicles (GUVs) and cultured cells. These experiments are complemented with computational studies to unravel the molecular mechanism that makes NAO cytotoxic. RESULTS: We have obtained direct evidence that NAO promotes strong membrane adhesion of negatively charged vesicles. The attractive forces are derived from van der Waals interactions between anti-parallel H-dimers of NAO molecules from opposing bilayers. Semi-empirical calculations have confirmed the supramolecular scenario by which anti-parallel NAO molecules form a zipper of bonds at the contact region. The membrane remodeling effect of NAO, as well as the formation of H dimers, was also confirmed in cultured fibroblasts, as shown by the ultrastructure alteration of the mitochondrial cristae. CONCLUSIONS: We conclude that membrane adhesion induced by NAO stacking accounts for the supramolecular basis of its cytotoxicity. GENERAL SIGNIFICANCE: Mitochondria are a potential target for cancer and gene therapies. The alteration of the mitochondrial structure by membrane remodeling agents able to form supramolecular assemblies via adhesion properties could be envisaged as a new therapeutic strategy. PMID- 30251674 TI - High-resolution atomic force microscopy visualization of metalloproteins and their complexes. AB - BACKGROUND: Metalloproteins myeloperoxidase (MPO), ceruloplasmin (CP) and lactoferrin (LF) play an important role in regulation of inflammation and oxidative stress in vertebrates. It was previously shown that these proteins may work synergetically as antimicrobial and anti-inflammatory agents by forming complexes, such as MPO-CP and LF-CP. However, interaction of metalloprotein molecules with each other has never been characterized at a single-molecule level. METHODS: In this study, the pairwise interactions of MPO, CP and LF molecules were investigated at a single-molecule level using high-resolution atomic force microscopy (AFM). Highly oriented pyrolytic graphite surface (HOPG) modified with oligoglycine-hydrocarbon graphite modifier (GM) was used as a substrate for protein deposition. RESULTS: The procedure for reliable AFM investigation of metalloproteins and their complexes has been developed. Using this procedure, we have visualized, for the first time, single MPO, CP and LF molecules, characterized the morphology of MPO-CP and LF-CP complexes and confirmed the absence of direct contacts between MPO and LF molecules. Moreover, we have revealed the novel chainlike shape of MPO-CP conjugates. CONCLUSIONS: GM HOPG was shown to be a convenient substrate for AFM investigation of metalloproteins and their complexes. Direct AFM visualization of MPO-CP and LF-CP complexes, on the one hand, complements previous data obtained from the "bulk techniques" and, on the other hand, provides new insight into the ultrastructure of MPO-CP complexes. GENERAL SIGNIFICANCE: The obtained results contribute to the better understanding of regulation of inflammation and oxidation stress mediated by collaborative action of the metalloproteins such as MPO, CP and LF. PMID- 30251675 TI - Protein topology determines substrate-binding mechanism in homologous enzymes. AB - During evolution, some homologs proteins appear with different connectivity between secondary structures (different topology) but conserving the tridimensional arrangement of them (same architecture). These events can produce two types of arrangements; circular permutation or non-cyclic permutations. The first one results in the N and C terminus transferring to a different position on a protein sequence while the second refers to a more complex arrangement of the structural elements. In ribokinase superfamily, two different topologies can be identified, which are related to each other as a non-cyclic permutation occurred during the evolution. Interestingly, this change in topology is correlated with the nucleotide specificity of its members. Thereby, the connectivity of the secondary elements allows us to distinguish an ATP-dependent and an ADP-dependent topology. Here we address the impact of introducing the topology of a homologous ATP-dependent kinase in an ADP-dependent kinase (Thermococcus litoralis glucokinase) in the structure, nucleotide specificity, and substrate binding order of the engineered enzyme. Structural evidence demonstrates that rewiring the topology of TlGK leads to an active and soluble enzyme without modifications on its three-dimensional architecture. The permuted enzyme (PerGK) retains the nucleotide preference of the parent TlGK enzyme but shows a change in the substrate binding order. Our results illustrate how the rearrangement of the protein folding topology during the evolution of the ribokinase superfamily enzymes may have dictated the substrate-binding order in homologous enzymes of this superfamily. PMID- 30251676 TI - Cln3 function is linked to osmoregulation in a Dictyostelium model of Batten disease. AB - Mutations in CLN3 cause a juvenile form of neuronal ceroid lipofuscinosis (NCL), commonly known as Batten disease. Currently, there is no cure for NCL and the mechanisms underlying the disease are not well understood. In the social amoeba Dictyostelium discoideum, the CLN3 homolog, Cln3, localizes predominantly to the contractile vacuole (CV) system. This dynamic organelle functions in osmoregulation, and intriguingly, osmoregulatory defects have been observed in mammalian cell models of CLN3 disease. Therefore, we used Dictyostelium to further study the involvement of CLN3 in this conserved cellular process. First, we assessed the localization of GFP-Cln3 during mitosis and cytokinesis, where CV system function is essential. GFP-Cln3 localized to the CV system during mitosis and cln3- cells displayed defects in cytokinesis. The recovery of cln3- cells from hypotonic stress and their progression through multicellular development was delayed and these effects were exaggerated when cells were treated with ammonium chloride. In addition, Cln3-deficiency reduced the viability of cells during hypotonic stress and impaired the integrity of spores. During hypertonic stress, Cln3-deficiency reduced cell viability and inhibited development. We then performed RNA sequencing to gain insight into the molecular pathways underlying the sensitivity of cln3- cells to osmotic stress. This analysis revealed that cln3-deficiency upregulated the expression of tpp1A, the Dictyostelium homolog of human TPP1/CLN2. We used this information to show a correlated increase in Tpp1 enzymatic activity in cln3- cells. In total, our study provides new insight in the mechanisms underlying the role of CLN3 in osmoregulation and neurodegeneration. PMID- 30251677 TI - Label-free FTIR spectroscopy detects and visualizes the early stage of pulmonary micrometastasis seeded from breast carcinoma. AB - An application of FTIR spectroscopic imaging for the identification and visualization of early micrometastasis from breast cancer to lungs in a murine model is shown. Spectroscopic and histological examination is focused on lung cross-sections derived from animals at the early phase of metastasis (early micrometastasis, EM) as compared to healthy control (HC) and late phase of metastasis (advanced macrometastasis, AM) using murine model of metastatic breast cancer with 4T1 cells orthotopically inoculated. FTIR imaging allows for a detailed, objective and label-free differentiation and visualization of EM foci including large and small micrometastases as well as single cancer cells grouped in clusters. An effect of the EM phase on the entire lung tissue matrix as well as characteristic biochemical profiles for HC and advanced macrometastasis were determined from morphological and spectroscopic points of view. The extraordinary sensitivity of FTIR imaging toward EM detection and discrimination of AM borders confirms its applicability as a complementary tool for the histopathological assessment of the metastatic cancer progression. PMID- 30251678 TI - Autophagy mediates calcium-sensing receptor-induced TNFalpha production in human preadipocytes. AB - Obesity is a major current public health problem worldwide due to the severe co morbid conditions that this disease entails. The development of obesity-related cardiometabolic disorders is in direct association with adipose tissue inflammation that leads to its functional impairment. Activation of the Calcium Sensing Receptor (CaSR) in adipose tissue contributes to inflammation and adipose dysfunction. Autophagy, a process of cell component degradation, is closely related to inflammation in many diseases, however, whether autophagy is associated with CaSR-induced inflammation remains unknown. Using LS14 and SW872 preadipose cell lines as well as primary human preadipocytes, we show that CaSR activation with the allosteric activator cinacalcet induces autophagosome formation. Cinacalcet-induced LC3II content elevation was precluded by knockdown of the CaSR and enhanced by CaSR overexpression, indicating a specific effect. Autophagy inhibition using 3-methyladenine prevented CaSR-induced TNFalpha production, indicating that autophagy contributes to CaSR-induced inflammation in human preadipocytes. Our results suggest that modulation of CaSR-induced autophagy is an attractive target in obese inflamed adipose tissue, to prevent the development of diseases triggered by adipose dysfunction. We describe a novel mechanism and possible new target to modulate and prevent adipose inflammation and hence the resulting disease-generating adipose tissue dysfunction. PMID- 30251679 TI - Reactive cysteine residues in the oxidative dimerization and Cu2+ induced aggregation of human gammaD-crystallin: Implications for age-related cataract. AB - Cysteine (Cys) residues are major causes of crystallin disulfide formation and aggregation in aging and cataractous human lenses. We recently found that disulfide linkages are highly and partly conserved in beta- and gamma crystallins, respectively, in human age-related nuclear cataract and glutathione depleted LEGSKO mouse lenses, and could be mimicked by in vitro oxidation. Here we determined which Cys residues are involved in disulfide-mediated crosslinking of recombinant human gammaD-crystallin (hgammaD). In vitro diamide oxidation revealed dimer formation by SDS-PAGE and LC-MS analysis with Cys 111-111 and C111 C19 as intermolecular disulfides and Cys 111-109 as intramolecular sites. Mutation of Cys111 to alanine completely abolished dimerization. Addition of alphaB-crystallin was unable to protect Cys 111 from dimerization. However, Cu2+ induced hgammaD-crystallin aggregation was suppressed up to 50% and 80% by mutants C109A and C111A, respectively, as well as by total glutathionylation. In contrast to our recently published results using ICAT-labeling method, manual mining of the same database confirmed the specific involvement of Cys111 in disulfides with no free Cys111 detectable in gammaD-crystallin from old and cataractous human lenses. Surface accessibility studies show that Cys111 in hgammaD is the most exposed Cys residue (29%), explaining thereby its high propensity toward oxidation and polymerization in the aging lens. PMID- 30251680 TI - Role of p38gamma MAPK in regulation of EMT and cancer stem cells. AB - p38gamma is a member of p38 MAPK family which contains four isoforms p38alpha, p38beta, p38gamma, and p38delta. p38gamma MAPK has unique function and is less investigated. Recent studies revealed that p38gamma MAPK may be involved in tumorigenesis and cancer aggressiveness. However, the underlying cellular/molecular mechanisms remain unclear. Epithelial-mesenchymal transition (EMT) is a process that epithelial cancer cells transform to facilitate the loss of epithelial features and gain of mesenchymal phenotype. EMT promotes cancer cell progression and metastasis, and is involved in the regulation of cancer stem cells (CSCs) which have self-renewal capacity and are resistant to chemotherapy and target therapy. We showed that p38gamma MAPK significantly increased EMT in breast cancer cells; over-expression of p38gamma MAPK enhanced EMT while its down regulation inhibited EMT. Meanwhile, p38gamma MAPK augmented CSC population while knock down of p38gamma MAPK decreased CSC ratio in breast cancer cells. MicroRNA 200b (miR-200b) was down-stream of p38gamma MAPK and inhibited by p38gamma MAPK; miR-200b mimics blocked p38gamma MAPK-induced EMT while miR-200b inhibitors promoted EMT. p38gamma MAPK regulated miR-200b through inhibiting GATA3. p38gamma MAPK induced GATA3 ubiquitination, leading to its proteasome-dependent degradation. Suz12, a Polycomb group protein, was down-stream of miR-200b and involved in miR-200b regulation of EMT. Thus, our study established an important role of p38gamma MAPK in EMT and identified a novel signaling pathway for p38gamma MAPK-mediated tumor promotion. PMID- 30251681 TI - Ectopic expression of OX1R in ulcerative colitis mediates anti-inflammatory effect of orexin-A. AB - Orexins (orexin-A and orexin-B) are hypothalamic peptides that are produced by the same precursor and are involved in sleep/wake control, which is mediated by two G protein-coupled receptor subtypes, OX1R and OX2R. Ulcerative colitis (UC) is an inflammatory bowel disease, (IBD) which is characterized by long-lasting inflammation and ulcers that affect the colon and rectum mucosa and is known to be a significant risk factor for colon cancer development. Based on our recent studies showing that OX1R is aberrantly expressed in colon cancer, we wondered whether orexin-A could play a role in UC. Immunohistochemistry studies revealed that OX1R is highly expressed in the affected colonic epithelium of most UC patients, but not in the non-affected colonic mucosa. Injection of exogenous orexin-A specifically improved the inflammatory symptoms in the two colitis murine models. Conversely, injection of inactive orexin-A analog, OxB7-28 or OX1R specific antagonist SB-408124 did not have anti-inflammatory effect. Moreover, treatment with orexin-A in DSS-colitis induced OX1R-/- knockout mice did not have any protective effect. The orexin-A anti-inflammatory effect was due to the decreased expression of pro-inflammatory cytokines in immune cells and specifically in T-cells isolated from colonic mucosa. Moreover, orexin-A inhibited canonical NFkappaB activation in an immune cell line and in intestinal epithelial cell line. These results suggest that orexin-A might represent a promising alternative to current UC therapies. PMID- 30251682 TI - Molecular and cellular basis of ornithine delta-aminotransferase deficiency caused by the V332M mutation associated with gyrate atrophy of the choroid and retina. AB - Gyrate atrophy (GA) is a rare recessive disorder characterized by progressive blindness, chorioretinal degeneration and systemic hyperornithinemia. GA is caused by point mutations in the gene encoding ornithine delta-aminotransferase (OAT), a tetrameric pyridoxal 5'-phosphate-dependent enzyme catalysing the transamination of l-ornithine and alpha-ketoglutarate to glutamic-gamma semialdehyde and l-glutamate in mitochondria. More than 50 OAT variants have been identified, but their molecular and cellular properties are mostly unknown. A subset of patients is responsive to pyridoxine administration, although the mechanisms underlying responsiveness have not been clarified. Herein, we studied the effects of the V332M mutation identified in pyridoxine-responsive patients. The Val332-to-Met substitution does not significantly affect the spectroscopic and kinetic properties of OAT, but during catalysis it makes the protein prone to convert into the apo-form, which undergoes unfolding and aggregation under physiological conditions. By using the CRISPR/Cas9 technology we generated a new cellular model of GA based on HEK293 cells knock-out for the OAT gene (HEK OAT_KO). When overexpressed in HEK-OAT_KO cells, the V332M variant is present in an inactive apodimeric form, but partly shifts to the catalytically-competent holotetrameric form in the presence of exogenous PLP, thus explaining the responsiveness of these patients to pyridoxine administration. Overall, our data represent the first integrated molecular and cellular analysis of the effects of a pathogenic mutation in OAT. In addition, we validated a novel cellular model for the disease that could prove instrumental to define the molecular defect of other GA-causing variants, as well as their responsiveness to pyridoxine and other putative drugs. PMID- 30251683 TI - Exosomal Mst1 transfer from cardiac microvascular endothelial cells to cardiomyocytes deteriorates diabetic cardiomyopathy. AB - Diabetic cardiomyopathy (DCM) is characterized by cardiac microvascular endothelial cells (CMECs) injury and cardiomyocyte (CM) dysfunction. Exosomes mediated cellular communication between CMECs and CM has emerging roles in the pathogenesis of DCM, but the underlining mechanisms are unclear. Mammalian sterile 20-like kinase 1 (Mst1), a key component in Hippo pathway which participates in regulating organ size, apoptosis and autophagy, is involved in the development of DCM. We generated the endothelial-specific Mst1 transgenic mice (Tg-Mst1EC) and constructed diabetic model with streptozotocin (STZ). Interestingly, Tg-Mst1EC mice suffered from worse cardiac function and aggravated insulin resistance compared with non-transgenic (NTg) diabetic mice. The content of Mst1 protein was increased, while Mst1 mRNA had no significant change in CM isolated from diabetic Tg-Mst1EC mice. In vitro, CMECs-derived exosomes were taken up by CM and increased Mst1 protein content which inhibited autophagy, as well as enhanced apoptosis in high glucose (HG) cultured CM as evidenced by immunofluorescence and western blot analysis. In addition, Mst1 inhibited glucose uptake under diabetic condition by disrupting the glucose transporter type 4 (GLUT4) membrane translocation through decreasing the interaction between Daxx and GLUT4, as well as enhancing the association of Mst1 and Daxx. Our study exemplifies pleiotropic effects of Mst1-enriched exosomes released from CMECs on inhibiting autophagy, promoting apoptosis and suppressing the glucose metabolism in CM. PMID- 30251684 TI - Barth syndrome cells display widespread remodeling of mitochondrial complexes without affecting metabolic flux distribution. AB - Barth syndrome (BTHS) is a rare X-linked disorder that is characterized by cardiac and skeletal myopathy, neutropenia and growth abnormalities. The disease is caused by mutations in the tafazzin (TAZ) gene encoding an enzyme involved in the acyl chain remodeling of the mitochondrial phospholipid cardiolipin (CL). Biochemically, this leads to decreased levels of mature CL and accumulation of the intermediate monolysocardiolipin (MLCL). At a cellular level, this causes mitochondrial fragmentation and reduced stability of the respiratory chain supercomplexes. However, the exact mechanism through which tafazzin deficiency leads to disease development remains unclear. We therefore aimed to elucidate the pathways affected in BTHS cells by employing proteomic and metabolic profiling assays. Complexome profiling of patient skin fibroblasts revealed significant effects for about 200 different mitochondrial proteins. Prominently, we found a specific destabilization of higher order oxidative phosphorylation (OXPHOS) supercomplexes, as well as changes in complexes involved in cristae organization and CL trafficking. Moreover, the key metabolic complexes 2-oxoglutarate dehydrogenase (OGDH) and branched-chain ketoacid dehydrogenase (BCKD) were profoundly destabilized in BTHS patient samples. Surprisingly, metabolic flux distribution assays using stable isotope tracer-based metabolomics did not show reduced flux through the TCA cycle. Overall, insights from analyzing the impact of TAZ mutations on the mitochondrial complexome provided a better understanding of the resulting functional and structural consequences and thus the pathological mechanisms leading to Barth syndrome. PMID- 30251685 TI - Erythrocyte heme-oxygenation status indicated as a risk factor in prehypertension by Raman spectroscopy. AB - Raman spectroscopy of erythrocytes provides detailed information about the structure and status of heme moiety, which can be used to provide new insights into molecular pathogenesis of several diseases. In this study, we present the first Raman spectroscopy investigations of the effect of hemoglobin oxygenation in the context of hypertensive disease. The experimental data was subjected to Logistic Regression, which indicated heme-oxygenation status as an important risk factor alongside other clinical parameters. The 1605/1621 cm-1 band ratio was selected as an optimal Raman metric for risk assessment and along with other band ratios (1583, 1639, 1310 cm-1) related to heme status and when combined with clinical data via logistic regression gave an Area Under the Curve (AUC) >0.95 for prehypertension risk prediction. The work demonstrates the feasibility of Raman spectroscopy to distinguish between prehypertensive and normotensive states. Simultaneously, it is implied that the etiology of the high blood pressure progression may be connected with the changes in hemoglobin oxygenation. PMID- 30251686 TI - Impaired mammary tumor formation and metastasis by the point mutation of a Smad3 linker phosphorylation site. AB - Triple-negative breast cancer (TNBC) is often aggressive and metastatic. Transforming growth factor-beta acts as a tumor-promoter in TNBC. Smad3, a major downstream effector protein in the TGF-beta signaling pathway, is regulated by phosphorylation at several sites. The functional significance of the phosphorylation of the linker region in Smad3 is poorly understood for TNBC. Among the four sites in the Smad3 linker region, threonine-179 (T179) appears to be unique as it serves as the binding site for multiple WW-domain-containing proteins upon phosphorylation, suggesting that this phosphorylation is a key for Smad3 to engage other pathways. Using genome editing, we introduced for the first time a knock-in (KI) mutation in the endogenous Smad3 gene in IV2, a lung-tropic subline of the human MDA-MB-231 TNBC cell line. In the resulting cell line, the Smad3 T179 phosphorylation site is replaced by non-phosphorylatable valine (T179V) with the mutation in both alleles. The T179V KI reduced cell growth rate and mammosphere formation. These phenomena were accompanied by a significant upregulation of p21Cip1 and downregulation of c-Myc. The T179V KI also reduced cell migration and invasion in vitro. In the mouse xenograft models, the T179V KI markedly reduced the establishment of primary tumor in the mammary fat pad and the lung metastasis. Our results using gene editing indicate the cancer-promoting role of Smad3 T179 phosphorylation in the human TNBC cells. Our findings highly suggest that controlling this phosphorylation may have therapeutic potential for TNBC. PMID- 30251689 TI - cPLA2 and desaturases underlie the tau hyperphosphorylation offset induced by BACE knock-down in neuronal primary cultures. AB - Inflammation has been suggested to play early and perhaps causative roles in Alzheimer's disease (AD) pathogenesis possibly in part by the overactivation of the aspartic acid protease named beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), which is responsible for the beta-amyloid cascade. We have described that BACE1 is involved in the lysophosphatidylethanolamine (LPE) (18:1/20:4/22:6) upregulation associated with tauopathy and inflammation signaling (cPLA2/arachidonic acid/COX2) in a triple transgenic model of Alzheimer's disease, where BACE1 silencing reversed the imbalanced profile and produced cognitive function improvement. In this study, we analyze the role of cPLA2 and desaturases (SCD1, FAD6) in the BACE1 knockdown-induced protective action under a glutamate excitotoxicity model. Glutamate (125 MUM) produced hyperphosphorylation of tau in cortical primary cultures along with increased apoptotic nuclei, LDH release, and cPLA2 expression, which were all reversed by BACE1-KD. This beneficial effect was reinforced by the silencing of cPLA2 but attenuated by the reduction in SCD1 and partially attenuated by the reduction in FAD6. Inversely, overexpression SCD1 and FAD6 recovered the neuroprotective effect produced by BACE1-KD, which was not achieved by the overexpression of each desaturase alone. These findings suggest that the hyperphosphorylation of tau and the creation of a pro-inflammatory cell environment are blocked in a desaturase dependent manner by targeting BACE1. PMID- 30251688 TI - IP3 receptor blockade restores autophagy and mitochondrial function in skeletal muscle fibers of dystrophic mice. AB - Duchenne muscular dystrophy (DMD) is characterized by a severe and progressive destruction of muscle fibers associated with altered Ca2+ homeostasis. We have previously shown that the IP3 receptor (IP3R) plays a role in elevating basal cytoplasmic Ca2+ and that pharmacological blockade of IP3R restores muscle function. Moreover, we have shown that the IP3R pathway negatively regulates autophagy by controlling mitochondrial Ca2+ levels. Nevertheless, it remains unclear whether IP3R is involved in abnormal mitochondrial Ca2+ levels, mitochondrial dynamics, or autophagy and mitophagy observed in adult DMD skeletal muscle. Here, we show that the elevated basal autophagy and autophagic flux levels were normalized when IP3R was downregulated in mdx fibers. Pharmacological blockade of IP3R in mdx fibers restored both increased mitochondrial Ca2+ levels and mitochondrial membrane potential under resting conditions. Interestingly, mdx mitochondria changed from a fission to an elongated state after IP3R knockdown, and the elevated mitophagy levels in mdx fibers were normalized. To our knowledge, this is the first study associating IP3R1 activity with changes in autophagy, mitochondrial Ca2+ levels, mitochondrial membrane potential, mitochondrial dynamics, and mitophagy in adult mouse skeletal muscle. Moreover, these results suggest that increased IP3R activity in mdx fibers plays an important role in the pathophysiology of DMD. Overall, these results lead us to propose the use of specific IP3R blockers as a new pharmacological treatment for DMD, given their ability to restore both autophagy/mitophagy and mitochondrial function. PMID- 30251687 TI - Small GTPases SAR1A and SAR1B regulate the trafficking of the cardiac sodium channel Nav1.5. AB - BACKGROUND: The cardiac sodium channel Nav1.5 is essential for the physiological function of the heart and causes cardiac arrhythmias and sudden death when mutated. Many disease-causing mutations in Nav1.5 cause defects in protein trafficking, a cellular process critical to the targeting of Nav1.5 to cell surface. However, the molecular mechanisms underlying the trafficking of Nav1.5, in particular, the exit from the endoplasmic reticulum (ER) for cell surface trafficking, remain poorly understood. METHODS AND RESULTS: Here we investigated the role of the SAR1 GTPases in trafficking of Nav1.5. Overexpression of dominant negative mutant SAR1A (T39N or H79G) or SAR1B (T39N or H79G) significantly reduces the expression level of Nav1.5 on cell surface, and decreases the peak sodium current density (INa) in HEK/Nav1.5 cells and neonatal rat cardiomyocytes. Simultaneous knockdown of SAR1A and SAR1B expression by siRNAs significantly reduces the INa density, whereas single knockdown of either SAR1A or SAR1B has minimal effect. Computer modeling showed that the three-dimensional structure of SAR1 is similar to RAN. RAN was reported to interact with MOG1, a small protein involved in regulation of the ER exit of Nav1.5. Co-immunoprecipitation showed that SAR1A or SAR1B interacted with MOG1. Interestingly, knockdown of SAR1A and SAR1B expression abolished the MOG1-mediated increases in both cell surface trafficking of Nav1.5 and the density of INa. CONCLUSIONS: These data suggest that SAR1A and SAR1B are the critical regulators of trafficking of Nav1.5. Moreover, SAR1A and SAR1B interact with MOG1, and are required for MOG1-mediated cell surface expression and function of Nav1.5. PMID- 30251691 TI - Alpha-lipoic acid regulates the autophagy of vascular smooth muscle cells in diabetes by elevating hydrogen sulfide level. AB - Dysfunctional vascular smooth muscle (VSM) plays a vital role in the process of atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Alpha-lipoic acid (ALA) can prevent the altered VSM induced by diabetes. However, the precise mechanism underlying the beneficial effect of ALA is not well understood. This study aimed to determine whether ALA ameliorates VSM function by elevating hydrogen sulfide (H2S) level in diabetes and whether this effect is associated with regulation of autophagy of VSM cells (VSMCs). We found decreased serum H2S levels in Chinese patients and rats with type 2 diabetes mellitus (T2DM). ALA treatment could increase H2S level, which reduced the autophagy-related index and activation of the 5'-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, thereby protecting vascular function in rats with T2DM. Propargylglycine (PPG), a cystathionine-gamma-lyase inhibitor, could weaken the ALA effect. In cultured VSMCs, high glucose level also reduced H2S level, upregulated the autophagy-related index and activated the AMPK/mTOR pathway, which were reversed by concomitant application of sodium hydrosulfide (NaHS, an H2S donor) or ALA. The protective effect of NaHS or ALA was attenuated by rapamycin (an autophagy activator), 5-amino-1-beta-d-ribofuranosyl-imidazole-4 carboxamide (an AMPK activator) or PPG. In contrast, Compound C (an AMPK inhibitor) enhanced the effect of ALA or NaHS. ALA may have a protective effect on VSMCs in T2DM by elevating H2S level and downregulating autophagy via the AMPK/mTOR pathway. This study provides a new target for addressing diabetic macroangiopathy. PMID- 30251690 TI - CoQ10 supplementation rescues nephrotic syndrome through normalization of H2S oxidation pathway. AB - Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q10 (CoQ10) deficiency and is very responsive to CoQ10 supplementation, although the pathomechanism is not clear. Here, using a mouse model of CoQ deficiency associated NS, we show that long-term oral CoQ10 supplementation prevents kidney failure by rescuing defects of sulfides oxidation and ameliorating oxidative stress, despite only incomplete normalization of kidney CoQ levels and lack of rescue of CoQ-dependent respiratory enzymes activities. Liver and kidney lipidomics, and urine metabolomics analyses, did not show CoQ metabolites. To further demonstrate that sulfides metabolism defects cause oxidative stress in CoQ deficiency, we show that silencing of sulfide quinone oxido-reductase (SQOR) in wild-type HeLa cells leads to similar increases of reactive oxygen species (ROS) observed in HeLa cells depleted of the CoQ biosynthesis regulatory protein COQ8A. While CoQ10 supplementation of COQ8A depleted cells decreases ROS and increases SQOR protein levels, knock-down of SQOR prevents CoQ10 antioxidant effects. We conclude that kidney failure in CoQ deficiency-associated NS is caused by oxidative stress mediated by impaired sulfides oxidation and propose that CoQ supplementation does not significantly increase the kidney pool of CoQ bound to the respiratory supercomplexes, but rather enhances the free pool of CoQ, which stabilizes SQOR protein levels rescuing oxidative stress. PMID- 30251692 TI - Reactive oxygen species mediate cancer stem-like cells and determine bortezomib sensitivity via Mcl-1 and Zeb-1 in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is an aggressive, incurable non-Hodgkin B-cell lymphoma with good initial response to therapy then subsequently relapse. Cancer stem cells (CSCs) are considered to be an underlying cause of these inevitable drug resistance and tumor regrowth, but how CSCs are regulated is largely unknown. We demonstrate here for the first time the existence of CSC-like subpopulations that are modulated by reactive oxygen species (ROS) in MCL cell lines and patient-derived primary cells in an inverse correlation with bortezomib (BTZ) sensitivity. Using various known donors and inhibitors of cellular superoxide (O2-), hydrogen peroxide (H2O2) and hydroxyl radical (OH), we unveil their distinct roles in the regulation of CSC-like subpopulations and thus MCL response to BTZ. O2- inhibits CSC-like cells and sensitizes BTZ-induced apoptosis, whereas H2O2 conversely enriches CSC-like cells and protects against apoptosis and OH has minimal effects. We further observed that an anti-apoptotic Mcl-1 and a transcription factor Zeb-1 are favorable targets of O2- and H2O2, respectively. Using small molecule inhibition, ectopic expression and CRISPR/Cas9 mediated gene manipulation, we verified the roles of Mcl-1 and Zeb-1 in CSC and apoptosis regulation by O2- and H2O2. Our findings provide a novel mechanistic insight into the significance of redox status of MCL cells in determining their drug response via CSC-like subpopulations, which are imperative to a better understanding of therapeutic resistance and relapse. PMID- 30251693 TI - CircSEMA4B targets miR-431 modulating IL-1beta-induced degradative changes in nucleus pulposus cells in intervertebral disc degeneration via Wnt pathway. AB - Intervertebral disc (IVD) degeneration (IDD), characterized by elevated levels of proinflammatory mediators, increased Aggrecan and collagen degradation, and increased degradation of extracellular matrix (ECM), has been widely regarded as a significant contributor to low back pain. Genetics are significant factors contribute to IDD. Based on previous data, circular RNA SEMA4B (circSEMA4B) is down-regulated in IDD specimens; herein, we demonstrated circSEMA4B overexpression could attenuate the effect of IL-1beta on nucleus pulposus cell (NPC) proliferation, senescence, and ECM and Aggrecan degradation in IDD via Wnt signaling. Moreover, miR-431, a direct target of circSEMA4B, could bind to the 3'UTR of SFRP1 or GSK-3beta, two inhibitory regulators of Wnt signaling, to inhibit their expression thus playing a role similar to the activator of Wnt signaling in NPCs. The effect of circSEMA4B knockdown on NPCs was partially reversed by miR-431 inhibition; circSEMA4B serves as a miR-431 sponge to compete with SFRP1 or GSK-3beta for miR-431 binding, thus inhibiting IL-1beta-induced degenerative process in NPCs through Wnt signaling. Rescuing circSEMA4B expression in NPCs in IDD might present a potential strategy for IDD improvement. PMID- 30251694 TI - Experimental acute pancreatitis is enhanced in mice with tissue nonspecific alkaline phoshatase haplodeficiency due to modulation of neutrophils and acinar cells. AB - Tissue nonspecific alkaline phosphatase (TNAP) has a well established role in bone homeostasis and in hepatic/biliary conditions. In addition, TNAP is expressed in the inflamed intestine and is relevant to T and B lymphocyte function. TNAP KO mice are only viable for a few days, but TNAP+/- haplodeficient mice are viable. Acute pancreatitis was induced by repeated caerulein injection in WT and TNAP+/- mice. TNAP+/- mice presented an increased expression of Cxcl2, Ccl2, Selplg (P-selectin ligand), Il6 and Il1b in the pancreas. Freshly isolated acinar cells showed a dramatic upregulation of Cxcl1, Cxcl2, Ccl2, Il6, Selpg or Bax in both pancreatitis groups. TNAP+/- cells displayed a 2-fold higher expression of Cxcl2, and a smaller increase in Il6. These findings could be partly replicated by in vitro treatment of primary acinar cells with caerulein. Furthermore, the proinflammatory effect on acinar cells could be partially reproduced in wild type cells treated with the TNAP inhibitor levamisole. TNAP mRNA levels were also markedly upregulated by pancreatitis in acinar cells. Neutrophil infiltration (MRP8+ cells) and activation (IL-6 and TNF production in LPS treated primary neutrophils) were increased in TNAP+/- vs WT mice. Neutrophil depletion greatly attenuated inflammation, indicating that this cell type is mainly responsible for the higher inflammatory status of TNAP+/- mice. In conclusion, our results show that altered TNAP expression results in heightened pancreatic inflammation, which may be explained by an augmented response of neutrophils and by a higher sensitivity of acinar cells to caerulein injury. PMID- 30251695 TI - Deficiency in augmenter of liver regeneration accelerates liver fibrosis by promoting migration of hepatic stellate cell. AB - BACKGROUND: Augmenter of liver regeneration (ALR) protects liver from various injuries, however, the association of ALR with liver fibrosis, particularly its effect on hepatic stellate cells (HSC), remains unclear. In this study, we investigated the impact of ALR on the activation of HSC, a pivotal event in occurrence of liver fibrosis. METHODS: Liver fibrosis was induced in vivo in mice with heterozygous ALR knockdown (ALR-KD) by administration of CCl4 or bile duct ligation. The effect of ALR-KD and ALR-overexpression on liver fibrosis was studied in mice and in HSC cells as well. RESULTS: Hepatic collagen deposition and expression of alpha-smooth muscle actin (alpha-SMA) were significantly increased in the ALR-KD mice compared to wild-type mice. In vitro, ALR-shRNA resulted in the activation of HSC cell line (LX-2). Furthermore, ALR-shRNA promoted LX-2 cell migration, accompanied by increased filamentous actin (F actin) assembly. The ALR-KD-mediated increase in HSC migration was associated with mitochondrial fusion, resulting in mitochondria elongation and enhancing ATP production. In contrast, ALR transfection (ALR-Tx) decelerated HSC migration and inhibited F-actin assembly, concomitantly enhancing mitochondrial fission and reducing ATP synthesis. Mechanically, stimulation of HSC migration by ALR-shRNA was attributed to the increased mitochondrial Ca2+ influx in HSCs. Treatment of ALR-shRNA-cells with Ruthenium Red (RuR), a specific inhibitor of mitochondrial calcium uniporter (MCU), significantly suppressed mitochondrial Ca2+ influx, HSC migration, mitochondrial fusion and ATP production. ALR-KD-induced HSC migration was verified in vitro in primary mouse HSCs. CONCLUSION: Inhibition of ALR expression aggravates liver fibrosis, probably via promoting HSC migration and mitochondrial fusion. PMID- 30251696 TI - Crosstalk between Na+,K+-ATPase and a volume-regulated anion channel in membrane microdomains of human cancer cells. AB - Low concentrations of cardiac glycosides including ouabain, digoxin, and digitoxin block cancer cell growth without affecting Na+,K+-ATPase activity, but the mechanism underlying this anti-cancer effect is not fully understood. Volume regulated anion channel (VRAC) plays an important role in cell death signaling pathway in addition to its fundamental role in the cell volume maintenance. Here, we report cardiac glycosides-induced signaling pathway mediated by the crosstalk between Na+,K+-ATPase and VRAC in human cancer cells. Submicromolar concentrations of ouabain enhanced VRAC currents concomitantly with a deceleration of cancer cell proliferation. The effects of ouabain were abrogated by a specific inhibitor of VRAC (DCPIB) and knockdown of an essential component of VRAC (LRRC8A), and they were also attenuated by the disruption of membrane microdomains or the inhibition of NADPH oxidase. Digoxin and digitoxin also showed anti-proliferative effects in cancer cells at their therapeutic concentration ranges, and these effects were blocked by DCPIB. In membrane microdomains of cancer cells, LRRC8A was found to be co-immunoprecipitated with Na+,K+-ATPase alpha1-isoform. These ouabain-induced effects were not observed in non-cancer cells. Therefore, cardiac glycosides were considered to interact with Na+,K+-ATPase to stimulate the production of reactive oxygen species, and they also apparently activated VRAC within membrane microdomains, thus producing anti proliferative effects. PMID- 30251697 TI - Type 2 diabetes - An autoinflammatory disease driven by metabolic stress. AB - Type 2 diabetes has traditionally been viewed as a metabolic disorder characterised by chronic high glucose levels, insulin resistance, and declining insulin secretion from the pancreas. Modern lifestyle, with abundant nutrient supply and reduced physical activity, has resulted in dramatic increases in the rates of obesity-associated disease conditions, including diabetes. The associated excess of nutrients induces a state of systemic low-grade chronic inflammation that results from production and secretion of inflammatory mediators from the expanded pool of activated adipocytes. Here, we review the mechanisms by which obesity induces adipose tissue dysregulation, detailing the roles of adipose tissue secreted factors and their action upon other cells and tissues central to glucose homeostasis and type 2 diabetes. Furthermore, given the emerging importance of adipokines, cytokines and chemokines in disease progression, we suggest that type 2 diabetes should now be viewed as an autoinflammatory disease, albeit one that is driven by metabolic dysregulation. PMID- 30251698 TI - Sphingosine kinase 2 cooperating with Fyn promotes kidney fibroblast activation and fibrosis via STAT3 and AKT. AB - Sphingosine kinases (Sphks) are the rate-limiting enzymes in the conversion of sphingosine to biologically active sphingosine-1-phosphate. The present study aimed to determine the role of Sphk2 and its downstream targets in renal fibroblast activation and interstitial fibrosis. In the kidney interstitium of patients with renal fibrosis, Sphk2high-expressing cells (mainly interstitial fibroblasts) were significantly elevated and highly correlated with disease progression in patients. In a murine model of renal interstitial fibrosis, Sphk2 was upregulated in the kidney of wild-type mice in response to disease progression. Importantly, Sphk2-knockout (KO) mice exhibited significantly lower levels of extracellular matrix (ECM) production and a suppressed inflammatory response in the kidney tissues, compared to those in their wild-type counterparts, whereas the expression of TGF-beta1 was unaffected. TGF-beta1 effectively upregulated Sphk2 expression in the renal interstitial fibroblast line, NRK-49F, independent of canonical Smad signaling activation. Furthermore, siRNA-mediated Sphk2 knockdown or suppression of Sphk2 activity by ABC294640 exposure effectively attenuated AKT and STAT3 activation and ECM production, but had no effects on Smad2 and Smad3 activation. Sphk2 phosphorylated Fyn to activate downstream STAT3 and AKT, thereby promoting ECM synthesis. Therefore, our findings indicate that targeting Sphk2-Fyn-STAT3/AKT signaling pathway may be a novel therapeutic approach for renal fibrosis. PMID- 30251699 TI - Overexpression of CXCR4 synergizes with LL-37 in the metastasis of breast cancer cells. AB - Chemokine receptor CXCR4 was involved in the progression of breast cancer to a metastatic phenotype, leading to the major cause of death in patients. A more in depth understanding of signaling mechanism underlying CXCR4 is critical to develop effective therapies toward metastasis. Recently, the role of antimicrobial peptide LL-37 in contributing to the metastasis of breast cancer cells was observed. Clinical analysis of data herein demonstrated for the first time that overexpression of LL-37 and CXCR4 co-existed in human primary breast tumors with lymph node metastases. Further study disclosed that forced expression of CXCR4 led to the enhancement of pro-migratory signaling and migration rate induced by LL-37 in breast cancer cells. Moreover, LL-37 affected tumor microenvironment including induction of migration of mesenchymal stem cells and CXCR4-dependent capillary-like tubule formation. Functional analysis showed that LL-37 induced the internalization of CXCR4 through approaching Glu268, the residue of CXCR4, independent of the binding pocket (Asp171, Asp262, and Glu288) for CXCR4 inhibitor AMD3100, signifying that LL-37 is a distinct agonist of CXCR4. These results suggest the reciprocal roles of LL-37 and CXCR4 in promoting breast cancer cell migration and provide new insight into the design of CXCR4 inhibitor for intervention of metastatic breast cancer. PMID- 30251701 TI - Time-resolved step-scan FTIR difference spectroscopy for the study of photosystem I with different benzoquinones incorporated into the A1 binding site. AB - Time-resolved step-scan FTIR difference spectroscopy has been used to study photosystem I (PSI) with plastoquinone-9 (PQ) and two other benzoquinones (2,6 dimethyl-1,4-benzoquinone and 2,3,5,6-tetrachloro-1,4-benzoquinone) incorporated into the A1 binding site. By subtracting a (P700+A1- - P700A1) FTIR difference spectrum for PSI with the native phylloquinone (PhQ) incorporated from corresponding spectra for PSI with different benzoquinones (BQs) incorporated, FTIR double difference spectra are produced, that display bands associated with vibrational modes of the quinones, without interference from features associated with protein vibrational modes. Molecular models for BQs involved in asymmetric hydrogen bonding were constructed and used in vibrational mode frequency calculations. The calculated data were used to aid in the interpretation and assignment of bands in the experimental spectra. We show that the calculations capture the general trends found in the experimental spectra. By comparing four different FTIR double difference spectra we are able to verify unambiguously bands associated with phyllosemiquinone in PSI at 1495 and 1415 cm-1. We also resolve a previously unrecognized band of phyllosemiquinone at 1476 cm-1 that calculations suggest is due in part to a C4-?O stretching mode. For PSI with PQ incorporated, calculations and experiment taken together indicate that the C1-?O and C4-?O vibrational modes of the semiquinone give rise to bands at 1487 and 1444 cm-1, respectively. This is very distinct compared to PSI with PhQ incorporated. From the calculated and experimental spectra, we show that it is possible to distinguish between two possible orientations of PQ in the A1 protein binding site. PMID- 30251700 TI - Mechanism of proton transfer through the KC proton pathway in the Vibrio cholerae cbb3 terminal oxidase. AB - The heme-copper oxidases (HCuOs) are terminal components of the respiratory chain, catalyzing oxygen reduction coupled to the generation of a proton motive force. The C-family HCuOs, found in many pathogenic bacteria under low oxygen tension, utilize a single proton uptake pathway to deliver protons both for O2 reduction and for proton pumping. This pathway, called the KC-pathway, starts at Glu-49P in the accessory subunit CcoP, and connects into the catalytic subunit CcoN via the polar residues Tyr-(Y)-227, Asn (N)-293, Ser (S)-244, Tyr (Y)-321 and internal water molecules, and continues to the active site. However, although the residues are known to be functionally important, little is known about the mechanism and dynamics of proton transfer in the KC-pathway. Here, we studied variants of Y227, N293 and Y321. Our results show that in the N293L variant, proton-coupled electron transfer is slowed during single-turnover oxygen reduction, and moreover it shows a pH dependence that is not observed in wildtype. This suggests that there is a shift in the pKa of an internal proton donor into an experimentally accessible range, from >10 in wildtype to ~8.8 in N293L. Furthermore, we show that there are distinct roles for the conserved Y321 and Y227. In Y321F, proton uptake from bulk solution is greatly impaired, whereas Y227F shows wildtype-like rates and retains ~50% turnover activity. These tyrosines have evolutionary counterparts in the K-pathway of B-family HCuOs, but they do not have the same roles, indicating diversity in the proton transfer dynamics in the HCuO superfamily. PMID- 30251702 TI - Palmitoylation is a post-translational modification of Alix regulating the membrane organization of exosome-like small extracellular vesicles. AB - BACKGROUND: Virtually all cell types have the capacity to secrete nanometer-sized extracellular vesicles, which have emerged in recent years as potent signal transducers and cell-cell communicators. The multifunctional protein Alix is a bona fide exosomal regulator and skeletal muscle cells can release Alix-positive nano-sized extracellular vesicles, offering a new paradigm for understanding how myofibers communicate within skeletal muscle and with other organs. S palmitoylation is a reversible lipid post-translational modification, involved in different biological processes, such as the trafficking of membrane proteins, achievement of stable protein conformations, and stabilization of protein interactions. METHODS: Here, we have used an integrated biochemical-biophysical approach to determine whether S-palmitoylation contributes to the regulation of extracellular vesicle production in skeletal muscle cells. RESULTS: We ascertained that Alix is S-palmitoylated and that this post-translational modification influences its protein-protein interaction with CD9, a member of the tetraspanin protein family. Furthermore, we showed that the structural organization of the lipid bilayer of the small (nano-sized) extracellular vesicle membrane with altered palmitoylation is qualitatively different compared to mock control vesicles. CONCLUSIONS: We propose that S-palmitoylation regulates the function of Alix in facilitating the interactions among extracellular vesicle specific regulators and maintains the proper structural organization of exosome like extracellular vesicle membranes. GENERAL SIGNIFICANCE: Beyond its biological relevance, our study also provides the means for a comprehensive structural characterization of EVs. PMID- 30251703 TI - Lysophosphatidylinositols in inflammation and macrophage activation: Altered levels and anti-inflammatory effects. AB - Lysophosphatidylinositols (LPI) are bioactive lipids that are implicated in several pathophysiological processes such as cell proliferation, migration and tumorigenesis and were shown to play a role in obesity and metabolic disorders. Often, these effects of LPI were due to activation of the G protein-coupled receptor GPR55. However, the role of LPI and GPR55 in inflammation and macrophage activation remains unclear. Therefore, we thought to study the effect of macrophage activation and inflammation on LPI levels and metabolism. To do so, we used J774 and BV2 cells in culture activated with lipopolysaccharides (LPS, 100 ng/mL) as well as primary mouse alveolar and peritoneal macrophages. We also quantified LPI levels in the cerebellum, lung, liver, spleen and colon of mice with a systemic inflammation induced by LPS (300 MUg/kg) and in the colon of mice with acute colitis induced by dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) and chronic DSS-induced colitis. Our data show that LPS induced macrophage activation leads to altered LPI levels in both the cells and culture medium. We also show that cytosolic phospholipase A2alpha (cPLA2alpha) and alpha/beta-hydrolase domain 6 (ABHD6) are among the enzymes implicated in LPI metabolism in J774 macrophages. Indeed, ABHD6 and cPLA2alpha inhibition increased 20:4-LPI levels in LPS-activated macrophages. Furthermore, incubation of LPS activated cells with LPI decreased J774 activation in a GPR55-dependent manner. In vivo, LPI levels were altered by inflammation in the liver, spleen and colon. These alterations are tissue dependent and could highlight a potential role for LPI in inflammatory processes. PMID- 30251704 TI - What Drives Young Vietnamese to Use Mobile Health Innovations? Implications for Health Communication and Behavioral Interventions. AB - BACKGROUND: Mobile phone use in Vietnam has become increasingly popular in recent years, with youth (people aged 15-24 years) being one of the groups with the heaviest use. Health-related apps on mobile phones (mobile health [mHealth] apps) appear to be a feasible approach for disease and health management, especially for self-management. However, there has been a scarcity of research on mobile phone usage for health care among youth and adolescents. OBJECTIVE: This study aims to identify the patterns of usage of mobile phone apps and the preferences for functionalities of mobile phone-based health-related apps among Vietnamese youth. METHODS: An online cross-sectional study was conducted in Vietnam in August to October 2015. Web-based respondent-driven sampling technique was adopted to recruit participants. The online questionnaire was developed and distributed using Google Forms. Chi square and Mann-Whitney tests were used to investigate the difference in attitude and preference for mobile phone apps between the two genders. RESULTS: Among 356 youths (age from 15 to 25 years) sampled, low prevalence was found of using mHealth apps such as beauty counseling (6.5%, 23/356), nutrition counseling (7.9%, 28/356), disease prevention (9.8%, 35/356), and disease treatment (7.6%, 27/356). The majority of users found the app(s) they used to be useful (72.7%, 48/356) and reported satisfaction with these apps (61.9%, 39/356). No significant differences were found between the genders in their perception of the usefulness of apps and their satisfaction with mobile health apps. Most of the participants (68.2%, 238/356) preferred apps which are conceptualized and designed to run on a mobile phone compared to Web based apps, and 50% (176/356) preferred visual materials. Approximately 53.9% (188/356) reported that it was integral for the mobile phone apps to have a sharing/social network functionality. Participants with a higher perceived stress score and EuroQol-5 Dimensions (EQ-5D) index were significantly less likely to use mHealth apps. CONCLUSIONS: This study found a low proportion using mHealth related mobile phone apps, but a high level of receptiveness and satisfaction among Vietnamese youth. Acceptance level and preferences toward mHealth apps as well as specifically preferred functionalities discovered in this study are essential not only in conceptualizing and developing appropriate mobile phone interventions targeting youth and adolescents, but also in the application of technically advanced solutions in disease prevention and health management. PMID- 30251705 TI - Static and dynamic structures of liquid Ba8Ga16Sn30: a melt of the thermoelectric clathrate compounds. AB - X-ray diffraction and inelastic x-ray scattering measurements of liquid Ba8Ga16Sn30 have been carried out to investigate local structure and atomic dynamics in the liquid. The pair distribution function shows shorter and longer interatomic distances in the first coordination shell. The dynamic structure factor exhibits the inelastic excitations on both sides of the quasielastic central peak. The inelastic excitations disperse with increasing the momentum transfer, suggesting the longitudinal acoustic mode. We found a low energy excitation in addition to the longitudinal acoustic excitation in the dynamic structure factor and it reminds us a strong relationship with a rattling motion of a guest (Ba) atom in the solid state. The temperature dependence of the pair distribution function and the longitudinal acoustic excitation energy is very weak in a range from 600 to 900 degrees C. The result suggests that Ba and other atoms in the melt are located around minimum positions of the effective pair potential approximated as a harmonic one. PMID- 30251706 TI - Well-ordered ZnO nanowires with controllable inclination on semipolar ZnO surfaces by chemical bath deposition. AB - Controlling the formation of ZnO nanowire (NW) arrays on a wide variety of substrates is crucial for their efficient integration into nanoscale devices. While their nucleation and growth by chemical bath deposition (CBD) have intensively been investigated on non-polar and polar c-plane ZnO surfaces, their formation on alternatively oriented ZnO surfaces has not been addressed yet. In this work, the standard CBD technique of ZnO is investigated on [Formula: see text] and [Formula: see text] semipolar ZnO single crystal surfaces. A uniform nanostructured layer consisting of tilted ZnO NWs is formed on the [Formula: see text] surface while elongated nanostructures are coalesced into a two-dimensional compact layer on the [Formula: see text] surface. By further combining the CBD with selective area growth (SAG) using electron beam-assisted lithography, highly tilted well-ordered ZnO NWs with high structural uniformity are grown on the [Formula: see text] patterned surface. The structural analysis reveals that ZnO NWs are homoepitaxially grown along the polar c-axis. The occurrence of quasi transverse and -longitudinal optical phonon modes in Raman spectra is detected and their origin and position are explained in the framework of the Loudon's model. These results highlight the possibility to form ZnO NWs on original semipolar ZnO surfaces. It also opens the way for comprehensively understanding the nucleation and growth of ZnO NW arrays on poorly and highly textured polycrystalline ZnO seed layers composed of nanoparticles with a wide range of non-polar, semipolar, and polar plane orientations. Eventually, the possibility to tune both the inclination and dimensions of well-ordered ZnO NW arrays by using SAG on semipolar surfaces is noteworthy for photonic and optoelectronic nanoscale devices. PMID- 30251707 TI - A novel method for comparing radiation dose and image quality, between and within different x-ray units in a series of hospitals. AB - OBJECTIVES: To develop a novel method for comparing radiation dose and image quality (IQ) to evaluate adult chest x-ray (CXR) imaging among several hospitals. METHODS: CDRAD 2.0 phantom was used to acquire images in eight hospitals (17 digital x-ray units) using local adult CXR protocols. IQ was represented by image quality figure inverse (IQFinv), measured using CDRAD analyser software. Signal to noise ratio, contrast to noise ratio and conspicuity index were calculated as additional measures of IQ. Incident air kerma (IAK) was measured using a solid state dosimeter for each acquisition. Figure of merit (FOM) was calculated to provide a single estimation of IQ and radiation dose. RESULTS: IQ, radiation dose and FOM varied considerably between hospitals and x-ray units. For IQFinv, the mean (range) between and within the hospitals were 1.42 (0.83-2.18) and 1.87 (1.52-2.18), respectively. For IAK, the mean (range) between and within the hospitals were 93.56 (17.26-239.15) MUGy and 180.85 (122.58-239.15) MUGy, respectively. For FOM, the mean (range) between and within hospitals were 0.05 (0.01-0.14) and 0.03 (0.02-0.05), respectively. CONCLUSIONS: The suggested method for comparing IQ and dose using FOM concept along with the new proposed FOM, is a valid, reliable and effective approach for monitoring and comparing IQ and dose between and within hospitals. It is also can be beneficial for the optimisation of x-ray units in clinical practice. Further optimisation for the hospitals/x-ray units with low FOM are required to minimise radiation dose without degrading IQ. PMID- 30251708 TI - Microwave-assisted synthesis and in vitro osteogenic analysis of novel bioactive glass fibers for biomedical and dental applications. AB - Glass fiber-based materials have gained interest for use in biomedical and dental applications. The aim of this study was to make E-glass fiber bioactive by a novel method using the microwave irradiation technique. Industrial E-glass fibers were used after surface activation with the hydrolysis method. The ratio of calcium and phosphorous precursors was set at 1.67. After maintaining the pH of the calcium solution, E-glass fibers in two ratios, i.e. 30% (nHA/E30) and 50% (nHA/E50) wt/wt, were added. The phosphorous precursor was added later and the solution was irradiated in a microwave to obtain nano-hydroxyapatite (nHA) particles on E-glass fibers. The structural, physical and in vitro biocompatibility analyses of the resulting materials were conducted. The expression of osteopontin (OPN) and collagen (Col) type 1 was measured by reverse transcription polymerase chain reaction (RT-PCR) and comparison was made between all the groups. Fourier transform infrared spectroscopy and x-ray diffraction showed characteristic peaks of nHA, and a change in the peak intensities was observed with an increase in the concentration of E-glass fibers. Scanning electron microscopic (SEM) images confirmed the homogenous adhesion of nHA spherical particles all over the fibers. Cell viability with mesenchymal stem cells showed growth, proliferation, and adhesion. All the materials were able to upregulate the expression of the OPN and Col, where gene expression was highest in nHA followed by nHA/E30 and nHA/E50. The bioactive glass fibers were synthesized in the shortest time and showed osteogenic properties. These materials have the potential for use in bone tissue engineering, dental prosthesis, and tooth restoration. PMID- 30251709 TI - Probing hotspots of plasmon-enhanced Raman scattering by nanomanipulation of carbon nanotubes. AB - We present a two-step procedure to probe hotspots of plasmon-enhanced Raman scattering with carbon nanotubes (CNTs). Dielectrophoretic deposition places a small CNT bundle on top of a plasmonic Au nanodimer. After 'pre-characterizing' both the nanotubes and dimer structure, we subsequently use the tip of an atomic force microscope to push the bundle into the plasmonic hotspot located in the 25 nm wide dimer gap, characterize its location inside the gap, and observe the onset of plasmon-enhanced Raman scattering. Evidence for the activation of the CNT's double-resonant D-mode by the near-field of the plasmonic hotspot is discussed. PMID- 30251710 TI - Development and Application of a No-Clog Surgical Suction Tip Using 3D Printing Technology. AB - BACKGROUND Clogging of the suction tip frequently occurs during orthopedic surgery. We developed a novel anti-clog suction tip using 3D printing technology to improve orthopedic surgery efficiency. MATERIAL AND METHODS We studied the root causes of obstructions in suction tips currently employed in orthopedic surgery during actual surgical cases. CAD software and 3D printer was used to design, modify, and print the novel suction tip. The frequency of clogging, the frequency of replacement of the suction tip, the time lost in replacing suction tips or connecting tubes, surgical duration, intraoperative surgical blood loss, and the satisfaction scores for the suction tips as rated by the surgeons were compared between the novel suction tip and the conventional suction tip. Comparisons were made first in laboratory experiments using a simulant liquid and then during total hip replacement surgeries. RESULTS In the simulant liquid experiments, the novel suction tips showed significantly reduced frequency of complete clogging and decreased time spent removing all fluid in comparison to the conventional suction tips (p<0.05). In the clinical trials, the novel suction tips exhibited significantly reduced frequency of complete clogging, shorter surgical duration, and reduced intraoperative surgical blood loss compared to the conventional suction tips (p<0.05). Surgeon satisfaction scores were higher for the novel tips than for the conventional tips (p<0.05). CONCLUSIONS Our surgeon designed and -produced surgical suction tip utilizing 3D desktop printing technology was highly effective in resolving the problem of clogged suction tips during orthopedic surgery and yielded high surgeon satisfaction. PMID- 30251719 TI - Isocyanide insertion into Au-H bonds: first gold iminoformyl complexes. AB - Isocyanides insert into gold(iii)-hydrogen bonds to give the first examples of gold iminoformyl complexes. The reaction is initiated by catalytic amounts of radicals; DFT calculations indicate that this is an equilibrium reaction driven forward by isocyanide in sufficient excess to trap the Au(ii) intermediate. PMID- 30251720 TI - Plutonium environmental chemistry: mechanisms for the surface-mediated reduction of Pu(v/vi). AB - In recent decades, interest in plutonium mobility has increased significantly due to the need of the United States, as well as other nations, to deal with commercial spent nuclear fuel, nuclear weapons disarmament, and the remediation of locations contaminated by nuclear weapons testing and production. Although there is a global consensus that geologic disposal is the safest existing approach to dealing with spent nuclear fuel and high-level nuclear waste, only a few nations are moving towards implementing a geologic repository due to technical and political barriers. Understanding the factors that affect the mobility of plutonium in the subsurface environment is critical to support the development of such repositories. The importance of redox chemistry in determining plutonium mobility cannot be understated. While Pu(iv) is generally assumed to be immobile in the subsurface environment due to sorption or precipitation, Pu(v) tends to be mobile due to its relatively low effective charge and weak complex formation. This review highlights one particularly important aspect of plutonium behaviour at the mineral-water interface-the concept of surface-mediated reduction, which describes the reduction of plutonium on a mineral surface. It provides a conceptual model for and evidence supporting or refuting each proposed mechanism for surface-mediated reduction including (i) radiolysis at the mineral surface, (ii) electron transfer via ferrous iron or manganese in the mineral structure, (iii) electron shuttling due to the semiconducting properties of the mineral, (iv) disproportionation of Pu(v), (v) facilitation by proton exchange sites, (vi) stabilisation of Pu(iv) due to the increased concentration gradient within the electrical double layer, and (vii) a Nernstian favourability of Pu(iv) surface complexes and colloids. It also provides new perspectives on future research directions. PMID- 30251722 TI - Metal-free visible-light synthesis of quaternary alpha-perfluoroalkyl aldehydes via an enamine intermediate. AB - Visible-light induced perfluoroalkylation of the alpha-position of aldehydes via enamines was developed. The reaction proceeds by electron donor-acceptor complexation of the enamine and perfluoroalkyl iodide without any additional redox catalyst. A variety of perfluoroalkyl groups are tolerated to give various quaternary alpha-perfluoroalkyl aldehydes. An example using proline-derived chiral amine gives high enantioselectivity. PMID- 30251724 TI - Tissue and plasma proteomics for early stage cancer detection. AB - The pursuit of novel and effective biomarkers is essential in the struggle against cancer, which is a leading cause of mortality worldwide. Biomarkers can be used as specific diagnostic tools, prognostic predictors, markers of the development of therapeutic resistance or even as therapeutic targets themselves. Through the application of sensitive and specific proteomic techniques, oncoproteomics investigates the proteins associated with cancer processes, to better understand their biological function/s and their associated pathways during tumorigenesis. Such studies seek to identify both potential biomarkers and drug targets in order to improve patient survival and quality of life whilst reducing the global health budget. Tissue and plasma are the most commonly utilised biological samples for such studies as they are readily available, non invasive and generally acceptable. Here, we outline the relative advantages and disadvantages of the most frequently used techniques for cancer diagnosis, prognosis, treatment and surveillance, concentrating on the latest advances and application of tissue and plasma proteomics for novel cancer biomarker discovery and disease surveillance. PMID- 30251729 TI - The re-awakening of hCG expression. Its role in the diagnosis of cervical squamous cell carcinoma. AB - OBJECTIVES: To compare immunohistochemical detection of Human chorionic gonadotropin (hCG) expression in paraffin embedded tissue of squamous cell carcinomas (SCC) and high grade squamous intraepithelial lesions (HSIL). METHODS: The samples in this retrospective study were obtained from the archives of the Pathology Department at Gaziantep University, Gaziantep, Turkey, over the period from January 2012 to September 2016. The study group consisted of 55 cases of SCC and 45 cases of HSIL. Tissue expression of hCG was detected by specific binding of anti-hCG antibody using an automated immunohistochemistry staining device. The categorical variables of intensity and coverage were analyzed statistically using Pearson Chi-Square test. RESULTS: High grade squamous cell lesions cases showed weak (84.4%, n=38/45) to no (15.6%, n=7/45) staining for hCG. None of the HSIL cases showed strong positivity. Strong positivity for hCG was detected in 90.9% (n=50/55) of SCC cases. CONCLUSION: Our study supports the association of ectopic hCG expression in cancer pathogenesis by demonstrating strong hCG immunoreactivity only in SCC cases. This finding can be helpful in supporting the diagnosis of invasive carcinoma in small or fragmented biopsies, which can on their own be confusing for the pathologists. PMID- 30251728 TI - Routine detection of carbapenem-resistant gram-negative bacilli in clinical laboratories. A review of current challenge. AB - The detection of carbapenem-resistant organisms (CROs) represents a substantial challenge for many clinical laboratories. In this review, several phenotypic and non-phenotypic methods for detecting CROs are discussed. However, no consensus has yet been reached with regards to the single most optimal method. Due to differences in carbapenem-resistant activity between carbapenemases, the simultaneous use of 2 or more phenotypic detection methods can improve the detection of CROs compared with a single technique. Molecular methods are currently favored because the majority can be performed rapidly with a high level of accuracy. Whole-genome sequencing (WGS) yields unambiguous data pertaining to complete analysis of the entire genome and may ultimately become a highly powerful tool in routine clinical settings. However, WGS is still relatively expensive and requires an automated data interpretation system. The routine implementation of this technique in clinical laboratories may not occur for several years, particularly in developing countries. PMID- 30251730 TI - The relationship between mortality and microbiological parameters in febrile neutropenic patients with hematological malignancies. AB - OBJECTIVES: To determine effective risk factors on mortality in febrile neutropenic cases with hematologic malignancy. Patients with hematologic diseases are more prone to infections and those are frequent causes of mortality. METHODS: This retrospective study was performed using data of 164 febrile neutropenic cases with hematologic malignancies who were followed up in a hematology clinic of a tertiary health care center between 2011-2015. The relationship between descriptive and clinical parameters rates and rates of mortality on the 7th and the 21st days were investigated. RESULTS: Patients with absolute neutrophil count less than 100/mm3, duration of neutropenia longer than 7 days, pneumonia or gastrointestinal foci of infection, central catheterization (p=0.025), isolation of Gram (-) bacteria in culture, carbapenem resistance, septic shock, and bacterial growth during intravenous administration of antibiotic treatment were under more risk for mortality on both the 7th and the 21st days. The final multivariate logistic regression results showed that pneumonia (p less than 0.0001), septic shock (p=0.004) and isolation of Gram-negative bacteria (p=0.032) were statistically significant risk factors. CONCLUSION: Early diagnosis and appropriate treatment of serious infections, which are important causes of morbidity and mortality, are crucial in patients with febrile neutropenia. Thus, each center should closely follow up causes of infection and establish their empirical antibiotherapy protocols to accomplish better results in the management of febrile neutropenia. PMID- 30251731 TI - Relationship between human leukocyte antigen DRB1 and psoriasis in Iraqi patients. AB - OBJECTIVES: To investigate the role of Human leukocyte antigen (HLA) Class II DRB1 in susceptibility to psoriasis in Iraqi patients. METHODS: A cross-sectional comparative study including 40 patients with psoriasis attending the Department of Dermatology, Al-Kindy teaching hospital in Baghdad, Iraq, between September 2013-2015. Patient selection was carried out by the dermatologists. Ninety healthy individuals were included in the study. Human leukocyte antigen genotyping was carried out by the sequence specific oligonucleotide (SSO) method using Auto LiPA 48 (Innogenetics, Belgium) in the HLA typing research unit of the Al-Kindy College of Medicine, Baghdad, Iraq. RESULTS: There is an increased frequency of HLA-DRB1*0102, *0306 in psoriatic patients with psoriasis p values=0.001, confidence interval(CI)=2.492-37.487 and odds ratio(OR)=9.666. Human leukocyte antigen-DRB1*1101 is significantly associated with plaque-type psoriasis with p=0.0434, CI=1.04-1.69, and OR=4.2. Human leukocyte antigen DRB1*0102 is significantly associated with other types of psoriasis with p=0.018, CI=0.0223-0.701, and OR=0.125. CONCLUSION: Human leukocyte antigen-DRB1*0102 and *0306 are significantly associated with psoriasis. Human leukocyte antigen DRB1*1101 is significantly associated with plaque-type psoriasis. Human leukocyte antigen-DRB1*0102 is significantly associated with other types of psoriasis rather than plaque-type psoriasis. PMID- 30251732 TI - The breast lesion excision system procedure: An optimal solution for the management of indeterminate BI-RADS category 3 breast lesions in women with severe anxiety. AB - OBJECTIVES: To evaluate the efficacy of the Breast lesion excision system (BLES) procedure as a primary excisional biopsy for the management of breast imaging reporting and data system (BI-RADS) category 3, small, and solid breast lesions in women having severe breast cancer anxiety. METHODS: A retospective study was conducted on 68 patients who underwent a BLES procedure. The study protocol was approved by the local ethical committee of Yeni Yuzyil University in Istanbul, Turkey. The study was carried out according to the principles of the Helsinki Declaration. Small breast lesions removed using a (12, 15 or 20 mm) wand from September 2011 to November 2014. These were category 3 lesions as determined by ultrasound (US) imaging according to BI-RADS. The radiological and pathological sizes of these lesions, the complete excision rates, the procedure durations, the pathological diagnosis, the complications, and the imaging findings before and after the procedure were all recorded. RESULTS: All the patients had a benign pathology. The mean duration of procedure was 12 (range=8-22) minutes. There was no major complication during the procedure and in the following period. Only some small hematomas were determined in 3 (4.2%) patients, and no additional surgical intervention was performed. Conclusion: The BLES procedure is an optimal solution for the management of indeterminate BI-RADS category 3 breast lesions in women with severe anxiety. PMID- 30251733 TI - Effects of cigarette smoking on coagulation screening tests and platelet counts in a Sudanese male adults population. AB - OBJECTIVES: To study the effects of heavy cigarette smoking on coagulation (CGG) screening tests and platelet counts (PLTs) in a Sudanese male adults population. METHODS: A case control study was conducted at both Kosti and Gabalein towns, Sudan, during October 2016 to May 2017. A 100 adult cigarette smokers were selected and another 100 matched non-smokers were selected as healthy controls. Blood samples were collected in trisodium citrate anti-coagulant for prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR), analyzed using standard methods (co-agulometer machine) and Ethylenediaminetetraacetic acid for the platelet counts, using an automated haematology analyzer (Sysmex, Tokoyo, Japan). Results: The results showed that the mean platelet counts were significantly lower in the smokers (183x103/cmm+/ 64x103/cmm) versus (244x103/cmm+/-38x103/cmm) in non-smokers, (p less than 0.000). Pearson correlation analysis suggested a weak negative correlation between platelet counts with the duration of smoking (r= -0.289, p less than 0.004) and the age of the smokers (r= -0.238, p less than 0.017). The mean PT and INR were also significantly lower in smokers (12.9+/-1.2 seconds) compared with the non-smokers (13.7+/-1.04 seconds, p less than 0.000), for PT and (0.95+/-0.09 versus 1.01+/-0.08, p less than 0.000) for INR. In contrast, PTT had no significant variation in smokers (30.5+/-3.8 seconds) and the non-smokers (37.9+/ 4.6 seconds). A p-value more than 0.05 was considered significant. CONCLUSION: Cigarette smokers tend to have lower platelet counts, shorter PT, and INR values, compared to non-smokers. Therefore, smoking might be associated with bleeding disorders but further investigations are needed. PMID- 30251734 TI - Women's perception and attitude to medical students' participation in obstetrics and gynecology care. AB - OBJECTIVES: To determine the attitudes of obstetric and gynecological patients towards medical students' participation in clinical care. METHODS: Patients in an obstetric and gynecological practice in Kingdom of Saudi Arabia, completed a structured self-administered online questionnaire to assess demographic, reproductive and lifestyle variables that affected their attitude towards the acceptance of medical students' participation in outpatient clinical care. RESULTS: Out of the 595 women surveyed, 64.7% received perinatal care, while 35.3% received gynecologic care. Women mostly held positive attitudes towards medical students' participation. Women expressed more comfort with medical students' involvement during limited clinical care roles such as obtaining patient's history and physical examinations without a pelvic examination. Women reported higher comfort levels in the presence of female medical students, especially during pelvic examinations. The presence of male medical students caused a significant reduction in patient's comfort. CONCLUSION: Our results suggest that women seeking obstetrics and gynecology medical services are accepting students' involvement during the healthcare encounter. Most patients are more comfortable if direct contact with students is minimized and students' participation in medical care is restricted to more limited roles. In addition, the student's gender is a significant determinant of patient's acceptance and comfort during the clinical encounter. PMID- 30251735 TI - Eating disorders and associated risk factors among Imam Abdulrahman bin Faisal university preparatory year female students in Kingdom of Saudi Arabia. AB - OBJECTIVES: To estimate the prevalence of eating disorders among Imam Abdulrahman bin Faisal University (IAU) in Dammam, Kingdom of Saudi Arabia, female students and to investigate the associated factors. Methods: A cross-sectional study was conducted at IAU, Dammam, Kingdom of Saudi Arabia, in 2016 with 670 participants. Data was collected by self-administered questionnaires, including the Eating attitude test 26 (EAT-26) and the sociocultural attitudes toward appearance questionnaire (SATAQ-4). Eating behavior questions were asked to determine whether the respondents should seek evaluation for an eating disorder (ED) from a professional. RESULTS: Eating attitude test 26 results showed that 29.4% of participants were categorized at a high level of concern for an ED, and 45.5% were categorized as at risk of having problematic feeding behaviors. Of the participants who scored above 20 on the EAT-26, 60.7% demonstrated high-risk feeding behavior attitudes, and approximately 11.5% who scored a body mass index (BMI) classified as underweight or very underweight required referral to a psychologist. A significant relationship was found between family stress to lose weight and EAT-26 scores above 20. The media was also found to represent external influence to lose weight. CONCLUSION: This study concluded that early detection of EDs or problematic feeding behaviors and attitude is vital to minimize the risks to physical health and well-being of the sufferers' experiences. PMID- 30251736 TI - Effect of Er: YAG laser etching on shear bond strength of orthodontic bracket. AB - OBJECTIVES: To evaluate and compare the shear bond strength (SBS) of Erbium laser etched enamel to acid etched and to detect morphological changes on laser etched enamel surface using scanning electron microscope (SEM). Moreover, Laser induced caries resistance is advantageous in Orthodontics. METHODS: This is an Ex vivo study between January 2016 and December 2017, which comprises a total of 50 human premolars, extracted for orthodontic purpose, were used in this study. The samples were randomly divided into 2 groups of 25 each. The first group was etched using 37% phosphoric for 30 seconds. As for the second group, enamel was treated by Er: YAG laser operating at wavelength 2.94um, power 1.5W and repetition rate 15Hz. Five teeth from each group were selected for SEM evaluation and the study were continued on 20 teeth from each group.Teeth were subjected to shear bond strength test. RESULTS: It showed, no-significant difference between the mean of shear bond strength and of the etched groups (p=0.016). CONCLUSION: It was concluded that, laser etched group (1.5W/15Hz) resulted in clinically accepted bond strength and could be an alternative to conventional acid etching. PMID- 30251737 TI - The characteristics of dental occlusion in patients with moderate to severe obstructive sleep apnea in Saudi Arabia. AB - OBJECTIVES: To evaluate characteristics of dental occlusion among non-obese Saudi adult patients suffering from moderate to severe obstructive sleep apnea(OSA). METHODS: Following ethical approval, a cross-sectional study was conducted at Sleep Disorders Center, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia, between January and March 2017. Non-obese adult Saudi patients with moderate/severe OSA (apnea-hypopnea index more than 15) and without history of malocclusion or edentulism were included with an estimated sample size of 50. Demographic details and severity of OSA as diagnosed by polysomnography were recorded. Characteristics of dental occlusion, namely molar, canine and incisor relationship, overjet, overbite, crossbite and arch form were obtained through calibrated examiners (kappa 0.81). Descriptive statistical analysis and Chi square test, with 95% significance level (p less than 0.05), were used to identify relationships between the severity of OSA and characteristics of dental occlusion. RESULTS: A total of 51 patients (31 males, 20 females; mean age 49.45+/-10.35 years), were enrolled in the study. Severity of OSA was moderate in 17 patients and severe in 34 patients. Severe form of OSA was more among males (64.7%) and in patients with Class-II division-1 incisor relationship (94.1%). Neither the demographic characteristics, nor characteristics of dental occlusion showed statistically significant relationship with the severity of OSA. CONCLUSION: The results of the present cross-sectional study indicate that the characteristics of dental occlusion are not related to the severity of OSA among non-obese adult Saudi patients. PMID- 30251738 TI - Fatal case of cerebral aspergilloma complicated by ventriculitis and bacteremia due to Salmonella species in a sickle cell disease patient. AB - To describe a fatal case of invasive Aspergillus flavus sinusitis in a 43-year old female with sickle cell disease (SCD) complicated by intracerebral aspergilloma and invasive Salmonella infection. Cerebral aspergilloma carries a very high mortality rate. The patient developed post-craniotomy intracerebral hemorrhage at the site of biopsy, Salmonella species sepsis and ventriculitis. She presented with a 2-month history of headache, dizziness, personality and behavioral changes, and vomiting. Initial clinical evaluation raised the suspicion of brain tumor. Brain magnetic resonance imaging revealed a left frontal, thick-walled ring-enhancing lesion with extensive surrounding edema suggestive of a neoplastic lesion, or a contiguous inflammatory or infectious process from the skull base. Despite early diagnosis and appropriate antifungal and surgical management, she eventually died from severe infection and respiratory arrest. In conclusion, invasive aspergillosis should be included in the differential diagnosis of SCD patients with central nervous system (CNS) lesions. PMID- 30251739 TI - Primary mucinous adenocarcinoma of the eyelid: A case report and literature review. AB - Primary mucinous adenocarcinoma (PMA) of the eyelid is an exceptionally rare clinical entity. Often, it mimics with benign lesions on clinical examination and with metastatic mucinous adenocarcinoma on histological examinations. We report a case of PMA in a 60-year- old male patient who came with a slow-growing, painless swelling near the lower lid of the left eye. Excisional biopsy from the mass revealed a mucinous adenocarcinoma. To differentiate it from a metastatic mucinous adenocarcinoma, a wide range of immunohistochemistry panel was run. The tumor cells showed strong positivity for cytokeratin7, cytokeratin5/6, P63, estrogen receptor, progesterone receptor and negativity for cytokeratin20. Moreover, extensive metastatic work-up did not show any primary malignancy elsewhere, hence a final diagnosis of PMA was made. We believe that, this is the second reported case from the Middle East and the first in the Madinah region of Saudi Arabia. PMID- 30251740 TI - Comparison of perceptions on the dental aesthetics of different malocclusions between orthodontists and schoolchildren. AB - OBJECTIVES: To compare perceptions on dental aesthetics of various malocclusions between schoolchildren and orthodontists with an orthodontic assessment of treatment needs. METHODS: The prospective study was conducted between late March December in 2017. A total of 32 orthodontists practicing in Shenyang, China and 116 schoolchildren (59 boys and 57 girls) aged 10-12 years (average= 11+/-0.60 years) from a 645 individual representing the population were selected via random sampling from a private primary school. Participants were questioned to assess 6 anterior dental photographs representing a variety degrees of aesthetic impairments, namely, reverse overjet (ROJ), anterior dental diastema and anterior open bite (OB) malocclusions. RESULTS: Perceptions on dental aesthetics were identical among genders (p more than 0.05). Compared with the orthodontists, schoolchildren perceived significantly greater aesthetic impairment for severe anterior OB and severe ROJ, mild anterior OB malocclusions (p less than 0.01). Anterior dental diastemas were evaluated based on least aesthetic impairment and with no significant difference in perception between schoolchildren and orthodontists. CONCLUSION: Schoolchildren perceived greater aesthetic impairment in severe anterior OB, severe ROJ, and mild anterior OB malocclusions than orthodontists. Median aesthetic components (AC) scores of schoolchildren for severe anterior OB and severe ROJ malocclusions corresponded with the category of "definite need" for treatment. PMID- 30251741 TI - A 36-year-old man with arthralgia and bone pain. AB - [No abstract available]. PMID- 30251742 TI - Comment on: Prevalence of hepatitis B, C, and HIV among patients attending a teaching dental hospital. A 7-year retrospective study from the United Arab Emirates. AB - [No abstract available]. PMID- 30251743 TI - Evaluation of Single Nucleotide Variants in Ethiopian Patients with Atopic Dermatitis. PMID- 30251744 TI - Influence of examiners experience on the reproducibility of different gold standard techniques and histological criteria for validation of the diagnosis of occlusal caries lesions. AB - : The aims of this study were to evaluate the influence (1) of the examiner experience and (2) three histological classification criteria on the reproducibility of two gold standard techniques (non-dye or dye) for validation of the diagnosis of occlusal caries. This study comprised a sample of 210 digital images of 105 permanent teeth (105 rhodamine B dyed and 105 dye-free hemisections) and six examiners. Images were evaluated on a laptop computer and categorised according to three different histological classification criteria (proposed by Ekstrand, Lussi or Downer) and repeated in order to allow reproducibility calculation. For data analysis, the six participants were divided into two groups: G1: examiners with previous experience in histological evaluation and G2: examiners with no experience in histological evaluation. Statistical significance was set at 0.05. RESULTS: The mean intra-examiner reproducibility values in G1 were higher than G2 in all variables. Intra-examiner reproducibility was lower for the dye-free technique in both groups. The mean values of inter-examiner reproducibility in G1 ranged from 0.60 to 0.68, and in G2 values ranged from 0.34 to 0.69. CONCLUSION: It can be concluded that: (1) the examiners' experience seems to influence the reproducibility of the two gold standard techniques studied and reproducibility tends to be lower when the dye free technique is used, and (2) the histological classification criterion does not appear to influence the reproducibility for validation of the diagnosis of occlusal caries. PMID- 30251745 TI - Second Transurethral Resection of Bladder Tumor: Is it Necessary in All T1 and/or High-Grade Tumors? AB - PURPOSE: To evaluate the role of second transurethral resection of bladder tumor (TURBT) in patients with T1 and/or high-grade bladder tumor regarding tumor size, multiplicity, and presence or absence of muscle in specimens of initial resection. MATERIALS AND METHODS: A total of 107 patients with either primary T1 or high-grade urothelial bladder cancer underwent second TURBT within 6 weeks after initial surgery and prior to starting intravesical immunotherapy. We assessed the incidence of residual disease and upstaging in second TURBT. RESULTS: Upstaging was noted in 11 (10.3%) patients and residual tumor was evident in 29 (27%) patients. Disease upstaging had a statistically significant association with tumor size, multifocality, and absence of muscle at initial resection in univariate analysis. Presence of residual tumor in second resection also showed significant association with tumor size and absence of muscle at initial resection but not multifocality. Multivariate logistic regression analysis revealed that absence of muscle at initial resection independently predicts disease upstaging during second TURBT (OR = 8.123, 95% CI: 1.478 44.632). Furthermore, both tumor size (OR = 13.573, 95% CI: 3.104-59.359) and absence of muscle (OR = 21.214, 95% CI: 6.062-74.244) were independent predictors of residual disease in second TURBT. CONCLUSION: We showed that second TURBT in a subset of patients with single, small T1 and/or high-grade tumor who underwent complete initial resection might be of limited value. PMID- 30251746 TI - Effects of Psychological Status on The Oxidation Parameters of Semen and Blood in Azoospermic Men. AB - PURPOSE: In limited number of studies performed concerning the psychological moods of female, and male with the diagnosis of infertility, data related to increased incidence of depression, and anxiety have been reported. The objective of this study is to determine whether azoospermia has any psychological effects on men, and investigate the potential effects of psychological mood on seminal, and plasma oxidative parametres. MATERIALS AND METHODS: Twenty-seven patients whose two consecutive semen analyses were reported as pellet -negative azoospermia constituted the azoospermic group, and 30 healthy individuals who applied to the infertility polyclinic with normal seminal parametres comprised the normozoospermic group. RESULTS: BECK Anxiety scores were statistically significant higher in the azoospermic group (P=0.009). When compared with the normozoospermic group, higher levels of oxidative parametres, but lower levels of the antioxidative parametre were detected in the azoospermic group (p<0.05). In the azoospermic group, a positive correlation was detected between BECK Anxiety and total oxidant status. Anxiety may increase oxidative parametres in both plasma, and seminal fluid (r=473, p=0.026). CONCLUSION: Oxidative milieu may impair sperm quality, and affect the success rates of assisted reproductive treatments. The determination of oxidative potential in infertile men, thiol, and prolidase may be used as biomarkers. PMID- 30251747 TI - A Nonspecific Penile Ulcer Leading to the Diagnosis of Wagner's Granulomatosis. AB - The presented case concerns a 53-year-old male who had been treated for nonspecific cutaneous lesions for two months without any improvement. After developing an erosive penile ulcer he was referred to our department. Investigation for sexually transmitted diseases and Mycobacterium tuberculosis ended with negative results. A penile ulcer biopsy suggested the diagnosis of Wagner's granulomatosis (WG). Patient during this period presented with upper respiratory tract symptoms. Measuring antineutrophil cytoplasmic antibodies (c ANCA), confirmed the diagnosis. Immunosuppressive therapy was initiated and resulted a favorable response. PMID- 30251748 TI - Ureteral stent removal using an extraction string after uncomplicated ureteroscopy: a cost-benefit analysis. AB - PURPOSE: Some urologists used the extraction strings for removal of ureteral stent without cystoscopy. While some urologists may have concern about perceived risks, including accidental dislodgement, infection, renal?colic?and lower urinary tract symptoms. Therefore, we performed a retrospective study to help address this conflict. MATERIALS AND METHODS: Patients who had an indwelling ureteral stent with(n=58) or without(n=82) extraction strings inserted after ureteroscopy for unilateral ureteral stones were enrolled. For ureteral stent removal, the strings were pulled by physician, no string-stents were removed by cystoscopic. Postoperative morbidity was assessed. Patients' medical expense due to postoperative morbidity was collected. RESULTS: Patients with extraction string had shorter stent dwell time((5.3+/-1.8 versus 11.2+/-3.2 day, P= .001) and less cost (8.97+/-3.07 versus 455+/-0 CNY, P = .001)) for ureteral stent removal. However, six patients with extraction string had an accidental dislodgement, additional medical expenses were 345+/-137.9 CNY. There was no difference in the cost due to urinary tract infection, renal?colic?and LUTS between the two groups. The overall cost in patients without an extraction string was significantly more than in patients with an extraction string (86.7+/-167.7 versus 507.9+/-147.8 CNY, p =.008). CONCLUSION: Despite an increase in stent dislodgement related risks to the extraction string, it results in significant cost savings for patients, and most of patients remove with extraction strings might benefit from it. INTRODUCTION Nowadays, most of urologists place an indwelling ureteral stent following uncomplicated ureteroscopy(URS). However, ureteral stent may impact quality of life (QoL) of patients. And the additional suffering due to cystoscopic extraction is even more painful. Current ureteral stents are manufactured with a string attached to the distal end, allowing for removal without cystoscopy, which may lead to a reduction of the dwell time(usually less than one week)[1-8]. Although stent extraction strings have many advantages, more than two-thirds of urologists remove extraction strings prior to their insertion[9]. Surgeons who do not adopt?this?method?may have concern about perceived risks, including accidental dislodgement, infection, renal?colic?and lower urinary tract symptoms(LUTS). But how about incidence?rate of the risk aforementioned??does this increase the patient's financial burden compared with patients remove without extraction strings? Whether patients remove with extraction strings might benefit from it? Therefore, we performed a retrospective study to help address these questions by comparing patients those who underwent ureteric stent placement with and without extraction strings after URS for stone disease. PMID- 30251749 TI - The Effect of Interfascial Injection on Obturator Nerve Block Compared with Nerve Stimulating Approach by Ultrasound-Guide: A Randomized Clinical Trial. AB - PURPOSE: This study was conducted to evaluate whether the ultrasound-guided interfascial injection technique is really compatible with the ultrasound-guided nerve stimulating technique for obturator nerve block (ONB) at the inguinal crease after bifurcation of the obturator nerve. MATERIALS AND METHODS: A total 62 ONBs were performed for transurethral resection of bladder tumors under spinal anesthesia, and divided into two groups, that is, to an ultrasound-guided ONB with nerve stimulation control group (the US-NS group) or an ultrasound-guided interfascial injection experimental group (the US-IFI group). In the US-IFI group, complete ONB was confirmed using a nerve stimulator at 5 min after completing the injection, and if residual twitching remained, another local anesthetic was injected; in such cases blocks were considered to have 'failed'. During TURB surgeries, two urology assistants determined obturator reflex grade (I-IV) at 15 min after injection completion in both groups. RESULTS: We assumed that the US-NS group achieved complete ONB in all cases. Six cases in the US-IFI group failed to achieve complete ONB (failure rate: 0% versus 19.4%, P = .012). There was one case of grade II obturator reflex in each group. CONCLUSION: The ultrasound-guided interfascial injection technique was not compatible with the ultrasound-guided nerve stimulating technique for ONB at the inguinal crease. PMID- 30251750 TI - Comparison of Two Different Retrograde Intrarenal Surgical Techniques: Is It Mandatory to Use Fluoroscopy During Retrograde Intrarenal Surgery? AB - PURPOSE: To evaluate the efficacy and reliability of fluoroscopy-free retrograde intrarenal surgery. MATERIALS AND METHODS: A retrospective evaluation was made of the data of 226 patients who underwent RIRS as kidney stone treatment between May 2015 and May 2017. When evaluation was made acccording to the exclusion criteria, the study continued with a total of 190 patients as 103 which where fluoroscopy was used (Group 1) and 87 who underwent a fluoroscopy-free procedure (Group 2). RESULTS: Group 1 patients comprised of 56 males and 47 females with a mean age of 41.5 +/- 13.9 years. Group 2 patients comprised of 48 males and 39 females with a mean age of 42.6 +/- 15.2 years. The mean stone size was 14.3 +/- 2.7 mm in Group 1 and 14.1 +/- 2.8 mm in Group 2. The mean operating time was calculated as 63.6 +/- 8.2 minute in Group 1 and 65.7+/-9.7 minute in Group 2. In Group 1, the success rate was determined as 83.5% on postoperative Day 1 and as 92.2% in the postoperative first month. In Group 2, these rates were 81.6% and 90.8% respectively. No statistically significant difference was determined between the groups in respect of stone size (P= .752), operating time (P=.108) and postoperative first day (P=.732) and first month success rates (P=.724). CONCLUSIONS: Fluoroscopy-free RIRS is a surgical technique with a high rate of success that can be applied safely to be able to protect patients at high risk of radiation and the surgical team, particularly in centers centres with high patient circulation. PMID- 30251751 TI - Association study of Retinoic Acid Related Orphan Receptor A (RORA) gene and risk of prostate disorders. AB - PURPOSE: Prostate cancer (PCa) and benign prostate hyperplasia (BPH) are two prevalent disorders among men with considerable mortality and morbidity. Several association studies have been conducted in different populations to find genetic loci linked with these disorders. Retinoic acid-receptor-related orphan receptor alpha (RORA) codes for a transcription factor which regulates expression of several cancer-related genes. Besides, RORA has been shown to be down-regulated in PCa tissues and cell lines. MATERIALS AND METHODS: In the present study we evaluated genotype and allele frequencies of rs11639084 and rs4774388 variants within RORA gene in PCa and BPH patients compared with healthy subjects. RESULTS: The rs11639084 and rs4774388 alleles were not different between PCa and normal groups 95% CI: 0.52-1.24, OR = 1.04, P = .34; 95% CI: 0.48-1.33, OR = .79, P = .39 respectively. Moreover, we did not detect any significant difference in allele, genotype or haplotype frequencies of these SNPs between the other study groups. CONCLUSION: The mentioned RORA variants are possibly not involved in the pathogenesis of PCa and BPH. Future studies are needed to assess the associations between other variant within this gene and PCa risk to suggest a putative mechanism for involvement of RORA in PCa. PMID- 30251752 TI - Mini-laparoscopic pyeloplasty in adults: Functional and cosmetic results. AB - PURPOSE: The study objective was to evaluate the safety and efficacy of mini laparoscopic pyeloplasty (mLP) in an adult population and to demonstrate the functional and cosmetic results. METHODS: Data for 29 patients (19 men and 10 women) undergoing mLP for ureteropelvic junction obstruction (UPJO) from May 2014 to December 2016 in Turkey were collected in this prospective study. Inclusion criteria were age ? 18 years, body mass index (BMI) ? 30 kg/m2 and primary UPJO, and no previous surgery on the affected kidney or previous abdominal surgery. Postoperative Visual Analogue Scale scores and the Patient Scar Assessment Questionnaire (PSAQ) were used. Demographic data, perioperative parameters, complications, and postoperative functional and cosmetic results were recorded. All statistical analyses were done by SPSS software. P value of <05 was considered statistically significant. RESULTS: Twenty-nine adults with a mean age of 29.4 +/- 10.2 years (19-38 years) were included. The patients' mean BMI was 22.4 +/- 4.3 kg/m2 (a range of 16-29 kg/m2). The procedures were performed using three ports (one 5 mm port for the camera and two 3 mm ports). Mean operative time was 119 +/- 28.5 minutes (85-144 minutes). Major complications were not observed, as per the Clavien-Dindo classification of surgical complications (grades IV-V). The mean VAS score was 1.2 +/- 0.2 points. Functional obstruction was reported in one patient on renal scintigraphy at 12 months postoperatively. The success rate of mLP was 97%. The minimum and maximum PSAQ scores at month 3 postoperatively were 24 and 86, respectively. All the patients were satisfied with the intervention and with their cosmetic results. CONCLUSION: mLP is a safe, effective and feasible treatment method for UPJO in adult patients. This treatment modality offers excellent cosmetic and functional results following treatment for UPJO. PMID- 30251753 TI - From eyes-closed to eyes-open: Role of cholinergic projections in EC-to-EO alpha reactivity revealed by combining EEG and MRI. AB - Alpha rhythm (8 to 12 Hz) observed in EEG over human posterior cortex is prominent during eyes-closed (EC) resting and attenuates during eyes-open (EO) resting. Research shows that the degree of EC-to-EO alpha blocking or alpha desynchronization, termed alpha reactivity here, is a neural marker of cognitive health. We tested the role of acetylcholine in EC-to-EO alpha reactivity by applying a multimodal neuroimaging approach to a cohort of young adults and a cohort of older adults. In the young cohort, simultaneous EEG-fMRI was recorded from twenty-one young adults during both EO and EC resting. In the older cohort, functional MRI was recorded from forty older adults during EO and EC resting, along with FLAIR and diffusion MRI. For a subset of twenty older adults, EEG was recorded during EO and EC resting in a separate session. In both young and older adults, functional connectivity between the basal nucleus of Meynert (BNM), the major source of cortical acetylcholine, and the visual cortex increased from EC to EO, and this connectivity increase was positively associated with alpha reactivity; namely, the stronger the BNM-visual cortex functional connectivity increase from EC to EO, the larger the EC-to-EO alpha desynchronization. In older adults, lesions of the fiber tracts linking BNM and visual cortex quantified by leukoaraiosis volume, associated with reduced alpha reactivity. These findings support a role of acetylcholine and particularly cholinergic pathways in mediating EC-to-EO alpha reactivity and suggest that impaired alpha reactivity could serve as a marker of the integrity of the cholinergic system. PMID- 30251754 TI - Association Development and Professional Transformation model for nurse leaders. AB - AIMS: This pilot study evaluated an Association Development and Professional Transformation (ADAPT) model for nursing leadership development and assessed satisfaction with the ADAPT workshop. BACKGROUND: Nurses often lack self confidence and self-efficacy in leadership roles. There is a need for nurses to take leadership opportunities that serve to advance the nursing profession. METHODS: A quasi-experimental pre-test post-test design was used. The sampling method selected professional nursing association (PNA) members. Novice participants completed a pre-assessment and post-assessment Leadership Practice Inventory-Self (LPI-S) survey and attended the ADAPT workshop. Experienced nurse leaders participated as mentors. Both groups completed a satisfaction survey after the workshop. RESULTS: Awareness of nursing leadership behaviours increased. Total mean scores for each subscale on the LPI-S increased but this was not statistically significant. All participants reported satisfaction with the ADAPT workshop. CONCLUSIONS: This study offers evidence that the ADAPT model influences leadership behaviours. The ADAPT workshop provided a method to gain a leadership perspective and to encourage nurses to fulfil a leadership role within professional nursing associations. IMPLICATIONS FOR NURSING MANAGEMENT: Organisations and professional nursing associations that support the leadership potential of nurses must invest in providing leadership development opportunities. PMID- 30251755 TI - Insufficient task-outcome association promotes task procrastination through a decrease of hippocampal-striatal interaction. AB - Theories on procrastination propose that associating tasks with higher valued incentive outcomes results in less task procrastination. However, it remains unknown how representation of incentive outcomes and task-outcome association are mediated by the human brain. Using event-related functional magnetic resonance imaging, we scanned human participants while they were thinking about both tasks and the incentive outcomes each task can yield in an unconstrained way. Results showed that tasks that are more likely to be procrastinated are associated with less value in incentive outcomes. Interestingly, procrastination was more likely if it was more difficult for participants to associate a task with its valued incentives when thinking about the task (i.e., the decreased task-outcome association). On the neural level, higher value of rewarding outcomes was correlated with increased putamen activations, which further negatively predicted task procrastination. On the other hand, when participants were associating tasks with the incentive outcomes, the decreasing task-outcome association corresponded to decreasing activation in putamen, and a decreasing hippocampus-putamen coupling which further mediated the effect of the insufficient task-outcome association on procrastination. In particular, the current findings show that procrastination is more likely when people are less able to associate tasks with highly valued incentives, which is accompanied by reduced hippocampal-striatal interactions during task construction. PMID- 30251756 TI - Establishing a multidisciplinary day-care surgery department: Challenges for nursing management. AB - AIM: To increase our understanding of challenges in implementing multidisciplinary organisational models in hospitals. BACKGROUND: Health-service policies internationally are pushing for multidisciplinary and patient-centred organising models but there are challenges involved in moving from profession- and discipline-based organising to the new solutions. METHOD: Qualitative case study, interview and document data collected in real time following the implementation process. RESULTS: It was possible to argue for and against the new department applying either a business-like logic or a professional logic. The respective logics gave different prescriptions for how a hospital department should be organised. CONCLUSION AND IMPLICATIONS FOR NURSING MANAGEMENT: The institutional logics perspective enables managers to understand resistance to new ways of organising work and may be useful in trying to foresee and handle challenges in implementing new organisation models. Managers need to analyse models carefully in terms of which parts may be seen as problematic in their own organisation, and invite all relevant stakeholders into participatory change processes. If the goal is to gather multiple professions and disciplines under one manager in order to increase patient centredness, arrangements must be made for professionals to stay connected to the wider community of practice centred around their specialized knowledge and skills. PMID- 30251757 TI - Inside bilingualism: Language background modulates selective attention to a talker's mouth. AB - Previous findings indicate that bilingual Catalan/Spanish-learning infants attend more to the highly salient audiovisual redundancy cues normally available in a talker's mouth than do monolingual infants. Presumably, greater attention to such cues renders the challenge of learning two languages easier. Spanish and Catalan are, however, rhythmically and phonologically close languages. This raises the possibility that bilinguals only rely on redundant audiovisual cues when their languages are close. To test this possibility, we exposed 15-month-old and 4- to 6-year-old close-language bilinguals (Spanish/Catalan) and distant-language bilinguals (Spanish/"other") to videos of a talker uttering Spanish or Catalan (native) and English (non-native) monologues and recorded eye-gaze to the talker's eyes and mouth. At both ages, the close-language bilinguals attended more to the talker's mouth than the distant-language bilinguals. This indicates that language proximity modulates selective attention to a talker's mouth during early childhood and suggests that reliance on the greater salience of audiovisual speech cues depends on the difficulty of the speech-processing task. PMID- 30251758 TI - Resting state functional connectivity of networks associated with reward and habit in anorexia nervosa. AB - Neurobiological disturbances associated with reward and/or habit learning are theorized to maintain symptoms of anorexia nervosa (AN). Although research has investigated responses in brain regions associated with reward and habit to disorder-specific cues (e.g., food) and presumed rewards (e.g., money), little is known about the functional organization of the circuits underlying these constructs independent of stimulus. This study aimed to provide initial data on the synchrony of networks associated with reward and habit in AN by comparing resting-state functional connectivity (RSFC) patterns between AN and healthy control (HC) participants in these circuits and delineating how these patterns relate to symptoms. Using theoretically selected seeds in the nucleus accumbens (NAcc), ventral caudate, and dorsal caudate, reflecting a continuum from reward- to habit- oriented regions, RSFC patterns were compared between AN restricting subtype (n = 19) and HC (n = 19) participants (cluster threshold: p < .01). Exploratory correlations between RSFC z-scores and Eating Disorder Examination (EDE) scores, BMI, and illness duration were conducted. The AN group demonstrated lower RSFC between the NAcc and superior frontal gyrus, between the ventral caudate and frontal and posterior regions, and between the dorsal caudate and frontal, temporal, and posterior regions. In the AN group, lower NAcc- superior frontal gyrus RSFC correlated with greater EDE Global scores (r = -.58, CI: -.83, -.13). These resting-state synchrony disruptions of the ventral and dorsal frontostriatal circuits, considered in context of the broader literature, support the utility of further investigating possible reward and habit disturbances supporting symptoms in AN. PMID- 30251759 TI - Individual and combined toxicity of T-2 toxin and deoxynivalenol on human C-28/I2 and rat primary chondrocytes. AB - Deoxynivalenol (DON) and T-2 toxin are prevalent mycotoxin contaminants in the food and feed stuffs worldwide, with non-negligible co-contamination and co exposure conditions. Meanwhile, they are considerable risk factors for Kashin Beck disease, a chronic endemic osteochondropathy. The aim of this study was to investigate the individual and combined cytotoxicity of DON and T-2 toxin on proliferating human C-28/I2 and newborn rat primary costal chondrocytes by MTT assay. Four molar concentration combination ratios of DON and T-2 toxin were used, 1:1 for R1 mixture, 10:1 for R10, 100:1 for R100 and 1000:1 for R1000. The toxicological interactions were quantified by the MixLow method. DON, T-2 toxin, and their mixtures all showed a clear dose-dependent toxicity for chondrocytes. The cytotoxicity of T-2 toxin was 285-fold higher than DON was in human chondrocytes, and 22-fold higher in the rat chondrocytes. The combination of DON and T-2 toxin was significantly synergistic at middle and high level concentrations of R10 mixtures in rat chondrocytes, but significantly antagonistic at the low concentrations of R100 mixtures in both cells and at the middle concentrations of R1000 mixtures in rat chondrocytes. These results indicated that the combined toxicity was influenced by the cell sensitivity for toxins, the difference between the combination ratio and equitoxic ratio, the concentrations and other factors. PMID- 30251760 TI - Functional connectivity with cortical depth assessed by resting state fMRI of subregions of S1 in squirrel monkeys. AB - Whereas resting state blood oxygenation-level dependent (BOLD) functional MRI has been widely used to assess functional connectivity between cortical regions, the laminar specificity of such measures is poorly understood. This study aims to determine: (a) whether the resting state functional connectivity (rsFC) between two functionally related cortical regions varies with cortical depth, (b) the relationship between layer-resolved tactile stimulus-evoked activation pattern and interlayer rsFC pattern between two functionally distinct but related somatosensory areas 3b and 1, and (c) the effects of spatial resolution on rsFC measures. We examined the interlayer rsFC between areas 3b and 1 of squirrel monkeys under anesthesia using tactile stimulus-driven and resting state BOLD acquisitions at submillimeter resolution. Consistent with previous observations in the areas 3b and 1, we detected robust stimulus-evoked BOLD activations with foci were confined mainly to the upper layers (centered at 21% of the cortical depth). By carefully placing seeds in upper, middle, and lower layers of areas 3b and 1, we observed strong rsFC between upper and middle layers of these two areas. The layer-resolved activation patterns in areas 3b and 1 agree with their interlayer rsFC patterns, and are consistent with the known anatomical connections between layers. In summary, using BOLD rsFC pattern, we identified an interlayer interareal microcircuit that shows strong intrinsic functional connections between upper and middle layer areas 3b and 1. RsFC can be used as a robust invasive tool to probe interlayer corticocortical microcircuits. PMID- 30251761 TI - White matter connectivity reductions in the pre-clinical continuum of psychosis: A connectome study. AB - Widespread white matter connectivity disruptions have commonly been reported in schizophrenia. However, it is questionable whether structural connectivity decline is specifically associated with schizophrenia or whether it extends along a continuum of psychosis into the healthy population. Elucidating brain structure changes associated with psychotic-like experiences in healthy individuals is insofar important as it is a necessary first step towards our understanding of brain pathology preceding florid psychosis. High resolution, multishell diffusion weighted magnetic resonance images (MRI) were acquired from 89 healthy individuals. Whole-brain white matter fibre tracking was performed to quantify the strength of white matter connections. Network-based statistics were applied to white matter connections in a regression model in order to test for a linear relationship between streamline count and psychotic-like experiences. A significant subnetwork was identified whereby streamline count declined with increasing psychotic-like experiences. This network of structural connectivity reductions affected all cortical lobes, subcortical structures and the cerebellum and spanned along prominent association and commissural white matter pathways. A widespread network of linearly declining connectivity strength with increasing number of psychotic-like experiences was identified in healthy individuals. This finding is in line with white matter connectivity reductions reported from early to chronic stages of schizophrenia and might therefore aid the development of tools to identify individuals at risk of transitioning to psychosis. PMID- 30251762 TI - Self-emulsifying drug delivery systems and cationic surfactants: do they potentiate each other in cytotoxicity? AB - OBJECTIVES: The aim of this study was to evaluate the cytotoxicity of self emulsifying drug delivery systems (SEDDS) containing five different cationic surfactants. METHODS: Cationic surfactants were added in a concentration of 1% and 5% (m/m) to SEDDS comprising 30% Capmul MCM, 30% Captex 355, 30% Cremophor EL and 10% propylene glycol. The resulting formulations were characterized in terms of size, zeta potential, in-vitro haemolytic activity and toxicity on Caco-2 via MTT assay and lactate dehydrogenase release assay. KEY FINDINGS: The evaluated surfactants had in both concentrations a minor impact on the size of SEDDS ranging from 30.2 +/- 0.6 to 55.4 +/- 1.1 nm, whereas zeta potential changed significantly from -9.0 +/- 0.3 to +28.8 +/- 1.6 mV. The overall cytotoxicity of cationic surfactants followed the rank order: hexadecylpyridinium chloride > benzalkonium chloride > alkyltrimethylammonium bromide > octylamine > 1-decyl-3 methylimidazolium. The haemolytic activity of the combination of cationic surfactants and SEDDS on human red blood cells was synergistic. Furthermore, cationic SEDDS exhibited higher cytotoxicity of Caco-2 cells compared to SEDDS without cationic surfactants. CONCLUSIONS: According to these results, SEDDS and cationic surfactants seem to bear an additive up to synergistic toxic risk. PMID- 30251763 TI - Parsing brain structural heterogeneity in males with autism spectrum disorder reveals distinct clinical subtypes. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder with considerable neuroanatomical heterogeneity. Thus, how and to what extent the brains of individuals with ASD differ from each other is still unclear. In this study, brain structural MRI data from 356 right-handed, male subjects with ASD and 403 right-handed male healthy controls were selected from the Autism Brain Image Data Exchange database (age range 5-35 years old). Voxel-based morphometry preprocessing steps were conducted to compute the gray matter volume maps for each subject. Individual neuroanatomical difference patterns for each ASD individual were calculated. A data-driven clustering method was next utilized to stratify individuals with ASD into several subtypes. Whole-brain functional connectivity and clinical severity were compared among individuals within the ASD subtypes identified. A searchlight analysis was applied to determine whether subtyping ASD could improve the classification accuracy between ASD and healthy controls. Three ASD subtypes with distinct neuroanatomical difference patterns were revealed. Different degrees of clinical severity and atypical brain functional connectivity patterns were observed among these three subtypes. By dividing ASD into three subtypes, the classification accuracy between subjects of two out of the three subtypes and healthy controls was improved. The current study confirms that ASD is not a disorder with a uniform neuroanatomical signature. Understanding neuroanatomical heterogeneity in ASD could help to explain divergent patterns of clinical severity and outcomes. PMID- 30251764 TI - Analysis of the Nature and Frequency of Domestic Transplant Tourism in the United States. PMID- 30251765 TI - The effects of individualised intermittent theta burst stimulation in the prefrontal cortex: A TMS-EEG study. AB - Recent studies have highlighted variability in response to theta burst stimulation (TBS) in humans. TBS paradigm was originally developed in rodents to mimic gamma bursts coupled with theta rhythms, and was shown to elicit long-term potentiation. The protocol was subsequently adapted for humans using standardised frequencies of stimulation. However, each individual has different rhythmic firing pattern. The present study sought to explore whether individualised intermittent TBS (Ind iTBS) could outperform the effects of two other iTBS variants. Twenty healthy volunteers received iTBS over left prefrontal cortex using 30 Hz at 6 Hz, 50 Hz at 5 Hz, or individualised frequency in separate sessions. Ind iTBS was determined using theta-gamma coupling during the 3-back task. Concurrent use of transcranial magnetic stimulation and electroencephalography (TMS-EEG) was used to track changes in cortical plasticity. We also utilised mood ratings using a visual analogue scale and assessed working memory via the 3-back task before and after stimulation. No group-level effect was observed following either 30 or 50 Hz iTBS in TMS-EEG. Ind iTBS significantly increased the amplitude of the TMS-evoked P60, and decreased N100 and P200 amplitudes. A significant positive correlation between neurophysiological change and change in mood rating was also observed. Improved accuracy in the 3-back task was observed following both 50 Hz and Ind iTBS conditions. These findings highlight the critical importance of frequency in the parameter space of iTBS. Tailored stimulation parameters appear more efficacious than standard paradigms in neurophysiological and mood changes. This novel approach presents a promising option and benefits may extend to clinical applications. PMID- 30251766 TI - Reward-related regions form a preferentially coupled system at rest. AB - Neuroimaging studies have implicated a set of striatal and orbitofrontal cortex (OFC) regions that are commonly activated during reward processing tasks. Resting state functional connectivity (RSFC) studies have demonstrated that the human brain is organized into several functional systems that show strong temporal coherence in the absence of goal-directed tasks. Here we use seed-based and graph theory RSFC approaches to characterize the systems-level organization of putative reward regions of at rest. Peaks of connectivity from seed-based RSFC patterns for the nucleus accumbens (NAcc) and orbitofrontal cortex (OFC) were used to identify candidate reward regions which were merged with a previously used set of regions (Power et al., 2011). Graph-theory was then used to determine system level membership for all regions. Several regions previously implicated in reward processing (NAcc, lateral and medial OFC, and ventromedial prefrontal cortex) comprised a distinct, preferentially coupled system. This RSFC system is stable across a range of connectivity thresholds and shares strong overlap with meta analyses of task-based reward studies. This reward system shares between-system connectivity with systems implicated in cognitive control and self-regulation, including the fronto-parietal, cingulo-opercular, and default systems. Differences may exist in the pathways through which control systems interact with reward system components. Whereas NAcc is functionally connected to cingulo opercular and default systems, OFC regions show stronger connectivity with the fronto-parietal system. We propose that future work may be able to interrogate group or individual differences in connectivity profiles using the regions delineated in this work to explore potential relationships to appetitive behaviors, self-regulation failure, and addiction. PMID- 30251767 TI - Potential immunomodulatory and antioxidant effects of walnut Juglans regia vegetable oil against lead-mediated hepatic damage and their interaction with lipase activity in rats. AB - Environmental pollutants, particularly lead, pose a serious threat to human and animal health that causes disturbances of several functions, including hepatotoxicity. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries remains a challenge. This study was carried out to investigate the protective efficacy of Juglans regia vegetable oil (JRVO) against the hepatotoxicity induced by lead. To achieve this aim, adults male rats were treated for 10 days with Pb (0.344 g/kg bw) associated or not with JRVO (0.9 g/kg bw). The rats intoxicated by lead exhibited oxidative stress determined by TBARS, protein carbonyls, liver tumor necrosis factor-alpha (TNF alpha), caspase-3, and antioxidant status: SOD, CAT, GPx, and GSH. Administration of lead increased the levels of plasma hepatic markers (AST, ALT, LDH) and bilirubin, the lipid profiles (total cholesterol, triglycerides, VLDL-Ch, LDL-Ch levels, TBARS, NOx, and PCO), the plasmatic lipase activity and the inflammatory markers, while the plasmatic ALP decreased. Coadministration of JRVO restored all the hepatic markers, the lipid profiles and the antioxidants to near-normal values and lowered the plasmatic lipase activity as well as the elevated thiobarbituric acid reactive substances. Hepatic histological studies confirmed the beneficial role of JRVO through the amelioration of all biochemical parameters. Our results suggest that Juglans regia vegetable oil contains promising substances to counteract the lead intoxication and may be efficient in the prevention of hepatotoxicity complications. PMID- 30251768 TI - White matter network connectivity deficits in developmental dyslexia. AB - A number of studies have shown an abnormal connectivity of certain white matter pathways in developmental dyslexia, as well as correlations between these white matter pathways and behavioral deficits. However, whether developmental dyslexia presents broader white matter network connectivity disruption is currently unknown. The present study reconstructed white matter networks for 26 dyslexic children (11.61 +/- 1.31 years) and 31 age-matched controls (11.49 +/- 1.36 years) using constrained spherical deconvolution tractography. Network-based statistics (NBS) analysis was performed to identify network connectivity deficits in dyslexic individuals. Network topological features were measured based on graph theory to examine whether these parameters correlate with literacy skills, and whether they explain additional variance over previously established white matter connectivity abnormalities in dyslexic children. The NBS analysis identified a network connecting the left-occipital-temporal cortex and temporo parietal cortex that had decreased streamlines in dyslexic children. Four network topological parameters (clustering coefficient, local efficiency, transitivity, and global efficiency) were positively correlated with literacy skills of dyslexic children, and explained a substantial proportion of additional variance in literacy skills beyond connectivity measures of white matter pathways. This study for the first time reports a disconnection in a local subnetwork in the left hemisphere in dyslexia and shows that the global white matter network topological properties contribute to reduced literacy skills in dyslexic children. PMID- 30251769 TI - Propamocarb exposure decreases the secretion of neurotransmitters and causes behavioral impairments in mice. AB - Propamocarb (PM) is a type of fungicide, which is widely used in the greenhouse based production of vegetables and fruits globally. It has been considered to have generally low toxicity. However, the teratogenicity or neurotoxicity for mammals remains unclear. In this study, we aimed to explore its effect on the secretion of neurotransmitters and behavioral impairments. Male adult mice were exposed to 10 and 40 mg/L PM for 2 weeks (acute exposure) or 3 and 10 mg/L PM for 10 weeks (chronic exposure). It was observed that acute or chronic exposure to PM changed the levels of serotonin (5-HT) and dopamine in the serum and colon and the transcription of TPH2 and DRD2 in the colons of mice. In addition, the locomotor test, the open field test, and the Morris water maze analysis also showed that acute exposure to PM caused behavioral impairments to some extent. The results obtained in the present study indicated that PM has the potential to induce neurotoxicity in animals. PMID- 30251770 TI - Vitamin D deficiency is associated with reduced hippocampal volume and disrupted structural connectivity in patients with mild cognitive impairment. AB - Vitamin D deficiency may exacerbate adverse neurocognitive outcomes in the progression of diseases such as Parkinson's, Alzheimer's, and other dementias. Mild cognitive impairment (MCI) is prodromal for these neurocognitive disorders and neuroimaging studies suggest that, in the elderly, this cognitive impairment is associated with a reduction in hippocampal volume and white matter structural integrity. To test whether vitamin D is associated with neuroanatomical correlates of MCI, we analyzed an existing structural and diffusion MRI dataset of elderly patients with MCI. Based on serum 25-OHD levels, patients were categorized into serum 25-OHD deficient (<12 ng/mL, n = 27) or not-deficient (>12 ng/mL, n = 29). Freesurfer 6.0 was used to parcellate the whole brain into 164 structures and segment the hippocampal subfields. Whole-brain structural connectomes were generated using probabilistic tractography with MRtrix. The network-based statistic (NBS) was used to identify subnetworks of connections that significantly differed between the groups. We found a significant reduction in total hippocampal volume in the serum 25-OHD deficient group especially in the CA1, molecular layer, dentate gyrus, and fimbria. We observed a connection deficit in 13 regions with the right hippocampus at the center of the disrupted network. Our results demonstrate that low vitamin D is associated with reduced volumes of hippocampal subfields and connection deficits in elderly people with MCI, which may exacerbate neurocognitive outcomes. Longitudinal studies are now required to determine if vitamin D can serve as a biomarker for Alzheimer's disease and if intervention can prevent the progression from MCI to major cognitive disorders. PMID- 30251771 TI - Cortical and subcortical areas involved in the regulation of reach movement speed in the human brain: An fMRI study. AB - Reach movements are characterized by multiple kinematic variables that can change with age or due to medical conditions such as movement disorders. While the neural control of reach direction is well investigated, the elements of the neural network regulating speed (the nondirectional component of velocity) remain uncertain. Here, we used a custom made magnetic resonance (MR)-compatible arm movement tracking system to capture the real kinematics of the arm movements while measuring brain activation with functional magnetic resonance imaging to reveal areas in the human brain in which BOLD-activation covaries with the speed of arm movements. We found significant activation in multiple cortical and subcortical brain regions positively correlated with endpoint (wrist) speed (speed-related activation), including contralateral premotor cortex (PMC), supplementary motor area (SMA), thalamus (putative VL/VA nuclei), and bilateral putamen. The hand and arm regions of primary sensorimotor cortex (SMC) and a posterior region of thalamus were significantly activated by reach movements but showed a more binary response characteristics (movement present or absent) than with continuously varying speed. Moreover, a subregion of contralateral SMA also showed binary movement activation but no speed-related BOLD-activation. Effect size analysis revealed bilateral putamen as the most speed-specific region among the speed-related clusters whereas primary SMC showed the strongest specificity for movement versus non-movement discrimination, independent of speed variations. The results reveal a network of multiple cortical and subcortical brain regions that are involved in speed regulation among which putamen, anterior thalamus, and PMC show highest specificity to speed, suggesting a basal-ganglia-thalamo cortical loop for speed regulation. PMID- 30251772 TI - Involvement of P38 and ERK1/2 in mitochondrial pathways independent cell apoptosis in oviduct magnum epithelial cells of layers challenged with vanadium. AB - Vanadium (V) can induce cell apoptosis in layers' oviduct resulting in egg quality reduction. In this study, we investigated the relationship between the mitogen-activated protein kinase (MAPK)-signaling pathway and V-induced apoptosis in poultry oviduct magnum epithelial cells (OMECs). Cultured OMECs were divided into 8 treatment groups: 0 MUmol/L V (control), 100 MUmol/L V (V100), V100 + P38MAPK inhibitor (SB203580), SB203580, V100 + extracellular signal-regulated kinases 1 and 2 (ERK1/2) inhibitor (U0126), U0126, V100 + c-JUN NH2 -terminal kinase (JNK) inhibitor (SP600125), and SP600125. The OMECs were pretreated with the MAPK inhibitors before their treatment with V100 for 12 h. V100 increased the apoptosis of OMECs (P < .05), while 3 MAPK inhibitors suppressed V100-induced apoptosis P < .05); V100 enhanced the depolarization of ?psim (P < .05), and SB203580 and U0126 alleviated the V100-induced ?psim decrease (P < .05); V100 downregulated B-cell lymphoma-2 (Bcl-2) and poly [Adenosine diphosphate ribose] polymerase 1 (PARP1) mRNA expression (P < .05), meanwhile it upregulated Bcl-2 associated x (Bax), Apaf1, cytochrome C (CytC) and cysteine aspartase (caspase) 3, 8, 9 mRNA expression (P < .05). All MAPKs inhibitors alleviated the up regulation of V100 for Bax and caspase 3 mRNA expression and down-regulation of V100 for Bcl-2 expression (P < .05). SB203580 and U0126 upregulated CytC expression treated by V100 (P < .05), except SP600125, while SB203580 administration resulted in a similar upregulation of PARP1 expression (P < .05). SP600125 can alleviated V triggered p-P38MAPK (phosphor-P38), p-ERK1/2 (phosphor ERK1/2), p-JNK (phosphor-JNK) increase on OME cells, and SB203580 and U0126 had a similar response to phosphor-P38 and p-JNK (P < .05). It concluded that V-induced apoptosis in OMECs through the activation of P38 and ERK1/2, and by increasing the ratio of Bax/Bcl-2, which resulted in ?psim decrease, CytC release into the cytosol; consequently caspase 3 is recruited and activated, PARP1 is cleaved, eventually leading to apoptosis. PMID- 30251773 TI - Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes. AB - AIMS: Klotho interacts with various membrane proteins, such as receptors for transforming growth factor (TGF)-beta and insulin-like growth factor (IGF), to alter their function. Renal expression of klotho is diminished in diabetes. The present study examined whether exogenous klotho protein supplementation ameliorates kidney injury and renin-angiotensin system (RAS) in db/db mice. METHODS: We investigated the effects of klotho supplementation on diabetic kidney injury and RAS. Recombinant human klotho protein (10 MUg/kg/d) was administered to db/db mice daily. RESULTS: Klotho protein supplementation reduced kidney weight, systolic blood pressure (SBP), albuminuria, glomerular filtration rate, and 8-epi-prostaglandin F2alpha excretion without affecting body weight. Although klotho supplementation did not alter glycated albumin, it reduced renal angiotensin II levels associated with reduced renal expression of angiotensinogen. Klotho supplementation improved renal expression of superoxide dismutase (SOD), and endogenous renal expression of klotho. Klotho supplementation reduced the levels of hypoxia-inducible factor, phosphorylated Akt, and phosphorylated mTOR and decreased the renal expression of TGF-beta, tumour necrosis factor (TNF), and fibronectin. CONCLUSIONS: These data indicate that klotho supplementation reduces blood pressure and albuminuria along with ameliorating renal RAS activation in db/db mice. Furthermore, these results suggest that klotho inhibits IGF signalling, induces SOD expression to reduce oxidative stress, and suppresses Akt-mTOR signalling to inhibit abnormal kidney growth. Collectively, the results suggest that klotho inhibits TGF-beta and TNF signalling, resulting in a decline in renal fibrosis. PMID- 30251774 TI - Family with premature cardiovascular aging: Lesser's Syndrome. PMID- 30251775 TI - Medical professionalism and transgender patients. PMID- 30251776 TI - Making sense of the MACRA final rule. PMID- 30251777 TI - Addressing abnormal test results in your practice. PMID- 30251778 TI - Somewhere over the rainbow. PMID- 30251779 TI - The future is now when it comes to the Medicare QPP. PMID- 30251780 TI - Therapy for drug refractory hypertrophic cardiomyopathy. PMID- 30251781 TI - The long ER stay. PMID- 30251782 TI - Improving radiographic image quality in primary care. PMID- 30251783 TI - Physician-patient relationships outside the office. PMID- 30251784 TI - The history of the FSMB. PMID- 30251785 TI - Making sense of the MACRA final rule. PMID- 30251787 TI - Changes in the Composition and Physiological and Biochemical Properties of Fungi during Passage through the Digestive Tract of Earthworms. AB - It was established that the biomass of fungal mycelium decreased by 30-50% during passage through the in- testine of the Aporrectodea caliginosa and Lumbricus terrestris earthworms, while its content in empty intes- tines was 40-60% less than in the soil. It was found that the amount of mycelium increases again in three-day-old coprolites due to the rapid growth of the species. It was demonstrated that the physiological activity of fungi (estimated according to the time of the appearance of colonies on the medium and probability of propagation) is lower in the intestine content, digestive tract, and fresh excrement of the worms than in the soil. It was noted that the activity and diversity of organic substrates (utilized by fungi), as well as proteolytic activity is lower in fungal isolates from the intestine than from the soil. It was registered that the death of a part of the fungi occurs in the worm intestine, while the physiological state changes in the animals withstanding the effect of the digestive medium. PMID- 30251786 TI - Some Characteristics of Transgenic Clones of Mouse R1 Line Embryonic Stem Cells. AB - Transgenic clones of mouse embryonic stem cells of the RI line were -received by transfection of plasmid linear vectors. The changes in the transgene structure during its integration into the genome of the target cells were investigated. Displacements were found on the flanks of the integrated transgene. It was found that multicopy tandem structures are formed in head- -tail orientation at the transgene integration. It was noted that the number of copies of the integrated transgenes varies considerably, but the introduction of DNA fragments from the nuclear shells into the flanks of the transgene normalizes the number of its copies. PMID- 30251788 TI - Pine Wilt Disease and Possible Causes of Its Incidence in Russia. AB - Surveys of forests and stockpiled timber of pine, spruce, larch, and silver fir in 14 administrative subjects of the Russian Federation revealed widespread occurrence of the coniferous wood parasitic nematode Bursaphelenchus mucronatus. Twenty species of bacteria belonging to 13 genera have been detected in 25 B. mucronatus isolates, and their identity has been determined by direct sequencing of the 16S- RNA gene. The most frequently occurring were bacteria from the genera Pseudomonas, -Stenotrophomonas, Pantoea, Bacillus, Burkholderia, and Serratia. Prevalence of Pseudomonas brenneri and P. fluorescence, which were also found in the nematode dauer larva (Liv) isolated from the fir sawyer beetle Monochamus urussovi, have also been assessed. Two nematode B. xylophilus isolates from Portugal and one isolate from the United States have been examined, and 10 symbiotic bacteria species have been isolated, including Agrobacterium tumefacience, P.fluorescens, P. brenneri, Rahnella aquatilis, Stenotrophomonas maltophilia, S. rhizophila, and Yersinia mollaretfi. PMID- 30251789 TI - Primary Plant Successions of Forest Belt Vegetation on the Tolbachinskii Dol Volcanic Plateau (Kamchatka). AB - Primary plant successions on volcanic deposits of the Tolbachinskii DoI Plateau (Central Kamchatka) were studied. The main factors determining the succession rate were revealed. The peculiarities of plant successions on lava flows and ash scoria deposits differed significantly. Some common mechanisms for all volcanic regions of the world were revealed. The leading factors of plant succession on lava flows were the type of lava surface, the texture of lava, and the fine tephra accumulation rate. The main factors determining plant succession on ash scoria deposits were wind and water erosion and the distance to the seed sources. The time of formation of a secondary permanent larch (Larix cajanderi Mayr.) forest should take about 1500-2000 years on lava flows and up to 1000 years (but not less than 300-500 years) on ash-scoria plains. PMID- 30251790 TI - Orosensory Food Testing in Fish: Chronology of Behavior. AB - The orosensory food testing behavior in fish was studied using the nine-spined stickleback Pungitiuspungitius as an example. The patterns of the chronology of manipulations performed by fish in testing food objects were identified. The existence of two stereotypical patterns of feeding behavior was confirmed, and their new characteristics were obtained. The relationship between the responsiveness to food and the predisposition of fish to feeding was revealed. PMID- 30251791 TI - Diphyllobothrium dendriticum (Cestoda: Diphyllobothriidae) in the Intestinal Tract of the Herring Gull Larus argentatus: Localization and Trophic Parameters. AB - We studied the activities both of digestive enzymes in the small intestine of the herring gull (Larus argentatus) and a tapeworm Diphyllobothrium dendriticum (Cestoda: Diphyllobothriidae) residing in the intestine. It was found that D. dendriticum infects the medial section of the small intestine of the herring gull. Such localization of D. dendriticum is caused by the maximal activity of proteases and glycosidases and by the high rate of membrane and cavitary digestion in this section. The activity of protease and glycosidase in gulls infected with D. dendriticum is decreased. The activity of proteases in the fractions desorbed from the tegument surface of D. dendriticum is significantly higher than that of glycosidases. PMID- 30251792 TI - Mitotypical Peculiarities of the Population of Moose Alces alces of Southeastern West Siberia. AB - Based on the structure of the D-loop control region of mitochondrial DNA, the genetic diversity of moose of West Siberia was evaluated and their placement within the structure of current species population was determined. It was noted that the values of genetic diversity exceed the values of analogous indices obtained for western groups of the species. Three haplogroups were identified in the population structure: European- Ural, West Siberian, and American. PMID- 30251793 TI - Seasonal Changes in Blood Cells and Biochemical Parameters in the Mongolian Hamster (Allocricetulus curtatus). AB - It was shown previously that the Mongolian hamster (Allocricetulus curtatus) is a mammalian species with irregular short hibernation. The purpose of the present study was to determine how this status affects seasonal changes in the biochemical and hematological parameters in A. curtatus males under a natural temperature and light regime. It was found that a reduction in circulating white blood cells, specifically lymphocytes, neutrophils, eosinophils, basophils, and monocytes, occurred in-winter. and bilirubin levels increased in spring. These characteristics make Mongolian hamsters closer to the true hibernating species. At the same time, the character of seasonal changes in the number of red blood cells, glucose, total protein, creatinine, and albumin is closer to species with torpor. PMID- 30251794 TI - The Effect of Commercial Cuttings on Faunal Associations in Taiga Ecosystems: A Case Study of Small Mammals in Eastern Fennoscandia. AB - The general patterns of the effect of cuttings on the habitat structure, abundance, territorial distribution, and specific ecological features of 11 small mammalian species are analyzed based on long-term studies (1958-2013) covering the overall area of eastern Fennoscandia. The responses to concentrated cuttings common for most of the examined species include a decrease in total population size, transition to an- arrhythmic population dynamics with drastic short-term rises and deep long depressions, formation of unstable mosaic spatial distribution, disturbances of the reproduction rates, and a decrease in reproduction intensity. PMID- 30251795 TI - Irregularity of the Linear Growth of the Margaritifera margaritifera (Bivalvia: Margaritiferidae) Population of the Nemina River, Karelia. AB - The dependence of shell growth in length and height during ontogeny has been studied in the pearl mussel Margaritifera margaritifera inhabiting the Nemina River (basin of Lake Onega, Karelia). It has been shown that the population is heterogenous based on the height-to-length ratio. It has been found that during ontogeny M. margaritifera from the studied population undergoes a constant change in the relative growth of the shell leading to either lengthening or rounding of the shell. PMID- 30251796 TI - Suppression of Histamine-Induced Relaxation of Rat Aorta and Calcium Signaling in Endothelial Cells by Two-Pore Channel Blocker trans-NED19 and Hydrogen Peroxide. AB - The blocker of two-pore channels trans-NED 19 and hydrogen peroxide were found to inhibit histamine-induced relaxation of rat-aorta. The degree of inhibition depended on histamine concentration. The relaxation in response to I MUM histamine of rat aorta preconstricted with 30 mM KCI, serotonin, or endothelin- 1, was completely abolished by 30 MUM trans-NED 19. On the other hand, trans-NED 19 decreased the relaxation of the aorta in the presence of 10 MUM histamine only by 2.1-fold to 2.4-fold, and there was almost no inhibition by trans-NED 19 of the relaxationinduced by 100 ptM histamine.) Relaxation of precontracted with serotonin aorta in response to 10 and 100 MUM histamine was reduced by hydrogen peroxide (200 M) by 10- and 2.5-fold, respectively. Suppression of aorta relaxation by trans-NED 19 and H202 correlated with their inhibitory effect on the histamine-induced increase in the cytoplasmic free calcium concentration in human umbilical vein endothelial cells. With the use of a fluorescent probe LysoTracker, the cis-NED19 binding sites were demonstrated to be localized in endolysosomes of the endothelial cells. These data indicate that two-pore calcium channels participate in the histamine-induced endothelium-dependent relaxation of rat aorta. Furthermore, their functional role is exhibited much more clearly at low histamine concentrations. We suggest that hydrogen peroxide evokes depletion of intracellular calcium depots thereby suppressing the response to histamine. PMID- 30251797 TI - The Diversity of Parasites in the Chinese Sleeper Perccottus glenii Dybowski 1877 (Actinopterygii: Perciformes) under the Conditions of Large-Scale Range Expansion. AB - It has been found that the species composition of parasites infesting the Chinese sleeper Perccottus glenii in water bodies from the nonnative part of its range is more depleted. Here, the phylogenetic distances between parasites exceed those in the native part of the range. It has been revealed that parasitological differences between P. glenii populations from the nonnative and native parts of the range, as well as between populations inside the nonnative part, have similar composition and abundance of the host-specific and euryxenous components in the parasitic fauna. It has been shown that these differences are determined by the genesis of sites from which P. glenii is introduced, as well as the local conditions of the recipient water bodies. PMID- 30251798 TI - President's Update. PMID- 30251799 TI - 4 Ways to Leverage Email in Your Practice's Marketing. PMID- 30251800 TI - Growth Driven Design. PMID- 30251801 TI - Alpha-tocopherol promotes metabolic activity and cell migration in human primary keratinocytes and fibroblasts from skin cancer patients. PMID- 30251802 TI - Behavioural and demographic factors associated with occurrence of non-melanoma skin cancer in organ transplant recipients. AB - BACKGROUND: Non-melanoma skin cancers (NMSC) are the most common epithelial malignancies in organ transplantation recipients (OTRs). In Italy, incidence rates of post- transplantation NMSC are approximately 5% after 5 years and 10% after 10 years since organ transplantation. The objective was to describe risk factors associated with NMSC in a cohort of renal and liver transplant recipients, in a single-center longitudinal study. METHODS: Renal and liver transplant patients, who underwent transplantation between June 1985 and December 2015, were visited for the first time or followed-up in a dedicated outpatient clinic every six months until July 2016. RESULTS: We included 356 renal and 76 liver transplant patients. 108 OTRs (25.6%) presented 299 NMSC. 74 patients developed actinic keratosis (17.1%), 36 patients squamous cell carcinoma (8.5%), and 52 patients basal cell carcinoma (12.3%). Time from transplantation and kidney transplant were the main risk factors for NMSC. Higher incidences of all NMSC were observed in patients >60 years, males and smokers, while decreased incidences were detected in individuals with higher educational levels. Multiple logistic regression models confirmed that male gender (RR 3.3, P=0.001), cigarette smoking (RR 2.0, P=0.026), light eye color (RR 2.9, P=0.001), and family history of cancer (RR 1.8, P=0.042) were independently associated with NMSC. CONCLUSIONS: Dermatological follow-up is important in OTRs, due to the higher risk of tumors and mainly NMSC. Clinical and environmental factors, including cigarette smoking, are useful in characterizing OTR with higher risk of NMSC. PMID- 30251803 TI - Psoriatic arthritis onset in psoriatic patients receiving UV phototherapy in Italy. AB - BACKGROUND: Psoriasis is a chronic, recurrent, and immune-mediated inflammatory disease that affects 2-3% of the world population. A substantial proportion of patients with psoriasis, approximately 40 %, develop a form of inflammatory arthritis known as psoriatic arthritis (PsA), the arthritis follows the development of psoriasis, and it will develop simultaneously or possibly before the appearance of skin lesions. The presence of PsA indicates a need for more active intervention rather than purely topical therapies or UV-based therapies. The aim of this multicenter, retrospective, epidemiological study was to estimate the incidence of PsA in psoriatic patients receiving UV treatment as monotherapy. METHODS: A retrospective epidemiological study was performed in 8 dermatological reference centre, located throughout Italy (2 from Northern, 3 from Centre, 3 from Southern); a period of 1 year was considered. Data from the overall study population including 326 patients with a diagnosis of psoriasis were analyzed. Furthermore, data coming from follow-up visits, including: screening for PsA onset through specific questionnaires were analyzed. RESULTS: PsA screening was positive in 27 patients (8.3%), whereas PsA diagnosis was confirmed by a rheumatologist in only 22/27 (81.5%) being therefore found in 22/326 (6.7%). Patients diagnosed with PsA had a statistically significantly higher abdominal circumference (96+/-15.3 vs. 88.9+/-18.3, p=0.048) and more commonly presented a positive past medical history for phototherapy (90.9% vs 57.6% p=0.004). CONCLUSIONS: In conclusion, our study showed that phototherapy is not able to prevent or slow down the risk of PsA development in psoriatic patients. PsA screening should be always carried out in those patients even if asymptomatic, especially in obese subjects which are at great risk to develop PsA due to their increased systemic inflammatory state. PMID- 30251804 TI - Anogenital warts treatment options: a pratical approach. AB - Anogenital warts (AGWs) are an important issue for public health centers dealing with Sexually Transmitted Infections. They are epidemiologically relevant, with significant morbidity and an established effective treatment is lacking. In this article, we examine the epidemiological, diagnostic, and therapeutic aspect of the problem in order to give an up to date picture of the situation and a practical clue for the management of AGWs. PMID- 30251805 TI - HERV-E expression in peripheral mononuclear cells of patient with Psoriasis. AB - BACKGROUND: Psoriasis is a common inflammatory skin disease characterized by uncontrolled proliferation of keratinocytes and recruitment of T lymphocytes into the skin. Possible triggers for psoriasis have been attributed to drugs or pathogens such as bacteria and possibly virus. Human endogenous retroviruses (HERVs) might play a role in triggering these anti-viral immune responses, since the role of HERVs in the pathogenesis of autoimmune diseases has generated considerable interest. Some studies have also reported an association of HERV-E and psoriasis. None of them investigate the HERV-E expression in peripheral blood of psoriasis. All these considerations have prompted us to perform a survey for HERV-E expression in PBMC from psoriatic patients. METHODS: Peripheral blood mononuclear cells from 69 psoriatic patients were analyzed. Total RNA was extracted and amplified with reverse transcription polymerase chain reaction. Results were compared with those obtained in a cohort of 20 healthy donors. RESULTS: HERV E was expressed in all samples analyzed but the level of expression was much lower in the psoriasis that in HC p<0.0001. CONCLUSIONS: The reasons for the unexpected, low levels of HERV expression in psoriatic patients are unclear and might be in part a consequence of anti-viral defense mechanisms. PMID- 30251806 TI - Onset of breast basal cell carcinomas during pregnancy: case report and state of the art. PMID- 30251807 TI - Pediatric dermatologic surgery: our experience. AB - BACKGROUND: Surgical treatment for pediatric skin disorders are used for diagnostic and therapeutic reasons. We underline these procedures are usually easy and uncomplicated without the need for general anesthesia. Objective of this study was to share our experience in the field of pediatric dermatologic surgery. METHODS: We retrospectively analysed records of all pediatric patients receiving surgical therapy at the Dermatology Department of Spedali Civili of Brescia. Demographic data and treatments characteristics were recorded and analysed. RESULTS: During the study period of one year, 670 surgical treatments concerning pediatric patients were collected. Number of procedures progressively grows with increasing age. All treatments were performed under local anesthesia except for a dermatofibrosarcoma protuberans for which general anesthesia was needed. CONCLUSIONS: Our data show that cryosurgery, electrodessication and excisional surgery constitute with equal proportion almost the whole of surgical procedures in dermatologic pediatric patients. Dermatologist's habit to perform surgery in local anesthesia avoids the risk of overtreatments, limits discomfort, anxiety, and pain perception linked to procedures performed. PMID- 30251808 TI - Immunohistochemical expression and prognostic role of CD10, CD271 and Nestin in primary and recurrent cutaneous melanoma. AB - BACKGROUND: CD10, CD271 and Nestin, which are proteins associated with tumor initiating properties and/or progression potential, have not been specifically studied on malignant melanoma (MM) with cutaneous recurrences. MATERIALS AND METHODS: We evaluated the expression of of CD10, CD271, and Nestin in 27 tumor samples from 16 patients. These tumor samples corresponded to 6 primary melanomas which developed 11 ITM and 10 primary melanomas without recurrences at 10-year follow-up from specimens obtained from surgical excisions of patients referred to the Unit of Dermatology, Department of Pathophysiology and Transplantation, University of Milan, between 2006 and 2016. RESULTS: We demonstrated a higher expression of CD271 and Nestin in primary tumors which recurred than control population, Nestin was expressed with significantly higher percentages in primary tumors than recurrences, and CD10 expression was statistically significant correlated with disease-free survival: cases with a lower score recurred lately than cases with higher scores. CONCLUSIONS: Our preliminary results suggest that CD271 and Nestin can be considered early biomarkers for the development of ITM, Nestin can be useful in differentiating primary MM from cutaneous recurrences, and CD10 is associated with a rapid disease progression and may be considered a potential prognostic marker. PMID- 30251809 TI - Chronic refractory leg ulcers in mosaic Klinefelter's syndrome: the importance of a prompt diagnosis and appropriate treatment. PMID- 30251810 TI - A multicentre retrospective case-control study on suspension of TNF-inhibitors and outcomes in psoriatic patients (STOP study). AB - BACKGROUND: There is limited information on patients undergoing withdrawal after long- term treatment with anti-TNF alpha drugs and their clinical evolution during the post- interruption period in real-life settings. The purpose of the present retrospective case-control study was to provide a clearer insight into the clinical management of psoriatic patients with adequate response to long-term adalimumab, etanercept and infliximab treatment once these biologic agents are interrupted. METHODS: A total of 270 patients undergoing anti-TNF alpha agents discontinuation and 253 controls treated with a continuous regimen were enrolled. The primary endpoint was the change in disease activity in each study group over six months (or until treatment of psoriatic recurrence) as measured by the PASI score every month. Then, we evaluated the rate of and time to relapse, the rate of clinical worsening (PASI >=5) and the clinical variables influencing the loss of response. RESULTS: Our study showed that about 50% of patients achieving a long-term and optimal response to the aforementioned anti-TNF alpha agents did not experience any relapse over a 6-month follow-up period after withdrawal. We also observed that subjects displaying a complete remission (PASI=0) at anti-TNF alpha therapy withdrawal experienced less frequently disease worsening and/or relapse compared to subjects having a PASI>0. CONCLUSIONS: Finally, our findings confirmed that all three anti-TNF alpha agents tend to retain their effectiveness upon re-administration in case of recurrence, even if they have been previously used for long time. PMID- 30251811 TI - Serial excision and Imiquimod for lentigo maligna melanoma: a proposal for a combined treatment. PMID- 30251812 TI - Dermoscopic findings in Ashy dermatosis. PMID- 30251813 TI - Formacion y competencias de la matrona competencias de la matron. PMID- 30251814 TI - [The Work Environment Climate of the Health Staff in the Surgical Areas at Hospital Universitari Vall D'Hebron (Barcelona)]. AB - Objective: To know the perception of the work environment climate among the health staff between all the surgical areas at Hospital Universitari Vall d'Hebron (HUVH). Design: Observational, descriptive and transversal research. Study Setting: The HUVH's four surgical areas in 2014. Study Subjects: HUVH's surgical block of health healthcare professionals. 138 questionnaires were delivered, 88 of which could actually be considered valid and thus taken into account in the present study. Variables: Sex gender, age professional status, workplace, years, worked in the surgical area (AQ), and career level. The perception of social climate with the WES scale was assessed performed after a descriptive analysis of the variables, mean and SD or median and minimum/maximum according to their distribution and qualitative variables with absolute frequencies and percentages. Kruskal Wallis and ANOVA for the association between the variables of interest were calculated. Results: Stability is almost the same in all four areas, slightly higher in the outpatient surgery unit (OS) and slightly more discomfort is perceived in the mother and child area (MCA). There is no relationship between the workplace and autonomy (F = 0.1; p = 0.959), organization (F = 0.94; p = 0.424), clarity (F = 0.03; p = 0.992), monitoring (F = 0.56; p = 0.64) and innovator (F =1.13; p = 0.34). Post hoc Scheffe test for relations were reviewed. Conclusions: There is more involvement in the MCA than in the general (GA) and trauma (TRA). There are more cohesion in MCA that OS and TRA and also more in GA that TRA. The least support is perceived in the trauma area. Less pressure is perceived and comfort is higher among OS workers. PMID- 30251815 TI - [Nurse Practice Sexual Assault]. AB - Gender violence is a serious problem as well as its serious consequences for women health. This fact contributes to a huge public health problem. Gender violence takes on different ways; being sexual assaults is one of these. Nursing staff plays a central role in addressing cases of acute sexual assault. The aim of this article is to present the role of nursing staff in acute sexual assault. Thus, a number of recommendations are made both from nursing's autonomous role as nursing's collaboration role. The most interesting issue of this article is that it can be used as a guide for nursing staff about what to do in sexual assault cases. PMID- 30251816 TI - Diagnosing and managing common genital emergencies in pediatric girls. AB - The presentation of genital injuries and emergencies in pediatric girls can sometimes be misleading. A traumatic injury with excessive bleeding may be a straddle injury that requires only conservative management, while a penetrating injury may have no recognizable signs or symptoms but require extensive surgery. This issue reviews the most common traumatic genital injuries in girls presenting to the emergency department, including straddle injuries, hematomas, and impalement injuries. Nontraumatic emergencies, including hematocolpos and urethral prolapse, are also discussed. Evidence-based recommendations are presented for identifying and managing these common genital injuries and emergencies in pediatric girls. PMID- 30251817 TI - CuInSe2 Quantum Dots Hybrid Hole Transfer Layer for Halide Perovskite Photodetectors. AB - A novel hybrid hole transport layer (HTL) of CuInSe2 quantum dots (QDs)/poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) was developed to enhance the performance of halide metal perovskite (MAPbI3)-based photodetectors. The introduction of CuInSe2 QDs not only improved the wettability of the PEDOT:PSS HTL for the growth of perovskite crystals but also facilitated the transportation of holes from the perovskite to the HTL. As a result, both responsivity and detectivity of the device were increased dramatically by CuInSe2 QDs hybrid HTL, showing excellent photoresponsivity of 240 mA/W, larger ratio of photocurrent density to dark current density of 4.1 * 106, fast on-off switching properties of <0.02 s, and remarkable detectivity values of 1.02 * 1013 Jones at 580 nm and above 5.01 * 1012 Jones over the visible light region without an external bias voltage. In addition, the photodetectors also showed excellent thermal stability in the range of 10-110 degrees C. Therefore, a unique design idea of a hole transport material would be an anticipated direction for efficient halide metal perovskite-based devices. PMID- 30251818 TI - Orbital-Engineering-Based Screening of pi-Conjugated d8 Transition-Metal Coordination Polymers for High-Performance n-Type Thermoelectric Applications. AB - Extraordinary progress has been achieved in polymer-based thermoelectric materials in recent years. New emerging pi-conjugated transition-metal coordination polymers are one of the best n-type polymer-based thermoelectric materials. However, the microscopic descriptions on geometric structures, orbital characteristics, and most importantly, thermoelectric properties remain elusive, which has seriously hampered the experimentalists to draw a straightforward design strategy for new n-type polymer-based thermoelectric materials. Herein, we assess the n-type thermoelectric properties of 20 pi-conjugated d8 metal center coordination polymers and rationalize their thermoelectric properties in terms of molecular geometry, orbital nature, and electron-phonon coupling based on first principles calculations. An explicit screening rule for high-performance n-type pi-conjugated transition-metal coordination polymeric thermoelectric materials was found, i.e., smaller metal center d orbital component ratio in the conduction band minimum, weaker electron-phonon coupling, higher intrinsic mobility, and thereby higher thermoelectric power factor can be achieved. Guided by this rule, poly(Pd-C2S4) and poly(Ni-C2Se4) show very high power factors. We built a map of high-performance pi-conjugated transition-metal coordination polymers for n-type thermoelectric applications, which will help to accelerate the screening and design of innovative n-type thermoelectric polymers. PMID- 30251819 TI - Efficient Photo- and Electroluminescence by Trap States Passivation in Vacuum Deposited Hybrid Perovskite Thin Films. AB - Methylammonium lead iodide (MAPI) has excellent properties for photovoltaic applications, although it typically shows low photoluminescence quantum yield. Here, we report on vacuum-deposited MAPI perovskites obtained by modifying the methylammonium iodide (MAI) to PbI2 ratio during vacuum deposition. By studying the excitation density dependence of the photoluminescence lifetime, a large concentration of trap states was deduced for the stoichiometric MAPI films. The use of excess MAI during vacuum processing is capable of passivating these traps, resulting in luminescent films which can be used to fabricate planar light emitting diodes with quantum efficiency approaching 2%. PMID- 30251820 TI - Morphology-Retained Photoconversion Reaction of Anthracene Single Crystal: A New Approach for Organic Heterostructures. AB - Morphology-retained solid-state photoconversion of anthracene (AN) to 9,10 anthraquinone (PC-ANQ) and dipara-anthracene (PC-DPA) was accomplished by irradiating mercury lamp light to plate-shaped AN single crystal in oxygen and argon atmosphere, respectively. The photoconverted crystals retained the original plate shape morphology of the starting AN crystal, whereas the emission profile and crystal structure were significantly changed. The electrical conductivity of PC-ANQ crystal is 5 orders of magnitude greater than that of the starting AN crystal, whereas the PC-DPA crystal exhibits a decreased conductivity. The AN/PC ANQ/PC-DPA heterostructures with smooth interface were successfully obtained by inducing the photoconversion only at the desired area. PMID- 30251821 TI - Understanding Structure-Activity Relationships in Sr1- xY xCoO3-delta through in Situ Neutron Diffraction and Electrochemical Measurements. AB - In this work, we report a systematic study on temperature-dependent local structural evolution, oxygen stoichiometry, and electrochemical properties of an oxygen-deficient perovskite Sr0.7Y0.3CoO3-delta (SYC30) for oxygen electrocatalysis. The obtained results are then closely compared with its analogue Sr0.9Y0.1CoO3-delta (SYC10) of different crystal structures to establish structure-activity relationships. The comparison shows that both SYC30 and SYC10 consist of alternate layers of oxygen-deficient Co1-polyhedra and oxygen saturated Co2-octahedra with Co1-polyhedra being responsible for Vo** migration. It is also found that the distribution and concentration of oxygen vacancies within the Co1-layer are, respectively, less symmetrical and lower in SYC30 than those in SYC10, making the former unfavorable for oxygen transport. A molecular orbital energy analysis reveals that the energy gap between Fermi level and O 2p level in the active Co1-polyhedra is larger in SYC30 than that in SYC10, further suggesting that SYC10 is a better oxide-ion conductor and thus a better electrocatalyst for oxygen reduction reaction, which is unambiguously confirmed by the subsequent electrochemical measurements. PMID- 30251822 TI - Polymer-Promoted Synthesis of Porous TiO2 Nanofibers Decorated with N-Doped Carbon by Mechanical Stirring for High-Performance Li-Ion Storage. AB - Extensive efforts have been devoted to developing simple, low-cost and high production yield methods to prepare hybrid materials with desired structural features for high-performance lithium storage. Here, a novel strategy is reported for fabricating the porous TiO2 nanofibers decorated with N-doped carbon (TiO2/C nanofibers) by a combination of mechanical stirring and the addition of a polymer in a beaker at ambient temperature, followed by calcination. The mechanical stirring process can provide homogeneous mixing of reactants in solution, while the polymer acts not only as a structure-directing agent for fabricating one dimensional nanofibers but also as the carbon and nitrogen sources to generate N doped carbon framework and porous structures. The TiO2/C nanofibers have average diameters of 500 nm and lengths up to 65 um and are further composed of intercrossed TiO2 nanocrystals with sizes of 8 nm, with micropores centered at 1.5 nm and mesopores at 3-6 nm. The TiO2/C electrodes demonstrated high reversible capacities (368 mAh g-1 at 0.25 C after 200 cycles and 176 mAh g-1 at 10 C over 2000 cycles) with good cycling and an excellent rate capability (97 mAh g-1 at 20 C). PMID- 30251823 TI - Water-Based Black Phosphorus Hybrid Nanosheets as a Moldable Platform for Wound Healing Applications. AB - Black phosphorus (BP) nanosheets with unique biocompatibility and superior optical performance have attracted enormous attention in material science. However, their instability and poor solution-processability severely limit their clinical applications. In this work, we demonstrate the use of silk fibroin (SF) as an exfoliating agent to produce thin-layer BP nanosheets with long-term stability and facile solution-processability. Presence of SF prevents rapid oxidation and degradation of the resultant BP nanosheets, enhancing their performance in physiological environment. The SF-modified BP nanosheets exhibit subtle solution-processability and are fabricated into various BP-based material formats. As superior photothermal agents, BP-based wound dressings effectively prevent bacterial infection and promote wound repair. Therefore, this work opens new avenues for unlocking current challenges of BP nanosheet applications for practical biomedical purposes. PMID- 30251824 TI - Multilayer ReS2 Photodetectors with Gate Tunability for High Responsivity and High-Speed Applications. AB - Rhenium disulfide (ReS2) is an attractive candidate for photodetection applications owing to its thickness-independent direct band gap. Despite various photodetection studies using two-dimensional semiconductors, the trade-off between responsivity and response time under varying measurement conditions has not been studied in detail. This report presents a comprehensive study of the architectural, laser power and gate bias dependence of responsivity and speed in supported and suspended ReS2 phototransistors. Photocurrent scans show uniform photogeneration across the entire channel because of enhanced optical absorption and a direct band gap in multilayer ReS2. A high responsivity of 4 A W-1 (at 50 ms response time) and a low response time of 20 MUs (at 4 mA W-1 responsivity) make this one of the fastest reported transition-metal dichalcogenide photodetectors. Occupancy of intrinsic (bulk ReS2) and extrinsic (ReS2/SiO2 interface) traps is modulated using gate bias to demonstrate tunability of the response time (responsivity) over 4 orders (15*) of magnitude, highlighting the versatility of these photodetectors. Differences in the trap distributions of suspended and supported channel architectures, and their occupancy under different gate biases enable switching the dominant operating mechanism between either photogating or photoconduction. Further, a new metric that captures intrinsic photodetector performance by including the trade-off between its responsivity and speed, besides normalizing for the applied bias and geometry, is proposed and benchmarked for this work. PMID- 30251825 TI - Assessment on the Self-Discharge Behavior of Lithium-Sulfur Batteries with LiNO3 Possessing Electrolytes. AB - It is generally understood that the reduction of nitrate on the metallic Li surface aids in the formation of a solid-electrolyte interphase. LiNO3 is, therefore, frequently used as an electrolyte additive to help suppress the polysulfide redox shuttle in lithium-sulfur (Li-S) batteries. Although LiNO3 enables cycling of cells with considerably improved Coulombic efficiency and cyclic performance, the self-discharge behavior has largely been neglected. We present in this work a basic but systematic study to assess self-discharge of Li S batteries with electrolytes possessing LiNO3. Comparative electrochemical tests and interfacial analysis reveal that the redox shuttle is fast enough to cause cells to self-discharge at a relatively rapid rate with limited concentration of the LiNO3 additive. Despite the capacity loss of a full-charged cell under rest for one day can be controlled to 2% with LiNO3 concentration as high as 0.5 M, the development of a practically viable Li-S technology looks like a daunting challenge. Further increasing LiNO3 would potentially cause more irreversible reduction of LiNO3 on the cathode during the first discharge. Therefore, a possible pathway for a long shelf life and low self-discharge is offered as well by the synergic protection of the separator and stabilization of the Li anode surface. The cell using a nanosized Al2O3-coated microporous membrane and a LiNO3 possessing electrolyte exhibits an extremely suppressed self-discharge, providing an alternative perspective for the practical use of Li-S batteries. PMID- 30251826 TI - Aligning Synthetic Hippocampal Neural Circuits via Self-Rolled-Up Silicon Nitride Microtube Arrays. AB - Directing neurons to form predetermined circuits with the intention of treating neurological disorders and neurodegenerative diseases is a fundamental goal and current challenge in neuroengineering. Until recently, only neuronal aggregates were studied and characterized in culture, which can limit information gathered to populations of cells. In this study, we use a substrate constructed of arrays of strain-induced self-rolled-up membrane 3D architectures. This results in changes in the neuronal architecture and altered growth dynamics of neurites. Hippocampal neurons from postnatal rats were cultured at low confluency (~250 cells mm-2) on an array of transparent rolled-up microtubes (MU-tubes; 4-5 MUm diameter) of varying topographical arrangements. Neurite growth on the MU-tubes was characterized and compared to controls in order to establish a baseline for alignment imposed by the topography. Compared to control substrates, neurites are significantly more aligned toward the 0 degrees reference on the MU-tube array. Pitch (20-60 and 100 MUm) and MU-tube length (30-80 MUm) of array elements were also varied to investigate their impact on neurite alignment. We found that alignment was improved by the gradient pitch arrangement and with longer MU tubes. Application of this technology will enhance the ability to construct intentional neural circuits through array design and manipulation of individual neurons and can be adapted to address challenges in neural repair, reinnervation, and neuroregeneration. PMID- 30251827 TI - Irreversible Made Reversible: Increasing the Electrochemical Capacity by Understanding the Structural Transformations of Na xCo0.5Ti0.5O2. AB - Two new structural forms of Na xCo0.5Ti0.5O2, the layered O3- and P3-forms, were synthesized and comprehensively characterized. Both materials show electrochemical activity as electrodes in Na-ion batteries. During cell charging (desodiation of the Na xCo0.5Ti0.5O2 cathode), we observed a structural phase transformation of O3-Na0.95Co0.5Ti0.5O2 into P3-Na xCo0.5Ti0.5O2, whereas no changes other than conventional unit cell volume shrinkage were detected for P3 Na0.65Co0.5Ti0.5O2. During Na insertion (cell discharging), the reconversion of the P3-form into O3-Na xCo0.5Ti0.5O2 was impeded for both materials and occurs well below 1 V versus Na+/Na only. The reconversion is hindered by the charge and spin transfers of Co (LS-Co3+ -> HS-Co2+) and by a significant unit cell volume expansion at the P3 -> O3 transformation, as revealed from the magnetization, crystallographic, and spectroscopic studies. As the kinetics of such transformations depend on numerous parameters such as time, temperature, and particle size, a large cell overpotential ensues. An extended cutoff voltage at 0.2 V versus Na+/Na during discharging allows to complete the P3 -> O3 transformation and increases the specific discharging capacity to 200 mA h g-1. Moreover, a quasi-symmetrical full cell, based on the O3- and P3-forms, was designed, eliminating safety concerns associated with sodium anodes and delivering a discharge capacity of 130 mA h g-1. PMID- 30251828 TI - Bifunctional Photo-Supercapacitor with a New Architecture Converts and Stores Solar Energy as Charge. AB - Photo-supercapacitors (PSCs) combine functions of energy harvesting and storage in a single device, and in this study, a new architecture for a PSC is designed and implemented. Cadmium sulfide (CdS) quantum dots/hibiscus (hb) dye co sensitized TiO2 is used as the solar cell. Poly(3,4-ethylenedioxypyrrole) (PEDOP)@manganese dioxide (MnO2) is employed as the counter electrode (CE) for the solar cell and also as the electrodes for the symmetric supercapacitor. The two ends of a long flat current collector support two spatially separated PEDOP@MnO2 coatings, which serve as the CEs for the TiO2/hb/CdS photoanode and yet another PEDOP@MnO2 electrode in sandwich configurations. In this cell, under 1 sun (100 mW cm-2) illumination, the TiO2/hb/CdS photoanode undergoes charge separation and by channeling the photocurrent to the PEDOP@MnO2 electrodes, the symmetric cell part is charged to a voltage of 0.72 V. The PSC delivers a specific capacitance of 183 F g-1, an energy density of 13.2 Wh kg-1, and a power density of 360 W kg-1 at a discharge current density of 1 A g-1. During the self discharge process, PEDOP@MnO2-based PSC retains a voltage of 0.72 V up to 500 s and maintains a stable voltage of 0.5 V thereafter. The TiO2/hb/CdS photoanode with the PEDOP@MnO2 CE in an aqueous polysulfide-silica gel electrolyte delivers a power conversion efficiency of 6.11%. This demonstration of a novel PSC opens up opportunities to develop new architectures for efficiently combining energy conversion and storage. PMID- 30251829 TI - Carrier Engineering in Polarization-Sensitive Black Phosphorus van der Waals Junctions. AB - van der Waals p-n heterostructures based on p-type black phosphorus (BP) integrated with other two-dimensional (2D) layered materials have shown potential applications in electronic and optoelectronic devices, including logic rectifiers and polarization-sensitive photodetectors. However, the engineering of carriers transport anisotropy, which is related to the linear dichroism, have not yet been investigated. Here, we demonstrate a novel van der Waals device of orientation perpendicular BP homojunction based on the anisotropic band structures between the armchair and zigzag directions. The structure exhibits good gate-tunable diode-like rectification characteristics caused by the barrier between the two perpendicular crystal orientations. Moreover, we demonstrate that the unique mechanisms of the polarization-sensitivity properties of this junction are involved with the linear dichroism and the anisotropic carriers transport engineering. These results were verified by the scanning photocurrent images experiments. This work paves the way for 2D anisotropic layered materials for next-generation electronic and optoelectronic devices. PMID- 30251830 TI - Tin(IV) Substitution in (CH3NH3)3Sb2I9: Toward Low-Band-Gap Defect-Ordered Hybrid Perovskite Solar Cells. AB - The prevailing issue of wide optical gap in defect-ordered hybrid iodide perovskites has been addressed in this effort by heterovalent substitution at the metal site. With the introduction of Sn4+ in the (CH3NH3)3Sb2I9 structure, we have successfully lowered the pristine optical gap (2 eV) of the perovskite to a close-to optimum one (1.55 eV). Upon such heterovalent substitution, a gradual shift in the type of electronic conduction of the perovskites was observed. As evidenced from scanning tunneling spectroscopy and correspondingly density-of state spectra, a significant shift of Fermi energy toward the conduction band edge occurred with an increase in the tin content in the host perovskite. This shift has resulted in tuning of the type of electronic conductivity from p-type to n-type and more importantly led to a better band alignment with the selective contacts of p-i-n heterojunctions. However, tin inclusion affected the surface roughness of the perovskite film in an adverse manner. Hence, the tin content was optimized by considering both the factors, namely, the band gap of the material and the surface roughness of thin films. In an energy-level-optimized planar heterojunction device, the short-circuit current density excelled with a power conversion efficiency of 2.69%. PMID- 30251831 TI - Complete Suppression of Bias-Induced Threshold Voltage Shift below 273 K in Solution-Processed High-Performance Organic Transistors. AB - Despite their importance for future applications, the operational electrical stability of organic thin-film transistors is far from being understood. Even in the most stable organic field-effect transistors (OFETs) operated under vacuum, a hitherto unknown source leads to bias stress. Here, we investigate the electrical characteristics and operational stability of a high-performance diketopyrrolopyrrole- alt-terthiophene organic semiconductor. Even though the OFETs are characterized by a high mobility of 3 cm2 V-1 s-1 and trap-free transport, the threshold voltage shift in all stress modes remains sensitive to the presence of water even when operating devices in high vacuum. Exponential fitting from current bias-stress measurement up to 500 000 s showed a bias voltage shift of <1 V, which corresponds to the density of the bias-induced trap states at infinite time NTinfinity = 7.6 * 1010 cm-2. We have surprisingly found that electrical stress could be completely suppressed when devices are cooled to below 273 K. We present evidence that H3O+ and OH- stemming from the autoionization of liquid water is the hitherto unidentified universal trap (i.e., an extrinsic trap not stemming from the semiconductor itself) causing threshold voltage shift even in the otherwise stable devices. This interpretation would also clarify why in the literature similar NT have been reported in various semiconductors, suggesting that this number is independent of the organic semiconductor, processing and measurement environment but only dependent on residual contaminants-most notably water. PMID- 30251832 TI - Atomic Layer Deposition of a Film of Al2O3 on Electrodeposited Copper Foams To Yield Highly Effective Oxygen Carriers for Chemical Looping Combustion-Based CO2 Capture. AB - A rapid electrochemical deposition protocol is reported to synthesize highly porous Cu foams serving as model oxygen carriers for chemical looping, a promising technology to reduce anthropogenic CO2 emission. To overcome the sintering-induced decay in the oxygen carrying capacity of unsupported Cu foams, Al2O3 films of different thicknesses (0.1-25 nm) are deposited onto the Cu foams via atomic layer deposition (ALD). An ALD-grown Al2O3 overcoat of 20 nm thickness (~4 wt % Al2O3) is shown to be sufficient to ensure excellent redox cyclic stability. Al2O3-coated Cu foams exhibit a capacity retention of 96% over 10 redox cycles, outperforming their coprecipitated counterpart (equal Al2O3 content). The structural evolution of the stabilized foams is probed in detail and compared to benchmark materials to elucidate the stabilizing role of the Al2O3 overcoat. Upon heat treatment, the initially conformal Al2O3 overcoat induces a fragmentation of large Cu(O) branches into small particles. After multiple redox cycles, the Al2O3 overcoat transforms into sub-micrometer-sized grains of aluminum-containing phases (delta-Al2O3, CuAl2O4, and CuAlO2) that are dispersed homogeneously within the CuO matrix. Finally, the diffusion of Cu through an Al2O3 layer upon heat treatment in an oxidizing atmosphere is probed in model thin films. PMID- 30251834 TI - Perovskite Quantum Dot Photovoltaic Materials beyond the Reach of Thin Films: Full-Range Tuning of A-Site Cation Composition. AB - We present a cation-exchange approach for tunable A-site alloys of cesium (Cs+) and formamidinium (FA+) lead triiodide perovskite nanocrystals that enables the formation of compositions spanning the complete range of Cs1- xFA xPbI3, unlike thin-film alloys or the direct synthesis of alloyed perovskite nanocrystals. These materials show bright and finely tunable emission in the red and near infrared range between 650 and 800 nm. The activation energy for the miscibility between Cs+ and FA+ is measured (~0.65 eV) and is shown to be higher than reported for X-site exchange in lead halide perovskites. We use these alloyed colloidal perovskite quantum dots to fabricate photovoltaic devices. In addition to the expanded compositional range for Cs1- xFA xPbI3 materials, the quantum dot solar cells exhibit high open-circuit voltage ( VOC) with a lower loss than the thin-film perovskite devices of similar compositions. PMID- 30251835 TI - Superior High-Rate and Ultralong-Lifespan Na3V2(PO4)3@C Cathode by Enhancing the Conductivity Both in Bulk and on Surface. AB - Na3V2(PO4)3 has shown great promise in next-generation cathode materials for sodium-ion batteries owning to its fast Na+ diffusion in the three-dimensional open NASICON framework and high theoretical energy density. However, Na3V2(PO4)3 suffers from undesirable rate performance and unstable cyclability arising from low electronic conductivity. Herein, we propose a facile approach for significantly enhancing the electrochemical properties of Na3V2(PO4)3 by Ti doping at V site and constructing nanoparticle@carbon core-shell nanostructure. This material design provides fast electron conduction network within the whole active particles because of the mixed valence Ti4+/3+ in bulk and highly conductive carbon shell on the surface. Lattice doping and carbon coating reduce the electrode polarization and facilitate the electrode reaction kinetics, while the nanostructure enhances the ionic conduction by shortening the diffusion distance and offers sufficient contact of active particles with organic electrolyte. The multiple synergetic effects enable a superior electrochemical performance. The optimized Na3V1.9Ti0.1(PO4)3@C cathode shows a high specific capacity (116.6 mAh g-1 at 1C), an unprecedented rate performance (93.4 mAh g-1 at 400C), and an exceptional long-term high-rate cycling stability (capacity retention of 69.5% after 14 000 cycles at 100C, corresponding to 0.0002% decay per cycle). PMID- 30251836 TI - Design, Synthesis, and Evaluation of Piperazinyl Pyrrolidin-2-ones as a Novel Series of Reversible Monoacylglycerol Lipase Inhibitors. AB - Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyzes 2 arachidonoylglycerol (2-AG) to arachidonic acid (AA) and glycerol in the brain. Because 2-AG and AA are endogenous biologically active ligands in the brain, inhibition of MAGL is an attractive therapeutic target for CNS disorders, particularly neurodegenerative diseases. In this study, we report the structure based drug design of novel piperazinyl pyrrolidin-2-ones starting from our hit compounds 2a and 2b. By enhancing the interaction of the piperazinyl pyrrolidin-2 one core and its substituents with the MAGL enzyme via design modifications, we identified a potent and reversible MAGL inhibitor, compound ( R)-3t. Oral administration of compound ( R)-3t to mice decreased AA levels and elevated 2-AG levels in the brain. PMID- 30251837 TI - Hybrid Catalyst of a Metal-Organic Framework, Metal Nanoparticles, and Oxide That Enables Strong Steric Constraint and Metal-Support Interaction for the Highly Effective and Selective Hydrogenation of Cinnamaldehyde. AB - In this work, we designed a hybrid catalyst composed of a metal-organic framework (MOF), Pt nanoparticles (NPs), and ferric oxide, namely, Co-MOF-74@(Pt@Fe2O3), which enables not only high turnover frequencies of up to 245.7 h-1 but also ultrahigh 100% selectivity toward cinnamyl alcohol in the hydrogenation of cinnamaldehyde under mild conditions. This excellent performance is attributed to the fact that such a hybrid catalyst enables not only strong steric constraint to provide the favored C?O adsorption of cinnamaldehyde but also strong metal support interaction to lower the electron density of Pt NPs. PMID- 30251838 TI - Single-Chain Magnet Based on 1D Polymeric Azido-Bridged Seven-Coordinate Fe(II) Complex with a Pyridine-Based Macrocyclic Ligand. AB - Peculiar magnetic behavior was found for 1D-polymeric seven-coordinate pentagonal bipyramidal Fe(II) complex {[Fe(L)(MU1,3-N3)](ClO4)} n (1) with a pentadentate macrocyclic ligand L (3,12,18-triaza-6,9-dioxabicyclo[12.3.1]octadeca-1(18),14,16 triene) coordinated in the pentagonal equatorial plane and with end-to-end bridging azido ligands in axial positions. The static and dynamic magnetic data revealed that spin-canting in the 1D-chain of 1 results in the single-chain magnet (SCM) behavior with high spin-reversal energy barrier Ueff (Deltatau) = 87.5 K, exhibiting magnetic hysteresis below 4 K and coexistence with the metamagnetism altogether resulting in weak 3D-ferromagnetic behavior. This is the first reported example of the exclusively azido-bridged homospin Fe(II)-based SCM. PMID- 30251839 TI - Four-Step Synthesis of B2N2-Embedded Corannulene. AB - A corannulene possessing two B-N units on the spoke, 10b1,18b1-diaza-10b,18b diboratetrabenzo [ a, g, j, m]corannulene, was synthesized on a multigram scale in four steps from commercially available compounds. Its shallow bowl-shaped structure was confirmed by X-ray crystallography. The B2N2-embedded corannulene showed strong blue fluorescence and was employed as an efficient emitter for an organic light-emitting diode. PMID- 30251840 TI - Triflimide (HNTf2) in Organic Synthesis. AB - Triflimide (HNTf2) is a commercially available and highly versatile super Bronsted acid. Owing to its strong acidity as well as good compatibility with organic solvents, it has been widely employed as an exceptional catalyst, promoter, or additive in a wide range of organic reactions. On many occasions, triflimide has been demonstrated to outperform triflic acid (TfOH). The uniquely outstanding performance of triflimide also benefits from the low nucleophilicity and noncoordinating property of its conjugate base (Tf2N-). Therefore, it has been employed as a precursor toward a variety of cationic metal complexes or organic intermediates with enhanced reactivity or catalytic activity. In this Review, we describe these features and applications of triflimide in organic synthesis, including its synthesis, physical properties, and role as catalyst or promoter in organic reactions. At the end of this Review, another closely related reagent, triflidic acid (HCTf3), is also briefly introduced. PMID- 30251841 TI - Theoretical Study of Alkylsulfonic Acids: Force-Field Development and Molecular Dynamics Simulations. AB - Potential model descriptions for alkylsulfonic acids, methanesulfonic, ethanesulfonic, and propanesulfonic acids, are developed based on CHARMM and OPLS parameters and protocols. Thermodynamic, structural, and transport properties of these alkylsulfonic acids, including density, heat of vaporization, radial and spatial distribution functions, hydrogen bond structure, shear viscosity, and translational diffusion coefficients, are examined via molecular dynamics simulations using these potential models. The results are compared with the predictions of ab initio molecular dynamics simulations as well as with available experimental information. A good overall agreement indicates that the force-field descriptions developed here provide a reliable framework to study liquid systems containing alkylsulfonic acids. PMID- 30251842 TI - ADMETopt: A Web Server for ADMET Optimization in Drug Design via Scaffold Hopping. AB - Drug-likeness, comprising absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, plays a significant role in early drug discovery. However, as for current strategies of lead optimization, in vitro potency is still the focus, which may cause "molecular obesity" (poor ADMET properties). Therefore, optimization of ADMET properties would be a preferable complement for drug discovery. In this paper, we present a web server, ADMETopt, that applies scaffold hopping and ADMET screening for lead optimization. More than 50 000 unique scaffolds were extracted by fragmenting chemicals deposited in the ChEMBL and Enamine databases. Up to 15 ADMET properties can be predicted to screen the potential molecules, including seven physicochemical properties and eight biological properties. All of the models were built in terms of our previous studies and are available in our web server admetSAR. For the plausibility measurement of the modified molecules, synthetic accessibility and quantitative evaluation of drug-likeness were then implemented. As a case study, a scaffold similarity network was constructed for compounds that have bioactivities on estrogen receptors. The results demonstrated that the feasibility and practicability of our web server are acceptable. The web server is publicly accessible at http://lmmd.ecust.edu.cn/admetsar2/admetopt/ . PMID- 30251843 TI - Solution and Solid-State Emission Toggling of a Photochromic Hydrazone. AB - The proliferation of light-activated switches in recent years has enabled their use in a broad range of applications encompassing an array of research fields and disciplines. All current systems, however, have limitations (e.g., from complicated synthesis to incompatibility in biologically relevant media and lack of switching in the solid-state) that can stifle their real-life application. Here we report on a system that packs most, if not all, the desired, targeted and sought-after traits from photochromic compounds (bistability, switching in various media ranging from serum to solid-state, while exhibiting ON/OFF fluorescence emission switching, and two-photon assisted near-infrared light toggling) in an easily accessible structure. PMID- 30251844 TI - Development of a PBPK Model for Silver Accumulation in Chub Infected with Acanthocephalan Parasites. AB - Simultaneous presence of metals and parasites in fish might lead to potential risks to human health. Parasites might influence metal accumulation and disturb detoxification in fish, thereby affecting biomarkers of fish responses as well as metal biomagnification in humans. It is, therefore, of importance to take into account parasite infection when investigating metal accumulation in fish. However, mechanisms of metal accumulation and distribution in fish-parasite systems are not integrated into current approaches. The present study proposes a new physiologically based pharmacokinetic model for mechanistic simulation of metal partitioning between intestinal parasites and their hosts. As a particular case, Ag accumulation in the system of chub Squalius cephalus and the acanthocephalan Pomphorhynchus tereticollis was investigated. As a novelty, fish cardiac output and organ-specific blood flow distribution were incorporated in our model. This approach distinguishes the current model from the ones developed previously. It also facilitates model extrapolation and application to varying conditions. In general, the model explained Ag accumulation in the system well, especially in chub gill, storage (including skin, muscle, and carcass), and liver. The highest concentration of Ag was found in the liver. The accumulation of Ag in the storage, liver, and gill compartments followed a similar pattern, i.e., increasing during the exposure and decreasing during the depuration. The model also generated this observed trend. However, the model had a weaker performance for simulating Ag accumulation in the intestine and the kidney. Silver accumulation in these organs was less evident with considerable variations. PMID- 30251845 TI - Copper Corrosion Products Catalyzed Reduction of N-Nitrosodimethylamine with Iron. AB - Copper corrosion products (Cu(OH)2, Cu2O, CuO and Cu2CO3(OH)2) were applied to catalyze the reduction of N-Nitrosodimethylamine (NDMA) with iron. All the copper corrosion products showed catalytic abilities. Lower pH values and DO concentrations facilitated NDMA reduction in most cases. 1,1-dimethylhydrazine (unsymmetrical dimethylhydrazine, UDMH) and dimethylamine (DMA) formed during the degradation of NDMA. There were also some undetected products. Catalytic hydrogenation was proposed as the mechanism. The catalytic systems did not promote the formation of hydrogen atoms. The dissolved copper ions in these systems were too sparse to enhance the reaction. The smooth iron surface and formation of Cu2O in each catalytic system explained the enhancement of NDMA removal. Different surface morphologies and states of Cu2O accounted for the differences in NDMA removal and kinetics between the reaction systems. This technique could be an alternative for NDMA reduction and could broaden the application of copper corrosion products. PMID- 30251846 TI - Quantities of Marine Debris Ingested by Sea Turtles: Global Meta-Analysis Highlights Need for Standardized Data Reporting Methods and Reveals Relative Risk. AB - Because of their propensity to ingest debris, sea turtles are excellent bioindicators of the global marine debris problem. This review covers five decades of research on debris ingestion in sea turtles from 131 studies with a novel focus on quantities. Previous reviews have focused solely on presence/absence data. Past reviews have called for standardization and highlight biases in the literature, yet none thoroughly describe improvements needed at the data reporting stage. Consequences of three reporting choices are discussed: not reporting quantities of ingested debris (32% of sea turtle studies reported only frequency of occurrence), excluding animals that did not ingest debris (64%), and not normalizing quantities to animal size (95%). Ingestion quantities, corrected for these factors, allowed a first-ever global meta-analysis on the units of grams/kilogram, revealing that hawksbill and green turtles rank highest among sea turtle species, and that the Central and Northwest Pacific and Southwest Atlantic Oceans are hotspots. Furthermore, this review discovered that monitoring efforts are disproportionate to the magnitude of the problem. Large efforts are focused in the Mediterranean Sea where international policies are hotly discussed versus the Central Pacific that has 5-fold greater debris ingestion quantities but represents only 3% of the global research effort. Future studies are recommended to report quantities of ingested debris using units described herein and make use of the pilot database provided. PMID- 30251847 TI - Generic Hapten Synthesis, Broad-Specificity Monoclonal Antibodies Preparation, and Ultrasensitive ELISA for Five Antibacterial Synergists in Chicken and Milk. AB - An antibody with broad specificity and principally depending on hapten structure and size is a key reagent for developing a class-selective immunoassay. In the present study, three new generic haptens of antibacterial synergists (ASGs) were proposed using trimethoprim as the starting molecule. These haptens contained carboxyl groups on the meta position of trimethoxybenzene for conjugating to protein, while, the common moiety of ASGs, i.e., diaminopyrimidine, was intentionally and maximally exposed to the immune system in animals in order to induce antibodies with broad specificity against ASGs. Five monoclonal antibodies (mAbs) were finally obtained, and 5C4 from the hapten with a short spacer arm, named Hapten A, showed not only uniform broad specificity but also high affinity to all five ASGs. We further determined the possible recognition mechanism of mAbs in terms of conformational and electronic aspects. An indirect competitive ELISA (icELISA)-based 5C4 was established and exhibited IC50 values of 0.067 0.139 MUg L-1 with cross-reactivity of 48.2%-418.7% for the five ASGs in buffer under optimal conditions. The calculated limits of detection of the icELISA for chicken and milk were 0.06-0.8 MUg kg-1 and 0.05-0.6 MUg L-1, respectively. The recoveries in spiked chicken and milk samples were 75.2%-101.4% with a coefficient of variation less than 14.3%. In summary, we have developed, for the first time, a rapid and reliable icELISA for ASGs with significantly improved sensitivity and class selectivity. PMID- 30251848 TI - Ion-Specific Confined Water Dynamics in Convex Nanopores of Gemini Surfactant Lyotropic Liquid Crystals. AB - The impact of pore geometry and functionality on the dynamics of water nanoconfined in porous media are the subject of some debate. We report the synthesis and small-angle X-ray scattering (SAXS) characterization of a series of perdeuterated gemini surfactant lyotropic liquid crystals (LLCs), in which convex, water-filled nanopores of well-defined dimensions are lined with carboxylate functionalities. Quasielastic neutron scattering (QENS) measurements of the translational water dynamics in these dicarboxylate LLC nanopores as functions of the surfactant hydration state and the charge compensating counterion (Na+, K+, NMe4+) reveal that the measured dynamics depend primarily on surfactant hydration, with an unexpected counterion dependence that varies with hydration number. We rationalize these trends in terms of a balance between counterion-water attractions and the nanopore volume excluded by the counterions. On the basis of electron density maps derived from SAXS analyses of these LLCs, we directly show that the volume excluded by the counterions depends on both their size and spatial distribution in the water-filled channels. The translational water dynamics in the convex pores of these LLCs are also slower than those reported in the concave pores of AOT reverse micelles, implying that water dynamics also depend on the nanopore curvature. PMID- 30251849 TI - Effect of Lactobacillus plantarum NCU116 Fermentation on Asparagus officinalis Polysaccharide: Characterization, Antioxidative, and Immunoregulatory Activities. AB - Lactic acid fermentation represents a novel method to produce bioactive functional ingredients, including polysaccharides. In this work, a selected lactic acid bacteria strain NCU116 was used to ferment Asparagus officinalis (asparagus) pulps. Two polysaccharides were subsequently separated from both unprocessed and fermented asparagus pulps, namely, asparagus polysaccharide (AOP) and fermented-AOP (F-AOP). The physicochemical and bioactive properties of AOP and F-AOP were characterized and investigated. High-performance anion-exchange chromatography showed that fermentation increased the proportions of rhamnose, galacturonic acid, and glucuronic acid in polysaccharides by 46.70, 114.09, and 12.750/00, respectively. High-performance size-exclusion chromatography revealed that fermentation decreased the average molecular weight from 181.3 kDa (AOP) to 152.8 kDa (F-AOP). Moreover, the fermentation reduced the particle size and changed the rheology property. In vitro, F-AOP displayed superior free radical scavenging properties compared to AOP, using 2,2-diphenyl-1-picryhydrazyl, hydroxyl, and superoxide anion radical scavenging assays. In vivo, F-AOP administration dose-dependently promoted a gradual shift from Th17-dominant acute inflammatory response (IL-17 and RORgammat) to Th1-dominant defensive immune response (IFN-gamma and T-bet). These results indicated that the Lactobacillus plantarum NCU116 fermentation was practical and useful to obtain promising bioactive polysaccharides. PMID- 30251850 TI - Triphenyl Phosphate (TPHP)-Induced Neurotoxicity in Adult Male Chinese Rare Minnows ( Gobiocypris rarus). AB - The neurotoxicity of triphenyl phosphate (TPHP) in exposed humans and laboratory animals is under debate. The rapid crossing of the blood-brain barrier (BBB) and high distribution of TPHP in fish brains have raised widespread concerns about potential neurotoxicity. Adult male Chinese rare minnows ( Gobiocypris rarus) were used as a model and exposed to 0, 20, or 100 MUg/L TPHP for 28 days. We evaluated the BBB permeability, neuroinflammatory response, cell proliferation and apoptosis, synaptic plasticity and synapse loss in fish brains via the learning/memory performance of fish following 28 days of TPHP exposure. TPHP significantly increased the BBB permeability, activated the neuroinflammatory response, and decreased the tight junction-related mRNA levels of claudin-5alpha and occludin in the fish brain. In addition, cell proliferation was inhibited by treatment with 100 MUg/L TPHP, but no significant apoptosis was observed in the brain. Fish exposed to 100 MUg/L TPHP exhibited significantly decreased dendritic arborization in pyramidal neurons in the cerebellum (Ce), and the maze test indicated impaired learning/memory performance. Taken together, these findings provide scientific evidence that TPHP is neurotoxic to fish and further suggest that TPHP may not be a safe alternative for aquatic organisms. PMID- 30251851 TI - Ulleungdin, a Lasso Peptide with Cancer Cell Migration Inhibitory Activity Discovered by the Genome Mining Approach. AB - The advances of genomic sequence analyses and genome mining tools have enabled the exploration of untapped microbial natural products. Through genome mining studies to discover cryptic natural products, we found biosynthetic genes encoding a new lasso peptide in the genome sequence of a soil bacterium, Streptomyces sp. KCB13F003 isolated from Ulleung Island (a small volcanic island), Korea. The production and purification of the encoded peptide, named ulleungdin, were achieved by optimizing the culture conditions followed by LC-MS targeted isolation. Structure elucidation was performed by NMR spectroscopic and MS spectrometric analyses and chemical means (Marfey's and GITC derivatizations), proving ulleungdin to be a new 15-mer class II lasso peptide with a threaded structure. Biological evaluation with the cell invasion assay and time-lapse cell tracking analysis revealed that ulleungdin has significant inhibitory activities against cancer cell invasion and migration. PMID- 30251853 TI - Ratiometric Fluorescence Coding for Multiplex Nucleic Acid Amplification Testing. AB - Although nucleic acid amplification testing (NAAT) has become the cornerstone for molecular diagnosis of diseases, expanding the multiplexed detection capacity of NAAT remains an important objective. To this end, encoding each nucleic acid target with a specific fluorescently labeled probe has been the most mature approach for multiplexed detection. Unfortunately, the number of targets that can be differentiated via this one-target-one-fluorophore multiplexed detection approach is restricted by spectral overlaps between fluorophores. In response, we present herein a new multiplexed detection approach termed ratiometric fluorescence coding, in which we encode each nucleic acid target with a specific ratio between two standard fluorophores. In ratiometric fluorescence coding, we employ the padlock probe chemistry to encode each nucleic acid target with a specific number of binding sites for two probes labeled with different fluorophores. Coupling the padlock probes with either rolling circle amplification (RCA) or hyperbranched rolling circle amplification (HRCA), we transform each nucleic acid target into a specific template that allows hybridization with the fluorescently labeled probes at predesigned ratios, thereby achieving multiplexed detection. For demonstration, we detected DNA targets from six infectious diseases and demonstrated the potential for further expanding the multiplexing capability of our approach. With further development, ratiometric fluorescence coding has the potential to enable highly multiplexed detection of nucleic acid targets and facilitate molecular diagnosis of diseases. PMID- 30251854 TI - Synthetic Approach to the Preparation of (2-Acetoxy)allyl Nitro Compounds. AB - A synthetic approach to a new class of allyl nitro derivatives is reported. (2 Acetoxy)allyl nitro compounds have been prepared for the first time in a four step procedure by a preliminary reaction of nitroalkanes with 2 (phenylselenyl)acetaldehyde. After the acetylation of the obtained nitro alcohols, the unsaturation is installed by an oxidation reaction involving the phenylselenyl group followed by a thermal elimination. The oxidation process is accomplished under flow conditions ensuring a notable lowering of overoxidation by products observed in batch. PMID- 30251852 TI - Kinetics of Membrane Protein-Detergent Interactions Depend on Protein Electrostatics. AB - Interactions of a membrane protein with a detergent micelle represent a fundamental process with practical implications in structural and chemical biology. Quantitative assessment of the kinetics of protein-detergent complex (PDC) interactions has always been challenged by complicated behavior of both membrane proteins and solubilizing detergents in aqueous phase. Here, we show the kinetic reads of the desorption of maltoside-containing detergents from beta barrel membrane proteins. Using steady-state fluorescence polarization (FP) anisotropy measurements, we recorded real-time, specific signatures of the PDC interactions. The results of these measurements were used to infer the model dependent rate constants of association and dissociation of the proteomicelles. Remarkably, the kinetics of the PDC interactions depend on the overall protein charge despite the nonionic nature of the detergent monomers. In the future, this approach might be employed for high-throughput screening of kinetic fingerprints of different membrane proteins stabilized in micelles that contain mixtures of various detergents. PMID- 30251855 TI - Tipping the Balance between S-pi and O-pi Interactions. AB - A comprehensive experimental survey consisting of 36 molecular balances was conducted to compare 18 pairs of S-pi versus O-pi interactions over a wide range of structural, geometric, and solvent parameters. A strong linear correlation was observed between the folding energies of the sulfur and oxygen balances across the entire library of balance pairs. The more stable interaction systematically switched from the O-pi to S-pi interaction. Computational studies of bimolecular PhSCH3-arene and PhOCH3-arene complexes were able to replicate the experimental trends in the molecular balances. The change in preference for the O-pi to S-pi interaction was due to the interplay of stabilizing (dispersion and solvophobic) and destabilizing (exchange-repulsion) terms arising from the differences in size and polarizability of the oxygen and sulfur atoms. PMID- 30251856 TI - Photo Oxidation Reaction Kinetics of Ethyl Propionate with Cl Atom and Formation of Propionic Acid. AB - Temperature-dependent rate coefficients for the photo oxidation reaction of ethyl propionate with Cl atom were investigated experimentally using the relative rate technique. Gas chromatography with flame ionization detector (GC-FID), gas chromatography-mass spectrometry (GC-MS), and GC-infrared spectroscopy (GC-IR) were used to follow the concentrations and identification of reactants and products. The kinetics of ethyl propionate with Cl atoms was investigated over the temperature range of 263-363 K at atmospheric pressure, relative to C2H6 and C2H4. Theoretical calculations were also performed at CCSD(T)/6 311++G(d,p)//BHandHLYP/6-311G(d,p) level of theory, and the rate coefficients for H-abstraction reactions were calculated using canonical variational transition state theory (CVT) with interpolated single point energies (ISPE) method over the temperature range of 200-800 K. The temperature-dependent rate coefficients for the reaction of ethyl propionate with Cl atom were obtained both experimentally as well as theoretically and are kExpt( T) = [(6.88 +/- 1.65) * 10-24] T4.5 exp[(1108 +/- 87)/ T] cm3 molecule-1 s-1 and kTheory( T) = (6.73 * 10-19) T2.74 exp[(571)/ T] cm3 molecule-1 s-1, respectively. On the basis of product analysis on the title reaction and the computational studies, we have proposed the atmospheric degradation mechanism and various pathways for Cl atom-initiated photo oxidation of EP. Propionic acid is identified as the major product in the degradation of ethyl propionate on reaction with Cl atom. The thermochemistry, branching ratios, and cumulative lifetime of ethyl propionate are calculated and presented in this Article. PMID- 30251857 TI - Mechanism of Proton-Coupled Electron Transfer in the S0-to-S1 Transition of Photosynthetic Water Oxidation As Revealed by Time-Resolved Infrared Spectroscopy. AB - Photosynthetic water oxidation takes place at the Mn4CaO5 cluster in photosystem II through a light-driven cycle of intermediates called S states (S0-S4). To unravel the mechanism of water oxidation, it is essential to understand the coupling of electron- and proton-transfer reactions during the S-state transitions. Here, we monitored the reaction process in the S0 -> S1 transition using time-resolved infrared (TRIR) spectroscopy. The TRIR signals of the pure contribution of the S0 -> S1 transition was obtained by measurement upon a flash after dark adaptation following three flashes. The S0 -> S1 traces at the vibrational frequencies of carboxylate groups and hydrogen bond networks around the Mn4CaO5 cluster showed a single phase with a time constant of ~45 MUs. A relatively small H/D kinetic isotope effect of ~1.2 together with the absence of a slower phase suggests that proton release is coupled with electron transfer, which is a rate-limiting step. The high rate of proton-coupled electron transfer, which is even higher than pure electron transfer in the S1 -> S2 transition, is consistent with the previous theoretical prediction that a hydroxo bridge of the Mn4CaO5 cluster gives rise to barrierless deprotonation upon S1 formation through a strongly hydrogen-bonded water molecule. PMID- 30251858 TI - Processive Nanostepping of Formin mDia1 Loosely Coupled with Actin Polymerization. AB - Formins are actin-binding proteins that construct nanoscale machinery with the growing barbed end of actin filaments and serve as key regulators of actin polymerization and depolymerization. To maintain the regulation of actin dynamics, formins have been proposed to processively move at every association or dissociation of a single actin molecule toward newly formed barbed ends. However, the current models for the motile mechanisms were established without direct observation of the elementary processes of this movement. Here, using optical tweezers, we demonstrate that formin mDia1 moves stepwise, observed at a nanometer spatial resolution. The movement was composed of forward and backward steps with unitary step sizes of 2.8 and -2.4 nm, respectively, which nearly equaled the actin subunit length (~2.7 nm), consistent with the generally accepted models. However, in addition to steps equivalent to the length of a single actin subunit, those equivalent to the length of two or three subunits were frequently observed. Our findings suggest that the coupling between mDia1 stepping and actin polymerization is not tight but loose, which may be achieved by the multiple binding states of mDia1, providing insights into the synergistic functions of biomolecules for the efficient construction and regulation of nanofilaments. PMID- 30251860 TI - Rapid Desorption of Polyelectrolytes from Solid Surfaces Induced by Changes of Aqueous Chemistry. AB - The short-term desorption induced by changes of aqueous chemistry of predeposited polyelectrolyte layers on solid surfaces was studied with reflectometry. The behavior of a strong polycation, polydiallydimethylammonium chloride (PDADMAC), interacting with flat silica was investigated in detail. Results showed that partial desorption of preadsorbed polymer chains can be quickly triggered by changes in ionic strength and pH. When lowering these parameters in the PDADMAC silica system, the increased lateral repulsive potential of neighboring chains drove the desorption of some of the polymer. Furthermore, layer desorption was favored when electrostatic interactions between a polyelectrolyte and the underlying surface became less attractive or switched to being repulsive. At the investigated timescales (<1 h), adlayer desorption was always partial and often incomplete. When initiating desorption from a condition of large adsorbed mass, desorption effects did not result in the plateau mass obtained by adsorption on a clean surface: an excess mass remained deposited. The results thus suggest that a relatively large energy barrier needs to be overcome to induce redissolution of predeposited chains and that this barrier may be a function of the number of polymer-surface interactions, which are in turn correlated with polymer molecular mass. These mechanisms have important implications for environmental processes and colloidal systems because they imply that, once adsorbed, polymeric chains may be redissolved but only to a limited degree at typical engineering timescales. PMID- 30251859 TI - Multifunctional Dendrimer-Entrapped Gold Nanoparticles Conjugated with Doxorubicin for pH-Responsive Drug Delivery and Targeted Computed Tomography Imaging. AB - Novel theranostic nanocarriers exhibit a desirable potential to treat diseases based on their ability to achieve targeted therapy while allowing for real-time imaging of the disease site. Development of such theranostic platforms is still quite challenging. Herein, we present the construction of multifunctional dendrimer-based theranostic nanosystem to achieve cancer cell chemotherapy and computed tomography (CT) imaging with targeting specificity. Doxorubicin (DOX), a model anticancer drug, was first covalently linked onto the partially acetylated poly(amidoamine) dendrimers of generation 5 (G5) prefunctionalized with folic acid (FA) through acid-sensitive cis-aconityl linkage to form G5.NHAc-FA-DOX conjugates, which were then entrapped with gold (Au) nanoparticles (NPs) to create dendrimer-entrapped Au NPs (Au DENPs). We demonstrate that the prepared DOX-Au DENPs possess an Au core size of 2.8 nm, have 9.0 DOX moieties conjugated onto each dendrimer, and are colloid stable under different conditions. The formed DOX-Au DENPs exhibit a pH-responsive release profile of DOX because of the cis-aconityl linkage, having a faster DOX release rate under a slightly acidic pH condition than under a physiological pH. Importantly, because of the coexistence of targeting ligand FA and Au core NPs as a CT imaging agent, the multifunctional DOX-loaded Au DENPs afford specific chemotherapy and CT imaging of FA receptor overexpressing cancer cells. The constructed DOX-conjugated Au DENPs hold a promising potential to be utilized for simultaneous chemotherapy and CT imaging of various types of cancer cells. PMID- 30251861 TI - Deep Eutectic Solvent-Induced Structural Transition of Microemulsions Explored with Small-Angle X-ray Scattering. AB - Microemulsions (MEs) containing deep eutectic solvents (DESs) and water in the inner phase for use in transdermal delivery of poorly soluble drugs were prepared using a mixture of polyoxyethylene sorbitan monooleate (Tween-80) and sorbitan laurate (Span-20) as surfactants. We investigated the effects of the ratios of surfactant (Tween-80/Span-20) and solvents (DES components/water) on the ME structure determined by the analysis of small-angle X-ray scattering profiles with the core-corona model. Tween-80 with an unsaturated long alkyl chain induced a structural transition of MEs from a sphere to a cylinder. DESs caused the aggregation of surfactants due to the solvophobic interactions between DESs and the alkyl chains of surfactants. Transmittance electron microscopy images of MEs indicated the presence of aggregates of the dispersed ME particles with each shape. PMID- 30251862 TI - Conformational Dynamics of a Single Protein Monitored for 24 h at Video Rate. AB - We use plasmon rulers to follow the conformational dynamics of a single protein for up to 24 h at a video rate. The plasmon ruler consists of two gold nanospheres connected by a single protein linker. In our experiment, we follow the dynamics of the molecular chaperone heat shock protein 90 (Hsp90), which is known to show "open" and "closed" conformations. Our measurements confirm the previously known conformational dynamics with transition times in the second to minute time scale and reveals new dynamics on the time scale of minutes to hours. Plasmon rulers thus extend the observation bandwidth 3-4 orders of magnitude with respect to single-molecule fluorescence resonance energy transfer and enable the study of molecular dynamics with unprecedented precision. PMID- 30251863 TI - Incorporation of Cesium Ions into MA1- xCs xPbI3 Single Crystals: Crystal Growth, Enhancement of Stability, and Optoelectronic Properties. AB - Organic-inorganic hybrid methylammonium lead iodide perovskite (MAPbI3) has attracted extensive attention in a series of optoelectronic devices. The photoelectric properties of the MAPbI3 single crystal have been revealed to be much better than those of it polycrystalline counterparts. However, its poor moisture and heat resistance severely limited further development. The introduction of Cs+ into polycrystalline films has shown to be an effective way to enhance its moisture resistance through a passivation effect. However, the entrance abilities of Cs+ into a MAPbI3 crystal lattice and the influence on photoelectric properties of a single crystal were not clear until now. Therefore, we attempted to grow large MA1- xCs xPbI3 single crystals to introduce Cs+ into the crystal lattice. The existence of Cs+ brought lattice shrinkage and enhanced stability of the MAPbI3 single crystal. A moderate quantity of Cs+ (2%) proved to heighten the photoelectric properties, whereas an excess quantity of Cs+ (5%) brought more shallow defects, which ultimately deteriorated the photoelectric properties. PMID- 30251864 TI - Encapsulation of Azithromycin Ion Pair in Liposome for Enhancing Ocular Delivery and Therapeutic Efficacy on Dry Eye. AB - The aim of this work was to design a novel ocular delivery carrier based on liposomes loaded with azithromycin (AZM) for the treatment of dry eye (DE) disease. To improve the drug loading efficiency, an AZM-cholesteryl hemisuccinate (CHEMS) ion pair (ACIP) was first prepared, and the successful formation of the ACIP was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD), which demonstrated a stable interaction between CHEMS and AZM. The ACIP-loaded liposome (ACIP-Lip) appeared as spherical particles under TEM, with a uniform particle size of 60 +/- 2 nm and zeta potential of -20.3 +/- 4.6 mV. The entrapment efficiency (EE) and drug loading (DL) of ACIP-Lip were greatly improved to 95.6 +/- 2.0 and 9.2 +/- 0.7%, respectively, which was attributed to the enhanced loading capacity of the liposomes through use of the ion pair and addition of MCT. ACIP-Lip also exhibited a high stability during a 3 month storage period at both 4 and 25 degrees C. In vitro release of AZM from ACIP-Lip was pH-dependent, with a more rapid release at pH 6.0 than at pH 7.4, which is beneficial for ocular therapy. Furthermore, the corneal permeation of AZM was enhanced by ACIP-Lip, demonstrating an apparent permeability coefficient ( Papp * 106) of 8.92 +/- 0.56 cm/s, which was approximately 2-fold greater that of the AZM solution. Finally, an in vivo pharmacodynamical study showed that the essential symptoms of DE rats were significantly improved by ACIP-Lip, as it was highly efficient and superior compared to hyaluronic acid sodium eye drops available on the market. Hence, ACIP-Lip is a promising formulation for DE treatment. PMID- 30251865 TI - Noninvasive Detection of HER2 Expression in Gastric Cancer by 64Cu-NOTA Trastuzumab in PDX Mouse Model and in Patients. AB - The purpose of this study was to establish the quality control and quantify the novel 64Cu-NOTA-Trastuzumab in gastric cancer patient-derived xenografts (PDX) mice models and patients by applying the molecular imaging technique. Trastuzumab was labeled with 64Cu using NCS-Bz-NOTA as bifunctional chelator, and hIgG1 was labeled with the same procedures as a negative control agent. HER2-positive (case 176, n = 12) and HER2-negative (case 168, n = 3) PDX models were established and validated by Western blot, DNA amplification, and immunohistochemistry (IHC). Both models were conducted for micro-PET imaging by tail injection of 18.5 MBq of 64Cu-NOTA-Trastuzumab or 64Cu-NOTA-hIgG1. Radioprobe uptake in tumor and main organs was quantified by region of interested (ROI) analysis of the micro-PET images and autoradiography. Finally, gastric cancer patients were enrolled in preliminary 64Cu-NOTA-Trastuzumab PET/CT scans. NOTA-Trastuzumab was efficiently radiolabeled with 64Cu over a 99% radiochemical purity and 17.5 GBq/MUmol specific activity. The immune activity was preserved as the nonmodified antibody, and the radiopharmaceutical proved to be stable for up to 5 half-decay lives of 64Cu both in vitro and in vivo. Two serials of PDX gastric cancer models were successfully established: case 176 for HER2 positive and case 168 for HER2 negative. In micro-PET imaging studies, 64Cu-NOTA-Trastuzumab exhibits a significant higher tumor uptake (11.45 +/- 0.42 ID%/g) compared with 64Cu-NOTA IgG1 (3.25 +/- 0.28 ID%/g, n = 5, p = 0.0004) at 36 h after intravenous injection. Lower level uptake of 64Cu-NOTA-Trastuzumab (6.35 +/- 0.48 ID%/g) in HER2-negative PDX tumor models further confirmed specific binding of the radioprobe. Interestingly, the coinjection of 2.0 mg of Trastuzumab (15.52 +/- 1.97 ID%/g) or 2.0 mg of hIgG1 (15.64 +/- 3.54 ID%/g) increased the 64Cu-NOTA Trastuzumab tumor uptake in PDX tumor (HER2+) models compared with 64Cu-NOTA Trastuzumab alone ( p < 0.05) at 36 h postinjection. There were good correlations between micro-PET images and IHC ( n = 4) and autoradiography in PDX (HER2+) tumor tissues. Therefore, 64Cu-NOTA-Trastuzumab successfully translated to clinical PET imaging, and 64Cu-NOTA-Trastuzumab PET/CT scan in gastric cancer patients showed good detection ability. In conclusion, we reported quality control and application of novel 64Cu-NOTA-Trastuzumab for HER2 expression in PDX gastric cancer mice models and gastric cancer patients. Moreover, 64Cu-NOTA Trastuzumab holds great potential for noninvasive PET detection, staging, and follow-up of HER2 expression in gastric cancer. PMID- 30251866 TI - A Heck-Based Strategy To Generate Anacardic Acids and Related Phenolic Lipids for Isoform-Specific Bioactivity Profiling. AB - A synthetic strategy for phenolic lipids such as anacardic acid and ginkgolic acid derivatives using an efficient and selective redox-relay Heck reaction followed by a stereoselective olefination is reported. This approach controls both the alkene position and stereochemistry, allowing the synthesis of natural and unnatural unsaturated lipids as single isomers. By this strategy, the activities of different anacardic acid and ginkgolic acid derivatives have been examined in a matrix metalloproteinase inhibition assay. PMID- 30251867 TI - Cation Molecular Exchanger Based on a Conformational Hinge. AB - A cation molecular exchanger has been developed that consists of the bipyridine and crown ether receptor subunits. It has been shown that binding of the zinc(II) cation to the bipyridine subunit induces the conformational switching of the crown ether subunits, which results in a release of the potassium cation. Two conformational states of the cation exchanger have been supported by the results from solution- and solid-state studies. It has been demonstrated that the cation exchanger is able to communicate with a cation sensor induced by a chemical stimulus. PMID- 30251869 TI - Stretch and Breakage of Wormlike Micelles under Uniaxial Strain: A Simulation Study and Comparison with Experimental Results. AB - We use coarse-grained (CG) molecular dynamics simulations to determine the effect of uniaxial strain on the stress, scission stress, and scission energy of solutions of wormlike micelles of cetyltrimethylammonium chloride/sodium salicylate (NaSal). We find that the breaking stress, stretch modulus, and scission energy of the charged micelles are nonmonotonic functions of oppositely charged hydrotrope (NaSal) concentration. While the stretch modulus shows a peak at a value of surfactant-to-hydrotrope concentration ratio ( R) close to unity as expected due to neutralization of head-group charge at R = 1, the breaking stress and scission energy produce a peak at R < 1.0 because of thinning of the micelle diameter with increased R. The breaking stress from the simulations depends on the rate of deformation and roughly agrees with the experimental values of Rothstein ( J. Rheol. 2003 , 47 , 1227 ) after extrapolation to the much lower experimental rates. The method and results can be used to predict the effects of flow and mechanical stress on rates of micellar breakage, which is important in the rheology of wormlike micellar solutions. PMID- 30251868 TI - Deterministic Positioning of Colloidal Quantum Dots on Silicon Nitride Nanobeam Cavities. AB - Engineering an array of precisely located cavity-coupled active media poses a major experimental challenge in the field of hybrid integrated photonics. We deterministically position solution-processed colloidal quantum dots (QDs) on high quality (Q)-factor silicon nitride nanobeam cavities and demonstrate light matter coupling. By lithographically defining a window on top of an encapsulated cavity that is cladded in a polymer resist, and spin coating the QD solution, we can precisely control the placement of the QDs, which subsequently couple to the cavity. We show rudimentary control of the number of QDs coupled to the cavity by modifying the size of the window. Furthermore, we demonstrate Purcell enhancement and saturable photoluminescence in this QD-cavity platform. Finally, we deterministically position QDs on a photonic molecule and observe QD-coupled cavity supermodes. Our results pave the way for precisely controlling the number of QDs coupled to a cavity by engineering the window size, the QD dimension, and the solution chemistry and will allow advanced studies in cavity enhanced single photon emission, ultralow power nonlinear optics, and quantum many-body simulations with interacting photons. PMID- 30251870 TI - Silver-Catalyzed Radical Cascade Cyclization toward 1,5-/1,3-Dicarbonyl Heterocycles: An Atom-/Step-Economical Strategy Leading to Chromenopyridines and Isoxazole-/Pyrazole-Containing Chroman-4-Ones. AB - A novel and convenient silver-catalyzed radical cascade cyclization toward a large variety of 1,5-/1,3-dicarbonyl heterocycles containing a chroman-4-one, indanone, or 2,3-dihydroquinolin-4(1 H)-one moiety was developed, by reacting various 2-functionalized benzaldehydes, including 2-allyloxy benzaldehydes, 2 allyl benzaldehyde, and 2-N(Ts)CH2-CH?CH2 substituted benzaldehyde, with 1,3 dicarbonyl compounds in the presence of AgNO3/K2S2O8 in one pot under mild reaction conditions. The newly obtained 1,5-/1,3-dicarbonyl-containing heterocycles were further used directly to synthesize more structurally diverse polyheterocycles, mainly including chromenopyridines as well as isoxazole- or pyrazole-containing chroman-4-ones. PMID- 30251871 TI - Real-Time and Simultaneous Monitoring of NO, NO2, and N2O Using Substrate Integrated Hollow Waveguides Coupled to a Compact Fourier Transform Infrared (FT IR) Spectrometer. AB - Nitrogen-based fertilizers have been used in modern agricultural activities resulting in a relevant emission source of nitrogen gases into the atmosphere, mainly nitric oxide (NO), nitrogen dioxide (NO2), and nitrous oxide (N2O). Furthermore, the burning of fossil fuels is the most significant emission source of NOx (i.e., NO + NO2), being the controlling of vehicle exhaust system an essential task. Those compounds can be related to air pollution effects either directly, by emitting a powerful greenhouse gas (i.e., N2O), or indirectly, by formation of nitric acid (HNO3) or ammonium nitrate (NH4NO3) from NO or NO2, responsible for the increase of acid rain and particulate material into the atmosphere. This context requires appropriate sensor technology facilitating in situ and simultaneous monitoring of nitrogen emitted gases, with easiness of operation and compact dimensions. In this communication, we describe an innovative mid-infrared chemical sensor platform for the in situ, real-time, and simultaneous quantification of gaseous NO, NO2, and N2O by combining a compact Fourier transform infrared (FT-IR) spectrometer with the so-called substrate integrated hollow waveguide (iHWG) as a miniaturized gas cell. The optical platform enabled limits of detection of 10, 1, and 0.5 ppm of NO, NO2, and N2O, respectively. The linear concentration range evaluated in this study is suitable for the application of the sensing platform in vehicle exhaust air samples. Given the high adaptability of the developed infrared sensing device toward preconcentration or ultraviolet conversion modules and also considering the potential for combining tunable interband cascade lasers (ICLs) in lieu of the FT IR spectrometer, we anticipate the application of the sensing platform for in situ determination of nitrogen gases in a wide range of scenarios. PMID- 30251872 TI - Vitamin D Metabolites in Aging HIV-Infected Men: Does Inflammation Play a Role? AB - The inflammatory context of HIV infection has been posited to contribute to the higher comorbidity risk noted in HIV-infected populations. One possible pathway may involve 1,25-dihydroxyvitamin D [1,25(OH)2D], which plays a wide biologic role in many tissues. We sought to investigate whether inflammation was associated with vitamin D metabolites in a cohort of HIV-infected (HIV+) men receiving treatment and HIV-uninfected (HIV-) men. Vitamin D metabolites, including 25-hydroxyvitamin D [25(OH)D] and 1,25(OH)2D, were measured along with 24 inflammatory markers among Multicenter AIDS Cohort Study participants. Exploratory factor analysis reduced inflammatory marker data to a smaller set of inflammatory processes (IPs). Multivariate linear regression was used to evaluate associations between vitamin D metabolites and IPs. There were 466 HIV+ and 100 HIV- men, who contributed 658 stored samples from 1998 to 2008. We found three IPs with IP 1 characterized by sTNF-R2, sIL-2Ralpha, sCD27, BAFF, sgp130, sCD14, CXCL10 (IP-10), and sIL-6R. While none of the three IPs was associated with 25(OH)D levels in either HIV+ or HIV-, higher levels of IP 1 were significantly associated with the reduced levels of 1,25(OH)2D in HIV+, and a similar although nonsignificant trend was seen in HIV-. The association between 1,25(OH)2D and inflammation found among HIV-infected men suggests a possible mechanism whereby inflammation leads to the increased comorbidity risk noted among HIV-infected individuals. PMID- 30251873 TI - A Pharmacochaperone-Based High-Throughput Screening Assay for the Discovery of Chemical Probes of Orphan Receptors. AB - G-protein-coupled receptors (GPCRs) have varying and diverse physiological roles, transmitting signals from a range of stimuli, including light, chemicals, peptides, and mechanical forces. More than 130 GPCRs are orphan receptors (i.e., their endogenous ligands are unknown), representing a large untapped reservoir of potential therapeutic targets for pharmaceutical intervention in a variety of diseases. Current deorphanization approaches are slow, laborious, and usually require some in-depth knowledge about the receptor pharmacology. In this study we describe a cell-based assay to identify small molecule probes of orphan receptors that requires no a priori knowledge of receptor pharmacology. Built upon the concept of pharmacochaperones, where cell-permeable small molecules facilitate the trafficking of mutant receptors to the plasma membrane, the simple and robust technology is readily accessible by most laboratories and is amenable to high throughput screening. The assay consists of a target harboring a synthetic point mutation that causes retention of the target in the endoplasmic reticulum. Coupled with a beta-galactosidase enzyme-fragment complementation reporter system, the assay identifies compounds that act as pharmacochaperones causing forward trafficking of the mutant GPCR. The assay can identify compounds with varying mechanisms of action including agonists and antagonists. A universal positive control compound circumvents the need for a target-specific ligand. The veracity of the approach is demonstrated using the beta-2-adrenergic receptor. Together with other existing assay technologies to validate the signaling pathways and the specificity of ligands identified, this pharmacochaperone-based approach can accelerate the identification of ligands for these potentially therapeutically useful receptors. PMID- 30251874 TI - Mars-Relevant Field Experiences in Morocco: The Importance of Spatial Scales and Subsurface Exploration. AB - During field work at the Ibn Battuta Mars analogue sites, two research questions were analyzed: (1) How do we identify sampling sites using remote and local imaging and (2) what kind of information can be gained from shallow subsurface exploration? While remote images help in targeting field activities in general, the connection between observations at different spatial scales for different rocky desert terrain types is not well established; in this, focused comparison of remote in situ images of well-selected analogues would help a great deal. Dried up lake beds as discerned in remotely acquired data may not show signatures of past water activity, while shallow subsurface exploration could reveal the lacustrine period. Acquisition of several satellite images of the same terrain under different geometries would help to support the planning of such in situ work. The selection of appropriate sampling sites in fluvial settings could be improved by analyzing long, meter-high, open-air outcrops that formed during most recent fluvial episodes. Such settings are abundant on Earth and could be present on Mars but may be just below the resolution of available data. By using 20-30-cm deep excavations, shallow subsurface exploration could reveal the last period of geological history that would have been unattainable by surface observation alone. Aggregates embedded in the original strata or from heavily pulverized samples could not be identified; only weakly fragmented samples viewed right after acquisition showed aggregates, and thus, the Close-Up Imager (CLUPI) on the ExoMover might provide information on cementation-related aggregation on the observing plate before crushing. The mechanical separation of different size grains (mainly clays and attached minerals) would also support the identification of individual components. To maximize context information during subsurface exploration, rover imaging should be accomplished before crushing; however, currently planned imaging may not be ideal for this. PMID- 30251875 TI - Amok: a mirror of time and people. A historical review of literature. AB - The conceptualization of psychiatric disorders changes continuously. This study examined 'amok', a culture-bound syndrome related to sudden mass homicide, to elucidate changing and varied concepts. A historical review of 88 English articles revealed that the meanings and assumed causes of amok have changed over time. These changes appear to have been affected by social events, medical discoveries, knowledge of descriptors and occasionally, the benefit to users. In other words, the concept of amok changes depending on the history of society and the knowledge and intention of people at the time. We should consider in detail what we focus on when diagnosing a disorder. PMID- 30251876 TI - Seeing the Wood for the Trees - Household Air Pollution and Lung Disease. PMID- 30251878 TI - Comments on "Drug combination studies of curcumin and genistein against rhodesain of Trypanosoma brucei rhodesiense". PMID- 30251877 TI - An Improved Background-Correction Algorithm for Raman Spectroscopy Based on the Wavelet Transform. AB - In the traditional background correction algorithm based on the wavelet transform, approximation coefficients considered as frequency responses of background signal are usually set to zero. However, there are many meaningless negative values generated in the background-corrected spectrum because of the calibration errors of this algorithm. Intensities of some weak peaks even become negative and these peaks will disappear after the calibration of negative values. To solve these problems for the background correction of Raman spectrum, an improved intelligent algorithm which utilizes a suppression coefficient to modify approximation coefficients is proposed in this paper. A series of simulation analyses, as well as experimental investigations, are made to test the performance of this algorithm. It is proved that the use of the suppression coefficient could increase the background correction accuracy and decrease the number of meaningless negative values in the reconstructed spectra, which will prevent the disappearance of weak Raman peaks after the calibration of negative values and increase the sensitivity of Raman spectral analysis. PMID- 30251879 TI - Intermittent Hypoxia-Hyperoxia Conditioning Improves Cardiorespiratory Fitness in Older Comorbid Cardiac Outpatients Without Hematological Changes: A Randomized Controlled Trial. AB - : Dudnik, Elena, Zagaynaya E, Glazachev OS, and Susta D. Intermittent Hypoxia Hyperoxia Conditioning Improves Cardiorespiratory Fitness in Older Comorbid Cardiac Outpatients Without Hematological Changes: A Randomized Controlled Trial. High Alt Med Biol 00:000-000, 2018. AIM: To compare a program based on intermittent hypoxia-hyperoxia training (IHHT) consisting of breathing hypoxic hyperoxic gas mixtures while resting to a standard exercise-based rehabilitation program with respect to cardiorespiratory fitness (CRF) in older, comorbid cardiac outpatients. MATERIALS AND METHODS: Thirty-two cardiac patients with comorbidities were randomly allocated to IHHT and control (CTRL) groups. IHHT completed a 5-week program of exposure to hypoxia-hyperoxia while resting, CTRL completed an 8-week tailored exercise program, and participants in the CTRL were also exposed to sham hypoxia exposure. CRF and relevant hematological biomarkers were measured at baseline and after treatment in both groups. RESULTS: After intervention, CRF in the IHHT group was not significantly different (n = 15, 19.9 +/- 6.1 mlO2 minutes-1 kg-1) compared with the CTRL group (n = 14, 20.6 +/- 4.9 mlO2 minutes-1 kg-1). CRF in IHHT increased significantly from baseline (6.05 +/- 1.6 mlO2 minutes-1 kg-1), while no difference was found in CTRL. Systolic and diastolic blood pressures were not significantly different between groups after treatment. Hemoglobin content was not significantly different between groups. Erythrocytes and reticulocytes did not change pre/post interventions in both experimental groups. CONCLUSIONS: IHHT is safe in patients with cardiac conditions and common comorbidities and it might be a suitable option for older patients who cannot exercise. A 5-week IHHT is as effective as an 8-week exercise program in improving CRF, without hematological changes. Further studies are needed to clarify the nonhematological adaptations to short, repeated exposure to normobaric hypoxia-hyperoxia. PMID- 30251880 TI - Uncontrolled severe asthma: starting from the unmet needs. PMID- 30251881 TI - Extreme Heat Considerations in International Football Venues: The Utility of Climatologic Data in Decision Making. AB - CONTEXT: : Exposure to severe heat can have detrimental effects on athletic performance and increase the risk of exertional heat injuries. Therefore, proactive assessment of the environmental characteristics of international football match venues becomes critical in ensuring the safety and optimal performance of the athletes. OBJECTIVE: : To propose the use of climatologic data (modeled wet-bulb globe temperature [WBGT]) in making athletic-event management decisions for the 2020 Summer Olympic Games and the 2022 Federation Internationale de Football Association World Cup. DESIGN: : Descriptive study. SETTING: : Hourly meteorologic input data for a WBGT model were obtained from the second Modern-Era Retrospective Analysis for Research and Applications for Japan (Yokohama and Saitama) and Qatar (Doha and Al-Daayen). MAIN OUTCOME MEASURE(S): : The pattern of hourly WBGT and percentage of hours between 30 degrees C and 32 degrees C and exceeding 32 degrees C WBGT during the expected competition periods for the 2020 Summer Olympic Games in Japan and the scheduled (November, December) and traditional (June, July) periods of the World Cup games in Qatar. RESULTS: : The WBGT during the 2020 Olympic football tournament in Japan may exceed 30 degrees C in 40% to 50% of the late mornings and early afternoons. The shift in tournament timing for the 2022 Federation Internationale de Football Association World Cup in Qatar from the summer to late fall will reduce the exposure to >=30 degrees C WBGT to null. CONCLUSIONS: : Directors of mass sporting events should consider using climatologic data in their organizational decision making to assess the potential heat illness risk and to implement risk-mitigation plans. PMID- 30251882 TI - Simultaneous Model Selection and Model Calibration for the Proliferation of Tumor and Normal Cells During In Vitro Chemotherapy Experiments. AB - In vitro experiments were conducted in this work to analyze the proliferation of tumor (DU-145) and normal (macrophage RAW 264.7) cells under the influence of a chemotherapeutic drug (doxorubicin). Approximate Bayesian Computation (ABC) was used to select among four competing models to represent the number of cells and to estimate the model parameters, based on the experimental data. For one case, the selected model was validated in a replicated experiment, through the solution of a state estimation problem with a particle filter algorithm, thus demonstrating the robustness of the ABC procedure used in this work. PMID- 30251883 TI - Some reflections concerning the assessment of patient adherence and persistence to medication. PMID- 30251884 TI - Social isolation is associated with 90-day rehospitalization due to heart failure. AB - BACKGROUND: Social isolation has been reported to be associated with decreased quality of life and the onset of organic diseases. The objective of this study was to investigate the prevalence of social isolation in patients with heart failure and whether it is associated with rehospitalization. METHODS AND RESULTS: The study included consecutive patients aged ?55 years who were hospitalized due to heart failure. Social isolation was assessed using total scores less than 12 on an abbreviated version of the Lubben Social Network Scale. The endpoint was heart failure rehospitalization within 90 days after discharge. Among 148 patients with heart failure (80+/-8 years old, 51% male), 73 (49%) were socially isolated. The patients with social isolation had similar comorbidities compared with those without social isolation. Heart failure rehospitalization occurred within 90 days for 25 patients and the heart failure rehospitalization rate was significantly higher in the social isolation group ( p=0.036). LASSO (least absolute shrinkage and selection operator) regression confirmed that social isolation was one of the strongest predictors of heart failure rehospitalization, showing larger effects than living alone, being unemployed, and other established risk factors. CONCLUSION: Half of the patients with heart failure reported social isolation, which had a strong association with heart failure rehospitalization. PMID- 30251885 TI - Evolution in the treatment landscape of non-small cell lung cancer with ALK gene alterations: from the first- to third-generation of ALK inhibitors. AB - INTRODUCTION: The medical treatment of non-small cell lung cancer (NSCLC) has radically changed over the last 10 years thanks to new molecular-targeted drugs able to act on biological mechanisms involved in tumor development. One such mechanism is the aberrant anaplastic lymphoma kinase (ALK) activation: patients with ALK-driven NSCLC benefit from treatments that selectively inhibit its pathogenetic mechanism. Areas covered: The first-generation ALK inhibitor is crizotinib, initially used in Europe as second-line treatment for ALK-positive metastatic NSCLC patients, then approved as the standard first-line (already approved in the USA as front-line therapy). However, most patients eventually experience disease progression due to the emergence of secondary resistance, partly linked to ALK-dependent mechanisms, hence the development of second- and third-generation ALK inhibitors: ceritinib, alectinib, and brigatinib are approved for ALK-positive NSCLC, lorlatinib is currently being evaluated while others are under development. Expert opinion: Despite the considerable responses to these new inhibitors, however, resistance mechanisms are described. Thus, while the therapeutic scenario of NSCLC has been soon revolutionized introducing next-generation ALK inhibitors in the first-line setting, future research should identify combined therapies or new generation drugs overcoming resistance in pretreated patients. PMID- 30251886 TI - Tunnel Formation in Basalt Glass. AB - We propose a model whereby microscopic tunnels form in basalt glass in response to a natural proton flux from seawater into the glass. This flux is generated by the alteration of the glass as protons from water replace cations in the glass. In our proton gradient model, cells are gateways through which protons enter and alter the glass and through which cations leave the glass. In the process, tunnels are formed, and cells derive energy from the proton and ion fluxes. Proton flux from seawater into basalt glass would have occurred on Earth as soon as water accumulated on the surface and would have preceded biological redox catalysis. Tunnels in modern basalts are similar to tunnels in Archean basalts, which may be our earliest physical evidence of life. Proton gradients like those described in this paper certainly exist on other planetary bodies where silicate rocks are exposed to acidic to slightly alkaline water. PMID- 30251887 TI - Improving peace and well-being among Syrian refugee youth through a higher education initiative in Jordan. AB - Forced migration affects overall health, especially when it happens at a young age. Focus group discussions and the Peace Evaluation Across Cultures and Environments (PEACE) survey were used to compare the effects of the programme on two groups: refugee university students who received full tuition support and a monthly living stipend (intervention group) and unsponsored Syrian students who were preparing for the end of high school examination (control group). The overall mean PEACE score among the intervention group was 152.0 (95% confidence interval [CI]: 147.4-156.5), while the control group mean score was 134.1 (95% CI: 129.1-139.1), p < 0.01. In addition to significantly higher mean total PEACE scores, the intervention group demonstrated better results for each of the seven constructs in the scale (t-test p < 0.05), with the largest differences seen in personal safety, group cohesion and agency. This effect was further elucidated in the focus group discussions, highlighting the psychosocial benefits of the scholarship programme due to improvements in their academic and financial status. This combined education and economic intervention for Syrian refugee youth has measurable positive effects on feelings of peace, security and well-being and can be used as a framework from which to design similar initiatives in other contexts of displacement. PMID- 30251888 TI - Hemoglobin Concentration in Children at Different Altitudes in Peru: Proposal for [Hb] Correction for Altitude to Diagnose Anemia and Polycythemia. AB - Ocas-Cordova, Silvana, Vilma Tapia, and Gustavo F. Gonzales. Hemoglobin concentration in children at different altitudes in Peru: proposal for [Hb] correction for altitude to diagnose anemia and polycythemia. High Alt Med Biol. 00:000-000, 2018.-The present study was designed to define the hemoglobin [Hb] increase with altitude in Peruvian children. We suggest the normal range of [Hb] as means +/-2 standard deviations (SD), with a value less than - 2 SD as a possible threshold to detect anemia. The prevalence of anemia was calculated. These values were compared to the World Health Organization (WHO) altitude correction parameter and the threshold for anemia of 11 g/dL. Likewise, polycythemia is suggested as [Hb] greater than 2 SD. 2,028,701 children aged 6-59 months were analyzed. The quadratic regression analysis shows that [Hb] is constant between sea level and 999 m. Thereafter, [Hb] increases from 11.32 g/dL (1000 m) up to ~14.54 g/dL at 4000 m. Applying the threshold for anemia defined by WHO (11 g/dL) results in a prevalence of ~35% for children living at altitudes <1000 m, and prevalence decreases to ~4.5% at >4000 m. After [Hb] altitude correction, the prevalence was ~36% (1000 m) and increases to ~66% above 4000 m. With our proposed threshold for anemia, the prevalence was ~15% below 1000 m and ~5% above 4000 m. For polycythemia ([Hb] >14.5 g/dL), increases were from 1.2% at <1000 m to 39.4% at 4000 m. After [Hb] correction for altitude, the prevalence of polycythemia decreases with altitude. Excessive erythrocytosis defined as [Hb] >19 g/dL shows the highest values at 4000 m, while polycythemia defined as [Hb] greater than 2 SD was reduced at high altitude (HA). In conclusion, using WHO thresholds for anemia and [Hb] correction by altitude most likely overestimates the prevalence of anemia and may underestimate polycythemia in Peruvian children living at HA. Therefore, new threshold values for anemia and polycythemia as mean [Hb] less than 2 SD and greater than 2 SD for populations living at a specific altitude are suggested. PMID- 30251889 TI - "Developing Experimental Design and Analysis Skills in Undergraduates": IUPS Teaching Satellite Meeting, Brazil, August 2017. AB - This workshop was held at the Teaching Satellite Meeting of the International Union of Physiological Sciences (IUPS), August 5-8, 2017, in Buzios, Rio de Janiero, Brazil. The satellite meeting was attended by physiology educators from across the globe, of whom 34 attended this workshop. The aim of the workshop was to explore how experimental design is taught to students of physiology in different institutions, to consider the aspects that students find challenging, to share good practice, and to think about how experimental design teaching could be improved. Through small-group discussions that were then shared with the whole group, participants were challenged to develop the outline of a research project to investigate a broad topic and then to identify the challenges that students might face if they were given that task. Finally, the group thought about what, in practical terms, could be done to help develop experimental design skills in undergraduates. The outcomes of the discussions are summarized in this report. PMID- 30251890 TI - Flipped classroom narrows the performance gap between low- and high-performing dental students in physiology. AB - The flipped classroom has been shown to have positive outcomes in learning. However, relatively little has been reported on the implementation of it in dental education. The purpose of this study was to evaluate the impact of the flipped classroom on predoctoral dental students' learning. Two consecutive classes of dental students learned the physiology of the autonomic nervous system through the nonflipped (traditional lecture) or the flipped approach. Students' learning was assessed with an identical quiz at the end of the module. The mean score in the flipped approach was higher than that in the nonflipped approach ( P < 0.01). Mean score on the content-based quiz questions in the flipped approach was higher than that in the nonflipped approach ( P < 0.05). Performance on case based questions did not show a significant difference ( P = 0.12). Mean quiz performance of the lower 27% scorers in the flipped approach was higher than that in the nonflipped approach ( P < 0.05). Mean quiz performance of the upper 27% scorers showed an increase in the flipped approach as well ( P < 0.05), but to a less extent than that of the lower 27% scorers ( P < 0.01). The flipped approach also increased peer collaboration ( P < 0.01). In summary, the flipped classroom improved dental students' performance on content-based questions in physiology. The flipped classroom narrowed the performance gap between the low- and high performing dental students. PMID- 30251891 TI - Question order and student understanding of structure and function. AB - The relationship between structure and function is a core concept in physiology education. Written formative assessments can provide insight into student learning of the structure and function relationship, which can then inform pedagogy. However, question order may influence student explanations. We explored how the order of questions from different cognitive levels affects student explanations. A junior level General Physiology class was randomly split in half. One-half of the students answered, "Define the principle: form reflects function," followed by "Give an example of the principle: form reflects function" (format DX), whereas the other half answered, "Give an example of the principle: form reflects function," followed by "Define the principle: form reflects function" (format XD). Human grading and computerized lexical analysis were used to evaluate student responses. Two percent of students in the format DX group related structure and function in their definition, whereas 48% of students related structure and function in their examples. In the format XD group, 17% related structure and function in their definition, and 26% related structure and function in their example of the principle. Overall, students performed better on the last question in the sequence, which may be evidence for conceptual priming. Computerized lexical analysis revealed that students draw on only a few levels of organization and may be used by instructors to quickly assess the levels of organization students use in their responses. Written assessment coupled with lexical analysis has the potential to reveal student understanding of core concepts in anatomy and physiology education. PMID- 30251892 TI - Comparison of knowledge retention between high-fidelity patient simulation and read-only participants in undergraduate biomedical science education. AB - High-fidelity patient simulation (HFPS) is expensive in money and faculty resources. There has been a recent push to increase the use of HFPS for undergraduates to teach basic science. However, it is still unclear if HFPS is superior to other cost-effective modalities for learning, and there have been limited studies comparing HFPS directly with other methods. The purpose of this study was to compare learning between three groups: 1) students who participated in a HFPS after reading material (RS); 2) students who reread material (RR) individually; and 3) students who had no intervention or reading (CON). Quizzes (10 true/false questions) were given presimulation, immediately after the simulation (post-sim 1), and 1 wk later to all groups (post-sim 2). Ninety-seven undergraduate students consented to include their data in the study. All groups scored the same on the presimulation quiz (median of 6). The RR and RS scored significantly higher than the CON group on post-sim 1 (medians 8 vs. 6). All groups performed similarly on post-sim 2. A questionnaire also showed that students had increased perceived confidence about pathophysiology. These data suggest that a single-time use of HFPS for knowledge learning for undergraduate students is not more effective than other methods. Future studies need to determine whether increasing the number of HFPS and developing social learning networks could make HFPS more effective for undergraduates. Additionally, future studies should focus on soft skill development, such as confidence, critical thinking, and teamwork/communication skills, as opposed to knowledge acquisition. PMID- 30251893 TI - Relationship between classroom attendance and examination performance in a second year medical pathophysiology class. AB - Studies completed with undergraduate populations have shown that attendance positively correlates with academic performance. A marked decline in classroom attendance within medical school has recently been noticed with the availability of video capture of lectures and other online material. This study compares these in the era of online material. It took place during the second-year Gastrointestinal and Renal Systems module. Attendance was mandatory at team-based learning and case-based learning sessions on new material and voluntary at lectures (29 sessions) and case-based learning on material previously covered (9 sessions). Attendance was recorded prospectively. All lectures were recorded, and all related files were available to students online. Performance was based on a 118 multiple-choice question final examination. Students voluntarily completed the Motivated Strategies for Learning Questionnaire (MSLQ). The study group consisted of 78 students (68% of 114 total) of whom 48 completed the MSLQ. Mean attendance was 24%, with 33% of students attending none of the nonmandatory sessions. The median score on the final exam for participants was 86.0 (range: 28.8). High levels of self-efficacy and the ability to self-regulate effort were predictive of low attendance. Attendance was positively predicted by an orientation toward peer learning and help seeking. There was no correlation between the percentage of classes attended and performance on the final exam. We conclude that different facets of self-regulated learning predict attendance, with highly confident students being the least likely to attend, and that attendance at in-class sessions is no longer a good marker for performance. PMID- 30251894 TI - Collaborative active learning: bioimpedance and anthropometry in higher education. AB - Research in the health sciences devotes much attention to overweight and obesity and, consequently, to body composition. In recent years, traditional body measures have been questioned as efficient variables in health sciences due to the fact that they cannot give information about body fat mass. Our aim is to teach how to analyze body composition through anthropometry and bioelectrical impedance analysis to our "Physiology of Vegetative and Reproductive Functions" students, who are studying for their degree in Biology. We proposed project oriented-learning to promote collaborative interactions among students. Fifty-two students voluntarily formed five groups; they worked with the concepts of basal metabolic rate and body composition from a theoretical point of view and later transformed these concepts into a practical perspective by preparing a manuscript in groups with objectives proposed by our teaching team. In this research, we show a collaborative educational scenario for university students in which students are tutored from a constructivist perspective to promote social interactions, resulting in new knowledge acquisition. PMID- 30251895 TI - Symposium report on "Examining the Changing Landscape of Course Delivery and Student Learning": Experimental Biology 2017. AB - An APS Teaching Section symposium entitled "Examining the Changing Landscape of Course Delivery and Student Learning" was offered at the Experimental Biology conference on April 24th, 2017, in Chicago, IL. The symposium focused on alternative delivery modes of physiology education, from undergraduate to professional programs. Lecture used to be the gold standard and proven method by which students learned, but the course delivery method is rapidly changing. While there is still significant skepticism about the quality and level of student engagement in online learning, it is being offered widely due to increased demand and due to other benefits, such as the flexibility and convenience. Universities with several campuses may now synchronize lectures between campuses, utilizing video conference technology, thus bypassing the need for instructors on each campus. Other modes of delivery include online lectures with laboratories scheduled on campus. Offering biology laboratories online is on the rise but to counter skepticism, more studies are needed to demonstrate that online laboratories effectively meet laboratory objectives. The Massive Open Online Course (MOOC) offers many courses for free and challenges the role of universities. Assessment of the effectiveness of MOOCs and online courses is critical, as some of the concerns raised about them include level of student engagement in learning and the social aspect of interaction with peers and faculty. PMID- 30251896 TI - Pharmacological treatment of anxiety disorders in adults with epilepsy. AB - INTRODUCTION: Anxiety disorders represent one of the most frequently encountered comorbidities in patients with epilepsy, affecting the quality of life and increasing, morbidity, mortality, and healthcare costs. However, they are still underdiagnosed and undertreated. Areas covered: This is a narrative review of the pharmacological treatment of anxiety disorders in adult patients with epilepsy discussing also major issues regarding pathophysiology and diagnosis. Expert opinion: There are a lack of studies concerning the treatment of anxiety disorders in epilepsy, which is a serious gap in the literature. There is an urgent need for treatment and outcome data in order to provide information to patients. Current evidence outside epilepsy focuses on Selective Serotonin Reuptake Inhibitors and Serotonin Noradrenalin Reuptake Inhibitor with strong evidence especially for the acute and long-term treatment of Generalized Anxiety Disorder and Social Anxiety Disorder. Although it is reasonable to adopt treatment guidelines outside of epilepsy, it is completely unknown whether anxiety disorders in people with epilepsy have the same response and remission rates observed outside epilepsy. Future research strategies for new drug treatments in epilepsy will probably take comorbidities into account. At this point, pregabalin and buspirone represent an interesting starting point for the development of new compounds potentially indicated in both conditions. PMID- 30251897 TI - Expert opinion on existing and developing drugs to treat female sexual dysfunction. AB - INTRODUCTION: Female sexual dysfunction (FSD) is a highly prevalent, yet commonly underdiagnosed and undertreated condition. This paper reviews the diagnostic terminology for FSD, and basic sexual physiology in women. The Food and Drug Administration (FDA) approved drugs for FSD are discussed, followed by investigational drugs for FSD currently in phase 2 or 3 clinical trials, reasons for failure of drug development, and potential future drug targets. Areas covered: A literature review was conducted for available treatments for FSD: flibanserin, estrogen, ospemifene and prasterone. Potential treatments are assessed, as was the Pharmaprojects database which includes clinical trial information. Testosterone, bremelanotide, bupropion-trazodone, PDE-5 inhibitors, prostaglandins, tibolone and combination therapies, and the theoretical basis of potential drug targets are discussed. Expert opinion: The lack of established endpoints for phase 3 studies of FSD has impeded approval of new treatments, and required additional studies for validation, resulting in proposed changes to the FDA draft guidance for FSD clinical trials in October 2016. Current DSM-5 diagnostic nosology also fails to capture the full range of symptomology. Several promising compounds have shown no movement for several years limiting women's options. Overcoming socio-cultural bias against women's sexual and reproductive health will be critical in the approval of new treatments for FSD. PMID- 30251898 TI - Metformin and its sulphonamide derivative simultaneously potentiateanti cholinesterase activity of donepezil and inhibit beta-amyloid aggregation. AB - The aim of this study was to assess in vitro the effects of sulphenamide and sulphonamide derivatives of metformin on the activity of human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), establish the type of inhibition, and assess the potential synergism between biguanides and donepezil towards both cholinesterases (ChEs) and the effects on the beta-amyloid aggregation. Sulphonamide 5 with para-trifluoromethyl- and ortho-nitro substituents in aromatic ring inhibited AChE in a mixed-type manner at micromolar concentrations (IC50 = 212.5 +/- 48.3 umol/L). The binary mixtures of donepezil and biguanides produce an anti-AChE effect, which was greater than either compound had alone. A combination of donepezil and sulphonamide 5 improved the IC50 value by 170 times. Compound 5 at 200 umol/L inhibited Abeta aggregation by ~20%. In conclusion, para-trifluoromethyl-ortho-nitro-benzenesulphonamide presents highly beneficial anti-AChE and anti-Abeta aggregation properties which could serve as a promising starting point for the design and development of novel biguanide-based candidates for AD treatment. PMID- 30251899 TI - Inhibition of O-acetylserine sulfhydrylase by fluoroalanine derivatives. AB - O-acetylserine sulfhydrylase (OASS) is the pyridoxal 5'-phosphate dependent enzyme that catalyses the formation of L-cysteine in bacteria and plants. Its inactivation is pursued as a strategy for the identification of novel antibiotics that, targeting dispensable proteins, holds a great promise for circumventing resistance development. In the present study, we have investigated the reactivity of Salmonella enterica serovar Typhimurium OASS-A and OASS-B isozymes with fluoroalanine derivatives. Monofluoroalanine reacts with OASS-A and OASS-B forming either a stable or a metastable alpha-aminoacrylate Schiff's base, respectively, as proved by spectral changes. This finding indicates that monofluoroalanine is a substrate analogue, as previously found for other beta halogenalanine derivatives. Trifluoroalanine caused different and time-dependent absorbance and fluorescence spectral changes for the two isozymes and is associated with irreversible inhibition. The time course of enzyme inactivation was found to be characterised by a biphasic behaviour. Partially distinct inactivation mechanisms for OASS-A and OASS-B are proposed. PMID- 30251901 TI - Life-Threatening Drug-Induced Liver Injury in a Patient with beta-Thalassemia Major and Severe Iron Overload on Polypharmacy. AB - A 20-year-old male affected by transfusion-dependent beta-thalassemia (beta thal), was prescribed intensive chelation therapy with deferoxamine (DFO) and deferiprone (DFP) because of severe hepatic and cardiac iron overload and beta blocker and warfarin to manage a previous event of atrial fibrillation (AFib) and heart failure. After a few months, he developed critical liver failure, renal tubulopathy and severe electrolyte imbalance. Laboratory and instrumental evaluations were performed to carry out differential diagnosis of acute liver failure and an exclusion diagnosis of drug induced liver injury (DILI) was made. The cholestatic pattern suggested warfarin as the main causative agent and polypharmacy, liver iron overload and heart failure as aggravating factors. Warfarin is a drug commonly prescribed in thalassemia patients who often need polypharmacy for the management of anemia- and iron-related complications. Strict monitoring and multidisciplinary approaches are mandatory to avoid preventable mortality in this fragile population. PMID- 30251902 TI - A Novel beta-Thalassemia Mutation in a Chinese family: IVS-II-203-205 (TCT>CC) (HBB: c.315+203TCT>CC). AB - beta-Thalassemia (beta-thal) is one of the most common inherited disorders in southern China. More than 300 beta-globin gene mutations around the world have been reported in the HbVar database. In this study, a novel mutation in a 30-year old Chinese woman [IVS-II-203-205 (TCT>CC), HBB: c.315+203TCT>CC] was first found by direct sequencing. Subsequently, investigation of her parents' genetic codes was completed, and the results showed that her father also carried this mutation. Based on the features observed in clinical practice, this novel mutation was regarded as a mild phenotype of beta-thal. PMID- 30251900 TI - Synthesis and cellular bioactivities of novel isoxazole derivatives incorporating an arylpiperazine moiety as anticancer agents. AB - In our endeavour towards the development of effective anticancer therapeutics, a novel series of isoxazole-piperazine hybrids were synthesized and evaluated for their cytotoxic activities against human liver (Huh7 and Mahlavu) and breast (MCF 7) cancer cell lines. Within series, compounds 5l-o showed the most potent cytotoxicity on all cell lines with IC50 values in the range of 0.3-3.7 MUM. To explore the mechanistic aspects fundamental to the observed activity, further biological studies with 5m and 5o in liver cancer cells were carried out. We have demonstrated that 5m and 5o induce oxidative stress in PTEN adequate Huh7 and PTEN deficient Mahlavu human liver cancer cells leading to apoptosis and cell cycle arrest at different phases. Further analysis of the proteins involved in apoptosis and cell cycle revealed that 5m and 5o caused an inhibition of cell survival pathway through Akt hyperphosphorylation and apoptosis and cell cycle arrest through p53 protein activation. PMID- 30251903 TI - Social Well-Being in Adolescent and Young Adult Cancer Survivors. AB - PURPOSE: Adolescents and young adults (AYAs) diagnosed with cancer between ages 15-39 years are a unique and vulnerable population, encountering many typical developmental challenges while also dealing with the demands of illness and its aftermath. Overwhelming evidence demonstrates the importance of social well-being in survivorship quality of life. For AYAs, social connections may be of heightened importance as they assert independence from their parents and create their own personal lives. Few studies have characterized AYA survivors' social well-being and its determinants over time, particularly how psychological adjustment might promote improved social well-being. METHODS: We assessed 83 AYA survivors at two time points across 1 year to characterize their social well being, identify common social connection concerns, describe how social well-being changes over time, examine how psychological adjustment relates to social well being at a given time point, and determine whether psychological adjustment predicts changes in social well-being over time. RESULTS: Our sample rated their quality of life as lower than population mean scores, and despite relatively high levels of social support and satisfaction, more than half of participants also reported concerns in specific social well-being domains. On average, social well being increased across the year. Psychological adjustment was strongly positively related to various aspects of social well-being, and it predicted improved social well-being over time. CONCLUSION: These results suggest that improving psychological adjustment may be important for strengthening social support networks and improving AYAs' lives in survivorship. PMID- 30251904 TI - Psychedelics and the new behaviourism: considering the integration of third-wave behaviour therapies with psychedelic-assisted therapy. AB - This narrative review examines evidence related to the potential for third wave behaviour therapies to serve as adjuncts to psychedelic-assisted therapy. It identifies shared theoretical foundations for both approaches, and notes enhanced mindfulness, decentering, emotion regulation, and distress tolerance as common mechanisms of action. It also identifies potential targets for which both approaches have demonstrated therapeutic potential, including problematic substance use, self-directed and other-directed violence, and mood disorders. Based on these commonalities, there is a call for research on the potential integration of psychedelic-assisted therapy and third wave behaviour therapies including Dialectical Behaviour Therapy, Acceptance and Commitment Therapy, and Mindfulness Based Cognitive Therapy. PMID- 30251905 TI - The potential of PTPN22 as a therapeutic target for rheumatoid arthritis. AB - INTRODUCTION: PTPN22 encodes a lymphoid-specific tyrosine phosphatase (LYP) that is a master regulator of the immune response. This gene is a major susceptibility factor for a wide range of autoimmune conditions, including rheumatoid arthritis (RA) for which it represents the strongest non-HLA contributor to disease risk. A missense PTPN22 allele (R620W) affecting the protein-protein interaction of LYP with other relevant players was described as the functional variant of the association. This review will focus on the role of PTPN22 in the pathogenic mechanisms underlying RA predisposition and discuss the possibility of developing LYP-based treatment strategies with a potential application in clinical practice. Areas covered: This review covers the literature showing how PTPN22 is implicated in signalling pathways involved in the autoimmune and autoinflammatory processes underlying RA. Insights obtained from studies aimed at developing novel selective LYP suppressors for treating RA are summarized. Expert opinion: Targeting key risk factors during the early steps of the disease may represent a good strategy to accomplish complete disease remission. As cumulating evidences suggest that PTPN22 R620W is a gain-of-function variant, a growing interest in developing LYP inhibitors has arisen. The potential efficacy and possible application of such compounds are discussed. PMID- 30251906 TI - 2018 Ottawa consensus statement: Selection and recruitment to the healthcare professions. AB - Selection and recruitment into healthcare education and practice is a key area of interest for educators with significant developments in research, policy, and practice in recent years. This updated consensus statement, developed through a multi-stage process, examines future opportunities and challenges in selection and recruitment. There is both a gap in the literature around and a compelling case for further theoretical and empirical literature to underpin the development of overall selection philosophes and policies and their enactment. More consistent evidence has emerged regarding the quality of different selection methods. Approaches to selection are context-dependent, requiring the consideration of an institution's philosophy regarding what they are trying to achieve, the communities it purports to serve, along with the system within which they are used. Diversity and globalization issues continue to be critically important topics. Further research is required to explore differential attainment and explain why there are substantial differences in culturally acceptable ways of approaching diversity and widening access. More sophisticated evaluation approaches using multi-disciplinary theoretical frameworks are required to address the issues. Following a discussion of these areas, 10 recommendations are presented to guide future research and practice and to encourage debate between colleagues across the globe. PMID- 30251907 TI - Emerging drugs for focal epilepsy. AB - INTRODUCTION: Epilepsy is one of the most serious neurological conditions, affecting almost 50 million people around the world. Despite more than 20 antiepileptic drugs (AEDs) available, seizures are still uncontrolled in one third of patients. Areas covered: The present paper reviews current compounds in preclinical and clinical development for the treatment of focal epilepsies and new potential molecular targets recently identified. Expert opinion: 1OP-2198, Cannabidavirin, Everolimus, FV-082, Ganaxolone, Minocycline, NAX 810-2, Padsevonil and Selurampanel seem to be particularly promising in focal epilepsy. Some of them, Everolimus and Ganaxolone, are already completing Phase III development while others are still at a preclinical stage. Everolimus represents the first example of precision-medicine in epilepsy and the first generation of disease-modifying agents but data on long-term safety are needed. Among AEDs in Phase II development, Cannabidavirin, Padsevonil and Selurampanel may represent a promising fourth generation of compounds for focal epilepsies if they successfully proceed to subsequent stages. Data on general tolerability, effects of cognition and behavior as well as the potential for interactions in polytherapy will be key element for the success or decline of these drugs. PMID- 30251908 TI - Multiple Puf proteins regulate the stability of ribosome biogenesis transcripts. AB - Cells must make careful use of the resources available to them. A key area of cellular regulation involves the biogenesis of ribosomes. Transcriptional regulation of ribosome biogenesis factor genes through alterations in histone acetylation has been well studied. This work identifies a post-transcriptional mechanism of ribosome biogenesis regulation by Puf protein control of mRNA stability. Puf proteins are eukaryotic mRNA binding proteins that play regulatory roles in mRNA degradation and translation via association with specific conserved elements in the 3' untranslated region (UTR) of target mRNAs and with degradation and translation factors. We demonstrate that several ribosome biogenesis factor mRNAs in Saccharomyces cerevisiae containing a canonical Puf4p element in their 3' UTRs are destabilized by Puf2p, Puf4, and Puf5p, yet stabilized by Puf1p and Puf3p. In the absence of all Puf proteins, these ribosome biogenesis mRNAs are destabilized by a secondary mechanism involving the same 3' UTR element. Unlike other targets of Puf4p regulation, the decay of these transcripts is not altered by carbon source. Overexpression of Puf4p results in delayed ribosomal RNA processing and altered ribosomal subunit trafficking. These results represent a novel role for Puf proteins in yeast as regulators of ribosome biogenesis transcript stability. PMID- 30251909 TI - The Quality of End-of-Life Care after Limitations of Medical Treatment as Defined by a Rapid Response Team: A Retrospective Cohort Study. AB - BACKGROUND: Despite the increase in the identification of patients at the end of life after the introduction of rapid response team (RRT), there is doubt as to whether there has been an improvement in the quality of care offered to these patients. Proper end-of-life care is the next expected step after identifying patients who are dying. OBJECTIVE: To evaluate the end-of-life care after limitations of medical treatment (LOMTs) as defined by an RRT. DESIGN: This is a single-center retrospective cohort study at a tertiary teaching hospital in Porto Alegre, Brazil, from July 2014 to July 2016. SETTING/SUBJECTS: We included 242 patients with an LOMT as defined by the RRT. MEASUREMENTS: Outcomes of interest included symptoms and palliative measures after RRT review. RESULTS: During the study period, there were 5396 calls to 2937 patients, representing 126 calls per 1000 hospital discharges. Of these calls, 4.9% (n = 242) resulted in an LOMT. The primary care team agreed with the LOMT decision proposed by the RRT in 91.7% of cases. Regarding end-of-life symptoms, 7.4% and 5.8% of patients presented with intense or moderate pain, respectively, and 62.4% of patients presented dyspnea in the last 48 hours of hospitalization. Less than 15% of patients received attention for their spiritual needs and/or received psychological support. CONCLUSIONS: Our data reinforce the important role of RRTs in the identification of end-of-life patients with clinical deterioration. Despite the increase in the identification of these patients, the quality of end-of-life care needs to be improved. PMID- 30251910 TI - A Focused Career Development Program for Women Faculty at an Academic Medical Center. AB - BACKGROUND: Within free-standing academic medical centers, women continue to be underrepresented at upper faculty ranks and in leadership positions. A career development program (CDP) at the Medical University of South Carolina (MUSC) was implemented with the goal of improving the number of women in the upper ranks and in leadership positions. The CDP was initiated in 2013 as a 2-day program. Beginning in 2015, a half-day promotion-focused program was offered alternating with the 2-day program. MATERIALS AND METHODS: The CDP has served ~200 women from 2013 to 2017 and was evaluated for reaction and learning through postprogram surveys. Promotion success of ~160 women who attended at least one of the programs through 2016 was assessed through an additional survey. Promotion information for ~3000 faculty members during the same 2013-2016 period (post CDP), as well as a 4-year time period before implementation of the CDP (pre-CDP), was collected using university-level personnel data. RESULTS: The majority of CDP attendees (94%) indicated overall satisfaction with the program and would recommend the program to a colleague. Of the 137 CDP attendees still employed at MUSC in 2017, 50 had applied for promotion and 42 (84%) were successfully promoted. Among all the MUSC faculty, overall and rank-sepcific promotion rates for women and men were similar during the post-CDP time period and there was a significant increase in the promotion rate of women to Full Professor from pre CDP to post-CDP time periods. CONCLUSIONS: CDP attendees were overwhelmingly satisfied with the program and were highly successful in being promoted. Since the overall university promotion rates of women and men were similar during the post-CDP time period and women are currently underrepresented at the upper faculty ranks, parity between men and women will likely not be achievable without additional programs to retain and/or recruit women in the upper ranks. PMID- 30251912 TI - Spheroids Spontaneously Generated In Vitro from Sheep Ovarian Cortical Cells Contain Integrating Cells That Exhibit Hallmarks of Neural Stem/Progenitor Cells. AB - Cell spheroids are inducible or spontaneously generated cell aggregates produced in vitro that can provide a valuable model for developmental biology, stem cell biology, and cancer therapy research. This investigation aimed to define the cellular identity of spheroids spontaneously generated in vitro from sheep ovarian cortical cells cultured under specific serum-free conditions. Spheroids were characterized during 21 days of culture by morphometric evaluation, detection of alkaline phosphatase (AP) activity, gene expression analyses of stemness transcription factors and several lineage markers, immunolocalization analyses, as well as assessment of self-renewal and differentiation potential. Cell aggregation, evidenced from day 3 of culture onward, resulted in efficient generation of 65-75 spheroids for every 500,000 cells seeded. The spheroids reached maximum diameter (187 +/- 15.9 MUm) during the second week of culture and exhibited AP activity. Sox2, Oct4, and Nanog were expressed throughout the culture period, with upregulation of Sox2. Neural lineage specification genes (eg, nestin, vimentin, Pax6, and p75NTR) were expressed from day 10 onward at levels above that of Oct4, Nanog and those for endoderm [alpha-fetoprotein (AFP)], and mesoderm (brachyury) specification. Neural stem cell (NSC)/neural progenitor cell (NPC) markers, nestin, Pax6, p75NTR, and vimentin, were extensively localized in cells on day 10, 15 (44.75% +/- 5.84%; 93.54% +/- 1.35%; 78.90% +/- 4.80%; 73.82% +/- 3.40%, respectively), and 21 (49.98% +/- 5.30%; 91.84% +/- 1.9%; 76.74% +/- 11.0%; 95.80% +/- 3.60%, respectively). Spheroid cell self-renewal was evidenced by cell proliferation and the generation of new spheroids during two consecutive expansion periods. Culture of spheroid cells under differentiation conditions gave rise to cells showing immunolocalization of the neuron-specific antigen NeuN and the astroglial antigen GFAP (glial fibrillary acidic protein). Our results indicate that spheroids spontaneously generated in this culture system were comprised of cells with molecular characteristics of NSC/NPC that can self-renew and differentiate into neurons and glia, supporting the identity of spheroids as neurospheres. PMID- 30251913 TI - Autologous hematopoietic stem cell transplantation improves fatigue in multiple sclerosis. AB - BACKGROUND: Fatigue is a common problem in multiple sclerosis (MS) affecting as many as 90% of patients. The Fatigue Impact Scale (FIS) is a validated measure of fatigue in MS patients. The cause of fatigue in MS is likely multifactorial, with some evidence that ongoing central nervous system (CNS) inflammation is a contributing factor. Immunoablation and autologous hematopoietic stem cell transplantation (aHSCT) have been shown to halt ongoing CNS inflammation. OBJECTIVE: To investigate whether halting all ongoing inflammation with aHSCT impacts FIS scores in patients with severe MS. METHODS: In the Canadian aHSCT study ( ClinicalTrials.gov , NCT01099930), 23 patients underwent aHSCT and had FIS prospectively collected every 6 months for 36 months of follow-up. Change in FIS was analysed by repeated-measures analysis of variance (RMANOVA) with multiple linear regression to determine independent predictors. RESULTS: The median FIS score decreased 36%, from 36 to 23 ( p = 0.001), and four patients had 100% reduction. Improvement in FIS correlated with lower age and Expanded Disability Status Scale at baseline, as well as increased independence as evidenced by a return to gainful employment and even driving. CONCLUSION: Patients had significantly less fatigue on average after aHSCT. This may serve to better understand the contribution of ongoing CNS inflammation to fatigue peculiar to MS. PMID- 30251911 TI - Competence-induced protein Ccs4 facilitates pneumococcal invasion into brain tissue and virulence in meningitis. AB - Streptococcus pneumoniae is a major pathogen that causes pneumonia, sepsis, and meningitis. The candidate combox site 4 (ccs4) gene has been reported to be a pneumococcal competence-induced gene. Such genes are involved in development of S. pneumoniae competence and virulence, though the functions of ccs4 remain unknown. In the present study, the role of Ccs4 in the pathogenesis of pneumococcal meningitis was examined. We initially constructed a ccs4 deletion mutant and complement strains, then examined their association with and invasion into human brain microvascular endothelial cells. Wild-type and Ccs4-complemented strains exhibited significantly higher rates of association and invasion as compared to the ccs4 mutant strain. Deletion of ccs4 did not change bacterial growth activity or expression of NanA and CbpA, known brain endothelial pneumococcal adhesins. Next, mice were infected either intravenously or intranasally with pneumococcal strains. In the intranasal infection model, survival rates were comparable between wild-type strain-infected and ccs4 mutant strain-infected mice, while the ccs4 mutant strain exhibited a lower level of virulence in the intravenous infection model. In addition, at 24 hours after intravenous infection, the bacterial burden in blood was comparable between the wild-type and ccs4 mutant strain-infected mice, whereas the wild-type strain infected mice showed a significantly higher bacterial burden in the brain. These results suggest that Ccs4 contributes to pneumococcal invasion of host brain tissues and functions as a virulence factor. PMID- 30251914 TI - Long-Term Effects of Intense Pulsed Light Combined with Meibomian Gland Expression in the Treatment of Meibomian Gland Dysfunction. AB - OBJECTIVE: To evaluate the long-term effects of intense pulsed light (IPL) combined with meibomian gland expression (MGX) in the treatment of meibomian gland dysfunction (MGD). BACKGROUND: Although IPL has been proven to be effective in the treatment of MGD, any report regarding its long-term efficacy is unavailable by now. METHODS: The randomly selected study eye received a series of three IPL treatments that were applied directly on eyelids with an interval of 4 weeks (treatment energy, 14-16 J/cm2). The control eye received three sham IPL treatments (0 J/cm2). MGX was performed on both eyes. Meibomian gland yielding secretion score (MGYSS) and tear film break-up time (TBUT) were evaluated at baseline and at 1, 3, 6, and 9 months after treatments. RESULTS: In the study eyes, MGYSS of both the upper and lower eyelids and TBUT improved at 1, 3, 6 months after treatments (p < 0.01). MGYSS in lower eyelids continued to improve at 9 months (p < 0.05). The changes in MGYSS and TBUT after treatment were larger in the study eyes than in the control eyes at 1, 3, 6 months (p < 0.01), but no difference at 9 months (p > 0.05). The percentage improvement in the MGYSS of lower eyelids after treatment was higher than that of upper eyelids. CONCLUSIONS: Three consecutive IPL treatments combined with MGX improved MG secretion function and TBUT by 6 months after treatment in MGD patients. The improvement in MG secretion function was greater in the lower eyelid than in the upper eyelid. PMID- 30251915 TI - Immunological Properties of Neural Crest Cells Derived from Human Induced Pluripotent Stem Cells. AB - Collecting sufficient quantities of primary neural crest cells (NCCs) for experiments is difficult, as NCCs are embryonic transient tissue that basically does not proliferate. We successfully induced NCCs from human induced pluripotent stem cells (iPSCs) in accordance with a previously described method with some modifications. The protocol used in this study efficiently produced large amounts of iPSC-derived NCCs (iPSC-NCCs). Many researchers have recently produced large amounts of iPSC-NCCs and used these to examine the physiological properties, such as migratory activity, and the potential for medical uses such as wound healing. Immunological properties of NCCs are yet to be reported. Therefore, the purpose of this study was to assess the immunological properties of human iPSC-NCCs. Our current study showed that iPSC-NCCs were hypoimmunogenic and had immunosuppressive properties in vitro. Expression of HLA class I molecules on iPSC-NCCs was lower than that observed for iPSCs, and there was no expression of HLA class II and costimulatory molecules on the cells. With regard to the immunosuppressive properties, iPSC-NCCs greatly inhibited T cell activation (cell proliferation and production of inflammatory cytokines) after stimulation. iPSC NCCs constitutively expressed membrane-bound TGF-beta, and TGF-beta produced by iPSC-NCCs played a critical role in T cell suppression. Thus, cultured human NCCs can fully suppress T cell activation in vitro. This study may contribute to the realization of using stem cell-derived NCCs in cell-based medicine. PMID- 30251916 TI - Injectable Chitosan Hydrogels with Enhanced Mechanical Properties for Nucleus Pulposus Regeneration. AB - Intervertebral disc (IVD) degeneration has been implicated as a major component of spine pathology. As the IVD degenerates, the tissue becomes dehydrated, fibrotic, fissured, acellular, and calcified. These changes can lead to disc bulging, herniation, Schmorl's nodes, inflammation, and hyperinnervation. Injectable hydrogels have received much attention in recent years as scaffold for seeding cells to replenish disc cellularity and restore disc properties and function. However, they generally present poor mechanical properties. In this study, we investigate several novel thermosensitive chitosan hydrogels for their ability to mimic the mechanical properties of the nucleus pulposus (NP) tissue, while being injectable, able to entrap and maintain viability of NP cells, and retain matrix proteins. These new hydrogels were prepared by mixing chitosan (CH) with various combinations of three gelling agents: sodium hydrogen carbonate (SHC) and/or beta-glycerophosphate (BGP) and/or phosphate buffer (PB). The kinetics of gelation was studied at room and body temperature by rheology. Mechanical properties of the hydrogels were characterized under compression and torsion, and compared with human NP tissue. NP cells were seeded in the hydrogel when still liquid at room temperature, before its gelation at 37 degrees C. Hydrogel cytocompatibility and functionality were assessed by measuring cell viability, metabolism, and proteoglycan synthesis. Although all the proposed hydrogels exhibited enhanced strength compared to CH-BGP thermosensitive hydrogels, and suitable cytocompatibility and rheological properties, one formulation (containing 2% chitosan, 7.5 mM of SHC, and 0.1 M of BGP) showed mechanical properties similar to human NP tissue, and stimulated better the synthesis and retention of proteoglycans from NP cells. Thus, this novel thermosensitive CH hydrogel shows promise for IVD regeneration. PMID- 30251917 TI - Multi-Potent Adult Progenitor Cells, but not Tissue Inhibitor of Matrix Metalloproteinase-3, Increase Tissue Sparing and Reduce Urological Complications following Spinal Cord Injury. AB - Following spinal cord injury (SCI), inflammation amplifies damage beyond the initial insult, providing an opportunity for targeted treatments. An ideal protective therapy would reduce both edema within the lesion area and the activation/infiltration of detrimental immune cells. Previous investigations demonstrated the efficacy of intravenous injection of multi-potent adult progenitor cells (MAPC(r)) to modulate immune response following SCI, leading to significant improvements in tissue sparing, locomotor and urological functions. Separate studies have demonstrated that tissue inhibitor of matrix metalloproteinase-3 (TIMP3) reduces blood-brain barrier permeability following traumatic brain injury in a mouse model, leading to improved functional recovery. This study examined whether TIMP3, delivered alone or in concert with MAPC cells, improves functional recovery from a contusion SCI in a rat model. The results suggest that intravenous delivery of MAPC cell therapy 1 day following acute SCI significantly improves tissue sparing and impacts functional recovery. TIMP3 treatment provided no significant benefit, and further, when co-administered with MAPC cells, it abrogated the therapeutic effects of MAPC cell therapy. Importantly, this study demonstrated for the first time that acute treatment of SCI with MAPC cells can significantly reduce the incidence of urinary tract infection (UTI) and the use of antibiotics for UTI treatment. PMID- 30251918 TI - Cell Identity, Proliferation, and Cytogenetic Assessment of Equine Umbilical Cord Blood Mesenchymal Stromal Cells. AB - The aim of the present work was to determine proliferation capacity, immunophenotype and genome integrity of mesenchymal stromal cells (MSCs) from horse umbilical cord blood (UCB) at passage stage 5 and 10. Passage 4 cryopreserved UCB-MSCs from six unrelated donors were evaluated. Immunophenotypic analysis of UCB-MSC revealed a cell identity consistent with equine MSC phenotype by high expression of CD90, CD44, CD29, and very low expression of CD4, CD11a/18, CD73, and MHC class I and II antigens. Proliferative differences were noted among the UCB-MSC cultures. UCB-MSCs karyotype characteristics at passage 5 (eg, 2n = 64; XY, or XX) included 20% polyploidy and 62% aneuploidy. At passage 10, the proportion of polyploidy and aneuploidy was 21% and 82%, respectively, with the increase in aneuploidy being significant compared with passage 5. Furthermore, conventional GTG-banded karyotyping revealed several structural chromosome abnormalities at both passage 5 and 10. The clinical relevance of such chromosome instability is unknown, but determination of MSC cytogenetic status and monitoring of patient response to MSC therapies would help address this question. PMID- 30251919 TI - Ventricular Drainage Catheters versus Intracranial Parenchymal Catheters for Intracranial Pressure Monitoring-Based Management of Traumatic Brain Injury: A Systematic Review and Meta-Analysis. AB - Intracranial pressure (ICP) monitoring is one of the mainstays in the treatment of severe traumatic brain injury (TBI), but different approaches to monitoring exist. The aim of this systematic review and meta-analysis is to compare the effectiveness and complication rate of ventricular drainage (VD) versus intracranial parenchymal (IP) catheters to monitor and treat raised ICP in patients with TBI. Pubmed, Embase, Web of Science, Google Scholar, and the Cochrane Database were searched for articles comparing ICP monitoring-based management with VDs and monitoring with IP monitors through March 2018. Study selection, data extraction, and quality assessment were performed independently by two authors. Outcomes assessed were mortality, functional outcome, need for decompressive craniectomy, length of stay, overall complications, such as infections, and hemorrhage. Pooled effect estimates were calculated with random effects models and expressed as relative risk (RR) for dichotomous outcomes and mean difference (MD) for ordinal outcomes, with corresponding 95% confidence intervals (CI). Six studies were included: one randomized controlled trial and five observational cohort studies. Three studies reported mortality, functional outcome, and the need for a surgical decompression, and three only reported complications. The quality of the studies was rated as poor, with critical or serious risk of bias. The pooled analysis did not show a statistically significant difference in mortality (RR = 0.90, 95% CI = 0.60-1.36, p = 0.41) or functional outcome (MD = 0.23, 95% CI = 0.67-1.13, p = 0.61). The complication rate of VDs was higher (RR = 2.56, 95% CI = 1.17-5.61, p = 0.02), and consisted mainly of infectious complications; that is, meningitis. VDs caused more complications, particularly more infections, but there was no difference in mortality or functional outcome between the two monitoring modalities. However, the studies had a high risk of bias. A need exists for high quality comparisons of VDs versus IP monitor-based management strategies on patient outcomes. PMID- 30251920 TI - Molecular insight to in vitro biocompatibility of phytofabricated copper oxide nanoparticles with human embryonic kidney cells. AB - AIM: To investigate the biocompatibility of green synthesized copper oxide nanoparticles (CuO Np) using floral extract of Calotropis gigantea in room condition. MATERIALS & METHODS: Green synthesized and characterized CuO Np was evaluated for their cellular and molecular biocompatibility by experimentally and computational molecular docking. RESULTS: Synthesized CuO NP was found to have a size 32 +/- 09 nm with zeta potential -35 +/- 12 mV. LC50 value was found to be 190 MUg/ml. In vitro and in silico cytotoxicity analysis with HEK293 cells revealed the cytotoxic effect of CuO Np as consequences of interaction with histidine and arginine amino acid residues of Sod3 and p53 proteins via hydrogen bond of length 3.09 and 3.32 A leading to oxidative stress ensuing toward apoptosis and cell cycle arrest. CONCLUSION: The outcomes proved the synthesized material as an alternative to the conventional method of synthesizing copper nanoparticles for biomedical and clinical applications. PMID- 30251921 TI - Smoking and its interaction with genetics in MS etiology. AB - The etiology of multiple sclerosis (MS) involves multifaceted interactions between genetic loci and environmental factors. Smoking is an important risk factor for MS that overall increases the risk of the disease with approximately 50%. However, the precise effects of smoking on MS development vary considerably in different contexts and in different populations. This review focuses on the influence of smoking on MS risk and its interaction with genetics in MS etiology. The possible biological mechanisms are presented in this paper. Further research is needed to establish the mechanisms of causality and to explore preventive strategies. PMID- 30251922 TI - Needle in a Haystack: Natural Language Processing to Identify Serious Illness. AB - BACKGROUND: Alone, administrative data poorly identifies patients with palliative care needs. OBJECTIVE: To identify patients with uncommon, yet devastating, illnesses using a combination of administrative data and natural language processing (NLP). DESIGN/SETTING: Retrospective cohort study using the electronic medical records of a healthcare network totaling over 2500 hospital beds. We sought to identify patient populations with two unique disease processes associated with a poor prognosis: pneumoperitoneum and leptomeningeal metastases from breast cancer. MEASUREMENTS: Patients with pneumoperitoneum or leptomeningeal metastasis from breast cancer were identified through administrative codes and NLP. RESULTS: Administrative codes alone resulted in identification of 6438 patients with possible pneumoperitoneum and 557 patients with possible leptomeningeal metastasis. Adding NLP to this analysis reduced the number of patients to 869 with pneumoperitoneum and 187 with leptomeningeal metastasis secondary to breast cancer. Administrative codes alone yielded a 13% positive predictive value (PPV) for pneumoperitoneum and 25% PPV for leptomeningeal metastasis. The combination of administrative codes and NLP achieved a PPV of 100%. The entire process was completed within hours. CONCLUSIONS: Adding NLP to the use of administrative codes allows for rapid identification of seriously ill patients with otherwise difficult to detect disease processes and eliminates costly, tedious, and time-intensive manual chart review. This method enables studies to evaluate the effectiveness of treatment, including palliative interventions, for unique populations of seriously ill patients who cannot be identified by administrative codes alone. PMID- 30251923 TI - In Vivo Analysis of Photobiomodulation Genotoxicity Using the Somatic Mutation and Recombination Test. AB - BACKGROUND: Photobiomodulation (PBM) has been studied mainly for its effects on the repair, regeneration, and healing of tissue due to its direct and indirect actions on cell proliferation. However, it is necessary to consider the way in which laser acts, that is, whether it affects the rates of spontaneous mutation and mitotic recombination of cells. OBJECTIVE: This study investigated the genotoxic potential of PBM (904 nm) based on an in vivo bioassay that concomitantly evaluates mitotic recombination and point and chromosomal mutations. METHODS: Strains of Drosophila melanogaster that carry specific marker genes were used to detect the induction of mutation and somatic recombination when exposed to different fluences (3, 5, 10, and 20 J/cm2). DNA damage was measured using the somatic mutation and recombination test (SMART), which is based on the identification of wing hair with mutant phenotypes that express lesions at DNA level. RESULTS: The doses 5, 10, and 20 J/cm2 induced significant increase in the total number of spots compared with the negative control. The highest frequency of spots was caused by the 10 J/cm2. CONCLUSIONS: Besides recombination events, the quantitative and qualitative analysis of mutant hairs revealed the occurrence of mutagenic events, both punctual and chromosomal. In addition, the results point to a dose-dependent response. PMID- 30251924 TI - Guiding peripheral arterial disease management with magnetic resonance imaging. AB - Peripheral arterial disease (PAD) management is exceptionally challenging. Despite advances in diagnostic and therapeutic technologies, long-term vessel patency and limb salvage rates are limited. Patients with PAD frequently require extensive workup with noninvasive tests and imaging to delineate their disease and help guide appropriate management. Ultrasound and computed tomography are commonly ordered in the workup of PAD. Magnetic resonance imaging (MRI), on the other hand, is less often acknowledged as a useful tool in this disease. Nevertheless, MRI is an important test that can effectively characterize atherosclerotic plaque, assess vessel patency in highly calcified disease, and measure lower extremity perfusion. PMID- 30251925 TI - Co-Occurrence of Chlamydia suis DNA and Chlamydia suis-Specific Antibodies in the Human Eye. AB - Chlamydia suis is a swine pathogen that causes economic losses due to reproductive failure. Recently, C. suis has been detected in human eyes. However, knowledge of the zoonotic potential is still limited. C. suis infections in swine could present a risk for public health because (1) tetracycline-resistant C. suis strains are emerging in the pork industry, (2) tetracycline resistance gene transfers in vitro from C. suis to the human pathogen Chlamydia trachomatis and as previously demonstrated, (3) C. suis and C. trachomatis can be both present in the human eye. Pig farmers were sampled during a seminar in West-Flanders. Conjunctival swabs for detection of C. suis and C. trachomatis and for the detection of mucosal antibodies against C. suis and C. trachomatis were collected. The farmers completed a questionnaire designed to assess information on the following: (1) the health status of their pigs, (2) administration of veterinary drugs, (3) their professional and nonprofessional activities, (4) general health status, (5) smoking habits, (6) use of medication, (7) allergies, and (8) clinical signs/history. Thirty-three on 40 (82.5%) farmers participated. None of the conjunctival swabs contained C. trachomatis DNA and mucosal antibodies against C. trachomatis were not detected. Six of 33 (18.2%) farmers had C. suis DNA in their eyes and 22 of 33 (67%) swabs contained C. suis-specific mucosal antibodies. The older the farmer, higher the chance of finding C. suis antibodies in the eye. There was a significant correlation between the presence of conjunctivitis in the pigs and the occurrence of C. suis DNA in the eye of their owner. This study shows that C. suis may transfer from pigs to the human eye as specific mucosal antibodies were detected in conjunctivae of pig farmers. Veterinarians, general practitioners, and occupational physicians should be aware of the zoonotic potential of C. suis. PMID- 30251927 TI - Can Postmortem Imaging Replace Autopsy and Reverse the Trend of Dwindling Postmortem Examinations? PMID- 30251926 TI - MRI in Patients with Cardiac Implantable Electronic Devices. AB - Indications for MRI have grown considerably in recent years. However, many patients with cardiac implantable electronic devices are denied imaging due to physician misinterpretation of the risks associated with MRI. This review discusses the theoretical basis for the perceived risk by exploring preclinical literature. It then presents a detailed examination of the true rates of adverse events in clinical studies across both MR nonconditional (legacy) and MR conditional devices. Indeed, many of these adverse events are rare, nonexistent, and/or clinically insignificant in the wealth of published data. The authors then address image quality and the constituents of a safety checklist that institutions should consider when performing MRI in patients with a cardiac implantable electronic device. Lastly, the authors conclude with an overview of future directions for advancement in the field. PMID- 30251928 TI - Four-dimensional CT Analysis of Wrist Kinematics during Radioulnar Deviation. AB - Purpose To determine the technical feasibility of four-dimensional (4D) CT for analysis of the variation of radioscaphoid angle (RSA) and lunocapitate angle (LCA) during wrist radioulnar deviation. Materials and Methods In this prospective study, 37 participants suspected of having scapholunate instability were evaluated from January 2015 to December 2016 with 4D CT and CT arthrography (mean age +/- standard deviation, 42.3 years +/- 15; range, 21-75 years; 27 men [mean age, 44 years +/- 15] and 10 women [mean age, 38 years +/- 14]). Five angular parameters for RSA and LCA variation during radioulnar deviation were calculated by two independent readers. CT arthrography was used as the reference standard method for scapholunate ligament tear identification. Results In the control group (n = 23), the mean values for RSA were 103 degrees +/- 8 and 104 degrees +/- 9, whereas the mean values for LCA were 86 degrees +/- 9 degrees and 90 degrees +/- 11 degrees with a coefficient of variation of 11% and 13% for reader 1 and reader 2, respectively. The interobserver and intraobserver agreements were excellent for RSA and substantial to excellent for LCA. In the pathologic group (n = 14), LCA amplitude, standard deviation, and maximal angle were lower for both readers with respect to the control group, measuring 36% and 44% (P = .003), 37% and 44% (P = .002), and 13% and 19% (P = .003), respectively. RSA amplitude did not show statistically significant results in the pathologic group (P > .13). LCA yielded the highest sensitivity (71%-93%), whereas RSA yielded the highest specificity (87%-100%). Conclusion Semiautomatic four dimensional CT analysis of the wrist during radioulnar deviation is technically feasible and reproducible for evaluation of carpal kinematic abnormalities. (c) RSNA, 2018 Online supplemental material is available for this article . PMID- 30251929 TI - Pancreatic Cancer CT: Prediction of Resectability according to NCCN Criteria. AB - Purpose To evaluate the diagnostic performance of CT in the determination of pancreatic cancer resectability according to the National Comprehensive Cancer Network (NCCN) criteria to predict R0 resection. Materials and Methods Structured reports of pancreatic CT clinically prepared by board-certified abdominal radiologists from January 2014 to March 2017 were retrospectively reviewed to assess resectability (resectable, borderline resectable, or unresectable) according to NCCN criteria (version 1.2017) in 616 patients (369 men, 247 women; mean age, 63 years +/- 10 [standard deviation]) with pancreatic cancer. Negative resection margin (R0) rates were assessed based on CT resectability status in patients who underwent upfront surgery. R0 resection-associated factors were identified by using logistic regression analysis. Results In 371 patients who underwent surgery, R0 resection rates were 73% (171 of 235), 55% (57 of 104), and 16% (five of 32) for resectable, borderline resectable, and unresectable disease, respectively (P < .001). At multivariable analysis, tumor diameter larger than 4 cm (P < .001) and abutment to the portomesenteric vein (P < .001) were significantly associated with margin-positive resection in patients with resectable disease at CT. R0 resection rates were 80% (123 of 154) for resectable disease without portomesenteric vein abutment, 59% (48 of 81) for resectable disease with portomesenteric vein abutment, 83% (57 of 69) for resectable disease 2 cm or smaller, and 29% (five of 17) for tumors larger than 4 cm. Conclusion CT resectability is used to stratify patients with pancreatic cancer according to the possibility of R0 resection. Larger tumor size and tumor abutment to the portomesenteric vein are associated with margin-positive resection in patients with resectable pancreatic cancer. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Fowler in this issue. PMID- 30251930 TI - Conventional Autopsy versus Minimally Invasive Autopsy with Postmortem MRI, CT, and CT-guided Biopsy: Comparison of Diagnostic Performance. AB - Purpose To compare the diagnostic performance of minimally invasive autopsy with that of conventional autopsy. Materials and Methods For this prospective, single center, cross-sectional study in an academic hospital, 295 of 2197 adult cadavers (mean age: 65 years [range, 18-99 years]; age range of male cadavers: 18-99 years; age range of female cadavers: 18-98 years) who died from 2012 through 2014 underwent conventional autopsy. Family consent for minimally invasive autopsy was obtained for 139 of the 295 cadavers; 99 of those 139 cadavers were included in this study. Those involved in minimally invasive autopsy and conventional autopsy were blinded to each other's findings. The minimally invasive autopsy procedure combined postmortem MRI, CT, and CT-guided biopsy of main organs and pathologic lesions. The primary outcome measure was performance of minimally invasive autopsy and conventional autopsy in establishing immediate cause of death, as compared with consensus cause of death. The secondary outcome measures were diagnostic yield of minimally invasive autopsy and conventional autopsy for all, major, and grouped major diagnoses; frequency of clinically unsuspected findings; and percentage of answered clinical questions. Results Cause of death determined with minimally invasive autopsy and conventional autopsy agreed in 91 of the 99 cadavers (92%). Agreement with consensus cause of death occurred in 96 of 99 cadavers (97%) with minimally invasive autopsy and in 94 of 99 cadavers (95%) with conventional autopsy (P = .73). All 288 grouped major diagnoses were related to consensus cause of death. Minimally invasive autopsy enabled diagnosis of 259 of them (90%) and conventional autopsy 224 (78%); 200 (69%) were found with both methods. At clinical examination, the cause of death was not suspected in 17 of the 99 cadavers (17%), and 124 of 288 grouped major diagnoses (43%) were not established. There were 219 additional clinical questions; 189 (86%) were answered with minimally invasive autopsy and 182 (83%) were answered with conventional autopsy (P = .35). Conclusion The performance of minimally invasive autopsy in the detection of cause of death was similar to that of conventional autopsy; however, minimally invasive autopsy has a higher yield of diagnoses. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Krombach in this issue. PMID- 30251931 TI - Liver Imaging Reporting and Data System (LI-RADS) Version 2018: Imaging of Hepatocellular Carcinoma in At-Risk Patients. AB - The Liver Imaging Reporting and Data System (LI-RADS) is composed of four individual algorithms intended to standardize the lexicon, as well as reporting and care, in patients with or at risk for hepatocellular carcinoma in the context of surveillance with US; diagnosis with CT, MRI, or contrast material-enhanced US; and assessment of treatment response with CT or MRI. This report provides a broad overview of LI-RADS, including its historic development, relationship to other imaging guidelines, composition, aims, and future directions. In addition, readers will understand the motivation for and key components of the 2018 update. PMID- 30251932 TI - CT Assessment of Pancreatic Cancer: What Are the Gaps in Predicting Surgical Outcomes? PMID- 30251933 TI - Soft-Tissue Imaging in a Human Mummy: Propagation-based Phase-Contrast CT. AB - Purpose To evaluate phase-contrast CT as a noninvasive alternative to histology in the study of ancient soft tissue. Materials and Methods The imaging was performed between May 8 and June 13, 2017. A mummified human hand from ancient Egypt was imaged in a laboratory phase-contrast CT arrangement with propagation based imaging. The experimental arrangement for propagation-based imaging included a microfocus x-ray source, a rotation stage for the sample, and an x-ray detector. The mummified hand was imaged in two different modes. First, a CT scan of the whole hand was performed in an overview arrangement. Then, a detailed scan of the tip of the middle finger was performed. With imaging distances tailored for a large magnification and to maximize the phase-contrast signal, the estimated resolution in the final images was 6-9 um. Results The overview CT allowed identification of the tendons of the hand, as well as identification of arteries and nerves in the dehydrated soft tissue. In the detailed phase-contrast setting, virtual histology of the soft tissues of the fingertip could be performed. Blood vessels in the nail bed and the microanatomy of the bone marrow and hypodermis were imaged, and the layers of the skin could be distinguished. Round structures in the adipose tissue were identified as the remains of adipocytes. Conclusion Laboratory phase-contrast CT enables imaging of the anatomy and microanatomy of mummified soft tissue with sub-10-um resolution and may serve as a complement or alternative to the classic invasive histologic methods used in soft-tissue paleopathology. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30251934 TI - Development and Validation of Deep Learning-based Automatic Detection Algorithm for Malignant Pulmonary Nodules on Chest Radiographs. AB - Purpose To develop and validate a deep learning-based automatic detection algorithm (DLAD) for malignant pulmonary nodules on chest radiographs and to compare its performance with physicians including thoracic radiologists. Materials and Methods For this retrospective study, DLAD was developed by using 43 292 chest radiographs (normal radiograph-to-nodule radiograph ratio, 34 067:9225) in 34 676 patients (healthy-to-nodule ratio, 30 784:3892; 19 230 men [mean age, 52.8 years; age range, 18-99 years]; 15 446 women [mean age, 52.3 years; age range, 18-98 years]) obtained between 2010 and 2015, which were labeled and partially annotated by 13 board-certified radiologists, in a convolutional neural network. Radiograph classification and nodule detection performances of DLAD were validated by using one internal and four external data sets from three South Korean hospitals and one U.S. hospital. For internal and external validation, radiograph classification and nodule detection performances of DLAD were evaluated by using the area under the receiver operating characteristic curve (AUROC) and jackknife alternative free-response receiver operating characteristic (JAFROC) figure of merit (FOM), respectively. An observer performance test involving 18 physicians, including nine board-certified radiologists, was conducted by using one of the four external validation data sets. Performances of DLAD, physicians, and physicians assisted with DLAD were evaluated and compared. Results According to one internal and four external validation data sets, radiograph classification and nodule detection performances of DLAD were a range of 0.92-0.99 (AUROC) and 0.831-0.924 (JAFROC FOM), respectively. DLAD showed a higher AUROC and JAFROC FOM at the observer performance test than 17 of 18 and 15 of 18 physicians, respectively (P < .05), and all physicians showed improved nodule detection performances with DLAD (mean JAFROC FOM improvement, 0.043; range, 0.006-0.190; P < .05). Conclusion This deep learning-based automatic detection algorithm outperformed physicians in radiograph classification and nodule detection performance for malignant pulmonary nodules on chest radiographs, and it enhanced physicians' performances when used as a second reader. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30251935 TI - Surveillance of Rabies Postexposure Prophylaxis in Greece: 4 Years Experience. AB - Rabies reemerged in Greek fauna during October 2012, 25 years after the last report in animals and 42 after the last human case. This study examined the administration of rabies postexposure prophylaxis (PEP) in humans over the period 2012-2016. A total of 1,454 individuals (62.6% males) received PEP. The vast majority (92.3%) of regimens was initiated in high risk for animal rabies areas (11.1 PEP per 100,000 residents per year). Among the exposed, 77.0% presented at a healthcare setting during the first 24 h after the incident; more severe injuries were associated with faster presentation (p < 0.05). A vaccine series was administered in 54.5% of exposed persons whereas 43.7% received both vaccine and immunoglobulin and 1.7% immunoglobulin only. Exposure to stray dogs represented 68.4% of all incidents. In exposures occurring in nonhigh risk for rabies areas, bat was the second most frequently involved animal (13.4% of incidents). All dogs and cats evaluated by a veterinarian and laboratory confirmed rabid were initially deemed suspect for rabies during clinical examination or according to history. No human rabies cases were recorded during the period of the study. Surveillance of PEP represents a valuable tool for aiding assessment of present and future demands in prophylaxis biologicals, outlining the epidemiological profile of exposures and planning effective policies for the management of exposure incidents. PMID- 30251936 TI - Maturity-Related Differences in Systemic Pulmonary and Localized Fatigue Threshold Among Youth Male Athletes. AB - PURPOSE: To examine the reliability and the maturity-related differences of fatigue thresholds (FTs) among youth males. METHODS: Twenty-nine youth males (11 17 y) completed 2 ramp exercise tests on a cycle ergometer. Systemic FTs were calculated from gas exchange and ventilation variables. Localized FTs were calculated from electromyography and near-infrared spectroscopy of the vastus lateralis. All FTs were determined using the maximal distance method and expressed relative to maximal oxygen consumption. All participants were grouped according to the number of years from peak height velocity into PRE- (< -1.5 y), PERI- (-1.5 to +1.5 y) and POST- (> +1.5 y) peak height velocity. Reliability was assessed with intraclass correlation coefficients, and differences between groups were assessed with analysis of variance and Cohen's d coefficients. RESULTS: Analysis of variance revealed significant group differences with PRE having significantly greater systemic pulmonary FTs than POST, while localized muscular FTs were significantly greater in PRE when compared with PERI and POST. All FTs exhibited excellent reliability (intraclass correlation coefficient > .75) in all maturity groups. CONCLUSION: Maturity status appears to influence the onset of FTs among youth male athletes, with FTs occurring later in younger athletes. Furthermore, all FTs were reliable measures regardless of maturity. PMID- 30251937 TI - Cervical Spinal Ependymoma With Hemorrhage in a Renal Transplant Patient. AB - Ependymomas are the most common intramedullary spinal tumors in adults and constitute around 20% of all spinal tumors in adults. There are 3 subgroups of ependymomas according to World Health Organization classification: subependymoma or myxopapillary (grade 1), ependymoma (grade 2), and anaplastic (grade 3). Therapy for patients is aimed at safe and total surgical removal and, in selected cases, postoperative radiotherapy. Bleeding from a spinal ependymoma, with subsequent urgent surgery, is extremely rare. Here, we present a case of a renal transplant patient who had a cervical ependymoma. Although a considerable volume of peritumoral blood was observed during surgery, the patient had no neurologic deficits and no signs of deterioration. PMID- 30251938 TI - Neoadjuvant Transarterial Chemoembolization Improves Survival After Liver Transplant in Patients With Hepatocellular Carcinoma. AB - OBJECTIVES: Our aims were to determine whether transarterial chemoembolization before liver transplant for hepatocellular carcinoma improves posttransplant survival and whether patients downstaged by transarterial chemoembolization within Milan criteria have a posttransplant survival benefit. MATERIALS AND METHODS: In this retrospective analysis of prospectively collected data, survival rates of 87 patients treated with and 68 patients not treated with transarterial chemoembolization before liver transplant were compared using 2-sample t tests and multivariate Cox regression. We also compared posttransplant survival of patients within Milan criteria versus those downstaged after transarterial chemoembolization. We controlled for disease severity by assessing, among other variables, tumor diameter before and at transplant and alpha-fetoprotein levels before transplant and transarterial chemoembolization. RESULTS: Overall 1-, 3-, and 5-year survival rates were 84%, 71%, and 63%, respectively. These rates were 91%, 78%, and 73% for patients who received and 76%, 63%, and 54% for patients who did not receive transarterial chemoembolization. Hazard ratios were 0.56 for having versus not having transarterial chemoembolization (P = .04), 1.06 for total tumor diameter on explantation (P = .01), 1.5 for largest tumor > 3 cm (P = .15), and 2.9 for pretransplant alpha-fetoprotein > 659 ng/mL (P = .006). A higher end-stage liver disease score correlated with poorer overall survival (hazard ratio = 1.53; P < .001). Laboratory values, lipiodol uptake, imaging response, and downstaging into Milan criteria were not correlated with survival. CONCLUSIONS: Patients with hepatocellular carcinoma who were treated with neoadjuvant transarterial chemoembolization had better survival rates posttransplant than those not treated with transarterial chemoembolization. A high pretransplant alpha-fetoprotein level was negatively correlated with survival. Patients downstaged to Milan criteria after transarterial chemoembolization fared equally well versus those who met Milan criteria initially. Pretreatment with transarterial chemoembolization was positively correlated with survival posttransplant, with patients having a 44% reduction in posttransplant mortality. PMID- 30251939 TI - Relationship Between Preoperative Diastolic Transpulmonary Gradient With Pulmonary Vascular Resistance and 1-Year and Overall Mortality Rates Among Patients Undergoing Cardiac Transplant. AB - OBJECTIVES: Cardiac transplant is a life-saving procedure for patients with end stage heart failure. Preoperative pulmonary vascular resistance is indicative of intrinsic pulmonary vascular disease and correlates with posttransplant survival. However, its measurement is costly and time consuming. Therefore, simpler techniques are required. Diastolic transpulmonary gradient reportedly indicates intrinsic pulmonary vascular disease. Here, we investigated the relationship between preoperative diastolic transpulmonary gradient with preoperative pulmonary vascular resistance and 1-year and overall mortality among cardiac transplant patients. MATERIALS AND METHODS: Fifty-one patients who underwent cardiac transplant between 2006 and 2017 were included. All patients underwent preoperative right and left heart catheterization and oxygen study. Among these, diastolic transpulmonary gradient, mean transpulmonary gradient, and pulmonary vascular resistance were correlated with one another and 1st-year and overall mortality rates. Patients were grouped according to whether they received diastolic transpulmonary gradient or not, and both groups were compared with respect to 1-year and overall mortality. Binary logistic regression analysis was done to test whether diastolic transpulmonary gradient was a significant predictor of 1-year and overall mortality. RESULTS: Mean patient age was 45.5 +/- 9.8 years. The 1-year and overall mortality rates were 21.6% (11/51) and 37.3% (19/51), respectively. Diastolic transpulmonary gradient was significantly correlated with pulmonary vascular resistance, 1-year mortality, and overall mortality (P < .05) and was a significant predictor of 1-year and overall mortality (odds ratio 6.0; 95% confidence interval, 1.4-25.3; P < .05 and odds ratio 4.8; 95% CI, 1.4-17.5; P < .05, respectively). Patients with a diastolic transpulmonary gradient of >= 7 mm Hg had significantly higher 1-year and overall mortality (P < .05). CONCLUSIONS: Diastolic transpulmonary gradient can be used as a promising easy-to-use parameter of intrinsic pulmonary vascular disease and a predictor of 1-year and overall mortality among patients undergoing cardiac transplant. PMID- 30251940 TI - Antifibrotic Effects of Decellularized and Lyophilized Human Amniotic Membrane Transplant on the Formation of Intrauterine Adhesion. AB - OBJECTIVES: Intrauterine adhesion is a disease involving endometrial fibrosis that arises from injury to the basal layer of the endometrium. Here, we aimed to explore the preventive effects of decellularized and lyophilized amniotic membrane on endometrial fibrosis in a rat model of intrauterine adhesion. MATERIALS AND METHODS: Twenty-four Sprague-Dawley rats were randomly divided into 2 groups. For the intrauterine adhesion group, endometria of left uteri were scraped without treatment. For the intrauterine adhesion plus decellularized and lyophilized amniotic membrane transplant group, decellularized and lyophilized amniotic membrane was sutured onto the scraped wound of left uteri. Right uteri were kept as the control group. At 3, 7, 14, and 28 days after transplant, uteri were sampled for histologic and immunohistochemical evaluation. RESULTS: Histology examination revealed extensive fibrosis with significantly reduced numbers of endometrial glands in uteri in the intrauterine adhesion group. Immunohistochemical staining showed a remarked increase in expression of transforming growth factor beta1 (P < .01) and decreased expression of matrix metalloproteinase-9 (P < .01) in the intrauterine adhesion group. In rats with transplant of decellularized and lyophilized amniotic membrane, endometrial fibrosis apparently improved (P < .05) with reduced expression of transforming growth factor beta1 and increased matrix metalloproteinase-9 expression (P < .05). However, there were no significant differences in the number of endometrial glands or endometrial thickness between the 2 groups (P > .05). CONCLUSIONS: Development of intrauterine adhesion was prevented with transplant of decellularized and lyophilized amniotic membrane via suppression of transforming growth factor beta1 and increased production of matrix metalloproteinase-9 in a rat model. PMID- 30251941 TI - The "UW-LPHS Test": A New Test to Predict the Outcome of Renal Autotransplant for Loin Pain Hematuria Syndrome. AB - OBJECTIVES: The objectives of this pilot study were twofold. First, we aimed to elicit whether the "UW-LPHS test" definitively localizes pain from patients' loin pain hematuria syndrome to the ureter and thus proves our hypothesis. Second, we aimed to understand whether a positive UW-LPHS test predicts a successful outcome after renal autotransplant. MATERIALS AND METHODS: The UW-LPHS test is described in detail in this manuscript. Briefly, 0.5% bupivacaine is injected into the ureter of the affected side and kept there using a balloon catheter for 5 minutes. RESULTS: All six patients studied had complete pain relief at a mean follow-up of 9.2 months after renal autotransplant. All patients were successfully weaned from opioids and have returned to a normal lifestyle. CONCLUSIONS: The UW-LPHS test can be used to predict renal autotransplant outcomes and should be applied to all patients who are being considered for this operation. PMID- 30251942 TI - Retrograde Intrarenal Surgery Through an Incision of the Ureter as a Good Treatment Option for Large Ureteropelvic Impacted Stones in Transplanted Kidneys. AB - Urolithiasis is a rare complication after kidney transplant. Over the years, treatment of kidney stones has evolved radically, but a standard approach for transplanted kidneys has not yet been defined. Here, we present a 69-year-old male patient who received successful treatment of nephrolithiasis of the transplanted kidney. The patient, who had received a kidney from a deceased donor, was admitted to our department following a posttransplant Doppler ultrasonography showing severe hydronephrosis of the transplanted kidney associated with acute renal function decay. Computed tomography scan confirmed the hydronephrosis of the transplanted kidney, showing a large, impacted, ureteropelvic 3-cm-diameter stone and other concretions around the ureteral stent. The patient was then treated with retrograde intrarenal surgery during an open ureterotomy. His postoperative course was uneventful, and he showed good functional reprise and a rapid decrease of serum creatinine levels. Intraoperative retrograde intrarenal surgery could be a valid option for treatment of kidney stones of the transplanted kidney during open surgery of the ureter or during ureterovesical anastomosis. PMID- 30251943 TI - Intraoperative Tissue-Immunosuppressive Therapy Reduces Rejection Episodes in Heart Transplant Recipients. AB - OBJECTIVES: Our study was conducted to determine the effects of intraoperative antithymocyte globulin administration on donor hearts procured after cardiocirculatory death. We evaluated the impact of antithymocyte globulin on graft function and related parameters during isothermic blood cardioplegia. MATERIALS AND METHODS: In this prospective and randomized single center study, 30 patients with orthotropic heart transplant were divided into 2 groups: group 1 included 15 patients who received retrograde antithymocyte globulin infusion via coronary sinus intraoperatively and immediately after organ procurement and group 2 included 15 patients who received traditional antithymocyte globulin infusion after implantation. RESULTS: Study patients had a mean age of 33.8 years (range, 15-56 y). All patients had panel reactive antibody less than 10% except for 3 patients. The cluster of differentiation 3-positive cell count decrease was more than 20%. The inotropic therapy dose required and the myocardial pressure (stiffness) were less for group 1 patients. These patients had less acute rejection episodes than group 2 (0% vs 13.3%; P < .05). CONCLUSIONS: Favorable clinical outcomes were observed in terms of less acute rejection episodes and better graft function at least during the early posttransplant period. Intraoperative antithymocyte globulin treatment may have a preventive effect for acute cellular rejection in heart transplant patients. PMID- 30251944 TI - Impact of Guideline-Driven Approach in Follow-Up of Long-Term Complications After Allogeneic Hematopoietic Cell Transplant: Single Center Experience. AB - OBJECTIVES: After allogeneic stem cell transplant, patients may experience psychiatric, endocrinologic, pulmonary, and cardiovascular problems, as well as secondary malignancies and chronic graft-versus-host disease over the long-term follow-up. These long-term complications not only increase mortality and morbidity of transplant survivors but also decrease their quality of life. In this study, we shared our experiences with our guideline-driven approach for follow-up of long-term complications. MATERIALS AND METHODS: Our study included 91 patients who received allogeneic hematopoietic cell transplant between July 2009 and March 2016 at our medical center. In accordance with the current guidelines, a screening program was applied to all patients seen between February 2016 and February 2017. RESULTS: Median posttransplant follow-up duration was 36 months (range, 12-84 mo), and the median follow-up duration after initial diagnosis was 51 months (range, 15-109 mo). Evaluations of patients posttransplant showed ocular complications (50.6% of patients), oral complications (15.4%), respiratory complications (8.8%), cardiac complications (5.5%), metabolic syndrome (37.4%), liver complications (2.2%), skeletal complications (66.7%), endocrine complications (12.1%), secondary cancers (2.2%), psychosocial adjustment (27.7%), hypertension (5.5%), and type 2 diabetes mellitus (8.8%). CONCLUSIONS: For long-term follow-up, detailed evaluations of body organs and systems are essential. Early recognition of the aforementioned complications could decrease mortality and morbidity. For patients to be monitored by transplant centers over many years, training and awareness should be provided to ensure adequate follow-up of patients. Based on our results, we believe that the long-term follow-up guidelines used in our clinic are applicable to others. PMID- 30251945 TI - Dental Student Knowledge and Willingness to Donate Corneas. AB - OBJECTIVES: Our aim was to assess the knowledge and willingness to donate corneas among undergraduate dental students in Hyderabad city, India. MATERIALS AND METHODS: We conducted a cross-sectional study among undergraduate dental students of Panineeya Institute of Dental Sciences (Hyderabad, India). A pretested questionnaire was used to obtain information on demographic details, knowledge of cornea donation (7 questions), and willingness to donate corneas (3 questions). For analyses, we used chi-square and multivariate modeling tests. P < .05 was considered significant. RESULTS: Our study included 56 male (16.5%) and 284 female (83.5%) dental students. The overall mean number of correct answers for knowledge questions for this study population was 2.98 +/- 1.43. A significant difference existed only for year of study (P < .001). Similar findings were noted when the study population was categorized into poor and good knowledge. The willingness to donate, which was referred to as a positive attitude, was expressed by 41%, with significance observed only for religion. The most common reason cited for unwillingness to donate was lack of sufficient information (52%). Regarding associations between ambiguity to donate and demographic factors, only religion was shown to be a significant factor. CONCLUSIONS: Although approximately 66% of respondents had poor knowledge, 40% were willing to donate. When demographics were considered, year of study was significantly associated with knowledge and religion was significantly associated with willingness to donate. PMID- 30251946 TI - QUALITY ASSURANCE OF REGISTRIES FOR HEALTH TECHNOLOGY ASSESSMENT. AB - OBJECTIVES: The aim of this study was to identify guidelines and assessment tools used by health technology agencies for quality assurance of registries and investigate the current use of registry data by HTA organizations worldwide. METHODS: As part of a European Network for Health Technology Assessment Joint Action work package, we undertook a literature search and sent a questionnaire to all partner organizations on the work package and all organizations listed in the International Society for Pharmaco-economics and Outcomes Research directory. RESULTS: We identified thirteen relevant documents relating to quality assurance of registries. We received fifty-five responses from organizations representing twenty-one different countries, a response rate of 40.5 percent (43/110). Many agencies, particularly in Europe, are already drawing on a range of registries to provide data for their HTA. Less than half, however, use criteria or standards to assess the quality of registry data. Nearly all criteria or standards in use have been internally defined by organizations rather than referring to those produced by an external body. A comparison of internal and external standards identified consistency in several quality dimensions, which can be used as a starting point for the development of a standardized tool. CONCLUSION: The use of registry data is more prevalent than expected, strengthening the need for a standardized registry quality assessment tool. A user-friendly tool developed in conjunction with stakeholders will support the consistent application of approved quality standards, and reassure critics who have traditionally considered registry data to be unreliable. PMID- 30251948 TI - Quality of care for frail older adults. AB - Our successes in improving life expectancy has led to increased years of life lived with multimorbidity and dementia with increased support needs. Much of the support given to frail older people is provided by family and informal support networks with significant impact on their physical, psychological, and financial well-being. Demographic and societal changes are reducing the capacity of family to offer this care. Formal home-based, center-based, and long term/residential/nursing home care services are predominately provided by untrained care staff working under supervision from nursing staff. Difficulties recruiting and retaining these staff is leading to major challenges to meeting the needs of older people (Chenoweth et al., 2010). This volume contains a number of studies focusing on ways to improve care provided by these services for frail older people. The approach underpinning these papers and many perspectives of good quality care for older people is the need to be person-centered where the older person identifies their own goals for care and assessment of need, employing a holistic and strength-based approach incorporating their interests, values, and capacities (Vernooij-Dassen and Moniz-Cook, 2016). PMID- 30251947 TI - PREFERENCES OF PATIENTS WITH MULTIPLE SCLEROSIS FOR ATTRIBUTES OF INJECTABLE MULTIPLE SCLEROSIS TREATMENTS IN THE UNITED KINGDOM AND FRANCE. AB - OBJECTIVES: Adherence to injectable disease-modifying treatments in patients with multiple sclerosis (MS) impacts outcomes and can be influenced by perceptions of treatment efficacy, side effects, injection frequency, and the duration of injection. This study aimed to quantify preferences for selected attributes of injectable treatments among individuals with MS in the United Kingdom and France. METHODS: Respondents with a self-reported diagnosis of MS completed an online discrete-choice-experiment survey, consisting of a series of treatment-choice questions. Each choice question presented two hypothetical treatments, each with six attributes (years until disability progression, relapses in the next 4 years, injection time, injection frequency, flu-like symptoms (FLS), and injection-site reactions), each with various levels. Mixed-logit regression analysis was used to estimate preference weights for attribute levels and to calculate the relative importance of changes in treatment attributes (vertical distance between preference weights). Minimum acceptable efficacy estimates indicate improvement in efficacy that respondents would require in exchange for worsening injection frequency and FLS. RESULTS: In both countries, 100 respondents completed the survey. In the United Kingdom and France, respectively, improving the time until disability progression from 2 to 4 years, reducing injection frequency from "daily" to "every 2 weeks", and reducing FLS from 3 days after every injection to none had a relative importance of 2.9 and 2.6, 3.0 and 3.5, and 2.5 and 3.1. Given the ranges included in the study, changes in these attributes were more important than most changes in other attributes assessed. CONCLUSIONS: Reductions in the injection frequency of MS treatments and FLS can be as important to patients as improvements in treatment efficacy. PMID- 30251949 TI - A genomic view of experimental intraspecies and interspecies transformation of a rifampicin-resistance allele into Neisseria meningitidis. AB - The spread of antibiotic resistance within and between different bacterial populations is a major health problem on a global scale. The identification of genetic transformation in genomic data from Neisseria meningitidis, the meningococcus (Mc), and other bacteria is problematic, since similar or even identical alleles may be involved. A particular challenge in naturally transformable bacteria generally is to distinguish between common ancestry and true recombined sites in sampled genome sequences. Furthermore, the identification of recombination following experimental transformation of homologous alleles requires identifiable differences between donor and recipient, which in itself influences the propensity for homologous recombination (HR). This study identifies the distribution of HR events following intraspecies and interspecies Mc transformations of rpoB alleles encoding rifampicin resistance by whole-genome DNA sequencing and single nucleotide variant analysis. The HR events analysed were confined to the genomic region surrounding the single nucleotide genetic marker used for selection. An exponential length distribution of these recombined events was found, ranging from a few nucleotides to about 72 kb stretches. The lengths of imported sequences were on average found to be longer following experimental transformation of the recipient with genomic DNA from an intraspecies versus an interspecies donor (P<0.001). The recombination events were generally observed to be mosaic, with donor sequences interspersed with recipient sequence. Here, we present four models to explain these observations, by fragmentation of the transformed DNA, by interruptions of the recombination mechanism, by secondary recombination of endogenous self-DNA, or by repair/replication mechanisms. PMID- 30251950 TI - An outbreak of Shigella boydii serotype 20 in January 2015 amongst United Kingdom healthcare workers involved in the Ebola response in Sierra Leone. AB - In January 2015, Public Health England and the United Kingdom (UK) Ministry of Defence investigated cases of diarrhoea and fever in military personnel recently returned to the UK after supporting the response to the Ebola epidemic in Sierra Leone. Tests for Ebola virus infection were negative. PCR tests detected the ipaH gene in 10/12 faecal specimens, and Shigella boydii serotype 20 was isolated from 7 patients. A case control study was undertaken and analysed using multivariable logistic regression. Consumption of a coronation chicken lunch at the transit camp in Sierra Leone (SL) 24-48 h prior to departure for the UK was significantly associated with disease [adjusted odds ratio (OR) 28.15, 95 % CI: 1.87-422.65]. In the context of heightened concern during the Ebola epidemic, this outbreak highlights the importance of rapid and effective microbiological and epidemiological investigations to identify the aetiological agent in patients presenting with fever and diarrhoea. PMID- 30251951 TI - Prevalence and antimicrobial susceptibilities of Acinetobacter baumannii and non baumannii Acinetobacters from Terengganu, Malaysia and their carriage of carbapenemase genes. AB - A total of 153 non-repeat Acinetobacter spp. clinical isolates obtained in 2015 from Hospital Sultanah Nur Zahirah (HSNZ) in Terengganu, Malaysia, were characterized. Identification of the isolates at species level was performed by ribosomal DNA restriction analysis (ARDRA) followed by sequencing of the rpoB gene. The majority of the isolates (n=128; 83.7 %) were A. baumannii while the rest were identified as A. nosocomialis (n=16), A. calcoaceticus (n=5), A. soli (n=2), A. berezeniae (n=1) and A. variabilis (n=1). Multidrug resistance (MDR) was most prevalent in A. baumannnii (66.4 %) whereas only one non-baumannii isolate (A. nosocomialis) was MDR. The blaOXA-23 gene was the predominant acquired carbapenemase gene (56.2 %) and was significantly associated (P<0.001) with carbapenem resistance. However, no significant association was found for carbapenem resistance and isolates that contained the ISAba1-blaOXA-51 configuration. PMID- 30251952 TI - First report on the sero-epidemiology of Toxoplasma gondii infection in German roe deer (Capreolus capreolus). AB - While the roe deer (Capreolus capeolus) is the most important game species in Germany and its venison is popular, there is limited knowledge about the prevalence of Toxoplasma gondii in this animal population in the country, and in wild ungulates in Germany generally. Between 2013 and 2015, we collected 295 blood samples from roe deer belonging to a central German population. Sera were analysed using a modified agglutination test (MAT, cut-off 1:20), and antibodies were detected in 86 of the 295 samples (29%). Seroprevalence values differed significantly between the different age classes, with antibodies more frequently observed in adults. In contrast, seroprevalence did not differ significantly between the sexes or collection years. Venison is frequently consumed raw or undercooked and may be a potential source of human infection with T. gondii. PMID- 30251953 TI - Induction of human somatostatin and parvalbumin neurons by expressing a single transcription factor LIM homeobox 6. AB - Human GABAergic interneurons (GIN) are implicated in normal brain function and in numerous mental disorders. However, the generation of functional human GIN subtypes from human pluripotent stem cells (hPSCs) has not been established. By expressing LHX6, a transcriptional factor that is critical for GIN development, we induced hPSCs to form GINs, including somatostatin (SST, 29%) and parvalbumin (PV, 21%) neurons. Our RNAseq results also confirmed the alteration of GIN identity with the overexpression of LHX6. Five months after transplantation into the mouse brain, the human GABA precursors generated increased population of SST and PV neurons by overexpressing LHX6. Importantly, the grafted human GINs exhibited functional electrophysiological properties and even fast-spiking-like action potentials. Thus, expression of the single transcription factor LHX6 under our GIN differentiation condition is sufficient to robustly induce human PV and SST subtypes. PMID- 30251956 TI - The Progress of Next Generation Sequencing in Assessment of Myeloid Malignancies AB - With increasing characterization of disease associated molecular markers, it is becoming challenging to perform multiple single-gene molecular assays. Specific molecular markers are helpful for diagnostic, prognostic evaluation and management of hematologic malignancies. Introduction and rapid progress on next generation sequencing has led to extensive modifications and offers a novel way to integrate concurrent assessment of multiple target genes in routine laboratory analysis especially in view of increasing clinical demands for testing of multiple genetic aberrations. Despite challenges in next generation sequencing particularly involving bioinformatics support and clinical annotation of novel variants, assessment of myeloid neoplasms with targeted next generation sequencing panels showing evidence to improve diagnosis, assist therapeutic decisions and provide better information about prognosis, as well as detection of minimal residual disease since it facilitates significant advantages over single gene assays. Herein, we provide information for application and utilization of next generation sequencing studies with a focus on the most important mutations in clinical assessment of hematologic neoplasms such as acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative neoplasms and other myelodysplastic/myeloproliferative neoplasms in order to integrate into daily clinical practice. PMID- 30251955 TI - Androgen Insensitivity Syndrome: Clinical Phenotype and Molecular Analysis in a Single Tertiary Center Cohort. AB - OBJECTIVE: The aim of this study was the molecular characterization of the AR gene as the cause of 46,XY DSD in our population. METHODS: We studied 41 non related 46,XY DSD index cases with characteristics consistent with AIS. Genomic DNA was isolated from peripheral blood leukocytes of all patients and 25 family members from 17 non-related families. RESULTS: The AR gene analysis revealed an abnormal sequence in58.5% of total index patients. All of the CAIS cases were genetically confirmed, while in PAIS only in 13 (43.3%) patients a mutation in AR was detected. Molecular studies revealed other affected/carrier relatives in 87% of the index cases. The AR mutations were found spread along the whole coding sequence, with a higher prevalence in LBD. Nine (39%) out of 23 AR mutations were novel. In 17% of AR-mutated gene patients, somatic mosaicism was detected in DNA derived from blood leukocytes. In our cohort long-term follow up gender dysphoria raised as male or female was not found. Finally,in suspected PAIS, the identification ofAR mutation was clearly less than in CAIS patients. CONCLUSION: The improvement of the knowledge of the components of the AR complex and signaling network might contribute to the long term outcome and genetic counseling in AIS patients. PMID- 30251954 TI - Structure of the human epithelial sodium channel by cryo-electron microscopy. AB - The epithelial sodium channel (ENaC), a member of the ENaC/DEG superfamily, regulates Na+ and water homeostasis. ENaCs assemble as heterotrimeric channels that harbor protease-sensitive domains critical for gating the channel. Here, we present the structure of human ENaC in the uncleaved state determined by single particle cryo-electron microscopy. The ion channel is composed of a large extracellular domain and a narrow transmembrane domain. The structure reveals that ENaC assembles with a 1:1:1 stoichiometry of alpha:beta:gamma subunits arranged in a counter-clockwise manner. The shape of each subunit is reminiscent of a hand with key gating domains of a 'finger' and a 'thumb.' Wedged between these domains is the elusive protease-sensitive inhibitory domain poised to regulate conformational changes of the 'finger' and 'thumb'; thus, the structure provides the first view of the architecture of inhibition of ENaC. PMID- 30251957 TI - Remarkable increase in the prevalence of overweight and obesity among school age children in Antalya, Turkey, between 2003 and 2015. AB - OBJECTIVE: Because childhood obesity is still a growing problem in the world, we conducted this study aiming to show the trend in obesity (OB) and overweight (OW) prevalence in the last decade, to observe the alteration of OB and OW prevalence according to age groups and to construct the new age and gender specific body mass index (BMI) reference percentile charts for Turkish children living in the city center of Antalya. METHODS: This cross-sectional study includes 1687 school aged children. International Obesity Task Force (IOTF) references were used to determine the obesity and overweight prevalence. OW was defined as BMI between 85th and 95th percentile, and OB above the 95th percentile. The data obtained were compared with another study carried out by the same unit in the same region in 2003. LMS method, which summarizes terms of three smooth age specific curves called L (lambda), M (mu), and S (sigma), was used to construct the BMI reference percentile charts for Turkish children living in Antalya. RESULTS: The prevalence of OB was 9.8 %, OW was 23.2 % and combined OW/OB was 33 %. Obesity prevalence was higher in boys than girls (p<0.05). The prevalence of combined OW/OB was highest at the age of 9-10 years. The prevalence of obesity has increased 2.9 times during twelve years in Antalya, Turkey. CONCLUSION: Comparing with the findings of previous decade, childhood obesity in Antalya has reached alarming level. Urgent measures should be taken to prevent obesity and more surveillance studies should be planned to show the future trend of obesity prevalence. PMID- 30251958 TI - The Investigation of Relationship Between Fok1 and Col1A1 Gene Polymorphisms and Development of Treatment-Related Bone Complications in Children with Acute Lymphoblastic Leukemia. AB - In acute Lymphoblasticlastic leukemia (ALL), various clinical risk factors and genetic predispositions contribute to the development of bone complications during and after chemotherapy. In this study, we aimed to investigate whether vitamin D receptor (VDR) Fok1 and collagen protein Col1A1 Sp1-binding site gene polymorphisms, which are important in bone mineral and matrix formation, have effects on the development of bone abnormalities in childhood ALL survivors. Fifty children with ALL who were treated with ALL BFM-95 protocol between 1998 2008 and followed-up at least 7 years were enrolled. The control group consisted of 96 healthy children. VDR Fok1 and Col1A1 Sp1-binding site gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymorphism. Bone mineral density (BMD) and markers of bone metabolism were all noted. All patients presented with pain in the joints were examined for bone pathologies while on chemotherapy or on long term follow-up. Low BMD (16%), osteoporosis (12%), and osteonecrosis (8%) were present in 18 patients (36%) totally. The frequency of osteonecrosis and total bone abnormalities was significantly higher in children aged >=10 years (p=0.001). The risk of low BMD and osteonecrosis was higher in those with vitamin D deficiency. Only the Col1A1 Sp1-binding site gene polymorphism showed a significant association in ALL patients with osteonecrosis. In conclusion, the development of therapy-induced bone mineral loss and osteonecrosis in children with ALL is frequent and the risk is higher especially in children aged >=10 years and with vitamin D deficiency. The association between Col1A1 Sp1-binding site gene polymorphisms and osteonecrosis has to be assessed in a larger group of ALL survivors. PMID- 30251960 TI - Mitigating the photocurrent persistence of single ZnO nanowires for low noise photodetection applications. AB - In this work, we investigate the optoelectronic properties of zinc oxide (ZnO) nanowires, which are good candidates for applications based on integrated optics. Single ZnO nanowire photodetectors were fabricated with ohmic contacts. By taking current transient measurements in different atmospheres (oxygen, air, vacuum and argon), and at various temperatures, we point out the importance of surface effects on the electrical behaviour. Results confirm that oxygen chemisorption is responsible for the existence of a high photoconductive gain in these devices, and for the first time a two step process in the photocurrent rise transient is reported. A maximum gain of G = 7.8 * 107 is achieved. However, under certain conditions, the persistence of the photocurrent can last up to several hours and as such may prevent the device from operating at useful rates. From a knowledge of the photocurrent response mechanisms, we establish a method to restore the photodetector to its initial state, with very low dark current, by applying an appropriate gate voltage sequence. This advances the state of the art for these detectors towards commercial applications. PMID- 30251961 TI - 2D vertical field-effect transistor. AB - Within the framework of 2D materials, we present four theoretical models of a vertical field-effect transistor (FET) composed of simple alternate graphene and MoS2 layers. The electronic transport properties at a specific graphene/MoS2 interface in each configuration are investigated by focusing in particular on the current as a function of the gate voltage. The gate voltage, simulated with a shift of the bands of a specific layer, allows us to tune the current at the interface and the charge transfer between the planes. This analysis of the charge transfer as a function of the gate voltage reveals a strong connection with the transport characteristics as the slope of the current curve. The analysis of physical phenomena at the graphene/MoS2 interface can further improve the 2D vertical FET performance and contribute to the development of new 2D nanotechnology. PMID- 30251959 TI - Synergistic antibacterial effect of tetracycline hydrochloride loaded functionalized graphene oxide nanostructures. AB - With the high demand for developing novel composites with integrated performance, graphene-based nanostructures have been drawing great attention in environmental and biomedical applications because of their extraordinary physicochemical properties and biocompatibility. Although graphene oxide (GO) nanosheets exhibit some antibacterial activities, novel GO based nanostructures with enhanced antibacterial activities are highly desired. To realize this aim, polyethyleneimine (PEI) modified GO as a tetracycline hydrochloride (TCH) carrier and release platform was constructed (pGO-TCH). The nanostructures were fully characterized by TEM, AFM, FTIR and Raman spectra, which demonstrated that TCH were uniformly and compactly deposited on PEI modified GO nanosheets. The antibacterial performances of the prepared nanostructures were investigated by disk diffusion method and bacterial growth kinetics method towards Gram-positive S. aureus and Gram-negative E. coli. Results show that pGO-TCH nanostructures exhibit good antibacterial behavior. The mechanism of antibacterial activity was studied. Moreover, the nanostructures showed good cytocompatibility. This study not only highlights a promising pGO-TCH nanostructure as a candidate of graphene based antibacterial agent, but also provides us antibacterial mechanism between bacteria and graphene-based nanomaterials. PMID- 30251962 TI - Multimodal atomic force microscopy with optimized higher eigenmode sensitivity using on-chip piezoelectric actuation and sensing. AB - Atomic force microscope (AFM) cantilevers with integrated actuation and sensing provide several distinct advantages over conventional cantilever instrumentation. These include clean frequency responses, the possibility of down-scaling and parallelization to cantilever arrays as well as the absence of optical interference. While cantilever microfabrication technology has continuously advanced over the years, the overall design has remained largely unchanged; a passive rectangular shaped cantilever design has been adopted as the industry wide standard. In this article, we demonstrate multimode AFM imaging on higher eigenmodes as well as bimodal AFM imaging with cantilevers using fully integrated piezoelectric actuation and sensing. The cantilever design maximizes the higher eigenmode deflection sensitivity by optimizing the transducer layout according to the strain mode shape. Without the need for feedthrough cancellation, the read out method achieves close to zero actuator/sensor feedthrough and the sensitivity is sufficient to resolve the cantilever Brownian motion. PMID- 30251963 TI - Water desorption in Kelvin-probe force microscopy: a generic model. AB - Nanoparticles or similar, nanoscale objects such as proteins or biological fibrils usually have to be deposited from aqueous suspension onto a solid support surface for further characterization by atomic force microscopy (AFM) and related methods such as Kelvin-probe force microscopy (KFM). Here we show, on the examples of functionalized nanoparticles and collagen fibrils, that water desorption after sample preparation affects their electrostatic potential determined by KFM in a predictable manner. We explain this effect with a simple, analytical model based on the capacitance of the partially dielectric-filled tip sample system. We also propose practical measures to avoid false interpretation of electrical AFM-based experiments. As the phenomenon is very generic it may have significant implications in the application of AFM to nanoparticles and other nanostructures including biological ones. PMID- 30251964 TI - Differences in arousal probability and duration after apnea and hypopnea events in adult obstructive sleep apnea patients. AB - OBJECTIVE: In obstructive sleep apnea (OSA), breathing cessations are often followed by arousals, leading to sleep fragmentation and thus impaired sleep quality. Arousals and fragmented sleep are also related to detrimental cardiovascular events. The key index for OSA diagnosis (i.e. the apnea-hypopnea index) attributes equal diagnostic value to apneas and hypopneas, despite the fact that the associated arousals and desaturations may be very different. Thus, considering the severity of the consequences of apneas and hypopneas could enhance the estimation of OSA severity. In this study, we investigate whether the probability and duration of apnea- and hypopnea-related arousals differ and whether the differences in desaturation severity following apneas and hypopneas are dependent on sleep stage. APPROACH: Polysomnographic recordings of 348 consecutive OSA patients were included for analysis. The severity of arousals and desaturations associated with hypopneas within different sleep stages was compared to that of arousals and desaturations associated with apneas. In addition, the probability of arousals related to apneas and hypopneas was evaluated within OSA severity categories. MAIN RESULTS: Apneas caused arousals less frequently than hypopneas in N1, N2, and N3 sleep in all OSA severity categories. However, the arousals caused by apneas were longer (p < 0.001) and the desaturations related to apneas were more severe (p < 0.001) than those related to hypopneas in N1, N2, and rapid eye movement sleep even after adjustment for respiratory event durations. SIGNIFICANCE: Desaturations and arousals related to apneas are more severe than those related to hypopneas. Therefore, apneas followed by arousal or desaturation should have a different diagnostic value than hypopneas when assessing OSA severity and related risk for cardiovascular consequences. PMID- 30251965 TI - Enhanced superconductivity of Ba0.5K0.5Fe2As2 under surface potassium dosing. AB - Surface potassium dosing has been proven to be an effective method in tuning the electron doping and enhancing the superconducting transition temperatures in both iron chalcogenides and electron doped iron pnictides. However, it is not clear how surface potassium dosing affects the hole doping and superconductivity in hole doped Fe-based superconductors. Here we performed K-dosing on Ba0.5K0.5Fe2As2, a prototypical hole-doped iron pnictide compound, and explored the electronic structure by in situ angle-resolved photoemission spectroscopy measurements. Starting from the slightly over-doped Ba0.5K0.5Fe2As2, surface K dosing effectively reduces the hole concentration towards optimal doping and enhances the superconductivity. Intriguingly, the enhancement of superconductivity does not slow down at optimal doping, and the gap further increases with K dosing even when the carrier doping effect is saturated. Meanwhile, the quasiparticle coherence of the inner hole pockets is enhanced by higher K dosing. Our results uncover a novel scattering-reduction effect of K dosing in Ba1-x K x Fe2As2, which collaborates with the carrier doping effect and enhances superconductivity. PMID- 30251966 TI - A large aperture row column addressed probe for in vivo 4D ultrafast doppler ultrasound imaging. AB - 4D Ultrafast ultrasound imaging was recently proposed to image and quantify blood flow with high sensitivity in 3D (Provost et al., 2014) as well as anatomical, mechanical or functional information. In 4D Ultrafast imaging, coherent compounding of tilted planes waves emitted by a 2-D matrix array are used to image the medium at high volume rate. 4D ultrafast imaging, however, requires high count electronics (>1000) to drive those probes. Alternatives approaches have been proposed and investigated to efficiently reduce the density of elements such as sparse or under-sampled arrays while maintaining a decent image quality and high volume rate. The row-columns configuration presents the advantage of keeping a large active surface with a low amount of elements (Morton and Lockwood, 2003) (Rasmussen et al., 2015) and a simple geometry. In this study, we designed and built a new Row and Column Adressed (RCA) probe dedicated to vascular imaging and investigated it with a specific Orthogonal Plane Wave (OPW) compounding strategy (Flesch et al., 2017). Using this prototype, 4D ultrafast Power Doppler imaging of a large volume of 25.6*25.6 mm2 up to 40 mm depth is demonstrated in vitro on flow phantoms and vivo on the carotid artery of a healthy volunteer at a volume rate of 834 Hz. PMID- 30251967 TI - Dynamics of GeSbTe phase-change nanoparticles deposited on graphene. AB - Phase-change Ge2Sb2Te5 nanoparticles (NPs), that are promising for next generation phase-change memory and other emerging optoelectronic applications, have been deposited on graphene support layers and analyzed using advanced transmission electron microscopy techniques allowing high quality atomic resolution imaging at accelerating voltages as low as 40 kV. The deposition results in about three times higher NP coverage on suspended graphene than on graphene containing an amorphous background support. We attribute this to the variation in surface energy of suspended and supported graphene, indicating that the former harvests NPs more effectively. Hydrocarbon contamination on the graphene profoundly enhances the mobility of the NP atoms and after prolonged (weeks) exposure to air resulted in more severe oxidation and spreading of NPs on the suspended graphene than on supported graphene because the network of hydrocarbons develops more extensively on the suspended rather than on the supported graphene. Due to this oxidation, GeO x shells are formed out of NPs having a uniform composition initially. The present work provides new insights into the structure and stability of phase-change NPs, graphene and their combinations. PMID- 30251968 TI - Fabrication of a thick three-dimensional scaffold with an open cellular-like structure using airbrushing and thermal cross-linking of molded short nanofibers. AB - Nanoscale fibers mimicking the extracellular matrix of natural tissue can be produced by conventional electrospinning, but this approach results in two dimensional thin dense fibrous mats which can hinder effective cell infiltration. The aim of the present study was to design a thick, three-dimensional (3D) cylindrical scaffold with an open pore structure assembled from short polycaprolactone (PCL) fibers using a facile airbrushing approach. In addition, magnesium particles were incorporated into the PCL solution to both enhance the mechanical properties of the scaffold and stimulate cellular activity following cell seeding. Separated short composite airbrushed fibers were assembled into a 3D cylindrical structure by cold-press molding and thermal cross-linking. The microstructure, chemical composition, porosity and thermal properties were subsequently investigated, along with changes in mechanical performance following immersion in PBS for 60 d. The results showed that the assembled 3D fibrous 10 mm thick cylindrical matrix had an interconnected fibrous network structure with 31.5%-60% porosity. Encapsulation of the Mg particles into the 3D assembled fibrous scaffold enhanced the mechanical properties of the plain PCL scaffolds. The results also demonstrated controlled release of Mg ions into the PBS media for up to 60 d, as evaluated by changes in Mg ion concentration and pH of the media. In addition, the 3D fibrous assembled matrix was shown to support human osteoblast-like cell adhesion, proliferation and penetration. The results suggest that this novel fabrication method of biodegradable thick 3D scaffolds with an open pore structure is promising for the production of a new generation of 3D scaffolds for tissue regeneration applications. PMID- 30251969 TI - Temperature dependence of Raman responses of few-layer PtS2. AB - Platinum disulfide (PtS2) is a newly emerging 2D material, which possesses relatively high carrier mobility, a widely tunable band gap from 0.25 to 1.6 eV, and ultra-high air stability, showing a potential in electronics and optoelectronics. Here, for the first time, we study the temperature-dependent Raman spectra on PtS2 with different thicknesses. It was found that with the temperature increase from 80 to 298 K, the [Formula: see text] and [Formula: see text] modes of all samples show linear softening. Moreover, the linear softening with temperature of PtS2 is much smaller than other 2D transition metal dichalcogenides, which could be attributed to the stronger interlayer coupling in PtS2. Our work gives fundamental temperature-dependent vibrational information of PtS2, which will be useful in future PtS2-based electronic devices. PMID- 30251970 TI - Electroencephalography as a predictor of self-report fatigue/sleepiness during monotonous driving in train drivers. AB - OBJECTIVE: In this study, electroencephalography activity recorded during monotonous driving was investigated to examine the predictive capability of monopolar EEG analysis for fatigue/sleepiness in a cohort of train drivers. APPROACH: Sixty-three train drivers participated in the study, where 32- lead monopolar EEG data was recorded during a monotonous driving task. Participant sleepiness was assessed using the Pittsburgh sleep quality index (PSQI), the Epworth sleepiness scale (ESS), the Karolinksa sleepiness scale (KSS) and the checklist of individual strength 20 (CIS20). MAIN RESULTS: Self-reported fatigue/sleepiness scores of the train driver cohort were primarily associated with EEG delta, theta, and alpha variables; however, some beta and gamma associations were also implicated. Furthermore, general linear models informed by these EEG variables were able to predict self-reported scores with varying degrees of success, representing between 48% and 54% of variance in fatigue scores. SIGNIFICANCE: Self-reported fatigue/sleepiness scores of train drivers were predicted with varying degrees of success (dependent upon the self-reported fatigue/sleepiness measure) by alterations to monopolar delta, theta, and alpha band activity variables, indicating EEG as a potential indicator for fatigue/sleepiness in train drivers. PMID- 30251971 TI - [Depression in patients with personality disorder in youth]. AB - AIM: To define clinical specifics of depression in patients with personality disorders (PD) in youth and work out differential/diagnostic criteria of these states. MATERIAL AND METHODS: One hundred and sixty patients (136 men, 24 women, mean age19.5+/-3.2 years) were studied. Later 42 patients from this group participated in the follow-up study. RESULTS: The following types of depression were described: 'with overvalued ideas', 'with neurotic disorders', 'with predominant addictions', 'with youth asthenic incapacity' and 'with attenuated psychotic symptoms'. These types clearly correlate with the type of PD. CONCLUSION: Personality abnormality plays a role in the pathogenesis of these states. This finding contributes to the more accurate diagnosis, prognostic and therapeutic solutions. PMID- 30251972 TI - [The features of emotional processing in patients with depressive disorders]. AB - AIM: To study neurocognitive symptoms in depressive disorders with the designation of their brain and psychological mechanisms. MATERIAL AND METHODS: Thirty-three patients diagnosed with depression and 33 healthy controls were studied using standardized neuropsychological tests and tests comprising emotiogenic stimuli. RESULTS: A neurocognitive deficit in patients with depression manifested as changes in speed of emotional processing and some cognitive functions. These patients demonstrate decreased attention to negative stimuli combined with decreased attention to positive stimuli. CONCLUSION: The abnormal processes of 'hot' cognition in patients with depressive disorders conceptualize such a core symptom of depression as anhedonia, which is a probable endophenotype of depression. PMID- 30251973 TI - [The prevalence of the palmo-mental reflex in patients with cervicocranialgia]. AB - AIM: To study characteristics of the palmo-mental reflex (PMR) in patients with cervicalgia accompanied by the most common forms of headaches: migraine, tension type headache (TTH) and cervicogenic headache (CGH). MATERIAL AND METHODS: Prevalence of PMR was studied in a sample of 142 patients with neck pain (mean age 39.1+/-12.1 years; 103 women and 39 men) accompanied by migraine, TTH or CGH. The first group included 66 patients (51 women and 15 men; mean age 39.4+/-12.8 years) with neck pain accompanied predominantly by migraine. The second group included 76 patients (52 women and 24 men; mean age 38.9+/-11.7 years) with TTH and/or CGH. RESULTS: The palmo-mental reflex was observed in 86.4% patients of the 1-st group and 7.0% of the second group (chi2=91.41; p=0.000). CONCLUSION: The results suggest the presence of anatomical and pathophysiological premises for occurrence of this reflex in patients with neck pain accompanied by migraine. PMID- 30251974 TI - [Cognitive functions, emotional status, MRI measurements in treatment-naive middle-aged patients with uncomplicated essential arterial hypertension]. AB - AIM: To study cognitive functions, anxiety and depression levels, 24-hour blood pressure (BP) profile, cerebral blood flow (CBF) perfusion in treatment-naive middle-aged patients with uncomplicated essential arterial hypertension (EAH) depending on the white matter hyperintensities (WMH) burden. MATERIAL AND METHODS: Forty-one hypertensive patients (mean age 46.2+/-4.6 years) and 41 healthy volunteers (mean age 50.3+/-6.7 years) were enrolled to the study. All subjects underwent brain MRI (MAGNETOM Skyra 3.0T, T1, T2 FSE, T2 FLAIR, T1 MPRAGE, ASL), Montreal cognitive assessment (MoCa), 10-word learning task, verbal fluency test, trail making test, Stroop color and word test, anxiety and depression assessment with Hamilton rating scales, 24-hour blood pressure monitoring (ABPM). RESULTS: WMH were found in 22 (53.7%) hypertensive patients and in 3 (7.3%) healthy volunteers (p=0.0002). Hypertensive patients had the significantly lower CBF compared to controls (p<0.001). CONCLUSION: WMH were identified in treatment-naive middle-aged patients with uncomplicated mild to moderate EAH. There was an association between WMH and lower CBF in the cortical plate of frontal lobes, SBP variability and worse cognition. Cerebral hypoperfusion can cause cognitive impairment even in the earliest stages of EAH, which increases due to emotional disorders. PMID- 30251975 TI - [The possibility of using combination therapy in patients with chronic cerebral ischemia]. AB - AIM: To evaluate the efficacy and tolerability of mexiB 6 and vinpotropil 10/800 in patients with chronic cerebral ischemia. MATERIAL AND METHODS: The study included 30 outpatients with chronic cerebral ischemia, 1-2 stages. The average age was 55,2+/-10,04 years. All patients underwent clinical/neurological examination. To assess the efficacy of therapy, the Visual-Analog Scale, the Test of feeling, activity and mood, the Montreal Cognitive Evaluation Scale, the Asthenia Scale, the Hospital Anxiety and Depression Scale were used. All patients were treated with mexicB 6 (1 tablet 3 times a day for 1 month), then vinpotropil 10/800 (1 tablet 3 times a day) was used in addition to mexiB 6. The total duration of follow-up was 2 months. RESULTS AND CONCLUSION: Treatment with mexiB 6 led to a significant regression of patients' complaints starting from the second week of therapy, the improvement in well-being was noted in all patients. Inclusion of vinpotropil in the therapy resulted in the additional symptom regression in 19 (63,3%) patients. At the end of combined therapy, there was a significant improvement on all the scales that indicated improvements in cognitive functions, asthenic and anxiety-depressive disorders. An increase in Mg in the blood (0,91+/-0,05 mmol/l), which did not change after 2 months of therapy (0,94+/-0,05 mmol/l) was observed. Undesirable phenomena during treatment were not recorded. MexiB 6 and vinpotropil were well-tolerated in both monotherapy and combined use. The proposed therapy scheme is effective and safe. PMID- 30251976 TI - [Non-drug therapy of vertigo]. AB - AIM: To study the efficacy of various methods of non-drug therapy of diseases manifested by vertigo and dizziness in neurological practice. MATERIAL AND METHODS: Referral and final diagnoses were compared after neurovestibular examination of 599 patients (177 men and 422 women), aged 25 to 79 years (mean age 55 years), with various causes of vertigo. Patients underwent vestibular rehabilitation, trainings on the stabiloplatform with biological feedback (biofeedback), repositioning maneuvers in patients with benign paroxysmal positional vertigo (BPPV). Severity of dizziness on a Visual analogue scale of dizziness (VAS-d) and balance on stabilography before and after a course of vestibular rehabilitation was analyzed. RESULTS: Before neurovestibular examination, the diagnoses of vertebrobasilar insufficiency (44%), hypertensive or atherosclerotic encephalopathy (35%), cervical spondyloarthrosis (8%), autonomic dystonia (11%)) are often considered mistakenly as the causes of vertigo and dizziness. After neurovestibular examination, the diagnoses were as follows: BPPV (39%), phobic postural vertigo (29%), Meniere's disease (14%), vestibular neuritis (11%), multisensory dizziness in elderly (5%). The effectiveness of repositioning maneuvers in BPPV was 90,2% after the first session and 100% after the second session. After a course of vestibular exercises and trainings on the stabiloplatform with biofeedback, there was the marked improvement in indicators of stabilography and VAS-d in patients with vestibular neuritis, Meniere's disease, phobic postural vertigo (p<0.05). Vestibular rehabilitation was most effective if started within the first month after vestibular neuritis. There was the high efficacy of complex rehabilitation, including vestibular exercises and trainings on stabilographic platform with biofeedback, in patients with Meniere's disease. In the rehabilitation of patients with phobic postural vertigo, better results were achieved when vestibular exercises were combined with trainings on stabilographic platform with biofeedback and psychotherapy. CONCLUSION: The results demonstrated the low accuracy of diagnosis of diseases manifested by vertigo and dizziness and high efficacy of non-drug therapy in most cases, especially BPPV, vestibular neuritis, Meniere's disease, postural phobic vertigo. PMID- 30251977 TI - [Post-stroke rehabilitation training with a brain-computer interface: a clinical and neuropsychological study]. AB - AIM: To evaluate the clinical efficacy of BCI-supported mental practice and to reveal specific cognitive impairment which determine mental practice ineffectiveness and inability to perform MI. MATERIAL AND METHODS: Fifty-five hemiplegic patients after first-time stroke (median age 54. 0 [44.0; 61.0], time from onset 6.0 [3.0; 13.0] month) were randomized into two groups - BCI and sham controlled. Severity of arm paresis was measured by Fugl-Meyer Assessment of Motor Recovery after Stroke (FMA) and Action Research Arm Test (ARAT). Twelve patients from the BCI group were examined using neuropsychological testing. After assessment, patients were trained to imagine kinesthetically a movement under control of BCI with the feedback presented via an exoskeleton. Patients underwent 12 training sessions lasting up to 30 min. In the end of the study, the scores on movement scales, electroencephalographic results obtained during training sessions were analyzed and compared to the results of neuropsychological testing. RESULTS: Evaluation of the UL clinical assessments indicated that both groups improved on ARAT and FMA (sections A-D, H, I) but only the BCI group showed an improvement in the ARAT's grasp score (p=0.012), pinch score (p=0.012), gross movement score (p=0,002). The significant correlation was revealed between particular neuropsychological tests (Taylor Figure test, choice reaction test, Head test) and online accuracy rate. CONCLUSION: These results suggest that adding BCI control to exoskeleton-assisted physical therapy can improve post stroke rehabilitation outcomes. Neuropsychological testing can be used for screening before mental practice admission and promote personalized rehabilitation. PMID- 30251978 TI - [Mono- and combination therapy with the mexidol in young patients with cerebral angiodystonia]. AB - AIM: To evaluate an effect of mono- and combined therapy with mexidol in young patients with cerebral angiodystonia. MATERIAL AND METHODS: Ninety patients (38 men and 52 women, aged from 25 to 44 years) with autonomic dysfunction syndrome in the form of asthenoautonomic and cephalgic syndromes treated with mexidol (group 1, 30 patients), vinpocetine (group 2, 30 patients) and with the combination of these drugs (group 3, 30 patients) were included in the study. Cerebral hemodynamics was assessed using the algorithm of complex ultrasound study, autonomic regulation with the analysis of heart rate variability, functional microcirculation with laser Doppler flowmetry before and 10 days after treatment. RESULTS AND CONCLUSION: Mexidol used both in mono- and combination therapies exerted autonomic stabilizing and cerebral protective effects in the treatment of cerebral angiodystonia. The improvement of cerebral hemodynamics and microhemocirculation was shown. When used in combination, mexidol and vinpocetine had the synergistic effect, moreover, the adaptation of cerebral circulation increased more rapidly compared to vinpocetine treatment. Therefore, the combined therapy (mexidol and vinpocetine) in patients with cerebrovascular pathology minimizes the likelihood of poor outcomes and can prevent the development of acute cerebral circulation disorder. PMID- 30251979 TI - [Cavinton Comforte in the correction of vascular cognitive disorders]. AB - AIM: To study the effect of cavinton comforte (CC) on the severity of cognitive impairment and motor awkwardness in patients with chronic brain ischemia (HIGM). MATERIAL AND METHODS: There were 30 patients (8 men, 22 women) aged 50-65 years (61.6+/-4.9 years on average) with AHU with cognitive impairment. We used tests of MINI-Cog, Munsterberg, TMT), ADL). QC appointed 10 mg 3 times a day for 3 months. RESULTS: Against the background of therapy, the improvement of constructive praxis and short-term memory, an increase in the speed of visual search and visual-motor function, an increase in the level of selectivity of attention, an improvement in the reproduction of visual images and perception, an increase in the speed of the motor task (drawing strokes). CONCLUSION: The obtained data can testify about the improvement of indicators of function of a small motility of brushes on the background of improvement of cognitive functions. PMID- 30251980 TI - [Neurophysiological assessment of persistent idiopathic facial pain]. AB - AIM: To study neurophysiological characteristics of persistent idiopathic facial pain (PIFP) in comparison to trigeminal neuralgia. MATERIAL AND METHODS: Forty five patients with PIFP at the age from 25 to 74 years (42 women and 3 men), 25 patients with trigeminal neuralgia at the age from 25 to 84 (15 women and 10 men) and 20 healthy volunteers were examined. Multimodal evoked potentials (EP): brainstem auditory (BAEPs), trigeminal (TEPs) and sympathetic skin responses (SSRs) evoked potentials were recorded. EEG with functional tests (hyperventilation, rhythmical photic stimulation and test with eye opening) was recorded as well. RESULTS: The neurophysiological pattern of PIFP includes: 1) shortening of the latent period (LP) and an increase in peak amplitudes of short latent components of the BAEPs on both sides in combination with signs of brainstem structure dysfunction (fusion of II-III or III-IV peaks, bifurcation of peaks and lengthening of inter-peaks intervals); 2) normal parameters of the TEPs; 3) an increase in the amplitude of autonomic components (sympathetic and parasympathetic without signs of predominance of the tone of this or that system), intensification of the autonomic reaction; 4) disorganization and acuity of the alpha rhythm, smoothing of zonal differences, presence of bilateral tapering alpha-, theta- or alpha-theta waves on the EEG. CONCLUSION: Patients with PIFP have significant changes in EP and EEG connected with brainstem structure dysfunction and irritation of subcortical structures and autonomic disorders. PMID- 30251981 TI - [The significance of EEG in the evaluation of arterial hypertension treatment]. AB - AIM: To assess the efficacy of the treatment of patients with arterial hypertension (AH) using electroencephalography (EEG). MATERIAL AND METHODS: Arterial pressure (AP) was recorded in 250 patients with AH, along with simultaneous recording of EEG with electrocardiography (ECG), computed CT of the brain, which did not reveal any pathological changes. Patients were examined during AH elevation and after its normalization and improvement of general health state. RESULTS AND CONCLUSION: Normalization of EEG parameters depended only on the AH level was observed in systolic AH <140 mm hg and diastolic AD <90 mm hg in the improvement of general health state during 1-2 month. AH normalization led to disappearance of monophasic spikes, synchronized to ECG R wave, an increase in alpha-rhythm index, absence of bilateral synchronized spikes. The method of simultaneous recording of AH, ECG and EEG can be used for assessment of AH treatment efficacy and medical-social expertise of patients. The method of biofeedback is effective only when used together with pharmacological treatment of AH according to current treatment standards. PMID- 30251982 TI - [The processes of alpha-synuclein amyloid protein complexes involved in the pathogenesis of Parkinson's disease]. AB - AIM: To analyze interactions between alpha-synuclein (alphaS) protein and lipids using biophysical methods. MATERIAL AND METHODS: Recombinant alpha-synuclein synthesized in prokaryotic cells was used. To characterize the interaction of alphaS with negatively charged vesicles of DOPS (1,2-dioleoyl-sn-glycero-3 phospho-L-serine, sodium salt) and DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1' rac-glycerol), sodium salt) and the consequences of such interactions on alphaS amyloid formation, combined circular dichroism, fluorescence and imaging methods in vitro were applied. RESULTS AND CONCLUSION: Lipid head-group chemistry modulates alphaS interactions and also affects amyloid fiber formation. Pre formed alphaS oligomers, typically present in a small amount in the alphaS starting material, acted as templates for linear growth of anomalous amyloid fibers in the presence of vesicles. At the same time, the remaining alphaS monomers were restricted from vesicle-mediated nucleation of amyloid fibers. Although not a dominant process in bulk experiments, this hidden alphaS aggregation pathway may be of importance in vivo. PMID- 30251983 TI - [Lipoprotein (a) in patients with carotid atherosclerosis]. AB - AIM: To evaluate the role of lipoprotein (a) in an atherosclerotic lesion of precerebral arteries and stroke development. MATERIAL AND METHODS: Thirty-eight patients with atherosclerotic lesions of the carotid arteries established by duplex scanning, including 28 post stroke patients and 10 patients with asymptomatic atherosclerosis, were examined. Lipoprotein (a) was determined by immunosorbent assay in the serum and supernatant after 3-day cultivation of neutrophils. RESULTS AND CONCLUSION: There was a correlation between serum lipoprotein (a) and endothelium-dependent vasodilation of the brachial artery, and the relationship of culture lipoprotein (a) with the severity of atherosclerotic lesions of precerebral arteries and prothrombin time. Thus, the effect of lipoprotein (a) on the atherogenesis may be mediated by endothelial dysfunction and the mechanism of realization of stroke development is prothrombogenic effects on hemostasis. PMID- 30251984 TI - [Circadian changes in the structure of cardiac rhythm during pre-symptomatic and symptomatic stages of Parkinson's disease]. AB - AIM: To study circadian regulation of heart rhythm during the pre-symptomatic (PS) and early symptomatic (ESS) stages of Parkinson's disease (PD) and determine the functionally most unfavorable periods during which there is a risk of life threatening arrhythmias. MATERIAL AND METHODS: The studies were performed on C57BL/6 mice. ECG monitoring was performed in online mode using a wireless telemetry system (ADInstruments Australia). RESULTS: Characteristics of circadian changes heart rate during PS and ESS of PD were detected. During PS changes in the autonomic regulation of the heart occur at night. The increase at this time of the parasympathetic tone indicates compensatory mechanisms that prevent changes in the total power spectrum. However, they can't prevent the high risk of life-threatening arrhythmias. The early symptomatic stage leads to the changes in mechanisms of not only sympathetic, but also parasympathetic regulation of the heart, increase in sympathetic tone and disturbed structure of the heart rhythm over most of the day. The decrease in the total power of the spectrum indicates a decrease in the adaptive capacity of the cardiovascular system. The increase in the intervals of QT, QTc and Tpeak Tend, indicates a risk of life-threatening arrhythmias. CONCLUSION: PD predetermines complications of circadian autonomic regulation of the heart during PS and ESS, which can become the pathogenetic basis for severe cerebrocardial disorders. PMID- 30251985 TI - [Dimebon correction of changes in phospholipid composition induced by tumor necrosis factor-alpha in experement]. AB - AIM: To investigate the ability of the neuroprotector dimebon to prevent alterations in brain lipid metabolism caused byTNF-alpha. MATERIAL AND METHODS: The ability of dimebon (2,8-Dimethyl-5-[2-(6-methyl-3-pyridinyl)ethyl]-2,3,4,5 tetrahydro-1H-pyrido[4,3-b]indole hydrochloride) to prevent alterations in brain lipid metabolism caused byTNF-alpha was studied in 65 male mice (20+2g weight). TNF-alpha (10 mkg/mouse), dimebon (0.2 mg/kg) and their combination were injected intraperitoneally. Thirty min, 2, 4 and 24 h after injection, lipid level alterations in total fractions and molecular species of phospholipids (phosphatidylcholine, lysophosphatidylcholine, sphingomyelin and phosphatidylethanolamine) were measured with mass-spectrometry in the hippocampus, cortex and cerebellum. RESULTS AND CONCLUSION: After injection of TNF-alpha into mice, there are significant changes in the level of all tested phospholipids. Dimebon at a dose of 0.2 mg/kg alone does not cause any changes in the content of all tested phospholipids, but injected together with TNF-alpha prevents cytokine induced alterations in the lipid content. The selectivity of TNF-alpha and dimebon influence on certain molecular species of various phospholipids in different parts of mouse brain is found. The presented data suggest protective properties of dimebon preventing the development of proinflammatory syndrome induced by TNF-alpha in the animal brain. PMID- 30251986 TI - [Cardiovascular mortality in the Russian Federation and possible mechanisms of its changes]. AB - The article presents data on the mortality trends in Russia during the last decade in comparison with other countries in Europe. It is shown that in spite the decline in death rates, Russia remains among the countries with the highest mortality rates from CVD. The specifics of mortality that distinguish Russia from other countries are described: a large variability between regions in mortality levels, differences between sexes, dependence on geographical location and socio economic development of the regions, and late referral to a doctor in life threatening conditions. The article emphasizes the role of risk factors and accessibility and quality of medical care to the population, as the two main components of the mechanism for changing mortality from CVD. PMID- 30251987 TI - [Mikhail Sergeyevich Dobrohotov (To the 140th anniversary of his birth)]. PMID- 30251988 TI - [The genetic predictors of cognitive impairment in Parkinson's disease]. AB - Parkinson's disease (PD) is a common neurodegenerative disorder that can be both sporadic and familial. A number of studies are devoted to the study of non-motor symptoms in PD today. Cognitive deficits, and especially dementia, are one of the most severe and disabling non-motor symptoms of PD. More than a quarter of patients in the early stages of PD have a moderate cognitive impairment, more than half of patients with PD develop dementia within 10 years from the date of diagnosis. Using genome-wide association studies (GWAS), a number of genes associated with cognitive impairment have been identified based on a comparison of genetic and clinical phenotypes. These genes can be divided into three groups: genes that lead to the development of PD and are inherited according to the laws of Mendel (SNCA), genes that are risk factors for PD development (GBA, MAPT) and genes associated with the development of cognitive impairment, but not with PD (COMT, APOE, BDNF). This review examines the effect of genetic variants in the above-mentioned genes on cognitive functions in patients with PD. The elucidation of the genetic basis of cognitive deficits in PD could help in choice of treatment tactics and in development of new therapeutic strategies. PMID- 30251989 TI - [Speech and language neurodevelopmental disorders in epilepsy: pathophysiologic mechanisms and therapeutic approaches]. AB - Speech and language development may be impaired in all forms of epilepsy involving specialized functional areas in the dominant cerebral hemisphere and their connections. The concept of epilepsy-aphasia clinical spectrum was recently proposed, but the notion of aphasia is quite conditional here as many of these patients demonstrate disorders of speech and language development from their infancy. Those forms of epilepsy are considered as continuum from the most severe Landau-Kleffner syndrome (LKS) and epilepsy with continuous spike-and-wave during sleep (CSWS) (also indicating as electrical status epilepticus during sleep - ESES) to intermediate epilepsy-aphasia disorders (with incomplete correspondence to diagnostic criteria of LKS and epilepsy with CSWS). The mild end of the spectrum is represented by benign childhood epilepsy with centrotemporal spikes (rolandic), which is often associated with speech and language disorders. The importance of genetic factors is discussed, including mutations in SRPX2, GRIN2A and other genes. The perspectives of individualized pharmacotherapy in epilepsy, co-morbid with neurodevelopmental disorders or impairments of speech and language development, are depending on the progress in genetic studies. In the new generation of antiepileptic drugs the positive influence on neuroplasticity mechanisms and higher cerebral functions are supposed for levetiracetam. PMID- 30251990 TI - [Comorbidity of type 2 diabetes mellitus and low back pain]. AB - Diabetes mellitus (DM) and back pain are widespread and often develop simultaneously. In patients with DM 2 type, the incidence of back pain is increased. The association of DM with the severity of pain and the frequency of its chronization and recurrence has been revealed. The most likely mechanism of such an association is the lesion of intervertebral discs mediated by the accumulation of advanced glycation end-products (EGP). In DM the concentration of EGP increases significantly; they initiate ectopic calcification, a decrease in cell density in the end plates, and changes in vertebras. Cells of the pulpous nuclei begin to produce pro-inflammatory cytokines and chemokines that trigger the processes of angio- and neurogenesis. Dorsopathies develop due to other etiological factors, but the mechanisms of systemic inflammation are similar. Thus, DM and back pain are comorbid pathologies with common elements in pathogenesis. To prevent the development of dorsopathy in DM 2 type it is considered promising to use drugs that reduce the intensity of accumulation of AGP and inhibitors of pro-inflammatory cytokines, for example, symptomatic slow acting drugs. PMID- 30251991 TI - De novo transcriptome assembly of fluorine accumulator tea plant Camellia sinensis with fluoride treatments. AB - Tea plant (Camellia sinensis) is a typical fluoride (F) hyperaccumulator enriching most F in old leaves. There is association between the risk of fluorosis and excessive consumption of teas prepared using the old leaves. It is meaningful to develop methods for controlling F levels in tea leaves. We generated a comprehensive RNA-seq dataset from tea plants grown at various F levels for different durations by hydroponics, aiming at providing information on mechanism of F metabolism in tea plant. Besides raw reads of the RNA-seq dataset, we present assembled unigenes and aligned unigenes with annotations versus the Gene Ontology (GO) databases, Kyoto Encyclopaedia of Genes and Genomes (KEGG) databases, and Nonredundant (Nr) protein databases with low e-values. 69,488 unigenes were obtained in total, in which 40,894 were given Nr annotations. PMID- 30251992 TI - An open database of productivity in Vietnam's social sciences and humanities for public use. AB - This study presents a description of an open database on scientific output of Vietnamese researchers in social sciences and humanities, one that corrects for the shortcomings in current research publication databases such as data duplication, slow update, and a substantial cost of doing science. Here, using scientists' self-reports, open online sources and cross-checking with Scopus database, we introduce a manual system and its semi-automated version of the database on the profiles of 657 Vietnamese researchers in social sciences and humanities who have published in Scopus-indexed journals from 2008 to 2018. The final system also records 973 foreign co-authors, 1,289 papers, and 789 affiliations. The data collection method, highly applicable for other sources, could be replicated in other developing countries while its content be used in cross-section, multivariate, and network data analyses. The open database is expected to help Vietnam revamp its research capacity and meet the public demand for greater transparency in science management. PMID- 30251993 TI - Open data, open curation. PMID- 30251994 TI - Mimi-PAGE, an open-source implementation of the PAGE09 integrated assessment model. AB - Integrated Assessment Models (IAMs) have become critical tools for assessing the costs and benefits of policies to reduce greenhouse gas emissions. Three models currently inform the social cost of carbon dioxide (SCCO2, the net present value of damages from one additional ton of CO2) used by the US federal government, several states, and Canada. Here we present a new open-source implementation of one of these models (PAGE09) in the Julia programming language using a modular modeling framework (Mimi). Mimi-PAGE was coded using best coding practices (such as multiple code reviews by different individuals during development, automated testing of newly-committed code, and provision of documentation and usage notes) and is publicly available in a GitHub repository for community inspection and use under an open source license. In this paper we describe the Julia implementation of PAGE09, show that output from Mimi-PAGE matches that of the original model, and perform comparisons of the run time between the two implementations. PMID- 30251997 TI - A novel fluorescent aptasensor for ultrasensitive and selective detection of acetamiprid pesticide based on the inner filter effect between gold nanoparticles and carbon dots. AB - This paper reports a novel fluorescent aptasensor for the detection of acetamiprid pesticide with high sensitivity and selectivity based on the inner filter effect (IFE) of gold nanoparticles (AuNPs) toward fluorescent carbon dots (CDs). The aptasensor employs S-18 aptamer as the specific target recognition molecule and CDs as the signal transmission element. Free S-18 aptamer sequences can wrap the surfaces of AuNPs and enable their dispersion state even in the presence of high amounts of Tris-HCl salt, which can effectively quench the fluorescence of the CDs through the IFE. Upon adding acetamiprid pesticide, the free S-18 aptamer sequences are firstly exhausted to form some complexes; thus, the AuNPs tend to aggregate and their absorption spectrum no longer overlaps with the fluorescence emission spectrum of the CDs, which leads to obvious fluorescence recovery of the aptasensor. The properties of the CDs were extensively characterized, and the fluorescence quenching effects of the AuNPs toward the CDs were fully investigated. Additionally, the effects of some vital parameters, such as the type and amount of AuNPs, on the fluorescent aptasensor were also investigated. The proposed aptasensor has a detection limit as low as 1.08 MUg L-1 with a linear range of 5 to 100 MUg L-1 and shows high selectivity for acetamiprid over other control pesticides. Moreover, the aptasensor displays excellent accuracy and recovery in the detection of spiked real samples, suggesting that this fluorescent aptasensor can play important roles in the fields of food analysis and environmental detection. PMID- 30251995 TI - Reference data on thickness and mechanics of tissue layers and anthropometry of musculoskeletal extremities. AB - Musculoskeletal extremities exhibit a multi-layer tissue structure that is composed of skin, fat, and muscle. Body composition and anthropometric measurements have been used to assess health status and build anatomically accurate biomechanical models of the limbs. However, comprehensive datasets inclusive of regional tissue anatomy and response under mechanical manipulation are missing. The goal of this study was to acquire and disseminate anatomical and mechanical data collected on extremities of the general population. An ultrasound system, instrumented with a load transducer, was used for in vivo characterization of skin, fat, and muscle thicknesses in the extremities of 100 subjects at unloaded (minimal force) and loaded (through indentation) states. For each subject, the unloaded and loaded state provided anatomic tissue layer measures and tissue indentation response for 48 and 8 regions, respectively. A publicly available web-based system has been used for data management and dissemination. This comprehensive database will provide the foundation for comparative studies in regional musculoskeletal composition and improve visual and haptic realism for computational models of the limbs. PMID- 30251996 TI - Generation and characterization of thiol-deficient Mycobacterium tuberculosis mutants. AB - Mycothiol (MSH) and ergothioneine (ERG) are thiols able to compensate for each other to protect mycobacteria against oxidative stress. Gamma-glutamylcysteine (GGC), another thiol and an intermediate in ERG biosynthesis has detoxification abilities. Five enzymes are involved in ERG biosynthesis, namely EgtA, EgtB, EgtC, EgtD and EgtE. The role of these enzymes in the production of ERG had been unclear. On the other hand, the enzyme MshA is known to be essential for MSH biosynthesis. In this manuscript, we describe the raw data of the generation and characterization of Mycobacterium tuberculosis (M.tb) mutants harbouring a deletion of the gene coding for each of these enzymes, and the raw data of the phenotypic characterization of the obtained thiol-deficient M.tb mutants. High throughput screening (HTS) of off-patent drugs and natural compounds revealed few compounds that displayed a higher activity against the thiol-deficient mutants relative to the wild-type strain. The mode of action of these drugs was further investigated. Raw data displaying these results are described here. PMID- 30251998 TI - A background-subtraction strategy leads to ratiometric sensing of oxygen without recalibration. AB - Luminescence-quenching based optical oxygen sensors have wide applications in many fields, which have already replaced almost 40% of the commercial market share dominated previously by the Clark oxygen electrode. The majority of optical oxygen sensors are based on lifetime measurement, which are precise, but are relatively expensive, and require high-speed electronics and detecting circuits. Alternatively, oxygen concentration can be measured via a luminescence intensity change, which is a referenced approach according to the Stern-Volmer equation. However, luminescence intensity based measurement tends to be highly influenced by background light. At a given sensor composition, different instrumentation setups, sensor surface roughnesses and thicknesses, and environmental light will result in significantly different calibration curves and sensitivities. This makes luminescence-intensity based optical sensors almost impossible to use practically, because each sensor needs to be recalibrated before use, and the calibration curve each time is quite different. We have solved this problem by introducing a new background-subtraction strategy. After background subtraction, oxygen sensors with different probe concentrations, instrumentation setups, surface roughnesses, supporting matrixes, and at different temperatures present identical calibration curves. This could greatly reduce the calibration task during practical use. Combined with the advantages of low price and a simple optical configuration, the new method will significantly promote wider applications of optical oxygen sensors. PMID- 30252001 TI - Impact-induced gelation in aqueous methylcellulose solutions. AB - Aqueous methylcellulose is an "abnormal" inverse-freezing fluid, which gelates when heated. We ventured to stimulate this phase-transition by mechanical impact, whose resulting shockwaves and local heat could be uptaken by the endothermic gelation. High-speed photography was used to observe this transition in microsecond timescales. This phenomenon enables attenuation of shockwaves. PMID- 30252003 TI - The impact of sulfur functionalisation on nitrogen-based ionic liquid cations. AB - It has been demonstrated that bonding and interactions within ionic liquids (ILs) can be elegantly tuned by manipulation of structure and the introduction of functional groups. Here we use XPS to investigate the impact of sulfur containing substituents on the electronic structure of a series of N-based cations, all with a common anion, [NTf2]-. The experiments reveal complexity and perturbation of delocalised systems which cannot be easily interpreted by NMR and XPS alone, DFT provides critical insight into bonding and underpins the assignment of spectra and development of deconstruction models for each system studied. PMID- 30252002 TI - A cell-penetrating peptide induces the self-reproduction of phospholipid vesicles: understanding the role of the bilayer rigidity. AB - Model lipid vesicles self-reproduce to generate unilamellar daughter vesicles in the presence of a cell-penetrating peptide. Fluorescence lifetime and anisotropy image analysis exquisitely capture the change in the lipid bilayer rigidity throughout the process, whereas a solvation dynamic study delineates the change in the dynamics of the encapsulated water inside the vesicles. Overall, our results provide an experimental underpinning of the role of the lipid bilayer structural changes in self-reproduction, which can exhibit great potential for interpreting the protein-membrane interaction in the emergence of life and for developing new therapeutic strategies. PMID- 30252007 TI - Rational design of MnCo2O4@NC@MnO2 three-layered core-shell octahedron for high rate and long-life lithium storage. AB - With the depletion of fossil energy and rapid development of electronic equipment, the commercial lithium-ion batteries (LIBs) do not meet the current energy demand. There is an urgent need to develop novel LIBs with high capacity, long life, and low cost. In this work, we design and synthesize a MnCo2O4@NC@MnO2 three-layered core-shell octahedron with good electrochemical performance using binary transition metal oxide (MnCo2O4), N-doped carbon (NC), and high-capacity manganese oxide (MnO2). The three-layered structure is effective in relieving the volume expansion, improving the electronic conductivity, and strengthening the structural stability. The MnCo2O4@NC@MnO2 three-layered core-shell octahedron displays a high discharge capacity of 894 mA h g-1 at a current density of 500 mA g-1 after 120 cycles. Even at a high current density of 1000 mA g-1, the discharge capacity remains at 839 mA h g-1 after 600 cycles. Furthermore, this material possesses pretty good rate performance. All the results show that this ternary composite is a good anode alternative for lithium storage. PMID- 30252008 TI - Bis(pentalene)dititanium chemistry: C-H, C-X and H-H bond activation. AB - The reaction of the bis(pentalene)dititanium complex Ti2(MU:eta5,eta5-Pn?)2 (Pn? = C8H4(1,4-SiiPr3)2) (1) with the N-heterocyclic carbene 1,3,4,5 tetramethylimidazol-2-ylidene results in intramolecular C-H activation of an isopropyl substituent to form a tucked-in hydride (3). Whilst pyridine will also effect this cyclometallation reaction to form (5), the pyridine analogue of (3), the bases 1,2,4,5-tetramethyl-imidazole, 2,6-lutidine, DABCO or trimethylphosphine are ineffective. The reaction of (1) with 2,6-dichloro pyridine affords crystallographically characterised (6) which is the product of oxidative addition of one of the C-Cl bonds in 2,6-dichloro-pyridine across the Ti-Ti double bond in (1). The tucked-in hydride (3) reacts with hydrogen to afford a dihydride complex (4) in which the tuck-in process has been reversed; detailed experimental and computational studies on this reaction using D2, HD or H2/D2 support a mechanism for the formation of (4) which does not involve sigma bond metathesis of H2 with the tucked-in C-H bond in (3). The reaction of (3) with tBuCCH yields the corresponding acetylide hydrido complex (7), where deuteration studies show that again the reaction does not proceed via sigma-bond metathesis. Finally, treatment of (3) with HCl affords the chloro-derivative (9) [(NHC)Ti(MU-H)Ti{(MU,eta5:eta5)Pn?}2Cl], whereas protonation with [NEt3H]BPh4 yielded a cationic hydride (10) featuring an agostic interaction between a Ti centre and an iPr Me group. PMID- 30252009 TI - A La3+-selective metallohydrogel with a facile gelator of a phenylalanine derivative containing an imidazole group. AB - The first La3+-selective metallohydrogel was constructed by using a facile gelator of a phenylalanine derivative containing an imidazole group, N-(1H imidazol-4-yl)methylidene-l-phenylalanine, namely La-ImF, which exhibits multi stimuli responsive properties, including to heat, shearing, pH, etc. Various measurements were also carried out to obtain insights into the mechanism of gelation. Moreover, the La-ImF hydrogel can adsorb toxic dyes, making it a potential candidate for sewage treatment. PMID- 30252010 TI - Formation of N-nitrosamines by micelle-catalysed nitrosation of aliphatic secondary amines. AB - N-Nitrosamines are an important class of potent human carcinogens and mutagens that can be present in water and wastewater. For instance, N-nitrosamines can be formed by reaction of nitrosating agents such as NO+ or N2O3 formed from nitrite under acidic conditions with secondary amine precursors by an acid-catalysed nitrosation pathway. This study investigates the catalytic effect of cationic and anionic micelles on the nitrosation of secondary aliphatic amines in the presence of nitrite at different pH values. The results of this study demonstrate that the nitrosation of hydrophobic secondary amines (e.g., dipropylamine and dibutylamine) by nitrite was significantly enhanced in the presence of micelles of the cationic surfactant cetyltrimethylammonium chloride whereas anionic micelles formed by sodium dodecylsulfate did not significantly enhance the formation of N-nitrosamines. Rate enhancements of up to 100-fold were observed for the formation of N-nitrosodibutylamine in the presence of cetyltrimethylammonium chloride. The magnitude of the catalytic effect of cationic micelles on the nitrosation reaction depended mainly of the hydrophobicity of the amine precursors (i.e., alkyl chain length), the stability and the charge of the micelles and pH. One important enhancement factor is the lowering of the pKa of the precursor alkylammonium ion due to the electrical potential at the micelle-water interface by up to ~2.5 pH units. These results suggest that cationic micelle-forming surfactants might play a role in the formation of N-nitrosamines in wastewater, consumer products and in industrial processes using high concentrations of cationic surfactants. PMID- 30252011 TI - A promising PMHS/PEO blend polymer electrolyte for all-solid-state lithium ion batteries. AB - Solid-state lithium metal batteries have emerged as a promising alternative to existing liquid Li-ion batteries and can power the future storage market considering their higher energy outputs and better safety. Among various solid electrolytes, polymer electrolytes have received more attention due to their potential advantages, including wide electrochemical windows, ease of processing, low interface impedance and low cost. Polymeric electrolytes based on poly(ethylene oxide) (PEO) as a well-known polymer matrix have been extensively studied because of their highly flexible EO segments in the amorphous phase that can provide channels for lithium ion transport. However, obtaining a PEO-based solid electrolyte with high Li ion conductivity and without sacrificing mechanical strength is still a huge challenge. In this study, polymethylhydrogen siloxane (PMHS) with low glass transition temperature and good flexibility was blended into the PEO to optimize ion transportation by the solution casting technique. The hybrid electrolyte membrane with 40% PMHS exhibited high ionic conductivity (2.0 * 10-2 S cm-1 at 80 degrees C), large electrochemical windows (5.2 V), a high degree of flexibility, and thermal stability. When assembling a Li/LiFePO4 battery, a reversible capacity close to 140 mA h g-1 (0.1 C) at 60 degrees C was delivered. In addition, a cell with this polymer electrolyte exhibits excellent stability. These results demonstrate that solid polymer electrolyte systems are eligible for next-generation high energy density all solid-state lithium ion batteries. PMID- 30252012 TI - A liver-immune coculture array for predicting systemic drug-induced skin sensitization. AB - Drug-induced skin sensitization is prevalent worldwide and can trigger life threatening health conditions, such as Stevens Johnson Syndrome. However, existing in vitro skin models cannot adequately predict the skin sensitization effects of drugs administered into the systemic circulation because dermal inflammation and injury are preceded by conversion of parent drugs into antigenic reactive metabolites in the liver and subsequent activation of the immune system. Here, we demonstrate that recapitulation of these early tandem cellular processes in a compartmentalized liver-immune coculture array is sufficient to predict the skin sensitization potential of systemic drugs. Human progenitor cell (HepaRG) derived hepatocyte spheroids and U937 myeloid cells, a representative antigen presenting cell (APC), can maintain their respective functions in 2 concentric micro-chambers, which are connected by a diffusion microchannel network. Paradigm drugs that are reported to cause severe cutaneous drug reactions (i.e. carbamazepine, phenytoin and allopurinol) can be metabolized into their reactive metabolites, which diffuse efficiently into the adjoining immune compartment within a 48 hour period. By measuring the extent of U937 activation as indicated by IL8, IL1beta and CD86 upregulation upon drug administration, we show that the liver-immune coculture array more consistently and reliably distinguish all 3 paradigm skin sensitizing drugs from a non-skin sensitizer than conventional bulk Transwell coculture. Given its miniaturized format, design simplicity and prediction capability, this novel in vitro system can be readily scaled into a screenable platform to identify the skin sensitization potential of systemically administered drugs. PMID- 30252013 TI - Azlactone-based heterobifunctional linkers with orthogonal clickable groups: efficient tools for bioconjugation with complete atom economy. AB - We report the efficient synthesis of a series of new azlactone-based heterofunctional linkers bearing two orthogonal clickable groups that proceed with full atom economy. These new linkers comprise an azlactone (oxazolone) group that quickly reacts with amino groups in biologically relevant medium without byproduct elimination and a (bio)orthogonal handle which further undergoes facile and selective click reactions such as thiol-ene coupling, Diels-Alder or azide alkyne cycloadditions. As an example, the application of this methodology to lysozyme PEGylation in aqueous medium is described. PMID- 30252014 TI - Biosurfactant-functionalized porphyrin chromophore that forms J-aggregates. AB - Structurally complex biosynthesized building blocks whose structures can be systematically varied are of great interest for the synthesis of manipulable self organizing supramolecular systems. Sophorolipids (SLs) are an important class of glycolipid biosurfactants that consists of a sophorose (glucose disaccharide) polar head group that allows structural diversification by full or selective acetylation at the 6'- and 6''-positions. Porphyrins are a group of naturally occurring heterocyclic macromolecular organic compounds that have efficient charge transfer properties. Herein we describe the synthesis of SL-porphyrin conjugates where the number of sophorolipid arms, availability of hydrogen bonding sophorose hydroxyl groups and rigidity of the lipid chain were systematically varied. SLs differing in 'sophorose acetylation' and 'lipid unsaturation' were conjugated to zinc-porphyrin dyes by copper(i)-catalyzed azide alkyne cycloaddition (CuAAC) 'click' chemistry. Mono-, di-, and tetra-conjugation of SL-arms to the zinc-porphyrin core provided variation in SL-arm steric effects. UV-vis spectra in methanol/water reveal features indicative of supramolecular J-type aggregates. The synthesized compounds were designed to provide a library of unique bio-based molecules with built-in variation in non covalent interactions, hydrogen-bonding, pi-pi stacking, metal-ligand coordination, dipole-dipole, van der Waals, and hydrophobic interactions for future interrogation of supramolecular self-assembly into functional materials for electro-optical applications. PMID- 30252015 TI - Adaptable ligand donor strength: tracking transannular bond interactions in tris(2-pyridylmethyl)-azaphosphatrane (TPAP). AB - Flexible ligands that can adapt their donor strength have enabled unique reactivity in a wide range of inorganic complexes. Most examples are composed of flexible multi-dentate ligands containing a donor that can vary its interaction through its distance to the metal center. We describe an alternative type of adaptable ligand interaction in the neutral multi-dentate ligand tris(2 pyridylmethyl)-azaphosphatrane (TPAP), which contains a proazaphosphatrane unit. Prozaphosphatranes are intrinsically strong phosphorus donors; upon coordination to more Lewis acidic atoms the phosphorus can accept additional electron density from a tertiary nitrogen to form a transannular bond, increasing its donor strength. An experimental and computational investigation of the varying degree of transannular interaction in TPAP when coordinated to late transition metals is reported. The synthesis and characterization of the complexes M(TPAP), where M = Co(i)Cl, Ni(0)(1,5-cyclooctadiene), Ni(ii)(CH3CN)(BF4)2, Pd(ii)(CH3CN)(BF4)2, or Pt(ii)Cl(PF6) is described. Structural characterization and density functional theory calculation of these complexes, along with the previously reported [Co(ii)(TPAP)(CH3CN)](BF4)2 establish significant increases in the degree of transannular interaction of the proazaphosphatrane unit when coordinated to more electron deficient metal ions. PMID- 30252016 TI - Ruthenium complexes featuring cooperative phosphine-pyridine-iminophosphorane (PNN) ligands: synthesis, reactivity and catalytic activity. AB - The coordination to ruthenium(ii) centres of two phosphine-pyridine iminophosphorane ligands LR (PPh2CH2(C6H3N)CH2N[double bond, length as m dash]PR3, R = Ph or Cy) differing by the nature of the substituent of the P[double bond, length as m-dash]N phosphorus was explored. Coordination to [RuCl2(PPh3)3] afforded the complexes [RuLRCl2(PPh3)] that were successfully deprotonated at the acidic phosphinomethyl position. With LCy, coordination led to a mixture of two isomers. The complexes [RuLRHCl(PPh3)] were similarly obtained from [RuHCl(PPh3)3]. The stability of these complexes depends on the ligand substitution pattern; with LPh a CH activation process took place, while [RuLCyHCl(PPh3)] was thermally stable. Deprotonation of this latter complex was achieved and gave a catalytically competent species for the acceptorless dehydrogenative coupling of alcohols. PMID- 30252018 TI - Late aortic sinus thrombosis after aortic root replacement using a totally biological aortic valve conduit. PMID- 30252019 TI - A framework and an algorithm to detect low-abundance DNA by a handy sequencer and a palm-sized computer. PMID- 30252017 TI - Spatiotemporal Patterns and Diffusion of the 1918 Influenza Pandemic in British India. AB - The factors that drive spatial heterogeneity and diffusion of pandemic influenza remain debated. We characterized the spatiotemporal mortality patterns of the 1918 influenza pandemic in British India and studied the role of demographic factors, environmental variables, and mobility processes on the observed patterns of spread. Fever-related and all-cause excess mortality data across 206 districts in India from January 1916 to December 1920 were analyzed while controlling for variation in seasonality particular to India. Aspects of the 1918 autumn wave in India matched signature features of influenza pandemics, with high disease burden among young adults, (moderate) spatial heterogeneity in burden, and highly synchronized outbreaks across the country deviating from annual seasonality. Importantly, we found population density and rainfall explained the spatial variation in excess mortality, and long-distance travel via railroad was predictive of the observed spatial diffusion of disease. A spatiotemporal analysis of mortality patterns during the 1918 influenza pandemic in India was integrated in this study with data on underlying factors and processes to reveal transmission mechanisms in a large, intensely connected setting with significant climatic variability. The characterization of such heterogeneity during historical pandemics is crucial to prepare for future pandemics. PMID- 30252021 TI - A Bayesian mixture modeling approach for public health surveillance. AB - Spatial monitoring of trends in health data plays an important part of public health surveillance. Most commonly, it is used to understand the etiology of a public health issue, to assess the impact of an intervention, or to provide detection of unusual behavior. In this article, we present a Bayesian mixture model for public health surveillance, which is able to provide estimates of the disease risk in space and time, and also to detect areas with unusual behavior. The model is designed to deal with a range of spatial and temporal patterns in the data, and with time series of different lengths. We carry out a simulation study to assess the performance of the model under different scenarios, and we compare it against a recently proposed Bayesian model for short time series. Finally, the proposed model is used for surveillance of road traffic accidents data in England over the years 2005-2015. PMID- 30252022 TI - The role of attributable fraction in the exposed (AFE) in assessing the association of microorganisms with pneumonia. PMID- 30252020 TI - Association of circadian rhythm of blood pressure and cerebral small vessel disease in community-based elderly. AB - Background: Although it is accepted that the etiology of cerebral small vessel disease (CSVD) is associated with cardiovascular risk factors, the association between CSVD and the circadian rhythm of blood pressure is unclear. We aimed to determine if such an association existed in the elderly. Method: White matter hyperintensities (WMHs), lacunes, microbleeds, nocturnal dipping pattern (NDP), and morning surge in systolic blood pressure (SBP) were assessed in 2,091 participants >=60 years of age. Results: During an average of 63 months of follow up, WMH and the WMH-to-intracranial volume ratio were significantly increased in extreme dippers, non-dippers, and reverse dippers than those in dippers (P<.001). For new-incident Fazekas scale >=2, the hazard ratios were 1.77 (95% confidence interval [CI], 1.09-2.86) for extreme dippers, 2.20 (95% CI, 1.48-3.28) for non dippers, and 2.43 (95% CI, 1.59-3.70) for reverse dippers compared with dippers, and 1.04 (95% CI, 0.81-1.35) for higher morning surge compared with lower morning surge. Non-dippers and reverse dippers were associated with higher risks of new incident lacunes and microbleeds than dippers (P<.05). Higher morning surge was associated with a higher risk of new-incident microbleeds than lower morning surge (P<.05). Conclusion: NDPs in SBP played an important role in CSVD, and the morning surge in SBP was associated with cerebral microbleeds in community-based elderly beyond the average SBP level. PMID- 30252023 TI - MSPminer: abundance-based reconstitution of microbial pan-genomes from shotgun metagenomic data. AB - Motivation: Analysis toolkits for shotgun metagenomic data achieve strain-level characterization of complex microbial communities by capturing intra-species gene content variation. Yet, these tools are hampered by the extent of reference genomes that are far from covering all microbial variability, as many species are still not sequenced or have only few strains available. Binning co-abundant genes obtained from de novo assembly is a powerful reference-free technique to discover and reconstitute gene repertoire of microbial species. While current methods accurately identify species core parts, they miss many accessory genes or split them into small gene groups that remain unassociated to core clusters. Results: We introduce MSPminer, a computationally efficient software tool that reconstitutes Metagenomic Species Pan-genomes (MSPs) by binning co-abundant genes across metagenomic samples. MSPminer relies on a new robust measure of proportionality coupled with an empirical classifier to group and distinguish not only species core genes but accessory genes also. Applied to a large scale metagenomic dataset, MSPminer successfully delineates in a few hours the gene repertoires of 1 661 microbial species with similar specificity and higher sensitivity than existing tools. The taxonomic annotation of MSPs reveals microorganisms hitherto unknown and brings coherence in the nomenclature of the species of the human gut microbiota. The provided MSPs can be readily used for taxonomic profiling and biomarkers discovery in human gut metagenomic samples. In addition, MSPminer can be applied on gene count tables from other ecosystems to perform similar analyses. Availability: The binary is freely available for non commercial users at www.enterome.com/downloads. Supplementary information: Available in the file named Supplementary Information.pdf. PMID- 30252024 TI - Novel method for mass producing genetically sterile fish from surrogate broodstock via spermatogonial transplantation. AB - A stable system for producing sterile domesticated fish is required to prevent genetic contamination to native populations caused by aquaculture escapees. The objective of this study was to develop a system to mass produce stock for aquaculture that are genetically sterile by surrogate broodstock via spermatogonial transplantation (SGTP). We previously discovered that female medaka carrying mutations on the follicle-stimulating hormone receptor (fshr) gene become sterile. In this study, we demonstrated that sterile hybrid recipient females that received spermatogonia isolated from sex-reversed XX males (fshr (-/ )) recovered their fertility and produced only donor-derived fshr (-) X eggs. Natural mating between these females and fshr (-/-) sex-reversed XX males successfully produced large numbers of sterile fshr (-/-) female offspring. In conclusion, we established a new strategy for efficient and mass production of sterile fish. This system can be applied to any aquaculture species for which SGTP and methods for producing sterile recipients can be established. PMID- 30252025 TI - A nationwide survey of pediatric-onset Japanese encephalitis in Japan. AB - Background: Japanese encephalitis (JE) is the leading cause of viral encephalitis with high mortality and morbidity in Asia. In Japan, however, the active recommendation of JE vaccine was retracted in 2005 because of the potential risk of acute disseminated encephalomyelitis. We aimed to determine the recent incidence of childhood-onset JE after the domestic change of vaccination policy in Japan, and to analyze the clinical features of affected children. Methods: A retrospective nationwide survey was conducted for pediatric patients with JE in Japan from 1995 to 2015. The national surveillance system was used to identify the pediatric patients with JE. Follow-up questionnaires were sent to analyze their clinical and neuroimaging profiles. Results: Among a total of 109 patients registered to the national surveillance, 10 (9%) were under age 15 years. The annual incidence rate of childhood-onset JE was higher during 2005-2015 than that during 1995-2004 (4.3 x 10 -3 vs. 1.1 x 10 -3 per 100,000, respectively; P = 0.04). Endemic regions overlapped with prefectures that farmed pigs harboring antibodies against JE virus with high prevalence. Detailed clinical data were collected from 9 patients. None of them died, but 5 of 9 patients (56%) had neurological sequelae after recovery. One patient who was partially vaccinated with 2 doses of JE vaccine fully recovered from coma. The age of 3 years or under was associated with unfavorable neurological prognosis. Conclusions: Our data provide evidence for the importance and prophylactic effect of the JE vaccine in young children in the endemic area. PMID- 30252026 TI - The upstrap. AB - The bootstrap, introduced in Efron (1979. Bootstrap methods: another look at the jackknife. The Annals of Statistics7, 1-26), is a landmark method for quantifying variability. It uses sampling with replacement with a sample size equal to that of the original data. We propose the upstrap, which samples with replacement either more or fewer samples than the original sample size. We illustrate the upstrap by solving a hard, but common, sample size calculation problem. The data and code used for the analysis in this article are available on GitHub (2018. https://github.com/ccrainic/upstrap). PMID- 30252027 TI - Glucomannan Hydrolysate Promotes Gut Proliferative Homeostasis and Extends Life Span in Drosophila melanogaster. AB - Dietary supplementation of glucomannan has been shown to have multiple health benefits, but its effect on life span has not been investigated. Here, we show that glucomannan hydrolysate (GMH) treatment extends mean life span of the model organism Drosophila melanogaster. To unravel the underlying mechanisms, we first examined the effect of GMH on the gut microbiota. We found that GMH treatment is associated with an elevated bacterial load in aged flies but overall has limited effects on the relative microbiota composition. We also demonstrated that GMH inhibits age-associated hyperproliferation of intestinal stem cells and thus delays the deterioration of gut integrity. Further analysis of the midgut transcriptome revealed that both EGFR/MAPK and JAK/STAT signaling pathways are suppressed in GMH groups. Multiple key regulators or effectors of EGFR/MAPK pathway, Ets21c, Mkp3, and Rho, are downregulated by GMH treatment. In the JAK/STAT pathway, major ligands (eg, Upd2 and Upd3) and negative feedback inhibitors (eg, Socs36e) are all significantly downregulated. Additionally, the expression of genes encoding antimicrobial peptides is elevated by GMH treatment. Taken together, our study shows that dietary supplementation of GMH can prolong life span, possibly through regulating gut proliferative homeostasis. PMID- 30252028 TI - Effect of an intra-aortic balloon pump with venoarterial extracorporeal membrane oxygenation on mortality of patients with cardiogenic shock: a systematic review and meta-analysis. AB - An intra-aortic balloon pump (IABP) concomitant with venoarterial extracorporeal membrane oxygenation (VA-ECMO) is frequently used to support patients with refractory cardiogenic shock (CS). Because of the lack of evidence of the adjunctive benefit, the goal of the study was to compare the effect of VA-ECMO plus IABP with that of VA-ECMO alone. Systematic searches were conducted to identify studies using PubMed, Embase, the Cochrane Library and the International Clinical Trials Registry Platform. Studies reporting on patients with adult CS treated with VA-ECMO plus IABP or VA-ECMO alone were identified and included. The primary outcome was in-hospital death. The secondary outcomes included neurological, gastrointestinal and limb-related complications. The study protocol was registered at PROSPERO (CRD42017069259). A total of 29 studies comprising 4576 patients were included. The pooled in-hospital deaths of patients on VA-ECMO were 1441/2285 (63.1%) compared with 1339/2291 (58.4%) for patients with adjunctive IABP. VA-ECMO plus IABP was associated with decreased in-hospital deaths [risk ratio (RR) 0.90; 95% confidence interval (CI) 0.85-0.95; P < 0.0001]. Moreover, IABP was related to decreased in-hospital deaths of patients with extracorporeal cardiopulmonary resuscitation, postcardiotomy CS and ischaemic heart disease (RR 0.78; 95% CI 0.64-0.95; P = 0.01; RR 0.91; 95% CI: 0.85-0.98; P = 0.008; RR 0.83; 95% CI 0.73-0.96, P = 0.009). Neurological, gastrointestinal and limb-related complications did not differ significantly between patients on ECMO with and without concurrent IABP. VA-ECMO plus IABP was associated with decreased in-hospital deaths in patients with CS. PMID- 30252029 TI - Sexual dimorphism in the response to broad-spectrum antibiotics during T cell mediated colitis. AB - Background: Broad spectrum antibiotics, including combination therapy with ciprofloxacin and metronidazole (Abx) are often prescribed during the treatment of IBD to alleviate symptoms, but with varying success. In this pilot study, we studied the effects of Abx in the course of experimental colitis, with a particular focus on sex as a determinant of the microbial and inflammatory responses. Methods: The effects of Abx was tested on colonic inflammation and microbiome in male and female Rag-/- mice using adoptive transfer of naive T cells to induce colitis in a short-term (two-week) and long-term (9-week) study. Results: We observed disparities between sexes in both the response to adoptive T cell transfer and the effects of Abx. At baseline, without Abx, female mice displayed a trend toward a more severe colitis than males. In both the short- and the long-term experiments, gut microbiota of some female mice exposed to Abx showed weak, delayed, or negligible shifts. Cecum weight was significantly lower in Abx-treated females. Abx exposure favored a quick and persistent rise in Enterococcaceae exclusively in females. Males had higher relative abundance of Lactobacillaceae following Abx exposure relative to females. Abx-treated females trended toward higher colitis scores than Abx-treated males, and towards higher levels of IL-17A, NOS2, and IL-22. Conclusion: While preliminary, our results suggest a differential response to both inflammation and Abx between male and female mice, The findings may be relevant to current practice and as the basis for further studies on the differential gender effects during long term antibiotic exposure in IBD. PMID- 30252030 TI - The influence of age and cardiorespiratory fitness on bioactive lipids in muscle. AB - Reduced insulin sensitivity is observed with aging and often explained by decreased physical activity. The mechanisms involved are not clarified, but bioactive lipids may play a role. We aimed to evaluate the influence of age and cardiorespiratory fitness on ceramide and diacylglycerol content in muscle and key proteins in lipid metabolism and insulin signaling.Healthy males were stratified by age into trained and untrained groups including 27 young (23.2+/ 0.3 yrs.) and 33 aged (65.2+/-0.6 yrs.). Maximal oxygen uptake and body composition were measured and fasting blood samples and muscle biopsies obtained. Muscle ceramide and diacylglycerol were determined by thin-layer and gas-liquid chromatography and proteins by western blotting.We show that HOMA-IR was higher and VO2peak lower in aged compared to young. Total, saturated,C16:0 and C18:0 ceramide content were lower in muscle from aged compared to young. Intramuscular C18:1n9 and C20:4n6 content were higher in trained versus untrained. Content of total unsaturated and C16:1n7 diacylglycerol fatty acids were higher and C24:0 lower in muscle of aged versus young. Cardiorespiratory fitness had no impact on total diacylglycerol content. In conclusion, these data argue against intramuscular ceramide or diacylglycerol accumulation as driver of age-related insulin resistance in lean individuals. PMID- 30252031 TI - The Impact of Vaccination and Prior Exposure on Stool Shedding of Salmonella Typhi and Salmonella Paratyphi in 6 Controlled Human Infection Studies. AB - Background: Shedding of Salmonella Typhi or Paratyphi in the stool or urine leads to contamination of food or water, which is a prerequisite for transmission of enteric fever. Currently, there are limited data on the effect of vaccination or prior exposure on stool shedding. Methods: Six Salmonella Typhi or Paratyphi human challenge studies were conducted between 2011 and 2017. Participants were either unvaccinated or vaccinated with 1 of 4 vaccines: Vi-polysaccharide (Vi PS), Vi-tetanus-toxoid conjugate vaccine (Vi-TT), live oral Ty21a vaccine, or an experimental vaccine (M01ZH09). Daily stool cultures were collected for 14 days after challenge. Results: There were 4934 stool samples collected from 430 volunteers. Participants who received Vi-PS or Vi-TT shed less than unvaccinated participants (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.15-0.77; P = .010 and OR, 0.41; 95% CI, 0.19-0.91, P = .029 for Vi-PS and Vi-TT, respectively). Higher anti-Vi immunoglobulin G titers were associated with less shedding of S. Typhi (P < .0001). A nonsignificant reduction in shedding was associated with Ty21a vaccine (OR, 0.57; 95% CI, 0.27-1.20; P = .140). Individuals previously exposed to S. Typhi shed less than previously unexposed individuals (OR, 0.30; 95% CI, 0.1-0.8; P = .016). Shedding of S. Typhi was more common than S. Paratyphi. Conclusions: Prior vaccination with Vi vaccines, or natural infection, reduces onward transmission of S. Typhi. Field trials of Vi-TT should be designed to detect indirect protection, reflecting the consequence of reduced stool shedding observed in the human challenge model. PMID- 30252032 TI - Association Between Age and Plasmodium falciparum Infection Dynamics. AB - Few data exist on the incidence or duration of natural Plasmodium falciparum infections in high transmission settings. School-aged children (SAC) carry a disproportionate burden of infections, suggesting either increased incidence or duration. We estimated the incidence and duration of unique infections by age groups. The Mfera Cohort Study (2012-2017) had two years of follow-up with 120 participants tested monthly and during sick visits. Blood samples were collected to detect P. falciparum by microscopy and polymerase chain reaction. Positive samples underwent genotyping. Simulation was used to account for high non detection of infection among low parasitemia infections, which increase in frequency with age. Adults had significantly fewer unique infections per person per year (median, 2.5) compared to SAC and under-five children (6.3 and 6.6, respectively). Over half of all genotypes were persistent. Infections lasted significantly longer in adults (median, 180 days) and SAC (median, 163 days) compared to under-five children (median, 97 days), after accounting for age dependent, non-detection of infection. SAC acquired new infections at the same rate as under-five children, but maintained these infections for longer periods of time, similar to adults. This study provides new insights into P. falciparum infection dynamics that should be considered when designing malaria control strategies. PMID- 30252033 TI - Penetrating cardiac injury caused by a crossbow arrow. PMID- 30252034 TI - Giant sinus of Valsalva aneurysm causing acute myocardial infarction and repaired by valve-sparing partial aortic root remodelling. PMID- 30252035 TI - Health policy analysis of the non-implementation of HPV vaccination coverage in the pay for performance scheme in France. AB - Background: The French National Cancer Control Plan (NCCP) launched in 2014 set the objective to improve human papillomavirus (HPV) vaccination coverage (VC). The NCCP included a measure to integrate a VC indicator in the pay for performance (P4P) scheme for general practitioners (GPs), which was not implemented. The objective of the study was to analyse the reasons for non implementation of this measure, using the health policy analysis framework. Methods: The policy from proposal to non-implementation of the HPV VC indicator into the P4P scheme was analysed through the actors involved, the content of the measure, the contextual factors and the processes of policy-making. Results: The actors were the Ministry of Health (MOH) and National Cancer Institute as policy makers, the public health insurance as an indirect target, and GPs as direct targets. The content of the policy was not evidence-informed and was not included into the NCCP preparation report. The context included vaccine hesitancy and ethical concerns from GPs in opposition with MOH. The process involved a diversity of stakeholders with a complex governance and no strict monitoring of the measure. Conclusions: Complex vaccination policy governance associated with a non-evidence-informed policy content and an unfavourable context may have been the reasons for the policy failure. PMID- 30252036 TI - Improving control in microbial cell factories: from single-cell to large-scale bioproduction. AB - Bioprocess deviations are likely to occur at different operating scales, leading in most of the case to substrate deviation from main metabolic routes and impact product synthesis. Correlating qS and qP is of utmost importance for bioprocess observability and control and can be modeled actually by advanced metabolic flux models. However, if most of these models are able to make prediction about metabolic switches, they still do not incorporate deviation due to biological noise, i.e. phenotypic and genotypic heterogeneity. These limitations impair observability and thus the use of fundamental knowledge about biological network for practical application, i.e. metabolic engineering or bioprocess scale-up. PMID- 30252037 TI - A novel sucrose-based expression system for heterologous proteins expression in thermotolerant methylotrophic yeast Ogataea thermomethanolica. AB - The thermotolerant methylotrophic yeast Ogataea thermomethanolica TBRC656 is a potential host for heterologous protein expression. In this study, a novel expression system was developed for O. thermomethanolica based on the maltase (mal) gene promoter from this organism. The OtMal promoter function was tested for expression of fungal enzymes as reporter genes. Measurement of xylanase reporter enzyme activity showed that the OtMal promoter was repressed during growth on glucose and was activated by sucrose. When sucrose was used as a carbon source, the OtMal promoter was approximately twice as strong as the constitutive OtGAP promoter. Comparison of the OtMal promoter with the methanol-inducible OtAOX promoter showed that OtMal promoter drove 1.2 and 1.7-fold higher expression of xylanase and phytase reporter, respectively, than OtAOX promoter under inducing conditions at 24 h. Our results indicated that this novel expression system could be useful for the production of heterologous proteins from sucrose in yeast O. thermomethanolica. PMID- 30252038 TI - A shocking experience: inappropriate subcutaneous implantable cardioverter defibrillator shock at a public swimming pool. PMID- 30252040 TI - Sequential unipolar endocardial and epicardial ablation for focal atrial tachycardia originating from the deep left atrial appendage. PMID- 30252039 TI - Decoupling between sulfate reduction and the anaerobic oxidation of methane in the shallow methane seep of the Black sea. AB - Methane seepages are widespread in the Black Sea. However, microbiological research has been carried out only at the continental shelf seeps. The present work dealt with coastal gas seepages of the Kalamit Bay (Black Sea). High throughput 16S rRNA gene sequencing and radiotracer analysis (14S and 35S) were used to determine the composition of the microbial community and the rates of microbial sulfate reduction and methane oxidation. The phylum Proteobacteria, represented mainly by sulfate reducers of the class Deltaproteobacteria, was the predominant in sequence dataset. Bacteroidetes and Planctomycetes were other numerous phyla. Among archaea, the phylum Woesearchaeota and Marine Benthic Group B were predominant in the upper horizons. Relative abundance of Euryarchaeota of the families Methanomicrobiaceae and Methanosarcinaceae (including ANME-3 archaea) increased in deeper sediment layers. Sulfate reduction rate (up to 2.9 mmol/L * day) was considerably higher than the rate of anaerobic methane oxidation (up to 43.4 MUmol/L * day), which indicated insignificant contribution of anaerobic methane oxidation to the total sulfide production. PMID- 30252041 TI - Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers. AB - Background: Complex clusters of rearrangements in cancer genomes are a challenge to interpret. Some are clear amplifications of driver oncogenes but others are less well understood. Detailed analysis of rearrangements within these complex clusters could reveal new insights into selection, and underlying mutational mechanisms. Results: Here, we systematically investigate rearrangements that are densely clustered in individual tumours in a cohort of 560 breast cancers. Applying an agnostic approach, we identify 21 hotspots where clustered rearrangements recur across cancers. Some hotspots coincide with known oncogene loci including CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC. Others contain cancer genes not typically associated with breast cancer: MCL1, PTP4A1 and MYB. Intriguingly, we identify clustered rearrangements that physically connect distant hotspots. In particular, we observe simultaneous amplification of chr8:ZNF703/FGFR1 and chr11:CCND1 where deep analysis reveals that a chr8-chr11 translocation is likely to be an early, critical, initiating event. Conclusions: We present an overview of complex rearrangements in breast cancer, highlighting a potential new way for detecting drivers and revealing novel mechanistic insights into the formation of two common amplicons. PMID- 30252042 TI - Selective Osteotomies to Correct Deviated Bony Vaults of Asian Noses. AB - Background: Standard osteotomies for the correction of deviated noses are bilateral and comprise a combination of medial and lateral osteotomy procedures. However, their uniform application to the small/delicate Asian bony vault is inappropriate and often results in suboptimal outcomes. Objectives: This study describes how asymmetric bony pyramids were defined through 3-component analysis, which was then used to inform selective/individualized osteotomies. Methods: Bony vault deviations were categorized after 3-component analysis in 117 patients seeking correction of a deviated nose. Selective osteotomies were applied accordingly. Pre- and postoperative photographs were compared and rated by 2 independent evaluators. Patients' subjective evaluations were also included. Results: Selective osteotomies were possible in 79 (68%) out of 117 patients. Among the 79 study subjects, outcome ratings were excellent in 37 (47%), acceptable in 25 (32%), unsatisfactory in 8 (10%), and unspecified in 9 (11%). Unspecified cases aside, satisfactory correction was achieved in 88% (62/70 patients). Of the 54 patients who responded to telephone interviews, patient satisfaction was excellent in 43 (80%), improved in 10 (18.2%), and unchanged in 1 (1.8%). Follow-up of the 88% of patients with satisfactory correction showed a stable long-term outcome. Conclusions: Each bony vault in deviated noses is different, and thus, its correction must be individualized for each patient and for each side. The protocol described herein achieves a controlled correction of deviated bony vault. Restoration of bony pyramid symmetry via current techniques is best suited to short Asian bony vaults, where additional structural needs from routine nasal augmentation/lengthening are required. Level of Evidence 4: PMID- 30252043 TI - SanXoT: a modular and versatile package for the quantitative analysis of high throughput proteomics experiments. AB - Summary: Mass spectrometry-based proteomics has had a formidable development in recent years, increasing the amount of data handled and the complexity of the statistical resources needed. Here we present SanXoT, an open-source, standalone software package for the statistical analysis of high-throughput, quantitative proteomics experiments. SanXoT is based on our previously developed WSPP statistical model and has been specifically designed to be modular, scalable, and user-configurable. SanXoT allows limitless workflows that adapt to most experimental setups, including quantitative protein analysis in multiple experiments, systems biology, quantification of post-translational modifications and comparison and merging of experimental data from technical or biological replicates. Availability and implementation: Download links for the SanXoT Software Package, source code, and documentation are available at https://wikis.cnic.es/proteomica/index.php/SSP. Supplementary information: Supplementary Information is available at Bioinformatics online. PMID- 30252046 TI - Plant Cuttings. PMID- 30252047 TI - Prenatal Exposure to Cadmium and Child Growth, Obesity and Cardiometabolic Traits. AB - Prenatal cadmium exposure has been associated with impaired fetal growth, much less is known about the impact during later childhood on growth and cardiometabolic traits. To elucidate the impact of prenatal cadmium exposure on child growth, adiposity and cardiometabolic traits in 515 mother-child pairs in the "Rhea" cohort (Heraklion-Greece, 2007-2012), we measured urinary cadmium concentrations during early pregnancy, and assessed associations with repeated weight and height measurements from birth through childhood, and waist circumference, skinfold thicknesses, blood pressure, serum levels of lipids, leptin, and C-reactive protein at 4-years. Adjusted regression and mixed models were used, with interactions term for child sex and maternal smoking added. Elevated prenatal cadmium levels [third vs. first and second tertile of urinary cadmium (MUg/L)] were significantly associated with slower weight trajectory (per standard deviation score) in all children (beta; 95% confidence interval: -0.17; 0.32, -0.02), and slower height trajectory in girls (-0.30; -0.5,-0.09, Pinteraction = 0.025) and in children born to mothers who smoked during pregnancy (-0.48; -0.83, -1.13, Pinteraction = 0.027). To conclude, prenatal cadmium exposure was associated with delayed growth in early childhood. Further research is needed to understand cadmium-related sex differences and the role of co exposure to maternal smoking during early pregnancy. PMID- 30252045 TI - Coverage and composition of cuticular waxes on the fronds of the temperate ferns Pteridium aquilinum, Cryptogramma crispa, Polypodium glycyrrhiza, Polystichum munitum and Gymnocarpium dryopteris. AB - Background and Aims: The cuticular waxes sealing plant surfaces against excessive water loss are complex mixtures of very-long-chain aliphatics, with compositions that vary widely between plant species. To help fill the gap in our knowledge about waxes of non-flowering plant taxa, and thus about the cuticle of ancestral land plants, this study provides comprehensive analyses of waxes on temperate fern species from five different families. Methods: The wax mixtures on fronds of Pteridium aquilinum, Cryptogramma crispa, Polypodium glycyrrhiza, Polystichum munitum and Gymnocarpium dryopteris were analysed using gas chromatography-mass spectrometry for identification, and gas chromatography-flame ionization detection for quantification. Key Results: The wax mixtures from all five fern species contained large amounts of C36-C54 alkyl esters, with species-specific homologue distributions. They were accompanied by minor amounts of fatty acids, primary alcohols, aldehydes and/or alkanes, whose chain length profiles also varied widely between species. In the frond wax of G. dryopteris, C27-C33 secondary alcohols and C27-C35 ketones with functional groups exclusively on even numbered carbons (C-10 to C-16) were identified; these are characteristic structures similar to secondary alcohols and ketones in moss, gymnosperm and basal angiosperm waxes. The ferns had total wax amounts varying from 3.9 MUg cm-2 on P. glycyrrhiza to 16.9 MUg cm-2 on G. dryopteris, thus spanning a range comparable with that on leaves of flowering plants. Conclusions: The characteristic compound class compositions indicate that all five fern species contain the full complement of wax biosynthesis enzymes previously described for the angiosperm arabidopsis. Based on the isomer profiles, we predict that each fern species, in contrast to arabidopsis, has multiple ester synthase enzymes, each with unique substrate specificities. PMID- 30252049 TI - Corrigendum to: 'Elimination through collaboration: success factors in a global consortium'. PMID- 30252048 TI - The Escherichia coli bcsB gene is a conditional essential gene in the context of functional cellulose synthesis. AB - The understanding of why a gene is essential for a bacterium has implications in different research areas, such as bacterial evolution, synthetic biology and biotechnology, making the identification of essential genes a very active research field. Bacterial essential genes have been defined, among other criteria, by the inability to obtain viable mutants in such genes. In the case of Escherichia coli this approach led to the construction of the Keio collection of single-gene knockout mutants that contains deletions of all the open reading frames present in the genome with the exception of 303 genes that were found to be essential for the growth of this bacterium. One of the genes that was identified as essential is bcsB, which is involved in synthesis of extracellular cellulose. However, the reason for the essential nature of BcsB for E. coli viability has not been determined. In this work we show that bcsB is essential only in strains that have a functional capacity to synthesize cellulose, presumably due to the activity of BcsB in the translocation of this polymer across the periplasm. Thus, we propose that bcsB is a conditionally essential gene in E. coli. PMID- 30252050 TI - Individualizing piperacillin/tazobactam dosing in adult patients with cystic fibrosis: can tobramycin measurements help? AB - Background: Empirical models to predict beta-lactam pharmacokinetics (PK) using information from routine aminoglycoside therapeutic drug monitoring (TDM) have been proposed for critically ill patients; however, no such models exist for patients with cystic fibrosis (CF). Objectives: To investigate whether PK parameters of tobramycin could be used to predict those of piperacillin. Methods: A non-interventional, open-label PK study was conducted in hospitalized adults treated with piperacillin/tazobactam and tobramycin for acute pulmonary exacerbations of CF. Six serum samples per patient were collected and analysed. One- and two-compartment population PK models with linear, Michaelis-Menten or mixed elimination were evaluated for both drugs within the PmetricsTM package for R. Models were developed and compared iteratively using the log-likelihood and Akaike information criterion (AIC) objective functions. Results: Nine primarily female (n = 8) and Caucasian (100%) adult CF patients were enrolled. The median (IQR) age, height, weight and serum creatinine of included patients was 31 (27 32) years, 51.4 (49.9-55.8) kg, 162.6 (160.0-165.1) cm and 0.6 (0.5-0.6) mg/dL, respectively. The final model with the lowest objective function values consisted of one compartment with first-order elimination for tobramycin and two compartments with mixed-order elimination for piperacillin with the elimination rate constant of piperacillin modelled as a linear function of the elimination rate constant of tobramycin. Conclusions: A relationship was identified between the elimination rate constants of tobramycin and piperacillin. Validation of this relationship in larger studies of adult patients with CF is needed before application to the precision dosing of piperacillin/tazobactam in this patient population. PMID- 30252052 TI - Knowledge acquisition after Helping Babies Survive training in rural Tanzania. AB - Background: While the effectiveness of Helping Babies Breathe (HBB) training in Tanzania has been reported, no published studies of Essential Care for Every Baby (ECEB) and Essential Care for Small Babies (ECSB) in this setting have been found. This study compared knowledge before and after HBB, ECEB and ECSB training in Tanzania. Methods: Training was provided to future facilitators (n=16) and learners (n=24) in Tanzania. Using standardized multiple-choice questions, knowledge was assessed pre- and post-HBB and ECEB courses for both learners and facilitators, while ECSB assessment was conducted with facilitators only. A >80% score was considered to be a pass. Paired t-tests were used for hypothesis testing. Results: Knowledge significantly improved for both facilitators and learners on HBB and ECEB (p<0.001) and for facilitators on ECSB (p<0.001). After training, learners had difficulty identifying correct responses on one HBB item (21% incorrect) and three ECEB items (25-29% incorrect). After training, facilitators had difficulty identifying correct responses on five ECSB items (22 44% incorrect). Conclusions: Training improved knowledge in Tanzania, but not sufficiently for feeding, especially for low birthweight babies. Targeted training on feeding is warranted both within the Helping Babies Survive program and in preclinical training to improve knowledge and skill to enhance essential newborn care. PMID- 30252051 TI - Estimating the cost and cost-effectiveness for obstetric fistula repair in hospitals in Uganda: a low income country. AB - In Africa, about 33 000 cases of obstetric fistula occur each year. Women with fistula experience debilitating incontinence of urine and/or faeces and are often socially ostracized. Worldwide, Uganda ranks third among countries with the highest burden of obstetric fistula. Obstetric fistula repair competes for scarce resources with other healthcare interventions in resource-limited settings, even though it is surgically efficacious. There is limited documentation of its cost effectiveness in the most affected settings. We therefore sought to assess the cost-effectiveness of surgical intervention for obstetric fistula in Uganda so as to provide appropriate data for policy-makers to prioritize fistula repair and reduce women's suffering in similarly burdened countries. We built a decision analytic model from the perspective of Uganda's National Health System to estimate the cost-effectiveness of vesico-vaginal and recto-vaginal fistula surgery vs a competing strategy of no surgery for Ugandan women with fistula. Long-term disability outcomes were assessed based on a lifetime Markov state transition cohort and effectiveness of surgery. Surgical costs were estimated by micro-costing local Ugandan health resources. Disability weights associated with vesico-vaginal, recto-vaginal fistula and mortality rates among the general population in Uganda were based on published sources. The cost of providing fistula repair surgery in Uganda was estimated at $378 per procedure. For a hypothetical 20-year-old woman, surgery was estimated to decrease the lifetime disability burden from 8.53 DALYs to 1.51 DALYs, yielding a cost per DALY averted of $54. The results were robust to variations in model inputs in one-way and probabilistic sensitivity analyses. Surgery for obstetric fistula appears highly cost-effective in Uganda. In similar low-income countries, governments and non governmental organizations need to prioritize training and strengthening surgical capacity to increase access to fistula surgical care, which would be an important step towards achieving universal health coverage. PMID- 30252053 TI - Impact of a diagnostics-driven antifungal stewardship programme in a UK tertiary referral teaching hospital. AB - Objectives: A concise invasive candidosis guideline (based on the ESCMID candidaemia guideline) utilizing an informative biomarker [serum beta-1-3-d glucan (BDG)] was developed in 2013 by an antifungal stewardship (AFS) team and implemented with the help of an AFS champion in 2014. The main aims of the AFS programme were to reduce inappropriate use of antifungals and improve patient outcomes. The aim of this project was to evaluate the compliance of the ICU teams with the invasive candidosis guideline and the impact of the AFS programme on mortality and antifungal consumption on the ICUs (total of 71 beds). Methods: All patients who were prescribed micafungin for suspected or proven invasive candidosis during 4 month audit periods in 2014 and 2016 were included. Prescriptions and patient records were reviewed against the guideline. Antifungal consumption and mortality data were analysed. Results: The number of patients treated for invasive candidosis decreased from 39 in 2014 to 29 in 2016. This was mainly due to the reduction in patients initiated on antifungal therapy inappropriately: 18 in 2014 and 2 in 2016. Antifungal therapy was stopped following negative biomarker results in 12 patients in 2014 and 10 patients in 2016. Crude mortality due to proven or probable invasive candidosis decreased to 19% from 45% over the period 2003-07. Antifungal consumption reduced by 49% from 2014 to 2016. Conclusions: The AFS programme was successful in reducing the number of inappropriate initiations of antifungals by 90%. Concurrently, mortality due to invasive candidosis was reduced by 58%. BDG testing can guide safe cessation of antifungals in ICU patients at risk of invasive candidosis. PMID- 30252054 TI - Fasted High-Intensity Interval and Moderate-Intensity Exercise Do Not Lead to Detrimental 24-Hour Blood Glucose Profiles. AB - Aims: To compare the effect of a bout of high-intensity interval training (HIT) with a bout of moderate-intensity continuous training (MICT) on glucose concentrations over the subsequent 24-hour period. Methods: Fourteen people with type 1 diabetes [T1D (duration of T1D, 8.2 +/- 1.4 years)], all on a basal-bolus regimen, completed a randomized, counterbalanced, crossover study. Continuous glucose monitoring was used to assess glycemic control after a single bout of HIT (six 1-minute intervals) and 30 minutes of MICT on separate days compared with a nonexercise control day (CON). Exercise was undertaken after an overnight fast with omission of short-acting insulin. Capillary blood glucose samples were recorded before and after exercise to assess the acute changes in glycemia during HIT and MICT. Results: There was no difference in the incidence of or percentage of time spent in hypoglycemia, hyperglycemia, or target glucose range over the 24 hour and nocturnal period (12:00 am to 6:00 am) between CON, HIT, and MICT (P > 0.05). Blood glucose concentrations were not significantly (P = 0.49) different from pre-exercise to post-exercise, with HIT (0.39 +/- 0.42 mmol/L) or MICT ( 0.39 +/- 0.66 mmol/L). There was no difference between exercise modes (P = 1.00). Conclusions: HIT or 30 minutes of MICT can be carried out after an overnight fast with no increased risk of hypoglycemia or hyperglycemia. If the pre-exercise glucose concentration is 7 to 14 mmol/L, no additional carbohydrate ingestion is necessary to undertake these exercises. Because HIT is a time-efficient form of exercise, the efficacy and safety of long-term HIT should now be explored. PMID- 30252044 TI - A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers. AB - The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis. PMID- 30252055 TI - Molecular characterization of plasmid-encoded Tripoli MBL 1 (TMB-1) in Enterobacteriaceae. AB - Objectives: Available commercial tools (molecular methods or immunochromatographic assays) usually allow the detection of the five most prevalent carbapenemases (KPC, NDM, VIM, IMP and OXA-48-like), but miss minor carbapenemases. Here, we characterize two enterobacterial isolates with reduced susceptibility to carbapenems and negative for the most commonly encountered carbapenemase genes. Methods: Enterobacter hormaechei and Citrobacter freundii isolates were recovered from a bile sample and rectal screening, respectively. Both isolates were investigated by WGS. Resistance genes were detected using ResFinder. The blaTMB-1-harbouring plasmid was reconstructed using CLC genomic workbench 10.0 and was annotated using the RAST tool. Transfer frequency was determined by conjugation experiments using the laboratory strain Escherichia coli J53. Results: The two isolates were resistant to broad-spectrum cephalosporins and carbapenems. WGS revealed the presence of blaTMB-1, which has previously only been described in non-fermenters. blaTMB-1 was located within an ISKpn19-based composite class 1 transposon. Comparative genomics revealed that this structure was carried on a conjugative IncN-type plasmid within an integration hotspot. Conjugation experiments revealed high transfer frequencies of ~1 * 10-3. Conclusions: To the best of our knowledge, this study corresponds to the first report of Tripoli MBL 1-producing Enterobacteriaceae. Despite always being described as likely to be chromosomally located in non-fermenters, the blaTMB-1 gene is now found to be carried by a conjugative plasmid among Enterobacteriaceae, raising concern about the possible dissemination of this carbapenemase. The blaTMB-1 gene should now be suspected when PCRs targeting the main carbapenemases remain negative. PMID- 30252056 TI - Assessing feasibility of resources at health facilities in Uganda to diagnose pregnancy and neonatal outcomes. AB - Background: Standardized case definitions for obstetric and neonatal outcomes were developed by the Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project. These definitions can facilitate comparable assessment of maternal immunization safety surveillance and research. This study assessed the capabilities of health centers (HC) in Uganda to implement these definitions in a low income country, which has not been explored. Methods: Healthcare practitioners at 15 government-accredited health centers and one government funded district hospital in the Iganga-Mayuge Health and Demographic Surveillance Site (IMHDSS) in Uganda were interviewed about the facility's clinical diagnostic and laboratory capabilities. Five obstetric and five neonatal case definitions were evaluated. Definitions with the highest diagnostic certainty were designated as level 1, while definitions that decreased in certainty were designated as level 2 or 4. HCs were evaluated on diagnostic and laboratory capabilities to apply the GAIA definitions. Results: Higher-level facilities in the IMHDSS demonstrated the ability to diagnose more specific levels of the GAIA obstetric and neonatal outcomes than lower-level facilities. Furthermore, for the neonatal outcome assessment, there was an increased ability to diagnose outcomes moving from GAIA level 1 to level 3. Conclusions: The ability of health centers to implement globally standardized definitions is promising for implementation of standardized data collection methods for global vaccine safety surveillance and research. PMID- 30252057 TI - Safety and Pharmacokinetics of Single Dose Novel Oral Androgen 11beta-Methyl-19 Nortestosterone-17beta-dodecylcarbonate in Mena. AB - Context: 11beta-methyl-19-nortestosterone-17beta-dodecylcarbonate (11beta-MNTDC) is an orally bioavailable prodrug of 11beta-methyl-19-nortestosterone (11beta MNT) with androgenic and progestational activity. Objectives: 1) Quantify 11beta MNT binding to androgen and progesterone receptors. 2) Evaluate safety, tolerability and serum gonadotropin and testosterone suppression by 11beta-MNTDC in men. Design and setting: 1) In vitro receptor binding and transactivation studies and 2) Randomized, double-blind, placebo-controlled single dose, dose escalating Phase I study at 2 academic medical centers. Participants and Intervention: 12 healthy male volunteers were randomized (5 active:1 placebo) to escalating single oral doses (100, 200, 400, and 800 mg) of 11beta-MNTDC or placebo given with or without food. Main outcome measures: 1) In vitro 11beta MNT/11beta-MNTDC human receptor binding and transactivation and 2) Safety and tolerability, pharmacokinetics, and quantification of serum gonadotropin and testosterone concentrations for 24h following dosing. Results: 11beta-MNT avidly binds and activates human androgen and progesterone receptors, but 11beta-MNTDC has minimal activity. Single oral doses of 11beta-MNTDC were well-tolerated without serious adverse events. Administration of 11beta-MNTDC with food markedly increased average 11beta-MNTDC and 11beta-MNT serum concentrations (p<0.001 for all doses) compared to fasting with a significant dose-related effect on average serum drug concentrations (p<0.0001). The 200, 400, and 800 mg doses significantly suppressed average serum testosterone concentrations (p<0.002). Conclusions: A single, oral dose of 11beta-MNTDC up to 800 mg administered with food is safe and well-tolerated in healthy men. The active drug 11beta-MNT has androgenic and progestational activity, rapidly suppresses serum testosterone, and is a promising candidate for an effective once-daily oral male hormonal contraceptive. PMID- 30252058 TI - Two decades of the impact of Tasmanian Devil Facial Tumour Disease (DFTD). AB - The Tasmanian Devil, a marsupial carnivore, has been restricted to the island state of Tasmania since its extinction on the Australian mainland about three thousand years ago. In the past two decades, this species has experienced severe population decline due to the emergence of devil facial tumour disease (DFTD), a transmissible cancer. During these twenty years, scientists have puzzled over the immunological and evolutionary responses by the Tasmanian devil to this transmissible cancer. Targeted strategies in population management and disease control have been developed as well as comparative processes to identify variation in tumor and host genetics. A multi-disciplinary approach with multi institutional teams has produced considerable advances over the last decade. This has led to a greater understanding of the molecular pathogenesis and genomic classification of this cancer. New and promising developments in the Tasmanian devil's story include evidence that most immunized, and some wild devils, can produce an immune response to DFTD. Furthermore, epidemiology combined with genomic studies suggest a rapid evolution to the disease and that DFTD will become an endemic disease. Since 1998 there have been more than 350 publications, distributed over 37 Web of Science categories. A unique endemic island species has become an international curiosity that is in the spotlight of integrative and comparative biology research. PMID- 30252059 TI - Health promotion and prevention among the unemployed: a systematic review. AB - The interactions between unemployment and health create a need for specific interventions for health promotion and prevention. This overview provides information on how health promotion for the unemployed has been approached with an analysis of controlled intervention studies between 1996 and 2016. The literature search consulted 11 international databases in medicine, social sciences and psychology. A total of 30 health interventions for the unemployed were identified, with 43 articles that included the effects of intervention. A controlled-study design was used in 14 studies. The health promotion measures were generally based on individual counselling, case management, training or group services. The overview demonstrates the breadth of variation in target groups and types of measures. Their result indicators for health and integration into the labor market vary substantially, as do the employment promotion effects. There is evidence of improved health and labor market integration for established approaches like the JOBS Program and JobFit. Effects are rather moderate or low in magnitude and the effect mechanisms often remain unclear. Effects weaken over time. While success is more common in the areas of health, physical activity, nutrition and stress relief, there was no impact on smoking behavior. A significant evolution can be observed in the quality and quantity of health promotion for the unemployed over time. There is a need for further research on the effectiveness and sustainability of interventions. Intervention strategies should be developed that take account of the diversity of the unemployed and their different needs. PMID- 30252060 TI - Field Attraction of Striped Cucumber Beetles to a Synthetic Vittatalactone Mixture. AB - The striped cucumber beetle, Acalymma vittatum (F.) (Coleoptera: Chrysomelidae), is a key pest of cucurbits in eastern North America, rapidly colonizing young plantings and vectoring bacterial wilt of cucurbits. Its aggregation pheromone has been identified and synthesized stereospecifically, but has not been field tested to date. Here, we present field bioassays of this pheromone, using mixed vittatalactone made with a novel and cost-efficient semispecific synthesis. This mixture of eight stereoisomers of (2R,3R)-vittatalactone proved highly attractive to both sexes of striped cucumber beetle, using two different trap types and a pilot attract-and-kill combination with watermelon containing the diabroticine feeding stimulant cucurbitacin-E-glycoside, under field conditions in cucurbit vegetable plantings. Availability of mixed vittatalactones could enable highly effective and specific management of striped cucumber beetle. PMID- 30252061 TI - Effects of 28 Days of Oral Dimethandrolone Undecanoate in Healthy Men: A Prototype Male Pill. AB - Context: Dimethandrolone (DMA) has androgenic and progestational activity in pre clinical studies. Single oral doses of DMA undecanoate (DMAU) were well-tolerated and reversibly suppressed serum LH and testosterone (T) in men. Objective: Assess safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of oral DMAU. Design: Double-blind, randomized, placebo-controlled study. Setting: Two academic medical centers. Participants: Healthy men (18-50 years). Interventions: 100 men received DMAU (0, 100, 200 or 400mg, formulated in castor oil/benzyl benzoate (C) or powder (P)) for 28 days. Subjects underwent 24-h PK blood sampling on days 1 and 28, and twice weekly ambulatory visits throughout treatment. Main outcome measures: Primary outcomes were safety and tolerability parameters (vitals, laboratory data, mood and sexual function scores) and adverse events. Secondary outcomes were drug PK profiles and PD effects (serum LH, FSH, sex-hormones). Results: 82 subjects completed the study and were included in the analysis. There were no serious adverse events. No clinically significant changes developed in safety laboratory parameters. A significant dose effect was seen for weight, hematocrit, HDL-C, QTc, and sexual desire. Serum 24h average concentrations of DMAU and DMA showed dose-related increases (p<0.001). All six subjects in the P400 group and 12/13 subjects in the C400 group achieved marked suppression of both LH and FSH (<1.0 IU/L) and serum T (<50 ng/dL). Conclusions: Daily oral administration of DMAU for 28 days in healthy men is well tolerated. Doses of >=200 mg markedly suppress serum T, LH and FSH. These results support further testing of DMAU as a male contraceptive. PMID- 30252063 TI - A survey on antimicrobial stewardship prerequisites, objectives and improvement strategies: systematic development and nationwide assessment in Dutch acute care hospitals. AB - Background: Stewardship guidelines define three essential building blocks for successful hospital antimicrobial stewardship programmes (ASPs): stewardship prerequisites, stewardship objectives and improvement strategies. Objectives: We systematically developed a survey, based on these building blocks, to evaluate the current state of antimicrobial stewardship in hospitals. We tested this survey in 64 Dutch acute care hospitals. Methods: We performed a literature review on surveys of antimicrobial stewardship. After extraction and categorization of survey questions, five experts merged and rephrased questions during a consensus meeting. After a pilot study, the survey was sent to 80 Dutch hospitals. Results: The final survey consisted of 46 questions, categorized into hospital characteristics, stewardship prerequisites, stewardship objectives and stewardship strategies. The response rate was 80% (n = 64). Ninety-four percent of hospitals had established an antimicrobial stewardship team, consisting of at least one hospital pharmacist and one clinical microbiologist. An infectious diseases specialist was present in 68% of the teams. Nine percent had dedicated IT support. Forty-one percent of the teams were financially supported, with a median of 0.6 full-time equivalents (FTE; 0.1-1.8). The majority of hospitals performed monitoring of restricted antibiotic agents (91%), dose optimization (65%), bedside consultation (56%) and intravenous-to-oral switch (53%). Fifty eight percent of the hospitals provided education to residents and 28% to specialists. Conclusions: The survey provides information on the progress that is being made in hospitals regarding the three building blocks of a successful ASP, and provides clear aims to strengthen ASPs. Ultimately, these data will be related to national data on antibiotic consumption and resistance. PMID- 30252062 TI - Reassessment of requirements for anaerobic xylose fermentation by engineered, non evolved Saccharomyces cerevisiae strains. AB - Expression of a heterologous xylose isomerase, deletion of the GRE3 aldose reductase gene and overexpression of genes encoding xylulokinase (XKS1) and non oxidative pentose-phosphate-pathway enzymes (RKI1, RPE1, TAL1, TKL1) enables aerobic growth of Saccharomyces cerevisiae on d-xylose. However, literature reports differ on whether anaerobic growth on d-xylose requires additional mutations. Here, CRISPR-Cas9-assisted reconstruction and physiological analysis confirmed an early report that this basic set of genetic modifications suffices to enable anaerobic growth on d-xylose in the CEN.PK genetic background. Strains that additionally carried overexpression cassettes for the transaldolase and transketolase paralogs NQM1 and TKL2 only exhibited anaerobic growth on d-xylose after a 7-10 day lag phase. This extended lag phase was eliminated by increasing inoculum concentrations from 0.02 to 0.2 g biomass L-1. Alternatively, a long lag phase could be prevented by sparging low-inoculum-density bioreactor cultures with a CO2/N2-mixture, thus mimicking initial CO2 concentrations in high-inoculum density, nitrogen-sparged cultures, or by using l-aspartate instead of ammonium as nitrogen source. This study resolves apparent contradictions in the literature on the genetic interventions required for anaerobic growth of CEN.PK-derived strains on d-xylose. Additionally, it indicates the potential relevance of CO2 availability and anaplerotic carboxylation reactions for anaerobic growth of engineered S. cerevisiae strains on d-xylose. PMID- 30252064 TI - Porcine sperm binding to oviduct cells and glycans as supplements to traditional laboratory semen analysis. AB - Accurate semen evaluation is necessary to maintain high reproductive efficiency but difficult to accomplish. The objective was to determine if the ability to bind oviduct cells or oviduct glycans are useful supplements to traditional semen analyses. Measuring binding to specific soluble glycans is less laborious than assessing binding to oviduct cell aggregates and more suitable for routine use. Previous work has shown that sperm binding to oviduct cells improves fertility prediction, possibly by estimating the ability of sperm to form an oviduct reservoir. The two oviduct glycan motifs, biantennary 6-sialylated N acetyllactosamine (bi-SiaLN) and LewisX trisaccharide (LeX), that bind boar spermatozoa with high affinity and specificity were tested. Semen from 30 boars was shipped overnight for laboratory analysis and for inseminations to determine fertility (n = 3 replicates). Oviduct cell binding and traditional sperm analyses including motility and morphology were completed. Additionally, binding to soluble fluoresceinated glycans bi-SiaLN, sulfated LeX (suLeX), and the control lactosamine disaccharide (LacNAc) was measured. Inseminations were at 15 farms (>50 matings per boar) in the Midwest and farrowing data from all matings were used. Pregnancy rate (PR) and litter size (LS) were adjusted to account for different farms, number of services, number of doses inseminated, and sow parity, using the MIXED procedure in SAS 9.4. A fertility index (FI) was generated, consisting of PR * LS, to estimate boar overall fertility. Finally, the GLMSELECT procedure was used to select variables having a significant impact on PR, LS, and FI. The predictive models constructed were further analyzed using the REG procedure and accounted for 58% or more of the variation in PR, LS, and FI [PR (P < 0.001, r2 = 0.60), LS (P < 0.001, r2 = 0.58), and FI (P < 0.001, r2 = 0.63)]. The final model for PR includes oviduct cell binding as well as boar age, % distal droplets, head morphology, tail morphology, beat/cross frequency, and curvilinear velocity. The final model for LS includes boar age, % distal droplets, tail morphology, and overall morphology. Finally, the FI model included boar age, % distal droplets, head morphology, tail morphology, curvilinear velocity, and semen volume per ejaculate. Although binding to intact oviduct cells was impactful as a means to predict PR, binding to specific soluble oviduct glycans was not a useful supplement to traditional semen analysis. PMID- 30252066 TI - Emerald Ash Borer (Coleoptera: Buprestidae) Densities Over a 6-yr Period on Untreated Trees and Trees Treated With Systemic Insecticides at 1-, 2-, and 3-yr Intervals in a Central Michigan Forest. AB - We assessed density of emerald ash borer (Agrilus planipennis Fairmaire) (Coleoptera: Buprestidae) larvae over a 6-yr period by felling and sampling a total of 315 green ash (Fraxinus pennsylvanica Marsh.) trees that were left untreated or treated with imidacloprid, dinotefuran, or emamectin benzoate products at 1-yr, 2-yr, or 3-yr intervals. Our study, conducted across a 32-ha forested area, began soon after emerald ash borer became established and continued through the peak and eventual decline of the emerald ash borer population. Less than half of the 96 trees in the pretreatment sample were infested and larval densities were very low. Densities of emerald ash borer remained low for 3 yr, then increased exponentially, eventually resulting in mortality of most untreated overstory ash. Trees treated with either low or moderate rates of emamectin benzoate applied via trunk injection had few or no emerald ash borer galleries, even 3 yr post-treatment. Basal trunk sprays of dinotefuran applied annually were also effective at preventing larval densities from reaching damaging levels. Average larval densities on trees treated with a trunk injection of imidacloprid were lower but did not differ from untreated trees, regardless of treatment frequency. Larval parasitism was rare, while woodpecker predation was common and accounted for nearly all natural larval mortality, even on trees with very low densities of larvae. PMID- 30252065 TI - The Natural History of Adrenal Insufficiency in X-Linked Adrenoleukodystrophy: An International Collaboration. AB - Context: Primary adrenal insufficiency is an important clinical manifestation of X-linked adrenoleukodystrophy (ALD). Other manifestations include spinal cord disease and/or inflammatory demyelinating cerebral disease. Implementation of newborn screening requires natural history data to develop follow-up recommendations. Objective: To delineate the natural history of adrenal insufficiency in male patients with ALD and to assess associations between the risk for developing adrenal insufficiency, spinal cord disease, or cerebral disease and plasma C26:0/C22:0 and C24:0/C22:0 ratios, which are diagnostic biomarkers for ALD. Design: Retrospective review of medical records. Setting: Two international tertiary referral centers of expertise for ALD. Patients: Male patients with ALD followed at the centers between 2002 and 2016. Main Outcome Measures: The primary endpoint was adrenal insufficiency; secondary endpoints were spinal cord and cerebral disease. Results: Data on 159 male patients was available. The probability of developing adrenal insufficiency was described with survival analysis. Median time until adrenal insufficiency was 14 years (95% CI, 9.70 to 18.30 years). The cumulative proportion of patients who developed adrenal insufficiency was age-dependent and highest in early childhood [0 to 10 years, 46.8% (SEM 0.041%); 11 to 40 years, 28.6% (SEM, 0.037%); >40 years, 5.6% (SEM, 0.038%)]. No association between clinical manifestations and plasma ratios was detected with Cox model or Spearman correlation. Conclusions: Lifetime prevalence of adrenal insufficiency in male patients with ALD is ~80%. Adrenal insufficiency risk is time-dependent and warrants age-dependent follow-up. Besides on-demand testing if symptoms manifest, we suggest a minimum of adrenal testing every 4 to 6 months for patients age <=10 years, annual testing for those age 11 to 40 years, and solely on-demand testing for those age >40 years. PMID- 30252067 TI - Effect of Hypoglycemia on Inflammatory Responses and the Response to Low Dose Endotoxemia in Humans. AB - Context: Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. Objective: To determine whether hypoglycemia modifies subsequent innate immune system responses. Design and Setting: Single-blinded, prospective study of three independent parallel groups. Participants and Interventions: Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/l), euglycemic (6.0 mmol/l) or sham saline clamp (n=8 for each group). Forty-eight hours later, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. Main outcome measures: We studied in-vivo monocyte mobilization and monocyte-platelet interactions. Results: Hypoglycemia increased total leucocytes (9.98+/-1.14 x109/l vs euglycemia: 4.38+/-0.53 x109/l; P<0.001 vs sham-saline: 4.76+/-0.36 x109/l; P<0.001) (mean+/-SEM), mobilized proinflammatory intermediate monocytes (42.20+/ 7.52/MUl vs euglycemia: 20.66+/-3.43/MUl; P<0.01 vs sham-saline: 26.20+/ 3.86/MUl; P<0.05) and non-classical monocytes (36.16+/-4.66/MUl vs euglycemia: 12.72+/-2.42/MUl; P<0.001 vs sham-saline: 19.05+/-3.81/MUl; P<0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (AUC) increased (73.87+/-7.30 vs 52.50+/-4.04; P<0.05) and formation of monocyte-platelet aggregates increased (96.05+/-14.51/MUl vs 49.32+/-6.41/MUl; P<0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51+/-1.42/MUl vs euglycemia: 4.19+/-1.08/MUl; P<0.05 vs sham-saline: 3.81+/ 1.42/MUl; P<0.05) and non-classical monocytes (9.53+/-1.08/MUl vs euglycemia: 2.86+/-0.72/MUl; P<0.01 vs sham-saline: 3.08+/-1.01/MUl; P<0.05) with platelets compared to controls. Hypoglycemia led to greater leucocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96+/-0.97 vs euglycemia: 8.21+/-0.85 x109/l; P<0.05). Conclusions: Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute towards increased cardiovascular risk observed in people with diabetes. PMID- 30252069 TI - ImmuneCheckpoint Inhibitor-Induced Hypoparathyroidism Associated with Calcium Sensing Receptor-Activating Autoantibodies. AB - Context: While therapy with immune checkpoint inhibitors such as nivolumab have substantially improved survival in several types of cancer, increased attention has been given to adverse immune events associated with their use, including the development of endocrine autoimmunity. Objectives: First, to describe a patient with a two-year history of metastatic small cell lung cancer who had been treated with nivolumab a few months prior to presentation with the signs and symptoms of severe hypocalcemia and hypoparathyroidism. Second, to investigate the etiology of the patient's hypoparathyroidism, including the presence of activating autoantibodies against the calcium-sensing receptor (CaSR), since humoral and cellular immune responses against the CaSR have been reported in patients with autoimmune hypoparathyroidism. Case and Results: A 61-year-old female was admitted with persistent nausea, vomiting, epigastric pain, constipation, and generalized weakness. Laboratory analyses showed low total serum calcium, ionized calcium, and parathyroid hormone (PTH). The patient was diagnosed with severe hypocalcemia as a result of autoimmune hypoparathyroidism after testing positive for CaSR-activating autoantibodies. She was treated with intravenous calcium gluconate infusions followed by a transition to oral calcium carbonate plus calcitriol which normalized her serum calcium. Her serum PTH remained low0 during her hospitalization and initial outpatient follow-up despite adequate repletion of magnesium. Conclusions: This case illustrates autoimmune hypoparathyroidism induced by immune checkpoint inhibitor-blockade. As immune checkpoint inhibitors are now used to treat many cancers, clinicians should be aware of the potential risk for hypocalcemia that may be associated with their use. PMID- 30252068 TI - Gonadal function and pubertal development in patients with Silver-Russell syndrome. AB - STUDY QUESTION: Is gonadal function affected in males and females with Silver Russell Syndrome (SRS)? SUMMARY ANSWER: Sertoli cell dysfunction is more common in males with SRS, with 11p15 LOM, but gonadal function seems to be unaffected in females with SRS. WHAT IS KNOWN ALREADY: Males with SRS have an increased risk for genital abnormalities such as cryptorchidism and hypospadias, which could be associated with reproductive problems in later life. In SRS females, an association has been described with Mayer-Rokitansky-Kuster-Hauser syndrome, which might compromise their reproductive function. STUDY DESIGN, SIZE, DURATION: Longitudinal follow-up study, involving 154 subjects, over a time period of 20 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Thirty-one SRS patients (14 males) and 123 non-SRS patients born at same gestational age (SGA; 65 males). All received growth hormone and 27.3% received additional gonadotropin-releasing hormone analog treatment (GnRHa). MAIN RESULTS AND THE ROLE OF CHANCE: Mean age at onset of puberty was 11.5 years in SRS males versus 11.6 years in non-SRS males (P = 0.51), and 10.5 years in SRS females versus 10.7 years in non-SRS females (P = 0.50). Four of the 14 SRS males had a post-pubertal inhibin-B level below the fifth percentile compared to healthy controls, and two of them an FSH above the 95th percentile, indicating Sertoli cell dysfunction. One of them had a history of bilateral cryptorchidism and orchiopexy. All SRS females had AMH, LH and FSH levels within the reference range. Pubertal duration to Tanner stage five was similar in SRS and non-SRS. Pubertal height gain was better in SRS patients who additionally received GnRHa (P < 0.01). Mean age at menarche was 13.1 years in SRS versus 13.3 years in non-SRS (P = 0.62). One SRS female had primary amenorrhea due to Mullerian agenesis. LIMITATIONS, REASONS FOR CAUTION: As this is a rare syndrome, the SRS group had a small size. WIDER IMPLICATIONS OF THE FINDINGS: As gonadal function is not affected in females with SRS, it is likely that reproductive function is also not affected. Sertoli cell dysfunction in males with SRS could cause impaired reproductive function and should be assessed during pubertal development. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for the study. The authors have no conflicts of interest. PMID- 30252070 TI - Diversity and Evolution of Sensor Histidine Kinases in Eukaryotes. AB - Histidine kinases (HKs) are primary sensor proteins that act in cell signaling pathways generically referred to as "two component systems" (TCSs). TCSs are among the most widely distributed transduction systems used by both prokaryotic and eukaryotic organisms to detect and respond to a broad range of environmental cues. The structure and distribution of HK proteins are now well documented in prokaryotes but information is still fragmentary for eukaryotes. Here, we have taken advantage of recent genomic resources to explore the structural diversity and the phylogenetic distribution of HKs in the prominent eukaryotic supergroups. Searches of the genomes of 67 eukaryotic species spread evenly throughout the phylogenetic tree of life identified 748 predicted HK proteins. Independent phylogenetic analyses of predicted HK proteins were carried out for each of the major eukaryotic supergroups. This allowed most of the compiled sequences to be categorised into previously described HK groups. Beyond the phylogenetic analysis of eukaryotic HKs, this study revealed some interesting findings: (i) characterisation of some previously undescribed eukaryotic HK groups with predicted functions putatively related to physiological traits; (ii) discovery of HK groups that were previously believed to be restricted to a single kingdom in additional supergroups and (iii) indications that some evolutionary paths have led to the appearance, transfer, duplication, and loss of HK genes in some phylogenetic lineages. This study provides an unprecedented overview of the structure and distribution of HKs in the Eukaryota and represents a first step towards deciphering the evolution of TCS signaling in living organisms. PMID- 30252071 TI - Relationship of Landscape Type on Neonicotinoid Insecticide Exposure Risks to Honey Bee Colonies: A Statewide Survey. AB - Neonicotinoid insecticide use has been suggested as a cause of honey bee colony decline; however, detection rates and concentrations of neonicotinoid insecticide residues in field-collected honey bees have been low. We collected honey bee and beebread samples from apiaries in agricultural, developed, and undeveloped areas during 2 years in Virginia to assess whether landscape type or county pesticide use was predictive of honey bee colony exposure to neonicotinoid insecticides. Trace concentrations of the neonicotinoid imidacloprid were detected in honey bees (3 of 84 samples, 2.02-3.97 ng/g), whereas higher concentrations were detected in beebread (5 of 84 samples, 4.68-11.5 ng/g) and pollen (three of five pollen trap samples, 7.86-12.6 ng/g). Imidacloprid was only detected in samples collected during July and August and was not detected in honey bees from hives where neonicotinoids were detected in pollen or beebread. The number of hives sampled at a site, county pesticide use, and landscape characteristics were not predictive of neonicotinoid detections in honey bees or beebread (all P > 0.05). Field surveys may underestimate honey bee exposure to field-realistic levels of pesticides or the risk of exposure in different landscapes because of low detection rates. Undetectably low levels of exposure or high levels of exposure that go undetected raise questions with regard to potential threats to honey bees and other pollinators. PMID- 30252072 TI - Population Structure of Riverine and Coastal Dolphins Sotalia fluviatilis and Sotalia guianensis: Patterns of Nuclear and Mitochondrial Diversity and Implications for Conservation. AB - Coastal and freshwater cetaceans are particularly vulnerable due to their proximity to human activity, localized distributions, and small home ranges. These species include Sotalia guianensis, found in the Atlantic and Caribbean coastal areas of central and South America, and Sotalia fluviatilis, distributed in the Amazon River and tributaries. We investigated the population structure and genetic diversity of these 2 species by analyses of mtDNA control region and 8-10 microsatellite loci. MtDNA analyses revealed strong regional structuring for S. guianensis (i.e., Colombian Caribbean vs. Brazilian Coast, FST = 0.807, PhiST = 0.878, P < 0.001) especially north and south of the Amazon River mouth. For S. fluviatilis, population structuring was detected between the western and eastern Amazon (i.e., Colombian Amazon vs. Brazilian Amazon, FST = 0.085, PhiST = 0.277, P < 0.001). Haplotype and nucleotide diversity were higher for S. fluviatilis. Population differentiation was supported by analysis of the microsatellite loci (S. guianensis, northern South America vs. southern South America FST = 0.275, Jost's D = 0.476, P < 0.001; S. fluviatilis, western and eastern Amazon FST = 0.197, Jost's D = 0.364, P < 0.001). Most estimated migration rates in both species overlapped with zero, suggesting no measurable migration between most of the sampling locations. However, for S. guianensis, there was measurable migration in neighboring sampling locations. These results indicate that the small home ranges of these species may act to restrict gene flow between populations separated by relatively short distances, increasing the risk of extirpation of some localized populations in the future if existing threats are not minimized. PMID- 30252073 TI - The Evolution of Small-RNA-Mediated Silencing of an Invading Transposable Element. AB - Transposable elements (TEs) are genomic parasites that impose fitness costs on their hosts by producing deleterious mutations and disrupting gametogenesis. Host genomes avoid these costs by regulating TE activity, particularly in germline cells where new insertions are heritable and TEs are exceptionally active. However, the capacity of different TE-associated fitness costs to select for repression in the host, and the role of selection in the evolution of TE regulation more generally remain controversial. In this study, we use forward, individual-based simulations to examine the evolution of small-RNA-mediated TE regulation, a conserved mechanism for TE repression that is employed by both prokaryotes and eukaryotes. To design and parameterize a biologically realistic model, we drew on an extensive survey of empirical studies of the transposition and regulation of P-element DNA transposons in Drosophila melanogaster. We observed that even under conservative assumptions, where small-RNA-mediated regulation reduces transposition only, repression evolves rapidly and adaptively after the genome is invaded by a new TE in simulated populations. We further show that the spread of repressor alleles through simulated populations is greatly enhanced by two additional TE-imposed fitness costs: dysgenic sterility and ectopic recombination. Finally, we demonstrate that the adaptive mutation rate to repression is a critical parameter that influences both the evolutionary trajectory of host repression and the associated proliferation of TEs after invasion in simulated populations. Our findings suggest that adaptive evolution of TE regulation may be stronger and more prevalent than previously appreciated, and provide a framework for interpreting empirical data. PMID- 30252074 TI - Low-value clinical practices and harm caused by non-adherence to 'do not do' recommendations in primary care in Spain: a Delphi study. AB - Objective: To determine the non-adherence to the primary care 'do not do' recommendations (DNDs) and their likelihood to cause harm. Design: Delphi study. Setting: Spanish National Health System. Participants: A total of 128 professionals were recruited (50 general practitioners [GPs], 28 pediatricians [PEDs], 31 nurses who care for adult patients [RNs] and 19 pediatric nurses [PNs]). Interventions: A selection of 27 DNDs directed at GPs, 8 at PEDs, 9 at RNs and 4 at PNs were included in the Delphi technique. A 10-point scale was used to assess whether a given practice was still present and the likelihood of it causing of an adverse event. Main outcome measure: Impact calculated by multiplying an event's frequency and likelihood to cause harm. Results: A total of 100 professionals responded to wave 1 (78% response rate) and 97 of them to wave 2 (97% response rate). In all, 22% (6/27) of the practices for GPs, 12% (1/8) for PEDs, 33% (3/9) for RNs and none for PNs were cataloged as frequent. A total of 37% (10/27) of these practices for GPs, 25% (2/8) for PEDs, 33% (3/9) for RNs and 25% (1/4) for PNs were considered as potential causes of harm. Only 26% (7/27) of the DNDs for GPs showed scores equal to or higher than 36 points. The impact measure was higher for ordering benzodiazepines to treat insomnia, agitation or delirium in elderly patients (mean = 57.8, SD = 25.3). Conclusions: Low-value and potentially dangerous practices were identified; avoiding these could improve care quality. PMID- 30252075 TI - Physical activity, BMI and oral health behaviour among adolescents: Finnish School Health Promotion Study. AB - Background: To assess associations between oral health behaviour and physical activity and related factors among adolescents. Methods: The study population (n = 76 529) consisted of a representative sample of 16- to 18-year-old Finnish adolescents (boys: 37 211, girls: 39 318). An anonymous, confidential and voluntary classroom-administered questionnaire included questions about tooth brushing frequency, physical activity, BMI and eating habits. Moderate-to vigorous physical activity (MVPA) was used to assess the adolescents' physical activity. The chi-square test and multiple binary logistic regression were used for statistical analyses. Adjusted odds ratios (OR) and their 95% confidence intervals (CI) were calculated for MVPA, BMI, breakfast, smoking and socioeconomic factors as parents' education and school type. Results: The prevalence of twice daily tooth brushing was highest among adolescents reporting 4 hours or more of MVPA (51-77%). Obese and smoking adolescents exercised less often than normal weighted and non-smokers. Girls brushed their teeth twice daily significantly more often than boys (P < 0.001), and high-school students brushed their teeth significantly more often than vocational school students (P < 0.001). Logistic regression models showed that obesity (OR = 2.14, 95% CI 1.92-2.37) and irregular breakfast eating (OR = 2.35, 95% CI 2.19-2.52) among boys, and obesity (OR = 2.81, 95% CI 2.48-3.17), physical inactivity (OR = 1.89, 95% CI 1.78-2.00) and irregular breakfast eating (OR = 1.91, 95% CI 1.79-2.04) among girls were strong predictors for poor tooth brushing. Conclusions: Physically active adolescents had better oral health behaviour than less active adolescents. Obesity and smoking were associated with infrequent tooth brushing. PMID- 30252076 TI - Identifying Drivers of Parallel Evolution: A Regression Model Approach. AB - Parallel evolution, defined as identical changes arising in independent populations, is often attributed to similar selective pressures favoring the fixation of identical genetic changes. However, some level of parallel evolution is also expected if mutation rates are heterogeneous across regions of the genome. Theory suggests that mutation and selection can have equal impacts on patterns of parallel evolution; however, empirical studies have yet to jointly quantify the importance of these two processes. Here, we introduce several statistical models to examine the contributions of mutation and selection heterogeneity to shaping parallel evolutionary changes at the gene-level. Using this framework, we analyze published data from forty experimentally evolved Saccharomyces cerevisiae populations. We can partition the effects of a number of genomic variables into those affecting patterns of parallel evolution via effects on the rate of arising mutations, and those affecting the retention versus loss of the arising mutations (i.e., selection). Our results suggest that gene-to-gene heterogeneity in both mutation and selection, associated with gene length, recombination rate, and number of protein domains drive parallel evolution at both synonymous and nonsynonymous sites. While there are still a number of parallel changes that are not well described, we show that allowing for heterogeneous rates of mutation and selection can provide improved predictions of the prevalence and degree of parallel evolution. PMID- 30252077 TI - Common Data Elements in the Assessment of Military-Related PTSD Research Applied in the Consortium to Alleviate PTSD. AB - Introduction: Driven by the need to share data, sufficiently power studies, and allow for cross-study comparisons of medical and psychiatric diseases, the President's National Research Action Plan issued in 2013 called for the use of state-of-the-art common data elements (CDEs) for research studies. CDEs are variables measured across independent studies that facilitate methodologically sound data aggregation and study replication. Researchers in the field of military-related post-traumatic stress disorder (PTSD) have suggested applicable CDEs; however, to date, these recommendations have been conceptual and not field tested. The Consortium to Alleviate PTSD (CAP) - an interdisciplinary and multi institutional, military-related PTSD research consortium funded by the Departments of Defense and Veterans Affairs - generated and applied CDEs that can be used to combine data from disparate studies to improve the methodological and statistical capabilities of study findings. We provide a description and rationale for the CAP CDEs and details about administration with two main goals: (1) to encourage military-related PTSD researchers to use these measures in future studies and (2) to facilitate comparison, replication, and data aggregation. Materials and Methods: The CAP compiled mandated (core) and optional CDEs based on the following criteria: (1) construct applicability to military related PTSD; (2) precedence (use) in prior, related research; (3) published and strong psychometric evidence; (4) no cost (public domain); and (5) brevity, to limit participant burden. We provided descriptive statistics and internal consistency reliabilities for mandated measures from an initial cohort of around 400 participants enrolled in CAP studies. Results: Mandated CDEs in the CAP were found to have very good internal consistency reliability. Conclusion: Although further research is needed to determine the incremental validity of these CDEs, preliminary analyses indicated that each mandated measure has very good internal consistency reliability. Investigators designing military-related PTSD research should consider using these field-tested CDEs to facilitate future data aggregation. Feedback based on empirical evidence or practical concerns to improve these CDEs is welcome. PMID- 30252078 TI - A Survey of Family Planning Training, Knowledge, and Practices Among Health Care Providers Within the Military Health System at Joint Base Lewis-McChord. AB - Introduction: Within the active duty U.S. military population, the age-adjusted unintended pregnancy rate is higher than the national average. Unplanned pregnancy within the military impacts individual and unit medical readiness. Contraceptive education and availability are means to reduce unintended pregnancy rates; health care providers are key facilitators in provision of contraception. Understanding provider knowledge and practices related to contraceptive provision may identify strengths and gaps in order to provide focal points for sustainment or improvement in family planning practices. The purpose of this study was to assess family planning knowledge, training, and practices among health care providers serving military and dependent beneficiaries within the military health care system at Fort Lewis, Washington. Material and Methods: This was a cross sectional survey of health care providers on Joint Base Lewis-McChord in Tacoma, Washington who deliver health care services to U.S. uniformed service members and their dependents in varied settings, including outpatient clinics and a tertiary care center. The survey included questions regarding prior contraceptive training, and current contraceptive knowledge and practices. Survey results were evaluated using descriptive and bivariate analyses. The study was approved by both Institutional Review Boards at Emory University and at Madigan Army Medical Center. Results: Overall, 79 eligible health care providers completed the survey. Eighty-six percent of women's health providers consistently ("always or most of the time") provided family planning services to female service members, compared with 38% of primary care providers. Women's health providers were more likely to counsel by method effectiveness and adapt their counseling to consider patients' reproductive life plans. There were no differences between provider type in considering service members' deployment status during contraceptive counseling. Overall, providers identified the correct effectiveness of long-acting contraceptive methods, but tended to overestimate the effectiveness of short acting methods. Conclusions: Family planning services available to service members may be improved through enhanced provider education, targeting efficacy based counseling and identification of barriers to access and provision of long acting reversible contraceptive methods. PMID- 30252079 TI - Recommendations for Research and Practice to Improve Work Outcomes Among Cancer Survivors. AB - Major knowledge gaps limit the development and implementation of interventions to improve employment outcomes among people with cancer. To identify research priorities to improve employment outcomes after cancer, the National Cancer Institute sponsored the meeting "Evidence-Based Approaches for Optimizing Employment Outcomes among Cancer Survivors." This article describes research recommendations stemming from the meeting. At the patient level, longitudinal studies are needed to better understand how patient sociodemographic and clinical characteristics and their experiences at work shape employment outcomes. Interventions that mitigate the impact of cancer and its treatment on employment are critical. At the provider-level, future research is needed to characterize the extent to which physicians and other healthcare providers talk to their patients about employment concerns and how that information is used to inform care. Additionally, there is a need to test models of care delivery that support routine screening of employment concerns, the capture of employment outcomes in electronic health records, and the effective use of this information to improve care. At the employer level, evidence-based training programs are needed to prepare supervisors, managers, human resources staff, and occupational health professionals to address health issues in the workplace; and future interventions are needed to improve patient -employer communication and facilitate workplace accommodations. Importantly, research is needed that reflects the perspectives and priorities of patients and their families, providers and healthcare systems, and employers. Transdisciplinary partnerships and stakeholder engagement are essential to ensure that employment-focused interventions and policies are developed, implemented, and sustained in real-world healthcare delivery and workplace settings. PMID- 30252080 TI - Military Health Provider Training and Evaluation of a Problem-Solving Intervention to Reduce Distress and Enhance Readiness Among Service Members. AB - Introduction: Department of Defense (DoD) has identified problem-solving training (PST) as a promising prevention/early intervention for mental health disorders. PST is a four-session group intervention that emphasizes building problem-solving and coping skills to mitigate emotional dysregulation and the adverse effects of stressful events. It was adapted from problem-solving therapy, which is an evidence-based, cognitive-behavioral approach that has shown effectiveness with treating depression and managing suicide risk. The current evaluation examined a pilot program that: (1) trained DoD providers in the delivery of PST, (2) conducted PST intervention groups with active duty personnel, and (3) developed PST master trainers to train other providers. Materials and Methods: Clinical (e.g., psychologists) and non-clinical (e.g., chaplains) providers attended a 2.5 day workshop of didactic coursework and experiential training on conducting PST, with a subset of providers selected to attend an additional workshop to become master trainers in PST. Providers (n = 82) who attended a PST Facilitator Workshop completed pre- and post-workshop assessments of self-efficacy in PST skills. Eight providers evaluated a Master Trainer Workshop. After completing workshop training, providers conducted PST intervention groups with service members (n = 435), who were experiencing distress, with or without a mental health diagnosis, and whose needs were appropriate for a prevention/resiliency based skills group. Service members completed the following pre- and post-PST group outcome measures: (a) Outcome Questionnaire-30 (OQ-30) and Patient Health Questionnaire-9 (PHQ-9) as measures of distress; and (b) Brief Resilience Scale (BRS) to assess resilience, which contributes to readiness. They also completed the Social Problem Solving Inventory-Revised: Short Form (SPSI-R:S), as a process measure for the intervention. The SPSI-R:S, which assesses how individuals cope when faced with problems, includes the following subscales: (1) positive problem orientation, (2) negative problem orientation, (3) rational problem-solving, (4) impulsivity/carelessness style, and (5) avoidance style. Service members also completed a post-group evaluation of PST. Data were analyzed with descriptive statistics, paired sample t-tests, and correlational analyses. Results: Providers showed pre- to post-facilitator workshop increases in self-efficacy of PST skills (all p < 0.001) and those selected as master trainers evaluated their workshop training favorably, particularly the role-playing exercises. Analyses of pre- vs. post-PST group intervention measures among service members indicated that OQ-30 and PHQ-9 scores declined, while BRS and SPSI-R:S total scores increased (all p < 0.001). In addition, correlational analyses of change scores showed that the SPSI R:S subscales negative problem orientation and avoidance style were negatively correlated with BRS and positively correlated with OQ-30 and PHQ-9 (all p < 0.001). Service members gave positive post-group evaluations of PST effectiveness and program materials. Conclusion: DoD providers reported increased self-efficacy in skills required for the delivery of a four-session PST group intervention after participating in a pilot program of training workshops. The pilot of the PST group intervention showed an association with improvements on service members' self-reported measures related to distress, readiness, and coping. In addition, changes in problem-solving measures were associated with changes in outcome measures. Follow-on research is needed to further investigate if PST is effective in preventing more severe forms of distress. PMID- 30252081 TI - A Single Pheromone Receptor Gene Conserved across 400 My of Vertebrate Evolution. AB - Pheromones are crucial for eliciting social and sexual behaviors in diverse animal species. The vomeronasal receptor type-1 (V1R) genes, encoding members of a pheromone receptor family, are highly variable in number and repertoire among mammals due to extensive gene gain and loss. Here, we report a novel pheromone receptor gene belonging to the V1R family, named ancient V1R (ancV1R), which is shared among most Osteichthyes (bony vertebrates) from the basal lineage of ray finned fishes to mammals. Phylogenetic and syntenic analyses of ancV1R using 115 vertebrate genomes revealed that it represents an orthologous gene conserved for >400 My of vertebrate evolution. Interestingly, the loss of ancV1R in some tetrapods is coincident with the degeneration of the vomeronasal organ in higher primates, cetaceans, and some reptiles including birds and crocodilians. In addition, ancV1R is expressed in most mature vomeronasal sensory neurons in contrast with canonical V1Rs, which are sparsely expressed in a manner that is consistent with the "one neuron-one receptor" rule. Our results imply that a previously undescribed V1R gene inherited from an ancient Silurian ancestor may have played an important functional role in the evolution of vertebrate vomeronasal organ. PMID- 30252082 TI - PWD: Treatment Platform for Both Prolonged Field Care and Definitive Treatment of Burn-Injured Warfighters. AB - Introduction: Burns are a very frequent injury type in the battlefield, comprising 5-20% of combat casualties in the recent conflicts. Almost 80% of the burns occur to the face, in part because the face is often not protected. Immediate treatment is critical in the first hours after severe burn injury in order to prevent infection and wound progression. Immediate treatment in the battlefield can be a serious challenge especially if the injury occurs in a remote area with limited transport options. Therefore, novel treatment modalities for prolonged field care when transport to the definitive care is delayed are needed. The purpose of this study was to utilize the platform wound device (PWD) with negative pressure capabilities for the immediate and definitive treatment of porcine full-thickness head burns. Materials and Methods: Full-thickness burn wounds were created on foreheads of seven Yorkshire pigs. Burns were created on day 0, immediately enclosed with the PWD and treated topically with minocycline and lidocaine. On day 3, the burns were surgically debrided. Subsequently, new PWDs were placed on the wounds and continuous negative pressure wound therapy was initiated with either -50 mmHg or -80 mmHg. On day 7, the animals were euthanized and wounds were harvested for analyses. Control wounds were treated with silver sulfadiazine cream. Results: The PWD treatment with negative pressure significantly reduced erythema and edema in the injured tissue and promoted granulation tissue and neocollagen formation by day 7 in comparison to control wounds. In addition, the PWD with both topical minocycline and negative pressure (-80 mmHg or -50 mmHg) reduced bacterial counts in the wounds similar to the current standard of care. Conclusion: This study demonstrates that the PWD is an effective platform for delivery of antibiotics and negative pressure wound therapy for the treatment of full-thickness burns. Therefore, the PWD may be utilized for both prolonged field care and definitive treatment of burn- and blast-injured warfighters. PMID- 30252083 TI - Employment and occupational outcomes following adolescent-onset mental illness: analysis of a nationally representative French cohort. AB - Background: There has been little work into the relative effects of adolescent onset, as compared to lifetime, mental illness on employment, income and occupational outcomes in adulthood. Methods: Using data from the Sante et Itineraire Professionnel Survey, a nationally representative survey of 13 648 French working-age people to investigate prospective associations between self reported mental illness and employment, income and occupational outcomes. We further investigated whether these outcomes would differ for those reporting an onset of mental illness prior to 18 years of age. Results: Adolescent-onset mental illness was associated with poorer employment outcomes, significantly increased risk of employment in low-skilled occupations, as well as reduced monthly wage earnings. Conclusions: Results extend understandings of the risks of adolescent-onset mental illness on employment and occupational outcomes and suggest that vocational recovery services should take these factors into account when designing support services for adolescents with mental health problems, particularly for males. PMID- 30252084 TI - Deployment Among Active-Duty Military Women and Pregnancy-Related Hypertensive Disorders. AB - Introduction: Today women comprise 15% of the U.S. active-duty military, but are often overlooked in research of the Armed Forces. While some of the challenges faced by women are similar to men, they encounter unique stressors, including pregnancy-related issues. Hypertensive disorders of pregnancy (HDPs) affect 5-10% of pregnancies annually and have been linked to maternal stress, but no studies have assessed the impact of maternal military deployment on HDP incidence. Thus, the purpose of the current study was to quantify the risk of HDP among active duty U.S. military mothers who deployed in the post-9/11/2001 era. Materials and Methods: We conducted a retrospective cohort study using a U.S. Department of Defense database comprised of all active-duty women who gave birth to their first, live-born singleton infant using Tricare from January 1, 2004 to December 31, 2008. The database included records for maternal/infant birth hospitalizations and deployment. HDP was defined with ICD-9-CM codes in the maternal birth hospitalization record. We evaluated the risk of HDP associated with several deployment measures for the cohort overall and among racial/ethnic groups: (1) deployment in general (yes vs. no); (2) timing of deployment ending prior to birth (<12 months or >=12 months prior vs. non-deployed); and, (3) cumulative time spent deployed since 9/11/2001. We used multivariable logistic regression and reported odds-ratios (OR) and 95% confidence intervals (CI). We also explored meaningful categorization of certain continuous deployment measures associated with HDP incidence. The study was approved by the University of South Florida Institutional Review Board. Results: There were a total of 36,667 births and 13.4% of mothers experienced at least one HDP. No increased risk of HDP was observed for deployed mothers compared with non-deployed mothers in the complete cohort (OR = 1.02, 95% CI: 0.95-1.09), but cumulative deployment length >=1 year was identified as a potential risk factor for HDP vs. <1 year deployment (OR = 1.17, 95% CI: 1.00-1.36). Conclusion: Our study was the first to quantify the incidence of HDP among active-duty military women giving birth to their first child. It was slightly higher than in the general population, but deployment overall is seemingly not responsible for the elevated incidence. PMID- 30252085 TI - Genetics and Distribution Modeling: The Demographic History of the Cactophilic Drosophila buzzatii Species Cluster in Open Areas of South America. AB - Biodiversity is the result of historical and recurrent events acting on populations and species. The Drosophila buzzatii species cluster is distributed along a diagonal of open areas in South America. Combining genetic analyses with species distribution models we evaluated the influence of climatic changes in the demography history of this cluster. We performed a Bayesian Skyline analysis and reconstructed the ancestral areas based on mitochondrial cytochrome oxidase I (mtCOI) gene. We modeled the current distribution and projected it to past (mid Holocene and Last Glacial Maximum) and future. Our results demonstrate that climate change plays a critical role in historical demography and in defining the current and future geographic ranges of these species. The inter-Andean dry valleys and the Chiquitano Seasonally Dry Tropical Forests (SDTF) in Bolivia are considered the ancestral area for the D. buzzatii cluster. From this area, the migration route was through a west-east corridor from central Andes, throughout Bolivia, Paraguay and Argentina toward eastern and northeastern Brazil, along the edges of rain forest. The responses of the species to the climatic changes differ from the dominant assumptions of expansion during dry/cold weather and contraction during wet/warm weather that characterized the glacial cycles. We suggest that the influence of ecology and the potential responsiveness of each taxon to the environmental dynamics should be considered as well. Predictions for the future suggest a decline of suitable areas for the cluster, threatening biodiversity of these habitats. This work showed the importance of an integrative analysis of genetics and geography information to improve the inferences about demographic history hypotheses for the cluster. PMID- 30252086 TI - Perceived Impact of Participation in a One-Time Expressive Arts Workshop. AB - Introduction: This 2015 study examined the use of art to express the experience of the cancer journey of military cancer patients/cancer survivors, family and friends, caregivers, volunteers, and staff members through a one-time art-making workshop, administered by non-art therapists. Using art to express a medical/cancer journey may give participants, who cannot express their feelings in words, the ability to articulate their experience through art that looks at the creative process rather than the end result - expressive art. Materials and Methods: This mixed methods study examined the use of art to express the cancer journey of participants. Twenty-eight adults participated in a one-time expressive arts workshop conducted by non-professional art therapists at a military medical center. The five domains of the Emotion Thermometer were analyzed to determine if the pre-event and post-event assessment results would differ. The Silver Drawing Test and Draw-a-Story assessment tools were used to identify emotions and attitudinal stance on six separate five-point scales. A qualitative analysis was done using the phenomenological method of the post interviews that facilitated open expression to identify themes. Results: A significant difference was found between the pre-event and post-event analyses using the Emotion Thermometer, with post-assessment results revealing lower levels in the three domains of distress, anxiety, and depression. The Silver Drawing Test and Draw-a-Story were analyzed for six components using a five-point scale, with the highest scores being content/meaning, ability to combine, and creativity. A qualitative analysis was done using the phenomenological method; post-interviews provided information to categorize the experience into four key themes: environment, connection, emotions, and discoveries. Conclusions: Using art to express one's journey through cancer allows participants to articulate that journey "beyond language." This mixed methods study was administered by five non-professional art therapists with three having no expressive arts background. This study established that an expressive arts workshop can effectively be conducted by non-professional art therapists. The team of non-professional art therapists, who facilitated this one-time art-making workshop, demonstrated that a military member's stress can be decreased by giving them "a voice" through expressive art. PMID- 30252087 TI - Military Family Physicians' Practices and Perceptions About Reproductive Health Services for Deploying Women. AB - Introduction: Incomplete or inadequate provision of contraceptive services to servicewomen can have a profound impact on military health, readiness, and financial outcomes. This study examined the reproductive health practices and perceptions among family medicine physicians caring for servicewomen. Materials and Methods: We conducted an anonymous survey of 568 registered attendees at the March, 2018 Uniformed Services Academy of Family Physicians annual meeting. The response rate was 52.8% and 69% of responders met inclusion criteria. Results: Our sample of family medicine physicians was 58.3% male and 85.3% Caucasian. In all, 18.3% were current residents, 42.9% graduated between 2008 and 2017, and 38.7% graduated before 2008. A previous deployment was reported by 55.1%. Among physicians with a deployment history, 20.8% reported difficulty prescribing contraception during deployment because they were unable to obtain a patient's desired method, 2.6% reported servicewomen not accessing contraception because of fear and stigma associated with sexual activity in the deployed setting, and 22.1% reported problems with both factors. Among physicians performing pre deployment and other readiness visits for active duty servicewomen, 17.4% reported not discussing contraception at these encounters because of competing priorities and 1.5% because of ethical/religious concerns. Physicians who could offer more rapid access to subdermal implants (within 2 weeks) were more likely to discuss contraception (87.0% versus 64.7%, p = 0.005). When discussing the use of contraception in the deployed environment, 15.8% of physicians would not prescribe oral contraceptives, 12.3% would not prescribe intrauterine methods, and 14.3% would not prescribe subdermal implants. Physicians who previously deployed were more likely to report they would offer oral contraceptives (91% versus 75.0%, OR 3.4 [95% CI 1.44-8.48], p = 0.002) for women in the deployed setting compared to those who have not deployed. More timely (<2 weeks) access to subdermal implant insertion was associated with a greater rate of offering subdermal implants (91.9% versus 79.6%, p = 0.02). When discussing contraceptive options with all women, 27.3% of physicians do not prescribe emergency contraception because of training, ethical, and/or religious reasons. Some reported they would neither prescribe nor refer women for the following methods: emergency contraception (4.5%), intrauterine contraception (9.3%), and subdermal implants (7.3%). Conclusions: The results of this study support the need to develop a consistent, standardized, and evidence-based pre-deployment process and expanded resources in deployed environments for services related to the provision of reproductive health. Optimal strategies may aim to reduce barriers to care and enable the highest quality of health care through provider education, resource allocation, revised appointment times and content, and diversity among provider experience. Further research is needed to determine the influence of physician practice patterns on patient reproductive health outcomes and interventions to modify these practices to improve patient outcomes and military readiness. PMID- 30252088 TI - Character Strengths of Junior Australian Army Officers. AB - Introduction: Armed forces view their officers' character as foundational to their ability to lead the personnel entrusted to them. The character of junior officers is of particular interest, because they must increasingly make quick, morally-laden decisions while dispersed among civilians without time to consult their commanders. However, little is systematically known about the character of officers. Accordingly, the present study was aimed at mapping Australian Army junior officers' perceptions of the chief aspects of their own character and also those of their main role models, specifically, their senior officers, including their trustworthiness as an essential aspect of effective leadership. The present study also tested whether these character perceptions were aligned with four core values of the Australian Army - courage, initiative, teamwork, and respect - which are intended to shape the character of its personnel. Materials and Methods: The respondents (N = 171 lieutenants) ranked how well each of 24 positive character strengths applied to themselves as individuals. To test the alignment of these rankings with the respondents' perception of their leaders' character, respondents nominated the five top strengths of their effective leaders. This study was approved by the Australian Defence Human Research Ethics Committee (ADHREC 009-2013). Results: With regard to the first aim, five character strengths - integrity, leadership, good judgment, trustworthy, and teamworker - were ranked by the respondents as being their chief personal strengths at frequencies significantly above those expected from random allocation. With regard to the second aim, the respondents aligned the rankings of their character strengths with those of their effective leaders through the entire list, not just the highest-ranking items. Nevertheless, there were two significant differences. The respondents assigned their leaders higher ranks for wisdom than for themselves, but assigned lower ranks to their leaders for being trustworthy. With regard to the third aim, the respondents' perceptions of their chief character strengths were not well aligned with the four core values of the Australian Army. Teamworker was given a significant top ranking, but courage, initiative, and respectful were not. Thus, the respondents did not appear to respond according to organizational demand characteristics. Conclusions: The present study achieved its aims. First, it revealed five character strengths that junior officers in the Australian Army tended to see as their own chief strengths. Second, the junior officers saw their character strengths as aligned with those of their senior officers. By and large, this alignment extended across all the character strengths, regardless of their specific ranking. Subject to further experimental testing, this finding provides correlational evidence that junior officers may model their character on what they see in their senior officers. Third, in contrast, the junior officers' rankings were not well aligned with the Australian Army's stated core values. The junior officers saw teamworker as one of their chief strengths, but not courage, initiative, or respectful. This pattern does not imply that the junior officers rejected strengths as valuable but only that they are not among the junior officers' own chief strengths. PMID- 30252089 TI - The Physiology and Biomechanics of Load Carriage Performance. AB - Introduction: The weight that soldiers are required to carry in training and in combat has continually increased over the years. Changes in load carried or pace of activity will alter the physiological and biomechanical stress associated with the activity. Whether it is part of the soldier's training or an actual operation, managing the proper load and speed to minimize fatigue can be integral to the soldier's success. Without a proper understanding of the multitude of factors that may affect load carriage performance, mission success may be jeopardized. The purpose of this review is to summarize and clarify the findings of load carriage research and to propose a new method for analyzing the intensity of load carriage tasks, the Load-Speed Index. Materials and Methods: We reviewed studies that examined military load carriage at walking speeds and included articles that featured non-military participants as deemed necessary. Results: Major factors that can affect load carriage performance, such as speed of movement, load carried, load placement, body armor, and environmental extremes all influence the soldier's energy expenditure. A critical aspect of load carriage performance is determining the appropriate combination of speed and load that will maximize efficiency of the activity. At the higher end of walking speeds, the walk-to-run transition represents a potential problem of efficiency, as it may vary on an individual or population basis. Conclusions: This review provides a comprehensive overview of these factors and suggests a new Load-Speed Index, which can be utilized to define thresholds for load and speed combinations and contribute to the understanding of the physiological and biomechanical demands of load carriage marches. The literature recommends that load and speed should be managed in order to maintain an exercise intensity ~45% VO2 max to delay time to fatigue during prolonged marches, and the Load-Speed Index corroborated this finding, identifying 47% VO2 max as a threshold above which intensity increases at a greater rate with increases in load and speed. The Load Speed Index requires validation as a predictive tool. There are no definitive findings as to how load affects the speed at which the walk-to-run transition occurs, as no investigations have specifically examined this interaction. Additional research is clearly needed by examining a wide range of loads that will facilitate a clearer understanding of speed and load combinations that optimize marching pace and reduce energy expenditure. PMID- 30252090 TI - Galectin-4, a Negative Regulator of Oligodendrocyte Differentiation, Is Persistently Present in Axons and Microglia/Macrophages in Multiple Sclerosis Lesions. AB - Neuron-derived molecules are potent regulators of oligodendrocyte differentiation and myelination during brain development and upon demyelination. Their analysis will thus contribute to understanding remyelination failure in demyelinating diseases, such as multiple sclerosis (MS). Previously, we have identified neuronal galectin-4 as a novel negative soluble regulator in the timing of developmental myelination. Here, we investigated whether galectin-4 is re expressed in axons upon demyelination to regulate the timing of remyelination. Our findings revealed that galectin-4 is transiently localized to axons in demyelinated areas upon cuprizone-induced demyelination. In contrast, in chronic demyelinated MS lesions, where remyelination fails, galectin-4 is permanently present on axons. Remarkably, microglia/macrophages in cuprizone-demyelinated areas also harbor galectin-4, as also observed in activated microglia/macrophages that are present in active MS lesions and in inflammatory infiltrates in chronic relapsing experimental autoimmune encephalomyelitis. In vitro analysis showed that galectin-4 is effectively endocytosed by macrophages, and may scavenge galectin-4 from oligodendrocytes, and that endogenous galectin-4 levels are increased in alternatively interleukin-4-activated macrophages and microglia. Hence, similar to developmental myelination, the (re)expressed galectin-4 upon demyelination may act as factor in the timing of oligodendrocyte differentiation, while the persistent presence of galectin-4 on demyelinated axons may disrupt this fine-tuning of remyelination. PMID- 30252091 TI - Successful Use of Colistin Monotherapy as Outpatient Parenteral Antibiotic Therapy for XDR Acinetobacter Hepatic Abscesses. AB - Acinetobacter baumannii is naturally resistant to several classes of antibiotics and readily develops further resistance mechanisms under antibiotic pressure. For patients infected with extremely drug-resistant organisms, effective antibiotic treatments are intravenous and often require inpatient hospitalization for monitoring and dose adjustment. A 31-year-old active duty service member, stationed in Southeast Asia, sustained thermal burns from an electrical arc injury to over 40% of his total body surface area. His hospital course was complicated by multiple extensively drug resistant (XDR) A. baumanii infections including bacteremia and hepatic abscesses. To facilitate discharge to his family, his hepatic abscesses were treated successfully as an outpatient with several weeks of parenteral colistin monotherapy. With regular renal function testing, his dosages were held and/or adjusted to compensate for acute kidney injuries, and he was successfully cleared of his infection. Up to 50% of A. baumannii isolates in American hospitals, including major DOD facilities, are carbapenem resistant. As a result, historically last-line therapies, such as polymyxins, are increasingly used as treatment. New dosing guidance is emphasized to minimize renal toxicities. This case demonstrates the ability to administer parenteral colistin as an outpatient under close supervision. PMID- 30252093 TI - iProX: an integrated proteome resource. AB - Sharing of research data in public repositories has become best practice in academia. With the accumulation of massive data, network bandwidth and storage requirements are rapidly increasing. The ProteomeXchange (PX) consortium implements a mode of centralized metadata and distributed raw data management, which promotes effective data sharing. To facilitate open access of proteome data worldwide, we have developed the integrated proteome resource iProX (http://www.iprox.org) as a public platform for collecting and sharing raw data, analysis results and metadata obtained from proteomics experiments. The iProX repository employs a web-based proteome data submission process and open sharing of mass spectrometry-based proteomics datasets. Also, it deploys extensive controlled vocabularies and ontologies to annotate proteomics datasets. Users can use a GUI to provide and access data through a fast Aspera-based transfer tool. iProX is a full member of the PX consortium; all released datasets are freely accessible to the public. iProX is based on a high availability architecture and has been deployed as part of the proteomics infrastructure of China, ensuring long-term and stable resource support. iProX will facilitate worldwide data analysis and sharing of proteomics experiments. PMID- 30252094 TI - Formal Training for Ethical Dilemmas in Global Health. PMID- 30252092 TI - Patient Health Beliefs and Characteristics Predict Longitudinal Antihypertensive Medication Adherence in Adolescents With CKD. AB - Objective: To investigate longitudinal associations of health beliefs, which included self-efficacy, outcome expectancies, and perceived barriers, and demographic risk factors (i.e., age, gender, race, and family income) with antihypertensive medication adherence in adolescents with chronic kidney disease (CKD) over 24 months. Method: The sample included 114 adolescents (M age = 15.03 years, SD = 2.44) diagnosed with CKD. Adolescents reported their self-efficacy for taking medications, medication outcome expectancies, and barriers to adherence at baseline and 12 and 24 months after baseline. Antihypertensive medication adherence was assessed via electronic monitoring for 2 weeks at baseline and 6, 12, 18, and 24 months after baseline. Results: Adherence increased and then decreased over the 2-year study period (inverted U-shape). Self-efficacy, outcome expectancies, and barriers did not change over time. Older adolescent age, female gender, African American race, <$50,000 annual family income, and public health insurance were associated with lower adherence. However, family income was the primary demographic risk factor that predicted adherence over time (>=$50,000 annual family income was longitudinally associated with higher adherence). Higher self-efficacy and more positive and less negative outcome expectancies across time were also associated with higher antihypertensive medication adherence across time. Conclusions: Clinical interventions should be developed to target medication self-efficacy and outcome expectancies to improve long-term antihypertensive medication adherence in adolescents with CKD. Family income may be considered when conceptualizing contextual factors that likely contribute to adolescents' consistent challenges with medication adherence over time. PMID- 30252095 TI - Monitored eCLIP: high accuracy mapping of RNA-protein interactions. AB - CLIP-seq methods provide transcriptome-wide snapshots of RNA-protein interactions in live cells. Reverse transcriptases stopping at cross-linked nucleotides sign for RNA-protein binding sites. Reading through cross-linked positions results in false binding site assignments. In the 'monitored enhanced CLIP' (meCLIP) method, a barcoded biotinylated linker is ligated at the 5' end of cross-linked RNA fragments to purify RNA prior to the reverse transcription. cDNAs keeping the barcode sequence correspond to reverse transcription read-throughs. Read through occurs in unpredictable proportions, representing up to one fourth of total reads. Filtering out those reads strongly improves reliability and precision in protein binding site assignment. PMID- 30252096 TI - Major risk factors for sexual minority young people's mental and physical health: findings from a county-wide school-based health needs assessment. AB - Background: Childhood health is an important adult health predictor. Sexual orientation is increasingly recognized as influential on children and young people's (CYP) mental and physical health. Methods: Data came from a cross sectional survey of year 9 children attending schools in two local authorities in the north-west of England, including mental and physical health indicators, and demographic characteristics including sexual orientation. The sample of 8058 represented 67.8% of the eligible population. Data were analysed by sexual orientation, sexual majority or sexual minority. Results: Children reporting their sexual orientation as sexual minority reported worse mental and physical health outcomes and behaviours than sexual majority peers; had higher odds of being lonely (odds ratios (OR) = 8.24, 95% C.I.: 6.56-10.37), having self-harmed (OR = 7.28, 95% C.I.: 5.78-9.15), being bullied (OR = 4.76, 95% C.I.: 3.74-6.05) or perceiving themselves as overweight (OR = 2.40, 95% C.I.: 1.89-3.06). Conclusions: It is important to identify and support children in a sexual minority. Research is required to understand differences between children within sexual minorities and the impact on outcomes and rights. Health and social policy and services, should respond to the vulnerabilities of sexual minority CYP. PMID- 30252097 TI - Respiratory syncytial virus (RSV) infects primary neonatal and adult natural killer cells and affects their anti-viral effector function. AB - Background: Respiratory syncytial virus (RSV) is a major cause of severe acute lower respiratory tract infections in infants. Natural killer (NK) cells are important anti-viral effector cells that likely encounter RSV in the presence of virus-specific (maternal) antibodies. Since NK cells potentially contribute to immunopathology, we investigated whether RSV affects their anti-viral effector functions. Methods: We assessed the phenotype and functionality of primary neonatal and adult NK cells by flow cytometry after stimulation with RSV or RSV antibody complexes. Results: We demonstrate for the first time that RSV infects neonatal and adult NK cells in vitro. Pre-incubation of virus with sub neutralizing concentrations of RSV-specific antibodies significantly increased the percentage of infected NK cells. Upon infection, NK cells were significantly more prone to produce IFN-gamma, while secretion of the cytotoxicity molecule perforin was not enhanced. Conclusions: Our findings suggest that (antibody enhanced) RSV infection of NK cells induces a pro-inflammatory rather than a cytotoxic response, which may contribute to immunopathology. Considering that most RSV vaccines currently being developed aim at inducing (maternal) antibodies, these results highlight the importance of understanding the interactions between innate effector cells and virus-specific antibodies. PMID- 30252098 TI - Primary Care in American Samoa: How Nurse Practitioners Created a Bridge Across an Ocean. PMID- 30252099 TI - Trypomastigote Excretory Secretory Antigen (TESA) blot is associated in neonates with parasite load and detects congenital T. cruzi infection using anti-SAPA IgM. AB - Background: Congenital Trypanosoma cruzi accounts for an estimated 22% of new cases in Latin America. However, neonatal diagnosis is challenging, as 9-month follow-up for IgG testing is poor, qPCR is not routinely performed, and micromethod misses more than 40% of congenital infections. Methods: Biorepository samples from new mothers and their infants from Piura, Peru (non-endemic area), and Santa Cruz, Bolivia (endemic) were accessed. Infant specimens were assessed using micromethod, qPCR and TESA blot for IgM SAPA bands, using qPCR as the gold standard. Results: When compared to qPCR, IgM TESA blot was both sensitive and specific for congenital Chagas diagnosis. Cumulative sensitivity (whether only four bands or all six bands were present) was 80% (59-92%). Specificity was 94% (92-96%) in endemic areas and 100% in non-endemic. SAPA bands occurred sequentially, and in pairs, and parasite load correlated highly with the number of SAPA bands present. Micromethod detected less than half of infected infants. Conclusions: The IgM blot for SAPA bands demonstrates that SAPA antigen may be able to provide a Point of Care test for congenital infection that is rapid, relatively inexpensive, and more sensitive than micromethod. PMID- 30252100 TI - Sex Differences in Glucose and Fatty Acid Metabolism in Asians Who Are Nonobese. AB - Context: The prevalence of diabetes is increasing throughout Asia, even in the absence of obesity, and is lower in women than in men. The underlying mechanisms are not well understood. Objective: To evaluate the sex differences in glucose and fatty acid metabolism in Asians who are nonobese. Design: Cross-sectional study. Setting: Clinical Nutrition Research Centre, Singapore. Participants: Healthy Asian men (n = 32; body mass index, 21.8 +/- 1.5 kg/m2; age, 42 +/- 14 years) and women (n = 28; body mass index, 21.4 +/- 2.0 kg/m2; age, 41 +/- 13 years). Main Outcome Measures: Insulin sensitivity (insulin-mediated glucose uptake normalized for steady-state insulin; hyperinsulinemic-euglycemic clamp), postprandial glucose, insulin and fatty acid concentrations, insulin secretion (mixed meal tolerance test with mathematical modeling), insulin clearance, body composition and fat distribution (dual-energy X-ray absorptiometry, MRI, and spectroscopy), cardiorespiratory fitness (maximal oxygen uptake; graded exercise test), and handgrip strength (dynamometry). Results: Women had more total body fat but less visceral fat than men; liver and muscle lipid contents were not different. Maximal oxygen uptake and handgrip strength were lower in women than men. The postprandial glucose concentrations were ~8% lower, the insulin-mediated glucose uptake was ~16% greater, and the meal-induced suppression of fatty acid concentrations was significantly greater in women than in men (P < 0.05 for all). However, muscle insulin sensitivity was not different between the sexes. No differences were found in postprandial insulin secretion and clearance rates; however, the steady-state insulin clearance was ~17% lower in women. Conclusions: Asian women who are nonobese are more insulin-sensitive than men at the level of adipose tissue but not skeletal muscle. Therefore, sex differences in glucose tolerance are likely the result of sexual dimorphism in hepatic insulin action. PMID- 30252101 TI - DNA-methylation profiling is a method of choice for molecular verification of pediatric WNT activated medulloblastomas. AB - Background: WNT activated medulloblastoma (WNT MB) represent a well-characterized molecular variant accounting for 10-15% of all MB and is associated with a favorable clinical outcome. Patients with localized WNT MBs could benefit from de intensification of combined treatment, which would require an accurate diagnosis of these tumors. However, despite the presence of molecular features related with a WNT MB signature (nuclear beta-catenin immunoexpression, CTNNB1 mutation and monosomy 6), a prompt and reliable diagnostic verification of these tumors is not yet feasible. Methods: In the current study, we analyzed 78 samples of WNT MB treated in a single institute through genome-wide DNA methylation and targeted next generation sequencing to elaborate an optimal method for WNT MB molecular verification. Results: We found that DNA-methylation profiling discloses significant advantages for molecular diagnostic of WNT MB. All other "routine" methods applied such as beta-catenin immunohistochemistry, CTNNB1 mutation analysis, and detection of monosomy 6 failed to identify all WNT MB cases. Survival analysis revealed that application of a reduced radiotherapy protocol for WNT MB treatment had no influence on patients' survival. Only one patient died due to local relapse but recurrent tumor was pathologically and molecularly diagnosed as a secondary glioblastoma. Conclusions: 1. DNA methylation analysis should be considered as a method of choice for further clinically relevant stratification of WNT MB and for correct diagnosis of the recurrent tumors. 2. WNT MB patients with localized disease could benefit from treatment de intensification. PMID- 30252103 TI - New classification of hydronephrosis on 18F-FDG-PET/CT predicts post-operative renal function and muscle-invasive disease in patients with upper urinary tract urothelial carcinoma. AB - Objectives: To evaluate the value of a classification of hydronephrosis on 18F flurodeoxyglucose (FDG)-PET/CT in predicting post-operative renal function and pathological outcomes among patients with upper urinary tract urothelial carcinoma. Methods: We retrospectively reviewed 71 patients treated with nephroureterectomy (NU) for upper urinary tract urothelial carcinoma after FDG PET/CT between 2010 and 2016. Eight patients treated with ureteral stent or nephrostomy at the time of FDG-PET/CT were excluded. We classified hydronephrosis based on renal excretion of FDG as follows: Type 0, no hydronephrosis; Type 1, hydronephrosis with FDG excretion; and Type 2, hydronephrosis without FDG excretion. eGFR was recorded before pre-operataive FDG-PET/CT examination and after nephroureterectomy. Results: Thirty-three patients (52%) had hydronephrosis, classified as Type 1 in 19 patients (30%) and Type 2 in 14 (22%). Type 2 hydronephrosis was associated with ureteral cancer and severe hydronephrosis on CT. Median changes in eGFR before and after nephroureterectomy in patients classified as Type 0, 1 and 2 were -23.9, -18.8 and 2.0 ml/min/1.73 m2, respectively. On multivariate analysis, Type 2 hydronephrosis was a significant predictor of change in eGFR (P = 0.001). Rates of muscle-invasive upper urinary tract urothelial carcinoma among Type 0, 1 and 2 patients were 37, 42 and 86%, respectively. On multivariate analysis, Type 2 hydronephrosis was a significant predictor of muscle-invasive upper urinary tract urothelial carcinoma (P = 0.032, OR 6.491). Conclusions: This classification of hydronephrosis from FDG-PET/CT is simple and useful for predicting post-operative renal function and muscle-invasive disease in patients with upper urinary tract urothelial carcinoma, especially with ureteral cancer. This classification can help in deciding eligibility for lymphadenectomy or perioperative cisplatin-based chemotherapy. PMID- 30252104 TI - Socioeconomic Status and Biological Risks for Health and Illness across the Life Course. AB - Objectives: We assess the temporal properties and biosocial mechanisms underlying the associations between early-life SES and later health. Using a life course design spanning adolescence to older adulthood, we assess how early-life and various dimensions of adult SES are associated with immune and metabolic function in different life stages and examine possible bio-behavioral and psychosocial mechanisms underlying these associations. Method: Data for this study come from three national studies that collectively cover multiple stages of the life course (Add Health, MIDUS, and HRS). We estimated generalized linear models to examine the prospective associations between early-life SES, adult SES, and biomarkers of chronic inflammation and metabolic disorder assessed at follow-up. We further conducted formal tests of mediation to assess the role of adult SES in linking early SES to biological functions. Results: We found that early-life SES exerted consistent protective effects for metabolic disorder across the life span, but waned with time for CRP. The protective effect of respondent education remained persistent for CRP but declined with age for metabolic disorder. Adult income and assets primarily protected respondents against physiological dysregulation in middle and old ages, but not in early adulthood. Discussion: These findings are the first to elucidate the life course patterns of SES that matter for underlying physiological functioning during the aging process to produce social gradients in health. PMID- 30252102 TI - How bacterial xenogeneic silencer rok distinguishes foreign from self DNA in its resident genome. AB - Bacterial xenogeneic silencers play important roles in bacterial evolution by recognizing and inhibiting expression from foreign genes acquired through horizontal gene transfer, thereby buffering against potential fitness consequences of their misregulated expression. Here, the detailed DNA binding properties of Rok, a xenogeneic silencer in Bacillus subtilis, was studied using protein binding microarray, and the solution structure of its C-terminal DNA binding domain was determined in complex with DNA. The C-terminal domain of Rok adopts a typical winged helix fold, with a novel DNA recognition mechanism different from other winged helix proteins or xenogeneic silencers. Rok binds the DNA minor groove by forming hydrogen bonds to bases through N154, T156 at the N terminal of alpha3 helix and R174 of wing W1, assisted by four lysine residues interacting electrostatically with DNA backbone phosphate groups. These structural features endow Rok with preference towards DNA sequences harboring AACTA, TACTA, and flexible multiple TpA steps, while rigid A-tracts are disfavored. Correspondingly, the Bacillus genomes containing Rok are rich in A tracts and show a dramatic underrepresentation of AACTA and TACTA, which are significantly enriched in Rok binding regions. These observations suggest that the xenogeneic silencing protein and its resident genome may have evolved cooperatively. PMID- 30252105 TI - Minimally Invasive Transforaminal Interbody Fusion With Robotically Assisted Bilateral Pedicle Screw Fixation: 2-Dimensional Operative Video. AB - Minimally invasive surgery (MIS) techniques may enable faster patient recovery and reduce the incidence of postoperative infections. Image-guided approaches to spinal instrumentation and interbody fusion have gained popularity in MIS, reducing radiation exposure and improving screw placement accuracy. Use of a novel computed tomography (CT) navigation-based robotic arm provides for live image-guided surgery, with the potential for augmenting existing MIS approaches and improving the accuracy of instrumentation placement. We report on the surgical technique of MIS transforaminal lumbar interbody fusion (TLIF) performed with the assistance of a new robotic device (ExcelsiusGPS, Globus Medical Inc, Audubon, Pennsylvania) and intraoperative CT guidance in a patient with single level lumbar spondylolisthesis. The patient gave written informed consent before treatment. Institutional review board approval was deemed unnecessary. The patient was positioned prone on the operating room table, and an intraoperative CT was obtained with stereotactic arrays placed bilaterally in the posterior superior iliac spine. Screw trajectories were planned using the ExcelsiusGPS software and placed percutaneously with the robotic arm without using a Kirschner wire. Interbody placement was performed via an expandable retractor after muscle dilation. Screw placement accuracy was determined with postoperative CT, which demonstrated good screw positioning without breach. The patient recovered well and was discharged home without complications. The combined use of the new robotic device and intraoperative CT enables accurate and safe fixation for the treatment of symptomatic lumbar spondylolisthesis. The operative video demonstrates the technical nuances of positioning, stereotactic marker placement, work flow, and screw placement.Used with permission from Barrow Neurological Institute, Phoenix, Arizona. PMID- 30252106 TI - Microsurgical Management of a Spinal Dural Arteriovenous Fistula With Shared Blood Supply to the Artery of Adamkiewicz: 3-Dimensional Operative Video. AB - The presented case is of a 65-yr-old gentleman referred for thoracic myelopathy. He developed bilateral, nondermatomal foot dysesthesia 14 mo prior to presentation, which progressed to numbness below the L3 level. He reported progressive gait instability, bilateral lower extremity weakness, and required a cane for ambulation. He subsequently developed urinary incontinence, while bowel function was spared. The neurological examination upon presentation revealed lower extremity strength was reduced to 4/5 in all major muscle groups bilaterally, while sensation and proprioception were reduced below the L3 level. Patellar and Achilles reflexes were not elicited and clonus was absent. Gait was unsteady and slow. The patient was not able to perform heel, toe and tandem gait. MRI revealed abnormal T2 hyper-intense signal and spinal cord expansion from T6 through the conus medullaris. Angiography revealed a dural arteriovenous fistula (dAVF) originating from the left T9 radicomedullary pedicle, which also supplied the Artery of Adamkiewicz (AoA). The patient underwent T8-10 laminectomies. Prior to disconnection of the fistula, an aneurysm clip was applied to the fistulous point and an indocyanine green video angiogram was completed to show that the fistula no longer opacified, but that the AoA remained patent, which was later confirmed with angiography. As of discharge, the patient's motor exam had improved substantially, though his sensory deficits persisted. This case demonstrates that surgical disconnection is requisite in the treatment of spinal dAVF that have a shared blood supply with the AoA, as embolization risks spinal cord infarction. The patient consented to presentation of this case in a de identified fashion. PMID- 30252107 TI - The Impact of Scaling Factor Variability on Risk-Relevant Pharmacokinetic Outcomes in Children: A Case Study using Bromodichloromethane (BDCM). AB - Biotransformation rates extrapolated from in vitro data are used increasingly in human physiologically based pharmacokinetic (PBPK) models. This practice requires use of scaling factors, including microsomal content (mg of microsomal protein/g liver, MPPGL), enzyme specific content, and liver mass as a fraction of body weight (FVL). Previous analyses indicated that scaling factor variability impacts pharmacokinetic (PK) outcomes used in adult population dose-response studies. This analysis was extended to pediatric populations because large inter individual differences in enzyme ontogeny likely would further contribute to scaling factor variability. An adult bromodichloromethane (BDCM) model (Kenyon et al., 2016a) was re-parameterized for neonates, infants and toddlers. Monte Carlo analysis was used to assess the impact of pediatric scaling factor variation on model-derived PK outcomes compared with adult findings. BDCM dose metrics were estimated following a single 0.05-liter drink of water or a 20-minute bath, under typical (5 ug/L) and plausible higher (20 ug/L) BDCM concentrations. MPPGL, CYP2E1 and FVL values reflected the distribution of reported pediatric population values. The impact of scaling factor variability on PK outcome variation was different for each exposure scenario, but similar for each BDCM water concentration. The higher CYP2E1 expression variability during early childhood was reflected in greater variability in predicted PK outcomes in younger age groups, particularly for the oral exposure route. Sensitivity analysis confirmed the most influential parameter for this variability was CYP2E1, particularly in neonates. These findings demonstrate the importance of age-dependent scaling factor variation used for in vitro to in vivo extrapolation of biotransformation rates. PMID- 30252108 TI - An investigation of the Plasmodium falciparum malaria epidemic in Kavango and Zambezi regions of Namibia in 2016. AB - Background: Namibia is one of the countries among the eight that are targeting malaria elimination in southern Africa. However, the country has encountered malaria epidemics in recent years. The objective of this study was to investigate malaria epidemics and to contribute to strengthening malaria surveillance and control in an effort to move Namibia toward eliminating malaria. Method: Malaria epidemiology data for 2014-2015 were collected from the weekly surveillance system. All consenting household members within a 100-m radius of index households were screened in 2016 using a Carestart malaria HRP2/pLDH combined rapid diagnostic test after epidemics. All houses within this radius were sprayed in 2016 with the pyrethroid deltamethrin and K-Othrine WG 250. Anopheles mosquito positive breeding sites were identified and treated with the organophosphate larvicide temephos. Insecticide susceptibility and bioassay tests were conducted. Results: During the epidemic response period in 2016, 56 parasitologically confirmed Plasmodium falciparum malaria cases in the Zambezi region were detected from active screening. The majority of those cases (83%) were asymptomatic infections. In the Kavango region, the malaria epidemic persisted, with 228 P. falciparum malaria cases recorded, but only 97 were investigated. In Namibia, malaria vector susceptibility was detected to 4% dichlorodiphenyltrichloroethane. Indoor residual spraying was conducted in 377 (90%) of the targeted households along with community awareness through health education of 1499 people and distribution of more than 2000 information, education and communication materials. The P. falciparum malaria cases in the Zambezi decreased from 122 in week 9 to 97 after week 15. Conclusions: Malaria epidemics along with the persistence of asymptomatic reservoir infections pose a serious challenge in Namibia's elimination effort. The country needs to ensure sustainable interventions to target asymptomatic reservoir infections and prevent epidemics in order to successfully achieve its goal of eliminating malaria. PMID- 30252109 TI - Renal Mucormycosis: A Rare Cause of Urinary Tract Infection Leading to End-stage Renal Disease (ESRD). AB - Mucormycosis is a rare fungal infection often seen in immunocompromised hosts. Isolated renal mucormycosis may however present in immunocompetent children as renal failure and has a uniformly poor prognosis if not detected and treated early into the course of illness. We present a 3-year-old boy with unrelenting pyelonephritis in whom serial urine cultures done were negative. A final diagnosis of isolated renal mucormycosis was made by magnetic resonance imaging and renal biopsy. PMID- 30252110 TI - Environmental controls on light inhibition of respiration and leaf and canopy daytime carbon exchange in a temperate deciduous forest. AB - Uncertainty in the estimation of daytime ecosystem carbon cycling due to the light inhibition of leaf respiration and photorespiration, and how these small fluxes vary through the growing season in the field, remains a confounding element in calculations of gross primary productivity and ecosystem respiration. Our study focuses on how phenology, short-term temperature changes and canopy position influence leaf-level carbon exchange in Quercus rubra L. (red oak) at Harvard Forest in central Massachusetts, USA. Using leaf measurements and eddy covariance, we also quantify the effect of light inhibition on estimates of daytime respiration at leaf and ecosystem scales. Measured rates of leaf respiration in the light and dark were highest in the early growing season and declined in response to 10-day prior air temperatures (P < 0.01), evidence of within-season thermal acclimation. Leaf respiration was significantly inhibited by light (27.1 +/- 2.82% inhibited across all measurements), and this inhibition varied with the month of measurement; greater inhibition was observed in mid summer leaves compared with early- and late-season leaves. Increases in measurement temperature led to higher rates of respiration and photorespiration, though with a less pronounced positive effect on photosynthesis; as a result, carbon-use efficiency declined with increasing leaf temperature. Over the growing season when we account for seasonally variable light inhibition and basal respiration rates, our modeling approaches found a cumulative 12.9% reduction of leaf-level respiration and a 12.8% reduction of canopy leaf respiration, resulting in a 3.7% decrease in total ecosystem respiration compared with estimates that do not account for light inhibition in leaves. Our study sheds light on the environmental controls of the light inhibition of daytime leaf respiration and how integrating this phenomenon and other small fluxes can reduce uncertainty in current and future projections of terrestrial carbon cycling. PMID- 30252111 TI - Surgical Resection of Cervical Meningioma: 3-Dimensional Operative Video. AB - Spinal cord meningiomas are rare, benign lesions typically found at the cervical or thoracic spinal region. They can cause symptoms through compression of the spinal cord and nerve roots. These tumors often have a challenging surgical course due to their location in relation to spinal cord and nerve rootlets. We present a 33-yr-old female who presented with cervical radicular and myelopathy symptoms. MRI of the cervical spinal demonstrated an anterolateral, 3 cm intradural, extrameduallary tumor causing significant cord compression at C6-7 level. The patient was taken to surgery for cervical laminoplasty and microsurgical tumor removal. The current 3-dimensional video demonstrates the steps involved during the microsurgical resection of the tumor. In order to facilitate spinal cord rotation without compromising blood supply the dentate ligaments at 3 levels (C5-C7) were identified and transected, the anterolateral situated tumor was separated from the exiting right C6 and C7 nerve rootlet followed by circumferential dissection, and subsequent en bloc resection. No complications were encountered during the procedure; somatosensory and motor evoked potential registration remained intact. The patient recovered well from the procedure and was discharged on postoperative day three with improvement in her presenting symptoms. PMID- 30252112 TI - Hospital Medicine: The U.S. Navy Experience to Date and a Proposal for Future Codification and Growth. PMID- 30252113 TI - The Effects of a Life Stress Emotional Awareness and Expression Interview for Women with Chronic Urogenital Pain: A Randomized Controlled Trial. AB - Objective: Women with chronic urogenital pain (CUP) conditions have elevated rates of lifetime trauma, relational stress, and emotional conflicts, but directly assessing and treating psychological stress is rarely done in women's health care settings. We developed and tested the effects on patients' somatic and psychological symptoms of a life stress interview that encourages disclosure about stressors and uses experiential techniques to increase awareness of links between stress, emotions, and symptoms. Methods: In this randomized trial, women with CUP recruited at a multidisciplinary women's urology center received either a single 90-minute life stress interview (N = 37) or no interview (treatment-as usual control; N = 25). Self-report measures of pain severity (primary outcome), pain interference, pelvic floor symptoms, and psychological symptoms (anxiety and depression) were completed at baseline and six-week follow-up. Results: Differences between the life stress interview and control conditions at follow-up were tested with analyses of covariance, controlling for baseline level of the outcome and baseline depression. Compared with the control condition, the interview resulted in significantly lower pain severity and pelvic floor symptoms, but the interview had no effect on pain interference or psychological symptoms. Conclusions: An intensive life stress emotional awareness expression interview improved physical but not psychological symptoms among women with CUP seen in a tertiary care clinic. This study suggests that targeting stress and avoided emotions and linking them to symptoms may be beneficial for this complex group of patients. PMID- 30252114 TI - Sodium propionate and sodium butyrate effects on histone deacetylase (HDAC) activity, histone acetylation, and inflammatory gene expression in bovine mammary epithelial cells. AB - Histone deacetylase (HDAC) inhibition attenuates inflammation in rodents and short-chain fatty acids (SCFAs) are effective HDAC inhibitors. Therefore, the objective of this study was to evaluate the role of the SCFAs sodium propionate (SP) and sodium butyrate (SB) as HDAC-dependent regulators of inflammatory gene expression in bovine mammary epithelial cells (MAC-Ts). We postulated that SP and SB would decrease inflammation in MAC-Ts by inhibiting HDAC activity and increasing histone H3 acetylation and consequently decreasing inflammatory gene expression. For this study, MAC-Ts stimulated with lipopolysaccharide (LPS) were used as a model for bovine mammary epithelial cell inflammation. MAC-Ts were cultured in a basal medium. Cell lysates were incubated with SP or SB (0 to 5 mM) for 2 h prior to HDAC substrates incubation for an additional 2 h and HDACs activity was determined. Next, cells were pretreated with SP or SB (0 to 3.0 mM) for 2 h prior to LPS (1 ug/mL) stimulation for an additional 2 h and assessed for histone H3 acetylation. Then, cells were pretreated with SP or SB (1 mM) for 24 h prior to LPS (1 ug/mL) stimulation for an additional 2 h and RNA was isolated for inflammatory gene expression evaluation by PCR array and gene validation was performed using quantitative real-time PCR. One-way ANOVA followed by Tukey post hoc analysis was conducted and statistical significance set at P < 0.05. SP and SB concentration-dependently and selectively inhibited class I HDAC activity, which differed between SCFAs, where SB inhibited (P < 0.05) HDACs 2, 3, and 8, while SP inhibited (P < 0.05) HDACs 2 and 8. Histone H3 acetylation was concentration-dependently increased by SCFAs and likewise the differential regulation of HDAC activity, SCFAs effected differently histone H3 acetylation, where SB increased (P < 0.05) H3K9/14, H3K18 and H3K27 acetylation, while SP increased (P < 0.05) H3K9/14 and H3K18 acetylation. However, SCFAs did not decrease (P > 0.05) overall inflammatory gene expression. Under our experimental conditions, findings suggest that in MAC-Ts, SCFAs regulate epigenetic markers on nucleosomal DNA in addition to regulation of inflammatory gene events independent of HDAC activity. Nevertheless, examination of SCFAs and/or HDACs inhibitors in bovine mammary gland is worth being further investigated to delineate the potential impact of HDAC inhibition and histones hyperacetylation on mammary gland tissue inflammation. PMID- 30252116 TI - The Wounded Warrior Recovery Project: A Longitudinal Examination of Patient Reported Outcomes Among Deployment-Injured Military Personnel. PMID- 30252115 TI - Pseudogenes Provide Evolutionary Evidence for the Competitive Endogenous RNA Hypothesis. AB - The competitive endogenous RNA (ceRNA) hypothesis is an attractively simple model to explain the biological role of many putatively functionless noncoding RNAs. Under this model, there exist transcripts in the cell whose role is to titrate out microRNAs such that the expression level of another target sequence is altered. That it is logistically possible for expression of one microRNA recognition element (MRE)-containing transcript to affect another is seen in the multiple examples of pathogenic effects of inappropriate expression of MRE containing RNAs. However, the role, if any, of ceRNAs in normal biological processes and at physiological levels is disputed. By comparison of parent genes and pseudogenes we show, both for a specific example and genome-wide, that the pseudo-3' untranslated regions (3'UTRs) of expressed pseudogenes are frequently retained and are under selective constraint in mammalian genomes. We found that the pseudo-3'UTR of BRAFP1, a previously described oncogenic ceRNA, has reduced substitutions relative to its pseudo-coding sequence, and we show sequence constraint on MREs shared between the parent gene, BRAF, and the pseudogene. Investigation of RNA-seq data reveals expression of BRAFP1 in normal somatic tissues in human and in other primates, consistent with biological ceRNA functionality of this pseudogene in nonpathogenic cellular contexts. Furthermore, we find that on a genome-wide scale pseudo-3'UTRs of mammalian pseudogenes (n = 1,629) are under stronger selective constraint than their pseudo-coding sequence counterparts, and are more often retained and expressed. Our results suggest that many human pseudogenes, often considered nonfunctional, may have an evolutionarily constrained role, consistent with the ceRNA hypothesis. PMID- 30252117 TI - Improving health equity for ethnic minority women in Thai Nguyen, Vietnam: qualitative results from an mHealth intervention targeting maternal and infant health service access. AB - Background: Ethnic minority women (EMW) in Vietnam experience disproportionately high infant and maternal mortality rates due to low social status, poverty and remoteness from health centres. This project piloted and evaluated a low-cost mobile health (mHealth) intervention called mMom utilizing behaviour change communication (BCC) to improve access to maternal, newborn and child health (MNCH) services and health equity among EMW living in remote areas. Methods: The mMom intervention built an integrated mHealth platform which sent timely MNCH information and BCC text messages to participants, and engaged health workers towards increasing their interaction and building demand for quality natal care. Mid-term and final qualitative evaluations were conducted to assess the intervention's acceptability and impact. Results: In evaluations, all participants expressed satisfaction with the quality, timeliness and convenience of the messages, and health workers reported increased efficiency and quality of care. The use of BCC increased care-seeking from EMW and strengthened relationships with health providers. Conclusion: The mMom project demonstrated the acceptability of mHealth in a remote Vietnamese region with a high proportion of disadvantaged EMW. The messages promoted increased contact between participants and health providers, which holds potential to address the marginalization of EMW from the health system. PMID- 30252118 TI - A single synonymous mutation determines the phosphorylation and stability of the nascent protein. AB - p53 is an intrinsically disordered protein with a large number of post translational modifications and interacting partners. The hierarchical order and subcellular location of these events are still poorly understood. The activation of p53 during the DNA damage response (DDR) requires a switch in the activity of the E3 ubiquitin ligase MDM2 from a negative to a positive regulator of p53. This is mediated by the ATM kinase that regulates the binding of MDM2 to the p53 mRNA facilitating an increase in p53 synthesis. Here we show that the binding of MDM2 to the p53 mRNA brings ATM to the p53 polysome where it phosphorylates the nascent p53 at serine 15 and prevents MDM2-mediated degradation of p53. A single synonymous mutation in p53 codon 22 (L22L) prevents the phosphorylation of the nascent p53 protein and the stabilization of p53 following genotoxic stress. The ATM trafficking from the nucleus to the p53 polysome is mediated by MDM2 and requires its interaction with the ribosomal proteins RPL5 and RPL11. These results show how the ATM kinase phosphorylates the p53 protein while it is being synthesized and offer a novel mechanism whereby a single synonymous mutation controls the stability and activity of the encoded protein. PMID- 30252119 TI - Zika Virus Infection during Pregnancy and Sensorineural Hearing Loss among Children at 3 and 24 Months Post-Partum. AB - Objective: The objectives of this study were to describe the findings of the auditory screening in children of mothers with ZIKV during pregnancy or suspicious of congenital ZIKV, and to determine whether hearing loss was in the first 2 years in life, regardless of whether microcephaly was also present. Methods: This is a cases report. The information was collected and recorded in a database between January 2016 and April 2018. We perform two auditory tests to 3 and 24 months of life. The study was developed in Aguachica (Cesar, Colombia). It is considered a high-risk area for ZIKV infection. Participants included children of mothers with confirmed ZIKV during pregnancy or suspicious of congenital ZIKV exposure of ZIKV infection during an epidemic period in a tropical area. We defined a positive case according to the epidemiological definition and clinical criteria based on maternal symptoms. However, other children of mothers without clinical signs of Zika were evaluated at the same time. The main outcome was the presence of sensorineural hearing loss. Results: The median age in the study group (n = 43) was 3.5 months (rank: 0-6) and the comparison group (n: 23, children of mothers without clinical signs of ZIKV) was 3 months (rank: 0-12). Screening hearing test was done using distortion product otoacustic emissions. At 3 months follow-up, children were evaluated using distortion product otoacustic emissions and automatized auditory brainstem response. None of the patients evaluated in this study were found to have sensorineural hearing loss. Conclusions: We did not find hearing loss during the first 2 years in the children whose mother showed Zika during pregnancy. We recommend these children must be assessed to closed because there is a high risk the hearing loss as it usually may occur with CMV. PMID- 30252120 TI - My Take on the Biopsychosocial Model of Patient-Centered Care. PMID- 30252121 TI - ? PMID- 30252122 TI - [Esophageal endoscopic submucosal dissection for the treatment early esophageal neoplasia: results from a reference center in Scandinavia]. AB - Endoscopic submucosal dissection (ESD) is an established and effective treatment modality for endoscopic resection of premalignant and early-stage malignant gastrointestinal lesions. Compared to endoscopic mucosal resection (EMR), ESD is generally associated with higher rates of en bloc, R0, and curative resections and lower rates of local recurrence. As in ESD the whole lesion is resected in one piece, it enables the best possible T-staging based on pathology assessment of the resected lesion. So far, there have been few reports of esophageal ESD in the West and none from Scandinavia. We aim to describe for the first time in Scandinavia, the implementation and results of ESD for the treatment of esophageal neoplasia, namely early esophageal squamous cell neoplasia (ESCN) and Barrett's esophageal neoplasia (BEN). PMID- 30252123 TI - [Common cold or whooping cough]. AB - By 2017 IVO has examined two cases with serious illnesses in two children under 6 months of age. In one case, the 4-week old child died. Factors that may have affected the treatment may have been lacking knowledge that the disease is present in society and requests to be restrictive with antibiotic treatment. The current disease cases occurred during a period when RS virus was common. In case of suspicion of whooping cough, prophylaxis and treatment should begin early for optimal effect. Prophylactic treatment of infants younger than 6 months should start without waiting for test results if you suspect that the child is exposed to whooping cough infection. PMID- 30252124 TI - ? PMID- 30252125 TI - Teacher-student interaction and lower secondary school students' situational engagement. AB - BACKGROUND: Prior research has shown that engagement plays a significant role in students' academic learning. AIMS: The present study sought to expand the current understanding of students' engagement by examining how situational engagement during a particular lesson is associated with the observed teacher-student classroom interactions (i.e., emotional support, instructional support, and classroom organization) in the same lesson. SAMPLE: The participants were 709 Grade 7 students (47.7% girls) from 59 classrooms in 26 lower secondary schools and 51 teachers. METHODS: The data consisted of 155 video-recorded lessons (90 language arts and 65 mathematics lessons) coded using the Classroom Assessment Scoring System - Secondary (CLASS-S) observational instrument. Students' self ratings of their situation-specific engagement were collected using the mobile based In Situations (InSitu) Instrument at the end of each lesson. The data were analyzed with cross-classified two-level hierarchical modelling. RESULTS AND CONCLUSIONS: The results indicated that emotional support in the classroom was positively associated with students' emotional engagement and help-seeking, whereas classroom organization was associated with students' behavioural and cognitive engagement. Overall, the findings provide novel evidence suggesting that students' engagement can be fostered by supportive teacher-student interactions. PMID- 30252126 TI - Calculations of second harmonic generation with radially polarized excitations by elliptical mirror focusing. AB - : Second harmonic generation (SHG) polarization intensity distribution illuminated with radially polarized beams by lens focusing appears two peaks, when the nonlinear optical coefficients dominate that is relevant to the transverse electric field components. Such two peaks pattern may result in ghosting and the decrement of imaging resolution. In this paper, an elliptical mirror based system is proposed in the case of radially polarized beams illumination for SHG. The calculated predictions and numerical simulations demonstrate that for radially polarized beams, the proportion of transverse field components at the focal plane under the condition of elliptical mirror focusing is 2.6 times smaller than that with lens focusing when its numerical aperture (NA) is 1. Furthermore, the full width at half maximum (FWHM) of the total field intensity profile is approximately 81% of that in a lens focusing system. Due to the enhancement of longitudinal components of incident field, the distribution of SHG polarization presents a single-peak pattern, in which two peaks can be observed with lens focusing. The SHG polarizations in collagen fiber, KTiOPO4 , and LiNbO3 have been numerical simulated and discussed in detail to verify the validity of the proposed method. LAY DESCRIPTION: A novel focusing mode for second harmonic generation (SHG) microscopy is described in this paper. In the case of radially polarized excitations, the SHG polarization distributions of some specimens appear two peaks pattern with traditional lens focusing. Such two peaks pattern may result in ghosting and the decrement of imaging resolution. By introducing elliptical mirror, the modulation of electric field at the focal plane can be realized. Thus, the distribution of SHG polarization is converted into a single-peak pattern which eliminates the ghosting and improves the spatial resolution on SHG images. This proposed method can be used for SHG in various materials and the full width at half maximum (FWHM) of SHG polarization will compress in different degrees. Besides, there is a significant improvement on signal-to-noise ratio in SHG imaging when an annular aperture illumination is applied. The focusing mode with elliptical mirror can also be utilized in other nonlinear optics areas such as polarized third harmonic generation (THG) measurements and two-photon fluorescence (TPF) microscopy. PMID- 30252127 TI - Annual Research Review: Developmental computational psychiatry. AB - Most psychiatric disorders emerge during childhood and adolescence. This is also a period that coincides with the brain undergoing substantial growth and reorganisation. However, it remains unclear how a heightened vulnerability to psychiatric disorder relates to this brain maturation. Here, we propose 'developmental computational psychiatry' as a framework for linking brain maturation to cognitive development. We argue that through modelling some of the brain's fundamental cognitive computations, and relating them to brain development, we can bridge the gap between brain and cognitive development. This in turn can lead to a richer understanding of the ontogeny of psychiatric disorders. We illustrate this perspective with examples from reinforcement learning and dopamine function. Specifically, we show how computational modelling deepens an understanding of how cognitive processes, such as reward learning, effort learning, and social learning might go awry in psychiatric disorders. Finally, we sketch the promises and limitations of a developmental computational psychiatry. PMID- 30252128 TI - Properties and Biotechnological Applications of Acyl-CoA:diacylglycerol Acyltransferase and Phospholipid:diacylglycerol Acyltransferase from Terrestrial Plants and Microalgae. AB - Triacylglycerol (TAG) is the major storage lipid in most terrestrial plants and microalgae, and has great nutritional and industrial value. Since the demand for vegetable oil is consistently increasing, numerous studies have been focused on improving the TAG content and modifying the fatty-acid compositions of plant seed oils. In addition, there is a strong research interest in establishing plant vegetative tissues and microalgae as platforms for lipid production. In higher plants and microalgae, TAG biosynthesis occurs via acyl-CoA-dependent or acyl-CoA independent pathways. Diacylglycerol acyltransferase (DGAT) catalyzes the last and committed step in the acyl-CoA-dependent biosynthesis of TAG, which appears to represent a bottleneck in oil accumulation in some oilseed species. Membrane bound and soluble forms of DGAT have been identified with very different amino acid sequences and biochemical properties. Alternatively, TAG can be formed through acyl-CoA-independent pathways via the catalytic action of membrane-bound phospholipid:diacylglycerol acyltransferase (PDAT). As the enzymes catalyzing the terminal steps of TAG formation, DGAT and PDAT play crucial roles in determining the flux of carbon into seed TAG and thus have been considered as the key targets for engineering oil production. Here, we summarize the most recent knowledge on DGAT and PDAT in higher plants and microalgae, with the emphasis on their physiological roles, structural features, and regulation. The development of various metabolic engineering strategies to enhance the TAG content and alter the fatty-acid composition of TAG is also discussed. PMID- 30252129 TI - Removal of carbon contamination in ETEM by introducing Ar during electron beam irradiation. AB - : Organic materials, including carbon, exist inside the transmission electron microscope (TEM) chamber and are adsorbed onto samples under observation during TEM. When these adsorbed organic materials are irradiated by an electron beam, the adsorbed gas is decomposed. Carbon atoms remain on the sample and bond with each other forming a material with an amorphous structure. Due to the carbon deposition on the observation area of the sample, it is contaminated and the TEM image quality is decreased. Ar was introduced into environmental TEM (ETEM) to purge organic material from the sample chamber to reduce contamination growth. After Ar gas was introduced, the contamination was gradually removed. The contamination removal rate was dependent on the Ar pressure. Moreover, it was clear that Ar was ionised by electron beam irradiation and the Ar ions were produced in the ETEM during electron beam irradiation. It is proposed that the Ar ions removed the carbon contamination. LAY DESCRIPTION: Organic materials, including carbon, exist inside the transmission electron microscope (TEM) chamber and are adsorbed onto samples under observation during TEM. When these adsorbed organic materials are irradiated by an electron beam, the adsorbed gas is decomposed. Carbon atoms remain on the sample and bond with each other forming a material with an amorphous structure. Due to the carbon deposition on the observation area of the sample, it is contaminated and the TEM image quality is decreased. Ar was introduced into environmental TEM (ETEM) to purge organic material from the sample chamber to reduce contamination growth. After Ar gas was introduced, the contamination was gradually removed. The contamination removal rate was dependent on the Ar pressure. Moreover, it was clear that Ar was ionised by electron beam irradiation and the Ar ions were produced in the ETEM during electron beam irradiation. It is proposed that the Ar ions removed the carbon contamination. PMID- 30252131 TI - Sialylation of vasorin by ST3Gal1 facilitates TGF-beta1 mediated tumor angiogenesis and progression. AB - ST3Gal1 is a key sialyltransferase which adds alpha2,3-linked sialic acid to substrates and generates core 1 O-glycan structure. Up-regulation of ST3Gal1 has been associated with worse prognosis of breast cancer patients. However, the protein substrates of ST3Gal1 implicated in tumor progression remain elusive. In this study, we demonstrated that ST3GAL1-silencing significantly reduced tumor growth along with a notable decrease in vascularity of MCF7 xenograft tumors. We identified vasorin (VASN) which was shown to bind TGF-beta1, as a potential candidate that links ST3Gal1 to angiogenesis. LC/MS/MS analysis of VASN secreted from MCF7, revealed that more than 80% of its O-glycans are sialyl-3T and disialyl-T. ST3GAL1-silencing or desialylation of VASN by neuraminidase enhanced its binding to TGF-beta1 by 2 to 3-fold and thereby dampening TGF-beta1 signaling and angiogenesis, as indicated by impaired tube formation of HUVECs, suppressed angiogenesis gene expression and reduced activation of Smad2 and Smad3 in HUVEC cells. Examination of 114 fresh primary breast cancer and their adjacent normal tissues showed that the expression levels of ST3Gal1 and TGFB1 were high in tumor part and the expression of two genes was positively correlated. Kaplan Meier survival analysis showed a significantly shorter relapse-free survival for those with lower expression VASN, notably, the combination of low VASN with high ST3GAL1 yielded even higher risk of recurrence (P=0.025, HR= 2.967, 95% CI=1.14 7.67). Since TGF-beta1 is known to transcriptionally activate ST3Gal1, our findings illustrated a feedback regulatory loop in which TGF-beta1 up-regulates ST3Gal1 to circumvent the negative impact of VASN. This article is protected by copyright. All rights reserved. PMID- 30252132 TI - Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer. AB - Expression of the epidermal growth factor ligands amphiregulin (AREG) and epiregulin (EREG) is positively correlated with a response to EGFR-targeted therapies in colorectal cancer. Gene-body methylation sites, which show a strong inverse correlation with AREG and EREG gene expression, were identified in cell lines using targeted 454 FLX-bisulfite sequencing and SIRPH analyses for AREG/EREG promoters and intragenic CpGs. Upon treatment of colorectal cancer cells with 5-aza-2'-desoxycytidine, methylation decreases at specific intragenic CpGs accompanied by upregulation of AREG and EREG gene expression. The same AREG gene-body methylation was also found in human colorectal cancer samples and is independent of KRAS and NRAS mutations. Methylation is specifically decreased in the tumor epithelial compartment as compared to stromal tissue and normal epithelium. Investigation of a promoter/enhancer function of the AREG exon 2 region revealed a potential promoter function in reverse orientation. Retrospective comparison of the predictive power of AREG gene-body methylation versus AREG gene expression using samples from colorectal cancer patients treated with anti-EGFR inhibitors with complete clinical follow-up revealed that AREG expression is superior to AREG gene methylation. AREG and EREG genes undergo a complex regulation involving both intragenic methylation and promoter-dependent control. PMID- 30252133 TI - Interaction of the EGFR signaling pathway with porcine cumulus oocyte complexes and oviduct cells in a coculture system. AB - It has become increasingly recognized that coculture has a beneficial effect on the in vitro maturation (IVM) of oocytes and embryo development in many species. However, these effects of coculture on IVM have been documented only for their positive conditioning roles without any evidence on the precise mechanisms underlying the action of coculture systems on the development of cumulus oocyte complexes (COCs). It has been suggested that the epidermal growth factor receptor (EGFR) signaling pathway is important for development of COCs, mediated by several epidermal growth factor (EGF)-like proteins with downstream mitogen activated protein kinase 1/3 signaling. Therefore, we hypothesized that canine oviduct cells (OCs) in a coculture system, which shows improvement of oocyte quality in several species, are associated with EGFR signaling by exposure to progesterone (P4; imitating its production before ovulation and its continuous increase while oocytes reside in the oviduct to complete maturation in dogs). We designed three experimental groups: control, OCs coculture exposed to P4, and OCs coculture without exposure to P4. The result showed that the OCs coculture exposed to P4 strongly expressed EGF-like proteins and significantly improved COCs and subsequent embryo development. Furthermore, the expression of EGFR related genes in cumulus cells and GDF9 and BMP15 in oocytes was upregulated in the P4-treated group. This study provides the first evidence that OCs exposed to P4 can induce strong expression of EGF-like proteins, and OCs effectively mediate improved porcine COCs development and subsequent embryo development by altering EGFR signaling related mRNA expression. PMID- 30252130 TI - Input-output organization of the mouse claustrum. AB - Progress in determining the precise organization and function of the claustrum (CLA) has been hindered by the difficulty in reliably targeting these neurons. To overcome this, we used a projection-based targeting strategy to selectively label CLA principal neurons. Combined with adeno-associated virus (AAV) and monosynaptic rabies tracing techniques, we systematically examined the pre synaptic input and axonal output of this structure. We found that CLA neurons projecting to retrosplenial cortex (RSP) collateralize extensively to innervate a variety of higher-order cortical regions. No subcortical labeling was found, with the exception of sparse terminals in the basolateral amygdala (BLA). This pattern of output was similar to cingulate- and visual cortex-projecting CLA neurons, suggesting a common targeting scheme among these projection-defined populations. Rabies virus tracing directly demonstrated widespread synaptic inputs to RSP projecting CLA neurons from both cortical and subcortical areas. The strongest inputs arose from classically defined limbic regions, including medial prefrontal cortex, anterior cingulate, BLA, ventral hippocampus, and neuromodulatory systems such as the dorsal raphe and cholinergic basal forebrain. These results suggest that the CLA may integrate information related to the emotional salience of stimuli and may globally modulate cortical state by broadcasting its output uniformly across a variety of higher cognitive centers. PMID- 30252134 TI - Use of hormonal contraceptives among immigrant women and their daughters in Norway: Data from the Norwegian Prescription Database. AB - INTRODUCTION: Immigrants and their offspring constitute 16.3% of the population in Norway. Knowledge about their contraceptive use is important in order to inform adequate family planning services. Prior research has shown less use of contraception among first-generation immigrants than among non-immigrant women. Our aim is to compare the use of hormonal contraceptives between immigrants and their adult daughters. MATERIAL AND METHODS: Information from the Norwegian Prescription Database on all hormonal contraceptives dispensed at all pharmacies in Norway in 2008 was merged with demographic, socioeconomic and immigration data from the National Population Register and information from the Regular General Practitioner Database and the Medical Birth Registry Norway. A total of 10 451 women aged 16-30 from 5 countries with relatively large numbers of immigrants and adult daughters living in Norway in 2008 were included in the study. Descriptive statistics and logistic regression analyses were conducted. The main outcome measure was use of any hormonal contraceptive. RESULTS: More daughters of immigrants from Vietnam compared with immigrant women from these countries (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.8-2.8) and Poland (OR 2.3, 95% CI: 1.6-3.3) used hormonal contraceptives. However, no adjusted differences between generations were detected for immigrants from Pakistan (OR 1.2, 95% CI 1.0-1.4), Morocco (OR 1.0, 95% CI 0.7-1.4) or Chile (OR 1.3, 95% CI 0.8-1.9). CONCLUSIONS: Further research should explore the reasons for heterogeneity in use of contraception among daughters of immigrants from different origins and explore whether daughters of immigrant mothers from some areas have unmet needs of contraception. PMID- 30252135 TI - Sex-biased gene expression in flowers, but not leaves, reveals secondary sexual dimorphism in Populus balsamifera. AB - Because sexual dimorphism in plants is often less morphologically conspicuous than in animals, studies of sex-biased gene expression may provide a quantitative metric to better address their commonality, molecular pathways, consistency across tissues and taxa, and evolution. The presence of sex-biased gene expression in tissues other than the androecium or gynoecium, termed secondary sexual characters, suggests that these traits arose after the initial evolution of dioecy. Patterns of sequence evolution may provide evidence of positive selection that drove sexual specialization. We compared gene expression in male and female flowers and leaves of Populus balsamifera to assess the extent of sex biased expression, and tested whether sex-biased genes exhibit elevated rates of protein evolution. Sex-biased expression was pervasive in floral tissue, but nearly absent in leaf tissue. Female-biased genes in flowers were associated with photosynthesis, whereas male-biased genes were associated with mitochondrial function. Sex-biased genes did not exhibit elevated rates of protein evolution, contrary to results from other studies in animals and plants. Our results suggest that the ecological and physiological constraints associated with the energetics of flowering, rather than sexual conflict, have probably shaped the differences in male and female gene expression in P. balsamifera. PMID- 30252136 TI - TGACG-BINDING FACTORs (TGAs) and TGA-interacting CC-type glutaredoxins modulate hyponastic growth in Arabidopsis thaliana. AB - TGACG-BINDING FACTORs (TGAs) control the developmental or defense-related processes. In Arabidopsis thaliana, the functions of at least TGA2 and PERIANTHIA (PAN) can be repressed by interacting with CC-type glutaredoxins, which have the potential to control the redox state of target proteins. As TGA1 can be redox modulated in planta, we analyzed whether some of the 21 CC-type glutaredoxins (ROXYs) encoded in the Arabidopsis genome can influence TGA1 activity in planta and whether the redox active cysteines of TGA1 are functionally important. We show that the tga1 tga4 mutant and plants ectopically expressing ROXY8 or ROXY9 are impaired in hyponastic growth. As expression of ROXY8 and ROXY9 is activated upon transfer of plants from hyponasty-inducing low light to normal light, they might interfere with the growth-promoting function of TGA1/TGA4 to facilitate reversal of hyponastic growth. The redox-sensitive cysteines of TGA1 are not required for induction or reversal of hyponastic growth. TGA1 and TGA4 interact with ROXYs 8, 9, 18, and 19/GRX480, but ectopically expressed ROXY18 and ROXY19/GRX480 do not interfere with hyponastic growth. Our results therefore demonstrate functional specificities of individual ROXYs for distinct TGAs despite promiscuous protein-protein interactions and point to different repression mechanisms, depending on the TGA/ROXY combination. PMID- 30252137 TI - EFFECTOR OF TRANSCRIPTION factors are novel plant-specific regulators associated with genomic DNA methylation in Arabidopsis. AB - Plant-specific EFFECTORS OF TRANSCRIPTION (ET) are characterised by a variable number of highly conserved ET repeats, which are involved in zinc and DNA binding. In addition, ETs share a GIY-YIG domain, involved in DNA nicking activity. It was hypothesised that ETs might act as epigenetic regulators. Here, methylome, transcriptome and phenotypic analyses were performed to investigate the role of ET factors and their involvement in DNA methylation in Arabidopsis thaliana. Comparative DNA methylation and transcriptome analyses in flowers and seedlings of et mutants revealed ET-specific differentially expressed genes and mostly independently characteristic, ET-specific differentially methylated regions. Loss of ET function results in pleiotropic developmental defects. The accumulation of cyclobutane pyrimidine dimers after ultraviolet stress in et mutants suggests an ET function in DNA repair. PMID- 30252138 TI - Quantitative profiling of cytokines and chemokines in DOCK8-deficient and atopic dermatitis patients. AB - BACKGROUND: Hyper-IgE syndromes (HIES) are a clinically overlapping, heterogeneous group of inborn errors of immunity characterized by elevated serum IgE level, eosinophilia, atopy, and immune dysregulation. Deficiency of DOCK8 protein is potentially a life-threatening autosomal recessive HIES and only curable with bone marrow transplantation. Hence, the diagnosis of DOCK8 deficiency is critical and should be sought at an early stage to initiate definitive therapy. METHODS: Serum samples from patients with DOCK8 deficiency and atopic dermatitis were profiled on a cytokine/chemokine panel for potential differential expression. RESULTS: CXCL10 and TNF-A were upregulated in DOCK8 patients when compared to AD, possibly contributing toward increased susceptibility to infections and cancer. In contrast, epidermal growth factor (EGF) was significantly downregulated in a subgroup of DOCK8-deficient and AD patients, while IL-31 expression was comparable between both DOCK8-deficient and AD cohorts, possibly contributing toward pruritus seen in both groups. CONCLUSION: This comprehensive cytokine profile in HIES patients reveals distinctive biomarkers that differentiate between the DOCK8-deficient and AD patients. The unique expression profile of various inflammatory cytokines in patients with DOCK8 deficiency vs atopic dermatitis likely reflects disease specific perturbations in multiple cellular processes and pathways leading to a predisposition to infections and allergies seen in these patients. These data agree with the role for EGF replacement therapy in EGF-deficient individuals with AD as well as DOCK8 deficiency through a potential shared pathway. In addition, these novel biomarkers may be potentially useful in distinguishing DOCK8 deficiency from AD allowing early-targeted treatment options. PMID- 30252139 TI - Folic Acid Supplementation Attenuates Chronic Hepatic Inflammation in High-Fat Diet Fed Mice. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. Hepatic inflammation is an important pathogenic mediator of NAFLD. There is currently no pharmacological agent approved for the treatment of NAFLD. Folic acid is a water-soluble B vitamin that has been shown to have lipid lowering and antioxidant effects. The objective of this study was to investigate the effect of folic acid supplementation on hepatic inflammation and to identify the underlying mechanisms. Male C57BL/6 J mice were fed a control diet (10% kcal fat), a high-fat diet (HFD) (60% kcal fat), or a HFD supplemented with folic acid (26 mg/kg diet) for 8 weeks. HFD feeding led to increased body mass gain, lipid accumulation, activation of transcription factor nuclear factor-kappaB (NF kappaB), and elevation of inflammatory cytokine gene expression in the liver. Folic acid supplementation attenuated hepatic lipid accumulation and aggregation of inflammatory foci induced by HFD feeding. This was associated with a significant reduction of NF-kappaB activation and inflammatory cytokine expression. These results suggest that the hepatoprotective effect of folic acid in NAFLD may be attributed, in part, to its anti-inflammatory action. PMID- 30252140 TI - The impact of dyspnea and threat of dyspnea on error processing. AB - Dyspnea (breathlessness) is a threatening and aversive bodily sensation and a major symptom of various diseases. It has been suggested to impair several aspects of functioning in affected patients, but experimental proof for this assumption is widely absent. Error processing is an important domain of functioning and has intensively been studied using electrophysiological measures. Specifically, the error-related negativity (ERN) has been suggested to reflect early performance monitoring and error detection, while the error positivity (Pe) has been linked to subsequent error awareness. So far, little is known about the effects of anticipated or perceived dyspnea on error processing. Therefore, in 49 healthy participants, we studied the effects of experimentally induced dyspnea and threat of dyspnea on the ERN/Pe and behavioral task performance. Participants performed the arrowhead version of the flanker task during three experimental conditions: an unloaded baseline condition, a dyspnea condition, and a threat of dyspnea condition. Dyspnea was induced by breathing through inspiratory resistive loads, while high-density EEG was continuously measured. No differences in task performance (reaction times, error rates) and ERN mean amplitudes were found between conditions. However, mean amplitudes for the Pe differed between conditions with smaller Pe amplitudes during threat of dyspnea compared to baseline and dyspnea conditions, with the latter two conditions showing no difference. These results may suggest that threat of dyspnea, but not dyspnea itself, reduces error awareness, while both seem to have no impact on early error processing and related behavioral performance. PMID- 30252142 TI - Assessment of Coagulase-Negative Staphylococci and Lactic Acid Bacteria Isolated from Portuguese Dry Fermented Sausages as Potential Starters Based on Their Biogenic Amine Profile. AB - : The aim of this study was to evaluate the decarboxylase activity of coagulase negative staphylococci (CNS) and lactic acid bacteria (LAB) involved in meat products fermentation, in order to characterize and select the strains most suitable to be used as safe starter cultures. Isolates were obtained from traditional Portuguese dry fermented meat sausages, identified by PCR and characterized according to their technological properties. Lactobacilli and enterococci were assessed for their bacteriocinogenic potential. Biogenic amines (BA) were screened by culture method and analyzed by RP-HPLC/UV. The screening method, compared with chromatographic analysis, was not reliable for CNS and LAB strains selection. Tyramine decarboxylase activity was present in CNS strains, with a slight production of amines. No other hazardous BA were produced. Among lactobacilli, moderate production of tyramine was related only to Lactobacillus curvatus, with some strains producing putrescine or 2-phenylethylamine. Enterococci were high and moderate producers of tyramine and 2-phenylethylamine, respectively. Staphylococcus xylosus, Staphylococcus equorum, and Staphylococcus carnosus, independent of their genetic and technological profiles and BA production, were adequate for use in meat products, according to the data. Lactobacillus plantarum and Lactobacillus sakei strains could also be selected for starters. PRACTICAL APPLICATION: The selection of coagulase-negative staphylococci and lactic acid bacteria (LAB) isolates were based on their production of biogenic amines in order to avoid this potential hazard production in meat products. The most suitable isolates could be used as safe starter cultures in meat products industry. The staphylococci and LAB selected will achieve particular organoleptic characteristics in meat products and bioprotection from pathogens. PMID- 30252141 TI - Associations Between Alcohol Involvement and Drive for Thinness and Body Dissatisfaction in Adolescent Twins: A Bivariate Twin Study. AB - BACKGROUND: Alcohol involvement has familial associations with bulimic symptoms (i.e., binge eating, inappropriate compensatory behaviors), with several studies indicating a genetic overlap between the two. It is unclear whether overlapping familial risk with alcohol involvement extends to other eating disorder symptoms. Understanding the genetic overlap between alcohol involvement and other eating disorder symptoms may aid in more targeted interventions for comorbid alcohol use eating disorder symptoms. Thus, we investigated associations between alcohol involvement and 2 core eating disorder symptoms: drive for thinness and body dissatisfaction in adolescent female and male twins. METHODS: We assessed 3 levels of alcohol involvement: alcohol use in the last month, having ever been intoxicated, and alcohol intoxication frequency via self-report. The Eating Disorder Inventory-II assessed drive for thinness and body dissatisfaction. Sex specific biometrical twin modeling examined the genetic overlap between alcohol involvement and eating disorder symptoms. RESULTS: Phenotypic associations between alcohol involvement, drive for thinness, and body dissatisfaction were significantly greater in girls compared with boys. A majority of the associations between alcohol involvement, drive for thinness, and body dissatisfaction in girls, but not boys, met our threshold for twin modeling (phenotypic r > 0.20). Moderate genetic correlations were observed between the 3 aspects of alcohol involvement and drive for thinness. Moderate genetic correlations were observed between alcohol use and intoxication frequency and body dissatisfaction. CONCLUSIONS: Together with the literature on alcohol involvement and bulimic symptoms, these findings suggest a generalized association between alcohol involvement and eating disorder symptoms in girls, whereas this association may be symptom specific in boys. Genetic correlations indicate that the amount and direction of this genetic overlap differs across specific symptoms. When intervening on comorbid alcohol involvement and eating disorder symptoms, it may be important to target-specific eating disorder symptoms. PMID- 30252143 TI - Independent and Joint-GWAS for growth traits in Eucalyptus by assembling genome wide data for 3373 individuals across four breeding populations. AB - Genome-wide association studies (GWAS) in plants typically suffer from limited statistical power. An alternative to the logistical and cost challenge of increasing sample sizes is to gain power by meta-analysis using information from independent studies. We carried out GWAS for growth traits with six single-marker models and regional heritability mapping (RHM) in four Eucalyptus breeding populations independently and by Joint-GWAS, using gene and segment-based models, with data for 3373 individuals genotyped with a communal EUChip60KSNP platform. While single-single nucleotide polymorphism (SNP) GWAS hardly detected significant associations at high-stringency in each population, gene-based Joint GWAS revealed nine genes significantly associated with tree height. Associations detected using single-SNP GWAS, RHM and Joint-GWAS set-based models explained on average 3-20% of the phenotypic variance. Whole-genome regression, conversely, captured 64-89% of the pedigree-based heritability in all populations. Several associations independently detected for the same SNPs in different populations provided unprecedented GWAS validation results in forest trees. Rare and common associations were discovered in eight genes involved in cell wall biosynthesis and lignification. With the increasing adoption of genomic prediction of complex phenotypes using shared SNPs and much larger tree breeding populations, Joint GWAS approaches should provide increasing power to pinpoint discrete associations potentially useful toward tree breeding and molecular applications. PMID- 30252144 TI - Comparing Arabidopsis receptor kinase and receptor protein-mediated immune signaling reveals BIK1-dependent differences. AB - Pattern recognition receptors (PRRs) sense microbial patterns and activate innate immunity against attempted microbial invasions. The leucine-rich repeat receptor kinases (LRR-RK) FLS2 and EFR, and the LRR receptor protein (LRR-RP) receptors RLP23 and RLP42, respectively, represent prototypical members of these two prominent and closely related PRR families. We conducted a survey of Arabidopsis thaliana immune signaling mediated by these receptors to address the question of commonalities and differences between LRR-RK and LRR-RP signaling. Quantitative differences in timing and amplitude were observed for several early immune responses, with RP-mediated responses typically being slower and more prolonged than those mediated by RKs. Activation of RLP23, but not FLS2, induced the production of camalexin. Transcriptomic analysis revealed that RLP23-regulated genes represent only a fraction of those genes differentially expressed upon FLS2 activation. Several positive and negative regulators of FLS2-signaling play similar roles in RLP23 signaling. Intriguingly, the cytoplasmic receptor kinase BIK1, a positive regulator of RK signaling, acts as a negative regulator of RP type immune receptors in a manner dependent on BIK1 kinase activity. Our study unveiled unexpected differences in two closely related receptor systems and reports a new negative role of BIK1 in plant immunity. PMID- 30252147 TI - Expression and metabolic activity of flavin-containing monooxygenase 1 in cynomolgus macaque kidney. AB - Flavin-containing monooxygenase 1 (FMO1) largely remains to be characterized in cynomolgus macaque kidney. Immunoblotting showed expression of cynomolgus FMO1 in kidneys where activities of FMO1 (benzydamine N-oxygenation) were detected. No sex differences were observed in their contents or activities. These results suggest the functional role of cynomolgus FMO1 in kidney. PMID- 30252145 TI - Minimizing resurgence of destructive behavior using behavioral momentum theory. AB - The resurgence of destructive behavior can occur during functional communication training (FCT) if the alternative response contacts a challenge (e.g., extinction). Behavioral momentum theory (BMT) suggests that refinements to FCT could mitigate resurgence of destructive behavior during periods of extinction. Following a functional analysis and treatment with FCT, we combined three refinements to FCT (i.e., the use of a lean schedule of reinforcement for destructive behavior during baseline, a lean schedule for the alternative response during FCT, and an increase in the duration of treatment) and compared the magnitude of resurgence relative to a condition in which FCT was implemented in a traditional manner. Results suggested that the combination of these three refinements to FCT was successful in decreasing the resurgence of destructive behavior during an extinction challenge. We discuss the implications of these findings, as well as areas for future research. PMID- 30252146 TI - Population Pharmacokinetics of Lopinavir/Ritonavir: Changes Across Formulations and Human Development From Infancy Through Adulthood. AB - Lopinavir/ritonavir (LPV/r) is recommended by the World Health Organization as first-line treatment for HIV-infected infants and young children. We performed a composite population pharmacokinetic (PK) analysis on LPV plasma concentration data from 6 pediatric and adult studies to determine maturation and formulation effects from infancy to adulthood. Intensive PK data were available for infants, children, adolescents, and adults (297 intensive profiles/1662 LPV concentrations). LPV PK data included 1 adult, 1 combined pediatric-adult, and 4 pediatric studies (age 6 weeks to 63 years) with 3 formulations (gel-capsule, liquid, melt-extrusion tablets). LPV concentrations were modeled using nonlinear mixed effects modeling (NONMEM v. 7.3; GloboMax, Hanover, Maryland) with a one compartment semiphysiologic model. LPV clearance was described by hepatic plasma flow (QHP ) times hepatic extraction (EH ), with EH estimated from the PK data. Volume was scaled by linear weight (WT/70)1.0 . Bioavailability was assessed separately as a function of hepatic extraction and the fraction absorbed from the gastrointestinal tract. The absorption component of bioavailability increased with age and tablet formulation. Monte Carlo simulations of the final model using current World Health Organization weight-band dosing recommendations demonstrated that participants younger than 6 months of age had a lower area under the drug concentration-time curve (94.8 vs >107.4 MUg hr/mL) and minimum observed concentration of drug in blood plasma (5.0 vs > 7.1 MUg/mL) values compared to older children and adults. Although World Health Organization dosing recommendations include a larger dosage (mg/m2 ) in infants to account for higher apparent clearance, they still result in low LPV concentrations in many infants younger than 6 months of age receiving the liquid formulation. PMID- 30252148 TI - A Bayesian latent class approach for EHR-based phenotyping. AB - Phenotyping, ie, identification of patients possessing a characteristic of interest, is a fundamental task for research conducted using electronic health records. However, challenges to this task include imperfect sensitivity and specificity of clinical codes and inconsistent availability of more detailed data such as laboratory test results. Despite these challenges, most existing electronic health records-derived phenotypes are rule-based, consisting of a series of Boolean arguments informed by expert knowledge of the disease of interest and its coding. The objective of this paper is to introduce a Bayesian latent phenotyping approach that accounts for imperfect data elements and missing not at random missingness patterns that can be used when no gold-standard data are available. We conducted simulation studies to compare alternative phenotyping methods under different patterns of missingness and applied these approaches to a cohort of 68 265 children at elevated risk for type 2 diabetes mellitus (T2DM). In simulation studies, the latent class approach had similar sensitivity to a rule-based approach (95.9% vs 91.9%) while substantially improving specificity (99.7% vs 90.8%). In the PEDSnet cohort, we found that biomarkers and clinical codes were strongly associated with latent T2DM status. The latent T2DM class was also strongly predictive of missingness in biomarkers. Glucose was missing in 83.4% of patients (odds ratio for latent T2DM status = 0.52) while hemoglobin A1c was missing in 91.2% (odds ratio for latent T2DM status = 0.03 ), suggesting missing not at random missingness. The latent phenotype approach may substantially improve on rule-based phenotyping. PMID- 30252149 TI - Inverse relationship of serum albumin to the risk of venous thromboembolism among acutely ill hospitalized patients: Analysis from the APEX trial. AB - Hypoalbuminemia is a common finding and independent predictor for unfavorable prognosis. The prognostic value of albumin measurement for short-term VTE prediction in hospitalized patients remains unclear. In the APEX trial (ClinicalTrials.gov identifier: NCT01583218), medical inpatients were randomized to receive either extended-duration betrixaban or shorter-duration enoxaparin and followed for 77 days. Baseline albumin concentrations were obtained in 7266 subjects with evaluable VTE endpoints. The association of baseline albumin to VTE was assessed, with adjustment for patient characteristics, thromboprophylaxis, and biomarkers for fibrinolysis and inflammation (ie, D-dimer and C-reactive protein [CRP]). VTE risk refinement was evaluated by incorporation of albumin to well-validated risk assessment models. A stepwise increase in the risk of VTE (P < .0001) was observed with lower levels of albumin. Patients at the bottom albumin quartile (<35 g/L) had a two-fold greater odds for developing VTE compared with the top quartile (>=42 g/L) (OR = 2.119 [95% CI, 1.592-2.820]; adjusted OR = 2.079 [1.485-2.911]). The odds for VTE increased by 1.368 (95% CI, 1.240-1.509) times per SD decrement of albumin (5.24 g/L). Compared with the propensity score-matched pairs of patients with albumin >=35 g/L, patients with albumin <35 g/L had a greater risk of VTE (OR = 1.623 [1.260-2.090]; adjusted OR = 1.658 [1.209-2.272]). Albumin measurement also refined VTE risk discrimination and reclassification after inclusion in the risk assessment models. In conclusion, acutely ill hospitalized patients with low serum albumin had an increased VTE risk through 77 days. VTE risk assessment models for medical inpatients should consider incorporation of baseline albumin measurement. PMID- 30252150 TI - Inflammatory markers in women with postpartum depressive symptoms. AB - Postpartum depression (PPD) is a devastating disorder affecting not only more than 10% of all women giving birth, but also the baby, the family, and the society. Compiling evidence suggests the involvement of the immune system in the pathophysiology of major depression; yet, the immune response in perinatal depression is not as well studied. The aim of this study was to investigate the alterations in peripheral levels of inflammatory biomarkers in 169 Swedish women with and without depressive symptoms according to the Edinburgh postnatal depression scale or the M.I.N.I neuropsychiatric interview at eight weeks postpartum. Among the 70 markers analyzed with multiplex proximity extension assay, five were significantly elevated in women with postpartum depressive symptoms in the adjusted LASSO logistic regression analysis: Tumor necrosis factor ligand superfamily member (TRANCE) (OR-per 1 SD increase = 1.20), Hepatocyte growth factor (HGF) (OR = 1.17) Interleukin (IL)-18 (OR = 1.06), Fibroblast growth factor 23 (FGF-23) (OR = 1.25), and C-X-C motif chemokine 1 (CXCL1) (OR 1.11). These results indicate that women with PPD have elevated levels of some inflammatory biomarkers. It is, therefore, plausible that PPD is associated with a compromised adaptability of the immune system. PMID- 30252151 TI - Caring science research in the ambulance services: an integrative systematic review. AB - BACKGROUND: The ambulance services are associated with emergency medicine, traumatology and disaster medicine, which is also reflected in previous research. Caring science research is limited and, since no systematic reviews have yet been produced, its focus is unclear. This makes it difficult for researchers to identify current knowledge gaps and clinicians to implement research findings. AIM: This integrative systematic review aims to describe caring science research content and scope in the ambulance services. DATA SOURCES: Databases included were MEDLINE (PubMed), CINAHL, Web of Science, ProQDiss, LibrisDiss and The Cochrane Library. The electronic search strategy was carried out between March and April 2015. The review was conducted in line with the standards of the PRISMA statement, registration number: PROSPERO 2016:CRD42016034156. REVIEW METHODS: The review process involved problem identification, literature search, data evaluation, data analysis and reporting. Thematic data analysis was undertaken using a five-stage method. Studies included were evaluated with methodological and/or theoretical rigour on a 3-level scale, and data relevance was evaluated on a 2-level scale. RESULTS: After the screening process, a total of 78 studies were included. The majority of these were conducted in Sweden (n = 42), fourteen in the United States and eleven in the United Kingdom. The number of study participants varied, from a case study with one participant to a survey with 2420 participants, and 28 (36%) of the studies were directly related to patients. The findings were identified under the themes: Caregiving in unpredictable situations; Independent and shared decision-making; Public environment and patient safety; Life-changing situations; and Ethics and values. CONCLUSION: Caring science research with an explicit patient perspective is limited. Areas of particular interest for future research are the impact of unpredictable encounters on openness and sensitivity in the professional-patient relation, with special focus on value conflicts in emergency situations. PMID- 30252152 TI - Dietary supplementation with Rehmannia glutinosa affects the composition of intestinal microorganisms in common carp. AB - A feeding experiment was conducted to investigate the effects of Rehmannia glutinosa (RG) on the bacterial, archaeal, and fungal community composition in the gut of common carp (Cyprinus carpio L.). Common carp were given a control diet and an RG-supplemented diet (basal diet plus 4% prepared Rehmannia root powder) over a period of 80 days. Our results indicated that the bacteria Fusobacteria, Proteobacteria, and Bacteroidetes; the archaea Crenarchaeota and Euryarchaeota; and the fungi Basidiomycota are the most abundant microbial taxa in the gut of common carp. Compared with the common carp fed a control diet, the common carp fed an RG-supplemented diet contained a higher content of Akkermansia sp., and a lower proportion of Aeromonas sp. These results indicate that the consumption of a diet containing RG can lead to the accumulation of more beneficial microorganisms while inhibiting the growth of potential pathogens. Moreover, Crenarchaeota, the methanogenic, and Basidiomycota were detected in this study, these populations may be of high physiological relevance in carp because they have been implicated in human health and disease. Our results suggest that an RG-supplemented diet changes the intestinal microbial composition of common carp, which could have positive effects on the immune response of carp. PMID- 30252153 TI - Modeling time-varying effects of multilevel risk factors of hospitalizations in patients on dialysis. AB - For chronic dialysis patients, a unique population requiring continuous medical care, methodologies to monitor patient outcomes, such as hospitalizations, over time, after initiation of dialysis, are of particular interest. Contributing to patient hospitalizations is a number of multilevel covariates such as demographics and comorbidities at the patient level and staffing composition at the dialysis facility level. We propose a varying coefficient model for multilevel risk factors (VCM-MR) to study the time-varying effects of covariates on patient hospitalization risk as a function of time on dialysis. The proposed VCM-MR also includes subject-specific random effects to account for within subject correlation and dialysis facility-specific fixed effect varying coefficient functions to allow for the modeling of flexible time-varying facility specific risk trajectories. An approximate EM algorithm and an iterative Newton Raphson approach are proposed to address the challenge of estimation of high dimensional parameters (varying coefficient functions) for thousands of dialysis facilities in the United States. The proposed modeling allows for comparisons between time-varying effects of multilevel risk factors as well as testing of facility-specific fixed effects. The method is applied to model hospitalization risk using the rich hierarchical data available on dialysis patients initiating dialysis between January 1, 2006 and December 31, 2008 from the United States Renal Data System, a large national database, where 331 443 hospitalizations over time are nested within patients, and 89 889 patients are nested within 2201 dialysis facilities. Patients are followed-up until December 31, 2013, where the follow-up time is truncated five years after the initiation of dialysis. Finite sample properties are studied through extensive simulations. PMID- 30252154 TI - I-Tiao-Gung extract through its active component daidzin improves cyclophosphamide-induced bladder dysfunction in rat model. AB - AIMS: We explored the therapeutic potential of intragastric administration traditional Chinese medicine Glycine tomentella Hayata (I-Tiao-Gung, ITG) extract and its active component Daidzin on cyclophosphamide (CYP)-induced cystitis and bladder hyperactivity in rats. METHODS: Female Wistar rats were divided into control, CYP (200 mg/kg), CYP + ITG (1.17 g/kg/day), CYP + Daidzin (12.5 mg/kg/day), and 1 week of ITG preconditioning with CYP (ITG + CYP) groups. We determined the trans cystometrogram associated with external urethral sphincter electromyogram, and the expression of M2 and M3 muscarinic and P2 * 2 and P2 * 3 purinergic receptors by Western blot in these animals. RESULTS: ITG extract contains 1.07% of Daidzin and 0.77% of Daidzein by high-performance liquid chromatography. Daidzin was more efficient than Daidzein in scavenging H2 O2 activity by a chemiluminescence analyzer. CYP induced higher frequency, shorter intercontraction interval, lower maximal voiding pressure, lower threshold pressure, and Phase-2 emptying contraction with a depressed external urethral sphincter electromyogram activity, and hemorrhagic cystitis in the bladders. The altered parameters by CYP were significantly improved in CYP + ITG, CYP + Daidzin, and ITG + CYP groups. The P2 * 2 and P2 * 3 expressions were significantly upregulated in CYP group, but were depressed in CYP + ITG, CYP + Daidzin, and ITG + CYP groups. The M2 expression was not significantly different among these five groups. The M3 expression was significantly upregulated in CYP group, but was significantly depressed in CYP + ITG, CYP + Daidzin, and ITG + CYP groups. CONCLUSIONS: These data suggest that ITG extract through its active component Daidzin effectively improved CYP-induced cystitis by the action of restoring Phase 2 activity and inhibiting the expressions of P2 * 2, P2 * 3, and M3 receptors. PMID- 30252155 TI - Validation of pressure drop assessment using 4D flow MRI-based turbulence production in various shapes of aortic stenoses. AB - PURPOSE: To validate pressure drop measurements using 4D flow MRI-based turbulence production in various shapes of stenotic stenoses. METHODS: In vitro flow phantoms with seven different 3D-printed aortic valve geometries were constructed and scanned with 4D flow MRI with six-directional flow encoding (ICOSA6). The pressure drop through the valve was non-invasively predicted based on the simplified Bernoulli, the extended Bernoulli, the turbulence production, and the shear-scaling methods. Linear regression and agreement of the predictions with invasively measured pressure drop were analyzed. RESULTS: All pressure drop predictions using 4D Flow MRI were linearly correlated to the true pressure drop but resulted in different regression slopes. The regression slope and 95% limits of agreement for the simplified Bernoulli method were 1.35 and 11.99 +/- 21.72 mm Hg. The regression slope and 95% limits of agreement for the extended Bernoulli method were 1.02 and 0.74 +/- 8.48 mm Hg. The regression slope and 95% limits of agreement for the turbulence production method were 0.89 and 0.96 +/- 8.01 mm Hg. The shear-scaling method presented good correlation with an invasively measured pressure drop, but the regression slope varied between 0.36 and 1.00 depending on the shear-scaling coefficient. CONCLUSION: The pressure drop assessment based on the turbulence production method agrees well with the extended Bernoulli method and invasively measured pressure drop in various shapes of the aortic valve. Turbulence-based pressure drop estimation can, as a complement to the conventional Bernoulli method, play a role in the assessment of valve diseases. PMID- 30252156 TI - Zero-gradient-excitation ramped hybrid encoding (zGRF -RHE) sodium MRI. AB - PURPOSE: Fast bi-exponential transverse signal decay compounds sodium image quality. This work aims at enhancing image characteristics using a special case of ramped hybrid encoding (RHE). Zero-gradient-excitation (zGRF )-RHE provides (1) gradient-free excitation for high flip angle, artifact-free excitation profiles and (2) gradient ramping during dead-time for the optimization of encoding time (tenc ) to reduce T2* signal decay influence during acquisition. METHODS: Radial zGRF -RHE and standard radial UTE were investigated over a range of receiver bandwidths in simulations, phantom and in vivo brain experiments. Central k-space in zGRF -RHE was acquired through single point measurements at the minimum achievable TE. T2* blurring artifacts and image SNR and CNR were assessed. RESULTS: zGRF -RHE enabled 90 degrees flip angle artifact-free excitation, whereas gradient pre-ramping provided greater tenc efficiency for any readout bandwidths. Experiments confirmed simulation results, revealing sharper edge characteristics particularly at short readout durations (TRO ). Significant SNR improvements of up to 4.8% were observed for longer TRO . CONCLUSION: zGRF RHE allows for artifact-free high flip angle excitation with time-efficient encoding improving on image characteristics. This hybrid encoding concept with gradient pre-ramping is trajectory independent and can be introduced in any center-out UTE trajectory design. PMID- 30252157 TI - Wave-LORAKS: Combining wave encoding with structured low-rank matrix modeling for more highly accelerated 3D imaging. AB - PURPOSE: Wave-CAIPI is a novel acquisition approach that enables highly accelerated 3D imaging. This paper investigates the combination of Wave-CAIPI with LORAKS-based reconstruction (Wave-LORAKS) to enable even further acceleration. METHODS: LORAKS is a constrained image reconstruction framework that can impose spatial support, smooth phase, sparsity, and/or parallel imaging constraints. LORAKS requires minimal prior information, and instead uses the low rank subspace structure of the raw data to automatically learn which constraints to impose and how to impose them. Previous LORAKS implementations addressed 2D image reconstruction problems. In this work, several recent advances in structured low-rank matrix recovery were combined to enable large-scale 3D Wave LORAKS reconstruction with improved quality and computational efficiency. Wave LORAKS was investigated by retrospective subsampling of two fully sampled Wave encoded 3D MPRAGE datasets, and comparisons were made against existing Wave reconstruction approaches. RESULTS: Results show that Wave-LORAKS can yield higher reconstruction quality with 16*-accelerated data than is obtained by traditional Wave-CAIPI with 9*-accerated data. CONCLUSIONS: There are strong synergies between Wave encoding and LORAKS, which enables Wave-LORAKS to achieve higher acceleration and more flexible sampling compared to Wave-CAIPI. PMID- 30252158 TI - On locating the metaparadigm concept environment within caring science. PMID- 30252159 TI - DelPhiPKa: Including salt in the calculations and enabling polar residues to titrate. AB - DelPhiPKa is a widely used and unique approach to compute pKa 's of ionizable groups that does not require molecular surface to be defined. Instead, it uses smooth Gaussian-based dielectric function to treat computational space via Poisson-Boltzmann equation (PBE). Here, we report an expansion of DelPhiPKa functionality to enable inclusion of salt in the modeling protocol. The method considers the salt mobile ions in solvent phase without defining solute-solvent boundary. Instead, the ions are penalized to enter solute interior via a desolvation penalty term in the Boltzmann factor in the framework of PBE. Hence, the concentration of ions near the protein is balanced by the desolvation penalty and electrostatic interactions. The study reveals that correlation between experimental and calculated pKa 's is improved significantly by taking into consideration the presence of salt. Furthermore, it is demonstrated that DelphiPKa reproduces the salt sensitivity of experimentally measured pKa 's. Another new development of DelPhiPKa allows for computing the pKa 's of polar residues such as cysteine, serine, threonine and tyrosine. With this regard, DelPhiPKa is benchmarked against experimentally measured cysteine and tyrosine pKa 's and for cysteine it is shown to outperform other existing methods (DelPhiPKa RMSD of 1.73 vs RMSD between 2.40 and 4.72 obtained by other existing pKa prediction methods). PMID- 30252160 TI - Morphologic variations of the dorsal tarsometatarsal ligaments of the foot. AB - This study investigated the anatomical features of the dorsal tarsometatarsal ligaments of the foot for the purpose of analyzing the ligamentous components and classifying their types. Fifty embalmed cadaveric feet from 27 adult cadavers were dissected in this study. The dorsal tarsometatarsal ligaments comprised nine components (first cuneiform-first metatarsal, dCn1-M1; first cuneiform-second metatarsal, dCn1-M2; second cuneiform-second metatarsal, dCn2-M2; third cuneiform second metatarsal, dCn3-M2; third cuneiform-third metatarsal, dCn3-M3; third cuneiform-fourth metatarsal, dCn3-M4; cuboid-third metatarsal, dCb-M3; cuboid fourth metatarsal, dCb-M4; cuboid-fifth metatarsal, dCb-M5). The dCn3-M4 and dCb M3 had not been previously reported. The dCn1-M1, dCn1-M2, dCn3-M2, dCn3-M4, and dCb-M3 had only one band, the dCn2-M2 had two bands, and the others had one or two bands. The ligaments originating from Cb attached simultaneously to M3 and M4 (4/50), M4 and M5 (7/50), or M3 and M5 (5/50), which were Y-shaped (dCb-M3, 4 and dCb-M3, 5), or V-shaped (dCb-M4, 5). The dorsal tarsometatarsal ligaments were classified into four types according to the presence of each component. In Type I (52%), Type II (36%), Type III (10%), and Type IV (2%), all components were observed except for one, two, three, and four components, respectively. The dimensions of each component were measured, and as a result the dCn1-M1 was found to be the widest and longest of the dorsal ligaments while the dCn1-M2 was found to be the thickest. The dorsal tarsometatarsal ligaments comprised nine components and were classified into four types. Clin. Anat., 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30252161 TI - A Trinuclear Iron(III) Complex of a Triple Noninnocent Ligand for Spin-Structured Molecular Conductors. AB - N,N',N'',N''',N'''',N'''''-(Triphenylene-2,3,6,7,10,11-hexayl)hexapicolinamide (H6 hptp), a triangular ligand containing three noninnocent coordination sites, and its trinuclear iron(III) complex (PPh4 )3 [FeIII 3 (hptp)6 (CN)6 ] were prepared. In this complex, three low-spin Fe3+ ions are coordinated by the triangular hptp6- bridging ligand at its apices. Cyclic voltammetry of (PPh4 )3 [FeIII 3 (hptp)6 (CN)6 ] in PhCN solution showed one reductive wave for 3 Fe2+ /3 Fe3+ and three oxidative waves for the hptp6- ligand. The controlled-potential electronic spectra of the solution presented broad absorption bands in the near IR (NIR) region for oxidations because a pi-radical is generated on the hptp6- ligand. The EPR spectra of frozen solutions also showed large oxidization-state dependent differences caused by the strong exchange interactions between the electrons in the d orbitals of the Fe3+ ions and those of the pi-radicals in the hptp6- ligand. The electronic and magnetic states of the oxidized species were investigated using density functional theory. PMID- 30252163 TI - Enhanced insulin production and reprogramming efficiency of mesenchymal stem cells derived from porcine pancreas using suitable induction medium. AB - BACKGROUND: Genetic reprogramming is a powerful method for altering cell properties and inducing differentiation. However, even if the same gene is reprogrammed, the results vary among cells. Therefore, a better possible strategy involves treating cells with factors that further stimulate differentiation while using stem cells with the same tissue origin. This study aimed to increase induction efficiency and insulin production in reprogrammed cells using a combination of factors that promote cell differentiation. METHODS: Porcine pancreatic cells were cultured to obtain mesenchymal stem cells expressing pancreatic cell-specific markers through sequential passages. The characteristics of these cells were identified, and the M3 gene (Pdx1, Ngn3, MafA) was reprogrammed to induce differentiation into insulin-producing cells. Additionally, the differentiation efficiency of insulin-producing cells was compared by treating reprogrammed cells with a differentiation-promoting factor. RESULTS: Mesenchymal stem cells isolated from porcine pancreatic tissues expressed exocrine cell markers, including amylase and cytokeratin 18, and most cells continuously expressed the beta cell transcription factors Ngn3 and NeuroD. Reprogramming of the M3 gene resulted in differentiation into insulin-producing cells. Moreover, significantly increased insulin and glucagon expressions were observed in the suitable induction medium, and the characteristic beta cell transcription factors Pdx1, Ngn3, and MafA were expressed at levels as high as those in pancreatic islet cells. CONCLUSIONS: Differentiation into insulin producing cells represents an alternative therapy for insufficient pancreatic islet cells when treating diabetes. Therefore, cells with the characteristics of the target cell should be used to improve differentiation efficiency by creating an environment that promotes reprogramming and differentiation. PMID- 30252162 TI - Enhancing the n-Type Conductivity and Thermoelectric Performance of Donor Acceptor Copolymers through Donor Engineering. AB - Conjugated polymers with high thermoelectric performance enable the fabrication of low-cost, large-area, low-toxicity, and highly flexible thermoelectric devices. However, compared to their p-type counterparts, n-type polymer thermoelectric materials show much lower performance, which is largely due to inefficient doping and a much lower conductivity. Herein, it is reported that the development of a donor-acceptor (D-A) polymer with enhanced n-doping efficiency through donor engineering of the polymer backbone. Both a high n-type electrical conductivity of 1.30 S cm-1 and an excellent power factor (PF) of 4.65 uW mK-2 are obtained, which are the highest reported values among D-A polymers. The results of multiple characterization techniques indicate that electron withdrawing modification of the donor units enhances the electron affinity of the polymer and changes the polymer packing orientation, leading to substantially improved miscibility and n-doping efficiency. Unlike previous studies in which improving the polymer-dopant miscibility typically resulted in lower mobilities, the strategy maintains the mobility of the polymer. All these factors lead to prominent enhancement of three orders magnitude in both the electrical conductivity and the PF compared to those of the non-engineered polymer. The results demonstrate that proper donor engineering can enhance the n-doping efficiency, electrical conductivity, and thermoelectric performance of D-A copolymers. PMID- 30252164 TI - A morphometric analysis of developmental instability in children born with unilateral cleft lip and palate. AB - Unilateral cleft lip and palate (UCLP) is a congenital deformity that occurs due to inadequate merging of the nasal and maxillary prominences during fetal development. Randomly distributed bilateral asymmetries known as fluctuating asymmetry (FA) occur in normally symmetric organisms when evolved mechanisms of developmental stability or equilibrium are disturbed by genetic, environmental, or unknown factors. Here, we hypothesize that facial skeleton FA will be increased in a sample of individuals born with UCLP (n = 24) relative to sex- and age-matched controls (n = 24). To test this hypothesis, 23 anatomical landmarks were measured on individual anonymized cone-beam computerized tomography (CBCT) images in children and adolescents (7-17 years). For each individual, 81 pairs of linear distances were used to estimate FAs across the face. To explore sample variation and statistical differences, a principal components analysis and Euclidean Distance Matrix Analysis multivariate bootstrap approach were carried out. Samples show some separation in multivariate space with 44.44% of FA differences being significantly different. The magnitude of FA was larger in the UCLP sample for every significant measurement. The magnitude of significant FA is highest near regions derived from the maxillary and nasal prominences, such as the nasal aperture. These results are useful for medical and dental practitioners when developing treatment options for children and adolescents with UCLP. Clin. Anat., 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30252166 TI - Prognostic values of long noncoding RNA PVT1 in various carcinomas: An updated systematic review and meta-analysis. AB - Cancers have been a worldwide health problem with a high mortality rate, but ideal biomarkers are not available to effectively screen and diagnose patients. Currently, an increasing number of long noncoding RNAs have been reported to be abnormally expressed in human carcinomas and play a vital role in tumourigenesis. Plasmacytoma variant translocation 1 (PVT1) is upregulated in various carcinomas, and its overexpression is associated with poor survival in cancer patients. We conduct an updated meta-analysis to determine its potential in prognosis for tumours. In total, 14 studies comprising 2435 patients were enrolled according to Reporting Recommendations for Tumour Marker Prognostic Studies guidelines. High PVT1 expression indicated poor overall survival (hazard ratio [HR] = 1.98, 95% confidence interval [CI]: 1.62-2.42, P < 0.00001) and disease-free survival (HR = 1.63, 95% CI: 1.45-1.84, P < 0.00001). Additionally, increased PVT1 expression was positively associated with lymphatic node metastasis (odd ratio [OR] = 2.87, 95% CI: 1.66-4.96, P = 0.0002), distant metastasis (OR = 2.47, 95% CI: 1.74-3.50, P < 0.00001), advanced tumour-node-metastasis stages (OR = 2.59, 95% CI: 1.38 4.88, P = 0.003). New findings highlight that PVT1 acts as competing RNA to microRNAs to protect mRNAs from miRNAs repression. Therefore, we also discuss PVT1-related microRNAs and their interaction in tumourigenesis. In conclusion, PVT1 may be a potential biomarker of poor prognosis for patients with different cancer types. PMID- 30252165 TI - Comparison of Artemisiae argyi Folium and Artemisiae lavandulaefoliae Folium by simultaneous determination of multi-components with single reference standard method and chemometric analysis. AB - INTRODUCTION: Artemisiae argyi Folium and Artemisiae lavandulaefoliae Folium, two morphologically similar herbal medicines derived from Artemisia genus. Although the two Artemisia herbs have been used as medicines for a long time in China, the study of their phytochemical and bioactive composition is limited. OBJECTIVE: To comprehensively compare and evaluate the composition of Artemisiae argyi Folium and Artemisiae lavandulaefoliae Folium, and find the chemical makers for quality evaluation of the two Artemisia herbal medicines. METHODOLOGY: Eight compounds including six phenolic acids and two flavonoids were assayed by a single reference standard for simultaneous determination of multi-components method using 3-caffeoylquinic acid as the reference standard. The quantitative data were further analysed by chemometric approaches to compare and distinguish the two herbal medicines. RESULTS: The credibility and feasibility of the single reference standard for simultaneous determination of the multi-components method were carefully validated. The validated method was applied to analyse 16 batches of Artemisiae argyi Folium and 10 batches of Artemisiae lavandulaefoliae Folium samples. The quantitative results showed that 3,5-di-O-caffeoylquinic acid was the most abundant constituent, and the contents of flavonoids were notably different between the two herbal medicines. The chemometric analysis results indicated the two flavonoids, jaceosidin and eupatilin could be used as chemical markers for quality evaluation of the two herbal medicines. CONCLUSION: The single reference standard for simultaneous determination of the multi-components method coupled with chemometrics analysis could be a well-acceptable strategy to compare and evaluate the quality of Artemisiae argyi Folium and Artemisiae lavandulaefoliae Folium. PMID- 30252167 TI - Impact of nitrate contamination on the analysis of carbon and oxygen isotopes in carbonate and a low temperature phosphoric acid digestion approach for online sample preparation. AB - RATIONALE: High temperature phosphoric acid digestion combined with continuous flow isotope ratio mass spectrometry (CF-IRMS) is one of the standard methods for the determination of carbon and oxygen isotopes in carbonate. However, the routine purification protocol has not been tested by samples with nitrate contamination. Here we show that the standard protocol is not capable of measuring such samples with satisfactory accuracy and precision. METHODS: We tested the low temperature (25 degrees C) phosphoric acid digestion method combined with CF-IRMS for the measurement of natural carbonate samples with ~1 % nitrate concentration and nitrate-doped carbonate standards. We also measured the Raman spectra of the gases extracted from the nitrate-doped carbonate standards to identify the gas species that affect the results. RESULTS: The accuracy and precision of delta18 O values for nitrate doped carbonate standards digested at 72 degrees C are much worse than routine measurements. For the measurements of doped standards reacted at 25 degrees C, the accuracy and precision of the delta13 C and delta18 O values are indistinguishable from normal results. Raman spectra demonstrate that NO2 generated from high temperature digestion is the possible interference species for oxygen isotope measurement. CONCLUSIONS: Low temperature digestion is a reliable method for the measurement of carbon and oxygen isotopes in nitrate-contaminated carbonate sample, because the formation of NO2 can be largely reduced. This approach can be applied to some nitrate-rich speleothems, evaporites and other samples with nitrate contamination. PMID- 30252168 TI - Characterization of N-methylcanadine and N-methylstylopine metabolites in rat liver S9 by high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - RATIONALE: N-Methylcanadine and N-methylstylopine are two types of isoquinoline alkaloids which are considered to be the main medicinally active constituents of the genus Papaveraceae. However, to date, no metabolism studies of N methylcanadine and N-methylstylopine have been reported. Therefore, the purpose of the present study was to investigate the in vitro metabolism of these two alkaloids in rat liver S9. METHODS: N-Methylcanadine or N-methylstylopine was incubated with rat liver S9 for 1 h, and then the incubation mixture was processed with 15% trichloroacetic acid. High-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (HPLC/QqTOF-MS) as a reliable analytical method was used. The structural characterization of these metabolites was performed by the combination of the accurate MS/MS spectra and the known elemental composition. RESULTS: As a result, a total of four metabolites of N methylcanadine and five metabolites of N-methylstylopine in rat liver S9 were tentatively identified. The cleavage of the methylenedioxy group of the drugs was the main metabolic pathway of N-methylcanadine and N-methylstylopine. CONCLUSIONS: The present study is the first in vitro metabolic investigation of N methylcanadine and N-methylstylopine in rat liver S9 using a reliable HPLC/QqTOF MS method. The metabolic pathways of N-methylcanadine and N-methylstylopine are tentatively proposed. This work lays the foundation for the in vivo metabolism of the two compounds in animals. PMID- 30252169 TI - Mass Production of Large-Sized, Nonlayered 2D Nanosheets: Their Directed Synthesis by a Rapid "Gel-Blowing" Strategy, and Applications in Li/Na Storage and Catalysis. AB - 2D nanomaterials are well suited for energy conversion and storage because of their thickness-dependent physical and chemical properties. However, current synthetic methods for translating 2D materials from the laboratory to industry cannot integrate both advantages of liquid-phase method (i.e., solution processibility, homogeneity, and massive production), and gas-phase method (i.e., high quality and large lateral size). Here, inspired by Chinese Sugar Figure Blowing Art, a rapid "gel-blowing" strategy is proposed for the mass production of 2D nonlayered nanosheets by thermally expanding the viscous gel precursors within a short time (~1 min). A wide variety of 2D nanosheets including oxides, carbon, oxides/carbon and metal/carbon composites are synthesized on a large scale and with no impurities. Importantly, this method unifies the merits of both liquid-phase and gas-phase syntheses, giving rise to 2D products with high uniformity, nanometer thickness, and large lateral sizes (up to hundreds of micrometers) simultaneously. The success of this strategy highly relies on the speed of "blowing" and control of the amount of reactants. The as-synthesized nanosheet electrodes manifest excellent electrochemical performance for alkali ion batteries and electrocatalysis. This method opens up a new avenue for economical and massive preparation of good-quality nonlayered 2D nanosheets for energy-related applications and beyond. PMID- 30252170 TI - Association mapping desiccation resistance within chromosomal inversions in the African malaria vector Anopheles gambiae. AB - Inversion polymorphisms are responsible for many ecologically important phenotypes and are often found under balancing selection. However, the same features that ensure their large role in local adaptation-especially reduced recombination between alternate arrangements-mean that uncovering the precise loci within inversions that control these phenotypes is unachievable using standard mapping approaches. Here, we take advantage of long-term balancing selection on a pair of inversions in the mosquito Anopheles gambiae to map desiccation tolerance via pool-GWAS. Two polymorphic inversions on chromosome 2 of this species (denoted 2La and 2Rb) are associated with arid and hot conditions in Africa and are maintained in spatially and temporally heterogeneous environments. After measuring thousands of wild-caught individuals for survival under desiccation stress, we used phenotypically extreme individuals homozygous for alternative arrangements at the 2La inversion to construct pools for whole genome sequencing. Genomewide association mapping using these pools revealed dozens of significant SNPs within both 2La and 2Rb, many of which neighboured genes controlling ion channels or related functions. Our results point to the promise of similar approaches in systems with inversions maintained by balancing selection and provide a list of candidate genes underlying the specific phenotypes controlled by the two inversions studied here. PMID- 30252171 TI - Local and non-local topological information in the denatured state ensemble of a beta-barrel protein. AB - The folding of predominantly beta-sheet proteins is complicated by the presence of a large number of non-local interactions in their native states, which increase the ruggedness of their folding energy landscapes. However, forming non local contacts early in folding or even in the unfolded state can smooth the energy landscape and facilitate productive folding. We report that several sequence regions of a beta-barrel protein, cellular retinoic acid-binding protein 1 (CRABP1), populate native-like secondary structure to a significant extent in the denatured state in 8 M urea. In addition, we provide evidence for both local and non-local interactions in the denatured state of CRABP1. NMR chemical shift perturbations (CSPs) under denaturing conditions upon substitution of single residues by mutation support the presence of several non-local interactions in topologically key sites, arguing that the denatured state is conformationally restricted and contains topological information for the native fold. Among the most striking non-local interactions are those between the N- and C-terminal regions, which are involved in closure of the native beta-barrel. In addition, CSPs support the presence of two features in the denatured state: a major hydrophobic cluster involving residues from various parts of the sequence and a native-like interaction similar to one identified in previous studies as forming early in folding (Budyak et al., Structure 21, 476 [2013]). Taken together, our data support a model in which transient structures involving nonlocal interactions prime early folding interactions in CRABP1, determine its barrel topology, and may protect this predominantly beta-sheet protein against aggregation. PMID- 30252172 TI - Increased risk for new-onset hypertension in midlife male snorers: The 14-year follow-up study. AB - While the association between sleep-related breathing disorders such as snoring and hypertension has been well established, it still remains unclear whether the association differs by age and gender. Therefore, in this 14-year follow-up study, we examined the independent association between self-reported snoring and the incidence of hypertension by gender and age groups in a large cohort of Korean adults. A total of 4,954 adults, aged 40-69 years, free of hypertension at baseline were enrolled. Participants were divided into three groups based on a self-reported snoring frequency: never; occasional (snoring <4 nights per week); and habitual snorer (snoring >=4 nights). At baseline and biennial follow-up visits, blood pressure was measured by trained examiners. Incident hypertension was defined as the first occurrence at any follow-up examination where the participants had blood pressure >=140/90 mmHg or were being treated with antihypertensive medication. After adjusting for known cardiovascular risk factors, only in men aged <=45 years was habitual snoring significantly associated with a 1.5 times higher risk for incident hypertension than never snoring. In this age group, habitual snoring was significantly associated with increased risk for the development of hypertension, regardless of the presence of excessive daytime sleepiness. In women, snoring was not significantly associated with hypertension incidence in any age group. The present study suggests that young male snorers may be at high risk for the future development of hypertension, which has important clinical implications for early detection and treatment of snoring to reduce the burden of cardiovascular disease. PMID- 30252173 TI - Enablers and challenges to advanced nursing and midwifery practice roles. AB - AIM: To describe the enablers and challenges to the development and implementation of advanced nursing and midwifery practice roles in Ireland. BACKGROUND: Leadership strategies need to be put in place to enhance the development and implementation of advanced nursing and midwifery practice roles. METHOD: A descriptive qualitative approach using semi-structured interviews with key stakeholders (n = 15) was undertaken with nurses and midwives working in specialist and advanced practice roles and participants from other areas such as legislative, regulatory, policy, pharmacy, medicine and education. RESULTS: Participant's perspectives on the enablers and challenges to enacting specialist and advanced practice roles resulted in the generation of three themes: organisational factors; collegial, interprofessional and interpersonal support; and role clarity, economic and regulatory contexts. CONCLUSION: Addressing organisational factors, encouraging collegial and interprofessional support and establishing role clarity contribute to the effective development and implementation of the role of advanced practitioners. IMPLICATIONS FOR NURSING AND MIDWIFERY MANAGEMENT: Managers of nursing services need to provide leadership in developing strategies to enhance the enablers and overcome the challenges to advanced practice role development in their own organisation. PMID- 30252174 TI - Testicular cancer guideline adherence and patterns of care in Germany: A nationwide survey. AB - Testicular cancer has excellent cure rates; however, poor guideline adherence can lead to inappropriate management, with a detrimental effect on outcomes. Therefore, we aimed to investigate the current patterns of care for testicular cancer patients and to evaluate guideline adherence. A 19-item survey was distributed among German urologists between September 2015 and September 2016. The response rate was 45% (411/920). Staging imaging of the chest was performed by computed tomography (CT) in 85.5% and X-ray in 17.7%, and for the abdomen, by CT in 83.7% and by magnetic resonance imaging (MRI) in 21.1%. Areas of discrepancy with respect to guideline recommendations included underuse of MRI and infrequent follow-up examinations for changes in the cardiovascular, endocrine, neurological, and pulmonary systems, in addition to psychological burden. Further deviations of reported routine procedures from guideline recommendations were identified in the fields of active surveillance in Stage I seminoma, contralateral biopsies (63.1% overuse) and cryopreservation (19.2% underuse). Moreover, we found that hospital-based clinicians and younger specialists, with <=5 years of practice following board certification, perform a more accurate and thorough follow-up. German urologists show relatively strong guideline adherence in staging patterns. Significant improvements are necessary in the following areas: recommending cryopreservation, imaging modalities and accurate follow-up examinations with a focus on late toxicities. PMID- 30252175 TI - Experiences of pharmacy staff during the introduction of the checking technician role in New Zealand. AB - OBJECTIVES: To investigate the experiences of the participants in a study introducing a Pharmacy Accuracy Checking Technician (PACT) role, and specifically their perceptions of any advantages and disadvantages. METHODS: Self-administered surveys were distributed during the introduction of a checking technician role in eight community and four hospital pharmacy sites. Surveys were conducted at three time points; at baseline, at mid-point and a final data collection. Questions covered staff perceptions on; technicians' ability to take on this role, impact on workflow, impact on pharmacists' time spent with patients and any perceived advantages or disadvantages. KEY FINDINGS: Three hundred and fifty-five responses were received from participants. There was significant support for the introduction of this new role, and the greatest advantage identified was an increase in time available to pharmacists to increase potential clinical activities. Many staff felt that this role could easily fit into their current workplace and workflow with minor adjustments. There was a perception that this new role would increase safety and decrease errors as a result of the separation of clinical and checking tasks. Respondents identified a need for more technicians; however, conversely concern was expressed of a negative impact on the number of pharmacists' jobs. CONCLUSIONS: Despite the disruption caused by the training process, the respondents believed this new role to be beneficial to both staff and patients, and that the new model would allow for increased error identification and enhanced safety. PMID- 30252176 TI - sRANKL and its correlation with metabolic syndrome parameters in children. AB - BACKGROUND: Activating receptor ligand for nuclear factor (RANKL) has been identified as a ligand attached to the cell membrane of osteoblasts and odontoclasts. AIM: To determine a possible association of sRANKL in saliva and serum with the parameters of metabolic syndrome (MS) in paediatric population aged 8-12 years. DESIGN: This was a clinical, analytical and comparative study. Students between 6 and 12 years with good oral hygiene were included. Anthropometry, clinical analysis, dentobacterial plaque registration were registered as well as sRANKL in total saliva and serum through the ELISA technique. RESULTS: A total of 43 children were enrolled, with a mean age of 9.7 (+/-0.8 years). Contrasting the groups by the presence or absence of the waist circumference above the normal limit, the difference in serum sRANKL concentration was statistically significant (P <= 0.05). A negative statistical significance was found in the correlation between serum sRANKL and HDLc (r2 = 0.310, P = 0.046). Saliva sRANKL did not show statistical difference between neither gender nor body mass index and was not correlated with any parameter of the MS. CONCLUSIONS: A good oral hygiene seems to avoid the effects of MS on the oral cavity. PMID- 30252177 TI - Differential gene regulation underlies variation in melanic plumage coloration in the dark-eyed junco (Junco hyemalis). AB - Colour plays a prominent role in species recognition; therefore, understanding the proximate basis of pigmentation can provide insight into reproductive isolation and speciation. Colour differences between taxa may be the result of regulatory differences or be caused by mutations in coding regions of the expressed genes. To investigate these two alternatives, we studied the pigment composition and the genetic basis of coloration in two divergent dark-eyed junco (Junco hyemalis) subspecies, the slate-coloured and Oregon juncos, which have evolved marked differences in plumage coloration since the Last Glacial Maximum. We used HPLC and light microscopy to investigate pigment composition and deposition in feathers from four body areas. We then used RNA-seq to compare the relative roles of differential gene expression in developing feathers and sequence divergence in transcribed loci under common-garden conditions. Junco feathers differed in eumelanin and pheomelanin content and distribution. Within subspecies, in lighter feathers melanin synthesis genes were downregulated (including PMEL, TYR, TYRP1, OCA2 and MLANA), and ASIP was upregulated. Feathers from different body regions also showed differential expression of HOX and WNT genes. Feathers from the same body regions that differed in colour between the two subspecies showed differential expression of ASIP and three other genes (MFSD12, KCNJ13 and HAND2) associated with pigmentation in other taxa. Sequence variation in the expressed genes was not related to colour differences. Our findings support the hypothesis that differential regulation of a few genes can account for marked differences in coloration, a mechanism that may facilitate the rapid phenotypic diversification of juncos. PMID- 30252178 TI - The budding-yeast RWD protein Csm1 scaffolds diverse protein complexes through a conserved structural mechanism. AB - RWD domains mediate protein-protein interactions in a variety of pathways in eukaryotes. In budding yeast, the RWD domain protein Csm1 is particularly versatile, assembling key complexes in the nucleolus and at meiotic kinetochores through multiple protein interaction surfaces. Here, we reveal a third functional context for Csm1 by identifying a new Csm1-interacting protein, Dse3. We show that Dse3 interacts with Csm1 in a structurally equivalent manner to its known binding partners Mam1 and Ulp2, despite these three proteins' lack of overall sequence homology. We theorize that the unique "clamp" structure of Csm1 and the loose sequence requirements for Csm1 binding have led to its incorporation into at least three different structural/signaling pathways in budding yeast. PMID- 30252179 TI - Enhanced Thermal Boundary Conductance in Few-Layer Ti3 C2 MXene with Encapsulation. AB - Van der Waals interactions in 2D materials have enabled the realization of nanoelectronics with high-density vertical integration. Yet, poor energy transport through such 2D-2D and 2D-3D interfaces can limit a device's performance due to overheating. One long-standing question in the field is how different encapsulating layers (e.g., contact metals or gate oxides) contribute to the thermal transport at the interface of 2D materials with their 3D substrates. Here, a novel self-heating/self-sensing electrical thermometry platform is developed based on atomically thin, metallic Ti3 C2 MXene sheets, which enables experimental investigation of the thermal transport at a Ti3 C2 /SiO2 interface, with and without an aluminum oxide (AlOx ) encapsulating layer. It is found that at room temperature, the thermal boundary conductance (TBC) increases from 10.8 to 19.5 MW m-2 K-1 upon AlOx encapsulation. Boltzmann transport modeling reveals that the TBC can be understood as a series combination of an external resistance between the MXene and the substrate, due to the coupling of low-frequency flexural acoustic (ZA) phonons to substrate modes, and an internal resistance between ZA and in-plane phonon modes. It is revealed that internal resistance is a bottle-neck to heat removal and that encapsulation speeds up the heat transfer into low-frequency ZA modes and reduces their depopulation, thus increasing the effective TBC. PMID- 30252180 TI - The validity of the Distress Thermometer in female partners of men with prostate cancer. AB - Female partners of prostate cancer (PCa) survivors experience heightened psychological distress that may be greater than that expressed by PCa patients. However, optimal approaches to detect distressed, or at risk of distress, partners are unclear. This study applied receiver operating characteristics analysis to evaluate diagnostic accuracy, sensitivity and specificity of the Distress Thermometer (DT) compared to widely used measures of general (Hospital Anxiety and Depression Scale) and cancer-specific (Impact of Events Scale Revised) distress. Participants were partners of men with localised PCa (recruited around diagnosis) about to undergo or had received surgical treatment (N = 189), and partners of men diagnosed with PCa who were 2-4 years post treatment (N = 460). In both studies, diagnostic utility of the DT overall was not optimal. Although area under the curve scores were acceptable (ranges: 0.71 0.92 and 0.83-0.94 for general and cancer-specific distress, respectively), sensitivity, specificity and optimal DT cut-offs for partner distress varied for general (range: >=2 to >=5) and cancer-specific (range: >=3 to >=5) distress both across time and between cohorts. Thus, it is difficult to draw firm conclusions about the diagnostic capabilities of the DT for partners or recommend its use in this population. More comprehensive screening measures may be needed to detect partners needing psychological intervention. PMID- 30252181 TI - Concurrent AFG3L2 and SPG7 mutations associated with syndromic parkinsonism and optic atrophy with aberrant OPA1 processing and mitochondrial network fragmentation. AB - Mitochondrial dynamics and quality control are crucial for neuronal survival and their perturbation is a major cause of neurodegeneration. m-AAA complex is an ATP dependent metalloprotease located in the inner mitochondrial membrane and involved in protein quality control. Mutations in the m-AAA subunits AFG3L2 and paraplegin are associated with autosomal dominant spinocerebellar ataxia (SCA28) and autosomal recessive hereditary spastic paraplegia (SPG7), respectively. We report a novel m-AAA-associated phenotype characterized by early-onset optic atrophy with spastic ataxia and L-dopa-responsive parkinsonism. The proband carried a de novo AFG3L2 heterozygous mutation (p.R468C) along with a heterozygous maternally inherited intragenic deletion of SPG7. Functional analysis in yeast demonstrated the pathogenic role of AFG3L2 p.R468C mutation shedding light on its pathogenic mechanism. Analysis of patient's fibroblasts showed an abnormal processing pattern of OPA1, a dynamin-related protein essential for mitochondrial fusion and responsible for most cases of hereditary optic atrophy. Consistently, assessment of mitochondrial morphology revealed a severe fragmentation of the mitochondrial network, not observed in SCA28 and SPG7 patients' cells. This case suggests that coincidental mutations in both components of the mitochondrial m-AAA protease may result in a complex phenotype and reveals a crucial role for OPA1 processing in the pathogenesis of neurodegenerative disease caused by m-AAA defects. PMID- 30252182 TI - Antihypertensives prescribed for pregnant women in Japan: Prevalence and timing determined from a database of health insurance claims. AB - PURPOSE: The purpose of the study is to evaluate the status of prescribed antihypertensives primarily during pregnancy, but also before pregnancy and after delivery, using a large claims database in Japan. METHODS: The dates of pregnancy onset and delivery were identified using reported algorithms and the birth months of infants. The prevalence and timing of prescribed antihypertensives during pregnancy were descriptively evaluated. Time trends in prescriptions were evaluated using multivariate logistic regression analyses. We also evaluated the prevalence of antihypertensives prescribed within 180 days before pregnancy and 180 days after delivery among women who were covered by health insurers during the entire period. RESULTS: At least one antihypertensive agent was prescribed for 1144 (2.74%) of 41 693 pregnant women. The most frequently prescribed oral antihypertensive during pregnancy was nifedipine, followed by methyldopa, hydralazine, and furosemide. Drugs targeting the renin-angiotensin system were prescribed for 21 pregnant women (0.05%), including angiotensin II receptor blockers that were prescribed for 19 (0.05%) of them. Nicardipine was the most frequently prescribed injectable antihypertensive during pregnancy, followed by furosemide, hydralazine, and nitroglycerin. Annual prescription trends remained similar except for a significant decrease in those for oral and injectable furosemide and an annual increase in those for organic nitrate. Based on an evaluation of 33 941 pregnant women, the number of prescriptions for antihypertensives increased particularly during the third trimester, then decreased from 91 to 180 days after delivery. CONCLUSIONS: Various types of antihypertensives are prescribed for Japanese pregnant women. The effects of exposing pregnant Japanese women to these agents should be evaluated. PMID- 30252183 TI - [Motivation and Incentives at Work in Nursing Management]. AB - From the hypothesis that the exclusive use of monetary incentives may undermine intrinsic motivation of health professionals, causing the opposite effect to that intended, this paper analyzes the factors that are associated with intrinsic motivation of professionals responsible for nursing management. To this end, we designed a questionnaire on Work Motivation in Nursing Management based on Intrinsic Motivation Inventory (IMI), which was distributed at the National Conference of Supervisors of Nursing (Bilbao, 2010). After analyzing the results, we obtained a motivational profile that can guide health managers in the redesign of a system of incentives that, aligned with professional values, influence the efficient performance of health workers, and to invest in a new type of capital that we call "motivational capital". PMID- 30252184 TI - Ointment vehicles regulate the wound-healing process by modifying the hyaluronan rich matrix. AB - Topical ointment consists of an active ingredient and vehicle, and the vehicle largely comprises the volume of the ointment. During the treatment of chronic wounds, such as pressure ulcers, the vehicle has been considered inactive, only serving as a carrier of the main pharmaceutical. However, recent reports have indicated that the vehicle has distinct clinical effects that depend on its physicochemical properties. Therefore, an understanding of the action mechanism of the ointment vehicle in wound tissue is necessary. In this study, we established a mouse model to analyze tissue reactions induced by the following ointment vehicles, an oil-in-water emulsion (EM) vehicle; a macrogol ointment (MO), which is a water-soluble, hydrophilic vehicle; and a MOs containing sucrose (MS). EM-treated wounds exhibited an inflammatory reaction characterized by tissue edema and thick granulation tissue; however, MO- and MS-treated wounds did not exhibit this reaction. Moreover, EM-treated wounds exhibited infiltration of inflammatory cells unlike MO-treated wounds. In contrast, the formation of collagenous tissue was dominantly observed in MO-treated wounds. Because the vehicle regulates the water environment of the wound, the water-holding extracellular matrix molecules, including hyaluronan (HA) and proteoglycan, were examined using immunohistochemical and biochemical methods. The versican G1 fragment, serum-derived HA-associated protein (SHAP) and HA (the VG1F-SHAP-HA) complex characteristically found in inflammatory conditions of pressure ulcers was found in EM-treated wounds. To histologically analyze the mechanism of action of the vehicle, we evaluated the ointment vehicle-wound tissue interface in an en bloc manner. Formation of the HA-containing complex was observed locally between the vehicle and wound surface. On the basis of these data, ointment vehicles regulate the wound-healing process through the formation of HA-rich extracellular matrices at the ointment-wound interface. This study provides a better understanding of the treatment of deep-pressure ulcers with focus on ointment vehicles. PMID- 30252185 TI - Developmental changes of sleep spindles and their impact on sleep-dependent memory consolidation and general cognitive abilities: A longitudinal approach. AB - Sleep spindles are related to sleep-dependent memory consolidation and general cognitive abilities. However, they undergo drastic maturational changes during adolescence. Here we used a longitudinal approach (across 7 years) to explore whether developmental changes in sleep spindle density can explain individual differences in sleep-dependent memory consolidation and general cognitive abilities. Ambulatory polysomnography was recorded during four nights in 34 healthy subjects (24 female) with two nights (baseline and experimental) at initial recording (age range 8-11 years) and two nights at follow-up recording (age range 14-18 years). For declarative learning, participants encoded word pairs with a subsequent recall before and after sleep. General cognitive abilities were measured by the Wechsler Intelligence Scale. Higher slow (11-13 Hz) than fast (13-15 Hz) spindle density at frontal, central, and parietal sites during initial recordings, followed by a shift to higher fast than slow spindle density at central and parietal sites during follow-up recordings, suggest that mature spindle topography develops throughout adolescence. Fast spindle density increases from baseline to experimental night were positively related to sleep dependent memory consolidation. In addition, we found that the development of fast spindles predicted the improvement in memory consolidation across the two longitudinal measurements, a finding that underlines a crucial role for mature fast spindles for sleep-dependent memory consolidation. Furthermore, slow spindle changes across adolescence were related to general cognitive abilities, a relationship that could indicate the maturation of frontal networks relevant for efficient cognitive processing. PMID- 30252186 TI - Inhibition of mitochondrial translation in fibroblasts from a patient expressing the KARS p.(Pro228Leu) variant and presenting with sensorineural deafness, developmental delay, and lactic acidosis. AB - Aminoacyl-tRNA synthetases are ubiquitous enzymes, which universally charge tRNAs with their cognate amino acids for use in cytosolic or organellar translation. In humans, mutations in mitochondrial tRNA synthetases have been linked to different tissue-specific pathologies. Mutations in the KARS gene, which encodes both the cytosolic and mitochondrial isoform of lysyl-tRNA synthetase, cause predominantly neurological diseases that often involve deafness, but have also been linked to cardiomyopathy, developmental delay, and lactic acidosis. Using whole exome sequencing, we identified two compound heterozygous mutations, NM_001130089.1:c.683C>T p.(Pro228Leu) and NM_001130089.1:c.1438del p.(Leu480TrpfsX3), in a patient presenting with sensorineural deafness, developmental delay, hypotonia, and lactic acidosis. Nonsense-mediated mRNA decay eliminated the truncated mRNA transcript, rendering the patient hemizygous for the missense mutation. The c.683C>T mutation was previously described, but its pathogenicity remained unexamined. Molecular characterization of patient fibroblasts revealed a multiple oxidative phosphorylation deficiency due to impaired mitochondrial translation, but no evidence of inhibition of cytosolic translation. Reintroduction of wild-type mitochondrial KARS, but not the cytosolic isoform, rescued this phenotype confirming the disease-causing nature of p.(Pro228Leu) exchange and demonstrating the mitochondrial etiology of the disease. We propose that mitochondrial translation deficiency is the probable disease culprit in this and possibly other patients with mutations in KARS. PMID- 30252187 TI - No need for urgent revisiting of kalaemia levels in guidelines despite use of mineralocorticoid receptor antagonists: bring in more evidence. PMID- 30252188 TI - Circumferential root strains generated during lateral compaction with stainless steel vs. nickel-titanium finger spreaders. AB - The circumferential strains created in the radicular dentin by nickel-titanium (NiTi) and stainless steel (SS) finger spreaders (FSs) during a simulated clinical procedure of lateral compaction were compared after minimal (size 50) and extensive (size 100) canal preparations. Nineteen maxillary central incisors underwent minimal preparation, while 10 underwent an extra phase of extensive preparation. Four miniature strain gauges were bonded circumferentially in the apical third of the root (buccal, lingual, mesial, and distal). Lateral compaction was performed using either NiTi-FSs or SS-FSs. Force and strains were continuously recorded. The maximal strains (with and without normalization according to force) were recorded. The SS-FSs generated higher maximal strains normalized according to force compared with the NiTi-FSs. The maximal normalized strains were higher by 37%-43% for the mesial and distal aspects and by 6%-14% for the buccal and lingual aspects after the minimal preparation and by 24%-28% for the mesial and distal aspects and by 19%-20% for the buccal and lingual aspects after extensive preparation. The maximal normalized strains increased by 30%-70% from minimal to extensive preparations, with two teeth exhibiting vertical root fracture while compaction with SS-FS. The NiTi-FSs induce less strain in root dentin than the SS-FSs and thus may contribute less to the risk of vertical root fracture. PMID- 30252189 TI - The association of serum leptin levels with food addiction is moderated by weight status in adolescent psychiatric inpatients. AB - Leptin is essential for the control of energy homeostasis and eating behaviour. We investigated potential associations between serum leptin levels and food addiction in adolescent psychiatric inpatients (n = 228). The most frequent psychiatric diagnoses were mood disorders, anxiety disorders, and substance use disorders. More than three quarters of the study group suffered from more than one psychiatric disorder. Food addiction was assessed with the Yale Food Addiction Scale. Leptin was determined in serum. Analyses were conducted for the whole body weight range and for distinct weight categories to evaluate a potential impact of known nonlinearity between leptin levels and satiety due to leptin resistance in obese. A weak negative association between food addiction and leptin in normal weight patients (beta = -0.11, p = .022) was detected. In contrast, food addiction was associated with a significantly higher serum leptin (beta = 0.16. p = .038) in overweight patients. Food addiction in normal weight patients might be associated with restrained eating, previously shown to involve reduced leptin levels. The small positive association of food addiction with higher serum leptin in overweight patients might reflect leptin resistance and overeating. PMID- 30252190 TI - Decarboxylative Negishi Coupling of Redox-Active Aliphatic Esters by Cobalt Catalysis. AB - A cobalt-catalyzed decarboxylative Negishi coupling reaction of redox-active aliphatic esters with organozinc reagents was developed. The method enabled efficient alkyl-aryl, alkyl-alkenyl, and alkyl-alkynyl coupling reactions under mild reaction conditions with no external ligand or additive needed. The success of an in situ activation protocol and the facile synthesis of the drug molecule (+/-)-preclamol highlight the synthetic potential of this method. Mechanistic studies indicated that a radical mechanism is involved. PMID- 30252191 TI - Discovery of Cu3Pb. AB - Materials discovery enables both realization and understanding of new, exotic, physical phenomena. An emerging approach to the discovery of novel phases is high pressure synthesis within diamond anvil cells, thereby enabling in situ monitoring of phase formation. Now, the discovery via high-pressure synthesis of the first intermetallic compound in the Cu-Pb system, Cu3Pb is reported. Cu3Pb is notably the first structurally characterized mid- to late-first-row transition metal plumbide. The structure of Cu3Pb can be envisioned as a direct mixture of the two elemental lattices. From this new framework, we gain insight into the structure as a function of pressure and hypothesize that the high-pressure polymorph of lead is a possible prerequisite for the formation of Cu3Pb. Crucially, electronic structure computations reveal band crossings near the Fermi level, suggesting that chemically doped Cu3Pb could be a topologically nontrivial material. PMID- 30252192 TI - Detection of early-stage changes in people with chronic diseases: A telehome monitoring-based telenursing feasibility study. AB - Chronic diseases, such as chronic obstructive pulmonary disease, amyotrophic lateral sclerosis, and diabetes mellitus, require long-term management, which daily telenurse monitoring can provide. The aim of the present feasibility study was to determine if using a telenursing protocol with home monitoring during a 12 week implementation could also identify early signs of deterioration and factors correlated with participants' change in status, while attaining patient acceptance and satisfaction. The purposive sample of 43 participants provided 4533 combined days of monitoring. Outcome feasibility indicators were the range of triggering protocol alerts (70~100%) and diagnoses with exacerbations (20~29.3%). Highly correlated were participants' activity limitation and palpitations with chronic obstructive pulmonary disease, activity limitation and ineffective sputum clearance with amyotrophic lateral sclerosis, and fatigue with diabetes. Acceptance and adherence were high with daily monitoring, including "feelings of safety," and "understanding own condition". Telenursing with home monitoring indicated a trend to accurately detect early-stage changes. Participant acceptance was acceptable. It would be feasible to conduct a randomized, controlled trial using this model with some modifications. PMID- 30252193 TI - Efficient Conversion of Carbon Dioxide with Si-based Reducing Agents Catalyzed by Metal Complexes and Salts. AB - Homogeneous metal complex and salt catalysts were developed for the reductive transformation of CO2 with Si-based reducing agents. Cu-bisphosphine complexes were found to be excellent catalysts for the hydrosilylation of CO2 with polymethylhydrosiloxane (PMHS). The Cu complexes also showed high catalytic activity and a wide substrate scope for formamide synthesis from amines, CO2 , and PMHS. Simple fluoride salts such as tetrabutylammonium fluoride acted as good catalysts for the reductive conversion of CO2 to formic acid in the presence of hydrosilane, disilane, and metallic Si. Based on the kinetics, isotopic experiments, and in-situ NMR measurements, the reaction mechanism for both catalyst systems, the Cu complex and the fluoride salt, have been proposed. PMID- 30252194 TI - Density Functional Theory Investigation of Carbon Dots as Hole-transport Material in Perovskite Solar Cells. AB - Charge transfer in solar cells is crucial, and so is the hole transporting layer (HTL) component in perovskite solar cells (PSCs). Finding a suitable material for this purpose that is inexpensive - either organic or inorganic - is currently one of the prime research objectives to improve the performance, through charge transfer dynamics, of PSCs.< One such recent finding is carbon quantum dots (C dots), which is a simple and low-cost organic material that could be an alternative option to the currently employed high-cost and complex-structured hole transporting materials (HTMs) utilized in perovskite solar cells. A series of C-dots functionalized with hydrogen, hydroxyl (-OH), and carboxyl (-COOH) groups are considered in this study for their hole-transporting properties. The results reveal that simple hexagonal structured C-dots including -OH and -COOH group substituted C-dots have suitable valance band maximum (VBM) positions, which are suitable for hole transport. It is discovered that the position of the functional moieties on the C-dots would impact the band-edge positions of the C dots. This implies that tuning the band position is possible so that these two dimensional C-dots could, in principle, be used for other solar-cell applications that may require different band positions for optimal performance. As a representative example, we studied the perovskite/C-Dot interface of two different possible surfaces (i. e. MAI and PbI2 terminated perovskites) combined with a hexagonal C-Dot layer and found that there is a good probability of charge transfer between the perovskite layer and the C-dots, which promotes hole transfer between the perovskite and the C-dots.Introduction. PMID- 30252196 TI - Bacterial ornithine lipid, a surrogate membrane lipid under phosphate-limiting conditions, plays important roles in bacterial persistence and interaction with host. AB - Ornithine lipids (OLs) are bacteria-specific lipids that are found in the outer membrane of Gram (-) bacteria and increase as surrogates of phospholipids under phosphate-limited environmental conditions. We investigated the effects of OL increase in bacterial membranes on pathogen virulence and the host immune response. In Pseudomonas aeruginosa, we increased OL levels in membranes by overexpressing the OL-synthesizing operon (olsBA). These increases changed the bacterial surface charge and hydrophobicity, which reduced bacterial susceptibility to antibiotics and antimicrobial peptides (AMPs), interfered with the binding of macrophages to bacterial cells and enhanced bacterial biofilm formation. When grown under low phosphate conditions, P. aeruginosa became more persistent in the treatment of antibiotics and AMPs in an olsBA-dependent manner. While OLs increased persistence, they attenuated P. aeruginosa virulence; in host cells, they reduced the production of inflammatory factors (iNOS, COX-2, PGE2 and nitric oxide) and increased intracellular Ca2+ release. Exogenously added OL had similar effects on P. aeruginosa and host cells. Our results suggest that bacterial OL plays important roles in bacteria-host interaction in a way that enhances bacterial persistence and develops chronic adaptation to infection. PMID- 30252195 TI - Transient LTRE analysis reveals the demographic and trait-mediated processes that buffer population growth. AB - Temporal variation in environmental conditions affects population growth directly via its impact on vital rates, and indirectly through induced variation in demographic structure and phenotypic trait distributions. We currently know very little about how these processes jointly mediate population responses to their environment. To address this gap, we develop a general transient life table response experiment (LTRE) which partitions the contributions to population growth arising from variation in (1) survival and reproduction, (2) demographic structure, (3) trait values and (4) climatic drivers. We apply the LTRE to a population of yellow-bellied marmots (Marmota flaviventer) to demonstrate the impact of demographic and trait-mediated processes. Our analysis provides a new perspective on demographic buffering, which may be a more subtle phenomena than is currently assumed. The new LTRE framework presents opportunities to improve our understanding of how trait variation influences population dynamics and adaptation in stochastic environments. PMID- 30252197 TI - Rapid Generation of Molecular Complexity by Chemical Synthesis: Highly Efficient Total Synthesis of Hexacyclic Alkaloid (-)-Chaetominine and Its Biosynthetic Implications. AB - The efficiency becomes a key issue in today's natural product total synthesis. While biomimetic synthesis is one of the most elegant strategies to achieve synthetic efficiency and thus to approach the ideal synthesis, most biogenetic pathways are unknown or unconfirmed. In this account, we demonstrate, through the shortest and also the most efficient asymmetric total syntheses of the hexacyclic alkaloid (-)-chaetominine to date, that on the basis of biogenetic thinking, one can develop quite efficient bio-inspired total synthesis, which in turn serves to suggest and chemically validate plausible biosynthetic routes for the natural product. The synthetic strategy thus developed is also inspiring for the development of other synthetic methods and efficient total synthesis of other natural products. PMID- 30252198 TI - Essential role of NbNOG1 in ribosomal RNA processing. AB - Nucleolar GTP-binding protein 1 (NOG1) is a highly conserved GTPase first reported in Trypanosoma as required for ribosome biogenesis. We characterized NbNOG1, a Nicotiana benthamiana NOG1 ortholog sharing more than 45% amino acid identity with Trypanosoma, yeast, and human NOG1. N. benthamiana plants silenced for NbNOG1 were stunted and produced sterile flowers. NbNOG1 is functionally interchangeable with yeast NOG1 (ScNOG1), rescuing yeast lethality caused by loss of ScNOG1. Finally, NbNOG1 silencing caused over-accumulation of pre-rRNA processing intermediates, and concomitant loss of mature rRNAs. Collectively, these data support a role for NbNOG1 in ribosomal RNA processing. PMID- 30252199 TI - The association between concerns toward adverse reactions during pre-approval drug reviews and the post-approval addition of clinically significant adverse reactions to package inserts: A retrospective analysis of pre-approval drug review reports and safety updates. AB - PURPOSE: To determine if concerns toward adverse reactions (ARs) identified during the drug approval process are associated with their post-approval addition to package inserts. METHODS: Pre-approval concerns toward 24 target ARs were identified in the drug review reports and initial package inserts of 126 target drugs approved for use in Japan between April 2004 and March 2009. Each target drug was monitored for 5 years after approval for the addition of these ARs as clinically significant adverse reactions (CSARs) in the package inserts. Positive predictive values (PPVs) and negative predictive value (NPVs) were calculated. The odds ratios (ORs) and 95% confidence intervals (CIs) were also analyzed to test the association between pre-approval concerns and post-approval CSAR additions. RESULTS: Target ARs with pre-approval concerns were added as CSARs in 88 of 406 AR-drug pairs (PPV: 21.7%). In contrast, target ARs without pre approval concerns were added as CSARs in 93 of 2304 drugs (NPV: 96.0%). Hypoglycemia had the highest PPV (100%), whereas hepatitis and myocardial infarction had the lowest PPVs (0.0%). Abnormal hepatic function had the lowest NPV (85.4%), whereas myocardial infarction and convulsions had the highest NPVs (100%). Pre-approval concerns showed a significantly positive association with post-approval CSAR additions (OR: 6.57, 95% CI: 4.74, 9.11; P < 0.001). CONCLUSIONS: The significant association between pre-approval concerns and post approval CSAR additions indicates that Japan's drug regulatory agency has generally conducted rigorous examination of the safety information available in the submitted data packages during drug review for approval. PMID- 30252200 TI - Blue or red photoluminescence emission in alpha-Bi2 O3 needles: Effect of synthesis method. AB - Monoclinic bismuth oxide (alpha-Bi2 O3 ) has attractive optical properties and, therefore, its photoluminescence (PL) behavior has been increasingly explored. Besides this fact, the influence of synthesis methods on PL properties of alpha Bi2 O3 still requires research. This paper describes the influence of precipitation (PPT) and microwave-assisted hydrothermal (MAH) methods on PL properties of acicular alpha-Bi2 O3 microcrystals. The synthesis method promoted structural modifications on alpha-Bi2 O3 , in particular PPT increased the density of oxygen vacancies significantly. As a result, the PL properties of samples were different depending on the method of synthesis. PPT samples presented their maximum PL emission at 1.91 eV (red), while MAH samples had their maximum at 2.61 eV (blue). These results indicate the possibility of controlling PL properties of alpha-Bi2 O3 by simply choosing the adequate synthesis method. PMID- 30252201 TI - Dynamic and reversible RNA N6 -methyladenosine methylation. AB - N6 -methyladenosine (m6 A) is the most abundant internal chemical modification in eukaryotic messenger RNAs (mRNAs). The discovery in 2011 that m6 A is reversed by the fat mass and obesity-associated protein stimulated extensive worldwide research efforts on the regulatory biological functions of dynamic m6 A and other RNA modifications. The epitranscriptomic mark m6 A is written, read, and erased through the activities of a complicated network of enzymes and other proteins. m6 A-binding proteins read m6 A marks and transduce their downstream regulatory effects by altering RNA metabolic processes. In this review, we summarize the current knowledge of m6 A modifications, with particular focus on the functions of its writer, eraser, and reader proteins in posttranscriptional gene regulation and discuss the impact of m6 A marks on human health. This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease. PMID- 30252202 TI - A recap of RNA recapping. AB - The N7-methylguanosine cap is a hallmark of the 5' end of eukaryotic mRNAs and is required for gene expression. Loss of the cap was believed to lead irreversibly to decay. However, nearly a decade ago, it was discovered that mammalian cells contain enzymes in the cytoplasm that are capable of restoring caps onto uncapped RNAs. In this review, we summarize recent advances in our understanding of cytoplasmic RNA recapping and discuss the biochemistry of this process and its impact on regulating and diversifying the transcriptome. Although most studies focus on mammalian RNA recapping, we also highlight new observations for recapping in disparate eukaryotic organisms, with the trypanosome recapping system appearing to be a fascinating example of convergent evolution. We conclude with emerging insights into the biological significance of RNA recapping and prospects for the future of this evolving area of study. RNA Processing > RNA Editing and Modification Translation > Translation Regulation RNA Processing > Capping and 5' End Modifications RNA Turnover and Surveillance > Regulation of RNA Stability. PMID- 30252203 TI - Oestrogen promotes tumorigenesis of bladder cancer by inducing the enhancer RNA eGREB1. AB - In recent years, studies have shown that enhancer RNAs (eRNAs) can be transcribed from enhancers. Increasing evidence has revealed that eRNAs play critical roles in the development of various cancers. Oestrogen-associated eRNAs are closely related to breast cancer. In view of the gender differences in bladder cancer (BCa), we suppose that oestrogen-associated eRNAs are also involved in tumorigenesis of BCa. In our study, we first demonstrated that eGREB1 derived from the enhancer of an oestrogen-responsive gene-GREB1 was up-regulated in BCa tissues, and the expression level of eGREB1 is positively associated with the histological grade and TNM stage of BCa. Knockdown of eGREB1 by CRISPR-Cas13a could inhibit cell proliferation, migration and invasion and induce apoptosis in BCa cells T24 and 5637. Besides, we exhibited the promoting effect of oestrogen on BCa cells. What's more, down-regulation of eGREB1 could improve the malignant biological characteristics of BCa cells induced by oestrogen. In conclusion, our data indicated that eGREB1 plays oncogenic role and oestrogen may promote the occurrence and progression of BCa by inducing eGREB1 production. Our findings provide new insights into the prevention of BCa and develop a novel therapeutic target for the treatment of BCa. PMID- 30252204 TI - Determination and pharmacokinetic study of AZD-3759 in rat plasma by ultra performance liquid chromatography with triple quadrupole mass spectrometer. AB - BACKGROUND: AZD-3759 is a new, potent, oral, active central nervous system penetrant EGFR inhibitor. Despite promising clinical activity among patients pretreated and never treated with EGFR-tyrosine kinase inhibitors, no time saving pharmacokinetic study method has been reported in an animal model. METHODS: Protein was precipitated with acetonitrile and then used for sample pre processing. A CORTECS BEH C18 column was used to separate the analytes at 40 degrees C. Acetonitrile and water (containing 0.1% formic acid) were chosen as the mobile phase at a flow rate of 0.4 mL/min. The analytes were quantified by multiple reaction monitoring mode with positive electrospray ionization. RESULTS: The target fragment ions were m/z 460.38->141 for AZD-3759 and m/z 285.1->193.1 for internal standard diazepam. The calibration curve exhibited good linearity for AZD-3759 at a range of 1-500 ng/mL. The intra-run and inter-run precision variations were both < 8.22%. The recovery rate of AZD-3759 from plasma was > 76.4%. CONCLUSION: An accurate, simple ultra performance liquid chromatography with triple quadrupole mass spectrometer method was developed and validated to determine AZD-3759 in rat plasma. Our validated method can be applied to the pharmacokinetic study of AZD-3759 at an oral dosage of 10 mg/kg. PMID- 30252205 TI - Chemosystematic Significance of Essential Oil Constituents and Furanocoumarins of Underground Parts and Fruits of Nine Heracleum L. Taxa from Southeastern Europe. AB - The composition of the essential oils and the furanocoumarin profiles of CH2 Cl2 extracts from underground parts and fruits of nine Heracleum taxa (Apiaceae) from Southeastern Europe were statistically analyzed to evaluate their chemosystematic significance. Eight investigated taxa (H. orphanidis and members of H. sphondylium group: H. sphondylium, H. sibiricum, H. montanum, H. ternatum, H. pyrenaicum subsp. pollinianum, H. pyrenaicum subsp. orsinii and H. verticillatum) belong to the type section of the genus. Additionally analyzed taxon, H. austriacum subsp. siifolium, belongs to H. sect. Wendia. Qualitative and quantitative analysis of the essential oils was performed by GC-FID and GC/MS, and of the furanocoumarins by LC/MS. Furanocoumarins were identified using standards and/or based on UV, MS, 1 H- and ROESY NMR spectra. Multivariate statistics (PCA, nMDS, UPGMA) of analyzed metabolites showed that the investigated taxa were grouped according to their taxonomic classification. PCA revealed the significance of some monoterpenes and (Z)-falcarinol of the underground parts oils, octyl esters of the fruit oils, and most of the total of 12 identified furanocoumarins. PMID- 30252206 TI - Controlling Self-Assembly in Gyroid Terpolymer Films By Solvent Vapor Annealing. AB - The efficacy with which solvent vapor annealing (SVA) can control block copolymer self-assembly has so far been demonstrated primarily for the simplest class of copolymer, the linear diblock copolymer. Adding a third distinct block-thereby creating a triblock terpolymer-not only provides convenient access to complex continuous network morphologies, particularly the gyroid phases, but also opens up a route toward the fabrication of novel nanoscale devices such as optical metamaterials. Such applications, however, require the generation of well-ordered 3D continuous networks, which in turn requires a detailed understanding of the SVA process in terpolymer network morphologies. Here, in situ grazing-incidence small-angle X-ray scattering (GISAXS) is employed to study the self-assembly of a gyroid-forming triblock terpolymer during SVA, revealing the effects of several key SVA parameters on the morphology, lateral order, and, in particular, its preservation in the dried film. The robustness of the terpolymer gyroid morphology is a key requirement for successful SVA, allowing the exploration of annealing parameters which may enable the generation of films with long-range order, e.g., for optical metamaterial applications. PMID- 30252207 TI - Recent developments in pleurodesis for malignant pleural disease. AB - OBJECTIVE: Metastatic pleural effusion (MPE) is one of the most frequent causes of pleural effusion. The aims of the therapeutic management are palliation of symptoms and improvement in patient's quality of life. The first step is a therapeutic thoracentesis. In case of a recurrent MPE, pleural maneuvers can be used to manage symptoms based on either ambulatory pleural drainage or pleurodesis to prevent fluid accumulation. The aim of this review is to describe recent advances, according to the best available evidence, in the field of pleurodesis for the management of MPE. DATA SOURCE AND STUDY SELECTION: Three different searches of the most clinically relevant articles and up-to-date results in the field of pleurodesis for the management of MPE were performed using PubMed. Different indexing terms and time restriction were chosen. From these PubMed searches, 322 articles were respectively found. After cross-checking these three lists and the selection of articles published after January 2010 specially dedicated to the management of MPE by pleurodesis, the abstracts of 106 articles were extracted to feed the corpus of this review. RESULTS AND CONCLUSION: Treatment approaches of recurrent MPE should take into account multiple factors in particular patient's life expectancy and preference. If talc is the best sclerosing agent alone or in combination with indwelling pleural catheter which is a promising strategy, the pathophysiology of MPE has to be revisited in order to propose a personalized management targeting intrapleural key molecules involved in the genesis of malignant process. PMID- 30252208 TI - Auranofin and its Analogues Show Potent Antimicrobial Activity against Multidrug Resistant Pathogens: Structure-Activity Relationships. AB - Due to the so-called "antibiotic resistance crisis" new antibacterial agents are urgently sought to treat multidrug-resistant pathogens. A group of gold- or silver-based complexes, of general formula [M(PEt3 )X] (with M=Au or Ag, and X=Cl, Br or I), alongside with three complexes bearing a positive or negative charge-[Au(PEt3 )2 ]Cl, K[Au(CN)2 ] and [Ag(PEt3 )2 ]NO3 -were prepared and comparatively tested with auranofin on a representative panel of pathogens including Gram-positive, Gram-negative and Candida strains. Interestingly, all the gold and silver complexes tested were active on Gram-positive strains, with the gold complexes having greater efficacy. The effects of the gold compounds were potentiated to a larger extent than silver compounds when tested in combination with a permeabilizing agent. A number of relevant structure-activity relationships emerged from the comparative analysis of the observed antibacterial profiles, shedding new light on the underlying molecular mechanisms of the action of these compounds. PMID- 30252209 TI - Systematic analysis of genetic variants in patients with essential tremor. AB - BACKGROUND: Essential tremor (ET), a prevalent neurological disorder, is featured by postural and kinetic tremors in upper limbs. Studies of twins and families indicate an important role for genetic factors in ET development. There are substantial overlaps between ET and Parkinson's disease (PD). The aim of this study was to examine the possible roles of genetic variants in ET development. METHODS: A total of 200 Han Chinese ET patients and 432 ethnically matched normal controls were enrolled, and genetic analysis of 23 variants in 15 genes was performed. RESULTS: Genotypic and allelic frequencies of the melanocortin 1 receptor gene (MC1R) variant rs34090186 showed statistically significant differences in ET patients and controls (p = 0.027 and 0.028, odds ratio = 2.789 and 2.744, 95% confidence interval: 1.084-7.179 and 1.075-7.005). No statistically significant difference was revealed in either genotypic or allelic distributions of other variants or haplotypes (all p > 0.05). CONCLUSIONS: The discrepancies found in this study indicate the variant rs34090186 in the MC1R gene, some variants of which were reported to be related to increased risk of PD and melanoma, may play a risk role in ET, confirming a potential association between ET and PD. Evidence supporting ET-PD link will continue to accumulate and improve our understanding of any underlying mechanisms for both disorders. PMID- 30252211 TI - Control of pellicle biogenesis involves the diguanylate cyclases PdgA and PdgB, the c-di-GMP binding protein MxdA and the chemotaxis response regulator CheY3 in Shewanella oneidensis. AB - Shewanella oneidensis is an aquatic proteobacterium with remarkable respiratory and chemotactic abilities. It is also capable of forming biofilms either associated to surfaces (SSA-biofilm) or at the air-liquid interface (pellicle). We have previously shown that pellicle biogenesis in S. oneidensis requires the flagellum and the chemotaxis regulatory system including CheA3 kinase and CheY3 response regulator. Here we searched for additional factors involved in pellicle development. Using a multicopy library of S. oneidensis chromosomal fragments, we identified two genes encoding putative diguanylate cyclases (pdgA and pdgB) and allowing pellicle formation in the non-pellicle-forming cheY3-deleted mutant. A mutant deleted of both pdgA and pdgB is affected during pellicle development. By overexpressing phosphodiesterase encoding genes, we confirmed the key role of c di-GMP in pellicle biogenesis. The mxd operon, previously proposed to encode proteins involved in exopolysaccharide biosynthesis, is also essential for pellicle formation. In addition, we showed that the MxdA protein, containing a degenerate GGDEF motif, binds c-di-GMP and interacts with both CheY3 and PdgA. Therefore, we propose that pellicle biogenesis in S. oneidensis is controlled by a complex pathway that involves the chemotaxis response regulator CheY3, the two putative diguanylate cyclases PdgA and PdgB, and the c-di-GMP binding protein MxdA. PMID- 30252212 TI - Living out the mission. PMID- 30252210 TI - Myostatin inhibits glucose uptake via suppression of insulin-dependent and independent signaling pathways in myoblasts. AB - The glucose transporter 4 (Glut4) mediates insulin-dependent glucose uptake. Glut4 expression levels are correlated with whole-body glucose homeostasis. Insulin signaling is known to recruit Glut4 to the cell surface. Expression of Glut4 is subject to tissue-specific hormonal and metabolic regulation. The molecular mechanisms regulating skeletal muscle Glut4 expression remain to be elucidated. Myostatin (Mstn) is reported to be involved in the regulation of energy metabolism. While elevated Mstn levels in muscle are associated with obesity and type-2 diabetes in both human and mouse models, Mstn null mice exhibit immunity to dietary-induced obesity and insulin resistance. The molecular mechanisms by which Mstn initiates the development of insulin resistance and disorders of glucose disposal are not well delineated. Here we investigated effects of Mstn on insulin action in C2C12 cells. Mstn significantly reduced basal and insulin-induced IRS-1 tyrosine (Tyr495) phosphorylation, and expression and activation of PI3K, associated with diminished AKT phosphorylation and elevated GSK3beta phosphorylation at Ser9. In addition, Mstn inhibited Glut4 mRNA and protein expression, and reduced insulin-induced Glut4 membrane translocation and glucose uptake. Conversely, SB431542, a Smad2/3 inhibitor, significantly increased cellular response to insulin. Mstn decreased AMP-activated protein kinase (AMPK) activity accompanied by reduced Glut4 gene expression and glucose uptake, which were partially reversed by AICAR, an AMPK activator. These data suggest that Mstn inhibits Glut4 expression and insulin-induced Glut4 integration into cytoplasmic membranes and glucose uptake and that these changes are mediated by direct insulin-desensitizing effect and indirect suppression of AMPK activation. PMID- 30252213 TI - Winning Palliative Care Programs are Truly Patient- and Family-Centered. PMID- 30252214 TI - Untraditional Networks to Improve Population Health. PMID- 30252215 TI - SKILL OF THE FUTURE: Hospitals aim to cultivate management skills of the future on the front line. PMID- 30252217 TI - MOST WIRED: Hardwiring quality measures into care processes. PMID- 30252216 TI - ASSISTANCE WANTED: Stopping traffic. PMID- 30252219 TI - FREEZE FRAME: Youthful Resiliance. PMID- 30252218 TI - SERIOUS FUNDRAISING: Hospitals increasing efforts in philanthropy. PMID- 30252220 TI - ELECTROCHEMICAL REACTION: Cutting down on the carbons. PMID- 30252222 TI - Patient-Centered Care Isn't Good Enough. PMID- 30252221 TI - Behavioral Health Care: Four ways hospitals are improving. PMID- 30252223 TI - URGENT CARE 2.0 The evolution of an old model. PMID- 30252224 TI - A Hard Look at CANCER SERVICES Four health systems are testing new models of care and navment for cancer. PMID- 30252225 TI - Building Bonds with Nursing Homes. PMID- 30252226 TI - The four major domains of clinical transformation. PMID- 30252227 TI - From dances to barbecues to livestock 'drops'. PMID- 30252228 TI - Updates and controversies in the early management of sepsis and septic shock. AB - Sepsis is a common and life-threatening condition that requires early recognition and swift initial management. Diagnosis and treatment of sepsis and septic shock are fundamental for emergency clinicians, and include knowledge of clinical and laboratory indicators of subtle and overt organ dysfunction, infection source control, and protocols for prompt identification of the early signs of septic shock. This issue is a structured review of the literature on the management of sepsis, focusing on the current evidence, guidelines, and protocols. PMID- 30252229 TI - [Study of Social Skills or Assertive Behaviour in the Students of the Escuela Universitaria de Enfermeria of Huesca (Spain)]. AB - Objective: To know the level and characteristics of social skills (SS) in nursing students from the Escuela Universitaria de Enfermeria of Huesca (EUEH) during undergraduate training and its relationship with personal, educational and employment variables. Method: A descriptive cross-sectional study was conducted on 126 students enrolled in the course 2012-2013. As an evaluation instrument the Social Skills Scale of Gismero [1] was used. Results: The overall level of SS is 96.15 (SD = 12.06), which is in the 75th percentile of the sample scales of the Social Skills Scale. The Students of the second course are significantly more skilled (< 0.005) in dimension "defend their rights" (DII), with a score of 15.17 (SD = 1.95). In the students under 21 years, are significant differences <0.033) for the dimension "express requests' (DV) with result of 14.82 (SD = 2.73). Students without prior experience, with health scores of 14.84 (SD = 2.76), show significant differences (<0.002) in expression of requests (DV). Conclusions: The overall level of SS of our students is superior to the sample scales of the Social Skills Scale. In the assessment of Social Skills, deficits do not appear in any of the evaluated dimensions. The SS taken together have not been modified by the variables analyzed; only have responded to the effect of variables "grade", "age' and "previous experience", DII ("ability to defend their rights") and DV ("ability to express requests"). PMID- 30252230 TI - [User Perception After Participating in Group Education in Which the Active Patient Therapy was Applied. Qualitative Study]. AB - Introduction: The purpose of this study is to find the user opinion regarding the active patient dynamics, to analyze if the users think that their knowledge increased after taking part in the group education and to determine if they think that what they have learnt will help them modify their daily habits. Material and Methods: Phenomenological qualitative study. Participants: patients older than 14 years of age without cognitive impairment. Registering techniques: survey and field notes. The software NVIVO was used to analyze the results. Results: The active patient dynamics were positively valued by the participants, specially the following categories: attention, participation, personal resolutions, opinions, suggestions and recommendations. 74% of participants deemed their knowledge to have increased substantially and 52% expressed that the lessons learnt will help them modify their daily habits. Discussion and Conclusions: The Spanish department of health has a strategy to empower patients to take a more active role in their health through the Active Patient Therapy. This study concurs with it and it is positively valued by the users. This type of education is increasingly demanded and the nursing community is an ideal position to enlighten the population. The majority of participants thought that the lessons learnt will help them modify their daily habits. It would be interesting to analyze the realization of those resolutions in other workshops or as a follow-up in the nursing consults to reach healthy goals. PMID- 30252231 TI - [The Right to Information in the Older Person]. AB - Population aging is and will be a reality that should be paid attention to, not only because of the progressive increase in their share, but also because of the growing numbers of people living in dependency and, by extension, human and technical qualification as it is required by the nurse who takes care of them. Patients in Spain have gone from being passive recipients of health care to be a key part of the healthcare system, with health professionals being increasingly aware of this situation. The development of legislation on autonomy and rights of people contributed to that sick people are being better informed, and can participate in their health process. Nurses act on the basis of both the Spanish Legislation and the Code of Ethics of the Spanish Nursing, where key guidelines for ethical and legal performance of nurse are compiled. Nurses provide information on health status on a daily basis and as a consequence have to face major ethical dilemmas very often. As a general premise flight ends should be clear. Ends, such as the malfeasance produced the so-called information obstinacy (report a negative diagnosis or prognosis to a patient who does not want to know), as the conspiracy of silence in front of a patient who wants to be informed. Therefore, communication on the state of health of a person, in most cases, makes it easier so you can take appropriate measures to ensure the success of treatment and care or acceptance of their situation. PMID- 30252393 TI - ? PMID- 30252394 TI - [Nursing Care in the Limitation of Therapeutic Effort: Right To Life, Right to Die]. AB - Summary: Nowadays, technological development makes possible to keep alive a person by using life support in the ICU. However, extending life does not always entail a benefit for the patient. Sometimes it could produce some damages, causing the situation known like "therapeutic obstinacy]. Objective: Knowing the role played by nurses in the limitation of therapeutic effort (LTE). Methods: Literature review of original articles in both Spanish and English languages, published in Enfispo, Cuiden, IBECS, IME, SciELO and PubMed in the last 10 years. Results: A sort of 41 articles based in some kind of selective process. Conclusion: Decision-making in the nursing role is not currently described. Therefore, the proposal is to create a clinical practice guidelines related to LET in order to clarify the role of professionals involved in their practice. PMID- 30252395 TI - [Why, and How, Undertake Mixed Methods Design in Health Research: A Concrete Experience]. AB - Summary: The use of mixed methods to address health problems generates more knowledge of reality to get a more complete analysis of the problem under investigation. This is based on the fact that answers to the questions posed are as subjective as the individuals themselves. In that way, it is necessary quantitative and qualitative data for comprehensiveness (a more realistic and comprehensive approach to the object of the study). Objective: Reflect on this methodology through a practical example. Synthesis: We explain, through Participatory Education Program Focused on Colorectal Cancer Surgery Patient (mixed methods research project: multistrand, sequential and mixed in each of its three phases), what is this methodology and its advantages. The second phase of the study emerges from the results of the first one, and so on. At the end of the study a metaresult, that gives meaning and response to the study in its entirety, arises. Conclusion: Despite the challenges, mixed methods gives us a more accurate perspective of the phenomenon of study; it helps us to formulate the problem statement and the most appropriate way to study it; and finally, the scientific inferences obtained are more solidly supported. PMID- 30252396 TI - [The Care and the People and the ITC]. AB - The advancement and consolidation of information and communications technologies (ICT) has favored electronic medical records as the link between the clinical and patient health information. Appropriate use of ICT can improve and ensure coordination between different health professionals and levels of care. The aim of ICT is to facilitate the continuum of care and foster care efficiency and quality. However, professionals should make appropriate use of ICT based primarily on non-maleficence and confidentiality. The ICT:1. Improve care continuity.2. Facilitate integration and coordination, in order to provide personalized and excellent care between different levels of care.3. Reduce health costs (in patients of high complexity, for example).The ICT facilitate the non contact care, spacing the time between visits. The disadvantage of ICT are related to confidentiality and depersonalization of patient care. Nurses, by using ICT, play a leading role, given its role in health promotion and disease prevention. In these contexts, ICT can help innovate and improve the quality of care and health outcomes. In this regard, nurses have a great opportunity to innovate in care and take leadership in remote monitoring of patients. ICT have created new professionals, patients and providers challenges that should be studied in order to minimize problems and seek solutions. Social networks are useful for refining and deepening the relationship between nurses and patients, disseminating nursing research among nurses and nurse visibility. PMID- 30252397 TI - [Protocol in the Triage of Infant]. AB - Introduction: Infant triage system is used in emergency units to establish by means of a protocol, the really vital situations and classify the infant with a certain level of priority. Triage of these patients is complex due to the characteristics of the same and it is necessary to establish a clear protocol for the care of these patients. Objective: This study's objective is to define, identify and improve nursery performance on triage's area with this kind of patients with the aim to develope an improvement on patient's welfare and optimization of the emergency service. Conclusions: It is clearly identified by most authors and experts the importance of nursing training from the experience of professionals in pediatric emergency units and implementation of services that complement the infant patient care. PMID- 30252417 TI - Depression in Adolescents: AAP Updates Guidelines on Diagnosis and Treatment. PMID- 30252418 TI - Abdominal Wall Pain: Clinical Evaluation, Differential Diagnosis, and Treatment. AB - Abdominal wall pain is often mistaken for intra-abdominal visceral pain, resulting in expensive and unnecessary laboratory tests, imaging studies, consultations, and invasive procedures. Those evaluations generally are nondiagnostic, and lingering pain can become frustrating to the patient and clinician. Common causes of abdominal wall pain include nerve entrapment, hernia, and surgical or procedural complications. Anterior cutaneous nerve entrapment syndrome is the most common and frequently missed type of abdominal wall pain. This condition typically presents with acute or chronic localized pain at the lateral edge of the rectus abdominis that worsens with position changes or increased abdominal muscle tension. Abdominal wall pain should be suspected in patients with no symptoms or signs of visceral etiology and a localized small tender spot. A positive Carnett test, in which tenderness stays the same or worsens when the patient tenses the abdominal muscles, suggests abdominal wall pain. A local anesthetic injection can confirm the diagnosis when there is 50% postprocedural pain improvement. Point-of-care ultrasonography may help rule out other abdominal wall pathologies and guide injections. The management of abdominal wall pain depends on the etiology. Reassurance and patient education can be helpful. Local injection with an anesthetic and a corticosteroid is an effective treatment for anterior cutaneous nerve entrapment syndrome, with an overall response rate of 70% to 99%. For refractory cases that require more than two injections, surgical neurectomy generally resolves the pain. PMID- 30252419 TI - Aging Well: Poetry Can Help. PMID- 30252421 TI - Fleshy Mass Passed Vaginally by a Young Woman. PMID- 30252420 TI - Anemia in Older Adults. AB - Anemia is associated with increased morbidity and mortality in older adults. Diagnostic cutoff values for defining anemia vary with age, sex, and possibly race. Anemia is often asymptomatic and discovered incidentally on laboratory testing. Patients may present with symptoms related to associated conditions, such as blood loss, or related to decreased oxygen-carrying capacity, such as weakness, fatigue, and shortness of breath. Causes of anemia in older adults include nutritional deficiency, chronic kidney disease, chronic inflammation, and occult blood loss from gastrointestinal malignancy, although in many patients the etiology is unknown. The evaluation includes a detailed history and physical examination, assessment of risk factors for underlying conditions, and assessment of mean corpuscular volume. A serum ferritin level should be obtained for patients with normocytic or microcytic anemia. A low serum ferritin level in a patient with normocytic or microcytic anemia is associated with iron deficiency anemia. In older patients with suspected iron deficiency anemia, endoscopy is warranted to evaluate for gastrointestinal malignancy. Patients with an elevated serum ferritin level or macrocytic anemia should be evaluated for underlying conditions, including vitamin B12 or folate deficiency, myelodysplastic syndrome, and malignancy. Treatment is directed at the underlying cause. Symptomatic patients with serum hemoglobin levels of 8 g per dL or less may require blood transfusion. Patients with suspected iron deficiency anemia should be given a trial of oral iron replacement. Lower-dose formulations may be as effective and have a lower risk of adverse effects. Normalization of hemoglobin typically occurs by eight weeks after treatment in most patients. Parenteral iron infusion is reserved for patients who have not responded to or cannot tolerate oral iron therapy. PMID- 30252422 TI - Interventions for Increasing Fruit and Vegetable Consumption in Children Five Years and Younger. PMID- 30252423 TI - Family Physicians Can Manage Adults with Hepatitis C. PMID- 30252424 TI - Hormone Therapy for Primary Prevention of Cardiovascular Disease in Postmenopausal Women. PMID- 30252427 TI - Therapist-Guided, Internet-Delivered Cognitive Behavior Therapy for Anxiety. PMID- 30252425 TI - Mechanical Low Back Pain. AB - Low back pain is usually nonspecific or mechanical. Mechanical low back pain arises intrinsically from the spine, intervertebral disks, or surrounding soft tissues. Clinical clues, or red flags, may help identify cases of nonmechanical low back pain and prompt further evaluation or imaging. Red flags include progressive motor or sensory loss, new urinary retention or overflow incontinence, history of cancer, recent invasive spinal procedure, and significant trauma relative to age. Imaging on initial presentation should be reserved for when there is suspicion for cauda equina syndrome, malignancy, fracture, or infection. Plain radiography of the lumbar spine is appropriate to assess for fracture and bony abnormality, whereas magnetic resonance imaging is better for identifying the source of neurologic or soft tissue abnormalities. There are multiple treatment modalities for mechanical low back pain, but strong evidence of benefit is often lacking. Moderate evidence supports the use of nonsteroidal anti-inflammatory drugs, opioids, and topiramate in the short-term treatment of mechanical low back pain. There is little or no evidence of benefit for acetaminophen, antidepressants (except duloxetine), skeletal muscle relaxants, lidocaine patches, and transcutaneous electrical nerve stimulation in the treatment of chronic low back pain. There is strong evidence for short-term effectiveness and moderate-quality evidence for long-term effectiveness of yoga in the treatment of chronic low back pain. Various spinal manipulative techniques (osteopathic manipulative treatment, spinal manipulative therapy) have shown mixed benefits in the acute and chronic setting. Physical therapy modalities such as the McKenzie method may decrease the recurrence of low back pain and health care expenditures. Physical therapy modalities such as the McKenzie method may decrease the recurrence of low back pain and use of health care. Educating patients on prognosis and incorporating psychosocial components of care such as identifying comorbid psychological problems and barriers to treatment are essential components of long-term management. PMID- 30252428 TI - Consider Muscle Strengthening for Plantar Fasciitis. PMID- 30252429 TI - Low Back Pain. PMID- 30252430 TI - Z-Scheme Au@Void@g-C3N4/SnS Yolk-Shell Heterostructures for Superior Photocatalytic CO2 Reduction under Visible Light. AB - Au@g-C3N4/SnS yolk-shell Z-scheme photocatalysts are fabricated by a simple template-assisted strategy. The l-cysteine can offer the amine groups and meanwhile anchor on the surface of g-C3N4 during solvothermal reaction and thus contributes greatly to the enhanced carbon dioxide adsorption capability. This Z scheme photocatalytic reduction mechanism of Au@g-C3N4/SnS performs valuable functions in the reaction, leading to CH4 generation much earlier and higher concentration than that of Au@g-C3N4. Meanwhile, the unique yolk-shell structure can make the light bounce back and forth in the cavity and thus enhances the availability ratio of light. The application of small amount of noble metal cocatalysts and the large Brunauer-Emmett-Teller surface areas are also benefited for the enhanced photocatalytic activities. Hence, this novel material exhibits a distinguished reduction performance for CO2 reduction under visible light. The highest yields of CH4 (3.8 MUmol g-1), CH3OH (5.3 MUmol g-1), and CO (17.1 MUmol g-1) can be obtained for the sample of Au@g-C3N4/SnS (SnS 41.5%), which is higher than other latest reported g-C3N4-based photocatalysts for CO2 photoreduction including coupled with semiconductors and noble metal cocatalysts. This strategy might represent a novel way for the effective transition of CO2 to clean fuels and can also be enormous feasible utilization in the photocatalytic field. PMID- 30252431 TI - Three-Electron Redox Enabled Dithiocarboxylate Electrode for Superior Lithium Storage Performance. AB - Organic carboxyl compounds are promising anode candidates for lithium ion batteries in which oxygen-related redox dominates the reaction mechanisms. Herein, two nanostructured organic electrodes of pi-extended naphthyl-based dicarboxylate and dithiocarboxylate compounds, namely sodium naphthalene-2,6 dicarboxylate (SND) and sodium naphthalene-2,6-bis(carbothioate) (SNB) are first synthesized and investigated systematically for lithium ion battery. Through introducing less electronegative sulfur atoms into carboxylic groups at molecular level, SNB exhibits a different voltage profile and delivers higher reversible capacity of 280 mAh g-1 than SND (198 mAh g-1) at a current density of 50 mA g-1. A combination of electrochemical properties and DFT calculations reveals that SNB could reversibly store three Li+ per formula unit, while SND only stores two Li+. The present work offers a new strategy to develop redox molecules with tunable redox potentials and accommodation more alkaline ions for high performance battery systems. PMID- 30252432 TI - Photomechanical and Chemomechanical Actuation Behavior of Graphene Poly(dimethylsiloxane)/Gold Bilayer Tube for Multimode Soft Grippers and Volatile Organic Compounds Detection Applications. AB - Graphene polymers-based soft actuators driven by infrared (IR) light have attracted wide attention recently. However, the scientific fraternity is striving hard in unraveling the area of actuators that could be triggered by IR light along with chemicals. The fabricating methodology of multiresponsive soft actuators based on graphene nanoplatelets (GNPs)-poly(dimethylsiloxane) (PDMS) nanocomposite/gold bilayers, ensuring large, fast, and reversible response, has been illustrated. The actuators display a novel dual-mode operation as photomechanical and chemomechanical actuation. The actuators are realized by depositing a thin film (100 nm) of gold on GNP-PDMS nanocomposite films resulting tubular structure on account of thermal residual stress. The actuation response of this structure upon its exposure to IR light and chemicals was measured in terms of percentage opening and degree of unscroll, respectively. The three dimensional tubular structure is transformed into a two-dimensional sheet within 8 s under IR light irradiation. The same structures were also tested in various organic solvents like methanol, ethanol, acetone, isopropyl alcohol, and aldehydes, but the actuation has been observed only in acetone and aldehydes. This tubular actuator unscrolls completely and then scrolls in opposite direction along with tube axis shift through 90 degrees during its exposure to acetone (liquid/vapors) and aldehydes. Few applications of these actuators, such as multimode soft grippers for on-demand capture/release of objects (with weight 1.2 times the actuator's own weight) and volatile organic compounds detection module, have been demonstrated. The combination of surface micromachining techniques of microelectromechanical systems process with this smart material may find applications in drug-delivery systems with precise control, soft robotics, and noninvasive diagnosis of diabetes and breast/lung cancers. PMID- 30252433 TI - Interface Properties Probed by Active THz Surface Emission in Graphene/SiO2/Si Heterostructures. AB - Graphene/semiconductor heterostructures demonstrate an improvement of traditional electronic and optoelectronic devices because of their outstanding charge transport properties inside and at the interfaces. However, very limited information has been accessed from the interfacial properties by traditional measurement. Herein, we present an active THz surface emission spectroscopy for the interface build-in potential and charge detrapping time constant evaluation from the interface of graphene on SiO2/Si (Gr/SiO2/Si). The active THz generation presents an intuitive insight into the depletion case, weak inversion case, and strong inversion case at the interface in the heterostructure. By analyzing the interface electric-field-induced optical rectification (EFIOR) in a strong inversion case, the intrinsic build-in potential is identified as -0.15 V at Gr/SiO2/Si interface. The interface depletion layer presents 44% positive THz intrinsic modulation by the reverse gate voltage and 70% negative THz intrinsic modulation by the forward gate voltage. Moreover, a time-dependent THz generation measurement has been used to deduce the charge detrapping decay time constant. The investigation will not only highlight the THz surface emission spectroscopy for the graphene-based interface analysis but also demonstrate the potential for the efficient THz intrinsic modulation as well as the enhancement of THz emission by the heterostructures. PMID- 30252434 TI - Relationships Between Crystal, Internal Microstructures, and Physicochemical Properties of Copper-Zinc-Iron Multinary Spinel Hierarchical Nano-microspheres. AB - Rational design and fabrication of high quality complex multicomponent spinel ferrite with specific microstructures and solar light harvestings toward CO2 reduction and antibiotic degradation to future energetic and catalytic applications are highly desirable. In this study, novel copper-zinc-iron multinary spinel hierarchical nano-microspheres (MSHMs) with different internal structures (solid nano-microspheres, yolk-shell hollow nano-microspheres, and double-shelled hollow nano-microspheres) have been successfully developed by a facile self-templated solvothermal strategy. The morphology and structure, optical, as well as photoinduced redox reactions including interfacial charge carrier behaviors and the intrinsic relationship of structure-property between intrinsic nano-microstructures and physicochemical performance of copper-zinc iron ferrite MSHMs composites were systematically investigated with the assistance of various on- and/or off- line physical-chemical means and deeply elucidated in terms of the research outcomes. It is demonstrated that the modification of the interior microstructures can be applied to tune the catalytic properties of multinary spinel by tailoring the temperature programming to fine control the two opposite forces of contraction (Fc) and adhesion (Fa). Among various internal microstructures, the obtained double-shelled copper-zinc-iron MSHMs exhibited the superior catalytic performance toward 8.8 and 38 MUmol for H2 and CO productions as well as 80.4% removal of sulfamethoxazole antibiotics. As evidenced from primary characterizations, for example, combined steady-state PL, ns-TAS, and Mossbauer and sequential investigations, the remarkable improvements in the catalytic activity can be primarily attributed to several crucial factors, for example, the more effective e--h+ spatial separations and interfacial transfers, multiple internal light scattering, higher photonic energy harvesting and effective reactive oxygen species generation with long radical lifetimes. The current research provides new insights into the molecular design of novel copper zinc-iron multinary spinels and the intrinsic relationship of structure-property between interior structures (e.g., different crystal texture, morphologies structures) and the physicochemical performance of the aforementioned multinary spinels. PMID- 30252435 TI - Modular Design of Porous Soft Materials via Self-Organization of Metal-Organic Cages. AB - Metal-organic frameworks (MOFs) and porous coordination polymers (PCPs) have been well-recognized as emerging porous materials that afford highly tailorable and well-defined nanoporous structures with three-dimensional lattices. Because of their microporous nature, MOFs can accommodate small molecules in their lattice structure, thus discriminating them on the basis of their size and physical properties and enabling their separation even in the gas phase. Such characteristics of MOFs have attracted significant attention in recent years for diverse applications and have ignited a worldwide race toward their development in both academic and industrial fields. Most recently, new challenges in porous materials science demand processable liquid, melt, and amorphous forms of MOFs. This trend will provide a new fundamental class of microporous materials for further widespread applications in many fields. In particular, the application of flexible membranes for gas separation is expected as an efficient solution to tackle current energy-intensive issues. To date, amorphous MOFs have been prepared in a top-down approach by the introduction of disorder into the parent frameworks. However, this new paradigm is still in its infancy with respect to the rational design principles that need to be developed for any approach that may include bottom-up synthesis of porous soft materials. Herein we describe recent progress in bottom-up "modular" approaches for the synthesis of porous, processable MOF-based materials, wherein metal-organic cages (MOCs), alternatively called metal-organic polyhedra (MOPs), are used as "modular cavities" to build porous soft materials. The outer periphery of a MOP is decorated with polymeric and dendritic side chains to obtain a polymer-grafted MOP, imparting both solution and thermal processability to the MOP cages, which have an inherent nanocavity along with high tailorability analogous to MOFs. Well ordered MOP assemblies can be designed to obtain phases ranging from crystals to liquid crystals, allowing the fabrication of flexible free-standing sheets with preservation of the long-range ordering of MOPs. Furthermore, future prospects of the modular design for porous soft materials are provided with the anticipation that the bottom-up design will combine porous materials and soft matter sciences, leading to the discovery and development of many unexplored new materials and devices such as MOF-based self-healing membranes possessing well-defined nanochannels. The macroscopic alignment of channels can be controlled by external factors, including electric and magnetic fields, external forces, and modified surfaces (templating and patterning), which are conventionally used for engineering of soft materials. PMID- 30252436 TI - Caffeine Modulates Spontaneous Adenosine and Oxygen Changes during Ischemia and Reperfusion. AB - Adenosine is an endogenous neuroprotectant that modulates vasodilation in the central nervous system. Oxygen changes occur when there is an increase in local cerebral blood flow and thus are a measure of vasodilation. Transient oxygen events following rapid adenosine events have been recently discovered, but the relationship between adenosine and blood flow change during ischemia/reperfusion (I/R) has not been characterized. Caffeine is a nonselective adenosine receptor antagonist that can modulate the effects of adenosine in the brain, but how it affects adenosine and oxygen levels during I/R is also unknown. In this study, extracellular changes in adenosine and oxygen were simultaneously monitored using fast-scan cyclic voltammetry during bilateral common carotid artery occlusion (BCCAO) and the effects of a specific A2A antagonist, SCH 442416, or general antagonist, caffeine, were studied. Measurements were made in the caudate-putamen for 1 h of normoxia, followed by 30 min of BCCAO and 30 min of reperfusion. The frequency and number of both adenosine and oxygen transient events significantly increased during I/R. The specific A2A antagonist, SCH 442416 (3 mg/kg, i.p.), eliminated the increase in adenosine and oxygen events caused by I/R. The general adenosine receptor antagonist, caffeine (100 mg/kg, i.p.), decreased the frequency of adenosine and oxygen transient events during I/R. These results demonstrate that, during BCCAO, there are more rapid release events of the neuromodulator adenosine and correlated local oxygen changes, and these rapid, local effects are dampened by caffeine and other A2A antagonists. PMID- 30252437 TI - Understanding Central Nervous System Effects of Deliriant Hallucinogenic Drugs through Experimental Animal Models. AB - Hallucinogenic drugs potently alter human behavior and have a millennia-long history of use for medicinal and religious purposes. Interest is rapidly growing in their potential as CNS modulators and therapeutic agents for brain conditions. Antimuscarinic cholinergic drugs, such as atropine and scopolamine, induce characteristic hyperactivity and dream-like hallucinations and form a separate group of hallucinogens known as "deliriants". Although atropine and scopolamine are relatively well-studied drugs in cholinergic physiology, deliriants represent the least-studied class of hallucinogens in terms of their behavioral and neurological phenotypes. As such, novel approaches and new model organisms are needed to investigate the CNS effects of these compounds. Here, we comprehensively evaluate the preclinical effects of deliriant hallucinogens in various animal models, their mechanisms of action, and potential interplay with other signaling pathways. We also parallel experimental and clinical findings on deliriant agents and outline future directions of translational research in this field. PMID- 30252438 TI - Stress-Induced Alterations of Norepinephrine Release in the Bed Nucleus of the Stria Terminalis of Mice. AB - Stress can drive adaptive changes to maintain survival during threatening stimuli. Chronic stress exposure, however, may result in pathological adaptations. A key neurotransmitter involved in stress signaling is norepinephrine. Previous studies show that acute stress elevates norepinephrine levels in the bed nucleus of the stria terminalis (BNST), a critical node regulating anxiety and upstream of stress responses. Here, we use mice expressing channelrhodopsin in norepinephrine neurons to selectively activate terminals in the BNST, and measure norepinephrine release with optogenetics-assisted fast-scan cyclic voltammetry (FSCV). We demonstrate that while corticosterone habituates to chronic restraint stress, cFos activation of medullary norepinephrine neurons shows equivalent activation under both acute and chronic stress conditions. Mice exposed to a single restraint session show an identical optically stimulated norepinephrine release profile compared to that of unexposed mice. Mice experiencing 5 days of restraint stress, however, show elevated norepinephrine release across multiple stimulation parameters, and reduced sensitivity to the alpha2-adrenergic receptor (AR) antagonist idazoxan. These data are the first to examine norepinephrine release in the BNST to tonic and phasic stimulation frequencies, and confirm that repeated stress alters autoreceptor sensitivity. PMID- 30252439 TI - Design, Synthesis, and Biological Evaluation of Dual-Target Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 9A (PDE9A) for the Treatment of Alzheimer's Disease. AB - A series of dual-target AChE/PDE9A inhibitor compounds were designed, synthesized, and evaluated as anti-Alzheimer's Disease (AD) agents. Among these target compounds, 11a (AChE: IC50 = 0.048 MUM; PDE9A: IC50 = 0.530 MUM) and 11b (AChE: IC50 = 0.223 MUM; PDE9A: IC50 = 0.285 MUM) exhibited excellent and balanced dual-target AChE/PDE9A inhibitory activities. Meanwhile, those two compounds possess good blood-brain barrier (BBB) penetrability and low neurotoxicity. Especially, 11a and 11b could ameliorate learning deficits induced by scopolamine (Scop). Moreover, 11a could also improve cognitive and spatial memory in Abeta25-35-induced cognitive deficit mice in the Morris water-maze test. In summary, our research developed a series of potential dual-target AChE/PDE9A inhibitors, and the data indicated that 11a was a promising candidate drug for the treatment of AD. PMID- 30252440 TI - Trapped Aqueous Films Lubricate Highly Hydrophobic Surfaces. AB - Friction at hydrophobic surfaces in aqueous media is ubiquitous ( e.g., prosthetic implants, contact lenses, microfluidic devices, biological tissue) but is not well understood. Here, we measure directly, using a surface force balance, both normal stresses and sliding friction in an aqueous environment between a hydrophilic surface (single-crystal mica) and the stable, molecularly smooth, highly hydrophobic surface of a spin-cast fluoropolymer film. Normal force versus surface separation profiles indicate a high negative charge density at the water immersed fluoropolymer surface, consistent with previous studies. Sliding of the compressed surfaces under water or in physiological-level salt solution (0.1 M NaCl) reveals strikingly low boundary friction (friction coefficient MU ~ 0.003 0.009) up to contact pressures of at least 50 atm. This is attributed largely to hydrated counterions (protons and Na+ ions) trapped in thin interfacial films between the compressed, sliding surfaces. Our results reveal how frictional dissipation may occur at hydrophobic surfaces in water and how modification of such surfaces may suppress this dissipation. PMID- 30252441 TI - Small Molecule Nanodrug Assembled of Dual-Anticancer Drug Conjugate for Synergetic Cancer Metastasis Therapy. AB - The nanocarrier-based delivery system has emerged as a promising candidate for cancer therapy; nevertheless, their quality problems, variation between batches, and carrier-related toxicity issues have restricted their clinical utilization. Compared with traditional carrier-based nanoparticles, carrier-free nanodrug delivery systems preferred to overcome all these drawbacks and will have a wide range of applications in biomedicine and nanotechnology. Herein, we developed a novel carrier-free nanodrug Asp-UA consisted of the classical drug aspirin and the natural plant drug UA via a green and simple approach. The Asp-UA NPs were investigated for shape, particle size, zeta potential, stability, and UV-vis spectroscopy absorption. Cellular uptake study showed that Asp-UA NPs could be easily internalized by HepG2 cells; cellular study demonstrated that Asp-UA NPs held better inhibitory efficiency on tumor metastasis with low toxicity in vitro and in vivo. Moreover, Asp-UA NPs could obviously suppress the progress of cancer metastasis by H22 cells in vivo. Overall, Asp-UA NPs possess a variety of advantages and hold promise to become an alternative to the treatment of cancer metastasis. PMID- 30252442 TI - Optimal Navigation of Self-Propelled Colloids. AB - Controlling the navigation of self-propelled, Brownian colloids in complex microstructured environments ( e.g., porous media and tumor vasculature) is important to emerging applications ( e.g., enhanced oil recovery and drug delivery). Here, we report a feedback control strategy by which to navigate self propelled colloids through free space and increasingly complex mazes. Colloid rod position and orientation within mazes is sensed in real time, and instantaneous propulsion along the rod long axis can be actuated via light intensity. However, because uncontrolled rod rotational diffusion determines the propulsion direction, feedback control based on a policy is required to decide how to actuate propulsion magnitude versus colloid position and orientation within mazes. By considering stochastic rod dynamics including self-propulsion, translational-rotational diffusion, and rod-maze interactions, a Markov decision process framework is used to determine optimal control policies to navigate between start and end points in minimal time. The free-space navigation optimal policy effectively reduces to a simple heuristic in which propulsion is actuated only when particles point toward the target. The emergent structure of optimal control policies in mazes is based on the practice of globally following the shortest geometric paths; however, locally, propulsion is actuated to either follow paths toward the target or to produce collisions with maze features as part of generating more-favorable positions and orientations. Findings show how the coupled effects of maze size, propulsion speed, control update time, and relative particle translational and rotational diffusivities influence navigation performance. PMID- 30252443 TI - Directed Assembly of Au-Tipped 1D Inorganic Nanostructures via Nanolithographic Docking. AB - Controlled assembly of nanostructures is a key challenge in nanotechnology. In this work, we introduce an approach for the controlled assembly of 1D nanodumbbells-Au-tipped semiconductor nanorods-into arbitrary 2D higher architectures, by their chemical docking to nanopatterned functionalities. We realized the docking functionalities via nanoimprinted metallic nanodots functionalized with an organic monolayer, whose terminal thiol groups chemically bind the nanodumbbell tips. We demonstrated that the functional nanopattern encodes the nanodumbbell assembly and can be designed to deterministically position nanodumbbells in two possible modes. In the single-docking mode, the nanodot arrays are designed with a spacing that exceeds the nanodumbbell length, restricting each nanodumbbell to dock with one edge and physically connect with its free edge to one of the neighboring nanodumbbells. Alternatively, in the double-docking mode, the nanodots are spaced to exactly fit the nanodumbbell length, allowing nanodumbbell docking with both edges. We found that the docking kinetics can be described by a random attachment model, and verified that for the used docking chemistry, nanodumbbells that are docked to the same dot do not interact with each other. Our work demonstrates the possibility for massively parallel positioning of sub-100 nm 1D semiconductor nanostructures, and can potentially enable their future integration into functional nanodevices and nanosystems. PMID- 30252444 TI - Maximizing Sequence Coverage in Top-Down Proteomics By Automated Multimodal Gas Phase Protein Fragmentation. AB - Intact protein sequencing by tandem mass spectrometry (MS/MS), known as top-down protein sequencing, relies on efficient gas-phase fragmentation at multiple experimental conditions to achieve extensive amino acid sequence coverage. We developed the "topdownr" R-package for automated construction of multimodal (i.e., involving CID, HCD, ETD, ETciD, EThcD, and UVPD) MS/MS fragmentation methods on an orbitrap instrument platform and systematic analysis of the resultant spectra. We used topdownr to generate and analyze thousands of MS/MS spectra for five intact proteins of 10-30 kDa. We achieved 90-100% coverage for the proteins tested and derived guiding principles for efficient sequencing of intact proteins. The data analysis workflow and statistical models of topdownr software and multimodal MS/MS experiments provide a framework for optimizing MS/MS sequencing for any intact protein. Refined topdownr software will be suited for comprehensive characterization of protein pharmaceuticals and eventually also for de novo sequencing and detailed characterization of intact proteins. PMID- 30252445 TI - glyXtoolMS: An Open-Source Pipeline for Semiautomated Analysis of Glycopeptide Mass Spectrometry Data. AB - For glycoproteomic analyses several web tools and standalone software packages have been developed over the recent years. These tools support or replace the time-consuming, cumbersome, and error-prone manual spectra analysis and glycopeptide identification. However, existing software tools are usually tailored to one fragmentation technique and only present the final analysis results. This makes manual inspection and correction of intermediate results difficult or even impossible. We solved this problem by dividing the analysis tasks into modular tools with defined functions, which are executed within a software pipeline with a graphical editor. This gives users a maximum of flexibility and control over the progress of analyses. Here, we present the open source Python software suite glyXtoolMS, developed for the semiautomated analysis of N- and O-glycopeptide fragmentation data. glyXtoolMS is built around the pipeline engine of OpenMS (TOPPAS) and provides a glycopeptide analysis toolbox for the analysis, interpretation, and visualization of glycopeptide spectra. The toolbox encompasses (a) filtering of fragment spectra using a scoring scheme for oxonium ions, (b) in silico digest of protein sequences to collect glycopeptide candidates, (c) precursor matching to possible glycan compositions and peptide sequences, and finally, (d) an annotation tool for glycopeptide fragment ions. The resulting analysis file can be visualized by the glyXtool MS Evaluator, enabling further manual analysis, including inspection, verification, and various other options. Using higher-energy collisional dissociation data from human immunoglobulin gamma (IgG) and human fibrinogen tryptic digests, we show that glyXtoolMS enables a fast, flexible, and transparent analysis of N- and O glycopeptide samples, providing the user a versatile tool even for explorative data analysis. glyXtoolMS is freely available online on https://github.com/glyXera/glyXtoolMS licensed under the GPL-3.0 open-source license. The test data are available via ProteomeXchange with identifier PXD009716. PMID- 30252446 TI - Modulating the Electronic Properties of Graphene by Self-Organized Sulfur Identical Nanoclusters and Atomic Superlattices Confined at an Interface. AB - Ordered atomic-scale superlattices on a surface hold great interest both for basic science and for potential applications in advanced technology. However, controlled fabrication of superlattices down to the atomic scale has proven exceptionally challenging. Here we develop a segregation method to realize self organization of S superlattices at the interface of graphene and S-rich Cu substrates. Via scanning tunneling microscope measurements, we directly image well-ordered identical nanocluster superlattices and atomic superlattices under the cover of graphene. Scanning tunneling spectra show that the superlattices in turn could modulate the electronic structure of top-layer graphene. Importantly, a special-ordered S monatomic superlattice commensurate with a graphene lattice is found to drive semimetal graphene into a symmetry-broken phase-the electronic Kekule distortion phase-which opens a bandgap of ~245 meV. PMID- 30252448 TI - Structural and Biochemical Analysis of the Citrate-Responsive Mechanism of the Regulatory Domain of Catabolite Control Protein E from Staphylococcus aureus. AB - Catabolite control protein E (CcpE) is a LysR-type transcriptional regulator that positively regulates the transcription of the first two enzymes of the TCA cycle, namely, citZ and citB, by sensing accumulated intracellular citrate. CcpE comprises an N-terminal DNA-binding domain and a C-terminal regulatory domain (RD) and senses citrate with conserved arginine residues in the RD. Although the crystal structure of the apo SaCcpE-RD has been reported, the citrate-responsive and DNA-binding mechanisms by which CcpE regulates TCA activity remain unclear. Here, we report the crystal structure of the apo and citrate-bound SaCcpE-RDs. The SaCcpE-RD exhibits conformational changes between the two subdomains via hinge motion of the central beta4 and beta10 strands. The citrate molecule is located in a positively charged cavity between the two subdomains and interacts with the highly conserved Ser98, Leu100, Arg145, and Arg256 residues. Compared with that of the apo SaCcpE-RD, the distance between the two subdomains of the citrate-bound SaCcpE-RD is more than ~3 A due to the binding of the citrate molecule, and this form exhibits a closed structure. The SaCcpE-RD exhibits various citrate-binding-independent conformational changes at the contacting interface. The SaCcpE-RD prefers the dimeric state in solution, whereas the SaCcpE-FL prefers the tetrameric state. Our results provide insight into the molecular function of SaCcpE. PMID- 30252447 TI - Multiplexed Middle-Down Mass Spectrometry as a Method for Revealing Light and Heavy Chain Connectivity in a Monoclonal Antibody. AB - Pairing light and heavy chains in monoclonal antibodies (mAbs) using top-down (TD) or middle-down (MD) mass spectrometry (MS) may complement the sequence information on single chains provided by high-throughput genomic sequencing and bottom-up proteomics, favoring the rational selection of drug candidates. The 50 kDa F(ab) subunits of mAbs are the smallest structural units that contain the required information on chain pairing. These subunits can be enzymatically produced from whole mAbs and interrogated in their intact form by TD/MD MS approaches. However, the high structural complexity of F(ab) subunits requires increased sensitivity of the modern TD/MD MS for a comprehensive structural analysis. To address this and similar challenges, we developed and applied a multiplexed TD/MD MS workflow based on spectral averaging of tandem mass spectra (MS/MS) across multiple liquid chromatography (LC)-MS/MS runs acquired in reduced or full profile mode using an Orbitrap Fourier transform mass spectrometer (FTMS). We first benchmark the workflow using myoglobin as a reference protein, and then validate it for the analysis of the 50 kDa F(ab) subunit of a therapeutic mAb, trastuzumab. Obtained results confirm the envisioned benefits in terms of increased signal-to-noise ratio of product ions from utilizing multiple LC-MS/MS runs for TD/MD protein analysis using mass spectral averaging. The workflow performance is compared with the earlier introduced multiplexed TD/MD MS workflow based on transient averaging in Orbitrap FTMS. For the latter, we also report on enabling absorption mode FT processing and demonstrate its comparable performance to the enhanced FT (eFT) spectral representation. PMID- 30252449 TI - A Porphyrin Dimer-GdDOTA Conjugate as a Theranostic Agent for One- and Two-Photon Photodynamic Therapy and MRI. AB - A molecular theranostic agent designed for photodynamic therapy (PDT) treatment in the near-infrared and for imaging tissue tumors with magnetic resonance imaging (MRI) is reported. It consists of a linear pi-conjugated Zn(II) porphyrin dimer linked at each extremity to a GdDOTA-type complex. This agent has shown very promising potential for PDT applications with good singlet oxygen generation in DMSO and high linear absorption in the near-infrared (lambdamax = 746 nm, epsilon ~ 105 M-1 cm-1). Moreover, this molecule has a propensity for two-photon excited PDT with high two-photon cross sections (~8000 GM in 880-930 nm range), which should allow for deeper tumor treatments and higher spatial precision as compared to conventional one-photon PDT. Regarding the MRI contrast agent properties, the molecule has shown superior relaxivity (14.4 mM-1 s-1 at 40 MHz, 298 K) in comparison to clinical contrast agents and the ability to be internalized in cells, thanks to its amphiphilic character. Irradiation of HeLa cells using either one-photon (740 nm) or two-photon excitation (910 nm) has led in both cases to important cell death. PMID- 30252451 TI - Influence of Regioselectively Sulfated Cellulose on in Vitro Vascularization of Biomimetic Bone Matrices. AB - Vascularization is essential for the regeneration of bone tissue within composite material. We measured the effect of regioselectively modified cellulose/hemicellulose as an additive for porous scaffolds of collagen/hydroxyapatite nanocomposite on the tubule formation of human vascular endothelial cells. Using a coculture of endothelial cells and fibroblasts, endothelial cells formed a network of tubules within an incubation time of 14 to 24 days. A cellulose sulfate with irregular sulfation pattern along the polysaccharide backbone (13-TACS-01) led to an additional increase in vascular endothelial growth factor (VEGF)-induced tubule formation, as observed in an in vitro angiogenesis assays. In contrast with structurally different heparin, these cellulose sulfates have no apparent affinity to VEGF. Their impact on endothelial function may possibly be due to interactions with cell surface receptors/soluble factors not yet defined. PMID- 30252450 TI - Self-Assembly of Cellulose in Super-Cooled Ionic Liquid under the Impact of Decelerated Antisolvent Infusion: An Approach toward Anisotropic Gels and Aerogels. AB - Assembly of (bio)polymers into long-range anisotropic nanostructured gels and aerogels is of great interest in advanced material engineering since it enables directional tuning of properties, such as diffusivity, light, heat, and sound propagation, cell proliferation, and mechanical properties. Here we present an approach toward anisotropic cellulose II gels and aerogels that employs specific diffusion and phase separation phenomena occurring during decelerated infusion of an antisolvent into isotropic supercooled solutions of cellulose in an ionic liquid to effectuate supramolecular assembly of cellulose in anisotropic colloidal network structures. At the example of the distillable ionic liquid 1,1,3,3-tetramethylguanidinium acetate, the antisolvent ethanol, and spherocylindrical porous molds, we demonstrate that the proposed facile, environmental-benign and versatile route affords gels and aerogels whose specific anisotropic nanomorphology and properties reflect the preferred supramolecular cellulose orientation during phase separation, which is perpendicular to the direction of antisolvent diffusion. Comprehensive X-ray scattering experiments revealed that the (aero)gels are composed of an interconnected, fibrous, highly crystalline (CrI ~ 72%), cellulose II with a cross-sectional Guinier radius of the struts of about 2.5 nm, and an order parameter gradient from about 0.1 to 0.2. The obtained gels and aerogels feature high specific surface areas (350-630 m2 g-1) and excellent mechanical properties like high toughness (up to 471 kJ m-3 for a 60% compression, rhoB = 80 mg cm-3) and resilience (up to 13.4 kJ m-3, rhoB = 65 mg cm-3). PMID- 30252452 TI - Comment on "Examining Natural Attenuation and Acute Toxicity of Petroleum-Derived Dissolved Organic Matter with Optical Spectroscopy". PMID- 30252453 TI - Is seasonal households' consumption good for the nexus carbon/water footprint? The Spanish fruits and vegetables case. AB - Proximity and in-season consumption criteria have been suggested as solutions for fruits and vegetables consumers to drive the economy to a more sustainable development. Using a new concept, seasonal avoided footprint by imports, we disentangle the role of period and country of origin. Although, as a general rule, consumers could reduce its footprint by choosing domestic produce, this is not always the case. Due to the high efficiency of Spanish domestic production in terms of both CO2e and water use (except for scarce water), imports from some regions, like Africa (green beans, pepper, tomato, banana, strawberry, oranges), contribute to significantly increase both water and carbon impacts. However, a monthly-basis analysis shows unsustainable hotspots for domestic production. Importing from France (apple, potato) or Portugal (tomato, strawberry) reduces both footprints, so Spanish local consumption would be bad for the environment. Hotspots are mainly concentrated in scarce water and, especially, for out-of season vegetables during eleven months a year (savings up to 389%), nine months for out-of-season fruits and five months for in-season fruits. The results suggest the difficulty to generalize an easy environmental recommendation based on buying local fruits and vegetables: consumption must be analyzed on monthly/seasonal, products and countries basis. PMID- 30252454 TI - Formation and Aggregation of Lead Phosphate Particles: Implications for Lead Immobilization in Water Supply Systems. AB - Phosphate is commonly added to drinking water to inhibit lead release from lead service lines and lead-containing materials in premise plumbing. Phosphate addition promotes the formation of lead phosphate particles, and their aggregation behaviors may affect their transport in pipes. Here, lead phosphate formation and aggregation were studied under varied aqueous conditions typical of water supply systems. Under high aqueous PO4/Pb molar ratios (>1), phosphate adsorption made the particles more negatively charged. Therefore, enhanced stability of lead phosphate particles was observed, suggesting that although addition of excess phosphate can lower the dissolved lead concentrations in tap water, it may increase concentrations of particulate lead. Adsorption of divalent cations (Ca2+ and Mg2+) onto lead phosphate particles neutralized their negative surface charges and promoted their aggregation at pH 7, indicating that phosphate addition for lead immobilization may be more efficient in harder waters. The presence of natural organic matter (NOM, >= 0.05 mg C/L humic acid and >= 0.5 mg C/L fulvic acid) retarded particle aggregation at pH 7. Consequently, removal of organic carbon during water treatment to lower the formation of disinfection byproducts (DBPs) may have the additional benefit of minimizing the mobility of lead-containing particles. This study provided insight into fundamental mechanisms controlling lead phosphate aggregation. Such understanding is helpful to understand the observed trends of total lead in water after phosphate addition in both field and pilot-scale lead pipe studies. Also, it can help optimize lead immobilization by better controlling the water chemistry during phosphate addition. PMID- 30252456 TI - A Dual Inhibition, a Better Solution: Development of a JAK1/TYK2 inhibitor. PMID- 30252455 TI - Chloride Supports O2 Activation in the D201G Facial Triad Variant of Factor Inhibiting Hypoxia Inducible Factor, an alpha-Ketoglutarate Dependent Oxygenase. AB - alpha-Ketoglutarate (alphaKG) dependent oxygenases comprise a large superfamily of enzymes that activate O2 for varied reactions. While most of these enzymes contain a nonheme Fe bound by a His2(Asp/Glu) facial triad, a small number of alphaKG-dependent halogenases require only the two His ligands to bind Fe and activate O2. The enzyme "factor inhibiting HIF" (FIH) contains a His2Asp facial triad and selectively hydroxylates polypeptides; however, removal of the Asp ligand in the Asp201->Gly variant leads to a highly active enzyme, seemingly without a complete facial triad. Herein, we report on the formation of an Fe-Cl cofactor structure for the Asp201->Gly FIH variant using X-ray absorption spectroscopy (XAS), which provides insight into the structure of the His2Cl facial triad found in halogenases. The Asp201->Gly variant supports anion dependent peptide hydroxylation, demonstrating the requirement for a complete His2X facial triad to support O2 reactivity. Our results indicated that exogenous ligand binding to form a complete His2X facial triad was essential for O2 activation and provides a structural model for the His2Cl-bound nonheme Fe found in halogenases. PMID- 30252457 TI - Questions of Noninnocence and Ease of Azo Reduction in Diruthenium Frameworks with a 1,8-Bis(( E)-phenyldiazenyl)naphthalene-2,7-dioxido Bridge. AB - Ligands containing the azo group are often used in various metal complexes owing to their facile one-electron reduction, which in effect extends the means of degrading environmentally harmful azo dyes. In order to probe the idea of the generally accepted ease of reduction of azo-containing compounds, we present here three different diruthenium complexes [(acac)2RuIII(MU-L2-)RuIII(acac)2] (diastereomeric 1/2), [(bpy)2RuII(MU-L2-)RuII(bpy)2](ClO4)2 ([3](ClO4)2), and [(pap)2RuII(MU-L2-)RuII(pap)2](ClO4)2 ([4](ClO4)2 ) with a bridging ligand (L2- = 1,8-bis(( E)-phenyldiazenyl)naphthalene-2,7-dioxido) that contains azo groups in addition to phenoxide-type donors. The RuIII-RuIII complexes (1/2) display interesting one-dimensional-chain effects, as revealed by temperature-dependent magnetic studies. The stability of the RuIII oxidation state in 1/2 under ambient conditions correlates well with the sigma-donating acetylacetonato (acac) coligands. However, with pi-accepting 2,2/-bipyridine (bpy) or phenylazopyridine (pap) the RuII state is preferably stabilized in 32+ or 42+, respectively, but there are interesting differences in their oxidative chemistry. The moderately pi accepting bpy allows for the RuII to RuIII oxidation at reasonably low anodic potentials. However, for the strongly pi accepting pap, no RuII to RuIII oxidation is observed within the solvent window. Instead, a phenoxide to phenoxyl radical type of oxidation based on the bridging ligand is observed. Surprisingly, the reductive chemistry of all three complexes is dominated by either the ruthenium centers or the coligands (bpy or pap), with no reductions observed on the azo function associated with the central bridging ligand (L2-). All of the above conclusions were drawn from combined structural, electrochemical, magnetic, spectroelectrochemical, and DFT investigations. Our results thus conclusively establish that the ease of reduction of an azo group in a particular compound is critically dependent on its substituents and that the noninnocence of the bridging ligands (L2-) in the dinuclear complexes can be decisively tuned by the appropriate choice of ancillary ligands. PMID- 30252458 TI - Low-Temperature Restructuring of CeO2-Supported Ru Nanoparticles Determines Selectivity in CO2 Catalytic Reduction. AB - CO2 reduction to higher value products is a promising way to produce fuels and key chemical building blocks while reducing CO2 emissions. The reaction at atmospheric pressure mainly yields CH4 via methanation and CO via the reverse water-gas shift (RWGS) reaction. Describing catalyst features that control the selectivity of these two pathways is important to determine the formation of specific products. At the same time, identification of morphological changes occurring to catalysts under reaction conditions can be crucial to tune their catalytic performance. In this contribution we investigate the dependency of selectivity for CO2 reduction on the size of Ru nanoparticles (NPs) and on support. We find that even at rather low temperatures (210 degrees C), oxidative pretreatment induces redispersion of Ru NPs supported on CeO2 and leads to a complete switch in the performance of this material from a well-known selective methanation catalyst to an active and selective RWGS catalyst. By utilizing in situ X-ray absorption spectroscopy, we demonstrate that the low-temperature redispersion process occurs via decomposition of the metal oxide phase with size dependent kinetics, producing stable single-site RuO x/CeO2 species strongly bound to the CeO2 support that are remarkably selective for CO production. These results show that reaction selectivity can be heavily dependent on catalyst structure and that structural changes of the catalyst can occur even at low temperatures and can go unseen in materials with less defined structures. PMID- 30252459 TI - Palladium-Catalyzed Ligand-Free Decarboxylative Coupling of alpha- Oxocarboxylic Acid with Aryl Diazonium Tetrafluoroborate: An Access to Unsymmetrical Diaryl Ketones. AB - Diaryl ketones are of much importance in organic synthesis as versatile intermediates and in industry for their useful properties. A mild and efficient palladium-catalyzed traditional ligand-free decarboxylative coupling of aryl alpha-keto carboxylic acid with aryl diazonium fluoroborate has been developed. A series of unsymmetrical diaryl ketones has been synthesized in moderate to good yields using this procedure. A radical pathway involving the acyl radical has been suggested. PMID- 30252460 TI - Impact of Delivery System Type on Curcumin Bioaccessibility: Comparison of Curcumin-Loaded Nanoemulsions with Commercial Curcumin Supplements. AB - In this study, nanoemulsion-based delivery systems fabricated using three different methods were compared with three commercially available curcumin supplements. Powdered curcumin was dispersed into the oil-in-water nanoemulsions using three methods: the conventional oil-loading method, the heat-driven method, and the pH-driven method. The conventional method involved dissolving powdered curcumin in the oil phase (60 degrees C, 2 h) and then forming a nanoemulsion. The heat-driven method involved forming a nanoemulsion and then adding powdered curcumin and incubating at an elevated temperature (100 degrees C, 15 min). The pH-driven method involved dissolving curcumin in an alkaline solution (pH 12.5) and then adding this solution to an acidified nanoemulsion (pH 6.0). The three commercial curcumin products were capsules or tablets purchased from an online supplier: Nature Made, Full Spectrum, and CurcuWin. Initially, the encapsulation efficiency of the curcumin in the three nanoemulsions was determined and decreased in the following order: pH-driven (93%) > heat-driven (76%) > conventional (56%) method. The different curcumin formulations were then subjected to a simulated gastrointestinal tract (GIT) model consisting of mouth, stomach, and small intestine phases. All three nanoemulsions had fairly similar curcumin bioaccessibility values (74-79%) but the absolute amount of curcumin in the mixed micelle phase was highest for the pH-driven method. A comparison of these nanoemulsions and commercial products indicated that the curcumin concentration in the mixed micelles decreased in the following order: CurcuWin ~ pH-driven method > heat-driven method > conventional method ? Full spectrum > Nature Made. This study provides valuable information about the impact of the delivery system type on curcumin bioavailability. It suggests that encapsulating curcumin within small lipid particles may be advantageous for improving its absorption form the GIT. PMID- 30252461 TI - A Chemical Signature for Cytidine Acetylation in RNA. AB - N4-acetylcytidine (ac4C) is a highly conserved modified RNA nucleobase whose formation is catalyzed by the disease-associated N-acetyltransferase 10 (NAT10). Here we report a sensitive chemical method to localize ac4C in RNA. Specifically, we characterize the susceptibility of ac4C to borohydride-based reduction and show this reaction can cause introduction of noncognate base pairs during reverse transcription (RT). Combining borohydride-dependent misincorporation with ac4C's known base-sensitivity provides a unique chemical signature for this modified nucleobase. We show this unique reactivity can be used to quantitatively analyze cellular RNA acetylation, study adapters responsible for ac4C targeting, and probe the timing of RNA acetylation during ribosome biogenesis. Overall, our studies provide a chemical foundation for defining an expanding landscape of cytidine acetyltransferase activity and its impact on biology and disease. PMID- 30252462 TI - The Mechanism of Decreased IgG/IgE-Binding of Ovalbumin by Preheating Treatment Combined with Glycation Identified by Liquid Chromatography and High-Resolution Mass Spectrometry. AB - Ovalbumin is one of the most important sensitizing ingredients in allergens of egg albumin, which restricts the application of egg in the field of food processing. Previous research has indicated that glycation could cause the protein to partially expand, which may bring about the destruction of the structural IgG and IgE epitopes and induce the decline of the IgG- and IgE binding ability of ovalbumin. In this research, the effect of a preheating treatment integrated with glycation on the IgG- and IgE-binding capability and the conformation changes of ovalbumin was studied by detecting the glycated sites and the values of degree of substitution per peptide (DSP) by liquid chromatography and high-resolution mass spectrometry (LC-HRMS). Interestingly, we found that a glycation site (K227) attached by two ribose molecules was detected in glycated ovalbumin with preheating treatment. In addition, a new glycation site (K323) appeared in G-60. The results displayed that preheating treament could strengthen the changes in the secondary and tertiary structure of ovalbumin by enhancing glycation and further reduce the IgG/IgE-binding ability by integrating with glycation because of the cover of IgG and IgE epitopes. Therefore, preheating treatment integrated with glycation may offer a way for ovalbumin to reduce sensitization. PMID- 30252463 TI - Correction to Design of MC1R Selective gamma-MSH Analogues with Canonical Amino Acids Leads to Potency and Pigmentation. PMID- 30252465 TI - Origin of and a Solution for Uneven Efficiency by Cinchona Alkaloid-Derived, Pseudoenantiomeric Catalysts for Asymmetric Reactions. AB - Cinchona alkaloid-derived chiral catalysts represent one of the most widely applied classes of organocatalysts, which have been successfully utilized in the promotion of a wide variety of asymmetric reactions. Cinchona alkaloids exist in nature as pseudoenantiomers, which allow cinchona alkaloid-catalyzed reactions to provide high enantioselectivities and yields toward both enantiomers of interest in many reactions. On the other hand, the subtle structural difference between pseudoenantiomeric cinchona alkaloids could also lead to uneven efficiency that severely limits the applicability of some cinchona alkaloid-catalyzed reactions. We describe here the elucidation of the origin of and the consequent development of novel modified cinchona alkaloids to address such a problem in asymmetric imine umpolung reactions by cinchonium salts. PMID- 30252464 TI - In Situ Spectroscopic Studies of Highly Transparent Nanoparticle Dispersions Enable Assessment of Trithiocarbonate Chain-End Fidelity during RAFT Dispersion Polymerization in Nonpolar Media. AB - We report the synthesis of highly transparent poly(stearyl methacrylate) poly(2,2,2-trifluoroethyl methacrylate) (PSMA-PTFEMA) diblock copolymer nanoparticles via polymerization-induced self-assembly (PISA) in nonpolar media at 70 degrees C. This was achieved by chain-extending a PSMA precursor block via reversible addition-fragmentation chain transfer (RAFT) dispersion polymerization of TFEMA in n-tetradecane. This n-alkane has the same refractive index as the PTFEMA core-forming block at 70 degrees C, which ensures high light transmittance when targeting 33 nm spherical nanoparticles. Such isorefractivity enables visible absorption spectra to be recorded with minimal light scattering even at 30% w/w solids. However, in situ monitoring of the trithiocarbonate RAFT end-groups during PISA requires selection of a weak n -> pi* band at 446 nm. Conversion of TFEMA into PTFEMA causes a contraction in the reaction solution volume, leading to an initial increase in absorbance that enables the kinetics of polymerization to be monitored via dilatometry. At ~98% TFEMA conversion, this 446 nm band remains constant for 2 h at 70 degrees C, indicating surprisingly high RAFT chain-end fidelity (and hence pseudoliving character) under monomer starved conditions. In situ 19F NMR spectroscopy studies provide evidence for (i) the onset of micellar nucleation, (ii) solvation of the nanoparticle cores by TFEMA monomer, and (iii) surface plasticization of the nanoparticle cores by n tetradecane at 70 degrees C. Finally, the kinetics of RAFT chain-end removal can be conveniently monitored by in situ visible absorption spectroscopy: addition of excess initiator at 70 degrees C causes complete discoloration of the dispersion, with small-angle X-ray scattering studies confirming no change in nanoparticle morphology under these conditions. PMID- 30252466 TI - Single Amino Acid Substitution in alpha-Conotoxin TxID Reveals a Specific alpha3beta4 Nicotinic Acetylcholine Receptor Antagonist. AB - The alpha3beta4 nicotinic acetylcholine receptor (nAChR) is an important target implicated in various disease states. alpha-Conotoxin TxID (1) is the most potent antagonist of alpha3beta4 nAChR, but it also exhibits inhibition of alpha6/alpha3beta4 nAChR. The results of alanine scanning of 1 suggested a vital role for Ser9 in the selectivity of the peptide. In this study, Ser9 was substituted with a series of 14 amino acids, including some non-natural amino acids, displaying different physicochemical characteristics to further improve the selectivity of 1 toward alpha3beta4 nAChR. The pharmacological activities of the mutants were evaluated using an electrophysiological approach. The best selectivity was obtained with [S9K]TxID, 12, which inhibited alpha3beta4 nAChR with an IC50 of 6.9 nM and had no effects on other nAChRs. Molecular modeling suggested a possible explanation for the high selectivity of 12 toward alpha3beta4 nAChR, providing deeper insight into the interaction between alpha conotoxins and nAChRs as well as potential treatments for nAChR-related diseases. PMID- 30252467 TI - State-Averaged Pair Natural Orbitals for Excited States: A Route toward Efficient Equation of Motion Coupled-Cluster. AB - A reduced-complexity variant of equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) method is formulated in terms of state-averaged excited-state pair natural orbitals (PNO) designed to describe manifolds of excited states. State-averaged excited-state PNOs for the target manifold are determined by averaging CIS(D) pair densities over the model manifold. The performance of the PNO-EOM-CCSD approach has been tested with the help of a distributed-memory parallel canonical EOM-CCSD implementation within the Massively Parallel Quantum Chemistry program that allows treatment of systems with 50+ atoms using realistic basis sets with 1000+ functions. The use of state-averaged PNOs offers several potential advantages relative to the recently proposed state-specific PNOs: our approach is robust with respect to root flipping and state degeneracies, it is more economical when computing large manifolds of states, and it simplifies evaluation of transition-specific observables such as dipole moments. With the PNO truncation threshold of 10-7, the errors in excitation energies are on average below 0.02 eV for the first six singlet states of 28 organic molecules included in the standard test set of Thiel and co-workers ( J. Chem. Phys. 2008, 128, 134110) with 50-70 state-averaged PNOs per pair. PMID- 30252468 TI - Novel Hypoxia-Inducible Factor 1alpha (HIF-1alpha) Inhibitors for Angiogenesis Related Ocular Diseases: Discovery of a Novel Scaffold via Ring-Truncation Strategy. AB - Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1alpha, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1alpha inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1alpha inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1alpha inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1alpha inhibitors that can be used in lieu of a chromene ring. PMID- 30252469 TI - Unveiling Controlling Factors of the S0/S1 Minimum Energy Conical Intersection: A Theoretical Study. AB - The minimum energy conical intersection (MECI) geometries play an important role in photophysics and photochemistry. Although a number of MECI geometries can be identified using quantum chemical methods, their chemical interpretation remains unclear. In this study, a systematic analysis was performed on the MECIs between the singlet (S0) and lowest singlet excited (S1) states of organic molecules. The frozen orbital analysis (FZOA), which approximates the excited states with minimal main configurations, was adopted to analyze the excitation energy components at the S0/S1 MECI geometries as well as the S0 and S1 equilibrium geometries. At the S0/S1 MECI geometries, the HOMO-LUMO gaps decreased as expected but did not disappear. The remaining gaps were balanced with the HOMO LUMO Coulomb integrals. Furthermore, we discovered that the HOMO-LUMO exchange integrals became approximately zero. On the basis of this fact, a systematic interpretation of the S0/S1 MECI geometries has been described. PMID- 30252470 TI - TopScore: Using Deep Neural Networks and Large Diverse Data Sets for Accurate Protein Model Quality Assessment. AB - The value of protein models obtained with automated protein structure prediction depends primarily on their accuracy. Protein model quality assessment is thus critical to select the model that can best answer biologically relevant questions from an ensemble of predictions. However, despite many advances in the field, different methods capture different types of errors, begging the question of which method to use. We introduce TopScore, a meta Model Quality Assessment Program (meta-MQAP) that uses deep neural networks to combine scores from 15 different primary predictors to predict accurate residue-wise and whole-protein error estimates. The predictions on six large independent data sets are highly correlated to superposition-independent errors in the model, achieving a Pearson's Rall2 of 0.93 and 0.78 for whole-protein and residue-wise error predictions, respectively. This is a significant improvement over any of the investigated primary MQAPs, demonstrating that much can be gained by optimally combining different methods and using different and very large data sets. PMID- 30252471 TI - Iron-Catalyzed Prins-Peterson Reaction for the Direct Synthesis of Delta4-2,7 Disubstituted Oxepenes. AB - A direct iron(III)-catalyzed Prins-Peterson reaction involving alpha-substituted gamma-triphenylsilyl bis-homoallylic alcohols and aldehydes is described. Thus, cis-Delta4-2,7-disubstituted oxepenes were synthesized in a diastereoselective reaction using sustainable catalytic conditions (3-5 mol %). This highly productive process is the result of a cascade of three chemical events with the concomitant formation of a C-O bond, a C-C bond, and a Delta4 endocyclic double bond, through a Prins cyclization followed by a Peterson-type elimination. This tandem reaction is chemoselective vs the classical Prins cyclization. PMID- 30252472 TI - Spatially Resolved Optical Emission and Modeling Studies of Microwave-Activated Hydrogen Plasmas Operating under Conditions Relevant for Diamond Chemical Vapor Deposition. AB - A microwave (MW) activated hydrogen plasma operating under conditions relevant to contemporary diamond chemical vapor deposition reactors has been investigated using a combination of experiment and self-consistent 2-D modeling. The experimental study returns spatially and wavelength resolved optical emission spectra of the d -> a (Fulcher), G -> B, and e -> a emissions of molecular hydrogen and of the Balmer-alpha emission of atomic hydrogen as functions of pressure, applied MW power, and substrate diameter. The modeling contains specific blocks devoted to calculating (i) the MW electromagnetic fields (using Maxwell's equations) self-consistently with (ii) the plasma chemistry and electron kinetics, (iii) heat and species transfer, and (iv) gas-surface interactions. Comparing the experimental and model outputs allows characterization of the dominant plasma (and plasma emission) generation mechanisms, identifies important coupling reactions between hydrogen atoms and molecules (e.g., the quenching of H( n > 2) atoms and electronically excited H2 molecules (H2*) by the alternate ground-state species and H3+ ion formation by the associative ionization reaction of H( n = 2) atoms with H2), and illustrates how spatially resolved H2* (and Halpha) emission measurements offer a detailed and sensitive probe of the hyperthermal component of the electron energy distribution function. PMID- 30252473 TI - t-Distributed Stochastic Neighbor Embedding Method with the Least Information Loss for Macromolecular Simulations. AB - Dimensionality reduction methods are usually applied on molecular dynamics simulations of macromolecules for analysis and visualization purposes. It is normally desired that suitable dimensionality reduction methods could clearly distinguish functionally important states with different conformations for the systems of interest. However, common dimensionality reduction methods for macromolecules simulations, including predefined order parameters and collective variables (CVs), principal component analysis (PCA), and time-structure based independent component analysis (t-ICA), only have limited success due to significant key structural information loss. Here, we introduced the t distributed stochastic neighbor embedding (t-SNE) method as a dimensionality reduction method with minimum structural information loss widely used in bioinformatics for analyses of macromolecules, especially biomacromolecules simulations. It is demonstrated that both one-dimensional (1D) and two dimensional (2D) models of the t-SNE method are superior to distinguish important functional states of a model allosteric protein system for free energy and mechanistic analysis. Projections of the model protein simulations onto 1D and 2D t-SNE surfaces provide both clear visual cues and quantitative information, which is not readily available using other methods, regarding the transition mechanism between two important functional states of this protein. PMID- 30252474 TI - Electron Propagator Methods for Vertical Electron Detachment Energies of Anions: Benchmarks and Case Studies. AB - Ab initio electron propagator methods are efficient and accurate means of calculating vertical electron detachment energies of closed-shell, molecular anions with nuclei from the first three periods. Basis set extrapolations enable definitive comparisons between electron propagator results and benchmarks defined by total energy differences obtained with coupled-cluster, single, double, plus perturbative triple substitution theory. The best compromises of accuracy and efficiency are provided by the renormalized, partial third-order, diagonal (P3+) self-energy and by the nondiagonal, renormalized, second-order (NR2) approximation. The outer-valence Green function, the two-particle-one-hole Tamm Dancoff approximation, the third-order algebraic diagrammatic construction, and the renormalized third-order methods also are examined. A detailed analysis of errors for small anions is performed. Case studies include F-(H2O) and Cl-(H2O) complexes, C5H5-, two P2N3- pentagonal rings, and a superhalide, Al(BO2)4-, whose electron detachment energy is more than double those of the halide anions. These applications illustrate the versatility of electron propagator methods, their utility for interpreting negative-ion photoelectron spectra, and their promise in the discovery of unusual properties and patterns of chemical bonding. Composite methods, which combine basis set effects calculated at the relatively efficient diagonal, second-order level and higher correlation effects calculated with small basis sets, provide excellent estimates of basis set-extrapolated P3+ or NR2 results and facilitate applications to large molecules. In the P3+ and NR2 methods, a judicious choice of low-order couplings between hole operators that correspond to the assumptions of Koopmans's theorem and operators that describe final-state relaxation and polarization and initial-state correlation leads to predictive accuracy, computational efficiency, and interpretive lucidity. PMID- 30252475 TI - Monte Carlo Diffusion-Enhanced Photon Inference: Distance Distributions and Conformational Dynamics in Single-Molecule FRET. AB - Single-molecule Forster resonance energy transfer (smFRET) is utilized to study the structure and dynamics of many biomolecules, such as proteins, DNA, and their various complexes. The structural assessment is based on the well-known Forster relationship between the measured efficiency of energy transfer between a donor (D) and an acceptor (A) dye and the distance between them. Classical smFRET analysis methods called photon distribution analysis (PDA) take into account photon shot-noise, D-A distance distribution, and, more recently, interconversion between states in order to extract accurate distance information. It is known that rapid D-A distance fluctuations on the order of the D lifetime (or shorter) can increase the measured mean FRET efficiency and thus decrease the estimated D A distance. Nonetheless, this effect has been so far neglected in smFRET experiments, potentially leading to biases in estimated distances. Here we introduce a PDA approach dubbed Monte Carlo diffusion-enhanced photon inference (MC-DEPI). MC-DEPI recolor detected photons of smFRET experiments taking into account dynamics of D-A distance fluctuations, multiple interconverting states, and photoblinking. Using this approach, we show how different underlying conditions may yield identical FRET histograms and how the additional information from fluorescence decays helps in distinguishing between the different conditions. We also introduce a machine learning fitting approach for retrieving the D-A distance distribution, decoupled from the above-mentioned effects. We show that distance interpretation of smFRET experiments of even the simplest dsDNA is nontrivial and requires decoupling the effects of rapid D-A distance fluctuations on FRET in order to avoid systematic biases in the estimation of the D-A distance distribution. PMID- 30252476 TI - Heterogeneous Solvation in Distinctive Protein-Protein Interfaces Revealed by Molecular Dynamics Simulations. AB - Water, despite being a driving force in biochemical processes, has an elusively complex microscopic behavior. While water can increase its local density near amphiphilic protein surfaces, water is also thought to evaporate from hydrophobic surfaces and cavities, an effect known as "dewetting". The existence and extent of dewetting effects remains elusive due to the difficulty in observing clear "drying" transitions in experiments or simulations. Here, we use explicit solvent molecular dynamics (MD) simulations to study the molecular solvation at the binding interfaces of two distinctive molecular complexes: the highly hydrophilic barnase-barstar and the highly hydrophobic MDM2-p53. Our simulations, in conjunction with simple volumetric analyses, reveal a strikingly different water behavior at the binding interfaces of these two molecular complexes. In both complexes, we observe significant changes in the water local density as the two proteins approach, supporting the existence of a clear dewetting transition in the case of MDM2-p53, with an onset distance of 5.6-7.6 A. Furthermore, the solvation analysis reported herein is a valuable tool to capture and quantify persistent or transient dewetting events in future explicit solvent MD simulations. PMID- 30252477 TI - Vibrational and Molecular Properties of Mg2+ Binding and Ion Selectivity in the Magnesium Channel MgtE. AB - Magnesium ions (Mg2+) are crucial for various biological processes. A bacterial Mg2+ channel, MgtE, tightly regulates the intracellular Mg2+ concentration. Previous X-ray crystal structures showed that MgtE forms a dimeric structure composed of a total of 10 transmembrane alpha helices forming a central pore, and intracellular soluble domains constituting a Mg2+ sensor. The ion selectivity for Mg2+ over Ca2+ resides at a central cavity in the transmembrane pore of MgtE, involving a conserved aspartate residue (Asp432) from each monomer. Here, we applied ion-exchange-induced difference FTIR spectroscopy to analyze the interactions between MgtE and divalent cations, Mg2+ and Ca2+. Using site directed mutagenesis, vibrational bands at 1421 (Mg2+), 1407 (Mg2+), ~1440 (Ca2+), and 1390 (Ca2+) cm-1 were assigned to symmetric carboxylate stretching modes of Asp432, involved in the ion coordination. Conservative modifications of the central cavity by Asp432Glu or Ala417Leu mutations resulted in the disappearance of the Mg2+-sensitive carboxylate bands, suggesting a highly optimized geometry for accommodating a Mg2+ ion. The dependency of the vibrational changes on Mg2+ and Ca2+ concentrations revealed the presence of a two different classes of binding sites: a high affinity site for Mg2+ ( Kd ~ 0.3 mM) with low Ca2+ affinity ( Kd ~ 80 mM), and a medium affinity site for Mg2+ ( Kd ~ 2 mM) and Ca2+ ( Kd ~ 6 mM), tentatively assigned to the central cavity and the sensor domain, respectively. With the aid of molecular dynamics simulation and normal-mode analysis by quantum chemistry, we confirm that changes in carboxylate bands of the high affinity binding site originate from Asp432 in the central cavity. PMID- 30252479 TI - Near-Field Spectroscopy of Nanoscale Molecular Aggregates. AB - When molecules are assembled into an aggregate, their mutual dipole-dipole interaction leads to electronic eigenstates that are coherently delocalized over many molecules. Knowledge about these states is important to understand the optical and transfer properties of the aggregates. Optical spectroscopy, in principle, allows one to infer information on these eigenstates and about the interactions between the molecules. However, traditional optical techniques using an electromagnetic field which is uniform over the relevant size of the aggregate cannot access most of the excited states because of selection rules. We demonstrate that by using localized fields one can obtain information about these otherwise inaccessible states. As an example, we discuss in detail the case of local excitation via radiation from the apex of a metallic tip, which allows also scanning across the aggregate. The resulting spatially resolved spectra provide extensive information on the eigenenergies and wave functions. Finally we show that the technique will elucidate the anomalous temperature dependence of superradiance found recently for two-dimensional aggregates of the semiconductor PTCDA formed on a KCl surface. PMID- 30252478 TI - Dynamics of the Proline-Rich C-Terminus of Huntingtin Exon-1 Fibrils. AB - Intrinsically disordered protein domains not only are found in soluble proteins but also can be part of large protein complexes or protein aggregates. For example, several amyloid fibrils have intrinsically disordered domains framing a rigid beta-sheet-rich core. These disordered domains can often be observed using solution NMR methods in combination with modest magic angle spinning and without perdeuteration. But how can these regions be detected using solution NMR methods when they are part of a fibril that is not tumbling isotropically in solution? Here we addressed this question by investigating the dynamic C-terminus of huntingtin exon-1 (HTTex1) fibrils that are important in Huntington's disease. We assigned the most dynamic regions of the C-terminus of three HTTex1 variants. On the basis of this assignment, we measured site-specific secondary chemical shifts, peak intensities, and R1, R'2, and R1rho 15N relaxation rates. In addition, we determined the residual 1H-15N dipolar couplings of this region. Our results show that the dipolar couplings are averaged to a very high degree, resulting in an order parameter that is essentially zero. Together, our data show that the C-terminus of HTTex1 is intrinsically disordered and undergoes motions in the high picosecond to low nanosecond range. PMID- 30252480 TI - Size- and Shape-Controlled Synthesis of Calcium Silicate Particles Enables Self Assembly and Enhanced Mechanical and Durability Properties. AB - Calcium silicate (CS)-based materials are ubiquitous in diverse industries ranging from cementitious materials to bone tissue engineering and drug delivery. As a symbolic example, concrete is the most widely used synthetic material on the planet. This large consumption entails significant negative environmental footprint, which calls for innovative strategies to develop greener concrete with improved properties (to do more with less). Herein, we focus on the physicochemical properties of novel spherical calcium silicate particles with an extremely narrow size distribution and report their promising potential as fundamental building blocks. We demonstrate a scalable size- and shape-controlled synthesis protocol to yield highly spherical CS submicron particles, leading to favorable aggregation mechanisms and thus self-assembly of the bulk ensemble. This optimized kinetics-controlled synthesis is governed by suitable stoichiometric ratio of calcium over silicon, type and concentration of the surfactant, and molar ratio of the alkaline solution. Our extensive nano/micro/macro-characterization results show that the bulk ensemble exhibits many superior properties, such as improved strength, toughness, ductility, and durability, paving the path for bottom-up science-based engineering of concrete. PMID- 30252481 TI - Phase Diagrams of Polymer-Dispersed Liquid Crystal Systems of Itraconazole/Component Immiscibility Induced by Molecular Anisotropy. AB - Liquid crystalline (LC) materials and their nonmedical applications have been known for decades, especially in the production of displays; however, the pharmaceutical implications of the LC state are inadequately appreciated, and the misunderstanding of experimental data is leading to possible errors, especially in relation to the physical stability of medicines. The aim of this work was to study LC phases of itraconazole (ITZ), an azole antifungal active molecule, and for the first time, to generate full thermodynamic phase diagrams for ITZ/polymer systems, taking into account isotropic and anisotropic phases that this drug can form. It was found that supercooled ITZ does not form an amorphous but a vitrified smectic (vSm) phase with a glass transition temperature of 59.35 degrees C (determined using a 10 degrees C/min heating rate), as is evident from X-ray diffraction and thermomicroscopic (PLM) experiments. Two endothermic LC events with the onset temperature values for a smectic to nematic transition of 73.2 +/- 0.4 degrees C and a nematic to isotropic transformation at 90.4 +/- 0.35 degrees C and enthalpies of transition of 416 +/- 34 J/mol and 842 +/- 10 J/mol, respectively, were recorded. For the binary supercooled mixtures, PLM and differential scanning calorimetry showed a phase separation with birefringent vSm persistent over a wide polymer range, as noticed especially for the hypromellose acetate succinate (HAS) systems. Both, smectic and nematic, phases were detected for the supercooled ITZ/HAS and ITZ/methacrylic acid-ethyl acrylate copolymer (EUD) mixtures, while geometric restrictions inhibited the smectic formation in the ITZ/poly(acrylic acid) (CAR) systems. The Flory-Huggins lattice theory coupled with the Maier-Saupe-McMillan approach to model anisotropic ordering of molecules was successfully utilized to create phase diagrams for all ITZ/polymer mixtures. It was concluded that in a supercooled ITR/polymer mix, if ITZ is present in a LC phase, immiscibility as a result of molecule anisotropy is afforded. This study shows that the LC nature of ITZ cannot be disregarded when designing stable formulations containing this molecule. PMID- 30252482 TI - Minisci-Photoredox-Mediated alpha-Heteroarylation of N-Protected Secondary Amines: Remarkable Selectivity of Azetidines. AB - The development of a general, mild, and functional-group-tolerant direct functionalization of N-heteroarenes by C-H functionalization with N-protected amines, including azetidines under Minisci-mediated photoredox conditions, is reported. A broad scope of substituted azetidines, including spirocyclic derivatives, and heterocycles were explored. This reaction enables the production of sp3-rich complex druglike structures in one step from unactivated feedstock amines and heterocycles. PMID- 30252483 TI - Palladium-Catalyzed Domino Allenamide Carbopalladation/Direct C-H Allylation of Heteroarenes: Synthesis of Primprinine and Papaverine Analogues. AB - Palladium-catalyzed intramolecular carbopalladation onto allenamides completed by direct C-H allylation of heterocycles is studied. The domino construction/heteroarylation of isoquinolone process is first achieved. A general three-step one-pot strategy, involving in situ generation of allenamide, pi-allyl Pd complex generation, and interception with heteroarenes, has been subsequently set up. This methodology has been extended to the construction/heteroarylation of indoles, dihydroquinolines, isoquinolin(on)es, and medium-sized nitrogen heterocycles, which are known to be key challenging structural motifs with pharmaceutical significance. PMID- 30252484 TI - ABCB1 Attenuates the Brain Penetration of the PARP Inhibitor AZD2461. AB - Poly (ADP-ribose) polymerase (PARP) inhibitors are a relatively new class of anticancer agents that have attracted attention for treatment of glioblastoma because of their ability to potentiate temozolomide chemotherapy. Previous studies have demonstrated that sufficient brain penetration is a prerequisite for efficacy of PARP inhibitors in glioma mouse models. Unfortunately, however, most of the PARP inhibitors developed to date have a limited brain penetration due to the presence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) at the blood-brain barrier. AZD2461 is a novel PARP inhibitor that is unaffected by P-gp mediated resistance in breast cancer models and thus appears to have promising characteristics for brain penetration. We here use a comprehensive set of in vitro and in vivo models to study the brain penetration and oral bioavailability of AZD2461. We report that AZD2461 has a good membrane permeability. However, it is a substrate of P-gp and BCRP, and P-gp in particular limits its brain penetration in vivo. We show that AZD2461 has a low oral bioavailability, although it is not affected by P-gp and BCRP. Together, these findings are not in favor of further development of AZD2461 for treatment of glioblastoma. PMID- 30252485 TI - Silicon-Phosphorene Nanocavity-Enhanced Optical Emission at Telecommunications Wavelengths. AB - Generating and amplifying light in silicon (Si) continues to attract significant attention due to the possibility of integrating optical and electronic components in a single material platform. Unfortunately, silicon is an indirect band gap material and therefore an inefficient emitter of light. With the rise of integrated photonics, the search for silicon-based light sources has evolved from a scientific quest to a major technological bottleneck for scalable, CMOS compatible, light sources. Recently, emerging two-dimensional materials have opened the prospect of tailoring material properties based on atomic layers. Few layer phosphorene, which is isolated through exfoliation from black phosphorus (BP), is a great candidate to partner with silicon due to its layer-tunable direct band gap in the near-infrared where silicon is transparent. Here we demonstrate a hybrid silicon optical emitter composed of few-layer phosphorene nanomaterial flakes coupled to silicon photonic crystal resonators. We show single-mode emission in the telecommunications band of 1.55 MUm ( Eg = 0.8 eV) under continuous wave optical excitation at room temperature. The solution processed few-layer BP flakes enable tunable emission across a broad range of wavelengths and the simultaneous creation of multiple devices. Our work highlights the versatility of the Si-BP material platform for creating optically active devices in integrated silicon chips. PMID- 30252486 TI - Endotracheal Aerosolization Device for Laboratory Investigation of Pulmonary Delivery of Nanoparticle Suspensions: In Vitro and in Vivo Validation. AB - The objective of this study was to perform the in vitro and in vivo validation of an endotracheal aerosolization (ETA) device (HRH MAG-4, HM). Solid lipid nanoparticle suspension (SLNS) formulations with particle sizes of approximately 120, 240, 360, and 480 nm were selected as model nanoparticle suspensions for the validation. The emission rate (ER) of the in vitro aerosolization and the influence of aerosolization on the physicochemical properties were investigated. A high ER of up to 90% was obtained, and no significant alterations in physicochemical properties were observed after the aerosolization. The pulmonary deposition of model drug budesonide in Sprague-Dawley rats was determined to be approximately 80%, which was satisfactory for pulmonary delivery. Additionally, a fluorescent probe with aggregation-caused quenching property was encapsulated in SLNS formulations for in vivo bioimaging, after excluding the effect of aerosolization on its fluorescence spectrum. It was verified that SLNS formulations were deposited in the lung region. The results demonstrated the feasibility and reliability of the HM device for ETA in laboratory investigation. PMID- 30252487 TI - Brain Penetrating Bifunctional Erythropoietin-Transferrin Receptor Antibody Fusion Protein for Alzheimer's Disease. AB - Erythropoietin (EPO), a glycoprotein cytokine essential to hematopoiesis, has neuroprotective effects in rodent models of Alzheimer's disease (AD). However, high therapeutic doses or invasive routes of administration of EPO are required to achieve effective brain concentrations due to low blood-brain barrier (BBB) penetrability, and high EPO doses result in hematopoietic side effects. These obstacles can be overcome by engineering a BBB-penetrable analog of EPO, which is rapidly cleared from the blood, by fusing EPO to a chimeric monoclonal antibody targeting the transferrin receptor (cTfRMAb), which acts as a molecular Trojan horse to ferry the EPO into the brain via the transvascular route. In the current study, we investigated the effects of the BBB-penetrable analog of EPO on AD pathology in a double transgenic mouse model of AD. Five and a half month old male APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with saline ( n = 10) or the BBB-penetrable EPO ( n = 10) 3 days/week intraperitoneally for 8 weeks, compared to same-aged C57BL/6J wild-type mice treated with saline ( n = 8) with identical regiment. At 9 weeks following treatment initiation, exploration and spatial memory were assessed with the open-field and Y-maze test, mice were sacrificed, and brains were evaluated for Abeta peptide load, synaptic loss, BBB disruption, microglial activation, and microhemorrhages. APP/PS1 mice treated with the BBB-penetrable cTfRMAb-EPO fusion protein had significantly lower cortical and hippocampal Abeta peptide number ( p < 0.05) and immune-positive area ( p < 0.05), a decrease in hippocampal synaptic loss ( p < 0.05) and cortical microglial activation ( p < 0.001), and improved spatial memory ( p < 0.05) compared with APP/PS1 saline controls. BBB-penetrating EPO was not associated with microhemorrhage development. The cTfRMAb-EPO fusion protein offers therapeutic benefits by targeting multiple targets of AD pathogenesis and progression (Abeta load, synaptic loss, microglial activation) and improving spatial memory in the APP/PS1 mouse model of AD. PMID- 30252488 TI - Liquid Leaks: Dripping Versus Evaporation. AB - Liquid leaks often reveal themselves as pendant drops or drips emanating from a low point on a fluid handling component. For volatile liquids, understanding the contributions of interfacial properties, such as diffusivity of the liquid and wettability of the solid, is crucial to determining leak rates. To estimate the resolution of hydrostatic leak testing, the competing factors of leak and evaporation rates were analyzed. We used drop volumes and contact angles along with intrinsic fluid properties to calculate the detection limit of hydrostatic leak tests. For water and ethanol, we reckon that it is approximately 10-4 to 10 5 cm3/s in dry air. PMID- 30252489 TI - Cu-Catalyzed Denitrogenative Ring-Opening of 3-Aminoindazoles for the Synthesis of Aromatic Nitrile-Containing (Hetero)Arenes. AB - An unprecedented Cu-catalyzed oxidative cleavage of two C-N bonds of 3 aminoindazoles is reported herein, which represents the first example for denitrogenative ring-opening of 3-aminoindazoles. This novel reactivity of 3 aminoindazoles enables the production of diverse aromatic nitrile-containing (hetero)arenes via C-H arylation of (hetero)arenes with wide subsrate scope under mild conditions. PMID- 30252490 TI - AFM-Based Probing of the Flexibility and Surface Attachment of Immobilized DNA Origami. AB - The flexible and precise immobilization of self-organizing DNA nanostructures represents a key step in the integration of DNA-based material for potential electronic or sensor applications. However, the involved processes have still not been well studied and are not yet fully understood. Thus, we investigated the potential for the mechanical manipulation of DNA origami by atomic force microscopy (AFM) in order to study the interaction between intramolecular flexibility and surface-attachment forces. AFM is particularly suitable for nanoscale manipulation. Previous studies showed the potential for pushing, bending, and cutting double-stranded DNA (dsDNA) with an AFM tip. Understanding the involved parameters may enable control over different processes such as nanointegration, precise cutting, and stretching of preassembled DNA origami. We demonstrate the defined manipulation and flexibility of DNA origami immobilized on mica in the nanometer range: controlled cutting, folding, and stretching as a function of the magnesium concentration. PMID- 30252491 TI - Chiral Receptors for Lysine Based on Covalently Linked Bis- and Tris binaphthylphosphoric Acids. AB - The synthesis and application of three chiral receptors based on the covalent linkage of 1,1'-binaphthylphosphoric acids is reported. The binding of the lysine enantiomers to the chiral receptors was investigated by DOSY-NMR and NMR titrations, revealing that the bisphosphoric acid 1d acts as a highly stereoselective receptor for binding of d-lysine. PMID- 30252492 TI - Total Synthesis of Anti-tuberculosis Natural Products Ilamycins E1 and F. AB - The first total synthesis of the potent anti-tuberculosis cyclopeptide natural products ilamycins E1 and F was achieved. This highly convergent strategy consists of the synthesis of the two units 10 and 11 and linking them together to form the macrocyclic lactam 31. The upper unit 10 was prepared from tryptophan in five steps, and the lower unit 11 was prepared from glutamic acid in thirteen steps. Conversion of ilamycin F, the most abundant of the cyclopeptides, into the more active congener, ilamycin E1, was also accomplished. This would provide sufficient material of ilamycin E1 for more extensive biological studies. PMID- 30252494 TI - The Y Chromosome Regulates BMPR2 Expression via SRY: A Possible Reason 'Why' Fewer Males Develop PAH. PMID- 30252493 TI - Selective Ortho-pi-Extension of Perylene Diimides for Rylene Dyes. AB - A range of ortho-pi-extended PDI derivatives are straightforwardly synthesized in good yields through highly regioselective heteroannulations of ortho-alkynyl substituted PDI derivatives with sulfur, selenium, or nitrogen nucleophiles. Successful synthesis of pyrrole-fused rylene dyes by using primary amines as nucleophiles indicates the great synthetic potential of this facile annulation route. Further opto-electrochemical study of these novel thiophene-, selenophene , and pyrrole-fused PDIs suggests that effective pi-conjugation enlargement combined with distortion of the perylene core renders these PDI derivatives tunable and desirable physical properties. PMID- 30252495 TI - An RNA Sensor Protects from Pulmonary Hypertension. PMID- 30252496 TI - Xpert MTB/RIF Assay as a Substitute for Smear Microscopy in an Intermediate Burden Setting. AB - RATIONALE: Use of Xpert MTB/RIF assay as a substitute for smear microscopy in routine clinical practice remains unexplored in an intermediate tuberculosis burden setting. OBJECTIVES: To compare the diagnostic performance of Xpert and smear microscopy, based on sampling time and location, correlation of Xpert semiquantitative category with smear grade and time-to-culture positivity, and compliance of reporting time with defined standard time. METHODS: Consecutive sputum samples collected from 2,952 suspected pulmonary tuberculosis patients over a 3-year-period were tested by Xpert, smear microscopy, and liquid culture as part of routine diagnostics in South Korea. MEASUREMENTS AND MAIN RESULTS: Based on the analysis of a single-sputum-specimen per patient, of 2,952 samples, 263 (8.9%) were culture-confirmed tuberculosis and 265 (9.0%) were nontuberculous mycobacteria. The overall sensitivity and specificity were 74.1% and 97.5% for Xpert versus 38.8% and 96.7% for smear microscopy, respectively (P<0.0001; P>0.05). Of 82 smear-positive nontuberculous mycobacteria, 81 (98.8%) were accurately excluded by Xpert. Sampling time and location significantly affected the performance of smear microscopy, but not that of Xpert. Xpert semiquantitative category strongly correlated with smear grade (gammaGoodman Kruskal=0.982, P<0.0001) and time-to-culture positivity (gammaGoodman-Kruskal= 0.962, P<0.0001). Median reporting time and its compliance rate within 24h were 3.1h and 96.3% for Xpert versus 19.1h and 88.7% for smear microscopy, respectively (P<0.0001; P<0.05). CONCLUSIONS: Xpert provides faster, more stable, and superior results compared to smear microscopy, in addition to its strong correlation with smear grade. Xpert might replace smear microscopy as the first line diagnostic test for pulmonary tuberculosis in routine clinical practice in an intermediate-burden setting. PMID- 30252497 TI - Dawn of a New Era in the Diagnosis and Treatment of Airway Mucus Dysfunction. PMID- 30252498 TI - EXPRESS: The Nature of Cation-Anion Interactions in Magnetic Ionic Liquids as Revealed Using High-Pressure Fourier Transform Infrared (FT-IR) Spectroscopy. PMID- 30252499 TI - Circulating liver-specific microRNAs as noninvasive diagnostic biomarkers of hepatic diseases in human. AB - CONTEXT: Hepatitis is an endemic disease worldwide leading to chronic and debilitating cancers. The viral agents and hepatotoxic substances lead to damage of hepatocytes and release of damage associated molecules in circulation. The lack of timely and rapid diagnosis of hepatitis results in chronic disease. OBJECTIVE: The present review aimed to describe regulation, release and functions of microRNAs (miR) during human liver pathology and insights into their promising use as noninvasive biomarkers of hepatitis. METHODS: Comprehensive data were collected from PubMed, ScienceDirect and the Web of Science databases utilizing the keywords "biomarkers", "microRNAs" and "hepatic diseases". RESULTS: The miRs are readily released in the body fluids and blood during HBV/HCV associated hepatitis as well as metabolic, alcoholic, drug induced and autoimmune hepatitis. The liver-specific microRNAs including miR-122, miR-130, miR-183, miR-196, miR 209 and miR-96 are potential indicators of liver injury (mainly via apoptosis, necrosis and necroptosis) or hepatitis with their varied expression during acute/fulminant, chronic, liver fibrosis/cirrhosis and hepato-cellular carcinoma. CONCLUSIONS: The liver-specific miRs can be used as rapid and noninvasive biomarkers of hepatitis to discern different stages of hepatitis. Blocking or stimulating pathways associated with miR regulation in liver could unveil novel therapeutic strategies in the management of liver diseases. Clinical significance Liver specific microRNAs interact with cellular proteins and signaling molecules to regulate the expression of various genes controlling biological processes. The circulatory level of liver specific microRNAs is indicator of severity of HBV and HCV infections as well as prognostic and therapeutic candidates. The expression of liver specific microRNAs is strongly associated with infectious, drug-induced, hepatotoxic, nonalcoholic steatohepatitis and nonalcoholic fatty liver diseases. PMID- 30252500 TI - Sudden Death Due to Complete Airway Obstruction by Bronchial Casts. PMID- 30252501 TI - Urinary D-serine level as a predictive biomarker for deterioration of renal function in patients with atherosclerotic risk factors. AB - BACKGROUND: D-serine, the enantiomer of L-serine, was identified in mammals 20 years ago. Although a close relationship between D-serine and renal dysfunction has been shown, the clinical implications of urinary D- and L-serine in humans are poorly understood. The aim of this study was to evaluate the relationship between urinary D- and L-serine with well-known renal biomarkers, and clarify the prognostic value of D- and L-serine for renal events. METHODS: This cross sectional, prospective study included 65 patients with atherosclerotic risk factors, who were followed up for a median of 16 months. The primary endpoint was a composite of end-stage renal disease and a decline in estimated glomerular filtration rate (eGFR) >= 25% from baseline. RESULTS: Urinary D-serine concentrations showed a better correlation with eGFR than did urinary L-serine, whereas neither urinary D- nor L-serine correlated with tubular markers such as urinary liver-type fatty acid-binding protein and N-acetyl-beta-D glucosaminidase. A Cox regression analysis revealed that low urinary D-serine levels were significantly associated with the primary endpoint after adjusting for confounding factors (hazard ratio 12.60; 95% confidence interval, 3.49 45.51). CONCLUSIONS: Urinary D-serine is associated with glomerular filtration and can be a prognostic biomarker of renal dysfunction in patients with atherosclerotic risk factors. PMID- 30252502 TI - Measuring postnatal demoralisation: adaptation of the Demoralisation Scale-II (DS II) for postnatal use. AB - OBJECTIVE: To examine the psychometric properties of the Demoralisation Scale II (DS-II) and adapt it for use with women in the postnatal period. BACKGROUND: Demoralisation is a psychological state characterised by a sense of incompetence and feelings of helplessness and hopelessness in response to a stressful situation. The postnatal period is a life stage of many disruptions. Women may lose their confidence and become demoralised if feeling unprepared for the tasks of motherhood. The DS-II is a 16-item scale developed among cancer patients, but with content that is also relevant postnatally, including items on sense of failure, helplessness, hopelessness, isolation, entrapment and loss of purpose. METHODS: Rasch analysis was used to investigate the psychometric properties of the DS-II and refine the scale for postnatal use. RESULTS: Participants were 209 women admitted with their babies to a residential early parenting programme. A 14 item revised scale was derived, the Postnatal DS-II, showing good psychometric properties, discriminant validity and sensitivity to change, and being well targeted to the sample. CONCLUSION: The Postnatal DS-II could have utility as an assessment tool, helping clinicians to understand better women's postnatal experiences, assess the effectiveness of interventions and communicate with women in a meaningful and non-stigmatising way. PMID- 30252503 TI - Why some obese people become depressed whilst others do not: exploring links between cognitive reactivity, depression and obesity. AB - Obesity and depression are two major public health concerns, particularly when they co-occur. To date, mechanisms underlying this association have not been established and it is unclear why some obese people become depressed whilst others do not. However, considering the strong association between depression and cognitive reactivity (CR), the present study explores possible associations between obesity, depression and CR in light of the scarce and conflicting nature of past literature. 254 participants were included for measures of depression, CR and obesity. Multivariate analyses of covariance examined the effects of depression and obesity as well as interaction effects of depression x obesity controlling for age and gender. Directions of effects were analysed by means of regression analyses and group contrasts. Linear analyses revealed (1) a significant effect of obesity on the rumination (RUM) and control/perfectionism subscales of CR, (2) a significant effect of depression on CR and all of its subscales, and (3) a significant interaction effect between obesity x depression on RUM. Results may support the 'Jolly Fat Hypothesis' and the existence of a psychologically protected subgroup of obese patients characterised by a lower ruminative thinking style and fewer depressive symptoms. Thus, incorporating anti rumination therapy into treatment for obese individuals may be beneficial to prevent the development of comorbid depression. PMID- 30252504 TI - A Critical Review of the Properties and Analytical Methods for the Determination of Curcumin in Biological and Pharmaceutical Matrices. AB - Curcumin, a natural compound extracted from turmeric (Curcuma longa), has been extensively studied because of its various pharmacological properties, such as anti-inflammatory, antioxidant, antibiotic, antiprotozoal, immunomodulatory, anti proliferative, antitumor, and anticarcinogenic effects. However, low solubility in aqueous media has limited its therapeutic applications. To overcome these bioavailability issues, the use of drug delivery systems providing localized or targeted delivery of this drug may represent a more viable therapeutic option. Several drug delivery systems have been shown to significantly enhance the therapeutic efficacy of curcumin. Additionally, a wide variety of analytical methods are available for the qualitative and quantitative analysis of curcumin in different matrices, including plant extracts, biological fluids, and drug delivery systems. There are a variety of methodologies to quantify curcumin, but chromatographic and spectroscopic techniques are the ones most commonly used. Thus, in this review, we evaluate the biological properties of curcumin, as well as its nanotechnology-based delivery systems and methods of analysis. PMID- 30252505 TI - Adherence to and Persistence with Antidepressant Medication during Pregnancy: Does It Differ by the Class of Antidepressant Medication Prescribed? AB - OBJECTIVE: Pregnant women are often concerned about the impact of medication use on their pregnancy, such as congenital abnormalities. This study examined the rate of adherence to and persistence with antidepressant medications during pregnancy based on the class of antidepressants prescribed. METHODS: Women who gave birth between 2012 and 2015 in Alberta, Canada; had >=1 diagnosis of depression within 1 year of preconception in outpatient physician claims, emergency department, or hospitalization administrative data; and were adherent (medication possession ratio >=80%) to >=2 consecutive antidepressant prescriptions during the preconception year ( n = 1865) were included in this retrospective cohort study. The rates of adherence and persistence (prescription refill gap <=30 days) were calculated by antidepressant class and were compared using chi-square tests. RESULTS: During pregnancy, 834 (44.7%; 95% CI, 42.4% to 47.0%) women discontinued antidepressants. Among those continuing antidepressants, the overall rate of adherence was 62.6% (95% CI, 59.4% to 65.7%). The rate differed significantly by medication class ( P < 0.0001), with a rate of 75.1% (95% CI, 68.3% to 80.9%) for serotonin-norepinephrine inhibitors, 60.9% (95% CI, 57.2% to 64.5%) for selective serotonin reuptake inhibitors, 42.8% (95% CI, 19.9% to 69.3%) for nonselective monoamine reuptake inhibitors, and 37.5% (95% CI, 22.5% to 55.4%) for atypical antidepressants. Only, 40.7% (95% CI, 37.5 to 44.1) of women were persistent with antidepressants for the full pregnancy period-the rate differed significantly by medication class ( P < 0.0001). CONCLUSIONS: Adherence to and persistence with antidepressants is low during pregnancy and varies by medication class. Low adherence and persistence can interfere with a therapeutic effect of antidepressants, which may contribute to the worsening of depression symptoms. PMID- 30252507 TI - Physical Activity and Sleep Quality and Duration During Pregnancy Among Hispanic Women: Estudio PARTO. AB - OBJECTIVE/BACKGROUND: Poor sleep during pregnancy is common and is associated with pregnancy complications. Physical activity (PA) is associated with better sleep in nonpregnant populations. However, studies among pregnant women are sparse, conflicting, and none have been conducted among Hispanic women, who face a disproportionate burden of poor sleep and pregnancy complications. Therefore, our objective was to examine the relationship between intensity- and domain specific PA, respectively, on sleep quality and duration among Hispanic pregnant women. PARTICIPANTS: We evaluated these associations among participants (n = 251) in Estudio PARTO, an ongoing randomized controlled trial aimed at reducing type 2 diabetes among women at high risk. METHODS: We assessed the cross-sectional relationship between PA (via Pregnancy PA Questionnaire) and sleep quality and duration (via Pittsburgh Sleep Quality Index) using baseline data (26.5 +/- 6.9 weeks gestation). RESULTS: In multivariable logistic models, household and caregiving activities were associated with higher odds of very poor sleep quality (OR = 2.69; 95% CI = 1.04 to 7.04) and with short (vs. medium) sleep duration (OR = 2.85; 95% CI = 1.07 to 7.56). In contrast, occupational PA was associated with lower odds of very poor sleep quality (OR = 0.39; 95% CI = 0.17 to 0.89). Light intensity PA was associated with lower odds of long (vs. medium) sleep duration (OR = 0.13; 95% CI = 0.03 to 0.52). There were no statistically significant relationships between PA in any other domain and sleep. CONCLUSIONS: Prospective studies will be critical in evaluating the potential adverse impact of household and caregiving activities on poor sleep quality. PMID- 30252506 TI - Internet-Based Cognitive-Behavioral Therapy for Insomnia in Adults With Asthma: A Pilot Study. AB - BACKGROUND/OBJECTIVE: Insomnia is common among adults with asthma and is associated with worse asthma control. Cognitive-behavioral therapy for insomnia (CBT-I) is an effective treatment for insomnia with medical comorbidities, but it has not been tested in asthma. The purpose of this study was to assess the feasibility and acceptability of an Internet-based CBT-I intervention, called Sleep Healthy Using the Internet (SHUTi), among adults with asthma and comorbid insomnia, and to gather preliminary efficacy data on changes in insomnia severity, sleep quality, asthma control, and asthma-related quality of life. METHODS: A single-group, pretest-posttest design was employed, where all participants completed the SHUTi program. Online questionnaires were completed pre- and postintervention. Individual telephone interviews were conducted after posttreatment data collection to obtain participants' experiences with SHUTi and suggestions for improvement. RESULTS: The sample (N = 23) comprised men and women aged 18-75 years with moderate to severe, not well-controlled asthma, and comorbid insomnia. Nineteen (83%) completed postintervention assessments. Improvements on the Insomnia Severity Index, Pittsburgh Sleep Quality Index, Asthma Control Test, and Asthma Quality of Life Questionnair-Marks were observed at postintervention. Data from the telephone interviews suggest that most participants had a positive experience with SHUTi. Participants suggested incorporating asthma-specific content into future versions of the intervention. CONCLUSIONS: Internet-based CBT-I is a potential treatment option for adults with asthma and comorbid insomnia. PMID- 30252508 TI - Reliability and Validity of the Minnesota Multiphasic Personality Inventory - 2 - Restructured Form (MMPI-2-RF) in Spine Surgery and Spinal Cord Stimulator Samples. AB - It is not uncommon for patients to report diminished outcomes as a result of spine surgery or a spinal cord stimulator implant. Presurgical psychological evaluations are increasingly used to identify patients at increased risk for such outcomes and use of personality assessment instruments in these evaluations provides incremental information beyond a clinical interview and medical chart review. This investigation explores the psychometric properties of the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) in a sample of spine surgery patients (n = 810) and in a sample of spinal cord stimulator patients (n = 533). Results indicated that MMPI-2-RF substantive scale scores are reliable, with evidence of good convergent and discriminant validity in both samples. Incorporating the MMPI-2-RF as part of the presurgical evaluation of spine surgery and spinal cord stimulator patients can provide meaningful insight into patients' functioning and help guide pre- and postsurgical treatment in these settings. PMID- 30252509 TI - Processing and roles of snoRNA-ended long noncoding RNAs. AB - Small nucleolar RNAs (snoRNAs) are a family of conserved nuclear RNAs that function in the modification of small nuclear RNAs (snRNAs) or ribosomal RNAs (rRNAs), or participate in the processing of rRNAs during ribosome subunit maturation. Eukaryotic DNA transcription and RNA processing produce many long noncoding RNA (lncRNA) species. Although most lncRNAs are processed like typical mRNAs to be 5' capped and 3' polyadenylated, other types of lncRNAs are stabilized from primary Pol II transcripts by alternative mechanisms. One way to generate stable lncRNAs is to co-operate with snoRNA processing to produce snoRNA ended lncRNAs (sno-lncRNAs) and 5' snoRNA-ended and 3'-polyadenylated lncRNAs (SPAs). Rather than silently accumulating in the nucleus, some sno-lncRNAs and SPAs are involved in the regulation of pre-rRNA transcription and alternative splicing of pre-mRNAs. Here we provide a mini-review to discuss the biogenesis and functions of these unusually processed lncRNAs. PMID- 30252510 TI - Genito-Pelvic Pain Through a Dyadic Lens: Moving Toward an Interpersonal Emotion Regulation Model of Women's Sexual Dysfunction. AB - Researchers and clinicians alike widely acknowledge the inherently interpersonal nature of women's sexual dysfunctions given that both partners impact and are impacted by these difficulties. Yet theoretical models for understanding the role of interpersonal factors in women's sexual dysfunctions are severely lacking and have the potential to guide future research and inform more effective interventions. The most widely studied sexual dysfunction in women that has espoused a dyadic approach by including both members of affected couples is genito-pelvic pain/penetration disorder (GPPPD). In this article we use the example of GPPPD to introduce a novel interpersonal emotion regulation model of women's sexual dysfunction. We first review current knowledge regarding distal and proximal interpersonal factors in GPPPD. Then, we describe our theoretical model and consider relevant pain and sex-related research on emotion regulation processes-emotional awareness, expression, and experience-in the context of GPPPD, including sexual function, satisfaction, and distress. Next, we review how existing theories from the fields of chronic pain and sex and relationships research have informed our model and how our model further builds on them. Finally, we discuss the implications of our model and its applications, including to other sexual dysfunctions in women. PMID- 30252511 TI - The Spanish Flu, Epidemics, and the Turn to Biomedical Responses. AB - A century ago, nonpharmaceutical interventions such as school closings, restrictions on large gatherings, and isolation and quarantine were the centerpiece of the response to the Spanish Flu. Yet, even though its cause was unknown and the science of vaccine development was in its infancy, considerable enthusiasm also existed for using vaccines to prevent its spread. This desire far exceeded the scientific knowledge and technological capabilities of the time. Beginning in the early 1930s, however, advances in virology and influenza vaccine development reshaped the relative priority given to biomedical approaches in epidemic response over traditional public health activities. Today, the large scale implementation of nonpharmaceutical interventions akin to the response to the Spanish Flu would face enormous legal, ethical, and political challenges, but the enthusiasm for vaccines and other biomedical interventions that was emerging in 1918 has flourished. The Spanish Flu functioned as an inflection point in the history of epidemic responses, a critical moment in the long transition from approaches dominated by traditional public health activities to those in which biomedical interventions are viewed as the most potent and promising tools in the epidemic response arsenal. PMID- 30252512 TI - Early Child Development, Residential Crowding, and Commute Time in 8 US States, 2010-2017. AB - OBJECTIVES: To examine relationships of residential crowding and commute time with early child development. METHODS: We used the Early Development Instrument (EDI), a teacher-reported, population-health measure of child development. The sample included child-level observations spanning 8 US states from 2010 to 2017 (n = 185 012), aggregated to the census tract (n= 2793), stratified by percentage of households in poverty. To test the association of commute times, crowding, and child development, we tested overall readiness and 5 EDI domains by using adjusted census tract-level multivariate regression with fixed effects. RESULTS: In the full sample, a 1-standard-deviation increase in crowding was associated with 0.064- and 0.084-point decreases in mean score for cognitive development and communication skills, respectively. For the high-poverty subsample, a 1-standard deviation increase in commute time was associated with 0.081- and 0.066-point decreases in social competence and emotional maturity. CONCLUSIONS: In neighborhoods with increased crowding or commute time, early child development suffers. POLICY IMPLICATIONS: This study suggests a potential relationship between the changing urban landscape and child health. Children would benefit from more multisector collaboration between urban planning and public health. PMID- 30252513 TI - "Spanish Flu": When Infectious Disease Names Blur Origins and Stigmatize Those Infected. AB - Despite not originating in Spain, the 1918 influenza pandemic is commonly known as the "Spanish flu"-a name that reflects a tendency in public health history to associate new infectious diseases with foreign nationals and foreign countries. Intentional or not, an effect of this naming convention is to communicate a causal relationship between foreign populations and the spread of infectious disease, potentially promoting irrational fear and stigma. I address two relevant issues to help contextualize these naming practices. First is whether, in an age of global hyperinterconnectedness, fear of the other is truly irrational or has a rational basis. The empirical literature assessing whether restricting global airline travel can mitigate the global spread of modern epidemics suggests that the role of travel may be overemphasized. Second is the persistence of xenophobic responses to infectious disease in the face of contrary evidence. To help explain this, I turn to the health communication literature. Scholars argue that promoting an association between foreigners and a particular epidemic can be a rhetorical strategy for either promoting fear or, alternatively, imparting a sense of safety to the public. PMID- 30252514 TI - Promoting Condom Use Through a Youth-Focused Community-Wide Free Condom Distribution Initiative. AB - We describe the implementation of a youth-focused condom distribution initiative in Omaha, Nebraska, developed by the Women's Fund of Omaha. During a 2.5-year period, initiative partners distributed nearly 1.4 million free condoms to community members via outreach events and 197 condom distribution boxes. The Women's Fund of Omaha also implemented seven media campaigns encouraging condom use. The number of condoms distributed per month increased from 9840 in September 2015 to 71 220 in February 2018. Condom distribution initiatives can play an important role in increasing condom access. PMID- 30252515 TI - Sexual, Social, and Genetic Network Overlap: A Socio-Molecular Approach Toward Public Health Intervention of HIV. AB - OBJECTIVES: To determine how network-level factors influence individual risk of HIV acquisition, which is key in preventing disease transmission. METHODS: We recruited a cohort of young Black men who have sex with men (n = 618) in Chicago, Illinois, from 2013 to 2016. We identified potential molecular ties via pairwise genetic distance analysis of HIV pol sequences with links inferred between individuals whose sequences were 1.5% or less genetically distant. We defined clusters as 1 or more connections to another individual. We conducted entity resolution between confidant, sexual, referral, and Facebook network data between network types. RESULTS: Of 266 (43.0%) participants identified as HIV-positive, we obtained 86 (32.3%) genetic sequences. Of these, 35 (40.7%) were linked to 1 or more other sequence; however, none of these were identified in first-, second , or third-degree confidant and sexual networks. Minimal overlap existed between genetic and Facebook ties. CONCLUSIONS: These results suggest that HIV transmissions may have occurred before elicitation of network data; future studies should expand the data collection timeframe to more accurately determine risk networks. Virtual network data, such as Facebook, may be particularly useful in developing one's risk environment. PMID- 30252517 TI - The Physician's Duty to Treat During Pandemics. AB - Physicians assume a primary ethical duty to place the welfare of their patients above their own interests. Thus, for example, physicians must not exploit the patient-physician relationship for personal financial gain through the practice of self-referral. But how far does the duty to patient welfare extend? Must physicians assume a serious risk to their own health to ensure that patients receive needed care? In the past, physicians were expected to provide care during pandemics without regard to the risk to their own health. In recent decades, however, the duty to treat during pandemics has suffered from erosion even while the risks to physicians from meeting the duty has gone down. After exploring the historical evolution of the duty to treat and the reasons for the duty, I conclude that restoring a strong duty to treat would protect patient welfare without subjecting physicians to undue health risks. PMID- 30252516 TI - Evaluating the Evidence on Sitting, Smoking, and Health: Is Sitting Really the New Smoking? AB - Sitting has frequently been equated with smoking, with some sources even suggesting that smoking is safer than sitting. This commentary highlights how sitting and smoking are not comparable. The most recent meta-analysis of sedentary behavior and health outcomes reported a hazard ratio of 1.22 (95% confidence interval [CI] = 1.09, 1.41) for all-cause mortality. The relative risk (RR) of death from all causes among current smokers, compared with those who have never smoked, is 2.80 (95% CI = 2.72, 2.88) for men and 2.76 for women (95% CI = 2.69, 2.84). The risk is substantially higher for heavy smokers (> 40 cigarettes per day: RR = 4.08 [95% CI = 3.68, 4.52] for men, and 4.41 [95% CI = 3.70, 5.25] for women). These estimates correspond to absolute risk differences of more than 2000 excess deaths from any cause per 100 000 persons per year among the heaviest smokers compared with never smokers, versus 190 excess deaths per 100 000 persons per year when comparing people with the highest volume of sitting with the lowest. Conflicting or distorted information about health risks related to behavioral choices and environmental exposures can lead to confusion and public doubt with respect to health recommendations. PMID- 30252518 TI - Three Metaphors to Aid Interdisciplinary Dialogue in Public Health. AB - Within this journal, authors have recently called for or discussed the benefits of interdisciplinary collaboration. However, in practice such collaborations are extremely challenging, and little guidance is available to support researchers' efforts to communicate with colleagues from other disciplines. This article presents three metaphors from the sociology of scientific knowledge that can inform and support consideration and discussion of disciplinary issues. Disciplinary training acts as a "flashlight," highlighting certain features of reality and leaving others in shadow. Our disciplinary sense of normal science is the metaphorical "box" into which we hope nature will fit, determining the manner in which we advance the frontier by recognizing the familiar in the unfamiliar. Finally, scientific training is a "lens" through which the world is perceived and understood. In interdisciplinary and some multidisciplinary contexts, researchers are encouraged to (1) identify the set of fundamental concepts underpinning their approach to public health, (2) discuss methodological choices in terms that do not depend on familiarity with a common tradition of research excellence, and (3) maintain awareness that colleagues from other fields potentially hold different understandings of key public health concepts. PMID- 30252520 TI - Better Prepare Than React: Reordering Public Health Priorities 100 Years After the Spanish Flu Epidemic. AB - This commentary argues that 100 years after the deadly Spanish flu, the public health emergency community's responses to much more limited pandemics and outbreaks demonstrate a critical shortage of personnel and resources. Rather than relying on nonpharmaceutical interventions, such as quarantine, the United States must reorder its health priorities to ensure adequate preparation for a large scale pandemic. PMID- 30252519 TI - Culturally Adapted, Web-Based Cognitive Behavioral Therapy for Spanish-Speaking Individuals With Substance Use Disorders: A Randomized Clinical Trial. AB - OBJECTIVES: To evaluate whether adding Web-based cognitive behavioral treatment (CBT) to standard outpatient psychiatric or addiction treatment improved substance use outcomes. METHODS: We conducted a randomized clinical trial in New Haven, Connecticut, between 2014 and 2017 comparing 8 weeks of standard outpatient treatment to the same treatment with access to a culturally adapted version of Web-based CBT with a 6-month follow-up. Participants were 92 treatment seeking individuals with Spanish as their primary language and current substance use disorder, with few other restrictions. RESULTS: Treatment completion and data availability were high (98% of the randomized sample). For the primary outcome (change in frequency of primary substance used), there was a significant effect of treatment condition by time (t 1, 718 = -2.64; 95% confidence interval = 0.61, 0.09; P = .01), indicating significantly greater reductions for those assigned to Web CBT, which were durable through the 6-month follow-up. The knowledge test indicated significantly greater increases for those assigned to Web CBT. CONCLUSIONS: Adding a culturally adapted version of Web-based CBT to standard treatment improved substance use outcomes. Public Health Implications. This approach has high potential to address health disparities by providing an easily accessible, inexpensive form of evidence-based treatment to a range of Latinos with substance use disorders. PMID- 30252521 TI - Parent-Based Intervention to Improve Child Restraint Use Among Kindergarteners in China. AB - OBJECTIVES: To evaluate the effectiveness of parent-based child restraint system (CRS) education and hands-on CRS installation training. METHODS: We conducted a randomized trial with cluster sampling from May 2016 to January 2017 in 6 selected kindergarten classes in Shantou and Chaozhou, China. Parents were randomly assigned to receive 1 of the 3 study conditions: CRS education only, CRS education plus hands-on CRS installation training, or control (child electricity safety). RESULTS: Three months after the intervention, significantly higher CRS use was reported in the CRS education plus hands-on CRS installation training group than was reported in the control group (41.2% vs 18.5%; P = .011). However, no significant difference in CRS use was found between the CRS education only and the control groups (26.7% vs 18.5%; P = .33). The ratings on child passenger safety awareness increased significantly in both intervention groups but remained unchanged in the control group after the intervention. CONCLUSIONS: The CRS education plus hands-on CRS installation training increased the use of child restraints, but the CRS education only condition did not. Both intervention methods helped to improve child passenger safety awareness. PMID- 30252522 TI - America's Declining Well-Being, Health, and Life Expectancy: Not Just a White Problem. AB - Although recent declines in life expectancy among non-Hispanic Whites, coined "deaths of despair," grabbed the headlines of most major media outlets, this is neither a recent problem nor is it confined to Whites. The decline in America's health has been described in the public health literature for decades and has long been hypothesized to be attributable to an array of worsening psychosocial problems that are not specific to Whites. To test some of the dominant hypotheses, we show how various measures of despair have been increasing in the United States since 1980 and how these trends relate to changes in health and longevity. We show that mortality increases among Whites caused by the opioid epidemic come on the heels of the crack and HIV syndemic among Blacks. Both occurred on top of already higher mortality rates among all Americans relative to people in other nations, and both occurred among declines in measures of well being. We believe that the attention given to Whites is distracting researchers and policymakers from much more serious, longer-term structural problems that affect all Americans. PMID- 30252523 TI - The Effect of the Australian National Firearms Agreement on Suicide and Homicide Mortality, 1978-2015. AB - OBJECTIVES: To investigate the impact of the Australian National Firearms Agreement (NFA) on suicide and assault mortality. METHODS: We conducted a retrospective cross-sectional difference-in-difference study of the impact of the NFA on national mortality rates in the Australian population from 1961 to 2015. RESULTS: The NFA had no additional statistically observable impact on firearm related suicides in women (P = .09) and was associated with a statistically significant increase in the trend in men (P < .001). Trends in non-firearm related suicide deaths declined by 4.4% per year (95% confidence interval [CI] = 4.1%, 4.8%) in men after the introduction of the NFA and increased in women by 0.3% (95% CI = 0.1%, 0.7%). Trends in non-firearm-related homicides declined by 2.2% per year (95% CI = 1.5, 3.8%) in women and 2.9% per year (95% CI = 2.0%, 3.7%) in men after the introduction of the NFA, with a statistically significant improvement in trends for women (P = .04) but not for men (P = .80). CONCLUSIONS: The NFA had no statistically observable additional impact on suicide or assault mortality attributable to firearms in Australia. PMID- 30252524 TI - "Pay for Success" Projects: Financing Interventions That Address Social Determinants of Health in 20 Countries. AB - Over the past eight years, there has been an increase in the use of pay for success (PFS) as a financing tool whereby private investors provide initial funding for preventive health and human service interventions. If an independent evaluator deems the interventions successful, investors are repaid by the government. To better understand how PFS is used, we created a global landscape surveillance system to track and analyze data on all PFS projects that have launched through 2017. We focus on the potential for PFS to improve population health by funding interventions that target the social determinants of health. Our findings show that all launched projects to date have implemented interventions aimed at improving the structural and intermediary social determinants of health, primarily in socioeconomically disadvantaged populations. Although there are some challenges associated with PFS, we believe it is a promising tool for financing interventions aimed at social determinants of health in underserved and marginalized populations. PMID- 30252525 TI - 100 Years of Medical Countermeasures and Pandemic Influenza Preparedness. AB - The 1918 influenza pandemic spread rapidly around the globe, leading to high mortality and social disruption. The countermeasures available to mitigate the pandemic were limited and relied on nonpharmaceutical interventions. Over the past 100 years, improvements in medical care, influenza vaccines, antiviral medications, community mitigation efforts, diagnosis, and communications have improved pandemic response. A number of gaps remain, including vaccines that are more rapidly manufactured, antiviral drugs that are more effective and available, and better respiratory protective devices. PMID- 30252526 TI - Determinants of Tenancy Sustainment Following Homelessness: A Systematic Review. AB - BACKGROUND: Tenancy sustainment-maintenance of a tenancy to avoid a premature end of tenure-is fundamental to prevention of homelessness. Understanding what enables a successful tenancy is essential in informing interventions designed to support people in leaving homelessness. OBJECTIVES: To conduct a systematic review identifying determinants associated with tenancy sustainment following homelessness. SEARCH METHODS: A detailed search of 12 electronic databases, as well as gray literature sources, was conducted in 2015 and updated in 2016. SELECTION CRITERIA: We included all study designs with a population of homeless or formerly homeless individuals in which tenancy sustainment was the primary outcome. Two reviewers independently carried out abstract and full-text reviews. QualSyst, a validated quality appraisal tool, was used in assessing the methodological quality of articles. DATA COLLECTION AND ANALYSIS: A data extraction form was developed for the review and was completed by a pair of reviewers to ensure accuracy. The heterogeneity of the studies included indicated that a narrative overview of the results was most appropriate. MAIN RESULTS: Forty-three articles reporting 38 studies were included. Determinants were categorized at 4 levels: individual, interpersonal, community, and structural. Participation in specific programs (e.g., Housing First), receipt of social support, and older age were identified as positive determinants of tenancy sustainment. CONCLUSIONS: This systematic review is the first, to our knowledge, to focus solely on tenancy sustainment as a primary outcome. Although a range of determinants associated with tenancy sustainment were identified, it was difficult to draw strong conclusions owing to the heterogeneity of the studies. Despite being a fundamental concept in homelessness research, tenancy sustainment is poorly defined and conceptualized. A deeper understanding of tenancy sustainment will inform the development and evaluation of interventions that support people in leaving homelessness and maintaining tenancies. Public Health Implications. Housing stability is central to preventing homelessness and addressing the numerous public health concerns that can co-occur with homelessness. Our review highlights that a standardized approach to measuring housing stability and more high-quality intervention studies are essential. PMID- 30252527 TI - School Gardens in the United States: Current Barriers to Integration and Sustainability. AB - OBJECTIVES: To elucidate details about the barriers (time, funding, staffing, and space) to integrating and sustaining school gardens. METHODS: A total of 99 school gardeners from 15 states participated in an online survey in June 2017. The 29-item survey contained qualitative and quantitative items that we analyzed using descriptive statistics and inductive content analysis. RESULTS: In order of greatest to least barrier, gardeners ranked time, staff, funding, curriculum, and space. Time for classes to use the garden (66% of respondents) and time for staff training (62%) were the most frequently listed time-related challenges. Respondents also reported low engagement within the school community. An overall lack of funding was the most common funding-related barrier, and gardeners were unaware of how to obtain more funding. CONCLUSIONS: We identified 3 aspects of school gardens as opportunities to address time- and staff-related issues: strengthening of garden committees, professional development, and community outreach. Better channels are needed to disseminate funding opportunities within schools and to communicate with communities at large. Ultimately, doing so will strengthen existing school gardens as a vehicle to promote dietary, physical, and social health within communities. PMID- 30252528 TI - The Mother of All Pandemics Is 100 Years Old (and Going Strong)! AB - This year marks the 100th anniversary of the deadliest event in human history. In 1918-1919, pandemic influenza appeared nearly simultaneously around the globe and caused extraordinary mortality (an estimated 50-100 million deaths) associated with unexpected clinical and epidemiological features. The descendants of the 1918 virus remain today; as endemic influenza viruses, they cause significant mortality each year. Although the ability to predict influenza pandemics remains no better than it was a century ago, numerous scientific advances provide an important head start in limiting severe disease and death from both current and future influenza viruses: identification and substantial characterization of the natural history and pathogenesis of the 1918 causative virus itself, as well as hundreds of its viral descendants; development of moderately effective vaccines; improved diagnosis and treatment of influenza-associated pneumonia; and effective prevention and control measures. Remaining challenges include development of vaccines eliciting significantly broader protection (against antigenically different influenza viruses) that can prevent or significantly downregulate viral replication; more complete characterization of natural history and pathogenesis emphasizing the protective role of mucosal immunity; and biomarkers of impending influenza-associated pneumonia. PMID- 30252529 TI - Trends in Pelvic Inflammatory Disease Among American Indian and Alaska Native Women, Indian Health Service, 2001-2015. AB - OBJECTIVES: To describe trends in rates of pelvic inflammatory disease (PID) encounters among American Indian/Alaska Native (AI/AN) women aged 15 to 44 years in the United States receiving care within the Indian Health Service (IHS). METHODS: We analyzed IHS discharge data sets for PID encounters during 2001 to 2015 with International Classification of Diseases, Ninth Revision, Clinical Modification, diagnosis codes. We calculated rates of PID encounters per 100 000 women overall and stratified by age group, region, and health care setting. We used regression to identify trends in the total, annual, and average annual percent changes in the rate of PID encounters. RESULTS: There were 44 042 PID encounters during 2001 to 2015 (rate = 825 per 100 000). The highest rates were among women aged 20 to 24 years (1104) and from the Alaska region (1556). Rates significantly decreased overall (2001: 1084; 2015: 512; P < .001) and within all age groups and health care settings. There was variability in Alaska, with large increases during 2001 to 2010 followed by large decreases during 2010 to 2015. CONCLUSIONS: We observed decreasing trends in PID encounters among AI/AN women aged 15 to 44 years during 2001 to 2015, with the exception of increases in the Alaska region. PMID- 30252531 TI - The Influence of Industry Sponsorship on the Research Agenda: A Scoping Review. AB - BACKGROUND: Corporate interests have the potential to influence public debate and policymaking by influencing the research agenda, namely the initial step in conducting research, in which the purpose of the study is defined and the questions are framed. OBJECTIVES: We conducted a scoping review to identify and synthesize studies that explored the influence of industry sponsorship on research agendas across different fields. SEARCH METHODS: We searched MEDLINE, Scopus, and Embase (from inception to September 2017) for all original research and systematic reviews addressing corporate influence on the research agenda. We hand searched the reference lists of included studies and contacted experts in the field to identify additional studies. SELECTION CRITERIA: We included empirical articles and systematic reviews that explored industry sponsorship of research and its influence on research agendas in any field. There were no restrictions on study design, language, or outcomes measured. We excluded editorials, letters, and commentaries as well as articles that exclusively focused on the influence of industry sponsorship on other phases of research such as methods, results, and conclusions or if industry sponsorship was not reported separately from other funding sources. DATA COLLECTION AND ANALYSIS: At least 2 authors independently screened and then extracted any quantitative or qualitative data from each study. We grouped studies thematically for descriptive analysis by design and outcome reported. We developed the themes inductively until all studies were accounted for. Two investigators independently rated the level of evidence of the included studies using the Oxford Centre for Evidence-Based Medicine ratings. MAIN RESULTS: We included 36 articles. Nineteen cross-sectional studies quantitatively analyzed patterns in research topics by sponsorship and showed that industry tends to prioritize lines of inquiry that focus on products, processes, or activities that can be commercialized. Seven studies analyzed internal industry documents and provided insight on the strategies the industry used to reshape entire fields of research through the prioritization of topics that supported its policy and legal positions. Ten studies used surveys and interviews to explore the researchers' experiences and perceptions of the influence of industry funding on research agendas, showing that they were generally aware of the risk that sponsorship could influence the choice of research priorities. CONCLUSIONS: Corporate interests can drive research agendas away from questions that are the most relevant for public health. Strategies to counteract corporate influence on the research agenda are needed, including heightened disclosure of funding sources and conflicts of interest in published articles to allow an assessment of commercial biases. We also recommend policy actions beyond disclosure such as increasing funding for independent research and strict guidelines to regulate the interaction of research institutes with commercial entities. Public Health Implications. The influence on the research agenda has given the industry the potential to affect policymaking by influencing the type of evidence that is available and the kinds of public health solutions considered. The results of our scoping review support the need to develop strategies to counteract corporate influence on the research agenda. PMID- 30252530 TI - Rollover Protective Structures, Worker Safety, and Cost-Effectiveness: New York, 2011-2017. AB - OBJECTIVES: To measure cost-effectiveness of an intervention to increase retrofitting of rollover protective structures (ROPS) on tractors. METHODS: Tractor overturns are the leading cause of farm fatalities. ROPS prevent these deaths. This study updates a 2011 cost-effectiveness assessment of a New York State intervention to increase use of ROPS. We subtracted intervention cost from the cost of injuries averted, then divided this figure by the number of averted injuries. We used related probabilities and costs of fatalities and injuries from published literature to calculate the program's cost-effectiveness. RESULTS: The total cost of the injuries averted from 2007 to 2017 was $6 018 742 versus a total program cost of $1 776 608. The one-time retrofit costs will continue to prevent injuries as long as the tractors are used, generating additional (projected) future savings of $12 136 512, $15 781 027, and $18 924 818 if retrofitted tractors remain in operation 15, 20, or 25 years after their retrofit. CONCLUSIONS: Social marketing was cost-effective for reducing injuries from tractor overturns. Public Health Implications. These results indicate that the intervention model is effective from both a public health and economic standpoint and should be expanded into other states. PMID- 30252532 TI - Endothelial cell-secreted MIF reduces pericyte contractility and enhances neutrophil extravasation. AB - Dysregulated neutrophil extravasation contributes to the pathogenesis of many inflammatory disorders. Pericytes (PCs) have been implicated in the regulation of neutrophil transmigration, and previous work demonstrates that endothelial cell (EC)-derived signals reduce PC barrier function; however, the signaling mechanisms are unknown. Here, we demonstrate a novel role for EC-derived macrophage migration inhibitory factor (MIF) in inhibiting PC contractility and facilitating neutrophil transmigration. With the use of micro-ELISAs, RNA sequencing, quantitative PCR, and flow cytometry, we found that ECs secrete MIF, and PCs upregulate CD74 in response to TNF-alpha. We demonstrate that EC-derived MIF decreases PC contractility on 2-dimensional silicone substrates via reduction of phosphorylated myosin light chain. With the use of an in vitro microvascular model of the human EC-PC barrier, we demonstrate that MIF decreases the PC barrier to human neutrophil transmigration by increasing intercellular PC gap formation. For the first time, an EC-specific MIF knockout mouse was used to investigate the effects of selective deletion of EC MIF. In a model of acute lung injury, selective deletion of EC MIF decreases neutrophil infiltration to the bronchoalveolar lavage and tissue and simultaneously decreases PC relaxation by increasing myosin light-chain phosphorylation. We conclude that paracrine signals from EC via MIF decrease PC contraction and enhance PC-regulated neutrophil transmigration.-Pellowe, A. S., Sauler, M., Hou, Y., Merola, J., Liu, R., Calderon, B., Lauridsen, H. M., Harris, M. R., Leng, L., Zhang, Y., Tilstam, P. V., Pober, J. S., Bucala, R., Lee, P. J., Gonzalez, A. L. Endothelial cell secreted MIF reduces pericyte contractility and enhances neutrophil extravasation. PMID- 30252533 TI - Urinary concentrating defect in mice lacking Epac1 or Epac2. AB - cAMP is a universal second messenger regulating a plethora of processes in the kidney. Two downstream effectors of cAMP are PKA and exchange protein directly activated by cAMP (Epac), which, unlike PKA, is often linked to elevation of [Ca2+]i. While both Epac isoforms (Epac1 and Epac2) are expressed along the nephron, their relevance in the kidney remains obscure. We combined ratiometric calcium imaging with quantitative immunoblotting, immunofluorescent confocal microscopy, and balance studies in mice lacking Epac1 or Epac2 to determine the role of Epac in renal water-solute handling. Epac1-/- and Epac2-/- mice developed polyuria despite elevated arginine vasopressin levels. We did not detect major deficiencies in arginine vasopressin [Ca2+]i signaling in split-opened collecting ducts or decreases in aquaporin water channel type 2 levels. Instead, sodium hydrogen exchanger type 3 levels in the proximal tubule were dramatically reduced in Epac1-/- and Epac2-/- mice. Water deprivation revealed persisting polyuria, impaired urinary concentration ability, and augmented urinary excretion of Na+ and urea in both mutant mice. In summary, we report a nonredundant contribution of Epac isoforms to renal function. Deletion of Epac1 and Epac2 decreases sodium hydrogen exchanger type 3 expression in the proximal tubule, leading to polyuria and osmotic diuresis.-Cherezova, A., Tomilin, V., Buncha, V., Zaika, O., Ortiz, P. A., Mei, F., Cheng, X., Mamenko, M., Pochynyuk, O. Urinary concentrating defect in mice lacking Epac1 or Epac2. PMID- 30252534 TI - Monitoring alpha-synuclein multimerization in vivo. AB - The pathophysiology of Parkinson's disease is characterized by the abnormal accumulation of alpha-synuclein (alpha-Syn), eventually resulting in the formation of Lewy bodies and neurites in surviving neurons in the brain. Although alpha-Syn aggregation has been extensively studied in vitro, there is limited in vivo knowledge on alpha-Syn aggregation. Here, we used the powerful genetics of Drosophila melanogaster and developed an in vivo assay to monitor alpha-Syn accumulation by using a bimolecular fluorescence complementation assay. We found that both genetic and pharmacologic manipulations affected alpha-Syn accumulation. Interestingly, we also found that alterations in the cellular protein degradation mechanisms strongly influenced alpha-Syn accumulation. Administration of compounds identified as risk factors for Parkinson's disease, such as rotenone or heavy metal ions, had only mild or even no impact on alpha Syn accumulation in vivo. Finally, we show that increasing phosphorylation of alpha-Syn at serine 129 enhances the accumulation and toxicity of alpha-Syn. Altogether, our study establishes a novel model to study alpha-Syn accumulation and illustrates the complexity of manipulating proteostasis in vivo.-Prasad, V., Wasser, Y., Hans, F., Goswami, A., Katona, I., Outeiro, T. F., Kahle, P. J., Schulz, J. B., Voigt, A. Monitoring alpha-synuclein multimerization in vivo. PMID- 30252535 TI - The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation. AB - Epithelial barrier maintenance and regulation requires an intact perijunctional actomyosin ring underneath the cell-cell junctions. By searching for known factors affecting the actin cytoskeleton, we identified Krev interaction trapped protein 1 (KRIT1) as a major regulator for epithelial barrier function through multiple mechanisms. KRIT1 is expressed in both small intestinal and colonic epithelium, and KRIT1 knockdown in differentiated Caco-2 intestinal epithelium decreases epithelial barrier function and increases cation selectivity. KRIT1 knockdown abolished Rho-associated protein kinase-induced and myosin II motor inhibitor-induced barrier loss by limiting both small and large molecule permeability but did not affect myosin light chain kinase-induced increases in epithelial barrier function. These data suggest that KRIT1 participates in Rho associated protein kinase- and myosin II motor-dependent (but not myosin light chain kinase-dependent) epithelial barrier regulation. KRIT1 knockdown exacerbated low-dose TNF-induced barrier loss, along with increased cleaved caspase-3 production. Both events are blocked by pan-caspase inhibition, indicating that KRIT1 regulates TNF-induced barrier loss through limiting epithelial apoptosis. These data indicate that KRIT1 controls epithelial barrier maintenance and regulation through multiple pathways, suggesting that KRIT1 mutation in cerebral cavernous malformation disease may alter epithelial function and affect human health.-Wang, Y., Li, Y., Zou, J., Polster, S. P., Lightle, R., Moore, T., Dimaano, M., He, T.-C., Weber, C. R., Awad, I. A., Shen, L. The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation. PMID- 30252537 TI - Complexation of novel thiomers and insulin to protect against in vitro enzymatic degradation - towards oral insulin delivery. AB - A significant barrier to oral insulin delivery is its enzymatic degradation in the gut. Nano-sized polymer-insulin polyelectrolyte complexes (PECS) have been developed to protect insulin against enzymatic degradation. Poly(allylamine) (Paa) was trimethylated to yield QPaa. Thiolation of Paa and QPaa was achieved by attaching either N-acetylcysteine (NAC) or thiobutylamidine (TBA) ligands (Paa NAC/QPaa-NAC and Paa-TBA/QPaa-TBA thiomers). PEC formulations were prepared in Tris buffer (pH 7.4) at various polymer: insulin mass ratios (0.2:1-2:1). PECS were characterized by %transmittance of light and photon correlation spectroscopy. Insulin complexation efficiency and enzyme-protective effect of these complexes were determined by HPLC. Complexation with insulin was found to be optimal at mass ratios of 0.4-1:1 for all polymers. PECS in this mass range were positively-charged (20-40 mV), nanoparticles (50-200 nm), with high insulin complexation efficiency (>90%). Complexation with TBA polymers appeared to result in disulfide bridge formation between the polymers and insulin. In vitro enzymatic degradation assays of QPaa, Paa-NAC, and QPaa-NAC PECS showed that they all offered some protection against insulin degradation by trypsin and alpha chymotrypsin, but not from pepsin. QPaa-NAC complexes with insulin are the most promising formulation for future work, given their ability to offer protection against intestinal enzymes. This work highlights the importance of optimizing polymer structure in the delivery of proteins. PMID- 30252536 TI - RARbeta acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells. AB - This study investigates the mechanism and consequences of microRNA-22 ( miR-22) induction. Our data revealed for the first time that retinoic acid (RA) and histone deacetylase (HDAC) inhibitors, including short-chain fatty acids and suberanilohydroxamic acid (SAHA), could individually or in combination induce miR 22. This induction was mediated via RA receptor beta (RARbeta) binding to a direct repeat 5 (DR5) motif. In addition, we uncovered HDAC1 as a novel miR-22 target. In an miR-22-dependent manner, HDAC inhibitors and RA reduced HDAC1, HDAC4, and sirtuin 1 (SIRT1), which were involved in chromatin remodeling of the RARbeta and nerve growth factor IB ( NUR77). Thus, HDAC inhibitors and RA-induced miR-22 resulted in simultaneous induction of cytoplasmic RARbeta and NUR77, leading to apoptosis of colon cancer cells. In mice, miR-22 and its inducers inhibited the growth of xenograft colon cancer. Moreover, tumor size reduction was accompanied by elevated miR-22, NUR77, and RARbeta and by reduced HDACs. In human colon polyps and adenocarcinomas, miR-22 and RARbeta were consistently reduced, which was associated with elevated HDAC1, HDAC4, and SIRT1 in colon adenocarcinomas. Results from this study revealed a novel anticancer mechanism of RARbeta via miR-22 induction to epigenetically regulate itself and NUR77, providing a promising cancer treatment modality using miR-22 and its inducers. Hu, Y., French, S. W., Chau, T., Liu, H.-X., Sheng, L., Wei, F., Stondell, J., Garcia, J. C., Du, Y., Bowlus, C. L., Wan, Y.-J. Y. RARbeta acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells. PMID- 30252538 TI - Time-restricted foraging under natural light/dark condition shifts the molecular clock in the honey bee, Apis mellifera. AB - Honey bees have a remarkable sense of time and individual honey bee foragers are capable of adjusting their foraging activity with respect to the time of food availability. Although, there is compelling experimental evidence that foraging behavior is guided by the circadian clock, nothing is known about the underlying molecular mechanisms. Here we present for the first time a study that explores whether time-restricted foraging under natural light-dark (LD) condition affects the molecular clock in honey bees. Food was presented in an enclosed flight chamber (12 m * 4 m * 4 m) either for 2 hours in the morning or 2 hours in the afternoon for several consecutive days and daily cycling of the two major clock genes, cryptochrome2 (cry2) and period (per), were analyzed for three different parts of the nervous system involved in feeding-related behaviors: brain, subesophageal ganglion (SEG), and the antennae with olfactory sensory neurons. We found that morning and afternoon trained foragers showed significant phase differences in the cycling of both clock genes in all three tissues. In addition, the phase differences were more pronounced when the feeder was scented with the common plant odor, linalool. Together our findings suggest that foraging time may function as a Zeitgeber that might have the capability to modulate the light entrained molecular clock. PMID- 30252539 TI - Ethics in clinical trial regulation: ethically relevant issues from EMA inspection reports. AB - BACKGROUND: Within the EU, regulators are obliged to take ethical issues into consideration during marketing authorization deliberation. The goal of this manuscript is to identify what kinds of ethical issues regulators encounter during marketing authorization application deliberations, and the incidence of these ethical issues. METHODS: This study used an EMA-provided Excel file that contains all the GCP non-compliance findings from all inspection reports from 2008-2012. There were 112 medicinal products and a total of 288 clinical trial sites. There were a total of 4014 GCP non-compliance findings. The findings that were ethically relevant were extracted using NVivo 10.0 and categories for the ethically relevant findings (ERFs) were created. Note was taken of the incidence of ERFs for each category and the inspectors' gradings of these findings were extracted. This study also looked at the mean and the maximum number of ERFs per grading per medicinal product application, as well as the number of medicinal products with at least one ERF and those with at least major ERFs. RESULTS: With multiple coding, there were 1685 ERFs. ERFs were present in almost all of the medicinal products (97.3%). The majority of ERFs were graded as major. At least major ERFs were present in almost all medicinal products with ERFs. The categories with the highest number of ERFs were protocol issues, patient safety, and professionalism issues. In terms of the density of combined critical and major findings, monitoring and oversight, protocol issues, and respect for persons top the list. This study also showed that, on average, there were 7.54 major and 2.95 critical ERFs per medicinal product application, although ERFs can increase to 30 major and 12 critical. CONCLUSION: Regulators regularly encounter ERFs that at least "might adversely affect the rights, safety or well-being of the subjects". It remains to be explored how regulators respond to these ethical issues. PMID- 30252540 TI - Application of titanium dioxide (TiO2) nanoparticles in cancer therapies. AB - Cancer is one of the most common diseases all over the world; many people suffer from diverse types of cancer. However, currently there is no exact cure or therapy developed for cancer. On the other hand, nanoparticles are defined as microscopic particles that have dimensions less than 100 nm and they are known for their usage in health sciences and medicine, however a few harmful effects on different animal cells. Therefore, researchers began to use nanoparticles for cancer therapies and to develop new methods for much more effective therapies. Nanoparticles in cancer studies are commonly used in photodynamic therapy (PDT) and sonodynamic therapy (SDT) as a sensitising agent, in computed tomography imaging (CT) and radiation therapy as an enhancement agent, in dual-mode image contrast and enhancement therapy as an image contrast agent. Titanium dioxide nanoparticles (TiO2 NPs) are known as commonly used nanoparticles in medical applications and hence in cancer studies. They are used in PDT, SDT and drug delivery systems. As cancer continues to affect people, new therapeutics and therapies will be developed and nanotechnology for this aim will be an important approach for the researchers. PMID- 30252541 TI - Intention to Seek Depression Treatment in Latina Immigrant Mothers. AB - BACKGROUND: Postpartum depression in Latina immigrant mothers can lead to adverse outcomes in both mothers and babies, yet depression treatment remains suboptimal. AIMS: The aims were to determine predictors of intention to seek depression treatment and to determine if intention to seek depression treatment differed in those with significant symptoms of depression. METHODS: Based upon the theory of planned behavior (TPB), a cross-sectional study design was used. A convenience sample of Latina immigrant mothers (n = 50) were interviewed in Spanish. Certified translation services were used to translate study instruments to Spanish. Descriptive analysis and multivariable logistic regression techniques were used for data analysis. RESULTS: While increases in attitudes were associated with intention to seek depression treatment, increased social support and perceived control were associated with a decrease in intention to seek treatment. CONCLUSIONS: The differing role of social support in Latina immigrant mothers should be explored. PMID- 30252542 TI - Perspectives and Experiences of Primary Caregivers of Individuals with Schizophrenia in Thailand. AB - This study investigates primary caregiver perspectives on long-term experiences of caring for individuals with schizophrenia in Thailand. Study participants were 30 caregivers in the Bangkok Metropolitan Area (BMA). Data were collected by semi structured qualitative interview and analyzed by thematic analysis. Participants defined psychotic symptoms as symptoms requiring prevention and good care, which caregivers must learn to live with. Caregivers were reported to have "acquired experience in controlling psychotic symptoms and recognizing frequency, timing, content, warning signs, and patient response." Schizophrenic patients experienced difficulty engaging in community activities and encountered teasing, stigma, and social isolation. These findings suggest that caregivers saw psychotic symptoms as necessarily leading to ongoing serious problems. The difficulty of dealing with such symptoms was aggravated by caregiver poverty, emotional condition, and advanced age. Innovations in psychiatric and mental health nursing intervention are needed, including psycho-educational community activities to confront the teasing, stigma, and social isolation of individuals with schizophrenia. Simulation applications on mobile phones and Internet are recommended. PMID- 30252543 TI - Asthma control and quality of life in a real-life setting: a cross-sectional study of adult asthma patients in Japan (ACQUIRE-2). AB - OBJECTIVE: The level of asthma control in adult asthma patients receiving treatment in clinical practice from allergy and/or respiratory specialists in Japan remains unclear. We conducted the ACQUIRE-2 study (NCT02640742) to evaluate level of asthma control, asthma symptoms, health-related quality of life (HR QoL), and reliever medication use in this setting. METHODS: This observational study was undertaken between December 2015 and June 2016 in 58 medical institutions across Japan. We enrolled outpatients aged >=20 years diagnosed with asthma for >=1 year who were being managed by specialists. Criteria to evaluate the level of asthma control were based on modified definitions of the Asthma Prevention and Management Guideline 2015, Japan (JGL 2015) and Global Initiative for Asthma (GINA) 2012. Asthma symptoms, HR-QoL, and reliever medication use were also evaluated. RESULTS: Of 1250 enrolled patients, 1175 were analyzed, 62.9% of whom were women. Mean (+/- standard deviation) age and duration of asthma were 59.7 +/- 14.5 years and 16.9 +/- 14.0 years, respectively. Using JGL 2015-based criteria, 24.4%, 69.2%, and 6.5% of patients had well-controlled, insufficiently controlled, and poorly-controlled asthma, respectively. Using GINA-based criteria, 35.1%, 49.8%, and 15.1% of patients had controlled, partly controlled, and uncontrolled asthma, respectively. Daytime and nighttime asthma symptoms were experienced by 51.5% and 44.9% of patients, respectively. The mean MiniAQLQ score was 5.8 +/- 1.0 (7-point scale). CONCLUSIONS: Asthma was not well-controlled in the majority of patients in this study. To achieve better asthma control, improvements in symptom monitoring and management may be required. PMID- 30252544 TI - Asthma dissemination around patient-centered treatments in North Carolina (ADAPT NC): a cluster randomized control trial evaluating dissemination of an evidence based shared decision-making intervention for asthma management. AB - OBJECTIVE: To compare three dissemination approaches for implementing an asthma shared decision-making (SDM) intervention into primary care practices. METHODS: We randomized thirty practices into three study arms: (1) a facilitator-led approach to implementing SDM; (2) a one-hour lunch-and-learn training on SDM; and (3) a control group with no active intervention. Patient perceptions of SDM were assessed in the active intervention arms using a one-question anonymous survey. Logistic regression models compared the frequency of asthma exacerbations (emergency department (ED) visits, hospitalizations, and oral steroid prescriptions) between the three arms. RESULTS: We collected 705 surveys from facilitator-led sites and 523 from lunch-and-learn sites. Patients were more likely to report that they participated equally with the provider in making the treatment decision in the facilitator-led sites (75% vs. 66%, p = 0.001). Comparisons of outcomes for patients in the facilitator-led (n = 1,658) and lunch and-learn (n = 2,613) arms respectively vs. control (n = 2,273) showed no significant differences for ED visits (Odds Ratio [OR] [95%CI] = 0.77[0.57-1.04]; 0.83[0.66-1.07]), hospitalizations (OR [95%CI] = 1.30[0.59-2.89]; 1.40 [0.68 3.06]), or oral steroids (OR [95%CI] =0.95[0.79-1.15]; 1.03[0.81-1.06]). CONCLUSION: Facilitator-led dissemination was associated with a significantly higher proportion of patients sharing equally in decision-making with the provider compared to a traditional lunch-and-learn approach. While there was no significant difference in health outcomes between the three arms, the results were most likely confounded by a concurrent statewide asthma initiative and the pragmatic implementation of the intervention. These results offer support for the use of structured approaches such as facilitator-led dissemination of complex interventions into primary care practices. PMID- 30252545 TI - Wedelolactone suppresses cell proliferation and migration through AKT and AMPK signaling in melanoma. AB - PURPOSE: Melanoma is a malignant tumor with high degree of malignancy, metastasis and high mortality. As melanoma is not sensitive to treatments, searching for new therapeutic agent is the priority. Wedelolactone (WDL) is a natural compound which has antiproliferation activities. In the current study, the effects of WDL on melanoma are evaluated and the underlying mechanisms are explored. MATERIALS AND METHODS: We treated melanoma cell line MV3 cells with WDL and monitored the cell proliferation, invasion and migration, the mRNA and protein levels of Bax and Bcl-2, expression of cell-cycle regulators including cyclin D, proliferating cell nuclear antigen (PCNA) and p21. We detected the effect of WDL on AKT and AMPK signaling pathways activations. Finally, we evaluated the inhibitory effect of WDL in xenograft nude mice model in vivo. RESULTS: WDL inhibited MV3 cell proliferation, migration and invasion. WDL induced pro-apoptotic protein Bax expression but inhibited antiapoptotic protein Bcl-2 expression. WDL inhibited cyclin D expression while increased p21 expression. WDL inhibited AKT activation but induced AMPK activation. The induction of p21expression by WDL depended on AMPK signaling pathway. WDL inhibited melanoma in xenograft nude mice. CONCLUSION: WDL suppressed cell proliferation and regulated MV3 cell-cycle proteins through AKT and AMPK signaling in melanoma. PMID- 30252546 TI - Introducing a Conversational Model Therapy Approach as a Team Model of Care: The Clinician Experience in a Sexual Assault Service. AB - This article examines clinician experience in adopting a contemporary psychodynamic model of care by exploring the experiences and perspectives of staff at an Australian hospital-based sexual assault service (SAS), reflecting then on implications for how to best engage clinicians in a model of care change and training. The Conversational Model of Therapy (CMT) is a contemporary psychodynamic approach integrating evidence from developmental psychology, neuroscience and trauma. Training was provided in the CMT approach to Short-Term Intensive Psychodynamic Psychotherapy seeking to enable the service to better provide for the needs of adult clients with less recent sexual assault experiences and/or those able to receive a short-term psychotherapy. Five semi structured individual interviews and one focus group (with four participants) were undertaken to identify SAS staff perceptions of their experiences after initial training of up to 13 sessions with CMT. Thematic analysis was performed to identify, analyse and report patterns in the responses with the following themes emerging: the challenges staff face in providing a service to clients; coping mechanisms staff utilise in their work; the current service structure and how this compares with their experiences of CMT, and; feelings and thoughts on SAS staff being evaluated. Findings provide evidence that the majority of staff understood the need for change and were able to undertake training towards this due to effective coping mechanisms within their work and good support from within their team. The research also highlights the need to ensure effective training to evaluate participants' understanding of the model being taught. In the context of training experience elsewhere, learning and synthesis of all of the knowledge relevant to a psychodynamic model of care may require experiential learning through supervision of audio-recorded sessions, although this has challenges in the SAS context. PMID- 30252547 TI - How far have we reached in development of effective influenza vaccine? AB - Despite of ongoing research programs and numerous clinical trials, seasonal influenza epidemics remain a major concern globally. Vaccination remains the most effective method to prevent influenza infection. However, current flu vaccines have several limitations, including limited vaccine capacity, long production times, inconsistence efficacy in certain populations, and lack of a "universal" solution. Different next-generation approaches such as cell line-based culture, reverse genetics, and virus expression technology are currently under development to address the aforementioned challenges in conventional vaccine manufacture pipeline. Such approaches hope for safe and scalable production, induce broad spectrum immunity, create premade libraries of vaccine strains, and target nonvariable regions of antigenic proteins for "universal" vaccination. Here, we discuss the process and challenges of the current influenza vaccine platform as well as new approaches that are being investigated. These developments indicate that an exciting future lies ahead in the influenza vaccine field. PMID- 30252548 TI - A comparative study between suction blistering graft, mini punch graft, and hair follicle transplant in treatment of patients with stable vitiligo. AB - BACKGROUND: Vitiligo is an acquired disfiguring common depigmented skin disease. OBJECTIVES: This study aimed to compare the clinical efficacy and safety of suction blistering graft, mini punch and hair follicle techniques in treatment of patients with stable vitiligo. METHODS: Thirty patients with stable vitiligo were included. Patients were divided into 3 groups, in group (A) 10 patient underwent suction blistering technique, in group (B) 10 patients underwent mini punch technique and in group (C) 10 patients underwent hair follicle technique. Then all patients in the three techniques were subjected to narrow-band ultraviolet B (NB-UVB) phototherapy for 3 months. All patients were assessed by determining the percentage of repigmentation and Dermatology Life Quality Index (DLQI) before and 3 months after the operation. RESULTS: The percentage of repigmentation of vitiligo in suction blister technique was significantly higher than both mini punch and hair follicle techniques (p value .001 and .0001 respectively). There was a statistically significant difference between the three techniques regarding DLQI score after operation (p value = .0001). CONCLUSION: This study concluded that suction blistering technique is more effective and safe than mini punch technique and hair follicle technique in treatment of stable vitiligo. PMID- 30252550 TI - Shedding light on the FDA's 510(k) approvals process: low-level laser therapy devices used in the treatment of androgenetic alopecia. AB - INTRODUCTION: Low-level laser therapy has demonstrated superior efficacy relative to other nonsurgical treatment options for the treatment of androgenetic alopecia. METHODS: Records from a public U.S. FDA database for premarket approval of low-level laser therapy devices approved between January 1 2000 and July 15 2018 were reviewed. RESULTS: 47 devices received 510(k) premarket approval, with an increasing number of devices available since 2007. More options are now available and product indications have expanded for use in a wider audience, including both men and women. DISCUSSION: Growing recognition of lasers has led to an increasing number of devices available as well as innovative options in terms of design and convenience. In the past few years, these devices have adopted broader indications for use in both men and women. However, marketed indications have not been adequately explored and current devices on the market have the potential to mislead consumers. PMID- 30252549 TI - Analyzing intent-to-treat and per-protocol effects on safety outcomes using a medical information database: an application to the risk assessment of antibiotic induced liver injury. AB - OBJECTIVE: To apply a causal analysis approach to estimate the intent-to-treat and per-protocol effects in a safety outcome study of the 30-day risk of liver injury associated with antibiotic use (macrolides, penicillin-based antibiotics, and fluoroquinolones). RESEARCH DESIGN AND METHODS: For each antibiotic class, we constructed a pooled cohort of treated episodes matched with untreated episodes using an electronic medical record database from a university hospital. High dimensional propensity scores were calculated using baseline patient characteristics, concomitant medications and medical history as surrogate confounders. Intent-to-treat hazard ratios (HRs) were estimated using inverse probability of treatment weighted discrete hazard models that ignored subsequent treatment changes. Per-protocol HRs were calculated using inverse probability of treatment and censoring weighted models after terminating each episode's observation at the first treatment change. RESULTS: For macrolides, the intent-to treat HR (95% confidence interval) was 1.22 (0.75-1.98) and the per-protocol HR was 1.22 (0.67-2.22). For penicillin-based antibiotics, the intent-to-treat HR was 4.01 (3.16-5.08) and the per-protocol HR was 7.25 (5.58-9.41). For fluoroquinolones, the intent-to-treat HR was 1.60 (1.27-2.03) and the per protocol HR was 1.69 (1.23-2.30). CONCLUSION: Researchers should clearly define the target estimands, and carefully estimate and interpret both effects. PMID- 30252551 TI - College Education on Dietary Supplements May Promote Responsible Use In Young Adults. AB - Dietary supplement (DS) use is increasing among college students. Early adulthood is a critical developmental stage when behavioral trends are established with potential health implications. Many studies have suggested a proper college education on DSs is needed, but no follow-up reports exist in the literature. The purpose of the study was to compare DS use in college students with and without a formal education on DSs. An anonymous survey was sent over electronic mailing lists of different social and professional student groups, including students in the health and wellness studies (HWS) minor (HM) at Binghamton University. A total of 308 students completed the study. A statistical framework using multivariate analyses was designed to assess pattern of use and identify variables of interest. Principal component analysis recognized five patterns collectively contributing to 66.75% of the variance. PC 1 characterized as tobacco use, PC 2 labeled as body weight, PC 3 categorized as exercise, PC 4 labeled as educated use, and PC 5 is considered Greek-life lifestyle. Participants were then partitioned into HM versus HWS nonminor (NM). Common factor analysis was performed to extract significant variables pertaining to each pattern. Results reflected driving forces common to both groups. However, new trends surfaced in HM. A regression analysis suggests that DS use in HM is based on knowledge, whereas NM use is specifically targeted toward certain lifestyles. In addition, HM are more likely to discontinue a DS with formal knowledge. Therefore, college education on DS may be promoting a healthy pattern of supplement use. PMID- 30252552 TI - Mathematical models of tumor cell proliferation: A review of the literature. AB - INTRODUCTION: A defining hallmark of cancer is aberrant cell proliferation. Efforts to understand the generative properties of cancer cells span all biological scales: from genetic deviations and alterations of metabolic pathways to physical stresses due to overcrowding, as well as the effects of therapeutics and the immune system. While these factors have long been studied in the laboratory, mathematical and computational techniques are being increasingly applied to help understand and forecast tumor growth and treatment response. Advantages of mathematical modeling of proliferation include the ability to simulate and predict the spatiotemporal development of tumors across multiple experimental scales. Central to proliferation modeling is the incorporation of available biological data and validation with experimental data. Areas covered: We present an overview of past and current mathematical strategies directed at understanding tumor cell proliferation. We identify areas for mathematical development as motivated by available experimental and clinical evidence, with a particular emphasis on emerging, non-invasive imaging technologies. Expert commentary: The data required to legitimize mathematical models are often difficult or (currently) impossible to obtain. We suggest areas for further investigation to establish mathematical models that more effectively utilize available data to make informed predictions on tumor cell proliferation. PMID- 30252553 TI - Management of fluid status and cardiovascular function in patients with diffuse skin inflammation. AB - BACKGROUND: Skin inflammation causes vasodilation and increased vascular permeability, which may result in decreased blood pressure and peripheral edema. Patients with erythroderma usually compensate for low blood pressure with fluid retention and increased cardiac output. However, if the heart cannot support increased cardiac output, blood pressure will stay low, resulting in severe compensatory fluid retention, which leads to decompensated congestive heart failure, and pulmonary edema. Treatment for high-output congestive heart failure focuses on the primary pathology, which is skin inflammation. However, aggressive treatment of the inflammation with glucocorticoids may result in rapid resorption of extravascular fluid into the intravascular space and occurrence or aggravation of pulmonary edema. Erythrodermic patients with no clinical heart failure are also at risk for developing pulmonary edema if they receive glucocorticoids and/or intravascular fluids. Most hospitalists and dermatologists are not familiar with fluid administration and ways to manage cardiovascular function and blood pressure in patients with skin inflammation. OBJECTIVES AND METHODS: In this article, we discuss the pathophysiology of vascular and fluid changes in the context of diffuse skin inflammation and provide some basic guidelines that can be presented to hospitalists by dermatologists. LIMITATIONS: Most of the recommendations and guidelines in the article are based on basic science and on the personal experience of the authors and are not supported by controlled trials. Capsule summary Diffuse skin inflammation causes major changes in the cardiovascular system and in the perfusion of internal organs. We provide guidelines for management of fluid status and cardiovascular function in patients with diffuse skin inflammation. Dermatologists can provide hospitalists or primary care providers with these guidelines to help them with creating better treatment plans. PMID- 30252554 TI - Prescribers' compliance is part of benefit-risk assessment of medicines and it can lead to failure of risk minimization measures and withdrawals of medicines. PMID- 30252555 TI - The Relationship between Hopelessness and Clinical Characteristics of Hospitalized Patients with Recent Suicide Attempt. AB - This study aimed to assess hopelessness in 170 hospitalized individuals with recent suicide attempt and examine its association with patients' characteristics, with a view to improving awareness in health professionals and especially nurses, who are among the first to take care of these patients. Participants completed Beck Hopelessness Scale and Beck Depression Inventory. More than half (51.18%) experienced moderate-to-severe hopelessness. A multiple linear regression analysis showed that age, attempted suicide method, past suicide attempt, and psychiatric diagnosis contributed statistically significantly to hopelessness prediction. Hopelessness assessment could efficiently help health professionals to minimize both inpatient suicide and suicidal acts after discharge. PMID- 30252556 TI - Diurnal and circadian variations in indole contents in the goose pineal gland. AB - The diurnal and circadian profiles of pineal indoles, except melatonin, are poorly characterized in birds. Moreover, there are no data on the effect of sudden changes in the light-dark cycle on these profiles. Therefore, we investigated the diurnal (Experiment I) and circadian variation (Experiment II) of nine pineal indoles (tryptophan, 5-hydroxytryptophan, serotonin, N acetylserotonin, melatonin, 5-hydroxyindole acetic acid, 5-methoxytryptophol, 5 methoxyindole acetic acid, 5-methoxytryptamine) in geese, as well as the changes in the profiles of these substances in geese subjected to a reversed light-dark cycle (Experiment III). For the first 12 weeks of life, all geese were kept under a diurnal cycle of 12 h of light and 12 h of darkness (12L:12D). In Experiment I (n = 48), they were kept under these conditions for another 14 days before being sacrificed at 2-h intervals for sampling of the pineal glands. In Experiment II, the geese (n = 48) were divided into three groups (12L:12D, 24L:0D, 0L:24D) for 10 days before sampling at 6-h intervals. In Experiment III, 24 geese were exposed to a reversed light-dark cycle before sampling at 14:00 and 02:00 on the first, second and third days after light-dark cycle reversal. To determine the content of the indoles in the goose pineals, HPLC with fluorescence detection was used. We found that, with the exception of tryptophan, all the investigated indoles showed statistically significant diurnal variation. When geese were kept in constant darkness, most of the indoles continued to show this variation, but when geese were kept in constant light, the indoles did not show significant variation. When the light-dark cycle was reversed (12L:12D to 12D:12L), the profiles of NAS, melatonin, 5-MTAM and 5-MTOL reflected the new cycle within 2 days. The content of serotonin in geese in 12L:12D was higher than that observed in other birds under these conditions, which suggests that this compound may play a special role in the pineal physiology of this species. In conclusion, our results show that the daily variations in the metabolism of melatonin-synthesis related indoles in the goose pineal gland are generated endogenously and controlled by environmental light conditions, as in other birds. However, comparison of the results obtained with the goose to those obtained with other species (chicken, duck) unambiguously shows that the profiles of pineal indoles differ markedly between species, in both the quantitative proportions of the compounds and the characteristics of the diurnal changes. These findings provide strong arguments for the need for comparative studies. PMID- 30252557 TI - Dynamic platelet function is markedly different in patients with cancer compared to healthy donors. AB - Despite a fivefold increased risk of thromboembolism in patients with cancer, the mechanism of arterial thromboembolism is poorly understood. To address this, we investigated platelet function in cancer patients and healthy controls using an assay that mimics the arterial vasculature. Blood samples from cancer patients (n = 36) and healthy controls (n = 22) were perfused through custom-made parallel plate flow chambers coated with von Willebrand factor (VWF) under arterial shear (1,500 s-1). Multiparameter measurements of platelet interactions with the immobilized VWF surface were recorded by digital-image microscopy and analyzed using custom-designed platelet-tracking software. Six measured parameters that characterize in detail the surface motion and surface binding of several hundred platelets per blood sample differed significantly in those with cancer from the healthy donors. In particular, it was found that patients with cancer had decreased numbers of platelets interacting, translocating and adhering to VWF. There were also reductions in the speed and distances that platelets traveled on VWF in comparison to healthy controls. Platelet function differed between those with early-stage cancer compared to those with later stage cancer. Patients with advanced cancer had an increased number of platelets stably adhering to VWF and greater platelet surface coverage after a given time of interaction. To the best of our knowledge, our results demonstrate for the first time that dynamic platelet function is markedly different in patients with cancer compared to healthy donors. PMID- 30252559 TI - The post-intensive care syndrome in children. AB - Improvements in devices and techniques used to provide life support for patients at intensive care units have reduced patient mortality. Increases in the number of survivors from a critical illness have brought long-term complications experienced during the post-intensive care period into question. The term post intensive care syndrome (PICS) is defined as a new and deteriorating disorder in the cognitive, mental, and physical health status experienced by the survivor after intensive care unit discharge that might continue for months or even years. Opioid and sedation exposure, the severity of illnesses and injuries, dense life support interventions, length of stay in the intensive care unit, and social isolation constitute risk factors for PICS in children. These factors cause the child to experience deterioration in physical, cognitive, and psychological health domains. Such deteriorations occur on various levels and have negative effects on quality of life. The purpose of this article is to raise awareness and help pediatric nurses to develop an understanding of the condition. Increasing awareness by pediatric nurses about the magnitude and effects of complications after discharge from the intensive care unit will be the first step to protect survivors from new problems, to provide assistance for ongoing problems, and to develop follow-up strategies. PICS-related morbidities affect the majority of children discharged from PICUs. We need to understand the scope of those morbidities and develop efficient nursing interventions accordingly. It is time to expand our goal for critical and noncritical care from life-saving into improvement of functional health status and quality of life. PMID- 30252558 TI - Clinical Manifestations and Characteristics of In Vivo Confocal Microscopy in Varicella Zoster Virus-Related Corneal Endotheliitis. AB - OBJECTIVE: To explore the clinical characteristics and in vivo confocal microscopic (IVCM) findings of varicella zoster virus (VZV)-related corneal endotheliitis. METHODS: Retrospectively reviewed 20 eyes with corneal edema which were diagnosed by real-time polymerase chain reaction. RESULTS: one had VZV infection. Three had epithelial lesions. Six had mydriasis. Four had loss of iris pigment. Keratic precipitates (KPs) were mixed. Subbasal nerves had disappeared in 12 eyes. Langerhans cells were observed in seven eyes. The deviations in endothelial cell layers consisted of guttate (n = 1), enlarged intercellular gaps (n = 11), infiltration of inflammatory cells (n = 8), loss of defined cell boundaries (n = 1) and anomalous nucleus (n = 9). The shape of KPs in IVCM included type I (n = 6), type III (n = 3) and type IV (n = 4). CONCLUSION: VZV related corneal endotheliitis is remarkably difficult to detect clinically. Most cases have no typical skin lesions. The typical clinical feature is that of segmental iris atrophy and mixed KPs. PMID- 30252560 TI - Supportive Peer Relationships and Mental Health in Adolescence: An Integrative Review. AB - In the United States, nearly one in five adolescents has a diagnosable mental health disorder. Beginning in the teenage years, adolescents become less reliant on their parents for support and begin to turn to their peer group for support; therefore, it is important to understand the role of peers during this developmental time, especially in relation to mental health. The purpose of this project is to review the literature regarding positive peer support and mental health in adolescence. CINAHL, PubMed, and PsycINFO were used to conduct the review. The inclusive years of the search were 2007-2017. A total of 15 studies were included for review. The results were consistent over time and settings, demonstrating the positive role of peer support in adolescences with mental health care needs. Following a synthesis of the literature, gaps in research and implications for practice and further research, are discussed. PMID- 30252561 TI - Eyes on communication: trialling eye-gaze control technology in young children with dyskinetic cerebral palsy. AB - PURPOSE: This study aims to identify eye-gaze control technology outcomes, parent perception of the technology and support received, and gauge the feasibility of available measures. METHODS: Five children with dyskinetic cerebral palsy, mean age 4 years, 4 months (1 year, 0 months); n = 4 males; trialled two eye-gaze control technology systems, each for six weeks. Parents completed pre- and post questionnaires. RESULTS: Parents found the 6-week home-based trial period to be the right length. Written guidelines and instructions about set-up, calibration, and play and learning activities were perceived as important. Children demonstrated improvements in goal achievement and performance. Parents found questionnaires on quality of life, participation, behaviours involved in mastering a skill and communication outcomes challenging to complete resulting in substantial missing data. CONCLUSION: Eye-gaze control technology warrants further investigation for young children with dyskinetic cerebral palsy in a large international study. PMID- 30252562 TI - Assays for phenotypic and functional characterization of cryopreserved platelets. AB - Platelet concentrates for transfusion have a limited shelf-life, and cryopreservation offers a means of extending platelet shelf-life for at least 2 years. Cryopreservation, however, has some disadvantages, as platelets can be damaged during the freezing and thawing process. Consequently the phenotype of cryopreserved platelets is very different to that of freshly collected, liquid stored platelets. To obtain a reliable overview of cryopreserved platelet quality and function, specific testing methodologies should be considered. Whilst light transmission aggregometry (LTA) is the gold standard for measuring in vitro platelet reactivity in liquid stored platelets, it is not suited for cryopreserved platelets, as they retain little response to typical platelet agonists, even at high doses. Instead, phenotypic characterization by flow cytometry in combination with global assays of coagulation provides a clearer delineation of the phenotype and function of cryopreserved platelets. With increasing international uptake of platelet cryopreservation, it is important to recognize the need for appropriate measures of platelet quality and function. PMID- 30252563 TI - Ultrastructural identification of a proximal tubulopathy without crystals in a relapsed multiple myeloma patient. AB - A multiple myeloma patient, who had been treated with a hematopoietic stem cell transplant, underwent a renal biopsy for investigation of a possible relapse of disease as indicated by increased serum creatinine and positive urinary Bence Jones protein containing increased kappa light chain. Paraprotein-related renal disease was not evident by light microscopy or immunofluorescence microscopy however electron microscopy demonstrated a proximal tubulopathy with intracytoplasmic non-crystalline inclusions. The ultrastructural findings suggested possible end-organ involvement by the disease and follow-up studies subsequently revealed a relapsed multiple myeloma in the patient. The case exemplifies the usefulness of electron microscopy in detecting paraproteins that, in some instances, may be difficult to demonstrate by other techniques. PMID- 30252564 TI - The relationship between histone posttranslational modification and DNA damage signaling and repair. AB - PURPOSE: The cellular response to DNA damage occurs in the context of an organized chromatin environment in order to maintain genome integrity. Immediately after DNA damage, an array of histone modifications are induced to relieve the physical constraints of the chromatin environment, mark the site as damaged, and function as a platform for the assembly of mediator and effector proteins of DNA damage response signaling pathway. Changes in chromatin structure in the vicinity of the DNA double-strand break (DSB) facilitates the efficient initiation of the DNA damage signaling cascade. Failure of induction of DNA damage responsive histone modifications may lead to genome instability and cancer. Here we will discuss our current understanding of the DNA damage responsive histone modifications and their role in DNA repair as well as their implications for genome stability. We further discuss recent studies which highlight not only how histone modification has involved in the signaling and remodeling at the DSB but also how it influences the DNA repair pathway choice. CONCLUSIONS: Histone modifications pattern alter during the induction of DNA DSBs induction as well as during the repair and recovery phase of DNA damage response. It will be interesting to understand more precisely, how DSBs within chromatin are repaired by HR and NHEJ. The emergence of proteomic and genomic technologies in combination with advanced microscopy and imaging methods will help in better understanding the role of chromatin environment in the regulation of genome stability. PMID- 30252565 TI - Review: Chlorpromazine Versus Penfluridol for Schizophrenia. PMID- 30252566 TI - Comparison of Surgical Outcomes Between Bilateral Medial Rectus Recession and Unilateral Recess-Resect for Infantile Esotropia. AB - PURPOSE: To compare surgical outcomes between bilateral medial rectus recession (BMR) and unilateral medial rectus recession-lateral rectus resection (RR) for infantile esotropia. METHODS: In this retrospective study, BMR was performed on 57 patients (BMR group) and RR on 23 (RR group) for treatment of infantile esotropia with the postoperative follow-up period of 6 months or more. The main outcome measures were angle of esodeviation, rate of surgical success, rate of reoperation, rate of postoperative development of DVD, and postoperative sensory status. Surgical success was defined as esotropia or exotropia of 10 PD or less. RESULTS: The mean preoperative esodeviation at near was 44.1 prism diopters (PD) in BMR, and 40.2 PD in RR (p = 0.161). There was no statistically significant difference in angles of deviation between BMR and RR from postoperative day 1 to final follow-up, respectively (p > 0.05). Whereas until postoperative month 6 the surgical success rate did not significantly differ, from postoperative year 1 to final follow-up it was significantly higher in BMR than in RR (p < 0.05). The final success rates were 80.70% and 56.52% for BMR and RR, respectively (p = 0.047). The reoperation rate, correspondingly, was significantly lower for BMR (17.54%) than for RR (60.78%) (p = 0.000). CONCLUSION: There was no significant difference in the mean postoperative angle of deviation between BMR and RR for infantile esotropia. However, the final success rate was higher (p = 0.047) and the reoperation rate was lower for BMR than for RR (p = 0.000). PMID- 30252567 TI - Mutations of genes including DNMT3A detected by next-generation sequencing in thyroid cancer. AB - More than 90% of thyroid cancer belongs to the papillary and follicular thyroid carcinomas based on pathological subtypes. Papillary and follicular thyroid carcinoma are generally associated with a good prognosis. In contrast, other pathological subtypes such as poorly-differentiated and anaplastic thyroid carcinoma (PDTC and ATC) have a poor clinical outcome with a short life expectancy. To identify the genetic variations and biomarkers that may potentially distinguish the aggressive form of thyroid cancer, we performed a retrospective analysis of the formalin-fixed paraffin-embedded tumor samples from 50 patients who mainly displayed aggressive thyroid cancer using next-generation sequencing of 416 solid tumor-related genes. We adopted extensive bioinformatic analysis to vigorously remove germline single-nucleotide polymorphism and systematic sequencing errors, and report here that mutation in DNMT3A gene was significantly enriched in patients with PDTC or ATC. PMID- 30252568 TI - A 4-month-old boy with gastrointestinal stromal tumor of mesocolon. AB - Gastrointestinal stromal tumors (GISTs) are very uncommon in pediatric patients, and they are distinct clinical-pathological and molecular deviations from their adult counterparts. Most pediatric GISTs lack the c-kit or platelet-derived growth factor receptor alpha (PDGFRA) genes mutations. To date, there is no published standard guidelines available for the best treatment of pediatric GISTs, especially for infant GIST. Therefore, we report a case of 4-month-old infant with GIST of mesocolon without KIT/PDGFRA mutation. We also review the clinical, biological, and genetic features of pediatric GISTs and re-think several questions that could affect clinical practice. PMID- 30252569 TI - miRNA-based therapeutic potential of stem cell-derived extracellular vesicles: a safe cell-free treatment to ameliorate radiation-induced brain injury. AB - PURPOSE: This review compiles what is known about extracellular vesicles (EVs), their bioactive cargo, and how they might be used to treat radiation-induced brain injury. Radiotherapy (RT) is effective in cancer treatment, but can cause substantial damage to normal central nervous system tissue. Stem cell therapy has been shown to be effective in treating cognitive dysfunction arising from RT, but there remain safety concerns when grafting foreign stem cells into the brain (i.e. immunogenicity, teratoma). These limitations prompted the search for cell free alternatives, and pointed to EVs that have been shown to have similar ameliorating effects in other tissues and injury models. CONCLUSIONS: EVs are nano-scale and lipid-bound vesicles that readily pass the blood-brain barrier. Arguably the most important bioactive cargo within EVs are RNAs, in particular microRNAs (miRNA). A single miRNA can modulate entire gene networks and signalling within the recipient cell. Determining functionally relevant miRNA could lead to therapeutic treatments where synthetically-derived EVs are used as delivery vectors for miRNA. Stem cell-derived EVs can be effective in treating brain injury including radiation-induced cognitive deficits. Of particular interest are systemic modes of administration which obviate the need for invasive procedures. PMID- 30252570 TI - Mitochondrial quality control mediated by PINK1 and PRKN: links to iron metabolism and tumor immunity. AB - Mitochondrial quality control is an essential process required to maintain cellular homeostasis and functions. Mutations of PINK1 and PRKN/PARK2 contribute to the risk of Parkinson disease. Our recent findings indicate that depletion of Pink1 and Prkn promotes pancreatic tumorigenesis in KRAS-driven engineered mouse models. Mechanistically, PINK1- and PRKN-mediated autophagic degradation of mitochondrial iron importers (e.g., SLC25A37 and SLC25A28) suppresses pancreatic tumor growth by attenuating mitochondrial iron accumulation, inflammasome activation, HMGB1 release, and subsequent immune checkpoint expression. Consequently, pharmacological or genetic inhibition of mitochondrial iron dependent signals prolongs animal survival and reverses pancreatic tumor phenotype in vivo. Thus, PINK1- and PRKN-mediated immunometabolism provides new insights into the tumor microenvironment and could be a suitable target for new pancreatic cancer treatments. PMID- 30252571 TI - Effects of different doses of ticagrelor on platelet aggregation and endothelial function in diabetic patients with stable coronary artery disease. AB - We performed this study to observe the effects of different doses of ticagrelor and standard-dose clopidogrel on platelet reactivity and endothelial function in diabetic patients with stable coronary artery disease (CAD). Sixty type 2 diabetic patients were assigned to one-quarter standard-dose ticagrelor, half standard-dose ticagrelor, standard-dose ticagrelor and standard-dose clopidogrel groups. Light transmission aggregometry (LTA) and VerifyNow assay were used to measure platelet function. Endothelial function was assessed by measurement of flow-mediated vasodilation (FMD) and plasma von Willebrand factor (VWF) levels were detected. Enzyme-linked immunosorbent assay (ELISA) examined the Interleukin 8(IL-8) and IL-10. The results suggested that the one-quarter dose (34.0%+/- 14.7%), half-dose (26.9%+/- 11.6%) and standard-dose (17.3%+/- 10.3%) ticagrelor showed lower platelet aggregation rate than clopidogrel (52.8%+/- 18.3%; P <0.0001). PRU values in three ticagrelor groups were lower than that in clopidogrel group (102 (76-184);75 (33-88);38 (11-52) versus 194 (138-271) and;P <0.0001). FMD levels were higher in ticagrelor groups compared with baseline levels while lower in clopidogrel group after treatment. However, no significant differences were found in the percentage increase in the FMD between ticagrelor groups and clopidogrel group. The levels of VWF after treatment were lower than the baseline levels, but there was no statistically significant difference between ticagrelor group and clopidogrel group after treatment. The concentration of IL-8 and IL-10 were decreased in patients with half and standard-dose ticagrelor group. In conclusion, one-quarter standard-dose ticagrelor produced similar inhibitory effects on platelet aggregation as standard-dose clopidogrel in diabetic patients with stable CAD. The half standard-dose ticagrelor had a similar inhibitory effect on platelet inhibition as standard-dose ticagrelor, which was stronger than that of clopidogrel. Moreover, the half-dose ticagrelor had equal protection of endothelial function and inhibition of inflammatory factor as standard-dose ticagrelor. PMID- 30252573 TI - Have We Really MET a New Target? PMID- 30252572 TI - Optimizing Cervical Cancer Screening and Triage in Low-Resource Settings. PMID- 30252574 TI - The platelet shape change: biophysical basis and physiological consequences. AB - The well-known platelet shape change is the universal hallmark of activation. This review uncovers the biophysics underlying this rapid and dramatic transformation. We aim to give a broad vision of the interplay between different cytoskeletal subsystems, which is based on physical considerations and recent advances in mathematics and computational biology. These novel findings lead to the understanding that the ring of microtubules counterbalances cortical tension in the resting platelet, making it a "mechanically charged" system. Platelet activation breaks the balance via several mechanisms, triggering rapid ring buckling and cell rounding. Based on the review of known data concerning the relations between platelet shape and function, we hypothesize that disk-to-sphere transformation facilitates platelet adhesion under flow. Conclusions of the paper may be useful for the development of novel, cytoskeletal-based strategies of antiplatelet therapy. PMID- 30252575 TI - The Perspectives of Volunteer Counselors of Korean Immigrant Women Experiencing Intimate Partner Violence. AB - This study investigates what needs to be considered in our current health services to appropriately respond to abused Korean immigrant women. Using a community-based participatory approach, this qualitative interpretive description analyzed counseling documents and semi-structured interviews. Data analyses suggested that intimate partner violence (IPV) screening for ethnic minority women in health care settings can be improved by informing patients about the role of health care providers in addressing IPV, establishing rapport before IPV screening, assuring confidentiality is maintained, respecting Korean immigrant women's unique perspectives and response toward IPV, providing translation services, and collaborating with ethnic minority women's community organizations. PMID- 30252576 TI - Circ0043898 acts as a tumor inhibitor and performs regulatory effect on the inhibition of esophageal carcinoma. AB - OBJECTIVE: The study aimed to investigate candidate circular RNAs (circRNAs) in regulating the pathogenic process of esophageal carcinoma. METHODS: Specimens were collected from the patients with esophageal carcinoma. Total RNA was purified and treated with RNase R followed by RNA-seq in the purpose of screening the circRNAs in significant differentially expression. The expression level of the screened circRNAs were further validated using RT-PCR. The circular structure of the circRNA was validated with divergent and convergent primers. Overexpression vector was prepared in the purpose of raising the expression level of circ0043898 in the ECA-109 and Kyse-520 cells. The cell colony assay and MTS assay were conducted to determine the capacity of cell proliferation. Chamber assays were applied to determine the capacity of cell migration and invasion while flowcytometry was applied to determine the cell cycle and cell apoptosis. In vivo animal assay was conducted by injecting the cells to the chest of the mice. RNA-seq was performed followed by GO and KEGG study to further verify the regulation mechanism of circ0043898. RESULTS: circ0043898 was validated that down regulated expressed in the specimens from the patients with esophageal carcinoma. The cell assays proved that overexpression of circ0043898 can obviously inhibit the cell proliferation, cell migration and invasion and induce cell apoptosis and death in the cancerous cells. The in vivo animal study also suggested that the circ0043898 performed inhibitory functions on oncogenesis. The RNA-seq presented the potential regulation mechanism of circ0043898. Histone H3 and BMI1 were presented significantly differential expression in both ECA-109 and Kyse-520 cells, indicating they might be the targets of circ0043898. CONCLUSION: circ0043898 is presented as tumor inhibitor and could be a candidate biomarker in the therapeutic target and diagnosis of esophageal carcinoma. PMID- 30252577 TI - Knee extensor and flexor strength before and after anterior cruciate ligament reconstruction in a large sample of patients: influence of graft type. AB - OBJECTIVE: Hamstring and patellar tendon autografts are the most frequently-used graft types for anterior cruciate ligament (ACL) reconstruction, with no consensus on their respective effects on thigh muscle strength. The objective of this study was to re-examine isokinetic knee extensor and flexor strength before and after ACL reconstruction with patellar and hamstring tendon grafts using a single-center and a relatively large database, where surgical, rehabilitation and testing procedures were strictly standardized for all patients. METHODS: A total of 464 patients with a unilateral ACL rupture underwent arthroscopic ACL reconstruction with either patellar or hamstring tendon grafts. Isokinetic concentric strength was evaluated prior to surgery and at 5- and 9-month postoperative follow-ups in different patient subgroups (n = 140, 464 and 215, respectively). RESULTS: Knee extensor strength was lower in patients operated with the patellar tendon graft at the 5-month (p < 0.05) but not at the 9-month follow-up. Knee flexor strength was lower in patients operated with the hamstring tendon graft at both postoperative time points (p < 0.05). The prevalence of quadriceps weakness was high (66-91%) in both patient groups at both follow-ups. CONCLUSION: Overall, postoperative recovery of thigh muscle function seems to be better with the patellar than with the hamstring tendon graft due to the fact that both, knee extensor and flexor strength, were more impaired after ACL reconstruction with the hamstring tendon autograft. PMID- 30252578 TI - Benzodiazepines in anxiety disorders: Reassessment of usefulness and safety. AB - IMPORTANCE: Benzodiazepines (BZs) are still widely prescribed for the treatment of anxiety disorders despite many publications in the literature which favour antidepressants (ADs) instead. What is the evidence? OBSERVATIONS: Treatment guidelines favour ADs over BZs for treatment of anxiety disorders without any head-to-head comparison of both drug groups with placebo. BZs are claimed to cause less efficacy and more safety issues than ADs, yet ADs also cause disturbing adverse events and, similar to BZs, discontinuation symptoms. Until evidence-based data become available, a look at two 6-month generalized anxiety disorder trials conducted by the same research group, one with a BZ and the other with an AD, might provide some guidance for the clinician. Most improvement with a BZ was obtained by 4 weeks, suggesting that BZ treatment longer than 4 weeks should only be offered to patients maximally improved at 4 weeks. In contrast, ADs may have to be prescribed for 3-6 months to obtain maximal benefits. CONCLUSION: Results of a controlled trial as proposed will go a long way in providing clinicians missing information to guide them in the appropriate use of both BZs and ADs in anxiety disorders. PMID- 30252579 TI - Learning from the research on amebiasis and gut microbiome: Is stimulation by gut flora essential for effective neutrophil mediated protection from external pathogens? AB - Amebiasis, caused by intestinal infection with Entamoeba histolytica, is one of the leading causes of parasite infection-related mortality and morbidity globally. Although its pathogenesis, including determinant factors of infection outcome, remains unclear, recent clinical data indicate that the gut microbiome plays a role in determining the severity of amebiasis. Recently, we investigated the effects of the gut microbiome on neutrophil mediated protection from E. histolytica infection using a mouse model. We identified that surface expression of CXCR2 on neutrophils was diminished in mice with dysbiosis, which resulted in decreased neutrophil recruitment to the infection site, allowing more aggressive intestinal tissue damage by E. histolytica. Our results indicated that oxidase activity during E. histolytica infection was also diminished after dysbiosis, consistent with the results from prior research. Thus, the gut microbiome plays an important role in regulating neutrophil phenotype when fighting against external pathogens. PMID- 30252580 TI - Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction. AB - The MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but their role in platelet function and haemostasis is ambiguous as previous reports have been contradictory. It is therefore unclear if MEK inhibitors might be causing platelet dysfunction and contributing to increased hemorrhage. In the present study we performed pharmacological characterisation of cobimetinib and trametinib in vitro to investigate potential for MEK inhibitors to cause platelet dysfunction. We report that whilst both cobimetinib and trametinib are potent inhibitors of platelet MEK activity, treatment with trametinib did not alter platelet function. Treatment with cobimetinib results in inhibition of platelet aggregation, integrin activation, alpha-granule secretion and adhesion but only at suprapharmacological concentrations. We identified that the inhibitory effects of high concentrations of cobimetinib are associated with off-target inhibition on Akt and PKC. Neither inhibitor caused any alteration in thrombus formation on collagen under flow conditions in vitro. Our findings demonstrate that platelets are able to function normally when MEK activity is fully inhibited, indicating MEK activity is dispensable for normal platelet function. We conclude that the MEK inhibitors cobimetinib and trametinib do not induce platelet dysfunction and are therefore unlikely to contribute to increased incidence of bleeding reported during MEK inhibitor therapy. PMID- 30252581 TI - Chylous Ascites in an Infant with Thanatophoric Dysplasia Type I with FGFR3 Mutation Surviving Five Months. AB - BACKGROUND: Thanatophoric dysplasia (TD) results from sporadic de novo mutations in the FGFR3 gene. Upon confirming intrauterine diagnosis of this perinatal disease, pregnancy termination is recommended. There is limited information on the natural history of longer-term survivors with type 1 TD. CASE REPORT: A full term neonate was confirmed via postnatal genetic testing to have type 1 TD. At 28 days, chylous ascites developed. Medium-chain triglyceride use improved the ascites. Cerebral ventriculomegaly worsened throughout life. Death due to respiratory failure occurred at age 5 months. CONCLUSION: The chylous ascites in this child with type 1 TD and survival past the neonatal stage suggests that type 1 TD may be accompanied by abnormalities of the lymphatic channels. Moreover, ventriculomegaly can be progressive. PMID- 30252582 TI - Metagenomic analysis of intestinal mucosa revealed a specific eukaryotic gut virome signature in early-diagnosed inflammatory bowel disease. AB - Intestinal dysbiosis is one of the causes underlying the pathogenesis of inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD). Besides bacteria, microbiota comprises both prokaryotic and eukaryotic viruses, that together compose the gut virome. Few works have defined the viral composition of stools, while the virome populating intestinal mucosae from early-diagnosed IBD patients has never been studied. Here we show that, by in-depth metagenomic analysis of RNA-Seq data obtained from gut mucosae of young treatment-naive patients, early-diagnosed for CD and UC, and from healthy subjects (Ctrl), UC patients display significantly higher levels of eukaryotic Hepadnaviridae transcripts by comparison with both Ctrl and CD patients, whereas CD patients show increased abundance of Hepeviridae versus Ctrl. Moreover, we found that UC gut mucosa is characterized by lower levels of Polydnaviridae and Tymoviridae, whereas the mucosa of patients with CD showed a reduced abundance of Virgaviridae. Our findings support the idea that certain eukaryotic viruses might trigger intestinal inflammation and contribute to IBD pathogenesis and pave the way not only for the discovery of novel diagnostic biomarkers but also for the development of anti-viral drugs for the treatment of IBD. PMID- 30252583 TI - Antibody persistence after a single dose of quadrivalent HPV vaccine and the effect of a dose of nonavalent vaccine given 3-8 years later - an exploratory study. AB - The objective of this study was to assess the persistence of antibodies after a single dose of quadrivalent HPV vaccine (4vHPV) and the effect of a dose of nonavalent HPV vaccine (9vHPV) given 3-8 years later. Such data might be of interest in the decision-making process regarding the 2-dose course completion in non-compliant vaccinees in jurisdictions which switched from 4vHPV to 9vHPV. Girls who previously received a single dose of 4vHPV were eligible to participate. Blood specimens were collected just before and one month post-9vHPV administration. The specimens were tested by ELISA for the presence of antibodies to 9 HPV types included in the 9vHPV. Thirty-one girls aged 13-18 years (mean 15.5 years) participated in the study. Pre-9vHPV administration, all participants were seropositive to 4 HPV types included in 4vHPV and 58%-87% were seropositive to the five other HPV types included in the 9vHPV. GMTs were 6.1 AU/ml, 7.7 AU/ml, 20.1 IU/ml and 6.3 IU/ml to HPV6, HPV11, HPV16 and HPV18, respectively. The GMTs for the other five HPV types varied from 1.0 to 2.9 AU/ml. One month post-9vHPV administration all 31 participants were seropositive to all 9 HPV types with a 36.1 to 89.1-fold increase of GMTs. High seropositivity rates observed several years after a single dose of 4vHPV and 100% seropositivity after a dose of 9vHPV suggest that this schedule might be used in non-compliant vaccinees or when switching immunization programs from 4vHPV to 9vHPV. PMID- 30252584 TI - Double amplifications of CDK4 and MDM2 in a gastric inflammatory myofibroblastic tumor mimicking cancer with local invasion of the spleen and diaphragm. AB - Inflammatory myofibroblastic tumor (IMT) is currently recognized as an intermediate mesenchymal neoplasm. It can arise anywhere in the body, but it is particularly common in the lungs. Gastric IMT is very rare in adults. In this study, we report a case of a 68-year-old woman with IMT in the gastric cardia, with invasion into the spleen and diaphragm. Because of its location and aggressive clinical features, it was first mistaken for gastric cancer. However, pathology and immunohistochemistry were used to finally confirm the diagnosis of IMT after total resection of the tumor and spleen and partial resection of the diaphragm. In order to provide better understanding of this rare tumor, targeted next-generation sequencing (NGS) and IHC were performed to assess genetic and protein abnormalities of the tumor. Both IHC and NGS were found to be negative for ALK or other gene fusions. However, double amplification of CDK4 and MDM2 were found by NGS, and IHC also found CDK4 and MDM2 to be positive. To the best of our knowledge, this is the first gastric IMT report to show double invasion of the spleen and the diaphragm, and double amplification of CDK4 and MDM2 in IMT are also reported for the first time. This genomic aberration with protein overexpression is the most likely tumorigenic driver of this rare and aggressive tumor. PMID- 30252585 TI - A new aspect of in vitro antimicrobial leukocyte- and platelet-rich plasma activity based on flow cytometry assessment. AB - The current literature suggests that the antibacterial effect of leukocyte- and platelet-rich plasma (L-PRP) is directly related to platelet and leukocyte concentrations. The aim of this study was twofold: first, to evaluate the antimicrobial effect of L-PRP against selected bacterial strains in vitro, and second, to correlate this effect with leukocyte and platelet content in the final concentration. Blood was collected from 20 healthy males, and L-PRP, acellular plasma (AP), and autologous thrombin were consecutively prepared. Flow cytometry analysis of the blood, L-PRP, and AP was performed. The L-PRP gel, liquid L-PRP, and thrombin samples were tested in vitro for their antibacterial properties against seven selected bacterial strains using the Kirby-Bauer disk-diffusion method. There was notable antimicrobial activity against selected bacterial strains. No statistically significant correlations between antimicrobial activities and the platelet concentration in L-PRP were observed. Statistically significant positive correlations between selected leukocyte subtypes and antimicrobial activity were noted. A negative correlation was found between elevated monocyte count and antimicrobial activity of L-PRP against one bacterial strain studied. L-PRP possesses antimicrobial activity and can be potentially useful in the fight against certain postoperative infections. The bactericidal effect of L-PRP is caused by leukocytes, and there exists a relationship among selected leukocyte subtypes and L-PRP antimicrobial activity. PMID- 30252586 TI - Rebuilding a better home for transplanted islets. AB - Diabetes can be treated with beta cell replacement therapy, where a patient is transplanted with cadaveric human islets to restore glycemic control. Despite this being an effective treatment, the process of isolating islets from the pancreas requires collagenase digestion which disrupts the islet extracellular matrix (ECM) and activates anoikis-mediated apoptosis. To improve islet survival in culture and after transplantation, the islet microenvironment may be enhanced with the addition of ECM components which are lost during isolation. Furthermore, novel beta cell replacement strategies, such as stem cell-derived beta cell (SCbetaC) treatments or alternative transplant sites and devices, could benefit from a better understanding of how beta cells interact with ECM. In this mini review, we discuss the current understanding of the pancreas and islet ECM composition and review decellularization approaches to generate a native pancreatic ECM scaffold for use in both islet and SCbetaC culture and transplantation. PMID- 30252588 TI - Akkermansia muciniphila strain ATCC BAA-835 does not promote short-term intestinal inflammation in gnotobiotic interleukin-10-deficient mice. AB - Akkermansia muciniphila is a common member of the intestinal microbiota of healthy human individuals. Its abundance is negatively associated with inflammatory bowel disease and metabolic disorders and the oral administration of A. muciniphila improves the symptoms of metabolic disease in mice. Therefore, A. muciniphila is a promising candidate for the treatment of type-2 diabetes and obesity. However, some studies using animal models of intestinal inflammation reported that A. muciniphila may exacerbate gut inflammation. Because of these contradictory reports the present study aimed to clarify the role of A. muciniphila in the development of intestinal inflammation and the conditions promoting it. For this purpose, the short-term colitogenic potential of A. muciniphila strain ATCC BAA-835 was investigated in colitis-prone, gnotobiotic IL 10-deficient (Il10-/-) mice. Il10-/- mice mono-associated with A. muciniphila showed no signs of intestinal inflammation based on body-weight change, histopathological scoring and inflammatory markers. Additional association of the mice with the colitogenic Escherichia coli strain NC101 led to cecal but not colonic inflammation. However, the severity of the inflammation did not exceed that observed in mice mono-associated with E. coli NC101. Il10-/- mice colonized with a simplified human intestinal microbiota showed increased histopathology, but no increase in inflammatory markers. Furthermore, co-colonization with A. muciniphila did not modify histopathology. The turnover of intestinal mucus was similar in all groups despite the mucus-degrading property of A. muciniphila. Overall, the data do not support a short-term pro-inflammatory effect of A. muciniphila strain ATCC BAA-835 in the Il10-/- mouse model for inflammatory bowel disease. PMID- 30252587 TI - Loss of miR-16 contributes to tumor progression by activation of tousled-like kinase 1 in oral squamous cell carcinoma. AB - A different expression signature of miRNA in oral squamous cell carcinoma (OSCC) has been validated. MicroRNA-16 (miR-16) as one of the distinctly dysregulated miRNAs in OSCC, its functional role in progression of OSCC remains not fully clear. Herein, miR-16 expression was significantly lower in OSCC tissues compared to that in adjacent normal tissues (n = 131). A lower level of miR-16 was found to be associated with poor prognosis on a cohort of 131 patients with OSCC, and on an extensive public data (457) from TCGA database. Additionally, expression of TLK1 was significantly higher in OSCC tissues compared to that in adjacent normal tissues, which is negatively correlated with miR-16 expression in OSCC. Bioinformatics analyses exhibited that TLK1 is a potential downstream effector of miR-16 by directly targeting the 3'-untranslated regions (3'-UTR) of mRNA. Forced expression of miR-16 in OSCC cell lines inhibits cell proliferation in vitro, and tumor growth in vivo by inhibition of TLK1. Mechanistically, downregulation of TLK1 by miR-16 enhances higher level of DNA damage leading to a significant increase of G2/M arrest in SCC9 cells. And, overexpression of TLK1 substantially reduces DNA damage and G2/M arrest by activation of TLK1-dependent cell cycle checkpoint response. To conclude, miR-16 is downregulated in OSCC and serves as tumor suppressor in OSCC progression by targeting TLK1, which has potential to be the novel therapeutic targets and diagnostic biomarkers for OSCC. PMID- 30252589 TI - The responsiveness and validity of the Early Clinical Assessment of Balance in toddlers with cerebral palsy: Brief report. AB - PURPOSE: The Early Clinical Assessment of Balance (ECAB) is a measure of postural stability for children with cerebral palsy (CP). The purpose of this research was to investigate the relationship between the ECAB and Gross Motor Function Measure 66 (GMFM-66) and to determine the responsiveness of the ECAB in children with CP under three years of age. METHODS: Twenty seven children (mean age of 25 months) participated. Data were collected before and after 3 and 6 months of physical therapy. Responsiveness was calculated using standardized response means (SRM). RESULTS: Significant relationships were observed between the ECAB, GMFM-66 score (r = 0.87), and GMFM subscales (r = 0.63-0.86). A moderate effect size (SRM = 0.62) and a large effect size (SRM = 0.92) for the ECAB were found over the 3- and 6-month intervention periods, respectively. CONCLUSION: These results support the validity and responsiveness of the ECAB in young children with CP. PMID- 30252590 TI - Motility and biofilm formation of the emerging gastrointestinal pathogen Campylobacter concisus differs under microaerophilic and anaerobic environments. AB - Campylobacter concisus has been isolated from patients with gastroenteritis and inflammatory bowel disease (IBD), as well as healthy subjects. While strain differences may plausibly explain virulence differentials, an alternative hypothesis posits that the pathogenic potential of this species may depend on altered ecosystem conditions in the inflamed gut. One potential difference is oxygen availability, which is frequently increased under conditions of inflammation and is known to regulate bacterial virulence. Hence, we hypothesized that oxygen influences C. concisus physiology. We therefore characterized the effect of microaerophilic or anaerobic environments on C. concisus motility and biofilm formation, two important determinants of host colonization and dissemination. C. concisus isolates (n = 46) sourced from saliva, gut mucosal biopsies and feces of patients with IBD (n = 23), gastroenteritis (n = 8) and healthy subjects (n = 13), were used for this study. Capacity to form biofilms was determined using crystal violet assay, while assessment of dispersion through soft agar permitted motility to be assessed. No association existed between GI disease and either motility or biofilm forming capacity. Oral isolates exhibited significantly greater capacity for biofilm formation compared to fecal isolates (p<0.03), and showed a strong negative correlation between motility and biofilm formation (r = -0.7; p = 0.01). Motility significantly increased when strains were cultured under microaerophilic compared to anaerobic conditions (p<0.001). Increased biofilm formation under microaerophillic conditions was also observed for a subset of isolates. Hence, differences in oxygen availability appear to influence key physiological aspects of the opportunistic gastrointestinal pathogen C. concisus. PMID- 30252591 TI - Update on Campylobacter vaccine development. AB - BACKGROUND: Acute diarrheal disease caused by viral, bacterial and parasitic infections are a major global health problem with substantial mortality and morbidity in children under five years of age in lower and middle income countries. However, a number of these infections also impact large segments of populations in upper income countries, as well as individuals who travel overseas for work, business or pleasure. Campylobacter has been and continues to be a leading cause of disease burden globally across all income countries. AIMS: The aim of this review is to describe recent understanding in burden of disease, consider the current landscape of Campylobacter vaccine development, and address the challenges that need to be overcome. SOURCES: Relevant data from the literature as well as clinical trials described in European and US registries were used to conduct this review. CONTENT: Despite advances in population health, food security, improved sanitation, water quality and the reduction of poverty, Campylobacter infections continue to plague global populations. The emerging recognition of chronic health consequences attributed to this pathogen is changing the potential valuation of preventive interventions. Advancing development of new vaccines is a present opportunity and holds promise. PMID- 30252592 TI - Comprehensive manipulation of glycosylation profiles across development scales. AB - The extent and pattern of glycosylation on therapeutic antibodies can influence their circulatory half-life, engagement of effector functions, and immunogenicity, with direct consequences to efficacy and patient safety. Hence, controlling glycosylation patterns is central to any drug development program, yet poses a formidable challenge to the bio-manufacturing industry. Process changes, which can affect glycosylation patterns, range from manufacturing at different scales or sites, to switching production process mode, all the way to using alternative host cell lines. In the emerging space of biosimilars development, often times all of these aspects apply. Gaining a deep understanding of the direction and extent to which glycosylation quality attributes can be modulated is key for efficient fine-tuning of glycan profiles in a stage appropriate manner, but establishment of such platform knowledge is time consuming and resource intensive. Here we report an inexpensive and highly adaptable screening system for comprehensive modulation of glycans on antibodies expressed in CHO cells. We characterize 10 media additives in univariable studies and in combination, using a design of experiments approach to map the design space for tuning glycosylation profile attributes. We introduce a robust workflow that does not require automation, yet enables rapid process optimization. We demonstrate scalability across deep wells, shake flasks, AMBR-15 cell culture system, and 2 L single-use bioreactors. Further, we show that it is broadly applicable to different molecules and host cell lineages. This universal approach permits fine-tuned modulation of glycan product quality, reduces development costs, and enables agile implementation of process changes throughout the product lifecycle. PMID- 30252593 TI - Serum level of interleukin 36 in patients with multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis is a chronic autoimmune demyelinating disorder of central nervous system with unknown origin. In MS disease, T cells are pointed to myelin antigens and it leads to myelin loss and axonal degeneration. Cytokines are important regulators of immune system and has critical roles in MS pathogenesis. Interleukin 36, a member of interleukin 1 family, has been shown having important roles in some autoimmune disorders due to its proinflammatory actions and its role in host immunity. METHODS AND MATERIALS: In the current study, 49 relapsing remitting multiple sclerosis patients and 41 healthy individuals were recruited. IL36 measurement was performed using enzyme-linked immunosorbent assay technique. RESULTS: Mean age of RRMS patient and control group were 31.84 +/- 6.89 and 34.27 +/- 8.83 years, respectively. Serum level of IL36 were 61.91 +/- 16.29 in MS patients and 42.26 +/- 17.54 in healthy group (P < 0.001). CONCLUSION: in this study for the first time, significantly higher serum level of IL36 was determined in RRMS patients comparing healthy individuals. This data may suggest important roles of this cytokine in MS pathogenesis. PMID- 30252594 TI - Direct screening of plasma circulating microRNAs. AB - Circulating microRNAs (miRNAs) are considered as reliable candidates for biomarker discovery. RNA-Sequencing has become the most suitable technique to accurately quantify the miRNAome. However, RNA-Sequencing relies on several technical passages before reaching the final-end. HTG EdgeSeq technology, thanks to the abrogation of RNA extraction step, allows productivity enhancement by reducing the number of hands-on steps, the time for sample preparation and, therefore, the costs. We found a strong correlation between qPCR and dPCR with HTG (Pearson's coefficient of 0.93 and 0.94, respectively). In conclusion, we showed that HTG EdgeSeq, performed on human plasma specimens without RNA extraction, is reliable, allows the simultaneous screening of more than 2,000 miRNAs, and thus, it could be applied to biomarker discovery in large cohorts. PMID- 30252595 TI - The Francisella novicida Cas12a is sensitive to the structure downstream of the terminal repeat in CRISPR arrays. AB - The Class 2 Type V-A CRISPR effector protein Cas12a/Cpf1 has gained widespread attention in part because of the ease in achieving multiplexed genome editing, gene regulation, and DNA detection. Multiplexing derives from the ability of Cas12a alone to generate multiple guide RNAs from a transcribed CRISPR array encoding alternating conserved repeats and targeting spacers. While array design has focused on how to optimize guide-RNA sequences, little attention has been paid to sequences outside of the CRISPR array. Here, we show that a structured hairpin located immediately downstream of the 3' repeat interferes with utilization of the adjacent encoded guide RNA by Francisella novicida (Fn)Cas12a. We first observed that a synthetic Rho-independent terminator immediately downstream of an array impaired DNA cleavage based on plasmid clearance in E. coli and DNA cleavage in a cell-free transcription-translation (TXTL) system. TXTL-based cleavage assays further revealed that inhibition was associated with incomplete processing of the transcribed CRISPR array and could be attributed to the stable hairpin formed by the terminator. We also found that the inhibitory effect partially extended to upstream spacers in a multi-spacer array. Finally, we found that removing the terminal repeat from the array increased the inhibitory effect, while replacing this repeat with an unprocessable terminal repeat from a native FnCas12a array restored cleavage activity directed by the adjacent encoded guide RNA. Our study thus revealed that sequences surrounding a CRISPR array can interfere with the function of a CRISPR nuclease, with implications for the design and evolution of CRISPR arrays. PMID- 30252597 TI - FOXD4 induces tumor progression in colorectal cancer by regulation of the SNAI3/CDH1 axis. AB - Colorectal cancer (CRC) is ranked third as the most common malignancy, and it develops into metastasis at a high rate. Importantly, distant metastasis is considered to be a key factor for colorectal therapy. In the present study, we identified FOXD4, a transcription factor belonging to the forkhead/winged helix box (FOX) family, as a novel biomarker for diagnosis and treatment of patients with CRC. We revealed that FOXD4 was up-regulated in CRC tissues and increased the metastatic ability of CRC cells. Additionally, FOXD4 affected the metastasis of CRC by inducing the epithelial-mesenchymal transition (EMT) process. Furthermore, FOXD4 could directly bind the SNAI3 promoter during EMT in CRC and then facilitate CRC metastasis. In summary, the present research strongly suggests that FOXD4 is a valuable marker for CRC, and that targeting FOXD4 may be a novel strategy for enhancing the treatment outcomes of CRC therapy. PMID- 30252598 TI - Xenotransplantation. AB - The transplantation of living cells, tissues or organs from one species to another is termed xenotransplantation. The history of xenotransplantation is as old as allogeneic transplantation itself. Early attempts were made at a time when the immunologic basis of organ rejection were poorly understood. The advent of potent immunosuppressive medications along with the parallel advances in the field of genetic engineering has provided a fresh perspective on the role of xenotransplantation as a means to alleviate the disparity between the number of candidates on the waitlist and the available organs. As the science behind xenotransplantation advances, the transplantation community must take it upon themselves to educate the community at large regarding both the benefits and potential risks of this promising field. PMID- 30252596 TI - Moonlighting proteins: putting the spotlight on enzymes. AB - AROGENATE DEHAYDRATASE2 (ADT2) is a member of the Arabidopsis thaliana ADT family. All members of this family act as arogenate dehydratases in phenylalanine biosynthesis, decarboxylating/dehydrating arogenate to phenylalanine. ADT2 is detected in stromules, and as a ring around the equatorial plane of dividing chloroplasts, indicating it has a second, non-enzymatic function in chloroplast division. Here, we provide further evidence for this alternative role of ADT2. First, we demonstrate that ADT2 and FtsZ co-localize around the equatorial plane at the same time. Second, FtsZ expression in an adt2 mutant was analyzed, as well as ADT2 expression in three Arabidopsis chloroplast division mutants, ACCUMULATION AND REPLICATION OF CHLOROPLASTS3 (ARC3), ARC5 and ARC6. In arc3 and arc6 mutants, ADT2 is misexpressed and resembles the expression of FtsZ in the same mutants. However, in the arc5 mutant, ADT2 ring positioning is observed at constriction points indicating proper relative timing. ADT2 expression in the arc mutants shows that the role of ADT2 in chloroplast division occurs prior to ARC5, but is dependent on ARC3 and ARC6. Abbreviations used: ADT: arogenate dehydratase, ARC: accumulation and replication of chloroplasts, CFP: cyan fluorescent protein, dpi: days post infiltration, FtsZ: filamentous temperature sensitive Z, PD: plastid division, Phe: phenylalanine, YFP: yellow fluorescent protein. PMID- 30252599 TI - Cell culture models of oral mucosal barriers: A review with a focus on applications, culture conditions and barrier properties. AB - Understanding the function of oral mucosal epithelial barriers is essential for a plethora of research fields such as tumor biology, inflammation and infection diseases, microbiomics, pharmacology, drug delivery, dental and biomarker research. The barrier properties are comprised by a physical, a transport and a metabolic barrier, and all these barrier components play pivotal roles in the communication between saliva and blood. The sum of all epithelia of the oral cavity and salivary glands is defined as the blood-saliva barrier. The functionality of the barrier is regulated by its microenvironment and often altered during diseases. A huge array of cell culture models have been developed to mimic specific parts of the blood-saliva barrier, but no ultimate standard in vitro models have been established. This review provides a comprehensive overview about developed in vitro models of oral mucosal barriers, their applications, various cultivation protocols and corresponding barrier properties. PMID- 30252600 TI - RNA-Seq employing a novel rRNA depletion strategy reveals a rich repertoire of snoRNAs in Euglena gracilis including box C/D and Psi-guide RNAs targeting the modification of rRNA extremities. AB - Previous mRNA transcriptome studies of Euglena gracilis have shown that this organism possesses a large and diverse complement of protein coding genes; however, the study of non-coding RNA classes has been limited. The natural extensive fragmentation of the E. gracilis large subunit ribosomal RNA presents additional barriers to the identification of non-coding RNAs as size-selected small RNA libraries will be dominated by rRNA sequences. In this study we have developed a strategy to significantly reduce rRNA amplification prior to RNA-Seq analysis thereby producing a ncRNA library allowing for the identification of many new E. gracilis small RNAs. Library analysis reveals 113 unique new small nucleolar (sno) RNAs and a large collection of snoRNA isoforms, as well as the first significant collection of nuclear tRNAs in this organism. A 3' end AGAUGN consensus motif and conserved structural features can now be defined for E. gracilis pseudouridine guide RNAs. snoRNAs of both classes were identified that target modification of the 3' extremities of rRNAs utilizing predicted base pairing interactions with internally transcribed spacers (ITS), providing insight into the timing of steps in rRNA maturation. Cumulatively, this represents the most comprehensive analysis of small ncRNAs in Euglena gracilis to date. PMID- 30252601 TI - Monovalent TNF receptor 1-selective antibody with improved affinity and neutralizing activity. AB - Selective inhibition of tumor necrosis factor (TNF) signaling through the proinflammatory axis of TNF-receptor 1 (TNFR1) while leaving pro-survival and regeneration-promoting signals via TNFR2 unaffected is a promising strategy to circumvent limitations of complete inhibition of TNF action by the approved anti TNF drugs. A previously developed humanized antagonistic TNFR1-specific antibody, ATROSAB, showed potent inhibition of TNFR1-mediated cellular responses. Because the parental mouse antibody H398 possesses even stronger inhibitory potential, we scrutinized the specific binding parameters of the two molecules and revealed a faster dissociation of ATROSAB compared to H398. Applying affinity maturation and re-engineering of humanized variable domains, we generated a monovalent Fab derivative (13.7) of ATROSAB that exhibited increased binding to TNFR1 and superior inhibition of TNF-mediated TNFR1 activation, while lacking any agonistic activity even in the presence of cross-linking antibodies. In order to improve its pharmacokinetic properties, several Fab13.7-derived molecules were generated, including a PEGylated Fab, a mouse serum albumin fusion protein, a half-IgG with a dimerization-deficient Fc, and a newly designed Fv-Fc format, employing the knobs-into-holes technology. Among these derivatives, the Fv13.7-Fc displayed the best combination of improved pharmacokinetic properties and antagonistic activity, thus representing a promising candidate for further clinical development. PMID- 30252603 TI - Immunogenicity and safety of the Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine co-administered with human rotavirus, hepatitis A and 13-valent pneumococcal conjugate vaccines: results from a phase III, randomized, multicenter study in infants. AB - This phase III, open-label, randomized study (NCT01978093) evaluated the immunogenicity and safety of co-administered Haemophilus influenzae type b Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (Hib MenCY-TT) with human rotavirus vaccine (HRV), hepatitis A vaccine (HAV) and 13 valent pneumococcal conjugate vaccine (PCV13). We randomized 600 infants (1:1) to receive 4 doses of Hib-MenCY-TT at 2, 4, 6 and 12-15 months of age or 3 doses of Hib vaccine conjugated to N. meningitidis outer membrane protein complex (Hib OMP) at 2, 4 and 12-15 months of age. All infants received HRV at 2 and 4 months of age, PCV13 at 2, 4, 6 and 12-15 months of age, HAV at 12-15 and 18-21 months of age, and diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus vaccine at 2, 4 and 6 months of age. We measured immune responses against HRV, HAV and Hib with enzyme-linked immunosorbent assays, and against MenC/MenY with serum bactericidal assays using human complement. The 4-dose vaccination series with Hib-MenCY-TT induced a robust immune response against Hib, which was non-inferior to that induced by a 3-dose vaccination series with Hib-OMP, and against MenC and MenY. Hib-MenCY-TT did not interfere with immune responses to concomitantly administered HRV, PCV13 and HAV. We did not identify any safety concern. In conclusion, we showed that 4-dose vaccination series with Hib-MenCY-TT during infancy did not interfere with immune responses of co administered HRV, PCV13 and HAV, induced robust immune responses against Hib, MenC and MenY, and had a clinically acceptable safety profile. PMID- 30252604 TI - Otolaryngologists and their role in vaccination for prevention of HPV associated head & neck cancer. AB - As Otolaryngologists we have witnessed a rise in a new disease with human papilloma virus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC). As of 2018, HPV associated OPSCC has surpassed the incidence of HPV associated cervical cancer within the United States. Non-HPV related head and neck cancer is largely a preventable disease through avoidance of various environmental factors, and we have seen a significant decline in cancer rates through anti-tobacco campaigns and other public health efforts. Given the success of HPV vaccination campaigns and reduction in HPV associated cervical and other anogenital cancers, some would argue HPV OPSCC is largely a preventable disease through vaccination as well. The question remains is how do we as otolaryngologist, non-primary care providers yet surgeons for this disease, help to promote public health efforts to reduce HPV related OPSCC. Within this article, we discuss preliminary data that supports HPV vaccination with HPV related OPSCC and the ongoing needs by our profession to help support public efforts in reducing the burden of this HPV related cancer. PMID- 30252602 TI - Prediction of methionine oxidation risk in monoclonal antibodies using a machine learning method. AB - Monoclonal antibodies (mAbs) have become a major class of protein therapeutics that target a spectrum of diseases ranging from cancers to infectious diseases. Similar to any protein molecule, mAbs are susceptible to chemical modifications during the manufacturing process, long-term storage, and in vivo circulation that can impair their potency. One such modification is the oxidation of methionine residues. Chemical modifications that occur in the complementarity-determining regions (CDRs) of mAbs can lead to the abrogation of antigen binding and reduce the drug's potency and efficacy. Thus, it is highly desirable to identify and eliminate any chemically unstable residues in the CDRs during the therapeutic antibody discovery process. To provide increased throughput over experimental methods, we extracted features from the mAbs' sequences, structures, and dynamics, used random forests to identify important features and develop a quantitative and highly predictive in silico methionine oxidation model. PMID- 30252605 TI - Identification of novel G-protein coupled receptor 40 (GPR40) agonists by hybrid in silico screening techniques and molecular dynamics simulations thereof. AB - Diabetes is a major health problem worldwide predisposing to increased mortality and morbidity. The current antidiabetic therapies have serious side effects and thus, emphasis on further need to develop effective medication therapy. Free fatty acid1 receptor (FFA1R) or GPR40 represents an interesting target for developing novel antidiabetic drug. In the current study, the FFA1R agonistic activity of drug like molecules were screened by employing pharmacophore modeling, docking and molecular dynamics simulation. Hierarchcial screening of virtual library of drug like compounds was performed. This combined computational approach of pharmacophore mapping and structure based approach was use to identify common hits and the ADME prediction supported the analysis of their pharmacokinetic potential. Molecular dynamics (MD) simulation studies of the GPR40 complex with the most promising hit found in this study further validated are approach. The key residues Arg183, Arg258, Tyr91 and Tyr240 of the binding pocket were acknowledged as essential and were found to be associated in the key interactions with the most potential hit. These studies will hopefully provide scope for efficiently designing and screening new compounds as active drug candidates with more selectivity for hGPR40. To the best of our knowledge, this is the first example of the successful application of both ligand and structure based virtual screening techniques to discover novel GPR40 agonists. PMID- 30252607 TI - Plant defensin peptides have antifungal and antibacterial activity against human and plant pathogens. AB - Plant defensins are small, cysteine-rich antimicrobial peptides. These peptides have previously been shown to primarily inhibit the growth of fungal plant pathogens. Plant defensins have a gamma-core motif, defined as GXCX3-9C, which is required for their antifungal activity. To evaluate plant defensins as a potential control for a problematic agricultural disease, alfalfa crown rot, short chemically synthesized peptides containing gamma-core motif sequences were screened for activity against numerous crown rot pathogens. These peptides showed both antifungal and, surprisingly, antibacterial activity. Core motif peptides from Medicago truncatula defensins (MtDef4 and MtDef5) displayed high activity against both plant and human bacterial pathogens in vitro. Full-length defensins had higher antimicrobial activity compared to the peptides containing their predictive gamma-core motifs. These results show the future promise for controlling a wide array of economically important fungal and bacterial plant pathogens through the transgenic expression of a plant defensin. They also suggest that plant defensins may be an untapped reservoir for development of therapeutic compounds for combating human and animal pathogens. PMID- 30252606 TI - Dietary destabilisation of the balance between the microbiota and the colonic mucus barrier. AB - It has long been acknowledged that dietary fibres are important to maintain a healthy gut. Over the past decade, several studies have shown that loss of complex polysaccharides from the Western diet has resulted in alterations to our colonic microbiota. The concurrent increase in the incidence of inflammatory bowel disease in the Western world has driven us to explore the potential mechanistic link between diet, the microbiota and the host defence systems that normally prevent inflammation. Using mice fed a low fibre Western-style diet and robust live tissue analytical methods we have now provided evidence that this diet impairs the colonic inner mucus layer that normally separates bacteria from host cells. Western societies urgently need to develop their understanding of the molecular mechanisms of the diet-microbiota-mucus axis and its implications for inflammatory diseases. PMID- 30252608 TI - Prevalence of Comorbidities among Older Head and Neck Cancer Survivors in the United States. AB - Objective The aim of this study was to evaluate the prevalence of comorbidities among patients with head and neck squamous cell carcinoma (HNSCC) at the time of their cancer diagnosis and during their survivorship trajectory. The second aim was to evaluate the differences in comorbidities developed according to treatment type received. Study Design Retrospective cross-sectional. Setting SEER (Surveillance, Epidemiology, and End Results)-Medicare linked database. Subjects and Methods Individuals with a first-incident primary diagnosis of HNSCC from 2004 to 2011 per the SEER-Medicare database were included in analysis. The presence or absence of 30 comorbid conditions of interest was identified during distinct periods and analyzed according to treatment with surgery alone, primary (chemo)radiation, or surgery with (chemo)radiation. Results The study population consisted of 10,524 individuals diagnosed with HNSCC, with a mean age of 74.8 years. At diagnosis, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and diabetes were the most prevalent comorbidities, and they increased over time. The probability of developing treatment-related comorbidities such as pneumonia, dysphagia, weight loss, malnutrition, and dental issues rose significantly in the short and long term following treatment ( P < .05). By 5 years from cancer diagnosis, patients were most likely to have newly diagnosed hypertension, dysphagia, anemia, and weight loss. Primary surgery alone was associated with a lower risk of diagnosis with these treatment-related comorbidities, as compared with treatments involving radiation therapy and/or chemotherapy in the primary or adjuvant settings ( P < .05). Conclusions There is a large burden of comorbidities among patients following HNSCC treatment, which warrant clinical attention during surveillance. PMID- 30252609 TI - Maternal vaccine knowledge in low- and middle-income countries-and why it matters. AB - Maternal vaccines have the potential to reduce the global burden of neonatal morbidity and mortality by accessing the infant immune system before a vaccine administered in childhood would be effective. Maternal vaccines for influenza, tetanus, and pertussis have been shown to reduce neonatal disease and mortality, and other candidate vaccines for group B streptococcus and respiratory syncytial virus are being developed to continue this trend. However, safe and effective maternal vaccines will only successfully reduce neonatal illness if mothers decide to receive them. Maternal knowledge, attitudes, and beliefs around vaccines are key determinants to vaccine acceptance or vaccine hesitancy, and yet this issue is often understudied in low and middle-income country settings. A deeper understanding of these factors and how they influence maternal decision making will allow public health practitioners and global and national policymakers to design more effective interventions. Addressing barriers to immunization at the policy and programmatic levels such as mothers' knowledge, attitudes, and beliefs of maternal vaccines is essential to increasing vaccination rates at a global scale and reducing global vaccine-preventable neonatal deaths. PMID- 30252610 TI - Evidence-Based Medicine in Otolaryngology Part 9: Valuing Health Outcomes. AB - Decisions about resource allocation are increasingly based on value trade-offs between health outcomes and cost. This process relies on comprehensive and standardized definitions of health status that accurately measure the physical, mental, and social well-being of patients across disease states. These metrics, assessed through clinical trials, observational studies, and health surveys, can facilitate the integration of patient preferences into clinical practice. This ninth installment in the Evidence-Based Medicine in Otolaryngology Series is a practical overview of health outcome valuation, as well as the integration of both quality and quantity of life into standardized metrics for health research, program planning, and resource allocation. Tools for measuring preference-based health states, measures of effectiveness, and the application of metrics in economic evaluations are discussed. PMID- 30252611 TI - Implications on older women of age- and sex-related differences in activation patterns of shoulder muscles: A cross-sectional study. AB - We conducted a cross-sectional study to assess differences in neuromotor attributes of shoulder muscles between age groups in both sexes and to better understand functional disorders in older women. Twenty young (20-42 years old), 20 middle-aged (43-67), and 20 older (> 68) adults participated in a comparative surface-electromyography study of five muscles. We identified age-related differences in women, especially in scapula stabilizer muscles. There was a tendency for both sexes of delayed onset times with increasing age, excepting the upper trapezius muscle in females. The results highlight the importance of understanding musculoskeletal aging in women to adequately guide physical therapeutic approaches. PMID- 30252612 TI - Impact of early-life events on the susceptibility to Clostridium difficile colonisation and infection in the offspring of the pig. AB - Clostridium difficile has been documented as a major cause of uncontrolled outbreaks of enteritis in neonatal pigs and antibiotic-associated infections in clinical settings. It belongs to the natural cohort of early colonisers of the gastrointestinal tract of pigs and can be detected in faeces up to two weeks post partum. In older pigs, it often remains under the detection limit. Most neonatal pigs show no clinical signs of disease although C. difficile and its toxins can be detected at high levels in faeces. Increased mortality rates associated with C. difficile on pig farms are, so far, considered "spontaneous" and the predisposing factors are mostly not defined. The infection caused by C. difficile is multifactorial and it is likely that the repertoire of maternal factors, host physiology, the individually developing gut microbiota, co-infections and environmental stress define the conditions for disease development. In this addendum to our recently published work on CDI in neonatal piglets, we discuss the "early-life events" that influence C. difficile spread and infection in neonatal piglets. PMID- 30252613 TI - Inflammatory Potential of Diet: Association With Chemerin, Omentin, Lipopolysaccharide-Binding Protein, and Insulin Resistance in the Apparently Healthy Obese. AB - OBJECTIVE: Low-grade inflammation is a characteristic of various conditions, including obesity. Diet is regarded as a strong modifier of inflammation. The potential links between inflammatory properties of diet and adipokines as well as insulin resistance (IR) warrant further investigation. Therefore, this study aimed to examine the associations of the dietary inflammatory index (DII) with serum chemerin, omentin, and lipopolysaccharide-binding protein (LBP) as well as IR among apparently healthy obese adults. DESIGN: In this cross-sectional study, 171 abdominally obese subjects were recruited in the northwest of Iran. Demographic data, dietary intake, anthropometric indices, and physical activity (PA) were assessed. DII scores were calculated based on dietary intake, using a validated 168-item food frequency questionnaire (FFQ). Basal blood samples were collected to determine the biochemical parameters. A linear regression test with adjusted beta estimates was applied for data analysis. RESULT: Compared to those with higher DII score, the group with lower DII score (anti-inflammatory diet) had higher protein (83.62 +/- 36.42 g vs. 71.61 +/- 25.94 g) and lower carbohydrate (325.00 +/- 125.76 g vs. 378.19 +/- 137.69 g) intake. Participants with higher DII score had lower consumption of polyunsaturated and monounsaturated fats as well as fiber and higher saturated fats (p < .001). Those with elevated DII score had higher levels of chemerin (p = .034) and LBP (p = .040), compared to those with lower DII. Omentin showed no significant differences between groups with different DII scores. Additionally, people with a more proinflammatory diet had higher FBS (p = .005); however, other markers of IR did not differ by DII scores. CONCLUSIONS: The results suggest that increased inflammatory potential of diet, as indicated by higher DII score, is associated with elevated levels of chemerin and LBP. While DII was positively associated with FBS, no significant correlation was found for insulin and other indices of IR. PMID- 30252614 TI - Grief in a biography of losses: Meaning-making in hard drug users' grief narratives on drug-related death. AB - The focus in grief theories has been increasingly shifting toward questions of meaning. In this study, we draw on the meaning-reconstruction model of grief for studying the unique case of hard drug users who have experienced a drug-related death. The social context of hard drug use, as well as the death and grief circumstances, is problematic and stigmatized. Grief narratives of 10 respondents were analyzed according to the principles of grounded theory. We identified four main themes: (1) the inhibition of emotion by drugs leading to fragmented grief reactions, (2) social exclusion and notions of disenfranchized grief, (3) the acceptance of death, and (4) meaningfulness in a "biography of losses." Connecting these results with the literature on meaning, we find that meaning making is a multidimensional and layered process, where some layers result in meanings made while others do not. Finally, this study emphasizes the importance of social and emotional aspects of grieving, as well as the ambiguity of the notion of successful meaning-making in relation to grief. PMID- 30252615 TI - Low-dose computed tomography lung cancer screening as a teachable moment for smoking cessation among African American smokers: A feasibility study. AB - Low-dose computed tomography (LDCT) screening may be a teachable moment for smoking cessation among African Americans. African Americans have been understudied within the context of LDCT and smoking cessation. The study objective was to evaluate the feasibility of recruiting African Americans to a future longitudinal trial and to obtain sample size estimates for that trial. Participants (N = 18) were African Americans eligible for LDCT screening who completed a questionnaire at three time points. Self-efficacy and intention to quit smoking were compared. The results of the current study show that it is feasible to recruit African Americans eligible for LDCT. PMID- 30252616 TI - On the other hand.... PMID- 30252617 TI - The beneficial root-colonizing fungus Mortierella hyalina promotes the aerial growth of Arabidopsis and activates calcium-dependent responses which restrict Alternaria brassicae-induced disease development in roots. AB - The endophytic fungus Mortierella hyalina colonizes the roots of Arabidopsis thaliana and stimulates growth and biomass production of the aerial parts, but not of roots. An exudate fraction from the fungus induces rapid and transient cytoplasmic Ca2+elevation in the roots. The Ca2+ response does not require the well-characterized (co-)receptors BAK1, CERK1 and FLS2 for pathogen-associated molecular patterns, and the Ca2+ channels GLR-2.4, -2.5 and -3.3 or the vacuolar TWO PORE CHANNEL1 which might be involved in cytoplasmic Ca2+ elevation. We isolated an ethyl-methane-sulfonate-induced Arabidopsis mutant which is impaired in this Ca2+ response. The roots of the mutant are impaired in M. hyalina mediated suppression of immune responses after Alternaria brassicae infection, i.e. jasmonate accumulation, generation of reactive oxygen species, as well as the activation of jasmonate-related defense genes. Furthermore, they are more colonized by M. hyalina than wild-type roots. We propose that the mutant gene product is involved in a Ca2+-dependent signaling pathway activated by M. hyalina to suppress immune responses in Arabidopsis roots. PMID- 30252618 TI - Legume Nodules: Massive Infection in the Absence of Defense Induction. AB - Plants of the legume family host massive intracellular bacterial populations in the tissues of specialized organs, the nodules. In these organs, the bacteria, named rhizobia, can fix atmospheric nitrogen and transfer it to the plant. This special metabolic skill provides to the legumes an advantage when they grow on nitrogen-scarce substrates. While packed with rhizobia, the nodule cells remain alive, metabolically active, and do not develop defense reactions. Here, we review our knowledge on the control of plant immunity during the rhizobia-legume symbiosis. We present the results of an evolutionary process that selected both divergence of microbial-associated molecular motifs and active suppressors of immunity on the rhizobial side and, on the legume side, active mechanisms that contribute to suppression of immunity. PMID- 30252619 TI - "Why did he choose to die?": A meaning-searching approach to parental suicide bereavement in youth. AB - This article analyzes from a narrative perspective how young people talk about their experience of parental suicide in different social contexts. The results show how these young grievers are preoccupied with the question of Why the parent committed suicide. Moreover, they tend primarily to interpret the suicide in line with stigmatizing discourses regarding Who is to blame, which has negative impacts on their identities. In contrast, a "meaning-searching approach" seeks to answer the question of What caused the suicide and to identify a combination of internal vulnerabilities and external stressors. Professional interventions are recommended to foster the latter health promoting coping strategy. PMID- 30252620 TI - The effectiveness of alternating rapid maxillary expansion and constriction combined with maxillary protraction in the treatment of patients with a class III malocclusion: a systematic review and meta-analysis. AB - OBJECTIVES: To establish the effectiveness of Alternate Rapid Maxillary Expansion and Constriction combined with Protraction Facial Mask (Alt-RAMEC/PFM) approach in treating Class III growing patients compared with PFM combined with conventional Rapid Maxillary Expansion (RME/PFM). Search sources: Unrestricted search in five electronic databases and manual searching were undertaken up to February 2018. DATA SELECTION: Randomised clinical trials (RCTs) evaluating the effectiveness of Alt-RAMEC/PFM were selected. DATA EXTRACTION: Screening of references, data extraction and assessment of bias risk were evaluated independently by two reviewers. RESULTS: Five RCTs comparing the Alt-RAMEC/PFM with RME/PFM met the inclusion criteria. Small but statistically significant mean differences favouring Alt-RAMEC/PFM protocol as measured by SNA angle (1.16 degrees ; 95% CI 0.65 to 1.66), SNB angle (0.67 degrees ; 95% CI 0.32 to 1.02) and ANB angle (0.66 degrees ; 95% CI 0.08 to 1.25) were noted. Alt-RAMEC/PFM exhibited a more favourable overjet correction when compared to RME/PFM, however, differences in other dental changes were insignificant. CONCLUSION: There is limited evidence with high risk of bias that Alt-RAMEC/PFM can result in a statistically significant increase in maxillary protraction compared with RME/PFM in Chinese subjects over the short-term. High-quality long-term RCTs with inclusion of patient-reported outcomes are required. PMID- 30252621 TI - Impacts of prescribed fires and benefits from their reduction for air quality, health and visibility in the Pacific Northwest of the United States. AB - Using a WRF-SMOKE-CMAQ modeling framework, we investigate the impacts of smoke from prescribed fires on model performance, regional and local air quality, health impacts, and visibility in protected natural environments using three different prescribed fire emission scenarios - 100% fire, no fire, and 30% fire. The 30% fire case reflects a 70% reduction in fire activities due to harvesting of logging residues for use as a feedstock for a potential aviation biofuel supply chain. Overall model performance improves for several performance metrics when fire emissions are included, especially for organic carbon, irrespective of the model goals and criteria used. This effect on model performance is more pronounced for the rural and remote IMPROVE sites for organic carbon and total PM2.5. A reduction in prescribed fire emissions (30% fire case) results in significant improvement in air quality in areas in western Oregon, northern Idaho and western Montana where most prescribed fires occur. Prescribed burning contributes to visibility impairment and a relatively large portion of protected class I areas will benefit from a reduced emission scenario. For the haziest 20% days, prescribed burning is an important source of visibility impairment and approximately 50% of IMPROVE sites in the model domain show a significant improvement in visibility for the reduced fire case. Using BenMAP, a health impact assessment tool, we show that several hundred additional deaths, several thousand upper and lower respiratory symptom cases, several hundred bronchitis cases, and more than 35,000 work day losses can be attributed to prescribed fires and these health impacts decrease by 25-30% when a 30% fire emission scenario is considered. Implications This study assesses the potential regional and local air quality, public health and visibility impacts from prescribed burning activities as well as benefits that can be achieved by a potential reduction in emissions for a scenario where biomass is harvested for conversion to biofuel. As prescribed burning activities become more frequent, they can be more detrimental for air quality and health. Forest residue based biofuel industry can be source of cleaner fuel with co-benefits of improved air quality, reduction in health impacts and improved visibility. PMID- 30252622 TI - Social Networking Sites (SNSs) in medical education: a student's perspective. PMID- 30252624 TI - Identification and Characterization of Alternaria Species Associated with Moldy Core of Apple in Chile. AB - Moldy core (MC) of apple is an important disease in Chile, with prevalence observed between 4 and 46% in Fuji, Oregon Spur Red Chief, and Scarlet apple in the 2014-15 and 2015-16 growing seasons. However, there is no information on the identity of the causal agents associated with MC in Chile. The analysis of 653 MC fruit revealed the presence of several genera of filamentous fungi. However, species of Alternaria (67.7%) were by far the most frequently fungi isolated. In total, 41 Alternaria isolates were characterized morphologically and molecularly using Alternaria major allergen Alt a1, calmodulin, and plasma membrane ATPase gene regions. Six small-spored Alternaria spp. were identified; namely, in order of importance, Alternaria tenuissima, A. arborescens, A. alternata, and A. dumosa in sect. Alternaria; A. frumenti in sect. Infectoriae; and A. kordkuyana in sect. Pseudoalternaria. MC symptoms were reproducible and consisted of a light gray to dark olive-green mycelium over the carpel and seed of immature and mature fruit, confirming that the isolates of these Alternaria spp. were pathogenic. These isolates caused brown necrotic lesions with concentric rings on wounded detached apple leaves. This study demonstrated that at least six Alternaria spp. are the cause of MC of apple in Chile. These Alternaria spp. were isolated alone, or with two or more species coexisting in the same fruit. This is the first report of A. tenuissima, A. arborescens, A. frumenti, A. dumosa, and A. kordkuyana associated with MC of apple in Chile and the first report of A. frumenti, A. kordkuyana, and A. dumosa causing MC of apple worldwide. PMID- 30252623 TI - The effects of aging, diabetes mellitus, and antiplatelet drugs on growth factors and anti-aging proteins in platelet-rich plasma. AB - As the aged population continues to markedly increase worldwide, the incidences of diabetes mellitus (DM) and cardiovascular disease (CVD) are increasing. In this study, we investigated the effects of aging, DM, and antiplatelet drugs on growth factors and anti-aging proteins in platelet-rich plasma (PRP). The study participants were classified into the following four groups: Group A, healthy individuals aged <=45 years; Group B, healthy individuals aged >45 years; Group C, DM patients aged >45 years; and Group D, CVD patients aged >45 years taking antiplatelet drugs. The concentrations of epidermal growth factor (EGF), fibroblast growth factor (FGF)-2, platelet-derived growth factor (PDGF)-AA, PDGF AB/BB, vascular endothelial growth factor (VEGF)-A, tissue inhibitor of metalloproteinase 2 (TIMP2), insulin-like growth factor 1 (IGF-1), growth differentiation factor (GDF)11, and clusterin in PRP samples were determined to analyze the effects of aging, DM, and antiplatelet drugs. Overall, the concentrations of IGF-1, TIMP2, and clusterin did not vary significantly between the four groups. The concentrations of PDGF-AB/BB (P = 0.010), VEGF-A (P = 0.000), and GDF11 (P = 0.026) were significantly different between Group A and Group B. Further, the concentrations of EGF (P = 0.000) and GDF11 (P = 0.000) were significantly different between Groups B and C. The concentrations of EGF (P = 0.001), VEGF-A (P = 0.000), and GDF11 (P = 0.002) significantly differed between Groups A and C. The concentrations of FGF-2 (P = 0.048), PDGF-AA (P = 0.03), and GDF11 (P = 0.001) were significantly different between Groups B and D. The concentrations of PDGF-AB/BB (P = 0.032), VEGF-A (P = 0.010), and GDF11 (P = 0.02) significantly differed between Groups A and D. We found that PRP contains high concentrations of the growth factors, TIMP2 and GDF11. Aging, DM, and antiplatelet drugs can decrease the concentration of some growth factors and GDF11, which weakens the regenerative capacity and anti-aging effects of PRP and reduces the quality of PRP. PMID- 30252625 TI - Comprehensive Surveys of Bean common mosaic virus and Bean common mosaic necrosis virus and Molecular Evidence for Occurrence of Other Phaseolus vulgaris Viruses in Tanzania. AB - Virus diseases are among the main biotic factors constraining common bean (Phaseolus vulgaris L.) production in Tanzania. Disease management requires information on types, distribution, incidence, and genetic variation of the causal viruses, which is currently limited. Thus, a countrywide comprehensive survey was conducted. Use of a next-generation sequencing technique enabled simultaneous detection of 15 viruses belonging to 11 genera. De novo assembly resulted in many contigs, including complete or nearly complete sequences of Bean common mosaic virus (BCMV), Bean common mosaic necrosis virus (BCMNV), and Southern bean mosaic virus (SBMV). Some viruses (for example, SBMV and Tomato leaf curl Uganda virus-related begomovirus) were detected for the first time in common bean in Tanzania. Visually assessed virus-like disease incidence ranged from 0 to 98% but reverse-transcription polymerase chain reaction-based incidence of BCMV and BCMNV (7,756 samples) was mostly less than 40%. The Sanger-based nucleotide sequences encoding coat proteins of BCMV and BCMNV isolates were 90.2 to 100% and 97.1 to 100% identical to each other, respectively. Phylogenetic analysis showed that BCMV isolates were more diverse than BCMNV isolates. The information generated in this study will contribute to the development of molecular diagnostic tools and strategies for management of virus diseases nationally and internationally. [Formula: see text] Copyright (c) 2018 The Author(s). This is an open access article distributed under the CC BY 4.0 International license . PMID- 30252626 TI - Effect of Wheat Cultivar on the Concentration of Fusarium Mycotoxins in Wheat Stems. AB - Effective control of Fusarium-mycotoxin accumulation in grain affected by Fusarium head blight (FHB) (caused by Fusarium graminearum) begins with selecting moderately resistant wheat cultivars; however, little is known about how this resistance affects mycotoxin levels in the stem. A study was conducted from 2011 to 2014 in a mist-irrigated FHB nursery in Urbana, IL to determine whether the FHB resistance class of a cultivar (very susceptible, susceptible, moderately susceptible, and moderately resistant) affects the concentration of Fusarium mycotoxins in the stem. FHB incidence, FHB severity, and Fusarium-damaged kernel ratings were collected and used to calculate FHB index; incidence, severity, and kernel damage (ISK) index; and deoxynivalenol (DON), incidence, severity, and kernel damage (DISK) index. Grain was assayed for levels of DON, and the bottom 25 cm of plant stems was collected from each plot and assayed for DON, 3-acetyl deoxynivalenol (3ADON), and 15-acetyl-deoxynivalenol (15ADON). Significant differences in DON concentration in the grain were detected among cultivars (P = 0.0001) and for the concentration of all DON (P = 0.003), 3ADON (P = 0.03), and 15ADON (P < 0.0001) in the stem. Significant differences among resistance classes were observed for FHB index value (P < 0.0001), ISK index (P = 0.006), and DISK index (P = 0.004). In all years of this study, the concentration of DON in the grain and the concentrations of all mycotoxins in the stem were consistently lower in the moderately resistant cultivars. All three indices were poor indicators of mycotoxin concentrations in the stem. Overall, the selection of a moderately resistant cultivar provides effective control of DON accumulation in the grain and mycotoxin accumulation in the stem. PMID- 30252627 TI - ToxA Is Present in the U.S. Bipolaris sorokiniana Population and Is a Significant Virulence Factor on Wheat Harboring Tsn1. AB - ToxA, a necrotrophic effector originally identified from the tan spot fungus Pyrenophora tritici-repentis in 1987, was subsequently identified from Parastagonospora nodorum in 2006. More recently, the ToxA gene was identified in the spot blotch fungus Bipolaris sorokiniana in Australia. Here we show that the ToxA gene is also present in the B. sorokiniana population in the winter wheat region of southcentral Texas. Leaves from 'Duster' wheat showing strong necrotic lesions were collected in Castroville, TX. Fifteen single-spore isolates were collected from separate lesions, and 13 of them harbored the BsToxA gene and secreted ToxA in culture based on sensitivity of BG261, the differential line containing the dominant ToxA sensitivity gene, Tsn1. Four isolates harboring BsToxA and one deficient in BsToxA were used to infiltrate two wheat lines harboring Tsn1 as well as their corresponding tsn1 mutant lines. Culture filtrates of the isolate lacking BsToxA did not induce necrosis on any of the lines. Culture filtrates of the four BsToxA-containing isolates induced necrosis on the wild type (Tsn1) lines but not on the corresponding tsn1 mutant lines. Sensitivity to these culture filtrates also mapped to the previously identified location for Tsn1 in the winter wheat mapping population Arina * Forno. Inoculation of one of these ToxA-producing isolates on the same population showed that the Tsn1 locus accounted for 24.4% of the disease variation. All 13 isolates harbored the same BsToxA nucleotide sequence, which was identical to one of the two haplotypes previously identified in Australia. Sensitivity to ToxA is prevalent in popular hard winter wheat cultivars in the central and southcentral winter wheat regions of the United States, showing the potential of a selective advantage for B. sorokiniana isolates that harbor the ToxA gene. PMID- 30252628 TI - Impact of Premorbid Malnutrition and Dysphagia on Ischemic Stroke Outcome in Elderly Patients: A Community-Based Study. AB - OBJECTIVE: The present study was performed to assess nutritional status and its relationship with clinical outcomes in elderly stroke patients. METHOD: In this cross-sectional study, 253 stroke patients were studied. Mini Nutritional Assessment (MNA) was used to assign patients to three groups: malnourished, at risk of malnutrition, and well nourished. Northwestern Dysphagia Patient Check Sheet was administered to all patients. Anthropometric measures, including body mass index (BMI), calf circumferences (CC), mid-arm circumferences (MAC), and triceps skinfold thickness were brought out. In addition, National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), and biochemical tests were performed. RESULTS: Of 253 patients, 34.4% were malnourished, 42.3% were at risk of malnutrition, and 23.3% were well nourished. The malnourished patients had significantly lower BMI, CC, and MAC (p < 0.05). The levels of albumin and high-sensitivity C-reactive protein were significantly different among the groups (p < 0.001). The admission and 3-month follow-up mRS scores, as well as dysphagia, were significantly higher in the malnourished patients and those at risk of malnutrition (p < 0.001). In addition, mRS scores at admission and 3 month follow-up scores, as well as the length of hospital stay (LOS), were significantly correlated with MNA score, dysphagia, BMI, CC, MAC, albumin, and high-sensitivity C-reactive protein (p < 0.05). Significant unadjusted associations were observed among MNA scores, BMI, CC, MAC, dysphagia scores, NIHSS scores, length of hospital stay (LOS), albumin, hs-C-reactive protein (hs CRP), and erythrocyte sedimentation rate (ESR) with a poor outcome. With a multivariate logistic regression analysis, NIHSS scores and MNA scores remained significantly associated with the poor outcome in patients with ischemic stroke. CONCLUSIONS: The findings of the present study underline the importance of nutritional status in elderly stroke patients. PMID- 30252629 TI - New Promise for Vaccines against Tuberculosis. PMID- 30252630 TI - Antibody-drug conjugate library prepared by scanning insertion of the aldehyde tag into IgG1 constant regions. AB - The advantages of site-specific over stochastic bioconjugation technologies include homogeneity of product, minimal perturbation of protein structure/function, and - increasingly - the ability to perform structure activity relationship studies at the conjugate level. When selecting the optimal location for site-specific payload placement, many researchers turn to in silico modeling of protein structure to identify regions predicted to offer solvent exposed conjugatable sites while conserving protein function. Here, using the aldehyde tag as our site-specific technology platform and human IgG1 antibody as our target protein, we demonstrate the power of taking an unbiased scanning approach instead. Scanning insertion of the human formylglycine generating enzyme (FGE) recognition sequence, LCTPSR, at each of the 436 positions in the light and heavy chain antibody constant regions followed by co-expression with FGE yielded a library of antibodies bearing an aldehyde functional group ready for conjugation. Each of the variants was expressed, purified, and conjugated to a cytotoxic payload using the Hydrazinyl Iso-Pictet-Spengler ligation to generate an antibody-drug conjugate (ADC), which was analyzed in terms of conjugatability (assessed by drug-to-antibody ratio, DAR) and percent aggregate. We searched for insertion sites that could generate manufacturable ADCs, defined as those variants yielding reasonable antibody titers, DARs of >= 1.3, and >= 95% monomeric species. Through this process, we discovered 58 tag insertion sites that met these metrics, including 14 sites in the light chain, a location that had proved refractory to the placement of manufacturable tag sites using in silico modeling/rational approaches. PMID- 30252631 TI - Correction. PMID- 30252632 TI - The changes in maximal oxygen uptake (VO2MAX) induced by physical exertion during an Antarctic expedition depend on the initial VO2MAX of the individuals: a case study of the Brazilian expedition. AB - Antarctic climate is challenging, since the cold, wind and sensory monotony are stressful stimuli to individuals. Moreover, camp activities and heavy clothes may contribute to increase physiological strain. Thus, we aimed to characterise the physiological demand of a 24-day period in the Antarctic field and then to evaluate the effect of this expedition on the aerobic fitness in individuals with heterogeneous initial aerobic fitness (as determined by estimating maximum oxygen consumption - VO2MAX). Before and after the 24-day period in Antarctica, 7 researchers and 2 mountaineers were subjected to incremental tests to estimate their VO2MAX. Field effort was characterised by measuring heart rate (HR). During the field trips, their HR remained 33.4% of the recording time between 50-60% HRMAX, 22.3% between 60-70% HRMAX, and only 1.4% between 80 and 90% HRMAX. The changes in estimated VO2MAX during the expedition depended on the pre-expedition aerobic fitness. The post-expedition VO2MAX increased by 5.9% and decreased by 14.3%in individuals with lower (researchers) and higher (mountaineers) initial VO2MAX, respectively. We concluded that physical effort in the Antarctic field is characterised as predominantly of low- to moderate-intensity. This effort represented an effective training load for individuals with lower initial VO2MAX, but not for those with higher VO2MAX. PMID- 30252633 TI - Association of Serum Vitamin D Concentration With Clinical Symptoms and Quality of Life in Patients With Irritable Bowel Syndrome. AB - OBJECTIVE: A high prevalence of vitamin D deficiency (VDD) in gastrointestinal (GI) disorders and the role of vitamin D in the function of the gut have been shown previously. Therefore, we aimed to evaluated the VDD and the possible association of the GI symptoms severity and quality of life (QoL) score with the serum levels of vitamin D in irritable bowel syndrome (IBS). METHODS: A total of 90 patients with IBS based on Rome III criteria enrolled in the study from the tertiary referral university hospital. In addition, 90 sex- and age-matched healthy controls (HCs) were recruited. To measure the serum levels of 25(OH)D3, blood samples were taken from all the participants. Severity of clinical symptoms, IBS quality of life (IBS-QoL), and IBS symptom severity score (IBSSS) were assessed. RESULTS: In 66.7% of IBS patients, serum 25(OH)D3 concentrations were <20 ng/mL. The mean serum 25(OH)D3 of IBS patients was statistically (p < 0.05) lower vs. HCs. When different subtypes were analyzed, the serum 25(OH)D3 concentrations in diarrhea-predominant IBS were statistically (p < 0.05) lower as compared to HCs. Furthermore, the lower serum concentrations of 25(OH)D3 were associated (p < 0.05) with higher severity of abdominal pain and distention, flatulence, overall GI symptoms, and IBSSS. However, a direct significant association was seen between IBS-QoL and serum 25(OH)D3. CONCLUSION: Results of this study showed a high prevalence of VDD in patients with IBS. In addition, VDD was associated with a higher severity of clinical symptoms and lower QoL in IBS. PMID- 30252640 TI - Paenibacillus paeoniae sp. nov., a novel endophytic bacterium isolated from leaf of Paeonia lactiflora Pall. AB - A Gram-stain-positive, aerobic, rod-shaped, endospore-forming bacterium, designated strain M4BSY-1T, was originally isolated from a surface-sterilized leaf of Paeonia lactiflora Pall. in Guizhou, China. The bacterium was characterized by a polyphasic approach to determine its taxonomic position. 16S rRNA gene sequence comparison revealed that strain M4BSY-1T belongs to the genus Paenibacillus and most closely to Paenibacilluspinioli NB5T (98.31 % similarity). Neither substrate nor aerial mycelia formed, and no diffusible pigments were observed on the media tested. Strain M4BSY-1T grew in the pH range 7.0-13.0 (optimum, 7.0-8.0), at temperatures between 10-37 degrees C (optimum, 30 degrees C) and at 0-5 % (w/v) NaCl (optimum, 1-2 %). The predominant menaquinone was MK-7. The major fatty acids were anteiso-C15 : 0, C16 : 0 and iso-C16 : 0. The polar lipids comprised diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, two unidentified unknown aminophospholipids and three unidentified phospholipids. The DNA G+C content was 48.8 mol%. According to the phylogenetic, phenotypic and chemotaxonomic evidence, strain M4BSY-1T was clearly distinguishable from other species with validly published names in the genus Paenibacillus and should therefore be classified as a novel species, and we suggest the name Paenibacillus paeoniae sp. nov. The type strain is M4BSY-1T (=KCTC 33997T=CGMCC 1.13667T). PMID- 30252641 TI - Sphingomonas oleivorans sp. nov., isolated from oil-contaminated soil. AB - Strain FW-11T was isolated from oil-contaminated soil from Panjin in Liaoning, China. It was a Gram-stain-negative, aerobic and rod-shaped bacterium. The strain was confirmed to be a member of the genus Sphingomonas based on phylogenetic inference and phenotypic characteristics. The best growth of strain FW-11T occurred at 30 degrees C and pH 6.0-7.0. The strain was non-spore-forming, catalase-negative and oxidase-negative. The main polar lipids were sphingoglycolipid, phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and unidentified lipids. The cell-wall peptidoglycan of strain FW-11T included alanine, glycine, glutamic acid, aspartic acid and meso-diaminopimelate. The predominant isoprenoid quinones were ubiquinone Q-10 (93.2 %) and Q-9 (6.8 %). The fatty acid profile (>5 %) included C18 : 1omega6c (43.1 %), C16 : 0 (14.6 %), C17 : 1omega6c (14.0 %) and C14 : 0 2-OH (11.1 %). The most similar neighbours of FW-11T were Sphingomonas fennica K101T (97.4 %) and Sphingomonas haloaromaticamans A175T (97.0 %). The average nucleotide identity relatedness values between strain FW-11T and the two type strains (S. fennica K101T and S. haloaromaticamans A175T) were 73.2 and 75.3 %, respectively. The genome size of FW-11T was 3.8 Mbp, comprising 3735 predicted genes with a DNA G+C content of 64.0 mol%. Based on phenotypic, chemotaxonomic and phylogenetic data, strain FW-11T represents a novel species of the genus Sphingomonas, for which the name Sphingomonas oleivorans sp. nov. is proposed. The type strain is FW-11T (=LMG 29274T=HAMBI 3659T). PMID- 30252642 TI - Genetic diversity of hepatitis B virus in Yunnan, China: identification of novel subgenotype C17, an intergenotypic B/I recombinant, and B/C recombinants. AB - Yunnan is considered to be a geographical hotspot for the introduction, mutation and recombination of several viruses in China. However, there are limited data regarding the genotypic profiles of hepatitis B virus (HBV) in this region. In this study, we characterized 206 HBV strains isolated from chronic hepatitis B patients in Yunnan, China. Initial genotyping based on 1.5 kb sequences revealed that genotype C was the most prevalent at 52.4 % (108/206), followed by genotype B at 30.6 % (63/206) and unclassified genotypes at 17.0 % (35/206). To characterize the 35 unclassified strains, 32 complete HBV genomes were amplified and analysed; 17 isolates were classified within a known subgenotype, 8 were classified as B/C recombinants, 1 was classified as a B/I recombinant and 6 constituted a potentially novel C subgenotype that we designated as C17, based on the characteristics of a monophyletic cluster, >4 % genetic distances, no significant evidence of recombination and no epidemiological link among individuals. Thus, multiple subgenotypes - namely B1, B2, B4, C1, C2, C3, C4, C8 and C17 - and two distinct intergenotypic recombinants exist in Yunnan, China, highlighting the complex and diverse distribution pattern of HBV genotypic profiles. PMID- 30252643 TI - Development of a replicating plasmid based on the native oriC in Mycoplasma pneumoniae. AB - Bacteria of the genus Mycoplasma have recently attracted considerable interest as model organisms in synthetic and systems biology. In particular, Mycoplasma pneumoniae is one of the most intensively studied organisms in the field of systems biology. However, the genetic manipulation of these bacteria is often difficult due to the lack of efficient genetic systems and some intrinsic peculiarities such as an aberrant genetic code. One major disadvantage in working with M. pneumoniae is the lack of replicating plasmids that can be used for the complementation of mutants and the expression of proteins. In this study, we have analysed the genomic region around the gene encoding the replication initiation protein, DnaA, and detected putative binding sites for DnaA (DnaA boxes) that are, however, less conserved than in other bacteria. The construction of several plasmids encompassing this region allowed the selection of plasmid pGP2756 that is stably inherited and that can be used for genetic experiments, as shown by the complementation assays with the glpQ gene encoding the glycerophosphoryl diester phosphodiesterase. Plasmid-borne complementation of the glpQ mutant restored the formation of hydrogen peroxide when bacteria were cultivated in the presence of glycerol phosphocholine. Interestingly, the replicating plasmid can also be used in the close relative, Mycoplasma genitalium but not in more distantly related members of the genus Mycoplasma. Thus, plasmid pGP2756 is a valuable tool for the genetic analysis of M. pneumoniae and M. genitalium. PMID- 30252644 TI - Methylobacterium currus sp. nov., isolated from a car air conditioning system. AB - A novel bacterial strain, designated PR1016AT, was isolated from a car air conditioning system. This rod-shaped strain showed catalase and oxidase activities, was aerobic and methylotrophic, and had a reddish pink colour. The genomic DNA G+C content of strain PR1016AT was 70.2 mol%, as determined by genome sequencing. Phylogenetic analysis based on 16S rRNA gene sequence similarity showed that strain PR1016AT was most closely related to Methylobacterium aquaticum GR16T (98.86 %), M. variabile GR3T (98.43 %), M. platani PMB 02T (98.36 %) and M. tarhaniae N4211T (98.14 %). The average nucleotide identity and digital DNA-DNA hybridization values between strain PR1016AT and M. aquaticum GR16T, M. platani PMB02T and M. variabile GR3T were 88.61, 88.14 and 87.88 %, and 36.4, 35.8 and 34.7 %, respectively. Numerous insertion sequences are present in the genome of strain PR1016AT, which has a larger genome than the four Methylobacterium species described above. Cells grew at 18-42 degrees C (optimum, 30 degrees C), at pH 4.0-9.0 (optimum, pH 7.0) and in the presence of 0-1.0 % (w/v) NaCl (optimum, 0 %). The major respiratory quinone was Q10. Fatty acid methyl ester analysis revealed that summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) was the predominant cellular fatty acid in strain PR1016AT. Two dimensional TLC indicated that the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylcholine. The genotypic and phenotypic characteristics indicate that strain PR1016AT represents a novel species of the genus Methylobacterium, for which the name Methylobacterium currus sp. nov. is proposed. The type strain is PR1016AT (=KACC 19662T=JCM 32670T). PMID- 30252645 TI - Spencerozyma siamensis sp. nov., a novel anamorphic basidiomycetous yeast species in Puccinomycotina isolated from coral in Thailand. AB - Strain DMKU13-2T, representing a novel anamorphic yeast species in the class Microbotryomycetes, subphylum Puccinomycotina, phylum Basidiomycota, was isolated from a soft coral collected in the sea off Ko Mu island, Thailand. The phylogenetic analysis based on the concatenated sequences of the internal transcribed spacer (ITS) region and the D1/D2 region of the large subunit ribosomal RNA (LSU rRNA) gene indicated that this strain was a novel species in the genus Spencerozyma and distant from Spencerozyma crocea, the only species of the genus. The novel species differed from the type of S. crocea (CBS 2029T) by 5.2 % nucleotides (31 nucleotide substitutions out of 594 bp) in the D1/D2 region of the LSU rRNA gene and 9.0 % nucleotides (66 nucleotide substitutions out of 735 bp) in the ITS region. The name Spencerozyma siamensis sp. nov. is proposed. The type is DMKU13-2T (=CBS 14683=TBRC 7039). The MycoBank number is MB 824889. PMID- 30252646 TI - Effect of Inactivated Poliovirus Vaccine Campaigns, Pakistan, 2014-2017. AB - Pakistan began using inactivated poliovirus vaccine alongside oral vaccine in mass campaigns to accelerate eradication of wild-type poliovirus in 2014. Using case-based and environmental surveillance data for January 2014-October 2017, we found that these campaigns reduced wild-type poliovirus detection more than campaigns that used only oral vaccine. PMID- 30252648 TI - Follow-up in children with non-obese and non-autoimmune subclinical hypothyroidism. AB - Background The aim of our study was to evaluate clinical, laboratory and imaging findings and to have an idea about the clinical course of subclinical hypothyroidism in children. Methods Our study included 25 patients who were diagnosed with non-autoimmune subclinical hypothyroidism without goitre, between the ages of 3 and 18 and with body mass index (BMI) below the 85th percentile. Results The mean thyroid-stimulating hormone (TSH) level was 6.92+/-0.92 MUIU/mL at diagnosis, 4.77+/-1.57 MUIU/mL in the third month and 4.51+/-1.79 MUIU/mL in the first year of follow-up. About 73.7% of subclinical hypothyroidism was recovered. There was no statistically significant difference between heart rate, diastolic blood pressure, lipid profile, fasting blood glucose (FBG), fasting insulin level, homeostatic model assessment of insulin resistance (HOMA-IR), hemoglobin, white blood cell, platelet, C-reactive protein (CRP) levels and thyroid volume at diagnosis and in the first year of follow-up. In the first year of follow-up, systolic blood pressure and high-sensitivity CRP value were significantly higher than at diagnosis. However, it was observed that these values were similar in the present group with subclinical hypothyroidism. Conclusions We concluded that there was no progression to overt hypothyroidism during 1-year follow-up and that subclinical hypothyroidism had no effect on height standard deviation score (SDS), BMI SDS, blood pressure, glucose and lipid metabolism during follow-up without treatment. PMID- 30252649 TI - Experimental validation of the FLUKA Monte Carlo code for dose and [Formula: see text]-emitter predictions of radioactive ion beams. AB - In the context of hadrontherapy, whilst ions are capable of effectively destroying radio resistant, deep seated tumors, their treatment localization must be well assessed to ensure the sparing of surrounding healthy tissue and treatment effectiveness. Thus, range verification techniques, such as online positron-emission-tomography (PET) imaging, hold great potential in clinical practice, providing information on the in vivo beam range and consequent tumor targeting. Furthermore, [Formula: see text] emitting radioactive ions can be an asset in online PET imaging, depending on their half-life, compared to their stable counterparts. It is expected that using these radioactive ions the signal obtained by a PET apparatus during beam delivery will be greatly increased, and exhibit a better correlation to the Bragg Peak. To this end, FLUKA Monte Carlo particle transport and interaction code was used to evaluate, in terms of annihilation events at rest and dose, the figure of merit in using [Formula: see text] emitter, radioactive ion beams (RI [Formula: see text]). For this purpose, the simulation results were compared with experimental data obtained with an openPET prototype in various online PET acquisitions at the Heavy Ion Medical Accelerator in Chiba (HIMAC), in collaboration with colleagues from the National Institute of Radiological Sciences' (NIRS) Imaging Physics Team. The dosimetry performance evaluation with FLUKA benefits from its recent developments in fragmentation production models. The present work estimated that irradiations with RI [Formula: see text], produced via projectile fragmentation and their signal acquisition with state-of-the-art PET scanner, lead to nearly a factor of two more accurate definition of the signals' peak position. In addition to its more advantageous distribution shape, it was observed at least an order magnitude higher signal acquired from 11C and 15O irradiations, with respect to their stable counterparts. PMID- 30252650 TI - Adsorption of Cu2+ and mechanism by natural biofilm. AB - The biofilm culturing device fixed on the slides was vertically placed in the commonly called small Li Lake of Jiangnan University. The adsorption experiment of Cu2+ was carried out by mature biofilm. Besides, scanning electron microscope (SEM), polymerase chain reaction and denaturing gradient gel electrophoresis (PCR DGGE), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy-energy spectrum (SEM-EDX) were used to analysis the effect of Cu2+ on the morphological structure of biofilm. The result indicated that when the initial concentration of Cu2+ was 5 mg.L-1, the absorption capacity of Cu2+ by unit mass biofilm is the maximum. More extracellular polymeric substances (EPS) were released by biofilm due to the stimulation of Cu2+. EPS was beneficial to the adsorption of Cu2+ by biofilm. After the adsorption of Cu2+, the bacterial diversity index decreased, while there were no significant differences in microbial communities on biofilm. Moreover, the main groups combining Cu2+ were the hydroxyl groups and amide groups in S-EPS and B-EPS. Ion exchange is a mechanism of the adsorption of Cu2+ by EPS. PMID- 30252647 TI - Unlocking a dark past. AB - A transcription factor called SALL4 could be the missing link between thalidomide and the limb defects caused by the drug. PMID- 30252651 TI - Adsorptive removal of cationic and anionic dyes using graphene oxide. AB - This paper presents the results of comparative study on the application of graphene oxide (GO) for the adsorptive removal of crystal violet (CV) and methyl orange (MO) in batch mode. GO, synthesised from graphite, was characterised by field emission scanning electron microscopy (FESEM), Fourier transform infrared (FTIR) spectroscopy, point of zero charge (pHPZC) and ultra violet (UV) spectroscopy. Dispersion of GO in water revealed the conversion of hydrophobic graphite into hydrophilic. Performance with regard to adsorption of CV and MO on GO was evaluated at different values of the operational parameters such as contact time between GO and the dye molecules, dosage of GO, and initial concentration and pH of the dye solution. Uptake and percentage removal of the dyes increased with increase in contact time and adsorbent dosage, but declined with increase in initial concentration of the dye. Experimental data on the uptake of dye molecules by GO showed good fit with the Freundlich isotherm model and the pseudo second order kinetic model. The maximum uptake by GO was higher for CV (207.4 mg/g) than that for MO (37.2 mg/g). Results indicate that GO is an effective adsorbent for the removal of CV but not for MO. PMID- 30252652 TI - Removal of phenols-like substances in pharmaceutical wastewater with fungal bioreactors by adding Trametes versicolor. AB - Fungi are known to be more resistant to toxic compounds and more effective in removing recalcitrant organics such as phenols than bacteria. Here we examined the removal of phenols (as a component of Zopliclone drugs), added to non-sterile pharmaceutical wastewater with continuous treatment fungal bioreactor by its augmentation with mono-species of white-rot fungi (WRF) Trametes versicolor. Results showed that WRF in a sterile reactor (a batch mode) were moderately effective for removal of phenols (40% in seven days); however, native wastewater microbes at optimal conditions for fungi (pH 5.5, 25 degrees C) were more effective (90%, both in batch and continuous flow modes). In continuous flow mode, addition of WRF was an effective way to mitigate high loads of phenols (up to 400 mg/L), by both fungal enzymes (growth rate 0.075 h-1, laccase enzymatic activity 4 nkat/mL) and biosorption. The study confirmed that naturaly occuring fungi in combination with fungus-augmentation is an effective approach for treatment of high-strength pharmaceutical wastewater. PMID- 30252654 TI - Biodegradation of main carbon sources in vinasse stillage by a mixed culture of bacteria: influence of temperature and pH of the medium. AB - The aim of the study was to examine how temperature and the pH influence the progress and efficiency of an aerobic biodegradation process, where major organic pollutants are removed from beet molasses vinasse by a mixed culture of Bacillus bacteria. It was conducted in an aerated bioreactor with a stirring system in four experimental series, each composed of five processes run at temperatures of 27, 36, 45, 54 and 63 degrees C. In the first and second series, medium pH was not controlled, the initial pH amounted to 6.5 and 8.0, respectively. In the third and fourth series, medium pH was controlled at 6.5 and 8.0, respectively. Under optimal conditions, the pollution load of the vinasse stillage expressed as soluble chemical oxygen demand was removed with an 88.73% efficiency. The bacterial culture assimilated all organic pollutants simultaneously, but the rate of assimilation was different. An exception was the process of betaine assimilation, which intensified only when readily available carbon sources were depleted in the medium. Synthesis and assimilation of organic acids were observed in all experiments. Advantages of the proposed method include: possibility of its use at high temperatures, and no necessity for medium pH adjustment during the process. PMID- 30252653 TI - Adsorption of phosphorus by alkaline Tunisian soil in a fixed bed column. AB - The present study evaluates the phosphorus (P) adsorption by alkaline soil in fixed bed column mode operation. The effects of flow rate, bed height, and initial P concentration on breakthrough curves were evaluated. Data confirmed that both the breakthrough and exhaustion time increased in parallel with the rise in bed height and the decline in flow rate and initial P concentration. The adsorption capacity was observed to increase with decreasing flow rate and bed height and increasing initial concentration. Moreover, continuous adsorption experiments were conducted using three salts (NaCl, KCl and CaCl2) with the same concentration (0.01 M) to investigate the P adsorption behavior in saline conditions. The results showed that all three salts improve the P adsorption in the soil column. Consequently, the bed performance was significantly enhanced with salts addition. The maximum adsorption capacity of 13.47 mg g-1 for P, 16.13 mg g-1 for P-NaCl, 22.10 mg g-1 for P-KCl, 30.05 mg g-1 for P-CaCl2 was attained at an initial influent concentration of 300 mg g-1, bed height of 22 cm, and flow rate of 10 mL min-1. TheCaCl2 addition was therefore the most effective in increasing P adsorption. Thomas, Yoon-Nelson and Clark models were applied to experimental results to forecast the breakthrough curves by nonlinear regression analysis. Meanwhile, the bed depth service time model was employed to examine the effective model parameters in scaling up the process using linear regression analysis. The values of correlation coefficient (R2) and the sum of squared error evidenced that the Thomas model is the most appropriate model to fit the experimental data. The reusability experiment showed that the adsorbent material still had high P adsorption capacity, and tolerable desorption efficiency. PMID- 30252655 TI - Performance evaluation of hybrid OMBR-MD using organic and inorganic draw solutions. AB - The performance of two inorganic divalent salts (CaCl2, and MgCl2) and two organic salts (CH3COONa and Mg(CH3COO)2) was compared with commonly used NaCl in an osmotic membrane bioreactor (OMBR) integrated with a membrane distillation (MD) system. The system was investigated in terms of salinity buildup, flux stability, draw solution (DS) recovery and contaminants removal efficiency. Results indicated that organic DSs not only lessen the salt accumulation within the bioreactor but also increase the pollutant removal efficiency by improving biological treatment. Of all the draw solutions, NaCl and CaCl2 produced rapid declines in water flux because of the high salt accumulation in the bio-tank as compared to other salts. The DCMD system successfully recovered all organic and inorganic draw solute concentrations as per OMBR requirements. Membrane flushing frequency for the MD system followed the order Mg(CH3COO)2 > CH3COONa > CaCl2 > MgCl2 > NaCl. More than 90% removal of chemical oxygen demand (COD), NH4+-N, and PO43--P was achieved in the permeate for each salt because of the dual barriers of high-retention membranes i.e., forward osmosis and MD. PMID- 30252656 TI - Numerical simulation and experimental study of electrocoagulation grid flocculation tank. AB - In recent years, electrocoagulation has been extensively studied on the removal of refractory pollutants. However, the application of electrocoagulation in actual flocculation tank is limited because of its high energy consumption, especially under the condition of large electrode plate spacing. In this study, the computational fluid dynamics (CFD) software - ANSYS Fluent had been used to simulate the flow state of grid flocculation tank, for the purposes of optimizing the design parameters. The simulation results showed that vortex velocity gradient was stronger, the grid plate spacing was smaller when the velocity was 0.13 m s-1, perforation size was 25 * 25 mm, porosity was 31.25%. And the optimal grid plate spacing was 250 mm. Moreover, in order to prove the reasonableness of simulation results, the humic acid wastewater was treated by electrocoagulation process in the specific device which was built based on simulation results. The results showed that the optimal condition of orthogonal test were as follows: the initial pH was 8, the concentration of sodium chloride was 5 mmol L-1, the voltage was 15 V; and the power time was 60 min. This study greatly narrowed the grid plate spacing, optimized design parameters under the circumstances of strong turbulent intensity and provided a theoretical basis for the combination of electrocoagulation and hydraulic flocculation. PMID- 30252657 TI - Neural network for fractal dimension evolution. AB - The coagulation/flocculation process is an essential step in drinking water treatment. The process of formation, growth, breakage and rearrangement of the formed aggregates is key to enhancing the understanding of the flocculation process. Artificial neural networks (ANNs) are a powerful technique, which can be used to model complex problems in several areas, such as water treatment. This work evaluated the evolution of the fractal dimension of aggregates obtained through ANN modeling in the coagulation/flocculation process conducted in high apparent color water (100 +/- 5 PtCo), using alum as coagulant in dosages varying from 1 to 12 mg Al3+ L-1, and shear rates from 20 to 60 s-1 for flocculation times from 1 to 60 minutes. Based on raw data, the ANN model resulted in optimized condition of 9.5 mg Al3+ L-1 and pH 6.1, for color removal of 90.5%. For fractal dimension evolution, the ANN was able to represent from 95% to 99% of the results. PMID- 30252658 TI - Enhanced adsorption performance of methylene blue from aqueous solutions onto modified adsorbents prepared from sewage sludge. AB - In the present work, an attractive and creative adsorbent derived from sewage sludge was freshly fabricated via pyrolysis technology, followed by modification for improving the absorptive ability. First, the (NH4)2S2O8 modified pyrolytic sludge (MSAP) was selected from 19 modified pyrolytic sludges for the highest removal efficiency and adsorption capacity for methylene blue (MB). Then, the adsorption performance for MB of MSAP was compared systematically with the pristine adsorbent (MSDW) by batch adsorption experiments. The main conclusions were that the adsorption process was better fitted with the Langmuir model, and the maximum adsorption capacity (qmax) of MSAP was observed to be 149.05 mg g-1. Moreover, the adsorption kinetics data showed a good fit with the pseudo second order model; when the addition of MSAP was 1.0 g.L-1, the rate constant was 0.05 g.mg-1.min-1, which was far greater than that of the other modified adsorbents. PMID- 30252660 TI - The use of sea shell (Donax trunculus) powder to remove Sr(II) ions from aqueous solutions. AB - This study aimed to investigate and explore the possibility of using ground sea shell powder (Donax trunculus) (SSP) for sorption of Sr(II) ions from aqueous solutions. The maximum removal of Sr(II) removal in SSP was 60% at initial Sr(II) concentration of 25 mg/L, at pH 6.0, contact time 120 min, temperature 25 degrees C and volume/mass ratio equivalent to 500. Sorption data were interpreted considering the adsorption isotherms and thermodynamic parameters calculated. The maximum Sr(II) adsorption on SSP was 25.45 mg/g at pH 6.0. Freundlich isotherm and Dubinin-Radushkevich models were seen to be more compatible with the sorption equilibrium. The nature of the process was spontaneous and exothermic. The results suggest that SSP could be used as an efficient and cost-effective adsorbent to remove strontium ion. PMID- 30252659 TI - Substrate and operational conditions as regulators of fluid properties in full scale continuous stirred-tank biogas reactors - implications for rheology-driven power requirements. AB - Understanding fluid rheology is important for optimal design and operation of continuous stirred-tank biogas reactors (CSTBRs) and is the basis for power requirement estimates. Conflicting results have been reported regarding the applicability of total solid (TS) and/or total volatile solid (TVS) contents of CSTBR fluids as proxies for rheological properties. Thus, the present study investigates relationships between rheological properties of 12 full-scale CSTBR fluids, their substrate profiles, and major operational conditions, including pH, TS and TVS contents, organic loading rate, hydraulic retention time, and temperature. Rheology-driven power requirements based on various fluid characteristics were evaluated for a general biogas reactor setup. The results revealed a significant correlation only between the rheological fluid properties and TS or TVS contents for sewage sludge digesters and thermophilic co-digesters (CD), but not for mesophilic CD. Furthermore, the calculated power requirements for pumping and mixing, based on the various fluid characteristics of the studied CSTBRs, varied broadly irrespective of TS and TVS contents. Thus, this study shows that the TS and/or TVS contents of digester fluid are not reliable estimators of the rheological properties in CSTBRs digesting substrates other than sewage sludge. PMID- 30252661 TI - Application of hybrid bead, persimmon leaf and chitosan for the treatment of aqueous solution contaminated with toxic heavy metal ions. AB - In this study, hybrid beads, which are made by mixing persimmon leaf and chitosan, was used to remove Pb(II) and Cd(II) from aqueous solution. According to the Fourier transform infrared spectrometry (FT-IR) analysis, the hybrid bead has a structure that enables the easy adsorption of heavy metals because it has carboxylic, carbonyl groups, O-H carboxylic acid, and bonded -OH groups. The adsorption of Pb(II) and Cd(II) by hybrid beads was more suitable with the Langmuir isothermal adsorption and showed an ion exchange reaction which occurred in the uneven adsorption surface layer. The maximum adsorption capacity of Pb(II) and Cd(II) was determined to be 278.68 mg/g and 87.91 mg/g, respectively. Furthermore, the adsorption removal process of Pb(II) and Cd(II) using hybrid beads is a spontaneous exothermic reaction and the affinity of the adsorbed material for the adsorbent is excellent. Hybrid beads are inexpensive, have a high removal efficiency of heavy metals, and are environmentally friendly. PMID- 30252662 TI - Performance of the first stage of the French system of vertical flow constructed wetlands with only two units in parallel: influence of pulse time and instantaneous hydraulic loading rate. AB - The technology of vertical flow constructed wetlands - French system for treating raw wastewater depends on several hydraulic factors, one of them being the duration of the pulse feeding and the resulting instantaneous hydraulic loading rate. This paper analyses two scenarios in the same system, the first of a faster feeding by pump and the second of a slower feeding by siphon, both with instantaneous hydraulic loading rate values lower than the literature recommendations. The system treated raw wastewater from a population equivalent of 100 p.e. in Brazil, and was comprised by only the first stage and two units in parallel. The shorter duration of feeding time and higher instantaneous hydraulic loading rate were associated with significantly higher chemical oxygen demand and total Kjeldahl nitrogen removal efficiencies, but with no significant differences in terms of biochemical oxygen demand (BOD) and suspended solids (SS). Oxygen concentrations and redox potential in the effluent were evaluated, together with the effluent flow rate profiles. The removal efficiencies were associated with the accumulation of solids in the upper part of the filter resulting from seven years of operation and to the operating hydraulic conditions, which are important elements in the performance of the system. PMID- 30252663 TI - Improving aeration systems in saline water: measurement of local bubble size and volumetric mass transfer coefficient of conventional membrane diffusers. AB - In this study, for the first time, the influence of the design of conventional membrane diffusers on the volumetric mass transfer coefficient (kLa) and bubble size in tap water (TW) and saline water (SW) was investigated (up to 15 g/L NaCl). By using a new analytical approach, kLa and the bubble size along the ascent of the bubble swarm were measured simultaneously and in real time. The results show that in TW, after collision bubbles merge into larger bubbles by coalescence. In SW, coalescence is inhibited by salt. Due to the smaller bubble size, kLa increases to more than double compared to TW. The results show that in SW, membrane diffusers with dense slit patterns and smaller slit lengths are to be recommended in order to enable improved utilization of oxygen in saline water. PMID- 30252664 TI - Equilibrium, kinetics and thermodynamics of Cu(II) biosorption on Chinese chestnut shell pretreated with steam explosion. AB - The shells of Chinese chestnuts (Castanea mollissima) are an agricultural residue. This work aimed to evaluate this feasibility of using steam explosion to modify this residue for Cu(II) biosorption from aqueous solutions. Equilibrium, kinetic and thermodynamic parameters were evaluated. The steam-explosion pretreatment increased the surface area of the chestnut shell and exposed more hydroxyl and carboxyl groups, which are binding sites for Cu(II). It changed the sorption from a spontaneous process driven by enthalpy to a nonspontaneous one driven by entropy. It increased the Cu(II) sorption capacity at higher temperatures while it decreased the capacity at lower ones. Compared with untreated chestnut shell, the steam-exploded shell is preferable for Cu(II) sorption at higher temperatures. PMID- 30252666 TI - Performance of enhanced biological phosphorus removal and population dynamics of phosphorus accumulating organisms in sludge-shifting sequencing batch reactors. AB - The sludge-shifting sequencing batch reactor (SBR) is an enhanced biological phosphorus removal (EBPR) process for wastewater treatment. In this study, the enrichment of phosphorus accumulating organisms (PAOs) will be attempted by using different high concentration of substrates. In sludge-shifting SBR, activated sludge can be continuously shifted from the bottom of SBR to anaerobic zone/selector, which contains high concentration of substrates, through an orderly reflux between the paralleled SBRs. Denaturing gradient gel electrophoresis (DGGE) methods were used to monitor microbial diversity in sludge. Fluorescence in situ hybridization (FISH) was used to determine the microbial population profile and distribution map under different sludge shifting volumes. The synthesis of intracellular polymers in this process was also analyzed. Phosphorus removal efficiency as high as 96% +/- 1.3% was achieved under a sludge shifting ratio of 30%. Synthetic efficiencies of polyhydroxybutyrate (PHB) by PAOs were improved at high sludge shifting ratios. FISH results demonstrated that the population of PAOs in the process increased under properly sludge shifting ratio and it significantly improved phosphorus removal efficiency. Sequencing results indicated that determined sequences (11 OTUs) belonged to Proteobacterium, Actinobacteria and Firmicutes, Pseudomonas kuykendallii, which played an important role in the process of P removal. PMID- 30252665 TI - Recovery of ammonia in anaerobic digestate using vacuum thermal stripping - acid absorption process: scale-up considerations. AB - A vacuum thermal stripping process coupled with acid absorption has been developed at laboratory scale to recover ammonia in anaerobic digestate. To make this ammonia recovery process scalable, this study investigated the effects of feed depth on vacuum thermal stripping in a pilot system, developed sodium hydroxide dosages required to raise feed pH for stripping, and simulated the dynamics of ammonia reduction in batch stripping tests. As feed depth was increased from 8.5 to 34.0 cm, the ammonia mass transfer coefficient and ammonia stripping efficiency decreased while the mass of stripped ammonia increased. Digested municipal sludge had a greater ammonia mass transfer coefficient than digested dairy manure at each feed depth, which could be attributed to the difference in suspended and dissolved solids concentrations. The optimum feed depth was 18 cm of the digested sludge and 14 cm of the digested manure. Sodium hydroxide dosage for the digested manure was higher than that for the digested sludge and co-digested foodwaste. The dosages were correlated to concentrations of total dissolved solids and ammonia. Total ammonia concentration decreased exponentially in batch stripping of the digested sludge at 25.5 cm deep, with a first-order stripping rate coefficient of 0.087-0.144 h-1. PMID- 30252667 TI - Greenhouse gas emissions from membrane bioreactors: analysis of a two-year survey on different MBR configurations. AB - This study aimed at evaluating the nitrous oxide (N2O) emissions from membrane bioreactors (MBRs) for wastewater treatment. The study investigated the N2O emissions considering multiple influential factors over a two-year period: (i) different MBR based process configurations; (ii) wastewater composition (municipal or industrial); (iii) operational conditions (i.e. sludge retention time, carbon-to-nitrogen ratio, C/N, hydraulic retention time); (iv) membrane modules. Among the overall analysed configurations, the highest N2O emission occurred from the aerated reactors. The treatment of industrial wastewater, contaminated with salt and hydrocarbons, provided the highest N2O emission factor (EF): 16% of the influent nitrogen for the denitrification/nitrification-MBR plant. The lowest N2O emission (EF = 0.5% of the influent nitrogen) was obtained in the biological phosphorus removal-moving bed-MBR plant likely due to an improvement in biological performances exerted by the co-presence of both suspended and attached biomass. The influent C/N ratio has been identified as a key factor affecting the N2O production. Indeed, a decrease of the C/N ratio (from 10 to 2) promoted the increase of N2O emissions in both gaseous and dissolved phases, mainly related to a decreased efficiency of the denitrification processes. PMID- 30252668 TI - Formation and performance of self-forming dynamic membrane (SFDM) in membrane bioreactor (MBR) for treating low-strength wastewater. AB - This study introduces a self-forming dynamic membrane (SFDM) with large-pore mesh filter materials instead of conventional MF/UF membranes for wastewater treatment. Development of SFDM on the mesh filter surface plays a major role in reducing the wastewater turbidity and its performance in a self-formation dynamic membrane bioreactor (SFDMBR). To evaluate formation of the dynamic membrane, biological and hydrodynamic parameters, including mixed liquor suspended solids (MLSS) and aeration rate, were examined. The experimental results showed that with elevation of MLSS in the bioreactor (up to MLSS = 9,000 mg/L), the effluent turbidity diminishes with rapid formation of SFDM, with the shortest formation time (5 min) obtained in SFDM operations, though it results in increased membrane fouling. SFDM was well formed at low aeration rates of 2.5 L/min and 5 L/min, due to very low shear stress on the mesh filter surface, given the results of turbidity in comparison with aeration rates of 10 L/min and 15 L/min. The filtration performance of SFDM in treatment of synthetic wastewater was tested under a constant operational flux (58 L/m2 h). Total chemical oxygen demand (COD) and NH4-N removals were 88-93% and 96-98.8%, respectively. These results indicated that the treatment process can be performed effectively by SFDMBR. PMID- 30252669 TI - Preparation and performance of Cu2O/TiO2 nanocomposite thin film and photocatalytic degradation of Rhodamine B. AB - A constant current electrodeposition approach was employed to prepare Cu2O/TiO2 nanocomposite thin film. X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), Raman, ultraviolet visible light spectrophotometer (UV-Vis), and photoluminescence (PL) measurements were used to characterize and analyze the thin film microstructure, surface morphology, and photoelectric properties. The effect of annealing treatment on the thin film properties is discussed. The response surface methodology (RSM) was employed to optimize the Rhodamine B (RhB) photocatalytic degradation by thin films, and the quadratic multinomial mathematical model was established. The photocatalytic degradation process of RhB was also studied. The results indicate that the prepared Cu2O thin film was of high purity, with a (111) crystal plane preferred orientation. The average particle diameter was approximately 100-200 nm, and the absorbing boundary was approximately 600 nm. After annealing treatment, the absorbing boundary and open-circuit voltage increased, and Cu2O thin film exhibited an obvious absorbance response in the visible-light range. The established model has better fitness and higher reliability, and the R2 value of established quadratic model is 0.9818. The optimal degradation conditions were obtained by RSM. Under optimum conditions, the RhB degradation rate could reach 98.4% in 3 h and the total organic carbon (TOC) removal rate was 48.2%. Recycling results reveal that RhB degradation rate can still reach 94.5% after eight cycles. PMID- 30252670 TI - Genetic algorithm and artificial neural network model for prediction of discoloration dye from an electro-oxidation process in a press-type reactor. AB - This study evaluates the effectiveness of an artificial neural network-genetic algorithm (ANN-GA) artificial intelligence (AI) model in the prediction of behavior and optimization of an electro-oxidation pilot press-type reactor, which treats a synthetic wastewater prepared with a dye. The ANN was built from real experimental data using as input the following variables: time, flow, j, dye concentration, and as output discoloration. The performance of the ANN was measured with MAPE (8.3868%), calculated from real and predicted values. The coupled AI model was used to find the best operational conditions: discoloration efficiency (above 90%) at j = 27 mA/cm2 and dye concentration of 230 mg/L. PMID- 30252671 TI - Treatment of methyl orange by the catalytic wet peroxide oxidation process in batch and continuous fixed bed reactors using Fe-impregnated 13X as catalyst. AB - Fe-impregnated 13X (Fe-13X) catalysts were prepared for catalytic wet peroxide oxidation (CWPO) of methyl orange (MO) solution in batch and continuous fixed bed reactors. A systematical study was carried out to investigate the influence of the main operating parameters on the batch reactor performance. The kinetic curves were analyzed by using a pseudo-first-order kinetic equation over the 30 70 degrees C temperature range. In addition, the effects of catalysts filling amount and feed flow rate on the catalytic performance of Fe-13X catalysts in a fixed bed reactor were studied. The experimental results showed that the Fe-13X catalysts achieved the highest activity (100% MO conversion and 74.5% chemical oxygen demand (COD) elimination ratio, respectively) at 25 min with trace mount of Fe leaching concentration (<2.1 mg/L) at the optimized reaction conditions (namely 1.0 g/L catalyst concentration, pH 2.0, 17.6 mM H2O2, 70 degrees C) in a batch reactor. Kinetic studies showed that two different reaction regions existed, and an activation energy of 51.9 kJ/mol for the second region was found. Under the optimal operating conditions found (namely, catalysts filling amount of 3.5 g, feed flow rate of 4 mL/min), the Fe-13X catalysts displayed high MO conversion (99.4%) and COD elimination ratio (77.1%) after continuously ran for 200 min in a fixed bed reactor. PMID- 30252672 TI - Removal of organic contaminant by municipal sewage sludge-derived hydrochar: kinetics, thermodynamics and mechanisms. AB - In this work, a microporous municipal sewage sludge-derived hydrochar (MSSH) with relatively high surface area and abundant surface organic functional groups was produced through hydrothermal carbonization. Based on the adsorption results over a wide range of conditions, the prepared MSSH was suggested as a promising adsorbent for CV because of its high and efficient adsorption capability. The experimental data were fitted to several kinetic models. Based on calculated respective parameters such as rate constants, equilibrium adsorption capacities and correlation coefficients, the pseudo second-order model proved the best in describing the adsorption behavior of MSSH. Through kinetics, thermodynamic modeling studies and material characterization, a plausible adsorption process was discussed under the conditions used in this study. It can be confirmed that the adsorption of CV onto MSSH is via both physical interactions (electrostatic interaction and Van der Waals' force) and chemical interactions (formation of H bonding). PMID- 30252674 TI - Hydrodynamic performance of a hybrid anaerobic baffled reactor (HABR): effects of number of chambers, hydraulic retention time, and influent temperature. AB - Hydrodynamic performance of a biological reactor is an important design concern since it directly affects the treatment efficiency. In this research, a hybrid anaerobic baffled reactor (HABR) was proposed with improved design concepts and principles. The HABR consisted of a front sedimentation chamber, four regular baffled chambers followed by two floated filter media chambers. The effects of operating variables 5-20 hr hydraulic retention time (HRT) and 10-40 degrees C of influent temperature, as well as their interactive effects, on the hydrodynamic behaviour were investigated by residence time distributions study and response surface methodology. The study suggests that the hydrodynamic performance is greatly influenced by the number of chambers in the reactor rather than HRT and influent temperature. The influence of HRT and feed temperature were mainly observed on the front chambers (1-4) rather than rear chambers (5-7). The optimum reactor performance - low dead space (<10%), excellent hydraulic efficiency (>0.75), and intermediate mixing pattern (Peclet number > 10) - were achieved using the proposed HABR with more than five chambers. PMID- 30252673 TI - Application of online instrumentation in industrial wastewater treatment plants - a survey in Flanders, Belgium. AB - A survey regarding online instrumentation and control was conducted among 90 companies managing their own biological wastewater treatment plant in Flanders, Belgium. In this study, all types of online instrumentation have been found suitable for automatic process control. However, its integration in general process control as well as in nitrogen removal and chemical dosing control appeared to be rather limited. Only dissolved oxygen and pH sensors were widely applied, being present in 96% and 69% of the plants, respectively. Widespread process integration is mainly obstructed by the fact that companies, especially small and medium-sized, still do not regard wastewater treatment as a full fledged part of the production process. Operators often lack technical expertise in this domain and tend to be skeptical towards automated control mechanisms. In addition, the price of online instrumentation is still perceived as too high, in particular at smaller companies. Lastly, the design of the existing wastewater treatment plant does not always allow for real-time control. Certain measures such as operator training, monitoring of energy and chemical consumption and reduction of instrumentation costs are essential for widespread application of online process control in future years. Additionally, water reuse can create an important incentive. PMID- 30252675 TI - Efficient removal of heavy metals from melting effluent using multifunctional hydrogel adsorbents. AB - It is hard to balance high water permeability and good mechanical strength of hydrogel adsorbents. In this study, an enhanced double network hydrogel adsorbent of poly (vinyl alcohol)/poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (PVA/PAMPS) was prepared via simple free-radical polymerization. Hydrophilic PAMPS guaranteed high swellability of the adsorbent, which made the sufficient diffusion of metal ions towards adsorbent inside. Meanwhile, the cross-linkage between PVA and PAMPS chains ensured good mechanical strength of the adsorbent. Significantly, the introduction of multifunctional groups (-NHR, -SO3H and -OH) endowed the adsorbent with both chelation and ion exchange function for enhancing heavy metal adsorption. The maximum adsorption capacities of Pb2+ and Cd2+ reached 340 and 155.1 mg/g, respectively. The adsorbent could efficiently remove heavy metals in melting effluent, especially Pb2+ and Cd2+. The removal efficiencies reached 88.1% for Pb2+, 91.4% for Cd2+, 70.4% for Zn2+, 77.4% for Cu2+, 42.5% for Mn2+, 45.1% for Ni2+ and 95.4% for Fe3+ using 2 g/L adsorbent in 2 h. Moreover, the adsorbent showed a good reusability, and the removal efficiencies maintained 94% for Pb2+ and 93% for Cd2+ in the fifth cycle (m/V = 1 g dry gel/L). This work developed a highly practical hydrogel adsorbent for heavy metal removal from wastewater. PMID- 30252676 TI - A feasibility study of disinfection by-product precursor removal from surface water by a membrane bioreactor acclimatized with wastewater organic matter. AB - A membrane bioreactor (MBR) acclimatized with wastewater organic matter was employed for surface water treatment, and the feasibility of the MBR for the removal of disinfection by-product (DBP) precursors was studied. With a low pressure microfiltration hollow-fiber membrane module, a hydraulic retention time of 1.5 hours and a solids retention time of 180 days, the MBR was able to achieve 35% removal of trichloroacetic acid precursors and 21% removal of dichloroacetic acid precursors. The removal of trichloromethane (TCM) and brominated DBP precursors was unsatisfactory. The TCM yield and bromine substitution factors for trihalomethanes and dihaloacetic acids increased. The phenomena could be attributed to an extended treatment time for hydrophobic dissolved organic matter (DOM), production of soluble microbial products from biomass activities, and an increased Br/DOM ratio by the MBR. Since the MBR treatment would lead to the production of some new DBP precursors and a change of DOM composition, the toxic potency of the DBPs formed needs to be taken into consideration if this process is employed for surface water treatment. PMID- 30252679 TI - Tenofovir-Associated Acute Kidney Disease: Is it Different in HIV- and HBV Infected Patients? PMID- 30252678 TI - Thrombocytopenia-associated mutations in Ser/Thr kinase MASTL deregulate actin cytoskeletal dynamics in platelets. AB - MASTL, a Ser/Thr kinase that inhibits PP2A-B55 complexes during mitosis, is mutated in autosomal dominant thrombocytopenia. However, the connections between the cell-cycle machinery and this human disease remain unexplored. We report here that, whereas Mastl ablation in megakaryocytes prevented proper maturation of these cells, mice carrying the thrombocytopenia-associated mutation developed thrombocytopenia as a consequence of aberrant activation and survival of platelets. Activation of mutant platelets was characterized by hyperstabilized pseudopods mimicking the effect of PP2A inhibition and actin polymerization defects. These aberrations were accompanied by abnormal hyperphosphorylation of multiple components of the actin cytoskeleton and were rescued both in vitro and in vivo by inhibiting upstream kinases such as PKA, PKC, or AMPK. These data reveal an unexpected role of Mastl in actin cytoskeletal dynamics in postmitotic cells and suggest that the thrombocytopenia-associated mutation in MASTL is a pathogenic dominant mutation that mimics decreased PP2A activity resulting in altered phosphorylation of cytoskeletal regulatory pathways. PMID- 30252677 TI - Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells. AB - Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Transcriptomic analysis of stem and progenitor populations in MDS and AML demonstrated overexpression of STAT3 that was validated in an independent cohort. STAT3 overexpression was predictive of a shorter survival and worse clinical features in a large MDS cohort. High STAT3 expression signature in MDS CD34+ cells was similar to known preleukemic gene signatures. Functionally, STAT3 inhibition by a clinical, antisense oligonucleotide, AZD9150, led to reduced viability and increased apoptosis in leukemic cell lines. AZD9150 was rapidly incorporated by primary MDS/AML stem and progenitor cells and led to increased hematopoietic differentiation. STAT3 knockdown also impaired leukemic growth in vivo and led to decreased expression of MCL1 and other oncogenic genes in malignant cells. These studies demonstrate that STAT3 is an adverse prognostic factor in MDS/AML and provide a preclinical rationale for studies using AZD9150 in these diseases. PMID- 30252680 TI - Interaction Between Direct Factor Xa Inhibitors and Digoxin. PMID- 30252681 TI - Clinical Outcome After Rectal Replacement With Side-to-End, Colon-J-Pouch, or Straight Colorectal Anastomosis Following Total Mesorectal Excision: A Swiss Prospective, Randomized, Multicenter Trial (SAKK 40/04). AB - OBJECTIVE: To compare, in a phase 3, prospective, randomized, multi-center clinical trial functional outcome of reconstruction procedures following total mesorectal excision (TME). SUMMARY BACKGROUND DATA: Intestinal continuity reconstruction following TME is accompanied by postoperative defecation dysfunctions known as "anterior resection syndrome." Commonly used reconstruction techniques are straight colorectal anastomosis (SCA), colon J -pouch (CJP), and side-to-end anastomosis (SEA). Comparison of their functional outcomes in prospective, randomized, multi-center studies, including long-term assessments, is lacking. METHODS: Patients requiring TME for histologically proven rectal tumor, with or without neoadjuvant treatment, age >= 18 years, normal sphincter function without history of incontinence, any pretreatment staging or adenoma, expected R0-resection, were randomized for standardized SCA, CJP, or SEA procedures. Primary endpoint was comparison of composite evacuation scores 12 months after TME. Comparison of composite evacuation and incontinence scores at 6, 18 and 24 months after surgery, morbidity, and overall survival represented secondary endpoints. Analysis was based on "per protocol" (PP) population, fully complying with trial requirements, and intention-to treat (ITT) population. RESULTS: Three hundred thirty-six patients from 15 hospitals were randomized. PP population included 257 patients (JCP = 63; SEA = 95; SCA = 99). Composite evacuation scores of PP and ITT populations did not show statistically significant differences among the 3 groups at any time point. Similarly, composite incontinence scores for PP and ITT populations showed no statistically significant difference among the 3 trial arms at any time point. CONCLUSIONS: Within boundaries of investigated procedures, surgeons in charge may continue to perform reconstruction of intestinal continuity following TME at their technical preference. PMID- 30252682 TI - Role of pvdE Pyoverdine Synthesis in Pseudomonas aeruginosa Keratitis. AB - PURPOSE: Pseudomonas aeruginosa produces pyoverdine, encoded by the pvdE gene, for high-affinity iron uptake from transferrin and lactoferrin. This study investigated the contribution of pyoverdine to P. aeruginosa keratitis pathogenesis using in vitro and in vivo models. METHODS: The P. aeruginosa strains examined were parental strain PAO1 and isogenic mutant strain pvdE (DeltapvdE) defective in pyoverdine. Bacterial growth in vitro was determined by PAO1 and DeltapvdE optical densities in Luria-Bertani (LB) broth. PAO1 or DeltapvdE (10 colony-forming units/mL) was inoculated onto cultured human corneal epithelial cells (HCECs) for 1 hour. The monolayers were examined for bacterial adhesion and invasion. In addition, the corneas of C57BL/6 mice were infected with PAO1 or DeltapvdE. Corneal virulence was evaluated by determining clinical scores and bacterial counts during infection. RESULTS: The growth of PAO1 and DeltapvdE in LB broth was similar. Although adhesion of DeltapvdE onto HCECs was significantly increased compared with PAO1, the invasive capacity of DeltapvdE was significantly decreased. Clinical scores and bacterial numbers were significantly lower in DeltapvdE-infected eyes compared with PAO1-infected eyes at 6, 24, and 48 hours (P < 0.001). DeltapvdE was not detected in mouse corneas and did not induce corneal opacity at 6, 24, or 48 hours. CONCLUSIONS: DeltapvdE lost invasive ability toward HCECs. Moreover, DeltapvdE did not cause keratitis in vivo. Thus, pvdE pyoverdine synthesis has critical roles in proliferation and invasion on ocular surfaces and could be a target for prevention of P. aeruginosa keratitis. PMID- 30252683 TI - Fuchs Endothelial Corneal Dystrophy and Mitochondria. AB - Fuchs endothelial corneal dystrophy (FECD) is a bilateral progressive corneal endothelial disease characterized by guttae, which present as partial Descemet membrane thickening, inducing corneal edema at the final stage. Oxidative stress has been reported to play an important role in the pathogenesis of FECD. The electron transport chain and oxidative phosphorylation (oxphos) system in mitochondria are the main sources of endogenous oxidative stress, arising from superoxide generation through premature electron leakage to oxygen. In FECD, corneal endothelial cells have altered mitochondria with mitochondrial DNA damage, decreased oxphos proteins, and lower mitochondrial membrane potential. Mitochondrial dynamics and mitophagy comprise the organelle-level mitochondrial quality control system. Mitochondrial dynamics includes fusion and fission processes. When mitochondria are severely damaged, fission becomes the dominant process to remove damaged mitochondria. Mitophagy is a selective autophagy pathway that removes damaged mitochondria, and is triggered by mitochondrial membrane potential depolarization. In the FECD corneal endothelium, mitochondria have a fission-dominant morphology and low density through mitophagy upregulation because of quality control processes against altered mitochondria. PMID- 30252685 TI - Electric-Acoustic Stimulation Outcomes in Children. AB - OBJECTIVES: This study investigates outcomes in children fit with electric acoustic stimulation (EAS) and addresses three main questions: (1) Are outcomes with EAS superior to outcomes with conventional electric-only stimulation in children? (2) Do children with residual hearing benefit from EAS and conventional electric-only stimulation when compared with the preoperative hearing aid (HA) condition? (3) Can children with residual hearing derive benefit from EAS after several years of listening with conventional electric-only stimulation? DESIGN: Sixteen pediatric cochlear implant (CI) recipients between 4 and 16 years of age with an unaided low-frequency pure tone average of 75 dB HL in the implanted ear were included in two study arms. Arm 1 included new recipients, and Arm 2 included children with at least 1 year of CI experience. Using a within-subject design, participants were evaluated unilaterally with the Consonant-Nucleus Consonant (CNC) word list in quiet and the Baby Bio at a +5 dB SNR using an EAS program and a conventional full electric (FE) program. Arm 1 participants' scores were also compared with preoperative scores. RESULTS: Speech perception outcomes were statistically higher with the EAS program than the FE program. For new recipients, scores were significantly higher with EAS than preoperative HA scores for both the CNC and Baby Bio in noise; however, after 6 months of device use, results in the FE condition were not significantly better than preoperative scores. Long-term FE users benefited from EAS over their FE programs based on CNC word scores. CONCLUSIONS: Whether newly implanted or long-term CI users, children with residual hearing after CI surgery can benefit from EAS. Cochlear implantation with EAS fitting is a viable option for children with HAs who have residual hearing but have insufficient access to high-frequency sounds and poor speech perception.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30252684 TI - Oral Immunotherapy for Allergic Conjunctivitis Using Transgenic Rice Expressing Hypoallergenic Antigens. AB - Pollinosis, or allergic conjunctivitis and rhinitis induced by pollen, is one of the most common diseases worldwide. In Japan, Japanese cedar (Cryptomeria japonica) pollinosis is a predominant allergic condition that affects more than one-third of all Japanese individuals. Pharmacological treatments of allergic conjunctivitis include administration of antiallergic eye drops containing an antihistamine or mast cell stabilizer. However, these topical treatments provide transient relief from symptoms. The only available curative treatment for allergic diseases is allergen-specific immunotherapy. Sublingual immunotherapy for pollinosis has been found to be effective for suppression of ocular and nasal symptoms, but patient compliance is low. Oral administration of staple foods engineered to express allergens is a possible means of delivering antigens for immunotherapy, and its convenience would be expected to improve compliance. With the aim of developing more convenient, effective, and safe immunotherapies for allergic diseases, we have generated rice-based edible vaccines expressing antigens derived from dust mites or pollen from Japanese cedar, birch, or ragweed. In this study, we summarize the results of our immunotherapy studies using transgenic rice. Oral immunotherapy with transgenic rice seeds containing hypoallergenic modified forms of Japanese cedar pollen antigens was effective for both preventing allergic conjunctivitis and suppressing established disease in mice. Oral administration of transgenic rice seeds is thus a promising approach to immunotherapy for conjunctivitis and rhinitis induced by Japanese cedar pollen. PMID- 30252686 TI - A Policy Brief: Climate Change and Epidemiology. PMID- 30252688 TI - Efficacy of Plate Expression of Meibum on Tear Function and Ocular Surface Findings in Meibomian Gland Disease. AB - PURPOSE: To evaluate the clinical effectiveness of expression treatment on meibomian gland disease (MGD). METHODS: Seventeen right eyes of 17 patients with MGD were divided into 3 groups in this randomized prospective clinical study: no expression group: routine treatment with no expression (five patients, five eyes); digital expression group: routine treatment with digital expression (five patients, five eyes); and plate expression group: routine treatment with plate expression (seven patients, seven eyes). All groups received the same routine treatment for 1 month. Tear film break-up time (TBUT), vital staining scores, meibum expressibility, and the dry eye-related quality of life score (DEQS) questionnaire results were assessed before and 1 month after treatment. RESULTS: There was a statistically significant difference of posttreatment TBUT among groups as determined by one-way analysis of variance (P<0.05). A post hoc test revealed that TBUT was statistically significantly higher in plate expression group compared with digital expression group. The fluorescein staining score did not show a statistically significant difference among the groups. Meibum expressibility and the DEQS scores improved in all groups. CONCLUSION: Plate expression when used as an adjunct to routine medical management of MGD has been found to be a comparatively effective treatment in terms of improvement of tear film stability compared with no expression or digital expression. PMID- 30252689 TI - Substance Use Disorder Assessment, Diagnosis, and Management for Patients Hospitalized With Severe Infections Due to Injection Drug Use. AB - OBJECTIVES: Persons with injection drug use (IDU) have high healthcare utilization. Consequently, healthcare providers have opportunities to identify and treat underlying substance use disorders (SUD) that drive these hospitalizations. The study purpose was to characterize current SUD evaluation and treatment practices by primary and consulting services during hospitalization for severe infections related to IDU. METHODS: This study is a retrospective chart review of inpatient admissions to an academic medical center. The 2 inclusion criteria were documentation of IDU in clinical notes and the presence of an infection likely related to IDU. Demographic and clinical data were extracted from electronic medical records. RESULTS: A total of 108 inpatient admissions met inclusion criteria and were included in the study. The most common infections related to IDU were endocarditis (n = 65, 60.2%) and osteomyelitis (n = 27, 25.0%). The primary team explicitly documented substance use in the H&P and progress notes in 103 (95.4%) hospitalizations and in 84 (77.8%) at discharge. Opioid use disorder was coded by International Classification of Diseases, Ninth Revision in 62 (57.4%). The most frequent intervention was screening, brief intervention, and referral to treatment in 99 (91.7%) episodes. The vast majority of patients did not have specific plans or recommendations for SUD treatment upon discharge. CONCLUSIONS: Though more than half of the patients in this study had opioid use disorder, pharmacotherapy for opioid use disorder was typically not provided, and screening, brief intervention, and referral to treatment (SBIRT) was the most common intervention. There are significant gaps in the clinical assessment, diagnosis, and management of SUD in persons hospitalized with life threatening complications of IDU, leaving many opportunities to improve care for this complex patient population. PMID- 30252687 TI - Diagnostic Assessment of Assumptions for External Validity: An Example Using Data in Metastatic Colorectal Cancer. AB - BACKGROUND: Methods developed to estimate intervention effects in external target populations assume that all important effect measure modifiers have been identified and appropriately modeled. Propensity score-based diagnostics can be used to assess the plausibility of these assumptions for weighting methods. METHODS: We demonstrate the use of these diagnostics when assessing the transportability of treatment effects from the standard of care for metastatic colorectal cancer control arm in a phase III trial (HORIZON III) to a target population of 1,942 Medicare beneficiaries age 65+ years. RESULTS: In an unadjusted comparison, control arm participants had lower mortality compared with target population patients treated with the standard of care therapy (trial vs. target hazard ratio [HR] = 0.72, 95% confidence interval [CI], 0.58, 0.89). Applying inverse odds of sampling weights attenuated the trial versus target HR (weighted HR = 0.96, 95% CI = 0.73, 1.26). However, whether unadjusted or weighted, hazards did not appear proportional. At 6 months of follow-up, mortality was lower in the weighted trial population than the target population (weighted trial vs. target risk difference [RD] = -0.07, 95% CI = -0.13, -0.01), but not at 12 months (weighted RD = 0.00, 95% CI = -0.09, 0.09). CONCLUSION: These diagnostics suggest that direct transport of treatment effects from HORIZON III to the Medicare population is not valid. However, the proposed sampling model might allow valid transport of the treatment effects on longer-term mortality from HORIZON III to the Medicare population treated in clinical practice. See video abstract at, http://links.lww.com/EDE/B435. PMID- 30252690 TI - Outcome Differences in Neonates Exposed In-Utero to Opioids Managed in the NICU Versus Pediatric Floor. AB - OBJECTIVE: The aim of the study is to determine length of stay and length of treatment in infants with neonatal abstinence syndrome (NAS) in the neonatal intensive care unit (NICU) compared to those in the pediatric floor. METHODS: Retrospective cohort of infants >=34 weeks gestation admitted with diagnosis of NAS at a single regional perinatal referral center from July 2014 to October 2015. A standardized NAS protocol for both the NICU and pediatric floor, which included guidelines for the initiation of oral morphine, escalation, and weaning, was followed. Initial location of treatment, NICU or pediatric floor, was determined by physiological stability following birth. Statistical analysis included 1-way analysis of variance and chi-square. Multivariable analysis was performed using generalized linear models to account for confounding. RESULTS: The study included 235 infants, 80 (34%) were cared for in the NICU. Infants in the NICU had a longer length of stay (27.1 +/- 19.1 vs 14.2 +/- 10.2 days, P < 0.01), and length of pharmacological treatment (18.0 +/- 19.9 vs 9.0 +/- 10.2 days, P < 0.01) compared to those on the pediatric floor, respectively. Forty seven infants were transferred from the NICU to the pediatric floor for the remainder of their hospital stay with a mean time on the pediatric floor of 17.4 +/- 14.5 days. After controlling for confounding, admission to the NICU was associated with an increased length of treatment of 12.6 days (95% confidence interval 8.3-16.8) and length of stay of 12.3 days (95% confidence interval 7.9 16.6). CONCLUSIONS: In our population, admission to the pediatric floor compared to the NICU was associated with a shorter length of stay, and a shorter length of pharmacological treatment. Our data suggest that caring for infants with NAS outside of the NICU setting has the potential to improve short-term outcomes and reduce associated costs. PMID- 30252691 TI - A Rare Case of Enoxaparin Induced Skin Necrosis Without Thrombocytopenia. PMID- 30252693 TI - Langerhans Cell Histiocytoma: A Benign Histiocytic Neoplasm of Diverse Lines of Terminal Differentiation. AB - Langerhans cell (LC) histiocytoma is a neonatal tumor that often consists of a single, ulcerated nodule. Systemic involvement is rare, and LC histiocytoma is considered to be a variant of congenital, self-healing LC histiocytosis (also referred to as Hashimoto-Pritzker disease). In view of its low prevalence, LC histiocytoma is not always diagnosed in a clinical examination and requires histological confirmation. Furthermore, the histological and molecular features of LC histiocytoma have not been well characterized. Here, we report on 6 cases of this rare disease and review the corresponding literature. LC histiocytoma differs from classical self-healing LC histiocytosis with regard to the pathological features; we found that LC histiocytoma was associated with massive infiltration by histiocytes of various sizes and shapes (although often large) throughout the dermis and the superficial subcutis. Epidermotropism was rare, mitotic figures were not inconspicuous, and necrotic or calcified areas were often present. Immunohistochemical assessment revealed a mixture of different types of histiocytes (with CD1a CD207, CD1a CD207, and CD1a CD207 CD163 cells). Genetic testing was performed in 5 cases; it revealed a BRAF mutation (p.V600E and p.485_490delinsF) in 2 cases, a HRAS mutation (p.T58I) in 1 case, a combination of 2 PTEN mutations in another case (p.I224M and p. R234W), and no mutations in the fifth case. All the lesions regressed spontaneously, and none recurred during follow-up. PMID- 30252694 TI - Eosinophilic Dermatosis of Myeloproliferative Disease in a Young Adult With Diffuse Large B-Cell Lymphoma. AB - Exaggerated insect bite reactions present as exuberant papular and vesiculobullous lesions in patients with hematologic malignant neoplasms. The most commonly reported hematological malignancy with exaggerated insect bite reactions is chronic lymphocytic leukemia. Other reported reactions have been seen in patients with mantle cell lymphoma. Clinical presentation may vary with many patients unaware of a previous insect bite. Therefore, the terms "exaggerated bite-like reaction" and "eosinophilic dermatosis of myeloproliferative disease" have been proposed. The lesions may wax and wane or persist for many years, and they seem to be unrelated to the underlying hematologic disorder course or therapy. In some circumstances, the lesions may actually precede the diagnosis of the hematological malignancy. In this study, we describe a case of "eosinophilic eruption of myeloproliferative disease" associated with diffuse large B-cell lymphoma in a young adult. To the best of our knowledge, this is the first case reported in association with diffuse large B-cell lymphoma. PMID- 30252695 TI - Cutaneous Mastocytosis With Predominant Infiltration of Promastocytes. AB - Mastocytosis is a heterogeneous group of disorders with a variable clinical course, ranging from indolent disease with normal life expectancy to highly aggressive disease. In the skin, mast cells may show a spindle-shape appearance or appear as round cells with wide, polygonal cytoplasm. In this study, we present a case series of 4 patients with cutaneous childhood-onset mastocytosis in whom skin mast cells showed striking nuclear pleomorphism with bilobed and multilobed nuclei. Such finding does not seem to represent a malignant phenotype of the disease in the skin, although the true biological significance and the potential prognostic impact remain to be determined. PMID- 30252696 TI - Mucinous Metaplasia of the Vulva in Zoon Vulvitis and Lichen Sclerosus et Atrophicus. Description of 3 Additional Cases of a Rarely Reported Histopathologic Finding. AB - Mucinous metaplasia of the vulva (MMV) is a histopathologic finding that has been reported previously in only 3 patients and needs to be distinguished from vulvar extramammary Paget disease. We report 3 additional instances of MMV associated to Zoon vulvitis and vulvar lichen sclerosus et atrophicus. Histochemical and immunohistochemical studies were performed on biopsies from erythematous and erosive vulvar lesions of 3 women aged 64, 80 and 84 years, with features of Zoon vulvitis (2 cases) and lichen sclerosus et atrophicus (1 case). Mucin-containing epithelial cells were present on the uppermost layers of the squamous epithelium. On immunohistochemical study the metaplastic cells were positive for cytokeratin 7, epithelial membrane antigen and carcinoembryonic antigen, thus mimicking the phenotype of Paget disease. MMV is most likely related to chronic inflammation. Cytological and architectural features allow for distinction from Paget disease because the mucin-containing cells of mucinous metaplasia of the vulva lack atypia and are predominantly located on the most superficial layers of the surface epithelium. PMID- 30252697 TI - Brooke-Spiegler Syndrome: Two Patients From a Turkish Family With Multiple Familial Trichoepithelioma. PMID- 30252698 TI - Follicle and Sebaceous Gland Multinucleated Cells in Measles. AB - We report the case of a 32-year-old man with measles in which skin biopsy helped to establish a definitive diagnosis. Follicular involvement is a common histopathologic feature of measles. Multinucleated epidermal and follicular cells are distinctive findings. PMID- 30252699 TI - Performance of Air Seal of Flexible Reinforced Laryngeal Mask Airway in Thyroid Surgery Compared With Endotracheal Tube: A Randomized Controlled Trial. AB - BACKGROUND: Flexible reinforced laryngeal mask airway (FLMA(r)) has gained popularity in thyroid surgery, but air leak and displacement are still concerns. METHODS: In this randomized, single-blinded, noninferiority, controlled trial, we randomized patients scheduled for elective radical thyroidectomy to an endotracheal tube (ETT) group or a FLMA group. The primary outcomes were ventilation leak volume, peak airway pressure, and partial pressure of end-tidal carbon dioxide (PetCO2). Data for primary outcomes were collected after insertion of ETT/FLMA, at incision, and at 10-minute intervals during surgery. Ten milliliters, 5 cm H2O, and 10 mm Hg were used as the noninferiority deltas for ventilation leak volume, peak airway pressure, and PetCO2, respectively. We assessed noninferiority of FLMA to ETT on the primary outcomes over time using the results of a linear mixed-effects model. The position of FLMA mask was evaluated before and after surgery, and the airway complications were recorded. RESULTS: A total of 132 patients were included: 65 in ETT group and 67 in FLMA group. Differences (FLMA group minus ETT group) of ventilation leak volume, peak airway pressure, and PetCO2 from the mixed-effects models were 2.09 mL (98.3% confidence interval [CI], -6.46 to 10.64), -0.60 cm H2O (98.3% CI, -2.15 to 0.96), and 1.02 mm Hg (98.3% CI, 0.04-1.99), respectively. Score of fiber-optic position of FLMA was significantly higher after surgery than before. There was no severe shift, loss of the mask seal, regurgitation, or aspiration in the FLMA group. One patient in the FLMA group experienced brief and easily controlled laryngospasm. CONCLUSIONS: In thyroid surgery, FLMA is noninferior to ETT in the peak airway pressure and PetCO2 although mild to moderate mask shift could occur during surgical manipulation. There is no evidence for a higher complication rate when FLMA is used. PMID- 30252700 TI - Bronchial Blocker Use in the Difficult Airway Patient Requiring Lung Isolation: Clarification as to What Blockers Are Actually Available. PMID- 30252701 TI - Intraoperative Considerations for Transgender Patients. PMID- 30252702 TI - In Response. PMID- 30252703 TI - In Response. PMID- 30252705 TI - Obstetric Anesthesiology in the United States: Current and Future Demand for Fellowship-Trained Subspecialists. PMID- 30252704 TI - Programmed Intermittent Bolus Regimen for Erector Spinae Plane Blocks in Children: A Retrospective Review of a Single-Institution Experience. AB - With few published reports on erector spinae plane block use in children, limited guidance on perioperative local anesthetic dosing exists. We present a series of 22 patients who received erector spinae plane catheters with programmed intermittent bolus for various surgeries. Median loading dose of 0.4 mL/kg (interquartile range [IQR], 0.1 mL/kg) ropivacaine 0.5%, intraoperative bolus of 0.3 mL/kg/h (IQR, 0.1 mL/kg) ropivacaine 0.2%, and a postoperative programmed intermittent bolus regimen of maximum 0.6 mg/kg/h resulted in highest pain scores on postoperative day 1 with a median score of 1.7 of 10 (IQR, 1.8) and highest morphine equivalents consumed on postoperative day 2 with a median score of 0.16 mg/kg up to 120 hours after surgery. PMID- 30252706 TI - Lack of Bias Evaluation and Inadequate Study Selection May Produce Misleading Results. PMID- 30252707 TI - Should We Always Continue beta-Blocking Agents Preoperatively? PMID- 30252708 TI - Is Tube Thermosoftening Helpful for Videolaryngoscope-Guided Nasotracheal Intubation?: A Randomized Controlled Trial. AB - BACKGROUND: Thermosoftening of the endotracheal tube (ETT) and telescoping the ETT into a rubber catheter have been suggested as a method for reducing epistaxis during nasotracheal intubation (NTI). However, thermosoftening technique is known to make it difficult to navigate the ETT into trachea without the use of Magill forceps during NTI. The cuff inflation technique has been suggested as an effective alternative to the use of Magill forceps to improve the oropharyngeal navigation of the ETT, irrespective of their stiffness, during direct laryngoscope-guided NTI. We evaluated whether thermosoftening of the ETT telescoped into rubber catheters has an additional benefit in reducing nasal injury. Simultaneously, we also evaluated whether thermosoftening of the ETT worsened orotracheal navigability during cuff inflation-supplemented videolaryngoscope-guided NTI. METHODS: One hundred forty patients were randomly assigned to 1 of the 2 groups depending on whether the ETT was softened by warming or not. The primary outcome was the incidence of epistaxis during NTI. The secondary outcome was nasotracheal navigability of the ETT, assessed by navigation grade and time required for insertion of ETT in each phase (from nose to oropharynx, from oropharynx to glottic inlet aided by cuff inflation if needed, and from glottic inlet to trachea). RESULTS: The ETTs were successfully inserted through the selected nostril of all 140 patients. In the thermosoftening group, the incidence and severity of epistaxis was significantly lower (7% vs 51%; difference of 44.2%; 95% confidence interval, 29.9%-56.2%; P < .001), and the ETT passed through the nasal cavity with lower resistance (P = .001) and less time (P < .001) when compared to the control group. No difference was found in the ease of ETT insertion (navigation grade and time required) from the oropharynx to the glottic inlet (P > .99 and P = .054, respectively) and from the glottic inlet to the trachea (P > .99 and P = .750, respectively) between the 2 groups. In both groups, all ETTs could be navigated into the trachea without the use of Magill forceps. CONCLUSIONS: Supplemented with cuff inflation during videolaryngoscope-guided NTI, thermosoftening of the ETT telescoped into rubber catheters has a substantial benefit because it significantly reduces the incidence of epistaxis without worsening the oropharyngeal navigability of the ETT. PMID- 30252710 TI - Fact or Fiction? Adipose-Derived Stem Cells and Platelet-Rich Plasma for the Treatment of Vulvar Lichen Sclerosus. AB - OBJECTIVE: The aim of the study was to summarize and review the evidence for the efficacy and safety of adipose-derived stem cells (ADSCs) and platelet-rich plasma (PRP) for the treatment of vulvar lichen sclerosus (LS). MATERIALS AND METHODS: PubMed/MEDLINE, Ovid, Web of Science, and clinicaltrials.gov were searched from inception up to May 7, 2018. RESULTS: Seven observational studies were identified, with a total of 98 patients. Both ADSCs and PRP were reported to improve symptoms, quality of life measures, as well as clinical and histological signs of vulvar LS. There is a strong risk of biased estimates of treatment effect. CONCLUSIONS: Current evidence is weak for ADSCs and/or PRP as treatment for vulvar LS. Further research is needed before recommending this therapy. PMID- 30252709 TI - Multimodal General Anesthesia: Theory and Practice. AB - Balanced general anesthesia, the most common management strategy used in anesthesia care, entails the administration of different drugs together to create the anesthetic state. Anesthesiologists developed this approach to avoid sole reliance on ether for general anesthesia maintenance. Balanced general anesthesia uses less of each drug than if the drug were administered alone, thereby increasing the likelihood of its desired effects and reducing the likelihood of its side effects. To manage nociception intraoperatively and pain postoperatively, the current practice of balanced general anesthesia relies almost exclusively on opioids. While opioids are the most effective antinociceptive agents, they have undesirable side effects. Moreover, overreliance on opioids has contributed to the opioid epidemic in the United States. Spurred by concern of opioid overuse, balanced general anesthesia strategies are now using more agents to create the anesthetic state. Under these approaches, called "multimodal general anesthesia," the additional drugs may include agents with specific central nervous system targets such as dexmedetomidine and ones with less specific targets, such as magnesium. It is postulated that use of more agents at smaller doses further maximizes desired effects while minimizing side effects. Although this approach appears to maximize the benefit-to-side effect ratio, no rational strategy has been provided for choosing the drug combinations. Nociception induced by surgery is the primary reason for placing a patient in a state of general anesthesia. Hence, any rational strategy should focus on nociception control intraoperatively and pain control postoperatively. In this Special Article, we review the anatomy and physiology of the nociceptive and arousal circuits, and the mechanisms through which commonly used anesthetics and anesthetic adjuncts act in these systems. We propose a rational strategy for multimodal general anesthesia predicated on choosing a combination of agents that act at different targets in the nociceptive system to control nociception intraoperatively and pain postoperatively. Because these agents also decrease arousal, the doses of hypnotics and/or inhaled ethers needed to control unconsciousness are reduced. Effective use of this strategy requires simultaneous monitoring of antinociception and level of unconsciousness. We illustrate the application of this strategy by summarizing anesthetic management for 4 representative surgeries. PMID- 30252711 TI - Systemic Inflammatory Response Syndrome as Predictor of Poor Outcome in Nontraumatic Subarachnoid Hemorrhage Patients. AB - OBJECTIVES: Subarachnoid hemorrhage is a life-threatening disease associated with high mortality and morbidity. A substantial number of patients develop systemic inflammatory response syndrome. We aimed to identify risk factors for systemic inflammatory response syndrome development and to evaluate the role of systemic inflammatory response syndrome on patients' outcome. DESIGN: Retrospective observational cohort study of prospectively collected data. SETTING: Neurocritical care unit at a tertiary academic medical center. PATIENTS: Two hundred and ninety-seven consecutive nontraumatic subarachnoid hemorrhage patients admitted to the neurologic ICU between 2010 and 2017. INTERVENTIONS: Systemic inflammatory response syndrome was diagnosed based on greater than or equal to two criteria (hypo-/hyperthermia, tachypnea, leukopenia/leukocytosis, tachycardia) and defined as early (<= 3 d) and delayed (days 6-10) systemic inflammatory response syndrome burden (systemic inflammatory response syndrome positive days within the first 10 d). Using multivariate analysis, risk factors for the development of early and delayed systemic inflammatory response syndrome and the relationship of systemic inflammatory response syndrome with poor 3-month functional outcome (modified Rankin Scale score >= 3) were analyzed. MEASUREMENTS AND MAIN RESULTS: Seventy-eight percent of subarachnoid hemorrhage patients had early systemic inflammatory response syndrome, and 69% developed delayed systemic inflammatory response syndrome. Median systemic inflammatory response syndrome burden was 60% (interquartile range, 10-90%). Risk factors for early systemic inflammatory response syndrome were higher admission Hunt and Hess grade (odds ratio, 1.75; 95% CI, 1.09-2.83; p = 0.02), aneurysm clipping (odds ratio, 4.84; 95% CI, 1.02-23.05; p = 0.048), and higher modified Fisher Scale score (odds ratio, 1.88; 95% CI, 1.25-2.89; p = 0.003). Hunt and Hess grade and pneumonia were independently associated with delayed systemic inflammatory response syndrome development. Systemic inflammatory response syndrome burden (area under the curve, 0.84; 95% CI, 0.79-0.88) had a higher predictive value for 3-month poor outcome compared with early systemic inflammatory response syndrome (area under the curve, 0.76; 95% CI, 0.70-0.81; p < 0.001). CONCLUSIONS: Systemic inflammatory response syndrome is common after subarachnoid hemorrhage and independently contributes to poor functional outcome. Systemic inflammatory response syndrome burden more accurately predicts poor outcome than early systemic inflammatory response syndrome. PMID- 30252713 TI - Radiation Protection Around High-intensity Laser Interactions with Solid Targets. AB - Interaction of a high-intensity optical laser with a solid target can generate an ionizing radiation hazard in the form of high-energy "hot" electrons and bremsstrahlung, resulting from hot electrons interacting with the target itself and the surrounding target chamber. Previous studies have characterized the bremsstrahlung dose yields generated by such interactions for lasers in the range of 10 to 10 W cm using particle-in-cell code EPOCH and Monte Carlo code FLUKA. In this paper, electron measurements based on a depth-dose approach are presented for two laser intensities, which indicate a Maxwellian distribution is more suitable for estimating the hot electrons' energy distribution. Also, transmission factors for the resulting bremsstrahlung for common shielding materials are calculated with FLUKA, and shielding tenth-value-layer thicknesses are also derived. In combination with the bremsstrahlung dose yield, the tenth value layers provide radiation protection programs the means to evaluate radiation hazards and design shielding for high-intensity laser facilities. PMID- 30252712 TI - Variation in Case-Mix Adjusted Unplanned Pediatric Cardiac ICU Readmission Rates. AB - OBJECTIVES: To identify modifiable factors leading to unplanned readmission and characterize differences in adjusted unplanned readmission rates across hospitals. DESIGN: Retrospective cohort study using prospectively collected clinical registry data SETTING:: Pediatric Cardiac Critical Care Consortium clinical registry. PATIENTS: Patients admitted to a pediatric cardiac ICU at Pediatric Cardiac Critical Care Consortium hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We examined pediatric cardiac ICU encounters in the Pediatric Cardiac Critical Care Consortium registry from October 2013 to March 2016. The primary outcomes were early (< 48 hr from pediatric cardiac ICU transfer) and late (2-7 d) unplanned readmission. Generalized logit models identified independent predictors of unplanned readmission. We then calculated observed-to-expected ratios of unplanned readmission and identified higher-than or lower-than-expected unplanned readmission rates for those with an observed-to expected ratios greater than or less than 1, respectively, and a 95% CI that did not cross 1. Of 11,301 pediatric cardiac ICU encounters (16 hospitals), 62% were surgical, and 18% were neonates. There were 175 (1.6%) early unplanned readmission, and 300 (2.7%) late unplanned readmission, most commonly for respiratory (31%), or cardiac (28%) indications. In multivariable analysis, unique modifiable factors were associated with unplanned readmission. Although shorter time between discontinuation of vasoactive infusions and pediatric cardiac ICU transfer was associated with early unplanned readmission, nighttime discharge was independently associated with a greater likelihood of late unplanned readmission. Two hospitals had lower-than-expected unplanned readmission in both the early and late categories, whereas two other hospitals were higher-than-expected in both. CONCLUSIONS: This analysis demonstrated time from discontinuation of critical care therapies to pediatric cardiac ICU transfer as a significant, modifiable predictor of unplanned readmission. We identified two hospitals with lower-than-expected adjusted rates of both early and late unplanned readmission, suggesting that their systems are well designed to prevent unplanned readmission. This offers the possibility of disseminating best practices to other hospitals through collaborative learning. PMID- 30252714 TI - Keeping abreast of human papillomavirus in Iran. PMID- 30252715 TI - Esophageal cancer mortality in a high-incidence area (Golestan Province, north of Iran): which risk factors are causative? PMID- 30252716 TI - Resolved hepatitis B virus infection: an unresolved issue of terminology. PMID- 30252718 TI - Access to Orthopaedic Care. PMID- 30252719 TI - The Role of Arthroscopic Simulation in Teaching Surgical Skills: A Systematic Review of the Literature. AB - BACKGROUND: Following the introduction of worktime regulations across the world along with existing concerns over the nonuniform nature of the traditional apprenticeship model, an alternative method for teaching surgical skills is being sought. Simulation training offers a safe and standardized environment to develop and improve surgical skills. The purpose of the present study was to review the existing and most recent research into the utility of arthroscopic simulators in training and the teaching of surgical skills. METHODS: A systematic review of the MEDLINE, Embase, and Cochrane Library databases for English-language articles published between 2014 and November 2017 was conducted. Search terms included arthroscopy or arthroscopic with simulation or simulator. RESULTS: We identified a total of 27 relevant studies involving simulated ankle, knee, shoulder, hip, and simple box arthroscopic environments. The majority of these studies demonstrated construct validity, while a few demonstrated transfer, face, and content validity. CONCLUSIONS: Our review suggests that there is a considerable evidence base regarding the use of arthroscopic simulators for training purposes. Further work should focus on the development of a standardized simulator training course that can be contrasted against current intraoperative training in large scale multicenter trials with long-term follow-up. PMID- 30252720 TI - Biomarkers of Rotator Cuff Disease Severity and Repair Healing. PMID- 30252721 TI - Factors Associated with Presenteeism at Work in Type 2 Diabetes Mellitus. AB - OBJECTIVE: Our study aimed to identify factors associated with decreased presenteeism in type 2 Diabetes Mellitus (T2DM). METHODS: Data were collected from 147 T2DM participants. Questionnaires were completed: Stanford Presenteeism Scale (SPS-6) assessing health status and employee productivity, Hospital Anxiety and Depression Scale (HADS) for mental health, SF-36 for quality of life, Problem Areas in Diabetes (PAID) to measure diabetes-related emotional distress, and Michigan Neuropathy Screening Instrument for diabetic neuropathy. RESULTS: PAID score was negatively related to the SPS-6 score (r = -0.527, P < 0.001). Both anxiety and depression were negatively correlated with SPS-6 (r = -0.377, P < 0.001 and r = -0.603, P < 0.001 respectively). Seven out of 8 different categories of SF-36 were significantly associated with SPS-6 score. Neuropathy was negatively related to presenteeism (r = -0.228, P = 0.07). CONCLUSIONS: Factors related to decreased presenteeism in T2DM include diabetes associated stress, poor mental health, poor quality of life, and an history of neuropathy. PMID- 30252722 TI - Comparative Analysis of Impairment Ratings from the 5th and 6th editions of the AMA Guides. AB - OBJECTIVE: The association of AMA Guides edition with impairment ratings is uncertain. METHODS: We used data from a consecutive sample of 249 injured workers referred for an independent evaluation 10 months before and after assessors switched from the 5 to the 6 edition of the AMA Guides. RESULTS: The median whole person impairment rating was 7.0% (interquartile range [IQR]: 4 to 14) for 131 claimants assessed with the 5 edition of the Guides, and 4.0% (IQR: 2 to 8) for 118 claimants assessed with the 6th edition (p-value for difference: 0.002). Multivariable analysis showed a 36.4% relative reduction (95% confidence interval [CI] 17.2% to 57.3%) in impairment rating with the 6 edition of the Guides vs. the 5 edition. CONCLUSIONS: The 6 edition of the AMA Guides provides systematically lower impairment ratings for injured workers than the 5 edition. PMID- 30252723 TI - Effects of Environmental Heat and Antioxidant Ingestion on Blood Markers of Oxidative Stress in Professional Firefighters Performing Structural Fire Exercises. AB - OBJECTIVE: Firefighters (FFs) involved in fire suppression have the greatest on duty risk of cardiovascular disease (CVD), which may be caused by oxidative stress (OS). METHODS: Healthy, active FFs performed a victim "search and clear" exercise involving three conditions: (1) no heat, (2) heat + antioxidant, and (3) heat + placebo. Blood samples were analyzed for OS markers glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), catalase (CAT), and advanced oxidation protein products (AOPP). RESULTS: Increased GSH was found during both heat conditions compared with no heat. CAT activity was higher immediately post exercise. AOPP was reduced post exercise. CONCLUSIONS: Antioxidant supplementation did not impact the OS response to exercise. Added heat did not cause OS and exercise resulted in reductions in OS markers. These findings can be attributed to the training status of the FFs involved. PMID- 30252724 TI - The Economic Effect of Chronic Comorbidities in Carpal Tunnel Syndrome Workers' Compensation Claimants, Washington State. AB - OBJECTIVE: Assess the effect of chronic comorbidities on hours and earnings recovery following a carpal tunnel syndrome (CTS) claim. METHODS: The hours and earnings profiles of Washington State workers' compensation claimants with CTS and controls, upper extremity fractures (UEF) claimants, were collected by linking to unemployment insurance data during 2007 to 2014. Chronic comorbidity status was determined from workers' compensation bills. RESULTS: More (43%) CTS claimants had diagnosed chronic comorbidities than UEF (24%). CTS claimants and claimants with multiple chronic comorbidities had significantly higher odds of not working post injury and poorer hours and earnings recovery compared with UEF claimants and those with no chronic comorbidities. CONCLUSIONS: This research suggests that chronic conditions should be considered as barriers to return to work among injured workers. PMID- 30252725 TI - Carbon Emission Mitigation Strategies: What Occupational Physicians Need to Know. PMID- 30252726 TI - YWHAE-NUTM2A/B Translocated High-grade Endometrial Stromal Sarcoma Commonly Expresses CD56 and CD99. AB - YWHAE-NUTM2A/B translocated high-grade endometrial stromal sarcoma is an uncommon and clinically aggressive uterine mesenchymal neoplasm which is sometimes associated with a low-grade fibromyxoid component. Although the diagnosis is confirmed using molecular techniques, it is possible to make the diagnosis based on the characteristic morphology and the immunophenotype; the latter typically includes diffuse positive staining of the high-grade component with cyclin D1 and CD117 and negative staining with CD10 and hormone receptors. Especially in a small biopsy specimen, in cases without a low-grade component or when presenting with extrauterine disease, the differential diagnosis may be wide and potentially include "small round cell tumors" such as a high-grade neuroendocrine carcinoma and a tumor in the Ewing family. In this study, we report consistent CD56 and CD99 immunoreactivity in YWHAE-NUTM2A/B translocated high-grade endometrial stromal sarcoma. We stained 20 of these neoplasms (10 molecularly confirmed and 10 where diagnosis was based on the morphology and immunophenotype) with CD56 and CD99; in one case, CD56 staining was not performed. Nineteen of 19 (100%) and 17 of 20 (85%) were positive with CD56 and CD99, respectively. Staining was usually diffuse with membranous and cytoplasmic immunoreactivity. Pathologists should be aware that YWHAE-NUTM2A/B translocated high-grade endometrial stromal sarcoma is commonly positive with CD56 and CD99; as well as potentially assisting in diagnosis, positivity with these markers may also result in consideration of other neoplasms in the differential diagnosis. PMID- 30252727 TI - Cerebellar Metastasis From Ovarian Carcinoma Harboring PIK3CA-Activating Mutation: A "Clear" Explanation for an Unexpected "Vertigo". AB - Brain metastasis is a rare and generally late manifestation of an advanced-stage, high-grade serous ovarian carcinoma. Nowadays, the improved control of intra abdominal disease by surgery and platinum-based chemotherapy results in a longer survival, allowing distant metastasis to implant and grow in the brain parenchyma also. Herein, we describe a unique case of cerebellar metastasis from a particular type of ovarian tumor, clear cell that initially presented as a FIGO Stage IC cancer. Surprisingly, 6 mo after surgery, the patient shows good general conditions with complete disappearance of symptoms and no evidence of recurrence. This relatively good biologic behavior may be explained by the presence of PIK3CA activating mutation in exon 9 which as previously reported in the literature, may be associated with better prognosis. To the best of our knowledge, this is the first reported case of cerebellar metastasis from ovarian clear cell carcinoma. In the presence of neurological symptoms, both clinicians and pathologists must be aware of this rare possibility, to assure the patient correct management and effective therapeutic options. Generally, the prognosis of epithelial ovarian cancer patients with brain metastases is poor. PIK3CA mutations could be a good prognostic indicator in clear cell carcinomas. PMID- 30252728 TI - Histologic Features of Hysterectomy Specimens From Female-Male Transgender Individuals. AB - Histologic changes in the female genital tract after prolonged androgen stimulation have been described in the past. However, these changes have not been systematically addressed in hysterectomy specimens from subjects undergoing surgical gender-reassignment, typically after treatment with exogenous androgens. The current study aims to provide practicing pathologists with a list of expected histologic features in hysterectomy specimens from female-male transgender individuals. Twenty-seven hysterectomy with bilateral salpingo-oophorectomy specimens were identified from our Laboratory Information System. Slides were retrieved and reviewed for features associated with androgen exposure. Clinical information for the 27 subjects (20-46 yr old, mean=29 yr) was obtained from the electronic medical records. Twenty-four subjects had received androgen 19 mo to 24 yr preoperatively. Focal decidua-like endometrial stromal change with glandular paucity was present in 16/27 (59%) uteri associated with predominantly inactive endometrial glands. Ectocervical or transformation zone transitional cell metaplasia was present in 17/27 (63%) subjects. Bilateral cystic follicles were present in all 23 subjects who underwent bilateral salpingo-oophorectomy and had preoperative androgen exposure. In these ovaries, follicular density appeared higher than that expected for age with counts ranging from 1.5 to 32.5 follicles/mm (average=10.7 follicles/mm). Predominantly inactive, sparse endometrial glands with focal decidua-like stromal change, cervical transitional cell metaplasia, bilateral cystic follicles and higher follicular density are observed in the majority of specimens from female-male transgender individuals. These histologic changes correlate with prolonged preoperative androgen administration. The significance of these findings relies on recognizing the spectrum of androgen-related histologic alterations and not confusing transitional cell metaplasia with cervical dysplasia. PMID- 30252729 TI - Audit of Endometrial Cancer Pathology for a Regional Gynaecological Oncology Multidisciplinary Meeting. AB - Endometrial cancer is a common disease, and in England all cancer cases are discussed at a central multidisciplinary meeting (MDT) with pathology review. We reviewed cases discussed/reviewed at a regional Gynecology MDT comparing (i) original referral histology with review histology and (ii) final review histology with the final hysterectomy histology. Cases identified as potentially eligible for the study (n=884) were found over a 4-yr period. This was reduced to 630 due to data and other issues for the primary biopsy review, and to 488 for both biopsy and hysterectomy sample. Cases were classed by agreement by grade/type and compared by clinical management (low grade vs. high grade). Of the original biopsies, central review agreed exactly with 67% and disagreed with 33%. A total of 11.6% of low-grade cancers were upgraded to high grade on review, and 6.1% of high-grade cancers were downgraded. For the biopsy/hysterectomy comparison, this was 72.5% agreement and 27.5% disagreement, with 3.5% upgraded to high from low grade, and 7.5% downgraded from high to low grade. The main areas of significant change was the identification of high-grade serous carcinoma from low-grade endometrial cancers, as well some other high grade types (clear cell and carcinosarcoma) and the confident diagnosis of cancer as opposed to an atypical hyperplasia. Central pathology review for MDT discussion does highlight significant areas of pathologic disagreement that would affect clinical management. The audit highlights that a significant disagreement rate in reporting such material between pathologists may be inescapable, but can be reduced by review. PMID- 30252731 TI - Implementing Curriculum Change: Choosing Strategies, Overcoming Resistance, and Embracing Values. PMID- 30252730 TI - Classic and "Dissecting" Gonadoblastoma in a Phenotypic Girl With a 46, XX Peripheral Karyotype and No Evidence of a Disorder of Sex Development. AB - Herein, we report a case of a 9-yr-old girl who had a 46, XX peripheral karyotype and apparent developmentally normal ovaries. She presented with abdominal pain and a right adnexal mass. No clinical or pathologic evidence of gonadal dysgenesis or undifferentiated gonadal tissue was detected. She underwent right salpingo-oophorectomy with rupture of the tumor at the time of operation due to recent adnexal torsion. The original pathologic diagnosis was gonadoblastoma and mixed germ cell tumor. Most significantly in our study, we identified a rare and novel pathway for the development of malignant mixed germ cell tumor from gonadoblastoma in the absence of identifiable dysgerminoma. The histologically identifiable steps of progression in our case were as follows: (1) residual islands of classic gonadoblastoma, (2) overgrowth by "dissecting" gonadoblastoma composed of transformed germ cells with clear cytoplasm and sex cord elements surrounded by a basement membrane, (3) stromal infiltration by dedifferentiated germ cells with loss of basement membrane, (4) formation of malignant mixed germ cell tumor. The dedifferentiated areas were composed of anaplastic germ cells with amphophilic cytoplasm that gradually replaced the sex cord elements by clonal expansion. Both the original transformed and the anaplastic germ cell components strongly expressed OCT4. We believe that the mixed germ cell tumor arose from the dedifferentiated germ cell component through neoplastic progression. This premise suggests that the germ cell component of "dissecting" gonadoblastoma rarely undergoes anaplastic change in the absence of transition to germinoma and can be the direct precursor of mixed germ cell tumor. PMID- 30252732 TI - The Need to Control for Learning Effects in Simulation Studies. PMID- 30252733 TI - In Reply to Kendall and Castro-Alves. PMID- 30252734 TI - Hearing the Patient Voice: Patients as Educators in Medical Education. PMID- 30252735 TI - In Reply to Wald. PMID- 30252736 TI - Creating Structured Opportunities for Social Interactions to Promote Wellness: One Residency Program's Experience. PMID- 30252737 TI - In Reply to Hernandez. PMID- 30252738 TI - Paving the Way to More NIH Funding for Clinician-Researchers. PMID- 30252739 TI - Toward a More Perfect Match: Improving the Residency Application Process. PMID- 30252740 TI - It Is Time to Implement Comprehensive Graduate Monitoring Programs. PMID- 30252741 TI - Et Tu? PMID- 30252742 TI - Birds of Prey. PMID- 30252743 TI - Artist's Statement: Physicians Must Speak for the Voiceless and the Vulnerable. PMID- 30252744 TI - Magnetism: [Excerpt]. PMID- 30252745 TI - Commentary on an Excerpt From "Magnetism". PMID- 30252746 TI - 2018 Hope Babette Tang Humanism in Healthcare Essay Contest: Third Place Medical Student Essay. PMID- 30252747 TI - 2018 Hope Babette Tang Humanism in Healthcare Essay Contest: Third Place Nursing Student Essay: The Fish Tank. PMID- 30252748 TI - Morbihan Disease Treatment: Two Case Reports and a Systematic Literature Review. AB - PURPOSE: To assess the effectiveness of treatments for Morbihan disease. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review of the literature was performed on April 1, 2018, using PubMed, Google Scholar, and Excerpta Medica dataBASE with terms used to describe Morbihan disease, including "Morbihan Disease," "Morbihan Syndrome," "lymphedema rosacea," and "lymphedematous rosacea". Case reports or case series were included if they fulfilled the following criteria: published in English, peer-reviewed, and reported Morbihan disease. RESULTS: A total of 89 patients-87 patients from 49 articles and 2 cases from the authors' institution-were included in the final analysis. The median age of patients was 51 years (range: 14-79), and 66 of 89 (74%) patients were men. Male gender correlated with lack of complete response to treatment (odds ratio: 0.25; 95% confidence interval: 0.06 0.97; p = 0.02), while presence of papules or pustules correlated with complete response to treatment (odds ratio: 4.07; 95% confidence interval: 1.04-17.68; p = 0.03). Longer antibiotic duration correlated with response to treatment (p = 0.03), favoring complete over partial response (p= 0.02). Mean antibiotic duration in patients who responded was 4.43 months (standard deviation: 3.49), with complete responders requiring 6.50 months (standard deviation: 4.57). Oral corticosteroids, isotretinoins, and combination therapies did not correlate with treatment response. CONCLUSIONS: The presence of papules and pustules correlates with a complete response to treatment, while male gender correlates with a partial response. Patients may benefit from 4- to 6-month duration of tetracycline-based antibiotics. Prospective studies are needed to assess the impact of antibiotic and isotretinoin dose and duration on treatment response. PMID- 30252749 TI - Microstructural differences in visual white matter tracts in people with aniridia. AB - Aniridia is a panocular disorder characterized chiefly by iris hypoplasia. Most cases result from mutations of the PAX6 gene, which is important in both eye and brain development. In addition to ocular alterations, differences in global brain volume and functional connectivity have been reported in humans with aniridia. Understanding neural alterations in aniridia may require examination of possible differences in white matter structure, as few studies have assessed white matter in this population. The current study utilized diffusion-weighted imaging to assess white matter structure in 11 people with aniridia and 11 healthy comparison participants, matched for sex and age. A map of the local connectome was calculated to compare quantitative anisotropy (QA), an index of white matter tract density, in all white matter voxels, revealing subcomponents of white matter tracts with differing QA between people with aniridia and healthy comparisons. The analysis indicated that QA was lower for people with aniridia in portions of bilateral optic tract [t(20)=-4.23, P=0.001, d=-1.80], bilateral optic radiation [t(20)=-4.06, P=0.001, d=-1.73], forceps major [t(20)=-3.65, P=0.002, d=-1.55], bilateral superior longitudinal fasciculus [left: t(20)=-3.15, P=0.005, d=-1.34; right, t(20)=-4.28, P<0.001, d=-1.83], and right posterior corona radiata [t(20)=-3.19, P=0.006, d=-1.36]. These differences demonstrate that white matter structure is altered in people with aniridia in both visual tracts and associated posterior visual pathways. PMID- 30252750 TI - Relationships and Reliability Between a Drive Block Test and Traditional Football Performance Tests in High School Offensive Line Players. AB - Collins, KS, Coburn, JW, Galpin, AJ, and Lockie, RG. Relationships and reliability between a drive block test and traditional football performance tests in high school offensive line players. J Strength Cond Res 32(12): 3432-3441, 2018-The offensive line (OL) is a specialized football position responsible for blocking tasks. Little research exists on OL-specific movements and relationships to performance tests in high school players. This study investigated the reliability of the average and peak velocity (avgV, peakV) and momentum (avgM, peakM) of a drive block test (DBT) in 15 high school OL and relationships to performance tests. A linear position transducer attached to the OL waist measured the DBT from a 3-point stance into a blocking pad. Linear speed was measured by a 36.58-m sprint. Change-of-direction (COD) ability was measured by the pro-agility shuttle (first COD, second COD, and total time) and COD deficit from the first (COD deficit 1) and second COD (COD deficit 2) of the pro-agility shuttle. Vertical jump, standing broad jump (SBJ), and 1 repetition maximum (1RM) back squat were also measured. Pearson's correlations (p < 0.05) investigated relationships between the DBT and performance tests. Intraclass correlation coefficients (ICCs), dependent t-tests, and coefficient of variation (CV) assessed DBT reliability. Drive block test variables were reliable (ICC > 0.90; CV = 6.46-8.29%) and correlated with the second pro-agility shuttle COD and COD deficit 2 (r = -0.515 to -0.721). One repetition maximum back squat correlated with avgM and peakM (r = 0.551-0.582); SBJ correlated with avgV and peakV (r = 0.557-0.571). The pro-agility shuttle splits, COD deficit, and SBJ may provide useful information about DBT qualities important for high school OL. It is recommended high school OL training focus on strength, COD performance, and jumping ability to aid drive block performance. PMID- 30252751 TI - "The Science of Breast Implants" Supplement. PMID- 30252752 TI - Financial Disclosure Appendix for "The Science of Breast Implants". PMID- 30252753 TI - Introduction to "The Science of Breast Implants". PMID- 30252754 TI - Breast Implant Engineering and Performance. AB - The engineering of breast implants for both augmentation and reconstruction is centered on facilitating optimal aesthetic results pleasing to the patient, while minimizing both short- and long-term complications. Some of the key individual design elements that have been the primary focus over time have included gel cohesivity, shell thickness, shell surface, and implant gel fill. A review of these separate elements points to the potential benefits of increased focus on a combined overall performance perspective for engineering of new implants as exemplified in the recently introduced MemoryGel Xtra Breast Implants. Such an approach is expected to provide an improved and expanded range of options to facilitate obtaining desired aesthetic outcomes and long-term clinical performance. PMID- 30252755 TI - Implant Testing and the "Strain Energy" Concept. AB - Benchtop performance test methodologies differ between manufacturers as regulatory agencies often leave the interpretation of testing standards up to manufacturer discretion, resulting in an inability to directly compare implants across manufacturers. Furthermore, traditional benchtop test methodologies focus on mechanical performance standards to address objective endpoints such as shell strength. However, other more difficult to define clinical performance requirements such as softness and natural feel are often difficult to measure via these methods. This review aims to discuss the evolution of breast implant testing standards, discuss the discrepancies in benchtop characterizations of implants, and highlight one manufacturer's novel approach to utilizing benchtop methodologies to quantify previously subjective endpoints such as firmness and natural feel and define their clinical relevance. PMID- 30252756 TI - Evolution in Tissue Expander Design for Breast Reconstruction: Technological Innovation to Optimize Patient Outcomes. AB - Tissue expander design in breast reconstruction has evolved substantially over the last 60 years. An insightful appreciation of breast aesthetics, coupled with competition among industry partners, has resulted in innovative and disruptive technology to benefit patients desiring immediate reconstruction following mastectomy. In this article, we discuss the evolution of breast expander technology and the implications in improving patient outcomes in breast reconstruction. PMID- 30252757 TI - Clinical Results on Innovation in Breast Implant Design. AB - Breast implants have been shadowed in controversy since their introduction to the market; however, they represent a multi-million dollar industry and play a critical role both for cosmetic augmentation and enhancement and for reconstruction following treatment for cancer. With advancements in technology, breast implants have evolved tremendously over the years. Further, with the cessation of the FDA implemented moratorium on silicone, the use of silicone implants has grown exponentially over the years. Novel designs in the outer shell, breast implant fill particularly the cohesivity of the silicone gel, texturing of the outer shell, and the shape and projection of breast implants have produced a broad array of implants that can be employed by plastic and reconstructive surgeons to maximize outcomes for patients. However, despite the innovations in breast implant design and engineering, it is unclear whether these have had any influence on outcomes and patient satisfaction. The present article aims to provide a comprehensive review of the technological advancements in breast implant technology in optimizing patient outcomes and minimizing complications associated with placement of breast implants for aesthetic as well as reconstructive procedures. The article will provide a synopsis of round versus shaped breast implants, saline versus silicone especially the advent of cohesive silicone gel implants, and the texturing of the outer shell, and how each of these components should be considered when counseling patients and deciding which implants offer the optimal benefits for each individual patient. PMID- 30252758 TI - What are the new vaccination recommendations for herpes zoster? AB - A new vaccine to prevent herpes zoster (shingles) has been included in the 2018 Advisory Committee on Immunization Practices' adult immunization schedule as the preferred herpes zoster vaccination for all immunocompetent adults age 50 years and older. This article discusses new vaccination recommendations for herpes zoster. PMID- 30252760 TI - Abdominal point tenderness and an impending aneurysmal rupture. AB - Although isolated iliac artery aneurysms are rare and occur in only 2% of patients, isolated internal iliac artery aneurysms are even more uncommon. Patients with these aneurysms require urgent vascular surgery consultation and evaluation; untreated aneurysms have a high propensity to increase in size and rupture. Providers should be aware of this critical incidental finding on CT scan and MRI and know when to initiate an emergency workup and therapy. PMID- 30252761 TI - Changing theories on the pathogenesis and risk factors for diverticulitis. AB - Diverticulitis was thought to be a simple complication of an even simpler disease (diverticulosis), but may in fact result from an entirely new set of complex pathologies. Considering diverticulitis is increasing in annual incidence and becoming more prevalent in younger populations, the implications of appropriate management become more vital than ever. This article reviews old and new understandings of diverticulitis and current recommendations for prevention and clinical management. PMID- 30252762 TI - Implementing standardized substance use disorder screening in primary care. AB - OBJECTIVES: This quality improvement initiative aimed to develop and implement a protocol for an alcohol and substance use disorder screening for primary care. METHODS: The Two Item Conjoint Screen was selected and a process was piloted by care teams. Quality improvement tools were used to improve the protocol. Primary care providers (PCPs) were surveyed about their use of the screening protocol in the primary care setting. Data on total number of screenings were collected through the electronic health record. RESULTS: Implementation resulted in more than 30,000 screenings completed in 2016. PCP survey results indicated that PCPs felt screening was helpful in identifying potential substance use problems (100%) and that most providers (76%) felt that overall patient care improved after screening was initiated. CONCLUSIONS: Brief alcohol and substance use disorder screenings can be easily implemented and well integrated into primary care settings. PCPs found screenings to be valuable in caring for patients. PMID- 30252763 TI - Employers of excellence create positive environments to attract and retain PAs. PMID- 30252765 TI - Scleroderma. PMID- 30252766 TI - What is causing this pulsatile nodule? PMID- 30252764 TI - Opioid use disorder: A public health emergency. AB - The treatment of patients with acute and chronic pain not attributed to cancer or end-of-life conditions is a challenge for many clinicians. Although CDC guidelines that focus on the primary care setting have provided critical recommendations, evidence-based guidance is lacking on optimal duration of opioid treatment for postoperative and acute care in specialty settings. Over the last 2 decades, the liberal use of opioids has resulted in many unintended consequences, including dependence and abuse, illicit distribution of legally and illegally prescribed opioid medication, progression to IV heroin and an epidemic of overdoses, and most recently an increase in the incidence of HIV among patients sharing syringes, frequently in communities with historically low HIV rates. This article analyzes these complex issues and proposes strategies to help clinicians improve patient care through education and responsible prescribing. PMID- 30252767 TI - Making it up as you go along. PMID- 30252768 TI - Before each curtain, I must repair myself, I must adapt. PMID- 30252769 TI - Kidney transplant wait list: Review and current trends. AB - Renal transplantation is the treatment of choice for patients with end-stage renal disease. Improved success of renal transplantation has led to a growing number of US patients waiting for a transplant and longer waits to obtain kidneys. This article discusses the process and challenges of getting on the wait list, kidney organ allocation, and areas being explored to increase available organs for renal transplantation. PMID- 30252771 TI - Antithrombotic Stewardship: Assessing Use of Computerized Clinical Decision Support Tools to Enhance Safe Prescribing of Direct Oral Anticoagulants in Hospitalized Patients. AB - Prescribing patterns for oral anticoagulants in patients with nonvalvular atrial fibrillation and venous thromboembolism is shifting from vitamin K antagonists, such as warfarin to the direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, and apixaban. Although many hospital systems have implemented clinical decision support or enhanced monitoring for patients prescribed warfarin, there is limited evidence to suggest similar levels of enhanced monitoring for DOACs. The antithrombotic stewardship team at our institution developed guidelines and implemented computerized clinical decision support (CCDS) tools to enhance medication and patient safety related to the DOACs. We sought to assess the safety and effectiveness of these CCDS tools available to clinicians upon DOAC prescription in hospitalized patients. We performed a retrospective review of 121 patients who received at least two doses of a DOAC from January 2013 to July 2014. We assessed dosing of the DOAC according to the CCDS provided upon order entry. Adherence to CCDS was 80% (n = 24), 75% (n = 46), and 87% (n = 27) in the dabigatran, apixaban, and rivaroxaban group, respectively. Our data demonstrate that implementing CCDS for DOACs into the electronic medical record may ensure safe prescribing of high-risk medications. PMID- 30252772 TI - Perceptions of gendered and ungendered pain relief norms and stereotypes using Q methodology. AB - Pain is ubiquitous, but effective pain relief eludes many. Research has shown that some pain behaviours are perceived as gendered, and this may influence the way men and women express and cope with pain, but such enquiries have not extended to specific methods of pain relief. Our aim was to explore perceptions of the most socially acceptable ways for men and women to relieve pain. Across 2 studies, 60 participants (50% men) aged 18 to 78 years completed a Q-sort task, sorting different pain relief strategies by the social acceptability for either women (study 1; N = 30) or men (study 2; N = 30). Analyses revealed 2 stereotypes for each sex. The overarching stereotype for women suggested it is most acceptable for them to use pain relief strategies considered conventional and effective. However, a second stereotype suggested it is most acceptable for women to use strategies that generally conform to feminine gender norms and stereotypes. The overarching male stereotype suggested it is most acceptable for men to use pain relief aligned with stereotypical masculinity; however, a second stereotype also emerged, characterised by conventional and effective responses to pain, much like the overarching stereotype for women. These differing viewpoints seem to depend on whether gender norm conformity or perceived analgesic efficacy is believed to determine social acceptability. These studies provide initial evidence of both a gendered and ungendered lens through which pain relief can be viewed, which may influence how men and women use pain relief. PMID- 30252773 TI - Association of functional polymorphisms in 3'-untranslated regions of COMT, DISC1, and DTNBP1 with schizophrenia: a meta-analysis. AB - INTRODUCTION: In recent years, various studies have accumulated evidence of the involvement of single nucleotide polymorphisms (SNPs) in introns and exons in schizophrenia. The association of functional SNPs in the 3'-untranslated regions with schizophrenia has been explored in a number of studies, but the results are inconclusive because of limited meta-analyses. To systematically analyze the association between SNPs in 3'-untranslated regions and schizophrenia, we conducted a meta-analysis by combining all available studies on schizophrenia candidate genes. MATERIALS AND METHODS: We searched candidate genes from the schizophrenia database and performed a comprehensive meta-analysis using all the available data up to August 2017. The association between susceptible SNPs and schizophrenia was assessed by the pooled odds ratio with 95% confidence interval using fixed-effect and random-effect models. RESULTS: A total of 21 studies including 8291 cases and 9638 controls were used for meta-analysis. Three investigated SNPs were rs165599, rs3737597, and rs1047631 of COMT, DISC1, and DTNBP1, respectively. Our results suggested that rs3737597 showed a significant association with schizophrenia in Europeans (odds ratio: 1.584, P: 0.002, 95% confidence interval: 1.176-2.134) under a random-effect framework. CONCLUSION: This meta-analysis indicated that rs3737597 of DISC1 was significantly associated with schizophrenia in Europeans, and it can be suggested as an ethnic-specific risk genetic factor. PMID- 30252774 TI - The Effect of Dietary Protein on Protein Metabolism and Performance in Endurance trained Males. AB - : Recommendations for dietary protein are based primarily intakes that maintain nitrogen (i.e. protein) balance rather than optimize metabolism and/or performance. PURPOSE: To determine how varying protein intakes, including a new tracer-derived safe intake, alter whole body protein metabolism and exercise performance during training. METHODS: Using a double-blind randomized crossover design, 10 male endurance-trained runners (age, 32+/-8 yr; VO2peak, 65.9+/-7.9 ml O2.kg.min) performed 3 trials consisting of 4 days of controlled training (20, 5, 10, 20 km.d, respectively) while consuming diets providing 0.94 (LOW), 1.20 (MOD), and 1.83 (HIGH) g protein.kg.d. Whole body protein synthesis (S), breakdown (B), and net balance (NB) were determined by oral [N]glycine on the first and last day of the 4-d controlled training period whereas exercise performance was determined from maximum voluntary isometric contraction (MVC), 5 km Time Trial (5kmTT), and countermovement jump Impulse (IMP) and peak force (PF) before and immediately after the 4-d intervention. RESULTS: S and B were not affected by protein intake whereas NB showed a dose-response (HIGH > MOD > LOW, P<0.05) with only HIGH being in positive balance (P<0.05). There was a trend (P=0.06) towards an interaction in 5kmTT with HIGH having a moderate effect over LOW (ES=0.57) and small effect over MOD (ES = 0.26). IMP decreased with time (P<0.01) with no effect of protein (P=0.56). There was no effect of protein intake (P>=0.06) on MVC, IMP, or PF performance. CONCLUSION: Our data suggest that athletes who consume dietary protein towards the upper end of current ACSM recommendations (1.2-2 g.kg) would better maintain protein metabolism and potentially exercise performance during training. PMID- 30252775 TI - Dynamic Cerebral Autoregulation Is Maintained during High-Intensity Interval Exercise. AB - INTRODUCTION: High-intensity interval exercise (HIIE) is more effective at increasing metabolic and cardiovascular health compared to moderate-intensity continuous exercise for patients with cardiovascular disease, but exhaustive high intensity continuous exercise (HICE) attenuates dynamic cerebral autoregulation (CA). This study assessed the effect of HIIE on dynamic CA. METHODS: Nine healthy men (age: 24 +/- 3 years; mean +/- SD) warmed up at 50%-60% maximal workload (Wmax) for 5 min before HIIE including four 4 min bouts of exercise at 80%-90% Wmax interspaced by four 3 min bouts at 50%-60% Wmax. Transcranial Doppler determined middle cerebral artery mean blood velocity (MCA Vmean), and brachial artery catheterization determined mean arterial pressure (MAP). Dynamic CA was evaluated by transfer function analysis of changes in MAP and MCA Vmean. RESULTS: The HIIE increased MAP (from 92 +/- 9 to 104 +/- 10 mmHg; P < 0.0125), while MCA Vmean did not change. Transfer function phase increased and coherence decreased during HIIE (P < 0.0125 vs. rest, respectively), while gain was unchanged. CONCLUSION: The results suggest that dynamic CA is unaffected during HIIE, indicating that the brain is protected from fluctuations in MAP. Thus, we propose that HIIE may be beneficial for brain-related health as maintenance of cerebral perfusion in contrast to HICE. PMID- 30252777 TI - Aortic Branch Vessel Flow During Resuscitative Endovascular Balloon Occlusion of the Aorta. AB - BACKGROUND: REBOA (Resuscitative Endovascular Balloon Occlusion of the Aorta) is a torso hemorrhage control adjunct. Aortic branch vessel flow (BVF) during REBOA is poorly characterized and has implications for ischemia-reperfusion (I-R) injury. The aim of this study is to quantify branch vessel flow in hypovolemic shock with and without REBOA. METHODS: Female swine (79-90kg) underwent anesthesia, 40% controlled hemorrhage and sonographic flow monitoring of the carotid, hepatic, superior mesenteric, renal and femoral arteries. Animals were randomized to REBOA (n=5) or no-REBOA (n=5) for 4 hours, followed by full resuscitation and balloon deflation for 1-hour. RESULTS: All animals were successfully induced into hemorrhagic shock with a mean decrease of flow in all vessels of 50% from baseline (p<0.001). Deployment of REBOA resulted in a 200 400% increase in carotid flow, but near complete abolition of BVF distal to the balloon (Figure). The no-REBOA group saw recovery of BVF to 100% of baseline in all measured vessels, except the hepatic at 50-75%. 2-way ANOVA confirmed a significant difference between the groups throughout the protocol (p<0.001). During resuscitation, the REBOA group saw BVF restore to between 25-50%, but never achieving baseline values. The lactate at 4 hours was significantly higher in the REBOA vs. no-REBOA group (17.2+/-0.1 vs. 4.9+/-1.4; p<0.001). CONCLUSIONS: REBOA not only abolishing BVF during occlusion, but appears to have a post-REBOA effect, reducing visceral perfusion. This may be a source of REBOA associated I-R injury and warrants further investigation in order to mitigate this effect. LEVEL OF EVIDENCE: Level 3. PMID- 30252776 TI - Effects of a restrictive blood transfusion protocol on acute pediatric burn care: Transfusion threshold in pediatric burns. AB - BACKGROUND: Blood transfusion is costly and associated with various medical risks. Studies in critically ill adult and pediatric patients suggest that implementation of more restrictive transfusion protocols based on lower threshold hemoglobin concentrations can be medically and economically advantageous. The purpose of this study was to evaluate the implications of a hemoglobin threshold change in pediatric burn patients. METHODS: We implemented a change in hemoglobin threshold from 10 g/dL to 7 g/dL and compared data from patients before and after this protocol change in a retrospective review. Primary endpoints were hemoglobin concentration at baseline, before transfusion, and after transfusion; amount of blood product administered; and mortality. Secondary endpoints were the incidence of sepsis based on the American Burn Association physiological criteria for sepsis and mean number of septic days per patient. All endpoint analyses were adjusted for relevant clinical covariates via generalized additive models or Cox proportional hazard model. Statistical significance was accepted at p less than 0.05. RESULTS: Patient characteristics and baseline hemoglobin concentrations (pre, 13.5 g/dL; post, 13.3 g/dL; p > 0.05) were comparable between groups. The group transfused based on the more restrictive hemoglobin threshold had lower hemoglobin concentrations before and after transfusion throughout acute hospitalization, received lower volumes of blood during operations (pre, 1012 mL; post, 824 mL; p < 0.001) and on days without surgical procedures (pre, 602 mL; post, 353 mL; p < 0.001), and had a lower mortality (pre, 8.0%; post, 3.9%; mortality hazard decline, 0.55 [45%]; p < 0.05). Both groups had a comparable incidence of physiological sepsis, though the more restrictive threshold group had a lower number of sepsis days per patient. CONCLUSION: More restrictive transfusion protocols are safe and efficacious in pediatric burn patients. The associated reduction of transfused blood may lessen medical risks of blood transfusion and lower economic burden. LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 30252778 TI - Biomechanical Analysis of Superior and Anterior Precontoured Plate Fixation Techniques for Neer Type II-A Clavicle Fractures. AB - OBJECTIVE: There are limited biomechanical data supporting the use of anterior or superior-lateral precontoured clavicle plates for the treatment of displaced Neer type II-A clavicle fractures. The objectives of this study were as follows: (a) compare noncontoured versus precontoured superior plating; (b) compare use of locking versus nonlocking screws in the lateral fragment for superior precontoured plates; and (c) compare superior versus anterior precontoured plates with locking lateral fragment screws. METHODS: The following constructs were tested on a synthetic clavicle model simulating a Neer type II-A fracture: (a) superior precontoured plate with locking (SUP-L, n = 6); (b) superior precontoured plate with nonlocking (SUP-NL, n = 8); (c) anterior precontoured plate with locking (ANT-L, n = 7); and (d) superior noncontoured locking compression plate (SUP-LCP, n = 6). Constructs were subjected to cyclical cantilever loads. Construct stiffness and survival (cycles to failure) were documented. Mann-Whitney U tests were performed for group-wise statistical comparison (alpha = 0.05) of data. RESULTS: The SUP-L construct was significantly stiffer than both SUP-LCP and ANT-L constructs (P < 0.02). The SUP-NL construct was stiffer than the SUP-L (P = 0.03) construct. Both SUP-L and ANT-L precontoured constructs survived longer than the noncontoured SUP-LCP construct (P < 0.022). The SUP-L construct survived longer than the SUP-NL (P = 0.013) and the ANT-L (P = 0.008) constructs. CONCLUSIONS: Superior precontoured plates yielded biomechanically superior constructs compared with anterior precontoured and superior noncontoured plates. Using locking screws in the lateral fragment over nonlocking screws may improve overall superior precontoured plate construct survivability. However, our results were limited to a synthetic biomechanical model and require further investigation to establish a clinical correlation. PMID- 30252780 TI - Participation in Pulmonary Rehabilitation by Veterans Health Administration and Medicare Beneficiaries After Hospitalization for Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Hospitalization with acute exacerbation of chronic obstructive pulmonary disease (COPD) is common and costly to the health care system. Pulmonary rehabilitation (PR) can improve symptom burden and morbidity associated with COPD. The use of PR among Medicare beneficiaries is poor, and the use by Veterans Health Administration (VHA) beneficiaries is unknown. We sought to determine whether participation in PR was similarly poor among eligible veterans compared with Medicare beneficiaries. METHODS: We performed a retrospective study using national VHA and Medicare data to determine the proportion of eligible patients who participated in PR after hospitalization for an acute exacerbation of COPD between January 2007 and December 2011. We also evaluated patient characteristics including demographic factors and comorbid medical history associated with participation. RESULTS: Over the 5-year study period, 485 (1.5%) of 32 856 VHA and 3199 (2.0%) of 158 137 Medicare beneficiaries hospitalized for COPD attended at least 1 session of PR. Among both VHA and Medicare beneficiaries, participation was higher in those who had had comorbid pneumonia or pulmonary hypertension and was lower in older patients. Although participation increased in both groups over time, it remained exceedingly low overall. CONCLUSION: Pulmonary rehabilitation is significantly underused in both the VHA and Medicare populations. Although comorbid pulmonary disease is associated with higher use, the proportion of eligible patients who participate remains extremely low. PMID- 30252779 TI - Dietary Micronutrient Intake of Participants in a "Partners Together in Health" Cardiac Rehabilitation Intervention. AB - PURPOSE: Current guidelines for cardiovascular health emphasize a "dietary pattern" approach that could be expected to increase intakes of micronutrients in addition to altering the macronutrient profile. However, the effect of interventions such as cardiac rehabilitation on the micronutrient quality of the diet has not been evaluated. Therefore, the goal of this study was to investigate changes in micronutrient intake of cardiac rehabilitation participants over time. METHODS: This was a secondary analysis of data from a randomized clinical trial that assessed the effects of the Partners Together in Health intervention on physical activity and healthy eating behaviors. The intake of 9 micronutrients important in cardiovascular health was assessed using 3-d food records. A micronutrient adequacy score was evaluated at 3 time points (baseline, 3 and 6 mo). Changes over time in micronutrient intake were assessed using a general linear model. RESULTS: Sixty-eight participants who were enrolled in the Partners Together in Health interventional trial completed the study. There was no significant difference in the mean micronutrient score at any time point. Intake of individual micronutrients did not improve over the 6-mo time frame with the exception of vitamin E, (8.7 mg vs 6.5 mg for at 6 vs 3 mo, P = .02). The proportion of participants with intakes meeting the Dietary Recommended Intake for each nutrient also remained the same over time. CONCLUSION: Although cardiac rehabilitation programs may be effective in altering the macronutrient composition, improvements to overall diet quality may be tempered by a lack of improvement in intake of micronutrients. PMID- 30252781 TI - Home-Based, Moderate-Intensity Exercise Training Using a Metronome Improves the Breathing Pattern and Oxygen Saturation During Exercise in Patients With COPD. AB - PURPOSE: One of the well-known but less-investigated effects of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) is the change in breathing pattern toward a more efficient one (higher tidal volume [VT], lower breathing frequency). Evidence suggests this change can be obtained only with supervised, high-intensity exercise training (ExTr). However, some patients either do not have such programs available or are unable to exercise at higher intensity. We evaluated the effects of a 12-wk, moderate-intensity, home monitored ExTr program using a metronome on the breathing pattern, oxygen saturation (SpO2), and dyspnea during exercise in patients with COPD. METHODS: Twenty-one patients with COPD (7 female, aged 64-85 yr) performed spirometry, incremental, and endurance walking tests (at 60% of maximal walking speed) on a treadmill before and after training. During the endurance test, patients were equipped with an instrument that continuously monitored ventilation ((Equation is included in full-text article.)E), breathing pattern, and SpO2. Patients trained at home for 12 wk, 30 min/d for at least 4 d/wk at moderate intensity. A metronome paced the walking speed. RESULTS: Sixteen patients completed the program. After training, a significant change was observed in breathing pattern (lower (Equation is included in full-text article.)E and (Equation is included in full-text article.)E/VT ratio; P < .001), a higher SpO2 (P < .001), and a lower dyspnea perception at the same work intensity (P < .01). The (Equation is included in full-text article.)E/VT ratio and SpO2 during exercise were significantly related (r = 0.56, P = .001). CONCLUSION: A change in breathing pattern towards more efficient ventilation can be obtained with a moderate, home monitored ExTr program with a pace that is controlled by a metronome. Decreased (Equation is included in full-text article.)E/VT was associated with an improved SpO2 during exercise. PMID- 30252782 TI - Physiological Responses and Prognostic Value of Common Exercise Testing Modalities in Idiopathic Pulmonary Fibrosis. AB - PURPOSE: This pilot study aimed to compare physiological responses between cycle cardiopulmonary exercise tests (CPETs) and 6-min walk tests (6MWTs) and to assess their prognostic value among patients with idiopathic pulmonary fibrosis (IPF). METHODS: Thirty-four patients with IPF (68 +/- 8 yr) underwent CPETs and 6MWTs and were followed up for 40 mo. Differences, levels of agreement, and relative risks for mortality were analyzed between measured and estimated peak responses for the 2 tests. RESULTS: Compared with the CPET, oxygen uptake (VO2), heart rate (HR), and the nadir of SpO2 were lower during the 6MWT, whereas work rate (WR) was higher. Mean differences were as follows: VO2 =-1.9 mL/kg/min, 95% CI, -1.1 to -2.7, P < .001; HR =-9 beats/min, 95% CI, -4 to -14, P = .002; SpO2 =-6%, 95% CI, -4 to -7, P < .001; and WR = 9 W/min, 95% CI, 3 to 16, P = .008. Interclass correlations ranged from 0.84 to 0.90 and both tests demonstrated prognostic value for mortality. CONCLUSIONS: Significant differences and variation in peak physiological responses were observed between cycle CPETs and 6MWTs in patients with IPF. However, good agreement was evident, suggesting that both tests provide value for clinical and research settings. Future studies should compare the physiological responses between treadmill CPETs and 6MWTs for prognostic utility in IPF. PMID- 30252784 TI - Greater Sleep Fragmentation Is Associated With Less Physical Activity in Adults With Cystic Fibrosis. AB - BACKGROUND: Sleep quality in people with cystic fibrosis (CF) is known to be poor, whereas participating in regular physical activity is associated with less decline in lung function (forced expiratory volume in 1 sec [FEV1]). The relationship between sleep quality and physical activity in people with CF is unknown. METHODS: Secondary analysis of sleep and activity data collected via actigraphy. Adults with CF in stable health, participating in a study of physical activity (including assessment of exercise capacity), completed 7 d of activity and sleep assessment (SenseWear Armband [SWA]; BodyMedia). Sleep characteristics were derived from accelerometer positional data and registration of sleep state by the SWA, determined by energy expenditure. RESULTS: Sleep and activity data were available for 47 participants [n = 28 male; mean +/- standard deviation age = 29 +/- 8 yr; median (IQR) FEV1 = 60 (50, 82) % predicted]. More fragmented sleep was associated with poorer exercise capacity (rs = -0.303, P = .04), less time spent in moderate-vigorous physical activity (rs = -0.337, P = .020), and poorer FEV1 (rs = -0.344, P = .018). Regression analysis showed that less fragmented sleep was an independent predictor of more total daily activity time (beta =-1.0, standard error [SE] of beta = .4, P = .02) and trended toward significance for more moderate-vigorous physical activity (beta =-.3, SE of beta =-.26, P = .08). Greater total sleep time and sleep efficiency were related to better exercise capacity and lung function (P < .05). CONCLUSION: This secondary analysis demonstrated a modest relationship between sleep parameters and physical activity and exercise capacity in adults with CF. Future studies of interventions to promote physical activity participation in this group should consider the relationship between sleep and activity performance. PMID- 30252783 TI - Sex- and Gender-Related Factors Associated With Cardiac Rehabilitation Enrollment: A SECONDARY ANALYSIS AMONG SYSTEMATICALLY REFERRED PATIENTS. AB - PURPOSE: To assess sex- and gender-related factors associated with cardiac rehabilitation (CR) enrollment following acute coronary syndrome among systematically referred patients. METHODS: This secondary analysis of a randomized controlled trial used an exploratory approach to examine the TRANSITion process for patients between the coronary care unit and CR (TRANSIT UC). The present analysis examined the relationship between sex- and gender related factors and CR enrollment in systematically referred women (n = 35) and men (n = 207). We performed chi and logistic regression analyses to identify statistically significant results. Using the Bonferroni method, a P value of .002 or less was considered a significant statistical result. A raw difference of 15% or more between enrolled and nonenrolled participants was considered a difference worthy of further investigation. RESULTS: Men who were regularly engaged in physical activity prior to their hospitalization and who lived near the CR center showed a statistically higher CR enrollment rate. In women and men, a radial entry site for percutaneous coronary intervention resulted in a clinically significant difference in favor of CR enrollment. In women, 3 sex-related and 9 gender-related variables were associated with a difference of 15% or more between enrolled and nonenrolled participants. CONCLUSION: Factors related to CR enrollment in women and men are suggested. As women keep showing a lower rate of CR enrolment, the investigation of these factors in a larger sample of patients may hold valuable insights to improve CR enrolment. PMID- 30252785 TI - The Effects of Cardiac Rehabilitation on Mortality and Morbidity in Women: A META ANALYSIS ATTEMPT. AB - PURPOSE: Cardiac rehabilitation (CR) is associated with significant reductions in mortality and morbidity, but few women are included in trials. Therefore, a meta analysis of the effects of CR in women is warranted. METHODS: Randomized controlled trials from recent systematic reviews that included women attending comprehensive CR and reporting the outcomes of mortality and morbidity (hospitalization, myocardial infarction, bypass surgery, percutaneous coronary intervention) were considered for inclusion. An updated search of the literature was performed from the end date of the last search, based on the Cochrane strategy. Authors were contacted to provide results on women where none were reported. RESULTS: On the basis of 2 recent systematic reviews, 80 trials were identified. Fifty (62.5%) were excluded, most commonly due to lack of inclusion of women (n = 18; 22.5%). One trial was identified through the search update. Of 31 potential trials meeting inclusion criteria, 1 reported results on women and many were old, and hence data by sex were no longer available. Ultimately, data for women were available in 2 trials. Therefore, it was deemed inappropriate to undertake this meta-analysis. CONCLUSIONS: This review corroborates the dearth of data on CR in women despite the fact that cardiovascular disease is the leading cause of death in women. Given the totality of evidence, including reductions in mortality and morbidity in nonrandomized studies, and evidence of benefit for other important outcomes such as functional capacity and quality of life, women should continue to be referred to CR. PMID- 30252786 TI - Comparison of Short-term Complication Rates Between Cephalomedullary Hip Screw Devices and Sliding Hip Screws: An Analysis of the National Surgical Quality Improvement Program Database. AB - BACKGROUND: The literature pertaining to the management of intertrochanteric hip fractures using cephalomedullary hip screws (CMHSs) and sliding hip screws (SHSs) has shown varying results. CMHS use has increased over time without validation of its superiority in the literature. METHODS: We conducted a retrospective cohort study using the American College of Surgeons National Quality Improvement Program database. Patients who had sustained a peritrochanteric hip fracture were identified. Short-term (<30 day) complications were identified with adjustments made for preoperative comorbidities. We also examined the relative percentages of CMHS and SHS surgeries over time. RESULTS: A total of 14,415 subjects met the inclusion criteria. Patients undergoing SHS surgery were generally healthier, having a lower American College of Surgeon class, preoperative bleeding, hypertension, pulmonary risk factors, congestive heart failure, and higher preoperative hematocrit. After adjusting for demographics and comorbidities, we noted a higher rate of 30-day mortality (odds ratio [OR] = 1.19; P = 0.024), bleeding (OR = 1.10; P = 0.007), pulmonary complications (OR = 1.19; P = 0.049), and clotting events (OR = 1.35; P = 0.035) in the CMHS group. We observed a higher rate of urinary tract infection (OR = 0.81; P = 0.023) and length of stay (1.0 days; P < 0.0001) in the SHS group. The overall percentage of SHS cases was 33% and trended lower over time. CONCLUSIONS: Although differences in complication subtypes and the overall complication rate were found, further multicenter, randomized controlled trials would be helpful in elucidating differences between the treatment groups. The popularity of the CMHS continues to increase over time. PMID- 30252787 TI - Bundled Payment Arrangements: Keys to Success. AB - The Centers for Medicare & Medicaid Services is committed to moving 50% of its fee-for-service care to value-based alternative payment models by 2018. The Comprehensive Care for Joint Replacement model is a mandatory agency program that bundles lower extremity joint arthroplasties into episodes of care that extend from the index admission to 90 days after discharge. This program, which began on April 1, 2016, includes many of the hospitals that perform total joint arthroplasties. As with other bundled payment arrangements, this model is built around seven principles that orthopaedic surgeons should be familiar with to maximize participation. PMID- 30252788 TI - Factors Predictive of Orthopaedic In-training Examination Performance and Research Productivity Among Orthopaedic Residents. AB - INTRODUCTION: Selection of qualified candidates for orthopaedic residency is necessary for growth and innovation. The purpose of this study was to determine predictors of Orthopaedic In-training Exam (OITE) performance and research productivity. METHODS: A survey was distributed to 13 residency programs collecting demographics, United States Medical Licensing Examination (USMLE) and OITE scores, and authored publications. Associations between preresidency qualifications and OITE scores and publications were determined. RESULTS: A total of 274 of 294 surveys were returned (93.2%). We found a positive correlation between USMLE step 1 and 2 scores with recent OITE percentile (P < 0.001). Preresidency authorship (P < 0.001) and postgraduate training year (P < 0.001) were independent predictors of authorship during residency, whereas USMLE step 1 score was not (P = 0.094). CONCLUSION: Candidates who perform well on the USMLE are likely to perform well on the OITE, whereas those with greater authored publications are likely to continue research during residency. PMID- 30252789 TI - Elective Total Shoulder Arthroplasty in Octogenarians: A Safe Procedure. AB - INTRODUCTION: There has been a lack of studies investigating the perioperative course of total shoulder arthroplasty (TSA) performed in the increasingly octogenarian (>=80 years old) population in a large sample size. The purpose of this study was to compare perioperative complications between primary TSA performed in octogenarians and that performed in younger populations (<70 and 70 to 79 years old) from the National Surgical Quality Improvement Program database. METHODS: Patients who underwent primary TSA between January 2005 and December 2015 were identified from the National Surgical Quality Improvement Program database and stratified into three age groups: <70, 70 to 79, and >=80 years old. Patient characteristics and comorbidities were compared between the three groups. Propensity score-matched comparisons were then performed for length of hospital stay, 30-day perioperative complications, and readmissions. Risk factors and reasons for readmission in the octogenarians were characterized. RESULTS: This study included 3,007 patients who were <70 years old, 2,155 patients who were 70 to 79 years old, and 900 octogenarian patients. Statistical analysis was carried out after matching for propensity score. While no significant differences in perioperative complications were observed between the octogenarians and 70- to 79 year-olds, significantly higher rates of readmission (4.2% versus 1.7%; P = 0.002), pneumonia (1.1% versus 0.0%; P = 0.002), and urinary tract infection (1.8% versus 0.2%; P = 0.001) were found in the octogenarians compared with <70 year-olds. In addition, the octogenarians also had a slightly longer length of hospital stay compared with the younger populations (0.6 days longer than <70 year-olds and 0.4 days longer than 70- to 79-year-olds; both P < 0.001). CONCLUSION: These data suggest that primary TSA can safely be considered for octogenarians with only mildly increased morbidities. However, greater preoperative optimization or post-discharge care for octogenarians may be warranted to reduce the rates of readmission. PMID- 30252790 TI - The Spinal Structure and Lung Function Relationship in an Untreated Nonambulatory Myelomeningocele Group of Patients. AB - INTRODUCTION: The relationship between spinal structure and respiratory function has been coined as thoracic insufficiency syndrome and is defined as the inability of the thorax to support normal respiratory function or lung growth. Little is known about what supports this relationship in untreated nonambulatory myelomeningocele patients. METHODS: A prospective cross-sectional study of nonambulatory myelodysplasia patients was performed. Anatomic, radiographic, and functional parameters were evaluated to validate the respiratory-spinal structure relationship. Thirty-one patients diagnosed with nonambulatory myelomeningocele fulfilled the inclusion criteria. RESULTS: The imaging study confirmed the spinal deformity. Lung functions measured in this patient population describe reduced lung volumes by CT lung volume reconstruction, reduced vital capacity by spirometry, and reduced total lung capacity by the nitrogen washout method. Together, these findings suggest moderate restrictive respiratory disease. The blood count study did not show evidence of anemia or other blood disturbances. Echocardiogram analysis did not show pulmonary hypertension in any patient. CONCLUSION: The data validate the relationship between spinal structure and lung function. However, there is no simple structural feature that could help to diagnose thoracic insufficiency syndrome. Thus, the diagnosis continues to be based on a combination of clinical findings and radiological and respiratory function evaluations. LEVEL OF EVIDENCE: Level III. PMID- 30252791 TI - World Digestive Health Day 2017 Inflammatory Bowel Disease. PMID- 30252792 TI - Surgical site infection following elective nonspinal paediatric orthopaedic surgery: a prospective review. AB - The aim of this study was to determine the rate of surgical site infection (SSI) and the factors that predispose to it in children undergoing nonspinal orthopaedic surgery. Over a 6-month period, 326 children who underwent 334 nonspinal elective orthopaedic surgical procedures were prospectively reviewed for the development of surgical site infections. A total of 14 sites became infected, with an overall infection rate of 4.19%. All the infections were superficial, and the only causative organism detected was Staphylococcus aureus. Operating times longer than 1 h and surgical wounds greater than 10 cm in length were positively associated with SSIs. Although there were differences between male and females, type of admission, the use of prophylactic antibiotics, degree of wound contamination and the grades of surgeons, these differences were not statistically significant. The results of this prospective study provide valuable information that was not previously available to the practicing paediatric orthopaedic surgeon. PMID- 30252793 TI - Missed proximal radioulnar joint translocation with ulnar nerve entrapment: an unusual injury in a child. AB - Traumatic elbow dislocation in a child is rare, and it is usually associated with fractures. Simultaneous proximal radioulnar joint (PRUJ) translocation with ulnar nerve palsy is even rarer. We report an unusual case of a missed PRUJ translocation with ulnar nerve entrapment in a 10-year-old child. The key to diagnosing the translocation is the position of the proximal radius, which lies medial to the ulna. This was treated by open reduction and release of the entrapped nerve. The ulnar nerve palsy recovered fully at the 1-year follow-up. Although PRUJ translocation with ulnar nerve entrapment is a rare injury, a successful outcome is possible with timely open reduction and release of the ulnar nerve. PMID- 30252794 TI - Proposal of an innovative casting technique for correction of clubfoot according to Ponseti method: a pilot study. AB - A total of 70 clubfeet were treated by a posterior above-knee cast (pressure points on the talus and on the first metatarsal) according to Ponseti method. At diagnosis, average Pirani score was 4.44, and mean time of treatment was 50.32 days. Overall, 27 (38.6%) clubfeet had only conservative treatment (5.29 casts) and 43 (61.4%) also had Achilles tenotomy (6.38 casts). At the end 61/70 feet (87,14%) had Pirani score 0; 10/70 feet (5,71%) had Pirani score 0,5 . The Pirani score gain/cast was beta=-0.432 (P<0.001). This new casting technique is safe and effective at avoiding some adverse issues related to the removal of the conventional cast. PMID- 30252795 TI - Femoral trochlea does not remodel after patellar stabilization in children older than 10 years of age. AB - : Trochlear dysplasia is a major risk factor for patellar instability. It has been sparsely reported that the trochlea can remodel when patellar stabilization is performed in skeletally immature patients before the age of 10 years. It is not known whether trochlea can remodel significantly after the age of 10 years. The purpose of the study was to evaluate trochlear remodeling in skeletally immature patients after patellar stabilization surgery, with a focus on children older than 10 years of age. In a retrospective study, knee MRI of 21 patients who had undergone patellar stabilization surgery, were evaluated. Twenty of these 21 patients were older than 10 years of age at time of surgery. The measurements of cartilaginous and bony sulcus angles, trochlear depth, and cartilaginous trochlear bump were compared between preoperative and postoperative MRI, using paired t-tests. In 20 patients older than 10 years of age, the mean cartilaginous sulcus angle change between preoperative and postoperative axial MRI was not significant (2.2 degrees +/-7.9 degrees , P=0.6). The mean change in the bony sulcus angle value was not significant (3.6 degrees +/-6.8 degrees , P=0.07). Similarly, there was no significant change in trochlear depth (P=0.8), or size of the trochlear bump (P=0.1). For one patient under 10 years of age at the time of surgery, there was a 21 degrees and a 15 degrees improvement in cartilaginous and bony sulcus angle, respectively. There were no significant changes in the trochlear parameters and trochlear remodeling in patients older than 10 years of age. Patellar stabilization at a younger age (<10 years), may allow for trochlear remodeling. LEVEL OF EVIDENCE: Level IV, case series. PMID- 30252796 TI - Standardized traction versus side-bending radiographs in adolescent idiopathic scoliosis: a preliminary study. AB - The aim of this study was to develop a new type of preoperative flexibility test for adolescent idiopathic scoliosis. The objective was to develop a test that was standardized and allow for the measurement of in-vivo forces required for curve correction. It was undertaken to compare the results of this new test with side bending radiographs. Various preoperative radiographic techniques have been used to assess flexibility in patients awaiting scoliosis correction surgery. The major limitation of these investigations is a lack of standardization. The side bending radiograph is the current gold standard, against which this new test was compared. A prospective clinical study was conducted. An axial traction force of 1.5 times body weight was applied through the spine of patients using a traction jig. Posteroanterior, side-bending and traction radiographs were taken. Cobb angle and apical vertebra axial rotation measurements were obtained. Flexibility indices in the coronal and axial planes were calculated. Cobb angle reduction and axial derotation were compared between the two methods. A total of 15 (12 female and three male) patients, with a mean age of 15.1 years, were assessed. The mean force imparted on traction films was 800 N. The major curve Cobb angle measurements were 60.4 degrees on standing posteroanterior radiograph, 52.7 degrees on side-bend film and 44.5 degrees on traction at 1.5 times body weight. The corresponding apical vertebrae axial rotations were 23.9 degrees , 22.2 degrees and 16.5 degrees , respectively. The mean Cobb angle reduction was 15.9 for traction and 7.7 for side-bend radiographs (P<0.0001). The mean apical vertebra derotation was 7.4 for traction and 1.7 degrees for side-bend radiographs (P=0.0083). The mean flexibility index in the coronal plane was 0.479. The mean flexibility index in the axial plane was 0.240. Our novel method of traction radiographs at 1.5 times body weight is a safe and reproducible method of assessing curve flexibility in patients with scoliosis. This method achieves a larger Cobb angle and axial derotation when compared with side-bending radiographs. PMID- 30252798 TI - Blunting of the Anterior Tympanomeatal Angle Following Tympanoplasty. PMID- 30252797 TI - Environmental Sound Awareness in Experienced Cochlear Implant Users and Cochlear Implant Candidates. AB - OBJECTIVE: To determine if postlingually deaf adult cochlear implant (CI) users have better environmental sound awareness (ESA) compared with adult patients eligible for CIs who have not yet undergone implantation. STUDY DESIGN: Cross sectional cohort study. SETTING: Tertiary referral center. PATIENTS: A group of 39 postlingually deaf adult patients who are experienced CI users (ECI), and a group of 20 postlingually deaf adult patients who are cochlear implant candidates (CIC) awaiting implantation. INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURE: Environmental sound awareness as measured by accuracy (percent correct) using the computerized, Familiar Environmental Sounds Test-Identification (FEST I). RESULTS: There was no significant difference between ESA in our sample of ECI users versus CIC patients. The ECI users scored an average FEST-I accuracy of 59.9% (SD 14.3). In comparison, the CICs had an average FEST-I accuracy of 54.7% (SD 26.4). This difference was not statistically significant. CONCLUSIONS: Our findings suggest that, despite the commonly held notion that improved ESA may be a benefit of cochlear implantation, our sample of ECI users did not demonstrate superior performance compared with CICs. PMID- 30252800 TI - The Cleating Stitch: An Adjunctive Technique for Percutaneous and Revision Osseointegration Screws. AB - OBJECTIVE: The bone anchored hearing aid (BAHA) has become a widely used and successful option in treatment of conductive and mixed hearing loss, and single sided deafness. Despite improvements in technique and cosmesis, complications remain that can result in implant revision or removal. Herein we describe a unique adjunctive technique, the cleating stitch, in placement of osseointegration screws and examine its impact on complication rates. STUDY DESIGN: Retrospective case review. SETTING: Tertiary academic medical center. PATIENTS: A total of 66 implants in 65 patients (35 men, 30 women) with an average age of 54 years (15-81 yr). Average follow up 10.8 months. INTERVENTION: All patients underwent BAHA implant placement by a single surgeon between April 2012 and June 2017 using the linear incision or punch techniques with soft tissue reduction and placement of a cleating stitch. MAIN OUTCOME MEASURE: Main outcome measures include rates of revision surgery, overgrowth, extrusion, and Holgers reaction >=2. Secondary outcome measures include associations between main outcome measures and outlying factors (obesity, smoking, diabetes mellitus, coronary artery disease, age). RESULTS: The overall rate of revision was 3%, rate of overgrowth 1.5%, rate of extrusion 1.5%, and Holgers reaction >=2 10.6%. Overgrowth and extrusion both required revision. Older age was associated with decreased risk of Holgers reaction >=2 (p = 0.03) with a hazard ratio of 0.95 (confidence interval 0.9-1.0). There were no other statistically significant associations between primary outcome measures and outlying factors. CONCLUSION: The cleating stitch is an effective adjunctive technique in placement of osseointegration screws associated with low rates of overgrowth and overall revision surgery. PMID- 30252799 TI - Otologic Outcomes After Blast Injury: The Brussels Bombing Experience. AB - OBJECTIVE: After the suicide bombings in Brussels on March 22, 2016, many victims consulted our emergency department with otologic symptoms. The aim of this study was to report the otologic morbidity and outcome after acute acoustic trauma in these patients. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center. PATIENTS: Patients reporting subjective hearing loss, tinnitus, feeling of pressure in the ear, vertigo or hyperacusis after witnessing these bombings were included. INTERVENTION: All included patients were treated with systemic corticosteroid therapy, concurrent hyperbaric oxygen therapy (HBOT) was advised to each and every included patient. MAIN OUTCOME MEASURES: Participants underwent a routine otologic work-up including otoscopy, liminal audiometry, and subjective outcome measures related to tinnitus at baseline and at follow-up. Primary outcome was to describe the otologic morbidity after acute acoustic trauma (AAT). Secondary outcome was to evaluate the recovery of hearing loss, subjective symptoms, and tympanic membrane perforations. RESULTS: Fifty-six patients were included in our population with an average age of 27 +/- 13 years, and 46% women/54% men. Thirty-two patients reported subjective hearing loss, 45 reported tinnitus, 45 reported a feeling of pressure in the ear, 2 patients experienced vertigo, and 18 patients reported hyperacusis. Otoscopic examination revealed three tympanic membrane perforation (TMP). Sensorineural hearing loss (SNHL) was observed in 41% (n = 23) and mixed hearing loss in 3.6% (n = 2). No conductive hearing loss (CHL) was observed. Follow-up was obtained in 76.8%, with the last follow-up available at 47 +/- 74 days. Two perforations closed spontaneously, while one persistent perforation was successfully reconstructed with complete air-bone gap closure. There was a significant improvement in subjective symptoms. SNHL improvement was observed in 52.6% (10/19), mixed hearing loss improved in both patients. Improvement in hearing thresholds was seen in patients treated with steroids and in those treated with steroids and HBOT, there was no significant difference in the degree of improvement between these two groups. CONCLUSIONS: Blast-related otologic injuries have a significant impact on morbidity. Comprehensive otologic evaluation and state-of-the-art treatment may lead to a significant improvement in symptoms and hearing loss. PMID- 30252801 TI - Nystagmus Findings and Hearing Recovery in Idiopathic Sudden Sensorineural Hearing Loss Without Dizziness. AB - OBJECTIVES: To investigate the incidence of nystagmus in patients with sudden sensorineural hearing loss (SSNHL) without dizziness, and to evaluate the correlation of the presence of nystagmus with hearing recovery in those patients. STUDY DESIGN: Retrospective study. SETTING: Tertiary referral academic medical center. PATIENTS: Thirty-eight patients with SSNHL who did not complained of dizziness were enrolled. MAIN OUTCOME MEASURE: The presence of nystagmus was evaluated by recording eye movements, and if present, nystagmus was classified as direction-fixed or positional nystagmus. Vestibular function tests were performed, including caloric test. RESULTS: Of 33 idiopathic SSNHL patients without dizziness, nystagmus was observed in 22 patients (67%), of which 14 patients exhibited direction-fixed nystagmus, and 8 patients exhibited direction changing nystagmus. Among the 14 patients with direction-fixed nystagmus, 9 displayed the paretic type, and 5 displayed the irritative type. Direction changing nystagmus (n = 8) was defined as that in which the direction of nystagmus was changed in a supine head-roll test, and the geotropic type and apogeotropic type were observed in two and six patients, respectively. The mean initial pure tone threshold was 58.2 +/- 28.1 dB and 57.3 +/- 20.0 dB in SSNHL patients with and without nystagmus, respectively, which was not significantly different (p = 0.925). When hearing improvement was compared according to the presence of nystagmus, 39% (8 of 21) of patients with nystagmus were found to belong in the good prognosis group, and 72% (8 of 11) of patients without nystagmus were found to belong in the good prognosis group, which showed marginal statistical significance (p = 0.063). CONCLUSION: Nystagmus was observed in two thirds of idiopathic SSNHL patients without dizziness, and the pattern of nystagmus was either direction fixed or direction changing. Because hearing recovery was worse in patients with nystagmus than those without it, the diagnosis of nystagmus, even in SSNHL patients without dizziness, may be important in evaluating the hearing prognosis. PMID- 30252802 TI - Adaptation and translation of the menopause-specific Utian Quality of Life (UQOL) scale to Yoruba language using middle-aged women attending a clinic in Nigeria. AB - OBJECTIVE: The main objective of the study is to translate and adapt the menopause-specific Utian Quality of Life (UQOL) scale to Yoruba, an indigenous Nigerian language, using middle-aged women attending a Family Medicine clinic in Nigeria. METHODS: A total of 322 middle-aged Nigerian women at various menopausal stages were recruited for the study. Their menopausal status was categorized using the Monash Women's Health Program Menopausal Staging Algorithm into pre-, peri-, and postmenopausal groups. The UQOL Yoruba version (YUQOL), Menopause Rating Scale (MRS), and a semistructured sociodemographic questionnaire were interviewer-administered to the women. The collected data were analyzed using IBM SPSS version 21 software. RESULTS: The overall scale and the four subscales of YUQOL all had acceptable internal consistency scores; they also demonstrated good construct and criterion validities, except the YUQOL sexual subscale had poor convergent validity (average variance extracted = 0.23). CONCLUSIONS: This study has validated the YUQOL as a psychometrically sound research instrument for measuring menopause-specific QOL among women undergoing menopausal transition. Its sexual subscale would, however, need to be further tested, preferably in sexually active menopausal women to fully confirm its true psychometric property. PMID- 30252803 TI - Menopausal symptoms in different substages of perimenopause and their relationships with social support and resilience. AB - OBJECTIVE: This study is designed to measure the prevalence and severity of menopausal symptoms at different substages of perimenopause, as well as the relationships of these symptoms with social support and resilience in perimenopausal women. METHODS: A convenience sample of 732 perimenopausal women was recruited from 3 communities of Jinan City, Shandong Province, China, between March 2015 and March 2017. The participants completed the Menopause Rating Scale, the 10-item Connor-Davidson Resilience Scale, the Perceived Social Support Scale, and a questionnaire regarding sociodemographic information. RESULTS: Of all perimenopausal women surveyed, 76.4% reported menopausal symptoms. The prevalence and severity of menopausal symptoms differed significantly by different substages of perimenopause (all P < 0.001); the severity of menopausal symptoms was the least during the early menopausal transition substage and the most during the early postmenopausal substage. Multivariable-adjusted linear regression showed that family support (beta = -0.169 to -0.240, P < 0.001) and resilience (beta = 0.140 to -0.202, P < 0.001) were negatively associated with the total and subscale scores of the Menopause Rating Scale, and higher family support and resilience had fewer menopausal symptoms. CONCLUSIONS: The present findings suggest that menopausal symptoms vary across different substages of perimenopause. Furthermore, higher family support and resilience were significantly associated with fewer menopausal symptoms, which might be helpful for medical staff to identify these symptoms and seek appropriate preventive intervention. PMID- 30252805 TI - Fulminant Intracranial Hypertension Managed With Temporary Lumbar Drain. PMID- 30252804 TI - Microablative fractional CO2 laser for the genitourinary syndrome of menopause: up to 12-month results. AB - OBJECTIVE: The aim of this study is to assess the efficacy of microablative fractional CO2 laser therapy for genitourinary syndrome of menopause (GSM) management, when three, four, or five laser therapies were applied in a follow-up period of 12 months. METHODS: Retrospective study evaluating GSM symptoms at baseline, and 1, 3, 6, and 12 months after last laser therapy. Visual analog scale, International Consultation on Incontinence Questionnaires- Female Urinary Tract Symptoms, International Consultation on Incontinence Questionnaires-Urinary Incontinence Short Form, Urogenital Distress Inventory-6, and Female Sexual Function Index were used for assessment of GSM symptoms' intensity or bothering and parameters of sexual function. RESULTS: Overall, 94 women were included (35, 35, and 24 received three, four, and five therapies, respectively). All GSM symptoms improved statistically significantly. Intensity of dyspareunia and dryness decreased from 9 (5-10) (median [minimum-maximum]) and 8 (0-10) at baseline to 0 (0-6) and 0 (0-8), 1 month after last laser therapy (all P < 0.001), respectively. FSFI and frequency of sexual intercourse increased from 10.8 (2-26.9) and 1 (0-8) at baseline to 27.8 (15.2-35.4) and 4 (2-8) 1 month after last laser therapy (all P < 0.001), respectively. The positive laser effect remained unchanged throughout the 12 months of follow-up. The same pattern was followed for symptom-free rates. Four or five laser therapies may be superior in lowering the intensity of GSM symptoms in comparison to three laser therapies, in short and long-term follow-up. Differences between four and five laser therapies were not found. CONCLUSIONS: Laser therapy may provide significant improvement and/or absence of GSM symptoms up to 12 months follow-up, irrespectively to the number of laser therapies applied. Symptoms intensity 1 month after last laser therapy may be indicative of GSM symptoms intensity at 12 months. One month after third laser therapy is the critical time to decide whether treatment extension should be offered. PMID- 30252806 TI - The Functional Influence of Breast Implant Outer Shell Morphology on Bacterial Attachment and Growth. AB - BACKGROUND: The introduction of texture to the outer shell of breast implants was aimed at increasing tissue incorporation and reducing capsular contracture. It has also been shown that textured surfaces promote a higher growth of bacteria and are linked to the development of breast implant-associated anaplastic large cell lymphoma. METHODS: The authors aimed to measure the surface area and surface roughness of 11 available implants. In addition, the authors aimed to subject these implant shells to an in vitro bacterial attachment assay with four bacterial pathogens (Staphylococcus epidermidis, S. aureus, Pseudomonas aeruginosa, and Ralstonia pickettii) and study the relationship among surface area, surface roughness, and bacterial growth. RESULTS: Surface area measurement showed grouping of implants into high, intermediate, low, and minimal. Surface roughness showed a correlation with surface area. The in vitro assay showed a significant linear relationship between surface area and bacterial attachment/growth. The high surface area/roughness implant texture grew significantly more bacteria at 24 hours, whereas the minimal surface area/roughness implant textures grew significantly fewer bacteria of all types at 24 hours. For implants with intermediate and low surface areas, some species differences were observed, indicating possible affinity of specific bacterial species to surface morphology. CONCLUSIONS: Implant shells should be reclassified using surface area/roughness into four categories (high, intermediate, low, and minimal). This classification is superior to the use of descriptive terms such as macrotexture, microtexture, and nanotexture, which are not well correlated with objective measurement and/or functional outcomes. PMID- 30252807 TI - Current Approaches to Prepectoral Breast Reconstruction. AB - Prepectoral prosthetic breast reconstruction has become an acceptable option for women following mastectomy. Benefits include no animation deformity, absence of pectoralis major muscle spasm, and less pain and discomfort. Important aspects of prepectoral reconstruction include working with breast surgeons that are adept at performing an optimal mastectomy. Tissue perfusion and reasonable thickness of the mastectomy are critical components of success. Tissue necrosis, infection, and delayed healing can lead to reconstructive failure. Given the risks and benefits of this procedure, questions regarding indications, patient selection, and specific details related to technique remain because there is no consensus. Whether it is safe to perform prepectoral reconstruction in obese or previously irradiated patients is controversial. The use of acellular dermal matrix is common but not universal. The amount of acellular dermal matrix used is variable, with success being demonstrated with the partial and total wrap techniques. Device selection can vary but is critical in the prepectoral setting. Postoperative care and the management of adverse events are important to understand and can impact surgical and aesthetic outcomes. This article provides current approaches, recommendations, and an algorithm for prepectoral breast reconstruction with an emphasis on patient selection, immediate versus delayed prepectoral reconstruction, specific technical details, and postoperative management. PMID- 30252808 TI - The Public Face of Rhinoplasty: Impact on Perceived Attractiveness and Personality. AB - BACKGROUND: The authors assess the impact of rhinoplasty on public perception of a patient's appearance and personality. METHODS: A survey was created using standardized before-and-after photographs of 10 Caucasian women who had undergone primary rhinoplasty. Photographs of two additional women who had not undergone facial surgery were randomly included as controls, for a total of 12 survey items. Preoperative and postoperative photographs were placed side by side. The survey was administered by means of crowd-sourcing. Respondents were asked to evaluate which photograph better represented 11 traits of appearance or personality, according to a seven-point Likert scale. A score of 1 meant the preoperative photograph was much better, 7 meant the postoperative photograph was much better, and 4 meant no difference. T tests and analyses of variance were used to evaluate rating changes for each trait and differences between demographic groups. RESULTS: There were 264 responses received. Averaged scores across the 10 survey patients produced a value for each appearance or personality trait. In 10 of 11 categories (i.e., symmetry, youthfulness, facial harmony, likeability, trustworthiness, confidence, femininity, attractiveness, approachability, and intelligence), the postoperative photograph was significantly favorable compared with the preoperative photograph (p < 0.00001). The preoperative photograph was rated higher only in aggressiveness (p < 0.001). The same scores were calculated for the controls; no significant difference in any category was seen except confidence, where the right image was viewed as more confident (mean, 4.19; p < 0.005). CONCLUSION: Aesthetic rhinoplasty improves the public perception of a person's appearance and personality in multiple aspects. PMID- 30252809 TI - Discussion: The Public Face of Rhinoplasty: Impact on Perceived Attractiveness and Personality. PMID- 30252811 TI - Defining the Aesthetic Units of the Male Chest and How They Relate to Gynecomastia Based on 635 Patients. AB - Gynecomastia awareness and treatment have increased significantly. Treatment of gynecomastia is now one of the most popular procedures requested by men. There are many gynecomastia classification systems that have been described. The usefulness of these classifications in the diagnosis and treatment of modern gynecomastia is unknown and has fostered confusion among surgeons and patients. This article elucidates the topographic pattern consistently seen in gynecomastia patients and relates this to the diagnosis and treatment of gynecomastia. The proposed gynecomastia zone classification is a simple and objective method to clinically describe gynecomastia and direct appropriate treatment. PMID- 30252810 TI - Postoperative Ketorolac in Breast and Body Contouring Procedures: A Nationwide Claims Analysis. AB - BACKGROUND: Nonsteroidal antiinflammatory drugs are useful alternatives to narcotics for analgesia. However, concerns remain regarding their safety. The authors evaluated ketorolac use and complications. We hypothesized that no association between ketorolac and morbidity exists in patients undergoing body contouring. METHODS: Truven MarketScan claims database was analyzed for patients undergoing breast and body contouring surgery. Patients selected received ketorolac and were enrolled a minimum of 90 days. The authors performed a multivariable logistic regression to calculate risk of morbidity, adjusting for clinical and sociodemographic factors. RESULTS: Among the 106,279 patients enrolled, 4924 (4.6 percent) received postoperative ketorolac. In multivariable regression analysis, ketorolac was not associated with hematoma (OR, 1.20; 95 percent CI, 0.99 to 1.46; p > 0.05). There was an increased rate of reoperation within 72 hours (OR, 1.22; 95 percent CI, 1.00 to 1.49; p < 0.05; number needed to harm, 262 patients). Ketorolac was associated with fewer readmissions (OR, 0.76; 95 percent CI, 0.62 to 0.93; p < 0.05; number needed to treat, 87 patients), with a reduction in the rate of pain as a readmission diagnosis (0.6 percent versus 4.3 percent; p = 0.021). Ketorolac was associated with seroma, but this association may not be causal (OR, 1.28; 95 percent CI, 1.05 to 1.57; p < 0.05; number needed to harm, 247 patients). Ketorolac provided an estimated savings of $157 per patient. CONCLUSIONS: The benefits of ketorolac likely outweigh the risks after surgery. Absolute differences in reoperation rates were low, and improved rates of hospital admission impact cost savings. The authors advocate postoperative ketorolac once the wound is hemostatic. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 30252812 TI - Discussion: Defining the Aesthetic Units of the Male Chest and How They Relate to Gynecomastia Based on 635 Patients. PMID- 30252813 TI - Influence of Massive Weight Loss on the Perception of Facial Age: The Facial Age Perceptions Cohort. AB - BACKGROUND: Knowledge is scarce about the role of massive weight loss in facial age perception. The aim of this study was to verify whether there is a change in the perception of facial age when comparing people with morbid obesity before surgery and 1 year after the procedure. METHODS: Patients with morbid obesity have been analyzed, through a prospective cohort, before and 1 year after undergoing bariatric surgery. Seven plastic surgeons estimated the age of each subject. RESULTS: Seventy patients participated. Five patients were excluded because of the exclusion criteria. There was no drop-off among the subjects participating in this cohort. Before surgery, the mean facial age perception was 40.8 years; after surgery, mean facial age perception was 43.7 years (95 percent CI, 0.58 to 2.95; p = 0.004). Men older than 40 years, with a preoperative body mass index between 40 and 49.9 kg/m, weight greater than 127.65 kg before surgery, and percentage of excess weight lost greater than 75.13 percent demonstrated greater perceived facial aging. CONCLUSION: Massive weight loss appears to produce facial aging. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 30252814 TI - Autologous Fat Grafting to the Chin: A Useful Adjunct in Complete Aesthetic Facial Rejuvenation. AB - The chin makes up the central unit of the face and neck, and is a significant factor in facial harmony and aesthetics. Historically, correction of microgenia required surgical intervention with a sliding genioplasty, or placement of a permanent implant. However, these techniques require more extensive surgical intervention, prolonged downtime, with higher costs and complications. Furthermore, chin rhytides and descent of chin fat lead to an aged appearance of the chin and lower face that is difficult to correct with a chin implant alone. Autologous fat grafting in facial rejuvenation has expanded in its application and can serve as an effective technique to correct and enhance chin aesthetics, including lateral chin hollowing, asymmetry, mild microgenia, and correction of deep labiomental sulcus or a bifid chin. This article and accompanying video demonstrate the authors' technique for chin augmentation and refinement with autologous fat. PMID- 30252815 TI - Discussion: Facial Implants: Controversies and Criticism. A Comprehensive Review of the Current Literature. PMID- 30252816 TI - Discussion: Incidents of Mandibular Distraction Osteogenesis for Hemifacial Microsomia. PMID- 30252817 TI - Discussion: Long-Term Results in Isolated Metopic Synostosis: The Oxford Experience over 22 Years. PMID- 30252818 TI - Surgical Treatment of Migraine Headache: Back to the Future. AB - Understanding the history and evolution of ideas is key to developing an understanding of complex phenomena and is the foundation for surgical innovation. This historical review on migraine surgery takes us back to the beginnings of interventional management for migraine centuries ago, and reflects on present practices to highlight how far we have come. From Al-Zahrawi and Ambroise Pare to Bahman Guyuron, two common themes of the past and present have emerged in the treatment of migraine headache. Extracranial treatment of both nerves and vessels is being performed and analyzed, with no consensus among current practitioners as to which structure is involved. Knowledge of past theories and new insights will help guide our efforts in the future. One thing is clear: Where we are going, there are no roads. At least not yet. PMID- 30252819 TI - Discussion: Anatomical Basis of the Gastroepiploic Vascularized Lymph Node Transfer: A Radiographic Evaluation Using Computed Tomographic Angiography. PMID- 30252820 TI - Inferior External Pudendal Artery Anastomosis: Additional Approach to Prevent Skin Necrosis in Replanted Penis. AB - BACKGROUND: Microsurgical anastomosis of the dorsal artery of the penis either with or without anastomosis of the cavernosal artery is the preferred technique for penile replantation. However, postoperative penile skin necrosis is commonly reported with this technique. This study aimed to characterize the anatomy of the vascular supply of the penis pertinent to penile replantation surgery and to report a successful case of penile replantation without postoperative necrosis using anastomosis of the inferior external pudendal artery. METHODS: The authors dissected 15 penises of fresh cadavers under acrylic dye injection by means of the inferior external pudendal and dorsal arteries of the penis to identify vascular anastomoses between arteries supplying the penis and to measure other parameters of the arteries. RESULTS: Mean diameters at the base of the penis of the inferior external pudendal, dorsal, and cavernosal arteries were 0.94, 1.43, and 0.80 mm, respectively. Penile skin is mainly supplied by the inferior external pudendal artery under three patterns with anastomoses across the midline. Preputial skin receives additional blood supply from perforators of the dorsal artery without visible anastomosis between the perforators and the inferior external pudendal artery. Deep structures receive blood supply from the dorsal, cavernosal, and urethral arteries, with visible anastomoses between the arteries. In a patient with amputated penis, the inferior external pudendal artery diameter was 0.7 mm, which was sufficient for microsurgical anastomosis. No postoperative necrosis developed, and patency of the inferior external pudendal artery was confirmed with duplex ultrasound. CONCLUSION: The diameter of the inferior external pudendal artery at the base and midshaft of the penis is sufficiently large for microsurgical anastomosis, and additional vascular anastomosis of at least one inferior external pudendal artery may help to prevent postoperative penile skin necrosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 30252821 TI - Safety in Hand Surgery: Eliminating Wrong-Site Surgery. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand the definition of wrong-site surgery and what it may encompass. 2. State the causes of wrong-site hand surgery. 3. Give examples of initiatives used to prevent wrong-site surgery. 4. Describe a process to minimize the risk of performing wrong-site surgery. SUMMARY: Wrong-site surgery remains a problem in our ever-evolving culture of surgical safety, and hand surgeons are at particularly high risk. Broadly speaking, wrong-site surgery is a procedure performed at an incorrect anatomical site. In hand surgery, this includes errors in laterality, wrong digit(s), wrong procedure(s), or even a failure to complete all indicated procedures. This article examines the scope of this safety issue, the current challenges to preventing wrong-site surgery, and the authors' proposed solutions to eliminating wrong-site surgery and establishing a culture of safety in hand surgery. PMID- 30252822 TI - The Price of Medical Tourism: The Legal Implications of Surgery Abroad. AB - Medical tourism, or traveling abroad to obtain medical services, has evolved into a global health care phenomenon, with over 15 million U.S. patients each year seeking medical care internationally, representing a $50 billion dollar industry in 2017. Speculation and media fascination about the growing industry, diverse destinations, and rationale behind the medical tourists is rampant; however, the legal implications of tourism medicine, particularly when it goes wrong, are often unclear. On the international stage, accreditation agencies are limited in scope and practice, legal jurisdiction is difficult to establish, and the enforcement of rulings is nearly impossible. Patients seeking tourism medicine have little legal recourse and shoulder all the legal burden. PMID- 30252823 TI - Treatment of Infected Wounds in the Age of Antimicrobial Resistance: Contemporary Alternative Therapeutic Options. AB - As antibiotic resistance increases and antimicrobial options diminish, there is a pressing need to identify and develop new and/or alternative (non-antimicrobial based) wound therapies. The authors describe the implications of antibiotic resistance on their current wound treatment paradigms and review the most promising non-antibiotic-based antimicrobial agents currently in research and development, with a focus on preclinical and human studies of therapeutic bacteriophages, antimicrobial peptides, cold plasma treatment, photodynamic therapy, honey, silver, and bioelectric dressings. PMID- 30252825 TI - beta-Catenin-Dependent Wnt Signaling: A Pathway in Acute Cutaneous Wounding: Retraction. PMID- 30252824 TI - Harnessing Social Media to Advance Research in Plastic Surgery. AB - BACKGROUND: Social media have transformed plastic surgery, intersecting patient education, provider marketing, and academic interactions across the globe. Despite this, social media are seldom used in research. The authors sought to understand the primary incentives and deterrents for patient participation in research efforts. METHODS: Facebook groups for craniosynostosis families were identified; the largest two had 11,000 and 7200 members. Facebook group administrators were asked to post an open invitation to enroll in the authors' study. Interested participants contacted study personnel directly. Materials and written/video instructions were provided for collecting genetic specimens. Participants completed a follow-up survey to assess satisfaction. The authors subsequently conducted virtual neurocognitive sessions for functional assessment. RESULTS: Three hundred thirty-one of 384 genetic study participants (86 percent) were recruited by means of social media. Three hundred forty-three of 472 mailed packages (73 percent) were returned. Novel mutations identified explained craniosynostosis in 10 percent of participants. One hundred ninety-five families completed the follow-up survey. One hundred percent and 95 percent reported that the written and video instructions were helpful, respectively. The most frequently cited obstacles barring participation in research studies was travel to the study site (63 percent), significantly more than indirect monetary costs (p = 0.007), information confidentiality (p < 0.001), time required to participate (p < 0.001), and invasive study procedures (p < 0.001). Ninety-nine percent preferred participating in a study from home rather than a research center. Follow-up neurocognitive studies are ongoing. CONCLUSIONS: With proper planning, participation in social media-based research is easy, cost-effective, and time conscious. Requiring travel to a research facility is the factor most likely to deter families from contributing to research. The results emphasize the unrealized potential of social media for advancing research in plastic surgery. PMID- 30252826 TI - Reply: Evaluation of Preoperative and Postoperative Patient Satisfaction and Quality of Life in Patients Undergoing Rhinoplasty: A Systematic Review and Meta Analysis. PMID- 30252827 TI - Reply: Do Bacteria and Biofilm Play a Role in Double-Capsule Formation around Macrotextured Implants? PMID- 30252828 TI - Reply: Lower Body Lift in the Massive Weight Loss Patient: A New Classification and Algorithm for Gluteal Augmentation. PMID- 30252829 TI - Noncontrast Magnetic Resonance Lymphography for Evaluation of Lymph Node Transfer for Secondary Upper Limb Lymphedema. PMID- 30252830 TI - Reply: Noncontrast Magnetic Resonance Lymphography for Evaluation of Lymph Node Transfer for Secondary Upper Limb Lymphedema. PMID- 30252831 TI - Prescription Opioid Use among Opioid-Naive Women Undergoing Immediate Breast Reconstruction. PMID- 30252832 TI - Prevalence and Natural History of Coronary Ostial Aneurysms in Marfan Patients. AB - OBJECTIVE: The aim of this study was to determine the prevalence and natural history of coronary ostial aneurysms in Marfan patients with aortic root replacement. METHODS: Thirty-one Marfan patients (mean age, 33.7 +/- 11.8 years) who underwent aortic root replacement and postoperative electrocardiogram-gated computed tomographic (CT) angiograms between January 2007 and December 2015 were retrospectively identified. A subset of 15 patients underwent follow-up CT angiograms. Computed tomographic angiograms were postprocessed on 3-dimensional software to measure maximal coronary ostial diameter. Coronary ostial aneurysm was defined as diameter of greater than 10 mm. RESULTS: Right coronary ostial aneurysms were present in 45.2% (14/31) of patients, and left main coronary ostial aneurysms were present in 51.6% (16/31) of patients. Mean ostial diameter was 10.1 +/- 1.9 mm for the right coronary artery and 10.0 +/- 1.8 mm for the left coronary artery. In a subset of patients with follow-up CT angiograms, there was no significant change in coronary ostial diameter on follow-up examinations (P > 0.05). CONCLUSIONS: Coronary ostial aneurysms were common in Marfan patients after aortic root replacement. These findings remain stable over time and may have little clinical consequence. PMID- 30252833 TI - Accuracy of Quantification of Iodine and Hounsfield Unit Values on Virtual Monochromatic Imaging Using Dual-Energy Computed Tomography: Comparison of Dual Layer Computed Tomography With Fast Kilovolt-Switching Computed Tomography. AB - OBJECTIVE: The aim of the study was to compare the accuracy of quantification of iodine and Hounsfield unit (HU) values on virtual monochromatic imaging (VMI) using dual-layer computed tomography (DLCT) and fast kilovolt-switching computed tomography (FKSCT). MATERIALS AND METHODS: This study was performed in 2 phantoms (large and small) using 16 rods representing different materials (iodine, calcium, blood, and adipose tissue) with different dimensions and concentrations. The absolute percentage errors (absolute ratio of measurement error to true iodine concentration) for iodine concentration and HU value on VMI at 50, 70, and 100 keV were compared between DLCT and FKSCT. The Mann-Whitney U test was used to assess statistical significance. RESULTS: Overall, the absolute percentage errors for iodine concentration and HU value on VMI were smaller for DLCT than for FKSCT. CONCLUSIONS: Overall, the accuracy of iodine and HU values was higher for DLCT than for FKSCT. PMID- 30252834 TI - Comparison of Androgen Levels, Endocrine and Metabolic Indices, and Clinical Findings in Women with Polycystic Ovary Syndrome in Uygur and Han Ethnic Groups from Xinjiang Province in China. AB - BACKGROUND The aim of this study was to compare androgen levels, endocrine and metabolic indices, and clinical findings in women with polycystic ovary syndrome (PCOS) in Uygur and Han ethnic groups from Xinjiang Province, China. MATERIAL AND METHODS Between January 2016 to May 2017 clinical data were collected from Uygur (N=82) and Han (N=100) women diagnosed with PCOS, including age, body mass index (BMI), the Ferriman-Gallwey (mFG) hirsutism score, and waist-to-hip ratio (WHR). Blood samples obtained from all study participants were used to measure androgenic steroid levels, including androgen, androstenedione, dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), and the free androgen index (FAI). Endocrine indices measured included sex-hormone binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and prolactin (PL). Metabolic indices measured included insulin, glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), triglyceride (TG), and low-density lipoprotein (LDL). RESULTS The FAI in Uygur women with PCOS (4.89) was significantly increased compared with Han women with PCOS (2.78) (p<0.05); androgen levels were significantly correlated with the FAI, glucose, insulin, TC, HDL, and LDL (p<0.05); androstenedione levels were positively correlated with glucose and insulin levels (p<0.05). In Han women with PCOS, androgen levels were negatively correlated with TG levels and positively correlated with TC levels (p<0.05); the FAI was positively correlated with glucose and insulin levels (p<0.05). CONCLUSIONS There were significant differences in androgen levels, endocrine, and metabolic indices in women with PCOS between the Uygur and Han ethnic groups from Xinjiang Province in China. PMID- 30252836 TI - Correction: WRAP53 Is Essential for Cajal Body Formation and for Targeting the Survival of Motor Neuron Complex to Cajal Bodies. AB - [This corrects the article DOI: 10.1371/journal.pbio.1000521.]. PMID- 30252835 TI - Comparison of fluctuations in global network topology of modeled and empirical brain functional connectivity. AB - Dynamic models of large-scale brain activity have been used for reproducing many empirical findings on human brain functional connectivity. Features that have been shown to be reproducible by comparing modeled to empirical data include functional connectivity measured over several minutes of resting-state functional magnetic resonance imaging, as well as its time-resolved fluctuations on a time scale of tens of seconds. However, comparison of modeled and empirical data has not been conducted yet for fluctuations in global network topology of functional connectivity, such as fluctuations between segregated and integrated topology or between high and low modularity topology. Since these global network-level fluctuations have been shown to be related to human cognition and behavior, there is an emerging need for clarifying their reproducibility with computational models. To address this problem, we directly compared fluctuations in global network topology of functional connectivity between modeled and empirical data, and clarified the degree to which a stationary model of spontaneous brain dynamics can reproduce the empirically observed fluctuations. Modeled fluctuations were simulated using a system of coupled phase oscillators wired according to brain structural connectivity. By performing model parameter search, we found that modeled fluctuations in global metrics quantifying network integration and modularity had more than 80% of magnitudes of those observed in the empirical data. Temporal properties of network states determined based on fluctuations in these metrics were also found to be reproducible, although their spatial patterns in functional connectivity did not perfectly matched. These results suggest that stationary models simulating resting-state activity can reproduce the magnitude of empirical fluctuations in segregation and integration, whereas additional factors, such as active mechanisms controlling non-stationary dynamics and/or greater accuracy of mapping brain structural connectivity, would be necessary for fully reproducing the spatial patterning associated with these fluctuations. PMID- 30252838 TI - Learning zero-cost portfolio selection with pattern matching. AB - We replicate and extend the adversarial expert based learning approach of Gyorfi et al to the situation of zero-cost portfolio selection implemented with a quadratic approximation derived from the mutual fund separation theorems. The algorithm is applied to daily sampled sequential Open-High-Low-Close data and sequential intraday 5-minute bar-data from the Johannesburg Stock Exchange (JSE). Statistical tests of the algorithms are considered. The algorithms are directly compared to standard NYSE test cases from prior literature. The learning algorithm is used to select parameters for experts generated by pattern matching past dynamics using a simple nearest-neighbour search algorithm. It is shown that there is a speed advantage associated with using an analytic solution of the mutual fund separation theorems. We argue that the strategies are on the boundary of profitability when considered in the context of their application to intraday quantitative trading but demonstrate that patterns in financial time-series on the JSE could be systematically exploited in collective and that they are persistent in the data investigated. We do not suggest that the strategies can be profitably implemented but argue that these types of patterns may exists for either structural of implementation cost reasons. PMID- 30252837 TI - Formation of phenotypic lineages in Salmonella enterica by a pleiotropic fimbrial switch. AB - The std locus of Salmonella enterica, an operon acquired by horizontal transfer, encodes fimbriae that permit adhesion to epithelial cells in the large intestine. Expression of the std operon is bistable, yielding a major subpopulation of StdOFF cells (99.7%) and a minor subpopulation of StdON cells (0.3%). In addition to fimbrial proteins, the std operon encodes two proteins, StdE and StdF, that have DNA binding capacity and control transcription of loci involved in flagellar synthesis, chemotaxis, virulence, conjugal transfer, biofilm formation, and other cellular functions. As a consequence of StdEF pleiotropic transcriptional control, StdON and StdOFF subpopulations may differ not only in the presence or absence of Std fimbriae but also in additional phenotypic traits. Separation of StdOFF and StdON lineages by cell sorting confirms the occurrence of lineage specific features. Formation of StdOFF and StdON lineages may thus be viewed as a rudimentary bacterial differentiation program. PMID- 30252839 TI - Filarial infection during pregnancy has profound consequences on immune response and disease outcome in children: A birth cohort study. AB - BACKGROUND: Current Global Program to Eliminate Lymphatic Filariasis (GPELF) that prohibits pregnant mothers and children below two years of age from coverage targeted interruption of transmission after 5-6 rounds of annual mass drug administration (MDA). However, after more than 10 rounds of MDA in India the target has not been achieved, which poses challenge to the researchers and policy makers. Several studies have shown that in utero exposure to maternal filarial infections plays certain role in determining the susceptibility and disease outcome in children. But the mechanism of which has not been studied extensively. Therefore the present study was undertaken to understand the mechanism of immune modulation in children born to filarial infected mother in a MDA ongoing area. METHODOLOGY AND PRINCIPAL FINDING: To our knowledge this is the first study to conduct both cellular and humoral immunological assays and follow up the children until older age in a W bancrofti endemic area,where the microfilariae (Mf) rate has come down to <1% after 10 rounds of MDA. A total 57 (32: born to infected, 25: born to uninfected mother) children were followed up. The infection status of children was measured by presence of Mf and circulating filarial antigen (CFA) assay. Filaria specific IgG1, IgG2, IgG3 and IgG4 responses were measured by ELISA. Plasma level of IL-10 and IFN-gamma were evaluated by using commercially available ELISA kit. The study reveals a high rate of acquisition of filarial infection among the children born to infected mother compared to uninfected mothers. A significantly high level of IgG1 and IgG4 was observed in children born to infected mother, whereas high level of IgG3 was marked in children born to uninfected mother. Significantly high level of IL-10 positively correlated with IgG4 have been observed in infected children born to infected mother, while high level of IFN-gamma positively correlated with IgG3 was found in infection free children born to mother free from infection at the time of pregnancy. Moreover a negative correlation between IL-10 and IFN-gamma has been observed only among the infected children born to infected mother. SIGNIFICANCE CONCLUSION: The study shows a causal association between maternal filarial infection and impaired or altered immune response in children more susceptible to filarial infection during early childhood. As lymphatic damage that commences in childhood during asymptomatic stage has major implications from public health point of view, understanding maternal programming of the newborn immune system could provide a basis for interventions promoting child health by implementing MDA campaigns towards all women of childbearing age and young children in achieving the target of global elimination of LF. PMID- 30252840 TI - Factors enabling comprehensive maternal health services in the benefits package of emerging financing schemes: A cross-sectional analysis from 1990 to 2014. AB - INTRODUCTION: Maternal delivery is the costliest event during pregnancy, especially if a complicated delivery occurs that requires emergency hospital services. A health financing scheme or program that covers comprehensive maternal services, including specialized hospital services in the benefits health package, enhances maternal survival and improves financial risk protection. OBJECTIVES: The objective of this study is to identify factors that enable the inclusion of comprehensive maternal services in the benefits package of emerging health financing schemes in low and middle-income countries across selected world regions. Comprehensive care is presumed if, in addition to normal delivery, primary health care, and secondary or tertiary hospital care are included. METHODS: Multilevel regression analysis is performed on 220 health financing schemes and programs initiated during the period 1990-2014, in 40 countries in Sub-Saharan Africa, Asia, and Latin America. FINDINGS: About two-thirds of emerging health financing schemes explicitly include maternal care in the benefits package, and less-than-half cover comprehensive maternal services. Provision of any type of maternal services and comprehensive services is significantly associated with the presence of donors/philanthropies as funders, and beneficiaries possessing an ID card that links them to entitled services. Other enabling factors are prepayment and risk pooling. However, private and community insurances are negatively associated with covering comprehensive maternal services, because they are subject to market failures, such as adverse and risk selection. CONCLUSIONS: Emerging health financing schemes in low and upper-middle-income countries lag in coverage of maternal care. Advancing financial protection of these services in the health package needs policy attention, including government oversight and mandatory regulations. The enabling factors identified can enrich the ongoing discourse on Universal Health Coverage. PMID- 30252841 TI - Positive selection in coding regions and motif duplication in regulatory regions of bottlenose dolphin MHC class II genes. AB - The vertebrate immune response is mediated through highly adaptive, quickly evolving cell surface receptors, the major histocompatibility complex (MHC). MHC molecules bind and present a diverse array of pathogenic molecules and trigger a cascade of defenses. Use of MHC variation as a marker for population health has also evolved quickly following advances in sequencing methods. We applied a combination of traditional and next generation sequencing methodology to characterize coding (peptide binding region) and regulatory (proximal promoter) sequence variation in MHC Class II DQA and DQB genes between estuarine and coastal populations of the bottlenose dolphin, Tursiops truncatus, an apex predator whose health status is indicative of anthropogenic impacts on the ecosystem. The coding regions had 10 alleles each at DQA and DQB; the promoters had 6 and 7 alleles at DQA and DQB, respectively with variation within key regulatory motifs. Positive selection was observed for the coding regions of both genes while both coding and promoter regions exhibited geographic differences in allele composition that likely indicates diversifying selection across habitats. Most notable was the discovery of a complete duplication of a 14-bp T-box motif in the DQA promoter. Four class II promoter regions (DQA, DQB, DRA, DRB) were characterized in species from four cetacean families (Delphinidae, Monodontidae, Lipotidae, and Physeteridae) and revealed substantial promoter structural diversity across this order. Peptide binding regions may not be the only source of adaptive potential within cetacean MHC for responding to pathogenic threats. These findings are the first analysis of cetacean MHC regulatory motifs, which may divulge unique immunogenetic strategies among cetaceans and reveal how MHC transcriptional control continues to evolve. The combined MHC regulatory and coding data provide new genetic context for distinct vulnerability profiles between coastal and estuarine populations, which are key concerns for health and risk management. PMID- 30252842 TI - The neurodevelopmental precursors of altruistic behavior in infancy. AB - Altruistic behavior is considered a key feature of the human cooperative makeup, with deep ontogenetic roots. The tendency to engage in altruistic behavior varies between individuals and has been linked to differences in responding to fearful faces. The current study tests the hypothesis that this link exists from early in human ontogeny. Using eye tracking, we examined whether attentional responses to fear in others at 7 months of age predict altruistic behavior at 14 months of age. Our analysis revealed that altruistic behavior in toddlerhood was predicted by infants' attention to fearful faces but not happy or angry faces. Specifically, infants who showed heightened initial attention to (i.e., prolonged first look) followed by greater disengagement (i.e., reduced attentional bias over 15 seconds) from fearful faces at 7 months displayed greater prosocial behavior at 14 months of age. Our data further show that infants' attentional bias to fearful faces and their altruistic behavior was predicted by brain responses in the dorsolateral prefrontal cortex (dlPFC), measured through functional near-infrared spectroscopy (fNIRS). This suggests that, from early in ontogeny, variability in altruistic helping behavior is linked to our responsiveness to seeing others in distress and brain processes implicated in attentional control. These findings critically advance our understanding of the emergence of altruism in humans by identifying responsiveness to fear in others as an early precursor contributing to variability in prosocial behavior. PMID- 30252843 TI - Reactive and pre-emptive vaccination strategies to control hepatitis E infection in emergency and refugee settings: A modelling study. AB - BACKGROUND: Hepatitis E Virus (HEV) is the leading cause of acute viral hepatitis globally. Symptomatic infection is associated with case fatality rates of ~20% in pregnant women and it is estimated to account for ~10,000 annual pregnancy related deaths in southern Asia alone. Recently, large and well-documented outbreaks with high mortality have occurred in displaced population camps in Sudan, Uganda and South Sudan. However, the epidemiology of HEV is poorly defined, and the value of different immunisation strategies in outbreak settings uncertain. We aimed to estimate the critical epidemiological parameters for HEV and to evaluate the potential impact of both reactive vaccination (initiated in response to an epidemic) and pre-emptive vaccination. METHODS: We analysed data from one of the world's largest recorded HEV epidemics, which occurred in internally-displaced persons camps in Uganda (2007-2009), using transmission dynamic models to estimate epidemiological parameters and assess the potential impact of reactive and pre-emptive vaccination strategies. RESULTS: Under baseline assumptions we estimated the basic reproduction number of HEV in three separate camps to range from 3.7 (95% Credible Interval [CrI] 2.8, 5.1) to 8.5 (5.3, 11.4). Mean latent and infectious periods were estimated to be 34 (95% CrI 28, 39) and 40 (95% CrI 23, 71) days respectively. Assuming 90% vaccine coverage, reactive two-dose vaccination of those aged 16-65 years excluding pregnant women (for whom vaccine is not licensed), if initiated after 50 reported cases, led to mean camp-specific reductions in mortality of 10 to 29%. Pre-emptive vaccination with two doses reduced mortality by 35 to 65%. Both strategies were more effective if coverage was extended to groups for whom the vaccine is not currently licensed. For example, two dose pre-emptive vaccination, if extended to include pregnant women, led to mean reductions in mortality of 66 to 82%. CONCLUSIONS: HEV has a high transmission potential in displaced population settings. Substantial reductions in mortality through vaccination are expected, even if used reactively. There is potential for greater impact if vaccine safety and effectiveness can be established in pregnant women. PMID- 30252846 TI - Multiple morbidities in pregnancy: Time for research, innovation, and action. AB - In a Guest Editorial, James Beeson and colleagues discuss the contribution of nonobstetric morbidity to mortality during and around pregnancy and what needs to be done to address this global health challenge. PMID- 30252844 TI - Low prevalence of depressive symptoms among stable patients on antiretroviral therapy in Johannesburg, South Africa. AB - BACKGROUND: Depression is a leading cause of disability and may be associated with decreased adherence to ART. We sought to describe the prevalence of depressive symptoms and outcomes one year after screening among patients receiving ART at a large HIV Clinic in Johannesburg, South Africa. METHODS: Adult (>=18) patients who had been on first-line ART between 6-18 months who could communicate in English were eligible. Depressive symptoms were evaluated using the Patient Health Questionnaire (PHQ)-9 and a score >=10 indicated depression. RESULTS: 97 patients enrolled. Patients had been on ART for a median (IQR) of 8 (7-10) months, 61% were female, the median (IQR) age at enrollment was 38 (33-42) years, and the median (IQR) CD4 count at ART initiation was 154.5 (65-263) cells/mm3. 7 (7%) patients were found to have symptoms of depression; 4 (4%) had symptoms of moderate depression (PHQ score of 10-14) and 3 (3%) had symptoms of moderate/severe depression (PHQ score of 15-19). Women (10%) were more likely to have symptoms of depression than men (3%; prevalence difference [PD]: 7.5%; 95% confidence interval [CI]:-1.7%-16.8%); as were patients under the age of 30 (14%) compared to those 30-39 (4%; PD: -10.2; 95% CI: -29.4-9.0%) or >=40 (9%; PD: 5.5%; -26.1%-15.2%), those with lower CD4 counts at ART initiation (<200 cells/mm3 vs >=200 cells/mm3: 8% vs 3%; PD: 4.8%; 95% CI: -4.5%-14.0%), and those with high viral loads (>1000 copies/mL vs. <400 copies/mL: 40% vs. 5%; PD: 34.6%; 95% CI: -8.6%-77.6%). No relationship between depressive symptoms and retention in HIV care one year after screening was observed. CONCLUSIONS: We found a lower prevalence of depressive symptoms compared to findings from other HIV-positive populations in South Africa but more than one-third of patients with an elevated viral load had evidence of depression. Further research on the relationship between depression, adherence, and viral failure is warranted as this may present an opportunity for early interventions to improve treatment outcomes and reduce the need for second-line treatment. PMID- 30252845 TI - Respiratory muscle training positively affects vasomotor response in young healthy women. AB - Vasomotor response is related to the capacity of the vessel to maintain vascular tone within a narrow range. Two main control mechanisms are involved: the autonomic control of the sympathetic neural drive (global control) and the endothelial smooth cells capacity to respond to mechanical stress by releasing vasoactive factors (peripheral control). The aim of this study was to evaluate the effects of respiratory muscle training (RMT) on vasomotor response, assessed by flow-mediated dilation (FMD) and heart rate variability, in young healthy females. The hypothesis was that RMT could enhance the balance between sympathetic and parasympathetic neural drive and reduce vessel shear stress. Thus, twenty-four women were randomly assigned to either RMT or SHAM group. Maximal inspiratory mouth pressure and maximum voluntary ventilation were utilized to assess the effectiveness of the RMT program, which consisted of three sessions of isocapnic hyperventilation/ week for eight weeks, (twenty-four training sessions). Heart rate variability assessed autonomic balance, a global factor regulating the vasomotor response. Endothelial function was determined by measuring brachial artery vasodilation normalized by shear rate (%FMD/SR). After RMT, but not SHAM, maximal inspiratory mouth pressure and maximum voluntary ventilation increased significantly (+31% and +16%, respectively). Changes in heart rate variability were negligible in both groups. Only RMT exhibited a significant increase in %FMD/SR (+45%; p<0.05). These data suggest a positive effect of RMT on vasomotor response that may be due to a reduction in arterial shear stress, and not through modulation of sympatho-vagal balance. PMID- 30252847 TI - Human cellular mitochondrial remodelling is governed by miR-2909 RNomics. AB - BACKGROUND: There exists a general recognition of the fact that mitochondrial remodelling as a result of aerobic glycolysis ensures human somatic cells to revert to a more primitive-form exhibiting stem-like phenotype. The present study is an attempt to demonstrate that miR-2909 RNomics within human peripheral blood mononuclear cells (PBMCs) has the inherent capacity to re-program these cells to exhibit mitochondrial remodelling paralleled by aerobic glycolysis together with intracellular lipid inclusions. Such re-programmed PBMCs also expressed genes having ability to sustain their de-differentiation state and survival. MATERIAL AND METHODS: Human PBMCs were programed to ectopically express miR-2909. Expression levels of genes including glucose transporter-1 (Glut-1), hexokinase (HK), hypoxia inducia factor-1 (HIF-1alpha), c-Myc, p53,mechanistic target of rapamycin complex (mTORC1), polycombcomplex protein (Bmi-1), Notch,Nanog,Tie-2, Oct-4,CD59, p53, CD34, B-cell lymphoma-2 (Bcl2),sterol regulatory element-binding protein2 (SREBP2), peroxisome proliferator-activated receptor gamma (PPARgamma) nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) within miR-2909 expression vector transfected human PBMCs as well as PBMCs transfected with control vector containing scrambled sequence after 48h post transfection using RT-qPCR and cellular ultrastructural features induced by miR 2909 ectopic expression were observed using transmission electron microscopy and morphometric analysis of an electron micrograph. RESULTS: Ectopic expression of miR-2909 within human PBMCs resulted in their reprogramming into stem-like phenotype indicated by mitochondrial globular shaped coupled with cristae-poor morphology. Nuclear to cytoplasmic ratio (N/C), quantification of ATP levels, GSSG/GSH ratio, mitochondrial cytochrome c oxidase activity, secreted lactate concentrations, activity of antioxidant enzymes, levels of esterified cholesterol and triglycerides and flow-cytometric detection of apoptosis confirmed the compromised nature of mitochondrial function induced by ectopic miR-2909 expression in human PBMCs. CONCLUSION: Based upon these results we propose that AATF gene-encoded miR-2909 may act as an epigenetic switch for cellular aerobic glycolysis to ensure de-differentiation. PMID- 30252848 TI - Standardising visual control devices for Tsetse: East and Central African Savannah species Glossina swynnertoni, Glossina morsitans centralis and Glossina pallidipes. AB - BACKGROUND: This study focused on the savannah tsetse species Glossina swynnertoni and G. morsitans centralis, both efficient vectors of human and animal trypanosomiasis in, respectively, East and Central Africa. The aim was to develop long-lasting, practical and cost-effective visually attractive devices that induce the strongest landing responses in these two species for use as insecticide-impregnated tools in population suppression. METHODS AND FINDINGS: Trials were conducted in different seasons and years in Tanzania (G. swynnertoni) and in Angola and the Democratic Republic of the Congo (DRC, G. m. centralis) to measure the performance of traps (pyramidal and epsilon) and targets of different sizes, shapes and colours, with and without chemical baits, at different population densities and under different environmental conditions. Adhesive film was used to catch flies landing on devices at the remote locations to compare tsetse-landing efficiencies. Landing rates by G. m. centralis in both Angola and the DRC were highest on blue-black 1 m2 oblong and 0.5 m2 square and oblong targets but were not significantly different from landings on the pyramidal trap. Landings by G. swynnertoni on 0.5 m2 blue-black oblong targets were likewise not significantly lower than on equivalent 1 m2 square targets. The length of target horizontal edge was closely correlated with landing rate. Blue-black 0.5 m2 targets performed better than equivalents in all-blue for both G. swynnertoni and G. m. centralis, although not consistently. Baiting with chemicals increased the proportion of G. m. centralis entering pyramidal traps. CONCLUSIONS: This study confirms earlier findings on G. swynnertoni that smaller visual targets, down to 0.5 m2, would be as efficient as using 1 m2 targets for population management of this species. This is also the case for G. m. centralis. An insecticide impregnated pyramidal trap would also constitute an effective control device for G. m. centralis. PMID- 30252849 TI - Variations in the quality of tuberculosis care in urban India: A cross-sectional, standardized patient study in two cities. AB - BACKGROUND: India has the highest burden of tuberculosis (TB). Although most patients with TB in India seek care from the private sector, there is limited evidence on quality of TB care or its correlates. Following our validation study on the standardized patient (SP) method for TB, we utilized SPs to examine quality of adult TB care among health providers with different qualifications in 2 Indian cities. METHODS AND FINDINGS: During 2014-2017, pilot programs engaged the private health sector to improve TB management in Mumbai and Patna. Nested within these projects, to obtain representative, baseline measures of quality of TB care at the city level, we recruited 24 adults to be SPs. They were trained to portray 4 TB "case scenarios" representing various stages of disease and diagnostic progression. Between November 2014 and August 2015, the SPs visited representatively sampled private providers stratified by qualification: (1) allopathic providers with Bachelor of Medicine, Bachelor of Surgery (MBBS) degrees or higher and (2) non-MBBS providers with alternative medicine, minimal, or no qualifications. Our main outcome was case-specific correct management benchmarked against the Standards for TB Care in India (STCI). Using ANOVA, we assessed variation in correct management and quality outcomes across (a) cities, (b) qualifications, and (c) case scenarios. Additionally, 2 micro-experiments identified sources of variation: first, quality in the presence of diagnostic test results certainty and second, provider consistency for different patients presenting the same case. A total of 2,652 SP-provider interactions across 1,203 health facilities were analyzed. Based on our sampling strategy and after removing 50 micro-experiment interactions, 2,602 interactions were weighted for city-representative interpretation. After weighting, the 473 Patna providers receiving SPs represent 3,179 eligible providers in Patna; in Mumbai, the 730 providers represent 7,115 eligible providers. Correct management was observed in 959 out of 2,602 interactions (37%; 35% weighted; 95% CI 32%-37%), primarily from referrals and ordering chest X-rays (CXRs). Unnecessary medicines were given to nearly all SPs, and antibiotic use was common. Anti-TB drugs were prescribed in 118 interactions (4.5%; 5% weighted), of which 45 were given in the case in which such treatment is considered correct management. MBBS and more qualified providers had higher odds of correctly managing cases than non-MBBS providers (odds ratio [OR] 2.80; 95% CI 2.05-3.82; p < 0.0001). Mumbai non-MBBS providers had higher odds of correct management than non-MBBS in Patna (OR 1.79; 95% CI 1.06-3.03), and MBBS providers' quality of care did not vary between cities (OR 1.15; 95% CI 0.79-1.68; p = 0.4642). In the micro-experiments, improving diagnostic certainty had a positive effect on correct management but not across all quality dimensions. Also, providers delivered idiosyncratically consistent care, repeating all observed actions, including mistakes, approximately 75% of the time. The SP method has limitations: it cannot account for patient mix or care-management practices reflecting more than one patient-provider interaction. CONCLUSIONS: Quality of TB care is suboptimal and variable in urban India's private health sector. Addressing this is critical for India's plans to end TB by 2025. For the first time, we have rich measures on representative levels of care quality from 2 cities, which can inform private-sector TB interventions and quality-improvement efforts. PMID- 30252851 TI - Development and validation of a scale to assess attitudes of health care providers towards persons affected by leprosy in southern India. AB - INTRODUCTION: Assessment of attitudes of health care professionals is important as negative attitude could constitute a major deterrent to care-seeking by persons affected by neglected tropical diseases (NTDs) such as leprosy. Leprosy continues to pose a major disease burden in India with an annual new case detection rate of 10.17 per 100,000 population. This paper reports on the development and validation of a culturally appropriate scale to measure attitude of health care providers (HCPs) towards persons affected by leprosy in Tamil Nadu, India. METHODOLOGY/PRINCIPAL FINDINGS: The Affective, Behavioural and Cognitive (ABC) model of attitudes guided the development of the scale. Steps in scale development included qualitative interviews and focus group discussions with medical officers and paramedical staff selected from high prevalence districts in Tamil Nadu, India which informed the development of the draft scale. Reviews of existing attitude questionnaires in related areas further contributed to scale development and together helped to generate a large pool of items which was then subjected to Thurston's scaling method for selection of items from this pool. Face and content validity were obtained, following which internal consistency and test, re-test reliability were assessed. Scaling exercise resulted in 11 items being discarded from an initial pool of 38, owing to the poor agreement among experts regarding relevance. Face and content validity were good with experts endorsing relevance and applicability of items. The intra-class correlation coefficient (ICC) for test re-test reliability of the 27 item scale was 0.6 (95% CI: 0.20-0.78) indicating marginal intra-class correlation. The overall Cronbach's alpha was 0.85 while the alphas for each of the affective and behavioural components was good at 0.78 and 0.69 respectively indicating a good degree of consistency and homogeneity between items but the alpha for the cognitive component was low at 0.53. CONCLUSIONS: The ABC model of attitudes guided the development of the scale, ensured a mix of 27 items tapping into the three domains of Affect, Behaviour and Cognition which best explained the attitude construct. With good validity and alphas for each of the affective, behavioural components and overall alpha estimates, this scale can be a valuable tool to provide accurate estimates of the true attitudes held by HCPs. This, in turn, would be useful to obtain insights for appropriate intervention programmes that would help change negative attitudes of HCPs towards persons affected by leprosy. With some adaptations, the scales can be validated for other NTDs as well. PMID- 30252850 TI - Individualised aspiration dynamics: Calculation by proofs. AB - Cooperation is key for the evolution of biological systems ranging from bacteria communities to human societies. Evolutionary processes can dramatically alter the cooperation level. Evolutionary processes are typically of two classes: comparison based and self-evaluation based. The fate of cooperation is extremely sensitive to the details of comparison based processes. For self-evaluation processes, however, it is still unclear whether the sensitivity remains. We concentrate on a class of self-evaluation processes based on aspiration, where all the individuals adjust behaviors based on their own aspirations. We prove that the evolutionary outcome with heterogeneous aspirations is the same as that of the homogeneous one for regular networks under weak selection limit. Simulation results further suggest that it is also valid for general networks across various distributions of personalised aspirations. Our result clearly indicates that self-evaluation processes are robust in contrast with comparison based rules. In addition, our result greatly simplifies the calculation of the aspiration dynamics, which is computationally expensive. PMID- 30252852 TI - Understanding arithmetic concepts: The role of domain-specific and domain-general skills. AB - A large body of research has identified cognitive skills associated with overall mathematics achievement, focusing primarily on identifying associates of procedural skills. Conceptual understanding, however, has received less attention, despite its importance for the development of mathematics proficiency. Consequently, we know little about the quantitative and domain-general skills associated with conceptual understanding. Here we investigated 8-10-year-old children's conceptual understanding of arithmetic, as well as a wide range of basic quantitative skills, numerical representations and domain-general skills. We found that conceptual understanding was most strongly associated with performance on a number line task. This relationship was not explained by the use of particular strategies on the number line task, and may instead reflect children's knowledge of the structure of the number system. Understanding the skills involved in conceptual learning is important to support efforts by educators to improve children's conceptual understanding of mathematics. PMID- 30252853 TI - Profiling of microorganism-binding serum antibody specificities in professional athletes. AB - The goal of this work was to elucidate similarities between microorganisms from the perspective of the humoral immune system reactivity in professional athletes. The reactivity of serum IgG of 14 young, individuals was analyzed to 23 selected microorganisms as antigens by use of the in house ELISA. Serum IgM and IgA reactivity was also analyzed and a control group of sex and age matched individuals was used for comparison. The obtained absorbance levels were used as a string of values to correlate the reactivity to different microorganisms. IgM was found to be the most cross reactive antibody class, Pearson's r = 0.7-0.92, for very distant bacterial species such as Lactobacillus and E. coli.High correlation in IgG levels was found for Gammaproteobacteria and LPS (from E. coli) (r = 0.77 for LPS vs. P. aeruginosa to r = 0.98 for LPS vs. E.coli), whereas this correlation was lower in the control group (r = 0.49 for LPS vs. P. aeruginosa to r = 0.66 for LPS vs. E.coli). The correlation was also analyzed between total IgG and IgG subclasses specific for the same microorganism, and IgG2 was identified as the main subclass recognising different microorganisms, as well as recognising LPS. Upon correlation of IgG with IgA for the same microorganism absence of or negative correlation was found between bacteria specific IgA and IgG in case of Lactobacillus and Staphylococcusgeni, whereas correlation was absent or positive for Candida albicans, Enterococcusfaecalis,Streptococcus species tested in professional athletes. Opposite results were obtained for the control group. Outlined here is a simple experimental procedure and data analysis which yields functional significance and which can be used for determining the similarities between microorganisms from the aspect of the humoral immune system, for determining the main IgG subclass involved in an immune response as well as for the analysis of different target populations. PMID- 30252854 TI - Human milk enriched with human milk lyophilisate for feeding very low birth weight preterm infants: A preclinical experimental study focusing on fatty acid profile. AB - BACKGROUND: Human milk, with essential nutrients and long chain polyunsaturated fatty acids (LC-PUFAs) such as the omega 3 and 6 fatty acids is important for development of the central nervous system and the retina in very low birth weight infants (<1,500 g). However, breast milk may not be sufficient to meet these needs. The possibility of supplementing breast milk with a lyophilisate of human milk was explored in this study. The objectives of this study were to determine the total lipid content and the lipid profile of the Human Milk on Baseline (HMB) and that of the Concentrates with the Human Milk + lyophilisate (with lyophilisate of milk in the immediate period (HMCI), at 3 months (HMC3m), and at 6 months (HMC6m) of storage). METHODS: Fifty donors from the Human Milk Bank of Children's Hospital provided consent, and donated milk samples. Macronutrient (including total lipids) quantification was performed using the MIRIS(r) Human Milk Analyzer, and the fatty acid profile was determined by gas chromatography (CG-FID, SHIMADZU(r)). RESULTS: There was a higher lipid concentration in HMCI relative to HMB. The concentrations of the main fatty acids (% of total) were as follows: palmitic acid (C16:0) HMB, 22.30%; HMCI, 21.46%; HMC3m, 21.54%; and HMC6m, 21.95% (p<0.01); oleic acid (C18:1n-9) HMB, 30.41%; HMCI, 30.47%; HMC3m, 30.55%; and HMC6m, 29.79% (p = 0.46); linoleic acid (C18:2n-6) HMB, 19.62%; HMCI, 19.88%; HMC3m, 19.49%; and HMC6m, 19.45% (p = 0.58); arachidonic acid (C20:4n-6) HMB, 0.35%; HMCI, 0.16%; HMC3m, 0.13%; and HMC6m, 0.15% (p<0.01); alpha-linolenic acid (C18:3n-3) HMB,1.32%; HMCI, 1.37%; HMC3m, 1.34%; and 1.34% HMC6m (p = 0.14); docosahexaenoic acid (C22:6n-3) HMB, 0.10%; HMCI, 0.06%; HMC3m, 0.05%; and HMC6m, 0.06% (p<0.01). There were no significant changes in the lipid profile when stored. There was no evidence of peroxidation during storage. CONCLUSIONS: Freeze dried human milk fortified with a human milk concentrate brings potential benefits to newborns, mainly by preserving the essential nutrients present only in breast milk; however, further clinical studies are required to evaluate the safety and efficacy of the concentrate as a standard nutritional food option for very low birth weight infants. PMID- 30252855 TI - Comparison of rituximab and conventional adjuvant therapy for pemphigus vulgaris: A retrospective analysis. AB - BACKGROUND: Rituximab is a promising steroid sparing agent used in the treatment of moderate to severe pemphigus vulgaris. Its exact place in the algorithm of pemphigus treatment, vis-a-vis other, conventional adjuvant therapy (CAT) is not known. OBJECTIVE: To describe and compare disease course outcomes and morbidity among patients with moderate to severe pemphigus who received rituximab therapy (RT) in addition to prednisone and CAT, versus those who were treated with prednisone and CAT alone. METHODS: A 16-year retrospective case control study was designed with adult patients who were seen at the Duke University Dermatology Immunodermatology clinic from 1999-2015, who had a diagnosis of pemphigus vulgaris, and required prednisone and at least 1 systemic CAT. All patients had at least 6 months follow up from the initial visit. Interventions included RT, systemic CAT, and prednisone. The main outcome measured was prednisone intake. Secondary outcomes were complete remission (CR) and partial remission (PR). RESULTS: 40 patients were included in the study. All initially received prednisone and at least 1 systemic CAT. 13/40 eventually went on to receive RT, while 27/40 remained on CAT (CAT-only). Patients in the RT group, pre-RT, had a median prednisone intake of 658.57 mg/month. Rituximab treatment significantly reduced this to 177.22 mg/month (p = 0.002). Median prednisone intake of the CAT only group was 141.33 mg/month. This was significantly less than Pre-RT (p = 0.01) and on par with Post-RT intake (p = 0.58). 54% of patients in the RT group and 64% of those in the CAT-only group achieved CR. All patients in the RT group and 96% of those in the CAT-only group achieved at least PR. CONCLUSIONS: 32.5% of our patients with moderate to severe pemphigus vulgaris failed prednisone and traditional CAT treatment and required rituximab therapy. Rituximab reduced the monthly prednisone intake in these patients by 73%. This suggests that a subset of patients with moderate to severe pemphigus may benefit from early institution of rituximab therapy. Rituximab significantly reduces the monthly prednisone requirement among CAT-resistant pemphigus vulgaris patients to levels on par with CAT-responsive patients. PMID- 30252856 TI - Impact of ivermectin administered for scabies treatment on the prevalence of head lice in Atoifi, Solomon Islands. AB - BACKGROUND: Scabies and head lice are ubiquitous ectoparasitic infestations that are common across the Pacific Islands. Ivermectin is an effective treatment for both conditions, although the doses used vary. At a community level, mass drug administration (MDA) with ivermectin is an effective strategy to decrease prevalence of scabies. To what extent MDA with ivermectin will also reduce prevalence of head lice is unknown. METHODOLOGY: Head lice prevalence was assessed before and after MDA with oral ivermectin (at a dose of 200 micrograms per kilogram of body weight) administered on day 1 and day 8. The primary outcome was the change in prevalence of head louse infestation at two weeks compared to baseline. Longer term efficacy was assessed three months after MDA. RESULTS: 118 participants were enrolled. Baseline prevalence of active head louse infestation was 25.4% (95% CI 18.4-34.0). At two-week follow-up, prevalence was 2.5% (95% CI 0.9-7.2), a relative reduction of 89.1% (95% CI 72.7-91.4%, p<0.001). At three month follow-up, prevalence was 7.5% (95% CI 2.7-12.3), a relative reduction of 70.6% (95% CI 72.7%-91.4%, p <0.001). Head louse infestation was associated with younger age (age <=10 years: prevalence 46.7%; adjusted odds ratio compared to adults of 7.2, 95%CI 2.0-25.9) and with having at least one other member of the household with active head louse infestation (adjusted odds ratio 4.3, 95%CI 1.7 11.1). CONCLUSIONS: Head louse infestation is common in the Solomon Islands. This proof of principle study shows that oral ivermectin at a dose of 200 micrograms per kilogram can reduce the burden of active head louse infestation, offering an additional collateral benefit of MDA with ivermectin for scabies control. TRIAL REGISTRATION: ClinicalTrials.gov NCT03236168. PMID- 30252857 TI - Corneal epithelial and stromal thickness changes in myopic orthokeratology and their relationship with refractive change. AB - PURPOSE: To investigate topographic changes in corneal epithelial thickness (CET) and stromal thickness following orthokeratology (OK) and to determine associated factors affecting refractive changes. METHODS: This study investigated the topographic changes in CET and stromal thickness in 60 myopic eyes that were fitted with OK lenses. CET and stromal thickness were obtained using spectral domain optical coherence tomography (OCT) before and after OK lens wear. Changes in refractive error and corneal topography data were obtained. The correlation between refractive change and corneal thickness change, and various refractive, lens, and topographic parameters were analyzed using simple regression analysis. RESULTS: Mean refractive error changed by 1.75 +/- 0.79 diopters (D). The mean CET of the center zone (2 mm in diameter), paracenter (2 to 5 mm annular ring: 1 to 2.5 mm from center), and mid-periphery (5 to 6 mm annular ring: 2.5 to 3 mm from center) changed by -8.4, -1.4, and +2.7 MUm, respectively, after OK lens wear. There was an increase of 2.0, 3.3, and 3.9 MUm, respectively, in the center, paracenter, and mid-periphery of the stroma. A larger refractive correction was associated with a flatter base curve of the lens, larger decrease in the central epithelium, and smaller treatment diameter in corneal topography. CONCLUSION: OK lenses caused the central corneal epithelium to thin while the mid peripheral epithelium and stroma became thicker. Refractive changes during OK are associated with changes in central epithelial thickness, while stromal changes did not contribute significantly. PMID- 30252858 TI - Sound Colless-like balance indices for multifurcating trees. AB - The Colless index is one of the most popular and natural balance indices for bifurcating phylogenetic trees, but it makes no sense for multifurcating trees. In this paper we propose a family of Colless-like balance indices [Formula: see text] that generalize the Colless index to multifurcating phylogenetic trees. Each [Formula: see text] is determined by the choice of a dissimilarity D and a weight function [Formula: see text]. A balance index is sound when the most balanced phylogenetic trees according to it are exactly the fully symmetric ones. Unfortunately, not every Colless-like balance index is sound in this sense. We prove then that taking f(n) = ln(n + e) or f(n) = en as weight functions, the resulting index [Formula: see text] is sound for every dissimilarity D. Next, for each one of these two functions f and for three popular dissimilarities D (the variance, the standard deviation, and the mean deviation from the median), we find the most unbalanced phylogenetic trees according to [Formula: see text] with any given number n of leaves. The results show that the growth pace of the function f influences the notion of "balance" measured by the indices it defines. Finally, we introduce our R package "CollessLike," which, among other functionalities, allows the computation of Colless-like indices of trees and their comparison to their distribution under Chen-Ford-Winkel's alpha-gamma-model for multifurcating phylogenetic trees. As an application, we show that the trees in TreeBASE do not seem to follow either the uniform model for multifurcating trees or the alpha-gamma-model, for any values of alpha and gamma. PMID- 30252859 TI - In-field determination of soil ion content using a handheld device and screen printed solid-state ion-selective electrodes. AB - Small-holding farmers in the developing world suffer from sub-optimal crop yields because they lack a soil diagnostic system that is affordable, usable, and actionable. This paper details the fabrication and characterization of an integrated point-of-use soil-testing system, comprised of disposable ion selective electrode strips and a handheld electrochemical reader. Together, the strips and reader transduce soil ion concentrations into to an alphanumeric output that can be communicated via text message to a central service provider offering immediate, customized fertilizer advisory. The solid-state ion-selective electrode (SS-ISE) strips employ a two-electrode design with screen-printable carbon nanotube ink serving as the electrical contacts for the working and reference electrodes. The working electrode comprises a plasticizer-free butyl acrylate ion-selective membrane (ISM), doped with an ion-selective ionophore and lipophilic salt. Meanwhile, the reference electrode includes a screen-printed silver-silver chloride ink and a polyvinyl-butyral membrane, which is doped with sodium chloride for stable reference potentials. As a proof of concept, potassium selective electrodes are studied, given potassium's essential role in plant growth and reproduction. The ISE-based system is reproducibly manufactured to yield a Nernstian response with a sub-micromolar detection limit (pK+ of 5.18 +/- 0.08) and near-Nernstian sensitivity (61 mV/decade) in the presence of a 0.02 M strontium chloride extraction solution. Analysis of soil samples using the printed electrodes and reader yielded a correlation coefficient of ??2 = 0.89 with respect to values measured via inductively coupled plasma atomic emission spectroscopy (ICP-AES). The reliable performance of this system is encouraging toward its deployment for soil nutrient management in resource-limited environments. PMID- 30252860 TI - Knowledge, perception and practice towards oxytocin stability and quality: A qualitative study of stakeholders in three resource-limited countries. AB - BACKGROUND: Oxytocin is the gold standard drug for the prevention of postpartum haemorrhage, but limitations in cold chain systems in resource-constrained settings can severely compromise the quality of oxytocin product available in these environments. This study investigated the perspectives and practices of stakeholders in low and lower-middle income countries towards oxytocin, its storage requirements and associated barriers, and the quality of product available. METHODS: Qualitative inquiries were undertaken in Ethiopia, India and Myanmar, where data was collected through Focus Group Discussions (FGDs) and In Depth Interviews (IDIs). A total of 12 FGDs and 106 IDIs were conducted with 158 healthcare providers (pharmacists, midwives, nurses, doctors and obstetricians) and 40 key informants (supply chain experts, program managers and policy-makers). Direct observations of oxytocin storage practices and cold chain resources were conducted at 51 healthcare facilities. Verbatim transcripts of FGDs and IDIs were translated to English and analysed according to a thematic content analysis framework. FINDINGS: Stakeholder awareness of oxytocin heat sensitivity and the requirement for cold storage of the drug was widespread in Ethiopia but more limited in Myanmar and India. A consistent finding across all study regions was the significant barriers to maintaining a consistent cold chain, with the lack of refrigeration facilities and unreliability of electricity cited as major challenges. Perceptions of compromised oxytocin quality were expressed by some stakeholders in each country. CONCLUSION: Knowledge of the heat sensitivity of oxytocin and the potential impacts of inconsistent cold storage on product quality is not widespread amongst healthcare providers, policy makers and supply chain experts in Myanmar, Ethiopia and India. Targeted training and advocacy messages are warranted to emphasise the importance of cold storage to maintain oxytocin quality. PMID- 30252862 TI - Vertical stratification of bacteria and the chemical compounds in crude oil contaminated soil layers of the semi-deserted Dzungharian Basin. AB - The largely semi-deserted and deserted Dzungharian Basin sites in the northwest of China geologically represent an extension of the Paleozoic Kazakhstan Block and were once part of an independent continent. For reasons of overdevelopment and unreasonable operations during the process of exploitation and transportation, oil pollutants that were discharged into the soil environment caused serious pollution in this weak ecosystem. To explore the bacterial community composition in detail and their possible origination and potential during the natural attenuation of petroleum contaminants in this type of ecologic niche, GC-MS and high-throughput sequencing techniques were used to resolve the organic compounds and bacterial communities in vertical soil layers. The degradation of petroleum contaminants in semi-deserted and deserted soils mainly occurred in the layer at a depth of 45-55 cm. During this process, aromatic and heterocyclic compounds were significantly enriched in soils. The bacterial communities in this basin exhibited a distinct vertical stratification from the surface layer down to the bottom soil layer. Considering the interaction between the community composition and the geochemical properties, we speculate that the degradation of petroleum contaminants in this semi-deserted and deserted soil might represent a microorganism-mediated process and mainly occur in the deeper soil layer. PMID- 30252861 TI - Ilex paraguariensis modulates fat metabolism in Caenorhabditis elegans through purinergic system (ADOR-1) and nuclear hormone receptor (NHR-49) pathways. AB - Ilex paraguariensis is a well-known plant that is widely consumed in South America, primarily as a drink called mate. Mate is described to have stimulant and medicinal properties. Considering the potential anti-lipid effects of I. paraguariensis infusion, we used an extract of this plant as a possible modulator of fat storage to control lipid metabolism in worms. Herein, the I. paraguariensis-dependent modulation of fat metabolism in Caenorhabditis elegans was investigated. C. elegans were treated with I. paraguariensis aqueous extract (1 mg/ml) from L1 larvae stage until adulthood, to simulate the primary form of consumption. Expression of adipocyte triglyceride lipase 1 (ATGL-1) and heat shock protein 16.2, lipid accumulation through C1-BODIPY-C12 (BODIPY) lipid staining, behavioral parameters, body length, total body energy expenditure and overall survival were analyzed. Total body energy expenditure was determined by the oxygen consumption rate in N2, nuclear hormone receptor knockout, nhr 49(nr2041), and adenosine receptor knockout, ador-1(ox489) strains. Ilex paraguariensis extract increased ATGL-1 expression 20.06% and decreased intestinal BODIPY fat staining 63.36%, compared with the respective control group, without affecting bacterial growth and energetic balance, while nhr 49(nr2041) and ador-1(ox489) strains blocked the worm fat loss. In addition, I. paraguariensis increased the oxygen consumption in N2 worms, but not in mutant strains, increased N2 worm survival following juglone exposure, and did not alter hsp-16.2 expression. We demonstrate for the first time that I. paraguariensis can decrease fat storage and increase body energy expenditure in worms. These effects depend on the purinergic system (ADOR-1) and NHR-49 pathways. Ilex paraguariensis upregulated the expression of ATGL-1 to modulate fat metabolism. Furthermore, our data corroborates with other studies that demonstrate that C. elegans is a useful tool for studies of fat metabolism and energy consumption. PMID- 30252863 TI - Hepatocellular carcinoma among US and non-US-born patients with chronic hepatitis B: Risk factors and age at diagnosis. AB - BACKGROUND: Risk factors for hepatocellular carcinoma (HCC) have not been well characterized among African immigrants with chronic hepatitis B virus (HBV) infection. We conducted a case-control study to identify demographic and clinical factors associated with HCC among a diverse cohort of patients with chronic HBV infection seen in a large academic health setting. METHODS: We identified a total of 278 patients with HCC and chronic HBV seen at two medical centers in a 14-year span from January 2002 to December 2015. These cases were age- and sex-matched in a 1:3 ratio with 823 non-cancer control subjects with chronic HBV. Conditional logistic regression was used to estimate the odds of HCC by race, with black race stratified by African-born status, after adjusting for diabetes, HIV or HCV coinfection, alcohol misuse and cirrhosis. RESULTS: Of the 278 HCC cases, 67% were 60 years of age or older, 78% were male, 87% had cirrhosis and 72% were Asian. HIV infection was present in 6% of cases. Only 7% (19 of 278) of HCC cases were black, of whom 14 were African immigrants. The median age at HCC diagnosis was 44 years in Africans. Notably, nearly all (93%) of the African-born patients with HCC were diagnosed at an age younger than 60 years compared with 52% of Asian cases (P<0.001). The main factors independently associated with greater odds of HCC overall were Asian race (adjusted odds ratio [aOR] 3.3, 95% confidence interval [CI] 1.9-5.5) and cirrhosis (aOR 19.7, 95% CI 12.2-31.8). CONCLUSION: African immigrants accounted for a small proportion of HBV-associated HCC cases overall compared with Asians but appeared to have greater likelihood of early-onset HCC. Optimal strategies for HCC prevention in these key subroups with chronic HBV warrant further study. PMID- 30252865 TI - Prevalence of intestinal parasites versus knowledge, attitude and practices (KAPs) with special emphasis to Schistosoma mansoni among individuals who have river water contact in Addiremets town, Western Tigray, Ethiopia. AB - BACKGROUND: Intestinal parasite infections are major public health problems in resource-limited countries that adversely affect the well-being of millions. Among these, intestinal schistosomiasis is a serious public health problem in tropical and sub-tropical countries. METHODS: A Community based cross sectional study was conducted from February to April 2017 in Addiremets town, Ethiopia. Socio-demographic associated risk factors and knowledge, attitude and practices of individuals regarding intestinal parasite infection including schistosomiasis were collected from 411 study participants using pretested structured questionnaires. From each study participant, a fresh stool sample was collected and direct microscopy, formol-ether concentration and Kato- Katz techniques were performed. Snails were checked and collected from the nearby study area river. The collected data was entered and analyzed using SPSS version 20. Bi-variant and multiple logistic regressions were used for correlation analysis. A P <0.05 was considered as statistically significant. RESULT: The overall intestinal parasite prevalence was 51.3% (211/411). The most prevalent parasites were S. mansoni 26.3%(108/411) and Hookworm 23.1%(95/411). The prevalence of intestinal parasites among males and females were 54.1%(131/242) and 47.3%(80/169) respectively. The highest proportion of parasite infection was reported among the age group of 5-9 year old participants, at 70.6%(36/51). The prevalence of S. mansoni was 26.3% (108/411) with mean infection intensity of 218 eggs per gram (range: 24 to 1728). Among study participants, 94.4% had good knowledge while 35.9% of them had poor practices towards intestinal parasite and Schistosomes infection prevention. CONCLUSION: High prevalence of intestinal parasitic infection was observed in Addiremets town and the most common parasites identified were S. mansoni and Hookworm. Most study participants had light infection intensity of Schistosomiasis, Ascariasis and Hookworm infection. Majority of the participants in the study area had good knowledge and positive attitude about intestinal parasitic infection and schistosomiasis control. Shells of Biomphalaria species, Bulinus species and Physa species were collected from the Mytsaeda river shore. PMID- 30252866 TI - An experimental study on the flocculating settling of unclassified tailings. AB - Unclassified tailings are the main backfilling aggregates in mines and their settling is the first step in the utilization of tailings; thus, it is very important to determine their settling behavior. The aim of this study was to understand the flocculating settling behavior of unclassified tailings with different factors. The combination of property detection, laboratory experiments and industrial tests were used to assess the flocculating settling behavior of unclassified tailings; the orthogonal experimental design and the control variate method were used for an experimental design. The results show that the flocculating settling velocity of unclassified tailings decreases with the increase of slurry concentration and that this settling velocity increases first and then decreases with the increase of flocculant unit consumption. The underflow concentration is positively correlated with the slurry concentration and negatively correlated with the flocculant unit consumption and flocculant concentration. Slower feed velocity could produce higher concentration underflow but lower clarity overflow water. The greater the mud height, the higher the underflow concentration and the suspended solids concentration in the overflow water. The underflow concentration has a maximum at the rake speed of 0.3 r/min, and the rake speed has little effect on the suspended solids concentration in the overflow water. By analyzing the settling velocity, the underflow concentration, the suspended solids concentration in the overflow water and the solid flux, the following parameters of the flocculating settling experiments were determined: the flocculant type is APAM with a molecular weight of 12 million, the flocculant unit consumption is 30 g/t, the slurry concentration is 6 vol.%, the flocculant concentration is 0.1 wt.%, the rake speed is 0.3 r/min, and the feed velocity is 0.4 L/min (its solid flux is 0.523 t/(m2.h)). The industrial tests were carried out based on the laboratory settling data, and the appropriate selection parameters of the industrial tests were estimated. PMID- 30252864 TI - Financial incentives for objectively-measured physical activity or weight loss in adults with chronic health conditions: A meta-analysis. AB - OBJECTIVE: We conducted a meta-analysis and systematic review of published randomized controlled trials (RCTs) to evaluate the impact of financial incentives (FI) on objectively-measured physical activity (PA) and weight loss (WL) in adults with sedentary behavior or chronic health conditions. EVIDENCE REVIEW: We performed a systematic search for RCTs published in English indexed in PubMed, Embase, or Web of Science through July 27, 2017. We limited our search to RCTs that involved an FI intervention with a monetary component, objectively measured PA or WL outcomes, samples with either sedentary lifestyles or chronic health conditions, and a comparator group that did not receive performance contingent FI. We calculated the mean difference and standardized mean difference (SMD) for each study and used a random effects model to summarize intervention efficacy. We used the Jadad scoring tool to assess the quality of the identified articles. RESULTS: We abstracted data from 11 RCTs. Two of the 11 included studies focused on PA, totaling 126 intervention and 116 control subjects. Nine RCTs evaluated the effect of FI on WL, totaling 1,799 intervention and 1,483 control subjects. The combined estimate for change in daily steps was 940 (95%CI [306-1,574]) more in PA intervention groups than in control groups and 2.36 (95%CI [1.80-2.93]) more kilograms lost by WL intervention groups compared to control groups. The overall estimated SMD for both outcomes combined was 0.395 (95%CI [0.243-0.546; p<0.001]), favoring FI interventions. CONCLUSION: FI interventions are efficacious in increasing PA and WL in adults with chronic conditions or sedentary adults. Public health programs to increase PA or prevent chronic disease should consider incorporating FI to improve outcomes. PMID- 30252867 TI - Participation in a school-based walking intervention changes the motivation to undertake physical activity in middle-school students. AB - The motivation to perform physical activity is a crucial factor in achieving a persistent active lifestyle. However, motivation decreases with increasing age from childhood to adolescence. The promotion of physical activity in educational settings might be an important tool to increase motivation and, consequently, to decrease sedentary behavior. The aim of this study was to explore the effect of a 4-month school-based walking intervention on motivation to participate in physical activity among Italian middle-school students. This study included 276 students (mean age 13 +/- 1 years, 41.3% female). A total of 138 students (intervention group) participated in a brief walking intervention that was added to their routine daily school activity, while a convenience sample of 138 students performed the routine daily school activity. The activity consisted of walking one kilometer outside of school buildings during the morning break. Motivation data were collected before and after the walking breaks using the Participation Motivation Questionnaire (PMQ). Controlling for age, significant interactions between group and time were observed in the "Social Status" [F(1,273) = 4.851; p = 0.028], "Team" [F(1,273) = 6.015; p = 0.015] and "Energy Release" components [F(1,273) = 8.527; p = 0.038]. Specifically, a significant decrease in the "Social Status" components of the PMQ and an increase in the "Team" and "Energy Release" components were observed in the intervention group. On the contrary. control group showed an increase in "Social Status" and a decrease in the "Team" and "Energy Release" components. Within this developmental context, incorporation of the walking activity helped to modify the motivational orientation towards physical activity to include more intrinsic factors, which were related to the possibility of remaining with classmates and peer groups and releasing a surplus of energy. PMID- 30252868 TI - Rheumatic heart disease awareness in the South West region of Cameroon: A hospital based survey in a Sub-Saharan African setting. AB - BACKGROUND: Early diagnosis and adequate treatment of Group A streptococcal throat infection is an important initial stage in the primary prevention of acute rheumatic fever and rheumatic heart disease. This preventable condition associated with high mortality rates mandates a thorough understanding by the general public and the health. OBJECTIVE: The aim of the study was to assess the level of awareness about different aspects of rheumatic heart disease in patients coming to the outpatient department of the Buea regional Hospital, South West region of Cameroon. METHODS: This was a cross-sectional descriptive study carried in the outpatient department of the Buea Regional Hospital, Cameroon. The study population was adults and children aged 9 years and above. Data collection was done by using a self-administered questionnaire addressed to assess awareness on rheumatic heart disease. RESULTS: A total of 256 participants were interviewed, of which 70 (27.3%) were males. Their mean age was 34.4 +/- 11.9 years (males: 36.2 +/- 12.7 years versus females: 33.7 +/- 11.6 years, p = 0.129). Most of the participants were in the 20 to 29 year old group (37.9%). More than two thirds (71.1%) of the participants reported having had sore throat at least once. The disease was treated with antibiotics in only 45.4%, with the treatment prescribed by a health care professional in 35.8% of the cases. About 73% of the respondents did not know what causes sore throat, and most (71.1%) were unaware of any complications that could arise from poorly treated sore throat. More than 70% of the participants did not know that sore throat can be associated with heart disease. Rheumatic heart disease was unknown to 82% of the participants and 95% of them did not know what causes RHD. Only 5.1% percent of the participants had an adequate knowledge of RHD. Age <= 35 years, post-secondary level of education, and having heard of RHD were significantly associated with an adequate knowledge. After adjusting for age, post-secondary education (aOR: 9, [95% C: 1.2-67.5], p = 0.019), and having heard of RHD (aOR: 18.1, [95% CI: 4.7-70.3], p<0.001) were still associated with a fair knowledge. CONCLUSIONS: Levels of knowledge and awareness on rheumatic heart disease is low. This study provides important insight into the perception and practices related to sore throat that can be used in the design of awareness activities aimed reducing the risk of RHD in Cameroon. The appropriateness of antibiotics prescribed, and the health care provider awareness and knowledge levels regarding RHD in Cameroon has not been reported yet in the literature. This grey area deserves more research. PMID- 30252869 TI - Green forage and fattening duration differentially modulate cecal microbiome of Wanxi white geese. AB - Gut microbial ecology is responsible for fatty acid metabolism in ruminants. The cecal microbiota composition of geese and their adaptation to fiber inclusion and feeding timeswere investigated in this study. A total of 116 Wanxi white geese were randomly selected at 70 days old. Eight geese were subjected to cecal sampling at 70 d of age, and the remaining 108 geese were divided into four groups with three replicates each (9 geese in each replicate). The geese in the four groups were fed 0, 15, 30, and 45% green forage (relative to dry matter), respectively. Three birds from each replicate were selected for cecal sampling at 80, 90, and 100 days old. All samples were subjected to 16S rRNA gene sequencing using the Illumina Ion Personal Genome Machine platform. Bacterial abundance was analyzed using two-way ANOVA analysis, and the relationship between the relative abundance of bacteria (phylum level) and fatty acids was analyzed using acanonical correspondence analysis. Cecal microbiota in geese were mainly composed of Bacteroidetes (68.46%), Firmicutes (20.04%), and Proteobacteria (7.89%). Dietary treatments had no significant effect on the alpha-diversity indices of the cecal bacterial community (P > 0.05), but a numerical increase occurred with increased fattening duration and green forage inclusion. The Selenomonadales order (P = 0.024), Negativicutes class (P = 0.026), and Megamonas (P = 0.012) and Oscillospira (P = 0.042) genera were affected by green forageinclusion level, and microflora abundance was mainly influenced by the fattening duration. Bacteria phyla were mostly set along the line of linolenic acid and oleic acid. Finally, Bacteroidales might be an intestinal promoter that improves unsaturated fatty acid synthesis in geese. PMID- 30252870 TI - Associations between graduated driver licensing and road trauma reductions in a later licensing age jurisdiction: Queensland, Australia. AB - The success of driver graduated licensing systems (GLS) is demonstrated primarily in jurisdictions that licence at young ages with requirements expiring at age 18. In Australia, GLS requirements typically apply for all applicants aged under 25. In 2007, the Queensland licensing system was strengthened, extending the learner and introducing a 100-hour supervised driving requirement, introducing restrictions on passenger carriage at night and high-powered vehicles for provisional drivers, and on phone use for all novice drivers (learner and provisional). The objective of the current research was to evaluate whether these changes were associated with reductions in crashes (all) and killed-and-serious injury (KSI) crashes involving novice drivers, and respective casualties. Government licensing and police crash records were linked and interrupted time series analysis was used to examine potential shifts in crash trends by rates of licensed drivers per month. Substantial declines were found in novice driver crashes (13.1% per year; 95%CI -0.0130, -0.0096), crash casualties (13.9% per year; 95%CI -0.0137, -0.0101), KSI crashes (5.4% per year; 95%CI -0.0080, 0.0046) and associated casualties (5.2% per year; 95%CI -0.0075, -0.0039). Compared to the total licensed driver population, declines in crashes (3.0% per year; 95%CI -0.0027, -0.0007) and crash casualties (2.9% per year; 95%CI -0.0029, -0.0006) but not KSI outcomes were observed. More narrowly, declines were found for provisional-licensed driver crashes (9.3% per year; 95%CI -0.0096, -0.0063) and KSI crashes (3.6% per year; 95%CI -0.0004, -0.0128) that were approximately 2.6% and 1.2% greater than respective declines for 25-29-year-old open-licensed drivers. Substantial declines also were observed in novice driver single-vehicle, night, passenger and alcohol crashes. Overall, these results demonstrate that GLS can be effective in a later age licensing jurisdiction. However, KSI outcomes were limited. Modelling research is recommended on ways to further strengthen Queensland's GLS to achieve greater trauma reductions. PMID- 30252872 TI - Smoothed particle hydrodynamics simulation of a laser pulse impact onto a liquid metal droplet. AB - The impact of a laser pulse onto a liquid metal droplet is numerically investigated by utilising a weakly compressible single phase model; the thermodynamic closure is achieved by the Tait equation of state (EoS) for the liquid metal. The smoothed particle hydrodynamics (SPH) method, which has been employed in the arbitrary Lagrangian Eulerian (ALE) framework, offers numerical efficiency, compared to grid related discretization methods. The latter would require modelling not only of the liquid metal phase, but also of the vacuum, which would necessitate special numerical schemes, suitable for high density ratios. In addition, SPH-ALE allows for the easy deformation handling of the droplet, compared to interface tracking methods where strong mesh deformation and most likely degenerate cells occur. Then, the laser-induced deformation of the droplet is simulated and cavitation formation is predicted. The ablation pattern due to the emitted shock wave and the two low pressure lobes created in the middle of the droplet because of the rarefaction waves are demonstrated. The liquid metal droplet is subject to material rupture, when the shock wave, the rarefaction wave and the free surface interact. Similar patterns regarding the wave dynamics and the hollow structure have been also noticed in prior experimental studies. PMID- 30252871 TI - Dexamethasone counteracts hepatic inflammation and oxidative stress in cholestatic rats via CAR activation. AB - Glucocorticoids (GCs) are currently used for the therapeutic management of cholestatic diseases, but their use and molecular mechanism remain controversial. The aims of this study were 1) to assess the therapeutic effect of a 2-week treatment with the GC dexamethasone on hepatic damage in bile duct-ligated rats; 2) to investigate its effect on the activation of the nuclear receptors (NRs) pregnane X receptor (PXR), constitutive androstane receptor (CAR) and GC receptor (GR), and NF-kB, as well as on oxidative stress and bile acid (BA) hepatic composition. Cholestasis was induced by ligation of bile duct (BDL animals) in 16 male Wistar-Kyoto rats, and eight of them were daily treated by oral gavage with 0.125 mg/ml/kg DEX for 14 days. Eight Sham-operated rats were used as controls. Severity of cholestasis was assessed histologically and on plasma biochemical parameters. The nuclear expression of NF-kB (p65), GR, PXR and CAR was measured in hepatic tissue by Western Blot. Oxidative stress was evaluated by measuring malondialdehyde, carbonylated proteins, GHS and ROS content in rat livers. LC-MS was used to measure the plasma and liver concentration of 7 BAs. Histological findings and a significant drop in several markers of inflammation (p65 nuclear translocation, mRNA expressions of TNF-alpha, IL-1beta, IL-6) showed that DEX treatment reversed cholestasis-induced inflammation, and similar results have been obtained with oxidative stress markers. The nuclear expression of p65 and CAR were inversely correlated, with the latter increasing significantly after DEX treatment (p<0.01 vs vehicle). Hepatic BA levels tended to drop in the untreated cholestatic rats, whereas they were similar to those of healthy rats in DEX treated animals. Plasma BAs decreased significantly in DEX-treated animals with respect to untreated cholestatic rats. In conclusion, DEX reduces inflammation and oxidative stress in BDL rats, and probably CAR is responsible for this effect. Therefore, this NR represents a promising pharmacological target for managing cholestatic and inflammatory liver diseases. PMID- 30252873 TI - Risks of treated anxiety, depression, and insomnia among nurses: A nationwide longitudinal cohort study. AB - The high level of occupational stress and burnout among nurses can lead to insomnia, anxiety, and depression. However, the actual risks for healthcare seeking for these stress-related mental health problems among nurses are still unclear. The aim of this study was to explore the risks and influencing factors of treated anxiety, depression, and insomnia among nurses. We used claims data obtained from the 2010 National Health Insurance Research Database (NHIRD) in Taiwan. Hospital nurses who had at least 3 coded ambulatory care claims or 1 inpatient claim with a principal diagnosis of anxiety, depression, or insomnia were identified. A cohort of 46,120 nurses and 92,240 matched controls were included. All the study subjects were followed up until the onset of any of the aforementioned outcomes, death, or the end of 2012. Results showed that the adjusted hazard ratios (HRs) for treated anxiety, depression, and insomnia among all the nurses were 0.91 (95% CI, 0.88-0.95), 0.59 (95% CI, 0.55-0.63), and 1.43 (95% CI, 1.38-1.48), respectively. Furthermore, the risks of these psychiatric problems in healthcare-seeking nurses were affected by age, gender, hospital level, and job tenure. Our findings suggest that hospital nurses have lower hazards of treated anxiety and depression than the general population, although they have a higher hazard of treated insomnia. There may be undertreatment in some subgroups of nurses with different demographic and working characteristics. PMID- 30252874 TI - Time-series clustering of cage-level sea lice data. AB - Sea lice Lepeophtheirus salmonis (Kroyer) are a major ectoparasite affecting farmed Atlantic salmon in most major salmon producing regions. Substantial resources are applied to sea lice control and the development of new technologies towards this end. Identifying and understanding how sea lice population patterns vary among cages on a salmon farm can be an important step in the design and analysis of any sea lice control strategy. Norway's intense monitoring efforts have provided salmon farmers and researchers with a wealth of sea lice infestation data. A frequently registered parameter is the number of adult female sea lice per cage. These time-series data can be analysed descriptively, the similarity between time-series quantified, so that groups and patterns can be identified among cages, using clustering algorithms capable of handling such dynamic data. We apply such algorithms to investigate the pattern of female sea lice counts among cages for three Atlantic salmon farms in Norway. A series of strategies involving a combination of distance measures and prototypes were explored and cluster evaluation was performed using cluster validity indices. Repeated agreement on cluster membership for different combinations of distance and centroids was taken to be a strong indicator of clustering while the stability of these results reinforced this likelihood. Though drivers behind clustering are not thoroughly investigated here, it appeared that fish weight at time of stocking and other management practices were strongly related to cluster membership. In addition to these internally driven factors it is also possible that external sources of infestation may drive patterns of sea lice infestation in groups of cages; for example, those most proximal to an external source. This exploratory method proved useful as a pattern discovery tool for cages in salmon farms. PMID- 30252875 TI - Association of men's exposure to family planning programming and reported discussion with partner and family planning use: The case of urban Senegal. AB - BACKGROUND: Family planning programs increasingly aim to encourage men to be involved in women's reproductive health decision-making as well as support men to be active agents of change for their own and the couple's reproductive health needs. This study contributes to this area of work by examining men's exposure to family planning (FP) program activities in urban Senegal and determining whether exposure is associated with reported FP use and discussion of family planning with female partners. METHODS: This study uses data from two cross-sectional surveys of men in four urban sites of Senegal (Dakar, Pikine, Guediawaye, Mbao). In 2011 and 2015, men ages 15-59 in a random sample of households from study clusters were approached and asked to participate in a survey about their fertility and family planning experiences. These data were used to determine the association between exposure to the Initiative Senegalaise de Sante Urbaine (in English: Senegal Urban Reproductive Health Initiative) family planning program interventions with men's reported modern family planning use and their reported discussion of FP with their partners. Since data come from the same study clusters at each time period, fixed effects methods at the cluster level allowed us to control for possible program targeting by geographic area. RESULTS: Multivariate models demonstrate that religious leaders speaking favorably about family planning, seeing FP messages on the television, hearing FP messages on the radio, and exposure to community outreach activities with a FP focus (e.g., house to house and community religious dialogues) are associated with reported modern family planning use and discussion of family planning with partners among men in the four urban sites of Senegal. CONCLUSIONS: This study demonstrates that it is possible to reach men with FP program activities in urban Senegal and that these activities are positively associated with reported FP behaviors. PMID- 30252876 TI - Extracellular matrix with defective collagen cross-linking affects the differentiation of bone cells. AB - Fibrillar type I collagen, the predominant organic component in bone, is stabilized by lysyl oxidase (LOX)-initiated covalent intermolecular cross linking, an important determinant of bone quality. However, the impact of collagen cross-linking on the activity of bone cells and subsequent tissue remodeling is not well understood. In this study, we investigated the effect of collagen cross-linking on bone cellular activities employing a loss-of-function approach, using a potent LOX inhibitor, beta-aminopropionitrile (BAPN). Osteoblastic cells (MC3T3-E1) were cultured for 2 weeks in the presence of 0-2 mM BAPN to obtain low cross-linked collagen matrices. The addition of BAPN to the cultures diminished collagen cross-links in a dose-dependent manner and, at 1 mM level, none of the major cross-links were detected without affecting collagen production. After the removal of cellular components from these cultures, MC3T3 E1, osteoclasts (RAW264.7), or mouse primary bone marrow-derived stromal cells (BMSCs) were seeded. MC3T3-E1 cells grown on low cross-link matrices showed increased alkaline phosphatase (ALP) activity. The number of multinucleate tartrate-resistant acid phosphatase (TRAP)-positive cells increased in RAW264.7 cells. Initial adhesion, proliferation, and ALP activity of BMSCs also increased. In the animal experiments, 4-week-old C57BL/6 mice were fed with BAPN-containing diet for 8 weeks. At this point, biochemical analysis of bone demonstrated that collagen cross-links decreased without affecting collagen content. Then, the diet was changed to a control diet to minimize the direct effect of BAPN. At 2 and 4 weeks after the change, histological samples were prepared. Histological examination of femur samples at 4 weeks showed a significant increase in the number of bone surface osteoblasts, while the bone volume and surface osteoclast numbers were not significantly affected. These results clearly demonstrated that the extent of collagen cross-linking of bone matrix affected the differentiation of bone cells, underscoring the importance of collagen cross-linking in the regulation of cell behaviors and tissue remodeling in bone. Characterization of collagen cross-linking in bone may be beneficial to obtain insight into not only bone mechanical property, but also bone cellular activities. PMID- 30252877 TI - Transcriptional profiling reveals that a MYB transcription factor MsMYB4 contributes to the salinity stress response of alfalfa. AB - MYB transcription factors are important regulators of the plant response to abiotic stress. Their participation in the salinity stress of the key forage legume species alfalfa (Medicago sativa) was investigated here by comparing the transcriptomes of the two cultivars Dryland (DL) and Sundory (SD), which differed with respect to their ability to tolerate salinity stress. When challenged by the stress, DL plants were better able than SD ones to scavenge reactive oxygen species. A large number of genes encoding transcription regulators, signal transducers and proteins involved in both primary and secondary metabolism were differentially transcribed in the two cultivars, especially when plants were subjected to salinity stress. The set of induced genes included 17 MYB family of transcription factors, all of which were subsequently isolated. The effect of constitutively expressing these genes on the salinity tolerance expressed by Arabidopsis thaliana was investigated. The introduction of MsMYB4 significantly increased the plants' salinity tolerance in an abscisic acid-dependent manner. A sub-cellular localization experiment and a transactivation assay indicated that MsMYB4 was deposited in the nucleus and was able to activate transcription in yeast. Based on this information, we propose that the MsMYB4 products is likely directly involved in alfalfa's response to salinity stress. PMID- 30252879 TI - Measuring vulnerability among female sex workers in India using a multidimensional framework. AB - Measuring vulnerability and identifying determinants of vulnerability are key to designing interventions for marginalized groups like sex workers. The current study introduces a new approach of measuring vulnerability among female sex workers (FSWs) by adopting a multidimensional poverty measurement framework. A multidimensional vulnerability index was created from four dimensions and 16 indicators using a dual cut-off approach. The study found that 55% of FSWs were multidimensionally vulnerable with 48% of intensity in vulnerability. The overall value of multidimensional vulnerability index was 0.265. FSWs in Maharashtra were most vulnerable (82%). Lack of financial security contributed mostly to FSWs' vulnerability. Further, compared to less vulnerable FSWs, multidimensionally vulnerable ones were more to engage in behaviors that put them at risk such as inconsistent use of condoms with clients, alcohol consumption, engaging in anal sex with clients and experiencing sexually transmitted infections. Findings suggest that structural, social and financial vulnerabilities of FSWs need to be addressed concurrently. PMID- 30252878 TI - Pharmacologic control of oxidative stress and inflammation determines whether diabetic glomerulosclerosis progresses or decreases: A pilot study in sclerosis prone mice. AB - Diabetic kidney disease (DKD) is characterized by progressive glomerulosclerosis (GS). ROP mice have a sclerosis-prone phenotype. However, they develop severe, rapidly progressive GS when rendered diabetic. Since GS also develops in aged C57Bl6 mice, and can be reversed using bone marrow from young mice which have lower oxidative stress and inflammation (OS/Infl), we postulated that this might also apply to DKD. Therefore, this pilot study asked whether reducing OS/Infl in young adult sclerosis-prone (ROP) diabetic mice leads to resolution of existing GS in early DKD using safe, FDA-approved drugs.After 4 weeks of stable streptozotocin-induced hyperglycemia 8-12 week-old female mice were randomized and treated for 22 weeks as follows: 1) enalapril (EN) (n = 8); 2) pyridoxamine (PYR)+EN (n = 8); 3) pentosan polysulfate (PPS)+EN (n = 7) and 4) PPS+PYR+EN (n = 7). Controls were untreated (non-DB, n = 7) and hyperglycemic (DB, n = 8) littermates. PPS+PYR+EN reduced albuminuria and reversed GS in DB. Treatment effects: 1) Anti-OS/Infl defenses: a) PPS+PYR+EN increased the levels of SIRT1, Nrf2, estrogen receptor alpha (ERalpha) and advanced glycation endproduct receptor1 (AGER1) levels; and b) PYR+EN increased ERalpha and AGER1 levels. 2) Pro-OS/Infl factors: a) PPS+PYR+EN reduced sTNFR1, b) all except EN reduced MCP1, c) RAGE was reduced by all treatments. In summary, PYR+PPS+EN modulated GS in sclerosis-prone hyperglycemic mice. PYR+PPS+EN also decreased albuminuria, OS/Infl and the sclerosis-prone phenotype. Thus, reducing OS/Infl may reverse GS in early diabetes in patients, and albuminuria may allow early detection of the sclerosis-prone phenotype. PMID- 30252880 TI - Whose emotion is it? Measuring self-other discrimination in romantic relationships during an emotional evaluation paradigm. AB - In healthy subjects, emotional stimuli, positive stimuli in particular, are processed in a facilitated manner as are stimuli related to the self. These preferential processing biases also seem to hold true for self-related positive stimuli when compared to self-related negative or other-related positive stimuli suggesting a self-positivity bias in affective processing. The present study investigates the stability of this self-positivity bias and its possible extension to the emotional other in a sample of N = 147 participants including single participants (n = 61) and individuals currently in a romantic relationship (n = 86) reporting moderate to high levels of passionate love. Participants were presented a series of emotional and neutral words that could be related to the reader's self (e.g., "my pleasure", "my fear"), or to an insignificant third person, unknown to the reader (e.g., "his pleasure", "his fear") or devoid of any person reference (e.g., "the pleasure", "the fear"). The task was to read the words silently and to evaluate the word pairs in reference to one's own feelings elicited during reading. Results showed a self-positivity bias in emotional judgments in all participants, particularly in men. Moreover, participants in a romantic relationship (women and men) evaluated positive, other-related stimuli more often as valence-congruent with one's own feelings than single participants. Taken together, these findings support the idea of a self-positivity bias in healthy subjects and an expansion of this bias while being in a romantic relationship. PMID- 30252881 TI - AIF-1 gene does not confer susceptibility to Behcet's disease: Analysis of extended haplotypes in Sardinian population. AB - BACKGROUND: Behcet's disease (BD) is a polygenic immune-mediated disorder characterized by a close association with the HLA-B*51 allele. The HLA region has a strong linkage disequilibrium (LD) and carries several genetic variants (e.g. MIC-A, TNF-alpha genes) identified as associated to BD because of their LD with HLA-B*51. In fact, the HLA-B*51 is inherited as part of extended HLA haplotypes which are well preserved in patients with BD. Sardinian population is highly differentiated from other Mediterranean populations because of a distinctive genetic structure with very highly preserved HLA haplotypes. PATIENTS AND METHODS: In order to identify other genes of susceptibility to BD within the HLA region we investigated the distribution of human Allograft Inflammatory Factor-1 (AIF-1) gene variants among BD patients and healthy controls from Sardinia. Six (rs2736182; rs2259571; rs2269475; rs2857597; rs13195276; rs4711274) AIF-1 single nucleotide polymorphisms (SNPs) and related extended haplotypes have been investigated as well as their LD within the HLA region and with HLA-B*51. Overall, 64 BD patients, 43 HLA-B*51 positive healthy controls (HC) and 70 random HC were enrolled in the study. RESULTS: HLA-B*51 was the only allele with significantly higher frequency (pc = 0.0021) in BD patients (40.6%) than in HC (9.8%). The rs2259571T AIF-1 variant had a significantly reduced phenotypic, but not allelic frequency in BD patients (72.1%; pc = 0.014) compared to healthy population (91.3%). That was likely due to the LD between HLA-B*51 and rs2259571G (pc = 9E-5), even though the rs2259571G distribution did not significantly differ between BD patients and HC. CONCLUSION: No significant difference in distribution of AIF-1 SNPs haplotypes was observed between BD patients and HC and between HLA B*51 positive BD patients and HLA-B*51 positive HC. Taken together, these results suggest that AIF-1 gene is not associated with susceptibility to BD in Sardinia. PMID- 30252882 TI - Characterization of zebrafish (Danio rerio) muscle ankyrin repeat proteins reveals their conserved response to endurance exercise. AB - Muscle proteins with ankyrin repeats (MARPs) ANKRD1 and ANKRD2 are titin associated proteins with a putative role as transcriptional co-regulators in striated muscle, involved in the cellular response to mechanical, oxidative and metabolic stress. Since many aspects of the biology of MARPs, particularly exact mechanisms of their action, in striated muscle are still elusive, research in this field will benefit from novel animal model system. Here we investigated the MARPs found in zebrafish for protein structure, evolutionary conservation, spatiotemporal expression profiles and response to increased muscle activity. Ankrd1 and Ankrd2 show overall moderate conservation at the protein level, more pronounced in the region of ankyrin repeats, motifs indispensable for their function. The two zebrafish genes, ankrd1a and ankrd1b, counterparts of mammalian ANKRD1/Ankrd1, have different expression profiles during first seven days of development. Mild increase of ankrd1a transcript levels was detected at 72 hpf (1.74+/-0.24 fold increase relative to 24 hpf time point), while ankrd1b expression was markedly upregulated from 24 hpf onward and peaked at 72 hpf (92.18+/-36.95 fold increase relative to 24 hpf time point). Spatially, they exhibited non-overlapping expression patterns during skeletal muscle development in trunk (ankrd1a) and tail (ankrd1b) somites. Expression of ankrd2 was barely detectable. Zebrafish MARPs, expressed at a relatively low level in adult striated muscle, were found to be responsive to endurance exercise training consisting of two bouts of 3 hours of forced swimming daily, for five consecutive days. Three hours after the last exercise bout, ankrd1a expression increased in cardiac muscle (6.19+/-5.05 fold change), while ankrd1b and ankrd2 were upregulated in skeletal muscle (1.97+/-1.05 and 1.84+/-0.58 fold change, respectively). This study provides the foundation to establish zebrafish as a novel in vivo model for further investigation of MARPs function in striated muscle. PMID- 30252884 TI - Association of physical activity and sedentary time with blood cell counts: National Health and Nutrition Survey 2003-2006. AB - OBJECTIVE: To assess the association of objectively measured levels of physical activity and sedentary time with major blood cell counts (e.g. white blood cells, red blood cells, platelets) among adults. METHODS: Data collected from the 2003 2004 and 2005-2006 cycles of the National Health and Nutrition Examination Survey (NHANES) was used to assess blood cell counts in relation to objectively measured physical activity and sedentary time (accelerometer). A series of linear regressions modes were used to assess these associations adjusting for a range of factors known to be associated with blood cell counts, including age, body mass index, dietary factors, and previous infections. RESULTS: Higher levels of moderate-vigorous physical activity (ptrend<0.001) and lower sedentary time (ptrend = 0.040) were associated with lower white blood cell counts. CONCLUSION: These results suggest that modifiable health behaviors, such as physical activity and sedentary time, may be associated with inflammatory status through white blood cell counts, which may be important for future disease risk. PMID- 30252885 TI - Molecular analysis of the chromosomal 16S rRNA gene and vapA plasmid gene of Polish field strains of R. equi. AB - Rhodococcus equi (R. hoagii) is an opportunistic pathogen commonly found in foals up to 6 months old and animal environment. The R. equi genome contains genetically stable chromosomal DNA and an 80-90 kb plasmid containing vapA gene, responsible for virulence. Most reports from around the world focus on the determination of R. equi plasmid profiles. Few studies have attempted to determine differences in nucleotide sequences between virulent strains of R. equi isolated from foals and breeding environment. The aim of the study was to perform a molecular analysis of a fragment of the chromosomal gene encoding the 16S rRNA subunit and the vapA plasmid gene of virulent R. equi strains isolated on Polish studs from foals and from the breeding environment of horses. The sequencing method was used to compare the primary structure of fragments of the chromosomal and plasmid DNA of the virulent R. equi strains. The sequences of 22 clinical and 18 environmental R. equi isolates were compared with the sequences of the gene fragments of reference strains available in the NCBI GenBank database. All sequenced 16S rRNA amplicons of Polish field strains were identical and showed 99.5% similarity to the four randomly selected sequences of this gene fragment in the GenBank database. The results confirm that fragments of the 16S rRNA gene of R. equi strains are highly conserved and do not undergo variation in field conditions. Analysis of the sequencing results for the vapA gene fragment of the strains used in our study revealed two polymorphic variants and clear differences between the sequences of strains isolated from foals and from soil samples. Presumably, R. equi strains present in the breeding environment are more exposed than clinical strains to adverse external factors. This may result in changes in the DNA sequence due to natural selection. PMID- 30252886 TI - Beyond the numbers: Human attitudes and conflict with lions (Panthera leo) in and around Gambella National Park, Ethiopia. AB - Human-lion conflict is one of the leading threats to lion populations and while livestock loss is a source of conflict, the degree to which livestock depredation is tolerated by people varies between regions and across cultures. Knowledge of local attitudes towards lions and identification of drivers of human-lion conflict can help formulate mitigation measures aimed at promoting coexistence of humans with lions. We assessed locals' attitudes towards lions in and around Gambella National Park and compared the findings with published data from Kafa Biosphere Reserve, both in western Ethiopia. We used household interviews to quantify livestock loss. We found that depredation was relatively low and that disease and theft were the top factors of livestock loss. Remarkably, however, tolerance of lions was lower around Gambella National Park than in Kafa Biosphere Reserve. Multivariate analysis revealed that education level, number of livestock per household, livestock loss due to depredation, and livestock loss due to theft were strong predictors of locals' attitude towards lion population growth and conservation. We show that the amount of livestock depredation alone is not sufficient to understand human-lion conflicts and we highlight the importance of accounting for cultural differences in lion conservation. The low cultural value of lions in the Gambella region corroborate the findings of our study. In combination with growing human population and land-use change pressures, low cultural value poses serious challenges to long-term lion conservation in the Gambella region. We recommend using Arnstein's ladder of participation in conservation education programs to move towards proactive involvement of locals in conservation. PMID- 30252883 TI - Systematic review update of observational studies further supports aspirin role in cancer treatment: Time to share evidence and decision-making with patients? AB - BACKGROUND: Evidence is growing that low-dose aspirin used as an adjuvant treatment of cancer is associated with an increased survival and a reduction in metastatic spread. We therefore extended up to August 2017 an earlier systematic search and meta-analyses of published studies of low-dose aspirin taken by patients with a diagnosis of cancer. METHODS: Searches were completed in Medline and Embase to August 2017 using a pre-defined search strategy to identify reports of relevant studies. References in all the selected papers were scanned. Two reviewers independently applied pre-determined eligibility criteria and extracted data on cause-specific cancer deaths, overall mortality and the occurrence of metastatic spread. Meta-analyses were then conducted for different cancers and heterogeneity and publication bias assessed. Sensitivity analyses and attempts to reduce heterogeneity were conducted. RESULTS: Analyses of 29 studies reported since an earlier review up to April 2015 are presented in this report, and these are then pooled with the 42 studies in our earlier publication. Overall meta analyses of the 71 studies are presented, based on a total of over 120 thousand patients taking aspirin. Ten of the studies also give evidence on the incidence of metastatic cancer spread. There are now twenty-nine observational studies describing colorectal cancer (CRC) and post-diagnostic aspirin. Pooling the estimates of reduction by aspirin which are reported as hazard ratios (HR), gives an overall HR for aspirin and CRC mortality 0.72 (95% CI 0.64-0.80). Fourteen observational studies have reported on aspirin and breast cancer mortality and pooling those that report the association with aspirin as a hazard ratio gives HR 0.69 (0.53-0.90). Sixteen studies report on aspirin and prostate cancer mortality and a pooled estimate yields an HR of 0.87 (95% CI 0.73-1.05). Data from 12 reports relating to other cancers are also listed. Ten studies give evidence of a reduction in metastatic spread; four give a pooled HR 0.31 (95% CI 0.18, 0.54) and five studies which reported odds ratio of metastatic spread give OR 0.79 (0.66 to 0.95). CONCLUSION: Being almost entirely from observational studies, the evidence of benefit from aspirin is limited. There is heterogeneity between studies and the results are subject to important biases, only some of which can be identified. Nevertheless, the evidence would seem to merit wide discussion regarding whether or not it is adequate to justify the recommendation of low-dose therapeutic aspirin, and if it is, for which cancers? PMID- 30252887 TI - Adult mortality trends in Qatar, 1989-2015: National population versus migrants. AB - INTRODUCTION: With the increase of Qatar's total population, primarily due to the influx of healthy male migrant labor, worldwide attention has been focused on deaths among these migrant workers. OBJECTIVE: To describe adult mortality trends in Qataris (nationals) and non-Qataris (migrants) from all causes, cardiovascular and circulatory disease, neoplasms, and injuries, 1989-2015. METHODS: We retrieved Qatar's vital registration data by nationality, sex, age group, year, and codes of the World Health Organization's International Classification of Diseases, Ninth and Tenth Revisions. We assessed age-standardized mortality rate (ASMR) trends in Qatar's total population, in Qataris and non-Qataris using Joinpoint regression. FINDINGS: During the study period, 26,673 deaths were recorded. In 2015, we estimated 60,716 years of life lost (82% in males) in the overall population. In Qataris (both sexes) and in non-Qatari females, all-cause rate decreased significantly and steadily between 1989-2015. In non-Qatari males, it decreased significantly between 1998-2010 probably attributed to a massive influx of healthy migrants. Yearly rates were significantly lower in non-Qataris over 27 years. Reduction in Qatar's total population rates for all causes and for neoplasms can be partially attributed to the healthy migrant effect. For injuries in males, it was lower in non-Qatari. Remarkably, for falls, cause-specific ASMR in non-Qatari males decreased significantly reaching 2.6/100,000 in 2014, suggesting improved safety in the work environment. However, while young adult males in Qatar die predominantly from injuries, young adult females die from neoplasms. CONCLUSION: Our study demonstrates that premature death in young adult males and females in Qatar is predominantly due to injuries and neoplasms respectively. These identified causes of death are for a large part preventable and should be addressed appropriately to lower premature mortality among young adults in Qatar. PMID- 30252888 TI - Technical-efficiency analysis of end-of-life care in long-term care facilities within Europe: A cross-sectional study of deceased residents in 6 EU countries (PACE). AB - BACKGROUND: An ageing population in the EU leads to a higher need of long-term institutional care at the end of life. At the same time, healthcare costs rise while resources remain limited. Consequently, an urgency to extend our knowledge on factors affecting efficiency of long-term care facilities (LTCFs) arises. This study aims to investigate and explain variation in technical efficiency of end-of life care within and between LTCFs of six EU countries: Belgium (Flanders), England, Finland, Italy, the Netherlands and Poland. In this study, technical efficiency reflects the LTCFs' ability to obtain maximal quality of life (QoL) and quality of dying (QoD) for residents from a given set of resource inputs (personnel and capacity). METHODS: Cross-sectional data were collected by means of questionnaires on deceased residents identified by LTCFs over a three-month period. An output-oriented data-envelopment analysis (DEA) was performed, producing efficiency scores, incorporating personnel and capacity as input and QoL and QoD as output. Scenario analysis was conducted. Regression analysis was performed on explanatory (country, LTCF type, ownership, availability of palliative care and opioids) and case mix (disease severity) variables. RESULTS: 133 LTCFs of only one type (onsite nurses and offsite GPs) were considered in order to reduce heterogeneity. Variation in LTCF efficiency was found across as well as within countries. This variation was not explained by country, ownership, availability of palliative care or opioids. However, in the 'hands-on care at the bedside' scenario, i.e. only taking into account nursing and care assistants as input, Poland (p = 0.00) and Finland (p = 0.04) seemed to be most efficient. CONCLUSIONS: Efficiency of LTCFs differed extensively across as well as within countries, indicating room for considerable efficiency improvement. Our findings should be interpreted cautiously, as comprehensive comparative EU-wide research is challenging as it is influenced by many factors. PMID- 30252889 TI - Spatial statistical tools for genome-wide mutation cluster detection under a microarray probe sampling system. AB - Mutation cluster analysis is critical for understanding certain mutational mechanisms relevant to genetic disease, diversity, and evolution. Yet, whole genome sequencing for detection of mutation clusters is prohibitive with high cost for most organisms and population surveys. Single nucleotide polymorphism (SNP) genotyping arrays, like the Mouse Diversity Genotyping Array, offer an alternative low-cost, screening for mutations at hundreds of thousands of loci across the genome using experimental designs that permit capture of de novo mutations in any tissue. Formal statistical tools for genome-wide detection of mutation clusters under a microarray probe sampling system are yet to be established. A challenge in the development of statistical methods is that microarray detection of mutation clusters is constrained to select SNP loci captured by probes on the array. This paper develops a Monte Carlo framework for cluster testing and assesses test statistics for capturing potential deviations from spatial randomness which are motivated by, and incorporate, the array design. While null distributions of the test statistics are established under spatial randomness via the homogeneous Poisson process, power performance of the test statistics is evaluated under postulated types of Neyman-Scott clustering processes through Monte Carlo simulation. A new statistic is developed and recommended as a screening tool for mutation cluster detection. The statistic is demonstrated to be excellent in terms of its robustness and power performance, and useful for cluster analysis in settings of missing data. The test statistic can also be generalized to any one dimensional system where every site is observed, such as DNA sequencing data. The paper illustrates how the informal graphical tools for detecting clusters may be misleading. The statistic is used for finding clusters of putative SNP differences in a mixture of different mouse genetic backgrounds and clusters of de novo SNP differences arising between tissues with development and carcinogenesis. PMID- 30252891 TI - To fight tuberculosis, fund basic research. AB - Tuberculosis (TB) is now the leading cause of death from infectious disease. On September 26, 2018, the United Nations (UN) General Assembly holds its first high level meeting on TB, a once-in-a-lifetime chance to commit governments around the world to redouble their TB control efforts. Here I share impressions from a preparatory meeting at the UN in June and make the case for basic research as a central component of any future TB control strategy. The pathogen that causes TB, Mycobacterium tuberculosis, is still largely a mystery. But if we do not understand the basic, fundamental workings of the pathogen, we cannot hope to develop 21st century interventions for the disease. PMID- 30252893 TI - Correction: Transcriptome analysis of tomato (Solanum lycopersicum L.) shoots reveals a crosstalk between auxin and strigolactone. AB - [This corrects the article DOI: 10.1371/journal.pone.0201124.]. PMID- 30252890 TI - Humidity as a non-pharmaceutical intervention for influenza A. AB - Influenza is a global problem infecting 5-10% of adults and 20-30% of children annually. Non-pharmaceutical interventions (NPIs) are attractive approaches to complement vaccination in the prevention and reduction of influenza. Strong cyclical reduction of absolute humidity has been associated with influenza outbreaks in temperate climates. This study tested the hypothesis that raising absolute humidity above seasonal lows would impact influenza virus survival and transmission in a key source of influenza virus distribution, a community school. Air samples and objects handled by students (e.g. blocks and markers) were collected from preschool classrooms. All samples were processed and PCR used to determine the presence of influenza virus and its amount. Additionally samples were tested for their ability to infect cells in cultures. We observed a significant reduction (p < 0.05) in the total number of influenza A virus positive samples (air and fomite) and viral genome copies upon humidification as compared to control rooms. This suggests the future potential of artificial humidification as a possible strategy to control influenza outbreaks in temperate climates. There were 2.3 times as many ILI cases in the control rooms compared to the humidified rooms, and whether there is a causal relationship, and its direction between the number of cases and levels of influenza virus in the rooms is not known. Additional research is required, but this is the first prospective study suggesting that exogenous humidification could serve as a scalable NPI for influenza or other viral outbreaks. PMID- 30252892 TI - Non-parametric estimation of survival in age-dependent genetic disease and application to the transthyretin-related hereditary amyloidosis. AB - In genetic diseases with variable age of onset, survival function estimation for the mutation carriers as well as estimation of the modifying factors effects are essential to provide individual risk assessment, both for mutation carriers management and prevention strategies. In practice, this survival function is classically estimated from pedigrees data where most genotypes are unobserved. In this article, we present a unifying Expectation-Maximization (EM) framework combining probabilistic computations in Bayesian networks with standard statistical survival procedures in order to provide mutation carrier survival estimates. The proposed approach allows to obtain previously published parametric estimates (e.g. Weibull survival) as particular cases as well as more general Kaplan-Meier non-parametric estimates, which is the main contribution. Note that covariates can also be taken into account using a proportional hazard model. The whole methodology is both validated on simulated data and applied to family samples with transthyretin-related hereditary amyloidosis (a rare autosomal dominant disease with highly variable age of onset), showing very promising results. PMID- 30252894 TI - Detection of slow port scans in flow-based network traffic. AB - Frequently, port scans are early indicators of more serious attacks. Unfortunately, the detection of slow port scans in company networks is challenging due to the massive amount of network data. This paper proposes an innovative approach for preprocessing flow-based data which is specifically tailored to the detection of slow port scans. The preprocessing chain generates new objects based on flow-based data aggregated over time windows while taking domain knowledge as well as additional knowledge about the network structure into account. The computed objects are used as input for the further analysis. Based on these objects, we propose two different approaches for detection of slow port scans. One approach is unsupervised and uses sequential hypothesis testing whereas the other approach is supervised and uses classification algorithms. We compare both approaches with existing port scan detection algorithms on the flow based CIDDS-001 data set. Experiments indicate that the proposed approaches achieve better detection rates and exhibit less false alarms than similar algorithms. PMID- 30252895 TI - Effect of transcranial pulsed electromagnetic fields (T-PEMF) on functional rate of force development and movement speed in persons with Parkinson's disease: A randomized clinical trial. AB - BACKGROUND: Parkinson's disease is caused by dopaminergic neurodegeneration resulting in motor impairments as slow movement speed and impaired balance and coordination. Pulsed electromagnetic fields are suggested to have neuroprotective effects, and could alleviate symptoms. OBJECTIVE: To study 1) effects of 8-week daily transcranial pulsed electromagnetic field treatment on functional rate of force development and movement speed during two motor tasks with different levels of complexity, 2) if treatment effects depend on motor performance at baseline. METHODS: Ninety-seven persons with Parkinson's disease were randomized to active transcranial pulsed electromagnetic field (squared bipolar 3 ms pulses, 50 Hz) or placebo treatment with homebased treatment 30 min/day for 8 weeks. Functional rate of force development and completion time of a sit-to-stand and a dynamic postural balance task were assessed pre and post intervention. Participants were sub-grouped in high- and low-performers according to their baseline motor performance level. Repeated measure ANOVAs were used. RESULTS: Active treatment tended to improve rate of force development during chair rise more than placebo (P = 0.064). High-performers receiving active treatment improved rate of force development during chair rise more than high-performers receiving placebo treatment (P = 0.049, active/placebo: 11.9+/-1.1 to 12.5+/-1.9 BW/s ~ 5% / 12.4+/ 1.3 to 12.2+/-1.3 BW/s, no change). No other between-treatment-group or between treatment-subgroup differences were found. Data on rate of force development of the dynamic balance task and completion times of both motor tasks improved but did not allow for between-treatment differentiation. CONCLUSION: Treatment with transcranial pulsed electromagnetic fields was superior to placebo regarding functional rate of force development during chair rise among high-performers. Active treatment tended to increase functional rate of force development while placebo did not. Our results suggest that mildly affected persons with Parkinson's disease have a larger potential for neural rehabilitation than more severely affected persons and indicate that early treatment initiation may be beneficial. PMID- 30252896 TI - Dynamics of high-sensitivity cardiac troponin T during therapy with balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. AB - AIMS: Balloon pulmonary angioplasty (BPA) is an interventional treatment modality for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Therapy monitoring, based on non-invasive biomarkers, is a clinical challenge. This post hoc study aimed to assess dynamics of high-sensitivity cardiac troponin T (hs cTnT) as a marker for myocardial damage and its relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels as a marker for cardiac wall stress. METHODS AND RESULTS: This study included 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between 3/2014 and 3/2017. Biomarker measurement was performed consecutively prior to each BPA and at 6-MFU. In total, the 51 patients underwent an average of 5 BPA procedures. The 6-month survival rate was 96.1%. The baseline (BL) meanPAP (39.5+/-12.1mmHg) and PVR (515.8+/-219.2dyn*sec*cm-5) decreased significantly within the 6-MFU (meanPAP: 32.6+/-12.6mmHg, P<0.001; PVR: 396.9+/-182.6dyn*sec*cm-5, P<0.001). At BL, the median hs-cTnT level was 11 (IQR 6-16) ng/L and the median NT-proBNP level was 820 (IQR 153-1872) ng/L. The levels of both biomarkers decreased steadily after every BPA, showing the first significant difference after the first procedure. Within the 6-MFU, hs-cTnT levels (7 [IQR 5-12] ng/L; P<0.001) and NT-proBNP levels (159 [IQR 84-464] ng/l; P<0.001) continued to decrease. The hs-cTnT levels correlated with the PVR (rrs = 0.42; p = 0.005), the meanPAP (rrs = 0.32; p = 0.029) and the NT-proBNP (rrs = 0.51; p<0.001) levels at BL. CONCLUSION: Non-invasive biomarker measurement provides valuable evidence for the decreasing impairment of myocardial function and structure during BPA therapy. Changes in hs-cTNT levels are suggestive for a reduction in ongoing myocardial damage. PMID- 30252897 TI - Arabidopsis thaliana alcohol dehydrogenase is differently affected by several redox modifications. AB - In plant cells, many stresses, including low oxygen availability, result in a higher production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These molecules can lead to redox-dependent post-translational modification of proteins Cys residues. Here, we studied the effect of different redox modifications on alcohol dehydrogenase (ADH) from Arabidopsis thaliana. ADH catalyzes the last step of the ethanol fermentation pathway used by plants to cope with energy deficiency during hypoxic stress. Arabidopsis suspension cell cultures showed decreased ADH activity upon exposure to H2O2, but not to the thiol oxidizing agent diamide. We purified recombinant ADH and observed a significant decrease in the enzyme activity by treatments with H2O2 and diethylamine NONOate (DEA/NO). Treatments leading to the formation of a disulfide bond between ADH and glutathione (protein S-glutathionylation) had no negative effect on the enzyme activity. LC-MS/MS analysis showed that Cys47 and Cys243 could make a stable disulfide bond with glutathione, suggesting redox sensitivity of these residues. Mutation of ADH Cys47 to Ser caused an almost complete loss of the enzyme activity while the Cys243 to Ser mutant had increased specific activity. Incubation of ADH with NAD+ or NADH prevented inhibition of the enzyme by H2O2 or DEA/NO. These results suggest that binding of ADH with its cofactors may limit availability of Cys residues to redox modifications. Our study demonstrates that ADH from A. thaliana is subject to different redox modifications. Implications of ADH sensitivity to ROS and RNS during hypoxic stress conditions are discussed. PMID- 30252898 TI - Factors associated with anemia in young children in Brazil. AB - BACKGROUND: Anemia is recognized as a major public health problem in childhood, especially in children under 24 months of age. Despite improvements in public health strategies to prevent and control anemia in Brazilian young children in the last decade, few studies have assessed the predictors for this condition in primary health care. Thus, this study aimed to assess the associated factors of anemia in young children who visited primary public health care facilities in Brazil. METHODS: A cross-sectional study was conducted with 520 children aged 11 to 15 months who visited the primary health care in four Brazilian cities. Anemia was defined as hemoglobin concentration < 110 g/L in venous blood samples. Multilevel Poisson regression models were used to describe the associations between anemia and independent variables. RESULTS: The frequency of anemia was 23.1%. A higher frequency was observed in children who live with more than one other child younger than 5 years in the house (Prevalence Ratio [PR] 1.47; 95% Confidence Interval [CI] 1.01-2.14), who started to receive fruits and vegetables after 8 months of age (PR 1.92; 95% CI 1.19-3.10), who were stunted (PR 2.44; 95% CI 1.32-4.50), who were hospitalized at least once in their life (PR 1.55; 95% CI 1.03-2.33) and who were in the lower tertile of serum folate concentration (PR 2.24; 95% CI 1.30-3.85). CONCLUSIONS: Inadequate complementary feeding practices and morbidity were the main predictors for anemia in early childhood in this population. Improvements in current strategies to promote healthy complementary feeding along with better control of morbidities are recommended to reduce anemia in Brazilian young children. PMID- 30252899 TI - Real-time carbon allocation into biogenic volatile organic compounds (BVOCs) and respiratory carbon dioxide (CO2) traced by PTR-TOF-MS, 13CO2 laser spectroscopy and 13C-pyruvate labelling. AB - Our understanding of biogenic volatile organic compound (BVOC) emissions improved substantially during the last years. Nevertheless, there are still large uncertainties of processes controlling plant carbon investment into BVOCs, of some biosynthetic pathways and their linkage to CO2 decarboxylation at central metabolic branching points. To shed more light on carbon partitioning during BVOC biosynthesis, we used an innovative approach combining delta13CO2 laser spectroscopy, high-sensitivity proton-transfer-reaction time-of-flight mass spectrometry and a multiple branch enclosure system in combination with position specific 13C-metabolite labelling. Feeding experiments with position-specific 13C labelled pyruvate, a central metabolite of BVOC synthesis, enabled online detection of carbon partitioning into 13C-BVOCs and respiratory 13CO2. Measurements of trace gas emissions of the Mediterranean shrub Halimium halimifolium revealed a broad range of emitted BVOCs. In general, [2-13C]-PYR was rapidly incorporated into emitted acetic acid, methyl acetate, toluene, cresol, trimethylbenzene, ethylphenol, monoterpenes and sesquiterpenes, indicating de novo BVOC biosynthesis of these compounds. In contrast, [1-13C]-pyruvate labelling substantially increased 13CO2 emissions in the light indicating C1 decarboxylation. Similar labelling patterns of methyl acetate and acetic acid suggested tightly connected biosynthetic pathways and, furthermore, there were hints of possible biosynthesis of benzenoids via the MEP-pathway. Overall, substantial CO2 emission from metabolic branching points during de novo BVOC biosynthesis indicated that decarboxylation of [1-13C]-pyruvate, as a non mitochondrial source of CO2, seems to contribute considerably to daytime CO2 release from leaves. Our approach, combining synchronised BVOC and CO2 measurements in combination with position-specific labelling opens the door for real-time analysis tracing metabolic pathways and carbon turnover under different environmental conditions, which may enhance our understanding of regulatory mechanisms in plant carbon metabolism and BVOC biosynthesis. PMID- 30252900 TI - Coevolution of public goods game and networks based on survival of the fittest. AB - We introduce a random strategy update rule for the evolutionary public goods game on networks based on survival of the fittest. A survival cost parameter is introduced to public goods game. Players whose payoffs are below the survival cost will be deleted from the network. The same number of new nodes are randomly connected to the network and randomly designated cooperation or defection. Numerical results show that cooperation can flourish if the multiplication factor of the public goods game is greater than the network degree. We present a simple analytical method to explain this result. The fraction of cooperators reaches the maximum for a suitable survival cost. Furthermore, the initial random network has evolved into a heterogeneous network which facilitates the emergence of the cooperation. Our work could be helpful to understand how natural selection favors cooperation. It suggests a new method to investigate the impact of the survival cost on the evolution of cooperation. PMID- 30252901 TI - Deciphering intra-species bacterial diversity of meat and seafood spoilage microbiota using gyrB amplicon sequencing: A comparative analysis with 16S rDNA V3-V4 amplicon sequencing. AB - Meat and seafood spoilage ecosystems harbor extensive bacterial genomic diversity that is mainly found within a small number of species but within a large number of strains with different spoilage metabolic potential. To decipher the intraspecies diversity of such microbiota, traditional metagenetic analysis using the 16S rRNA gene is inadequate. We therefore assessed the potential benefit of an alternative genetic marker, gyrB, which encodes the subunit B of DNA gyrase, a type II DNA topoisomerase. A comparison between 16S rDNA-based (V3-V4) amplicon sequencing and gyrB-based amplicon sequencing was carried out in five types of meat and seafood products, with five mock communities serving as quality controls. Our results revealed that bacterial richness in these mock communities and food samples was estimated with higher accuracy using gyrB than using16S rDNA. However, for Firmicutes species, 35% of putative gyrB reads were actually identified as sequences of a gyrB paralog, parE, which encodes subunit B of topoisomerase IV; we therefore constructed a reference database of published sequences of both gyrB and pare for use in all subsequent analyses. Despite this co-amplification, the deviation between relative sequencing quantification and absolute qPCR quantification was comparable to that observed for 16S rDNA for all the tested species. This confirms that gyrB can be used successfully alongside 16S rDNA to determine the species composition (richness and evenness) of food microbiota. The major benefit of gyrB sequencing is its potential for improving taxonomic assignment and for further investigating OTU richness at the subspecies level, thus allowing more accurate discrimination of samples. Indeed, 80% of the reads of the 16S rDNA dataset were represented by thirteen 16S rDNA-based OTUs that could not be assigned at the species-level. Instead, these same clades corresponded to 44 gyrB-based OTUs, which differentiated various lineages down to the subspecies level. The increased ability of gyrB-based analyses to track and trace phylogenetically different groups of strains will generate improved resolution and more reliable results for studies of the strains implicated in food processes. PMID- 30252902 TI - Novel radiomics evaluation of bone formation utilizing multimodal (SPECT/X-ray CT) in vivo imaging. AB - Although an extensive research is being undertaken, the ideal bone graft and evaluation method of the bone formation draw still a warranted attention. The purpose of this study was to develop a novel multimodal radiomics evaluation method, utilizing X-ray computed tomography (CT) and single photon emission computed tomography (SPECT) with Tc-99m-Methyl diphosphonate (Tc-99m-MDP) tracer. These modalities are intended to provide quantitative data concerning the mineral bone density (after evaluation it is referred to as opacity) and the osteoblast activity, at the same time. The properties of bone formation process within poly (methyl methacrylate)-based bone cement graft (PMMA) was compared to that of albumin coated, sterilized, antigen-extracted freeze-dried human bone grafts (HLBC), in caudal vertebrae (C5) of rats. The animals were scanned at 3 and 8 weeks after surgery. In both groups, the mean opacity increased, while the mean Tc-99m-MDP activity decreased. The later parameter was significant (n = 4, p = 0.002) only in HLBC group. The linear regression analysis of PMMA-treated group variables (mean opacity increase; mean Tc-99m-MDP activity decrease), revealed a negative correlation with the medium strength (r = 0.395, p = 0.605). Whereas, it showed strong positive correlation when HLBC group variables were analyzed (r = 0.772, p = 0.012). These results indicate that using HLBC grafts is advantageous in terms of the osteoblast activity and bone vascularization over PMMA cement. Using this regression analysis method, we were able to distinguish characteristics that otherwise could not be distinguished by a regular data analysis. Hence, we propose utilizing this novel method in preclinical tests, and in clinical monitoring of bone healing, in order to improve diagnosis of bone related diseases. PMID- 30252903 TI - Inter-rater and test-retest reliability of movement control tests for the neck, shoulder, thoracic, lumbar, and hip regions in military personnel. AB - Strategies are needed to mitigate the high rates and related risks of musculoskeletal complaints and injuries (MSCI) in the military aviator community. Previous work on Swedish Armed Forces (SwAF) soldiers have shown that proper screening methods have been successful in reducing early discharge from military training. Research has pointed at the importance of optimal spinal movement control in military aviators. The aim of this work was to investigate the inter rater and test-retest reliability of a battery of clinical tests for evaluating movement control in the neck, shoulders, thoracic, lumbar, and hip regions in a population of SwAF military personnel. Inter-rater and test-retest reliability of 15 movement control tests were assessed by crude and prevalence-adjusted kappa coefficient. The study included 37 (inter-rater) and 45 (test-retest) SwAF personnel and was performed with two physiotherapists simultaneously observing and rating the movements on the first occasion and repeated with one physiotherapist on the second occasion. For inter-rater reliability, the kappa coefficient ranged from .19 to .95. Seven tests showed substantial to almost perfect agreement (kappa > .60). With the adjusted kappa, three more tests reached the level of substantial agreement. The corresponding values for test retest reliability ranged from .26 to .65. Substantial agreement was attained for two tests, three with adjusted kappa. The following tests can reliably be used when screening for biomechanically less advantageous movement patters in military aviators: Shoulder flexion, and rotation, Neck flexion in sitting and supine, Neck extension and rotation in sitting, Pelvic tilt, Forward lean and Single and Double knee extension tests. Grading criteria for tests in supine and quadruped positions need to be further elaborated. PMID- 30252904 TI - Are death and loss to follow-up still high in people living with HIV on ART after national scale-up and earlier treatment initiation? A large cohort study in government hospital-based setting, Myanmar: 2013-2016. AB - SETTING: Myanmar National AIDS Program has had significant scale-up of services and changes in CD4 eligibility criterion for ART initiation from 2013 to 2016. This study assessed early death within 6 months and attrition (death and loss to follow-up, LTFU) after ART initiation and their associated factors. DESIGN: A retrospective cohort study on people living with HIV (PLHIV >15 year of age) enrolled at three specialist hospitals in Yangon from 1st June 2013 to 30th June 2016. Cox regression was used to calculate hazard ratios (HRs) of early death and attrition. RESULTS: Of 11,727 adults enrolled, 11,186 (95%) were initiated on ART, providing 15,964 person-years of follow-up. At baseline, median age was 36 years [IQR: 30-43], 58% were men and median CD4 count was 151 cells/mm3 (IQR: 54 310). There were 733(6%) early deaths, 961(9%) total deaths and 1371 (12%) LTFU during the study period. Independent risk factors for early death were older age (41-50 and >=51 years) [aHR 1.38, 1.07-1.78 and 1.68, 1.21-2.34], male (1.84, 1.44-2.35), low weight (2.06, 1.64-2.59), bedridden, (3.81, 2.57-5.66) and CD4 count <= 50 cells/mm3 (6.83, 2.52-18.57). In addition to above factors, high attrition was associated with an abacavir-based regimen. CONCLUSION: Although there was a low rate of early deaths, patients were being diagnosed late and there was a high attrition rate from specialist hospitals. Concerted effort is required to increase early diagnosis and ART initiation, and strengthen community systems for HIV care to achieve ambitious goal of ending AIDS epidemic by 2030. PMID- 30252905 TI - Time-resolved proteomics of adenovirus infected cells. AB - Viral infections cause large problems in the world and deeper understanding of the disease mechanisms is needed. Here we present an analytical strategy to investigate the host cell protein changes during human adenovirus type 2 (HAdV-C2 or Ad2) infection of lung fibroblasts by stable isotope labelling of amino acids in cell culture (SILAC) and nanoLC-MS/MS. This work focuses on early phase of infection (6 and 12 h post-infection (hpi)) but the data is combined with previously published late phase (24 and 36 hpi) proteomics data to produce a time series covering the complete infection. As many as 2169 proteins were quantitatively monitored from 6 to 36 hpi, while some proteins were time specific. After applying different filter criteria, 2027 and 2150 proteins were quantified at 6 and 12 hpi and among them, 431 and 544 were significantly altered at the two time points. Pathway analysis showed that the De novo purine and pyrimidine biosynthesis, Glycolysis and Cytoskeletal regulation by Rho GTPase pathways were activated early during infection while inactivation of the Integrin signalling pathway started between 6 and 12 hpi. Moreover, upstream regulator analysis predicted MYC to be activated with time of infection and protein and RNA data for genes controlled by this transcription factor showed good correlation, which validated the use of protein data for this prediction. Among the identified phosphorylation sites, a group related to glycolysis and cytoskeletal reorganization were up-regulated during infection. The results show specific aspects on how the host cell proteins, the final products in the genetic information flow, are influenced by Ad2 infection, which would be overlooked if only knowledge derived from mRNA data is considered. PMID- 30252906 TI - Abnormal CSF amyloid-beta42 and tau levels in hip fracture patients without dementia. AB - BACKGROUND: There is strong association of Alzheimer's disease (AD) pathology with gait disorder and falls in older adults without dementia. The goal of the study was to examine the prevalence and severity of AD pathology in older adults without dementia who fall and sustain hip fracture. METHODS: Cerebrospinal fluid (CSF) was obtained from 168 hip fracture patients. CSF Abeta42/40 ratio, p-tau, and t-tau measures were dichotomized into normal vs. abnormal, and categorized according to the A/T/N classification. RESULTS: Among the hip fracture patients, 88.6% of the cognitively normal (Clinical Dementia Rating-CDR 0; n = 70) and 98.8% with mild cognitive impairment (CDR 0.5; n = 81) fell in the abnormal biomarker categories by the A/T/N classification. CONCLUSIONS: A large proportion of older hip fracture patients have CSF evidence of AD pathology. Preoperative determination of AD biomarkers may play a crucial role in identifying persons without dementia who have underlying AD pathology in perioperative settings. PMID- 30252908 TI - A hierarchical clustering approach to identify repeated enrollments in web survey data. AB - INTRODUCTION: Online surveys are a valuable tool for social science research, but the perceived anonymity provided by online administration may lead to problematic behaviors from study participants. Particularly, if a study offers incentives, some participants may attempt to enroll multiple times. We propose a method to identify clusters of non-independent enrollments in a web-based study, motivated by an analysis of survey data which tests the effectiveness of an online skin cancer risk reduction program. METHODS: To identify groups of enrollments, we used a hierarchical clustering algorithm based on the Euclidean distance matrix formed by participant responses to a series of Likert-type eligibility questions. We then systematically identified clusters that are unusual in terms of both size and similarity, by repeatedly simulating datasets from the empirical distribution of responses under the assumption of independent enrollments. By performing the clustering algorithm on the simulated datasets, we determined the distribution of cluster size and similarity under independence, which is then used to identify groups of outliers in the observed data. Next, we assessed 12 other quality indicators, including previously proposed and study-specific measures. We summarized the quality measures by cluster membership, and compared the cluster groupings to those found when using the quality indicators with latent class modeling. RESULTS AND CONCLUSIONS: When we excluded the clustered enrollments and/or lower-quality latent classes from the analysis of study outcomes, the estimates of the intervention effect were larger. This demonstrates how including repeat or low quality participants can introduce bias into a web-based study. As much as is possible, web-based surveys should be designed to verify participant quality. Our method can be used to verify survey quality and identify problematic groups of enrollments when necessary. PMID- 30252907 TI - Colonic levels of vasoactive intestinal peptide decrease during infection and exogenous VIP protects epithelial mitochondria against the negative effects of IFNgamma and TNFalpha induced during Citrobacter rodentium infection. AB - Citrobacter rodentium infection is a model for infection with attaching and effacing pathogens, such as enteropathogenic Escherichia coli. The vasoactive intestinal peptide (VIP) has emerged as an anti-inflammatory agent, documented to inhibit Th1 immune responses and successfully treat animal models of inflammation. VIP is also a mucus secretagogue. Here, we found that colonic levels of VIP decrease during murine C. rodentium infection with a similar time dependency as measurements reflecting mitochondrial function and epithelial integrity. The decrease in VIP appears mainly driven by changes in the cytokine environment, as no changes in VIP levels were detected in infected mice lacking interferon gamma (IFNgamma). VIP supplementation alleviated the reduction of activity and levels of mitochondrial respiratory complexes I and IV, mitochondrial phosphorylation capacity, transmembrane potential and ATP generation caused by IFNgamma, TNFalpha and C. rodentium infection, in an in vitro mucosal surface. Similarly, VIP treatment regimens that included the day 5 10 post infection period alleviated decreases in enzyme complexes I and IV, phosphorylation capacity, mitochondrial transmembrane potential and ATP generation as well as increased apoptosis levels during murine infection with C. rodentium. However, VIP treatment failed to alleviate colitis, although there was a tendency to decreased pathogen density in contact with the epithelium and in the spleen. Both in vivo and in vitro, NO generation increased during C. rodentium infection, which was alleviated by VIP. Thus, therapeutic VIP administration to restore the decreased levels during infection had beneficial effects on epithelial cells and their mitochondria, but not on the overall infection outcome. PMID- 30252909 TI - Wish you were here: How defaunated is the Atlantic Forest biome of its medium- to large-bodied mammal fauna? AB - Mammals represent the largest-bodied elements of the world's surviving megafauna and provide several key ecosystems services, yet their populations are often under steep decline throughout the tropics. Anthropogenic defaunation is one the most important contemporary threats to modern mammal faunas. Although the Atlantic Forest biome of South America shows several clear signs of defaunation, the extent to which this biome has lost its mammal fauna remains poorly understood. Here, we collate and analyze a comprehensive body of secondary data to quantitatively assess the spatial patterns of defaunation of all medium- to large-bodied Atlantic Forest mammals which were then classed by morpho-ecological traits. We used a Defaunation Index, which was scaled-up to the entire biome using kriging interpolation, to examine the integrity of site-specific mammal faunas. We further use environmental and socioeconomic predictors to explain the drivers of defaunation. Our results show high levels of defaunation (>0.5) for most of the Atlantic Forest. Apex predators, other carnivores, large-bodied mammals and large herbivores were among the most defaunated functional groups. Remaining native vegetation cover, forest fragment size, and the largest neighboring forest remnant were the main negative predictors of defaunation. We conclude that medium- to large-bodied Atlantic Forest mammals are under high levels of threat due to historical population losses that continue today. A conservation action plan thus becomes imperative to prevent this biome from becoming an even "emptier forest", severely compromising patterns of diversity, ecological processes and ecosystem functioning. PMID- 30252910 TI - A synthetic glycosaminoglycan reduces sinonasal inflammation in a murine model of chronic rhinosinusitis. AB - Chronic rhinosinusitis (CRS) is characterized by sustained mucosal inflammation, impaired mucociliary clearance, loss of cilia and epithelial barrier breakdown, and tissue remodeling. Certain glycosaminoglycans inhibit various inflammatory mediators, suppress bacterial growth, and provide important functions in mucosal tissue repair and mucociliary clearance. Herein, we evaluated the effects of a synthetic glycosaminoglycan, GM-1111, on the clinical signs and inflammatory tissue changes associated with CRS in mice. CRS was generated by repeated intranasal applications of Aspergillus fumigatus (A. fumigatus) extracts over 4 weeks. Mice were then intranasally administered GM-1111 (600 MUg per dose, 5 times a week) or vehicle (phosphate buffered saline, PBS) for an additional 4 weeks while still being given A. fumigatus extracts to maintain a chronic inflammatory environment with acute exacerbations. Clinical signs indicative of sinonasal inflammation were recorded throughout the study. After 9 weeks, whole blood and sinonasal tissues were harvested for hematological, histological, and biochemical examination. The clinical signs, white blood cell counts, tissue markers of sinonasal inflammation, and histological changes caused by A. fumigatus extract administration were compared to the healthy (PBS vehicle) and GM-1111-treated groups (n = 12 per treatment group). Compared to vehicle-treated animals, animals treated with GM-1111 demonstrated significant reductions in clinical signs (p<0.05), degenerative tissue changes, goblet cell hyperplasia, inflammatory cell infiltration (p<0.01), innate immunity- (tlr2, tlr4, myd88, il1b, tnfa, il6, and il12) and adaptive immunity-associated (ccl11, ccl24, ccl5, il4, il5, and il13) cytokine gene expression (p<0.05 to p<0.0001) in sinonasal tissues, and serum IgE levels (p<0.01). Our data suggest that GM-1111 significantly reduces local and systemic effects of CRS-associated sinonasal inflammation. PMID- 30252911 TI - The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing. AB - Kinetoplastid parasites-trypanosomes and leishmanias-infect millions of humans and cause economically devastating diseases of livestock, and the few existing drugs have serious deficiencies. Benzoxaborole-based compounds are very promising potential novel anti-trypanosomal therapies, with candidates already in human and animal clinical trials. We investigated the mechanism of action of several benzoxaboroles, including AN7973, an early candidate for veterinary trypanosomosis. In all kinetoplastids, transcription is polycistronic. Individual mRNA 5'-ends are created by trans splicing of a short leader sequence, with coupled polyadenylation of the preceding mRNA. Treatment of Trypanosoma brucei with AN7973 inhibited trans splicing within 1h, as judged by loss of the Y structure splicing intermediate, reduced levels of mRNA, and accumulation of peri nuclear granules. Methylation of the spliced leader precursor RNA was not affected, but more prolonged AN7973 treatment caused an increase in S-adenosyl methionine and methylated lysine. Together, the results indicate that mRNA processing is a primary target of AN7973. Polyadenylation is required for kinetoplastid trans splicing, and the EC50 for AN7973 in T. brucei was increased three-fold by over-expression of the T. brucei cleavage and polyadenylation factor CPSF3, identifying CPSF3 as a potential molecular target. Molecular modeling results suggested that inhibition of CPSF3 by AN7973 is feasible. Our results thus chemically validate mRNA processing as a viable drug target in trypanosomes. Several other benzoxaboroles showed metabolomic and splicing effects that were similar to those of AN7973, identifying splicing inhibition as a common mode of action and suggesting that it might be linked to subsequent changes in methylated metabolites. Granule formation, splicing inhibition and resistance after CPSF3 expression did not, however, always correlate and prolonged selection of trypanosomes in AN7973 resulted in only 1.5-fold resistance. It is therefore possible that the modes of action of oxaboroles that target trypanosome mRNA processing might extend beyond CPSF3 inhibition. PMID- 30252912 TI - Diagnosis-related differences in the quality of end-of-life care: A comparison between cancer and non-cancer patients. AB - BACKGROUND: Cancer, chronic heart failure (CHF), and chronic obstructive pulmonary disease (COPD) in the advanced stages have similar symptom burdens and survival rates. Despite these similarities, the majority of the attention directed to improving the quality of end-of-life (EOL) care has focused on cancer. AIM: To assess the extent to which the quality of EOL care received by cancer, CHF, and COPD patients in the last month of life is diagnosis-sensitive. METHODS: This is a retrospective observational study based on administrative data. The study population includes all Tuscany region residents aged 18 years or older who died with a clinical history of cancer, CHF, or COPD. Decedents were categorized into two mutually exclusive diagnosis categories: cancer (CA) and cardiopulmonary failure (CPF). Several EOL care quality outcome measures were adopted. Multivariable generalized linear model for each outcome were performed. RESULTS: The sample included 30,217 decedents. CPF patients were about 1.5 times more likely than cancer patients to die in an acute care hospital (RR 1.59, 95% C.I.: 1.54-1.63). CPF patients were more likely to be hospitalized or admitted to the emergency department (RR 1.09, 95% C.I.: 1.07-1.10; RR 1.15, 95% C.I.: 1.13 1.18, respectively) and less likely to use hospice services (RR 0.08, 95% C.I.: 0.07-0.09) than cancer patients in the last month of life. CPF patients had a four- and two-fold higher risk of intensive care unit admission or of undergoing life-sustaining treatments, respectively, than cancer patients (RR 3.71, 95% C.I.: 3.40-4.04; RR 2.43, 95% C.I.: 2.27-2.60, respectively). CONCLUSION: The study has highlighted the presence of significant differences in the quality of EOL care received in the last month of life by COPD and CHF compared with cancer patients. Further studies are needed to better elucidate the extent and the avoidability of these diagnosis-related differences in the quality of EOL care. PMID- 30252914 TI - Correction: Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006843.]. PMID- 30252913 TI - Improved glycemic control with minimal systemic metformin exposure: Effects of Metformin Delayed-Release (Metformin DR) targeting the lower bowel over 16 weeks in a randomized trial in subjects with type 2 diabetes. AB - OBJECTIVE: Metformin use is restricted in patients with renal impairment due to potential excess systemic accumulation. This study evaluated the glycemic effects and safety of metformin delayed-release (Metformin DR), which targets metformin delivery to the ileum to leverage its gut-based mechanisms of action while minimizing systemic exposure. RESEARCH DESIGNS AND METHODS: Participants (T2DM [HbA1c 7-10.5%], eGFR >=60 mL/min/1.73m2, not taking metformin for >=2 months) were randomized to QD placebo (PBO); QD Metformin DR 600, 900, 1200, or 1500 mg; or to single-blind BID Metformin immediate-release (IR) 1000 mg. The primary endpoint was change in HbA1c for Metformin DR vs. PBO at 16 weeks in the modified intent-to-treat (mITT) population (>= 1 post-baseline HbA1c while on study drug), using a mixed-effects repeated measures model. RESULTS: 571 subjects were randomized (56 years, 53% male, 80% white; BMI 32.2+/-5.5 kg/m2; HbA1c 8.6+/ 0.9%; 51% metformin naive); 542 were in the mITT population. Metformin DR 1200 and 1500 mg significantly reduced HbA1c (-0.49+/-0.13% and -0.62+/-0.12%, respectively, vs. PBO -0.06+/-0.13%; p<0.05) and FPG (Caverage Weeks 4-16: 22.3+/-4.2 mg/dL and -25.1+/-4.1 mg/dL, respectively vs. -2.5+/-4.2 mg/dL p<0.05). Metformin IR elicited greater HbA1c improvement (-1.10+/-0.13%; p<0.01 vs. Placebo and all doses of Metformin DR) but with ~3-fold greater plasma metformin exposure. Normalizing efficacy to systemic exposure, glycemic improvements with Metformin DR were 1.5-fold (HbA1c) and 2.1-fold (FPG) greater than Metformin IR. Adverse events were primarily gastrointestinal but these were less frequent with Metformin DR (<16% incidence) vs. Metformin IR (28%), particularly nausea (1-3% vs 10%). CONCLUSION: Metformin DR exhibited greater efficacy per unit plasma exposure than Metformin IR. Future studies will evaluate the effects of Metformin DR in patients with type 2 diabetes and advanced renal disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT02526524. PMID- 30252915 TI - Patient-specific seizure prediction based on heart rate variability and recurrence quantification analysis. AB - Epilepsy is often associated with modifications in autonomic nervous system, which usually precede the onset of seizures of several minutes. Thus, there is a great interest in identifying these modifications enough time in advance to prevent a dangerous effect and to intervene. In addition, these changes can be a risk factor for epileptic patients and can increase the possibility of death. Notably autonomic changes associated to seizures are highly depended of seizure type, localization and lateralization. The aim of this study was to develop a patient-specific approach to predict seizures using electrocardiogram (ECG) features. Specifically, from the RR series, both time and frequency variables and features obtained by the recurrence quantification analysis were used. The algorithm was applied in a dataset of 15 patients with 38 different types of seizures. A feature selection step, was used to identify those features that were more significant in discriminating preictal and interictal phases. A preictal interval of 15 minutes was selected. A support vector machine (SVM) classifier was then built to classify preictal and interictal phases. First, a classifier was set up to classify preictal and interictal segments of each patient and an average sensibility of 89.06% was obtained, with a number of false positive per hour (FP/h) of 0.41. Then, in those patients who had at least 3 seizures, a double-cross-validation approach was used to predict unseen seizures on the basis of a training on previous ones. The results were quite variable according to seizure type, achieving the best performance in patients with more stereotypical seizure. The results of the proposed approach show that it is feasible to predict seizure in advance, considering patient-specific, and possible seizure specific, characteristics. PMID- 30252917 TI - Effects of thrombolysis on outcomes of patients with deep venous thrombosis: An updated meta-analysis. AB - BACKGROUND: Small randomized controlled studies and meta-analyses have shown that thrombolysis, especially catheter-directed thrombolysis, can reduce the incidence of post-thrombotic syndrome (PTS). However, the recent ATTRACT trial did not demonstrate the same effects. Given this confusing situation, we performed an updated meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of thrombolysis, especially catheter-directed thrombolysis, on the outcomes of deep venous thrombosis (DVT). METHODS: We searched PubMed, Embase, and the Cochrane Library for relevant studies comparing thrombolysis in combination with anticoagulation and with anticoagulation alone. The primary endpoint was PTS during the longest follow-up period. The safety endpoint was the incidence of major bleeding events. We also evaluated the outcomes of catheter directed thrombolysis as a subgroup analysis. RESULTS: Six RCTs, including 1418 patients with DVT, were included in our meta-analysis. Thrombolysis in combination with anticoagulation did not reduce PTS (RR: 0.90, [0.80-1.01], P = 0.19) and increased major bleeding (RR: 2.07, [1.12-3.81], P = 0.02). However, trial sequential analysis (TSA) showed that more patients are needed to support the conclusion that thrombolysis in combination with anticoagulation increased major bleeding. Catheter-directed thrombolysis did not reduce the incidence of PTS (RR: 0.88, [0.68-1.13], P = 0.31) and did increase the incidence of major bleeding events (RR: 1.89, [1.00-3.59], P = 0.05). CONCLUSION: Thrombolysis, including catheter-directed thrombolysis, did not reduce the incidence of PTS and increased the incidence of major bleeding. However, the results were not supported by TSA and sensitivity analysis, so more relevant studies are needed. PMID- 30252916 TI - Allergy-related disorders (ARDs) among Ethiopian primary school-aged children: Prevalence and associated risk factors. AB - BACKGROUND: There has been a noticeable increase in the prevalence of allergy related disorders (ARDs) in the modern era. Urbanization is believed to be a major environmental risk factor for the onset of ARDs but data from low- to middle-income countries is limited. OBJECTIVE: Our purpose was to assess the prevalence of ARDs and atopy among a population of rural Ethiopian school children and identify environmental and lifestyle factors associated with such disorders. METHODS: We performed a cross-sectional study on 541 school-children. An interviewer-led questionnaire administered to the mothers of each participant provided information on demographic and lifestyle variables. Questions on allergic disease symptoms were based on the International Study of Asthma and Allergies in Children (ISAAC) core allergy and environmental questionnaire. Skin prick test for common allergens German cockroach (Blattella germanica) and dust mite (Dermatophagoides) was performed to define atopy. Multiple logistic regression analyses were performed to determine the odds ratio between ARDs and atopy with specific environmental and lifestyle habits. RESULTS: 541 children responded to the survey questions: the majority of participants were female (60.3%) and aged 10-15 years-old. The prevalence of any ARD was 27%, while the rates of ever-having eczema, rhinitis, and wheeze was found to be 16.8%, 9.6%, and 8.6% respectively. Only 3.6% (19 school-children) tested positive for any skin sensitization. Analysis of associated factors for ARDs found that a family history of allergic disorders (AOR: 2.80; p-value<0.01), use of insecticides (AOR: 2.05; p-value<0.01), and wearing open-toed shoes (AOR: 2.19; p-value = 0.02) were all significantly associated factors. Insecticide use, river-bathing, and infection with intestinal parasites were found to be significantly associated factors for atopy. Other potential risk factors such as frequent use of soap, bacterial infection, and household crowding had no statistical significance. CONCLUSION: Our study suggests that the prevalence of skin sensitization and ARDs in rural populations of developing countries is still relatively low. We identified several possible risk factors for further investigation. Overall, the significance of identified risk factors appears to indicate that genetic predisposition and exposure to environmental pollution are more important to the etiology of ARDs and atopy than specific lifestyle behaviors. PMID- 30252919 TI - Heterogeneity in chromatic distance in images and characterization of massive painting data set. AB - Painting is an art form that has long functioned as a major channel for the creative expression and communication of humans, its evolution taking place under an interplay with the science, technology, and social environments of the times. Therefore, understanding the process based on comprehensive data could shed light on how humans acted and manifested creatively under changing conditions. Yet, there exist few systematic frameworks that characterize the process for painting, which would require robust statistical methods for defining painting characteristics and identifying human's creative developments, and data of high quality and sufficient quantity. Here we propose that the color contrast of a painting image signifying the heterogeneity in inter-pixel chromatic distance can be a useful representation of its style, integrating both the color and geometry. From the color contrasts of paintings from a large-scale, comprehensive archive of 179 853 high-quality images spanning several centuries we characterize the temporal evolutionary patterns of paintings, and present a deep study of an extraordinary expansion in creative diversity and individuality that came to define the modern era. PMID- 30252921 TI - Erratum: Medical physics staffing for radiation oncology: a decade of experience in Ontario, Canada. PMID- 30252920 TI - Use of off-label and unlicensed medicines in neonatal intensive care. AB - PURPOSE: To evaluate the use of off-label and unlicensed medicines in a neonatal intensive care unit (NICU) of a teaching maternity hospital specialized in high risk pregnancy. METHODS: A prospective cohort study was conducted between August 2015 and July 2016. All newborns admitted to the NICU who had at least one medication prescribed and a hospital stay longer than 24 hours were included. The classification of off-label and unlicensed drugs for the neonatal population was done according to the information of Food and Drug Administration. RESULTS: A total of 17421 medication items were analyzed in 3935 prescriptions of 220 newborns. The proportion of newborns exposed to off-label drugs was 96.4%, and to unlicensed medicines was 66.8%. About one-half (49.3%) of the medication items were off-label and 24.6% were unlicensed. The main reason for off-label and unlicensed classification was, respectively, frequency of administration and the administration of adaptations of pharmaceutical forms. CONCLUSIONS: Although there are actions to encourage the development of pharmacological studies with neonates, this study observed a high rate of prescription and exposure of newborns to off-label and unlicensed drugs in NICUs and pointed out areas of neonatal therapy that require scientific investment. PMID- 30252918 TI - Candida albicans Sfl1/Sfl2 regulatory network drives the formation of pathogenic microcolonies. AB - Candida albicans is an opportunistic fungal pathogen that can infect oral mucosal surfaces while being under continuous flow from saliva. Under specific conditions, C. albicans will form microcolonies that more closely resemble the biofilms formed in vivo than standard in vitro biofilm models. However, very little is known about these microcolonies, particularly genomic differences between these specialized biofilm structures and the traditional in vitro biofilms. In this study, we used a novel flow system, in which C. albicans spontaneously forms microcolonies, to further characterize the architecture of fungal microcolonies and their genomics compared to non-microcolony conditions. Fungal microcolonies arose from radially branching filamentous hyphae that increasingly intertwined with one another to form extremely dense biofilms, and closely resembled the architecture of in vivo oropharyngeal candidiasis. We identified 20 core microcolony genes that were differentially regulated in flow induced microcolonies using RNA-seq. These genes included HWP1, ECE1, IHD1, PLB1, HYR1, PGA10, and SAP5. A predictive algorithm was utilized to identify ten transcriptional regulators potentially involved in microcolony formation. Of these transcription factors, we found that Rob1, Ndt80, Sfl1 and Sfl2, played a key role in microcolony formation under both flow and static conditions and to epithelial surfaces. Expression of core microcolony genes were highly up regulated in Deltasfl1 cells and down-regulated in both Deltasfl2 and Deltarob1 strains. Microcolonies formed on oral epithelium using C. albicans Deltasfl1, Deltasfl2 and Deltarob1 deletion strains all had altered adhesion, invasion and cytotoxicity. Furthermore, epithelial cells infected with deletion mutants had reduced (SFL2, NDT80, and ROB1) or enhanced (SFL2) immune responses, evidenced by phosphorylation of MKP1 and c-Fos activation, key signal transducers in the hyphal invasion response. This profile of microcolony transcriptional regulators more closely reflects Sfl1 and Sfl2 hyphal regulatory networks than static biofilm regulatory networks, suggesting that microcolonies are a specialized pathogenic form of biofilm. PMID- 30252922 TI - HPV infection and pre-neoplastic cervical lesions among 321 HIV+ women in Florence, Italy, 2006-2016: prevalence and associated factors. AB - Women living with HIV (WLWH) are at higher risk for HPV-related malignancies. To estimate the factors associated to HPV infection and to pre-neoplastic cervical lesions, we observed 321 WLWH in an HIV care-centre in Florence, Italy. In 2006 2016, WLWH followed at S.Maria Annunziata Hospital underwent to gynaecological examination including HPV-test, Pap-smear, colposcopy and, if needed, cervical biopsy. Demographical and clinical information were collected and linear logistic regression was performed. Among 321 WLWH, 161 (50.2%) resulted HPV+. Multiple genotypes were identified in 35%, and cancer high-risk genotypes in 61%. Younger age, not-caucasic origin, increasing number of partners, and shorter duration of HIV are associated with HPV infection. A colposcopy was performed in 154 HIV+/HPV+ women: histological lesions were present in 47 (30%). Among these, CIN1, CIN2 and CIN3 were present in 16, 4, and 1 patients, respectively. Being caucasic, smoking 1-20 cigarettes/day, having 2 partners in the last year, and being an injective-drug-user are associated with cervical lesions. The use of bi valent, 4-valent and 9-valent HPV vaccines would potentially prevent lesions in 19%, 33%, and 48%. Among WLWH efficaciously in care for HIV, demographic and behavioral factors mainly contribute to acquisition of HPV and to development of cervical lesions. PMID- 30252923 TI - Glomerular filtration rate estimated by cystatin C formulas in HIV-1 patients treated with dolutegravir, rilpivirine or cobicistat. AB - As dolutegravir (DTG), rilpivirine (RPV) and cobicistat affect creatinine, but not cystatin C, tubular transport or serum concentration, the aim of the study was to compare estimated glomerular filtration rates (eGFRs) calculated by means of a standard creatinine formula with those calculated by means of the cystatin C formula in patients receiving these drugs. This was a cross-sectional study of HIV-1 infected patients with eGFR <90 ml/min/1.73m2 (CKD-EPI-creatinine formula) on-treatment with regimens including DTG, RVP or cobicistat; cystatin C was measured after the switch to these regimens. eGFR was calculated by means of the CKD-EPI formulas (CKD-EPI-creatinine: eGFRcrea; CKD-EPI-cystatin C: eGFRcyst). eGFRcyst was compared with the last eGFR assessed before (eGFRcreapre) and after the switch (eGFRcreapost). The primary end-point of the study was the difference between eGFRcyst and eGFRcreapost. One hundred and twenty patients were included. eGFRcreapre was 80 (70-92) ml/min/1.73m2. eGFRcreapost was significantly lower than eGFRcyst (65 [59-75] vs. 80 [69-95] mL/min/1.73m2; p<0.001); eGFRcyst did not differ from eGFRcreapre (p=0.544). The difference between eGFRcyst and eGFRcreapost was not significantly different among regimen groups (p=0.056). In HIV-patients with reduced eGFR treated with DTG, RPV or cobicistat, measuring eGFR by means of the CKD-EPI cystatin C formula is probably more relevant. PMID- 30252925 TI - Carbapenemase-producing Enterobacteriaceae isolates resistant to last-line antibiotics in an Italian general hospital. AB - The global dissemination of carbapenemase-producing Enterobacteriaceae (CPE) is of great concern for public health. These bacteria have the potential for rapid dissemination in healthcare settings and cause infections associated with high rates of morbidity and mortality. A total of 221 carbapenem non-susceptible Enterobacteriaceae isolates were collected from patients admitted to an Italian general hospital from January 2016 to March 2017. Among these isolates, 78.3% were carbapenemase producers: 96% were positive for the blaKPC gene and the remainder for the blaVIM gene (allelic variant VIM-1). CPE isolates were mainly Klebsiella pneumoniae, but we also detected carbapenemase enzymes in Citrobacter freundii, Enterobacter cloacae and Escherichia coli. Among CPE isolates, 79.2% exhibited co-resistance to two or more non-?-lactam agents and 38% of these isolates (all KPC-positive) were resistant to colistin. This percentage reached 55% among CPE isolated from the bloodstream. All patients with colistin-resistant CPE isolates recovered from blood samples showed an unfavorable outcome within 7 days from the first positive blood culture. Our data show the dissemination of a high percentage of CPE isolates co-resistant to last-line antibiotics. In addition, we report the first identification in our hospital of CPE isolates harboring the blaVIM gene and Escherichia coli harboring the blaKPC gene. These results underline the need to implement antibiotic stewardship and infection control programs, and emphasize the need for novel antimicrobial agents active against CPE. PMID- 30252924 TI - Helicobacter pylori infection: antibiotic resistance and eradication rate in patients with gastritis showing previous treatment failures. AB - Forty patients infected by Helicobacter pylori were studied. The treatment was based on the positivity or negativity of cultures (tailored therapy or empiric therapy). The eradication rate was 68% and 82% respectively. Genotypic susceptibility testing proved very useful in case of heteroresistance or mixed infections that represent a real problem possibly leading to a resistance underestimation. Real-time PCR detected the resistant population at a very low concentration not detectable by phenotypic tests. Bismuth quadruple therapy (PPI, bismuth, metronidazole, tetracycline, PBMT) was effective in the Hp eradication rate consistent with a high level of clarithromycin resistance. PMID- 30252926 TI - Tuberculosis transmission among children and adolescents in schools and other congregate settings: a systematic review. AB - Children, especially those aged <5 years, and adolescents are at increased risk of progression to active TB disease when infected. Management of childhood TB outbreaks is crucial for TB elimination especially in low burden countries. We searched the electronic databases MEDLINE-CINHAL-EMBASE up to July 2017 for primary studies reporting on TB incidents which involved teacher/child-caregiver, relative or students diagnosed with TB in a school/childcare setting or in other congregate settings attended by children and adolescents. Out of 10,481 citations, 74 studies, published mostly in low TB burden countries from 1950 to 2017, describing 128 incident investigations, were included. Overall 5025 (14.2%) LTBI and 811 (2.3%) TB cases were diagnosed among 35,331 screened individuals. Incidents occurred mainly in schools (89.1%) where index cases were more frequently students (63.3%) than teachers/caregivers; almost all of the incidents exposing children aged 2-5 were attributable to a teacher/caregiver index case. In 68 individual contact investigations the pooled proportions of TB and LTBI among those exposed were 0.03 (95%CI 0.02-0.04) and 0.15 (95%CI 0.13- 0.18). The overall risk of developing TB disease in school-congregate settings seems slightly lower than in high-income country household settings. Public health interventions targeting school-congregate settings may be critical to overall TB control and towards TB elimination in low-burden countries. PMID- 30252927 TI - Distribution of different HBV DNA forms in plasma and peripheral blood mononuclear cells (PBMCs) of chronically infected patients with low or undetectable HBV plasma viremia. AB - Few studies have documented hepatitis B virus (HBV) DNA in peripheral blood mononuclear cells (PBMCs). We developed real-time PCR methods for differential amplification of covalently closed circular (cccDNA) and total HBV DNA (tDNA). The different distribution of cccDNA and tDNA in plasma and PBMCs was evaluated in 37 patients with low or undetectable viremia. Plasma tDNA measured by the Abbott reference system and the in-house assay correlated well (Spearman rho = 0.804; P<0.0001). tDNA was detected in four PBMC samples, all from patients with detectable plasma viremia (range 633-6,406 IU/ml), cccDNA was not detected in any sample. The reasons for apparently discrepant results need further investigation but possibly include the high diversification of HBV status and plasma viremia levels. PMID- 30252928 TI - Insect egg deposition renders plant defence against hatching larvae more effective in a salicylic acid-dependent manner. AB - Plants can improve their antiherbivore defence by taking insect egg deposition as cue of impending feeding damage. Previous studies showed that Pieris brassicae larvae feeding upon egg-deposited Brassicaceae perform worse and gain less weight than larvae on egg-free plants. We investigated how P. brassicae oviposition on Arabidopsis thaliana affects the plant's molecular and chemical responses to larvae. A transcriptome comparison of feeding-damaged leaves without and with prior oviposition revealed about 200 differently expressed genes, including enhanced expression of PR5, which is involved in salicylic acid (SA)-signalling. SA levels were induced by larval feeding to a slightly greater extent in egg deposited than egg-free plants. The adverse effect of egg-deposited wild-type (WT) plants on larval weight was absent in an egg-deposited PR5-deficient mutant or other mutants impaired in SA-mediated signalling, that is, sid2/ics1, ald1, and pad4. In contrast, the adverse effect of egg-deposited WT plants on larvae was retained in egg-deposited npr1 and wrky70 mutants impaired further downstream in SA-signalling. Oviposition induced accumulation of flavonols in WT plants with and without feeding damage, but not in the PR5-deficient mutant. We demonstrated that egg-mediated improvement of A. thaliana's antiherbivore defence involves SA signalling in an NPR1-independent manner and is associated with accumulation of flavonols. PMID- 30252929 TI - Double hit and double expressors in lymphoma: Definition and treatment. AB - Emerging biologic subsets and new prognostic markers are significantly and adversely affecting curability after standard chemoimmunotherapy for aggressive B cell lymphomas. The identification of concurrent MYC and B-cell CLL/lymphoma 2 (BCL2) deregulation, whether at a genomic or protein level, has opened a new era of investigation within the most common subtype of aggressive B-cell lymphomas. Double-hit lymphoma (DHL), defined as a dual rearrangement of MYC and BCL2 and/or B-cell CLL/lymphoma 6 (BCL6) genes, is an uncommon subset accounting for 5% to 7% of all diffuse large B-cell lymphomas (DLBCLs), and long-term survivors are rare. Double-expressor lymphoma (DEL), defined as overexpression of MYC and BCL2 proteins not related to underlying chromosomal rearrangements, is not a distinct entity in the current World Health Organization classification but accounts for 20% to 30% of DLBCL cases and also has poor outcomes. There are many practical considerations related to identifying, determining the prognosis of, and managing DHL and DEL. PMID- 30252931 TI - Associations of adult-attained height and early life energy restriction with postmenopausal breast cancer risk according to estrogen and progesterone receptor status. AB - Adult-attained height is a marker for underlying mechanisms, such as cell growth, that may also influence postmenopausal breast cancer (BC) risk, perhaps specifically hormone-sensitive BC subtypes. Early life energy restriction may inhibit these mechanisms, resulting in shorter height and a reduced postmenopausal BC risk. Women (62,573) from the Netherlands Cohort Study completed a self-administered questionnaire in 1986 when 55-69 years old, and were followed-up for 20.3 years (case-cohort: Nsubcohort = 2,438; Ncases = 3,354). Cox multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated for BC risk overall and by estrogen and progesterone receptor subtypes in relation to height and early life energy restriction during the Hunger Winter, War Years, and Economic Depression. Although energy restriction can only influence longitudinal growth in women exposed before and/or during the growth spurt, it may also influence BC risk when occurring after the growth spurt, possibly through different growth processes. Therefore, Cox analyses were additionally conducted according to timing of energy restriction in relation to the growth spurt. Height was associated with an increased BC risk (HRper 5cm = 1.07, 95%CI:1.01-1.13), particularly hormone receptor-positive BC. Energy restriction before and/or during the growth spurt was associated with a decreased hormone receptor-positive BC risk. Energy restriction during the Hunger Winter increased the estrogen receptor-negative BC risk regardless of the timing of energy restriction. In conclusion, height and energy restriction before and/or during the growth spurt were both associated with hormone receptor-positive BC risk, in the direction as expected, indicating critical exposure windows for hormonal growth-related mechanisms. PMID- 30252930 TI - Omalizumab dampens type 2 inflammation in a group of long-term treated asthma patients and detaches IgE from FcepsilonRI. AB - Even if omalizumab is broadly used in the treatment of severe, allergic asthma, the immunological effects in long-term treated patients have not been fully elucidated. To this aim, a cohort of 15 allergic asthmatic patients treated with omalizumab for at least three years was compared with 12 allergic asthma patients treated with standard therapy. Omalizumab treated asthmatic patients showed lower frequencies of circulating plasmacytoid DCs, and lower CD154 expression on CD4 T helper cells than the control group. Moreover, basophils and DCs from omalizumab treated patients had lower surface expression of IgE compared to the control group. In a longitudinal evaluation of two patients that started omalizumab treatment, we show that FcepsilonRI free of IgE were evident on basophils just after four weeks of drug administration. Finally, in vitro experiments with basophils obtained from healthy donors confirm that omalizumab is able to detach IgE from high affinity IgE receptors. Collectively these data indicate that long term omalizumab treatment dampens type 2 inflammation acting on different cell types that play a pivotal role in the pathogenesis of allergic asthma. Moreover, we have identified a further mechanism of action of omalizumab, such as the ability to detach IgE from its receptor. PMID- 30252933 TI - Latent profiles of stress and their relationships with depression and problematic Internet use among college freshmen. AB - As noted in previously published literature, college students frequently experience academic stress, financial stress, and the stresses caused by intimate, peer, and parent-adolescent relationships. The present study uses latent profile analysis to identify stress profiles based on the aforementioned five stressors among 430 college freshmen. Thereafter, we compare the levels of depression and problematic Internet use (PIU) among the different profile groups and investigate whether background variables could predict each latent stress group. Three latent groups were labelled as follows: Ordinary (n = 257, 59.77%); all moderate-high (n = 98, 22.79%); and college-life moderate-high (n = 75, 17.44%). Compared with the ordinary group, the all moderate-high and college-life moderate-high groups displayed significantly higher levels of depression. Moreover, the all moderate-high group had a severer level of PIU than the college life moderate-high and ordinary groups. Interestingly, males and students who were dating were more likely to fall under the all moderate-high group than the college-life moderate-high group; but students who were more concerned with their academic performance were more likely to fall under the college-life moderate high group than the all moderate-high group. These findings have important implications for college educators and school counsellors with regard to developing appropriate interventions as required. PMID- 30252934 TI - Primary sclerosing cholangitis leads to dysfunction and loss of MAIT cells. AB - Primary sclerosing cholangitis (PSC) is a severe chronic liver disease of the small and large bile ducts. The pathogenesis is unknown but a strong immune cell component has been suggested. Mucosal-associated invariant T (MAIT) cells are abundant in human liver and localize around bile ducts. Yet, the role of MAIT cells in PSC remains unclear. Here, we performed a detailed characterization of MAIT cells in circulation and assessed their presence in bile ducts of PSC patients as well as non-PSC controls. We observed a dramatic reduction in MAIT cell levels in PSC patients. High-dimensional phenotypical analysis using stochastic neighbor embedding revealed the MAIT cells to be activated, a phenotype shared by the investigated disease control groups. In line with the noted phenotypic alterations, MAIT cell function was reduced in response to Escherichia coli and to cytokine stimulation in PSC patients as compared to healthy controls. Using a novel sampling approach of human bile ducts, we found MAIT cells to be specifically enriched within bile ducts. Finally, distinct from the dramatic decline observed in circulation, PSC-patients had retained levels of MAIT cells within bile ducts. Altogether, our results provide a detailed insight into how the human MAIT cell compartment is affected in PSC. PMID- 30252932 TI - Comparative effectiveness of radical prostatectomy with adjuvant radiotherapy versus radiotherapy plus androgen deprivation therapy for men with advanced prostate cancer. AB - BACKGROUND: Men with locally advanced prostate cancer (LAPCa) or regionally advanced prostate cancer (RAPCa) are at high risk for death from their disease. Clinical guidelines support multimodal approaches, which include radical prostatectomy (RP) followed by radiotherapy (XRT) and XRT plus androgen deprivation therapy (ADT). However, there are limited data comparing these substantially different treatment approaches. Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, this study compared survival outcomes and adverse effects associated with RP plus XRT versus XRT plus ADT in these men. METHODS: SEER-Medicare data were queried for men with cT3-T4N0M0 (LAPCa) or cT3 T4N1M0 (RAPCa) prostate cancer. Propensity score methods were used to balance cohort characteristics between the treatment arms. Survival analyses were analyzed with the Kaplan-Meier method and Cox proportional hazards models. RESULTS: From 1992 to 2009, 13,856 men (>=65 years old) were diagnosed with LAPCa or RAPCa: 6.1% received RP plus XRT, and 23.6% received XRT plus ADT. At a median follow-up of 14.6 years, there were 2189 deaths in the cohort, of which 702 were secondary to prostate cancer. Regardless of the tumor stage or the Gleason score, the adjusted 10-year prostate cancer-specific survival and 10-year overall survival favored men who underwent RP plus XRT over men who underwent XRT plus ADT. However, RP plus XRT versus XRT plus ADT was associated with higher rates of erectile dysfunction (28% vs 20%; P = .0212) and urinary incontinence (49% vs 19%; P < .001). CONCLUSIONS: Men with LAPCa or RAPCa treated initially with RP plus XRT had a lower risk of prostate cancer-specific death and improved overall survival in comparison with those men treated with XRT plus ADT, but they experienced higher rates of erectile dysfunction and urinary incontinence. PMID- 30252936 TI - Mumps outbreak investigation in Jaisalmer, Rajasthan, India, June-September 2016. AB - Mumps, a vaccine-preventable disease, cause inflammation of salivary glands and may cause severe complications, such as encephalitis, meningitis, deafness, and orchitis/oophoritis. In India, mumps vaccine is not included in the universal immunization program and during 2009 to 2014, 72 outbreaks with greater than 1500 cases were reported. In August 2016, a suspected mumps outbreak was reported in Jaisalmer block, Rajasthan. We investigated to confirm the etiology, describe the epidemiology, and recommend prevention and control measures. We defined a case as swelling in the parotid region in a Jaisalmer block resident between 23 June 2016 and 10 September 2016. We searched for cases in health facilities and house-to house in affected villages and hamlets. We tested blood samples of cases for mumps immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA). We found 162 cases (60% males) with a median age of 9.4 years (range: 7 month-38 years) and 65 (40%) were females. Symptoms included fever (70%) and bilateral swelling in neck (65%). None of them were vaccinated against mumps. Most (84%) cases were school-going children (3-16 years old). The overall attack rate was 2%. Village A, with two hamlets, had the highest attack rate (hamlet 1 = 13% and hamlet 2 = 12%). School A of village A, hamlet 1, which accommodated 200 children in two classrooms, had an attack rate of 55%. Of 18 blood samples from cases, 11 tested positive for mumps IgM ELISA. This was a confirmed mumps outbreak in Jaisalmer block that disproportionately affected school-going children. We recommended continued surveillance, 5-day absence from school, and vaccination. PMID- 30252935 TI - Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2. AB - BACKGROUND: Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures. Although previous studies of AW and relapse have highlighted the detrimental role of stress, little is known about genetic risk factors. METHODS: We conducted a genome-wide association study of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent AW subjects. RESULTS: The top association signal for AW severity was in sortilin family neurotrophin receptor gene SORCS2 on chromosome 4 (European American meta-analysis n = 1,478, p = 4.3 * 10-9 ). There were no genome-wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high throughput transcriptomic and epigenomic data sets, showing that in humans SORCS2 is most highly expressed in the nervous system. The identified SORCS2 risk haplotype is predicted to disrupt a stress hormone-modulated regulatory element that has tissue-specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels and SORCS2 expression, and show that SORCS2 levels in culture are increased upon ethanol exposure and withdrawal. CONCLUSIONS: Taken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation. PMID- 30252937 TI - Dietary Fatty-Acid Compositions Are more Strongly Reflected in Fatty than Lean Dorsal Fillets of Common Carp (Cyprinus carpio L.). AB - In this fish-feeding study, we tested similarity patterns between fatty acids (FA) in diets and common carp (Cyprinus carpio) of fish ponds used for semi intensive aquaculture, containing naturally occurring pond zooplankton and different feeds (marine or terrestrial feeds) until carp reached market size. We evaluated if and how total lipid contents in dorsal fillets can reflect dietary FA compositions in farm-raised common carp and hypothesized that increasing total lipid contents in dorsal fillets significantly increase the similarity between dietary and dorsal fillets' FA compositions. Results of this study showed that carps had higher total lipids when supplied with marine feeds and dietary FA compositions were indeed more strongly reflected in fatty (i.e. high total lipid contents) than in leaner dorsal fillets (low total lipid contents). Increasing total lipid contents in dorsal fillets significantly increased the similarity between the dietary and dorsal fillets' FA compositions. In contrast, leaner dorsal fillets had FA patterns that were more distinct from dietary FA. Total lipid contents higher than ~60 mg/g dry weight in dorsal fillets had only limited effects on increasing the similarity between FA compositions of diets and dorsal fillets, and were independent of feed sources. It is thus suggested that higher total lipid contents in dorsal fillets can be used as a proxy to predict dietary FA profiles in common carps, or perhaps even in farm-raised fish in general. PMID- 30252938 TI - The pearl necklace model in protein A chromatography: Molecular mechanisms at the resin interface. AB - Staphylococcal protein A chromatography is an established core technology for monoclonal antibody purification and capture in the downstream processing. MabSelect SuRe involves a tetrameric chain of a recombinant form of the B domain of staphylococcal protein A, called the Z-domain. Little is known about the stoichiometry, binding orientation, or preferred binding. We analyzed small-angle X-ray scattering data of the antibody-protein A complex immobilized in an industrial highly relevant chromatographic resin at different antibody concentrations. From scattering data, we computed the normalized radial density distributions. We designed three-dimensional (3D) models with protein data bank crystallographic structures of an IgG1 (the isoform of trastuzumab, used here; Protein Data Bank: 1HZH) and the staphylococcal protein A B domain (the native form of the recombinant structure contained in MabSelect SuRe resin; Protein Data Bank: 1BDD). We computed different binding conformations for different antibody to protein A stoichiometries (1:1, 2:1, and 3:1) and compared the normalized radial density distributions computed from 3D models with those obtained from the experimental data. In the linear range of the isotherm we favor a 1:1 ratio, with the antibody binding to the outer domains in the protein A chain at very low and high concentrations. In the saturation region, a 2:1 ratio is more likely to occur. A 3:1 stoichiometry is excluded because of steric effects. PMID- 30252939 TI - Midtrimester isolated short femur and perinatal outcomes: A systematic review and meta-analysis. AB - INTRODUCTION: Fetal femur length below the expected value has been described as a marker of aneuploidy, skeletal dysplasia, intrauterine growth restriction and small-for-gestational-age neonate. The aim of this systematic review and meta analysis was to evaluate the strength of association between isolated short femur length and intrauterine growth restriction or small-for-gestational-age, and perinatal adverse outcomes. MATERIAL AND METHODS: PubMed, EMBASE and Medline were searched from the inception of each database to May 2018. Selection criteria included prospective and retrospective cohort studies of singleton pregnancies between 18 and 28 weeks of gestation, with sonographic finding of isolated short femur length, without any structural chromosomal abnormality. The meta-analysis was performed by computing odds ratios using both fixed and random-effects models. Quality assessment of the included studies was performed using the Newcastle-Ottawa Scale. RESULTS: Six studies including 3078 cases of isolated short femur length (study group) and 222 303 normal femur length (control group) were included. The prevalence of intrauterine growth restriction or small-for gestational-age in the study group was 14.2%, compared with 5.2% in the control group (odds ratio of 4.04, 95% confidence interval 3.63-4.50). Isolated short femur length was associated with a higher incidence of low birthweight (study group: 22.10% vs control group: 8.57%, odds ratio 3.24, 95% confidence interval 2.34-4.48), Apgar <7 at 5 minutes (study group: 3.98% vs control group: 1.79%, odds ratio 3.56, 95% confidence interval 1.87-6.77), preterm birth (study group: 12.16% vs control group: 8.16%, odds ratio 3.09, 95% confidence interval 1.57 6.08), fetal death (study group: 1.83% vs control group: 0.44%, odds ratio 6.48, 95% confidence interval 3.70-11.35) and neonatal intensive care unit admission (study group: 15.34% vs control group: 14.81%, odds ratio 2.11, 95% confidence interval 0.56-7.93). CONCLUSIONS: There is a significant association between isolated short femur length and intrauterine growth restriction or small-for gestational-age and poor perinatal outcome. PMID- 30252940 TI - Two-stage carbon distribution and cofactor generation for improving l-threonine production of Escherichia coli. AB - L-Threonine, a kind of essential amino acid, has numerous applications in food, pharmaceutical, and aquaculture industries. Fermentative l-threonine production from glucose has been achieved in Escherichia coli. However, there are still several limiting factors hindering further improvement of l-threonine productivity, such as the conflict between cell growth and production, byproduct accumulation, and insufficient availability of cofactors (adenosine triphosphate, NADH, and NADPH). Here, a metabolic modification strategy of two-stage carbon distribution and cofactor generation was proposed to address the above challenges in E. coli THRD, an l-threonine producing strain. The glycolytic fluxes towards tricarboxylic acid cycle were increased in growth stage through heterologous expression of pyruvate carboxylase, phosphoenolpyruvate carboxykinase, and citrate synthase, leading to improved glucose utilization and growth performance. In the production stage, the carbon flux was redirected into l-threonine synthetic pathway via a synthetic genetic circuit. Meanwhile, to sustain the transaminase reaction for l-threonine production, we developed an l-glutamate and NADPH generation system through overexpression of glutamate dehydrogenase, formate dehydrogenase, and pyridine nucleotide transhydrogenase. This strategy not only exhibited 2.02- and 1.21-fold increase in l-threonine production in shake flask and bioreactor fermentation, respectively, but had potential to be applied in the production of many other desired oxaloacetate derivatives, especially those involving cofactor reactions. PMID- 30252941 TI - Application of Physiologically Based Pharmacokinetic Modeling to Predict Pharmacokinetics in Healthy Japanese Subjects. AB - Pharmacokinetics (PKs) in Japanese healthy subjects were simulated for nine compounds using physiologically based PK (PBPK) models parameterized with physicochemical properties, preclinical absorption, distribution, metabolism, and excretion (ADME) data, and clinical PK data from non-Japanese subjects. For each dosing regimen, 100 virtual trials were simulated and predicted/observed ratios for peak plasma concentration (Cmax ) and area under the curve (AUC) were calculated. As qualification criteria, it was prespecified that >80% of simulated trials should demonstrate ratios to observed data ranging from 0.5-2.0. Across all compounds and dose regimens studied, 93% of simulated Cmax values in Japanese subjects fulfilled the criteria. Similarly, for AUC, 77% of single-dosing regimens and 100% of multiple-dosing regimens fulfilled the criteria. In summary, mechanistically incorporating the appropriate ADME properties into PBPK models, followed by qualification using non-Japanese clinical data, can predict PKs in the Japanese population and lead to efficient trial design and conduct of Japanese phase I studies. PMID- 30252942 TI - Clinical and regulatory considerations for novel electrophysiology mapping systems: Lessons from FIRM. AB - Atrial fibrillation (AF) presents a growing clinical and public health burden for which better rhythm control therapies are needed. Focal impulse and rotor mapping (FIRM), currently marketed as a part of the Topera Rotor Mapping system (Abbott Laboratories, Austin, TX, USA), represents a potentially transformational approach to guide the invasive treatment of AF. However, many years after its initial marketing clearance, the clinical utility of this technology remains uncertain. In this article, we review the scientific rationale for this novel approach to AF ablation, evaluate the current clinical evidence for FIRM-guided ablation, and characterize its premarket regulatory assessment. Lessons for clinicians considering adoption of newly marketed mapping systems are presented. PMID- 30252943 TI - Effects of inactivation of the cyAbrB2 transcription factor together with glycogen synthesis on cellular metabolism and free fatty acid production in the cyanobacterium Synechocystis sp. PCC 6803. AB - Deletion of the cyAbrB2 (Sll0822) transcription factor in Synechocystis sp. PCC 6803 causes aberrant accumulation of glycogen. We previously tried to redirect the excess carbon stored as glycogen in the cyabrB2-disrupted (? cyabrB2) mutant by knockout of the glgC (slr1176) gene encoding glucose-1-phosphate adenylyltransferase. However, complete knockout could not be attained, suggesting that accumulation of glycogen is essential for the Delta cyabrB2 mutant. In this study, we introduced the cyabrB2 gene fused to the copper-inducible petE promoter into the ? cyabrB2 mutant. After complete knockout of glgC in the presence of copper, expression of P petE- cyabrB2 was turned off by copper removal to examine the effect of the double knockout of cyabrB2 and glgC. Metabolome analysis and electron microscopic observation revealed that the double knockout causes a large decrease of sugar phosphates in glycolytic and oxidative pentose phosphate pathways and an increase of organic acids in the tricarboxylic acid cycle, amino acids and storage compounds such as polyhydroxybutyrate. When the ability of production of free fatty acids was conferred, synergetic positive effects of knockout of cyabrB2 and glgC on productivity were observed by removal of both copper and nitrogen. The P petE- cyabrB2Delta glgC strain will further serve as a platform for studies on carbon allocation and metabolic engineering. PMID- 30252944 TI - Ectogenesis and a right to the death of the prenatal human being: A reply to Rasanen. AB - Both many critics of abortion and many defenders of abortion have suggested that artificial wombs could end the abortion debate. If the fetus is removed from the uterus, women have an end to an unwanted pregnancy. If the living fetus is then put in an artificial uterus for ectogenesis, there is no termination of the life of the fetus. Joona Rasanen challenges this view in his article, Ectogenesis, abortion and a right to the death of the fetus. Rasanen provides three arguments for a right to secure the death of the human being in utero, namely the 'right not to become a biological parent argument', the 'right to genetic privacy argument', and the 'right to property argument'. This article critiques these three arguments for a right to the death of the fetus. PMID- 30252945 TI - Assessment of Thrombelastography and Platelet Life Span in Ovines. AB - Ovines are a common animal model for the study of cardiovascular devices, where consideration of blood biocompatibility is an essential design criterion. In the ovine model, tools to assess blood biocompatibility are limited and continued investigation to identify and apply additional assays is merited. Toward this end, the thrombelastograph, clinically utilized to assess hemostasis, was used to characterize normal ovine parameters. In addition, platelet labeling with biotin was evaluated for its potential applicability to quantify ovine platelet life span. Mean ovine thrombelastograph values were reaction-time: 4.9 min, K-time: 2 min, angle: 64.1 degrees , maximum amplitude: 68.6mm, actual clot strength: 11.9 kd/s, and coagulation index: 1.5. Reaction time was significantly shorter and maximum amplitude, actual clot strength, and coagulation index were all significantly higher when compared to normal human thrombelastograph values suggesting some hypercoagulability of sheep blood. Biotinylation and reinfusion of ovine platelets allowed temporal tracking of the labeled platelet cohort with flow cytometry. These data indicated a mean ovine platelet life span of 188h with a half-life of 84h. The collection of these parameters for normal ovines demonstrates the applicability of these techniques for subsequent studies where cardiovascular devices may be evaluated and provides an indication of normal ovine values for comparison purposes. PMID- 30252946 TI - The mediator effect of cognition on the relationship between brain lesion location and dysphagia in patients with stroke: Applying a structural equation model. AB - BACKGROUND: Cognitive status is important for performing the assessment and treatment of dysphagia. Nonetheless, the cognitive neuropsychological profile of patients with stroke and dysphagia is not studied as deeply enough as it should be. On the one hand, focal and non-focal brain lesions may lead to dysphagia and cognitive disorders, and on the other hand, the cognitive status possibly affects swallowing. In this study, cognition is supposed to be a mediator between brain lesion and swallowing disorder (dysphagia). The role of cognition and attention as mediators between brain lesion and dysphagia was evaluated via three causal models in which the causal mechanisms of swallowing were explained. METHODS: Eighty-eight patients with their first stroke (34 women and 54 men) in the acute phase (mean: 3.5 days after stroke; SD: 2.7) participated in this research. The data of dysphagic and non-dysphagic patients were entered into structural equation models. Two relationships were estimated: a direct relationship between brain lesion and dysphagia and an indirect association between brain lesion and dysphagia through cognition and attention. RESULTS: The goodness-of-fit indices confirmed the three models. Our first model proved a good fit [CFI = 1.00; TLI = 1.00]. The second model revealed an appropriate goodness of fit [CFI = 1.00; TLI = 1.00]. Our third model also showed a good fit [CFI = 1.00; TLI = 1.00]. CONCLUSION: It is suggested that in the assessment and treatment of dysphagia, cognition is better to be considered as a mediator along with physical aspects of dysphagia. PMID- 30252947 TI - Self-Adapting Wettability of ReS2 under a Constant Stimulus. AB - Responsive materials (RMs) are attracting intense interest for their critical roles in intelligent designs. So far, only by means of applying complicated and multiple stimuli can physical properties of the solid surface realize a transition, limiting their practical applications. Here, the smart self-adapting wettability (SAW) of ReS2 under sustaining light irradiation, which breaks the stereotype that a single stimulus leads to a monotonic change in properties or structures, is presented. The additional valence electron and defects ensure ReS2 has a stronger gas adsorption and better hydrolysis capability. Combining theoretical calculations and experimental results, its mechanism, including three stages, namely, hydroxyl substitution, formation of hydrogen bonds, and water desorption, is confirmed. Notably, other transition metal dichalcogenides covering MoS2 and WS2 exhibit a similar automatic transition of hydrophobic hydrophilic-hydrophobic state. This unique SAW provides a brand-new insight to broaden the applications of RMs, which will undoubtedly pave a novel way in RMs design and further devices optimization. PMID- 30252948 TI - The impact and understanding of childhood drowning by a community in West Bengal, India, and the suggested preventive measures. AB - AIM: Our aim was to improve our understanding of the contextual factors contributing to child drowning in rural West Bengal, India. METHODS: This 2017 study used interviews, focus groups and observations and the participants included community leaders, household heads, parents and children aged 7-17 years from three remote villages. They included adults and children who had been directly affected by the loss of family members or friends. RESULTS: We conducted 19 in-depth interviews, six focus groups and three informal observations in public locations where people were exposed to water. The area contained a high number of natural open areas of water, which increased the drowning risk. Participants reported that children frequently played unsupervised near potentially hazardous water, as their parents worked long hours and there was a lack of safe recreational spaces. Suggested approaches to reducing the drowning risk included parental education to improve child supervision and establishing village committees to effectively communicate the drowning risks to local government. Low-cost, community-based approaches to improving child water safety need to be developed. CONCLUSION: Drowning was clearly a complex issue in rural West Bengal, with a significant impact on children and their families. Community based approaches are clearly needed. PMID- 30252949 TI - Temporomandibular joint magnetic resonance imaging findings in adolescents with anterior disk displacement compared to those with juvenile idiopathic arthritis. AB - BACKGROUND: Deformation of the mandibular condyle can be associated with anterior disk displacement (ADD) or involvement of the temporomandibular joint (TMJ) by juvenile idiopathic arthritis (JIA). Diagnostic differentiation is critical for proper management. OBJECTIVES: To compare morphology and inflammation between TMJs with ADD and JIA. METHODS: Retrospective assessment of contrast-enhanced TMJ MRI in 18 adolescents (15 female, mean age 15.1 +/- 1.9 years) with ADD and age- and gender-matched patients with JIA. Articular disk findings, inflammatory signs and osseous morphology were compared. RESULTS: In the ADD group, 31 of 36 disks were displaced. In total, 28 of 31 displaced disks showed thickening of the bilaminar zone. In JIA patients, the disks were mainly flattened (19/36), centrally perforated (12/36) and/or anteriorly displaced (2/36). In total, 19 of 31 TMJs with ADD showed various degrees of inflammation, with joint effusion, synovial thickening and joint enhancement not significantly different from JIA patients. Osseous deformity was present in 27 of 31 TMJs with ADD, with frequent erosions in both groups (ADD 25/31; JIA 32/36, P = 0.55) but lower grades of condylar and temporal bone flattening than in JIA (P <= 0.001). Glenoid fossa depth was preserved in 28 of 31 joints with ADD and decreased in 26 of 36 joints with JIA (P < 0.0001). Mandibular ramus height was decreased in both groups. CONCLUSION: In adolescents, inflammatory signs are common MRI findings in symptomatic TMJs with ADD and thus should not be considered diagnostic for JIA involvement. In this cohort, both entities had high rates of condylar deformity, while TMJs with ADD showed a better-preserved and often normal shape of the glenoid fossa. PMID- 30252950 TI - Embryonic macrophages and microglia ablation alter the development of dorsal root ganglion sensory neurons in mouse embryos. AB - Microglia are known to regulate several aspects of the development of the central nervous system. When microglia colonize the spinal cord, from E11.5 in the mouse embryo, they interact with growing central axons of dorsal root ganglion sensory neurons (SNs), which suggests that they may have some functions in SN development. To address this issue, we analyzed the effects of embryonic macrophage ablation on the early development of SNs using mouse embryo lacking embryonic macrophages (PU.1 knock-out mice) and immune cell ablation. We discovered that, in addition to microglia, embryonic macrophages contact tropomyosin receptor kinase (Trk) C+ SN, TrkB+ SN, and TrkA+ SN peripheral neurites from E11.5. Deprivation of immune cells resulted in an initial reduction of TrkC+ SN and TrkB+ SN populations at E11.5 that was unlikely to be related to an alteration in their developmental cell death (DCD), followed by a transitory increase in their number at E12.5. It also resulted in a reduction of TrkA+ SN number during the developmental period analyzed (E11.5-E15.5), although we did not observe any change in their DCD. Proliferation of cells negative for brain fatty acid-binding protein (BFABP- ), which likely correspond to neuronal progenitors, was increased at E11.5, while their proliferation was decreased at E12.5, which could partly explain the alterations of SN subtype production observed from E11.5. In addition, we observed alterations in the proliferation of glial cell progenitors (BFABP+ cells) in the absence of embryonic macrophages. Our data indicate that embryonic macrophages and microglia ablation alter the development of SNs. PMID- 30252951 TI - Co3 O4 /Fe0.33 Co0.66 P Interface Nanowire for Enhancing Water Oxidation Catalysis at High Current Density. AB - Designing well-defined nanointerfaces is of prime importance to enhance the activity of nanoelectrocatalysts for different catalytic reactions. However, studies on non-noble-metal-interface electrocatalysts with extremely high activity and superior stability at high current density still remains a great challenge. Herein, a class of Co3 O4 /Fe0.33 Co0.66 P interface nanowires is rationally designed for boosting oxygen evolution reaction (OER) catalysis at high current density by partial chemical etching of Co(CO3 )0.5 (OH).0.11H2 O (Co CHH) nanowires with Fe(CN)6 3- , followed by low-temperature phosphorization treatment. The resulting Co3 O4 /Fe0.33 Co0.66 P interface nanowires exhibit very high OER catalytic performance with an overpotential of only 215 mV at a current density of 50 mA cm-2 and a Tafel slope of 59.8 mV dec-1 in 1.0 m KOH. In particular, Co3 O4 /Fe0.33 Co0.66 P exhibits an obvious advantage in enhancing oxygen evolution at high current density by showing an overpotential of merely 291 mV at 800 mA cm-2 , much lower than that of RuO2 (446 mV). Co3 O4 /Fe0.33 Co0.66 P is remarkably stable for the OER with negligible current loss under overpotentials of 200 and 240 mV for 150 h. Theoretical calculations reveal that Co3 O4 /Fe0.33 Co0.66 P is more favorable for the OER since the electrochemical catalytic oxygen evolution barrier is optimally lowered by the active Co- and O sites from the Co3 O4 /Fe0.33 Co0.66 P interface. PMID- 30252952 TI - Vertex-Type Engineering of Pt-Cu-Rh Heterogeneous Nanocages for Highly Efficient Ethanol Electrooxidation. AB - Mastery over the architecture and elemental distribution of metal nanocrystals at the nanoscale can effectively tailor and improve their catalytic properties. Herein, the vertex-type-selective growth of metallic nanohorns on a central nanocrystal is constructed via a one-pot solvothermal synthesis, despite the fact that the site-selective epitaxy of the second phase proceeds on all the vertices of the seeds. The prepared vertex-type-selective Pt-Cu-Rh heterogeneous nanocages (HNCs) are composed of a Rh-decorated Pt-Cu rhombic dodecahedral nanocage and six Pt-Cu-Rh nanohorns protruding from the {100} rather than the {111} vertices of rhombic dodecahedron. Impressively, the Pt-Cu-Rh HNCs exhibit 8.1 times higher specific and 6.8 times higher mass activity toward the ethanol oxidation reaction under acidic conditions than commercial Pt/C catalysts. Besides, the peak potential for CO oxidation on Pt-Cu-Rh HNCs (370.4 mV vs SCE) is 182.0 mV more negative than that on Pt/C, indicating the dramatically enhanced CO tolerance. The excellent electrocatalytic property is attributed to the synergistic effect between Pt, Cu, and Rh components, high specific surface area of nanocages and nanohorns, as well as abundant concave/convex sites and various high-index facets around the surface. PMID- 30252953 TI - Decreased survival and increased rate of fibrotic progression in essential thrombocythemia chronicled after the FDA approval date of anagrelide. AB - First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second-line drugs of choice include pegylated interferon-alpha, busulfan and anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928-1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis free (MFFS) and thrombosis-free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1-1.7) and MFFS (P < .001; HR 4.2, 95% CI 2.7-6.5), in favor of patients diagnosed prior to 1997; the difference was sustained during multivariable analysis that included IPSET. Similarly stratified survival data in polycythemia vera (n = 665) and primary myelofibrosis (n = 1282) showed no similar impact on survival (P = .3 and .17, respectively). The current study represents a retrospective analysis and suggests significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of anagrelide. Whether or not anagrelide therapy was to blame for the worsening of OS and MFFS over time cannot be assumed and requires validation in a prospective study. PMID- 30252954 TI - Hypotonic stress response of human keratinocytes involves LRRC8A as component of volume-regulated anion channels. AB - The barrier function of the human epidermis is constantly challenged by environmental osmotic fluctuations. Hypotonic stress triggers cell swelling, which is counteracted by a compensatory mechanism called regulatory volume decrease (RVD) involving volume-regulated anion channels (VRACs). Recently, it was discovered that VRACs are composed of LRRC8 heteromers and that LRRC8A functions as the essential VRAC subunit in various mammalian cell types; however, the molecular identity of VRACs in the human epidermis remains to be determined. Here, we investigated the expression of LRRC8A and its role in hypotonic stress response of human keratinocytes. Immunohistological staining showed that LRRC8A is preferentially localized in basal and suprabasal epidermal layers. RNA sequencing revealed that LRRC8A is the most abundant subunit within the LRRC8 gene family in HaCaT cells as well as in primary normal human epidermal keratinocytes (NHEKs). To determine the contribution of LRRC8A to hypotonic stress response, we generated HaCaT- and NHEK-LRRC8A knockout cells by using CRISPR-Cas9. I- influx assays using halide-sensitive YFP showed that LRRC8A is crucially important for mediating VRAC activity in HaCaTs and NHEKs. Moreover, cell volume measurements using calcein-AM dye further revealed that LRRC8A also substantially contributes to RVD. In summary, our study provides new insights into hypotonic stress response and suggests an important role of LRRC8A as VRAC component in human keratinocytes. PMID- 30252955 TI - A Ferroelectric/Electrochemical Modulated Organic Synapse for Ultraflexible, Artificial Visual-Perception System. AB - Human eyes undertake the majority of information assimilation for learning and memory. Transduction of the color and intensity of the incident light into neural signals is the main process for visual perception. Besides light-sensitive elements that function as rods and cones, artificial retinal systems require neuromorphic devices to transform light stimuli into post-synaptic signals. In terms of plasticity timescale, synapses with short-term plasticity (STP) and long term potentiation (LTP) represent the neural foundation for experience acquisition and memory formation. Currently, electrochemical transistors are being researched as STP-LTP devices. However, their LTP timescale is confined to a second-to-minute level to give unreliable non-volatile memory. This issue limits multiple-plasticity synapses with tunable temporal characteristics and efficient sensory-memory systems. Herein, a ferroelectric/electrochemical modulated organic synapse is proposed, attaining three prototypes of plasticity: STP/LTP by electrochemical doping/de-doping and ferroelectric-LTP from dipole switching. The device supplements conventional electrochemical transistors with 10000-second-persistent non-volatile plasticity and unique threshold switching properties. As a proof-of-concept for an artificial visual-perception system, an ultraflexible, light-triggered organic neuromorphic device (LOND) is constructed by this synapse. The LOND transduces incident light signals with different frequency, intensity, and wavelength into synaptic signals, both volatile and non volatile. PMID- 30252956 TI - Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis. AB - The signaling cascade induced by the interaction of erythropoietin (EPO) with its receptor (EPO-R) is a key event of erythropoiesis. We present here data indicating that Fyn, a Src-family-kinase, participates in the EPO signaling pathway, since Fyn-/- mice exhibit reduced Tyr-phosphorylation of EPO-R and decreased STAT5-activity. The importance of Fyn in erythropoiesis is also supported by the blunted responsiveness of Fyn-/- mice to stress erythropoiesis. Fyn-/- mouse erythroblasts adapt to reactive oxygen species (ROS) by activating the redox-related-transcription-factor Nrf2. However, since Fyn is a physiologic repressor of Nrf2, absence of Fyn resulted in persistent-activation of Nrf2 and accumulation of nonfunctional proteins. ROS-induced over-activation of Jak2-Akt mTOR-pathway and repression of autophagy with perturbation of lysosomal-clearance were also noted. Treatment with Rapamycin, a mTOR-inhibitor and autophagy activator, ameliorates Fyn-/- mouse baseline erythropoiesis and erythropoietic response to oxidative-stress. These findings identify a novel multimodal action of Fyn in the regulation of normal and stress erythropoiesis. PMID- 30252957 TI - High tacrolimus clearance - a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single center cohort study. AB - Patients with high tacrolimus clearance are more likely to experience transient under-immunosuppression in case of a missed or delayed dose. We wanted to investigate the association between estimated tacrolimus clearance and development of graft interstitial fibrosis and tubular atrophy (IFTA) in kidney transplant recipients. Associations between estimated tacrolimus clearance [daily tacrolimus dose (mg)/trough concentration (MUg/l)] and changes in IFTA biopsy scores from week 7 to 1-year post-transplantation were investigated. Data from 504 patients transplanted between 2009 and 2013 with paired protocol biopsies (7 weeks + 1-year post-transplant) were included. There were no differences in baseline biopsy scores (7 weeks) in patients with different estimated tacrolimus clearance. Increasing tacrolimus clearance was significantly associated with increased ci + ct score of >=2 at 1 year, odds ratio of 1.67 (95% CI; 1.11-2.51). In patients without fibrosis (ci + ct <= 1) at 7 weeks (n = 233), increasing tacrolimus clearance was associated with development of de novo IFTA (i + t <= 1 and ci + ct >= 2) at 1 year, odds ratio of 2.01 (95% CI; 1.18-3.50) after adjusting for confounders. High tacrolimus clearance was significantly associated with development of IFTA the first year following renal transplantation. PMID- 30252958 TI - A Hollow Porous CdS Photocatalyst. AB - Efficient light harvesting and charge separation are of great importance in solar energy conversion on photocatalysts. Herein, the synthesis of a novel hollow porous CdS photocatalyst with effectively restrained electron-hole recombination is reported. By using microporous zeolites as a host and a hard template, ultrasmall Pd and PdS nanoparticles can be anchored separately onto the inner and outer surfaces of a hollow CdS structure. The metallic Pd pulls the photoexcited electrons away from CdS while PdS pushes the holes for more thorough oxidation of the sacrificial agent. The final Pd@CdS/PdS product exhibits superior visible light-driven photocatalytic H2 evolution rate of up to 144.8 mmol h-1 g-1 . This is among the highest values of all the reported CdS-based catalysts. This synthetic approach may be used to fabricate other highly efficient catalysts with spatially separated cocatalysts. PMID- 30252959 TI - High risk of peri-implant disease in periodontal Ehlers-Danlos Syndrome. A case series. AB - OBJECTIVES: Periodontal Ehlers-Danlos syndrome (pEDS) has recently been delineated as a molecularly defined cause of early severe periodontitis. Here we report that implant treatment failed in three affected individuals from one family. MATERIALS AND METHODS: Longitudinal data before and after implant treatment were examined for three individuals with genetically confirmed pEDS in the course of a large-scale pedigree analysis. RESULTS: Most detailed information was available for individual 1 in whom first periodontal bone loss was diagnosed at age 16 years. Rapid progression resulted in multiple tooth extractions at age 23 years and interforaminal placement of four implants. After primary implant success, peri-implant bone loss accompanied by highly inflamed tissues and receding gums led to explantation five years later. In individual 2, severe periodontitis was diagnosed at age 15 years and resulted in extraction of all mandibular teeth at age 28 years. Four interforaminal implants were placed. Peri implant bone loss was diagnosed four years later, when up to three implant threads were exposed. Individual 3 showed complete tooth loss at age 29 years. He was restored with ten implants and removable prosthesis. Peri-implant bone loss was diagnosed radiologically eight years later, when seven implant threads were exposed. CONCLUSION: This is the first report on severe peri-implant bone loss in pEDS. Retention of teeth as long as possible is the primary objective in pEDS as satisfying prosthetic solutions are missing. Further evaluation of dental management in individuals with pEDS is needed to develop concise treatment guidelines. PMID- 30252960 TI - HDAC2 dysregulation in the nucleus basalis of Meynert during the progression of Alzheimer's disease. AB - AIMS: Alzheimer's disease (AD) is characterized by degeneration of cholinergic basal forebrain (CBF) neurons in the nucleus basalis of Meynert (nbM), which provides the major cholinergic input to the cortical mantle and is related to cognitive decline in patients with AD. Cortical histone deacetylase (HDAC) dysregulation has been associated with neuronal degeneration during AD progression. However, whether HDAC alterations play a role in CBF degeneration during AD onset is unknown. We investigated global HDAC protein levels and nuclear HDAC2 immunoreactivity in tissue containing the nbM, changes and their association with neurofibrillary tangles (NFTs) during the progression of AD. METHODS: We used semi-quantitative western blotting and immunohistochemistry to evaluate HDAC and sirtuin (SIRT) levels in individuals that died with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD (mAD) or severe AD (sAD). Quantitative immunohistochemistry was used to identify HDAC2 protein levels in individual cholinergic nbM nuclei and their colocalization with the early phosphorylated tau marker AT8, the late-stage apoptotic tau marker TauC3 and Thioflavin-S, a marker of beta-pleated sheet structures in NFTs. RESULTS: In AD patients, HDAC2 protein levels were dysregulated in the basal forebrain region containing cholinergic neurons of the nbM. HDAC2 nuclear immunoreactivity was reduced in individual cholinergic nbM neurons across disease stages. HDAC2 nuclear reactivity correlated with multiple cognitive domains and with NFT formation. CONCLUSIONS: These findings suggest that HDAC2 dysregulation contributes to cholinergic nbM neuronal dysfunction, NFT pathology, and cognitive decline during clinical progression of AD. PMID- 30252961 TI - Controllable Epitaxial Growth of Core-Shell PbSe@CsPbBr3 Wire Heterostructures. AB - 1D semiconductor core-shell wire heterostructures are crucial for high performance optical and optoelectronic device applications, but they are limited to the traditional semiconductor families. Here, the conformal epitaxy of CsPbBr3 shell on PbSe wire core is realized to form the core-shell PbSe@CsPbBr3 wire heterostructures via a chemical vapor deposition route. The Pb-particle catalysts at the tips of the PbSe wires grown by vapor-liquid-solid provide the nucleation sites for the in situ rapid growth of CsPbBr3 cube crystals, which serve as the adatom collector for the following shell growth due to the faster adsorption of the evaporated source atoms on them than on the sidewalls of PbSe wires. This determines the directional growth of the shell along the PbSe wires from the tip to bottom. The spectral and transient photoluminescence reveals the efficient photogenerated carrier transfer from the shell to the core. Importantly, the photodetectors (PDs) based on the heterostructures show responsivity up to 4.7 * 104 A W-1 under 405 nm light illumination, and a wavelength-dependent photocurrent polarity with the excitation of the light from near- to mid-infrared (IR), which indicates potential applications in IR PDs and novel optoelectronic logical circuits. PMID- 30252962 TI - Hydrogel Interferometry for Ultrasensitive and Highly Selective Chemical Detection. AB - Developing ultrasensitive chemical sensors with small scale and fast response through simple design and low-cost fabrication is highly desired but still challenging. Herein, a simple and universal sensing platform based on a hydrogel interferometer with femtomol-level sensitivity in detecting (bio)chemical molecules is demonstrated. A unique local concentrating effect (up to 109 folds) in the hydrogel induced by the strong analyte binding and large amount of ligands, combined with the signal amplification effect by optical interference, endows this platform with an ultrahigh sensitivity, specifically 10-14 m for copper ions and 1.0 * 10-11 mg mL-1 for glycoprotein with 2-4 order-of-magnitude enhancement. The specific chemical reactions between selected ligands and target analytes provide high selectivity in detecting complex fluids. This universal principle with broad chemistry, simple physics, and modular design allows for high performance in detecting wide customer choices of analytes, including metal ions and proteins. The scale of the sensor can be down to micrometer size. The nature of the soft gel makes this platform transparent, flexible, stretchable, and compatible with a variety of substrates, showing high sensing stability and robustness after 200 cycles of bending or stretching. The outstanding sensing performance grants this platform great promise in broad practical applications. PMID- 30252963 TI - Microalga-Powered Microswimmers toward Active Cargo Delivery. AB - Nature presents intriguing biological swimmers with innate energy harvesting abilities from their local environments. Use of natural swimmers as cargo delivery agents presents an alternative strategy to transport therapeutics inside the body to locations otherwise difficult to access by traditional delivery strategies. Herein, a biocompatible biohybrid microswimmer powered by a unicellular freshwater green microalga, Chlamydomonas reinhardtii, is reported. Polyelectrolyte-functionalized magnetic spherical cargoes (1 um in diameter) are attached to surface of the microalgae via noncovalent interactions without the requirement for any chemical reaction. The 3D swimming motility of the constructed biohybrid algal microswimmers is characterized in the presence and absence of a uniform magnetic fields. In addition, motility of both microalgae and biohybrid algal microswimmers is investigated in various physiologically relevant conditions, including cell culture medium, human tubal fluid, plasma, and blood. Furthermore, it is demonstrated that the algal microswimmers are cytocompatible when co-cultured with healthy and cancerous cells. Finally, fluorescent isothiocyanate-dextran (a water-soluble polysaccharide) molecules are effectively delivered to mammalian cells using the biohybrid algal microswimmers as a proof-of-concept active cargo delivery demonstration. The microswimmer design described here presents a new class of biohybrid microswimmers with greater biocompatibility and motility for targeted delivery applications in medicine. PMID- 30252964 TI - Implications of the variation in biological 18 O natural abundance in body water to inform use of Bayesian methods for modelling total energy expenditure when using doubly labelled water. AB - RATIONALE: Variation in 18 O natural abundance can lead to errors in the calculation of total energy expenditure (TEE) when using the doubly labelled water (DLW) method. The use of Bayesian statistics allows a distribution to be assigned to 18 O natural abundance, thus allowing a best-fit value to be used in the calculation. The aim of this study was to calculate within-subject variation in 18 O natural abundance and apply this to our original working model for TEE calculation. METHODS: Urine samples from a cohort of 99 women, dosed with 50 g of 20% 2 H2 O, undertaking a 14-day breast milk intake protocol, were analysed for 18 O. The within-subject variance was calculated and applied to a Bayesian model for the calculation of TEE in a separate cohort of 36 women. This cohort of 36 women had taken part in a DLW study and had been dosed with 80 mg/kg body weight 2 H2 O and 150 mg/kg body weight H2 18 O. RESULTS: The average change in the delta18 O value from the 99 women was 1.140/00 (0.77) [0.99, 1.29], with the average within-subject 18 O natural abundance variance being 0.130/002 (0.25) [0.08, 0.18]. There were no significant differences in TEE (9745 (1414), 9804 (1460) and 9789 (1455) kJ/day, non-Bayesian, Bluck Bayesian and modified Bayesian models, respectively) between methods. CONCLUSIONS: Our findings demonstrate that using a reduced natural variation in 18 O as calculated from a population does not impact significantly on the calculation of TEE in our model. It may therefore be more conservative to allow a larger variance to account for individual extremes. PMID- 30252965 TI - T-Cell-Mimicking Nanoparticles Can Neutralize HIV Infectivity. AB - To improve human immunodeficiency virus (HIV) treatment and prevention, therapeutic strategies that can provide effective and broad-spectrum neutralization against viral infection are highly desirable. Inspired by recent advances of cell-membrane coating technology, herein, plasma membranes of CD4+ T cells are collected and coated onto polymeric cores. The resulting T-cell membrane-coated nanoparticles (denoted as "TNPs") inherit T cell surface antigens critical for HIV binding, such as CD4 receptor and CCR5 or CXCR4 coreceptors. The TNPs act as decoys for viral attack and neutralize HIV by diverting the viruses away from their intended host targets. This decoy strategy, which simulates host cell functions for viral neutralization rather than directly suppressing viral replication machinery, has the potential to overcome HIV genetic diversity while not eliciting high selective pressure. In this study, it is demonstrated that TNPs selectively bind with gp120, a key envelope glycoprotein of HIV, and inhibit gp120-induced killing of bystander CD4+ T cells. Furthermore, when added to HIV viruses, TNPs effectively neutralize the viral infection of peripheral mononuclear blood cells and human-monocyte-derived macrophages in a dose dependent manner. Overall, by leveraging natural T cell functions, TNPs show great potential as a new therapeutic agent against HIV infection. PMID- 30252966 TI - Non-carious cervical lesions and risk factors: A case-control study. AB - OBJECTIVES: To evaluate whether the presence of non-carious cervical lesions (NCCLs) was related to the considered risk factors and to show the corresponding odds ratio in a predictive model. METHODS: The sample was 280 dentistry students. In an initial clinical examination, 140 cases were selected that presented one or more teeth with non-carious cervical wear. For each case, a similar sex and age control without any tooth with non-carious cervical lesions was selected. An occlusal examination and periodontal probing were performed in all cases and controls by skilled dentists. All the subjects answered a questionnaire referring to factors of brushing, bruxism, preferred chewing side, consumption of extrinsic acids and the presence of intrinsic acids. Data were analysed by means of univariate and multivariate logistic regression. RESULTS: Of all the study variables, only the protrusion interferences, interferences on the non-working side, the brushing force, CPITN value and the consumption of salads increase the risk of NCCLs in the univariate regression. The best predictive model was formed by the combination of CPITN variables >1, the consumption of acidic salads, self reported bruxism, brushing force and attrition. However, it only correctly classifies 68.75% of subjects. CONCLUSIONS: This study supports the multifactorial aetiology of NCCLs, the combination of several factors being necessary to explain their presence. The risk factors that make up the predictive model are not sufficient to explain the appearance of NCCLs. Dentists should take into account all these risk factors in prevention, diagnosis and treatment. PMID- 30252967 TI - To Loop or Not to Loop: Influence of Hinge Flexibility on Self-Assembly Outcomes for Acridine-Based Triazolylpyridine Chelates with Zinc(II), Iron(II), and Copper(II). AB - Coordination-driven self-assembly has been established as an effective strategy for the efficient construction of intricate architectures in both natural and artificial systems, for applications ranging from gene regulation to metal organic frameworks. Central to these systems is the need for carefully designed organic ligands, generally with rigid components, that can undergo self-assembly with metal ions in a predictable manner. Herein, we report the synthesis and study of three novel organic ligands that feature 3,6-disubstituted acridine as a rigid spacer connected to two 2-(1,2,3-triazol-4-yl)pyridine "click" chelates through hinges of the same length but differing flexibility. The flexibility of these "three-atom" hinges was modulated by i) moving from secondary to tertiary amide functional groups and ii) replacing an sp2 amide carbon with an sp3 methylene carbon. In an effort to understand the role of hinge flexibility in directing self-assembly into mononuclear loops or dinuclear cylinders, the impact of these changes on self-assembly outcomes with zinc(II), iron(II), and copper(II) ions is described. PMID- 30252968 TI - Interactions between rheumatoid arthritis synovial fibroblast migration and endothelial cells. AB - Leukocytes travel within the circulation and enter connective tissues by interactions with endothelium of postcapillary venules mediated by cell adhesion molecules, summarized as the leukocyte adhesion cascade. In the severe combined immunodeficient (SCID) mouse model, rheumatoid arthritis (RA) synovial fibroblasts (SF) migrated to distant cartilage through the vasculature. Therefore, RASF adhesion toward endothelial cells (EC) and E- and P-selectins were analyzed. Cell-to-cell binding assays between SF and EC were performed. Interactions of SF with tumor necrosis factor alpha (TNFalpha)-activated EC or selectins were analyzed in flow adhesion assays. Immunohistochemistry for E selectin ligand CD15s was performed. CD15s induction in RASF by human serum or media was evaluated. Wild-type and E-/-/ P-/- Selectin-SCID mice were used for inverse-wrap surgery. After laser-mediated microdissection, real-time PCR for E /P-selectin/vascular cell adhesion molecule 1 was performed. Adhesion between SF/EC under static conditions was highest in Roswell Park Memorial Institute cultured RASF to TNFalphaalpha-activated human umbilical vein endothelial cells (2.25-fold) and RASF adhesion was higher toward venous than arterial EC (Dulbecco's modified eagle medium P = 0.0419, RPMI P = 0.0119). In flow chamber assays, RASF adhesion to E-selectin was higher than to P-selectin (e.g. 0.9 dyn cm-2 P = 0.0001). Osteoarthritis synovial fibroblasts showed lower rolling/adhesion properties (e.g. 0.5 dyn cm-2 , P = 0.0010). RASF adhesion to TNFalphaalpha-activated EC was increased (e.g. 0.9 dyn cm-2 , P = 0.0061). CD15s induction in RASF was strongest in RA serum. Vimentin/CD15s double-positive cells were detectable. In E-/P-selectin-deficient mice, contralateral invasion was reduced (P = 0.023). E- and P-selectin, and vascular cell adhesion molecule 1 expression in EC of implants was confirmed. Our data indicate that the milieu within vessels induces CD15s which enables RASF to interact with E-selectin/EC under flow. Therefore, RASF may migrate to distant sites and leave the vasculature similarly to leukocytes. PMID- 30252969 TI - Protein Glycosylation through Sulfur Fluoride Exchange (SuFEx) Chemistry: The Key Role of a Fluorosulfate Thiolactoside. AB - Protein glycosylation is the most complex post-translational modification process. More than 50 % of human cells proteins are glycosylated, whereas bacteria such as E. coli do not have this modification machinery. Indeed, the carbohydrate residues in natural proteins affect their folding, immunogenicity, and stability toward proteases, besides controlling biological properties and activities. It is therefore important to introduce such structural modification in bioengineered proteins lacking the presence of carbohydrate residues. This is not trivial as it requires reagents and conditions compatible with the protein's stability and reactivity. This work reports on the introduction of lactose moieties in two natural proteins, namely ubiquitin (Ub) and l-asparaginase II (ANSII). The synthetic route employed is based on the sulfur(VI) fluoride exchange (SuFEx) coupling of a lactose tethered arylfluorosulfate (Lact-Ar-OSO2 F) with the epsilon-NH2 group of lysine residues of the proteins. This metal-free click SuFEx reaction relies on the properties of the fluorosulfate employed, which is easily prepared in multigram scale from available precursors and reacts chemoselectively with the epsilon-NH2 group of lysine residues under mild conditions. Thus, iterative couplings of Lact-Ar-OSO2 F to Ub and ANSII, afforded multiple glycosylations of these proteins so that up to three and four Lact-Ar OSO2 groups were introduced in Ub and ANSII, respectively, via the formation of a sulfamoyl (OSO2 -NH) linkage. PMID- 30252970 TI - Fluorescence Regulation and Photoresponsivity in AIEE Supramolecular Gels Based on a Cyanostilbene Modified Benzene-1,3,5-Tricarboxamide Derivative. AB - Supramolecular interactions play an important role in regulating the optical properties of molecular materials. Different arrangements of identical molecules can afford a more straightforward insight into the contributions of supramolecular interactions. Herein, a novel gelator, BTTPA, composed of a benzene-1,3,5-tricarboxamide (BTA) central unit functionalized with three cyanostilbenes is designed, which forms two kinds of gels in DMSO/water mixtures. Depending on the water volume content, the gels exhibit quite different aggregation-induced emission enhancement (AIEE) properties, with one emitting a green emission (G-gel), and the second emitting a blue emission (B-gel). The main reason for this difference is that water affects H-bonding and pi-pi interactions, further resulting in disparate packing modes of gelators. In addition, only the G-gel displays gel-to-sol transition accompanied with fluorescence switching according to the trans-cis photoisomerization of cyanostilbene under UV light irradiation. The B-gel does not exhibit any change because of its tight hexagonal packing arrangement. Such packing modes restricted the space in which molecules were located and inhibited the transformation of configuration of cyanostilbene. These phenomena underline the incomparable status of packing modes and molecular configuration in regulating fluorescence properties and photoresponse behavior in organic solid-state luminescent materials. PMID- 30252971 TI - Artificial Intelligence Applied to Osteoporosis: A Performance Comparison of Machine Learning Algorithms in Predicting Fragility Fractures From MRI Data. AB - BACKGROUND: A current challenge in osteoporosis is identifying patients at risk of bone fracture. PURPOSE: To identify the machine learning classifiers that predict best osteoporotic bone fractures and, from the data, to highlight the imaging features and the anatomical regions that contribute most to prediction performance. STUDY TYPE: Prospective (cross-sectional) case-control study. POPULATION: Thirty-two women with prior fragility bone fractures, of mean age = 61.6 and body mass index (BMI) = 22.7 kg/m2 , and 60 women without fractures, of mean age = 62.3 and BMI = 21.4 kg/m2 . Field Strength/ Sequence: 3D FLASH at 3T. ASSESSMENT: Quantitative MRI outcomes by software algorithms. Mechanical and topological microstructural parameters of the trabecular bone were calculated for five femoral regions, and added to the vector of features together with bone mineral density measurement, fracture risk assessment tool (FRAX) score, and personal characteristics such as age, weight, and height. We fitted 15 classifiers using 200 randomized cross-validation datasets. Statistical Tests: Data: Kolmogorov-Smirnov test for normality. Model Performance: sensitivity, specificity, precision, accuracy, F1-test, receiver operating characteristic curve (ROC). Two-sided t-test, with P < 0.05 for statistical significance. RESULTS: The top three performing classifiers are RUS-boosted trees (in particular, performing best with head data, F1 = 0.64 +/- 0.03), the logistic regression and the linear discriminant (both best with trochanteric datasets, F1 = 0.65 +/- 0.03 and F1 = 0.67 +/- 0.03, respectively). A permutation of these classifiers comprised the best three performers for four out of five anatomical datasets. After averaging across all the anatomical datasets, the score for the best performer, the boosted trees, was F1 = 0.63 +/- 0.03 for All-features dataset, F1 = 0.52 +/- 0.05 for the no-MRI dataset, and F1 = 0.48 +/- 0.06 for the no-FRAX dataset. Data Conclusion: Of many classifiers, the RUS-boosted trees, the logistic regression, and the linear discriminant are best for predicting osteoporotic fracture. Both MRI and FRAX independently add value in identifying osteoporotic fractures. The femoral head, greater trochanter, and inter trochanter anatomical regions within the proximal femur yielded better F1-scores for the best three classifiers. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30252972 TI - Towards measuring growth rates of pathogens during infections by D2 O-labeling lipidomics. AB - RATIONALE: Microbial growth rate is an important physiological parameter that is challenging to measure in situ, partly because microbes grow slowly in many environments. Recently, it has been demonstrated that generation times of S. aureus in cystic fibrosis (CF) infections can be determined by D2 O-labeling of actively synthesized fatty acids. To improve species specificity and allow growth rate monitoring for a greater range of pathogens during the treatment of infections, it is desirable to accurately quantify trace incorporation of deuterium into phospholipids. METHODS: Lipid extracts of D2 O-treated E. coli cultures were measured on liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) instruments equipped with time-of-flight (TOF) and orbitrap mass analyzers, and used for comparison with the analysis of fatty acids by isotope-ratio gas chromatography (GC)/MS. We then developed an approach to enable tracking of lipid labeling, by following the transition from stationary into exponential growth in pure cultures. Lastly, we applied D2 O-labeling lipidomics to clinical samples from CF patients with chronic lung infections. RESULTS: Lipidomics facilitates deuterium quantification in lipids at levels that are useful for many labeling applications (>0.03 at% D). In the E. coli cultures, labeling dynamics of phospholipids depend largely on their acyl chains and between phospholipids we notice differences that are not obvious from absolute concentrations alone. For example, cyclopropyl-containing lipids reflect the regulation of cyclopropane fatty acid synthase, which is predominantly expressed at the beginning of stationary phase. The deuterium incorporation into a lipid that is specific for S. aureus in CF sputum indicates an average generation time of the pathogen on the order of one cell doubling per day. CONCLUSIONS: This study demonstrates how trace level measurement of stable isotopes in intact lipids can be used to quantify lipid metabolism in pure cultures and provides guidelines that enable growth rate measurements in microbiome samples after incubation with a low percentage of D2 O. PMID- 30252973 TI - Self-efficacy, cancer-related fatigue, and quality of life in patients with resected lung cancer. AB - We aim to investigate the relationship between self-efficacy, cancer-related fatigue, and quality of life in patients with resected lung cancer. A prospective cohort among 452 patients with resected NSCLC was conducted in 2014 to 2015. The self-efficacy, cancer-related fatigue, and quality of life assessments were investigated in the 3-month follow-up by General Self-Efficacy Scale (GSES), Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), and Short Form Health Survey (SF-36), respectively. Structural equation modelling was used to evaluate the relationships between the latent variables. Structural equation modelling analysis showed that both GSES (beta = 0.69, p < 0.05) and MFSI-SF (beta = -0.46, p < 0.01) had direct effect on SF-36; GSES also can indirect effect on SF-36 though MFSI-SF (beta = -0.42, p < 0.01). The model fit indices demonstrated a reasonable fit (chi2 = 27.221, CFI = 0.911, GFI = 0.962, RMSEA = 0.051). The results showed self-efficacy has direct and indirect effect on quality of life in patients with resected lung cancer. Furthermore, cancer related fatigue, as mediated variables, can mediate the relationship between self efficacy and quality of life. In the future, self-efficacy interventions are need for improving quality of life in patients with resected lung cancer. PMID- 30252974 TI - Photoreduction of Thioether Gold(III) Complexes: Mechanistic Insight and Homogeneous Catalysis. AB - Complexes formed between AuCl3 and thioether ligands underwent a photoinduced reductive elimination under homogeneous conditions in dichloromethane and toluene solutions to afford the corresponding AuI complexes. All the gold(III) complexes were rapidly reduced to the gold(I) chloride complexes under 365 nm irradiation or ambient light while being thermally stable below 55 degrees C. The mechanism of photoreduction through Cl2 elimination is discussed based on a kinetic study and the chemical trapping of chlorine species: Cl2 , radical Cl. , and possibly Cl+ . The catalytic activities of the gold(III) chloride complexes and the corresponding gold(I) complexes obtained by in situ reduction were evaluated in the cyclization of N-propargylic amides to oxazoles. The merits of such photoreducible complexes in homogeneous gold catalysis are illustrated by a cascade reaction catalyzed by thioether gold complexes that affords a 4H quinolizin-4-one in high yields. PMID- 30252975 TI - Transpacific coalescent pathways of coconut rhinoceros beetle biotypes: Resistance to biological control catalyses resurgence of an old pest. AB - Biological control agents have several advantages over chemical control for pest management, including the capability to restore ecosystem balance with minimal non-target effects and a lower propensity for targets to develop resistance. These factors are particularly important for invasive species control. The coconut rhinoceros beetle (Oryctes rhinoceros Linnaeus) is a major palm pest that invaded many Pacific islands in the early 20th century through human-mediated dispersal. Application of the Oryctes nudivirus in the 1960s successfully halted the beetle's first invasion wave and made it a textbook example of successful biological control. However, a recently discovered O. rhinoceros biotype that is resistant to the nudivirus appears to be correlated with a new invasion wave. We performed a population genomics analysis of 172 O. rhinoceros from seven regions, including native and invasive populations, to reconstruct invasion pathways and explore correlation between recent invasions and biotypes. With ddRAD sequencing, we generated data sets ranging from 4,000 to 209,000 loci using stacks and ipyrad software pipelines and compared genetic signal in downstream clustering and phylogenetic analyses. Analysis suggests that the O. rhinoceros resurgence is mediated by the nudivirus-resistant biotype. Genomic data have been proven essential to understanding the new O. rhinoceros biotype's invasion patterns and interactions with the original biotype. Such information is crucial to optimization of strategies for quarantine and control of resurgent pests. Our results demonstrate that while invasions are relatively rare events, new introductions can have significant ecological consequences, and quarantine vigilance is required even in previously invaded areas. PMID- 30252976 TI - Construction of Functional Hyperbranched Poly(phenyltriazolylcarboxylate)s by Metal-Free Phenylpropiolate-Azide Polycycloaddition. AB - The 1,3-dipolar cycloaddition of activated internal alkynes with azides has been developed into an efficient polymerization reaction for constructing functional linear 1,4,5-trisubstitued polytriazoles. However, it is rarely employed for the synthesis of hyperbranched polymers. In this work, metal-free polycycloadditions of tris(3-phenylpropiolate)s (1) and tetraphenylethene-containing diazides (2) are performed in dimethylformamide at 100 degrees C for 7 and 12 h, producing hyperbranched poly(phenyltriazolylcarboxylate)s (hb-PPTCs) with high molecular weights and satisfactory regioregularities in good yields. The hb-PPTCs have good solubility in common organic solvents and high thermal stability. They are non emissive in solutions, but emit intensively upon aggregation, showing an aggregation-induced emission effect. Their aggregates can work as fluorescent sensors for explosive detection with high sensitivity. Furthermore, the polymers can be utilized for the fabrication of 2D fluorescent patterns with high resolution by UV irradiation through copper grid masks. PMID- 30252977 TI - Intrapatient Comparison of the Hepatobiliary Phase of Gd-BOPTA and Gd-EOB-DTPA in the Differentiation of Hepatocellular Adenoma From Focal Nodular Hyperplasia. AB - BACKGROUND: Current imaging guidelines do not specify the preferred hepatobiliary contrast agent when differentiating hepatocellular adenoma (HCA) from focal nodular hyperplasia (FNH) on MRI. PURPOSE: To analyze intrapatient differences in the hepatobiliary phase (HBP) after use of both gadobenate dimeglumine (Gd-BOPTA) and gadoxetic acid (Gd-EOB-DTPA)-enhanced MRI to differentiate HCA from FNH. STUDY TYPE: Retrospective. POPULATION: Patients who underwent both Gd-BOPTA and Gd-EOB-DTPA-enhanced MRI, including 33 patients with 82 lesions (67 HCA; 15 FNH), with a step-down reference standard of pathology, 20% regression, identical appearance to earlier biopsied lesions, and stringent imaging findings. FIELD STRENGTH/SEQUENCE: 1.5T and 3T HBP of Gd-BOPTA and Gd-EOB-DTPA-enhanced MRI, precontrast fat-suppressed T1 -weighted sequence. ASSESSMENT: Signal intensities relative to the surrounding liver in the HBP were assessed by two observers. STATISTICAL TESTS: Sensitivity and specificity of HCA diagnosis were calculated for both contrast agents. Interobserver agreement was evaluated using Cohen's kappa; differences in degree of certainty for scoring a lesion were calculated by means of the Wilcoxon signed rank test. Differences in signal intensity between Gd-BOPTA and Gd-EOB-DTPA were calculated using McNemar's test. RESULTS: Almost perfect agreement was found between observers for scored signal intensities with both contrast agents. In 30 of the 82 lesions (37%) a difference was observed between contrast agents in the HBP, with Gd-EOB-DTPA proving correct in all but one of the discordant lesions. When distinguishing HCA from FNH, Gd-BOPTA showed a sensitivity of 46% (31/67) and a specificity of 87% (13/15), while the sensitivity and specificity of Gd-EOB-DTPA was 85% (57/67) and 100% (15/15), respectively. A risk of misclassifying HCA as FNH typically occurs for Gd-BOPTA when lesions are intrinsically hyperintense (P < 0.005). DATA CONCLUSION: The HBP of Gd-EOB-DTPA shows superior accuracy in ruling out HCA in comparison with Gd BOPTA, especially when the lesion is intrinsically hyperintense on T1 -weighted imaging. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018. PMID- 30252978 TI - Quantitative Identification of Nonmuscle-Invasive and Muscle-Invasive Bladder Carcinomas: A Multiparametric MRI Radiomics Analysis. AB - BACKGROUND: Preoperative discrimination between nonmuscle-invasive bladder carcinomas (NMIBC) and the muscle-invasive ones (MIBC) is very crucial in the management of patients with bladder cancer (BC). PURPOSE: To evaluate the discriminative performance of multiparametric MRI radiomics features for precise differentiation of NMIBC from MIBC, preoperatively. STUDY TYPE: Retrospective, radiomics. POPULATION: Fifty-four patients with postoperative pathologically proven BC lesions (24 in NMIBC and 30 in MIBC groups) were included. FIELD STRENGTH/SEQUENCE: 3.0T MRI/T2 -weighted (T2 W) and multi-b-value diffusion weighted (DW) sequences. ASSESSMENT: A total of 1104 radiomics features were extracted from carcinomatous regions of interest on T2 W and DW images, and the apparent diffusion coefficient maps. Support vector machine with recursive feature elimination (SVM-RFE) and synthetic minority oversampling technique (SMOTE) were used to construct an optimal discriminative model, and its performance was evaluated and compared with that of using visual diagnoses by experts. STATISTICAL TESTS: Chi-square test and Student's t-test were applied on clinical characteristics to analyze the significant differences between patient groups. RESULTS: Of the 1104 features, an optimal subset involving 19 features was selected from T2 W and DW sequences, which outperformed the other two subsets selected from T2 W or DW sequence in muscle invasion discrimination. The best performance for the differentiation task was achieved by the SVM-RFE+SMOTE classifier, with averaged sensitivity, specificity, accuracy, and area under the curve of receiver operating characteristic of 92.60%, 100%, 96.30%, and 0.9857, respectively, which outperformed the diagnostic accuracy by experts. DATA CONCLUSION: The proposed radiomics approach has potential for the accurate differentiation of muscle invasion in BC, preoperatively. The optimal feature subset selected from multiparametric MR images demonstrated better performance in identifying muscle invasiveness when compared with that from T2 W sequence or DW sequence only. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30252979 TI - Delimiting species of marine gastropods (Turridae, Conoidea) using RAD sequencing in an integrative taxonomy framework. AB - Species delimitation in poorly known and diverse taxa is usually performed based on monolocus, DNA-barcoding-like approaches, while multilocus data are often used to test alternative species hypotheses in well-studied groups. We combined both approaches to delimit species in the Xenuroturris/Iotyrris complex, a group of venomous marine gastropods from the Indo-Pacific. First, COI sequences were analysed using three methods of species delimitation to propose primary species hypotheses. Second, RAD sequencing data were also obtained and a maximum likelihood phylogenetic tree produced. We tested the impact of the level of missing data on the robustness of the phylogenetic tree obtained with the RAD-seq data. Alternative species partitions revealed with the COI data set were also tested using the RAD-seq data and the Bayes factor species delimitation method. The congruence between the species hypotheses proposed with the mitochondrial nuclear data sets, together with the morphological variability of the shell and the radula and the distribution pattern, was used to turn the primary species hypotheses into secondary species hypotheses. Allopatric primary species hypotheses defined with the COI gene were interpreted to correspond to intraspecific structure. Most of the species are found sympatrically in the Philippines, and only one is confidently identified as a new species and described as Iotyrris conotaxis n. sp. The results obtained demonstrate the efficiency of the combined monolocus/multilocus approach to delimit species. PMID- 30252980 TI - Selective binding of an organoruthenium complex to G-rich human telomeric sequence by tandem mass spectrometry. AB - RATIONALE: Human telomeric DNA is reported to be a potential target for anticancer organometallic ruthenium(II) complexes, however, the interaction sites were not clearly discriminated and identified. METHODS: In the current study, tandem mass spectrometry (MS/MS) using collision-induced dissociation (CID) was firstly introduced to identify the interaction sites of an organometallic ruthenium(II) complex [(eta6 -biphenyl)Ru(en)Cl][PF6 ] (1; en = ethylenediamine) with 5'-T1 T2 A3 G4 G5 G6 -3' (I), the repeating unit of human telomeric DNA, in both positive- and negative-ion mode at a low reaction molar ratio (1/I = 0.2) which was applied to preserve the site selectivity. RESULTS: Mass spectrometric results showed that mono-ruthenated I was the main product under the conditions. In positive-ion mode, MS/MS results indicated that ruthenium complex 1 binds to T2 or G6 in strand I. However, in negative-ion mode, no efficient information was obtained for exact identification of ruthenation sites which may be attributed to losses of fragment ions due to charge neutralization by the coordination of the positively charged ruthenium complex to the short MS/MS fragments. CONCLUSIONS: This is the first report of using top-down MS to characterize the interactions of organometallic ruthenium(II) complexes and human telomeric DNA. Thymine can be thermodynamically competitive with guanine for binding to ruthenium complexes even at low reaction molar ratio, which inspired us to explore in greater depth the significance of thymine binding. PMID- 30252981 TI - Reversible Thermoresponsive Plasmonic Core-Satellite Nanostructures That Exhibit Both Expansion and Contraction (UCST and LCST). AB - The assembly of sophisticated gold nanoparticle constructs where thermoresponsive core-satellite nanostructures are created and the satellites are close enough to the core for strong surface plasmon resonance coupling to occur, has begun to be developed. The linker between the core and the satellites being a thermoresponsive polymer means that a dispersion of these nanostructures will show temperature-dependent optical properties as the distance between the core and the satellites changes. Unlike previous related thermoresponsive core satellite systems that undergo a single thermoresponsive transition, herein a polymer system with dual thermoresponsive transitions (block copolymer with both lower critical solution temperature and upper critical solution temperature) is employed as a linker that modulates the gap distance between the "core" and "satellites" in response to the temperature. In this way, optical properties of dispersions can be dynamically tuned. The system permits wide and reversible control of the optical properties, which may render them excellent candidates for reversible nanosensors. PMID- 30252982 TI - The effects of living in an outdoor enclosure on hippocampal plasticity and anxiety-like behavior in response to nematode infection. AB - The hippocampus of rodents undergoes structural remodeling throughout adulthood, including the addition of new neurons. Adult neurogenesis is sensitive to environmental enrichment and stress. Microglia, the brain's resident immune cells, are involved in adult neurogenesis by engulfing dying new neurons. While previous studies using laboratory environmental enrichment have investigated alterations in brain structure and function, they do not provide an adequate reflection of living in the wild, in which stress and environmental instability are common. Here, we compared mice living in standard laboratory settings to mice living in outdoor enclosures to assess the complex interactions among environment, gut infection, and hippocampal plasticity. We infected mice with parasitic worms and studied their effects on adult neurogenesis, microglia, and functions associated with the hippocampus, including cognition and anxiety regulation. We found an increase in immature neuron numbers of mice living in outdoor enclosures regardless of infection. While outdoor living prevented increases in microglial reactivity induced by infection in both the dorsal and ventral hippocampus, outdoor mice with infection had fewer microglia and microglial processes in the ventral hippocampus. We observed no differences in cognitive performance on the hippocampus-dependent object location task between infected and uninfected mice living in either setting. However, we found that infection caused an increase in anxiety-like behavior in the open field test but only in outdoor mice. These findings suggest that living conditions, as well as gut infection, interact to produce complex effects on brain structure and function. PMID- 30252983 TI - Magnetic Susceptibility and Fat Content in the Lumbar Spine of Postmenopausal Women With Varying Bone Mineral Density. AB - BACKGROUND: Osteoporosis is a systemic disease characterized by low bone mass with increased fracture risk. Quantitative imaging biomarkers are important for accurately predicting fracture risk in patients with osteoporosis. PURPOSE: To prospectively study the changes of magnetic susceptibility and fat content in the lumbar spine of postmenopausal females with varying bone mineral density (BMD), and investigate their application to osteoporosis assessment. STUDY TYPE: Cohort. POPULATION: In all, 108 postmenopausal females (58.2 +/- 6.7 [range 45-79] years old). FIELD STRENGTH/SEQUENCE: Quantitative computed tomography (QCT) performed on a 64-detector CT scanner; quantitative susceptibility mapping (QSM) and mDixon quant MR imaging performed using a 3.0T imaging system with a 16-channel posterior coil. ASSESSMENT: QCT, QSM, and mDixon were performed in 108 postmenopausal females to measure vertebral BMD, susceptibility, and proton density fat fraction (PDFF). Mean vertebral QSM and PDFF were compared among three BMD cohorts (normal, osteopenic, and osteoporotic). Receiver operating characteristic analyses were performed to evaluate the performance of QSM, PDFF, and QSM+PDFF for assessing osteoporosis. STATISTICAL TESTS: Parameters were compared using Kruskal-Wallis test and Pearson test. RESULTS: Compared with that of the normal BMD group (-17.0 +/- 43.6 ppb), vertebral QSM was significantly increased in osteopenia (30.8 +/- 47.0 ppb, P < 0.001), and further increased in osteoporosis (82.0 +/- 39.9 ppb, P < 0.001). QSM was negatively correlated with BMD (r = -0.70, P < 0.001) and positively correlated with PDFF (r = 0.64, P < 0.001). Compared with the area under the curve (AUC) of PDFF, the AUC of QSM was higher in differentiating between normal and osteoporosis (P = 0.44), and between osteopenia and osteoporosis (P = 0.13), but without statistical significance. The AUC of QSM+PDFF was significantly higher than that of PDFF for differentiating between osteopenia and osteoporosis (0.82 vs. 0.70, P = 0.039). DATA CONCLUSION: The combination of vertebral susceptibility and fat content may be a promising marker for assessing postmenopausal osteoporosis. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30252984 TI - RADseq and mate choice assays reveal unidirectional gene flow among three lamprey ecotypes despite weak assortative mating: Insights into the formation and stability of multiple ecotypes in sympatry. AB - Adaptive divergence with gene flow often results in complex patterns of variation within taxa exhibiting substantial ecological differences among populations. One example where this may have occurred is the parallel evolution of freshwater resident nonparasitic lampreys from anadromous-parasitic ancestors. Previous studies have focused on transitions between these two phenotypic extremes, but here, we considered more complex evolutionary scenarios where an intermediate freshwater form that remains parasitic is found sympatrically with the other two ecotypes. Using population genomic analysis (restriction-associated DNA sequencing), we found that a freshwater-parasitic ecotype was highly distinct from an anadromous-parasitic form (Qlake-P = 96.8%, Fst = 0.154), but that a freshwater-nonparasitic form was almost completely admixed in Loch Lomond, Scotland. Demographic reconstructions indicated that both freshwater populations likely derived from a common freshwater ancestor. However, while the nonparasitic ecotype has experienced high levels of introgression from the anadromous parasitic ecotype (Qanad-P = 37.7%), there is no evidence of introgression into the freshwater-parasitic ecotype. Paradoxically, mate choice experiments predicted high potential for gene flow: Males from all ecotypes were stimulated to spawn with freshwater-parasitic females, which released gametes in response to all ecotypes. Differentially fixed single nucleotide polymorphisms identified genes associated with growth and development, which could possibly influence the timing of metamorphosis, resulting in significant ecological differences between forms. This suggests that multiple lamprey ecotypes can persist in sympatry following shifts in adaptive peaks, due to environmental change during their repeated colonization of post-glacial regions, followed by periods of extensive gene flow among such diverging populations. PMID- 30252985 TI - A new method for high-precision measurements of 17 O/16 O ratios in H2 O. PMID- 30252987 TI - REPAIRit: Improving Myocardial Nulling and Ghosting Artifacts of 3D Navigator Gated Late Gadolinium Enhancement Imaging During Arrhythmia. AB - BACKGROUND: Cardiac 3D navigator-gated late gadolinium enhancement (LGE) imaging is important for assessment of left atrial fibrosis, but the image quality is often degraded due to arrhythmia. PURPOSE: To investigate a novel 3D LGE sequence with improved myocardial nulling and reduced ghosting artifacts during arrhythmia. STUDY TYPE: Prospective. POPULATION: Arrhythmia patients (n = 14). SEQUENCE: The proposed technique, REPAIRit (Regrowth Equalization Pulse for Arrhythmias in Inversion Recovery with automatic inversion time calculation), inserts a saturation pulse with a dynamic flip angle into the 3D LGE sequence to minimize arrhythmia-induced signal fluctuations. Using ShMOLLI (shortened modified Look-Locker imaging) to estimate myocardial T1 , REPAIRit automatically calculates the optimal inversion time (TI) based on Bloch equations. ASSESSMENT: REPAIRit LGE and the standard LGE were compared with simulations, phantom imaging, and patient studies. Patient images were assessed quantitatively, based on ghost-to-noise ratio (GNR), blood signal-to-noise ratio (SNRb), myocardial signal-to-noise ratio (SNRm), and blood-to-myocardium contrast-to-noise ratio (CNR), and qualitatively on a 4-point scale. Patients were subgrouped based on the presence of arrhythmia to assess the image quality difference. STATISTICAL TESTS: The two LGE sequences were compared by Student's t-test and Wilcoxon signed-rank test. The two patient-subgroups were compared using Welch's t-test and Wilcoxon rank-sum test. RESULTS: In 14 analyzed patients, REPAIRit LGE significantly lowered GNR (1.25 +/- 0.41 vs. 1.42 +/- 0.42, P = 0.04), reduced SNRm (1.90 +/- 0.60 vs. 3.16 +/- 1.66, P = 0.01), improved ghosting artifact scores (2.5 +/- 0.6 vs. 2.2 +/- 0.9, P = 0.03), myocardial nulling scores (2.7 +/ 0.5 vs. 2.3 +/- 0.7, P = 0.02), and atrial quality scores (2.8 +/- 0.3 vs. 2.4 +/- 0.8, P = 0.03) compared with the standard LGE. Comparing patients with arrhythmia (n = 6) to those without (n = 8) during the scan, the former had lower left ventricular (LV) myocardial T1 s (430 +/- 26 msec vs. 469 +/- 39 msec, P = 0.06) but similar blood T1 s (318 +/- 55 msec vs. 316 +/- 27 msec, P = 0.96), and significantly lower blood SNR (5.2 +/- 1.8 vs. 9.2 +/- 3.0, P = 0.01) and significantly worse image quality (P = 0.01 for REPAIRit and P = 0.03 for standard). DATA CONCLUSION: REPAIRit improves myocardial nulling and reduces ghosting artifacts of 3D LGE under arrhythmia. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018. PMID- 30252990 TI - Spotlights are papers selected by editors published in peer-reviewed journals that may be more regionally specific or appearing in languages other than English. PMID- 30252988 TI - Quantitative Assessment of Regional Dynamic Airway Collapse in Neonates via Retrospectively Respiratory-Gated 1 H Ultrashort Echo Time MRI. AB - BACKGROUND: Neonatal dynamic tracheal collapse (tracheomalacia, TM) is a common and serious comorbidity in infants, particularly those with chronic lung disease of prematurity (bronchopulmonary dysplasia, BPD) or congenital airway or lung related conditions such as congenital diaphragmatic hernia (CDH), but the underlying pathology, impact on clinical outcomes, and response to therapy are not well understood. There is a pressing clinical need for an accurate, objective, and safe assessment of neonatal TM. PURPOSE: To use retrospectively respiratory-gated ultrashort echo-time (UTE) MRI to noninvasively analyze moving tracheal anatomy for regional, quantitative evaluation of dynamic airway collapse in quiet-breathing, nonsedated neonates. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Twenty-seven neonatal subjects with varying respiratory morbidities (control, BPD, CDH, abnormal polysomnogram). FIELD STRENGTH/SEQUENCE: High-resolution 3D radial UTE MRI (0.7 mm isotropic) on 1.5T scanner sited in the neonatal intensive care unit. ASSESSMENT: Images were retrospectively respiratory gated using the motion-modulated time-course of the k-space center. Tracheal surfaces were generated from segmentations of end-expiration/inspiration images and analyzed geometrically along the tracheal length to calculate percent-change in luminal cross-sectional area (A % ) and ratio of minor-to-major diameters at end-expiration (r D,exp ). Geometric results were compared to clinically available bronchoscopic findings (n = 14). STATISTICAL TESTS: Two-sample t-test. RESULTS: Maximum A % significantly identified subjects with/without a bronchoscopic TM diagnosis (with: 46.9 +/- 10.0%; without: 27.0 +/- 5.8%; P < 0.001), as did minimum r D,exp (with: 0.346 +/- 0.146; without: 0.671 +/- 0.218; P = 0.008). Subjects with severe BPD exhibited a far larger range of minimum r D,exp than subjects with mild/moderate BPD or controls (0.631 +/- 0.222, 0.782 +/ 0.075, and 0.776 +/- 0.030, respectively), while minimum r D,exp was reduced in CDH subjects (0.331 +/- 0.171) compared with controls (P < 0.001). DATA CONCLUSION: Respiratory-gated UTE MRI can quantitatively and safely evaluate neonatal dynamic tracheal collapse, as validated with the clinical standard of bronchoscopy, without requiring invasive procedures, anesthesia, or ionizing radiation. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018. PMID- 30252991 TI - Determination of potential oxidative damage, hepatotoxicity, and cytogenotoxicity in male Wistar rats: Role of indomethacin. AB - The present study demonstrated the indomethacin (INDO) induced oxidative stress, hepatotoxicity, and genotoxicity in male Wistar rats. Animals were orally administrated INDO at doses of 0.302 and 0.605 (mg/kg b.w.) for 2 weeks. Reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (LPO) activities/levels were measured in the liver, kidney, and brain tissues. The aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) activities, total bilirubin (TBIL) levels, and histopathological changes were determined in the liver tissues. Micronucleus frequency (micronucleus test) and DNA damage (comet assay) tests were performed in the bone marrow cells and leukocytes, respectively. Results show that INDO treatment decreased the GSH, SOD, and CAT levels/activities and increased the LPO, ALT, AST, ALP, and TBIL activities/levels. INDO induced significant hepatic injury and micronucleus and DNA damage. Thus, the current investigations confirm the oxidative stress, hepatotoxic, and genotoxic properties of INDO in the male Wistar rats. PMID- 30252989 TI - Simultaneous Evaluation of Lung Anatomy and Ventilation Using 4D Respiratory Motion-Resolved Ultrashort Echo Time Sparse MRI. AB - BACKGROUND: Computed tomography (CT) and spirometry are the current standard methods for assessing lung anatomy and pulmonary ventilation, respectively. However, CT provides limited ventilation information and spirometry only provides global measures of lung ventilation. Thus, a method that can enable simultaneous examination of lung anatomy and ventilation is of clinical interest. PURPOSE: To develop and test a 4D respiratory-resolved sparse lung MRI (XD-UTE: eXtra Dimensional Ultrashort TE imaging) approach for simultaneous evaluation of lung anatomy and pulmonary ventilation. STUDY TYPE: Prospective. POPULATION: In all, 23 subjects (11 volunteers and 12 patients, mean age = 63.6 +/- 8.4). FIELD STRENGTH/SEQUENCE: 3T MR; a prototype 3D golden-angle radial UTE sequence, a Cartesian breath-hold volumetric-interpolated examination (BH-VIBE) sequence. ASSESSMENT: All subjects were scanned using the 3D golden-angle radial UTE sequence during normal breathing. Ten subjects underwent an additional scan during alternating normal and deep breathing. Respiratory-motion-resolved sparse reconstruction was performed for all the acquired data to generate dynamic normal breathing or deep-breathing image series. For comparison, BH-VIBE was performed in 12 subjects. Lung images were visually scored by three experienced chest radiologists and were analyzed by two observers who segmented the left and right lung to derive ventilation parameters in comparison with spirometry. STATISTICAL TESTS: Nonparametric paired two-tailed Wilcoxon signed-rank test; intraclass correlation coefficient, Pearson correlation coefficient. RESULTS: XD-UTE achieved significantly improved image quality compared both with Cartesian BH VIBE and radial reconstruction without motion compensation (P < 0.05). The global ventilation parameters (a sum of the left and right lung measures) were in good correlation with spirometry in the same subjects (correlation coefficient = 0.724). There were excellent correlations between the results obtained by two observers (intraclass correlation coefficient ranged from 0.8855-0.9995). DATA CONCLUSION: Simultaneous evaluation of lung anatomy and ventilation using XD-UTE is demonstrated, which have shown good potential for improved diagnosis and management of patients with heterogeneous lung diseases. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30252992 TI - The Marriage of Aggregation-Induced Emission with Polymer Science. AB - Aggregation-induced emission (AIE) is a novel photophysical phenomenon coined in 2001 by our group and describes the enhanced light emission of some luminogens in the aggregate or solid state. The combination of AIE research and polymer science is a smart approach to produce functional luminescent materials with mechanical strength and excellent processability for real-world applications. In this feature article, recent progress in AIE polymeric systems, including chemical synthesis and physical blending strategies, is summarized. Through chemical synthesis, various AIE-active polymers, such as covalently bonded polymers, supramolecular polymers, and nonconjugated luminescent polymers, can be obtained. Serving as environmentally sensitive probes, AIE luminogens can also be physically doped into polymers to generate interesting systems. Finally, outlooks and perspectives on the future direction of AIE polymeric systems are discussed. PMID- 30252986 TI - The role of gene flow in rapid and repeated evolution of cave-related traits in Mexican tetra, Astyanax mexicanus. AB - Understanding the molecular basis of repeatedly evolved phenotypes can yield key insights into the evolutionary process. Quantifying gene flow between populations is especially important in interpreting mechanisms of repeated phenotypic evolution, and genomic analyses have revealed that admixture occurs more frequently between diverging lineages than previously thought. In this study, we resequenced 47 whole genomes of the Mexican tetra from three cave populations, two surface populations and outgroup samples. We confirmed that cave populations are polyphyletic and two Astyanax mexicanus lineages are present in our data set. The two lineages likely diverged much more recently than previous mitochondrial estimates of 5-7 mya. Divergence of cave populations from their phylogenetically closest surface population likely occurred between ~161 and 191 k generations ago. The favoured demographic model for most population pairs accounts for divergence with secondary contact and heterogeneous gene flow across the genome, and we rigorously identified gene flow among all lineages sampled. Therefore, the evolution of cave-related traits occurred more rapidly than previously thought, and trogolomorphic traits are maintained despite gene flow with surface populations. The recency of these estimated divergence events suggests that selection may drive the evolution of cave-derived traits, as opposed to disuse and drift. Finally, we show that a key trogolomorphic phenotype QTL is enriched for genomic regions with low divergence between caves, suggesting that regions important for cave phenotypes may be transferred between caves via gene flow. Our study shows that gene flow must be considered in studies of independent, repeated trait evolution. PMID- 30252993 TI - A Temperature-, pH- and Voltage-Responsive Nanogate with a Remarkably High Factor of Change in Ion Currents due to ON/OFF Switching. AB - In biological cells, nuclear pore complexes (NPCs) embedded in cell membranes are capable of controlling the flow of ions, for example, Na+ , K+ , and Ca2+ by responding to stimuli, for example, pH and voltage. Inspired by NPCs, researchers have been endeavoring to develop nanogates to achieve the control of ion transport, but the developed nanogates only have a low factor of change in ion currents due to ON/OFF switching. As such nanopores with high temperature and pH responsivities were developed in this work. According to the experimental results, at a voltage of 3 V, the change in ion currents due to pH change is up to a factor of 170, which is remarkably high compared to other nanogates reported. Quantum chemical (QC) calculation results show that a protonated cytosine molecule (C+ ) and an unprotonated cytosine molecule (C) form three pairs of hydrogen bonds and consequently a nucleobase pair, CC+ , leading to the binding of various strands, assembly of a strand net, and blockage of ion transport. The nanogate developed is capable of responding to temperature change. At a voltage of 3 V, the factor of change in ion currents in response to temperature variation is as high as 110. Further experiments were performed to investigate the influence of the NaCl concentrations and small opening diameters exerted on nanogate performance. PMID- 30252994 TI - Diffusion Tensor Imaging of Tibial and Common Peroneal Nerves in Patients With Guillain-Barre Syndrome: A Feasibility Study. AB - BACKGROUND: The development of a noninvasive, objective, and accurate method to assess peripheral nerve disorders in Guillain-Barre syndrome (GBS) is of clinical significance. Diffusion tensor imaging (DTI) has been used to evaluate some peripheral nerve disorders. PURPOSE: To investigate the feasibility of DTI in evaluating the peripheral nerve disorders in patients with GBS. STUDY TYPE: Case control. SUBJECTS: Twenty GBS patients and 16 healthy volunteers. FIELD STRENGTH/SEQUENCE: 3.0T, T1 WI-SE, T2 WI-SPAIR, DTI; electrophysiology. ASSESSMENT: MRI data were analyzed by two radiologists blindly and independently. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusion coefficient (AD), and radial diffusion coefficient (RD) values of tibial nerve (TN) and common peroneal nerve (CPN) were recorded. Motor nerve conduction velocity (MCV) and motor nerve conduction amplitude of TN and CPN were recorded. STATISTICAL TESTS: Intraclass correlation coefficient (ICC), t-test, receiver operating characteristic (ROC), and area under the curve (AUC) analysis, Pearson correlation coefficient. RESULTS: The FA and AD values of TN and CPN in the GBS group were significantly lower and the ADC and RD values were higher than those in the controls (P <0.05). The AUC of the FA values (0.970 for TN and 0.927 for CPN) were higher than that of the ADC, AD, and RD values. FA and AD values were positively correlated and ADC, RD values were negatively correlated with MCV and motor nerve conduction amplitude, respectively (P <0.05). The correlations between FA value and electrophysiology parameters were the highest. DATA CONCLUSION: DTI quantitative parameters could evaluate the disorders of peripheral nerves in patients with GBS. A moderate correlation was observed between DTI and electrophysiology parameters. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018. PMID- 30252995 TI - Pulsed capillary introduction applied to a miniature mass spectrometer for efficient liquid analysis. AB - RATIONALE: Capillary sampling of liquids for direct mass spectrometry (MS) analysis is introduced. The low transfer rate of the solution in the capillary will affect the analytical sensitivity and the response time; hence a pulsed capillary introduction (PCI) method was proposed and characterized. METHODS: The experiments were carried out using a miniature quadrupole mass spectrometer, and liquid can be spontaneously drawn into the vacuum chamber for subsequent ionization and detection. A simple up-and-down motor platform was used to control the brief contact of the capillary inlet with the liquid sample and implement pulsed injection. The pulsed sampling parameters were optimized based on the characterization and dynamic study of liquid transfer in capillaries. RESULTS: Compared with continuous capillary introduction (CCI), PCI can reduce the response time of MS analysis from more than half a minute to a few seconds. In addition, it provides better detection sensitivity as the ion signals of all solution components are enhanced and the acquired limit of detection (LOD) of toluene is about eight times lower than CCI analysis. For each analysis, the consumed sample volume is only a few nanoliters and the absolute consumption of the analyte can reach the femtogram level. CONCLUSIONS: The proposed PCI method is proved to be successful in improving the sampling efficiency when performing direct liquid analysis without increasing the vacuum load. A miniature MS instrument with a proper capillary inlet can possess flexible operation modes to meet different application demands. PMID- 30252996 TI - Radiomics Analysis of DTI Data to Assess Vision Outcome After Intravenous Methylprednisolone Therapy in Neuromyelitis Optic Neuritis. AB - BACKGROUND: Neuromyelitis optica-optic neuritis (NMO-ON) patients are routinely treated with intravenous methylprednisolone (IVMP). For the patients nonresponsive to IVMP, more effective but aggressive therapy of plasma exchange (PE) should be employed instead of IVMP in the first line. PURPOSE: To assess the visual outcomes of NMO-ON patients after IVMP by radiomics analysis of whole brain diffusion tensor imaging (DTI) data. STUDY TYPE: Retrospective. POPULATION: In all, 57 NMO-ON patients receiving IVMP therapy for 3 days. FIELD STRENGTH/SEQUENCE: 3.0T; DTI images acquired by a single-shot echo planar image sequence; T1 images acquired by 3D fast spoiled gradient echo (3D-FSPGR) MRI. ASSESSMENT: In all, 200 DTI measures were extracted from the DTI data and employed as features to construct a radiomics assessment model for visual outcomes of NMO-ON patients after IVMP. The assessment performance was evaluated by area under the receiver operating characteristic curve (AUC), classification accuracy (ACC), sensitivity, specificity, and positive and negative predicted values (PPV and NPV). The selected DTI measures would reveal the white matter impairments related to visual recovery of NMO-ON patients. STATISTICAL TESTS: The relationship between the selected DTI measures and the clinical visual characteristics were investigated by Pearson correlation, Spearman's rank correlation, and one-way analysis of variance analysis. RESULTS: The radiomics model obtained an ACC of 73.68% (P = 0.002), AUC of 0.7931, sensitivity of 0.6207, specificity of 0.8571, PPV of 0.8182, and NPV of 0.6857 in assessing visual outcomes of the NMO-ON patients after IVMP treatment. The selected DTI measures revealed white matter impairments related to the visual outcomes in the white matter tracts of vision-relevant regions, motor-related regions, and corpus callosum. The white matter impairments were found significantly correlated with the disease duration and the length of lesions in the optic nerve. DATA CONCLUSION: Radiomics analysis of DTI data has great potential in assessing visual outcomes of NMO-ON patients after IVMP therapy. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018. PMID- 30252997 TI - Repeatability of Arterial Spin Labeling MRI in Measuring Blood Perfusion in the Human Eye. AB - BACKGROUND: Quantifying blood perfusion in ocular tissues is challenging, partly because the majority of the blood is carried by the choroid, which is difficult to visualize because it is located between the retina and sclera. PURPOSE/HYPOTHESIS: To evaluate the intra- and interday repeatability of MRI measures of chorio-retinal blood perfusion. STUDY TYPE: Prospective, cross sectional, observational study. POPULATION: Twenty young healthy adults (six male, age: 25 +/- 5 years) scanned twice within a single session repeated at the same time of day on 2 days. FIELD STRENGTH/SEQUENCE: Arterial spin labeling (ASL) MRI at 3.0T using pseudocontinuous ASL (PCASL) labeling scheme and a 3D turbo gradient-spin-echo (TGSE) acquisition, including axial T2 -weighted structural images using a 2D turbo-spin-echo (TSE) sequence. ASSESSMENTS: Region-of-interest analysis for assessment of chorio-retinal blood perfusion. STATISTICAL TESTS: Intra- and interday repeatability of measures analyzed using intraclass correlation coefficients (ICC), Pearson's correlation analysis, paired t-tests, and Bland-Altman plots. RESULTS: The mean chorio-retinal perfusion was 77.86 (standard deviation [SD] = 29.80) ml/100ml/min. Perfusion measurements correlated strongly within a single session (r = 0.95, 95% confidence interval [CI] [0.880 0.980], P < 0.001) and between the two sessions based on a single run (r = 0.80 [0.582-0.913], P < 0.001), and two runs (r = 0.80 [0.479-0.918], P < 0.001). There were mean differences of 2.69 [16.85 to -22.23] ml/100ml/min for intraday measures, -7.44 [27.45 to -42.32] ml/100ml/min for single-run interday measures, and 5.73 [28.71 to -40.17] ml/100ml/min for two-run interday measures, but none were significant (all P > 0.05). DATA CONCLUSION: Quantitative ASL-MRI measurements of chorio-retinal blood perfusion showed high intra- and interday repeatability. The ASL-MRI technique provides reliable measures of chorio-retinal perfusion in vivo. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2018. PMID- 30252998 TI - An Alcohol Dehydrogenase from the Short-Chain Dehydrogenase/Reductase Family of Enzymes for the Lactonization of Hexane-1,6-diol. AB - Biocatalytic production of lactones, and in particular epsilon-caprolactone (CL), have gained increasing interest as a greener route to polymer building blocks, especially through the use of Baeyer-Villiger monooxygenases (BVMOs). Despite several advances in the field, BVMOs, however, still suffer several practical limitations. Alcohol dehydrogenase (ADH)-mediated lactonization of diols in turn has received far less attention and very few enzymes have been identified for the conversion of diols to lactones, with horse-liver ADH (HLADH) remaining the catalyst of choice. Screening of a diverse panel of ADHs, AaSDR-1, a member of the short-chain dehydrogenase/reductase family, was found to produce epsilon caprolactone from hexane-1,6-diol. Moreover, cofactor regeneration by an NADH oxidase eliminated the requirement of co-substrates, yielding water as the sole by-product. Despite lower turnover frequencies as compared to HLADH, higher selectivity was found for the production of CL, with HLADH forming significant amounts of 6-hydroxyhexanoic acid and adipic acid through aldehyde dehydrogenation/oxidation of the gem-diol intermediates. Also, CL yield were shown to be dependent on buffer choice, as structural elucidation of a Tris adduct confirmed the buffer amine to react with aliphatic aldehydes forming a Schiff-base intermediate which through further ADH oxidation, forms a tricyclic acetal product. PMID- 30252999 TI - Efficacy of topical calcineurin inhibitors in pyoderma gangrenosum. PMID- 30253000 TI - Intrinsic functional and structural connectivity of emotion regulation networks in obsessive-compulsive disorder. AB - Despite emotion regulation being altered in patients with obsessive-compulsive disorder (OCD), no studies have investigated its relation to multimodal amygdala connectivity. We compared corticolimbic functional and structural connectivity between OCD patients and healthy controls (HCs), and correlated this with the dispositional use of emotion regulation strategies and with OCD severity. OCD patients (n = 73) and HCs (n = 42) were assessed for suppression and reappraisal strategies using the Emotion Regulation Questionnaire (ERQ) and for OCD severity using the Yale-Brown Obsessive-Compulsive Scale. Resting-state functional magnetic resonance imaging (rs-fMRI) connectivity maps were generated using subject-specific left amygdala (LA) and right amygdala (RA) masks. We identified between-group differences in amygdala whole-brain connectivity, and evaluated the moderating effect of ERQ strategies. Significant regions and amygdala seeds were used as targets in probabilistic tractography analysis. Patients scored higher in suppression and lower in reappraisal. We observed higher rs-fMRI RA-right postcentral gyrus (PCG) connectivity in HC, and in patients this was correlated with symptom severity. Reappraisal scores were associated with higher negative LA left insula connectivity in HC, and suppression scores were negatively associated with LA-precuneus and angular gyri connectivity in OCD. Structurally, patients showed higher mean diffusivity in tracts connecting the amygdala with the other targets. RA-PCG connectivity is diminished in patients, while disrupted emotion regulation is related to altered amygdala connectivity with the insula and posterior brain regions. Our results are the first showing, from a multimodal perspective, the association between amygdala connectivity and specific emotional processing domains, emphasizing the importance of amygdala connectivity in OCD pathophysiology. PMID- 30253001 TI - Controversies in the treatment of androgenetic alopecia: The history of finasteride. AB - Male androgenetic alopecia (AGA) affects up to 60% of men by the age of 50. Currently, there are only two approved drugs for the treatment of male AGA: topical minoxidil and oral finasteride. Topical minoxidil is readily available over the counter and has a well-established safety record. However, following 24 weeks of treatment, less than 40% of men respond to the drug. Additionally, due to the topical route of administration, compliance with minoxidil remains low. In contrast, oral finasteride, a 5-alpha reductase inhibitor, demonstrated efficacy in arresting hair loss in more than 80% of patients following 12 months of treatment. However, controversy surrounding potential adverse sexual side effects has negatively affected public perception of the drug and may significantly reduce the number of patients that can benefit from the drug. PMID- 30253002 TI - Suppressor effects in associations between patient attachment to therapist and psychotherapy outcome. AB - OBJECTIVE: Several studies propose that patient attachment to therapist is associated with therapy outcome. However, the magnitude of the effect is diverse, which might be explicable by suppressor effects and the new concept of pseudo security. METHOD: Associations between patient attachment to therapist (client attachment-to-therapist-scale [CATS]) and psychotherapy outcome ("global severity index" of the Symptom Check List) were evaluated in N = 368 patients. Multilevel models were performed. RESULTS: When tested in separate models, secure attachment to therapist was associated with a more favourable outcome (p < 0.05), whereas avoidant and preoccupied attachment to therapist were correlated with a less favourable outcome (both p < 0.05). Avoidant but not preoccupied attachment to therapist suppressed the association between secure attachment to therapist and the outcome. When controlling for the other two CATS scales, avoidant as well as preoccupied attachment to therapist remained associated with a less favourable outcome (p < 0.05). CONCLUSION: Avoidant attachment to therapist suppresses the association between secure attachment to therapist and psychotherapy outcome. Pseudo-security has to be taken into consideration in self-report data on patient attachment to therapist. PMID- 30253003 TI - Carbonyl-Olefin Cross-Metathesis Through a Visible-Light-Induced 1,3-Diol Formation and Fragmentation Sequence. AB - A visible-light-mediated approach to carbonyl-olefin cross-metathesis is described. Photoinduced hole catalysis was used to promote the formation of 1,3 diols from aldehydes and styrenes, which were then readily fragmented under acidic conditions to form the cross-metathesis products. The use of 1,3-diols as intermediates, rather than the energetically more demanding oxetanes, provides a new, orthogonal mechanistic strategy for carbonyl-olefin cross-metathesis. Furthermore, this approach does not require any metals, ligands, or additives, and provides the products with high levels of E selectivity. A mechanistic rationale is provided and supported by both theoretical calculations and experiments. Additionally, a practical synthesis of a new acridinium-based photocatalyst, including full characterization, is presented. PMID- 30253004 TI - E-cigarettes for harm minimisation: absence of evidence or evidence of absence? PMID- 30253005 TI - Occlusion therapy in inflammatory cutaneous diseases. PMID- 30253006 TI - Modulation of the inflammatory response after sclerotherapy for hydrocoele/spermatocoele. AB - OBJECTIVE: To investigate the modulation of the inflammatory response after sclerotherapy for hydrocoele/spermatocoele. PATIENTS AND METHODS: All patients with hydrocoele or spermatocoele presenting at the Department of Urology, University Hospital, Linkoping, Sweden, from 2006 to 2012, were included in this prospective observational study of sclerotherapy for hydrocoele/spermatocoele using polidocanol as a sclerosing agent and adjuvant antibiotic and anti inflammatory medication (AAAM) for modulation of the inflammatory response. Patients were clinically evaluated within 24-48 h after a complication or adverse event possibly related to sclerotherapy. Evaluation of cure was scheduled after 3 months and re-treatment, if necessary was carried out in the same manner as the first treatment. Groups of patients were compared using the chi-squared test and logistic regression analysis. RESULTS: From a total of 191 patients, AAAM was given to 126, of whom 5% had subclinical epididymitis/swelling (SES) compared to 26% of the patients without AAAM (P < 0.001). No other complication was observed. The rate of cure for the whole group of patients was 93% after one or two treatments and significantly higher in the group with AAAM than in the group without AAAM (96% vs 88%, P = 0.03). CONCLUSIONS: Modulation of the inflammatory response after sclerotherapy resulted in a lower incidence of SES and an increased cure rate. PMID- 30253007 TI - Stress-driven increase in proline levels, and not proline levels themselves, correlates with the ability to withstand excess salt in a group of 17 Italian rice genotypes. AB - In most plant species, a rapid increase in free proline content occurs following exposure to hyperosmotic stress conditions. However, inconsistent results were reported concerning the role of such an increase on the plant response to water shortage or excess salt. Therefore, the possibility that proline accumulation may help the cell to withstand stress conditions, or that it simply represents a stress marker, is still a matter of debate. A possible relationship between proline accumulation and salt tolerance was investigated in a set of 17 Italian rice varieties. Rice seedlings were exposed to increasing salt concentrations during germination and early growth. The resulting levels of free proline were measured separately in shoots and roots and compared to those in untreated controls. Results were related to the corresponding ability of a given genotype to tolerate stress conditions. Neither absolute proline levels in untreated or in salt-stressed seedlings showed a straightforward relationship to the relative tolerance to salt, estimated as conductivity values able to reduce growth by 10 or 50%. Conversely, a highly significant correlation was found between the increase in proline levels in shoots and the ability to withstand stress. The results strengthen a recent hypothesis suggesting than an increase in proline metabolic rates, more than the resulting proline content, may help the cell to counteract the effects of abiotic stress conditions. PMID- 30253009 TI - Solvent-Mediated Synthesis of Cyclobutane Isomers in a Photoactive Cadmium(II) Porous Coordination Polymer. AB - Photochemical [2+2] cycloaddition of 1,4-bis[2-(4-pyridyl)ethenyl]benzene, carried out in a CdII porous coordination polymer (PCP), produces different isomeric products depending on the guest solvent present in the PCP during irradiation. The nature of the included guest influences the conformation of the ligand, and thus the outcome of the cycloaddition reaction. We demonstrate controlled production of the two isomers from the same PCP by simple exchange of solvent. PMID- 30253010 TI - Phenotypic plasticity as a clue for invasion success of the submerged aquatic plant Elodea nuttallii. AB - Two closely related alien submerged aquatic plants were introduced into Europe. The new invader (Elodea nuttallii) gradually displaced E. canadensis even at sites where the latter was well established. The aim of the study was to evaluate the combined effects of environmental factors on several phenotypic characteristics of the two Elodea species, and to relate these phenotypic characteristics to the invasion success of E. nuttallii over E. canadensis. In a factorial design, Elodea plants were grown in aquaria containing five different nitrogen concentrations and incubated at five different light intensities. We used six functional traits (apical shoot RGR), total shoot RGR, relative elongation, root length, lateral spread, branching degree) to measure the environmental response of the species. We calculated plasticity indices to express the phenotypic differences between species. Light and nitrogen jointly triggered the development of phenotypic characteristics that make E. nuttallii a more successful invader in eutrophic waters than E. canadensis. The stronger invader showed a wider range of phenotypic plasticity. The apical elongation was the main difference between the two species, with E. nuttallii being more than two times longer than E. canadensis. E. canadensis formed dense side shoots even under high shade and low nitrogen levels, whereas E. nuttallii required higher light and nitrogen levels. We found that under more eutrophic conditions, E. nuttallii reach the water surface sooner than E. canadensis and through intensive branching outcompetes all other plants including E. canadensis. Our findings support the theory that more successful invaders have wider phenotypic plasticity. PMID- 30253008 TI - Stereoselective Synthesis of Mechanically Planar Chiral Rotaxanes. AB - Chiral interlocked molecules in which the mechanical bond provides the sole stereogenic unit are typically produced with no control over the mechanical stereochemistry. Here we report a stereoselective approach to mechanically planar chiral rotaxanes in up to 98:2 d.r. using a readily available alpha-amino acid derived azide. Symmetrization of the covalent stereocenter yields a rotaxane in which the mechanical bond provides the only stereogenic element. PMID- 30253011 TI - Prevention and management of iatrogenic blindness associated with aesthetical filler injections. AB - Injectable fillers have become one of the most performed aesthetical treatments worldwide over the past two decades. They are frequently applied to the face, offering effective and safe alternatives to more invasive surgical procedures. Nevertheless, there are serious risks associated with filler-based treatment. Visual impairment stands as a rare yet catastrophic adverse event associated with intravascular embolization of injected material to the retina or other areas of the central nervous system; potentially leading to permanent visual loss. This article presents a comprehensive revision of blindness secondary to aesthetical filler injections, offering up-to-date strategies for prevention and management. PMID- 30253012 TI - Strategies to Enhance the Photosensitization: Polymerization and the Donor Acceptor Even-Odd Effect. AB - A particular challenge in the design of organic photosensitizers (PSs) with donor acceptor (D-A) structures is that it is based on trial and error rather than specific rules. Now these challenges are addressed by proposing two efficient strategies to enhance the photosensitization efficiency: polymerization facilitated photosensitization and the D-A even-odd effect. Conjugated polymers have been found to exhibit a higher 1 O2 generation efficiency than their small molecular counterparts. Furthermore, PSs with A-D-A structures show enhanced photosensitization efficiency over those with D-A-D structures. Theoretical calculations suggest an enhanced intersystem crossing (ISC) efficiency by these strategies. Both in vitro and in vivo experiments demonstrate that the resulting materials can be used as photosensitizers in image-guided photodynamic anticancer therapy. These guidelines are applicable to other polymers and small molecules to lead to the development of new PSs. PMID- 30253013 TI - Reversible Spasticity Suppression and Locomotion Change After Pulsed Radiofrequency on the Dorsal Root Ganglia of Rats With Spinal Cord Injury. AB - OBJECTIVES: Radiofrequency has been used to suppress spasticity affecting motion in patients with cerebral palsy and spinal cord injury. This study tested spasticity suppression and locomotion change after pulsed radiofrequency (PRF) at the dorsal root ganglion of rats with spasticity. MATERIALS AND METHODS: Twenty four rats that survived for 28 days after thoracic spinal cord injury and showed spasticity in the right hind limb were separated randomly to a PRF group or Sham operation group. PRF consisted of 2 Hz biphasic 25 msec trains of PRF (500 kHz, 5 V intensity) applied on the right L5 dorsal root ganglion for 300 sec. Muscle tension of the right triceps surae was measured at 450 deg/sec of passive ankle dorsiflexion on the day before and 3, 7, and 14 days after PRF or sham operation. Locomotive function was evaluated by obtaining Basso, Beattie, and Bresnahan (BBB) scores. RESULTS: Muscle tension of the triceps surae decreased significantly three days after PRF, and gradually returned to baseline 14 days later. In the sham operation group, muscle tension increased significantly more than 14 days. The BBB scores declined from 10 to 8 after PRF and returned to pre PRF levels 14 days later, while scores remained constant after sham operation. CONCLUSIONS: PRF produced significant and reversible suppression in spasticity, but this was accompanied by deterioration in locomotive function. Thus, caution should be exercised in considering the benefits and costs in suppressing spasticity in ambulatory patients, and implanted devices that apply titratable doses of PRF may be best to optimize patients' needs. PMID- 30253014 TI - Remittive effect of Dupilumab in atopic dermatitis. PMID- 30253015 TI - Comprehensive Vibrational Spectroscopic Characterization of Nylon-6 Precursors for Precise Tracking of the Beckmann Rearrangement. AB - As a key step in nylon-6 synthesis, the Beckmann rearrangement is an ongoing target of catalytic studies that seek to improve the sustainability of polymer manufacture. Whilst solid-acid catalysts (predominantly zeotypes) have proven effective for this transformation, the development of more active and selective systems demands an understanding of fundamental catalytic mechanisms. In this undertaking, in situ and operando characterization techniques can be informative, provided rigorous spectroscopic groundwork is in place. Thus, to facilitate mechanistic studies we present a detailed investigation of the vibrational spectra of cyclohexanone, cyclohexanone oxime, epsilon-caprolactam and their D10 isotopomers, in the solid state. Variable-temperature infrared (150-300 K) and Raman (10-300 K) spectra are reported alongside inelastic neutron scattering data. Moreover, where key vibrational modes have been assigned with the aid of periodic density functional theory calculations, it has been possible to include hydrogen-bonding interactions explicitly. PMID- 30253016 TI - Modification of Carbon Fibre Surfaces by Sulfur-Fluoride Exchange Click Chemistry. AB - Technologies that enable surface modification are in high demand and are critical for the implementation of new functional materials and devices. Here, we describe the first modification of a carbon surface (in this case carbon fiber) using the sulfur-fluoride exchange (SuFEx) reaction. The parent sulfur (VI) fluoride moiety can be installed directly to the surface via electrochemical deposition of the fluorosulfate phenyldiazonium tetrafluoroborate salt, or by 'SuFExing' a phenol on the carbon surface followed by treatment of the material with SO2 F2 ; similar to a 'graft to' or 'graft from' functionalization approach. We demonstrate that these SuFEx-able surfaces readily undergo exchange with aryl silyl ethers, and that the subsequent sulfate linkages are themselves stable under electrochemical redox conditions. Finally, we showcase the utility of the SuFEx chemistry by installing a pendant amino group to the fiber surface resulting in interfacial shear strength improvements of up to 130 % in epoxy resin. PMID- 30253017 TI - Arbuscular mycorrhizal fungi change host plant DNA methylation systemically. AB - DNA methylation is an important epigenetic mechanism regulating gene expression in plants. DNA methylation has been shown to vary among species and also among plant tissues. However, no study has evaluated whether arbuscular mycorrhizal (AM) fungi affect DNA methylation levels in a tissue-specific manner. We investigated whether symbiosis with AM fungi affects DNA methylation in the host, focusing on different plant tissues (roots versus leaves) and across time. We carried out a 6-month pot experiment using Geranium robertianum in symbiosis with the AM fungus Funneliformis mosseae. Our results show that the pattern of total DNA methylation differed between leaves and roots and was related to when plants were harvested, confirming that DNA methylation is a process that occurs dynamically throughout an organism's lifetime. More importantly, the presence of AM fungus in roots of our experimental plants had a positive effect on total DNA methylation in both tissues. This study shows that colonisation by AM fungi can affect DNA methylation levels in their hosts and that plant DNA methylation varies in an age- and tissue-specific manner. PMID- 30253018 TI - Patient-reported outcomes: A 5-year long study reveals previously unreported therapeutic, demographic, socio-economic, and other correlations in vitiligo. AB - Vitiligo is a non-lethal, non-communicable, immune-mediated, and generally progressive skin disease, with poorly understood etiopathogenesis and weak evidence base. The aim of the study is to contribute to the scant research on the patient-reported outcomes in vitiligo, and to examine the presence of associations between various inputs for possible use in clinical practice. The study was designed as a web-based questionnaire with 40 inputs across seven dimensions. The questions include demographics, skin type, eye and natural hair color, age of respondent and age of onset, possible triggers, disease extent, localization, progression and activity, the efficacy of most common treatment modalities, medication side-effects, heredity and diseases among parents, and out of-pocket expenses for treatments to date. The analysis presented with this work contributes to the discussion about the relation between therapies, socio economic factors, and treatment outcomes in vitiligo. All physicians should adequately manage patient expectations in terms of overall treatment duration and expected out-of-pocket expenses, and actively evaluate patients at shorter intervals. A more aggressive therapeutic approach using telehealth devices should be considered to supplement therapy, monitor treatment progress, and protocol compliance. PMID- 30253019 TI - Symptom clusters and quality of life in breast cancer survivors after cancer treatment in a tertiary hospital in Korea. AB - We investigated the symptom clusters and effects of symptom clusters on the quality of life of Korean breast cancer survivors. We recruited 241 breast cancer survivors and collected cross-sectional data on their symptoms. To determine inter-relationships among symptoms, a principal component analysis with varimax rotation was performed based on the patient's symptoms (fatigue, nausea/vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, anxiety, depression, systemic therapy side effects, breast symptoms and arm symptoms). The first symptom cluster consisted of psychological (anxiety and depression) and general (appetite loss, fatigue, insomnia and dyspnoea) symptoms, whereas the second symptom cluster consisted of physical (arm symptom, breast symptom, pain and systemic therapy side effects) and gastrointestinal (nausea/vomiting and constipation) symptoms. Subgroup cluster analysis showed that breast cancer survivors with higher-scoring symptoms had significantly poorer quality of life in both psychological-general symptom cluster and physical-gastrointestinal symptom cluster subgroups, with subgroup-specific patterns. The symptom clusters differed depending on stage and functional status of breast cancer survivors. Breast cancer survivors may have a specific pattern of symptom clusters. Some symptom clusters may have a negative impact on the quality of life. Identifying symptom clusters of breast cancer survivors may have clinical implications by improving symptom management. PMID- 30253020 TI - Tumour contact surface area as a predictor of postoperative complications and renal function in patients undergoing partial nephrectomy for renal tumours. AB - OBJECTIVES: To evaluate the ability of original tumour contact surface area (CSA) to predict postoperative complications and renal function impairment in a series of patients who underwent elective partial nephrectomy (PN) for renal masses. MATERIALS AND METHODS: We analysed the clinical records of 531 consecutive patients who underwent elective PN because of a suspicion of kidney cancer at five academic, high-volume centres between January 2014 and December 2016. Each participating centre evaluated prospectively the radiological images to evaluate the CSA and to assign a PADUA score. Several expert surgeons performed the surgical procedures in each participating centre. Binary logistic regression was used to perform both univariable and multivariable analyses to identify predictors of postoperative complications. Linear regression analysis was used to identify independent predictors of absolute change in estimated glomerular filtration rate (eGFR; ACE). RESULTS: The median (interquartile range) CSA value was 14.2 (7.4-25.1) cm2 . A total of 349 tumours (65.7%) had a CSA <= 20 cm2 and the remaining 182 (34.3%) had a CSA > 20 cm2 . PNs were performed using an open approach in 237 (44.6%) cases, a pure laparoscopic approach in 152 cases (28.6%), and a robot-assisted approach in the remaining 142 cases (26.7%). Multivariable analyses found that only age (odds ratio [OR] 1.037, 95% confidence interval [CI] 1.018-1.057) and PADUA score (OR 1.289, 95%CI 1.132-1.469) were independent predictors of postoperative complications. Tumour CSA (OR 1.020, 95%CI 1.010 1.030) was found to be an independent predictor of postoperative complications only when PADUA score was removed from the model. Age (from -0.639 to -0.306; P < 0.001); body mass index (from 0.267 to 1.076; P = 0.001), age-adjusted Charlson score (from -3.193 to -0.259; P = 0.02), preoperative eGFR value (from -0.939 to 0.862; P < 0.001) and tumour CSA (from -0.260 to -0.048; P = 0.005) were found to be independent predictors of ACE. CONCLUSIONS: Tumour CSA is an independent predictor of postoperative renal function. Conversely, at multivariable analysis, PADUA score outperformed tumour CSA to predict postoperative complications after PN. The complexity of The Leslie et al. formula for calculating tumour CSA is a potential limitation with regard to its diffusion and application in clinical practice. PMID- 30253021 TI - Tensor-based morphometry using scalar and directional information of diffusion tensor MRI data (DTBM): Application to hereditary spastic paraplegia. AB - Tensor-based morphometry (TBM) performed using T1-weighted images (T1WIs) is a well-established method for analyzing local morphological changes occurring in the brain due to normal aging and disease. However, in white matter regions that appear homogeneous on T1WIs, T1W-TBM may be inadequate for detecting changes that affect specific pathways. In these regions, diffusion tensor MRI (DTI) can identify white matter pathways on the basis of their different anisotropy and orientation. In this study, we propose performing TBM using deformation fields constructed using all scalar and directional information provided by the diffusion tensor (DTBM) with the goal of increasing sensitivity in detecting morphological abnormalities of specific white matter pathways. Previously, mostly fractional anisotropy (FA) has been used to drive registration in diffusion MRI based TBM (FA-TBM). However, FA does not have the directional information that the tensors contain, therefore, the registration based on tensors provides better alignment of brain structures and better localization of volume change. We compare our DTBM method to both T1W-TBM and FA-TBM in investigating differences in brain morphology between patients with complicated hereditary spastic paraplegia of type 11 (SPG11) and a group of healthy controls. Effect size maps of T1W-TBM of SPG11 patients showed diffuse atrophy of white matter. However, DTBM indicated that atrophy was more localized, predominantly affecting several long-range pathways. The results of our study suggest that DTBM could be a powerful tool for detecting morphological changes of specific white matter pathways in normal brain development and aging, as well as in degenerative disorders. PMID- 30253023 TI - Efficacy of oral tranexemic acid in refractory melasma: A clinico-immuno histopathological study. AB - Tranexamic acid (TXA), a plasmin inhibitor, is an antifibrinolytic drug widely used to prevent and treat hemorrhage. We evaluated the effects of oral TXA clinically and immunohistopathologically in patients of refractory melasma. To evaluate the efficacy of oral TXA in patients with refractory melasma and correlate histopathological and immunohistochemical changes in pretreatment and post-treatment skin biopsies in patients willing to undergo biopsy. Thirty patients with refractory melasma were treated with oral TXA 500 mg twice daily along with a sunscreen and followed up. Modified MASI score (MMASI) and melasma quality of life (MELASQOL) were noted at baseline and after treatment. In patients willing to undergo skin biopsy, a 2 mm punch biopsy was obtained for histopathology and immunohistochemistry examination both before and after treatment with TXA. Clinical, histopathological, and immunohistochemical parameters were compared and correlated. Clinical improvement in melasma correlated in a perfect linear relationship with quality of life, decrease in epidermal pigmentation and decrease in Melan A staining on immunohistochemistry. Based on our observations, TXA can be said to have an inhibitory action on melanin synthesis and melanocyte proliferation. Future studies are required to further characterize the effects of TXA on the histopathology and immunohistochemistry of melasma, to standardize dosing schedule, duration of treatment and long term outcome, of which there are no definitive guidelines at present. PMID- 30253022 TI - Selective C-N Borylation of Alkyl Amines Promoted by Lewis Base. AB - An efficient method for the metal-free deaminative borylation of alkylamines, using bis(catecholato)diboron as the boron source, to directly synthesize various alkyl potassium trifluoroborate salts is introduced. The key to this high reactivity is the utilization of pyridinium salt activated alkylamines, with a catalytic amount of a bipyridine-type Lewis base as a promoter. This transformation shows good functional-group compatibility (e.g., it is unimpeded by the presence of a ketone, indole, internal alkene, or unactivated alkyl chloride) and can serve as a powerful synthetic tool for borylation of amine groups in complex compounds. Mechanistic experiments and computations suggest a mechanism in which the Lewis base activated B2 cat2 unit intercepts an alkyl radical generated by single-electron transfer (SET) from a boron-based reductant. PMID- 30253024 TI - Analysis of a newly discovered antigen of Bacillus cereus biovar anthracis for its suitability in specific serological antibody testing. AB - AIMS: The aim of this work was to identify a protein which can be used for specific detection of antibodies against Bacillus cereus biovar anthracis (Bcbva), an anthrax-causing pathogen that so far has been described in African rainforest areas. METHODS AND RESULTS: Culture supernatants of Bcbva and classic Bacillus anthracis (Ba) were analysed by gel electrophoresis, and a 35-kDa protein secreted only by Bcbva and not Ba was detected. The protein was identified as pXO2-60 by mass spectrometry. Sequence analysis showed that Ba is unable to secrete this protein due to a premature stop codon in the sequence for the signal peptide. Immunization of five outbred mice with sterile bacterial culture supernatants of Bcbva revealed an immune response in ELISA against pXO2 60 (three mice positive, one borderline) and the protective antigen (PA; four mice). When supernatants of classic Ba were injected into mice or human sera from anthrax patients were analysed, only antibodies against PA were detected. CONCLUSIONS: In combination with PA, the pXO2-60 protein can be used for the detection of antibodies specific against Bcbva and discriminating from Ba. SIGNIFICANCE AND IMPACT OF THE STUDY: After further validation, serological assays based on pXO2-60 can be used to perform seroprevalence studies to determine the epidemiology of B. cereus bv anthracis in affected countries and assess its impact on the human population. PMID- 30253025 TI - Recurrence and cancer-specific death after adjuvant chemotherapy for Stage III colon cancer. AB - AIM: The recommended standard of care for patients after resection of Stage III colon cancer is adjuvant 5-fluorouracil based chemotherapy - FOLFOX (fluorouracil, leucovorin with oxaliplatin) - or CAPOX (capecitabine, oxaliplatin). This may be modified in older patients or depending on comorbidity. This has been challenged recently as the apparent benefit of adjuvant chemotherapy may arise from improvements in surgery or preoperative imaging or pathology staging. This study compares recurrence and colon-cancer-specific death between patients who received postoperative adjuvant chemotherapy and those who did not. METHOD: Prospectively recorded data from 363 consecutive patients who had a resection for Stage III colonic adenocarcinoma between 1995 and 2010 inclusive were analysed. Surviving patients were followed for at least 5 years. The suitability of patients for chemotherapy was discussed routinely at multidisciplinary team meetings. The incidence of recurrence and colon-cancer specific death was evaluated by competing risk methods. RESULTS: After adjustment for the competing risk of non-colorectal cancer death, there was no significant difference in recurrence between the 204 patients who received chemotherapy and the 159 who did not [hazard ratio (HR) 0.94, 95% CI 0.66-1.32, P = 0.700) and no significant difference in colon-cancer-specific death (HR 0.73, 95% CI 0.50-1.04, P = 0.084; HR 0.88, 95% CI 0.57-1.36, P = 0.577 after adjustment for relevant covariates). CONCLUSION: These findings question the routine use of chemotherapy after complete mesocolic excision for Stage III colon cancer. Recurrence and cancer-specific death, assessed by competing risk methods, should be the standard outcomes for evaluating the effectiveness of adjuvant chemotherapy after potentially curative resection. PMID- 30253026 TI - Efficacy and safety of polydimethylsiloxane injection (Macroplastique(r) ) for the treatment of female stress urinary incontinence: results of a series of 85 patients with >=3 years of follow-up. AB - OBJECTIVE: To assess the long-term efficacy and safety of polydimethylsiloxane injection (Macroplastique(r) , Cogentix Medical, Orangeburg, New York, USA) for the treatment of female stress urinary incontinence (SUI), with a minimum follow up of 3 years. PATIENTS AND METHODS: This is an observational analytical prospective cohort study conducted in a single uro-gynaecological unit. All consecutive women with urodynamically confirmed pure SUI treated with the Macroplastique procedure, were included. Data regarding patient outcomes (International Consultation on Incontinence Questionnaire-Short Form, Patient Global Impression of Improvement, and patient satisfaction scores), objective cure rates, and adverse events were collected during follow-up. Uni- and multivariable analyses were performed to investigate outcomes. Multiple logistic regression was performed to identify factors involved in the risk of failure of the procedures or recurrence of SUI. RESULTS: In all, 85 women had the Macroplastique procedure. At the 3-year follow-up, all 85 (100%) patients were available for the evaluation. We did not find any significant change in the surgical outcomes during this time. At 3 years after surgery, 42 of 85 patients (49%) declared themselves cured (P = 0.67). Similarly, at the 3-year evaluation, 40 of 85 patients (47%) were objectively cured. There was no significant deterioration of objective cure rates over time (P = 0.3). A history of radical pelvic surgery and a low surgeon's skill were significantly associated with the risk of failure of Macroplastique. The multivariate analysis confirmed these findings; a previous history of radical pelvic surgery and a low surgeon's skill independently predicted the subjective and objective failure of Macroplastique. CONCLUSIONS: The 3-year results of this study showed that Macroplastique could be an acceptable alternative for the treatment of SUI with stable results over time and a negligible complication rate. PMID- 30253027 TI - Sequential methyl-aminolevulinate daylight photodynamic therapy and diclofenac plus hyaluronic acid gel treatment for multiple actinic keratosis evaluation. PMID- 30253028 TI - Diatom populations in an upwelling environment decrease silica content to avoid growth limitation. AB - A mix of adaptive strategies enable diatoms to sustain rapid growth in dynamic ocean regions, making diatoms one of the most productive primary producers in the world. We illustrate one such strategy off coastal California that facilitates continued, high, cell division rates despite silicic acid stress. Using a fluorescent dye to measure single-cell diatom silica production rates, silicification (silica per unit area) and growth rates we show diatoms decrease silicification and maintain growth rate when silicon concentration limits silica production rates. While this physiological response to silicon stress was similar across taxa, in situ silicic acid concentration limited silica production rates by varying degrees for taxa within the same community. Despite this variability among taxa, silicon stress did not alter the contribution of specific taxa to total community silica production or to community composition. Maintenance of division rate at the expense of frustule thickness decreases cell density which could affect regional biogeochemical cycles. The reduction in frustule silicification also creates an ecological tradeoff: thinner frustules increase susceptibility to predation but reducing Si quotas maximizes cell abundance for a given pulse of silicic acid, thereby favouring a larger eventual population size which facilitates diatom persistence in habitats with pulsed resource supplies. PMID- 30253029 TI - Outcomes of long-term follow-up of asymptomatic renal stones and prediction of stone-related events. AB - OBJECTIVES: To evaluate the long-term outcomes of patients undergoing observation of asymptomatic renal calculi and identify factors associated with stone-related events. PATIENTS AND METHODS: Patients with asymptomatic renal calculi electing active surveillance of their stones were retrospectively reviewed. Patients underwent annual ultrasonography and clinical visits with standardised questions regarding the development of symptoms or complications from calculi. Spontaneous stone passage, stone growth, development of stone-related symptoms, and requirement for intervention during follow-up were deemed as stone-related events. RESULTS: Between 2007 and 2017, 293 patients were reviewed to evaluate the natural history of asymptomatic renal calculi. The mean follow-up was 4.2 years. Overall incidences of spontaneous passage, stone growth, development of stone-related symptoms, and requirement of intervention were 32.1%, 16.7%, 28.3% and 12.3%, respectively. Stones >5 mm and lower pole stones were significantly less likely to pass spontaneously. Patients with diabetes mellitus (DM), hyperuricaemia or non-lower calyceal stone were more likely to experience stone growth. Stones >5 mm or non-lower pole stones were more likely to become symptomatic. Significant predictors of surgical intervention were stone size (>5 mm) and patients' age (>60 years). Primary therapy was extracorporeal shockwave lithotripsy in 33 patients and flexible ureteroscopy in three. CONCLUSION: The natural history of asymptomatic renal stones rarely requires intervention, although they do have a slightly higher rate of symptomatic events and growth over the intermediate term. In particular, patients with stones >5 mm, DM, hyperuricaemia, or non-lower calyceal stones are at higher risk of developing stone-related events, and should therefore be recommended for regular follow-up. PMID- 30253030 TI - Do rim cracks and backside grinding affect the aging kinetics of alumina-matrix composite acetabular liners? AB - The acetabular liner malalignment and rim impingement have been problematic issues in ceramic-on-ceramic (CoC) total hip arthroplasty (THA). Commercial ceramic liners made of alumina-matrix composite (AMC) have polished articulation and rim, and roughly ground backside with a button-like apical projection (post) to resist tilting. In this study, we hypothesized that rim cracks and backside grind critically affect the aging kinetics of tetragonal zirconia dispersed in AMC structure. We analyzed phase transformation in the zirconia phase and residual stresses in the alumina matrix during aging by Raman and fluorescence spectroscopy. We demonstrated that the polished surfaces showed environmental stability in vitro, while the roughly-ground backside showed a significant stability loss and tensile stress accumulation as a consequence of enhancing the inter-component fixation between the liner and the metallic shell. Rim cracking locally produced a preferential transformation at the tip and the surrounding of the crack. Note that the tensile stress concentration at the crack tip was counteracted by the phase transformation after a few hours of aging. This suggests the presence of a time lag in vivo before further transformation around the crack could provide a crack shielding effect in the material. (c) 2018 Wiley Periodicals, Inc. J. Biomed. Mater. Res. Part B, 2018. PMID- 30253031 TI - Mortality after radical prostatectomy in a matched contemporary cohort in Sweden compared to the Scandinavian Prostate Cancer Group 4 (SPCG-4) study. AB - OBJECTIVE: To investigate if results in terms of absolute risk in mature randomised trials are relevant for contemporary decision-making. To do so, we compared the outcome for men in the radical prostatectomy (RP) arm of the Scandinavian Prostate Cancer Group Study number 4 (SPCG-4) randomised trial with matched men treated in a contemporary era before and after compensation for the grade migration and grade inflation that have occurred since the 1980s. PATIENTS AND METHODS: A propensity score-matched analysis of prostate cancer mortality and all-cause mortality in the SPCG-4 and matched men in the National Prostate Cancer Register (NPCR) of Sweden treated in 1998-2006 was conducted. Cumulative incidence of prostate cancer mortality and all-cause mortality was calculated. Cox proportional hazards regression analyses were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for a matching on original Gleason Grade Groups (GGG) and second, matching with GGG increased one unit for men in the NPCR. RESULTS: Matched men in the NPCR treated in 2005-2006 had half the risk of prostate cancer mortality compared to men in the SPCG-4 (HR 0.46, 95% CI 0.19 1.14). In analysis of men matched on an upgraded GGG in the NPCR, this difference was mitigated (HR 0.73, 95% CI 0.36-1.47). CONCLUSIONS: Outcomes after RP for men in the SPCG-4 cannot be directly applied to men in the current era, mainly due to grade inflation and grade migration. However, by compensating for changes in grading, similar outcomes after RP were seen in the SPCG-4 and NPCR. In order to compare historical trials with current treatments, data on temporal changes in detection, diagnostics, and treatment have to be accounted for. PMID- 30253033 TI - Use of botulinum toxin in the treatment of aquagenic keratoderma: One case report. PMID- 30253032 TI - A requirement for Fgfr2 in middle ear development. AB - The skeletal structure of the mammalian middle ear, which is composed of three endochondral ossicles suspended within a membranous air-filled capsule, plays a critical role in conducting sound. Gene mutations that alter skeletal development in the middle ear result in auditory impairment. Mutations in fibroblast growth factor receptor 2 (FGFR2), an important regulator of endochondral and intramembranous bone formation, cause a spectrum of congenital skeletal disorders featuring conductive hearing loss. Although the middle ear malformations in multiple FGFR2 gain-of-function disorders are clinically characterized, those in the FGFR2 loss-of-function disorder lacrimo-auriculo-dento-digital (LADD) syndrome are relatively undescribed. To better understand conductive hearing loss in LADD, we examined the middle ear skeleton of mice with conditional loss of Fgfr2. We find that decreased auditory function in Fgfr2 mutant mice correlates with hypoplasia of the auditory bulla and ectopic bone growth at sites of tendon/ligament attachment. We show that ectopic bone associated with the intra articular ligaments of the incudomalleal joint is derived from Scx-expressing cells and preceded by decreased expression of the joint progenitor marker Gdf5. Together, these results identify a role for Fgfr2 in development of the middle ear skeletal tissues and suggest potential causes for conductive hearing loss in LADD syndrome. PMID- 30253034 TI - A rare fatal complication of bleeding immediately following polytetrafluoroethylene arteriovenous grafting in a lady with Goodpasture syndrome. AB - We report a 28-year-old female with no history of allergies and recent onset of Goodpasture syndrome who developed life-threatening bleeding immediately after placement of a polytetrafluoroethylene (PTFE) graft as an access for hemodialysis in the left upper limb by an experienced vascular surgeon. In spite of transfusing fresh frozen plasma, packed cells and cryoprecipitate, her prothrombin time (PT), activated partial thromboplastin time and international normalized ratio became progressively worse which were normal at the beginning of the surgery. She had profound hypotension and succumbed within 8 hours. We suspect a rare phenomenon of the interaction of her blood with the PTFE graft causing activation of bleeding and coagulation factors leading to disseminated intravascular coagulation (DIC). PMID- 30253035 TI - Three-dimensional evaluation of the maxillary effects of two orthopaedic protocols for the treatment of Class III malocclusion: A prospective study. AB - OBJECTIVES: To compare the three-dimensional maxillary dentoskeletal effects of a modified alternate rapid maxillary expansion and constriction facemask protocol (Alt-RAMEC/FM) with the traditional rapid maxillary expansion facemask protocol (RME/FM) performed in deciduous or early mixed dentition Class III patients. SETTING AND SAMPLE POPULATION: Orthodontic Clinic of the Section of Dentistry of the Department of Surgery and Translational Medicine of the University of Florence. Thirty-four Class III patients were enrolled and allocated by alternating assignment to either Alt-RAMEC/FM or RME/FM therapy. MATERIALS AND METHODS: Prior to treatment, all patients were evaluated, and a cone beam computed tomography (CBCT) scan was acquired. After completion of the orthopaedic therapy (average interval 1.2 years), a follow-up CBCT scan was obtained. Anatomic landmark identification on the CBCTs and subsequent quantification of the changes were performed. The primary outcome variable was the anteroposterior displacement of the anterior nasal spine (ANS AP). The treatment groups were compared with independent samples t tests. RESULTS: The patients in the two treatment groups showed a similar degree of compliance. No statistically significant differences were recorded for any variable when comparing the Alt RAMEC/FM and RME/FM groups. In particular, the between-group difference for ANS AP was 0.0 mm (95%CI: -0.6;0.7, P = 0.933). CONCLUSIONS: Both Alt-RAMEC/FM and RME/FM produced favourable orthopaedic changes in Class III growing patients. Neither protocol was superior to the other in terms of maxillary protraction effectiveness. PMID- 30253036 TI - Healthcare transition from childhood to adulthood in Tuberous Sclerosis Complex. AB - Healthcare transition from childhood to adulthood is required to ensure continuity of care of an increasing number of individuals with chronic conditions surviving into adulthood. The transition for patients with tuberous sclerosis complex (TSC) is complicated by the multisystemic nature of this condition, age dependent manifestations, and high clinical variability and by the presence of intellectual disability in at least half of the individuals. In this article, we address the medical needs regarding each TSC-related manifestation in adulthood, and the services and support required. We review existing models of transition in different chronic conditions, discuss our experience in transitioning from the pediatric to the adult TSC Clinic at our Institution, and propose general rules to follow when establishing a transition program for TSC. Although a generalizable transition model for TSC is likely not feasible for all Institutions, a multidisciplinary TSC clinic is probably the best model, developed in accordance with the resources available and country-specific healthcare systems. Coordination of care and education of the adult team should be always sought regardless of the transition model. PMID- 30253037 TI - Association of IL-1beta, IL-1RN, and ESR1 genes polymorphism with risk of infection and response to sofosbuvir plus daclatasvir combination therapy in hepatitis C virus genotype-4 patients. AB - Sofosbuvir (SOF) and daclatasvir combination with or without ribavirin proved to be effective and safe in the treatment of hepatitis C virus infection. The study aimed to assess the efficacy of (SOF plus daclatasvir) combination + ribavirin in the treatment of treatment-experienced HCV genotype 4 Egyptian patients and to investigate the impact of IL-1beta _31, IL-1beta _511, and IL-1RN and T29C of ESR1 genes polymorphisms on treatment outcome. The study also aimed to assess the effect of the treatment on liver fibrosis. The sustained virologic response was assessed at 0, 4, 12, and 24 weeks from the beginning of treatment by RT-PCR. IL 1beta _31, IL-1beta _511, IL-1RN, and T29C genes polymorphisms were examined by PCR-based techniques in two groups of patients (responders and non-responders) and a control group of healthy subjects. A significant association between IL 1beta_511 gene polymorphism and SOF/DAV-induced response was observed, where the "CC" genotype was the most frequent in responders while the "CT" genotype was the most frequent among non-responders (P = 0.0001, OR = 39; 95% CI = 4.7-316). IL 1RN gene polymorphism also showed significant associations with response to treatment, genotypes that include allele "1" were the most frequent in responders, particularly the homozygous genotype "1/1" (P = 0.0001, OR = 2.3; 95% CI = 1.57-3.2). However, the genotypes "4/4" and "2/4" were the most frequent in non-responders; (P = 0.0001). At least 71% of the responders carry allele "1" while 54% of non-responders were allele "4" carriers (P value = 0.0001. OR = 2.8; 95% CI = 6.4-134.2). Liver fibrosis is significantly improved regardless of the response. (c) 2018 IUBMB Life, 70(11):1156-1163, 2018. PMID- 30253038 TI - Lanthanides-based catalysis in eukaryotes. AB - Rare earth elements play a pivotal role in high-technology devices, are used as contrast agents for magnetic resonance imaging in clinical settings, are explored as drug carriers for tumor photodynamic therapy, and are used as fertilizers. From the biochemical viewpoint, they act not only as antagonists of Ca2+ but have been proposed as alternative to Ca2+ in metallo-enzymes, in particular in Ce3+ based methanol dehydrogenases (MDHs). Up to now, the analysis of protein sequence databases identified Ce3+ -based MHDs only in Archea and Bacteria. Here, we report evidence that Ce3+ -based MDHs are also present in higher organisms. These enzymes, identified in the parasite Plasmodium yoelii yoelii, in the spider Nephila clavipes, in the Tibetan antelope Pantholops hodgsonii, and in Homo sapiens, are encoded by intronless genes, thus representing a case of multiple, independent lateral gene transfer from Prokaryotes to Eukaryotes. The conservation of residues involved in the Ce3+ coordination, pyrroquinoline quinone cofactor recognition and in the structure stabilization suggests that these enzymes belong to the Ce3+ -dependent MDH family, hitherto considered as exclusive of Prokaryotes. (c) 2018 IUBMB Life, 70(11):1067-1075, 2018. PMID- 30253039 TI - Bone regeneration in rabbit calvarial critical-sized defects filled with composite in situ formed xenogenic dentin and biphasic tricalcium phosphate/hyroxyapatite mixture. AB - The purpose of this study was to evaluate bone healing in calvarial defects using two bone graft substitute materials; biphasic beta-tricalcium phosphate/hydroxyapatite in hydrogel (beta-TCP/HA) versus composite non demineralized xenogenic dentin with beta-TCP/HA mixture. Full thickness critical sized defects were created bilaterally in 10 New Zealand male rabbits. Seven defects were left empty, six filled with biphasic tricalcium phosphate putty, and seven were filled with composite non-demineralized xenogenic dentin with biphasic tricalcium phosphate. Animals were sacrificed at eight weeks postoperatively and the healing of the biomaterial-filled defects was compared radiographically and by histomorphometry. Micro-computed tomography (MUCT) was utilized to analyze the osteogenesis and healing patterns of the defects. Quantitative analysis of volume fraction (%) of the newly formed bone and remaining graft material (FV=filling volume/TV=tissue volume) and mean intensity [HU] in the defects were evaluated. Defects filled with composite dentin with biphasic tri-calcium phosphate showed volume fraction (FV/TV) in the order of 55.81% +/- 17.72%, whereas defects filled with only biphasic tricalcium phosphate showed a fraction of 39.84% +/- 16.06%, which represent the ratio of remaining graft material and new bone formation to the tissue volume. The empty negative control defects showed a volume fraction of 19.14% +/- 8.787%. Histological analysis showed significant percentage increase in bone formation and residual graft with the composite Dentin/beta-TCP group after 8 weeks. The findings suggest that composite xenogenic dentin with biphasic tricalcium phosphate showed improved osteogenesis when compared to biphasic tricalcium phosphate without the addition of non-demineralized dentin. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 00B: 000-000, 2018. PMID- 30253040 TI - Symptomatic overlap in overactive bladder and interstitial cystitis/bladder pain syndrome: development of a new algorithm. AB - OBJECTIVES: To address challenges in the diagnosis and classification of storage lower urinary tract symptoms (LUTS), we sought to define the fundamental features of overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS), two conditions with considerable symptomatic overlap. Through retrospective comparison of self-reported symptoms in women with a range of clinical presentations and symptom severities, we have attempted to refine the diagnostic features of OAB and IC/BPS and to develop a novel clinical nomogram to improve patient screening and classification. MATERIALS AND METHODS: We performed a univariate analysis comparing responses to the female Genitourinary Pain Index (fGUPI), the OAB Questionnaire and O'Leary-Sant Indices (the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index) in an initial cohort of 50 patients with OAB, patients with IC/BPS and control subjects. Only eight questions differed significantly between the IC/BPS and OAB groups; we used five unique questions and three measuring bother to generate a novel composite scoring system and nomogram that included urgency incontinence, bladder pain and symptomatic bother domains to differentiate these populations, which was validated in a second cohort of 150 patients. The addition of a self-reported bother index resulted in the creation of a diagnostic algorithm to identify and classify LUTS clusters across the total population. RESULTS: While all validated questionnaires could distinguish between controls and patients with storage LUTS, no combined symptom scores differed significantly between the IC/BPS and OAB groups. These results are reflective of the prevalence of significant bladder pain (35%) in patients with OAB and the presence of urge incontinence (25%) in patients with IC/BPS. Only the fGUPI pain domain scores differed between patients in the OAB and IC/BPS groups, but it was not accurate enough for diagnostic evaluation (68% accuracy). Our composite scores and nomogram gave a much-improved diagnostic accuracy (94%) and demonstrated utility as a screening tool to identify storage LUTS in patients presenting for unrelated complaints, e.g. microhaematuria. CONCLUSIONS: There is significant overlap of urinary tract symptoms between OAB and IC/BPS. We present a novel algorithm that provides a binary output capable of guiding clinical diagnosis. Future studies aimed at assessing the diagnostic value of novel classification schemes that address symptoms rather than specific diagnoses may improve patient prognosis. PMID- 30253041 TI - Zirconia dental implants: A clinical and radiographic evaluation. AB - OBJECTIVE: Limited clinical evidence has been reported in dental literature regarding zirconia dental implants. The aim of the present retrospective consecutive case series was to evaluate the clinical outcome of zirconia dental implants with 1 to 5 years of follow-up. CLINICAL CONSIDERATIONS: The clinical outcome of 24 implants in 12 consecutive patients (male 5, female 7) with a mean age of 55 years (range 27-86) is reported. Radiographic crestal bone level was assessed by the use of "ImageJ" software program. Gingival and plaque indices were recorded at baseline and latest follow-up. CONCLUSION: The overall success rate of zirconia implants was 92%. Within the limitations of the present clinical evaluation, zirconia implants provided excellent clinical results and esthetic outcomes. A mean periimplant bone loss of 0.3 mm was measured in 33.3% of the implants and 66.7% were not affected by radiographic detectable periimplant bone loss. Two implants in two patients failed. Low gingival and plaque indices were predominant values for both interim and final restorations. The apparent less affinity to plaque accumulation may favor soft tissue health around zirconia dental implants and decrease the risk of inflammation or infection. Zirconia dental implant merits further investigation. CLINICAL SIGNIFICANCE: Zirconia dental implants are emerging as an option in clinical practice of implant dentistry providing stable clinical results and esthetic outcomes. PMID- 30253042 TI - Patient pad count is a poor measure of urinary incontinence compared with 48-h pad test: results of a large-scale multicentre study. AB - OBJECTIVE: To determine in a large population of community-dwelling incontinent patients the accuracy and determinants of pad count as a measure of urinary incontinence (UI), using data from a multicentre 48-h pad test study. MATERIALS AND METHODS: Incontinent patients, who were provided with absorbent products for the period January 2012 to March 2016, volunteered to perform a 48-h home-based pad test and to fill in a diary with information on pad usage. Correlations between UI measures (48-h pad count and pad weight gain, mean pad weight gain per pad) were calculated. Logistic regression analyses were conducted to investigate patient-related and pad usage-related factors influencing pad count. RESULTS: A total of 14 493 patients (median age 81 years) were included, with a total of 98 362 continence products used overall during the study period. The 48-h pad count showed a weak correlation with 48-h pad weight gain (R2 = 0.12; 0.19 for men and 0.11 for women) and mean pad weight gain per pad (R2 = -0.03). The weakest correlation was observed among patients using >6 pads/48 h (R2 = 0.02). A statistically significant negative association between pad absorption capacity and pad count was observed. Patients using products with a shaped and rectangular design had 34% and 40% higher propensity to use more pads than those using briefs (P < 0.001), respectively. CONCLUSIONS: The results of this very large observational study confirmed that pad count is a poor measure of UI severity. Pad count only measured 12% of the variability of UI volume and was affected by several patient-related and pad usage-related factors. Consequently, pad count should not be used instead of the pad test as an objective measure of UI when an accurate evaluation is required for research or clinical purposes. PMID- 30253043 TI - Relationship Between Three Commonly Used Non-invasive Fibrosis Biomarkers and Improvement in Fibrosis Stage in Patients With NASH. AB - BACKGROUND & AIMS: Non-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement. METHODS: In the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index, and non alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72, and 96. Liver biopsies were obtained at baseline and 72 weeks. RESULTS: In patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4, and 4% for NFS. Reductions in APRI (p=0.015) and FIB-4 (p=0.036), but not NFS (p=0.201) at week 24, significantly correlated with >=1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (p=0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (p<0.0001); NFS (p<0.05)]. CONCLUSIONS: Readily available non invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate end points in NASH clinical trials. This article is protected by copyright. All rights reserved. PMID- 30253044 TI - Structural heteropolysaccharides as air-tight sealants of the human pleura. AB - Pulmonary "air leaks," typically the result of pleural injury caused by lung surgery or chest trauma, result in the accumulation of air in the pleural space (pneumothorax). Air leaks are a major source of morbidity and prolonged hospitalization after pulmonary surgery. Previous work has demonstrated structural heteropolysaccharide (pectin) binding to the mouse pleural glycocalyx. The similar lectin-binding characteristics and ultrastructural features of the human and mouse pleural glycocalyx suggested the potential application of these polymers in humans. To investigate the utility of pectin-based polymers, we developed a simulacrum using freshly obtained human pleura. Pressure-decay leak testing was performed with an inflation maneuver that involved a 3 s ramp to a 3 s plateau pressure; the inflation was completely abrogated after needle perforation of the pleura. Using nonbiologic materials, pressure-decay leak testing demonstrated an exponential decay with a plateau phase in materials with a Young's modulus less than 5. In human pleural testing, the simulacrum was used to test the sealant function of four mixtures of pectin-based polymers. A 50% high-methoxyl pectin and 50% carboxymethylcellulose mixture demonstrated no sealant failures at transpleural pressures of 60 cmH2 O. In contrast, pectin mixtures containing 50% low-methoxyl pectin, 50% amidated low-methoxyl pectins, or 100% carboxymethylcellulose demonstrated frequent sealant failures at transpleural pressures of 40-50 cmH2 O (p < 0.001). Inhibition of sealant adhesion with enzyme treatment, dessication and 4 degrees C cooling suggested an adhesion mechanism dependent upon polysaccharide interpenetration. We conclude that pectin-based heteropolysaccharides are a promising air-tight sealant of human pleural injuries. (c) 2018 Wiley Periodicals, Inc. J. Biomed. Mater. Res. Part B, 2018. PMID- 30253045 TI - Oxytocin in metabolic homeostasis: implications for obesity and diabetes management. AB - Oxytocin was once understood solely as a neuropeptide with a central role in social bonding, reproduction, parturition, lactation and appetite regulation. Recent evidence indicates that oxytocin enhances glucose uptake and lipid utilization in adipose tissue and skeletal muscle, suggesting that dysfunction of the oxytocin system could underlie the pathogenesis of insulin resistance and dyslipidaemia. Murine studies revealed that deficiencies in oxytocin signalling and oxytocin receptor expression lead to obesity despite normal food intake, motor activity and increased leptin levels. In addition, plasma oxytocin concentration is notably lower in obese individuals with diabetes, which may suggest an involvement of the oxytocin system in the pathogenesis of cardiometabolic disease. More recently, small scale studies demonstrated that intranasal administration of oxytocin was associated with significant weight loss as well as improvements in insulin sensitivity and pancreatic beta-cell responsivity in human subjects. The multi-pronged effects of oxytocin signalling on improving peripheral insulin sensitivity, pancreatic function and lipid homeostasis strongly suggest a role for this system as a therapeutic target in obesity and diabetes management. The complexity of obesity aetiology and the pathogenesis of obesity-related metabolic complications underscore the need for a systems approach to better understand the role of oxytocin in metabolic function. PMID- 30253046 TI - Detection of Autoreactive Type II NKT Cells: A Pilot Study of Comparison Between Healthy Individuals and Patients with Vasculitis. AB - NKT cells are defined as T cells that recognize hydrophobic antigens presented by class I MHC-like molecules, including CD1d. Among CD1d-restricted NKT cells, type I and type II subsets have been noted. CD1d-restricted type I NKT cells are regarded as pro-inflammatory cells in general. On the contrary, accumulated evidence has demonstrated an anti-inflammatory property of CD1d-restricted type II NKT cells. In our earlier study using a rat model with vasculitis, we demonstrated the pro-inflammatory function of CD1d-restricted type II NKT cells and identified that one such cell recognized P518-532 of rat sterol carrier protein 2 (rSCP2518-532 ), which appeared on vascular endothelial cells presented by CD1d. Based on this evidence, we attempted to detect human CD1d-restricted type II NKT cells in peripheral blood using hSCP2518-532 , the human counterpart of rSCP2518-532, together with a CD1d tetramer in flow cytometry. First, we determined the binding of hSCP2518-532 to CD1d. Next, we detected CD3-positive hSCP2518-532 -loaded CD1d (hSCP2518-532 /CD1d) tetramer-binding cells in peripheral blood of healthy donors. The abundance of TGF-beta-producing cells rather than TNF-alpha-producing cells in CD3-positive hSCP2518-532 /CD1d tetramer binding cells suggests the anti-inflammatory property of SCP2-loaded CD1d (SCP2/CD1d) tetramer-binding type II NKT cells in healthy individuals. Furthermore, we compared cytokine profile between healthy individuals and patients with vasculitis in a pilot study. Interestingly, the percentage of TGF beta-producing cells in SCP2/CD1d tetramer-binding type II NKT cells in vasculitic patients was significantly lower than that in healthy controls despite the greater number of these cells. Although further studies to clarify the mechanism and significance of this phenomenon are needed, SCP2/CD1d tetramer binding type II NKT cells in peripheral blood should be examined in more detail to understand the pathophysiology of vasculitides in humans. (c) 2018 International Society for Advancement of Cytometry. PMID- 30253047 TI - Plasma-Activated Substrate with a Tropoelastin Anchor for the Maintenance and Delivery of Multipotent Adult Progenitor Cells. AB - Conventional wound therapy utilizes wound coverage to prevent infection, trauma, and fluid and thermal loss. However, this approach is often inadequate for large and/or chronic wounds, which require active intervention via therapeutic cells to promote healing. To address this need, a patch which delivers multipotent adult progenitor cells (MAPCs) is developed. Medical-grade polyurethane (PU) films are modified using plasma immersion ion implantation (PIII), which creates a radical rich layer capable of rapidly and covalently attaching biomolecules. It is demonstrated that a short treatment duration of 400 s maximizes surface activation and wettability, minimizes reduction in gas permeability, and preserves the hydrolytic resistance of the PU film. The reactivity of PIII treated PU is utilized to immobilize the extracellular matrix protein tropoelastin in a functional conformation that stably withstands medical-grade ethylene oxide sterilization. The PIII-treated tropoelastin-functionalized patch significantly promotes MAPC adhesion and proliferation over standard PU, while fully maintaining cell phenotype. Topical application of the MAPC-seeded patch transfers cells to a human skin model, while undelivered MAPCs repopulate the patch surface for subsequent cell transfer. The potential of this new wound patch as a reservoir for the sustained delivery of therapeutic MAPCs and cell-secreted factors for large and/or non-healing wounds is indicated in the findings. PMID- 30253048 TI - Distress in patients with renal cell carcinoma: a curious gap in knowledge. PMID- 30253050 TI - Weight loss associated with sodium-glucose cotransporter-2 inhibition: a review of evidence and underlying mechanisms. AB - With their novel, insulin-independent mechanism, sodium-glucose cotransporter-2 (SGLT2) inhibitors are a major turning point in the management of type 2 diabetes mellitus. At present, there are several SGLT2 inhibitors available or in development, and these oral anti-hyperglycaemic agents lower plasma glucose through the inhibition of SGLT2-mediated reuptake of filtered glucose in the kidney. This unique mechanism of action is also expected to result in other beneficial effects, such as weight loss and blood pressure reduction. In various studies, including randomized controlled trials and real-world studies, patients treated with SGLT2 inhibitors have reported weight loss of around 1 to 3 kg. This review describes the characteristics of weight loss associated with SGLT2 inhibitor therapy, the clinical factors affecting SGLT2 inhibitor-associated weight loss and the possible underlying mechanisms of SGLT2 inhibitor-associated weight loss, including changes in metabolism and body composition, and the role of a reduction in insulin dose and compensatory hyperphagia. Understanding the weight loss effect of SGLT2 inhibitors, its related factors and underlying mechanisms can aid clinicians in optimal treatment decision-making, provide valuable insight on both obesity and diabetes management and reveal areas of future research and new therapeutic options. PMID- 30253049 TI - Efficacy, safety, and cost-effectiveness of all-trans retinoic acid/Clobetasol Propionate Compound Ointment in the treatment of mild to moderate psoriasis vulgaris: A randomized, single-blind, multicenter clinical trial. AB - To assess the efficacy, safety, and cost-effectiveness of all-trans retinoic acid/Clobetasol Propionate Compound Ointment and calcipotriol/betamethasone dipropionate ointment in the treatment of mild-to-moderate patients with psoriasis vulgaris. This was a randomized, single-blind, multicenter clinical trial. A total of 240 patients were randomized to receive twice-daily all-trans retinoic acid/Clobetasol Propionate Compound Ointment (treatment group) or once daily calcipotriol/betamethasone dipropionate ointment (control group) for 4 weeks. The efficacy, safety, and cost-effectiveness were assessed at Weeks 2 and 4. After 4 weeks, both groups showed a significant clinical improvement compared to baseline (88.33% vs. 89.83%, respectively, p = .7112). But PASI 75 response in the treatment group was superior to the control group (44.12% vs. 28.57%, respectively, p = .0200), at Week 4. SSRI improvement rate in the treatment group was also superior to control group (67.11% vs. 59.43%, respectively, p = .0119) at Week 4. All-trans retinoic acid/Clobetasol Propionate Compound Ointment showed a significant clinical improvement in erythema, infiltration, and scales of skin lesions and PASI score compared to baseline. 1.67% of patients (treatment group) reported adverse reactions compared to 2.50% (control group) with no statistical significance. In addition, the cost-effectiveness assessment showed a higher cost effectiveness of the treatment group compared to the control group in 4 weeks (199.25 vs. 801.51). All-trans retinoic acid/Clobetasol Propionate Compound Ointment was effective and safe in the treatment of psoriasis vulgaris with similar efficacy as calcipotriol/betamethasone dipropionate ointment and lower treatment costs. PMID- 30253051 TI - Better graft outcomes from offspring donor kidneys among living donor kidney transplant recipients in the United States. AB - A recent study reported that kidney transplant recipients of offspring living donors had higher graft loss and mortality. This seemed counterintuitive, given the excellent HLA matching and younger age of offspring donors; we were concerned about residual confounding and other study design issues. We used Scientific Registry of Transplant Recipients data 2001-2016 to evaluate death-censored graft failure (DCGF) and mortality for recipients of offspring versus nonoffspring living donor kidneys, using Cox regression models with interaction terms. Recipients of offspring kidneys had lower DCGF than recipients of nonoffspring kidneys (15-year cumulative incidence 21.2% vs 26.1%, P < .001). This association remained after adjustment for recipient and transplant factors (adjusted hazard ratio [aHR] = 0.73 0.770.82 , P < .001), and was attenuated among African American donors (aHR 0.77 0.850.95 ; interaction: P = .01) and female recipients (aHR 0.77 0.840.91 , P < .001). Although offspring kidney recipients had higher mortality (15-year mortality 56.4% vs 37.2%, P < .001), this largely disappeared with adjustment for recipient age alone (aHR = 1.02 1.061.10 , P = .002) and was nonsignificant after further adjustment for other recipient characteristics (aHR = 0.93 0.971.01 , P = .1). Kidneys from offspring donors provided lower graft failure and comparable mortality. An otherwise eligible donor should not be dismissed because they are the offspring of the recipient, and we encourage continued individualized counseling for potential donors. PMID- 30253052 TI - Organ donor management and delayed graft function in kidney transplant recipients: A multicenter retrospective cohort study. AB - Meeting donor management goals (DMGs) has been reported to decrease the incidence of delayed graft function (DGF) after kidney transplant, but whether this relationship is independent of cold machine perfusion is unclear. We aimed to determine whether meeting DMGs is associated with a reduced incidence of DGF, independent of the use of machine perfusion. We collected data on consecutive brain-dead donors and their KT recipients (KTRs) between June 2013 and December 2016 in 5 adult transplant centers. We evaluated whether DMGs were met at donor neurologic death (DND) and later time points. We defined a priori meeting optimal DMG as achieving >=7 DMGs. Generalized estimating equations were used to predict DGF. Among 122 donors, 34% were extended-criteria donors (ECDs). The number of DMGs met increased over time (5.6 +/- 1.4 at DND and 6.1 +/- 1.3 at organ procurement [P < .001]). DGF occurred in 23% of 214 KTRs, and 55% received organs placed on machine perfusion. In multivariate analysis, ECD (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.13-4.45), use of machine perfusion (OR 0.45, 95% CI 0.22-0.94), and optimal DMG at DND (OR 0.39, 95% CI 0.16-0.99) were associated with DGF. Early achievement of DMGs was associated with a reduced risk of the development of DGF, independent of the use of machine perfusion. PMID- 30253055 TI - On the role of religion in articles this journal seeks to publish. PMID- 30253054 TI - African Perspectives in Global Bioethics. PMID- 30253057 TI - Multiple listing in lung transplant candidates: A cohort study. AB - Lung transplant candidates can be waitlisted at more than one transplant center, a practice known as multiple listing. The factors associated with multiple listing and whether multiple listing modifies waitlist mortality or likelihood of lung transplant is unknown. US lung transplant waitlist candidates were identified as either single or multiple listed using data from the Scientific Registry of Transplant Recipients. Characteristics of single and multiple listed candidates were compared and multivariable logistic regression was used to estimate associations with multiple listing. Multiple listed candidates were matched to single listed candidates using a combination of exact and propensity score matching methods. Cox proportional hazard models were used to estimate the relationship of multiple listing on waitlist mortality and receiving a transplant. Multiple listing occurred in 2.3% of lung transplant waitlist candidates. Younger age, female gender, white race, short stature, high antibody sensitization, college or postcollege education, lower lung allocation score, and a cystic fibrosis diagnosis were independently associated with multiple listing. Multiple listing was associated with an increased likelihood of lung transplant (adjusted hazard ratio [aHR] 2.74, 95% CI 2.37 to 3.16) but was not associated with waitlist mortality (aHR 0.99, 95% CI 0.68 to 1.44). PMID- 30253056 TI - Cardiovascular risk factors in non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Patients with non-alcoholic fatty liver disease (NAFLD) are at an increased risk for cardiovascular disease (CVD). It is unclear whether histological variables may help predict CVD risk. We evaluated histology and traditional CV risk factors as predictors of CVD outcomes in a large NAFLD cohort. METHODS: We included 603 biopsy-proven NAFLD patients free of baseline CVD and matched these (1:10, by age, sex and municipality) to 6269 population controls. All individuals were cross-linked to national registries to ascertain incident CVD events, defined as acute ischaemic heart disease or stroke. The presence of CV risk factors and liver histology were available in NAFLD patients only. Cox regression models were used to estimate hazard ratios (HR) for incident CVD. RESULTS: During a mean follow-up of 18.6 years, 168 (28%) of NAFLD patients and 1325 (21%) of controls experienced a CVD event (HR 1.54, 95%CI 1.30-1.83). Within the NAFLD cohort, age, male sex, type 2 diabetes, smoking and triglycerides were associated with risk of CVD. Taking these CV risk factors into account, no histological parameter, including presence of NASH and fibrosis stage, were associated with incident CVD. CONCLUSIONS: Patients with NAFLD are at an increased risk for CVD compared to matched controls, but histological parameters do not seem to independently predict this risk. PMID- 30253058 TI - Prognostic significance of AKR1B10 in patients with resected lung adenocarcinoma. AB - BACKGROUND: Aldo-keto reductases (AKRs) modify carbonyl groups on aldehyde or ketones to form primary or secondary alcohols, which are then conjugated with sulfates or glucuronide for excretion. The AKR1B10 gene encodes a member of the AKR superfamily. Overexpression of AKR1B10 plays an important role in the tumorigenesis of lung cancer cells; however, the prognostic value of AKR1B10 expression in patients with lung adenocarcinoma has not been well demonstrated. METHODS: A total of 96 patients with resected lung adenocarcinoma were included in the study. AKR1B10 expression was determined by immunohistochemistry in tumor specimens. The prognostic value of AKR1B10 overexpression and its relationship with clinicopathological variables were investigated. RESULTS: AKR1B10 overexpression was identified in 22 (22.9%) of the 96 patients and tended to be significantly associated with N1 or N2 status (P = 0.055). AKR1B10 overexpression was not a significant prognostic factor for overall survival (P = 0.301) but was a significant prognostic factor for poor recurrence-free survival (P = 0.015). T status (T3 or T4 vs. T1 or T2; P = 0.020), N1 or N2 (vs. N0; P = 0.019), predominant pattern group (lepidic/acinar/papillary vs. micropapillary/solid; P = 0.023), and AKR1B10 overexpression (P = 0.013) were significant prognostic factors for poor recurrence-free survival in multivariate analysis. CONCLUSIONS: AKR1B10 overexpression was a significant prognostic factor for poor recurrence free survival in patients with resected lung adenocarcinoma. This information is useful to stratify patients at high-risk of recurrence after lung adenocarcinoma resection. PMID- 30253059 TI - Quantification of Muscle Contraction In Vitro and In Vivo Using MUSCLEMOTION Software: From Stem Cell-Derived Cardiomyocytes to Zebrafish and Human Hearts. AB - Quantification of contraction is essential to the study of cardiac diseases, injury, and responses to drugs. While there are many techniques to assess contractility, most rely on costly, dedicated hardware and advanced informatics, and can only be used in specific experimental models. We have developed an automated open-source software tool (MUSCLEMOTION) for use with standard imaging equipment, to assess contractility in vitro and in vivo and quantify responses to drugs and diseases. We describe high-speed and disturbance-free acquisition of images from either electrically paced or non-paced human pluripotent stem cell derived cardiomyocytes, isolated adult cardiomyocytes, zebrafish hearts, and human echocardiograms. Recordings are then used as input for automated batch analysis by the MUSCLEMOTION software tool configured with specific settings and parameters tailored to the recording technique. Details on accuracy, interpretation, and troubleshooting are discussed. Acquisition duration depends on the experimental setup and aim, but quantification of drug or disease responses in an in vitro muscle model can typically be completed within a few hours. (c) 2018 by John Wiley & Sons, Inc. PMID- 30253061 TI - Phytochemical Composition, Antioxidant Potential and Cholinesterase Inhibition Potential of Extracts from Mentha pulegium L. AB - The aim of this work was to perform the phytochemical analysis as well as antioxidant and anticholinesterase potential of hot water and methanolic extracts from Mentha pulegium L., Lamiaceae, wild growing in Bosnia and Herzegovina. It is a plant that is traditionally used in Bosnia and Herzegovina medicine to treat gastrointestinal and neurological disorders. By HPLC-DAD analysis of tested extracts, 15 phenol compounds were identified and quantified. Rosmarinic acid was the most abundant compound in both extracts, followed by ellagic acid, eriodictyol, naringenin and chlorogenic acid. Both extracts were demonstrated good radical scavenging potential, reducing power and ability to inhibit lipid oxidation. The tested extracts also showed low ability to inhibit protein oxidation and low or no acetylcholinesterase and butyrylcholinesterase inhibition potential. The promising radical scavenging potential, reducing power and lipid protection potential of tested extracts indicates that the extracts of M. pulegium could be useful in preventing free radical linked diseases, as well as food protecting antioxidants. PMID- 30253060 TI - Fiber-Based Mini Tissue with Morphology-Controllable GelMA Microfibers. AB - The use of microscale fibers could facilitate nutrient diffusion in fiber-based tissue engineering and improve cell survival. However, in order to build a functional mini tissue such as muscle fibers, nerve conduits, and blood vessels, hydrogel microfibers should not only mimic the structural features of native tissues but also offer a cell-favorable environment and sufficient strength for tissue functionalization. Therefore, an important goal is to fabricate morphology controllable microfibers with appropriate hydrogel materials to mimic the structural and functional complexity of native tissues. Here, gelatin methacrylate (GelMA) is used as the fiber material due to its excellent biological performance, and a novel coaxial bioprinting method is developed to fabricate morphology-controllable GelMA microfibers encapsulated in calcium alginate. By adjusting the flow rates, GelMA microfibers with straight, wavy, and helical morphologies could be obtained. By varying the coaxial nozzle design, more complex GelMA microfibers such as Janus, multilayered, and double helix structures could be fabricated. Using these microfibers, mini tissues containing human umbilical cord vein endothelial cells are built, in which cells gradually migrate and connect to form lumen resembling blood vessels. The merits of cytocompatibility, structural diversity, and mechanical tunability of the versatile microfibers may open more avenues for further biomedical research. PMID- 30253062 TI - High-Performance Flexible Perovskite Solar Cells with Effective Interfacial Optimization Processed at Low Temperatures. AB - Exploration of low-temperature solution-processing methodologies for fabricating planar perovskite solar cells (PSCs) is important for industrial mass production and helps simplify the manufacture and design of flexible perovskite solar cells. However, the interface between electron-transport layers (ETLs) and perovskite layers is crucial for the development of highly efficient flexible PSCs. We report a drastically improved solar cell efficiency through surface optimization of TiO2 ETLs by using a simple and inexpensive ionic compound that shows high optical transparency and superior electron mobility. Solution-derived TiO2 nanocrystalline films are employed at low temperatures as ETLs through solution processing. The modification of TiO2 with NH4 Cl can increase the interactions between the surface and organic-inorganic hybrid perovskites; Cl anions lead to a stronger interfacial coupling between TiO2 and perovskite. Ammonium cations tend to combine with perovskite. Due to this strong combined effect of the ionic compound, the efficiency of PSC from low-temperature solution processing reaches 18.71 % on rigid glass/indium tin oxide (ITO) for an improvement of 12.6 % over a control device using bare TiO2 . Furthermore, the power conversion efficiency (PCE) can reach an efficiency of 17.69 % for the ITO/PEN substrates. This work contributes to the evolution of flexible PSCs with simple fabrication and high device performance. PMID- 30253063 TI - Does the age at adiposity rebound reflect a critical period? PMID- 30253064 TI - Neuroinflammation Quantification for Spinal Cord Injury. AB - Spinal cord injury (SCI) leads to irreversible devastating neurological disabilities. Accumulated evidence in the literature indicates that the inflammatory response that occurs in the spinal cord following injury contributes importantly to spread tissue damage to healthy regions adjacent to the lesion site, and consequently, to increase neurological deficits. Therefore, targeting inflammation could lead to the development of new therapies to prevent tissue damage and neurological impairments after SCI. Inflammation is regulated, in part, by the expression of pro-inflammatory and anti-inflammatory cytokines synthesized, mainly, by glial cells. Hence, methodologies that could ease the quantification of multiple cytokines and immune cells from spinal cord tissue samples are needed to assess the potential of new anti-inflammatory therapies. In the present unit, we describe how to induce contusion injuries in the mouse spinal cord, as well as, two useful methodologies to assess neuroinflammation in lesioned spinal cord tissue samples. (c) 2018 by John Wiley & Sons, Inc. PMID- 30253065 TI - Self-Assembly and C-H???Anion Hydrogen Bonding of Palladium(II)-based Metallacalixarenes Using Pyridyl- or Phenyl-Bridged Di-Naphthoimidazoles. AB - Metal-directed self-assembly approaches led to the formation of two novel boat shaped palladium(II)-based metallacalixarenes 1 (1 a, 1 b and 1 c) and 2 (2 a, 2 b and 2 c), by using the two new ligands 2,6-bis(1H-naphtho[2,3]imidazol-1 yl)pyridine (L1 ) and 1,3-bis(1H-naphtho[2,3]imidazol-1-yl)benzene (L2 ) with cis coordinated PdII precursor (tmeda)Pd(ONO2 )2 (tmeda=N, N, N', N'-tetra methylethylenediamine), repectively. All complexes with different counterions were systematically characterized in solution, and their structures were determined by X-ray single crystallography analyses in the solid state. The crystal architectures were subtly regulated among different anions through two types (inter- and intra-)molecular C-H hydrogen bonding interactions and other weak interactions. The anion complexation with the two metal-assembled anion receptors were further investigated in solution. PMID- 30253066 TI - Genomic divergence in cotton germplasm related to maturity and heterosis. AB - Commercial varieties of upland cotton (Gossypium hirsutum) have undergone extensive breeding for agronomic traits, such as fiber quality, disease resistance, and yield. Cotton breeding programs have widely used Chinese upland cotton source germplasm (CUCSG) with excellent agronomic traits. A better understanding of the genetic diversity and genomic characteristics of these accessions could accelerate the identification of desirable alleles. Here, we analyzed 10,522 high-quality single-nucleotide polymorphisms (SNP) with the CottonSNP63K microarray in 137 cotton accessions (including 12 hybrids of upland cotton). These data were used to investigate the genetic diversity, population structure, and genomic characteristics of each population and the contribution of these loci to heterosis. Three subgroups were identified, in agreement with their known pedigrees, geographical distributions, and times since introduction. For each group, we identified lineage-specific genomic divergence regions, which potentially harbor key alleles that determine the characteristics of each group, such as early maturity-related loci. Investigation of the distribution of heterozygous loci, among 12 commercial cotton hybrids, revealed a potential role for these regions in heterosis. Our study provides insight into the population structure of upland cotton germplasm. Furthermore, the overlap between lineage specific regions and heterozygous loci, in the high-yield hybrids, suggests a role for these regions in cotton heterosis. PMID- 30253067 TI - Mouse Model for Human Vitiligo. AB - Vitiligo is an autoimmune skin disease in which the pigment-producing melanocytes are destroyed by autoreactive CD8+ T cells. As a result, patients develop disfiguring white spots on the skin. This article discusses the first mouse model of vitiligo that develops epidermal depigmentation, similar to disease in human patients. To achieve epidermal depigmentation, mice are genetically engineered to retain melanocytes in the skin epidermis. Induction of disease occurs by adoptive transfer of melanocyte-specific CD8+ T cells into recipient mice and the subsequent activation of these T cells using a viral vector. Depigmentation of the epidermis occurs within 5 to 7 weeks in a patchy pattern similar to patients with vitiligo. This article describes the methods of vitiligo induction, quantification of lesion progression and regression, processing of the skin for detailed analysis, and how to use this model to inform clinical studies. (c) 2018 by John Wiley & Sons, Inc. PMID- 30253068 TI - In vitro Assays for Targeting and Insertion of Tail-Anchored Proteins Into the ER Membrane. AB - Membrane proteins mediate numerous essential cellular functions. Due to the aggregation propensity of hydrophobic transmembrane domains in aqueous environments, the targeting and insertion of membrane proteins pose major challenges to cells. In the Guided Entry of Tail-anchored protein (GET) pathway, an essential class of newly synthesized tail-anchored proteins (TAs) are chaperoned and guided by multiple targeting factors to the endoplasmic reticulum (ER) membrane. Deciphering the molecular mechanism of this cellular process has benefitted from successful in vitro reconstitution of individual molecular events in the GET pathway with purified components. Here we describe recently developed protocols for in vitro reconstitution of functional complexes of TA substrates with their targeting factors, for monitoring the transfer of TAs between targeting factors, and for the insertion of TA into the microsomal membrane. These procedures are generally applicable to the interrogation of other post translational membrane protein targeting pathways. (c) 2018 by John Wiley & Sons, Inc. PMID- 30253069 TI - Ionized magnesium and calcium concentration and their ratio in equine plasma samples as determined by a regulatory laboratory compared to a clinical reference laboratory. AB - Magnesium sulfate (MgSO4 ) was administered to calm competition horses. We evaluated the impact of regulatory requirements for the handling of blood samples on plasma ionized magnesium (iMg), ionized calcium (iCa), the iMg to iCa ratio, and pH. We hypothesized that iCa, iMg. and iMg/iCa would be similar among storage and collection methods. Four blood samples were collected from each of 50 horses on the same day: Group 1 - collection in a heparinized syringe and processed within hours in a clinical laboratory; Group 2 - collection into a plasma separator tube (PST) centrifuged just prior to analysis, and plasma processed as in (1); Group 3 - collection into a PST, refrigerated, shipped via overnight carrier to the United States Equestrian Federation (USEF) Equine Drug Testing and Research laboratory, centrifuged just prior to analysis, and plasma processed; and Group 4 - as in Group 3, but stored frozen at -80 degrees C for 90 days, thawed, and plasma processed as in Group 3. Results for iMg/iCa are unit-less, adjusted iMg for potential influence of plasma protein and iCa, and highly correlated with iMg pH (r = -.933; P < 0.01). Samples processed immediately in a clinical reference laboratory had the greatest iMg/iCa. Both iMg/iCa and pH predictably decreased after freezing (P < 0.001). These data suggest that the iMg/iCa mirrors alterations in iMg regardless of storage and collection methods. This understanding can facilitate the development of a regulatory threshold for the control of the nefarious use of magnesium sulfate in competing horses, and an understanding of potential changes to iMg/iCa with storage of B samples. PMID- 30253070 TI - Evidences of the Effect of GO and rGO in PCL Membranes on the Differentiation and Maturation of Human Neural Progenitor Cells. AB - The effect of doping graphene oxide (GO) and reduced graphene oxide (rGO) into poly(epsilon-caprolactone) (PCL) membranes prepared by solvent induced phase separation is evaluated in terms of nanomaterial distribution and compatibility with neural stem cell growth and functional differentiation. Raman spectra analyses demonstrate the homogeneous distribution of GO on the membrane surface while rGO concentration increases gradually toward the center of the membrane thickness. This behavior is associated with electrostatic repulsion that PCL exerted toward the polar GO and its affinity for the non-polar rGO. In vitro cell studies using human induced pluripotent cell derived neural progenitor cells (NPCs) show that rGO increases marker expression of NPCs differentiation with respect to GO (significantly to tissue culture plate (TCP)). Moreover, the distinctive nanomaterials distribution defines the cell-to-nanomaterial interaction on the PCL membranes: GO nanomaterials on the membrane surface favor higher number of active matured neurons, while PCL/rGO membranes present cells with significantly higher magnitude of neural activity compared to TCP and PCL/GO despite there being no direct contact of rGO with the cells on the membrane surface. Overall, this work evidences the important role of rGO electrical properties on the stimulation of neural cell electro-activity on PCL membrane scaffolds. PMID- 30253071 TI - Expression of clinically relevant drug-metabolizing enzymes along the human intestine and their correlation to drug transporters and nuclear receptors: An intra-subject analysis. AB - The oral bioavailability of many drugs is highly influenced not only by hepatic but also by intestinal biotransformation. To estimate the impact of intestinal phase I and II metabolism on oral drug absorption, knowledge on the expression levels of the respective enzymes is an essential prerequisite. In addition, the potential interplay of metabolism and transport contributes to drug disposition. Both mechanisms may be subjected to coordinative regulation by nuclear receptors, leading to unwanted drug-drug interactions due to induction of intestinal metabolism and transport. Thus, it was the aim of this study to comprehensively analyse the regional expression of clinically relevant phase I and II enzymes along the entire human intestine and to correlate these data to expression data of drug transporters and nuclear receptors of pharmacokinetic relevance. Gene expression of 11 drug-metabolizing enzymes (CYP2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5, SULT1A, UGT1A, UGT2B7, UGT2B15) was studied in duodenum, jejunum, ileum and colon from six organ donors by real-time RT-PCR. Enzyme expression was correlated with expression data of the nuclear receptors PXR, CAR and FXR as well as drug transporters observed in the same cohort. Intestinal expression of all studied metabolizing enzymes was significantly higher in the small intestine compared to colonic tissue. CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, SULT1A, UGT1A and UGT2B7 expression increased from the duodenum to jejunum but was markedly lower in the ileum. In the small intestine, that is, the predominant site of drug absorption, the highest expression has been observed for CYP3A4, CYP2C9, SULT1A and UGT1A. In addition, significant correlations were found between several enzymes and PXR as well as ABC transporters in the small intestine. In conclusion, the observed substantial site-dependent intestinal expression of several enzymes may explain regional differences in intestinal drug absorption. The detected correlations between intestinal enzymes, transporters and nuclear receptors provide indirect evidence for their coordinative expression, regulation and function in the human small intestine. PMID- 30253073 TI - LC3-Associated Phagocytosis and Antigen Presentation. AB - LC3-associated phagocytosis (LAP) is an unconventional form of autophagy that relies on parts of the canonical autophagy machinery for its function. LAP is triggered upon receptor-mediated phagocytosis and is characterized by the formation of a single-membrane vesicle decorated with the autophagy protein LC3. In professional phagocytic cells, such as macrophages, the role of LAP in immune processes has been characterized, although how LAP functions at the molecular level remains poorly defined. It is important to point out that as for all autophagic pathways, the study of LAP is still challenging for the scientific community because it is a dynamic and complex process, requiring interactions among several proteins. Here, we describe the most common methods used to monitor and quantify the formation of LC3-coated single-membrane endosomes, or so-called LAPosomes, and to validate the involvement of LAP in immunological processes of human macrophages. (c) 2018 by John Wiley & Sons, Inc. PMID- 30253072 TI - Virtual reality-assisted localization and three-dimensional printing-enhanced multidisciplinary decision to treat radiologically occult superficial endobronchial lung cancer. AB - Herein, we report the unique case of a 75-year-old male patient who had undergone a left upper lobectomy for lung cancer and developed an incidental superficial endobronchial squamous cell carcinoma in the right upper lobe that was not localizable on modern cross-sectional imaging modalities. The superficial endobronchial squamous cell carcinoma was successfully localized by computed tomography-driven virtual reality endoscopy and was identically matched with a small, whitish, patch lesion on bronchoscopy. The localized lesion was annotated on the corresponding computed tomography images, and illustrated in a fabricated three-dimensional (3D)-printed airway model. Because the exact anatomic location of the lesion and the acute angle of the adjacent bronchial trajectory were visible in the 3D model, enhanced multidisciplinary consultation resulted in the decision to treat the lesion using photodynamic therapy. Photodynamic therapy was successfully performed without complications. A follow-up bronchoscopy two months after treatment confirmed that the superficial endobronchial squamous cell carcinoma had been cured. PMID- 30253074 TI - Quantification of HIV DNA Using Droplet Digital PCR Techniques. AB - HIV persists, despite effective antiretroviral therapy, in long-lived cells, posing a major barrier toward a cure. A key step in the HIV replication cycle and a hallmark of the Retroviridae family is the integration of the viral DNA into the host genome. Once integrated, HIV expression is regulated by host machinery and the provirus persists until the cell dies. A reservoir of cells harboring replication-competent proviruses can survive for years, and mechanisms that maintain that reservoir are under investigation. The majority of integrated proviruses, however, are defective or have large deletions, and the composition of the proviral landscape during therapy remains unknown. Methods to quantify HIV proviruses are useful in investigating HIV persistence. Presented in this unit is a method for total HIV DNA quantification of various HIV genome targets that utilizes the next-generation PCR platform, digital PCR. The abundance of various HIV gene targets reflects the overall proviral composition. In this protocol, total genomic DNA is isolated from patient-derived cells and then used as a template for droplet digital PCR, in which the PCR reaction is partitioned into approximately 20,000 individual droplets, PCR amplified to an end point, and subjected to absolute quantification by counting the number of positive and negative droplets. Copy number is directly calculated using straightforward Poisson correction. Additionally, this methodological approach can be used to obtain absolute quantification of other DNA targets. (c) 2018 by John Wiley & Sons, Inc. PMID- 30253075 TI - Built environment and cardio-metabolic health: systematic review and meta analysis of longitudinal studies. AB - Built environment attributes may be related to cardio-metabolic diseases (e.g. type 2 diabetes, heart disease and stroke) and their risk factors, potentially by influencing residents' physical activity. However, existing literature reviews on the built environment and health for the most part focus on obesity as the outcome and rely on cross-sectional studies. This systematic review synthesized current evidence on longitudinal relationships between built environment attributes and cardio-metabolic health outcomes among adults and on the potential mediating role of physical inactivity. By searching eight databases for peer reviewed journal articles published in the English language between January 2000 and July 2016, the review identified 36 articles. A meta-analysis method, weighted Z-test, was used to quantify the strength of evidence by incorporating the methodological quality of the studies. We found strong evidence for longitudinal relationships of walkability with obesity, type 2 diabetes and hypertension outcomes in the expected direction. There was strong evidence for the impact of urban sprawl on obesity outcomes. The evidence on potential mediation by physical activity was inconclusive. Further longitudinal studies are warranted to examine which specific built environment attributes influence residents' cardio-metabolic health outcomes and how physical inactivity may be involved in these relationships. PMID- 30253077 TI - Essential Oil Composition, Antioxidant and Allelopathic Activities of Cleome droserifolia (Forssk.) Delile. AB - People rely on the synthetic chemical pesticides in most of the agricultural practices, which have a serious problem on human health and ecosystem. Essential oil (EO), derived from wild plants, offers a new opportunity to explore eco friendly green biocides. This study aimed to characterize the chemical constituents of EO from Egyptian ecospecies of Cleome droserifolia (Forssk.) Delile and evaluate its antioxidant and allelopathic potential. The EO was extracted from aerial parts by hydrodistillation and analyzed by GC/MS. To assess the allelopathic potential, EO concentrations from 50 to 200 MUL L-1 were tested on Trifolium repens and three weeds. Antioxidant activity was determined using DPPH. Hydrodistillation yielded 0.64 % of dark yellow oil, which comprises 35 compounds, in which sesquiterpene was a major class and represented by 61.97 % of the total essential oil. Moreover, the dominant sesquiterpenes are cis-nerolidol, alpha-cadinol, delta-cadinene, and gamma-muurolene. The speed of germination index, shoot and root length of clover and weeds were reduced in a concentration dependent manner. The IC50 values of C. droserifolia EO on germination of T. repens, Cuscuta trifolii, Melilotus indicus, and Chenopodium murale were 181.6, 183.5, 159.0, and 157.5 MUL L-1 , respectively. From the obtained data, we concluded that C. droserifolia EO could provide a hope to produce environment friendly bioherbicide as well as a natural resource of antioxidants. PMID- 30253076 TI - Diffuse alveolar hemorrhage with pseudoprogression during nivolumab therapy in a patient with malignant melanoma. AB - Nivolumab, an anti-PD-1 antibody, has been shown to be effective in many cancers, such as malignant melanoma and lung cancer; however, nivolumab therapy can result in pseudoprogression. Diffuse alveolar hemorrhage (DAH) is persistent or recurrent pulmonary hemorrhage as a result of drugs, autoimmune diseases, or infections. DAH with pseudoprogression during nivolumab administration has rarely been reported. Herein, we describe our experience with one such case. A 41-year old woman exhibited bloody sputum and ground glass opacities in the lungs along with tumor growth during nivolumab therapy for multiple lung metastases of malignant melanoma. We diagnosed DAH with pseudoprogression as a result of nivolumab and administered steroid therapy. The DAH subsequently improved and the tumor shrank. This case illustrates that nivolumab can cause DAH with pseudoprogression, which can be controlled by steroid therapy. Thus, if bloody sputum and ground glass opacities in the lungs are observed with tumor growth during nivolumab administration, steroid therapy should be considered to control DAH with pseudoprogression. PMID- 30253079 TI - Elevated metabolites of acetaminophen in cord blood of children with obesity. AB - BACKGROUND: High-throughput metabolomics has been used cross-sectionally to evaluate differential metabolic profiles associated with human obesity. OBJECTIVES: This study longitudinally assessed the cord blood metabolome to explore if metabolic signatures of obesity at age 3-5 are apparent at birth. METHODS: In a nested case-control design, metabolomics analysis was performed on umbilical cord blood of 25 children who developed obesity by age 3-5 years, compared with 25 sex-matched non-obese children enrolled as part of an ongoing birth cohort. Logistic regression models were used to identify significant metabolites, adjusting for maternal pre-pregnancy obesity. RESULTS: Children who had obesity by age 3-5 years had elevated levels of medium and long chain fatty acids including stearate, oleate and palmitate at birth. Children with obesity were also more likely to have elevated levels of acetaminophen metabolites at birth, specifically: 3-(N-acetyl-L-cystein-S-yl) acetaminophen, 2 hydroxyacetaminophen sulfate, 2-methoxyacetaminophen glucuronide and p acetamidophenyl glucuronide. CONCLUSION: Although the observed increases in lipids are consistent with previous metabolomic studies of obesity, this study is the first to report associations between acetaminophen metabolites and obesity in children; however, we lack mechanistic insights for this link. Larger human studies with longer follow-up and laboratory-controlled animal experiments are needed to clarify associations. PMID- 30253078 TI - Targeting immunotherapy for bladder cancer using anti-CD3* B7-H3 bispecific antibody. AB - OBJECTIVE: B7-H3 is attractive for cancer immunotherapy with B7-H3 overexpressed tumors. To explore whether B7-H3 is an effective target for patients with bladder cancer, anti-CD3* anti-B7-H3 bispecific antibodies (B7-H3Bi-Ab) was armed with activated T cells (ATC) to kill bladder cancer cells. METHODS: High expressions of B7-H3 on human bladder cancer cells were detected, including Pumc-91 and T24 cells, and their chemotherapeutic drug-resistant counterparts. ATC generated from healthy donors were stimulated with anti-CD3 monoclonal antibody and interleukin 2 (IL-2) for 13 days. The ability of ATC armed with B7-H3Bi-Ab to kill bladder cancer cells was detected by flow cytometry, LDH, Elisa, and luciferase quantitative assay. Moreover, ATC generated from bladder cancer patients was armed with B7-H3Bi-Ab to verity the cell killing by the methods as previously described. RESULTS: Compared with unarmed ATC, a significant increased cytotoxicity of B7-H3Bi-Ab-armed ATC against bladder cancer cells was discovered. The B7-H3Bi-Ab-armed ATC secreted more IFN-gamma, TNF-alpha, and expressed high levels of activation marker CD69. Interestingly, despite the presence of immunosuppression in patients and resistance in chemotherapeutic drug-resistant cancer cell lines, B7-H3Bi-Ab-armed ATC from patients with bladder cancer still showed significant cytotoxic activity against bladder cancer cells and their chemotherapeutic drug-resistant counterparts. CONCLUSION: B7-H3 is an effective target for bladder cancer. B7-H3Bi-Ab enhances the ability of ATC to kill bladder cancer cells. B7-H3Bi-Ab-armed ATC is promisingly to provide a novel strategy for current bladder cancer therapy. PMID- 30253080 TI - Pleural or pericardial metastasis: A significant factor affecting efficacy and adverse events in lung cancer patients treated with PD-1/PD-L1 inhibitors. AB - BACKGROUND: Immunotherapy is a new paradigm for the treatment of non-small-cell lung cancer (NSCLC), and targeting the PD-1 or PD-L1 pathway is a promising therapeutic option. Although PD-1/PD-L1 inhibitors are more effective than standard chemotherapy in lung cancer, clinicians are afraid to actively use them because of hyperprogression and pseudoprogression. The aim of this study was to investigate the factors associated with tumor response and serious outcomes. METHODS: We retrospectively collected the medical records of 51 patients with advanced NSCLC who received PD-1/PD-L1 inhibitors between January 2016 and February 2018. RESULTS: The mean patient age was 63.9 years, and 72.5% (37/51) were male. Most (92.2%, 47/51) had received previous systemic treatment. The overall response rate was 21.6% (11/51). The response rate was significantly lower in patients with pleural or pericardial metastasis than in patients without pleural or pericardial metastasis (4.3% vs. 35.7%; P = 0.007). Patients with pleural or pericardial metastasis had a significantly higher rate of adverse events of any grade (91.3% vs. 50.0%; P = 0.002) and grade 3-5 adverse events (52.2% vs. 25.0%; P = 0.046). CONCLUSION: Pleural or pericardial metastasis is a significant factor affecting the efficacy and rate of adverse events in advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. Clinicians should pay attention to the use of immune checkpoint inhibitors in lung cancer patients with pleural or pericardial metastasis. PMID- 30253081 TI - Voltaglue Bioadhesives Energized with Interdigitated 3D-Graphene Electrodes. AB - Soft tissue fixation of implant and bioelectrodes relies on mechanical means (e.g., sutures, staples, and screws), with associated complications of tissue perforation, scarring, and interfacial stress concentrations. Adhesive bioelectrodes address these shortcomings with voltage cured carbene-based bioadhesives, locally energized through graphene interdigitated electrodes. Electrorheometry and adhesion structure activity relationships are explored with respect to voltage and electrolyte on bioelectrodes synthesized from graphene 3D printed onto resorbable polyester substrates. Adhesive leachates effects on in vitro metabolism and human-derived platelet-rich plasma response serves to qualitatively assess biological response. The voltage activated bioadhesives are found to have gelation times of 60 s or less with maximum shear storage modulus (G') of 3 kPa. Shear modulus mimics reported values for human soft tissues (0.1 10 kPa). The maximum adhesion strength achieved for the ~50 mg bioelectrode films is 170 g cm-2 (17 kPa), which exceeds the force required for tethering of electrodes on dynamic soft tissues. The method provides the groundwork for implantable bio/electrodes that may be permanently incorporated into soft tissues, vis-a-vis graphene backscattering wireless electronics since all components are bioresorbable. PMID- 30253082 TI - Taq1a polymorphism (rs1800497) is associated with obesity-related outcomes and dietary intake in a multi-ethnic sample of children. AB - BACKGROUND: In adults, the Taq1a polymorphism (rs1800497) near the D2 receptor (DRD2) gene is associated with body mass index and binge eating and is more prevalent among non-Hispanic Blacks (NHB) and Hispanic-Americans (HA) relative to non-Hispanic Whites (NHW). We hypothesize Taq1a polymorphism (rs1800497) risk alleles contribute to paediatric racial/ethnic differences in obesity phenotypes. OBJECTIVES: This study aims to characterize the relationship between the Taq1a polymorphism (rs1800497), diet and adiposity in a multi-ethnic cohort of 286 children (98 NHB, 76 HA and 112 NHW), ages 7-12. METHODS: Dual-energy X-ray absorptiometry, computed tomography scans and two 24-h dietary recalls assessed body composition, fat distribution and dietary intakes, respectively. RESULTS: Children with two Taq1a risk alleles (NHB = 50.0%, HA = 43.3%, NHW = 6.7%) reported a 20% increase in total energy intake (P = 0.0034) and per cent of calories from sugar consumed (P = 0.0077) than did children with less than two risk alleles. Children with two Taq1a risk alleles demonstrated significantly higher total body fat (P = 0.0145), body fat percentage (P = 0.0377), intra abdominal adiposity (P = 0.0459), subcutaneous abdominal adiposity (P = 0.0213) and total abdominal adiposity (P = 0.0209) than did children with one or no Taq1a risk alleles. CONCLUSIONS: Our results suggest that having two Taq1a risk alleles is associated with an increase in reported calorie and sugar consumption and is a potential risk factor for early development of excess adiposity in multi-ethnic children. These results need to be confirmed in a larger sample. PMID- 30253085 TI - [Gender Analysis in the Agreement in Assessing the Signs Between Professionals and Parents Whose Children Have Attention Deficit and/or Hyperactivity Disorder]. AB - The attention deficit hyperactivity disorder (ADHD) is the most prevalent chronic neuropsychiatric illness in childhood. It interferes with normal development of children. Its impact transcends childhood to appear in adolescence and adulthood. Diagnosis would be developed if the child shows the main symptoms of inattention and/or hyperactivity-impulsivity, with consequences in different aspects of daily life, such as academic achievements, family life or social interactions with other children. These symptoms will come up along life in different ways. When the child is young, hyperactivity and impulsivity prevail, but as he/she grows, the dispersion and difficulty to remember things and facts will become more evident. The aim of the study was to assess with the Vanderbilt scale, based on DSM-IV diagnostic criteria, the differences of the impact of ADHD among parents, in comparison to the medical diagnosis. A retrospective study was carried out by using this questionnaire, which completed by both parents individually. A total of 78 children took part in this study, all of them diagnosed with ages ranging from 6 to 16 years old, who attended to Neuropedriatics at VAlle del Nalon Hospital(Asturias), between October 2011 and March 2013. Regarding attention deficit, the average responses given by mothers (7.38 +/- 1.81) was higher than that offered by fathers (647 +/- 2/46). The same is true for hyperactivity/impulsivity, with average scores of mothers (5.80 +/- 2.90) which were one positive response higher than those given by male patients (4.74 +/- 3.04). Mothers show a higher percentage of agreement with the medical diagnosis (86.3%) when the child was a girl and 66% with boys, whereas for fathers the percentage of agreement was less than 50% female children and 44.6% for male children. PMID- 30253084 TI - The role of prefrontal cortex in a moral judgment task using functional near infrared spectroscopy. AB - BACKGROUND: Understanding the neural basis of moral judgment (MJ) and human decision-making has been the subject of numerous studies because of their impact on daily life activities and social norms. Here, we aimed to investigate the neural process of MJ using functional near-infrared spectroscopy (fNIRS), a noninvasive, portable, and affordable neuroimaging modality. METHODS: We examined prefrontal cortex (PFC) activation in 33 healthy participants engaging in MJ exercises. We hypothesized that participants presented with personal (emotionally salient) and impersonal (less emotional) dilemmas would exhibit different brain activation observable through fNIRS. We also investigated the effects of utilitarian and nonutilitarian responses to MJ scenarios on PFC activation. Utilitarian responses are those that favor the greatest good while nonutilitarian responses favor moral actions. Mixed effect models were applied to model the cerebral hemodynamic changes that occurred during MJ dilemmas. RESULTS AND CONCLUSIONS: Our analysis found significant differences in PFC activation during personal versus impersonal dilemmas. Specifically, the left dorsolateral PFC was highly activated during impersonal MJ when a nonutilitarian decision was made. This is consistent with the majority of relevant fMRI studies, and demonstrates the feasibility of using fNIRS, with its portable and motion tolerant capacities, to investigate the neural basis of MJ dilemmas. PMID- 30253086 TI - A Focused Library of Psychotropic Analogues with Neuroprotective and Neuroregenerative Potential. AB - Overcoming the lack of effective treatments and the continuous clinical trial failures in neurodegenerative drug discovery might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting simultaneously neuroprotection and neuroregeneration. In the studies reported herein, we sought to identify small molecules that might exert neuroprotective and neuroregenerative potential as tools against neurodegenerative diseases. In doing so, we started from the reported neuroprotective/neuroregenerative mechanisms of psychotropic drugs featuring a tricyclic alkylamine scaffold. Thus, we designed a focused-chemical library of 36 entries aimed at exploring the structural requirements for efficient neuroprotective/neuroregenerative cellular activity, without the manifestation of toxicity. To this aim, we developed a synthetic protocol, which overcame the limited applicability of previously reported procedures. Next, we evaluated the synthesized compounds through a phenotypic screening pipeline, based on primary neuronal systems. Phenothiazine 2Bc showed improved neuroregenerative and neuroprotective properties with respect to reference drug desipramine (2Aa). Importantly, we have also shown that 2Bc outperformed currently available drugs in cell models of Alzheimer's and Parkinson's diseases and attenuates microglial activation by reducing iNOS expression. PMID- 30253087 TI - Heterostructure Manipulation via in Situ Localized Phase Transformation for High Rate and Highly Durable Lithium Ion Storage. AB - Recently, heterostructures have attracted much attention in widespread research fields. By tailoring the physicochemical properties of the two components, creating heterostructures endows composites with diverse functions due to the synergistic effects and interfacial interaction. Here, a simple in situ localized phase transformation method is proposed to transform the transition-metal oxide electrode materials into heterostructures. Taking molybdenum oxide as an example, quasi-core-shell MoO3@MoO2 heterostructures were successfully fabricated, which were uniformly anchored on reduced graphene oxide (rGO) for high-rate and highly durable lithium ion storage. The in situ introduction of the MoO2 shell not only effectively enhances the electronic conductivity but also creates MoO3@MoO2 heterojunctions with abundant oxygen vacancies, which induces an inbuilt driving force at the interface, enhancing ion/electron transfer. In operando synchrotron X-ray powder diffraction has confirmed the excellent phase reversibility of the MoO2 shell during charge/discharge cycling, which contributes to the excellent cycling stability of the MoO3@MoO2/rGO electrode (1208.9 mAh g-1 remaining at 5 A g-1 after 2000 cycles). This simple in situ heterostructure fabrication method provides a facile way to optimize electrode materials for high-performance lithium ion batteries and possibly other energy storage devices. PMID- 30253088 TI - Local GABAA Receptor-Mediated Suppression of Dopamine Release within the Nucleus Accumbens. AB - Benzodiazepines make up a class of psychoactive drugs that act as allosteric co activators of the inhibitory GABAA receptor. These drugs are useful for the treatment of several psychiatric disorders but also hold considerable abuse liability. Despite the common use and misuse of benzodiazepines, the mechanisms through which these drugs exert their reinforcing effects remain incompletely understood. Transient phasic increases in dopamine levels are believed to play an important role in defining the reinforcing properties of drugs of abuse, and we recently demonstrated that systemic administration of benzodiazepines increased the frequency of these events but concomitantly reduced their amplitude. This observation provides insight into the pharmacological effects of benzodiazepines on dopamine signaling, but the processes through which benzodiazepines drive changes in phasic dopamine signals remain unclear. In these studies, we investigated the mechanisms through which benzodiazepines may reduce the phasic dopamine transient amplitude. We tested the effect of the benzodiazepine diazepam and the GABAA agonist muscimol on evoked dopamine release from nucleus accumbens brain slices using fast scan cyclic voltammetry. We found that both diazepam and muscimol reduce dopamine release and that reductions in dopamine release following GABAA receptor activation can be blocked by co-application of a GABAB receptor antagonist. These results suggest that activation of GABAA receptors in the nucleus accumbens decreases dopamine release by disinhibition of local GABA signaling and subsequent activation of GABAB receptors. Overall, this work provides a putative mechanism through which benzodiazepines reduce the amplitude of phasic dopamine release in vivo. PMID- 30253083 TI - Real-world EGFR testing in patients with stage IIIB/IV non-small-cell lung cancer in North China: A multicenter, non-interventional study. AB - BACKGROUND: Before tyrosine kinase inhibitor (TKI) therapy can be administered in patients with advanced non-small cell lung cancer (NSCLC), EGFR mutation testing is required. However, few studies have evaluated the extent of EGFR testing in real-world practice in China. METHODS: A multicenter, observational study of EGFR testing in NSCLC patients in North China was conducted. Treatment-naive patients or those with postoperative recurrent stage IIIB/IV NSCLC were enrolled. The primary objective was EGFR testing rate. Secondary objectives included EGFR mutation status, EGFR testing methods and specimens, factors associated with EGFR testing, and overall survival with or without EGFR testing. RESULTS: Overall, 2809 patients with stage IIIB/IV NSCLC were enrolled; 90.78% had adenocarcinoma. The EGFR screening rate was 42.54%. EGFR testing rates were higher in tumor samples obtained by lymph node puncture, and in patients with urban medical insurance, adenocarcinoma, non-smokers, or those located in developed cities (all P < 0.001). The EGFR mutation rate was 46.44%. The most commonly used specimens for EGFR testing were biopsy tumor samples (67.53%). PCR-based methods (72.05%), Sanger sequencing (5.36%), and Luminex liquid chip (5.10%) were the most frequently used testing platforms. Similar positive EGFR mutation rates were achieved with different platforms. TKI therapy was the first-line treatment administered to most EGFR-positive patients (56.22%), and chemotherapy in EGFR negative patients (84.88%). Overall survival was higher in EGFR-tested than in untested patients (27.50 vs. 19.73 months; P = 0.007). CONCLUSION: Real-world EGFR testing rates for NSCLC in North China were relatively low because of clinical and social factors, including medical insurance coverage. PMID- 30253090 TI - Comparative Role of Chain Scission and Solvation in the Biodegradation of Polylactic Acid (PLA). AB - The molecular mechanism behind the process of biodegradation and consequently the loss in mechanical properties of polylactic acid (PLA) requires detailed understanding for the successful designing of various technological devices. In this study, we examine the role of free water and chain scission in this degradation process and quantify the mechanical properties of pristine and nanoparticle-reinforced PLA as it degrades over time. The in situ mechanical response of the degrading polymer is determined experimentally using nano-dynamic mechanical analysis (nanoDMA). Water present in the polymer matrix contributes to hydrolysis and subsequent scission of polymer chains. Water in excess of hydrolysis, however, alters the load transfer mechanism within the polymer chains. Molecular mechanism study applied in this work provides detailed insights into the relative role of these two mechanisms, (i) chain scission and (ii) solvation, in the reduction of mechanical properties during degradation. Functional groups such as ester (-COO-) and terminal acid (-COOH) interact with water molecules leading to the formation of water bridges and solvation shells, respectively. These are found to hinder the load transfer between polymer chains. It is observed that, compared to scission, solvation plays a more active role in the reduction of mechanical properties of degrading PLA. PMID- 30253091 TI - Capturing Phase Behavior of Ternary Lipid Mixtures with a Refined Martini Coarse Grained Force Field. AB - Whether lipid rafts are present in the membranes of living cells remains hotly disputed despite their incontrovertible existence in liposomes at 298 K. In attempts to resolve this debate, molecular dynamics (MD) simulations have been extensively used to study lipid phase separation at high resolution. However, computation has been of limited utility in this respect because the experimental distributions of phases in lamellar lipid mixtures are poorly reproduced by simulations. In particular, all-atom (AA) approaches suffer from restrictions on accessible time scales and system sizes whereas the more efficient coarse-grained (CG) force fields remain insufficiently accurate to achieve correspondence with experiment. In this work, we refine the CG Martini parameters for the high- and low-melting temperature ( Tm) lipids 1,2-dipalmitoyl- sn-glycero-3 phosphatidylcholine (DPPC) and 1,2-dioleoyl- sn-glycero-3-phosphatidylcholine (DOPC). Our approach involves the modification of bonded Martini parameters based on fitting to atomistic simulations conducted with the CHARMM36 lipid force field. The resulting CG parameters reproduce experimental structural and thermodynamic properties of homogeneous lipid membranes while concurrently improving simulation fidelity to experimental phase diagrams of DPPC, DOPC, and cholesterol lipid mixtures. Importantly, the refined parameters provide much better phase accuracy for regions near the critical point that mimic the lipid concentrations under physiological conditions. PMID- 30253089 TI - A Novel F3' 5' H Allele with 14 bp Deletion Is Associated with High Catechin Index Trait of Wild Tea Plants and Has Potential Use in Enhancing Tea Quality. AB - Catechins are important chemical components determining the quality of tea. The catechin index (CI, ratio of dihydroxylated catechin (DIC)/trihydroxylated catechin (TRIC)) in the green leaf has a major influence on the amounts of theaflavins in black tea. In this work, the major catechin profiles of wild tea plants originating from Guizhou Province with high CI trait were investigated. We identified a novel flavonoid 3',5' hydroxylase gene ( F3' 5' H) allele with a 14 bp deletion in the upstream regulation region and developed an insertion/deletion (InDel) marker accordingly. The 14 bp deletion in the novel F3' 5' H allele was associated with low F3' 5' H mRNA expression, thereby resulting in low TRIC content and high CI value. The allelic variant in the novel F3' 5' H allele associated with high CI values and DIC contents was confirmed by the introgression lines derived from a distant cross population. The novel F3' 5' H allele in wild tea plants is a valuable gene resource, which could be applied to breeding improvement on tea quality. PMID- 30253092 TI - Increased Cholinergic Response in alpha-Synuclein Transgenic Mice (h-alpha synL62). AB - Pathological accumulation of misfolded alpha-synuclein (alpha-syn) in the brain plays a key role in the pathogenesis of Parkinson's disease, leading to neuronal dysfunction and motor disorders. The underlying mechanisms linking alpha-syn aggregations with neurotransmitter disturbance in Parkinson's brains are not well characterized. In the present study, we investigated transgenic mice expressing an aggregation-prone form of full-length human alpha-syn (h-alpha-synL62) linked to a signal sequence. These mice display dopamine depletion and progressive motor deficits. We detected accumulation of alpha-syn in cholinergic interneurons where they are colocalized with choline acetyltransferase. Using microdialysis, we measured acetylcholine levels in the striatum at baseline and during stimulation in the open field and with scopolamine. While no difference between wild-type and transgenic mice was detected in 3 month old mice, striatal acetylcholine levels at 9 months of age were significantly higher in transgenic mice. Concomitantly, high-affinity choline uptake was also increased while choline acetyltransferase and acetylcholine esterase activities were unchanged. The results suggest a disinhibition of acetylcholine release in alpha-syn transgenic mice. PMID- 30253093 TI - Protease-Sensitive Hydrogel Biomaterials with Tunable Modulus and Adhesion Ligand Gradients for 3D Vascular Sprouting. AB - Biomaterial strategies focused on designing scaffolds with physiologically relevant gradients provide a promising means for elucidating 3D vascular cell responses to spatial and temporal variations in matrix properties. In this study, we present a photopolymerization approach, ascending photofrontal free-radical polymerization, to generate proteolytically degradable hydrogel scaffolds of poly(ethylene) glycol with tunable continuous gradients of (1) elastic modulus (slope of 80 Pa/mm) and uniform immobilized RGD concentration (2.06 +/- 0.12 mM) and (2) immobilized concentration of the RGD cell-adhesion peptide ligand (slope of 58.8 MUM/mm) and uniform elastic modulus (597 +/- 22 Pa). Using a coculture model of vascular sprouting, scaffolds embedded with gradients of elastic modulus induced increases in the number of vascular sprouts in the opposing gradient direction, whereas RGD gradient scaffolds promoted increases in the length of vascular sprouts toward the gradient. Furthermore, increases in vascular sprout length were found to be prominent in regions containing higher immobilized RGD concentration. PMID- 30253094 TI - Phytic Acid Reduction by Bioprocessing as a Tool To Improve the In Vitro Digestibility of Faba Bean Protein. AB - In legumes such as faba bean, phytic acid can form very stable complexes with proteins, thus hindering their accessibility for gastrointestinal digestion. This study was set up to investigate the influence of enzymatic phytase treatment and lactic acid bacteria fermentation ( Lactobacillus plantarum VTT E-78076) on phytic acid reduction as well as on the protein quality and digestibility of faba bean flour. The soluble protein and release of free amino acids from faba bean flours were followed during a simulated in vitro digestion process. Phytase treatment efficiently reduced the amount of phytic acid in faba bean flour up to 89% degradation. The reduction of phytic acid content caused a shift in the protein solubility curve, showing higher solubility levels at low pH. Further, the enzyme-aided degradation of phytic acid considerably enhanced the digestibility of faba bean proteins (dose-dependent) and the release of free amino nitrogen in the first stage of digestion (gastric phase). The results propose the benefits of phytase treatment in plant-based foods where the phytic acid content may hinder the digestion of protein. PMID- 30253096 TI - Diversification of Device Platforms by Molecular Layers: Hybrid Sensing Platforms, Monolayer Doping, and Modeling. AB - Inorganic materials such as semiconductors, oxides, and metals are ubiquitous in a wide range of device technologies owing to the outstanding robustness and mature processing technologies available for such materials. However, while the important contribution of inorganic materials to the advancement of device technologies has been well established for decades, organic-inorganic hybrid device systems, which merge molecular functionalities with inorganic platforms, represent a newer domain that is rapidly evolving at an increasing pace. Such devices benefit from the great versatility and flexibility of the organic building blocks merged with the robustness of the inorganic platforms. Given the overwhelming wealth of literature covering various approaches for modifying and using inorganic devices, this feature article selectively highlights some of the advances made in the context of the diversification of devices by surface chemistry. Particular attention is given to oxide-semiconductor systems and metallic surfaces modified with organic monolayers. The inorganic device components, such as semiconductors, metals, and oxides, are modified by organic monolayers, which may serve as either active, static, or sacrificial components. We portray research directions within the broader field of organic-inorganic hybrid device systems that can be viewed as specific examples of the potential of such hybrid device systems given their comprehensive capabilities of design and diversification. Monolayer doping techniques where sacrificial organic monolayers are introduced into semiconducting elements are reviewed as a specific case, together with associated requirements for nanosystems, devices, and sensors for controlling doping levels and doping profiles on the nanometric scale. Another series of examples of the flexibility provided by the marriage of organic functional monolayers and inorganic device components are represented by a new class of biosensors, where the organic layer functionality is exploited in a functioning device for sensing. Considerations for relying on oxide-terminated semiconductors rather than the pristine semiconductor material as a platform both for processing and sensing are discussed. Finally, we cover aspects related to the use of various theoretical and computational approaches to model organic inorganic systems. The main objectives of the topics covered here are (i) to present the advances made in each respective domain and (ii) to provide a comprehensive view of the potential uses of organic monolayers and self-assembly processes in the rapidly evolving field of molecular-inorganic hybrid device platforms and processing methodologies. The directions highlighted here provide a perspective on a future, not yet fully realized, integrated approach where organic monolayers are combined with inorganic platforms in order to obtain versatile, robust, and flexible systems with enhanced capabilities. PMID- 30253095 TI - Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor. AB - As regulators of transcription, epigenetic proteins that interpret post translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-epsilon acetylated lysine, selective inhibition of individual bromodomain-and-extra terminal (BET)-family bromodomains has proven challenging. We describe the >55 fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-kappaB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38alpha. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling. PMID- 30253098 TI - Reduced Free Energy Perturbation/Hamiltonian Replica Exchange Molecular Dynamics Method with Unbiased Alchemical Thermodynamic Axis. AB - Replica-exchange molecular dynamics (REMD) has been proven to efficiently improve the convergence of free-energy perturbation (FEP) calculations involving considerable reorganization of their surrounding. We previously introduced the FEP/(lambda,H)-REMD algorithm for ligand binding, in which replicas along the alchemical thermodynamic coupling axis lambda were expanded as a series of Hamiltonian boosted replicas along a second axis to form a two-dimensional replica-exchange exchange map [Jiang, W.; Roux, B., J. Chem. Theory Comput. 2010, 6 (9), 2559-2565]. Aiming to achieve a similar performance at a lower computational cost, we propose here a modified version of this algorithm in which only the end-states along the alchemical axis are augmented by boosted replicas. The reduced FEP/(lambda,H)-REMD method with one-dimensional unbiased alchemical thermodynamic coupling axis lambda is implemented on the basis of generic multiple copy algorithm (MCA) module of the biomolecular simulation program NAMD. The flexible MCA framework of NAMD enables a user to design customized replica exchange patterns through Tcl scripting in the context of a highly parallelized simulation program without touching the source code. Two Hamiltonian tempering boosting scheme were examined with the new algorithm: a first one based on potential energy rescaling of a preidentified "solute" and a second one via the introduction of flattening torsional free-energy barriers. As two illustrative examples with reliable experiment data, the absolute binding free energies of p xylene and n-butylbenzene to the nonpolar cavity of the L99A mutant of T4 lysozyme were calculated. The tests demonstrate that the new protocol efficiently enhances the sampling of torsional motions for backbone and side chains around the binding pocket and accelerates the convergence of the free-energy computations. PMID- 30253097 TI - BDPA-Nitroxide Biradicals Tailored for Efficient Dynamic Nuclear Polarization Enhanced Solid-State NMR at Magnetic Fields up to 21.1 T. AB - Dynamic nuclear polarization (DNP) solid-state nuclear magnetic resonance (NMR) has developed into an invaluable tool for the investigation of a wide range of materials. However, the sensitivity gain achieved with many polarizing agents suffers from an unfavorable field and magic angle spinning (MAS) frequency dependence. We present a series of new hybrid biradicals, soluble in organic solvents, that consist of an isotropic narrow electron paramagnetic resonance line radical, alpha,gamma-bisdiphenylene-beta-phenylallyl (BDPA), tethered to a broad line nitroxide. By tuning the distance between the two electrons and the substituents at the nitroxide moiety, correlations between the electron-electron interactions and the electron spin relaxation times on one hand and the DNP enhancement factors on the other hand are established. The best radical in this series has a short methylene linker and bears bulky phenyl spirocyclohexyl ligands. In a 1.3 mm prototype DNP probe, it yields enhancements of up to 185 at 18.8 T (800 MHz 1H resonance frequency) and 40 kHz MAS. We show that this radical gives enhancement factors of over 60 in 3.2 mm sapphire rotors at both 18.8 and 21.1 T (900 MHz 1H resonance frequency), the highest magnetic field available today for DNP. The effect of the rotor size and of the microwave irradiation inside the MAS rotor is discussed. Finally, we demonstrate the potential of this new series of polarizing agents by recording high field 27Al and 29Si DNP surface enhanced NMR spectra of amorphous aluminosilicates and 17O NMR on silica nanoparticles. PMID- 30253099 TI - Machine Learning Classification and Structure-Functional Analysis of Cancer Mutations Reveal Unique Dynamic and Network Signatures of Driver Sites in Oncogenes and Tumor Suppressor Genes. AB - In this study, we developed two cancer-specific machine learning classifiers for prediction of driver mutations in cancer-associated genes that were validated on canonical data sets of functionally validated mutations and applied to a large cancer genomics data set. By examining sequence, structure, and ensemble-based integrated features, we have shown that evolutionary conservation scores play a critical role in classification of cancer drivers and provide the strongest signal in the machine learning prediction. Through extensive comparative analysis with structure-functional experiments and multicenter mutational calling data from Pan Cancer Atlas studies, we have demonstrated the robustness of our models and addressed the validity of computational predictions. To address the interpretability of cancer-specific classification models and obtain novel insights about molecular signatures of driver mutations, we have complemented machine learning predictions with structure-functional analysis of cancer driver mutations in several important oncogenes and tumor suppressor genes. By examining structural and dynamic signatures of known mutational hotspots and the predicted driver mutations, we have shown that the greater flexibility of specific functional regions targeted by driver mutations in oncogenes may facilitate activating conformational changes, while loss-of-function driver mutations in tumor suppressor genes can preferentially target structurally rigid positions that mediate allosteric communications in residue interaction networks and modulate protein binding interfaces. By revealing molecular signatures of cancer driver mutations, our results highlighted limitations of the binary driver/passenger classification, suggesting that functionally relevant cancer mutations may span a continuum spectrum of driverlike effects. Based on this analysis, we propose for experimental testing a group of novel potential driver mutations that can act by altering structure, global dynamics, and allosteric interaction networks in important cancer genes. PMID- 30253100 TI - Consolidating Regionalized Global Characterization Factors for Soil Organic Carbon Depletion Due to Land Occupation and Transformation. AB - Land occupation and transformation change soil organic carbon (SOC) stocks, which are a priority indicator for biotic production potential (BPP) in life cycle impact assessment (LCIA). SOC is a potential umbrella indicator for land use related impacts, but global LCIA characterization models have never been sufficiently regionalized. Regeneration times required for the calculation of transformation impacts are unknown and can only be estimated through expert judgment or using additional assumptions. In this paper, we calculate global midpoint characterization factors (CF) for SOC depletion following land use and land use change using data from the European Soil Data Center with a resolution of 30 arc second. We used three possible calculation procedures to determine regeneration times: (1) estimations based on literature; (2) equal regeneration duration for all land uses; (3) equal regeneration rates for all land uses. We then propose an innovative approach for LCIA that combines all CFs in this paper as well as prior models using a spatial consolidation approach to arrive at a single set of CFs. We show that this procedure combines the strengths of each individual model and dilutes their shortcomings, and recommend the use of these consolidated CFs rather than individual sets of factors. For endpoints, we applied a nutrient replacement method using fertilizer input to compensate for organic matter depletion and obtained monetary CFs for SOC-related damages caused by land use on BPP. PMID- 30253101 TI - Control of Membrane Binding and Diffusion of Cholesteryl-Modified DNA Origami Nanostructures by DNA Spacers. AB - DNA origami nanotechnology is being increasingly used to mimic membrane associated biophysical phenomena. Although a variety of DNA origami nanostructures has already been produced to target lipid membranes, the requirements for membrane binding have so far not been systematically assessed. Here, we used a set of elongated DNA origami structures with varying placement and number of cholesteryl-based membrane anchors to compare different strategies for their incorporation. Single and multiple cholesteryl anchors were attached to DNA nanostructures using single- and double-stranded DNA spacers of varying length. The produced DNA nanostructures were studied in terms of their membrane binding and diffusion. Our results show that the location and number of anchoring moieties play a crucial role for membrane binding of DNA nanostructures mainly if the cholesteryl anchors are in close proximity to the bulky DNA nanostructures. Moreover, the use of DNA spacers largely overcomes local steric hindrances and thus enhances membrane binding. Fluorescence correlation spectroscopy measurements demonstrate that the distinct physical properties of single- and double-stranded DNA spacers control the interaction of the amphipathic DNA nanostructures with lipid membranes. Thus, we provide a rational basis for the design of amphipathic DNA origami nanostructures to efficiently bind lipid membranes in various environments. PMID- 30253102 TI - Light-Responsive Microstructures in Droplets of the Twist-Bend Nematic Phase. AB - We report on the structure and optical manipulation of the director configurations in emulsions of liquid-crystalline droplets of a compound exhibiting the nematic (N) and the twist-bend nematic (NTB) phases. We demonstrate a decrease in the ratio of the bent elastic constant K33 to the splay constant K11 by nearly 2 orders of magnitude with decreasing temperature in the N phase. The director structures in liquid-crystal droplets doped with a photoswitchable surfactant without and under ultraviolet (UV) light are discussed in light of the strong elastic anisotropy of the investigated compound. We also compare our findings with the results obtained in doped nematic droplets of a conventional 4-cyano-4'-pentylbiphenyl (5CB) liquid crystal. The dynamics of droplets in the NTB phase by UV light irradiation are also studied using polarizing and confocal microscopies. PMID- 30253103 TI - Single Crystals of Cubic Rare-Earth Pyrochlore Germanates: RE2Ge2O7 (RE = Yb and Lu) Grown by a High-Temperature Hydrothermal Technique. AB - Large single crystals of Yb2Ge2O7 in the cubic Fd3 m space group, are synthesized and characterized from a high-temperature hydrothermal method (650 degrees C/200 MPa in 1 M KF). The cubic phase displays spin frustration and possibly nonclassical quantum-spin behavior at low temperature. This is the first report of single crystals of this important phase of size and quality suitable for single-crystal neutron diffraction. PMID- 30253104 TI - Synthesis of 2'-Methyl-6-methoxyguanosine from the Parent Ribonucleoside Guanosine. AB - A short and efficient synthesis of the nucleoside fragment contained in the NS5B nucleoside inhibitor BMS-986094 was achieved in 23% overall yield on a gram scale. The synthesis uses the widely available starting material guanosine via a short sequence ending in a Mukaiyama hydration reaction to establish the key tertiary alcohol moiety and set the C-2' methyl stereogenic center. This work resulted in a robust and scalable approach to this complex nucleoside. PMID- 30253105 TI - Ultrafast Hydrogen Migration in Photoionized Glycine. AB - Hydrogen migration in the glycine cation has been investigated using a combination of a short train of attosecond extreme ultraviolet pulses with few optical-cycle near-infrared pulses. The yield of the photofragments produced has been measured as a function of pump-probe delay. These time-dependent measurements reveal the presence of a hydrogen migration process occurring in 48 fs. Previous mass spectrometric experiments and theoretical calculations have allowed us to identify the conformations and cation states involved in the process induced by the broad band extreme ultraviolet radiation. PMID- 30253106 TI - Neighboring Component Effect in a Tri-stable [2]Rotaxane. AB - The redox properties of cyclobis(paraquat- p-phenylene)cyclophane (CBPQT4+) render it a uniquely variable source of recognition in the context of mechanically interlocked molecules, through aromatic donor-acceptor interactions in its fully oxidized state (CPBQT4+) and radical-pairing interactions in its partially reduced state (CBPQT2(*+)). Although it is expected that the fully reduced neutral state (CBPQT(0)) might behave as a pi-donating recognition unit, resulting in a dramatic change in its binding properties when compared with the other two redox states, its role in rotaxanes has not yet been investigated. To address this challenge, we report herein the synthesis of a tri-stable [2]rotaxane in which a CBPQT4+ ring is mechanically interlocked with a dumbbell component containing five recognition sites-(i) a bipyridinium radical cation (BIPY(*+)) located centrally along the axis of the dumbbell, straddled by (ii) two tetrafluorophenylene units linked to (iii) two triazole rings. In addition to the selective recognition between (iv) the CBPQT4+ ring and the triazole units, and (v) the CBPQT2(*+) ring and the reduced BIPY(*+) unit in the dumbbell component, investigations in solution have now confirmed the presence of additional non-covalent bonding interactions between the CBPQT(0) ring, acting as a donor in its neutral state, and the two tetrafluorophenylene acceptors in the dumbbell component. The unveiling of this piece of molecular recognition in a [2]rotaxane is reminiscent of the existence in much simpler, covalently linked, organic molecules of neighboring group participation (anchimeric assistance giving way to transannular interactions) in small-, medium-, and large-membered rings. PMID- 30253107 TI - Self-Assembled Micellar Structures of Lipopeptides with Variable Number of Attached Lipid Chains Revealed by Atomistic Molecular Dynamics Simulations. AB - We present atomistic molecular dynamics simulation study of the self-assembly behavior of toll-like agonist lipopeptides (Pam nCSK4) in aqueous solutions. The variable number of hexadecyl lipid chains ( n = 1, 2, 3) per molecule has been experimentally suggested to have remarkable influence on their self-assembled nanostructures. Starting from preassembled spherical or bilayer configurations, the aggregates of lipopeptides, PamCSK4 and Pam2CSK4, which contain peptide sequences CSK4 linked to either mono- or dilipid chains (Pam), evolve into spherical-like micelles within 30 ns, whereas the self-assembled structure of trilipidated lipopeptides, Pam3CSK4, relaxes much slower and reaches an equilibrium state of flattened wormlike micelle with a bilayer packing structure. The geometric shapes and sizes, namely the gyration radii of spherical micelles and thickness of the flattened wormlike micelle, are found to be in good agreement with experimental measurements, which effectively validates the simulation models and employed force fields. Detailed analyses of molecular packing reveal that these self-assembled nanostructures all consist of a hydrophobic core constructed of lipid chains, a transitional layer, and a hydrophilic interfacial layer composed of peptide sequences. The average area per peptide head at the interfaces is found to be nearly constant for all micellar structures studied. The packing parameter of the lipopeptide molecules thus increases with the increase of the number of linked lipid chains, giving rise to the distinct micellar shape transition from spherical-like to flattened wormlike geometry with bilayer stacking, which is qualitatively different from the shape transitions of surfactant micelles induced by variation of concentration or salt type. To facilitate the close-packing of the lipid chains in the hydrophobic core, the lipopeptide molecules typically take the bent conformation with average tilt angles between the peptide sequences and the lipid chains ranging from 110 degrees to 140 degrees . This consequently affects the orientation angles of the lipid chains with respect to the radial or normal direction of the spherical-like or flattened wormlike micelles. In addition, the secondary structures of the peptides may also be altered by the number of lipid chains to which they are linked and the resultant micellar structures. Our simulation results on the microscopic structural features of the lipopeptide nanostructures may provide potential insights into their bioactivities and contribute to the design of bioactive medicines or drug carriers. The force fields built for these lipopeptides and the geometric packing discussions could also be adopted for simulating and understanding the self-assembly behavior of other bioactive amiphiphiles with similar chemical compositions. PMID- 30253108 TI - Temperature and serine phosphorylation regulate glycerol-3-phosphate dehydrogenase in skeletal muscle of hibernating Richardson's ground squirrels. AB - Glycerol-3-phosphate dehydrogenase (G3PDH) bridges carbohydrate and lipid metabolism by interconverting glycerol-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP). This reversible reaction converts G3P derived from triglyceride hydrolysis to DHAP that can then enter glycolysis or gluconeogenesis and, in the reverse reaction, makes G3P for use in triglyceride biosynthesis. Small hibernating mammals rely almost exclusively on triglyceride reserves as their fuel for energy production during torpor and the recovery of glycerol after lipolysis is an important source of carbohydrate over the non-feeding winter months. G3PDH (~37 kDa) was purified from skeletal muscle of euthermic and hibernating Richardson's ground squirrels (Urocitellus richardsonii) using three column chromatography steps. Analysis of enzyme kinetic properties revealed that G3PDH from hibernator muscle had higher affinities for G3P and NAD at low (5 degrees C) assay temperature compared to high (21 degrees C or 37 degrees C), and a greater stability in the presence of denaturing agents (urea, guanidine hydrochloride) or high temperature (50 degrees C). Immunoblotting showed that hibernator muscle G3PDH had a higher phosphoserine content than the enzyme from euthermic controls and incubation studies showed that enzyme affinity for G3P changed significantly by stimulating endogenous protein kinases or phosphatases. Overall, this study suggests that the properties of ground squirrel muscle G3PDH are modulated by temperature and post-translational phosphorylation to alter enzyme function under euthermic versus hibernating states. PMID- 30253109 TI - AMPK activation by A-769662 and 991 does not affect catecholamine-induced lipolysis in human adipocytes. AB - Activation of AMP-activated protein kinase (AMPK) is considered an attractive strategy for the treatment of type 2 diabetes. Favorable metabolic effects of AMPK activation are mainly observed in skeletal muscle and liver tissue whereas the effects in human adipose tissue are only poorly understood. Previous studies, which largely employed the AMPK activator 5-aminoimidazole-4-carboxamide-1-D ribofuranoside (AICAR), suggest an anti-lipolytic role of AMPK in adipocytes. The aim of this work was to re-investigate the role of AMPK in the regulation of lipolysis, using the novel allosteric small-molecule AMPK activators A-769662 and 991, with a focus on human adipocytes. For this purpose, human primary subcutaneous adipocytes were treated with A-769662, 991 or AICAR, as a control, before being stimulated with isoproterenol. AMPK activity status, glycerol release and the phosphorylation of hormone-sensitive lipase (HSL), a key regulator of lipolysis, was then monitored. Our results show that both A-769662 and 991 activated AMPK to a level which was similar to, or greater than that induced by AICAR. In contrast to AICAR, which as expected was anti-lipolytic, neither A-769662 nor 991 affected lipolysis in human adipocytes, although 991 treatment lead to altered HSL phosphorylation. Furthermore, we suggest that HSL Ser660 is an important regulator of lipolytic activity in human adipocytes. These data suggest that the anti-lipolytic effect observed with AICAR in previous studies is, at least to some extent, AMPK-independent. PMID- 30253110 TI - Increased bone mass in a mouse model with low fat mass. AB - Mice with impaired acute inflammatory responses within adipose tissue display reduced diet-induced fat mass gain associated with glucose intolerance and systemic inflammation. Therefore, acute adipose tissue inflammation is needed for a healthy expansion of adipose tissue. Because inflammatory disorders are associated with bone loss, we hypothesized that impaired acute adipose tissue inflammation leading to increased systemic inflammation results in a lower bone mass. To test this hypothesis, we used mice overexpressing an adenoviral protein complex - the receptor internalization and degradation (RID) complex that inhibits pro-inflammatory signaling - under the control of the aP2-promotor (RID tg mice), resulting in suppressed inflammatory signaling in adipocytes. As expected, RID tg mice had a lower high-fat diet-induced weight and fat mass gain and higher systemic inflammation than their littermate wild type controls. Contrary to our hypothesis, the RID tg mice had increased bone mass in long bones and vertebrae, affecting trabecular and cortical parameters, as well as improved humeral biomechanical properties. We did not find any differences in bone formation or resorption parameters as determined by histology or enzyme immunoassay. However, bone marrow adiposity, often negatively associated with bone mass, was decreased in male RID tg mice as determined by histological analysis of tibia. In conclusion, mice with reduced fat mass, due to impaired adipose tissue inflammation, have increased bone mass. PMID- 30253111 TI - Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice. AB - Brain-derived neurotrophic factor (BDNF) is a key neuropeptide in the central regulation of energy balance. The Bdnf gene contains nine promoters, each producing specific mRNA transcripts that encode a common protein. We sought to assess the phenotypic outcomes of disrupting BDNF production from individual Bdnf promoters. Mice with an intact coding region but selective disruption of BDNF production from Bdnf promoters I, II, IV or VI (Bdnf-e1-/-, -e2-/-, -e4-/-, and e6-/-) were created by inserting a GFP-STOP cassette upstream of the targeted promoter splice donor site. Body composition was measured by MRI weekly from age 4-22 weeks. Energy expenditure was measured by indirect calorimetry at 18 weeks. Food intake was measured in Bdnf-e1-/- and Bdnf-e2-/- mice, and pair-feeding was conducted. Weight gain, lean mass, fat mass, and percent fat of Bdnf-e1-/- and Bdnf-e2-/- mice (both sexes) were significantly increased compared to wild-type littermates. For Bdnf-e4-/- and Bdnf-e6-/- mice, obesity was not observed with either chow or high fat diet. Food intake was increased in Bdnf-e1-/- and Bdnf-e2 /- mice, and pair-feeding prevented obesity. Mutant and wild-type littermates for each strain (both sexes) had similar total energy expenditure after adjusting for body composition. These findings suggest that the obesity phenotype observed in Bdnf-e1-/- and Bdnf-e2-/- mice is attributable to hyperphagia and not altered energy expenditure. Our findings show that disruption of BDNF from specific promoters leads to distinct body composition effects, with disruption from promoters I or II, but not IV or VI, inducing obesity. PMID- 30253112 TI - The Prenatal Rating of Efficacy in Preparation to Breastfeed Scale: A New Measurement Instrument for Prenatal Breastfeeding Self-efficacy. AB - BACKGROUND: Breastfeeding self-efficacy and breastfeeding intention are two modifiable factors that influence rates of breastfeeding initiation. Research Aims: (1) To develop a scale to measure prenatal breastfeeding self-efficacy, and (2) test its psychometric properties by determining the internal consistency and reliability, and (3) assess the relationships between prenatal breastfeeding self efficacy and breastfeeding intention. METHODS: Cross-sectional prospective one group survey design was used. A convenience sample of pregnant patients attending an obstetrics and gynecology clinic ( N=124) completed a survey at the recruitment site that assessed demographics, breastfeeding intention, and breastfeeding self-efficacy theory constructs. Retest surveys ( n=14) were taken home and returned to the researcher by mail after completion. RESULTS: Cronbach's alpha for the 39-item scale was .98 (test) and .97 (retest) with an item-to-total correlation range of .54 to .78. A four-factor solution for the scale was retained. Test-retest indicated each factor was significant and highly correlated: Individual Processes (.88, p < .001), Interpersonal Processes (.893, p < .001), Professional Advice (.919, p < .001), and Social Support (.880, p < .001). Overall prenatal breastfeeding self-efficacy score was highly correlated (.610, p <.001) with breastfeeding intention scores. CONCLUSIONS: The Prenatal Rating of Efficacy in Preparation to Breastfeed Scale is a valid and reliable measure of a prenatal women's self-efficacy in preparation to breastfeed. Measuring the level of self-efficacy could alert prenatal women and health professionals to individual skill sets. PMID- 30253113 TI - Genetic Variation of the Pathogen Causing Impatiens Downy Mildew Predating and Including Twenty-first Century Epidemics on Impatiens walleriana. AB - Impatiens downy mildew (IDM) of cultivated Impatiens walleriana has had a significant economic impact on the ornamental horticulture industry in the United States and globally. Although recent IDM outbreaks started in 2003, downy mildews on noncultivated Impatiens species have been documented since the 1880s. To understand the relationship between the pathogen causing recent epidemics and the pathogen historically present in the United States, this work characterized genetic variation among a collection of 1,000 samples on 18 plant hosts. Samples included collections during recent IDM epidemics and historical herbarium specimens. Ten major genotypes were identified from cloned rDNA amplicon sequencing and endpoint SNP genotyping. Three genotypes accounted for >95% of the samples, with only one of these three genotypes found on samples predating recent IDM outbreaks. Based on phylogenetic analysis integrating data from three markers and the presence of individual genotypes on multiple Impatiens species, there was some evidence of pathogen-specific infection of I. noli-tangere, but the distinction between genotypes infecting I. walleriana and I. balsamina was not upheld. Overall, this work provides evidence that the majority of rDNA genotypes recovered from recent IDM epidemics are different from historical U.S. genotypes, and that these genotypes can infect Impatiens spp. other than I. walleriana. PMID- 30253114 TI - Identification and Characterization of Fungal Pathogens Causing Fruit Rot of Deciduous Holly. AB - Cut branches of deciduous holly (Ilex spp. L.) harboring colorful berries are traditionally used as ornaments in holiday decorations. Since 2012, a fruit rot of unspecified cause has resulted in significant yield reduction and economic losses across Midwestern and Eastern U.S. nurseries. In this study, symptomatic fruit samples collected from nine different locations over five years were analyzed, and several fungal species were isolated. A combination of morphological characterization, multilocus phylogenetic analyses, and pathogenicity assays revealed that Alternaria alternata and Diaporthe ilicicola sp. nov. were the primary pathogens associated with symptomatic fruit. Other fungi including A. arborescens, Colletotrichum fioriniae, C. nymphaeae, Epicoccum nigrum, and species in the D. eres species complex appeared to be minor pathogens in this disease complex. In detached fruit pathogenicity assays testing the role of wounding and inoculum concentration on disease development, disease incidence and severity increased when fruit was wounded and inoculated with a higher inoculum concentration. These findings indicate that management strategies that can protect fruit from injury or reduce inoculum may lower disease levels in the field. This research established the basis for further studies on this emerging disease and the design of research-based management strategies. To our knowledge, it also represents the first report of species of Alternaria, Colletotrichum, Diaporthe, and Epicoccum causing fruit rot of deciduous holly. PMID- 30253115 TI - Codex Alimentarius: What Has It To Do With Me? PMID- 30253116 TI - Long-Lasting Primed State in Maize Plants: Salicylic Acid and Steroid Signaling Pathways as Key Players in the Early Activation of Immune Responses in Silks. AB - In the present study, we investigated the induced systemic resistance (ISR) activated by the beneficial fungus Trichoderma atroviride in maize plants, and the early immunological responses triggered after challenge with the ear rot pathogen Fusarium verticillioides. By transcriptional analysis, we were able to identify the gene core set specifically modulated in silks of maize plants expressing ISR. Our results showed that the main transcriptional reprogramming falls into genes involved in five main functional categories: cell structure or cell wall, amino acid and protein metabolism, stress responses, signaling, and transport. Among these ISR-related genes, it is important to highlight novel findings regarding hormone metabolism and signaling. The expression of hormone dependent genes was in good agreement with the abscisic acid, jasmonic acid, and salicylic acid (SA) levels detected in the plants under study. The experimental design allowed the identification of novel regulatory elements related to a heightened state of defense in silks and suggests that steroids and SA are central components of a master regulatory network controlling the immunity of silks during ISR. The results presented also provide evidence about the molecular mechanisms used by maize silks against F. verticillioides to counteract pathogenic development and host invasion, including pathogenesis-related genes, plant cell-wall reinforcement, fungal cell-wall-degrading enzymes and secondary metabolism. PMID- 30253117 TI - Cautionary Notes on Use of the MoT3 Diagnostic Assay for Magnaporthe oryzae Wheat and Rice Blast Isolates. AB - The blast fungus Magnaporthe oryzae is comprised of lineages that exhibit varying degrees of specificity on about 50 grass hosts, including rice, wheat and barley. Reliable diagnostic tools are essential given that the pathogen has a propensity to jump to new hosts and spread to new geographic regions. Of particular concern is wheat blast, which has suddenly appeared in Bangladesh in 2016 before spreading to neighboring India. In these Asian countries, wheat blast strains are now co-occurring with the destructive rice blast pathogen raising the possibility of genetic exchange between these destructive pathogens. We assessed the recently described MoT3 diagnostic assay and found that it did not distinguish between wheat and rice blast isolates from Bangladesh. The assay is based on primers matching the WB12 sequence corresponding to a fragment of the M. oryzae MGG_02337 gene annotated as a short chain dehydrogenase. These primers could not reliably distinguish between wheat and rice blast isolates from Bangladesh based on DNA amplification experiments performed in separate laboratories in Bangladesh and in the UK. Specifically, all eight rice blast isolates tested in this study produced the WB12 amplicon. In addition, comparative genomics of the WB12 nucleotide sequence revealed a complex underlying genetic structure with related sequences across M. oryzae strains and in both rice and wheat blast isolates. We, therefore, caution against the indiscriminate use of this assay to identify wheat blast and encourage further development of the assay to ensure its value in diagnosis. PMID- 30253118 TI - Inheritance of Resistance to Colletotrichum gloeosporioides and C. acutatum in Strawberry. AB - Information on the inheritance of resistance to Colletotrichum gloeosporioides and C. acutatum hemi-biotrophic infections (HBI) in strawberry leaf tissue and the genetic control of anthracnose crown rot (ACR) in crown tissue are relatively unknown. Six parental genotypes were crossed in a half diallel mating design to generate 15 halffull-sib families. HBI and ACR experiments were conducted concurrently. Both seedlings and parental clones were inoculated with 1*106 conidia/ml of C. gloeosporioides or C. acutatum. Percent sporulating leaf area (PSLA), wilt symptoms, and relative area under the disease progress curve (rAUDPC) were calculated to characterize resistance among genotypes and halffull sib families. Low dominance to additive variance ratios for C. acutatum HBI (0.13) and C. gloeosporioides ACR (0.20) were observed, indicating additive genetic effects forcontrol of resistance to these traits. Heritability (H2h2) estimates were low for C. acutatum HBI (0.25) and C. gloeosporioides HBI (0.16) but moderate for C. gloeosporioides ACR (0.61). A high genetic correlation (rA = 0.98) between resistance to C. acutatum HBI and C. gloeosporioides HBI was observed, suggesting that resistance to these two Colletotrichum species may be controlled by common genes in strawberry leaf tissue. In contrast, negative genetic correlations between ACR and both HBI traits (rA = -0.85 and -0.61) suggest that resistance in crown tissue is inherited independently of resistance in leaf tissue in the populations tested. Overall, these findings provide valuable insight into the genetic basis of resistance, and the evaluation and deployment of resistance to HBIs and ACR in strawberry breeding programs. PMID- 30253119 TI - Genotyping of Phytophthora infestans in eastern-Africa reveals a dominating invasive European lineage. AB - Strains of Phytophthora infestans, the pathogen causing late blight of potato and tomato, are thought to be moved around the world through infected planting material. Since its first appearance in 1941, late blight has caused important losses to potato production in the eastern-Africa region (EAR). In the current study, the genetic structure of the population in Kenya, Uganda, Tanzania, Burundi and Rwanda was characterized using 12-plex microsatellite markers with the aim of testing the hypothesis that, a strain originating from Europe, 2_A1, has recently dominated the population in EAR. Analyses of 1,093 potato and 165 tomato samples collected between 2013 and 2016 revealed the dominance on potato in all countries of the 2_A1 clonal lineage. On tomato, a host-specialized form of the US-1 appears to persist in Rwanda, Uganda, and Tanzania, while in Kenya most samples from tomato (72.5%) were 2_A1. The US-1 lineage in Tanzania had two private alleles at the Pi02 marker, suggesting a possible independent introduction into the region. US-1 had higher genetic variability than 2_A1, consistent with the earlier establishment of the former. Continuous tracking of P. infestans population changes should help identify new virulent and aggressive strains, which would inform strategic disease management options. PMID- 30253120 TI - Fetal bovine serum promotes the development of invitro porcine blastocysts by activating the Rho-associated kinase signalling pathway. AB - Fetal bovine serum (FBS) supplementation has beneficial effects on in vitro porcine embryonic development, but the underlying mechanisms are unclear. In the present study we found that the addition of FBS to PZM-3 increased the number of cells in porcine blastocysts and hatching rate in vitro primarily by promoting proliferation of the inner cell mass and further differentiation. Moreover, based on the following results, we surmise that FBS benefits blastocyst development by activating Rho-associated kinase (ROCK) signalling: (1) the ROCK signalling inhibitor Y-27632 decreased the blastocyst rate and the number of cells in blastocysts, whereas FBS rescued the developmental failure induced by Y-27632; (2) the mRNA levels of two ROCK isoforms, ROCK1 and ROCK2, were significantly increased in blastocysts derived from medium containing FBS; and (3) FBS increased RhoA/Rho-kinase expression in the nucleus of embryonic cells. These results indicate that FBS promotes the in vitro development of porcine embryos by activating ROCK signalling in a chemically defined medium. PMID- 30253121 TI - Cell type-specific endometrial transcriptome changes during initial recognition of pregnancy in the mare. AB - Previous endometrial gene expression studies during the time of conceptus migration did not provide final conclusions on the mechanisms of maternal recognition of pregnancy (MRP) in the mare. This called for a cell type-specific endometrial gene expression analysis in response to embryo signals to improve the understanding of gene expression regulation in the context of MRP. Laser capture microdissection was used to collect luminal epithelium (LE), glandular epithelium and stroma from endometrial biopsies from Day 12 of pregnancy and Day 12 of the oestrous cycle. RNA sequencing (RNA-Seq) showed greater expression differences between cell types than between pregnant and cyclic states; differences between the pregnant and cyclic states were mainly found in LE. Comparison with a previous RNA-Seq dataset for whole biopsy samples revealed the specific origin of gene expression differences. Furthermore, genes specifically differentially expressed (DE) in one cell type were found that were not detectable as DE in biopsies. Overall, this study revealed spatial information about endometrial gene expression during the phase of initial MRP. The conceptus induced changes in the expression of genes involved in blood vessel development, specific spatial regulation of the immune system, growth factors, regulation of prostaglandin synthesis, transport prostaglandin receptors, specifically prostaglandin F receptor (PTGFR) in the context of prevention of luteolysis. PMID- 30253122 TI - The diagnostic value of serum UCHL-1 and S100-B levels in differentiate epileptic seizures from psychogenic attacks. AB - OBJECTIVE: To assess the value of postictal serum Ubiquitin C-terminal hydrolase (UCHL-1), a neuronal biomarker, and S100-B, a glial biomarker, levels, in differentiate epileptic seizures (ES) form psychogenic attacks. METHODS: In this analytical cross-sectional study, serum UCHL-1 and S100-B levels were measured within six hours of occurring seizure, in 43 patients with ES, 20 patients with psychogenic non-epileptic seizures (PNES) and 19 healthy individuals by electrochemiluminescence immunoassay. RESULTS: Both serum UCHL-1 and S100-B levels were significantly higher in patients with ES than PNES (P<0.05) and controls (P<0.01). PNES patients had significantly higher serum S100-B levels compared to controls (P<0.01). There was a significant correlation between the serum UCHL-1 and S100-B levels in patients with ES (r=0.46, P=0.002). CONCLUSIONS: Our study showed that serum UCHL-1 level could be potentially used in differentiate ES from PNES (sensitivity 72%, specificity 59%). Serum S100-B level had lower value compared to UCHL-1 (AUC 0.68 for UCHL-1 v/s 0.59 for S100B). Post-seizure serum UCHL-1 and S100-B levels could be used in future studies to better understand the underlying mechanism of seizures and may offer as an adjunctive diagnostic test in differentiate ES from PNES. PMID- 30253124 TI - The basolateral amygdala orexin 1 and 2 receptors' involvement in modulating spatial reference memory. PMID- 30253123 TI - Dendrobiumpolysaccharides attenuate cognitive impairment in senescence accelerated mouse prone 8 mice via modulation of microglial activation. AB - Dendrobium is one of the most important traditional Chinese medicinal foods used to treat age-related disorders. However, it remains unclear whether Dendrobium affects the progression of Alzheimer's disease (AD). In the present study, we investigated the effects of Dendrobium officinale polysaccharides (DOP) on the BV2 microglial cell line and the senescence-accelerated mouse prone 8 (SAMP8) mouse strain. In vitro experiments showed that DOP pretreatment contributed to BV2 cells shifting from proinflammatory to anti-inflammatory phenotypes with enhanced Abeta clearance in response to Abeta insults. For the in vivo study, mice were chronically treated with DOP in drinking water from 4 to 7 months of age. The results showed that DOP remarkably attenuated cognitive decline in SAMP8 mice. DOP also inhibited the increased hippocampal microglial activation in SAMP8 mice with downregulation of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6), while interleukin-10 (IL-10), neprilysin (NEP) and insulin-degrading enzyme (IDE) were upregulated. The accumulation of hippocampal Abeta42 and phosphated Tau proteins in SAMP8 mice was also reduced. Taken together, our data suggest that Dendrobium has the potential to provide neuroprotection against AD-related cognitive impairment via modulation of microglial activation. PMID- 30253126 TI - Fluorometric detection of influenza viral RNA using graphene oxide. AB - Simple and reliable detection of influenza viruses is important for timely prescription of antiviral therapy. Here, we developed a facile fluorometric system for detection of influenza subtype viral genes using graphene oxide (GO). A fluorescent DNA probe complementary to hemagglutinin gene of influenza virus is degraded by the 5' to 3' exonuclease activity of Taq polymerase during PCR. Upon addition of GO, the released fluorophore retains fluorescence without adsorption onto GO, whereas the intact fluorescent DNA probe is adsorbed onto GO with fluorescence quenching. Our multi well plate system can detect as low as 3.8 pg of influenza viral RNA. PMID- 30253125 TI - Testo and testo-Pt(II) bind DNA at different locations. AB - The development of new targeted anticancer agents able to efficiently and specifically destroy cancer cells with minimal toxic side effects is nowadays a subject of intensive research endeavors. We report the conjugation of testo and testo-Pt(II) (two semi-synthetic testosterone derivatives) with calf thymus DNA in aqueous solution at physiological pH. Multiple spectroscopic methods, thermodynamic analysis and modeling were used to determine the binding efficacy of these drugs to DNA duplex. Thermodynamic parameters showed drug-DNA conjugation occurs via ionic interactions with testo-Pt(II) forming more stable DNA adducts than testo with Ktesto-DNA = 1.80 (+/-0.5) x 105 M-1 and Ktesto Pt(II)-DNA = 2.3 (+/-0.8) x 105 M-1. Molecular modeling shows that testo and testo-Pt(II) bind DNA at different locations. PMID- 30253127 TI - Effects of mono- and di-valent metal cations on the morphology of lipid vesicles. AB - Lipid vesicles are an attractive model membrane experimental platform that is widely used in a biological context. The stability of vesicles can affect their performance and depends on various experimental conditions. How bio-related ions affect vesicle morphology is poorly understood in some cases. Herein, we investigated changes in vesicle morphology influenced by cation in the static and flowing environments. The effects of different mono- and di-valent metal cations on the morphology of lipid vesicles were systematically studied using the various techniques. The results showed that divalent cations caused significant aggregation or fusion of lipid vesicles, but monovalent cations had little effect on the vesicle morphology. Cation binding increased the net surface potential of vesicles, leading to changes in the zeta potential. The same qualitative kinetics were observed for cations that had the same valence at the same ionic strength. However, different types of cations gave different quantitative effects. The order of the ability to destroy the vesicle morphology was Cu2+ > Mg2+ > Ca2+ > Na+ > K+. These results are of practical value in the use of lipid vesicles as a bionic model, and help to shed light on the role of ions at membrane surfaces and interfaces. PMID- 30253128 TI - The effect of pH on the lytic activity of a synthetic mastoparan-like peptide in anionic model membranes. AB - Peptide sequences containing acidic and basic residues could potentially have their net charges modulated by bulk pH with a possible influence on their lytic activity in lipid vesicles. The present study reports on a biophysical investigation of these modulatory effects on the synthetic mastoparan-like peptide L1A (IDGLKAIWKKVADLLKNT-NH2). At pH 10.0 L1A was 6 times more efficient in lysing large anionic (1-palmitoyl-oleoyl-sn-glycero-3-phosphocholine (POPC):1 palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG)/(8:2)) unilamellar vesicles (LUVs) than at pH 4.0. Despite the reduction of 60% in the L1A net charge in basic pH its affinity for this vesicle was almost insensitive to pH. On the other hand, L1A insertion into monolayers was dramatically influenced by subphase condition, showing that, in the neutral and basic subphases, the peptide induced surface pressure changes that surpassed the membrane lateral pressure, being able to destabilize a bilayer structure. In addition, in the basic subphase, visualization of the compression isotherms of co-spread 1,2-dipalmitoyl sn-glycero-3-phosphocholine (DPPC):POPG (8:2) + 4.8 mol% L1A showed that the peptide induced significant changes in solid lipid domains, indicating its capability in perturbing lipid-packing. An insight into L1A lytic activity was also obtained in giant unilamellar vesicles (GUVs) using phase contrast microscopy. The suppression of L1A lytic activity at acidic pH is in keeping with its lower insertion capability and ability to disturb the lipid monolayer. The lytic activity observed under neutral and basic conditions showed a quick and stochastic leakage following a lag-time. The permeability and the leakage-time averaged over at least 14 single GUVs were dependent on the bulk condition. At basic pH, permeability is higher and quicker than in a neutral medium in good accordance with the lipid-packing perturbation. PMID- 30253129 TI - Personality Traits, State Positive and Negative Affect, and Professional Quality of Life in Neonatal Nurses. AB - OBJECTIVE: To explore the relationships of core self-evaluations of personality (self-esteem, generalized self-efficacy, emotional stability, and internal locus of control), the five-factor model personality traits (neuroticism, agreeableness, extraversion, conscientiousness, and openness), and positive and negative affect with neonatal nurses' professional quality of life (burnout, secondary traumatic stress, and compassion satisfaction). DESIGN: Cross-sectional cohort study. SETTING: Four Level 3-4 NICUs in New South Wales, Australia. PARTICIPANTS: One hundred forty-two (35%) of 405 eligible neonatal nurses. METHODS: Online self-report measures of personality traits, positive and negative affect, and professional quality of life. RESULTS: Core self-evaluations explained 33%, 21%, and 26% of the variance in burnout, secondary traumatic stress, and compassion satisfaction, respectively. After controlling for core self-evaluations, agreeableness, neuroticism, and extraversion contributed to the respective variances in burnout, secondary traumatic stress, and compassion satisfaction. After controlling for core self-evaluations and the five-factor model personality traits, positive affect contributed to the variance in burnout and compassion satisfaction, whereas negative affect contributed to the variance in secondary traumatic stress. No five-factor model personality trait contributed to the variance in professional quality of life in the final regression models. Positive affect mediated the effect of core self-evaluations on burnout and compassion satisfaction, whereas negative affect mediated the effect of core self evaluations on secondary traumatic stress. CONCLUSION: Neonatal nurses should be aware of and accept responsibility for personality traits and moods that benefit or detract from their professional quality of life. NICU nurse managers should ensure that neonatal nurses have ready access to psychological support services. PMID- 30253130 TI - SIKE of black carp is a substrate of TBK1 and suppresses TBK1-mediated antiviral signaling. AB - RIG-I like receptor (RLR) signaling functions importantly in host innate immune response against RNA virus, which is tightly regulated by a number of mechanisms to prevent aberrant interferon production. The suppressor of IKKepsilon (SIKE) has been identified as a suppressor of IKKepsilon and TBK1, which are key components of RLR signaling. In this study, SIKE homologue (bcSIKE) of black carp (Mylopharyngodon piceus) has been cloned and characterized. The transcription of bcSIKE varied in host cells in response to the stimulation of LPS, poly (I:C) and viruses. bcSIKE migrated around 27 KDa in immunoblot assay and distributed in both cytoplasm and nucleus of host cell in immunofluorescent (IF) staining test. bcSIKE showed no IFN-inducing ability in reporter assay and EPC cells expressing bcSIKE showed no enhanced antiviral ability against either grass carp reovirus (GCRV) or spring viremia of carp virus (SVCV). However, bcSIKE obviously dampened the IFN-inducing ability of RLR signaling members in reporter assay when bcSIKE was co-expressed with these molecules in EPC cells. The association between bcSIKE and bcTBK1 has been identified through IF and co-immunoprecipitation (co IP) assay. The plaque assay demonstrated clearly that bcTBK1-mediated antiviral activity in EPC cells against both GCRV and SVCV was down regulated by bcSIKE. All the data generated in this paper support the conclusion that bcSIKE interacts with bcTBK1 and inhibits bcTBK1-mediated antiviral signaling during host innate immune activation, which is reported in teleost for the first time. PMID- 30253131 TI - The sensory amphidial structures of Caenorhabditis elegans are involved in macrocyclic lactone uptake and anthelmintic resistance. AB - Parasitic nematodes represent formidable pathogens of humans, livestock and crop plants. Control of these parasites is almost exclusively dependent on a small group of anthelmintic drugs, the most important of which belong to the macrocyclic lactone class. The extensive use of these drugs to control the ubiquitous trichostrongylid parasites of grazing livestock has resulted in the emergence of both single and multi-drug resistance. The expectation is that this resistance will eventually occur in the human parasites such as the common and debilitating soil transmitted nematodes and vector-borne filarial nematodes. While the modes of action of anthelmintics such as ivermectin, have been elucidated, notably in the model nematode Caenorhabditis elegans, the molecular nature of this resistance remains to be fully determined. Here we show that the anterior amphids play a key role in ivermectin uptake and mutations in these sensory structures result in ivermectin resistance in C. elegans. Random genetic mutant screens, detailed analysis of existing amphid mutants and lipophilic dye uptake indicate that the non-motile ciliated amphid neurons are a major route of ivermectin ingress; the majority of the mutants characterised in this study are predicted to be involved in intraflagellar transport. In addition to a role in ivermectin resistance, a subset of the amphid mutants are resistant to the non related benzimidazole class of anthelmintics, raising the potential link to a multi-drug resistance mechanism. The amphid structures are present in all nematodes and are clearly defined in a drug-sensitive strain of Haemonchus contortus. It is predicted that amphidial drug uptake and intraflagellar transport may prove to be significant in the development of single and multi-drug resistance in the nematode pathogens of veterinary and human importance. PMID- 30253132 TI - Linezolid resistance genes and genetic elements enhancing their dissemination in enterococci and streptococci. AB - Linezolid is considered a last resort drug in treatment of severe infections caused by Gram-positive pathogens, resistant to other antibiotics, such as vancomycin-resistant enterococci (VRE), methicillin-resistant staphylococci and multidrug resistant pneumococci. Although the vast majority of Gram-positive pathogenic bacteria remain susceptible to linezolid, resistant isolates of enterococci, staphylococci and streptococci have been reported worldwide. In these bacteria, apart from mutations, affecting mostly the 23S rRNA genes, acquisition of such genes as cfr, cfr(B), optrA and poxtA, often associated with mobile genetic elements (MGE), plays an important role for resistance. The purpose of this paper is to provide an overview on diversity and epidemiology of MGE carrying linezolid-resistance genes among clinically-relevant Gram-positive pathogens such as enterococci and streptococci. PMID- 30253133 TI - Contribution of neutral sphingomyelinases to in vitro virulence of Entamoeba histolytica. AB - Amoebiasis is a worldwide health problem caused by the pathogen Entamoeba histolytica. Several virulence factors have been implicated in host invasion, immune evasion, and tissue damage. There are still new factors that remain to be elucidated and characterized. In this work, we obtained amoebic transfectants overexpressing three of the neutral sphingomyelinase enzymes encoded in the E. histolytica genome. The EhnSM3 overexpression induced an increase in hemolytic and cytotoxic activities, besides an increase in gene expression of amoebapore A, B, and C. Meanwhile the EhnSM1 and EhnSM2 overexpression caused an increase in cytopathic activity. In all the neutral sphingomyelinases overexpressing strains, the gene expression levels for cysteine proteinase 5, adhesin 112 and, heavy and light Gal/GalNAc lectin subunits were not affected. We propose that the increase of cytotoxic and lytic effect of EhnSM3 overexpressed strain can be related to the sum of the effect of EhnSM3 plus amoebapores, in a process cell contact dependent or as mediator by inducing the gene expression of amoebapores enabling a link between EhnSM3 with the virulence phenotype in E. histolytica. Our results suggest a differential role for neutral sphingomyelinases in E. histolytica virulence. PMID- 30253135 TI - Tat-HA-NR2B9c attenuate oxaliplatin-induced neuropathic pain. AB - Oxaliplatin is a commonly used chemotherapy drug, which can produce acute and chronic peripheral neurotoxicity. Currently, there is no good therapeutic drug in clinic. Excessive stimulation of N-methyl-d-aspartate receptors (NMDARs) is crucial for the transmission of pain signals. However, directly inhibiting NMDARs can cause severe side effects because they have key physiological functions in the Central nervous system (CNS). Several years ago, we prepared a polypeptide Tat-HA-NR2B9c which can disturb NMDARs-postsynaptic density protein-95 (PSD-95) interaction. In this study, we studied whether Tat-HA-NR2B9c could be an effective treatment for oxaliplatin-induced neuropathic pain. To conform it, a rat model of oxaliplatin-induced neuropathic was established, and analgesic effect of Tat-HA-NR2B9c was studied. Here, we show that oxaliplatin induces the interaction of NMDARs with PSD-95. Uncoupling the complex by Tat-HA-NR2B9c has potent analgesic effect in oxaliplatin-induced cold hyperalgesia and mechanical allodynia without suppressing general behavioral. Tat-HA-NR2B9c neither inhibits NMDARs function nor impacts antitumor activity of oxaliplatin. Thus, this new drug may serve as a treatment for oxaliplatin-induced neuropathic pain, perhaps without major side effects. PMID- 30253134 TI - Propranolol efficacy as a novel adjuvant for immunization against Toxoplasma gondii tachyzoites. AB - Severe or lethal damages, caused by Toxoplasma gondii infection in congenital cases and immunocompromised patients implies the necessity for development of a vaccine and an appropriate adjuvant would be needed to elicit a protective Th1 biased-immune response. The adjuvant activity of propranolol was surveyed and compared with alum by immunization of BALB/c mice with protein components of T. gondii tachyzoites. Five groups of BALB/c mice were immunized with phosphate buffered saline (negative control), Toxoplasma lysate antigen (TLA), alum plus TLA, Propranolol plus TLA, and alum, propranolol and TLA. Immunization efficacy was evaluated by lymphocyte proliferation and DTH tests, challenge with live tachyzoites, IFN-gamma production by spleen cells, serum TNF-alpha concentration and anti- Toxoplasma total IgG, IgG1 and IgG2a measurements. Mice of the PRP-TLA group induced significantly more IFN-gamma and TNF-alpha production and lymphocyte proliferation than other groups. This group of mice also showed more anti-T. gondii IgG2a and DTH responses and showed a significantly increased survival time after challenge. These findings indicate that propranolol as an adjuvant in combination with TLA, may enhance cellular immunity against T. gondii. PMID- 30253136 TI - The Aging Lung: Is Lung Health Good Health for Older Adults? AB - The prevalence of lung conditions, such as COPD and pulmonary fibrosis, and lung infections, such as pneumonia, increases sharply with age. The physiologic, cellular, and immunologic changes that occur during aging contribute to the development of lung disease. Studies of age-related changes in physiology and function are not only key to preventing or ameliorating disease, they are also essential for understanding healthy aging. Individuals with good lung function live longer, healthier lives, although the mechanisms by which this scenario occurs are not understood. The present article reviews changes in the aging lung that facilitate development of disease and the evidence supporting the idea that robust lung function reduces the risk of developing chronic inflammatory conditions that occur with age. PMID- 30253137 TI - Acclimation of C2C12 myoblasts to physiological glucose concentrations for in vitro diabetes research. AB - AIMS: The interplay between hyper-glycemia and -lipidemia in diabetes mellitus (DM) is important in simulating diabetic conditions. However, cell culture media typically contain supraphysiological levels of glucose to stimulate cellular growth, which also desensitizes cells to elevated glucose levels. Moreover, creating hyperlipidemic conditions in vitro requires specialized carriers because unbound lipids form micelles when introduced to liquid media. This study sought to develop a novel method for simulating DM conditions in vitro. MATERIALS AND METHODS: We acclimated the C2C12 mouse myoblasts to culture medium with 5.6 mM glucose, which mimics physiological levels, and created a bovine serum albumin palmitic acid conjugate for lipid transport to explore the effects of hyperlipidemia. We simulated diabetic conditions in vitro by using both hyper glycemic and -lipidemic conditions and compared the results to that of only hyperglycemic or hyperlipidemic conditions. KEY FINDINGS: Acclimated cells exposed to these hyper-glycemic (15 mM glucose) and/or -lipidemic (0.25 mM palmitate) conditions for 2 h showed increased mitochondrial fragmentation and membrane potential as well as elevated reactive oxygen species production compared to control cells. These findings suggest altered mitochondrial morphology and function, which have been confirmed using isolated rat flexor digitorum brevis myofibers. Hyper-glycemic and/or -lipidemic stimulations for 24 h significantly increased mitogen-activated protein kinase kinase MEK 1/2 protein expression, upregulated the early pro-apoptotic transcription factor C/EBP homologous protein (CHOP), and induced apoptosis. SIGNIFICANCE: Our results further support and confirm the utility of this method which will allow for subsequent investigations studying the effects of hyper-glycemia and/or lipidemia in vitro. PMID- 30253138 TI - Carrying capacity of a spatially-structured population: Disentangling the effects of dispersal, growth parameters, habitat heterogeneity and habitat clustering. AB - Carrying capacity, K, is a fundamental quantity in theoretical and applied ecology. When populations are distributed over space, carrying capacity becomes a complicated function of local, global and nearby environments, dispersal rate, and the relationship between population growth parameters, e.g., r and K. Expressions for the total carrying capacity, Ktotal, in an n-patch model that explicitly disentangle all of these factors are currently lacking. Therefore, here we derive Ktotal for a linear spatial array of n habitat patches with logistic growth and strong or weak random dispersal of individuals between adjacent patches. With strong dispersal, Ktotal depends on the mean r and K over all patches ( and ), the among-patch variance in K, and the linear regression coefficient of r on K, betar,K. Strong dispersal increases Ktotal only if betar, K > /, which requires a positive convex or negative concave association between r and K, and decreases Ktotal if betar, K < /. Alternatively, weak dispersal increases Ktotal only if the within-patch covariance of r and K, cov(r, K) is greater than the spatial covariance between r and K, cov(r, Km), defined as the average covariance between r in a focal patch and K in neighboring patches. Unlike the strong dispersal limit, this condition depends not only on the magnitude of environmental heterogeneity, but explicitly on the spatial distribution of heterogeneity (i.e., habitat clustering). This work clarifies how the interaction between dispersal, habitat heterogeneity, and population growth parameters shape carrying capacity in spatial populations, with implications for species management, conservation and evolution. PMID- 30253139 TI - The epidemiology of obesity. AB - Obesity is a complex multifactorial disease. The worldwide prevalence of overweight and obesity has doubled since 1980 to an extent that nearly a third of the world's population is now classified as overweight or obese. Obesity rates have increased in all ages and both sexes irrespective of geographical locality, ethnicity or socioeconomic status, although the prevalence of obesity is generally greater in older persons and women. This trend was similar across regions and countries, although absolute prevalence rates of overweight and obesity varied widely. For some developed countries, the prevalence rates of obesity seem to have levelled off during the past few years. Body mass index (BMI) is typically used to define overweight and obesity in epidemiological studies. However, BMI has low sensitivity and there is a large inter-individual variability in the percent body fat for any given BMI value, partly attributed to age, sex, and ethnicity. For instance, Asians have greater percent body fat than Caucasians for the same BMI. Greater cardiometabolic risk has also been associated with the localization of excess fat in the visceral adipose tissue and ectopic depots (such as muscle and liver), as well as in cases of increased fat to lean mass ratio (e.g. metabolically-obese normal-weight). These data suggest that obesity may be far more common and requires more urgent attention than what large epidemiological studies suggest. Simply relying on BMI to assess its prevalence could hinder future interventions aimed at obesity prevention and control. PMID- 30253141 TI - High-throughput genotyping of GC (vitamin D-binding protein) by melting analysis with locked nucleic acid-incorporating dual hybridization probe for improving mismatch discrimination. PMID- 30253142 TI - Clinical, biochemical and genetic analysis of Chinese patients with isobutyryl CoA dehydrogenase deficiency. AB - Isobutyryl-CoA dehydrogenase deficiency (IBDHD) is a rare autosomal recessive metabolic disorder related to valine catabolism and results from variants in ACAD8. Here, we present the clinical, biochemical, and genotypes of seven patients with IBDHD in China for the first time. Five patients remained asymptomatic during follow-up, whereas one juvenile had speech delay and one newborn exhibited clinical symptoms. All patients showed remarkably increased concentrations of C4-aclycarnitine with elevated C4/C2 and C4/C3 ratios. In urine organic acid tests, only one patient presented with an increased concentration of isobutyrylglycine excretion. Genetic testing was performed to detect the causative variants. Five previously unreported variants, c.235C > G, c.286G > A, c.444G > T c.1092 + 1G > A, and c.1176G > T, and one known variant, c.1000C > T, in ACAD8 were identified. These previously unreported variants in ACAD8 were predicted to be disease-causing and the c.1092 + 1G > A variant was confirmed to cause skipping of exon 9 by reverse transcription PCR. The most common variant was c.286G > A, which showed an allelic frequency of 50% (7/14), and thus may be a prevalent variant among Chinese patients. Our results broaden the mutational spectrum of ACAD8 and improve the understanding of the clinical phenotype of IBDHD. PMID- 30253143 TI - Mobbing. AB - Carlson and colleagues introduce mobbing an anti-predator behaviour found in many animals. PMID- 30253140 TI - Obesity modifies the stoichiometry of mitochondrial proteins in a way that is distinct to the subcellular localization of the mitochondria in skeletal muscle. AB - BACKGROUND: Skeletal muscle mitochondrial content and function appear to be altered in obesity. Mitochondria in muscle are found in well-defined regions within cells, and they are arranged in a way that form distinct subpopulations of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. We sought to investigate differences in the proteomes of SS and IMF mitochondria between lean subjects and subjects with obesity. METHODS: We performed comparative proteomic analyses on SS and IMF mitochondria isolated from muscle samples obtained from lean subjects and subjects with obesity. Mitochondria were isolated using differential centrifugation, and proteins were subjected to label-free quantitative tandem mass spectrometry analyses. Collected data were evaluated for abundance of mitochondrial proteins using spectral counting. The Reactome pathway database was used to determine metabolic pathways that are altered in obesity. RESULTS: Among proteins, 73 and 41 proteins showed different (mostly lower) expression in subjects with obesity in the SS and IMF mitochondria, respectively (false discovery rate-adjusted P <= 0.05). We specifically found an increase in proteins forming the tricarboxylic acid cycle and electron transport chain (ETC) complex II, but a decrease in proteins forming protein complexes I and III of the ETC and adenosine triphosphate (ATP) synthase in subjects with obesity in the IMF, but not SS, mitochondria. Obesity was associated with differential effects on metabolic pathways linked to protein translation in the SS mitochondria and ATP formation in the IMF mitochondria. CONCLUSIONS: Obesity alters the expression of mitochondrial proteins regulating key metabolic processes in skeletal muscle, and these effects are distinct to mitochondrial subpopulations located in different regions of the muscle fibers. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01824173). PMID- 30253144 TI - Orbitofrontal cortex. AB - The orbitofrontal cortex is a large and heterogeneous cortical area on the ventral surface of the frontal lobe and is intimately involved in emotion and executive function. In this Primer, Peter Rudebeck and Erin Rich summarize our understanding of the mechanisms through which orbitofrontal cortex adaptively shapes decision making and affective behavior. PMID- 30253145 TI - Heterosis in plants. AB - Heterosis, also known as 'hybrid vigor', is a well-known phenomenon whereby hybrid offspring resulting from cross pollination exhibit greater vigor than either parent. Here, Hochholdinger and Baldauf provide an overview of this fascinating biological phenomenon and what is known about the underlying genetics and mechanisms. PMID- 30253146 TI - Lateral eyes direct principal eyes as jumping spiders track objects. AB - One way of circumventing the functional tradeoffs on eye design [1,2] is to have different eyes for different tasks. For example, jumping spiders (Salticidae), known for elaborate, visually guided courtship and predatory behavior [3], view the same object simultaneously with two of their four pairs of eyes: the antero lateral eyes (ALEs) and the principal eyes (reviewed in [2]; Figure 1A). The ALEs, with immobile lenses and retinas, wide fields of view, and hyperacute sensitivity to moving stimuli [4], are structurally distinct from the principal eyes, which have the best spatial acuity known for terrestrial invertebrates and can discern fine details of stationary objects [5]. Behind the immobile corneal lenses of the principal eyes are miniature, boomerang-shaped retinas with correspondingly small fields of view (Figure 1B). The principal-eye visual fields are greatly expanded and overlap because of eye movements: these retinas are at the proximal ends of long, moveable tubes within the spider's cephalothorax [6]. By designing and using a specialized eyetracker, we tested whether principal-eye gaze direction is influenced by what the ALEs see. The principal eyes scanned stationary objects regardless of whether the ALEs were masked, but only when the ALEs were unmasked did the principal eyes smoothly track moving disks. The principal eyes, with high acuity but a narrow field of view, can thus precisely target moving stimuli, but only with the guidance of the secondary eyes. PMID- 30253148 TI - Cognitive Neuroscience: Exciting Developments in Schematic Learning. AB - Learning, in context of prior knowledge, engages NMDAR-independent mechanisms. However, which aspects of previous learning are responsible for this phenomenon remain unclear. New evidence shows that procedural similarity between learning events is the key determinant for engaging NMDAR-independent mechanisms. PMID- 30253147 TI - Medial prefrontal cortex supports perceptual memory. AB - Our visual environment constantly changes, yet we experience the world as a stable, unified whole. How is this stability achieved? It has been proposed that the brain preserves an implicit perceptual memory in sensory cortices [1] which stabilizes perception towards previously experienced states [2,3]. The role of higher-order areas, especially prefrontal cortex (PFC), in perceptual memory is less explored. Because PFC exhibits long neural time constants, invariance properties, and large receptive fields which may stabilize perception against time-varying inputs, it seems particularly suited to implement perceptual memory [4]. Support for this idea comes from a neuroimaging study reporting that dorsomedial PFC (dmPFC) correlates with perceptual memory [5]. But dmPFC also participates in decision making [6], so its contribution to perceptual memory could arise on a post-perceptual, decisional level [7]. To determine which role, if any, PFC plays in perceptual memory, we obtained direct intracranial recordings in six epilepsy patients while they performed sequential orientation judgements on ambiguous stimuli known to elicit perceptual memory [8]. We found that dmPFC activity in the high gamma frequency band (HGB, 70-150 Hz) correlates with perceptual memory. This effect is anatomically specific to dmPFC and functionally specific for memories of preceding percepts. Further, dmPFC appears to play a causal role, as a patient with a lesion in this area showed impaired perceptual memory. Thus, dmPFC integrates current sensory information with prior percepts, stabilizing visual experience against the perpetual variability of our surroundings. PMID- 30253149 TI - Plant Genetics: Two Steps on the Path to Maize Adaptation. AB - Two distinct variations in the promoter of a key flowering time gene were selected during the spread of maize from its tropical origin to northern North America. PMID- 30253150 TI - Speech Entrainment: Rhythmic Predictions Carried by Neural Oscillations. AB - It has been hypothesized that stimulus-aligned brain rhythms reflect predictions about upcoming input. New research shows that these rhythms bias subsequent speech perception, in line with a mechanism of prediction. PMID- 30253151 TI - Evolution: Plasticity versus Selection, or Plasticity and Selection? AB - Whether phenotypic plasticity enables or hinders genetic adaptation has been debated for over a century. A study of lizard coloration uncovers the means by which plasticity can facilitate colonization of novel environments and enable eventual adaptation by natural selection. PMID- 30253152 TI - Neuroscience: Intracranial Recordings of Value. AB - The role of orbitofrontal cortex in value-based choice is well-established from animal research, but there are challenges in relating neurophysiological recordings from animals to equivalent data from humans: a new study bridges this gap. PMID- 30253153 TI - Corvid Technologies: How Do New Caledonian Crows Get Their Tool Designs? AB - Recent research shows that New Caledonian crows can incorporate information from researcher-made objects into objects they subsequently manufacture. This 'mental template matching' is one of several possible - mutually compatible - mechanisms for the cultural transmission of tool designs among wild crows. PMID- 30253154 TI - Superior Colliculus: A Vision for Orienting. AB - The superior colliculus contains neurons sensitive to motion direction. New research shows that these neurons are anatomically clustered: those representing the region of visual space 'seen' by both eyes preferentially respond to nasal motion directions and others to opposite directions. PMID- 30253155 TI - Vision: Microcircuits Rage against the Dimming of the Light. AB - At sundown when light levels fall, rod photoreceptors take the night shift from the daylight-sensitive cones and a specialized mammalian microcircuit 'wires' the rods into the ancestral cone pathway. A recent study combines serial electron microscopy and simultaneous patch clamp recordings to shed light on this microcircuit in unprecedented detail. PMID- 30253156 TI - Gut Microbiota: IgA Protects the Pioneers. AB - The secretory antibody immunoglobulin A counteracts pathogenic infections at mucosal surfaces. Recent work now reveals that IgA responses can also stabilize intestinal colonization by symbiotic microorganisms and confer resistance to future invasion by exogenous competitors. PMID- 30253157 TI - Left Anterior Descending Coronary Artery Occlusion Due to Concussion by a Bullet. PMID- 30253159 TI - Introduction to Dr Joseph E. Bavaria's Presidential Address. PMID- 30253160 TI - Quality and Innovation in Cardiothoracic Surgery: Colliding Imperatives? PMID- 30253158 TI - Longitudinal Changes in Regional Cerebral Perfusion and Cognition After Cardiac Operation. AB - BACKGROUND: Cardiac operation has been associated with increased risk of postoperative cognitive decline, as well as dementia risk in the general population. Few studies, however, have examined the impact of coronary revascularization or valve replacement or repair operation on longitudinal cerebral perfusion changes or their association with cognitive function. METHODS: We examined longitudinal changes in cerebral perfusion among 54 individuals with cardiac disease; 27 undergoing cardiac operation and 27 matched control patients. Arterial spin labeling magnetic resonance perfusion imaging was used to quantify cerebral blood flow within the anterior communicating artery, middle cerebral artery (MCA), and posterior communicating artery vascular territories before operation and postoperatively at 6 weeks and 1 year. Cognitive performance was examined during the same intervals by using a battery of tests that tapped memory, executive, information processing and upper extremity motor functions. Repeated measures, mixed models were used to examine for perfusion changes and the association between perfusion changes and cognition. RESULTS: Significant postoperative increases in perfusion were observed at 6 weeks within the MCA vascular territory after cardiac operation (p = 0.035 for interaction). Perfusion changes were most notable in distal territories of the MCA and posterior communicating artery at 6 weeks, with no additional changes at 1 year. Postoperative increases in MCA perfusion at 6 weeks were associated with improved psychomotor speed (beta = 0.35, p = 0.016), whereas no important differences were found between the groups in vascular territory perfusion and cognition at 1 year. CONCLUSIONS: Cardiac operation is associated with important short-term increases in MCA perfusion with associated improvements in psychomotor speed. PMID- 30253161 TI - Cytoreductive Pleurectomy and Intra Thoracic Chemo Hyperthermia for Pleural Relapse of Thymomas. AB - Several surgical procedures, from debulking to extra pleural pneumonectomy, may be applied for stage IVa Masaoka thymomas but their efficiency is still controversial. Case studies favored R0 resection as the cornerstone of multimodal therapy for loco-regional metastatic extension. We report our standardized procedure associating cytoreductive surgery and intra thoracic chemo hyperthermia on a 46-years old patient presenting B2 thymoma and synchronous unilateral pleural metastasis. PMID- 30253162 TI - Penetration, Completeness, and Representativeness of the Society of Thoracic Surgeons General Thoracic Surgery Database for Lobectomy. AB - BACKGROUND: Not all surgeons performing lobectomy in the United States report outcomes to the Society of Thoracic Surgeons General Thoracic Surgery Database (GTSD). We examined penetration, completeness, and representativeness of the GTSD for lobectomy in the Centers for Medicare and Medicaid Services (CMS) population. METHODS: GTSD lobectomies from 2002-2013 were linked and matched to CMS data using a deterministic matching algorithm. Penetration at center- and patient level were determined by the number of CMS lobectomy sites and patients, matched to STS data, divided by the total number of CMS lobectomy sites and patients, respectively. Completeness was defined as the ratio of lobectomies linked to STS data, to the total number of lobectomies. Representativeness was determined by comparing STS-matched and unmatched lobectomy outcomes. RESULTS: A total of 9569 centers were included in the study. Center level penetration steadily increased from 1.2% (10/859 sites) in 2002 to 25% (169/675 sites) in 2013. Patient-level penetration was highest, 38% (4177/11018), in 2013. Completeness at GTSD sites varied from 59% to 78% over the study period. Postoperative length of stay was longer for non-participants than for GTSD surgeons (median 6 vs. 5 days, p<0.001); 30-day mortality was higher for non-participants than for GTSD participants (3.3% vs. 1.6%, p<0001). CONCLUSIONS: Participation in the GTSD has increased over time, but penetration lags behind that of the other STS National Databases. GTSD participants have superior observed perioperative outcomes for lobectomy compared to non-participants. Database participation may reflect high quality care, and ongoing efforts to increase surgeon participation in the GTSD should be continued. PMID- 30253163 TI - The Myofibroblasts' War on Drugs. AB - The intestinal lining faces a constant assault from harmful gut contents. A study by Chee and colleagues in this issue of Developmental Cell describes how a population of myofibroblasts resists these threats and boosts regeneration of the intestinal epithelium. PMID- 30253164 TI - Flies Eat Their Veggies to Survive the Cold. AB - Although Drosophila melanogaster fruit flies are cold-blooded, they can survive a wide range of temperatures. In this issue of Developmental Cell, Brankatschk et al. (2018) discover a mechanism by which flies extend their viable temperature range by altering their diet in response to environmental temperature. PMID- 30253165 TI - Super-Competitors Game the Fitness Sensing System. AB - Competitive interactions between neighboring cells require fitness comparison and local killing, but the signals regulating these processes are unknown. In this issue, Alpar et al. (2018) demonstrate that fitter cells secrete serine proteases to create a local burst of active Spatzle, triggering Toll signaling and apoptosis in less fit neighbors. PMID- 30253166 TI - Nothing to Be Sniffed At: Anosmin1 Tunes Fgf Diffusivity. AB - The extracellular matrix plays both positive and negative roles in growth factor diffusion, a process critical for organ formation. In this issue of Developmental Cell, Wang et al. (2018) identify the extracellular matrix protein Anosmin1 as a key regulator of Fgf diffusion during sensory organ formation in zebrafish. PMID- 30253167 TI - Myomaker and Myomerger: It Takes Two to Make One. AB - Muscle-forming myotubes are formed from the cell-cell fusion of myoblasts. In this issue of Developmental Cell, Leikina et al. (2018) provide compelling evidence that myoblast fusion is dependent on a two-component membrane fusion complex of Myomaker and Myomerger, which function in hemifusion and pore formation activity, respectively. PMID- 30253168 TI - Rapping about Mechanotransduction. AB - Mechanical cues can regulate cell proliferation and differentiation through the Hippo-YAP signaling network. Reporting in Nature, Meng et al. (2018) show that the Ras-related GTPase RAP2 connects extracellular matrix stiffness to Hippo pathway regulation, adding to our understanding of how mechanical cues are converted into changes in YAP activity. PMID- 30253169 TI - Spatiotemporal Coordination of FGF and Shh Signaling Underlies the Specification of Myoblasts in the Zebrafish Embryo. AB - Somitic cells give rise to a variety of cell types in response to Hh, BMP, and FGF signaling. Cell position within the developing zebrafish somite is highly dynamic: how, when, and where these signals specify cell fate is largely unknown. Combining four-dimensional imaging with pathway perturbations, we characterize the spatiotemporal specification and localization of somitic cells. Muscle formation is guided by highly orchestrated waves of cell specification. We find that FGF directly and indirectly controls the differentiation of fast and slow twitch muscle lineages, respectively. FGF signaling imposes tight temporal control on Shh induction of slow muscles by regulating the time at which fast twitch progenitors displace slow-twitch progenitors from contacting the Shh secreting notochord. Further, we find a reciprocal regulation of fast and slow muscle differentiation, morphogenesis, and migration. In conclusion, robust cell fate determination in the developing somite requires precise spatiotemporal coordination between distinct cell lineages and signaling pathways. PMID- 30253170 TI - A Temperature-Dependent Switch in Feeding Preference Improves Drosophila Development and Survival in the Cold. AB - How cold-blooded animals acclimate to temperature and what determines the limits of their viable temperature range are not understood. Here, we show that Drosophila alter their dietary preference from yeast to plants when temperatures drop below 15 degrees C and that the different lipids present in plants improve survival at low temperatures. We show that Drosophila require dietary unsaturated fatty acids present in plants to adjust membrane fluidity and maintain motor coordination. Feeding on plants extends lifespan and survival for many months at temperatures consistent with overwintering in temperate climates. Thus, physiological alterations caused by a temperature-dependent dietary shift could help Drosophila survive seasonal temperature changes. PMID- 30253171 TI - A Regulatory Response to Ribosomal Protein Mutations Controls Translation, Growth, and Cell Competition. PMID- 30253172 TI - Identification of 5-hydroxymethylfurfural in cigarette smoke extract as a new substrate metabolically activated by human cytochrome P450 2A13. AB - Cytochrome P450 2A13 (CYP2A13) is an extrahepatic enzyme mainly expressed in the human respiratory system and is reported to mediate tobacco-specific N nitrosamines (TSNA) metabolism in cigarette smoke. This study aimed to identify other new substrates of CYP2A13 in cigarette smoke and their corresponding respiratory toxicity. Following separation by HPLC, GC-MS/MS, NMR and cytotoxicity assays in BEAS-2B cells stably expressing CYP2A13 (B-2A13), 5 Hydroxymethylfurfural (5-HMF) was screened and identified in the 4-5 min section of cigarette smoke extract (CSE). In vitro metabolism results showed that CYP2A13 mediated the fast clearance of 5-HMF and formed the metabolite 5-HMF acid (5 HMFA). CSE 5-HMF (CSE-5-HMF) showed cytotoxicity similar to that of standard 5 HMF in B-2A13 and B-2A5 cells, which was inhibited by 8-methoxypsoralen (8-MOP), a CYP enzyme inhibitor. Mouse CYP2A5, a homologous CYP enzyme to CYP2A13, shares many substrates with CYP2A13 in cigarette smoke. Thus, CYP2A5-/- mice were generated to explore the role of CYP2A5 in 5-HMF bioactivation. Compared with CYP2A5-/- mice, WT mice showed serious histological lung and nasal olfactory mucosa damage, as well as increased inflammatory cells and elevated TNF-alpha and IL-6 levels in bronchoalveolar lavage fluid. Besides, nasal microsomes undertook fast 5-HMFA formation in WT mice than that in CYP2A5-/- mice, which could be inhibited by 8-MOP. This study is the first to identify 5-HMF as a new toxic substrate of human CYP2A13 in cigarette smoke, it may play a potential role in cigarette smoke-induced respiratory injuries. PMID- 30253173 TI - Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces hepatic steatosis and endoplasmic reticulum stress by inducing nuclear factor erythroid-derived 2 related factor 2 nuclear translocation. AB - Activation of endoplasmic reticulum (ER) stress is involved in the development of nonalcoholic fatty liver disease. Glucagon-like peptide-1 (GLP-1) has been reported to reduce hepatic steatosis, but the underlying mechanism has not been fully elucidated. Here, we investigated whether exendin-4 (EX-4), a GLP-1 receptor analogue, improves hepatic steatosis through ER stress reduction. Furthermore, we explored which ER stress pathway is involved in this process, with a focus on the protein kinase RNA-like ER kinase (PERK)-nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway. EX-4 treatment reduced hepatic lipid accumulation by suppressing the expression of lipogenic genes and restoring the expression of beta-oxidation genes in palmitate-treated HepG2 cells and high fat diet (HFD)-fed mice. In addition, EX-4 treatment suppressed hepatic ER stress activation in HFD-fed mice and tunicamycin-treated mice. In particular, EX-4 treatment restored HFD- and tunicamycin-induced Nrf2 nuclear translocation to control levels. Inhibition of Nrf2 by siRNA enhanced phosphorylation of PERK and eukaryotic translation initiation factor 2alpha (eIF2alpha), as well as other substrates of the PERK pathway. Nrf2 knockdown also inhibited the protective effects of EX-4 against lipid accumulation, ER stress activation, and cell death in palmitate-treated HepG2 cells. EX-4 treatment prevents hepatic steatosis and improves cell survival by regulating hepatic lipid metabolism and reducing ER stress activation, and Nrf2 plays an essential role in the protective effect of GLP-1 on hepatic steatosis. PMID- 30253174 TI - Occupancy of adenosine A2A receptors by istradefylline in patients with Parkinson's disease using 11C-preladenant PET. AB - Istradefylline, an adenosine A2A receptor (A2AR) antagonist, is effective as an adjunct to levodopa and can alleviate "off" time and motor symptoms in patients with Parkinson's disease (PD). The present study aimed to calculate occupancy rates of A2ARs by administrating istradefylline 20 mg or 40 mg, which is the currently approved dose for PD in Japan. Additionally, A2AR availability was compared between patients with PD and healthy controls. Ten patients with PD under levodopa therapy and six age-matched healthy controls were included. The patients underwent a total of two 11C-preladenant positron emission tomography scans before and after the administration of istradefylline 20 mg or 40 mg (both n = 5). Binding potential (BPND) was calculated to estimate A2AR availability in the ventral striatum, caudate, and putamen. Maximal A2AR occupancy and ED50 were estimated by modeling the dose-occupancy curves. All patients were around the middle stage of PD, and their characteristics were clinically heterogeneous. Maximal A2AR occupancy and ED50 were 93.5% and 28.6 mg in the ventral striatum, 69.5% and 10.8 mg in the caudate, and 66.8% and 14.8 mg in the putamen, respectively. There were no significant differences in BPND values in the ventral striatum (P = 0.42), caudate (P = 0.72), and putamen (P = 0.43) between the PD and control groups. In conclusion, the present study shows that istradefylline binds to A2ARs dose-dependently. A sufficient occupancy of A2ARs could be obtained by administrating the approved dose of istradefylline. PMID- 30253175 TI - Activation of lateral hypothalamic group III metabotropic glutamate receptors suppresses cocaine-seeking following abstinence and normalizes drug-associated increases in excitatory drive to orexin/hypocretin cells. AB - The perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced acutely and into withdrawal. These changes may augment orexin cell reactivity to drug-related cues during abstinence and contribute to relapse-like behavior. Studies in hypothalamic slices from drug naive animals indicate that agonism of group III metabotropic glutamate receptors (mGluRs) reduces presynaptic glutamate release onto orexin cells. Therefore, we examined the group III mGluR system as a potential target to reduce orexin cell excitability in-vivo, including in animals with cocaine experience. First, we verified that group III mGluRs regulate orexin cell activity in behaving animals by showing that intra-LHA infusions of the selective agonist L-(+)-2-Amino-4 phosphonobutyric acid (L-AP4) reduces c-fos expression in orexin cells following 24 h food deprivation. Next, we extended these findings to show that intra-LHA L AP4 infusions reduced discriminative stimulus-driven cocaine-seeking following withdrawal. Importantly, L-AP4 had no effect on lever pressing for sucrose pellets or general motoric behavior. Finally, using whole-cell patch-clamp recordings from identified orexin cells in orexin-GFP transgenic mice, we show enhanced presynaptic drive to orexin cells following 14d withdrawal and that this plasticity can be normalized by L-AP4. Together, these data indicate that activation of group III mGluRs in LHA reduces orexin cell activity in vivo and may be an effective strategy to suppress cocaine-seeking behavior following withdrawal. These effects are likely mediated, at least in part, by normalization of presynaptic plasticity at orexin cells that occurs as a result of cocaine exposure. PMID- 30253176 TI - Functional expression of two NADPH-cytochrome P450 reductases from Siraitia grosvenorii. AB - Cytochrome P450 reductase (CPR) is the redox partner of various P450s involved in primary and secondary metabolism. Here, we identified and characterized two paralogs of cytochrome P450 reductase from Siraitia grosvenorii. There were two full-length CPR isoforms in the S. grosvenorii fruit transcriptome dataset. They had the same open reading frames of 2, 124 bp, encoding 707 amino acids. A phylogenetic analysis characterized both SgCPR1 and SgCPR2 as Class II dicotyledonous CPRs. The recombinant proteins SgCPR1 and SgCPR2 could reduce cytochrome c and ferricyanide in a NADPH-dependent manner. The SgCPR1 and SgCPR2 transcripts were detected in all examined tissues of S. grosvenorii, and in fresh fruit, they had expression patterns similar to several key enzymes that require CPR as a partner during their biosynthesis. The expression levels of the SgCPRs were induced after a methyl jasmonate treatment. The extracts from yeast co expressing SgCPR1/SgCPR2 and the cytochrome P450 enzyme CYP76AH1 produced ferruginol, indicating the positive effects of SgCPR1/SgCPR2 on the CYP76AH1 activity. A docking analysis confirmed the experimentally deduced functional activities of SgCPR1 and SgCPR2 for NADPH, FAD and FMN. Thus, SgCRP1 and SgCPR2 are both likely to participate in secondary metabolism, especially mogroside biosynthesis in S. grosvenorii. PMID- 30253177 TI - Multiple thermostable enzyme hydrolases on magnetic nanoparticles: An immobilized enzyme-mediated approach to saccharification through simultaneous xylanase, cellulase and amylolytic glucanotransferase action. AB - Microbe-derived enzymes such as xylanases, cellulases and amylases, are efficient at hydrolyzing plant biomass. Efforts to harness the functionalities of these enzymes towards applications in energy and fuel biosciences, and food and nutrition, continue apace in many laboratories. Given that enzymes derived from mesophile proteomes undergo facile denaturation and/or degradation at ambient temperatures, and require frequent replenishment during bioprocessing, it is desirable that they be replaced by structurally-stable enzymes capable of functioning efficiently and resisting denaturation and degradation, immobilized on solid media to further add to stability and facilitate recovery and reuse. Towards these objectives, we used synthetic magnetic nanoparticles (MNPs) and immobilized upon their surfaces three different structurally-stable hydrolases: a thermostable xylanase (BSX) derived from Bacillus sp. NG-27, a cellulase (RMCel12A) derived from Rhodothermus marinus, and an amylase-cum glucanotransferase (PfuAmyGT) derived from Pyrococcus furiosus. The MNPs were activated with glutaraldehyde and BSX, RMCel12A, and PfuAmyGT, respectively, were covalently immobilized with efficiencies of ~92%, 45% and 93%. The enzymes and the MNPs were fully characterized before and after immobilization, and the immobilized enzymes were found to be active at 50 degrees C against synthetic substrates as well as pre-treated biomass derived from corn cob and rice husk. The enzyme-coupled MNPs displayed high stability upon storage properties, high operational stability as well as high reusability (retaining 69, 48, and 50% residual activity after 13 uses for BSX, RMCel12A and PfuAmyGT, respectively). Experiments were also conducted with MNPs loaded simultaneously with all three enzymes. Such immobilized enzyme combinations on MNPs can be used in the saccharification of plant biomass. PMID- 30253178 TI - Construction of crosslinked chitosan/nitrogen-doped graphene quantum dot nanocomposite for hydroxyapatite biomimetic mineralization. AB - Crosslinked Chitosan/nitrogen doped-graphene quantum dot nanocomposites (CCS/NGQD NC) with 10 wt% of glutaraldehyd as crosslinker were fabricated under ultrasonic cavitation. Structure and physicochemical properties of the prepared nanocomposites (NC) were systematically characterized by a number of techniques. The swelling capacity of the crosslinked films in the simulated intestinal (pH 7.4) media was evaluated. However, rate of water ingress of specimens was nearly same, but, the CCS/NGQD NC 8 wt% showed the more water absorption ability than the CCS. Bioactivity of the CCS and CCS/NGQD NCs were evaluated by studying their ability to form of apatite on their surface after soaking in a simulated body fluid (SBF) for 30 days. In images of field emission scan electron microscopy, small island-like agglomerated apatite deposited on the sample surface. Also, the pH fluctuation displayed that the hydroxyapatite was formed on the surface of the samples after one month of immersion in SBF. The finding showed that the CCS/NGQD NCs immersed into SBF had a better apatite-forming bioactivity compared with the CCS, which may be due to the high surface area, adequate function groups and appropriate swelling of the NCs. Such improved behaviors of CCS/NGQD NCs may have potential use in the bone tissue engineering. PMID- 30253179 TI - Localization and characterization of hematopoietic tissues in adult sea cucumber, Apostichopus japonicus. AB - Sea cucumber Apostichopus japonicus rely on the efficient innate immune mechanisms against invaders, in which the consumption and regeneration of coelomocytes take place at the same time. In the present study, histological features of putative hematopoietic tissues (HPTs) including the rete mirabile, the respiratory tree, the polian vesicle and the coelomic epithelium were characterized. The distribution of transcription factor GATA1 in coelomocytes and putative HPTs was examined by immunohistochemistry. In addition, cell proliferation using EdU labeling and coelomocyte distribution in different tissues using monoclonal antibody labeling were analyzed to further confirm the HPTs. The results showed that two homologs of GATA1 were detected with molecular weight of 43 and 90 kDa in coelomocytes, rete mirabile, respiratory tree and polian vesicle, whereas no signals were detected in the coelomic epithelium. A few cells were detected to be EdU-positive for coelomocytes, which accounted for approximately 9.5%. In the rete mirabile and the respiratory tree, the EdU signals were strong in cells of the tube wall. In the polian vesicle, numerous EdU-positive cells were detected in the cyst wall. In the coelomic epithelium, little EdU signaling was detected. Immunohistochemistry analysis by mAb 3F6 against A. japonicus coelomocytes showed that positive signals were observed in the tube wall of the rete mirabile, respiratory tree, cyst wall of the polian vesicle and in the coelomocyte antrum of coelomic epithelium. These results suggest that the rete mirabile, respiratory tree and polian vesicle are the HPTs of A. japonicus. PMID- 30253180 TI - JAK/STAT signalling regulates antimicrobial activities in Eriocheir sinensis. AB - The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling pathway plays a significant role in immune responses to pathogens. In invertebrates, three core components (Domeless, Hopscotch and STAT92E) of the JAK/STAT pathway were first identified in Drosophila melanogaster. In the present study, we report the cloning and characterisation of DOME, JAK and STAT from Eriocheir sinensis. EsDOME, EsJAK and EsSTAT are 1299, 1110 and 794 amino acid proteins encoded by 4200, 3333 and 2385 bp open reading frames, respectively. Bioinformatics analysis revealed that all three share specific domains with corresponding functions. Quantitative real-time PCR showed that all three components were highly expressed in various tissues including the gill, hepatopancreas and hemocytes. Moreover, EsDOME, EsJAK and EsSTAT were upregulated significantly in hemocytes after bacterial challenge. In addition, the JAK/STAT signalling pathway positively regulates antimicrobial peptide expression during the antibacterial immune response. Thus, the JAK/STAT pathway plays a critical role in bacterial immune responses in E. sinensis. PMID- 30253183 TI - Vitamin D attenuates the effect of advanced glycation end products on anti Mullerian hormone signaling. AB - Vitamin D3 (1,25-dihydroxyvitamin D3, VD3) in vitro attenuates the effect of the pro-inflammatory advanced glycation end products (AGEs) on steroidogenesis in human granulosa cells (GCs) by downregulating the receptor for AGEs (RAGE). It has been shown that VD3 alone downregulates anti-Mullerian hormone (AMH) type 2 receptor (AMHR-2) gene expression and suppresses AMH-induced SMAD 1/5/8 phosphorylation in granulosa cells. However, the effect of AGEs, in the absence or presence of VD3, on AMH action in GCs has not been studied. Using human GCs, this study showed that human glycated albumin (HGA), an in vitro representative for AGEs, upregulated AMHR-2 mRNA but did not alter AMH mRNA expression levels. VD3 inhibited the HGA-induced increase in AMHR-2 mRNA expression levels. In KGN granulosa cell line, recombinant AMH induced SMAD 1/5/8 phosphorylation. HGA augmented the recombinant AMH-induced SMAD 1/5/8 phosphorylation while the addition of VD3 to HGA attenuated the recombinant AMH-induced SMAD 1/5/8 phosphorylation. Thus, AGEs could potentially affect folliculogenesis as reflected by changes in AMH signaling. These findings have significant implications for women with polycystic ovary syndrome who have significantly elevated serum and ovarian AGEs. PMID- 30253181 TI - Genome-wide identification and analysis of the evolution and expression patterns of the GATA transcription factors in three species of Gossypium genus. AB - GATA transcription factors (TFs), which bind to DNA in regulatory regions, are involved in cell differentiation and possess a type-IV zinc finger and a DNA binding domain. GATA genes have been characterized in plant species such as Arabidopsis thaliana, Oryza sativa, and Glycine max, and their functions have been elucidated in A. thaliana. Although many Gossypium quantitative trait loci for fiber quality harbor GATA TFs, GATA genes have not yet been characterized in cotton. In this study, we identified 179 GATA genes from the genomes of three Gossypium species. We analyzed the phylogenetic relationships, chromosomal distribution, gene structure, expression pattern, and predicted promoters of all 179 Gossypium GATA genes (46 in G. raimondii, 46 in G. arboreum, and 87 in G. hirsutum). Phylogenetic analysis grouped the 179 GATA genes into four subfamilies. Domain analysis revealed that GATA domains in subfamilies I, II, and III were located near the C-terminal, whereas those in subfamily IV were adjacent to the N-terminal. RNA-seq and (Real-time PCR) qRT-PCR revealed that 39.1% (34/87) of GATA genes were expressed in growing plant tissues in G. hirsutum, but only 12.6% (11/87) were expressed during fiber development. In addition, 45.7% (21/46) and 26.1% (12/46) of GATA genes were expressed in G. arboreum and G. raimondii, respectively. Our results may be useful for elucidating the evolution, expression patterns, and functional divergence of GATA genes in Gossypium. PMID- 30253182 TI - Effect of water-deficit on tassel development in maize. AB - Maize often exhibits asynchronous pollination under abiotic and biotic stress conditions; however, the molecular basis of this developmental deficiency has not been elucidated. Tassel development is a key process affecting the anthesis silking interval (ASI) in maize. In this study, we showed that pollen shedding was delayed and ASI was significantly increased in B73 and Chang7-2 inbred lines under water deficit conditions, which resulted in longer barren tip length and decreased yields under both controlled and field conditions. Comparative transcriptome analysis performed on immature tassels derived from plants grown under well-watered and water deficit conditions identified 1931 and 1713 differentially expressed genes (DEGs) in B73 and Chang7-2, respectively. Further, 28 differentially co-expressed transcription factors were identified across both lines. Collectively, we demonstrated that the molecular regulation of tassel development is associated with water deficit stress at early vegetative stage in maize. This finding extends our understanding of the molecular basis of maize tassel development during abiotic stress. PMID- 30253184 TI - Therapeutic potential of arachidonyl trifluromethyl ketone, a cytosolic phospholipaseA2 IVA specific inhibitor, in cigarette smoke condensate-induced pathological conditions in alveolar type I & II epithelial cells. AB - Cigarette smoke is responsible for multiple disorders and causes almost 10 million annual deaths globally but underlying mechanisms are still underexplored. Continuous exposure of Cigarette smoke condensate (CSC) leads to cytosolic phospholipase A2 (cPLA2) mediated high free radicals where cPLA2s seems to play crucial role in generated various patho-physiological conditions such as chronic inflammation, oxidative stress and cancer. In this view, we assessed the therapeutic potential of arachidonyl trifluromethyl ketone (ATK), a cPLA2 inhibitor, via pharmacological inhibition of most expressible CSC-induced cPLA2 group IVA in type-I and type-II alveolar epithelial cells. The In Vitro inhibitory effect of ATK on CSC-induced PLA2 activity and its cellular role were assessed in terms of cell viability, fluorescein diacetate (FDA) dye uptake assay for membrane integrity, reactive oxygen species (ROS)/reactive nitrogen species (RNS) levels and pro apoptotic as well as anti apoptosis markers via flow cytometry, along with extracellular signal-regulated kinases (ERK) levels using enzyme-linked immunosorbent assay (ELISA). The experimental findings demonstrated that ATK acts as potent inhibitor of cPLA2 activity and shown its effectiveness as therapeutic agent by significantly mimicking CSC-induced levels of free radicals, primary apoptosis, ratio of pro-apoptotic/apoptotic proteins and levels of ERK whereas protected cells from loss of cell viability and membrane integrity. Thus, this study is an important step towards the opening up of avenues for the applicability of the cPLA2 isoform specific inhibitors such as ATK for pre-clinical and clinical studies and could be beneficial during smoking induced lung pathological conditions. PMID- 30253185 TI - S-preactivated thiolated glycol chitosan useful to combine mucoadhesion and drug delivery. AB - This work describes S-preactivated N-acetylcysteine (NAC)- and glutathione (GSH) glycol chitosan (GC) polymer conjugates engineered as potential mucoadhesive platform. Preactivated thiomers (GC-NAC-MNA, GC-GSH-MNA) were synthesized by bond formation between GC-NAC or GC-GSH and 2-mercaptonicotinic acid (MNA) used as ligand. The presence of protected thiol moieties on this new class of thiolated GC made them not subject to oxidation. The structural modifications of the resulting derivatives were confirmed by proton Nuclear Magnetic Resonance (1H NMR) and Size Exclusion Chromatography (SEC). The conjugates displayed 91.2% and 90.1% of S-preactivation for GC-NAC-MNA and GC-GSH-MNA, respectively. The polymers were tested in ex-vivo and in vitro for their mucoadhesive properties and toxicity. The results showed that the preactivation of GC-NAC and GC-GSH increased their mucoadhesive abilities compared to their thiolated precursors by 1.4-, 4.4-fold in time of adhesion evaluated using rotating cylinder method, 1.6 , 1.5-fold in total work of adhesion (TWA) and 2.0-, 1.3-fold in maximum detachment force (MDA) determined using tensile studies, respectively. Moreover, water-uptake studies showed an improved in weight indicating water-uptake strongly dependent on derivations, before erosion occurred, whereas disintegration took place for the thiolated polymers within the first hour. The S preactivated modification did not affect the cell viability of Caco2 cells exposed to the polymers. The release of the model drug sodium naproxen from tablets prepared with a lyophilized mixture of drug and polymer was studied via dissolution apparatus revealing that the preactivation on GC-GSH and GC-NAC involves a slowdown in the drug release rate. The results shown that the novel preactivated thiolated GC-derivatives can be considered promising excipients for the development of mucoadhesive drug delivery systems. PMID- 30253186 TI - Phase separation of supersaturated solution created from amorphous solid dispersions: Relevance to oral absorption. AB - Dissolution of amorphous solid dispersions (ASDs) is a complicated process, which may involve phase separation from the supersaturated state and formation of a colloidal phase. However, relevance of the phase separation behavior to oral absorption from ASDs is still not well understood. We investigated phase separation of a supersaturated fenofibrate (FEN) solution in the presence of polymers, in vitro dissolution of FEN ASDs, and their in vivo absorption. The supersaturation behavior was assessed based on turbidity measurement in an artificial supersaturation system, where FEN ethanol solutions were added to aqueous polymer solutions. The phase separation concentration of FEN was ca. 1 MUg/mL regardless of the presence/absence of the polymer, which was approximately 10-fold the equilibrium solubility. In the presence of 0.1% Tween 80 in the media, the phase separation concentration depended on the polymer species, presumably due to differences in their inhibitory effect of crystallization. The degrees of supersaturation achieved by the ASDs were similar to those found in the artificial system, suggesting that the artificial system works for comprehending the effect of polymer species on supersaturation ability for designing ASDs. A robust in vitro-in vivo correlation was achieved using the paddle and the flow-through cell methods by employing non-sink and pH-shift conditions. However, the phase separation concentration may rather be a good and simple indicator to estimate the absorption-enhancing ability of the polymeric excipients for ASDs, if the absorption is limited by solubility. PMID- 30253187 TI - The amino acid transporter PAT1 regulates mTORC1 in a nutrient-sensitive manner that requires its transport activity. AB - The proton-coupled amino acid transporter PAT1 has been postulated to regulate the amino acid-stimulated mTORC1 through two different mechanisms, either it activates mTORC1 by sensing and transducing the lysosomal amino acid signal to mTORC1, or it inhibits mTORC1 by decreasing the signal level, as increased PAT1 has been shown to either activate or inactivate mTORC1 in the human embryonic kidney HEK293 cells. The current study aims to clarify the cause of these controversial observations, which is promoted by the recent discovery that the lysosomal PAT1 can be induced by starvation. Here, we show that under the normal culture condition, overexpression of PAT1 did not apparently change the mTORC1 activity in the fast proliferating cells. However when these cells were synchronized by starvation, followed by nutrient replenishment for a short period of time, the mTORC1 activity was decreased by PAT1 overexpression; if the nutrient stimulation lasted for longer time, the mTORC1 activities could be recovered in the PAT1-overexpressing cells. In addition, we showed the starvation induced lysosomal PAT1 was gradually decreased during the nutrient replenishment. These results reveal that the influence of PAT1 on mTORC1 seems to be affected by the nutrient condition and the level of lysosomal PAT1. We further demonstrate that suppressing the transport activity of PAT1 abolished its inhibitory effect on mTORC1. Our data support a mechanism that PAT1 can negatively regulate mTORC1 by controlling the cellular nutrient signal level. PMID- 30253189 TI - Role of HSP70 protein in human periodontal ligament cell function and physiology. AB - OBJECTIVE: Heat pre-treatment of mechanically loaded human periodontal ligament cells (hPDL) dampens the inflammatory cellular response, as evidenced by a reduced expression of pro-inflammatory cytokines, inhibition of monocyte adhesion and osteoclastic differentiation. These findings imply heat shock proteins (HSP) as cell protective molecules acting in the PDL that are up-regulated upon ischemia caused by mechanical loading. HSP70 and its inhibition by VER155008 as the active agent in several pharmaceuticals are established targets and strategies, respectively, in the treatment of neoproliferative diseases. However, the effect of both players on periodontal remodeling in unknown. Therefore, we analyzed the role of HSP70 and its frequently used inhibitor VER155008 in the regulation of physiological hPDL cell functions and immune cell interaction. MATERIALS AND METHODS: Fifth passage hPDL cells were cultured in the presence of 25MUm HSP70 inactivating agent VER155008. At harvest, HSP70 expression, cell proliferation, and parameters of cell interaction, colony formation and wound healing were analyzed by means of real-time PCR, immunohistochemistry, Western blot, biochemical MTS assay, microscopy, and functional assays for monocyte adhesion and differentiation. RESULTS: Basal HSP70 expression and hPDL cell morphology were not affected by HSP70 inhibitor VER155008. In contrast, cell proliferation, tissue defect healing, and colony formation were reduced significantly following HSP70 inhibition, whereas apoptosis and necrosis, monocyte adhesion and osteoclastic differentiation were markedly increased. CONCLUSIONS: The present data indicate a regulatory role for HSP70 protein in hPDL cell biology. CLINICAL RELEVANCE: These findings identify HSP70 as a promising target in the attempt to modify periodontal remodeling and point to potential periodontal side effects of HSP70 pharmaceutical usage. PMID- 30253188 TI - Dual roles of different redox forms of complement factor H in protecting against age related macular degeneration. AB - Complement Factor H (CFH) is an important inhibitor of the alternate complement pathway in Bruch's membrane (BM), located between the choriocapillaris and the retinal pigment epithelium. Furthermore dysfunction of its activity as occurs with certain polymorphisms is associated with an increased risk of age related macular degeneration (AMD). The retina is a site of high generation of reactive oxygen species (ROS) and dysfunction of redox homeostasis in this milieu also contributes to AMD pathogenesis. In this study we wanted to explore if CFH exists in distinct redox forms and whether these species have unique protective biological functions. CFH can be reduced by the naturally occurring thioredoxin - 1 in CFH domains 1-4, 17-20. We found a duality of function between the oxidised and reduced forms of CFH. The oxidised form was more efficient in binding to C3b and lipid peroxidation by-products that are known to accumulate in the retinae and activate the alternate complement pathway. Oxidised CFH enhances Factor I mediated cleavage of C3 and C3b whereas the reduced form loses this activity. In the setting of oxidative stress (hydrogen peroxide)-mediated death of human retinal pigment epithelial cells as can occur in AMD, the free thiol form of CFH offers a protective function compared to the oxidised form. We found for the first time using a novel ELISA system we have developed for free thiol CFH, that both redox forms of CFH are found in the human plasma. Furthermore there is a distinct ratio of these redox forms in plasma depending if an individual has early or late AMD, with individuals with early AMD having higher levels of the free thiol form compared to late AMD. PMID- 30253190 TI - There Is Limited Value in the One Month Post Endovascular Aortic Aneurysm Repair Surveillance Computed Tomography Scan. AB - BACKGROUND: Endovascular aortic aneurysm repair (EVAR) is the preferred first line treatment for abdominal aortic aneurysms. Current postprocedure surveillance recommendations by manufacturers are a 1-month computed tomography angiography (CTA) followed by a 12-month CTA in most circumstances. The objective of this study is to determine the utility of the 1-month CTA following elective EVAR and determine if initial surveillance at 6-month CTA is appropriate. METHODS: A single-center retrospective chart review of all elective EVARs at a tertiary medical center over a 12-year period was conducted. Patients were excluded if postoperative surveillance imaging was not available. Data analysis encompassed demographics, chart review, and imaging including angiogram and cross-sectional imaging to asses for endoleaks and other findings. RESULTS: There were 363 patients who underwent elective EVAR and had available postoperative imaging during the study period. Within the 1-month follow-up, a CTA group of 316 patients was detected with 98 (31%) endoleaks. Of these, 5 (1.5%) required intervention: 1 for infolding of an iliac limb and 4 for type I endoleak which was present on completion angiogram-3 in patients treated outside of instructions for use and 1 with a type Ib endoleak on intraoperative completion imaging. In the 158 patients with 1 and 3-month CTAs, there were 47 persistent endoleaks, 9 previously undetected endoleaks not seen in 1-month CTA, and 13 resolved endoleaks. Three patients (1.2%) underwent intervention for type II endoleak and aneurysm expansion. In 47 patients with only a 6-month CTA, there were 16 endoleaks not seen on completion angiography and 2 of which were treated with reintervention-1 for a type I endoleak and 1 for a type II endoleak. CONCLUSIONS: There is limited utility to 1-month surveillance CTA in patients undergoing elective EVAR within the device instructions for use that has no evidence of type I endoleak on completion angiography. It is safe to start routine EVAR surveillance at 6 months in this patient population. This has implications when considering bundled and value-based payments in the longitudinal care of abdominal aortic aneurysm patients. PMID- 30253191 TI - FOXF1 promotes angiogenesis and accelerates bevacizumab resistance in colorectal cancer by transcriptionally activating VEGFA. AB - Forkhead box F1 (FOXF1) has been recently implicated in the progression and metastasis of lung cancer and breast cancer. However, the biological functions and underlying mechanisms by which FOXF1 regulates the progression of colorectal cancer (CRC) are largely unknown. As shown in our previous study, FOXF1 is upregulated in 182 CRC tissues, and elevated FOXF1 expression is significantly associated with microvessel density and advanced TNM (T = primary tumour; N = regional lymph nodes; M = distant metastasis) stages. In this study, 43 CRC tissues collected from patients who underwent treatment with first-line standard chemotherapeutic regimens in combination with bevacizumab were used to explore the correlation between FOXF1 expression and resistance to bevacizumab. In addition, FOXF1 regulated angiogenesis by inducing the transcription of vascular endothelial growth factor A1 (VEGFA) in vitro and in vivo. Furthermore, upregulation of FOXF1 enhanced bevacizumab resistance in CRC, and inhibition of VEGFA attenuated angiogenesis and bevacizumab resistance in FOXF1-overexpressing CRC cells. These results suggest that FOXF1 plays critical roles in CRC angiogenesis and bevacizumab resistance by inducing VEGFA transcription and that FOXF1 represents a potentially new therapeutic strategy and biomarker for anti angiogenic therapy against CRC. PMID- 30253192 TI - Interaction of miR-125b-5p with Human antigen R mRNA: Mechanism of controlling HCV replication. AB - Cellular miRNAs influence Hepatitis C virus (HCV) infection in multiple ways. In this study, we demonstrate that miR-125b-5p is upregulated in HCV infected patient serum samples as well as in HCV infected liver carcinoma cells and is involved in translational regulation of one of its predicted targets, Human antigen R (HuR). We used miRNA mimics and antagomiRs to confirm that HuR is a bonafide miR-125b target. Previously, we have shown that HuR is a positive regulator of HCV replication, whereas we noticed that miR-125b is a negative regulator of HCV infection. As a connecting link between these two observations, we showed that knockdown of miR-125b-5p increased HuR protein levels and rescued HCV replication when the availability of HuR in the cytoplasm was compromised using siRNAs against HuR or an inhibitor of HuR export to the cytoplasm. Overall, the study sheds light on the ability of host cell to use a miRNA as a tool to control virus propagation. PMID- 30253193 TI - Tree nut allergy and anxiety related factors modulate food consumption behaviour in peanut-allergic patients: Results of the MIRABEL survey. AB - BACKGROUND: In the absence of specific data on food consumption of allergic consumers, general population surveys are used for risk assessment. Most of allergy risk assessment's experts advise that an understanding of the food consumption habits of people with food allergies is crucial for correctly estimate the risk. OBJECTIVE: This study aims to detail the food consumption of patients with peanut allergy including products with precautionary allergen labelling (PAL) and to identify the factors influencing their consumption behaviour. METHODS: The MIRABEL study is a multi-center survey of peanut-allergic patients from France, Belgium and Luxemburg. It includes data on medical, socio demographic, and consumption of different food categories, including products with PAL. Anxiety score and allergy severity level variables were constructed and studied as potential consumption determinants. To study the association of modulator variables with food consumption, a logistic regression model was built to test the association with food category and ingredient choice. RESULTS: 443 of the 785 patients from MIRABEL survey were included in the consumption study. Tree nut allergy, knowledge of threshold dose, label reading and anxiety score significantly influenced the consumption of products which may contain unintended traces of peanut. The direction of influence depended on food categories and ingredient choices. Diet advice by allergists, severity of the allergy and threshold dose determined by oral food challenge did not significantly impact consumption. CONCLUSIONS: and clinical relevance: It showed, for the first time, that consumption of food products by peanut-allergic patients, including those with PAL, is modulated by factors related to anxiety such as label reading and knowledge of threshold and concomitant tree nut allergy. Knowledge of peanut allergic food behaviours will make it possible to improve risk assessment and help allergists and risk managers to make diet advices. PMID- 30253194 TI - From inflammatory reactions to neurotransmitter changes: Implications for understanding the neurobehavioral changes in mice chronically infected with Toxoplasma gondii. AB - Toxoplasma gondii is a protozoan parasite that can cause a latent infection in the central nervous system, leading to neurobehavioral abnormalities in the host. However, the mechanism underlying these changes remains relatively unexplored. In this study, we detected behavioral changes, pathological injury, secretion of neurotransmitters and related signal pathway in mice infected by T. gondii using behavioral test, histopathology, immunofluorescence staining, western blotting, HPLC and real time PCR. Mice showed neurobehavioral disturbances two months after infection with T. gondii. Histopathology revealed the activation of astrocytes and microglia, apoptosis of neurons and decreases in synapses in the brain of infected mice. Excessive secretion of cytokines and chemokines was detected in the brains of mice infected by T. gondii compared to uninfected mice. Furthermore, T. gondii infection led to abnormalities in neurotransmitters and the activation of NF-kappaB and dopamine (DA) signaling pathways in the infected mice. In conclusion, excessive activation of the inflammation in the brain could induce neuronal apoptosis in mice chronically infected with T. gondii. Dysregulation of the dopaminergic neurotransmitter could provide an explanation of neurobehavioral disorders in infected hosts. PMID- 30253195 TI - Southern Bahia, Brazil: KIR gene-content distribution in the highly admixed population from Ilheus. AB - We here describe the KIR gene-content genotypes in the highly admixed population from Ilheus, a city located in Bahia State, Northeast Brazil. Bahia is the State with the largest contribution of African ethnicity in comparison to other Brazilian areas and this is the first report of a population from this region. A total of 32 KIR gene-content genotypes have been found, from which 18 were observed in single individuals. The distinct KIR gene-content distribution observed in Ilheus, along with the elevated diversity of genotypes point to importance of describing KIR polymorphism in unique populations from Brazil. PMID- 30253197 TI - Pre-intervention test-retest reliability of EEG and ERP over four recording intervals. AB - In this study we present the test-retest reliability of pre-intervention EEG/ERP (electroencephalogram/event-related potentials) data across four recording intervals separated by a washout period (18-22 days). POz-recording-reference EEG/ERP (28 sites, average reference) were recorded from thirty-two healthy male participants. Participants were randomly allocated into different intervention sequences, each with four intervention regimens: 10 mg vortioxetine, 20 mg vortioxetine, 15 mg escitalopram and Placebo. We report classical EEG spectra: delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), gamma1 (30-45 Hz) and gamma2 (45-80 Hz) of resting state and vigilance-controlled, and of auditory steady state response, as well as ERP components N100, P200 and P300 in auditory oddball task and error related negativity (ERN) and error positivity (Pe) in hybrid flanker task. Reliability was quantified using intra-class correlation coefficient (ICC). We found that theta, alpha and beta of continuous EEG were highly reliable (ICCs >= 0.84). Evoked power of other tasks demonstrated larger variability and less reliability compared to the absolute power of continuous EEG. Furthermore, reliabilities of ERP measures were lower compared to those of the EEG spectra. We saw fair to excellent reliability of the amplitude of the components such as Pe (0.60-0.82) and P300 (0.55-0.80). Moreover, blood tests confirmed that there was no measurable drug carry-over from the previous intervention. The results support that EEG/ERP is reliable across four recording intervals, thus it can be used to assess the effect of different doses and types of drugs with CNS effects. PMID- 30253196 TI - Centella asiatica attenuates hippocampal mitochondrial dysfunction and improves memory and executive function in beta-amyloid overexpressing mice. AB - Centella asiatica is a medicinal plant used to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates beta-amyloid (Abeta)-induced spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its in vivo mechanism of improving Abeta-related cognitive impairment. This study investigates the effects of CAW on learning, memory and executive function as well as mitochondrial function and antioxidant response in the 5xFAD model of Abeta accumulation. Seven month old 5xFAD female mice were treated with CAW (2 mg/mL) in their drinking water for two weeks prior to behavioral testing. Learning, memory and executive function were assessed using the object location memory task (OLM), conditioned fear response (CFR) and odor discrimination reversal learning (ODRL) test. Mitochondrial function was profiled using the Seahorse XF platform in hippocampal mitochondria isolated from these animals and tissue was harvested for assessment of mitochondrial, antioxidant and synaptic proteins. CAW improved performance in all behavioral tests in the 5xFAD but had no effect on WT animals. Hippocampal mitochondrial function was improved and hippocampal and cortical expression of mitochondrial genes was increased in CAW treated 5xFAD mice. Gene expression of the transcription factor NRF2, as well as its antioxidant target enzymes, was also increased with CAW treatment in both WT and 5xFAD mice. CAW treatment also decreased Abeta-plaque burden in the hippocampus of treated 5xFAD mice but had no effect on plaques in the cortex. These data show that CAW can improve many facets of Abeta-related cognitive impairment in 5xFAD mice. Oral treatment with CAW also attenuates hippocampal mitochondrial dysfunction in these animals. Because mitochondrial dysfunction and oxidative stress accompany cognitive impairment in many pathological conditions beyond Alzheimer's disease, this suggests potentially broad therapeutic utility of CAW. PMID- 30253198 TI - A novel model of trauma-induced cerebellar injury and myelin loss in mouse organotypic cerebellar slice cultures using live imaging. AB - BACKGROUND: Traumatic brain injury (TBI) induces significant cognitive deficits correlated with white matter injury, involving both axonal and myelin damage. Several models of TBI ex vivo are available to mimic focal impact on brain tissue. However, none of them addressed the study of trauma-induced myelin damage. NEW METHOD: The aim of this study was to set up a novel ex vivo weight drop model on organotypic cultures obtained from mouse cerebellum, a highly myelinated structure, in order to study the temporal evolution of cerebellar lesion and demyelination. The extent of injury was measured by propidium iodide (PI) fluorescence and demyelination was evaluated by loss of GFP-fluorescence in cerebellar slices from PLP-eGFP mice. RESULTS: Live imaging of slices showed an increase of PI-fluorescence and a significant loss of GFP-fluorescence at 6 h, 24 h and 72 h post-injury. At the impact site, we observed a loss of Purkinje cells and myelin sheaths with a marked loss of myelin protein MBP at 72 h following injury. Etazolate, a known protective compound, was able to reduce both the PI fluorescence increase and the loss of GFP-fluorescence, emphasizing its protective effect on myelin loss. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: In line with the existing models of focal injury, we characterized trauma-induced cerebellar lesion with an increase of PI fluorescence by live imaging. Our findings describe a novel tool to study trauma-induced myelin damage in cerebellar slices and to test biomolecules of therapeutic interest for myelin protection. PMID- 30253199 TI - Estimating amperometric spike parameters resulting from quantal exocytosis using curve fitting seeded by a matched-filter algorithm. AB - BACKGROUND: Quantal exocytosis of oxidizable neurotransmitters can be detected as spikes of amperometric current using electrochemical microelectrodes. Measurements of spike parameters indicate the maximal transmitter flux, flux duration, and amount of transmitter released from individual vesicles. Automated analysis algorithms need to reject spikes that overlap in time. In addition, many spikes are preceded by small amplitude "foot" signals, attributed to slow release of transmitter through a fusion pore. Accurate pre-spike baseline determination is essential for estimating fusion-pore duration and the amount of transmitter released through the fusion pore. NEW METHOD: We developed an estimation approach that is based on fitting a multi-exponential function to the data. Our previously described matched-filter algorithm is used to identify the sections of data to fit and provides seed values to facilitate convergence of the iterative fit. The new estimation algorithm includes overlap rejection, a two-step fitting procedure and a novel baseline estimation procedure. RESULTS: Histograms of spike parameters demonstrate excellent agreement of the new approach with manually computed parameters. COMPARISON WITH EXISTING METHODS: Parameter estimates generated using the new approach are closer to blind manual estimates than commonly used existing methods. The improved performance is due to better detection of valid spikes and rejection of overlapping spikes. Moreover, since the complete time course of the spike is fit to a function, more complete information about the spike time course is captured. CONCLUSIONS: The matched filter seeded algorithm reliably rejects overlaps and estimates spike and foot signal parameters in a fully automated manner. PMID- 30253200 TI - Overshadowing between visual and tactile stimulus elements in an object recognition task. AB - In recent decades there has been great progress in discovering the conditions under which cue competition occurs during animal learning. In humans, however, the evidence remains equivocal regarding the degree to which stimuli compete with one another for behavioral control. We report here the results of a single experiment wherein thirty-nine college students completed a novel cue competition task with visual and tactile stimuli. Participants visually and/or haptically examined a series of novel objects. They were then asked to select the objects with which they had interacted from a larger pool of both novel and familiar objects. Potentiation (or facilitation) by simultaneous visual and haptic inspection was possible. Alternatively, stimulus elements may have competed with one another (i.e., overshadowing), which would present as poorer recognition at test for objects to which participants had simultaneous, dual-modality training exposure. We report the latter effect. We situate these findings in the broader context of associative learning and suggest that our data is relevant to applied settings. PMID- 30253201 TI - Utilizing microphysiological systems and induced pluripotent stem cells for disease modeling: a case study for blood brain barrier research in a pharmaceutical setting. AB - Microphysiological systems (MPS) may be able to provide the pharmaceutical industry models that can reflect human physiological responses to improve drug discovery and translational outcomes. With lack of efficacy being the primary cause for drug attrition, developing MPS disease models would help researchers identify novel targets, study mechanisms in more physiologically-relevant depth, screen for novel biomarkers and test/optimize various therapeutics (small molecules, nanoparticles and biologics). Furthermore, with advances in inducible pluripotent stem cell technology (iPSC), pharmaceutical companies can access cells from patients to help recreate specific disease phenotypes in MPS platforms. Combining iPSC and MPS technologies will contribute to our understanding of the complexities of neurodegenerative diseases and of the blood brain barrier (BBB) leading to development of enhanced therapeutics. PMID- 30253202 TI - miARma-Seq, a comprehensive pipeline for the simultaneous study and integration of miRNA and mRNA expression data. AB - Messenger RNAs (mRNAs) fulfil specific biological roles in cells and, thus, their expression may be adapted to suit specific circumstances. This is in part achieved through selective gene transcription and post-transcriptional events, the regulation of which must be tightly integrated and controlled. To comprehensively study the coordinated effects of transcriptional and post transcriptional regulatory elements, and to obtain coherent results, it is advisable to use different methodologies. Adequately integrating the data derived from these distinct methodologies then becomes critical to elucidating the relationships between the coordinated cellular effects assayed, particularly when applied to normal and disease states. Such integrated studies are likely to be particularly useful to identify markers suitable for early detection of diseases and to devise strategies for therapeutic interventions. Throughout this chapter, we will focus on the methods currently available to analyse mRNA and microRNA (miRNA) expression, paying special attention to the influence of miRNAs on mRNA metabolism. We will introduce miARma-Seq, a comprehensive pipeline that facilitates the simultaneous integration of mRNA and miRNA expression data. For illustrative purposes, we include a case study that incorporates data from RNASeq and small-RNASeq, detailing all the steps necessary to define the differential expression of both mRNA- and miRNA-encoding genes. Finally, we explore the possible regulatory relationships that drive significant and potentially relevant changes in mRNA and miRNA gene expression. PMID- 30253203 TI - P-glycoprotein and breast cancer resistance protein restrict brigatinib brain accumulation and toxicity, and, alongside CYP3A, limit its oral availability. AB - Brigatinib is an FDA-approved oral anaplastic lymphoma kinase (ALK) inhibitor for treatment of metastatic non-small cell lung cancer (NSCLC). Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3 A in plasma pharmacokinetics and tissue distribution of brigatinib. In vitro, brigatinib was exceptionally well transported by human ABCB1 and mouse Abcg2, and efficiently by human ABCG2. Following oral brigatinib administration (10 mg/kg), brain accumulation was dramatically increased in Abcb1a/1b-/- (19.3-fold) and Abcb1a/1b;Abcg2-/-(41.8-fold), but not in single Abcg2-/- mice compared to wild type mice. Brigatinib testis accumulation showed qualitatively similar behavior. mAbcb1a/1b and mAbcg2 together restricted systemic exposure of brigatinib: with both systems absent oral availability increased 1.9-fold. Coadministration of elacridar, an ABCB1/ABCG2 inhibitor, caused a pronounced increase (36-fold) in brain-to-plasma ratios of brigatinib, approaching the levels seen in Abcb1a/1b;Abcg2-/- mice. Unexpectedly, lethal toxicity of oral brigatinib was observed in mice with genetic knockout or pharmacological inhibition of mAbcb1a/1b and mAbcg2, indicating a pronounced protective role for these transporters. In Cyp3a-/- mice, brigatinib plasma exposure increased 1.3-fold, and was subsequently 1.8-fold reduced by transgenic overexpression of human CYP3 A4 in liver and intestine. The relative tissue distribution of brigatinib, however, remained unaltered. ABCB1 and ABCG2 thus limit brain accumulation, toxicity, and systemic exposure of brigatinib, whereas CYP3 A also markedly restricts its oral availability. Unexpected toxicities should therefore be carefully monitored when brigatinib is coadministered with ABCB1/ABCG2 inhibitors in patients. Collectively, these insights may support the clinical application of brigatinib. PMID- 30253204 TI - Atomistic mechanism of the constitutive activation of PDGFRA via its transmembrane domain. AB - Single-point mutations in the transmembrane (TM) region of receptor tyrosine kinases (RTKs) can lead to abnormal ligand-independent activation. We use a combination of computational modeling, NMR spectroscopy and cell experiments to analyze in detail the mechanism of how TM domains contribute to the activation of wild-type (WT) PDGFRA and its oncogenic V536E mutant. Using a computational framework, we scan all positions in PDGFRA TM helix for identification of potential functional mutations for the WT and the mutant and reveal the relationship between the receptor activity and TM dimerization via different interfaces. This strategy also allows us design a novel activating mutation in the WT (I537D) and a compensatory mutation in the V536E background eliminating its constitutive activity (S541G). We show both computationally and experimentally that single-point mutations in the TM region reshape the TM dimer ensemble and delineate the structural and dynamic determinants of spontaneous activation of PDGFRA via its TM domain. Our atomistic picture of the coupling between TM dimerization and PDGFRA activation corroborates the data obtained for other RTKs and provides a foundation for developing novel modulators of the pathological activity of PDGFRA. PMID- 30253205 TI - Identification of (4-(9H-fluoren-9-yl) piperazin-1-yl) methanone derivatives as falcipain 2 inhibitors active against Plasmodium falciparum cultures. AB - BACKGROUND: Falcipain 2 (FP-2) is the hemoglobin-degrading cysteine protease of Plasmodium falciparum most extensively targeted to develop novel antimalarials. However, no commercial antimalarial drugs based on FP-2 inhibition are available yet due to the low selectivity of most FP-2 inhibitors against the human cysteine proteases. METHODS: A structure-based virtual screening (SVBS) using Maybridge HitFinderTM compound database was conducted to identify potential FP-2 inhibitors. In vitro enzymatic and cell-growth inhibition assays were performed for the top-scoring compounds. Docking, molecular dynamics (MD) simulations and free energy calculations were employed to study the interaction of the best hits with FP-2 and other related enzymes. RESULTS AND CONCLUSIONS: Two hits based on 4 (9H-fluoren-9-yl) piperazin-1-yl) methanone scaffold, HTS07940 and HTS08262, were identified as inhibitors of FP-2 (half-maximal inhibitory concentration (IC50) = 64 MUM and 14.7 MUM, respectively) without a detectable inhibition against the human off-target cathepsin K (hCatK). HTS07940 and HTS08262 inhibited the growth of the multidrug-resistant P. falciparum strain FCR3 in culture (half-maximal inhibitory concentrations (IC50) = 2.91 MUM and 34 MUM, respectively) and exhibited only moderate cytotoxicity against HeLa cells (Half-maximal cytotoxic concentration (CC50) = 133 MUM and 350 MUM, respectively). Free energy calculations reproduced the experimental affinities of the hits for FP-2 and explained the selectivity with respect to hCatK. GENERAL SIGNIFICANCE: To the best of our knowledge, HTS07940 stands among the most selective FP-2 inhibitors identified by SBVS reported so far, displaying moderate antiplasmodial activity and low cytotoxicity against human cells. Hence, this compound constitutes a promising lead for the design of more potent and selective FP-2 inhibitors. PMID- 30253206 TI - Interactions between neural decision-making circuits predict long-term dietary treatment success in obesity. AB - Although dietary decision-making is regulated by multiple interacting neural controllers, their impact on dietary treatment success in obesity has only been investigated individually. Here, we used fMRI to test how well interactions between the Pavlovian system (automatically triggering urges of consumption after food cue exposure) and the goal-directed system (considering long-term consequences of food decisions) predict future dietary success achieved in 39 months. Activity of the Pavlovian system was measured with a cue-reactivity task by comparing perception of food versus control pictures, activity of the goal directed system with a food-specific delay discounting paradigm. Both tasks were applied in 30 individuals with obesity up to five times: Before a 12-week diet, immediately thereafter, and at three annual follow-up visits. Brain activity was analyzed in two steps. In the first, we searched for areas involved in Pavlovian processes and goal-directed control across the 39-month study period with voxel wise linear mixed-effects (LME) analyses. In the second, we computed network parameters reflecting the covariation of longitudinal voxel activity (i.e. principal components) in the regions identified in the first step and used them to predict body mass changes across the 39 months with LME models. Network analyses testing the link of dietary success with activity of the individual systems as reference found a moderate negative link to Pavlovian activity primarily in left hippocampus and a moderate positive association to goal directed activity primarily in right inferior parietal gyrus. A cross-paradigm network analysis that integrated activity measured in both tasks revealed a strong positive link for interactions between visual Pavlovian areas and goal directed decision-making regions mainly located in right insular cortex. We conclude that adaptation of food cue processing resources to goal-directed control activity is an important prerequisite of sustained dietary weight loss, presumably since the latter activity can modulate Pavlovian urges triggered by frequent cue exposure in everyday life. PMID- 30253207 TI - Estimating and accounting for the effect of MRI scanner changes on longitudinal whole-brain volume change measurements. AB - OBJECTIVE: Longitudinal MRI studies are often subjected to mid-study scanner changes, which may alter image characteristics such as contrast, signal-to-noise ratio, contrast-to-noise ratio, intensity non-uniformity and geometric distortion. Measuring brain volume loss under these conditions can render the results potentially unreliable across the timepoint of the change. Estimating and accounting for this effect may improve the reliability of estimates of brain atrophy rates. METHODS: We analyzed 237 subjects who were scanned at 1.5 T for the Alzheimer's Disease Neuroimaging Initiative (ADNI) study and were subject to intra-vendor or inter-vendor scanner changes during follow-up (up to 8 years). Sixty-three subjects scanned on GE Signa HDx and HDxt platforms were also subject to a T1-weighted sequence change from Magnetization Prepared Rapid Gradient Echo (MP-RAGE) to Fast Spoiled Gradient Echo with IR Preparation (IR-FSPGR), as part of the transition from ADNI-1 to ADNI-2/GO. Two-timepoint percentage brain volume changes (PBVCs) between the baseline "screening" and the follow-up scans were calculated using SIENA. A linear mixed-effects model with subject-specific random slopes and intercepts was applied to estimate the fixed effects of scanner hardware changes on the PBVC measures. The same model also included a term to estimate the fixed effects of the T1-weighted sequence change. RESULTS: Different hardware upgrade or change combinations led to different offsets in the PBVC (SE; p): Philips Intera to Siemens Avanto, -1.81% (0.30; p < 0.0001); GE Genesis Signa to Philips Intera, 0.99% (0.47, p = 0.042); GE Signa Excite to Signa HDx, 0.33% (0.095, p = 0.0005); GE Signa Excite to Signa HDxt, -0.023% (0.23, p = 0.92); GE Signa Excite to Signa HDx to Signa HDxt, 0.25% (0.095, p = 0.010) and 0.27% (0.16, p = 0.098), respectively; GE Signa HDx to Signa HDxt, -0.24% (0.25, p = 0.34); Siemens Symphony to Symphony TIM, -0.39% (0.16; p = 0.019). The sequence change from MP-RAGE to IR-SPGR was associated with an average -1.63% (0.12; p < 0.0001) change. CONCLUSION: Inter-vendor scanner changes generally led to greater effects on PBVC measurements than did intra-vendor scanner upgrades. The effect of T1-weighted sequence change was comparable to that of the inter-vendor scanner changes. Inclusion of the corrective fixed-effects terms for the scanner hardware and T1-weighted sequence changes yielded better model goodness-of-fits, and thus, potentially more reliable estimates of whole-brain atrophy rates. PMID- 30253208 TI - Commentary: New perspectives on protein aggregation during Biopharmaceutical development. AB - The occurrence of protein aggregation during bioprocessing steps such as purification, formulation and fill-finish, impacts yield and production costs, and must be controlled throughout the manufacturing process. Understanding aggregation mechanisms and developing mitigating strategies are imperative to ensure the clinical efficacy of the protein drug product and to reduce costs. This commentary reflects on recent progress made in the field of monoclonal antibody (mAb) aggregation with considerations on current and emerging measurement techniques, the use of novel excipients for preventing aggregation, interfacial phenomena and prediction of aggregation rates. The future direction of research is discussed based on academic and industrial perspectives. PMID- 30253209 TI - Utilizing glutathione-triggered nanoparticles to enhance chemotherapy of lung cancer by reprograming the tumor microenvironment. AB - In the present study, we have developed the robust nanoparticles (MGC-GNP/PTX), which are TAMs and tumor cells-dual recognizable, for targeting cancer therapy. Of great importance, the developed nano-platforms are glutathione (GSH) activable, which means it remains structure intact under normal physiological condition and can be disrupted when exposed to certain concentration of GSH. As demonstrated by the drug release assay in vitro, MGC-GNP/PTX exhibited an excellent structure stability under the normal condition with only 10% of cumulative drug release at 72 h. However, after increasing the concentration of GSH to 1 mM or 10 mM, the release of PTX from the nanoparticles was significantly accelerated and approximately 35% or 95% of drugs was released. Cellular experiments and in vivo tumor targeting assay displayed that the developed nanoparticles have a super capacity of tumor cells and TAMs-dual targeting drug delivery, which resulted in much stronger cytotoxicity when compared to the unmodified ones. Finally, the pharmacodynamic evaluation indicated that the mice treated with MGC-GNP/PTX displayed the strongest tumor suppression ability versus other groups. More importantly, the treatment of MGC-GNP/PTX did not significantly influence the body weight and pathological of the mice, indicated that the prepared nanoparticle system had a satisfactory bio-safety for targeting tumor drug delivery. PMID- 30253210 TI - An application of deep learning to detect process upset during pharmaceutical manufacturing using passive acoustic emissions. AB - The multivariate nature of a fluidized bed system creates process complexity that increases the risk of production upset. This research explores the use of passive acoustic emissions monitoring paired with an artificial neural network to detect fluidized bed distributor plate blockage. In many cases, early process failure detection can allow for immediate intervention, thus lowering operation costs. Blockages were simulated by actively covering portions of a top-spray fluidized bed distributor plate. Piezoelectric microphones were placed within the fluidized bed exhaust and attached externally to the vessel wall. Several time and frequency domain feature vectors were extracted from the monitoring data using the open source pyAudioAnalysis library in Python. Through deep learning, the artificial neural network used these feature vectors to train against each distributor plate blockage condition. The deep learning model was then evaluated using k-fold cross validation. The findings were very positive and successfully demonstrated an application of deep learning to detect process upset. PMID- 30253211 TI - Physicochemical and biopharmaceutical characterization of celecoxib nanoparticle: Avoidance of delayed oral absorption caused by impaired gastric motility. AB - The present study aimed to develop a celecoxib (CEL) nanoparticle with improved dissolution/dispersion and consistent absorption even in the presence of impaired gastric motility. CEL was pulverized by a wet-milling with hydroxypropyl cellulose (HPC), and the prepared nanoparticles were physicochemically characterized after freeze-drying. CEL nanoparticle with HPC-SSL (NP/CEL) exhibited better dissolution/dispersion behavior in pH1.2 solution compared with CEL nanoparticles with other polymers, as evidenced by a 21.8-fold higher initial dissolution/dispersion rate than crystalline CEL. The mean particle diameter of water suspended-NP/CEL was 250 nm, and the CEL nanoparticle existed in an amorphous state. Even after storage at 40 degrees C for 4 weeks, there were no significant changes in the dissolution/dispersion behavior. Oral absorption of CEL samples (5 mg-CEL/kg) was evaluated in normal and propantheline (PPT)-treated rats with simulated gastric motility impairment. In PPT-treated rats, oral crystalline CEL led to a decrease in oral absorption by 12% of the AUC0-4 compared with that in normal rats, whereas NP/CEL suppressed the pharmacokinetic transition of CEL by 43% of the AUC0-4 due to the improved dissolution/dispersion behavior of CEL. The NP/CEL system might be promising to avoid decreased absorption of CEL caused by impaired gastric motility. PMID- 30253212 TI - In vitro effect of mPEG2k-PCLx micelles on rat liver cytochrome P450 enzymes. AB - The present study was aimed to evaluate the effects of amphiphilic copolymer micelles on six major hepatic cytochrome P450 (CYP) isoforms. A series of mPEG2k PCLx polymeric micelles (mPEG2k-PCL2k, mPEG2k-PCL3.5k, mPEG2k-PCL5k and mPEG2k PCL10k) ranging from 20 to 100 nm were prepared to investigate the inhibitory or inductive activities by in vitro incubations of rat liver microsomes and primary rat hepatocytes. Inhibition of these polymeric micelles on CYP1A2, CYP2B1, CYP2C6, CYP2C11, CYP2D2 and CYP3A1/2 isoenzymes were observed above their critical micelle concentrations (>10 MUg.mL-1) and in a concentration-dependent manner. The mPEG2k-PCL2k micelles showed the strongest inhibition of CYP1A2, followed by CYP2C11. The micelles with lower molecular weight PCL segment exhibited more potent inhibitory potential. Induction on CYP1A2, CYP2B1 and CYP3A1/2 activity (2.1-7.2-fold, 1.5-2.4-fold and 1.3-3.0-fold, respectively) were detected at all tested concentrations (0.1-1000 MUg.mL-1 or 0.1-100 MUg.mL 1). Accordingly, most of the mRNA levels were upregulated. As demonstrated in ex vivo fluorescence imaging results, the mPEG2k-PCLx micelles mainly accumulated in the liver after intravenous administration. In conclusion, mPEG2k-PCLx micelles can interfere with the normal metabolic function of CYP450s in vitro, indicating polymeric micelles as promising drug nano-carriers might cause micelle-drug interaction and the in vivo interaction deserves further investigation. PMID- 30253213 TI - Binding and structure-kinetic relationship analysis of selective TLR4-targeted immunosuppressive self-assembling heparin nanoparticles. AB - Self-assembling aliphatic heparin derivatives were shown to inhibit the immune system by antagonizing Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD2). In the present study, glycol split heparin-d-erythro-sphingosine conjugates (NAHNP) and its regioselectively desulfated derivatives with shortened aliphatic chains were investigated regarding their biophysical properties in the interaction with TLR4/MD2. Two-dimensional nuclear Overhauser effect spectroscopy studies showed that upon glycol splitting, the heparin backbone gains extra adaptability that facilitates binding to proteins. However, unlike native heparin or glycol split non-anticoagulant heparin (NAH), hydrophobic derivatization of NAH forces sulfated iduronic acid residues to change configuration from a 2S0 skew-boat to a 1C4 chair form. Whereas neither heparin nor NAH had any appreciable effect, NAHNP significantly inhibited lipopolysaccharide-induced activation of the NF-kappaB transcription factor. We showed that NAHNP binds to TLR4/MD2 with an affinity of 62.3 nM. In line with computational studies, biosensor-based structure-kinetic relationship studies demonstrated that 6-O sulfo groups of d-glucosamine residue were essential in binding to arginines of both TLR4 and MD2 domains of the receptor complex. The desulfation of 6-O-sulfo groups decreases the association kinetics from 4.2 * 104 M-1 s-1 to 3.8 * 103 M-1 s-1, which results in a decreased affinity of 800 nM. Two aliphatic chains of NAHNP bound to the MD2 pocket similarly to lipopolysaccharide. A decrease in chain length resulted in a loss of inhibitory activity on NF-kappaB transcription and binding affinity to TLR4/MD2. In conclusion, the present study characterizes the immunosuppressive effect of aliphatic heparin derivatives and provides a promising strategy to develop selective immunosuppressants for acute and chronic inflammatory disorders. PMID- 30253214 TI - Soluplus micelles for acyclovir ocular delivery: Formulation and cornea and sclera permeability. AB - Nearly 20% of people affected by the herpes simplex virus (HSV) suffer from vision problems. The virus can infect all layers of the cornea or cause inflammatory diseases of the sclera. The aim of this work was to test whether encapsulation of acyclovir in Soluplus or Solutol polymeric micelles increases its solubility, corneal permeability and sclera penetration. The aqueous solubility of acyclovir is known to be low, and therefore approaches that increase both its solubility and ability to penetrate through the eye may favor the efficacy of the treatments. Copolymer dispersions (covering wide range of concentrations) were prepared in water and PBS 7.4 and characterized regarding size and Z-potential (close to zero). Solutol micelles increased their size when the drug was incorporated (135 vs. 19 nm), while Soluplus micelles showed little difference (137 nm). Only Soluplus micelles significantly enhanced acyclovir solubility and withstood dilution stability tests. Soluplus (12-20%) formulations showed a progressive increase in viscoelasticity as temperature rose, which may allow for easy dropping onto the eye and subsequent retention in the gel form. Drug permeability through bovine cornea and sclera was investigated in detail. Although similar permeability coefficients were recorded for the drug when applied as the free drug in solution or formulated in Soluplus micelles, the micelle formulation significantly shortened the permeation lag time through the cornea. Moreover, Soluplus micelles were advantageous compared to the drug solution in terms of greater amount of acyclovir accumulated in both cornea and sclera, and higher steady state flux. If compared with cornea, the amounts of drug permeated through the sclera were approx. 10 times greater, which opens the possibility of drug delivery to the posterior eye segment. PMID- 30253215 TI - Multimorbidity and comorbidity revisited: refining the concepts for international health research. PMID- 30253216 TI - A novel superior medication-based chronic disease score predicted all-cause mortality in independent geriatric cohorts. AB - OBJECTIVES: On the basis of current treatment guidelines, we developed and validated a medication-based chronic disease score (medCDS) and tested its association with all-cause mortality of older outpatients. STUDY DESIGN AND SETTING: Considering the most prevalent chronic diseases in the elderly German population, we compiled a list of evidence-based medicines used to treat these disorders. Based on this list, a score (medCDS) was developed to predict mortality using data of a large longitudinal cohort of older outpatients (training sample; MultiCare Cohort Study). By assessing receiver-operating characteristics (ROC) curves, the performance of medCDS was then confirmed in independent cohorts (ESTHER, KORA-Age) of community-dwelling older patients and compared with already existing medication-based scores and a score using selected anatomical-therapeutic-chemical (ATC) codes. RESULTS: The final medCDS score had an ROC area under the curve (AUC) of 0.73 (95% CI 0.70-0.76). In the validation cohorts, its ROC AUCs were 0.79 (0.76-0.82, KORA-Age) and 0.74 (0.71-0.78, ESTHER), which were superior to already existing medication-based scores (RxRisk, CDS) and scores based on pharmacological ATC code subgroups (ATC3) or age and sex alone (Age&Sex). CONCLUSIONS: A new medCDS, which is based on actual treatment standards, predicts mortality of older outpatients significantly better than already existing scores. PMID- 30253217 TI - GRADE approach to rate the certainty from a network meta-analysis: avoiding spurious judgments of imprecision in sparse networks. AB - When direct and indirect estimates of treatment effects are coherent, network meta-analysis (NMA) estimates should have increased precision (narrower confidence or credible intervals compared with relying on direct estimates alone), a benefit of NMA. We have, however, observed cases of sparse networks in which combining direct and indirect estimates results in marked widening of the confidence intervals. In many cases, the assumption of common between-study heterogeneity across the network seems to be responsible for this counterintuitive result. Although the assumption of common between-study heterogeneity across paired comparisons may, in many cases, not be appropriate, it is required to ensure the feasibility of estimating NMA treatment effects. This is especially the case in sparse networks, in which data are insufficient to reliably estimate different variances across the network. The result, however, may be spuriously wide confidence intervals for some of the comparisons in the network (and, in the Grading of Recommendations Assessment, Development, and Evaluation approach, inappropriately low ratings of the certainty of the evidence through rating down for serious imprecision). Systematic reviewers should be aware of the problem and plan sensitivity analyses that produce intuitively sensible confidence intervals. These sensitivity analyses may include using informative priors for the between-study heterogeneity parameter in the Bayesian framework and the use of fixed effects models. PMID- 30253218 TI - Cohort studies were found to be frequently biased by missing disease information due to death. AB - OBJECTIVES: In epidemiologic cohort studies with missing disease information due to death (MDID), conventional analyses right-censoring death cases at the last observation or at death may yield significant bias in relative risk and hazard ratio estimates. The aim of this study was to investigate susceptibility to this bias and assess its potential direction and magnitude. STUDY DESIGN AND SETTING: Literature review of selected epidemiologic, geriatric, and environmental journals in 2011-2012 and simulation study of various conventional approaches to handling missing disease data. A study was considered susceptible to MDID bias if disease information was collected at follow-up visits only, and a conventional analysis was performed on the data. RESULTS: Of 125 identified studies, 58 (46.4%, 95% confidence interval [CI]: 37.7-55.1%) were classified as susceptible to MDID bias, of which six (10.3%, 95% CI: 2.5-18.2%) attempted to address this in sensitivity analyses. The simulation revealed that depending on the analytic strategy for handling missing disease data, the potential exists for significant under- or over-estimation of risk factor effect estimates. CONCLUSION: Awareness of MDID bias is important as more adequate analysis methods exist permitting an unbiased analysis. Recommendations for better reporting and analysis of MDID are provided. PMID- 30253219 TI - Two valid and reliable work role functioning questionnaire short versions were developed: WRFQ 5 and WRFQ 10. AB - OBJECTIVE: The study aims to develop and validate short versions of the work role functioning questionnaire v2.0 (WRFQ) that retain the measurement properties of the full-length 27-item questionnaire. STUDY DESIGN AND SETTING: Six cross sectional Dutch samples (N = 2,433) were used, containing data on gender, self rated health, job type, and WRFQ scores. Indicators from classical test theory and item response theory methods were used along with evaluation of translatability and conceptual considerations to identify short version candidate items. To ensure content validity, the item selection was made within the five factor structure established for the WRFQ-leading to a 5-item and a 10-item short version. Bland-Altman analyses of agreement and interclass correlations with the full WRFQ were used to establish the best scoring procedure. Discriminant validity was evaluated for the short versions and compared with the full-length 27-item version. RESULTS: Both short versions showed acceptable agreement with the full-length 27-item version using simple scoring procedures. Both also showed comparable or stronger validity than the full WRFQ in known group comparisons. CONCLUSION: Both short versions can be used to measure work role functioning in working samples with mixed clinical conditions and job types. PMID- 30253220 TI - Outcomes that patients perceive and value are systematically unassessed in randomized clinical trials of endocrine-related illnesses: a systematic review. PMID- 30253221 TI - Evidence to Decision framework provides a structured "roadmap" for making GRADE guidelines recommendations. AB - OBJECTIVES: It is unclear how guidelines panelists discuss and consider factors (criteria) that are formally and not formally included in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. To describe the use of decision criteria, we explored how panelists adhered to GRADE criteria and sought to identify any emerging non-GRADE criteria when the panelists used the Evidence to Decision (EtD) framework as part of GRADE application. STUDY DESIGN AND SETTING: We used conventional and summative qualitative analyses to identify themes emerging from face-to-face, panel meeting discussions. Forty-eight members from 12 countries participated in the development of five guidelines for the management of venous thromboembolism by the American Society of Hematology. RESULTS: Ten themes corresponded to the GRADE approach and represented all panel discussions. Over half (53%) of the total panel discussions concerned the use of research evidence. When evidence was considered sufficient and clear, the decision-making process proved rapid. CONCLUSION: The GRADE EtD framework provides structure to guidelines panel meetings, and ensures that the panelists consider all established formal GRADE criteria as they decide on the recommendation text, strength, and direction (for or against an intervention). This is the first study assessing the use of GRADE's EtD framework during real-time guidelines development using panel discussions. Given the widespread use of GRADE, this study provides important information for practice recommendations generated when guidelines panels explicitly follow, in a transparent and systematic manner, the structured GRADE EtD framework. By recognizing the extent to which panels discuss and consider GRADE and other (non GRADE) criteria for producing guideline recommendations, we are one step closer to understanding the decision-making process in panels that use a structured framework such as the GRADE EtD framework. PMID- 30253222 TI - Repetitive Transcranial Magnetic Stimulation changes absolute theta power during cognitive/motor tasks. AB - Repetitive Transcranial Magnetic Stimulation (rTMS) studies are used to test motor imagery hypothesis. Motor Imagery (MI) represents conscious access to contents of movement intention, generally executed unconsciously during motor preparation. The main objective of this study was to investigate electrophysiological changes, which occurred before and after low-frequency rTMS application when we compared three different tasks: execution, action observation and motor imagery of finger movement. We hypothesize that absolute theta power over frontal regions would change between sensorimotor integration tasks and after 1 Hz of rTMS application. Eleven healthy, right-handed volunteers of both sexes (5 males, 6 females; mean age 28 +/- 5 years), with no history of psychiatric or neurological disorders, participated in the experiment. After performing the tasks randomly, subjects were submitted to 15 min of low-frequency rTMS applied on Superior Parietal Cortex (SPC) and performed the tasks again. All tasks were executed simultaneously with Eletroencephalography (EEG) signals recording. Our results clarified the specificity of each sub-region during MI activity. Frontopolar cortex presented involvement with motor process and showed main effect for task and moment. Inferior frontal gyrus presented involvement with long-term memory retrieval and showed interaction between task and moment in the left hemisphere while the right hemisphere showed a main effect for task and moment. The lack of the main effect for conditions on the anterior frontal cortex collaborates with the hypothesis that in this region an integrated circuit of performance monitoring exists. PMID- 30253223 TI - Miconazole stimulates post-ischemic neurogenesis and promotes functional restoration in rats. AB - Miconazole, a frequently used antifungal drug, has been identified with new functions to promote oligodendrocyte progenitor cells differentiation and to enhance remyelination. However, the neuroregenerative and therapeutic benefit of miconazole on ischemic stroke model have not been tested. In the present study, the effects of miconazole on a rat model of transient middle cerebral artery occlusion were evaluated. Rats received miconazole (10 mg/kg) or saline by intravenous administration for 7 days after stroke. A battery of neurobehavioral assessments, including rotarod test, open-field test, neurological severity score and novel object recognition task were evaluated. The results revealed a significant functional improvement in miconazole-treated rats compared with vehicle-treated control. Animals were sacrificed at 7 and 28 days after stroke. Double immunofluorescence staining for NeuN+/BrdU+, DCX+/BrdU+ and Nestin+/BrdU+ cells indicated miconazole significantly promoted neurogenesis. Western blotting analysis revealed miconazole upregulated the protein expression of brain derived neurotrophic factor, myocyte enhancer factor 2D, synaptophysin, and postsynaptic density protein 95, while downregulated the expression of cyclin-dependent kinase 5. Taken together, miconazole promoted functional recovery on ischemic stroke model via stimulating post-ischemic neurogenesis. PMID- 30253224 TI - GPER and ERalpha mediate estradiol enhancement of mitochondrial function in inflamed adipocytes through a PKA dependent mechanism. AB - Obesity is associated with inflammation, dysregulated adipokine secretion, and disrupted adipose tissue mitochondrial function. Estradiol (E2) has been previously reported to increase mitochondrial function and biogenesis in several cell lines, but neither the type of oestrogen receptor (ERalpha, ERbeta and GPER) involved nor the mechanism whereby such effects are exerted have been fully described. Considering the anti-inflammatory activity of E2 as well as its effects in enhancing mitochondrial biogenesis, the aim of this study was to investigate the contribution of ERalpha, ERbeta, and GPER signaling to the E2 mediated enhancement of adipocyte mitochondrial function in a pro-inflammatory situation. 3T3-L1 cells were treated for 24 h with ER agonists (PPT, DPN, and G1) and antagonists (MPP, PHTPP, and G15) in the presence or absence of interleukin 6 (IL6), as a pro-inflammatory stimulus. Inflammation, mitochondrial function and biogenesis markers were analyzed. To confirm the involvement of the PKA pathway, cells were treated with a GPER agonist, a PKA inhibitor, and IL6. Mitochondrial function markers were analyzed. Our results showed that activation of ERalpha and GPER, but not ERbeta, was able to counteract the proinflammatory effects of IL6 treatment, as well as mitochondrial biogenesis and function indicators. Inhibition of PKA prevented the E2- and G1-associated increase in mitochondrial function markers. In conclusion E2 prevents IL6 induced inflammation in adipocytes and promotes mitochondrial function through the combined activation of both GPER and ERalpha. These findings expand our understanding of ER interactions under inflammatory conditions in female rodent white adipose tissue. PMID- 30253225 TI - Synthesis of 1alpha,25-dihydroxyvitamin D3 analogues with alpha,alpha difluorocycloketone at the CD-ring side chains and their biological properties in ovariectomized rats. AB - Two novel 1alpha,25-dihydroxyvitamin D3 derivatives containing a alpha,alpha difluorocyclopentanone (3) or alpha,alpha-difluorocyclohexanone (4) moiety at the CD-ring side chains were designed, synthesized, and evaluated for their biological properties on restoring bone mass in ovariectomized (OVX) rats with established osteopenia. The synthesis of compounds 3 and 4 utilized the Wittig Horner coupling to build up the vitamin D conjugated triene system, followed by the introduction of the cycloketone fragments at the side chain, and subsequent alpha,alpha-difluorination of the ketone by the treatment of the derived silyl enol ether with Selectfluor, as the key synthetic steps. In comparison with the natural 1alpha,25-dihydroxyvitamin D3 (calcitriol; 200 ng/kg/day), oral administration of compounds 3 and 4 at the dose of 25 ng/kg/day for 6 weeks led to much improved bone mass and bone density related parameters, while maintaining normal serum calcium and serum phosphorus levels. The immunohistochemistry results showed that both compounds remarkably decreased in osteoclast number and moderately decreased in osteoblast number on trabecular bone surface. Therefore, our findings suggested that compounds 3 and 4 successfully rescue bone loss by suppression on bone turnover in OVX rat models. PMID- 30253226 TI - Chitosan-eurycomanone nanoformulation acts on steroidogenesis pathway genes to increase the reproduction rate in fish. AB - The study was undertaken to explore the molecular mechanism of eurycomanone, a major compound of Eurycoma longifolia plant in increasing the reproductive processes in the male fish model. Chitosan-nanoconjugated eurycomanone nanoparticles with a significant particle size [130 nm (CED1); 144.1 nm (CED2)] and stable zeta potentials (+49.1 mV and +30 mV) were synthesized and evaluated against naked eurycomanone (ED1 and ED2). In present study, short-term and long term experiments were conducted to evaluate the effect of nano-formulation on expression of endocrine-related genes, circulating hormone concentrations (Follicle stimulating hormone, FSH; luteinizing hormone, LH; progesterone, testosterone and 17-beta estradiol) and reproductive capacity of male Clarias magur. In short-term experiment, the sampling of tissues was done on hourly basis after injection of eurycomanone either alone or with chitosan and long-term experiment was carried for 21 days and in this the injection was repeated after 7 days and 14 days. Treatments CED1 and CED2 showed controlled and sustained surge of the transcript level of selected genes (except aromatase) and serum hormones (except 17beta-estradiol) compared to ED1 and ED2 groups. The transcript levels of aromatase and serum 17beta-estradiol hormone showed the declining trend in the chitosan conjugated groups. The gonadosomatic index (GSI), reproductive capacity, intracellular calcium and selenium and cellular structure of testes were improved in CED1 and CED2 groups compared to other treatments. Furthermore, the effect of chitosan conjugated eurycomanone was evaluated in primary testicular cells and an increase in the mRNA expression level of endocrine-related genes was detected. This is the first report of the use of chitosan conjugated eurycomanone and present study elucidates the molecular mechanism of eurycomanone in increasing the reproductive output in animals. PMID- 30253227 TI - Long-term neurological outcomes in out-of-hospital cardiac arrest patients treated with targeted-temperature management. AB - BACKGROUND: This study aimed to assess long-term cognitive and functional outcomes in out-of-hospital cardiac arrest (OHCA) patients treated with targeted temperature management, investigate the existence of prognostic factors that could be assessed during initial admission and evaluate the usefulness of classic neurological scales in this clinical scenario. METHODS: Patients admitted due to OHCA from August 2007 to November 2015 and surviving at least one year were included. Each patient completed a structured interview focused on the collection of clinical, social and demographic data. All available information in clinical records was reviewed and a battery of neurocognitive and psychometric tests was performed. RESULTS: Seventy-nine patients were finally included in the analysis. Forty-three patients (54.4%) scored below the usual cut-off points for the diagnosis of mild cognitive impairment, even though most of these deficits went unnoticed when patients were assessed using CPC and modified Rankin scale. Nineteen (24%) developed certain degree of impairment in their attention capacity and executive functions. A significant proportion developed new memory-related disorders (43%), depressive symptoms (17.7%), aggressive/uninhibited behavior (12.7%) and emotional lability (8.9%). A greater number of weekly hours of intellectual activity and a qualified job were independent protective factors for the development of cognitive impairment. However, being older at the time of the cardiac arrest was identified as a poor prognostic factor. CONCLUSIONS: There is a high prevalence of long-term cognitive deficits and functional limitations in OHCA survivors. Most commonly used clinical scales in clinical practice are crude and lack sensitivity to detect most of these deficits. PMID- 30253228 TI - Impact of pre-hospital vital parameters on the neurological outcome of out-of hospital cardiac arrest: Results from the French National Cardiac Arrest Registry. AB - INTRODUCTION: The targets for vital parameters following return of spontaneous circulation (ROSC) from an out-of-hospital cardiac arrest (OHCA) are based on studies carried out predominantly in intensive care units. Therefore, we studied the pre-hospital phase. METHOD: We included all adult OHCA from the French OHCA Registry. Vital parameters [peripheral oxygen saturation level (SpO2), end-tidal carbon dioxide (ETCO2) and systolic blood pressure (SBP)] documented during the pre-hospital phase by mobile medical team, were evaluated with regard to the neurological outcome on day 30 (classified as good for Cerebral Performance Category (CPC) 1 - 2, and poor for CPC 3 - 5 or death). RESULTS: When compared with a reference range of 94-98%, SpO2 values less than 94% were associated with a worse outcome on univariate analysis [relative risk (RR) = 1.108(1.069 - 1.147)]. An SpO2 of 99 - 100% did not appear to be harmful [RR = 0.9851(0.956 1.015)]. ETCO2 values that deviated from the reference of 30 - 40 mmHg were associated with a worse outcome on univariate analysis [<20, RR = 1.191(1.143 - 1.229); 20 - 29, RR = 1.092(1.061 - 1.123); 41 - 50, RR = 1.075(1.039 - 1.110); >50, RR = 1.136(1.085 - 1.179)]. When compared with a reference range of 100 - 130, higher or lower values of SBP were associated with a worse outcome on univariate analysis [<80, RR = 1.203(1.158 - 1.243); 80 - 99, RR = 1.069(1.033 - 1.105); 131 - 160, RR = 1.076(1.043 - 1.110); >160, RR = 1.168(1.126 - 1.208)]. The multivariate analysis yielded similar results. CONCLUSION: In comatose patients who have achieved ROSC after OHCA, vital parameters in the pre-hospital phase appear to have a real impact on the 30-day neurological outcome. We found that an SpO2 >= 94%, an ETCO2 of 30 - 40 mmHg, and an SBP of 100 - 130 mmHg were associated with a better prognosis. PMID- 30253229 TI - Predicting in-hospital mortality and unanticipated admissions to the intensive care unit using routinely collected blood tests and vital signs: Development and validation of a multivariable model. AB - AIM: The National Early Warning System (NEWS) is based on vital signs; the Laboratory Decision Tree Early Warning Score (LDT-EWS) on laboratory test results. We aimed to develop and validate a new EWS (the LDTEWS:NEWS risk index) by combining the two and evaluating the discrimination of the primary outcome of unanticipated intensive care unit (ICU) admission or in-hospital mortality, within 24 h. METHODS: We studied emergency medical admissions, aged 16 years or over, admitted to Oxford University Hospitals (OUH) and Portsmouth Hospitals (PH). Each admission had vital signs and laboratory tests measured within their hospital stay. We combined LDT-EWS and NEWS values using a linear time-decay weighting function imposed on the most recent blood tests. The LDTEWS:NEWS risk index was developed using data from 5 years of admissions to PH, and validated on a year of data from both PH and OUH. We tested the risk index's ability to discriminate the primary outcome using the c-statistic. RESULTS: The development cohort contained 97,933 admissions (median age = 73 years) of which 4723 (4.8%) resulted inhospital death and 1078 (1.1%) in unanticipated ICU admission. We validated the risk index using data from PH (n = 21,028) and OUH (n = 16,383). The risk index showed a higher discrimination in the validation sets (c-statistic value (95% CI)) (PH, 0.901 (0.898-0.905); OUH, 0.916 (0.911-0.921)), than NEWS alone (PH, 0.877 (0.873-0.882); OUH, 0.898 (0.893-0.904)). CONCLUSIONS: The LDTEWS:NEWS risk index increases the ability to identify patients at risk of deterioration, compared to NEWS alone. PMID- 30253230 TI - Comparison of manual pulse palpation, cardiac ultrasonography and Doppler ultrasonography to check the pulse in cardiopulmonary arrest patients. AB - OBJECTIVE: For health professionals, the absence of pulse checked by manual palpation is a primary indicator for initiating chest compressions in patients considered to have cardiopulmonary arrest (CA). However, using a pulse check to evaluate perfusion during CA may be associated with some risks of its own. Our objective was to compare the efficiency of cardiac ultrasonography (CUSG), Doppler ultrasonography (DUSG), and manual pulse palpation methods to check the pulse in CA patients. MATERIAL AND METHODS: This study was prospectively performed in 137 patients older than 16 years of age who underwent cardiopulmonary resuscitation (CPR). CUSG, DUSG, and manual pulse palpation were practiced simultaneously as suggested in the relevant guidelines. Findings of the patients were recorded at the first min, at min 15 and at the end of CPR. SPSS 18.0 was used for statistical analysis. FINDINGS: A total of 72.3% (n = 99) of the cardiopulmonary arrest incidents occurred out-of-hospital. CUSG (4.76 +/- 2.19, 4.33 +/- 2.17, and 3.68 +/- 2.14 s), DUSG (9.59 +/- 2.37, 8.22 +/- 2.86, and 7.60 +/- 2.83 s), and manual pulse palpation (10.76 +/- 1.03, 9.72 +/- 3.01, and 9.29 +/- 3.36 s) measurements of the first, second, and last inspections were detected, respectively. The false negative rates (100%, 28%, and 0%) and false positive rates (5.3%, 3.5%, and 0%) of manual pulse palpation the first, second, and last inspections were calculated, respectively, as well. CONCLUSION: The use of real-time CUSG during resuscitation provides a substantial contribution to the resuscitation team. CUSG will allow earlier and more accurate detection of pulse than manual pulse palpation and DUSG. PMID- 30253231 TI - Neural correlates of trauma-related single word processing in posttraumatic stress disorder. AB - Interpersonal violence (IPV) is one of the most frequent causes for the development of posttraumatic stress disorder (PTSD) in women. One key component in PTSD is altered processing of trauma-related cues, leading to emotional symptoms. In the everyday environment, words with trauma-associated semantic content represent typical, albeit abstract, trauma-related stimuli for patients suffering from PTSD. However, the functional neuroanatomy associated with processing single trauma-related words in IPV-PTSD is not understood. The present event-related functional magnetic resonance imaging study investigated the neural basis of trauma-related word processing in women with IPV-PTSD relative to healthy controls (HC) during a non-emotional vigilance task in which the emotional content of the words was task-irrelevant. On the behavioral level, trauma-related relative to neutral word stimuli evoked more unpleasant feelings, higher arousal as well as anxiety in IPV-PTSD patients as compared to HC. Functional imaging data showed hyperactivation to trauma-related versus neutral words in the basolateral amygdala (BLA) and cortical language-processing regions (inferior frontal gyrus, posterior cingulate cortex, angular/supramarginal gyrus) in IPV-PTSD compared to HC. These results propose a role of the BLA in hypervigilant responding to verbal trauma associated cues in IPV-PTSD. Furthermore, the particular involvement of cortical language-processing regions indicates enhanced processing of trauma-related words in brain regions associated with analysis and memory of verbal material. Taken together, our findings suggest that both subcortical and cortical mechanisms contribute to automatic responsivity to verbal trauma cues in PTSD. PMID- 30253232 TI - High frequency heart rate variability: Evidence for a transdiagnostic association with suicide ideation. AB - Low levels of high frequency heart rate variability (HF-HRV) have been shown to be associated with suicidal ideation and behavior in students and depressed patients. The goal of the present study was to examine associations between suicide ideation and resting HF-HRV as well as HF-HRV reactivity in a diagnostically heterogeneous sample of adult outpatients with or without concurrent suicide ideation. Participants were N = 85 outpatients (67.1% female; age: M = 38.8, SD = 13.72). HF-HRV reactivity was assessed using a sad film induction method. Associations between resting HF-HRV, HF-HRV reactivity and suicide ideation were analyzed using linear regression modeling - controlling for depression, anxiety and stress. HF-HRV reactivity towards the sad film, but not low resting HF-HRV baseline, was predictive of higher scores on suicidal ideation within the whole sample. In women, lower resting as well as perturbed HF-HRV reactivity was associated with higher scores on suicidal ideation. Results suggest that suicide ideators have a reduced capacity to regulate their response to stress. PMID- 30253233 TI - Target probability modulates fixation-related potentials in visual search. AB - This study investigated the influence of target probability on the neural response to target detection in free viewing visual search. Participants were asked to indicate the number of targets (one or two) among distractors in a visual search task while EEG and eye movements were co-registered. Target probability was manipulated by varying the set size of the displays between 10, 22, and 30 items. Fixation-related potentials time-locked to first target fixations revealed a pronounced P300 at the centro-parietal cortex with larger amplitudes for set sizes 22 and 30 than for set size 10. With increasing set size, more distractor fixations preceded the detection of the target, resulting in a decreased target probability and, consequently, a larger P300. For distractors, no increase of P300 amplitude with set size was observed. The findings suggest that set size specifically affects target but not distractor processing in overt serial visual search. PMID- 30253234 TI - Dosimetric benefits of mid-position compared with internal target volume strategy for esophageal cancer radiation therapy. AB - PURPOSE: Both mid-position (MidP) and internal target volume (ITV) strategies can take the respiration-induced target motion (RTM) into account. This study aimed to compare these two strategies in terms of clinical target volume (CTV) coverage and dose to organs at risk (OARs) for esophageal cancer radiation therapy (RT). MATERIALS AND METHODS: Fifteen esophageal cancer patients were retrospectively included for neoadjuvant RT planning. Per patient, a 10-phase 4D-CT was acquired with CTV and OARs delineated on the 20% phase. The MidP-CT was reconstructed based on deformable image registration (DIR) between the 20% phase and the other nine phases; thereby the CTV and OARs delineations were propagated and an ITV was constructed. Both MidP and ITV strategies were used for treatment planning, yielding the planned dose. Next, these plans were applied to the 10-phase 4D-CT to calculate the dose distribution for each phase of the 4D-CT. Based on the DIR, these calculated dose distributions were warped and averaged to yield the accumulated 4D-dose. Subsequently, we compared, in terms of CTV coverage and dose to OARs, the planned dose with the accumulated 4D-dose and also the MidP strategy with the ITV strategy. RESULTS: The differences between the planned dose and accumulated 4D-dose were limited and clinically irrelevant. In 14 patients, both MidP and ITV strategies showed V95%>98% for the CTV. Compared to the ITV strategy, the MidP strategy showed a significant reduction of approximately 10% in the dose-volume histogram parameters for the lungs, heart, and liver (p<0.001, Wilcoxon signed-rank test). CONCLUSIONS: Compared to the ITV strategy, the MidP strategy in treatment planning can lead to an approximately 10% reduction in the dose to OARs with an adequate CTV coverage for esophageal cancer RT. PMID- 30253235 TI - Pathologic Predictors of Local Recurrence in Atypical Meningiomas Following Gross Total Resection. AB - PURPOSE: To assess the local recurrence rate of gross totally resected atypical meningiomas and evaluate for pathologic predictors of recurrence. METHODS AND MATERIALS: All patients meeting the 2016 World Health Organization grade 2 meningioma criteria who received gross total resection were included in this retrospective analysis. A neuropathologist re-reviewed all surgical specimens for the following pathologic factors: brain invasion, macronuclei, necrosis, sheeting architecture, hypercellularity, high nuclear to cytoplasmic ratio, Ki67 proliferative index, mitotic number, and choroid or clear cell histology. Local recurrence and salvage therapy were recorded. RESULTS: Ninety-seven patients met the inclusion criteria and had a median radiographic follow-up of 53 months (range, 3-153). Necrosis was present in 41 specimens (42%), and brain invasion occurred in 30 (31%). Seventy-six patients (78%) had 3 of 5 World Health Organization grade 2 qualifying atypical features. Median mitotic number and Ki67 index were 3 (0-12) and 15 (2%-55%), respectively. Only Ki67 proliferative index and mitotic number predict for local recurrence. The Kaplan-Meier estimate of local recurrence was 30.3% at 3 years. CONCLUSIONS: In this cohort of gross totally resected atypical meningioma followed with observation, local recurrence occurred in 30.3% at 3 years. Ki67 index and mitotic number predict for local failure and could help stratify patients who would benefit from adjuvant therapy. PMID- 30253236 TI - Cost and Cost-Effectiveness of Image Guided Partial Breast Irradiation in Comparison to Hypofractionated Whole Breast Irradiation. AB - PURPOSE: Hypofractionated whole breast irradiation (HWBI) and accelerated partial breast irradiation (APBI) represent two adjuvant radiation therapy options following breast conserving surgery. We performed a cost and cost-effectiveness analysis of an external beam image guided APBI technique compared to HWBI. METHODS: HWBI was defined as 40 Gy/15 fractions to the whole breast with or without a 10 Gy/5 fraction boost. APBI was 30 Gy/5 fractions per Livi et al and was evaluated as both IMRT and SBRT. The decision analytic model measured effectiveness in quality-adjusted life years (QALYs). Micro-costing was conducted in order to estimate the true cost of the different treatment regimens and incremental cost-effectiveness analysis was performed. RESULTS: Based on micro costing, the cost of HWBI was $4,551 with boost and $3,666 without boost, compared to $2,966 for APBI. Including indirect costs, HWBI with boost cost $6,160, HWBI without boost cost $4,940 and APBI cost $3,569. Cost savings for APBI compared to HWBI with and without boost was $1,585/$700 based on direct costs and $2,591/$1,371 including indirect costs. APBI was also more effective, at .2300 QALYs compared to .2289 for HWBI with or without boost. Thus, APBI was both less costly and more effective. Basing cost on Medicare reimbursement (IMRT) leads to APBI again dominating HWBI, but basing cost for APBI on reimbursement billed as SBRT leads to HWBI being far more cost-effective. CONCLUSIONS: Image guided partial breast irradiation is less costly to deliver and has slightly improved efficacy compared to hypofractionated WBI, with or without a boost. IMRT APBI should be considered a standard of care option in appropriately selected patients based on efficacy and value. PMID- 30253237 TI - Local Relapse After Breast-Conserving Therapy Versus Mastectomy for Extensive Pure Ductal Carcinoma In Situ >=4 cm. AB - PURPOSE: The optimal treatment for patients with extensive pure ductal carcinoma in situ (DCIS) >=4 cm is controversial. This study evaluates local relapse according to type of local therapy: mastectomy, breast-conserving surgery (BCS) alone, and BCS + radiation therapy (RT). METHODS AND MATERIALS: Subjects were female patients who received diagnoses of pure DCIS >=4 cm between 1989 and 2010 and were referred to British Columbia Cancer. Clinicopathologic and treatment characteristics were compared between treatment cohorts. Local relapse (LR) was estimated using competing risk analysis. Multivariable analysis was performed using Cox regression analysis. RESULTS: Patients had the following treatments: 490 mastectomy, 38 BCS alone, and 192 BCS + RT. The 10-year cumulative incidence of LR was 16% after BCS (95% confidence interval [CI], 6-29%), 8% after BCS + RT (95% CI, 4-12%), and 2% after mastectomy (95% CI, 1-4%). On multivariable analysis, estrogen receptor-negative disease (hazard ratio [HR], 3.32; 95% CI, 1.08-10.18; P = .04) and positive margins (HR, 3.55; 95% CI, 1.56-8.05; P = .002) were associated with increased LR. BCS alone (HR, 7.87; 95% CI, 2.82-21.92; P < .0001), BCS + RT + no boost (HR, 3.80; 95% CI, 1.56-9.28; P = .003), and BCS + RT + boost (HR, 5.76; 95% CI, 2.59-12.83; P < .0001) were all associated with a higher risk of relapse relative to mastectomy. CONCLUSIONS: Mastectomy remains a standard local treatment option for extensive DCIS, but BCS + RT may also be reasonably considered in selected patients with a careful discussion of the benefits, side effects, and patient preferences. PMID- 30253238 TI - Building reliable evidence from real-world data: Needs, methods, cautiousness and recommendations. AB - National healthcare systems of advanced countries, including Italy, widely agree on the approach whereby public healthcare decisions should be driven by available evidence on effectiveness and safety of therapeutics. It is equally accepted that randomized controlled clinical trials (RCTs), although universally recognised as the most robust "evidence generators", are insufficient for guiding the decision making process since they are intrinsically unsuited to capture the impact of treatments in routine clinical practice. The complexity of treatments, as well as the demographic and clinical heterogeneity of patients receiving the treatments, and the long period of many treatments, explain the gap between the evidence generated in the controlled, but artificial, setting of RCTs and their current impact in the real world. The so-called pragmatic RCTs, despite guaranteeing greater flexibility compared to conventional trials, are not always able to reduce this gap. This explains the growing interest in the development of methods able to produce evidence on the real-world impact of care pathways (i.e., real world evidence). Among them, those based on the Electronic Healthcare Records (EHRs), as the databases on the healthcare services of the National Health System provided to beneficiaries, known as Healthcare Utilization Databases (HCU), are becoming established and receiving increasing attention from the scientific community and healthcare decision-makers. We described the research areas in which HCU databases may be particularly useful, jointly with strength, weakness and potential of this approach. It is concluded that HCU data cannot substitute RCTs but they can usefully complement RCT data for adequately supporting healthcare decision-makers. PMID- 30253240 TI - Intravenous dexmedetomidine augments the oculocardiac reflex. PMID- 30253239 TI - Embryology, anatomy, physiology and pathophysiology of the peritoneum and the peritoneal vasculature. AB - The peritoneum is a large serous membrane with both epithelial and mesenchymal features, and is essential for maintaining an intra-abdominal homeostatic equilibrium. The peritoneum plays a central role in the pathogenesis of a number of disorders. Pathological processes affecting the peritoneum such as inflammation and carcinomatosis can have serious clinical consequences, but the pathophysiology of these conditions is poorly understood. Understanding peritoneal embryology, anatomy and physiology is crucial to comprehend pathophysiological mechanisms and to devise a new focus for research. The vascular response to pathological processes appears to be of considerable importance, since the peritoneal vasculature plays a pivotal role in most associated diseases. Therefore, this review summarizes currently available literature with special emphasis on the development, anatomy and function of the peritoneal vasculature. Pathological processes are described to illustrate physiological and pathophysiological characteristics of the peritoneum. PMID- 30253241 TI - Recombinant Pregnancy-Specific Glycoprotein 1 Has a Protective Role in a Murine Model of Acute Graft-versus-Host Disease. AB - Acute graft-versus-host disease (aGVHD) is an immune-mediated reaction that can occur after hematopoietic stem cell transplantation in which donor T cells recognize the host antigens as foreign, destroying host tissues. Establishment of a tolerogenic immune environment while preserving the immune response to infectious agents is required for successful bone marrow transplantation. Pregnancy-specific glycoprotein 1 (PSG1), which is secreted by the human placenta into the maternal circulation throughout pregnancy, likely plays a role in maintaining immunotolerance to prevent rejection of the fetus by the maternal immune system. We have previously shown that PSG1 activates the latent form of transforming growth factor beta1 (TGF-beta), a cytokine essential for the differentiation of tolerance-inducing CD4+FoxP3+ regulatory T cells (Tregs). Consistent with this observation, treatment of naive murine T cells with PSG1 resulted in a significant increase in FoxP3+ cells that was blocked by a TGF-beta receptor I inhibitor. We also show here that PSG1 can increase the availability of active TGF-beta in vivo. As the role of CD4+FoxP3+ cells in the prevention of aGVHD is well established, we tested whether PSG1 has beneficial effects in a murine aGHVD transplantation model. PSG1-treated mice had reduced numbers of tissue-infiltrating inflammatory CD3+ T cells and had increased expression of FoxP3 in T cells compared with vehicle-treated mice. In addition, administration of PSG1 significantly inhibited aGVHD-associated weight loss and mortality. On the other hand, administration of PSG1 was less effective in managing aGVHD in the presence of an alloimmune reaction against a malignancy in a graft-versus leukemia experimental model. Combined, this data strongly suggests that PSG1 could be a promising treatment option for patients with aGVHD following bone marrow transplantation for a nonmalignant condition, such as an autoimmune disorder or a genetic immunodeficiency. PMID- 30253243 TI - Fusarium mycotoxins and in vitro species-specific approach with porcine intestinal and brain in vitro barriers: A review. AB - Fusarium mycotoxins, such as fumonisins, trichothecenes, zearalenone and emerging fusariotoxins, common contaminants of feed and food, have received increased interest, due to the possible impact on animal and human health. In this context, it is urgent to focus our attention on fusariotoxins adverse effects, considering and analysing data in relation to their species-specificity. The in vitro approach for fusariotoxins risk assessment evaluation, through porcine epithelial barriers model, allowed to collect information on their absorption profile, bioavailability and toxicity. The aim of this review is to give an overview on Fusarium mycotoxins and their interactions with porcine intestinal and brain in vitro barriers, because they represent direct target organs of toxicity and as tools to evaluate their permeability and transport. PMID- 30253244 TI - Biological markers of harm can be detected in mice exposed for two months to low doses of Third Hand Smoke under conditions that mimic human exposure. AB - Third-hand smoke (THS) is a recently discovered environmental health hazard that results from accumulation and aging of second-hand smoke (SHS) toxins on surfaces of environments where smoking has occurred. Our objective was to determine whether there is a dose-dependent effect of THS exposure on biological markers of harm (BMH) using an in vivo exposure system that mimics exposure of humans to THS. THS exposure generated from as low as the 10 cigarettes-smoking regimen, resulted in increased circulating inflammatory cytokines, tumor necrosis factor alpha, interleukin 1 alpha, and granulocyte macrophage colony-stimulating factor. We also found that there was an increase in adrenocorticotropic hormone and superoxide dismutase and a decrease in ATP levels in liver tissue. Many of the altered BMH that are related to oxidative stress and decrease in ATP levels, suggest mitochondrial dysfunction. THS exposure generated from the 20 and 40 cigarettes-smoking regimen resulted in further damage. Our studies are important because virtually nothing is known about the physiological damage caused by different levels of THS exposure. These studies can also serve to educate the public on the dangers of THS and the BMH we identified can potentially be used in the clinic, once verified in exposed humans. PMID- 30253242 TI - The development of piperidinones as potent MDM2-P53 protein-protein interaction inhibitors for cancer therapy. AB - In tumor cells, p53 is always inactivated due to the mutation or deletion of TP53 gene or inhibited by the overexpressed MDM2. Small-molecule induced restoring of p53 function by blocking MDM2-p53 protein-protein interactions has been highly pursued as an attractive therapeutic strategy for cancer therapy. To date, a large number of small-molecule inhibitors have been identified based on the compact and well-defined MDM2-p53 interactions, of which SAR405838, MK-8242, DS 3032b, NVP-CGM097, RG7112, HDM201, RG7388, ALRN-6924 and AMG 232 are undergoing clinical assessment at different phases for cancer therapy. This review is focused on the discovery and development of piperidinone-based MDM2-p53 inhibitors for cancer therapy, including the identification of hit compounds, hit to-lead optimizations, binding models of ligands in the active site of MDM2, metabolic studies, and preclinical data of advanced piperidinone-based MDM2-p53 inhibitors. Additionally, acquired resistance of MDM2 inhibitors and potential toxicity toward normal tissues are briefly discussed. PMID- 30253245 TI - In vitro safety pharmacology evaluation of 2-hydroxybenzylamine acetate. AB - 2-hydroxybenzylamine (2-HOBA), a compound found in buckwheat, is a potent scavenger of reactive gamma-ketoaldehydes, which are increased in diseases associated with inflammation and oxidative stress. While the potential of 2-HOBA is promising, studies were needed to characterize the safety of the compound before clinical trials. In a series of experiments, the risks of 2-HOBA-mediated mutagenicity and cardio-toxicity were assessed in vitro. The effects of 2-HOBA on the mRNA expression of select cytochrome P450 (CYP) enzymes were also assessed in cryopreserved human hepatocytes. Further, the distribution and metabolism of 2 HOBA in blood were determined. Our results indicate that 2-HOBA is not cytotoxic or mutagenic in vitro and does not induce the expression of CYP1A2, CYP2B6, or CYP3A4 in human hepatocytes. The results of the hERG testing showed a low risk of cardiac QT wave prolongation. Plasma protein binding and red blood cell distribution characteristics indicate low protein binding and no preferential distribution into erythrocytes. The major metabolites identified were salicylic acid and the glycoside conjugate of 2-HOBA. Together, these findings support development of 2-HOBA as a nutritional supplement and provide important information for the design of further preclinical safety studies in animals as well as for human clinical trials with 2-HOBA. PMID- 30253246 TI - Assessing the combined toxicity of the natural toxins, aflatoxin B1, fumonisin B1 and microcystin-LR by high content analysis. AB - As human co-exposure to natural toxins through food and water is inevitable, risk assessments to safeguard health are necessary. Aflatoxin B1 and fumonisin B1, frequent co-contaminants of maize and microcystin-LR, produced in freshwater by cyanobacteria are all naturally occurring potent toxins that threaten human health. Populations in the poorest regions of the world may suffer repeated simultaneous exposure to these contaminants. Using High Content Analysis, multiple cytotoxicity endpoints were measured for the individual toxins and mixtures in various cell lines. Results highlighted that significant cytotoxic effects were observed for aflatoxin B1 in all cell lines while no cytotoxic effects were observed for fumonisin B1 or microcystin-LR. Aflatoxin B1/microcystin-LR was cytotoxic in the order HepG2 > Caco-2 > MDBK. Fumonisin B1/microcystin-LR affected MDBK cells. The ternary mixture was cytotoxic to all cell lines. Most combinations were additive, however antagonism was observed for binary and ternary mixtures in HepG2 and MDBK cell lines at low and high concentrations. Synergy was observed in all cell lines, including at low concentrations. The combination of these natural toxins may pose a significant risk to populations in less developed countries. Furthermore, the study highlights the complexity around trying to regulate for human exposure to multiple contaminants. PMID- 30253247 TI - Rat feeding trials: A comprehensive assessment of contaminants in both genetically modified maize and resulting pellets. AB - We analyzed a comprehensive set of contaminants in MON810 and NK603 genetically modified (GM) maize, and their non-GM counterparts, used in a rat feeding study (the GMO90 + project). Both the maize grains and the manufactured pellets were characterized. Only minor differences in contaminant levels between GM and corresponding non-GM harvests were evidenced. Fumonisin and deoxynivalenol mycotoxins were the pollutants present in the highest amounts, with concentrations that were however largely below acceptance reference values. Our data reporting slightly lower levels of fumonisin in MON810 compared to its non GM counterpart corroborate the lower susceptibility of insect resistant Bt maize to fumonisin-producing fungi. Traces of glyphosate (0.016 mg/kg) were evidenced in grains from NK603 treated crops. Regarding the pellets, analysis of more than 650 potentially toxic substances revealed low amounts of various mycotoxins, pesticides and heavy metals. Concentrations of contaminants quantified in the pellets were however far below the maximum level of residues values set by regulatory agencies, and no substantial differences in contaminants between GM and non-GM pellets were observed. Moreover, when comparing the contamination status of grains and pellets, we demonstrate yet again that characterizing the grains is actually not sufficient to foresee the quality of the produced pellets. PMID- 30253248 TI - Functional slit lamp biomicroscopy metrics correlate with cardiovascular risk. AB - PURPOSE: Our aim was to correlate cardiovascular risk factor estimation with bulbar conjunctival blood flow metrics as measured through Functional Slit Lamp Biomicroscopy (FSLB). METHODS: Cross-sectional study of individuals with otherwise healthy eyelid and corneal anatomy recruited from the Miami Veterans Affairs (VA) Healthcare System eye clinic. We measured conjunctival microvascular hemodynamics by mounting a camera on a slit lamp and cardiovascular risk using the Framingham risk score. Our main outcome measures were correlations between conjunctival vessel parameters (axial and cross-sectional blood flow velocity, blood flow rate) and Framingham score. RESULTS: We included 84 patients who underwent FSLB. The mean age was 60 years, the majority were male (88%) and approximately half the patients were black (54%). Mean vessel diameter was similar between all Framingham score categories. Axial and cross-sectional blood flow velocities and blood flow rate were lower in individuals with higher Framingham risk score. Specifically, mean cross-sectional blood flow velocity in individuals with a low Framingham risk score was 0.37 +/- 0.0.9 mm/s, with an intermediate score was 0.30 +/- 0.09 mm/s, and with a high score was 0.29 +/- 0.10 mm/s, p = 0.04. Mean blood flow rate in individuals with a low Framingham risk score was 133.4 +/- 59.6 pl/s, with an intermediate score was 123.6 +/- 39.3 pl/s, and with a high score was 121.9 +/- 52.6 pl/s, p = 0.04. The beta coefficient of the blood flow rate for change in Framingham score was -0.73; 95% CI-1.34-0.13, p = 0.02, adjusted for race. CONCLUSION: FSLB correlates with cardiovascular risk estimation. Future studies should evaluate if FSLB can predict cardiovascular outcomes. PMID- 30253249 TI - Ethnic differences between the Asian and Caucasian ocular surface: A co-located adult migrant population cohort study. AB - PURPOSE: To investigate the ethnic differences in tear film quality, ocular surface parameters, and dry eye symptomology between co-located Asian and Caucasian populations. METHODS: Two hundred and six participants (103 Asian and 103 Caucasian) were recruited in an age and gender-matched cross-sectional study. Dry eye symptomology, ocular surface parameters, and tear film quality were evaluated for each participant within a single clinical session. RESULTS: The mean +/- SD age of the 206 participants (82 male, 124 female) was 45 +/- 16 years. Overall, a greater proportion of Asian participants were symptomatic of dry eye and fulfilled the TFOS DEWS II dry eye diagnostic criteria than Caucasian participants (74% versus 51%, p = 0.002), with an odds ratio (95% CI) of 2.7 (1.5 4.8) times. Poorer OSDI scores, tear film stability, lipid layer quality, tear osmolarity, lid wiper epitheliopathy, meibomian gland dropout, and expressed meibum quality were observed in the Asian group (all p < 0.05). A significantly higher proportion of participants exhibited incomplete blinking in the Asian group than the Caucasian group (81% versus 45%, p < 0.001). CONCLUSIONS: Asian participants exhibited more severe dry eye signs and symptoms than Caucasian participants. The poorer meibomian gland function and higher degree of incomplete blinking observed among Asian participants may potentially contribute towards the ethnic predisposition towards dry eye development. PMID- 30253250 TI - Optorelaxers: Achieving real-time control of NMR relaxation. AB - We present an approach to increase the detection sensitivity of NMR by shortening the spin-lattice relaxation time using transient paramagnetic species created by light irradiation of "optorelaxer" molecules. In the ultimate implementation of this concept, not yet realized here, these transient species are absent during the detection period, thereby avoiding the loss of spectral resolution caused by inhomogeneous broadening from paramagnetic species. Real-time control of NMR relaxation by visible light is demonstrated with Fe(II)(ptz)6(BF4)2, (ptz = 1 propyltetrazole), abbreviated FePTZ. Illumination of FePTZ at 30 K results in a decrease of the 1H NMR spin-lattice relaxation time T1 due to formation of a high spin photoexcited state. The 1H NMR of polystyrene containing a low concentration of FePTZ molecules shows a similar reduction in T1, establishing that FePTZ can act as an optorelaxer for the protons of a matrix. Numerical modeling of the spin diffusion processes from the protons in a FePTZ core to those in a shell of polystyrene accounts for the observed T1 effects under both dark and light conditions. Additionally, 1H MAS (magic-angle spinning) NMR results for pure FePTZ provide information on the isotropic and anisotropic portions of the electron-nuclear hyperfine interactions. PMID- 30253251 TI - Ultrastructural and histological characteristics of the endometrium during early embryo development in mares. AB - The aim of this study was to evaluate ultrastructural and histological changes in the endometrium on days 7, 10 and 13 post-ovulation in pregnant and cyclic mares. Mares were routinely examined by transrectal palpation and ultrasonographic examination of the reproductive tract until estrus was detected. In the first cycle, endometrial biopsies from 30 cyclic mares (Cyclic group) were collected on days 7, 10 and 13 post-ovulation. In the second cycle, the same mares were bred by a fertile stallion. At days 7, 10 and 13 post-ovulation intrauterine biopsies were collected. Immediately after sample collection, the mare's uteri were flushed, and those mares with embryo recovery were assigned to the Pregnant group. From ovulation detection until day of uterine biopsy, blood samples to measure Progesterone concentrations were collected daily in cyclic and pregnant mares. A larger blood vessel caliber was observed in pregnant mares than in cyclic from day 7-13. On the 7th day of pregnancy a large loss of ciliated cells was evident in the group of pregnant mares in comparison with the Cyclic group and the superficial cells of the endometrium were more protruded, and a small amount of histotrophic material between the folds was observed. On the 10th day of pregnancy, the glandular histotrophic secretion and the secretion of luminal epithelium became more intense than the secretion of cyclic mares. On the 13th day of pregnancy, a very large amount of histotroph was observed within large glandular openings surrounded by ciliated cells. The concentrations of P4 were affected by day (P < 0.001), but were not affected by group. Changes occurred in the uterine environment thereupon the entry of the embryo into the uterus. In the stroma and in the lumen, these modifications may aid to provide the necessary nutrition for the initial development of the embryo and to promote changes at cellular structures that will interact in the embryonic signaling and future fixation, implantation and placentation. PMID- 30253252 TI - Parallel worlds: An ethnography of care in an Afghan maternity hospital. AB - Aspirations of quality, equitable and respectful care for all women in childbirth have, so far, been unrealised. Sub-optimal care remains the norm in many settings despite decades of substantial investment, the introduction of evidence-based policies, procedures and training programmes. Improving the standard of facility based care for childbearing women in Afghanistan is an example. This ethnography of a large public Afghan maternity hospital explored the experiences, motivations and constraints of healthcare providers. The aim was to identify barriers and facilitators in the delivery of care. Participant observation, semi-structured interviews, and focus group discussions were used to gather diverse perspectives on childbirth and care between 2010 and 2012. The influences of the sociocultural setting and political economy on facility-based care are discussed in this paper. Under the surface of this maternity hospital, social norms were in conflict with the principles of biomedicine. Contested areas included the control of knowledge, equity and the primary goal of work. The institutional culture was further complicated by pressure from powerful elites. These unseen values and pressures explain much of the disconnection between policy and implementation, education and the everyday behaviours of healthcare providers. Improving the quality of care and equity in Afghan public maternity hospitals will require political will from all stakeholders to acknowledge these issues and find culturally attuned ways to address them. Furthermore, the notion of competing world-views on healthcare has relevance beyond Afghanistan. PMID- 30253253 TI - Hydrogen sulfide exposure induces jejunum injury via CYP450s/ROS pathway in broilers. AB - Hydrogen sulfide (H2S) is generally recognized as a highly poisonous environmental and industrial pollutant. Previous toxicological studies of H2S are mainly focused on the nervous and cardiovascular system. There are few reports on the H2S toxicity effects on jejunum to our knowledge. Our study examined the morphological changes and antioxidant functions of broiler jejunum after the 42 day exposure to H2S. Effects of H2S on morphological damage and immune function in the broiler jejunum were analyzed from the perspective of CYP450s and oxidative stress via transcriptomics and quantitative real-time PCR (qRT-PCR). It was found that the activities of GPx, CAT, SOD, and T-AOC and the level of GSH were observably decreased (P < 0.05), while the contents of MDA and H2O2 were remarkably increased (P < 0.05) in the jejunums of broilers exposed to H2S, which undergone a process of oxidative stress, and typical inflammatory changes and apoptosis could be observed. Transcriptional profiling results showed that 208 genes were significantly up-regulated while 295 genes were remarkably down regulated in H2S group. The expression of CYP450s, inflammation and apoptosis related genes were also significantly increased. In conclusion, H2S led to the redox homeostasis disorder through CYP450s differential expression in broiler jejunum. The jejunal inflammatory response, apoptosis along with the immune dysfunction were subsequently observed, which eventually caused jejunal morphology and functional damage. The present study further enriches and perfects the mechanism theory of H2S toxicity on broilers, which may be valuable for the risk assessment of H2S and human health protection. PMID- 30253254 TI - Environmentally relevant concentration of chromium activates Nrf2 and alters transcription of related XME genes in liver of zebrafish. AB - Fish is an excellent model to decipher the mechanism of toxicity of aquatic contaminants such as hexavalent chromium (Cr [VI]). The present study looked into the manifestation of stress in liver of zebrafish exposed to an environmentally relevant concentration (2 mgL-1), and the functioning of the cytoprotective machinery that pacifies the formed stress. The results lead us to hypothesize that oxidative stress plays a key role in chromium-induced toxicity resulting in lipid peroxidation and extensive changes in tissue ultrastructure. In treated fish, production of reactive oxygen species, increase in reduced glutathione content and increase in malondialdehyde content along with enhanced catalase activity were evident. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was found to increase both at transcriptional and translational level and its translocation into the nucleus was confirmed by fluorescence-based immunohistochemical studies. The mRNA levels of genes like Nqo1, Cyp1a and Cu/Zn Sod were found to increase whereas Ho1, Hsp70 and Ucp2 were down-regulated. The sensitivity of these genes towards Cr [VI] validates their candidature as important biomarkers of Cr [VI] exposure in zebrafish. PMID- 30253255 TI - Integrated application of sewage sludge, earthworms and Jatropha curcas on abandoned rare-earth mine land soil. AB - Improving soil fertility is a critical component of abandoned rare-earth mine land (ARL) revegetation. To study the effects of sewage sludge (SS), earthworms, and Jatropha curcas in ARL revegetation, SS (40% in mass ratio) and earthworms (0, 40, 60, and 80 individual adult Eisenia fetida kg-1) were applied to abandoned rare-earth mine land soil (ARLS) and then J. curcas was grown in a potting experiment. The organic carbon, nutrients (N, P, K) and heavy metals (HMs; Cd, Cu, Zn) contents in ARLS and the biomass and nutrients uptake in J. curcas were significantly increased by SS amendment. Application of 80 individual E. fetida kg-1 significantly increased availability of P and K in SS-amended ARLS relative to other treatments. Earthworms increased the height, ground diameter and biomass of J. curcas, but the promotion of biomass became weaker as earthworm density increased. After J. curcas harvest, the contents of Cd, Cu and Zn in SS amended ARLS were reduced by 15%, 23%, and 19%, respectively. With the joint application of J. curcas and earthworms, a much larger decrease in contents of Cd (34-40%), Cu (31-44%) and Zn (24-29%) in SS-amended ARLS were observed, and the HMs ecological risks were reduced from "moderate potential" to "low potential". Moreover, J. curcas and earthworms together exerted more reduction in the exchangeable fraction HMs in SS-amended ARLS than J. curcas alone. Our results suggest that the integrated application of SS, earthworms and J. curcas is an effective approach for ARL revegetation. PMID- 30253256 TI - Algae granulation for nutrients uptake and algae harvesting during wastewater treatment. AB - To overcome the high separation cost of microalgae, natural microalgae granulation was performed in open sequencing batch reactors (SBRs) by treating synthetic wastewater. After operation for 60 days, easily settled algae granules were obtained with an average size of 0.61 mm, sludge volume index (SVI) of 125 ml/g and settling velocity of 12.2 m/h. More extracellular polymeric substances (EPS) (~252 mg/g-VSS) were detected to excrete with a higher proteins/polysaccharides (PN/PS) ratio (~7) for the algae granules on day 60, which are beneficial for granulation. Meanwhile, the algae granules were found to have a higher phosphorus (P) content (33.4 mg-P/g-TSS) with higher P bioavailability (91.8%) when compared to the seed algae (20.4 mg-P/g-TSS). The obtained algae granules possess great potential for P recovery and reuse. PMID- 30253257 TI - Anabaenopeptins and cyanopeptolins induce systemic toxicity effects in a model organism the nematode Caenorhabditis elegans. AB - Cyanobacterial blooms represent a significant risk to environmental and human health due to their production of toxic secondary metabolites, cyanopeptides. Anabaenopeptins and cyanopeptolins are cyanopeptides increasingly detected in surface waters at concentrations exceeding regulatory toxicity levels for other cyanotoxins such as microcystins. Yet their toxicity to aquatic organisms are not well understood. Here we assessed the toxicological effects of three anabaenopeptins (AP-A, AP-B, and AP-F) and three cyanopeptolins (CYP-1007, CYP 1020, and CYP-1041) to a model organism the nematode Caenorhabditis elegans. Examined toxicity endpoints included reproduction, hatching time, growth rate, lifespan, and age-related vulval integrity. Microcystin RR (MC-RR) and microginin 690 were also included in the study for comparisons. At an identical mass concentration (10 MUg/L, corresponding to a molar concentration ranging 0.01 0.014 MUM depending on the specific peptide), anabaenopeptins (APs) showed the greatest toxicity among all cyanopeptides tested. APs decreased worm reproduction by 23%-34% and shortened worm lifespan by 5 days (a 30% reduction) compared to the controls. APs also induced a remarkable age-related vulval integrity defect (Avid phenotype) in the worm, where over 95% of exposed worms developed the phenotype, compared to a less than 15% in control worms. CYPs showed similar toxicity as MC-RR, and Microginin 690 was the least toxic. These findings suggest that APs and CYPs may pose significant health risks to aquatic organisms. More toxicological studies of these cyanopeptides using different species across different trophic levels are needed to gain a thorough understanding of their potential impact on ecological systems and human health. PMID- 30253258 TI - The lagged effects of environmentally relevant zinc on non-specific immunity in zebrafish. AB - Responses to zinc (Zn) during exposure have well studied but the effects after the exposure are commonly neglected. In the study, non-specific immune response to zinc in blood and spleen of zebrafish was evaluated after exposure. At first, fish were subjected to 0 (control) and 200 MUg/L zinc (Zn) for 6 weeks. Specific growth rate, survival rate, blood albumin level, and the activities of Cu/Zn-SOD and iNOS were not significantly changed by Zn exposure. Conversely, Zn increased the levels of globulin and hemoglobin, CAT activity, and mRNA levels of nrf2, sod1, cat, hsf1, hsp70, p65, il-6, il-1beta, tnf-alpha and inos. In the second experiment, zebrafish were transferred to a recovery period for 4 and 8 days. The increased activities of Cu/Zn-SOD and CAT and the up-regulated mRNA levels of nrf2, cat, p65, tnf-alpha, and inos still were observed. In the third experiment, zebrafish from 4 d post-exposure were re-exposed to the high levels of Zn and cadmium (Cd) (600, 1200 MUg/L Zn; 100, 200 MUg/L Cd) for 4 days. 100 MUg/L Cd caused a higher survival rate in the Zn-exposed fish than the control, suggesting Zn pre-exposure might develop the tolerance to Zn and Cd. Although transcriptional levels of sod1, hsf1, hsf2, hsp70, il-6 and il-1beta and activity levels of iNOS recovered to the control levels at 4 and 8 d post-exposure, differences in magnitude of responsiveness were observed between normal fish and Zn-exposed fish. Overall, Zn acclimation persisted when fish recovered, which provides a new perspective about Zn toxicology. PMID- 30253259 TI - Disentangling cognitive from motor control: Influence of response modality on updating, inhibiting, and shifting. AB - It is unclear whether cognitive and motor control are parallel and interactive or serial and independent processes. According to one view, cognitive control refers to a set of modality-nonspecific processes that act on supramodal representations and precede response modality-specific motor processes. An alternative view is that cognitive control represents a set of modality-specific operations that act directly on motor-related representations, implying dependence of cognitive control on motor control. Here, we examined the influence of response modality (vocal vs. manual) on three well-established subcomponent processes of cognitive control: shifting, inhibiting, and updating. We observed effects of all subcomponent processes in reaction times. The magnitude of these effects did not differ between response modalities for shifting and inhibiting, in line with a serial, supramodal view. However, the magnitude of the updating effect differed between modalities, in line with an interactive, modality-specific view. These results suggest that updating represents a modality-specific operation that depends on motor control, whereas shifting and inhibiting represent supramodal operations that act independently of motor control. PMID- 30253260 TI - The use of biofeedback for gait retraining: A mapping review. AB - BACKGROUND: Biofeedback seems to be a promising tool to improve gait outcomes for both healthy individuals and patient groups. However, due to differences in study designs and outcome measurements, it remains uncertain how different forms of feedback affect gait outcomes. Therefore, the aim of this study is to review primary biomechanical literature which has used biofeedback to alter gait-related outcomes in human participants. METHODS: Medline, Cinahl, Cochrane, SPORTDiscus and Pubmed were searched from inception to December 2017 using various keywords and the following MeSHterms: biofeedback, feedback, gait, walking and running. From the included studies, sixteen different study characteristics were extracted. FINDINGS: In this mapping review 173 studies were included. The most common feedback mode used was visual feedback (42%, n = 73) and the majority fed back kinematic parameters (36%, n = 62). The design of the studies was poor: only 8% (n = 13) of the studies had both a control group and a retention test; 69% (n = 120) of the studies had neither. A retention test after 6 months was performed in 3% (n = 5) of the studies, feedback was faded in 9% (n = 15) and feedback was given in the field rather than the laboratory in 4% (n = 8) of the studies. INTERPRETATION: Further work on biofeedback and gait should focus on the direct comparison between different modes of feedback or feedback parameters, along with better designed and field based studies. PMID- 30253261 TI - Stability of vacuum-packed meat from finishing steers fed different inclusion levels of brewer's spent grain. AB - Brewer's spent grain (BSG) as a partial substitute for corn silage (CS) was evaluated in finishing feedlot steers on the lipid, protein, color, and microbiological stability of vacuum-packed meat for 75 days under refrigerated storage. Twenty steers were distributed in four treatments in a completely randomized design with five replicates each: 50% concentrate + 50% CS; + 35% CS + 15% BSG; + 25% CS + 25% BSG; and 15% CS + 35% BSG for 90 days. After the animals were slaughtered and the carcasses cooled, the Longissimus thoracis muscle was collected for analyzes. The lipid and protein oxidation, color parameters and microbiological stability of the beef although not affected by the diets (P > .05) oscillated throughout the storage time (P < .05). BSG can be included in the finishing diets of beef cattle by up to 35% (dry basis) and as a forage source without adverse effects on beef shelf life. PMID- 30253262 TI - A comparison of the Nix Colour Sensor ProTM and HunterLab MiniScanTM colorimetric instruments when assessing aged beef colour stability over 72 h display. AB - We compared the capacity for the Nix Colour Sensor ProTM (NIX) and HunterLab MiniScanTM (HUNTER) to detect colour variation using aged (0, 3 and 5 weeks) and then displayed (0, 1, 2 and 3 d) beef M. longissimus lumborum samples (n = 8). NIX L* and hue values were found to be respectively higher and lower than for the HUNTER. No significant interactions between instrument and display or ageing periods were identified for a* - unlike for b* and chroma where NIX measures were observed to be lower than those from the HUNTER. Both instruments identified ageing and display period effects on colorimetric traits. Based on these results, the NIX cannot be considered comparable to the HUNTER when measuring beef colour albeit captured similar colorimetric trends over display and ageing periods which suggest its independent usefulness to beef colour assessment. PMID- 30253263 TI - Spontaneous Ca2+ transients in rat pulmonary vein cardiomyocytes are increased in frequency and become more synchronous following electrical stimulation. AB - The pulmonary veins have an external sleeve of cardiomyocytes that are a widely recognised source of ectopic electrical activity that can lead to atrial fibrillation. Although the mechanisms behind this activity are currently unknown, changes in intracellular calcium (Ca2+) signalling are purported to play a role. Therefore, the intracellular Ca2+ concentration was monitored in the pulmonary vein using fluo-4 and epifluorescence microscopy. Electrical field stimulation evoked a synchronous rise in Ca2+ in neighbouring cardiomyocytes; asynchronous spontaneous Ca2+ transients between electrical stimuli were also present. Immediately following termination of electrical field stimulation at 3 Hz or greater, the frequency of the spontaneous Ca2+ transients was increased from 0.45 +/- 0.06 Hz under basal conditions to between 0.59 +/- 0.05 and 0.65 +/- 0.06 Hz (P < 0.001). Increasing the extracellular Ca2+ concentration enhanced this effect, with the frequency of spontaneous Ca2+ transients increasing from 0.45 +/ 0.05 Hz to between 0.75 +/- 0.06 and 0.94 +/- 0.09 Hz after electrical stimulation at 3 to 9 Hz (P < 0.001), and this was accompanied by a significant increase in the velocity of Ca2+ transients that manifested as waves. Moreover, in the presence of high extracellular Ca2+, the spontaneous Ca2+ transients occurred more synchronously in the initial few seconds following electrical stimulation. The ryanodine receptors, which are the source of spontaneous Ca2+ transients in pulmonary vein cardiomyocytes, were found to be arranged in a striated pattern in the cell interior, as well as along the periphery of cell. Furthermore, labelling the sarcolemma with di-4-ANEPPS showed that over 90% of pulmonary vein cardiomyocytes possessed T-tubules. These findings demonstrate that the frequency of spontaneous Ca2+ transients in the rat pulmonary vein are increased following higher rates of electrical stimulation and increasing the extracellular Ca2+ concentration. PMID- 30253264 TI - Transcranial direct current stimulation enhances retention of a second (but not first) order conditional visuo-motor sequence. AB - This study examined the role of the left inferior frontal gyrus in the implicit learning and retention of a 'simple' first order conditional (FOC) sequence and a relatively 'complex' second order conditional (SOC) sequence, using anodal transcranial direct current stimulation (a-tDCS). Groups of healthy adults received either a-tDCS (n = 18) over the left inferior frontal gyrus or sham/placebo (n = 18) stimulation. On separate days, participants completed a serial reaction time (SRT) task whilst receiving stimulation. On one of the days, participants were presented with a FOC sequence and in another, a SOC sequence. Both the learning and short-term retention of the sequences were measured. Results showed a-tDCS enhanced the short-term retention of the SOC sequence but not the FOC sequence. There was no effect of a-tDCS on the learning of either FOC or SOC sequences. The results provide evidence of prefrontal involvement in the retention of a motor sequence. However, its role appears to be influenced by the complexity of the sequence's structure. Additionally, the results show a-tDCS can enhance retention of an implicitly learnt motor sequence. PMID- 30253265 TI - Event-related potential (ERP) evidence that encoding focus alters recollected features. AB - Event-related potential (ERP) evidence suggests that encoding focus alters the quality of information bound in memory, which can affect source memory. In the present study, participants studied product images with blue or and yellow filters while focusing either on the self (self-focus) or on the color of the filtered image (other-focus). Self-focus encoding produced more positive encoding ERPs, greater recognition for old/new judgments, and a greater Late Positive Component (LPC; the putative neural correlate for recollection). Other-focus encoding led to a greater FN400 component suggesting that features (i.e., filter color and product image) were unitized and increased the familiarity used to make memory judgments. The results indicate that encoding focus can alter the balance of features bound in memory. Some features support a specific memory query (diagnostic recollection), whereas other features are from the past do not necessarily inform the memory query (non-diagnostic recollection). Thus, recollection is a complex process that depends on interactions between encoding processes, characteristics of the encountered information, and the broad context of the memory probe. PMID- 30253266 TI - BIIDXI, a DUF642 cell wall protein, is involved in hypocotyl growth via auxin efflux. AB - Auxin is involved in hypocotyl elongation in response to different environmental factors. BIIDXI is a cell wall DUF642 protein that participates in the regulation of the degree of pectin-methylesterification of the cell wall in different tissues, including hypocotyls. Under continuous light, bdx-1 seedlings presented longer hypocotyls than those of WT, while BIIDXI-overexpressed hypocotyls were auxin resistant. Auxin accumulation was observed in epidermal cells from bdx-1 hypocotyls, and the distribution pattern of PIN1 proteins differed. Moreover, the gravitropic response of bdx-1, a process that is highly dependent on auxin flux, was increased. In this study, we determined that BIIDXI is involved in hypocotyl elongation through the regulation of auxin flux. PMID- 30253267 TI - Rice SDSFL1 plays a critical role in the regulation of plant structure through the control of different phytohormones and altered cell structure. AB - Semi-dwarfism is one of the most important agronomic traits for many cereal crops. In the present study, a mutant with semi-dwarf and short flag leaf 1, sdsfl1, was identified and characterized. The sdsfl1 mutant demonstrated some distinguished structural alterations, including shorter plant height and flag leaf length, increased tiller numbers and flag leaf width, and decreased panicle length compared with those of wild type (WT). Genetic analysis suggested that the mutant traits were completely controlled by a single recessive gene. The SDSFL1 gene was mapped to the long arm of chromosome 3 within a region of 44.6 kb between InDel markers A3P8.3 and A3P8.4. The DNA sequence analysis revealed that there was only a T to C substitution in the coding region of LOC_Os03g63970, resulting in the substitution of Tryptophan (Try) to Arginine (Arg) and encoding a GA 20 oxidase 1 protein of 372 amino acid residues. Photosynthesis analysis showed that the photosynthetic rate (Pn), stomatal conductance (Gs), and intercellular CO2 concentration (Ci) were significantly increased in sdsfl1. Chlorophyll a (Chl a), total Chl, and carotenoid contents were significantly increased in sdsfl1 compared with those in WT. sdsfl1 carried a reduced level of GA3 but reacted to exogenously applied gibberellins (GA). Moreover, the levels of abscisic acid (ABA), indole 3-acetic acid (IAA), and salicylic acid (SA) were notably improved in sdsfl1, whereas there was no noteworthy change in jasmonic acid (JA). The results thus offer a visible foundation for the molecular and physiological analysis of the SDSFL1 gene, which might participate in various functional pathways for controlling plant height and leaf length in rice breeding. PMID- 30253268 TI - Association between binge eating disorder and psychiatric comorbidity profiles in patients with obesity seeking bariatric surgery. AB - BACKGROUND: Eating disorders could be an important factor in the development of obesity, but psychiatric comorbidities are very heterogeneous in patients with obesity. Moreover, relationship between binge eating disorder and other psychiatric comorbidities is not clear. Our objective was to identify psychiatric comorbidity profiles of bariatric surgery candidates and to analyze the association between these profiles and binge-eating disorder. METHODS: Our sample consisted of bariatric surgery candidates (n = 92) with mean Body Mass Index at 41.3 +/- 0.6 kg/m2. To construct profiles, we classified patients according to their psychiatric comorbidities using cluster analysis techniques. We used logistic regression modelling to analyze associations between the presence of binge-eating disorder and the psychiatric comorbidity profiles. RESULTS: We identified four profiles of psychiatric phenotypes. One of these profiles was not associated with any psychiatric disorder. Binge eating disorder was significantly associated with two profiles (p < 0.05): a profile with bipolar and obsessive compulsive disorder (OR = 7.7 [1.7; 35.1]), and a profile with bipolar and panic disorder (OR = 20.7 [3.1; 137.5]). CONCLUSIONS: Our multidimensional approach identified certain profiles specifically associated with binge-eating disorder in patients with obesity seeking bariatric surgery. These results may lead to a better understanding of the relationship between obesity and psychiatric disorders. PMID- 30253269 TI - Exploring the moderating effects of dopaminergic polymorphisms and childhood adversity on brain morphology in schizophrenia-spectrum disorders. AB - Genetic and environmental etiologies may contribute to schizophrenia and its associated neurobiological profile. We examined the interaction between dopaminergic polymorphisms, childhood adversity and diagnosis (schizophrenia/schizoaffective disorder) on dopamine-related brain structures. Childhood adversity histories and structural MRI data were obtained from 249 (153 schizophrenia/schizoaffective, 96 controls) participants registered in the Australian Schizophrenia Research Bank. Polymorphisms in DRD2 and COMT were genotyped and a dopaminergic risk allelic load (RAL) was calculated. Regression analysis was used to test the main and interaction effects of RAL, childhood adversity and diagnosis on volumes of dopamine-related brain structures (caudate, putamen, nucleus accumbens, dorsolateral prefrontal cortex and hippocampus). A schizophrenia/schizoaffective diagnosis showed significant main effects on bilateral hippocampus, left dorsolateral prefrontal cortex and bilateral putamen volumes. RAL showed a significant main effect on left putamen volumes. Furthermore, across the whole sample, a significant two-way interaction between dopaminergic RAL and childhood adversity was found for left putamen volumes. No brain structure volumes were predicted by a three-way interaction that included diagnosis. Our finding suggests the left putamen may be particularly sensitive to dopaminergic gene-environment interactions regardless of diagnosis. However, larger studies are needed to assess whether these interactions are more or less pronounced in those with schizophrenia/schizoaffective disorders. PMID- 30253270 TI - MiR-188-3p upregulation results in the inhibition of macrophage proinflammatory activities and atherosclerosis in ApoE-deficient mice. AB - BACKGROUND: Atherosclerosis occurs as a result of a chronic inflammatory response in the arterial wall associated with an increased uptake of low-density lipoprotein by macrophages and the subsequent transformation of this lipoprotein into foam cells. It has been found that miR-188-3p can suppress autophagy and myocardial infarction. Therefore, we conducted the present study with determining the suppressive role played by miR-188-3p in atherosclerosis. METHODS: The atherosclerosis model was established using ApoE knockout mice. The healthy C57BL/6J wide-type mice were used as control, while miR-188-3p mimics or inhibitors were applied for the elevation or the depletion of the miR-188-3p expression in mice. The macrophage content was observed in atherosclerotic plaque. Once the miR-188-3p expression was determined, the effects of the over expression of miR-188-3p on the lipid accumulation and macrophage inflammatory response were accessed. The plasma levels of pro-inflammatory factors and serum RANTES level, as well as OLR1, iNOS, ABCA1 and KLF2 expression were determined in order to evaluate the potential anti-inflammatory and antioxidative activities of miR-188-3p. RESULTS: ApoE knockout mice with atherosclerosis presented with increased lipid accumulation and macrophage content. MiR-188-3p was found to reduce intravascular lipid accumulation in atherosclerotic mice. In addition to the alleviation of macrophage inflammatory response, the upregulation of miR-188 3p also leads to the suppression of oxidation with reduced macrophage accumulation, plasma expression of pro-inflammatory factors and serum RANTES level, OLR1 and iNOS, while it increases ABCA1 and KLF2. CONCLUSIONS: In conclusion, the findings from our study found a new potential therapy for atherosclerosis by investigating the inhibitory effects of miR-188-3p on macrophage inflammatory response and oxidation. PMID- 30253271 TI - Maximizing the generalization of fear extinction: Exposures to a peak generalization stimulus. AB - Experimental research has shown that generalization of fear extinction from a generalization stimulus (GS) is minimal compared to generalization of fear extinction from the conditional stimulus itself (CS+). This poses a challenge to extinction-based treatments of anxiety because the exact CS is often not known or unavailable. However, experimental studies failed to disentangle differences in stimulus identity (CS + or GS) from differences in the level of fear (GS typically elicits less fear than CS+). Here, we test the hypothesis that a high level of fear is key to extinction learning and generalization, rather than the identity of the stimulus under extinction (CS + or GS). For that purpose, we took advantage of the peak-shift phenomenon that describes the conditions under which a GS can elicit equal or higher levels of responding, compared to the CS+. Hence, we compared the generalizability of fear extinction following exposure to the CS + itself, to a 'weak' GS that elicits less fear, and to a 'peak' GS that elicits as much fear as the CS+. First, the results replicated, with a new set of stimuli, the observation that extinction of a skin conductance response and US expectancy generalizes only weakly from a weak GS to CS+. Second, extinction generalized strongly from a peak GS towards CS+, as hypothesized. Third, extinction with the peak GS even outperformed extinction with the CS+, as it generalized more strongly across the generalization gradient. Together, these results support exposure treatment strategies that focus on the fear-eliciting potential of stimuli (often described as a fear hierarchy), rather than their learning history. We propose that stimulus typicality and/or intensity may explain the enhanced effects of a 'peak' GS over the CS+ in enhancing the generalization of fear extinction. PMID- 30253272 TI - A computer simulation of short-term adaptations of cardiovascular hemodynamics in microgravity. AB - Astronauts in the microgravity environment experience significant changes in their cardiovascular hemodynamics. In this study, a system-level numerical model has been utilized to simulate the short-term adaptations of hemodynamic parameters due to the gravitational removal in space. The effect of lower body negative pressure (LBNP) as a countermeasure has also been simulated. The numerical model was built upon a lumped-parameter Windkessel model by incorporating gravity-induced hydrostatic pressure and transcapillary fluid exchange modules. The short-term (in the time scale of seconds and minutes) adaptations of the cardiac functions, blood pressure, and fluid volumes have been analyzed and compared with physiological data. The simulation results suggest microgravity induces a decrease in aortic pressure, heart rate, lower body capillary pressure and volume, and an increase in stroke volume, upper body capillary pressure and volume. The activation of LBNP causes an immediate increase in lower body blood volume and a gradual decrease in upper body blood volume. As a result, the fluid shift due to microgravity could be reversed by the LBNP application. LBNP also counters the impacts of microgravity on the cardiac functions, including heart rate and stroke volume. The simulation results have been validated using available physiological data obtained from spaceflight and parabolic flight experiments. PMID- 30253273 TI - Effect of diluted hydrolysate as yeast propagation medium on ethanol production. AB - Yeast propagation using 50% diluted hydrolysate in water was utilized for the fermentation of hydrolysate derived from pre-treated ensiled sweet sorghum. The purpose was to condition the yeast to the inhibitors generated during the ensiling of sweet sorghum. The conditioned seed cultures exhibited similar fermentation performance and superior kinetics than the inoculum prepared in YPD medium. Furthermore, the conditioned yeast showed increased tolerance to the increased levels of these inhibitors, including ethanol, acetic and lactic acids, demonstrating an effective way to increase the robustness of yeast fermentation for ethanol production. PMID- 30253274 TI - Chlorine migration mechanisms during torrefaction of fermentation residue from food waste. AB - Fermentation residue from food waster (FRFW) has a large amount of residual chlorine (Cl), and the high-salt of FRFW is either landfilled or treated as a fertilizer. The transfer of chlorine to the atmosphere and soil can cause pollution and soil salinization. This work primarily investigated the combined forms and migration mechanisms of Cl during the torrefaction of FRFW from 250 to 400 degrees C. The results showed that the form and amount of Cl released during the torrefaction of FRFW depended on temperature. The absolute content of soluble Cl and total Cl in torrefied solid products decreased, and the absolute content of insoluble Cl reached a maximum at 350 degrees C, which indicated that some soluble Cl was transferred to the insoluble Cl (CCl forms). The Cl-containing products in non-condensable gas was too little to be detected, so the majority of the reduced Cl was in liquids with different organic compounds. PMID- 30253275 TI - Construction and evaluation of HA-epitope-tag introduction onto the VP1 structural protein of a novel HY12 enterovirus. AB - In this study, we investigated the feasibility of using enterovirus HY12 as a vector to express an exogenous hemagglutinin (HA)-epitope tag onto the HY12 encoded VP1 protein via a reverse genetic system. Characteristics of recombinant (r) HY12-VP1-HA marker virus were determined by immunoperoxidase monolayer assay, western blot, electron microscopy, and serum-neutralisation assay. Sequence analysis demonstrated that the marker virus stably maintained the HA-epitope-tag in MDBK cells, with no changes in viral morphological features observed relative to those of the parental rHY12 virus. Furthermore, detection by immunofluorescence assay revealed the expression of HA-epitope tag and VP2 protein, which distinguish the marker virus from parental rHY12 virus. In addition, neonatal mice infected with the recombinant marker virus showed various microscopic pathological lesions and generated anti-HY12 virus and -HA-epitope tag antibodies. These results indicated that the recombinant marker virus represented a valuable platform to promote the development of novel genetic vaccines. PMID- 30253277 TI - Implementation of a perineal support programme for reduction of the incidence of obstetric anal sphincter injuries and the effect of non-compliance. AB - OBJECTIVE: Obstetric anal sphincter injury (OASI) is a serious complication of a vaginal delivery. In 2005, a Norwegian nation-wide training programme to reduce the OASI rate was successfully implemented. The aim of the present study was to assess the impact of a perineal support programme, inspired by the Norwegian programme, on the incidence of OASIs in a Dutch hospital with a low a priori rate. STUDY DESIGN: Prospective cohort study with historical comparison group. Three midwives and one obstetrician were trained on site by an expert midwife from Norway. These four trained the rest of the obstetrical staff. Data were prospectively recorded using the Dutch National Perinatal Registry, with additional recording whether the manual perineal support was actually applied in individual deliveries. OASI rates in three time periods were studied: the year preceding the training programme, the training period of 7 months and the year after the training period (respectively "control period", "training period" and "result period"). After exclusion of caesarean sections, preterm deliveries, breech and twin deliveries, a total of 4391 deliveries were recorded during the study period. RESULTS: During the training period, the OASI rate decreased significantly from 2.0 to 0.7% (aOR 0.34; 95%CI 0.15-0.76). In the result period, manual perineal support was performed in 72.7% of the deliveries and the overall OASI rate raised to 1.7% again, mainly because of non-compliance to the programme during vacuum deliveries. Nevertheless, multivariate logistic regression analysis with correction for known OASI risk factors showed that the OASI rate was 83% lower with application of perineal support (aOR 0.17; 95%CI 0.07-0.39). CONCLUSION: A perineal support programme decreases OASI rate. Continuous verification of application and repetitive training is necessary, especially during vacuum deliveries. PMID- 30253276 TI - Rotavirus RNAs sponge host cell RNA binding proteins and interfere with their subcellular localization. AB - Cellular mRNAs cycle between translating and non-translating pools, polysomes compose the translating pool, while RNA granules contain translationally-silenced mRNAs, where the RNAs are either stored in stress granules, or accumulate in processing bodies (PBs) or GW-bodies, which have an important role in RNA degradation. Viruses have developed measures to prevent the deleterious effects of these structures during their replication. Rotavirus, the most common agent of viral gastroenteritis, is capable of establishing a successful infection by counteracting several of the antiviral responses of its host. Here, we describe that in rotavirus-infected cells the distribution of several RNA binding proteins is changed causing the disaggregation of PBs, the relocalization of GW-body proteins, and the cytoplasmic accumulation of HuR, a predominantly nuclear protein. We show that this redistribution of proteins is more likely caused by the accumulation of viral RNA in the cytoplasm of infected-cells, where it might be acting as an RBP sponge. PMID- 30253278 TI - Testosterone represses urinary excretion of the alpha-tocopherol metabolite alpha carboxymethylhydroxychroman in rats. AB - In rats, plasma and tissue concentrations of alpha-tocopherol, a predominant form of vitamin E in mammals, are known to differ between the sexes. In order to examine sex differences in alpha-tocopherol metabolism, we investigated urinary excretion of the alpha-tocopherol metabolite alpha-carboxymethylhydroxychroman (alpha-CEHC) using Wistar rats. First, we measured alpha-CEHC in urine of 9-week old male and female rats in basal and alpha-tocopherol-administered conditions. We observed that female rats excrete significantly more alpha-CEHC than male rats via urine. This sex difference was observed in matured 9-week-old rats but not in premature 3-week-old rats, suggesting that the difference may relate to sex hormones. In order to confirm this, we examined the effect of ovariectomy and orchiectomy on female and male rats, respectively. The results of castration clearly demonstrated that orchiectomy enhanced urinary excretion of alpha-CEHC, supporting the hypothesis that testosterone repressed alpha-tocopherol metabolism. We then administered testosterone propionate to orchiectomized rats and observed down-regulation of alpha-CEHC excretion. Taken together, these results indicate that testosterone represses the metabolism and urinary excretion of alpha-tocopherol in rats. This is the first report to show a sex-dependent difference in urinary excretion rate of an alpha-tocopherol metabolite and contributes to the understanding of vitamin E metabolism. PMID- 30253280 TI - Feeding a slowly digestible carbohydrate diet during pregnancy of insulin resistant rats prevents the excess of adipogenesis in their offspring. AB - An obesogenic environment during pregnancy has been shown to increase the risk of dysregulation on adipogenesis and insulin resistance in the offspring. Being essential for the growing fetus, glucose supply is guaranteed by a number of modifications in the mother's metabolism, and thus, glucose control during pregnancy especially among obese or diabetic women is paramount to prevent adverse consequences in their children. Besides the election of low-glycemic index carbohydrates, the rate of carbohydrate digestion could be relevant to keep a good glucose control. In the present study, we compared the effects of two high fat diets with similar glycemic load but different rates of carbohydrate digestion given to pregnant insulin-resistant rats. After birth, all animals were fed a standard diet until age 14 weeks. We analyzed offspring body composition, plasma and adipocyte lipidomics, lipid metabolism in adipose tissue and insulin sensitivity. Those animals whose mothers were fed the rapid-digesting carbohydrate diet exhibited an excessive adipogenesis. Thus, these animals showed a marked lipidemia, increased lipid synthesis in the adipose tissue and reduced glucose transporter amount in the adipose. On the contrary, those animals whose mothers were fed the slow-digesting carbohydrate diet showed a profile in the measured parameters closer to that of the offspring of healthy mothers. These results support the hypothesis that not only glycemic index but the rate of carbohydrate digestion during gestation may be critical to regulate the programming of adipogenesis in the offspring. PMID- 30253281 TI - Inhibition of the whole number bias in decimal number comparison: A developmental negative priming study. AB - A major source of errors in decimal magnitude comparison tasks is the inappropriate application of whole number rules. Specifically, when comparing the magnitude of decimal numbers and the smallest number has the greatest number of digits after the decimal point (e.g., 0.9 vs. 0.476), using a property of whole numbers such as "the greater the number of digits, the greater its magnitude" may lead to erroneous answers. By using a negative priming paradigm, the current study aimed to determine whether the ability of seventh graders and adults to compare decimals where the smallest number has the greatest number of digits after the decimal point was partly rooted in the ability to inhibit the "the greater the number of digits, the greater its magnitude" misconception. We found that after participants needed to compare decimal numbers in which the smallest number has the greatest number of digits after the decimal point (e.g., 0.9 vs. 0.476), they were less efficient at comparing decimal numbers in which the largest number has the greatest number of digits after the decimal point (e.g., 0.826 vs. 0.3) than they were after comparing decimal numbers with the same number of digits after the decimal point (e.g., 0.981 vs. 0.444). The negative priming effects reported in seventh graders and adults suggest that inhibitory control is needed at all ages to avoid errors when comparing decimals where the smallest number has the greatest number of digits after the decimal point. PMID- 30253282 TI - On the misincorporation of nucleotides opposite mutagenic cyclic 1,N2 propanoguanine: A computational investigation. AB - The misincorporation properties of exocyclic DNA adduct, cyclic 1,N2 propanoguanine with nucleobases have been investigated using DFT and DFT-D methods. Number of possible and stable mispairing conformations of cyclic 1,N2 propanoguanine with A,T,G and C have been considered for our investigation. The single point energy calculations have been carried out at the M06/6-311++G**, omegaB97XD/6-311++G** and MP2/6-311++G** levels on corresponding optimized geometries. The reaction enthalpy values were employed at the M06/6-31 + G* and omegaB97XD/6-31 + G* levels. The energies have been compared among the cyclic 1,N2-propanoguanine adduct with nucleobases to find the most stable conformer. The CPCM model was utilized on account of solvent phase and overall polarizability. The computed binding energies follow the order as CPr-Gua-G(2)( 23.2 kcal/mol) > CPr-Gua-C(1) (-16.1 kcal/mol) > CPr-Gua-A(2)(-10.6 kcal/mol) > CPr-Gua-T(2)(-9.6 kcal/mol) in the gas phase at M06 level, which indicates the guanine and cytosine are favorable for mispairing with the cyclic 1,N2 propanoguanine adduct. The obtained results using computational tools are in good agreement with the experimental observation. PMID- 30253279 TI - Loss of NRF-2 and PGC-1alpha genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a multi-factorial disease that is the leading cause of irreversible and severe vision loss in the developed countries. It has been suggested that the pathogenesis of dry AMD involves impaired protein degradation in retinal pigment epithelial cells (RPE). RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, DNA and lipids and evoke tissue deterioration during the aging process. The ubiquitin-proteasome pathway and the lysosomal/autophagosomal pathway are the two major proteolytic systems in eukaryotic cells. NRF-2 (nuclear factor erythroid 2-related factor-2) and PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) are master transcription factors in the regulation of cellular detoxification. We investigated the role of NRF-2 and PGC 1alpha in the regulation of RPE cell structure and function by using global double knockout (dKO) mice. The NRF-2/PGC-1alpha dKO mice exhibited significant age-dependent RPE degeneration, accumulation of the oxidative stress marker, 4 HNE (4-hydroxynonenal), the endoplasmic reticulum stress markers GRP78 (glucose regulated protein 78) and ATF4 (activating transcription factor 4), and damaged mitochondria. Moreover, levels of protein ubiquitination and autophagy markers p62/SQSTM1 (sequestosome 1), Beclin-1 and LC3B (microtubule associated protein 1 light chain 3 beta) were significantly increased together with the Iba-1 (ionized calcium binding adaptor molecule 1) mononuclear phagocyte marker and an enlargement of RPE size. These histopathological changes of RPE were accompanied by photoreceptor dysmorphology and vision loss as revealed by electroretinography. Consequently, these novel findings suggest that the NRF 2/PGC-1alpha dKO mouse is a valuable model for investigating the role of proteasomal and autophagy clearance in the RPE and in the development of dry AMD. PMID- 30253283 TI - Identification and analyses of natural compounds as potential inhibitors of TRAF6 Basigin interactions in melanoma using structure-based virtual screening and molecular dynamics simulations. AB - The interaction of the proteins, tumor necrosis factor receptor-associated factor6 (TRAF6) and Basigin (CD147), is known to be associated with the over expression of matrix metalloproteinases (MMPs) in melanoma cells. MMPs are known to be responsible for melanoma metastasis. Hence, the TRAF6-Basigin complex can act as a potential therapeutic target. In previous studies, amino acid residues Lys340, Lys 384, Glu417 and Glu511 of TRAF6 were identified as the most vital residues on the basis of their contributions to interaction energy, relative solvent accessibility and electrostatic interactions in the TRAF6-Basigin protein protein interaction (PPI) scheme. In our current work, we performed structure based virtual screenings of some natural compounds obtained from ZINC database (n = 14509) to search for molecules which can act as inhibitors against the formation of TRAF6-Basigin complex. Three potential inhibitors were identified which were observed to make intermolecular interactions with Lys384 and Glu511 of TRAF6. Molecular dynamics simulation results suggested the substantial pharmacological importance of the ligand molecules as it was observed that there was total destabilization of TRAF6-Basigin complex upon binding of the molecule ZINC02578057. From our studies, we could conclude that the ligands termed as ZINC49048033, ZINC02578057 and ZINC72320240 could have great potentials to act as inhibitors to prevent melanoma metastasis. PMID- 30253284 TI - Responses of photosynthesis-related parameters and chloroplast ultrastructure to atrazine in alfalfa (Medicago sativa L.) inoculated with arbuscular mycorrhizal fungi. AB - Atrazine is an ingredient in photosynthesis-inhibiting herbicides and has been widely used to combat weeds in farmland. However, most atrazine that is applied fails to degrade in the soil and subsequently affects non-target plants. In this study, we investigated the influence of arbuscular mycorrhizal fungi (AMF), Funneliformis mosseae on the photosynthesis-related parameters, chlorophyll content, and chloroplast ultrastructure in alfalfa plants, some of which had been exposed to atrazine. Our results showed that the percentage of AMF hyphal colonization reached 91.23% 35 days after the alfalfa was planted, which suggests a symbiotic relationship between F. mosseae and alfalfa roots. F. mosseae alleviated the inhibition of net photosynthesis and stomatal function significantly in alfalfa exposed to atrazine for 24 h. A chlorophyll fluorescence analysis revealed that F. mosseae prevented a major reduction in the performance of photosystem II (PSII) photochemistry in the presence of atrazine, such as the relative decrease of Fv/Fm between the non-mycorrhizal and F. mosseae mycorrhizal treatments was 4.4% and 5.8% after 24 and 48 h of atrazine exposure time. However, F. mosseae has no significant alleviation on a sharp reduction in the chlorophyll a, chlorophyll b and carotenoid content in alfalfa exposed to atrazine. For the chloroplast ultrastructure in alfalfa exposed to atrazine, the number of both plastoglobules and partial granal stacks was greater in the presence of F. mosseae. In general, our results indicate that the F. mosseae inoculation was beneficial to sustain photosynthesis-related performance, such as net photosynthesis, stomatal conductance, the maximum quantum yield (Fv/Fm) and effective quantum yield (PhiPSII) of PSII photochemistry in alfalfa after exposure to atrazine, because the mycorrhizal alfalfa had a greater number of plastoglobules and granal stacks in the chloroplast, thereby enhancing its resistance to the oxidative damage induced by atrazine. PMID- 30253287 TI - Chemometric modeling of aquatic toxicity of contaminants of emerging concern (CECs) in Dugesia japonica and its interspecies correlation with daphnia and fish: QSTR and QSTTR approaches. AB - The contaminants of emerging concern (CEC) are universally detected in surface water and soil. They can affect the wild life, and their subsequent translocation through the food chain can affect human health, which is an issue of serious concern. Very few amounts of ecotoxicological data are available on the environmental behavior and ecotoxicity of CEC, thus modeling approaches are essential to bridge the existing gap in experimental data. In this present study, we have developed quantitative structure-toxicity relationship (QSTR) models using a data set of 75 compounds for the prediction of aquatic ecotoxicity of CECs on fresh water planarian (Dugesia japonica) by partial least squares (PLS) regression algorithm using simple molecular descriptors selected by genetic algorithm approach. We also explore the correlations between toxicity against D. japonica and those against daphnia (D. magna) and fish (P. promelas), and these were improved on addition of a few molecular descriptors (B08[C-O] and B09[N-O] in case of daphnia and C-006 and H-052 in case of fish) which allowed us to develop predictive interspecies quantitative structure toxicity-toxicity relationship (QSTTR) models, allowing to extrapolate data from one endpoint to another endpoint. The QSTR (Q2LOO ranging from 0.630 to 0.720 and R2pred ranging from 0.723 to 0.798) and QSTTR (Q2LOO = 0.60 and 0.67, R2pred = 0.88 and 0.84) models have desirable statistical qualities and acceptable internal and external validation measures, meeting rigorous criteria of different validation metrics and showing acceptability for regulatory purposes as proposed by Organization for Economic Cooperation and Development (OECD). Consensus predictions were also performed based on multiple models generated in this study by using the "Intelligent Consensus Predictor" (ICP) tool to enhance the prediction quality for external set compounds. PMID- 30253285 TI - A comparative study on effects of static electric field and power frequency electric field on hematology in mice. AB - With the development of the ultra high voltage transmission technology, the voltage level of transmission line rised. Accordingly, the strength of electric field in the vicinity of transmission line increased, thus possible health effects from electric field have caused many public attentions. In this study, in order to compare effects induced by static electric field (SEF) and power frequency electric field (PFEF) on immune function, Institute of Cancer Research (ICR) mice were exposed to 35 kV/m SEF (0 Hz) and PFEF (50 Hz),respectively. Several indicators of white blood cell, red blood cell as well as hemoglobin in peripheral blood were tested after exposure of 7, 14 and 21 days, respectively. There was no significant difference in any indicators under SEF exposure of 35 kV/m for 7d, 14d and 21d between experimental group and control group. Under the PFEF exposure of 35 kV/m, white blood cell count significantly reduced after exposure of 7d, 14d and 21d. Meanwhile, red blood cell count significantly reduced after exposure of 7d, and returned to normal level through the compensatory response of organism after exposure of 14d and 21d. Hemoglobin concentration significantly decreased only after exposure of 21d. Based on tested results of hematological indicators, SEF exposure of 35 kV/m did not affect immune functions in mice but PFEF exposure of 35 kV/m could cause a decline of immune function. This difference of effects from SEF and PFEF on immune function was possibly caused by the difference of the degree of molecular polarization and ion migration in organism under exposure of two kinds of electric fields. PMID- 30253286 TI - Response of soil micro-ecology to different levels of cadmium in alkaline soil. AB - Although the effect of heavy metal on soil microbial diversity was widely studied, the interaction among micro-ecological environment in heavy metal contaminated soil was less known. In this study, we systematically investigated the influence of cadmium (Cd) on soil micro-ecological environment (pH, nutrient content, soil enzyme activities, microbial biomass, bacterial and fungal diversities). Results showed that pH values slightly decreased with the Cd level increase, whereas the nutrient content including of Olsen-P (OSP), Alkeline-N (ALN), Olsen-K (OSK) and organic matter (OM) did not show significant difference in different treatments. In contrast to physicochemical properties, the biochemical qualities were easily influenced by Cd pollutant, resulting in soil microbial numbers and enzyme activities significantly decreased. High-throughput sequencing showed that microbial community composition was significantly affected by heavy metal. For bacteria, Actinobacteria abundance significantly decreased in Cd treated soil, corresponding to Proteobacteria and Firmicutes increased. For fungi, the most dominant phyla member (Ascomycota) was significantly decreased whereas Zygomycota significantly increased with Cd addition. These results further revealed the integral interrelation of micro-ecology environmental players under the stress of different Cd levels. PMID- 30253288 TI - Molecular basis of cucumber fruit domestication. AB - Cucumber (Cucumis sativus L.) is an economically important vegetable crop that is cultivated worldwide. Compared to the wild ancestor bearing small, bitter and seedy fruit, domesticated cucumbers exhibit significant variation in fruit appearance, size and flavor. Understanding the molecular basis of domestication related traits can provide insights into fruit evolution and make crop breeding more efficient. Here we review recent advances in relating to the genetic basis of fruit morphological traits (femaleness, fruit spine, wart, size, color and carpel development) and organoleptic features (bitterness) during cucumber domestication. PMID- 30253289 TI - CKD, arterial calcification, atherosclerosis and bone health: Inter-relationships and controversies. AB - Mineral bone disease (MBD) is a common complication of chronic kidney disease (CKD) characterized by disruption of normal mineral homeostasis within the body. One or more of the following may occur: hypocalcemia, hyperphosphatemia, secondary hyperparathyroidism (SHPT), decreased vitamin D and vascular calcification (VC). The greater the decrease in renal function, the worse the progression of CKD-MBD. These abnormalities may lead to bone loss, osteoporosis and fractures. CKD-MBD is a major contributor to the high morbidity and mortality among patients with CKD. Another well-known complication of CKD is cardiovascular disease (CVD) caused by increased atherosclerosis and VC. CVD is the leading cause of morbidity and mortality in CKD patients. VC is linked to reduced arterial compliance that may lead to widened pulse pressure and impaired cardiovascular function. VC is a strong predicator of cardiovascular mortality among patients with CKD. Elevated phosphorus levels and increased calcium phosphorus product promote VC. Controlling mineral disturbances such as hyperphosphatemia and SHPT is still considered among the current strategies for treatment of VC in CKD through restriction of calcium based phosphate binders in hyperphosphatemic patients across all severities of CKD along with dietary phosphate restriction and use of calciminetics. Additionally, Vitamin D insufficiency is common in CKD and dialysis patients. The causes are multifactorial and a serious consequence is SHPT. Vitamin D compounds remain the first-line therapy for prevention and treatment of SHPT in CKD. Vitamin D may also have atheroprotective effects on the arterial wall, but clinical studies do not show clear evidence of reduced cardiovascular mortality with vitamin D administration. This review discusses the issues surrounding CKD-MBD, cardiovascular disease and approaches to treatment. PMID- 30253290 TI - The association of adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) with cardiovascular disease in subjects with antiphospholipid antibodies. AB - BACKGROUND AND AIMS: Cardiovascular disease (CVD), including coronary artery disease and stroke/peripheral artery disease, is less commonly reported than venous thromboembolism in subjects with antiphospholipid antibodies (aPLs) and little is known about the association of CVD with adjusted Global AntiphosPholipid Syndrome Score (aGAPSS). METHODS: Consecutive aPLs subjects were enrolled to assess the association of CVD with aGAPSS. Moreover, additional risk factors of CVD were identified by means of multivariate analysis to design an aGAPSS specific for CVD (aGAPSSCVD). RESULTS: A total of 192 aPLs subjects (34 males, 158 females, mean age 49.84 +/- 12.0 years) were enrolled. CVD was reported in 52 subjects (27.1%), 26 episodes of coronary artery disease and 26 stroke/peripheral artery disease. The prevalence of CVD increased for increasing aGAPSS ranging from 20.5% in the lowest aGAPSS category, up to 37.9% in the highest category (p = 0.027). ROC analysis showed that aGAPSS detected 63.0% of CVD and was associated with OR for CVD of 2.52 (95%CI: 1.24-5.10, p = 0.010). When including obesity, diabetes and smoking habit in the score, we found that aGAPSSCVD detected 71.4% of CVD (72.4% for early-CVD and 69.0% for CVD after 50 years) with an OR for CVD of 4.68 (95%CI: 2.31-9.51, p < 0.001). CONCLUSIONS: The aGAPSSCVD, obtained after adding obesity, smoking habit and diabetes to the standard aGAPSS, showed a higher detection rate of CVD in aPLs subjects, particularly of early-CVD. These results need to be validated in ad hoc designed prospective studies. PMID- 30253291 TI - AAV8-mediated overexpression of mPCSK9 in liver differs between male and female mice. AB - BACKGROUND AND AIMS: The recombinant adeno-associated viral vector serotype 8 expressing the gain-of-function mutation of mouse proprotein convertase subtilisin/kexin type 9 (AAV8- PCSK9) is a new model for the induction of hypercholesterolemia. AAV8 preferentially infects hepatocytes and the incorporated liver-specific promoter should ensure expression of PCSK9 in the liver. Since tissue distribution of AAVs can differ between male and female mice, we investigated the differences in PCSK9 expression and hypercholesterolemia development between male and female mice using the AAV8-PCSK9 model. METHODS: Male and female C57BL/6 mice were injected with either a low-dose or high-dose of AAV8-PCSK9 and fed a high-fat diet. Plasma lipid levels were evaluated as a measure of the induction of hypercholesterolemia. RESULTS: Injection of mice with low dose AAV8-PCSK9 dramatically elevated both serum PCSK9 and cholesterol levels in male but not female mice. Increasing the dose of AAV8-PCSK9 threefold in female mice rescued the hypercholesterolemia phenotype but did not result in full restoration of AAV8-PCSK9 transduction of livers in female mice compared to the low-dose male mice. Our data demonstrate female mice respond differently to AAV8 PCSK9 injection compared to male mice. CONCLUSIONS: These differences do not hinder the use of female mice when AAV8-PCSK9 doses are taken into consideration. However, localization to and production of AAV8-PCSK9 in organs besides the liver in mice may introduce confounding factors into studies and should be considered during experimental design. PMID- 30253292 TI - Food craving frequency mediates the relationship between emotional eating and excess weight gain in pregnancy. AB - An estimated 50% of pregnancies in the U.S. are associated with maternal weight gain that exceeds Institute of Medicine recommendations. The numerous adverse consequences of obesity in gestation, delivery and the postpartum have been widely documented. The role of excess gestational weight gain (GWG) as a predictor of lifetime obesity risk in mothers and their children is also increasingly recognized. Cravings and negative affect are commonly cited triggers of overconsumption in pregnant women. We sought to examine the role of food craving frequency as a mediator in the relation between emotional eating and excess GWG. In this cross-sectional study, pregnant women (n = 113) completed the Dutch Eating Behavior Questionnaire, a measure of "restrained," "emotional," and "external" eating styles, along with the Food Craving Inventory, which quantifies cravings for "high fat foods," "fast food fats," "carbohydrates/starches," and "sweets." Participants also reported on pre-pregnancy weight and height, and GWG at the time of survey completion. Data supported the hypothesized mediation model, with frequency of "high fat foods" cravings fully mediating the relationship between "emotional" eating and excess GWG (Sobel test z = 2.40, p = .016). This study addresses the striking dearth of research examining potentially modifiable psychosocial predictors of excess GWG. Future longitudinal research should examine if salient affective states trigger food cravings, thus placing pregnant women at increased risk of excess weight gain. Findings have implications for treatment interventions targeting excess GWG, suggesting a need to teach skills to help patients better manage low moods and cravings. PMID- 30253293 TI - Hexachloronaphthalene (HxCN) as a potential endocrine disruptor in female rats. AB - Hexachloronaphthalene (HxCN) is one of the most toxic and most bioaccumulative congeners of polychlorinated naphthalenes (PCNs) known to be present in animal and human adipose tissue. Unfortunately, little data is available regarding the negative effect of PCNs on endocrine function. The aim of the study was to investigate the direct influence of subacute (two and four-week) and subchronic (13-week) daily oral exposure of female rats to 30, 100 and 300 MUg kg b.w.-1 HxCN on ovarian, thyroid function and neurotransmitters level. The levels of selected sex hormones (progesterone: P and estradiol: E2) in the serum and uterus, regularity of estrous cycle, levels of thyroid hormones (fT3 and fT4), TSH, gamma-aminobutyric acid and glutamate levels in selected brain areas and the activity of CYP1A1 and CYP2B in the liver were examined. Estrogenic action (elevated E2 concentration in the uterus and serum) was observed only after subacute exposure, and antiestrogenic activity (decreased E2 level and uterus weight) after 13 weeks administration of 300 MUg kg b.w.-1 day-1. Subchronic administration of HxCN significantly lengthens the estrous cycle, by up to almost 50%, and increases the number of irregular cycles. In addition, increased TSH and decreased fT4 serum levels were observed after all doses and durations of exposure to HxCN. Only subacute exposure led to a significant decrease in the level of examined neurotransmitters in all analyzed structures. Additionally, exposure to low doses of HxCN appears to lead to strong induction of CYP1A1 in a liver. It can be hypothesized that HxCN produces effects which are very similar to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like compounds (DLCs), particularly concerning endocrine and estrous cyclicity disorders. Therefore, HxCN exposure may exert unexpected effects on female fecundity among the general population. PMID- 30253294 TI - Nitrate loads in sub-tropical headwater streams driven by intensive horticulture. AB - Nitrogen runoff from fertiliser intensive land uses has become an issue worldwide, contributing to algal blooms, hypoxic waters and aquatic biodiversity losses. This study assessed potential nutrient pollution from blueberry farms in subtropical Australia and examines whether nutrient loads were driven by groundwater discharge and/or surface water runoff. Streams downstream of eight blueberry farms were compared to eight nearby control sites without any blueberry activity. In the 90 day sample period, there were three rain events >90 mm day-1 that produced runoff sufficient to create flooding. Overall, the results revealed a clear link between blueberry farming and nitrogen runoff in headwater streams. While NOX (nitrate + nitrite) was the dominant nitrogen species downstream of blueberry farms, dissolved organic nitrogen (DON) was the dominant species in control sites. The concentrations and loads of NOx were one order of magnitude lower in the eight non-blueberry (6.3 +/- 2.0 MUmol L-1; 1.6 +/- 1.2 kg N-NOX ha 1 yr-1) than the eight blueberry (56.9 +/- 14.2 MUmol L-1; 21.8 +/- 8.0 kg N-NOX ha-1 yr-1) sites. NOX concentrations and loads were highest following rain events. Radon (222Rn, a natural groundwater tracer) observations and low nitrogen concentration in groundwater samples further suggest that surface runoff dominates the delivery of nitrogen to the creeks investigated. NOX concentrations and loads in creeks correlated with blueberry farm density. At >15% of blueberry land use in a catchment, there was a detectable influence in NOX concentrations and loads in the headwater streams. Assuming that our load estimates can be up scaled to annual nitrogen creek exports, and that local farmers use the recommended amount of fertiliser (121 kg N ha-1 yr-1), between 18 and 25% of the used fertiliser was lost to the creeks. This implies that there are opportunities for decreasing the use of fertilisers in this catchment and managing any nitrogen that escapes to the creeks. PMID- 30253295 TI - Using multi-medium factors analysis to assess heavy metal health risks along the Yangtze River in Nanjing, Southeast China. AB - In the environmental ecosystem, there are no absolutely isolated risks. Each risk might be influenced by multiple environmental factors and the factors' interaction within the specific system. Hence, health risk assessments of heavy metal contamination must consider multiple environmental media and their transfer processes from one medium to another. Integrated assessments provide a new perspective for evaluating many factors, such as the potential ecological risks of soils, sediments, plants, and the transportation of heavy metals in these media, which influences the health risks. In this study, the main influencing factors for human health risk from heavy metals along the Yangtze River in Nanjing, Southeast China, were explored. The contents of five heavy metals were measured in sediment-soil-plant, including cadmium (Cd), lead (Pb), copper (Cu), zinc (Zn), and chromium (Cr). The Cd displayed the highest potential ecological risk in soils and sediments, as it possessed high bioaccessibility (BA; 0.17 +/- 0.211) and bioaccumulation factor (BCF; 0.35 +/- 0.33). The 5.97% of the target hazard quotient (THQ) of Cd were higher than 1, indicating a potential health risk in plant consumption. Based on the geodetector model, determinant power (DP) valves for factors influencing health risk strongly suggest that plant types (0.479) has a highest effect, followed by soil organic matter (SOM; 0.292), and the BA of heavy metals (0.107). The results also indicate that pollution from the upper reaches of the river, and agricultural activities, had a greater impact on health risk than did industrial activities in the study area. Thus, regular monitoring and source control for Cd, along with integrated agricultural management practices should be implemented to control and reduce heavy metal inputs and improve the safety of cultivated plants. PMID- 30253296 TI - Wintertime nitrate formation during haze days in the Guanzhong basin, China: A case study. AB - In this study, the formation of nitrate aerosol from 16 to 24 December 2015 in the Guanzhong basin, China is simulated using the WRF-Chem model. The predicted near-surface O3, NO2, and fine particulate matters (PM2.5) in the basin and inorganic aerosols and nitrous acid (HONO) in Xi'an are generally in good agreement with the observations. Sensitivity studies show that the heterogeneous HONO sources play an appreciable role in the nitrate formation in the basin, contributing 9.2% of nitrate mass concentrations during heavy haze days. Nitrate formation is also affected by sulfate due to their competition for ammonia, particularly in urban areas. A 50% decrease in SO2 emissions enhances the nitrate concentration by 6.2% during heavy haze days on average in the basin, and a 50% increase in SO2 emission reduces the nitrate concentration by 9.7%. The roles of HONO and sulfate competition in nitrate formation are strongly modulated by ammonia. Agricultural emissions predominate the nitrate level in the basin (93.5%), but the non-agricultural sources cannot substantially influence nitrate formation (3.7%-14.6%). Reducing agricultural emission is an effective control strategy to mitigate nitrate pollution in the basin. PMID- 30253297 TI - Enhanced heterogeneous Fenton-like systems based on highly dispersed Fe0-Fe2O3 nanoparticles embedded ordered mesoporous carbon composite catalyst. AB - Acceleration of Fe3+/Fe2+ cycle and simultaneous reduction of particle size with enhanced stability is extremely important for iron-based heterogeneous Fenton catalysts. In this work, Fe0-Fe2O3 composite nanoparticles embedded ordered mesoporous carbon hybrid materials (Fe0-Fe2O3/OMC) were rationally designed as efficient heterogeneous Fenton catalysts. Because of the confinement and reduction of OMC, highly dispersed Fe0-Fe2O3 active species with diameter of ~8 nm were generated by an optimized carbothermic reduction process. In addition, Fe0-Fe2O3/OMC possesses ordered mesoporous structure with uniform mesopore, high surface area and pore volume. For comparison, two other catalysts, including solely Fe0 nanoparticles supported on ordered mesoporous carbon (Fe0/OMC) and solely Fe2O3 nanoparticles supported on ordered mesoporous carbon (Fe2O3/OMC) were also prepared. The Fenton catalytic performance of synthesized catalysts was evaluated by using H2O2 as oxidizing agent to degrade Acid Orange II (AOII). The results show that almost 98.1% of 100 mg L-1 AOII was removed by Fe0-Fe2O3/OMC in condition of neutral pH and nearly room temperature, which is much higher than those of compared catalysts. The enhanced catalytic activity of Fe0-Fe2O3/OMC for AOII removal is due to the efficient electron transfer between the Fe0 and iron oxide and the accelerated Fe3+/Fe2+ cycle. The stability and reusability of the catalyst was also investigated, which showed a good performance even after five consecutive runs. The as-synthesized catalyst is proved to be an attractive candidate in heterogeneous Fenton chemistry and practical application. PMID- 30253298 TI - Bioavailability of tetracycline to antibiotic resistant Escherichia coli in water clay systems. AB - Tetracyclines are a class of antimicrobials frequently found in the environment, and have promoted the proliferation of antibiotic resistance. An unanswered research question is whether tetracycline sorbed to soils is still bioavailable to bacteria and exerts selective pressure on the bacterial community for the development of antibiotic resistance. In this study, bioreporter E. coli MC4100/pTGM strain was used to probe the bioavailability of tetracycline sorbed by smectite clay, a class of common soil minerals. Batch sorption experiments were conducted to prepare clay samples with a wide range of sorbed tetracycline concentration. The bioreporter was incubated with tetracycline-sorbed clay at different clay/solution ratios and water contents, as well as using dialysis tubings to prevent the direct contact between bacterial cells and clay particles. The expression of antibiotic resistance genes from the bioreporter was measured using a flow cytometer as a measurement of bioavailability/selective pressure. The direct contact of bioreporter cells to clay surfaces represented an important pathway facilitating bacterial access to clay-sorbed tetracycline. In clay-water suspensions, reducing solution volume rendered more bacteria to attach to clay surfaces enhancing the bioavailability of clay-sorbed tetracycline. The strong fluorescence emission from bioreporter cells on clay surfaces indicated that clay sorbed tetracycline was still bioavailable to bacteria. The formation of biofilms on clay surfaces could increase bacterial access to clay-sorbed tetracycline. In addition, desorption of loosely sorbed tetracycline into bulk solution contributed to bacterial exposure and activation of the antibiotic resistance genes. Tetracycline sorbed by soil geosorbents could exert selective pressure on the surrounding microbial communities via bacterial exposure to tetracycline in solution from desorption and to the geosorbent-sorbed tetracycline as well. PMID- 30253299 TI - The impact of cookstove operation on PM2.5 and CO emissions: A comparison of laboratory and field measurements. AB - Inefficient biomass combustion in traditional cookstoves generates high levels of household air pollution (HAP) that is associated with numerous adverse environmental and human health conditions. Many cookstoves have been evaluated using laboratory tests, but past studies revealed discrepancies between laboratory and field measurements. Fuel re-loading, a common operation in actual use but not required in the laboratory test, might be a contributing factor to this laboratory-field gap. In this study, we evaluated the pollutant emissions performance of a semi-gasifier cooking stove using both laboratory and field measurements. Emission factors and real-time properties of CO and PM2.5 were separately measured during the following 4 phases of a typical cooking event: lighting, stable combustion, fuel re-loading and post fuel re-loading. We quantified the CO and PM2.5 contributions to total cooking event emissions in each phase. We found over 70% lower PM2.5 emissions and 60% lower CO emissions during 3 no re-loading laboratory tests compared with all 16 field tests. Lighting generated 83.8% +/- 15.6% of the total PM2.5 and 39.1% +/- 7.8% of the total CO in laboratory tests without fuel re-loading, and 57.8% +/- 33.5% and 37.9% +/- 21.2% of the total PM2.5 and CO in field tests, respectively. On average, fuel re-loading led to 29.1% +/- 30.8% of PM2.5 emissions and 24.9% +/- 22.6% of CO emissions in 16 field tests, which also contributed to significant discrepancies between laboratory and field-based emissions. According to the ISO IWA tiered stove ratings for emissions, fuel re-loading led to at least one tier lower ranking in both laboratory and field cookstove tests. Fuel re-loading could be an important factor causing laboratory-field discrepancy of emissions, thus it could be considered in future cookstove selection and intervention projects. PMID- 30253300 TI - Untargeted NMR-based metabolomics for field-scale monitoring: Temporal reproducibility and biomarker discovery in mosquitofish (Gambusia holbrooki) from a metal(loid)-contaminated wetland. AB - There is considerable interest in applying omics techniques, which have proven extremely valuable for laboratory-based toxicology studies, towards field-scale ecotoxicology and environmental monitoring. Concerns that confounding factors in natural ecosystems may exacerbate variability in omics datasets must be addressed to validate the transition from laboratory to field. This study explores how temporal variability related to seasonal and climatic trends influence qualitative and quantitative metabolomics outcomes, in fish from reference and metal(loid)-polluted wetlands in Australia. Female mosquitofish (Gambusia holbrooki) were sampled on two separate occasions, from a rehabilitated tailings wetland at the site of historic antimony (Sb) processing and a reference wetland with comparable water quality. The first sampling coincided with greater monthly rainfall and colder water temperature, whereas the second sampling was drier and water was warmer. Despite temporal changes and associated differences in metal(loid) concentrations, site differences in metabolite profiles were qualitatively very similar between sampling events. However, quantitative differences were observed, with a greater number of significantly altered metabolites identified during the second sampling event, which coincided with greater metal(loid) concentrations in both water and fish. The majority of identified metabolites were elevated in fish from the contaminated wetland, but with notable decreases in several metabolites that are known to play a role in various aspects of metal(loid) binding, detoxification and excretion. Specifically, decreased aspartate, histidine, myo-inositol, taurine and choline were observed in fish from the contaminated wetland, and may therefore represent a metabolite suite that is broadly indicative of metal toxicity. Quantitative differences between sampling events are suggestive of a dose-response relationship observable at the cellular level which, if harnessed, may be useful for assigning levels of concern based on the degree of change in a multi parameter set of metabolite biomarkers. PMID- 30253301 TI - The combined toxicity effect of nanoplastics and glyphosate on Microcystis aeruginosa growth. AB - Waste plastics can be degraded to nanoplastics (NPs, diameter<1 MUm) by natural forces. NPs not only directly affect aquatic organisms but also adsorb other pollutants, causing combined pollution. Glyphosate is one of the most widely used herbicides and is commonly monitored in freshwater systems. In this study, the effects of the combined toxicity of polystyrene cationic amino-modified nanoparticles (nPS-NH2) and glyphosate on a blue-green alga, Microcystis aeruginosa, were investigated. Our results demonstrated that 5 mg/L glyphosate had a strong inhibitory effect on M. aeruginosa (the 96-h inhibitory rate was 27%), while 5 mg/L nPS-NH2 had no apparent effect on the growth of M. aeruginosa. Interestingly, nPS-NH2 combined with glyphosate showed antagonistic effects on the inhibition of algal growth because nPS-NH2 displayed a strong adsorption capacity for glyphosate, which significantly alleviated the inhibitory effect of glyphosate on M. aeruginosa growth. However, the presence of glyphosate enhanced the stability of the dispersion system, which allowed more nPS-NH2 to adsorb on the surface of M. aeruginosa and may result in greater enrichment of nPS-NH2 in the food chain to show potential repercussions to human life. Our current study provides a new theoretical basis for the combined effects of NPs and pesticide pollution. PMID- 30253302 TI - Detection of glyphosate residues in companion animal feeds. AB - The widespread adoption of genetically modified, glyphosate-tolerant corn and soybean varieties in US crop production has led to a dramatic increase in glyphosate usage. Though present at or below regulatory limits currently set for human foodstuffs, the concentration of glyphosate in companion animal feed is currently unknown. In the present study, 18 commercial companion animal feeds from eight manufacturers were analyzed for glyphosate residues using ELISA. Every product contained detectable glyphosate residues in the range of 7.83 * 101-2.14 * 103 MUg kg-1 dry weight, with the average and medians being 3.57 * 102 and 1.98 * 102 MUg kg-1 respectively. Three products were tested for within-bag variation and six were tested for lot to lot variation. Little within-bag variation was found, but the concentration of glyphosate varied by lot in half of the products tested. Glyphosate concentration was significantly correlated with crude fiber content, but not crude fat or crude protein. Average daily intakes by animals consuming feeds containing the median glyphosate concentration are estimated to result in exposures that are 0.68-2.5% of the Allowable Daily Intake (ADI) for humans in the US and EU, which are 1750 and 500 MUg kg-1 respectively. Consumption of the most contaminated feed, however, would result in exposure to 7.3% and 25% of the above ADIs, though the relevance of such an exposure to companion animals is currently unknown. Companion animal feeds contained 7.83 * 101-2.14 * 103 MUg kg-1 glyphosate which is likely to result in pet exposure that is 4-12 times higher than that of humans on a per Kg basis. PMID- 30253303 TI - Does sulfur fertilizer influence Cu migration and transformation in colloids of soil pore water from the rice (Oryza sativa L.) rhizosphere? AB - Colloids are ubiquitous in soils, and it has been reported that colloids can act as carriers to increase the mobility of poorly soluble contaminants in subsurface environments. Addition of sulfur (S) fertilizer greatly influences on heavy metal behavior in paddy soil, while the influence of S fertilizer on Cu migration and transformation in colloids of soil pore water has not yet been studied. The influence of S fertilizer (S0 and Na2SO4) applied in paddy soils on Cu migration and transformation in colloids of soil pore water from the rice rhizosphere region was explored in this study. The speciation of Cu in colloids of soil pore water from the rice rhizosphere region was explored by advanced synchrotron-based X-ray absorption near-edge spectroscopy (XANES) techniques. The morphology of colloids was characterized by field emission scanning electron microscopy coupled to energy dispersive X-ray spectroscopy (SEM-EDX). At a depth of 20 cm, the concentration of Cu in colloids of the rhizosphere soil pore water in the control was 2.4- and 6.5- fold higher than that in treatments of S0 and Na2SO4, respectively. The colloids in soil pore water were all positively charged, ranging from 2.4 to 7.8 mV, and the size of colloids was 440-740 nm. The proportion of Fe in colloids in the rhizosphere region decreased with S fertilizer application, while the proportions of C and O increased. Sulfur fertilizer application, increased the proportion of Cu-Cysteine, while the proportion of Cu2S decreased in soil colloids. In conclusion, application of sulfur fertilizer in paddy soil decreased the Cu concentration in soil pore water and colloids of the rhizosphere region, thereby decreasing the vertical migration of Cu in soil pore water. PMID- 30253304 TI - Effect modification of CPY2E1 and GSTZ1 genetic polymorphisms on associations between prenatal disinfection by-products exposure and birth outcomes. AB - BACKGROUND: Prenatal disinfection by-products (DBPs) exposure is linked with adverse birth outcomes. Genetic susceptibility to DBP metabolism may modify the exposure-outcome associations. OBJECT: To investigate whether CYP2E1 and GSTZ1 genetic polymorphisms modified the associations of prenatal DBP exposures with adverse birth outcomes. METHODS: Two biomarkers of DBP exposures including trihalomethanes (THMs) in blood and trichloroacetic acid (TCAA) in urine were determined among 426 pregnant women from a Chinese cohort study. CYP2E1 (rs2031920, rs3813867, and rs915906) and GSTZ1 (rs7975) polymorphisms in cord blood were genotyped. Statistical interactions between prenatal DBP exposures and newborns CYP2E1 and GSTZ1 polymorphisms on birth outcomes (birth weight, birth length, and gestational age) were examined by multivariable linear regression with adjustment for potential confounders. RESULTS: We found that newborns CYP2E1 genetic polymorphisms (rs2031920 and rs3813867) modified the associations of maternal blood THMs or urinary TCAA levels with birth outcomes. However, these interactions were nonsignificant after Bonferroni correction for multiple comparisons, except for the interaction between maternal blood BrTHMs [sum of dibromochloromethane (DBCM), bromodichloromethane (BDCM), and bromoform (TBM)] and newborns CYP2E1 gene rs2031920 polymorphisms on birth weight (P for interaction = 0.003). CONCLUSION: Newborns genetic variations of CYP2E1 rs2031920 may modify the impacts of prenatal BrTHM exposure on birth weight. This finding needs to be further confirmed. PMID- 30253305 TI - Semi-automatic lymphoma detection and segmentation using fully conditional random fields. AB - The detection and delineation of the lymphoma volume are a critical step for its treatment and its outcome prediction. Positron Emission Tomography (PET) is widely used for lymphoma detection. Two common types of approaches can be distinguished for lymphoma detection and segmentation in PET. The first one is ROI dependent which needs a ROI defined by physicians. The second one is based on machine learning methods which need a large learning database. However, such a large standard database is quite rare in medical field. Considering these problems, we propose a new approach that combines PET (metabolic information) with CT (anatomical information). Our approach is semi-automatic, it consists of three steps. First, an anatomical multi-atlas segmentation is applied on CT to locate and remove the organs having physiologic hypermetabolism in PET. Then, CRFs (Conditional Random Fields) detect and segment a set of possible lymphoma volumes in PET. The conditional probabilities used in CRFs are usually estimated by a learning step. In this work, we propose to estimate them in an unsupervised way. The final step is to visualize the detected lymphoma volumes and select the real ones by simply clicking on them. The false detection is low thanks to the first step. Our method is tested on 11 patients. The rate of good detection of lymphoma is 100%. The average of Dice indexes for measuring the lymphoma segmentation performance is 84.4% compared to the manual lymphoma segmentation. Comparing with other methods in terms of Dice index shows the best performance of our method. PMID- 30253307 TI - Seeing is better than believing: visualization of membrane transport in plants. AB - Recently, the plant transport field has shifted their research focus toward a more integrative investigation of transport networks thought to provide the basis for long-range transport routes. Substantial progress was provided by of a series of elegant techniques that allow for a visualization or prediction of substrate movements in plant tissues in contrast to established quantitative methods offering low spatial resolution. These methods are critically evaluated in respect to their spatio-temporal resolution, invasiveness, dynamics and overall quality. Current limitations of transport route predictions-based on transporter locations and transport modeling are addressed. Finally, the potential of new tools that have not yet been fully implemented into plant research is indicated. PMID- 30253306 TI - Quantitative 3D Analysis of Coronary Wall Morphology in Heart Transplant Patients: OCT-Assessed Cardiac Allograft Vasculopathy Progression. AB - Cardiac allograft vasculopathy (CAV) accounts for about 30% of all heart transplant (HTx) patient deaths. For patients at high risk for CAV complications after HTx, therapy must be initiated early to be effective. Therefore, new phenotyping approaches are needed to identify such HTx patients at the earliest possible time. Coronary optical coherence tomography (OCT) images were acquired from 50 HTx patients 1 and 12 months after HTx. Quantitative analysis of coronary wall morphology used LOGISMOS segmentation strategy to simultaneously identify three wall-layer surfaces for the entire pullback length in 3D: luminal, outer intimal, and outer medial surfaces. To quantify changes of coronary wall morphology between 1 and 12 months after HTx, the two pullbacks were mutually co registered. Validation of layer thickness measurements showed high accuracy of performed layer analyses with layer thickness measures correlating well with manually-defined independent standard (Rautomated2 = 0.93, y=1.0x-6.2MUm), average intimal+medial thickness errors were 4.98 +/- 31.24 um, comparable with inter-observer variability. Quantitative indices of coronary wall morphology 1 month and 12 months after HTx showed significant local as well as regional changes associated with CAV progression. Some of the newly available fully-3D baseline indices (intimal layer brightness, medial layer brightness, medial thickness, and intimal+medial thickness) were associated with CAV-related progression of intimal thickness showing promise of identifying patients subjected to rapid intimal thickening at 12 months after HTx from OCT-image data obtained just 1 month after HTx. Our approach allows quantification of location specific alterations of coronary wall morphology over time and is sensitive even to very small changes of wall layer thicknesses that occur in patients following heart transplant. PMID- 30253308 TI - Clinical and radiological risk factors for poststroke epilepsy in childhood. AB - BACKGROUND: There are few studies evaluating risk factors for poststroke epilepsy (PSE) after an arterial ischemic stroke (AIS) in childhood. This study aimed to evaluate clinical and radiological predictors for PSE in a cohort of children with a first-ever AIS. METHODS: A retrospective analysis of a single-center prospective consecutive cohort of children beyond neonatal age with a first-ever AIS admitted at the Pontifical Catholic University of Chile's Clinical Hospital between 2003 and 2013. All participants had a brain magnetic resonance imaging at the time of diagnosis. All children underwent follow-up for at least three years with an annual clinical evaluation. We used the current epilepsy definition of the International League Against Epilepsy. Studied variables include demographics, clinical manifestations at onset, stroke risk factors, and radiological characteristics of AIS. Cox proportional hazards regression analysis was used to evaluate PSE risk adjusted for clinical and radiological variables. RESULTS: Among 98 children who met the study criteria, 41 (41.8%) with PSE. Following multivariate analysis, it was determined that the predictors of PSE include young age at AIS (hazard ratio [HR] = 0.91; confidence interval [CI] = 0.84-0.99), the occurrence of acute symptomatic seizures (HR = 3.29; CI = 1.35 8.01), cortical infarction (HR = 5.01; CI = 2.00-12.6), and multifocal infarction (HR = 3.27; CI = 1.01-10.8). CONCLUSION: Seizures, young age, cortical lesions, and multiple infarction at the time of stroke are independent risk factors for PSE in children following a first-ever AIS. PMID- 30253310 TI - Effects of melatonin and tryptophol addition on fermentations carried out by Saccharomyces cerevisiae and non-Saccharomyces yeast species under different nitrogen conditions. AB - During wine fermentation, yeasts produce metabolites that are known growth regulators. The relationship between certain higher alcohols derived from aromatic amino acid metabolism and yeast signalling has previously been reported. In the present work, tryptophol (TrpOH) or melatonin (MEL), which are putative growth regulators, were added to alcoholic fermentations. Fermentations were performed with three different inocula, combining Saccharomyces cerevisiae and four non-Saccharomyces yeast species, under two nitrogen conditions. The combinations tested were: (i) only S. cerevisiae; (ii) the mixture of four non Saccharomyces species; and (iii) the combination of all five species together. The results revealed that the TrpOH and MEL addition caused changes in fermentation kinetics, viability and species distribution during fermentation, but it was dependent on the nitrogen present in the media and the composition of the inocula. Low nitrogen condition seemed to favour the presence of non Saccharomyces species until mid-fermentation, although at the end of fermentation the imposition of Saccharomyces was higher in this condition. The presence of high concentrations of TrpOH resulted in limited growth and a delay in fermentation, noticeably significant in fermentations performed with S. cerevisiae inocula. These effects were reversed by the presence of non Saccharomyces yeast in the medium. Low TrpOH concentration allowed faster fermentation with mixed non-Saccharomyces and Saccharomyces inocula. Moreover, in the absence of S. cerevisiae, a low concentration of TrpOH increased the presence of Torulaspora delbrueckii during fermentation with high nitrogen availability but not under low nitrogen conditions, when the population of S. bacillaris was higher than that in the control. The effects of MEL were particularly evident at the beginning and end of the process, primarily favouring the growth of non Saccharomyces strains, especially the first hours after inoculation. PMID- 30253309 TI - Reduction of acrylamide formation in fried potato chips by Aureobasidum pullulans L1 strain. AB - Acrylamide is a potential carcinogenic molecule formed during food heat processing at high temperature (Maillard reaction). In the present study, the ability of the yeast Aureobasidium pullulans to deplete the acrylamide precursor free asparagine in fresh potatoes was investigated. A. pullulans applied before final frying changes the free amino acid composition of potatoes, decreasing the content of free asparagine by 16% and reducing acrylamide by 83% in fried potatoes. Potato browning was also reduced by yeast treatment without negative drawbacks on chip taste. This yeast, commonly used in fruit postharvest disease control, can therefore also be applied in potato and bakery industries to reduce food acrylamide content. PMID- 30253311 TI - Quantitative antifungal activity of reuterin against food isolates of yeasts and moulds and its potential application in yogurt. AB - Reuterin is an antimicrobial agent produced by conversion of glycerol and excreted by several bacterial species including the food grade lactic acid bacterium Lactobacillus reuteri. Several inhibitory activities have been reported to reuterin against a broad range of Gram-positive and Gram-negative bacteria, bacterial spores, moulds, yeasts and protozoa. However, the antifungal and anti yeast activity of reuterin is poorly documented. The aim of the current work was:1) To quantify the minimum inhibitory activity (MIC) and the minimum fungicidal activity (MFC) of reuterin against a representative panel of the most abundant fungi and yeast species associated with food contamination; 2) To investigate the application of reuterin as antifungal agent for biopreservation of yogurt. Reuterin was produced by L. reuteri ATCC 53608 in MRS and glycerol solution then purified before using. Our data showed that purified reuterin inhibited the growth of tested microorganisms at a concentration of 11 mM or less. Moreover, reuterin showed a fungicidal activity (killed 99.9% of all tested microorganisms) at concentrations equal or below 15.6 mM as indicated by MFC. Values of MFC were comprised between 1.0 and 4.8 of the MIC values, suggesting a potent fungicidal mechanism on both yeasts and filamentous moulds with one exception only. In yogurt, reuterin showed a fungistatic effect at a concentration of 1.38 mM while a fungicidal effect was obtained at 6.9 mM. Therefore, reuterin has a high potential as a food preservative, particularly owing to its biochemical properties and antibacterial and antifungal activities. PMID- 30253312 TI - Wastewater used for urban agriculture in West Africa as a reservoir for antibacterial resistance dissemination. AB - State of art metagenomics were used to investigate the microbial population, antibiotic resistance genes and plasmids of medical interest in wastewater used for urban agriculture in Ouagadougou (Burkina Faso). Wastewater samples were collected from three canals near agricultural fields in three neighbourhoods. Assessment of microbial population diversity revealed different microbial patterns among the different samples. Sequencing reads from the wastewaters revealed different functional specializations of microbial communities, with the predominance of carbohydrates and proteins metabolism functions. Eleven pathogen specific and 56 orthologous virulence factor genes were detected in the wastewater samples. These virulence factors are usually found in human pathogens that cause gastroenteritis and/or diarrhoea. A wide range of antibiotic resistance genes was identified; 81 are transmissible by mobile genetic elements. These included seven different extended spectrum beta-lactamase genes encoding synthesis of four enzyme families, including two metallo-beta-lactamases (blaAIM 1 and blaGES-21). Ten different incompatibility groups of Enterobacteriaceae plasmid replicons (ColE, FIB, FIC, FII, P, Q, R, U, Y, and A/C), and 30 plasmid replicon types from Gram-positive bacteria. All are implicated in the wide distribution of antibiotic resistance genes. We conclude that wastewater used for urban agriculture in the city represents a high risk for spreading bacteria and antimicrobial resistance among humans and animals. PMID- 30253313 TI - Ambient wintertime particulate air pollution and hypertensive disorders of pregnancy in Monroe County, New York. AB - BACKGROUND: Previous studies have reported associations between ambient fine particle (PM2.5) concentrations and hypertensive disorders of pregnancy (HDP). However, none have examined whether ultrafine particles (UFP; < 100 nm), accumulation mode particles (AMP; 100-500 nm), markers of traffic pollution (black carbon; BC), or wood burning (Delta-C; (30% of ambient wintertime PM2.5 in Monroe County, NY is from wood burning)) are associated with an increased odds of HDP. We estimated the odds of HDP associated with increased concentrations of PM2.5, UFP, AMP, BC, and Delta-C in each gestational month during winter months. METHODS: Electronic medical records and birth certificate data were linked with land-use regression models in Monroe County, New York in 2009-2013 to predict monthly pollutant concentrations during winter (November-April) based on maternal residential address for 16,637 births. Using multivariable logistic regression, we estimated the odds of HDP associated with each interquartile range (IQR) increase in PM2.5, UFP, AMP, BC, and Delta-C concentrations during each gestational month, adjusting for maternal characteristics, birth hospital, temperature, and relative humidity. RESULTS: Each 0.52 ug/m3 increase in Delta-C concentration during the 7th gestational month was associated with an increased odds of HDP (odds ratio (OR) = 1.21; 95% confidence interval (CI) = 1.01, 1.45), with a similar sized estimate in month 8 (OR = 1.18; 95%CI = 0.98, 1.43). Non statistically significant increased odds of HDP associated with IQR increases in BC concentrations during months 3 (OR = 1.12; 95%CI = 0.98, 1.28) and 7 (OR = 1.12; 95%CI = 0.96, 1.29) were observed. Increased odds of HDP were not observed for PM2.5, UFP, or AMP. CONCLUSIONS: Our findings suggest that maternal exposure to wood smoke in Monroe County during winter is associated with an increased odds of HDP during late gestation. Additional studies are needed to evaluate the effect of wood smoke on HDP and to explore effects on other pregnancy outcomes. PMID- 30253314 TI - Urinary bisphenol A in children, mothers and fathers from Slovenia: Overall results and determinants of exposure. AB - In the present study, urinary bisphenol A (BPA) levels were reported for the first time in the Slovenian general population and were evaluated with regard to dietary and non-dietary exposure sources, and compared according to age, gender and area of residence. First morning urine was collected from children (6-11 years), their mothers (30-52 years) and fathers (30-53 years), living in urban and rural areas of Slovenia. Besides basic questionnaire data on general population characteristics, socio-economic status and dietary habits, BPA specific data was also collected, including consumption of food and beverages from plastic and canned containers, presence of white dental fillings, the use of specific consumer products and hormonal treatments. Urine samples were analysed for both free and conjugated BPA using GC-MS/MS. The urinary levels of total BPA in children, mothers and fathers were low, with geometric means of 1.51, 0.79, and 0.20 MUg/g creatinine, respectively. The levels were comparable with the levels reported for other European countries and were all below the current health-based guidance values. In line with large-scale surveys, the data revealed age-dependant BPA urinary levels, with the highest levels in the youngest age group. In mothers, urinary levels of BPA were determined by hormonal interactions more than dietary sources, while a positive association between urinary BPA and diet was apparent in children (canned food/drink and food from plastic material) and fathers (canned food/drink). The study clearly shows that physiological and behavioural differences account for differences in levels of urinary BPA among study groups, a finding that sets the priorities for future research. PMID- 30253315 TI - Salmonella enterica recovery from river waters of the Maryland Eastern Shore reveals high serotype diversity and some multidrug resistance. AB - The Delmarva Peninsula, a major agricultural and recreational region for the U.S. states of Delaware, Maryland and Virginia, experiences recurrent salmonellosis disease. Previous studies point to water environments as a potential persistent environmental reservoir of Salmonella enterica. To evaluate this hypothesis, water from the four main rivers of the Maryland Eastern Shore on the Delmarva Peninsula was tested for the presence of S. enterica, and recovered isolates were characterized for antimicrobial resistance. Sampling was performed in autumn and spring to evaluate temporal persistence at twenty four sites along the Choptank, Nanticoke, Pocomoke and Wicomico Rivers. Water (10 L) was filtered through sterile modified Moore swabs in situ. Swabs were selectively enriched for S. enterica and presumptive salmonellae were confirmed by PCR amplification of the Salmonella-specific invA and hilA genes. The serogroup of 402 isolates was determined, followed by serotype characterization for 157 isolates selected to represent all the identified serogroups across all samples. S. enterica was isolated from all the rivers in both seasons and was detected in 35/46 (65%) of surface water samples, with equivalent recovery in spring (70%) and fall (61%). The likelihood of isolating S. enterica was higher for the Nanticoke and Pocomoke Rivers, chi2 (3, N = 46) = 12.75, p < 0.01. In total, 18 serotypes of S. enterica were identified, and serotype diversity differed between the fall and spring samplings. Newport was the most frequently isolated serotype, both overall and in the fall, identified in 8/46 samples (17%). Typhimurium was the predominant serotype in spring. Some temporal and biogeographic patterns were observed in S. enterica recovery, but 6/18 serotypes were identified in both seasons. The majority (84%) of isolates were pan-susceptible, including all those tested from the Wicomico River (N = 19). Twenty five isolates (16%) from 9 samples were resistant to at least one antimicrobial, including serotypes Typhimurium, Newport, Litchfield, III 17:z10: e,n,x,z15, III 60:I and IV_40:z4: z32: -. Of the isolates that were resistant to a single antimicrobial (N = 12), resistance was to streptomycin or sulfisoxazole. Thirteen isolates were multidrug resistant, nine exhibiting resistance to ampicillin, sulfisoxazole, tetracycline, amoxicillin/clavulanic acid, cefoxitin and ceftriaxone, and four to sulfisoxazole and tetracycline. The widespread presence and diversity of S. enterica in Delmarva rivers are concerning given the frequent use of rivers and tributaries as a source of irrigation and for recreation. Future research should seek to determine specific point sources of S. enterica for surface river waters, and risks associated with acquisition of antimicrobial resistance traits. PMID- 30253316 TI - Likelihood of cesarean birth among parous women after applying leading active labor diagnostic guidelines. AB - OBJECTIVES: Hospital admission during early labor may increase women's risk for medical and surgical interventions. However, it is unclear which diagnostic guideline is best suited for identifying the active phase of labor among parous women. Dr. Emanuel Friedman, the United Kingdom's National Institute for Health and Care Excellence (NICE), and the American College of Obstetricians and Gynecologists/Society for Maternal-Fetal Medicine (ACOG/SMFM) support different active labor diagnostic guidelines. Our aims were (1) to determine the proportions of parous women admitted to the hospital before or in active labor per these leading guidelines and (2) to compare associations of labor status at admission (i.e., early labor or active labor) with oxytocin augmentation, cesarean birth, and adverse birth outcomes when using the different active labor diagnostic guidelines. DESIGN: Active labor diagnostic guidelines were applied retrospectively to cervical examination data. Binomial logistic regression was used to assess associations of labor status at admission (i.e., early labor relative to active labor) and outcomes. SETTING: A large, academic, tertiary medical center in the Midwestern United States. PARTICIPANTS: Parous women with spontaneous labor onset who gave birth to a single, cephalic-presenting fetus at term gestation between 2006 and 2010 (n = 3,219). FINDINGS: At admission, 28.8%, 71.9%, and 24.4% of parous women were in active labor per Friedman, NICE, and ACOG/SMFM diagnostic guidelines, respectively. Oxytocin augmentation was more likely among women admitted in early labor, regardless of the diagnostic strategy used (p < 0.001 for each guideline). Cesarean birth was also more likely among women admitted before versus in active labor according to all guidelines (Friedman: adjusted odds ratio [AOR] 3.63 [95% CI 1.46-9.03]), NICE: AOR 2.71 [95% CI 1.47-4.99]), and ACOG/SMFM: AOR 2.11 [95% CI 1.02-4.34]). There were no differences in a composite measure of adverse outcomes within active labor diagnostic guidelines after adjusting for covariates. KEY CONCLUSIONS: Many parous women with spontaneous labor onset are admitted to the hospital before active labor. These women are more likely to receive oxytocin augmentation during labor and are more likely to have a cesarean birth. IMPLICATIONS FOR PRACTICE: Diagnosing active labor prior to admission or prior to intervention aimed at speeding labor after admission may decrease likelihoods for primary cesarean births. The NICE dilation-rate based active labor diagnostic guideline is more inclusive than Friedman or ACOG/SMFM guidelines and its use may be the most clinically-useful for improving the likelihood of vaginal birth among parous women. PMID- 30253318 TI - Micro and nanoscale characterization of poly(DL-lactic-co-glycolic acid) films subjected to the L929 cells and the cyclic mechanical load. AB - In this paper, the effect of the presence of L929 fibroblast cells and a cyclic load application on the kinetics of the degradation of amorphous PLGA films was examined. Complex micro and nano morphological, mechanical and physico-chemical studies were performed to assess the degradation of the tested material. For this purpose, molecular weight, glass transition temperature, specimen morphology (SEM, MUCT) and topography (AFM) as well as the stiffness of the material were measured. The study showed that the presence of living cells along with a mechanical load accelerates the PLGA degradation in comparison to the degradation occurring in acellular media: PBS and DMEM. The drop in molecular weight observed was accompanied by a distinct increase in the tensile modulus and surface roughness, especially in the case of the film degradation in the presence of cells. The suspected cause of the rise in stiffness during the degradation of PLGA films is a reduction in the molecular mobility of the distinctive superficial layer resulting from severe structural changes caused by the surface degradation. In conclusion, all the micro and nanoscale properties of amorphous PLGA considered in the study are sensitive to the presence of L929 cells, as well as to a cyclic load applied during the degradation process. PMID- 30253317 TI - Increased expression of WNK3 in dispersed granule cells in hippocampal sclerosis of mesial temporal lobe epilepsy patients. AB - Granule cell dispersion (GCD) is a common neuropathological feature of hippocampal sclerosis (HS) in patients with temporal lobe epilepsy (TLE). However, the underlying molecular mechanism of GCD formation remains unclear. The present study aimed to investigate the expressional changes of With No Lysine protein kinase subtype 3 (WNK3), a molecule upstream of cation-chloride cotransporters with reciprocal expression in sclerosed hippocampus of TLE patients. Using immunofluorescence staining, we analyzed WNK3 immunoreactivity in hippocampal specimens from histologically normal controls and TLE patients with HS. Our results showed that WNK3 expression was significantly increased in dispersed granule neurons in hippocampal tissues from patients with TLE compared with histologically normal hippocampus. These findings demonstrate a potential association between an increased expression of WNK3 and GCD formation during the chronic phase of epilepsy. Controlling WNK3 expression may thus be a novel therapeutic target in epileptogenesis. PMID- 30253319 TI - Child sexual abuse victims as witnesses: The influence of testifying on their recovery. AB - Victims of child sexual abuse (CSA) are likely to show a wide range of adaptation difficulties. In addition, some children and their families are involved in legal proceedings following the child's disclosure. However, little is known about the effects of legal involvement on CSA victim's mental health and recovery. In this longitudinal study, the effects of testifying were examined in a sample of 344 children at initial assessment (67% of girls) receiving services in a Child Advocacy Centre, of which 130 children testified. The participants' age ranged from 6 to 14 years old (M = 9.42 SD = 2.14). Children and their parents completed a series of measures to evaluate the child's mental health (e.g. depression, anxiety, PTSD) at four points in time over a 2-year period. Multilevel analysis indicates that all the children showed significant improvement over time but the group who testified more than once shows higher levels of emotional distress 2 years after the initial assessment. This study highlights the importance of documenting the experience of CSA victims in the justice system in order to establish the adequate conditions to support child witnesses. PMID- 30253320 TI - Risk-taking behaviors and stressors differentially predict suicidal preparation, non-fatal suicide attempts, and suicide deaths. AB - Negative life events are elevated in suicidal populations. Diathesis-stress and kindling effects models suggest different mechanisms by which negative life events increase suicide risk. Different forms of negative life events - risk taking behaviors and stressors - may have different effects on non-fatal suicide attempts and suicide. We assessed the effects of risk-taking behaviors and stressors on suicide, history of non-fatal suicide attempts, and active preparation for suicide in a sample of adults who died by suicide or other causes (N = 377). Psychological autopsy procedures using family member interviews and collateral record review were used to complete a risk-taking behaviors composite measure from the Structured Interview for DSM-IV Personality Disorders, the Modified Life Experiences Scale, and the planning subscale of the Suicide Intent Scale. Stressors were significantly associated with death by suicide, even when accounting for demographic and diagnostic characteristics. Risk-taking behaviors were significantly associated with non-fatal suicide attempts, even when accounting for demographic and diagnostic characteristics. Suicide decedents who did not actively prepare for suicide showed significantly higher risk-taking scores than suicide decedents who actively planned for suicide. Our results suggest that risk-taking behaviors and stressors impact suicide risk through separate mechanisms. Risk-taking behaviors may represent a longstanding vulnerability to act impulsively on suicidal thoughts. Stressors may impact risk for fatal suicidal behaviors in mood disordered populations. PMID- 30253321 TI - The family-oriented open dialogue approach in the treatment of first-episode psychosis: Nineteen-year outcomes. AB - Open Dialogue (OD) is a family-oriented early intervention approach which has demonstrated good outcomes in the treatment of first-episode psychosis (FEP). Nevertheless, more evidence is needed. In this register-based cohort study the long-term outcomes of OD were evaluated through a comparison with a control group over a period of approximately 19 years. We examined the mortality, the need for psychiatric treatment, and the granting of disability allowances. Data were obtained from Finnish national registers regarding all OD patients whose treatment for FEP commenced within the time of the original interventions (total N = 108). The control group consisted of all Finnish FEP patients who had a follow-up of 19-20 years and who were guided to other Finnish specialized mental healthcare facilities (N = 1763). No difference between the samples was found regarding the annual incidence of FEP, the diagnosis, and suicide rates. Over the entire follow-up, the figures for durations of hospital treatment, disability allowances, and the need for neuroleptics remained significantly lower with OD group. Findings indicated that many positive outcomes of OD are sustained over a long time period. Due to the observational nature of the study, randomized trials are still needed to provide more information on effectiveness of approach. PMID- 30253322 TI - Refocusing CSA during magic angle spinning rotating-frame relaxation experiments. AB - We examine coherent evolution of spin-locked magnetization during magic-angle spinning (MAS), in the context of relaxation experiments designed to probe chemical exchange (rotating-frame relaxation (R1rho)). Coherent evolution is expected in MAS based rotating-frame relaxation decay experiments if matching conditions are met (such as, omega1 = nomegar) and if the chemical shielding anisotropy (CSA) is substantial. We show here using numerical simulations and experiments that even when such matching requirements are avoided (e.g., omega1 < 0.5omegar, ~1.5omegar, >2.5omegar), coherent evolution of spin-locked magnetization with large CSA is still considerable. The coherent evolution has important consequences on the analysis of relaxation decay and the ability to extract accurate information of interest about dynamics. We present a pulse sequence that employs rotary echoes and refocuses CSA contributions, allowing for more sensitive measurement of rotating-frame relaxation with less interference from coherent evolution. In practice, the proposed pulse sequence, REfocused CSA Rotating-frame Relaxation (RECRR) is robust to carrier frequency offset, B1-field inhomogeneity, and slight miscalibrations of the refocusing pulses. PMID- 30253323 TI - Highly selective fluorescent visual detection of perfluorooctane sulfonate via blue fluorescent carbon dots and berberine chloride hydrate. AB - As a kind of emerging persistent organic pollutants, perfluorooctane sulfonate (PFOS) and its salts have caused global ecosystem pollution. To develop rapid, sensitive and low-cost detection method of PFOS is of great importance. In this work, a novel sensing method has been proposed for the highly selective fluorescent visual detection of PFOS in aqueous solution based on carbon dots (CDs) and berberine chloride hydrate (BH). It was found that the fluorescence of CDs decreased apparently in the presence of berberine chloride hydrate in pH 6.09 Britton-Robinson (BR) buffer solution. When PFOS was added to the system, the fluorescence was restored slightly at 448 nm and enhanced apparently at 533 nm, but no phenomenon occurred with other perfluorinated compounds. As a consequence, an obviously distinguishable fluorescence color variation (from blue to light yellow) of solution was observed. Under the optimized experimental conditions, the enhanced fluorescence intensities at 533 nm are in proportion to the concentration of PFOS in the range of 0.22-50.0 MUmol/L (R2 = 0.9919), with a detection limit of 21.7 nmol/L (3sigma). The proposed approach has been successfully applied to the detection of PFOS in environmental water samples with RSD <= 1.1%. PMID- 30253324 TI - Maternal support and deviance among rural adolescents: The mediating role of self esteem. AB - INTRODUCTION: Supportive mothering buffers against adolescent deviance, but the precise mechanisms underlying this relationship are poorly understood. The current investigation tested the extent to which self-esteem mediated the maternal support-deviance link and whether it varied by adolescent age and sex. METHODS: Data were collected from 911 middle and high school students in the rural South (53.6% female, Mage = 14.70 years). Main model tests were completed in SEM. RESULTS: Results indicated that maternal support and self-esteem were positively associated and negatively to deviance, and that self-esteem mediated the support-deviance link. These associations did not differ by adolescent age. However, moderating effects by sex were significant, where maternal support had a greater effect on girls' self-esteem, while self-esteem had a greater effect on boys' deviance. CONCLUSIONS: Findings provide some evidence of how maternal support is associated with a positive self-concept that in turn decreases the likelihood of engaging in deviant behaviors. PMID- 30253325 TI - Fraction and mobility of antimony and arsenic in three polluted soils: A comparison of single extraction and sequential extraction. AB - Co-contamination of arsenic (As) usually occurs with antimony (Sb) in Sb mine ores. However, the mobility and bio-availability of Sb and As in different types of mine impacted soils have received relatively little attention. This study aimed to investigate the fraction, mobility and removal of Sb and As in three types of polluted soils using environmentally friendly and cost-effective extractants. In the present study, lightly polluted (L), moderately polluted (M), and 3) highly polluted (H) soils were collected from the Xikuangshan (XKS) mine area in Hunan, China. Toxicity risk assessment, fraction and extraction of Sb and As were performed to evaluate Sb and As mobility and availability. According to the speciation fractions, the percent of residual Sb was larger than As in all studied soils, which suggested that As is far more mobile than Sb. Sb and As extractabilities from selected polluted soils were compared and ranked as: citric acid > tartaric acid > EDTA > HCl > Na2HPO4 > CaCl2. Citric acid showed the highest extractabilities for both Sb and As (up to 24% for total Sb and 41% for total As respectively). Moreover, obvious alteration of Sb and As fractionations in three types of soils were observed after chemical extractions. The mobility of Sb and As increased after extraction by citric acid and tartaric acid, suggesting that these organic acids can make soil trace metals more bio-available and that, Sb/As polluted soils can be remediated via phytoextraction. PMID- 30253326 TI - Circulating epinephrine is not required for chronic stress to enhance metastasis. AB - Signaling through beta-adrenergic receptors drives cancer progression and beta blockers are being evaluated as a novel therapeutic strategy to prevent metastasis. Orthotopic mouse models of breast cancer show that beta-adrenergic signaling induced by chronic stress accelerates metastasis, and that beta2 adrenergic receptors on tumor cells are critical for this. Endogenous catecholamines are released during chronic stress: norepinephrine from the adrenal medulla and sympathetic nerves, and epinephrine from the adrenal medulla. beta2-adrenergic receptors are much more sensitive to epinephrine than to norepinephrine. To determine if epinephrine is necessary in the effects of stress on cancer progression, we used a denervation strategy to eliminate circulating epinephrine, and quantified the effect on metastasis. Using both human xenograft and immune-intact murine models of breast cancer, we show that circulating epinephrine is dispensable for the effects of chronic stress on cancer progression. Measured levels of circulating norepinephrine were sufficiently low that they were unlikely to influence beta2-adrenergic signaling, suggesting a possible role for norepinephrine release from sympathetic nerve terminals. PMID- 30253327 TI - Children's cortisol response to the transition from preschool to formal schooling: A review. AB - This review examines the current state of knowledge regarding children's biological stress response during the transition from preschool to compulsory formal schooling, focusing on longitudinal studies that include repeated measures of cortisol concentrations in saliva or scalp hair. In all, eight independent studies (ten publications) were found and their results support the hypothesis that the transition from preschool to formal schooling coincides with an increase in cortisol concentration in both saliva and hair. Evidence of recovery (i.e. decrease in stress response over time) is more limited and suggests that it could take as many as 3-6 months before kindergarten children's cortisol concentration returns to baseline levels. However, important individual differences are observed. Potential predictors that have received some empirical support include child temperament (fearfulness/inhibition or surgency/extroversion) and prenatal maternal stress or anxiety. Very few studies, however, have examined whether there are actual functional consequences of individual differences in children's cortisol response associated with this transition. Finally, current methodological limitations and avenues for future studies are discussed. PMID- 30253328 TI - Intracellular mechanics: connecting rheology and mechanotransduction. AB - Cell mechanics is crucial for a wide range of cell functions, including proliferation, polarity, migration and differentiation. Cells sense external physical cues and translate them into a cellular response. While force sensing occurs in the vicinity of the plasma membrane, forces can reach deep in the cell interior and to the nucleus. We review here the recent developments in the field of intracellular mechanics. We focus first on intracellular rheology, the study of the mechanical properties of the cell interior, and recapitulate the contribution of active mechanisms, the cytoskeleton and intracellular organelles to cell rheology. We then discuss how forces are transmitted inside the cell during mechanotransduction events, through direct force transmission and biochemical signaling, and how intracellular rheology and mechanotransduction are connected. PMID- 30253329 TI - Chronotolerance for cisplatin ototoxicity in the rat. AB - Cisplatin is a potent chemotherapeutic compound for which ototoxicity is a significant side effect. Cisplatin has shown sensitivity to circadian time, in that cisplatin is most effective as an anti-tumor compound, and least nephrotoxic, when given in the active (dark) period of the light-dark cycle in rodents. The objective of the study was to determine the sensitivity of cisplatin ototoxicity to circadian time. Fifty-seven Fischer 344/NHsd rats were exposed to 12 mg/kg cisplatin by intra-peritoneal injection at one of six time points on a 12 h light-12 h dark cycle: 2, 6, or 10 h after light onset or 2, 6, or 10 h after light offset. Cochlear injury was evaluated using auditory brainstem response threshold shifts and postmortem outer hair cell counts. All animals experienced threshold shift in the highest frequencies tested (30 and 40 kHz). The animals exposed to cisplatin at 6 h after light onset (the inactive period) had significantly higher mid-frequency threshold shifts and outer hair cell losses than the groups exposed during the dark hours. The results indicate that cisplatin is less likely to cause ototoxicity in the Fischer 344/NHsd rat when given during the active period. This finding is consistent with the lower nephrotoxicity that has been detected in cisplatin-exposed animals treated during the dark hours, and the magnitude of differences in threshold shifts between the light and dark exposure indicates that circadian timing has a significant impact on susceptibility to cisplatin ototoxicity. PMID- 30253330 TI - miR-181a regulates Th17 cells distribution via up-regulated BCL-2 in primary biliary cholangitis. AB - BACKGROUND: Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by destruction of small intrahepatic bile ducts. Recent studies suggest that miRNAs play a critical role in the pathogenesis of liver diseases. However the role served by miRNAs in the pathogenesis of PBC is still not clear. METHODS: The differentially expressed genes and miRNAs were identified by bioinformatics analysis. Gene ontology and KEGG pathway analyses were conducted to explore the function of the differentially expressed genes. miRNA target genes were predicted using miRecords. The differentially expressed genes and miRNAs were validated by qRT-PCR in PBC patients along with healthy controls and chronic hepatitis B patients as control. Flow cytometric analysis was conducted to identify the Th17 and Treg cells frequency. RESULTS: 15 differentially expressed miRNAs and 1897 mRNAs were identified from the profile. miR-181a was validated as the differentially expressed miRNA. BCL-2 and CDKN1B were predicted as the target gene of miR-181a and validated differentially expressed in PBC patients. However, only BCL-2 was negative correlated with miR-181a. The Th17 cells frequency was increased in PBC patients while the Treg cells frequency was decreased. Moreover, the expression of BCL-2 was positive correlated with Th17 cells frequency. CONCLUSION: Down-regulated miR-181a in CD4+ T cells may decrease apoptosis of Th17 cells via up-regulated BCL-2 in the pathogenesis of PBC. PMID- 30253331 TI - MYD88 L265P mutation promoted malignant B cell resistance against T cell-mediated cytotoxicity via upregulating the IL-10/STAT3 cascade. AB - The myeloid differentiation factor 88 (MYD88) signaling plays critical roles in the developments of B cells. Recent studies demonstrated that in the activated B cell subtype of diffuse large B cell lymphoma (DLBCL), approximately one-third of the patients harbored somatically acquired MyD88 L265P mutation in their lymphomas. It remains unclear whether B cell lymphomas with MYD88 L265P mutation respond differently toward CD8+ T cell-mediated cytotoxicity. Here, we demonstrated that, when incubated with autologous CD8+ T cells, the MYD88 L265P mutant lymphomas were more resistant to granzyme B- and perforin-mediated killing than MYD88 wild-type (WT) lymphomas. Interestingly, in the absence of autologous lymphomas, the granzyme B and perforin expression levels in CD8+ T cells from patients with MYD88 WT lymphomas and from patients with MYD88 L265P mutant lymphomas were comparable; however, in the presence of autologous lymphomas, the CD8+ T cells from patients with MYD88 L265P mutant lymphomas presented significantly lower granzyme B and perforin expression than CD8+ T cells from patients with MYD88 WT lymphomas. We further found that the IL-10 expression level and the STAT3 activation level were significantly higher in MYD88 L265P mutant lymphomas than in MYD88 WT lymphomas. Suppressing IL-10 significantly reduced STAT3 activation in both MYD88 WT and MYD88 L265P mutant lymphomas. Blocking either STAT3 or IL-10 could significantly increase the susceptibility of MYD88 L265P mutant lymphomas toward CD8+ T cell-mediated cytotoxicity. Together, these data revealed a mechanism of immune evasion in MYD88 L265P mutant lymphomas. PMID- 30253332 TI - MiR-155 inhibition ameliorates 2, 4, 6-Trinitrobenzenesulfonic acid (TNBS) induced experimental colitis in rat via influencing the differentiation of Th17 cells by Jarid2. AB - Th17 cells play an important role in the immune imbalance and inflammatory state in colonic mucosa of Inflammatory Bowel Disease (IBD) and to clarify the mechanism that affect the differentiation of Th17 cells will help us find a new target for the treatment of IBD. MiR-155 which is reported to have an important role in regulating immune system function is also detected to be significantly up regulated in colonic tissues of IBD patients. However, whether and how miR-155 affects the differentiation of Th17 cells in the colon of IBD patients is still worth studying. Here, we investigated the role of miR-155 in TNBS-induced rat colitis. Firstly, we found that the disease activity index (DAI) and Colon pathological changes were significantly reduced (P < 0.05) by using miR-155 inhibition sequences delivered by lentiviral vector, which revealed that miR-155 inhibition ameliorated TNBS-Induced experimental colitis. Then, we carried out flow cytometry, ELISA, qRT-PCR, and found that in TNBS+miR-155 inhibition group, the proportion of Th17 cells in spleens and mesenteric lymph nodes (MLNs) and the level of the Th17 cell-associated cytokines IL-6, IL-17A, IL-17F and IL-21 in colon tissues were significantly reduced (P < 0.05), which revealed that miR-155 inhibition regulated the differentiation and function of Th17 cells. Finally, we discovered that Jarid2 was significantly elevated (P < 0.05) by miR-155 inhibition and notch1 expression was inversely correlated with Jarid2 by using Immunohistochemistry and western blot. This study suggests that miR-155 inhibition ameliorates TNBS-induced colitis by regulating the Th17 cells differentiation and function and Jarid2/notch1 is closely related with the process. PMID- 30253333 TI - Circulating tumour DNA is a potential biomarker for disease progression and response to targeted therapy in advanced thyroid cancer. AB - BACKGROUND: Conventional biomarkers in thyroid cancer are not disease specific and fluctuate in advanced disease, making interpretation difficult. Circulating tumour DNA (ctDNA) has been shown to be a useful biomarker in other solid tumours. This is a multimutational study of ctDNA over multiple timepoints, designed to test the hypothesis that ctDNA is a potential biomarker in patients with advanced thyroid cancer. METHODS: Mutational analysis of archival tumour tissue was performed using NGS with a targeted gene panel. Custom TaqMan assays were designed for plasma ctDNA testing using digital droplet polymerase chain reaction. Concentrations of detected ctDNA were correlated with the conventional biomarker concentration and axial imaging status defined by the Response Evaluation Criteria in Solid Tumours criteria. RESULTS: Tumour tissue from 51 patients was obtained, with the following histologies: 32 differentiated (differentiated thyroid cancer [DTC]), 15 medullary (medullary thyroid cancer [MTC]), three poorly differentiated and one anaplastic. NGS analysis detected variants in 42 (82%) of cases. Plasma was assayed for these patients in 190 samples, and ctDNA was detected in 67% of patients. Earlier detection of disease progression was noted in three patients with MTC. In two cases (PTC and ATC), where conventional biomarkers were not detectable, ctDNA was detected before disease progression. Changes in ctDNA concentration occurred earlier than conventional markers in response to disease progression in multiple patients with DTC receiving targeted therapies. CONCLUSION: The majority of patients with advanced thyroid cancer had detectable ctDNA. ctDNA measurement may offer superiority over conventional markers in several scenarios: earlier detection of progression in MTC; as an alternative biomarker when conventional markers are not available; more rapid assessment of the disease status in response to targeted therapies, thereby potentially allowing prompter discontinuation of futile therapies. These early results support the hypothesis that ctDNA may be a clinically useful biomarker in thyroid cancer. PMID- 30253334 TI - Imaging features of primary hyperoxaluria. AB - Primary hyperoxaluria (PH) is a group of autosomal recessive diseases that affect the metabolism of glyoxalate and oxalate. As a result of the enzymatic deficiency, there is overproduction and urinary excretion of oxalate with progressive renal damage and subsequent deposition of oxalate salts in various tissues. The definitive treatment in cases of end-stage kidney disease is a combined liver and kidney transplant. Imaging features are diverse and reflect the multiple organs that might be affected. These include nephrolithiasis and nephrocalcinosis, oxalate osteopathy, as well as other findings, such as splenomegaly and oxalate deposition in the heart. In this review article, we present various imaging findings that may appear in patients with PH. PMID- 30253335 TI - Acute effect of full time office work in real environment on postural actions and lumbar range of motion. AB - INTRODUCTION: Prolonged sitting is often proposed as a risk factor for low back pain development. The purpose of this study was to evaluate the acute effect of full time office work on sensorimotor trunk functions. METHODS: Seventeen healthy office workers participated in the study. Maximal lumbar flexion range of motion, anticipatory postural adjustments and postural reflex reactions were tested before and after full time office work in a real life environment. RESULTS: There were longer onset latencies of postural reflexive reactions and decreased response amplitudes of anticipatory postural adjustments after full time office work, but these were significant only for the obliquus externus abdominis muscle. No changes in lumbar range of motion was found. CONCLUSION: To our knowledge this is the first study that evaluates the effect of full time office work on postural actions and lumbar RoM. We found an absence of normal human circadian flexibility in the lumbar spine and some changes in postural actions. We propose that active trunk stiffness increase to compensate for decreased passive stiffness after prolonged seated work. Further studies are needed to confirm this assumption. PMID- 30253336 TI - 1,2,4-Triazole-based benzothiazole/benzoxazole derivatives: Design, synthesis, p38alpha MAP kinase inhibition, anti-inflammatory activity and molecular docking studies. AB - Novel N-(benzothiazol/oxazol-2-yl)-2-[(5-(phenoxymethyl)-4-aryl-4H-1,2,4-triazol 3-yl)thio] acetamide derivatives (5a-n) were synthesized and investigated for in vitro anti-inflammatory activity and p38alpha MAP kinase inhibition. Compounds showing good in vitro activities (5a, 5b, 5d, 5e, 5i, 5k and 5l) were studied for their in vivo anti-inflammatory activity using carrageenan induced rat paw edema model. Compound 5b emerged as the most active compound with an edema inhibition of 84.43%. It also showed improved GI safety profile with lower ulcer severity index and lipid peroxidation potential. Also, p38alpha MAP kinase assay of 5b showed superior inhibitory potency (IC50:0.031 +/- 0.14 uM) than the standard SB 203580 (IC50:0.043 +/- 0.14 uM). To predict their binding mode compounds were also docked against p38alpha MAP kinase enzyme. Compound 5b and SB 203580 showed hinge region interaction with MET 109. PMID- 30253338 TI - Modulation of the mobility of a key region in human galactokinase: Impacts on catalysis and stability. AB - Galactokinase catalyses the phosphorylation of alpha-d-galactose and some structurally related monosaccharides. The enzyme is of interest due to its potential as a biocatalyst for the production of sugar 1-phosphates and due to its involvement in the inherited metabolic disease type II galactosemia. It has been previously shown that a region (residues 231-245) in human galactokinase often has altered mobility when active site residues are varied. We hypothesised that the reverse may be true and that designing changes to this region might affect the functioning of the active site of the enzyme. Focussing on four residues (Leu-231, Gln-242, Glu-244 and Glu-245) we conducted molecular dynamics simulations to explore the effects of changing these residues to glycine or serine. In most cases the variations resulted in local changes to the 231-245 region and global changes to the root mean squared fluctuation (RMSF) of the protein. The four serine variants were expressed as recombinant proteins. All had altered steady state enzyme kinetic parameters with alpha-d-galactose as a substrate. However, these changes were generally less than ten-fold in magnitude. Changes were also observed with 2-deoxy-alpha-d-galactose, alpha-d-galactosamine and alpha-d-talose as substrates, including (in some cases) loss of detectable activity, suggesting that these variations can tune the specificity of the enzyme. This study demonstrates that activity and specificity of human galactokinase can be modulated by variations designed to affect active site flexibility. It is likely that this principle can be generalised to other enzymes. PMID- 30253337 TI - Synthesis of different thio-scaffolds bearing sulfonamide with subnanomolar carbonic anhydrase II and IX inhibitory properties and X-ray investigations for their inhibitory mechanism. AB - Several new molecules with different thio-scaffolds were designed, synthesised, and evaluated biologically as inhibitors of Carbonic Anhydrases (CAIs). The structure-activity relationship analysis identified thioether derivatives, here reported, as a potent and selective CAIs against hCA II and hCA IX. High resolution X-ray structure of inhibitor bound hCA II revealed extensive interactions with the hydrophobic pocket of active site and provided molecular insight into the binding properties of these new inhibitors. PMID- 30253339 TI - Benzylidine indane-1,3-diones: As novel urease inhibitors; synthesis, in vitro, and in silico studies. AB - Current study deals with the evaluation of indane-1,3-dione based compounds as new class of urease inhibitors. For that purpose, benzylidine indane-1,3-diones (1-30) were synthesized and fully characterized by different spectroscopic techniques including EI-MS, HREI-MS, 1H, and 13C NMR. All synthetic molecules 1 30 were evaluated for urease inhibitory activity and showed good to moderate inhibitory potential within the range of (IC50 = 11.60 +/- 0.3-257.05 +/- 0.7 uM) as compared to the standard acetohydroxamic acid (IC50 = 27.0 +/- 0.5 uM). Compound 1 (IC50 = 11.60 +/- 0.3 uM) was found to be most potent inhibitor amongst all derivatives. The key binding interactions of most active compounds within the enzyme pocket were evaluated through in silico studies. PMID- 30253340 TI - Discovery of novel cathepsin inhibitors with potent anti-metastatic effects in breast cancer cells. AB - It is still challenging to determine the potential targets of natural products, which is essential for further drug research and development. Due to its novel mechanism of action of inducing autophagy effects in breast cancer cells, asperphenamate has received our considerable attention. However, its unknown target inevitably impedes further study. In our previous work, the target enzyme of asperphenamate was predicted as cathepsin by the natural product consensus pharmacophore strategy. Then, asperphenamate and its three derivatives were chosen to study in detail by molecular docking calculations with AutoDock 4 suite. The docking results showed the three derivatives interacted more tightly with either cathepsin L or cathepsin S than with asperphenamate. The ortho benzyloxyl phenylacetyl derivative 1 andp-toluenesulfonyl derivative 3 showed similar interactions with cathepsin L and adopted a better geometric shape within the binding pocket than did the N-CBZ-piperidyl analog 2. On the other hand, compound 2 formed more hydrogen bonds than 1 and 3 to make it tightly bind within cathepsin S. The cathepsin inhibitory activity assay verified the molecular simulation results. Compound 2 was remarkably less active than 1 and 3 against cathepsin L. However, compound 2 showed the strongest potency against cathepsin S with IC50 of 13.12 +/- 0.29 MUM. Considering that cathepsin S plays a vital role in the process of metastasis in breast cancer cells, the inhibitory effect of 2 on migration and invasion was further studied in human breast cancer MDA-MB-231 cells by wound healing and transwell chamber assays. The results illustrated that 2 exhibited an apparent inhibitory ability to the metastasis of MDA-MB-231 cells. Next, 2 will be chosen as a lead compound to develop novel double functional chemotherapeutic agents with both novel mechanisms of action against apoptosis resistant cancer cells, such as inducing autophagy and inhibiting cancer metastasis. PMID- 30253341 TI - Do the benefits outweigh the costs? Societal benefit-cost analysis of three large truck safety technologies. AB - Although research has found advanced safety technologies to be effective at preventing large truck crashes, limited empirical data exists regarding their cost effectiveness to the U.S. society. Without these data, carriers are hesitant to adopt costly technologies and government agencies are hesitant to create regulation mandating their use. The objective of this study was to provide scientifically-based estimates of the societal benefits and costs of large truck automatic emergency braking (AEB), lane departure warning (LDW), and video-based onboard safety monitoring (OSM). For each technology, benefit-cost analyses were performed for installing the technology on all large trucks (including retrofitting existing trucks) and for equipping new large trucks only. Sensitivity analyses examined three cost estimates (low, average, high; values technology-specific), two estimates of system efficacy (low and high; values technology-specific), and three discount rates (0%, 3%, 7%) for each technology. Equipping trucks with LDW and video-based OSM systems were found to be cost effective for all combinations of costs, efficacy, and discount rates examined, for both new and existing trucks. Results for AEB and were mixed. Only a $500 AEB system was cost effective when equipping new trucks and retrofitting existing trucks. However, all cost estimates were cost effective with a 28% efficacy rate when only equipping new large trucks. Overall, these data suggested all three technologies can be cost-effective for new large trucks provided the current costs and efficacy rates can be maintained or improved upon. PMID- 30253342 TI - "Seatbelts don't save lives": Discovering and targeting the attitudes and behaviors of young Arab male drivers. AB - The paper presents a two-part study that discovered then targeted beliefs and attitudes towards seatbelt use in young Arab men. The purpose of part one was to discover their safe driving beliefs, attitudes and behaviors as well as their responses to safe driving campaigns to ascertain message elements that could incite reactance. Part two targeted selected beliefs and attitudes in a message that was designed based on the results from part one to both address relevant beliefs and attitudes as well as avoid reactance. One belief, that seatbelts are not necessary in the back seat, and two attitudes, avoidance of wearing the seatbelt to prevent clothing from being wrinkled and to avoid friends' derision, were targeted. Because the participants reported reactance to common safe driving campaigns, the options for the message were quite limited. Using fear appeals, shocking content or depicting the consequences of accidents was deemed likely to be ineffective, rather a novel approach was called for. Utilizing the collectivist and masculine nature of the culture, the resulting message featured a group of young Arab men who are convinced by a personified Seatbelt to wear their seatbelts after an adventure. The message succeeded in eliciting statistically reliable belief and attitudinal change on all three dependent variables after one exposure, suggesting that tailored messages that avoid triggering reactance and are culturally contextualized while aimed at specific beliefs and attitudes can be persuasive. Although risk taking behavior can result from group pressure, our message used culturally specific group pressure but depicted it as being against the risky behavior and positively reinforced the less risky behavior, demonstrating that such approaches can be effective. The film was not a typical safe driving message, utilized social norms from the target audience and was carefully matched to their attitudes and beliefs while not being an overtly persuasive. We argue that message campaigners can utilize both the method and results for subsequent campaigns aimed at young Arab men. PMID- 30253343 TI - Context and culture: Reasons young adults drink and drive in rural America. AB - Montana, a large and rural U.S. state, has a motor vehicle fatality rate almost double the national average. For young adults, the alcohol-related motor vehicle fatality rate in the state is almost three times the national average. Yet little research has explored the underlying reasons that young people in rural areas drink and drive. Drawing from the theory of triadic influence (TTI) and a series of qualitative focus group discussions, the current study examined how aspects of the landscape and culture of rural America promote and hinder drinking and driving among young people. In 2015 and 2016, 72 young adults (36 females) aged 18-25 years old (mean age = 20.2) participated in 11 semi-structured focus groups in 8 rural counties in Montana. Discussions were transcribed, and two reviewers independently coded text segments. Themes were identified and an inductive explanatory model was created. The results demonstrated that aspects of the social context (e.g., peer pressure and parental modeling), rural cultural values (e.g., independence, stoicism, and social cohesion), and the legal and physical environment (e.g., minimal police presence, sparse population, and no alternative transportation) promoted drinking and driving. The results also identified salient protective factors in each of these domains. Our findings demonstrate the importance of examining underlying distal determinants of drinking and driving. Furthermore, they suggest that future research and interventions should consider the complex ways in which cultural values and environmental factors intersect to shape the risky health behaviors of rural populations. PMID- 30253344 TI - Synthesis of novel antiproliferative hybrid bis-(3-indolyl)methane phosphonate derivatives. AB - An efficient synthetic methodology for the preparation of phosphorus substituted bis-(3-indolyl)methane through a double nucleophilic addition of indole derivatives to an in situ generated alpha-iminophosphonate is reported. In addition, bis-(3-indolyl)methane substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines A549 (carcinomic human alveolar basal epithelial cell) and SKOV03 (human ovarian carcinoma). PMID- 30253347 TI - Qualitative and quantitative correlation of physicochemical characteristics and lead sorption behaviors of crop residue-derived chars. AB - This study investigated the key physicochemical characteristics of char that control its ability to absorb Pb2+. Three type of crop residue-derived chars and their ball milled powder were characterized using multiple approaches. The Pb2+ sorption mechanisms of biochar were caused mainly by coprecipitation reactions, which were governed by ionic minerals on chars instead of mineral crystallization (e.g., SiO2 and Al2O3), while coprecipitation reactions and pi electronic interaction were the dominant mechanisms of activated carbon. Pearson analysis showed that adsorption quantity (Q) highly correlated with the cation exchange capacity (CEC) (P < 0.01)/oxygen functional groups (OFGs) (P < 0.05) and Q closely correlated with coprecipitation amount (P < 0.01)/complexation amount (P < 0.01). Linear regression equations of sorption amount and CEC (R2 > 0.8)/OFGs (R2 > 0.7) were established. CEC and OFGs of chars are the key factors controlled Pb2+ sorption. These results may promote the development of low-cost, engineered biochar with superior sorption qualities for environmental remediation. PMID- 30253345 TI - Synthesis and mechanistic studies of quinolin-chlorobenzothioate derivatives with proteasome inhibitory activity in pancreatic cancer cell lines. AB - Inhibition of proteasome activity blocks the degradation of dysfunctional proteins and induces cancer cell death due to cellular stress. Thus, proteasome inhibitors represent an attractive class of anticancer agents, and bortezomib, carfilzomib and ixazomib have been FDA-approved to treat multiple myeloma. However, cancer cells acquire resistance to these inhibitors through point mutations in the proteasome catalytic subunit or induction of alternative compensatory mechanisms. In this study, we identified a quinolin chlorobenzothioate, QCBT7, as a new proteasome inhibitor showing cytotoxicity in a panel of cancer cell lines. QCBT7 is a more stable derivative of quinoline-8 thiol that targets the regulatory subunit instead of the catalytic subunit of the proteasome. QCBT7 caused the accumulation of ubiquitylated proteins in the cancer cells, indicating its proteasome inhibitory activity. Additionally, QCBT7 increased the expression of a set of genes (PFKFB4, CHOP, HMOX1 and SLC7A11) at both nascent RNA and protein levels, similarly to the known proteasome inhibitors MG132 and ixazomib. Together, QCBT7 induces proteasome inhibition, hypoxic response, endoplasmic reticulum stress and glycolysis, finally leading to cell death. Importantly, we have identified PFKFB4 as a potential biomarker of proteasome inhibitors that can be used to monitor treatment response. PMID- 30253348 TI - Efficient gas phase VOC removal and electricity generation in an integrated bio photo-electro-catalytic reactor with bio-anode and TiO2 photo-electro-catalytic air cathode. AB - An efficient and cost-effective bio-photo-electro-catalytic reactor (BPEC) was developed, it combined bio-anode with TiO2 photo-electro-catalytic air cathode and could remove rapidly model gas phase VOC ethyl acetate (EA) and generate electricity simultaneously. This BPEC system exhibited a synergistic effect between the photo-electro-catalysis and microbial fuel cell (MFC) bio electrochemical process. Calculated kinetic constant of the BPEC system (0.085 min-1) was twice the sum of those of photocatalysis (only electrolyte in the anode, without microbes, 0.033 min-1) and MFC (no photocatalysis, 0.010 min-1) systems. Compared to BPEC with proton exchange membrane (PEM) separator (59.6 mW/cm2), the system with polyvinylidene fluoride (PVDF) membrane had a higher EA degradation rate and power generation (92.8 mW/cm2). A lower external resistance resulted in a faster EA degradation rate. This report provides a new platform for treating other kinds of gas pollutants via integrated bio-electrochemical and gas solid photo-electro-catalytic reactions, with energy generation and conversions. PMID- 30253346 TI - Discovery of 4-(((4-(5-chloro-2-(((1s,4s)-4-((2 methoxyethyl)amino)cyclohexyl)amino)pyridin-4-yl)thiazol-2 yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (JSH-150) as a novel highly selective and potent CDK9 kinase inhibitor. AB - Through a structure-guided rational drug design approach, we have discovered a highly selective inhibitor compound 40 (JSH-150), which exhibited an IC50 of 1 nM against CDK9 kinase in the biochemical assay and achieved around 300-10000-fold selectivity over other CDK kinase family members. In addition, it also displayed high selectivity over other 468 kinases/mutants (KINOMEscan S score(1) = 0.01). Compound 40 displayed potent antiproliferative effects against melanoma, neuroblastoma, hepatoma, colon cancer, lung cancer as well as leukemia cell lines. It could dose-dependently inhibit the phosphorylation of RNA Pol II, suppress the expression of MCL-1 and c-Myc, arrest the cell cycle and induce the apoptosis in the leukemia cells. In the MV4-11 cell-inoculated xenograft mouse model, 10 mg/kg dosage of 40 could almost completely suppress the tumor progression. The high selectivity and good in vivo PK/PD profile suggested that 40 would be a good pharmacological tool to study CDK9-mediated physiology and pathology as well as a potential drug candidate for leukemia and other cancers. PMID- 30253349 TI - A novel natural chitosan/activated carbon/iron bio-nanocomposite: Sonochemical synthesis, characterization, and application for cadmium removal in batch and continuous adsorption process. AB - The natural chitosan was synthesized using shrimp shells via sonochemical method, and activated carbon produced from grape stalks biomass. The novel bio nanocomposite of chitosan/activated carbon/iron nanoparticles was synthesized via the sonochemical method and characterized using FTIR, SEM, and BET techniques. This bio-based nanocomposite was utilized to cadmium removal from dilute solution. The adsorption process via batch method was optimized, and the impacts of pH of feed, the dosage of adsorbent, and concentration of cadmium were analyzed. The kinetics and equilibrium analysis was done, and results indicate the predomination of chemical absorption and the single-layer adsorption process. Langmuir data indicates that the synthesized bio-nanocomposite can adsorb 344 mg cadmium per each gram. To evaluate the ability of the synthesized nanocomposite in the industrial application, the adsorption tests were done in a continuous adsorption system in three cycles. PMID- 30253350 TI - A facile synthesis of biocompatible, glycol chitosan shelled CdSeS/ZnS QDs for live cell imaging. AB - We here report a facile synthesis of chitosan shelled quantum dot (QD/fGC) that holds essential properties requisite for biological applications, such as excellent water solubility, super colloidal stability, and low nonspecific adsorption as well as ease of functionalization. In this method, the amphiphilic glycol chitosan fragment (MW 1.0-1.7 kDa) was assembled on the top of CdSeS/ZnS nanocrystal through hydrophobic interaction in aqueous solution, without displacing the native coordinating ligands, which result in a higher quantum yield of about 0.26, 46% of the uncoated CdSeS/ZnS QDs in chloroform (0.57). In addition, the prepared QD/fGC composes an individual semiconductor core and presents an extremely small size of about 6.03 +/- 1.50 nm (n = 399) in diameter. By conjugation with bioactive amines via 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-based hydroxyl activation approach, the functionalized QD/fGC presented excellent recognition of specific cells in fluorescent imaging. Our work provides a new general method of chitosan modification of hydrophobic nanoparticles for biomedical applications. PMID- 30253352 TI - Deep-red emitting zinc and aluminium co-doped copper indium sulfide quantum dots for luminescent solar concentrators. AB - Pure CuInS2 quantum dots (CIS QDs) exhibited poor photoluminescent (PL) performance due to more dangling bonds on their surface and thus needed a shell to form core@shell structured QDs. However, conventional shells had a higher band gap than CIS QDs so that the core@shell structured QDs showed a blue-shifted PL peak below 700 nm and narrower light absorption range. Herein, Zn and Al co-doped CIS QDs were synthesized by a facile cation exchanged method which can significantly improve the PL property emitting at ~740 nm compared to pure CIS QDs. The enhancement of the PL property was probably attributed to ZnCu and AlCu defects in the CIS QDs which could cause electron-hole radiative recombination via defect levels, reduce the number of dangling bonds and thus minimize the nonradiative recombination through surface electron trapping. Furthermore, the PL intensity was controlled by doping time and reached the maximum at 30 min. The obtained deep-red emitting CIS QDs were employed to fabricate semi-transparent luminescent solar concentrators (LSCs) which exhibited an excellent optical efficiency of 6.97%. The success in using such Zn and Al co-doped CIS QDs could pave the way to realize high efficiency and environment-friendly LSCs for building integrated photovoltaics. PMID- 30253351 TI - Ni, Eu-Co doping effect on the photocatalytic activity and magnetic recyclability in multifunctional single-phase photocatalysts Bi5FeTi3O15. AB - Bi5-yEuyFe1-xNixTi3O15 (x = 0, 0.05, 0.10, 0.15, 0.20; y = 0, 0.1, 0.3, 0.5) nanosheet-based nanoflowers as magnetic recyclable visible-light photocatalysts toward Rhodamine B (RhB) degradation were successfully synthesized by a hydrothermal method. As started from Bi5FeTi3O15 (BFTO), Ni was firstly employed to substitute for Fe at B-site to improve the magnetism for magnetic recyclability. After Ni doping (Bi5Fe1-xNixTi3O15: BFNTO-x, x = 0, 0.05, 0.10, 0.15, 0.20), both the ferromagnetism and photocatalytic activity were obviously improved, where BFNTO-0.1 (Bi5Fe0.9Ni0.1Ti3O15) exhibited the maximum remnant and statured magnetization of 0.14 and 0.82 emu/g respectively. To further improve the magnetism and photocatalytic activity, Eu was chosen to substitute for Bi at A-site. Both ferromagnetism and photocatalytic properties of Bi5 yEuyFe0.9Ni0.1Ti3O15 (BEFNTO-y, y = 0, 0.1, 0.3, 0.5) were further improved by optimizing the doped europium content. The BEFNTO-0.1 (Bi4.9Eu0.1Fe0.9Ni0.1Ti3O15) showed enhanced photocatalytic activity and could be recycled simply by applying a magnet bar. This work may provide a basis for further developing new visible-light photocatalysts because the layer-structured Aurivillius phase has significant potential in elemental doping and further structural engineering applications. PMID- 30253353 TI - The effects of small molecule organic additives on the self-assembly and rheology of betaine wormlike micellar fluids. AB - A model zwitterionic surfactant, oleyl amidopropyl betaine (OAPB), that spontaneously forms viscoelastic wormlike micelles in aqueous solution is mixed with a variety of structurally diverse organic additives. By systematically varying the nature of these additives, insight into the effects of their aromaticity and polarity on the bulk assembly and fluid behaviour of these micelles is gained by the complementary use of small-angle neutron scattering and viscosity measurements. Inclusion of non-polar additives causes the wormlike aggregates to transition into microemulsions above a critical additive concentration; the precise partitioning within the micelle is determined using contrast variation. Alternatively, polar additives do not appear to cause evolution from the wormlike structure, but instead influence the fluid rheology, with some serving to significantly increase viscosity above that of the pure surfactant solution. Addition of these molecules is accompanied by an increase in fluid viscosity when the oxygenated group of the additive is resonance stabilised or acidic. This effect is thought to be a result of surfactant-additive synergism, in which charge screening of the surfactant head-groups causes stronger attractions between molecules, increasing the scission energy of the micelles (i.e. reducing their ability to break apart and reform). Further doping of acidic additives past a critical concentration causes phase separation of the wormlike mixtures. According to ultra-small-angle neutron scattering measurements, the incorporation of all additives (polar or non-polar, aromatic or non-aromatic) results in the formation of 'branched' wormlike networks. These findings emphasise the significant impact of impurities or additives on the properties of aqueous wormlike micellar systems formed by zwitterionic surfactants, and could also inform selection of solutes for controlling fluid rheology. PMID- 30253354 TI - Reactive keratin derivatives: A promising strategy for covalent binding to hair. AB - HYPOTHESIS: Restoration of damaged hair structure by replacing lost keratin is still of paramount interest. On account of the fact that native keratin is a highly cross-linked protein with numerous disulfide bonds but just a few nucleophilic thiol groups, binding affinity to hair is comparatively low. Hence, the design of reactive keratin derivatives bearing free sulfhydryl groups that are optionally S-protected and preactivated should enhance permanent binding to hair fibers. EXPERIMENTS: Keratin was extracted from human Caucasian hair and reduced with NaBH4 to obtain free sulfhydryl groups (keratin-SH). These thiol groups were S-protected via disulfide linkage to 2-mercaptonicotinic acid (keratin-MNA). Hair fibers were either utilized in their natural form or chemically damaged by bleaching. Amount of keratin derivatives being bound to hair fibers was quantified by fluorescence detection of fluorescein isothiocyanate labeled keratins. FINDINGS: Both modifications induced higher affinity of keratin to hair fibers, resulting in up to 1.7-fold (keratin-MNA) improved binding to natural hair and up to 3.6-fold (keratin-MNA) improved binding to bleached hair. Confocal laser microscopy confirmed the accumulation of keratin derivatives in distinct regions of the cuticle layer. Thiol functionalization seems therefore to be a promising strategy for efficient durable binding of keratin to hair. PMID- 30253356 TI - pH-sensitive and magnetically separable Fe/Cu bimetallic nanoparticles supported by graphene oxide (GO) for high-efficiency removal of tetracyclines. AB - Nanoscale zero-valent iron (nZVI) has been recognized as one of the most promising materials for the removal of a wide range of pharmaceuticals in water; however, aggregation and instability of nZVI in aqueous media reduces its efficacy. In this study, graphene oxide (GO) supported nZVI/copper bimetallic nanoparticles (BNPs) were fabricated for high-efficiency removal of tetracyclines (TCs). In comparison to pure nZVI, the addition of Cu to the nano-adsorbents enhanced the efficacy of TC removal by 13%. The GO supporter mitigated the aggregation of BNPs and reduced the dissolution of metal nanoparticles, thereby demonstrating a higher working efficacy than Fe/Cu BNPs, even over five consecutive runs. At the optimal condition (pH 5-7, [TCs]: [Fe/Cu-GO] = 1:2.5 w/w), the Fe/Cu-GO nanocomposite showed near-complete (~100%) TCs-removal within 15 min. The adsorption of TCs by Fe/Cu-GO fits the Freundlich model, with an adsorption capacity of 201.9 mg g-1. The Fe/Cu-GO nanocomposite showed pH dependent assembly behavior to potentially recycle GO at a pH > 9 condition to generate new nanoparticles. The high removal efficiency of TCs, combining with high stability and easy separation performance in the aqueous environment, makes Fe/Cu-GO nanocomposites a promising material for treating latent antibiotics in water. PMID- 30253355 TI - High internal phase water-in-oil emulsions stabilized by food-grade starch. AB - Water in oil emulsions would be prepared by silicones (SO), modified silicones (DC8500) and a food-grade stabilizer (starch 1). With increasing water contents, the emulsions turned from a liquid-like to gel-like behaviors with enhancing storage and loss modulus. When DC8500/SO was 1/17 with 10 wt% starch 1, a high internal phase emulsion can be obtained with 95 wt% water content. DC8500 and SO worked as efficient emulsifiers and possessed amphiphilic property to form emulsions with water in different ratios. A food-grade starch 1 was supplied as a stabilizer which can enhance both water content and strength of emulsion when added in a low concentration. Besides, it is indicated that the food-grade starches provided potential benefit on stabilizing emulsions in very low concentration. PMID- 30253357 TI - Maternal pre- and postnatal anxiety symptoms and infant attention disengagement from emotional faces. AB - BACKGROUND: Biases in socio-emotional attention may be early markers of risk for self-regulation difficulties and mental illness. We examined the associations between maternal pre- and postnatal anxiety symptoms and infant attention patterns to faces, with particular focus on attentional biases to threat, across male and female infants. METHODS: A general population, Caucasian sample of eight month old infants (N = 362) were tested using eye-tracking and an attention disengagement (overlap) paradigm, with happy, fearful, neutral, and phase scrambled faces and distractors. Maternal self-reported anxiety symptoms were assessed with the Symptom Checklist-90/anxiety subscale at five time points between gestational week 14 and 6 months postpartum. RESULTS: Probability of disengagement was lowest for fearful faces in the whole sample. Maternal pre- but not postnatal anxiety symptoms associated with higher threat bias in infants, and the relation between maternal anxiety symptoms in early pregnancy and higher threat bias in infants remained significant after controlling for maternal postnatal symptoms. Maternal postnatal anxiety symptoms, in turn, associated with higher overall probability of disengagement from faces to distractors, but the effects varied by child sex. LIMITATIONS: The small number of mothers suffering from very severe symptoms. No control for the comorbidity of depressive symptoms. CONCLUSIONS: Maternal prenatal anxiety symptoms associate with infant's heightened attention bias for threat. Maternal postnatal anxiety symptoms, in turn, associate with infant's overall disengagement probability differently for boys and girls. Boys may show enhanced vigilance for distractors, except when viewing fearful faces, and girls enhanced vigilance for all socio-emotional stimuli. Long-term implications of these findings remain to be explored. PMID- 30253358 TI - Isomer-specific biotransformation of perfluoroalkyl sulfonamide compounds in aerobic soil. AB - As an important reservoir of pollutants, soil may play a critical role in altering isomer ratios of perfluorooctane sulfonate (PFOS) or PFOS precursors (PrePFOS) via microbial processes, but this possibility has not yet been investigated, as well as the feasibility of using PFOS isomer ratio for source tracking in PFOS contaminated sites. In the present study, N-ethyl perfluorooctane sulfonamide ethanol (EtFOSE) of the technical grade was incubated in soil microcosms for 105 days to examine isomer-specific transformation processes. Experimental data combined with a mathematical model suggest new biotransformation pathways leading to PFOS, including a direct pathway to produce PFOS via hydrolysis of the sulfonamide bond. A similar rate of biotransformation was observed for EtFOSE with an estimated half-life of 8.7 and 9.6 days for the branched and linear isomers, respectively, without statistical difference. Two transformation intermediates, N-ethyl perfluorooctanoic acid (EtFOSAA) and perfluorooctane sulfonamide (FOSA), also showed preferential biotransformation of branched isomers. On the contrary, one intermediate N-ethyl perfluorooctane sulfonamide (EtFOSA) showed the preferred transformation of the linear isomer with an estimated half-life of 80.8 and 11.2 days for the branched and linear isomers, respectively. As PFOS is likely to be generated through more than one pathway or one precursor, its final isomer ratio is collectively determined by several upstream reactions, each having specific isomer-specific transformation kinetics. Though the soil showed enrichment of branched PFOS isomers during the 4 month incubation, compared to PFOS standards, some uncertainty arises in concluding preferential generation of branched PFOS from its precursors, due to the lack of standards for branched PreFOS. The complexity of isomer-specific biotransformation only reinforced the challenge of applying the PFOS isomer ratio for source tracking in environmental microbial systems. PMID- 30253359 TI - Investigating the effects of design and management factors on DBPs levels in indoor aquatic centres. AB - Disinfection by-products (DBPs) in indoor swimming pool water and air have long been a critical human health risk concern. This study investigated the effects of several indoor swimming pool design and management factors (e.g. ventilation, water treatment, pool operations, pool type) on the concentrations of DBPs, such as trihalomethanes (THMs) and chloramines, in pool water and air. Two sampling campaigns, A and B, were carried out to measure the concentrations of DBPs under different conditions. In both campaigns, 46 pool water samples, seven tap water samples, and 28 ambient air samples were collected and analyzed. Regression models were also developed and validated for investigating the combined effects of design and management factors on total trihalomethanes (TTHM) and trichloramine. The model results show that pool water characteristics (e.g., total organic content, temperature, conductivity, pH and alkalinity) and management factors (e.g., the number of bathers and sprayers) have direct effects on DBP concentrations. Pool water characteristics such as UV absorbance, hardness, and oxidation-reduction potential and a management factor UV intensity have inverse effects on DBPs levels. Based on the correlation analysis, other factors such as fan speed, fresh air, pool age, and basin area were found to be correlated with the concentrations of individual THMs and trichloramine in both water and air. It was also observed that the concentration of THMs varies with pool type. It is note worthy that the effects of the number of sprayers was quantified for the first time. This study comprehensively assessed pool design and management factors and identified their effects on DBPs, providing indoor swimming pool facilities with useful information to control DBPs in the indoor swimming environment. PMID- 30253360 TI - Comparison of different K-struvite crystallization processes for simultaneous potassium and phosphate recovery from source-separated urine. AB - Controlled K-struvite crystallization is an attractive technology to simultaneously recover phosphate and potassium from urine. This study investigated the recovery of phosphate and potassium from source-separated urine by K-struvite crystallization using different use models of low-grade MgO (LG MgO): LG-MgO alone (model 1, M1), LG-MgO plus phosphorus acid (model 2, M2), and a pre-formed stabilizing agent by adding LG-MgO plus phosphorus acid (model 3, M3). Results showed that 100% phosphate and 25% K could be recovered from urine by M1. M2 at an MgO:K:P molar ratio of 4:1:1.6 provided a maximum P and K recovery efficiency at 100% and 70%. M3 achieved a same K-removal efficiency as M2, but the phosphate recovery efficiency was lower than that of M2 due to the dissolution of phosphate in the stabilizing agent. K-struvite crystallization was closely accompanied by severe co-precipitation of Na-struvite. Increasing the Na concentration markedly improved the ability of Na co-precipitation, but the variation of pH did not affect the competition precipitation of K and Na. When the Na:K molar ratio was >10, the precipitation of Na was more than that of K. A process performance evaluation indicated that M3 is more suitable for simultaneous K and P recovery from source-separated urine. PMID- 30253361 TI - Long-term effect of biochar amendment on the biodegradation of petroleum hydrocarbons in soil microbial fuel cells. AB - Biochar is extensively applied in amendment of contaminated soils. However, the effect of biochar on the biodegradation of petroleum hydrocarbons and electricity generation in soil microbial fuel cells (MFCs) remains unclear. Here, three biochars respectively derived from poultry (chicken manure, CB), agriculture (wheat straw, SB) and forestry industries (wood sawdust, WB) were investigated after 223 days of amendment. Consequently, high removal for alkanes was in CB with the mineral nutrition and phosphorus while aromatics were in SB with the most N content and the highest molecular polarity. The lowest removal efficiency of total petroleum hydrocarbons was observed in WB with the highest surface area, whereas the most charge was obtained. The different performance of soil MFCs was due to physicochemical properties of biochar and colonized microbial communities of bacteria and archaea. The abundance of Actinotalea increased by 144-263% in SB and CB while that of Desulfatitalea distinctly increased in WB. Meanwhile, species from Methanosarcina, Methanoculleus, Halovivax and Natronorubrum exerted probably a methanogenic degrading role. This study revealed that the degrader, azotobacter and electricigens exhibited a close relationship in order to degrade hydrocarbons and generate electricity in soil bioelectrochemical remediation systems. PMID- 30253362 TI - Experimental equations of seawater salinity and desalination capacity to assess seawater irrigation. AB - A central question in science and technology of desalting is, can we predict optimal coastal sites to implement seawater irrigation? Freshwater only makes up 2.5% of all water on Earth but crop irrigation is responsible for 70% of freshwater demand. First, we compared the growth rates and the dehydration rates of 5 alternative seawater irrigation experiments of wheatgrass over 3 weeks' periods. The average salt tolerance threshold of wheatgrass is 6 dS m-1. When seawater salinity is increased >10.50 dS m-1, the growth, drainage volumes, leaching, and drainage salinities of wheatgrass did not show significant variations. When seawater salinity is increased to 12.25 dS m-1, grass leaves gradually turned light green, bent, and fell. Notably, pH in soil remained nearly constant in all experiments with mean pH of 6.05 +/- 0.25 (mean +/- SD). Next, we derived experimental equations to define a mechanistic link between salinity and desalination capacity in a Modified Saline Adjustable Desalination System (MSADS). A cost-benefit analysis for a MSADS in a coastal location of southern California indicated that this system is $0.84 m-3 more expensive than using water from a natural reservoir, but $0.08 m-3 less expensive than importing water. This study provides a general framework to assess the implementation of a desalination system in coastal locations. PMID- 30253363 TI - Biodegradation of high-molecular weight PAHs by Rhodococcus wratislaviensis strain 9: Overexpression of amidohydrolase induced by pyrene and BaP. AB - A Gram-positive bacterium, Rhodococcus wratislaviensis strain 9, completely degraded 280 MUM of phenanthrene, 40% of 50 MUM pyrene or 28% of 40 MUM benzo[a]pyrene (BaP), each supplemented in M9 medium, within 7 days. PCR screening with gene-specific primers indicated that the strain 9 harbors genes which code for 2,3-dihydroxybiphenyl 1,2-dioxygenase (bphC), 4-nitrophenol 2 monooxygenase component B (npcB) as well as oxygenase component (nphA1), 4 hydroxybenzoate 3-monooxygenase (phbH), extradiol dioxygenase (edo), and naphthalene dioxygenase (ndo), all of which are largely implicated in biodegradation of several aromatic hydrocarbons. An orthogonal design experiment revealed that BaP biodegradation was greatly enhanced by surfactants such as Tween 80, Triton X-100 and linoleic acid, suggesting that bioavailability is the major limiting factor in bacterial metabolism of BaP. Both pyrene and BaP induced the overexpression of amidohydrolase, a metallo-dependent hydrolase, possibly involved in their biodegradation by strain 9. The up-regulation of amidohydrolase gene induced by BaP, in particular, was also confirmed by semi-quantitative RT PCR. Catechol 2,3-dioxygenase and the large subunit of ndo, but not amidohydrolase, accumulated when the strain 9 was grown on phenanthrene. To our knowledge, this is the first report on overexpression of amidohydrolase and its possible implication in bacterial degradation of high-molecular weight PAHs. PMID- 30253364 TI - Lead and cadmium contamination in a large sample of United States infant formulas and baby foods. AB - Data is limited on lead and cadmium contamination in baby food, a population uniquely susceptible to the toxic effects of heavy metals. The goal of this study was to examine lead and cadmium concentrations in a large convenience sample of US baby foods. We identified the number of baby food product samples that exceeded US FDA and California Proposition 65 limits for daily lead consumption across a range of servings/calories, and the number of samples that exceeded World Health Organization and California Proposition 65 limits for daily cadmium consumption across a range of servings/calories. In total, 564 baby foods were tested across infant and toddler formula, cereals, meals, juices/drinks, jars, pouches, snacks, and electrolyte water. ICP-MS analysis of lead and cadmium was completed using a modified version of EPA method 6020A. Samples were analyzed using kinetic energy distribution mode. Lead was detected in 37% of samples (median = non-detect, 75% = 5.6, maximum = 183.6 MUg/kg), and cadmium in 57% (25% = non-detect, median = 2.8, 75% = 9.5, maximum = 103.90 MUg/kg). Of 91 infant formula samples, none exceeded FDA lead consumption guidelines in 31 oz, but 22% exceeded the Proposition 65 lead guidelines, 23% exceeded the Proposition 65 cadmium guidelines, and 14% exceeded the WHO tolerable cadmium intake levels for a four-month-old baby. In the solid baby food samples, 1% exceeded FDA lead guidelines in two servings (26% exceeded CA Proposition 65 limits), 3% in 300 cal (34% exceeded CA Proposition 65 limits). For cadmium, 6% exceeded Proposition 65 guidelines in two servings, 8% in 300 cal. There was no association between whether the product was certified organic and its heavy metal concentration. Products containing rice were higher in both lead and cadmium concentrations. Further research is needed to understand the long-term health effects of this chronic daily low level heavy metal exposure in babies. PMID- 30253365 TI - High highs and low lows: Elucidating striking seasonal variability in pesticide use and its environmental implications. AB - Despite substantial public and scientific concern regarding unintended environmental and health consequences of agricultural pesticide use, identifying when and where high levels of use occur is stymied by a dearth of data at biologically relevant spatial or temporal scales. Here we investigate intra annual patterns in pesticide use by crop and by pesticide type using unique pesticide use data from agriculturally diverse croplands of California, USA. We find that timing and type of pesticide use is strongly crop-dependent, and that for many high pesticide use crops, monthly application rates are highly consistent from year-to-year. Further, while pesticide use hotspots are concentrated in early summer, regions with very high use occur throughout the year with spatial distributions varying therein. The enormity of intra-annual variation in pesticide use, as well as the consistency in those patterns through time, suggests opportunities for crop-specific pest management and region specific mitigation approaches to limit environmental and human health hazards from agricultural pesticide use. PMID- 30253366 TI - Predicting the occurrence of chemicals of emerging concern in surface water and sediment across the U.S. portion of the Great Lakes Basin. AB - Chemicals of emerging concern (CECs) are introduced into the aquatic environment via various sources, posing a potential risk to aquatic organisms. Previous studies have identified relationships between the presence of CECs in water and broad-scale watershed characteristics. However, relationships between the presence of CECs and source-related watershed characteristics have not been explored across the Great Lakes basin. Boosted regression tree (BRT) analyses were used to develop predictive models of CEC occurrence in water and sediment throughout 24 U.S. tributaries to the Great Lakes. Models were based on the distribution of both broad-scale and source-related watershed characteristics. Twenty-one upstream watershed characteristics, including land cover, number of permitted point sources, and distance to point sources were used to develop models predicting the probability of CEC occurrence in surface water and bottom sediment. Total accuracy of BRT models ranged from 66% to 94% for both matrices. All 21 watershed characteristics were important predictor variables in at least one surface-water model; twenty were important in at least one bottom-sediment model. Among the model variables, developed land use and distance to point sources were important predictors of the presence of CEC classes in both water and sediment. Although limitations exist, BRT models are one tool available for assessing vulnerability of fisheries and aquatic resources to CEC occurrences. PMID- 30253367 TI - Human-induced and natural carbon storage in floodplains of the Central Valley of California. AB - Active floodplains can putatively store large amounts of organic carbon (SOC) in subsoils originating from catchment erosion processes with subsequent floodplain deposition. Our study focussed on the assessment of SOC pools associated with alluvial floodplain soils that are affected by human-induced changes in floodplain deposition and in situ SOC mineralisation due to land use change and drainage. We evaluated depth-dependent SOC contents based on 23 soil cores down to 3 m and 10 drillings down to 7 m in a floodplain area of the lower Cosumnes River. An estimate of 266 Mg C ha-1 or about 59% of the entire SOC stored within the 7 m profiles was found in the upper 2 m. Most profiles (n = 25) contained discrete buried A horizons at depths of approximately 0.8 m. These profiles had up to 130% higher SOC stocks. The mean delta13C of all deep soil profiles clearly indicated that arable land use has already altered the stable isotopic signature in the first meter of the profile. Radiocarbon dating showed that the 14C age in the buried horizon was younger than in overlaying soils indicating a substantial sedimentation phase for the overlaying soils. An additional analysis of total mercury contents in the soil profiles indicated that this sedimentation was associated with upstream hydraulic gold mining after the 1850s. In summary, deep alluvial soils in floodplains store large amounts of SOC not yet accounted for in global carbon models. Historic data give evidence that large amounts of sediment were transported into the floodplains of most rivers of the Central Valley and deposited over organically rich topsoil, which promoted the stabilization of SOC, and needs to be considered to improve our understanding of the human-induced interference with C cycling. PMID- 30253368 TI - Effect of anaerobic/aerobic duration on nitrogen removal and microbial community in a simultaneous partial nitrification and denitrification system under low salinity. AB - In this study, the simultaneous partial nitrification and denitrification (SPND) process was investigated in a hybrid sequencing batch biofilm reactor (HSBBR) fed with synthetic wastewater with 1.2% salinity. Different anaerobic/aerobic (An/Ae) durations were selected for evaluating the removal performance of contaminants and the succession of the microbial community in the reactor. The highest organic matter removal efficiency was obtained at An/Ae hour ratio of 0/6.5, with an average chemical oxygen demand (COD) removal of 89.6% at the steady state. Similarly high nitrogen removal efficiencies were achieved at An/Ae hour ratios of 1/5.5, 1.5/5 and 2/4.5,with over 92% of average total nitrogen removed. This represents an increase of more than 10% compared to the mode with An/Ae hour ratio of 0/6.5. High-throughput sequencing analysis revealed that the increase of the An/Ae hour ratio changed the characteristics of the community structures in the HSBBR. Azoarcus was the most dominant genus when the An/Ae hour ratio was 0/6.5 in both suspended sludge (S-sludge) and biofilm, while Candidatus_Competibacter was the most abundant genus at An/Ae hour ratios of 2/4.5 and 3/3.5. Nitrosomonas was the only ammonia oxidizing bacteria (AOB) detected in this study. Nitrospira, a kind of nitrite oxidizing bacteria (NOB), was sensitive to salinity and altering the An/Ae mode; this was detected only in S-sludge samples in a fully aerobic mode with a low percentage of 0.1%. S-sludge and biofilm samples shared a similar bacterial composition. This research demonstrated that efficient nitrogen and carbon removal could be achieved via the SPND process by the symbiotic functional groups in a hybrid S-sludge and biofilm reactor. PMID- 30253369 TI - Examining effects of ontogenic microplastic transference on Culex mosquito mortality and adult weight. AB - Microplastics (MPs) continue to proliferate and pollute aquatic and terrestrial environments globally. The impacts of MP pollution on ecosystems and their functioning remain poorly quantified, with most research hitherto focusing on marine ecosystems. There is a paucity of information on the impacts of MPs in freshwater ecosystems, despite the broad range of pathways through which MPs can proliferate and the extensive range of species which actively ingest MPs in these systems. Of particular interest are organisms that bridge aquatic and terrestrial habitats. The present study thus examines the uptake, ontogenic transference and effect of different concentrations (0, 50, 100 and 200 MPs mL-1) and sizes (2 and 15 MUm) of polystyrene MPs between aquatic and terrestrial life stages of Culex pipiens complex mosquitoes. Both 2 and 15 MUm MPs transferred from the aquatic larval to terrestrial adult stage of Culex mosquitoes, and uptake correlated tightly with initial exposure concentration. However, neither concentration nor size of MPs significantly influenced mortality rates between the aquatic larval and terrestrial adult stage. There was also no impact of MPs on the weight of emerging mosquito adults. We thus demonstrate that MPs can be transferred ontogenically through organisms with complex life histories, presenting a potential pathway for dispersal of MPs into terrestrial environments. We also show that MPs exposure does not affect mortality rates between life stages of freshwater Culex populations. This suggests that MPs do not impact nutritional uptakes, with unhampered development to adulthood facilitating subsequent dispersal of MPs aerially and between freshwater and terrestrial habitats. PMID- 30253370 TI - miRNA-1246 suppresses acute lung injury-induced inflammation and apoptosis via the NF-kappaB and Wnt/beta-catenin signal pathways. AB - Acute lung injury (ALI) is the common and complicated inflammatory lung disease. MicroRNAs (miRNA) have emerged as novel gene regulatory molecules which play a crucial role in multiple complicated diseases, including ALI. In this study, we aims to identify potential regulatory functions of miRNA-1246 in lipopolysaccharide (LPS)-induced ALI. In ALI mice, miRNA-1246 expression is effectively up-regulated, compared with the control group. miRNA-1246 overexpression effectively increases inflammation and apoptosis of in vitro ALI model. In contrast, miRNA-1246 knockdown effectively inhibits inflammation and cell apoptosis in vitro ALI model. Furthermore, up-regulation of miRNA-1246 significantly induces nuclear factor-kappa B (NF-kappaB) protein expression, and suppresses Wnt and beta-catenin protein expression in vitro ALI model. Following the inhibition of NF-kappaB or Wnt/beta-catenin signal using inhibitors, miRNA 1246 shows no significant effects on ALI-induced inflammation and apoptosis. Taken together, miRNA-1246 mediates ALI-induced lung inflammation and apoptosis via the NF-kappaB activation and Wnt/beta-catenin suppression. PMID- 30253371 TI - Vasorelaxant effect of the Lippia alba essential oil and its major constituent, citral, on the contractility of isolated rat aorta. AB - The Lippia alba (Mill.) N.E. Brown (Verbenaceae) species popularly known as lemon balm has sedative, analgesic and spasmolytic properties. This study aimed to evaluate the vasorelaxant effect of the L. alba essential oil (EOLa) and its major constituent, citral, rat on aorta. Isometric muscle contraction were induced by potassium (K 60 mM) or phenylephrine (PHE, 0.1 MUM) in isolated aortic rings. EOLa and citral promoted a smooth muscle relaxant action, which was potentiated by the presence of the endothelium; PHE-induced contractions (0.1 MUM) in aorta with endothelium, had EC50 values of 352.73 +/- 19.39 MUg/mL and 99.34 +/- 7.2 MUg/mL for EOLa and citral, respectively. In the presence of a nitric oxide synthase inhibitor, L-NAME, the EC50 values were 654.19 +/- 10.46 MUg/mL and 601.66 +/- 10.922 MUg/mL for EOLa and citral, respectively. EOLa and citral dose-dependently relaxed contractions induced by BAY-K 8644, a calcium channel agonist, and by Phorbol 12,13-dibutyrate an activator of protein kinase C. EOLa and citral produced a vasorelaxant effect in isolated aorta which was potentiated by the presence of endothelium. In summary, EOLa and citral, probably using several mechanisms of action, relaxed aortic smooth muscle with maximal pharmacologic efficacy. PMID- 30253372 TI - Evidence of the protective effect of l-arginine and vitamin D against monosodium glutamate-induced liver and kidney dysfunction in rats. AB - Monosodium glutamate (MSG) is frequently consumed as a flavor enhancer or food additive. Possible MSG-induced injurious effects on some organs have been stated in experimental animal models. Thus, in this study we tried to clarify effect and possible mechanism of action of MSG on liver and kidney, and if this results affected by the addition of l-Arginine or vitamin D to it. Animals divided into; Control, MSG treated, MSG + vitamin D treated, MSG + L-arginine treated group. Serum separated to determine liver and kidney function parameters. Kidneys and livers dissected out for histological examination and for assay of oxidative stress markers. RESULTS: MSG increased body weight and produced liver and kidney dysfunctions. The MSG-induced oxidative liver and kidney damage was proved. Vitamin D and l- Arginine have been shown to protect and restore the liver and the kidney capabilities in MSG models injury via inhibiting oxidative damage, vitamin D or l- Arginine suppresses the increased food intake and body weight gain induced by MSG. CONCLUSIONS: due to injurious effect of MSG, it should be avoided especially in liver or kidney disorders, foods containing excess MSG can be fortified with vitamin D or l- Arginine to overcome its adverse effects. PMID- 30253373 TI - Kaempferol suppresses proliferation but increases apoptosis and autophagy by up regulating microRNA-340 in human lung cancer cells. AB - BACKGROUND: Lung cancer is a leading cause of cancer-related deaths worldwide with unsatisfied prognosis. Kaempferol is a dietary flavonoid that inhibits tumorgenesis, and we aimed to uncover the underlying mechanism of kaempferol in lung cancer cells. METHODS: A549 cells were stimulated with kaempferol, and then cell proliferation, apoptosis, autophagy and expression of miR-340 were assessed. Subsequently, effects of kaempferol on protein expression of phosphatase with tensin homology (PTEN) and key kinases in the phosphatidylinositol-3-kinase (PI3K)/AKT pathways were detected by Western blot analysis. Moreover, the effects of miR-340 inhibition on kaempferol-induced alterations in A549 cells were also studied. RESULTS: Cell viability, proliferation and cyclinD1 expression level in A549 cells were all reduced by kaempferol. Conversely, cell apoptosis and autophagy were promoted by kaempferol. We found autophagy promoted apoptosis in kaempferol-treated A549 cells. Then, expression of miR-340 was identified to be up-regulated by kaempferol treatment. After treatments with kaempferol, PTEN level was elevated and levels of p-PI3K and p-AKT were decreased. Moreover, the alterations induced by kaempferol were abrogated by miR-340 inhibition. CONCLUSION: Kaempferol inhibited proliferation but induced apoptosis and autophagy in A549 cells. Additionally, kaempferol might function through up regulating miR-340, along with up-regulation of PTEN and inactivation of the PI3K/AKT pathway. PMID- 30253375 TI - The utility and application of electrophysiological methods in the study of visual hallucinations. AB - Visual hallucinations (VH) are a common symptom in multiple clinical and non clinical populations. Although structural and functional neuroimaging has informed the understanding of VH, temporal resolution is limited. Electrophysiological techniques provide a complementary perspective on dynamic and temporal aspects of neural functioning, offering greater insight into the mechanisms underlying their formation. In this review we examine and critically evaluate the emerging evidence base utilising electrophysiological approaches in the study of VH. Overall, increased visual system excitability, dysfunctional visual processing and network connectivity, and cholinergic dysfunction have been consistently observed in VH-prone pathologies. However, a major limitation is in the lack of robust experimental studies and the reliance on single case reports. We conclude that electrophysiology provides tentative evidence for the contribution of bottom-up, top-down, and network dysfunction in the aetiology of VH, supporting several existing VH models. Furthermore, we discuss how electrophysiology has been directly utilised in specific clinical interventions for VH. Further exploration utilising electrophysiology in combination with, for example, neuroimaging will help better understand VH aetiology while aiding in the development of novel therapeutic interventions for this difficult to treat symptom. PMID- 30253374 TI - Phototoxicity of flavoprotein miniSOG induced by bioluminescence resonance energy transfer in genetically encoded system NanoLuc-miniSOG is comparable with its LED excited phototoxicity. AB - Photodynamic therapy (PDT) is a clinical, minimally invasive method for destroying cancer cells in the presence of a photosensitizer, oxygen, and a light source. The main obstacle for the PDT treatment of deep tumors is a strong reduction of the excitation light intensity as a result of its refraction, reflection, and absorption by biological tissues. Internal light sources based on bioluminescence resonance energy transfer can be a solution of this problem. Here we show that luciferase NanoLuc being expressed as a fusion protein with phototoxic flavoprotein miniSOG in cancer cells in the presence of furimazine (highly specific NanoLuc substrate) induces a photodynamic effect of miniSOG comparable with its LED-excited (Light Emitting Diode) phototoxicity. Luminescence systems based on furimazine and hybrid protein NanoLuc-miniSOG targeted to mitochondria or cellular membranes possess the similar energy transfer efficiencies and similar BRET-induced cytotoxic effects on cancer cells, though the mechanisms of BRET-induced cell death are different. As the main components of the proposed system for BRET-mediated PDT are genetically encoded (luciferase and phototoxic protein), this system can potentially be delivered to any site in the organism and thus may be considered as a promising approach for simultaneous delivery of light source and photosensitizer in deep-lying tumors and metastasis anywhere in the body. PMID- 30253376 TI - The Valgent4 protocol: Robust analytical and clinical validation of 11 HPV assays with genotyping on cervical samples collected in SurePath medium. AB - BACKGROUND: The VALidation of HPV GENoyping Tests (VALGENT) is an international initiative designed to validate HPV assays with genotyping capability. The VALGENT4 protocol differs from previous VALGENT installments as the sample collection medium is SurePath, and exclusively includes samples from women >=30 years of age which is concordant with the majority of HPV primary screening guidelines. Here we present the protocol for the fourth installment of the VALGENT framework. OBJECTIVES: In VALGENT4 11 HPV assays will be evaluated using two comparator assays based on PCR with the GP5+/6+ primers. STUDY DESIGN: Overall, the VALGENT4 panel consists of 1,297 routine samples comprised of 998 unselected, consecutive samples, of which 51 samples had abnormal cytology with 13 women diagnosed with >=CIN2, and 299 consecutive samples enriched for >=ASCUS cytology (100 ASCUS, 100 LSIL, 99 HSIL) with 106 >=CIN2 upon follow up. Manipulated and DNA extracted panel samples were characterized with respect to human beta globin (HBB) and overall DNA content and composition to quality assess the panel prior to distribution to the collaborating sites. RESULT: The relative cellularity (mean CT value of HBB from the Onclarity assay) on the 1,297 LBC samples (CT=24.8) was compared with 293 un-manipulated routine cytology screening samples (CT=23.8). Furthermore, the DNA extracted panel samples was characterized using the Exome iPLEX pro assay, which reports amplifiable copies on individual samples as well as copies of five different base pair lengths. Here the data showed a slightly lower number of amplifiable DNA copies (ratio: 0.7, p=<0.01)) in the VALGENT4 panel samples compared to routine extracted cervical DNA samples CONCLUSION: The present manuscript details the manipulation, processing and quality assessment of samples used in VALGENT-4. This methodological document may be of value for future international projects of HPV test validation. PMID- 30253377 TI - Buprenorphine medication-assisted treatment during pregnancy: An exploratory factor analysis associated with adherence. AB - BACKGROUND: The treatment of pregnant women with opioid use disorder is challenging due to the myriad of physical, mental, and social complications. Factors influencing adherence to buprenorphine during pregnancy have not been identified. MATERIALS AND METHODS: Pregnant women with opioid use disorder followed in a tertiary clinic were included in a retrospective chart review from buprenorphine induction through delivery. All women who had been evaluated and treated with buprenorphine from January 1, 2014, to September 31, 2016, were included. Adherence was defined as follows: 1) adherent: attended follow up visits, negative urine toxicology screens, and phase advancement; 2) moderately adherent: attended follow up visits until delivery, had not completed six negative urine toxicology screens, or had positive urine toxicology screens (i.e., no phase advancement); 3) non-adherent: missed follow up visits and did not stay in treatment until delivery. Sociodemographic characteristics, family psychiatric history, current and lifetime psychiatric and childhood trauma along with treatment factors were compared by category of adherence. RESULTS: 64 women met criteria for inclusion in this study with 41 (64%) adherent; eight (13%) moderately adherent; and 15 (23%) non-adherent. In the non-adherent group compared to the adherent group, the clinician-rated opioid withdrawal scale score was significantly higher, and the daily buprenorphine dose at last visit was significantly lower. CONCLUSIONS: Women who were non-adherent to buprenorphine during pregnancy had higher severity of opioid withdrawal symptoms and lower doses of buprenorphine. These findings should be further explored with the goal of optimizing care without increasing risk for neonates. PMID- 30253378 TI - Children's home and school neighbourhood exposure to alcohol marketing: Using wearable camera and GPS data to directly examine the link between retailer availability and visual exposure to marketing. AB - BACKGROUND AND AIM: Neighbourhood alcohol availability has been associated with alcohol consumption by children, despite children rarely acquiring alcohol from retailers. This study explores one potential reason for this finding, by evaluating the relationships between neighbourhood alcohol availability and children's actual exposure to alcohol marketing. METHOD: Wearable cameras and GPS devices were worn by 167 children (aged 11-13 y) over a four-day period. Image and GPS data were linked and compared to known alcohol availability data. RESULTS: Off-licence retailer availability and ethnicity were positively associated with children's exposure to marketing in both residential and school neighbourhoods. CONCLUSION: Neighbourhood off-licence alcohol retailers are associated with increased childhood exposure to alcohol marketing. PMID- 30253379 TI - Development of a DNA methylation-based semen-specific SNP typing method: A new approach for genotyping from a mixture of body fluids. AB - Genotyping from samples containing different types of body fluids is a major difficulty in forensic investigations. Recently, CpG sites that are specifically methylated or unmethylated in different types of body fluids have been reported as novel markers for body fluid identification. In this study, we hypothesized that the simultaneous analysis of CpGs and neighboring polymorphic sites on the same molecule could be useful for individual DNA typing from mixed samples. We performed a proof-of-concept study of this approach by searching the genome-wide methylation dataset deposited at the National Center for Biotechnology Information Gene Expression Omnibus repository for semen-specific CpG markers adjacent to common single nucleotide polymorphisms. From the identified candidates, we selected 5 regions on different chromosomes and validated the presence of semen-specific methylation or unmethylation in each region by pyrosequencing analyses. By combining methylation-specific polymerase chain reaction and pyrosequencing technology, we developed a semen-specific DNA typing method for two semen-specific methylated regions and one semen-specific unmethylated region. Finally, the method successfully identified semen-derived alleles from mixed stains, indicating that this methylation-based approach can be applicable to actual forensic samples. Since existing separation techniques physically isolate cells derived from each type of body fluid, this approach may be useful when existing methods cannot be performed due to the degradation of samples. PMID- 30253381 TI - Free Pentosidine Assessment Based on Fluorescence Measurements in Spent Dialysate. AB - The aim of this study was to primarily explore the relationship between free pentosidine and the fluorescence properties of spent dialysate, and also to develop a model to assess the levels of free pentosidine in spent dialysate based on the fluorescence measurements. First, 40 patients (20 females and 20 males) were examined during 40 dialysis sessions. High-pressure liquid chromatography (HPLC) was used to measure the free pentosidine concentrations from the spent dialysate. The full fluorescence spectra of the spent dialysates were recorded and single- and multi-wavelength (MW) models were developed. The average free pentosidine concentrations in the spent dialysate measured by HPLC at the start and end of the dialysis session were (mean +/- SD) 4.25 +/- 3.11 and 0.94 +/- 0.69 MUg/L respectively. The removal ratios (RRs) between RR_lab and RR_MW were statistically similar (p > 0.2). The concentration of free pentosidine and the RR can therefore be estimated from the spent dialysate when utilising fluorescence measurements. PMID- 30253380 TI - Simulation and Synthesis in Medical Imaging. AB - This editorial introduces the Special Issue on Simulation and Synthesis in Medical Imaging. In this editorial, we define so-far ambiguous terms of simulation and synthesis in medical imaging. We also briefly discuss the synergistic importance of mechanistic (hypothesis-driven) and phenomenological (data-driven) models of medical image generation. Finally, we introduce the twelve papers published in this issue covering both mechanistic (5) and phenomenological (7) medical image generation. This rich selection of papers covers applications in cardiology, retinopathy, histopathology, neurosciences, and oncology. It also covers all mainstream diagnostic medical imaging modalities. We conclude the editorial with a personal view on the field and highlight some existing challenges and future research opportunities. PMID- 30253383 TI - Antihistamines: Recommended Dosage - Divergence between Clinical Practice and Guideline Recommendations. AB - The updosing of second-generation antihistamines for chronic urticaria is based on inconsistent findings. Herein, we report data on the treatment of children with chronic spontaneous urticaria (CSU) unresponsive to single doses of second generation H(1)-antihistamines in whom an increase in antihistamine was performed without improvement and with a high prevalence of adverse events. Thus, it appears that well-controlled, well-designed clinical trials are needed to clarify which nonsedating antihistamines should be used, in what dose, and for how long in patients not responding to the standard treatment, despite the improvement in health care that guidelines help to incorporate. Furthermore, a critical use of such guidelines should be done to improve the knowledge in CSU, especially in the pediatric population. PMID- 30253382 TI - Association Between Preoperative Vitamin D Status and Short-Term Physical Performance after Total Hip Arthroplasty: A Prospective Study. AB - BACKGROUND: Insufficient serum vitamin D concentrations (50-75 nmol/L) are prevalent in 40-65% of patients who require total hip arthroplasty (THA). This could impair physical recovery after surgery. This study investigated the association between preoperative vitamin D status and physical performance after THA. Additionally, postoperative changes in vitamin D concentrations were measured. METHODS: We included 87 patients scheduled for elective THA and aged >=65 years. Three groups were recruited: patients classified as vitamin D deficient (< 50 nmol/L, n = 23), insufficient (50-75 nmol/L, n = 32), or sufficient (> 75 nmol/L, n = 32). Serum 25-hydroxyvitamin D3 (25[OH]D3) concentration and physical performance were measured perioperatively. Linear mixed models were used to examine differences between groups. RESULTS: Change in physical performance over time was not affected by preoperative vitamin D status. In contrast, for physical activity, both vitamin D (p = 0.021) and time (p < 0.001) effect was seen: from 80.2 +/- 25.8 to 58.1 +/- 17.8 min/day in the deficient group, 143.7 +/- 19.8 to 92.9 +/- 11.5 min/day in the insufficient group, and 108.1 +/- 20.9 to 62.3 +/- 12.9 min/day in the sufficient group. The Chair Stand Test, Timed Up and Go test, and 10-Meter Walking Test also improved significantly over time, but independent of vitamin D status. An increase in 25(OH)D3 concentration 6 weeks postoperatively was correlated with improved hip function (Pearson's r = -0.471, p = 0.018). Overall, serum 25(OH)D3 declined with 32% one day after surgery (p < 0.001), to nearly return to baseline values 6 weeks later in all groups. CONCLUSION: Vitamin D status did not appear to affect physical recovery after THA. The drop in vitamin D after surgery deserves further investigation, but could possibly be explained by hemodilution. PMID- 30253385 TI - IUNS News. PMID- 30253384 TI - Chimeric Antigen Receptor-T Cells with 4-1BB Co-Stimulatory Domain Present a Superior Treatment Outcome than Those with CD28 Domain Based on Bioinformatics. AB - BACKGROUND: The second-generation CD19-chimeric antigen receptor (CAR)-T co stimulatory domain that is commonly used in clinical practice is CD28 or 4-1BB. Previous studies have shown that the persistence of CAR-T in the 4-1BB co stimulatory domain appears to be longer. METHODS: The expression profile data of GSE65856 were obtained from GEO database. After data preprocessing, the differentially expressed genes (DEGs) between the mock CAR versus CD19-28z CAR T cells and mock CAR versus CD19-BBz CAR T cells were identified using the limma package. Subsequently, functional enrichment analysis of DEGs was performed using the DAVID tool. Then, the protein-protein international (PPI) network of these DEGs was visualized by Cytoscape, and the miRNA-target gene-disease regulatory networks were predicted using Webgestal. RESULTS: A total of 18 common DEGs, 6 CD19-28z specific DEGs and 206 CD19-BBz specific DEGs were identified. Among CD19 28z specific DEGs, down-regulated PAX5 might be an important node in the PPI network and could be targeted by miR-496. In CD19-BBz group, JUN was a hub node in the PPI network and involved in the regulations of miR520D - early growth response gene 3 (EGR3)-JUN and mi-R489-AT-rich interaction domain 5A (ARID5A)-JUN networks. CONCLUSION: The 4-1BB co-stimulatory domain might play in important role in the treatment of CAR-T via miR-520D-EGR3-JUN and miR489-ARID5A-JUN regulation network, while CD28 had a negative effect on CAR-T treatment. PMID- 30253386 TI - Cyclic Dimeric Guanosine Monophosphate: Activation and Inhibition of Innate Immune Response. AB - Cyclic dimeric guanosine monophosphate (c-di-GMP) is a universally conserved second messenger that contributes to the pathogenicity of numerous bacterial species. In recent years, growing evidence has shown that bacterial extracellular c-di-GMP can interact with the innate immune system and regulate host immune responses. This review summarizes our current understanding on the dual roles of bacterial c-di-GMP in pathogen-host interaction: activation of the antibacterial innate immune response through the cytosolic surveillance pathway and inhibition of innate immune defense for iron restriction. PMID- 30253388 TI - Correlation of Vitamin D3 (Calcitriol) Serum Concentrations with Vitamin B12 and Folic Acid in Women Undergoing in vitro Fertilisation/Intracytoplasmatic Sperm Injection. AB - BACKGROUND: The important role of vitamin D3 in human health is well recognized. In this study, we measured serum concentrations of vitamin D3, vitamin B12 and B9 (folic acid) in 410 women undergoing in vitro fertilisation (IVF)/intracytoplasmatic sperm injection (ICSI) with dedicated focus on 3-month changes in consideration of patients' BMI. METHODS: Patients were of European origin and did not take any supplementation of D3. In preparing for pregnancy, patients took >=4 weeks 400 ug folic acid combined with 9 ug vitamin B12 and 150 ug iodide as recommended. RESULTS: We found a significant 3-month quartile change of D3 serum concentrations (p < 0.0001) with maximum levels in autumn and lowest in spring. D3 correlated significantly with B12 (p = 0.035, rho = 0.102) and folic acid (p < 0.0001, rho = 0.191). BMIs however showed a negative correlation with B12 (p = 0.031, rho = -0.105) and folic acid (p = 0.012, rho = -0.125). CONCLUSIONS: Our results suggest a model in which the sun exposure during summer months enables storage of D3 followed by a slow release as a major factor to maintain D3 levels throughout the year. Finally, our data indicate that B12 and folic acid uptake might be influenced by vitamin D receptor and D3, where D3 and the BMI appear to have an indirect relationship - via B12 and folic acid. PMID- 30253387 TI - The Risk of Clonal Evolution of Granulocyte Colony-Stimulating Factor for Acquired Aplastic Anemia: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: This meta-analysis aimed to evaluate the risk of clonal evolution of granulocyte colony-stimulating factor (G-CSF) in acquired aplastic anemia (AA), and whether the use of G-CSF increases the occurrence of secondary malignant neoplasms, mainly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) or paroxysmal nocturnal hemoglobinuria (PNH). METHODS: Data were gathered from randomized controlled trials (RCTs) to evaluate the effect of G-CSF versus no G CSF at the risk of developing the clonal complications of acquired AA. Electronic searches in PubMed, Embase, and the Cochrane Library were performed to identify studies up to 1 January 2017. Only RCTs performed on patients who were randomly assigned to receive G-CSF or not to receive G-CSF were included. RESULTS: Four relevant trials that met the inclusion criteria were identified. In a pooled analysis, the G-CSF groups of AA patients were not associated with a statistically significant higher occurrence of secondary malignant neoplasm, mainly MDS and AML (relative risk [RR] 0.86; 95% confidence interval [CI] 0.34 2.19; 4 trials). No significant heterogeneity was found (p = 0.67, I2 = 0%). There was no statistically significant higher occurrence of PNH in the G-CSF groups with AA (RR 1.17; 95% CI 0.51-2.71; 4 trials) and no significant heterogeneity was found (p = 0.42, I2 = 0%). CONCLUSIONS: G-CSF for patients with AA is not associated with a higher occurrence of secondary malignant neoplasm, mainly MDS/AML, or PNH. PMID- 30253389 TI - Influences of Surgical Volume on Perioperative and Oncological Outcomes Following Radical Prostatectomy. AB - INTRODUCTION: The purpose of this study was to evaluate whether the number of radical prostatectomies per hospital per year is associated with stage distribution, surgical techniques or quality related outcome in Germany. MATERIALS AND METHODS: A German Internet-based database was analyzed. Hospitals were categorized according to their yearly radical prostatectomy (RP) volume. Patient's characteristics, RP techniques, and outcome-related parameters were compared between the different hospital volume categories. RESULTS: A total of 6,447 patients were analyzed. The highest rate of organ-confined disease and the lowest rate of extracapsular invasion have been demonstrated in very low-volume centres (72.6% =3). High-volume centres had the highest rate of open (92%) and robot-assisted RP approaches (5.5%). Regarding outcome, the lowest rate of positive surgical margins (11.7%) and the lowest intraoperative blood loss (3.3 g/dL) have been observed in high-volume centres. CONCLUSION: A higher number or RPs per year was associated with better outcome regarding quality related parameters like surgical margin status and blood loss. However, the tumour stage distribution did not significantly differ between the low, intermediate and high-volume centres suggesting that till date the allocation of patients to the different centres is not triggered by the tumour risk classification. PMID- 30253390 TI - Introduction to the New Section "Oncology and Informatics". PMID- 30253391 TI - Attenuation of Remifentanil-Induced Hyperalgesia by Betulinic Acid Associates with Inhibiting Oxidative Stress and Inflammation in Spinal Dorsal Horn. AB - Remifentanil-induced hyperalgesia (RIH) is known to be associated with oxidative stress and inflammation. Betulinic acid (BA) was reported to reduce visceral pain owing to its anti-oxidative and anti-inflammatory potential. Here, we -explored whether BA can attenuate RIH through inhibiting oxidative stress and inflammation in spinal dorsal horn. Sprague-Dawley rats were randomly divided into 4 groups: Control, Incision, RIH, and RIH pre-treated with BA. After pretreated with BA (25 mg/kg, i.g.) for 7 days, rats were subcutaneously infused with remifentanil (40 MUg/kg) for 30 min during right plantar incision surgery to induce RIH. The paw withdrawal mechanical threshold (PWMT), paw withdrawal thermal latency (PWTL), spinal oxidative stress and inflammatory mediators were determined. Intraoperative remifentanil infusion induced postoperative hyperalgesia, as evidenced by the significant decrease in PWMT and PWTL (p < 0.01), and the significant increase in oxidative stress and inflammation evidenced by up regulations of malondialdehyde, 3-nitrotyrosine, interleukin-1beta and tumour necrosis factor-alpha (p < 0.01) in spinal dorsal horn and matrix metalloproteinase-9 (MMP-9) activity (p < 0.01) in dorsal root ganglion, as well as a decrease in manganese superoxide -dismutase activity (p < 0.01) compared with control and -incision groups. All these results mentioned above were markedly reversed by pre-treatment with BA (p < 0.01) compared with RIH group. These findings demonstrated that BA can effectively attenuate RIH, which associates with potentially inhibiting oxidative stress and subsequently down regulating MMP-9-related pro-inflammatory cyokines in spinal dorsal horn. PMID- 30253392 TI - The Safety and Efficacy of Regional Citrate Anticoagulation in Albumin-Assisted Liver Dialysis for Extracorporeal Liver Support in Pediatric Patients. AB - AIMS: To establish the safety and efficacy of regional citrate anticoagulation (RCA) for pediatric liver failure (LF) patients receiving extracorporeal liver support (ELS) with albumin-assisted dialysis. METHODS: Retrospective review of pediatric LF patients receiving ELS from April 2014 to December 2016 at a tertiary children's hospital pediatric intensive care unit. Demographic and ELS data collected by chart review. Citrate accumulation (CA) was defined as total calcium (mmol/L): ionized calcium (mmol/L) > 2.5 (tCa:iCa). Efficacy was assessed by treatment duration. Safety was assessed by adverse events: bleeding, hemodynamic instability, arrhythmias, unplanned treatment discontinuation. RESULTS: Fifteen patients (median age 3 [interquartile range (IQR) 0.7-8.0]) received 108 ELS treatments (median 5 [IQR 4-7.5]). Sixty-eight episodes of CA were identified. Of those, 6 coincided with intervention and 1 coincided with ELS discontinuation. There were no deaths attributed to ELS or RCA. CONCLUSION: RCA provides safe and effective anticoagulation for pediatric LF patients requiring ELS. PMID- 30253393 TI - Surgical Outcomes of Liver Resection Combined with Inferior Vena Cava Resection and Reconstruction with Artificial Vascular Graft. AB - BACKGROUND/AIM: Inferior vena cava (IVC) resection and reconstruction with concomitant liver resection sometimes represent the only chance for patients with liver tumors involving the IVC to get cured. However, surgical outcomes of liver resection with IVC resection and reconstruction using an artificial vascular graft have not been well investigated. METHODS: Out of a total of 1,179 cases, only 12 involving liver resection between 1998 and 2016 at our institution included IVC resection and reconstruction using an artificial vascular graft. An expanded polytetrafluoroethylene graft was used for the IVC reconstruction in all 12 cases. We investigated the surgical outcomes of these combined surgeries. RESULTS: The median operative time was 650 min and the median blood loss was 2,600 mL. Postoperative complications (>= grade III in the Clavien-Dindo classification) developed in 2 patients - 1 case of bleeding and one of bile leakage. There were no cases of operative mortality. No complications associated with the vascular graft were observed throughout the postoperative follow-up period, and the grafts remained patent in all cases. CONCLUSIONS: These results indicate favorable surgical outcomes of liver resection combined with IVC resection and reconstruction. PMID- 30253394 TI - Using Advances in Skin Imaging Technology and Genomics for the Early Detection and Prevention of Melanoma. PMID- 30253395 TI - Cytological Findings of Gastrointestinal Stromal Tumor-Derived Bone Metastasis. AB - OBJECTIVE: Procedures for diagnosing bone tumors should be rapid and minimally invasive. Thus, cytological examinations are more useful for such purposes than histological examinations. In order to identify cytomorphological findings that could be used to diagnose bone metastasis from gastrointestinal stromal tumors (GIST), previous cases were reviewed. STUDY DESIGN: Cytological samples of 7 lesions from 4 patients with GIST-derived bone metastasis, which were obtained from 2001 to 2017 at the JFCR Cancer Institute Hospital, were reviewed. RESULTS: The metastasis of GIST to the bone was clinically suspected before the cytological and histological examinations in all cases since they all involved other metastatic lesion(s), and characteristic osteolytic lesions were detected on radiological images. Although various cell shapes were encountered, spindle cell proliferation was seen in all cytological samples. No pleomorphism was apparent. Characteristic nuclear findings were observed. All of the cases could be diagnosed as GIST-derived bone metastasis. CONCLUSION: GIST-derived bone metastasis can be diagnosed by examining cytological samples. PMID- 30253396 TI - Preoperative Serum Thyroglobulin Level as a Useful Predictive Marker to Differentiate Thyroid Cancer. AB - INTRODUCTION: Thyroid cancer is the most common endocrine system cancer. Although fine-needle aspiration biopsy is the most commonly used method for diagnosis, it is not always sufficient. The aim of this study was to investigate the influence of preoperative serum thyroglobulin (Tg) concentration on differentiated thyroid cancer risk. MATERIAL AND METHODS: A total of 133 patients who underwent total thyroidectomy due to various indications at the Ear-Nose-Throat Department, Ataturk University Medical School, between April 2015 and December 2015, were included in this prospective study. Histopathological diagnosis and preoperative Tg levels were compared. Receiver operating characteristic (ROC) analysis was used for detection of the cut-off to discriminate malignant from benign thyroid masses using preoperative Tg as a variable. RESULTS: Malignant pathology (differentiated thyroid carcinoma) was detected in 59 out of 133 patients (44.4%) and benign pathology in 74 (55.6%). A statistically significant difference in preoperative Tg value was detected between malignant and benign cases (p < 0.05). CONCLUSION: The prevalence of differentiated thyroid carcinoma was higher among patients with a preoperative serum Tg value > 188.5 ng/mL, and this may thus be used as a marker for the diagnosis of this malignancy. PMID- 30253398 TI - Long Non-Coding RNA ZEB1-Antisense 1 Affects Cell Migration and Invasion of Cervical Cancer by Regulating Epithelial-Mesenchymal Transition via the p38MAPK Signaling Pathway. AB - AIM: To investigate whether long non-coding RNA (lncRNA) ZEB1 antisense 1 (ZEB1 AS1) affects cell migration and invasion of cervical cancer by regulating epithelial-mesenchymal transition (EMT) via the p38MAPK pathway. METHODS: Human cervical cancer cell line Hela was classified into Control, NC siRNA, ZEB1-AS1 siRNA, SB203580 (p38MAPK pathway inhibitor) and ZEB1-AS1 siRNA + Anisomycin (p38MAPK pathway activator) groups. Quantitative real-time polymerase chain reaction was performed for ZEB1-AS1 expression, Western blotting to measure p38MAPK signaling pathway-/EMT-related proteins, and Wound-healing and Transwell assays to evaluate cell migration and invasion respectively. RESULTS: ZEB1-AS1 was upregulated in cancer tissues and related to major clinicopathological features of cervical cancer. Besides, patients with lower-ZEB1-AS1-expression had a higher 5-year survival rate than those patients with higher-ZEB1-AS1 expression. High ZEB1-AS1 expression and advanced Federation of Gynecology and Obstetrics stage were independent risk factors for patients' prognosis. Both ZEB1 AS1 siRNA and SB203580 effectively reduced p-p38 expression and the migration and invasion of Hela cells, with elevation of E-cadherin and reduction of Vimentin and N-cadherin. However, inhibitory effects of ZEB1-AS1 siRNA on EMT as well as cell migration and invasion of the Hela cell were reversed by Anisomycin. CONCLUSION: Inhibition of ZEB1-AS1 can block the p38MAPK signaling pathway, ultimately restricting the EMT and suppressing cell migration and invasion of cervical cancer cells. PMID- 30253399 TI - Chronic Stress May Not Be a Factor in the Behavioral Response to Chronic Lithium in ICR Mice. AB - BACKGROUND: Lithium (Li) is the prototypic mood-stabilizing drug, but the individual response to Li is highly heterogeneous. Some evidence suggest interactions between Li and stress, and it is possible to hypothesize that lithium's effects are modified by stress conditions. The current study examines the interaction between 2 chronic stressors, constant light (CL) and restrain and the behavioral responses to chronic Li in female and male mice. METHODS: Female and male ICR mice were exposed to 3 weeks of either (1) CL; (2) daily restrain or (3) no stress control. One week after the start of the stress intervention, mice started chronic oral Li treatment or control. After 2 weeks of stress and Li, mice were tested in a number of behavioral tests including spontaneous activity, sweet solution preference, plus-maze and forced swim test. RESULTS: There were no effects of stressors on behavior. Effects of Li were demonstrated in males but not females with no interactions between stress and Li. CONCLUSIONS: The behavioral effects of Li in this study were not affected by stress. The lack of effects of the stressors themselves on behavior suggests that the application of more intrusive stressors might be needed to further explore the issue. PMID- 30253397 TI - The Derived Neutrophil-to-Lymphocyte Ratio Is an Independent Prognostic Factor in Transplantation Ineligible Patients with Multiple Myeloma. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is an independent prognostic marker in solid and hematological cancers. While the derived NLR (dNLR) was shown to be non-inferior to the NLR in large cohorts of patients with different cancer types, it has not been validated as a prognostic marker for multiple myeloma (MM) to date. METHODS: Between May 22, 2011 and May 29, 2014, 176 patients with MM from 38 centers who were ineligible for autologous stem cell transplantation were analyzed. The dNLR was calculated using complete blood count differential data. The optimal dNLR cut-off value according to receiver operating characteristic analysis of overall survival (OS) was 1.51. All patients were treated with melphalan and prednisone combined with bortezomib. RESULTS: The complete response rate was lower in the high dNLR group compared to the low dNLR group (7 vs. 26.1%, respectively; p = 0.0148); the corresponding 2-year OS rates were 72.2 and 84.7%, respectively (p = 0.0354). A high dNLR was an independent poor prognostic factor for OS (hazard ratio 2.217, 95% CI 1.015-4.842; p = 0.0458). CONCLUSION: The dNLR is a readily available and cheaply obtained parameter in clinical studies, and shows considerable potential as a new prognostic marker for transplantation-ineligible patients with MM. PMID- 30253400 TI - Plasmapheresis Therapy in Kidney Transplant Rejection. AB - Kidney transplantation (KT) is considered an optimal treatment strategy for end stage renal disease. But human leukocyte antigen-sensitized, ABO-incompatible and antibody-mediated rejection might be the alarming hurdles in KT. Therapeutic plasma exchange is the mainstay of the antibody reduction therapy for reducing autoantibody more effectively. Even in the treatment for highly sensitized patients, it has played an indispensable role. However, clinicians should tailor therapies to individual patient's needs and multimodal treatment will bring better outcomes. Early diagnosis and precise treatment would reduce morbidity, mortality, and economic costs. PMID- 30253401 TI - Expression of Duplex shRNAs through a Lentiviral Vector against Cellular and Viral Genes Inflicts Sustained Inhibition of Hepatitis C Virus Replication. AB - BACKGROUND: The RNAi-based transient therapeutic approach has been well explored for its potential against the hepatitis V virus (HCV). However, to achieve a sustained virological response, a consistent presence of siRNA is needed and it can be achieved by constitutively expressing shRNAs. In this context, the lentiviral vector has emerged as an attractive tool for shRNA delivery against HCV. METHODS: We monitored HCV inhibition after single and multiple rounds of siRNA treatments against La autoantigen and HCV-NS5B in Huh-7.5 cells infected with the FL-J6/JFH chimeric HCV strain. A bicistronic self-inactivating third generation lentiviral vector expressing shRNA under U6 and H1 promoters was constructed. To ascertain the long-term HCV inhibition, cells were transduced with lentiviral vectors and HCV inhibition was monitored by RT-PCR and Western blotting at regular intervals. RESULTS: We observed transient antiviral activity after a single round of siRNA treatment, and consecutive rounds of treatments with siRNA demonstrated a sustained HCV inhibition. Delivery of duplex shRNA expressing lentiviral vectors provided constant expression of shRNA leading to synergistic and sustained HCV inhibition. CONCLUSION: A lentiviral vector-based delivery system is a "single-shot" therapeutic strategy. It can express duplex shRNA for long-term synergistic inhibition of HCV and qualify as a promising therapeutic approach for sustained inhibition of HCV replication. PMID- 30253402 TI - Dysregulated Network of Immune, Endocrine and Metabolic Markers is Associated to More Severe Human Chronic Chagas Cardiomyopathy. AB - Individuals who are infected with Trypanosoma cruzi develop chronic Chagas cardiomyopathy (CCC), which is a complication involving a series of immune pathogenetic mechanisms, although an association between immune and metabolic alterations was more recently proposed. Accordingly, we investigated the immuno metabolic response in chagasic patients and their possible influence on CCC pathogenesis. To this end, T. cruzi-seropositive (asymptomatic or with CCC) and sero-negative individuals were studied. Serum tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, adipocytokines and the expression of their receptors in peripheral blood mononuclear cell (PBMC) were evaluated, together with other factors influencing the immune response. CCC patients showed major metabolic and hormonal abnormalities, in parallel with increased IL-6 and leptin serum levels. TNF-alpha receptor s, leptin and adiponectin receptors (ObR and Adipo-Rs respectively), as well as PPAR-gamma expression in PBMCs from CCC patients were compatible with a counteracting response leading to an unfavourable immune metabolic profile. These results suggest that persistently increased levels of immune-metabolic pro-inflammatory mediators along with the adverse endocrine anti inflammatory response of CCC individuals, may contribute to the underlying mechanisms dealing with myocardial tissue damage. PMID- 30253403 TI - Comparing Therapeutic Efficacy and Safety of Epoetin Beta and Epoetin Alfa in the Treatment of Anemia in End-Stage Renal Disease Hemodialysis Patients. AB - BACKGROUND: Anemia is one of the most prevalent complications in patients with chronic kidney disease, which is believed to be caused by the insufficient synthesis of erythropoietin by the kidney. This phase III study aimed to compare the efficacy and safety of CinnaPoietin(r) (epoetin beta, CinnaGen) with Eprex(r) (epoetin alfa, Janssen Cilag) in the treatment of anemia in ESRD hemodialysis patients. METHODS: In this randomized, active-controlled, double-blind, parallel, and non-inferiority trial, patients were randomized to receive either CinnaPoietin(r) or Eprex(r) for a 26-week period. The primary endpoints of this study were to assess the mean hemoglobin (Hb) change during the last 4 weeks of treatment from baseline along with the evaluation of the mean weekly epoetin dosage per kilogram of body weight that was necessary to maintain the Hb level within 10-12 g/dL during the last 4 weeks of treatment. As the secondary objective, safety was assessed along with other efficacy endpoints. RESULTS: A total of 156 patients were included in this clinical trial. There was no statistically significant difference between treatment groups regarding the mean Hb change (p = 0.21). In addition, the mean weekly epoetin dosage per kg of body weight for maintaining the Hb level within 10-12 g/dL showed no statistically significant difference between treatment arms (p = 0.63). Moreover, both products had comparable safety profiles. However, the incidence of Hb levels above 13 g/dL was significantly lower in the CinnaPoietin(r) group. CONCLUSION: CinnaPoietin(r) was proved to be non-inferior to Eprex(r) in the treatment of anemia in ESRD hemodialysis patients. The trial was registered in Clinicaltrials.gov (NCT03408639). PMID- 30253404 TI - Regional Citrate Anticoagulation During Coupled Plasma Filtration and Adsorption May Increase Survival in Septic Shock. PMID- 30253405 TI - The Effectiveness of Tamoxifen in the Prevention of Recurrent Urethral Strictures Following Internal Urethrotomy. AB - OBJECTIVE: Tamoxifen was not used earlier in clinical practice to decrease the urethral re-stricture rate after visual internal urethrotomy (VIU). In this study, we are the first to report the use of Tamoxifen as an adjuvant therapy to decrease the re-fibrosis and stricture recurrence post-VIU. PATIENTS AND METHODS: Between 2015 and 2017, 60 patients underwent VIU for post-traumatic bulbar urethral stricture <=1 cm. They were randomly divided into 2 groups (30 patients each). The Tamoxifen group cases received Tamoxifen 10 mg twice daily for 6 months post-VIU. The control group did not receive any medications. All patients were evaluated using the IPSS score, uroflowmetry, and perineal ultrasonography preoperatively at 3 and 6 months. RESULTS: At presentation, there was no significant difference between patients of both groups in terms of IPSS score, Qmax, stricture width, and length. At 6 months follow-up, the mean IPSS score for the Tamoxifen group was 12.3 (8-19) in comparison with 20 (12-26) in the control group (p < 0.001). The Tamoxifen group had mean Qmax 11.1 mL/s (9-14), while those of the control group had mean Qmax 8.2 mL/s (6-10; p < 0.001). Using perineal ultrasound, only stricture width showed to be significantly smaller in the Tamoxifen group (p = 0.001). CONCLUSION: Tamoxifen seemed to be effective in reducing the recurrence of urethral stricture post-VIU. There was a significant improvement of the clinical outcome regarding Qmax and IPSS score after Tamoxifen adjuvant therapy. PMID- 30253406 TI - Comparison of Ultrasound and Fluoroscopically Guided Percutaneous Transhepatic Biliary Drainage. AB - BACKGROUND: Percutaneous transhepatic biliary drainage (PTBD) plays a significant role especially in the palliation of an endoscopically inaccessible biliary system. Since a standard technique of PTBD is not defined, we compared a fluoroscopically guided technique (F-PTBD) with an ultrasound (US-PTBD) guided approach. PATIENTS AND METHODS: Procedure characteristics, success-rates and complication-rates of the different PTBD techniques were compared in patients who underwent PTBD between October 1, 2006, and -December 31, 2014. RESULTS: In 195 patients, 251 PTBDs (207 F-PTBDs, 44 US-PTBDs) were performed. F-PTBDs were mostly inserted from the right and US-PTBDs from the left. Patient age, gender and physical status were comparable in both techniques. There was no difference regarding overall procedure success (90%/86.4%), overall interventional complication rates (10.6%/9.1%), fluoroscopy times, intervention times or sedatives dosages. However, major complications were only encountered in F-PTBDs. There was a higher success rate for F-PTBD vs. US-PTBD from the right side (91.9 vs. 75%; p = 0.033) and a trend towards a higher success rate for US guidance from the left side (82.9 vs. 95.8%; p = 0.223). CONCLUSIONS: For drainage of the right biliary system F-PTBD seems superior over the US-PTBD technique used in this study. However, major complications can occur more frequently in F-PTBD. PMID- 30253407 TI - The Prognostic Value of the Derived Neutrophil-to-Lymphocyte Ratio in Transplantation-Ineligible Patients with Multiple Myeloma. PMID- 30253408 TI - FENS News. PMID- 30253409 TI - A New Series of Sorbent Devices for Multiple Clinical Purposes: Current Evidence and Future Directions. AB - Adsorption is an extracorporeal technique utilized for blood purification. It complements convection and diffusion (the main modalities of solute removal). It involves the passage of blood (or plasma) through an adsorption cartridge, where solutes are removed by direct binding to the sorbent material. Over the years, new adsorption cartridges, with improved characteristics have been developed. Furthermore, the therapeutic applications of adsorption have expanded. These now involve the treatment of inflammatory conditions, chronic uremic symptoms, and autoimmune disease, in addition to intoxication, which was once considered the classical indication for adsorption therapy. HA130, HA230, and HA330 (Jafron, Zhuhai City, China) are among the widely used adsorption cartridges in China. There has been sufficient body of evidence to support their effectiveness and safety. In this review, we aim to highlight their main clinical applications. PMID- 30253410 TI - Predicting Dysphagia with National Institute of Health Stroke Scale: Distinction between Infra- and Supratentorial Region is Essential. AB - BACKGROUND: For the early detection of post-stroke dysphagia (PSD), valid screening parameters are crucial as part of a step-wise diagnostic procedure. This study examines the role of the National Institute of Health Stroke Scale (NIH-SS) as a potential low-threshold screening parameter. METHODS: During a ten year period, 687 newly admitted patients at University Hospital Muenster were included in a retrospective analysis, if they had ischemic or haemorrhagic stroke confirmed by neuroimaging and had received NIH-SS scoring and endoscopic swallowing evaluation upon admission. The NIH-SS score was correlated with dysphagia severity as measured by the validated 6-point fiberoptic endoscopic dysphagia severity score (FEDSS), and the ideal cut-off score to predict PSD, defined as FEDSS > 1, was calculated. Supra- and infratentorial strokes were analysed separately due to their differing role in the pathophysiology of neurogenic dysphagia. RESULTS: NIH-SS and dysphagia severity show a significant positive correlation in the whole study population (R2 = 0.745) as well as in both analysed subgroups (R2 = 0.494 for supra- and R2 = 0.646 for infratentorial strokes, p < 0.0005, respectively). For supratentorial strokes, the ideal NIH-SS cut-off is > 9 (sensitivity 68.3%, specificity 61.5%, positive predictive value 89.7%, negative predictive value 28.4%). For infratentorial strokes, a lower ideal cut-off > 5 was calculated (sensitivity 67.4%, specificity 85.0%, positive predictive value 95.1%, negative predictive value 37.8%). CONCLUSIONS: NIH-SS may be used as an adjunct to predict dysphagia in acute stroke patients with moderate sensitivity and specificity. Differentiation between supra- and infratentorial regions is essential not to miss dysphagia in infratentorial stroke. PMID- 30253411 TI - Endoscopic Ultrasound with Bronchoscope-Guided Fine Needle Aspiration for the Diagnosis of Paraesophageally Located Lung Lesions. AB - BACKGROUND: Diagnosing centrally located lung tumors without endobronchial abnormalities and not located near the major airways is a diagnostic challenge. Tumors near or adjacent to the esophagus can be aspirated and detected with esophageal ultrasound (EUS) using gastrointestinal endoscopes. OBJECTIVE: To assess the feasibility and diagnostic yield of endoscopic ultrasound with bronchoscope-guided fine needle aspiration (EUS-B-FNA) in paraesophageally located lung tumors and its added value to bronchoscopy and endobronchial ultrasound (EBUS). METHODS: Retrospective, multicenter international study (from January 1, 2015 until January 1, 2018) of patients with suspected lung cancer, undergoing bronchoscopy, EBUS, and endoscopic ultrasound bronchoscopy (EUS-B) in one session by a single operator (pulmonologist), in whom the primary lung tumor was detected and aspirated by EUS-B. In the absence of malignancy following endoscopy, transthoracic ultrasound needle aspiration, clinical and radiological follow-up of at least 6 months was performed. The yield and sensitivity of EUS-B FNA and its added value to bronchoscopy and EBUS was assessed. RESULTS: 58 patients were identified with the following diagnosis: non-small-cell lung cancer (n = 43), small-cell lung cancer (n = 6), mesothelioma (n = 2), metastasis (n = 1), nonmalignant (n = 6). The yield and sensitivity of EUS-B-FNA for detecting lung cancer was 90%. In 26 patients (45%), the intrapulmonary tumor was exclusively detected by EUS-B. Adding EUS-B to conventional bronchoscopy and EBUS increased the diagnostic yield for diagnosing lung cancer in para-esophageally located lung tumors from 51 to 91%. No EUS-B-related complications were observed. CONCLUSION: EUS-B-FNA is a feasible and safe technique for diagnosing centrally located intrapulmonary tumors that are located near or adjacent to the esophagus. EUS-B should be considered in the same endoscopy session following nondiagnostic bronchoscopy and EBUS. PMID- 30253412 TI - Development of a Simple Risk Score Model to Predict Renal Artery Stenosis. AB - BACKGROUND/AIMS: Renal artery stenosis (RAS) is a known cause of secondary hypertension and renal failure. Although renal artery angiography is the gold standard for diagnosing RAS, a simple method to estimate if patients will develop RAS is required. The aim of this retrospective study was to develop a simple risk score to predict significant RAS. METHODS: Four thousand one hundred seventy seven patients who underwent renal angiography between 2002 and 2016 at Tehran Heart Center were included. Significant RAS was defined as narrowing of the renal artery by at least 70%. Multiple predictors of the RAS were determined using multivariable logistic regression with a backward elimination method. The scoring system obtained from the final model was presented as nomogram. The possible nonlinear effect of continuous variables was evaluated using restricted cubic splines. Overfitting of the final model was assessed applying the tenfold cross validation method. Model performance was checked using calibration plot as well as Hosmer-Lemeshow goodness of fit test, and area under the receiver operating characteristics (ROC) curve. RESULTS: The prevalence of RAS was 14.1%. Female sex (OR [95% CI]: 1.53 [1.26-1.85]), hypertension (OR [95% CI]: 1.38 [1.08-1.77]), estimated glomerular filtration rate (OR [95% CI]: 0.98 [0.97-0.98]), body mass index (OR [95% CI]: 0.97 [0.95-0.99]), and age (OR [95% CI]: 1.01 [1.00-1.02]) were determined as the multiple predictors of RAS. The area under the ROC curve of the final predictive model was 0.702 (95% CI: 0.679-0.725). CONCLUSION: This model assesses the risk of RAS using available information. This model can be used for both clinical and research purposes. PMID- 30253413 TI - Cytopathology of Solid Variant of Papillary Thyroid Carcinoma: Differential Diagnoses with other Thyroid Tumors. AB - OBJECTIVES: Solid variant of papillary thyroid carcinoma (SVPTC) is rare, differing from classical PTC (cPTC) in architecture and outcome. We evaluated the cytomorphology of SVPTC cases to assess the feasibility of a preoperative diagnosis. STUDY DESIGN: SVPTC cases were evaluated for architecture, nuclear features, and Bethesda category and were compared with noninvasive follicular thyroid neoplasm with papillary-like nuclear features/follicular variant of PTC (NIFTP/FVPTC), cPTC, and poorly differentiated thyroid carcinoma (PDTC). RESULTS: Nine SVPTCs, 29 NIFTP/FVPTCs, 12 cPTCs, and 4 PDTCs were included. The predominant architecture in most SVPTCs was solid fragment, which is helpful in differentiating them from NIFTP/FVPTC (p < 0.001) and cPTC (p = 0.006) but not from PDTC. The presence of microfollicles led to misinterpretation as NIFTP/FVPTC/follicular neoplasm in 4 patients. All but 1 SVPTC showed diffuse nuclear features. Intranuclear pseudoinclusions (INIs) were seen in 67% of SVPTCs as compared to 83% of cPTCs, 14% of NIFTP/FVPTCs (p = 0.005), and none of PDTCs. SVPTC cases were commonly (78%) categorized as intermediate/suspicious. CONCLUSIONS: The presence of solid fragments and lack of true papillae are helpful in differentiating SVPTC from cPTC. Solid fragments, trabeculae, the extent of nuclear features, and INIs should be looked for in cases with prominent microfollicles for distinguishing SVPTC from NIFTP/FVPTC. None of the features were helpful in differentiating SVPTC from PDTC. PMID- 30253414 TI - Serum Glutaredoxin Activity as a Marker of Oxidative Stress in Chronic Kidney Disease: A Pilot Study. AB - BACKGROUND: Inflammation and oxidative stress play important roles in the pathogenesis and progression of chronic kidney disease (CKD) and in its complications, in particular cardiovascular disease, a major cause of death among patients undergoing dialysis treatment. We recently described that Glutaredoxin1 (Grx), an intracellular antioxidant, catalyzes oxidoreductase reactions also extracellularly, and that serum Grx levels correlate to disease severity in type 2 diabetes. AIM: In the current study we assess Grx as a potential clinical marker of oxidative stress in CKD. METHODS: We examined Grx activity in 25 patients with different stages of chronic kidney failure, 19 control subjects, and 36 patients at initiation of dialysis and after 2 years of dialysis. RESULTS: We found that Grx activity was significantly higher in CKD patients compared to control subjects, indicating an oxidized extracellular environment in CKD. Grx levels correlated to interleukin-6 and pentosidine, but not to age or GFR. In dialysis patients with Grx sampling before dialysis start and after 2 years of dialysis, Grx levels increased more in hemodialysis (HD) patients than in peritoneal dialysis patients, indicating an increased oxidative stress imbalance in HD patients. Patients who experienced a stroke or myocardial infarction at any time had a significantly higher increase in Grx during the 2 years of dialysis, compared to patients without stroke or myocardial infarction, indicating a possible association between high Grx levels and a cardiovascular event. CONCLUSION: Our pilot study indicates that Grx may be a useful marker for assessing the degree of oxidative stress in CKD, however this needs further investigation in a larger prospective patient cohort. PMID- 30253415 TI - The Incidence Prognosis and Risk Factors of Cognitive Impairment in Maintenance Haemodialysis Patients. AB - OBJECTIVE: To investigate the incidence and the prognosis of cognitive impairment (CI) and to find out the risk factors associated with the outcome in maintenance haemodialysis (MHD) patients. METHODS: Enrolled the patients who met the criteria as below: MHD (>=3 months) patients before July 2014, >=18 years old and could carry on the cognitive function test (Montreal Cognitive Assessment [MoCA]). All enrolled patients were divided into 2 groups: CI group (MoCA < 26) and non-CI group (MoCA >=26). All patients were followed up for 36 months. The incidence, demography data, medical history, haemodialysis data, laboratory examination and prognosis of CI in haemodialysis patients were prospectively compared and analyzed. Multivariate logistic regression analysis was used to investigate the risk factors of CI. Kaplan-Meier survival curve was used for survival analysis. RESULTS: In the present study, 219 patients were enrolled. The ratio of male to female was 1.46: 1. Age was 60.07 +/- 12.44 and dialysis vintage was 100.79 +/- 70.23 months. One hundred thirteen patients' MoCA scores were lower than 26 were divided into CI group. Education status (OR 3.428), post-dialysis diastolic pressure (OR 2.234) and spKt/V (OR 1.982) were independent risk factors for CI in MHD patients. During the follow-up period, 15 patients died (13.2%) in the CI group and 5 died (4.72%) in the non-CI group (p < 0.05). The Kaplan-Meier survival curve analysis showed that the survival rate of patients with CI was lower than that of non-CI group in MHD patients during 3 years follow-up (p = 0.046). CONCLUSION: CI is one of the most common complications in MHD patients. The mortality is high in patients who had CI. Education status, post-dialysis diastolic pressure and spKt/V are independent risk factors for CI in MHD patients. PMID- 30253416 TI - Nitrosonifedipine, a Photodegradation Product of Nifedipine, Suppresses Pharmacologically Induced Aortic Aneurysm Formation. AB - BACKGROUND/AIMS: We have reported that nitrosonifedipine (NO-NIF), a photodegradation product of nifedipine, has strong antioxidant and endothelial protective effects, and can suppress several cardiovascular diseases in animal models. The objective of the present study was to investigate the effects of NO NIF on aortic aneurysm formation. METHODS: The mice were infused with beta aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. The oxidative stress was measured by dihydroethidium staining and nitrotyrosine staining. The expressions of inflammation-related genes were assessed by quantitative real-time PCR and immunohistochemical staining. To clarify the mechanisms of how NO-NIF suppresses vascular cell adhesion molecule (VCAM)-1, endothelial cells were used in in vitro system. RESULTS: NO-NIF suppressed pharmacologically induced the aortic aneurysm formation and aortic expansion without blood pressure changes. NO-NIF suppressed elastin degradation and matrix metalloproteinase-2 mRNA expression. NO-NIF suppressed the reactive oxygen species-cyclophilin A positive feedback loop. Upregulated mRNA expressions of inflammation-related genes and endothelial VCAM-1 were suppressed by NO-NIF co treatment in aortae. CONCLUSION: NO-NIF has the potential to be a new, nifedipine derived therapeutic drug for suppressing aortic aneurysm formation by directly improving aortic structure with its strong ability to reduce oxidative stress and inflammation. PMID- 30253417 TI - Aging and the Epidemiology of Epilepsy. AB - BACKGROUND: Epilepsy is a chronic disorder affecting all ages but with a peak in the elderly. The association of epilepsy with age can be explained by the predominance of brain diseases with epileptogenic potential (mostly stroke and dementia) and by the effects of the aging process through a number of molecular mechanisms involving networks of neurons with focal or diffuse distribution. SUMMARY: The prevalence of active epilepsy is 6.4 per 1,000 and the lifetime prevalence is 7.6 per 1,000. The prevalence tends to increase with age, with peaks in the oldest age groups and in socially deprived individuals. The incidence of epilepsy is 61.4 per 100,000 person-years. Epilepsy has a bimodal distribution according to age with peaks in the youngest individuals and in the elderly. The increased incidence of seizures and epilepsy in the elderly can be attributed to the increase of age-related and aging-related epileptogenic conditions. Key Messages: As the world population is steadily growing with parallel increase in the number of aged subjects, in the future, epilepsy will represent a huge burden for the society. Measures must thus be taken to prevent seizures and epilepsy through the reduction of preventable epileptogenic factors. PMID- 30253418 TI - Prognostic Value of the Detection of Lymphovascular Invasion in Hormone Receptor Positive Early Breast Cancer in the Era of Molecular Profiling. AB - BACKGROUND: Lymphovascular invasion (LVI) is considered a negative prognostic factor in early breast cancer, but its role in decision-making regarding adjuvant chemotherapy is unclear in the current era of molecular profiling. This study sought to evaluate the association of LVI status with the recurrence score (RS) on the multigene Oncotype DX (ODX) assay and its impact on outcome. METHODS: Patients with early estrogen receptor-positive breast cancer who underwent ODX analysis in 2005-2012 were retrospectively identified. Clinical data were collected from the medical records. The Cox proportional-hazards ratio was used to determine recurrence rates. The prognostic significance of LVI was evaluated by competing risks analysis. RESULTS: LVI was detected in 38 of 657 patients (6%). LVI was not associated with ODX RS (p = 0.225). However, it was significantly associated with other known prognostic factors and with worse 5 year disease-free survival (HR 2.93; 95% CI 1.02-8.39; p = 0.04). Overall survival (OS) analysis according to the ODX subgroups showed that the presence of LVI was associated with worse 5-year OS (p = 0.04) only in the intermediate-risk group, while LVI had no effect on the low- or high-risk groups. CONCLUSIONS: Although LVI was not significantly associated with a higher ODX RS, it may infer a worse outcome, especially in ODX intermediate-risk patients. PMID- 30253419 TI - Liver Resection for Hepatic Metastases from Soft Tissue Sarcoma: A Nationwide Study. AB - BACKGROUND: This study aims to evaluate the feasibility and safety of resection of sarcoma liver metastases, and to identify possible prognostic factors for long term survival. METHODS: All patients who underwent resection of liver metastases of sarcoma in the Netherlands from 1998 to 2014 were included. Study data was retrospectively collected from patient files. Survival rates were calculated using Kaplan-Meier survival analysis. RESULTS: Some 38 patients treated in 16 hospitals were included (15 male, 23 female). The median age was 57 years (37-80 years). The most common histological subtype was leiomyosarcoma (63%). The predominant site of primary tumour was the abdomen (59%). R0 resection was achieved in 16 patients. Mortality was 3 and 16% of included patients had 1 or more complications. The median follow-up period was 18 months (range 1-161). After liver resection, 1-, 3-, and 5-year survival were 88, 54, and 42% respectively. Median overall survival was 46 months (1-161 months). One- and three-year progression-free survival (PFS) after liver resection were 54 and 19% respectively. Median PFS was 16 months (1-61 months). CONCLUSIONS: Liver surgery for sarcoma metastases is safe and leads to a relatively good survival. The choice for surgical treatment should always be discussed in a multidisciplinary sarcoma and liver team. PMID- 30253421 TI - [Standardized Debriefing of Coercive Measures on Psychiatric Acute Wards: A Pilot Study]. AB - OBJECTIVE: The present pilot study investigates the feasibility of a standardized debriefing measure of coercive interventions, for which a guideline has been developed. METHODS: 12 debriefing sessions were conducted and participating patients and staff members were asked about their perception of the intervention and its benefits. A quantitative and qualitative questionnaire was used and 8 expert-interviews conducted. RESULTS: Patients and staff members found the intervention helpful, especially to support a trustful therapeutic relationship. The possibility to express feelings perceived during the coercive measure was also underlined as a core effect of the intervention. On the contrary, patients and staff members didn't regard the debriefing session as helpful when looking for alternatives to the coercive measure that took place. The debriefing session should be regularly offered to patients and the moment it takes place needs to be determined individually. CONCLUSION: The developed guideline can be implemented to conduct debriefing sessions of coercive measures. PMID- 30253420 TI - Differences in Cpg Island Distribution Between Subgenotypes of the Hepatitis B Virus Genotype. AB - BACKGROUND Hepatitis B virus (HBV) genotypes show genomic variations, resulting in different CpG islands in each HBV genotypes or subgenotype. This study aimed to establish reference sequences for each HBV subgenotype of A-H genotypes and to analyze the characteristics of the CpG islands. MATERIAL AND METHODS There were 3,037 retrieved whole-genome sequences of HBV genotypes A-H from GenBank, 28 subgenotype reference sequences were established for these genotypes. CpG islands of the subgenotype reference sequences were analyzed, and 939 strains were selected from the 3,037 genomic sequences. Differences in CpG islands between subgenotypes were compared using the chi-squared and non-parametric tests. RESULTS Of the 28 subgenotype reference sequences established, 11 subgenotype reference sequences lacked CpG island I, and only F4 contained a new CpG island. Of all selected strains, 48.35% (454/939) contained three traditional CpG islands I, II, and III (no new islands); 45.05% (423/939) lacked CpG island I; 38.98% (366/939) contained only CpG islands II and III; and 12.46% (117/939) contained new islands (genotypes A1, D7) (genotype G had no new islands). Strains with or without CpG island I, or new islands between subgenotypes of each HBV genotype were significantly different (P<0.05). Strains containing CpG islands I, II, and III and new islands among different subtypes in HBV genotypes A, C, and F were significantly different (P<0.05). CONCLUSIONS Different HBV genotypes and subgenotypes had characteristic CpG island patterns. Strains with or without CpG island I, or new islands among subgenotypes of each HBV genotype, were significantly different. PMID- 30253422 TI - The Mutual Relation of Platelet Activation and Innate Immunity. AB - Platelets are known to be central regulators of haemostasis, inflammation and immune response. Formed by megakaryocytes in the bone marrow and the lungs, platelets express a broad range of adhesion receptors and release cytokines and platelet microparticles which enable them to interact with both immune cells and pathogens. In bacterial and viral infections, thrombophilia and thrombocytopenia are commonly seen symptoms, indicating the close relationship between haemostasis and immune defence. Indeed, platelets contribute both directly and via immune mediation to pathogen clearance. In sterile inflammation, a pathogen-free process which is often triggered by cell necrosis and autoimmune reactions, platelets are also of central importance. Recently, platelet inflammasome has been extensively studied in this context. Both sterile inflammation and infection are affected by the interactions of platelets and innate immunity, notably the complement system. Although the general elements of this interplay have been known for long, more and more insights into disease-specific mechanisms could be gained recently. This review gives an outline of the current findings in the field of platelet-immune cell interactions and points out possible implications for clinical therapy. PMID- 30253424 TI - ? PMID- 30253423 TI - [Rapid Progressive Glomerulonephritis in Children]. AB - Rapid Progressive Glomerulonephritis (RPGN) is a rare but very severe disease in children that often leads to acute and/or chronic renal failure requiring dialysis therapy. In this review, diagnostic criteria of RPGN including renal biopsy are discussed. An overview on general therapeutic strategies is discussed. Entities/diseases that cause RPGN are then described and special diagnostic and therapeutic features are given. PMID- 30253425 TI - Hemostasis and Thrombosis in Extreme Physiological and Pathological Conditions. PMID- 30253426 TI - "Augmentative and Alternative Communication (AAC) Will Give You a Voice": Key Practices in AAC Assessment and Intervention as Described by Persons with Amyotrophic Lateral Sclerosis. AB - The purpose of this study was to describe the perceptions of persons with amyotrophic lateral sclerosis (pALS) who use augmentative and alternative communication (AAC) with the AAC assessment and intervention process. Twenty-one pALS with complex communication needs participated in a multipart survey (and follow-up e-mails) to provide information on their experiences with AAC assessment and intervention. A majority of the participants agreed with the importance of three key AAC intervention principles: appropriate staging of the timing of assessment and intervention activities, inclusion of communication partners, and the use of multiple modalities and strategies as communication supports. Most participants reported that their assessment and intervention experiences included at least some aspect of these three key practices. The results of this study suggest that the identified best practices in AAC should be reviewed and implemented on an individualized basis for pALS with complex communication needs. PMID- 30253427 TI - Follow-Up Studies of cf-DNA Testing from 101 Consecutive Fetuses and Related Ultrasound Findings. AB - PURPOSE: To determine the true- and false-positive rates of cf-DNA testing in a cohort of patients from tertiary care centers and assess the impact of ultrasound examinations in pregnancy management. MATERIALS AND METHODS: Clinical, cytogenetic and ultrasound data of 101 consecutive fetuses were collected retrospectively. Cases were classified into five groups according to the ultrasound findings. Karyotyping, interphase FISH and microarray techniques were used for follow-up studies. RESULTS: The overall false-positive rate was low for trisomy 21 (T21, 8.2 %), but significantly higher for trisomy 18 (T18, 40 %), monosomy X (MX, 50 %), X/Y trisomies (57.1 %), trisomy 13 (T13, 71.4 %). While single cases of trisomy 16, trisomy 22 and 8q duplication positive in cf-DNA were confirmed, 3 microdeletions (1p36 and two 22q11.2) were not. About 75 % of confirmed T21's and all confirmed T18 and T13 had major markers and/or malformations. While false-negative cases (two T21, one T18 and one T13) were identified due to abnormal ultrasound findings, all false-positive cases were normal sonographically. Ultrasound findings of confirmed trisomy 16, 22, dup8q, monosomy X and other X/Y aneuploidies were unspecific. Term placenta studies were helpful to assess the role of confined mosaicism in unconfirmed cf-DNA test results. A vanishing twin has been observed as the likely cause of one false positive T18. CONCLUSION: Our study contributes clinical data on discrepant cf DNA testing results, corroborates the need for confirmational invasive testing and underscores the benefit of expert ultrasound in the prevention of fatal diagnostic errors. PMID- 30253428 TI - Transient Isolated Polyhydramnios and Perinatal Outcomes. AB - PURPOSE: To evaluate labor and perinatal outcomes of transient isolated polyhydramnios. MATERIALS AND METHODS: A retrospective cohort study (2008 - 2013) at a university-affiliated, tertiary medical center. Eligibility was limited to patients with singleton gestations, no maternal diabetes or known structural/chromosomal anomalies, and no rupture of the membranes prior to delivery, at > 34 weeks of gestation. All women underwent routine sonogram for estimation of fetal weight (sEFW) between 28 - 34 weeks of gestation, and a second routine sonogram at admission. We compared women diagnosed with polyhydramnios at the time of the sEFW which later resolved, with women who had normal AFI during the sEFW. RESULTS: Overall, 44 263 women delivered during this time period, of which 292 (0.7 %) with transient polyhydramnios (study group) and 29 682 with a normal amniotic fluid level (control group) were eligible for analysis. Women with transient polyhydramnios had a higher risk for assisted vaginal delivery (AVD), mainly due to abnormal/intermediate fetal heart rate tracings (aOR 2.3, 95 % CI 1.2 - 5.5), and a higher risk for cesarean delivery (CD), mostly because of labor dystocia (aOR 2.5, 95 % CI 1.2 - 5.1 for 1st stage arrest and aOR 3.4, 95 % CI 1.6 - 7.2) for 2nd stage arrest), suspected macrosomia (aOR 3.2, 95 % CI 1.6 - 6.6) and malpresentation (aOR 6.6, 95 % CI 2.0 - 21.1). CONCLUSION: Transient isolated polyhydramnios detected during the sonogram at 28 - 32 weeks of gestation is an independent risk factor for the need for obstetrical intervention during labor. PMID- 30253429 TI - Standards of hygiene for ultrasound-guided core cut biopsies of the breast. AB - PURPOSE: The aim was to obtain an overview of the hygiene measures undertaken during ultrasound guided core cut biopsies of the breast by experts certified by the German Society for Ultrasound in Medicine in order to derive recommendations for clinical routine, taking into account the available literature and the lack of evidence based guidelines. MATERIALS AND METHODS: A survey was conducted with all members of the levels I to III of the breast ultrasound working group of the German Society for Ultrasound in Medicine. The estimation of the risk of infection after a core cut biopsy of the breast was asked for as well as the hygiene measures undertaken in practice to avoid infection. RESULTS: The risk of infection after a core cut biopsy of the breast was estimated to be one per thousand (median value). The most commonly performed hygiene measures were a spray, wipe, spray desinfection (98.1 %) and the use of sterile gloves (54.7 %). CONCLUSION: Due to the very low risk of infection we recommend the routine use of gloves and an adequate skin disinfection. Contact of the transducer or of an unsterile contact medium with the biopsy needle is considered highly unlikely und should be avoided. PMID- 30253430 TI - Fetal Abdominal Aorta: Doppler and Structural Evaluation of Endothelial Function in Intrauterine Growth Restriction and Controls. AB - PURPOSE: The human aorta stores strain energy in the distended wall during systole through the extracellular matrix of the tunica media that could be influenced by blood pressure, flow, or increased peripheral resistance. In intrauterine growth restriction (IUGR) fetuses, the increased aorta intima media thickness (aIMT) could reflect a different extracellular matrix composition and, therefore, functionality. The aim of this study was to analyze the resistance to flow in the fetal descending aorta and its relation to aIMT and systolic and diastolic fetal abdominal aorta diameters in IUGR fetuses and controls. MATERIALS AND METHODS: This is a prospective case control study of single pregnancies collected at a tertiary center for feto-maternal medicine in Northeast Italy. An IUGR group as cases and a group of fetuses appropriate for gestational age (AGA) as controls were included. RESULTS: We found a greater PI of the fetal abdominal aorta in the IUGR group (1.82) than in the AGA group (1.21) (p < 0.05). The change between the systolic and diastolic fetal abdominal aorta diameters was significantly greater in IUGR fetuses (0.10 mm (IQR 0.07 - 0.28)) than in the AGA group (0.04 mm (0.03 - 0.05)) (p < 0.05). In the IUGR group aIMT was significantly correlated with peak systolic velocity (PSV) and systolic-diastolic aorta diameter change, while these two correlations were not found in the control group. CONCLUSION: The change between the systolic and diastolic fetal abdominal aorta diameters in IUGR cases during the early third trimester of pregnancy was significantly increased and aIMT in the IUGR group was significantly correlated to systolic-diastolic diameter change and PSV, probably reflecting aortic wall adaptation to blood flow changes in IUGR fetuses. PMID- 30253432 TI - ? PMID- 30253433 TI - ? PMID- 30253431 TI - Correlations Between Ultrasonographic Findings of Invasive Lobular Carcinoma of the Breast and Intrinsic Subtypes. AB - PURPOSE: To analyze the ultrasonographic findings of invasive lobular carcinoma (ILC) of the breast in 360 women and the correlations between the characteristics and the intrinsic subtypes. MATERIALS AND METHODS: We evaluated the imaging findings according to the lexicon of the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS). The included ultrasonographic features were shape, orientation, margin, echo pattern, posterior features, calcifications, the vascularity of the masses and the presence of architectural distortions. The associations between those features and the intrinsic ILC subtypes were investigated. RESULTS: The most common manifestations of ILC on ultrasound (US) were hypoechoic masses with irregular shape, parallel orientation, spiculated margin, posterior acoustic shadowing, no calcification and blood vessels in the rim. The patients in the luminal A subtype were the youngest, and the patients in the HER2 overexpression subtype were the oldest (p = 0.01). On US, the HER2 overexpression subtype was characterized by microlobulated margins (p = 0.002), while the luminal A subtype and the luminal B subtype mostly had spiculated margins. The basal-like subtype was distinctive in that it had no posterior features (p = 0.041), rather than acoustic shadowing, and the masses in the HER2 and basal-like subtypes were larger than in the other two groups (p = 0.03). CONCLUSION: There were significant differences and several trends in the ultrasonographic characteristics of different intrinsic subtypes, which may supply accurate imaging diagnostic criteria to assist in the management of individuals with ILC. PMID- 30253434 TI - ? PMID- 30253435 TI - ? PMID- 30253436 TI - ? PMID- 30253437 TI - ? PMID- 30253438 TI - ? PMID- 30253439 TI - ? PMID- 30253440 TI - Impact of vulvovaginal atrophy on pelvic floor muscle strength in healthy continent women. AB - OBJECTIVES: To assess the correlation between hormonal status and pelvic floor muscle strength. METHODS: A total of 140 continent women were prospectively evaluated, and divided into four groups according to age: group 1 (n = 34) aged 30-40 years; group 2 (n = 38) aged 41-50 years; group 3 (n = 35) aged 51-60; and group 4 (n = 33) aged >60 years. The following parameters were evaluated: demographic data using clinical questionnaire; hypermobility of the bladder neck using swab test; vaginal trophism by gynecological examination; hormonal status of the vagina by cytology; and pelvic floor muscle strength using a perineometer and electromyography. RESULTS: There were no statistical differences between pelvic floor muscle strength, demographic characteristics, vaginal trophism and hypermobility of the bladder neck between groups (P > 0.05). There was a larger number of women with vaginal atrophy among those aged >60 years. Vaginal trophism assessed by pelvic examination was highly consistent with the findings of colpocytology (kappa test = 0.888). Electromyography showed that women with hypermobility had lower muscle resistance (endurance) when compared with those without hypermobility. CONCLUSIONS: Although vaginal atrophy is more intense in women aged >60 years, no difference can be found in the pelvic floor muscle strength during the physiological aging process in continent women. As a consequence, trophism is not the only factor related to pelvic floor muscle strength, and it should not preclude the selection of patients who are referred to prophylaxis. PMID- 30253441 TI - 'There is such a thing as too healthy!' The impact of minimum nutritional guidelines on school food practices in secondary schools. AB - BACKGROUND: Pressure to improve school meals has resulted in stringent nutritional guidelines across the UK. In Wales, the 'Appetite for Life' guidelines of 2008 resulted in significant changes to the provision of food in Welsh schools. Although evaluation of these changes has focussed on nutritional quality, there is little evidence of how pupils perceive these changes and their impact on school food practices. Using a Collective Lifestyles approach, the present study reports how secondary school pupils perceive and negotiate menu changes and the implications for lunchtime practices. METHODS: Seven focus groups (52 pupils) were undertaken in four secondary schools within one local authority in Wales. Participatory techniques were used to facilitate discussion, and the focus groups were recorded, transcribed and analysed using a framework approach. Analysis was underpinned by a Collective Lifestyles approach, which provides a framework to understand behaviour in context using three domains: (i) patterns of consumption; (ii) the construction and maintenance of identity; and (iii) power relationships. RESULTS: Pupils reported that the new menus were unpopular in terms of content and meal type; the preference was for portable and snack style foods. In terms of power relationships, pupils' ability to negotiate within the school setting was constrained by the institutional nature of school dining. As a result, pupils tended to opt out of school food provision, accessing alternatives where possible. CONCLUSIONS: The development of the healthy eating agenda within the school setting needs to consider the complexities of adolescent consumption preferences, identities and social networks if they are to be successful. PMID- 30253442 TI - Surgical treatment of early stage breast cancer in the Auckland and Waikato regions of New Zealand. AB - BACKGROUND: The aim of this study was to understand the factors influencing the use of surgical options by New Zealand women with newly diagnosed breast cancer. METHODS: Using data from the Auckland and Waikato breast cancer registers, we included 11 798 women diagnosed with stage I-III breast cancer from June 2000 to May 2013. The characteristics of women receiving different surgical treatments and having immediate breast reconstruction following mastectomy were examined. A logistic regression was used to estimate the odds ratio of having breast conserving surgery (BCS) versus mastectomy and immediate post-mastectomy reconstruction. Bilateral breast cancer cases and women with unilateral breast cancer, but who had bilateral surgery, were also identified. RESULTS: Fifty-two percent of women received BCS and 44% had mastectomy over the study period. Key influences associated with BCS were age, mode of diagnosis, socio-economic status and public or private treatment. Just under half of the women who underwent bilateral surgery did not have bilateral cancer. Nineteen percent of women undergoing mastectomy underwent immediate reconstruction. Implant use increased slightly over the study period but there was a decrease in the use of autologous flap procedures. CONCLUSION: Surgical management of women with localized breast cancer was generally in line with guidelines, but with potential to further increase the use of breast conservation and immediate reconstruction in suitable cases. PMID- 30253443 TI - Visual rehabilitation using microperimetric acoustic biofeedback training in individuals with central scotoma. AB - BACKGROUND: Patients with central scotoma have poor fixation stability and poor visual acuity. Acoustic biofeedback training can be an effective way to train such patients to eccentrically fixate. This study analyses the mean retinal sensitivity, saccadic velocity, and fixation stability after acoustic biofeedback training and shows correlation with age and scotoma size. METHODS: Patients with irreversible central scotoma in both the eyes secondary to macular diseases were selected. After undergoing comprehensive low vision assessment, 19 patients who were willing were recruited for the acoustic biofeedback training to the better eye in 10 sessions, using the MP-1 Microperimeter. Mean retinal sensitivity, saccadic velocity, fixation stability before and after the acoustic biofeedback were recorded. RESULTS: There were 17 men and two women. Ages ranged from 19-94 years (mean 54.63 +/- 24.66). The scotoma size ranged from four to 20 degrees. Ten patients had age-related macular degeneration, four had Stargardt disease, three had traumatic macular scar, two had scarred myopic choroidal neovascular membrane, and one had myopic macular degeneration. The vision improved from 1.06 +/- 0.36 to 0.86 +/- 0.33 logMAR (p < 0.0001). The mean retinal sensitivity improved from 2.1 +/- 2.9 dB to 2.7 +/- 3.1 dB (p = 0.01), with negative correlation with age (p = 0.01) and scotoma size (p = 0.02). Fixation stability improved with reduction in the bivariate contour ellipse area (p = 0.01). It showed negative correlation with age (p = 0.02) and scotoma size (p = 0.10). The saccadic velocity reduced from 0.34 degrees /second to 0.26 degrees /second but was not significant (p > 0.99). The majority (58 per cent) had their preferred retinal locus superior to the fovea. There was good agreement between bivariate contour ellipse area and MP-1 Microperimeter inbuilt fixation parameters. The effect was maintained at six months with slight reduction in fixation stability. CONCLUSION: Acoustic biofeedback can improve fixation behaviour, visual acuity and retinal sensitivity in patients with central scotoma. The results are better with younger age and smaller scotoma size. PMID- 30253444 TI - State of emergency medicine in Indonesia. AB - OBJECTIVES: As an emerging country with the fourth largest population in the world, Indonesia's purchasing power has strengthened, leading to socioeconomic changes that affect its healthcare system. Additionally, there is a surge of healthcare utilisation after the implementation of a new national insurance scheme, particularly within emergency departments. Similar to other low- to middle-income countries, Indonesia has not prioritised the progress of emergency medicine despite existing evidence that suggests that the early intervention of many acute conditions lowers the rates of morbidity and mortality. This article will review the past and current state of emergency medicine in Indonesia. METHODS: The information gathered through PubMed, Ovid, and private and government institution databases, using the search term 'Indonesia', 'Emergency Medicine', 'Emergency Medical Services', and 'Disaster Medicine'. Additionally, we interviewed physicians who are involved in the development of emergency medicine in Indonesia. RESULTS: Indonesia's emergency medicine can be broken down into three sections: pre-hospital, hospital and the development of emergency medicine as a specialty. At the pre-hospital setting, disaster medicine and emergency medical service have not been established well enough to meet the demands of the population. For hospitals, there are two types of emergency departments - academic versus non-academic. Currently, there is no accredited emergency medicine residency programme despite the recognition of the specialty. CONCLUSION: The development of emergency medicine in Indonesia is in its infancy and will require rapid improvement to meet its country's demand. Academic, private and government sectors need to collaborate to promote and invest in emergency medicine. PMID- 30253447 TI - Coupled agent-based and hyperelastic modelling of the left ventricle post myocardial infarction. AB - Understanding the healing and remodelling processes induced by myocardial infarction (MI) of the heart is important, and the mechanical properties of the myocardium post-MI can be indicative for effective treatments aimed at avoiding eventual heart failure. MI remodelling is a multiscale feedback process between the mechanical loading and cellular adaptation. In this paper, we use an agent based model to describe collagen remodelling by fibroblasts regulated by chemical and mechanical cues after acute MI, and upscale into a finite element 3D left ventricular model. We model the dispersed collagen fibre structure using the angular integration method and have incorporated a collagen fibre tension compression switch in the left ventricle (LV) model. This enables us to study the scar healing (collagen deposition, degradation, and reorientation) of a rat heart post-MI. Our results, in terms of collagen accumulation and alignment, compare well with published experimental data. In addition, we show that different shapes of the MI region can affect the collagen remodelling, and in particular, the mechanical cue plays an important role in the healing process. PMID- 30253445 TI - Occurrence and characterization of carbapenem-resistant Gram-negative bacilli: A collaborative study of antibiotic-resistant bacteria between Indonesia and Japan. AB - OBJECTIVES: To explore the occurrence and characterization of carbapenemase producing pathogens among carbapenem-resistant Gram-negative bacilli isolated from hospitalized patients with urinary tract infection in Indonesia. METHODS: This was a study promoted by the Japanese-Indonesian collaborative research program in the Japan Initiative for Global Research Network on Infectious Diseases. Bacterial pathogens were prospectively isolated from urine specimens of hospitalized urinary tract infection patients at Dr. Soetomo Hospital (Surabaya, Indonesia). All Gram-negative bacteria resistant to third-generation cephalosporin or carbapenem were included in this study. Carbapenemase genes were investigated for phenotype and genotype. RESULTS: In total, 1082 Gram-negative bacilli were isolated, of which 116 strains were resistant to imipenem or meropenem (carbapenem-resistant Gram-negative bacilli), and 22 strains were carbapenemase-producing Gram-negative bacilli. Carbapenemase-producing Gram negative bacilli consisted of Acinetobacter baumannii (n = 4), Pseudomonas aeruginosa (n = 4), Klebsiella pneumoniae (n = 5), Providencia rettgeri (n = 4) and five others. The carbapenemase-producing Gram-negative bacilli included NDM-1 (n = 18, 81.8%, in Enterobacteriaceae and Acinetobacter spp.) and IMP-7 (n = 4, 18.2%, all in P. aeruginosa). Among carbapenem-resistant Gram-negative bacilli, all four P. aeruginosa were sensitive to colistin, and all six Acinetobacter spp. were sensitive to minocycline, colistin and tigecycline. Of those patients harboring carbapenemase-producing Gram-negative bacilli, 12 (54.5%) were seriously ill at the time of admission, with longer hospital stays and three deaths (13.6% mortality rate). CONCLUSIONS: Urinary tract infection-causing carbapenem-resistant Gram-negative bacilli are widely disseminated in Indonesia. The NDM-1 phenotype seems to be dominant, and it can be treated with colistin and tigecycline in most cases. Most patients harboring carbapenemase-producing Gram negative bacilli are seriously ill, have a bad prognosis, with a longer hospital stay and a significant mortality rate. PMID- 30253446 TI - Impact of prior local therapy on overall survival in men with metastatic castration-resistant prostate cancer: Results from Shared Equal Access Regional Cancer Hospital. AB - OBJECTIVES: To evaluate the impact of previous local treatment on survival in men with newly diagnosed metastatic castration-resistant prostate cancer. METHODS: We carried out a retrospective study of patients newly diagnosed with metastatic castration-resistant prostate cancer in the year 2000 or later from eight Veterans Affairs Medical Centers. Patients were categorized based on prior local therapy (none, prostatectomy +/- radiation or radiation alone). Overall and cancer-specific survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression models were used to test the association between prior local treatment and survival. RESULTS: Of 729 patients, 284 (39%) underwent no local treatment, 176 (24%) underwent radical prostatectomy +/- radiation and 269 (37%) underwent radiation alone. On multivariable analysis, men with prior prostatectomy had improved overall (hazard ratio 0.71, P = 0.005) and cancer specific survival (hazard ratio 0.55, P < 0.001) compared with men with no prior local therapy. This improvement in overall (hazard ratio 0.89, P = 0.219) and cancer-specific survival (hazard ratio 0.87, P = 0.170) was not seen in men with prior radiation alone. After further adjusting for comorbidity with the Charlson Comorbidity Index, patients with prior prostatectomy still had improved overall survival (hazard ratio 0.70, P = 0.003), whereas this was not seen in patients who received prior radiation alone (hazard ratio 0.88, P = 0.185). CONCLUSIONS: Independent of patient- and disease-related factors, men with metastatic castration-resistant prostate cancer who had undergone prior radical prostatectomy have improved overall and cancer-specific survival compared with those with no prior local therapy. PMID- 30253448 TI - Role of systemic inflammatory response markers in urological malignancy. AB - The systemic inflammatory response is associated with survival in patients with a variety of cancers. This inflammatory response is measured in the peripheral blood, and can be monitored using two categories of indices: concentration of specific serum proteins (albumin, C-reactive protein) and differential blood cell count (neutrophils, lymphocytes and platelets). Furthermore, combinations of these indices, such as the Glasgow Prognostic Score, which consists of the serum C-reactive protein and albumin level; the neutrophil-to-lymphocyte ratio; the platelet-to-lymphocyte ratio; and the prognostic nutritional index, which is based on peripheral blood lymphocyte count and serum albumin level, have also been evaluated and compared in cancer research. To date, there are hundreds of studies that have shown the prognostic value of systemic inflammatory response markers in patients with urological cancer. Most studies have evaluated the prognostic and predictive role of the pretreatment value of the markers, although some have focused on the role of the post-treatment value at specific points during the clinical course. The advantages of systemic inflammatory response markers are that they are easily measurable and inexpensive in the clinical setting. However, it is important to consider how clinicians use these markers in clinical practice. The present review provides a concise overview regarding systemic inflammatory markers in urological cancers, specifically C-reactive protein, Glasgow Prognostic Score/modified Glasgow Prognostic Score, neutrophil to-lymphocyte ratio, platelet-to-lymphocyte ratio and prognostic nutritional index. PMID- 30253451 TI - Editorial Comment to Superiority of dutasteride 0.5 mg and tamsulosin 0.2 mg for the treatment of moderate-to-severe benign prostatic hyperplasia in Asian men. PMID- 30253449 TI - Acute kidney injury and intermediate-term renal function after clampless partial nephrectomy. AB - OBJECTIVES: To evaluate the incidence and predictors of acute kidney injury after clampless partial nephrectomy, and its impact on intermediate-term renal function. METHODS: The incidence and severity of acute kidney injury were assessed for 262 patients undergoing clampless partial nephrectomy between 2010 and 2015. The association between perioperative covariates and acute kidney injury was evaluated using multivariate logistic regression analysis. An annual change in estimated glomerular filtration rate from 1 year after surgery was calculated according to the presence or absence of acute kidney injury. An impact of acute kidney injury on postoperative renal impairment, defined as a >=25% estimated glomerular filtration rate decrease, was evaluated. RESULTS: Overall, 21 (8.0%) patients experienced grade 1 acute kidney injury after clampless partial nephrectomy, and grade >=2 acute kidney injury was not observed. High tumor complexity was the only independent predictor of acute kidney injury. Estimated glomerular filtration rate in patients with acute kidney injury improved within 1 year, and annual estimated glomerular filtration rate changes were similar among patients with or without acute kidney injury. Ultimately, 13 (5.0%) patients showed postoperative renal impairment during the median follow-up period of 37 months. Advanced age and diabetes mellitus were independent risk factors for renal impairment, but acute kidney injury was not. CONCLUSIONS: The incidence and severity of acute kidney injury after clampless partial nephrectomy are low. Low-grade acute kidney injury after clampless partial nephrectomy does not seem to affect intermediate-term renal function. PMID- 30253452 TI - Point-of-care viscoelastic assay devices (rotational thromboelastometry and thromboelastography): a primer for surgeons. AB - BACKGROUND: Bleeding is a common occurrence in surgery. Point-of-care testing with viscoelastic (VE) assays such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) has become more common place. TEG and ROTEM have the potential to guide management of coagulopathy. Many healthcare professionals still rely upon standard laboratory tests (SLTs) to manage a bleeding patient. It was our aim to investigate the literature surrounding management of the surgically bleeding patient via VE assays. METHODS: Literature review of Embase, MEDLINE, PubMed and the Cochrane Library using 'TEG, ROTEM and surgery' search terms was conducted. RESULTS: Through the literature search and reference lists reviewed by both authors, a total of 62 articles have been evaluated, 35 of these have been included in this review. CONCLUSION: VE assays are used most commonly during orthotopic liver transplantation, trauma, postpartum haemorrhage and cardiac surgery. Although the evidence is not overwhelming, we have identified recurrent themes where VE assays seem to be beneficial. VE assay use, especially when incorporated into an algorithm, appears to reduce blood product administration which in turn reduces cost and potential adverse events. They are quicker than SLTs and they can detect hyperfibrinolysis, the hallmark of coagulopathy, via in vivo clot analyses which SLTs are unable to do. Ultimately more randomized controlled trials are required. PMID- 30253450 TI - The value of ankle-branchial index screening for cardiovascular disease in type 2 diabetes. AB - OBJECTIVE: To investigate the relationship between ankle-branchial index (ABI) and cardiovascular disease in type 2 diabetes patients. METHODS: A total of 634 inpatients with type 2 diabetes were recruited in this cross-sectional study. All patients were measured with ABI and computed tomography angiography (CTA) scan for coronary artery disease (CAD). According to ABI values, patients were divided into three groups: low-ABI group (ABI < 0.9, n = 259), normal-ABI group (ABI = 0.9-1.3, n = 272), and high-ABI group (ABI > 1.3, n = 103). According to the manifestation of coronary CTA, the patients were divided into CAD group (n = 348) and non-CAD group (n = 286). Their clinical data and biochemical parameters were compared and analysed. RESULTS: The prevalence of CAD in low-ABI group (90%) was significantly higher than that of normal-ABI group (33%) and high-ABI group (25%) (both P < 0.01). Spearman correlation analysis showed that age, sex, duration, spontaneous bacterial peritonitis, total cholesterol (TC), triglyceride, low density lipoprotein cholesterol (LDL-C), serum creatinine, and glycosylated haemoglobin (HbA1c ) were positively correlated with CAD, and high-density lipoprotein cholesterol (HDL-C), glomerular filtration rate, and ABI were negatively correlated with CAD. Logistic regression analysis further revealed that age, sex, duration, TC, HDL-C, LDL-C, HbA1c , and ABI were independent risk factors of CAD. After all potential confounders is adjusted, the risk of CAD in low-ABI group still increased over four times than the normal-ABI group (odds ratio [OR], 5.32; 95% CI, 1.973-16.5; P < 0.001). In female patients, this risk increased more than nine times (OR, 10.63; 95% CI, 3.416-17.8; P < 0.001). Receiver-operating characteristic analysis indicated that ABI < 1.045 predicted the occurrence of CAD (sensitivity, 79.7%; specificity, 71.5%; P < 0.01). CONCLUSIONS: ABI is an independent risk factor for CAD and may be a potential simple screening instrument for CAD in Chinese type 2 diabetic patients, especially in elder women. PMID- 30253453 TI - Statistical Approach to Identify Threshold and Point of Departure in Dose Response Data. AB - The study presents an integrated, rigorous statistical approach to define the likelihood of a threshold and point of departure (POD) based on dose-response data using nested family of bent-hyperbola models. The family includes four models: the full bent-hyperbola model, which allows for transition between two linear regiments with various levels of smoothness; a bent-hyperbola model reduced to a spline model, where the transition is fixed to a knot; a bent hyperbola model with a restricted negative asymptote slope of zero, named hockey stick with arc (HS-Arc); and spline model reduced further to a hockey-stick type model (HS), where the first linear segment has a slope of zero. A likelihood ratio test is used to discriminate between the models and determine if the more flexible versions of the model provide better or significantly better fit than a hockey-stick type model. The full bent-hyperbola model can accommodate both threshold and nonthreshold behavior, can take on concave up and concave down shapes with various levels of curvature, can approximate the biochemically relevant Michaelis-Menten model, and even be reduced to a straight line. Therefore, with the use of this model, the presence or absence of a threshold may even become irrelevant and the best fit of the full bent-hyperbola model be used to characterize the dose-response behavior and risk levels, with no need for mode of action (MOA) information. Point of departure (POD), characterized by exposure level at which some predetermined response is reached, can be defined using the full model or one of the better fitting reduced models. PMID- 30253454 TI - Peculiar clinical features of cellulitis in peripheral lymphedema. AB - Although the occurrence of cellulitis in lymphedema (LE) is believed to be an infection-related event, many findings in its clinical course seem to suggest that it is unlikely to be an infection. Therefore, we tried to clarify the specific features of cellulitis in LE. In-hospital courses of cellulitis obtained from medical charts were reviewed in the patients with leg LE (LE; 24 patients, 72admissions), chronic venous insufficiency (CVI; 28 patients, 29 admissions), and leg cellulitis secondary to wound infection without underlying disease (N; 42 patients, 42 admissions). The patients with LE complained of less local pain (peak numerical scale; LE: 1.4 +/- 1.7, CVI: 4.1 +/- 2.5, N: 3.2 +/-2.0, p < 0.0001), showed an abnormally higher peak procalcitonin level (LE: 33.8 +/- 34.8 (N = 7), CVI: 2.9 +/- 5.8 (N = 8), N: 0.4 +/- 0.6(N = 10), p < 0.05), and required fewer antibiotics (LE: 1.1 +/- 0.3, CVI: 1.8 +/- 0.9, N: 1.5 +/- 0.9, p < 0.0001). These findings suggested that the occurrence of cellulitis in LE seems unlikely to be an infection-related type of cellulitis similar to that found in CVI. PMID- 30253455 TI - Cellulitis and bacteria in peripheral lymphedema. AB - Counterpoint to the article: Peculiar Clinical Features of Cellulitis in Peripheral Lymphedema, K. Suehiro, et al. Lymphology Vol 51, No 2, pp 47-53. PMID- 30253456 TI - Decreasing and preventing lymphatic-injury-related complications in patients undergoing venous surgery: A new diagnostic and therapeutic protocol. AB - Lymphatic complications following great and small saphenous vein surgery show a varying and non-negligible incidence in the literature. We undertook this study to investigate a new protocol to reduce lymphatic injuries in patients undergoing venous surgery. Eighty-six patients with lower limb venous insufficiency and varices were treated. Lymphoscintigraphy was performed preoperatively in 65 of them and postoperatively in 19. Blue dye was used in all patients and blue lymph nodes and lymphatics were identified intra-operatively and preserved or used to perform multiple lymphatic-venous anastomoses (MLVA). Patients were followed up fora period varying from 3 months to 6 years. Sixty-six patients were treated by greater saphenectomy and varicectomy, 12 patients had crossectomy and varicectomy, 4 patients underwent greater saphenectomy and varicectomy associated with MLVA, and 4 patients were treated by small saphenous vein stripping and varicectomy. No lymphatic complications occurred in any of the patients. A decrease of over 75% of excess volume was observed in 4 patients treated by MLVA. Lymphoscintigraphy showed normalization in the Transport Index in 4 patients treated with MLVA. Our results demonstrate that accurate diagnostic investigation and proper surgical technique is of paramount importance in the effort to avoid lymphatic complications during venous surgery. PMID- 30253457 TI - Proprioception sense in lymphedema affected upper limb. AB - This study aimed to provide information on proprioception alterations in lymphedema-affected limbs. Blindfolded subjects sat at a table with their forearms positioned on paddles. The hinges of the paddles were aligned with the elbow joint and an electronic goniometer was positioned to measure the angle of the forearm. Paddles were moved by an electric servomotor with a slow angular speed that was barely appreciated by the subjects. Subjects were then asked to guess the position of the affected arm in comparison with the unaffected arm to study the position sense of the lymphedema-affected arm. The study investigated 50 women affected by secondary upper limb lymphedema by measuring the difference in terms of degrees of arch of movement in comparison with the unaffected arm and also both duration of lymphedema and the circumference of the forearm. Results were matched with a control group of 50 unaffected women providing proof of compromised proprioception in lymphedema-affected arms. In addition, results also showed a correlation with duration of lymphedema but not with size (stage) of the lymphedematous arm. PMID- 30253458 TI - Exploring the mesenteric lymphatic apparatus: A morphological and immunohistochemical investigation with clinical correlations. AB - Modern immunohistochemical techniques allow a detailed study of the lymphatic system in many organs and areas of the body. We performed an in-depth study on lymphatic vessels of the ileal and colonic mesenteries, together with the greater omentum where they appear particularly numerous and mainly represented by capillaries interconnected among themselves and with lymph nodes. The capillary wall consists of a fine single sheath of endothelial cells wrapped around by a subtle collagen membrane and deprived of valves. The progression of lymph flow is promoted by external forces acting on the capillary walls. Only at the mesenteric roots can pre- and post-lymph nodal collector vessels be observed. Our observations help to explain different patho-physiological correlations and the possible presence of skip lymph node metastases. PMID- 30253459 TI - Lymphatic tract reconstruction using a pedicled deep inferior epigastric perforator flap. AB - We encountered a case in which we used a pedicled deep inferior epigastric perforator(DIEP) flap to repair a lymphatic leak. This case shows that such repairs can lead to the reconstruction of the lymphatic tract and prevent lymphatic leak recurrences. The present report describes a 45-year-old woman with ovarian cancer who underwent hysterectomy, bilateral salpingo-oophorectomy, pelvic lymphadenectomy, para-aortic lymphadenectomy, and omentectomy. She presented with a pelvic lymphocele with lower-extremity swelling. Lymphovenous anastomosis was performed and swelling of the lower extremity abated. However, because of the occurrence of deep vein thrombosis and the recurrence of swelling, we used a 6-cm-long and 14-cm-wideDIEP flap after lymphocele fenestration. The flap was de-epithelialized and fixed into the peritoneum, with the cutis side facing the leakage point. The postoperative course was uneventful, and no recurrence was observed. We obtained good results by providing abundant blood flow to abundant lymph tissue at the fenestration point. It is known that lymphatic vessels can spontaneously connect with each other. We hypothesize that the DIEP flap improved the edema in this case by regenerating the lymphatic network and improving flow into the bridging flap. PMID- 30253460 TI - From childhood onset lymphedema to fatal fetal hydrops: Possible modifying genes for a FOXC2 mutation. AB - We performed whole exome sequencing in a family with FOXC2 mutation where the phenotype in one generation was strikingly more severe. Although there were 3 mutations shared by 2 fatal fetal hydrops cases and not the mildly affected mother, none of them were likely to be the cause of the marked phenotypic change. PMID- 30253461 TI - Successful multi-modal treatment of grade IV lymphedema in lymphatic filariasis: A case study. AB - We present an integrated therapeutic approach performed on a 37 year old female with giant lymphedema (Grade IV) due to lymphatic filariasis of 27 years duration. Our therapeutic approaches consisted of a basic foot care program for two weeks, followed by a course of oral penicillin for a week including conservative treatment with complete decongestive therapy (CDT) together with respiratory physiotherapy and walking exercises. In addition, advanced surgical techniques with supra-fascial excision of alternate lumps in three stages over an interval of ten days followed by a nodo-venal shunt resulted in reversing the stage IV lymphedema condition. Over a ten year follow-up, the patient remains essentially unchanged confirming the success of the treatment without any recurrence or complications. Finally, by combining multimodal treatment, we were able to achieve a near normal limb in Stage III and Stage IV lymphedema of the lower limb in lymphatic filariasis. PMID- 30253462 TI - Percolation thresholds and Fisher exponents in hypercubic lattices. AB - We use invasion percolation to compute highly accurate numerical values for bond and site percolation thresholds p_{c} on the hypercubic lattice Z^{d} for d=4,...,13. We also compute the Fisher exponent tau governing the cluster size distribution at criticality. Our results support the claim that the mean-field value tau=5/2 holds for d>=6, with logarithmic corrections to power-law scaling at d=6. PMID- 30253463 TI - Active phase separation: A universal approach. AB - We identify active phase separation as a generic demixing phenomenon in nonequilibrium systems with conservation constraints. Examples range from cell polarization to cell populations communicating via chemotaxis, and from self propelled particle communities to mussels in ecology. We show that system spanning properties of active phase separation in nonequilibrium systems near onset are described by the classical Cahn-Hilliard (CH) model. This result is rather surprising since the CH equation is famous as a model for phase separation at thermal equilibrium. We introduce a general reduction scheme to establish a unique mathematical link between the generic CH equation and system-specific models for active phase separation. This approach is exemplarily applied to a model for polarization of cells and a model for chemotactic cell communities. For cell polarization, we also estimate the validity range of the CH model. PMID- 30253464 TI - Fluidization of epithelial sheets by active cell rearrangements. AB - We theoretically explore fluidization of epithelial tissues by active T1 neighbor exchanges. We show that the geometry of cell-cell junctions encodes important information about the local features of the energy landscape, which we support by an elastic theory of T1 transformations. Using a 3D vertex model, we show that the degree of active noise driving forced cell rearrangements governs the stress relaxation timescale of the tissue. We study tissue response to in-plane shear at different timescales. At short time, the tissue behaves as a solid, whereas its long-time fluid behavior can be associated with an effective viscosity which scales with the rate of active T1 transformations. Furthermore, we develop a coarse-grained theory, where we treat the tissue as an active fluid and confirm the results of the vertex model. The impact of cell rearrangements on tissue shape is illustrated by studying axial compression of an epithelial tube. PMID- 30253465 TI - Plastic flow and localization in an amorphous material: Experimental interpretation of the fluidity. AB - We present a thorough study of the plastic response of a granular material progressively loaded. We study experimentally the evolution of the plastic field from a homogeneous one to a heterogeneous one and its fluctuations in terms of incremental strain. We show that the plastic field can be decomposed in two components evolving on two decoupled strain increment scales. We argue that the slowly varying part of the field can be identified with the so-called fluidity field introduced recently to interpret the rheological behavior of amorphous materials. This fluidity field progressively concentrates along a macroscopic direction corresponding to the Mohr-Coulomb angle. PMID- 30253466 TI - Time-dependent fracture under unloading in a fiber bundle model. AB - We investigate the fracture of heterogeneous materials occurring under unloading from an initial load. Based on a fiber bundle model of time-dependent fracture, we show that depending on the unloading rate the system has two phases: for rapid unloading the system suffers only partial failure and it has an infinite lifetime, while at slow unloading macroscopic failure occurs in a finite time. The transition between the two phases proved to be analogous to continuous phase transitions. Computer simulations revealed that during unloading the fracture proceeds in bursts of local breakings triggered by slowly accumulating damage. In both phases the time evolution starts with a relaxation of the bursting activity characterized by a universal power-law decay of the burst rate. In the phase of finite lifetime the initial slowdown is followed by an acceleration towards macroscopic failure where the increasing rate of bursts obeys the (inverse) Omori law of earthquakes. We pointed out a strong correlation between the time where the event rate reaches a minimum value and of the lifetime of the system which allows for forecasting of the imminent catastrophic failure. PMID- 30253467 TI - Construction of quasipotentials for stochastic dynamical systems: An optimization approach. AB - The construction of effective and informative landscapes for stochastic dynamical systems has proven a long-standing and complex problem. In many situations, the dynamics may be described by a Langevin equation while constructing a landscape comes down to obtaining the quasipotential, a scalar function that quantifies the likelihood of reaching each point in the state space. In this work we provide a novel method for constructing such landscapes by extending a tool from control theory: the sum-of-squares method for generating Lyapunov functions. Applicable to any system described by polynomials, this method provides an analytical polynomial expression for the potential landscape, in which the coefficients of the polynomial are obtained via a convex optimization problem. The resulting landscapes are based on a decomposition of the deterministic dynamics of the original system, formed in terms of the gradient of the potential and a remaining "curl" component. By satisfying the condition that the inner product of the gradient of the potential and the remaining dynamics is everywhere negative, our derived landscapes provide both upper and lower bounds on the true quasipotential; these bounds becoming tight if the decomposition is orthogonal. The method is demonstrated to correctly compute the quasipotential for high dimensional linear systems and also for a number of nonlinear examples. PMID- 30253468 TI - Shape and fluctuations of positively curved ribbons. AB - We study the shape and shape fluctuations of incompatible, positively curved ribbons, with a flat reference metric and a spherelike reference curvature. Such incompatible geometry is likely to occur in many self-assembled materials and other experimental systems. Ribbons of this geometry exhibit a sharp transition between a rigid ring and an anomalously soft spring as a function of their width. As a result, the temperature dependence of these ribbons' shape is unique, exhibiting a nonmonotonic dependence of the persistence and Kuhn lengths on the temperature and width. We map the possible configuration phase space and show the existence of three phases: At high temperatures it is the ideal chain phase, where the ribbon is well described by classical models (e.g., wormlike chain model). The second phase, for cold and narrow ribbons, is the plane ergodic phase; a ribbon in this phase might be thought of as made out of segments that gyrate within an oblate spheroid with extreme aspect ratio. The third phase, for cold, wide ribbons, is a direct result of the residual stress caused by the incompatibility, called the random structured phase. A ribbon in this phase behaves on large scales as an ideal chain. However, the segments of this chain are not straight; rather they may have different shapes, mainly helices (both left and right handed) of various pitches. PMID- 30253469 TI - Reducing the variance in the translocation times by prestretching the polymer. AB - Langevin dynamics simulations of polymer translocation are performed where the polymer is stretched via two opposing forces applied on the first and last monomer before and during translocation. In this setup, polymer translocation is achieved by imposing a bias between the two pulling forces such that there is net displacement towards the trans side. Under the influence of stretching forces, the elongated polymer ensemble contains less variations in conformations compared to an unstretched ensemble. Simulations demonstrate that this reduced spread in initial conformations yields a reduced variation in translocation times relative to the mean translocation time. This effect is explored for different ratios of the amplitude of thermal fluctuations to driving forces to control for the relative influence of the thermal path sampled by the polymer. Since the variance in translocation times is due to contributions coming from sampling both thermal noise and initial conformations, our simulations offer independent control over the two main sources of noise and allow us to shed light on how they both contribute to translocation dynamics. Simulation parameter space corresponding to experimentally relevant conditions is highlighted and shown to correspond to a significant decrease in the spread of translocation times, thus indicating that stretching DNA prior to translocation could assist nanopore-based sequencing and sizing applications. PMID- 30253470 TI - Laning and clustering transitions in driven binary active matter systems. AB - It is well known that a binary system of nonactive disks that experience driving in opposite directions exhibits jammed, phase separated, disordered, and laning states. In active matter systems, such as a crowd of pedestrians, driving in opposite directions is common and relevant, especially in conditions which are characterized by high pedestrian density and emergency. In such cases, the transition from laning to disordered states may be associated with the onset of a panic state. We simulate a laning system containing active disks that obey run and-tumble dynamics, and we measure the drift mobility and structure as a function of run length, disk density, and drift force. The activity of each disk can be quantified based on the correlation timescale of the velocity vector. We find that in some cases, increasing the activity can increase the system mobility by breaking up jammed configurations; however, an activity level that is too high can reduce the mobility by increasing the probability of disk-disk collisions. In the laning state, the increase of activity induces a sharp transition to a disordered strongly fluctuating state with reduced mobility. We identify a novel drive-induced clustered laning state that remains stable even at densities below the activity-induced clustering transition of the undriven system. We map out the dynamic phase diagrams highlighting transitions between the different phases as a function of activity, drive, and density. PMID- 30253471 TI - Effects of collectively induced scattering of gas stream by impurity ensembles: Shock-wave enhancement and disorder-stimulated nonlinear screening. AB - We report on specific effects of collective scattering for a cloud of heavy impurities exposed to a gas stream. Formation is presented of a common density perturbation and shock waves, both generated collectively by a system of scatterers at sudden application of the stream-inducing external field. Our results demonstrate that (i) the scattering of gas stream can be essentially amplified, due to nonlinear collective effects, upon fragmentation of a solid obstacle into a cluster of impurities (heterogeneously fractured obstacle); (ii) a cluster of disordered impurities can produce considerably stronger scattering accompanied by enhanced and accelerated shock wave, as compared to a regularly ordered cluster. We also show that the final steady-state density distribution is formed as a residual perturbation left after the shock front passage. In particular, a kinklike steady distribution profile can be formed as a result of shock front stopping effect. The possibility of the onset of solitary diffusive density waves, reminiscent of precursor solitons, is shown and briefly discussed. PMID- 30253472 TI - Ion partitioning effect on the electrophoresis of a soft particle with hydrophobic core. AB - A theoretical study on the electrophoresis of a soft particle made up of a charged hydrophobic inner core surrounded by polyelectrolyte layer (PEL) is made. The dielectric permittivity of the PEL and aqueous solution are considered to be different, which creates the ion partitioning effect. The ion partitioning effect, which is accounted by the Born energy difference, modifies the distribution of mobile ions in the PEL and hence alters the particle electrophoresis. The combined effects of core hydrophobicity and the ion partitioning effect on the mobility are determined based on the Debye-Huckel approximation under a thin Debye layer assumption. An analytic expression for the electrophoretic mobility taking into account the core hydrophobicity and ion partitioning effect is obtained. The occurrence of zero mobility and reversal of mobility of the soft particle is illustrated. PMID- 30253473 TI - Nonlinear spectral analysis of Peregrine solitons observed in optics and in hydrodynamic experiments. AB - The data recorded in optical fiber and in hydrodynamic experiments reported the pioneering observation of nonlinear waves with spatiotemporal localization similar to the Peregrine soliton are examined by using nonlinear spectral analysis. Our approach is based on the integrable nature of the one-dimensional focusing nonlinear Schrodinger equation (1D-NLSE) that governs at leading order the propagation of the optical and hydrodynamic waves in the two experiments. Nonlinear spectral analysis provides certain spectral portraits of the analyzed structures that are composed of bands lying in the complex plane. The spectral portraits can be interpreted within the framework of the so-called finite gap theory (or periodic inverse scattering transform). In particular, the number N of bands composing the nonlinear spectrum determines the genus g=N-1 of the solution that can be viewed as a measure of complexity of the space-time evolution of the considered solution. Within this setting the ideal, rational Peregrine soliton represents a special, degenerate genus 2 solution. While the fitting procedures previously employed show that the experimentally observed structures are quite well approximated by the Peregrine solitons, nonlinear spectral analysis of the breathers observed both in the optical fiber and in the water tank experiments reveals that they exhibit spectral portraits associated with more general, genus 4 finite-gap NLSE solutions. Moreover, the nonlinear spectral analysis shows that the nonlinear spectrum of the breathers observed in the experiments slowly changes with the propagation distance, thus confirming the influence of unavoidable perturbative higher-order effects or dissipation in the experiments. PMID- 30253474 TI - Replica symmetry breaking in bipartite spin glasses and neural networks. AB - Some interesting recent advances in the theoretical understanding of neural networks have been informed by results from the physics of disordered many-body systems. Motivated by these findings, this work uses the replica technique to study the mathematically tractable bipartite Sherrington-Kirkpatrick (SK) spin glass model, which is formally similar to a restricted Boltzmann machine (RBM) neural network. The bipartite SK model has been previously studied assuming replica symmetry; here this assumption is relaxed and a replica symmetry breaking analysis is performed. The bipartite SK model is found to have many features in common with Parisi's solution of the original, unipartite SK model, including the existence of a multitude of pure states which are related in a hierarchical, ultrametric fashion. As an application of this analysis, the optimal cost for a graph partitioning problem is shown to be simply related to the ground state energy of the bipartite SK model. As a second application, empirical investigations reveal that the Gibbs sampled outputs of an RBM trained on the MNIST data set are more ultrametrically distributed than the input data themselves. PMID- 30253475 TI - Analyzing the competition of gamma rhythms with delayed pulse-coupled oscillators in phase representation. AB - Networks of neurons can generate oscillatory activity as result of various types of coupling that lead to synchronization. A prominent type of oscillatory activity is gamma (30-80 Hz) rhythms, which may play an important role in neuronal information processing. Two mechanisms have mainly been proposed for their generation: (1) interneuron network gamma (ING) and (2) pyramidal interneuron network gamma (PING). In vitro and in vivo experiments have shown that both mechanisms can exist in the same cortical circuits. This raises the questions: How do ING and PING interact when both can in principle occur? Are the network dynamics a superposition, or do ING and PING interact in a nonlinear way and if so, how? In this article, we first generalize the phase representation for nonlinear one-dimensional pulse coupled oscillators as introduced by Mirollo and Strogatz to type II oscillators whose phase response curve (PRC) has zero crossings. We then give a full theoretical analysis for the regular gamma-like oscillations of simple networks consisting of two neural oscillators, an "E neuron" mimicking a synchronized group of pyramidal cells, and an "I neuron" representing such a group of interneurons. Motivated by experimental findings, we choose the E neuron to have a type I PRC [leaky integrate-and-fire (LIF) neuron], while the I neuron has either a type I or type II PRC (LIF or "sine" neuron). The phase representation allows us to define in a simple manner scenarios of interaction between the two neurons, which are independent of the types and the details of the neuron models. The presence of delay in the couplings leads to an increased number of scenarios relevant for gamma-like oscillatory patterns. We analytically derive the set of such scenarios and describe their occurrence in terms of parameter values such as synaptic connectivity and drive to the E and I neurons. The networks can be tuned to oscillate in an ING or PING mode. We focus particularly on the transition region where both rhythms compete to govern the network dynamics and compare with oscillations in reduced networks, which can only generate either ING or PING. Our analytically derived oscillation frequency diagrams indicate that except for small coexistence regions, the networks generate ING if the oscillation frequency of the reduced ING network exceeds that of the reduced PING network, and vice versa. For networks with the LIF I neuron, the network oscillation frequency slightly exceeds the frequencies of corresponding reduced networks, while it lies between them for networks with the sine I neuron. In networks oscillating in ING (PING) mode, the oscillation frequency responds faster to changes in the drive to the I (E) neuron than to changes in the drive to the E (I) neuron. This finding suggests a method to analyze which mechanism governs an observed network oscillation. Notably, also when the network operates in ING mode, the E neuron can spike before the I neuron such that relative spike times of the pyramidal cells and the interneurons alone are not conclusive for distinguishing ING and PING. PMID- 30253476 TI - Synchronization of conservative parallel discrete event simulations on a small world network. AB - We examine the question of the influence of sparse long-range communications on the synchronization in parallel discrete event simulations. We build a model of the evolution of local virtual times in a conservative algorithm including several choices of local links. All network realizations belong to the small world network class. We find that synchronization depends on the average shortest path of the network. The time profile dynamics are similar to the surface profile growth, which helps to analyze synchronization effects using a statistical physics approach. Without long-range links of the nodes, the model belongs to the universality class of the Kardar-Parisi-Zhang equation for surface growth. We find that the critical exponents depend logarithmically on the fraction of long range links. We present the results of simulations and discuss our observations. PMID- 30253477 TI - Mass conservative lattice Boltzmann scheme for a three-dimensional diffuse interface model with Peng-Robinson equation of state. AB - Peng-Robinson (P-R) equation of state (EOS) has been widely used in the petroleum industry for hydrocarbon fluids. In this work, a three-dimensional diffuse interface model with P-R EOS for two-phase fluid system is solved by the lattice Boltzmann (LB) method. In this diffuse interface model, an Allen-Cahn (A-C) type phase equation with strong nonlinear source term is derived. Using the multiscale Chapman-Enskog analysis, the A-C type phase equation can be recovered from the proposed LB method. Besides, a Lagrange multiplier is introduced based on the mesoscopic character of the LB scheme so that total mass of the hydrocarbon system is preserved. Three-dimensional numerical simulations of realistic hydrocarbon components, such as isobutane and propane, are implemented to illustrate the effectiveness of the proposed mass conservative LB scheme. Numerical results reach a better agreement with laboratory data compared to previous results of two-dimensional numerical simulations. PMID- 30253479 TI - Structure, size, and statistical properties of chaotic components in a mixed-type Hamiltonian system. AB - We perform a detailed study of the chaotic component in mixed-type Hamiltonian systems on the example of a family of billiards [introduced by Robnik in J. Phys. A: Math. Gen. 16, 3971 (1983)JPHAC50305-447010.1088/0305-4470/16/17/014]. The phase space is divided into a grid of cells and a chaotic orbit is iterated a large number of times. The structure of the chaotic component is discerned from the cells visited by the chaotic orbit. The fractal dimension of the border of the chaotic component for various values of the billiard shape parameter is determined with the box-counting method. The cell-filling dynamics is compared to a model of uncorrelated motion, the so-called random model [Robnik et al. J. Phys. A: Math. Gen. 30, L803 (1997)JPHAC50305-447010.1088/0305-4470/30/23/003], and deviations attributed to sticky objects in the phase space are found. The statistics of the number of orbit visits to the cells is analyzed and found to be in agreement with the random model in the long run. The stickiness of the various structures in the phase space is quantified in terms of the cell recurrence times. The recurrence time distributions in a few selected cells as well as the mean and standard deviation of recurrence times for all cells are analyzed. The standard deviation of cell recurrence time is found to be a good quantifier of stickiness on a global scale. Three methods for determining the measure of the chaotic component are compared and the measure is calculated for various values of the billiard shape parameter. Lastly, the decay of correlations and the diffusion of momenta is analyzed. PMID- 30253478 TI - Optical solitons, self-focusing, and wave collapse in a space-fractional Schrodinger equation with a Kerr-type nonlinearity. AB - We investigate the nonlinear dynamics of (1+1)-dimensional optical beam in the system described by the space-fractional Schrodinger equation with the Kerr nonlinearity. Using the variational method, the analytical soliton solutions are obtained for different values of the fractional Levy index alpha. All solitons are demonstrated to be stable for 1infinity. This large deviation observable, defined as the eigenvalue distribution conditioned to have a fixed fraction k of eigenvalues smaller than x?R, provides the spectrum of random matrix samples that deviate atypically from the average behavior. We apply our theory to sparse random matrices and unveil strikingly different and generic properties, namely, (i) their conditioned spectral density has compact support, (ii) it does not experience any abrupt transition for k around its typical value, and (iii) its eigenvalues do not accumulate at x. Moreover, our work points towards other types of transitions in the conditioned spectral density for values of k away from its typical value. These properties follow from the weak or absent eigenvalue repulsion in sparse ensembles and they are in sharp contrast to those displayed by classic or rotationally invariant random matrices. The exactness of our theoretical findings are confirmed through numerical diagonalization of finite random matrices. PMID- 30253506 TI - Dusty plasma experiment to confirm an expression for the decay of autocorrelation functions. AB - Statistical physicists recently proposed an expression for an autocorrelation function (ACF) [Belousov and Cohen, Phys. Rev. E 94, 062124 (2016)2470 004510.1103/PhysRevE.94.062124] that has, until now, not been tested experimentally. The expression captures the early behavior of the ACF decay, when the ACF is flattened. Using experimental data from a nonequilibrium steady-state dusty plasma, we confirm that the expression's use extends to liquidlike strongly coupled plasmas. A transition in the shape of the ACF is identified, and we suggest that it corresponds to the onset of collisional scattering. PMID- 30253507 TI - Theory of electromagnetic wave frequency upconversion in dynamic media. AB - Frequency upconversion of an electromagnetic wave can occur in ionized plasma with decreasing electric permittivity and in split-ring resonator-structure metamaterials with decreasing magnetic permeability. We develop a general theory to describe the evolution of the wave frequency, amplitude, and energy density in homogeneous media with a temporally decreasing refractive index. We find that upconversion of the wave frequency is necessarily accompanied by partitioning of the wave energy into low-frequency modes, which sets an upper limit on the energy conversion efficiency. The efficiency limits are obtained for both varying permittivity and varying permeability. PMID- 30253508 TI - Collective behavior of self-propelled rods with quorum sensing. AB - Active agents-like phoretic particles, bacteria, sperm, and cytoskeletal filaments in motility assays-show a large variety of motility-induced collective behaviors, such as aggregation, clustering, and phase separation. The behavior of dense suspensions of engineered phoretic particles and of bacteria during biofilm formation is determined by two qualitatively different physical mechanisms: (i) volume exclusion (short-range steric repulsion) and (ii) quorum sensing (longer range reduced propulsion due to alteration of the local chemical environment). To systematically characterize such systems, we study semi-penetrable self-propelled rods in two dimensions, with a propulsion force that decreases with increasing local rod density, by employing Brownian dynamics simulations. Volume exclusion and quorum sensing both lead to phase separation; however, the structure of the systems and the rod dynamics vastly differ. Quorum sensing enhances the polarity of the clusters, induces perpendicularity of rods at the cluster borders, and enhances cluster formation. For systems where the rods essentially become passive at high densities, formation of asters and stripes is observed. Systems of rods with larger aspect ratios show more ordered structures compared to those with smaller aspect ratios, due to their stronger alignment, with almost circular asters for strongly density-dependent propulsion force. With increasing range of the quorum-sensing interaction, the local density decreases, asters become less stable, and polar hedgehog clusters and clusters with domains appear. PMID- 30253509 TI - Eden model with nonlocal growth rules and kinetic roughening in biological systems. AB - We investigate an off-lattice Eden model where the growth of new cells is performed with a probability dependent on the availability of resources coming externally towards the growing aggregate. The concentration of nutrients necessary for replication is assumed to be proportional to the voids connecting the replicating cells to the outer region, introducing therefore a nonlocal dependence on the replication rule. Our simulations point out that the Kadar Parisi-Zhang (KPZ) universality class is a transient that can last for long periods in plentiful environments. For conditions of nutrient scarcity, we observe a crossover from regular KPZ to unstable growth, passing by a transient consistent with the quenched KPZ class at the pinning transition. Our analysis sheds light on results reporting on the universality class of kinetic roughening in akin experiments of biological growth. PMID- 30253510 TI - Comment on "Nodal infection in Markovian susceptible-infected-susceptible and susceptible-infected-removed epidemics on networks are non-negatively correlated". AB - Cator and Van Mieghem [Phys. Rev. E 89, 052802 (2014)PLEEE81539 375510.1103/PhysRevE.89.052802] stated that the correlation of infection at the same time between any pair of nodes in a network is non-negative for the Markovian susceptible-infected-susceptible (SIS) and susceptible-infected-removed (SIR) epidemic models. The arguments used to obtain this result rely strongly on the graphical construction of the stochastic process, as well as the Fortuin, Kasteleyn, and Ginibre (FKG) inequality. In this Comment, we show that although the approach used by the authors applies to the SIS model, it cannot be used for the SIR model as stated in their work. In particular, we observe that monotonicity in the process is crucial for invoking the FKG inequality. Moreover, we provide an example of a simple graph for which the nodal infection in the SIR Markovian model is negatively correlated. PMID- 30253511 TI - Effective two-dimensional model for granular matter with phase separation. AB - Granular systems confined in vertically vibrated shallow horizontal boxes (quasi two-dimensional geometry) present a liquid-to-solid phase transition when the frequency of the periodic forcing is increased. An effective model, where grains move and collide in two-dimensions is presented, which reproduces the aforementioned phase transition. The key element is that besides the two dimensional degrees of freedom, each grain has an additional variable E that accounts for the kinetic energy stored in the vertical motion in the real quasi two-dimensional motion. This energy grows monotonically during free flight, mimicking the energy gained by collisions with the vibrating walls and, at collisions, this energy is instantaneously transferred to the horizontal degrees of freedom. As a result, the average values of E and the kinetic temperature are decreasing functions of the local density, giving rise to an effective pressure that can present van der Waals loops. A kinetic theory approach predicts the conditions that must satisfy the energy growth function to obtain the phase separation, which are verified with molecular dynamics simulations. Notably, the effective equation of state and the critical points computed considering the velocity-time-of-flight correlations differ only slightly from those obtained by simple kinetic theory calculations that neglect those correlations. PMID- 30253512 TI - Energy transfer mechanisms in a dipole chain: From energy equipartition to the formation of breathers. AB - We study the energy transfer in a classical dipole chain of N interacting rigid rotating dipoles. The underlying high-dimensional potential energy landscape is analyzed in particular by determining the equilibrium points and their stability in the common plane of rotation. Starting from the minimal energy configuration, the response of the chain to excitation of a single dipole is investigated. Using both the linearized and the exact Hamiltonian of the dipole chain, we detect an approximate excitation energy threshold between a weakly and a strongly nonlinear dynamics. In the weakly nonlinear regime, the chain approaches in the course of time the expected energy equipartition among the dipoles. For excitations of higher energy, strongly localized excitations appear whose trajectories in time are either periodic or irregular, relating to the well-known discrete or chaotic breathers, respectively. The phenomenon of spontaneous formation of domains of opposite polarization and phase locking is found to commonly accompany the time evolution of the chaotic breathers. Finally, the sensitivity of the dipole chain dynamics to the initial conditions is studied as a function of the initial excitation energy by computing a fast chaos indicator. The results of this study confirm the aforementioned approximate threshold value for the initial excitation energy, below which the dynamics of the dipole chain is regular and above which it is chaotic. PMID- 30253513 TI - Investigation concerning the uniqueness of separatrix lines separating liquidlike from gaslike regimes deep in the supercritical phase of water with a focus on Widom line concepts. AB - The supercritical phase of fluids has long been known to feature significantly different liquidlike and gaslike regimes. However, it is textbook knowledge that the supercritical state is a homogeneous fluid phase where properties change continuously. Nevertheless, there has been an increasing amount of evidence published that suggests that there might exist a unique line that rigorously separates different regimes in supercritical phases, particularly in the case of water. Here, we use the quasiexact IAPWS95 equation of state to rigorously assess the macroscopic thermodynamic properties of supercritical water without invoking any water model or related approximations. We focus on how these properties change deep in the supercritical phase, in particular if they allow one to introduce a unique "thermodynamic separatrix." Our rigorous thermodynamic analysis, which relies exclusively on accurate experimental data, makes clear that there is no unique separatrix in real supercritical water-such as the recently much-invoked "Widom line." A comparison to the van der Waals equation of state reproduces qualitatively all our findings for real water, thereby suggesting that our analysis should be transferable to other fluids and critical points. Topological analysis of the H-bond network structure of supercritical water, as obtained from molecular-dynamics simulations using a standard water model, demonstrates that also the percolation line does not provide a meaningful separatrix to rigorously distinguish liquidlike from gaslike regimes. PMID- 30253514 TI - Two-dimensional bicontinuous structures from symmetric surface-directed spinodal decomposition in thin films. AB - We present numerical simulations of symmetric surface-directed spinodal decomposition in thin films with varying film thickness and film composition. The simulations utilize a Cahn-Hilliard model to describe phase separation kinetics in confined film geometries. The systems consist of two phases: a wetting phase that completely wets the top and bottom surfaces, and a nonwetting phase. Three distinct morphologies emerge including a discrete nonwetting morphology, a discrete wetting morphology, as well as a unique two-dimensional bicontinuous morphology that forms for specific values of film thickness and composition. The morphologies are analyzed with a Hoshen-Kopelman algorithm to quantify the degree of continuity of the nonwetting phase, and a morphology map is presented to guide future work. PMID- 30253515 TI - Oscillatory instability in a reaction front separating fluids of different densities. AB - Reaction fronts described by the Kuramoto-Sivashinsky (KS) equation can exhibit complex behavior as they separate reacted from unreacted fluids. If the fluid of higher density is above a fluid of lower density, then the Rayleigh-Taylor instability can lead to fluid motion. In the reverse situation, where the lighter fluid is on top, gravitationally driven forces can stabilize a convectionless flat front inhibiting the complex front propagation described by the KS equation. In these cases, a critical density difference is required to provide stability to the flat front. A linear stability analysis shows that the transition from stable to unstable flat fronts can be oscillatory for viscous fluid motion. Once the transition takes place, the fronts exhibit oscillatory convection resulting in oscillations of the shape and speed of the front. PMID- 30253516 TI - Ergodicity, rejuvenation, enhancement, and slow relaxation of diffusion in biased continuous-time random walks. AB - Bias plays an important role in the enhancement of diffusion in periodic potentials. Using the continuous-time random walk in the presence of a bias, we report on an interesting phenomenon for the enhancement of diffusion by the start of the measurement in a random energy landscape. When the variance of the waiting time diverges, in contrast to the bias-free case, the dynamics with bias becomes superdiffusive. In the superdiffusive regime, we find a distinct initial ensemble dependence of the diffusivity. Moreover, the diffusivity can be increased by the aging time when the initial ensemble is not in equilibrium. We show that the time averaged variance converges to the corresponding ensemble-averaged variance; i.e., ergodicity is preserved. However, trajectory-to-trajectory fluctuations of the time-averaged variance decay unexpectedly slowly. Our findings provide a rejuvenation phenomenon in the superdiffusive regime, that is, the diffusivity for a nonequilibrium initial ensemble gradually increases to that for an equilibrium ensemble when the start of the measurement is delayed. PMID- 30253517 TI - Record-breaking statistics near second-order phase transitions. AB - When a quantity reaches a value higher (or lower) than its value at any time before, it is said to have made a record. We numerically study the statistical properties of records in the time series of order parameters in different models near their critical points. Specifically, we choose the transversely driven Edwards-Wilkinson model for interface depinning in (1+1) dimensions and the Ising model in two dimensions, as paradigmatic and simple examples of nonequilibrium and equilibrium critical behaviors, respectively. The total number of record breaking events in the time series of the order parameters of the models show maxima when the system is near criticality. The number of record-breaking events and associated quantities, such as the distribution of the waiting time between successive record events, show power-law scaling near the critical point. The exponent values are specific to the universality classes of the respective models. Such behaviors near criticality can be used as a precursor to imminent criticality, i.e., abrupt and catastrophic changes in the system. Due to the extreme nature of the records, its measurements are relatively free of detection errors and thus provide a clear signal regarding the state of the system in which they are measured. PMID- 30253518 TI - Dynamical density-functional-theory-based modeling of tissue dynamics: Application to tumor growth. AB - We present a theoretical framework based on an extension of dynamical density functional theory (DDFT) for describing the structure and dynamics of cells in living tissues and tumors. DDFT is a microscopic statistical mechanical theory for the time evolution of the density distribution of interacting many-particle systems. The theory accounts for cell-pair interactions, different cell types, phenotypes, and cell birth and death processes (including cell division), to provide a biophysically consistent description of processes bridging across the scales, including describing the tissue structure down to the level of the individual cells. Analysis of the model is presented for single-species and two species cases, the latter aimed at describing competition between tumor and healthy cells. In suitable parameter regimes, model results are consistent with biological observations. Of particular note, divergent tumor growth behavior, mirroring metastatic and benign growth characteristics, are shown to be dependent on the cell-pair-interaction parameters. PMID- 30253519 TI - Opinion modeling on social media and marketing aspects. AB - We introduce and discuss kinetic models of opinion formation on social networks in which the distribution function depends on both the opinion and the connectivity of the agents. The opinion formation model is subsequently coupled with a kinetic model describing the spreading of popularity of a product on the Web through a social network. Numerical experiments on the underlying kinetic models show a good qualitative agreement with some measured trends of hashtags on social media websites and illustrate how companies can take advantage of the network structure to obtain at best the advertisement of their products. PMID- 30253520 TI - Calculating the free energy difference by applying the Jarzynski equality to a virtual integrable system. AB - The Jarzynski equality (JE) provides a nonequilibrium method to measure and calculate the free energy difference (FED). Note that if two systems share the same Hamiltonian at two equilibrium states, respectively, they share the same FED between these two equilibrium states as well. Therefore the calculation of the FED of a system may be facilitated by considering instead another virtual system designed to this end. Taking advantage of this flexibility and the JE, we show that by introducing an integrable virtual system, the evolution problem involved in the JE can be solved. As a consequence, FED is expressed in the form of an equilibrium equality, in contrast with the nonequilibrium JE it is based on. Numerically, this result allows FED to be computed by sampling the canonical ensemble directly and the computational cost can be significantly reduced. The effectiveness and efficiency of this scheme are illustrated with numerical studies of several representative model systems. PMID- 30253521 TI - Identifying nodal properties that are crucial for the dynamical robustness of multistable networks. AB - We investigate the collective dynamics of bistable elements connected in different network topologies and estimate the network response to localized perturbations on different classes of nodes by introducing a variant of the concept of multinode basin stability. We show that perturbations on nodes with high closeness and betweeness centrality drastically reduces the capacity of the system to return to the original state. This effect is most pronounced for a star network, where perturbation of the single hub node can destroy the collective state, while the system manages to recover even when a majority of the peripheral nodes are strongly perturbed. This demonstrates the extreme effect of the centrality of the perturbed node on the stability of the network. Further, we exploit the difference in centrality distributions in random scale-free networks with m=1 and m=2 to probe which property most influences the collective dynamics in heterogeneous networks. Significantly, we find clear evidence that the betweeness centrality of the perturbed node is more crucial for dynamical robustness than closeness centrality or degree of the node. This allows us to decide which nodes to safeguard in order to maintain the collective state of a network against targeted localized attacks. PMID- 30253522 TI - Theoretical and experimental investigation of the equation of state of boron plasmas. AB - We report a theoretical equation of state (EOS) table for boron across a wide range of temperatures (5.1*10^{4}-5.2*10^{8} K) and densities (0.25-49 g/cm^{3}) and experimental shock Hugoniot data at unprecedented high pressures (5608+/-118 GPa). The calculations are performed with first-principles methods combining path integral Monte Carlo (PIMC) at high temperatures and density-functional-theory molecular-dynamics (DFT-MD) methods at lower temperatures. PIMC and DFT-MD cross validate each other by providing coherent EOS (difference <1.5 Hartree/boron in energy and <5% in pressure) at 5.1*10^{5} K. The Hugoniot measurement is conducted at the National Ignition Facility using a planar shock platform. The pressure-density relation found in our shock experiment is on top of the shock Hugoniot profile predicted with our first-principles EOS and a semiempirical EOS table (LEOS 50). We investigate the self-diffusivity and the effect of thermal and pressure-driven ionization on the EOS and shock compression behavior in high pressure and -temperature conditions. We also study the sensitivity of a polar direct-drive exploding pusher platform to pressure variations based on applying pressure multipliers to LEOS 50 and by utilizing a new EOS model based on our ab initio simulations via one-dimensional radiation-hydrodynamic calculations. The results are valuable for future theoretical and experimental studies and engineering design in high-energy density research. PMID- 30253523 TI - Information ratchets exploiting spatially structured information reservoirs. AB - Fully mechanized Maxwell's demons, also called information ratchets, are an important conceptual link between computation, information theory, and statistical physics. They exploit low-entropy information reservoirs to extract work from a heat reservoir. Previous models of such demons have either ignored the cost of delivering bits to the demon from the information reservoir or assumed random access or infinite-dimensional information reservoirs to avoid such an issue. In this work we account for this cost when exploiting information reservoirs with physical structure and show that the dimensionality of the reservoir has a significant impact on the performance and phase diagram of the demon. We find that for conventional one-dimensional tapes the scope for work extraction is greatly reduced. An expression for the net-extracted work by demons exploring information reservoirs by means of biased random walks on d dimensional, Z^{d}, information reservoirs is presented. Furthermore, we derive exact probabilities of recurrence in these systems, generalizing previously known results. We find that the demon is characterized by two critical dimensions. First, to extract work at zero bias the dimensionality of the information reservoir must be larger than d=2, corresponding to the dimensions where a simple random walker is transient. Second, for integer dimensions d>4 the unbiased random walk optimizes work extraction corresponding to the dimensions where a simple random walker is strongly transient. PMID- 30253524 TI - Non-Gaussianity of the van Hove function and dynamic-heterogeneity length scale. AB - Non-Gaussian nature of the probability distribution of particles' displacements in the supercooled temperature regime in glass-forming liquids are believed to be one of the major hallmarks of glass transition. It has already been established that this probability distribution, which is also known as the van Hove function, shows universal exponential tail. The origin of such an exponential tail in the distribution function is attributed to the hopping motion of particles observed in the supercooled regime. The non-Gaussian nature can also be explained if one assumes that the system has heterogeneous dynamics in space and time. Thus exponential tail is the manifestation of dynamic heterogeneity. In this work we directly show that non-Gaussianity of the distribution of particles' displacements occur over the dynamic heterogeneity length scale and the dynamical behavior course grained over this length scale becomes homogeneous. We study the non-Gaussianity of the van Hove function by systematically coarse graining at different length scales and extract the length scale of dynamic heterogeneity at which the shape of the van Hove function crosses over from non-Gaussian to Gaussian. The obtained dynamic heterogeneity scale is found to be in very good agreement with the scale obtained from other conventional methods. PMID- 30253525 TI - Sensitivity of asymmetric rate-dependent critical systems to initial conditions: Insights into cellular decision making. AB - The work reported here aims to address the effects of time-dependent parameters and stochasticity on decision making in biological systems. We achieve this by extending previous studies that resorted to simple bifurcation normal forms, although in the present case we focus primarily on the issue of the system's sensitivity to initial conditions in the presence of two different noise distributions, Gaussian and Levy. In addition, we also assess the impact of two way sweeping at different rates through the critical region of a canonical Pitchfork bifurcation with a constant external asymmetry. The parallel with decision making in biocircuits is performed on this simple system since it is equivalent in its available states and dynamics to more complex genetic circuits published previously. Overall we verify that rate-dependent effects, previously reported as being important features of bifurcating systems, are specific to particular initial conditions. Processing of each starting state, which for the normal form underlying this study is akin to a classification task, is affected by the balance between sweeping speed through critical regions and the type of fluctuations added. For the heavy-tailed noise, two-way dynamic bifurcations are more efficient in processing the external signals, here understood to be jointly represented by the critical parameter profile and the external asymmetry amplitude, when compared to the system relying on escape dynamics. This is particular to the case when the system starts at an attractor not favored by the asymmetry and, in conjunction, when the sweeping amplitude is large. PMID- 30253526 TI - Strain localization in dry sheared granular materials: A compactivity-based approach. AB - Shear banding is widely observed in natural fault zones as well as in laboratory experiments on granular materials. Understanding the dynamics of strain localization under different loading conditions is essential for quantifying strength evolution of fault gouge and energy partitioning during earthquakes and characterizing rheological transitions and fault zone structure changes. To that end, we develop a physics-based continuum model for strain localization in sheared granular materials. The grain-scale dynamics is described by the shear transformation zone (STZ) theory, a nonequilibrium statistical thermodynamic framework for viscoplastic deformation in amorphous materials. Using a finite strain computational framework, we investigate the initiation and growth of complex shear bands under a variety of loading conditions and identify implications for strength evolution and the ductile to brittle transition. Our numerical results show similar localization patterns to field and laboratory observations and suggest that shear zones show more ductile response at higher confining pressures, lower dilatancy, and loose initial conditions. Lower pressures, higher dilatancy, and dense initial conditions favor a brittle response and larger strength drops. These findings shed light on a range of mechanisms for strength evolution in dry sheared granular materials and provide a critical input to physics-based multiscale models of fault zone instabilities. PMID- 30253527 TI - Renormalization group for the phi^{4} theory with long-range interaction and the critical exponent eta of the Ising model. AB - We calculate the critical exponent eta of the D-dimensional Ising model from a simple truncation of the functional renormalization group flow equations for a scalar field theory with long-range interaction. Our approach relies on the smallness of the inverse range of the interaction and on the assumption that the Ginzburg momentum defining the width of the scaling regime in momentum space is larger than the scale where the renormalized interaction crosses over from long range to short range; the numerical value of eta can then be estimated by stopping the renormalization group flow at this scale. In three dimensions our result eta=0.03651 is in good agreement with recent conformal bootstrap and Monte Carlo calculations. We extend our calculations to fractional dimensions D and obtain the resulting critical exponent eta(D) between two and four dimensions. For dimensions 2<=D<=3 our result for eta is consistent with previous calculations. PMID- 30253528 TI - Nonlinear graph-based theory for dynamical network observability. AB - A faithful description of the state of a complex dynamical network would require, in principle, the measurement of all its d variables, an infeasible task for high dimensional systems due to practical limitations. However the network dynamics might be observable from a reduced set of measured variables but how to reliably identify the minimum set of variables providing full observability still remains an unsolved problem. In order to tackle this issue from the Jacobian matrix of the governing equations, we construct a pruned fluence graph in which the nodes are the state variables and the links represent only the linear dynamical interdependences after having ignored the nonlinear ones. From this graph, we identify the largest connected subgraphs with no outgoing links in which every node can be reached from any other node in the subgraph. In each one of them, at least one node must be measured to correctly monitor the state of the system in a d-dimensional reconstructed space. Our procedure is here tested by investigating large-dimensional reaction networks. Our results are validated by comparing them with the determinant of the observability matrix which provides a rigorous assessment of the system's observability. PMID- 30253529 TI - Simulation of spatial systems with demographic noise. AB - The demographic (shot) noise in population dynamics scales with the square root of the population size. This process is very important, as it yields an absorbing state at zero field, but simulating it, especially on spatial domains, is a nontrivial task. Here, we analyze two similar methods that were suggested for simulating the corresponding Langevin equation, one by Pechenik and Levine and the other by Dornic, Chate, and Munoz (DCM). These methods are based on operator splitting techniques and the essential difference between them lies in which terms are bundled together in the splitting process. Both these methods are first order in the time step so one may expect that their performance will be similar. We find, surprisingly, that when simulating the stochastic Ginzburg-Landau equation with two deterministic metastable states, the DCM method exhibits two anomalous behaviors. First, the stochastic stall point moves away from its deterministic counterpart, the Maxwell point, when decreasing the noise. Second, the errors induced by the finite time step are larger by a significant factor (i.e., >10*) in the DCM method. We show that both these behaviors are the result of a finite-time-step induced shift in the deterministic Maxwell point in the DCM method, due to the particular operator splitting employed. In light of these results, care must be exercised when computing quantities like phase-transition boundaries (as opposed to universal quantities such as critical exponents) in such stochastic spatial systems. PMID- 30253530 TI - Tumbling dynamics of inertial inextensible chains in extensional flow. AB - This paper investigates the effect of inertia on the dynamics of elongated chains to go beyond the overdamped case that is often used to study such systems. For that purpose, numerical simulations are performed considering the motion of freely jointed bead-rod chains in an extensional flow in the presence of thermal noise. The coil-stretch transition and the tumbling instability are characterized as a function of three parameters: the Peclet number, the Stokes number, and the chain length. Numerical results show that the coil-stretch transition remains when inertia is present and that it depends nonlinearly on the Stokes and Peclet numbers. Theoretical and numerical analyses also highlight the role of intermediate stable configurations in the dynamics of elongated chains: chains can indeed remain trapped for a certain time in these configurations, especially while undergoing a tumbling event. PMID- 30253531 TI - Microchaos in human postural balance: Sensory dead zones and sampled time-delayed feedback. AB - Models for the stabilization of an inverted pendulum figure prominently in studies of human balance control. Surprisingly, fluctuations in measures related to the vertical displacement angle for quietly standing adults with eyes closed exhibit chaos. Here we show that small-amplitude chaotic fluctuations ("microchaos") can be generated by the interplay between three essential components of human neural balance control, namely time-delayed feedback, a sensory dead zone, and frequency-dependent encoding of force. When the sampling frequency of the force encoding is decreased, the sensitivity of the balance control to changes in the initial conditions increases. The sampled, time-delayed nature of the balance control may provide insights into why falls are more common in the very young and the elderly. PMID- 30253532 TI - Role of many-body interactions in the structure of coarse-grained polymers. AB - In developing coarse-grained (CG) polymer models it is important to reproduce both local and molecule-scale structure. We develop a procedure for fast calculation of the bond-orientation correlation and the internal squared distance through evaluation of the probability distribution functions that represent a CG model. Different CG models inherently contain or omit correlations between CG variables. Here, we construct CG models that contain specific correlations between CG variables. The importance of different correlations is tested on CG models of polyethylene, polytetrafluoroethylene, and poly-L-lactic acid. The chain stiffness and are calculated using both analytic evaluation and Monte Carlo sampling, and approximate model results are compared with exact results from all-atom simulations. For polymers with an exponential correlation decay, the bond-orientation correlation and indicate which CG variable correlations are most important to reproduce molecule-scale structure. Analysis of the bond-orientation correlation and internal-squared distance indicates that for poly-L-lactic acid the bond-orientation correlation requires qualitatively different additional terms in CG models and quantifies the error in neglecting this important behavior. PMID- 30253533 TI - Phase-field model for growth and dissolution of a stoichiometric compound in a binary liquid. AB - We propose a simple formulation of the phase-field model for a stoichiometric compound growing in a binary liquid. In previous models, chemical free energies of stoichiometric compounds have been approximated by parabolic functions of composition; however, the curvature has been determined arbitrarily in spite of the fact that the stoichiometric composition was undesirably modified depending on the curvature. To avoid this uncertainty, we supposed that the chemical free energy of the stoichiometric compound is represented by a single value at a given temperature and derived the phase-field equations without the parabolic free energy approximation. The phase mobility was derived both for diffusion- and interface-controlled solidification based on a thin interface limit analysis. We carried out numerical simulations of one-dimensional calculations both in diffusion-controlled and interface-controlled cases and found that the growth velocities agreed with the analytic predictions. We also examined two-dimensional solidification of a circular crystal and confirmed that the equilibrium state was shifted, as suggested by the Gibbs-Thomson effect. This study is an important step for phase-field modeling that includes stoichiometric compounds with their accurate thermodynamic properties. PMID- 30253534 TI - Distortions in structures of the twist bend nematic phase of a bent-core liquid crystal by the electric field. AB - The dielectric spectra of the twist bend nematic phase (N_{TB}) of an achiral asymmetric bent-core liquid crystalline compound are studied for determining the various relaxation modes. Dielectric measurements are also carried out under the bias field E up to 8 V/um. Two molecular and two collective relaxation processes are observed. The orientational order parameters with respect to the local and the main directors determined using molecular modes are used to find the heliconical angle. The results also show that the order parameter with reference to the main director reverses its trend from increasing to decreasing at temperatures of a few degrees above the N_{TB} to N transition. The collective relaxation modes are assigned to (a) distortions of the local director by the electric field at a frequency of ~100kHz while the periodic helical structure remains unaltered (mode attributed to flexoelectricity); (b) changes in the periodic structure arising from a coupling of the dielectric anisotropy with the electric field at the lowest frequency in the range of 100 Hz-10 kHz. Frequency of the higher frequency collective mode (~100kHz) depends primarily on the heliconical angle and has anomalous softeninglike behavior at the N-N_{TB} transition. The lowest frequency mode is studied under the bias field E; the modulus of the wave vector gradually vanishes on increasing E (except for an initial behavior, E^{2}<0.1V^{2}/MUm^{2}, which is just the opposite). The transition from the twist bend to splay bend structure is observed by a sudden drop in the frequency of this mode, followed by a linear decrease in frequency by increasing E. The results agree with the predictions made from the currently proposed models for a periodically distorted N_{TB} phase. PMID- 30253535 TI - Macroscopic chimeralike behavior in a multiplex network. AB - In this paper we study the dynamics of a multiplex multilayer network, where each layer is composed of identical Kuramoto-Sakaguchi phase oscillators with nonlocal coupling. We focus on a three-layer multiplex network and observe a specific form of multiplex network behavior, the macroscopic chimeralike state. It is decomposed by a splitting of the layers with initially close dynamics into subgroups. The first group consists of two layers performing one type of dynamics, whereas the rest perform the other type, after the introduction of interlayer coupling. Based on an intensive computational analysis, we show that areas of macroscopic chimeralike states are observed close to the critical transition points of intralayer (microscopic) states in the parameter space. We find that this macroscopic chimeralike state is excited at weak and medium interlayer coupling strength, wherein the interlayer phase lag here plays an important role, since this is a network parameter which controls macroscopic dynamics and transforms boundaries between intralayer states. The obtained numerical results are validated analytically by considering the multiplex network dynamics using the Ott-Antonsen reduction of the governing network equations. PMID- 30253537 TI - Machine-learning inference of fluid variables from data using reservoir computing. AB - We infer both microscopic and macroscopic behaviors of a three-dimensional chaotic fluid flow using reservoir computing. In our procedure of the inference, we assume no prior knowledge of a physical process of a fluid flow except that its behavior is complex but deterministic. We present two ways of inference of the complex behavior: the first, called partial inference, requires continued knowledge of partial time-series data during the inference as well as past time series data, while the second, called full inference, requires only past time series data as training data. For the first case, we are able to infer long-time motion of microscopic fluid variables. For the second case, we show that the reservoir dynamics constructed from only past data of energy functions can infer the future behavior of energy functions and reproduce the energy spectrum. It is also shown that we can infer time-series data from only one measurement by using the delay coordinates. This implies that the obtained reservoir systems constructed without the knowledge of microscopic data are equivalent to the dynamical systems describing the macroscopic behavior of energy functions. PMID- 30253536 TI - Degree correlations amplify the growth of cascades in networks. AB - Networks facilitate the spread of cascades, allowing a local perturbation to percolate via interactions between nodes and their neighbors. We investigate how network structure affects the dynamics of a spreading cascade. By accounting for the joint degree distribution of a network within a generating function framework, we can quantify how degree correlations affect both the onset of global cascades and the propensity of nodes of specific degree class to trigger large cascades. However, not all degree correlations are equally important in a spreading process. We introduce a new measure of degree assortativity that accounts for correlations among nodes relevant to a spreading cascade. We show that the critical point defining the onset of global cascades has a monotone relationship to this new assortativity measure. In addition, we show that the choice of nodes to seed the largest cascades is strongly affected by degree correlations. Contrary to traditional wisdom, when degree assortativity is positive, low degree nodes are more likely to generate largest cascades. Our work suggests that it may be possible to tailor spreading processes by manipulating the higher-order structure of networks. PMID- 30253538 TI - Reversals in infinite-Prandtl-number Rayleigh-Benard convection. AB - Using direct numerical simulations, we study the statistical properties of reversals in two-dimensional Rayleigh-Benard convection for infinite Prandtl number. We find that the large-scale circulation reverses irregularly, with the waiting time between two consecutive genuine reversals exhibiting a Poisson distribution on long timescales, while the interval between successive crossings on short timescales shows a power-law distribution. We observe that the vertical velocities near the sidewall and at the center show different statistical properties. The velocity near the sidewall shows a longer autocorrelation and 1/f^{2} power spectrum for a wide range of frequencies, compared to shorter autocorrelation and a narrower scaling range for the velocity at the center. The probability distribution of the velocity near the sidewall is bimodal, indicating a reversing velocity field. We also find that the dominant Fourier modes capture the dynamics at the sidewall and at the center very well. Moreover, we show a signature of weak intermittency in the fluctuations of velocity near the sidewall by computing temporal structure functions. PMID- 30253539 TI - Hidden entropy production and work fluctuations in an ideal active gas. AB - Collections of self-propelled particles that move persistently by continuously consuming free energy are a paradigmatic example of active matter. In these systems, unlike Brownian "hot colloids," the breakdown of detailed balance yields a continuous production of entropy at steady state, even for an ideal active gas. We quantify the irreversibility for a noninteracting active particle in two dimensions by treating both conjugated and time-reversed dynamics. By starting with underdamped dynamics, we identify a hidden rate of entropy production required to maintain persistence and prevent the rapidly relaxing momenta from thermalizing, even in the limit of very large friction. Additionally, comparing two popular models of self-propulsion with identical dissipation on average, we find that the fluctuations and large deviations in work done are markedly different, providing thermodynamic insight into the varying extents to which macroscopically similar active matter systems may depart from equilibrium. PMID- 30253540 TI - Sampling rare events in stochastic reaction-diffusion systems within trajectory looping. AB - In bistable reaction-diffusion systems, transitions between stable states typically occur on timescales orders of magnitude longer than the chemical equilibration time. Estimation of transition rates within explicit Brownian dynamics simulations is computationally prohibitively costly. We present a method that exploits a single trajectory, generated by a prior simulation of diffusive motions of molecules, to sample chemical kinetic processes on timescales several orders of magnitude longer than the duration of the diffusive trajectory. In this approach, we "loop" the diffusive trajectory by transferring chemical states of the molecules from the last to the first time step of the trajectory. Trajectory looping can be applied to enhance sampling of rare events in biochemical systems in which the number of reacting molecules is constant, as in cellular signal transduction pathways. As an example, we consider a bistable system of autophosphorylating kinases, for which we calculate state-to-state transition rates and traveling wave velocities. We provide an open-source implementation of the method. PMID- 30253541 TI - Low-dimensional dynamics of the Kuramoto model with rational frequency distributions. AB - The Kuramoto model is a paradigmatic tool for studying the dynamics of collective behavior in large ensembles of coupled dynamical systems. Over the past decade a great deal of progress has been made in analytical descriptions of the macroscopic dynamics of the Kuramoto model, facilitated by the discovery of Ott and Antonsen's dimensionality reduction method. However, the vast majority of these works relies on a critical assumption where the oscillators' natural frequencies are drawn from a Cauchy, or Lorentzian, distribution, which allows for a convenient closure of the evolution equations from the dimensionality reduction. In this paper we investigate the low-dimensional dynamics that emerge from a broader family of natural frequency distributions, in particular, a family of rational distribution functions. We show that, as the polynomials that characterize the frequency distribution increase in order, the low-dimensional evolution equations become more complicated, but nonetheless the system dynamics remain simple, displaying a transition from incoherence to partial synchronization at a critical coupling strength. Using the low-dimensional equations we analytically calculate the critical coupling strength corresponding to the onset of synchronization and investigate the scaling properties of the order parameter near the onset of synchronization. These results agree with calculations from Kuramoto's original self-consistency framework, but we emphasize that the low-dimensional equations approach used here allows for a true stability analysis categorizing the bifurcations. PMID- 30253542 TI - Correlations between thresholds and degrees: An analytic approach to model attacks and failure cascades. AB - Two node variables determine the evolution of cascades in random networks: a node's degree and threshold. Correlations between both fundamentally change the robustness of a network, yet they are disregarded in standard analytic methods as local tree or heterogeneous mean field approximations, since order statistics are difficult to capture analytically because of their combinatorial nature. We show how they become tractable in the thermodynamic limit of infinite network size. This enables the analytic description of node attacks that are characterized by threshold allocations based on node degree. Using two examples, we discuss possible implications of irregular phase transitions and different speeds of cascade evolution for the control of cascades. PMID- 30253543 TI - Supercanonical probability distributions. AB - The canonical probability distribution describes a system in thermal equilibrium with an infinite heat bath. When the bath is finite the distribution is modified. These modifications can be derived by truncating a Taylor-series expansion of the entropy of the heat bath, but their form depends on the expansion parameter chosen. We consider two such expansions, which yield supercanonical (i.e., higher order canonical) distributions of exponential and power-law form. The latter is identical in form to the "Tsallis distribution," which is therefore a valid asymptotic approximation for an arbitrary finite heat bath, but bears no intrinsic relation to Tsallis entropy. PMID- 30253544 TI - Granular silo flow of inelastic dumbbells: Clogging and its reduction. AB - We study the discharge of inelastic, two-dimensional dumbbells through an orifice in the bottom wall of a silo using discrete element method (DEM) simulations. As with spherical particles, clogging may occur due to the formation of arches of particles around the orifice. The clogging probability decreases with increasing orifice width in both cases. For a given width, however, the clogging probability is much higher for the nonspherical particles due to their arbitrary orientations and the possibility of geometrical interlocking. We also examine the effect of placing a fixed, circular obstacle above the orifice. The clogging probability depends strongly on the vertical and lateral position of the obstacle, as well as its size. By suitably placing the obstacle the clogging probability can be significantly reduced compared to a system with no obstacle. We attempt to elucidate the clogging reduction mechanism by examining the packing fraction, granular temperature, and velocity distributions of the particles in the vicinity of the orifice. PMID- 30253545 TI - Influence of the degree of a complex network on heat conduction. AB - Devices made of nanotubes and nanowires networks are of great interest for applications and have caught increasing attention in recent years. In this work, we study heat conduction in a network model with nodes being atoms and links being one-dimensional chains of atoms. It is found that heat conduction in the complex network is fundamentally different from that of regular lattices. It depends very sensitively on the average degrees of complex networks and the degrees of nodes that are attached to the two heat baths. For example, when the two heat source nodes have the same degree k_{0}, the heat flux reaches a maximum at an optimized value of k_{0} and decreases with the increase of the average degree . In other words, the source nodes with optimal degree k_{0} and the sparse network are more favorable to heat flux. Thermal rectification effect is found when the two heat source nodes have different degrees or the network model has multiple heat source nodes. Theoretical analysis is provided to explain the numerical results. PMID- 30253546 TI - Hierarchical burst model for complex bursty dynamics. AB - Temporal inhomogeneities observed in various natural and social phenomena have often been characterized in terms of scaling behaviors in the autocorrelation function with a decaying exponent gamma, the interevent time distribution with a power-law exponent alpha, and the burst size distributions. Here the interevent time is defined as a time interval between two consecutive events in the event sequence, and the burst size denotes the number of events in a bursty train detected for a given time window. To understand such temporal scaling behaviors implying a hierarchical temporal structure, we devise a hierarchical burst model by assuming that each observed event might be a consequence of the multilevel causal or decision-making process. By studying our model analytically and numerically, we confirm the scaling relation alpha+gamma=2, established for the uncorrelated interevent times, despite of the existence of correlations between interevent times. Such correlations between interevent times are supported by the stretched exponential burst size distributions, for which we provide an analytic argument. In addition, by imposing conditions for the ordering of events, we observe an additional feature of log-periodic behavior in the autocorrelation function. Our modeling approach for the hierarchical temporal structure can help us better understand the underlying mechanisms behind complex bursty dynamics showing temporal scaling behaviors. PMID- 30253548 TI - Inertial spheroids in homogeneous, isotropic turbulence. AB - We study the rotational dynamics of inertial disks and rods in three-dimensional, homogeneous, isotropic turbulence. In particular, we show how the alignment and the decorrelation timescales of such spheroids depend, critically, on both the level of inertia and the aspect ratio of these particles. These results illustrate the effect of inertia-which leads to a preferential sampling of the local flow geometry-on the statistics of both disks and rods in a turbulent flow. Our results are important for a variety of natural and industrial settings where the turbulent transport of asymmetric, spheroidal inertial particles is ubiquitous. PMID- 30253547 TI - Kuramoto dilemma alleviated by optimizing connectivity and rationality. AB - Recently, Antonioni and Cardillo proposed a coevolutionary model based on the intertwining of oscillator synchronization and evolutionary game theory [Phys. Rev. Lett. 118, 238301 (2017)PRLTAO0031-900710.1103/PhysRevLett.118.238301], in which each Kuramoto oscillator can decide whether to interact or not with its neighbors, and all oscillators can receive some benefits from the local synchronization, but those who choose to interact must pay a cost. Oscillators are allowed to update their strategies according to payoff difference, wherein the strategy of an oscillator who has obtained higher payoff is more likely to be followed. Utilizing this coevolutionary model, we find that the global synchronization level reaches the highest level when the average degree of the underlying interaction network is moderate. We also study how synchronization is affected by the individual rationality in choosing strategy. PMID- 30253549 TI - Periodic soliton trains and informational code structures in an improved soliton model for biomembranes and nerves. AB - Many experiments have shown that the action potential propagating in a nerve fiber is an electromechanical density pulse. A mathematical model proposed by Heimburg and Jackson is an important step in explaining the propagation of electromechanical pulses in nerves. In this work, we consider the dynamics of modulated waves in an improved soliton model for nerve pulses. Application of the reductive perturbation method on the resulting generalized Boussinesq equation in the low-amplitude and weak damping limit yields a damped nonlinear Schrodinger equation that is shown to admit soliton trains. This solution contains an undershoot beneath the baseline ("hyperpolarization") and a "refractory period," i.e., a minimum distance between pulses, and therefore it represents typical nerve profiles. Likewise, the linear stability of wave trains is analyzed. It is shown that the amplitude of the fourth-order mixed dispersive term introduced here can be used to control the amount of information transmitted along the nerve fiber. The results from the linear stability analysis show that, in addition to the main periodic wave trains observed in most nerve experiments, five other localized background modes can copropagate along the nerve. These modes could eventually be responsible for various fundamental processes in the nerve, such as phase transitions and electrical and mechanical changes. Furthermore, analytical and numerical analyses show that increasing the fourth-order mixed dispersion coefficient improves the stability of the nerve signal. PMID- 30253550 TI - Three-dimensional billiards: Visualization of regular structures and trapping of chaotic trajectories. AB - The dynamics in three-dimensional (3D) billiards leads, using a Poincare section, to a four-dimensional map, which is challenging to visualize. By means of the recently introduced 3D phase-space slices, an intuitive representation of the organization of the mixed phase space with regular and chaotic dynamics is obtained. Of particular interest for applications are constraints to classical transport between different regions of phase space which manifest in the statistics of Poincare recurrence times. For a 3D paraboloid billiard we observe a slow power-law decay caused by long-trapped trajectories, which we analyze in phase space and in frequency space. Consistent with previous results for 4D maps, we find that (i) trapping takes place close to regular structures outside the Arnold web, (ii) trapping is not due to a generalized island-around-island hierarchy, and (iii) the dynamics of sticky orbits is governed by resonance channels which extend far into the chaotic sea. We find clear signatures of partial transport barriers. Moreover, we visualize the geometry of stochastic layers in resonance channels explored by sticky orbits. PMID- 30253551 TI - Expansion of a collisionless hypersonic plasma plume into a vacuum. AB - Both fully kinetic and hybrid particle-in-cell (PIC) simulations are performed to investigate the two-dimensional (2D) expansion of a collisionless, hypersonic plasma plume into a vacuum. The fully kinetic PIC simulations are carried out using the real ion-to-electron mass ratios of H^{+}, Ar^{+}, and Xe^{+}, while the hybrid PIC model assumes the electrons to be a massless, isothermal fluid. We find that the hypersonic plasma plume exhibits four distinct regions, the unperturbed, quasisteady expansion, self-similar expansion and electron front regions. The behavior of electrons is strongly anisotropic, causing considerably different expansion characteristics between the plume direction and the transverse direction. Along the plume direction, the expansion dynamics is similar to that of the classical one-dimensional (1D) semi-infinite plasma expansion and the electrons are almost isothermal. In the transverse direction, the expansion process can be considered analogous to the 1D expansion of a finite plasma where the effect of electron cooling is important. This anisotropic characteristic is attributed to the amount of electron thermal energy available from the source in different directions. A direct comparison between the hybrid and full PIC simulations shows that the widely used equilibrium isothermal electron fluid model is in general not valid for modeling the expansion of a collisionless plasma plume. PMID- 30253552 TI - Quantum transport senses community structure in networks. AB - Quantum time evolution exhibits rich physics, attributable to the interplay between the density and phase of a wave function. However, unlike classical heat diffusion, the wave nature of quantum mechanics has not yet been extensively explored in modern data analysis. We propose that the Laplace transform of quantum transport (QT) can be used to construct an ensemble of maps from a given complex network to a circle S^{1}, such that closely related nodes on the network are grouped into sharply concentrated clusters on S^{1}. The resulting QT clustering (QTC) algorithm is as powerful as the state-of-the-art spectral clustering in discerning complex geometric patterns and more robust when clusters show strong density variations or heterogeneity in size. The observed phenomenon of QTC can be interpreted as a collective behavior of the microscopic nodes that evolve as macroscopic cluster "orbitals" in an effective tight-binding model recapitulating the network. python source code implementing the algorithm and examples are available at https://github.com/jssong-lab/QTC. PMID- 30253553 TI - Generalized voterlike model on activity-driven networks with attractiveness. AB - We study the behavior of a generalized consensus dynamics on a temporal network of interactions, the activity-driven network with attractiveness. In this temporal network model, agents are endowed with an intrinsic activity a, ruling the rate at which they generate connections, and an intrinsic attractiveness b, modulating the rate at which they receive connections. The consensus dynamics considered is a mixed voter and Moran dynamics. Each agent, either in state 0 or 1, modifies his or her state when connecting with a peer. Thus, an active agent copies his or her state from the peer (with probability p) or imposes his or her state to him or her (with the complementary probability 1-p). Applying a heterogeneous mean-field approach, we derive a differential equation for the average density of voters with activity a and attractiveness b in state 1, which we use to evaluate the average time to reach consensus and the exit probability, defined as the probability that a single agent with activity a and attractiveness b eventually imposes his or her state to a pool of initially unanimous population in the opposite state. We study a number of particular cases, finding an excellent agreement with numerical simulations of the model. Interestingly, we observe a symmetry between voter and Moran dynamics in pure activity-driven networks and their static integrated counterparts that exemplifies the strong differences that a time-varying network can impose on dynamical processes. PMID- 30253554 TI - Levy flights on a comb and the plasma staircase. AB - We formulate the problem of confined Levy flight on a comb. The comb represents a sawtoothlike potential field V(x), with the asymmetric teeth favoring net transport in a preferred direction. The shape effect is modeled as a power-law dependence V(x)?|Deltax|^{n} within the sawtooth period, followed by an abrupt drop-off to zero, after which the initial power-law dependence is reset. It is found that the Levy flights will be confined in the sense of generalized central limit theorem if (i) the spacing between the teeth is sufficiently broad, and (ii) n>4-MU, where MU is the fractal dimension of the flights. In particular, for the Cauchy flights (MU=1), n>3. The study is motivated by recent observations of localization-delocalization of transport avalanches in banded flows in the Tore Supra tokamak and is intended to devise a theory basis to explain the observed phenomenology. PMID- 30253555 TI - Single-component multiphase lattice Boltzmann simulation of free bubble and crevice heterogeneous cavitation nucleation. AB - This work serves as an important extension of previous work on cavitation simulation [Sukop and Or, Phys. Rev. E 71, 046703 (2005)10.1103/PhysRevE.71.046703]. A modified Shan-Chen single-component multiphase lattice Boltzmann method is used to simulate two different heterogeneous cavitation nucleation mechanisms, the free gas bubble model and the crevice nucleation model. Improvements include the use of a real-gas equation of state, a redefined effective mass function, and the exact difference method forcing scheme. As a result, much larger density ratios, better thermodynamic consistency, and improved numerical accuracy are achieved. In addition, the crevice nucleation model is numerically investigated using the lattice Boltzmann method. The simulations show excellent qualitative and quantitative agreement with the heterogeneous nucleation theories. PMID- 30253556 TI - Structural characteristics of strongly coupled ions in a dense quantum plasma. AB - The structural properties of strongly coupled ions in dense plasmas with moderately to strongly degenerate electrons are investigated in the framework of the one-component plasma model of ions interacting through a screened pair interaction potential. Special focus is put on the description of the electronic screening in the Singwi-Tosi-Land-Sjolander (STLS) approximation. Different cross checks and analyses using ion potentials obtained from ground-state quantum Monte Carlo data, the random phase approximation (RPA), and existing analytical models are presented for the computation of the structural properties, such as the pair distribution and the static structure factor, of strongly coupled ions. The results are highly sensitive to the features of the screened pair interaction potential. This effect is particularly visible in the static structure factor. The applicability range of the screened potential computed from STLS is identified in terms of density and temperature of the electrons. It is demonstrated that at r_{s}>1, where r_{s} is the ratio of the mean interelectronic distance to the Bohr radius, electronic correlations beyond RPA have a nonnegligible effect on the structural properties. Additionally, the applicability of the hypernetted chain approximation for the calculation of the structural properties using the screened pair interaction potential is analyzed employing the effective coupling parameter approach. PMID- 30253557 TI - Collapse of generalized Euler and surface quasigeostrophic point vortices. AB - Point-vortex models are presented for the generalized Euler equations, which are characterized by a fractional Laplacian relation between the active scalar and the stream function. Special focus is given to the case of the surface quasigeostrophic (SQG) equations, for which the existence of finite-time singularities is still a matter of debate. Point-vortex trajectories are expressed using Nambu dynamics. The formulation is based on a noncanonical bracket and allows for a geometrical interpretation of trajectories as intersections of level sets of the Hamiltonian and Casimir. Within this setting, we focus on the collapse of solutions for the three-point-vortex model. In particular, we show that for SQG the collapse can be either self-similar or non self-similar. Self-similarity occurs only when the Hamiltonian is zero, while non self-similarity appears for nonzero values of the same. For both cases, collapse is allowed for any choice of circulations within a permitted interval. These results differ strikingly from the classical point-vortex model, where collapse is self-similar for any value of the Hamiltonian, but the vortex circulations must satisfy a strict relationship. Results may also shed a light on the formation of singularities in the SQG partial differential equations, where the singularity is thought to be reached only in a self-similar way. PMID- 30253558 TI - Power law observed in the motion of an asymmetric camphor boat under viscous conditions. AB - We investigated the velocity of an asymmetric camphor boat moving on aqueous solutions with glycerol. The viscosity was controlled by using several concentrations of glycerol into the solution. The velocity decreased with an increase in the glycerol concentration. We proposed a phenomenological model, and we showed that the velocity decreased with an increase in the viscosity according to power law. Our experimental result agreed with the one obtained from our model. These results suggest that a decay length of the camphor concentration at the front side of the boat is sufficiently shorter than that of the rear side. PMID- 30253559 TI - Grand-potential-based phase-field model for multiple phases, grains, and chemical components. AB - Grand-potential-based phase-field model for multiple phases, grains, and chemical components is derived from a grand-potential functional. Due to the grand potential formulation, the chemical energy does not contribute to the interfacial energy between phases, simplifying parametrization and decoupling interface thickness from interfacial energy, which can potentially allow increased interface thicknesses and therefore improved computational efficiency. Two-phase interfaces are stable with respect to the formation of additional phases, simplifying implementation and allowing the variational form of the evolution equations to be used. Additionally, we show that grand-potential-based phase field models are capable of simulating phase separation, and we derive conditions under which this is possible. PMID- 30253560 TI - Wake effects of a stationary charged grain in streaming magnetized ions. AB - A systematic numerical study of wake potential and ion density distribution of a single grain in flowing ions under the influence of a magnetic field applied along the flow is presented. A strong magnetic field introduces ion focus depletion behind grains, facilitating the entrance of electrons far in the downstream towards the grain. It is shown that the magnetic field suppresses the amplitude of the wake potential and modifies the ion density distribution substantially. The wake peak potential and position characteristics and density distribution of plasma constituents in the presence of a magnetic field and charge-exchange collisions for the subsonic, sonic, and supersonic regime are also delineated. In the subsonic regime, simulations demonstrate the accumulation of ions near the dust grain in the transverse direction, while complete suppression of oscillations in the transverse direction takes place for the sonic and supersonic regime. PMID- 30253561 TI - Active regeneration unites high- and low-temperature features in cooperative self assembly. AB - Cytoskeletal filaments are capable of self-assembly in the absence of externally supplied chemical energy, but the rapid turnover rates essential for their biological function require a constant flux of adenosine triphosphate (ATP) or guanosine triphosphate (GTP) hydrolysis. The same is true for two-dimensional protein assemblies employed in the formation of vesicles from cellular membranes, which rely on ATP-hydrolyzing enzymes to rapidly disassemble upon completion of the process. Recent observations suggest that the nucleolus, p granules, and other three-dimensional membraneless organelles may also demand dissipation of chemical energy to maintain their fluidity. Cooperative binding plays a crucial role in the dynamics of these higher-dimensional structures, but is absent from classic models of one-dimensional cytoskeletal assembly. In this paper, we present a thermodynamically consistent model of active regeneration with cooperative assembly, and compute the maximum turnover rate and minimum disassembly time as a function of the chemical driving force and the binding energy. We find that these driven structures resemble different equilibrium states above and below the nucleation barrier. In particular, we show that the maximal acceleration under large binding energies unites infinite-temperature local fluctuations with low-temperature nucleation kinetics. PMID- 30253562 TI - Phase diagram of the J_{1}-J_{2} frustrated anisotropic antiferromagnet with spin S=1 on the quadratic lattice. AB - In the paper the phase diagram of J_{1}-J_{2} frustrated antiferromagnet with spin S=1 and single-ion anisotropy is studied on the planar quadratic lattice in the cluster approximation. The Bogolyubov inequality is adopted for the Gibbs energy calculation for the case of 2*2 and 4*4 clusters. On this basis, the ranges of existence of the antiferromagnetic, superantiferromagnetic, and paramagnetic phases are investigated for the antiferromagnetic nearest-neighbor (J_{1}<0) and next-nearest-neighbor (J_{2}<0) interactions. In particular, the occurrence of tricritical and triple points is discussed and a comparison between the results for 2*2 and 4*4 clusters is made. The results are also compared with the classical MFA method, adopted here for the model in question, as well as with selected literature results for particular choices of interaction parameters. PMID- 30253563 TI - Passive swimming of a microcapsule in vertical fluid oscillation. AB - The artificial microswimmer is a cutting-edge technology with applications in drug delivery and micro-total-analysis systems. The flow field around a microswimmer can be regarded as Stokes flow, in which reciprocal body deformation cannot induce migration. In this study, we propose a microcapsule swimmer that undergoes amoeboidlike shape deformations under fluid oscillation conditions. This is a study on the propulsion principle using a capsule with a solid membrane, and one of only a few studies using fluid oscillation. The microswimmer consists of an elastic capsule containing fluid and a rigid sphere. Opposing forces are generated when fluid oscillations are applied, because the densities of the internal fluid and sphere are different. The opposing forces induce nonreciprocal body deformation, which leads to migration of the microswimmer under Stokes flow conditions. Using numerical simulations, we found that the microswimmer propels itself in one of two modes, i.e., stroke swimming or drag swimming. We discuss the feasibility of the proposed microswimmer and show that the most efficient swimmer can migrate tens of micrometers per second. These findings pave the way for future artificial microswimmer designs. PMID- 30253564 TI - Optimal noise in a stochastic model for local search. AB - We develop a prototypical stochastic model for a local search around a given home. The stochastic dynamic model is motivated by experimental findings of the motion of a fruit fly around a given spot of food but will generally describe the local search behavior. The local search consists of a sequence of two epochs. In the first the searcher explores new space around the home, whereas it returns to the home during the second epoch. In the proposed two-dimensional model both tasks are described by the same stochastic dynamics. The searcher moves with constant speed and its angular dynamics is driven by a symmetric alpha-stable noise source. The latter stands for the uncertainty to decide the new direction of motion. The main ingredient of the model is the nonlinear interaction dynamics of the searcher with its home. In order to determine the new heading direction, the searcher has to know the actual angles of its position to the home and of the heading vector. A bound state to the home is realized by a permanent switch of a repulsive and attractive forcing of the heading direction from the position direction corresponding to search and return epochs. Our investigation elucidates the analytic tractability of the deterministic and stochastic dynamics. Noise transforms the conservative deterministic dynamics into a dissipative one of the moments. The noise enables a faster finding of a target distinct from the home with optimal intensity. This optimal situation is related to the noise-dependent relaxation time. It is uniquely defined for all alpha and distinguishes between the stochastic dynamics before and after its value. For times large compared to this, we derive the corresponding Smoluchowski equation and find diffusive spreading of the searcher in the space. We report on the qualitative agreement with the experimentally observed spatial distribution, noisy oscillatory return times, and spatial autocorrelation function of the fruit fly. However, as a result of its simplicity, the model aims to reproduce the local search behavior of other units during their exploration of surrounding space and their quasiperiodic return to a home. PMID- 30253565 TI - Spectral properties of simple classical and quantum reset processes. AB - We study the spectral properties of classical and quantum Markovian processes that are reset at random times to a specific configuration or state with a reset rate that is independent of the current state of the system. We demonstrate that this simple reset dynamics causes a uniform shift in the eigenvalues of the Markov generator, excluding the zero mode corresponding to the stationary state, which has the effect of accelerating or even inducing relaxation to a stationary state. Based on this result, we provide expressions for the stationary state and probability current of the reset process in terms of weighted sums over dynamical modes of the reset-free process. We also discuss the effect of resets on processes that display metastability. We illustrate our results with two classical stochastic processes, the totally asymmetric random walk and the one dimensional Brownian motion, as well as two quantum models: a particle coherently hopping on a chain and the dissipative transverse field Ising model, known to exhibit metastability. PMID- 30253566 TI - Self-organization of dragon king failures. AB - The mechanisms underlying cascading failures are often modeled via the paradigm of self-organized criticality. Here we introduce a simple network model where nodes self-organize to be either weakly or strongly protected against failure in a manner that captures the trade-off between degradation and reinforcement of nodes inherent in many network systems. If strong nodes cannot fail, any failure is contained to a single, isolated cluster of weak nodes and the model produces power-law distributions of failure sizes. We classify the large, rare events that involve the failure of only a single cluster as "black swans." In contrast, if strong nodes fail once a sufficient fraction of their neighbors fail, then failure can cascade across multiple clusters of weak nodes. If over 99.9% of the nodes fail due to this cluster hopping mechanism, we classify this as a "dragon king," which are massive failures caused by mechanisms distinct from smaller failures. The dragon kings observed are self-organized, existing over a wide range of reinforcement rates and system sizes. We find that once an initial cluster of failing weak nodes is above a critical size, the dragon king mechanism kicks in, leading to piggybacking system-wide failures. We demonstrate that the size of the initial failed weak cluster predicts the likelihood of a dragon king event with high accuracy and we develop a simple control strategy that can dramatically reduce dragon kings and other large failures. PMID- 30253567 TI - Propagative and diffusive regimes of acoustic damping in bulk amorphous material. AB - In amorphous solids, a non-negligible part of thermal conductivity results from phonon scattering on the structural disorder. The conversion of acoustic energy into thermal energy is often measured by the dynamical dtructure factor (DSF) thanks to inelastic neutron or x-ray scattering. The DSF is used to quantify the dispersion relation of phonons, together with their damping. However, the connection of the dynamical structure factor with dynamical attenuation of wave packets in glasses is still a matter of debate. We focus here on the analysis of wave-packet propagation in numerical models of amorphous silicon. We show that the damped harmonic oscillator model fits of the dynamical structure factors give a good estimate of the wave packets mean free path, only below the Ioffe-Regel frequency. Above the Ioffe-Regel frequency and below the mobility edge, a pure diffusive regime without a definite mean free path is observed. The high frequency mobility edge is characteristic of a transition to localized vibrations. Below the Ioffe-Regel frequency, a mixed regime is evidenced at intermediate frequencies, with a coexistence of propagative and diffusive wave fronts. The transition between these different regimes is analyzed in detail and reveals a complex dynamics for energy transport, thus raising the question of the correct modeling of thermal transport in amorphous materials. PMID- 30253568 TI - Ecological efficiency of finite-time thermodynamics: A molecular dynamics study. AB - We present a molecular dynamics simulation of a two-dimensional Carnot engine. The optimization of this engine is achieved through the velocity of the piston, allowing not only the optimization of power output but also some other figures of merit involving entropy production. The maximum power and maximum ecological efficiencies are computed. It is shown that the near ideal gas working substance displays an endoreversible Carnot-like engine behavior. This can be considered as a prove of the validity of the Carnot-like endoreversible model. An effective reversible cycle different than the Carnot one is obtained, in agreement with the endoreversible hypothesis flexibility. We compare the efficiencies stemming from an ideal gas approximation with those of the simulation, and then we propose a suitable approximation to an endoreversible heat engine and to a reversible Joule Brayton cycle which fits very well to the simulation results. Finally, we show that the maximum ecological efficiency eta=1-tau^{3/4}, which is also very close to the upper bound of the low-dissipation heat engine under maximum ecological (and Omega) conditions, is close for describing the dynamics of the simulated cycle under maximum power and maximum ecological conditions in the so-named heat engine operability region. PMID- 30253570 TI - Limits on reconstruction of dynamics in networks. AB - An observability condition number is defined for physical systems modeled by network dynamics. Assuming that the dynamical equations of the network are known and a noisy trajectory is observed at a subset of the nodes, we calculate the expected distance to the nearest correct trajectory as a function of the observation noise level and discuss how it varies over the unobserved nodes of the network. When the condition number is sufficiently large, reconstructing the trajectory from observations from the subset will be infeasible. This knowledge can be used to choose an optimal subset from which to observe a network. PMID- 30253569 TI - Time averages and their statistical variation for the Ornstein-Uhlenbeck process: Role of initial particle distributions and relaxation to stationarity. AB - How ergodic is diffusion under harmonic confinements? How strongly do ensemble- and time-averaged displacements differ for a thermally-agitated particle performing confined motion for different initial conditions? We here study these questions for the generic Ornstein-Uhlenbeck (OU) process and derive the analytical expressions for the second and fourth moment. These quantifiers are particularly relevant for the increasing number of single-particle tracking experiments using optical traps. For a fixed starting position, we discuss the definitions underlying the ensemble averages. We also quantify effects of equilibrium and nonequilibrium initial particle distributions onto the relaxation properties and emerging nonequivalence of the ensemble- and time-averaged displacements (even in the limit of long trajectories). We derive analytical expressions for the ergodicity breaking parameter quantifying the amplitude scatter of individual time-averaged trajectories, both for equilibrium and out-of equilibrium initial particle positions, in the entire range of lag times. Our analytical predictions are in excellent agreement with results of computer simulations of the Langevin equation in a parabolic potential. We also examine the validity of the Einstein relation for the ensemble- and time-averaged moments of the OU-particle. Some physical systems, in which the relaxation and nonergodic features we unveiled may be observable, are discussed. PMID- 30253571 TI - Molding the asymmetry of localized frequency-locking waves by a generalized forcing and implications to the inner ear. AB - Frequency locking to an external forcing frequency is a well-known phenomenon. In the auditory system, it results in a localized traveling wave, the shape of which is essential for efficient discrimination between incoming frequencies. An amplitude equation approach is used to show that the shape of the localized traveling wave depends crucially on the relative strength of additive versus parametric forcing components; the stronger the parametric forcing, the more asymmetric is the response profile and the sharper is the traveling-wave front. The analysis qualitatively captures the empirically observed regions of linear and nonlinear responses and highlights the potential significance of parametric forcing mechanisms in shaping the resonant response in the inner ear. PMID- 30253572 TI - Multiscale velocity correlations in turbulence and Burgers turbulence: Fusion rules, Markov processes in scale, and multifractal predictions. AB - We compare different approaches towards an effective description of multiscale velocity field correlations in turbulence. Predictions made by the operator product expansion, the so-called fusion rules, are placed in juxtaposition to an approach that interprets the turbulent energy cascade in terms of a Markov process of velocity increments in scale. We explicitly show that the fusion rules are a direct consequence of the Markov property provided that the structure functions exhibit scaling in the inertial range. Furthermore, the limit case of joint velocity gradient and velocity increment statistics is discussed and put into the context of the notion of dissipative anomaly. We generalize a prediction made by the multifractal model derived by Benzi et al. [R. Benzi et al., Phys. Rev. Lett. 80, 3244 (1998)PRLTAO0031-900710.1103/PhysRevLett.80.3244] to correlations among inertial range velocity increment and velocity gradients of any order. We show that for the case of squared velocity gradients such a relation can be derived from first principles in the case of Burgers equations. Our results are benchmarked by intensive direct numerical simulations of Burgers turbulence. PMID- 30253573 TI - Anomalous dynamics in tracer-particle motions in an electrohydrodynamically driven oil-in-oil system. AB - We characterize the superdiffusive dynamics of tracer particles in an electrohydrodynamically driven emulsion of oil droplets in an immiscible oil medium, where the amplitude and frequency of an external electric field are the control parameters. In the weakly driven electrohydrodynamic regime, the droplets are trapped dielectrophoretically on a patterned electrode, and the driving is therefore spatially varying. We find excellent agreement with a ~t^{1.5} power law and find that this superdiffusive dynamics arises from an underlying displacement distribution that is distinctly non-Gaussian and exponential for small displacements and short times. While these results are comparable with a random-velocity field model, the tracer particle speeds are in fact spatially varying in two dimensions, arising from a spatially varying electrohydrodynamic driving force. This suggests that the important ingredient for the superdiffusive t^{1.5} behavior observed is a velocity field that is isotropic in the plane and spatially correlated. Finally, we can extract, from the superdiffusive dynamics, a experimental length scale that corresponds to the lateral range of the hydrodynamic flows. This experimental length scale is non zero only above a threshold ion mobility length. PMID- 30253574 TI - Pressure-induced phase transitions in liquid crystals: A molecular field approach. AB - A rigorous microscopic treatment of a nematic fluid system based on a pairwise interaction potential is immensely complex. For studying such systems molecular field theories are often the standard method of choice. In this paper we have chosen a simple effective potential U=u_{4}/v^{4}-u_{2}/v^{2} Au_{2}/v^{2}P_{2}(costheta) to study an isothermal-isobaric ensemble describing a liquid crystalline system. Using this we have studied in particular the pressure dependence of liquid crystalline phase transitions. PMID- 30253575 TI - Crossover in nonstandard random-matrix spectral fluctuations without unfolding. AB - Recently, singular value decomposition (SVD) was applied to standard Gaussian ensembles of random-matrix theory to determine the scale invariance in spectral fluctuations without performing any unfolding procedure. Here, SVD is applied directly to the beta-Hermite ensemble and to a sparse matrix ensemble, decomposing the corresponding spectra in trend and fluctuation modes. In correspondence with known results, we obtain that fluctuation modes exhibit a crossover between soft and rigid behavior. In this way, possible artifacts introduced applying unfolding techniques are avoided. By using the trend modes, we perform data-adaptive unfolding, and we calculate traditional spectral fluctuation measures. Additionally, ensemble-averaged and individual-spectrum averaged statistics are calculated consistently within the same basis of normal modes. PMID- 30253576 TI - Fiber-bundle model with time-dependent healing mechanisms to simulate progressive failure of snow. AB - Snow is a heterogeneous material with strain- and/or load-rate-dependent strength. In particular, a transition from ductile-to-brittle failure behavior with increasing load rate is observed. The rate-dependent behavior can partly be explained with the existence of a unique healing mechanism in snow that stems from its high homologous temperature (temperature close to melting point). As soon as broken elements in the ice matrix get in contact, they start sintering and the structure may regain strength. Moreover, the ice matrix is subjected to viscous deformation, inducing a relaxation of local load concentrations and, therefore, further counteracting the damage process. Ideal tools for studying the failure process of heterogeneous materials are the fiber-bundle models (FBMs), which allow investigating the effects of basic microstructural characteristics on the general macroscopic failure behavior. We present an FBM with two concurrent time-dependent healing mechanisms: sintering of broken fibers and relaxation of load inhomogeneities. Sintering compensates damage by creating additional intact, load-supporting fibers which lead to an increase of the bundle strength. However, the character of the failure is not changed by sintering alone. With combined sintering and load relaxation, load is distributed from old stronger fibers to new fibers that carry fewer load. So as we additionally incorporated load redistribution to the FBM, the failure occurred suddenly without decrease of the order parameter-describing the amount of damage in the bundle-and without divergence of the fiber failure rate. Moreover, the b value, i.e., the power-law exponent of frequency-magnitude statistics of fibers breaking in load redistribution steps, at failure converged to b~2, a value higher than that of a classical FBM without healing (b=3/2). These results indicate that healing, as the combined effect of sintering and load relaxation, changes the type of the phase transition at failure. This change of the phase transition is important for quantifying or predicting the failure (e.g., by monitoring acoustic emissions) of snow or other materials for which healing plays an important role. PMID- 30253577 TI - Ordering of sedimenting paramagnetic colloids in a monolayer. AB - Sedimentation enables self-assembly of colloidal particles into crystalline structures, as needed for catalysis or photonics applications. Here we combine experiments, theory, and simulations to investigate the equilibrium structure of a colloidal monolayer with tunable interparticle repulsion via an applied external magnetic field. Experimental observations of the equilibrium structure are in excellent agreement with density functional theory. Within a (zero temperature) local density approximation, we derive a simple analytical expression that quantitatively captures the inhomogeneous ordering ranging from solid to liquidlike states. Monte Carlo simulations corroborate these findings and explore an even wider range of sedimentation conditions, thus providing a global view of the sedimentation-mediated ordering in colloidal monolayers with tunable long-ranged interparticle repulsions. Our findings shed further light on the classical sedimentation problem in colloidal science and related areas. PMID- 30253578 TI - Dynamical effects of breaking rotational symmetry in counter-rotating Stuart Landau oscillators. AB - Stuart-Landau oscillators can be coupled so as to either preserve or destroy the rotational symmetry that the uncoupled system possesses. We examine some of the simplest cases of such couplings for a system of two nonidentical oscillators. When the coupling breaks the rotational invariance, there is a qualitative difference between oscillators wherein the phase velocity has the same sign (termed co-rotation) or opposite signs (termed counter-rotation). In the regime of oscillation death the relative sense of the phase rotations plays a major role. In particular, when rotational invariance is broken, counter-rotation or phase velocities of opposite signs appear to destabilize existing fixed points, thereby preserving and possibly extending the range of oscillatory behavior. The dynamical "frustration" induced by counter-rotations can thus suppress oscillation quenching when coupling breaks the symmetry. PMID- 30253579 TI - Chemical aging of large-scale randomly rough frictional contacts. AB - It has been shown that contact aging due to chemical reactions in single asperity contacts can have a significant effect on friction. However, it is currently unknown how chemically induced contact aging of friction depends on roughness that is typically encountered in macroscopic rough contacts. Here we develop an approach that brings together a kinetic Monte Carlo model of chemical aging with a contact mechanics model of rough surfaces based on the boundary element method to determine the magnitude of chemical aging in silica-silica contacts with random roughness. Our multiscale model predicts that chemical aging for randomly rough contacts has a logarithmic dependence on time. It also shows that friction aging switches from a linear to a nonlinear dependence on the applied load as the load increase. We discover that surface roughness affects the aging behavior primarily by modifying the real contact area and the local contact pressure, whereas the effect of contact morphology is relatively small. Our results demonstrate how understanding of chemical aging can be translated from studies of single asperity contacts to macroscopic rough contacts. PMID- 30253580 TI - Complex saddle trajectories for multidimensional quantum wave packet and coherent state propagation: Application to a many-body system. AB - A practical search technique for finding the complex saddle points used in wave packet and coherent state propagation is developed which works for a large class of Hamiltonian dynamical systems with many degrees of freedom. The method can be applied to problems in atomic, molecular, and optical physics and other domains. A Bose-Hubbard model is used to illustrate the application to a many-body system where discrete symmetries play an important and fascinating role. For multidimensional wave packet propagation, locating the necessary saddles involves the seemingly insurmountable difficulty of solving a boundary value problem in a high-dimensional complex space, followed by determining whether each particular saddle found actually contributes. In principle, this must be done for each propagation time considered. The method derived here identifies a real search space of minimal dimension, which leads to a complete set of contributing saddles up to intermediate times much longer than the Ehrenfest timescale for the system. The analysis also gives a powerful tool for rapidly identifying the various dynamical regimes of the system. PMID- 30253581 TI - Critical Polya urn. AB - We propose a variant model of the Polya urn process, where the dynamics consist of two competing elements: suppression of growth and enhancement of dormant character. Here the level of such features is controlled by an internal parameter in a random manner, so that the system self-organizes and characteristic observables exhibit scale invariance, suggesting the existence of criticality. Varying the internal control parameter, one can explain interesting universality classes for avalanche-type events. We also discuss different versions of the model. It is pointed out that such an underlying mechanism has earlier been noted to operate in a neural network. PMID- 30253582 TI - Mass transfer in the Frenkel-Kontorova chain initiated by molecule impact. AB - The Frenkel-Kontorova chain with a free end is used to study initiation and propagation of crowdions (antikinks) caused by impact of a molecule consisting of K atoms. It is found that molecules with 1